PMID- 10089995 TI - Metabolic acidosis and thiamine deficiency. AB - We describe a 19-year-old patient who was receiving home parenteral nutrition in whom lactic acidosis developed. A review of her home parenteral nutrition formula revealed the absence of multivitamins, most significantly thiamine. After thiamine administration, the acidosis resolved, and the patient experienced pronounced clinical improvement. Clinicians must be aware that thiamine is essential for normal glucose metabolism and that thiamine deficiency can lead to lactic acidosis. Thiamine deficiency should be included in the differential diagnosis of lactic acidosis. The recent shortage of intravenous multivitamin preparations has led to documented cases of lactic acidosis as a result of thiamine deficiency, and a previous shortage led to several deaths due to lactic acidosis as a consequence of thiamine deficiency. All patients receiving parenteral nutrition must also receive adequate vitamin supplementation. PMID- 10089996 TI - Pulmonary edema after resection of a fourth ventricle tumor: possible evidence for a medulla-mediated mechanism. AB - A well-recognized fact is that some patients may have development of pulmonary edema in association with disorders of the central nervous system. The origin of this phenomenon, known as neurogenic pulmonary edema, is unclear but may result, in part, from select pulmonary venoconstriction modulated by autonomic outflow from the medulla oblongata. We describe a 21-year-old man who had development of pulmonary edema in association with surgical resection of a brain tumor that was close to the medulla. Other than the possibility of medullary dysfunction, which could have occurred after surgical manipulation, no other risk factor for pulmonary edema was identified. Of note, the patient's blood pressure remained normal throughout the perioperative period, and no fluid overload or primary cardiac dysfunction was evident. This case supports the theory that the medulla is an important anatomic site of origin for neurogenic pulmonary edema and that alterations in medullary function can induce pulmonary edema in humans, independent of systemic hypertension. PMID- 10089997 TI - A practical approach to the management of patients with chronic renal failure. AB - The number of patients with significant chronic renal failure is expanding rapidly in the United States. All physicians and medical-care providers will have an increasingly important role in the detection and management of renal failure in patients who are not undergoing dialysis. Patients with diabetes or hypertension should be carefully monitored for the development of renal insufficiency by using screening tools such as blood pressure measurement, determination of serum creatinine, urinalysis, and determination of 24-hour urinary microalbuminuria. In order to slow the progression of renal disease, attenuate uremic complications, and prepare patients with renal failure for renal replacement therapy, all medical-care providers should "take care of the BEANS." Blood pressure should be maintained in a target range lower than 130/85 mm Hg, and in many patients, angiotensin-converting enzyme inhibitors may be beneficial. Erythropoietin should be used to maintain the hemoglobin level at 10 to 12 g/dL. Access for long-term dialysis should be created when the serum creatinine value increases above 4.0 mg/dL or the glomerular filtration rate declines below 20 mL/min. Nutritional status must be closely monitored in order to avoid protein malnutrition and to initiate dialysis before the patient's nutritional status has deteriorated. Nutritional care also involves correction of acidosis, prevention and treatment of hyperphosphatemia, and administration of vitamin supplements to provide folic acid. Specialty referral to nephrology should occur when the creatinine level increases above 3.0 mg/dL or when the involvement of a nephrologist would be beneficial for ongoing management of the patient. PMID- 10089998 TI - Cardiac involvement in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE), a connective tissue disease characterized by the production of autoantibodies, can affect all organ systems. Cardiac involvement in patients with SLE has been described since the early 20th century. The manifestations are numerous and can involve all components of the heart, including the pericardium, conduction system, myocardium, valves, and coronary arteries. In recent years, echocardiography has yielded additional information about the heart in patients who have SLE with and without clinical cardiac involvement. Moreover, antiphospholipid antibodies have been linked to several cardiac manifestations in patients with SLE, including valvular abnormalities and possibly coronary artery disease. This updated, comprehensive review summarizes the new literature on SLE and the heart. PMID- 10089999 TI - 64-year-old man with venous thrombosis and abnormal liver enzymes. PMID- 10090000 TI - The penicillins. AB - The penicillin family of antibiotics remains an important part of our antimicrobial armamentarium. In general, these agents have bactericidal activity, excellent distribution throughout the body, low toxicity, and efficacy against infections caused by susceptible bacteria. The initial introduction of aqueous penicillin G for treatment of streptococcal and staphylococcal infections was an important pharmacologic landmark. The emergence of penicillinase-producing Staphylococcus aureus prompted the development of the penicillinase-resistant penicillins (for example, methicillin, oxacillin, and nafcillin), in which an acyl side chain prevented disruption of the beta-lactamase ring. Subsequently, the aminopenicillins (ampicillin, amoxicillin, and bacampicillin) were developed because of the need for gram-negative antimicrobial activity. Their spectrum initially included Escherichia coli, Proteus mirabilis, Shigella, Salmonella, Listeria, Haemophilus, and Neisseria. The search for a penicillin with additional antimicrobial activity against the Enterobacteriaceae and Pseudomonas aeruginosa led to the development of the carboxypenicillins (carbenicillin and ticarcillin) and the ureidopenicillins (mezlocillin, azlocillin, and piperacillin). Finally, the combination of a beta-lactamase inhibitor (clavulanic acid, sulbactam, or tazobactam) and an aminopenicillin, ticarcillin, or piperacillin has further extended their antibacterial spectra by inhibiting certain beta-lactamases (non group 1) of resistant bacteria. The development of an ideal penicillin that is rapidly bactericidal, nonsensitizing, nontoxic, bioavailable, and resistant to beta-lactamases and that has a high affinity for penicillin-binding proteins remains the goal. PMID- 10090001 TI - Management of the young child with diabetes mellitus: how do we measure success? PMID- 10090002 TI - Genetically engineered mice: the holes in the sum of the parts. PMID- 10090003 TI - Care and use of fish as laboratory animals: current state of knowledge. PMID- 10090004 TI - Use of polymerase chain reaction to diagnose a natural outbreak of mouse hepatitis virus infection in nude mice. AB - The enormous cost of eliminating mouse hepatitis virus (MHV) from a mouse colony demands that a confirmed etiologic diagnosis be made to justify the necessary remedial action. We describe an outbreak of MHV in nude mice in which histopathologic findings provided a presumptive diagnosis, but results of serologic testing of affected nude mice and immunocompetent sentinels were negative. Results of transmission electron microscopy of liver specimens from affected mice were equivocal. Confirmation of the etiopathogenesis was eventually provided by reverse transcriptase-polymerase chain reaction (RT-PCR), using primers with nested sequences directed to two separate but highly conserved regions of the MHV genome. This procedure detected MHV in the liver of an affected nude mouse and in a sentinel, although in the latter a positive result was obtained only because of the increased sensitivity of nested primers used in a second round of amplification. Virus was not detected in cell lines that had been injected into the mice, and the source of the outbreak was not found. These results indicate the applicability of RT-PCR for detecting MHV in a field situation while also illustrating that conventional, complementary techniques still have an essential role in reaching a diagnosis. It is recommended that specimens should be taken for histologic examination and serologic testing, as well as for molecular studies when MHV infection is suspected. PMID- 10090005 TI - Diminished reproduction, failure to thrive, and altered immunologic function in a colony of T-cell receptor transgenic mice: possible role of Citrobacter rodentium. AB - Citrobacter rodentium from an undetermined source was detected in a breeding colony of T-cell receptor transgenic mice housed in a conventional mouse facility in which murine hepatitis virus had been endemic and Helicobacter spp. had been detected. Citrobacter rodentium, isolated from blood, spleen, and colon, correlated with a significant increase in mortality and morbidity in this breeding colony. Transgenic mice of all ages were affected by chronic debilitation, loss in reproductive efficiency, rectal prolapse, and acute death, resulting in the near loss of these noncommercially available strains. Several alterations in immunologic parameters were observed, including outgrowth of an unusual population of cells in the spleen and blood, reduction in ascites production, loss of the capacity of peritoneal exudate cells to serve as feeders for the cloning of long-term T-cell lines, and inhibition of antigen-specific cytotoxic T-cell activity. These altered immune functions also were apparent in commercially-derived nontransgenic mice cohoused with the infected colony and in overtly healthy transgenic and nontransgenic littermates. Citrobacter rodentium and murine hepatitis virus were eliminated ultimately on rederivation of the affected strains by embryo transfer. However, the rapid decrease in the health of the colony necessitated more immediate action. To reduce mortality and allow breeding to continue during rederivation of the transgenic lines, animals were treated with enrofloxacin and moved to a barrier facility. Antibiotic therapy significantly reduced morbidity and mortality, markedly increased litter size and frequency, and resulted in the normalization of many of the immunologic assays. The involvement of C. rodentium in altering viability of the colony and perturbing immunologic assays is suggested by correlation of the onset of the syndrome with the appearance of Citrobacter sp. and its resolution with the elimination of Citrobacter sp. from the colony. Whether infection with Citrobacter alone is causative or whether superinfection of murine hepatitis virus- and Helicobacter-infected mice is required remains to be determined. PMID- 10090006 TI - Spontaneous cholangiofibrosis in Long-Evans Cinnamon rats: a rodent model for Wilson's disease. AB - The Long-Evans Cinnamon (LEC) rat is a rodent model of Wilson's disease characterized by ceruloplasmin deficiency, hepatic copper accumulation, and hepatocellular injury. So far, the LEC rat appears to be the only strain in which cholangiofibrosis develops spontaneously. The aim of the study reported here was to characterize the time course of development and investigate the structural and ultrastructural features of cholangiofibrosis and their possible relationship to hepatic copper and iron content. The livers of 54 rats (22 males), ages 5 to 113 weeks, were examined by light microscopy and graded for statistical analysis, with respect to extent of replacement of liver tissue by cholangiofibrosis. The study was complemented by electron microscopy, and by measurements of copper and iron contents by atomic absorption spectroscopy. Cholangiofibrosis was present in LEC rats by 20 weeks of age. The hyperplastic biliary epithelial cells varied markedly in size and shape, ranging from flat to cuboidal or elongated. Epithelial cells did not exhibit characteristics of intestinal cells. Some basement membranes had splits, duplications, or multiplications. Cytoplasmic organelles within hyperplastic biliary cells appeared unremarkable in contrast to the characteristic mitochondrial abnormalities present in neighboring hepatocytes. There was a positive correlation between histologic grades of cholangiofibrosis and ages of the animals (r = 0.68, P < 0.001), but no significant correlation between histologic grade and hepatic copper or iron content. We conclude that cholangiofibrosis is the predominant pathologic response to chronic liver injury induced by excess copper in LEC rats. The pathogenic role of copper in the development of cholangiofibrosis requires clearer definition. PMID- 10090007 TI - Tumorigenicity of green turtle fibropapilloma-derived fibroblast lines in immunodeficient mice. AB - Fibroblast lines derived from normal skin and spontaneous or experimentally induced fibropapillomas of green turtles (Chelonia mydas) were established and propagated in medium composed of a combination of Dulbecco's minimal essential with F12 medium plus 10% fetal bovine serum at 30 degrees C. Fibropapilloma derived fibroblasts were indistinguishable from normal skin fibroblasts in vitro. Tumor lines did not exhibit loss of contact inhibition, anchorage independence, or reduced serum requirements. Inoculation of primary and early-passage tumor cells into the medial margin of the pinna of C57BL/6J-nu/nu, C.B17-scid/scid, or NOD-scid/scid mice, however, resulted in fibroma formation, whereas inoculation of normal skin fibroblasts did not. Tumor-derived cells inoculated into the flanks of mice did not form tumors. The turtle origin of fibroblasts in tumors from mouse ears was confirmed by immunohistochemical and karyotype analysis. Fibroblast lines that were established from mouse ear fibromas had the normal karyotype (modal 2N = 55) of C. mydas. The cooler anatomic sites (ears) of immunodeficient mice are useful for confirming the tumorigenic (transformed) phenotype of green turtle fibropapillomatosis-derived fibroblasts. This mouse ear tumorigenicity test should facilitate studies of mechanisms of cellular transformation in green turtle fibropapillomatosis and other neoplastic diseases of poikilothermic vertebrates. PMID- 10090008 TI - Lyme borreliosis in laboratory mice. PMID- 10090009 TI - Streptozotocin-induced diabetes mellitus in cynomolgus monkeys: changes in carbohydrate metabolism, skin glycation, and pancreatic islets. AB - Chronic hyperglycemia has been implicated in a number of diabetes mellitus related conditions in the human population, including retinopathy, neuropathy, nephropathy, and vasculopathy. However, it has been difficult to evaluate the effect of long-term hyperglycemia in a research setting because of the disease's slow progression. In this study, we used streptozotocin (30 mg/kg of body weight, intravenously) to induce a state of chronic hyperglycemia in eight cynomolgus monkeys, and compared these monkeys with a matched control group (n = 8). Seven of eight monkeys with streptozotocin-induced diabetes required insulin therapy to avoid ketosis. After disease induction, all diabetic monkeys had significantly higher preprandial plasma glucose and glycated hemoglobin values, compared with their baseline values or values for control monkeys. Diabetic monkeys also had abnormal responses to an intravenous glucose tolerance test. Consistent with the chronic hyperglycemic state and formation of advanced glycation end products, diabetic monkeys had a significant increase in skin fluorescence over the course of the 6-month study. Plasma triglyceride and cholesterol concentrations increased, but not significantly so, in the diabetic monkeys after disease induction and were not significantly different from concentrations in control monkeys. Six months after disease induction, monkeys were necropsied, and immunohistochemical staining for insulin in the pancreatic islets indicated that diabetic monkeys had a significantly decreased amount of staining for the hormone. The percentage of islet insulin staining was significantly correlated with physiologic responses to the postinduction intravenous glucose tolerance test in all monkeys. Because cynomolgus monkeys are well-characterized models of atherosclerosis, this model may be useful for determining mechanisms whereby diabetes mellitus increases cardiovascular disease. PMID- 10090010 TI - Hypoxanthine phosphoribosyltransferase cDNA in gerbils (Meriones unguiculatus). AB - Hypoxanthine phosphoribosyltransferase (HPRT) is a purine salvage enzyme that catalyzes conversion of hypoxanthine and guanine to their respective mononucleotides. Because of its ubiquitous nature, HPRT is known as a "housekeeping" gene and has been frequently used as an internal control in reverse transcriptase-polymerase chain reaction (RT-PCR) quantification of cytokine mRNA. Cloning and sequencing of the gerbil HPRT cDNA sequence is an important step in the development of RT-PCR procedures in this model. Two forms of gerbil HPRT cDNA were isolated and molecularly characterized. PMID- 10090011 TI - Absence of a significant mixed lymphocyte reaction in a marsupial (Monodelphis domestica). AB - Previously we reported preliminary results suggesting that the marsupial Monodelphis domestica fails to exhibit a mixed lymphocyte reaction with allogeneic lymphocytes. To test whether this observation is simply a matter of a response too weak to detect, but capable of being augmented by immunization, we performed mixed lymphocyte culture tests on 23 of these animals that had been immunized with lymphocytes. Despite the fact that all recipients were sensitized to the lymphocytes of the donors, none of the animals had a substantial mixed lymphocyte response. Significant stimulation was noted with the mitogen concanavalin A; thus, the T cells were immunologically competent. It seems likely that the failure of this species to exhibit a significant mixed lymphocyte response is due to T cells whose ontogeny differs from that of the T cells of eutherian mammals. PMID- 10090012 TI - Diagnostic exercise: lethal pneumonia in neonatal kittens. PMID- 10090013 TI - Further evaluation of a diagnostic polymerase chain reaction assay for Pasteurella pneumotropica. PMID- 10090014 TI - Comparison of bile chemistry between humans, baboons, and pigs: implications for clinical and experimental liver xenotransplantation. PMID- 10090015 TI - Modified technique for abdominal heterotopic cardiac transplantation in the rabbit. PMID- 10090016 TI - Doppler echocardiographic analysis of effects of tribromoethanol anesthesia on cardiac function in the mouse embryo: a comparison with pentobarbital. PMID- 10090017 TI - Detection of Mycoplasma pulmonis from rats and mice of Sao Paulo/SP, Brazil. PMID- 10090018 TI - Relationship between inspiratory pressure and tidal volume in the anesthetized canine. PMID- 10090019 TI - Mouse sperm cryopreservation: a legacy in the making. PMID- 10090020 TI - Xenotransplant-associated infections. AB - Xenotransplantation is considered increasingly as a solution to the current shortage of human organs for allotransplantation. In addition, it is being investigated as a treatment for a number of other diseases such as Parkinson's disease, diabetes mellitus, and acquired immunodeficiency disease. The potential risk of novel zoonotic infections is a concern associated with these procedures. Accordingly, the role of animal microbial agents must be critically examined. This review examines the concerns and proposed mechanisms for xenogeneic infections and details what is known and what still needs to be learned as the field of xenotransplantation progresses. Emphasis is placed on microbial agents of baboons and swine because they are currently the most common species considered as donor sources for xenotransplantation. PMID- 10090021 TI - Antigenic analyses of cilia-associated respiratory (CAR) bacillus isolates by use of monoclonal antibodies. AB - Mouse monoclonal antibodies (MAbs) developed to a rat isolate (R-3) of cilia associated respiratory (CAR) bacillus were used to assess antigenic relationships among three rat and five rabbit CAR bacillus isolates. Evaluation of MAbs by enzyme-linked immunosorbent assays (ELISAs) indicated that 87 of 241 hybridomas secreted CAR bacillus-reactive antibodies that could be grouped into four major groups. Group-I MAbs reacted with epitopes expressed by all CAR bacillus isolates and at least two or more nonrelated species of bacteria. Group-II, -III, and -IV MAbs reacted with only one or more of the rat CAR bacillus isolates; no MAbs reacted only with rat and rabbit CAR bacillus isolates. Western blot analyses indicated that 41-, 50-, and 105-kDa peptides of rat CAR bacillus isolates expressed rat CAR bacillus group- and isolate-specific epitopes. Hyperimmune anti CAR bacillus antiserum and serum specimens from a CAR bacillus histologically positive mouse and rat also reacted with the 41-, 50-, and 105-kDa peptides. Sera from CAR bacillus histologically negative rats did not react with these peptides. These results suggest that the 41-, 50-, and 105-kDa peptides may represent suitable antigens for development of a specific ELISA for detection of rodent CAR bacillus infections. Furthermore, these data indicate that use of crude CAR bacillus preparations for either rat or rabbit CAR bacillus ELISAs is inappropriate. PMID- 10090022 TI - Mucosotropic papillomavirus infections. PMID- 10090023 TI - Familial megacecum and colon in the rat: a new model of gastrointestinal neuromuscular dysfunction. AB - Gastrointestinal motility disorders are of considerable clinical importance in humans and animals. Abnormalities of smooth muscle and the enteric nervous system have been described. We have identified and characterized a new mutant stock of rats that develops severe megacecum and colon with pseudo-obstruction, Familial Megacecum and Colon (FMC). The inheritance pattern of FMC was characterized by selective breeding. Gastrointestinal motility was evaluated radiographically. Complete pathologic evaluations, including ultrastructural examination and staining of colonic segments for acetylcholinesterase, peripherin, vasoactive intestinal peptide, substance P, nitric oxide synthase, and somatostatin, were performed. Spontaneous contractility and contractile force in isolated colonic muscle strips were examined. Familial megacecum and colon is inherited as an autosomal recessive trait. The markedly dilated cecum and proximal portion of the colon are followed by a short, funnel-shaped segment and distal portion of the colon with normal or slightly reduced lumen. Although clinical features and gross anatomic changes of the colon resemble those of Hirschsprung's disease in humans and animals, aganglionosis is not a feature of FMC. An increase in somatostatin staining was observed in dilated regions of bowel. The spontaneous contractile frequency and contractile force were diminished in the affected colon. Familial megacecum and colon is a new mutant, distinct from previously described hereditary and targeted mutant rodent models that develop megacecum and colon as a result of distal colonic dysfunction. The functional or morphologic defect(s) that result in colonic dysfunction in rats with FMC was not determined. The disease may result from an absence or overexpression of a single or group of neurotransmitters or their respective neurons, receptor abnormalities, or defects in the intestinal pacemaker system. PMID- 10090024 TI - Effect of feeding of a cholesterol-reducing bacterium, Eubacterium coprostanoligenes, to germ-free mice. AB - Twelve germ-free mice were used to evaluate the effect of orally administered Eubacterium coprostanoligenes (ATCC 51222) on serum cholesterol concentration. After 1 week of bacterial administration, serum cholesterol concentration of the experimental group (204.9 +/- 5.3 mg/dl, mean +/- SEM) tended to be lower than that of controls (213.7 +/- 5.9 mg/dl, mean +/- SEM). The hypocholesterolemic effect, however, was transient. Greater coprostanol-to-cholesterol ratios in feces of bacteria-fed mice also indicated a transient cholesterol-reducing action of E. coprostanoligenes in the intestine. Eubacterium coprostanoligenes did not colonize the intestine of E. coprostanoligenes-fed mice. Results indicate that the transient occurrence of E. coprostanoligenes in the digestive tract of E. coprostanoligenes-fed mice may decrease plasma cholesterol concentration, but colonization of the tract depends on monoassociation with another bacterium. Results also indicate that feeding of E. coprostanoligenes decreases blood cholesterol concentration. PMID- 10090025 TI - Age-related changes in blood pressure in the senescence-accelerated mouse (SAM): aged SAMP1 mice manifest hypertensive vascular disease. AB - Age-related changes in systolic blood pressure were assessed, using the senescence-accelerated mouse (SAM) model for aging research with strains SAMR1, SAMP1, and SAMP8. Each of the strains manifested a characteristic change in blood pressure with age. The SAMR1 strain, with normal aging, did not have chronologic changes from 2 to 27 months of age. The SAMP1 strain, with accelerated senescence, had a significant increase in blood pressure with age, and some (8 of 39) mice manifested hypertensive vascular disease characterized by high blood pressure, cardiac hypertrophy, and arteriolar fibrinoid necrosis at 11 to 14 months of age. The gradual increase in blood pressure after 8 to 10 months was considered to be preceded by progressive renal changes, from glomerulonephritis to contraction of the kidney, suggesting that the high blood pressure in the SAMP1 strain was of renal origin. Blood pressure in the SAMP8 strain, with age related deficits in learning and memory, gradually decreased after 5 to 7 months of age, and was suggested to be due to the astrogliotic changes in response to spongiform degeneration in the medulla oblongata at 11 to 14 and 15 to 18 months of age. PMID- 10090026 TI - Growth variation in common marmoset monkeys (Callithrix jacchus) fed a purified diet: relation to care-giving and weaning behaviors. AB - Significant relations were observed between select infant-care and weaning behaviors and growth in body weight in common marmoset monkeys (Callithrix jacchus). The patterns of these relations suggest that earlier occurrence of developmental milestones, such as cessation of transport (being off carriers) and weaning to solid food, were associated with slower growth during the subsequent period. In contrast, more frequent nursing bouts during the period in which weaning was initiated were associated with higher growth rates. In the case of being off carriers, these effects did not carry over to older ages, suggesting that any deficits in growth were temporary. In the case of earlier, more frequent consumption of solid food, there was some suggestion that there were longer-term effects, followed by catch-up growth. The knee-to-heel length of subjects was not related to the measured behaviors. There was no relation between early weaning to solid food and leanness at day 75, suggesting that, although this behavior was affecting overall weight, it did not affect relative gains of fat versus lean mass. There were, however, significant correlations between cessation of transport or frequency of nursing bouts during the weaning period and leanness, with earlier cessation of transport and less frequent nursing associated with leaner infants, after weaning. Our results differed from those of a previous study that found a relation between linear growth and abuse in this species, with abuse defined as physical injury by other members of the group. We found no differences in growth between abused and nonabused infants. However, abused infants had lower birth weight. PMID- 10090027 TI - Effects of single and multiple injections of ketamine hydrochloride on serum hormone concentrations in male cynomolgus monkeys. AB - Using simulated short- and long-term effect studies, we evaluated the effect of ketamine anesthesia on serum cortisol, testosterone, and immunoreactive luteinizing hormone (ILH) and bioactive LH (BioLH) concentrations in adult male cynomolgus monkeys. Cortisol, testosterone, and ILH were measured by use of radioimmunoassay, and BioLH was measured by use of a radioreceptor assay method. For the acute effect, the first group (eight monkeys) was given four successive intramuscular injections of ketamine (10, 5, 5, and 5 mg/kg of body weight at 0, 30, 60, and 110 min respectively). Blood samples were taken at 0, 15, 30, 45, 60, and 120 min. For the long-term effect, the second group (10 monkeys) was given a single injection of ketamine (10 mg/kg) once a week for 4 consecutive weeks. Blood samples were taken 5 to 10 min after each injection, then were used to determine the variation in hormone concentrations among the monkeys (inter individual variation) and within each monkey (intra-individual variation). There were no statistically significant differences in serum cortisol, testosterone, ILH, and BioLH values between the first blood sample (before the ketamine injection) and sequential blood samples in monkeys of the first group. Although intra-individual variation in the hormones (i.e., hormonal change within each monkey) was not statistically significant, inter-individual variation (among the monkeys) was significantly (0.00001 < P < 0.033) different in monkeys of the second group. These results indicate that an adequate number of animals must be used to minimize animal-to-animal variability. Our results confirm that ketamine is a suitable anesthetic agent to immobilize male cynomolgus monkeys in experimental studies (short- and long-term studies) aimed at elucidating hormonal changes. PMID- 10090028 TI - Live mice from cryopreserved embryos derived in vitro with cryopreserved ejaculated spermatozoa. AB - This study was undertaken to try to reduce the number of animals required to maintain mouse strains by banking of embryos or spermatozoa. The principal objective was to cryopreserve ejaculated mouse spermatozoa, using a method recently developed for epididymal spermatozoa. Within 30 min after mating, ejaculated spermatozoa were flushed from the uterus of mated females; shortly afterwards, epididymal spermatozoa were also collected from the same males that had mated with the females. The average values for spermatozoal motility and viability of ejaculated specimens of nine males were 43 and 46%, respectively, and for epididymal specimens, the corresponding values were 60 and 52%. In experiment 1, ejaculated or epididymal spermatozoa were incubated with oocytes for 0.5 to 4 h. As evidenced by development into two-cell embryos within 24 h, kinetics of fertilization of the two spermatozoa types were similar. In experiment 2, ejaculated and epididymal spermatozoa of three males were separately cryopreserved in medium containing raffinose, glycerol, and egg yolk. Samples were cooled and seeded at -4 degrees C, cooled to -70 degrees C at 20 degrees C/min, and then were placed into liquid nitrogen for storage. When cryopreserved epididymal or ejaculated spermatozoa were thawed at > 1,000 degrees C/min and used for in vitro fertilization, > 60% of oocytes cleaved, and approximately 95% of cleaved embryos developed into morulae or blastocysts. When embryos produced with cryopreserved spermatozoa were transferred into recipients, 18 and 22 live pups were obtained from 62 and 54 embryos resulting from ejaculated or epididymal spermatozoa, respectively. This study documented the feasibility of cryopreserving ejaculated spermatozoa as an effective alternative to preserving germ plasm from genetically valuable mice. PMID- 10090029 TI - Hypothermia reduces neurologic deficits associated with placement of a vascular prosthesis in the abdominal aorta of rabbits. AB - Treatment for atherosclerotic vascular disease in human beings ranges from medical management to interventional therapy, such as angioplasty, atherectomy, and bypass grafting. Recently, bypass grafting with a vascular prosthesis has received increased attention and clinical use. In the course of studies to optimize use of a small-caliber vascular prosthesis, five of six rabbits undergoing implantation of a polytetrafluoroethylene vascular prosthesis in the infrarenal abdominal aorta developed hind limb neurologic deficits, which resulted from focal ischemic damage to the spinal cord attributable to temporary vascular occlusion of the abdominal aorta during placement of the vascular prosthesis. In subsequent studies, induction of systemic hypothermia decreased the rate of development of neurologic deficits from 83 to 9% without any apparent perioperative complications associated with decreased body temperature. We determined that mild hypothermia (rectal temperature of 32 to 35 degrees C), combined with aortic occlusion time of < 40 min, is sufficient to afford protection from ischemic injury to the spinal cord in the rabbit. PMID- 10090030 TI - Diagnostic exercise: erythrocytosis in an aged beagle dog. PMID- 10090031 TI - Transmission of Helicobacter hepaticus infection to sentinel mice by contaminated bedding. PMID- 10090032 TI - Characterization of mouse parvovirus infection among BALB/c mice from an enzootically infected colony. PMID- 10090033 TI - Hyaluronidase treatment and preimplantation development of mouse embryos. PMID- 10090034 TI - Evaluation of mutant mouse production by mice that are heterogeneous for the Mcfsop gene. PMID- 10090035 TI - Experimentally induced infection with Helicobacter pylori in squirrel monkeys (Saimiri spp.): clinical, microbiological, and histopathologic findings. PMID- 10090036 TI - Spontaneous pre-Descemet's membrane corneal opacities in rabbits. PMID- 10090037 TI - Shigella infection in macaque colonies: case report of an eradication and control program. AB - A primate colony comprising three distinct but interrelated units had long-term history of undiagnosed diarrhea and associated deaths for many years. In 1989, the clinical problem was recognized as a confounding factor for the experimental work, and steps were taken to eradicate the disease. This was done by a combined approach involving improved sample collection techniques and microbiological methods, treatment of all animals in the colony, and improvement in management. These management changes included alterations in basic facility and cage design, disinfection procedures, and continuous routine microbiological sampling of all groups of animals on a random basis, as well as sampling of those suspected to be at risk for stress-associated Shigella shedding. Using this approach, we have eliminated clinical cases of shigellosis and have not have any further isolations of Shigella from this colony. PMID- 10090038 TI - Enterohepatic lesions in SCID mice infected with Helicobacter bilis. AB - Helicobacter bilis is a recently identified species that colonizes the intestine and liver of mice. In immunocompetent mice, infections have been associated with mild hepatitis, and in immunocompromised mice, inflammatory bowel disease has been induced by intraperitoneal inoculation of the organism. We report inoculation of 6-week-old C.B-17 scid/scid mice by gastric gavage with approximately 10(7) H. bilis colony-forming units. Groups of mice were euthanized and necropsied 12, 24, and 36 weeks after inoculation. Mild to moderate proliferative typhlitis was evident in all mice at 12 and 36 weeks after inoculation and in most mice 24 weeks after inoculation. Mild to severe chronic active hepatitis was detected in 10 of 10 male mice and 3 of 10 female mice. These results indicate that H. bilis can cause moderate to severe enterohepatic disease in immunocompromised mice. PMID- 10090039 TI - Fatal trematodiasis in research turtles. AB - During a 5-year period, 16 freshwater turtles (Trachemys scripta elegans and Chrysemys picta) that were purchased for research purposes died spontaneously. Clinical signs of disease included lethargy, constant swimming, swimming sideways, hemiplegia, and ulcerative lesions on the carapace. At necropsy, subcutaneous edema, hepatic necrosis, pancreatic necrosis, splenic necrosis, and intestinal parasites were identified. Histologically, trematode eggs were seen within the liver, brain, spleen, kidney, myocardium, lung, pancreas, testes, and bladder, and were associated with granulomatous reactions. The size and distribution of the eggs were consistent with Spirorchis sp. infection, although adults could not be found to confirm the species. Spirorchid flukes are 1 to 2 mm long and inhabit the heart and blood vessels where they produce eggs. Spirorchis parvus are capable of invading various tissues, including pancreas and the central nervous system. The pathogenicity of the flukes seems to be related to widespread deposition of the eggs, which may block small blood vessels within the intestines, causing necrosis and bacteremia. Antemortem diagnosis is made by direct examination of fecal smears for eggs. Postmortem diagnosis is accomplished by examination of tissues for adult parasites and microgranulomas associated with the fluke eggs. The parasite requires a snail intermediate host to complete its life cycle. Intramuscular or oral administration of praziquantel is reported to be an effective treatment. PMID- 10090040 TI - Lymphoproliferative disease induced by murine herpesvirus-68. PMID- 10090041 TI - Comparison of sensitization to crude and purified house dust mite allergens in inbred mice. AB - To establish a murine model for house dust mite allergy to purified mite allergens, we studied the immune response to two major mite allergens, native Dermatophagoides farinae 1 (nDer f 1) and recombinant Der f 2 (rDer f 2), and crude mite extract in four mouse strains, A/J, BALB/c, C57BL/6, and C3H/He. Mice were immunized with mite extract, nDer f 1 or rDer f 2, three times at 2-week intervals. Then mice were examined to determine status of sensitization to the antigen. Anti-mite extract IgE production was induced in all strains, and plasma IgE concentration did not differ much among the four strains. In contrast, IgE response to nDer f 1 and rDer f 2 indicated an intra-strain difference. The A/J mice had high responses to both antigens, whereas BALB/c did not respond to rDer f 2. The C57BL/6 and C3H/He mice had moderate to low IgE responses to nDer f 1 and rDer f 2. Immediate airway constriction was provoked by inhalation of mite extract or rDer f 2 in sensitized mice, and the degree of the immediate response was almost proportional to antigen-specific IgE concentration. We concluded that immunization of inbred mice with nDer f 1 and rDer f 2 achieved sensitization to mite allergens. Among the four strains, A/J mice with H-2a haplotype were the highest responder to mite allergens. PMID- 10090042 TI - Model of emotional stress in rats. AB - A new experimental rat model for suppression of release of arginine vasopressin (AVP) was evaluated. Release of AVP is potentiated by physiologic stimuli, but is suppressed by emotional stress. Rats were exposed to the aggressive behavior of other rats injected with 6-hydroxydopamine hydrochloride (6-OHDA) in both lateral ventricles and subjected to a pain stimulus applied to the tail. To ascertain whether emotional stress is induced by use of this method, plasma corticosterone, glucose, and AVP concentrations were measured in the stressed group of rats (n = 8) placed near a group of aggressive (fighting) rats. Characteristic changes in behavior, significant increases in plasma corticosterone and glucose values, and lack of increase in plasma AVP concentration in stressed rats confirmed that they experienced emotional stress. This new model meets the experimental requirements for suppression of AVP release in rats. PMID- 10090043 TI - Hemodynamic response to anesthesia in pregnant and nonpregnant ICR mice. AB - Mean arterial blood pressure (BP) and heart rate (HR) during and after recovery from anesthesia in pregnant and nonpregnant ICR mice were evaluated. Mice were evaluated during mechanical ventilation, from 15 to 60 min after induction of anesthesia. The anesthetic protocols were pentobarbital (80 mg/kg, given intraperitoneally [i.p.]); two low doses of ketamine and xylazine (90 mg/kg, 7.5 mg/kg, respectively, i.p., with a second dose given 20 min after the initial dose); and a single high dose of ketamine and xylazine (150 mg/kg, 12.5 mg/kg, respectively, i.p.). The BP was measured in the right carotid artery, using a fluid-filled catheter connected to a chamber containing a solid-state pressure transducer. Mechanical ventilation was performed via tracheotomy, using a normalized minute ventilation of 3.5 ml*min-1*g-1 for nonpregnant mice and 3.0 ml*min-1*g-1 for pregnant mice. Mean BP was lower and HR was higher in pregnant than in nonpregnant mice for each anesthetic protocol. Pentobarbital induced significantly greater tachycardia and hypotension than did the other protocols. The average BP and HR were similar between two low doses and a single high dose of ketamine and xylazine. During spontaneous breathing from 30 to 180 min after recovery from anesthesia by use of a single low dose, ketamine and xylazine induced similar HR profiles, but mean BP in pregnant mice recovered earlier than did that in nonpregnant mice. These results suggest that ketamine and xylazine induced adequate anesthesia for superficial surgical procedures in pregnant and nonpregnant mice while inducing small changes in HR and BP, and pregnancy resulted in a different hemodynamic reaction in response to ketamine and xylazine. These data will be useful for the design and interpretation of physiologic protocols using pregnant and nonpregnant genetically targeted mice. PMID- 10090044 TI - Glucocorticoid-resistant B-lymphoblast cell line derived from the Bolivian squirrel monkey (Saimiri boliviensis boliviensis). AB - The goal of the study reported here was to develop a continuous cell line from the squirrel monkey that expresses the species-specific phenotype of impaired sensitivity to glucocorticoids. Thirty milliliters of blood from a male Bolivian squirrel monkey (Saimiri boliviensis boliviensis) was fractionated, and the buffy coat was obtained and incubated in the presence of B95-8 cell-conditioned medium, an abundant source of Epstein-Barr virus (EBV), and 2 micrograms of cyclosporin A/ml. Cell growth was detected within 8 weeks, after which the cells were cloned by use of the limiting dilution method. One clone (4D8) was characterized in detail. The chromosomal count and G-banding pattern confirmed that the cells were of Bolivian squirrel monkey origin. The B-cell origin of these cells was indicated by electron microscopic analysis and was confirmed by expression of CD20. The cells stained strongly for LMP1, a marker of latent EBV infection, and occasionally for the lytic infection marker ZEBRA (BZLF1). The responsiveness of clone 4D8 cells to glucocorticoids was determined by comparing the effects of dexamethasone on cell growth and the induction of a glucocorticoid-inducible mRNA in 4D8 cells with the effects on a human EBV-transformed B-lymphoblast cell line (HL). Dexamethasone inhibited the growth of HL cells, with IC50 of approximately 9 nM, but had no effect on the growth of 4D8 cells. The induction of FK506 binding protein FKBP51 mRNA by dexamethasone was also significantly blunted in 4D8 cells. Thus, we have developed and characterized a squirrel monkey lymphoblastic cell line derived by transformation of B-lymphocytes with EBV; the cell line has diminished growth and transcriptional responses to glucocorticoids. PMID- 10090045 TI - Oral anticoagulant therapy and international normalized ratios in swine. AB - While monitoring coagulation testing in Yucatan miniature swine being given oral anticoagulants, we noticed instances of high international normalized ratios (INR) without clinical complications in our animal model. All pigs (n = 17) weighed approximately 35.2 kg and were dosed daily with 2 to 3 mg of coumadin. Plasma samples were obtained and assayed for prothrombin time (PT), calculated INR, and activated partial thromboplastin time (APTT) at baseline, and after 7 and 14 days of coumadin therapy. Results of initial testing indicated high INR values after anticoagulation and short APTT values at baseline, which led us to consider the activity of vitamin K-dependent coagulation factors in the pig. This information was not available in literature concerning this strain of swine, and was surprising given that pigs are frequently used cardiac research models. Using the same plasma samples, we repeated the PT, INR, and APTT determinations using different reagents and a different analyzer. We also determined activities of coagulation factors II, VII, IX, and X. Large PT and INR differences were seen between the two instrument/reagent combinations, possibly due to the differences in the thromboplastins used and differences in the photo-optic versus manual clot detection method of the instruments. Vitamin K-dependent factors in all pigs responded to coumadin by decreasing to < 30.0% activity, except for factor IX. The high INR values were not as pronounced when the second instrument/reagent combination was used, and the results seemed more in line with the animals' clinical condition. With this instrument/reagent combination, the pig can be considered a good model for research requiring oral anticoagulant medication. PMID- 10090046 TI - Myocardial injury in the mouse induced by transthoracic cauterization. AB - A simplified transthoracic procedure using electrocauterization was used to induce myocardial injury in mice. After a single small incision through the skin and dissection of the underlying musculature, a modified electrocautery probe consisting of an insulated 20-gauge blunt needle with a polyethylene sleeve was inserted through the interior intercostal muscle at the fourth intercostal space and positioned on the anterior surface of the heart. The placement of the probe on the heart was indicated by mechanical motion of the exterior section of the needle. Electrocautery was applied to the distal exposed end of the probe. Of 10 mice that underwent this procedure, nine survived. After 10 days, myocardial damage was assessed by visual and histologic examination of the heart. In eight of nine surviving mice, transmural injury was induced in the left ventricle. The region of myocardial tissue damage on the surface of the left ventricle was 4.6 +/- 0.5 mm in diameter. This method provides a simple, noninvasive technique using a transthoracic electrocautery procedure to induce myocardial injury in the mouse heart with a low incidence of postoperative mortality. PMID- 10090047 TI - Method for continuous infusion into the portal vein of mice. AB - Recombinant retroviral vectors are attractive for in vivo gene transfer into the liver because they integrate into the host-cell genome, resulting in permanent gene expression. Gene-transfer efficiency can be improved by increasing the number of retroviral particles delivered to hepatocytes. For this purpose, we report a mouse model for continuous infusion into the portal circulation permitting large-volume vector administration, which will allow marked increase in gene-transfer efficiency. Continuous saline infusion was evaluated, using various parameters, and an infusion rate of 6 ml/24 h was found safe and well tolerated for at least 2 weeks. No significant changes in liver and kidney function and electrolyte balance were observed during the infusion. In addition to providing a valuable method for in vivo hepatic gene therapy, this model has a number of other potential applications, including mouse studies of hepatic tumor therapy, pharmacology, toxicology, and liver biology. PMID- 10090048 TI - Diagnostic exercise: vesicular epidermal rash, mucosal ulcerations, and hepatic necrosis in a cynomolgus monkey (Macaca fascicularis). PMID- 10090049 TI - Stress-related hormonal and metabolic responses to restraint, with and without butorphanol administration, in pre-conditioned goats. PMID- 10090050 TI - Systemic yeast infection in owl monkeys (Aotus vociferans): ante-mortem screening and diagnosis by examination of bone marrow aspirates. PMID- 10090051 TI - Maternal transfer of Hantavirus antibodies in rats. PMID- 10090052 TI - Arterial blood gas changes in New Zealand white rabbits during carbon dioxide induced pneumoperitoneum. PMID- 10090053 TI - Longstanding problem of continued availability of microbial strains. PMID- 10090054 TI - Specific-pathogen-free conditions enhance inflammatory bowel disease in T-cell receptor knockout, but not C3H/HeJBir mice. PMID- 10090055 TI - Rodent quarantine programs: purpose, principles, and practice. AB - In animal research, validity and reproducibility of data are critically influenced by the microbial status of the experimental animals. One of the most crucial aspects of assuring quality in animal research is providing research personnel with confidence that experimental results will not be invalidated due to interference caused by infectious disease. An effective quarantine program is essential to providing this assurance. Quarantine programs are generally instituted to prevent the introduction of rodent pathogens into established specific-pathogen-free colonies in a facility. Therefore, programs should be designed to isolate newly acquired rodents until their health status can be determined and to maximize the probability that microorganisms of interest will be detected before the animals are introduced into (and thus, could potentially contaminate) established colonies. Important principles that are critical to designing an effective quarantine program will be discussed here, as will the practical implementation of these principles. Although quarantine programs may be costly in terms of time and effort, these costs must be balanced against the potential costs of disease outbreaks that could invalidate long-term studies, alter normal biological baselines, and cause the loss or necessitate re derivation of rare or valuable strains of rodents. Reducing the incidence of quarantine failures through appropriate program design and implementation helps to maintain the confidence of research personnel in the value of quarantine programs and in our competence as specialists in laboratory animal management and as partners in the research process. PMID- 10090056 TI - Catheter-tract infections in rhesus macaques (Macaca mulatta) with indwelling intravenous catheters. AB - Development of catheter-tract infections in experimental animals can have devastating consequences on animal health and the functional lifespan of surgical implants. To measure the incidence of catheter-tract infections in animals with exteriorized intravenous catheters in this facility and assess the effects of these infections on mean catheter lifespan, health records of 31 Macaca mulatta with catheters were reviewed. Records spanned the interval of January 1, 1996 through October 1, 1997. Catheter-tract infections in 16 of 53 (30.2%) monkeys with catheters were diagnosed based on a combination of clinical signs of infection and results of bacterial culture. Segmental catheter-tract infections reduced mean catheter lifespan to 147 days, compared with 354 days for uninfected catheters. Exit-wound, local tunnel, and surgical-site infections did not significantly reduce catheter lifespan. Bacterial culture reports documented 31 isolates; 41.9% (13 of 31) were coagulase-negative staphylococci, and 22.6% (7 of 31) were Staphylococcus aureus. Of 20 isolates tested, 15 (75%) were resistant to methicillin/oxacillin in vitro. Antimicrobial susceptibility testing of methicillin-resistant and methicillin-susceptible isolates indicated that, compared with methicillin-sensitive isolates, methicillin-resistant isolates had a pattern of multiple antibiotic resistance. Catheter-tract infections were common in this colony of rhesus macaques, and clinically severe infections caused a drastic reduction in catheter lifespan. Approximately half (48%) the bacterial isolates were methicillin-resistant gram-positive bacteria. PMID- 10090057 TI - Helicobacter bilis/Helicobacter rodentium co-infection associated with diarrhea in a colony of scid mice. AB - An outbreak of diarrhea spanning 3 months occurred in a breeding colony of scid/Trp53 knockout mice. Approximately a third of the 150 mice were clinically affected, with signs ranging from mucoid or watery diarrhea to severe hemorrhagic diarrhea with mortality. Helicobacter bilis and the newly recognized urease negative organism H. rodentium were isolated from microaerobic culture of feces or cecal specimens from affected mice. Dual infection with H. bilis and H. rodentium were confirmed by culture and polymerase chain reaction (PCR) in several animals. Both Helicobacter species rapidly colonized immunocompetent sentinel mice exposed to bedding from cages containing affected mice, but the sentinel remained asymptomatic. Mice with diarrhea had multifocal to segmental proliferative typhlitis, colitis, and proctitis. Several affected mice had multifocal mucosal necrosis with a few focal ulcers in the cecum, colon, and rectum. Mice with diarrhea were treated with antibiotic food wafers (1.5 mg of amoxicillin, 0.69 mg of metronidazole, and 0.185 mg of bismuth/mouse per day) previously shown to eradicate H. hepaticus in immunocompetent mice. Antibiotic treatment resulted in resolution of diarrhea, but not eradication of H. bilis and H. rodentium; mice continued to have positive PCR results after a 2-week treatment regimen, and clinical signs of diarrhea returned in some mice when treatment was suspended. To the authors' knowledge, this is the first report of natural infection with either H. bilis and/or H. rodentium causing acute diarrheal disease and suggests that H. bilis and/or H. rodentium can be an important pathogen for scid mice. PMID- 10090058 TI - Genetic deficiency in alpha 1 proteinase inhibitor (alpha 1 PI) associated with emphysema. PMID- 10090059 TI - Immune response of chimpanzees infected with human mycoplasmas. AB - Seven chimpanzees were inoculated intra-articularly with one of three Mycoplasma species. Three chimpanzees were inoculated with clinical synovial isolate 1620, and one was inoculated with type strain PG-21 of M. hominis. The fifth animal was inoculated with clinical synovial isolate 2010B, and the sixth was inoculated with the type strain CO of Ureaplasma urealyticum. The seventh animal was inoculated with clinical isolate PI-1428 of M. pneumoniae. The synovial isolates induced intense antibody responses, antibodies recognized more antigens, and the reactive antigens were distinct from the corresponding type strains. Chimpanzees infected with synovial isolate 1620, but not type strain PG-21, recognized antigens of molecular mass 223, 208, 168, 165, 155, 150, 142, 134, 115, 105, 52, 50, 45, 38, and 36 kDa. The chimpanzee infected with synovial isolate 2010B, but not type strain CO, recognized antigens at about 277, 237, 62, 57, and 43 kDa. The major antibody reactive antigens of M. pneumoniae isolate PI-1428 migrated at about 170, 90, 56, 40, 32, and 30 kDa. The reported biologic activities of antigenic proteins derived from these Mycoplasma species are reviewed. PMID- 10090060 TI - Efficacy of hydroquinone in the treatment of cutaneous hyperpigmentation in hairless descendants of Mexican hairless dogs (Xoloitzcuintli). AB - The skin of adult hairless dogs is clinically nonpigmented, clinically lightly pigmented, or clinically hyperpigmented (spotty pigmented). The pigment noted clinically is attributable to melanin granules in the epidermis. Spotty pigmentation in the skin of adult hairless dogs was treated by administration of the depigmenting agent (3% hydroquinone, HQ) for 1 month. Depigmenting effects were examined by use of three methods: skin color, dihydroxyphenylalanine (DOPA) positive melanocyte count, and histologic evaluation. The treated skin of hairless dogs began to become depigmented after application of HQ for 1 week. After 1 month of treatment with HQ, depigmentation spread over a quarter of the body. The number of DOPA-positive melanocytes in the HQ-treated sites decreased to less than approximately a fifth of that before treatment. In HQ-treated skin, histologic staining by use of Fontana-Masson's (FM) method revealed complete absence of melanin pigment. These results suggested that hairless dogs should be a useful animal model for investigating the effects and cutaneous toxicity of depigmenting agents. PMID- 10090061 TI - Genetic galactocerebrosidase deficiency (globoid cell leukodystrophy, Krabbe disease) in rhesus monkeys (Macaca mulatta). AB - Globoid cell leukodystrophy, or Krabbe disease, is a severe disorder of the peripheral and central nervous system myelin caused by deficient galactocerebrosidase (GALC) activity. This autosomal recessive disease affects humans and animals including dogs, mice, and rhesus monkeys. Cloning of the human and animal GALC genes opened opportunities for therapeutic trials using animal models. We describe the clinical, pathologic, and biochemical features of the affected rhesus monkey. Affected monkeys had very low GALC activity and a two base pair deletion in both copies of the GALC gene. Clinical signs of tremors, hypertonia, and incoordination led to humane euthanasia by 5 months of age. At necropsy, peripheral nerves were enlarged. Microscopically, the cerebral, cerebellar, and spinal cord white matter was infiltrated with periodic acid Schiff-positive multinucleated globoid cells, and there was a striking lack of myelin. Peripheral nerve fibers were decreased in number and separated by Alcian blue- and safranin O-positive material. Myelin sheaths were greatly diminished. Lipid analysis of brains of 12-day-old and 158-day-old affected monkeys revealed a great excess of psychosine in white matter. The rhesus monkey model will be especially useful for exploring treatment options, including prenatal bone marrow transplantation and various approaches to gene therapy. PMID- 10090062 TI - Latissimus dorsi cardiomyoplasty: a chronic experimental porcine model. Feasibility study of cardiomyoplasty in Danish Landrace pigs and Gottingen minipigs. AB - Cardiomyoplasty is an experimental treatment for end-stage heart failure. We hypothesized that the porcine latissimus dorsi muscle (LDM) in an experimental porcine model is a suitable surrogate for a clinically relevant evaluation of this concept. Fourteen Danish Landrace (DL) pigs and six Gottingen minipigs (GM) were studied. The LDM was evaluated immediately after surgical dissection and in various phases: phase 1 (n = 4)--outcome of a partial vascular isolation (vascular delay), 2 to 3 weeks prior to heart wrapping in DL pigs; phase 2 (n = 6)--long-term flap survival of nonstimulated LDM cardiomyoplasty in DL pigs; phase 3 (n = 6)--outcome of nonstimulated cardiomyoplasty in GM; phase 4--one DL pig had dynamic cardiomyoplasty performed and was subjected to low-intensity LDM stimulation for 8 months. Isolation of the LDM of DL pigs and GM as a pedicled graft had no acute deleterious impact on the global blood supply. In phase 1a, partial vascular isolation and in situ recovery of the LDM resulted in a muscle encapsulated in fibrotic tissue, which hampered a later heart wrap. In phase 1b, a less extensive dissection diminished fibrosis and allowed subsequent wrapping. In phase 2, after 6 weeks of nonstimulated LDM cardiomyoplasty, the LDM of DL pigs was viable, with excellent heart-muscle integration. In phase 3, the same procedure applied in GM yielded the same result as that in DL pigs, but with a higher success rate owing to the learning phase. PMID- 10090063 TI - Characterization of platelet abnormalities of Tester Moriyama (TM) rats with storage pool deficiency. AB - Platelet abnormalities of Tester Moriyama (TM) rats, which have prolonged bleeding time with normal platelet count, were characterized by comparison with those of fawn-hooded (FH) rats with platelet storage pool deficiency (SPD). Morphologically, the dense granules were virtually lacking in platelets from TM and FH rats. Platelets from TM and FH rats aggregated in response to adenosine diphosphate (ADP), but failed to have secondary aggregation. In contrast, platelet aggregation was completely absent in response to 1 to 20 micrograms of collagen/ml, although partial aggregation was observed at the higher dosage of 50 micrograms/ml. Normal amounts of platelet membrane glycoproteins IIb/IIIa were expressed in TM and FH rats, but platelet adenosine triphosphate (ATP) and ADP contents were lower than those in platelets from control Wistar rats. Platelet ATP-to-ADP ratio of TM and FH rats was significantly higher than that of Wistar rats. Serotonin content in platelets from TM and FH rats was 20 to 25% that of Wistar rat platelets. These results suggested that platelet abnormalities of TM rats are a typical characteristic of platelet SPD and are similar to those of FH rats, which are genetically different from TM rats. Therefore, TM rats may serve as a useful animal model for the study of platelet SPD. PMID- 10090064 TI - Evaluation and characterization of congenital hypothyroidism in rdw dwarf rats. AB - The rdw rat is a new strain of dwarf mutant that has decreased blood thyroxine (T4) and growth hormone (GH) concentrations and testicular enlargement during development and aging. To confirm whether this strain can be used as a new hypothyroid model, the experiments reported here were carried out, using adult rdw rats, rdw rats treated with thyroxine, and clinically normal (N) Wistar Imamichi rats. Clinical parameters of deficient thyroid function in rdw rats were chosen for evaluation and characterization. Body weight, hemoglobin (Hb) concentration, hematocrit (Hct), glucose (GLU), and systolic blood pressure were significantly lower, and serum values for aspartate transaminase (AST), total cholesterol (TC), total protein (TP), and blood urea nitrogen (BUN) were higher in rdw than in N rats. Serum concentrations of total T4 and free triiodothyronine (FT3) were significantly lower, and serum thyroid-stimulation hormone (TSH) concentration was markedly higher in rdw than in N rats. Serum GH concentration was significantly lower in rdw than in N rats. Results of histologic examination indicated that the thyroid gland of rdw rats was markedly atrophied, compared with that of N rats. Results of clinical examination of organs and hematologic and biochemical values in rdw rats corresponded to those of the hypothyroid state in humans. Most organ weights (heart, kidney, spleen, and adrenal gland), hematologic and biochemical values (Hb, Hct TC, TP, BUN), blood pressure, and serum hormone (TSH and GH) values underwent substantial restoration (partial or complete) toward normal in response to replacement therapy. In conclusion, the rdw rat is a useful model of congenital hypothyroidism. PMID- 10090065 TI - Morphologic and hematologic characteristics of storage pool deficiency in beige rats (Chediak-Higashi syndrome of rats). AB - Characterization of beige rats as having a platelet storage pool deficiency (SPD) was undertaken. Platelets from beige rats, an animal model of Chediak-Higashi syndrome (CHS), completely lacked the ability to aggregate when stimulated with high dosages of collagen (50 micrograms/ml), and lacked secondary aggregation induced by adenosine diphosphate (ADP). Concentrations of ADP, ATP, and serotonin in the platelets of beige rats were significantly lower than those of control rats. However, platelet count remained within normal values. Electron microscopy revealed that platelets had fewer dense granules, whereas other organelles had normal structure. This morphologic and functional evidence confirms that platelets of beige rats have the typical characteristics of SPD. PMID- 10090066 TI - Sheep model for study of maternal adrenal gland function during pregnancy. AB - Our goal was to develop a model for the study of maternal adrenal gland regulation and the effects of maternal cortisol secretion on fetal homeostasis. At about 108 days of gestation, before the time of rapid fetal growth or fetal adrenocortical maturation, ewes, under halothane anesthesia with controlled ventilation and positioned in sternal recumbency, were adrenalectomized. Ewes were treated with aldosterone by intravenous infusion (3 micrograms/kg of body weight per day) to induce normal late-gestation aldosterone concentration. Ewes were also treated with cortisol; for 2 postoperative days, this infusion (1 to 2 micrograms/kg per min) induced plasma concentration similar to that associated with stress. Thereafter, the dosage of cortisol was reduced to induce plasma values similar to normal late-gestation cortisol concentration in ewes (1 mg/kg per day), or to values in nonpregnant ewes (0.6 mg/kg per day). Administration of cortisol and aldosterone was required to prevent electrolyte imbalance and signs of hypoadrenocorticism. With steroid replacement, plasma protein, electrolyte, and glucose concentrations in adrenalectomized ewes were not different from those in sham-operated pregnant ewes. Of 11 adrenalectomized ewes, one died as a result of failure of the infusion pump, and one died as a result of inappropriate treatment for hypoglycemia. Of the remaining ewes, two aborted fetuses, three ewes each delivered one live and one dead fetus, two delivered live singleton fetuses, and two delivered twins. Therefore, this model of relative hypoadrenocorticism in pregnancy is feasible and practical for studying the influence of maternal cortisol concentration on maternal and fetal homeostasis. PMID- 10090067 TI - Plasma electrolyte and metabolite concentrations associated with pentobarbital or pentobarbital-propofol anesthesia during three weeks' mechanical ventilation and intensive care in dogs. AB - Propofol and pentobarbital were used for deep sedation during prolonged mechanical ventilation (3 weeks) and nutritional supplementation in 17 clinically normal dogs in an intensive care setting. Tolerance developed to both drugs. Propofol, in combination with pentobarbital, at an infusion rate of 75 micrograms/kg of body weight per minute was preferred. Pentobarbital infusion alone, begun at the rate of 5 to 6 mg.kg-1.h-1, was satisfactory. The combination of both drugs provided smooth, stable anesthesia and required minimal interventions by intensive care unit personnel. Blood gas tensions and electrolyte, parathyroid hormone (PTH), and metabolite concentrations were generally stable throughout, unless condition of the dog deteriorated (e.g., infection, pneumothorax). Hematocrit and red blood cell count decreased with time, likely attributable principally to multiple blood sample collections. White blood cell count, alkaline phosphatase, phosphate, fibrinogen, cholesterol, and triglyceride values increased with time, in association with pentobarbital and the combination of pentobarbital and propofol. Some of these changes appear to have been related to generic responses to stress and inflammation, some to altered metabolism, and some to the lipid solvent of propofol. The increase in triglyceride concentration was greater when propofol was used. Mortality was 47%, with death occurring between days 2 and 18. PMID- 10090068 TI - Effects of water dilution, housing, and food on rat urine collected from the metabolism cage. AB - The objective of the study reported here was to investigate three factors that may affect the amounts of water consumed and urine excreted by a rat in the metabolism cage: water dilution, housing, and food. Young F344/N rats (eight per group) were used for all experiments. Food was withheld from rats before each 16 h urine collection, then rats were transferred into a metabolism cage. For trial A (water dilution), urine was collected from rats supplied with dyed water (0.05%, vol/vol). This was repeated three times over a 2-week period. Dye in water or urine was quantified, using a spectrophotometer. For trial B (housing), rats were individually housed in wire cages for 3 weeks before the first urine collection. Then they were group housed in the solid-bottom cage (four per cage). After 2 weeks of acclimation, urine collection was repeated. For trial C (food), one group of rats was provided with food, the other was not, during urine collection. About 8% of urine samples of small volume (< or = 3 ml) from trial A were contaminated with drinking water up to 13% of volume. The average urine volume associated with individual housing was approximately twice as large as that associated with group housing. When food was provided during urine collection, rats consumed similar amounts of water but excreted significantly smaller amounts of urine than did rats without food. It was concluded that water dilution of a urine sample from a sipper bottle is relatively small; rats individually housed in wire caging before urine collection can consume and excrete a larger quantity of water, compared with rats group housed in solid bottom cages; and highly variable urine volumes are, in part, associated with lack of access to food during urine collection. PMID- 10090069 TI - Antibody response in baboons (Papio cynocephalus anubis) to a commercially available encephalomyocarditis virus vaccine. PMID- 10090070 TI - The ferret as a model for myocardial infarct size reduction by use of a selectin inhibitor. PMID- 10090071 TI - Postnatal blood cell counts of Japanese house mice (Mus musculus molossinus): maintenance of low numbers of white blood cells. PMID- 10090072 TI - Changes in electrical impedance of vaginal mucus during the menstrual cycle in cynomolgus monkeys (Macaca fascicularis). PMID- 10090073 TI - Intraduodenal inoculation of adult rabbits for evaluating the immunogenicity of genetically attenuated Vibrio cholerae strains. PMID- 10090074 TI - Detection of Pasteurellaceae in rodents by polymerase chain reaction analysis. PMID- 10090075 TI - Pathogen status in the 1990s: abused terminology and compromised principles. PMID- 10090076 TI - Animal models of human disease for the 21st century. PMID- 10090077 TI - The contribution of avian models to our understanding of atherosclerosis and their promise for the future. PMID- 10090078 TI - Nonhuman primate models of atherosclerosis. PMID- 10090079 TI - Mouse models of atherosclerosis. PMID- 10090080 TI - A ret transgenic mouse model of thyroid carcinogenesis. PMID- 10090081 TI - Animal models of human microsporidial infections. AB - Two new models have been described for Enterocytozoon bieneusi, non-human primates and immuno-suppressed gnotobiotic pigs, but there still is no successful cell culture system. The intestinal xenograft system holds promise as an animal model for Encephalitozoon intestinalis. Encephalitozoon hellem is easily propagated in mice, and also may be an important cause of spontaneous disease of psittacine birds. Encephalitozoon cuniculi occurs spontaneously in a wide variety of animals and can be induced experimentally in athymic mice. This is a useful experimental system and animal model, but the infection is relatively rare in man. Mammalian microsporidioses first were recognized as spontaneous diseases of animals that later confounded studies intended to elucidate the nature of diseases of humans. Much was learned about both experimental and spontaneous animal microsporidial infections that subsequently has been applied to the human diseases. In addition, new diseases have appeared, in both animals and humans, for which models are being developed. Since there are now animal models for almost all the known human microsporidioses, information on pathogenesis, host defenses, and effective treatments may become available soon. The microsporidioses provide a good example of the value of comparative pathology. Dr. Payne: Joe Payne. How much accidental infection has occurred with adjacent laboratory animals? Dr. Shadduck: A hard question. The organisms are thought to spread horizontally, and there is some pretty good evidence for that in rabbits. One assumes that this also is the explanation for the occurrence in infected kennels. Horizontal transmission probably occurs via contaminated urine, at least in the case of rabbits and dogs. Experimentally, horizontal transmission has been difficult to demonstrate in mice. Relative to the danger in people, I don't know how to answer that. I have always treated this as one of those things where you should be careful, but you shouldn't get paranoid. So, we have handled infected cell cultures and animals as if they were potentially infectious for man, but not as if they were something as hot as the human AIDS virus, for example. With the increasing number of reports in humans, I think it is clear that one would never want anybody who was at risk of being immunocompromised to work with these organisms. Dr. Fenkel: Are there other questions? Dr. Mysore: How do the parasites spread within the infected hosts? Dr. Shadduck: The usual answer is hematogenously via infected macrophages, but data that actually support that statement are rare. One does see infected macrophages in tissues, so it is not unreasonable to think that some of them escape and lodge in other tissues. But that has never actually been formally demonstrated. Dr. Nakeeb: Is E. bieneusi a human pathogen? Dr. Shadduck: The answer depends on which paper you read and what approach the authors took. There are papers in which the authors argue that the organism is not a cause of clinical disease in AIDS patients, but the general belief today is that the parasite does cause diarrhea and enteritis. I think the evidence for pathogenicity is quite strong for the various species of the Encephalitozoon, based on the severity and distribution of the lesions. PMID- 10090082 TI - Animal models of human hepatitides. PMID- 10090083 TI - Animal models of Helicobacter infection. PMID- 10090084 TI - Inherited neurodegenerative diseases and transgenic models. PMID- 10090085 TI - Nonhuman primates as models for aging and Alzheimer's disease. PMID- 10090086 TI - Primate models of osteoporosis. PMID- 10090087 TI - Non-primate models of osteoporosis. PMID- 10090088 TI - CNS regulation of energy balance and body weight: insights from rodent models. PMID- 10090089 TI - Training in laboratory animal medicine and comparative medicine. PMID- 10090090 TI - The existence of differing monkey B virus genotypes with possible implications for degree of virulence in humans. PMID- 10090091 TI - Spontaneous and engineered mutant mice as models for experimental and comparative pathology: history, comparison, and developmental technology. AB - During the last half-century pathologists have explored the biologic mechanisms associated with inherited human and veterinary diseases by using inbred and inbred mutant (spontaneous) strains of mice. The first successful gene transfer to mice by pronuclear injection of the herpes simplex virus thymidine kinase gene and rabbit and human beta-globulin genes was achieved in the early 1980s. This accomplishment was followed a few years later with the creation of a mouse bearing a disrupted hypoxanthine phosphoribosyl transferase (hrpt) gene (targeted mutation based on ES cell blastocyst injection). Since then, hundreds of genetically engineered models of biomedical importance have been created. The unprecedented scale and scope of development of engineered models present great opportunities as well as experimental challenges to the investigator. The aim of the present review is to provide a framework of information on engineered mouse models from the perspective of experimental and comparative pathology research. Sections include: 1) a brief historical account of the development of mouse models of disease, with increasing progression of genetic refinement as represented by inbred (spontaneous) and congenic (targeted) mutant strains of mice; 2) a synopsis of spontaneous and targeted mutations, with anecdotal examples of expression of individual genes and interactions between multiple mutant genes; 3) selected examples of targeted mutations of interest to developmental and cancer biologists and immunologists; 4) an overview of the technology of development of transgenic mice; and 5) an introduction to on-line database resources of current multi-species genomic information. PMID- 10090092 TI - Lymphoid organ alterations enhanced by sub-lethal doses of coronaviruses in experimentally induced Trypanosoma cruzi infection in mice. AB - The effect of sub-lethal doses of coronaviruses on the course of disease in CBA mice experimentally infected with a mildly pathogenic strain of Trypanosoma cruzi was investigated. Mice were inoculated with either T. cruzi, 0.1 median lethal dose (LD50) of coronavirus (mouse hepatitis virus [MHV-3] or virus X), or both pathogens. Levels of parasitemia, mortality, and the extent of pathologic alterations in lymphoid organs were determined. Mice inoculated with T. cruzi had mild alterations in their lymphoid organs and survived infection. In contrast, mice inoculated with both pathogens died, and had significantly higher levels of parasitemia and profound alterations in lymphoid organs. These results indicate that the pathologic profile of T. cruzi infection can be profoundly altered by subclinical infection with coronaviruses. PMID- 10090093 TI - Management of a measles outbreak among Old World nonhuman primates. AB - BACKGROUND AND PURPOSE: A measles outbreak in a facility housing Old World nonhuman primates developed over a 2-month period in 1996, providing an opportunity to study the epidemiology of this highly infectious disease in an animal-handling setting. METHODS: Serum and urine specimens were collected from monkeys housed in the room where the initial measles cases were identified, other monkeys with suspicious measles-like signs, and employees working in the affected areas. Serum specimens were tested for measles virus-specific IgG and IgM antibodies, and urine specimens were tested for measles virus by virus isolation or reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: A total of 94 monkeys in two separate facilities had evidence of an acute measles infection. The outbreak was caused by a wild-type virus that had been associated with recent human cases of acute measles in the United States; however, an investigation was unable to identify the original source of the outbreak. Quarantine and massive vaccination helped to control further spread of infection. CONCLUSIONS: Results emphasize the value of having a measles control plan in place that includes a preventive measles vaccination program involving human and nonhuman primates to decrease the likelihood of a facility outbreak. PMID- 10090094 TI - Identification by 16S rDNA fragment amplification and determination of genetic diversity by random amplified polymorphic DNA analysis of Pasteurella pneumotropica isolated from laboratory rodents. AB - Pasteurella pneumotropica is an opportunistic bacterium frequently isolated from colonies of various laboratory rodents. Identification of this species, including its differentiation into two distinct biotypes (Jawetz and Heyl), is usually based on the use of conventional bacteriologic methods. In this study, a 16S rDNA fragment amplification procedure was developed for use as an alternative method for identification and differentiation of P. pneumotropica. Polymerase chain reaction (PCR) products were two distinctive fragments of 937 and 564 bp specific for biotypes Jawetz and Heyl, respectively. Specificity of PCR products could be achieved by EcoRI cleavage, leading to 596 plus 341-bp and 346 plus 218-bp fragments for each of the amplification products. Use of this procedure confirmed identification of 34 field isolates and allowed definitive identification of some strains that could not have been done by use of bacteriologic examinations. Field isolates subjected to random amplified polymorphic DNA (RAPD) analysis had high genetic diversity among biotype Jawetz strains in contrast to biotype Heyl strains. In conclusion, RAPD could represent an additional means for identification of ambiguous strains of biotype Heyl and a valuable epidemiologic tool for identification of biotype Jawetz strains of P. pneumotropica. PMID- 10090095 TI - Pelizaeus-Merzbacher disease. PMID- 10090096 TI - Increased nonenzymatically glycosylated proteins in the vitreous humor of diabetic animals. AB - One of the earliest pathologic changes of diabetes mellitus is increased nonenzymatic glycosylation (i.e., glycation) of proteins, which results in abnormal aggregation of collagen fibrils and production of superoxide radicals. These abnormalities may be responsible for the precocious senescence of connective tissue associated with the disease. We sought to determine whether glycation is increased in the vitreous humor of short-term diabetic cats (6 months' duration) and rabbits (2 months' duration), using a nitroblue tetrazolium colorimetric assay for fructosamine. Vitreous protein fructosamine concentration was significantly higher in diabetic cats and rabbits, compared with that in control (nondiabetic) animals. These results indicate that glycation is increased in the vitreous humor of short-term diabetic animals, and therefore may be one of the initial triggers for clinically apparent diabetic retinopathy. PMID- 10090097 TI - Bacterial lipopolysaccharide induces a conduction block in the sciatic nerves of rats. AB - A single injection of Escherichia coli lipopolysaccharide (LPS; intraperitoneally [i.p.] and intravenously [i.v.]) reliably induces peripheral nerve disturbances in the hindlimbs of inbred Australian albino Wistar (AaW) rats. In the series of experiments presented here, we aimed to characterize this syndrome by examining electrophysiologic, immunologic, and immunochemical features. The LPS-induced neurologic sequelae in AaW rats were transient, at least partly reversible by drug treatment, and were not associated with any detectable neuropathologic findings by light microscopy. Neurologic sequelae were prevented by administration of dexamethasone and by pretreatment with the macrophage inhibitor gadolinium chloride, suggesting that they were caused by LPS-induced activation of peripheral macrophages. Sequelae were associated with early decreases in compound muscle-action potential amplitudes, indicating impaired functioning of either proximal sciatic nerve axons and/or neuromuscular synapses. Spinal somatosensory-evoked potential latencies also were increased, indicating impaired somatosensory function at the sciatic nerve, dorsal roots, spinal cord, and/or postsynaptic interneurons, although the precise location of impairment could not be delineated. Similarities between this syndrome and immune-mediated polyneuropathies in humans are discussed. PMID- 10090098 TI - Monoclonal antibody production in murine ascites. I. Clinical and pathologic features. AB - BACKGROUND AND PURPOSE: Murine ascites production has been associated with appreciable morbidity and mortality, thus raising animal-welfare concerns. To address these concerns, the clinicopathologic changes associated with in vivo production of monoclonal antibodies in mice were characterized, and results were compared among cell lines. METHODS: Five hybridoma cell lines were grown in groups of 20 mice. Fourteen days prior to inoculation with 10(6) hybridoma cells, mice were primed with 0.5 ml of pristane given intraperitoneally; 12 mice were sham treated (controls). Ascites fluid was collected a maximum of three times by abdominal paracentesis. Clinical observations and pre- and postabdominal tap body weights were recorded. Necropsies were performed on all mice. RESULTS: For all groups combined, overall survival to tap 1 was 98%, to tap 2 was 96%, and to tap 3 was 79%; survival among groups ranged from 90 to 100% for tap 1, 85 to 100% for tap 2, and 35 to 100% for tap 3. Disseminated intra-abdominal seeding with irregular soft tissue and/or solid tumor masses was observed at necropsy. CONCLUSIONS: Significant clinicopathologic changes were associated with monoclonal antibody production in mice, and differences between various hybridoma cell lines were apparent. PMID- 10090099 TI - Monoclonal antibody production in murine ascites. II. Production characteristics. AB - OBJECTIVE: To characterize monoclonal antibody production parameters of five hybridoma cell lines in murine ascites for correlation with clinicopathologic changes in mice. METHODS: Five hybridoma cell lines were grown in groups of 20 mice. Fourteen days prior to inoculation with 10(6) hybridoma cells, mice were primed with 0.5 ml of pristane given intraperitoneally. Ascites fluid was collected a maximum of three times by abdominal paracentesis; volume was measured and antibody concentration was determined by ELISA for each sample. RESULTS: Trends differed among cell lines when comparing ascites volumes and antibody concentrations over time from the first to the third tap. Antibody production was greatest at tap 1 for Groups 2B11 and 2C6D9; tap 2 for Group 3C9; and tap 3 for Groups RMK and 3D6. Total antibody production ranged from 422.90 to 996.64 mg; total ascites fluid volume ranged from 74.2 to 115.7 ml; and mean antibody concentration for taps 1, 2, and 3 ranged from 2.50 to 15.03 mg/ml among cell lines. CONCLUSION: Production characteristics were significantly different among hybridoma cell lines. Determination of production characteristics of hybridomas and correlation with clinicopathologic changes in mice may be valuable in making recommendations for managing mice with ascites. PMID- 10090100 TI - Rib biopsy technique for cortical bone evaluation in rhesus monkeys (Macaca mulatta). AB - Old World primates are often studied to model human skeletal physiology. An important advantage of monkeys over other animal models (i.e., rodents) is the presence of cortical bone Haversian remodeling. Seventy-five female rhesus monkeys (Macaca mulatta) were subjected to bone biopsy. With monkeys in lateral decubitus position, the tenth rib was surgically exposed and freed from periosteum by use of careful sharp and blunt dissection. The rib section was resected, using bone cutters, and the surgical wound was closed. This procedure was repeated for the contralateral rib at a later time point in 65 monkeys. There was no mortality or appreciable morbidity. The bone specimens were (mean +/- SD) 2.50 +/- 0.25 cm long, with 5.5 +/- 1.0 mm2 total cross-sectional area. They were adequate for histologic, immunohistochemical, and quantitative histomorphometric examinations. Prevalence of pneumothorax was approximately 8.0% for the 140 procedures. This complication was immediately and successfully corrected by insertion of a small thoracic tube, evacuation of pneumothorax, and closure of the incision. This well-tolerated, repeatable procedure yields excellent specimens for performance of cortical bone histologic examination without euthanasia, allowing longitudinal evaluation. PMID- 10090101 TI - Embryo transfer in the rat as a tool to determine genetic components of the gestational environment. AB - Embryo transfer, with the recipient dam nursing the transferred progeny, was used to study the impact of the gestational environment on adult blood pressure (BP) in three inbred rat strains, the hypertensive Dahl salt-sensitive SS/JrCtr, the normotensive Dahl salt-hypertension resistant SR/Jr, and the normotensive Dark Agouti rat. Rats that had been cross-fostered within 6 h of birth were included as a control for lactational and nurturing factors. Systolic BP was measured by tail-cuff plethysmography twice a week in rats after the age of 7 weeks. Embryo transfer success, measured as the percentage of embryos transferred resulting in pups weaned at 4 weeks, was 27% between the SS/JrCtr and SR/Jr and 53% for the SS/JrCtr and Dark Agouti. This assessment included all failures, some of which probably were not associated with the transfer. If only the number of embryos transferred to dams with successful pregnancies was included, the success rate was 48% between the SS/JrCtr and SR/Jr and 82% between the SS/JrCtr and Dark Agouti strains. Anomalies in pups were not evident. In contrast to the lactational environment, the gestational milieu had a profound effect on basal blood pressure of the hypertensive SS/JrCtr progeny, less of an effect on that of the Dark Agouti, and no effect on that of the SR/Jr. Although the SS/JrCtr strain is significantly larger than the SR/Jr and Dark Agouti strains, neither embryo transfer nor cross-fostering altered body weight of rats at the age of 6 weeks. These data indicate that embryo transfer can be an easy and efficient method of isolating genetically determined factors of the gestational environment. PMID- 10090102 TI - Virulence Enhancement Agents for Haemophilus influenzae type B infection in mice. PMID- 10090103 TI - Transgenic mouse strain rescue by frozen ovaries. PMID- 10090104 TI - Plasma cytokine concentrations and splenic changes in cynomolgus monkeys (Macaca fascicularis) with malaria. PMID- 10090105 TI - Bilateral prolapse of the deep gland of the third eyelid in a rabbit: diagnosis and treatment. PMID- 10090106 TI - Surgical induction of cryptorchidism in rabbit pups. PMID- 10090107 TI - Detection of cilia-associated respiratory (CAR) bacillus in nasal-swab specimens from infected rats by use of polymerase chain reaction. PMID- 10090108 TI - Antihypertensives: much ado about lipids. PMID- 10090109 TI - Antihypertensive agents in diabetic patients: great benefits, special risks. PMID- 10090110 TI - The rule of double effect: clearing up the double talk. PMID- 10090111 TI - Diuretics and beta-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. AB - BACKGROUND: Concern based on the reported short-term adverse effects of antihypertensive agents on plasma lipid and lipoprotein profiles (PLPPs) has complicated the therapy for hypertension. OBJECTIVE: To compare the long-term (1 year) effects of 6 different antihypertensive drugs and placebo on PLPPs in a multicenter, randomized, double-blind, parallel-group clinical trial in 15 US Veterans Affairs medical centers. PATIENTS AND METHODS: A total of 1292 ambulatory men, 21 years or older, with diastolic blood pressures (DBPs) ranging from 95 to 109 mm Hg taking placebo were randomized to receive placebo or 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, or prazosin. After drug titration, patients with a DBP of less than 90 mm Hg were followed up for 1 year. Plasma lipids and lipoprotein profiles were determined at baseline, after initial titration, and at 1 year. RESULTS: After 8 weeks on a regimen of hydrochlorothiazide, increases of 3.3 mg/dL (0.09 mmol/L) in total cholesterol and 2.7 mg/dL in apolipoprotein B were significantly different (P< or =.05) from decreases of 9.3 mg/dL in total cholesterol and 5.4 mg/dL in ApoB levels while receiving prazosin but not from placebo. Patients achieving positive DBP control using hydrochlorothiazide (responders) showed no adverse changes in PLPPs, whereas nonresponders exhibited increases in triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. Plasma lipids and lipoprotein profiles did not change significantly among treatment groups after 1 year except for minor decreases in high-density lipoprotein 2 levels using hydrochlorothiazide, clonidine, and atenolol. CONCLUSIONS: None of these 6 antihypertensive drugs has any long-term adverse effects on PLPPs and, therefore, may be safely prescribed. Previously reported short-term adverse effects from using hydrochlorothiazide are limited to nonresponders. PMID- 10090112 TI - Use of aspirin, beta-blockers, and lipid-lowering medications before recurrent acute myocardial infarction: missed opportunities for prevention? AB - BACKGROUND: For patients who have had a previous myocardial infarction (MI), the use of aspirin, beta-blockers, and lipid-lowering agents reduces the risk of recurrent MI and death. OBJECTIVE: To examine trends in and determinants of receipt of these 3 medications before hospitalization for recurrent acute MI (AMI). METHODS: The study population consisted of 1710 patients with a previous history of MI hospitalized with a validated recurrent AMI in all hospitals in Worcester, Mass, during 1986, 1988, 1990, 1991, 1993, and 1995. Logistic regression analyses were used to assess the effect of demographic, clinical, and temporal factors on the receipt of aspirin, beta-blockers, and lipid-lowering medications before hospital admission for recurrent AMI. RESULTS: More than 47% of patients in each study year were not receiving each medication before admission, although significant increases in use were noted over time for aspirin (from 13.5% to 52.6%), beta-blockers (from 33.2% to 44.4%), and lipid-lowering medications (from 0.8% to 11.7%). In multivariate analyses, advancing age was associated with not receiving aspirin (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.51-0.89), lipid-lowering medications (OR, 0.14; 95% CI, 0.08 0.25), and beta-blockers (OR, 0.75; 95% CI, 0.57-1.00), although this effect was of borderline significance for beta-blockers. Being a woman was associated with not receiving aspirin (OR, 0.78; 95% CI, 0.62-0.98) but was positively associated with receiving lipid-lowering medications (OR, 1.59; 95% CI, 1.04-2.43). Coexisting medical conditions and concurrent use of other cardiovascular medications were also associated with receipt of each medication. CONCLUSION: Despite encouraging increases over time, the low absolute levels of receipt of medications shown to be efficacious in the long-term treatment of patients after an MI, and their variation by age and sex, suggest that substantial opportunities may exist to prevent recurrent AMIs through the increased use of aspirin, beta blockers, and lipid-lowering medications. PMID- 10090113 TI - Forecasting patient outcomes in the management of hyperlipidemia. AB - BACKGROUND: To forecast adult patient outcomes in the management of hyperlipidemia using adult National Health and Examination Survey III (NHANES III) population statistics and National Cholesterol Education Program (NCEP) guidelines for goals of therapy. METHODS: Review of the hyperlipidemia drug therapy English-language medical literature with emphasis on randomized controlled trials of more than 6 weeks' duration published in the last 7 years, product package inserts, US Food and Drug Administration submission information, and NHANES III population statistics. Data were extracted from studies of lipid lowering therapy to modify low-density lipoprotein (LDL) levels for primary and secondary prevention of coronary heart disease. The data that were evaluated included sample size, study design, therapeutic intervention, length of study, percentage change in LDL levels, and patient demographics. RESULTS: Cumulative frequency curves of the LDL distribution among the US adult population were constructed. The mean efficacy of drug therapy from qualified studies was used to extrapolate the percentage of the population expected to respond to the intervention and to forecast the patient outcome. CONCLUSIONS: A useful tool for clinicians was constructed to approximate the percentage of patients, based on risk stratification, who would reach NCEP target goal after a given pharmacotherapeutic intervention to decrease LDL levels. PMID- 10090114 TI - Corticosteroid requirements in polymyalgia rheumatica. AB - BACKGROUND: Polymyalgia rheumatica (PMR) is a systemic inflammatory disease of unknown cause that affects older individuals. Clinical symptoms respond promptly to corticosteroids, but treatment is often required for several years, frequently resulting in adverse drug effects. Guidelines for the optimal use of corticosteroids that maximize relief of symptoms but minimize adverse effects of the therapy are needed. OBJECTIVE: To determine whether clinical or laboratory parameters in PMR could be identified that allow for stratifying patients into subsets with differences in corticosteroid requirements. PATIENTS AND METHODS: We studied 27 patients with PMR treated with a standardized schedule of prednisone. Patients were reevaluated at monthly intervals for pain scores and physician and patient assessments. Plasma interleukin 6 level and the erythrocyte sedimentation rate were measured at each visit. The duration of steroid therapy and the cumulative steroid dose were calculated. RESULTS: Based on the initial response to therapy and the duration of disease, the 27 patients could be subdivided into 3 distinct groups. Eight with low erythrocyte sedimentation rates responded rapidly and required corticosteroids for less than 1 year with rare disease flares on tapering of prednisone. Twelve others responded well initially but did not tolerate reduction to lower doses and had remitting disease of more than 1 year. Seven patients had only a partial response to the initial steroid regimen. After 4 weeks of therapy, the erythrocyte sedimentation rates improved, but levels of interleukin 6 remained elevated. Pretreatment pain scores were also higher in these partial responder patients (P = .05). CONCLUSIONS: Polymyalgia rheumatica is a heterogeneous disease with variations in the treatment duration and dose of corticosteroids required for suppression of symptoms. Pretreatment erythrocyte sedimentation rate and nonresponsiveness of interleukin 6 to steroid therapy are helpful in dividing patients into subsets with different treatment requirements. PMID- 10090115 TI - High heart rate: a risk factor for cardiovascular death in elderly men. AB - OBJECTIVE: To examine the association between heart rate and 12-year incidence rates of total and cardiovascular death in a cohort of elderly subjects stratified by sex. SUBJECTS AND METHODS: The study was carried out in 763 white men and 1175 women aged 65 years or older who were participating in the Cardiovascular Study in the Elderly. Subjects were divided into quintiles of heart rate; the top quintile comprised those with a heart rate of greater than 80/min and the bottom quintile, those with a heart rate of less than 64/min. RESULTS: In the men, the number of deaths from cardiovascular causes was significantly increased in those in the top quintile of heart rate (crude relative risk, 1.55) but decreased in those in the bottom quintile (crude relative risk, 0.65). Similar relationships were found in the women, but the associations did not reach statistical significance (all-cause, P = .11; cardiovascular, P = .15). After adjustment for baseline age, body mass index, hypertension, diabetes mellitus, angina or previous myocardial infarction (coronary heart disease), regular medication, lipid levels, smoking, alcohol intake, forced expiratory volume in 1 second, and other confounders, the relative risk for cardiovascular death in the men was 1.38 (95% confidence interval, 0.94 2.03) for the subjects in the top quintile of heart rate and 0.82 (95% confidence interval, 0.52-1.28) for those in the bottom quintile. In the Cox analysis, predictors of time to cardiovascular death were heart rate (P < .001), age (P < .001), coronary heart disease (P < .001), clinical heart failure (P = .001), diabetes mellitus (P = .001), hypertension (P = .02), and triglyceride levels (P = .04), whereas total (P = .20) and high-density lipoprotein-cholesterol (P = .21) levels and smoking (P = .74) were found to be nonsignificant by the model. The heart rate-cardiovascular death association held true when subjects who died in 2 years after enrollment were excluded (P = .008). CONCLUSIONS: An elevated heart rate may be a strong predictor of cardiovascular death in elderly men. Conversely, a low heart rate is related to a better outcome in these subjects. PMID- 10090116 TI - Cost-effectiveness of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the secondary prevention of cardiovascular disease: forecasting the incremental benefits of preventing coronary and cerebrovascular events. AB - OBJECTIVE: To forecast the long-term benefits and cost-effectiveness of lipid modification in the secondary prevention of cardiovascular disease. METHODS: A validated model based on data from the Lipid Research Clinics cohort was used to estimate the benefits and cost-effectiveness of lipid modification with 3-hydroxy 3-methylglutaryl-coenzyme A reductase inhibitors (statins) based on results from the Scandinavian Simvastatin Survival Study (4S), including a 35% decrease in low density-lipoprotein (LDL)-cholesterol levels and an 8% increase in high-density lipoprotein (HDL)-cholesterol levels. After comparing the short-term outcomes predicted for the 4S with the results actually observed, we forecast the long term risk of recurrent myocardial infarction, congestive heart failure, transient ischemic attacks, arrhythmias, and strokes and the need for surgical procedures such as coronary artery bypass grafting, catheterization, angioplasty, and pacemaker insertions. Outpatient follow-up care costs were estimated, as were the costs of hospital care and drug therapy. All costs were expressed in 1996 US dollars. RESULTS: The short-term outcomes predicted for the 4S were consistent with the observed results. The long-term benefits of lipid modification among low risk subjects (normotensive nonsmokers) with a baseline LDL/ HDL ratio of 5 but no other risk factors ranged from $5424 to $9548 per year of life saved for men and $8389 to $13747 per year of life saved for women. In high-risk subjects (hypertensive smokers) with an LDL/HDL ratio of 5, the estimated costs ranged from $4487 to $8532 per year of life saved in men and $5138 to $8389 per year of life saved in women. Assuming that lipid modification has no effect on the risk of stroke, cost-effectiveness increased by as much as 100%. CONCLUSIONS: These long-term cost estimates are consistent with the short-term economic analyses of the published 4S results. The long-term treatment of hyperlipidemia in secondary prevention is forecasted to be cost-effective across a broad range of patients between 40 and 70 years of age. Recognizing the additional effects of lipid changes on cerebrovascular events can substantially improve the cost effectiveness of treating hyperlipidemia. PMID- 10090117 TI - Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. AB - BACKGROUND: Hypokalemia is a well-known, consistent finding in thyrotoxic periodic paralysis (TPP). It is less well known that hypophosphatemia and mild hypomagnesemia are often present in TPP and that rebound hyperkalemia can occur as a result of potassium therapy. OBJECTIVE: To report the prevalence of these electrolyte abnormalities in 24 episodes of TPP in 19 patients admitted to a single university-affiliated public hospital during a 15-year period. METHODS: The medical records of all patients admitted to the Santa Clara Valley Medical Center in San Jose, Calif, between August 1, 1982, and June 1, 1997, with any type of hypokalemic periodic paralysis were reviewed. In patients with TPP, serum potassium, phosphorus, and magnesium levels were evaluated during and after episodes of paralysis. The administered dose of potassium chloride, recovery time from hypokalemia, and prevalence of rebound hyperkalemia after recovery were also ascertained. Data are presented as mean +/- SD. RESULTS: Hypokalemia was present in all 24 initial episodes of TPP, with serum potassium levels ranging from 1.1 to 3.4 mmol/L (mean, 1.9+/-0.5 mmol/L). After recovery from hypokalemia, the maximum serum potassium level significantly increased, ranging from 4.0 to 6.6 mmol/L (mean, 4.9+/-0.5 mmol/L; P<.001). In 10 (42%) of 24 episodes, rebound hyperkalemia (serum potassium level >5.0 mmol/L) was present. Recovery time did not correlate with the potassium chloride dose administered (r = 0.17). Initial serum phosphorus levels ranged from 0.36 to 0.97 mmol/L (mean, 0.61+/-0.23 mmol/L) (1.1-3.0 mg/dL [mean, 1.9+/-0.7 mg/dL]), with hypophosphatemia present in 12 (80%) of 15 episodes. Serum phosphorus levels significantly increased (P<.01), to 1.26 to 1.74 mmol/L (mean, 1.48+/-0.16 mmol/L) (3.9-5.4 mg/dL [mean, 4.6+/-0.5 mg/dL]), with or without phosphorus replacement therapy. A slight increase in serum magnesium levels after paralysis resolved was observed in all patients (P<.07). No further episodes of paralysis occurred in any patients after they became euthyroid. CONCLUSIONS: Hypokalemia, hypophosphatemia, and mild hypomagnesemia are characteristic features of TPP. Hypokalemia occurred in 100% and hypophosphatemia in 80% of the episodes in our study. Rebound hyperkalemia is a potential hazard of potassium administration and occurred in 42% of 24 episodes. PMID- 10090118 TI - Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis. AB - BACKGROUND: Long-term parenteral beta-lactam treatment is often complicated by adverse reactions that necessitate drug withdrawal. OBJECTIVE: To evaluate the incidence and mechanism of beta-lactam adverse reactions during an 8-year period in all episodes of suspected infective endocarditis in patients treated at a university-affiliated institution. METHODS: Patients with 215 consecutive episodes of beta-lactam treatment for 10 days or more were prospectively enrolled during 2 periods, January 1984 through December 1988 and January 1993 through December 1995, and compared with 51 episodes of vancomycin hydrochloride treatment for 10 days or more. Incidents of adverse reactions, such as fever, rash, or neutropenia, were registered. Neutrophil counts, eosinophil counts, and penicillin antibodies were studied. Patients with delayed adverse reactions to penicillin G sodium were rechallenged with penicillin v potassium. RESULTS: Incidence of delayed adverse reactions during treatment was 33% with beta-lactams compared with 4% with vancomycin. Rates of adverse event for beta-lactams increased continuously from treatment day 15 to day 30. A 6-fold difference in capacity to induce adverse events was found with different beta-lactams. Penicillin G induced neutropenia in 14% and any adverse event in 51% of treated episodes. Mean daily doses significantly influenced the frequency of adverse events. Occurrence of hemagglutinating penicillin antibodies was significantly related to patients whose penicillin-treated episodes were complicated with adverse events. Patients with delayed adverse reactions to penicillin G were safely rechallenged with penicillin. CONCLUSIONS: Incidence of delayed adverse reactions to beta-lactams increases sharply when parenteral treatment is extended beyond 2 weeks. Penicillin G is the most frequent inducer of adverse reactions among beta-lactams studied. An immunological reaction mediated by antibodies to the penicilloyl determinant may be involved in the pathogenesis, possibly enhanced by a dose-related toxic trigger mechanism. Beta-Lactam-induced neutropenia followed a uniform pattern, occurring after, on average, 21 days of treatment, and might be due to both immunologic and toxic effects of treatment. Patients with a late adverse reaction to penicillin can safely be re-treated with penicillin, although they should remain under close surveillance if treatment extends beyond 2 weeks. PMID- 10090119 TI - Relation of serum ascorbic acid to serum vitamin B12, serum ferritin, and kidney stones in US adults. AB - BACKGROUND: Concern has been raised that high levels of ascorbic acid consumption may lead to potential adverse effects, such as vitamin B12 deficiency, iron overload, and kidney stones. OBJECTIVE: To examine the relation of serum ascorbic acid level, which reflects intake, to serum vitamin B12 level, serum ferritin level, and kidney stones. METHODS: We analyzed data collected on a random sample of the US population enrolled in the Second National Health and Nutrition Examination Survey, 1976-1980. We analyzed data using linear and logistic regression models. Serum ascorbic acid, serum vitamin B12, hemoglobin, red blood cell mean corpuscular volume (MCV), and serum ferritin levels were measured using standardized protocols. History of kidney stones was determined by self-report. RESULTS: After multivariate adjustment, serum ascorbic acid level was associated with higher serum vitamin B12 levels among women in regression models that assumed a linear relationship; each 57-pmol/L (1.0-mg/dL) increase in serum ascorbic acid level (range, 6-153 micromol/L [0.1 to 2.7 mg/dL]) was independently associated with a serum vitamin B12 level increase of 60 pmol/L (81 pg/ mL) (P<.001). Among men, serum ascorbic acid level was marginally associated with higher serum vitamin B12 levels: each 57-micromol/L (1.0-mg/dL) increase in serum ascorbic acid level was associated with a serum vitamin B12 level increase of 27 pmol/L (36 pg/mL) (P = .10). In addition, serum ascorbic acid level was not associated with correlates of vitamin B12 deficiency, such as higher MCV levels, macrocytosis (MCV >100), or lower hemoglobin concentrations. Serum ascorbic acid level was not independently associated with serum ferritin levels. However, among women only, serum ascorbic acid levels were associated in a nonlinear fashion with prevalence of elevated serum ferritin levels (P = .02). We found no association between serum ascorbic acid level and prevalence of kidney stones in women or men (both P>.05). CONCLUSIONS: Serum ascorbic acid levels were not associated with decreased serum vitamin B12 levels (or indicators of vitamin B12 deficiency), prevalence of kidney stones, serum ferritin levels, or-among men prevalence of elevated serum ferritin levels. Serum ascorbic acid levels were associated with prevalence of elevated serum ferritin levels among women. Although the clinical relevance of these findings is uncertain, it seems prudent to suggest that women with a genetic susceptibility to iron overload should consider moderating their intake of ascorbic acid. PMID- 10090120 TI - Neurally mediated syncope in 2 patients with extracardiac disease. AB - We describe the cases of 2 patients with repetitive episodes of syncope with profound bradycardia and hypotension. In both patients, the symptoms were initially thought to be neurally mediated and idiopathic but were ultimately determined to be triggered by serious underlying pathologic processes: a massive and locally invasive tumor of the hypopharynx in 1 patient and a gangrenous gallbladder in the other. Appropriate treatment resulted in a resolution of this syndrome in both patients. These cases emphasize the importance of an appropriate evaluation and broad differential diagnoses for patients with severe bradycardia and hypotension. PMID- 10090121 TI - Making doctors. PMID- 10090122 TI - Interrelationships of bladder compliance with age, detrusor instability, and obstruction in elderly men with lower urinary tract symptoms. AB - Data on the interrelationships of bladder compliance (BC), detrusor instability (DI), and bladder outflow obstruction (BOO) in elderly men with lower urinary tract symptoms (LUTS) are scarce and were therefore assessed in this study. Principle inclusion criteria for this study were men aged > or = 50 years suffering from LUTS as defined by an International Prostate Symptoms Score (IPSS) of > or = 7 and a peak flow rate (Qmax) of < or = 15 ml/sec. Patients with previous surgery of the bladder, prostate, or urethra as well as a pathological neurourological status were excluded from this study. The following parameters were studied in all patients: IPSS, prostate volume calculated by transrectal ultrasonography, free uroflow study, post-void residual volume determined by transurethral catheterization, and a multichannel pressure flow study (pQS). A group of 170 men were included in the analysis. The mean BC in the overall group was 32 +/- 2 ml/cm H2O (mean +/- standard error of the mean [SEM]; range, 4-100 ml/cm H2O). In 36.5% of patients, BC was significantly reduced (< or = 20 ml/cm H2O), and in a further 37.1%, it ranged from 20 to 40 ml/cm H2O. BC decreased statistically significantly (p < 0.05) in patients with advanced age, lower Qmax, higher voiding pressures, and larger prostates. In men with DI (n = 61), mean BC was significantly lower (22 +/- 3 ml/cm H2O) compared to those without (37 +/- 3 ml/cm H2O; p = 0.001; n = 109). Patients with severe BOO as defined by a linear passive urethral resistance relationship of > or = 3 (n = 109), had a significantly lower BC (23 +/- 2 ml/cm H2O) compared to those without or minimal obstruction only (39 +/- 3 ml/cm H2O; p = 0.0002; n = 61). Stepwise logistic regression analysis revealed that DI, a low bladder capacity, and a high maximum detrusor pressure were independent predictors of markedly reduced BC (< 20 ml/cm H2O). BC is decreased in elderly men with high voiding pressures, BOO, and DI. The mechanism leading to the reduction of BC under these circumstances is largely unknown and could result from cytostructural alterations of the detrusor and changes in detrusor innervation. PMID- 10090123 TI - Repeated pressure-flow studies in the evaluation of bladder outlet obstruction due to benign prostatic enlargement. Finasteride Urodynamics Study Group. AB - Test-retest reliability of repeated voids in pressure-flow studies and the influence on maximum flow rate (Q(max)pQ), detrusor pressure at maximum flow rate (p(det)Qmax), voided volume, and residual urine were studied. Also the agreement in interpretation of pressure-flow tracings between investigators and a single blinded central reader acting as a quality control center (QCC) were assessed. In addition, correlations between p(det)Qmax and patient age, International Prostate Symptom Score (IPSS), free maximum flow rate (Qmax), and prostate volume were calculated. Using suprapubic pressure recording, 216 men with lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE) were investigated in 11 centers. In each pressure-flow study, three sequential voids were performed, and quality controlled recordings were analyzed for Q(max)pQ and p(det)Qmax by the QCC. Trans rectal ultrasound was used to measure the prostate volume. Mean Q(max)pQ did not change, but p(det)Qmax decreased significantly in the second and third sequential voids. Using the Abrams-Griffiths nomogram definition of obstruction, 125 patients (67%) were classified as obstructed from the first void, but only 111 patients (59%) from the third void. The agreement between the investigator assessment and that of a single blinded reader was good. There was no significant correlation between p(det)Qmax and patient age, IPSS, and Qmax, whereas a modest correlation was found between p(det)Qmax and prostate volume. In summary, there was no significant change in Q(max)pQ, but p(det)Qmax decreased for the three consecutive voids, which can be explained by a decrease in outlet resistance. The agreement between the investigator and QCC interpretations shows the value of a standardized technique, supporting the feasibility of multicenter urodynamic studies. There is a modest, but statistically significant, correlation between detrusor pressure and prostate size, supporting the hypothesis that prostate size is a contributing factor in symptomatic BPH. PMID- 10090124 TI - Home uroflowmetry: improved accuracy in outflow assessment. AB - To study home uroflowmetry and to compare this method to free or "traditional" uroflowmetry in the evaluation of the patient with symptomatic benign prostatic hyperplasia (BPH), and the relationship between the values of home uroflowmetry parameters and bladder outlet obstruction (BOO). Twenty-five patients (mean age, 67 years) with symptomatic BPH were examined with home uroflowmetry, free uroflowmetry, and pressure-flow measurement. The patients were assessed using the International Prostate Symptom score; digital rectal examination; routine blood chemistry, including serum prostate-specific antigen level; urinanalysis; transrectal ultrasonography; and post-void residual urine. The 24 hr were divided into "active time" (AT) and "sleep time" (ST). AT home uroflowmetry parameters were compared to ST ones. The home uroflowmetry parameters were compared to respective ones of the free uroflowmetry as well and those obtained by pressure flow measurement. The patients were asked about their opinion of home uroflowmetry. Home uroflowmetry was found to be a simpler and more acceptable method than free uroflowmetry. The mean Qmax of AT was significantly greater than the mean Qmax of ST, but the mean voided volume and mean voiding time of ST were significantly larger than those of AT. There was a close relationship between the mean Qmax at home and the Qmax in hospital, but the voided volume and voiding time measured in hospital were significantly larger than those at home. Home uroflowmetry provided an estimation of BOO for 46% of the patients as low if the home mean Qmax was >14 ml/sec, and as high if the home mean Qmax was <10 ml/sec. Home uroflowmetry was well accepted by the patients and gave more information than free uroflowmetry. In 46% of the cases, an estimation of BOO was obtained with home uroflowmetry. PMID- 10090125 TI - In vitro electrostimulation-induced urethral relaxation in the guinea pig is blocked by prazosin. AB - The purpose of this study was to characterize the electrostimulation-induced relaxation in guinea pig urethral rings. From sacrificed male guinea pigs, urethral rings were cut between the bladder neck and the penile crura and mounted in an in vitro bath. The drop in baseline tension in response to electrical stimulation (rectangular pulses of 0.8-msec pulse duration, a frequency of 3, 5, 10, and 20 Hz, and 75-mA current) was measured in the presence of various pharmacologic agents. In urethral tissue precontracted with 10(-5) norepinephrine, a significant relaxation of 34.8% was found at 10 Hz. This relaxation was not affected by the addition of neuropeptide Y (NPY, 10(-8)-10(-6) M), 10(-6) M atropine, 10(-5) M alpha-beta-methylene-adenosine,5'-triphosphate (alpha-beta-methylene-ATP, a purinergic antagonist), and tolazoline (alpha2 antagonist, 10(-8)-10(-4) M). However, with the alpha1 antagonist prazosin (5 x 10(-8)-5 x 10(-7) M), no relaxation occurred. The tissue response was of neurogenic origin as it was blocked by 10(-7) M tetrodotoxin. Norepinephrine precontracted urethral rings of male guinea pigs exhibit a relaxation response at 10 Hz that is alpha1-adrenergic, non-cholinergic, non-purinergic, and independent of NPY. PMID- 10090126 TI - Smooth muscle fatigue due to repeated urinary bladder neurostimulation: an in vivo study. AB - The presented study investigates the influence of different pause lengths between two consecutive stimulations of the S3 roots on intravesical pressure during bladder neurostimulation. In eight male foxhounds (aged 7-18 months), laminectomy and placement of a modified Brindley electrode were performed. In four series with different pause lengths between two consecutive stimulations (1, 3, 5, and 15 min), the maximum intravesical pressure was measured during stimulation. The changes in intravesical pressure were registered in these four series, each series with six stimulations. A 15-min interval elapsed before the commencement of each series. In the series with a pause length of 15 min, the consecutive stimulations did not result in significant changes in maximum intravesical pressure. In the 5-min series, a significant decrease in intravesical pressure was not observed after the third stimulation. In the 3-min series, a significant decrease was seen at almost every stimulation (average decrease of 3.8% per stimulation) and in the 1-min series, a significant decrease was also observed at almost every stimulation (average decrease of 5.9% per stimulation). The results of repeated bladder neurostimulation demonstrate that the maximum intravesical pressure is dependent on the pause length between two consecutive stimulations. The detrusor muscle showed reversible and short-lived signs of fatigue. This implies the importance of a minimum 5-min interval between two subsequent stimulations. A pause length <5 min leads to a falsification of the results and thus to lower validity of the investigation. PMID- 10090127 TI - Altered bladder function in transgenic mice expressing rat elastin. AB - The elasticity of tissues subjected to repeated deformation is provided by the presence of elastic fibers in the extracellular matrix (ECM). The most abundant component of elastic fibers is elastin, whose soluble precursor is tropoelastin. To establish the role elastin plays in the bladder, this study describes the biosynthetic, histologic, and physiologic consequences of expression of an isoform of rat tropoelastin in transgenic mouse bladder. The polymerase chain reaction (PCR) was used to determine expression of a rat tropoelastin minigene in transgenic mice. Histochemical methods were used to demonstrate changes in elastic fibers in frozen sections of bladder. Cystometric analysis was carried out in transgenic and non-transgenic mice, prior to and after 3 weeks of partial outlet obstruction. The PCR assay demonstrated that bladder tissue of transgenic mice expressed rat tropoelastin mRNA, whereas non-transgenes did not. Increased deposition of elastic fibers was demonstrated with the Verhoeff-van Gieson stain. Bladders of transgenic animals were more compliant than bladders of their non transgenic littermates. Partial outlet obstruction resulted in increased bladder volume and more compliant bladders in non-transgenic mice. In contrast, the bladder volume and compliance in transgenes was almost unchanged by obstruction. This study demonstrates that normal elastic fiber assembly is prerequisite for the compliant properties of the bladder wall. Moreover, the response of the bladder to obstruction is critically influenced by elastin synthesis. PMID- 10090128 TI - Re: "The pelvic floor muscles: muscle thickness in healthy and urinary incontinent women measured by perineal ultrasonography with reference to the effect of pelvic floor training. Estrogen receptor studies." Neurourol. Urodynam. 1997;16:237-275. PMID- 10090129 TI - Circulating levels of cardiac natriuretic hormones measured in women during menstrual cycle. AB - Alterations in fluid and electrolyte balance represent a common complaint by women during different stages of the menstrual cycle; however, conflicting results concerning the possible role of plasma Atrial Natriuretic Peptide (ANP) modifications during the menstrual cycle have been reported. This may be due to differences in assay methods or in the clinical protocol adopted. Moreover, possible variations in plasma Brain Natriuretic Peptide (BNP) levels during the menstrual cycle have not been studied. We measured the plasma levels of ANP and BNP by means of two highly sensitive and specific immunoradiometric assay (IRMA) methods in 19 normal women without premenstrual symptoms, in order to evaluate whether significant modifications of these hormones are present during the menstrual cycle. Because it is well-known that circulating levels of cardiac hormones show great variations in normal subjects due to their rapid plasma half lives, blood samples were collected at 2.5-min intervals over a 15-min period on the 5th and 24th days of the cycle. The mean (+/-SD) values of ANP (follicular phase=15.1+/-8.7 pg/ml; luteal phase=14.8+/-9.5 pg/ml) and of BNP (follicular phase=13.0+/-15.0 pg/ml; luteal phase=11.2+/-11.4 pg/ml) did not show significant variations during the menstrual cycle. Moreover, the variability of ANP values (CV=24.8+/-13.2%) was significantly higher (p=0.0318) than that of BNP values (CV=16.5+/-8.9%), and a significant correlation was found between the mean ANP and BNP values of the individual women studied (R=0.407, p=0.0437). The values of estradiol, progesterone, LH, FSH and prolactin did not correlate with the ANP or BNP values. In conclusion, our results indicate that circulating levels of cardiac hormones do not show any significant modifications during the menstrual cycle in healthy women. PMID- 10090130 TI - Serum leptin levels in males with delayed puberty during short-term pulsatile GnRH administration. AB - Leptin may be a possible trigger for puberty. In normal males, it has been shown that leptin increases from the pre-pubertal to the early pubertal stage, and then declines in the late pubertal stage. We examined leptin levels in six male adolescents (mean age 16.3+/-0.6 yr; range 14.2-17.6 yr) with delayed puberty (constitutional delay of puberty no.=2; idiopathic hypogonadotropic hypogonadism no.=4) during 120 days of subcutaneous pulsatile GnRH administration. A group of subjects in pre-puberty (no.=11), early-puberty (n=10) and mid-puberty (no.=7) were evaluated as controls. Morning blood samples were taken for determination of leptin, testosterone, LH and FSH levels. In delayed puberty subjects blood samples were taken every 30 days after the start of GnRH administration. At each examination BMI and testicular volume were evaluated. A follow-up examination was performed in the 6 patients 1.3-7.5 yr after the end of the 120 days of GnRH therapy. At baseline evaluation in delayed puberty mean leptin levels were 11.3+/ 2.0 microg/l (median 11.3 microg/l; range 4.7-17.3 microg/l) and were higher than those found in pre-puberty (p=0.04) and mid-puberty (p=0.001). During GnRH administration there was no change in BMI and leptin levels but there was an increase in gonadotrophin levels, testosterone and testicular volume. One hundred and twenty days after, mean serum leptin were 10.1+/-2.1 microg/l (median 9.1 microg/l; range 3.4-16.8 microg/l). At the end of the study, leptin levels were higher in delayed puberty than in mid-puberty (p=0.002). At the follow-up examination leptin levels were 4.3+/-1.3 microg/l (median 3.4 microg/l; range 1.4 9.1 microg/l) (p=0.03 vs end of 120 days GnRH therapy) while testosterone and BMI were not changed. In conclusion 120-day pulsatile GnRH administration induced in males with delayed puberty physiological-like pubertal changes but not the decline in leptin levels reported during the progression of puberty. Therefore, in males with delayed puberty an impairment in the phenomenon of leptin decline associated with progression of puberty could be suggested. However after retrospective diagnosis of pubertal delay and long-term therapy in subjects with idiopathic hypogonadotropic hypogonadism leptin levels declined. These data seem to indicate that time more than increase in testosterone levels and testicular volume is the determinant of leptin decline at puberty. PMID- 10090131 TI - IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in man. AB - Glucocorticoid excess is associated with a blunted GH response to GHRH. IGF-I levels in hypercortisolism are controversial and have been reported as low, normal or high. The aim of this study was to evaluate longitudinally time dependent changes in the GH response to GHRH, IGF-I, IGFBP-3 and albumin values in patients during corticotherapy. Six patients received GHRH before and after one week and one month of prednisone administration (20-60 mg/d, orally). IGF-I, IGFBP-3 and albumin were determined in each test, at time 0. Ten normal controls were also evaluated in one occasion. There were no differences in basal GH values, GH response to GHRH, IGF-I and IGFBP-3 levels between controls and patients before starting corticotherapy. Albumin (g/l; mean+/-SE) values were lower in patients before treatment (31+/-4) than in controls (43+/-1). After one week of prednisone administration there was a significant decrease in peak GH (microg/l) levels (before: 18.8+/-7.4; 1 week: 5.0+/-1.3), which was maintained after one month (8.1+/-3.5). IGF-I (microg/l) levels increased significantly, from 145+/-23 to 205+/-52 after one week of therapy, reaching levels of 262+/-32 after one month. IGFBP-3 (mg/l) values did not increase significantly (before: 2.1+/-0.2; 1 week: 2.5+/-0.3; 1 month: 2.8+/-0.2). Albumin levels showed a significant rise both after one week (36+/-4) and one month (42+/-3) of corticotherapy. In summary, we observed a marked decrease in the GH response to GHRH after one week and one month of prednisone administration associated with an increase in circulating IGF-I and albumin values. The physiological implications of these findings are still uncertain. It is possible that glucocorticoids increase hepatic IGF-I and albumin synthesis, although other mechanisms may have a role. PMID- 10090132 TI - Analysis of splice variants of the fibronectin gene in thyroid carcinomas by reverse transcription-polymerase chain reaction: increased expression of oncofetal fibronectin mRNA in papillary carcinomas is not caused by the alternation in splicing. AB - The expression levels of each splice variant of the fibronectin gene in the normal thyroid and in thyroid tumors were examined by reverse transcription polymerase chain reaction (RT-PCR). In thyroid papillary carcinomas, insertion of a variant exon in the ED-A and ED-B domains, and three of five types of splice variants in the IIICS domain were observed. In spite of the marked increase in the expression of oncofetal fibronectin mRNA with the IIICS sequence in papillary and anaplastic carcinomas in the previous reports, the relative expression levels of each splice variant with or without the IIICS sequence showed no difference among all the tumor types. Therefore, the much increased expression of oncofetal fibronectin mRNA in these carcinomas is not caused by the alternation in splicing, but may be caused by an increase in promoter activity or stability of mRNA of the fibronectin gene. PMID- 10090133 TI - Effects of the combined administration of hexarelin, a synthetic peptidyl GH secretagogue, and hCRH on ACTH, cortisol and GH secretion in patients with Cushing's disease. AB - Hexarelin (HEX) is a peptidyl GH secretagogue (GHS) which markedly stimulates GH release but, like other GHS, possesses also CNS-mediated ACTH- and cortisol releasing activity. Interestingly, the stimulatory effect of HEX on ACTH and cortisol release is exaggerated and higher than that of hCRH in patients with Cushing's disease (CD). To further clarify the mechanisms by which HEX stimulates the activity of hypothalamo-pituitary-adrenal (HPA) axis in man, in 6 patients with CD (6 women, 38-68 yr old) and in 7 control subjects (CS, 7 women, 22-29 yr old) we studied the effects of HEX (2.0 microg/kg i.v.) and/or hCRH (2.0 microg/kg i.v.) on ACTH and cortisol (F) secretion. The GH responses to HEX alone and combined with hCRH were also studied in all subjects. Basal ACTH and F levels in CD were higher than in CS (66.3+/-5.1 vs 16.5+/-0.6 pg/ml and 217.8+/-18.5 vs 134.4+/-4.6 microg/l, respectively; p<0.02). In CS, the ACTH and F responses to HEX, evaluated as deltaAUC (mean+/-SE: 128.7+/-39.2 pg x min/ml and 328.5+/-93.2 microg x min/l, respectively) were lower, though not significantly, than those after hCRH (375.8+/-128.4 pg x min/ml and 1714.2+/-598.0 microg x min/l, respectively), though the peak ACTH and F responses to both stimuli were similar. The co-administration of HEX and hCRH had an additive effect on both ACTH (1189.6+/-237.2 pg x min/ml) and F secretion (3452.9+/-648.6 microg x min/l). In fact, the ACTH and F responses to HEX+/-hCRH were significantly higher (p<0.01) than those elicited by single stimuli. In CD, HEX induced ACTH and F responses (3603.8+/-970.7 pg x min/ml and 10955.9+/-6184.6 microg x min/l, respectively) clearly higher (p<0.002) than those in CS. The HEX-induced ACTH and F responses in CD were higher, though not significantly, than those recorded after hCRH (1432.7+/-793.5 pg x min/ml and 4832.7+/-2146.5 microg x min/l, respectively). On the other hand, the hCRH-induced ACTH and F responses in CD were similar to those in CS. In CD, the coadministration of HEX and hCRH had an additive effect on ACTH (8035.7+/-1191.1 pg x min/ml) but not on F (10985.4+/-3900.8 microg x min/l) secretion. In fact, the ACTH, but not the F response to HEX+hCRH was significantly higher (p<0.02) than that elicited by single stimuli. In conclusion, the present study demonstrates that in patients with Cushing's disease as well as in subjects control Hexarelin and hCRH have an additive effect on ACTH secretion. Considering that, at least in humans, differently from hCRH, GHS have no interaction with AVP, our present findings further agree with the hypothesis that the ACTH-releasing activity of GHS is, at least partially, independent of CRH-mediated mechanisms. PMID- 10090134 TI - Evaluation of disease activity by IGF-I and IGF binding protein-3 (IGFBP3) in acromegaly patients distributed according to a clinical score. AB - To facilitate the estimation of acromegalic activity a prospective study was done comparing, against a clinical score, the effectiveness of serum IGF-I, IGFBP3 and the IGF-I/IGFBP3 molar ratio. Sixty nine observations were distributed in three groups: Group I=patients before surgery; group II=patients improved but still clinically active; group III=patients clinically inactive. Suppression of serum GH levels one hour after an oral glucose load was in agreement with the clinical score in 21/22 observations. Increases in serum IGF-I and IGFBP3 levels were similarly frequent: both 100% in group I, 80% and 95% in group II, 9% and 36% in group III, respectively. The frequency of abnormal molar ratios was 95%, 40% and 0% in the same groups. Log IGF-I, log IGFBP3, and log molar ratio correlated significantly with the clinical scores (r=0.873, r=0.692, and r=0.829, respectively). CONCLUSIONS: The IGF-I/IGFBP3 molar ratio was not better than either IGF-I or IGFBP3 in detecting activity in the three groups of patients studied. Both IGF-I and IGFBP3 appear comparably useful for the diagnosis and follow-up of acromegalic patients. Since IGF-I is a more biologically meaningful parameter it might be preferable. PMID- 10090135 TI - Prevalence and severity of hyponatremia and hypercreatininemia in short-term uncomplicated hypothyroidism. AB - Hypothyroidism is widely accepted as a cause of hyponatremia and hypercreatininemia. However, the prevalence and severity of hyponatremia and hypercreatininemia in hypothyroid patients without comorbid conditions have not been well documented. We retrospectively studied serum sodium and creatinine levels in thyroid-ablated patients with differentiated thyroid cancer off (no.=128) and on (no.=60) thyroid hormone therapy. In the hypothyroid state, mean(+/-SD) TSH, sodium, and creatinine levels were 130.3+/-104.8 mU/l, 139.3+/ 2.7 mEq/l, and 89.4+/-20 mmol/l respectively. Twenty-four patients (18.8%) had creatinine levels above the age- and sex-adjusted normal range, whereas only five patients (3.9%) had sodium levels below 135 mEq/l. No patient had a sodium level less than 130 mEq/l. Compared to their euthyroid values, mean sodium and creatinine levels of the hypothyroid patients changed by -1.18 mEq/l (p=0.003) and 17.2 mmol/l (p<0.0001), respectively. There was significant correlation of TSH levels in the hypothyroid state with the changes from the euthyroid state to the hypothyroid state in creatinine levels (r=0.29, p=0.02) but not with the corresponding changes in sodium levels (r=0.06, p=0.6). In thirty-seven patients studied in two hypothyroid episodes, there was a significant correlation between a) TSH levels in hypothyroid state 1 and hypothyroid state 2 (r=0.56, p=0.0003), and b) the change in creatinine levels from the euthyroid state to hypothyroid state 1 and the corresponding change from the euthyroid state to hypothyroid state 2 (r=0.48, p=0.003). There was no significant correlation between the change in sodium levels from the euthyroid state to hypothyroid state 1 and the corresponding change from the euthyroid state to hypothyroid state 2 (r=0.32, p=0.05). We conclude that hyponatremia is very uncommon, whereas mild to moderate elevation in serum creatinine level is not uncommon in patients with short-term uncomplicated hypothyroidism. PMID- 10090136 TI - Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly. AB - This single-center open sequential study aimed at comparing the efficacy of a 6 month treatment with lanreotide (LAN) (60-90 mg/month i.m.), to that of octreotide (OCT) (0.3-0.6 mg/day s.c.) in 45 patients with active acromegaly (GH, 63.2+/-12.1 ng/ml, IGF-I, 757+/-67.1 ng/ml). After 6 months of OCT treatment, safe GH (fasting <2.5, glucose suppressed <1 ng/ml) and IGF-I (normalized for age) levels were achieved in 23 patients. After treatment withdrawal, GH levels significantly increased in all patients, though remaining slightly lower than pre OCT therapy (39.2+/-5.8 ng/ml) while plasma IGF-I levels were unchanged (654+/ 59.4 ng/ml). After 6 months of LAN treatment, safe GH and IGF-I levels were achieved in 26 patients (57.7%). After OCT or LAN treatments, no significant difference was found between nadir GH (6+/-1 vs 5.9+/-1.1 ng/ml) and IGF-I levels (281+/-23.3 vs 262+/-20.6 ng/ml). Four out of the 20 patients poorly responsive to OCT achieved safe GH and IGF-I levels after LAN treatment. Among the 20 non operated patients, a significant tumor shrinkage was documented by CT and/or MRI in 5 patients after OCT and in 1 patient after LAN treatment. All patients referred a notable improvement of soft tissue swelling, arthralgia, headache and weakness, both after OCT and LAN treatments. During the first days of OCT treatment, abdominal discomfort was referred by 12 patients and steatorrhea by 5 patients: side effects disappeared spontaneously in 6 cases while during treatment with pancreatic enzymes in the remaining ones. After the first injections of LAN, abdominal discomfort was referred by 10 patients and steatorrhea by 2 of them. No difference in the prevalence of both early and late side effects was noted after treatment with OCT and LAN (chi2, 0.49). The majority of these poorly tolerant patients had side effects with both compounds. During LAN treatment, side effects were mild and spontaneously disappeared but recurred after the injection of the drug in six patients. Gallstones were detected in one patient during OCT and in another during LAN, sludge was noted in 6 patients after OCT and in 2 after LAN treatment. In conclusion, the treatment with LAN allowed to achieve safe GH and IGF-I levels in 57.7% of acromegalics with an excellent patients' compliance. LAN treatment possessed similar efficacy and caused side effects with a similar incidence of OCT treatment. The recurrence of side effects after LAN injection suggests the necessity of a careful monitoring of adverse reactions. PMID- 10090137 TI - Twenty-four hour profile of blood pressure in patients with acromegaly. Correlation with demographic, clinical and hormonal features. AB - Cardiovascular events are frequently reported in patients with acromegaly and they are usually related to arterial hypertension. Aim of the present study was to assess the 24-hour profile of blood pressure (BP) and heart rate (HR) in patients with active acromegaly and to correlate them with clinical and hormonal data. Sixteen patients and 16 healthy, age and sex matched subjects underwent ambulatory blood pressure monitoring by means of a portable automatic device (SpaceLabs monitor 90207, Kontron) with measurements every 20 minutes for 24 hours. The presence of the nocturnal fall was assessed by the calculation of the night-day systolic and diastolic ratio. The mean 24-hour diastolic BP was significantly higher in acromegalic patients than in controls (79.1+/-11.5 mmHg vs 70.8+/-5.3 mmHg, p<0.05) and the circadian diastolic profile was flatten. In fact, 10/16 patients were defined as nondippers while this figure was 2/16 in the control group (62% vs 12%, p<0.01). Also the mean 24-hour systolic BP was higher in acromegalic patients than in controls (124.8+/-17.2 mmHg vs 114.1+/-8.6 mmHg, p<0.05). The circadian systolic profile paralleled that of diastolic and was flatten, without a significant nocturnal fall. Ten out of 16 patients were nondippers compared to 2/16 controls (62 vs 12%, p<0.01). No significant correlation was found between mean 24-hour BP, either diastolic or systolic, and demographic or hormonal characteristics of the patients. HR patterns did not differ between patients and controls and were characterized by a prominent nocturnal fall. PMID- 10090138 TI - High prevalence of thyroid dysfunction in adult patients with beta-thalassemia major submitted to amiodarone treatment. AB - Amiodarone may induce hyper- or hypothyroidism. Patients with beta-Thalassemia Major (beta-Thal) have an increased prevalence of primary hypothyroidism and often require amiodarone for hemosyderotic cardiomyopathy. Aim of this study was to retrospectively evaluate thyroid function in beta-Thal adult patients on long term amiodarone. The study group consisted of twenty-two (21 males, 1 female; age: 23-36 yr) beta-Thal patients submitted to long-term (3-48 months) amiodarone therapy from January 1991 to July 1996. Controls included 73 beta-Thal patients (23 males and 50 females aged 25-35 yr) not treated with amiodarone. In all cases serum free thyroid hormones, thyrotropin and thyroid autoantibodies were evaluated. A higher prevalence of overt hypothyroidism (5/22 [22.7%]) as compared to controls (3/73 [4.1%], p=0.02) was found in beta-Thal patients < or = 3 months after starting amiodarone, while the prevalence of subclinical hypothyroidism was similar in amiodarone-treated (18.2%) and untreated (15%) beta-Thal patients. Overt hypothyroidism resolved spontaneously after amiodarone withdrawal in 1 case, while the remaining patients were maintained euthyroid on amiodarone by L thyroxine administration. After 21-47 months of amiodarone therapy, 3 patients (13.6%) developed thyrotoxicosis (2 overt and 1 subclinical), which remitted shortly after amiodarone withdrawal. No case of hyperthyroidism was observed in beta-Thal controls (p=0.012 vs amiodarone-treated patients). In conclusion, amiodarone administration is often associated in adult beta-Thal patients to a rapid progression of the pre-existing subclinical hypothyroidism, but transient thyrotoxicosis may also be observed after a longer period of therapy. These findings should be carefully considered in the management of these patients. PMID- 10090139 TI - TSH-secreting pituitary macroadenoma: rapid tumor shrinkage and recovery from hyperthyroidism with octreotide. AB - A 44-year-old man with atrial fibrillation caused by hyperthyroidism is described. The underlying disease was a TSH-secreting macroadenoma of the pituitary. Treatment with the somatostatin analog octreotide eliminated hyperthyroidism and atrial fibrillation within 4 days and the tumor size diminished substantially within 3 weeks. PMID- 10090140 TI - Growth hormone insufficiency in a girl with the autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inherited disease which may comprise many endocrine and non-endocrine components. GH insufficiency has not been recognised as a classical manifestation of this syndrome. We describe the case of a girl with APECED, who presented with four endocrine (hypoparathyroidism, Addison's disease, hypothyroidism, gonadal failure) and three non-endocrine components (candidiasis, ectodermal dystrophy and lichen ruber planus). In addition, growth failure was documented beginning at approximately 8 years; bone age was delayed and stimulated GH peaks after clonidine and arginine were 2.2 and 9.2 microg/l, respectively. A partial empty sella was found on a computed tomography scan of the hypothalamic-pituitary region. At 10.5 years rhGH therapy was started and height gain of 26 cm was observed after 2.7 years of treatment. Puberty started at 11.2 years and menarche occurred at 12.7 years. At 13.25 years rhGH therapy was discontinued owing to frequent hypocalcemic crises; serum IGF-1 levels were persistently low in the following years (between 160 and 180 microg/l, normal range for age 250-600 microg/l). The patient attained a final height of 160.8 cm, which was appropriate for her target height. The presence of lichen ruber planus and GH insufficiency probably secondary to empty sella are two unusual findings in patients with APECED. PMID- 10090141 TI - Progression of a Nelson's adenoma to pituitary carcinoma; a case report and review of the literature. AB - A 25-year-old woman developed Nelson's syndrome, 3 years after successful bilateral adrenalectomy for Cushing's disease. Despite pituitary surgery and radiotherapy the tumour showed invasive growth, leading to visual disturbance, paresis of the oculomotor nerve and, 34 years after adrenalectomy, to death by widespread purulent leptomeningitis. Autopsy revealed a large adenohypophyseal carcinoma with a metastasis attached to the dura, both tumours showing immunocytochemical staining for ACTH and TSH. We review the literature on metastatic adenohypophyseal carcinoma in Cushing's disease and Nelson's syndrome and discuss the role of proliferation markers as indicators of malignant progression. PMID- 10090142 TI - Is the hypothalamic-pituitary-adrenal axis really hyperactivated in visceral obesity? PMID- 10090144 TI - Temperature-dependent sex determination: upregulation of SOX9 expression after commitment to male development. AB - In mammals, birds and reptiles the morphological development of the gonads appear to be conserved. This conservation is evident despite the different sex determining switches employed by these vertebrate groups. Mammals exhibit chromosomal sex determination (CSD) where the key sex determining switch is the Y linked gene, SRY. Although SRY is the trigger for testis determination in mammals, it is not conserved in other vertebrate groups. However, a gene closely related to SRY, the highly conserved transcription factor, SOX9, plays an important role in the testis pathway of mammals and birds. In contrast to the CSD mechanism evident in mammals and birds, many reptiles exhibit temperature dependent sex determination (TSD) where the egg incubation temperature triggers sex determination. Here we examine the expression of SOX9 during gonadogenesis in the American alligator, (Alligator mississippiensis), a reptile that exhibits TSD. Alligator SOX9 is expressed in the embryonic testis but not in the ovary. However, the timing of SOX9 upregulation in the developing testis is not consistent with a role for this gene in the early stages of alligator sex determination. Since SOX9 upregulation in male embryos coincides with the structural organisation of the testis, SOX9 may operate farther downstream in the vertebrate sex differentiation pathway than previously postulated. PMID- 10090145 TI - Myotube heterogeneity in developing chick craniofacial skeletal muscles. AB - Avian skeletal muscles consist of myotubes that can be categorized according to contraction and fatigue properties, which are based largely on the types of myosins and metabolic enzymes present in the cells. Most mature muscles in the head are mixed, but they display a variety of ratios and distributions of fast and slow muscle cells. We examine the development of all head muscles in chick and quail embryos, using immunohistochemical assays that distinguish between fast and slow myosin heavy chain (MyHC) isoforms. Some muscles exhibit the mature spatial organization from the onset of primary myotube differentiation (e.g., jaw adductor complex). Many other muscles undergo substantial transformation during the transition from primary to secondary myogenesis, becoming mixed after having started as exclusively slow (e.g., oculorotatory, neck muscles) or fast (e.g., mandibular depressor) myotube populations. A few muscles are comprised exclusively of fast myotubes throughout their development and in the adult (e.g., the quail quadratus and pyramidalis muscles, chick stylohyoideus muscles). Most developing quail and chick head muscles exhibit identical fiber type composition; exceptions include the genioglossal (chick: initially slow, quail: mixed), quadratus and pyramidalis (chick: mixed, quail: fast), and stylohyoid (chick: fast, quail: mixed). The great diversity of spatial and temporal scenarios during myogenesis of head muscles exceeds that observed in the limbs and trunk, and these observations, coupled with the results of precursor mapping studies, make it unlikely that a lineage based model, in which individual myoblasts are restricted to fast or slow fates, is in operation. More likely, spatiotemporal patterning of muscle fiber types is coupled with the interactions that direct the movements of muscle precursors and subsequent segregation of individual muscles from common myogenic condensations. In the head, most of these events are facilitated by connective tissue precursors derived from the neural crest. Whether these influences act upon uncommitted, or biased but not restricted, myogenic mesenchymal cells remains to be tested. PMID- 10090143 TI - Receptor imaging in the diagnosis and treatment of pituitary tumors. PMID- 10090146 TI - Differential expression of AP-2alpha and AP-2beta in the developing chick retina: repression of R-FABP promoter activity by AP-2. AB - Retinal fatty acid binding protein (R-FABP) is the avian counterpart of murine brain FABP implicated in glial cell differentiation and neuronal cell migration. R-FABP is highly expressed in the undifferentiated retina and brain of chick embryos. We have previously shown by in vitro studies that the AP-2 transcription factor binds to a consensus AP-2 binding site in the R-FABP promoter region. Based on the expression pattern of AP-2 in the developing retina and on mutational analysis of the AP-2 binding site in DNA transfection experiments, we proposed that AP-2 could be involved in the down-regulation of R-FABP transcription. Here, we describe the cDNA isolation of two members of the AP-2 family expressed in the chick retina, AP-2alpha and AP-2beta. We show that R-FABP mRNA and the AP-2 factors are expressed in mutually exclusive patterns in the differentiating retina: whereas AP-2alpha and AP-2beta are selectively expressed either in amacrine, or in amacrine and horizontal cells, respectively, R-FABP mRNAis found in Muller glial cells and/or bipolar cells. Furthermore, a decrease in R-FABP-dependent expression is obtained upon cotransfection of primary retinal cultures with AP-2 expression vectors and a CAT reporter construct. The early and cell-specific expression of AP-2alpha and AP-2beta in the developing retina suggest a role for this transcription factor family in the early steps of amacrine and horizontal cell differentiation. Repression of the R-FABP gene in these cells may be an important component of their developmental program. PMID- 10090147 TI - Epidermal expression of apolipoprotein E gene during fin and scale development and fin regeneration in zebrafish. AB - Apolipoprotein E (apoE) plays an important role in systemic and local lipid homeostasis. We have examined the expression of apoE during morphogenesis and regeneration of paired and unpaired fins and during scale development in zebrafish (Danio rerio). In situ hybridization analysis revealed that, during embryogenesis, apoE is expressed in the epithelial cells of the median fin fold and of the pectoral fin buds. ApoE remains expressed in the elongating fin folds throughout development of the fins. During the larval to juvenile transition, apoE transcripts were present in the distal, interray and lateral epidermis of developing fins. Furthermore, as scale buds started to form, apoE was expressed in large scale domains which later, became restricted to the external posterior epidermal part of scales. A low level of transcripts could be observed at later developmental stages at these locations probably because fins and scales continue to grow throughout the animal's life. During regeneration of both pectoral and caudal fins, a marked increase in apoE expression is observed as early as 12 hours after amputation in the wound epidermis. High levels of apoE transcripts are then localized primarily in the basal cell layer of the apical epidermis. The levels of apoE expression were maximum between the second to fourth days and then progressively declined to basal level by day 14. ApoE transcripts were also observed in putative macrophages infiltrated in the mesenchymal compartment of regenerating fins a few hours after amputation. In conclusion, apoE is highly expressed in the epidermis of developing fins and scales and during fin regeneration while no expression can be detected in the skin of the trunk. ApoE may play a specific role in fin and scale differentiation at sites where important epidermo-dermal interactions occur for the elaboration of the dermal skeleton and/or for lipid uptake and redistribution within these rapidly growing structures. PMID- 10090148 TI - Alpha9 and beta8 integrin expression correlates with the merger of the developing mouse eyelids. AB - As previously reported, alpha9 integrin is expressed between the merged or fused eyelids of mice at birth, and changes in alpha9 localization occur during lid opening. To determine whether alpha9 and/or additional integrin subunits mediate the emergence and temporary fusion of the eyelids, immunofluorescence and confocal microscopy were used to evaluate the localization of various integrin subunits in the developing ocular surface of the mouse. No detectable beta5, beta6, or beta7 integrins were observed on the epithelia of the ocular surface. alpha2, alpha3, alphav, and beta1 integrins were most abundant in the basal cells beginning at 13.5 days post conception and remained primarily localized to the basal cell layers throughout development. beta4 was localized at the basal surface of the epidermal basal cells beginning at 13.5 days post conception but was not found on the corneal epithelial basal cells until after birth. alpha9 and beta8 integrins were present on suprabasal cells of the epidermis at the leading edge of the eyelid before merger and on the epithelial bridge that forms immediately after these tissues merge, suggesting that they play a role in the initial fusion of the epithelial tissues of the eyelid and in stabilizing the epithelial junction. After birth and into adulthood, beta8 was retained within the suprabasal cell layers of the epidermis, whereas alpha9 became localized to the basal cells of the epidermis, the conjunctiva, and the limbus. The lack of co localization of beta4 with either alpha9 or beta8 in double-labeling studies suggests that alpha9 and beta8 are restricted to the lateral and apical aspects of those cells in which they are expressed. The presence of tenascin-C and laminin-5 at the epithelial junction site suggests that alpha9: tenascin-C and beta4: laminin-5 interactions may play a role in stabilizing the fusion between lids early on but do not appear to be involved in the movement of the lids across the cornea. The data presented identify specific integrins and matrix proteins that are likely to mediate eyelid fusion. PMID- 10090149 TI - The LIM protein, CRP1, is a smooth muscle marker. AB - LIM domains are double zinc-finger motifs found in many proteins that play central roles in cell differentiation. Members of the cysteine-rich protein (CRP) family display two LIM domains and are implicated in muscle development. Here we describe the characterization of one member of this family, CRP1, in the mouse. We have isolated and sequenced murine cDNAs that encode CRP1. We have determined by Northern analysis and in situ hybridization that CRP1 expression is developmentally regulated in the embryonic mouse and displays organ specific regulation in adults. The gene encoding CRP1 is expressed in the smooth muscle cells (SMCs) of the dorsal aorta at E9.5, thus illustrating that CRP1 is an early marker for SMC differentiation at that site. As development proceeds, CRP1 transcripts are observed throughout the SMC lineage, with minimal, transient expression detected in skeletal and cardiac muscle. Interestingly, although several markers of mature smooth muscle are already expressed, CRP1 expression in the bladder is not upregulated until the onset of bladder expansion at embryonic day 16.5, at which time its expression becomes very prominent. CRP1 expression persists into adulthood with prominent expression observed in both vascular and visceral smooth muscle. The results reported here define CRP1 as a general marker of smooth muscle lineages. PMID- 10090150 TI - Catenary cultures of embryonic gastrointestinal tract support organ morphogenesis, motility, neural crest cell migration, and cell differentiation. AB - The embryonic gastrointestinal tract develops from a simple tube into a coiled, flexed, and regionalized structure. The changes in gut morphology coincide with the differentiation of multiple cell types in concentric layers, and include colonization by migratory neuron precursors, and the development of gastrointestinal motility. We describe a reliable method for growing embryonic mouse intestine in vitro by the attachment of segments of intestinal tract by their cut ends, with the intervening region suspended in the culture medium. These are termed "catenary cultures." E11-E11.5 mouse midgut, hindgut, or mid- plus hindgut segments were grown in catenary culture for up to 10 days and their growth, morphology, cell differentiation, ability to support neural precursor migration, and contractile activity were assessed. The increase in size of the cultured explants was not large, but morphogenesis proceeded, best exemplified by elongation of the caecum. Cell differentiation also proceeded. In the mucosa, goblet cells differentiated. Muscle layers, characterized by desmin expression, and kit-positive interstitial cells of Cajal differentiated in the correct positions. Where segments initially included neural precursors in a small sub region, these migrated and proliferated to form uniform neuronal networks throughout the entire explant, and the cells expressed the neuron markers nitric oxide synthase and neuron specific enolase. Gut motility was attained 5-6 days into the culture period, and both contractile- and mixing-type movements were observed. Thus, cell types representative of all three germ layer contributions developed, and in addition, the gut, being mainly free, was able to elongate and bend (unlike on solid support cultures), while retaining its rostrocaudal identity. PMID- 10090151 TI - Expression of matrix metalloproteinases during murine chorioallantoic placenta maturation. AB - A large body of experimental evidence supports the participation of two groups of extracellular proteases, matrix metalloproteinases (MMPs), and plasminogen activators/plasmin, in tissue remodeling in physiological and pathological invasion. In the late mouse placenta, several tissue remodeling and cell invasion processes take place. Spongiotrophoblast migration into maternal decidua, as well as decidual extracellular matrix remodeling require the coordinated action of extracellular proteolytic enzymes. Via Northern and in situ hybridization, we have analyzed the spatio-temporal expression patterns of members of the MMP family (stromelysin-3, gelatinases A and B), as well as their inhibitors TIMP-1, 2 and -3 in late murine placenta (days 10.5 to 18.5 of gestation). Gelatinase activity in placental extracts was assessed by substrate zymography. Gelatinase A and stromelysin-3 were found to be prominently expressed in decidual tissue; shortly after midpregnancy, the decidual expression patterns of gelatinase A and stromelysin-3 became overlapping with each other, as well as with the expression domain of TIMP-2. On the other hand, gelatinase B transcripts were expressed only by trophoblast giant cells at day 10.5, and were downregulated at later stages. TIMP-1 and TIMP-3 transcripts were detected in decidual periphery at day 10.5, while later the expression was restricted to the endometrial stroma and spongiotrophoblasts, respectively. The areas of stromelysin-3 expression were the same (giant trophoblasts) or adjacent (decidua) to those where urokinase (uPA) transcripts were detected, suggesting a possible cooperation between these proteinases in placental remodeling. We generated mice doubly deficient for stromelysin-3 and uPA, and report here that these mice are viable and fertile. Furthermore, these animals do not manifest obvious placental abnormalities, thereby suggesting the existence of compensatory/redundant mechanisms involving other proteolytic enzymes. Our findings document the participation of MMPs and their inhibitors in the process of late murine placenta maturation, and warrant the characterization of other members of the MMP family, like membrane type-MMPs, in this process. PMID- 10090152 TI - Molecular cloning of the Notophthalmus viridescens radical fringe cDNA and characterization of its expression during forelimb development and adult forelimb regeneration. AB - Larval and adult newts provide important experimental models to study limb development and regeneration. These animals have exceptional ability to regenerate their appendages, as well as other vital structures. Our research examines the role of the fringe gene (fng) in the developing and regenerating adult newt forelimb. Fringe codes for a secretory protein. It was first discovered in Drosophila, and later homologues were isolated in Xenopus laevis, chick and mouse. This gene has been highly conserved throughout evolution, indicating its crucial role in vertebrate and invertebrate development. We have isolated, cloned, and sequenced the full length of the Notophthalmus viridescens radical fringe cDNA (nrFng) by screening a newt forelimb blastema cDNA library with a 500-bp fragment of the Xenopus lunatic fringe cDNA. The newt fringe cDNA codes for a 396 amino acid protein with a predicted N-terminal signal sequence. Newt fringe shows high homology with radical fringe homologues of many species. Whole mount mRNA in situ hybridization on several stages of newt limb development reveals that nrFng is first expressed in the limb field, with intense expression as the limb bud develops. However, gene expression diminishes with more advanced digit development. A significant role in adult forelimb regeneration is also evident, as we isolated the cDNA from a regeneration-specific library and found it highly expressed during the regenerative phases of active cell division and then down regulated at sites undergoing differentiation and morphogenesis. PMID- 10090153 TI - A molecular basis for Smad specificity. AB - Bone morphogenetic proteins (BMPs) and activins are members of the TGFbeta superfamily of growth factors, a crucial group of regulators of induction and patterning of embryonic germ layers in metazoa. In early Xenopus embryos, activin, Vgl, and nodal are potent inducers of dorsal mesoderm, whereas BMPs can ventralize mesoderm, repress neural fate, and induce blood differentiation. These characteristic responses rely on ligand-specific signaling pathways, encompassing transmembrane kinase receptors and signal transducers belonging to the Smad family. The overexpression in Xenopus embryos of BMP-activated Smad1 and of activin/Vg1/ nodal-activated Smad2 is sufficient to specifically recapitulate ligand responses. In a search for determinants of a Smad specificity code, we have identified two small regions within the conserved carboxyl-domain that are necessary and sufficient for specific Smad action. Swapping both residue clusters (C1 and C2) between Smadl and Smad2 completely switches Smad effects in vivo. Thus, Smadl with swapped Smad2 clusters responds specifically to BMP but elicits an activin response, while a Smad2 protein containing the Smadl clusters is activated by activin and elicits a BMP response. Furthermore, association between Smads and FAST-1, a mediator of mesoderm induction by activin, is dependent upon the presence of the Smad2 C1 sequence. Finally, the Smadl-specific antagonist Smad6 can inhibit a Smad2 molecule harboring Smadl C1 and C2 sequences. Thus, the C1 and C2 regions of Smads specify the association between Smads and pathway specific partners, such as FAST-1 and Smad6, and account for activin- and BMP- specific responses in vertebrate embryogenesis. PMID- 10090154 TI - Can fibromyalgia be separated from regional pain syndrome affecting the arm? PMID- 10090155 TI - Polymyalgia rheumatica: a disorder of extraarticular synovial structures? PMID- 10090156 TI - Downregulation of intercellular adhesion molecule-1 expression on human synovial fibroblasts by endothelin-1. AB - OBJECTIVE: To study the effect of endothelin-1 (ET-1) on the expression of intercellular adhesion molecule-1 (ICAM-1) by synovial fibroblasts derived from individuals with rheumatoid arthritis (RA) or osteoarthritis (OA). METHODS: The expression of ICAM-1 protein and the abundance of ICAM-1 mRNA in synovial fibroblasts derived from individuals with RA or OA, or healthy controls, was assessed by flow cytometry and Northern blot analysis, respectively. mRNA expression of ET type A (ETA) and ET type B (ETB) receptors was assessed by reverse transcription polymerase chain reaction. RESULTS: Tumor necrosis factor alpha (TNF-alpha) increased the expression of ICAM-1 by RA and OA fibroblasts. While ET-1 alone had no significant effect on ICAM-1 expression by either cell type, it inhibited the TNF-alpha induced increase in ICAM-1 expression, and this effect was more marked in RA fibroblasts. TNF-alpha also increased the amount of ICAM-1 mRNA in both cell types, and ET-1 inhibited this increase to a greater extent in RA fibroblasts than in OA fibroblasts. This inhibitory effect of ET-1 was reversed by addition of specific antagonist of ETA receptor. mRNA expression of ETA and ETB receptors was significantly greater in RA fibroblasts stimulated with TNF-alpha or even medium alone than in OA fibroblasts. CONCLUSION: These results suggest that ICAM-1 expression by fibroblasts is regulated not only by proinflammatory cytokines such as TNF-alpha and interleukin-1beta, but also by the vasoactive peptide ET-1, and that ET-1 may play an important role in inflammatory responses, especially in rheumatoid synovitis. PMID- 10090157 TI - Immunohistochemical localization of somatostatin receptor sst2A in human rheumatoid synovium. AB - OBJECTIVE: To identify the somatostatin receptor-expressing cells in rheumatoid synovium using a recently developed antiserum directed against the somatostatin receptor subtype 2A (sst2A). METHODS: We carried out immunohistochemical studies of synovial biopsies from 7 patients with rheumatoid arthritis (RA) and one non RA patient, using a rabbit polyclonal antiserum directed against sst2A and monoclonal antibodies directed against phenotypic markers. RESULTS: SSt2A was expressed by the endothelial cells of the synovial venules but also by a subset of synovial macrophages. CONCLUSION: The identification of somatostatin receptors on macrophages, which are thought to be important effector cells in RA, may offer mechanistic insights into the potential therapeutic effect of somatostatin (analogs) in RA. PMID- 10090158 TI - Self-administered joint counts in rheumatoid arthritis: comparison with standard joint counts. AB - OBJECTIVE: To test the reliability and validity of a self-administered 36 joint count developed after the Rapid Assessment of Disease Activity in Rheumatology (RADAR) questionnaire for assessing pain/tenderness. METHODS: Two self administered formats (mannequin and text) were evaluated in 60 patients with rheumatoid arthritis (RA). Reliability between both formats was tested by Spearman rank correlation. Criterion validity/accuracy was tested by Spearman correlation coefficient between each self-report format and a joint count performed by a physician. Construct validity was ascertained by correlation of each format with other variables of disease activity. RESULTS: Reliability between the 2 formats was high (R = 0.94). Correlations between each format and the physician's joint count were also high (R = 0.77 for mannequin, 0.75 for text). Patients consistently rated their joint pain/tenderness higher than the physician (means 29, 27, and 12 for text, mannequin, and physician, respectively; p < 0.01). Construct validity of the text, mannequin, and physician formats compared with the modified Health Assessment Questionnaire showed R = 0.61, 0.65, 0.63; with Steinbrocker functional class R = 0.41, 0.46, 0.56; with pain R = 0.59, 0.61, 0.62; with global evaluation R = 0.66, 0.71, 0.84; and with morning stiffness R = 0.64, 0.59, 0.60, respectively. CONCLUSION: Although both self administered formats exhibited adequate reliability and construct validity, a systematic difference between patient and physician/trained assistant performed joint counts was observed, with patients consistently rating their pain/tenderness higher. We thus do not believe they can replace standard physician/trained assistant evaluation in obtaining clinical research data in rheumatology. PMID- 10090159 TI - Prognostic factors for the development of rheumatoid arthritis and other connective tissue diseases in patients with palindromic rheumatism. AB - OBJECTIVE: Palindromic rheumatism is characterized by attacks of acute arthritis of short duration. In the long term, a substantial proportion of patients will develop rheumatoid arthritis (RA) or other connective tissue diseases, but the determinants of subsequent chronic disease have not been adequately established. We identify clinical prognostic factors for the development of RA and other connective tissue diseases in patients with palindromic rheumatism in a retrospective cohort study. METHODS: The medical records of 4900 patients with arthritis referred from 1986 to 1996 to 3 rheumatologists at an academic center were reviewed. One hundred sixty patients were diagnosed as having palindromic rheumatism. After review, 127 complied with diagnostic criteria for palindromic rheumatism. Disease duration was estimated as time of first attack until the last consultation, or the development of RA or other connective tissue disease. Survival analysis including Cox regression was used to identify clinical variables associated with the risk of developing RA or other connective tissue disease, adjusting for varying disease duration. RESULTS: Sixty-five percent of the patients were female. Age at onset was 40+/-12 years. Mean disease duration was 6+/-6 years, and mean followup by the rheumatologists was 40+/-45 months. Joints more frequently affected were wrist, knee, and metacarpophalangeal. Forty three patients (34%) subsequently developed a connective tissue disease including 36 (28%) RA, 3 (2%) systemic lupus erythematosus, and 4 (3%) other connective tissue diseases. In the final Cox regression model the hazard ratio for development of a connective tissue disease in the presence of a positive rheumatoid factor (RF) was 2.9 (p = 0.002), for proximal interphalangeal (PIP) joint involvement 2.4 (p = 0.02), for wrist involvement 2.5 (p = 0.05), for female sex 2.2 (p = 0.05), and for age at onset 1.03 (per year) (p = 0.001). Female patients with positive RF and involvement of the hands had an 8-fold risk of developing disease, compared with patients with one or fewer of these features. CONCLUSION: Positive RF and early involvement of the wrist and PIP joints predict the subsequent development of RA or other connective tissue disease in patients with palindromic rheumatism, and identify a group of patients at increased risk. PMID- 10090160 TI - Trends in the use of disease modifying antirheumatic medications in rheumatoid arthritis, 1980-1995: results from the National Ambulatory Medical Care Surveys. AB - OBJECTIVE: Current treatment of rheumatoid arthritis (RA) emphasizes the early and consistent use of disease modifying antirheumatic drugs (DMARD). We studied how often these medications were used to treat patients with RA, and whether use of these medications has increased over time. METHODS: We used the National Ambulatory Medical Care Surveys to determine national probability estimates of the use of DMARD [hydroxychloroquine, intramuscular gold, auranofin, methotrexate (MTX), sulfasalazine, azathioprine, D-penicillamine, and cyclosporine] by patients with RA. The National Ambulatory Medical Care Surveys record information about treatments provided in outpatient settings by a nationally representative cross sectional sample of physicians. Estimates of the use of DMARD were based on the treatments reported on 502 visits by patients with RA in 1980-81, 339 visits by patients with RA in 1985, 386 visits by patients with RA in 1989-91, and 383 visits by patients with RA in 1993-95. RESULTS: DMARD were used in 30.3% of visits in 1980-81, 36.3% of visits in 1985, 24.9% of visits in 1989-91, and 43.6% of visits in 1993-95 (p for trend < 0.0001). Increased use of MTX accounted for most of the increased prevalence of DMARD use; MTX was used in 27.3% of visits in 1993-95. Use of DMARD increased in 1993-95 in all age, sex, and racial subgroups, and among visits reported by rheumatologists, but did not increase over time among visits reported by physicians other than rheumatologists. CONCLUSION: Use of DMARD in RA has increased in the recent past, but DMARD are currently used by fewer than 44% of patients with RA. Use of DMARD has not increased over time among patients of physicians other than rheumatologists. PMID- 10090161 TI - Soluble adhesion molecules and anti-endothelial cell antibodies in patients with rheumatoid arthritis complicated by peripheral neuropathy. AB - OBJECTIVE: To examine whether levels of soluble adhesion molecules and anti endothelial cell antibodies (AECA) were elevated in rheumatoid arthritis (RA) complicated by peripheral neuropathy compared to controls with no neurological complications. METHODS: Levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin, and AECA were determined by ELISA in 33 patients with RA neuropathy, 23 patients with vasculitis who had no neurological complications, 29 patients with RA without neuropathy, and 25 healthy volunteer controls. RESULTS: The patients with neuropathy had significantly higher levels of serum sVCAM-1 (mean 1119+/-368 ng/ml) than patients without neuropathy (mean 869+/-214 ng/ml) and healthy controls (mean 578+/-204 ng/ml). Serum levels of sE-selectin were higher among neuropathic patients with RA (mean 73+/-34 ng/ml) than RA controls (mean 45+/-27 ng/ml) and healthy controls(mean 32+/-10 ng/ml). There was no significant difference in serum levels of sVCAM-1, sE-selectin, and AECA between patients with RA with neuropathy and patients with vasculitis uncomplicated by neurological disease. Abnormal levels of sVCAM-1, sE-selectin, or AECA were found in sera from 28 (85%) patients with RA neuropathy, 15 (65%) patients with vasculitis, 9 (31%) RA controls, and 2(8%) healthy controls. CONCLUSION: Serum levels of sVCAM-1, sE-selectin, and AECA are higher in patients with RA neuropathy than in patients with RA uncomplicated by neurological disease. These data suggest that development of peripheral neuropathy in RA is associated with increased endothelial cell activation. PMID- 10090162 TI - Conversion of patients with rheumatoid arthritis from the conventional to a microemulsion formulation of cyclosporine: a double blind comparison to screen for differences in safety, efficacy, and pharmacokinetics. AB - OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) may be converted, on a milligram-to-milligram basis, from conventional cyclosporin A (CyA, Sandimmun) to the microemulsion formulation (Neoral) with maintenance of longterm safety, and to compare cyclosporin A (CyA) pharmacokinetics between formulations. METHODS: In this double blind, multicenter, parallel group study, 51 patients receiving stable conventional CyA maintenance treatment were randomized to continue conventional CyA (n = 27) or to convert to CyA microemulsion (n = 24) and were monitored for 52 weeks. Trough blood CyA levels were measured before and at intervals after conversion. CyA steady-state area under the curve was assessed one week before and 2 and 6 weeks after randomization in 15 patients in each treatment arm. CyA trough levels and pharmacokinetic results remained unknown to investigators throughout the study. CyA doses were titrated as necessary on the basis of clinical evaluation and disease activity assessments. RESULTS: Initial mean daily doses were 3.5 mg/kg/day (conventional CyA) and 3.3 mg/kg/day (CyA microemulsion) and did not change significantly during the study. The mean bioavailability of CyA from the microemulsion formulation was 23% higher than from conventional CyA. Replicate assessments indicated a more reproducible pharmacokinetic profile with CyA microemulsion. The overall incidence and nature of adverse events and changes in vital signs and laboratory variables were similar in both groups. No clinically relevant differences in efficacy were found between treatments. No loss of efficacy and no tolerability problems occurred after conversion from conventional to microemulsion CyA. CONCLUSION: Existing CyA dosing guidelines, formulated for conventional CyA, are suitable for longterm CyA microemulsion therapy of patients with RA. These results indicate the pharmacokinetic advantages of the microemulsion formulation. PMID- 10090163 TI - Clinical and serological associations of anti-Ku antibody. AB - OBJECTIVE: To ascertain the clinical and serological associations of anti-Ku antibody. METHODS: Twenty-seven patients over a 7 year period (1987-1996) had anti-Ku antibody detected by counterimmunoelectrophoresis (CIEP). Nineteen patients were available for clinical review. Five patients were assessed by chart review. Serum was taken at review for repeat antibody analysis. Patients were assigned to diagnostic groups based on the American College of Rheumatology criteria. RESULTS: There were 22 women and 5 men. The duration of symptoms ranged from one year to 28 years. Nine patients fulfilled criteria for systemic lupus erythematosus (SLE), 4 scleroderma, 3 rheumatoid arthritis (RA), one discoid lupus, and 7 had an undifferentiated connective tissue disease. There was a low incidence of renal (2/24) and central nervous system involvement (1/24); 19/24 had Raynaud's phenomenon, 15/24 had inflammatory arthritis but only one had erosions on radiograph; 11/24 reported esophageal reflux symptoms. Three of 24 patients had myositis. All patients had anti-nuclear antibody using indirect immunofluorescence of > 640 titer with a speckled and nucleolar pattern. Anti-Ku antibody was detected on CIEP in 15/19 sera available for repeat testing. Three patients had anti-Ro antibody, 2 had anti-U1RNP antibody, one patient had anti topoisomerase-1 and anti-Ro. CONCLUSION: Anti-Ku antibody is found in a wide variety of connective tissue syndromes. While several patients fulfilled diagnostic criteria for SLE, scleroderma, and RA, their clinical features were usually mild and did not form a distinctive clinical pattern. Common features associated with anti-Ku were Raynaud's phenomenon, arthralgia, skin thickening, and esophageal reflux. Few patients had associated autoantibody specificities found in SLE or scleroderma. PMID- 10090164 TI - Circulating levels of beta-chemokines in systemic lupus erythematosus. AB - OBJECTIVE: Recent evidence suggests the role of beta-chemokines and their receptors in human immunodeficiency virus infection. We examined the serum levels of beta-chemokines in patients with systemic lupus erythematosus (SLE). METHODS: The serum levels of beta-chemokines, macrophage inflammatory protein-1alpha (MIP 1alpha), MIP-1beta, RANTES, and monocyte chemoattractant protein-1 (MCP-1) in patients with SLE were determined by ELISA. RESULTS: There were significant differences between the patients with SLE and healthy controls in the serum concentrations of RANTES (p < 0.001) and MCP-1 (p < 0.01), but not MIP-1alpha (p = 0.07) and MIP-1beta (p = 0.68). A decrease of RANTES and an increase of MCP-1 was observed with the progression of disease activity in the patients with SLE. CONCLUSION: Changes in the serum levels of RANTES and MCP-1 may indicate an interaction between SLE disease activity and the production of beta-chemokines. PMID- 10090165 TI - Periarticular calcification in systemic lupus erythematosus. AB - OBJECTIVE: To describe the radiologic manifestations of periarticular calcification in patients with systemic lupus erythematosus (SLE) and to investigate clinical variables associated with its occurrence. METHODS: Hand radiographs and clinical records of 52 patients who had 4 or more features of the 1982 revised criteria for classifying SLE and who had no other collagen vascular diseases were analyzed retrospectively. RESULTS: Periarticular calcifications were found in 7 patients (13.5%) near the distal and proximal interphalangeal (DIP and PIP) joints and metacarpophalangeal (MCP) joints. No significant association with calcification was noted for the following variables: age at disease onset, duration of the disease, sex, the maximum value of the serum calcium, organic phosphate, and uric acid, Raynaud's phenomenon, lupus nephritis, femoral avascular necrosis, central nervous system lupus, proteinuria, or the use of drugs such as corticosteroids, synthetic vitamin D, and nonsteroidal antiinflammatory drugs. However, a significant association was noted with the use of furosemide (p < 0.01 by chi-square). In 5 patients periarticular calcification was observed during or just after hyperuricemia had developed while taking diuretics. CONCLUSION: Periarticular calcification in patients with SLE was seen in the DIP, PIP, and MCP joints, and appeared to be associated with the use of diuretics. If patients with SLE are prescribed a diuretic regimen, crystal associated arthritis should be considered as a possibility when diagnosing oligoarthritis. PMID- 10090166 TI - Detergent and antigen fragility affect the ELISA for measurement of anti prothrombin autoantibodies. AB - OBJECTIVE: Some investigators have reported that anti-prothrombin autoantibodies (aPT) in lupus anticoagulant positive sera were detectable by ELISA. Discrepancies in aPT ELISA were observed by some investigators. To clarify this situation, we tested the binding of aPT positive sera to purified prothrombin under various conditions. METHODS: We performed aPT ELISA under different conditions. The variables we tested were: ELISA plate (untreated or gamma irradiated polystyrene plates), buffer (phosphate buffered saline or Tris buffered saline), detergent (presence or absence of Tween-20), and antigen condition (intact or fragmented prothrombin). RESULTS: Anti-PT from patients with lupus or antiphospholipid syndrome were similarly bound to prothrombin with both buffers. Addition of Tween-20 to the buffer increased reactivity in the irradiated plate assay, but decreased reactivity in the untreated plate assay. Reactivities in 90% of lupus sera were decreased by the use of fragmented prothrombin. In contrast, the reactivity of serum from a healthy subject was remarkably increased by antigen fragmentation. CONCLUSION: The discrepant ELISA results in measurement of aPT in the various reports may have been due to the use of detergent in the buffer and condition of the prothrombin used as antigen. In our experiments the best ELISA condition for measurement of aPT was achieved using buffer with Tween-20 detergent, with prothrombin directly coated onto irradiated polystyrene plates. PMID- 10090167 TI - Risk of thrombosis in patients with antiphospholipid antibodies and factor V Leiden mutation. AB - OBJECTIVE: Antiphospholipid antibodies (aPL) are thrombophilic risk markers in patients with systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). The risk factors for recurrent venous or arterial thrombosis and indications for longterm anticoagulation therapy are debated. We hypothesized that carrying a second thrombophilic defect, factor V Leiden mutation, would increase the risk for thrombosis in patients with aPL. METHODS: Seventy-five patients with primary APS and 83 with SLE and aPL with or without thrombosis followed at 2 university hospitals were studied. Factor V mutation rate was analyzed in patients and in 200 healthy blood donors by polymerase chain reaction analysis. RESULTS: The prevalence of factor V Leiden mutation in patients with SLE and aPL or primary APS was similar to controls. Patients with deep vein thrombosis or arterial thrombosis did not have a significantly increased rate of factor V mutation compared to controls or to patients with aPL without thrombosis. CONCLUSION: Factor V Leiden mutation is not significantly associated with vein thrombosis in patients with aPL. However, due to the sample size we cannot rule out synergy between both factor V Leiden and aPL. A trend toward increased risk for thrombosis was detected in patients with the mutation and this should be analyzed in a larger study. PMID- 10090168 TI - Comparison between the standard anticardiolipin antibody test and a new phospholipid test in patients with connective tissue diseases. AB - OBJECTIVE: Antiphospholipid (aPL) antibodies are present in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody syndrome (APS) and are associated with recurrent thromboses, thrombocytopenia, and pregnancy losses. The presence of aPL antibodies is routinely tested using a standardized ELISA that utilizes cardiolipin as antigen (aCL ELISA). This test, although sensitive, is frequently positive in patients with nonrelated autoimmune disorders and some infectious diseases, making the test less specific. Thus there is a need for more specific tests for aCL with equivalent sensitivity to the standard assay. We evaluated the diagnostic utility of a new aPL antibody test kit with a unique phospholipid mixture designed to be more specific than the standard anticardiolipin ELISA. METHODS: aPL antibodies (IgG, IgM) were measured by both a standard ELISA and a new ELISA kit (APhL ELISA Kit, Louisville APL Diagnostics, Inc., Louisville, KY, USA) in the baseline serum from patients enrolled in a 5 year inception cohort, prospective study of early rheumatoid diseases: rheumatoid arthritis (N = 70), SLE (70), scleroderma (45), inflammatory myositis (36), and early undifferentiated connective tissue disease (CTD) (165). Diagnosis was based on standardized criteria and determined at the last study visit. A nested group of patients with Sjogren's syndrome (44) was also defined. Serum from 200 blood donors (BD) served as controls. Patients with known APS (33) and antinuclear cytoplasmic antibody positive renal vasculitis (52) were also studied. Laboratory personnel were blinded to sample diagnostic group. RESULTS: The kit was 90.9% sensitive for detecting APS. Seven patients missed by the kit all had standard aCL values < 40 PL units. Assuming controls do not have APS, the kit was 99.5% specific vs 96.0% for the standard assay. For the patients with CTD, the kit never detected a patient that was not also detected by the standard aCL assay. CONCLUSION: The APhL ELISA Kit appears to be more specific than the standard aCL ELISA without adding potential false positive results. The new test may be useful for followup study for patients found to be aCL positive by standard assays to increase specificity for aCL screening. PMID- 10090169 TI - Systemic lupus erythematosus, a disease associated with low levels of clusterin/apoJ, an antiinflammatory protein. AB - OBJECTIVE: To measure the serum levels of clusterin, an antiinflammatory protein, which binds and inactivates complement, in patients with systemic lupus erythematosus (SLE) to determine whether the levels correlate with disease. METHODS: The levels of serum clusterin were measured by ELISA in 80 patients with SLE (76 female, 4 male). Clinical and serological information was gathered on 115 visits. Overall disease activity scores were determined using the Systemic Lupus Activity Measure-Revised. RESULTS: Serum clusterin levels were significantly decreased in patients with SLE and correlated inversely with disease activity (p < 0.00001). Low clusterin levels were significantly associated with skin ulcers (p < 0.0001), loss of hair (p = 0.002), proteinuria (p = 0.018), low platelet count (p = 0.03), and arthritis (p < 0.0001). The clusterin levels did not correlate with either systemic complement consumption, as measured by C3 or C4, or with prednisone use. CONCLUSION: A highly significant correlation was observed between low levels of serum clusterin and a number of SLE disease features. This deficiency of clusterin could directly or indirectly affect the disease process. Individuals lacking sufficient amounts of clusterin systemically likely have poor control of antibody mediated inflammation at sites of apoptosis where autoantigens are exposed. PMID- 10090170 TI - Reliability and sensitivity of diagnostic tests for primary Sjogren's syndrome. AB - OBJECTIVE: To investigate whether diagnostic tests for primary Sjogren's syndrome (pSS) are reproducible when repeated after one year (reliability). To evaluate whether the sensitivity of the diagnostic tests increases with repeated testing. METHODS: A structured interview investigating the subjective sensation of dry eyes and dry mouth, and the diagnostic tests Schirmer I, unstimulated whole saliva collection (UWSC), serological tests for antinuclear antibodies (ANA), for anti-Ro/SSA and anti-La/SSB antibodies as well as Waaler's test for rheumatoid factor, were performed twice with a one year interval in 66 patients with pSS. Reliability was given as the percentage of positive tests remaining positive at the second examination, while sensitivity was given as the percentage of patients with positive tests. RESULTS: Highest reliability was obtained for the sensation of dry mouth (98.2%) and sensation of dry eyes (96.4%), and anti-SSA/SSB antibodies (93.3%). Lowest reliability was obtained for rheumatoid factor at cutoff titer 1:32 (70.6%) and positive Schirmer I in one eye (77.4%). The reliability for ANA was 80% at cutoff titer 1:32, and increased to 93.3% at cutoff titer 1:128. UWSC had a reliability of 84.2%. The pooled sensitivity for all the tests increased significantly (p < 0.05) compared to the examination, which had the lowest sensitivity. CONCLUSION: The diagnostic tests for pSS are generally highly reliable when performed twice with a one year interval. The gain in sensitivity by repeating the tests is limited, being most marked for Schirmer I. PMID- 10090171 TI - Fibroblast proliferation by bleomycin stimulated peripheral blood mononuclear cell factors. AB - OBJECTIVE: To evaluate the role of bleomycin for cutaneous fibrosis, we investigated the effects of bleomycin stimulated peripheral blood mononuclear cell (PBMC) factors on in vitro proliferation of mouse 3T3 fibroblasts. METHODS: PBMC were incubated with 10(-4) to 10 microg/ml of bleomycin, and the supernatants (conditioned media) were collected after 48 h. 3H-TdR incorporation was assayed to examine the effects of conditioned medium on 3T3 fibroblast proliferation, which was also compared between 8 patients with systemic sclerosis (SSc) and 8 control subjects. RESULTS: Conditioned medium stimulated 3T3 fibroblasts to proliferate in a dose dependent manner, while culture supernatant without stimulation of bleomycin showed no growth stimulatory activity. Conditioned medium derived from PBMC of patients with SSc exhibited a significantly higher growth activity than that from controls (p < 0.05). Among PBMC subpopulations, macrophages showed the most increased growth effect on 3T3 fibroblasts, although T lymphocyte populations also showed growth activity. The growth activity was inhibited up to 35% by anti-platelet derived growth factor (PDGF) antibody. In addition, growth activity was also partially blocked by antibodies against basic fibroblast growth factor (bFGF) (20%), interleukin 1beta (IL-1beta) (15%), tumor necrosis factor-alpha(TNF-alpha) (7.9%), and transforming growth factor-beta (TGF-beta)(9.5%). The cellular release of IL-1beta, TNF-alpha, and IL-6 was elevated in response to bleomycin exposure in both controls and patients with SSc. Reverse transcriptase-polymerase chain reaction revealed that conditioned medium derived from both patients with SSc and controls induced mRNA expression of several fibrogenic cytokines such as IL-6, TNF-alpha, TGF-beta, and PDGF. IL-1alpha was induced only by conditioned medium derived from patients with SSc. CONCLUSION: These results suggest that bleomycin induced cutaneous fibrosis as well as pulmonary fibrosis may be induced by inflammatory cells through several fibrogenic cytokines. PMID- 10090172 TI - Magnetic resonance imaging and clinical assessment of temporomandibular joint pathology in ankylosing spondylitis. AB - OBJECTIVE: To evaluate temporomandibular joint (TMJ) articular disc position and osseous degenerative changes using magnetic resonance imaging (MRI) as well as clinical symptoms of temporomandibular disorders in patients with ankylosing spondylitis (AS). METHODS: A sample of 43 patients with AS (38 males, age 45.9+/ 10.7 years) and 16 controls (all male, age 41.3+/-6.3 years) were studied. All subjects completed a self-administered questionnaire and underwent clinical examination and MRI survey. Recorded variables included disease characteristics, subjective neck and TMJ disorder symptoms, and axial mobility measurements. MRI variables included TMJ disc position and severity of osseous degenerative change. RESULTS: TMJ disorder symptoms of headache duration and frequency, TMJ pain duration and frequency, and painful jaw movement were more frequent in patients with AS (p < 0.05). Significant differences were also observed in MRI indices for disc displacement (AS, 0.89; controls, 0.36; p = 0.005) and degenerative changes (AS, 0.55; controls, 0.06; p = 0.01). A total of 50 (62%) joints in the AS group had disc displacement compared to 11 (34%) joints in the controls. A total of 16 (20%) joints in the AS group had degenerative change compared to 2 (6%) joints in the controls. CONCLUSION: TMJ internal derangement, degenerative changes, and subjective pain complaints are frequent in patients with AS. Physicians should be aware of potential TMJ involvement in these patients, which may require specific assessment and therapy. PMID- 10090173 TI - Bone density and bone turnover in patients with osteoarthritis and osteoporosis. AB - OBJECTIVE: Osteoarthritis (OA) and osteoporosis (OP) are reported to be rare in the same patient. We examined bone mass, bone turnover, and radiological presence of OA in a group of patients with OA with previous hip fractures and age matched controls. METHODS: Bone mass was assessed by bone mineral density (BMD), using dual energy x-ray absorptiometry (DEXA) of the hip and total body, and quantitative ultrasound of the os calcis, measuring broadband ultrasound attenuation and velocity of sound. Bone turnover was assessed by measuring urinary pyridinium crosslinks and serum osteocalcin. RESULTS: There were differences in bone density, the patients with OP having lower bone density, while patients with OA had similar or increased bone density compared to controls, Serum osteocalcin showed no significant differences among the 3 groups of patients. Urinary pyridinium crosslinks excretion was significantly elevated in the OA group but not in the OP group compared with controls. CONCLUSION: Increased bone turnover was restricted to the OA group. PMID- 10090174 TI - High resolution imaging of normal and osteoarthritic cartilage with optical coherence tomography. AB - OBJECTIVE: We describe optical coherence tomography (OCT), a high resolution micron scale imaging technology, for assessment of osteoarthritic articular cartilage microstructure. OCT is analogous to ultrasound, measuring the intensity of backreflected infrared light rather than acoustical waves. METHODS: OCT imaging was performed on over 100 sites on 20 normal and osteoarthritic cartilage specimens in vitro. RESULTS: Microstructures that were identified included fibrillations, fibrosis, cartilage thickness, and new bone growth at resolutions between 5 and 15 microm. In addition, the polarization sensitivity of imaging suggested a diagnostic role of polarization spectroscopy. CONCLUSION: OCT represents an attractive new technology for intraarticular imaging due to its high resolution (greater than any available clinical technology), ability to be integrated into small arthroscopes, compact portable design, and relatively low cost. PMID- 10090175 TI - The pattern of bone mineral density in the proximal femur and radiographic signs of early joint degeneration. AB - OBJECTIVE: To determine if the presence of early radiographic signs of degenerative changes in the hip is associated with the pattern of bone mineral density (BMD) in the proximal femur. METHODS: Twenty-eight patients scheduled for unilateral hip replacement were placed into one of 2 groups based on the preoperative radiographic findings in the asymptomatic hip: Group 1 (no changes) or Group 2 (doubtful or minimal changes). Both femora and the lumbar spine were scanned by dual energy x-ray absorptiometry. RESULTS: The BMD z scores of the asymptomatic hip were significantly higher at the neck and Ward's triangle sites in Group 2 compared to Group 1 (p < 0.05). There were no differences between the groups in the symptomatic hip except at Ward's triangle, where Group 2 had higher z scores than Group 1 (p < 0.05). The lumbar BMD z scores were elevated in both groups (p < 0.05). CONCLUSION: Proximal femur BMD in the asymptomatic hip of patients scheduled for unilateral hip replacement is elevated when there are early radiographic signs of hip osteoarthritis (OA), consistent with the idea that early OA involves bone as well as cartilage. PMID- 10090176 TI - Radiographic grading for knee osteoarthritis. A revised scheme that relates to alignment and deformity. AB - OBJECTIVE: To develop a radiographic grading scheme for osteoarthritis of the knee that would relate to arthritic progression and deformity. METHODS: The scheme of Scott, et al was revised to include new fields of Tibial Erosion and Subluxation; the fields of Tibial Osteophytes and Sclerosis were removed. The worst affected compartment only was scored on frontal Standardized Knee Images, which were used to define knee alignment variables. RESULTS: The interreader reliability (kappa = 0.92) and correlation for total scores (r = 0.94) were both excellent (p < 0.001). Individual field scores and total knee scores both correlated well with most limb alignment variables, especially the hip-knee-ankle angle (r = 0.77, p < 0.001). CONCLUSION: These findings encourage further evaluations for outcome measurement, diagnostic sensitivity, and sensitivity to define arthritic change over time. PMID- 10090177 TI - Preferential expression of tumor necrosis factor receptor 55 (TNF-R55) on human articular chondrocytes: selective transcriptional upregulation of TNF-R75 by proinflammatory cytokines interleukin 1beta, tumor necrosis factor-alpha, and basis fibroblast growth factor. AB - OBJECTIVE: Articular cartilage is the main target for tumor necrosis factor-alpha (TNF-alpha) and interleukin 1(IL-1) actions. These cytokines are believed to mediate cartilage degradation in arthritis. We studied the expression of TNF receptors (TNF-R) on human articular chondrocytes and their regulation by IL 1beta, TNF-alpha, and basic fibroblast growth factor (bFGF). METHODS: The expression of TNF-R55 and TNF-R75 on human nonarthritic articular chondrocytes was analyzed on protein and mRNA levels by ligand binding studies and reverse transcription polymerase chain reaction (RT-PCR) technique. The regulation of these receptors induced by IL-1 TNF-alpha, and bFGF on mRNA level was studied using RT-PCR. RESULTS: Both TNF-R55 and TNF-R75 are expressed constitutively on human articular chondrocytes, and the number of both receptors varied between 822 and 3880 receptors per cell, depending on the donor cartilage used. Using TNF receptor-specific antibodies, we show that normal chondrocytes express mainly TNF R55. These results are consistent with the mRNA data obtained by RT-PCR. mRNA expression of TNF receptors is regulated by IL-1beta, TNF-alpha, and bFGF. On human chondrocytes the expression of TNF-R75 mRNA was markedly upregulated by IL ID, TNF-alpha, and bFGF, whereas the expression of TNF-R55 mRNA remained largely unchanged. A combination of IL-1beta and TNF-alpha, but not of IL-1beta and bFGF, showed an additive effect on TNF-R75 mRNA expression. CONCLUSION: The expression of TNF-R55 and TNF-R75 on human articular chondrocytes is modulated independently by IL-1beta, TNF-alpha, and bFGF, suggesting a role of these regulatory mechanisms in the degradation processes of human articular cartilage in inflammatory joint diseases. PMID- 10090178 TI - Esculetin (dihydroxycoumarin) inhibits the production of matrix metalloproteinases in cartilage explants, and oral administration of its prodrug, CPA-926, suppresses cartilage destruction in rabbit experimental osteoarthritis. AB - OBJECTIVE: To investigate the in vitro effects of 6,7-dihydroxycoumarin (esculetin) on the production of matrix metalloproteinases (MMP) in rabbit articular cartilage, and the in vivo effects of orally administered CPA-926, a prodrug of esculetin, on cartilage destruction in rabbit experimental osteoarthritis (OA). METHODS: In vitro studies were performed using rabbit articular cartilage explants. Esculetin 10-100 microM was added to cartilage explants in the presence or absence of interleukin 1alpha (IL-1alpha). Effects of esculetin on cartilage metabolism were assessed. Proteoglycan release into medium was determined by dye precipitation with 1,9-dimethylmethylene blue, synthesis of proMMP-1 (interstitial procollagenase) and proMMP-3 (prostromelysin 1) by Western blotting, and collagen degradation activity using FITC labeled collagen. In vivo experimental OA was induced in the knee joints of 15 Japanese adult white rabbits by partial lateral meniscectomy. Ten rabbits were orally administered 200 or 400 mg/kg/day of CPA-926 from the day of surgery for 14 days. The size of the macroscopic erosive area on the femoral condyle and tibial plateau was measured, and cartilage destruction was histologically evaluated. Collagenolytic activities in synovial fluid were measured using FITC labeled collagen as a substrate. RESULTS: In vitro, esculetin inhibited the IL-1alpha induced release of proteoglycan into the medium in a dose dependent manner. The collagenolytic activities in cartilage explant medium induced by IL-1alpha were also suppressed with the addition of 33-100 microM esculetin (p = 0.0209 at 33 and 100 microM, p = 0.0202 at 66 microM). Western blotting of cartilage explant medium showed a decrease in the levels of proMMP-1 and proMMP-3 in the medium by treatment with esculetin. In vivo: At 14 days after surgery, the femoral condyle and tibial plateau in the control group showed macroscopic erosions of cartilage. Compared with the control group, the rabbits treated with CPA-926 at the dose of 400 mg/kg exhibited reduction of the size of the erosive area on the tibial plateau (p = 0.009). Histological evaluation indicated protection against the development of destructive changes in the tibial plateau cartilage at a dose of 200 mg/kg (p = 0.0442) and 400 mg/kg (p = 0.0446) of CPA-926. CONCLUSION: These results indicate that esculetin inhibits matrix degradation in rabbit joint cartilage explants through the suppression of MMP synthesis, secretion, or activity. Prophylactic administration of its prodrug, CPA-926, appears to provide some protection against cartilage destruction in a short term rabbit experimental OA model. PMID- 10090179 TI - The clinical spectrum of severe septic bursitis in northwestern Spain: a 10 year study. AB - OBJECTIVE: To assess the clinical and microbiological characteristics of septic bursitis in those cases that required treatment at the hospital during the past 10 years in a northwestern area of Spain. METHODS: The charts of all patients diagnosed as having septic bursitis at Hospital Xeral-Calde, Lugo, Spain, from October 1987 through September 1997 were reviewed based on published criteria and graded according to severity. RESULTS: Sixty-nine patients diagnosed with definite and 6 with probable septic bursitis met the criteria for severe septic bursitis. Sixty-two were male (82.7%). The mean age at the time of diagnosis was 51 years. The most frequently involved sites were olecranon (47%) and prepatellar (44%) bursae. Among predisposing factors, the presence of prepatellar bursitis was correlated with a job that involved frequent trauma on the bursae. The main clinical and laboratory findings were cellulitis and/or erythema (94.7%), fever (77.3%), and leukocytosis (72%). Noninflammatory synovial fluid (SF, < 2,000 leukocytes/mm3) was observed in 4/32 (12.5%) cases. Positive SF cultures were obtained in 69 of 75 patients (92%). Staphylococcus aureus was the most common pathogen (84%). Blood cultures were positive in 12 of 62 patients (19.4%). Three patients had osteomyelitis. This complication was associated with a longer delay to diagnosis from the onset of symptoms (> 3 weeks vs 9.3+/-13.3 days for the group as a whole). Apart from these 3 cases, overall outcome was excellent. CONCLUSION: Severe septic bursitis is a common disease. Local trauma is the most common risk factor for this infection. Although the most common pathogen is S. aureus, other pathogens such as Brucella abortus play an important role in this infection in our area. PMID- 10090180 TI - Shoulder involvement in rheumatic diseases. Sonographic findings. AB - OBJECTIVE: To distinguish using shoulder sonography the different changes present in rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), and periarticular disorders (PD) of soft tissue of the shoulder. METHODS: Ninety shoulders of patients with RA, 32 with PMR, 122 with PD, and 108 controls were studied sonographically, using a 7.5 MHz linear probe. The following structures were evaluated: long head of biceps tendon, supraspinatus, infraspinatus and subscapularis tendons, subacromial and subscapularis bursae, rotator cuff (thickness), calcifications, and glenohumeral and acromioclavicular joints. Statistical analysis was by Student's t test and chi-squared test. RESULTS: Involvement of long head of biceps tendon (peritendinous fluid collection, changes of thickness, and/or echotexture) was significantly different between RA and PMR and between PD and PMR. Alterations in thickness and/or fibrillar pattern were evaluated in rotator cuff tendons: supraspinatus tendon was involved with significant differences between PD and both RA and PMR; the changes of subscapularis tendon were present, with significant differences between PD and both the other groups; the alterations of infraspinatus tendon were not statistically different between the 3 groups. Effusion within bursae was present, with significant differences only between RA and PD. The mean thickness of rotator cuff was significantly different between controls (6.2 mm) and both PD (5.3 mm) and RA (5.8 mm), and between PMR (6 mm) and PD. Evaluation of effusion within the glenohumeral joint (capsule-bone distance) showed significant differences between controls (2.4 mm) and both RA (4.2 mm) and PMR (4 mm), between RA and PD (2.6 mm), and between PMR and PD. Calcifications were present only in PD (21.3%) and RA (6.7%), with significant differences. Effusion within the acromioclavicular joint was present in RA (35.5%) and PD (20.5%), with significant differences. CONCLUSION: Shoulder sonography showed involvement of all structures in RA, the prevalence of effusion in PMR, and involvement mainly of tendons in PD. PMID- 10090181 TI - One year outcome of preadolescents with fibromyalgia. AB - OBJECTIVE: Twenty-two children with fibromyalgia (FM), found in a population based study of 1756 Finnish preadolescents, were prospectively and blindly followed for one year to investigate their physical and psychological background factors and to determine the one year persistence of FM. METHODS: The American College of Rheumatology 1990 criteria for FM were used. Widespread pain was determined with a structured, pretested pain questionnaire, including items on disability both at baseline and at followup. At baseline, hypermobility was tested with Beighton's method and aerobic capacity with a 20 m shuttle run test, and psychological data were collected using the Children's Depression Inventory (CDI), a sleep questionnaire, and the Child Behavior Checklist and Teacher's Report Form. At followup, evaluations with the CDI and sleep questionnaire were repeated. RESULTS: At baseline, the prevalence of FM was 1.3% (95% CI 0.8 to 1.9). At followup, 16/22 (73%) children were available for evaluation; 4 (25%) had persistent FM. Children with FM had low pain thresholds. Only one of 19 children had hypermobility. Those with persistent FM had persistent subjective disability. Depressive symptoms diminished, but there was still comorbidity of pain and depressive symptoms at followup. CONCLUSION: This study supports a previous one, in which FM in children had a good outcome. However, fluctuation of pain symptoms in children might partly explain the outcome. Children with persistent FM showed persistent disability with a number of distress symptoms. PMID- 10090182 TI - Childhood lipoma arborescens presenting as bilateral suprapatellar masses. AB - Synovial lipomatous proliferations are uncommon idiopathic lesions. Suprapatellar synovial plicae commonly are diagnosed with mechanical knee problems. However, it is not widely known that these plicae can isolate the suprapatellar pouch from the rest of the knee joint. We describe a case of complete bilateral compartmentalization of the suprapatellar pouch (plica synovialis suprapatellaris) in which a 10-year-old boy developed articular tumors isolated in this area. Arthroscopic synovectomy specimens revealed the lesions to represent lipoma arborescens. Rheumatologists should be aware of these two findings when examining a child with swollen knee. PMID- 10090183 TI - Anteroposterior atlantoaxial subluxation in cervical spine osteoarthritis: case reports and review of the literature. AB - Nontraumatic anteroposterior atlantoaxial subluxation (AAS) has been described in several rheumatic or inherited disorders, especially rheumatoid arthritis and to a lesser extent the inflammatory spondyloarthropathies. We describe AAS secondary to osteoarthritis (OA) of the cervical spine in a 76-year-old man and a 73-year old woman with severe cervical OA, symptomatic C1-C2 facet joints, and signs of generalized OA. Only 6 similar cases exist in the literature. OA should be added to the causes of AAS, and conversely AAS should be assessed in cases with severe OA of the upper cervical spine. PMID- 10090184 TI - "Centripetal flagellate erythema": a cutaneous manifestation associated with dermatomyositis. AB - We describe 3 patients with dermatomyositis who presented with flagellate erythema. This cutaneous eruption is characterized by erythematous linear lesions on the trunk and proximal extremities. Histologic examination of this eruption in one of our cases revealed an interface dermatitis. Review of the literature and records of 183 patients with connective tissue diseases from our institution has shown that this peculiar eruption has been reported only in dermatomyositis. Because of the location of this eruption, we encourage the use of the term "centripetal flagellate erythema" to distinguish this entity from other linear eruptions seen in patients with connective tissue diseases. PMID- 10090185 TI - Synovial non-Hodgkin's lymphoma in a human immunodeficiency virus infected patient. AB - We describe a case of articular non-Hodgkin's lymphoma (NHL) with malignant lymphoma cells observed in synovial fluid. Bone involvement in NHL is common, but an English language Medline search revealed only 14 reported cases of synovial NHL. Although NHL is a well recognized complication of human immunodeficiency virus (HIV) infection, this is the first report of synovial NHL in an HIV infected patient. PMID- 10090186 TI - Severe migratory granulomatous reactions to silicone gel in 3 patients. AB - In humans implanted with silicone gel breast prostheses, a mild foreign body response results in the formation of a collagenous capsule around the prosthesis. Although many such patients may show evidence of a microscopic granulomatous foreign body reaction upon examination of capsular material at explantation of a prosthesis, it is unusual to have large, palpable granulomas, even in the presence of rupture or leakage. Rare patients have had severe local inflammation and complications resulting from silicone migration to the axilla, arm, or abdominal wall. We describe 3 patients who had deforming granulomas after implant rupture, along with other consequences of silicone gel migrating down the upper extremity. Silicone gel, once it leaves the implant, is not biologically inert and in some persons can elicit profound pathologic responses. PMID- 10090187 TI - ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. American College of Rheumatology European League of Associations for Rheumatology. AB - We compared the validity of the American College of Rheumatology (ACR) and the European League of Associations for Rheumatology (EULAR) definitions of response in rheumatoid arthritis (RA) clinical trials. US: ACR and EULAR improvement criteria were calculated in 7 large randomized RA clinical trials. The discriminant validity of the response criteria between treatment groups was studied using the Mantel-Haenszel chi-squared value. To compare both sets of criteria the chi-squared ratio was determined for each trial. Europe: In 2 large randomized RA clinical trials, ACR and EULAR criteria were calculated, once with extensive and once with 28 joint counts. The classification of patients with these 4 criteria were compared with each other using cross tables. We further studied the difference in response between treatment groups per trial, the association of response with patient and investigator assessment of improvement, and the association of response with radiological progression. US: The chi squared ratio for most trials was close to 1. There was no clear pattern suggesting that the discriminant validity of the ACR criteria was stronger than the discriminant validity of the EULAR definition of response or vice versa. Europe: Conflicting results between ACR and EULAR were present in only 3% of patients in both trials. The discriminant validity of all 4 criteria (ACR and EULAR with reduced and extensive joint counts) was comparable. All criteria were related with the overall assessment of improvement by both investigator and patient. The association with radiographic progression was comparable for EULAR and ACR improvement criteria. There is a high level of agreement between ACR and EULAR improvement classification, and their validity is equivalent. The discriminating potential of the criteria between treatment groups is comparable, as is the association with patient's and investigator's overall assessment and with radiographic progression. PMID- 10090188 TI - Validity of area-under-the-curve analysis to summarize effect in rheumatoid arthritis clinical trials. AB - There is a continuing interest in increasing the statistical efficiency of the analysis of clinically meaningful endpoints in rheumatology. One issue that is attracting increasing attention is whether the conventional practice of only reporting the outcome at the end of the study (EOS) might be replaced or complemented by a longitudinal summary that better reflects the clinical course of the disease. The area under the curve (AUC) is a summary measure that integrates serial assessments of a patient's endpoint over the duration of the study. We evaluated the utility of AUC as a summary measure for the analysis and reporting of two RA trials: (i) methotrexate combined with cyclosporine versus methotrexate and placebo in partial methotrexate responders in relatively late disease, and (ii) prednisone plus methotrexate plus sulfasalazine versus sulfasalazine alone in relatively early disease. We replicated the published results of each trial first using the conventional EOS and then AUC summaries. For each patient, the changes from baseline over time were transformed into a summary measure by calculating AUC using the trapezium rule and then standardizing it by the study duration. Using an approach similar to the index of responsiveness to change, we scaled treatment differences derived from EOS and AUC summary measures by their standard deviation of the control group. This signal-versus-noise ratio captures the treatment discrimination ability of each summary measure. Compared to EOS and within each treatment group, the AUC summary reported smaller effects (i.e., change from baseline) with reduced errors in the estimates. AUC measures preserved discriminant validity in treatment comparisons and reported smaller but more precise treatment effect estimates. In the COBRA trial with rapidly-acting medications, AUC seemed to be more sensitive than EOS to detect treatment difference. With slow acting medications and in relatively late disease patients as in the cyclosporine trial, EOS was more sensitive to detect treatment difference than was AUC. In this setting, AUC, however, still seemed to be more sensitive than EOS for the two responsive-to-change endpoints: tender joint counts and pain by visual analog scale. AUC integrates repeated assessments during the trial duration into summary measures. Compared to EOS, the report of RA trial results using AUC summary provides smaller estimates of treatment effects but with better precision. AUC summary is likely to preserve treatment group discrimination taking into account the appropriate onset and offset of the drug action. Trial reports using AUC summary have smaller effect sizes. For trials with long acting medications and short duration similar to the cyclosporine trial, AUC still preserves treatment discrimination but may not be as sensitive as EOS. The calculations of AUC require some additional work in the analysis of each endpoint. PMID- 10090189 TI - Pathogenesis of joint damage in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is characterized by the appearance of progressive joint damage that may be identified only months after the onset of symptoms. Early cartilage and bone erosion is associated with the accumulation of several cell populations in the synovial membrane (SM) and the formation of a proliferating pannus. The synovial sublining layer contains several cell populations including macrophages, T and B lymphocytes, dendritic cells, and polymorphonuclear leukocytes. The lining layer contains large numbers of macrophages and fibroblast like synoviocytes. The interface between pannus and cartilage is occupied predominantly by activated macrophage populations and synoviocytes capable of secreting destructive proteases in abundance. We have observed that macrophages aggregate preferentially adjacent to the cartilage-pannus junction (CPJ) and express differentiation phenotypes that are absent from the lining layer macrophages of more remote SM. Moreover, in a prospective study, the number of SM macrophages correlated with the degree of joint damage occurring over one year. Similar results were obtained when SM biopsy samples were analyzed and correlated with clinical and radiological changes occurring over 6 years. Macrophages and synoviocytes at the CPJ express matrix metalloproteinase and cathepsin mRNA from the earliest stage of RA. The mechanisms involved in the secretion of tissue degrading enzymes by macrophages and synoviocytes are undergoing further investigation and preliminary results suggest that different regulation pathways may exist. PMID- 10090190 TI - Conceptual issues in scoring radiographic progression in rheumatoid arthritis. AB - Radiographic scoring systems for rheumatoid arthritis (RA) should be based on current understanding of disease pathology. Evidence suggests that there may be at least two intraarticular pathologies that may result in change in different radiographic features. There is therefore a strong argument for devising a radiographic score based on the observation of features rather than broad categorizations of the total radiographic change. Features may subsequently be amalgamated in relation to other criteria such as sensitivity, specificity, and responsiveness to change, and may be related to subsequent developments in understanding the biology of RA. A second challenge is in elucidating the relationship between radiographic change and the longterm consequences of RA for the patient. Current practice is predicated on the assumption that in the longterm radiographic change correlates well with functional loss and possibly noninflammatory, endstage joint pain. Although hand and feet radiographs broadly represent destructive change in all joints, in cross sectional studies they correlate only moderately with late stage functional loss. The issue may be resolved by longterm observational studies of radiographic change and functional loss. It is recommended that specific radiographic features relevant to joint pathophysiology be used to create a radiographic damage index for comparison with current scoring systems and that longterm observational studies specifically address the relationship between radiographic joint damage and functional outcome. PMID- 10090191 TI - Methodological issues in radiographic scoring methods in rheumatoid arthritis. AB - Radiographs are important endpoints in clinical trials in rheumatoid arthritis (RA). Several scoring methods exist. However, many methodological issues are unsolved and require more attention. The following issues will be addressed: the abnormalities that should be scored; joints that should be included in a scoring method; whether both right and left hands and feet should be scored; views that should be used; the order in which radiographs should be scored; how data should be evaluated; how intra/interobserver variation and sensitivity to change should be assessed; the optimum number of readers to assess radiographs; the score to be used if there are multiple readers; quality assurance, international training, a validation set of radiographs, and automated scoring of radiographs. PMID- 10090192 TI - Smallest detectable difference in radiological progression. AB - Omeract IV started a discussion on the development of radiological response criteria in rheumatoid arthritis (RA). Such criteria depend on the definition of what constitutes the minimum clinically important progression of damage. Because such a definition is currently not available, as a first step we have used the concept of random measurement error to determine what is the smallest detectable difference (SDD) in radiological progression between 2 radiographs of a particular patient. Baseline and 12 month radiographs (hands, wrists, feet) of 52 patients representative of the spectrum of radiological progression were selected from a randomized controlled trial of early rheumatoid arthritis (COBRA study) and were read paired and chronologically by 2 observers using the van der Heijde modified Sharp method (0-448 scale) and another 2 observers using the Scott modified Larsen method (0-200). The measurement error of progression was determined using the metric 95% limits of agreement method of Bland and Altman. In the setting of early RA the SDD is 11 modified Sharp score units and 8 modified Larsen score units if there is an equal distribution of baseline damage and progression in the sample and the mean score of the same trained observers is always used. The SDD is 15.5 modified Sharp score units and 11 modified Larsen score units if there is an equal distribution of baseline damage and progression in the sample and the mean score of any 2 trained observers is used. Other SDD were determined depending on the context of measurement. Although this exercise needs repetition in other settings, the SDD is a useful starting point in the development of radiological response criteria. PMID- 10090193 TI - Introduction to reading radiographs by the Scott modification of the Larsen method. AB - To examine its ability to evaluate progressive radiological damage, the Scott modification of the Larsen score was used for the hands, wrists, and feet (metatarsophalangeal joints) at time zero and at 12 months in 52 patients with early rheumatoid arthritis taking part in a therapeutic intervention study. The major practical difficulty was the technical discrepancy between initial and followup films in some patients. The metrological problems are discussed in the analysis, which compares the score on the same films using the Sharp score. PMID- 10090194 TI - How to read radiographs according to the Sharp/van der Heijde method. AB - This article is a short overview of the development of the Sharp/van der Heijde method for scoring radiographs of hands and feet in rheumatoid arthritis, in addition to a detailed description on how to use the scoring method. PMID- 10090195 TI - A practical exercise in reading RA radiographs by the larsen and sharp methods. AB - A plenary radiograph reading session was conducted prior to the rheumatoid arthritis imaging group sessions to familiarize participants with radiograph scoring methods and their problems, and to introduce the concept of measurement error. After brief reviews on how to score radiographs using the Larsen and Sharp method, photographic slides of metacarpophalangeal joints of 2 patients were shown. Participants were asked to register their absolute scores on paper, and their progression scores on an interactive voting keypad, allowing immediate visualization of the results. The objectives of the session were clearly met, as evidenced by lively discussions in the groups. Participant mean scores agreed well with the expert scores. Sharp scores showed wider scatter between participants than Larsen scores. This was only partially explained by the greater score range inherent in the method. In addition, participants needed more time to score according to Sharp than Larsen. Participants were sensitized to the challenges of radiographic measurement of damage. PMID- 10090196 TI - Imaging in rheumatoid arthritis: results of group discussions. AB - None of the current scoring methods for radiological damage in rheumatoid arthritis (RA) is ideal. The objective for RA imaging at OMERACT IV was to start discussion about the problems and applicability of the current scoring methods for radiological damage and to start discussion on the challenge of new imaging techniques. The RA imaging module comprised preconference reading material, plenary sessions, small group discussions, and a plenary report of the group sessions, combined with interactive voting. The OMERACT filter guided the discussions. Priorities for further research in imaging studies were: (1) pathologies versus features on radiographs; (2) relation with longterm outcome; and (3) definition of minimum clinically important difference. PMID- 10090197 TI - Postmenopausal estrogen replacement therapy and risk of developing systemic lupus erythematosus or discoid lupus. PMID- 10090198 TI - Osteonecrosis and human immunodeficiency virus infection. PMID- 10090199 TI - Rheumatology training at the American University of Beirut. PMID- 10090200 TI - Achilles tendinitis in spondyloarthropathy. PMID- 10090201 TI - Incidence of postpartum onset of disease among patients with rheumatoid arthritis. PMID- 10090202 TI - Treatment of whiplash associated neck pain with botulinum toxin-A: report of 8 cases. PMID- 10090203 TI - Calcitonin and mandibular bone resorption in systemic sclerosis. PMID- 10090204 TI - Increased plasma adrenomedullin concentrations in patients with Raynaud's phenomenon. PMID- 10090205 TI - Persistent hiccups associated with intraarticular corticosteroid injection. PMID- 10090206 TI - Quality assessment of atomic force microscopy probes by scanning electron microscopy: correlation of tip structure with rendered images. AB - While image quality from instruments such as electron microscopes, light microscopes, and confocal laser scanning microscopes is mostly influenced by the alignment of optical train components, the atomic force microscope differs in that image quality is highly dependent upon a consumable component, the scanning probe. Although many types of scanning probes are commercially available, specific configurations and styles are generally recommended for specific applications. For instance, in our area of interest, tapping mode imaging of biological constituents in fluid, double ended, oxide-sharpened pyramidal silicon nitride probes are most often employed. These cantilevers contain four differently sized probes; thick- and thin-legged 100 microm long and thick- and thin-legged 200 microm long, with only one probe used per cantilever. In a recent investigation [Taatjes et al. (1997) Cell Biol. Int. 21:715-726], we used the scanning electron microscope to modify the oxide-sharpened pyramidal probe by creating an electron beam deposited tip with a higher aspect ratio than unmodified tips. Placing the probes in the scanning electron microscope for modification prompted us to begin to examine the probes for defects both before and after use with the atomic force microscope. The most frequently encountered defect was a mis-centered probe, or a probe hanging off the end of the cantilever. If we had difficulty imaging with a probe, we would examine the probe in the scanning electron microscope to determine if any defects were present, or if the tip had become contaminated during scanning. Moreover, we observed that electron beam deposited tips were blunted by the act of scanning a hard specimen, such as colloidal gold with the atomic force microscope. We also present a mathematical geometric model for deducing the interaction between an electron beam deposited tip and either a spherical or elliptical specimen. Examination of probes in the scanning electron microscope may assist in interpreting images generated by the atomic force microscope. PMID- 10090207 TI - How dry are dried samples? Water adsorption measured by STM. AB - When operating scanning probe microscopes, like STM or AFM, under ambient conditions, the presence of water on the sample and the tip always plays an important role. The water not only influences the structure of the sample itself, but also the imaging process; in the case of the STM using a wet etched w-tip, by interfering with the electron transfer process, and in the case of the AFM, due to the capillary forces in the micro Newton range that dominate the tip surface interaction forces. In this paper, the distribution and the amount of adsorbed water on different surfaces is investigated with the help of the STM, which can provide information by imaging and by current/distance spectroscopy. Hydrophilic and hydrophobic surfaces like titanium, gold, and graphite were studied at a relative humidity between 10 and 90%. Under very dry conditions with relative humidity below 15%, the presence of water was only detectable by the longer decay length of the measured current with distance compared to samples prepared in UHV completely free of water. At less dry conditions on gold surfaces, water was found as droplets. With increasing humidity, the quantity and the size of these droplets increased until the whole surface became covered with water. Above 55% humidity, the thickness of the water film increased with increasing humidity up to several 10 nm. On titanium and graphite, water was always present in the form of closed layers growing in thickness with increasing humidity. PMID- 10090208 TI - Microscopy for recognition of individual biomolecules. AB - One frontier challenge in microscopy and analytical chemistry is the analysis of soft matter at the single molecule level with biological systems as most complex examples. Towards this goal we have developed two novel microscopy methods. Both employ highly specific molecular recognition schemes used by nature-the recognition of specific protein sites by antibodies and ligands. One method uses fluorescence labeled ligands for detecting single molecules in fluid systems like membranes (Fig. 1B). Unitary signals are reliably resolved even for millisecond illumination periods. The knowledge of the unitary signal from single molecules permits the determination of stoichiometries of component association (Fig. 3). Direct imaging of the diffusional path of single molecules became possible for the first time (Fig. 4). Using linear polarized excitation, the angular orientation of single molecules can be analyzed (single molecule linear dichroism, (Fig. 5), which opens a new perspective for detecting conformational changes of single biomolecules. In the other method, an antibody is flexibly linked to the tip of an atomic-force microscope. This permits the identification of receptors in multi-component systems. Molecular mapping of biosurfaces and the study of molecular dynamics in the ms to s range become possible with atomic force microscopy. PMID- 10090209 TI - Imaging of collagen type III in fluid by atomic force microscopy. AB - Type III collagen is a component of the basement membrane of endothelial cells, and may play a role in the interaction between hemostatic system proteins and the basement membrane of blood vessels. To begin to investigate these structural interactions, we have imaged type III collagen in solution by atomic force microscopy. A 20 microg/ml solution of type III collagen in bicarbonate buffer (pH 9.5) from calf skin was deposited onto a freshly cleaved mica substrate. Atomic force microscopy images were acquired using a fluid cell and tapping mode with oxide-sharpened silicon nitride probes 2, 3, and 4 hours after deposition of the collagen onto the mica. Two-hour preparations displayed fibrillar networks with well-defined sites of nucleation and lateral growth. At 3 and 4 hour polymerizations, more mature fibrils of increasing lengths, diameters, and complexity were observed. Fibrils appeared to be aligning and twisting (helical formation) to form a mature fibril with a higher mass per unit area. Interestingly, the mature fibrils appeared larger centrally with tapered ends displaying declining slopes. These observations compare favorably with those previously published on collagen type I assembly [Gale et al. (1995) Biophys. J. 68:2124-2128]. High resolution atomic force microscopy images of type III collagen in solution should provide a template for observation of the interactions between basement membrane components and hemostatic system proteins present in cardiovascular disease. PMID- 10090210 TI - Heptameric structures of two alpha-hemolysin mutants imaged with in situ atomic force microscopy. AB - Atomic force microscopy has been used to study self-assembled structures of two alpha-hemolysin mutants. For a mutant (alphaHL-H5) that was locked into the prepore state on fluid phase egg-PC membranes, we visualized, for the first time, heptameric prepores and showed that the 7-fold axis in the prepore lies perpendicular to the membrane surface. For another mutant (TCM) with the transmembrane domain, the self-assembled oligomer that assumes the conformation of the fully assembled pore is also a heptamer. These results show that heptamers are the preferred oligomerization state of alpha-hemolysin. PMID- 10090211 TI - Salt-dependent chromosome viscoelasticity characterized by scanning force microscopy-based volume measurements. AB - Metaphase chromosomes prepared according to the standard spreading procedure exhibit viscoelastical behavior after rehydration. The salt-dependency of this elasticity was investigated using contact mode scanning force microscopy (SFM). Therefore, chromosomes were imaged in solutions of different ionic strength (0.3 x PBS and water). The elasticity was probed by stepwise increase of the loading force of the scanning tip, resulting in a set of images. The images were used for the determination of the height and the apparent volume of each chromosome, and these values were the base for a characterization of the viscoelastical response of the chromosomes under different salt conditions. Lower ionic strength resulted in a greater response of the chromosome structures to applied loading forces. PMID- 10090212 TI - Binding forces of hepatic microsomal and plasma membrane proteins in normal and pancreatitic rats: an AFM force spectroscopic study. AB - The docking and fusion of membrane-bound vesicles at the cell plasma membrane are brought about by several participating vesicle membrane, plasma membrane, and soluble cytosolic proteins. An understanding of the interactions between these participating proteins will provide an estimate of the potency and efficacy of secretory vesicle docking and fusion at the plasma membrane in cells of a given tissue. Earlier studies suggest that in chronic pancreatitis, glucose intolerance may be associated with impaired exocytosis/endocytosis of hepatic insulin receptor and glucose transporter proteins. In this study, the binding force profiles between microsome membrane proteins and plasma membrane proteins in liver obtained from normal and pancreatitic rats have been examined using atomic force microscopy. The ability of a VAMP-specific antibody to alter binding between microsome- and plasma membrane-associated membrane proteins was examined. In pancreatitic livers, a significant loss in microsome-plasma membrane binding is observed. Furthermore, our study shows that, in contrast to control livers, the microsome-plasma membrane binding in pancreatitic livers is VAMP-independent, which suggests an absence of VAMP participation in membrane-microsome binding. In confirmation with our earlier findings, these studies suggest altered membrane recycling in liver of rats with chronic pancreatitis. PMID- 10090213 TI - Investigation of protein partnerships using atomic force microscopy. AB - The origin of contrast in atomic force microscopy (AFM) lies in the probe's response to forces between itself and the sample. These forces most commonly result from changes in height as the tip is scanned over the surface, but can also originate in properties inherent in the sample. These have been exploited as further means of contrast and have spawned an array of similar imaging techniques, such as chemical force microscopy, magnetic force microscopy, and frictional force microscopy. All of these techniques use AFM as an extremely sensitive gauge to map forces at discrete sites on the surface. A natural extension of this approach is to map forces in an array, in order to create a force map. AFM can be used in aqueous or fluid environments, thus allowing the exploration of forces in biological systems under physiologically relevant conditions. By immobilizing one half of an interacting pair of proteins onto the tip and the other half onto the substrate, it is possible to investigate the electrostatic and hydrophobic interactions between them. We employed these techniques to examine the interaction between a pair of proteins of known affinity that are involved in exocytosis (NSF and alpha-SNAP) and separately to demonstrate how two-dimensional force mapping can be applied to the nuclear envelope to identify nuclear pore complexes. PMID- 10090214 TI - Three-dimensional high-resolution particle tracking for optical tweezers by forward scattered light. AB - A quadrant photodiode placed in the back-focal plane of the microscope of a laser trap provides a high-resolution position sensor. We show that in addition to the lateral displacement of a trapped sphere, its axial position can be measured by the ratio of the intensity of scattered laser light to the total amount of the light reaching the detector. The addition of the axial information offers true three-dimensional position detection in solution, creating, together with a position control, a photonic force microscope with nanometer spatial and microsecond temporal resolution. The measured position signals are explained as interference of the unscattered trapping laser beam with the laser light scattered by the trapped bead. Our model explains experimental data for trapped particles in the Rayleigh regime (radius a <0.2lambda) for displacements up to the focal dimensions. The cross-talk between the signals in the three directions is explained and it is shown that this cross-talk can be neglected for lateral displacements smaller than 75 nm and axial displacements below 150 nm. The advantages of three-dimensional single-particle tracking over conventional video tracking are shown through the example of the diffusion of the GPI-anchored membrane protein Thy1.1 on a neurite. PMID- 10090215 TI - Heterogeneous changes in electrophysiologic properties in the paroxysmal and chronically fibrillating human atrium. AB - INTRODUCTION: The regional changes in atrial electrophysiologic properties related to atrial fibrillation (AF) in patients with paroxysmal AF (PAF) and chronic AF (CAF) remain unclear. The purpose of this study was to investigate the regional changes in atrial electrophysiology in patients with AF. METHODS AND RESULTS: We evaluated the atrial electrophysiology at different sites (high right atrium, low right atrium [LRA], and distal coronary sinus [DCS]) in 11 patients with CAF, 8 patients with PAF, and 10 controls. Patients with CAF had significantly prolonged interatrial conduction and corrected sinus node recovery time, and shortened atrial effective refractory period (ERP) with loss of rate related adaptation in the DCS, but had paradoxic prolongation of atrial ERP in the LRA, as compared with patients with PAF and the controls. As a result, the spatial distribution of atrial ERP that was observed in the controls and in patients with PAF was reversed in patients with CAF, without an increase in the dispersion of atrial refractoriness. Patients with PAF showed intermediate changes in atrial conduction times and atrial refractoriness as compared with patients with CAF and controls. CONCLUSION: There was a regional heterogeneity on the changes of atrial electrophysiology in different parts of the atrium, and the "normal" spatial distribution of atrial refractoriness was reversed in patients with CAF. The electrophysiologic changes observed in patients with PAF appear to behave as if in transition from the control state to CAF, suggesting progressive changes in atrial electrophysiologic properties. PMID- 10090216 TI - Double multielectrode mapping catheters facilitate radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. AB - INTRODUCTION: Several reports have demonstrated that focal atrial fibrillation (AF) may arise from pulmonary veins (PVs). The purpose of this study was to investigate the safety and efficacy of using double multielectrode mapping catheters in ablation of focal AF. METHODS AND RESULTS: Forty-two patients (30 men, 12 women, age 65+/-14 years) with frequent attacks of paroxysmal AF were referred for catheter ablation. After atrial transseptal procedure, two long sheaths were put into the left atrium. Two decapolar catheters were put into the right superior PV (RSPV) and left superior PV (LSPV), or inferior PVs if necessary, guided by pulmonary venography. All the patients had spontaneous initiation of AF either during baseline (2 patients), after isoproterenol infusion (8 patients) or high-dose adenosine (2 patients), after short duration burst pacing under isoproterenol (14 patients), or after cardioversion of pacing induced AF (16 patients). The trigger points of AF were from the LSPV (12 patients), RSPV (8 patients), and both superior PVs (19 patients). The trigger points from PVs (total 61 points) were 18 (30%) in the ostium of PVs and 43 inside the PVs (9 to 40 mm). After 6+/-3 applications of radiofrequency energy, 57 of 61 triggers were completely eliminated, and the other 4 triggers were partially eliminated. During a follow-up period of 8+/-2 months, 37 patients (88%) were free of symptomatic AF without any antiarrhythmic drugs. Twenty patients received a transesophageal echocardiogram, and 19 showed small atrial septal defects (2.8+/-1.2 mm) with trivial shunt. Fifteen defects closed spontaneously 1 month later. CONCLUSION: The technique using double multielectrode mapping catheters is a relatively safe and highly effective method for mapping and ablation of focal AF originating from PVs. PMID- 10090217 TI - Efficacy and safety of the initial use of stability and onset criteria in implantable cardioverter defibrillators. AB - INTRODUCTION: Inappropriate therapies are the most frequent adverse event in patients with implantable cardioverter defibrillators (ICDs). Most ICDs offer a stability criterion to discriminate ventricular tachycardia (VT) from atrial fibrillation and an onset criterion to discriminate VT from sinus tachycardia. The efficacy and safety of these criteria, if used immediately after implantation, is unknown. METHODS AND RESULTS: In a case control study, 87 patients in whom stability and onset criteria had been activated immediately after ICD implantation were matched to 87 patients in whom these criteria had not been activated. The groups were matched for known predictors of inappropriate therapies. With stability and onset criteria off, 24 patients (28%) received inappropriate therapies due to atrial fibrillation (n = 14) or sinus tachycardia (n = 11); with stability and onset on, only 11 patients (13%) were treated by the ICD due to atrial fibrillation (n = 5) or sinus tachycardia (n = 7) (log rank: P = 0.029). Five patients suffered inappropriate therapies despite the fact that onset (n = 4) or stability (n = 1) criteria were not fulfilled once tachycardias continued for a prespecified duration. Only one patient experienced a failure to detect VT due to the onset criterion; none because of stability. CONCLUSION: The immediate use of stability and onset criteria after ICD implantation reduces inappropriate therapies due to atrial fibrillation and sinus tachycardia. Because of the potential for underdetection of VT, this approach should be limited to tachycardia rates hemodynamically tolerated by the patient. PMID- 10090218 TI - Sodium pentobarbital reduces transmural dispersion of repolarization and prevents torsades de Pointes in models of acquired and congenital long QT syndrome. AB - INTRODUCTION: Sodium pentobarbital is widely used for anesthesia in experimental studies as well as in clinics, and it is known to prevent the development of torsades de pointes (TdP) in in vivo models of the long QT syndrome (LQTS). METHODS AND RESULTS: This study examines the effects of pentobarbital on transmural dispersion of repolarization (TDR) and induction of TdP in arterially perfused canine left ventricular wedge preparations in which transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial regions using floating glass microelectrodes together with a transmural ECG. d Sotalol and ATX-II were used to mimic the LQT2 and LQT3 forms of congenital LQTS. Both d-sotalol (100 micromol/L, n = 6) and ATX-II (20 nmol/L, n = 6) preferentially prolonged the action potential duration (APD90) of the M cell, thus increasing in the QT interval and TDR, and leading to the development of spontaneous and stimulation-induced TdP. In the absence and presence of d sotalol, pentobarbital (10, 20, and 50 microg/mL) prolonged the APD90 of epicardial and endocardial cells, and, to a lesser extent, that of the M cell, thus prolonging the QT interval but reducing TDR. In the ATX-II model, the effects of pentobarbital on the QT interval and APD90 were biphasic: 10 microg/mL pentobarbital further prolonged APD90 of epicardial and endocardial cells more than that of the M cell; 20 to 50 microg/mL pentobarbital abbreviated the APD90 of epicardial and endocardial cells less than that of the M cell, thus abbreviating the QT interval and markedly reducing TDR. Twenty to 50 microg/mL pentobarbital totally suppressed spontaneous as well as stimulation-induced TdP in both models CONCLUSION: Our data indicate that pentobarbital reduces TDR in control and under conditions of congenital and acquired LQTS, and suggest that this mechanism may contribute to the ability of the anesthetic to prevent the development of spontaneous as well as stimulation-induced TdP under conditions mimicking LQT2, LQT3, and acquired (drug-induced) forms of the LQTS. The data also serve to illustrate that there are circumstances under which QT prolongation may not be arrhythmogenic. PMID- 10090219 TI - Tale of two (or three or more) cities. PMID- 10090220 TI - ECG of the "newborn" mouse (Mus domesticus) with specific reference to comparative AV transmission. AB - INTRODUCTION: The objective of this study was to record the ECG of the smallest living mammal to extend the domain of data for comparative AV nodal electrophysiologic purposes. These data are needed to establish the relationship between the PR interval and heart size in mammalian species of all sizes. METHODS AND RESULTS: In recently born mice (age 1.5 to 8 weeks) weighing between 2.5 and 10 g and with estimated heart weights between 15 and 60 mg, ECGs, using bipolar limb leads, were recorded during general anesthesia. The PR interval, representing AV transmission time was about 40 msec, which is quite long for hearts of this size. On the basis of detailed analysis of the data, we postulate the presence of a fixed delay or discontinuous propagation in the AV node not only in newborn mice, but in mammals of all sizes. CONCLUSION: AV transmission times obtained in mammals (including humans) cannot be explained on the basis of generally accepted, classic AV conduction theories. The acceptance of the presence of a fixed delay in the AV node may ultimately be of value to better understand AV node function during sinus rhythm and supraventricular arrhythmias. PMID- 10090221 TI - Functional origin of mammalian PR interval variations: a challenge for the 21st century. PMID- 10090222 TI - Pharmacologic cardioversion of chronic atrial fibrillation in the goat by class IA, IC, and III drugs: a comparison between hydroquinidine, cibenzoline, flecainide, and d-sotalol. AB - INTRODUCTION: Recently, we reported that repetitive induction of atrial fibrillation (AF) in the goat causes electrical remodeling of the atria leading to the development of sustained AF. The aim of the present study was to compare Class IA, IC, and III drugs in their ability to cardiovert chronic AF in remodeled atria. METHODS AND RESULTS: In 16 goats with sustained AF, hydroquinidine (HQ), cibenzoline (Ci), flecainide (FI), and d-sotalol (dS) were infused. HQ, Ci, Fl, and dS restored sinus rhythm (SR) in 83%, 91%, 67%, and 92% of the cases, while adverse drug effects occurred in 17%, 36%, 56%, and 8%. Prior to restoration of SR, AF cycle length prolonged by 68%, 103%, 53%, and 20%, respectively. The QRS width increased by 14%, 64%, and 58% (HQ, Ci, and Fl), and remained unchanged by administration of dS. RR intervals were slightly prolonged by HQ, Ci, and Fl, and markedly prolonged by dS (48%). The QT interval was moderately prolonged by HQ, Ci, and Fl, and considerably by dS (34%). QTc was only slightly prolonged by each of the drugs. Directly after cardioversion of AF, the atrial refractory period was 87+/-29 (HQ), 119+/-32 (Ci), 66+/-10 (Fl), and 73+/-18 msec (dS) (control: 146+/-18 msec). Atrial conduction velocity was 85+/ 6, 71+/-11, 86+/-12, and 110+/-11 cm/sec compared with a control value of 116+/ 10 cm/sec. Because directly after cardioversion the atrial wavelength was still very short (5.7 to 8.4 cm), the vulnerability for AF was still very high, and a single premature beat reinduced AF in 71% (Ci) to 100% (HQ, Fl, and dS) of the cases. CONCLUSION: In a goat model of sustained AF, Class IA, IC, and III drugs restored sinus rhythm in 67% to 92% of the cases. However, after cardioversion, the atrial wavelength was still abnormally short, and AF was readily inducible in 71% to 100% of the cases. PMID- 10090223 TI - Dynamic changes in electrogram morphology at functional lines of block in reentrant circuits during ventricular tachycardia in the infarcted canine heart: a new method to localize reentrant circuits from electrogram features using adaptive template matching. AB - INTRODUCTION: Fractionated, low-amplitude or long-duration electrograms have limited specificity for locating reentrant circuits causing ventricular tachycardia (VT). In this study a new method is described, adaptive template matching (ATM), based on the quantification of beat-to-beat changes in electrograms, for locating functional reentrant circuits that are relatively stable and cause monomorphic VT. METHODS AND RESULTS: Monomorphic VTs were induced in 4-day-old infarcted canine hearts by programmed stimulation and reentrant circuits mapped in the epicardial border zone with a 196 or 312 bipolar electrode array. For ATM analysis, a template electrogram from each electrode, during an early cycle, was matched with all subsequent (input) electrograms at the same site by weighting the inputs of amplitude, duration, average baseline, and phase lag. The mean square error (MSE) between template and input was the criterion used to adapt the weights, and was also a measure of changes in electrogram shape that occur from cycle to cycle. The variance of each of the weighting parameters at all electrode sites were plotted on a representation of the electrode array, and the location of the functional lines of block bounding the central common pathway of reentrant circuits with figure-of-eight characteristics, overlaid on the ATM map. Peaks of high variance were found to be coincident with functional lines of block during all tachycardia episodes. CONCLUSION: Specific beat-to-beat changes in electrograms occur at functional lines of block in reentrant circuits that can be quantified by ATM analysis, suggesting that these regions might be located without activation mapping. The method might be useful to guide ablation catheter position. PMID- 10090224 TI - ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs: insight into the mechanism of Brugada syndrome. AB - We evaluated two patients without previous episodes of syncope who showed characteristic ECG changes similar to Brugada syndrome following administration of Class IC drugs, flecainide and pilsicainide, but not following Class IA drugs. Patient 1 had frequent episodes of paroxysmal atrial fibrillation resistant to Class IA drugs. After treatment with flecainide, the ECG showed a marked ST elevation in leads V2 and V3, and the coved-type configuration of ST segment in lead V2. A signal-averaged ECG showed late potentials that became more prominent after flecainide. Pilsicainide, a Class IC drug, induced the same ST segment elevation as flecainide, but procainamide did not. Patient 2 also had frequent episodes of paroxysmal atrial fibrillation. Pilsicainide changed atrial fibrillation to atrial flutter with 2:1 ventricular response, and the ECG showed right bundle branch block and a marked coved-type ST elevation in leads V1 and V2. After termination of atrial flutter, ST segment elevation in leads V1 and V2 continued. In this patient, procainamide and quinidine did not induce this type of ECG change. In conclusion, strong Na channel blocking drugs induce ST segment elevation similar to Brugada syndrome even in patients without any history of syncope or ventricular fibrillation. PMID- 10090225 TI - Drug-induced J point elevation: a marker for genetic risk of sudden death or ECG curiosity? PMID- 10090226 TI - Left ventricular ischemia due to coronary stenosis as an unexpected treatable cause of paroxysmal atrial fibrillation. AB - We present a patient with exercise-induced paroxysmal atrial fibrillation who was eventually scheduled for a Cox-maze operation due to persistence of his complaints of fatigue, impaired exercise tolerance, and predominantly exercise related irregular palpitations despite treatment with several antiarrhythmic drugs. A preoperative exercise stress test without antiarrhythmic or negative chronotropic drugs, however, showed clear evidence of myocardial ischemia. After coronary angioplasty of a significant stenosis in the left anterior descending artery, there was no recurrence of atrial fibrillation during a follow-up of 7 months. PMID- 10090227 TI - Long-term (subacute) potassium treatment in congenital HERG-related long QT syndrome (LQTS2). AB - INTRODUCTION: Congenital long QT syndrome (LQTS) is subdivided according to the underlying gene defect. In LQTS2, an aberrant HERG gene that encodes the potassium channel IKr leads to insufficient IKr activity and delayed repolarization, causing ECG abnormalities and torsades de pointes (TdP). Increasing serum potassium levels by potassium infusion normalizes the ECG in LQTS2 because IKr activity varies with serum potassium levels. METHODS AND RESULTS: In an LQTS2 patient who presented with TdP, we attempted to achieve a long-term (subacute) elevation of serum potassium by increased potassium intake and potassium-sparing drugs. However, due to renal potassium homeostasis, it was impossible to achieve a long-lasting rise of serum potassium above 4.0 mmol/L. CONCLUSION: Although raising serum potassium reverses the ECG abnormalities in LQTS2, a long-lasting rise of serum potassium is only partially achievable because in the presence of normal renal function, potassium homeostasis limits the amount of serum potassium increase. PMID- 10090228 TI - Review of mechanisms by which electrical stimulation alters the transmembrane potential. AB - Electrical stimuli pace, cardiovert, or defibrillate the heart by changing transmembrane potential (deltaVm). Recent simulation studies provide insights into mechanisms by which stimuli establish deltaVm. This review attempts a nonmathematical description of these mechanisms. We start with the cable model in which the intracellular core conductor is bounded by a highly resistive and capacitive membrane that separates the intracellular and extracellular spaces. Intracellular and extracellular resistances are assumed to vary linearly with position. Although this model predicts anodal extracellular stimuli hyperpolarize adjacent tissue and cathodal extracellular stimuli depolarize that tissue, it fails to reproduce regions of opposite deltaVm distant from the electrodes. We then consider the sawtooth model in which microscopic discontinuities in intracellular resistance represent gap junctions. While model studies with such discontinuities demonstrate large deltaVm at cell ends, experimental validation of such deltaVm remains elusive. Extending the analysis to the two- and three dimensional syncytium, we also consider the bidomain model in which intracellular, extracellular, and interstitial currents are explicitly characterized. Differences in resistance to these currents gives rise to virtual electrodes, which are experimentally observed regions of large deltaVm that arise distant from the stimulating electrode. Distant deltaVm regions are also evident when macroscopic discontinuities in intracellular resistance are introduced into the bidomain model. Such discontinuities are associated with clefts or scars that give rise to "secondary sources." Albeit the cable model offers remarkable insight the bidomain model and the concept of secondary sources provide a more complete understanding of membrane excitation, especially when combined into a unifying activating function. PMID- 10090229 TI - The controversial M cell. AB - A recent publication by us has been interpreted by some as arguing against the existence and importance of M cells. We suppose this is the reason we have been asked to write this "controversy." Regrettably for the controversy, neither our work nor we deny the existence of M cells. Rather, we have confirmed, conceivably ad nauseum, that M cells do exist and contribute importantly to the expression of electrical activity in the intact myocardium. What controversy there is relates to (1) whether there is an inhomogeneous transmural gradient for ventricular repolarization in normal hearts, and (2) why the electrophysiologic properties of different myocardial sites differ so markedly at the level of the isolated tissue and single cell and yet become so much more homogenous in the intact ventricle. These issues are addressed on the following pages. PMID- 10090230 TI - Paroxysmal long RP tachycardia in a three year old: what is the rhythm? PMID- 10090231 TI - Aborted sudden cardiac death in hypertrophic cardiomyopathy. PMID- 10090232 TI - Noncontact mapping of diseased left ventricles in patients with abnormally activated regions. PMID- 10090233 TI - An overview of arrhythmias and antiarrhythmic approaches. AB - Although treatment of cardiac arrhythmias has been revolutionized in the past decade, patients with atrial fibrillation (AF) still represent a major challenge. With the graying of the population, AF is increasing in prevalence and is responsible for significant morbidity, mortality, and health care expenditures. Drug therapy will be required for the majority of patients with this disorder. Patients with ventricular tachyarrhythmias represent the other major challenge to the cardiac electrophysiologist. The use of implantable cardioverter defibrillators (ICDs) has reduced the sudden death mortality to 1% or less per year in patients at risk of dying from a ventricular tachyarrhythmia. Unfortunately, high-risk patients who receive an ICD are only a small proportion of the patients who die suddenly each year. Considering the number of at-risk patients, it is likely that drug therapy will remain the mainstay of treatment of patients with ventricular tachyarrhythmias. Therefore, the major challenge is to recognize patients at risk and treat them with antiarrhythmic drugs to prevent sudden cardiac death. Consequently, it has become clear that we have come to a crossroad with regard to antiarrhythmic drugs. Our knowledge of the molecular biology of cardiac ion channels, electrophysiology, and emerging antiarrhythmic drugs provides us an opportunity to create new pharmacologic stratagems. PMID- 10090234 TI - The molecular and ionic specificity of antiarrhythmic drug actions. AB - Virtually all clinical antiarrhythmic agents act by reducing ion channel conductance, with sodium (Na+), potassium (K+), and calcium (Ca++) channels the primary targets. Na+ channel blockers increase the risk of ischemic ventricular fibrillation and are relatively contraindicated in the presence of active coronary heart disease. Ca++ channel blockers suppress AV nodal conduction and are used to terminate reentrant supraventricular arrhythmias and control the ventricular response to atrial fibrillation. K+ channels constitute the most diverse group of cardiac ion channels. They are the primary targets of Class III antiarrhythmic drugs, the category of such agents presently undergoing the most active development. The rapid delayed rectifier, IKr, plays a key role in repolarization of all cardiac tissues and is the most common (and often only) target of action potential-prolonging drugs. Unfortunately, because of the ubiquity of IKr and the reverse use-dependent action potential prolongation that results from blocking it, IKr blockers are likely to cause torsades de pointes ventricular proarrhythmia. K+ channel blockers, such as amiodarone and azimilide, that affect the slow delayed rectifier IKs as well as IKr, appear to produce a more desirable rate-dependent profile of Class III action. Recently, much has been learned about the molecular basis of K+ channels based on their role in the congenital long QT syndrome. The availability of molecular clones that encode many of the channels in the human heart allows for the rapid screening of many potential new drugs, making possible the development of "designer" antiarrhythmic drugs with specific profiles of channel-blocking selectivity. PMID- 10090235 TI - Current antiarrhythmic drugs: an overview of mechanisms of action and potential clinical utility. AB - Reorientation in drug therapy to control cardiac arrhythmias continues to evolve in the wake of ongoing refinements in techniques and indications for radiofrequency ablation and the use of implantable devices for atrial and ventricular arrhythmias. The role of sodium channel blockers continues to be questioned, and data from clinical trials indicate that the use of this class of drugs should be limited to control symptoms in patients who have arrhythmias and either no or minimal heart disease. The decline in the use of sodium channel blockers has led to greater use of beta blockers and complex Class III agents, such as sotalol and amiodarone, as both primary therapy and adjunctive therapy with implantable defibrillators in patients with cardiac disease of varying degrees of ventricular dysfunction. Success with these Class III agents in the context of their side effects has led to the synthesis and characterization of compounds with simpler ion channel-blocking properties. The need for such compounds stemmed from the observation that atrial fibrillation (AF) as an arrhythmia is, for the most part, still not amenable to curative therapy by interventional procedures. The isolated block of the rapid component of the delayed rectifier current (IKr) has been found to have either a neutral (e.g., dofetilide) or deleterious (e.g., d-sotalol) effect on mortality in survivors of myocardial infarction. Thus, the objective of drug development should be the appropriate match between the substrate and an antiarrhythmic drug. The so-called pure Class III agents have been shown to have beneficial antifibrillatory effects in patients with AF. They are effective in inducing acute chemical conversion, preventing paroxysmal AF, and maintaining sinus rhythm in patients with persistent AF restored to sinus rhythm with DC cardioversion. AF is a complex arrhythmia, undoubtedly a result of multifaceted derangement of atrial ionic currents. Attention has therefore focused on newer compounds that have the propensity to block more than one ion channel. Examples of such agents are tedisamil and azimilide, the latter having been studied extensively in humans. It is the first of the Class III agents that block both components (IKr and IKs) of the delayed rectifier current, which results in a spectrum of electrophysiologic properties that includes lack of rate or use dependency in terms of effect on repolarization and refractoriness of atrial and ventricular myocardium. Available but unpublished clinical data indicate that azimilide may be effective over a wide range of tachycardia cycle lengths with a low incidence of torsades de pointes. In these respects, its properties, at least in terms of its use in AF, resemble those of amiodarone. However, the drug has little or no effect on AV conduction, which precludes the modulation of ventricular response in patients relapsing to AF. PMID- 10090236 TI - Predicting antiarrhythmic performance. AB - Antiarrhythmic therapy in the past was guided by observational studies. However, optimum patient care now demands evidence derived from large clinical trials. Unfortunately, because large-scale mortality trials are expensive and time consuming, surrogate markers were used in many clinical studies. However, the use of surrogate markers for antiarrhythmic drug efficacy was called into question after the publication of studies such as the Cardiac Arrhythmia Suppression Trial (CAST) and the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial. Currently, in order to predict antiarrhythmic performance, clinicians must rely on mortality trials for guidance in treating atrial and ventricular arrhythmias. Although the practicing physician has a large number of studies to draw from, the study design and patient population are critical variables that must be understood before trial results can be applied to patient care. This review focuses on the results of the major clinical antiarrhythmic drug trials published in the last 10 years. Patient variables (e.g., the presence or absence of structural heart disease) and problems in study design that may have affected outcome are emphasized as an aid to interpreting results of current and future clinical trials. PMID- 10090237 TI - What should we expect from the next generation of antiarrhythmic drugs? AB - Five drugs currently constitute approximately 70% of the world market for antiarrhythmic medications. Since the publication of studies documenting that certain Class I drugs may increase mortality in high-risk postinfarction patients, basic science and clinical studies have focused on Class III antiarrhythmic drugs. However, drugs that prolong repolarization and cardiac refractoriness are sometimes associated with potentially lethal torsades de pointes. Amiodarone, a multichannel blocker, may be the exception to this observation, but it nevertheless fails to reduce total mortality compared with placebo in high-risk patients following myocardial infarction. However, Class III agents remain the focus of drug development efforts because they lack the negative hemodynamic effects, affect both atrial and ventricular tissue, and can be administered as either parenteral or oral preparations. Developers of newer antiarrhythmic agents have focused on identifying antiarrhythmic medications with the following characteristics: appropriate modification of the arrhythmia substrate, suppression of arrhythmia triggers, efficacy in pathologic tissues and states, positive rate dependency, appropriate pharmacokinetics, equally effective oral and parenteral formulations, similar efficacy in arrhythmias and their surrogates, few side effects, positive frequency blocking actions, and cardiac selective ion channel blockade. New and investigational agents that more closely approach these goals include azimilide, dofetilide, dronedarone, ersentilide, ibutilide, tedisamil, and trecetilide. In the near future, medications will increasingly constitute only part of an antiarrhythmic strategy. Instead of monotherapy, they will often be used in conjunction with an implanted device. Combination therapy offers many potential advantages. Long-term goals of antiarrhythmic therapy include upstream approaches, such as identification of the biochemical intermediaries of the process and, eventually, of molecular and genetic lesions involved in arrhythmogenesis. PMID- 10090238 TI - pH-dependent stationary-phase acid resistance response of enterohemorrhagic Escherichia coli in the presence of various acidulants. AB - The effect of acidulant identity on the pH-dependent stationary-phase acid resistance response of enterohemorrhagic Escherichia coli was studied. Nine strains of E. coli (seven O157:H7, one O111:H-, and one biotype 1 reference strain) were cultured individually for 18 h at 37 degrees C in tryptic soy broth (TSB) plus 1% dextrose and in TSB without dextrose to yield acid resistance induced and noninduced stationary-phase cells, respectively. These cultures were then inoculated into brain heart infusion broth (BHI) supplemented with 0.5% citric, malic, lactic, or acetic acid and adjusted to pH 3.0 with HCl. The BHI tubes were incubated at 37 degrees C for up to 7 h and samples were removed after 0, 2, 5, and 7 h and plated for counting CFU on BHI agar and MacConkey agar (MA). The results were compared to data previously obtained with HCl only. Acid resistance varied substantially among the isolates, being dependent on the strain, the acidulant, and the induction of pH-dependent acid resistance. Hydrochloric acid was consistently the least damaging to cells; lactic acid was the most detrimental. The relative activity of the other acids was strain dependent. Inducing pH-dependent acid resistance increased the already substantial acid tolerance of stationary-phase E. coli. The extent of injury also varied with acid and strain, with as much as a 5-log-cycle differential between BHI agar and MA CFU counts. The accurate determination of the survival of enterohemorrhagic E. coli in acidic foods must take into account the biological variability of the microorganism with respect to its acid resistance and its ability to enhance survival through the induction of physiological stress responses. PMID- 10090239 TI - Effects of pH and acid resistance on the radiation resistance of enterohemorrhagic Escherichia coli. AB - The effects of pH and the induction of pH-dependent stationary-phase acid resistance on the radiation resistance of Escherichia coli were determined for seven enterohemorrhagic strains and one nonenterohemorrhagic strain. The isolates were grown in acidogenic or nonacidogenic media to pH levels of approximately 4.7 and 7.2, respectively. The cells were then transferred to brain heart infusion (BHI) broth adjusted to pH 4.0, 4.5, 5.0, and 5.5 (with HCl) that was preequilibrated to 2 degrees C, and cultures were then irradiated using a 137Cs source. Surviving cells and the extent of injury were determined by plating on BHI and MacConkey agars both immediately after irradiation and after subsequent storage at 2 degrees C for 7 days. Decreasing the pH of the BHI in which E. coli was irradiated had relatively little effect on the microorganism's radiation resistance. Substantial differences in radiation resistance were noted among strains, and induction of acid resistance consistently increased radiation resistance. Comparison of E. coli levels immediately after irradiation and after 7 days of refrigerated storage suggested that irradiation enhanced pH-mediated inactivation of the pathogen. These results demonstrate that prior growth under conditions that induce a pH-dependent stationary phase cross-protects E. coli against radiation inactivation and must be taken into account when determining the microorganism's irradiation D value. PMID- 10090240 TI - Inhibitory effects of competitive exclusion and fructooligosaccharide, singly and in combination, on Salmonella colonization of chicks. AB - The inhibitory effects of competitive exclusion (CE) and 0.1% concentration of fructooligosaccharide (FOS), singly and in combination, on Salmonella colonization of chicks were investigated. Moreover, quantitation of the major cecal flora (Bifidobacterium, Bacteroides, Lactobacillus, and Escherichia coli) was performed. One-day-old birds were divided into four groups: (i) control, (ii) CE, (iii) FOS, and (iv) CE plus FOS. Chicks received Salmonella Enteritidis at 7 days (experiment 1) or 21 days (experiment 2). Birds in each group were killed at 1 day, 7 days, and 14 days after inoculation of Salmonella Enteritidis for count of salmonella in cecal contents. In experiment 1, the mean number of Salmonella Enteritidis in the chicks inoculated with CE was significantly decreased compared with the other three groups at 1 day postinoculation. In experiment 2, the mean numbers of Salmonella Enteritidis in the chicks of the FOS group and the FOS plus CE group were significantly decreased compared with the control group at 1 day and 7 days postinoculation. On 7- and 21-day-old chicks, few changes on number of total bacteria, Bifidobacterium, Bacteroides, Lactobacillus, and E. coli were observed in the cecal contents of treated groups compared with the control group. Low-dose feeding of FOS in the diet of chicks with a CE treatment may result in reduced susceptibility to Salmonella colonization but may not lead to a shift in the intestinal gut microflora on 7- and 21-day-old chicks. PMID- 10090241 TI - Extent of beef carcass contamination with Escherichia coli and probabilities of passing U.S. regulatory criteria. AB - In the 1996 U.S. Meat and Poultry Inspection Regulations, Escherichia coli biotype I counts were included as "performance criteria" of the slaughtering process. The criteria were based on a three-class attributes sampling plan applied in a moving window. The values for m and M and c and n were set at 5 and 100 CFU/cm2, and 3 and 13 samples, respectively, for beef carcasses after overnight chilling following slaughter. In this study, beef carcasses were analyzed for counts of E. coli, and the results were expressed according to the above criteria. Furthermore, probabilities of passing E. coli performance criteria were determined. Carcasses were sampled in seven slaughtering plants (four steer and heifer; three cow and bull), during two seasons, and at three plant locations (pre-evisceration, after final carcass washing, and after 24 h of carcass chilling). Each entire carcass sample (100 cm2 from the brisket, flank, and rump) was analyzed individually for E. coli counts. Compared with the regulation, which set the value of m and the acceptable range based on the 80th percentile of E. coli contamination data from U. S. Food Safety and Inspection Service nationwide baseline studies, our results showed that, on the average and depending on plant and season, 84.2 to 100% of the chilled carcass samples were in the acceptable range. The average percentages of chilled samples in the unacceptable range, set at the 98th percentile, were 0 to 6.7%. Depending on plant and season, the overall probabilities of chilled carcasses passing the regulatory requirement were 0.597 to 1.0 (brisket), 0.471 to 1.0 (flank), and 0.485 to 1.0 (rump). The results indicated substantial variation among plants and between seasons in ability to meet the E. coli performance criteria. PMID- 10090242 TI - Antibacterial activity of shrimp chitosan against Escherichia coli. AB - The effects of cell age, reaction temperature, pH value, and salts on the inhibitory activity of shrimp chitosan (98% deacetylated) against Escherichia coli were investigated. The age of a bacterial culture affected its susceptibility to chitosan, with cells in the late exponential phase being most sensitive to chitosan. Higher temperature (25 and 37 degrees C) and acidic pH increased the bactericidal effects of chitosan. Sodium ions (100 mM Na+) might complex with chitosan and accordingly reduce chitosan's activity against E. coli. Divalent cations at concentrations of 10 and 25 mM reduced the antibacterial activity of chitosan, in the order of Ba2+ > Ca2+ > Mg2+. Chitosan also caused leakage of glucose and lactate dehydrogenase from E. coli cells. These data support the hypothesis that the mechanism of chitosan antibacterial action involves a cross-linkage between the polycations of chitosan and the anions on the bacterial surface that changes the membrane permeability. PMID- 10090243 TI - Isolation and detection of Listeria monocytogenes using fluorogenic and chromogenic substrates for phosphatidylinositol-specific phospholipase C. AB - The BCM Listeria monocytogenes detection system (LMDS) consists of a selective preenrichment broth (LMPEB), selective enrichment broth (LMSEB), selective/differential plating medium (LMPM), and identification on a confirmatory plating medium (LMCM). The efficacy of the BCM LMDS was determined using pure cultures and naturally and artificially contaminated environmental sponges. The BCM LMPEB allowed the growth of Listeria and resuscitation of heat injured L. monocytogenes. The BCM LMSEB, which contains the fluorogenic substrate 4-methylumbelliferyl-myo-inositol-1-phosphate and detects phosphatidylinositol phospholipase C (PI-PLC) activity, provided a presumptive positive test for the presence of pathogenic Listeria (L. monocytogenes and L. ivanovii) after 24 h at 35 degrees C. An initial inoculum of 10 to 100 CFU/ml of L. monocytogenes in BCM LMSEB yielded a fluorogenic response after 24 h. On BCM LMPM, L. monocytogenes and L. ivanovii were the two Listeria species forming turquoise convex colonies (1.0 to 2.5 mm in diameter) from PI-PLC activity on the chromogenic substrate, 5 bromo-4-chloro-3-indoxyl-myo-inositol-1-phosphate. L. monocytogenes was distinguished from L. ivanovii by either its fluorescence on BCM LMCM or acid production from rhamnose. False-positive organisms (Bacillus cereus, Staphylococcus aureus, Bacillus thuringiensis, and yeasts) were eliminated by at least one of the media in the BCM LMDS. Using a pure culture system, the BCM LMDS detected one to two L. monocytogenes cells from a sponge rehydrated in 10 ml of DE neutralizing broth. In an analysis of 162 environmental sponges from facilities inspected by the U.S. Department of Agriculture (USDA), the values for identification of L. monocytogenes by BCM LMDS and the USDA method were 30 and 14 sites, respectively, with sensitivity and specificity values of 85.7 and 100.0% versus 40.0 and 66.1%, respectively. No false-positive organisms were isolated by BCM LMDS, whereas 26.5% of the sponges tested by the USDA method produced false positive results. PMID- 10090244 TI - Lactobacilli isolated from chicken intestines: potential use as probiotics. AB - Lactobacillus strains were tested for their in vitro probiotic properties. Cell surface hydrophobicity was found to be very high for Lactobacillus fermentum subsp. cellobiosus and Salmonella Gallinarum; high values could indicate a greater ability to adhere to epithelial cells. Studies on Lactobacillus animalis indicated relative cell surface hydrophobicities smaller than those of L. fermentum subsp. cellobiosus and L. fermentum. L. animalis and Enterococcus faecalis were able to coaggregate with L. fermentum subsp. cellobiosus and L. fermentum, respectively, but not with Salmonella Gallinarum. After mixed-culture studies for determining suitable growth behavior, the pair of strains L. animalis plus L. fermentum subsp. cellobiosus was selected for an attempted challenge against Salmonella Gallinarum. Double and triple mixed-culture studies indicated that selected lactobacillus strains were able to retain their beneficial characteristics in the presence of Salmonella Gallinarum such as presence of lectins, production of antimicrobial compounds, and ability to grow and compete. The selected microorganisms can be considered as potential ingredients for a chicken probiotic feed formulation intended to control salmonellosis and also improve poultry sanitation. PMID- 10090245 TI - Application of reuterin produced by Lactobacillus reuteri 12002 for meat decontamination and preservation. AB - Lactobacillus reuteri strain 12002 was used for reuterin production in the two step fermentation process. A batch culture fermentation was used to produce a maximum biomass of L. reuteri. Then cells were harvested, resuspended in a glycerol-water solution, and anaerobically incubated to produce reuterin. The lyophilized supernatants (approximately 4000 activity units (AU) of reuterin per ml) were diluted in distilled water for decontamination and preservation trials. The MIC values of reuterin for Escherichia coli O157:H7 and Listeria monocytogenes were 4 and 8 AU/ml, respectively. In meat decontamination experiments, the surface of cooked pork was inoculated with either L. monocytogenes or E. coli O157:H7 at a level of approximately log10 5 CFU/cm2, incubated for 30 min at 7 degrees C, and decontaminated by exposure to reuterin (500 AU/ml). The bactericidal effect of reuterin was analyzed 15 s and 24 h after exposure at 7 degrees C. After 15 s of exposure to reuterin, viable numbers decreased by 0.45 and 0.3 log10 CFU/cm2 for E. coli O157:H7 and L. monocytogenes, respectively. After 24 h the numbers decreased by 2.7 log10 CFU/cm2 for E. coli O157:H7 and by 0.63 log10 CFU/cm2 for L. monocytogenes. In the same experiment, the combined effect of reuterin and lactic acid was also investigated. Adding lactic acid (5%, vol/vol) to reuterin significantly enhanced (P < or = 0.05) the efficacy of reuterin. No additional effect (P < or = 0.05) was found when ethanol (40%) was added to the mixture of reuterin and lactic acid. To evaluate the preservative effect of reuterin during meat storage, reuterin was added to raw ground pork contaminated with E. coli O157:H7 or L. monocytogenes. Reuterin at a concentration of 100 AU/g resulted in a 5.0-log10 reduction of the viability of E. coli O157:H7 after 1 day of storage at 7 degrees C. Reuterin at a concentration of 250 AU/g reduced the number of the viable cells of L. monocytogenes by log10 3.0 cycles after 1 week of storage at 7 degrees C. PMID- 10090246 TI - Efficacy of oxonia active against selected spore formers. AB - Alternatives to hydrogen peroxide are being sought for use in aseptic packaging systems because this sterilant is efficacious at temperatures higher than some of the newer packaging materials can tolerate. Earlier in this century, peracetic acid was known to be bactericidal, sporicidal, and virucidal but was not widely used because of handling, toxicity, and stability problems. Sanitizer suppliers have capitalized on the efficacy of hydrogen peroxide, acetic acid, and peracetic acid stabilized with a sequestering agent. Formulations have been improved and marketed as Oxonia Active, and its use as an alternative sterilant to hydrogen peroxide merits evaluation. Oxonia was assessed at a concentration of 2% and a temperature of 40 degrees C against a number of spore-forming organisms, including foodborne pathogens. Spores tested in aqueous suspension showed an order of sensitivity (least to greatest) to Oxonia as follows: Bacillus cereus > B. subtilis A > B. stearothermophilus > B. subtilis var. globigii > B. coagulans > Clostridium sporogenes (PA3679) > C. butyricum > C. botulinum type B (nonproteolytic) > C. botulinum type B (proteolytic) = C. botulinum type A = C. botulinum type E. B. subtilis A and B. stearothermophilus spores tested in the dry state were less sensitive to Oxonia than when tested in aqueous suspension. B. cereus, a foodborne pathogen, proved to be markedly less sensitive to Oxonia under the described test conditions. The decreased sensitivity to Oxonia by the foodborne pathogen B. cereus raises concern about the efficacy of the sterilant for aseptic packaging of low-acid foods. Further work will be needed to determine if this decreased sensitivity is an inherent property of the organism that affords unusual protection against Oxonia or if the challenge parameters selected were at the minimum conditions for efficacy. PMID- 10090247 TI - Development of an integrated procedure for the detection of central nervous tissue in meat products using cholesterol and neuron-specific enolase as markers. AB - The emergence of a new variant of Creutzfeldt-Jakob disease during the bovine spongiform encephalopathy epidemic has focused attention on the use of tissue from the central nervous system (CNS) in food. So far, the banning of CNS tissue could not be effectively controlled because procedures for detection were missing. With regard to preventive health protection and labeling law enforcement, we have developed an integrated procedure for the detection of CNS tissue in meat products. Herein, we show that antigenic characteristics of neuron specific enolase (NSE) quantitatively survive technological treatment including severe homogenization and pressure heating. Using both poly- and monoclonal antibodies against NSE in the Western blot, bovine and porcine brain could be detected in sausages, albeit with varying sensitivity (1 to 4%). Sensitivity was increased after reduction of fat content (30 to 40%) of the samples by means of a soxhlet extraction. This made possible the detection of brain addition as low as 0.25% when using monoclonal antibodies. Immunohistology showed distribution of CNS tissue in heat-treated meat products to be homogeneous. Immunoreaction was not found to be bound to morphologically intact histological or cytological structures; however, it proved to be highly specific. The quantification of cholesterol provides a low-cost screening method for the rapid identification of meat products, suspicious with regard to CNS tissue addition. Cholesterol content increased by 26 mg per 100 g of fresh substance for each percentage of brain added to internally produced reference material. Using three different approaches (internal reference material, raw material, and field samples), a provisional cutoff point of normal cholesterol content was calculated for emulsion-type cooked sausages to be 115 mg/100 g (P < 0.05). PMID- 10090248 TI - Inactivation of Escherichia coli O157:H7 in orange juice using a combination of high pressure and mild heat. AB - The effect of high pressure on the survival of a pressure-resistant strain of Escherichia coli O157:H7 (NCTC 12079) in orange juice was investigated over the pH range 3.4 to 5.0. The pH of commercial, sterile orange juice was adjusted to 3.4, 3.6, 3.9, 4.5, or 5.0. The juice was then inoculated with 10(8) CFU ml(-1) of E. coli O157:H7. The inoculated orange juice was subjected to pressure treatments of 400, 500, or 550 MPa at 20 degrees C or 30 degrees C to determine the conditions that would give a 6-log10 inactivation of E. coli O157:H7. A pressure treatment of 550 MPa for 5 min at 20 degrees C produced this level of kill at pH 3.4, 3.6, 3.9, and 4.5 but not at pH 5.0. Combining pressure treatment with mild heat (30 degrees C) did result in a 6-log10 inactivation at pH 5.0. Thus, the processing conditions (temperature and time) must be considered when pressure-treating orange juice to ensure microbiological safety. PMID- 10090249 TI - Combination spray washes of saponin with water or acetic acid to reduce aerobic and pathogenic bacteria on lean beef surfaces. AB - Saponins are naturally occurring compounds known as triterpenoid glycosides found in a variety of plant species. Saponins are approved for use in the food industry as foaming agents. When combined with water or organic acid in spray treatments, saponins' foaming property may improve carcass decontamination. In the first experiment of this study, lean beef carcass surfaces were experimentally inoculated with a fecal slurry containing antibiotic-resistant Escherichia coli O157:H7 and Salmonella Typhimurium. Spray-washing treatments with 1% saponin followed by a water wash, or 1% saponin followed by 2% acetic acid, were more effective for reducing aerobic bacteria than saponin, water, or 2% acetic acid washes alone. However, 1% saponin followed by a either a water or 2% acetic acid wash was no more effective than a 2% acetic acid wash for reducing populations of E. coli O157:H7 or Salmonella Typhimurium. In the second experiment, experimentally inoculated beef surfaces were subjected to spray treatments with water followed by another water wash, water followed by a 2% acetic acid wash, 1% saponin followed by a water wash, or 1% saponin followed by a 2% acetic acid wash. When examined for effectiveness against all bacterial populations, 1% saponin followed by a water wash and 1% saponin followed by a 2% acetic acid wash were as effective as two water washes or a water wash followed by 2% acetic acid for reducing aerobic bacteria, E. coli O157:H7, and Salmonella Typhimurium from beef surfaces. Under the conditions described, reductions associated with combination spray washes may be attributed to the physical removal of bacteria during the spraying process, not to any specific action of saponin. PMID- 10090250 TI - Broiler skin sampling for optimum recovery of Salmonella spp. AB - The objective of this research was to determine the appropriate sample size (1, 5, or 10 g) and location (neck, breast, or vent) from which to sample processed poultry skin for Salmonella spp. Postkill, prescald broiler carcasses were used to help ensure that Salmonella spp. would be found. Mean Salmonella spp. counts from skin samples of 1 g (2.91 log10 CFU/g) were significantly lower (P < 0.05) than skin samples of 5 and 10 g: 3.52 log10 CFU/g and 3.42 log10 CFU/g, respectively. Mean Salmonella spp. counts from breast (3.62 log10 CFU/g) or neck (3.40 log10 CFU/g) skin samples were significantly higher (P < 0.05) than counts from vent skin samples (2.84 log10 CFU/g). Neck skin is the preferred sampling location because it contained a representative number of Salmonella spp., it had a slightly higher incidence of Salmonella spp. than vent skin, and removal of neck skin for microbiological testing did not decrease the quality grade of the bird, as would the removal of breast skin. Research results will increase the accuracy and precision of the microbiological analytical procedures for processed poultry by providing guidelines for the amount and location of skin to be sampled, as well as the preparatory procedures involved to release the Salmonella spp. from the skin samples. PMID- 10090251 TI - Effects of lactic acid bacteria ingestion of basal cytokine mRNA and immunoglobulin levels in the mouse. AB - An increasing number of functional foods and pharmaceutical preparations containing lactic acid bacteria are being promoted with health claims based on the potential probiotic characteristics and on their capacity for stimulating the host immune system. However, the specific immune effects of oral administration of these microbes remain undefined. In this study, we tested the hypothesis that basal gastrointestinal immune status in mice is affected by orally administered lactic acid bacteria. The specific objective of this research was to evaluate the effects of repeated oral exposure to viable and nonviable lactic acid bacteria (Lactobacillus acidophilus, L. bulgaricus, L. casei, and Streptococcus thermophilus) in mice on basal cytokine mRNA expression in mucosal (Peyer's patches), systemic (spleen), and lymphoid tissue and on immunoglobulin levels. The results indicated that oral exposure to 10(9) CFU/day for up to 14 days did not significantly affect basal interferon-gamma, tumor necrosis factor-alpha, or interleukin-6 mRNA expression or total serum and intestinal immunoglobulins. PMID- 10090252 TI - Natural and in vitro coproduction of cyclopiazonic acid and aflatoxins. AB - Eighty samples of animal feeds of different origins were screened for the natural co-occurrence of cyclopiazonic acid (CPA) and aflatoxins in Portugal. Forty-five strains of Aspergillus flavus were collected from those samples and studied for their ability to produce these mycotoxins, in vitro. CPA was detected by thin layer chromatography using Erhlich's reagent for confirmation. Aflatoxins were determined by high-pressure liquid chromatography with postcolumn iodination. Only 5 of the 80 samples (6.2%) were naturally contaminated with cyclopiazonic acid (0.16 mg/kg) and 36 (45.0%) with aflatoxin B1 (AFB1) (from 0.001 to 0.016 mg/kg). An in vitro study of the 45 strains of A. flavus was performed in cracked corn at 25 degrees C (water activity, a(w) = 0.96), incubated for 21 days to CPA production. For in vitro production of aflatoxins, the same substrate was incubated at 28 degrees C for 14 days. Nineteen of the strains (42.2%) produced CPA (ranging from 0.5 to 1.45 mg of CPA/kg) and 23 of them (51.1%) produced AFB1 (from 0.001 to 0.844 mg/kg). Only 10 isolates (22.2%) produced both CPA and AFB1 (0.05 to 0.10 mg/kg and 0.001 to 0.230 mg/kg, respectively). Thirteen strains did not produce either CPA nor AFB1. PMID- 10090253 TI - Distribution of antifungal proteins in maize kernel tissues using immunochemistry. AB - This study examined the distribution of two antifungal proteins, ribosome inactivating protein (RIP) and zeamatin, in maize kernel tissues. Proteins were extracted from endosperm (including aleurone layer) and embryo tissues of imbibed maize kernels. Western blot analyses revealed that RIP-like protein was present at higher levels in endosperm than in embryo tissues, whereas zeamatin-like protein was more concentrated in embryo tissues than in endosperm tissues. However, there were three protein bands in the endosperm and two bands in the embryo that reacted to anti-RIP antibody in Western blot analyses. Tissue prints were conducted to localize the antifungal proteins. Imbibed kernels were cut longitudinally and transversely and blotted onto nitrocellulose membranes. Using antibodies against maize RIP and zeamatin, RIP was found primarily in the aleurone layer of the endosperm and glandular layer of scutellum, whereas zeamatin was located mainly in the kernel embryo. These results provide insight into the potential functions of these antifungal proteins, especially since the presence of RIP and zeamatin within maize kernels uniquely protects kernels from pathogens. PMID- 10090254 TI - Discounted expressions of traits in broiler breeding programs. AB - The commercially grown broiler usually is a crossbred from specialized purebred sire and dam lines. The position of a purebred line in the crossbreeding system influences its genetic contribution to expression of productive and reproductive performance at different stages of the production column and, thus, influences the breeding goal for a given line. In broiler breeding, cumulative discounted expressions (CDE) should be considered to define breeding goals for multi-trait selection. In the present study, a systematic design for the application of discounted gene flow methodology to derive CDE for production and reproduction traits in broiler breeding was developed. Factors considered as influencing the magnitude of CDE were: crossbreeding system (two-way, three-way, and four-way cross), selection scheme (with and without progeny testing and intensity of selection), selection path, trait (production at commercial stage and reproduction at either nucleus or multiplier stage), interest rate, and time horizon for evaluation. Performance data from a commercial breeding stock were applied in the analysis. Results indicated that levels of CDE were significantly affected by all factors studied. The more that pure lines were included in the crossbreeding system, the lower the CDE for a particular selection path. However, the summation of all selection paths did not differ much among crossbreeding systems. Progeny testing decreased CDE by increasing generation intervals. The CDE for reproduction traits were higher than those for production traits mainly as a result of earlier expression of the reproduction traits. PMID- 10090255 TI - Patterns of growth and feed intake in divergent lines of laying domestic fowl selected for residual feed consumption. AB - At Generations 15 (males) and 18 (females) of a divergent selection experiment on residual feed consumption (RFC) in laying poultry, patterns of growth, feed consumption, and associated traits were monitored between the ages of 4 and 34 wk. This monitoring was done to determine how the well-established RFC and feed intake (FI) divergences between adults of the low intake R- line and of the high intake R+ line took place, in relation to the evolution of correlated traits. In males and females, BW and BW gain were higher in the R- line in the first weeks of test, but patterns of BW were quite similar in both lines afterwards. However, R- hens remained heavier than R+ females to the end of the experiment. Line difference for BW was achieved by 28 wk of age, at 2,974 and 2,094 g, and the R- line was then 135 and 133 g heavier, respectively, for males and females. After a fast initial increase in both sexes, FI diverged quickly around 16 to 18 wk of age (sexual maturity), to attain 13 g/d in males and 28 g/d in females, well before the end of the experiment. At the same time, a divergence was observed for wattle length, which was 21% higher in R+ females. Residual feed consumption gradually diverged in the two lines, and the difference became significant at 14 wk of age. At the same age, shanks were 8% longer in R+ hens. Finally, levels of triiodothyronine decreased faster in the R- line, as FI divergence was increasing. These results indicate that the RFC difference between R- and R+, lines obtained in adult birds by divergent selection lines, starts somewhat early in life. In addition, the RFC difference appears to be associated with specific growth periods, around 14 wk and 18 to 20 wk. It is at this time that large differences appear in morphological traits involved in body heat loss. No significant correlations were found between early (6 wk) measures of FI, feed efficiency, and RFC, with adult values (32 to 34 wk) for RFC and FI. PMID- 10090256 TI - Effects on commercial broiler chicks of constant exposure to ultraviolet light from insect traps. AB - Constant exposure of newly hatched Avian x Avian broilers to ultraviolet light from insect traps for 42 d resulted in no significant differences in mortality, weight gain, feed consumption, or feed conversion. Birds were exposed to greater intensities of ultraviolet light for longer periods than could be expected under commercial conditions. Although house flies are rarely a problem in broiler houses, our results indicate that insect traps with ultraviolet light as an attractant would not be detrimental to production of broilers. The need for additional testing of light traps for nuisance fly control in commercial broiler houses is discussed. PMID- 10090257 TI - Tryptophan methylester modulation of poult responses to Bordetella avium. AB - On the day of hatching, four groups of poults [Control, L-tryptophan methylester (LTME), Bordetella avium-infected, and B. avium-infected plus LTME] were established and placed into heated metal brooding batteries. Bordetella avium infection caused a significant depression in body temperature within 24 h after intranasal challenge with the W strain, and the hypothermia persisted through 21 d of age. L-Tryptophan methylester, a water-soluble form of tryptophan, was given by oral gavage daily in saline at a concentration of 50 mg per poult beginning 4 d after hatch. Within 2 d after initiation of LTME treatments, colonic temperature of B. avium-infected poults was elevated to the level of Controls and remained at that level throughout the experimental period. The BW of B. avium infected poults were reduced significantly. The LTME treatment caused a significant BW increase in the B. avium-infected poults, but the increase was not to the level of Controls. The anti-sheep red blood cell antibody titers in B. avium-infected poults were not affected significantly. However, LTME treatment induced a significant increase in anti-sheep red blood cell antibody titers in both the infected and Control poults. Based upon data reported herein, it was concluded that feed intake depression associated with development of bordetellosis caused the poults to react more specifically to a mild tryptophan deficiency than to other nutrient deficiencies. The tryptophan deficiency caused a growth depression that was only partially alleviated by daily supplementation of LTME. The physiological responses to daily supplementation of LTME to B. avium infected poults suggested that growth depression and poor performance was not limited to dietary deficiency of tryptophan. PMID- 10090258 TI - The effect of photoperiod:scotoperiod on leg weakness in broiler chickens. AB - Four trials were conducted to investigate whether manipulations of photoperiod:scotoperiod affected the prevalence of leg weakness in broiler chickens. Modified photoperiods were applied from 3 until 21 d of age, followed by gradual or immediate return to 23 h light. The photoperiods tested were 8, 16, 21, and 23 h light. Leg weakness was assessed by measuring walking ability by gait scoring (GS) and tibial dyschondroplasia by x-ray (TD). Foot burn, hock burn, angulation of the hock joint, and BW were also measured. In total, 4,640 birds were assessed. The responses of the birds across the four trials were consistent. Increased photoperiod was associated with increased BW and prevalence of TD. There was no clear relationship between photoperiod and GS but foot pad burns were reduced by longer photoperiod. When the data were adjusted for differences in BW, increased photoperiod was associated with increased prevalence of TD, better walking ability (GS), and fewer hock and foot pad burns. Strong correlations were found between GS and live weight, and weak correlations with hock burn and TD. Tibial dyschondroplasia was weakly correlated with BW. The linear regressions of GS on live weight, within sex, across trials, were not different, but there was a difference between sexes, with males having a higher intercept but lower slope than females. It was concluded that shorter photoperiod affected walking ability and TD, but that these effects were largely a result of BW. PMID- 10090259 TI - Oxytetracycline transfer into chicken egg yolk or albumen. AB - This study was conducted to determine whether the approved doses of oxytetracycline (OTC) for breeder hens and meat-type poultry would produce drug residue transfer into egg components when fed to laying hens. Twenty hens were assigned to equal groups (n = 10) and fed either 50 or 200 g/ton OTC for 5 d. Oxytetracycline concentrations in egg components were determined daily during a 2 d pretreatment control period, the 5-d dosing period, and following drug withdrawal. The stability and drug content of the medicated feed were determined the day dosing was started and the day of withdrawal. Residues of OTC were not detectable during the predosing, dosing, or withdrawal period in egg yolks. Oxytetracycline residues were detectable, however, in egg albumen during the 5th d of treatment and the 1st d of medicated feed withdrawal. These concentrations were close to the limit of the assay's sensitivity (117 ppb). These data indicate that illegal or unintentional dosing of laying hens with feed medicated at the doses allowed for breeder hens or meat-type poultry should not produce consistently detectable levels of residues of OTC in eggs. PMID- 10090260 TI - Induction of the delayed footpad and wattle reaction to killed Staphylococcus aureus in chickens. AB - Two experiments were conducted to induce the delayed footpad reaction (DFR) to killed Staphylococcus aureus antigen. In Experiment 1, tracheal, cloacal, and choanal swabs were collected from chickens prior to sensitization with S. aureus to determine the carrier status of S. aureus. The second experiment compared the DFR to the delayed wattle reaction (DWR). Chickens were subjected to single or multiple sensitizations in the neck with S. aureus antigen between 4 and 6 wk of age. One week later, birds were challenged with S. aureus either in the right footpad or wattle. The left footpad or wattle was injected with PBS. The thicknesses of the footpad or the wattle were measured up to 96 h postchallenge. The recoveries of S. aureus from the choanal slit and trachea were significantly higher than that of the cloaca (P < 0.001). Birds of Experiment 1 showed a significant DFR (P < 0.0001) following intradermal challenge with killed S. aureus that was sustained through 48 h postchallenge with no difference in the DFR between carrier and noncarrier birds. In Experiment 2, the thicknesses of the footpad and wattle were significantly increased following challenge with S. aureus (P < 0.0001), with the footpad showing a greater response than the wattle (P < 0.001). Three sensitizing dosages, as compared to two dosages, resulted in a less pronounced DFR and DWR (P < 0.02). These results indicate that the DFR can be used as a delayed reaction model in the study of staphylococcosis in poultry. PMID- 10090261 TI - The recycling of L-citrulline to L-arginine in a chicken macrophage cell line. AB - L-Arginine is the only biological substrate of nitric oxide synthase in a reaction yielding NO and L-citrulline as co-products. The resynthesis of L arginine from L-citrulline has been observed in murine macrophages. However, it is not known whether avian macrophages have a similar capacity for the synthesis of arginine. The present studies were carried out to determine whether L citrulline can support NO (measured as nitrite) production in the HD11 cell, a chicken macrophage cell line. When added to media lacking L-arginine, L citrulline supported a low level of nitrite accumulation: about 4 to 11% of the amount of nitrite formed from an equivalent concentration of L-arginine. Aspartic acid was not limiting for NO production from citrulline. PMID- 10090262 TI - n-3 enrichment of chicken meat using fish oil: alternative substitution with rapeseed and linseed oils. AB - Two sequential experiments were conducted to assess the effect of replacing a fish oil diet with vegetable oil diets on broiler chicken performance and fatty acid (FA) composition and sensory traits of broiler meat. A diet enriched with 8.2% fish oil (FO) was fed to the birds throughout the 5-wk growth period (T1), the same basal diet being supplemented with 8.2% linseed oil (LO, Experiment 1) or rapeseed oil (RO, Experiment 2) in three different periods: the last week before slaughtering at 35 d (T2), the last 2 wk (T3), and throughout the experiment (T4). A sensory evaluation of the meat was carried out and its FA profile was determined. Performance parameters were not significantly different among treatments. Removing FO resulted in lower values of saturated and higher n 6 FA content, the latter because of the increase in linoleic acid in both experiments. The amounts of long-chain n-3 polyunsaturated fatty acids (PUFA) were significantly depressed when FO was replaced. However, replacing FO by LO resulted in minimal effects on total n-3 FA, due to the increase in linolenic acid. The substitution of FO by RO resulted in a decrease in the n-3 FA content, whereas levels of monounsaturated FA (MUFA) increased in direct relation to the larger amounts of oleic acid in the diet. Sensory panelists scored as unacceptable those meats from T1 in both experiments. Replacing 1 (T2) or 2 (T3) wk FO with vegetable oil clearly resulted in the improved sensory quality of meat. PMID- 10090263 TI - Microbial phytase in finisher diets of White Pekin ducks: effects on growth performance, plasma phosphorus concentration, and leg bone characteristics. AB - Two experiments (Exp.) were conducted to determine the growth response of White Pekin ducks to inclusion of microbial phytase in finisher diet. In Exp. 1, 1-d old male ducks (240 total) were reared in litter-floor pens and fed regular starter diet until 3 wk of age. At 3 wk of age, ducks were randomly divided into six groups of 10 ducks each and each group was fed one of four diets. Three finisher diets containing 16% CP and 0.18% available phosphorus (AP) without supplemental P were formulated with microbial phytase (Natuphos) added at 0, 750, or 1,500 phytase units/kg of diet. The fourth diet was a control finisher diet that was supplemented with dicalcium phosphate (DCP) to supply dietary AP of 0.41%. Group BW and feed intake were measured weekly to assess growth response. At 6 wk of age, leg bones (tibia, femur, metatarsus) from five randomly selected ducks were removed and analyzed for bone characteristics. In Exp. 2, a total of 120 ducks reared as in Exp. 1 were randomly divided into six groups of five ducks each and fed one of four diets. A basal finisher diet was formulated to contain 16% CP and 0.18% AP. Monosodium phosphate was added to the basal diet to give dietary AP levels of 0.18, 0.27, and 0.36%. The fourth diet was the basal diet supplemented with microbial phytase (750 phytase units/kg of diet). Ducks were fed these diets from 3 to 6 wk of age. At the end of the study, ducks were bled by cardiac puncture and blood plasma was analyzed for P concentration. Leg bones from all ducks were removed and analyzed for bone characteristics as in Exp. 1. Feed intake increased linearly with increased level of dietary phytase, whereas the weight gain response was quadratic only during the last week of Exp. 1. In Exp. 2, there was a quadratic response for weight gain due to dietary AP. Weight gain due to phytase (750 units) was not different from ducks fed diets at 0 or 0.18% AP. Plasma P concentration increased linearly as dietary AP increased. Plasma P levels of ducks fed phytase were similar to those of ducks fed 0.18% AP but lower than in ducks fed 0.27% AP. Estimates of AP resulting from the addition of 750 units of phytase to basal diet were 0.05 and 0.07% based on plasma P concentration and weight gain, respectively. Using regression analysis, the AP due to phytase effect in the diet was estimated to range from 0.06 to 0.08%. Results suggest that phytase can be used in finisher diets similar to the one used in this study for ducks from 3 to 6 wk of age to improve growth performance and leg bone development similar to ducks fed diets supplemented with P from inorganic sources. PMID- 10090264 TI - Effect of fatty acid saturation in broiler diets on abdominal fat and breast muscle fatty acid composition and susceptibility to lipid oxidation. AB - A total of 600 1-d-old Hybro N broiler chicks were randomly distributed into 24 litter pens and fed from 21 to 52 d of age isocaloric and isonitrogenous diets containing 8% of three different fat sources (tallow, lard or sunflower oil). Dietary treatment produced a significant effect (P < 0.05) in fatty acid composition of the intramuscular neutral lipids among all dietary treatments and for all lipid classes. A similar range of variation was obtained for abdominal fat fatty acid composition. In the intramuscular polar lipid fraction, dietary fat led to a narrow range in the variation of poly- and monounsaturated fatty acid composition, while the concentration of saturated fatty acids was maintained constant in all groups. A wide range in the melting point temperature of abdominal fat was observed (mean values of dietary treatments from 8.49 to 30.91 C), which indicates a major effect of dietary fatty acids on fat consistency. The variation of breast meat oxidation was small (mean values from 7.68 to 9.76 nmol malonaldehyde/mg protein). A dietary fat source rich in linoleic acid produces a marked effect on fat consistency, but only a moderately higher susceptibility to lipid oxidation of meat compared to tallow or lard. PMID- 10090265 TI - Ahemeral lighting of turkey breeder hens. 3. Temporary application and early age at lighting. AB - Ahemeral (non-24 h) light-dark cycles are known to increase egg size but when applied continuously have adverse effects on egg production. The purpose of this experiment was to determine whether temporary application of ahemeral light-dark cycles (AH) can overcome the adverse effects of continuous AH and provide improved reproductive performance of turkey hens photostimulated at an early age. Of particular interest was the effect of temporary AH on increasing egg weight at the start of lay because decreased egg weight is a major problem associated with early lighting of turkey hens. The AH treatments started at 26 wk of age and were given for 2 wk, 5 wk, or continuously. Each consisted of 15 h of light per cycle with a cycle length of 28 h duration, that is, 15 h light (L):13 h dark (D). The experiment was started in the winter season and continued for 28 wk. The following variables were measured: BW, feed intake, onset and rate of lay, fertility, hatchability, incidence of floor eggs, egg weight, poult production, and poult weight. It was clear that 5 wk or more of AH followed by standard lighting (15L:9D) increased initial egg weights from those of 26-wk controls and were similar to those of 30-wk controls. This effect was temporary, as it was absent by 8 wk of photostimulation. Also, cumulative eggs per hen to 54 wk of age were increased by 5 wk of AH treatment as compared to those of controls photo stimulated at 30 wk of age. These eggs had normal fertility, hatchability, and poults per hen in two evaluation periods. A high incidence of AH floor eggs was reduced to that of the controls following a shift to standard light-dark cycles. We concluded that temporary use of AH at the start of photostimulation is better than continuous use of AH throughout lay and resulted in improved reproductive performance of hens photostimulated at an early age. PMID- 10090266 TI - Bioavailability of lysine from a liquid lysine source in chicks. AB - Two experiments were conducted to assess the bioavailability of lysine from a liquid lysine product (LLP; 60% lysine) relative to crystalline L-lysine.HCl. In the first experiment, four groups of five chicks were fed a lysine-deficient basal diet containing corn, soybean meal, and feather meal or the basal diet supplemented with 0.1 or 0.2% lysine from L-lysine.HCl or LLP from Day 8 to 22 posthatching. Weight gain and feed efficiency responded linearly (P < 0.01) to increasing levels of lysine from either lysine source, and multiple linear regression analysis of weight gain regressed on supplemental lysine intake indicated no difference (P > 0.05) in the response to lysine from L-lysine.HCl or LLP. Experiment 2 was conducted using a lysine-deficient basal diet containing corn, peanut meal, and feather meal, and all diets were fed to five groups of five chicks from Day 8 to 21 posthatching. Treatment additions again consisted of 0.1 or 0.2% lysine from L-lysine.HCl or LLP. Weight gain and feed efficiency responded linearly (P < 0.01) to increasing levels of lysine from L-lysine-HCl and LLP, and multiple linear regression analysis of weight gain regressed on supplemental lysine intake indicated no difference (P > 0.05) in the response to lysine from L-lysine.HCl or LLP. These data indicate that lysine from LLP is fully bioavailable relative to lysine from crystalline L-lysine.HCl, and could therefore be used as a source of lysine in practical poultry diets. PMID- 10090267 TI - Cardiac output in four-, five-, and six-week-old broilers, and hemodynamic responses to intravenous injections of epinephrine. AB - Female broilers were evaluated at 4, 5, and 6 wk of age (1.2, 1.8, and 2.3 kg BW, respectively) to assess changes in cardiac output and related hemodynamics associated with BW gain, and to evaluate cardiopulmonary hemodynamic adjustments occurring secondary to i.v. injections of epinephrine (0.1 mg/ kg BW). Cardiac output increased with BW (253, 348, and 434 mL/min at 4, 5, and 6 wk, respectively) due to increases in stroke volume (0.70, 1.03, and 1.33 mL/beat) that more than compensated for reductions in heart rate (362, 337, and 328 bpm). Normalization for BW eliminated the differences in cardiac output and stroke volume. Increases in cardiac output were not associated with age- or BW-related increases in mean systemic arterial pressure (101.5, 108.6, and 108.0 mm Hg) due to corresponding reductions in total peripheral resistance (0.41, 0.32, and 0.26 relative resistance units). Epinephrine initially triggered immediate (within 90 s) threefold increases in total peripheral resistance and pulmonary vascular resistance, which, in turn, increased the systemic arterial pressure and pulmonary arterial pressure in spite of concurrent reductions in cardiac output that were associated with diminished venous return and dependent reductions in stroke volume and heart rate. Within 150 s after epinephrine injection, the systemic and pulmonary vascular resistances returned to preinjection control levels. By 300 s postinjection, stroke volume and heart rate increased, causing cardiac output to rise above preinjection control levels, which, in turn, elicited variable pulmonary arterial pressure responses apparently reflecting individual variability in the capacity for flow-dependent pulmonary vasodilation. These studies demonstrate that chronic (age- and BW-related) and acute (epinephrine-induced) changes in cardiac output in broilers reflect complex interactions among hemodynamic variables that include stroke volume, heart rate, and systemic and pulmonary vascular resistances. PMID- 10090268 TI - Broiler breeder survivors of chronic unilateral pulmonary artery occlusion produce progeny resistant to pulmonary hypertension syndrome (ascites) induced by cool temperatures. AB - Chronic occlusion of one pulmonary artery triggers a high incidence of pulmonary hypertension syndrome (PHS, ascites) in broilers. In the present study, the left pulmonary artery was chronically occluded in 295 male and 255 female chicks pedigreed from 18 sire families, leading to PHS in 74% of the males and 45% of the females. Survivors were reared to breeding age and served as parents for the resulting PHS-resistant chicks (Resistant), whereas control chicks were produced from the base population for this line (Base). In two experiments, male and female Resistant and Base chicks were reared separately by sex but mixed by group within environmental chambers, where they were exposed to cool (14 C) temperatures. In both experiments, the incidence of PHS was at least 50% lower in the Resistant males and females than in the Base males and females, respectively. When compared within a sex, the Base and Resistant broilers surviving to the end of both experiments did not differ in final body weight or body weight gain, nor did their right:total ventricular weight (RV:TV) ratios differ. These results demonstrate that broiler breeders capable of thriving after having their entire cardiac output forced to flow through one lung, subsequently produced male and female progeny with substantially improved resistance to the onset of PHS induced by fast growth and exposure to cool environmental temperatures. Fast growth and cool temperatures are primary triggers for PHS under most conditions of commercial broiler growout. In both experiments, final necropsies revealed higher RV:TV ratios in ascitic than in nonascitic broilers, whereas normalizing the left ventricle plus septum weight for differences in body weight generated similar values for ascitic and nonascitic males or females, respectively. These results support a primary role for pulmonary hypertension but not cardiomyopathy in the pathogenesis of ascites triggered by cool temperatures in both the Base and Resistant populations. PMID- 10090269 TI - A geneticist's perspective from within a broiler primary breeder company. AB - Recent trends occurring in broiler primary breeding companies are described. The structure and operation of broiler primary breeder companies are described from pedigree elite populations, through great-grandparent and grandparent generations, down to the parent stock. The relatively low value of fertility and hatchability, compared with yield and feed efficiency as selection traits, is assessed. The impact of the last 10 yr of genetic improvement in broiler and breeder traits are quantified and discussed, and predictions for future performance are made. It is concluded that artificial insemination will not be used in broiler primary breeder grandparent flocks or broiler breeder flocks until there is a 20% decline in fertility. PMID- 10090270 TI - Lessons for the poultry industry gleaned from experiences with other commodity species. AB - Do breeders really know how well or poorly they are managing reproduction? Poultry breeders could benefit from application of proven concepts of reproductive management used to exploit elite mammalian males, via selection for reproductive traits and extensive use of AI. Use of elite males could dramatically increase the impact of genes of economic importance transferred to the producer level. Testes weight has up to a 35-fold range among males within most lines of poultry, as does number of sperm that can be harvested from a male. These observations should not be ignored. Males with small testes will provide few sperm and they should be culled. Similarly, identification and elimination of males whose sperm are likely to have low fertilizing potential should be beneficial. Approaches to maximize harvest of those sperm produced by an elite male and minimize wastage of these valuable cells are emphasized. To this end, semen should be extended to allow insemination of a minimal volume containing just sufficient sperm consistent with the breeder's goal. Presumably, the goal should be obtaining the maximum number of offspring from a unique male or great grandparent family, while minimizing cost of producing each chick. This goal might not require maximizing "fertility". A 10-fold increase in dissemination of DNA from elite males to the next generation is realistic. Over three generations, this increase equals a 1,000-fold increase in the number of birds with the desirable traits! Appropriate biotechnology is available. Will decision makers evaluate new (to them) approaches and progress into the next millennium using modern technology, when cost-effective, or will they continue to manage reproduction with methods more than 50 yr old? Those who choose the latter path may risk extinction. PMID- 10090271 TI - Measuring sperm:egg interaction to assess breeding efficiency in chickens and turkeys. AB - Systems used to measure fertility in poultry have themselves presented a major impediment to progress in maintaining or improving fertility. Generally, these systems have been time-consuming, quantitatively inadequate, or both. A simplistic illustration of the basis of the problem is that if six fertile eggs were laid by a turkey hen during 1 wk after insemination, then all we know is what happened to six sperm: they fertilized the eggs. If 100 million sperm were inseminated, then information on the other 999,999,994 is missing. A better approach for quantitating breeding efficiency is to estimate the numbers of sperm that interact with the egg in the infundibulum. These can be identified in laid eggs, as sperm in the outer perivitelline layer (OPVL sperm), or holes produced by sperm in the inner perivitelline layer (IPVL holes). Eggs can contain up to 250,000 OPVL sperm, so the scale improves on binary estimation of fertilization status. The number of spermatozoa interacting with the perivitelline layer is related to the artificial insemination (AI) dose, the number of oviducal sperm, and the probability of fertilization, not just for one egg, but for subsequent eggs laid by the same hen. Practical applications of sperm:egg interaction measurements include: replacement of fertility trials for evaluation of semen; general fertility evaluation; and monitoring breeding efficiency of commercial turkey and broiler breeders. Furthermore, studies of sperm transfer into eggs raise interesting questions about the efficiency of turkey hens' response to AI or mating frequency of broiler hens in commercial flocks. PMID- 10090272 TI - Prospective approaches to avoid flock fertility problems: predictive assessment of sperm function traits in poultry. AB - This paper discusses why it is important to evaluate males as individuals and how advances made in understanding and measurement of sperm function can be used to improve reproductive efficiency in poultry. Commercial turkey breeding relies on pooling semen from multiple toms. It generally is assumed that sperm in good quality semen from all toms are equally fecund. (Fecund is defined, for males, as an individual whose semen contains a majority of sperm with the potential of producing fertilized eggs, which includes success at all steps in the fertilization process: sperm movement, storage in the hens' sperm storage tubules, binding and penetrating the perivitelline layer, and fertilization.) However, when DNA fingerprinting was used to determine paternity efficiency after pooling ejaculates from seven or more toms, it was found that 18 of 26 males produced very few, or no, offspring. In addition, the traditional measures of poultry semen quality: semen volume, sperm concentration, sperm viability, and subjective motility assessment, were poor predictors of paternity. In recent years, a concentrated effort has been made to develop and evaluate methods that quantify sperm function in poultry. Methods to measure some of these traits are reviewed: sperm motility, sperm storage in the hen, and sperm binding and penetration of the ovum. Data supporting use of these tools for managing flock fertility from the male perspective are explored. PMID- 10090273 TI - Genetic relationships between selection for growth and reproductive effectiveness. AB - The domestic and international poultry industries have gone through many changes over the last 50 yr. One constant in the meat-type poultry industry has been the emphasis on genetic improvement of growth. Using lines from a double, divergent selection experiment, data are presented on the genetic relationships between growth to different ages and reproductive parameters. During the last three generations of selection an in vitro sperm binding assay was used and evaluated for its usefulness in a selection program for growth-related phenotypes. Growth to different ages can have markedly different genetic architecture, compared to evaluating body weight at a fixed age. Growth is a nonlinear phenomenon and should be evaluated as such within the context of a genetics program. Fertility is positively correlated with growth to 14 d of age (EGR14), but negatively correlated with growth to 42 d of age (EGR42). This difference is primarily due to the high, negative correlation between exponential growth from 14 to 42 d of age (EGR14/42) and reproductive phenotypes. Roosters were also evaluated with an in vitro sperm binding assay, which is highly correlated with fertility. The genetic architecture of the sperm binding assay was very similar to that of fertility, with an additive genetic correlation of 0.75. Further, it was shown that culling the worst 25% roosters on the basis of the sperm binding assay would have very little effect on the growth performance of the resulting progeny, yet increased the number of chicks produced per rooster by 10 to 25% (depending upon the population). PMID- 10090274 TI - Optimizing delivery of genetic merit in subtropical climates through advanced reproductive technologies. AB - The poultry industry in subtropical climates faces the challenges of climate and variable feed quality, in addition to those challenges encountered in temperate zones. These challenges aggravate the problem associated with the progressive decline in reproductive performance due to genetic selection for growth and yield traits. Heat stress is the major cause of lower fertility in both males and females, regardless of age. Under such situations, nongenetic factors play critical roles in maintaining or increasing reproductive efficiency in broiler breeders. The relatively low cost of skilled labor in subtropical countries enables consideration of artificial insemination for hens in cages or on the floor as an alternative to conventional floor mating, and also identification and culling of males producing few sperm or sperm of inferior quality. Artificial insemination allows extended use of superior males and setting up rooster stud farms. Such operations, plus selection for economic growth and carcass traits in pedigree lines known to tolerate the climate, will be important for continued growth of market share. PMID- 10090275 TI - Symposium summary and challenges for the future. AB - The poultry industry has grown and prospered over the past 50 yr by a repeated pattern of careful analysis of factors limiting production, followed by replacement of biological functions with management practices. Examples include assisted incubation, selection of sires, and survival via novel housing. Each resulted in a period of enhanced product output. Trends developing over the past decade raise the potential for consideration of another intervention, that of assisted reproduction. Examples illustrating the need to consider, and adopt at several levels, assisted reproduction are provided. Three critical aspects of poultry production should be monitored by careful documentation of: 1) genetic throughput from pedigree to product, best assessed by monitoring number of chicks produced per male; 2) product cost, best assessed by optimizing rate of lay and fertility of laid eggs for each hen; and 3) product quality, reflected in the homogeneity of progeny for desired traits. Each segment of the industry (turkey, egg or broiler; breeder or producer) will find unique solutions to these interacting factors. Presentations within the symposium are reviewed and integrated, and comments are provided relative to challenges facing the industry in the 21st century. PMID- 10090277 TI - Rapid postmortem pH decline and delayed chilling reduce quality of turkey breast meat. AB - Effects of rapid postmortem metabolism and delayed chilling on turkey breast meat quality were assessed using color measurements, protein extractability, and gelation characteristics. Based on 15 min postmortem breast muscle pH, tom turkey carcasses were classified as rapid glycolyzing (RG), pH < 5.80, or normal glycolyzing (NG), pH > 6.00. Two carcasses per group with similar ultimate pH values were selected on four occasions for a total of 16 carcasses. One half of each carcass was immersion-chilled at 20 min postmortem, the other half was maintained at body temperature for 110 min and then chilled. Breast meat from RG carcasses had higher carcass temperature (15 min) and lower protein (sarcoplasmic and myofibrillar) extractability than breast meat from NG carcasses. Delayed chilling increased all breast meat color values (L*, a*, b*), and decreased protein extractability and cook yield compared to breast meat from immediately chilled carcass halves. The true strain of cooked gels was reduced for RG carcasses. Delayed chilling reduced both true strain and stress of meat gels. There were no interactions between the rate of postmortem pH decline and initiation of chilling, indicating that reductions in meat quality due to delayed chilling were independent of the carcass classification for rate of postmortem glycolysis. Results indicate that factors that affect both rate of postmortem glycolysis and carcass temperature decline are important to turkey breast meat quality. PMID- 10090276 TI - Hemoglobin and myoglobin content in muscles of broiler chickens. AB - The two main heme proteins, hemoglobin and myoglobin, are important factors determining meat quality aspects such as color and hemorrhage. The extent of hemorrhage in muscle tissue can probably be determined by measuring the hemoglobin content. The objective of this study was twofold: 1) to develop a specific and reproducible method to quantify the hemoglobin and myoglobin content in muscle tissue of broiler chickens, and 2) to study the effect of hemorrhage on the hemoglobin content in muscle tissue. We tested several methods to determine the total heme, hemoglobin, and myoglobin content in broiler chicken muscles on their specificity, sensitivity, and reproducibility. Methods based on immunological techniques appeared to be very specific and sensitive. The results obtained applying these methods on muscle tissue extracts were, however, not reproducible due to concentration effects. A combination of spectrophotometric analysis of the total heme protein concentration and measurement of the myoglobin concentration, applying size exclusion chromatography, proved to be a reliable and reproducible method to determine the hemoglobin and myoglobin content in chicken muscles. The total heme, hemoglobin, and myoglobin contents were related to muscle type. Extensive hemorrhage increased the hemoglobin content. PMID- 10090278 TI - The effect of current frequency during waterbath stunning on the physical recovery and rate and extent of bleed out in turkeys. AB - Two experiments were carried out to evaluate the influence of the frequency of a sinusoidal stunning current (150 mA, 4 s) on the physical recovery of turkey hens and toms and on the rate and extent of blood loss. In the first experiment, physical recovery of 72 hens and 78 toms was estimated after stunning with one of five different frequencies. The incidence of cardiac arrest after stunning at 50, 300, 480, 550, and 600 Hz was, respectively, 100, 60, 30, 30, and 0% in hens and 53, 38, 0, 0, and 0% in toms. In hens, time to return of corneal reflex and neck tension and the onset of wing flapping decreased as frequency increased. In contrast to hens, about half of the toms stunned at 50 Hz did not show cardiac arrest. In these animals, recovery after 50 Hz was significantly longer than recovery at the four other frequencies. In the second experiment, 50 hens and 53 toms were bled out by a unilateral neck cut 10 s after stunning with one of four different frequencies (50, 300, 480, and 600 Hz). The rate and extent of blood loss within 3 min, relative to live weight, increased as stunning frequency increased. Large differences in the rate and extent of blood loss were observed between turkeys stunned at 50 or 300 Hz, according to the occurrence of cardiac arrest: cardiac activity was associated with significantly higher rate and extent of blood loss in both sexes. Overall, the results suggest that the duration of unconsciousness decreases as stunning frequency increases. PMID- 10090279 TI - The effects of antemortem electrical stunning and postmortem electrical stimulation on biochemical and textural properties of broiler breast meat. AB - Experiments were conducted to determine the combined effects of antemortem electrical stunning (STUN) and postmortem electrical stimulation (STIM) on breast muscle rigor development and meat quality attributes. Birds were either unstunned, stunned with low voltage (LV), or stunned with high current (HC) prior to conventional killing. Immediately after exsanguination, birds were either unstimulated, or were subjected to electrical stimulation with 12 1s on/1s off pulses of 440 V AC and allowed to bleed for 90 s to determine the effect of treatment on blood loss. Breast fillets (Pectoralis major) were removed from carcasses immediately after evisceration (0.25 h) or after aging in a static ice water slush for 1 or 2 h, and analyzed for muscle pH, R-value (ratio of inosine to adenosine nucleotides), and sarcomere length. Raw breast meat color (CIELAB), cook loss, and shear values were determined on samples held at 2 C for 24 h. Results showed both STUN and STIM significantly affected blood loss, pH, R-value, sarcomere length, color, and shear, and there were significant STUN by STIM interactions. Blood loss was significantly lower for the HC STUN and all the STIM treatments. STIM at 440 V resulted in accelerated rigor development as measured by pH, R-value, and sarcomere length, similar to the unstunned or LV STUN samples, but different from the HC STUN birds. These results indicate that electrical stimulation may accelerate rigor most effectively following high current stunning, which tends to delay early rigor development. PMID- 10090280 TI - Tenderness of broiler breast fillets from carcasses treated with electrical stimulation and extended chilling times. AB - Postmortem electrical stimulation (ES) (450 V, 450 mA, 2 s on, 1 s off for five pulses) has been shown to decrease the toughness associated with early deboning. Most studies involving this system have been concerned with obtaining "acceptable" tenderness in fillets deboned at about 1 h postmortem, the time of carcass exit from an immersion chiller. However, the effects of ES combined with deboning at 2 h postmortem needs to be evaluated because some processors are considering extended immersion chilling and those already using air chilling require approximately 2 h for this process. Two 32-bird trials were conducted to compare tenderness in broiler breast fillets from ES-treated carcasses deboned at 1 and 2 h postmortem and fillets from control (C) carcasses deboned at 1 and 4 h postmortem. The Allo-Kramer shear value means of ES-2 h and C-4 h fillets were not different from each other and were significantly lower than that of the ES-lh fillets, which was significantly lower than the C-lh fillets. There was no significant difference among treatments associated with thaw loss or cook loss. The ES-2 h, ES-1 h, and C-4 h samples had significantly higher R-values and lower pH values than the C-1 h samples, indicating more advanced rigor development. These results indicate that deboning fillets from ES-treated carcasses at 2 h postmortem yields meat with a tenderness equivalent to the value reached with 4 h aging on the carcass. This is a 50% reduction in the time needed to achieve this level of tenderness. PMID- 10090281 TI - The crystal structure of recombinant rat pancreatic RNase A. AB - The three-dimensional structure of rat pancreatic RNase A expressed in Escherichia coli was determined. The backbone conformations of certain critical loops are significantly different in this enzyme compared to its bovine counterpart. However, the core structure of rat RNase A is similar to that of the other members of the pancreatic ribonuclease family. The structural variations within a loop bordering the active site can be correlated with the subtle differences in the enzymatic activities of bovine and rat ribonucleases for different substrates. The most significant difference in the backbone conformation was observed in the loop 15-25. This loop incorporates the subtilisin cleavage site which is responsible for RNase A to RNase S conversion in the bovine enzyme. The rat enzyme does not get cleaved under identical conditions. Molecular docking of this region of the rat enzyme in the active site of subtilisin shows steric incompatibility, although the bovine pancreatic ribonuclease A appropriately fits into this active site. It is therefore inferred that the local conformation of the substrate governs the specificity of subtilisin. PMID- 10090282 TI - Crystal structure of Escherichia coli uracil DNA glycosylase and its complexes with uracil and glycerol: structure and glycosylase mechanism revisited. AB - The DNA repair enzyme uracil DNA glycosylase (UDG) catalyzes the hydrolysis of premutagenic uracil residues from single-stranded or duplex DNA, producing free uracil and abasic DNA. Here we report the high-resolution crystal structures of free UDG from Escherichia coli strain B (1.60 A), its complex with uracil (1.50 A), and a second active-site complex with glycerol (1.43 A). These represent the first high-resolution structures of a prokaryotic UDG to be reported. The overall structure of the E. coli enzyme is more similar to the human UDG than the herpes virus enzyme. Significant differences between the bacterial and viral structures are seen in the side-chain positions of the putative general-acid (His187) and base (Asp64), similar to differences previously observed between the viral and human enzymes. In general, the active-site loop that contains His187 appears preorganized in comparison with the viral and human enzymes, requiring smaller substrate-induced conformational changes to bring active-site groups into catalytic position. These structural differences may be related to the large differences in the mechanism of uracil recognition used by the E. coli and viral enzymes. The pH dependence of k(cat) for wild-type UDG and the D64N and H187Q mutant enzymes is consistent with general-base catalysis by Asp64, but provides no evidence for a general-acid catalyst. The catalytic mechanism of UDG is critically discussed with respect to these results. PMID- 10090283 TI - New features and enhancements in the X-PLOR computer program. AB - This article describes new methods for X-ray crystallographic refinement and nuclear magnetic resonance (NMR) structure determination that are available in the recent release of the X-PLOR software, X-PLOR 98.0. The major new features of the X-PLOR 98.0 software are: (i) the introduction of maximum likelihood methods (Pannu and Read, Acta Crystallogr 1996;A52:659-668) for X-ray crystallographic refinement with structure factor amplitude, intensity and phase probability targets, (ii) the addition of the Andersen thermal coupling method for temperature control during simulated annealing refinements, (iii) a new utility function for converting reflection data in to the X-PLOR format, (iv) validated scripts and performance enhancements for structure determination from NMR distance restraints using torsion angle dynamics, (v) fast code for direct nuclear Oberhauser effect (NOE) refinement using matrix doubling and gaussian quadratures, (vi) methodologies for using ambiguous restraint information to perform automated iterative peak assignment and structure determination (Nilges et al., J Mol Biol 1997;269: 408-422). Additional developments in methodology for refining crystal structures from poor initial models include the implementation of a fast adaptive bulk solvent scattering correction and an energy minimization routine that makes use of second derivative information. Trial crystallographic refinements with an energy minimization protocol that includes these enhancements indicate significantly improved convergence. The quality of the resulting models appears comparable to models obtained from refinement protocols that incorporate torsion angle dynamics. Test applications of the new energy minimizer to NMR structure refinement with using NOE calculations also show improved convergence, leading to more optimized final models. PMID- 10090284 TI - Factors that affect the folding ability of proteins. AB - The folding ability of a heteropolymer model for proteins subject to Monte Carlo dynamics on a simple cubic lattice is shown to be strongly correlated with the stability of the native state. We consider a number of estimates of the stability that can be determined without simulation, including the energy gap between the native state and the structurally dissimilar part of the spectrum (Z score) and, for sequences with fully compact native states, the gap in energy between the native and first excited fully compact states. These estimates are found to be more robust predictors of folding ability than a parameter sigma that requires simulation for its evaluation: sigma = 1 - Tf/Ttheta, where Tf is the temperature at which the fluctuation of an order parameter is at its maximum and Ttheta is the temperature at which the specific heat is at its maximum. We show that the interpretation of Ttheta as the collapse transition temperature is not correct in general and that the correlation between sigma and the folding ability arises from the fact that sigma is related to the energy gap (Z score). PMID- 10090285 TI - Protein tertiary structure prediction using a branch and bound algorithm. AB - We report a new method for predicting protein tertiary structure from sequence and secondary structure information. The predictions result from global optimization of a potential energy function, including van der Waals, hydrophobic, and excluded volume terms. The optimization algorithm, which is based on the alphaBB method developed by Floudas and coworkers (Costas and Floudas, J Chem Phys 1994;100:1247-1261), uses a reduced model of the protein and is implemented in both distance and dihedral angle space, enabling a side-by-side comparison of methodologies. For a set of eight small proteins, representing the three basic types--all alpha, all beta, and mixed alpha/beta--the algorithm locates low-energy native-like structures (less than 6A root mean square deviation from the native coordinates) starting from an unfolded state. Serial and parallel implementations of this methodology are discussed. PMID- 10090286 TI - Variability in quaternary association of proteins with the same tertiary fold: a case study and rationalization involving legume lectins. AB - Legume lectins constitute a family of proteins in which small alterations arising from sequence variations in essentially the same tertiary structure lead to large changes in quaternary association. All of them are dimers or tetramers made up of dimers. Dimerization involves side-by-side or back-to-back association of the flat six-membered beta-sheets in the protomers. Variations within these modes of dimerization can be satisfactorily described in terms of angles defining the mutual disposition of the two subunits. In all tetrameric lectins, except peanut lectin, oligomerization involves the back-to-back association of side-by-side dimers. An attempt has been made to rationalize the observed modes of oligomerization in terms of hydrophobic surface area buried on association, interaction energy and shape complementarity, by constructing energy minimised models in each of which the subunit of one legume lectin is fitted in the quaternary structure of another. The results indicate that all the three indices favor and, thus, provide a rationale for the observed arrangements. However, the discrimination provided by buried hydrophobic surface area is marginal in a few instances. The same is true, to a lesser extent, about that provided by shape complementarity. The relative values of interaction energy turns out to be a still better discriminator than the other two indices. Variability in the quaternary association of homologous proteins is a widely observed phenomenon and the present study is relevant to the general problem of protein folding. PMID- 10090287 TI - Identification of homologous core structures. AB - Using a large database of protein structure-structure alignments, we test a new method for distinguishing homologous and "analogous" structural neighbors. The homologous neighbors included in the test set show no detectable sequence similarity, but they may be well superimposed and show functional similarity or other evidence of evolutionary relationship. Analogous neighbors also show no sequence similarity and may be well superimposed, but they have different functions and their structural similarity may be the result of convergent evolution. Confirming results of other analyses, we find that remote homologs and analogs are not well distinguished by measures of pairwise structural similarity, including the percentage of identical residues and root-mean-square (RMS) superposition residual. We show, however, that with structure-structure alignments of analogous neighbors rarely superimpose the particular substructure that is shared among homologous neighbors. We call this characteristic substructure the homologous core structure (HCS), and we show that a cross validated test for presence of the HCS correctly identifies 75% of remote homologs with a false-positive rate of 16% analogs, significantly better than discrimination by RMS or other measures of pairwise similarity. The HCS describes conservation of spatial structure within a protein family in much the way that a sequence motif describes sequence conservation. We suggest that it may be used in the same way, to identify homologous neighbors at greater evolutionary distance than is possible by pairwise comparison. PMID- 10090288 TI - Modeling of acanthoxin A1, a PLA2 enzyme from the venom of the common death adder (Acanthophis antarcticus). AB - The phospholipase A2 enzyme, acanthoxin, found in the venom of the common death adder (Acanthophis antarcticus) as with other snake PLA2 enzymes displays neurotoxic activity. It is unclear whether this neurotoxic activity particular to some snake PLA2 enzymes is a result of structural differences solely within the catalytic sites or at a distant location upon the molecules. We have predicted the three-dimensional structure of one of the two predominant isoforms of acanthoxin (A1) using comparative protein modeling techniques. Given the high degree of homology and the availability of a high quality crystallographic structure, notexin was used as a molecular template to construct an all atom model of acanthoxin. The model was made using the program MODELLER3 and then refined with X-PLOR. Comparison between the predicted structure of acanthoxin and several X-ray structures of toxic and nontoxic PLA2 enzymes has led to a testable two-step proposal of neurotoxic PLA2 activity; involving the favorable binding to acceptor molecules followed by enzymatic intrusion upon the target membrane. The electrostatic potentials across the molecular surfaces of toxic and nontoxic PLA2 enzymes were calculated (GRASP) and it was found that the toxic PLA2 enzymes possessed a charge distribution on the noncatalytic surface not identified in the nontoxic PLA2 enzymes. Thus we have identified residues potentially involved in the interaction of the PLA2 enzymes with their acceptor molecules. Furthermore, the proposed acceptor molecule recognition site is distant from the catalytic site which upon binding of the PLA2 to the acceptor molecule may enhance the enzymatic ability of the toxic PLA2 enzymes on particular cell types. PMID- 10090289 TI - Molecular dynamics simulations of the Ras:Raf and Rap:Raf complexes. AB - The protein Raf is an immediate downstream target of Ras in the MAP kinase signalling pathway. The complex of Ras with the Ras-binding domain (RBD) of Raf has been modelled by homology to the (E30D,K31E)-Rap1A:RBD complex, and both have been subjected to multiple molecular dynamics simulations in solution. While both complexes are stable, several rearrangements occur in the Ras:RBD simulations: the RBD loop 100-109 moves closer to Ras, Arg73 in the RBD moves towards Ras to form a salt bridge with Ras-Asp33, and Loop 4 of the Ras switch II region shifts upwards toward the RBD. The Ras:RBD interactions (including the RBD-Arg73 interaction) are consistent with available NMR and mutagenesis data on the Ras: RBD complex in solution. The Ras switch II region does not interact directly with the RBD, although indirect interactions exist through the effector domain and bridging water molecules. No large-scale RBD motion is seen in the Ras:RBD complex, compared to the Rap:RBD complex, to suggest an allosteric activation of Raf by Ras. This may be because the Raf kinase domain (whose structure is unknown) is not included in the model. PMID- 10090290 TI - Effect of G40R mutation on the binding of human SRY protein to DNA: a molecular dynamics view. AB - Molecular dynamics simulation was conducted to investigate the reason why the mutant G40R of hSRY protein has a low affinity for DNA. Compared with the previous dynamics results of the wild-type hSRY-HMG-DNA complex, the results of molecular dynamics simulation on the mutant G40R hSRY-HMG-DNA system demonstrated that the whole structure of DNA (especially the second strand) had a major deviation away from the short arm of the HMG box. Consequently, the DNA and the mutant protein could not specifically recognize each other, that is, very different, and low-occupancy, direct, and water-mediated hydrogen bonds were detected at the protein-DNA interface, no conformational changes occurred at the loop region around Met9 during the simulation, and residue IIe13 did not intercalate between the bases of A5 and A6. These results indicated that the mutant G40R did not form a specific complex with the DNA target, hence led to complete gonadal dysgenesis. From the simulation, we realized that the residue Gly40 played a critical structural role in the hSRY-DNA recognition. It might be a structural supporting point of DNA binding because of the absence of a side chain. The reason for the difficulty of the mutant G40R to form a complex with DNA might be that the long and positively charged side chain of Arg40 by its bulk and positive charge hindered the DNA's access to the active sites of the protein. PMID- 10090291 TI - Structure-based prediction of DNA target sites by regulatory proteins. AB - Regulatory proteins play a critical role in controlling complex spatial and temporal patterns of gene expression in higher organism, by recognizing multiple DNA sequences and regulating multiple target genes. Increasing amounts of structural data on the protein-DNA complex provides clues for the mechanism of target recognition by regulatory proteins. The analyses of the propensities of base-amino acid interactions observed in those structural data show that there is no one-to-one correspondence in the interaction, but clear preferences exist. On the other hand, the analysis of spatial distribution of amino acids around bases shows that even those amino acids with strong base preference such as Arg with G are distributed in a wide space around bases. Thus, amino acids with many different geometries can form a similar type of interaction with bases. The redundancy and structural flexibility in the interaction suggest that there are no simple rules in the sequence recognition, and its prediction is not straightforward. However, the spatial distributions of amino acids around bases indicate a possibility that the structural data can be used to derive empirical interaction potentials between amino acids and bases. Such information extracted from structural databases has been successfully used to predict amino acid sequences that fold into particular protein structures. We surmised that the structures of protein-DNA complexes could be used to predict DNA target sites for regulatory proteins, because determining DNA sequences that bind to a particular protein structure should be similar to finding amino acid sequences that fold into a particular structure. Here we demonstrate that the structural data can be used to predict DNA target sequences for regulatory proteins. Pairwise potentials that determine the interaction between bases and amino acids were empirically derived from the structural data. These potentials were then used to examine the compatibility between DNA sequences and the protein-DNA complex structure in a combinatorial "threading" procedure. We applied this strategy to the structures of protein-DNA complexes to predict DNA binding sites recognized by regulatory proteins. To test the applicability of this method in target-site prediction, we examined the effects of cognate and noncognate binding, cooperative binding, and DNA deformation on the binding specificity, and predicted binding sites in real promoters and compared with experimental data. These results show that target binding sites for several regulatory proteins are successfully predicted, and our data suggest that this method can serve as a powerful tool for predicting multiple target sites and target genes for regulatory proteins. PMID- 10090292 TI - A chronotherapeutic approach to the management of high-risk patients with hypertension/ischemic heart disease: introduction. PMID- 10090293 TI - Circadian variation in cardiovascular events. AB - Serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, frequently result from thrombotic processes and rupture of atherosclerotic plaques. These events exhibit a pronounced circadian rhythmicity, with a marked peak in the morning hours when the patient assumes an upright posture and begins daily activities. However, it is not known if plaques rupture more frequently in the morning. This review will examine the epidemiologic evidence documenting this circadian phenomenon, consider its physiologic underpinnings, and discuss the implications of this pattern for rational pharmaceutical development. Finally, some practical implications regarding potential triggers of cardiovascular events will be discussed. PMID- 10090294 TI - Circadian variation in blood pressure: implications for the elderly patient. AB - In most people, blood pressure (BP) displays a characteristic diurnal pattern, with a decline during sleep and a sharp increase around the time of awakening. The early morning surge in BP is synchronous with an increase in the risk of catastrophic cardiovascular events, including acute myocardial infarction, sudden cardiac death, and stroke. Although most clinical investigations have centered on modulating or even preventing the morning surge, emerging data suggest that it may be important to avoid nocturnal hypotension, especially in elderly patients and in those with established atherosclerotic disease. Considerable evidence has been accumulated to suggest that excessive lowering of BP at night (whether naturally or through the use of antihypertensive medications) can result in untoward ischemic phenomena, including silent cerebral damage (Binswanger's disease) or ophthalmologic symptoms (eg, anterior ischemic optic neuropathy). Controlled-onset extended-release verapamil, through its unique delivery system, tends to diminish the morning BP surge, whereas it preserves a normal nocturnal BP decline; its effect on preventing early morning cardiovascular catastrophes (while preserving relatively normal nocturnal BP) is currently being tested in a large, international clinical trial. PMID- 10090295 TI - Heart rate and the rate-pressure product as determinants of cardiovascular risk in patients with hypertension. AB - Inability to supply oxygen to the myocardium when demand is high appears to be related to several cardiovascular events, including transient myocardial ischemia, acute myocardial infarction, and sudden death. Myocardial oxygen consumption is correlated with the rate-pressure product (heart rate x systolic blood pressure) and this hemodynamic parameter has been shown to follow a circadian pattern similar to that observed with cardiovascular events. However, the clinical implications of this observation and the appropriate clinical interventions have not been studied. Therefore, the impact of the chronotherapeutic controlled-onset extended release delivery (COER-verapamil) on heart rate and the rate-pressure product was assessed and compared with that of nifedipine gastrointestinal therapeutic system (GITS), which is designed to provide a constant or homeostatic drug effect. A total of 557 hypertensive patients were enrolled in the 51-center, randomized, double-blind prospective study. Twenty-four-hour ambulatory blood pressure (BP) monitoring was performed at baseline, after 4 weeks of stable-dose therapy, and after 10 weeks of treatment; heart rate was assessed concomitantly. Heart rate, rate of rise (slope) of BP and heart rate, and the rate-pressure product were all reduced to a greater extent by COER-verapamil during the early morning hours compared with the nifedipine GITS treatment. Thus, COER-verapamil exerted a beneficial hemodynamic profile for the treatment of the increases in rate-pressure product typically observed in the early morning in patients with hypertension. PMID- 10090296 TI - Management of the hypertensive patient with coronary artery disease. AB - Hypertension, a major risk factor for cardiovascular disease worldwide, remains inadequately diagnosed and treated, particularly in certain at-risk populations. Hypertension, often in association with other factors, increases the risk for the development of coronary artery disease (CAD). In turn, CAD increases the risk for related morbidity and mortality and presents treatment challenges. The chronobiology of many cardiovascular events offers a pathway for selecting optimal therapy for the hypertensive patient with CAD. Choosing a long-acting agent that achieves high plasma drug levels during critical hours may reduce the risk for cardiovascular morbidity and mortality. PMID- 10090297 TI - Exercise clinical trials in cancer prevention research: a call to action. AB - The experimental study design can yield valuable information in measuring the association between physical activity and occurrence of cancers. Randomized clinical exercise trials can provide insight into the avenues through which physical activity might affect cancer development and can provide experience with diffusing an exercise intervention into certain populations. This report describes the potential utility of the randomized clinical trial design in providing answers about bias, mechanisms, behavior change, and dose-response in defining the causal pathway between physical activity and cancer. The challenges and limitations of exercise clinical trial are discussed. The research experience in cardiovascular disease and exercise is used as a model for developing a research agenda to explore the potential role of physical activity as a cancer prevention modality. We recommend that a series of small clinical trials of exercise interventions be conducted to measure exercise change effects on biomarkers for cancer risk, to learn about exercise behavior change in individuals at risk for cancer, and to serve as feasibility studies for larger randomized controlled trials of cancer and precursor end points and for community intervention studies. PMID- 10090298 TI - A prospective study on folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer. AB - To investigate the incidence of breast cancer and prediagnostic serum levels of folate, B12, and pyridoxal 5'-phosphate (B6), we conducted a nested case-control study using resources from the Washington County (Maryland) serum bank. In 1974, 12,450 serum specimens were donated, and in 1989, 14,625 plasma specimens were donated by female residents of Washington County. One hundred ninety-five incident breast cancer cases and 195 controls were matched by age, race, menopausal status at donation, and cohort participation as well as by date of blood donation. In both cohorts and all menopausal subgroups, median B12 concentrations were lower among cases than controls. Differences reached statistical significance only among women who were postmenopausal at donation (1974 cohort, 413 versus 482 pg/ml, P = 0.03; 1989 cohort, 406 versus 452 pg/ml, P = 0.02). Among women postmenopausal at blood donation, observed associations of B12 suggested a threshold effect with increased risk of breast cancer in the lowest one-fifth compared to the higher four-fifths of the control distribution [lowest versus highest fifth: 1974 cohort, matched odds ratio = 4.00 (95% confidence interval = 1.05-15.20); 1989 cohort, matched odds ratio = 2.25 (95% confidence interval = 0.86-5.91)]. We found no evidence for an association between folate, B6, and homocysteine and breast cancer. Findings suggested a threshold effect for serum B12 with an increased risk of breast cancer among postmenopausal women in the lowest one-fifth compared to the higher four-fifths of the control distribution. These results should stimulate further investigations of potentially modifiable risk factors, such as these B-vitamins, for prevention of breast cancer. PMID- 10090299 TI - Dietary determinants of colorectal proliferation in the normal mucosa of subjects with previous colon adenomas. AB - Dietary determinants of colorectal mucosa proliferation were studied in 69 subjects previously operated for at least two sporadic colon adenomas. Information on recent dietary habits was collected by a validated food frequency questionnaire, and proliferation was measured by [3H]thymidine incorporation in colorectal biopsies by determining the labeling index (LI) and the percentage of LI in the upper part of the crypt, two parameters that are increased in subjects at high risk of colon cancer. The LI was significantly higher in women as compared with men (P = 0.01). Diet showed several associations with colorectal mucosa proliferation: (a) subjects in the highest tertile of fish consumption had a significantly lower LI (P = 0.0013) compared with those in the lower tertiles [5.20 +/- 1.87 versus 6.80 +/- 2.18 (mean +/- SD)]; (b) subjects with a low red meat consumption had lower proliferation in the upper part of the crypt [2.38 +/- 2.10, 5.30 +/- 4.62, and 5.89 +/- 4.82 in the low, middle, and high tertile of consumption, respectively (mean +/- SD); P = 0.0093]; (c) according to estimated nutrient intakes, the LI was lower in subjects reporting a high intake of starch (P = 0.006) and higher in subjects with a low intake of beta-carotene (P = 0.002). The results show that subjects reporting a diet rich in fish, starch, and beta-carotene and low in red meat had lower colorectal mucosa proliferation and a normal pattern of proliferation along the crypt. Given the correlation between colorectal proliferative activity and colon cancer risk, such a dietary pattern might be beneficial for subjects at high risk of colon cancer. PMID- 10090300 TI - Comparison of serum carotenoid responses between women consuming vegetable juice and women consuming raw or cooked vegetables. AB - The objective of this study was to examine serum concentrations of alpha carotene, beta-carotene, lutein, lycopene, and beta-cryptoxanthin due to consumption of vegetable juice versus raw or cooked vegetables. Subjects included female breast cancer patients who had undergone surgical resection and who were enrolled in a feasibility study for a trial examining the influence of diet on breast cancer recurrence. A high-vegetable, low-fat diet was the focus of the intervention, and some of the subjects were specifically encouraged to consume vegetable juice. At 12 months, blood samples were collected and analyzed for carotenoid concentrations via high-performance liquid chromatography methodology. Matched analysis and paired t test were conducted on two groups: those who consumed vegetable juice (the juice group) and those who consumed raw or cooked vegetables (no juice group). Serum concentrations of alpha-carotene and lutein were significantly higher in the vegetable juice group than in the raw or cooked vegetable group (P < 0.05 and P = 0.05, respectively). Paired t test analysis did not demonstrate a significant difference in serum values of beta-carotene, lycopene, and beta-cryptoxanthin between subjects consuming juice and those not consuming any juice. These results suggest that alpha-carotene and lutein appear to be more bioavailable in the juice form than in raw or cooked vegetables. Therefore, the food form consumed may contribute to the variability in serum carotenoid response to vegetable and fruit interventions in clinical studies. PMID- 10090301 TI - N-acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk. AB - N-Acetyltransferase 1 (NAT1), encoded by the polymorphic NAT1 gene, has been shown to be one of the major enzymes in human breast tissue that activates aromatic and heterocyclic amines. Humans are mainly exposed to these carcinogens through cigarette smoking and consumption of well-done meat. To test the hypothesis that variations in the NAT1 gene are related to breast cancer risk, particularly among women who smoke or consume high levels of well-done meat, a nested case-control study was conducted in a prospective cohort study of 41,837 postmenopausal Iowa women. Information on cigarette smoking and other breast cancer risk factors was obtained at the baseline survey conducted in 1986. DNA samples and information on the consumption of well-done meat were obtained, in the case-control study, from breast cancer cases diagnosed from 1992 to 1994 and a random sample of cancer-free cohort members. Genomic DNA samples obtained from 154 cases and 330 controls were assayed for 11 NAT1 alleles (NAT1*3, *4, *5, *10, *11, *14, *15, *16, *17, *19, and *22). The NAT1*4 allele was the predominant allele observed in this study population, accounting for 73.2% (72.4% in cases versus 73.8% in controls) of the total alleles analyzed. Compared to controls, breast cancer cases had a slightly higher frequency of the NAT1*10 allele (18.8% in cases versus 17.3% in controls) and a substantially higher frequency of the NAT1*11 allele (3.6% versus 1.2%). In multivariate analyses, we found a 30% [95% confidence interval (CI) = 0.8-1.9] elevated risk of breast cancer associated with the NAT1*10 allele and a nearly 4-fold (95% CI = 1.5-10.5) elevated risk associated with the NAT1*11 allele. The positive association of breast cancer with the NAT1*11 allele was more evident among smokers [odds ratio (OR) = 13.2, 95% CI = 1.5-116.0] and those who consumed a high level of red meat (OR = 6.1, 95% CI = 1.1-33.2) or consistently consumed their red meat well done (OR = 5.6, 95% CI = 0.5-62.7). The association of the NAT1*10 allele with breast cancer was mainly confined to former smokers (OR = 3.3, 95% CI = 1.2-9.5). These findings are consistent with a role for the NAT1 gene in the etiology of human breast cancer. PMID- 10090302 TI - Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23 dihydroxyvitamin D (calcitriol) and EB1089. AB - The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 microg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (+/- 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 microg/kg) developed 10.4 (+/- 2.81) and 7.70 (+/- 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 +/- 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089-treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 +/- 0.21 mg/dl versus 14.47 +/ 0.46 mg/dl; 1.0 microg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 +/- 1.9% and 26.3 +/- 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (+/- 2.9) %. Moreover, rats treated with low-dose EB1089 gained 5.2 (+/- 3.7) % of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia. PMID- 10090303 TI - Soluble interleukin 2 receptor levels and cervical neoplasia: results from a population-based case-control study in Costa Rica. AB - Progression from infection with human papillomavirus (HPV) to cervical cancer in some women is thought to involve a permissive host environment, one in which immune response is mobilized in an inappropriate manner. In a previous study (A. Hildesheim et al., Cancer Epidemiol. Biomark. Prev., 6: 807-813, 1997), increasing levels of soluble interleukin 2 receptor (sIL-2R), a known proxy for general immune activation, was found to be positively associated with increasing levels of cervical neoplasia. We attempted to confirm this finding by conducting a nested case-control study of 478 women within a 10,000-woman population-based cohort in Costa Rica. We selected for the study all of the women diagnosed (at enrollment into the cohort) with: (a) low-grade squamous intraepithelial lesions (LSIL, n = 191); (b) high-grade squamous intraepithelial lesions (HSIL, n = 130); or (c) cancer (n = 37). Controls were 120 cytologically normal, HPV-negative women selected from a random sample of the entire cohort. A questionnaire was administered to participants to elicit information on cervical cancer risk factors. All of the women received a pelvic examination during which cervical cells were collected and used for HPV DNA testing by PCR. Blood samples were also collected. Plasma obtained from the blood samples was tested for sIL-2R levels by ELISA. Results indicated that sIL-2R levels increased with age. Among controls, we observed that 44.3% of women over the age of 50 had high levels of sIL-2R (defined as >735 units/ml) compared with 15.8% of women <30 years of age (P = 0.008). When women with cervical disease (LSIL+) were compared with controls, women in the upper quartile of the sIL-2R distribution had an age-adjusted odds ratio (OR) of 2.1 [95% confidence interval (CI), 1.1-4.1]. Comparing each advancing state of neoplasia with its precursor, we found that women with LSIL had higher sIL-2R levels than controls (OR for upper quartile of sIL-2R, 2.3; 95% CI, 1.1-5.2; comparing LSIL cases with controls); women diagnosed with HSIL were similar to the LSIL group (OR for upper quartile of sIL-2R, 1.1; 95% CI, 0.5-2.4; comparing HSIL cases with LSIL cases); and those with cancer had higher sIL-2R levels than subjects with an HSIL diagnosis (OR for upper quartile of sIL-2R = 1.8; 95% CI, 0.5-7.1; comparing cancer cases with HSIL cases). These data suggest that among our study subjects, sIL-2R levels most likely rise as a response to the events of infection and cancerous invasion, but that sIL-2R levels are unlikely to be predictive of disease progression among women with LSIL. PMID- 10090304 TI - Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women. AB - p53 mutations may be a fingerprint for cigarette smoking and other environmental carcinogens, including breast carcinogens. This study was undertaken to explore whether p53 mutations are associated with environmental or other suspected or established risk factors for breast cancer. p53 protein detection by immunohistochemistry (which is more easily quantified in large epidemiological studies than are mutations, and are highly correlated with them) was determined for 378 patients from a case-control study of breast cancer. In this population based sample of women under the age of 45 years, 44.4% (168/378) of the cases had p53 protein detected by immunohistochemistry (p53+). Polytomous logistic regression was used to calculate the odds ratios (ORs) for p53+ and p53- breast cancer, as compared with the controls, in relation to cigarette smoking and other factors. The ratio of the ORs was used as an indicator of heterogeneity in risk for p53+ versus p53- cancer. The ratio of the ORs in a multivariate model was substantially elevated among women with a greater than high school education [2.39; 95% confidence interval (CI), 1.43-4.00], current cigarette smokers (1.96; 95% CI, 1.10-3.52), and users of electric blankets, water beds, or mattresses (1.78; 95% CI, 1.11-2.86). Nonsignificant heterogeneity was noted for family history of breast cancer and ethnicity but not for other known or suspected risk factors. Coupled with the strong biological plausibility of the association, our data support the hypothesis that in breast cancer, as with other tumors, p53 protein immunohistochemical detection may be associated with exposure to environmental carcinogens such as cigarette smoking. PMID- 10090305 TI - Serum levels of ochratoxin A in healthy adults in Tuscany: correlation with individual characteristics and between repeat measurements. AB - Ochratoxin A (OTA), a mycotoxin widely contaminating staple foods and beverages, has been classified as a "possible human carcinogen (Group 2B)" by the IARC. Serum levels of OTA were measured in a group of 138 healthy adults (age, 35-65 years) living in the area surrounding Florence (Tuscany, central Italy) and detected in all but four samples (97%). After the exclusion of one subject with a peak value of 57.2 ng/ml, OTA levels ranged between 0.12 and 2.84 ng/ml, with mean and median values of 0.56 and 0.48 ng/ml, respectively. OTA levels were significantly higher in men than in women (0.64 versus 0.50) and correlated positively with height. A strong association was found with the season in which blood samples were obtained, with summer values higher than autumn values. On the other hand, OTA levels tended to be negatively associated with blood pressure, either systolic or diastolic; no association was evident with age, weight, body mass index, and smoking history. The associations with height and season persisted in a multivariate regression analysis. A subgroup of subjects provided a repeat blood sample approximately 1 year later. The Spearman correlation coefficient between 68 pairs of original and repeat measurements was practically null (r = 0.05). Only two subjects (2.9%) had OTA levels of >1 ng/ml on both occasions. These results suggest that OTA contamination is widespread in foods consumed by this population, in agreement with previous reports from Italy and other countries. A strong seasonal variation, which possibly differs from year to year, was observed. OTA serum levels are a short-term biomarker with a high within-subject variability; therefore they have limited use at the individual level but can be used to characterize populations or subgroups of subjects. Additional analyses are needed to explore the dietary determinants of OTA levels in this population. PMID- 10090306 TI - Breast cancer risk in monozygotic and dizygotic female twins: a 20-year population-based cohort study in Finland from 1976 to 1995. AB - This population-based study investigated the occurrence of breast cancer over a 20-year period in a cohort of monozygotic (MZ) and dizygotic (DZ) twins in Finland. Altogether, 13,176 female twins of known zygosity who were living in Finland at the end of 1975 were identified from the Finnish Twin Cohort Study and followed-up for cancer through the Finnish Cancer Registry for the years 1976 1995. Standardized incidence ratios (SIRs) were calculated, based on national cancer incidence rates. The relative risk of breast cancer for MZ twins compared to DZ twins was decreased [SIR(MZ)/SIR(DZ) ratio = 0.78; 95% confidence interval (CI), 0.58-1.0]; the decreased risk for MZ twins (SIR = 0.76; 95% CI, 0.58-1.0) accounted for this result, whereas the risk for DZ twins did not differ from the general population risk (SIR = 0.98; 95% CI, 0.84-1.1). There was no risk decrease among MZ twins in other cancers related to reproductive behavior; i.e., number of children and age at first birth seem not to explain the decreased risk of breast cancer. Our results, which are in line with earlier studies on the same topic, suggest that prenatal influences or postnatal behavioral factors may protect MZ female twins from breast cancer. PMID- 10090307 TI - Oncocytic (Hurthle cell) tumors of the thyroid: distinct growth patterns comparedwith clinicopathological features. AB - Neoplastic growth results from cell production that exceeds cell loss. We registered mitotic and apoptotic indices (MI and AI) in 97 immunohistochemically verified oncocytic (Hurthle cell) tumors of the thyroid (OT; 50 adenomas [OA], 20 atypical adenomas [aOA], and 27 carcinomas [OC]) and compared these kinetic data with histological diagnoses and other parameters. MI, although very low in all, was significantly higher in carcinomas than in adenomas. Conversely, AI did not differ as much among the 3 groups. This indicates that the magnitude of cell deletion did not play a prominent role in determining the disparate growth of the 3 types of oncocytic tumors. Cluster analysis with MI and AI per case as variables revealed the existence of 3 groups of neoplasms with highly distinct growth characteristics: (1) near-steady state (n = 78, all diagnostic categories represented); (2) progressive (n = 9, mostly carcinomas); and (3) regressive (n = 10, mostly adenomas). MI distinguished between histologically benign and malignant with the greatest discriminant power of the variables tested. Proliferative indices should thus be included in the differential diagnostic evaluation of oncocytic thyroid tumors. Our study also suggests that invasiveness and growth are 2 diverging properties of carcinomas. PMID- 10090308 TI - Role of thyroglobulin measurement in fine-needle aspiration biopsies of cervical lymph nodes in patients with differentiated thyroid cancer. AB - The identification of metastatic neck lymph nodes in patients awaiting surgery for differentiated thyroid tumor permits their excision during thyroidectomy. In order to detect thyroid cancer lymphatic metastasis before surgery, we measured thyroglobulin (Tg) in the needle wash-out of fine-needle aspiration biopsy (FNAB). Ultrasound-guided FNAB on enlarged neck nodes was performed in 23 patients awaiting surgery for differentiated thyroid tumor (n = 33 lymph nodes), 47 patients previously thyroidectomized for thyroid tumor (n = 89 lymph nodes), and 60 patients without thyroid disease (n = 94 lymph nodes). Immediately after aspiration biopsy, the needle was rinsed with 1 mL of normal saline solution and Tg levels were measured on the needle wash-out (FNAB-Tg). FNAB-Tg levels were markedly elevated in metastatic lymph nodes both in patients awaiting thyroidectomy (metastatic vs. negative lymph nodes, mean +/- SEM, 16,593 +/- 7,050 ng/mL vs. 4.91 +/- 1.61 ng/mL; p < 0.001) and in thyroidectomized patients (11,541 +/- 7,283 ng/mL vs. 0.45 +/- 0.07 ng/mL; p < 0.001). FNAB-Tg sensitivity, evaluated through histological examination in 69 lymph nodes, was 84.0%. The combination of cytology plus FNAB-Tg increased FNAB sensitivity from 76% to 92.0%. In conclusion, FNAB-Tg measurement is a useful technique for early diagnosis of lymph node metastasis originating from differentiated thyroid cancer. PMID- 10090309 TI - Expression of inducible nitric oxide synthase in human thyroid papillary carcinomas. AB - To evaluate the relationship between nitric oxide (NO) and carcinogenesis, we assayed 4 human thyroid papillary carcinomas (TPC) and 3 normal thyroid glands for the presence of inducible nitric oxide synthase (iNOS). Using an antibody against iNOS, we observed immunohistochemical staining if iNOS in the TPC samples, but not in normal thyroid. When we incubated TPC samples with antibodies against both iNOS and human leukocyte antigen (LCA), a macrophage marker, we found that while most TPC cells were stained with anti-iNOS antibody, only a few were stained with both. Reverse transcription polymerase chain reaction (RT-PCR) showed that iNOS mRNA was expressed in the samples of TPC, but not in normal thyroid. The sequence of iNOS message in the TPC samples was identical to that previously detected in a human colon cancer cell line. These results suggest that iNOS in human TPC is mostly derived from tumor cells, rather than macrophages, and that it may play a direct role in carcinogenesis. PMID- 10090310 TI - Expression of transforming growth factor beta1, beta2, and beta3 in multinodular goiters and differentiated thyroid carcinomas: a comparative study. AB - The various isoforms of transforming growth factor-beta (TGFbeta) are growth inhibiting cytokines for cells of epithelial origin. In malignant thyroid tumors, several studies documented a high expression of TGFbeta in the majority of thyroid follicular cells suggesting a possible role as an inhibitor of cell proliferation. In contrast to this uniform pattern of TGFbeta expression in thyroid cancer, scarce and controversial data have been reported on the expression of TGFbeta in benign multinodular goiter. In the present study, we therefore analyzed the expression of TGFbeta1, TGFbeta2, and TGFbeta3 in normal thyroid tissue, multinodular goiters and papillary thyroid carcinomas by immunohistochemistry. In normal thyroid tissue, expression of the 3 TGFbeta isoforms was barely detectable. However, in the carcinomas, almost all epithelial cells displayed immunoreactivity for the three TGFbeta isoforms. In the nodules from multinodular goiters, all 3 isoforms were found to be expressed although the immunolocalization of the 3 proteins was highly variable. TGFbeta-immunostaining was found in scattered clusters of variable size and, its expression pattern was heterogenous among individual cells within single follicles. TGFbeta-positivity was present in spite of immunostaining for proliferating cell nuclear antigen (PCNA), a marker for actively proliferating cells. In conclusion, this study shows that thyroid carcinomas and benign tumors express the TGFbeta1, TGFbeta2, and TGFbeta3 isoforms. In contrast to the abundant and homogeneous expression in differentiated thyroid carcinomas, TGFbeta expression displays a highly variable interfollicular and intrafollicular pattern in multinodular goiters, suggesting an important role of TGFbeta isoforms in tumorigenesis of thyroid cells. PMID- 10090311 TI - Normal thyroid pathology in patients undergoing thyroidectomy for finding a RETgene germline mutation: a report of three cases and review of the literature. AB - Genetic screening for germline RET proto-oncogene mutation in hereditary medullary thyroid cancer (MTC) is accurate and allows for preventive total thyroidectomy to be performed early in patients who are gene carriers. We report 3 children who underwent preventive total thyroidectomy based on the finding of a RETgene germline mutation, but who had no evidence of MTC or C-cell hyperplasia on permanent histology, even after calcitonin immunostaining. Review of the English literature of patients undergoing preventive thyroidectomy for a positive RETgene germline mutation, shows that 3.4% of these patients (a total of 209 patients) had normal thyroid glands. Also, 8.6% of patients undergoing preventive total thyroidectomy with prophylactic central neck node dissection had cervical node metastases. We conclude that preventive thyroidectomy in patients screened early for germline RETgene mutation allows for earlier diagnosis and treatment of patients, sometimes even before any hyperplasia or neoplasia can be demonstrated because cervical node metastases can occur early and be demonstrated even with small tumors (< 1 cm), we recommend prophylactic central neck node dissection at the time of preventive thyroidectomy. PMID- 10090312 TI - Expression of thyroid-related genes in human thymus. AB - There are several thyroid antigens including human sodium iodide symporter (hNIS), thyrotropin receptor (TSH-R), thyroid peroxidase (TPO), and thyroglobulin (Tg) that have been considered to be thyroid-specific proteins involved in the pathogenesis of autoimmune thyroid diseases. We examined the expression of these thyroid-tolerance related genes in normal human thymus, the lymphoid organ responsible for the induction of central T-cell self. Reverse transcription polymerase chain reaction (RT-PCR) amplifications were performed with 4 pairs of oligonucleotide primers specific for the hNIS, TSH-R, TPO, and Tg genes, respectively. Gene-specific transcripts were confirmed by Southern hybridization using digoxigenin-labeled internal oligonucleotide probes. To monitor cDNA integrity and quantity, all samples were coamplified with a pair of intron spanning human beta-actin-specific oligonucleotide primers. Furthermore, using a highly sensitive immunostaining technique and antibodies specific for these 4 antigens, we examined whether NIS-, TSH-R-, TPO-, and Tg-specific immunoreactivity can be detected and localized in normal human thymus. RT-PCR and Southern hybridization revealed expression of each of these 4 thyroid-related genes in normal human thymus. In addition, immunohistochemical analysis of frozen tissue sections derived from normal human thymus showed marked immunoreactivity for NIS, TSH-R, and Tg as well as weaker staining for TPO. Control reactions using isotype matched nonimmune immunoglobulins were consistently negative. Taken together, our results suggest that NIS-, TSH-R-, TPO-, and Tg-RNA are present and actively processed to immunoreactive NIS-, TSH-R-, TPO-, and Tg-like protein in human thymus. These data support the concept that pre-T lymphocytes may be educated to recognize thyroid-related epitopes expressed in thymus, and, thus, to generate self-tolerance against these thyroid-related antigens. PMID- 10090313 TI - Adipose S14 mRNA is abnormally regulated in obese subjects. AB - In rat hepatocyte culture, the S14 gene is necessary for induction of lipogenesis by carbohydrate metabolism and thyroid hormone. To determine if this gene plays a role in regulation of lipid storage in humans we compared the response to fasting of the human S14 gene between obese and nonobese subjects. We measured the relative content of human S14 mRNA in abdominal subcutaneous fat before and after a 48-hour fast. We found that mRNA-S14 is strongly downregulated in nonobese subjects in response to the fast, but only minimally down-regulated in obese subjects. There is an excellent correlation between the body mass index, and the fasting induced fall in S14 mRNA. There was no difference in the postfasting glucose, insulin, and ketone levels between the 2 groups of subjects. Therefore, the S14 gene is abnormally downregulated during fasting in adipose tissue of obese individuals. Further study of this gene could provide important information on the mechanism of the acquisition or maintenance of obesity in humans. PMID- 10090314 TI - Increased serum concentration of interleukin-12 in patients with silent thyroiditis and Graves' disease. AB - We previously reported that interleukin-5 (IL-5), secreted from Th2 cells, was increased in patients with Graves' disease, but not in patients with silent thyroiditis. In this study, we investigated serum levels of interleukin-12 (IL 12) in order to examine the role of Th1-type immune response in the pathogenesis of autoimmune thyroid diseases. Serum levels of IL-12 were determined by a highly sensitive sandwich enzyme-linked immunosorbent assay in 68 patients with Hashimoto's thyroiditis (26 of whom had silent thyroiditis), 74 patients with Graves' disease, 8 patients with subacute thyroiditis, and 27 normal controls. Serum levels of IL-12 in thyrotoxic patients with silent thyroiditis (385.2 +/- 164.5 pg/mL, mean +/- SD), and in thyrotoxic patients with Graves' disease (343.6 +/- 163.8 pg/mL) were significantly increased compared with serum levels in normal subjects (163.9 +/- 66.8 pg/mL, p < 0.0001, p < 0.0001, respectively) or in thyrotoxic patients with subacute thyroiditis (241.9 +/- 46.5 pg/mL, p < 0.01, < 0.05, respectively). The ratio of IL-12 to IL-5 in thyrotoxic patients with silent thyroiditis (64.2 +/- 39.7) was significantly higher than that in normal controls (33.7 +/- 13.3, p < 0.01) or in thyrotoxic patients with Graves' disease (40.6 +/- 36.0, p < 0.05). These data suggest that Th1-type immune response is predominant in silent thyroiditis, and that not only Th2-type immune response but also Th1-type immune response is important in the pathogenesis of Graves' disease. PMID- 10090315 TI - Severe short-term hypothyroidism is not associated with an increased incidence of myocardial ischemia as assessed by thallium-201 stress/rest myocardial scintigraphy. AB - Reversible silent myocardial ischemia associated with treatment of long-standing hypothyroidism has recently been reported using thallium-201 (201Tl) myocardial single photon emission tomography (SPET). The aim of the present study was to evaluate whether patients with short-term hypothyroidism (serum thyrotropin [TSH] levels above 30 mU/L) have an increased risk of silent myocardial ischemia. We studied 20 patients with differentiated thyroid carcinoma that had undergone thyroidectomy and ablative (131)I therapy. None of the patients had a known history of atherosclerotic cardiovascular disease. In the course of a planned follow-up examination, suppressive levothyroxine (LT4) therapy was discontinued 7 weeks prior to scintigraphy and replaced by triiodothyronine (T3) therapy for 4 weeks. No thyroid hormone medication was given during the 3 weeks preceding the diagnostic procedures. All patients were hypothyroid (TSH 87.2 +/- 30.8 mU/L, mean +/- SD) at the time of the examination. 20lTl-SPET was performed immediately after bicycle exercise stress test and again after a delay of 4 hours. In case of abnormal results, (n = 3) the examination was repeated after patients were euthyroid. Two patients showed effects of soft-tissue attenuation (breast attenuation in a female and diaphragmatic attenuation in a male subject). Myocardial ischemia was revealed in 1 patient but was seen in both hypothyroid and euthyroid examinations. The results of the present study show that short-term severe hypothyroidism as encountered in athyreotic patients after cessation of thyroxine medication for several weeks, is not associated with an impairment of myocardial perfusion. PMID- 10090316 TI - Autosomally transmitted low concentration of thyroxine-binding globulin. AB - The gene coding for thyroxine-binding globulin (TBG) is located on the long arm of the X chromosome; thus anomalies of TBG are transmitted in an X-linked fashion. We report a family with decreased concentration of circulating TBG and an unusual pattern of inheritance. In this family, a number of members showed decreased levels of serum TBG. The unusual finding was that the low TBG was transmitted from the male proband to his son. Thyroxine (T4) binding affinity and heat lability of serum TBG of the proband was not different from values obtained from a normal control. All exons and the critical region in the upstream of the TBG gene were sequenced and no alterations were found. The mechanism that causes decreased concentration of TBG of the proband and family members is unknown, but an abnormality in transcription factors that are important for TBG gene expression might be considered. PMID- 10090317 TI - A novel resistance to thyroid hormone associated with a new mutation (T329N) in the thyroid hormone receptor beta gene. AB - Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone responsiveness associated with point mutations in the thyroid hormone receptor beta (TRbeta) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that results in the substitution of threonine for asparagine (T329N). This mutation was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH. Dextrothyroxine (D-T4) therapy was instituted. At 8 mg per day 2 pregnancies followed with the delivery of a healthy boy and an RTH-affected girl another miscarriage occurred on D-T4 treatment at 6 mg per day. The T329N mutation, which was also identified in the daughter, markedly reduces the affinity of TRbeta for triiodothyronine (T3). Formation of T329N mutant TR homodimers and heterodimers with RXRalpha on thyroid hormone response element F2 (TRE F2) was not affected, but the ability of T3 to interrupt T329N mutant TRbeta homodimerization was markedly reduced. The T329N mutant TRbeta was transcriptionally inactive in transient expression assays. In cotransfection assays with wild-type TRbeta1, the mutant TRbeta1 functioned in a dominant negative manner. The results suggest that the T329N mutation in the T3-binding domain of TRbeta is responsible for RTH in the proposita's family. PMID- 10090318 TI - Severe thyrotoxicosis due to hyperfunctioning liver metastasis from follicular carcinoma: treatment with (131)I and interstitial laser ablation. AB - Liver metastases from differentiated thyroid tumors are unusual clinical findings, and are only rarely hyperfunctioning. We report a case of thyrotoxicosis caused by a huge and surgically unresectable liver metastasis from follicular thyroid cancer, unresponsive to treatment with large doses of thionamides. To avoid the hazardous side effects of (131)I treatment in a severely thyrotoxic patient, a preliminary debulking of the liver mass was performed by means of percutaneous interstitial laser photocoagulation. Three treatments (total energy delivery: 7200 J) were performed under ultrasound guidance, with no serious complications, during a 2-week period. One month later, serum thyroid hormones had decreased, general condition was improved, and magnetic resonance evaluation revealed large and well-defined areas of necrosis of metastatic tissue. During the following 10 months, the patient underwent 3 radioiodine treatments. Eighteen months after diagnosis, thyroid hormones were within normal levels, liver mass decreased, and the clinical condition markedly improved. The combination of percutaneous interstitial laser photocoagulation treatment and radioiodine therapy made possible the effective management of a hyperfunctioning and surgically untreatable liver metastasis from thyroid follicular carcinoma, avoiding the side effects of (131)I therapy in a thyrotoxic patient and increasing the effectiveness of radioiodine-induced neoplastic tissue ablation. PMID- 10090319 TI - Development of primary hypothyroidism with the appearance of blocking-type antibody to thyrotropin receptor in Graves' disease in late pregnancy. AB - Spontaneous remission of Graves' disease with a decrease of thyroid stimulating antibody (TSAb) activity is commonly observed in pregnancy. In this article, however, a Graves' patient who developed primary hypothyroidism with an appearance of thyroid stimulation-blocking antibody (TSBAb) activity in late pregnancy is reported. A 25-year-old woman presented with clinical and biochemical hyperthyroidism with an elevation of 99mTcO4- thyroid uptake (4.7%; normal range, 0.7%-3.0%) and mildly elevated activity of thyrotropin-binding inhibitory immunoglobulin (TBII; 30.4%). She was euthyroid with normal TBII (8.0%) and TSAb (126%) before pregnancy, when the patient was taking a 5-mg daily dose of methimazole (MMI). MMI was stopped by the patient when she became pregnant. Subsequently, the patient progressed into primary hypothyroidism with a marked elevation of TBII activity (78.4%) in the third trimester of the pregnancy (at that time, TSAb activity was not detected). TSBAb measured 2 weeks later was detected at the activity of 85.0%. Replacement therapy was initiated with levothyroxine (LT4) (0.05-0.1 mg/day), which was discontinued on the 55th day postpartum because of the onset of mild thyrotoxicosis followed by short-term euthyroid state despite high TSBAb activity. Subsequently, because the patient developed primary hypothyroidism 5 months after delivery, replacement therapy with LT4 (0.1-0.125 mg/day) was readministered. Thus, it is suggested that the development of hypothyroidism with the appearance of TSBAb in Graves' patients can occur even in late pregnancy. PMID- 10090320 TI - Development of Graves' hyperthyroidism from primary hypothyroidism in a case of thyroid hemiagenesis. AB - We report a 42-year-old female with right thyroid hemiagenesis who initially presented with hypothyroidism and then developed hyperthyroidism. The serum titer of thyroid-stimulating antibody was weakly positive in the initial hypothyroid state, and then markedly increased along with the development of hyperthyroidism, while thyroid stimulation-blocking antibody was continuously negative throughout the observation period. Thyroid histology of biopsied specimens during the hypothyroid state demonstrated diffuse thyroiditis with mononuclear cell infiltrations; however, the histology during the hyperthyroid state showed hyperplasia in follicular epithelial cells accompanied by partial lymphocyte infiltration. This is the first case of thyroid hemiagenesis associated with a conversion from primary hypothyroidism due to Hashimoto's thyroiditis to hyperthyroidism due to Graves' disease. PMID- 10090321 TI - Malignant ophthalmopathy presenting one week after radioiodine treatment of hyperthyroidism. AB - A 46-year-old woman presented with malignant ophthalmopathy 1 week after a therapeutic dose of radioiodine for treatment of hyperthyroidism. The patient was a smoker and had clinical evidence of mild thyroid-associated ophthalmopathy (TAO) prior to treatment with radioiodine. Anti-thyrotropin (TSH) receptor antibodies and antiflavoprotein antibodies were not detected at the time of presentation with malignant ophthalmopathy. The patient responded rapidly to anti inflammatory treatment with intravenous methylprednisolone and orbital radiation. PMID- 10090322 TI - Relationship between systemic blood pressure, airway blood flow and plasma exudation in guinea-pig. AB - Plasma exudation in the airways is mainly dependent on microvascular permeability of the tracheobronchial circulation and may be affected by local blood flow. Aortic blood pressure provides the major inflow pressure to tracheobronchial circulation. Therefore, systemically administered vasoconstrictors, in doses enough to increase systemic blood pressure, may theoretically increase the blood flow in the tracheobronchial circulation by enhancing inflow pressure. Consequently, this may influence plasma exudation induced by inflammatory mediators in the airways. To test this hypothesis, we used guinea-pigs to study: (1) the effects of i.v. vasoconstrictors (methoxamine and angiotensin II) on blood flow in the tracheal mucosa and in the leg skeletal muscle (Laser-Doppler flowmetry); (2) the effects of i.v. vasoconstrictors on plasma exudation induced by tracheal administration of the inflammatory mediator bradykinin (150 nmol). We found that i.v. methoxamine and angiotensin II significantly increase tracheal mucosa blood flow and systemic blood pressure. The increase in tracheal mucosa blood flow was, in the case of angiotensin II, found to be significantly related to the increase in systemic blood pressure. In separate experiments, pre treatment with i.v. methoxamine and angiotensin II significantly potentiates Evan's Blue dye exudation induced by bradykinin in the trachea and main bronchi. We conclude that i.v. methoxamine and angiotensin II potentiate bradykinin induced plasma exudation in the guinea-pig airways, possibly by increasing the local blood flow. The increase in the local blood flow is most likely induced by enhanced systemic blood pressure (inflow pressure), owing to a redistribution of the total body blood flow. PMID- 10090323 TI - Diabetic alteration of cardiac vago-sympathetic modulation assessed with tone entropy analysis. AB - No clear evidence of diabetic alteration of cardiac sympatho-vagal balance has been reported to date. We assessed heart rate variability of diabetic patients with the tone-entropy analysis that has been published elsewhere (Oida et al. 1997). Tone reflects the cardiac vago-sympathetic balance and entropy the total autonomic efferent activity. Diabetic influence on tone and entropy was examined in two groups of patients (38-52 years and 60-69 year, total 106) stratified according to the occurrence of impaired glucose tolerance or diabetes mellitus. Ten healthy middle-aged volunteers were also examined as a reference. Electrocardiographic data were collected at rest for 10 min. Tone increased and entropy decreased significantly with severity of diabetic disorders. The alterations were depicted as a curvi-linear relation in tone-entropy space, which superimposed adequately on the standard tone-entropy values obtained in a pharmacological experiment. The results demonstrate that the vago-sympathetic balance is altered with diabetic disorders: vagal predominance is impaired significantly in proportion to a withdrawal of total autonomic efferent activity. PMID- 10090324 TI - Telemetric registration of heart rate and blood pressure in the same unrestrained goats during pregnancy, lactation and the non-pregnant, non-lactating period. AB - The purpose of this study was to investigate how changes in heart rate and arterial blood pressure relate to the time of day, reproductive period and feeding routines in dairy goats (Capra hircus). Registrations were made by radiotelemetry in the same four goats during pregnancy, lactation and the non pregnant, non-lactating (dry) period. Heart rate rose around the morning and afternoon feedings, whereas blood pressure did not show any diurnal rhythm. Comparison between reproductive periods revealed that heart rate was higher during the fifth month of pregnancy than during lactation and the dry period, whereas for blood pressure no such differences between periods were found. Withholding three meals from lactating goats resulted in a continuous slowdown of the heart rate, whereas blood pressure fluctuated. Re-feeding temporarily increased the heart rate but had no effect on blood pressure which continued to fluctuate. After another 2 days, blood pressure (but not heart rate) had stabilized. Food-restriction, aimed at terminating milk production resulted in a consistently depressed heart rate and reduced the mean and systolic blood pressures at night. The results show that with this implantable telemetry device it is possible to measure both heart rate and blood pressure day and night in the same unrestrained animals over a length of time long enough to include all reproductive periods. Our results emphasize that when planning experiments it is important that the exact stage in each reproductive period, the act of feeding and the amount of food given be taken into account. PMID- 10090325 TI - Interaction between the renin-angiotensin system and insulin-like growth factor I in aorto-caval fistula-induced cardiac hypertrophy in rats. AB - The effects of angiotensin converting enzyme inhibition and angiotensin II receptor blockade on the development of cardiac hypertrophy and myocardial insulin-like growth factor I (IGF-I) in volume overload were studied in male Wistar rats with aorto-caval fistulas (ACF). Rats were treated with ramipril (RAM, 3 mg kg(-1) day(-1)) for 4-20 days or losartan (LOS, 10 mg kg(-1) day(-1)) for 2-7 days. Myocardial IGF-I and IGF-I receptor (IGF-I-R) mRNA were determined by solution hybridization. ACF caused hypertrophy of left (LV) and right ventricles (RV). Hypertrophy appeared on day 2 and reached maximal values of +60% in LV and +75% in RV at day 12. Systolic blood pressure was initially reduced 15% but recovered by day 12. RAM abolished the recovery of blood pressure. Furthermore, RAM attenuated RV hypertrophy by 17% on day 7 and on day 20, RV weights were close to values found in controls. Beginning on day 9, RAM reduced LV weight back to control levels in parallel to blood pressure. In contrast, LOS affected neither RV nor LV hypertrophy. RV IGF-I mRNA increased 60-100% on day 7 alone in RV in ACF. RAM potentiated the increase in RV IGF-I to +400% and induced an increase in RV IGF-I-R mRNA on day 7 (+90%) in ACF. LOS did not affect RV IGF I. Development of cardiac hypertrophy in ACF seemed independent of angiotensin II. RV hypertrophy was associated with activation of IGF-I independent of the renin-angiotensin system. IGF-I was further potentiated when development of hypertrophy was attenuated, possibly indicative of a greater urge for compensational growth in a relatively thinner and more volume-distended chamber. PMID- 10090327 TI - Haemodynamic influence and endothelin-1 plasma concentrations by selective or non selective endothelin receptor antagonists in the pig in vivo. AB - In the present study the haemodynamical effects of endothelin (ET)-receptor antagonism was evaluated using selective and non-selective ET(A)- and ET(B) receptor blockade in normoxic pigs in vivo. In addition, the influence of the ET antagonists on circulating plasma ET-1 levels was determined. BMS-182874 (10 and 30 mg kg(-1) i.v.), a selective ET(A)-receptor antagonist decreased the pulmonary and systemic vascular resistances. bosentan (10 and 30 mg(-1) i.v.), a non selective ET(A)- and ET(B)-receptor antagonist caused principally similar effects as ETA-antagonism alone. No effects were observed by selective ET(B)-blockade using BQ-788 (30 microg kg(-1) i.v.). Of the three antagonists used only bosentan increased the circulating plasma ET-1 levels. It may therefore be concluded that ET contributes to basal systemic and pulmonary vascular tone through ET(A) receptor activation. ET(B)-receptors are likely to cause the elevated plasma levels of ET-1 observed after bosentan administration. Furthermore, circulating plasma levels of ET-1 do not reflect the physiological effects of ET-1. PMID- 10090326 TI - Relationship between blood pressure and heart-rate variability during graded head up tilt. AB - To investigate the relationship between change in blood pressure and autonomic nerve activity, two types of head-up tilt experiments were performed. One was a 30 degrees, 45 degrees, 60 degrees, and 90 degrees graded tilt-up, in which tilt angles were changed at 6-min intervals and 5 min were spent at each angle. The other was a 10-min lasting head-up tilt at 60 degrees. Electrocardiogram (ECG) and blood pressure (Finapres) of 18 healthy non-smoking subjects (9 men, 9 women) were recorded during the experiments. Heart-rate variability was examined by general spectral analysis (GSA). The high-frequency/total-area ratio (HF/TO) showed a decrease as the tilt angle increased. Compared with the values at the 0 degrees position, these changes were statistically significant (P < 0.05). The low-frequency/HF ratio (LF/HF) showed a significant (P < 0.05) difference between 0 degrees and 90 degrees, and between 30 degrees and 90 degrees. Some of the subjects could not maintain their blood pressure during either of the head-up tilt experiments, and they showed only a slight change in HF/TO and LF/HF. This result confirmed that immediate responses to head-up tilt reflect autonomic nerve activity. Hence, changes in the frequency components were found to be an index of autonomic nerve activity, and they explained the individual differences observed in the ability to control blood pressure during a transition to upright posture. PMID- 10090328 TI - Effects of nitric oxide inhalation on pulmonary gas exchange during exercise in highly trained athletes. AB - The pathophysiology of exercise-induced hypoxaemia in elite athletes is still unclear but several studies indicate that a diffusion limitation, which could be explained by an interstitial pulmonary oedema, is a major contributing factor. Stress failure would induce a haemodynamical interstitial oedema with inflammatory reaction and release of mediators like histamine. Histamine release was found to be correlated with the hypoxaemia in elite athletes. If stress failure is involved, inhalation of pulmonary vasodilatators such as nitric oxide during exercise in athletes should induce an inhibition of the histamine release and a reversal of the hypoxaemia. Nine male endurance-trained young athletes performed two randomized exercise tests: one without and the other with 15 p.p.m. of inhaled NO. Measurements of histamine release and arterial blood gas analysis were performed at rest and at 50, 75 and 100% VO2max. At rest, inhaled NO induced a decrease in PaO2 and an increase in (Ai-a)DO2 suggesting increased perfusion of units with low V(A)/Q. During exercise, NO inhalation suppressed the histamine release observed without NO and induced a moderation in the decrease in PaO2 and the increase in (Ai-a)DO2 observed between 75 and 100% of VO2max (P < 0.005). In conclusion, this study showed that NO inhalation inhibited exercise-induced histamine release in highly trained athletes, but we were unable to confirm the suppression of exercise-induced hypoxaemia (EIH). An unexpected result was that inhaled NO seemed to have a marked effect on arterial oxygenation in highly trained-athletes, by disturbing gas exchanges. PMID- 10090329 TI - Serial effects of high-resistance and prolonged endurance training on Na+-K+ pump concentration and enzymatic activities in human vastus lateralis. AB - The purpose of this study was to compare two contrasting training models, namely high-resistance training and prolonged submaximal training on the expression of Na+-K+ ATPase and changes in the potential of pathways involved in energy production in human vastus lateralis. The high-resistance training group (VO2peak = 45.3 +/- 1.9 mL kg(-1) min(-1), mean +/- SE, n = 9) performed three sets of six to eight repetitions maximal, each of squats, leg presses and leg extensions, three times per week for 12 weeks, while the prolonged submaximal training group (VO2peak = 44.4 +/- 6.6 mL kg(-1) min(-1), n = 7) cycled 5-6 times per week for 2 h day(-1) at 68% VO2peak for 11 weeks. In the HRT group, Na+-K+ ATPase (pmol g( 1) wet wt), measured with the 3H-ouabain binding technique, showed no change from 0 (289 +/- 22) to 4 weeks (283 +/- 15), increased (P < 0.05) by 16% at 7 weeks and remained stable until 12 weeks (319 +/- 19). For prolonged submaximal training, a 22% increase (P < 0.05) was observed from 0 (278 +/- 31) until 3 weeks (339 +/- 29) with no further changes observed at either 9 weeks (345 +/- 25) or 11 weeks (359 +/- 34). In contrast to high-resistance training, where a 15% increase (P < 0.05) was observed, only in the maximal activity of phosphorylase, prolonged submaximal training resulted in increases in malate dehydrogenase, beta-hydroxyl-CoA dehydrogenase, hexokinase and phosphofructokinase. In contrast to high-resistance training which failed to result in an increase in VO2peak, prolonged submaximal training increased VO2peak by approximately 15%. Only for prolonged exercise training was a relationship observed for VO2peak and Na+-K+-ATPase (r = 0.59; P < 0.05). Correlations between VO2peak and mitochondrial enzyme activities were not significant (P > 0.05) for either training programme. It is concluded that although both training programmes stimulate an up-regulation in Na+-K+ ATPase concentration, only the prolonged submaximal training programme enhances the potential for beta-oxidation, oxidative phosphorylation and glucose phosphorylation. PMID- 10090330 TI - Changes in myosin heavy chain profile of mature regenerated muscle with endurance training in rat. AB - The objective of the present study was to examine the response of fast-twitch muscle to endurance training long after the muscle had regenerated from toxin injury. Seventeen male Wistar rats were randomly assigned to a sedentary (S, n = 10) or a trained group (T, n = 7). Endurance training by treadmill running (5 days week(-1), 30 m min(-1), 7% grade, 2 h day(-1) for 5 weeks) was initiated 5 weeks after myofibre degeneration was induced in the right extensor digitorum longus muscle (EDL) by two injections of 0.2 mL of the unfractionated venom from Naja nigricollis snake. Gel electrophoresis analyses showed that training alone resulted in a 140% increase in type IIX myosin heavy chain (MHC) (P < 0.01) and a slight decrease in type IIB MHC (-14% P < 0.05). Regeneration alone induced an increase in both type IIA and IIX MHC expression (103%, P < 0.05, and 131%, P < 0.01, respectively), and a concomitant decrease in the percentage of type IIB MHC (P < 0.05). The shift from type IIB toward type IIA MHC composition observed in regenerated muscles of T rats resulted not only from an additive, but from a cumulative effect of training and regeneration. Immunohistochemical analysis of MHC content in individual fibres showed similar changes. These data suggest that the impact of endurance training on fast-type MHCs was more marked in mature regenerated muscles than in regenerating ones, and provide evidence of the heightened plasticity of fully regenerated muscles to repeated exercise. PMID- 10090332 TI - Body composition, resting and running metabolic rates, and net cost of running in rats during starvation. AB - Resting metabolic rate decreases during starvation. However, effects of starvation on the cost of running are not clear. The aim of this study was to examine the effects of 5 days starvation on body composition, resting metabolic rates, running metabolic rates, and net cost of running in male rats. Five days starvation resulted in reductions of 70% fat, 8% protein and 12% carbohydrates. Mass(-0.75) specific resting metabolic rate was significantly reduced from 3.69 +/- 0.27 to 2.73 +/- 0.17 W kg(-0.75) after 5 days starvation. The reduction in metabolic rate after 5 days starvation was maintained during running, in that running metabolic rate was reduced from 10.65 +/- 0.41 to 8.97 +/- 0.47 W kg( 0.75). The net costs of running were calculated and expressed as the costs of moving 1 kg a distance of 1 m. After 5 days of starvation it was reduced from 31.16 +/- 2.03-29.79 +/- 1.69 J m(-1) kg(-1). The reduction however was not significant. The present results therefore suggest that 5 days starvation resulted in a metabolic depression of the resting metabolic rate that was maintained during running. However, the net cost of running remained unchanged, suggesting that the muscle tissues are not significantly involved in the metabolic changes during starvation. PMID- 10090331 TI - Regulation of GLUT4 protein expression and glycogen storage after prolonged exercise. AB - The purpose of this study was to determine the time course of GLUT4 protein accumulation following an exercise-carbohydrate supplementation regimen, and to evaluate the effect of this regimen on GLUT4 mRNA regulation. Rats were exercised by swimming and intubated with 1 mL of a 50% glucose solution immediately post exercise. Exercise significantly reduced muscle glycogen by 50%. By 1.5 h of recovery, muscle glycogen was normalized, but continued to increase above the control level during the next 16 h. A faster and larger repletion of glycogen occurred in the fast-twitch red compared with the fast-twitch white muscle during the 16 h of recovery. GLUT4 protein concentration in fast-twitch red muscle was significantly increased above control by 1.5 h of recovery, and progressively increased throughout the recovery period. Fast-twitch white muscle demonstrated a similar trend, but the increase in GLUT4 protein did not reach significance until 5 h of recovery. Fast-twitch red muscle GLUT4 mRNA was increased by 53% above control immediately post-exercise, but returned to the control level by 1.5 h of recovery. GLUT4 mRNA associated with polysomes, however, increased significantly during this time and remained elevated for a minimum of 5 h. The results suggest that the increased GLUT4 protein expression following a regimen of exercise carbohydrate supplementation occurs sufficiently fast to contribute to the resynthesis of muscle glycogen, and is controlled by both pre-translational and translational mechanisms. PMID- 10090333 TI - Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes. AB - Carbonic anhydrase (CA) cytoplasmic isozymes CA I and CA II were found in human erythrocyte membrane ghosts, when prepared at pH 5.4 and pH 7.4, but not in ghosts prepared at pH 8.2. These findings could indicate that previously reported CA activity of ghosts was owing to contamination by CA I and CA II during the preparation of the ghosts. However, using a sensitive micro-assay, CA activity was also found in ghosts prepared at pH 8.2. This activity constitutes 0.2% of the erythrocytes' total CA-activity, and originates from a membrane-associated isoform of CA, located at the exterior membrane surface. It has immunochemical and kinetic properties like those of the membrane-bound CA IV, previously isolated from kidney, lung and small blood vessels. Its function is possibly to interact with the red cell membrane anionic transport protein, band 3, for the bicarbonate/chloride exchange. PMID- 10090334 TI - Localization of carbonic anhydrase in swimbladder of European eel (Anguilla anguilla) and perch (Perca fluviatilis). AB - The distribution of carbonic anhydrase in swimbladder tissue and especially in gas gland cells of the European eel (Anguilla anguilla) and the perch (Perca fluviatilis) was analysed using histochemical staining according to Hansson (1967), with modifications proposed by Ridderstrale (1991). While in the European eel, gas gland cells are distributed as a single layered epithelium over the whole secretory part of the swimbladder, the gas gland of the perch consists of a compact, richly vascularized 'multilayered' epithelium, in which gas gland cells have contact with the swimbladder lumen via small channels. In spite of these differences in organization, membranes of gas gland cells near blood vessels are richly folded in both species. A strong histochemical staining for carbonic anhydrase was observed in these membrane foldings. With prolonged incubation times a positive reaction was also observed in the cytoplasm of gas gland cells. In addition, the vascular endothelium and the erythrocytes showed a positive histochemical reaction. No staining, however, was visible in apical membranes towards the lumen of the swimbladder. In the perch, swimbladder epithelial cells outside the gas gland showed no positive staining of carbonic anhydrase. The results thus indicate that carbonic anhydrase activity is especially concentrated in membranes facing blood vessels. This suggests that a rapid equilibrium of the CO2/HCO3- reaction in the intracellular as well as in the extracellular space is essential for swimbladder function. PMID- 10090335 TI - Vasoactive intestinal peptide suppresses migrating myoelectric complex of rat small intestine independent of nitric oxide. AB - The involvement of nitric oxide (NO) in the biological response to vasoactive intestinal peptide (VIP) on the migrating myoelectric complex (MMC) of small bowel and systemic arterial blood pressure was investigated in the rat. Animals were supplied with bipolar electrodes for electromyography of the small intestine and blood pressure was assessed by a pressure transducer connected to a carotid artery. In the first session, Nomega-nitro-L-arginine (L-NNA) was administered intravenously at 1, 2, 4 and 20 mg kg(-1). Effects of L-NNA at 1 and 20 mg kg(-1) were also studied after L-arginine 300 mg kg(-1). In the second session, intravenous infusion of VIP 500 pmol kg(-1) min(-1) was administered before and after L-NNA at 1 and 20 mg kg(-1). L-NNA at increasing doses stimulated myoelectric spiking of the small bowel until at 4 mg kg(-1) the MMC was disrupted and irregular spiking induced. Neither at 1 nor 20 mg kg(-1) did L-NNA affect the inhibitory motility response or decrease of blood pressure induced by VIP at a dose of 500 pmol kg(-1) min(-1). Our results show that effects of VIP on motility of the small intestine and systemic arterial blood pressure are direct and not dependent on NO as a common final link. PMID- 10090336 TI - Plasma leptin and insulin in C57BI/6J mice on a high-fat diet: relation to subsequent changes in body weight. AB - It has been proposed that leptin and insulin through central effects are involved in the regulation of energy balance and body weight. Whether circulating leptin or insulin levels predict subsequent changes in body weight is, however, not known. We examined plasma leptin and insulin at 2, 3, 6, 9 and 12 months of age in C57BI/6J mice given a normal diet (n = 12) or a high-fat diet (58% fat on a caloric base; n = 15). Plasma leptin levels increased by age and correlated with body weight in the entire material (r = 0.81, P < 0.001). Also plasma insulin increased by high-fat diet and correlated across all age periods with body weight (r = 0.56, P < 0.001). In mice, given normal diet, plasma leptin or insulin did not correlate to subsequent changes in body weight at any of the time points studied. However, in mice given the high-fat diet, plasma leptin at 6 (r = -0.57, P = 0.027) and 9 months of age (r = -0.56, P = 0.042) as well as plasma insulin at 6 (r = - 0.51, P = 0.049) and 9 months (r = -0.58, P = 0.037) correlated inversely to the change in body weight during the subsequent 3-month period. Hence, both leptin and insulin are negative predictors for future weight gain in high-fat fed mice. This suggests that when the regulation of body weight is challenged by a high-fat diet, leptin and insulin act to restrain or prevent future weight gain. This in turn may suggest that impairment of these (probably central) actions of leptin and insulin might underlie excessive increase in body weight under such conditions. PMID- 10090337 TI - Platelet aggregation in young men with contrasting predisposition to high blood pressure. AB - In essential hypertension, abnormal platelet function may induce vasospasm and predispose to thrombotic vascular occlusion. We studied in vitro aggregability in platelets from young men with contrasting predisposition to hypertension, defined by their own blood pressure and blood pressures of their parents. Among offspring of parents with low blood pressure, higher blood pressure was associated with impaired aggregation in response to epinephrine (2 x 10(-8) to 5 x 10(-6) mol/L), which was unaffected by endothelin-1 (10(-9) mol/L). By contrast, among offspring of parents with high blood pressure, higher blood pressure was associated with normal aggregation to epinephrine and potentiation of the primary phase of aggregation by endothelin-1. We conclude that enhanced platelet sensitivity to endothelin-1 appears to be a feature of the familial predisposition to hypertension, rather than a nonspecific consequence of high blood pressure. PMID- 10090338 TI - The relationship between Ca2+-ATPase and freely exchangeable Ca2+ in the dense tubules: a study in platelets from women. AB - The main aims of this work were to examine in women: the relationship between the freely exchangeable Ca2+ (FECa2+) in the dense tubules and the activity of the sarco(endo)plasmic reticulum (SER) Ca2+-ATPase (SERCA) in platelets, and the relationship of these parameters with blood pressure and serum lipoproteins. Platelets from 14 white and 13 black women in good health were studied. The FECa2+ was measured as the ionomycin-evoked Ca2+ release (in the presence of thapsigargin) in Ca2+-free medium. SERCA activity was measured as the thapsigargin sensitive, Ca2+ dependent and ouabain resistant, ATP hydrolyses in platelet membranes. Relative expressions of SERCA 2 and 3 isoforms and Ras related protein (Rap) 1 in platelet membranes were determined by Western immunoblots. Highly significant correlations were observed for FECa2+ in the dense tubules with: 1) the maximal reaction velocity (Vmax) of the SERCA (r = 0.592, P = .0014), and 2) Rapl (r = 0.551, P = .0035). In addition, negative correlations were observed between FECa2+ in the dense tubules and age. No correlations were observed for these variables with blood pressure or serum lipoproteins. We conclude the FECa2+ and the Vmax of the SERCA are reliable indicators of Ca2+ load in platelets from women. However, in women, unlike previous observations in men, these platelet parameters are not correlated with blood pressure and serum lipoproteins. PMID- 10090339 TI - Changes in plasma, erythrocyte, and platelet magnesium levels in normotensive and hypertensive obese subjects during oral glucose tolerance test. AB - We evaluated the 75-g oral glucose tolerance test (OGTT)-induced modifications in glucose, insulin, and norepinephrine plasma concentrations, and in plasma, erythrocyte, and platelet magnesium levels in two groups of obese subjects (normotensive obese, NT-Ob, N = 19; hypertensive obese, HT-Ob, N = 15), and in a group of healthy control subjects (N = 12). During OGTT we detected a reduction in plasma magnesium concentrations and an increase in erythrocyte and platelet magnesium levels in the controls, whereas in both normotensive and hypertensive obese subjects, there was a reduction in plasma, erythrocyte, and platelet magnesium levels. Furthermore, no statistically significant difference was detected among the groups studied as regards delta-plasma magnesium. On the other hand, delta-erythrocyte magnesium and delta-platelet magnesium were negative in the NT-Ob (delta-erythrocyte magnesium: -0.24+/-0.08 mmol/L; delta-platelet magnesium: -0.49+/-0.09 micromol/10(8) cells) and HT-Ob (delta-erythrocyte magnesium: -0.20+/-0.10 mmol/L; delta-platelet magnesium: -0.50+/-0.11 micromol/10(8) cells) groups, and positive in control subjects (delta-erythrocyte magnesium: 0.40+/-0.08 micromol/L; delta-platelet magnesium: 0.47+/-0.09 mmol/ 10(8) cells). Finally, a direct correlation was found between delta norepinephrine and delta-erythrocyte magnesium (r = 0.80, P < .01) in the control group, and a negative correlation was detected between delta-norepinephrine and delta-platelet magnesium (r = -0.58, P < .05) in the HT-Ob group. Our results seem to indicate that the insulin resistance status, the hyperglycemia, and the disregulation of the adrenergic system in obese subjects could be involved in the pathogenesis of the magnesium homeostasis impairment observed in the obese subjects. PMID- 10090340 TI - Noninvasive detection of vascular dysfunction in alcoholic patients. AB - Vasodilation is impaired in various conditions, such as hypercholesterolemia and tobacco use. We evaluated brachial artery flow-mediated vasodilation (FMD) after blood pressure (BP) cuff occlusion using high-resolution B-mode ultrasound in 20 alcoholics, without any coexisting conditions such as smoking, hypertension, or cholesterolemia, after a 3-month period of abstinence. They were compared with a control group of 20 alcohol-free healthy subjects. We measured the diameter of the brachial artery under baseline conditions, during reactive hyperemia (with increased flow causing endothelium-dependent dilatation), and after administration of sublingual glyceryl trinitrate (GTN), an endothelium independent dilator. We performed an echocardiographic study (Esaote Au3) according to guidelines of the American Society of Echocardiography to assess left ventricular mass (LVM), wall thickness, systolic stress, and diastolic function changes. FMD (% diameter change) was significantly less in the alcoholic patients than in the controls (6.03+/-3.67 v 13.7+/-4.65; P < .05), whereas no difference was noted after GTN administration (13.7+/-7.97 v 16.0+/-5.12, P = NS). Echocardiographic study showed no differences between the study group for LVM, wall thickness, and systolic stress; diastolic function expressed as E/A ratio inversion was significantly impaired. These data demonstrate an impairment of endothelial-dependent vasodilatation in chronic alcohol abusers, which may contribute to the excess prevalence of cardiovascular diseases in these individuals. PMID- 10090341 TI - Impaired adaptation of cardiopulmonary receptors to Western diet in normotensive black immigrants. AB - A blood pressure increase was reported in black immigrants from Africa to Western countries. The present study was undertaken to evaluate whether an impairment of the cardiopulmonary reflex might make blacks unable to adapt peripheral vascular resistance to increased sodium intake. Ten normotensive clinically healthy blacks (aged 38+/-6 years) who had recently migrated from Mogadishu, Somalia to Florence and 10 age- and gender-matched healthy white subjects were investigated. Cardiopulmonary baroreceptor reflex was studied after 7 days of normal (108 mEq) and low (30 mEq) sodium intake by assessing forearm vascular resistance (FVR) and central venous pressure (CVP) during the application of lower body negative pressure (LBNP) at -10 and -20 mm Hg. With a normal sodium diet the gain in cardiopulmonary baroreceptor reflex, expressed as the FVR increase per mm Hg of CVP reduction, was significantly lower in blacks than in white subjects (2.6+/ 1.1 v 5.1+/-1.1 U per mm Hg of CVP, P < .001). Differences between the groups disappeared with a low-sodium diet because the reduction of the efficiency of the cardiopulmonary baroreceptor reflex was lower in blacks than in whites (2.4+/-0.7 v 3.3+/-0.7 U per mm Hg of CVP, P = .09). In conclusion, the efficiency of the cardiopulmonary reflex is lower in normotensive black immigrants than in whites. The lower adaptation of the cardiovascular system to the Western sodium diet could contribute to reported long-term blood pressure increase. PMID- 10090343 TI - Ambulatory blood pressure nondipping status in salt-sensitive and salt-resistant black adolescents. AB - This study examined the relationship between salt sensitivity and ambulatory blood pressure in 53 healthy black adolescents. Salt sensitivity was defined as an increase in mean blood pressure greater than or exceeding 5 mm Hg from a 5-day low-salt diet (50 mmol/24 h) to a 10-day high-salt diet (150 mmol/24 h NaCl supplement). Sixteen subjects were salt sensitive and 37 subjects were salt resistant (showed < 5 mm Hg increase in mean blood pressure). Subjects were classified as dippers (> or =10% decrease in blood pressure from awake to asleep) based on their 24-h ambulatory blood pressure values. Nondippers showed higher systolic, diastolic, and mean asleep blood pressures than dippers (P < .05 for all). Salt-sensitive subjects showed greater daytime diastolic and mean blood pressures than salt-resistant subjects (P < .05 for both). A significantly greater percentage of nondippers were salt sensitive, compared with salt resistant for diastolic blood pressure (P < .001) and mean blood pressure (P < .05). For both of these blood pressure measures, 50% of the salt-sensitive subjects had a nondipping status, compared with only 5.4% of the salt-resistant subjects for diastolic blood pressure, and 18.9% of the salt-resistant subjects for mean blood pressure. These results are the first to indicate that salt sensitivity is associated with nondipper blood pressure status in a black normotensive adolescent population. PMID- 10090342 TI - Effects of age and hypertension on cardiac responses to the alpha1-agonist phenylephrine in humans. AB - Both aging and hypertension decrease the responsiveness of several receptor systems. The purpose of this study was to investigate the effect of aging versus hypertension on the blood pressure (BP), heart rate, and left ventricular (LV) responses to the alpha1-agonist phenylephrine in humans. Fourteen young (age, 21 40 years; range, 30+/-1 years; mean +/- SEM), and 18 older (age, 50-73 years; range, 60+/-1 years) healthy volunteers, as well as 10 young (age, 30-39 years; range, 36+/-1 years) and 15 older (age, 50- 64 years; range, 58+/-1 years) hypertensive subjects were studied. Phenylephrine was administered at four incremental rates for 8 min each. Cardiac responses were assessed by echocardiography. Phenylephrine caused twofold larger increases in systolic BP in young and older hypertensives and older normotensives, compared with young normotensives, but similar decreases in heart rate in all four groups. Younger normotensive subjects exhibited the largest decreases in stroke volume index, ejection fraction, and cardiac index in response to phenylephrine, despite similar increases in end-systolic stress for all groups. There is an age- and hypertension-related decrease in reflex vagal restraint in response to alpha1 adrenoceptor stimulation in humans, which leads to significant attenuation of the decrease in heart rate as well as in LV function in response to a pressor stimulus, and presumably therefore to enhanced systolic BP responses relative to young normotensive subjects. PMID- 10090344 TI - The role of adrenomedullin. PMID- 10090345 TI - Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase. AB - The inducible nitric oxide synthase isoform (iNOS) is upregulated by cytokines and endotoxins in many types of cells, including cardiac myocytes. Nitric oxide (NO) induced by cytokines can be cytotoxic, and has been implicated in the pathophysiology of myocardial infarction, cardiomyopathy, and septic shock. To examine the role of iNOS in the ischemic myocardium, we studied: 1) the time course of expression of iNOS mRNA after myocardial infarction (MI) in male Sprague-Dawley rat hearts and expression of iNOS protein in the infarcted region; 2) whether hypoxia in vitro is a potential mediator of the induction of iNOS mRNA; and 3) whether inhibition of iNOS by two different selective inhibitors (aminoguanidine and S-methylisothiourea sulfate) in vivo influences infarct size. Myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD), and tissue was collected at selected times thereafter from both ligated and sham-operated rats. iNOS mRNA was induced in the infarcted region of the left ventricle for 7 days; iNOS protein was also detected in the infarcted area. We next tested whether hypoxia would induce iNOS in vitro. In cultured neonatal ventricular myocytes, iNOS mRNA was slightly induced by 6 to 24 h of hypoxia; however, iNOS protein was only detected when the cytokine interleukin-1beta was present. To study whether iNOS activity contributed to myocardial damage (eg, infarct size), we administered the first dose of the NOS inhibitors 24 h before LAD occlusion and then a second dose after surgery. Inhibition of iNOS activity with aminoguanidine reduced infarct size by 20% but had no effect on infiltration by neutrophils, whereas the more selective inhibitor S-methylisothiourea sulfate reduced infarct size by 41%. These data suggest that NO derived from the iNOS isoform contributes to some of the myocardial injury following MI, possibly by causing myocardial cell death in areas bordering the ischemic region of the heart. PMID- 10090346 TI - A high sucrose, high linoleic acid diet potentiates hypertension in the Dahl salt sensitive rat. AB - Insulin resistance can be induced by diets high in simple carbohydrates or fatty acids. To determine whether these nutrients also affect arterial pressure in genetic models of salt sensitive and salt resistant hypertension, Dahl salt sensitive (S) and salt resistant (R) rats were each fed the following isocaloric diets containing 3% NaCl for 4 weeks (10 rats/group): 1) control; 2) high sucrose (60%); 3) high linoleic acid (LA, provided as 10% safflower oil); and 4) high sucrose plus high LA. Tail systolic blood pressures (SBP) were measured weekly, and at 4 weeks, direct mean arterial pressures (MBP) were measured in conscious animals. Insulin sensitivity was assessed by in vitro uptake of tritiated glucose by adipocytes in response to graded doses of insulin. Weight gain did not differ among groups. High sucrose alone and high LA alone did not affect blood pressure in either strain. However, SBP and MBP were increased (P < .05) by the high sucrose plus high LA diet in Dahl-S but not in Dahl-R rats. Sucrose alone and LA alone decreased (P < .05) insulin sensitivity in Dahl-S and Dahl-R rats. In both strains, sucrose plus LA decreased insulin sensitivity to a greater extent (P < .05) than sucrose alone or LA alone. Thus, the sucrose plus LA diet decreased insulin sensitivity in both Dahl-S and Dahl-R rats, whereas blood pressure was increased only in Dahl-S rats. The phenotype of elevated arterial pressure is influenced both by a genetic-nutrient interaction and by an interaction among specific nutrients resulting in insulin resistance. PMID- 10090348 TI - Antihypertensive monotherapy with nisoldipine CC is superior to enalapril in black patients with severe hypertension. AB - A single-center, prospective double-blind randomized trial was conducted to compare the efficacy and safety of the calcium channel blocker nisoldipine in a sustained release coat-core formulation (CC), titrated from 10 mg to 40 mg daily, with the angiotensin converting enzyme inhibitor enalapril, titrated from 10 to 40 mg daily, in the treatment of black South African patients with severe hypertension (sitting diastolic blood pressure [DBP] between 115 and 140 mm Hg, confirmed by 24-h ambulatory blood pressure monitoring). Treatment target was a sitting DBP < 95 mm Hg by the 9th week of treatment. This was followed by a 4 month open phase using nisoldipine CC 10 to 60 mg daily. Ninety-six patients had complete data at baseline, and at the end of the double-blind and open phases, and were included in this analysis. In both groups, all patients required titration up to the maximal dose of double-blind medication. Monotherapy with nisoldipine CC, but not enalapril, significantly reduced both sitting and 24-h ambulatory blood pressure (BP). Twenty-four-hour BP in the nisoldipine CC group decreased from 179+/-14 / 118+/-7 to 144+/-16 / 94+/-10 mm Hg (P < .0001) versus 181+/-13 / 117+/-5 to 171+/-17 / 110+/-11 mm Hg in the enalapril group (P = ns). The profound decrease in blood pressure achieved with nisoldipine CC was accompanied by a significant reduction in left ventricular [LV] mass index, observed after only 2 months of treatment (from 146+/-40 to 129+/-35 g/m2, P = .05). In contrast, enalapril had no effect on LV mass (from 139+/-36 to 142+/-50 g/m2, P = NS). The antihypertensive effect of nisoldipine CC was further demonstrated in the open phase, during which 24-h BP decreased from 180+/-14 / 118+/-6 mm Hg (at baseline) to 142+/-16 / 92+/-10 mm Hg at the end of the 16-week open phase (P < .0001). This effect was sustained with trough-to-peak ratio of 74% for systolic and 67% for diastolic BP, with further regression in LV mass. Reduction in 24-h systolic BP to < 135 mm Hg was associated with a greater degree of regression of LV mass index in patients treated with nisoldipine CC. The incidence of adverse events in both groups was low and both nisoldipine CC and enalapril were well tolerated. The incidence of significant ventricular arrhythmia was also low and did not change with treatment. In conclusion, our findings suggest that nisoldipine CC administered once daily could be considered as a suitable first-line antihypertensive agent in black patients with severe hypertension, based on its profound and sustained blood-pressure-lowering effect, associated with significant regression of left ventricular mass and its low side effect profile. PMID- 10090347 TI - V2-receptor-mediated relaxation of human renal arteries in response to desmopressin. AB - The effects of deamino-8-D-arginine vasopressin (desmopressin), a V2 receptor antidiuretic agonist, were studied in isolated rings from branches of renal arteries obtained from 22 patients undergoing nephrectomy. The rings were suspended in organ bath chambers for isometric recording of tension. In precontracted rings with norepinephrine (10(-6) to 3 x 10(-6) mol/L), desmopressin (10(-11) to 3 x 10(-7) mol/L) caused endothelium-dependent relaxation (81%+/-4% reversal of the initial contraction in arteries with endothelium; 20%+/-4% in arteries without endothelium; P < .05). The relaxation to desmopressin in rings with endothelium was reduced significantly by indomethacin (10(-6) mol/L) and unaffected by the inhibitor of nitric oxide synthase NG-nitro-L-arginine methyl ester (10(-4) mol/L). Two V1 receptor antagonists (a peptidic and a nonpeptidic) had no effect on desmopressin-induced relaxation. However, V2 receptor antagonists (three peptidic and a nonpeptidic) reduced significantly (P < .05) the maximal response to desmopressin. The results of this study show that desmopressin exerts powerful endothelium-dependent relaxation of human renal arteries, probably through stimulation of V2-like receptors that may bring about the release of dilating prostaglandins. PMID- 10090349 TI - Blood pressure and the risk of complex arrhythmia in renal insufficiency, hemodialysis, and renal transplant patients. AB - Complex arrhythmia is frequent in hemodialysis patients but it is not clear if this is a consequence of dialysis or uremia or is secondary to the hemodynamic and cardiovascular alterations often associated with chronic renal failure. The incidence of complex ventricular arrhythmia (frequent multiform premature beats, couplets, and runs) in 31 subjects who had their uremic status recently corrected by renal transplant (Group 1) and in 23 predialysis (Group 2) and 73 hemodialysis (Group 3) chronic renal failure patients were studied with 24-h Holter monitoring. Patients were not receiving antiarrhythmic drugs or digitalis and significant coronary artery disease was excluded by clinical and noninvasive methods. Complex arrhythmia was two times more frequent in dialysis patients but the difference did not reach statistical significance (Group 1: 16%; Group 2: 17%; Group 3: 34%; chi2 4.9, P = .086). The stepwise model of logistic regression analysis identified systolic blood pressure (odds ratio 1.015, 95% confidence interval [CI] 1.001-1.027, P = .03) and left ventricular systolic dysfunction (odds ratio 7.04, 95% CI 1.3-36.7, P = .02) as the only factors that independently influenced the probability of complex arrhythmia. Age, gender, race, diabetes, smoking status, body mass index, diastolic blood pressure, serum creatinine, hematocrit, left ventricular mass index, and use of diuretics, beta blockers, angiotensin converting enzyme (ACE) inhibitors, sympatolytics, and calcium channel blockers did not influence the occurrence of complex arrhythmia. The data indicate that blood pressure and myocardial dysfunction are more important determinants of complex arrhythmia than dialysis or uremia in chronic renal disease patients. PMID- 10090350 TI - Hemodynamic and renal effects of indomethacin in losartan-treated hypertensive individuals. AB - This study was undertaken to examine whether prostaglandin (PG) inhibition with indomethacin interferes with angiotensin II receptor blockade (losartan) during treatment for arterial hypertension. In a double-blind crossover design 10 patients with essential arterial hypertension and treated with losartan were randomized to supplementary treatment with indomethacin or placebo for 1 week, with a 2-week washout period interposed. At the end of each treatment period the following examinations were performed, preceded by 4 days on sodium-fixed diet: 24-h blood pressure (BP), 24-h sodium excretion (UNaV), supine BP, glomerular filtration rate (GFR), renal resistive index (RRI), extracellular fluid volume (ECV), sodium clearance (Cl(Na)), body weight, peripheral blood flow (PBF), and plasma concentrations of aldosterone, renin (PRC), and atrial natriuretic peptide (ANP). Indomethacin did not change BP. Indomethacin increased weight (P < .05) and ECV (P < .05). A nonsignificant decrease in UNaV was seen after indomethacin, as in 24-h Cl(Na). Conversely, in the laboratory in the supine position Cl(Na) increased after indomethacin (P = .05). Indomethacin increased plasma ANP (P < .01). No changes were observed in GFR, RRI, PBF, PRC, or plasma aldosterone. Thus indomethacin did not attenuate the antihypertensive effect of losartan, neither was peripheral blood flow affected. Indomethacin caused sodium retention in the nonresting situation, which was not counterbalanced by the increased Cl(Na) in the resting supine position. The observed changes during prostaglandin (PG) inhibition seem most likely due to lack of PG "protection" of renal function, when the sympathetic nervous system is activated throughout the day. PMID- 10090351 TI - Fosinopril decreases levels of soluble vascular cell adhesion molecule-1 in borderline hypertensive type II diabetic patients with microalbuminuria. AB - Angiotensin converting enzyme inhibitors (ACE-I) are a mainstay for the treatment of heart failure, and of diabetic microalbuminuria. Recently ACE-I have been found to decrease plasma levels of circulating vascular cell adhesion molecule-1 (cVCAM-1) in patients with congestive heart failure. As increased cVCAM-1 levels are pathognomonic for diabetics with microangiopathy, we investigated the effects of ACE-I on plasma levels of cVCAM-1, intercellular adhesion molecule (cICAM-1), and cE-selectin in microalbuminuric diabetics. In addition, the effects of ACE-I on plasma levels of plasminogen activator inhibitor (PAI-1) and of tissue plasminogen activator (TPA) were studied. Fosinopril (10 mg/day) was administered over 12 weeks to 11 microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM). As expected, baseline plasma concentrations of cE-selectin, cICAM-1, and cVCAM-1 were markedly higher in patients than in healthy control subjects (n = 82; P < .001). PAI-1 levels in NIDDM were similar to those in control subjects, whereas TPA levels were about 25% lower in patients than in control subjects (P = .013). Serum levels of cVCAM-1 decreased by -19% (CI: -25% to -13%) after treatment with fosinopril (P = .003) and were no longer different from those of the control group. In contrast, plasma levels of cE-selectin, cICAM 1, PAI-1, and TPA were unaffected. As expected microalbuminuria decreased by -44% (CI: -65 to -22; P = .004). In conclusion, fosinopril lowered cVCAM-1 levels along with microalbuminuria in NIDDM. This may represent a novel mechanism of action of ACE-I in diabetes-associated endothelial dysfunction. Whether decreased VCAM-1 expression is responsible for the observed reduction in microalbuminuria, deserves further investigation. PMID- 10090352 TI - White coat hypertension detected during screening of male adolescent athletes. AB - We investigated the utility of the selective use of ambulatory BP monitoring (ABPM) and echocardiography in detecting truly hypertensive adolescents from a cohort of young adolescent athletes undergoing BP screening. A total of 410 athletes (aged 16.4+/-2.6 years) were screened and, if initial BP measurement detected a persistently elevated BP (>140 mm Hg systolic or >90 mm Hg diastolic), ABPM and echocardiography were performed. Eighteen clinically hypertensive cases (4.4%) were detected and evaluated with a 24-h ABPM. Sixteen of them were defined as having "white coat hypertension" because they were detected to have normal daytime and nocturnal BP. An elevated level of BP confirmed on ABPM was recorded in only two (0.5%) athletes. Echocardiography failed to demonstrate significant abnormalities. PMID- 10090353 TI - Marital cohesion and ambulatory blood pressure in early hypertension. AB - One hundred thirty-four men and seventy-one women, unmedicated mild hypertensives, underwent 24-h ambulatory blood pressure (BP) monitoring (ABP) and completed standardized questionnaires measuring marital and job stress. Of these, 44.8% had daytime diastolic BP < 90 mm Hg; 96.1% had left ventricular mass index in the normal range (N = 176). Lower marital cohesion (Cohesion, subscale of the Dyadic Adjustment Scale) was related to elevated nighttime ABP (P < or = .05) and 24-h diastolic BP (P < .05). With low Cohesion (N = 83), more reported spousal contact was associated with elevated nighttime ABP (P < .031). The 7.3% of subjects with very low Cohesion demonstrated approximately 6 mm Hg elevation of all ABP variables, controlling for other significant variables (P < .05, except for nighttime SBP). This study shows an association between marital cohesion and ABP and suggests that marital factors may have a role in sustaining BP in early hypertension. PMID- 10090354 TI - Ambulatory measurement of the timing of Korotkoff sounds in a group of normal subjects: influence of age and height. AB - Ambulatory measurement of timing of Korotkoff sounds (QKD interval) gives an estimate of arterial distensibility derived from the velocity of the pulse wave over a vascular territory that includes the ascending aorta. The main advantages of the method are that it is entirely automatic, non-operator-dependent, and highly reproducible, and produces a measure independent of instantaneous blood pressure. This study of a group of 180 normal subjects aged between 10 and 78 years was designed to produce references values and to study the influence of height. The results confirmed the reduction with age of arterial distensibility in the whole population. However before the age of 30, QKD100-60 was positively correlated with height according to the relationship QKD100-60 = 0.73 height (cm) + 91, but not with age. This equation enables calculation of the theoretical value of QKD100-60 as a function of height for any patient to which the observed value can be expressed as a percentage. This effectively eliminates the influence of height, which reflects the length of the arterial segment under investigation. PMID- 10090355 TI - Dose-dependent biphasic effect of ethanol on 24-h blood pressure in normotensive subjects. AB - The vasodilation that follows acute alcohol intake is hard to conciliate with the high prevalence of hypertension detected in those persons who consume regular amounts of alcohol. In this experiment we examined early and late hemodynamic effects of acute administration of water and of 15 g, 30 g, and 60 g of alcohol in 40 normal men, aged 19 to 30 years, using 24-h ambulatory blood pressure monitoring (ABPM). Mean systolic and diastolic blood pressures were each approximately 4 mm Hg lower during the period immediately after ingestion of 60 g (v 0 g) of ethanol, and were 7 and 4 mm Hg higher, respectively, at night. The day minus night differences displayed a dose-response curve both for systolic (P < .001) and diastolic blood pressure (P = .045). Three subjects in the 60-g group had more than 50% of nightly blood pressure loads in the hypertensive range against none in the remaining groups (P < .01). In conclusion, our findings suggest that acute alcohol intake elicits a biphasic hemodynamic response, causing, first, vasodilatation and, later, a pressor effect. The higher prevalence of hypertension in alcohol abusers seen in epidemiological surveys may be, in part, a result of measurements done in the period of transiently increased blood pressure during ethanol washout. PMID- 10090356 TI - Is nocturnal blood pressure dipping reproducible? PMID- 10090357 TI - Hypertension specialists: ready or not, here we come. PMID- 10090358 TI - Classification of herpes simplex virus keratitis and anterior uveitis. AB - PURPOSE: To review the classification of herpes simplex virus (HSV) keratitis and anterior uveitis using the available clinical, pathologic, and laboratory models of disease. METHODS: The literature was reviewed to establish prior classifications of herpes simplex keratitis and uveitis. The author introduces a classification attempting to encompass all patients with this disease process, taking into account the newer proposed mechanisms of disease. RESULTS: A classification of HSV keratitis and uveitis is introduced based on the literature and the experience of the author in treating patients with this condition. CONCLUSIONS: There are multiple mechanisms of disease after ocular HSV infection, including damage from live virus, from immune and inflammatory mechanisms, and from structural damage in the aftermath of HSV infection (metaherpetic disease). Clinical, pathologic, and etiologic descriptions of these disease manifestations are offered. This may allow better communication between clinicians and authors of research protocols by defining the different aspects of this complex disease process. PMID- 10090359 TI - Classification of herpes simplex virus keratitis. AB - PURPOSE: We propose a nomenclature for classification of herpes simplex virus (HSV) keratitis. We hope that a more consistent classification system will lead to a better understanding of the disease processes, thus resulting in improved diagnosis, treatment, and patient outcomes. METHODS: A review of the literature was performed to evaluate current HSV classification systems. These systems were evaluated in the context of both current clinical and basic science studies and our own clinical observations. RESULTS: The proposed classification system is based on the anatomy and pathophysiology of the specific presentations of HSV keratitis. Anatomically, the primary level of corneal involvement, whether epithelium, stroma, or endothelium, must be elucidated. Pathophysiologically, the cause of the inflammation. whether immunologic, infectious, or neurotrophic, must be determined. There are four major categories of HSV keratitis. (1) Infectious epithelial keratitis, which is made up of cornea vesicles, dendritic ulcer, geographic ulcer, and marginal ulcer. (2) Neurotrophic keratopathy, which includes punctate epithelial erosions and neurotrophic ulcer. (3) Stromal keratitis, which is subdivided into necrotizing stromal keratitis and immune stromal keratitis. (4) Endotheliitis, which has three clinical presentations: disciform, diffuse, and linear. CONCLUSION: We believe that by categorizing cases of HSV keratitis by their primary anatomic and pathophysiologic etiologic characteristics, clinicians can better understand and therefore treat all types of HSV keratitis. The four main categories of HSV keratitis are infectious epithelial keratitis, neurotrophic keratopathy, stromal keratitis, and endotheliitis. Each of these is subdivided to more specific clinical presentations. PMID- 10090360 TI - The BioMask for treatment of corneal surface irregularities with excimer laser phototherapeutic keratectomy. AB - PURPOSE: To assess the characteristics of BioMask as a potential masking agent for use with the excimer laser. METHOD: We addressed ablation rate, smoothness, ease of use, dioptric shift, treatment of standardized irregular topography, and ability of BioMask to induce dioptric change in vivo. RESULTS: BioMask ablates at a rate of 0.28 microm per pulse. The BioMask conforms to the base curve of a contact lens in the excimer blank, eye bank eye, and rabbit eye with a r2 of 0.9982, 0.9844, 0.9858, respectively. We are readily able to create 20 diopters of flattening or steepening (r2 = 0.9944). Standardized irregular topography generation in the rabbit eye and then removal with BioMask was successful. The central corneal topography of the rabbit cornea showed predictable changes with various contact lens base curves with the BioMask (r2 = 0.875). CONCLUSIONS: BioMask has excellent potential as an ablatable mask material in the treatment of superficial corneal scars. PMID- 10090361 TI - Limbal autografting: comparison of results in the acute and chronic phases of ocular surface burns. AB - PURPOSE: To compare outcomes of limbal autograft transplantation (LAT) in the acute and chronic phases of ocular surface burns. METHODS: Retrospective analysis of case records of 16 consecutive patients who underwent LAT for ocular surface burns, at our institute, between April 1994 and March 1997. RESULTS: Limbal autograft transplantation was successful in reconstructing the corneal surface and restoring ocular comfort in 15 (93.8%) eyes. Limbal autografting failed to reconstruct the ocular surface in one patient undergoing surgery 2 weeks after grade IV alkali burns. In 13 eyes with counting fingers or worse vision, functional success (visual acuity >20/400) was attained after LAT in nine (69.2%) eyes. Visual acuity > or = 20/80 was achieved in two (25%) of eight eyes undergoing surgery for a persistent epithelial defect (PED) and five of six (83.3%) eyes undergoing surgery after the epithelial defect had healed (p = 0.03). Nine patients underwent simultaneous superior and inferior limbal autografting. Mean epithelial healing time in six of these patients undergoing surgery in the acute phase of injury (<4 months) was 15+/-6.1 days. In three patients undergoing a similar procedure in the chronic phase of injury, the healing time was 8.3+/-6.7 days. CONCLUSIONS: Limbal autograft transplantation is successful in reconstructing the corneal surface and restoring ocular comfort after ocular surface burns. Surgery in the acute phase of injury (<4 months), in the presence of a PED, could result in delayed corneal reepithelialization and poorer visual prognosis. If performed in the acute phase of injury, LAT should be performed after adequate limbal vascularization and resolution of surface inflammation in the recipient eye, avoiding graft placement over ischemic limbus. PMID- 10090362 TI - Deep lamellar keratoplasty versus penetrating keratoplasty for corneal lesions. AB - PURPOSE: To compare the effectiveness of deep lamellar keratoplasty (DLK) with that of penetrating keratoplasty (PKP) in cases of corneal lesions not involving the endothelium. METHODS: Forty-eight eyes with leukomatous corneal opacity (n = 33), keratoconus with apical scarring (n = 6), granular corneal dystrophy (n = 5), lattice corneal dystrophy (n = 2), and multiple corneal foreign bodies (n = 2) in an age group varying from 16 to 53 years underwent DLK (n = 24) and PKP (n = 24) by utilizing B and (B+ and A) grade M-K preserved donor tissue, respectively. The patients were followed up closely, and the graft clarity, visual achievement, astigmatism and endothelial cell count were evaluated at repeated occasions up to 1 year. RESULTS: Astigmatism of <3 diopters (D) and > or = 5D was obtained in 19 eyes and one eye, respectively, after DLK at 6 months, whereas six eyes of the PKP group had astigmatism <3D, and 12 eyes had > or = 5D at the end of 6 months. The same at 1 year was observed in 20 and one eye in the DLK and eight and five eyes of the PKP group. Astigmatism of > or = 5D at the end of 6 months in both the groups showed highly significant changes (p < 0.001). Best corrected visual acuity of 6/18 or more was achieved in 18 and 12 eyes at 6 months after DLK and PKP, respectively, which were statistically highly significant (p < 0.001), whereas at 1 year, it was seen in 17 and 15 eyes of the DLK and PKP groups, respectively, which was nonsignificant. The mean endothelial cell count was 2,233.3+/-64.453 cells/mm2 and 2,219.6+/-102.48 cells/mm2 at 6 months and I year, respectively, after DLK, which was nonsignificant. The mean cell count of the donor eyes used for PKP was 2,191+/-52.164 cells/mm2, 1,902.8+/ 70.346 cells/mm2 at 6 months, and 1,579.0+/-80.24 cells/mm2 at 1 year. All the values showed highly significant changes (p < 0.001). Further, the graft clarity of > or = 3+ was achieved in 20 and 18 eyes at 6 months postoperatively in the DLK and PKP groups, whereas the same was observed in 19 and 13 eyes of both the groups, respectively, at 1-year follow-up. CONCLUSION: DLK is a promising procedure and should be practiced more frequently for corneal pathology not involving the endothelium. PMID- 10090363 TI - Treatment outcome of Moraxella keratitis: our experience with 18 cases--a retrospective review. AB - PURPOSE: To analyze the clinical presentation, predisposing risk factors, in vitro antimicrobial susceptibility, and especially the outcome of therapy of Moraxella keratitis. METHODS: Retrospective review of 18 culture-proven cases of Morarella keratitis. RESULTS: Morarella keratitis was associated with Hansen's disease, uncontrolled diabetes mellitus, herpes zoster ophthalmicus, and chickenpox of the recent past and severe protein energy malnutrition. Other associated ocular conditions included lagophthalmos, blepharitis, steroid therapy, corneal degeneration, and scleritis. In four patients, no systemic or ocular predisposing factors could be identified. Three patients presented with an indolent peripheral, anterior stromal infiltrate while the remaining patients showed a central or paracentral ulceration with or without hypopyon. Moraxella species was the only pathogen isolated in 11 cases, whereas mixed infection was seen in seven cases. All isolates were sensitive to ciprofloxacin. Eight of 18 strains of Moraxella were resistant to cefazolin. All 14 eyes for which the follow-up data were available responded to medical treatment alone. CONCLUSIONS: Although considered to be associated with poor outcome, our experience suggests that a favorable outcome can be expected in Moraxella keratitis. Cefazolin resistance (as seen in our series) may pose a problem and, hence, monitoring of antimicrobial susceptibility would be beneficial. In view of cefazolin resistance, ciprofloxacin monotherapy appears to be an effective method in the medical management of these cases. PMID- 10090364 TI - Outcomes of penetrating keratoplasty with imported donor corneas. AB - PURPOSE: To analyze factors influencing the surgical success of penetrating keratoplasty and long-term graft survival when using imported donor corneas. METHODS: Sixty-three donor corneas imported to Taipei from the Cincinnati Eye Bank from July 1992-June 1993 were used for penetrating keratoplasty. The corneal endothelium was examined using specular microscopy on arrival in Taiwan. The endothelial morphology and endothelial cell density (ECD) were compared with the photograph of the same cornea taken in the United States. The relationships of the surgical success rate with donor age, death to enucleation time, death to surgery time, and ECD were analyzed. The long-term graft survival and ECD of clear grafts were analyzed 4 years after surgery. RESULTS: On specular microscopic examination. the imported corneas showed diminished endothelial reflection, blurred cellular borders, and increased dark areas, which were markedly different from the pictures of the corneal endothelium taken in the United States. The average ECD before transportation was 2,525+/-267/mm2 and decreased to 1,934+/-250/mm2 after transportation (p < 0.001), with an average endothelial cell loss of 590+/-247/mm2. The overall surgical success rate was 89% and did not correlate with any of the donor factors tested except death to surgery time. The surgical success rate decreased when the time from death to surgery was >7 days (p = 0.05), mainly because of poor reepithelialization. Four years after surgery, 24 grafts remained clear. The ECD had decreased by 72+/-5% in the clear grafts. CONCLUSIONS: Our findings show that endothelial changes in imported donor corneas do occur after transportation, but the surgical success rate may not be influenced significantly if the penetrating keratoplasty is performed within 7 days after donor death. However, the ECD in the clear grafts 4 years after surgery is low. PMID- 10090365 TI - Efficacy and safety of infrared warming of the eyelids. AB - PURPOSE: To evaluate our newly developed infrared heater (IRH) and compare it to a broad-spectrum heater (BSH) for warming the eyelids. MATERIALS AND METHODS: Ten normal subjects were enrolled in this study. All measurements were recorded in a room with temperature 23 degrees C, 40% humidity, and no wind. The IRH is composed of two hard eye patches that have light-emitting diodes (LEDs) emitting near-infrared radiation. We first compared the temperature rises in the cornea, lacrimal gland, and eyelids after warming through closed eyelids with the IRH for 5 and 10 min. Next, we compared warming with the IRH or BSH for 30 min. We then used the IRH for 5 min with the eyes open to confirm its safety. Finally, we determined subjective feeling after warming the eyes. RESULTS: Direct comparison of 5 versus 10 min of warming with the IRH showed no significant differences in temperature rises in the upper eyelid (p = 0.09). The IRH caused significantly more heating (p < 0.05) than did the BSH everywhere except the cornea. The temperatures never rose above 37.7 degrees C for either heater during 30 min or with the IRH with the eyes open for 5 min. The subjects' comfort level rose significantly (p < 0.05) after treatment with the IRH. CONCLUSIONS: Our study showed the efficacy and safety of warming the eyelids with a newly developed IRH. Only 5 min is necessary to increase ocular temperature and enhance comfort. PMID- 10090366 TI - Levels of alpha1-proteinase inhibitor and alpha2-macroglobulin in the tear film of patients with keratoconus. AB - PURPOSE: Levels of alpha1-proteinase inhibitor and alpha2-macroglobulin in the tear film of patients with keratoconus were measured to elucidate their possible roles in the pathogenesis of keratoconus. METHODS: Tear samples were collected from 15 keratoconus patients and 14 age-similar human control subjects. Levels of alpha1-proteinase inhibitor and alpha2-macroglobulin in each tear sample were quantified and compared between the two groups. RESULTS: Mean values for alpha1 proteinase inhibitor were 101.0+/-35.5 and 106.1+/-41.7 ng/microg protein for the keratoconus and control groups, respectively. The corresponding mean values for alpha2-macroglobulin were 13.5+/-6.8 and 14.8+/-7.5 ng/microg protein. Neither inhibitor showed a statistically significant difference between the keratoconus and control specimens. Subset analysis to evaluate the effects of contact lens wear and the presence of a graft in the fellow eye did not reveal a statistically significant difference. CONCLUSION: The tear film of patients with keratoconus contains normal levels of protease inhibitors. Therefore, the tear film may not be a source of the reduced inhibitor levels shown in the corneas of patients with keratoconus. PMID- 10090367 TI - Transplantation of adult human or porcine corneal endothelial cells onto human recipients in vitro. Part I: Cell culturing and transplantation procedure. AB - PURPOSE: To develop a method for grafting endothelial cells isolated from organ cultured adult human corneas onto the denuded Descemet's membrane of human recipients. METHODS: Adult human or porcine corneal endothelial cells were isolated and maintained in monolayer cultures before seeding. Recipient corneas were stripped of their own endothelium by one of three different methods (mechanical, chemical, or physical) and the completeness of removal assessed after vital staining. The utility of each method was evaluated by monitoring the quality of attachment of the seeded-cell population. The seeding density of transplanted cells required for optimal results also was determined and the final numeric cell density achieved on recipient corneas after culturing for 7-20 days ascertained. The influence of incubating source cells with fibroblast growth factor (FGF), both on this latter parameter and on cell morphology, also was evaluated. The functional integrity of regrafted endothelium was assessed in 24-h perfusion experiments. RESULTS: The seeding of between 150,000 and 700,000 cells onto recipient corneas, followed by gentle centrifugation to improve attachment, yielded maximal final numeric cell densities of 3,450/mm2 and 1,850/mm2 in porcine and human lines, respectively. Recipient corneas were most effectively denuded of their own endothelium by freezing-and-thawing. The newly established endothelial monolayer remained stable for up to 20 days in organ culture (longest period monitored). FGF treatment did not enhance the final numeric density of cells attained on recipient corneas, but it did have a beneficial effect on their morphology. Only those recipient corneas that exhibited a well-differentiated monolayer of seeded endothelial cells underwent stromal deswelling near to physiologic levels. CONCLUSION: A practical working model has been developed, whereby recipient corneas stripped of their own endothelium can be furnished with a "new," near-normal endothelium by appropriate manipulations of the seeded-cell population. This now paves the way for a realistic tackling of the problem of endothelial cell paucity in donor corneas destined for transplantation. PMID- 10090368 TI - Transplantation of cultured adult human or porcine corneal endothelial cells onto human recipients in vitro. Part II: Evaluation in the scanning electron microscope. AB - PURPOSE: To evaluate the morphology of endothelial monolayers, which have been regrafted onto the denuded Descemet's membrane, with scanning electron microscopy (SEM). METHODS: Material derived from each of the experimental groups described in part I of this investigation was evaluated in the current study. Recipient corneas, denuded of their native endothelium by mechanical, chemical, or physical debridement, were examined to assess the effectiveness of each technique in killing and removing cells. Porcine or human donor corneal endothelial cells maintained in monolayer culture for up to 10 passages then were seeded onto the denuded Descemet's membranes of recipients in the absence or presence of fibroblast growth factor (FGF). The monolayers thereby established were examined in the SEM, and the morphologic status of individual cells compared with that manifested in normal human donor corneas maintained for 4 weeks in organ culture (reference control). Isolated and cultured human keratocytes regrafted onto the denuded Descemet's membranes of recipient corneas served as nonendothelial control specimens. Tissue was processed for examination in the SEM according to standard techniques. RESULTS: Each of the three methods used to strip recipient corneas of their native endothelium was effective and elicited no gross structural damage to Descemet's membrane. Some small focal defects within this latter layer were, however, observed, these being encountered at higher frequency after mechanical debridement than after chemical or physical stripping. Porcine or human endothelial cells seeded onto the denuded Descemet's membranes of recipient corneas formed stable monolayers. The morphologic status of regrafted cells corresponded to that manifested in monolayer cultures before seeding, porcine ones always being more differentiated than their human counterparts. Poorly differentiated human endothelial cells had a slender, elongated, fibroblast-like appearance, whereas more highly differentiated ones manifested broad, flat, polygonal profiles. Monolayers covered the entire corneal surface and impinged to a variable degree onto the trabecular meshwork, at which juncture cells always assumed a less well-differentiated morphology. FGF consistently effected an increase in differentiation status, and as this became augmented, the capacity of monolayers to violate the corneal-trabecular meshwork border was correspondingly repressed. Seeded keratocytes formed dense, multilayered sheaths, resembling retrocorneal membranes, across the entire corneal surface, trabecular meshwork, and iris root. The surface characteristics of the constituent cells were quite distinct from those manifested by endothelial cells, even the least well-differentiated ones. CONCLUSION: Regrafting of human corneal endothelial cells onto the denuded Descemet's membranes of recipients resulted in the formation of stable monolayers. Because the morphologic status of seeded cells closely mimicked that manifested in monolayer cultures before transplantation, it may be anticipated that efforts to refine and optimize culturing conditions would yield improvements in this parameter after regrafting. If these expectations can be realized, then the possibility of successfully establishing a "new" and functional endothelium on recipient corneas destined for clinical grafting may well be brought to fruition in the not-too-distant future. PMID- 10090369 TI - Corneal indentation during ultrasonic pachometry. AB - PURPOSE: This study attempted to determine whether the indentation of the cornea with an ultrasonic probe affects the corneal-thickness measurement. METHODS: A solid-tip ultrasonic transducer was mounted into the spring arm of a standard Goldmann Applanation Tonometer. Five human subjects were studied. The visual axis of each cornea was marked with a corneal marker, and the ultrasonic transducer was placed on the visual axis. Corneal-thickness measurements were made during five tension settings of the tonometer: 0, 10, 20, 40, and 80. The R-F signals were received by using a 475 Textronix oscilloscope, and the thicknesses were digitally measured. RESULTS: There was no trend for decreasing or increasing thickness measurements with increasing tension settings. CONCLUSION: Corneal thickness measurements by ultrasonic pachometry are not significantly affected by corneal indentation with the ultrasonic probe. PMID- 10090370 TI - Conjunctival epithelial cells cultured on human amniotic membrane fail to transdifferentiate into corneal epithelial-type cells. AB - PURPOSE: Previous studies on the use of human amniotic membrane (HAM) in rabbit stem cell deficiency models have found the new epithelium growing over the HAM to express cornea-specific keratins (K3 and K12) in 40% of the cases, suggesting that HAM may have induced conjunctival epithelial cells to transdifferentiate into cornea-type epithelial cells. The current study was performed to determine whether HAM could induce transdifferentiation of conjunctival epithelia] cells when cultured in vitro. METHODS: Conjunctival grafts taken from the fornices of New Zealand white rabbits (6-12 weeks old) were placed over HAMs and lifted to an air-media interface using polypropylene double rings. These cultures were maintained in supplemented hormonal epithelial medium with and without 3T3 feeder cells. Rabbit corneal epithelial cells were cultured similarly using strips of keratolimbal grafts placed over HAM. The cultures were terminated at various times between the 8th and 15th day. The cultured epithelial cells were examined histologically and immunohistochemically using monoclonal antibodies AK-2 (to K12 keratin), AM-3 (to goblet cell mucin), and AE-5 (to K3 keratin). RESULTS: Both conjunctival and corneal epithelial cells cultured on HAMs showed multilayered, differentiated epithelial structures. On immunohistochemical examination, both epithelial cells stained positive for AE-5. None of the cultured conjunctival epithelial cells stained positively for AK-2, while the corneal epithelial cells showed positive staining with AK-2. There were no AM-3-positive goblet cells in either epithelial cell culture. There was no difference in the immunohistochemical patterns between cultures with or without 3T3 feeder cells. However, culture without feeder cells seemed to manifest a more degenerative appearance than those with feeders. CONCLUSION: HAM does not induce transdifferentiation of conjunctival epithelial cells into corneal-type epithelial cells under the in vitro culture conditions used in this study. PMID- 10090371 TI - The fine structure of chromatin alterations in conjunctival epithelial cells in keratoconjunctivitis sicca. AB - PURPOSE: To study the ultrastructure of nuclear chromatin changes of conjunctival epithelial cells in imprints of dry-eye patients. METHODS: Imprints with nuclear chromatin changes of the conjunctival epithelium from dry-eye patients were first selected by light microscopy (LM). The latter allowed processing material with special interest (chromatin changes) for electron microscopy (EM). Ultrathin sections were cut tangential to the filter surface to obtain an large overview of the collected imprints. For scanning electron microscopy (SEM), selected specimens were dehydrated in ethanol and dried by the critical-point method or in some cases only air-dried. As controls, imprints of healthy patients were used. RESULTS: EM of the control samples showed sheets of well-preserved conjunctival nongoblet epithelial cells and goblet cells filled with secretory granules. Intercellular processes contributed to the formation of a cohesive sheet of epithelial cells. In dry-eye patients, signs of squamous metaplasia such as enlargement of nongoblet epithelial cells, increased keratinization, and nuclear chromatin changes were disclosed. The goblet cell density was drastically reduced or lost. Nuclear chromatin changes showed a pathologic distribution of eu- and heterochromatin, resulting in an axial snake- or stick-like chromatin condensation. Intracellular filament-like structures were identified in severe cases to cause a segmentation of nuclei. CONCLUSION: The fine structure of cellular and nuclear changes occurring in KCS are shown in detail. The data are in line with EM observations of impression cytology of contact lens wearers, thus confirming the ubiquitous origin of squamous metaplasia and authenticity of the snake phenomenon in squamous metaplasia. Potential pathomechanisms that might be involved in the development of chromatin alterations in conjunctival epithelial cells undergoing squamous metaplasia are discussed. PMID- 10090372 TI - Peripheral lamellar keratoplasty for corneoscleral cyst: three case reports. AB - PURPOSE: To examine whether peripheral lamellar keratoplasty (LKP) using preserved cornea was effective for the treatment of corneoscleral cysts. METHODS: Three patients with corneoscleral cysts underwent peripheral lamellar keratoplasty. Two patients had no history of trauma or ocular surgery and were considered to have congenital cysts. The other patient had a history of strabismus surgery that had been performed 7 years previously. The anterior wall of the cysts was removed by trephination, and the epithelial membrane lining the posterior wall was peeled off. Lamellar corneal buttons obtained from preserved corneas then were put in place and secured with 8-10 interrupted sutures. In one case, because the cyst was large and extended to the pupillary axis, peripheral LKP was performed for removal of the scleral and peripheral corneal cyst, and the inner wall of the central corneal cyst was removed with vigorous irrigation and a spatula. RESULTS: Histologic examination showed that all of the cysts were lined with nonkeratinizing epithelial cells. In all three cases, cysts have not reformed after a 1-5-year follow-up. CONCLUSIONS: The cysts were lined in epithelial cells, and removal of these epithelial cells was considered to be important for the prevention of recurrence. Peripheral LKP is effective for the treatment of corneoscleral cysts, since this procedure removes displaced epithelial cells and reconstructs the thin part of the cornea and sclera. PMID- 10090373 TI - Epikeratoplasty for traumatic corneal ectasia. AB - PURPOSE: To evaluate the efficacy of epikeratoplasty in a case of traumatic corneal ectasia. METHOD: Epikeratoplasty using a manually dissected donor lenticule was used to treat traumatic corneal ectasia after an iron nail injury. RESULT: No intra- or postoperative complication was encountered. At the end of 6 months' follow-up, the patient's best corrected visual acuity was 6/12. CONCLUSION: Epikeratoplasty is a useful technique to treat traumatic corneal ectasia. PMID- 10090374 TI - Double anterior chamber deep lamellar keratoplasty: case report. AB - PURPOSE AND METHODS: We report a case in which, although we planned to perform a penetrating keratoplasty for corneal stromal opacity with normal corneal endothelium, the host's Descemet's membrane became inadvertently detached and the operation resulted in double anterior chamber deep lamellar keratoplasty (DLKP). RESULT: After surgery, the patient's corrected visual acuity was 20/30. CONCLUSION: Double anterior chamber DLKP is safe and valuable. PMID- 10090375 TI - Corneal iron ring after hyperopic laser-assisted in situ keratomileusis. AB - PURPOSE: To report a new corneal iron ring after hyperopic laser-assisted in situ keratomileusis (LASIK). METHODS: Three patients underwent hyperopic LASIK for the correction of hyperopia in both eyes. Spherical equivalent refraction of the patients ranged from +3.37 to +6.50 diopters. LASIK procedure was performed using automated corneal shaper and 193-nm argon fluoride excimer laser. RESULTS: Both eyes of the patients were noted to have a corneal iron ring located at the paracentral area at 6-7 months after surgery. The localization of iron ring corresponded with outside border of central steep zone. Twelve-month examination showed there was no change in color, shape, and density of corneal iron ring. CONCLUSIONS: Corneal topographic changes induced by hyperopic LASIK may cause corneal iron ring to develop. PMID- 10090376 TI - Clinical indications for penetrating keratoplasty: an update. PMID- 10090377 TI - Burn patients, then and now. PMID- 10090379 TI - Antimicrobial resistance. PMID- 10090378 TI - The neuroendocrine stress response and modern intensive care: the concept revisited. PMID- 10090380 TI - Measurements of quality of life: then and now. PMID- 10090381 TI - The effects of human burn injury on urinary nitrate excretion. AB - Different studies have demonstrated both an increase and a decrease in the biosynthesis of nitric oxide (NO) during the first 2 days following experimental and human burn trauma. This study investigated changes in urinary nitrate excretion in humans following thermal injury in order to determine the temporal relationship between NO release and the initial injury. Urinary nitrate was measured in daily 24-h urine collections taken on days 1-7 following burn injury from 15 patients. The control group consisted of 11 healthy, age- and sex-matched patients who kept a nitrate-restricted diet for five days prior to collection of a single 24-h urine sample. The burns group had a mean age of 41.9 +/- 19.4 (mean +/- S.D.) years and a mean total burn surface area (TBSA) of 30.2 +/- 24.9% (mean +/- S.D.). In the burn injured patients, urinary nitrate levels peaked at day 4 and a 2-fold increase relative to day 1 was observed. Urinary nitrate levels were significantly higher in the burns group than the control group on days 4 and 5 only (p < 0.05 for both days). There was no correlation between TBSA and the measured urinary nitrate levels. This study confirms that the biosynthesis of NO is increased during the first week following burn trauma and establishes that the renal elimination of the by-products of NO metabolism is not increased during the first three days after injury. Notwithstanding the potential effects of burns on nitrate distribution, our findings may reflect a delay in the release of NO following the initial insult. PMID- 10090382 TI - Improvement of early postburn cardiac function by use of Panax notoginseng and immediate total eschar excision in one operation. AB - Cardiac dysfunction development in the early stage postburn has been an important problem in burn treatment. However, no effective therapies are available for use in clinical practice. In this study, we sought to determine whether early total eschar excision (EEE) in one operation and the traditional Chinese herb Panax notoginseng (PNS) would be helpful in improving early postburn cardiac function. 160 Wistar rats were randomly divided into burn (burn group, n = 50), burn treated with EEE (EEE group, n = 50), burn treated with PNS (PNS group, n = 50) groups and normal controls (n = 10). All rats except the normal control were given a 30% TBSA full skin thickness burn and resuscitated with Ringer's lactate. EEE was performed immediately after the burn group received the first intraperitoneal injection of Ringer's lactate. The wound was covered with homoskin from normal rats. In the PNS group, two doses of PNS (200 mg/kg for each dose) were given intraperitoneally immediately and 4 h postburn. Cardiac contractile function and cardiac troponin T (TnT) were determined at 1, 3, 6, 12 and 24 h postburn. Results showed that cardiac contractile parameters including AOSP, AODP, LVSP and +dp/dt(max) all declined and were still significantly lower than the control values at 24 h postburn. Cardiac TnT was elevated markedly and reached a level 25 times higher than control at 12 h postburn. In EEE and PNS groups, the reduction of cardiac contractile function was limited as compared with that in the burn group. Levels of TnT in both EEE and PNS groups were significantly lower than in the burn group 6 h postburn later. The findings of this study demonstrated that both EEE and PNS were effective in improving early postburn cardiac function. PMID- 10090383 TI - Functional analysis of T lymphocytes infiltrating the dermis and epidermis of post-burn hypertrophic scar tissues. AB - The cytokine profile of T cell clones (TCC) from the dermis and epidermis of burn patients with hypertrophic scars (HS) in active (AHS) and remission phases (RHS) was determined in this study. We found that AHS tissues are heavily infiltrated by Type 0-Type 1 polarized CD3+ lymphocytes producing high IFN-gamma and low IL-4 levels. Analysis of their surface marker phenotype showed that the high IFN-gamma production was shared equally between the CD4+ TCRalpha/beta and CD8+ TCRalpha/beta clones. The profile of TCC from RHS tissues revealed pronounced infiltration of Type 0-Type 1 polarized lymphocytes with an even more evident Type 1 profile. However, the levels of IFN-gamma produced by RHS-derived TCC were 4-6 times lower than those produced by AHS-derived TCC. These data show that high levels of IFN-gamma produced by Type 0-Type 1 lymphocytes infiltrating HS are a feature of AHS, whereas reduction of this ability to produce high levels of IFN gamma, though without a shift towards a Type 0-Type 2 phenotype through an increase in IL-4, is characteristic of RHS. PMID- 10090384 TI - On burn injuries related to airbag deployment. AB - Airbags have been shown as a vital, supplemental restraining device that save lives and reduce morbidity associated with motor vehicles crashes. However, as with any developing technology, airbags have also been identified in some instances, as the source of injuries which, have been well described in the literature. To a significantly lesser degree, burns due to airbag deployment (about 7-8% of these injuries) have been reported. These injuries will be seen more frequently as more vehicles are equipped with airbags and should be suspected in drivers and passengers involved in accidents in which airbags have been activated. This article, reviews the various types of burns and their pathogenesis, found in crashes involving airbag deployments. PMID- 10090385 TI - Firework related injury and legislation: the epidemiology of firework injuries and the effect of legislation in Northern Ireland. AB - The efficacy of legislation in reducing firework associated injuries is uncertain as is the nature of the problem within the United Kingdom (UK). In September 1996 the legislation governing firework sale in Northern Ireland was relaxed thus equalling that of the rest of the UK. For the 2 years following the change in legislation we prospectively assessed those patients who were admitted with a firework injury over the Halloween period. We then compared these results with retrospective data for the 3 years prior to the change in firework law. In the pre-legislation series the mean number of patients admitted annually was 0.38 per 100,000 while in the post-legislation series the mean was 0.43 per 100,000. Blast injury to the hand was the commonest injury accounting for 53% of cases in both series. Burn injuries were the second commonest form of injury comprising 30% of all admissions. Of those admitted with a hand injury 47% had at least one finger terminalised and nearly half of those patients admitted with burns (44%) required skin grafting. We conclude that early evidence suggests that liberalisation of the law on firework sale has not resulted in a significant increase in firework related injuries requiring hospital admission. PMID- 10090386 TI - Reflecting on 35 years at the Glasgow burns unit. PMID- 10090387 TI - The changing face of burn care: the Adelaide Children's Hospital Burn Unit: 1960 1996. AB - There have been considerable changes in burn care since the inception of the Adelaide Children's Hospital Burn Unit in 1960, resulting in a marked improvement in both morbidity and mortality. A burn of 30% T.B.S.A. is no longer considered life threatening, whilst a burn of 80% T.B.S.A. is now not only expected to survive, but to have a satisfactory functional and cosmetic outcome. An outline of these changes, as reflected in a review of 37 years of care, is discussed with particular reference to the improvements in scar management. PMID- 10090388 TI - Child burn: accident, neglect or abuse. A case report. AB - The authors report a case of a child who has suffered three episodes of burn injuries in a short period of time, probably provoked by neglect or abuse from the parents. This mode of injury is of great importance because of the high mortality, as well as the physical, psychological and social sequelae that it causes. The absence of care and attention from the parents or caretakers contribute to the high frequency of this kind of trauma. In these cases, the admission of the child to the hospital is justifiable, regardless of the size or depth of the burn wound. Aspects concerning the epidemiology are discussed in this article, as are comments based on the literature about infant abuse and neglect. PMID- 10090389 TI - Symptomatic tracheal stenosis in burns. AB - Tracheal stenosis in burns is rare and usually results from prolonged intubation or tracheostomy. Inhalation injury itself has the potential risk of tracheal stenosis. We reviewed the records of 1878 burn patients during 1987 to 1995 and found seven with tracheal stenosis (0.37%) after an average of 4.4 years follow up. There were 4 males and 3 females with an average age of 27.3 years. The tracheal stenosis developed 1-22 months after burn (average 7 months). Five patients had their inhalation injury confirmed by bronchoscopic examination. The incidence of tracheal stenosis among inhalation injury patients was 5.49% (5/92). Six patients needed intubation in the initial stage either for respiratory distress or prophylaxis, with an average duration of 195.2 h. In addition to prolonged intubation, the presence of inhalation injury, repeated intubations and severe neck scar contractures are also contributors to tracheal stenosis in burns. We favor T-tube insertion as the first treatment choice; permanent tracheostomy was unsatisfactory in our study. PMID- 10090390 TI - Development of a colocutaneous fistula in a patient with a large surface area burn. AB - A 61 year old female sustained a large surface area burn, complicated by inhalation injury. One month before the incident, she had undergone a left hemicolectomy with colorectal anastomosis for diverticular disease. Due to the severity of her burns, multiple surgical debridement and skin grafting procedures were required, including a large fascial debridement of her flank and back. Her hospital course was complicated by recurrent episodes of pulmonary and systemic infection, as well as pre-existing malnutrition. Prior to her discharge to a rehabilitation center, stool began to drain from her left posterior flank. This complication represented a colonic fistula arising from the recent colon anastomosis. The fistula was managed nonoperatively and gradually closed. To our knowledge, this is the first report of a colocutaneous fistula spontaneously draining from the abdomen via the retroperitoneum in a burn victim, not related to direct thermal injury to the peritoneal cavity. PMID- 10090391 TI - Duodenal perforation as a complication of routine endoscopic nasoenteral feeding tube placement. PMID- 10090392 TI - Treatment of a neck burn contracture with a super-thin occipito-cervico-dorsal flap: a case report. AB - Postburn neck contractures still represent a surgical challenge due to their exposed location; and early operative treatment is necessary for both functional as well as aesthetic reasons. An excellent functional result was obtained by using a supercharged super-thin occipito-cervico-dorsal flap described by Hyakusoku to repair a large defect of the anterior neck following a very wide neck burn contracture release. In this case report, the technique and its advantages among the other reconstructive modalities are discussed briefly. PMID- 10090393 TI - Recent references. PMID- 10090394 TI - Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease. AB - Endothelial cells, by virtue of their capacity to express adhesion molecules and cytokines, are intricately involved in inflammatory processes. Endothelial cells have been shown to express interleukin-1 (IL-1), IL-5, IL-6, IL-8, IL-11, IL-15, several colony-stimulating factors (CSF), granulocyte-CSF (G-CSF), macrophage CSF (M-CSF) and granulocyte-macrophage CSF (GM-CSF), and the chemokines, monocyte chemotactic protein-1 (MCP-1), RANTES, and growth-related oncogene protein-alpha (GRO-alpha). IL-1 and tumor necrosis factor-alpha (TNF-alpha) produced by infiltrating inflammatory cells can induce endothelial cells to express several of these cytokines as well as adhesion molecules. Induction of these cytokines in endothelial cells has been demonstrated by such diverse processes as hypoxia and bacterial infection. Recent studies have demonstrated that adhesive interactions between endothelial cells and recruited inflammatory cells can also signal the secretion of inflammatory cytokines. This cross-talk between inflammatory cells and the endothelium may be critical to the development of chronic inflammatory states. Endothelial-derived cytokines may be involved in hematopoiesis, cellular chemotaxis and recruitment, bone resorption, coagulation, and the acute-phase protein synthesis. As many of these processes are critical to the maturation of an inflammatory and reparative state, it appears likely that endothelial-derived cytokines play a crucial role in several diseases, including atherosclerosis, graft rejection, asthma, vasculitis, and sepsis. Genetic and pharmacologic manipulation of endothelial-derived cytokines provides an additional approach to the management of chronic inflammatory diseases. PMID- 10090395 TI - Serum levels of tumor necrosis factor-alpha, interleukin-1, and interferon-gamma in beta(o)-thalassemia/HbE and their clinical significance. AB - Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL 1alpha), and interferon-gamma (IFN-gamma) were estimated by conventional ELISA kits in 60, 42, and 58 Thai patients, respectively, with beta(o)-thalassemia HbE and found to be above the normal range in 13%, 21%, and 33% of the patients, respectively. Using high-sensitivity ELISA systems, an additional 10 beta(o) thal/HbE patients were compared with 9 controls for concentrations of circulating TNF-alpha and IL-1beta, and 9 and 5 patients, respectively, but only 1 and none of the controls, respectively, showed values above the normal ranges. In patients with abnormally high IFN-gamma levels, basal hemoglobin values were significantly lower than in those with normal levels of the cytokine (mean +/- SEM: 6.03+/-0.24 vs. 7.08+/-0.18, p < 0.05), although circulating concentrations of soluble transferrin receptors (sTrF) and absolute reticulocyte counts were similar in the two groups. Patients with raised or normal levels of TNF-alpha, IL-1alpha, or IL 1beta had similar basal hemoglobin values. In a phagocytosis assay, monocytes of patients with raised serum levels of IFN-gamma showed significantly more attached or ingested IgG-coated red cells than those of patients with normal concentrations of the cytokine (mean +/- SEM: 192+/-22 vs. 140+/-14 per 100 monocytes, p < 0.05). Moreover, in 3 of 4 of the former patients, the number of attached or ingested IgG-coated red cells per 100 monocytes was above the 95% reference limit for the latter patients. The results suggest that IFN-gamma aggravates the anemia of beta(o)-thal/HbE by activating mononuclear phagocytes for destruction of red cells but not by inhibiting erythropoiesis. The elevated serum levels of TNF-alpha and IL-1 could contribute to complications of the disease, such as cachexia and thromboembolic phenomena. PMID- 10090396 TI - Full activation of RNaseL in animal cells requires binding of 2-5A within ankyrin repeats 6 to 9 of this interferon-inducible enzyme. AB - To define protein domains important for activation of the interferon (IFN) induced enzyme 2-5A-dependent RNaseL, we have generated vaccinia virus (VV) recombinants able to express in cultured cells truncated forms of this protein and compared their biologic activities with those producing the wild-type enzyme, with and without coexpression of 2-5A synthetase. Our results show that full activation of RNaseL requires binding of 2-5A oligonucleotides within amino acid positions 212-339, corresponding to ankyrin repeats 6 to 9. The protein kinase and ribonuclease domains of RNaseL, amino acids 340-741, are sufficient for a constitutively active enzyme that is unresponsive to excess 2-5A. These results demonstrate in vivo the importance of the ankyrin domains in the biologic function of RNaseL. We suggest that ankyrin repeats act as key modulators of RNaseL activity. PMID- 10090397 TI - Cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC): response to genistein and pyrrolidine dithiocarbamate. AB - Using an immortalized astrocyte cell line (DITNC), we showed that lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) but not interferon-alpha (IFN-alpha) could individually induce secretory phospholipase A2 (sPLA2) mRNA and enzymatic activity. However, induction of inducible nitric oxide synthase (iNOS) mRNA and NO production by cytokines required the presence of IFN-gamma. Using a three cytokine mixture (TNF-alpha, IL-1beta, and IFN-gamma) that could maximally induce both iNOS and sPLA2, the increase in these mRNA species reached a maximum by 4-8 h, followed by a decline up to 48 h. L-N6-(1-Iminoethyl)lysine acetate (L-NIL) inhibited cytokine-induced NO production with IC50 of 25 microM, but this compound did not affect iNOS mRNA. Furthermore, L-NIL exerted no effect on sPLA2 mRNA or sPLA2 activity. Pyrrolidine dithiocarbamate (PDTC), an inhibitor for NF kappaB, was more effective in inhibiting iNOS mRNA and NO production than for sPLA2. Surprisingly, genistein inhibited both NO production and sPLA2 activity with IC50 of 72 microM and 88 microM, respectively. On the other hand, daidzein, a genistein analog lacking tyrosine kinase inhibitor activity, was not effective in inhibition of NO production at 250 microM. These results demonstrate distinct pathways for induction of iNOS and sPLA2 in DITNC cells by cytokines and shed new insight on transcriptional regulation for these two mRNA species. PMID- 10090398 TI - In vitro and in vivo expression analysis of the interferon-inducible 203 gene. AB - The interferon (IFN)-inducible protein family 200 is encoded by structurally related genes located on mouse chromosome 1. The encoded proteins so far characterized and designated p202, p204, and pD3 contain at least one copy of a conserved 200 amino acid domain in addition to other regions that are different or missing among the various family members. We have recently characterized a cDNA clone (203 cDNA) encoding a 408 amino acid protein bearing structural similarities to p202 and p204. Here, we report its pattern of expression in vitro and in vivo. In vitro, the mRNA and protein encoded by the 203 gene were increased by IFN-alpha in several cell lines of different histologic origin. By contrast, no significant induction was observed in vivo in mice from C57BL/6 and BALB/c strains even after treatment with the IFN-inducer poly rI:rC. In addition, the constitutive expression of 203 gene was restricted to some myeloid and lymphoid tissues, namely, thymus, bone marrow, and spleen. Comparison of the expression pattern of the 203 and 202 genes in three mouse strains revealed that they exhibit a differential inducibility by IFN and a reciprocal expression pattern. The 203 mRNA was constitutively expressed in C57BL/6 and BALB/c mice and undetectable in the spleen of DBA/2 mice. The 202 mRNA was strongly induced by poly rI:rC in the spleen of DBA/2 and BALB/c mice but absent in C57BL/6 mice. Southern analysis revealed a restriction fragment length polymorphism in the 203 locus. Taken as a whole, these results demonstrate a remarkable difference in the in vivo IFN responsiveness of two members belonging to the same gene family with a similar degree of IFN inducibility in vitro. Moreover, the reciprocal expression pattern in C57BL/6 and DBA/2 mice could mean that p203 and p202 play the same role in a mouse strain in which only one of them is expressed. PMID- 10090399 TI - Efficient human IFN-gamma expression in the mammary gland of transgenic mice. AB - Two hybrid genes (BLG-HuIFN-gamma2 and BLG-HuIFN-gamma3) were constructed on the basis of sheep beta-lactoglobulin (BLG) and human interferon-gamma (HuIFN-gamma) gene sequences. They were used to direct HuIFN-gamma synthesis in the mammary gland of transgenic mice. HuIFN-gamma was efficiently produced in the mammary gland of transgenic mice. BLG-HuIFN-gamma2 transgenic females expressed HuIFN gamma in the milk at concentrations up to 570 mg/ml, and BLG-HuIFN-gamma3 transgenic females expressed up to 350 mg/ml. All females carrying the BLG-HuIFN gamma3 gene expressed HuIFN-gamma in their milk. No significant changes were observed in the HuIFN-gamma expression level during the lactation period. Using RT-PCR analysis, ectopic expression for both hybrid genes was found in transgenic mice. Despite ectopic expression of HuIFN-gamma in transgenic mice, their development and pregnancy were normal. The heritability of the HuIFN-gamma expression level in milk was demonstrated up to the F2 generation. This work demonstrates that hybrid genes have the potential to develop in transgenic domestic animals producing HuIFN-gamma in milk. PMID- 10090400 TI - Oromucosal interferon therapy: marked antiviral and antitumor activity. AB - Oromucosal administration of murine interferon-alpha/beta (IFN-alpha/beta) or individual recombinant species of murine IFN-alpha, IFN-beta, or IFN-gamma or recombinant human IFN-alpha1-8, which is active in the mouse, exerted a marked antiviral activity in mice challenged systemically with a lethal dose of encephalomyocarditis virus (EMCV), vesicular stomatitis virus (VSV), or varicella zoster virus (VZV). The effects observed were dose dependent and similar in magnitude to those observed following parenteral administration of the same dose of IFN. No antiviral activity was observed after oromucosal administration of murine IFN-alpha/beta in animals in which the IFN receptor had been inactivated by homologous recombination. In contrast to parenteral treatment, oromucosal IFN therapy was found to be ineffective when IFNs were administered before virus infection. Oromucosal administration of IFN-alpha also exerted a marked antitumor activity in mice injected i.v. with highly malignant Friend erythroleukemia cells or other transplantable tumors, such as L1210 leukemia, which has no known viral etiology, the EL4 tumor, or the highly metastatic B16 melanoma. These results show that high doses of IFN can be administered by the oromucosal route apparently without ill effect, raising the possibility that the oromucosal route will prove to be an effective means of administering high doses of IFN that are clinically effective but poorly tolerated. PMID- 10090401 TI - Oromucosal interferon therapy: pharmacokinetics and pharmacodynamics. AB - Oromucosal administration of [125I]-labeled recombinant human interferon-alpha1-8 (IFN-alpha1-8), which is biologically active in the mouse, resulted in readily detectable levels of radioactivity in the serum of animals within 5 min. Biologically active IFN could not be detected in the serum at any time after oromucosal administration, however, and SDS-PAGE analysis showed that the material present in the serum was of low molecular weight and most probably reflected absorption of degradation products following digestion of IFN in the stomach and small intestine. Furthermore, oromucosal administration of murine IFN alpha/beta (MuIFN-alpha/beta) had no significant effect on the expression of IFN responsive genes in either peripheral blood mononuclear cells or splenic lymphocytes even though in the same animals IFN treatment activated gene transcription locally in the lymphoid tissue of the oropharyngeal cavity and caused a marked systemic antiviral activity. Oromucosal administration of MuIFN alpha/beta had no significant effect on either the number of circulating peripheral blood leukocytes or the number of granulocyte-macrophage colonies recovered from the bone marrow of IFN-treated animals. These results suggest that the mechanism of action of oromucosal IFN therapy is distinct from that of parenterally administered IFN and may involve, in the abundant lymphoid or epithelial tissue of the oropharyngeal cavity, either production of a soluble factor or activation of a specific cell population that enters the circulation to mediate the elimination of virus-infected or neoplastic cells. PMID- 10090402 TI - Expression of ICAM-1 during IFN-alpha-based treatment of metastatic malignant melanoma: relation to tumor-infiltrating mononuclear cells and regressive tumor changes. AB - Intercellular adhesion molecule-1 (ICAM-1) plays an important role in cell to cell interactions. In malignant melanoma, ICAM-1 expression correlates with malignant behavior. We used monoclonal antibodies, anti-ICAM-1, anti-CD4+, anti CD8+, and anti-CD11c+ to study the effect of interferon-alpha (IFN-alpha) on the expression of ICAM-1 by melanoma cells in regional metastases and its correlation to the occurrence of CD4+, CD8+, and CD11c+ cells close to tumor cells and in the tumor stroma. We also estimated the expression of ICAM-1 and regressive changes in malignant melanoma metastases, correlating the duration of treatment to these effects of IFN-alpha. Twenty-three IFN-alpha-treated and 10 untreated patients with regional metastatic malignant melanoma were studied. The duration of IFN alpha treatment influenced the expression of ICAM-1. In metastases from patients treated for 1 week only, 1 of 5 showed high expression of ICAM-1 compared with 6 of 11 of those treated for 3 weeks (p = 0.01, chi-square test for trend comparing untreated patients and patients with various durations of IFN-alpha treatment). In IFN-alpha-treated patients with low expression of ICAM-1, none of 7 metastases showed CD4+ cells infiltrating close to tumor cells, in contrast to 6 of 10 metastases expressing high amounts of ICAM-1 (p = 0.03). Similarly, the expression of ICAM-1 was found to correlate with the occurrence of CD8+ cells close to the tumor cells (p = 0.04). We also showed a correlation between ICAM-1 expression and histologic evidence of tumor regression (p = 0.02). PMID- 10090403 TI - Upregulation of interleukin-4 and IFN-gamma expression by IFN-tau, a member of the type I IFN family. AB - Trophoblast interferon-tau (IFN-tau) is a new member of the type I IFN family that is produced in large quantities by the ruminant conceptus. Like other type I IFN, IFN-tau inhibits viral replication and activates natural killer (NK) mediated cytotoxicity. In mice and humans, type I IFN enhances type 1 T helper (Th) cell responses, but the effects of type I IFN, including IFN-tau, on cytokine expression by bovine Th cells have not been described. The present study determined the effects of IFN-tau on interleukin-4 (IL-4), IFN-gamma, and IL-10 expression by antigen-specific, CD4+ T cell lines derived from cattle immune to either Babesia bovis, Babesia bigemina rhoptry-associated protein-1, or Anaplasma marginale. IFN-tau upregulated IFN-gamma secretion and steady-state levels of IFN gamma and IL-4 mRNA by cell lines cultured for 3-6 weeks. In contrast, the steady state levels of IL-10 mRNA were either not changed or inhibited at these times. Similar effects were obtained with human IFN-alpha. Comparison of the quantities of IFN-gamma, IL-4, and IL-10 transcripts in IFN-tau-treated or IFN-alpha-treated cultures revealed that even though IFN-gamma was the predominant cytokine expressed by all T cell lines, both IFN-gamma and IL-4 steady-state transcript levels were upregulated by a comparable degree. Thus, these studies demonstrate that IFN-tau is an immunomodulatory cytokine that promotes enhanced IL-4 and IFN gamma responses by effector T cells but not, strictly speaking, Thl-biased responses in cattle. These results indicate the potential use of this cytokine as an adjuvant in ruminants to boost cell-mediated immune responses. PMID- 10090404 TI - Involvement of receptor-bound protein methyltransferase PRMT1 in antiviral and antiproliferative effects of type I interferons. AB - Protein arginine N-methyltransferase (PRMT1) is one of the proteins that bind to the intracytoplasmatic domain of the IFNAR-1 chain of the type I interferon (IFN) receptor system. The attachment is specific and is not seen with PRMT2, another member of this protein family. Antisense PRMT1 cDNA constructs expressed under the early cytomegalovirus (CMV) promoter were transfected into HeLa cells, and stable transformants were selected. Antibodies to PRMT1 were used to identify clones with reduced PRMT1 expression. In such clones, IFN-beta inhibited three to five times less the replication of vesicular stomatitis virus (VSV) than in the original HeLa cells. The antiproliferative effect of IFN-beta was also reduced up to fivefold in the clones with low PRMT1 expression. No difference was seen when IFN-gamma was used alone to inhibit cell growth. The protein methylating enzyme, bound to IFNAR-1, appears to regulate positively the biologic activity of type I IFN. PMID- 10090405 TI - The proinflammatory and chondral activities of leukemia inhibitory factor in goat joints are partially a function of interleukin-1. AB - We wished to determine if the effects of injected recombinant human leukemia inhibitory factor (LIF) are a function of endogenous goat interleukin-1 (IL-1) production and, conversely, if the effects of injected recombinant human IL-1 are a function of endogenous LIF production in goat radiocarpal joints (RCJ). In preliminary experiments, murine LIF binding protein (MuLBP) and recombinant HuIL 1RA were found to independently attenuate the cartilage proteoglycan resorbing activity of goat synovial membrane-conditioned medium (GSMCM), implying activity against goat LIF and goat IL-1, respectively. The present study shows that the proinflammatory and chondral actions of rHuLIF in goat RCJ are partially attenuated by rHuIL-1RA. This implies that a small but important component of the in vivo activity of rHuLIF is a result of IL-1 production in the synovial joint. With the exception of proteoglycan synthesis, the absence of significant effects by MuLBP on the actions of rHuIL-1alpha in goat RCJ suggests that the proinflammatory and chondral effects of IL-1alpha in vivo are probably not mediated by LIF. PMID- 10090406 TI - Role of interleukin-8 and transforming growth factor-beta1 in enhancement of human cytomegalovirus replication by human T cell leukemia-lymphoma virus type I in macrophages coinfected with both viruses. AB - Human cytomegalovirus (HCMV) is one of the most frequent opportunistic agents causing severe illness in chronic human T cell leukemia-lymphoma virus type I (HTLV-I) infection. Our previous studies have shown that coinfection of macrophages with HCMV and HTLV-I significantly enhances HCMV replication, resulting in release of infectious HCMV from dually infected cells. We found that double infection of macrophages with HCMV and HTLV-I induced a rapid production of substantial amounts of interleukin-8 (IL-8) and transforming growth factor beta1 (TGF-beta1). Results of transfection studies demonstrated that the tax gene product of HTLV-I was able to induce secretion of IL-8 and TGF-beta1. In addition to its cytokine-inducing effect, the Tax protein could interact with HCMV synergistically to result in production of much higher levels of IL-8 and TGF beta1 than expected on the basis of their separate activities. Treatment of dually infected macrophage cultures with neutralizing antibodies to IL-8 and TGF beta1 led to a nearly 1000-fold decrease in release of infectious HCMV from coinfected cells. Similar results were obtained when anti-IL-8 and anti-TGF-beta1 treatments were combined in macrophage cultures transfected with the tax gene before HCMV infection. Our results suggest that the stimulatory effect of HTLV-I Tax protein on HCMV replication in coinfected macrophages is largely mediated by high levels of IL-8 and TGF-beta1 production. PMID- 10090407 TI - Utility of fluorescence in situ hybridization in pancreatic ductal adenocarcinoma. AB - Often the diagnosis of pancreas cancer needs to be established from limited cytology specimens or small biopsies. Most ductal adenocarcinomas are histologically well to moderately differentiated and mimicked closely by pancreatitis, and therefore the microscopic diagnosis can be difficult. In addition, there appears to be significant heterogeneity in the outcome of the patients with pancreatic cancer, which cannot be predicted accurately by current prognosticators such as the grade and stage of the tumor. Therefore, there is need for methods that can be used as adjuncts to routine diagnostic and prognostic parameters. This study was designed to test the utility of the fluorescent in situ hybridization (FISH) method in identifying the molecular alterations, particularly the ones that have been detected with relatively high frequency in pancreas cancer. Formalin-fixed and paraffin-embedded tissues of 10 cases were enumerated for chromosome 7, 8, 17, 18, and 20 copy numbers by using alpha-satellite probes, and for c-myc by using a gene-specific probe. The number of signals per nucleus (reflecting chromosomal copy number and status of c-myc amplification) were counted in more than two areas containing 50-500 cells. Because of tumor heterogeneity, monosomy (loss of one chromosome copy) was defined arbitrarily as one signal in >25% of nuclei. C-myc amplification was defined as more than two gene copies in >20% of the cells. The most frequent signal losses were found in chromosomes 8 (four of 10 cases) and chromosome 17 (four of 10), followed by 20 (three of 10) and 18 (two of 10). No loss of chromosome 7 was detected. In contrast, gains in chromosome copy number were identified in only one of 10 tumors, which showed gain of both chromosome 7 and 18. Amplification of c-myc gene was detected in two of 10 cases, but neither of the two had aneuploidy for chromosome 8, where the c-myc gene is located. In addition, loss in c-myc signal was observed in one case that also showed loss of chromosome 8 copy number. FISH can be used to detect chromosomal changes in pancreatic cancer; abundance of lytic enzymes in this organ is not an impediment for the applicability of this technique. Therefore it can potentially be used in the future as an adjunct to the conventional diagnostic and prognostic markers. This study confirms that loss of chromosomes, particularly chromosomes 17 and 18, which carry the p53 and DCC genes, are common in pancreas cancer. Chromosome 20 is also frequently lost. In addition, in this study, alterations of chromosome 8, which is seen commonly in prostatic adenocarcinoma but has not been previously documented in pancreatic cancer, also was detected in five of 10 tumors. Furthermore, amplification of the c-myc gene, which is located in chromosome 8, was found in the two of the remaining five cases. Further studies are needed to confirm this high incidence of chromosome 8 and c-myc alterations and their possible role in the pathogenesis of pancreatic adenocarcinoma. PMID- 10090409 TI - Computed tomography under endoscopic retrograde pancreatography (ERP-CT) to investigate the drainage area of the pancreatic head. AB - The aim of this study was to evaluate the drainage area of the pancreatic head with computed tomography under endoscopic retrograde pancreatography (ERP-CT). ERP-CT was performed in 26 patients without lesions of the pancreatic head. By comparing ERP-CT images with ERP images, we evaluated the drainage area of the inferior branch of the pancreatic head. In 77% of these cases, the drainage function of Santorini's duct system (including the accessory papilla) was impaired. In 13 cases with the normal duct pattern, all inferior branches from Santorini's duct drained the anterior inferior area and all inferior branches from Wirsung's duct drained the posterior inferior area. In six cases with an ansa-type duct pattern, all inferior branches from Wirsung's duct drained the posterior inferior area, and inferior branches from Santorini's duct were divided into branches draining the anterior inferior area and branches draining the posterior inferior area. ERP-CT is a useful method for evaluating the three dimensional anatomic variations of the pancreatic duct. PMID- 10090408 TI - Comparative significance of p53 and WAF/1-p21 expression on the efficacy of adjuvant chemotherapy for resectable invasive ductal carcinoma of the pancreas. AB - p53 tumor-suppressor gene has a dual role as a trigger of apoptosis and as an initiator of DNA repair. The cyclin-dependent kinase inhibitor WAF/1-p21 is induced by wild-type p53 and has been implicated as a downstream mediator of the growth-suppressing and apoptosis-promoting function of wild-type p53, suggesting an impact on the effectiveness of chemotherapy. This study was designed to assess the significance of p53 and WAF/1-p21 expression in the prognosis of patients and the efficacy of adjuvant chemotherapy for resectable invasive ductal carcinoma (IDC) of the pancreas. A total of 58 patients with primary IDC of the pancreas underwent pancreatectomy between 1982 and 1996: 28 patients underwent surgery alone, and 30 patients received postsurgical adjuvant chemotherapy. p53 and WAF/1 p21 were stained immunohistochemically with anti-p53 monoclonal antibody (mAb) and anti-WAF/1-p21 mAb. p53 was positively expressed in 29 (50%) of 58 primary lesions, and p21 was expressed in 24 (41%) lesions; however, p21 expression did not necessarily correlate with p53 expression. The survival curve of the patients with p53(+) IDC was significantly lower than that of those with p53(-) IDC, and p21(+) patients showed a higher survival curve than did p21(-) patients, but this difference was not statistically significant. When p53 and p21 expression were analyzed in combination, the patients with p53(+)p21(-) IDC were found to have a significantly poorer prognosis than others. On the other hand, the survival curve of the adjuvant chemotherapy group was also higher than that of the surgery-alone group, but this difference was not significant. In a multivariate analysis, p21 expression was a significantly low risk factor for death due to IDC overall, and adjuvant chemotherapy was found to decrease the risk of death from IDC in p53(+) patients. Evaluation of expression of p53 and WAF/1-p21 may be beneficial in the prediction of the patient's prognosis as well as prediction of the effects of adjuvant chemotherapy in pancreatic cancer patients. PMID- 10090410 TI - Analysis of K-ras codon 12 point mutations using duodenal lavage fluid for diagnosis of pancreatic carcinoma. AB - We evaluated the diagnostic significance of the K-ras point mutations at codon 12 in duodenal lavage fluid (DLF) compared with pure pancreatic juice (PPJ). The DLF was easily and safely collected by injecting distilled water into the duodenum and then aspirating through the working channel of the endoscope during endoscopic retrograde cholangiopancreatography. Two types of DLF are collected this way: DLF 1 is collected just after insertion of the endoscope into the duodenum and DLF 2 is collected after cholangiopancreatography and/or collection of the PPJ using secretin. Analysis of K-ras mutations was performed using enriched polymerase chain reaction. In patients with pancreatic carcinoma (PC), K ras mutations were detected in 14 of 23 (60.9%) in DLF 1, 16 of 21 (76.2%) in DLF 2, 14 of 20 (70.0%) in PPJ, and 19 of 21 (90.5%) in either DLF 1 or DLF 2. In patients with noncancerous pancreatic diseases consisting of pancreatic cystic diseases and chronic pancreatitis, the incidence of K-ras mutations was 2 of 21 (9.5%) in DLF 1 and 7 of 19 (36.8%) in DLF 2. These values were lower than that in PPJ, and there was significant difference between the incidence in DLF 1 and PPJ. These results suggested that DLF may provide a new and useful material for analysis of K-ras codon 12 point mutations in the diagnosis of PC. PMID- 10090411 TI - Specific induction of adhesion molecules in human vascular endothelial cells by rat experimental pancreatitis-associated ascitic fluids. AB - The molecular mechanisms that link acute pancreatitis (AP) and multiple organ failure remain unknown. To clarify the role of endothelial activation, we examined the effects of ascitic fluids from rats with experimental pancreatitis on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). Necrotizing hemorrhagic pancreatitis was induced with sodium taurocholate. Six and 24 h later, peritoneal exudates were collected, centrifuged and HUVECs were treated with the supernatants. The expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was quantified by enzyme-linked immunosorbent assay. Induction of mRNA was assessed by reverse-transcriptase polymerase chain reaction. The activation of transcription factors was examined by electrophoretic mobility shift assay. The expression of ICAM-1 in the tissues was examined immunohistochemically. ICAM 1 and VCAM-1, but not E-selectin expression was upregulated with comparable mRNA induction. Nuclear factor kappaB was activated, while activator protein-1 binding activity was not altered. Immunohistochemically, enhanced ICAM-1 expression was observed in the pancreas and lung, but not in the liver. Ascitic fluids may contain soluble factors responsible for the transcriptional activation of endothelial adhesion molecules, and ICAM-1 may play roles in the pathogenesis of complicated AP. PMID- 10090412 TI - Screening for the Gly40Ser mutation in the glucagon receptor gene among patients with type 2 diabetes or essential hypertension in Taiwan. AB - As a major counterregulatory hormone of insulin, glucagon plays an important role in regulating glucose homeostasis through its binding to the glucagon receptor. Recently a missense mutation in the glucagon-receptor gene (Gly40Ser) was found to be associated with type 2 diabetes in France and Sardinia, with a frequency as high as 4.6% and 8.3%, respectively. This mutation was also found to be associated with essential hypertension in the white population with a frequency of 5.4%. To investigate the role of this mutation in the pathogenesis of type 2 diabetes and essential hypertension in Taiwanese population, we screened 121 normal controls, 213 unrelated subjects with type 2 diabetes, and 107 unrelated subjects with essential hypertension by use of polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). None of the Taiwanese subjects recruited in the study had this receptor mutation. Our results demonstrate a strong genetic heterogeneity among the ethnic group and suggest that the Gly40Ser mutation of the glucagon receptor gene plays little role, if any, in the pathogenesis of type 2 diabetes and essential hypertension in the Taiwanese population. PMID- 10090413 TI - Pharmacologic profile of TS-941, a new benzodiazepine derivative cholecystokinin receptor antagonist, in in vitro isolated rat pancreatic acini. AB - We investigated the pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-(-)-N-[2,3-dihydro-2-oxo-5-phenyl-1-[(1H-tetrazol-5 yl)methyl] -1H-1,4-benzodiazepine-3-yl]-2-indolecarboxamide (TS-941), a cholecystokinin type A (CCK-A)-receptor antagonist, in the isolated rat pancreatic acini and compared with those of well-known CCK-A-receptor antagonists, devazepide and loxiglumide. TS-941 inhibited CCK-8-stimulated amylase release concentration dependently, as did devazepide and loxiglumide, with a half-maximal inhibition (IC50) at 78.6 +/- 10.3 nM. TS-941 was approximately 23 times less potent than devazepide (IC50, 3.4 +/- 0.3 nM), but was 50 times more potent than loxiglumide (IC50, 3,966 +/- 544 nM) in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. TS-941 had a fivefold lower selectivity than devazepide for pancreatic CCK (CCK-A) over brain CCK (CCK-B) receptors but fourfold greater than loxiglumide when IC50 values for inhibition of [125I]CCK-8 binding in isolated acini and cerebral cortex were compared. The antagonism produced by TS-941 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. TS-941 caused a parallel rightward shift of the entire dose-response curve for CCK-8-stimulated amylase release without altering the maximal increase, as did devazepide and loxiglumide. TS-941, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. TS-941 caused a concentration-dependent residual inhibition of the action of CCK-8. The acini, once incubated with a high concentration of TS-941 (10 microM; 127 times IC50) for 30 min, was 10-fold less sensitive to CCK-8 than the acini preincubated without TS-941, whereas the sensitivity and the responsiveness to CCK-8 stimulation of those incubated with a low concentration of TS-941 (1.0 microM) were similar to the control acini. These results indicate that TS-941 is a potent, competitive, and selective CCK-A receptor antagonist for the pancreas. PMID- 10090414 TI - Guanidino group is involved in the stimulation of exocrine pancreatic secretion by protamine in normal and chronic bile-pancreatic juice-diverted rats. AB - We previously demonstrated that the feeding of guanidinated casein, whose lysine residues are converted to homoarginine, stimulates pancreatic secretion much higher than that of intact casein in chronic bile-pancreatic juice (BPJ)-diverted rats, which suggests that the guanidino group is involved in BPJ-independent enhancement of pancreatic secretion. However, the role of the guanidino group in the protein for the enhancement of pancreatic secretion has not been clarified. In this study, we examined the stimulation of pancreatic secretion by a arginine rich dietary protein, protamine (25, 50 mg/ml), and then determined whether the guanidino group in protamine was responsible for the secretory responses in normal and BPJ-diverted rat by comparison with pancreatic secretion between intact and deguanidinated protamine. The deguanidinated protamine was prepared by converting arginine residues of salmon protamine to ornithine using heated hydrazine (conversion rate of arginine residue was 87%). In normal rats, pancreatic protein and chymotrypsin secretion were stimulated in dose-response fashion after a duodenal instillation of native protamine solution (25, 50 mg in 1 ml). In chronic BPJ-diverted rats, native protamine (25 mg) maximally stimulated pancreatic protein and protease secretion. In contrast, deguanidinated protamine (50 mg in 1 ml) did not stimulate pancreatic secretion in both normal and BPJ-diverted rats. In addition, the duodenal administration of arginine, which is equal to the amount contained in 50 mg of native protamine, had no effect on pancreatic secretion in both rats. These results suggest that a naturally occurring protein, protamine, stimulates pancreatic secretion by a luminal BPJ-independent mechanism and that the guanidino group in this protein is responsible for stimulating pancreatic secretion in BPJ-diverted rats. PMID- 10090415 TI - Decreased pancreatic exocrine function in the mutant Eisai hyperbilirubinemic rat (EHBR). AB - The Eisai hyperbilirubinemic rat (EHBR) is a Sprague-Dawley rat (SDR) mutant with conjugated hyperbilirubinemia as an autosomal recessive trait. EHBRs manifest jaundice from birth, which is permanent except for a transient decrease at 6-8 weeks of age. To investigate whether the hyperbilirubinemia affects pancreatic exocrine function and acinar cell growth, EHBRs at 6 (without jaundice) and 12 weeks (with jaundice) of age were compared, along with SDRs as controls. Pancreatic wet weights did not significantly differ, but amylase content of acini was lower in EHBRs than SDRs. No correlation was found between pancreatic wet weight and serum bilirubin levels in EHBRs. In vitro amylase release in response to 1-100 pM cholecystokinin octapeptide (CCK-8), 1 microM 12-O tetradecanoylphorbol 13-acetate, and 2.5 microM calcium ionophore A23187, and in vivo pancreatic secretion stimulated by CCK-8 (0.08 microg/kg body weight/h) were significantly lower in the EHBR cases than in the SDRs. At the electron microscopic level, many acinar cell nuclei were pyknotic, most elements of their Golgi complexes were atrophied, some mitochondria demonstrated fusion, and the rough-surfaced endoplasmic reticulum (RER) was dilated in EHBRs. These findings are indicative of a hypofunctional state. However, no differences between EHBRs at 6 and 12 weeks of age were evident, suggesting that the hyperbilirubinemia does not exert any pronounced influence on acinar cell growth or pancreatic exocrine function. PMID- 10090416 TI - Modulatory role of adrenergic nerves on dexamethasone-induced islet cell NPY expression in the rat: evidence from chemical sympathectomy. AB - We previously demonstrated induction of neuropeptide Y (NPY) in rat islet beta cells by the glucocorticoid dexamethasone (DEX). Because noradrenergic nerves appear to regulate NPY expression in the central nervous system (CNS), we investigated whether DEX-induced islet cell expression of NPY could be modulated by catecholaminergic nerves. Therefore rats were treated with DEX (2 mg/kg, i.p., for 12 days) and received injections of 6-hydroxydopamine (6-OHDA; 80 mg/kg, i.v., at day 1 or 10). 6-OHDA treatment eliminated islet adrenergic nerves. The frequency of NPY-immunoreactive islet cells and the levels of islet cell NPY messenger RNA (mRNA) were markedly lower in rats given 6-OHDA at day 1 of the DEX treatment period. In contrast, the frequency of NPY-immunoreactive cells and levels of islet cell NPY mRNA in DEX-treated rats receiving 6-OHDA at day 10 did not differ from those treated with DEX alone. The findings suggest that DEX induced islet cell expression of NPY is partially dependent on adrenergic nerves and that the effect of sympathectomy is exerted at an early stage of the NPY induction. PMID- 10090417 TI - Calcium signaling induced by angiotensin II in the pancreatic acinar cell line AR42J. AB - The purpose of this study was to characterize the nature and mechanisms of angiotensin II-evoked calcium signaling in AR42J cells. Cytosolic calcium concentrations were determined using fura-2-based microfluorimetry. Angiotensin II causes elevations in free cytosolic calcium ([Ca2+]i) in the rat pancreatic acinar cell line AR42J. The mechanisms of angiotensin II-evoked calcium signaling were examined using fura-2-based fluorescent digital microscopy. Angiotensin II caused dose-dependent increments in [Ca2+]i over a concentration range of 0.1 1,000 nM, with an average increment of 243 +/- 16 nM at an angiotensin II concentration of 1,000 nM. Dup753, an AT1-specific antagonist, inhibited angiotensin II-evoked signaling, whereas the AT2 antagonist PD123,319 had no effect. Preincubation with the phospholipase C inhibitor U73122 reduced the response in [Ca2+]i to 25% of that of the control. Thapsigargin abolished angiotensin II-evoked calcium signaling. The inositol 1,4,5-trisphosphate receptor antagonist heparin introduced by radiofrequency electroporation inhibited responses to 46 +/- 6% of controls. Angiotensin II-evoked signals were reduced in magnitude and duration by elimination of Ca2+ from the extracellular buffer. Preincubation with pertussis toxin (100 ng/ml) had no effect. Angiotensin II did not stimulate cyclic AMP or suppress vasoactive intestinal peptide stimulated cyclic AMP production over the concentration range that caused Ca2+ signaling. PMID- 10090418 TI - Effect of a liquid meal given as a bolus into the jejunum on human pancreatic secretion. AB - Major features of pancreatic secretion stimulated by a meal depend on intestinal phase mechanisms. However, an intrajejunal (i.j.) meal infusion is widely used for the treatment of inflammatory pancreatic diseases when the resting of the gland is desired. This study was undertaken to compare the effects of an intragastric (i.g.) and an i.j. complete fluid (Lundh) test meal on pancreatic enzyme secretion. Eight men (mean age, 43 years; range, 31-48) free from pancreatic disease were studied. Pancreatic secretion was measured via a multiple lumen tube by aspiration of the duodenal juice. After a fasting period, the Lundh test meal was placed in the stomach or the upper jejunum. After the i.g. administration of the test meal, the aspirated duodenal juice was reinfused into the jejunum. The effect of atropine infusion (0.5 microg/kg/h) on the pancreatic enzyme secretion was studied. The pancreatic amylase, trypsin, and lipase outputs were determined. The plasma levels of cholecystokinin (CCK) and of gastrin were measured by bioassay and radioimmunoassay, respectively. The trypsin, amylase, and lipase secretions increased significantly after either an i.g. or an i.j. test meal intake. The trypsin, amylase, and lipase outputs were significantly decreased during the i.j. perfusion as compared with i.g. administration. The gastrin levels increased significantly after i.g., but remained unchanged after i.j. administration. The CCK release attained its maximum 40 and 60 min after the i.g. and i.j. test meal, respectively. However, the CCK release was significantly lower during the i.j. administration as compared with i.g. perfusion. An atropine infusion significantly reduced the i.g. and i.j. test meal-stimulated enzyme outputs. An i.j.-administered meal stimulates the pancreatic enzyme secretion, but this effect is significantly lower than that which occurs on i.g. administration. The i.j. meal-stimulated secretion of pancreatic enzymes is subject to both cholinergic and peptidergic regulation. The deficiency of gastrin and the delayed and decreased CCK release are believed to account for the reduced enzyme output. PMID- 10090419 TI - Accuracy of the plasma amino acid-consumption test in detecting pancreatic diseases is due to different methods. AB - The aim of this study was to evaluate the controversial specificity of the plasma amino acid (AA)-consumption test in detecting pancreatic diseases by using two different quantitative methods. A total of 55 subjects: 13 healthy subjects, 13 patients with chronic pancreatitis (three mild/moderate, eight severe), 13 patients with pancreatectomy and complete suppression of the exocrine pancreatic secretion, eight patients with chronic liver disease (five with impaired synthetic function), and eight patients with chronic renal failure. Total plasma AAs were quantified by a colorimetric method (p-benzoquinone) in all subjects, at 0, 30, 45, and 60 min during and 30 min after minute 60 of i.v. cerulein infusion (50 ng/kg/h). Either total and individual AAs were quantified by chromatography (high-performance liquid chromatography; HPLC) in 10 healthy subjects, 10 patients with pancreatectomy, and 10 with chronic pancreatitis at 0 and 60 min after the start of the cerulein infusion. For the colorimetric method, healthy subjects had maximal percentage decreases of total AA concentrations not significantly different from those of patients with pancreatectomy and significantly higher than those of patients with chronic pancreatitis (p < 0.0001) or chronic liver disease (p < 0.001). Pancreatic function, as assessed by fecal elastase-1 test, was not significantly correlated to the maximal percentage decrease in total plasma AAs. For the chromatographic method, total AA concentrations were not significantly correlated to those determined by colorimetry. The concentration of each of the individual plasma AAs varied considerably in each group. Fecal elastase-1 values were normal (> or = 200 microg/g) in all patients without pancreatic disease and in only one of 11 patients with chronic pancreatitis and exocrine insufficiency. The type of method used can explain the different results of the AA-consumption test. This test is not very specific for the pancreas. PMID- 10090420 TI - An unusual cause of recurrent pleural effusion in a child. PMID- 10090421 TI - Hypoplasia of ventral pancreas shows a threadlike ventral pancreatic duct. PMID- 10090422 TI - Annular pancreas: MR imaging including MR cholangiopancreatography (MRCP) PMID- 10090423 TI - Expanded activity and utility of the new fluoroquinolones: a review. AB - In general, the fluoroquinolones developed over the past few years have greater potency, a broader spectrum of antimicrobial activity, greater in vitro efficacy against resistant organisms, and a better safety profile than other antimicrobial agents, including the older quinolones. The present review focuses on 4 new quinolones that are commercially available (levofloxacin, trovafloxacin, grepafloxacin, and sparfloxacin) and 3 that are currently undergoing clinical trials (gatifloxacin, moxifloxacin, and clinafloxacin). Examination of the minimum inhibitory concentrations of these drugs against gram-positive, gram negative, anaerobic, and atypical organisms demonstrates their increased potency in vitro. The available clinical evidence, although sparse, suggests the potential enhanced efficacy of these drugs in the treatment of various community acquired and nosocomial infections (eg, respiratory, urinary tract, and skin infections and sexually transmitted diseases). Compared with ciprofloxacin, their pharmacokinetic profiles demonstrate equivalent or greater bioavailability, higher plasma concentrations, and increased tissue penetration, as reflected in greater volume of distribution. Adverse events seen with most quinolones are mild. Serious adverse effects that may occur are phototoxicity (particularly with sparfloxacin) and prolongation of the QTc interval (seen with sparfloxacin and grepafloxacin). Drug interactions are possible between multivalent cation containing compounds and all quinolones and between theophylline and both ciprofloxacin and grepafloxacin. Drugs that prolong the QTc interval should not be coadministered with sparfloxacin and grepafloxacin. Step-down therapy, a therapeutic and cost-saving advantage possible with gatifloxacin, levofloxacin, and moxifloxacin, allows the switching of patients from intravenous to oral therapy without having to change the dosage regimen or class of antibiotics. In addition to shortening the hospital stay and reducing the risk of venous complications, step-down therapy has been shown to cut hospital drug costs by 40% and hospitalization costs by 20%. PMID- 10090424 TI - Oral micronized progesterone. AB - This review sought to examine the rationale for selecting an oral micronized progesterone formulation rather than a synthetic progestin for some of the main indications for progestogens. Unopposed estrogen use is associated with a high risk (relative risk, 2.1 to 5.7) of endometrial hyperplasia and adenocarcinoma, and it has been understood for some time that a progestogen must be added for at least 10 to 14 days per month to prevent these effects. However, the most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum. The inconvenience associated with the use of injectable, rectal, or vaginal formulations of natural progesterone can be circumvented by using orally administered micronized progesterone. The bioavailability of micronized progesterone is similar to that of other natural steroids, and interindividual and intraindividual variability of area under the curve is similar to that seen with synthetic progestins. A clear dose-ranging effect has been demonstrated, and long-term protection of the endometrium has been established. Micronized progesterone has been used widely in Europe since 1980 at dosages ranging from 300 mg/d (taken at bedtime) 10 days a month for women wishing regular monthly bleeding to 200 mg 14 days a month or 100 mg 25 days a month for women willing to remain amenorrheic. This therapy is well tolerated, with the only specific side effect being mild and transient drowsiness, an effect minimized by taking the drug at bedtime. The prospective, comparative Postmenopausal Estrogens/Progestin Intervention trial has recommended oral micronized progesterone as the first choice for opposing estrogen therapy in nonhysterectomized postmenopausal women. PMID- 10090425 TI - Grepafloxacin: a review of its safety profile based on clinical trials and postmarketing surveillance. AB - The safety profile of grepafloxacin has been characterized in a number of preclinical and clinical studies. Preclinical investigations have shown that its toxicologic profile is similar to that of other fluoroquinolones, and phase I studies in humans have confirmed these data. A photosensitivity study demonstrated equivalence with ciprofloxacin, and a study in elderly patients taking the highest clinical dose of grepafloxacin indicated that prolongation of the QTc interval by grepafloxacin was less than 2 ms, 15 times less than that observed in a study of erythromycin. In phase II and III clinical investigations conducted in the United States and the United Kingdom, safety data have been gathered from more than 3000 patients with either community-acquired pneumonia or acute bacterial exacerbations of chronic bronchitis. The most common adverse events with grepafloxacin 400 or 600 mg were gastrointestinal, such as nausea, vomiting, and diarrhea. The frequency of these adverse events was similar to that seen with ciprofloxacin. Significantly more patients reported a mild, unpleasant metallic taste with grepafloxacin than with ciprofloxacin, but <1% of patients withdrew from therapy because of this. Headache was observed significantly more often in ciprofloxacin-treated patients than in grepafloxacin-treated patients. Recent postmarketing data confirm the good tolerability and safety profile of grepafloxacin. These data, from a case-report study of more than 9000 patients in Germany, demonstrated that only 2.3% of patients reported adverse events when grepafloxacin was used in routine clinical practice. The most frequently reported events were nausea (0.8%) and gastrointestinal symptoms (0.4%). Dizziness was reported by only 0.3% of patients, and only 4 patients (0.04%) reported photosensitization. Adverse events did not appear to be either dose dependent or related to diagnosis. More than 400,000 patients world-wide have received grepafloxacin treatment. No new safety issues have arisen from the spontaneous report data and, with the exception of rare reports of an unpleasant taste, the most commonly reported events have been the same as those seen in clinical studies. These data support grepafloxacin as a well-tolerated fluoroquinolone suitable for the treatment of community-acquired respiratory tract infections. PMID- 10090426 TI - Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis. AB - The US adult rheumatoid arthritis (RA) population numbers approximately 2.1 million, with a greater proportion of cases in women. RA is a disease of the immune system that has no known cure, and current drugs do not affect the underlying cause. The side effects such drugs produce limit their usefulness, and many patients stop responding to these treatments over time. Etanercept, a biologic inflammation modulator, is a novel human recombinant version of the soluble p75 tumor necrosis factor (TNF) receptor that is linked to the Fc receptor of human immunoglobulin G subclass 1. It acts as a competitive inhibitor of the binding of TNF-alpha to cell-surface TNF receptors and thereby inhibits TNF-alpha-induced proinflammatory activity in the joints of RA patients. Etanercept acts as a cytokine "carrier" and TNF-alpha antagonist, rendering TNF alpha biologically inactive, even though prolonging its half-life. In Phase I, II, and III clinical studies in patients with active, severe RA who had not responded to disease-modifying antirheumatic drug (DMARD) therapy, etanercept treatment decreased disease activity, increased functional activity, and improved health-related quality of life. In a recent 12-month continuation of an earlier 6 month study, 105 patients who received etanercept 25 mg subcutaneously twice weekly demonstrated rapid and sustained improvements in disease activity. The US Food and Drug Administration has approved etanercept for marketing for the treatment of moderately to severely active RA in patients who have not responded adequately to other DMARDs. PMID- 10090427 TI - Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: a randomized, double-masked, placebo-controlled trial. Metrifonate Study Group. AB - This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading dose regimen versus the loading-dose regimen observed in this study, the no loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity. PMID- 10090428 TI - Sparfloxacin versus clarithromycin in the treatment of community-acquired pneumonia. AB - Community-acquired pneumonia remains a significant health concern despite the availability of effective antibiotics. This randomized, double-masked, double dummy, multicenter comparative trial was undertaken to compare the efficacy and safety of sparfloxacin with those of clarithromycin in the treatment of community acquired pneumonia. In 54 centers throughout the United States, 342 patients aged > or = 18 years with community-acquired pneumonia were enrolled in this trial. A total of 167 patients, 98 males and 69 females with a mean age of 51.0 years (range, 18-87), received a 400-mg loading dose of sparfloxacin on the first day, followed by 200 mg once daily for a total of 10 days. A total of 175 patients, 85 males and 90 females with a mean age of 51.3 years (range, 18-91), received clarithromycin 250 mg twice daily for 10 days. In the intent-to-treat population, 133 (79.6%) patients in the sparfloxacin group and 145 (82.9%) in the clarithromycin group were cured or improved (the 95% confidence interval [CI] for the differences in success rate between sparfloxacin and clarithromycin was 11.5% to 5.1%). Success rates for the per-protocol patients were 88.7% (133/150) in the sparfloxacin group and 88.9% (144/162) in the clarithromycin groups (95% CI, -7.2% to 6.8%). There were no significant differences in success rate between treatment groups based on age > or = 65 years. The overall bacteriologic response rates in the bacteriologically assessable population were 97.0% (64/66 isolates) in the sparfloxacin group and 91.4% (74/81 isolates) in the clarithromycin group. Recurrence occurred in 6.0% of per-protocol patients in the sparfloxacin group and 6.3% of patients in the clarithromycin group. The overall frequency of adverse events was 56.3% in the sparfloxacin group and 65.1% in the clarithromycin group. Gastrointestinal disturbances were the most common adverse event in both groups. Abnormal taste related to study drug was reported by 17 patients (9.7%) treated with clarithromycin, versus 3 patients (1.8%) treated with sparfloxacin (P = 0.002). Photosensitivity reactions were reported in 10 patients (6.0%) treated with sparfloxacin, versus 1 patient (0.6%) treated with clarithromycin (P = 0.002). QT-interval prolongation was documented in 4 patients (2.4%) in the sparfloxacin group and no patients in the clarithromycin group. Thus sparfloxacin was as well tolerated and as effective as clarithromycin in the treatment of community-acquired pneumonia. PMID- 10090429 TI - International clinical experience with a new low-dose, monophasic oral contraceptive containing levonorgestrel 100 microg and ethinyl estradiol 20 microg. AB - Manufacturers have steadily been decreasing the amounts of estrogen and progestin in oral contraceptives (OCs) in an effort to enhance safety and tolerability while preserving contraceptive efficacy. A new formulation containing 20 microg ethinyl estradiol (EE) and 100 microg levonorgestrel (LNG)--representing the lowest available contraceptive dose of each hormone--has undergone extensive clinical testing in the United States and Germany. A total of 1590 women in 61 centers received 20 microg EE and 100 microg LNG for 6 cycles. Overall, 4 pregnancies possibly related to treatment failure were reported, reflecting an overall Pearl Index (number of pregnancies per 100 woman-years of treatment) of 0.65 and a failure rate of 0.34%. Cycle control was typical of low-dose OC use. Spotting and breakthrough bleeding occurred most commonly during the earlier cycles in each study. Adverse events were typical of those seen with OC use and led to study discontinuation in 6.6% of the women. Intermenstrual bleeding was the cause for early study withdrawal in 2.6% of women. The study results suggest that the combination of 20 microg EE and 100 microg LNG offers the benefits of low hormone content with good contraceptive efficacy, cycle control, and tolerability. PMID- 10090430 TI - Nonimmunogenicity of eptifibatide, a cyclic heptapeptide inhibitor of platelet glycoprotein IIb-IIIa. AB - Inhibitors of platelet glycoprotein (GP) IIb-IIIa have been demonstrated to be effective in controlling acute cardiac complications in patients presenting with acute ischemic coronary syndromes (AICS). Since patients with atherosclerotic coronary vascular disease may present with AICS on multiple occasions, it is important to have documented evidence that novel antithrombotic agents are nonimmunogenic and thus safe for repeated administration. Eptifibatide (Integrilin) is a cyclic heptapeptide inhibitor that contains a modified lysine glycine-aspartic acid sequence that recognizes the binding site of platelet GP IIb-IIIa, resulting in potent and selective inhibition of its binding to fibrinogen. An enzyme-linked immunosorbent assay sensitive to all classes of immunoglobulins was developed to test the immunogenicity of eptifibatide in humans. In two clinical studies, Integrilin to Minimize and Prevent Acute Coronary Thrombosis (IMPACT) and IMPACT II, samples were obtained from 414 patients undergoing coronary angioplasty to determine anti-eptifibatide antibodies at baseline and 30 days after treatment. In a separate clinical pharmacology study, 28 healthy volunteers received 2 infusions of eptifibatide 28 days apart and were monitored at baseline (immediately before the first infusion), at 28 days (immediately before the second infusion), and at 42, 56, 84, and 112 days after enrollment to monitor for an anamnestic anti-eptifibatide response. Eptifibatide administration did not result in an antibody response in any of the 3 studies, even after repeated administration. Eptifibatide represents a potent, specific inhibitor of the platelet GP IIb-IIIa complex that has not been observed to be immunogenic in clinical studies and is thus safe for repeated administration. This finding suggests that small, peptide-based therapeutic agents, which are becoming increasingly common, may be used in humans without inciting an immune response. PMID- 10090431 TI - Patient preference, efficacy, and compliance with timolol maleate ophthalmic gel forming solution versus timolol maleate ophthalmic solution in patients with ocular hypertension or open-angle glaucoma. AB - This study was designed to compare timolol maleate ophthalmic gel-forming solution 0.5% (timolol gel) once daily with timolol maleate ophthalmic solution 0.5% (timolol solution) twice daily with respect to patient preference, intraocular pressure (IOP)-lowering effect, and tolerability. A total of 202 patients with ocular hypertension or open-angle glaucoma and an IOP > or = 22 mm Hg were enrolled in this 12-week, randomized, observer-masked, two-period crossover study. Significantly more patients preferred timolol gel to timolol solution (P < 0.001). Ninety-two percent of patients preferring timolol gel strongly agreed or agreed that once-daily dosing was a reason for their preference. Those who preferred timolol solution did so because of fewer side effects. The mean IOP-lowering effects of the 2 treatments were similar at both morning trough and peak time points. The incidence of drug-related adverse experiences was similar (timolol gel 11.4% vs timolol solution 10.9%). Because both treatments were well tolerated and effective in lowering IOP, timolol gel, with its once-daily dosing regimen, should be considered in patients who are candidates for therapy with an ophthalmic beta-blocking agent. PMID- 10090432 TI - Safety profile of sparfloxacin, a new fluoroquinolone antibiotic. AB - The safety profile of sparfloxacin, a newer fluoroquinolone antibiotic, was examined through an integrated analysis of safety data from 6 multicenter phase III trials. These consisted of 5 double-masked, randomized, comparative trials of sparfloxacin (a 400-mg oral loading dose followed by 200 mg/d for 10 days) versus standard therapies (erythromycin, cefaclor, ofloxacin, clarithromycin, and ciprofloxacin) and I open-label trial (noncomparative) in patients with: community-acquired pneumonia (2 trials); acute bacterial exacerbations of chronic bronchitis (1 trial); acute maxillary sinusitis (2 trials, one of which was the noncomparative trial); and complicated skin and skin-structure infections (1 trial). Overall, 401 (25.3%) of 1585 patients treated with sparfloxacin and 374 (28.1%) of 1331 receiving a comparator regimen experienced at least 1 adverse event considered to be related to the study medication. Photosensitivity reactions, usually of mild-to-moderate severity, were seen more frequently with sparfloxacin (7.4%) than with comparator agents (0.5%), whereas gastrointestinal reactions (diarrhea, nausea, dyspepsia, abdominal pain, vomiting, and flatulence), insomnia, and taste perversion were more common in patients taking comparator drugs (22.3% vs 12.1%, 4.3% vs 1.5%, and 2.9% vs 1.2%, respectively). Analysis of electrocardiographic findings showed that the mean change from baseline in QT interval corrected for heart rate (QTc) was significantly greater in sparfloxacin-treated patients (10 msec) than in patients given comparator drugs (3 msec), but no associated ventricular arrhythmias were detected. Adverse events led to discontinuation of study medication in 104 (6.6%) patients receiving sparfloxacin and 118 (8.9%) given com parator drugs. Sparfloxacin may be considered an appropriate choice for the treatment of certain community acquired infections for patients who are not at risk for photosensitivity reactions or adverse events associated with prolongation of the QTc interval. PMID- 10090433 TI - Reduced intrapatient variability of cyclosporine pharmacokinetics in renal transplant recipients switched from oral Sandimmune to Neoral. AB - Sixty-six renal transplant patients maintained on Sandimmune, the traditional formulation of cyclosporine, participated in an open-label, sequential trial to compare intrapatient variability in drug exposure before and after a switch to Neoral. Three 12-hour cyclosporine pharmacokinetic profiles were obtained over approximately 6 weeks while patients were receiving Sandimmune. Patients were then switched to Neoral, with the dose adjusted as necessary to maintain target trough blood cyclosporine concentrations. At approximately 4 and 6 weeks postconversion, 2 additional pharmacokinetic profiles were obtained. Key pharmacokinetic variables analyzed were area under the concentration-time curve (AUC), maximum concentration (Cmax), and predose trough concentration (C0). Intrapatient variability in drug exposure for dose-normalized mean AUC, Cmax, and C0 was significantly reduced with Neoral, with 50 (76%), 57 (86%), and 45 (68%) patients experiencing reduced variability in AUC, Cmax, and C0, respectively (P < 0.001). Additionally, the total exposure to cyclosporine was more predictable from the trough level of cyclosporine with Neoral; the relationship between AUC and C0 was 0.81 for Neoral at both pharmacokinetic profiling time points but ranged from 0.49 to 0.69 for the 3 Sandimmune time points. The large reductions in intrapatient variability of pharmacokinetic variables for cyclosporine provided by Neoral indicate an improvement in the consistency of drug exposure, which may translate into important clinical benefits. PMID- 10090435 TI - Sumatriptan treatment for migraine in a health maintenance organization: economic, humanistic, and clinical outcomes. AB - This study was undertaken to assess the impact of 12 months of sumatriptan therapy (6 mg subcutaneously) for migraine on health care use, health-related quality of life, productivity, patient satisfaction with the medication, and clinical efficacy in a health maintenance organization (HMO). One hundred forty eight patients received open-label sumatriptan for 12 months for the treatment of migraine. Medical records were reviewed to obtain information on the frequency of migraine-related health care use during the 12 months before and during sumatriptan treatment. Patients completed questionnaires on their productivity at work, health-related quality of life, and satisfaction with medication at baseline and after 3, 6, and 12 months of sumatriptan treatment. For each migraine, patients recorded pain severity scores before and after taking sumatriptan and the time between dosing and onset of meaningful relief. Sumatriptan was associated with significant reductions in migraine-related use of general outpatient services, telephone calls, urgent care services, and emergency department visits (P < 0.05); a significant increase in the use of pharmacy services (P < 0.05); and significant and sustained improvements in health-related quality-of-life scores compared with baseline (P < 0.001). Patients lost significantly less time from work and were significantly more satisfied with sumatriptan compared with their usual therapy (P < 0.05). Two hours after dosing, 81% of patients experienced reduction of moderate or severe pain to mild or no pain, and 90% of all patients experienced meaningful relief of pain. The use of sumatriptan for 12 months in an HMO was associated with reductions in health care use and improved health-related quality of life, productivity, and patient satisfaction with medication. PMID- 10090434 TI - Effectiveness of short-course therapy (5 days) with grepafloxacin in the treatment of acute bacterial exacerbations of chronic bronchitis. AB - Three hundred eighty-nine patients were enrolled in a double-masked, multicenter, randomized clinical trial comparing the clinical and bacteriologic efficacies and safety of a 5-day course (n = 195) versus a 10-day course (n = 194) of grepafloxacin 400 mg once daily in the treatment of acute bacterial exacerbations of chronic bronchitis (ABECB). Patients in the 5-day treatment group received placebo on days 6 through 10. Bacteriologic assessments were based on cultures of sputum specimens obtained before and, when possible, during and after treatment. Organisms were isolated from the pretreatment sputum specimens of 332 of 388 (86%) patients, the primary pathogens being Haemophilus parainfluenzae, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus (29%, 19%, 4%, 5%, and 5% of isolates, respectively). Among isolates tested for beta-lactamase production, results were positive in 25% of H influenzae isolates and 90% of M catarrhalis isolates. Forty-two percent of S pneumoniae isolates demonstrated reduced susceptibility (intermediate or high level resistance) to penicillin. A satisfactory clinical outcome (cure or improvement) was achieved in 83% (128 of 155) and 81% (122 of 150) of clinically evaluable patients treated with grepafloxacin for 5 or 10 days, respectively. Pathogens were eradicated or presumed eradicated in 77% (106 of 138) and 80% (98 of 123) of bacteriologically evaluable patients treated with grepafloxacin for 5 or 10 days, respectively. The 2 treatment groups were equivalent with respect to both clinical and bacteriologic efficacy, and no statistically significant differences in the incidence of drug-related adverse events were seen between the 2 groups. Substantial symptom relief was evident with both treatment regimens by the first during-treatment measurement, which occurred between days 3 through 5. These results indicate that treatment with 400 mg grepafloxacin once daily for 5 days is as well tolerated and effective as treatment for 10 days in patients with ABECB. The lower cost compared with a 10-day regimen and the increased likelihood that patients will complete the entire shorter, once-daily regimen make the 5-day grepafloxacin regimen a useful therapeutic option in the treatment of ABECB. PMID- 10090436 TI - Health-related quality-of-life effects of oxaprozin and nabumetone in patients with osteoarthritis of the knee. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of signs and symptoms of osteoarthritis (OA). Nabumetone and oxaprozin are 2 of the newer NSAIDs and have been shown to have similar safety and efficacy profiles. Nabumetone 1000 mg to 1500 mg once a day (QD) and oxaprozin 1200 mg QD are commonly recommended doses. This study compared the health-related quality of life (HRQOL) of patients receiving oxaprozin 1200 mg QD with that of patients receiving nabumetone 1000 mg QD or nabumetone 1500 mg QD for the treatment of signs and symptoms of OA of the knee. Two similarly designed, independent, randomized, double-masked, placebo-controlled clinical trials were conducted. In trial 1, patients were randomized to receive oxaprozin 1200 mg QD (n = 109), nabumetone 1000 mg QD (n = 110), or placebo (n = 109); in trial 2, patients received oxaprozin 1200 mg QD (n = 116), nabumetone 1500 mg QD (n = 115), or placebo (n = 116). HRQOL was measured by the Medical Outcomes Study Short-Form-36 Health Survey (1-week recall period) at baseline and weeks 2 and 6. Data from the 2 trials were combined to assess differences across the 4 groups in 8 domains and 2 summary scores at baseline, and changes in HRQOL scores at weeks 2 and 6. At week 2, the oxaprozin group showed significantly greater improvement than the placebo group in role physical, vitality, and mental component summary (MCS) scores (P < 0.05), and in physical functioning, bodily pain, social functioning, and physical component summary (PCS) scores (P < 0.01). The nabumetone 1500-mg group showed significantly greater improvement than the placebo group in bodily pain and social functioning (P < 0.05), and in vitality and MCS score (P < 0.01). No significant differences were observed between the nabumetone 1000-mg and placebo groups. At week 2, the oxaprozin group showed a greater change than the nabumetone 1000-mg group in PCS score (P < 0.05). At week 6, oxaprozin treatment resulted in significantly greater improvement than placebo in physical functioning, role physical, and bodily pain (P < 0.05); social functioning, role emotional, and mental health (P < 0.01); and vitality and MCS score (P < 0.001). The nabumetone 1500-mg group showed significantly greater responses than the placebo group in vitality (P < 0.05), mental health (P < 0.01), and MCS score (P < 0.001). The oxaprozin group had significantly better scores than the nabumetone 1500-mg group in the PCS (P < 0.05), and it showed significantly greater improvement than the nabumetone 1000 mg group in role physical and PCS score (P < 0.01) and in role emotional (P < 0.05). No statistically significant differences were found between placebo and nabumetone 1000 mg at week 6. Results of this study suggest that oxaprozin 1200 mg QD has a significant positive impact on the HRQOL of patients with OA of the knee compared with nabumetone 1000 mg QD and placebo. PMID- 10090437 TI - Use of diagnostic cluster methodology for therapeutic costing and drug surveillance of HMG-CoA reductase-inhibitor therapy. AB - Diagnostic cluster methodology groups patients having similar medical conditions according to their International Classification of Diseases, 9th Revision codes. Episodes of care related to the diagnostic cluster can then be tracked from the claims data to determine the total charges associated with patient management. A retrospective claims analysis using an episode registry database was conducted to determine the 1-year (July 1, 1995, to June 30, 1996) covered charge for statin therapy, the overall cost of treating related cardiovascular (CV) disease, and the cost impact of coadministration of drugs that potentially compete for hepatic metabolism. The three statin treatment groups (lovastatin, pravastatin, and simvastatin) were similar with respect to age, gender, mean number of prescription refills, rate of refill compliance, and prevalence of the coadministration of potentially interacting agents. Before adjustment for severity of illness, there were no significant differences between groups in prescription drugs/services (statin Rx/Svc) or total CV charges. After adjustment for severity of illness, the pravastatin group had the lowest statin Rx/Svc and total CV charges. Within the group with the greatest severity of illness, statin Rx/Svc charges were significantly lower with pravastatin than with lovastatin and simvastatin. The statin Rx/Svc charges were not significantly different between lovastatin and simvastatin. Coadministration of a potentially interacting agent significantly increased both the statin Rx/Svc and total CV charges within the simvastatin-treated group but did not significantly influence costs in the lovastatin- or pravastatin-treated groups. The estimates of direct costs derived from this analysis are consistent with findings in the published literature and demonstrate that pravastatin has cost advantages compared with lovastatin and simvastatin. Diagnostic cluster methodology also generated valuable information regarding drug surveillance and the health care cost impact of potential drug drug interactions with selected statins. PMID- 10090438 TI - The technology of metered-dose inhalers and treatment costs in asthma: a retrospective study of breath actuation versus traditional press-and-breathe inhalers. AB - This paper reviews the impact of the use of technologically dissimilar beta agonist aerosols--the Maxair Autohaler (pirbuterol acetate) breath-actuated aerosol and the traditional albuterol press-and-breathe inhaler-on the treatment costs of asthma. If, as clinical evidence would suggest, the breath-actuated aerosol is not only as effective as an albuterol inhaler with a spacer, but is easier to use and results in more optimal beta-agonist use by patients, then one might consider the hypothesis that patients possessing a breath-actuated inhaler would, ceteris paribus, experience lower asthma-related treatment costs principally, those medical costs associated with fewer emergency room visits and hospitalizations. This hypothesis is considered from the perspective of a retrospective claims database study of patients who used one or the other beta agonist inhaler exclusively. At the descriptive level, costs of treatment for patients using the press-and-breathe inhaler are estimated to be 16.5% greater than costs for patients using the breath-actuated inhaler. In the multivariate analysis, the presence of the breath-actuated inhaler (in a dummy variable analysis) was not only statistically significant (P < 0.05), but entered with the expected negative sign. Estimated cost impacts under various model specifications are consistent with the magnitude of the cost differences reported in the descriptive analysis. Total cost savings with the Maxair Autohaler ranged from 8.7% to 11.7%, with medical cost savings estimated at 14.6%. PMID- 10090439 TI - Productivity-cost controversies in cost-effectiveness analysis: review and research agenda. AB - Productivity costs represent true costs to society and should not be ignored in a cost-effectiveness analysis. However, there is dissension among health economists regarding measurement of productivity costs. Certain health economists argue for inclusion of productivity costs in the denominator of the cost-effectiveness ratio, measured in quality-adjusted life-years. Others argue that productivity costs should be included in the numerator of the cost-effectiveness ratio, measured in dollars using the friction-cost method or the human-capital method. This paper reviews the productivity-cost controversies and offers suggestions for future research addressing the debated issues. PMID- 10090440 TI - Link between patient preferences and treatment outcomes in seasonal allergic rhinitis: an empiric investigation. AB - In a multicenter, parallel-group, double-masked, randomized study, two questionnaires were administered to a clinical study population to identify which specific symptoms of seasonal allergic rhinitis patients perceived as most important to relieve (personal preferences) and to learn whether any relationship existed between patient preferences and the severity of their symptoms during treatment with antihistamines. The group was composed of 256 males and 313 females. Their mean age was 32.4 years, and mean duration of seasonal allergic rhinitis was 14.5 years, with mean age of onset of 17.7 years. After receiving placebo for 1 week, patients were randomly allocated to receive an antihistamine (fexofenadine or loratadine) for 2 weeks. Patient preferences for relief of individual allergy symptoms (rhinitis; sneezing; itchy, watery, red eyes; itchy nose, palate, or throat) and related conditions (fatigue, physical limitations) were scored using 2 different questionnaires before treatment (0-to-10 category rating scale for assessing the 4 symptoms of allergic rhinitis) and after receiving placebo for 1 week (Feeling Thermometer). Symptom severity was reported in patient diaries after 1 and 2 weeks of antihistamine treatment and was measured by patient self-assessment. All symptoms were considered by the patients to be important to relieve, the most important being itchy, watery, red eyes and rhinorrhea. The severity of allergy symptoms was consistently related to the importance of symptoms identified before treatment. Therefore, including patient preferences in medical evaluations might be a useful tool in evaluating the success of their treatment. PMID- 10090441 TI - Iris arteriovenous communication: clinical and angiographic features. AB - BACKGROUND: Iris arteriovenous communication (IAVC) represents a quite rare congenital anomaly, consisting of abnormal vascular connection bypassing the iris capillary bed. The aim of the present study is to describe clinical and angiographic pattern of IAVC on iris fluorescein angiography (IFA) and on indocyanine green videoangiography (IICGV). METHODS: During a mean follow-up period of 33.5 months, eight patients affected by IAVC underwent at least three ophthalmological examinations completed by IFA and IICGV. RESULTS: IFA allows the detection of IAVC vascular structures, evidencing afferent and efferent branches, which show a rapid filling, without any evidence of leakage or iris hypoperfusion. IICGV shows more precisely the entire vascular pattern of IAVC, revealing also the presence of iris hypoperfusion in the sector in which the IAVC lay. One patient underwent cataract surgery; three months later, two neovascular tufts appeared in the hypoperfused area related to IAVC. In all other patients, periodical examinations did not reveal any clinical or angiographic changes. CONCLUSION: In IAVC, the clinical picture appears stable throughout the follow up; both angiographic techniques seem able to precisely delineate the vascular pattern. Nevertheless, IICGV is superior in showing iris hypoperfusion surrounding the vascular abnormality. Particular care must be drawn to patients affected by IAVC who need cataract surgery. PMID- 10090442 TI - Erythrocyte deformability in high-tension and normal tension glaucoma. AB - The exact cause of primary open angle glaucoma is still unknown. Intraocular pressure is a major factor but it is impossible to explain the whole mechanism of glaucomatous optic nerve damage with only increased intraocular pressure. Other factors play important roles in the development of glaucoma. With this point of view, vascular factors have been implicated in the pathogenesis of glaucoma. We tried to determine the etiopathogenetic role of decreased erythrocyte deformability in normal tension glaucoma and high-tension glaucoma. The study group consisted of 16 patients with the diagnosis of normal tension glaucoma, 17 patients with the diagnosis of high-tension glaucoma, and 24 patients as controls. Independent t-tests were used to compare the three groups two by two for age, hematocrit, mean cell volume, plasma protein level, cardiovascular risk factors, and erythrocyte deformability. There was no statistically significant relationship (p>0.05) between the groups concerning the erythrocyte deformability. When we consider all of 57 patients, we found that both increasing age (>60 years) and greater mean cell volume (>84 fl) had a statistically significant relationship with decreased erythrocyte deformability (p<0.05). When we performed Pearson correlation analysis, we found that only mean cell volume and erythrocyte deformability had a statistically significant relationship (r = 0.31, p = 0.02). We conclude that decreased erythrocyte deformability is not a major factor in the ethiopathogenesis of normal tension glaucoma and high-tension glaucoma. PMID- 10090443 TI - An evaluation of methylated collagen as a substitute for vitreous and aqueous humor. AB - PURPOSE: To evaluate ocular tolerance of methylated collagen gel injected intravitreally and into the anterior chamber. METHODS: Methylated collagen (type I/III) was tested in New Zealand white rabbits. Vitreous cavity: After pars plana vitrectomy, methylated collagen gel was injected intravitreally. The eyes were examined clinically; electroretinogram recordings were made before and after surgery. Vitreous samples were taken for immunological analysis for the presence of the injected collagen. The rabbits were sacrificed 6 months after surgery; the retina was evaluated by light microscopy. Anterior chamber: In another group of rabbits, methylated collagen gel (0.2 ml, 0.1 ml, or 0.05 ml) was injected into the anterior chamber after paracentesis. The eyes were examined with a slit lamp; intraocular pressure was measured postinjection. The rabbits were sacrificed after 4 months; the corneas were evaluated histologically. RESULTS: Vitreous cavity: The fundus view was clear for 6 months after intravitreal injection. Scotopic and photopic electroretinograms were normal in 6/7 eyes; one eye experienced a mild decrease one month postoperatively. No abnormal changes were found in the retinal histology. Anterior chamber: Some corneas were hazy and edematous around the injection site for one week. The injected collagen appeared in bundles, patches, and little pieces in the anterior chamber with precipitates on the corneal endothelium, pupillary margin, and the anterior capsule of the lens. The collagen diminished gradually, without causing permanent opacity. Histologically, the corneal endothelium in the eye which received 0.2 ml collagen showed a mild distention of the mitochondriae and vesicle formation between endothelial cells under transmission electron microscope. CONCLUSION: Methylated collagen gel was tolerated by the eye after intravitreal injection. Localized temporary clinical and mild ultrastructural corneal changes were observed after anterior chamber injection. PMID- 10090444 TI - Ambulatory blood pressure monitoring in glaucoma patients. The nocturnal systolic dip and its relationship with disease progression. AB - PURPOSE: This study was designed to uncover a new sensitive and specific factor for predicting the progression of glaucoma. METHODS: The 24-hour ambulatory blood pressure and diurnal curve of intra-ocular pressure were recorded in seventy patients: 51 primary open angle glaucoma (POAG) and 19 normal tension glaucoma (NTG). The mean systolic, diastolic and average arterial blood pressure were calculated, along with the nocturnal dip of systolic pressure and diastolic blood pressure. Two-year disease progression was assessed for all patients by means of retrospective analysis of visual fields defects on repeated perimetries. RESULTS: Abnormal (absence or increased) nocturnal dip of systolic blood pressure was found to be correlated with disease progression in POAG and NTG patients with a sensitivity of 86% and a specificity of 85%, whereas no significant correlation was found for the other risks factors envisaged. Furthermore, a significant relationship between stable visual field defects and the use of diuretics/laser procedure was evidenced. CONCLUSION: The nocturnal dip of systolic blood pressure should be considered as a predictive factor of disease progression in NTG and POAG. Further prospective studies are needed to ascertain whether dip normalization could help slow down the visual field loss in these patients. PMID- 10090445 TI - Changes in pattern reversal evoked potentials during menstrual cycle. AB - Hormonal changes that occur during the menstrual cycle of women influence the visual function of females. Estrogen is reported to cause a decrease in the visual transmission time by increasing the sensitivity of receptors in the optic pathways to dopamine. The aim of this study was to search if pattern reversal evoked potentials (PRVEPs) changed during the different phases of the menstrual cycle. PRVEPs of both eyes of 30 healthy women were recorded in 4 different phases of the menstrual cycle, namely, menstrual, follicular, ovulatory and luteal. The highest mean PRVEP latency and the lowest mean P100 amplitude were recorded during the menstrual phase. The mean PRVEP latency recorded during the ovulatory phase (when estrogen level rises to 3-5 times that of other phases' without an increase in progesterone levels) was statistically significantly shorter than that of other phases' (p<0.05). Although not statistically significant, the mean P100 amplitude recorded during the ovulatory phase was higher than the other phases. Looking at these results, sex steroids seemed to affect the generation of PRVEPs. The significant decrease in PRVEP latencies when estrogen levels peaked was thought to be due to facilitating effect of estrogen on the neural transmission of the visual pathways. PMID- 10090446 TI - Adverse effects of topical antiglaucomatous medications on the conjunctiva and the lachrymal (Brit. Engl) response. AB - BACKGROUND: Increasing evidence indicates that long-term use of topically administered medication can induce changes in the conjunctiva and lachrymal function. METHODS: In order to evaluate changes in the conjunctiva and lachrymal response after prolonged use of topically administered antiglaucoma medications and preservatives found in antiglaucomatous medication solutions (benzalkonium chloride), we tested lachrymal function (Schirmer I., Jones, BUT, Ferning tests) and used the conjunctival impression cytology technique. MATERIALS: A group of patients with primary open angle glaucoma (POAG) receiving topical antiglaucomatous medication were recruited. A second group received only preservative instillations while a control group was formed of similarly aged subjects with no eye disease and was given topical or systemic medical therapy. Excluded from the trial were patients with a history of external eye disease or who had received conjunctival surgery. RESULTS: Tear secretion was reduced against that of the control group in those subjects who received protracted administration of antiglaucomatous eyedrops (timolol and/or pilocarpine). A statistically significant degree of conjunctival metaplasia was associated with long-term use of topical medication. The subjective symptoms reported by those patients receiving chronic topical antiglaucomatous therapy and the objective observations on them were found to be proportional to the observed tearing response. Changes were more pronounced in subjects who received only benzalkonium chloride. CONCLUSION: Our study results suggest that long-term use of antiglaucoma medication induces changes in both tear film and conjunctival surface. Such changes may be related to the medication or the duration of treatment, but may also be due to the preservatives used in the commercial product. PMID- 10090448 TI - Effect of a somatostatin analogue (SMS 201-995) on tear secretion in rats. AB - PURPOSE: In this study we investigated the effect of a somatostatin analogue, octreotide, (SMS 201-995) on tear secretion in rats. METHOD: The animals were anaesthetized intraperitoneally (ip) with urethan (1.2 g/kg) The drugs were injected subcutaneously (sc.). Tear samples were collected by folding a 5 mm section of the Schirmer strip over the lower lid margin to absorb tear fluid from the lower conjunctival sac for 5 mm. Forty animals were divided into four groups (n = 10). Group I (control) received 1 ml of saline, group 2 received 100 microg/kg of SMS 201-995, group 3 received 50 microg/kg of acetylcholine (Ach), group 4 received 100 microg/kg of SMS 201-995 and 30 min later 50 microg/kg of Ach. At t = 0 the local anesthetic proparacain HCI was instilled onto the ocular surface to minimize reflex secretion. Baseline secretion was measured before administering the various treatments. RESULTS: While Ach alone significantly increased tear secretion, SMS 201-995 reduced it compared to saline (control) (p<0.0001, p<0.001, respectively). SMS 201-995 combined with Ach decreased tear secretion compared to Ach alone (p<0.03). CONCLUSION: SMS 201-995 significantly inhibits Ach stimulated tear secretion in rats. PMID- 10090447 TI - Additive effect of latanoprost and dorzolamide in patients with elevated intraocular pressure. AB - PURPOSE: To evaluate the additive ocular hypotensive effect of latanoprost and dorzolamide in combination, on intraocular pressure reduction in patients with elevated intraocular pressure (IOP). METHODS: Thirty patients with ocular hypertension or early capsular or primary open-angle glaucoma and elevated IOP were randomly assigned to two parallel treatment groups. The treatment period was twenty days. Fifteen patients (Group 1) received latanoprost once daily during the first ten days and, in addition, dorzolamide three times daily during the second ten days. Fifteen patients (Group 2) received dorzolamide three times daily during the first ten days and, in addition latanoprost, once daily during the second ten days. IOP was measured and conjunctival hyperemia was evaluated. RESULTS: In Group 1, the mean IOP on day 0 was 26.8 mm Hg; on day 10, 18.7 mm Hg; and on day 20, 15.9 mm Hg. In Group 2, the mean IOP on day 0 was 26.3 mm Hg; on day 10, 21.2 mm Hg; and on day 20, 16.1 mm Hg. Both groups had clinically significant IOP-lowering effect on day 10 as compared with baseline day (30.2% and 19.4% respectively) (p<0.01). When dorzolamide was added to latanoprost, the additional IOP reduction was 2.8 mm Hg (15%) (p<0.01) compared with 5.1 mm Hg (24.1%) (p<0.01) when latanoprost was added to dorzolamide. No local serious adverse reactions were observed. A mild but statistically significant increase in conjunctival hyperemia was seen in latanoprost applied patients. CONCLUSIONS: The results showed that latanoprost and dorzolamide can be combined successfully to reduce IOP with their additive effects. PMID- 10090449 TI - Topical pefloxacin in bacterial keratitis. AB - PROBLEM: To evaluate the clinical efficacy and safety of topical pefloxacin 0.3% drops as the sole antibiotic used to treat culture positive bacterial corneal ulcers. METHODS: Forty two consecutive Gram's smear-positive cases of bacterial corneal ulcers were enrolled for this prospective open labelled clinical trial. All patients underwent a complete clinical and microbiological work up and were put on topical 0.3% pefloxacin drops with supportive cycloplegic, vitamins and antiglaucoma therapy. Of 42 cases, 4 cases of mycotic keratitis and 6 culture negative cases were excluded from the study. RESULTS: Positive microbiologic cultures were obtained in 84.2% (32 of 38) cases. Staphylococcus aureus (14/32; 43.7%) and coagulase negative Staphylococci (12/32; 37.5%) were the two most common organisms isolated. Resolution of the corneal ulcer was achieved in 31 out of 32 cases (96.9%) with a mean duration of 9.3+/-5.3 days (range 3-21 days). Best corrected visual acuity of 20/200 or better was achieved in 65.6% of cases at 4 weeks post resolution. Corneal deposits were observed in one case which disappeared 8 days following discontinuation of therapy. CONCLUSIONS: Topical pefloxacin is effective as a single antibiotic agent for the treatment of bacterial keratitis. PMID- 10090450 TI - Toxicity and efficacy of intravitreal injection of spartanamicin B in the treatment of Candida endophthalmitis. AB - AIMS/BACKGROUND: We evaluated the retinal toxicity of spartanamicin B and its efficacy in a rabbit model of Candidal endophthalmitis. METHODS: Toxicity. Fourteen albino rabbit eyes were injected intravitreally with spartanamicin B (1, 2, 5, 10, 25, 50, and 100 microg); 2 eyes received the vehicle alone. Efficacy. Ten rabbit eyes were inoculated with 3000 Candida organisms which caused endophthalmitis in 24 hours. Eight eyes were treated with intravitreal spartanamicin B in doses of 1, 2, 5, or 10 microg/0.1 ml; 2 untreated eyes served as controls. RESULTS: Toxicity. The eyes injected with < or =10 microg and the control group eyes exhibited no clinical, histological, or electroretinographic evidence of retinal toxicity. Doses >10 microg caused vitritis. Efficacy. Clinical examination of the treated eyes showed a gradual improvement over 3-6 days; mild opacities remained until day 14. Results of cultures performed 15 days after infection were negative in all treated eyes. CONCLUSIONS: Intravitreally injected spartanamicin B (10 microg) is nontoxic to the retina, effective against C. albicans in the endophthalmitis model in the rabbit eye and caused no discernible histological changes in the retina. PMID- 10090451 TI - Giant cell arteritis in Saudi Arabia. AB - PURPOSE: To obtain information about the incidence of giant cell arteritis in Saudi Arabia. METHODS: Retrospective review of all temporal artery biopsies performed at the King Khaled Eye Specialist Hospital from December 1982 to January 1998. RESULTS: Seventy-two temporal artery biopsies were performed over this 15 year period, of which four were positive for giant cell arteritis. CONCLUSIONS: The incidence of GCA in Saudi Arabia is probably less than in the United States and Western Europe. PMID- 10090452 TI - Long term visual results of vitrectomy for Eales disease complications. AB - BACKGROUND AND OBJECTIVES: Complications of Eales disease can cause visual loss. Long term visual prognosis following vitrectomy for Eales disease complications has been studied. PATIENTS AND METHODS: Retrospective analysis of 64 eyes of 57 patients who underwent vitrectomy for Eales disease complications with a minimum follow-up of 60 months. RESULTS: 62.4% eyes at 2 months and 71.8% at 60 months had 6/60 or better visual acuity. Visual acuities for individual cases were quite stable at the 60 month follow up with 50 eyes (78.5%) either maintaining or improving upon their 2 month post operative visual acuity. CONCLUSION: Visual acuity improves after vitrectomy in majority of patients with Eales disease complications and remains stable on long term follow-up. PMID- 10090453 TI - VO2 kinetics determined by PRBS techniques differentiate elite endurance runners from elite sprinters. AB - The aim of the study was to examine whether a measure of oxygen uptake (VO2) kinetics could differentiate between 12 elite male endurance (3000-10,000 m) runners and 12 elite male sprint (100-400 m) runners using a pseudo random binary sequence (PRBS) exercise protocol. All exercise tests were performed on an electrically braked cycle ergometer at a constant pedal frequency of 1 Hz. The PRBS exercise intensities alternated between 25 W and 85 W for three consecutive PRBS cycles of 300 s. VO2 was measured breath-by-breath and results were analysed by Fourier techniques in the frequency domain. Blood lactate concentrations taken pre and post testing were below 2 mM. Significantly greater amplitude components were observed in the endurance runners than sprinters at frequencies 6.7 mHz (6.71 +/- 1.09 and 5.47 +/- 0.95 ml x min(-1) x W(-1), respectively) P<0.05 and 10 mHz (4.97 +/- 0.98 and 3.56 +/- 0.69 ml x min(-1) x W(-1) respectively) P<0.01. Phase shift components were significantly shorter in the endurance runners compared to the sprinters at frequency 3.3 mHz (-35.45 +/- 4.31 and 41.26 +/- 5.82 degrees respectively) P<0.05. The results of this study show that VO2 kinetics are differentially faster in elite endurance runners than in elite sprinters. This supports the development of the PRBS technique as a test of sports performance. PMID- 10090454 TI - Coactivation of the flexor muscles as a synergist with the extensors during ballistic finger extension movement in trained kendo and karate athletes. AB - To analyse the effects of ballistic property training on ballistic finger extension movement, surface electromyographic pattern (EMGs) of the finger extensor and flexor muscles and the acceleration signal of the middle finger were recorded in trained kendo and karate athletes, and sedentary non-athletic men. Ballistic finger extension did not show the characteristic triphasic EMG pattern reported in single joint, but a coactivation of flexor and extensor muscles. Reaction time (RT) in kendo (143 +/- 12 msec) and karate (146 +/- 11 msec) athletes were significantly shorter than that in the control (176 +/- 12 msec). The shortenings of the RT were attributed to both the shortenings of premotor time and motor time. The delay of the flexor muscles discharge after those of the extensors in kendo (0.8 +/- 7.0 msec) and karate (-0.2 +/- 5.0 msec) athletes was significantly shorter than in control (12.7 +/-5.6 msec). These results suggest that the RT is shortened through motor learning in the kendo and karate athletes who trained for momentary movements; and that the flexor muscles may play an important role as a synergist in heightening the efficiency of ballistic finger extension in coordination with the extensor muscles. PMID- 10090455 TI - Serum testosterone responses to continuous and intermittent exercise training in male rats. AB - Serum testosterone (T) were investigated at rest and following exercise during 6 weeks of continuous and intermittent swimming training in male rats, and the regulatory mechanisms of the changes were discussed by evaluating serum luteinizing hormone (LH), and conducting GnRH (gonadotropin releasing hormone, 1.5 microg/kg body weight) or hCG (human chorionic gonadotropin, 25 IU/kg body weight) challenge tests. Relative to the resting level, serum T increased after intermittent exercise (6.47 +/- 1.58 vs 3.08 +/- 2.85 nmol/l), which was followed with the same changes in LH (12.81 +/- 4.21 vs 5.70 +/- 1.56 nmol/l). Serum T was lower after continuous exercise compared to the resting level (2.02 +/- 0.53 vs 10.96 +/- 3.11 nmol/l), while LH level was higher than that in sedentary group (11.23 +/- 5.61 vs 5.00 +/- 1.61 nmol/l). No significant changes were observed in resting T during and after intermittent training. A lower resting T level was shown at the end of 3 weeks of continuous training as compared to the sedentary group (1.88 +/- 0.69 vs 12.36 +/- 2.10 nmol/l), but it increased after 6 weeks of training. Serum T increased significantly in the intermittent training group after hCG treatment as compared to the saline treatment (52.42 +/- 12.10 vs 6.81 +/- 6.22 nmol/l), but insignificantly in the continuous training group. The similar increases in serum LH were observed in all the groups after GnRH treatment. PMID- 10090456 TI - Effects of portal injection of 2,5-anhydro-D-mannitol on pancreatic hormone responses to exercise in rats. AB - The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) has been shown to act specifically in liver by decreasing liver ATP and by blocking glycogenolysis and gluconeogenesis. The present investigation was designed to determine the effects of the administration of 2,5-AM on pancreatic hormone responses during a situation of increased energy demand such as physical exercise, and by comparison to the resting response, to test the possibility that the hormonal effects of 2,5 AM during exercise may be dissociated from a decrease in blood glucose levels. Adrenodemedullated rats were injected intraportally with a dose of 200 mg/kg of 2,5-AM (50 mg/ml) or by an equivalent volume of saline (0.9% NaCl) before being submitted to a 30-min treadmill run (26 m/min, 0% grade). Administration of 2,5 AM at rest resulted in a significant (P < 0.05) decrease of plasma glucose and insulin levels and an increase in beta-hydroxybutyrate concentrations. During exercise, administration of 2,5-AM, as compared to resting values, resulted in a larger decrease in glucose, a similar decrease in insulin, and a much larger increase in glucagon, glucagon/insulin molar ratio, and beta-hydroxybutyrate concentrations. It is concluded that exercise amplifies some of the metabolic and hormonal effects of 2,5-AM, and that these effects cannot all be explained by the decrease in blood glucose levels. PMID- 10090457 TI - How much physical activity is needed for good health? AB - The Harvard Alumni study is reviewed critically with a view to resolving the apparent conflict between the conclusions drawn from this research and the current consensus on optimal patterns of physical activity for health. The optimal energy expenditure reported for the Harvard data set is less than at first appears, since the estimated expenditures are gross rather than net values. Further, the optimal energy expenditure has been over-estimated, because too high a cost was assumed for stair climbing, and sport involvement may also have been over-reported. The data do not as yet allow the assertion that benefit is obtained only from vigorous physical activity, and there seems little conflict with the current consensus on the benefits of moderate physical activity. PMID- 10090458 TI - Changing the number of submaximal exercise bouts effects calculation of MAOD. AB - The aim of this present study was to evaluate the effect of the number of submaximal exercise bouts used to construct the power-VO2 regression, on calculations of MAOD through the sequential and systematic removal of the highest and lowest submaximal VO2 values from the standard ten point regression line. Eight trained male cyclists participated in this study. The mean (+/- SD) age, height, weight and VO2max for the subjects were 25+/-7 yr, 178.2+/-3.0 cm, 69.9+/ 4.9 kg and 57.5+/-6.9 ml x kg(-1) x min(-1). After VO2max testing each subject undertook ten submaximal exercise bouts at between 30% and 90% VO2max and one supramaximal bout calculated to elicit 100% VO2max. Expired gases were measured via open circuit spirometry. The mean power output of the supramaximal bout was 336.5+/-442.5 W and the mean duration was 269.4+/-42.9 s. The correlation coefficients ranged from 0.981 to 0.996 while the MAOD values ranged from 29.6+/ 15.7 ml O2 eq x kg(-1) to 61.3+/-44.7 ml O2 eq x kg(-1). When compared to the standard ten points, as a percentage difference, this difference ranged from 4.1+/-3.6% to 83.7+/-54.9%. The main finding of this study is that inaccuracies occur in the measurement of MAOD when less than ten points are used in the calculation. Further study is required for the development of a standardised protocol for the accurate, valid and reliable measurement of MAOD. PMID- 10090459 TI - Substantial influence of level of endurance capacity on the association of perceived exertion with blood lactate accumulation. AB - Capillary blood lactate assessment is increasingly used by well-trained runners to monitor the intensity of endurance exercise. In order to examine the known association of exercise intensity with blood lactate accumulation also in less trained subjects, we analysed data from a standardized incremental maximal test on the treadmill of 319 men (age 22.9 +/- 5.5 years, [means +/- S.D.]) and 145 women (22.7 +/- 4.5 years) characterized by a wide variation in endurance capacity. Results showed that the running velocity eliciting a blood lactate concentration of 4 mmol/l did not correspond to the same exercise intensity in well endurance-trained vs poorly endurance-trained subjects. At 4 mmol/l blood lactate, the slowest decile of men (i.e. 32 out of 319) ran at 71 +/- 4.7% (corresponding to 2.9 +/- 0.3 m/s) of their maximal treadmill velocity attained during the test (4.1 +/- 0.4 m/s), indicating a rating of perceived exertion (RPE) of 12.3 +/- 1.8 points (Borg scale, range 6-20 points), while the fastest decile of men (n = 32) ran at 91 +/- 3.1% (corresponding to 5.4 +/- 0.2 m/s) of their maximal treadmill speed (5.9 +/- 0.2 m/s), indicating a RPE of 16.6 +/- 1.1 points. Very similar results were observed in women. There was a highly significant, positive correlation between running speed eliciting a blood lactate concentration of 4 mmol/l and RPE when running at this speed, with r = 0.64 in men and r = 0.55 in women. At the same proportional level of maximal running velocity, poorly endurance-trained athletes showed a 2-3 mmol/l higher capillary lactate concentration than well endurance-trained athletes, with both groups indicating the same RPE. These results suggest that fixed blood lactate concentrations not at all mean the same exercise intensity for well vs poorly endurance-trained subjects; this systemic trend should be considered when using blood lactate assessment for individual exercise counselling. PMID- 10090460 TI - A new rating scale of perceived exertion based on subjective estimation of exhaustion time: a preliminary study. AB - Perceived exertion has been investigated during incremental exercise to exhaustion with athletes, according to the 6-20 scale proposed by Borg (RPE, 1970) and a new scale based on the estimation of exhaustion time (t(lim)) (Estimated Time Limit or ETL, from 1 to 20; ETL= 21 - 2 n, with n = log2t(lim)). ETL increased linearly with the percentage of maximal aerobic power (%MAP) up to the ventilatory threshold (VT). Beyond VT, an inflection of the ETL-%MAP relationship was observed. RPE and ETL calculated at VT were equal to 15 +/- 1.7, i.e. an exercise intensity perceived as "hard", and 10 +/- 2.3, i.e. an estimated exhaustion time equal approximately to 45 minutes. Standard deviations for RPE and ETL at VT were too large for an accurate estimation of this threshold. The results of the present study suggest that RPE and ETL should be used in addition to physiological data, but not replace them in the prescription of a training program. PMID- 10090461 TI - Perceptual responses to exercise: the effect of load-awareness on physiological responses during an isometric bout. AB - To evaluate the effect of awareness of load on cardiovascular and metabolic responses, thirty males were compared in three different loads during upright deadlift isometric exercise, at 25%, 30% and 35% of maximal voluntary contraction for 3 min. Significant differences (P < 0.05) were found from rest to 25%, 30% and 35% for all physiological variables, heart rate (66.5+/-9.0, 104.0+/-12.0, 115.0+/-9.0, and 123.0+/-11.0 beats x min(-1), respectively), and for lactic acid (2.2+/-0.4, 4.6+/-0.7, 5.7+/-1.1, and 6.3+/-1.5 mM x l(-1), respectively). However, no significant differences were revealed between the various conditions when rate-perceived exertion data were analyzed, despite increased absolute loads. These data indicate that the psychological manipulation introduced in this study did not affect physiological responses during isometric exercise, in contrast to that seen during dynamic exercise. PMID- 10090462 TI - Carbohydrate intake and multiple sprint sports: with special reference to football (soccer). AB - Six male football players competed in a 90 min game (4-a-side) on two occasions following an exercise and diet (either high- approximately 65% or low- approximately 30% carbohydrate intake) regimen designed to manipulate muscle glycogen concentrations. Movement and technical parameters of performance and selected physiological responses were measured. Pre-game muscle glycogen concentrations following the high carbohydrate diet (mean +/- SD) (395.6 +/- 78.3 mmol x kg(-1) dw) were significantly higher than following the low carbohydrate diet (287.1 +/- 85.4 mmol x kg(-1) dw). The results of the movement analysis showed that the players performed significantly more (approximately 33%) high intensity exercise in the game played following the high carbohydrate diet. No significant differences were found, between the two dietary conditions, in any of the measured technical variables. Plasma FFA and glycerol concentrations in the game played following the low carbohydrate diet were significantly higher after 45 min (905 +/- 103 and 293 +/- 23 micromol x l(-1)) and post exercise (1388 +/- 122 and 366 +/- 36 micromol x l(-1)) compared to the game played following the high carbohydrate diet (532 +/- 137 and 202 +/- 55 micromol x l(-1) and 888 +/- 192 and 266 +/- 27 micromol x l(-1), respectively). Post-exercise blood glucose levels were significantly lower in the game played following the low carbohydrate diet (5.8 +/- 0.3 vs 7.2 +/- 0.3 mmol x l(-1)). No significant differences were found in the mean blood lactate values (3.5 +/- 0.6 and 3.9 +/- 0.5 mmol x l(-1)) or mean heart rates (162 vs. 163.5 beats x min(-1)) between the high and low carbohydrate conditions, respectively. The main finding from this study was that the carbohydrate content of the diet influenced the amount of high intensity exercise performed during a small-sided football game. This suggests that to optimise performances, in not only football but possibly also other multiple sprint sports of similar duration, a high carbohydrate diet should be administered in preparation for intense training and competition. PMID- 10090463 TI - Overuse epiphyseal injury of the coracoid process as a result of archery. AB - A previously unreported overuse injury of the coracoid process in an eleven years old archer is presented. Diagnosis was made on clinical grounds in association with the radiographic appearance of the unfused physis. The pathology and the management are presented and discussed. PMID- 10090464 TI - Spondylolysis at three sites in the same lumbar vertebra. AB - We report a rare case of spondylolysis that occurred at 3 sites in the fifth lumbar vertebra involving the bilateral pars interarticularis and the center of the right lamina. This is the first such case in the world literature. PMID- 10090465 TI - Risk of degenerative ankle joint disease in volleyball players: study of former elite athletes. AB - To estimate the influence of long-term, high-intensity volleyball playing on premature osteoarthritis (OA) of the ankle joint, we examined a group of 22 former elite volleyball-players age (34 +/- 6 yrs.) who had played for at least 3 years in the highest volleyball league in Switzerland, and 19 normal healthy untrained controls (35 +/- 6 yrs.). Volleyball-athletes had played during an average of 5.5 (+/- 2) h/wk for 8.5 (+/- 3) yrs. Twenty of the 22 players had suffered from at least one ankle sprain (average: 3.5), 10 had had ruptures of the lateral ligaments (8 of them operated). Four players had severe mechanical instability, 5 a talar varus tilt in the stress X-ray of more than 8 degrees. Subchondral sclerosis and osteophytes were more prevalent in volleyballers than in controls (p < 0.001), while the difference in joint space was not significant. No severe grades of OA could be observed in these former elite volleyball players. Yet, a radiologic score of degenerative ankle disease was elevated in 19/22 of them, but only in 2/19 controls (p<0.001). In multiple regression analysis among athletes, the anterior drawer sign and a feeling of instability were the only significant and independent predictors of an increased radiological index (p = 0.003 and p = 0.02, respectively) from an initial set of 9 variables covering career length and intensity as volleyball player, clinical signs of ankle instability and age. Even if in the present study, athletes had clearly more radiologic findings than controls--such as spur formation and subchondral sclerosis--long-term, high-intensity volleyball playing alone could not be confirmed as an independent risk factor for OA of the ankle joint however, a combination of chronic lateral ankle instability with intensive volleyball playing could marginally increase the risk of ankle OA. PMID- 10090466 TI - Spinal cord injuries in ice hockey in Finland and Sweden from 1980 to 1996. AB - Traumatic spinal cord injury (SCI) in the cervical or thoracic region is one of the most catastrophic types of sport injuries. This study was designed to determine incidence and mechanisms of major SCI in ice hockey in Finland and Sweden from 1980 to 1996 in order to find possibilities for prevention. Retrospective analysis of injury occurrence were carried out. Medical case records were reviewed and injured players were interviewed to complete the data. From 1980 to 1996, there were 16 accidents involving spinal cord injury with permanent disability. All players were male. The mean age was 21.1 years (range = 14 to 33 yr). In 50% of the cases the mechanism was body checking from behind and a blow to the head from the boards. In 69% of the cases the vertebral injury was fracture or/and luxation between C5 and C7. The neurological endstate was tetraplegia/paresis in 10 cases and paraplegia/paresis of the lower extremities in 6 cases. Ice hockey is one of the most popular sports in Europe, and the number of participants is still increasing. The typical mechanism in SCI is body checking from behind, falling down and a head-first blow from the boards. These serious injuries may be prevented by changing the rules (banning body checking near the boards) with strict refereeing and education of trainers and players. PMID- 10090467 TI - Re: Dalton, B., L. McNaughton, B. Davoren: Circadian rhythms have no effect on cycling performance. Int J Sports Med 1997; 18: 538-542. PMID- 10090468 TI - DNA vaccines: a ray of hope. AB - Vaccines represent the most commonly employed immunologic intervention in medicine today. DNA vaccination or genetic immunization is a rapidly developing technology that offers new approaches for the prevention of disease. This method of vaccination provides a stable and long-lived source of the protein vaccine, and it is a simple, robust, and effective means of eliciting both antibody- and cell-mediated immune responses. Furthermore, DNA vaccines have a number of potential advantages such as they can address several diseases in one vaccine, they are cheap and easy to produce and have no special cold storage requirement because they are extremely stable. It has proven to be a generally applicable technology in various preclinical animal models of infectious and noninfectious diseases, and several DNA vaccines have now entered phase I/II, human clinical trials. There are several hurdles that need to be overcome on the road to the use of DNA vaccines widely. These include the technical challenges of improving delivery and/or potency so that low doses of DNA can achieve the efficacy of conventional vaccines. PMID- 10090469 TI - Oxysterols and apoptosis: evidence for gene regulation outside the cholesterol pathway. PMID- 10090470 TI - Biochemistry and molecular biology of sterol synthesis in Saccharomyces cerevisiae. PMID- 10090471 TI - Variability of metabolism and function of sterols in insects. PMID- 10090472 TI - Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. AB - Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis to search for germline mutations in the members of 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 25 conformational variants representing germline mutations that are predicted to result in loss of normal menin function. Twenty different disease-associated mutations were identified: five resulting in potential abnormal RNA splicing, two missense mutations, seven nonsense mutations, and six frameshift mutations. The aberrant splice products were identified and confirmed by RT-PCR and direct sequence analysis for two of the five splice mutations. Sixteen of the 20 (80%) mutations identified have not been previously reported. Mutations were not identified in eight kindreds with signs and symptoms consistent with MEN 1. The SSCV analysis revealed mutations in 76% (25 of 33) of the kindreds investigated, thus showing SSCV analysis to be a reliable mutation detection strategy. One-fifth of the mutations identified in this study involve intron sequences, therefore, highlighting the importance of including intron sequences in the search for germline mutations in the MEN1 gene. The need to investigate the entire gene when characterizing new MEN 1 families presents challenges in the translation of genetic studies to efficient clinical diagnostic tests. PMID- 10090473 TI - Mutant transcripts of the LDL receptor gene: mRNA structure and quantity. AB - mRNA of the low-density lipoprotein receptor (LDLR) gene from 22 heterozygous familial hypercholesterolemic subjects possessing different mutations in this gene was analyzed by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) in order to detect abnormally spliced transcripts. These analyses revealed abnormally spliced transcripts for the two splice-site mutations 1359-1G-->A and 1705 + 1G-->T. The abnormally spliced transcript for mutation 1359-1G-->A was caused by activation of a cryptic acceptor splice site in exon 10. As a result, seven nucleotides of exon 10 were deleted. For mutation 1705 + 1G-->T, two mutant transcripts were observed. In the first transcript, exon 10 was spliced to exon 13, and in the second transcript intron 11 was retained. The relative amount of mutant transcripts from 14 of the 22 subjects was determined by use of an RT-PCR-based method. Quantitation of the relative amounts of mutant transcripts for five missense mutations resulted in a mean value (+/-SD) of 52.8% (+/-4.55). In comparison, quantitation of the relative amounts of mutant transcripts for five nonsense mutations resulted in a mean value of 31.8% (+/-6.91). This value was significantly lower than the value of 54.2% (+/-2.38) obtained for nine healthy subjects (P < 0.0001). The relative amount of mutant transcripts for the 1705 + 1G-->T mutation was 36%. Thus, transcripts from alleles containing premature stop codons are present in reduced amounts, whereas transcripts from alleles containing missense mutations are present in normal amounts. These findings underscore the importance of determining how mutations affect mRNA structure and quantity in order to understand how mutations cause disease. PMID- 10090474 TI - Mutation analysis in adenylosuccinate lyase deficiency: eight novel mutations in the re-evaluated full ADSL coding sequence. AB - The deficiency of adenylosuccinate lyase (ADSL, also termed adenylosuccinase) is an autosomal recessive disorder characterized by the accumulation in body fluids of succinylaminoimidazole-carboxamide riboside (SAICA-riboside) and succinyladenosine (S-Ado). Most ADSL-deficient children display marked psychomotor delay, often accompanied by epilepsy or autistic features, or both, although some patients may be less profoundly retarded. Occasionally, growth retardation and muscular wasting are also present. Up to now, nine missense mutations of the ADSL gene had been reported in six apparently unrelated sibships. In the present study of 10 additional patients with ADSL deficiency, nine point mutations, among which seven unreported missense mutations, and the first splicing error reported in this disorder, have been identified. These mutations have been characterized, taking into account the finding that the cDNA of human ADSL is 75 nucleotides longer at its 5'-end, and encodes a protein of 484 rather than 459 amino acids as previously reported. Five apparently unrelated patients were found to carry a R426H mutation. With the exceptions of the latter mutation, of a R190Q mutation that had been reported previously, and of a K246E mutation that was found in two unrelated patients, all other mutations were found only in a single family. PMID- 10090475 TI - A novel heteroplasmic point mutation in the mitochondrial tRNA(Lys) gene in a sporadic case of mitochondrial encephalomyopathy: de novo mutation and no transmission to the offspring. AB - We have identified a new mutation in the tRNA(Lys) gene of mtDNA, in a 49-year old patient with mitochondrial encephalomyopathy. The mutation is a heteroplasmic G-->A transition at position 8328, which affects the anticodon stem loop at a conserved site. The mutation was neither found in 100 controls nor in the maternal relatives of the patient. The level of mutated mtDNA was 57% in muscle, 13% in fibroblasts, and 10% in lymphocytes. Histochemistry of muscle tissue revealed cytochrome c oxidase-deficient fibers with abnormal accumulation of mitochondria. Biochemistry of muscle mitochondria showed slight cytochrome c oxidase deficiency. The mean ratio of mutant mtDNA to normal mtDNA in cytochrome c oxidase-positive muscle fibers was 59%, whereas a mean ratio of 95% was found in cytochrome c oxidase-negative fibers. The difference between cytochrome c oxidase-positive and cytochrome c oxidase-negative fibers was highly significant (P < 0.001). The mutation was not found in muscle or lymphocytes of the mother and daughter of the proband. This is the first report of a de novo point mutation in the tRNA(Lys) gene in an individual expressing disease and the first report of lack of transmission of the mutation to the offspring of a patient expressing a mitochondrial encephalomyopathy caused by a point mutation in mtDNA. PMID- 10090476 TI - Novel mutations associated with carnitine palmitoyltransferase II deficiency. AB - The most common form of carnitine palmitoyltransferase II (CPT II) deficiency occurs in adults and is characterized by muscle pain, stiffness, and myoglobinuria, triggered by exercise, fasting, or other metabolic stress. This study reports the molecular heterogeneity of CPT2 mutations and their biochemical consequences among a series of 59 individuals who were suspected of having CPT II deficiency based on the decreased CPT activity observed in muscle or leukocytes samples, clinical findings, or referral for mutation analysis from other laboratories. Only 19 subjects were considered to be at particularly high risk of CPT II deficiency based on review of their clinical symptoms and residual CPT activity. The samples were initially screened for 11 mutations with allele specific oligonucleotides (ASO). Extensive sequence analysis was subsequently performed on 14 samples which either had a CPT2 mutation detected by ASO screening or the residual CPT activity was below that observed in ASO positive samples. Three known (P50H, S113L, and F448L) and three novel mutations were identified among 13 individuals in this study. A single nucleotide polymorphism was also identified 11 bp distal to the CPT2 polyadenylation site that will be useful for linkage analysis. Two of the new mutations were single nucleotide missense mutations, R503C and G549D, that occurred in highly conserved regions of the CPT isoforms, and the third was a frameshift mutation, 413 delAG, caused by a 2-bp deletion upstream of a previously identified missense mutation, F448L. The 413 delAG mutation was the second most common mutation identified in our study (20% of mutant alleles) and all individuals with the mutation were of Ashkenazi Jewish ancestry suggesting a defined ethnic origin for the mutation. Despite rigorous mutation analysis, six of 13 individuals identified with CPT2 mutations remained as heterozygotes. We propose that heterozygosity for certain CPT2 mutations, S113L and R503C, is sufficient to render individuals at risk of clinical symptoms. PMID- 10090477 TI - Reported in vivo splice-site mutations in the factor IX gene: severity of splicing defects and a hypothesis for predicting deleterious splice donor mutations. AB - Small consensus sequences have been defined for RNA splicing, but questions about splicing in humans remain unanswered. Analysis of germline mutations in the factor IX gene offers a highly advantageous system for studying the mutational process in humans. In a sample of 860 families with hemophilia B, 9% of independent mutations are likely to disrupt splicing as their primary mode of action. This includes 26 splicing mutations reported herein. When combined with the factor IX splice mutations reported by others, at least 104 independent mutations have been observed, 80 of which are single base substitutions within the splice donor and splice acceptor consensus sequences. After analysis of these mutations, the following inferences emerge: (1) the susceptibility of a splice donor sequence to deleterious mutation depends on the degree of similarity with the donor consensus sequence, suggesting a simple "5-6 hypothesis" for predicting deleterious vs. neutral mutations; (2) the great majority of mutations that disrupt the splice donor or splice acceptor sequences result in at least a 100 fold decrement in factor IX coagulant activity, indicating that the mutations at these sites generally function as an on/off switch; (3) mutations that create cryptic splice junctions or that shorten but do not interrupt the polypyrimidine tract in the splice acceptor sequence can reduce splicing by a variable amount; and (4) there are thousands of potential donor-acceptor consensus sequence combinations in the 38-kb factor IX gene region apparently not reduced by evolutionary selective pressure, presenting an apparent paradox; i.e., mutations in the donor and acceptor consensus sequences at intron/exon splice junctions can dramatically alter normal splicing, yet, appropriately spaced, good matches to the consensus sequences do not predispose to significant amounts of alternative splicing. PMID- 10090478 TI - A novel PCR-based approach for the detection of the Huntington disease associated trinucleotide repeat expansion. AB - Huntington disease (HD) is an autosomal dominant neurodegenerative disorder associated with expansions of an unstable CAG trinucleotide repeat in exon 1 of the IT15 gene. In normal individuals, IT15 contains up to 35 CAG repeats, while in affected the repeat length is >36. Polymerase chain reaction (PCR) is used to estimate the number of CAG repeats but may be inefficient in long repeats because of the high C+G content of the HD locus. We present a novel PCR approach for the diagnosis of HD, which permits direct visualization of the amplified products on agarose gel, using ethidium bromide. It is based on the methylation-sensitive conversion of C residues to U by bisulfite treatment of single-stranded DNA and subsequent amplification of the sense strand with specific primers. The bisulfite treatment dramatically reduces the C + G content of the region; thus, the high Tm and stable secondary structures are no longer obstacles to PCR. In both normal and affected individuals, UAG repeats (5'- CAG-3', before bisulfite treatment) in the sense strand can easily be amplified and visualized on a gel by ethidium bromide staining. The method has considerable advantages compared with other described PCR-based diagnostic tests for HD. PMID- 10090479 TI - The FANCA gene in Japanese Fanconi anemia: reports of eight novel mutations and analysis of sequence variability. AB - Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. At least eight complementation groups (FA-A to FA-H) have been identified with their relative prevalence varying among the ethnical backgrounds. Recently, responsible genes, FANCA and FANCC, have been cloned. This report describes mutations of the FANCA gene, which we studied by direct sequencing of cDNA with confirmation on genomic DNA in 15 unclassified Japanese FA patients. A total of 19 sequence alterations were identified, of which 10 (six missense and four silent alterations) were likely to be nonpathogenic polymorphism. The remaining nine alterations, of which eight were novel mutations, were assumed to be pathogenic and consisted of two missense mutations and seven mutations resulting in truncation of gene product, demonstrating a wide allelic heterogeneity. The pathogenic mutations were found in 12 patients (80%); they were either homozygous or compound heterozygous in 10 patients, apparently heterozygous in two patients and none in three patients. We conclude that the sequence variability is intrinsic to the FANCA gene and that the relative prevalence of the FA-A subtype is unusually high in Japanese FA patients. PMID- 10090480 TI - Repopulation of rho0 cells with mitochondria from a patient with a mitochondrial DNA point mutation in tRNA(Gly) results in respiratory chain dysfunction. AB - Familial hypertrophic ventricular cardiomyopathy has been demonstrated to be associated with a number of mitochondrial DNA (mtDNA) mutations. A fibroblast cell line carrying a mutation in its mtDNA at position 9997 in the gene encoding tRNA glycine was obtained from a patient with hypertrophic cardiomyopathy. To demonstrate that the etiology of this disease was a result of the mtDNA mutation, cybrid clones were constructed by fusion of enucleated patient skin fibroblasts to rho0 osteosarcoma cells. Clones carrying high levels of mutant mtDNA showed predominantly cytochrome c oxidase and complex I deficiency, as well as an elevated lactate/pyruvate (L/P) ratio, a biochemical marker characteristic of respiratory chain deficiencies. Pulse-labeling experiments demonstrated a strong negative correlation between the levels of newly synthesized mtDNA-encoded polypeptides and glycine content. These data suggest that the T9997C mutation in mtDNA is causative of respiratory chain dysfunction when present at high levels of heteroplasmy. PMID- 10090481 TI - Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. AB - Familial Alzheimer's disease (AD) is an autosomal dominant disorder characterized by memory impairment and multiple cognitive deficits which occurs in mid to late life. Early onset AD has been associated with mutations in three genes, of which presenilin 1 (PS1) mutations are the most frequent. We sequenced the open reading frame from genomic DNA of a series of 21 early onset AD (AD3) UK families in which there were at least two affected individuals in two or more generations with a diagnosis of probable or definite AD. We found PS1 mutations in six of these families with no sequence variation in the remaining 15. The six families contained between them five different mutations of which two, I143F and P436S, have not been found elsewhere. I143F shows incomplete penetration within the affected family. P436S is the most carboxy-terminal presenilin 1 mutation reported to date. PMID- 10090482 TI - Mutation analysis of the BRCA1 and BRCA2 genes results in the identification of novel and recurrent mutations in 6/16 flemish families with breast and/or ovarian cancer but not in 12 sporadic patients with early-onset disease. Mutations in brief no. 224. Online. AB - Since the identification of the BRCA1 and BRCA2 genes (MIM#s 113705 and 600185), more than hundred different mutations throughout both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. We analyzed 12 sporadic female patients with breast cancer before age 35, as well as 16 unrelated families, presenting with either (i) at least 3 first degree relatives with breast and/or ovarian cancer diagnosed at any age, or (ii) at least 2 first and/or second degree relatives with breast and/or ovarian cancer before age 45 years. We performed a protein truncation test for BRCA1 exon 11 and BRCA2 exons 10 and 11 and heteroduplex analysis for all the remaining exons of BRCA1 and 2. Presence of genomic deletions encompassing exons 13 or 22 of BRCA1, known to be Dutch founder mutations, was investigated by PCR. In 6/16 (37.5%) unrelated families the causal mutation in either the BRCA1 or BRCA2 gene was identified. Four different mutations were found in the BRCA1 gene: IVS5+3A>G (intron 5), 1191delC (exon 11), R1443X (exon 13), IVS22+5G>A (intron 22) and two in the BRCA2 gene: 6503delTT (exon 11), 6831delTG (exon 11). 1191delC (BRCA1) and 6831delTG (BRCA2) are novel mutations. IVS5+3A>G in exon 5 of BRCA1 published by Peelen et al. (1997) as a novel Belgian mutation, was identified in one additional family, not fulfilling our inclusion criteria. In the group of 12 sporadic female patients no mutations were found. PMID- 10090483 TI - Familial adenomatous polyposis coli: five novel mutations in exon 15 of the adenomatous polyposis coli (APC) gene in Italian patients. Mutations in brief no. 225. Online. AB - Germline mutations within the adenomatous polyposis coli (APC) gene, a tumor suppressor gene, are responsible for most cases of familial adenomatous polyposis (FAP), an autosomal dominantly inherited predisposition to colorectal cancer. To date, more than 300 germ-line causative mutations within this gene have been described (Beroud and Soussi, 1996). Of these, about 95% are chain-terminating mutations, and more than 60% have been localized within exon 15 (Nagase and Nakamura, 1993, Beroud and Soussi, 1996). Using polymerase chain reaction-single strand conformation polymorphism, protein truncation test (PTT) and DNA sequencing we have identified five new frameshift mutations (2523insCTTA, 2638delA, 2803insA, 3185delAA, 4145delTCATGT), all occurring within exon 15 and giving rise to truncated protein products. Two of these new mutations are of particular interest because of the unusual phenotypic features shown by probands. The phenotype of the proband bearing the 2523insCTTA mutation at codon 842 was very aggressive with onset of the symptoms at 12 years, while the patient bearing the 3185delAA mutation at codon 1062 exhibited features of an attenuated form of FAP (AAPC). Our data reiterate the great heterogeneity of the mutational spectrum in FAP that gives rise to an extreme variability of the clinical expression. PMID- 10090484 TI - Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online. AB - In order to obtain a survey of the mutations being prevalent in Northern Germany and to enable molecular genetic testing for families with clinically diagnosed familial hypercholesterolemia (FH), we screened 46 unrelated German individuals with elevated LDL levels for mutations in the 18 exons and their flanking intron sequences including the promotor region of the LDL receptor (LDLR) gene. In addition, we tested all patients for the presence of mutations in the gene coding for apolipoprotein B-100 (apoB-100). We detected 15 mutations affecting the LDLR gene, 8 of which, designated A29S, 195insAT, 313+1insG, 553insG, 680insGGACAAATCTG, D200N, E267K and L411V have not yet been reported. One patient is heterozygous for the double mutant N543H and 2393del9Bp. Two patients carried the mutation R3500Q (Arg-->Glu) within the apoB-100 gene. PMID- 10090485 TI - Peutz-Jeghers syndrome: four novel inactivating germline mutations in the STK11 gene. Mutations in brief no. 227. Online. AB - The diagnosis of Peutz-Jeghers syndrome is based on the occurrence of hamartomatous gastrointestinal polyps and perioral pigment spots. In view of the development of hamartomatous polyps in several syndromes and the variability of pigment spots in Peutz-Jeghers patients, identification of affected individuals is difficult. Recently, germline mutations in the STK11 gene have been reported as a molecular cause of Peutz-Jeghers syndrome. We present four novel inactivating mutations identified by direct sequencing of all 9 exons of the STK11 gene in 4 patients suggestive of Peutz-Jeghers syndrome: three frameshift mutations (125-137del; 474-480del; 516-517insT) and one nonsense mutation (Q220X). Our data obtained in these patients and in those reported previously emphasize the diagnostic value of histological discrimination between different types of hamartomatous polyps and of molecular analysis, particularly in cases with no family history of the disease. PMID- 10090486 TI - Beta-thalassemia in the German population: mediterranean, Asian and novel mutations. Mutations in brief no.228. Online. AB - The beta-thalassemia mutations of 13 unrelated heterozygous Germans who remained unidentified in a previous study of 40 subjects were investigated at the DNA level. Two Mediterranean, one Asian and three novel mutations (CD6 -G, CDs 108 /112-12nt, CDs 130/131 + GCCT) were identified. Altogether, in 30 of the 35 subjects (86%) in which a mutation in the beta-globin gene was identified, the mutation was of Mediterranean origin. The geographical distribution suggests recent migration from the Mediterranean region as cause of the high proportion of frequent Mediterranean beta-thalassemia mutations in the German population. Our results support the notion that the majority of beta-thalassemia genes in the western and central European population are of Mediterranean origin. PMID- 10090487 TI - Mutation screening of neurofibromatosis type 1 (NF1) exons 28 and 29 with single strand conformation polymorphism (SSCP): five novel mutations, one recurrent transition and two polymorphisms in a panel of 118 unrelated NF1 patients. Mutations in brief no. 229. Online. AB - Neurofibromatosis type 1 is a clinically variable disorder caused mostly by small mutations within the NF1 gene on chromosome 17q11.2. We used Single Strand Conformation Polymorphism (SSCP) and radioactive sequencing to screen NF1 exons 28 and 29 from 118 unrelated patients, diagnosed with NF1 according to the NIH criteria, identifying five novel and one recurrent germline mutations, two novel polymorphisms and a variant base exchange. All but one cause protein truncation and represent typical NF1 mutations. There are reports that NF1 patients with mutations in exons 28 and 29 could be at greater risk of developing myeloid leukemia. This question was given consideration in this investigation, but none of the children involved have yet shown any symptoms of myeloid leukemia. 4 out of the 6 mutations were de novo. PMID- 10090488 TI - Gestational age standardized nuchal thickness values for estimating mid-trimester Down's syndrome risk. AB - OBJECTIVE: Our aim was to develop gestational age standardized indices of fetal nuchal thickening. In addition, we wanted to develop a method for combining nuchal thickness data with maternal age for calculating individual Down's syndrome risk. METHODS: Nuchal thickness was measured prospectively in pregnancies undergoing genetic amniocentesis. A regression equation for expected median nuchal thickness based on the biparietal diameter (BPD) was developed. Nuchal thickness values were expressed as multiples of the median (MoM). Additionally, a new parameter, percentage increase in nuchal thickness (PIN) (measured minus expected nuchal thickness) X100/expected nuchal thickness, was used. Receiver operator characteristics curves for Down's syndrome detection based on nuchal thickness values expressed as MoM, PIN, and in mm were compared. Log10 transformation of MoM data resulted in a Gaussian distribution, and the Down's syndrome likelihood ratios were calculated based on the heights of the Gaussian curves. Likelihood ratios were also calculated based on PIN values. The screening efficiency of maternal age alone was compared to age plus MoM, and age plus PIN values by multiplying age-related risk by the likelihood ratio corresponding to the given nuchal thickness MoM or PIN values. RESULTS: There were 3,574 chromosomally normal and 50 Down's syndrome fetuses in the study. Both PIN and MoM values for nuchal thickness were closely correlated (R = 1.00, P<0.001) and each was poorly correlated with gestational age (R = 0.018, P = 0.28). The Down's syndrome screening efficiency of PIN, MoM, and nuchal thickness values in mm were not significantly different. The addition of nuchal thickness data to maternal age-related risk significantly improved the Down's syndrome screening efficiency: Area under the ROC curve for maternal age risk = 0.58, maternal age + PIN area = 0.79 (P<0.001 compared to maternal age alone) and for maternal age + MoM = 0.77 (P<0.005 compared to maternal age alone). CONCLUSIONS: The development of gestational age standardized nuchal thickness indices makes it possible to combine ultrasound and maternal age-related risk to derive individual Down's syndrome odds. PMID- 10090489 TI - Incidence of chromosomopathies and cystic fibrosis mutations in second trimester fetuses with isolated hyperechoic bowel. AB - OBJECTIVE: Fetal echoic bowel can be a normal second trimester ultrasonographic finding which usually disappears by 20 weeks on serial sonograms. Recent studies have suggested a possible association of hyperechoic fetal bowel with chromosomopathies and cystic fibrosis. The aim of our study is to determine the incidence of chromosomopathies and cystic fibrosis mutations among the fetuses with isolated hyperechoic bowel. METHODS: Sixteen fetuses with isolated echoic bowel were detected: 13 fetuses < or =20 weeks gestation (group I) and 3 fetuses at 20-26 weeks gestation (group II). Cytogenetic studies were performed in all 16 cases and 11 families had deoxyribonucleic acid-based risk assessment for cystic fibrosis. The echogenity of bowel was that of surrounding bone. RESULTS: Two cases of trisomy 21 and 1 case of trisomy 13 were detected (18.7%). The other ultrasonographic markers begin to appear after 21 weeks gestation in fetuses with trisomy 13. Two of 3 pregnant women with pathological karyotype were younger than 35 years. One of 11 cases (9%) was found to be a heterozygote carrier for deltaF508 mutation. CONCLUSIONS: Isolated hyperechoic bowel in the second trimester was found to be associated with a significantly higher risk of fetal aneuploidy. PMID- 10090490 TI - Vaginal misoprostol vs. concentrated oxytocin plus low-dose prostaglandin E2 for second trimester pregnancy termination. AB - OBJECTIVE: To examine the efficacy of vaginal misoprostol for mid-trimester pregnancy termination. METHODS: This randomized trial compared misoprostol, 200 microg per vaginum q 12 h to a protocol of concentrated oxytocin plus low-dose vaginal prostaglandin E2 suppositories (10 mg q 6 h). Success was defined as an induction-to-delivery interval < or =24 h. RESULTS: Interim analysis of the first 30 (15-misoprostol, 15-concentrated oxytocin) women demonstrated that the 2 groups were similar with regard to indication for delivery, gestational age, and demographic characteristics. Misoprostol was associated with a lower success rate (67 vs. 87%, P = .2), a longer induction-delivery interval (22 h vs. 18 h, P = .09), a higher rate of retained placenta requiring curettage (27 vs. 13%, P = .65), and a higher live birth rate (50 vs. 0%, P = .006). CONCLUSIONS: Compared to a regimen of concentrated oxytocin plus low-dose prostaglandin E2, misoprostol administered as vaginal tablets in a dose of 200 microg q 12 h is not satisfactory for mid-trimester pregnancy termination in an unselected population. PMID- 10090491 TI - Prediction of difficult vaginal birth and of cesarean section for cephalopelvic disproportion in early labor. AB - OBJECTIVE: A total of 1,692 patients were evaluated in early labor, and predictions were made for easy labor-vaginal birth, difficult labor-vaginal birth, or improbable vaginal birth-cesarean section. METHODS: The prediction was based on clinical evaluation of pelvic dimensions, and fetal measurements by sonography at term. RESULTS: The combined prediction that a patient would have either a difficult labor-vaginal birth or cesarean section was very accurate (362 out of 370, or 97.8%). However, the separate prediction of difficult labor vaginal birth and a cesarean section was less accurate, although still significant (73.4% and 90.2%, respectively). A similar study on 141 vaginal birth after cesarean (VBAC) candidates showed that by sectioning electively patients in whom cesarean sections were predicted, the cesarean section rate barely increased. CONCLUSION: Careful evaluation of a patient in early labor could help to recognize the dystocic labor-delivery and early indication for cesarean sections. This would avoid unnecessary and prolonged labor without necessarily increasing the cesarean section rate. PMID- 10090492 TI - Neonatal 24-hour urinary C-peptide and birth weight in infants of diabetic mothers. AB - OBJECTIVE: Our purpose was to investigate the relationship between the birth weights and 24-h urinary C-peptide in infants of diabetic mothers. METHODS: Sixty pregnancies with gestational diabetes mellitus (DM) were enrolled. Neonatal urine was collected for the first and second 24 h for measuring C-peptide. Birth weights were classified into 3 categories according to the Japanese standard curves; heavy-for-date (HFD), appropriate-for-date (AFD), and light-for-date (LFD). Unpaired t-test was used for comparison of 24-h urinary C-peptide in the 3 birth weight categories, with P-value <0.05. There were 7 HFD, 47 AFD, and 6 LFD infants. Birth weight averaged 3.9+/-0.7, 3.0+/-0.4, and 2.3+/-0.3 kg, respectively. RESULTS: Insulin concentrations of the umbilical artery were significantly higher in HFD than in AFD, and significantly higher in AFD than in LFD (49.5+/-45.1, 16.8+/-15.2, and 6.3+/-6.1 microU/ml). During the first 24 h, urinary C-peptide was significantly higher in HFD than in AFD (2.73+/-1.52 vs. 0.76+/-0.81 microg/day), and significantly higher in AFD than in LFD (0.27+/ 0.27). On the second day, there was no longer statistical significance. CONCLUSIONS: Measurement of 24-h urinary C-peptide revealed that, among infants of diabetic mothers, HFD infants continue to secrete more insulin than AFD and LFD infants for the first 24 h. PMID- 10090493 TI - Folate status during labor: relationship with pregnancy outcome. AB - OBJECTIVE: The purpose of our study was to determine the folate status of pregnant women at labor, and to detect probable relationships with the gestational age at delivery, the birth weight of the newborns, as well as the mode of the delivery, taking into account any changes in the fetal heart rate (FHR) at labor and, subsequently, operative delivery. METHODS: Maternal serum folate levels were determined using automated fluorometric enzyme-linked assays. Gestational age was determined by ultrasound in the first trimester followed by serial fetal biometry. RESULTS: The results of our study in 101 consecutive pregnant women revealed that the mean (+/-SD) maternal serum concentration of the folate during labor was 12.01 (+/-4.16) ng/ml (range 2.50-23). The mean (+/-SD) gestational age at labor was 38.5 (+/-1.2) weeks (range 35-41 wks) as also the mean (+/-SD) birth weight of the newborns was 3.217 (+/-403) g (range 2,000-4,250 g). CONCLUSIONS: No significant correlation (p>0.05) between folate levels of the maternal serum and gestational age at delivery or birth weight was found. The mode of delivery as a result of probable relationship between operative delivery and maternal serum folate levels was also not found. PMID- 10090494 TI - Routine obstetrical ultrasound at 18-22 weeks: our experience on 7,236 fetuses. AB - OBJECTIVE: This study aimed at examining the detection rate of congenital abnormalities by using routine ultrasonography at 18-22 weeks of gestation. METHODS: The sample included 7,236 fetuses. A detailed sonographic examination was performed in each fetus and a neonatal evaluation or pathology examination was made to confirm the prenatal findings. RESULTS: The total prevalence of fetal abnormalities in our sample was 2.24% (162/7,236). There were 29/162 (17.9%) fetuses with CNS abnormalities, 27/162 (16.7%) fetuses with gastrointestinal abnormalities, and 28/162 (17.3%) fetuses with urinary tract abnormalities. There were also 31/162 (19.1%) fetuses with cardiovascular abnormalities, 26/162 (16.0%) with malformation of the limbs and musculoskeletal system, and 21/162 (13%) fetuses with other various abnormalities. The overall sensitivity in detecting fetuses with congenital abnormalities was 80.25% (130/162). The sensitivity per system was 93.1% (27/29) for CNS, 45.2% (14/31) for cardiovascular system, 85.2% (23/27) for gastrointestinal system, 85.7% (24/28) for urinary system, 84.6% (22/26) for musculoskeletal system, and 95.2% (20/21) for the rest of the abnormalities detected. We performed 40 pregnancy terminations in the group of malformed fetuses. Among the fetuses considered as normal, 1.7% had chromosomal abnormalities. CONCLUSIONS: The results indicate that routine sonographic examination at 18-22 weeks of gestation can detect the majority of congenital abnormalities. More experience is needed for the examination of the cardiovascular system, where the sensitivity was particularly low (14/31 or 45.2%). PMID- 10090495 TI - Prediction of preterm delivery by combined use of simple clinical tests. AB - OBJECTIVE: To investigate the usefulness of 4 clinical tests in detecting both the major symptoms (premature uterine contractility and cervical change) and causes (intrauterine infection) of preterm delivery (PTD). These were performed simultaneously on 683 pregnant women at 26 to 28 weeks of gestation. METHODS: The following four tests were performed at study entry: 1) uterine contractility by the nipple stimulation test (NST); 2) cervical length (CL) measured by transvaginal ultrasonography; 3) measurement of granulocyte elastase in cervical secretion; and 4) measurement of oncofetal fibronectin in vaginal secretion. Pregnancy outcomes were followed up and recorded for the 683 women. RESULTS: Those women with a CL <25 mm showed a significantly higher PTD rate than those with a CL > or =30 mm (13.3 vs. 2.3%). This difference was dominant in primiparous women. Those women with a CL of 25 to 29 mm formed a potentially high risk group in which a positive NST was associated with a high incidence of PTD. In contrast, granulocyte elastase in cervical secretion had no predictive efficacy for PTD during these weeks of gestation. The oncofetal fibronectin test had a very low (0.5%) positivity rate and proved to be unsuitable for routine clinical use. CONCLUSION: The data demonstrated the usefulness of the uterine contraction induction test by nipple stimulation (NST) and cervical length (CL) measurement by transvaginal ultrasonography. The combined evaluation of the NST, CL measurement, and fibronectin assay, when necessary, was useful for the prediction of PTD. PMID- 10090496 TI - Leprosy--new perspectives on an old disease. PMID- 10090497 TI - Prophylaxis against disseminated Mycobacterium avium complex in AIDS. PMID- 10090498 TI - CCR5 genotype and HIV-1 infection in perinatally-exposed infants. AB - The CCR5 chemokine receptor is required by non-syncytium HIV-1 strains to infect target cells. A 32 base pair deletion (delta32) in the CCR5 gene causes a structural CCR5 modification that does not permit HIV-1 entry into cells. The rate of the CCR5 delta32 was investigated in 137 children born from HIV-infected mothers. Overall, five (10.6%) of 47 HIV-infected infants showed the defect in heterozygosis vs. eight (8.9%) of 90 uninfected children. No CCR5 delta32 homozygotes were found. Interestingly, among infected children, five (21.7%) of 23 showing a slow disease progression were heterozygous for the CCR5 delta32, meanwhile none of the 24 infants with rapid disease course had the deletion (P = 0.022). In conclusion, the CCR5 delta32 defect does not protect against vertical HIV-1 transmission, but is associated with a delayed disease progression in HIV infected children. PMID- 10090499 TI - Detection of Chlamydia trachomatis DNA in cervical samples with regard to infection by human papillomavirus. AB - OBJECTIVE: The correlation between human papillomavirus (HPV) and Chlamydia, trachomatis infections was evaluated in 144 patients with normal cytology or with atypical squamous cells of undetermined significance (ASCUS). METHODS: Cervical samples were analysed using polymerase chain reaction (PCR) and non-radioactive Southern blot analysis. Specificity and sensitivity of two C. trachomatis PCR systems: major outer membrane protein (MOMP)-PCR and plasmid-PCR were determined. Southern blot hybridization of the PCR amplicons was done using 5' and 3' biotinylated oligonucleotide probes. RESULTS: All cervical samples were tested by the plasmid-PCR due to a 10 times higher sensitivity compared to the MOMP-PCR. To determine the specificity of our C. trachomatis primer sets different bacteria and viruses which can cause urogenital infections were analysed. Comparison of the probes revealed an increased sensitivity of the 5' and 3' double-biotinylated probe vs. the 5' biotinylated probe. The infection rate of C. trachomatis in cervical samples of HPV-positive patients was 10.3% (three out of 29) vs. 1.7% (two out of 115; P< or =0.05) in HPV-negative patients. In patients HPV-X (unsequenced HPV-types) positive the rate was 14.3% (one out of seven) vs. 2.9% (four out of 137: P = 0.2) in HPV-X negative patients. In high risk (HR) HPV positive cervical samples the infection rate was 9.1% (two out of 22) vs. 2.5% (three out of 122; P = 0.14) in HR HPV-negative samples. Chlamydia trachomatis frequency of patients with cytological changes (ASCUS) was 27.3% (three out of 11) vs. 1.5% (two out of 1 33) in patients with normal cytology (P = 0.003). The highest prevalence rate of C. trachomatis-positive cervical samples (50%; one out of two) was found in HR HPV-positive patients with cytological changes (ASCUS) vs. 5% (one out of 20) in HR HPV-positive patients with normal cytology (P = 0.17). Patients negative for HPV and positive for ASCIIS have a C. trachomatis rate of 22.2% (two out of nine) vs. HPV-negative patients with normal cytology (none out of 106; P = 0.006) and vs. HR HPV-negative patients with normal cytology (0.9%; one out of 113; P = 0.014). CONCLUSIONS: There appears to be a correlation between cervical HPV and cervical C. trachomatis infections. The prevalence rate of C. trachomatis was significantly higher in patients with abnormal cytology (ASCUS) vs. normal cytology. PMID- 10090500 TI - Elevated non-transferrin bound iron in the lungs of patients with Pneumocystis carinii pneumonia. AB - OBJECTIVE: The aim of the present work was to determine the concentrations of iron and iron-binding proteins in the lungs of patients suffering from Pneumocystis carinii (PCP), which is crucial for justifying the treatment with iron-chelating agents in this disease. PATIENTS AND METHODS: Bronchoalveolar lavage was performed in 10 HIV patients with PCP and five healthy controls. Total iron and iron-binding proteins (transferrin, ferritin and lactoferrin) were measured in acellular bronchoalveolar lavage fluid (BALF) in both groups. Iron was determined by atomic absorption spectrometry; transferrin and lactoferrin were measured using specific enzyme-linked immunosorbent assays (ELISA); and ferritin concentration was quantified by automated immunonephelometry. RESULTS: Our findings in patients with PCP demonstrated a six- to seven-fold increase of total iron levels and an eight-fold increase of ferritin in bronchoalveolar lavage fluid when compared with controls. No significant differences were found in transferrin or lactoferrin levels. Moreover, our results suggest that this iron is non-transferrin bound. CONCLUSION: Non-transferrin bound iron is increased in the lower respiratory tracts of PCP patients. This finding would lend experiment support to the use of iron-chelating agents in this disease. PMID- 10090501 TI - Transmissibility from horses to humans of a novel paramyxovirus, equine morbillivirus (EMV). AB - OBJECTIVES: Determination of potential infectivity of a new paramyxovirus equine morbillivirus (EMV) from horses to humans and humans to humans as a result of two outbreaks in Queensland which involved 23 horses and three humans. METHODS: Seroepidemiological testing using neutralizing and immunofluorescing antibodies on people with variable levels of exposure to infected horses and humans. RESULTS: All serological testing on a total of 298 individual contacts was negative. CONCLUSIONS: While the three human cases of EMV were probably infected as a result of very close contact with horses, these data suggest that infectivity from horses or humans is very low. PMID- 10090502 TI - Convalescent excretion of Salmonella enteritidis in infants. AB - OBJECTIVES: To review the excretion of Salmonella enteritidis PT4 in the faeces of infants involved in a point-source outbreak in a nursery, and to relate these findings to advice given by the Outbreak Control Team (OCT). METHODS: Retrospective laboratory-based survey. RESULTS: Infection with S. enteritidis PT4 was microbiologically confirmed in 33 primary cases and one secondary case. Of the faeces submitted 4 weeks from exposure, 96% remained positive. None of the infants was symptomatic by this time, and none received antimicrobial treatment. Two infants aged less than 1 year were still excreting 22 weeks after the onset of the outbreak. CONCLUSIONS: As for other serotypes, S. enteritidis PT4 causes prolonged symptomless excretion after infection, particularly in infants aged less than 1 year. Infection control measures, including exclusion criteria, may need to be modified as an outbreak progresses. PMID- 10090503 TI - Two cases of toxoplasmic encephalitis in patients with acute T-cell leukaemia and lymphoma. AB - Two cases of opportunistic cerebral infections in HIV-negative cancer patients due to chemotherapy induced immunosuppression are reported. A 61-year-old patient with low grade lymphoma (immunocytoma as referred to the Kiel classification) developed stereotactical biopsy proven toxoplasmic encephalitis 6 months after initiation of fludarabine treatment. The lymphoma had been diagnosed 8 years earlier and had been treated with several different regimens. In the second case, a 55-year-old patient developed neurological symptoms while in complete remission from acute T-cell leukaemia. The patient had been treated with a multidrug chemotherapy regimen including radiotherapy of the brain and intrathecal chemotherapy. When toxoplasmic encephalitis was bioptically diagnosed the patient was on maintenance chemotherapy with methotrexate and mercaptopurine for 12 months. The patients' characteristics and outcome are reported and the potential pathogenesis is discussed. PMID- 10090505 TI - Risk of cytomegalovirus infection among educators and health care personnel serving mentally disabled children. AB - AIM: To determine the risk of cytomegalovirus (CMV) infection for personnel providing services to young disabled children. METHODS: The prevalence and incidence of CMV in a group of educators were compared with a group of nurses working in homes for the elderly. RESULTS: The prevalence was measured in 283 educators and 294 nurses. Both groups were comparable for well-established risk factors for CMV infection. The prevalence of seropositivity was 15.9% in the educators and 18.4% in the nurses. After a 1-year period 182 of the educators and 157 of the nurses who were initially seronegative for CMV were retested for serologic evidence of CMV infection. The annual conversion rate was 1.03% in educators and 1.42% in nurses. CONCLUSION: The prevalence of CMV antibodies among both educators and nurses did not differ and was lower to that observed in American studies of comparable populations. Annual seroconversion rates were not different between these groups. PMID- 10090504 TI - Serologic study of human parvovirus B19 infection in pregnancy in Japan. AB - OBJECTIVES: To clarify the relationship between hydrops fetalis and parvovirus outbreaks in the community, seroprevalence of B19 antibody among women of childbearing age, and adverse effects of intrauterine B19 infection. METHODS: Sera were collected from 168 cases of hydrops fetalis which were diagnosed between 1987 and 1997 in Miyagi prefecture, Japan, from 232 healthy pregnant women in 1987 and 277 healthy pregnant women in 1997 in Miyagi, and from 48 women infected with B19 during pregnancy. The sera were examined for B19 IgG and IgM antibodies by enzyme-linked immunosorbent assay and for B19 DNA by polymerase chain reaction. The number of cases of erythema infectiosum in Miyagi had been monitored each month. RESULTS: Thirteen of the 168 cases of hydrops fetalis were found to be caused by intrauterine B19 infection and 12 of the 13 cases clustered in two periods of outbreaks of erythema infectiosum in the community. The positive rates of B19 IgG antibody between 1987 and 1997 were significantly different: 33% in 1987 and 46% in 1997. Nine of the 48 women infected during pregnancy showed adverse effects of the fetus: eight hydrops fetalis and one early abortion with positive B19 DNA. The fetal death rate (>12 weeks of gestation) among them was 15% (7/48), far higher than the calculated 1% among the general population. The nine mothers with adverse fetal outcomes had contact with the infectious source at the 16 weeks of gestation or earlier. CONCLUSIONS: These data clearly showed a relationship between hydrops fetalis and parvovirus outbreaks in the community, and it may be important to follow the seroprevalence for an extrapolated period time to predict occurrence of hydrops fetalis caused by B19. Also the data indicated that the gestational week infection occurred is the most important determinant of an adverse effect to the fetus as described previously. PMID- 10090506 TI - Arcanobacterium haemolyticum and Mycoplasma pneumoniae co-infection. AB - Systemic infection caused by Arcanobacterium haemolyticum is uncommon. We report a case of empyema and bacteraemia caused by this organism concomitant with Mycoplasma pneumoniae infection. PMID- 10090507 TI - Massive pulmonary haemorrhage caused by leptospirosis successfully treated with nitric oxide inhalation and haemofiltration. AB - A patient with leptospirosis who developed oliguric renal failure, massive pulmonary haemorrhage and respiratory failure is described. The patient's clinical condition and arterial oxygenation failed to improve despite vigorous supportive measures. Nitric oxide inhalation and haemofiltration resulted in a marked clinical improvement and subsequent full recovery. We suggest that the addition of haemofiltration and nitric oxide inhalation therapy should be considered in patients with pulmonary haemorrhage and renal failure caused by leptospirosis, in whom conventional therapy fails. PMID- 10090508 TI - Identification of the cause of a brain abscess by direct 16S ribosomal DNA sequencing. AB - We report the case of a young man who apparently suffered successive episodes of meningitis and cerebral abscess over a 1-month period, both of which were diagnosed by two different molecular approaches; PCR for Neisseria meningitidis IS1106 from CSF and 16S rRNA gene sequencing on a specimen of brain pus. In each case, cultures were negative due to prior antibiotic therapy. PMID- 10090509 TI - Guillain-Barre syndrome following malaria. AB - Two adult males were admitted with acute are flexic quadriplegia and bifacial and bulbar weakness 2 weeks after an acute episode of malaria, one due to Plasmodium falciparum infection (patient 1) and the other due to Plasmodium vivax (patient 2). Cerebrospinal fluid analysis and nerve conduction studies confirmed the diagnosis of Guillain-Barre syndrome (GBS). Patient 1 progressed to develop respiratory paralysis and required mechanical ventilation. He received intravenous immunoglobulins for the GBS and made a complete recovery in 6 weeks. A review of 11 cases of GBS (nine previously reported and the present two) revealed that eight patients had preceding falciparum malaria and three had vivax infection. All but two patients had distal symmetric sensory deficits. Paralysis was mild in seven cases (three due to P. vivax and four due to P. falciparum) and recovered completely in 2-6 weeks without any specific treatment. Four patients with falciparum malaria developed severe paralysis with respiratory failure, and three patients died. One patient who received intravenous immunoglobulins recovered completely (patient 1 in this report). PMID- 10090510 TI - Successful treatment of candidal osteomyelitis with fluconazole following failure with liposomal amphotericin B. AB - A case of multiple relapses of Candida albicans infection of deep tissues is described. Treatment was complicated by renal impairment, but therapy with a liposomal amphotericin product failed to eradicate the third recurrence which subsequently resolved after protracted exposure to oral fluconazole. PMID- 10090511 TI - Anaerobic infections in an Indian tertiary care hospital with special reference to bacteroidaceae. PMID- 10090512 TI - Brain abscess due to Corynebacterium xerosis. PMID- 10090513 TI - A case report of renal abscess caused by Salmonella virchow phage type 1 associated with a papillary renal cell carcinoma. PMID- 10090514 TI - Group C streptococcal endocarditis. PMID- 10090515 TI - A complete remission of recalcitrant molluscum contagiosum in an AIDS patient following highly active antiretroviral therapy (HAART) PMID- 10090516 TI - Evidence of hepatitis C virus in cervical smears. PMID- 10090517 TI - Specific IgG avidity--a supplementary assay in serological screening for toxoplasmosis in pregnancy. PMID- 10090518 TI - Overwhelming Streptococcus bovis infection as a cause of intrauterine death. PMID- 10090519 TI - How clinicians should use the diagnostic laboratory in a changing medical world. AB - In developed countries, clinicians are faced with a plethora of diagnostic tests to apply to patients to guide their clinical management. The quality, effectiveness, and efficiency of patient care should be foremost in the clinician's mind. Laboratory directors should make every effort to guide clinicians in appropriate laboratory test ordering, interpretation, and resulting actions. Medicine, being at its center a moral enterprise grounded in a covenant of trust, and laboratory medicine being a subset of medicine, must first care and advocate for the patient, and consider clinical outcomes as most important. PMID- 10090520 TI - The laboratory and the general practitioner. AB - Clinical laboratories provide vital services for primary care and such work will inevitably increase with the moves to increase the extent to which patients are treated in the primary care setting, an increase in day-case surgery and shorter in-patient stay. The relationship between clinical laboratories and general practitioners should be a partnership with both the parties communicating efficiently in the interest of the patient. In particular, a close relationship between general practitioners and specialists in laboratory medicine is mandatory for handling the increasing number and complexity of laboratory tests, assuring the appropriateness of their request and utilization. In addition, the enormous increase in near-patient testing procedures claims for joint efforts to assure the quality of laboratory results. The General Practitioner always has the responsibility to understand the relevance of a test result and, where appropriate, to investigate further or to refer, irrespective of where the test has been done, but laboratory consultation can assure a better utilization of laboratory services for improving patient outcomes. PMID- 10090521 TI - Clinical and laboratory logic. AB - After elucidating the controversy that accompanied the birth of laboratory medicine, the Authors define and examine the concepts underlying clinical methodology. The mental operations of the clinician are analyzed, a distinction being made between the processes of: a) "categorization" of the patient's disease, and b) "explanation" for pathologic phenomena. The diagnostic procedure is usually based above all on categorization. In the first phase of this procedure the clinician searches for data that are of the greatest possible "informative value", and then goes works out a certain number of "syndromic complexes". In the second phase, on the basis of these "groups of signs", the physician must formulate a certain number of diagnostic hypotheses and evaluate the probability of the presence of a particular disease, in view of the presence of particular signs. Finally, two fundamental arguments of clinician are dealt with: "the confirmatory argument" and "the falsifying argument", and the value of these two inferences in conferring certainty or a certain grade of reliability on clinical judgement is analyzed and discussed. PMID- 10090522 TI - The clinical importance of laboratory reasoning. AB - The radical changes made in the delivery of modern health care have serious implications for laboratory services, because reasoning in laboratory medicine should follow a clinical rather than a technological logic. Appropriate test requesting and interpretation coupled with a patient-oriented vision improve the outcomes for patients, and so ensure the best cost containment strategy. The fact that analytical operations are standardized and quality controlled, may lead to a greater recognition of the importance of pre- and post-analytical issues. Particularly critical aspects are the formulation of the clinical question and the interpretation of laboratory results. Laboratory-clinic communication is fundamental in achieving and maintaining total quality in laboratory services. Effective consultancy stands or falls with the knowledge and experience of laboratorians, as well as continuous education is required to maintain the best utilization of laboratory information in clinical decision-making. As clinical audit is an important tool for reviewing and improving the quality of the service in clinical laboratories, it should make up an important part of programs for accreditation and quality improvement. If a patient-centered vision predominates, the clinical laboratory will be linked to both physicians and patients, making it more tangible to the latter. PMID- 10090523 TI - Clinical audit and the contribution of the laboratory to clinical outcome. AB - Medical and clinical audit are tools introduced in an attempt to assess clinical performance. Clinical audit implementation in practice should follow that of the audit and the learning cycles. Ideally, audit should assess the outcome of clinical care. However, many audit projects concentrate on the process of care, which is more amenable to review. One of the cornerstones of audit is the setting up of agreed standards of care. This takes the form of clinical practice guidelines derived, preferably from the outcome of randomised double-blind controlled trials as the basis of evidence-based medicine. The assessment of the contribution of the clinical laboratory to patient outcome could be seen as a further extension of clinical audit in the practice of laboratory medicine. Areas where this contribution may be assessed include validity and usefulness of diagnostic tests, the assessment of analytical goals in relation to patient outcome, variation in inter-laboratory performance and its effect on decision limits and whether any measurement or set of measurements contribute to improved outcome. The practice of clinical audit and the application of evidence-based medicine are seen as powerful educational tools, though there is much work to be done to assess their contribution to clinical outcome. Randomised clinical trials could form the basis for the assessment of the value and contribution of the laboratory to the outcome. PMID- 10090524 TI - Biochemical risk factors and patient's outcome: the case of lipoprotein(a). AB - Lipoprotein(a) (Lp(a)) is a genetic variant of low density lipoproteins and consists of the covalent association of the unique and enigmatic apolipoprotein(a) to apoliprotein B100. Despite the high degree of homology with low density lipoproteins, Lp(a) displays distinctive physico-chemical properties, function and metabolism. The present article reviews the main biological and clinical evidences about the association between raised concentration of Lp(a) and atherothrombotic diseases and provides tentative guidelines to improve the clinical usefulness of Lp(a) measurements. PMID- 10090525 TI - Molecular diagnosis of inherited diseases. AB - The importance of the interaction between basic science and clinical practice has long been known but it has become even more evident in the past few decades with the impressive rate of development in the field of molecular genetics. This short article reviews molecular diagnosis of two different diseases for which scientific progress has immediately been translated into a dramatic improvement of the quality of medical care: the Fragile X Syndrome, paradigm of the new mutational mechanism of the unstable triplet repeats, and von Hippel-Lindau disease, a recent acquisition in the growing number of familial cancer syndromes. PMID- 10090526 TI - The multiple cases of Fabry disease in a Russian family caused by an E341K amino acid substitution in the alpha-galactosidase A. AB - A large Russian family with multiple cases of Fabry disease in several generations is presented. Fourteen family members were clinico-biochemically examined. Among 12 adult children (19-32 years old) of one couple, five sons manifested angiokeratotic skin lesions and other Fabry symptoms. Biochemical studies including an enzyme assay, the analysis of glycosphingolipid excretion and isoelectric focusing of a patient leukocyte extract allowed us to identify Fabry disease in four affected brothers and to establish the heterozygous status of their mother. The analysis of genomic DNA of four patients and their mother revealed a novel E341K missense mutation caused by a G to A transition (codon 341 GAA-AAA) in the alpha-galactosidase A gene. PMID- 10090527 TI - Evaluation of the thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine chloromethylketone (PPACK) with the factor Xa inhibitor 1,5-dansyl-L-glutamyl-L glycyl-L-arginine chloromethylketone (GGACK) as anticoagulants for critical care clinical chemistry specimens. AB - The objective of this study was to determine whether a thrombin inhibitor (PPACK) and a factor Xa inhibitor (GGACK) either alone or in combination can anticoagulate whole blood without biasing the analysis of several critical care analytes. Whole blood clot time was used to assess anticoagulant efficacy. The analytical biases mediated by the anticoagulants on glucose, urea, creatinine, electrolytes, amylase, lactate dehydrogenase, creatine kinase, ionized calcium and pH were assessed. The protease inhibitor mixture (100 micrommol/l PPACK + 500 micromol/l GGACK) was more a potent anticoagulant than the individual agents at the same concentrations. Both PPACK and GGACK, alone and in combination, reduced the activity of creatine kinase and amylase by 3-10% while the remaining critical care analytes were less affected. In conclusion, PPACK and GGACK mixtures can effectively anticoagulate whole blood, but the mixtures exert pre-analytical influences that limit the analytical versatility of these novel plasma-matrices. PMID- 10090528 TI - A simple, sensitive and reproducible assay for pyridoxal 5'-phosphate and 4 pyridoxic acid in human plasma. AB - We describe a procedure for the measurement of pyridoxal 5'-phosphate and of 4 pyridoxic acid in human plasma samples. It is based on the conversion of pyridoxal 5'-phosphate to 4-pyridoxic acid 5'-phosphate by cyanide in alkaline medium, followed by a high pressure liquid chromatographic separation, with fluorescence detection at acid pH. The assay is robust, sensitive, linear over a wide range, reproducible, and simple to perform. Samples stored at -80 degrees C are stable. Satisfactory agreement was obtained with results from the tyrosine decarboxylase-based assay for pyridoxal 5'-phosphate, in two other laboratories. Plasma samples from a National Survey of older British people were analyzed, and reference intervals for plasma pyridoxal 5'-phosphate intervals were derived. From the lower 2.5 percentile of the reference group, taken as the lower cut-off of the normal range, ca. 20% of elderly men and 11% of elderly women in the UK showed evidence of biochemical deficiency. PMID- 10090529 TI - A single strand conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in 15 exons of the KVLQT1 gene, associated with long QT syndrome. AB - Congenital long QT syndrome (LQTS) is characterised by prolongation of the QT interval on ECG and cardiac arrhythmias, syncopes and sudden death. A rapid and reliable genetic diagnosis of the disease may be of great importance for diagnosis and treatment of LQTS. Mutations in the KVLQT1 gene, encoding a potassium-channel subunit of importance for the depolarisation of cardiac myocytes, is believed to be associated with 50% of all LQTS cases. Our data confirms that KvLQT1 isoform 1 is encoded by 16 exons, and not 15, as reported previously. We have used genomic DNA sequences to design intronic PCR primers for amplification of 15 exons of KVLQT1 and optimised a non-radioactive single stranded conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in KVLQT1. The sensitivity of the method was 100% when it was tested on 15 in vitro constructed mutants. By multiplexing the PCR amplification of KVLQT1, it is possible to cover all 15 exons in four PCR reactions. PMID- 10090530 TI - Cytokines and adhesion molecules in the course of acute myocardial infarction. AB - The plasma levels of interleukin 1 beta (IL 1beta), interleukin 6 (IL 6), interleukin 8 (IL 8), tumor necrosis factor alpha (TNF-alpha), E-selectin, ICAM 1 and C-reactive protein (CRP) have been studied in 24 patients with acute myocardial infarction in the course of 96 h. The plasma IL 1beta and IL 6 levels were continually elevated during the 96 h study period (the peak of plasma IL 1beta level was 22.2 pg/ml, S.D. 8.6, P < 0.001, normal values of IL 1beta are less than 10 pg/ml, the mean peak plasma concentration of IL 6 was 184.9 pg/ml, S.D. 134.7, vs. normal values of 15.57 pg/ml, S.D. 2.4, P < 0.001). The mean plasma IL 8 level was increased for the duration of the study, the mean plasma IL 8 level was 103.0 pg/ml, S.D. 23.4 (normal value was below 30 pg/l, S.D. 8.0) P < 0.001. The plasma TNF-alpha level was elevated throughout the time of observation without any significant peak. The mean plasma TNF-alpha concentration was 46.8 pg/ml, S.D. 2.13, vs. normal value 4.35 pg/ml, S.D. 1.23, P < 0.001. The plasma E selectin level reached the mean level of 145.1 ng/ml, S.D. 75.4, vs. normal value 29.1-63.4 ng/ml, P < 0.001 at an interval of 15-42 h after the onset of the symptoms. The plasma ICAM 1 level showed only a slight significant increase during the first 36 h. The plasma CRP concentration increased later than IL 6, and reached a peak at 42 h after the onset of the symptoms (69.2 mg/l, S.D. 29.9, vs. 1.2 mg/l, S.D. 4.7, P < 0.0001). We conclude that cytokines and adhesion molecules can play an important role in the mechanisms of tissue injury in the process of ischemia and reperfusion. PMID- 10090531 TI - Commutability and traceability: their repercussions on analytical bias and inaccuracy. AB - The commutability of calibrators and accuracy control materials affects the traceable link between patient sample results and standards. We sought to identify the repercussions of commutability on various aspects of laboratory practice (calibration, control of bias and accuracy assessment) and to discover the solutions that can reduce the problems produced by non-commutability with presently available resources. Ten serum constituents, ten comparison procedures and 37 analytical procedures were studied. The information concerning accuracy and bias provided from materials found to be commutable in previous works was challenged with native serum results for each routine and reference method compared, using Passing-Bablok regression and decision limits derived from biological variation. We found that: (1) Use of commutable control materials did not assure reliable information on the bias (systematic component of analytical error) of analytical procedures, and (2) Results from native serum and commutable controls were very highly concordant, indicating that these materials provide a good indication of the inaccuracy (total analytical error) of results. We suggest that the performance of individual laboratories would be better evaluated by occasional use of native sera with values assigned by reference methods in EQAS schemes. Moreover, our findings support the idea that manufacturers should assign values to calibrators using reference methods and native sera to reduce matrix effects and promote traceability. PMID- 10090532 TI - Biochemical assay for amyloid beta deposits to distinguish Alzheimer's disease from other dementias. AB - Biochemical markers for Alzheimer's disease (AD) are of great value for precise diagnosis and in studies of the pathogenetic processes of this disease. A new biochemical assay allowing to differentiate AD from other forms of dementia is described. The assay is based on the extraction of amyloid beta (A beta) from milligram amounts of brain tissue by using 20% acetonitrile in 0.1% trifluoroacetic acid and its detection by Western blotting. The presence of the 4 kDa A beta was demonstrated in all cases of AD (n = 8) that were diagnosed by the independent histopathological examination of the postmortem tissues. No A beta was found in tissue extracts from seven out of eight cases of other forms of dementia. In contrast to other biochemical techniques of A beta detection in brain, the developed assay is simple; it does not require any special equipment and allows detection of A beta using milligram amounts of brain tissue. PMID- 10090533 TI - Evaluation of alpha-fetoprotein assay in ascitic fluid for the diagnosis of hepatocellular carcinoma. AB - Ascites and hepatocellular carcinoma are frequently associated. We evaluated the usefulness of alpha-fetoprotein assay in ascitic fluid versus the serum assay, for the diagnosis of hepatocellular carcinoma, in 125 patients with peritoneal effusions (31 patients with hepatocellular carcinoma, 14 with extra-hepatic malignancies and 80 with a benign effusion). Albumin and total protein were also assayed and cytological analysis of the ascitic fluid performed. Alpha fetoprotein appeared to be lower in ascitic fluid than in serum. For a diagnostic specificity of 95%, the thresholds were 18.9 microg/l in serum and 4 microg/l in ascitic fluid and the diagnostic sensitivity of alpha-fetoprotein was identical in serum and ascitic fluid (67.7%). Various ratios between alpha-fetoprotein and albumin or total protein did not enhance the diagnostic performance. Thus alpha fetoprotein concentration in ascitic fluid reflected the serum concentration and proved to be of similar value for the diagnosis of hepatocellular carcinoma, providing that the appropriate thresholds are considered. PMID- 10090534 TI - Elevated lysosomal pH in Mucolipidosis type IV cells. AB - The lysosomal pH in Mucolipidosis type IV (ML-IV) and several other storage disease fibroblasts (Niemann Pick, type A; Niemann Pick, type C; Hunter (MPS II); and Farber) and in normal human skin fibroblasts was determined in situ. Cells were pulse labeled with a fluorescein-conjugated dextran to label the lysosomes. Quantitative fluorescence microscopy was then carried out on living cells to measure the ratio of fluorescence at two different excitation wavelengths. An image processing routine was used to quantify fluorescence from individual lysosomes. Ratiometric data were converted to an absolute value of pH using an appropriate standard curve. Lysosomal pH varied between 4.3 and 4.5 for all the cell types examined except ML-IV cells which was almost one pH unit higher (pH approximately 5.2). Qualitatively similar results were obtained using acridine orange, another fluorophore whose fluorescence emission is pH dependent, ruling out the possibility that the stored molecules in ML-IV cells might induce an artifact in the fluorescein-based pH measurements. We conclude that elevated lysosomal pH is unique to ML-IV cells. This property may be an important factor, if not the cause, for the accumulation of the broad spectrum of substances, including sphingolipids, phospholipids, and acid mucopolysaccharides, even though the lysosomal hydrolases participating in the catabolism of these molecules appear to be normal. PMID- 10090535 TI - Reflex testing I: algorithm for lipid and lipoprotein measurement in coronary heart disease risk assessment. AB - We reviewed the current literature in order to construct a reflex testing algorithm that maximizes clinical utility and cost-effectiveness of lipid and lipoprotein testing. The algorithm was based on the 2nd Report of the National Cholesterol Education Program Adult Treatment Panel guidelines for use of total cholesterol (TC), triglycerides (TG), HDL-C, and LDL-C, and published reports describing the clinical use of apolipoprotein B and lipoprotein (a). The success of this algorithm was tested in a low-risk general and a high-risk hyperlipidemic patient population. Lipid data and non-lipid risk factors were obtained from a national database and from patients seen at two lipid clinics. A total of 16,968 individuals from the National Health and Nutrition Examination Survey III database comprised the low-risk group, and 239 patients examined in the Hartford Hospital and Washington University Lipid Clinics comprised the high-risk group. We found a solid scientific base to support the NCEP guidelines and reasonable support for limited testing of apoB and Lp(a). According to the algorithm, the direct LDL-C assay was deemed unnecessary in 98% and 91% of low- and high-risk subjects, respectively, if one assumes that the Friedewald equation is adequate with TG < or = 4.00 g/l. With a more conservative cutoff of TG < or = 2.50 g/l, the algorithm canceled 92% and 81% of direct LDL tests, respectively. The algorithm also limited TG to 20 and 64%, apoB to 6 and 20%, and Lp(a) to 15 and 56%, of low- and high-risk groups, respectively. Use of a comprehensive, reflex algorithm for coronary heart disease risk assessment will substantially reduce the utilization of laboratory services without diminishing the clinical value of these tests. The algorithm will prevent the overuse of certain expensive tests (direct LDL) while promoting the limited use of underutilized tests [apoB and Lp(a)]. PMID- 10090536 TI - Levels of free prostate-specific antigen (PSA) can be selectively measured by heat treatment of serum: free/total-PSA ratios improve detection of prostate carcinoma. AB - We studied a simple heat treatment method for measuring free prostate-specific antigen (PSA). Samples were incubated at 56, 58, and 60 degrees C for 5, 15, 30, 45, and 60 min. Then, 1 ml samples were fractionated on a Sephacryl S-200 gel filtration column to separate alpha1-antichymotrypsin-complexed PSA (ACT-PSA) and free PSA. Values of ACT-PSA decreased with increasing incubation temperature and time, whereas free-PSA remained relatively constant. The optimal temperature and time for incubation were 58 degrees C and 30 min. Using free/total-PSA ratios, we were able to distinguish between benign prostatic hyperplasia and prostate carcinoma in patients whose PSA was in the diagnostic 'grey zone', i.e. 4.1 to 10.0 ng/ml. Through receiver operating characteristic curve analysis, the area under the curve increased from 0.675 to 0.871 when comparing the performance of total PSA to the free/total-PSA ratio. Thus, clinical application of our present methodology may reduce the need to obtain prostatic biopsies in patients whose PSA level is within the diagnostic 'grey zone'. PMID- 10090537 TI - Is acetone a normal breath constituent in Japanese? PMID- 10090539 TI - Effects of maternal dietary avoidance during lactation on allergy in children at 10 years of age. AB - This study investigated the long-term effects of maternal dietary avoidance during lactation on the occurrence of atopic symptoms, development of immunoglobulin E (IgE) antibodies to food and inhaled allergens and occurrence of positive skin-prick tests (SPT) in 65 children with a family history of atopy whose mothers adhered to a diet devoid of eggs, cow's milk and fish during the first 3 months of lactation (D group) and in a matched group of 50 children with mothers not practising such a diet (ND group). The diets of the D and ND children were similar. All children attended 7 follow-ups from the age of 3 months to the age of 10 y. After the first follow-up there was a 100% retention of participants. The results of the seventh follow-up at 10 y are presented. Total IgE values and IgE antibodies to seven food and seven inhaled allergens were determined by the Phadebas IgE CAP and the Phadebas RAST, respectively. SPT were conducted for five food and seven inhaled allergens. High rates of atopic symptoms occurred in both groups, but there were no differences between the groups. Sensitization to the three foods avoided by the mothers during lactation was similar, but the overall test reactivity to foods was lower in the D group. Sensitization to inhaled allergens was similar in the two groups. During the 10 y of follow-up, there was no difference between the groups in the occurrence of indoor furred animals, tobacco smoking, changes in heredity for atopy or development of total IgE, but a higher rate of maternal sensitization was found in the ND group, as judged by a screening test for IgE antibodies to inhalants (Phadiatop). The results do not support general recommendations to implement prophylactic maternal dietary avoidance during lactation in allergy-prone families. PMID- 10090538 TI - Plasma lipids and apolipoproteins in breastfed and formula-fed Swedish infants. AB - This study was carried out to compare plasma lipid pattern in breastfed and formula-fed infants and the effects of exchanging breast milk for formula and of introducing weaning foods. Healthy infants, exclusively breastfed at least until 3 mo, were at this age randomly assigned to infant formulas with similar fat composition. Formula was gradually introduced when breastfeeding was discontinued. One group continued to breastfeed beyond 6 mo of age. All infants received the same weaning foods and were studied between 3 and 12 mo of age. Decreased plasma concentrations of total and low-density lipoprotein cholesterol (TC, LDL-C), apolipoprotein B (apo B) and A1 (p < 0.001), and of high-density lipoprotein cholesterol (p < 0.05) were found when breast milk was exchanged for formula before 6 mo. At this age plasma TC, LDL-C and apo B were lower in formula fed than in breastfed infants (p < 0.001). These plasma lipids then increased (p < 0.01) when the intake of formula decreased and that of weaning foods increased. However, plasma TC and/or LDL-C remained lower at 12 mo in formula-fed than in breastfed infants (p < 0.05). Our results indicate that the plasma lipid profile of infants is highly responsive to the dietary nutrient intake, as indicated by the decrease in plasma lipids and apolipoproteins when breast milk was exchanged for formula and by the increase in these concentrations when the intake of weaning foods gradually increased. PMID- 10090540 TI - The amount of brainstem gliosis in sudden infant death syndrome (SIDS) victims correlates with maternal cigarette smoking during pregnancy. AB - Brainstem gliosis is elevated in some SIDS victims and has been associated with hypoxic-ischaemic events. Factors which increase the risk of SIDS include possible risk factors for hypoxic-ischaemic events during foetal and perinatal life. In this study a scoring system was developed whereby possible risk factors for hypoxic-ischaemic events during pregnancy, birth and in the perinatal period were correlated with the level of gliosis in the nucleus olivaris inferior in SIDS victims (n = 19). The mothers' antenatal care and obstetric records and the SIDS infants' perinatal hospital records were investigated, and each possible risk factor for hypoxic-ischaemic events was given one point. The points were summarized for each infant, and this sum was correlated with the level of gliosis in the infant's nucleus olivaris inferior. The number of cigarettes the mothers smoked during pregnancy was also compared with the level of gliosis. Our results show that in SIDS victims there is 41% probability that the more the mothers smoked during pregnancy, the more gliosis in the nucleus olivaris inferior is found in their infants (p < 0.01). Gliosis in the nucleus olivaris inferior also correlated with the possible risk factors for hypoxic-ischaemic events during pregnancy, birth and the perinatal period (r2 = 0.28, p < 0.05). However, if cigarette smoking was excluded as a possible hypoxic-ischaemic risk factor, no correlation was found. PMID- 10090541 TI - Atherogenic diet and blood lipid profile in children and adolescents from Galicia, NW Spain. The Galinut Study. AB - We studied serum levels of total cholesterol, lipoproteins and triglycerides in venous blood samples and the intake of nutrients using the subject's daily record of food eaten during a period of 7 d. The material comprised 7367 children and adolescents. The overall average lipid levels (4.55 +/- 0.91 mmol/L for TC, 1.42 +/- 0.47 mmol/L for HDL-C, 2.74 +/- 0.96 mmol/L for LDL-C) are high and similar to those found in other regions of Spain in the 1990s. The proportion of children with TC > or = 5.17 mmol/L (200 mg/dl) was 19%; that of children with HDL-C < or = 0.91 mmol/L (35 mg/dL) 6.5%. There is a striking and statistically significant difference between the proportions of boys and girls aged 15-20 y who have HDL-C levels in this range (15.8% for boys and only 4.2% for girls). We also demonstrate a high total fat (44% of TCV), saturated fat (16% TCV) and cholesterol (387 mg) intake. Because of the elevated fat and saturated fat intake and the increment of a more atherogenic lipid profile in our children, preventive nutritional measures are necessary, and life habits such as physical exercise and actively reducing fat and saturated fat intake have to be applied and inculcated in children from an early age. PMID- 10090542 TI - Long-term outcome of 51 liveborn neonates with non-immune hydrops fetalis. AB - To search for an efficient method of management of non-immune hydrops fetalis (NIHF), the clinical outcome of 51 newborns with NIHF was retrospectively assessed in a single centre. As the short-term outcome, the mortality rate was mainly dependent on the causes of NIHF and the presence of pleural effusion. The survival rate of the patients with pleural effusion (7/28; 25%) was significantly lower than that of those without it (14/23; 61%) (p < 0.02). All 7 survivors with pleural effusion were diagnosed antenatally after 29 weeks of gestation and were delivered after 31 weeks of gestation. With respect to the long-term outcome, 13 (68.4%) of 19 patients who survived beyond 1 y of age showed normal development, 2 mild developmental delay at 1 y of age and 1 mental retardation at 8 y of age, while 3 (15.8%) had severe psychomotor retardation with marked growth failure. Two of these three patients were born as very-low-birthweight infants. The follow up results indicate that pleural drainage in utero and prevention of premature delivery should be proposed to improve the outcome of NIHF patients. PMID- 10090544 TI - Rehydration of moderately dehydrated children with transient glucose intolerance using rice oral rehydration solution. AB - Following the successful rehydration of two moderately dehydrated patients with transient glucose intolerance (TGI) using rice-oral rehydration solution (R-ORS), R-ORS has been used in Hacettepe University Ihsan Dogramaci Children's Hospital Diarrhea Training and Treatment Unit (DTTU) to rehydrate moderately dehydrated children with TGI. The files of children with moderate dehydration and glucose intolerance admitted to the unit were reviewed retrospectively within two periods according to the availability of R-ORS. The clinical and laboratory findings were analysed where available. Before R-ORS became available (September 1993) 6 patients were admitted, all of whom deteriorated with glucose (G)-ORS treatment in 7.0 +/- 3.8 h and were hospitalized for i.v. fluid treatment. During the second period 22 moderately dehydrated children with TGI were admitted. The clinical and laboratory characteristics on admission of the children in the two periods were not statistically different (p > 0.05). Among the 22 patients admitted during the second period 10 were administered G-ORS in the unit and 12 had already received G-ORS at home. Clinical and laboratory deterioration was observed in these 10 patients while receiving G-ORS in the unit within 6.3 +/- 3.7 h and rehydration was continued with R-ORS. Clinical and laboratory improvement were demonstrated in 8 patients within 18.2 +/- 6.5 h. Overall, 17 patients were rehydrated successfully with R-ORS, with a mean time of 18.0 +/- 7.2 h. Five patients were hospitalized. The overall success rate of R-ORS was 77.3%. R-ORS may be considered as an alternative mode of therapy to i.v. treatment in the rehydration of moderately dehydrated children with TGI. PMID- 10090543 TI - Suppression of GH secretion in pituitary gigantism by continuous subcutaneous octreotide infusion in a pubertal boy. AB - We describe a 12-y-old boy with excessive growth hormone and prolactin secretion presumably due to diffuse somatotroph hyperplasia. Until mid-puberty, his growth rate was under reasonable control, with high-dose octreotide injections every 8 h combined with a dopamine agonist. As his growth velocity started to increase, the efficacy of continuous s.c. octreotide infusion on GH secretion was tested. Similar total daily doses (600 microg) of octreotide were administered either by incremental s.c. injections at 8 h intervals, or by continuous s.c. infusion, two thirds of the amount during night-time to control the presumed high nocturnal growth hormone (GH) peaks of the pubertal growth spurt. An overnight GH profile showed inadequate suppression of GH levels by incremental injections, while continuous s.c. infusion efficiently brought down the GH secretion. Another somatostatin analogue, lanreotide as a single depot injection was not effective. A 6-mo trial on the s.c. infusion regimen significantly reduced growth hormone secretion (as judged by IGF-I and IGFBP3 concentrations), and normalized growth velocity overcoming the pubertal growth spurt. It also caused a decrease in the pituitary size in magnetic resonance images. We conclude that the efficacy of octreotide infusion in suppressing GH secretion is superior to incremental injections with the same dose. PMID- 10090545 TI - Systematic review of N-acetylcysteine in cystic fibrosis. AB - A systematic review was carried out to evaluate whether the use of N acetylcysteine to improve lung function in patients with cystic fibrosis is supported by published evidence. Medline and the Cochrane Library were searched and the reference lists of all retrieved papers and of relevant chapters of three major textbooks were scanned. Data on lung function (forced expiratory volume in one second (FEV1)) were extracted from controlled clinical trials and pooled as weighted mean differences for analysis. Twenty-three studies, mostly uncontrolled clinical observations, were retrieved. Only three randomized controlled clinical trials on nebulized N-acetylcysteine in cystic fibrosis were found, not showing any beneficial effect on lung function. Six randomized controlled clinical trials on oral N-acetylcysteine in cystic fibrosis were found, with a total number of 181 patients. There was a tendency towards a beneficial effect on lung function of oral N-acetylcysteine therapy on FEV1 but it was small (2.3%, 95% CI from ( 0.3 to 4.9% of predicted) and of doubtful clinical relevance. In all studies, follow-up was 3 months or shorter. In conclusion, at present there is no evidence supporting the use of N-acetylcysteine in cystic fibrosis, although a beneficial effect with long-term use of N-acetylcysteine in cystic fibrosis cannot be excluded. PMID- 10090546 TI - Prophylactic intermittent treatment with inhaled corticosteroids of asthma exacerbations due to airway infections in toddlers. AB - The aim of this study was to investigate whether budesonide, for 10 d, administered at the first sign of an upper respiratory tract infection, could reduce asthma symptoms in 1-3-y-old children with asthma during infections. The primary efficacy variable was symptom scores. The study had a multicentre, randomized, double-blind, placebo-controlled design with parallel groups. Fifty five children with a mean age of 26 months received either budesonide or placebo via a spacer with a facemask. Each child was monitored for 1 y. Budesonide was given 400 microg q.i.d. for the first 3 d and b.i.d. for 7 d. Symptoms (cough, wheeze, noisy breathing and breathlessness) were scored (0-3) daily by the parents. Asthma symptom scores were lower in children treated with budesonide than in those given placebo. The effect was most pronounced for cough and noisy breathing, but it did not affect the need for hospital care. In conclusion, treatment with budesonide, started at the first sign of a respiratory infection, reduced asthma symptoms in toddlers with episodic asthma. PMID- 10090548 TI - Frequency of fever episodes related to febrile seizure recurrence. AB - The aim of this study was to assess the number of fever episodes as a risk factor for febrile seizure recurrence during the first 6 months after the last previous febrile seizure. In a 6-month follow-up study of 155 children, aged 3 months to 5 y, with a first or a recurrent febrile seizure, the occurrence of fever episodes and febrile seizure recurrences was prospectively documented. Using logistic regression analysis the association between the baseline characteristics and the number of fever episodes and the outcome, a febrile seizure recurrence, was studied. In total, 260 fever episodes were registered; 29 children experienced 1 or more febrile seizure recurrence during follow-up. Two factors were associated with febrile seizure recurrence: the number of fever episodes [odds ratio (OR)= 1.8; 95% confidence interval (CI): 1.4-2.4)] and age at study entry (OR=0.6; 95% CI: 0.3-1.1). In a multivariable model, only the number of fever episodes remained significant. In conclusion, the number of fever episodes increases the risk of a febrile seizure recurrence with a factor of 1.8 per fever episode in the first 6 months after a febrile seizure. PMID- 10090547 TI - Systemic effects of a short course of betamethasone compared with high-dose inhaled budesonide in early childhood asthma. AB - Forty children aged 1-3 y completed a placebo-controlled study on the effects of 10 d of inhaled budesonide for asthma caused by respiratory tract infection. The effects on symptoms were significantly better in the active than in the placebo group. In 20 of these children the systemic effects of high-dose inhaled budesonide for 10 d and the effect of a 3-d course of oral betamethasone on asthma exacerbation were evaluated. Systemic effects were evaluated by measuring morning cortisol in serum and urine, and the bone markers osteocalcin, ICTP (the C-terminal telopeptide region of type I collagen) and PIIINP (an N-terminal propeptide of type III procollagen) in serum before and at the end (d 7-10) of treatment (1600 microg budesonide d(-1) for 3 d and 800 microg for 7 d). In 9 children, measurements were taken on d 3 of a 3-d course of betamethasone (6, 4 and 2 mg) for asthma exacerbation and 14 d later. There were no signs of systemic effects after 7-10 d of budesonide. After 3 d of betamethasone, serum cortisol decreased from a median of 263 to 26 nmol l(-1), urine cortisol/creatinine from 19.9 to 7.2 nmol l(-1), osteocalcin from 31.4 to 5.5 microg l(-1), ICTP from 19.4 to 8.5 microg l(-1) and PIIINP from 12.3 to 5.9 microg l(-1). Two weeks later, the levels were back to normal. In conclusion, short courses of oral betamethasone have pronounced systemic effects, whereas 10 d of high doses of budesonide do not produce significant systemic effects. PMID- 10090549 TI - Growth and weight gain in children with vesicoureteral reflux receiving medical versus surgical treatment: 10-year results of a prospective, randomized study. International Reflux Study in Children (European Branch). AB - In children with vesicoureteral reflux (VUR) and urinary tract infection, retardation of growth and weight gain at the time of diagnosis and catch-up growth during follow-up, mostly after operating for VUR, have been reported. A controlled trial comparing the effect on growth of surgical treatment and long term prophylactic antibiotic treatment has not been reported previously. Between 1980 and 1985, 306 children younger than 11 y with non-obstructive grade III or IV VUR, with a history of symptomatic urinary tract infection, were randomly allocated to surgical or medical treatment. Of these, 236 were followed for 10 y, 118 randomized to surgical treatment (mean age at entry 3.5 +/- 2.3 y) and 118 to medical treatment (mean age at entry 3.8 +/- 2.5 y). All children had renal function and blood pressure in the normal range. Body height, measured at start and after 1, 5 and 10 y, was transformed to standard deviation score of height for chronological age (SDSH-CA) and body weight to percentage of ideal body weight for height (%IBW). The evolution of SDSH-CA and %IBW was similar in both treatment groups (SDSH-CA: surgical: start, 0.23 +/- 1.4; 10 y, 0.40 +/- 1.0; medical: start, 0.14 +/- 1.2; 10 y, 0.44 +/- 1.2; %IBW: surgical: start, 99 +/- 9%; 10 y, 107 +/- 14%; medical: start, 98 +/- 10%; 10 y, 105 +/- 16%). While children starting the study below the age of 3 y (SDSH-CA 0.55 +/- 1.34) started significantly taller than those older than 3 y (SDSH-CA -0.1 +/- 1.39), the young ones demonstrated a significant drop in SDSH-CA during the 1st year (SDSH-CA 0.19 +/- 1.23), which was regained up to the 10th year (SDSH-CA 0.6 +/- 1.13), and the older ones steadily gained height up to an SDSH-CA of 0.28 +/- 1.05 at 10 y. During all of the study period, treatment protocol, grade of VUR, renal parenchymal scars at entrance and urinary tract infections did not influence growth and weight gain. Age at entry and gender were the only significant correlates with growth and weight gain. PMID- 10090550 TI - Short stature in Duchenne muscular dystrophy: a study of 34 patients. AB - In Duchenne muscular dystrophy (DMD), short stature is a feature of unknown cause. This cross-sectional study of 34 male patients (mean age 8.0 y, age range 1.2-13.7 y) was conducted to examine the relationship between auxological parameters, markers of growth and the extent of muscular weakness. Weight and length at birth (SDS +/- SD; 0.0 +/- 1.2; 0.2 +/- 1.5) and target height SDS ( 0.2 +/- 0.7) were normal. Height (HT) SDS (-1.0 +/- 1.1) was lower than the normal population (p < 0.001) and did not correlate with age. Body mass index SDS (-0.1 +/- 1.6) was normal. Tests of insulin-like growth factor-I SDS (-0.6 +/- 1.2) and insulin-like growth factor binding protein-3 SDS (0.1 +/- 1.3) ruled out a severe derangement in the GH-IGF-axis. The carboxy-terminal propeptide of type I procollagen (PICP) SDS (0.6 +/- 1.5) was normal, but bone-specific alkaline phosphatase (BAP) SDS (-1.7 +/- 0.8) was low (p <0.001). HT SDS did not correlate with BAP SDS. The Vignos scale, a grading of muscular function (score: 0 = unaffected; 11 = confined to bed) (median (range): 3 (0-9)) correlated strongly with age (r = 0.77, p < 0.0001), but did not correlate with HT SDS, PICP SDS or BAP SDS. In conclusion, DMD patients are significantly shorter than the normal population, though the HT SDS does not change with age. Growth hormone deficiency does not seem to be the cause of short stature in DMD. Significantly low BAP levels are probably the result of the reduced muscle mass, which leads to a lower biomechanical load on the bone and thus a reduction in bone turnover. The short stature observed in our study is unlikely to be the result of muscular weakness. PMID- 10090551 TI - Air transport of the sick newborn infant: audit from a sparsely populated county in Norway. AB - The aim of this study was to describe principal problems and to analyse transport times, stabilizing procedures, adverse events during transfer, outcome, effectiveness and the care of infants transferred by air from district general hospitals and maternity homes to a central hospital. Transfer times, equipment adverse events and clinical deterioration were recorded as they occurred. Data regarding clinical problems, diagnoses and outcome were collected retrospectively from hospital records. During the study period (1984-95) 275 infants (267 transports) were transferred by fixed-wing aircraft (233) or helicopter (34). Median time from request of transfer to arrival of the transport team (usually a neonatal nurse and a paediatrician) was 120 min, median stabilizing time 60 min. Ninety-six infants (35%) were intubated, 62 (22.5%) by the transport team. During 34 transports (12.7%), equipment-related adverse events occurred making six infants worse. Ten more infants deteriorated during transit. A significant correlation between birthweight and after-transfer temperature was recorded. After-transfer temperature for very low birthweight (<1500 g, VLBW) infants was significantly higher when the transport team attended the delivery than when they did not (35.9 degrees C vs 34.7 degrees C). All nine infants (3.2%) with after transfer temperature <34.0 degrees C died, 15 infants (5.5%) died within 24 h after transfer and 20 (7.3%) died later. Adjusted OR for death among transported versus in utero transferred VLBW infants was 3.8 (1.4-10.4). Every effort should be taken to transfer VLBW infants in utero. If preterm deliveries at 26-28 weeks of gestation at district general hospitals is unavoidable, an early request for the neonatal transport team to be there at delivery is advisable. Transport of very immature infants <26 weeks gestational age is not recommended. An outreach educational program ("Team Pink Newborn") has been created. Staff training to combat hypothermia and regular inspection and control of the transport equipment by three neonatal intensive care nurses has now been implemented. PMID- 10090552 TI - Hospital policies and their influence on newborn body weight. AB - On the basis of data collected in a survey of the practices in maternity wards in Poland, we analysed newborn body weight differences between two groups of hospitals: one with the highest percentage of exclusive breastfeeding and other supportive practices, the other with the lowest. The aim of the study was to investigate whether hospital procedures can influence the newborn weight profile in the first days after birth. Healthy infants--normal birth, birthweight > or = 2500 g, discharged within 2-7 days, no missing data--were chosen for the analyses. The difference between discharge and birthweight, percentage of birthweight loss or gain on the day of discharge and percentage of the infants who at least regain birthweight on the day of discharge were compared between the two groups of hospitals. All analyses indicated the positive influence of exclusive breastfeeding and practices supporting it on infant body weight profile while in hospital. PMID- 10090553 TI - Inappropriately high plasma insulin levels in suspected perinatal asphyxia. AB - The aim of this study was to determine differences in levels of the major hormones responsible for glucose homeostasis (insulin and glucagon) in babies with acute neonatal encephalopathy secondary to perinatal asphyxia and to correlate these with outcome. In a prospective observational study, plasma insulin, C-peptide, glucagon and serum glucose levels were determined using standard techniques at specified times in term babies with a diagnosis on admission of perinatal asphyxia or acute neonatal encephalopathy. The setting comprised two university-affiliated, regional, tertiary level neonatal intensive care units. Thirty-one babies with a diagnosis of perinatal asphyxia or acute neonatal encephalopathy were entered into the study over 15 months and neurodevelopmental outcomes at 18 months of age for 28 babies were available for analysis. Babies with a poor neurodevelopmental outcome had significantly higher insulin and C-peptide levels than those who had a good outcome. Glucose delivery, serum glucose and glucagon levels did not differ significantly between the babies with a poor outcome and those with a good outcome. In conclusion, babies with significant foetal or neonatal asphyxia frequently have inappropriately high plasma insulin levels. This, either alone or in combination with other hormonal disturbances, may lead to the hypoglycaemia often associated with severe asphyxia and may predict a poor outcome. PMID- 10090554 TI - Effect of the cyclo-oxygenase blocker ibuprofen on cerebral blood volume and cerebral blood flow during normocarbia and hypercarbia in newborn piglets. AB - Indomethacin modifies baseline cerebral haemodynamics and metabolism, as well as vasomotor adaptive responses. However, the significance of arachidonic acid metabolites in the regulation of cerebral circulation remains unclear. A study was made of the effect of inhibition of the cyclo-oxygenase pathway on baseline cerebral haemodynamics and CO2-induced vasodilation using the more specific cyclo oxygenase blocker ibuprofen in a neonatal pig model. Two methods were used: radiolabelled microspheres to measure cerebral blood flow and near infrared spectroscopy to calculate absolute changes in cerebral blood volume. The relationship between CO2-induced changes in these two haemodynamic parameters was evaluated. Fifteen newborn piglets <7 d old received an i.v. infusion of either ibuprofen (30 mg/kg) (IB group, n = 8) or saline (control group, n = 7). Cerebral blood flow and absolute changes in cerebral blood volume were measured while the piglets were breathing room air at baseline and 30 min after infusion of ibuprofen or saline, and 15 min and 30 min after inducing hypercarbia. Global and regional cerebral blood flow (ml/hg/min) and absolute changes in cerebral blood volume (ml/hg) did not vary between baseline and 30 min after infusion of ibuprofen or saline. During hypercarbia, global and regional cerebral blood flow and absolute changes in cerebral blood volume increased significantly in both the ibuprofen and control groups (p < 0.01). The mean percentage increases in blood flow and blood volume at each measurement were almost identical, with approximately 90% of the increase in both parameters occurring after 15 min of hypercarbia, then reaching a plateau. However, we found no agreement between cerebral blood flow changes and absolute changes in cerebral blood volume. We conclude that ibuprofen did not alter either baseline cerebral circulation or physiological CO2-induced vasodilation in newborn pigs. We speculate that hypercarbic cerebral vasodilation could be caused either by mediators other than the cyclo-oxygenase metabolites of arachidonic acid or by a direct effect on vessel walls. PMID- 10090555 TI - Nebulization of drugs in a nasal CPAP system. AB - Aerosolized drugs have been used in infants for the treatment of respiratory distress syndrome and bronchopulmonary dysplasia (beta-agonists, steroids and surfactant) and bronchiolitis due to respiratory syncytial virus (epinephrine and ribavirin). Controlled clinical trials have, however, produced conflicting results, probably due in part to problems with the transportation of the aerosol from the nebulizer to the bronchioli. We have modified a nasal continuous positive airway pressure (CPAP) system permitting an aerosol to flow through a canal to the nasal prongs and into the airways of the infant. It has been used successfully for the administration of epinephrine, salbutamol, budesonide, acetylcysteine, natural surfactant and ribavirin to sick infants. The modified nasal CPAP system is a simple, safe, cost-efficient and baby-friendly system for respiratory support and drug treatment, which can be used in future trials of aerosolized drugs. PMID- 10090556 TI - Diffuse neonatal haemangiomatosis: new views on diagnostic criteria and prognosis. AB - Diffuse neonatal haemangiomatosis (DNH) is a rare and life-threatening congenital disorder. An extensive retrospective analysis of the literature was performed to evaluate the clinical features, therapies and prognostic factors of DNH. Reports on 68 patients with DNH were obtained. The skin, liver, lungs, brain and intestine were the organs most commonly involved. Congestive heart failure (CHF) was the primary cause of death. The mortality rate was 77.4% in untreated patients and 27% in treated patients. CHF, Kasabach-Merritt syndrome (KMS) and the involvement of five or more organs were important risk factors in DNH. The measurement of cardiac output might give more insight into the potential prognostic value of total blood-volume loss through shunting in the haemangiomas. Reports on 64 patients with neonatal haemangiomatosis limited to only the skin and liver were also obtained. The clinical features and outcome of patients with only cutaneous and hepatic haemangiomas were similar to those of patients with DNH. The inclusion criteria for DNH should be expanded to include similar patients with only cutaneous and hepatic haemangiomas. PMID- 10090557 TI - Clinical, pathological and molecular genetic findings in a case of neonatal Marfan syndrome. AB - An infant with neonatal Marfan syndrome is described who presented with arachnodactyly, distinctive dysmorphic features and prolapse of both atrioventricular valves and dilatation of both the aortic and pulmonary root. She died in cardiac failure shortly after pacemaker implantation, due to dysrhythmia and severe mitral insufficiency. At autopsy, apart from myxomatous changes of the valves and dilated aortic and pulmonary roots, an aneurysm of the sinus of Valsalva of the pulmonary valve and abnormal myxomatous connective tissue surrounding the AV node were also found. Molecular genetic studies showed a point mutation in the fibrillin 1 gene that creates a new N-glycosylation site, which has been described once before. PMID- 10090558 TI - Serum cholesterol in infants fed with an anti-regurgitation milk formula containing bean gum. PMID- 10090559 TI - Leptin correlates with the skinfold thickness in prepubertal and pubertal girls. PMID- 10090560 TI - Clinical significance of Gaucher cells in cerebrospinal fluid. PMID- 10090561 TI - Epidermolysis bullosa and pyloric atresia. PMID- 10090562 TI - European Consensus Statement on Neonatal Hearing Screening. Finalized at the European Consensus Development Conference on Neonatal Hearing Screening. Milan, 15-16 May 1998. PMID- 10090563 TI - Ovarian follicular dynamics in suckled zebu (Bos indicus) cows monitored by real time ultrasonography. AB - The pattern of follicular growth was studied in 17 suckled zebu cows with average body condition and under extensive management in a tropical environment (23 degrees C, 78% humidity; 2200 mm annual rainfall; 1000 m altitude). The study covered the period from parturition to weaning at 12 months postpartum (PP). Data were collected by transrectal ultrasonography (7.5 MHz) at 48 h intervals, and progesterone (P4) measurements were performed by RIA. The sequential development of ovarian follicles greater than 4 mm was followed until regression or ovulation. Ovarian activity as characterized by growth and regression of follicles of 4 to 6 mm, with sporadic dominance, and a long interdominance interval was observed in every cow and from as early as 26 +/- 2 days PP. This follicular pattern was highly variable during the first 6 months: cows presented 2 to 20 follicular waves (FW) in which a dominant follicle (DF) grew to 8 +/- 1 mm with daily growth rates of 1.1 +/- 0.5 mm/day. The duration of dominance varied from 2 to 8 days and the interdominance time interval was 0 (overlapped waves) to 60 days. Neither behavioural oestrus nor ovulation was observed during this period. From 6 to 12 months PP, cows presented 7 to 20 FW, some with ovulation and/or corpora lutea (CL) formation. The ovulation was preceded by oestrus in some cases (43%). The mean (+/- sem) diameter of DF was 9 +/- 2.7 mm, their mean growth rate 1.4 +/- 0.2 mm/day, their duration of dominance was 2 to 8 days and the interdominance interval was 0 to 14 days. Progesterone concentrations (P4) from 1.0 to 13 ng/ml were found when a CL was present. Once cyclicity re-commenced at 217 to 278 days PP, the cows presented either normal (21 +/- 3 days), short (10 +/- 2 days), or long (50 +/- 4 days) cycles. The resumption of cyclicity was characterized by an increased frequency of emerging follicular waves. Under the conditions of this study, the suckled Bos indicus cows re-commenced ovarian follicular activity as early as described in B. taurus breeds, but the establishment of cyclicity was substantially later. These data add further to the panorama of postpartum reproductive physiology in tropical cattle. PMID- 10090564 TI - Fertility of beef cattle females with mating stimuli around insemination. AB - An experiment was conducted to test the hypothesis that sterile mounts around insemination improves pregnancy rate to artificial insemination (AI) and to define the effects of age, season, time to complete AI and time of day of insemination. A total of 178 Simbrah females were randomly assigned by calving date and body condition to one of three treatments during two consecutive years: (1) mating stimuli with a sterile bull at the time the cows were detected in estrus; (2) mating stimuli immediately after completing AI; (3) without mating stimuli. All cows and heifers were maintained under the same conditions of handling and feeding within the two breeding seasons (winter 1995 and summer 1996). Vasectomized bulls were used for the sterile mounts. Cows and heifers that were given a sterile mount at the time of detection of estrus, had an increased pregnancy rate (60.0%) compared with females given a sterile mount after completing AI (25.4%) or females without the sterile mount (35.6%) (P < 0.01). Age, season, time to complete AI and time of day of AI were all non-significant (P > 0.05). Therefore, there is a biostimulatory effect of mating at the time beef cattle females are detected in estrus, on pregnancy rates to AI. PMID- 10090565 TI - Evaluation of the effects of different trypsin treatments on semen quality after BHV-1 inactivation, and a comparison of the results before and after freezing, assessed by a computer image analyzer. AB - Semen infected experimentally with infectious bovine rhinotracheitis virus (BHV 1) was treated with trypsin at concentrations of 0.30%, 0.25% and 0.15%, with or without (w or w/o) trypsin inhibitor in order to render the semen virus free. The trypsin treatments (at 0.30% and 0.25% by concentration) inactivating the virus up to 10(4) TCID50/ml, and its effects on semen quality were assessed weekly from the 1st to 20th week after being frozen. The following parameters were determined using a computerized semen analysis system (Hamilton Thorn motility analyzer, HTM): total motility, progressive motility and linearity of sperm cells. The results showed that the total and progressive motility of sperm cells were reduced in frozen/thawed semen, principally in the semen treated with trypsin at concentrations of 0.30%. Moreover, the plasma membranes were damaged by trypsin treatments (0.30% by concentration), as determined by the hypoosmotic swelling test (HOS test). These findings suggest that trypsin treatments were effective against the virus however the effects on semen quality and the possibility of a decrease in semen fertility were clear. Trypsin treatment could be recommended at a maximum concentration of 0.25% (w/o trypsin inhibitor) on semen with a high concentration and high motility values of spermatozoa before freezing. PMID- 10090566 TI - Effects of bull exposure on postpartum ovarian activity of dairy cows. AB - The effects of bull exposure on postpartum reproduction have been previously studied in beef, but not in dairy cattle. The objective of this experiment was to investigate effects of bull exposure on postpartum reproductive characteristics during early lactation in high-producing Holstein dairy cattle. Forty-five multiparous dairy cows (9764 +/- 140 kg milk/lactation) were randomly grouped at the time of calving. Treatment 1 (NBE) was never exposed to the bull, treatment 2 (2 x BE) experienced fenceline contact with a mature Holstein bull twice daily during routine detection of oestrus, and treatment 3 (CBE) was in continuous proximity to the bull. All cows were observed for oestrous behaviour twice daily for 1/2 h following milking. Blood samples were collected every other day for progesterone (P4) assay. Postpartum ovarian reactivation, indicated by the occurrence of the first sustained rise in P4, was later (P = 0.02) during the postpartum period in both bull-exposed (2 x BE, CBE) treatments compared to the NBE treatment. Time postpartum until completion of the first ovarian cycle tended (P = 0.08) to be shorter in NBE cows compared to bull-exposed cows. Peak P4 concentrations were higher (P = 0.05) in NBE cows compared to bull-exposed cows prior to the second postpartum ovulation. Results indicate an extended period to ovarian reactivation in dairy cattle exposed to a bull, but bull exposure had no effect on long-term reproductive performance of exposed cows. PMID- 10090567 TI - Plasma progesterone in alpaca (Lama pacos) during pregnancy, parturition and early postpartum. AB - Plasma progesterone concentration during pregnancy and the early postpartum period was measured by radioimmunoassay in five alpacas (Lama pacos), of the Huacaya breed, whose pregnancy length had a mean of 344.8 +/- 4.4 days. Concentration of progesterone increased (P < 0.001) from low premating values (0.11 +/- 0.06 nmol/l) to greater values at 30 days of pregnancy (8.05 +/- 1.13 nmol/l) and remained high up to 2 months of pregnancy. A slight transitory decline was observed between 3 to 7 months. Concentration of plasma progesterone dropped markedly during the 72 h before parturition especially, at the day of parturition. PMID- 10090568 TI - Effects of medium containing heparin and theophylline on capacitation and metabolic enzyme activities of ejaculated spermatozoa from dogs with asthenozoospermia. AB - The percentages of motile sperm (%MO), hyperactivated sperm (%HA), and acrosome reacted sperm (%AR) of four beagle dogs with asthenozoospermia (AS) and five normal beagle dogs were determined during 7 h of incubation. The metabolic enzyme activities of the sperm was examined after 0 and 4 h of incubation. The sperm were incubated in canine capacitation medium (CCM) and CCM containing either 20 microg ml(-1) heparin (HE), 10 microg ml(-1) theophylline (TH) or 20 microg ml( 1) HE + 10 microg ml(-1) TH in glass tubes at 38 degrees C under 5% CO2 in air. The %HA and %AR were determined by counting the sperm exhibiting star-spin like movement and by the triple stain technique. The spermatozoa in HE + TH CCM were homogenized and centrifuged, and the metabolic activities of hexokinase, fructokinase, glucose-6-phosphodehydrogenase (G6PD), and pyruvate kinase in the sperm cytosol in the supernatant was measured with a spectrophotometer. The mean %MO and %HA values of both AS and normal dogs in the four types of CCM were highest in HE + TH CCM, with a mean %HA in HE + TH CCM of 78 +/- 5% (S.E.) after 7 h of incubation. However, there was little difference in %AR among the four types of CCM. The mean activities of the four enzymes in the sperm of AS dogs before incubation was significantly lower than in the sperm of normal dogs (P < 0.05, 0.01). However, after 4 h of incubation the activities of all enzymes in the sperm of both AS and normal dogs was clearly higher in HE + TH CCM than in the control CCM. These findings indicate that HE and TH in the medium are effective inactivating metabolic enzymes, maintaining longer sperm motility, and efficiently inducing HA even of the sperm of AS dogs. PMID- 10090569 TI - Comparison of in-situ hybridization, direct and indirect in-situ PCR as well as tyramide signal amplification for the detection of HPV. AB - One hundred paraffin-embedded cervical biopsy specimens were tested for the presence of human papilloma virus (HPV) by in situ hybridization (ISH), and by direct and indirect in situ PCR (IS-PCR) in order to evaluate the efficiency of the different in situ methods in detecting HPV infection. ISH was performed using either commercial DNA probes or a cocktail of 5'-digoxigenin labeled oligoprimers. The same were used for ISH during indirect IS-PCR. To enhance the sensitivity of ISH several polymers, i.e., polyvinyl alcohol (PVA), polyethylene glycol, and polyvinylpyrrolidone were added to the alkaline phosphatase nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate (NBT/BCIP) reaction. Furthermore, tyramide signal amplification (TSA) was tried for signal amplification. Those samples treated with PVA during the NBT/BCIP reaction did not show any signal amplification whereas those treated with TSA exhibited a dramatic increase in sensitivity with usually acceptable signal to noise ratios. Our results show that, regarding sensitivity, ISH with subsequent signal amplification by TSA can be used as an almost equivalent alternative to the more cumbersome IS-PCR on routinely processed tissue specimens. When considering reproducibility, it is superior to IS-PCR. PMID- 10090570 TI - Postnatal development of H+ ATPase (proton-pump)-rich cells in rat epididymis. AB - Active proton secretion and bicarbonate reabsorption by epithelial cells of the mammalian excurrent duct system maintains an acidic luminal pH that is involved in creating a suitable environment for sperm maturation and storage. Both an apical Na/H exchanger and an apical H+ ATPase have been implicated in luminal acidification. The H+ ATPase is located in apical and/or narrow cells in the caput epididymidis, and clear cells in the corpus and cauda epididymidis. As a step toward understanding the acute and chronic regulation of luminal acidification in excurrent ducts, we have followed the appearance of H+ ATPase rich cells in rat epididymis during postnatal development, using antibodies to subunits of the H+ ATPase. In addition, we performed double staining with antibodies against carbonic anhydrase type II (CAII). H+ ATPase-rich cells were already detectable 2 weeks after birth in all regions of the epididymis, and reached maximum numbers after 3-4 weeks. CAII-rich cells followed a similar developmental pattern. In adult rats, the number of H+ ATPase/CAII-positive cells in the cauda was on average more than double the number in the caput epididymidis, although considerable intertubule variability was seen in both regions. Double immunostaining showed that CAII and H+ ATPase were colocalized in the same cells in the caput and cauda, but H+ ATPase-rich cells in the corpus contained low levels of CAII. These results demonstrate that differentiated subpopulations of proton-secreting epithelial cells appear early during epididymal development, and that the induction of H+ ATPase in these cells occurs prior to sexual maturation. PMID- 10090571 TI - Identification of renal podocytes in multiple species: higher vertebrates are vimentin positive/lower vertebrates are desmin positive. AB - We sought to characterize podocytes in the kidneys of numerous species from amphibians to mammals because of the pivotal function of these cells in renal diseases. For this purpose, intermediate filament (IF) proteins of podocytes were examined by immunofluorescence microscopy using antibodies against vimentin, cytokeratins, and desmin. These staining patterns were then compared to those of parietal cells of Bowman's capsule and tubular cells of the first portion of the proximal tubule from the same sources. As a result, podocytes from mammals (rat, rabbit, dog, cow, and human) and birds (chicken) showed intense vimentin staining without exception, but rarely staining for cytokeratins or desmin. Parietal cells from all these animals were highly heterogeneous with respect to cytokeratin or vimentin staining. Of the tubular cells, only those from humans and chickens were reactive and then only with anti-cytokeratin antibodies. In the reptiles (Chrysemys scripta elegans, Chinemys reeveri, Elaphe quadrivirgata, and Anolis carolinensis), podocytes and other epithelial cells were positive for cytokeratins. Vimentin staining differed among the species, but was not characteristic for podocytes. Anti-desmin antibody reacted strongly only with podocytes from Anolis. In amphibians (Rana catesbeiana and Xenopus laevis), anti desmin antibody stained podocytes more intensely than any other cell. Cytokeratin and vimentin staining did not differentiate podocytes from the other cell types. These findings indicate that podocytes are characterized by intense vimentin staining in the higher vertebrates and by desmin staining in the lower vertebrates denoting potentially distinctive physiological functions of IF proteins in podocytes from each of these groups. PMID- 10090572 TI - Fiber type composition of four hindlimb muscles of adult Fisher 344 rats. AB - The limb and trunk muscles of adult rats express four myosin heavy chain (MHC) isoforms, one slow (MHCI) and three fast (MHCIIa, MHCIId, and MHCIIb). The distribution of these isoforms correlates with fiber types delineated using myofibrillar actomyosin adenosine triphosphatase (mATPase) histochemistry. For example, type I fibers express MHCI and fiber types IIA, IID, and IIB express MHCIIa, MHCIId, and MHC-IIb, respectively. Fibers containing only one MHC isoform have been termed "pure" fibers. Recent evidence suggests that a population of "hybrid" fibers exist in rat skeletal muscle which contain two MHC isoforms. The purpose of the present investigation was to document the entire range of histochemically defined "pure" and "hybrid" fiber types in untreated muscles of the young adult Fisher 344 rat hindlimb. The selected hindlimb muscles (soleus, tibialis anterior, extensor digitorum longus, and gastrocnemius muscles) were removed from 12 male rats and analyzed for muscle fiber type distribution, cross sectional area, and MHC content. Care was taken to delineate eight fiber types (I, IC, IIC, IIA, IIAD, IID, IIDB, and IIB) using refined histochemical techniques. Hybrid fibers were found to make up a considerable portion of the muscles examined (a range of 8.8-17.8% of the total). The deep red portion of the gastrocnemius muscle contained the largest number of hybrid fibers, most of which were the fast types IIAD (8.5+/-2.8%) and IIDB (5.2+/-2.3%). In conclusion, hybrid fibers make up a considerable portion of normal rat limb musculature and are an important population that should not be ignored. PMID- 10090573 TI - Expression of estrogen receptor-alpha in cells of the osteoclastic lineage. AB - Estrogen deficiency at the menopause is associated with an increased rate of bone loss and subsequent risk of skeletal fracture. Whilst cells of the osteoblastic lineage are known to express estrogen receptors, the presence of estrogen receptors in osteoclasts remains controversial. We have examined expression of the classic estrogen receptor, estrogen receptor-alpha (ERalpha), during osteoclast differentiation. In situ mRNA hybridisation with a digoxygenin labelled riboprobe to ERalpha mRNA, together with immunocytochemical analysis using a human ERalpha-specific monoclonal antibody demonstrated similar findings and confirmed the expression of ERalpha in chondroblasts and osteoblasts from human fetal bone and mineralising human bone marrow cultures. ERalpha expression was detected in human bone marrow cultures treated with 1,25(OH)2D3 and macrophage colony-stimulating factor and in macrophage cultures treated with 1,25(OH)2D3. However, in an in vitro model of human osteoclast formation, no ERalpha expression was observed in the osteoclasts that developed. The human preosteoclast TCG 51 cell line showed strong expression of ERalpha in contrast to the low levels observed in the more mature bone resorptive TCG 23 cell line. No expression was detectable in osteoclasts cultured from giant cell tumour of bone (GCTB) tissue or in osteoclasts in Pagetic, GCTB, or hyperparathyroid bone tissues. In conclusion, preosteoclasts express detectable levels of ERalpha, but osteoclast maturation and bone resorption is associated with loss of ERalpha expression. This indicates that ERalpha expression and regulation may play a role in osteoclast formation. PMID- 10090574 TI - A non-receptor-type protein phosphotyrosine phosphatase is enriched in secretory vesicles of glucagon - and pancreatic polypeptide - secreting cells of the endocrine pancreas. AB - The secretory vesicles of some cells of the islets of Langerhans of the pancreas contain high amounts of immunoreactive tyrosine phosphatase of the PTP1B/TCPTP subfamily. The cells are located in the peripheral parts of the islets and were identified as glucagon- and pancreatic polypeptide-forming cells. The tyrosine phosphatase is also enriched in some of the somatostatin-producing cells but is not elevated either in insulin-producing B-cells or in the exocrine pancreas. Virtually the same patterns were found in pancretic tissues of rats, guinea pigs, pigs, and mice. High levels of detergent-soluble tyrosine phosphatase were measured in the particular fraction of pancreatic islets with a substrate preferred by PTP1B/TCPTP-type protein tyrosine phosphatases. PMID- 10090575 TI - Regional expression of sulfatides in rat kidney: immunohistochemical staining by use of monospecific polyclonal antibodies. AB - Sulfatides are quantitatively prominent glycosphingolipids of rat kidney. In order to gain insight into their possible physiological significance in this organ, and their possible role in Heymann's nephritis, the main sulfatide components were localized immunohistochemically. The antibodies used recognized the sulfatides Sgal1, Stri1, Stri2, and Stet2a. Stri1 epitopes were expressed in the brush border of proximal tubuli, whereas Stri2-specific immuno staining was observed in cortical and medullar collecting ducts. Both Stri1 and Stri2 were also expressed by interstitial cells of the inner medulla. Stet2a was visualized in epithelia of the distal tubules of Henle's loop and the juxtaglomerular apparatus, including the macula densa. The mAb Sulph-I, that recognizes the SO3( )-3Galbeta or = 0.4) as well as 10 age- and sex-matched control subjects (10 eyes) were evaluated. FERGs were recorded from the macular region (9 degrees) in response to sinusoidal stimuli flickered at 32 Hz. Amplitude and phase angle of the Fourier-analyzed FERG fundamental component were measured. Fundus lesions were graded from color slides according to the Wisconsin age related maculopathy grading system . Fluorescein angiograms were evaluated by an image analysis technique to compute the area with pathological hyperfluorescence (associated with drusen and/or retinal pigment epithelial atrophy) within the macular (approximately 9 degrees x 9 degrees) region. RESULTS: Compared to control eyes, NE-AMD eyes had a reduction in the mean FERG amplitude (57% loss, P<0.001) with no phase changes. Amplitudes of individual affected eyes were negatively correlated with either the Wisconsin grading score (r = -0.63, P < 0.001) or the percentage area of pathological hyperfluorescence (r = -0.70, P<0.01). Eyes with minimal NE-AMD lesions (Wisconsin score < or = 6) and normal acuity had a lower mean amplitude (47% loss, P < 0.05) than that of control eyes. CONCLUSIONS: The results indicate that, in NE-AMD, the FERG is altered in parallel with the extent and severity of fundus lesions. However, a functional impairment of outer macular layers, which is detected by FERG losses, could precede morphological changes typical of more advanced disease. PMID- 10090582 TI - A new way of removing silicone oil from the surface of silicone intraocular lenses. AB - PURPOSE: This study was performed to ascertain the efficacy of Perfluorhexyl octan, C14F13H17 (F6H8), in dissolving silicone oil from the surface of silicone intraocular lenses. So far F6H8 is the only solvent of silicone oil that is tolerated by intraocular tissues. MATERIALS AND METHODS: Intraocular silicone lenses (Domilens) were examined after application of small droplets of silicone oil of two different viscosities (AdatoSIL-OL 1000 and 5000) followed by rinsing with F6H8. To allow distinction between silicone oil and F6H8 the silicone oil was stained. Microscopic examination was carried out under video control. RESULTS: One hundred microliters of AdatoSIL-OL 1000 could be easily removed with about 800 microl of F6H8; 50 microl of AdatoSIL-OL 5000 also disappeared after 800 microl of F6H8. A larger drop of the latter oil could not be removed even after application of 2 ml of F6H8. CONCLUSION: Silicone oil 1000 can be easily dissolved by F6H8, whereas silicone oil 5000 is more difficult to remove because of its higher viscosity. PMID- 10090583 TI - Pupillary light reflexes in patients with Leber's hereditary optic neuropathy. AB - BACKGROUND: According to a recent pupillographic study, patients with Leber's hereditary optic neuropathy (LHON) show the same pupillary behaviour as normals. Because this raises many questions concerning the real nature of LHON and challenges our concept of the afferent pupillary system, we tried to verify the results of this study. METHODS: Pupillary function was assessed in 34 normal subjects and 40 patients with LHON. Pupillary light reflexes were recorded by means of the Compact Integrated Pupillograph (CIP, AMTech). Under mesopic conditions 200-ms stimuli were presented at two different stimulus intensities. Latency, constriction amplitude and baseline diameter were defined automatically. Pupil light reflexes were compared between LHON patients and normals and between the better and the worse eye in 20 LHON patients with different visual acuities. RESULTS: For both stimuli there were significant differences in latency between LHON patients and controls. The latency of the pupil light reflex proved to be about 20 ms longer for LHON patients, and the amplitude was significantly smaller for the bright stimulus. Within LHON patients, the eyes with the worse visual acuity had a significantly smaller constriction amplitude than the eyes with the better visual acuity. CONCLUSION: The results of our study confirm that LHON really is an optic nerve disease and that the pupillary light reflexes are not normal. PMID- 10090584 TI - Immune-mediated retinopathy in a patient with stiff-man syndrome. AB - BACKGROUND: Stiff-man syndrome is a rare neurological disorder characterised by rigidity and violent spasms of the body musculature. In the majority of patients, presence of antibodies against glutamic acid decarboxylase (GAD), the enzyme synthesizing gamma-aminobutyric acid (GABA), suggests an autoimmune attack against GABA-ergic inhibitory neurons. We report a 32-year-old patient with stiff man syndrome and anti-GAD antibodies who developed subacute progressive loss of vision in the right eye, and in the left eye 18 months thereafter. METHODS: Ophthalmological work-up included electro-retinogram (ERG), visual evoked potentials (VEP) and fluorescein angiography. Antiretinal antibodies were investigated using an indirect immunofluorescence technique on frozen sections of macaque retina with patients serum and FITC-conjugated goat antihuman immunoglobulin. Staining with monoclonal anti-GAD65 antibodies and with serum from three healthy normals served as controls. RESULTS: Visual acuity of both eyes decreased to 0.16 within a span of 6 weeks. Perimetry revealed a central scotoma in the visual field of both eyes. VEP and flash ERG were progressively disturbed on the right eye. On the left eye, initially only pattern ERG and photopic responses were abnormal. Follow-up recordings revealed widespread pathology of photopic single and flicker responses. Immunofluorescence revealed strong reactivity of the inner plexiform layer and to a lesser extent staining of the outer plexiform layer at dilutions of 1:1000 with patients serum. The same retinal staining pattern was obtained with monoclonal anti-GAD65 antibodies. CONCLUSIONS: These findings suggest autoimmune retinopathy, mediated by anti GAD65 autoantibodies as the underlying cause of visual loss. PMID- 10090585 TI - Falsely elevated intraocular pressure due to increased central corneal thickness. AB - PURPOSE: To evaluate whether ocular hypertensive subjects have a higher central corneal thickness than other individuals. METHODS: In this prospective study, 48 subjects with ocular hypertension, 63 patients with open-angle glaucoma, 56 nonglaucomatous patients with diabetes mellitus, and 106 control subjects were evaluated. Corneal thickness was measured by ultrasound pachymetry, and intraocular pressure was determined by Goldmann applanation tonometry. RESULTS: Central corneal thickness was significantly higher in the ocular hypertensive subjects, mean +/- S.D., 592+/-39 microm, than in the patients with glaucoma (536+/-34 microm), the nonglaucomatous patients with diabetes mellitus (550+/-31 microm), and the normal subjects (545+/-33 microm), P<0.001. The three latter groups did not vary significantly in central corneal thickness, P>0.05. CONCLUSION: In some individuals with increased transcorneal measurements of intraocular pressure, the cornea is thicker than in subjects with normal intraocular pressure readings or patients with glaucoma. It suggests that in ocular hypertensive subjects, corneal pachymetry should be performed to rule out an abnormally thick cornea as a reason for falsely high measurements of intraocular pressure. PMID- 10090586 TI - The laboratory diagnosis of ocular Lyme borreliosis. AB - BACKGROUND: A study was carried out to evaluate indirect enzyme-linked immunosorbent assay (ELISA), immunoblot analysis, and polymerase chain reaction (PCR) in the diagnostic work-up of ocular Lyme borreliosis. METHODS: Twenty patients with ocular Lyme borreliosis were examined. IgG and IgM antibodies to Borrelia burgdorferi were measured by ELISA in serum, and in cerebrospinal fluid (CSF) when indicated, and immunoblot analysis of B. burgdorferi IgG antibodies in serum was performed. A nested PCR was used to detect a segment of a gene coding for B. burgdorferi endoflagellin. The samples used in PCR testing were serum and CSF and in isolated cases conjunctiva and vitreous. RESULTS: Seventeen patients had elevated Borrelia antibodies in serum or CSF by ELISA. Seven patients, including two with negative ELISA, had a positive immunoblot. Seven of the 13 patients in whom PCR was examined during clinically active disease had a positive PCR result. Immunoblot analysis gave a negative result from the sera of five PCR positive patients. CONCLUSIONS: For efficient diagnosis of ocular Lyme borreliosis, immunoblot analysis and PCR should be used in addition to ELISA. A positive PCR seems to be associated with a negative immunoblot. PMID- 10090587 TI - Human trabecular meshwork cells as a thyroid hormone target tissue: presence of functional thyroid hormone receptors. AB - PURPOSE: To determine whether human trabecular meshwork cells (HTM) are a potential target tissue for thyroid hormone (3,3',5-triiodothyronine, T3). METHODS: Cultured HTM were assayed for the presence of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs) by reverse-transcriptase polymerase chain reaction (RT-PCR) to detected TR and RXR mRNA, and by immunohistochemistry to detect nuclear TR and RXR proteins. Functionality of the TR was determined by analysis of 125I-T3 binding affinity and capacity in HTM nuclear extracts. Effects of T3 on modulation of hyaluronic acid (HA) levels in HTM were measured as a function of dose and duration of T3 administration. RESULTS: Analysis of RT PCR and immunohistochemistry demonstrated that cultured HTM expressed TRalpha1, TRalpha2, and TRbeta1 but not TRbeta2; and RXRalpha but not RXRbeta and RXRgamma isoforms. Saturation binding and analysis of 125I-T3 to HTM nuclear extracts revealed Kd of 57 pM. The number of T3 binding sites extrapolated from a Scatchard plot was 7.3 x 10(10)/microg of HTM nuclear protein extract. T3 supplementation reduced the concentration of HA in the cell medium by 32-43% compared to cells grown in the absence of T3. CONCLUSIONS: Cultured HTM express three TR isoforms and one RXR isoform, bind T3 with an affinity similar to that of TR in responsive cells, and modulate their HA production in response to T3. These findings indicate that the human trabecular meshwork tissue has the capacity to respond to thyroid hormones. PMID- 10090589 TI - Morphological study on cataractogenesis of the Nakano mouse lens. AB - BACKGROUND: Although some histopathological features on the Nakano mouse lens have been pointed out by a few investigators, there seem to have been no detailed studies on the sequential changes that occur. METHODS: We used the following two approaches: (1) Observation of the whole lens by dissection microscopy and (2) light and electron microscopic examination of the sectioned lens specimen. RESULTS: (1) The Nakano mouse lens showed sustained transparency up to 19 days after birth, fine opacity at the 20th day, and development of a mature cataract around the 30th day. In addition, although the Y-shaped posterior suture was normal at the 15th day, bending of the suture line appeared around the 19th day. (2) The cataractous lens revealed degeneration of the epithelial cells and adjacent anterior cortical fibers at the 10th day. Swelling of the anterior cortical fibers became prominent, and swelling of the posterior cortical fibers occurred by the 15th day. Upon separation of the suture around the 20th day, fine opacity occurred in the perinuclear zone, which extended to the anterior cortex and finally led to the formation of a mature cataract. CONCLUSIONS: These results indicate that epithelial degeneration is a major feature of cataract in the Nakano mouse, and the subsequent lens fiber swelling and posterior sutural separation are the underlying causes of the development of opacity. PMID- 10090588 TI - Growth of human fetal retinal pigment epithelium as microspheres. AB - BACKGROUND: The aim was to develop a three-dimensional cell culture system for human fetal retinal pigment epithelial (HFRPE) cells for in vitro cellular studies and for possible application in subretinal transplantation. METHODS: Pieces of freshly isolated HFRPE monolayer tissue were grown on crosslinked fibrinogen (CLF) films. The growth pattern and morphologic characteristics of the implanted tissue were studied using phase-contrast microscopy, photography, and light and electron microscopy. The cells were screened immunohistochemically for HLA-ABC, HLA-DR, ICAM-1, B7, and Cytokeratin. Cell proliferation was studied using 5-bromo-2-deoxyuridine incorporation. RESULTS: After attachment to CLF, HFRPE monolayer tissue formed small tumor-like formations, i.e. microspheres. HFRPE microspheres survived and proliferated in a floating state for at least 4 months. After attachment of the microspheres to the culture dish floor, formation of a confluent HFRPE cell monolayer with high proliferative activity was noted around the microspheres. HFRPE cells stained positive for HLA-ABC, ICAM-1, and cytokeratin and negative for B7 and HLA-DR. The microspheres could be easily detached from the dish and they were able to initiate similar growth after reattachment. CONCLUSION: HFRPE grown on CLF resemble a three-dimensional culture system with high yield of pure cells that can be useful for a wide variety of in vitro studies. Because of their adjustable size, spherical shape, and ability to initiate growth of cells with a high proliferative potential, HFRPE microspheres may be successfully utilized as a source of donor cells for subretinal transplantation. PMID- 10090590 TI - Multifocal fibrosclerosis presenting as Grave's orbitopathy. Bilateral exophthalmos associated with retroperitoneal and sellar fibrosis. AB - BACKGROUND: Multifocal fibrosclerosis (MF) is a rare disease that may be misdiagnosed as Graves' orbitopathy. The combination of localisations of MF presented here has not been reported before. CASE REPORT: A 44-year-old man was referred with progressive bilateral exophthalmos. CT of his chest and abdomen revealed an intrathoracic and retroperitoneal peri-aortal soft-tissue process with hydronephrosis. Histological examination of orbital masses showed a fibrous process with low inflammatory activity. Later the sella was found to be involved as well. A diagnosis of MF was made. CONCLUSION: MF should be considered in the differential diagnosis of bilateral exophthalmos. PMID- 10090591 TI - The Liverpool Delphi evaluation. PMID- 10090592 TI - Clearance, promiscuity, and the megalin morality. PMID- 10090593 TI - The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism. AB - The low-density lipoprotein receptor gene family encompasses a class of endocytic receptors that exhibit structural similarities to the low-density lipoprotein receptor. Members of this gene family are present in both vertebrate and nonvertebrate species. The identification of naturally occurring mutations and the application of gene targeting to inactivate receptor genes enabled us to develop animal models to investigate the consequences of individual receptor defects in vivo. Analysis of these animal models revealed exciting new functions of lipoprotein receptors not only in systemic clearance of lipoproteins but also in other important biological processes including reproduction, brain development. and adipositas. PMID- 10090594 TI - Loss of heterozygosity of APC and DCC tumor suppressor genes in human sporadic colon cancer. AB - We examined 36 cases of human sporadic colon carcinoma and corresponding normal tissue samples to evaluate loss of heterozygosity at the APC and DCC tumor suppressor genes loci using restriction fragment length polymorphism polymerase chain reaction and variable nucleotide tandem repeat analysis. Observed informativity was 83% for APC and 75% for DCC. DNA from 6 (20%) of 30 informative tumors exhibited loss of heterozygosity at the APC locus. Loss of heterozygosity at the DCC locus was observed in 7 (26%) of 27 informative tumor DNAs. Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression. PMID- 10090595 TI - T cell mediated immunotherapy for B cell lymphoma. AB - Increasing evidence suggests that chemotherapy does not cure the majority of patients with B cell non-Hodgkin's lymphoma (NHL). Therefore new treatment modalities are necessary. Immunotherapy of B cell lymphomas using monoclonal antibodies has been shown to be efficacious in murine model systems and also in patients. With the identification of tumor-specific antigens as targets for autologous T cells, T cell mediated immunity has been revived as an immunotherapeutic modality in B cell lymphomas. For B cell lymphomas the lymphoma specific idiotype can be used as a tumor-specific antigen to stimulate T cells. Alternatively, the malignant B cells can be modified to become efficient antigen presenting cells and present peptides from their own tumor-specific antigens to the autologous T cells. Here we discuss previous and currently explored immunotherapeutic strategies for B cell lymphoma. PMID- 10090596 TI - Chemotherapy of Chagas' disease: the how and the why. AB - Current developments in experimental chemotherapy of Chagas' disease are reviewed, in particular the demonstration that fourth-generation azole derivatives (inhibitors of sterol C14alpha demethylase), with particular selectivity against Trypanosoma cruzi and special pharmacokinetic properties, are capable of inducing radical parasitological cures in murine models of both acute and chronic disease. These are the first reports of parasitological cure of this disease in its chronic phase. We also discuss the relevance of etiological treatment in the clinical outcome of patients with chronic Chagas' disease. Although previous studies have suggested an important autoimmune component in the pathogenesis of this disease, recent results obtained using highly sensitive polymerase chain reaction based detection methods and detailed immunological characterization of the inflammatory process associated with chagasic cardiomyopathy indicate a positive correlation between tissue parasitism and the severity of cardiac pathological findings. Effective antiparasitic treatment can lead to regression of the inflammatory heart lesions and fibrosis in experimental animals and to stop the progression of the disease in humans. Taken together, these findings support the notion that the presence of the parasite is a necessary and sufficient condition for chagasic cardiomyopathy and confirm the importance of specific etiological treatment in the management of chronic chagasic patients. PMID- 10090597 TI - Angiotensin peptides and inducible transcription factors. AB - Transcription factors are DNA-binding proteins which are able to identify specific nucleotide sequences and by binding to them may regulate the expression of genes at the level of transcription. In addition to the general transcription factors, which are basically the same for each gene transcribed by eukaryotic RNA polymerase II, more than 100 specific transcription factors have been identified so far. These specific transcription factors regulate the expression patterns of various sets of inducible genes during growth and development and enable the adjustment of cells and tissues to environmental changes. Especially the AP-1 proteins have found increasing interest, since members of these families such as c-Fos and c-Jun seem to be involved in trophic changes in peripheral organs. Many studies have also used them as marker proteins for activated neurons in the central nervous system to identify functional pathways and connections between brain nuclei. The renin-angiotensin system is implicated both in the hormonal and the central regulation of blood pressure and volume homeostasis. By binding to their specific receptors angiotensin peptides, namely angiotensin (Ang) II, have also been reported to induce the expression of a variety of inducible transcription factors (ITF) of the AP-1 and other families in peripheral organs such as kidney and blood vessels and in specific brain regions. By activating ITF, transient ligand receptor signals are transformed into long-lasting genetic changes. While the Ang II induced expression of ITF in peripheral organs seems to be associated with trophism, the physiological significance of this expression in brain nuclei with their postmitotic cells is much less clear. This contribution reviews the Ang II induced ITF expression in various tissues and discusses the possible physiological and pathophysiological consequences of the resulting changes in genetic patterns. PMID- 10090598 TI - Cerebral blood-flow responses to induced hypotension and to CO2 inhalation in patients with major cerebral artery occlusive disease: a positron-emission tomography study. AB - Our aim was to study the relationship between cerebral blood flow (CBF) responses to induced hypotension and to CO2 inhalation in patients with occlusive disease of the carotid or middle cerebral arteries. In 13 patients (8 men, 5 women) aged 31-73 years (mean +/- 1 SD = 63.2 +/- 10.6), regional CBF values during the resting state (CBFrest), 7% CO2 inhalation (CBFhypercapnia), and hypotension induced by 10-20 microg/kg/min intravenous trimethaphan (CBFhypotension) were measured using positron-emission tomography (PET) with H2(15)O. The % CBF change during induced hypotension (% CBFhypotension) was defined as (CBFhypotension - CBFrest)/CBFrest multiplied by 100. The % CBF change during CO2 inhalation (% CBFhypercapnia) was defined as (CBFhypercapnia - CBFrest)/CBFrest/mm Hg arterial partial pressure of CO2 x 100. We defined symptomatic hemispheres as those with a stenotic or occlusive lesion with neurological symptoms or signs and asymptomatic hemispheres as those which had a similar lesion and/or were influenced by the collateral flow pattern without neurological symptoms. In the territory of the occlusive lesion, % CBFhypotension correlated significantly with % CBFhypercapnia (r = 0.793, P < 0.002) in the symptomatic hemispheres. In the brain regions in which trimethaphan did not induce a reduction in CBF. % CBFhypercapnia was 6.13 +/- 1.79. In those in which % CBFhypotension ranged from 0 to -5, from -5 to -10, and more than -10%, % CBFhypercapnia was 4.05 +/- 1.99, 3.21 +/- 1.17, and 1.73 +/- 1.61, respectively, with significant differences between each pair of groups. In the asymptomatic hemispheres, % CBFhypotension also correlated with % CBFhypercapnia (r = 0.979, P < 0.0001). Failure to maintain CBF during induced hypotension was associated with diminished cerebrovascular vasoreactivity to hypercapnia in patients with arterial disease. This may indicate that failure of autoregulation can be assessed by the CBF response to both induced hypotension and CO2 inhalation. From the technical point of view, estimation of the CO2 response may be useful for assessing failure of autoregulation. PMID- 10090599 TI - The cerebral intravascular enhancement sign is not specific: a contrast-enhanced MRI study. AB - The intravascular enhancement (IVE) sign, also known as the "arterial enhancement sign", is an abnormal finding in the brain on contrast-enhanced MRI studies. IVE has been described in arterial cerebrovascular disorders, most commonly in acute or subacute arterial ischemic infarcts. However, the specificity of this sign has not been established. We describe four patients with disorders other than arterial strokes in whom gadolinium-enhanced high-field (1.5 T) MRI suggested IVE. The conditions were herpes simplex viral encephalitis, idiopathic cerebellitis, pneumococcal meningitis, and superior sagittal sinus thrombosis with venous infarction. IVE in these cases may be due to multiple factors, including arterial, venous, perivascular, and leptomeningeal or sulcal contrast medium accumulation. Our observations suggest that arterial ischemia, previously described as the cardinal cause of IVE, probably does not explain all instances, and urge caution in interpreting this sign as a specific MRI manifestation of acute arterial infarction or ischemia. PMID- 10090600 TI - Demonstration of cerebral perfusion abnormalities in moyamoya disease using susceptibility perfusion- and diffusion-weighted MRI. AB - We describe the use of diffusion-weighted imaging and perfusion MRI using a contrast-medium bolus in the preoperative investigation for young man presenting with a cerebral ischaemic episode as a manifestation of moyamoya disease. PMID- 10090601 TI - Pitfalls in the use of spiral CT for identification of intracranial aneurysms. AB - We describe problems encountered in our first 136 patients, with 95 aneurysms, who underwent spiral CT for investigation of possible aneurysms involving the circle of Willis and adjacent major vessels, and who had surgical and/or angiographic confirmation. There were seven false-positive cases, of which the first three could be explained by operator inexperience. There were four false negatives, all small aneurysms; two were not seen because of operator error and two were hidden by an adjacent larger aneurysm. Clip artefacts prevented diagnostic studies in six of 21 postoperative studies. One aneurysm was outside the CT field of view, being on a pericallosal artery. One basilar artery tip aneurysm was excluded from the field of the CT study because of a planning error. Inspection of the axial source images is critical if the diagnosis of small or thrombosed aneurysms is to be made. Close attention to image acquisition and computer modelling is required to reduce errors in spiral CT angiography of intracranial aneurysms. PMID- 10090602 TI - Primary nerve-sheath tumours of the trigeminal nerve: clinical and MRI findings. AB - We reviewed the clinical and MRI findings in primary nerve-sheath tumours of the trigeminal nerve. We retrospectively reviewed the medical records, imaging and histological specimens of 10 patients with 11 primary tumours of the trigeminal nerve. We assessed whether tumour site, size, morphology or signal characteristics were related to symptoms and signs or histological findings. Histological proof was available for 8 of 11 tumours: six schwannomas and two plexiform neurofibromas. The other three tumours were thought to be schwannomas, because they were present in patients with neurofibromatosis type 2 and followed the course of the trigeminal nerve. Uncommon MRI appearances were observed in three schwannomas and included a large intratumoral haemorrhage, a mainly low signal appearance on T2-weighted images and a rim-enhancing, multicystic appearance. Only four of nine schwannomas caused trigeminal nerve symptoms, including two with large cystic components, one haemorrhagic and one solid tumor. Of the five schwannomas which did not cause any trigeminal nerve symptoms, two were large. Only one of the plexiform neurofibromas caused trigeminal nerve symptoms. Additional neurological symptoms and signs, not related to the trigeminal nerve, could be attributed to the location of the tumour in three patients. PMID- 10090603 TI - Characteristics of symptomatic chronic subdural haematomas on high-field MRI. AB - We studied the frequency of various features of the appearances on high-field MRI in symptomatic patients with chronic subdural haematomas (CSDH). The ability to predict recurrence after treatment with one burr-hole procedure using MRI was evaluated. A total of 40 patients with symptomatic CSDH underwent MRI at 1.5 T. All haematomas were evacuated within a few days of the MRI examination. Symptomatic CSDH were divided into five groups according to the MRI findings: group A (11 cases), isointense or low signal on T1- and low signal on T2-weighted images; group B (18 cases), high signal on T1- and low signal on T2-weighted images; group C (5 cases), high signal on both T1- and T2-weighting; group D (1 case), low signal on T1- and high signal on T2-weighted images; group E (5 cases), heterogeneous intensity on T1- and T2-weighting throughout the haematoma cavity. The mean interval between onset of symptoms and MRI for group A was 5.0 +/- 4.1 days, which was significantly shorter than that for group B (9.4 +/- 4.4 days, P < 0.02), group C (27.8 +/- 20 days, P < 0.005) or group E (17.8 +/- 12.2 days, P < 0.01). Recurrence was seen in three haematomas of group A and one of group B. Reoperation was most closely correlated with diffuse low signal on T2 weighted images but not with a multiloculated appearance. Low signal on T2 weighting was surprisingly high (72.5%) and the age of the haematomas as estimated on the MRI correlated well with the interval between the onset of symptoms and MRI. Our findings support the causative role of recurrent bleeding in the enlargement of CSDH. PMID- 10090604 TI - Constructive interference in steady-state 3D Fourier-transform MRI in the management of hydrocephalus and third ventriculostomy. AB - We describe the use of three-dimensional Fourier transform constructive imaging in the steady state (CISS) MRI in the assessment of patients with hydrocephalus. We have found it of value both as a diagnostic investigation and in the follow-up of patients treated by third ventriculostomy. PMID- 10090605 TI - Relative quantification of signal on T2-weighted images in the basal ganglia: limited value in differential diagnosis of patients with parkinsonism. AB - A reduction in signal in the basal ganglia on T2-weighted images is said to correlate with a poor response to L-DOPA and may help to identify patients with non-idiopathic parkinsonism. Our aim in this prospective study was to use the contrast-to-noise ratio of the MRI signal on T2-weighted images in various parts of the basal ganglia in 43 patients with de novo parkinsonism. Signal intensity measurements were compared to the response to the dopamine agonist apomorphine and dopamine-D2 receptor binding obtained by 3-iodo-6-methoxybenzamine single photon emission computed tomography (IBZM-SPECT). A reduced contrast-to-noise ratio in the putamen correlated significantly with a negative response to apomorphine and reduced striatal IBZM binding. No additional signal intensity measurement correlated with response to apomorphine or specific IBZM binding. However, there was a considerable overlap of contrast-to-noise ratios between patients with a positive or negative response to apomorphine or normal and reduced IBZM binding. We suggest that semiquantitative assessment of signal intensity in the putamen shows a significant reduction in patients with probably nonidiopathic parkinsonism compared with patients with probably idiopathic parkinsonism. However, this method does not exclude idiopathic parkinsonism in a given patient. PMID- 10090606 TI - Cryptococcus meningoencephalitis in AIDS: parenchymal and meningeal forms. AB - CT and MRI in one case of Cryptococcus neoformans infection showed contrast enhancing parenchymal lesions resembling granulomata or abscesses. After an initial phase without contrast enhancement, the full extent of the lesions was visible within 2 weeks of presentation. The enhancing masses were assumed to represent intracerebral cryptococcomas. Despite evidence of massive meningeal infection on cerebrospinal fluid (CSF) examination, no radiological signs of meningitis, invasion of the Virchow-Robin spaces or ventriculitis could be demonstrated. With antimycotic treatment the contrast enhancement disappeared and cystic, partly calcified lesions remained. Recurrence of meningeal infection without radiological correlates was apparent in this stage. In a second case of proven cryptococcus meningitis, dilation of Virchow-Robin spaces or cysts in the adjacent parenchyma were the main abnormalities on MRI. Enhancing masses were not detected. These cases may represent two different reactions of the immunocompromised hosts to infection with C. neoformans: widening of the perivascular spaces as a correlate of the more typical meningeal infection and enhancing parenchymal lesions as a sign of further invasion from the CSF spaces. Enhancement of cryptococcomas, indicating an inflammatory response in the surrounding brain, is not typical in patients with impairment of immune function. PMID- 10090607 TI - Leukoencephalopathy complicating an Ommaya reservoir and chemotherapy. AB - We describe the imaging findings in an unusual case of biopsy-proven, methotrexate-induced leukoencephalopathy complicating a malfunctioning Ommaya reservoir in a patient with lymphoma. PMID- 10090608 TI - Chronic spinal subdural haematoma associated with intracranial subdural haematoma: CT and MRI. AB - Chronic spinal subdural haematoma is a uncommon. We describe the CT and MRI appearances of chronic spinal and intracranial subdural haematomas following minor trauma. The aetiology, pathogenesis and differential diagnosis are discussed. PMID- 10090609 TI - Head and neck haemangiomas: contrast-enhanced three-dimensional MR angiography. AB - We evaluated the clinical effectiveness of contrast-enhanced three-dimensional (3D) magnetic resonance angiography (MRA) for diagnosing head and neck haemangiomas. We studied six patients using a magnetization prepared rapid acquisition gradient-echo (MP-RAGE) sequence on a 1.5-T system. Conventional T1- and T2-weighted and contrast-enhanced images were also obtained. The images were compared with histological findings. In four cavernous haemangiomas, a mass was partially visible as an enhancing lesion on the early phase of MRA, and was completely visible as a larger enhancing lesion in the late phase, showing slow blood flow. In two capillary haemangiomas, a mass was completely visible in the early phase showing fast flow. In all patients, MRA clearly showed both the haemangiomas and the external carotid artery branches. MRA allowed assessment of the relationship between the haemangiomas and the feeding arteries, and of the haemodynamics. PMID- 10090610 TI - Cerebral bleeding, infarcts, and presumed extrapontine myelinolysis in hypernatraemic dehydration. AB - The neuroimaging findings in an infant with hypernatremic dehydration are presented. Brain parenchymal haemorrhage and extensive multiple infarcts were present in the acute stage. Follow-up CT showed bilateral, symmetrical changes presumed to indicate extrapontine myelinolysis in the thalamus and globus pallidus. MRI confirmed sparing of the pons. Only three previous cases of neuroimaging abnormalities due to hypernatraemia have been described in the radiological literature. PMID- 10090611 TI - Differences in the recognition by CTL of peptides presented by the HLA-B*4402 and the HLA-B*4403 molecules which differ by a single amino acid. AB - The HLA-B*4402 and B*4403 molecules differ only at residue 156, which borders the peptide binding site. Strong in vivo allogeneic reactions mediated by cytolytic T lymphocytes (CTLs) were reported in patients who received a bone marrow graft mismatched for these B44 subtypes, indicating that HLA-B*4402 and B*4403 molecules present distinct antigens. This could be due either to the presentation of different sets of antigenic peptides or to the recognition by CTLs of conformational epitopes formed by the MHC molecules alone or in association with antigenic peptides. To address this question, we compared the two B44 subtypes in their presentation to tumor-specific CTLs of three peptides, encoded by genes MAGE-3, MUM-1 and Tyrosinase. The peptides bound with similar affinities to B*4402 or B*4403 molecules, as assessed by lytic competition assays. One HLA B*4402-restricted and one HLA-B*4403-restricted CTL clone were derived against each peptide. When tested for lysis of B*4402 and B*4403 cells incubated with the antigenic peptides, most CTLs showed a marked preference for one of the two B44 subtypes. Using variant peptides incorporating single alanine substitutions, we compared a given CTLs' recognition of its antigenic peptide presented by both B44 subtypes. Some substitutions, which had no effect on the binding of the peptide, affected its recognition by the same CTL differently on B*4402 and B*4403 molecules. These results imply that the conformations adopted by the same peptide on the two HLA-B44 subtypes are different. We conclude that the B44 subtype specificity of T cells results mostly from distinct conformations adopted by the same peptides in the two B44 molecules. This does not exclude the possibility that in some cases the B44 subtype specificity results from the selective binding of a peptide to one subtype. We found several peptides, different from the three mentioned above, that contain the canonical HLA-B44 binding motif and bind to B*4403 but not to B*4402 molecules. PMID- 10090612 TI - Rapid screening of T-cell receptor (TCR) variable gene usage by multiplex PCR: application for assessment of clonal composition. AB - The selection of various T-cell receptor (TCR) gene families and complex rearrangements during intra-thymic differentiation provide the basis for the expression of antigen specificity by mature T cells. TCR beta variable (TCRBV) transcripts can be identified by RT-PCR, but multiple reactions are required to detect all genes of the TCRBV subfamilies. We describe here a multiplex PCR method that amplifies 46 functional genes comparing 23 TCRBV families in 5 reactions where each reaction contains 4 to 7 specific primers together with a single fluorescence-tagged TCR beta constant region primer. Between 8 and 10 distinct subtypes within each of the 23 TCRBV families can be identified by analysis of the CDR3 length. Multiplex PCR products isolated from agarose gels can be subjected to direct sequencing for confirmation and definitive clonotyping if necessary. The data illustrated here show that the multiplex PCR technique is useful for screening TCRBV usage and can be easily adapted for analysis of clonal composition in T-cell populations. PMID- 10090613 TI - Linkage disequilibrium analysis of familial psoriasis: identification of multiple disease-associated MHC haplotypes. AB - Although psoriasis vulgaris (PsV) is strongly associated with certain human leukocyte antigens, the pathogenetic nature of these associations remains elusive. The objectives of this study were: (i) to determine whether HLA loci directly determine susceptibility or merely serve as markers for the susceptibility allele; and (ii) to identify additional disease-associated haplotypes. By applying maximum likelihood linkage disequilibrium analysis (LDA) in cases vs. controls, we found the susceptibility gene to be more strongly associated with specific HLA haplotypes than with their component alleles. Stronger linkage disequilibrium between PsV and HLA alleles was detected at HLA-C and HLA-B than at DRB1 and DQB1. Parametric linkage analysis accounting for marker-trait disequilibrium in psoriasis vulgaris pedigrees yielded most significant results for a locus close to HLA-B and -C. Furthermore, we found that susceptibility is linked to at least three different ancestral HLA haplotypes; among them, HLA-Cw7-B8-DRB1*0301-DQB1*02 is linked to PsV for the first time. These results identify a major PsV susceptibility locus in the immediate vicinity of, but distinct from HLA-B or HLA-C, and suggest that multiple disease alleles have arisen during human evolution. PMID- 10090615 TI - Evolutionary relationships between HLA-B alleles as indicated by an analysis of intron sequences. AB - The HLA-B locus is the most polymorphic of the class I genes encoded within the human major histocompatibility complex. This polymorphism is mainly located in exons 2 and 3, which code for the molecule's alpha1 and alpha2 domains and includes the antigenic peptide binding site. However, information about adjacent non-coding regions (introns 1 and 2) has not been extensively reported but could be very important in establishing an understanding of the evolutionary mechanisms involved in the polymorphism generation of HLA-B and the Mhc loci. In the present work, introns 1 and 2 of 14 HLA-B alleles are studied and their significance is discussed; 10 have been sequenced in our own laboratory and the other 4 have been previously reported by others. Different serological families share the complete intron 1 sequence; at this region, 12 out of 14 HLA-B alleles could be included in four groups with the same intron 1 sequence: a) B*0702, B*4201, B*4801; b) B*27052, B*4002, B*4011; c) B*40012, B*4101, including B*4501, B*5001 (these latter two alleles have specific characteristics in both introns 1 and 2, which may reflect a common evolutionary pathway); and d) B*44031, B*44032. The other alleles, B*1402, and B*1801, do not have identical intron 1 sequences compared to any of the described groups, but share many similarities with them. The B*1801 evolutionary pathway seems to be very specific since it branches separately from other alleles both in intron 1 and intron 2 dendrograms. On the other hand, HLA-B allelic group distribution and similarities according to intron 1 sequences were not confirmed when using intron 2, especially in the cases of B*4002, B*4101 and B*4801. This would suggest that both point mutations fixed by genetic drift and gene conversion events are involved in HLA-B diversification. The latter events could be supported by the strong homology between intron 1 and, to a lesser extent, intron 2, and also the CG content within them. Finally, the precise knowledge of these non-coding regions could be important for developing DNA base typing strategies for the HLA-B alleles. PMID- 10090614 TI - Significant association of HLA-B and HLA-DRB1 alleles with cleft lip with or without cleft palate. AB - Nucleotide sequence level typing of HLA-B, -DRB1, and -DPB1 alleles was performed on Japanese patients with cleft lip with or without cleft palate (CL/P). Two HLA B alleles, B*1501 and B*5101, showed a significant positive association with CL/P. The increase of B*1501 was evident in female patients (OR=3.6, Pc=0.003), whereas the increase of B*5101 was evident in male patients (OR=3.7, Pc < 0.001). One HLA-DRB1 allele, HLA-DRB1*0802 also showed an increase in CL/P patients. Conversely, HLA-B*4403 and DRB1*1302 were not observed in the patient group (Pc=0.01 and Pc=0.02, respectively). No HLA-DPB1 alleles showed significant association with CL/P. Thus, the present study indicates that HLA alleles, or closely linked loci, may be involved in the pathogenesis of CL/P. PMID- 10090616 TI - HLA-A*9, a probable secondary susceptibility marker to ankylosing spondylitis in Basque patients. AB - HLA-B27 is strongly associated to ankylosing spondylitis (AS). The objective of our study was to analyze HLA-B27 association, B27 subtype distribution and frequency of other HLA class I and DR antigens in a group of Basque AS patients. HLA class I antigens were typed serologically and HLA-B27 and A9 subtypes were determined by DNA typing in samples from 46 patients with AS, 54 B27-positive spondyloarthropathies, 82 healthy subjects and 20 B27-positive controls. A class I HLA 9.2 kb PvuII restriction fragment length polymorphism (RFLP), previously associated with AS, was analyzed in a representative group of patients and controls. We found that HLA-B*2705 conferred a relative risk of 126 for AS in this group. HLA-A9 (A*2402) allele was significantly increased in AS patients compared with healthy controls and B27-positive control group (Pcorr<0.0001) and also increased in patients affected with peripheral arthritis. No association between class I HLA 9.2 Kb RFLP and AS was found. These results suggest that HLA A*9 allele itself or another linked gene could act as a secondary and independent susceptibility allele to AS. PMID- 10090617 TI - Towards a molecular phototyping system for allelic variants of MICA, encoded by polymorphisms in exons 2, 3 and 4 of MHC class I chain-related genes. AB - In this study we have developed a polymerase chain reaction-sequence-specific primer (PCR-SSP) or phototyping system to analyse the polymorphism of the human MICA gene locus. By scrutinising the reported MICA sequence variations in exons 2, 3 and 4 which encode the extracellular protein domains, we have selected and tested 20 MICA-specific primer mixes that should discriminate between the majority of homozygous and heterozygous combinations of MICA alleles 001-016. We have tested this scheme on DNA prepared from a large number of well-characterised tissue culture cell lines with previously reported MICA nucleotide sequences and found an excellent correlation with the observed PCR-SSP phototypes. We believe that this scheme can also be modified to detect new MICA alleles when they are characterised, as well as be incorporated into standard phototyping protocols to generate allele and haplotype profiles of both classical and non-classical HLA gene loci in test DNA samples. PMID- 10090618 TI - Molecular typing for HLA class I using ARMS-PCR: further developments following the 12th International Histocompatibility Workshop. AB - Molecular typing for HLA class I was introduced in the 12th International Histocompatibility Workshop. Following a pilot study using three methods, sequence specific oligotyping (SSO), reverse dot blot and amplification refractory mutation system (ARMS)-PCR, the ARMS-PCR method was selected for use. A great advantage of an ARMS-PCR method is that, unlike the other two methods, it can determine whether sequence motifs are in cis or in trans, as ARMS-PCR detects two cis located motifs per reaction using forward and reverse sequence specific primers. Resolution was designed to be low to medium level for HLA-A, -B and -C alleles. Two hundred and fifty class I kits and 83 HLA-A2 subtyping kits were distributed. The A2 subtyping kit used a two round nested PCR system to identify all of the A2 alleles known at the time. Typing results on control DNA samples distributed with both the kits showed a very satisfactory performance. Since the 12th Workshop, the kits have been developed with the addition of new primers and primer mixes to increase the resolution of the test. PMID- 10090619 TI - DLA-DRB1 polymorphisms in dogs defined by sequence-specific oligonucleotide probes (SSOP). AB - To date, DNA sequences for 29 dog DLA-DRB1 alleles have been reported. However, no data exists on the frequencies of these alleles within the general dog population, nor is there any indication of whether there is interbreed variation of allele distribution. We have addressed this by establishing a molecular based sequence-specific oligonucleotide probing (SSOP) method to identify all of the known broad DRB1 types and we have used this to type a random panel of dogs. A series of oligonucleotide probes were designed to detect known polymorphisms in the three DRB1 hypervariable regions, together with two distinctive motifs in other regions of exon 2. This set of probes enabled us to assign broad DRB1 types. Two hundred and eighteen dogs were SSOP typed for DRB1. All but 4 of the published DLA-DRB1 alleles were identified in these animals. Interbreed variation in both allele distributions and allele frequencies were observed, which may be useful in the study of genetic variation between breeds. This variation also has implications for the selection of control groups for studies aimed at identifying MHC associations with disease susceptibility in the dog. PMID- 10090620 TI - Identification of HLA-A*0224: implications for PCR-SSP HLA typing. AB - We describe a novel HLA-A*02 allele, A*0224, that was identified after a comparison of DNA and serological typing revealed a discrepancy in the HLA-A types: HLA-A2 was defined by serology but was not detected by the polymerase chain reaction using sequence-specific primers (PCR-SSP). DNA sequencing indicated the presence of a variant HLA-A*02 allele that differed from A*0201 by a single base (C/A) at position 453. This base substitution corresponded to the annealing site of a primer common to the two A*02-amplifying PCR-SSP mixtures used in the method. This provides an explanation for the results and highlights a limitation of PCR-SSP methods even where two PCR mixtures are used to detect alleles. Serological titration studies suggested that A*0201, A*0205 and A*0224 are unlikely to be differentiated during routine serological typing. PMID- 10090621 TI - A novel HLA allele, HLA-B*5113, identified in the Kolla Amerindians of North-West Argentina. AB - A novel HLA-B51 allele, B*5113, was identified in a Kolla Amerindian individual from North-West Argentina. HLA-B*5113 differs from B*51011 by two nucleotide substitutions, one synonymous, the other nonsynonymous. The resulting amino acid difference at residue 116 in the HLA-B molecule's peptide binding site is likely to affect the nature of the peptides which bind to this molecule. The finding of this novel allele supports previous findings of increased diversity at HLA-B in Amerindian groups. PMID- 10090622 TI - Identification of a novel HLA-C allele, Cw*0406, in a Singapore Malay. AB - A novel allele, C*0406, has been identified and is characterised by a single nucleotide substitution at position 196 of exon 3 when compared with its closest related allele, C*0403. The latter is found in 4/69 Chinese and 7/80 Malays while Cw*0406 was found in only one Malay individual within the study populations. The data suggest that Cw*0406 may have arisen as a relatively recent genetic event either by gene conversion or as a simple point mutation variant of Cw*0403. PMID- 10090623 TI - Four new DP alleles identified in a study of 500 unrelated bone marrow donor recipient pairs. AB - HLA-DP genotyping of 500 donor recipient pairs in a retrospective analysis sponsored by the National Marrow Donor Program (NMDP) identified four new DP alleles, two DPB1 and two DPA1. DNA sequencing confirmed that DPB1*8001 and *8101, each found in a single individual, are novel combinations of previously described sequence motifs in the six variable regions of DPB1. DPA1*02014, found in two individuals, is identical to DPA1*02011 except for a novel silent substitution, a G to A transition at the third position of codon 14. DPA1*01032, found in one individual, is identical to DPB1*01031 except for a silent G to A transition at the third position of codon 20. The identification of these novel alleles brings the total number of reported DPB1 alleles to 85 and DPA1 alleles to 15. PMID- 10090624 TI - Nomenclature for factors of the HLA system, update October 1998. WHO Nomenclature Committee for Factors of the HLA System. PMID- 10090625 TI - Nomenclature for factors of the HLA system, update November 1998. WHO Nomenclature Committee for Factors of the HLA System. PMID- 10090626 TI - Nomenclature for factors of the HLA system, update December 1998. WHO Nomenclature Committee for Factors of the HLA System. PMID- 10090627 TI - Decreased exercise blood lactate concentrations after respiratory endurance training in humans. AB - For many years, it was believed that ventilation does not limit performance in healthy humans. Recently, however, it has been shown that inspiratory muscles can become fatigued during intense endurance exercise and decrease their exercise performance. Therefore, it is not surprising that respiratory endurance training can prolong intense constant-intensity cycling exercise. To investigate the effects of respiratory endurance training on blood lactate concentration and oxygen consumption (VO2) during exercise and their relationship to performance, 20 healthy, active subjects underwent 30 min of voluntary, isocapnic hyperpnoea 5 days a week, for 4 weeks. Respiratory endurance tests, as well as incremental and constant-intensity exercise tests on a cycle ergometer, were performed before and after the 4-week period. Respiratory endurance increased from 4.6 (SD 2.5) to 29.1 (SD 4.0) min (P < 0.001) and cycling endurance time was prolonged from 20.9 (SD 5.5) to 26.6 (SD 11.8) min (P < 0.01) after respiratory training. The VO2 did not change at any exercise intensity whereas blood lactate concentration was lower at the end of the incremental [10.4 (SD 2.1) vs 8.8 (SD 1.9) mmol x l(-1), P < 0.001] as well as at the end of the endurance exercise [10.4 (SD 3.6) vs 9.6 (SD 2.7) mmol x l(-1), P < 0.01] test after respiratory training. We speculate that the reduction in blood lactate concentration was most likely caused by an improved lactate uptake by the trained respiratory muscles. However, reduced exercise blood lactate concentrations per se are unlikely to explain the improved cycling performance after respiratory endurance training. PMID- 10090628 TI - Influence of vibration on mechanical power and electromyogram activity in human arm flexor muscles. AB - The aim of this study was to evaluate the influence of vibration on the mechanical properties of arm flexors. A group of 12 international level boxers, all members of the Italian national team, voluntarily participated in the experiment: all were engaged in regular boxing training. At the beginning of the study they were tested whilst performing forearm flexion with an extra load equal to 5% of the subjects' body mass. Following this. one arm was given the experimental treatment (E; mechanical vibration) and the other was the control (no treatment). The E treatment consisted of five repetitions lasting 1-min each of mechanical vibration applied during arm flexion in isometric conditions with 1 min rest between them. Further tests were performed 5 min immediately after the treatment on both limbs. The results showed statistically significant enhancement of the average power in the arm treated with vibrations. The root mean square electromyogram (EMGrms) had not changed following the treatment but, when divided by mechanical power, (P) as an index of neural efficiency, it showed statistically significant increases. It was concluded that mechanical vibrations enhanced muscle P and decreased the related EMG/P relationship in elite athletes. Moreover, the analysis of EMGrms recorded before the treatment and during the treatment itself showed an enormous increase in neural activity during vibration up to more than twice the baseline values. This would indicate that this type of treatment is able to stimulate the neuromuscular system more than other treatments used to improve neuromuscular properties. PMID- 10090629 TI - Adaptation of rat lateral gastrocnemius muscle motor units during hindlimb unloading. AB - Contractile and fatigue-resistance properties of 71 lateral gastrocnemius muscle (LG) motor units (MU) following 14 days of hindlimb unloading (HU) were compared to those of 60 LG MU from control rats. The MU properties were assessed from isolated and stimulated individual motor axons. The MU were classified using standard criteria (shape of unfused tetani and fatigue resistance). The HU did not affect LG MU composition, but diminished the maximal tetanic tension (Po) of all MU types: P0 was significantly reduced by about 40% for the slow and fast resistant MU, and by 18% for the fast-fatigable ones. The speed-related properties of fast-resistant MU became more similar to those of slower MU. The fatigue properties of MU were evaluated during a 5-min exercise test, using two fatigue indexes, FI2 and FI5, which expressed the relative capacity of MU to generate tension after 2 and 5 min, respectively. Results showed that 14 days of HU did not change the fatigue sensitivity of the LG MU. However, when F15 was compared to FI2, a greater decrease was observed after HU than in control conditions for the fast-resistant and fast-intermediate MU. It was concluded that a prolonged fatigue test may show changes in metabolic properties of muscle fibres during 14 days of HU. Specific adaptations of LG MU as well as comparisons with those of the soleus muscle under the same conditions are discussed. PMID- 10090630 TI - Effect of acute and chronic exercise on plasma amino acids and prolactin concentrations and on [3H]ketanserin binding to serotonin2A receptors on human platelets. AB - The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been shown to modulate various physiological and psychological functions such as fatigue. Altered regulation of the serotonergic system has been suggested to play a role in response to exercise stress. In the present study, the influence was investigated of acute endurance exercise and short-term increase in the amount of training on the concentrations of the 5-HT precursor tryptophan (TRP), of prolactin (PRL) and of branched-chain amino acids (BCAA) in the blood, as well as on the binding of [3H]ketanserin to the serotonin-2A (5-HT2A) receptors on platelets. Nine healthy endurance-trained men were tested the day before (I) and after (II) a 9-day training programme. Samples of venous blood were drawn after an overnight fast and following 5 h of cycling. Fasted and post-exercise plasma concentrations of free TRP, BCAA and free TRP:BCAA ratio did not differ between I and II. A significant decrease of plasma BCAA (P < 0.01) and significant augmentations of plasma free TRP, free TRP:BCAA ratio and PRL (P < 0.01) were found post-exercise. The increase in plasma PRL was smaller in II compared with I. Acute endurance exercise reduced the density of platelet 5-HT2A receptor [3H]ketanserin binding sites at I and II (P < 0.05). The basal density of the binding sites and the affinity of [3H]ketanserin for these binding sites were unaffected by an increase in the amount of training. The present results support the hypothesis that acute endurance exercise may increase 5-HT availability. This was reflected in the periphery by increased concentration of the 5-HT precursor free TRP, by increased plasma PRL concentration, and by a reduction of 5-HT2A receptors on platelets. It remains to be resolved whether these alterations in the periphery occur in parallel with an increase in the availability of 5-HT in the brain. PMID- 10090631 TI - Altered control of submaximal bite force during bruxism in humans. AB - The control of bite force during varying submaximal loads was examined in patients suffering from bruxism compared to healthy humans not showing these symptoms. The subjects raised a bar (preload) with their incisor teeth and held it between their upper and lower incisors using the minimal bite force required to keep the bar in a horizontal position. Further loading was added during the preload phase. A sham load was also used. Depending on the session, the teeth were loaded by the experimenter or the subject and in one session the subject did not see the load (no visual feedback). The bite force was measured continuously using a calibrated force transducer. In all the subjects, the bite force increased with increasing load. Following the addition of the load, the level of the tonic bite force was reached rapidly with no marked overshoot. The patients with bruxism used significantly higher bite forces to hold the submaximal loads compared to the control subjects. In the control subjects, the holding forces for each submaximal load were identical in the men and the women and were independent of subject maximal bite force. Sham loading evoked no marked responses in biting force. Whether the subject or the experimenter added the load or whether the subject had visual feedback or not were not significant factors in determining the level of bite force. The results indicated that the patients with bruxism used excessively large biting forces for each given submaximal load. This study showed no evidence that the inappropriate control of bite force by patients with bruxism was due to an abnormality in the higher cortical circuits that regulates the function of trigeminal motoneurons in the brainstem. This was shown by a lack of abnormality in coordination of voluntary hand movement with biting force, a lack of abnormal anticipation response to a sham load and a lack of any effect of visual feedback. The results were in line with the hypothesis that afferent input from oral (periodontal or masticatory muscle) tissues does not provide an appropriate control of motor command in bruxism. PMID- 10090632 TI - Effect of moderate physical activity on plasma leptin concentration in humans. AB - In subjects who maintain a constant body mass, the increased energy expenditure induced by exercise must be compensated by a similar increase in energy intake. Since leptin has been shown to decrease food intake in animals, it can be expected that physical exercise would increase energy intake by lowering plasma leptin concentrations. This effect may be secondary either to exercise-induced negative energy balance or to other effects of exercise. To delineate the effects of moderate physical activity on plasma leptin concentrations, 11 healthy lean subjects (4 men, 7 women) were studied on three occasions over 3 days; in study 1 they consumed an isoenergetic diet (1.3 times resting energy expenditure) over 3 days with no physical activity; in study 2 the subjects received the same diet as in study 1, but they exercised twice daily during the 3 days (cycling at 60 W for 30 min); in study 3 the subjects exercised twice daily during the 3 days, and their energy intake was increased by 18% to cover the extra energy expenditure induced by the physical activity. Fasting plasma leptin concentration (measured on the morning of day 4) was unaltered by exercise [8.64 (SEM 2.22) 7.17 (SEM 1.66), 7.33 (SEM 1.72) 1 microg x l(-1) in studies 1, 2 and 3, respectively]. It was concluded that a moderate physical activity performed over a 3-day period does not alter plasma leptin concentrations, even when energy balance is slightly negative. This argues against a direct effect of physical exercise on plasma leptin concentrations, when body composition is unaltered. PMID- 10090633 TI - Effects of a short-term strength training programme on lymphocyte subsets at rest in elderly humans. AB - The effects of a short-term strength training programme on resting lymphocyte subsets and stress hormone concentrations were analysed in 32 elderly sedentary subjects. Out of these 32 subjects, 8 women and 8 men [mean age 70.1 (SEM 1.0) years] were randomly assigned to a 8-week strength training programme which consisted of three sets of eight repetitions at 80% of one repetition maximum, for leg press, bilateral leg extension and seated chest press, 3 days a week. The remaining 8 women and 8 men [mean age 70.5 (SEM 0.9) years] served as controls. Absolute counts of lymphocyte subsets (CD20+, CD3+, CD3+CD4+, CD3+CD8+, CD3 CD56+CD16+) were measured with a new technique combining fluorescent microspheres and flow cytometry. In the trained subjects, substantial increases in strength took place in one repetition maximum during the 8-week training period for leg press [from means of 20.7 (SEM 1.0) to 23.6 (SEM 1.0) N x kg(-1) LBM (lean body mass)], chest press [from means of 5.4 (SEM 0.3) to 6.2 (SEM 0.3) N x kg(-1) LBM] and bilateral leg extension [from means of 6.3 (SEM 0.2) to 7.4 (SEM 0.3) N x kg( 1) LBM] movements. Baseline cortisol concentration (P < 0.01), CD20+ cell count (P < 0.05), CD3+ cell count (P < 0.05), and CD4+ cell count (P < 0.01) decreased in both groups secondary to circannual variations between winter and summer. No significant effect of strength training on resting adrenaline, noradrenaline and cortisol concentrations or distributions of lymphocyte subsets at rest was observed. The main finding of this study was to demonstrate that 8-week is too short a duration for a strength training programme to modify counts of lymphocyte subsets at rest in elderly sedentary adults. PMID- 10090634 TI - Evaluation of miniature data loggers for body temperature measurement during sporting activities. AB - We recorded body temperatures in four runners, two squash players and one swimmer at 1-min intervals using miniature data loggers. These single-channel loggers are small and light (25 g), and were easily carried by the athletes during their sporting activities. Wide-range loggers (-37 degrees C to +46 degrees C), which had a temperature resolution of 0.4 degrees C, were used to measure thigh skin temperature. Auditory canal temperature and rectal temperature were measured with narrow-range loggers (+34 degrees C to + 46 degrees C) which had a considerably higher resolution (0.04 degrees C). With the aid of visual analogue scales subjects reported that the thermometric equipment caused very little discomfort or impairment of exercise performance. Loggers connected to uncoated bead thermistors (used for skin and auditory canal temperatures) had a thermal time constant of 0.4 s, and that of the coated thermistors (rectal probes) was 6 s. We were able to waterproof the equipment and measure rectal temperature in a swimmer. Hot (35 degrees C) or cold (5 degrees C) ambient temperatures had an insignificant effect on the intrinsic accuracy of the data loggers, even when used without recalibration at those temperatures. We believe that miniature temperature loggers are convenient and accurate thermometers for use during sporting activities and may provide new insights into thermoregulation during exercise. PMID- 10090635 TI - Maintenance of myoglobin concentration in human skeletal muscle after heavy resistance training. AB - The aim of this study was to determine the effects of 8 weeks of resistance training (RT) on the myoglobin concentration ([Mb]) in human skeletal muscle, and to compare the change in the [Mb] in two different RT protocols. The two types of protocol used were interval RT (IRT) of moderate to low intensity with a high number of repetitions and a short recovery time, and repetition RT (RRT) of high intensity with a low number of repetitions and a long recovery time. A group of 11 healthy male adults voluntarily participated in this study and were divided into IRT (n = 6) and RRT (n = 5) groups. Both training protocols were carried out twice a week for 8 weeks. At the completion of the training period, the one repetition maximal force values and isometric force were increased significantly in all the subjects, by about 38.8% and 26.0%, respectively (P < 0.01). The muscle fibre composition was unchanged by the 8 weeks of training. The muscle fibre cross-sectional areas were increased significantly by both types of training in all fibre types (I, IIa and IIb, mean + 16.1 %, P < 0.05). The [Mb] showed no significant changes at the completion of the training [IRT from 4.63 (SD 0.63) to 4.48 (SD 0.72), RRT from 4.47 (SD 0.75) to 4.24 (SD 0.80) mg x g(-1) wet tissue] despite a significant decrease in citrate synthase activity [IRT from 5.27 (SD 1.45) to 4.49 (SD 1.48), RRT from 5.33 (SD 2.09) to 4.85 (SD 1.87) micromol x min(-1) x g(-1) wet tissue; P < 0.05] observed after both protocols. These results suggested that myoglobin and mitochondria enzymes were regulated by different mechanisms in response to either type of RT. Moreover, the maintained [Mb] in hypertrophied muscle should preserve oxygen transport from capillaries to mitochondria even when diffusion distance is increased. PMID- 10090636 TI - Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptake. AB - A group of 15 competitive male cyclists [mean peak oxygen uptake, VO2peak 68.5 (SEM 1.5 ml x kg(-1) x min(-1))] exercised on a cycle ergometer in a protocol which began at an intensity of 150 W and was increased by 25 W every 2 min until the subject was exhausted. Blood samples were taken from the radial artery at the end of each exercise intensity to determine the partial pressures of blood gases and oxyhaemoglobin saturation (SaO2), with all values corrected for rectal temperature. The SaO2 was also monitored continuously by ear oximetry. A significant decrease in the partial pressure of oxygen in arterial blood (PaO2) was seen at the first exercise intensity (150 W, about 40% VO2peak). A further significant decrease in PaO2 occurred at 200 W, whereafter it remained stable but still significantly below the values at rest, with the lowest value being measured at 350 W [87.0 (SEM 1.9) mmHg]. The partial pressure of carbon dioxide in arterial blood (PaCO2) was unchanged up to an exercise intensity of 250 W whereafter it exhibited a significant downward trend to reach its lowest value at an exercise intensity of 375 W [34.5 (SEM 0.5) mmHg]. During both the first (150 W) and final exercise intensities (VO2peak) PaO2 was correlated significantly with both partial pressure of oxygen in alveolar gas (P(A)O2, r = 0.81 and r = 0.70, respectively) and alveolar-arterial difference in oxygen partial pressure (P(A-a)O2, r = 0.63 and r = 0.86, respectively) but not with PaCO2. At VO2peak PaO2 was significantly correlated with the ventilatory equivalents for both oxygen uptake and carbon dioxide output (r = 0.58 and r = 0.53, respectively). When both P(A)O2 and P(A-a)O2 were combined in a multiple linear regression model, at least 95% of the variance in PaO2 could be explained at both 150 W and VO2peak. A significant downward trend in SaO2 was seen with increasing exercise intensity with the lowest value at 375 W [94.6 (SEM 0.3)%]. Oximetry estimates of SaO2 were significantly higher than blood measurements at all times throughout exercise and no significant decrease from rest was seen until 350 W. The significant correlations between PaO2 and P(A)O2 with the first exercise intensity and at VO2peak led to the conclusion that inadequate hyperventilation is a major contributor to exercise-induced hypoxaemia. PMID- 10090637 TI - Human power output during repeated sprint cycle exercise: the influence of thermal stress. AB - Thermal stress is known to impair endurance capacity during moderate prolonged exercise. However, there is relatively little available information concerning the effects of thermal stress on the performance of high-intensity short-duration exercise. The present experiment examined human power output during repeated bouts of short-term maximal exercise. On two separate occasions, seven healthy males performed two 30-s bouts of sprint exercise (sprints I and II), with 4 min of passive recovery in between, on a cycle ergometer. The sprints were performed in both a normal environment [18.7 (1.5) degrees C, 40 (7)% relative humidity (RH; mean SD)] and a hot environment [30.1 (0.5) degrees C, 55 (9)% RH]. The order of exercise trials was randomised and separated by a minimum of 4 days. Mean power, peak power and decline in power output were calculated from the flywheel velocity after correction for flywheel acceleration. Peak power output was higher when exercise was performed in the heat compared to the normal environment in both sprint I [910 (172) W vs 656 (58) W; P < 0.01] and sprint II [907 (150) vs 646 (37) W; P < 0.05]. Mean power output was higher in the heat compared to the normal environment in both sprint I [634 (91) W vs 510 (59) W; P < 0.05] and sprint II [589 (70) W vs 482 (47) W; P < 0.05]. There was a faster rate of fatigue (P < 0.05) when exercise was performed in the heat compared to the normal environment. Arterialised-venous blood samples were taken for the determination of acid-base status and blood lactate and blood glucose before exercise, 2 min after sprint I, and at several time points after sprint II. Before exercise there was no difference in resting acid-base status or blood metabolites between environmental conditions. There was a decrease in blood pH, plasma bicarbonate and base excess after sprint I and after sprint II. The degree of post-exercise acidosis was similar when exercise was performed in either of the environmental conditions. The metabolic response to exercise was similar between environmental conditions; the concentration of blood lactate increased (P < 0.01) after sprint I and sprint II but there were no differences in lactate concentration when comparing the exercise bouts performed in a normal and a hot environment. These data demonstrate that when brief intense exercise is performed in the heat, peak power output increases by about 25% and mean power output increases by 15%; this was due to achieving a higher pedal cadence in the heat. PMID- 10090638 TI - Effect of head-down tilt on brain water distribution. AB - Vascular and tissue fluid dynamics in the microgravity of space environments is commonly simulated by head-down tilt (HDT). Previous reports have indicated that intracranial pressure and extracranial vascular pressures increase during acute HDT and may cause cerebral edema. Tissue water changes within the cranium are detectable by T2 magnetic resonance imaging. We obtained T2 images of sagittal slices from five subjects while they were supine and during -13 degrees HDT using a 1.5-Tesla whole-body magnet. The analysis of difference images demonstrated that HDT leads to a 21% reduction of T2 in the subarachnoid cerebrospinal fluid (CSF) compartment and a 11% reduction in the eyes, which implies a reduction of water content; no increase in T2 was observed in other brain regions that have been associated with cerebral edema. These findings suggest that water leaves the CSF and ocular compartments by exudation as a result of increased transmural pressure causing water to leave the cranium via the spinal CSF compartment or the venous circulation. PMID- 10090639 TI - Reliability of leg muscle electromyography in vertical jumping. AB - In this study we aimed to determine the reliability of the surface electromyography (EMG) of leg muscles during vertical jumping between two test sessions, held 2 weeks apart. Fifteen females performed three maximal vertical jumps with countermovement. The displacement of the body centre of mass (BCM), duration of propulsion phase (time), range of motion (ROM) and angular velocity of the knee and surface EMG of four leg muscles (rectus femoris, vastus medialis. biceps femoris and gastrocnemius) were recorded during the jumps. All variables were analysed throughout the propulsion and mid-propulsion phases. Intraclass correlation coefficients (ICC) for the rectus femoris, vastus medialis, biceps femoris and gastrocnemius were calculated to be 0.88, 0.70, 0.24 and 0.01, respectively. BCM, ROM and time values all indicated ICC values greater than 0.90, and the mean knee angular velocity was slightly lower, at 0.75. ICCs between displacement of the BCM and integrated EMG (IEMG) of the muscles studied were less than 0.50. The angular velocity of the knee did not correlate well with muscle activity. Factors that may have affected reliability were variations in the position of electrode replacement, skin resistance, cross-talk between muscles and jump mechanics. The results of this study suggest that while kinematic variables are reproducible over successive vertical jumps, the degree of repeatability of an IEMG signal is dependent upon the muscle studied. PMID- 10090640 TI - Effects of caffeine, ephedrine and their combinations on time to exhaustion during high-intensity exercise. PMID- 10090641 TI - In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol. AB - The present study uses increased atmospheric pressure as an ethanol antagonist to test the hypothesis that allosteric coupling pathways in the GABA(A) receptor complex represent initial sites of action for ethanol. This was accomplished using behavioral and in vitro measures to determine the effects of pressure on ethanol and other GABAergic drugs in C57BL/6 and LS mice. Behaviorally, exposure to 12 times normal atmospheric pressure (ATA) of a helium-oxygen gas mixture (heliox) antagonized loss of righting reflex (LORR) induced by the allosteric modulators ethanol and pentobarbital, but did not antagonize LORR induced by the direct GABA agonist 4,5,6,7-tetrahydroisoxazolo-pyridin-3-ol (THIP). Similarly, exposure to 12 ATA heliox antagonized the anticonvulsant effects verses isoniazid of ethanol, diazepam and pentobarbital. Biochemically, exposure to 12 ATA heliox antagonized potentiation of GABA-activated 36Cl-uptake by ethanol, flunitrazepam and pentobarbital in LS mouse brain preparations, but did not alter GABA activated 36Cl- uptake per se. In contrast to its antagonist effect versus other allosteric modulators, pressure did not antagonize these behavioral or in vitro effects induced by the neuroactive steroid, 3alpha-hydroxy-5beta-pregnan-20-one (3alpha,5beta-P). These findings add to evidence that pressure directly and selectively antagonizes drug effects mediated through allosteric coupling pathways. The results fit predictions, and thus support the hypothesis that allosteric coupling pathways in GABA(A) receptors represent initial sites of action for ethanol. Collectively, the results suggest that there may be common physicochemical and underlying structural characteristics that define ethanol sensitive regions of receptor proteins and/or their associated membranes that can be identified by pressure within (e.g., GABA(A)) and possibly across (e.g., GABA(A), NMDA, 5HT3) receptors. PMID- 10090642 TI - Can the "state-dependency" hypothesis explain prevention of amphetamine sensitization in rats by NMDA receptor antagonists? AB - Many laboratories have reported that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative "state dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK 801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the "state dependency" hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction. PMID- 10090643 TI - Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. AB - Serotonin (5-hydroxytryptamine; 5-HT) circuits may play a role in cognitive performance, particularly in learning and memory. Cognitive impairment is often seen in depressed patients, in whom 5-HT turnover in the brain is thought to be lowered. A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects. In this study, the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion. Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan, according to a double-blind, cross-over design. Tryptophan depletion specifically impaired long-term memory performance in all subjects: delayed recall performance, recognition sensitivity, and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo. Short-term memory and perceptual and psychomotor functions were unchanged. There were no differences between groups with a positive and a negative family history for depression. On the basis of these results, it is concluded that tryptophan depletion specifically impairs long-term memory formation, presumably as a result of an acute decrease in 5-HT turnover in the brain. PMID- 10090644 TI - Evidence of the activity of lithium on 5-HT1B receptors in the mouse forced swimming test: comparison with carbamazepine and sodium valproate. AB - The use of lithium in combination with various antidepressant drugs (e.g., heterocyclics and monoamine oxidase inhibitors) has been reported rapidly to improve antidepressant response in otherwise treatment-resistant patients. Carbamazepine and sodium valproate have also been shown to be effective in the treatment of several forms of affective disorders, such as treatment-resistant depression and bipolar depression. The present study, using the mouse forced swimming test, was undertaken to test the hypothesis of the action of lithium, carbamazepine or sodium valproate on some 5-HT receptor subtypes. Results showed that lithium significantly potentiated the anti-immobility effects of RU 24969 (P<0.01) and anpirtoline (P<0.01). Pretreatment with lithium did not induce any significant antidepressant-like effects when tested in combination with 8-OH DPAT, NAN-190 or (+/-) pindolol. Pretreatment with carbamazepine provoked anti immobility effects when tested in combination with RU 24969 (P<0.01) and 8-OH DPAT (P<0.01), whereas prior administration of sodium valproate enhanced the antidepressant-like effects of (+/-) pindolol (P<0.01), 8-OH-DPAT (P<0.01) and RU 24969 (P<0.01). In conclusion, the results of the present study suggest that lithium may be acting through 5-HT1B receptors, whereas the action of carbamazepine and sodium valproate seems to involve 5-HT1A receptors in the mouse forced swimming test. However, considering the complexity of the actions of these compounds, it is possible that other neurotransmitter systems/receptors may be involved. PMID- 10090645 TI - The effect of naloxone on food-motivated behavior in the obese Zucker rat. AB - We assessed differences in food reinforced behavior between obese and lean Zucker rats with a progressive ratio schedule 3 (PR3) in which a subject emitted three additional lever-presses each time a reinforcer was delivered. The number of responses required for a reinforcer eventually exceeded its value, termed the "break point", a sensitive measure of food motivated behavior. Break points were higher in obese rats than lean controls for grain pellets (27.5 versus 9.5, P = 0.01) but not for sweet pellets (51.6 versus 38.5, P = 0.31). We determined if naloxone (0.01-3.0 mg/kg, SC), which reduces free food intake in obese Zucker rats, affects food motivated behavior in obese Zuckers and lean controls. Naloxone reduced break points in both obese and lean rats to a similar extent when working for either grain pellets or sweet pellets. Under free-access feeding conditions, naloxone again decreased pellet intake similarly in the obese and lean Zucker rats. Naloxone appeared to decrease free-access pellet consumption to a greater extent than break point in both groups. These results show that (1) obese rats exhibit higher levels of performance for food than lean rats only when working for the less valued grain pellet, (2) naloxone reduces both break points and free-access pellet consumption independent of genotype, and (3) naloxone appears to decrease food more effectively in rats given free access to food than in rats working for food. PMID- 10090646 TI - Abstinence symptoms following oral THC administration to humans. AB - Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral delta9-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915-1700 hours), and in the evening engaged in private or social recreational activities (1700-2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1-3, 8-11, and 16-19. Active THC was administered on days 4 7 (20 mg qid) and on days 12-15 (30 mg qid). Both active doses of THC increased ratings of "High," "Good Drug Effect," and "Willingness to Take Dose Again" compared to baseline (days 1-3). THC also increased food intake by 35-45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of "Anxious," "Depressed," and "Irritable," decreased the reported quantity and quality of sleep, and decreased food intake by 20-30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use. PMID- 10090647 TI - Abstinence symptoms following smoked marijuana in humans. AB - Symptoms of withdrawal after oral delta9-tetrahydrocannabinol (THC) administration have been reported, yet little is known about the development of dependence on smoked marijuana in humans. In a 21-day residential study, marijuana smokers (n = 12) worked on five psychomotor tasks during the day (0915 1700 hours), and in the evening engaged in recreational activities (1700-2330 hours); subjective-effects measures were completed 10 times/day. Food and beverages were available ad libitum from 0830 to 2330 hours. Marijuana cigarettes (0.0, 1.8, 3.1% THC) were smoked at 1000, 1400, 1800, and 2200 hours. Placebo marijuana was administered on days 1-4 . One of the active marijuana doses was administered on days 5-8, followed by 4 days of placebo marijuana (days 9-12). The other concentration of active marijuana cigarettes was administered on days 13-16, followed by 4 days of placebo marijuana (days 17-20); the order in which the high and low THC-concentration marijuana cigarettes were administered was counter-balanced between groups. Both active doses of marijuana increased ratings of "High," and "Good Drug Effect," and increased food intake, while decreasing verbal interaction compared to the placebo baseline (days 1-4). Abstinence from active marijuana increased ratings such as "Anxious," "Irritable," and "Stomach pain," and significantly decreased food intake compared to baseline. This empirical demonstration of withdrawal from smoked marijuana may suggest that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms. PMID- 10090648 TI - Intracerebral administration of metabotropic glutamate receptor agonists disrupts prepulse inhibition of acoustic startle in Sprague-Dawley rats. AB - The functional role of striatal metabotropic glutamate receptors (mGluRs) was examined by measuring prepulse inhibition (PPI) of an acoustic startle response following the intracerebral administration of selective agonists in male Sprague Dawley rats prepared with bilateral cannulae aimed at either the nucleus accumbens or dorsal striatum. mGluR subtypes (1-8) are classed in three groups based on sequence homology, signal transduction mechanism and pharmacology. Intra accumbens IS,3R-ACPD, an agonist at group 1 and 2 mGluRs (0.5-1.0 micromol/2 microl), caused a dose-dependent loss of PPI. The effect of 1S,3R-ACPD was diminished when injected into dorsal striatum. Intra-accumbens infusion of the group 1 selective agonist 3,5-DHPG (1 micromol) and the group 2 selective agonist L-CCG-I (100 nmol) also led to statistically significant disruptions of PPI, while the group 3 selective agonist L-AP4 (0.4-1.0 micromol) had no significant effect. Although the group 1/2 mGluR antagonist (+) MCPG (0.5 micromol) had no significant effect of its own on PPI, co-administration with IS,3R-ACPD (1 micromol) blocked ACPD-induced loss of PPI. In addition, pretreatment (30 min) with haloperidol (0.3 mg/kg IP) attenuated the PPI disruption induced by 1 micromol 1S,3R-ACPD, suggesting dopamine may play a role in mGluR agonist induced loss of PPI. These results support a role for group 1 and group 2 mGluRs in the nucleus accumbens in the regulation of PPI, a measure of sensory gating. As PPI is abnormal in some patient populations, such as Huntington's and schizophrenia, mGluRs may have potential as novel therapeutic targets for these diseases. PMID- 10090649 TI - Attenuation of cocaine-induced response-rate increases during repeated administration despite increases in rate of reinforcement. AB - Repeated administration of cocaine often results in tolerance to its effects on operant behavior. The tolerance is often associated with an initial drug effect that results in loss of reinforcement. Cocaine can also produce effects that result in a gain of reinforcement, and it is not known if tolerance will be observed in such a circumstance. The present experiments investigated whether tolerance would develop when cocaine was administered repeatedly to subjects who experienced an increase in the frequency of reinforcement when cocaine was administered acutely. Pigeons were trained to peck a response key under fixed ratio schedules of food presentation. The ratio value for each pigeon was chosen such that performance indicated that the ratio was relatively large, and produced "ratio strain.". Cocaine was administered acutely (once per week), and then subsequently a dose was chosen and administered before each session. Once performance under the daily drug regimen was stable, other doses occasionally were substituted for the usual daily dose. Acute administration of cocaine (0.3 10.0 mg/kg) revealed substantial increases of 100% or more in response rate, and therefore equivalent increases in rate of food presentation, at some doses. That finding permitted examination of the role of drug-induced increases in rate of reinforcement during repeated administration of a response-rate-increasing dose. Repeated, daily administration of a rate-increasing dose resulted in attenuation of the effects of that dose, and subsequent administration of other doses that previously had increased response rates revealed that these doses, too, had lost their ability to increase rates. That is, "tolerance" developed to the rate increasing effects, even though the rate increases were associated with more frequent access to food. These findings suggest that "reinforcement gain" may not be sufficient to prevent tolerance from developing to effects of cocaine on operant behavior. PMID- 10090650 TI - Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine induced nucleus accumbens dopamine release: possible pharmacokinetic interaction. AB - Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5-1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes. PMID- 10090651 TI - The mu opioid agonist DAMGO alters the intravenous self-administration of cocaine in rats: mechanisms in the ventral tegmental area. AB - Microinfusions of the opioid subtype-selective agonist DAMGO and antagonist CTOP into the ventral tegmental area (VTA) were used to examine the role of mu opioid receptors in this area of the mesolimbic dopamine system in regulating cocaine reinforcement. Long-Evans rats were trained to self-administer cocaine intravenously and prepared with intracranial cannulae directed to the VTA. At doses of cocaine on the descending limb of the cocaine dose-response curve, the mu-selective agonist DAMGO produced a dose-related decrease in cocaine self administration when delivered by microinfusion into the VTA. At a dose of cocaine on the ascending limb of the self-administration dose-response curve, DAMGO microinfusions produced an increase in responding for the drug. The mu-selective antagonist CTOP produced small effects on cocaine self-administration. A kappa selective agonist and antagonist (U50,488 and norbinaltorphimine, respectively) produced either no effects or small effects that did not show consistent trends with dose. These experiments suggest that the mu agonist DAMGO is able to shift the dose-response curve for cocaine self-administration to the left. This effect appears to be specific for mu as compared to kappa agonists. These data are consistent with the known differential distribution of opioid receptor subtypes within the VTA, and with the effects of opioid compounds in the VTA on dopamine release in the mesolimbic synaptic field. The data show that a mu opioid mechanism in the somatodendritic region can alter reinforcement processes for cocaine, which acts predominantly at the terminal field of dopamine cells. PMID- 10090652 TI - Naltrexone pretreatment decreases the reinforcing effectiveness of ethanol and saccharin but not PCP or food under concurrent progressive-ratio schedules in rhesus monkeys. AB - The purpose of this experiment was to determine whether attenuation of ethanol consumption by naltrexone is the result of selective changes in the reinforcing effectiveness of drug and non-drug reinforcers. A range of naltrexone doses (0.1 1.0 mg/kg) was administered for 5 days, and the effects on the reinforcing effects of orally delivered 8% (w/v) ethanol, 0.25 mg/ml phencyclidine (PCP), 0.03% (w/v) saccharin and food were studied in eight rhesus monkeys. Food and liquids were available under independent and concurrent progressive-ratio (PR) schedules (ratio range 8-4096) during daily 3-h sessions. Ethanol-maintained responding was attenuated by 0.3 and 1.0 mg/kg doses of naltrexone, while saccharin-maintained responding was decreased at the 1.0 mg/kg dose. Furthermore, there was a significant linear trend that consumption of available ethanol and saccharin was attenuated dose-dependently by naltrexone. Following 5 days of naltrexone pretreatment, ethanol- and saccharin-maintained responding immediately returned to or exceeded baseline levels. Food- and PCP-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. The decreased break point (BP) values for ethanol and saccharin suggest that their reinforcing effects are mediated through opioid reinforcement mechanisms. The lack of naltrexone attenuation of PCP- and food-maintained responding suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability. PMID- 10090653 TI - Dorsal root potentials and dorsal root reflexes: a double-edged sword. AB - The nature of dorsal root reflexes (DRRs) and their possible role in peripheral inflammation and the consequent hyperalgesia are reviewed. The history of DRRs and the relationship of DRRs to primary afferent depolarization and presynaptic inhibition in pathways formed by both large and fine afferents are discussed. Emphasis is placed on the mechanisms underlying primary afferent depolarization, including the anatomical arrangement of the synapses involved, how depolarization can result in inhibition by decreasing transmitter release, the role of excitatory amino acids and GABA, the manner in which the equilibrium potential for chloride ions is determined in primary afferent fibers, and forms of presynaptic inhibition that do not utilize GABA(A) receptors. There is then a discussion of neurogenic inflammation, including the role of the release of neuropeptides such as substance P and calcitonin gene-related peptide from sensory nerve endings. Evidence is reviewed that links DRRs to a substantial part of the swelling of the knee joint in acute experimental arthritis and to the flare reaction in the skin following intradermal injection of capsaicin. Possible mechanisms by which the level of DRR activity might be enhanced following inflammation are suggested. The consequences of this increase in DRRs may include exacerbation of hyperalgesia as well as of peripheral inflammation. The conversion of an inhibitory process, presynaptic inhibition, to an excitatory one by DRRs can thus lead to pathological consequences. PMID- 10090654 TI - Object size effects on initial lifting forces under microgravity conditions. AB - Individuals usually report for two objects of equal mass but different volume that the larger object feels lighter. This so-called size-weight illusion has been investigated for more than a century. The illusion is accompanied by increased forces, used to lift the larger object, resulting in a higher initial lifting speed and acceleration. The illusion holds when subjects know that the mass of the two objects is equal and it is likely that this also counts for the enlarged initial effort in lifting a larger box. Why should this happen? Under microgravity, subjects might be able to eliminate largely the weight-related component of the lifting force. Then, if persistent upward scaling of the weight related force component had been the main cause of the elevated initial lifting force under normal gravity, this elevated force might disappear under microgravity. On the other hand, the elevated initial lifting effort in the large box would be preserved if it had been caused mainly by a persistent upward scaling of the force component, necessary to accelerate the object. To test whether the elevated initial lifting effort either persists or disappears under microgravity, a lifting experiment was carried out during brief periods of microgravity in parabolic flights. Subjects performed whole-body lifting movements with their feet strapped to the floor of the aircraft, using two 8-kg boxes of different volume. The subjects were aware of the equality of the box masses. The peak lifting forces declined almost instantaneously with approx. a factor 9 in the first lifting movements under microgravity compared with normal gravity, suggesting a rapid adaptation to the loss of weight. Though the overall speed of the lifting movement decreased under microgravity, the mean initial acceleration of the box over the first 200 ms of the lifting movement remained higher (P=0.030) in the large box (1.87+/-0.127 m/s2) compared with the small box (1.47+/-0.122 m/s2). Under normal gravity these accelerations were 3.30+/-0.159 m/s2 and 2.67+/-0.159 m/s2, respectively (P=0.008). A comparable trend was found in the initial lifting forces, being significant in the pooled gravity conditions (P=0.036) but not in separate tests on the normal gravity (P=0.109) and microgravity (P=0.169) condition. It is concluded that the elevated initial lifting effort with larger objects holds during short-term exposure to microgravity. This suggests that upward scaling of the force component, required to accelerate the larger box, is an important factor in the elevated initial lifting effort (and the associated size-weight illusion) under normal gravity. PMID- 10090655 TI - Reversible inactivation of macaque dorsomedial frontal cortex: effects on saccades and fixations. AB - Neural recording and electrical stimulation results suggest that the dorsomedial frontal cortex (DMFC) of macaque is involved in oculomotor behavior. We reversibly inactivated the DMFC using lidocaine and examined how saccadic eye movements and fixations were affected. The inactivation methods and monkeys were the same as those used in a previous study of the frontal eye field (FEF), another frontal oculomotor region. In the first stage of the present study, monkeys performed tasks that required the generation of single saccades and fixations. During 15 DMFC inactivations, we found only mild, infrequent deficits. This contrasts with our prior finding that FEF inactivation causes severe, reliable deficits in performance of these tasks. In the second stage of the study, we investigated whether DMFC inactivation affected behavior when a monkey was required to make more than one saccade and fixation. We used a double-step task: two targets were flashed in rapid succession and the monkey had to make two saccades to foveate the target locations. In each of five experiments, DMFC inactivation caused a moderate, significant deficit. Both ipsi- and contraversive saccades were disrupted. In two experiments, the first saccades were made to the wrong place and had increased latencies. In one experiment, first saccades were unaffected, but second saccades were made to the wrong place and had increased latencies. In the remaining two experiments, specific reasons for the deficit were not detected. Saline infusions into DMFC had no effect. Inactivation of FEF caused a larger double-step deficit than did inactivation of DMFC. The FEF inactivation impaired contraversive first or second saccades of the sequence. In conclusion, our results suggest that the DMFC makes an important contribution to generating sequential saccades and fixations but not single saccades and fixations. Compared with the FEF, the DMFC has a weaker, less directional, more task-dependent oculomotor influence. PMID- 10090656 TI - Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation. AB - To evaluate changes in the motor system during the silent period (SP) induced by transcranial magnetic stimulation (TMS) of the motor cortex, we investigated motor thresholds as parameters of the excitability of the cortico-muscular pathway after a suprathreshold conditioning stimulus in the abductor digiti minimi muscle (ADM) of normal humans. Since the unconditioned motor threshold was lower during voluntary tonic contraction than at rest (31.9+/-5.4% vs. 45.6+/ 7.5%), it is suggested that the difference between active and resting motor threshold indicates the magnitude of the voluntary drive on the cortico-muscular pathway. Therefore, we compared conditioned resting and active motor threshold (cRMT and cAMT) during the SP. cRMT showed an intensity-dependent period of elevation of more than 200 ms in duration and approximately 17% of the maximum stimulator output above the unconditioned threshold, due to decreased excitability of the cortico-muscular pathway after the conditioning stimulus. Some 3040 ms after the conditioning stimulus, cAMT approximated cRMT, indicating complete suppression of the voluntary motor drive. This suppression did not start directly after the conditioning stimulus since cAMT was still significantly lower than the cRMT within the first 30-40 ms. Threshold elevation was significantly longer than the SP (220+/-41 vs. 151+/-28 ms). Recovery of the voluntary motor drive started late in the SP and was nearly complete at the end of the SP, although thresholds were still significantly elevated. We conclude that the SP is largely due to a suppression of voluntary motor drive, while the threshold elevation is a different inhibitory phenomenon that is of less importance for the generation of the SP, at least in its late part. It is argued that the pathway of fast cortico-spinal fibers activated by TMS is partially different from the pathway involved in the maintenance of tonic voluntary muscle activation. PMID- 10090657 TI - Sigma-optokinetic nystagmus in squirrel monkeys elicited by stationary stripe patterns illuminated by regular and random-interval flash sequences. AB - Eye position and angular velocity were measured in squirrel monkeys (Saimiri sciureus) by means of the electromagnetic scleral search-coil technique. Horizontal sigma-optokinetic nystagmus (sigma-OKN) was elicited by a stationary, stroboscopically illuminated, periodic, vertical-stripe pattern lining a vertical cylinder. The relationship between the mean slow-phase eye angular velocity, Ve, of sigma-OKN and the product of pattern period, Ps, and flash frequency, f(s), was determined. When Ve approximated k x Ps x f(s) (deg x s(-1)) and k was an integer > or = 1, the sigma-paradigm was fulfilled. Sigma-OKN could be evoked in different "modes", whereby k approximated 1, 2,...n. The sigma-OKN properties of squirrel monkeys were similar to those measured for sigma-OKN in the "stare" mode in man, with the exception of a long-lasting optokinetic afternystagmus (sigma OKAN) appearing in the monkey. A considerable amount of temporal variability in flash sequence intervals ("temporal noise"), causing retinal error signals that interfered with the sigma-paradigm, was accepted by the visuo-motor system without interruption of sigma-OKN. This observation was explained by the operation of a short memory device for perception of visual motion. The internal gain, g(i), which relates the retinal "error" displacement velocity, Vr, and Ve depended, in turn, on Vr according to a function resembling the known relationship between neuronal activity of NOT (nucleus of the optic tract) nerve cells and Vr. This observation may be taken as direct proof that sigma-OKN can be explained by a centrally preprogrammed relationship between the retinal velocity, Vr, and the OKN slow-phase eye velocity, Ve. It is stipulated that the sum of Vr and efference copy signals generated in cortical or subcortical gaze centers is the essential component controlling the perceived velocity of the sigma-movement, whereby a short-term integrator plays a role for squirrel monkey sigma-OKN. When the flash frequency, f(s), was modulated periodically according to a sinewave or "triangular" function at a rate below 0.5 cycles x s(-1), Ve was found to respond with a corresponding modulation, provided the modulation amplitude did not exceed 50% of the mean flash rate. When the latter occurred, nonlinear responses could be observed. A similar response was found when the speed of "real" optokinetic stimuli was varied sinusoidally. Under these experimental conditions, however, the amplitude of the Ve variation yielded up to 1.0 approximately linear responses. PMID- 10090658 TI - Development of dynamic vision based on motion contrast. AB - The development of dynamic vision was investigated in 400 healthy subjects (200 females and 200 males) aged between 4 and 24 years. The test consisted of a computer-generated random-dot kinematogram in which a Landolt ring was briefly presented as a form-from-motion stimulus. Motion contrast between the ring and background was varied in terms of the percentage of dots moving coherently within the ring in four levels (100%, 50%, 30%, and 20%). The subject's task was to indicate the position of a gap in the ring (left, right, top, bottom). Results show a clear increase in performance with age for all motion contrast levels, with the greatest changes for the lowest levels. Adult performance was reached at the age of 15 years. Luminance-based static acuity measured with the Landolt test was poorly correlated with acuity for its form-from-motion analogue. PMID- 10090659 TI - Interaction of the Jendrassik maneuver with segmental presynaptic inhibition. AB - Since its initial description in 1883, the Jendrassik maneuver (JM) has been used in clinical neurological practice as an effective means of potentiating the tendon tap in neurologically impaired patients. The JM also potentiates its electrical analogue, the Hoffman (H-) reflex, but the mechanism of the reflex modulation has not been clearly established. We studied soleus H-reflex modulation in neurologically intact subjects while at rest and during a mild plantarflexion contraction (EMG level equivalent to approximately 10% maximum voluntary contraction). The control H-reflex was elicited by stimulating the tibial nerve in the popliteal fossa with single pulses of 1 ms duration. Conditioning of the reflex was by: (1) increasing segmental presynaptic inhibition via common peroneal nerve (CP) stimulation; (2) pulling the arms and clenching the teeth (JM); or (3) applying both together (JM+CP). CP stimulation significantly (P<0.05) suppressed the H-reflex (50% Hmax), while JM significantly (P<0.05) facilitated it during contraction. From either an analysis of the grouped data or by a within-subject analysis, we found that the combined effect of stimulating JM+CP was significantly lower than JM alone, but did not differ from control values or from CP alone. The simplest mechanism would be that the effects of the two sum algebraically on the interneurones producing segmental presynaptic inhibition of the H-reflex. PMID- 10090660 TI - Are automatic postural responses in patients with Parkinson's disease abnormal due to their stooped posture? AB - Abnormal automatic postural responses are thought to contribute to balance impairment in Parkinson's disease. However, because postural responses are modifiable by stance, we have speculated that some postural abnormalities in patients with Parkinson's disease are secondary to their stooped stance. We have studied this assumption by assessing automatic postural responses in 30 healthy subjects who were instructed either to stand upright or to assume a typical parkinsonian posture. During both conditions, subjects received 20 serial 4 degrees 'toe-up' rotational perturbations from a supporting forceplate. We recorded short-latency (SL) and medium-latency (ML) responses from stretched gastrocnemius muscles and long-latency (LL) responses from shortened tibialis anterior muscles. We also assessed changes in the center of foot pressure (CFP) and the center of gravity (COG). The results were qualitatively compared to a previously described group of patients with Parkinson's disease who, under these circumstances, typically have large ML responses, small LL responses and insufficient voluntary postural corrections, accompanied by a slow rate of backward CFP displacement and an increased posterior COG displacement. The stooped posture resulted in unloading of medial gastrocnemius muscles and loading of tibialis anterior muscles. Onset latencies of stretch responses in gastrocnemius muscles were delayed in stooped subjects, but the onset of LL responses was markedly reduced. Amplitudes of both ML and LL responses were reduced in stooped subjects. Prestimulus COG and, to a lesser extent, CFP were shifted forwards in stooped subjects. Posterior COG displacement and the rate of backward CFP displacement were diminished in stooped subjects. Voluntary postural corrections were unchanged while standing stooped. These results indicate that some postural abnormalities of patients with Parkinson's disease (most notably the reduced LL responses) can be reproduced in healthy subjects mimicking a stooped parkinsonian posture. Other postural abnormalities (most notably the increased ML responses and insufficient voluntary responses) did not appear in stooped controls and may contribute to balance impairment in Parkinson's disease. PMID- 10090661 TI - Firing properties of chopper and delay neurons in the lateral superior olive of the rat. AB - Neurons in the lateral superior olivary nucleus (LSO) respond to acoustic stimuli with the "chopper response", a regular repetitive firing pattern with a short and precise latency. In the past, this pattern has been attributed to dendritic integration of synaptic inputs. We investigated a possible contribution of intrinsic membrane properties using intracellular recording techniques in a tissue slice preparation. We found two electrophysiological classes of neurons in the LSO. Chopper neurons responded to depolarizing current pulses with a single onset spike at short, precise latency close to threshold and with repetitive, regular, but accommodating discharges at greater current intensities. An emphasis of response onset and subsequent rate accommodation resulted from the activation of a voltage- and time-dependent sustained outward rectification in a range depolarized from rest. Responses to hyperpolarizing pulses were characterized by an inward rectification, which caused a depolarizing voltage sag in a range negative to -65 mV. Peristimulus time histograms were multimodal, and discharge regularity was evident in narrow unimodal interspike interval time histograms and low coefficients of variation. The accommodation time course was usually fit best by two exponentials with time constants of tau1=3-8 ms and tau2=32-97 ms. Delay neurons responded with a regular repetitive firing to depolarization by current pulses. However, repetitive spike discharge occurred with a prolonged, variable delay of 25-180 ms. High current intensities evoked an additional onset spike with short, precise latency. Activation of a transient outward conductance in the depolarized voltage range caused an early repolarization, which terminated as a depolarizing ramp, reaching spike threshold after the delay. Flat peristimulus time histograms characterized the repetitive discharge in spite of narrow unimodal interspike interval time histograms and low coefficients of variation. Intracellular neurobiotin injections revealed morphological differences between these classes. Chopper neurons were large and fusiform, with a bipolar dendritic distribution oriented perpendicular to the curvature of the LSO. Delay neurons were small and spherical, with highly branched tortuous dendritic arbours of bipolar origin and variable orientation. Chopper and delay neurons are probably LSO principal cells and lateral olivocochlear efferent neurons, respectively. Our findings suggest that the pattern of firing activity of LSO neurons to sound, in vivo, is determined to a large extent by intrinsic membrane properties. Somato dendritic integration of synaptic inputs are fundamental to the encoding of interaural sound differences, but membrane non-linearities play an important role in determining postsynaptic response patterns. PMID- 10090662 TI - Remembered positions: stored locations or stored postures? AB - Many recent studies indicate that memory for final position is superior to memory for movement. There is ambiguity about what is meant by the term final position, however. Is it final spatial location or final posture? According to a recently proposed theory by Rosenbaum et al., which maintains that stored postures form the basis for movement planning, when people try to return to recently reached positions, they should try to adopt the postures they just occupied. An alternative view, which holds that movements are primarily planned with respect to spatial locations, predicts that subjects should tend to return to places in external space. We describe an experiment that tested these opposing predictions. The experiment relied on the notion that if people store and use postures, they should "copy" the posture adopted with one arm to the other arm when possible. The results support this hypothesis. In this article, we review previous work that bears on the question of what is learned when people move repeatedly to a given position. Then we present two theoretical perspectives which make diverging predictions about what should be learned in repositioning tasks. One perspective predicts that final positions are remembered as postures; the other predicts that final positions are remembered as locations. We describe an experiment designed to distinguish between these two predictions. The experiment indicates that final postures are remembered and are "copied" from one arm to the other when subjects try to reach repeatedly to the same location in the midsagittal plane with alternating arms or when subjects try to reach repeatedly to the same location anywhere in the workspace with the same arm. In the last section of the article, we discuss the implications of our findings. PMID- 10090663 TI - Time-dependent influence of sensorimotor set on automatic responses in perturbed stance. AB - These experiments tested the hypothesis that the ability to change sensorimotor set quickly for automatic responses depends on the time interval between successive surface perturbations. Sensorimotor set refers to the influence of prior experience or context on the state of the sensorimotor system. Sensorimotor set for postural responses was influenced by first giving subjects a block of identical backward translations of the support surface, causing forward sway and automatic gastrocnemius responses. The ability to change set quickly was inferred by measuring the suppression of the stretched antagonist gastrocnemius responses to toes-up rotations causing backward sway, following the translations. Responses were examined under short (10-14 s) and long (19-24 s) inter-trial intervals in young healthy subjects. The results showed that subjects in the long-interval group changed set immediately by suppressing gastrocnemius to 51% of translation responses within the first rotation and continued to suppress them over succeeding rotations. In contrast, subjects in the short-interval group did not change set immediately, but required two or more rotations to suppress gastrocnemius responses. By the last rotation, the short-interval group suppressed gastrocnemius responses to 33%, similar to the long-interval group of 29%. Associated surface plantarflexor torque resulting from these responses showed similar results. When rotation and translation perturbations alternated, however, the short-interval group was not able to suppress gastrocnemius responses to rotations as much as the long-interval group, although they did suppress more than in the first rotation trial after a series of translations. Set for automatic responses appears to linger, from one trial to the next. Specifically, sensorimotor set is more difficult to change when surface perturbations are given in close succession, making it appear as if set has become progressively stronger. A strong set does not mean that responses become larger over consecutive trials. Rather, it is inferred by the extent of difficulty in changing a response when it is appropriate to do so. These results suggest that the ability to change sensorimotor set quickly is sensitive to whether the change is required after a long or a short series of a prior different response, which in turn depends on the time interval between successive trials. Different rate of gastrocnemius suppression to toes-up rotation of the support surface have been reported in previous studies. This may be partially explained by different inter-trial time intervals demonstrated in this study. PMID- 10090664 TI - Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation. AB - Electromyographic (EMG) responses evoked in hand muscles by a magnetic test stimulus over the motor cortex can be suppressed if a conditioning stimulus is applied to the opposite hemisphere 6-30 ms earlier. In order to define the mechanism and the site of action of this inhibitory phenomenon, we recorded descending volleys produced by the test stimulus through high cervical, epidural electrodes implanted for pain relief in three conscious subjects. These could be compared with simultaneously recorded EMG responses in hand muscles. When the test stimulus was given on its own it evoked three waves of activity (I-waves) in the spinal cord, and a small EMG response in the hand. A prior conditioning stimulus to the other hemisphere suppressed the size of both the descending spinal cord volleys and the EMG responses evoked by the test stimulus when the interstimulus interval was greater than 6 ms. In the spinal recordings, the effect was most marked for the last I-wave (I3), whereas the second I2-wave was only slightly inhibited, and the first I-wave (I1) was not inhibited at all. We conclude that transcranial stimulation over the lateral part of the motor cortex of one hemisphere can suppress the excitability of the contralateral motor cortex. PMID- 10090665 TI - Effects of voluntary contraction on descending volleys evoked by transcranial electrical stimulation over the motor cortex hand area in conscious humans. AB - The spinal volleys evoked by electric anodal and cathodal stimulation over the cerebral motor cortex hand area were recorded from a bipolar electrode inserted into the cervical epidural space of two conscious human subjects. We measured the size of volleys elicited by electric stimulation at active motor threshold and at 3% of maximum stimulator output above this value with subjects at rest and during maximum voluntary contraction of the contralateral first dorsal interosseous muscle. Surface EMG activity was recorded at the same time. Electrical anodal stimulation evoked a single negative wave that we termed D-wave in analogy with data in experimental animals. Cathodal stimulation evoked a single negative wave with a latency of 0.2 ms longer than the D-wave recruited by anodal stimulation. At both intensities tested, voluntary contraction did not modify the amplitude of the descending waves. We conclude that changes in cortical excitability induced by voluntary activity do not modify the corticospinal volley evoked by electric stimulation and that the D-waves evoked by both anodal and cathodal electric stimulation are probably initiated several nodes distant to the cell body. PMID- 10090666 TI - GABAergic inhibition in the rat pontine nuclei is exclusively extrinsic: evidence from an in situ hybridization study for GAD67 mRNA. AB - As clearly indicated by our electrophysiological work, GABAergic inhibition plays a powerful role in the pontine nuclei (PN), the major link between cerebral cortex and the cerebellum. Using the technique of in situ hybridization for the mRNA encoding for the gamma-aminobutyric acid (GABA)-synthesizing isoenzyme glutamic acid decarboxylase67 (GAD67), we demonstrate here the total absence of potentially GABAergic neurons from the rat PN. This negative finding supports the notion that GABAergic inhibition in the PN of rats, unlike that of higher mammals, is exclusively based on extrapontine GABAergic afferents. PMID- 10090667 TI - Inducible nitric oxide synthase expression in human cerebral infarcts. AB - The inducible or "immunological" isoform of nitric oxide synthase (iNOS) is induced in many cell types by inflammatory stimuli and synthesizes toxic amounts of NO. In rodent models of focal cerebral ischemia, iNOS is expressed in neutrophils invading the injured brain and in local blood vessels. Studies with iNOS inhibitors and iNOS null mice indicate that NO produced by iNOS contributes to ischemic brain injury. In the present study, we sought to determine whether iNOS is also expressed in the human brain after ischemic stroke. Studies were conducted using immunohistochemistry on autopsy brains with neuropathological evidence of acute cerebral infarction. iNOS immunoreactivity was observed in neutrophils infiltrating the ischemic brain and in blood vessels within the ischemic territory. iNOS-positive cells also were immunoreactive for nitrotyrosine, reflecting protein nitration by NO-derived peroxynitrite and nitrites. iNOS or nitrotyrosine immunoreactivity was not detected outside the region of the infarct. These observations provide evidence that iNOS is expressed in the human brain after ischemic infarction and support the hypothesis that iNOS inhibitors may be useful in the treatment of ischemic stroke in humans. PMID- 10090668 TI - Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration. AB - Neuronal inclusions with bundles of abnormal filaments made of tau polymers are found in numerous diseases with neurofibrillary degeneration. Tau proteins are the basic components of paired helical filaments (PHF) in Alzheimer's disease (AD), and are abnormally phosphorylated. A disease-specific phosphorylation site at serine422 was demonstrated on PHF, but not on tau proteins from biopsy-derived brain samples. In the present study, we report the characterization of a polyclonal antibody (988) against the serine422 phosphorylation site. By using biochemical and immunohistochemical methods, we confirmed that it is not found on tau proteins from biopsy- or autopsy-derived control samples, and we investigated the presence of this epitope on tau proteins in several neurodegenerative disorders, including AD, Down syndrome (DS), Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), postencephalitic parkinsonism (PEP) and Pick's disease (PiD). By Western blotting, antibody 988 labeled the characteristic tau triplet (tau 55, 64, 69) in AD, DS, Guamanian ALS/PDC and PEP. PSP and CBD exhibited their typical tau doublet (tau 64, 69), whereas the doublet tau 55 and 64 was detected in PiD. In all of these neurodegenerative disorders, antibody 988 clearly labeled NFT and dystrophic neurites, as well as Pick bodies in PiD cases, whereas no staining was observed in control cases. These data indicate that phosphorylation of serine422 on tau proteins is a common feature among neurodegenerative disorders and is therefore not specific of AD. Moreover, phosphorylation of this epitope permits the distinction between normal tau proteins and pathological tau proteins. PMID- 10090669 TI - Extracellular matrix-induced cell migration from glioblastoma biopsy specimens in vitro. AB - The present knowledge about the interaction between the extracellular matrix (ECM) and gliomas is mostly based on studies of permanent cell lines. Since such cultures have undergone an extensive clonal selection in vitro, the experimental results obtained may be quite different from those obtained from studies on true biopsy specimens. The present work demonstrates how different ECM components affect tumor cell migration from human glioblastoma specimens grown as biopsy sample spheroids. Biopsy specimens from 12 glioblastomas and 1 gemistocytic astrocytoma were included in this study. Spheroids were directly initiated from the biopsy specimens, and after 3-4 weeks in culture, they were used in a migration assay. A custom-made filtered medium, where the high molecular weight (>100 kDa) proteins were removed, was supplemented with the following ECM components: laminin, fibronectin, collagen type IV and vitronectin. The cell migration was negligible when spheroids were propagated in the filtered medium. The ECM components as well as complete DMEM evoked strong stimulatory effects on different biopsy specimens. Opposed to that observed earlier for permanent glioma cell lines, highly variable responses were observed between the different biopsy samples on the various ECM components. In general, correlation analyses revealed that specimens that were strongly stimulated by laminin were also stimulated strongly by fibronectin, collagen type IV and vitronectin. This suggests that the capacity to migrate as a response to ECM was confined more to each biopsy specimen than to any specific ECM component. Since biopsy sample spheroids, as original tumors, consist of different cell types, an immunohistochemical characterization of the migrating cells was also performed. Anti-glial fibrillary acidic protein (GFAP) staining revealed both GFAP-positive and -negative migrating cells. Immunostaining for von Willebrand factor and CD11b indicated that the migrating cells were neither endothelial nor microglial cells. This study, therefore, indicates that migratory responses of glioma biopsy specimens to different ECM components is much more heterogeneous than that observed earlier for cell lines. Furthermore, the presented findings support the notion that gliomas may utilize different cell surface receptors for their migration, depending on the cell substrates available. PMID- 10090670 TI - Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. AB - To determine the role of advanced glycation endproducts (AGE) in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) mutation, we investigated the immunohistochemical localization of N(epsilon)-carboxymethyl-lysine (CML), one of the major AGE structures, in spinal cords from three familial ALS patients with a heterozygous Ala to Val substitution at codon 4 in the gene for SOD1. Neuronal hyaline inclusions (NHIs), the abnormal structures seen in some of the remaining lower motor neurons of familial ALS patients with SOD1 mutation, were intensely stained by a monoclonal antibody specific for CML in contrast to the only weakly stained cytoplasm. Immunoelectron microscopy depicted the CML determinants restricted to the granule associated thick linear structures that mainly compose the NHIs. The NHIs were also recognized by antibodies to SOD1, phosphorylated neurofilament protein and ubiquitin. No focal collection of either CML or SOD1 was found in neurons of the control individuals. Our results indicate that CML is a component of the NHIs of familial ALS patients with SOD1 mutation, and suggest that the CML formation may be mediated by protein glycoxidation or lipid peroxidation in the presence of oxidative stress from mutant SOD1, in association with motor neuron degeneration. PMID- 10090671 TI - Quantitation of argyrophilic nucleolar organizer regions in regenerating muscle fibers in Duchenne and Becker muscular dystrophies and polymyositis. AB - We have investigated the quantity of argyrophilic nucleolar organizer region (AgNOR) proteins in vastus lateralis muscle samples from 13 patients with Duchenne muscular dystrophy (DMD) (6 months-12 years), 9 with Becker muscular dystrophy (BMD) (13 months-36 years), 9 with polymyositis (PM) (8-77 years) and 10 normal subjects (5 months-32 years). AgNORs were visualized on 4-microm-thick cryostat sections and quantified according to the guidelines of the Committee on AgNOR Quantitation; statistical analysis was performed on the mean AgNOR area (NORA) values. The mean NORA values encountered in DMD (4.327+/-0.791 microm2), BMD (3.534+/-0.312 microm2) and PM (3.785+/-0.424 microm2) samples were significantly (P<0.001) higher than those of normal muscle (1.682+/-0.288 microm2); a value of P<0.001 was also obtained when NORA values found in DMD were compared with those of BMD or PM. In addition, when NORA values were exclusively calculated in regenerating myofibers in DMD, BMD and PM, no differences were appreciable. On the other hand, in non-regenerating myofibers, the NORA values showed a significant increase in DMD versus BMD and PM (P<0.001) as well as in each disease group versus controls. Our study documents that muscle diseases, such as DMD, BMD and PM in which regeneration is a constant finding, have a high rDNA transcriptional activity. In particular, our findings suggest that (1) regenerating nuclei behave in the same way in dystrophinopathies or PM; (2) virtually all nuclei, including quiescent-looking ones, are activated to realize an increased intracellular protein synthesis for proliferative and/or functional purposes; and (3) the quantity of AgNOR does not seem related to age of patients at the time of biopsy. PMID- 10090672 TI - Age-related morphologic changes of the central canal of the human spinal cord. AB - To elucidate the role of the human central canal on the physiology and pathogenesis of acquired syringomyelia, we analyzed the age-related morphologic changes in the normal human central canal of the spinal cord. The subjects included 158 autopsy cases ranging in age from 1 week postnatally to 116 years of age. Each segment of the whole spinal cords was investigated from the C3 to S3 levels. The microscopic pictures of the central canal were classified as patent or occluded at each level for each age decade. The patency rate under 1 year of age was 100% in almost all the segments, which markedly decreased in the second decade, and the canals were occluded in all the segments with advancing age. According to the longitudinal pattern of the central canal occlusion, 19 of 20 cases where the canals were patent in all segment levels were less than 10 years of age. Cases in which the canals were occluded in all segment levels appeared in the second decade, and their number increased gradually with advancing age. The occlusion of the central canal started at the T6 and L5 to S2 levels. We suggest that the central canal does not function after infancy because of its occlusion, and that it is not involved in the development of syringomyelia in adult patients. PMID- 10090673 TI - Astrocytic hyaline inclusions contain advanced glycation endproducts in familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutation: immunohistochemical and immunoelectron microscopical analyses. AB - To clarify the neuropathological significance of the deposition of N(epsilon) carboxymethyl lysine (CML), an advanced glycation endproduct, in astrocytic hyaline inclusions in familial amyotrophic lateral sclerosis (FALS), autopsy specimens from five members of two different families who had the superoxide dismutase 1 (SOD1) gene mutations were analysed. Immunohistochemically, most of the neuronal and astrocytic hyaline inclusions were intensely stained by the antibody against CML. The distributions and intensities of the immunoreactivities for CML and SOD1 were similar in the inclusions in both cell types. Immunoelectron microscopy showed that both inclusions consisted of CML-positive granule-coated fibrils and granular materials. No significant CML or SOD1 immunoreactivity was observed in the neurons and astrocytes of the normal control subjects. Our results suggest that astrocytic hyaline inclusions contain CML and SOD1 in FALS patients with SOD1 gene mutations, and that the formation of CML modified protein (probably CML-modified SOD1) is related to the cell degeneration. PMID- 10090674 TI - Study of some components of the cytoskeleton in muscular disorders with nonspecific cytoplasmic bodies. AB - To gain a better understanding of the mechanisms involved in the formation of cytoplasmic bodies (CBs), the immunohistochemical and biochemical features of muscle samples with nonspecific CBs were compared to those previously described by our group in cytoplasmic body myopathy (CBM), a congenital disease in which specific CBs are found. Accordingly, we studied nonspecific CBs found in the muscle biopsies of 15 patients with the following diseases: peripheral neuropathy (n = 5), polymyositis (n = 3), myotonic dystrophy (n = 2), sarcoidosis (n = 1), inclusion body myositis (n = 1), hereditary inclusion body myopathy (n = 1), hypothyroidism (n = 1), and muscle atrophy in a patient with multiple brain infarctions (n = 1). Nonspecific inclusions were stained at their periphery by anti-desmin but not by anti-dystrophin antibodies, except in the case of hypothyroidism in which immunostaining was observed with both antibodies. Biochemical studies showed normal amounts of desmin and phosphorylation pattern (the latter data are available for only four patients) as compared to control specimens. Our results differ from those previously reported in CBM, in which CBs were stained by both antidesmin and anti-dystrophin antibodies and in which a hyperphosphorylation of desmin was found. Hypothyroidism is, thus, the only disease in which nonspecific CBs show the same immunostaining pattern as specific CBs from CBM patients. These findings indicate that CBs may result from different mechanisms, and that one of these mechanisms may be shared by CBM and hypothyroidism. PMID- 10090675 TI - The up-regulation of metabotropic glutamate receptor 5 (mGluR5) in Down's syndrome brains. AB - We investigated the expression of metabotropic glutamate receptor 5 (mGluR5), a subtype of group I mGluRs, in the cerebral cortex of cases with Down's syndrome (DS), using immunohistochemistry and immunoblotting with this receptor. The up regulation of mGluR5 was observed in DS by immunohistochemistry, and atrophic pyramidal neurons were immunolabelled in elderly DS cases. Western blotting confirmed the increased expression in DS brains. Since group I mGluR regulates the metabolism of amyloid precursor protein (APP) and accelerates its processing into non-amyloidogenic APP, the overexpression of mGluR5 may be related to the pathological state of APP metabolism in DS. PMID- 10090676 TI - Oligodendroglial degeneration in distemper: apoptosis or necrosis? AB - Canine distemper virus (CDV) causes a multifocal demyelinating disease in dogs. It was previously shown that the initial demyelinating lesions are directly virus induced since a correlation between the occurrence of demyelination and CDV replication in white matter cells was observed. During the course of infection oligodendrocytes undergo distinct morphological alterations, partly due to a restricted CDV infection of these cells, and eventually disappear from the lesions. This phenomenon has been described in vivo as well as in vitro. However, the reason for the morphological alterations and the following oligodendroglial depletion remained unclear. Since virus infection can induce cell death, it was investigated whether apoptosis or necrosis plays a role in the pathogenesis of demyelination in canine distemper. In brain tissue sections from dogs with acute distemper apoptotic cells were not detected within the demyelinating lesions using morphological and biochemical cell death criteria. In chronic distemper, apoptotic cells - presumably inflammatory cells - were seen within the perivascular cuffs. These in vivo findings were correlated to the in vitro situation using CDV-infected primary dog brain cell cultures as well as Vero cells. Infection with culture-adapted CDV lead to massive necrosis but not to apoptosis. After infection with virulent CDV neither apoptosis nor necrosis was a predominant feature in either culture system. These findings suggest that virus induced demyelination in canine distemper is not the direct consequence of apoptosis or necrosis. It is speculated that another mechanism must be responsible for the observed morphological alterations of oligodendrocytes, ultimately leading to demyelination. PMID- 10090677 TI - Ultrastructural localization of alpha-, beta- and gamma-sarcoglycan and their mutual relation, and their relation to dystrophin, beta-dystroglycan and beta spectrin in normal skeletal myofiber. AB - Ultrastructural localization of alpha-, beta- and gamma-sarcoglycan and their mutual relation, and their relation to dystrophin, beta-dystroglycan and beta spectrin were investigated in normal skeletal myofibers. Single-immunogold labeling electron microscopy showed that the signals of rabbit and sheep polyclonal antibodies against the synthetic peptide of the cytoplasmic domain of alpha-, beta or gamma-sarcoglycan were present along the inside surface of muscle plasma membrane and at the sarcoplasmic side of plasma membrane invaginations and vesicular structures in subsarcolemmal areas. These localizations were similar to that of dystrophin, beta-dystroglycan and beta-spectrin. Double-immunogold labeling disclosed the close association of alpha-, beta- and gamma-sarcoglycan each other and alpha-, beta-, gamma-sarcoglycan with dystrophin or beta dystroglycan, and this was confirmed by statistical analysis. Monoclonal antibody against the extracellular domain of alpha-sarcoglycan was used with above mentioned polyclonal anti-beta- and -gamma-sarcoglycan antibodies for triple immunogold labeling, in which signals of alpha-sarcoglycan localized at the outer surface of muscle plasmalemma and those of beta- and gamma-sarcoglycans were present at the inside surface of plasma membrane. The triple immunolabeling showed an occasional closely associated presence of the three signals for alpha-, beta-and gamma-sarcoglycans, and a more frequent association for two signals out of alpha-, beta- and gamma-sarcoglycans. This study demonstrated that alpha-, beta- and gamma-sarcoglycan are closely located to one another and to dystrophin and beta-dystroglycan at the muscle plasma membrane. PMID- 10090678 TI - Substance P-induced enhanced permeability of dura mater microvessels is accompanied by pronounced ultrastructural changes, but is not dependent on the density of endothelial cell anionic sites. AB - Experimental data point to a determinant role for endothelial cell (EC) anionic sites in the regulation of vascular permeability. Previous studies have shown that EC anionic sites density is reduced in conditions of enhanced permeability. The pathophysiology of migraine and vascular headache encompasses dilatation of dural vessels and extravasation of plasma proteins. The current study was carried out to determine if the density of EC anionic sites is reduced in enhanced permeability of dural vessels. Enhanced permeability was chemically induced in rats by intravenous injection of substance P and was tested by assessing leakage of horseradish peroxidase (HRP). Anionic sites were labelled with cationic colloidal gold and their density was quantified from electron microscopy negatives. Experimental animals showed increased leakage of HRP from dural vessels. However, anionic sites in EC membranes (luminal and abluminal) showed no statistical differences when their mean densities in experimental and control animals were compared. The results indicate that in this model, factors other than the density of anionic sites may be important determinants in the permeability of dural vessels. Such factors may include structural alteration of ECs consistent with an increased permeability. In this study pronounced ultrastructural changes in ECs were noted in experimental animals including widening of intercellular junctions and an increase in the number of EC gaps and vesicles. PMID- 10090679 TI - Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. AB - Eleven autopsies of patients from the large founder-population with dominantly inherited spinocerebellar ataxia 2 (SCA2) in Holguin, Cuba, were analyzed by the same observers, including quantitative microscopic evaluation. As expected in this disease with highly unstable polyglutamine expansions, considerable variability was observed, which correlated to age at onset and to progression of clinical symptoms. The degeneration of the olivopontocerebellar regions as in classical olivopontocerebellar atrophy occurred early and severely in SCA2. The neuropathological progression soon included neuronal loss in the substantia nigra, striatum, pallidum and later even the neocortex, while the dentate nucleus was consistently spared. This widespread degeneration pattern goes clearly beyond purely cerebellar degenerations such as SCA5 and 6 and beyond spinocerebellar degenerations such as SCA1, 3, 7, also involves regions known to degenerate in Huntington's disease, and is quite similar to the degeneration pattern in sporadic patients with multi-system atrophy. PMID- 10090680 TI - Intrasellar malignant lymphoma developing within pituitary adenoma. AB - A mixed lymphoblastic T cell lymphoma and gonadotroph cell pituitary adenoma occurred 25 years after first resection of the adenoma. Within 1 year the lymphoma overgrew the adenoma, but was still restricted to the sellar region. Histologically, lymphoma and adenoma components were tightly admixed. Possible pathogenetic pathways for intra-adenomatous lymphoma development include monoclonal expansion of T cell infiltrates, expression of adhesion molecules specific for adenoma endothelium, and production of mitogenic pituitary hormones. PMID- 10090681 TI - Amyotrophic lateral sclerosis in an adult following acute paralytic poliomyelitis in early childhood. AB - About 30% of polio survivors develop a post-polio syndrome. Some of these patients develop slowly progressive muscle weakness known as post-poliomyelitis muscular atrophy (PPMA). We describe an unusual form of amyotrophic lateral sclerosis (ALS) in a patient with acute poliomyelitis in childhood. An 80-year old woman had acute poliomyelitis at 2 years of age and developed weakness limited to the lower extremities. Residual weakness was stable until the age of 75 when she developed rapidly progressive weakness that first affected her left arm and subsequently the right arm. Neurological examination revealed both upper and lower motor neuron signs. These clinical features were more consistent with ALS than PPMA. At autopsy, there was marked atrophy of the precentral gyrus. Microscopic examination revealed a severe loss of all nerve cells and pronounced fibrillary astrocytosis of the lumbar ventral horns in the spinal cord, presumably a result of poliomyelitis. Superimposed on these spinal cord alterations were the pathological features of ALS, consisting of loss of Betz cells, corticospinal tract degeneration and loss of motor neurons of other levels of the spinal cord. The findings included some atypical features for ALS, namely, sparing of the hypoglossal nucleus, absence of Bunina bodies and absence of ubiquitin-immunoreactive inclusions. Although poliomyelitis and ALS may be coincidental, the unusual pathological expression of ALS raise the possibility that it is related to the antecedent poliomyelitis. PMID- 10090682 TI - Incomplete lacunar infarction: an alternative hypothesis. PMID- 10090683 TI - Radiotherapy in rectal cancer. PMID- 10090684 TI - Indications for and results of combined modality treatment of colorectal cancer. AB - Combined modality chemoirradiation is commonly used as a component of treatment in combination with maximum resection for both high-risk resectable and locally advanced primary or recurrent rectal cancers. With surgically resected but high risk rectal cancers, postoperative chemoirradiation has been shown to improve both disease control (local and distant) and survival (disease-free and overall) and was recommended as standard adjuvant treatment at the 1990 National Institute of Health (NIH) Consensus Conference on Adjuvant treatment for patients with rectal and colon cancers. Subsequent intergroup trials are being conducted to help define optimal combinations of postoperative chemoirradiation for resected high-risk rectal cancers and to test sequencing issues of preoperative versus postoperative chemoirradiation. With locally unresectable primary or recurrent colorectal cancers, standard therapy with surgery, external beam irradiation (EBRT) and chemotherapy is often unsuccessful. When intraoperative electron irradiation (IOERT) is combined with standard treatment, local control and survival appear to be improved in separate analyses from the Mayo Clinic and the Massachusetts General Hospital (MGH). However, routine use of systemic therapy is also needed as a component of treatment, in view of high rates of systemic failure. PMID- 10090685 TI - Perioperative radiotherapy in rectal cancer. AB - Local failure of rectal cancer is one of the principal causes of morbidity and mortality. In order to lower unacceptably high local failure rates, pre- or postoperative radiotherapy has been extensively investigated. The collected information from all controlled trials reported so far shows that the proportion of local recurrences is reduced to less than half when radiotherapy up to moderately high doses is given preoperatively. This reduction is smaller after postoperative radiotherapy, even if higher doses are used. In addition, there is a positive influence on survival from preoperative radiotherapy. Improved survival has also been seen in trials using postoperative radiotherapy, but only when combined with chemotherapy. With proper radiation techniques, sufficiently high doses can be given preoperatively with little, if any, increase in postoperative mortality and morbidity. Furthermore, late toxicity can be anticipated to be low provided the technique is optimal. The beneficial effects noted so far have been achieved in trials where 'standard' surgery has been used, followed by a local recurrence rate of more than 20% (average 29%, range 23-46%) of the patients. It is, however, possible that the reduction in local failure rates is proportionally even greater added to 'optimal' surgery, although the absolute number of failures prevented is lower. PMID- 10090686 TI - Setting priorities versus managing closures--what is the ethically most sound way of handling changes in the health care system? AB - The answer to the question of the title depends on a number of circumstances, and I go through and comment on five of them. Then an attempt is made to keep some of these circumstances constant and vary others in order to highlight the importance of their ethical points of departure. The pros and cons of various choices are discussed and conclusions are suggested. To make further progress, the original question in the title is replaced by two new questions: under what conditions is managing closures the ethically soundest way of handling changes in the health care system? And, under what conditions is setting priorities the ethically soundest way of handling changes in the health care system? Some tentative answers to these questions are outlined towards the end of this paper. PMID- 10090687 TI - Where do we stand? Research and policy issues concerning inequalities in health and in healthcare. AB - There are signs that the seriousness of the challenge posed by social inequalities in health and in healthcare is filtering through to governments in an increasing number of countries. The problem includes a large, and in some cases widening, gap between the health of the rich and the poor within countries, coupled with serious social and economic inequalities across society in general. Healthcare reforms are posing further dilemmas in relation to equity. The first part of this paper outlines some of the latest evidence on the scale and nature of the problem and the key research questions selected for future study in the national research programmes set up on the subject. The second part considers unemployment and health in more detail, illustrating some of the policy issues which this raises. The last part focuses on practical strategies for the health sector to adopt to build a more equitable policy response. PMID- 10090688 TI - Ethics and allocation of health resources--the influence of poverty on health. AB - Poverty and health are examined from the global and Nordic perspectives. The data from global social policy research, Nordic comparisons and equity in health research provide a basis for the discussion. At the global level the consequences of poverty are growing and the resultant problems posed are becoming increasingly evident. Poverty and sickness are interwoven; poverty aggravates mental problems, a situation regarding which we have seen steady deterioration. Research suggests that social cohesion, the factor that creates social capital and empowerment in societies, is a major factor that promotes health and the economy. Structural measures to combat poverty would require a global social policy: global redistribution, global regulation and global provision. However, the international community is not yet fully prepared for this discussion. At the Nordic level, Finland is a laboratory in which the viability of the welfare state has been tested in the worst recession ever to hit an OECD country. On the whole, it seems that income disparity has not grown during the recession and that services have functioned moderately well despite budget cuts. However, during that period the correlation between unemployment and sickness became apparent, and the challenges to healthcare more evident. We must make headway in untangling these relationships, because the tendency towards greater income disparity is growing in the post-recession boom. At the social welfare and health service level even the Nordic welfare states are not in full command of the means to alleviate poverty and its related health problems. Has the time come to dispel our Nordic arrogance and look at how the present services may in fact be generating inequity? PMID- 10090689 TI - Inequalities in health--future threats to equity. AB - In discussions about equity there is a tendency to focus on the inequalities in health status that appear to be the result of the material and immaterial consequences of a lower income, professional or social status in society. If we look at publications such as the Black Report in the UK or Ongelijke gezondheid in The Netherlands, we have to accept that despite our universal access to healthcare and the existence in many Western countries of social security measures that preclude 'real' poverty, considerable differences in health continue to exist between socioeconomic groups. This is corroborated for many other European countries in the research carried out by a concerted action led by Mackenbach. These inequalities in health have been referred to in many countries as inequities, meaning that society finds them unjust and expects them to be 'avoidable' or amenable to policy interventions. However, the research on the causal networks underlying the occurrence and the avoidability of inequalities in health remains sparse and intervention studies seem to focus on policy measures that can be evaluated, but which will most likely have a limited impact on the inequalities measured at the population level. Thus the research community leaves policymakers with very little evidence on which to build policy initiatives that are nevertheless requested by many governments. The third element, which needs to be addressed in this context, is the ominous inequality in access to healthcare. Since the debate on equity in health has rightly been initiated in the context of a broader, more intersectoral approach to health policy, very little attention has been paid, so far, to the issue of universal access to quality healthcare services. This is because in the second half of this century most Western (European) countries have created a healthcare system with universal access, financed either through taxation or through social insurance schemes. It is these financing systems that will be threatened in the years to come by the considerable demographic shift occasioned by the ageing of the post-war baby boom and the incentives for risk selection that have been introduced in many systems as part of the 'market' mechanisms. The benefits of these incentives have clearly been a greater efficiency at the patient or service level, but there is still the question of whether it will be a more efficient system also at a population level if equity considerations continue to require a system of universal access to all the healthcare technology that will become available in the coming years. The other side of the coin of risk solidarity is the delimitation of the collective responsibility, thus of a basic benefit package. It is important to realize that equity has been a fundamental underlying value that has led to the creation of the healthcare systems as we know them but which may have become so accepted that it is no longer carefully considered when looking at issues of rationing or health reforms. PMID- 10090690 TI - Sliced down to the moral backbone? Ethical issues of structural reforms in healthcare organizations. AB - Throughout the 1990s we have experienced a wave of healthcare reforms. This article assesses central issues in policy and systems as well as structural changes in the provision of services against the ethical principles of non maleficence, beneficence, autonomy and justice. The lack of universal coverage is a serious threat to a just and equitable healthcare system. Doubts have recently been expressed concerning the benefits of competition, even within a regulated internal market. Service reorganization raises fewer ethical concerns. Cost cutting has followed in the aftermath of the financial crises of the early 1990s, and when carried out by restricting access, it may be in conflict with principles of justice and autonomy. Mere cost-cutting does not, however, establish a viable political agenda. It is argued that changes in healthcare need to be implemented in a way that does not lead to conflict with professional values. PMID- 10090691 TI - Data needs in studies on equity in health and access to care--ethical considerations. AB - In order to study equity in health and access to care in an appropriate way, data are needed on an individual level and must include information about health, mortality, morbidity, utilization of care, age, sex, residential area, family situation and the social and economic circumstances of each individual. These data must be collected at several points of time during a life cycle. This is a demanding task requiring many resources and methodological and ethical considerations. The ethical and political trade-off is between our demand for knowledge and a fair distribution of resources in order to achieve equity in health and access to care and the need to administrate sensitive data without threatening personal integrity. In presenting results from Swedish studies, it is argued that the benefits of using registers for this kind of epidemiological research by far outweigh the risk of using registers. PMID- 10090692 TI - Screening for early detection of cancer--ethical aspects. AB - Ethical principles to be followed in cancer screening programmes are intended mainly to minimize unnecessary harm for the participating individuals. The principles that have been recommended by the Council of Europe, Committee of Ministers are: 1) Effectiveness is a necessary prerequisite for a screening activity to be ethical. 2) The need for a balance between the advantages and disadvantages of screening for a target population and an individual, between social and economic costs, equity and individual rights and freedoms. 3) The need for information about both the positive and the negative aspects of a screening programme. 4) The decision to participate in a screening programme or in research should be taken freely. 5) The right to integrity, i.e., the results of the tests are not communicated to those who do not wish to be informed, and the need to have laws and regulations on any communication of personal data derived from screening to third parties. PMID- 10090693 TI - Understanding informed consent. AB - Properly understood, informed consent is a process of communication between researcher and subject. The purpose of the informed consent form is to document the informed consent discussion. The place of informed consent in leading international codes of research ethics is reviewed. Some prominent examples of past violations of informed consent are discussed. Even when properly understood, informed consent presents an array of ongoing problems and unanswered questions. These include the question of how much information must be given to research subjects, and how much is too much; and how to ensure the full voluntariness of subjects' consent, especially when the researcher is also the patient's physician. An ongoing problem is the 'therapeutic misconception'--the belief that proposed research is a promising treatment intended to benefit the subjects. The complexity of the technical language in which consent forms are written remains a problem, though this can easily be remedied. PMID- 10090694 TI - Misconduct in clinical research--the Scandinavian experience and actions for prevention. AB - The Nordic countries, Denmark, Norway, Sweden and Finland, started relatively early with the establishment of national committees dealing with scientific misconduct within the health sciences. They originally included slightly different parts of the dishonesty spectrum, when launching their independent control bodies, but have since then converged, with the end result that all four countries now include all aspects of the spectrum. In other words, the ranges now cover alleged fabrication and plagiarism on one side, and quarrels about authorship and terms of procedure within cooperating groups of scientists on the other. The Nordic experiences have made it possible to estimate a prevalence rate of 1-2 presented cases per million inhabitants, of which only approximately 1/5 is serious. The preventive actions have been publications of guidelines for: scientific co-operation; raw data storage; authorship. Further, educational initiatives include postgraduate courses for senior scientists; postgraduate courses for junior scientists; influence via inquiries and investigations. The Nordic experiences point strongly to the necessity of an independent national control body. PMID- 10090695 TI - Research misconduct in clinical research--the American experience and response. AB - Research misconduct in the United States has occurred sporadically since 1961 in the laboratories of some of our most distinguished scientists. In view of the enormous number of research grants funded, cases of this kind are relatively uncommon, but have none the less attracted governmental supervision and calls for reform. The scientific community, universities and government have addressed the issue in various ways and changes have been proposed and some actually instituted. In view of human nature, no one seriously believes that dishonesty in research can be prevented to any greater extent than in any other human activity. However, some practices may discourage and mitigate such occurrences. These include: education in sound laboratory research practices, a fair distribution of authorship assignment, and adequate supervision of research personnel including appropriate reviewing of primary data. Other measures which might be considered include: an adequate check of the credentials of all new personnel, audits for clinical research, especially for those involving significant numbers of patients and multiple institutions, and the introduction of quality control concepts into research procedures. The hope is that the senior individual scientist responsible for the quality and integrity of the research will institute such measures as needed, and that institutional and government supervision will not interfere with the creative process. PMID- 10090696 TI - Ethics of randomized clinical trials and the 'ALARA' approach. AB - A balanced discussion on the ethics of randomized clinical trials should not be based on a single ethical aspect such as respect for the patient's autonomy. Rather, the analysis should consider the four ethical principles--respect for autonomy, non-maleficence, beneficence, and justice--as applicable to all groups of persons concerned. We present the ethical benefits and costs of the present practice of randomized clinical trials for four groups: patients involved in clinical trials, patients not involved in trials, participating physicians and society. The ALARA (As Low As Reasonably Achievable) approach is then introduced and practical measures to achieve a positive balance between ethical benefits and costs of randomized trials are proposed. PMID- 10090697 TI - An ethical analysis of the phenomenon of misconduct in research. AB - Ethical problems of research misconduct can be viewed in many ways. The main issue at stake is the reliability of what is presented as scientific facts. If we cannot trust research findings, the consequences can be fatal for all affected parties. There are several actors in the context of research integrity and misconduct, especially the individual scientist and the scientific community. The honesty of scientists is important but this in itself is not a sufficient condition for research integrity. We need guidelines and rules. Researchers accused of misconduct must be guaranteed legal security. A closed definition of scientific misconduct seems to be the best one for protecting the legal security, but on the other hand, an open definition is better for the protection of science. There is a gap between ethics and law in the view of research misconduct. Some actions that are regarded as unethical are quite well within the law. In order to deal with real cases of alleged research misconduct, there must be a way of closing this gap. PMID- 10090698 TI - Stevens-Johnson syndrome in patients on phenytoin and cranial radiotherapy. AB - The use of phenytoin as a prophylactic anticonvulsant after brain surgery, particularly for brain tumors, is a common practice, regardless of whether the patient has a previous history of convulsions. This treatment policy assumes that the benefits exceed the risks. Four cases are described of adverse reactions to phenytoin during the concomitant use of cranial radiotherapy. In one patient this proved fatal. There is increasing anecdotal support in the literature for a synergistic effect between phenytoin therapy and cranial radiotherapy that can result in the life-threatening Stevens-Johnson syndrome. While the association is uncommon, four cases within 24 months in one department suggest that the routine use of postoperative phenytoin as a prophylactic anticonvulsant in the absence of a history of seizures may not be warranted, particularly if the patient is to receive cranial radiotherapy. PMID- 10090699 TI - High-grade non-Hodgkin's lymphoma treated in northern Norway--treatment, outcome, and prognostic factors. AB - In an unselected group of patients with high-grade non-Hodgkin's lymphoma (HG NHL) treated at our institution during a 10-year period (1986-1995), we studied treatment outcome and influence of possible prognostic factors. 187 HG-NHL patients were analysed retrospectively with regard to personal, treatment and disease-specific characteristics. Median age was 65 years and the male:female ratio was 1.2:1. Over a median follow-up of 57 months the overall response rate was 87% (complete response 72%, partial response 15%). The 2- and 5-year cumulative disease-specific survival rates were 64+/-4% (mean +/- SEM) and 48+/ 5%, respectively. In a univariate analysis, the following variables were associated with prognosis in terms of survival: Patient age, clinical stage, performance status, bone-marrow infiltration, haemoglobin, erythrocyte sedimentation rate, lactate dehydrogenase (LDH), and serum albumin. In multivariate analyses, patient age, performance status, LDH, and haemoglobin came out as independent prognostic factors for survival. PMID- 10090700 TI - The use of etidronate in therapy-resistant hypercalcemia. PMID- 10090701 TI - Hazardous wastes in eastern and central Europe: technology and health effects. AB - Issues of hazardous waste management are major concerns in the countries of eastern and central Europe. A National Institute of Environmental Health Sciences supported conference was held in Prague, Czech Republic, as a part of a continuing effort to provide information and promote discussion among the countries of eastern and central Europe on issues related to hazardous wastes. The focus was on incineration as a means of disposal of hazardous wastes, with discussions on both engineering methods for safe incineration, and possible human health effects from incineration by-products. Representatives from government agencies, academic institutions, and local industries from 14 countries in the region participated along with a few U.S. and western European experts in this field. A series of 12 country reports documented national issues relating to the environment, with a focus on use of incineration for hazardous waste disposal. A particularly valuable contribution was made by junior scientists from the region, who described results of environmental issues in their countries. PMID- 10090702 TI - Water pollution and human health in China. AB - China's extraordinary economic growth, industrialization, and urbanization, coupled with inadequate investment in basic water supply and treatment infrastructure, have resulted in widespread water pollution. In China today approximately 700 million people--over half the population--consume drinking water contaminated with levels of animal and human excreta that exceed maximum permissible levels by as much as 86% in rural areas and 28% in urban areas. By the year 2000, the volume of wastewater produced could double from 1990 levels to almost 78 billion tons. These are alarming trends with potentially serious consequences for human health. This paper reviews and analyzes recent Chinese reports on public health and water resources to shed light on what recent trends imply for China's environmental risk transition. This paper has two major conclusions. First, the critical deficits in basic water supply and sewage treatment infrastructure have increased the risk of exposure to infectious and parasitic disease and to a growing volume of industrial chemicals, heavy metals, and algal toxins. Second, the lack of coordination between environmental and public health objectives, a complex and fragmented system to manage water resources, and the general treatment of water as a common property resource mean that the water quality and quantity problems observed as well as the health threats identified are likely to become more acute. PMID- 10090703 TI - Impact of diet on lead in blood and urine in female adults and relevance to mobilization of lead from bone stores. AB - We measured high precision lead isotope ratios and lead concentrations in blood, urine, and environmental samples to assess the significance of diet as a contributing factor to blood and urine lead levels in a cohort of 23 migrant women and 5 Australian-born women. We evaluated possible correlations between levels of dietary lead intake and changes observed in blood and urine lead levels and isotopic composition during pregnancy and postpartum. Mean blood lead concentrations for both groups were approximately 3 microg/dl. The concentration of lead in the diet was 5.8 +/- 3 microg Pb/kg [geometric mean (GM) 5.2] and mean daily dietary intake was 8.5 microg/kg/day (GM 7.4), with a range of 2-39 microg/kg/day. Analysis of 6-day duplicate dietary samples for individual subjects commonly showed major spikes in lead concentration and isotopic composition that were not reflected by associated changes in either blood lead concentration or isotopic composition. Changes in blood lead levels and isotopic composition observed during and after pregnancy could not be solely explained by dietary lead. These data are consistent with earlier conclusions that, in cases where levels of environmental lead exposure and dietary lead intake are low, skeletal contribution is the dominant contributor to blood lead, especially during pregnancy and postpartum. PMID- 10090704 TI - Tetrachloroethylene-contaminated drinking water in Massachusetts and the risk of colon-rectum, lung, and other cancers. AB - We conducted a population-based case-control study to evaluate the relationship between cancer of the colon-rectum (n = 326), lung (n = 252), brain (n = 37), and pancreas (n = 37), and exposure to tetrachloroethylene (PCE) from public drinking water. Subjects were exposed to PCE when it leached from the vinyl lining of drinking-water distribution pipes. Relative delivered dose of PCE was estimated using a model that took into account residential location, years of residence, water flow, and pipe characteristics. Adjusted odds ratios (ORs) for lung cancer were moderately elevated among subjects whose exposure level was above the 90th percentile whether or not a latent period was assumed [ORs and 95% confidence intervals (CIs), 3.7 (1.0-11.7), 3.3 (0.6-13.4), 6.2 (1.1-31.6), and 19.3 (2.5 141.7) for 0, 5, 7, and 9 years of latency, respectively]. The adjusted ORs for colon-rectum cancer were modestly elevated among ever-exposed subjects as more years of latency were assumed [OR and CI, 1.7 (0.8-3.8) and 2.0 (0.6-5.8) for 11 and 13 years of latency, respectively]. These elevated ORs stemmed mainly from associations with rectal cancer. Adjusted ORs for rectal cancer among ever exposed subjects were more elevated [OR and CI, 2.6 (0. 8-6.7) and 3.1 (0.7-10.9) for 11 and 13 years of latency, respectively] than were corresponding estimates for colon cancer [OR and CI, 1.3 (0.5-3.5) and 1.5 (0.3-5.8) for 11 and 13 years of latency, respectively]. These results provide evidence for an association between PCE-contaminated public drinking water and cancer of the lung and, possibly, cancer of the colon-rectum. PMID- 10090705 TI - Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid binding globulin. AB - Organochlorine compounds, particularly polychlorinated biphenyls (PCBs), alter serum thyroid hormone levels in humans. Hydroxylated organochlorines have relatively high affinities for the serum transport protein transthyretin, but the ability of these compounds to interact with the human thyroid receptor is unknown. Using a baculovirus expression system in insect cells (Sf9 cells), we produced recombinant human thyroid receptor ss (hTRss). In competitive binding experiments, the recombinant receptor had the expected relative affinity for thyroid hormones and their analogs. In competitive inhibition experiments with PCBs, hydroxylated PCBs (OH-PCBs), DDT and its metabolites, and several organochlorine herbicides, only the OH-PCBs competed for binding. The affinity of hTRss for OH-PCBs was 10,000-fold lower (Ki = 20-50 microM) than its affinity for thyroid hormone (3,3',5-triiodothyronine, T3; Ki = 10 nM). Because their relative affinity for the receptor was low, we tested the ability of OH-PCBs to interact with the serum transport proteins--transthyretin and thyroid-binding globulin (TBG). With the exception of one compound, the OH-PCBs had the same affinity (Ki = 10-80 nM) for transthyretin as thyroid hormone (thyroxine; T4). Only two of the OH-PCBs bound TBG (Ki = 3-7 microM), but with a 100-fold lower affinity than T4. Hydroxylated PCBs have relatively low affinities for the human thyroid receptor in vitro, but they have a thyroid hormonelike affinity for the serum transport protein transthyretin. Based on these results, OH-PCBs in vivo are more likely to compete for binding to serum transport proteins than for binding to the thyroid receptor. PMID- 10090706 TI - High concentrations of heavy metals in neighborhoods near ore smelters in northern Mexico. AB - In developing countries, rapid industrialization without environmental controls has resulted in heavy metal contamination of communities. We hypothesized that residential neighborhoods located near ore industries in three northern Mexican cities would be heavily polluted with multiple contaminants (arsenic, cadmium, and lead) and that these sites would be point sources for the heavy metals. To evaluate these hypotheses, we obtained samples of roadside surface dust from residential neighborhoods within 2 m of metal smelters [Torreon (n = 19)] and Chihuahua (n = 19)] and a metal refinery [Monterrey (n = 23)]. Heavy metal concentrations in dust were mapped with respect to distance from the industrial sites. Correlation between dust metal concentration and distance was estimated with least-squares regression using log-transformed data. Median dust arsenic, cadmium, and lead concentrations were 32, 10, and 277 microg/g, respectively, in Chihuahua; 42, 2, and 467 microg/g, respectively, in Monterrey, and 113, 112, and 2,448 microg/g, respectively, in Torreon. Dust concentrations of all heavy metals were significantly higher around the active smelter in Torreon, where more than 90% of samples exceeded Superfund cleanup goals. At all sites, dust concentrations were inversely related to distance from the industrial source, implicating these industries as the likely source of the contamination. We concluded that residential neighborhoods around metal smelting and refining sites in these three cities are contaminated by heavy metals at concentrations likely to pose a health threat to people living nearby. Evaluations of human exposure near these sites should be conducted. Because multiple heavy metal pollutants may exist near smelter sites, researchers should avoid attributing toxicity to one heavy metal unless others have been measured and shown not to coexist. PMID- 10090707 TI - Effects of endocrine-disrupting contaminants on amphibian oogenesis: methoxychlor inhibits progesterone-induced maturation of Xenopus laevis oocytes in vitro. AB - There is currently little evidence of pollution-induced endocrine dysfunction in amphibia, in spite of widespread concern over global declines in this ecologically diverse group. Data regarding the potential effects of endocrine disrupting contaminants (EDCs) on reproductive function in amphibia are particularly lacking. We hypothesized that estrogenic EDCs may disrupt progesterone-induced oocyte maturation in the adult amphibian ovary, and tested this with an in vitro germinal vesicle breakdown assay using defolliculated oocytes from the African clawed frog, Xenopus laevis. While a variety of natural and synthetic estrogens and xenoestrogens were inactive in this system, the proestrogenic pesticide methoxychlor was a surprisingly potent inhibitor of progesterone-induced oocyte maturation (median inhibitive concentration, 72 nM). This inhibitory activity was specific to methoxychlor, rather than to its estrogenic contaminants or metabolites, and was not antagonized by the estrogen receptor antagonist ICI 182,780, suggesting that this activity is not estrogenic per se. The inhibitory activity of methoxychlor was dose dependent, reversible, and early acting. However, washout was unable to reverse the effect of short methoxychlor exposure, and methoxychlor did not competitively displace [3H]progesterone from a specific binding site in the oocyte plasma membrane. Therefore, methoxychlor may exert its action not directly at the site of progesterone action, but downstream on early events in maturational signaling, although the precise mechanism of action is unclear. The activity of methoxychlor in this system indicates that xenobiotics may exert endocrine-disrupting effects through interference with progestin-regulated processes and through mechanisms other than receptor antagonism. PMID- 10090708 TI - The role of humic substances in drinking water in Kashin-Beck disease in China. AB - We conducted in vitro and in vivo assays in a selenium-deficient system to determine if organic matter (mainly fulvic acid; FA) is involved in a free radical mechanism of action for Kashin-Beck disease. Cartilage cell culture experiments indicated that the oxy or hydroxy functional groups in FA may interfere with the cell membrane and result in enhancement of lipid peroxidation. Experiments with rats demonstrated that toxicity from FA was reduced when the hydroxy group was blocked. Induction of lipid peroxidation by FA in liver and blood of rats was similar to that exhibited by acetyl phenyl hydrazine. FA accumulated in bone and cartilage, where selenium rarely concentrates. In addition, selenium supplementation in rats' drinking water inhibited the generation of oxy-free radicals in bone. We hypothesized that FA in drinking water is an etiological factor of Kashin-Beck disease and that the mechanism of action involves the oxy and hydroxy groups in FA for the generation of free radicals. Selenium was confirmed to be a preventive factor for Kashin-Beck disease. PMID- 10090709 TI - International trends in rates of hypospadias and cryptorchidism. AB - Researchers from seven European nations and the United States have published reports of increasing rates of hypospadias during the 1960s, 1970s, and 1980s. Reports of increasing rates of cryptorchidism have come primarily from England. In recent years, these reports have become one focus of the debate over endocrine disruption. This study examines more recent data from a larger number of countries participating in the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) to address the questions of whether such increases are worldwide and continuing and whether there are geographic patterns to any observed increases. The ICBDMS headquarters and individual systems provided the data. Systems were categorized into five groups based on gross domestic product in 1984. Hypospadias increases were most marked in two American systems and in Scandinavia and Japan. The increases leveled off in many systems after 1985. Increases were not seen in less affluent nations. Cryptorchidism rates were available for 10 systems. Clear increases in this anomaly were seen in two U.S. systems and in the South American system, but not elsewhere. Since 1985, rates declined in most systems. Numerous artifacts may contribute to or cause upward trends in hypospadias. Possible "real" causes include demographic changes and endocrine disruption, among others. PMID- 10090710 TI - Juvenile hypothyroidism among two populations exposed to radioiodine. AB - We found an epidemic of juvenile hypothyroidism among a population of self defined "downwinders" living near the Hanford nuclear facility located in southeast Washington State. The episode followed massive releases of 131I. Self reported data on 60 cases of juvenile hypothyroidism (<20 years of age) among a group of 801 Hanford downwinders are presented, as well as data concerning the thyroid status of approximately 160,000 children exposed to radioiodine before 10 years of age as a result of the 26 April 1986 Chernobyl explosion in the former Soviet Union. These children were residents of five regions near Chernobyl. They were examined by standardized screening protocols over a period of 5 years from 1991 to 1996. They are a well-defined group of 10 samples. Fifty-six cases of hypothyroidism were found among boys and 92 among girls. Body burdens of 137Cs have been correlated with hypothyroidism prevalence rates. On the other hand, the group of juvenile (<20 years of age) Hanford downwinders is not a representative sample. Most of the 77 cases of juvenile hypothyroidism in the Hanford group were diagnosed from 1945 to 1970. However, the ratio of reported cases to the county population under 20 years of age is roughly correlated with officially estimated mean levels of cumulative thyroid 131I uptake in these counties, providing evidence that juvenile hypothyroidism was associated with radioiodine exposures. Because even subtle hypothyroidism may be of clinical significance in childhood and can be treated, it may be useful to screen for the condition in populations exposed to radioiodine fallout. Although radiation exposure is associated with hypothyroidism, its excess among fallout-exposed children has not been previously quantified. PMID- 10090711 TI - Animals as sentinels of human health hazards of environmental chemicals. AB - A workshop titled "Using Sentinel Species Data to Address the Potential Human Health Effects of Chemicals in the Environment," sponsored by the U.S. Army Center for Environmental Health Research, the National Center for Environmental Assessment of the EPA, and the Agency for Toxic Substances and Disease Registry, was held to consider the use of sentinel and surrogate animal species data for evaluating the potential human health effects of chemicals in the environment. The workshop took a broad view of the sentinel species concept, and included mammalian and nonmammalian species, companion animals, food animals, fish, amphibians, and other wildlife. Sentinel species data included observations of wild animals in field situations as well as experimental animal data. Workshop participants identified potential applications for sentinel species data derived from monitoring programs or serendipitous observations and explored the potential use of such information in human health hazard and risk assessments and for evaluating causes or mechanisms of effect. Although it is unlikely that sentinel species data will be used as the sole determinative factor in evaluating human health concerns, such data can be useful as for additional weight of evidence in a risk assessment, for providing early warning of situations requiring further study, or for monitoring the course of remedial activities. Attention was given to the factors impeding the application of sentinel species approaches and their acceptance in the scientific and regulatory communities. Workshop participants identified a number of critical research needs and opportunities for interagency collaboration that could help advance the use of sentinel species approaches. PMID- 10090712 TI - Polycyclic aromatic hydrocarbons in carcinogenesis. AB - A symposium on "Polycyclic Aromatic Hydrocarbons (PAHs) in Carcinogenesis" was presented at the third International Congress of Pathophysiology held in Lathi, Finland, 28 June-3 July 1998. The congress was also sponsored by the International Union of Biological Sciences and the International Society of Free Radical Research. Institutional support for the symposium included the Electric Power Research Institute, National Center for Toxicological Research, and EPA/National Health and Environmental Effects Research Laboratory and the Office of Solid Waste and Emergency Response. The symposium focused on the sources, carcinogenicity, genotoxicity, and risk assessment of individual and mixtures of PAHs that are found in solid wastes, Superfund sites, and other hazardous waste sites. Based on the occurrence of PAHs at numerous Superfund sites and the significant data gaps on the toxic potential of certain PAHs, the information developed during this symposium would be of value in assessing health risks of these chemicals at Superfund and other hazardous waste sites. PMID- 10090713 TI - A retired shipyard worker with rapidly progressive pulmonary interstitial fibrosis. AB - We present a case of progressive interstitial fibrosis in a retired shipyard worker who was exposed to asbestos during the postwar era of the late 1940s and 1950s, when asbestos exposures in the workplace were not regulated. Forty years later, at 63 years of age, the patient presented with restrictive lung disease. The patient was diagnosed with asbestos-related pleural disease and parenchymal asbestosis. He remained stable for the next 7 years, but then he began to manifest rapid clinical progression, which raised the possibility of an unusual variant of asbestosis, a concomitant interstitial process, or an unrelated disease. Lung biopsy was not undertaken because of the patient's low pulmonary reserve and limited treatment options. An empiric trial of oral steroids was initiated, but his pulmonary status continued to deteriorate and he died of pulmonary failure at 72 years of age. Many diseases result in pulmonary interstitial fibrosis. Ideally, open lung biopsy should be performed, but this procedure inevitably causes complications in many patients with end-stage restrictive lung disease. Furthermore, while the presence of asbestos bodies in tissue sections is a sensitive and specific marker of asbestos exposure, neither this finding nor any other charge is a marker indicative of asbestosis or the severity of asbestosis. With the enactment of the Asbestos Standard in the United States, asbestos exposures have been decreasing in this country. However, industries that produce asbestos products and wastes continue to expand in developing countries. Prevention of asbestos-related lung disease should be a global endeavor, and asbestos exposures should be regulated in both developed and developing countries. PMID- 10090714 TI - NIEHS reaches out with town meetings. PMID- 10090715 TI - Double exposure. Environmental tobacco smoke. AB - One study after another is finding strong associations between a variety of human illness and exposure to environmental tobacco smoke (ETS). A 1986 report by the U.S. Surgeon General concluded that ETS is a cause of disease, including lung cancer, in healthy nonsmokers. Other reports have documented causal associations between ETS and lower respiratory tract infections, middle ear disease and exacerbation of asthma in children, heart disease, retardation of fetal growth, sudden infant death syndrome, and nasal sinus cancer. However, the findings from many of these studies remain controversial. A number of scientists remain skeptical about the association between ETS and serious illness in nonsmokers, charging that scientific journals either fail to publish pro-tobacco findings and meta-analyses or disregard those that are published. They also claim that many epidemiological studies declare causal associations based on marginal odds ratios. PMID- 10090716 TI - Settling for less? Tobacco industry. AB - In November 1998, a coalition of state negotiators and five tobacco companies reached an agreement in which the cigarette makers would pay out the biggest financial settlement in history, $206 billion over the next 25 years to 46 states, to compensate for the medical treatment of patients suffering from tobacco-related health problems. Critics of the settlement say the tobacco companies are getting off the hook too easily, and that the deal's public health provisions are unacceptably riddled with loopholes. But the attorneys general who negotiated the settlement defended it as a good deal-but clearly not as a panacea. Ultimately, they feel, Congress should pass legislation to provide essential reforms, including full Food and Drug Administration authority over tobacco. PMID- 10090717 TI - Turning over a new leaf. Tobacco. AB - Anticipating a diminishing market for cigarettes and other tobacco products in the future, researchers around the country are studying alternative uses for tobacco plants. The most promising field of research for tobacco involves the genetic engineering of tobacco plants to produce various substances such as industrial chemicals, pharmaceuticals, and consumer product ingredients. Tobacco has been called the "fruit fly of the plant kingdom" because of the ease with which it can be genetically engineered. There are countless possibilities for the use of tobacco, but current efforts are concentrating on engineering tobacco to produce vaccines, human enzymes, and plastics. Tobacco researchers have been successful in expressing bovine lysozyme, an enzyme with antibacterial properties, and insulin. PMID- 10090718 TI - An RNA thermometer. PMID- 10090719 TI - Chromatin remodeling and activation of chromosomal DNA replication by an acidic transcriptional activation domain from BRCA1. AB - An increasing number of transcription factors have been shown to activate DNA replication. However, the underlying mechanism remains to be elucidated. Here it is shown that when tethered to a cellular replication origin, the acidic transcriptional activation domain of the breast cancer protein BRCA1 alters the local chromatin structure and stimulates chromosomal DNA replication. Cancer predisposing mutations in BRCA1 that abolish transcriptional activation also prevent chromatin remodeling and activation of replication. Chromatin remodeling occurs even in the absence of a functional replication origin. Thus, increasing chromatin accessibility may be an important mechanism used by transcription factors to facilitate multiple nuclear processes. PMID- 10090720 TI - Reelin-induced tyrosine [corrected] phosphorylation of disabled 1 during neuronal positioning. AB - The reelin (reln) and disabled 1 (dab1) genes both ensure correct neuronal positioning during brain development. We have found that the intracellular Dab1 protein receives a tyrosine phosphorylation signal from extracellular Reln protein. Genetic analysis shows that reln function depends on dab1, and vice versa, as expected if both genes are in the same pathway. Dab1 is expressed at a higher level, yet phosphorylated at a lower level, in reln mutant embryo brains. In primary neuronal cultures, Dab1 tyrosine phosphorylation is stimulated by exogenous Reln. These results suggest that Reln regulates neuronal positioning by stimulating Dab1 tyrosine phosphorylation. PMID- 10090721 TI - Six3 overexpression initiates the formation of ectopic retina. AB - The homeobox gene sine oculis (so) is essential for visual system formation in Drosophila. A vertebrate member of the so/Six gene family, Six3, is expressed in the developing eye and forebrain. Injection of Six3 RNA into medaka fish embryos causes ectopic Pax6 and Rx2 expression in midbrain and cerebellum, resulting in the formation of ectopic retinal primordia. Injected mouse Six3 RNA initiates ectopic expression of endogenous medaka Six3, uncovering a feedback control of Six3 expression. Initiation of ectopic retina formation reveals a pivotal role for Six3 in vertebrate retina development and hints at a conserved regulatory network underlying vertebrate and invertebrate eye development. PMID- 10090722 TI - Translational induction of heat shock transcription factor sigma32: evidence for a built-in RNA thermosensor. AB - Induction of heat shock proteins in Escherichia coli is primarily caused by increased cellular levels of the heat shock sigma-factor sigma32 encoded by the rpoH gene. Increased sigma32 levels result from both enhanced synthesis and stabilization. Previous work indicated that sigma32 synthesis is induced at the translational level and is mediated by the mRNA secondary structure formed within the 5'-coding sequence of rpoH, including the translation initiation region. To understand the mechanism of heat induction of sigma32 synthesis further, we analyzed expression of rpoH-lacZ gene fusions with altered stability of mRNA structure before and after heat shock. A clear correlation was found between the stability and expression or the extent of heat induction. Temperature-melting profiles of mRNAs with or without mutations correlated well with the expression patterns of fusion genes carrying the corresponding mutations in vivo. Furthermore, temperature dependence of mRNA-30S ribosome-tRNAfMet complex formation with wild-type or mutant mRNAs in vitro agreed well with that of the expression of gene fusions in vivo. Our results support a novel mechanism in which partial melting of mRNA secondary structure at high temperature enhances ribosome entry and translational initiation without involvement of other cellular components, that is, intrinsic mRNA stability controls synthesis of a transcriptional regulator. PMID- 10090723 TI - Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. AB - The E2F and DP protein families form heterodimeric transcription factors that play a central role in the expression of cell cycle-regulated genes. The crystal structure of an E2F4-DP2-DNA complex shows that the DNA-binding domains of the E2F and DP proteins both have a fold related to the winged-helix DNA-binding motif. Recognition of the central c/gGCGCg/c sequence of the consensus DNA binding site is symmetric, and amino acids that contact these bases are conserved among all known E2F and DP proteins. The asymmetry in the extended binding site TTTc/gGCGCc/g is associated with an amino-terminal extension of E2F4, in which an arginine binds in the minor groove near the TTT stretch. This arginine is invariant among E2Fs but not present in DPs. E2F4 and DP2 interact through an extensive protein-protein interface, and structural features of this interface suggest it contributes to the preference for heterodimers over homodimers in DNA binding. PMID- 10090724 TI - Association of Chk1 with 14-3-3 proteins is stimulated by DNA damage. AB - The protein kinase Chk1 is required for cell cycle arrest in response to DNA damage. We have found that the 14-3-3 proteins Rad24 and Rad25 physically interact with Chk1 in fission yeast. Association of Chk1 with 14-3-3 proteins is stimulated in response to DNA damage. DNA damage results in phosphorylation of Chk1 and the 14-3-3 proteins bind preferentially to the phosphorylated form. Genetic analysis has independently implicated both Rad24 and Rad25 in the DNA damage checkpoint pathway. We suggest that DNA damage-dependent association of phosphorylated Chk1 with 14-3-3 proteins mediates an important step along the DNA damage checkpoint pathway, perhaps by directing Chk1 to a particular substrate or to a particular location within the cell. An additional role for 14-3-3 proteins in the DNA-damage checkpoint has been suggested based on the observation that human Chk1 can phosphorylate Cdc25C in vitro creating a 14-3-3 binding site. Our results suggest that in fission yeast the interaction between the 14-3-3 proteins and Cdc25 does not require Chk1 function and is unaffected by DNA damage, in sharp contrast to the interaction between the 14-3-3 proteins and Chk1. PMID- 10090725 TI - Characterization of the imitation switch subfamily of ATP-dependent chromatin remodeling factors in Saccharomyces cerevisiae. AB - We have identified and characterized two Imitation Switch genes in Saccharomyces cerevisiae, ISW1 and ISW2, which are highly related to Drosophila ISWI, encoding the putative ATPase subunit of three ATP-dependent chromatin remodeling factors. Purification of ISW1p reveals a four-subunit complex with nucleosome-stimulated ATPase activity, as well as ATP-dependent nucleosome disruption and spacing activities. Purification of ISW2p reveals a two-subunit complex also with nucleosome-stimulated ATPase and ATP-dependent nucleosome spacing activities but no detectable nucleosome disruption activity. Null mutations of ISW1, ISW2, and CHD1 genes cause synthetic lethality in various stress conditions in yeast cells, revealing the first in vivo functions of the ISWI subfamily of chromatin remodeling complexes and demonstrating their genetic interactions. A single point mutation within the ATPase domain of both ISW1p and ISW2p inactivated all ATP dependent biochemical activities of the complexes, as well as the ability of the genes to rescue the mutant phenotypes. This demonstrates that the ATP-dependent chromatin-remodeling activities are essential for the in vivo functions of both ISW1 and ISW2 complexes. PMID- 10090726 TI - The boundaries of the silenced HMR domain in Saccharomyces cerevisiae. AB - The chromosomes of eukaryotes are organized into structurally and functionally discrete domains that provide a mechanism to compact the DNA as well as delineate independent units of gene activity. It is believed that insulator/boundary elements separate these domains. Here we report the identification and characterization of boundary elements that flank the transcriptionally repressed HMR locus in the yeast Saccharomyces cerevisiae. Deletion of these boundary elements led to the spread of silenced chromatin, whereas the ectopic insertion of these elements between a silencer and a promoter blocked the repressive effects of the silencer on that promoter at HMR and at telomeres. Sequence analysis indicated that the boundary element contained a TY1 LTR, and a tRNA gene and mutational analysis has implicated the Smc proteins, which encode structural components of chromosomes, in boundary element function. PMID- 10090727 TI - Wnt3a-/--like phenotype and limb deficiency in Lef1(-/-)Tcf1(-/-) mice. AB - Members of the LEF-1/TCF family of transcription factors have been implicated in the transduction of Wnt signals. However, targeted gene inactivations of Lef1, Tcf1, or Tcf4 in the mouse do not produce phenotypes that mimic any known Wnt mutation. Here we show that null mutations in both Lef1 and Tcf1, which are expressed in an overlapping pattern in the early mouse embryo, cause a severe defect in the differentiation of paraxial mesoderm and lead to the formation of additional neural tubes, phenotypes identical to those reported for Wnt3a deficient mice. In addition, Lef1(-/-)Tcf1(-/-) embryos have defects in the formation of the placenta and in the development of limb buds, which fail both to express Fgf8 and to form an apical ectodermal ridge. Together, these data provide evidence for a redundant role of LEF-1 and TCF-1 in Wnt signaling during mouse development. PMID- 10090729 TI - Uncoupling integrin adhesion and signaling: the betaPS cytoplasmic domain is sufficient to regulate gene expression in the Drosophila embryo. AB - Integrin cell surface receptors are ideally suited to coordinate cellular differentiation and tissue assembly during embryogenesis, as they can mediate both signaling and adhesion. We show that integrins regulate gene expression in the intact developing embryo by identifying two genes that require integrin function for their normal expression in Drosophila midgut endodermal cells. We determined the relative roles of integrin adhesion versus signaling in the regulation of these integrin target genes. We find that integrin-mediated adhesion is not required between the endodermal cells and the surrounding visceral mesoderm for integrin target gene expression. In addition, a chimeric protein that lacks integrin-adhesive function, but maintains the ability to signal, can substitute for the endogenous integrin and regulate integrin target genes. This chimera consists of an oligomeric extracellular domain fused to the integrin betaPS subunit cytoplasmic domain; a control monomeric extracellular domain fusion does not alter integrin target gene expression. Therefore, oligomerization of the 47-amino-acid betaPS intracellular domain is sufficient to initiate a signaling pathway that regulates gene expression in the developing embryo. PMID- 10090728 TI - Role of Nr13 in regulation of programmed cell death in the bursa of Fabricius. AB - Apoptotic cell death is developmentally regulated in the chicken bursa of Fabricius. Although apoptosis is low in the embryonic bursa, cell death increases markedly after hatching. The expression of Bcl2 family cell death antagonists was examined to identify the genes that regulate bursal cell apoptosis. The expression of Bcl-xL, A1, and Mcl1 was detected in both embryos and hatched birds, whereas Nr13 was expressed at high levels in embryonic bursa, and decreased significantly after hatching, correlating inversely with apoptosis. The oncogene v-reland phorbol myristate acetate, two known inhibitors of bursal cell apoptosis, induced Nr13 expression. Overexpression of Nr13 in DT40 bursal lymphoma cells protected them from low serum-induced apoptosis. The mechanism of inhibition of apoptosis by Nr13 is likely to involve a critical BH4 domain and interaction with death agonist Bax. Deletion of the BH4 domain converted Nr13 into a death agonist. Bax coimmunoprecipitated with Nr13 and Bax was induced, whereas Nr13 levels diminished when bursal lymphoblasts were induced to apoptosis by dispersion. Bursal transplantation studies demonstrated that Nr13 could prevent the in vivo programmed elimination of bursal stem cells after hatching, suggesting that Nr13 plays a role in maintaining bursal stem cells. PMID- 10090731 TI - Binding of etoposide to topoisomerase II in the absence of DNA: decreased affinity as a mechanism of drug resistance. AB - Despite the prevalence of topoisomerase II-targeted drugs in cancer chemotherapy and the impact of drug resistance on the efficacy of treatment, interactions between these agents and topoisomerase II are not well understood. Therefore, to further define interactions between anticancer drugs and the type II enzyme, a nitrocellulose filter assay was used to characterize the binding of etoposide to yeast topoisomerase II. Results indicate that etoposide binds to the enzyme in the absence of DNA. The apparent Kd value for the interaction was approximately 5 microM drug. Etoposide also bound to ytop2H1012Y, a mutant yeast type II enzyme that is approximately 3-4-fold resistant to etoposide. However, the apparent Kd value for the drug (approximately 16 microM) was approximately 3 times higher than that determined for wild-type topoisomerase II. Although it has been widely speculated that resistance to topoisomerase II-targeted anticancer agents results from a decreased drug-enzyme binding affinity, these data provide the first direct evidence in support of this hypothesis. Finally, the ability of yeast topoisomerase II to bind etoposide was dependent on the presence of the hydroxyl moiety of Tyr783, suggesting specific interactions between etoposide and the active site residue that is involved in DNA scission. PMID- 10090730 TI - Antagonism between RSF1 and SR proteins for both splice-site recognition in vitro and Drosophila development. AB - Specific recognition of splice sites within metazoan mRNA precursors (pre-mRNAs) is a potential stage for gene regulation by alternative splicing. Splicing factors of the SR protein family play a major role in this regulation, as they are required for early recognition of splice sites during spliceosome assembly. Here, we describe the characterization of RSF1, a splicing repressor isolated from Drosophila, that functionally antagonizes SR proteins. Like the latter, RSF1 comprises an amino-terminal RRM-type RNA-binding domain, whereas its carboxy terminal part is enriched in glycine (G), arginine (R), and serine (S) residues (GRS domain). RSF1 induces a dose-sensitive inhibition of splicing for several reporter pre-mRNAs, an inhibition that occurs at the level of early splicing complexes formation. RSF1 interacts, through its GRS domain, with the RS domain of the SR protein SF2/ASF and prevents the latter from cooperating with the U1 small nuclear ribonucleoprotein particle (U1 snRNP) in binding pre-mRNA. Furthermore, overproduction of RSF 1 in the fly rescues several developmental defects caused by overexpression of the splicing activator SR protein B52/ SRp55. Therefore, RSF1 may correspond to the prototypical member of a novel family of general splicing repressors that selectively antagonize the effect of SR proteins on 5' splice-site recognition. PMID- 10090732 TI - New light on allostery: dynamic resonance Raman spectroscopy of hemoglobin kempsey. AB - On the basis of static and time-resolved resonance Raman spectroscopy of HbA and of a mutant, HbK (Dalpha99N), a specific reaction coordinate is proposed for the allosteric transition in human hemoglobin. The heme is held between proximal (F) and distal (E) helices, whose orientation is responsive to forces generated by ligation and deligation. The E and F helices are in turn tethered via H-bonds to the A and H helices. These outer helices follow the E-F motion, thereby repositioning the N- and C-termini, which form the intersubunit salt bridges in the T quaternary structure. When the T state interface is weakened by Asp --> Asn substitution at a quaternary H-bond (HbK), the Fe-His bond is relaxed and becomes responsive to allosteric effectors. The same E-F motion is observed in HbK, but the A-H following motion is delayed, relative to HbA, as is the Asn H-bond formation. PMID- 10090733 TI - Nearest-neighbor thermodynamics and NMR of DNA sequences with internal A.A, C.C, G.G, and T.T mismatches. AB - Thermodynamic measurements are reported for 51 DNA duplexes with A.A, C.C, G.G, and T.T single mismatches in all possible Watson-Crick contexts. These measurements were used to test the applicability of the nearest-neighbor model and to calculate the 16 unique nearest-neighbor parameters for the 4 single like with like base mismatches next to a Watson-Crick pair. The observed trend in stabilities of mismatches at 37 degrees C is G.G > T.T approximately A.A > C.C. The observed stability trend for the closing Watson-Crick pair on the 5' side of the mismatch is G.C >/= C.G >/= A.T >/= T.A. The mismatch contribution to duplex stability ranges from -2.22 kcal/mol for GGC.GGC to +2.66 kcal/mol for ACT.ACT. The mismatch nearest-neighbor parameters predict the measured thermodynamics with average deviations of DeltaG degrees 37 = 3.3%, DeltaH degrees = 7. 4%, DeltaS degrees = 8.1%, and TM = 1.1 degrees C. The imino proton region of 1-D NMR spectra shows that G.G and T.T mismatches form hydrogen-bonded structures that vary depending on the Watson-Crick context. The data reported here combined with our previous work provide for the first time a complete set of thermodynamic parameters for molecular recognition of DNA by DNA with or without single internal mismatches. The results are useful for primer design and understanding the mechanism of triplet repeat diseases. PMID- 10090734 TI - Cooperative fluctuations and subunit communication in tryptophan synthase. AB - Tryptophan synthase (TRPS), with linearly arrayed subunits alphabetabetaalpha, catalyzes the last two reactions in the biosynthesis of L-tryptophan. The two reactions take place in the respective alpha- and beta-subunits of the enzyme, and the intermediate product, indole, is transferred from the alpha- to the beta site through a 25 A long hydrophobic tunnel. The occurrence of a unique ligand mediated long-range cooperativity for substrate channeling, and a quest to understand the mechanism of allosteric control and coordination in metabolic cycles, have motivated many experimental studies on the structure and catalytic activity of the TRPS alpha2beta2 complex and its mutants. The dynamics of these complexes are analyzed here using a simple but rigorous theoretical approach, the Gaussian network model. Both wild-type and mutant structures, in the unliganded and various liganded forms, are considered. The substrate binding site in the beta-subunit is found to be closely coupled to a group of hinge residues (beta77 beta89 and beta376-beta379) near the beta-beta interface. These residues simultaneously control the anticorrelated motion of the two beta-subunits, and the opening or closing of the hydrophobic tunnel. The latter process is achieved by the large amplitude fluctuations of the so-called COMM domain in the same subunit. Intersubunit communications are strengthened in the presence of external aldimines bound to the beta-site. The motions of the COMM core residues are coordinated with those of the alpha-beta hinge residues beta174-beta179 on the interfacial helix betaH6 at the entrance of the hydrophobic tunnel. And the motions of betaH6 are coupled, via helix betaH1 and alphaL6, to those of the loop alphaL2 that includes the alpha-subunit catalytically active residue Asp60. Overall, our analysis sheds light on the molecular machinery underlying subunit communication, and identifies the residues playing a key role in the cooperative transmission of conformational motions across the two reaction sites. PMID- 10090735 TI - Flexibility of interdomain contacts revealed by topological isomers of bivalent consolidated ligands to the dual Src homology domain SH(32) of abelson. AB - Src homology (SH)2 and SH3 domains are found in a variety of proteins involved in the control of cellular signaling and architecture. The possible interrelationships between domains are not easily investigated, even though several cases of multiple domain-containing constructs have been studied structurally. As a complement to direct structural methods, we have developed consolidated ligands and tested their binding to the Abl SH(32) complex. Consolidated ligands combine in the same molecule peptide sequences recognized by SH2 and SH3 domains, i.e., Pro-Val-pTyr-Glu-Asn-Val and Pro-Pro-Ala-Tyr-Pro-Pro Pro-Pro-Val-Pro, respectively; these are joined by oligoglycyl linkers. Four types of ligands were chemically synthesized, representing all the possible relative orientations of ligands. Their affinities were found to vary with binding portion topologies and linker lengths. Two of these types were shown to bind to both SH2 and SH3 dual domains with high affinities and specificities, showing increases of one order of magnitude, as compared to the most strongly bound monovalent equivalent. These results suggest that the relative orientation of SH2 and SH3 in Abl SH(32) is not fixed, and this synthetic approach may be generally useful for determining the structures of ligated complexes and for developing reagents with high affinities and specificities. PMID- 10090736 TI - Role of the extracellular loops of G protein-coupled receptors in ligand recognition: a molecular modeling study of the human P2Y1 receptor. AB - The P2Y1 receptor is a G protein-coupled receptor (GPCR) and is stimulated by extracellular ADP and ATP. Site-directed mutagenesis of the three extracellular loops (ELs) of the human P2Y1 receptor indicates the existence of two essential disulfide bridges (Cys124 in EL1 and Cys202 in EL2; Cys42 in the N-terminal segment and Cys296 in EL3) and several specific ionic and H-bonding interactions (involving Glu209 and Arg287). Through molecular modeling and molecular dynamics simulations, an energetically sound conformational hypothesis for the receptor has been calculated that includes transmembrane (TM) domains (using the electron density map of rhodopsin as a template), extracellular loops, and a truncated N terminal region. ATP may be docked in the receptor, both within the previously defined TM cleft and within two other regions of the receptor, termed meta binding sites, defined by the extracellular loops. The first meta-binding site is located outside of the TM bundle, between EL2 and EL3, and the second higher energy site is positioned immediately underneath EL2. Binding at both the principal TM binding site and the lower energy meta-binding sites potentially affects the observed ligand potency. In meta-binding site I, the side chain of Glu209 (EL2) is within hydrogen-bonding distance (2.8 A) of the ribose O3', and Arg287 (EL3) coordinates both alpha- and beta-phosphates of the triphosphate chain, consistent with the insensitivity in potency of the 5'-monophosphate agonist, HT-AMP, to mutation of Arg287 to Lys. Moreover, the selective reduction in potency of 3'NH2-ATP in activating the E209R mutant receptor is consistent with the hypothesis of direct contact between EL2 and nucleotide ligands. Our findings support ATP binding to at least two distinct domains of the P2Y1 receptor, both outside and within the TM core. The two disulfide bridges present in the human P2Y1 receptor play a major role in the structure and stability of the receptor, to constrain the loops within the receptor, specifically stretching the EL2 over the opening of the TM cleft and thus defining the path of access to the binding site. PMID- 10090737 TI - Crystal structures of Escherichia coli glycerol kinase variant S58-->W in complex with nonhydrolyzable ATP analogues reveal a putative active conformation of the enzyme as a result of domain motion. AB - Escherichia coli glycerol kinase (GK) displays "half-of-the-sites" reactivity toward ATP and allosteric regulation by fructose 1, 6-bisphosphate (FBP), which has been shown to promote dimer-tetramer assembly and to inhibit only tetramers. To probe the role of tetramer assembly, a mutation (Ser58-->Trp) was designed to sterically block formation of the dimer-dimer interface near the FBP binding site [Ormo, M., Bystrom, C., and Remington, S. J. (1998) Biochemistry 37, 16565 16572]. The substitution did not substantially change the Michaelis constants or alter allosteric regulation of GK by a second effector, the phosphocarrier protein IIAGlc; however, it eliminated FBP inhibition. Crystal structures of GK in complex with different nontransferable ATP analogues and glycerol revealed an asymmetric dimer with one subunit adopting an open conformation and the other adopting the closed conformation found in previously determined structures. The conformational difference is produced by a approximately 6.0 degrees rigid-body rotation of the N-terminal domain with respect to the C-terminal domain, similar to that observed for hexokinase and actin, members of the same ATPase superfamily. Two of the ATP analogues bound in nonproductive conformations in both subunits. However, beta, gamma-difluoromethyleneadenosine 5'-triphosphate (AMP-PCF2P), a potent inhibitor of GK, bound nonproductively in the closed subunit and in a putative productive conformation in the open subunit, with the gamma-phosphate placed for in-line transfer to glycerol. This asymmetry is consistent with "half-of-the-sites" reactivity and suggests that the inhibition of GK by FBP is due to restriction of domain motion. PMID- 10090738 TI - Alternative routes for entry of HgX2 into the active site of mercuric ion reductase depend on the nature of the X ligands. AB - Wild-type mercuric ion reductase (CCCC enzyme) possesses four cysteines in each of its Hg(II) binding sites, a redox-active pair and a C-terminal pair. Mutation of the C-terminal cysteines to alanines (CCAA enzyme) leads to a loss of steady state mercuric ion reductase activity using Hg(SR)2 substrates. However, CCCC and CCAA enzymes exhibit an equally high rate of binding and turnover using HgBr2 as substrate under pre-steady-state conditions [Engst and Miller (1998) Biochemistry 37, 11496-11507.]. Since the ligands in these HgX2 substrates differ both in size and in affinity for Hg(II), one or both of these properties may contribute to their different reactivities with CCAA enzyme. To further explore the importance of these two properties, we have examined the pre-steady-state reactions of CCCC and CCAA with Hg(CN)2, which has small, high-affinity ligands, and with Hg(Cys)2, which has bulky, high-affinity ligands. The results indicate that HgX2 substrates with small ligands can rapidly access the redox-active cysteines in the absence of the C-terminal cysteines, but those with large ligands require the C-terminal cysteines for rapid access. In addition, it is concluded that the C-terminal cysteines play a critical role in removing the high-affinity ligands before Hg(II) reaches the redox-active cysteines in the inner active site, since direct access of HgX2 substrates with high-affinity ligands leads to formation of an inhibited complex. Consistent with the results, both a narrow channel leading directly to the redox-active cysteines and a wider channel leading to the redox active cysteines via initial contact with the C-terminal cysteines can be identified in the structure of the enzyme from Bacillus sp. RC607. PMID- 10090739 TI - Kinetic analysis of the effect on Fab binding of identical substitutions in a peptide and its parent protein. AB - Monoclonal antibody 57P, which was raised against tobacco mosaic virus protein, cross-reacts with a peptide corresponding to residues 134-146 of this protein. Previous studies using peptide variants suggested that the peptide in the antibody combining site adopts a helical configuration that mimics the structure in the protein. In this study, we carried out a detailed comparison of Fab peptide and Fab-protein interactions. The same five amino acid substitutions were introduced in the peptide (residues 134-151) and the parent protein, and the effect of these substitutions on antibody binding parameters have been measured with a Biacore instrument. Fabs that recognize epitopes located away from the site of mutations were used as indirect probes for the conformational integrity of protein antigens. Their interaction kinetics with all proteins were similar, suggesting that the substitutions had no drastic effect on their conformation. The five substitutions introduced in the peptide and the protein had minor effects on association rate constants (ka) and significant effects on dissociation rate constants (kd) of the antigen-Fab 57P interactions. In four out of five cases, the effect on binding affinity of the substitutions was identical when the epitope was presented in the form of a peptide or a protein antigen, indicating that antibody binding specifity was not affected by epitope presentation. However, ka values were about 10 times larger and kd values about 5 times larger for the peptide-Fab compared to the protein-Fab interaction, suggesting a different binding mechanism. Circular dichroism measurements performed for three of the peptides showed that they were mainly lacking structure in solution. Differences in conformational properties of the peptide and protein antigens in solution and/or in the paratope could explain differences in binding kinetics. Our results demonstrate that the peptides were able to mimic correctly some but not all properties of the protein-Fab 57P interaction and highlight the importance of quantitative analysis of both equilibrium and kinetic binding parameters in the design of synthetic vaccines and drugs. PMID- 10090740 TI - 3-Bromotyrosine and 3,5-dibromotyrosine are major products of protein oxidation by eosinophil peroxidase: potential markers for eosinophil-dependent tissue injury in vivo. AB - Detection of specific reaction products is a powerful approach for dissecting out pathways that mediate oxidative damage in vivo. Eosinophil peroxidase (EPO), an abundant protein secreted from activated eosinophils, has been implicated in promoting oxidative tissue injury in conditions such as asthma, allergic inflammatory disorders, cancer, and helminthic infections. This unique heme protein amplifies the oxidizing potential of H2O2 by utilizing plasma levels of Br- as a cosubstrate to form potent brominating agents. Brominated products might thus serve as powerful tools for identifying sites of eosinophil-mediated tissue injury in vivo; however, structural identification and characterization of specific brominated products formed during EPO-catalyzed oxidation have not yet been reported. Here we explore the role of EPO and myeloperoxidase (MPO), a related leukocyte protein, in promoting protein oxidative damage through bromination and demonstrate that protein tyrosine residues serve as endogenous traps of reactive brominating species forming stable ring-brominated adducts. Exposure of the amino acid L-tyrosine to EPO, H2O2, and physiological concentrations of halides (100 mM Cl-, 100-fold decrease in kcat and >500-fold decrease in kcat/Km relative to WT for the reductive half-reaction. The oxidation of benzylamine by all three mutants is severely impaired, with very significant effects seen in the oxidative half reaction. CAO activity was studied as a function of pH for WT and Y305A proteins. Profiles for WT-catalyzed methylamine oxidation and Y305A-catalyzed ethylamine oxidation are comparable, while profiles of Y305A-catalyzed methylamine oxidation suggest the pH-dependent build-up of an inhibitory intermediate, which was subsequently observed spectrophotometrically and is attributed to the product Schiff base. The relative effects of mutations at Y305 on catalytic turnover are, thus, concluded to be dependent on the nature of the amino acid which substitutes for tyrosine and the substrate used in amine oxidase assays. TPQ biogenesis experiments demonstrate a approximately 800-fold decrease in kobs for apo-Y305A compared to WT. Despite the strict conservation of Tyr305 in all CAOs, neither biogenesis nor catalytic turnover is abolished upon mutation of this residue. We propose an important, but nonessential, role for Tyr305 in the positioning of the TPQ precursor for biogenesis, and in the maintenance of the correct conformation for TPQ-derived intermediates during catalytic turnover. PMID- 10090757 TI - The heme component of the neutrophil NADPH oxidase complex is a target for aryliodonium compounds. AB - The redox core of the neutrophil NADPH oxidase complex is a membrane-bound flavocytochrome b in which FAD and heme b are the two prosthetic redox groups. Both FAD and heme b are able to react with diphenylene iodonium (DPI) and iodonium biphenyl (IBP), two inhibitors of NADPH oxidase activity. In this study, we show that the iodonium modification of heme b contributes predominantly to the inhibition of NADPH oxidase. This conclusion is based on the finding that both iodonium compounds decreased the absorbance of the Soret peak of flavocytochrome b in neutrophil membranes incubated with NADPH, and that this decrease was strictly correlated with the loss of oxidase activity. Furthermore, the heme component of purified flavocytochrome b reduced to no more than 95% by a limited amount of sodium dithionite could be oxidized by DPI or IBP. Butylisocyanide which binds to heme iron precludes heme b oxidation. In activated neutrophil membranes, competitive inhibition of O2 uptake by DPI or IBP occurred transiently and was followed by a noncompetitive inhibition. These results, together with those of EPR spectroscopy experiments, lead us to postulate that DPI or IBP first captures an electron from the reduced heme iron of flavocytochrome b to generate a free radical. Then, the binding of this radical to the proximate environment of the heme iron, most probably on the porphyrin ring, results in inhibition of oxidase activity. In the presence of an excess of sodium dithionite, DPI and IBP produced a biphasic decrease of the Soret band of flavocytochrome b, with a break in the dose effect curve occurring at 50% of the absorbance loss. This was consistent with the presence of two hemes in flavocytochrome b that differ by their sensitivity to DPI or IBP. PMID- 10090758 TI - ENDOR spectroscopic evidence for the position and structure of NG-hydroxy-L arginine bound to holo-neuronal nitric oxide synthase. AB - Recently, we used 35 GHz pulsed 15N ENDOR spectroscopy to determine the position of the reactive guanidino nitrogen of substrate L-arginine relative to the high spin ferriheme iron of holo-neuronal nitric oxide synthase (nNOS) [Tierney, D. L., et al. (1998) J. Am. Chem. Soc. 120, 2983-2984]. Analogous studies of the enzyme-bound reaction intermediate, NG-hydroxy-L-arginine (NOHA), singly labeled with 15N at the hydroxylated nitrogen (denoted NR), show that NR is held 3.8 A from the Fe, closer than the corresponding guanidino N of L-Arg (4.05 A). 1,2H ENDOR of NOHA bound to holo-nNOS in H2O and D2O discloses the presence of a single resolved exchangeable proton (H1) 4.8 A from Fe and very near the heme normal. The ENDOR data indicate that NOHA does not bind as the resonance stabilized cation in which the terminal nitrogens share a positive charge. ENDOR determined structural constraints permit two alternate structural models for the interaction of NOHA with the high-spin heme iron. In one model, H1 is assigned to the O-H proton; in the other, it is the NR-H proton. However, the alternatives differ in the placement of the N-O bond relative to the heme iron. Thus, a combination of the ENDOR data with appropriate diffraction studies can achieve a definitive determination of the protonation state of NR and thus of the tautomeric form that is present in the enzyme-NOHA complex. The mechanistic implications of this result are further discussed. PMID- 10090759 TI - Lysine-313 of 5-aminolevulinate synthase acts as a general base during formation of the quinonoid reaction intermediates. AB - 5-Aminolevulinate synthase catalyzes the condensation of glycine and succinyl-CoA to form CoA, carbon dioxide, and 5-aminolevulinate. This represents the first committed step of heme biosynthesis in animals and some bacteria. Lysine 313 (K313) of mature murine erythroid 5-aminolevulinate synthase forms a Schiff base linkage to the pyridoxal 5'-phosphate cofactor. In the presence of glycine and succinyl-CoA, a quinonoid intermediate absorption is transiently observed in the visible spectrum of purified murine erythroid ALAS. Mutant enzymes with K313 replaced by glycine, histidine, or arginine exhibit no spectral evidence of quinonoid intermediate formation in the presence of glycine and succinyl-CoA. The wild-type 5-aminolevulinate synthase additionally forms a stable quinonoid intermediate in the presence of the product, 5-aminolevulinate. Only conservative mutation of K313 to histidine or arginine produces a variant that forms a quinonoid intermediate with 5-aminolevulinate. The quinonoid intermediate absorption of these mutants is markedly less than that of the wild-type enzyme, however. Whereas the wild-type enzyme catalyzes loss of tritium from [2-3H2] glycine, mutation of K313 to glycine results in loss of this activity. Titration of the quinonoid intermediate formed upon binding of 5-aminolevulinate to the wild-type enzyme indicated that the quinonoid intermediate forms by transfer of a single proton with a pK of 8.1 +/- 0.1. Conservative mutation of K313 to histidine raises this value to 8.6 +/- 0.1. We propose that K313 acts as a general base catalyst to effect quinonoid intermediate formation during the 5 aminolevulinate synthase catalytic cycle. PMID- 10090760 TI - Activating anions that replace Cl- in the O2-evolving complex of photosystem II slow the kinetics of the terminal step in water oxidation and destabilize the S2 and S3 states. AB - Photosystem II, the multisubunit protein complex that oxidizes water to O2, requires the inorganic cofactors Ca2+ and Cl- to exhibit optimal activity. Chloride can be replaced functionally by a small number of anionic cofactors (Br , NO3-, NO2-, I-), but among these anions, only Br- is capable of restoring rates of oxygen evolution comparable to those observed with Cl-. UV absorption difference spectroscopy was utilized in the experiments described here as a probe to monitor donor side reactions in photosystem II in the presence of Cl- or surrogate anions. The rate of the final step of the water oxidation cycle was found to depend on the activating anion bound at the Cl- site, but the kinetics of this step did not limit the light-saturated rate of oxygen evolution. Instead, the lower oxygen evolution rates supported by surrogate anions appeared to be correlated with an instability of the higher oxidation states of the oxygen evolving complex that was induced by addition of these anions. Reduction of these states takes place not only with I- but also with NO2- and to a lesser extent even with NO3- and Br- and is not related to the ability of these anions to bind at the Cl- binding site. Rather, it appears that these anions can attack higher oxidation states of the oxygen evolving complex from a second site that is not shielded by the extrinsic 17 and 23 kDa polypeptides and cause a one-electron reduction. The decrease of the oxygen evolution rate may result from accumulated damage to the reaction center protein by the one-electron oxidation product of the anion. PMID- 10090761 TI - Deuteration effects on the in vivo EPR spectrum of the reduced secondary photosystem I electron acceptor A1 in cyanobacteria. AB - The photoreduction of the secondary PSI electron acceptor A1 in vivo has recently been detected via X-band EPR spectroscopy in intact spinach chloroplasts and in marine cyanobacteria Synechococcus PCC 7002 [Klughammer, C., and Pace, R. J. (1997) Biochim. Biophys. Acta 1318, 133-144]. A further study of the A1- EPR spectrum of Synechococcus PCC 7002 at room temperature with higher-field resolution revealed partially resolved hyperfine structure which was dominated by 0.4 mT splittings of three equivalent protons. The hyperfine splitting was not significantly affected by incubation of the cyanobacteria in 2H2O medium for 20 h, but was absent in fully deuterated cyanobacteria that were grown in 2H2O medium. Anisotropic g-factors consistent with a phylloquinone radical were derived by spectra simulation. Biosynthetic protonation of quinones via the CH3 donor L-methionine in deuterated cells maintained hyperfine structure in the A1- spectrum, indicating the incorporation of CH3 groups in 60% of the deuterated, photoactive A1 molecules. Conversely, biosynthetic quinone deuteration via L [methyl-d3]methionine in protonated cells led to the loss of the 0. 4 mT splittings in 54% of the A1 molecules. These observations confirm the conclusion of Heathcote et al. [(1996) Biochemistry 35, 6644-6650] of the identity of EPR detected, photoreduced A1- in vivo with a phylloquinone (vitamin K1) radical in PSI. The partially resolved hyperfine structure of the A1- spectrum indicates an altered spin distribution in the bound vitamin K1- radical in vivo compared to that of unbound vitamin K1- in vitro. PMID- 10090762 TI - Replacement of the proximal histidine iron ligand by a cysteine or tyrosine converts heme oxygenase to an oxidase. AB - The H25C and H25Y mutants of human heme oxygenase-1 (hHO-1), in which the proximal iron ligand is replaced by a cysteine or tyrosine, have been expressed and characterized. Resonance Raman studies indicate that the ferric heme complexes of these proteins, like the complex of the H25A mutant but unlike that of the wild type, are 5-coordinate high-spin. Labeling of the iron with 54Fe confirms that the proximal ligand in the ferric H25C protein is a cysteine thiolate. Resonance-enhanced tyrosinate modes in the resonance Raman spectrum of the H25Y.heme complex provide direct evidence for tyrosinate ligation in this protein. The H25C and H25Y heme complexes are reduced to the ferrous state by cytochrome P450 reductase but do not catalyze alpha-meso-hydroxylation of the heme or its conversion to biliverdin. Exposure of the ferrous heme complexes to O2 does not give detectable ferrous-dioxy complexes and leads to the uncoupled reduction of O2 to H2O2. Resonance Raman studies show that the ferrous H25C and H25Y heme complexes are present in both 5-coordinate high-spin and 4-coordinate intermediate-spin configurations. This finding indicates that the proximal cysteine and tyrosine ligand in the ferric H25C and H25Y complexes, respectively, dissociates upon reduction to the ferrous state. This is confirmed by the spectroscopic properties of the ferrous-CO complexes. Reduction potential measurements establish that reduction of the mutants by NADPH-cytochrome P450 reductase, as observed, is thermodynamically allowed. The two proximal ligand mutations thus destabilize the ferrous-dioxy complex and uncouple the reduction of O2 from oxidation of the heme group. The proximal histidine ligand, for geometric or electronic reasons, is specifically required for normal heme oxygenase catalysis. PMID- 10090763 TI - Examination of the nickel site structure and reaction mechanism in Streptomyces seoulensis superoxide dismutase. AB - Superoxide dismutases are metalloenzymes involved in protecting cells from oxidative damage arising from superoxide radical or reactive oxygen species produced from superoxide. Examples of enzymes containing Cu, Mn, and Fe as the redox-active metal have been characterized. Recently, a SOD containing one Ni atom per subunit was reported. The amino acid sequence of the NiSOD deduced from the nucleotide sequence of the structural gene sodN from Streptomyces seoulensis is reported and has no homology with other SODs. X-ray absorption spectroscopic studies coupled with EPR of the Ni center show that the Ni in the oxidized (as isolated) enzyme is in a five-coordinate site composed of three S-donor ligands, one N-donor, and one other O- or N-donor. This unique coordination environment is modified by the loss of one N- (or O-) donor ligand in the dithionite-reduced enzyme. The NiSOD activity was determined by pulse radiolysis, and a value of kcat = 1.3 x 10(9) M-1 s-1 per Ni was obtained. The rate is pH sensitive and drops off rapidly above pH 8. The results characterize a novel class of metal center active in catalyzing the redox chemistry of superoxide and, when placed in context with other nickel enzymes, suggest that thiolate ligation is a prerequisite for redox-active nickel sites in metalloenzymes. PMID- 10090764 TI - pH-dependent spectroscopic changes associated with the hydroquinone of FMN in flavodoxins. AB - Photoreduction with a 5-deazaflavin as the catalyst was used to convert flavodoxins from Desulfovibrio vulgaris, Megasphaera elsdenii, Anabaena PCC 7119, and Azotobacter vinelandii to their hydroquinone forms. The optical spectra of the fully reduced flavodoxins were found to vary with pH in the pH range of 5.0 8.5. The changes correspond to apparent pKa values of 6.5 and 5.8 for flavodoxins from D. vulgaris and M. elsdenii, respectively, values that are similar to the apparent pKa values reported earlier from the effects of pH on the redox potential for the semiquinone-hydroquinone couples of these two proteins (7 and 5.8, respectively). The changes in the spectra resemble those occurring with the free two-electron-reduced flavin for which the pKa is 6.7, but they are red shifted compared with those of the free flavin. The optical changes occurring with flavodoxins from D. vulgaris and A. vinelandii flavodoxins are larger than those of free reduced FMN. The absorbance of the free and bound flavin increases in the region of 370-390 nm (Delta epsilon = 1-1.8 mM-1 cm-1) with increases of pH. Qualitatively similar pH-dependent changes occur when FMN in D. vulgaris flavodoxin is replaced by iso-FMN, and in the following mutants of D. vulgaris flavodoxin in which the residues mutated are close to the isoalloxazine of the bound flavin: D95A, D95E, D95A/D127A, W60A, Y98S, W60M/Y98W, S96R, and G61A. The 13C NMR spectrum of reduced D. vulgaris [2,4a-13C2]FMN flavodoxin shows two peaks. The peak due to C(4a) is unaffected by pH, but the peak due to C(2) broadens with decreasing pH; the apparent pKa for the change is 6.2. It is concluded that a decrease in pH induces a change in the electronic structure of the reduced flavin due to a change in the ionization state of the flavin, a change in the polarization of the flavin environment, a change in the hydrogen bonding network around the flavin, and/or possibly a change in the bend along the N(5)-N(10) axis of the flavin. A change in the ionization state of the flavin is the simplest explanation, with the site of protonation differing from that of free FMNH-. The pH effect is unlikely to result from protonation of D95 or D127, the negatively charged amino acids closest to the flavin of D. vulgaris flavodoxin, because the optical changes observed with alanine mutants at these positions are similar to those occurring with the wild-type protein. PMID- 10090765 TI - Phospholipase D1 in caveolae: regulation by protein kinase Calpha and caveolin-1. AB - Caveolae are small plasma membrane invaginations that have been implicated in cell signaling, and caveolin is a principal structural component of the caveolar membrane. Previously we have demonstrated that protein kinase Calpha (PKCalpha) directly interacts with phospholipase D1 (PLD1), activating the enzymatic activity of PLD1 in the presence of phorbol 12-myristate 13-acetate (PMA) [Lee, T. G., et al. (1997) Biochim. Biophys. Acta 1347, 199-204]. In this study, using a detergent-free procedure for the purification of a caveolin-enriched membrane fraction (CEM) and immunoblot analysis, we show that PLD1 is enriched in the CEMs of 3Y1 rat fibroblasts. Purified PLD1 directly bound to a glutathione S transferase-caveolin-1 fusion protein in in vitro binding assays. The association of PLD1 with caveolin-1 could be completely eliminated by preincubation of PLD1 with an oligopeptide corresponding to the scaffolding domain (amino acids 82-101) of caveolin-1, indicating that caveolin-1 interacts with PLD1 through the scaffolding domain. The peptide also inhibited PKCalpha-stimulated PLD1 activity and the interaction between PLD1 and PKCalpha with an IC50 of 0.5 microM. PMA elicits translocation of PKCalpha to the CEMs, inducing PLD activation through the interaction of PKCalpha with PLD1 in the CEMs. Caveolin-1 also coimmunoprecipitated with PLD1 in the absence of PMA, and the amounts of coimmunoprecipitated caveolin-1 decreased in response to treatment with PMA. Taken together, our results suggest a new mechanism for the regulation of the PKCalpha-dependent PLD activity through the molecular interaction between PLD1, PKCalpha, and caveolin-1 in caveolae. PMID- 10090766 TI - Rhodopsin's carboxyl-terminal threonines are required for wild-type arrestin mediated quench of transducin activation in vitro. AB - Many recent reports have demonstrated that rhodopsin's carboxyl-terminal serine residues are the main targets for phosphorylation by rhodopsin kinase. Phosphorylation at the serines would therefore be expected to promote high affinity arrestin binding. We have examined the roles of the carboxyl serine and threonine residues during arrestin-mediated deactivation of rhodopsin using an in vitro transducin activation assay. Mutations were introduced into a synthetic bovine rhodopsin gene and expressed in COS-7 cells. Individual serine and threonine residues were substituted with neutral amino acids. The ability of the mutants to act as substrates for rhodopsin kinase was analyzed. The effect of arrestin on the activities of the phosphorylated mutant rhodopsins was measured in a GTPgammaS binding assay involving purified bovine arrestin, rhodopsin kinase, and transducin. A rhodopsin mutant lacking the carboxyl serine and threonine residues was not phosphorylated by rhodopsin kinase, demonstrating that phosphorylation is restricted to the seven putative phosphorylation sites. A rhodopsin mutant possessing a single phosphorylatable serine at 338 demonstrated no phosphorylation-dependent quench by arrestin. These results suggest that singly phosphorylated rhodopsin is deactivated through a mechanism that does not involve arrestin. Analysis of additional mutants revealed that the presence of threonine in the carboxyl tail of rhodopsin provides for greater arrestin mediated quench than does serine. These results suggest that phosphorylation site selection could serve as a mechanism to modulate the ability of arrestin to quench rhodopsin. PMID- 10090767 TI - Calponin binds to the 20-kilodalton regulatory light chain of myosin. AB - Calponin (CaP) is a 34 kDa smooth muscle-specific protein that has been implicated in regulation of smooth muscle contractility. Two CaP binding sites on smooth muscle myosin rod have been recently described [Szymanski and Tao (1997) J.Biol.Chem. 272, 11142-11146]. We used a combination of cosedimentation, overlay, and fluorescence assays to determine the interaction between CaP and both subfragment 1 of myosin and isolated 20 kDa regulatory light chain of myosin (RLC). Subfragment 1, which was generated by cleavage of myosin with Staphylococcus aureus protease (myosin S1SA) inhibits cosedimentation of CaP with myosin filaments. Fluorescence assay showed that CaP labeled with fluorescent label (DAN-CaP) interacts with myosin S1SA in solution via a single class of binding sites. The binding constant (kaff) of this interaction at 50 mM NaCl is (2. 1 +/- 0.2) x 10(6) M-1 (n = 3). The interaction between DAN-CaP and myosin S1SA depends on ionic strength, and the EC50 of inhibition of this interaction occurs at about 130 mM NaCl. In contrast, the subfragment 1 that was generated by papain digestion (myosin S1PA), which cleaves RLC 4 kDa away from the NH2 terminal end of the molecule, does not interact with DAN-CaP. Overlay and fluorescent assay in solution showed that CaP binds to isolated RLC, suggesting that the interaction between CaP and subfragment 1 of myosin is due to a direct binding of CaP to RLC. CaP binding to myosin S1SA is stronger than to subfragment 2 in physiological salt concentrations. CaP binding to myosin head strengthened upon phosphorylation of RLC by Ca2+/calmodulin-dependent myosin light chain kinase. We suggest that CaP binds to subfragment 1 of myosin, exclusively via the NH2-terminal end of RLC, and this interaction could play a role in regulation of the actin-myosin interaction in smooth muscle contractility. PMID- 10090768 TI - The sequence of the myosin 50-20K loop affects Myosin's affinity for actin throughout the actin-myosin ATPase cycle and its maximum ATPase activity. AB - We are interested in the role that solvent-exposed, proteolytically sensitive surface loops play in myosin function. The 25-50K loop, or loop 1, is near the ATP binding site, while the 50-20K loop (loop 2) is in the actin binding site. Through chimeric studies, we have found that loop 1 affects ADP release [Murphy, C. T., and Spudich, J. A. (1998) Biochemistry 37, 6738-44], while loop 2 affects the actin-activated ATPase activity [Uyeda, T. Q.-P., et al. (1994) Nature 368, 567-9]. In the study described here, we have found that the kcat of the actin activated ATPase activity is changed by the loop 2 substitutions in a manner that reflects the relative actin-activated ATPase activities of the donor myosins. Additionally, changes in loop 2 affect the affinity of myosin for actin both in the presence and in the absence of nucleotides. Pre-steady-state studies together with the ATPase and affinity data suggest that while loop 2 does not affect interactions between myosin and nucleotide, it plays a role in determining the affinity of myosin for actin in various nucleotide states and in the rate limiting transition allowing phosphate release. PMID- 10090769 TI - Potent and highly selective inhibitors of the protein tyrosine phosphatase 1B. AB - Several protein tyrosine phosphatases (PTPases) have been implicated as regulatory agents in the insulin-stimulated signal transduction pathway, including PTP1B, PTPalpha, and LAR. Furthermore, since all three enzymes are suggested to serve as negative regulators of insulin signaling, one or more may play a pivotal role in the pathogenesis of insulin resistance. We report herein the acquisition of highly selective PTP1B-targeted inhibitors. We recently demonstrated that PTP1B contains two proximal aromatic phosphate binding sites [Puius, Y. A., Zhao, Y., Sullivan, M., Lawrence, D. S., Almo S. C., and Zhang, Z. Y. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 13420-5], and we have now employed this structural feature to design and synthesize an array of bis(aryldifluorophosphonates). Not only do the lead compounds serve as potent inhibitors of PTP1B but, in addition, several exhibit selectivities for PTP1B versus PTPalpha, LAR, and VHR that are greater than 2 orders in magnitude. PMID- 10090770 TI - Synergistic activation of protein kinase Calpha, -betaI, and -gamma isoforms induced by diacylglycerol and phorbol ester: roles of membrane association and activating conformational changes. AB - Protein kinase Calpha (PKCalpha) has been shown to contain two discrete activator sites with differing binding affinities for phorbol esters and diacylglycerols. The interaction of diacylglycerol with a low-affinity phorbol ester binding site leads to enhanced high-affinity phorbol ester binding and to a potentiated level of activity [Slater, S. J., Ho, C., Kelly, M. B., Larkin, J. D. , Taddeo, F. J., Yeager, M. D., and Stubbs, C. D. (1996) J. Biol. Chem. 271, 4627-4631]. In this study, the mechanism of this enhancement of activity was examined with respect to the Ca2+ dependences of membrane association and accompanying conformational changes that lead to activation. The association of PKCalpha with membranes containing 12-O-tetradecanoylphorbol 13-acetate (TPA) or 1, 2-dioleoylglycerol (DAG), determined from tryptophan to dansyl-PE resonance energy transfer (RET) measurements, was found to occur at relatively low Ca2+ levels ( duplex DNA > single stranded DNA. In contrast, their resolubilization at high polyamine concentrations followed a reverse order. The effective concentration of spermine to precipitate DNA increased with Na+ in the medium. Tm data indicated the DNA stabilizing effect of spermine even in the resolubilized state. CD spectroscopy revealed a series of sequential conformational alterations of duplex and triplex DNA, with the duplex form regaining the B-DNA conformation at high concentrations (approximately 200 mM) of spermine. The triplex DNA, however, remained in a Psi DNA conformation in the resolubilized state. Chemical structural specificity effects were exerted by spermidine and spermine analogues in precipitating and resolubilizing sonicated calf thymus DNA, with N4-methyl substitution of spermidine and a heptamethylene separation of the imino groups of spermine having the maximal difference in the precipitating ability of the analogues compared to spermidine and spermine, respectively. Therapeutically important bis(ethyl) substitution reduced the precipitating ability of the analogues compared to spermine. The effect of the cationicity of polyamines was evident with the pentamines being much more efficacious than the tetramines and triamines. These results provide new insights into the mechanism of DNA precipitation by polyamines, and suggest the importance of polyamine structure in developing gene delivery vehicles for therapeutic applications. PMID- 10090773 TI - A thermodynamic comparison of mesophilic and thermophilic ribonucleases H. AB - The mechanisms by which thermophilic proteins attain their increased thermostability remain unclear, as usually the sequence and structure of these proteins are very similar to those of their mesophilic homologues. To gain insight into the basis of thermostability, we have determined protein stability curves describing the temperature dependence of the free energy of unfolding for two ribonucleases H, one from the mesophile Escherichia coli and one from the thermophile Thermus thermophilus. The circular dichroism signal was monitored as a function of temperature and guanidinium chloride concentration, and the resulting free energies of unfolding were fit to the Gibbs-Helmholtz equation to obtain a set of thermodynamic parameters for these proteins. Although the maximal stabilities for these proteins occur at similar temperatures, the heat capacity of unfolding for T. thermophilus RNase H is lower, resulting in a smaller temperature dependence of the free energy of unfolding and therefore a higher thermal melting temperature. In addition, the stabilities of these proteins are similar at the optimal growth temperatures for their respective organisms, suggesting that a balance of thermodynamic stability and flexibility is important for function. PMID- 10090774 TI - Molybdate inhibits hsp90, induces structural changes in its C-terminal domain, and alters its interactions with substrates. AB - To examine the biochemical mechanism by which hsp90 exerts its essential positive function on certain signal transduction proteins, we characterized the effects of molybdate and geldanamycin on hsp90 function and structure. Molybdate inhibited hsp90-mediated p56lck biogenesis and luciferase renaturation while enforcing salt stable interactions with these substrates. Molybdate also reduced the amount of free hsp90 present in cell lysates, inhibited hsp90's ability to bind geldanamycin, and induced resistance to proteolysis at a specific region within the C-terminal domain of hsp90. In contrast, the hsp90 inhibitor geldanamycin prevented hsp90 from assuming natural or molybdate-induced conformations that allow salt-stable interactions with substrates. When these compounds were applied sequentially, the order of addition determined the effects observed, indicating that these agents had opposing effects on hsp90. We conclude that a specific region within the C-terminal domain of hsp90 (near residue 600) determines the mode by which hsp90 interacts with substrates and that the ability of hsp90 to cycle between alternative modes of interaction is obligatory for hsp90 function. PMID- 10090775 TI - Effects of two familial hypertrophic cardiomyopathy-causing mutations on alpha tropomyosin structure and function PMID- 10090776 TI - Postsynthetic generation of a major acrolein adduct of 2'-deoxyguanosine in oligomeric DNA. PMID- 10090777 TI - Novel inhibitors of carboxypeptidase G2 (CPG2): potential use in antibody directed enzyme prodrug therapy. AB - The design and synthesis of potent thiocarbamate inhibitors for carboxypeptidase G2 are described. The best thiocarbamate inhibitor N-(p methoxybenzenethiocarbonyl)amino-L-glutamic acid 6d, chosen for preliminary investigations of in vitro antibody-directed enzyme prodrug therapy (ADEPT), abrogated the cytotoxicity of a combination of A5B7-carboxypeptidase G2 conjugate and prodrug PGP (N-p-{N,N-bis (2-chloroethyl)amino}phenoxycarbonyl-L-glutamate) toward LS174T cells. This is the first report of a small-molecule enzyme inhibitor proposed for use in conjunction with the ADEPT approach. PMID- 10090778 TI - Design, synthesis, and evaluation of conformationally constrained tongs, new inhibitors of HIV-1 protease dimerization. AB - The active form of human immunodeficiency virus type 1 protease (HIV-1 PR) is a homodimeric structure in which two subunits are linked through a two-stranded antiparallel beta-sheet consisting of the N- and C-termini of each monomer. To inhibit the dimerization process or disrupt the dimeric interface leading to inactive enzyme, conformationally constrained "molecular tongs" have been designed and synthesized to interfere with one monomer end in a beta-sheet fashion. These molecules are based on two peptidic strands attached to an aromatic scaffold. Inhibitions (submicromolar range) were obtained with molecular tongs containing tripeptidic or tetrapeptidic arms attached to a pyridinediol- or naphthalenediol-based scaffold (Kid = 0.56-4.5 microM at pH 4.7 and 30 degrees C). Kinetic studies are in agreement with an interface inhibition mechanism. PMID- 10090779 TI - Structure--activity relationships of lysophosphatidic acid: conformationally restricted backbone mimetics. AB - Lysophosphatidic acid (LPA) has associated with it an intriguing cell biology that is thought to be mediated through its interaction with G-protein coupled receptor(s). In an effort to extend the structure-activity relationships of LPA, we have produced a series of LPA analogues in which the glycerol core in LPA was replaced with conformationally restricted aryl substructures. The aryl substructures encompassed aminophenol, resorcinol, dihydroxy benzophenone, and tocopherol systems. The benzophenone moiety was investigated both as a conformationally restricting substructure for LPA and as a possible photoreactive alkylating agent for the LPA receptor(s). All LPA analogues were evaluated for their potency and efficacy in mobilizing calcium ions from internal stores in MDA MB-231 cells. Ten of the 14 analogues exhibited activity in this assay at doses up to 5 microM; none of the compounds exhibited nonreceptor-mediated lytic activity at this maximal concentration. The receptor response showed surprising tolerance for manipulation in the backbone region of LPA, although none of the compounds were equipotent to LPA. This tolerance for a variety of structures has given us new leads into the realization of novel agonists and antagonists of the LPA receptor(s). PMID- 10090780 TI - Structural and conformational requirements for high-affinity binding to the SH2 domain of Grb2(1). AB - Following earlier work on cystine-bridged peptides, cyclic phosphopeptides containing nonreducible mimics of cystine were synthesized that show high affinity and specificity toward the Src homology (SH2) domain of the growth factor receptor-binding protein (Grb2). Replacement of the cystine in the cyclic heptapeptide cyclo(CYVNVPC) by D-alpha-acetylthialysine or D-alpha-lysine gave cyclo(YVNVP(D-alpha-acetyl-thiaK)) (22) and cyclo(YVNVP(D-alpha-acetyl-K)) (30), which showed improved binding 10-fold relative to that of the control peptide KPFYVNVEF (1). NMR spectroscopy and molecular modeling experiments indicate that a beta-turn conformation centered around YVNV is essential for high-affinity binding. X-ray structure analyses show that the linear peptide 1 and the cyclic compound 21 adopt a similar binding mode with a beta-turn conformation. Our data confirm the unique structural requirements of the ligand binding site of the SH2 domain of Grb2. Moreover, the potency of our cyclic lactams can be explained by the stabilization of the beta-turn conformation by three intramolecular hydrogen bonds (one mediated by an H2O molecule). These stable and easily accessible cyclic peptides can serve as templates for the evaluation of phosphotyrosine surrogates and further chemical elaboration. PMID- 10090781 TI - 6-Substituted benzopyrans as potassium channel activators: synthesis, vasodilator properties, and multivariate analysis. AB - During the last 10 years compounds have been discovered which can activate or block KATP channels. In particular, K channel activators (KCA) have been found to be smooth muscle relaxants with their main utility in hypertension and bronchodilation. In this paper we describe the synthesis of new KCA of the benzopyran type with a fixed 4-substituent and a systematic variation in the 6 position. The relaxant potency in rat aorta and trachea was used for biological characterization of the benzopyrans. In both biological test systems, they exhibit potency ranges of more than 3 log units. Structure-activity relationships are investigated by principal component analysis (PCA) and partial least-squares (PLS) analysis. Most striking outliers in an initial PLS analysis of the entire database were the unsubstituted 6-H compound 13 as well as 34 and 35. For the remaining set of 31 compounds, a 3-component PLS model explains the variance in biological activity to 81% in the aortic and to 82% in the tracheal test system. 6-Substituents influence affinity by a direct (presumably dipolar) interaction with the receptor site. According to the 2D-plot of the partial PLS weights, a strong electronegativity as well as high values for the integy moment and for the heat of formation in water dominate the first component; low values for substituent size (as defined by globularity or surface) are in addition favorable for high potency. High lipophilicity and low minimum energies of interaction dominate the second component. Chemical descriptors for the biological potency of the test set in rat aorta and rat trachea are very similar according to the almost identical projection of the Y-variables onto the X-component space. PMID- 10090782 TI - Diversity analysis of 14 156 molecules tested by the National Cancer Institute for anti-HIV activity using the quantitative structure-activity relational expert system MCASE. AB - Using the MCASE program, a procedure to analyze the diversity of the large amount of available HIV-1 antiviral data was proposed. A subset of 1 819 chemicals was logically selected from the original 14 156 chemicals tested by NCI. This subset of chemicals was shown to contain most of the structural and the functional information of the original database. A full analysis of the 1 819 chemicals by the MCASE program produced a correlation between chemical structures and HIV antiviral activity. In our model, 74 fragments were identified as being responsible for all the chemical's HIV antiviral activity. These fragments may be related to different inhibiting mechanisms, some known and some probably still unknown. The expert system resulting from this analysis can be used to predict the activity of new chemicals and to design new agents that can target multiple enzymes. This was shown to be the case by using the model to predict the activity of 10 diverse chemicals whose activities were not known at the time of model development. Of these, 8 were predicted in agreement with experimental observations. As far as we can tell, this is probably the first project ever to attempt to create a quantitative model of activity for such a massive database of diverse chemicals. PMID- 10090783 TI - Cytotoxicity of (2,2':6',2''-terpyridine)platinum(II) complexes to Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei. AB - A range of (2,2':6',2''-terpyridine)platinum(II) complexes are shown to possess antiprotozoal activity in vitro against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei,the causative organisms of tropical diseases leishmaniasis and trypanosomiasis. The best compounds caused 100% and 78% inhibition of growth of the intracellular amastigote forms of L. donovani and T. cruzi, respectively, at a concentration of 1 microM and 100% inhibition of growth of the bloodstream trypomastigote forms of T. brucei at a concentration of 0.03 microM. The results obtained with complexes in which the fourth ligand to platinum(II) is capable of being substituted with a substitution inert hydroxyethanethiolate complex are compared. The ammine complexes show high antiprotozoal activity suggesting that the trans influence of the 2,2':6',2''-terpyridine ligand has a profound effect on the ease of displacement of the fourth ligand in (2,2':6',2'' terpyridine)platinum(II) complexes, although nonbonded interaction between the ammine ligand and the 6 and 6' ' hydrogens probably also weakens the ligation to Pt(II). PMID- 10090784 TI - Synthesis and antiparasitic and antitumor activity of 2, 4-diamino-6-(arylmethyl) 5,6,7,8-tetrahydroquinazoline analogues of piritrexim. AB - Nineteen previously undescribed 2,4-diamino-6-(arylmethyl)-5,6,7, 8 tetrahydroquinazolines (5a-m, 10-12) were synthesized as part of a larger effort to assess the therapeutic potential of lipophilic dihydrofolate reductase (DHFR) inhibitors against opportunistic infections of AIDS. Condensation of appropriately substituted (arylmethyl)triphenylphosphoranes with 4, 4 ethylenedioxycyclohexanone, followed by hydrogenation (H2/Pd-C) and acidolysis, yielded the corresponding 4-(arylmethyl)cyclohexanones, which were then condensed with cyanoguanidine to form the tetrahydroquinazolines. Three simple 2, 4-diamino 6-alkyl-5,6,7,8-tetrahydroquinazoline model compounds (9a-c) were also prepared in one step from commercially available 4-alkylcyclohexanones by this method. Enzyme inhibition assays against rat liver DHFR, Pneumocystis carinii DHFR, and the bifunctional DHFR-TS enzyme from Toxoplasma gondii were carried out, and the selectivity ratios IC50(rat)/IC50(P. carinii) and IC50(rat)/IC50(T. gondii) were compared. The three most potent inhibitors of P. carinii DHFR were the 2,5 dimethoxybenzyl (5j), 3, 4-dimethoxybenzyl (5k), and 3,4,5-trimethoxybenzyl (5l) analogues, with IC50 values of 0.057, 0.10, and 0.091 microM, respectively. The remaining compounds generally had IC50 values in the 0.1-1.0 microM range. However all the compounds were more potent against the rat liver enzyme than the P. carinii enzyme and thus were nonselective. The T. gondii enzyme was always more sensitive than the P. carinii enzyme, with most of the analogues giving IC50 values of 0.01-0.1 microM. Moderate 5-10-fold selectivity for T. gondii versus rat liver DHFR was observed with five compounds, the best combination of potency and selectivity being achieved with the 2-methoxybenzyl analogue 5d, which had an IC50 of 0.014 microM and a selectivity ratio of 8.6. One compound (5l) was tested for antiproliferative activity against P. carinii trophozoites in culture at a concentration of 10 microgram/mL and was found to completely suppress growth over 7 days. The suppressive effect of 5l was the same as that of trimethoprim (10 microgram/mL) + sulfamethoxazole (250 microgram/mL), a standard clinical combination for the treatment of P. carinii pneumonia in AIDS patients. Four compounds (5a,h,k,l) were tested against T. gondii tachyzoites in culture and were found to have a potency (IC50 = 0.1-0.5 microM) similar to that of pyrimethamine (IC50 = 0.69 microM), a standard clinical agent for the treatment of cerebral toxoplasmosis in AIDS patients. Compound 5h was also active against T. gondii infection in mice when given qdx8 by peritoneal injection at doses ranging from 62.5 (initial dose) to 25 mg/kg. Survival was prolonged to the same degree as with 25 mg/kg clindamycin, another widely used drug against toxoplasmosis. Three compounds (5j-l) were tested for antiproliferative activity against human tumor cells in culture. Among the 25 cell lines in the National Cancer Institute panel for which data were confirmed in two independent experiments, the IC50 for at least two of these compounds was <10 microM against 17 cell lines (68%) and in the 0. 1-1 microM range against 13 cell lines (52%). One compound (5j) had an IC50 of <0.01 microM against four of the cell lines. The activity profiles of 5k,l were generally similar to that of 5j except that there were no cells against which the IC50 was <0.01 microM. PMID- 10090785 TI - Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones. AB - Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the Hck tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in 1, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3' chlorophenylamino)-6, 7-dimethoxyquinazoline (4) led to 3'-chloro-5,7 dihydroxyisoflavone (6) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of 11 did not further improve enzyme inhibitory activity but led to derivatives with cellular activity in the lower micromolar range. PMID- 10090786 TI - Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6 dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. AB - As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-) 2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2 thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6 dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/ 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo. PMID- 10090787 TI - Structure-activity relationship of diaryl phosphonate esters as potent irreversible dipeptidyl peptidase IV inhibitors. AB - The previously reported diphenyl 1-(S)-prolylpyrrolidine-2(R, S)-phosphonate (5) was used as a lead compound for the development of potent and irreversible inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). The synthesis of a series of diaryl 1-(S)-prolylpyrrolidine-2(R,S)-phosphonates with different substituents on the aryl rings (hydroxyl, methoxy, acylamino, sulfonylamino, ureyl, methoxycarbonyl, and alkylaminocarbonyl) started from the corresponding phosphites. A good correlation was found between the electronic properties of the substituent and the inhibitory activity and stability. The most striking divergence of this correlation was the high potency combined with a high stability of the 4-acetylamino-substituted derivative 11e. This compound shows low cytotoxicity in human peripheral blood mononuclear cells and also has favorable properties in vivo. Therefore bis(4-acetamidophenyl) 1-(S) prolylpyrrolidine-2(R,S)-phosphonate (11e) is considered as a major improvement and will be a highly valuable DPP IV inhibitor for further studies on the biological function of the enzyme and the therapeutic value of its inhibition. PMID- 10090788 TI - Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3-hydroxy-2 phenylquinoline-4-carboxamide (SB 223412). AB - Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SB 223412, hNK-3-CHO binding Ki = 1.4 nM) and 55 (3-NH2, hNK-3-CHO binding Ki = 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK 2 receptor, with no affinity for the hNK-1 at concentrations up to 100 microM. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2 phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK 3 receptor antagonists. PMID- 10090789 TI - Glutathione-mediated metabolism of technetium-99m SNS/S mixed ligand complexes: a proposed mechanism of brain retention. AB - Two series of [99mTc](SNS/S) mixed ligand complexes each carrying the N diethylaminoethyl or the N-ethyl-substituted bis(2-mercaptoethyl)amine ligand (SNS) are produced at tracer level using tin chloride as reductant and glucoheptonate as transfer ligand. The identity of [99mTc](SNS/S) complexes is established by high-performance liquid chromatographic (HPLC) comparison with authentic rhenium samples. The para substituent R on the phenylthiolate coligand (S) ranges from electron-donating (-NH2) to electron-withdrawing (-NO2) groups, to study complex stability against nucleophiles as a result of N- and R substitution. The relative resistance of [99mTc](SNS/S) complexes against nucleophilic attack of glutathione (GSH), a native nucleophilic thiol of 2 mM intracerebral concentration, is investigated in vitro by HPLC. The reaction of [99mTc](SNS/S) complexes with GSH is reversible and advances via substitution of the monothiolate ligand by GS- and concomitant formation of the hydrophilic [99mTc](SNS/GS) daughter compound. The N-diethylaminoethyl complexes are found to be more reactive against GSH as compared to the N-ethyl ones. Complex reactivity as a result of R-substitution follows the sequence -NO2 >> -H > -NH2. These in vitro findings correlate well with in vivo distribution data in mice. Thus, brain retention parallels complex susceptibility to GSH attack. Furthermore, isolation of the hydrophilic [99mTc](SNS/GS) metabolite from biological fluids and brain homogenates provides additional evidence that the brain retention mechanism of [99mTc](SNS/S) complexes is GSH-mediated. PMID- 10090790 TI - Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine sigma ligands as potential antipsychotic drugs. AB - sigma Receptor antagonists may be effective antipsychotic drugs that do not induce motor side effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy-6H dibenzo[b,d]pyran hydrochloride 2a had selective affinity for sigma receptor over dopamine D2 receptor. This compound was designed to eliminate two bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH2O- bond to maintain the planar structure. In light of the evidence, N, N-dipropyl-2-(4-methoxy-3-benzyloxylphenyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran derivative 2a, it might be more released from the rigid structure of apomorphine 1 than compound 2a. The chemical modification of compound 10b led to the discovery that N, N-dipropyl-2- [4-methoxy-3-(2 phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for sigma receptor and had a potent activity in an animal model when the drug was given orally. We report here the design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine derivatives 3. PMID- 10090791 TI - Novel, potent, and selective phosphodiesterase-4 inhibitors as antiasthmatic agents: synthesis and biological activities of a series of 1-pyridylnaphthalene derivatives. AB - The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T 2585.HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0. 85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050). PMID- 10090792 TI - Melatonergic properties of the (+)- and (-)-enantiomers of N-(4-methoxy-2,3 dihydro-1H-phenalen-2-yl)amide derivatives. AB - N-(4-Methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives, conformationally restricted ligands for melatonin receptors, were synthesized by an alternative synthetic method from the corresponding 1,8-naphthalic anhydride which was transformed into the phenalenecarboxylic acid 7. A Curtius reaction on 7 gave the amino compound which was acylated to give compounds 4a-c. The (+)- and (-)-4a-c enantiomers were separated by semipreparative chiral HPLC. Compounds were evaluated for their affinity for chicken brain melatonin receptors in binding assays using 2-[125I]iodomelatonin and for their potency to lighten the skin of Xenopus laevis tadpoles. The butyramido derivative 4c was the most potent ligand (Ki = 1.7 nM). No enantioselectivity was observed with the enantiomers which were equipotent to the racemic mixture. In contrast to the reference compounds, melatonin, agomelatine (S 20098), and N-[2-(2, 7-dimethoxynaphth-1 yl)ethyl]acetamide, which were very potent at lightening the skin of X. laevis tadpoles, compounds 4a-c were inactive or weakly active (EC50 > 1 microM). In this bioassay, compound 4a was characterized as a putative antagonist of melatonin receptors. PMID- 10090795 TI - Editorial PMID- 10090794 TI - Bis- and mixed-tetrahydroisoquinolinium chlorofumarates: new ultra-short-acting nondepolarizing neuromuscular blockers PMID- 10090793 TI - Thieno[3,2-b]- and thieno[2,3-b]pyrrole bioisosteric analogues of the hallucinogen and serotonin agonist N,N-dimethyltryptamine. AB - The synthesis and biological activity of 6-[2-(N, N-dimethylamino)ethyl]-4H thieno[3,2-b]pyrrole (3a) and 4-[2-(N, N-dimethylamino)ethyl]-6H-thieno[2,3 b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N dimethyltryptamine (1a), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b substituted for LSD or DOI up to doses of 50 micromol/kg. By comparison, 1a fully substituted in LSD-trained rats. However, 3a and 3b fully substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n propylamino)-1,3,4, 5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor activation. At the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice the affinity of 3b. Therefore, thiophene lacks equivalence as a replacement for the phenyl ring in the indole nucleus of tryptamines that bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects. Whereas both of the thienopyrroles had lower affinity than the corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a potent bioisostere for the indole nucleus in compounds that bind to the serotonin 5-HT1A receptor. These differences in biological activity suggest that serotonin receptor isoforms are very sensitive to subtle changes in the electronic character of the aromatic systems of indole compounds. PMID- 10090796 TI - Belief and decision: the continuing legacy of amos tversky PMID- 10090797 TI - Subjective probability of disjunctive hypotheses: local-weight models for decomposition of evidential support. AB - When the probability of a single member of a set of mutually exclusive and exhaustive possibilities is judged, its alternatives are evaluated as a composite "residual" hypothesis. Support theory (Rottenstreich & Tversky, 1997; Tversky & Koehler, 1994) implies that the process of packing alternatives together in the residual reduces the perceived evidential support for the set of alternatives and consequently inflates the judged probability of the focal hypothesis. Previous work has investigated the global weights that determine the extent to which the overall evidential support for the alternatives is discounted by this packing operation (Koehler, Brenner, & Tversky, 1997). In the present investigation, we analyze this issue in greater detail, examining the local weights that measure the specific contribution of each component hypothesis included implicitly in the residual. We describe a procedure for estimating local weights and introduce a set of plausible properties that impose systematic ordinal relationships among local weights. Results from four experiments testing these properties are reported, and a local-weight model is developed that accounts for nearly all of the variance in the probability judgments in these empirical tests. Local weights appear to be sensitive both to the individual component with which they are associated and to the residual hypothesis in which the component resides. PMID- 10090798 TI - Frequency, probability, and prediction: easy solutions to cognitive illusions? AB - Many errors in probabilistic judgment have been attributed to people's inability to think in statistical terms when faced with information about a single case. Prior theoretical analyses and empirical results imply that the errors associated with case-specific reasoning may be reduced when people make frequentistic predictions about a set of cases. In studies of three previously identified cognitive biases, we find that frequency-based predictions are different from-but no better than-case-specific judgments of probability. First, in studies of the "planning fallacy, " we compare the accuracy of aggregate frequency and case specific probability judgments in predictions of students' real-life projects. When aggregate and single-case predictions are collected from different respondents, there is little difference between the two: Both are overly optimistic and show little predictive validity. However, in within-subject comparisons, the aggregate judgments are significantly more conservative than the single-case predictions, though still optimistically biased. Results from studies of overconfidence in general knowledge and base rate neglect in categorical prediction underline a general conclusion. Frequentistic predictions made for sets of events are no more statistically sophisticated, nor more accurate, than predictions made for individual events using subjective probability. PMID- 10090799 TI - Goals as reference points. AB - We argue that goals serve as reference points and alter outcomes in a manner consistent with the value function of Prospect Theory (Kahneman & Tversky, 1979; Tversky & Kahneman, 1992). We present new evidence that goals inherit the properties of the value function-not only a reference point, but also loss aversion and diminishing sensitivity. We also use the value function to explain previous empirical results in the goal literature on affect, effort, persistence, and performance. PMID- 10090800 TI - Similarity between hypotheses and evidence. AB - We explore two novel consequences of similarity-based likelihood judgment. In Section I, we distinguish between the evidence on which judgments are based and the hypotheses that serve as the objects of judgment. The location of a feature, whether in the evidence or the hypotheses, influences the perceived similarity between evidence and hypotheses and consequently yields judgments that are inconsistent with the requirements of probability theory. In Section II, we examine judgment of disjunctive hypotheses. For certain types of disjunctions, the assessment of similarity produces consistent nonmonotonicities: the support of a disjunction is smaller than that of one of its components. Finally, we discuss the implications of our findings in terms of support theory and the principle of context independence. PMID- 10090801 TI - On the shape of the probability weighting function. AB - Empirical studies have shown that decision makers do not usually treat probabilities linearly. Instead, people tend to overweight small probabilities and underweight large probabilities. One way to model such distortions in decision making under risk is through a probability weighting function. We present a nonparametric estimation procedure for assessing the probability weighting function and value function at the level of the individual subject. The evidence in the domain of gains supports a two-parameter weighting function, where each parameter is given a psychological interpretation: one parameter measures how the decision maker discriminates probabilities, and the other parameter measures how attractive the decision maker views gambling. These findings are consistent with a growing body of empirical and theoretical work attempting to establish a psychological rationale for the probability weighting function. PMID- 10090802 TI - Strength of evidence, judged probability, and choice under uncertainty. AB - This paper traces, within subjects, the relationship between assessed strength of evidence, judgments of probability, and decisions under uncertainty. The investigation relies on the theoretical framework provided by support theory (Tversky & Koehler, 1994; Rottenstreich & Tversky, 1997), a nonextensional model of judgment under uncertainty. Fans of professional basketball (N = 50) judged the probability that each of eight teams, four divisions, and two conferences would win the National Basketball Association championship. Additionally, participants rated the relative strength of each team, judged the probability that a given team would win the championship assuming a particular pairing in the finals, priced prospects contingent on the winner of the championship, and made choices between chance prospects. The data conformed to the major tenets of support theory, and the predicted relationships between assessed strength of evidence, hypothetical support, judged probabilities, and choices under uncertainty also held quite well. PMID- 10090803 TI - The probability heuristics model of syllogistic reasoning. AB - A probability heuristic model (PHM) for syllogistic reasoning is proposed. An informational ordering over quantified statements suggests simple probability based heuristics for syllogistic reasoning. The most important is the "min heuristic": choose the type of the least informative premise as the type of the conclusion. The rationality of this heuristic is confirmed by an analysis of the probabilistic validity of syllogistic reasoning which treats logical inference as a limiting case of probabilistic inference. A meta-analysis of past experiments reveals close fits with PHM. PHM also compares favorably with alternative accounts, including mental logics, mental models, and deduction as verbal reasoning. Crucially, PHM extends naturally to generalized quantifiers, such as Most and Few, which have not been characterized logically and are, consequently, beyond the scope of current mental logic and mental model theories. Two experiments confirm the novel predictions of PHM when generalized quantifiers are used in syllogistic arguments. PHM suggests that syllogistic reasoning performance may be determined by simple but rational informational strategies justified by probability theory rather than by logic. PMID- 10090804 TI - Tracking multiple items through occlusion: clues to visual objecthood. AB - In three experiments, subjects attempted to track multiple items as they moved independently and unpredictably about a display. Performance was not impaired when the items were briefly (but completely) occluded at various times during their motion, suggesting that occlusion is taken into account when computing enduring perceptual objecthood. Unimpaired performance required the presence of accretion and deletion cues along fixed contours at the occluding boundaries. Performance was impaired when items were present on the visual field at the same times and to the same degrees as in the occlusion conditions, but disappeared and reappeared in ways which did not implicate the presence of occluding surfaces (e.g., by imploding and exploding into and out of existence instead of accreting and deleting along a fixed contour). Unimpaired performance did not require visible occluders (i.e., Michotte's tunnel effect) or globally consistent occluder positions. We discuss implications of these results for theories of objecthood in visual attention. PMID- 10090805 TI - A structural account of global and local processing. AB - The order of processing, whether global forms are processed prior to local forms or vice versa, has been of considerable interest. Many current theories hold that the more perceptually conspicuous form is identified first. An alternative view is presented here in which the stuctural relations among elements are an important factor in explaining the relative speeds of global and local processing. We equated the conspicuity of the global and local forms in three experiments and still found advantages in the processing of global forms. Subjects were able to process the relations among the elements quickly, even before the elements themselves were identified. According to our alternative view, subjects created equivalence classes of similar and proximate local elements before identifying the constituent elements. The experiments required subjects to decide whether two displays were the same or different, and consequently, the results are relevant to work in higher-level cognition that stresses the importance of comparison processes (e.g., analogy and conceptual combination). We conclude by evaluating related work in higher-level cognition in light of our findings. PMID- 10090807 TI - Acknowledgment PMID- 10090806 TI - Intuitive theories of information: beliefs about the value of redundancy. AB - In many situations, quantity estimates from multiple experts or diagnostic instruments must be collected and combined. Normatively, and all else equal, one should value information sources that are nonredundant, in the sense that correlation in forecast errors should be minimized. Past research on the preference for redundancy has been inconclusive. While some studies have suggested that people correctly place higher value on uncorrelated inputs when collecting estimates, others have shown that people either ignore correlation or, in some cases, even prefer it. The present experiments show that the preference for redundancy depends on one's intuitive theory of information. The most common intuitive theory identified is the Error Tradeoff Model (ETM), which explicitly distinguishes between measurement error and bias. According to ETM, measurement error can only be averaged out by consulting the same source multiple times (normatively false), and bias can only be averaged out by consulting different sources (normatively true). As a result, ETM leads people to prefer redundant estimates when the ratio of measurement error to bias is relatively high. Other participants favored different theories. Some adopted the normative model, while others were reluctant to mathematically average estimates from different sources in any circumstance. In a post hoc analysis, science majors were more likely than others to subscribe to the normative model. While tentative, this result lends insight into how intuitive theories might develop and also has potential ramifications for how statistical concepts such as correlation might best be learned and internalized. PMID- 10090808 TI - Effect of natural dissolved humic material on bioavailability and acute toxicity of fenpropathrin to the grass carp, Ctenopharyngodon idellus. AB - The effects of aquatic humic acids on the bioconcentration and acute toxicity of fenpropathrin were evaluated using grass carp, Ctenopharyngodon idellus, in laboratory freshwater systems. The results demonstrated that both bioavailability and acute toxicity decreased in the presence of aquatic humic acid 5 and 10 mg/liter. In addition, the extent of influence increased with increasing concentration of aquatic humic acid. PMID- 10090809 TI - Monitoring of labile zinc in cultures of Skeletonema costatum using a salt groundwater. AB - Labile Zn concentration was monitored by differential pulse anodic stripping voltammetry (DPASV) throughout the exponential growth phase of the marine diatom Skeletonema costatum (Grev.) Cleve. Algal blooms were induced both under natural conditions and in laboratory experiments using a salt groundwater (salinity 33) from the Bay of Bourgneuf, northwest coast of France. Salt groundwater is a very complex medium containing high concentrations of dissolved organic matter and other trace metal adsorbents, such as phosphate, iron oxyhydroxides, and manganese and silicon oxides, which can bind metal ions, reducing their availability and toxicity to algae. Besides metal uptake by algae and complexation of Zn by algal exudates, the rapid decrease in the labile Zn concentration during the algal blooms was ascribed mainly to the adsorption or coprecipitation of Zn ion onto freshly formed iron hydroxides. PMID- 10090810 TI - Altered challenge response in whitefish subchronically exposed in areas polluted by bleached kraft mill effluents. AB - Exposure to impaired water quality, as in bleached kraft mill effluents (BKMEs), has recently been demonstrated to impair the ability of fish to elicit an acute stress response. Acute stress caused by catching is, in most field studies, an unavoidable incident that may markedly affect physiological functions. Consistently, dissimilar stress responses to catching procedures in exposed and reference animals may lead to altered results. In this study, juvenile whitefish (Coregonus levaretus) were caged for 30 days in two reference areas and three areas affected by different BKMEs, and the immediate effects of low-level handling on physiological functions in four periods within an hour of the start of the disturbance were clarified. Both primary and secondary stress responses were evident and consistent in fish caged in the two reference areas. Instead, despite the strong cortisol response in fish caged in polluted areas, the secondary stress response was weak or altered with respect to all other measured parameters excluding blood glucose in two of the three polluted areas. Thus, exposed fish may, when compared with reference fish, give different results depending on the exact period from the onset of the catching disturbance to sampling, and therefore, the results may be masked or totally inverted. Because the impacts of acute stress on physiological parameters are immediate and, in exposed areas after low-level handling, dissimilar in nature, this study points to the necessity for time-dependent standardization in field studies whenever sampling is delayed. PMID- 10090811 TI - Indicators of immunotoxicity in populations of cotton rats (Sigmodon hispidus) inhabiting an abandoned oil refinery. AB - Wildlife species inhabiting contaminated sites are often exposed to complex mixtures of chemicals, many of which have known effects on physiological and biochemical function. Although sensitivity of the immune system to chemical exposure has been documented in laboratory animal and wildlife species, little work has been conducted on feral wildlife populations inhabiting contaminated sites. Immune function was measured in populations of wild cotton rats (Sigmodon hispidus) inhabiting replicated reference and contaminated study sites at an abandoned oil refinery in Oklahoma four times from 1991 to 1992. Several measures of immunocompetence were examined including immune organ mass and cellularity, hematology, in vivo hypersensitivity, macrophage function, killer cell activity, and lymphoproliferative responsiveness. In vitro proliferation of splenocytes, either spontaneous or induced with concanavalin A (Con A), was the most consistent and reliable indicator of immunotoxicity. Spontaneous proliferation of splenocytes was 48 and 24% higher for cotton rats collected from contaminated than reference sites in September 1991 and September 1992, respectively. Likewise, Con A-induced proliferation of splenocytes ranged form 20 to 53% higher in animals collected from contaminated than reference sites in three of four collection periods. The percentage of splenocytes (mean+/-SE) staining positive for Con A receptors was lower on contaminated sites (73.7+/-1.2%) than reference sites (77.0+/-1.4%) in September 1991. Other measures of immune function including macrophage metabolism, hypersensitivity, blood cellularity, and mass and cellularity of immune organs varied between contaminated and reference sites. PMID- 10090812 TI - Temperature-time relationship in collembolan response to chemical exposure. AB - Effects of temperature on chemical toxicity to a collembolan, Folsomia candida, in relation to time were studied in this experiment. Field soil was used as a test substrate. Collembolans were incubated at three different temperatures (+13, +16, and +19 degrees C) and in two different dimethoate concentrations (1 and 3 mg/kg), clean soil serving as the control. Four destructive samplings were done at 2-week intervals. Dimethoate degradation was also analyzed. Dimethoate 1 mg/kg had a slight effect on both adult growth and reproduction, whereas 3 mg/kg was fatal to F. candida in the soil used. Toxic effects tended to last longer at low temperature than at high temperature, but the differences were not extensive. Temperature was negatively correlated with adult growth but positively correlated with reproduction. The dimethoate degradation rate was similar at all temperatures but differed with the concentration. PMID- 10090813 TI - Selective reduction method for separate determination of inorganic and total mercury in mussel tissue by flow-injection cold vapor technique. AB - A flow-injection cold vapor atomic absorption spectrometry (FI-CV-AAS) method was developed to determine inorganic mercury and total mercury in mussel samples obtained from the Galicia coasts. The mussel samples were digested in a microwave oven using an HNO3/H2O2 mixture and then total mercury was determined using sodium borohydride as reducing agent. In a separate subsample, following ultrasonic extraction in hydrochloric acid medium, inorganic mercury was determined by selective reduction using stannous chloride in acid medium as reducing agent. The accuracy of the digestion method was checked by analyzing BCR Reference Material No. 278 Mussel Tissue (Mytilus edulis). There were no significant differences between the certified and found concentration values. As a certified reference material of mussel tissue containing both methylmercury and inorganic mercury was not available, recovery studies on mussel tissue samples spiked with inorganic mercury and methylmercury were done to check the reliability of the method. The results revealed that the mercury contained in mussel samples was methylmercury. PMID- 10090814 TI - Alterations in physiological parameters of rainbow trout (Oncorhynchus mykiss) with exposure to copper and copper/zinc mixtures. AB - Rainbow trout (Oncorhynchus mykiss) were exposed to sublethal concentrations of copper (Cu, 14 microgram/liter) and zinc (Zn, 57 and 81 microgram/liter) for a 21 day period. The four treatments included a control, a Cu control, a Cu and low-Zn treatment and a Cu and high-Zn treatment. Selected parameters [e.g., hemoglobin (Hb), hematocrit (Hct), plasma glucose, lactate and cortisol, differential leukocyte count, respiratory burst, tissue metal concentrations, hepatic metallothionein (MT), brain acetylcholinesterase (AChE)] were evaluated at 2, 7, 14, and 21 days of exposure. Whole blood and plasma parameters were not altered by exposure to metals. The percentage of lymphocytes was consistently decreased in the three metal treatments, while percentages of neutrophils and monocytes were increased. Respiratory burst activity was elevated in all metal treatments. Gill Zn concentration was highly variable, with no significant alterations occurring. Gill Cu concentration was elevated above control levels in all metal treatments. Gill Cu concentration in the two Cu/Zn treatments was also elevated above levels in the Cu control. Hepatic metal concentrations and MT levels were not altered from control values. Measurements of brain AChE indicated an elevation in this parameter across metal treatments. In general, alterations in physiological parameters appeared to be due to Cu, with Zn having no interactive effect. PMID- 10090815 TI - Effects of polychlorinated biphenyls on liver ultrastructure, hepatic monooxygenases, and reproductive success in the barbel. AB - Polychlorinated biphenyls (PCBs) are organochlorinated micropollutants ubiquitously distributed in the environment. They are known to be strong inducers of hepatic monooxygenases in fish. This can adversely affect reproduction by increasing steroid metabolism. In this work, adult barbels were contaminated with food containing Aroclor 1260, a commercial PCB mixture from Monsanto, at environmentally relevant concentrations. A significant increase in cytochrome P450 was observed, and two particularly sensitive enzymes, ethoxyresorufin o deethylase (EROD) and ethoxycoumarin o-deethylase (ECOD), were strongly induced. Electron microscopy revealed alterations in liver ultrastructure in contaminated fish, principally an increase in the number of cisternae of the rough endoplasmic reticulum, drastic glycogen depletion, dissolution of mitochondrial contents, and appearance of myelin figures. Contamination was also studied in relation to reproductive success in a hatchery. Contaminated males displayed no alteration in milt quality, but PCBs did alter female reproductive parameters. Total mortality of eggs and larvae increased significantly with the level of PCBs in the eggs. The most highly contaminated fish did not even spawn. All the adverse effects recorded here tended to be reversible when the intoxication ended, sometimes after only a 1-year detoxication period. PMID- 10090816 TI - Environmental risk assessment for the widely used iodinated X-ray contrast agent iopromide (Ultravist). AB - Iodinated X-ray contrast media are diagnostic pharmaceuticals that are applied to enhance the contrast between organs or vessels examined and surrounding tissues during radiography. These substances are applied in doses up to ca. 200 g per person (corresponding to approx 100 g iodine) and are rapidly excreted. In the sewage system they contribute to the burden of adsorbable organic halogens (AOX). To assess the potential environmental impact of this release, studies on environmental fate and effects were conducted for a risk assessment of the frequently used X-ray contrast medium iopromide (brand name: Ultravist). A screening test for biological degradation (OECD Screening Test 301 E) led to iopromide being classified as not readily biodegradable. Therefore, the predicted environmental concentration (PEC) in surface water was calculated in a first step. The resulting concentration of 2 microgram/liter was then compared in a second step with the predicted no-effect concentration as derived from a battery of ecotoxicity tests. In short-term toxicity tests with bacteria (Vibrio fisheri, Pseudomonas putida), algae (Scenedesmus subspicatus), crustaceans (Daphnia magna), and fish (Danio rerio, Leuciscus idus) no toxic effects were detected at the highest tested concentration of 10 g/liter. In a chronic toxicity test with D. magna no effect was observed at the highest tested concentration of 1 g/liter. Using an assessment factor of 100 the ratio between the predicted environmental concentration (PEC) and the predicted no-effect concentration (PNEC) was calculated to be /=25 cigarettes/day, age-standardized mean number of cigarettes smoked per day, and multivariate odds ratios (OR) of being a heavy smoker (>/=25 cigarettes/day) according to age at starting smoking (<15, 15-17, 18-19, >/=20 years) were computed. RESULTS: Men who started smoking before the age of 15 smoked on average 5.5 cigarettes more than those who started at age 19 or over. Women who started smoking early in life smoked, on average, 6.8 cigarettes/day more than women who started later. The proportion of smokers of <15 cigarettes/day was higher among subjects who started smoking later. Both for males and for females, the OR of being a heavy smoker significantly increased with decreasing age at starting smoking (OR = 2.4 for males and 4.5 for females who started at age <15 versus >/=20 years). The level of education did not modify the relationship in males, whereas the association with age at starting was only apparent for more educated women. CONCLUSIONS: This study confirms that age at starting smoking is inversely and strongly associated to the number of cigarettes smoked per day. Thus, actions aimed at the prevention or delay of smoking onset among adolescents would have an important beneficial effect. PMID- 10090866 TI - Intrafamilial relations of cardiovascular disease risk factors in African Americans: longitudinal results from DC SCAN. AB - BACKGROUND: Few studies have examined intrafamilial patterns of cardiovascular disease (CVD) risk factors in African-American families or identified potential influences on these patterns. This study examines the effects of age and sex of child on correlations between siblings during childhood as well as between mothers and their offspring in African-American families at two points in time. METHODS: CVD risk factors were assessed in a sample of 267 pairs of African American siblings and their mothers. One hundred nine of these families were selected for a second assessment of CVD risk factors approximately 28 months later. RESULTS: Older siblings had significantly greater correlations than younger siblings with mothers' low-density lipoproteins (r = 0.61 versus r = 0.43 for older and younger siblings, respectively), apolipoprotein A-I (r = 0. 46 versus r = 0.16), and lipoprotein (a) (r = 0.71 versus r = 0.34). Correlations between female siblings were significantly higher than between male siblings for total cholesterol (r = 0.74 versus r = 0. 18 for female versus male siblings), triglycerides (r = 0.56 versus r = 0.05), and apolipoprotein B (r = 0.72 versus r = 0.31); they were also higher between female siblings than between mixed-sex siblings for measures of adiposity (r = 0.46 versus r = 0.19) and total cholesterol (r = 0.74 versus r = 0.27). CONCLUSIONS: Significant intrafamilial correlations for African-American children were influenced by both age and sex of siblings, reflecting potential genetic and environmental influences. Assessing family patterns of CVD risk factors in high-risk populations may assist in the early identification of children who can benefit most from intervention. PMID- 10090867 TI - Smoking and lipid cardiovascular risk factors in Vietnamese refugees in Australia. AB - BACKGROUND: The effects of smoking and sex on lipid risk factors for cardiovascular disease were examined among Vietnamese people newly arrived in Australia. METHODS: Immigrants recruited through Refugee Screening had anthropometric data recorded and blood collected to measure total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) by Reflotron; apolipoprotein A-1 (apo A-1) and apolipoprotein B-100 (apo B) by immunoturbidimetric analyses (Turbitimer); and lipoprotein (a) (LP (a)) by ELISA. A questionnaire determined behavioral variables known to influence cardiovascular risk and Statview, Minitab, and SPSS were employed for data analysis. RESULTS: Lipoprotein profiles of men (n = 242) and women (n = 159) were compared. Crude TC and apo B were similar; HDL, apo A-1, and LP (a) were higher in women, TG was higher in men. After adjustment (age, BMI, WHR, years of smoking, and drinks per week), only apo A-1 and LP (a), were higher in women. "At risk" levels of TC or apo B did not differ by gender; risk of low apo A-1 was higher among men. Smokers had a significant risk (crude and adjusted) of low HDL, low apo A-1, and high LP (a). The sex difference in HDL was removed by a single adjustment for smoking; male smokers had higher LP (a) than male nonsmokers. CONCLUSION: Male and female Vietnamese immigrants had similar adjusted lipid profiles. Smoking had a marked detrimental effect on lipids. PMID- 10090868 TI - Compliance with mammography guidelines: physician recommendation and patient adherence. AB - BACKGROUND: Guidelines recommend that women ages 50-75 years receive screening mammography every 1-2 years. We related receipt of physician recommendations for mammography and patient adherence to such recommendations to several patient characteristics. METHODS: We retrospectively reviewed medical records of 1,111 women ages 50-75 attending three clinics in an urban university medical center. We ascertained overall compliance with mammography guidelines and two components of compliance: receipt of a physician recommendation and adherence to a recommendation. Outcome measures were the proportion of patients demonstrating each type of compliance and adjusted odds ratios, according to several patient related characteristics. RESULTS: Overall, 66% of women received a recommendation. Of women receiving a documented recommendation, 75% adhered. Factors showing significant positive associations with receiving a recommendation included being a patient in the general internal medicine clinic, having private insurance, visiting the clinic more often, and having a recent Pap smear. Patient adherence was positively associated with private insurance and Pap smear history, negatively associated with internal medicine, and not associated with visit frequency. CONCLUSIONS: Patient factors influencing physician mammography recommendations may be different from those associated with patient adherence, except for having private health insurance, which was a predictor of both. PMID- 10090869 TI - Effect of a media-led education campaign on breast and cervical cancer screening among Vietnamese-American women. AB - BACKGROUND: Previous research has shown that breast and cervical cancer screening rates are low among Vietnamese women. METHODS: Over a 24-month period, we implemented a media-led community education campaign to promote recognition, intention, receipt, and currency of routine checkups, clinical breast examinations, mammograms, and Pap tests among Vietnamese-American women in Alameda and Santa Clara Counties in northern California. Women in Los Angeles and Orange Counties in southern California served as controls. To evaluate its impact, pretest telephone interviews were conducted of 451 randomly selected women in the intervention area and 482 women in the control area and posttest interviews with 454 and 422 women, respectively. RESULTS: At posttest, after controlling for demographic differences in the surveyed populations, the odds ratios for the intervention effect were statistically significant for having heard of a general checkup, Paptest, and clinical breast examination (CBE); planning to have a checkup, Pap test, CBE, and mammogram; and having had a checkup and Pap test. The intervention had no effect on being up to date for any of the tests. CONCLUSIONS: A media-led education intervention succeeded in increasing recognition of and intention to undertake screening tests more than receipt of or currency with the tests. PMID- 10090870 TI - Cigarette smoking, alcohol consumption, and screening mammography among women ages 50 and older. AB - BACKGROUND: The associations among cigarette smoking and alcohol consumption with recent screening mammograms were evaluated among women ages 50 years and older. METHODS: The sample included 946 white and African-American women ages 50 years and older from the 1995 Maryland Behavioral Risk Factor Survey. Bivariate and logistic regression analyses were performed to evaluate the associations between current cigarette smoking and alcohol consumption in the past month (none, 1-7 drinks, >7 drinks) with obtaining a screening mammogram in the past 2 years (recent mammogram), controlling for sociodemographic and health variables. RESULTS: Seventy-eight percent of respondents had recent mammograms, 15% smoked cigarettes, 18% reported 1-7 drinks, and 12% reported >7 drinks in the past month. Smokers had lower mammography rates than nonsmokers (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.30-0.75). Women who drank alcoholic beverages had higher mammography rates than nondrinkers (OR = 1.37, 95% CI = 1.03 1.83). Smokers had the lowest mammography rates, regardless of their consumption of alcohol. An interaction was observed among white but not African-American women: nonsmokers who consumed moderate amounts of alcohol (1-7 drinks) had the highest mammography rates in this subgroup. CONCLUSIONS: To reduce breast cancer mortality, it is important to increase screening mammography among all women over age 50 and especially among smokers and the oldest women. PMID- 10090871 TI - Breast and cervix cancer screening among multiethnic women: role of age, health, and source of care. AB - OBJECTIVE: The aim of this study was to evaluate the relationships between age, health status, access to care, and breast and cervical cancer screening among multiethnic elderly and nonelderly women. METHODS: A structured telephone survey of a quota sample of 1,420 New York City women from four Hispanic groups (Columbian, Dominican, Puerto Rican, Ecuadorian) and three black groups (U.S., Caribbean, and Haitian) was performed. Outcome measures included "ever" and "recent" self-reported use of mammography, clinical breast examination (CBE), and Pap smears. Logistic regression models assessed the predictors of screening use. RESULTS: Having a regular source of care significantly predicted all screening use for both elderly and nonelderly, controlling for ethnicity, sociodemographics, health status, access to care, proportion of life in the United States, and cancer attitudes. Elderly women (>/=65 years) were significantly less likely to have ever had (OR = 0.79, 95% CI 0.65-0. 96) and to have recently had (OR = 0.67, 95% CI 0.57-0.79) Pap smears than younger women, controlling for the other variables; being elderly also tended to be an independent predictor of ever and recent mammography and CBE use. Interestingly, there was a trend for health status to act differently in predicting Pap smear use for the two age groups. For younger women, being in poor health increased the odds of Pap smear screening, while for elderly women, being in good health increased the odds of screening. CONCLUSIONS: Elderly women reported being screened less than younger women; interactions between health status and age need further exploration. PMID- 10090872 TI - The paucity of effects in community trials: is secular trend the culprit? AB - BACKGROUND: The most recent major U.S. trials that evaluated community-level programs to influence risk factors and health behaviors identified secular trends in the risk factors and health behaviors among the factors that might have limited community-level effects. The research reported in this paper uses data from one of the trials to examine the secular trend explanation directly. METHODS: Data from the 22-community Community Intervention Trial for Smoking Cessation (COMMIT) were analyzed to test a hypothesis based on secular trend reasoning: program effects for smoking prevalence were larger for treatment communities matched to control communities with small declines in smoking than in treatment communities matched to control communities with larger declines in smoking. RESULTS: Consistent with the secular trend explanation, program effects were larger when control communities had relatively small declines in smoking prevalence. CONCLUSIONS: The findings suggest that secular trends masked community-level program effects in COMMIT. PMID- 10090873 TI - Predictors and correlates of prevention research careers: a national study of residency graduates. AB - BACKGROUND: Factors associated with research productivity among residency graduates are not well understood. The objectives of this study are to describe research productivity among preventive medicine residency (PMR) graduates and to identify factors that are correlated with high levels of productivity. METHODS: A detailed survey was mailed to all (n = 1,070) graduates from U.S. PMRs between 1979 and 1989. Main outcome measures for this analysis were (1) 25% of the workweek or more research time and (2) 20 or more publications since training completion. RESULTS: A total of 797 completed surveys were received for a response rate of 75%. Among respondents, 33% devoted at least 25% of their time to research and 13% had 20 or more publications. Independent positive predictors (P < 0.05) based on education and training of high research productivity as measured by both outcomes included research self-motivation, training at the Centers for Disease Control and Prevention, and clinical board certification. Concurrent correlates of current high research productivity by both outcomes included employment by the federal government or academia and academic appointment. CONCLUSIONS: Factors associated with high research productivity could be utilized to improve the resident selection process and promote research careers. This could enhance research programs and education and promote the overall prevention research agenda. PMID- 10090874 TI - Preventing tuberculosis among HIV-infected persons: a survey of physicians' knowledge and practices. AB - BACKGROUND: Guidelines exist for screening, diagnosing, and preventing tuberculosis (TB) among HIV-infected persons, but their application and utility are unknown. METHODS: We conducted a survey of knowledge and practices among 1,300 physicians in the San Francisco Bay area to assess their practices towards TB among HIV-infected persons. RESULTS: Of 630 respondents, 350 (56%) provided care for HIV-infected persons. Thirty-four percent of the respondents had seen the most recent guidelines for preventing tuberculosis among HIV-infected persons; 65% routinely provide information to HIV-infected patients about the risks of exposure to Mycobacterium tuberculosis; 39% provide annual tuberculin skin testing (TST) to HIV-infected patients without a history of a positive test; 86% knew that >/=5-mm induration is considered a positive TST result in HIV infected persons; and 47% provide a 12-month regimen of chemoprophylaxis for HIV infected persons who have a positive TST but not active tuberculosis. Physician specialty and experience with HIV-infected persons were not strongly correlated; experience was a better predictor of correct knowledge and practices. CONCLUSIONS: Many physicians were not aware of the standards of care for preventing tuberculosis among HIV-infected patients, even in a geographic area with a high prevalence of M. tuberculosis and HIV. PMID- 10090875 TI - Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. PMID- 10090876 TI - Sex Chromosome Genetics '99. Male infertility and the Y chromosome. PMID- 10090877 TI - Sex Chromosome Genetics '99. The X chromosome and recurrent spontaneous abortion: the significance of transmanifesting carriers. PMID- 10090878 TI - The genetic basis for periodic fever. PMID- 10090879 TI - BRCA1 and BRCA2 testing: weighing the demand against the benefits. PMID- 10090880 TI - Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. AB - Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region. PMID- 10090881 TI - The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. AB - Three founder mutations in the cancer-associated genes BRCA1 and BRCA2 occur frequently enough among Ashkenazi Jews to warrant consideration of genetic testing outside the setting of high-risk families with multiple cases of breast or ovarian cancer. We estimated the prevalence of these founder mutations in BRCA1 and BRCA2 in the general population of Ashkenazi Jews according to age at testing, personal cancer history, and family cancer history. We compared the results of anonymous genetic testing of blood samples obtained in a survey of >5,000 Jewish participants from the Washington, DC, area with personal and family cancer histories obtained from questionnaires completed by the participants. In all subgroups defined by age and cancer history, fewer mutations were found in this community sample than in clinical series studied to date. For example, 11 (10%) of 109 Jewish women who had been given a diagnosis of breast cancer in their forties carried one of the mutations. The most important predictor of mutation status was a previous diagnosis of breast or ovarian cancer. In men and in women never given a diagnosis of cancer, family history of breast cancer before age 50 years was the strongest predictor. As interest in genetic testing for BRCA1 and BRCA2 in the Jewish community broadens, community-based estimates such as these help guide those seeking and those offering such testing. Even with accurate estimates of the likelihood of carrying a mutation and the likelihood of developing cancer if a mutation is detected, the most vexing clinical problems remain. PMID- 10090882 TI - Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene. AB - Family ZMK is a large Irish kindred that segregates progressive sensorineural hearing loss and retinitis pigmentosa. The symptoms in the family are almost identical to those observed in Usher syndrome type III. Unlike that in Usher syndrome type III, the inheritance pattern in this family is compatible with dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and >90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, it is notable that no markers were found at zero recombination with respect to the disease gene. The marked variability in symptoms, together with the observation of subclinical muscle abnormalities in a single muscle biopsy, stimulated sequencing of the entire mtDNA in affected and unaffected individuals. This revealed a number of previously reported polymorphisms and/or silent substitutions. However, a C-->A transversion at position 12258 in the gene encoding the second mitochondrial serine tRNA, MTTS2, was heteroplasmic and was found in family members only. This sequence change was not present in 270 normal individuals from the same ethnic background. The consensus C at this position is highly conserved and is present in species as divergent from Homo sapiens as vulture and platypus. The mutation probably disrupts the amino acid-acceptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation. In summary, the data presented provide substantial evidence that the C12258A mtDNA mutation is causative of the disease phenotype in family ZMK. PMID- 10090883 TI - Germ-line mosaicism in tuberous sclerosis: how common? AB - Two-thirds of cases of tuberous sclerosis complex (TSC) are sporadic and usually are attributed to new mutations, but unaffected parents sometimes have more than one affected child. We sought to determine how many of these cases represent germ line mosaicism, as has been reported for other genetic diseases. In our sample of 120 families with TSC, 7 families had two affected children and clinically unaffected parents. These families were tested for mutations in the TSC1 and TSC2 genes, by Southern blotting and by single-strand conformational analysis. Unique variants were detected in six families. Each variant was present and identical in both affected children of a family but was absent in both parents and the unaffected siblings. Sequencing of the variants yielded two frameshift mutations, one missense mutation, and two nonsense mutations in TSC2 and one nonsense mutation in TSC1. To determine which parent contributed the affected gametes, the families were analyzed for linkage to TSC1 and TSC2, by construction of haplotypes with markers flanking the two genes. Linkage analysis and loss-of heterozygosity studies indicated maternal origin in three families, paternal origin in one family, and either being possible in two families. To evaluate the possibility of low-level somatic mosaicism for TSC, DNA from lymphocytes of members of the six families were tested by allele-specific PCR. In all the families, the mutant allele was detected only in the known affected individuals. We conclude that germ-line mosaicism was present in five families with mutations in the TSC2 gene and in one family with the causative mutation in the TSC1 gene. The results have implications for genetic counseling of families with seemingly sporadic TSC. PMID- 10090884 TI - Recurrence of Marfan syndrome as a result of parental germ-line mosaicism for an FBN1 mutation. AB - Mutations in the FBN1 gene cause Marfan syndrome (MFS), a dominantly inherited connective tissue disease. Almost all the identified FBN1mutations have been family specific, and the rate of new mutations is high. We report here a de novo FBN1mutation that was identified in two sisters with MFS born to clinically unaffected parents. The paternity and maternity were unequivocally confirmed by genotyping. Although one of the parents had to be an obligatory carrier for the mutation, we could not detect the mutation in the leukocyte DNA of either parent. To identify which parent was a mosaic for the mutation we analyzed several tissues from both parents, with a quantitative and sensitive solid-phase minisequencing method. The mutation was not, however, detectable in any of the analyzed tissues. Although the mutation could not be identified in a sperm sample from the father or in samples of multiple tissue from the mother, we concluded that the mother was the likely mosaic parent and that the mutation must have occurred during the early development of her germ-line cells. Mosaicism confined to germ-line cells has rarely been reported, and this report of mosaicism for the FBN1 mutation in MFS represents an important case, in light of the evaluation of the recurrence risk in genetic counseling of families with MFS. PMID- 10090885 TI - Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. AB - Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS. PMID- 10090886 TI - Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias. AB - The long QT syndrome is characterized by prolonged cardiac repolarization and a high risk of sudden death. Mutations in the KCNQ1 gene, which encodes the cardiac KvLQT1 potassium ion (K+) channel, cause both the autosomal dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome. JLN presents with cardiac arrhythmias and congenital deafness, and heterozygous carriers of JLN mutations exhibit a very mild cardiac phenotype. Despite the phenotypic differences between heterozygotes with RW and those with JLN mutations, both classes of variant protein fail to produce K+ currents in cultured cells. We have shown that an N-terminus-truncated KvLQT1 isoform endogenously expressed in the human heart exerts strong dominant-negative effects on the full-length KvLQT1 protein. Because RW and JLN mutations concern both truncated and full-length KvLQT1 isoforms, we investigated whether RW or JLN mutations would have different impacts on the dominant-negative properties of the truncated KvLQT1 splice variant. In a mammalian expression system, we found that JLN, but not RW, mutations suppress the dominant-negative effects of the truncated KvLQT1. Thus, in JLN heterozygous carriers, the full-length KvLQT1 protein encoded by the unaffected allele should not be subject to the negative influence of the mutated truncated isoform, leaving some cardiac K+ current available for repolarization. This is the first report of a genetic disease in which the impact of a mutation on a dominant-negative isoform correlates with the phenotype. PMID- 10090887 TI - The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. AB - In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype. PMID- 10090888 TI - COL9A3: A third locus for multiple epiphyseal dysplasia. AB - Multiple epiphyseal dysplasia (MED), an autosomal dominant osteochondrodysplasia, is a clinically and genetically heterogeneous disorder characterized by mild short stature and early-onset osteoarthritis. The phenotypic spectrum includes the mild Ribbing type, the more severe Fairbank type, and some unclassified forms. Linkage studies have identified two loci for MED. One of these, EDM1, is on chromosome 19, in a region that contains the cartilage oligomeric matrix protein (COMP) gene. Mutations have been identified in this gene in patients with the Ribbing type, the Fairbank type, and unclassified forms of MED. The second locus, EDM2, maps to chromosome 1, in a region spanning COL9A2. Recently, a splice-site mutation was found in COL9A2, causing skipping of exon 3 in one family with MED. Because of the exclusion of the EDM1 and EDM2 loci in some families, the existence of a third locus has been postulated. We report here one family with MED, evaluated clinically and radiologically and tested for linkage with candidate genes, including COMP, COL9A1, COL9A2, and COL9A3. No linkage was found with COMP, COL9A1, or COL9A2, but an inheritance pattern consistent with linkage was observed with COL9A3. Mutation analysis of COL9A3 identified an A-->T transversion in the acceptor splice site of intron 2 in affected family members. The mutation led to skipping of exon 3 and an in-frame deletion of 12 amino acid residues in the COL3 domain of the alpha3(IX) chain and thus appeared to be similar to that reported for COL9A2. This is the first disease-causing mutation identified in COL9A3. Our results also show that COL9A3, located on chromosome 20, is a third locus for MED. PMID- 10090889 TI - The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother. AB - Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype. PMID- 10090890 TI - Multicentric origin of hemochromatosis gene (HFE) mutations. AB - Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends 70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation-associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the basis of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation. PMID- 10090892 TI - Age estimates of two common mutations causing factor XI deficiency: recent genetic drift is not necessary for elevated disease incidence among Ashkenazi Jews. AB - The type II and type III mutations at the FXI locus, which cause coagulation factor XI deficiency, have high frequencies in Jewish populations. The type III mutation is largely restricted to Ashkenazi Jews, but the type II mutation is observed at high frequency in both Ashkenazi and Iraqi Jews, suggesting the possibility that the mutation appeared before the separation of these communities. Here we report estimates of the ages of the type II and type III mutations, based on the observed distribution of allelic variants at a flanking microsatellite marker (D4S171). The results are consistent with a recent origin for the type III mutation but suggest that the type II mutation appeared >120 generations ago. This finding demonstrates that the high frequency of the type II mutation among Jews is independent of the demographic upheavals among Ashkenazi Jews in the 16th and 17th centuries. PMID- 10090893 TI - Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio facial syndrome. AB - Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans. It occurs with an estimated frequency of 1 in 4, 000 live births. Most cases occur sporadically, indicating that the deletion is recurrent in the population. More than 90% of patients with VCFS and a 22q11 deletion have a similar 3-Mb hemizygous deletion, suggesting that sequences at the breakpoints confer susceptibility to rearrangements. To define the region containing the chromosome breakpoints, we constructed an 8-kb-resolution physical map. We identified a low-copy repeat in the vicinity of both breakpoints. A set of genetic markers were integrated into the physical map to determine whether the deletions occur within the repeat. Haplotype analysis with genetic markers that flank the repeats showed that most patients with VCFS had deletion breakpoints in the repeat. Within the repeat is a 200-kb duplication of sequences, including a tandem repeat of genes/pseudogenes, surrounding the breakpoints. The genes in the repeat are GGT, BCRL, V7-rel, POM121-like, and GGT-rel. Physical mapping and genomic fingerprint analysis showed that the repeats are virtually identical in the 200-kb region, suggesting that the deletion is mediated by homologous recombination. Examination of two three-generation families showed that meiotic intrachromosomal recombination mediated the deletion. PMID- 10090894 TI - Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer. AB - One hundred fifty-two families with prostate cancer were analyzed for linkage to markers spanning a 20-cM region of 1q42.2-43, the location of a putative prostate cancer-susceptibility locus (PCAP). No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in our total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, pedigrees were stratified into homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although LOD scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least five affected men (nonparametric linkage score of 1.2; P=.1). If heterogeneity is assumed, an estimated 4%-9% of these 152 families may show linkage in this region. We conclude that the putative PCAP locus does not account for a large proportion of these families with prostate cancer, although the linkage of a small subset is compatible with these data. PMID- 10090895 TI - Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition. AB - Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic susceptibility to IgAD is shared with a less prevalent, but more profound, defect called "common variable immunodeficiency" (CVID). Here we show an increased allele sharing at 6p21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicating the presence of a predisposing locus, designated "IGAD1," in the proximal part of the major histocompatibility complex (MHC). The recurrence risk of IgAD was found to depend on the sex of parents transmitting the defect: affected mothers were more likely to produce offspring with IgAD than were affected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected under random segregation. The differential parent-of-origin penetrance is proposed to reflect a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This is supported by higher frequency of anti-IgA-positive females transmitting the disorder to children, in comparison with female IgAD nontransmitters, and by linkage data in the former group. Such pathogenic mechanisms may be shared by other MHC-linked complex traits associated with the production of specific autoantibodies, parental effects, and a particular MHC haplotype. PMID- 10090896 TI - Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31. AB - Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype. PMID- 10090897 TI - Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. AB - Deletions in the distal region of chromosome 8p (del8p) are associated with congenital heart malformations. Other major manifestations include microcephaly, intrauterine growth retardation, mental retardation, and a characteristic hyperactive, impulsive behavior. We studied genotype-phenotype correlations in nine unrelated patients with a de novo del8p, by using the combination of classic cytogenetics, FISH, and the analysis of polymorphic DNA markers. With the exception of one large terminal deletion, all deletions were interstitial. In five patients, a commonly deleted region of approximately 6 Mb was present, with breakpoints clustering in the same regions. One patient without a heart defect or microcephaly but with mild mental retardation and characteristic behavior had a smaller deletion within this commonly deleted region. Two patients without a heart defect had a more proximal interstitial deletion that did not overlap with the commonly deleted region. Taken together, these data allowed us to define the critical deletion regions for the major features of a del8p. PMID- 10090899 TI - A gene for X-linked idiopathic congenital nystagmus (NYS1) maps to chromosome Xp11.4-p11.3. AB - Congenital nystagmus (CN) is a common oculomotor disorder (frequency of 1/1,500 live births) characterized by bilateral uncontrollable ocular oscillations, with onset typically at birth or within the first few months of life. This condition is regarded as idiopathic, after exclusion of nervous and ocular diseases. X linked, autosomal dominant, and autosomal recessive modes of inheritance have been reported, but X-linked inheritance is probably the most common. In this article, we report the mapping of a gene for X-linked dominant CN (NYS1) to the short arm of chromosome X, by showing close linkage of NYS1 to polymorphic markers on chromosome Xp11.4-p11.3 (maximum LOD score of 3.20, over locus DXS993). Because no candidate gene, by virtue of its function, has been found in this region of chromosome Xp, further studies are required, to reduce the genetic interval encompassing the NYS1 gene. It is hoped that the complete gene characterization will address the complex pathophysiology of CN. PMID- 10090898 TI - Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. AB - Since little is known about chromosomal locations harboring type 2 diabetes susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q. PMID- 10090900 TI - Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism. AB - Two of the three class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode known functional variants that act on alcohol with different efficiencies. Variants at both these genes have been implicated in alcoholism in some populations because allele frequencies differ between alcoholics and controls. Specifically, controls have higher frequencies of the variants with higher Vmax (ADH2*2 and ADH3*1). In samples both of alcoholics and of controls from three Taiwanese populations (Chinese, Ami, and Atayal) we found significant pairwise disequilibrium for all comparisons of the two functional polymorphisms and a third, presumably neutral, intronic polymorphism in ADH2. The class I ADH genes all lie within 80 kb on chromosome 4; thus, variants are not inherited independently, and haplotypes must be analyzed when evaluating the risk of alcoholism. In the Taiwanese Chinese we found that, only among those chromosomes containing the ADH3*1 variant (high Vmax), the proportions of chromosomes with ADH2*1 (low Vmax) and those with ADH2*2 (high Vmax) are significantly different between alcoholics and controls (P<10-5). The proportions of chromosomes with ADH3*1 and those with ADH3*2 are not significantly different between alcoholics and controls, on a constant ADH2 background (with ADH2*1, P=.83; with ADH2*2, P=.53). Thus, the observed differences in the frequency of the functional polymorphism at ADH3, between alcoholics and controls, can be accounted for by the disequilibrium with ADH2 in this population. PMID- 10090901 TI - Relaxed replication of mtDNA: A model with implications for the expression of disease. AB - Heteroplasmic mtDNA defects are an important cause of human disease with clinical features that primarily involve nondividing (postmitotic) tissues. Within single cells the percentage level of mutated mtDNA must exceed a critical threshold level before the genetic defect is expressed. Although the level of mutated mtDNA may alter over time, the mechanism behind the change is not understood. It currently is not possible to directly measure the level of mutant mtDNA within living cells. We therefore developed a mathematical model of human mtDNA replication, based on a solid foundation of experimentally derived parameters, and studied the dynamics of intracellular heteroplasmy in postmitotic cells. Our simulations show that the level of intracellular heteroplasmy can vary greatly over a short period of time and that a high copy number of mtDNA molecules delays the time to fixation of an allele. We made the assumption that the optimal state for a cell is to contain 100% wild-type molecules. For cells that contain pathogenic mutations, the nonselective proliferation of mutant and wild-type mtDNA molecules further delays the fixation of both alleles, but this leads to a rapid increase in the mean percentage level of mutant mtDNA within a tissue. On its own, this mechanism will lead to the appearance of a critical threshold level of mutant mtDNA that must be exceeded before a cell expresses a biochemical defect. The hypothesis that we present is in accordance with the available data and may explain the late presentation and insidious progression of mtDNA diseases. PMID- 10090902 TI - mtDNA analysis of Nile River Valley populations: A genetic corridor or a barrier to migration? AB - To assess the extent to which the Nile River Valley has been a corridor for human migrations between Egypt and sub-Saharan Africa, we analyzed mtDNA variation in 224 individuals from various locations along the river. Sequences of the first hypervariable segment (HV1) of the mtDNA control region and a polymorphic HpaI site at position 3592 allowed us to designate each mtDNA as being of "northern" or "southern" affiliation. Proportions of northern and southern mtDNA differed significantly between Egypt, Nubia, and the southern Sudan. At slowly evolving sites within HV1, northern-mtDNA diversity was highest in Egypt and lowest in the southern Sudan, and southern-mtDNA diversity was highest in the southern Sudan and lowest in Egypt, indicating that migrations had occurred bidirectionally along the Nile River Valley. Egypt and Nubia have low and similar amounts of divergence for both mtDNA types, which is consistent with historical evidence for long-term interactions between Egypt and Nubia. Spatial autocorrelation analysis demonstrates a smooth gradient of decreasing genetic similarity of mtDNA types as geographic distance between sampling localities increases, strongly suggesting gene flow along the Nile, with no evident barriers. We conclude that these migrations probably occurred within the past few hundred to few thousand years and that the migration from north to south was either earlier or lesser in the extent of gene flow than the migration from south to north. PMID- 10090903 TI - A note on power approximations for the transmission/disequilibrium test. AB - The transmission/disequilibrium test (TDT) is a popular method for detection of the genetic basis of a disease. Investigators planning such studies require computation of sample size and power, allowing for a general genetic model. Here, a rigorous method is presented for obtaining the power approximations of the TDT for samples consisting of families with either a single affected child or affected sib pairs. Power calculations based on simulation show that these approximations are quite precise. By this method, it is also shown that a previously published power approximation of the TDT is erroneous. PMID- 10090904 TI - Allowing for missing parents in genetic studies of case-parent triads. AB - In earlier work, my colleagues and I described a log-linear model for genetic data from triads composed of affected probands and their parents. This model allows detection of and discrimination between effects of an inherited haplotype versus effects of the maternal haplotype, which presumably would be mediated by prenatal factors. Like the transmission disequilibrium test (TDT), the likelihood ratio test (LRT) based on this model is not sensitive to associations that are due to genetic admixture. When used as a method for testing for linkage disequilibrium, the LRT can be regarded as an alternative to the TDT. When one or both parents are missing, the resulting incomplete triad must be discarded to ensure validity of the TDT, thereby sacrificing information. By contrast, when the problem is set in a likelihood framework, the expectation-maximization algorithm allows the incomplete triads to contribute their information to the LRT without invalidation of the analysis. Simulations demonstrate that much of the lost statistical power can be recaptured by means of this missing-data technique. In fact, power is reasonably good even when no triad is complete-for example, when a study is designed to include only mothers of cases. Information from siblings also can be incorporated to further improve the statistical power when genetic data from parents or probands are missing. PMID- 10090905 TI - Comparison of linkage-disequilibrium methods for localization of genes influencing quantitative traits in humans. AB - Linkage disequilibrium has been used to help in the identification of genes predisposing to certain qualitative diseases. Although several linkage disequilibrium tests have been developed for localization of genes influencing quantitative traits, these tests have not been thoroughly compared with one another. In this report we compare, under a variety of conditions, several different linkage-disequilibrium tests for identification of loci affecting quantitative traits. These tests use either single individuals or parent-child trios. When we compared tests with equal samples, we found that the truncated measured allele (TMA) test was the most powerful. The trait allele frequencies, the stringency of sample ascertainment, the number of marker alleles, and the linked genetic variance affected the power, but the presence of polygenes did not. When there were more than two trait alleles at a locus in the population, power to detect disequilibrium was greatly diminished. The presence of unlinked disequilibrium (D'*) increased the false-positive error rates of disequilibrium tests involving single individuals but did not affect the error rates of tests using family trios. The increase in error rates was affected by the stringency of selection, the trait allele frequency, and the linked genetic variance but not by polygenic factors. In an equilibrium population, the TMA test is most powerful, but, when adjusted for the presence of admixture, Allison test 3 becomes the most powerful whenever D'*>.15. PMID- 10090906 TI - A novel NTRK1 mutation associated with congenital insensitivity to pain with anhidrosis. PMID- 10090907 TI - Mutations in the RP2 gene cause disease in 10% of families with familial X-linked retinitis pigmentosa assessed in this study. PMID- 10090909 TI - A mutation (2314delG) in the Usher syndrome type IIA gene: high prevalence and phenotypic variation. PMID- 10090908 TI - Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. PMID- 10090911 TI - The APC I1307K allele and BRCA-associated ovarian cancer risk. PMID- 10090910 TI - Different functional outcome of RetGC1 and RPE65 gene mutations in Leber congenital amaurosis. PMID- 10090912 TI - Germ-line NF2 mutations and disease severity in neurofibromatosis type 2 patients with retinal abnormalities. PMID- 10090913 TI - Gaucher disease: the N370S mutation in Ashkenazi Jewish and Spanish patients has a common origin and arose several thousand years ago. PMID- 10090914 TI - Deafness locus DFNB16 is located on chromosome 15q13-q21 within a 5-cM interval flanked by markers D15S994 and D15S132. PMID- 10090915 TI - Prevalence of Bloom syndrome heterozygotes among Ashkenazi Jews. PMID- 10090916 TI - Optimal ascertainment strategies to detect linkage to common disease alleles. PMID- 10090918 TI - Down-weighting of multiple affected sib pairs leads to biased likelihood-ratio tests, under the assumption of no linkage. PMID- 10090920 TI - Seed versus soil: the importance of the target cell for transgenic models of human leukemias. PMID- 10090921 TI - Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. PMID- 10090922 TI - Role of amplified genes in the production of autoantibodies. AB - A variety of previously published studies have shown the presence of autoantibodies directed against oncogenic proteins in the sera of patients with tumors. Generally the underlying genetic aberration responsible for the induction of an immune response directed against an abnormal protein is unknown. In our studies we analyzed the role of gene amplification in the production of autoantibodies in squamous cell lung carcinoma. We screened a cDNA expression library with autologous patient serum and characterized the isolated cDNA clones encoding tumor expressed antigens termed LCEA (lung carcinoma expressed antigens). As determined by sequence analysis, the 35 identified cDNA clones represent 19 different genes of both known and unknown function. The spectrum of different clones were mapped by polymerase chain reaction (PCR) and fluorescence in-situ hybridization, showing that a majority are located on chromosome 3, which is frequently affected by chromosomal abnormalities in lung cancer. Gene amplification of 14 genes was analyzed by comparative PCR. Nine genes (65% of all analyzed genes) were found to be amplified; furthermore, most of them are also overrepresented in the pool of cDNA clones, suggesting an overexpression in the corresponding tumor. These results strongly suggest that gene amplification is one possible mechanism for the expression of immunoreactive antigens in squamous cell lung carcinoma. PMID- 10090923 TI - Nonimmunoglobulin gene hypermutation in germinal center B cells. AB - Somatic hypermutation is the most critical mechanism underlying the diversification of Ig genes. Although mutation occurs specifically in B cells during the germinal center reaction, it remains a matter of debate whether the mutation machinery also targets non-Ig genes. We have studied mutations in the 5' noncoding region of the Bcl6 gene in different subtypes of lymphomas. We found frequent hypermutation in follicular lymphoma (25 of 59 = 42%) (germinal center cell origin) and mucosa-associated lymphoid tissue (MALT) lymphoma (19 of 45 = 42%) (postgerminal center), but only occasionally in mantle cell lymphoma (1 of 21 = 4.8%) (pregerminal center). Most mutations were outside the motifs potentially important for transcription, suggesting they were not important in lymphomagenesis but may, like Ig mutation, represent an inherent feature of the lymphoma precursor cells. Therefore, we investigated their normal cell counterparts microdissected from a reactive tonsil. Bcl6 mutation was found in 13 of 24 (54%) clones from the germinal centre but only in 1 of 24 (4%) clones from the naive B cells of the mantle zone. The frequency, distribution, and nature of these mutations were similar to those resulting from the Ig hypermutation process. The results show unequivocal evidence of non-Ig gene hypermutation in germinal center B cells and provide fresh insights into the process of hypermutation and lymphomagenesis. PMID- 10090924 TI - Metalloproteinases are involved in lipopolysaccharide- and tumor necrosis factor alpha-mediated regulation of CXCR1 and CXCR2 chemokine receptor expression. AB - The neutrophil-specific G-protein-coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) did not induce CXCR1 internalization but instead mediated a significant loss of membrane proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-alpha-induced downmodulation of IL 8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF-alpha was most dramatically inhibited by metalloproteinase inhibitors; 1, 10-phenanthroline and EDTA significantly attenuated LPS- and TNF-alpha-induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-alpha-stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF-alpha inhibited IL-8 receptor-mediated calcium mobilization and IL-8-directed neutrophil chemotaxis, both 1, 10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL 8-mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses. PMID- 10090925 TI - Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males. AB - Several recent studies evaluated a possible effect of the prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C - > T, factor V (F V) nt 1691G --> A (F V Leiden), and factor II (F II) nt 20210 G -> A on the risk of myocardial infarction. In the present study, we analyzed the effect of these prothrombotic polymorphisms, as well as apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, on the risk of myocardial infarction in young males. We conducted a case-control study of 112 young males with first acute myocardial infarction (AMI) before the age of 52 and 187 healthy controls of similar age. The prevalences of heterozygotes for F V G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among cases and controls, respectively). In contrast, the prevalence of MTHFR 677T homozygosity and the allele frequency of Apo E4 were significantly higher among patients (24.1% v 10.7% and 9.4% v 5.3% among cases and controls, respectively). Concomitant presence of hypertension, hypercholesterolemia, or diabetes and one or more of the four examined polymorphisms increased the risk by almost ninefold (odds ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5) and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed simultaneously by a logistic model, the combination of prothrombotic and Apo E4 polymorphisms with current smoking increased the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9). The presented data suggest a synergistic effect between atherogenic and thrombogenic risk factors in the pathogenesis of AMI, as was recently found in a similar cohort of women. PMID- 10090926 TI - Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. AB - We report the results of the first prospective randomized multicenter study of immunosuppressive treatment in patients with previously untreated nonsevere aplastic anemia (AA) as defined by a neutrophil count of at least 0.5 x 10(9)/L and transfusion dependence. Patients were randomized to receive cyclosporin (CSA) alone or the combination of horse antithymocyte globulin ([ATG] Lymphoglobuline; Merieux, Lyon, France) and CSA. The endpoint of the study was the hematologic response at 6 months. One hundred fifteen patients were randomized and assessable with a median follow-up period of 36 months; 61 received CSA and 54 ATG and CSA. In the CSA group, the percentage of complete and partial responders was 23% and 23%, respectively, for an overall response rate of 46%. A significantly higher overall response rate of 74% was found in the ATG and CSA group, with 57% complete and 17% partial responders (P =. 02). Compared with CSA alone, the combination of ATG and CSA resulted in a significantly higher median hemoglobin level and platelet count at 6 months. Fewer patients required a second course of treatment before 6 months due to a nonresponse. In the CSA group, 15 of 61 (25%) patients required a course of ATG before 6 months because of disease progression, compared with only 3 of 54 (6%) in the ATG and CSA group. The survival probabilities for the two groups were comparable, 93% (CSA group) and 91% (ATG and CSA group), but at 180 days, the prevalence of patients surviving free of transfusions, which excluded patients requiring second treatment because of nonresponse, death, disease progression, or relapse, was 67% in the CSA group and 90% in the ATG and CSA group (P =.001). We conclude that the combination of ATG and CSA is superior to CSA alone in terms of the hematologic response, the quality of response, and early mortality, and a second course of immunosuppression is less frequently required. PMID- 10090927 TI - Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. AB - Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to treatment with either busulfan 16 mg/kg (n = 88) or total body irradiation ([TBI] n = 79) in addition to cyclophosphamide 120 mg/kg. The patients were observed for a period of 5 to 9 years. Busulfan-treated patients had an increased risk of veno-occlusive disease (VOD) of the liver (12% v 1%, P =.01) and hemorrhagic cystitis (32% v 10%, P =.003). Acute graft-versus-host disease (GVHD) was similar in the two groups, but the 7-year cumulative incidence of chronic GVHD was 59% in the busulfan-treated group versus 47% in the TBI group (P =.05). Death from GVHD was more common in the busulfan group (22% v 3%, P <.001). Obstructive bronchiolitis occurred in 26% of the busulfan patients but in only 5% of the TBI patients (P <.01). Complete alopecia developed in 8 busulfan patients and partial alopecia in 17, versus five with partial alopecia in the TBI group (P <.001). Cataracts occurred in 5 busulfan-treated patients and 16 TBI patients (P =.02). The incidence of relapse after 7 years was 29% in both groups. Seven-year transplant-related mortality (TRM) in patients with early disease was 21% in the busulfan group and 12% in the TBI group. In patients with more advanced disease, the corresponding figures were 64% and 22%, respectively (P =.004). Leukemia-free survival (LFS) in patients with early disease was 68% in busulfan-treated patients and 66% in TBI patients. However, 7-year LFS in patients with more advanced disease was 17% in the busulfan group versus 49% in the TBI group (P <.01). In patients with chronic myeloid leukemia (CML) in first chronic phase, 7-year LFS was 72% and 83% in the two groups, respectively. PMID- 10090928 TI - Follicular large cell lymphoma: an aggressive lymphoma that often presents with favorable prognostic features. AB - It is debated whether follicular large cell lymphoma (FLCL) has a clinical behavior that is distinct from indolent follicular lymphomas, and whether there is a subset of patients who can be potentially cured. We report here our experience with 100 FLCL patients treated at our institution since 1984 with three successive programs. We evaluated the predictive value of pretreatment clinical features, including two risk models, the Tumor Score System and the International Prognostic Index (IPI). With a median follow-up of 67 months, the 5 year survival is 72% and the failure-free survival (FFS) is 67%, with a possible plateau in the FFS curve, particularly for patients with stage I-III disease. Features associated with shorter survival included age >/=60, elevated lactic dehydrogenase (LDH) or beta-2-microglobulin (beta2M), advanced stage, and bone marrow involvement. Stage III patients had significantly better survival than stage IV patients (P <.05). By the IPI and Tumor Score System, 80% of the patients were in the lower risk groups; both systems stratified patients into prognostic groups. Patients with FLCL have clinical features and response to treatment similar to that reported for diffuse large cell lymphoma. Prognostic risk systems for aggressive lymphomas are useful for FLCL. A meaningful fraction of patients may possibly be cured when treated as aggressive lymphomas. PMID- 10090929 TI - Development of viral vectors for gene therapy of beta-chain hemoglobinopathies: optimization of a gamma-globin gene expression cassette. AB - Progress toward gene therapy of beta-chain hemoglobinopathies has been limited in part by poor expression of globin genes in virus vectors. To derive an optimal expression cassette, we systematically analyzed the sequence requirements and relative strengths of the Agamma- and beta-globin promoters, the activities of various erythroid-specific enhancers, and the importance of flanking and intronic sequences. Expression was analyzed by RNase protection after stable plasmid transfection of the murine erythroleukemia cell line, MEL585. Promoter truncation studies showed that the Agamma-globin promoter could be deleted to -159 without affecting expression, while deleting the beta-globin promoter to -127 actually increased expression compared with longer fragments. Expression from the optimal beta-globin gene promoter was consistently higher than that from the optimal Agamma-globin promoter, regardless of the enhancer used. Enhancers tested included a 2.5-kb composite of the beta-globin locus control region (termed a muLCR), a combination of the HS2 and HS3 core elements of the LCR, and the HS-40 core element of the alpha-globin locus. All three enhancers increased expression from the beta-globin gene to roughly the same extent, while the HS-40 element was notably less effective with the Agamma-globin gene. However, the HS-40 element was able to efficiently enhance expression of a Agamma-globin gene linked to the beta-globin promoter. Inclusion of extended 3' sequences from either the beta globin or the Agamma-globin genes had no significant effect on expression. A 714 bp internal deletion of Agamma-globin intron 2 unexpectedly increased expression more than twofold. With the combination of a -127 beta-globin promoter, an Agamma globin gene with the internal deletion of intron 2, and a single copy of the HS 40 enhancer, gamma-globin expression averaged 166% of murine alpha-globin mRNA per copy in six pools and 105% in nine clones. When placed in a retrovirus vector, this cassette was also expressed at high levels in MEL585 cells (averaging 75% of murine alpha-globin mRNA per copy) without reducing virus titers. However, recombined provirus or aberrant splicing was observed in 5 of 12 clones, indicating a significant degree of genetic instability. Taken together, these data demonstrate the development of an optimal expression cassette for gamma-globin capable of efficient expression in a retrovirus vector and form the basis for further refinement of vectors containing this cassette. PMID- 10090930 TI - One-day ex vivo culture allows effective gene transfer into human nonobese diabetic/severe combined immune-deficient repopulating cells using high-titer vesicular stomatitis virus G protein pseudotyped retrovirus. AB - Retrovirus-mediated gene transfer into long-lived human pluripotent hematopoietic stem cells (HSCs) is a widely sought but elusive goal. A major problem is the quiescent nature of most HSCs, with the perceived requirement for ex vivo prestimulation in cytokines to induce stem cell cycling and allow stable gene integration. However, ex vivo culture may impair stem cell function, and could explain the disappointing clinical results in many current gene transfer trials. To address this possibility, we examined the ex vivo survival of nonobese diabetic/severe combined immune-deficient (NOD/SCID) repopulating cells (SRCs) over 3 days. After 1 day of culture, the SRC number and proliferation declined twofold, and was further reduced by day 3; self-renewal was only detectable in noncultured cells. To determine if the period of ex vivo culture could be shortened, we used a vesicular stomatitis virus G protein (VSV-G) pseudotyped retrovirus vector that was concentrated to high titer. The results showed that gene transfer rates were similar without or with 48 hours prestimulation. Thus, the use of high-titer VSV-G pseudotyped retrovirus may minimize the loss of HSCs during culture, because efficient gene transfer can be obtained without the need for extended ex vivo culture. PMID- 10090932 TI - Quantification of T-cell progenitors during ontogeny: thymus colonization depends on blood delivery of progenitors. AB - An in vivo thymus reconstitution assay based on intrathymic injection of hematopoietic progenitors into irradiated chicks was used to determine the number of T-cell progenitors in peripheral blood, paraaortic foci, bone marrow (BM), and spleen during ontogeny. This study allowed us to analyze the regulation of thymus colonization occurring in three waves during embryogenesis. It confirmed that progenitors of the first wave of thymus colonization originate from the paraaortic foci, whereas progenitors of the second and the third waves originate from the BM. The analysis of the number of T-cell progenitors indicates that each wave of thymus colonization is correlated with a peak number of T-cell progenitors in peripheral blood, whereas they are almost absent during the periods defined as refractory for colonization. Moreover, injection of T-cell progenitors into the blood circulation showed that they homed into the thymus without delay during the refractory periods. Thus, thymus colonization kinetics depend mainly on the blood delivery of T-cell progenitors during embryogenesis. PMID- 10090931 TI - 1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid-resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1). AB - Retinoic acid (RA) resistance is a serious problem for patients with acute promyelocytic leukemia (APL) who are receiving all-trans RA. However, the mechanisms and strategies to overcome RA resistance by APL cells are still unclear. The biologic effects of RA are mediated by two distinct families of transcriptional factors: RA receptors (RARs) and retinoid X receptors (RXRs). RXRs heterodimerize with 1, 25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), enabling their efficient transcriptional activation. The cyclin-dependent kinase (cdk) inhibitor p21(WAF1/CIP1) has a vitamin D3-responsive element (VDRE) in its promoter, and 1,25(OH)2D3 enhances the expression of p21(WAF1/CIP1) and induces differentiation of selected myeloid leukemic cell lines. We have recently established a novel APL cell line (UF-1) with features of RA resistance. 1,25(OH)2D3 can induce growth inhibition and G1 arrest of UF-1 cells, resulting in differentiation of these cells toward granulocytes. This 1, 25(OH)2D3-induced G1 arrest is enhanced by all-trans RA. Also, 1, 25(OH)2D3 (10(-10) to 10(-7) mol/L) in combination with RA markedly inhibits cellular proliferation in a dose- and time-dependent manner. Associated with these findings, the levels of p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) transcripts were induced after 6 hours' exposure to 1,25(OH)2D3 and then decreased to basal levels over 48 hours. Western blot experiments showed that p21(WAF1/CIP1) protein levels increased and became detectable after 12 hours of 1,25(OH)2D3 treatment and induction of p27(KIP1) protein was much more gradual and sustained in UF-1 cells. Interestingly, the combination of 1, 25(OH)2D3 and RA markedly enhanced the levels of p27(KIP1) transcript and protein as compared with levels induced by 1, 25(OH)2D3 alone. In addition, exogenous p27(KIP1) expression can enhance the level of CD11b antigen in myeloid leukemic cells. In contrast, RA alone can induce G1 arrest of UF-1 cells; however, it did not result in an increase of p21(WAF1/CIP1) and p27(KIP1) transcript and protein expression in RA-resistant cells. Taken together, we conclude that 1,25(OH)2D3 induces increased expression of cdk inhibitors, which mediates a G1 arrest, and this may be associated with differentiation of RA-resistant UF-1 cells toward mature granulocytes. PMID- 10090933 TI - Long-term culture of human CD34(+) progenitors with FLT3-ligand, thrombopoietin, and stem cell factor induces extensive amplification of a CD34(-)CD14(-) and a CD34(-)CD14(+) dendritic cell precursor. AB - Current in vitro culture systems allow the generation of human dendritic cells (DCs), but the output of mature cells remains modest. This contrasts with the extensive amplification of hematopoietic progenitors achieved when culturing CD34(+) cells with FLT3-ligand and thrombopoietin. To test whether such cultures contained DC precursors, CD34(+) cord blood cells were incubated with the above cytokines, inducing on the mean a 250-fold and a 16,600-fold increase in total cell number after 4 and 8 weeks, respectively. The addition of stem cell factor induced a further fivefold increase in proliferation. The majority of the cells produced were CD34(-)CD1a- CD14(+) (p14(+)) and CD34(-)CD1a-CD14(-) (p14(-)) and did not display the morphology, surface markers, or allostimulatory capacity of DC. When cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), both subsets differentiated without further proliferation into immature (CD1a+, CD14(-), CD83(-)) macropinocytic DC. Mature (CD1a+, CD14(-), CD83(+)) DCs with high allostimulatory activity were generated if such cultures were supplemented with tumor necrosis factor-alpha (TNF). In addition, p14(-) cells generated CD14(+) cells with GM-CSF and TNF, which in turn, differentiated into DC when exposed to GM-CSF and IL-4. Similar results were obtained with frozen DC precursors and also when using pooled human serum AB+ instead of bovine serum, emphasizing that this system using CD34(+) cells may improve future prospects for immunotherapy. PMID- 10090934 TI - Molecular analysis of the ERGIC-53 gene in 35 families with combined factor V factor VIII deficiency. AB - Combined factor V-factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder in which the levels of both coagulation factors V and VIII are diminished. The F5F8D locus was previously mapped to a 1-cM interval on chromosome 18q21. Mutations in a candidate gene in this region, ERGIC-53, were recently found to be associated with the coagulation defect in nine Jewish families. We performed single-strand conformation and sequence analysis of the ERGIC-53 gene in 35 F5F8D families of different ethnic origins. We identified 13 distinct mutations accounting for 52 of 70 mutant alleles. These were 3 splice site mutations, 6 insertions and deletions resulting in translational frameshifts, 3 nonsense codons, and elimination of the translation initiation codon. These mutations are predicted to result in synthesis of either a truncated protein product or no protein at all. This study revealed that F5F8D shows extensive allelic heterogeneity and all ERGIC-53 mutations resulting in F5F8D are "null." Approximately 26% of the mutations have not been identified, suggesting that lesions in regulatory elements or severe abnormalities within the introns may be responsible for the disease in these individuals. In two such families, ERGIC-53 protein was detectable at normal levels in patients' lymphocytes, raising the further possibility of defects at other genetic loci. PMID- 10090935 TI - ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families. AB - Combined factors V and VIII deficiency is an autosomal recessive bleeding disorder associated with plasma levels of coagulation factors V and VIII approximately 5% to 30% of normal. The disease gene was recently identified as the endoplasmic reticulum-Golgi intermediate compartment protein ERGIC-53 by positional cloning, with the detection of two founder mutations in 10 Jewish families. To identify mutations in additional families, the structure of the ERGIC-53 gene was determined by genomic polymerase chain reaction (PCR) and sequence analysis of bacterial artificial chromosome clones containing the ERGIC 53 gene. Nineteen additional families were analyzed by direct sequence analysis of the entire coding region and the intron/exon junctions. Seven novel mutations were identified in 10 families, with one additional family found to harbor one of the two previously described mutations. All of the identified mutations would be predicted to result in complete absence of functional ERGIC-53 protein. In 8 of 19 families, no mutation was identified. Genotyping data indicate that at least two of these families are not linked to the ERGIC-53 locus. Taken together, these results suggest that a significant subset of combined factors V and VIII deficiency is due to mutation in one or more additional genes. PMID- 10090936 TI - Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A. AB - Two unrelated patients with the same Arg2150His mutation in the factor VIII (FVIII) C1 domain, a residual FVIII activity of 0.09 IU/mL, and inhibitor titres of 300 and 6 Bethesda Units, respectively, were studied. Further analysis of patient LE, with the highest inhibitor titer, showed that (1) plasma or polyclonal IgG antibodies prepared from LE plasma inhibited the activity of allogeneic (wild-type) but not of self FVIII; (2) the presence of von Willebrand factor (vWF) increased by over 10-fold the inhibitory activity on wild-type FVIII; (3) the kinetics of FVIII inhibition followed a type II pattern, but in contrast to previously described type II inhibitors, LE IgG was potentiated by the presence of vWF instead of being in competition with it; (4) polyclonal LE IgG recognized the FVIII light chain in enzyme-linked immunosorbent assay and the recombinant A3-C1 domains in an immunoprecipitation assay, indicating that at least part of LE antibodies reacted with the FVIII domain encompassing the mutation site; and (5) LE IgG inhibited FVIII activity by decreasing the rate of FVIIIa release from vWF, but LE IgG recognized an epitope distinct from ESH8, a murine monoclonal antibody exhibiting the same property. We conclude that the present inhibitors are unique in that they clearly distinguish wild-type from self, mutated FVIII. The inhibition of wild-type FVIII by LE antibody is enhanced by vWF and is associated with an antibody-dependent reduced rate of FVIIIa release from vWF. PMID- 10090937 TI - Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. AB - alpha2-antiplasmin (alpha2-AP) is the main physiologic plasmin inhibitor in mammalian plasma. Inactivation of the murine alpha2-AP gene was achieved by replacing, through homologous recombination in embryonic stem cells, a 7-kb genomic sequence encoding the entire murine protein (exon 2 through part of exon 10, including the stop codon) with the neomycin resistance expression cassette. Germline transmission of the mutated allele was confirmed by Southern blot analysis. Mendelian inheritance of the inactivated alpha2-AP allele was observed, and homozygous deficient (alpha2-AP-/-) mice displayed normal fertility, viability, and development. Reverse transcription-polymerase chain reaction confirmed the absence of alpha2-AP mRNA in kidney and liver from alpha2-AP-/- mice, in contrast to wild-type (alpha2-AP+/+) mice. Immunologic and functional alpha2-AP levels were undetectable in plasma of alpha2-AP-/- mice, and were about half of wild-type in heterozygous littermates (alpha2-AP+/-). Other hemostasis parameters, including plasminogen activator inhibitor-1, plasminogen, fibrinogen, hemoglobin, hematocrit, and blood cell counts were comparable for alpha2-AP+/+, alpha2-AP+/-, and alpha2-AP-/- mice. After amputation of tail or toe tips, bleeding stopped spontaneously in alpha2-AP+/+, as well as in alpha2-AP+/- and alpha2-AP-/- mice. Spontaneous lysis after 4 hours of intravenously injected 125I fibrin-labeled plasma clots was significantly higher in alpha2-AP-/- than in alpha2-AP+/+ mice when injecting clots prepared from alpha2-AP+/+ plasma (78% +/- 5% v 46% +/- 9%; mean +/- SEM, n = 6 to 7; P =.02) or from alpha2-AP-/- plasma (81% +/- 5% v 46% +/- 5%; mean +/- SEM, n = 5; P =.008). Four to 8 hours after endotoxin injection, fibrin deposition in the kidneys was significantly reduced in alpha2-AP-/- mice, as compared with alpha2-AP+/+ mice (P TGC polymorphic change at amino acid 122. We propose a role for the alternative splicing of CD79b gene in causing the reduced expression of BCR on the surface of B-CLL cells. As normal B cells also present this variant, the mechanism of CD79b posttranscriptional regulation might reflect the activation stage of the normal B cell from which B-CLL derives. PMID- 10090944 TI - Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. AB - Allogeneic bone marrow transplantation (BMT) is a common treatment of hematologic malignancies. Recurrence of the underlying malignancy is a major cause of treatment failure. Donor-derived cytotoxic T lymphocytes (CTLs) specific for patients' minor histocompatibility antigens (mHags) play an important role in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivities. mHags HA-1 and HA-2 induce HLA-A*0201-restricted CTLs in vivo and are exclusively expressed on hematopoietic cells, including leukemic cells and leukemic precursors, but not on fibroblasts, keratinocytes, or liver cells. The chemical nature of the mHags HA-1 and HA-2 is known. We investigated the feasibility of ex vivo generation of mHag HA-1- and HA-2-specific CTLs from unprimed mHag HA-1- and/or HA-2-negative healthy blood donors. HA-1 and HA-2 synthetic peptide-pulsed dendritic cells (DCs) were used as antigen-presenting cells (APC) to stimulate autologous unprimed CD8(+) T cells. The ex vivo generated HA-1- and HA-2-specific CTLs efficiently lyse leukemic cells derived from acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) patients. No lytic reactivity was detected against nonhematopoietic cells. Sufficient numbers of the CTLs can be obtained for the adoptive immunotherapy purposes. In conclusion, we present a feasible, novel therapy for the treatment for relapsed leukemia after BMT with a low risk of GVHD. PMID- 10090945 TI - Nitric-oxide-induced apoptosis in human leukemic lines requires mitochondrial lipid degradation and cytochrome C release. AB - We have previously shown that nitric oxide (NO) stimulates apoptosis in different human neoplastic lymphoid cell lines through activation of caspases not only via CD95/CD95L interaction, but also independently of such death receptors. Here we investigated mitochondria-dependent mechanisms of NO-induced apoptosis in Jurkat leukemic cells. NO donor glycerol trinitrate (at the concentration, which induces apoptotic cell death) caused (1) a significant decrease in the concentration of cardiolipin, a major mitochondrial lipid; (2) a downregulation in respiratory chain complex activities; (3) a release of the mitochondrial protein cytochrome c into the cytosol; and (4) an activation of caspase-9 and caspase-3. These changes were accompanied by an increase in the number of cells with low mitochondrial transmembrane potential and with a high level of reactive oxygen species production. Higher resistance of the CD95-resistant Jurkat subclone (APO-R) cells to NO-mediated apoptosis correlated with the absence of cytochrome c release and with less alterations in other mitochondrial parameters. An inhibitor of lipid peroxidation, trolox, significantly suppressed NO-mediated apoptosis in APO-S Jurkat cells, whereas bongkrekic acid (BA), which blocks mitochondrial permeability transition, provided only a moderate antiapoptotic effect. Transfection of Jurkat cells with bcl-2 led to a complete block of apoptosis due to the prevention of changes in mitochondrial functions. We suggest that the mitochondrial damage (in particular, cardiolipin degradation and cytochrome c release) induced by NO in human leukemia cells plays a crucial role in the subsequent activation of caspase and apoptosis. PMID- 10090946 TI - Subcellular distribution and redistribution of Bcl-2 family proteins in human leukemia cells undergoing apoptosis. AB - It has been suggested that the ratio of Bcl-2 family proapoptotic proteins to antiapoptotic proteins determines the sensitivity of leukemic cells to apoptosis. However, it is believed that Bcl-2 family proteins exert their function on apoptosis only when they target to the mitochondrial outer membrane. The vinblastine-resistant T-lymphoblastic leukemic cell line CEM/VLB100 has increased sensitivity to tumor necrosis factor-alpha (TNF-alpha)-induced cytochrome c release, mitochondrial respiratory inhibition, and consequently apoptosis, compared with parental CEM cells. However, there was no difference between the two cell lines in the expression of Bcl-2 family proteins Bcl-2, Bcl-XL, Bcl-XS, Bad, and Bax at the whole cell level, as analyzed by Western blotting. Bcl-2 mainly located to mitochondria and light membrane as a membrane-bound protein, whereas Bcl-XL was located in both mitochondria and cytosol. Similar levels of both Bcl-2 and Bcl-XL were present in the resting mitochondria of the two cell lines. Although the proapoptotic proteins Bcl-XS, Bad, and Bax were mainly located in the cytosol, CEM/VLB100 mitochondria expressed higher levels of these proapoptotic proteins. Subcellular redistribution of the Bcl-2 family proteins was detected in a cell-free system by both Western blotting and flow cytometry after exposure to TNF-alpha. The levels of Bcl-2 family proteins were not altered at the whole cell level by TNF-alpha. However, after exposure to TNF-alpha, Bax, Bad, and Bcl-XS translocated from the cytosol to the mitochondria of both cell lines. An increase in Bcl-2 levels was observed in CEM mitochondria, which showed resistance to TNF-alpha-induced cytochrome c release. By contrast, decreased mitochondrial Bcl-2 was observed in CEM/VLB100 cells, which released cytochrome c from the mitochondria and underwent apoptosis as detected by fluorescence microscopy. We conclude that mitochondrial levels of Bcl-2 family proteins may determine the sensitivity of leukemic cells to apoptosis and that, furthermore, these levels may change rapidly after exposure of cells to toxic stimuli. PMID- 10090947 TI - Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells. AB - Human T-cell leukemia virus type I (HTLV-I) is an etiologic agent of adult T-cell leukemia (ATL). The viral protein Tax induces the activation and nuclear translocalization of transcription factor NF-kappaB, which is proposed to play a crucial role in the transformation of T cells by HTLV-I. However, the HTLV-I genes including Tax are not expressed significantly in primary leukemic cells from ATL patients. In this study, we examined the basis for NF-kappaB activation in freshly isolated leukemic cells from ATL patients. We found that leukemic cells from ATL patients, like HTLV-I-infected T-cell lines, display constitutive NF-kappaB DNA binding activity and increased degradation of IkappaBalpha (an inhibitor of NF-kappaB). Whereas the NF-kappaB binding activity in Tax-expressing T-cell lines consisted mostly of p50/c-Rel, fresh ATL samples contained p50/p50 and p50/p65 heterodimers. One T-cell line derived from ATL leukemic cells, TL Om1, displayed constitutive NF-kappaB activity, as well as enhanced degradation of IkappaBalpha, despite the lack of detectable Tax expression. Interestingly, the NF-kappaB in TL-Om1 consists of p50/p50 and p50/p65 like that in fresh primary leukemic cells. Our results suggest that activation of NF-kappaB occurs through a Tax-independent mechanism in leukemic cells of ATL patients, possibly due to differential NF-kappaB subunit activation. PMID- 10090948 TI - Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. AB - The factor-independent Dami/HEL and Meg-01 and factor-dependent Mo7e leukemic cell lines were used as models to investigate JAK/STAT signal transduction pathways in leukemic cell proliferation. Although Dami/HEL and Meg-01 cell proliferation in vitro was independent of and unresponsive to exogenous cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), IL-6, thrombopoietin (TPO), and tumor necrosis factor-alpha (TNF alpha), the growth of Mo7e cells was dependent on hematopoietic growth factors. When these cell lines were cultured in medium without cytokines, a constitutively activated STAT-like DNA-binding factor was detected in nuclear extracts from both Dami/HEL and Meg-01 cells. However, the STAT-like factor was not detectable in untreated Mo7e cells, but was activated transiently in Mo7e cells in response to cytokine treatments. The constitutively activated and cytokine-induced STAT-like DNA-binding factor in these three cell lines was identified as STAT5 by oligonucleotide competition gel mobility assays and by specific anti-STAT antibody gel supershift assays. Constitutive activation of JAK2 also was detected in the factor-independent cell lines, but not in Mo7e cells without cytokine exposure. Meg-01 cells express a p185 BCR/ABL oncogene, which may be responsible for the constitutive activation of STAT5. Dami/HEL cells do not express the BCR/ABL oncogene, but increased constitutive phosphorylation of Raf-1 oncoprotein was detected. In cytokine bioassays using growth factor-dependent Mo7e and TF-1 cells as targets, conditioned media from Dami/HEL and Meg-01 cells did not show stimulatory effects on cell proliferation. Our results indicate that the constitutive activation of JAK2/STAT5 correlates with the factor-independent growth of Dami/HEL and Meg-01 cells. The constitutive activation of JAK2/STAT5 in Dami/HEL cells is triggered by a mechanism other than autocrine cytokines or the BCR/ABL oncoprotein. PMID- 10090949 TI - Acquisition of p16(INK4A) and p15(INK4B) gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia. AB - Although numerous somatic mutations that contribute to the pathogenesis of childhood acute lymphoblastic leukemia (ALL) have been identified, no specific cytogenetic or molecular abnormalities are known to be consistently associated with relapse. The p16(INK4A) (p16), which encodes for both p16(INK4A) and p19(ARF) proteins, and p15(INK4B) (p15) genes are inactivated by homozygous deletion and/or p15 promoter hypermethylation in a significant proportion of cases of childhood ALL at the time of initial diagnosis. To determine whether alterations in these genes play a role in disease progression, we analyzed a panel of 18 matched specimen pairs collected from children with ALL at the time of initial diagnosis and first bone marrow relapse for homozygous p16 and/or p15 deletions or p15 promoter hypermethylation. Four sample pairs contained homozygous p16 and p15 deletions at both diagnosis and relapse. Among the 14 pairs that were p16/p15 germline at diagnosis, three ALLs developed homozygous deletions of both p16 and p15, and two developed homozygous p16 deletions and retained p15 germline status at relapse. In two patients, p15 promoter hypermethylation developed in the interval between initial diagnosis and relapse. In total, homozygous p16 deletions were present in nine of 18 cases, homozygous p15 deletions in seven of 18 cases, and p15 promoter hypermethylation in two of eight cases at relapse. These findings indicate that loss of function of proteins encoded by p16 and/or p15 plays an important role in the biology of relapsed childhood ALL, and is associated with disease progression in a subset of cases. PMID- 10090950 TI - Sodium salicylate activates caspases and induces apoptosis of myeloid leukemia cell lines. AB - Nonsteroidal antiinflammatory agents (NSAIA) have been shown to exert potent chemopreventive activity against colon, lung, and breast cancers. In this study, we show that at pharmacological concentrations (1 to 3 mmol/L) sodium salicylate (Na-Sal) can potently induce programmed cell death in several human myeloid leukemia cell lines, including TF-1, U937, CMK-1, HL-60, and Mo7e. TF-1 cells undergo rapid apoptosis on treatment with Na-Sal, as indicated by increased annexin V binding capacity, cpp-32 (caspase-3) activation, and cleavage of poly (ADP-ribose) polymerase (PARP) and gelsolin. In addition, the expression of MCL 1, an antiapoptotic member of the BCL-2 family, is downregulated during Na-Sal induced cell death, whereas the expression of BCL-2, BAX, and BCL-XL is unchanged. Z-VAD, a potent caspase inhibitor, prevents the cleavage of PARP and gelsolin and rescues cells from Na-Sal-induced apoptosis. In addition, we show that Na-Sal accelerates growth factor withdrawal-induced apoptosis and synergizes with daunorubicin to induce apoptosis in TF-1 cells. Thus, our data provide a potential mechanism for the chemopreventive activity of NSAIA and suggest that salicylates may have therapeutic potential for the treatment of human leukemia. PMID- 10090951 TI - Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria. AB - Neutrophils are recruited into the airway in the early phase of uncomplicated influenza A virus (IAV) infection and during the bacterial superinfections that are a significant cause of morbidity and mortality in IAV-infected subjects. In this report, we show that IAV accelerates neutrophil apoptosis. Unopsonized Escherichia coli had similar effects, although apoptotic effects of opsonized E coli were greater. When neutrophils were treated with both IAV and unopsonized E coli, a marked enhancement of the rate and extent of neutrophil apoptosis occurred as compared with that caused by either pathogen alone. Treatment of neutrophils with IAV markedly increased phagocytosis of E coli. Simultaneous treatment of neutrophils with IAV and E coli also elicited greater hydrogen peroxide production than did either pathogen alone. IAV increased neutrophil expression of Fas antigen and Fas ligand, and it also increased release of Fas ligand into the cell supernatant. These findings may have relevance to the understanding of inflammatory responses to IAV in vivo and of bacterial superinfection of IAV-infected subjects. PMID- 10090952 TI - Stomatocytosis is absent in "stomatin"-deficient murine red blood cells. AB - To examine the relationship between erythrocyte membrane protein 7. 2b deficiency and the hemolytic anemia of human hereditary stomatocytosis, we created 7.2b knock-out mice by standard gene targeting approaches. Immunoblots showed that homozygous knock-out mice completely lacked erythrocyte protein 7.2b. Despite the absence of protein 7.2b, there was no hemolytic anemia and mouse red blood cells (RBCs) were normal in morphology, cell indices, hydration status, monovalent cation content, and ability to translocate lipids. The absence of the phenotype of hereditary stomatocytosis implies that protein 7.2b deficiency plays no direct role in the etiology of this disorder and casts doubt on the previously proposed role of this protein as a mediator of cation transport in RBC. PMID- 10090954 TI - Evidence-based medicine and complementary medicine. PMID- 10090953 TI - Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma--a feasibility study. AB - The idiotype (Id) determinant on the multiple myeloma (MM) protein can be regarded as a tumor-specific marker. Immunotherapy directed at the MM Id may stem the progression of this disease. We report here on the first 12 MM patients treated at our institution with high-dose therapy and peripheral blood stem cell transplantation (PBSCT) followed by Id immunizations. MM patients received PBSCT to eradicate the majority of the disease. PBSCT produced a complete response in 2 patients, a partial response in 9 patients and stable disease in 1 patient. Three to 7 months after high-dose therapy, patients received a series of monthly immunizations that consisted of two intravenous infusions of Id-pulsed autologous dendritic cells (DC) followed by five subcutaneous boosts of Id/keyhole limpet hemocyanin (KLH) administered with adjuvant. Between 1 and 11 x 10(6) DC were obtained by leukapheresis in all patients even after PBSCT. The administration of Id-pulsed DC and Id/KLH vaccines were well tolerated with patients experiencing only minor and transient side effects. Two of 12 patients developed an Id specific, cellular proliferative immune response and one of three patients studied developed a transient but Id-specific cytotoxic T-cell (CTL) response. Eleven of the 12 patients generated strong KLH-specific cellular proliferative immune responses showing the patients' immunocompetence at the time of vaccination. The two patients who developed a cellular Id-specific immune response remain in complete remission. Of the 12 treated patients, 9 are currently alive after autologous transplantation with a minimum follow-up of 16 months, 2 patients died because of recurrent MM and 1 patient succumbed to acute leukemia. These studies show that patients make strong anti-KLH responses despite recent high-dose therapy and that DC-based Id vaccination is feasible after PBSCT and can induce Id-specific T-cell responses. Further vaccine development is necessary to increase the proportion of patients that make Id-specific immune responses. The clinical benefits of Id vaccination in MM remain to be determined. PMID- 10090955 TI - [Restructuring of the Royal Belgian Society for Surgery]. PMID- 10090957 TI - Nutritional protocol after acute thermal injury. AB - Nutritional requirements drastically change after a serious burn injury. In this article the feeding protocol of the Burn Unit of the University Hospital Louvain Belgium is presented. Patients who are victim of large cutaneous burns are characterized by an elevated metabolic rate and weight loss. To contend with this syndrome, a rigorous nutritional support program is essential. Care must be taken to provide an appropriate nutritional regimen in order to minimize protein catabolism and to promote wound healing and immune defence. Simultaneously, a review of the literature summarizes current methods of procuring nutritional support to the burn patient, adult and paediatric, especially as micronutrients are concerned. PMID- 10090958 TI - Repairing great duodenal defects in rabbits by ePTFE patch. AB - The aim of this experimental study was to evaluate the results of repairing large duodenal defects in rabbits by an ePTFE (Gore-Tex) soft tissue patch graft. A defect as large as 50% of the total circumference of the duodenum (i.e. Grade 3 injury) on anterior surface of the second part in 14 white New Zealand rabbits was done and repaired by 1 mm ePTFE graft. The stomach and duodenum were inspected for evidence of either leak or obstruction, and completeness of the mucosa covering the defect. Neither leak nor obstruction were observed and the whole grafted area was covered by the mucosa at the end of the sixth month. The main conclusion is that the method we used, is easy and reliable. Further experience will appropriate animal models is needed before this technique can be considered for application (in human duodenal injuries). PMID- 10090959 TI - Invaginating versus classic stripping of the long saphenous vein. A randomized prospective study. AB - Although sound evidence is lacking, many surgeons claim that stripping of the long saphenous vein (LSV) is best performed by invagination. The aim of this prospective, randomized study was to test the hypothesis that invaginating stripping of the LSV is associated with less pain, smaller haematomas and less frequent injury to the saphenous nerve. Thirty patients with bilateral varicose veins and incompetent LSV, but normal short saphenous veins and deep venous systems, were treated by high ligation and stripping of the LSV and multiple stab avulsions. At one side the stripping was performed by invagination (group I), while a classic stripping was done on the other side (group C), so that one leg served as the control of the other. The results were analysed on an intention to treat basis. The median surface of the thigh haematoma between post-operative day seven and ten was 115 cm2 in group I and 135 cm2 in group C (NS). The median pain score was 0.25 and 1.75 respectively (NS). The incidence of saphenous nerve injury was 13% in group I and 17% in group C (NS). At one month 23% of patients stated that the leg with the invaginating stripping had been the more painful, while 33% of patients claimed that the side of the classic stripping had been more painful. The results show that the benefit of invaginating stripping is not as obvious as is generally suggested. PMID- 10090960 TI - Contribution of hook-guided breast biopsy to the pathological diagnosis of mammographic lesions. AB - This study was carried out to evaluate the reliability of a diagnostic approach with close cooperation between radiologists and surgeons for minimal breast disease. From 1993 to 1995, 152 evaluable patients with non palpable breast lesions were examined by mammography and their lesion was localized with a hook wire before being referred to the surgeon for biopsy. Comparison of mammography findings with pathological diagnosis indicated a good predictive value for benign lesions with only 8% non concordant diagnosis and a rather low predictive value in case of suspect mammograms with only 64% positive diagnosis. With hook-guided breast biopsy, a correct diagnosis was established in 93% of the cases. The remaining breast samples were either non contributory or necessitated a second biopsy. Several recommendations are proposed for improving accuracy of breast sampling such as securing the hook into the gland, orienting the limits of resection, sending specimen for X-ray study and inking the margins for the pathologist. This field experience revealed that some progress are to be made in diagnosis in particular by standardization of mammography and pathological criteria, more precise localization of the lesions with the hook and more refined surgical techniques for breast biopsy. PMID- 10090961 TI - The value of DNA content in predicting the prognosis of thyroid carcinoma in an endemic iodine deficiency region. AB - DNA content of tumour was found to correlate with various prognostic factors and survival, especially in well differentiated thyroid carcinoma. The aim of this investigation was to evaluate the correlation between the DNA ploidy and the prognosis as well as the survival in thyroid carcinoma in our country, being an endemic iodine deficiency region. DNA flowcytometry was performed on paraffin embedded archival tissue blocs of 74 patients with thyroid carcinoma (70 well differentiated, 3 anaplastic and Hurthle cell carcinoma) and 12 patients with multinodular goitre. DNA ploidy was defined as diploidy or aneuploidy. Aneuploidy was detected in 5 (6.8%) patients with thyroid carcinoma (3 anaplastic, 1 papillary and 1 Hurthle cell carcinoma). Aneuploidy was significantly more frequent in patients with anaplastic carcinoma (n: 3/3, 100%) compared to well differentiated thyroid carcinoma (n: 1/70, 1.4%) (p < 0.0001). Aneuploid DNA content significantly correlated with advanced age (p < 0.01), large tumour size (p < 0.001), and low survival (p < 0.01). Mean survival period of patients with anaplastic carcinoma in whom aneuploidy was frequently encountered, was shorter compared to patients with diploid well differentiated tumours (p < 0.01). In conclusion, although anaplastic and follicular carcinoma are more frequently diagnosed in endemic areas, the rate on aneuploidy was found to be lower in thyroid carcinoma in our country compared to data reported to nonendemic areas. As the prognostic predictive value of DNA ploidy is reliable in well differentiated thyroid carcinoma, DNA measurement of FNA biopsy may influence the extent of surgery. Thyroid carcinoma, other than well differentiated types, require radical operations independent of the DNA content. However, adjunctive treatment methods may be used earlier postoperatively according to quantitative DNA measurement. PMID- 10090962 TI - Subacute ischaemic proctitis: a rare condition requiring extensive rectal surgery. AB - Subacute ischaemic proctitis is a rare condition. We describe the case of a 60 year-old male patient who developed, after aortic aneurysm repair, a transient ischaemic colitis that totally healed without sequelae. He eventually developed symptoms of severe proctitis. Investigations identified a stenosis of the mid rectum, while the upper rectum was inflammatory. On angiogram, there was a poor blood flow through the Riolan's arcade and a stenosis of the proximal aorto-graft anastomosis. Diagnosis of subacute ischaemic proctitis due to poor blood supply through the internal iliac arteries was made. Anti-inflammatory drugs and dilations were inefficient. A subtotal proctectomy with low colorectal anastomosis was required. On pathological specimen, the lesions were strongly suggestive of an ischaemic process. The patient had an excellent recovery and was asymptomatic 8 months after the operation. PMID- 10090963 TI - Residual appendicitis following incomplete laparoscopic appendectomy. AB - Growing popularity of laparoscopic interventions must bring along a thorough knowledge of possible complications inherent to the laparoscopic technique. With these two cases of residual appendicitis following incomplete appendectomy, the authors want to warn for this complication. Surgeons should be aware of residual appendicitis as a possible cause of acute abdomen at any time following a laparoscopic appendectomy. PMID- 10090964 TI - A case of chordoma in association with rectal carcinoma. AB - A 74-year-old male patient presented with anal and sacral pain 18 months after abdomino-perineal resection for rectal cancer. Computerized tomography (CT) of the pelvis demonstrated a well defined mass anterior to the lower sacrum, posteriorly infiltrating and destroying the fourth and fifth sacral nerves and invading the right gluteal fossa. A 7.5 x 15 x 2 cm encapsulated mass was demonstrated during the operation using a posterior approach and the lower sacral segments together with the tumour were removed by amputation at S3 level. Histopathology revealed chordoma. This case is unique because of the rarity of chordoma in association with rectal tumour at the sacrococcygeal region. PMID- 10090965 TI - Typical presentation of intramural aortic haemorrhage (IAH) with evidence of intimal tear at MRI and angiography. AB - A typical appearance of IAH was evidenced by CT and TEE in a 56-year-old hypertensive female suspected of developping classical acute aortic dissection (AAD). Further examination with MRI and aortography showed unequivocally the presence of an intimal tear in the aortic arch. This coexistence of intimal tear has never been evidenced preoperatively in patients with IAH. This observation demonstrates at the outset that IAH is part of the spectrum of AAD. PMID- 10090966 TI - Cranio-facial and humeral melorrheostosis. AB - First described by LERY and JOANNY in 1992, melorrheostosis is an uncommon linear hyperostosis of unknown aetiology, which may be associated with soft tissures changes. Although all bones may be affected, cranio-facial involvement is very rare. Only six such cases have been found in the literature. This report describes a case of cranio-facial and left humeral melorrheostosis with symptomatic radial nerve involvement. Resection of the melorrheostotic bone was performed because of involvement of the radial nerve. PMID- 10090967 TI - Fluorescent allele-specific PCR (FAS-PCR) improves the reliability of single nucleotide polymorphism screening. PMID- 10090968 TI - Site-directed mutagenesis by fusion of contiguous DNA fragments. PMID- 10090969 TI - Reliable PCR-based method for cloning cDNA in plasmid vectors by frequency estimation. PMID- 10090970 TI - High-throughput transformation and plating using petristrips. PMID- 10090971 TI - Faster recombinant DNA procedures for Streptomyces. PMID- 10090972 TI - Preparation of YAC end fragments from the whitehead/MIT mouse YAC library pRML vectors. PMID- 10090973 TI - Isolation of pcDNAI-based mammalian expression vectors from Escherichia coli strain MC1061/P3. PMID- 10090974 TI - Fluorescence in situ hybridization (FISH) screening of frozen cell lines in large numbers. PMID- 10090975 TI - Efficient nuclear FISH on paraffin-embedded tissue sections using microwave pretreatment. PMID- 10090976 TI - Quantitative recovery of nucleic acids from excised gel pieces by isotachophoresis. PMID- 10090977 TI - Improved electrophoretic resolution of DNA fragments in samples containing high concentrations of salts. PMID- 10090978 TI - Capillary transfer as an efficient method of transferring proteins from SDS-PAGE gels to membranes. PMID- 10090979 TI - Tissue fixation prevents contamination of tritium-sensitive storage phosphor imaging plates. PMID- 10090980 TI - Elimination of background due to discharge of static electricity from X-ray film. PMID- 10090981 TI - Enhanced chemiluminescent assay for transglutaminases. PMID- 10090982 TI - JavaScript-based program for converting the relative centrifugal force and speed of common rotors. PMID- 10090983 TI - Gene transfer into retinoblastoma cells. PMID- 10090984 TI - Inverse PCR-generated internally deleted constructs for direct characterization of promoter regulatory regions. PMID- 10090985 TI - Immunofluorescence localization of glycoproteins using tissue printing: detection of pistil extensin-like proteins in tobacco. PMID- 10090986 TI - Direct PCR of symbiotic fungi using microslides. PMID- 10090987 TI - JavaScript program for browser-based presentations. PMID- 10090988 TI - Improved protocol for a microsphere-adhesion assay on living tissue slices. AB - Here, we describe a simple microsphere-adhesion assay to characterize adhesive cues on living tissue slices, which we use to study pattern formation in neural tissue. This assay was developed by modifying a cell-adhesion assay on living tissue slices. We replaced dissociated cells by fluorescent microspheres and then coated the microspheres with isolated membranes from these cells. The membrane coated microspheres were seeded on living tissue slices, and after a short incubation time, nonadherent microspheres were eliminated by washing. Then, the tissue slices with the adherent microspheres were analyzed using epifluorescence microscopy. As an example, it is shown that membrane-coated adherent microspheres were found to be distributed in a characteristic pattern on living slices of hippocampus, mimicking the adhesion pattern of dissociated living cells. The adhesion assay should be suitable to detect and to analyze adhesive cues on living slices of different tissues and, thus, might have numerous applications in tissue research and developmental studies. Here, we describe and discuss a detailed and improved protocol of the microsphere-adhesion assay. PMID- 10090989 TI - Defined oligonucleotide tag pools and PCR screening in signature-tagged mutagenesis of essential genes from bacteria. AB - We describe a fast and simple method for signature-tagged mutagenesis (STM) using defined oligonucleotides for tag construction into mini-Tn5 and PCR instead of hybridization for rapid screening of bacterial mutants in vivo. A collection of 12 unique 21-mers were synthesized as complementary DNA strands to tag bacterial mutants constructed by insertional mutagenesis using pUTmini-Tn5Km2 plasmids. Tags were tested in a combination of assays by PCR and compared to hybridization for specificity and for large-scale screening. Each defined tag has the same melting temperature, an invariable region to optimize PCRs and a variable region for specific amplification by PCR. A series of "suicide" plasmids carrying mini Tn5s, each with a specific tag, were transferred into Pseudomonas aeruginosa, giving 12 libraries of mutants; groups of 12 mutants were pooled and arrayed into 96-well microplates, representing approximately one-sixth of the P. aeruginosa 5.9-Mb genome. This simple STM method can be adapted to any bacterial system and used for genome scanning in various growth conditions. PMID- 10090991 TI - Computer quantification of intracellular gold particles. AB - We describe the use of image software programs available for both PC and Macintosh computers to quantify the accumulation and distribution of gold-labeled constructs within two-dimensional cell sections. The compartmentalization of a biotinylated-peptide was visualized in radiation-induced fibrosarcoma cells by transmission electron microscopy, using a gold particle-streptavidin conjugate. This study illustrates the ease of tabulating gold particles observed in scanned electron micrographs, using Adobe Photoshop in conjunction with the public domain NIH Image program (Version 1.61). Quantitative information regarding the localization of molecules inside cells is crucial in defining their sites of action and in developing more effective therapeutic agents. PMID- 10090990 TI - Quantitative measurement of proteins by western blotting with Cy5-coupled secondary antibodies. AB - The concentration of proteins in cells is an important parameter that determines how a protein will interact with other proteins or pharmacological agents. Recent developments in Western blotting techniques have now made this a method of choice to measure protein concentration in complex solutions such as total cell extracts. We show that detection of Cy5-coupled secondary antibodies by PhosphorImager analysis produces signals that approach linearity with respect to protein concentration over a 20-fold range. We used this technique to estimate cellular levels of zyxin, which is an important protein component of the actin cytoskeleton in mammalian cells. By producing specific protein standards based on sequences that are available from public databases, it is now possible to estimate the concentration of almost any protein by this technique. PMID- 10090992 TI - Novel cloning method for recombinant adenovirus construction in Escherichia coli. AB - pAd(vantage) is a rapid cloning system for generating recombinant adenoviruses. The system is based on manipulating the full-length adenovirus genome as a stable plasmid in E. coli using intron-encoded endonucleases. These intron-encoded endonucleases cut their recognition sequences, which range from 15-39 bp, with high specificity. Their unusual long homing sequence makes them rare-cutting and ideal for use as cloning sites. We report how transgenes can easily be cloned directly into the E1 region of an adenoviral plasmid, followed by transfection into a mammalian packaging cell line, to produce homogeneous recombinant viruses without the need for plaque purification. PMID- 10090993 TI - Rat porphobilinogen deaminase gene: a pseudogene-free internal standard for laser assisted cell picking. AB - Analysis of gene expression and its transcriptional regulation requires a reliable access to target mRNA. However, mRNA extractions from homogenized tissue are limited because only average data are obtained, and cell-specific expression may not be addressed. Here, we describe a new method that combines the microscopic selection of oligocellular clusters or a few isotypic cell profiles from complex tissues by UV-laser-assisted cell picking with a simplified and highly efficient protocol for mRNA amplification. For positive control and quantitation reference, a reliable housekeeping gene is needed. For this purpose, we designed primers of the rat porphobilinogen deaminase (PBGD) gene. In contrast to many commonly used housekeeping primer pairs that co-amplify processed pseudogenes, this sequence allowed detection of a pseudogene-free rat cDNA sequence, thus eliminating the need for a DNase-digestion step. PBGD mRNA was consistently expressed in all complex tissues investigated and in 21 specific cell types harvested by laser-assisted cell picking. PBGD is suggested as a reliable new rat housekeeping gene, particularly suitable for analysis of oligocellular samples such as those obtained by laser-assisted cell picking in complex tissues. PMID- 10090994 TI - Fast and accurate method for quantitating E. coli host-cell DNA contamination in plasmid DNA preparations. AB - Plasmid DNA is being used successfully as a gene delivery vector in a variety of clinical applications. Similar to other pharmaceutical products for clinical use, the plasmid vectors must meet rigorous purity standards. One important contaminant is the DNA of the host cell used to produce the plasmids. We have developed a new method to accurately quantitate E. coli host-cell DNA in plasmid preparations. This method is based on kinetic PCR using the ABI PRISM 7700 with 23S rDNA as a target. This precise assay is significantly faster and has a lower limit of quantitation than the currently used Southern-based methods. PMID- 10090995 TI - Semiquantitative chemiluminescent detection of UV-B-induced point mutations in the p53 tumor-suppressor gene. AB - The technique of allele-specific PCR (AS-PCR) enables the detection of a small number of mutant alleles in a large number of wild-type (WT) alleles. We used the AS-PCR technique and Southern blotting, using a nonradioactive labeled probe to analyze the formation of point mutations in the tumor-suppressor gene p53 of primary keratinocytes after UV-B irradiation. These permanent mutations resulting from CC dimers occur at distinct "hot-spots", one of which is affected in the human keratinocyte cell line HaCaT. This enabled us to establish the method with a defined positive control template, which also allowed semiquantitative determination of the mutation frequency. This, and the determination of the detection limit, was done with the use of serial dilutions of WT genomic DNA from primary keratinocytes with mutant genomic HaCaT DNA in the AS-PCR assay. PMID- 10090996 TI - Detection of chromosome aberrations by FISH as a function of cell division cycle (harlequin-FISH). AB - Chromosome aberrations are a sensitive indicator of genetic change, and the measurement of chromosome aberration frequency in peripheral blood lymphocytes is often used as a biological dosimeter of exposure (1,4). The length of time that cells are maintained in culture before cytogenetic analysis is probably the most important in vitro factor that influences both the frequency and types of aberrations that are seen following exposure to mutagens. Therefore, for accurate cytogenetic measurements of genetic damage, cells must be analyzed in their first mitosis following exposure. As cells progress through subsequent mitotic division cycles, cells with unstable types of aberrations, e.g., dicentrics and acentric fragments, are eliminated (1,3,4). Even the use of synchronized populations of cells does not guarantee that all cells analyzed will be in their first division following treatment. Small variations in growth rate after irradiation can lead to large variations in the proportion of cells that are in their first vs. a subsequent mitosis. For example, 48 h after G0 lymphocytes are stimulated to enter the cell cycle (the standard sampling time for cytogenetic analysis), up to 50% of the cells in mitosis can be in their second division cycle (10). While there are methods available to distinguish cells in different division cycles (see Introduction), they are not easily adapted for use with standard fluorescence in situ hybridization (FISH) procedures. The goal of this study was to develop a simple approach to detect aberrations by FISH whereby cells in different division cycles could be distinguished. PMID- 10090997 TI - Green fluorescent protein-based system for analysis of E-selectin-mediated adhesion. AB - Numerous cell-based or cell-free systems for study of selectin adhesion use radiolabeled tracers. However, in addition to handling problems associated with the use of radioisotopes, these assays have difficulty relating a number of counts to a number of adherent cells. Here, we describe an assay that uses the natural fluorescence of the green fluorescent protein (GFP) to measure binding of cells to E-selectin. We elaborated an adhesion system composed of a cell monolayer expressing E-selectin ligand to which monodispersed fluorescent Chinese hamster ovary (CHO) cells expressing E-selectin are added. Due to GFP autofluorescence, adhered cells can be easily distinguished from cell monolayers by fluorescence microscopy, and adhesion can be measured by cytofluorometry. We applied this GFP-based adhesion assay to measure the adherence of a pancreatic tumor cell line and found that the binding parameters of these cells satisfy a number of E-selectin-specific criteria. PMID- 10090998 TI - Representative cDNA libraries and their utility in gene expression profiling. AB - An increasing interest in gene expression profiles in human diseases has led to the use of microdissected tumors and biopsies in gene discovery approaches. Since many of these clinical samples yield extremely small amounts of RNA, reproducible methods are needed to amplify this RNA while maintaining the original message profile. Using the SMART cDNA Synthesis Method, we show that high-, medium- and low-abundance transcripts can be amplified in a representative fashion and that the resulting cDNA can also be used as a complex probe to confirm gene expression differences identified by other techniques. PMID- 10090999 TI - Detection of telomerase activity utilizing energy transfer primers: comparison with gel- and ELISA-based detection. AB - We have developed a closed-tube format telomeric repeat amplification protocol (TRAP) assay for direct quantification of telomerase activity within the PCR vessel. The assay utilizes energy transfer (ET) primers, which emit fluorescence only upon incorporation into PCR products. This novel ET primer system (Amplifluor primers) has major advantages over existing detection methods because it eliminates the need for post-PCR processing and thus reduces greatly the risk of carryover contamination and the time required for the sample analysis. The assay is as sensitive, specific and quantitative as the polyacrylamide gel-based or ELISA-based TRAP assay. PMID- 10091000 TI - PBXL-1: a new fluorochrome applied to detection of proteins on membranes. AB - An easy, sensitive and direct fluorescent immunodetection method for proteins is described using the new fluorochrome PBXL-1 imaged with the FMBIO II Laser Scanning Imaging System. PBXL-1 is derived from a protein supra-molecular complex that contains a large number of chromophores. This complex, the phycobilisome, is extracted from a red alga then chemically stabilized to allow its use in specific binding assays. PBXL-1 was cross-linked to goat anti-rabbit IgG or streptavidin with heterobifunctional cross-linkers. The detection limit of PBXL-1 was determined by applying it on nitrocellulose membranes then imaging the membrane using an ytterbium aluminum garnet (YAG) laser. Evaluation of PBXL-1 sensitivity in a specific binding assay was tested on streptavidin/biotin and an antibody system. PBXL-1 provides high sensitivity in direct fluorescent applications due to a physical amplification of signal (i.e., a large number of fluorophores per binding event). PBXL-1 provides a linear response over two orders of magnitude while providing sub-amol sensitivity, indicating broad applicability for detection of a variety of targets. To our knowledge, this is the most sensitive direct fluorescent detection method available. PMID- 10091001 TI - Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. AB - Electrophysiological studies of neurons reveal different Ca2+ currents designated L-, N-, P-, Q-, R-, and T-type. High-voltage-activated neuronal Ca2+ channels are complexes of a pore-forming alpha 1 subunit of about 190-250 kDa, a transmembrane, disulfide-linked complex of alpha 2 and delta subunits, and an intracellular beta subunit, similar to the alpha 1, alpha 2 delta, and beta subunits previously described for skeletal muscle Ca2+ channels. The primary structures of these subunits have all been determined by homology cDNA cloning using the corresponding subunits of skeletal muscle Ca2+ channels as probes. In most neurons, L-type channels contain alpha 1C or alpha 1D subunits, N-type contain alpha 1B subunits, P- and Q-types contain alternatively spliced forms of alpha 1A subunits, R-type contain alpha 1E subunits, and T-type contain alpha 1G or alpha 1H subunits. Association with different beta subunits also influences Ca2+ channel gating substantially, yielding a remarkable diversity of functionally distinct molecular species of Ca2+ channels in neurons. PMID- 10091002 TI - Calcium permeability of ligand-gated channels. AB - Ligand-gated channels activated by excitatory neurotransmitters: glutamate, acetylcholine, ATP or serotonin are cation channels permeable to Ca2+. Molecular cloning revealed a large variety of the ligand-gated channel subunits differentially expressed in mammalian brain. Many of them have different Ca2+ permeability providing immense diversity in Ca2+ entry mediated by ligand-gated channels during synaptic transmission. Functional analysis of cloned channels allowed to identify structural elements in the pore forming regions determining Ca2+ permeability for many types of ligand-gated channels. The functional role of the Ca2+ entry mediated by various ligand-gated channels in mammalian central nervous system is less understood. The studies reviewed in this article provide information about known structural determinants of Ca2+ permeability of the ligand-gated channels and the role of this particular pathway of Ca2+ entry in cell function. PMID- 10091003 TI - Neuronal calcium stores. AB - Neuronal calcium stores associated with specialized intracellular organelles, such as endoplasmic reticulum and mitochondria, dynamically participate in generation of cytoplasmic calcium signals which accompany neuronal activity. They fulfil a dual role in neuronal Ca2+ homeostasis being involved in both buffering the excess of Ca2+ entering the cytoplasm through plasmalemmal channels and providing an intracellular source for Ca2+. Increase of Ca2+ content within the stores regulates the availability and magnitude of intracellular calcium release, thereby providing a mechanism which couples the neuronal activity with functional state of intracellular Ca2+ stores. Apart of 'classical' calcium stores (endoplasmic reticulum and mitochondria) other organelles (e.g. nuclear envelope and neurotransmitter vesicles) may potentially act as a functional Ca2+ storage compartments. Calcium ions released from internal stores participate in many neuronal functions, and might be primarily involved in regulation of various aspects of neuronal plasticity. PMID- 10091004 TI - Usefulness and limitations of linear approximations to the understanding of Ca++ signals. AB - Simple approximations to some limiting cases of Ca++ signalling provide insight into the complex problems of buffered diffusion and of Ca++ homeostasis in the presence of buffers. Three cases are presented, where the influence of Ca++ buffers can readily be understood in the limit of small signals: the return of global cellular [Ca++] following a short stimulus in a 'Single Compartment', buffered diffusion along a cylindrical axon in the 'Rapid Buffer Approximation', and nonequilibrium microdomains of elevated [Ca++] in the immediate vicinity of open Ca++ channels. PMID- 10091005 TI - Local Ca2+ signaling in neurons. PMID- 10091007 TI - Ca2+ and synaptic plasticity. AB - A major effort in neuroscience is directed towards understanding the roles of Ca2+ signalling in the induction of synaptic plasticity. Here, we summarize the evidence concerning Ca2+ signalling, paying particular attention to CA1 excitatory synapses, and its relationship to the induction of long-term potentiation and long-term depression. We discuss the ways in which synaptic activation can elevate Ca2+ postsynaptically and how dendritic spines may act as a Ca2+ compartment which can both isolate and integrate Ca2+ signals. PMID- 10091006 TI - Calcium sensors in regulated exocytosis. AB - Neurotransmitter release, hormone secretion and a variety of other secretory process are tightly regulated with exocytotic fusion of secretory vesicles being triggered by a rise in cytosolic Ca2+ concentration. A series of proteins that act as part of a conserved core machinery for vesicle docking and fusion throughout the cell have been identified. In regulated exocytosis this core machinery must be controlled by Ca(2+)-sensor proteins that allow rapid activation of the fusion process following elevation of cytosolic Ca2+ concentration. The properties of such Ca2+ sensors are known from physiological studies but their molecular identity remains to be unequivocally established. The multiple Ca(2+)-dependent steps in the exocytotic pathway suggest the likely involvement of several Ca(2+)-binding proteins with distinct properties. Functional evidence for the role of various Ca(2+)-binding proteins and their possible sites of action is accumulating but a definitive identification of the major Ca(2+)-sensor in the final step of Ca(2+)-triggered membrane fusion in different cell types awaits further analysis. PMID- 10091008 TI - Apoptosis and cell death in neuronal cells: where does Ca2+ fit in? AB - Mounting evidence shows that neuronal death is an important and essential component of brain tissue homeostasis, with major forms of cell death occurring: necrosis and apoptosis. No general consensus exists as to whether these two forms of neuronal death represent separate cellular processes or just two different forms of a common 'death pathway'. One difference between them is the role played by intracellular Ca2+: central and obligatory, in necrosis and possible, but not always necessary in triggering apoptosis. Furthermore, the same assessment of the involvement of Ca2+ signalling could also distinguish between two possible apoptotic states in the nervous system: one, the 'developmental apoptosis', involving immature and developing neurons, in which Ca2+ plays mainly an apoprotector role, and another one, associated mainly with pathological instances and involving fully matured and established neurons, in which Ca2+ plays an apo inducing role. PMID- 10091009 TI - Calcium signalling in glial cells. AB - Calcium signals are the universal way of glial responses to the various types of stimulation. Glial cells express numerous receptors and ion channels linked to the generation of complex cytoplasmic calcium responses. The glial calcium signals are able to propagate within glial cells and to create a spreading intercellular Ca2+ wave which allow information exchange within the glial networks. These propagating Ca2+ waves are primarily mediated by intracellular excitable media formed by intracellular calcium storage organelles. The glial calcium signals could be evoked by neuronal activity and vice versa they may initiate electrical and Ca2+ responses in adjacent neurones. Thus glial calcium signals could integrate glial and neuronal compartments being therefore involved in the information processing in the brain. PMID- 10091010 TI - Calcium dysregulation in neuronal aging and Alzheimer's disease: history and new directions. PMID- 10091011 TI - Treatment of bacterial meningitis. AB - Major epidemiological changes have altered the empiric therapy of patients with bacterial meningitis, a disease with significant morbidity and mortality. We offer recommendations for empiric management decisions and specific antibiotic choices for patients with bacterial meningitis. PMID- 10091012 TI - Meconium aspiration syndrome: current concepts and management. AB - Meconium aspiration syndrome (MAS) is a common neonatal problem with significant morbidity and mortality. This article reviews pathophysiology as well as several current approaches to the management of MAS, including high-frequency ventilation and exogenous surfactant replacement, among others. PMID- 10091013 TI - Use of oral sildenafil (Viagra) in the treatment of erectile dysfunction. AB - Erectile dysfunction is a common problem affecting men. Sildenafil (Viagra) is the first oral medication approved for the treatment of erectile dysfunction. It has proven to be an effective option in the treatment of erectile dysfunction of different etiologies. PMID- 10091014 TI - The nutritional aspects of hypertension. AB - This article reports dramatic results achieved by the Dietary Approaches to Stop Hypertension (DASH) and other clinical trials and studies in lowering blood pressure in both hypertensives and normotensives, suggesting that it could be useful in both preventing and managing blood pressure. PMID- 10091015 TI - Determining surgical priorities in rheumatoid arthritis. AB - Rheumatoid arthritis often affects multiple joints simultaneously with pain, deformity and loss of function. The indications for surgical treatment are presented along with guidelines for determining the surgical priorities along with guidelines for determining the surgical priorities when multiple joints require surgery. PMID- 10091016 TI - A review of selective infections in the adult diabetic. AB - Diabetic patients are at risk to develop traditional and unique infections. These infections have suggestive symptoms and signs, but often require radiography and/or tissue biopsy for confirmation. Management of these unique infections typically requires a multidisciplinary approach (medical and surgical). PMID- 10091017 TI - Estrogen replacement therapy and coronary artery disease. AB - Coronary artery disease (CAD) is the number one cause of death and disability in women and men in the United States. In women, CAD typically develops after menopause, and, therefore, it has been hypothesized that estrogen replacement therapy (ERT) may have a role in preventing and treating CAD. Indeed, a body of epidemiologic data suggests that estrogen does protect against CAD. Much information is also available on the mechanisms by which estrogen may confer protection versus CAD. For example, ERT has been shown to have an overall beneficial effect on cardiac risk factors such as hyperlipidemia in postmenopausal women, but the degree to which ERT affects the lipid profile and other risk factors is relatively modest and does not seem to account for all of the benefits of estrogen. Thus, this review focuses not only on the effects of ERT on cardiac risk factors but also on other aspects of CAD, such as atherogenesis, lipid oxidation, vasomotor tone, and thrombosis and thrombolysis. The recent literature on the effect of ERT on secondary prevention of cardiovascular events after percutaneous coronary interventions or coronary artery bypass surgery is also reviewed. PMID- 10091018 TI - New intracoronary stent designs: form follows function versus function follows form. AB - Intracoronary stenting improves the acute and long-term safety and efficacy of percutaneous coronary interventions by minimizing the risks of abrupt closure and late restenosis. Enhanced designs of new coronary stents will continue to expand the spectrum of coronary anatomy and clinical settings amenable to nonsurgical revascularization. Improvements in deliverability, application to complex lesions, and durability of results are direct effects of improved design characteristics. Future design features may also include incorporating adjunctive therapies such as antithrombotic or antiproliferative agents with stent-based delivery systems. Results of new stent registries and randomized clinical trials are reviewed. PMID- 10091019 TI - Rotablator plus stent therapy (rotastent). AB - Over 400,000 percutaneous transluminal coronary angioplasties (PTCAs) are currently performed annually in the United States. Approximately 10% of these procedures include rotational atherectomy, although the national average rate of stent placements continues to increase in some centers to as high as 75%. The combination of rotational atherectomy and intra-coronary stent placement is between 2% and 7.5% of interventional procedures per year in the United States. This article reviews the existing literature on rotational atherectomy and stent implantation for complex lesions and describes the upcoming prospective, multicenter randomized Stent Implantation, Postrotational Atherectomy (SPORT) trial. PMID- 10091020 TI - Diagnostic testing of the emergency department patient with chest pain. AB - In evaluating patients with nondiagnostic initial clinical or electrocardiogram (ECG) findings for acute cardiac ischemia, continuous 12-lead ECG monitoring increases the detection of diagnostic ECG findings, including ST-segment elevation, in patients awaiting hospital admission. Rest scanning with technitium 99m sestamibi is able to risk stratify low-moderate risk patients into lower and higher risk groups for cardiac events. Caveats include the reduced sensitivity of scanning of patients who are pain free and the need for follow-up exercise scans for patients free of perfusion defects at rest. Cardiac markers, particularly the troponins, show great promise for the detection of a larger part of the spectrum of acute coronary syndromes in the emergency department, including patients with minimal myocardial damage and higher risk for short-term death and nonfatal acute myocardial infarction. Accelerated diagnostic protocols using serial testing with cardiac markers, ECGs and then provocative testing over a 14-hour period, are feasible, safe, and cost-effective. PMID- 10091021 TI - Time to treatment of acute myocardial infarction revisited. AB - Time to treatment in acute myocardial infarction (MI) has been of great interest since the advent of thrombolytic therapy. The paradigm that has emerged is that rapid achievement of reperfusion, with either thrombolysis or primary angioplasty, minimizes infarct size, reduces the degree of left ventricular dysfunction, and improves survival. Recent studies have confirmed the benefit of reducing time to treatment with thrombolysis (between onset of pain to initiation of thrombolysis) and that of more rapid drug reperfusion time with more aggressive thrombolytic regimens (between initiation of thrombolytic therapy and actual achievement of reperfusion). Furthermore, their effects are additive (and in some cases synergistic), confirming the benefit of rapid reperfusion. For primary angioplasty, the same relationship has been observed: More rapid treatment seems to be associated with improved outcome. The "door-to-balloon" time is a major determinant of overall time to reperfusion and, as such, is a crucial component of the overall strategy. This paradigm can also be extended to the prehospital phase of treating acute MI in two ways: 1) for patients to rapidly identify the symptoms of acute MI and to present earlier to the hospital is critical in reducing overall time to treatment and 2) in emergency medical care, rapid identification of MI patients, electrocardiographic monitoring, and defibrillation as needed for ventricular arrhythmias has been shown to be lifesaving. Thus, time to treatment in the current era of aggressive management of acute MI extends far beyond the original description to every aspect of acute MI care. PMID- 10091022 TI - Therapy with thrombolytic agents in coronary artery disease. AB - Over the past two decades, new thrombolytic agents with sufficient pharmacologic potency and acceptable clinical safety profiles to treat thrombotic vascular occlusive syndromes, such as acute myocardial infarction, pulmonary embolism, acute peripheral and arterial thrombotic occlusions, and deep vein thrombosis, have been developed and evaluated. The evolution of thrombolysis and its application to clinical cardiology came as a consequence of understanding the systems of coagulation and fibrinolysis and their role in the pathogenesis of acute coronary syndromes. PMID- 10091023 TI - Platelet glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. AB - There are many limitations to reperfusion therapy for acute myocardial infarction. Preliminary studies have explored the potential of using more potent antiplatelet therapy. Abciximab, eptifibatide, and lamifiban are new agents that inhibit platelet glycoprotein IIb/IIIa, which serves as the final common pathway for platelet aggregation. Infarct artery patency occurs more rapidly, normal coronary blood flow is more often restored, and reperfusion is more stable when these agents are used with standard- or reduced-dose fibrinolytic therapy. Moreover, abciximab monotherapy has thrombolytic activity and facilitates primary angioplasty or stenting. Further studies are needed to define safety, efficacy, and cost effectiveness. PMID- 10091024 TI - Stents in acute myocardial infarction. AB - It has been widely reported throughout studies comparing mechanical reperfusion by primary percutaneous transluminal coronary angioplasty (PTCA) with thrombolytic therapy in acute myocardial infarction (AMI) that PTCA results in reduced rates of in-hospital mortality, reinfarction, recurrent ischemia, and stroke, allowing earlier hospital discharge with similar total costs. The attraction of primary PTCA is its relative simplicity and predictability with operators who have a wide range of experience with PTCA. With these results, it is legitimate to wonder what, if any, possible advantages other reperfusion approaches, such as stenting, might offer compared with primary PTCA. In addition, there is concern that newer reperfusion modalities may complicate an otherwise straightforward procedure and increase hospital expenditures. However, as effective as primary PTCA is, there is still room for improvement. Limitations of reperfusion by primary PTCA in AMI include recurrent ischemia in 10% to 15% of patients, restenosis in 37% to 49%, and late infarct artery reocclusion in 9% to 14%. By reducing the residual stenosis and sealing dissection planes created by PTCA, primary stenting may further improve short- and long-term outcomes after mechanical reperfusion. Consequently, interest in using stents in the setting of AMI has increased dramatically in the past several years. The results of various recent clinical studies confirm that primary stenting is safe and reasonable in the majority of patients with AMI and produces short-term outcomes superior to experience with primary PTCA. PMID- 10091025 TI - Rescue percutaneous transluminal coronary angioplasty. AB - Fibrinolytic therapy for acute myocardial infarction, even with the most efficient regimens available, is fraught with a substantial proportion of failures to reopen the occluded vessel. The term rescue percutaneous transluminal coronary angioplasty (PTCA) has been introduced to describe an attempt to mechanically recanalize the infarct vessel if fibrinolytic reperfusion fails. Despite the intuitive appeal and widespread use of rescue PTCA, only a limited amount of data (mostly observational retrospective data) is available to confirm the clinical benefit of this therapeutic option. PMID- 10091026 TI - Bibliography. Current world literature. Ischemic heart disease. PMID- 10091027 TI - Methods of identifying patients at high risk of subsequent arrhythmic death after myocardial infarction. PMID- 10091028 TI - IgM antibody response to the hepatitis C virus core protein in intravenous drug users. AB - To verify whether a solid-phase enzyme immunoassay for serum IgM antibodies to the hepatitis C virus (HCV) core protein (IgM anti-HCVcore) might be proposed as a surrogate test for serum HCV RNA, we studied 86 anti-HCV antibody-positive intravenous drug users. Serum HCV RNA was demonstrated by RT-PCR with primers derived from the 5' non-coding and the core region. IgM anti-HCVcore antibodies were found in 62/86 (72%) subjects; circulating HCV RNA was detected by the 5' noncoding assay in 53/86 samples (62%) and by the core region assay in 35/86 samples (41%). IgM anti-HCVcore reactivity was associated with core HCV RNA seropositivity (p < 0.05) but not with 5' noncoding HCV RNA seropositivity (p = NS). Patients infected by HCV type 1a were more-often positive for IgM anti HCVcore (p < 0.05) and for core HCV RNA (p = 0.005) than patients infected by other HCV genotypes. IgM anti-HCVcore reactivity was significantly more common in subjects positive for core HCV RNA (p < 0.005) and in subjects aged > 30 years (p < 0.05). In conclusion, the IgM anti-HCVcore assay frequently tests positive in intravenous drug users, particularly when infected by HCV 1a, but is not a surrogate of testing for serum HCV RNA. PMID- 10091029 TI - In vitro pharmacodynamic properties of MK-0991 determined by time-kill methods. AB - MK-0991 has demonstrated activity against a variety of fungal pathogens. We evaluated the MIC endpoint for MK-0991 by reading the endpoint using three methods and comparing these results with minimum fungicidal concentrations and electron micrographs. The concentration that resulted in 80% inhibition of fungal growth compared with control, similar to the endpoint for the azole antifungal agents, provided the most consistent results. Additionally, we investigated the time-kill properties of this agent against two isolates each of Candida albicans, Candida glabrata and Candida tropicalis at concentrations ranging from 0.125 x MIC to 16 x MIC. Kill curves were performed using RPMI buffered with morpholine propanesulfonic acid as growth media. Samples were obtained at predetermined time points over 24 h and plated for colony counting. Fungicidal activity was observed with one isolate of C. albicans, two isolates of C. glabrata, and one isolate of C. tropicalis. MK-0991 displayed concentration-dependent activity, which was fungicidal or fungistatic depending on the isolate tested. PMID- 10091030 TI - In vitro activity of ciprofloxacin, levofloxacin, and trovafloxacin, alone and in combination with beta-lactams, against clinical isolates of Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia. AB - We tested three fluoroquinolones (ciprofloxacin, levofloxacin, and trovafloxacin), each combined with each of four beta-lactams (cefoperazone, ceftriaxone, imipenem, and meropenem) for synergy against clinical isolates of nosocomial strains of Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia. The ciprofloxacin-beta-lactam combinations showed synergy against none or only a small fraction (7 to 10%) of the P. aeruginosa and B. cepacia isolates. Ciprofloxacin-cefoperazone, -ceftriaxone, and -meropenem were synergic against 50%, 25%, and 30% of the S. maltophilia isolates, respectively. Among the levofloxacin combinations, only those with cefoperazone and imipenem showed significant synergy, and this only against B. cepacia (50% and 30%, respectively). Trovafloxacin-cefoperazone and -imipenem showed modest synergy against P. aeruginosa (23% and 27%, respectively), as did trovafloxacin cefoperazone and -ceftriaxone against B. cepacia (30%). The trovafloxacin imipenem combination was synergic against all isolates of B. cepacia. Because of their synergy, the following combinations may be useful in the nosocomial setting: trovafloxacin-cefoperazone or -imipenem against P. aeruginosa; ciprofloxacin-cefoperazone, -ceftriaxone, or -meropenem against S. maltophilia; levofloxacin-cefoperazone and trovafloxacin-imipenem against B. cepacia. PMID- 10091031 TI - Anti-streptococcal activity of SB-265805 (LB20304), a novel fluoronaphthyridone, compared with five other compounds, including quality control guidelines. AB - SB-265805 (formerly LB20304) is a novel C-7 pyrrolidine-substituted naphthyridone that has a broad spectrum of activity, especially against Gram-positive cocci. SB 265805 activity was compared with ciprofloxacin, grepafloxacin, moxifloxacin, sparfloxacin, and penicillin against 599 Streptococcus spp. isolated recently from more than 30 medical centers in North and South America. These included 70 isolates with decreased susceptibility to recently released fluoroquinolones (levofloxacin MIC, > or = 4 micrograms/mL). All strains were tested by reference microdilution methods in lysed horse blood-supplemented Mueller-Hinton broth. Sixteen percent of 148 beta-haemolytic streptococci (strains of gr. B and C) were not susceptible to penicillin, whereas 38% and 42% of viridans group streptococci and Streptococcus pneumoniae were resistant to penicillin, respectively. SB 265805 potency against 301 pneumococci (MIC90, 0.06 microgram/mL) was fourfold more active than moxifloxacin and was > or = eightfold more potent than other quinolones. Against beta-haemolytic streptococci, SB-265805 and moxifloxacin were the most active (MIC90, 0.06 and 0.25 microgram/mL, respectively), whereas sparfloxacin, grepafloxacin, and ciprofloxacin (MIC90, 0.5-1 microgram/mL) were less potent. SB-265805 MICs versus viridans group streptococci (MIC90, 0.12 microgram/mL) were fourfold lower than sparfloxacin or grepafloxacin, and twofold more active than moxifloxacin. A nine-laboratory quality control (QC) protocol conforming to NCCLS M23-T3 guidelines demonstrated a modal SB-265805 MIC of 0.016 microgram/mL for S. pneumoniae ATCC 49619 (proposed QC range, 0.008 to 0.03 microgram/mL). The SB-265805 disk (5-microgram) QC range was 28-34 mm (97.3% of qualifying results). In general, SB-265805 in vitro activity against Streptococcus species was superior to sparfloxacin, grepafloxacin, and moxifloxacin and markedly greater than ciprofloxacin. This degree of antimicrobial potency warrants further investigation of this newer drug for its potential human clinical application against streptococcal infections. PMID- 10091032 TI - Gram-positive infections: pharmacy issues and strategy for quinupristin/dalfopristin. AB - The development of the first streptogramin antibiotic, quinupristin/dalfopristin represents an attempt to bring new antimicrobial strategies on line to combat the menacing problem of Gram-positive-resistant bacteria. With introduction to the medical center formulary, the pharmacy will need to be aware of several practical issues surrounding the use of quinupristin/dalfopristin. Cost and unit size will be important issues. Initially, this drug will only be available in 500-mg vials which may not always accommodate the suggested dose of 7.5 mg/kg of actual body weight. In addition, the drug can only be reconstituted with D5W or sterile water, and it can not be mixed with normal saline, heparin, or other drugs. Institutions adding this drug to their formularies must address the expected logistical concerns with their medical, nursing, and pharmacy staffs prior to patient usage. PMID- 10091034 TI - Vancomycin-resistant enterococci: the clinical effect of a common nosocomial pathogen. AB - Enterococcus spp. is now the third most common pathogen among hospitalized patients, accounting for nearly 12% of nosocomial infections. Enterococcus faecalis is the most prevalent enterococcal species (85%-89%), whereas Enterococcus faecium accounts for 10%-15% of enterococcal isolates. Only 5% of E. faecalis isolates are resistant to glycopeptides. E. faecium has also been shown to be resistant to nonglycopeptide compounds, such as penicillins (97%), high level gentamicin (52.1%), and high-level streptomycin (58.3%). Numerous risk factors for vancomycin-resistant enterococci (VRE) have been identified, including as length of hospital- or ICU-stay, proximity to a hospitalized, colonized VRE, patient severity of illness, renal failure, recent surgery, immunosuppression, and organ recipient status. An important risk factor is prior exposure to antibiotics such as vancomycin, ceftazidime, ciprofloxacin, and metronidazole, as well as the number and duration of recent antibiotics. Interventions to reduce nosocomial VRE cross-transmission have also been studied. Using gowns in addition to gloves diminished the incidence of VRE in one study, but had a negligible effect in a second study. Studies have shown that in many cases (> 60%) vancomycin usage is inappropriate. While controlling the use of vancomycin alone has only variably diminished VRE colonization, other efforts such as narrowing the spectrum of antibiotics, antiseptics, and reducing immunosuppression may be salutary. Attempts to eradicate VRE intestinal carriage with enteral agents (bacitracin, tetracycline + rifampin, novobiocin) have been reported but seem to have only a transient effect. Non-antimicrobial interventions such as removal of intravenous or bladder catheters and/or surgical or percutaneous drainage may be beneficial. In addition, the development of new antimicrobial agents such as streptogramins, glycopeptides, everninomicins, and oxazalididones will hopefully play an important role in reducing morbidity from these pathogens. PMID- 10091033 TI - Epidemiologic trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds. AB - The Gram-positive cocci have clearly re-emerged as important pathogens world-wide in the past two decades. Staphylococci, including the coagulase-negative staphylococci and Staphylococcus aureus, and the enterococci account for approximately one-third of all blood stream infections and as much as 50% of nosocomial blood stream infections. Although Streptococcus pneumoniae is often considered a community-acquired pathogen, it is also an important cause of nosocomial infection. The hallmark of these Gram-positive pathogens is increasing resistance to available antimicrobial agents. Of particular note is resistance to glycopeptides (vancomycin and teicoplanin), aminoglycosides (high-level), and penicillins among the enterococci (especially E. faecium), resistance to penicillinase-resistant penicillins (oxacillin and methicillin) and fluoroquinolones (ciprofloxacin and ofloxacin) among staphylococci, and resistance to penicillin, other beta-lactams and macrolides among the pneumococci. The recent detection of decreased susceptibility to vancomycin among S. aureus is also quite ominous. In many instances the ability of the clinical laboratory to accurately characterize these resistant isolates is suboptimal, further compounding the problem. Increased understanding of resistance mechanisms and correlations of resistance genes with the phenotypic expression of resistance has allowed for modifications and improvements of reference susceptibility tests and interpretive breakpoints. New compounds for effective therapy of infection with multi-resistant Gram-positive species are clearly needed. To this end, the streptogramin combination, quinupristin/dalfopristin, has demonstrated significant activity against oxacillin-resistant staphylococci, penicillin resistant streptococci, and vancomycin-resistant E. faecium. Other candidate drugs including Gram-positive active fluoroquinolones (clinafloxacin, grepafloxacin, moxifloxacin, gatifloxacin, and trovafloxacin) and novel compounds such as the everninomicin derivatives (SCH27899), ketolides, and oxazolidinones (linezolid) have been shown to be active against these organisms and are under rapid clinical development. PMID- 10091035 TI - Management of bacterial complications in critically ill patients: surgical wound and catheter-related infections. AB - The occurrence of surgical wound infections and/or bacteremia associated with central venous catheter use are of growing concern to all physicians who treat critically ill patients. The physician must be aware that some patients have an even greater risk for infection, such as those with multiple risk factors, those who are on central lines, or those patients who undergo multiple invasive diagnostic or therapeutic procedures. The emergence of resistant pathogens, particularly Gram-positive pathogens, is an important factor in the morbidity and mortality of hospitalized patients. In the face of this growing resistance among target organisms, the selection of the correct antimicrobial and nonpharmacologic interventions, based on correct identification and susceptibility test data, has become increasingly challenging. Methicillin-resistant Staphylococcus aureus and, more recently, glycopeptide-resistant enterococci and staphylococci represent a significant danger to the patient. As a consequence, earlier and more precise identification of the pathogens most frequently associated with infection is essential. The role of exacting surgical technique, infection control measures, and the appropriate use of prophylactic and therapeutic antibiotics cannot be overestimated in helping to reduce potential morbidity and mortality associated with severe surgical infection. The development of new antibiotics may help treat the difficult cases attributable to resistant Gram-positive bacteria. PMID- 10091036 TI - The diagnosis and treatment challenges in nosocomial pneumonia. AB - Pneumonia is the second most common type of nosocomial infection and is most prevalent in patients who are mechanically ventilated. Nosocomial pneumonia (NP) is the leading contributor to mortality in patients, accounting for approximately 50% of deaths in patients with hospital-acquired infections. Several factors place patients at risk for developing NP, including prolonged length of hospital stay and local epidemiology. Gram-positive pathogens such as Streptococcus pneumoniae and, more recently, Staphylococcus aureus, as well as atypical organisms such as Legionella spp are increasingly associated with NP. Emerging antimicrobial resistance among these organisms confounds treatment interventions. Lack of local definitive information and patient comorbidities further complicate the physician's treatment decisions. The role of invasive pulmonary diagnostic techniques remains problematic and controversial. Studies, however, have shown that early initiation of appropriate empiric therapy is essential to improving patient outcome and reducing mortality. This article will review therapeutic options and appropriate antimicrobial agents for use in the treatment of nosocomial pneumonia in the era of emerging drug resistances. PMID- 10091037 TI - With 'cancer undefeated' in western populations--what is the future for Africans in southern Africa? PMID- 10091038 TI - Cancer screening: an educational challenge? AB - Advances in identification of the risk factors for cancer development in different organs imply more effective screening for early malignancies. The associated increase in the predictive value, as well as the introduction of procedures with high sensitivity and specificity, provide promise that early intervention will result in a marked decrease in the mortality and morbidity due to a wide range of major cancers. Furthermore, a variety of methods are now available to detect lesions at a sufficiently early stage for curative surgery to be attempted. However, for the full promise to be realized, it is of paramount importance that both physicians and the public at large are fully aware of the potential benefits. PMID- 10091039 TI - Protection against cancer by wheat bran: role of dietary fibre and phytochemicals. AB - Human intervention and animal studies have shown that supplementing the diet with wheat bran can protect against the development of a range of cancers, especially those of the colon and breast. Wheat bran is a rich source of dietary fibres (plant cell walls) that have structures and compositions which indicate that they may protect against cancer. Nevertheless, dietary fibre makes up less than half of wheat bran. Other nutrients and phytochemicals are present in wheat bran, some of which may also protect against cancer. These include phytic acid and various phenolic components such as phenolic acids, lignans and flavonoids. A major goal of future research on wheat bran should be to determine the relative roles in cancer prevention of the different components in wheat bran. PMID- 10091040 TI - Sun-related behaviour and melanoma awareness among Swedish university students. AB - The relationship between knowledge, attitude and sun-related behaviour among Swedish students was examined in the present study. A total of 296 of 305 questionnaires, distributed among university students (medical school and economy programme) were analysed (157 men, 139 women, mean age 24 years). The percentage of students sunbathing with the intention of getting a tan was 75%. Thirteen per cent reported having experienced at least one painful sunburn every year and 93% stated at least one burn during the last ten years. The majority of the students had used a sun bed, 12% more than ten times during the last year. Subjects with high frequency of sun bed use also scored high on sunbathing and sunburns. Significantly more women (70%) than men (51%) used sunscreen. The overall knowledge of melanoma was high. No difference in knowledge was found between the high- and low-exposure group. Medical students scored higher on knowledge than economy students, but did not differ in exposure score. Our findings reveal an excessive sun exposure among university students. A high level of knowledge of risk does not lead to a sun-protective behaviour. Future preventative campaigns targeting young people must focus on strategies to change attitudes towards tanning as being healthy and attractive. PMID- 10091041 TI - Steroid metabolism along the gastrointestinal tract of the cannulated pig. AB - Steroid metabolism along the gastrointestinal tract of the cannulated pig was studied. Thi was achieved by fitting simple gut cannulas in the terminal ileum, caecum and mid-colon of three Landrace x large white boars, which enabled convenient collection of digesta and faecal samples at defined time points. Biochemical analyses showed that the neutral steroid profile of the pig is similar to that of man, dominated by cholesterol and its bacterial metabolite coprostanol. In contrast, pigs consuming a normal diet excrete appreciably lower quantities of neutral sterols in faeces. The major primary bile acids detected were the glycine and taurine amidates of hyocholic and chenodeoxycholic acids, which were rapidly converted to the free bile acids and subsequently dehydroxylated to hyodeoxycholic and lithocholic acids respectively, in the terminal ileum and caecum. Bacterial deconjugation and 7 alpha-dehyrdoxylation are virtually complete in the caecum with negligible further metabolism in the colon and faeces. On a wet weight basis the concentration of both neutral and acid steroids was shown to increase aborally. Inclusion of dietary fibre in the form of cellulose (Solka floc) and guar gum reduced steroid concentration considerably at all sites of the large intestine, which is consistent with their stool bulking effects. In conclusion, this study shows that intestinal steroid metabolism in the pig is similar to that in man despite slightly different bile acid profiles and, therefore, the multicannulated pig may serve as a useful model of man in chemoprevention studies of colorectal cancer. PMID- 10091042 TI - Diet and gastric cancer in Portugal--a multivariate model. AB - Diet and gastric cancer mortality in Portugal was studied using a multivariate ecological model. The factors investigated over 18 districts were the relationship between gastric cancer mortality (1994-96), dietary habits, and socio-economic factors (1980-81). Mortality geographical pattern was established using age-standardized mortality rates, per capita dietary consumption of foodstuffs and nutrients was obtained from the National Alimentary Survey (1980 81), and data on socio-economic factors from the 1981 National Census. Pearson correlation coefficients and simple and multiple linear regression models were used. The mortality geographical pattern resembled a north-south gradient, and dietary habits and socio-economic factors had great variability throughout the country. The highest negative correlation coefficients between dietary consumption and gastric cancer mortality were obtained for vegetables, fruit, vitamin A and carotene consumption, and the highest positive coefficients were for rice, wine and carbohydrate consumption. No significant correlations were obtained for socio-economic factors. In multiple regression analysis, vegetable and rice consumption could account for 79% of the gastric cancer mortality variability for males, and vegetable and meat consumption could account for 69% of this variability for females. Interestingly, meat consumption was found to be protective. A mean increase of 100 g/person/day in vegetable consumption would imply a mean predicted decrease of 10 (95% CI 6-14) and 5 (95% CI 3-7) gastric cancer deaths per 100,000 persons/year, for males and females respectively, in simple regression analysis. Such a decrease represents about one-third of the mean national gastric cancer mortality rate. Therefore, an increase in vegetable consumption is strongly recommended. PMID- 10091043 TI - The burden of cancer in Austria. AB - The aim of this study was to assess the overall progress against cancer in Austria by analysing changes in age-adjusted mortality rates from 1970 to 1996. For the years 1970 to 1996, age-adjusted rates for all malignant neoplasms and for selected sites were calculated for men and women, according to year, age and sex. The number of cancer deaths were obtained from the Austrian Central Statistical Office--age-adjusted mortality rates of all malignant neoplasms decreased in men between 1971 and 1996 by 13% (from 289.1 to 251.4 deaths per 100,000), and in women between 1970 and 1996 by 19.1% (from 276.6 to 223.7 deaths per 100,000). Among older people (> or = 55 years) the mortality decreased by 13% in men and by 17% in women; among younger people (< 55 years) by 12% and 30%, respectively. The decrease in total cancer mortality is promoted by three tumour sites (the leading causes of cancer deaths in 1970). In both sexes, the decrease of stomach cancer mortality had the major impact, followed by colorectal cancer in women and by lung cancer in men. The observed changes in mortality are primarily related to changing incidence and early detection, rather than improvements in treatment. Unfortunately, there is evidence that prevention is losing ground in Austria. The implementation of the well-established knowledge of cancer prevention and the strengthening of preventative research is urgently needed. PMID- 10091044 TI - WHO consensus statement on the role of nutrition in colorectal cancer. PMID- 10091045 TI - Cancer associations at the country level and shared risk factors--a fuzzy concept? PMID- 10091046 TI - Cross-country comparisons of colon and rectal cancer mortality suggest the existence of differences in risk factors in eastern and western Europe. AB - A comparison of relative mortality rates from colon and rectal cancers in World Health Organization data for various countries in Europe was undertaken to determine whether the two sites demonstrate a direct link. A significant correlation between figures for colon and rectal cancers was found throughout Europe but limited to males and only at the p < 0.05 level. Cluster analysis revealed marked differences between countries of the former west and east European blocks, the latter having much higher values for rectal cancers. Separation of countries on this basis gave rise to significant correlation between the two sites for both sexes (p < 0.05 and p < 0.001, respectively, for western and eastern males; and p < 0.05 and p < 0.001 for females). In order to assess the possible contribution of factors associated with squamous cell cancers (SCCs), data for buccal and cervical cancers, both more prevalent in eastern than in western Europe, were also compared. Whereas a significant correlation was evident between female rectal and cervical cancers overall and in the western countries (p < 0.05) this was not the case for the eastern countries. The results suggest that the observed excess of rectal cancer mortality in eastern European countries may not be simply due to factors contributing to SCCs, but that country level comparisons of individual harmful and beneficial influences, alone and in combination, might allow the underlying reasons to be explained. PMID- 10091048 TI - Physiologic monitoring systems. AB - Physiologic monitoring systems, which monitor vital physiologic parameters so that clinicians can be informed of changes in a patient's condition, typically consist of several distinct components, including a central station, bedside monitors, and ambulatory telemetry transmitters and receivers. For this study, rather than focusing on how each component performs individually, we evaluated how the entire system functions as a whole to better parallel the acquisition practices followed by most hospitals. We evaluated systems from eight suppliers, focusing primarily on adaptability, alarm implementation, and human factors design. We included only systems that offer (1) a central station that can concurrently receive information from bedside monitors and ambulatory telemetry transmitters, (2) one or more bedside monitors that can be used in critical care and intermediate care areas, as well as during transport, and (3) ambulatory telemetry monitoring. We rated the evaluated systems based on their capabilities for each of six applications: critical care unit, emergency department, intermediate care unit and general medical/surgical floor, operating room, postanesthesia care unit, and transport. We found that many of the systems are suitable for some applications, but are unable to meet the requirements for others. PMID- 10091049 TI - Fracture of bronchoscopic biopsy valve. PMID- 10091050 TI - Absence of alarm defaults on Hewlett-Packard central station monitors. PMID- 10091051 TI - Furby toys are not likely to interfere with hospital equipment. PMID- 10091052 TI - Interference between telemetry transmitters programmed to the same frequency. PMID- 10091053 TI - The modulation of sperm function by fertilization promoting peptide. AB - Fertilization promoting peptide (FPP; pGlu-Glu-ProNH2) is a peptide produced by the prostate gland and then secreted into seminal plasma. Recent studies have shown that the addition of FPP to uncapacitated mouse and human sperm suspensions stimulates capacitation as demonstrated by cytological assessment and increased fertilizing/penetrating ability in vitro, hence its name. Interestingly, the addition of FPP also has an effect on capacitated cells, namely inhibition of spontaneous acrosome loss; these spermatozoa retain high fertilizing ability, however, when tested with unfertilized oocytes. Adenosine, which is known to modulate adenylate cyclase activity, has been shown to elicit responses similar to those obtained with FPP in both uncapacitated and capacitated spermatozoa. Because the use of FPP and adenosine simultaneously is more effective than either used individually, it has been proposed that these two molecules interact with different receptors to modulate the adenylate cyclase/cAMP signal transduction pathway. FPP-related peptides have been found to vary in their biological activity in vitro, the most interesting one being Gln-FPP (pGlu-Gln-ProNH2). This peptide, identified in human seminal plasma and possibly produced by men with prostatic dysfunction, had no intrinsic activity itself but was able to competitively inhibit responses to FPP. Finally, very recent evidence suggests that the protein TCP-11, coded for by a mouse t-complex gene, may be the receptor for FPP. The existence of a human homologue for Tcp-11 suggests that TCP-11 and FPP could well play an important role in human fertility/subfertility. In vitro, FPP's ability to stimulate capacitation might reduce the incidence of delayed fertilization which results in impaired embryonic development and implantation. PMID- 10091054 TI - Sperm nuclear DNA damage and altered chromatin structure: effect on fertilization and embryo development. AB - In the first part of this report we investigate whether chromatin anomalies in human spermatozoa can influence fertilization after intracytoplasmic sperm injection (ICSI). We have examined the sperm chromatin packaging quality using the chromomycin A3 (CMA3) fluorochrome and the presence of DNA damage in spermatozoa using in-situ nick translation. When comparing the spermatozoa of patients undergoing in-vitro fertilization (IVF) and ICSI distinct differences are evident in that ICSI males have a higher CMA3 fluorescence, indicating spermatozoa with loosely packed chromatin, and more spermatozoa containing endogenous DNA nicks. When examining the unfertilized oocytes of ICSI patients we found that men who had a high percentage of anomalies in their chromatin, i.e. > 30% CMA3 fluorescence and > 10% nicks, had more than double the number of unfertilized oocytes containing spermatozoa that had remained condensed. The observation that failed fertilized oocytes, injected with spermatozoa from patients with a higher percentage of sperm nuclear anomalies, contain more condensed spermatozoa indicates that a selection process against these spermatozoa may be in place at the time of fertilization. In the second part of the study we show that spare ICSI embryos have significantly lower rates of development to the blastocyst stage compared with those developed after routine IVF. These results show that a greater understanding of the molecular basis of male infertility is therefore needed to broaden our knowledge on the effect that abnormal spermatozoa have on fertilization and embryo development. PMID- 10091055 TI - Role of the ionic environment and internal pH on sperm activity. AB - In most species, once formed in the testis, spermatozoa are bathed in a fluid where they remained immobile and with a very low level of metabolism. This immotile status is understandable in view of the need to preserve the sperm energy reserve and to decrease the risk of alteration to membranes, internal structures and biochemical compounds by endogenous oxidizing agents produced by mitochondrial activity. This quiescent phase can be of different lengths and finishes when the semen is released into the external environment where the spermatozoa become motile and metabolically active. For invertebrates, and some fish, sexual activity is generally seasonal and fertilization is external. Spermatozoa, once differentiated in the gonad, remain there completely quiescent until they are released into the external medium, which is either fresh water or sea water. Dilution of the testicular fluid surrounding the spermatozoa allows the initiation of motility and metabolism. In fact, this seminal fluid has an inhibitory effect on sperm activity. For birds and mammals (including humans), the situation is much more complex. In these species, sperm production is almost continuous although for some of them, seasonal variations occur. When spermatozoa are released from the Sertoli cells, they are rapidly exported from the testis to the epididymis where the composition of the surrounding medium is profoundly modified. For most species, the spermatozoa remain immobile in the lower part of the epididymis, even though they have gained the capability to be fully motile as shown by dilution in an adequate medium. In vivo, motility is activated when the spermatozoa are mixed with secretions from the different accessory glands during ejaculation. This paper will review the role played by environmental factors, such as ions, in the activation of sperm motility and metabolism of different species of invertebrates and vertebrates. Special attention is given to changes in sperm internal pH, its regulation and role in the activation of sperm axonemal movement. PMID- 10091056 TI - Role of integrins during fertilization in mammals. AB - Fertilization includes sperm-oocyte recognition, adhesion, binding, fusion and egg activation. Integrin receptors, which are adhesion molecules, are expressed on sea urchin, mouse, hamster and human unfertilized oocytes. Potential sperm ligands have been identified. A role for integrins during fertilization is supported by inhibition of sperm-egg adhesion and/or fusion by means of anti integrin monoclonal antibodies, Arg-Gly-Asp (RGD) or disintegrin-like peptides. In several cell-cell interactions, such as lymphocyte activation, viral fusion, bacterial infection or macrophage phagocytosis, integrins act as co-receptors after activation and, by clustering in a multimolecular complex, are able to transduce signals through cytoskeletal proteins and adaptor kinases. Experimental data suggest that they may act in a similar way during fertilization and may participate to initiation and/or propagation of the calcium signal via stimulation of phospholipase C gamma and inositol trisphosphate production. PMID- 10091057 TI - Assisted reproduction for the treatment of azoospermia. AB - Azoospermia, the most severe form of male infertility, is caused by obstructions in the genital tract or by testicular failure. Microsurgical techniques are available for the correction of some of these obstructions but no effective treatment is available for testicular failure. In recent years, methods have been developed for direct surgical sperm sampling from either the epididymis or the testis to be used by intracytoplasmic sperm injection. The main approach proven to be effective for the retrieval of spermatozoa from the epididymis in patients with obstructive azoospermia is microsurgical epididymal sperm aspiration, although recently the retrieval of spermatozoa by fine needle aspiration was shown to be equally effective. Recovery of spermatozoa is also now performed in patients with severely deficient spermatogenesis using testicular open biopsy as well as aspiration by fine needle. The ultimate choice of sperm retrieval method in these patients will depend not only on sperm availability, but also on the physiological consequences of the different techniques on testicular function. This article summarizes the recent advances achieved in the treatment of azoospermic patients using these assisted reproduction surgical techniques. PMID- 10091058 TI - The first births and ongoing pregnancies associated with sperm cryopreservation within evacuated egg zonae. AB - This new procedure principally aims to avoid a second or possibly multiple surgical procedures for sperm extraction from the male partner in cases of limited amounts of sperm cells, where normal freeze-thaw protocols would fail. Patients (n = 34) diagnosed as azoospermic, extreme oligozoospermic, or oligoasthenozoospermic underwent the process of sperm cryopreservation within evacuated egg zonae. Other samples were allocated to conventional sperm freezing. Sperm samples were acquired using testicular sperm extraction (TESE), microepididymal sperm aspiration (MESA), or fresh ejaculate. Subsequently, five of these 34 couples have undergone in-vitro fertilization (IVF) and achieved normal fertilization using post-thawed spermatozoa frozen under zonae pellucidae in conjunction with intracytoplasmic sperm injection (ICSI). The average fertilization rate for the post-thaw injected spermatozoa was 65%. This is comparable with the regular fertilization rate of 65% for combined MESA and TESE using fresh spermatozoa. All patients underwent embryo transfer. The average implantation rate per embryo was 31%; nearly the same for regular MESA/TESE ICSI cycles (32%). The first pregnancy associated with this procedure concluded with the full term delivery of healthy twin girls on July 18, 1997. The remaining four thaw procedures resulted in another twin delivery, an ongoing singleton gestation, a negative pregnancy test and a biochemical pregnancy respectively. PMID- 10091059 TI - Is there a future for spermatid injections? AB - Microinjection of spermatids into oocytes has proven to be a successful assisted reproduction procedure in the animal model. In the human, low fertilization and cleavage to the 4-cell stage were reported after intracytoplasmic sperm injection (ICSI) with round spermatids. In comparison with a conventional ICSI-testicular sperm extraction (TESE) programme, the implantation rate after round spermatid injection is dramatically low. Different problems have been encountered during the development of the spermatid injection technique and they could be partially responsible for the lower outcome when using round spermatids. Compared with the round spermatid cells, spermatids in the elongation phase are easy to isolate and identify from other round cells present in a wet preparation. The morphological identification does not reveal anything about the viability or the genetic normality of the round spermatids. Severe testicular dysfunction may have consequences on the quality of the few spermatogenic cells present. Others factors, such as the pathology of the patient, play an important role in the successful treatment. Even if the results are extremely low, spermatid injection seems more favourable for men who have already proven their capacity to produce some spermatozoa. A spermatogenic block at the round spermatid level has led to early abortions, increasing the suspicion of the role of a genetic factor. In order for this technique to be safe for use in clinics, more intensive work is needed to improve the selection and handling of cells and to ascertain the genomic imprinting and gene expression necessary for embryonic development. Hence, when using immature cells for conception, the screening of the patient and the follow-up of the pregnancies and babies should be mandatory. PMID- 10091060 TI - Cell-to-cell communication in the ovarian follicle: developmental and hormonal regulation of the expression of connexin43. AB - The extensively developed network of cell-to-cell communication in the ovarian follicle is generated by gap junctions. In addition to the transmission of nutrients from the follicular cells to the oocyte, junctional communication in the ovarian follicle mediates the transfer of cAMP, the regulatory signal that maintains the oocyte in meiotic arrest. Luteinizing hormone (LH) interrupts cell to-cell communication within the ovarian follicle, leading to a decrease in intra oocyte concentrations of cAMP followed by resumption of meiosis. The developmental and hormonal regulation of the ovarian gap junction protein connexin43 (Cx43) and gene expression throughout folliculogenesis is reviewed in this article. An age-dependent increase in the amount of the Cx43 protein that was accompanied by its phosphorylation in preovulatory follicles has been observed. This protein disappeared after ovulation. The changes in both the amount and phosphorylation state of Cx43 were mimicked by exogenous administration of hormones as follows. Pregnant mare serum gonadotrophin increased Cx43 protein expression with a concurrent induction of its phosphorylation while a further human chorionic gonadotrophin injection resulted in a significant decrease of the protein. Cx43 mRNA showed a similar pattern of expression. In-vitro analysis of isolated ovarian follicles revealed that short time exposure (10 min) to LH stimulates phosphorylation of Cx43 followed by its immediate dephosphorylation, while longer incubations (8 and 24 h) with this hormone result in elimination of the protein. A significant decrease in Cx43 mRNA concentration at 24 h of incubation with LH was observed in these follicles. These results suggest that: (i) the presence of the gap junction protein in the ovary is developmentally regulated; (ii) after sexual maturation, both the amount of the Cx43 ovarian gap junction protein and its phosphorylation state are subjected to regulation by gonadotrophins; (iii) the LH-induced gating mechanism of the gap junctions in rat ovarian follicles is comprised of two steps: the immediate response is represented by a change in the phosphorylation state of the Cx43 protein, and the later response is manifested by a reduction of Cx43 protein concentration, due to attenuation of its gene expression. PMID- 10091062 TI - Cryopreservation of activated mouse oocytes and zygote reconstitution after thaw. AB - A new approach to cryopreservation of unfertilized oocytes is proposed using techniques of artificial egg activation combined with nuclear transplantation. Matured mouse oocytes were released from metaphase II arrest by brief exposure to alcohol, allowed to progress to the pronuclear stage and then frozen according to a standard freezing protocol in propandiol. After thaw the female pronuclei were enucleated and fused with a male karyoplasts that were divided from in-vivo fertilized zygotes. Reconstituted zygotes, fresh and cryopreserved culture control zygotes were cultured to the blastocyst stage and transferred to pseudopregnant recipients. The rate of blastocyst formation was 75.8, 91.6 and 44.1% respectively. A total of 110, 215 and 70 blastocysts were transferred to pseudopregnant females respectively. The implantation rates were 36.4, 72.0 and 75.7% while the rates of fetal viability at mid-gestation were 15.5 (P < 0.0001), 51.1 and 37.1% respectively. PMID- 10091061 TI - Oocyte cryopreservation. AB - Cryopreservation of human oocytes has been employed with little success in clinical practice, even though it may solve the legal and ethical problems linked to embryo freezing. Various attempts to cryopreserve human oocytes have mostly been unsuccessful, leading to low oocyte survival rates after thawing, and the search for an optimal protocol for oocyte cryopreservation remains elusive. A preliminary study was undertaken to evaluate some of the factors influencing the survival rate of human oocytes and the efficiency of intracytoplasmic sperm injection (ICSI) as an insemination procedure. A total of 38 women with tubal infertility were enrolled in the study. The cryopreservation procedure consisted of a slow freeze-rapid thawing technique using 1,2 propanediol and sucrose as cryoprotectants. The overall oocyte survival rate was approximately 60%. A better survival rate was obtained when the oocytes were cryopreserved in the presence of partially removed cumulus oophorus rather than in the presence of totally enzymatically removed cumulus oophorus. The cryoprotectant concentration and the equilibration time also appear to influence the oocyte survival rate. ICSI may be an efficient method of achieving a satisfactory outcome in terms of fertilization in cryopreserved human oocytes. Embryonic morphological quality does not seem to be compromised by cryopreservation. In conclusion, these data show that cryopreservation may ensure that the integrity of the human oocyte is adequate for normal fertilization and embryo development. PMID- 10091063 TI - Ovarian markers of implantation potential in assisted reproduction. AB - In-vitro fertilization provides evidence for the heterogeneity of human embryos; data from the UK indicating that approximately 90% of embryos selected for transfer fail to implant. The need to identify factors that promote implantation or markers of implantation is self-evident. There is an increasing awareness that the heterogeneity of follicles may have a significant impact on oocyte competence and embryo viability and that factors which contribute to the heterogeneity of follicles may provide markers of implantation in assisted conception. The markers of implantation described include the expression of 11 beta-hydroxysteroid dehydrogenase by granulosa cells in vitro; adhesion and proliferation of cumulus cells in vitro; steroidogenic activity of cumulus in vitro and perifollicular vascularity and vascular endothelial growth factors bound to granulosa and cumulus cells. These factors may provide clinically useful markers of implantation potential. PMID- 10091064 TI - Early events in mammalian egg activation. AB - The fertilizing spermatozoon initiates a series of events in the mammalian egg, referred to as 'egg activation'. These biochemical and morphological events include a transient rise in intracellular Ca2+ concentration ([Ca2+]i) that leads to the cortical reaction (CR) and the establishment of the block to polyspermy on the one hand, and to the resumption of meiosis and later embryonic mitotic divisions on the other. The initial increase in [Ca2+]i appears to be critical for the initiation of egg activation. However, another second messenger, protein kinase C (PKC), was also suggested as a possible inducer of some aspects of egg activation. The review focuses on early events during mammalian sperm-egg interaction and discusses possible roles of Ca2+ and PKC in egg activation. PMID- 10091065 TI - The origin, effects and control of air pollution in laboratories used for human embryo culture. AB - Testing shows that most laboratories conducting human gamete and embryo culture have air quality and sources of contamination that exceed the levels measured in homes, businesses and schools. The sources of these contaminants have been shown to be either from activities outside the laboratory, or emitted from materials used in the facility, such as compressed gas, cleaning and sterilizing agents, plastic and stored materials. Both the laboratory structure and the air handling systems may affect the air composition. The significance of these findings is being validated by the accumulation of field case studies and now by assay procedures. Products given off by road sealant were shown to have accumulated in one of the examined laboratories, adjacent to a large re-surfaced parking area. Aldehydes such as acrolein, hexanal, decanal, pentanal and others were detected at elevated concentrations that were statistically significant. Since it is not appropriate to add potentially suspect chemicals to human embryos, we used a mouse-model to study the effect of acrolein. The growth of mouse embryos was significantly affected after acrolein was added at different concentrations to the culture environment. The physiological effect was noted at concentrations in the low ppm range. The testing end-point of embryo death must still be considered to be a crude basis for evaluating toxicological effects, since it involves addition of compounds to culture media and unprotected growth until the blastocyst stage. The findings may, however, support observations of decreased pregnancy rate following exposure of human embryos to aldehydes or other adverse conditions. With proper engineering and material selection, it is possible to reduce such contamination. The usefulness of this approach for controlling aldehydes has been demonstrated by decreasing levels in the laboratory to below those of the outside air. PMID- 10091066 TI - Internal quality control and external quality assurance in the IVF laboratory. AB - The existence of internal quality control programmes and external quality assurance schemes is important in enabling the maintenance of good service to patients. All aspects of our work in laboratories involved in the diagnosis and treatment of human infertility can benefit from such programmes and schemes, moving the work from being a subjective art form to an objective science. Equally, many clinical procedures are amenable to such scrutiny. Acceptance and introduction of such schemes and programmes will rely initially on the self motivation of the laboratories themselves and then pressure brought to bear by accrediting authorities. PMID- 10091067 TI - The importance of water quality for media preparation. AB - The variability in pregnancy rates achieved among in-vitro fertilization (IVF) clinics may be partially attributable to the disparate quality of the water used in the preparation of culture media. The removal of contaminants in the water is of paramount importance since water constitutes the predominant component in any media formulation. To assist in the selection, operation and maintenance of a water purification system, the level of contaminants must be carefully monitored. Conductivity and resistance are used to measure the purity of natural and ultrapure water respectively. Feed water is analysed by an assortment of direct chemical means to determine the necessary system filtration steps. In general, high quality water can be produced by combined reverse osmosis and electrodeionization of treated tap water. Processed water is supplied to an ultrapure water system to provide final polished water. A detailed water processing protocol is presented along with quality assurance guidelines to ensure the consistent production of high quality ultrapure water suitable for in vitro human embryo culture. PMID- 10091068 TI - Is the mouse a good model for the human with respect to the development of the preimplantation embryo in vitro? AB - A comparison has been made of various aspects of preimplantation development of mouse and human embryos in vitro. Changes in substrate utilization follow similar patterns in both species. This similarity in metabolic parameters between the two species has facilitated the use of the mouse as a model to study the formulation of culture media to be used at different stages over the preimplantation period from fertilization to the fully expanded blastocyst stage. It has also prescribed the mouse embryo as a practical tool for quality control testing of the laboratory system in human in-vitro fertilization. Aspects of the physiology of both species that require further study are the physiological levels of endogenous inorganic phosphate in the female reproductive tract, the requirement for inorganic phosphate in culture medium, the specificity of the amino acid requirements for optimal development before and after compaction and the importance of including EDTA in culture medium. PMID- 10091069 TI - Human assisted conception: a cautionary tale. Lessons from domestic animals. AB - A variety of embryo-based technologies used in farm animal reproduction, including embryo culture, nuclear transfer, embryo-somatic cell co-culture and asynchronous embryo transfer can lead to the production of large offspring; the so-called large calf/lamb syndrome. In some cases, abnormalities in the fetus and newborn are apparent. The nature of these associations is explored with emphasis on the biological differences between in-vivo- and in-vitro-produced embryos. A unifying framework and research programme aimed at explaining anomalies in early embryo development is then proposed in terms of the response of somatic cells and embryos to cellular stress. The review concludes with a caution against developments in assisted conception technologies, in man and domestic animals, being determined too much by the needs of commerce at the expense of research on the molecular, biochemical and physiological basis of early mammalian development. PMID- 10091070 TI - Does glucose affect fertilization, development and pregnancy rates of human in vitro fertilized oocytes? AB - The study was conducted to examine whether the presence of glucose in the incubation medium affects fertilization, development and implantation rates of human oocytes of patients who were attending our in-vitro fertilization programme. Harvested oocytes were transferred into one of four different media: human tubal fluid (HTF), P1, M3 and IVF-Universal (IVF-Med). Three of these contained glucose; the fourth (P1), contained no glucose or phosphate ions. In an independent preliminary study, some of the oocytes of each patient were incubated in IVF-Med, which lacks phosphate ions, but not glucose. Comparisons of fertilization rates between media pairs showed differences among all pairs except HTF and M3. When comparing the four study groups, no difference was noticed in embryo development or embryo quality 48 h post-ovum retrieval. A higher development rate was demonstrated in embryos incubated in M3 medium, in comparison with the P1 and IVF-Med embryos after incubation for 72 h. No difference in pregnancy rate was found after embryo transfers of preimplantation embryos which were incubated in one of the following media: HTF, M3 and IVF-Med (seven out of 22, 18 of 54 and 32 of 69 treatment cycles respectively). A lower incidence of pregnancies occurred following transfers of embryos which were incubated in P1 medium (seven pregnancies out of 37 cycles). We suggest that the presence of glucose in the incubation medium enhances implantation potential of in-vitro-developing preimplantation embryos. PMID- 10091071 TI - Randomized comparison of three media used for embryo culture after intracytoplasmic sperm injection. AB - Since the metabolic requirements of fertilization and early embryonic development are very different, we have tested a new culture medium (EllioStep2, Ellios Bio Media, Paris, France) specially designed for the first cleavages and compared it with two conventional media: BM1 (Ellios Bio-Media, Paris, France) and IVF50 (Scandinavian IVF Science, Gothenburg, Sweden). In order to avoid any interference with fertilization, the test was performed as part of an intracytoplasmic sperm injection (ICSI) study. A total of 416 ICSI attempts were randomly performed using one or other of the media. After sperm injection, oocytes were incubated either in EllioStep2 or in BM1 or in IVF50. The embryo quality, pregnancy and implantation rates, number of frozen embryos were compared in the different media. The percentage of fair embryos (grades 4 and 3) was significantly higher when EllioStep2 was used than when oocytes was cultured in BM1 medium (54 versus 47%; P < 0.01) or in IVF50 (69 versus 61%; P < 0.01). The pregnancy rate per transfer and the implantation rate were not significantly higher with EllioStep2 than with BM1 or IVF50. However, the percentage of embryo freezings per attempt was significantly higher with EllioStep2 than with BM1 (47/105 versus 28/105; P < 0.01). In conclusion, the use of EllioStep2 is associated with an increase in embryo quality permitting a higher number of embryo freezings. PMID- 10091072 TI - Development of serum-free media for the culture and transfer of human blastocysts. AB - The culture and transfer of the blastocyst stage embryo has several advantages for assisted reproduction in the human. However, due to inadequacies of present culture conditions in human in-vitro fertilization (IVF), embryos are routinely transferred to the uterus on either day 2 or day 3 of development around the 4- to 8-cell stage, with resultant implantation rates of only 10-25%. In other mammalian species the transfer of cleavage stage embryos, which normally reside in the oviduct, results in a significantly lower implantation rate compared with the transfer of blastocysts. Extended culture of human embryos in vitro will help to identify those embryos with little, if any, developmental potential. It is therefore plausible that the blastocyst has an intrinsically higher viability than the cleavage stage embryo. It has now been shown in human IVF that sequential serum-free media can support > 50% blastocyst development, with an implantation rate per blastocysts of 50%, double that obtained for cleavage stage embryos. As the implantation rate of the blastocyst is higher than the cleavage stage embryo, fewer blastocysts are required for transfer. The development of completely defined embryo culture media may prove feasible by the replacement of protein with the glycosaminoglycan hyaluronate. Hyaluronate, which is protein free, is more suitable than albumin in supporting implantation in the mouse, and can eliminate the biological variation inherent when using protein and the potential for contamination when using blood products such as albumin. PMID- 10091073 TI - The application of co-culture in assisted reproduction: 10 years of experience with human embryos. AB - Co-culture techniques using fetal bovine uterine fibroblasts or bovine oviductal epithelial cells have improved embryonic development prior to replacement in humans. In initial co-culture trials, embryo development and implantation rates increased after just 1 day in culture. The most overt characteristics noted following co-culture were improved blastomere development and characteristics, reduced fragmentation, and the appearance of swollen blastomeres. In addition, an increase in the incidence of zona thickness variation was detected. Improved development of polyspermic and supernumerary embryos to the blastocyst stage was noted in initial trials. Retrospective analysis indicated that certain patient subgroups benefit the most from co-culture. As a result, co-culture is now applied routinely to patients that have previously failed attempts at in-vitro fertilization (IVF) and/or have endocrine imbalances such as polycystic ovarian syndrome and elevated day 3 concentrations of follicle stimulating hormone (FSH). The use of co-culture prior to or following cryopreservation has also proven to be beneficial to human embryos. The proposed beneficial mechanisms thought to improve embryonic development include a secretory and/or a scavenging role. Evidence describing the postulated benefits is discussed. PMID- 10091074 TI - The use of recombinant growth factors to promote human embryo development in serum-free medium. AB - Research into human implantation requires embryo culture systems that yield high numbers of good quality blastocysts. One approach is to use co-culture but the presence of feeder cells and serum may confound analysis of paracrine or autocrine factors involving blastocyst implantation. An alternative approach is to produce a defined serum-free culture medium supplemented with growth factors. We have shown that the addition of Leukaemia Inhibitory Factor increased blastocyst formation from 18.4-43.6% but none of these embryos developed beyond day 7 or hatched, suggesting that additional factors are required. Development to the blastocyst stage was significantly increased to 71.0% in the presence of 100 nM heparin-binding epidermal growth factor (HB-EGF) and 81.0% of these embryos went on to hatch. No difference in blastocyst quality between the control and HB EGF-treated embryos was found. These experiments clearly demonstrate the potential of this system to generate blastocysts in vitro. Further investigation of the normality of these blastocysts must be carried out before they are used clinically, since it has been demonstrated in other species that apparent improvements in culture conditions may be detrimental to pregnancy outcome. PMID- 10091075 TI - The future of preimplantation genetic diagnosis. AB - This paper reviews the current status of preimplantation genetic diagnosis (PGD), outlining the methods currently in use for the diagnosis of sex and single-gene defects. New approaches under development are described, e.g. fluorescent polymerase chain reaction (PCR), the use of sub-telomeric probes for patients with balanced reciprocal translocations, the analysis of first and second polar bodies, the use of lasers to facilitate the biopsy of embryos, and ways forward for infertile patients. PMID- 10091076 TI - Improved methods for blastocyst formation and culture. AB - Transfer at the blastocyst stage has been proposed to increase the pregnancy rates after in-vitro fertilization (IVF) and embryo transfer. In the first period of experiments, culture in a single medium, from fertilization to blastocyst led to disappointing results: low blastocyst formation rates and low implantation rates per blastocyst transferred. Then the period of co-culture began (starting with animals in the early 1980s and with humans in the early 1990s). With this technique, using tubal or granulosa cells or layers obtained from established cell lines of transport epithelium origin, blastocyst formation has reached approximately 50% and the overall implantation rate is approximately 25%. The embryos obtained have high numbers of cells (> 200 cells for a day 6 expanded blastocyst). Co-culture with fibroblasts has been found to be useless. This technology has been proven reliable and reproducible: Blastocyst formation is highly dependent on maternal and paternal factors. It has enabled the design of efficient freezing and thawing protocols. Numerous interesting observations have been obtained to reach the third period, i.e. the use of sequential media. A simple medium is used for fertilization, then another one is used from fertilization up to the 4-cell stage (beginning of waves of transcription), then a third medium is used for development up to the blastocyst stage. The results obtained seem very similar to the one obtained with co-culture. Obviously it is now time, in humans, to switch to sequential media. PMID- 10091077 TI - Film based X-ray cardiac angiography. PMID- 10091078 TI - The DICOM image formatting standard: its role in echocardiography and angiography. AB - Both echocardiography and angiography have traditionally used analog media for long-term storage, but increasingly there is the desire to develop digital storage and exchange methodology. Before digital storage can become a reality, though, standards must be agreed to by the vendor and user community to ensure global intra operability of medical instrumentation. To this end, the National Electrical Manufacturers' Association and various professional organizations from around the world have collaborated to develop the DICOM (Digital Imaging and Communications in Medicine) image formatting standard. This standard specifies the exact way in which digital images are exchanged between instruments, either using a network or storage medium, and distinct standards have been developed for angiography and echocardiography. In angiography, only gray scale images are considered, whereas in echocardiography several different types of image formats are allowed to account for color Doppler echocardiography. Distinct standards have also evolved for disk-based storage. For angiography, only storage on the writable CD-ROM is allowed, whereas echocardiograms may be stored on re-writable magneto-optical disks, floppy disks, and CD-ROMs. Only lossless compression is allowed in the angiographic standard, whereas echocardiography allows the use of the JPEG (Joint Photographic Expert Group) lossy compression algorithm. Currently, all major angiographic and echocardiographic vendors have agreed to support the DICOM standard, and products are beginning to appear, first with disk based storage but increasingly with network-based exchange of image data. PMID- 10091079 TI - The effect of DICOM on QCA and clinical trials. AB - Almost without any exemption, new cardiac catheterization laboratories are entirely digital without 35 mm cinefilm as the storage medium. In addition, existing laboratories are increasingly converting to the digital world. Aside from the organizational aspects, this has significant implications for the daily diagnostic review process of the procedures, and for the quantitative analysis of selected frames by QCA. The DICOM standard has now been well accepted in the catheterization laboratories. In stead of mechanical cine projectors, a department must decide on so-called DICOM-Viewers or 'digital Tagarno's'. In this paper the effects of DICOM on image quality and therefore on the visual interpretation of these images, as well as on QCA are discussed. Since the digital images can be enhanced, these look sharper than the conventional cinefilm images. However, edge enhancement has an effect on QCA, reason why the digital data must be stored in raw format. With the enormous amounts of digital data produced in a catheterization laboratory, image compression is of great importance. Currently, an international study is being carried out to determine which compression level is still acceptable from a visual interpretation and QCA point of view. Finally, the implications of the digital era on clinical trials are discussed. One of the important conclusions is that one should be encouraged not to switch from cinefilm to digital in the course of a trial, while a mixed population from the beginning is no problem, as long as the proper statistical calculations are carried out. In conclusion, despite the fact that there are still a number of items to be checked and possibly modified in the standard, the existing DICOM standard has succeeded in bringing widespread utilization of QCA in cardiac angiography closer than ever. PMID- 10091080 TI - Digital image in cardiology now and for the future. AB - Siemens has a logical stepwise approach and employs proven technology. Siemens historically remains focused on efficiently handling image data in the cardiac cath lab as evidenced by: the 1990 introduction of HICOR and timely introduction of ACOM in 1995 together with the extension of the DICOM 3 standard by ACC/NEMA. Today and into the future Siemens is building the strength with the powerful synergy developed between our medical division and computer division (Siemens Nixdorf) to assure even greater success with tomorrow's ACOM.net (Figure 3). Siemens statement: All HICORs can be upgraded with ACOM. All ACOMs can be interfaced to the ACOM net. PMID- 10091081 TI - Philips CD-medical digital cardiac review, exchange and archiving: today and tomorrow. PMID- 10091082 TI - Filmless cardiac imaging: motion or commotion? AB - At present times the medical cardiology imaging is still arguing about the usefulness of X-Ray Cine film in comparison with digital and filmless imaging. It is clear that both techniques have their advantages. X-Ray Cine film is a well established technique of which the possibilities are well known. At a first glance filmless imaging offers nothing but advantages. However the whole picture becomes clear when trying to implement these systems in a clinical environment, because at that time aspects of investments, technological continuity and risks, needed skills and effects on the workflow appear. This article has the purpose to clarify some of these aspects and give guidance in the difficult process of making the right decision. PMID- 10091083 TI - The digital cardiac network: today and the future. AB - Cine replacement or cineless angiography is now a serious consideration for any new cardiac catheterization laboratory installation. Standards have been set by the Dicom committee, and CD's are rapidly appearing instead of angiogram film. Core labs. are geared to perform CD interpretation as well as film during this transition phase. Attempts are made to network multiple labs. and maintain the same kind of flow encountered in an analog lab. Labour and material costs seem to be cheaper for cineless labs. The future will see faster and deeper storage and commercially available means to network hospitals. This technology may be the forerunner of the digital patient record. PMID- 10091084 TI - Toshiba's approach to the digital catheterization laboratory--full-digital system with DVD and network. PMID- 10091085 TI - The ICN story--1899-1999. AB - Despite wars, political and economic chaos and racial and religious strife the International Council of Nurses (ICN) has been held together for 100 years by a "special glue" concocted by dedicated nurses. Its ingredients: friendship, collegial support and enthusiasm. Today ICN is still thriving, leading and representing nurses from all over the world. Below, a part of its fascinating history based on Nurses of all Nations: A History of the International Council of Nurses, 1899-1999 to be published this Spring by Lippincott Williams and Wilkins. PMID- 10091086 TI - Inventing international nursing: the first decade (1899-1910). AB - Below, a window is opened on some of the thoughts of ICN founders as they planned and worked at the turn of the 20th century and how they viewed themselves and nursing, based on a detailed written record of their first substantial discussions about broad nursing issues. PMID- 10091087 TI - 100 flying years and a challenging future. AB - Above, current ICN President Kirsten Stallknecht in 1967, when she was first becoming known in Denmark and a year before she became president of the Danish Nurses Organization, a post she held for 28 years. Below, she reflects on her 30 years of active involvement with ICN and international nursing and on her hopes for the future. PMID- 10091088 TI - The future is ours. PMID- 10091089 TI - Former ICN leaders look back and ahead. AB - INR asked former ICN presidents (Eunice Muringo Kiereini, Nelly Garzon, Mo-Im Kim and Margretta Madden Styles) and executive directors (Winifred Logan Gordon, Dame Sheila Quinn and Connie Holleran) to give their thoughts on ICN's past major achievements, the issues facing nursing today and tomorrow and what ICN's role should be in future. Below the questions and a summary of their response. PMID- 10091090 TI - Nursing at the turn of the century. PMID- 10091091 TI - Getting organized: the first seven. AB - What drove nurses to unite: it was lack of nursing education standards, deplorable work conditions, exploitation of nursing students as cheap sources of labour and the need for statutory registration. They believed that strength came with unity ... and they were right. PMID- 10091092 TI - Nursing: a new perspective. PMID- 10091093 TI - Christopher Reeve champions nursing as honorary patron for ICN centennial year. PMID- 10091094 TI - Margaret Hilson is first winner of the ICN achievement award. PMID- 10091095 TI - Natural history of hepatitis C. PMID- 10091096 TI - Histological and functional recovery in patients with multifocal atrophic gastritis after eradication of Helicobacter pylori infection. AB - BACKGROUND/AIMS: To assess the effect of Helicobacter pylori eradication on gastric histology and physiology in patients with multifocal atrophic gastritis over 1-year period. PATIENTS: Fourteen consecutive patients with histological evidence of chronic gastritis and Helicobacter pylori infection diagnosed by histology and serology entered this study. Patients with pernicious anaemia, gastric ulcer or carcinoma, duodenal ulcer, reflux oesophagitis and regular intake of nonsteroidal anti-inflammatory drugs were excluded. METHODS: Patients underwent triple anti-Helicobacter treatment for one week, which resulted successful in all subjects on the basis of negative CLO test and histology as well as 50% decrease in IgG antibodies after 4 weeks and 6 months of treatment, respectively. Histological and functional investigations were performed at baseline, 6 and 12 months after Helicobacter pylori eradication. Histological assessment of inflammatory cell infiltrates was performed on multiple biopsy specimens of the corpus and fundus. Functional tests were 24-hour continuous gastric pH-metry, fasting serum gastrin assay and pepsinogen I levels. RESULTS: There was a progressive significant improvement (p < 0.01-0.001) in acute and chronic inflammatory cell infiltrates in the gastric mucosa throughout the 12 month period. Functional recovery with increase in gastric acidity (p < 0.01) and decrease in gastrin and pepsinogen I levels (p < 0.001) was more evident at the 6 month than at the 12-month checkpoint after Helicobacter pylori eradication (p = NS for gastric pH and p < 0.02 for the other two variables) between 6 and 12 months. CONCLUSIONS: Eradication of Helicobacter pylori infection significantly improves the inflammatory status of oxyntic mucosa and this promotes an almost complete functional recovery. However, the non-parallel behaviour of gastric acidity, which was maximal at 6-month checkpoint, and histological parameters which continued to improve throughout the entire 12-month observation period, seems to indicate that removal of acid-inhibitory substances induced by Helicobacter pylori infection was also responsible for the more rapid recovery of gastric secretory function. PMID- 10091097 TI - Recovery after Helicobacter pylori eradication: how long does it take? PMID- 10091098 TI - Epidemiology of cancer of the large bowel--the 12-year experience of a specialized registry in northern Italy. AB - BACKGROUND: In 1984, a specialized colorectal cancer registry was instituted in Modena; aims of the Registry were: the evaluation of incidence and mortality, the study of morphological aspects, staging, survival and familiarity of the registered patients. AIMS: Purpose of the research was to provide an updated description of the main findings (in particular, incidence, staging, morphology and survival) observed in the 12-year registration period. PATIENTS AND METHODS: Between January 1984 and December 1995, 1,899 malignancies of the large bowel in 1,831 patients were registered. Tumours were classified according to the International Classification of the Diseases for Oncology (ICDO) and staged with the TNM system. Cancer specific survival was assessed with life table analysis and Log-Rank tests. RESULTS: Crude incidence rate showed minor fluctuations between 1984 and 1989, but tended to rise in the following years. Tumours were mostly located distal to the splenic flexure (73.3% of the total), with a slight tendency over time to a gradual "shift" to the right colon. Staging became progressively more favourable throughout the registration; in 1984 both stages I, II and stage IV + unstaged lesions represented 40% of the total, but in 1995 the former rose to 50% whereas the latter fell to 21.6% (p < 0.001). This move to earlier stages resulted in an improved survival of patients registered in 1990-91 versus 1984-85 (Log-Rank 14.3 p < 0.002). Factors associated with a poor survival were the advanced age of patients at diagnosis (> 74) and clinical stage. PMID- 10091099 TI - Registries and the prevention of colorectal cancer. PMID- 10091100 TI - Single dose of octreotide stabilize metastatic gastro-entero-pancreatic endocrine tumours. AB - BACKGROUND AND AIM: Somatostatin analogues are able to control symptoms and to detect tumour localisation in gastro-entero-pancreatic endocrine tumour patients. Few studies have evaluated the efficacy of somatostatin analogues in controlling tumoural growth during long-term treatment and, generally, a low efficacy has been reported in studies using multiple daily octreotide dosages. In the present study a single daily dose of octreotide (500 micrograms) for 1 year was used in the treatment of 10 patients with progressive gastro-entero-pancreatic metastatic tumour. PATIENTS: Ten consecutive patients (3 females, 7 males age range 40-62 years) were studied of whom 4 had Zollinger-Ellison syndrome (2 with MEN-1), 3 had a carcinoid syndrome, and 3 had a non-functional neuro-endocrine tumour. All patients, 6-12 months before octreotide treatment, showed tumour progression. In all patients, somatostatin receptor status was assessed by Somatostatin Receptor Scintigraphy and tumoural lesions by Magnetic Resonance Imaging. Appropriate tumoural markers were also evaluated. RESULTS: At the three-month control, two patients (non-functional) showed an aggressive progression of tumoural growth despite treatment and were excluded from the study. One patient was lost during follow-up. Of the 7 remaining patients, imaging evaluation studies revealed, after 1 year of treatment, stable disease in 6 patients, whereas a partial tumoural response was observed in one patient (gastrinoma). Biochemical tumoural markers decreased with respect to basal values of 53-78% in these seven patients at the end of therapy. CONCLUSIONS: These results suggest that one year of octreotide in a single daily dose (500 micrograms) is effective in the long-term stabilization of tumoural progression in metastatic gastro-entero-pancreatic tumour patients. PMID- 10091101 TI - Natural history of chronic hepatitis C. AB - BACKGROUND AND AIMS: A comprehensive overview on the course of hepatitis C is not available despite the many studies published. The aim was to review the course and prognostic variables of untreated hepatitis C. METHODS: English-language articles published between January 1989 and December 1997 were identified and data extracted to answer predefined relevant questions. RESULTS: Median chronicization rate, mostly assessed in transfusion-associated hepatitis, was 67%. In retrospective studies, the interval between date of infection and diagnosis of cirrhosis or hepatocellular carcinoma was 20-40 years. Median progression rate from chronic hepatitis to cirrhosis was 27.9% after 8-12 years. Studies obtaining this figure included selected groups of patients and could reflect the worst prognostic segment of the disease. The course of hepatitis C virus infection may be more favourable: cirrhosis rarely or never occurred in young females infected by con-taminated anti-D-immunglobulins; hepatitis was histologically mild in most hepatitis C virus-RNA positive subjects with normal or near normal transminases, predicting non-progressive or very slowly progressive disease; in a population survey from Italy, among 170 infected subjects only 4% had raised transaminases, and none overt liver disease. Increasing age, histological severity, alcohol, possibly male sex and liver iron content were predictors of cirrhosis or increased fibrosis. CONCLUSIONS: Chronicization rate of hepatitis C virus infection is very high. Hepatitis C virus infection can result in a wide prognostic spectrum of liver disease, ranging from cirrhosis and hepatocellular carcinoma to subclinical, nonprogressive disease. Cofactors such as alcohol excess are important in determining the outcome of hepatitis C virus-related chronic liver disease. PMID- 10091102 TI - Cryoglobulinaemic membranoproliferative glomerulonephritis and hepatitis C virus infection. AB - BACKGROUND/AIM: A striking correlation between mixed cryoglobulinaemia and chronic hepatitis C virus infection has recently been described. Since membrano proliferative glomerulonephritis is a rare complication of mixed cryoglobulinaemia, this study was undertaken to determine the prevalence of Hepatitis C virus infection in membrano-proliferative glomerulonephritis. PATIENTS: Eighteen patients, selected among a group of 121 affected by mixed cryoglobulinaemia, with renal involvement were included in the present study. A group of 148 patients affected by renal disease of different aetiology and the general population (6,917 people) were used as control groups. METHODS: The presence of anti-hepatitis C virus antibodies was determined by a commercial kit. The hepatitis C virus genotype was determined according to Okamoto. All patients underwent kidney and bone marrow biopsy, while the hepatic biopsy was performed in those showing signs of chronic liver disease. RESULTS: In patients with renal involvement, the kidney biopsy showed the presence of membrano-proliferative glomerulonephritis Type I in all cases. Chronic liver disease was present in eleven patients (61%). All patients were positive for serum hepatitis C virus RNA. Bone marrow biopsy was normal in five cases, while in the others paratrabecular foci of infiltration by small lymphocytes were present. In six of these, the massive bone marrow infiltration by lymphoplas-macytoid lymphocytes suggested the diagnosis of low grade non-Hodgkin's lymphoma. In the group of patients affected by other chronic renal disease, the prevalence of hepatitis C virus infection (3.1%) was not different from that of the general population (3.2%). CONCLUSIONS: Hepatitis C virus seems to be the aetiologic agent of mixed cryoglobulinaemia and, consequently, of membrano-proliferative glomerulonephritis. PMID- 10091103 TI - HCV infection, cryoglobulinaemia, membranoproliferative glomerulonephritis and low grade non-Hodgkin lymphoma. PMID- 10091104 TI - Tumour necrosis factor alpha and cellular proliferation in primary biliary cirrhosis. AB - AIMS: 1) To evaluate serum levels and tissue expression of Tumour necrosis factor alpha in primary biliary cirrhosis: 2) to correlate serum tumour necrosis factor alpha levels and cellular proliferation with the severity and prognosis of liver disease. METHODS: Twenty-nine primary biliary cirrhosis patients (6 stage I, 8 II, 8 III, and 7 IV) entered the study. Serum tumour necrosis factor alpha was measured by EIA (Innogenetics, Antwerp, Belgium). Tissue tumour necrosis factor alpha and Ki-67 were tested by indirect immunoperoxidase staining on liver sections. RESULTS: Serum tumour necrosis factor alpha increased with the severity of histological stage (from 10.8 +/- 11 pg/ml in stage II to 17.1 +/- 10 in stage III and 22.8 +/- 8.7 in stage IV, p < 0.036). A positive correlation was also found between tumour necrosis factor alpha serum levels and the Mayo score (p < 0.05). A weak and sporadic expression of tumour necrosis factor alpha was observed in the inflammatory infiltrate around the bile ducts. Tissue Ki-67 (expressed as the labelling index in the hepatocellular nuclei) was evaluated in all stages of the disease (1.09 +/- 0.6% in stage I, 1.14 +/- 0.6% in stage II, 2.11 +/- 1.9% in stage III, and 2.67 +/- 2.8% in stage IV; the labelling index was significantly lower in early stages (I/II) than in late stages (III/IV), p < 0.05. A strong correlation between Ki-67 and the Mayo score was observed (p < 0.0005). CONCLUSIONS: 1) tumour necrosis factor alpha production seems related to the severity and the prognosis of primary biliary cirrhosis; 2) liver mononuclear cells in the inflammatory infiltrate do not seem to be the major site of tumour necrosis factor alpha release; 3) cellular proliferation is correlated with the severity of liver disease. PMID- 10091105 TI - May plasma cholesterol level be considered a neoplastic marker in liver disease from cirrhosis to hepatocellular carcinoma? AB - BACKGROUND: Although the role of cholesterol in tumourigenesis is unclear, it is used by the tumoural cells for biosynthetic processes and for steroid synthesis. AIM: To accertain whether plasma cholesterol levels might be a reliable neoplastic marker of a developing hepatocellular carcinoma in patients with liver cirrhosis. PATIENTS: Plasma cholesterol has been studied in 287 liver cirrhosis patients without hepatocellular carcinoma and in 132 patients with hepatocellular carcinoma. RESULTS: Cholesterol (mean +/- SEM) was higher in hepatocellular carcinoma patients when compared with age-, sex- and Child-Pugh class matched cirrhotic controls. In Child-Pugh class A, B and C with uncomplicated liver cirrhosis these values were, respectively, 142.0 +/- 2.5, 117.3 +/- 2.5, 97.4 +/- 2.9 vs 172.5 +/- 4.7, 163.8 +/- 7.9, 153.5 +/- 8.0 +/- mg/dl in patients with hepatocellular carcinoma (p < 0.001). A significant increase of cholesterol (p < 0.001) has been reported in the patients with liver cirrhosis when complicated by hepatocellular carcinoma and it was not related to cholestasis. CONCLUSIONS: This observation seems to suggest that the enhanced cholesterol biosynthesis by tumoural cells leads to a rise in plasma cholesterol of patients with cancer, and, moreover, that, this increase may be used as a neoplastic marker indicating the development of a tumour in patients with liver cirrhosis. PMID- 10091106 TI - Exacerbation of chronic hepatitis D during interferon alpha administration. AB - Acute and severe impairment of liver function with jaundice and ascites occurred in two out of seven patients with chronic hepatitis D during interferon alpha administration (10 MU three times a week). Both of them were young women with histological diagnoses of moderate to severe chronic hepatitis and cirrhosis with no signs of portal hypertension. Only a slow and partial recovery was observed after interferon withdrawal. Autoantibodies against basal cell layer tested positive in these two patients. In the remaining five patients with hepatitis D who did not experience liver impairment during interferon administration, basal cell layer antibodies were found only in one case. We conclude that severe decompensation of liver cirrhosis related to hepatitis D may occur during interferon administration. Positivity of basal cell layer antibodies may be associated with the risk of developing such an adverse event but our data are not sufficient to prove this association. PMID- 10091107 TI - Detection of Tropheryma whippelii DNA (Whipple's disease) in faeces. AB - To date the diagnosis of Whipple's disease is based mainly on the histopathological analysis of duodenal biopsies since Tropheryma whippelii cannot be cultured in vitro. We investigated the possibility to diagnose Whipple's disease by detection of bacterial DNA in faces. Nested polymerase chain reaction with amplification of part of the 16S rRNA gene of this bacterium in DNA extracted from faeces of a patient with Whipple's disease was performed. Sequencing of the polymerase chain reaction product revealed the sequence of Tropheryma whippelii. We conclude that Whipple's disease will be able to be diagnosed non-invasively by DNA analysis from the faeces as soon as more specific sequences of this bacteria are known. PMID- 10091108 TI - Liver and apoptosis. AB - Apoptosis is an energy-requiring mechanism of cell death which is a physiological event in organ morphogenesis, clone selection of lymphoid cells and cell turnover, but also occurs in many pathological conditions. It is under genetic control, bcl-2 being the major apoptosis suppressing gene, while p53 and c-myc are apoptosis promoting genes. Other factors, such as the Fas/Fas1 system, the caspases cascade, cytokines and enzymes also play a role in determining apoptosis. The term apoptosis was introduced by Kerr to describe this type of death in ischaemic rat liver, and the same Councilman bodies are now considered an example of apoptotic death. Virus-infected hepatocytes bear Fas receptors and apoptosis is induced by binding to the Fas ligand which is expressed by activated T cells; this action is probably mediated by enzymes of the caspase family and/or by granzyme B. The Fas/Fas1 system is also involved in apoptosis occurring in chronic non suppurative destructive cholangitis, in transplant rejection and in other liver diseases, including neoplasms; in the latter Bcl-2 protein and mutations of p53 also seem to play an important role. Cytokines are also frequently involved. Toxins like alcohol probably induce apoptosis by producing active oxidants. Whether aging enhances apopstosis in liver is still controversial. Although many molecular mechanisms have been suggested to be involved the switch on/off of apoptosis is still poorly understood and will be a matter of further investigations. PMID- 10091109 TI - Biliary epithelium: a new chapter in cell biology. AB - The intrahepatic biliary epithelium lines the biliary tree from the duct of Hering to the extrahepatic bile ducts. Until the early '90's, the biliary tree was considered to play only a mechanic role in transporting bile into the duodenum. In the last few years, a number of experimental models have generated a bulk of new knowledge showing how the biliary epithelium displays extraordinary properties in term of secretion, absorption, proliferation and signalling toward the other liver parenchymal and mesenchymal cells. It is now clearly emerging that the functions of biliary epithelium are tightly regulated by a number of hormones and neuropeptities. This heralds a number of nonvelities not only from a physiolgic point of view but also in terms of pathology and pharmacological management of the diseases targeting the intrahepatic biliary epithelium. The aim of this manuscript is to revise recent knowledge on cell biology of the biliary epithelium. PMID- 10091110 TI - High prevalence of HBV infection markers in refugees from eastern countries. PMID- 10091111 TI - Severe hepatitis in a HIV-positive subject under treatment with protease inhibitor. PMID- 10091112 TI - Endometrial evaluation is not predictive for in vitro fertilization treatment. AB - PURPOSE: The main purpose of this study was to evaluate ovarian function by clomiphene citrate (CC) challenge test in a group of tubal infertile women and to study endometrial morphological maturation in the early luteal phase of CC stimulated cycles as compared to in vitro fertilization (IVF) treatment outcome. METHODS AND RESULTS: Four women presented with strongly retarded, proliferative endometrium in the luteal phase. Of these, three presented with impaired ovarian function, high basal follicle-stimulating hormone, and high follicle-stimulating hormone levels after clomiphene stimulation on cycle day 10. In the remaining 30 women, showing an in-phase endometrium after CC stimulation, a comparison of six morphological characteristics did not reveal any significant differences between the 14 women who did become pregnant and the 16 who did not. No significant differences in endometrial thickness were observed between the groups. Significant differences were found when comparing estradiol and progesterone area under the curve during the luteal phase (P < 0.001 and P < 0.01, respectively) between those who did and those who did not become pregnant. CONCLUSIONS: Luteal endometrium morphology was not a sharp instrument to detect differences between women who did and women who did not become pregnant following IVF treatment, while ovarian function, as measured by hormonal markers, seemed to be a more reliable prognostic factor for IVF treatment outcome. PMID- 10091113 TI - Serum progesterone in predicting pregnancy outcome after assisted reproductive technology. AB - PURPOSE: Our purpose was to determine whether serum progesterone predicts pregnancy outcome after superovulation. METHODS: One hundred twenty-three consecutively pregnant patients were divided into three groups: group I, 55 patients following superovulation for assisted reproductive technologies; group II, 23 patients after correction of oligoovulation; and group III, 45 patients who conceived spontaneously. When beta-human chorionic gonadotropin was positive, progesterone was measured on the same serum sample. A serum progesterone level of 45 microns/L was set to differentiate between nonviable pregnancy and ongoing pregnancy. RESULTS: In group I, zero (0%) of 38 ongoing pregnancies and 10 (59%) of 17 nonviable pregnancies were observed with a progesterone level of < 45 microns/L [14.2 ng/ml (P < 0.001)]. In group II, 4 (27%) of 15 ongoing pregnancies and 5 (63%) of 8 nonviable pregnancies had a progesterone level of < 45 microns/L (P = NS). In group III, 10 (42%) of 24 ongoing pregnancies and 15 (71%) of 21 nonviable pregnancies were observed with a progesterone level of < 45 microns/L (14.2 ng/ml) (P = NS). CONCLUSIONS: A serum progesterone level of < 45 nM predicts nonviable pregnancy after superovulation for assisted reproductive technology. PMID- 10091114 TI - Autologous endometrial co-culture in patients with repeated failures of implantation after in vitro fertilization-embryo transfer. AB - PURPOSE: Our purpose was to evaluate the effect of coculture on preembryo development and clinical outcome. METHODS: Enrolled patients underwent a luteal phase endometrial biopsy. The tissue was then enzymatically digested (collagenase) and the stromal and glandular cells were separated by differential sedimentation rates. These cells were cultured to confluence, released, and then cryopreserved until the patient's in vitro fertilization (IVF)-embryo transfer (ET) cycle. All normally fertilized oocytes were then placed on the co-cultured cells until transfer on day 3. Preembryo development on co-culture was compared to that in the patient's noncocultured previous cycle. Implantation and clinical pregnancy rates were compared to those in a control group of patients undergoing IVF during the study period who were matched for age, stimulation protocol, number of oocytes retrieved, and preembryos transferred. RESULTS: Twenty-nine women underwent 31 cycles of IVF-ET. On day 3 the overall mean number of blastomeres per preembryo on co-culture compared to that in the patient's previous cycle was 6.3 +/- 1.8 vs. 5.6 +/- 1.2 (P = 0.04). The average percentage of cytoplasmic fragments on co-culture compared to the previous cycle was 16 +/- 9% vs. 19 +/- 9% (P = 0.32). At transfer, after preembryo selection, the mean number of blastomeres per preembryo on co-culture compared to that in the patient's previous cycle was 6.8 +/- 1.6 vs. 6.6 +/- 1.3 (P = 0.5). The implantation and clinical pregnancy rates between co-culture and the matched control group were 15% (14/93) vs. 13% (16/124) (P = 0.79) and 29% (9/31) vs. 25% (10/40) (P = 0.45). CONCLUSIONS: There was a significant improvement in the average number of blastomeres per preembryo on co-culture compared to that in the patient's previous noncoculture cycle. The overall implantation and clinical pregnancy rates between co-culture and a matched control group were not significantly different. PMID- 10091115 TI - Destruction of protamine in human sperm inhibits sperm binding and penetration in the zona-free hamster penetration test but increases sperm head decondensation and male pronuclear formation in the hamster-ICSI assay. AB - PURPOSE: Our purpose was to investigate the fertilizing ability of human protamine-damaged sperm in a heterologous system using hamster oocytes. METHODS: The protamine of the sperm were damaged by exposure to dithiothreitol, a disulfide-reducing agent. Their ability to penetrate and form male pronuclei were investigated using the zona-free hamster penetration test and the hamster intracytoplasmic sperm injection assay, respectively. RESULTS: The zona-free hamster penetration test revealed that protamine-damaged sperm are unable to bind and penetrate the hamster oocyte. On the other hand, hamster-intracytoplasmic sperm injection assay results showed that 56.9% and 39.2% of the injected oocytes developed male pronuclei in protamine-damaged and live-intact sperm groups, respectively, with a significant difference in these rates (P < 0.01). CONCLUSIONS: This study shows that protamine-damaged sperm are able to undergo sperm head decondensation and male pronuclear formation only when injected into the ooplasm, although they cannot bind and penetrate through the zona and enter the ooplasm. PMID- 10091116 TI - Visualization of chromosomes in single human blastomeres. PMID- 10091117 TI - Scoring functions: a view from the bench. AB - Computational approaches to drug design are presently hindered by the complexity of the physical chemistry which underlies weak, non-covalent interactions between protein targets and small molecule ligands. Although a number of programs are now available for the design of novel potential ligands, it remains a key problem to rank these rapidly and reliably by estimated binding affinity. Such a step is necessary to select only the most promising candidates for synthesis and experimental characterisation. To calculate ligand affinity quickly and reliably is an extremely difficult problem, but it may well prove possible to estimate sufficiently accurately given an appropriate set of parameters to 'score' individual protein-ligand interactions. Improvements in the situation will require a wider set of thermodynamically characterised systems than is currently available. PMID- 10091118 TI - Predicting relative binding affinities of non-peptide HIV protease inhibitors with free energy perturbation calculations. AB - The relative binding free energies in HIV protease of haloperidol thioketal (THK) and three of its derivatives were examined with free energy calculations. THK is a weak inhibitor (IC50 = 15 microM) for which two cocrystal structures with HIV type 1 proteases have been solved [Rutenber, E. et al., J. Biol. Chem., 268 (1993) 15343]. A THK derivative with a phenyl group on C2 of the piperidine ring was expected to be a poor inhibitor based on experiments with haloperidol ketal and its 2-phenyl derivative (Caldera, P., personal communication). Our calculations predict that a 5-phenyl THK derivative, suggested based on examination of the crystal structure, will bind significantly better than THK. Although there are large error bars as estimated from hysteresis, the calculations predict that the 5-phenyl substituent is clearly favored over the 2 phenyl derivative as well as the parent compound. The unfavorable free energies of solvation of both phenyl THK derivatives relative to the parent compound contributed to their predicted binding free energies. In a third simulation, the change in binding free energy for 5-benzyl THK relative to THK was calculated. Although this derivative has a lower free energy in the protein, its decreased free energy of solvation increases the predicted delta delta G (bind) to the same range as that of the 2-phenyl derivative. PMID- 10091120 TI - Fractional description of free energies of solvation. AB - A new and rigorous method for the fractional description of solvation and transfer free energies is presented. The method is based on the use of the Miertus-Scrocco-Tomasi self-consistent reaction field method (MST-SCRF), and allows for a rigorous partition of the total solvation free energy into surface elements. The method gives a complete picture of the hydrophobicity/hydrophilicity of molecules. Present results allow us to expect that the method might provide useful information in drug design and molecular modeling studies. PMID- 10091119 TI - Major versus minor groove DNA binding of a bisarginylporphyrin hybrid molecule: a molecular mechanics investigation. AB - On the basis of theoretical computations, we have recently synthesised [Perree Fauvet, M. and Gresh, N., Tetrahedron Lett., 36 (1995) 4227] a bisarginyl conjugate of a tricationic porphyrin (BAP), designed to target, in the major groove of DNA, the d(GGC GCC)2 sequence which is part of the primary binding site of the HIV-1 retrovirus site [Wain-Hobson, S. et al., Cell, 40 (1985) 9]. In the theoretical model, the chromophore intercalates at the central d(CpG)2 step and each of the arginyl arms targets O6/N7 belonging to guanine bases flanking the intercalation site. Recent IR and UV-visible spectroscopic studies have confirmed the essential features of these theoretical predictions [Mohammadi, S. et al., Biochemistry, 37 (1998) 6165]. In the present study, we compare the energies of competing intercalation modes of BAP to several double-stranded oligonucleotides, according to whether one, two or three N-methylpyridinium rings project into the major groove. Correspondingly, three minor groove binding modes were considered, the arginyl arms now targeting N3, O2 sites belonging to the purine or pyrimidine bases flanking the intercalation site. This investigation has shown that: (i) in both the major and minor grooves, the best-bound complexes have the three N methylpyridinium rings in the groove opposite to that of the phenyl group bearing the arginyl arms; (ii) major groove binding is preferred over minor groove binding by a significant energy (29 kcal/mol); and (iii) the best-bound sequence in the major groove is d(GGC GCC)2 with two successive guanines upstream from the intercalation. On the other hand, due to the flexibility of the arginyl arms, other GC-rich sequences have close binding energies, two of them being less stable than it by less than 8 kcal/mol. These results serve as the basis for the design of derivatives of BAP with enhanced sequence selectivities in the major groove. PMID- 10091121 TI - Ab initio calculations on peptide-derived oxazoles and thiazoles: improved molecular mechanics parameters for the AMBER force field. AB - Ab initio calculations at the RHF/6-31G* and MP2/6-31G*//RHF/6-31G* levels of theory are performed for 2-methyl-4-carboxamido-oxazoles and -thiazoles, including rotational profiles for the ring-carboxamide bond, which showed the expected conjugation and hydrogen bonding effects. On the basis of these data, newly optimised stretch, bend and torsional parameters for the AMBER* force field are derived, along with CHELPG-fitted partial atomic charges. PMID- 10091122 TI - Comparison of two implementations of the incremental construction algorithm in flexible docking of thrombin inhibitors. AB - A set of 32 known thrombin inhibitors representing different chemical classes has been used to evaluate the performance of two implementations of incremental construction algorithms for flexible molecular docking: DOCK 4.0 and FlexX 1.5. Both docking tools are able to dock 10-35% of our test set within 2 A of their known, bound conformations using default sampling and scoring parameters. Although flexible docking with DOCK or FlexX is not able to reconstruct all native complexes, it does offer a significant improvement over rigid body docking of single, rule-based conformations, which is still often used for docking of large databases. Docking of sets of multiple conformers of each inhibitor, obtained with a novel protocol for diverse conformer generation and selection, yielded results comparable to those obtained by flexible docking. Chemical scoring, which is an empirically modified force field scoring method implemented in DOCK 4.0, outperforms both interaction energy scoring by DOCK and the Bohm scoring function used by FlexX in rigid and flexible docking of thrombin inhibitors. Our results indicate that for reliable docking of flexible ligands the selection of anchor fragments, conformational sampling and currently available scoring methods still require improvement. PMID- 10091123 TI - An extensive ecdysteroid CoMFA. AB - The ecdysteroid agonist activity of 71 HPLC-purified ecdysteroids was measured in the Drosophila melanogaster BII tumorous blood cell line assay. The resultant log(ED50) values, spanning almost 6 orders of magnitude, were used to construct a comparative molecular field analysis (CoMFA) model in which conformations were selected by homology to the crystal structure of ecdysone. Model A was constructed by utilization of the region-focused electrostatic indicator field (q2 = 0.631, r2 = 0.903, 5 components, 4 outliers). Model B made use of region focused electrostatic and steric indicator fields along with MlogP (q2 = 0.694, r2 = 0.892, 5 components, 4 outliers). The model and its underlying bioassay data support a pharmacophore hypothesis in which ecdysteroid binding is understood to be due principally to the summation of localized interactions from approximately six specific loci. This is in contrast to previous structure-activity relationship hypotheses which are formulated in terms of the presence or absence of essential functional groups, without which ecdysteroid receptor affinity would be completely absent. The present CoMFA model is utilized to predict the activities of heretofore unknown ecdysteroids. PMID- 10091124 TI - History of USDA poisonous plant research. AB - Research on poisonous plants was instituted by the United States Department of Agriculture (USDA) as a result of serious livestock poisoning by plants as the pioneers moved west in the mid-to-late 1800s and early 1900s. Historical records indicate the USDA began poisonous plant research in 1894 under the direction of Mr. V. K. Chestnut, a botanist (Table 1 briefly summarizes those who have directed poisonous plant research from the inception to the present). Mr. Chestnut's responsibility (1894-1904) was primarily administrative, although he did extensive field work in Washington and Montana. Temporary field stations were set up to study specific poisonous plant problems. These included field stations at Hugo and Woodland Park, Colorado, and Imperial, Nebraska (1905-1909), to study locoweed; Gunnison, Colorado (1910-1912), to primarily study larkspur; and Greycliff, Montana (1912-1915), to study the poisonous plants of the Yellowstone Valley. Dr. Rodney True replaced Mr. Chestnut in 1904 and in 1905 hired Dr. C. D. Marsh (1905-1930) to establish the temporary field stations listed above. In 1915 a permanent facility was established at Salina, Utah, under the direction of C. D. Marsh who remained in charge until 1930 when he retired; he was followed by A. B. Clawson until 1937 when Dr. Ward Huffman was placed in charge. Research on poisonous plants was located at the Salina Experiment Station until 1955 when the station was closed and the laboratory moved to the campus of Utah State Agricultural College at Logan, Utah, where it is currently located. Dr. Wayne Binns was hired as the director of the laboratory in 1954 and retired in 1972. In 1972 Dr. Lynn F. James, who joined the PRPL staff in July 1957, was appointed as Research Leader and presently directs the research at the Poisonous Plant Research Laboratory. PMID- 10091125 TI - Ponderosa pine and broom snakeweed: poisonous plants that affect livestock. AB - Ponderosa pine (Pinus ponderosa) and the snakeweeds (Gutierrezia sarothrae and G. microcephala) are two groups of range plants that are poisonous to livestock. Ponderosa pine causes late-term abortions in cattle, and the snakeweeds are toxic and also cause abortions in cattle, sheep, and goats. Research is underway at the USDA-ARS-Poisonous Plants Research Laboratory to better understand livestock poisonings caused by grazing ponderosa pine needles and the snakeweeds and to provide methods of reducing losses to the livestock and supporting industries. This review includes the history of the problem, a brief description of the signs of poisoning, the research, to identify the chemical toxins, and current management practices on prevention of poisonings. PMID- 10091126 TI - The pathogenesis and toxicokinetics of locoweed (Astragalus and Oxytropis spp.) poisoning in livestock. AB - Locoweed poisoning is a chronic disease that develops in livestock grazing for several weeks on certain Astragalus and Oxytropis spp. that contain the locoweed toxin, swainsonine. The purpose of this review is to present recent research on swainsonine toxicokinetics and locoweed-induced clinical and histologic lesions. Swainsonine inhibits cellular mannosidases resulting in lysosomal storage disease similar to genetic mannosidosis. Diagnosis of clinical poisoning is generally made by documenting exposure, identifying the neurologic signs, and analyzing serum for alpha-mannosidase activity and swainsonine. All tissues of poisoned animals contained swainsonine, and the clearance rates from most tissues was about 20 hours (T1/2 half life). The liver and kidney had longer rate of about 60 hours (T1/2). This suggests that poisoned animals should be allowed a 28-day withdrawal to insure complete swainsonine clearance. Poisoning results in vacuolation of most tissues that is most obvious in neurons and epithelial cells. Most of these histologic lesions resolved shortly after poisoning is discontinued; however, some neurologic changes are irreversible and permanent. PMID- 10091127 TI - Locoweed grazing. AB - Locoweed is the most widespread poisonous plant problem in the western U. S. Eleven species of Astragalus and Oxytropis (and many varieties within these species) cause locoism. Many locoweed species are endemic and are restricted to a narrow niche or habitat. Other locoweed species experience extreme population cycles; the population explodes in wet years and dies off in drought. A few species, such as O. sericea, are relatively stable and cause persistent poisoning problems. Knowledge of where locoweeds grow and the environmental conditions when they become a threat is important to manage livestock and avoid poisoning. Locoweeds are relatively palatable. Many locoweeds are the first plants to begin growth in the spring and regrow in the fall. Livestock generally prefer the green growing locoweeds to other forage that is dormant in the late fall, winter, and spring. The most effective management strategy is to deny livestock access to locoweeds during critical periods when they are more palatable than the associated forage. Herbicides can control existing locoweed populations and provide "safe" pastures for critical periods. However, locoweed seed in soil will germinate and re-establish when environmental condition are favorable. Good range management and wise grazing strategies can provide adequate forage for livestock and prevent them from grazing locoweed during non-critical periods of the year when it is relatively less palatable than associated forages. PMID- 10091128 TI - Locoweeds: effects on reproduction in livestock. AB - Locoweeds (species of Oxytropis and Astragalus containing the toxin swainsonine) cause severe adverse effects on reproductive function in livestock. All aspects of reproduction can be affected: mating behavior and libido in males; estrus in females; abortion/embryonic loss of the fetus; and behavioral retardation of offspring. While much research has been done to describe and histologically characterize these effects, we have only begun to understand the magnitude of the problem, to define the mechanisms involved, or to develop strategies to prevent losses. Recent research has described the effects of locoweed ingestion in cycling cows and ewes. Briefly, feeding trials with locoweeds in cycling and pregnant cows have demonstrated ovarian dysfunction in a dose-dependent pattern, delayed estrus, extended estrous cycle length during the follicular and luteal phases, delayed conception (repeat breeders), and hydrops and abortion. Similar effects were observed in sheep. In rams, locoweed consumption altered breeding behavior, changed libido, and inhibited normal spermatogenesis. Neurological dysfunction also inhibited normal reproductive behavior, and some of these effects were permanent and progressive. In this article we briefly review the pathophysiological effects of locoweeds on reproduction. PMID- 10091129 TI - Teratological research at the USDA-ARS poisonous plant research laboratory. AB - Research on teratogenic plants started at the USDA-Agricultural Research Service Poisonous Plant Research Laboratory in the mid 1950s when Dr. Wayne Binns, Director of the laboratory, was asked to investigate the cause of a cyclopian facial/skeletal birth defect in lambs. Dr. Lynn F. James joined the staff shortly after. These two people worked as a team wherein most planning was done jointly with Binns supervising most of the laboratory work and James the field studies. It was determined that when pregnant ewes grazed Veratrum californicum on day 14 of gestation a significant number of lambs had the cyclopic defect. Skeletal and cleft palate birth defects in calves was associated with pregnant cows grazing certain lupine species during 40-70 days of gestation. Shortly thereafter research work was initiated on locoweed which caused abortions, wasting, right heart failure, skeletal birth defects, and fetal right heart failure. Dr. Richard F. Keeler, a chemist who joined the staff in the early 1960s, isolated and characterized the teratogens in V. californicum as the steroidal alkaloids cyclopamine, jervine, and cycloposine. He also described the teratogen in lupines as the quinolizidine alkaloid anagyrine and the piperidine alkaloid ammodendrine. Drs. Russell Molyneux and James identified the toxin in locoweed as the indolizidine alkaloid swainsonine. In 1974 the editor of Nutrition Today (Vols. 9 and 4) wrote "The idea that birth defects occurring in humans may be in some way related to diet is not widely held ..." Dr. Lynn James pointed out in this issue that such defects in animals can be produced with absolute predictability and regularity by foods ordinarily beneficial to livestock. Management strategies have been developed to prevent or minimize the economic impact of the cyclopian lamb and the crooked calf condition on livestock producers and well on the way to doing the same with locoweed. It is of interest to note that livestock research on Veratrum, lupines and locoweed and toxins therefrom are now significant research tools for specific human health problems. PMID- 10091130 TI - Larkspur (Delphinium spp.) poisoning in livestock. AB - Larkspurs (Delphinium spp.) are toxic plants that contain numerous diterpenoid alkaloids which occur as one of two structural types: (1) lycotonine, and (2) 7,8 methylenedioxylycoctonine (MDL-type). Among the lycoctonine type alkaloids are three N-(methylsuccinimido) anthranoyllycoctonine (MSAL-type) alkaloids which appear to be most toxic: methyllycaconitine (MLA), 14-deacetylnudicauline (DAN), and nudicauline. An ester function at C-18 is an important structural requirement for toxicity. Intoxication results from neuromuscular paralysis, as nicotinic acetylcholine receptors in the muscle and brain are blocked by toxic alkaloids. Clinical signs include labored breathing, rapid and irregular heartbeat, muscular weakness, and collapse. Toxic alkaloid concentration generally declines in tall larkspurs with maturation, but alkaloid concentration varies over years and from plant to plant, and is of little use for predicting consumption by cattle. Knowledge of toxic alkaloid concentration is valuable for management purposes when cattle begin to eat larkspur. Cattle generally begin consuming tall larkspur after flowering racemes are elongated, and consumption increases as larkspur matures. Weather is also a major factor in cattle consumption, as cattle tend to eat more larkspur during or just after summer storms. Management options that may be useful for livestock producers include conditioning cattle to avoid larkspur (food aversion learning), grazing tall larkspur ranges before flowering (early grazing) and after seed shatter (late grazing), grazing sheep before cattle, herbicidal control of larkspur plants, and drug therapy for intoxicated animals. Some potentially fruitful research avenues include examining alkaloid chemistry in low and plains larkspurs, developing immunologic methods for analyzing larkspur alkaloids, developing drug therapy, and devising grazing regimes specifically for low and plains larkspur. PMID- 10091131 TI - Pyrrolizidine alkaloid plants, metabolism and toxicity. AB - More than 350 PAs have been identified in over 6,000 plants in the Boraginaceae, Compositae, and Leguminosae families (Table 1). About half of the identified PAs are toxic and several have been shown to be carcinogenic in rodents. PA containing plants have worldwide distribution, and they probably are the most common poisonous plants affecting livestock, wildlife, and humans. In many locations, PA-containing plants are introduced species that are considered invasive, noxious weeds. Both native and introduced PA-containing plants often infest open ranges and fields, replacing nutritious plants. Many are not palatable and livestock avoid eating them if other forages are available. However, as they invade fields or crops, plant parts or seeds can contaminate prepared feeds and grains which are then readily eaten by many animals. Human poisonings most often are a result of food contamination or when PA-containing plants areused for medicinal purposes. This is a review of current information on the diagnosis, pathogenesis, and molecular mechanisms of PA toxicity. Additional discussion includes current and future research objectives with an emphasis on the development of better diagnostics, pyrrole kinetics, and the effects of low dose PA exposure. PMID- 10091132 TI - Lupines, poison-hemlock and Nicotiana spp: toxicity and teratogenicity in livestock. AB - Many species of lupines contain quinolizidine or piperidine alkaloids known to be toxic or teratogenic to livestock. Poison-hemlock (Conium maculatum) and Nicotiana spp. including N. tabacum and N. glauca contain toxic and teratogenic piperidine alkaloids. The toxic and teratogenic effects from these plant species have distinct similarities including maternal muscular weakness and ataxia and fetal contracture-type skeletal defects and cleft palate. It is believed that the mechanism of action of the piperidine and quinolizidine alkaloid-induced teratogenesis is the same; however, there are some differences in incidence, susceptible gestational periods, and severity between livestock species. Wildlife species have also been poisoned after eating poison-hemlock but no terata have been reported. The most widespread problem for livestock producers in recent times has been lupine-induced "crooked calf disease." Crooked calf disease is characterized as skeletal contracture-type malformations and occasional cleft palate in calves after maternal ingestion of lupines containing the quinolizidine alkaloid anagyrine during gestation days 40-100. Similar malformations have been induced in cattle and goats with lupines containing the piperidine alkaloids ammodendrine, N-methyl ammodendrine, and N-acetyl hystrine and in cattle, sheep, goats, and pigs with poison-hemlock containing predominantly coniine or gamma coniceine and N. glauca containing anabasine. Toxic and teratogenic effects have been linked to structural aspects of these alkaloids, and the mechanism of action is believed to be associated with an alkaloid-induced inhibition of fetal movement during specific gestational periods. This review presents a historical perspective, description and distribution of lupines, poison-hemlock and Nicotiana spp., toxic and teratogenic effects and management information to reduce losses. PMID- 10091133 TI - Genus specific neutralization of Bungarus snake venoms by Thai Red Cross banded krait antivenom. AB - Thai commercial antivenom raised to Bungarus fasciatus venom neutralized the lethal activity of all Thai Bungarus venoms tested in in vitro neutralization experiments. The neutralizing capacities against B. fasciatus and B. candidus venoms were almost the same, but that against B. flaviceps venom was significantly greater. The efficacy of the antivenom was confirmed in in vivo neutralization experiments also. Results of immunochemical analyses supported results of the animal experiments suggesting the presence of genus specific neutralization. PMID- 10091134 TI - Acute goby poisoning in southern Taiwan. AB - Food poisoning due to ingestion of two fishes, Yongeichthys nebulosus and Sillago japonica, occurred in Kaohsiung, Taiwan, in February 1997. Two male persons (48 and 58 years old) were poisoned, with symptoms featured by dizziness, nausea, vomiting, numbness, and difficulty in respiration. All of the specimens of fish retained by the victims were combined and consisted of Yongeichthys nebulosus and Sillago japonica. These retained specimens were assayed for anatomical distribution of toxicity (as tetrodotoxin) and all specimens were found to be toxic. The highest toxicity of specimen was 7,650 mouse units (MU) in Y. nebulosus and 1,460 MU in S. japonica. However, the other specimens re-collected from that fish pier were also found to be highly toxic in Y. nebulosus, but nontoxic in S. japonica. Hence, Y. nebulosus was judged as the real causative fish in this food poisoning. The toxins were partially purified from the methanolic extracts of toxic fishes by ultrafiltration and Bio-Gel P-2 column chromatography. Cellulose acetate membrane electrophoresis and high performance liquid chromatography analyses demonstrated that tetrodotoxin was the causative agent of this food poisoning. PMID- 10091135 TI - Metabolism of diet pill to amphetamine and methamphetamine. PMID- 10091136 TI - Manganese in gasoline. Council on Scientific Affairs, American Medical Association. AB - This report responds to a resolution that asked the American Medical Association (AMA) to take action to reduce potential health risks from the use of methylcyclopentadienyl manganese tricarbonyl (MMT) in gasoline. Information for this report was derived from a search of the MEDLINE database and references listed in pertinent articles, as well as through communications with medical and public health experts. Based on this information, the AMA Council on Scientific Affairs determined that there is insufficient scientific evidence to assess the public health impact of MMT use. While limited evidence indicates that general population exposures to manganese from the use of MMT in gasoline are low, more research is needed to determine possible health effects from long-term, low-dose exposures to MMT and its combustion products. Until such data are available, educational and informational strategies should be developed to improve public awareness of the health and environmental issues surrounding MMT use. PMID- 10091137 TI - Occurrence of urinary tract tumors in miners highly exposed to dinitrotoluene. AB - Between 1984 and 1997, six cases of urothelial cancer and 14 cases of renal cell cancer occurred in a group of 500 underground mining workers in the copper-mining industry of the former German Democratic Republic, with high exposures to explosives containing technical dinitrotoluene. Exposure durations ranged from 7 to 37 years, and latency periods ranged from 21 to 46 years. The incidences of both urothelial and renal cell tumors in this group were much higher than anticipated on the basis of the cancer registers of the German Democratic Republic by factors of 4.5 and 14.3, respectively. The cancer cases and a representative group of 183 formerly dinitrotoluene-exposed miners of this local industry were interviewed for their working history and grouped into four exposure categories. This categorization of the 14 renal cell tumor cases revealed no dose-dependency concerning explosives in any of the four exposure categories and was similar to that of the representative group of employees, whereas the urothelial tumor cases were predominantly confined to the high exposure categories. Furthermore, all identified tumor patients were genotyped by polymerase chain reaction, using lymphocyte DNA, regarding their genetic status of the polymorphic xenobiotic metabolizing enzymes, including the N acetyltransferase 2 and the glutathione-S-transferases M1 and T1. This genotyping revealed remarkable distributions only for the urothelial tumor cases, who were exclusively identified as "slow acetylators." This points to the possibility of human carcinogenicity of dinitrotoluene, with regard to the urothelium as the target tissue. PMID- 10091138 TI - An environmental hazard assessment of low-level dermal exposure to hexavalent chromium in solution among chromium-sensitized volunteers. AB - To evaluate the potential for elicitation of allergic contact dermatitis from contact with standing water in the environment, 26 persons known to be allergic to hexavalent chromium [Cr(VI)] were exposed to 25 to 29 mg/L Cr(VI) by immersion of one arm for 30 minutes per day on 3 consecutive days in a potassium dichromate bath. Sixteen of the 26 volunteers demonstrated either no or an equivocal response to the Cr(VI) challenge. Ten of the volunteers developed a few papules or vesicles (1 to approximately 15), mild redness, and pruritus on the Cr(VI) challenged arm. Histopathological examination of the papules revealed spongiosis and perieccrine and perivascular inflammation. The responses were diagnosed as acute perieccrine reactions. It was concluded that exposure to similar concentrations of Cr(VI) in the environment does not pose an allergic contact dermatitis hazard, even to Cr-sensitized persons. PMID- 10091139 TI - Mortality in male and female capacitor workers exposed to polychlorinated biphenyls. AB - A mortality study was conducted in workers with at least 90 days' exposure to polychlorinated biphenyls (PCBs) between 1946 and 1977. Vital status was established for 98.7% of the 7075 workers studied. In hourly male workers, the mortality from all cancers was significantly below expected (standardized mortality ratio [SMR] = 81; 95% confidence interval [CI], = 68 to 97) and comparable to expected (SMR = 110; 95% CI, 93 to 129) in hourly female workers. No significant elevations in mortality for any site-specific cause were found in the hourly cohort. All-cancer mortality was significantly below expected in salaried males (SMR = 69; 95% CI, 52 to 90) and comparable to expected in salaried females (SMR = 75; 95% CI, 45 to 118). No significant elevations were seen in the most highly exposed workers, nor did SMRs increase with length of cumulative employment and latency. None of the previously reported specific excesses in cancer mortality were seen. This is the largest cohort of male and female workers exposed to PCBs. The lack of any significant elevations in the site-specific cancer mortality of the production workers adds important information about human health effects of PCBs. PMID- 10091140 TI - Functional ability assessment: guidelines for the workplace. AB - Short- and long-term disability certification is required in all Western countries for extended time away from work. The Americans With Disabilities Act mandates that medical providers use rational thought and justifiable criteria when evaluating an employee's "fitness for duty". In order to facilitate employment/disability decisions, physicians must now serve as an advisor to the employer. Both the employer and the physician are legally obligated to carefully justify any recommendations for placement or exclusion from the workplace. We propose a uniform methodology that both physicians and employers could use together to determine the performance capability of an individual with a temporary or permanent impairment or disability in terms of essential job functions as defined under the Americans With Disabilities Act. PMID- 10091141 TI - Compliance with universal precautions in correctional health care facilities. AB - There were three main objectives of this cross-sectional study of Maryland State correctional health care workers. The first was to evaluate compliance with work practices designed to minimize exposure to blood and body fluids; the second, to identify correlates of compliance with universal precautions (UPs); and the third was to determine the relationship, if any, between compliance and exposures. Of 216 responding health care workers, 34% reported overall compliance across all 15 items on a compliance scale. Rates for specific items were particularly low for use of certain types of personal protective equipment, such as protective eyewear (53.5%), face mask (47.2%) and protective clothing (33.9%). Compliance rates were highest for glove use (93.2%) waste disposal (89.8%), and sharps disposal (80.8%). Compliance rates were generally not associated with demographic factors, except for age; younger workers were more likely to be compliant with safe work practices than were older workers (P < 0.05). Compliance was positively associated with several work-related variables, including perceived safety climate (i.e., management's commitment to infection control and the overall safety program) and job satisfaction, and was found to be inversely associated with security-related work constraints, job/task factors, adverse working conditions, workplace discrimination, and perceived work stress. Bloodborne exposures were not uncommon; 13.8% of all respondents had at least one bloodborne exposure within the previous 6 months, and compliance was inversely related to blood and body fluid exposures. This study identified several potentially modifiable correlates of compliance, including factors unique to the correctional setting. Infection-control interventional strategies specifically tailored to these health care workers may therefore be most effective in reducing the risk of bloodborne exposures. PMID- 10091142 TI - Immunoglobulin E antibody against environmental allergens in subjects with trimellitic anhydride-induced asthma. AB - The purpose of this study was to assess the relationship between atopy and the development of occupational asthma as a consequence of exposure to trimellitic anhydride (TMA). A case-control study was performed, which comprised 16 employees identified as having TMA-induced asthma and 44 similarly exposed controls. Specific immunoglobulin E measurements in response to cat, dust mite, ryegrass, and ragweed antigens were performed. Fifty-six percent of cases and 29% of controls were found to be atopic (P = 0.098). We demonstrated that there was a trend toward employees with TMA asthma being more atopic than those without TMA asthma. Atopy as an assessment of risk for the development of TMA asthma is unlikely to be useful, although further investigation may be warranted. PMID- 10091143 TI - New approach in the evaluation of a fitness program at a worksite. AB - The most common methods for the economic evaluation of a fitness program at a worksite are cost-effectiveness, cost-benefit, and cost-utility analyses. In this study, we applied a basic microeconomic theory, "neoclassical firm's problems," as the new approach for it. The optimal number of physical-exercise classes that constitute the core of the fitness program are determined using the cubic health production function. The optimal number is defined as the number that maximizes the profit of the program. The optimal number corresponding to any willingness-to pay amount of the participants for the effectiveness of the program is presented using a graph. For example, if the willingness-to-pay is $800, the optimal number of classes is 23. Our method can be applied to the evaluation of any health care program if the health production function can be estimated. PMID- 10091144 TI - A pilot study of a headache program in the workplace. The effect of education. AB - Headache is a frequent problem in the workplace and contributes to absenteeism and productivity loss. Disease-management programs targeting headache may reduce its impact on employees, employers, and society. A pilot study was conducted in an employer setting (J.P. Morgan & Co., Incorporated; four locations in New York City and two in Delaware) to evaluate a multimedia computer-based (kiosk) headache program. Study objectives included assessing the effect of the program on participant outcomes and evaluating the educational component of the program. Through the kiosk, participants were questioned about the types, severity, and frequency of their headaches; the impact of headaches on their daily activities; and lost workdays as a result of headache. All participants received personalized reports about their headaches, and the participants in New York were given access to an on-site neurologist and additional educational information. A follow-up assessment was requested 3 months after the baseline screening to evaluate the effect of the program. A total of 185 participants completed both a baseline and follow-up session. Of 177 evaluable participants, 19% saw a physician for headache after their initial kiosk session. Fifty-six percent of evaluable participants reported overall improvement in headache symptoms at follow-up (P < 0.01), with decreased headache frequency and better understanding of headache most often selected as reasons for improvement. Participants also reported higher satisfaction with headache management after using the program and fewer urgent care/emergency room visits for headache (P < 0.01). For participants who reported lost workdays because of headache, the number of days missed had decreased by the follow-up. The results of this study indicate that the headache program improved outcomes. Because all participants received educational materials, it is likely that education played a role in the improvements observed. These results are encouraging and warrant further study in larger, controlled trials. PMID- 10091145 TI - Multicentre study on prevalence of fractures in transfusion-dependent thalassaemic patients. AB - The objective of this study was to determine the prevalence of fractures in transfusion-dependent thalassaemic patients in Italy. Examination of the patients' records revealed that 193 of the 977 observed patients had sustained fractures, with prevalence of 19.7%. Many patients showed multiple and recurrent fractures. Children and adolescents sustained fractures more frequently than adults. The majority of observed patients sustained fractures because of moderate or mild trauma. Our results seem to indicate that Hb pretransfusional levels over 9 or 10 gr% and serum ferritin levels under 1,000 ng/ml cannot always prevent the risk of fracture. PMID- 10091146 TI - Bone pain in thalassaemia: assessment of DEXA and MRI findings. AB - An increasing number of adult thalassaemics have been complaining of aches and pains of varying degrees of severity. In a minority the pains are debilitating and there is stiffness in movement. This study is an attempt to understand the osteoporosis of thalassaemia using DEXA and MRI as the main investigative tools. 122 patients with homozygous beta-thalassaemia were examined by DEXA. It was found that almost half had BMD below two standard deviations from the mean for the normal population, especially in the lumbar spine. There was no marked worsening with age. However the proportion of patients who had their first transfusion after the 3rd year (especially after the 6th) was significantly greater in those with the low BMD. There is also an excess of hypogonadic thalassaemics amongst those with low BMD. 72 thalassaemics were examined by MRI of marrow. Hypercellular, dark marrow on T1 weighted images found in young patients (20-30 yr) was replaced by fatty marrow in later life (30-40 yr). In a group of 21 older thalassaemics (33-62 yr) extreme bone marrow expansion was expressed by the reappearance of hypercellular areas, giving the impression of patchiness which affects not only the diaphyses but also the metaphyses. These patients mostly (66%) had thalassaemia intermedia and had started irregular transfusion after the 6th year of life. About 75% had a BMD below 2 SD. The conclusion is that patients who were late in receiving blood and especially those with thalassaemia intermedia had a more expanded bone marrow with pressure on cortical bone which caused pain in several cases. An attempt was made in 10 patients to reduce marrow hyperplasia by using hydroxyurea. Results showed a relief of pain and modification of magnetic signal intensity. PMID- 10091147 TI - Bone density and metabolism in thalassaemia. AB - Twenty-seven thalassaemic patients (13 F, 14 M, aged 8.1-14.9 yr), regularly transfused and chelated with desferrioxamine (30-40 mg/kg/day) were studied. Every patient was submitted to auxological evaluations, dual X-ray absorptiometry to measure bone mineral density (BMD), and to the determination of bone metabolic markers of osteoclastic activity (total urinary hydroxylysylpyridinoline crosslinks, carboxyterminal pyridinoline crosslinked telopeptide of type I collagen [ICTP]) and of osteoblastic activity (bone Gla protein [BGP] and carboxyterminal propeptide of type I procollagen [PIPC]). The evaluations were repeated after 1 year, during which 13 patients continued desferrioxamine chelation while 14 underwent deferiprone chelation (75 mg/kg/day in 3 doses). The data demonstrate widespread bone alterations consisting of osteoporosis, growth failure and bone age delay. Lumber spine (L2-L4) BMD areal values (Z score) inversely correlated with age, as did height SDS of both male and female patients, indicating osteoporosis progressing with age in parallel with growth insufficiency. No clear-cut alterations in bone mineral metabolism were found in basal state and after 1 year. Extensive MR imaging studies are needed to define the contribution of residual bone marrow hyperplasia to thalassaemic osteopathy suggested by subtle radiological signs as enlargement of bone marrow cavities with thinning of the cortical bone and abnormalities of the trabecules of spongy bone. PMID- 10091148 TI - pQCT (quantitative peripheral tomography) and data evaluation of phosphocalcic metabolism in thalassaemic patients. AB - pQCT is a method which allows the separate determination of cortical and trabecular bone mineral density in the peripheral skeleton. 21 thalassaemic patients (8 females, 13 males) aged from 10 to 32 years, were examined using pQCT at the ultra distal radius to evaluate SSI (Stress-Strain Index). ALP, serum calcium, hydroxyproline, magnesium, IGF-I, and body surface were determined. The results show a good correlation between cortical BMD and age, concentration of hydroxyproline in urine, serum bone Gla protein, body surface index, bone density of trabecular bone and SSI. Good correlation was found between trabecular bone density and age, IGF-I, BGP and PTH, and between SSI and cortical BMD, age and BSI. The linear relationships between age and cortical and trabecular density show an increase of cortical BMD with age and a decrease of trabecular density with age. The same results were obtained considering trabecular and cortical density versus SSI. PMID- 10091149 TI - Genetic and acquired predisposing factors and treatment of osteoporosis in thalassaemia major. AB - We have previously shown a high incidence of osteopenia and osteoporosis in patients with thalassaemia major. These bone changes, were more severe in males than females, in those with diabetes mellitus and with hypogonadal-hypogonadism. Our recent studies concern the relationship of erythroid activity, assessed by serum transferrin receptors as an overall measure of anaemia, to osteoporosis. Serum transferrin receptor levels correlated with the mean pre-transfusion haemoglobin level, but there was no correlation with the incidence of osteopenia and osteoporosis. As osteoporosis has a strong genetic component we have also studied the COLIA1 and COLIA2 genes which code for the major protein of bone (type 1 collagen). Studies by others have shown in non-thalassaemic patients that a polymorphism G-->T or TT in a regulatory region of COLIA1 at the recognition site for transcription factor Sp1 is associated with the presence of osteoporosis. Our studies suggest that Sp1 polymorphism is not specific to any one ethnic group; the polymorphism occurs more commonly in females (female to male ratio 2:1). In male thalassaemia major patients the presence of the Sp1 mutation was associated with more severe osteoporosis of the spine and the hip compared with female patients. There is failure of improvement in spinal osteoporosis with bisphosphonate therapy (intravenous Pamidronate) in male patients with the Sp1 mutation. PMID- 10091150 TI - The diagnosis of childhood growth hormone insufficiency and growth hormone resistance. AB - Growth hormone insufficiency (GHI) is an uncommon though treatable cause of retarded growth velocity and short stature in childhood, the diagnosis generally requiring the demonstration of a subnormal growth hormone (GH) response to a physiological or pharmacological stimulus. Physiological and pharmacological GH release is a continuous variable and the relationship between spontaneous GH secretion and height velocity is asymptotic. Cut-off points for defining GH insufficiency are largely derived from adult observations, but have been extrapolated to children, for whom normative data are relatively scanty. There is no absolute cut-off that discriminates between normal and abnormal GH response. Moreover, poor reproducibility, sensitivity and specificity of the many dynamic tests available, particularly when performed in the very young child or in early adolescence, together with the confounding effects of assay performance, further weaken the diagnostic efficiency of biochemical investigations. Between 20-40% of children retested at the completion of GH therapy demonstrate a normal GH response to a provocative stimulus. Such limitations mitigate against over reliance on GH provocation tests in diagnosis, and further emphasize the importance of careful auxology in evaluating the short child. PMID- 10091151 TI - Short stature and body proportion in thalassaemia. AB - Short stature and short trunk have been reported in thalassaemic patients. We report a study on stature and body proportions in 476 patients (2-36 years old) with beta-thalassaemia major, followed in 12 Italian centres. Auxological data (standing height, sitting height, subischial leg length, target height), haematological data (age at first transfusion, age at start of desferrioxamine [DFX] chelation, mean dose of DFX, ferritin values) and information regarding the presence of endocrine disorders and of bone lesions, were collected and analysed according to the age of the patients, in order to investigate the natural history of the disproportion and the role of siderosis, DFX toxicity and endocrine disorders. Our data indicate that about 18% of thalassaemic patients exhibit short stature; disproportion between the upper and lower body segments is present in 14%; however, a short trunk despite normal stature is present in another 40% of patients. This is due to a spinal growth impairment which starts in infancy and progressively aggravates. We think that a short trunk is peculiar to the disease itself; however, other factors such as hypogonadism, siderosis, or DFX induced bone dysplasia are probably involved in aggravating the body disproportion in these patients. PMID- 10091152 TI - Long-term follow-up of skeletal dysplasia in thalassaemia major. AB - We report skeletal changes due to deferoxamine (DF) in 15/29 patients with transfusion-dependent thalassaemia major (TM), followed longitudinally for growth assessment. Clinically the earliest signs were decline in height and/or sitting height growth rate, leg and back pain with restricted movement and limb deformity. Radiologically metaphyseal and spinal changes were seen in 5 subjects and vertebral lesions alone in 10. The metaphyseal changes were mild, moderate or severe and affected all long bones, but were most pronounced at wrists and knees. They progressed from widening of the growth plate and defects of metaphyseal margins to appearance of radiolucent pseudocystic areas and, in severe cases, of cupped, rickets-like metaphyses. The spinal changes proceeded from osseous defects of ventral upper and lower edges of vertebrae and biconvex contours of end-plates to platyspondyly with decreased vertebral body height. After DF dose reduction, metaphyseal changes regressed in 2 patients, while they progressed in 3, requiring corrective surgery for severe valgus knee. Spinal abnormalities either remained unchanged or progressed. Final height was very short in patients with spondylometaphyseal lesions, short and disproportionate in patients with only spinal involvement. PMID- 10091153 TI - Growth hormone secretion and bone histomorphometric study in thalassaemic patients with acquired skeletal dysplasia secondary to desferrioxamine. AB - An auxological and endocrinological study was performed in 21 thalassaemic patients with growth retardation and skeletal dysplasia secondary to desferrioxamine. Bone metaphyseal proximal tibial or iliac crest biopsy was performed in six patients with severe genu valgum or non-traumatic vertebral compression. GH insufficiency/deficiency (GH deficiency: peak after stimulation test below 6 ng/ml) was found in 72% of our thalassaemic patients with skeletal dysplasia, but in only 41% of patients without skeletal dysplasia. Bone histology showed abnormal chondrocytes, alteration of staining pattern of cartilage, irregular columnar cartilage and lacunae in the cartilaginous tissue. The behaviour of bone tissue was unpredictable (presence of thick or thin osteoid layer). Bone microfractures were sometimes present. The bone microstructure showed scarce mineralization, which was evenly or irregularly distributed. The bone tissue apatitic phase was quantitatively reduced. The hardness of bone tissue was remarkably lower than that of normal bone in three out of six patients. In conclusion, iron chelation therapy in patients with acquired skeletal dysplasia seems to interfere with GH secretion. The early identification of clinical and radiological abnormalities of skeletal dysplasia is of paramount importance in preventing severe bone destruction. PMID- 10091154 TI - Growth and management of short stature in thalassaemia major. AB - With modern treatment and longer survival of patients with homozygous beta thalassaemia endocrine dysfunction assumes greater importance. Short stature, delayed puberty and hypogonadism are major problems in both adolescent and adult patients. Growth failure has been attributed to GH deficiency (hypothalamic or pituitary), hypothyroidism, delayed sexual maturation, hypogonadism, diabetes mellitus, zinc deficit, low Hb levels, bone disorders and desferrioxamine toxicity. The present report concentrates on the incidence of short stature among children aged 7-8 years (n = 50) and young adults aged 20-29 years (n = 93) with blood transfusion dependent homozygous beta-thalassaemia appropriately treated who have entered and completed puberty spontaneously (n = 45) or with treatment (n = 48) and have attained final height. It also concentrates on the role of GH in the growth retardation of 65 blood transfusion dependent thalassaemia major patients, their GH response to provocative stimulation, the effect of rhGH therapy on growth and final height in 13 patients who had GH deficiency and the effect of long acting androgens on growth and final height of 11 short boys with thalassaemia major, delayed puberty and normal GH secretion. CONCLUSION: 8% of young boys with thalassaemia major aged 7-8 years have short stature. 12% of the older boys and 15% of the older girls without endocrinopathies had height < 3rd percentile. This incidence was 29% when endocrinopathies were present. GH deficiency is rare among short blood transfusion dependent thalassaemia major patients (20%) and seems to play a limited role in the etiology of growth retardation. One year treatment with rhGH improved growth rate and predicted height without causing serious metabolic problems. Long term administration of rhGH is also safe and promising. Patients with thalassaemia major can achieve acceptable final heights but below their target heights with rhGH therapy. Low dose long acting sex steroid treatment in boys with delayed puberty, delayed bone age and without GH deficiency for a year or more is safe and can produce similar results to those obtained with rhGH therapy. PMID- 10091155 TI - Short-term therapy with recombinant growth hormone in polytransfused thalassaemia major patients with growth deficiency. AB - Growth failure is commonly described in polytransfused thalassaemia major patients (Th) with or without growth hormone (GH) releasing hormone-GH axis impairment. We have investigated the efficacy of short-term recombinant GH (rhGH) therapy (Saizen [Serono] 0.1 IU/kg/day 6 evenings/week administered s.c. for 12 months) on growth and predicted final height in 28 (19M, 9F) regularly transfused Th with growth deficiency (aged 14.8 +/- 2.0 yr) on long term desferrioxamine s.c. therapy. All Th had no evidence of congestive heart failure, hypothyroidism or impaired glucose tolerance; in all patients the GH peak (evaluated during both insulin and clonidine test) was < or = 20 mIU/l; hypergonadotropic hypogonadism was excluded in Th with delayed puberty. At the start of therapy height age (HA)/bone age (BA) ratio was 0.92 +/- 0.12. Bone age delay was positively correlated to chronological age (CA), serum ferritin levels (mean of the last three years), the age at the start of chelation therapy, growth velocity calculated for CA during the last year; a positive correlation was also found between circulating IGF-I levels and age at the start of chelation therapy. After 1 year on rhGH therapy there was a significant increase of height calculated for CA (not for BA), of growth velocity calculated for both CA and BA and of circulating IGF-I levels; the HA variation/BA variation ratio was 1.85 +/- 1.71, without any significant difference between predicted final height at the start ( 1.08 +/- 1.28 SDS) and at the end of rhGH therapy (-0.88 +/- 1.13). The variation of height calculated for CA was positively correlated to both CA and growth velocity during the last year before rhGH therapy (calculated for CA) and negatively to the height at the start (calculated for CA). There were no side effects and haematological parameters did not show significant changes. In conclusion, our data, obtained in a relatively large group of Th, confirm the emerging results of short-term (12 months) rhGH therapy on growth, as shown by the increase of both growth velocity and height calculated for CA. With regard to final height, although the mean variation of HA/variation of BA ratio was 1.85, no significant increase of the predicted final height was found between the start and the end of rhGH therapy. We are evaluating the effect of long-term rhGH therapy on growth in these patients. PMID- 10091156 TI - Acute metabolic effects of human growth hormone on 15N-nitrogen balance in patients with thalassaemia as compared to patients with other types of short stature. AB - The acute response to various doses of human growth hormone (hGH) was determined in short patients with thalassaemia and compared to that in patients with classic growth hormone deficiency and Turner's syndrome. Nitrogen balance was analyzed using the stable isotope 15N. While patients with growth hormone deficiency responded with a marked nitrogen retention (+2.9 +/- 0.4 to +6.1 +/- 0.6 mg 15N/kg) to small doses of hGH (2 x 3 IU/m2), those with Turner's syndrome had a higher basal balance, but responded much less (+3.1 +/- 0.7 to +3.7 +/- 1.8 mg 15N/kg). They required a double dose of hGH (2 x 6 IU/m2) to achieve a significant retention (+4.1 +/- 1.0 to +7.1 +/- 0.4 mg 15N/kg). The thalassaemic patients responded still less than the patients with Turner's syndrome to 2 x 6 IU/m2 (+7.7 +/- 0.3 to +8.0 +/- 0.4 mg 15N/kg), and even hGH doses up to 2 x 12 IU/m2 had little effect, indicating a relative resistance to hGH. In conclusion, no or little effect is to be expected from long-term hGH treatment at low doses in thalassaemic patients. When it is decided to treat these patients, the dose should be about 4 times higher than a regular replacement dose in growth hormone deficiency. PMID- 10091157 TI - New GH secretagogues and potential usefulness in thalassemia. AB - Thalassemic patients today undergo intensive transfusion and chelation regimes that offer them prolonged survival and improved quality of life. Nevertheless, they face the consequences of chronic illness and therapies which affect multiple bodily functions. Endocrine derangements involve, among others, the GH-IGF-I axis with consequent impairment of growth. In such cases, GH release, as assessed with stimulation tests, may be normal whereas ultradian GH secretion seems to be subnormal. New GH secretagogues (GHRs) are agents that stimulate pituitary GH release by acting upon different receptors than the endogenous hypothalamic secretagogue, growth hormone-releasing hormone (GHRH). Examples are the growth hormone releasing peptides (GHRPs) GHRP-6, GHRP-1, GHRP-2, Hexarelin and the nonpeptidyl MK-0677. These can be administered by multiple routes, even per os or intranasally, thus obviating the need for injections. Their GH releasing capacity is more pronounced and prolonged than that of GHRH and their use is devoid of serious side effects. The most recently developed GHRs seem to be capable of producing sustained GH release in many cases and can thus be viewed as therapeutic candidates in cases of reduced GH secretion with intact pituitary, as seems to be the case in a group of thalassemic patients. PMID- 10091158 TI - Glucose tolerance, insulin secretion and peripheral sensitivity in thalassaemia major. AB - Glyco-metabolic status was evaluated in 29 pubertal homozygous thalassaemics aged from 17 to 42 years and in 12 age-matched healthy subjects. Diagnosis of diabetes mellitus was assessed in 4 patients (13.8%), who became diabetic after the age of 18 years. With respect to controls non-diabetic patients exhibited significantly higher fasting plasma glucose levels and more sustained glycemic responses to oral glucose tolerance test, whereas their overall insulin output was significantly lower. Moreover non-diabetic thalassaemic patients showed a clear reduction of both beta-cell function and insulin resistance indices (HOMA model). In conclusion our data show a high prevalence of diabetes but do not support the existence of an insulin resistant status in thalassaemia major, at least in adulthood. PMID- 10091159 TI - Epidemiology and chelation therapy effects on glucose homeostasis in thalassaemic patients. AB - The incidence and prevalence of insulin-dependent diabetes mellitus (IDDM) and impaired glucose tolerance (IGT) were studied in a series of 273 patients with thalassaemia major followed in Ferrara from 1954 to 1998. It was found that the prevalence of glucose metabolism abnormalities has decreased and that the mean age of diagnosis has increased over the years. Risk factors associated with IDDM and IGT were lack of compliance with chelation therapy, iron overload and the presence of cirrhosis and severe fibrosis. PMID- 10091160 TI - Glucose disturbances and regulation with glibenclamide in thalassemia. AB - Specific laboratory and clinical characteristics indicate that the pathogenesis of diabetes in patients with thalassemia resembles the pathogenesis of maturity onset diabetes (type II). Thus oral hypoglycemic agents may be used to regulate blood glucose levels by induction of insulin secretion and reduction of insulin resistance. The efficacy of glibenclamide administration in the management of glucose disturbances was evaluated in 33 patients with thalassemia, aged 12-30 years (mean 17.4 +/- 3.7), in whom diet and exercise failed to regulate hyperglycemia. The results were compared to 30 thalassemic patients (mean age 18.4 +/- 4.8 yr), who followed only diet and exercise. Improvement of OGTT was observed in 73% of the treated patients versus 43% of the control group for a mean period of 59 months. Deterioration of OGTT occurred more rapidly (33.7 +/- 26.1 vs 40.7 +/- 34.5 mos), and in more patients of the untreated group (57%) than in treated patients (27%). Among treated patients, effectiveness of oral hypoglycemic agents lasted longer in patients with diabetic (64.1 +/- 40.3 mos) than in patients with impaired curves (54.2 +/- 31 mos). PMID- 10091161 TI - Prevalence of retinopathy in diabetic thalassaemic patients. AB - Thalassaemic patients with diabetes mellitus are at risk of developing retinopathy. To evaluate the prevalence and the characteristics of diabetic retinopathy in thalassaemics we examined 46 patients with beta-thalassaemia major and insulin-dependent diabetes by fluorescein angiography. The study group was matched for sex, age and diabetes duration with a control group of 46 type 1 diabetic patients. Diabetic retinopathy was detected in 26% (12/46) of thalassaemics and in 50% (23/46) of the controls. In thalassaemics the diabetic retinopathy was significantly less severe than in controls (P < 0.0001). The influence of risk factors for diabetic retinopathy (duration of diabetes and metabolic control) was confirmed in the control group. In thalassaemic patients we found no significant correlation between these risk variables and the presence of diabetic retinopathy. Various factors may protect thalassaemics from diabetic retinopathy: heterogeneity of pancreatic functions; high incidence of hypogonadism; contemporary dysfunction of GH and/or glucagon secretion. PMID- 10091162 TI - Hormonal replacement therapy with HCG and HU-FSH in thalassaemic patients affected by hypogonadotropic hypogonadism. AB - Gonadotropin (Gn) replacement therapy using HCG plus HU-FSH was administered to 24 patients affected by beta-thalassaemia major with hypogonadotropic hypogonadism aged 18-40 years (25.2 +/- 5.4 yr, m +/- SEM). The age range at the start of treatment was 14.5-24.5 years (16.7 +/- 2.6 yr); the mean duration of Gn treatment was 8.6 +/- 3.9 years (range 1-15.2 yr). Gn therapy was begun with HCG alone, the dosage being initially 500 IU twice a week and then increased to a maximum of 3000 IU twice a week, according to the individual serum testosterone levels obtained. HU-FSH (75 IU twice a week) was added to initiate spermatogenesis in all cases when the HCG-induced testosterone serum levels normalized. The duration of HU-FSH treatment ranged from 1-2 years and then therapy was continued with HCG alone. In nine patients Gn therapy was discontinued after 6-14 years and was replaced by testosterone depot therapy, 75 100 mg i.m. twice a month, for a period ranging from 1-1.5 years. Using Gn therapy, the testosterone levels normalized. The compliant patients obtained good virilization and normal sexual function; testicular volume increased within the normal adult range and spermatogenesis was achieved. When Gn therapy was replaced by testosterone-depot therapy, a marked decrease in testicular volume and sperm count was observed, but the patients complied better and showed a slight increase in coarse hair. In conclusion gonadotropins are an effective replacement therapy for male hypogonadism in thalassaemic patients. If we consider the advantages and disadvantages of this therapy, the former seem to outweigh the latter. Finally, it should be emphasized that physicians caring for these patients must foster compliance during frequent check-ups and examinations. PMID- 10091163 TI - Clinical experience using the Androderm testosterone transdermal system in hypogonadal adolescents and young men with beta-thalassemia major. AB - beta-Thalassemia major is associated with a high prevalence of hypogonadotropic hypogonadism affecting adolescents and young men with this disease. The pharmacokinetics of Androderm, a non-scrotal permeation-enhanced testosterone transdermal system, was previously studied in this population using three application regimens designed to mimic the nocturnal secretion and circadian patterns of testosterone production characteristics of puberty and young adulthood. In regimen I, designed for prepubertal 14 to 16 year-olds, a single Androderm patch (2.5 mg/day nominal delivery rate) is applied at night and removed 12 hours later in the morning. In regimen II, designed for partially virilized 17 to 19 year-olds, a single Androderm patch is applied nightly for 24 hours. In regimen III, intended for virilized men aged 20 years and older, two Androderm patches (total dose of 5 mg/day) are applied nightly for 24 hours. This report presents the results of a 12-month open label study using these three Androderm regimens to treat nine hypogonadal males with beta-thalassemia (ages 16.8 to 31.8 yr). Our data show that Androderm produced physiologically appropriate testosterone levels, lowered SHBG levels, promoted growth and virilization, increased bone mineral density, and was generally well tolerated in this population of hypogonadal adolescents and young men with beta-thalassemia. PMID- 10091164 TI - Transfusional transmitted viruses in pregnancy. AB - Blood has long been recognized as a vehicle for transmission of infectious organisms and as molecular laboratory technology has advanced, a seemingly endless array of infectious agents has occasionally been documented to be blood transmitted. Transfusion associated hepatitis (TAH) has been the most common serious consequence of blood transfusion although in recent years this has been significantly reduced (blood donor screening, blood processing, etc.). Thalassaemia major is classically associated with increased susceptibility to infections caused by those agents that are blood transmitted such as HBV, HCV, HIV, CMV, HPV B-19 (frequency rates vary from country to country). Monitoring the prevalence of transfusion transmitted infections in thalassaemics has been in recent years an indispensable part of their clinical management protocol. As a number of these viruses have been documented to be efficiently transmitted through the vertical route, the issue of blood transmitted viral infection monitoring becomes particularly important in order to provide protection or treatment both to the pregnant thalassaemic patient herself and to her foetus/newborn. Hepatitis (mainly B and C) and HIV in the obstetric thalassaemic is what the clinician is faced with most frequently. Although preventative measures have been very successful in the case of HBV infection and recently to an encouraging extent in the case of HIV (recommendations have been constructed), the mechanisms and frequency of HCV vertical transmission as well as the clinical outcome of children born to HCV carriers are not yet completely clarified. No vaccines are available and HIGB or antivirals do not appear to offer protection to the foetus against infection with HCV. Thalassaemics are frequently seropositive to markers of other transfusion transmitted viruses, such as CMV and HPV B-19, particularly by the age of pregnancy. Infection with a second or multiple strains as well as reactivation of existing CMV strain(s) are possible events in thalassaemics. However, the frequency of "recurrency" episodes, their implication in vertical transmission and clinical outcome for the foetus/newborn are issues requiring further investigation. PMID- 10091165 TI - Thrombotic risk in thalassemic patients. AB - Hemostatic parameters of 495 beta-thalassemic patients (421 with thalassemia major and 74 with thalassemia intermedia) were analyzed, to assess their association with the described thrombophilic condition and to verify the role of additional risk factors (e.g. persistent postsplenectomy thrombocytosis, insulin dependent diabetes mellitus, estrogen-progestin treatment and atrial fibrillation). The prevalence of thromboembolic accidents was 5.2% and in four patients (15.3%) inherited or acquired predisposing defects were recognized. The incidence of thromboembolic events and the associated relative risk due to hemocoagulative abnormalities in these patients are discussed. PMID- 10091166 TI - Pregnancy management and outcomes in women with thalassaemia major. AB - The health background, management and outcomes of 25 pregnancies in 18 women with transfusion dependent beta thalassaemia are described with particular consideration of appropriate preconceptual guidance for such women. This is an observation study of women attending three collaborating London hospitals. Nine of the pregnancies required induction of ovulation. Two pregnancies were complicated by diabetes and three by hepatitis C. One patient was hepatitis B positive. Two pregnancies were in women with cardiac problems, one of whom died of cardiac failure nine months after delivery of a live child. Two of the pregnancies miscarried and three were terminated, with the others resulting in 21 live children (including one set of twins). 14 of the pregnancies were delivered by caesarean section. After pregnancy five women developed secondary amenorrhoea, two developed cardiac problems and two developed diabetes. PMID- 10091167 TI - Preliminary observations about assisted reproduction in thalassaemia. PMID- 10091168 TI - Fertility in female patients with thalassemia. AB - With recent therapeutic advances, thalassemic patients can now reach adulthood and attain reproductive capacity. Endocrine complications due to hemosiderosis and especially hypogonatotropic hypogonadism, which present either with sexual infantilism and primary amenorrhea or with secondary amenorrhea, are common in thalassemic women. The aim of this study was to estimate the frequency of fertility among our female thalassemic patients. Our population included 50 married women with thalassemia major (TM) and 12 with thalassemia intermedia (TI) who are regularly followed in our thalassemic centers. Of the 50 patients with TM, 7 had primary amenorrhea (PA), 9 had secondary amenorrhea (SA), and 34 had normal menstrual function (NM), as did all the patients with TI. Overall we had 62 women who were able to achieve 90 pregnancies and give birth to 87 healthy babies. Most of our patients became pregnant around the age of 25 years. Associated endocrine complications were rare except in the group of patients with PA, as expected. In all patients with PA and SA, the 17 pregnancies were induced (intercourse 10, insemination 3, IVF 4). In the patients with NM and TI, 66 pregnancies were achieved spontaneously and 7 following induction (insemination 3, IVF 4). There were four twin and one triple pregnancies, which all resulted in premature deliveries. Among the seven couples in which both partners had thalassemia major, sperm donation was used in 5 cases, ovum donation in one case, and one pregnancy was achieved spontaneously. These 90 pregnancies resulted in 69 full-term, 12 pre-term, 7 abortions and 2 stillbirths. No severe obstetric complication was observed except for two patients with preeclampsia. One patient with PA who carried the triple pregnancy developed severe cardiac failure, which was successfully treated. Transfusion requirements were increased during pregnancy. Discontinuation of desferrioxamine resulted in elevation of ferritin levels during the second and third trimesters of pregnancy and after delivery. Nine patients who were examined with cardiac echo had a transient increase of ESD and EDD during pregnancy, with return to normal after delivery. Labor was performed by Caesarian section in 26 births (26%) out of the 81 successful pregnancies. These collected data represent the largest number of pregnancies in thalassemic females reported so far and are clearly encouraging for the ultimate improvement of the quality of life in thalassemic patients. PMID- 10091169 TI - Fertility in thalassemia: the Greek experience. AB - Pregnancy in beta-thalassemic patients has become a not unusual event, especially in the last 10 years. The course and outcome of 19 pregnancies in 16 thalassemic women, followed in our unit, 12 with thalassemia major and 4 with thalassemia intermedia, were studied. Genetic counselling was provided and counselling regarding the planning or the continuation of the pregnancy was based mainly on cardiac performance at rest. Cardiac, endocrine and liver function were evaluated at baseline, monitored throughout pregnancy and reevaluated after delivery. Desferrioxamine treatment was discontinued as early as possible. During pregnancy the Hb level was maintained at about 10 g/dl in all women by transfusion. The course of pregnancy was essentially uneventful and elective Cesarean section was performed in all cases. The mean birth weight of the newborns was 3000 g. All babies were normal except for one with exomphalus. Pregnancy was well tolerated by the heart in all women and no endocrinological disorders were observed. In conclusion, pregnancies in beta-thalassemia can be safe for both mothers and their babies with careful selection and appropriate care. PMID- 10091170 TI - Glucose intolerance in patients with thalassemia major: insulin resistance and hyperproinsulinemia. PMID- 10091171 TI - Growth failure and bone lesions due to desferrioxamine in thalassaemic patients. PMID- 10091172 TI - Evaluation of spine and hip bone density by DXA and QCT in thalassemic patients. PMID- 10091173 TI - Bone density study of thalassemic patients from Reggio Calabria Province. PMID- 10091174 TI - Final height and endocrine function in thalassaemia intermedia. AB - We present data of a detailed study of endocrine function in 50 patients (21 males, 29 females) with thalassaemia intermedia, 15-46 years old (mean age 28.7 yr), with raised serum ferritin levels (mean 1540 micrograms/l). Mean haemoglobin concentration was 8.1 g/dl. Half of them had had more than 50 transfusions in their life and had received irregular intramuscular or subcutaneous chelation therapy. Delayed puberty was one of the most frequent (36%) clinical endocrine abnormalities found in our patients. Primary amenorrhea was observed in two patients and secondary amenorrhea in four patients. Two males, aged 19 and 36 years, had hypogonadism. A poor response to GnRH, found in three females and in both males tested, suggested that pituitary dysfunction was wholly or partially responsible for hypogonadism. Gonadal function was normal in all patients studied. Glucose intolerance and primary hypothyroidism were less frequent (24 and 5.7%, respectively) and milder than in thalassaemia major patients. Two patients had low T3 and T4 and normal basal and stimulated response of TSH to TRH. This condition has been found in euthyroid sick syndrome and it is likely that it represents an adaptive response by the body to minimize catabolism when undergoing major stress. As a consequence, we believe that periodic endocrine evaluation should be carried out in subjects with beta-thalassaemia intermedia, particularly in those over 14 years old, in order to detect and to treat endocrine dysfunction. PMID- 10091175 TI - beta-cell secretion in thalassemia major patients. PMID- 10091176 TI - High incidence of osteoporosis in thalassaemia major. PMID- 10091177 TI - Rachitic rosary in a well chelated thalassaemic patient with primary amenorrhea (patient report). PMID- 10091178 TI - Zinc deficiency and cell-mediated and humoral autoimmunity of insulin-dependent diabetes in thalassemic subjects. PMID- 10091179 TI - Glucose tolerance and beta-cell secretion in patients with thalassaemia major. PMID- 10091180 TI - Induction of ovulation in thalassemic patients. AB - The authors studied 19 thalassemic patients: 14 patients with secondary amenorrhea (group A), 5 patients with primary amenorrhea (group B) and 1 patient with anovulation (group C). All the patients underwent three cycles of induction of ovulation with FSH. The level of 17 beta-estradiol and the diameter of follicles were evaluated every three days. Normal gonadal function was maintained in three patients with positive response at Step 1 of the treatment. PMID- 10091181 TI - Osteopenia in female beta-thalassemic patients. AB - Sixty-four women with thalassemia major aged 13-28 years were studied. 49 patients had primary amenorrhea and 15 had secondary amenorrhea. Bone density of the spine was performed using lunar DPX. The Z score was used to evaluate the degree of osteopenia. In 82% of the patients a Z score less than -2 was found. BMD correlated negatively with the duration of amenorrhea and age of thalassemic patients. PMID- 10091182 TI - Screening for beta-thalassemia heterozygotes in pregnant women. PMID- 10091183 TI - Human chorionic gonadotrophin therapy in hypogonadal thalassaemic patients with osteopenia: increase in bone mineral density. PMID- 10091184 TI - Pituitary deficiency and lack of gonads in an XY pseudohermaphrodite with beta 39/lepore haemoglobinopathy. AB - We describe the occurrence of hypothyroidism and hypogonadotropic hypogonadism in an XY pseudohermaphrodite subject affected by beta-thalassemia. The patient, reared as female, diagnosed at 14 months of age as having a beta 39/Lepore hemoglobinopathy, treated with multiple transfusion therapy, was referred at age of 15 years because of delayed puberty. Complete endocrine evaluation showed low levels, both basal and after combined LHRH-TRH and hCG stimuli, of FSH, LH, TSH, estradiol (E2), testosterone (T), progesterone (P), androstenedione (A), and FT4 levels, and normal PRL, cortisol, 17OHP and ACTH levels. Imaging studies (ultrasound, magnetic resonance, radioisotope scanning and gonadal vessels phlebography) did not show internal genitalia and gonads. Karyotype resulted 46,XY. PCR amplification of the SRY gene confirmed the presence of the Y chromosome. Female genitalia without uterus in a subject with Y chromosome SRY gene, and no detectable testes indicate a condition of male pseudohermaphroditism associated with testicular regression. Low gonadotropin and sex steroid levels are suggestive of combined acquired hypothalamic-pituitary and gonadal impairment, due to iron deposition in both organs. We cannot exclude congenital failure of testosterone synthesis and action in this case, because lack of gonads is an unusual finding in thalassemic hypogonadic subjects. PMID- 10091185 TI - An endocrinologist's commentary. PMID- 10091186 TI - Dr. David E. Rogers and his legacy: the Robert Wood Johnson Health Policy Fellowship. PMID- 10091187 TI - Health policy agenda for the early 21st century. PMID- 10091188 TI - The changing elderly population and future health care needs. AB - The impending growth of the elderly population requires both fiscal and substantive changes in Medicare and Medicaid that are responsive to cost issues and to changing patterns of need. More emphasis is required on chronic disease management, on meaningful integration between acute and long-term care services, and on improved coordination between Medicare and Medicaid initiatives. This paper reviews various trends, including the growth in managed-care approaches, experience with social health maintenance organizations and Program of All Inclusive Care for the Elderly demonstrations, and the need for a coherent long term care policy. Such policies, however, transcend health care and require a broad range of community initiatives. PMID- 10091189 TI - The Montefiore community children's project: a controlled study of cognitive and emotional problems of homeless mothers and children. AB - OBJECTIVES: This study compares the prevalence of emotional, academic, and cognitive impairment in children and mothers living in the community with those living in shelters for the homeless. METHOD: In New York City, 82 homeless mothers and their 102 children, aged 6 to 11, recruited from family shelters were compared to 115 nonhomeless mothers with 176 children recruited from classmates of the homeless children. Assessments included standardized tests and interviews. RESULTS: Mothers in shelters for the homeless showed higher rates of depression and anxiety than did nonhomeless mothers. Boys in homeless shelters showed higher rates of serious emotional and behavioral problems. Both boys and girls in homeless shelters showed more academic problems than did nonhomeless children. CONCLUSION: Study findings suggest a need among homeless children for special attention to academic problems that are not attributable to intellectual deficits in either children or their mothers. Although high rates of emotional and behavioral problems characterized poor children living in both settings, boys in shelters for the homeless may be particularly in need of professional attention. PMID- 10091190 TI - Cardiovascular mortality of Chinese in New York City. AB - To determine cardiovascular disease mortality among Chinese migrants in New York City and compare it to both that of residents in China and whites in New York City, mortality records for 1988 through 1992 for New York City and the 1990 US census data for New York City were linked. Age-specific death rates for urban China, reported by the World Health Organization, were used for comparison. The results show that male and female Chinese residents in New York City had lower mortality rates for all causes and total cardiovascular disease than did either New York City whites or Chinese in China. Coronary heart disease deaths among New York City Chinese were intermediate between Chinese in China (lowest) and New York City whites (highest). Stroke death rates for New York City Chinese were substantially lower than those in China and, in general, were similar to those for New York City whites. However, New York City Chinese had higher death rates for hemorrhagic stroke and lower for atherosclerotic stroke than did New York City whites. In conclusion, cardiovascular mortality rates among Chinese migrants in New York City fall below those of both Chinese in China and whites in New York City. PMID- 10091191 TI - Safer sex strategies for women: the hierarchical model in methadone treatment clinics. AB - Women clients of a methadone maintenance treatment clinic were targeted for an intervention aimed to reduce unsafe sex. The hierarchical model was the basis of the single intervention session, tested among 63 volunteers. This model requires the educator to discuss and demonstrate a full range of barriers that women might use for protection, ranking these in the order of their known efficacy. The model stresses that no one should go without protection. Two objections, both untested, have been voiced against the model. One is that, because of its complexity, women will have difficulty comprehending the message. The second is that, by demonstrating alternative strategies to the male condom, the educator is offering women a way out from persisting with the male condom, so that instead they will use an easier, but less effective, method of protection. The present research aimed at testing both objections in a high-risk and disadvantaged group of women. By comparing before and after performance on a knowledge test, it was established that, at least among these women, the complex message was well understood. By comparing baseline and follow-up reports of barriers used by sexually active women before and after intervention, a reduction in reports of unsafe sexual encounters was demonstrated. The reduction could be attributed directly to adoption of the female condom. Although some women who had used male condoms previously adopted the female condom, most of those who did so had not used the male condom previously. Since neither theoretical objection to the hierarchical model is sustained in this population, fresh weight is given to emphasizing choice of barriers, especially to women who are at high risk and relatively disempowered. As experience with the female condom grows and its unfamiliarity decreases, it would seem appropriate to encourage women who do not succeed with the male condom to try to use the female condom, over which they have more control. PMID- 10091192 TI - Disease patterns of the homeless in Tokyo. AB - In recent years, homelessness has been recognized as a growing urban social problem in various countries throughout the world. The health problems of the homeless are considerable. The purpose of this study was to elicit, with sociodemographic profiles, the disease patterns among Tokyo's homeless. The subjects were 1,938 men who stayed at a welfare institution from 1992 to 1996. Diagnosed diseases/injuries and sociodemographic profiles were analyzed. The disease patterns of the homeless were compared to those of the male general population. Of the subjects, 8.3% were admitted to the hospital; 64.0% received outpatient care. Their observed morbidity rates by disease category were greater than those of the male general population in both Japan and Tokyo. Comorbidity of alcoholic psychosis/alcohol-dependent syndrome to both liver disease and pulmonary tuberculosis were greater than the average (P < .01). Construction work brought a higher risk of pulmonary tuberculosis (odds ratio = 2.0) and dorsopathies (odds ratio = 1.4) than did other jobs (P < .05). Disease patterns among the homeless in Tokyo were characterized by alcoholic psychosis/alcohol dependence syndrome; liver disease; pulmonary tuberculosis; diabetes mellitus; fractures, dislocations, sprains, strains; hypertension; and cerebrovascular disease. Although the sociodemographic backgrounds of Tokyo's homeless have become more diverse, the principal occupation of the homeless was unskilled daily construction work, which underlay the characteristics of their disease patterns. PMID- 10091193 TI - Marijuana use among minority youths living in public housing developments. AB - Youths residing in public housing developments appear to be at markedly heightened risk for drug use because of their constant exposure to violence, poverty, and drug-related activity. The purpose of this study was to develop and test a model of marijuana etiology with adolescents (N = 624) residing in public housing. African-American and Hispanic seventh graders completed questionnaires about their marijuana use, social influences to smoke marijuana, and sociodemographic and psychosocial characteristics. Results indicated that social influences, such as friends' marijuana use and perceived ease of availability of marijuana, significantly predicted both occasional and future use of marijuana. Individual characteristics such as antimarijuana attitudes and drug refusal skills also predicted marijuana use. The findings imply that effective prevention approaches that target urban youths residing in public housing developments should provide them with an awareness of social influences to use marijuana, correct misperceptions about the prevalence of marijuana smoking, and train adolescents in relevant psychosocial skills. PMID- 10091194 TI - Mediators of ethnic-associated differences in infant birth weight. AB - PURPOSE: To examine whether ethnic differences in low birth weight babies of low income women may be explained in part by group differences in prenatal health behaviors and psychosocial factors. METHODS: A prospective, survey of 1,071 low income, primiparous African-American and Mexican-origin women was conducted in Los Angeles County, California. In face-to-face interviews, data were obtained on substance use, prenatal stress, social support, attitudes toward pregnancy, initiation of prenatal care, and medical risk. Medical chart data were abstracted regarding medical risk factors and labor, delivery, and neonatal data. Interview data were linked with birth outcome data retrieved from maternal medical records. Structural equation modeling was used to test a hypothesized model in which differences in birth weight were expected to be mediated by ethnic differences in substance use, psychosocial factors, and medical risk. RESULTS: As expected, African-American women delivered babies of earlier gestational age and lower birth weight than did women of Mexican origin. Direct predictors of low birth weight were use of drugs and cigarettes, prenatal stress, and positive attitudes toward pregnancy; together, these factors accounted for the observed ethnic differences in birth weight. CONCLUSION: These data contribute to our understanding of the factors that may account for ethnic-associated differences in low birth weight. PMID- 10091195 TI - The role of curriculum in influencing students to select generalist training: a 21-year longitudinal study. AB - To determine if specific curricula or backgrounds influence selection of generalist careers, the curricular choices of graduates of Mount Sinai School of Medicine between 1970 and 1990 were reviewed based on admission category. Students were divided into three groups: Group 1, those who started their first year of training at the School of Medicine; Group 2, those accepted with advanced standing into their third year of training from the Sophie Davis School of Biomedical Education, a five-year program developed to select and produce students likely to enter primary care fields; and Group 3, those accepted with advanced standing into the third year who spent the first two years at a foreign medical school. All three groups took the identical last two years of clinical training at the School of Medicine. These were no significant differences with respect to initial choice of generalist training programs among all three groups, with 46% of the total cohort selecting generalist training. Of those students who chose generalist programs, 58% in Group 1, 51% in Group 2, and 41% in Group 3 remained in these fields rather than progressing to fellowship training. This difference was significant only with respect to Group 3. However, when an analysis was performed among those students providing only primary care as compared to only specialty care, there were no significant differences. Analysis by gender revealed women to be more likely to select generalist fields and remain in these fields without taking specialty training (P < .0001). Differentiating characteristics with respect to choosing generalist fields were not related to either Part I or Part II scores on National Board Examinations or selection to AOA. However, with respect to those specific specialties considered quite competitive (general surgery, obstetrics and gynecology, and ophthalmology), total test scores on Part I and Part II were significantly higher than those of all other students. The analysis indicated that, despite the diverse characteristics of students entering the third year at the School of Medicine, no one group produced a statistically greater proportion of generalists positions than any other, and academic performance while in medical school did not have a significant influence on whether a student entered a generalist field. PMID- 10091196 TI - Myxoedema, acquired and congenital, and the use of the thyroid extract. 1893. PMID- 10091197 TI - Foreign-born tuberculosis cases exceed US-born tuberculosis cases: New York City, 1997. PMID- 10091198 TI - Coronary heart disease in women, randomized clinical trials, HERS and RUTH. PMID- 10091199 TI - The heart and estrogen/progestin replacement study (HERS). PMID- 10091200 TI - A critical European view of the HERS trial. PMID- 10091201 TI - Association of dehydroepiandrosterone sulfate with serum HDL-cholesterol concentrations in post-menopausal Japanese women. AB - OBJECTIVES: Positive association between serum dehydroepiandrosterone sulfate (DHEAS) and high-density lipoprotein (HDL) cholesterol has been observed in men but not women. We aimed to examine the cross-sectional relationships of DHEAS, estradiol (E2), and sex hormone-binding globulin (SHBG) to serum lipid concentrations in post-menopausal Japanese women. METHODS: A total of 56 post menopausal Japanese women were derived from female residents in Takayama City in Japan. The information on body size, disease history, reproductive history, diet, and physical activity were obtained by a self-administered questionnaire. RESULTS: DHEAS was significantly and positively correlated with HDL-cholesterol after controlling for age and body mass index (BMI) (r = 0.28). There was no correlation between DHEAS and total-cholesterol (r = -0.02). E2 was not significantly correlated with total- and HDL-cholesterol and triglyceride. However, SHBG-unbound E2 was significantly positively correlated with HDL cholesterol (r = 0.34) and negatively correlated with triglyceride (r = -0.27) after controlling for age and BMI. SHBG was negatively correlated with triglyceride, although the correlation was not statistically significant (r = 0.22). CONCLUSION: These data suggest favorable effect of DHEAS as well as E2 and SHBG on lipid profile in Japanese post-menopausal women. PMID- 10091202 TI - The relationship between stress-coping and vasomotor symptoms in postmenopausal women. AB - OBJECTIVE: The objective was to assess whether menopausal women with vasomotor symptoms had a lower stress-coping than menopausal women without symptoms and if stress-coping changed when vasomotor symptoms had been effectively treated with estrogens. The objective was also to assess whether menopausal women, effectively treated for vasomotor symptoms, had a higher neuroticism score than women without such symptoms. METHODS: Two groups of physically and mentally healthy postmenopausal women were recruited from the outpatient clinic at the Department of Obstetrics and Gynaecology, University Hospital of Linkoping, Sweden. Sixteen women with vasomotor symptoms (target group) were treated with oral 17 beta estradiol, 2 mg/day during 3 months. A comparison group was formed comprising 17 women without vasomotor symptoms. The Kupperman Index was used to cover menopausal characteristics in all women at baseline as well as at the second visit after 3 months. Stress-coping was measured by means of the Stress Coping Inventory, which is an instrument developed to measure of the individual's appraisal of having adaptive resources for handling stressful situations. At the second visit all women were also asked to complete the Eysenck Personality Inventory. RESULTS: Women in the target group had a significantly lower stress coping than women in the comparison group at baseline as well as after 3 months. Stress-coping did not change after estrogen therapy, although the vasomotor symptoms had virtually disappeared. Women in the target group successfully treated for vasomotor symptoms, had a significantly higher neuroticism score compared to the comparison group. CONCLUSIONS: Differences in behaviour patterns and personality are probably two reasons why some women report or seek advice due to vasomotor symptoms and some women do not. Stress-coping in women with moderate to severe vasomotor symptoms is unaffected by estrogens. PMID- 10091203 TI - Placebo-controlled multicenter study of oral alendronate in postmenopausal osteoporotic women. FOSIT-Study-Group. Fosamax International Trial. AB - OBJECTIVES: To evaluate effects on bone mineral density (BMD), safety, and tolerability of a single daily dose of alendronate (10 mg), administered for 1 year to postmenopausal women with osteoporosis. METHODS: This interim analysis includes the first approximately 20% of patients to complete treatment in a large, placebo-controlled study (the Fosamax International Trial (Fosit)), which enrolled 1908 patients from 34 countries. Patients < or = 85-year-old with osteoporosis (lumbar spinal BMD > or = 2 S.D. below mean for mature premenopausal Caucasian women) were randomly assigned to treatment with alendronate or placebo once daily in the morning; all patients received supplemental calcium (500 mg/day). Dual-Energy X-ray Absorptiometry (DXA) was used to measure BMD in spine and proximal femur. RESULTS: A total of 297 patients had BMD data available for analysis. Patients treated with alendronate showed progressive increase of BMD during treatment. At 12 months, mean BMD had increased significantly (P < 0.001) at the lumbar spine (5.6%), trochanter (3.6%), and femoral neck (2.6%) in the alendronate group. Increases in BMD were significantly (P < 0.001) greater than in the placebo group at all sites. Among 442 patients assessed for safety, there were no statistically or clinically significant differences between treatment groups in the incidence of adverse events, including upper gastrointestinal adverse events, or laboratory abnormalities. CONCLUSIONS: Results of this multinational study show that oral alendronate, administered as 10 mg once daily for 1 year, is generally well tolerated and produces significant, progressive increases in BMD at the lumbar spine and proximal femur of postmenopausal women with osteoporosis. PMID- 10091204 TI - HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. AB - OBJECTIVES: We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS: A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13,100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth years); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS: Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-vertebral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17 1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS: This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved. PMID- 10091205 TI - Vertebral morphometric X-ray absorptiometry (MXA): relationship with bone mineral density in perimenopausal women. AB - OBJECTIVE: To evaluate the relationship between vertebral morphometry and vertebral bone mineral density (BMD) in a population of perimenopausal women. METHOD: We studied 120 healthy women (mean age (S.D.) 53.4 (8.3) years) referred for baseline bone densitometry around the menopause. Morphometric X-ray absorptiometry (MXA) was performed using a Hologic QDR 4500 A apparatus and assessed the anterior, mid and posterior heights of the third lumbar vertebra (L3). The anterior to posterior height ratio (AH/PH index) and the mid to posterior height ratio (MH/PH index) were calculated. Simultaneously, BMD of L3 was measured as antero-posterior dual energy X-ray BMD (AP-BMD DXA) and as lateral DXA BMD (L-BMD DXA). Subsequently, BMD of L3 was measured using single energy quantitative computed tomography, with a Siemens Somatom device (BMD QCT). RESULTS: The AH/PH index ranged from 0.840 to 1.150, with a mean of 0.995, the MH/PH index 0.880-0.980, with a mean of 0.937. The AH/PH index showed significant correlation with either L-BMD DXA (r = 0.54, P < 0.001) or BMD-QCT (r = 0.50, P < 0.001) but not with AP-BMD DXA (r = 0.05). Using an AH/PH index threshold of 0.97 we categorized the subjects into 42 women (group A) with an AH/PH index < 0.97 and 78 women (group B) with an AH/PH index greater than or equal to 0.97. BMD values were found to be lower in group A than in group B. The difference was not significant with AP-BMD DXA (1011.5 (155.7)) versus 988.5 (193.5) mg/cm2, P = 0.47) but reached high significance (P < 0.0001) with L-BMD DXA (797.2 (166.8) versus 462.9 (131.1) mg/cm2) and with BMD QCT (135.5 (24.8) versus 83.6 (18.3) mg/cm3). CONCLUSIONS: These results suggest that the AH/PH index of L3, assessed using MXA, shows some degree of correlation with BMD in perimenopausal women. PMID- 10091206 TI - Changes in body composition in women treated with gonadotropin-releasing hormone agonists. AB - OBJECTIVE: The changes that agonists of gonadotropin-releasing hormone (GnRH) produce in mineral bone mass are known, but, as far as we know, those produced by these agents in other body compartments are unknown. METHODS: We studied these changes using dual-energy X-ray absorptiometry in 50 eugonadal women treated with decapeptyl (Triptoreline), 3.75 mg injected intramuscularly, at 28-day intervals for 6 months. RESULTS: There were significant increases in fat content (9.5%, P < 0.0005) and weight (1.3%, P < 0.01), and significant decreases in fat-free mass ( 1.9%, P < 0.0001) and water content (-1.8%, P < 0.0002). Bone mass was lost in the axial skeleton (-3.6%, P < 0.0001) but not in the peripheral skeleton. CONCLUSIONS: The changes induced in body composition by the GnRH agonists are similar to those of natural menopause. PMID- 10091207 TI - Results of the colposuspension operation in pre and postmenopausal incontinent women. AB - OBJECTIVE: To compare the results of Burch colposuspension in premenopausal and postmenopausal women with urinary stress incontinence (USI). METHODS: A total of 85 women with urodynamic diagnosis of genuine urinary stress incontinence were divided into two groups, according to their menstrual status (premenopausal and postmenopausal group). All of them underwent the Burch colposuspension procedure. Clinical and urodynamic data were compared preoperatively and postoperatively and between the two groups. RESULTS: Cure rate was significantly higher after Burch colposuspension in the premenopausal as compared to the postmenopausal patients (90.9 vs 73.1%, respectively, P < 0.01). A significant reduction of the diurnal and nocturnal frequency and urgency was noted in both groups postoperatively. The reduction of urgency was more prominent in the premenopausal women (P < 0.001). There were no statistically significant differences between the preoperative and postoperative values of bladder capacity, residual volume, maximal voiding pressure, peak flow rate, absolute urethral length, functional urethral length, urethral pressure and maximum urethral closure pressure both preoperatively and postoperatively within the groups and between the two groups. Comparing the two groups postoperatively, the pressure transmission ratios in the postmenopausal women were found to be significantly lower in the middle two quarters of the urethra as compared to the premenopausal patients (P < 0.001). CONCLUSION: Burch colposuspension for urinary stress incontinence has better cure rate in premenopausal than in postmenopausal women. Nevertheless, the above procedure remains an acceptable method for treatment of USI in postmenopausal patients. PMID- 10091208 TI - [Helicobacter pylori and digestive hemorrhage due to duodenal ulcer: the prevalence of the infection, the efficacy of 3 triple therapies and the role of eradication in preventing a hemorrhagic recurrence]. AB - BACKGROUND: To report the prevalence of Helicobacter pylori in patients with bleeding duodenal ulcer and to verify the effect of eradication on hemorrhage recurrence. To evaluate the efficacy on H. pylori eradication and on ulcer healing of three one-week triple therapies and to compare their efficacy with that of a dual therapy. PATIENTS AND METHODS: One-hundred and eleven patients with bleeding duodenal ulcer not taking gastroerosive drugs were prospectively studied. At endoscopy, biopsies from gastric antrum and body were obtained (haematoxylin-eosin), and a 13C-urea breath test was also performed. Both diagnostic methods were repeated one month after completing one of the following treatments (randomized study): omeprazole (20 mg/12 h), amoxycillin (1 g/12 h) and clarithromycin (500 mg/12 h) (OAC, n = 27); omeprazole (20 mg/12 h), clarithromycin (500 mg/12 h) and metronidazole (500 mg/12 h) (OCM, n = 27); lansoprazole (30 mg/12 h), amoxycillin (1 g/12 h) and clarithromycin (500 mg/12 h) (LAC, n = 27); and lansoprazole (30 mg/12 h) and clarithromycin (500 mg/8 h) (LC, n = 27). The first three therapies were administered for one week, and LC for two weeks. Once eradication was confirmed no antisecretory therapy was administered. A breath test was performed in the follow-up at 6 months and at one year. RESULTS: The prevalence of H. pylori infection was 97.3% (95% CI: 92-99%). Five patients were lost from the study during follow-up. The eradication efficacy (intention-to-treat) was: OAC, 89% (72-96%); OCM: 93% (77-98%); LAC, 93% (77 98%), and LC, 70% (51-84%). Overall triple therapy efficacy was higher than that of dual therapy (91% vs 70%; p < 0.05). Thirteen patients needed a 2nd or 3rd therapy, and eradication success was finally achieved in all cases. The type of therapy was the only variable which influenced on H. pylori eradication (OR: 4.5; 95% CI: 1.4-14%; p < 0.01) and H. pylori eradication was the only variable which influenced on ulcer healing (OR: 4.7; 95% CI: 1.2-19%; p < 0.05). The yearly reinfection rate was 2.8% (0.9-7.8%). No hemorrhage recurrences occurred during the one year follow-up period. CONCLUSIONS: H. pylori prevalence in bleeding doudenal ulcer is almost 100%. These patients will be spared of hemorrhage recurrence at least for one year if infection is eradicated. Therefore, eradication therapy is the therapy of choice, and maintenance therapy with antisecretory drugs is no longer needed. One-week triple therapies with a proton pump inhibitor and two antibiotics (clarithromycin plus amoxycillin or metronidazole) have a high efficacy in patients with bleeding duodenal ulcer. PMID- 10091209 TI - [Ambulatory arterial pressure and left ventricular hypertrophy in untreated hypertensive patients]. AB - BACKGROUND: The study was designed to evaluate blood pressure (BP) values related to left ventricular hypertrophy (LVH) in a group of never treated middle-aged hypertensive subjects. PATIENTS AND METHOD: Non-invasive ambulatory blood pressure monitoring (ABPM) and echocardiography were performed in 149 hypertensive patients (25-50 years old) with diastolic blood pressure (DBP) 90 114 mmHg. LVH was considered when left ventricular mass (LVM) was > 134 g/m2 in males and > 110 g/m2 in females. RESULTS: 43% of patients had LVH. Patients with LVH had higher clinic and ambulatory BP values. The greatest differences were in mean 24-h SBP (p = 0.001) and in 24-h DBP (p = 0.006). With respect to LVH, there were no differences between dippers and non-dippers, males or females, and circadian or BP variability. LVM was positively correlated with clinical DBP (p = 0.24), 24 h SBP (p = 0.41), pulse pressure (PP) (p = 0.36) and absolute BP variability (p = 0.23). Multiple regression analysis confirmed that 24-h SBP and sex where positively associated with LVH independent of others factors. The existence of 24-h SBP > 150 mmHg dramatically increased the risk of LVH (odds ratio [OR] = 9.2; CI 95%: 2.8-29.3; p = 0.002). CONCLUSIONS: The present study indicates that in never treated middle-aged essential hypertensive patients the principal factor related to the presence of LVH is the value of systolic blood pressure throughout a 24-h period. PMID- 10091210 TI - [The prevalence of asthma-related symptoms in 13-14-year-old children from 9 Spanish populations. The Spanish Group of the ISAAC Study (International Study of Asthma and Allergies in Childhood)]. AB - BACKGROUND: Asthma is one of the more prevalent diseases in childhood. Geographical differences have been found but it is unknown if they are true or are a consequence of the different methods used in the study of asthma. POPULATION AND METHODS: In 9 Spanish populations: Almeria, Barcelona, Bilbao, Bahia de Cadiz, Cartagena, Castellon, Pamplona, Valencia and Valladolid, 27,407 children aged 13-14 years were interviewed using the asthma written and video questionnaires of the ISAAC protocol. Comparisons among geographical areas were performed using a cluster analysis and a Poisson regression model adjusting by gender. RESULTS: The prevalence of resting wheezing using the video questionnaire was higher in males than in females (15.4% versus 12.6%) for wheezing ever. In the last year the prevalence of wheezing was 7.8% in males versus 7.0% in females. The analysis shows a group of centers with low prevalence of asthma symptoms: Valladolid, Almeria, Castellon and Pamplona. Nevertheless there are also centers with higher prevalences as Bilbao, Barcelona and Bahia de Cadiz. CONCLUSIONS: Prevalence of asthma and asthmatic symptoms is high in Spanish children aged 13-14 years. There are true geographical differences in Spain, being Valladolid, Almeria, Castellon and Pamplona the areas with lowest prevalence. PMID- 10091211 TI - [Tobaccoism and albuminuria in hypertension and diabetes: is tobacco also harmful for the kidney?]. PMID- 10091212 TI - [The identification of a new mutation in the BRCA2 gene by protein truncation analysis in a Spanish family with hereditary breast cancer]. AB - The BRCA2 mutations are implicated in a high percentage of hereditary breast cancer cases. We report a novel mutation in a Spanish breast cancer family. We analyzed DNA samples of the proband and of the living first and second degree relatives. Exon 11 of BRCA2 gene were screened by the protein truncation test and direct sequencing. We identified a novel mutation, 6857 delAA, in three affected women, diagnosed of breast cancer at 29, 51 and 45 years of age, respectively, and in a healthy male. The BRCA2 mutation seems to be implicated in the development of early-onset breast cancer cases in this family. Identification of this novel mutation adds to the information on BRCA2 gene in hereditary breast cancer in Spanish population. PMID- 10091213 TI - [Biomedical research in Spain (I). An evaluation of the Fondo de Investigacion Sanitaria (FIS) through research projects financed in the 1988-1995 period in health-care institutions (hospitals)]. PMID- 10091214 TI - [The limitations on the minimum basic data set as an information system for the hospital services of a university center]. PMID- 10091215 TI - [A bibliometric study of works on medical terminology published in Spanish journals and included in the database of the Spanish Medical Index]. PMID- 10091216 TI - [Mitral valve prosthetic endocarditis due to Hafnia alvei]. PMID- 10091217 TI - In vitro activity of aminoglycosides on the respiratory burst response in human polymorphonuclear neutrophils. AB - In response to phagocytosis of microbes or chemical stimuli, neutrophils generate reactive oxygen species which represent the major bactericidal mechanism of these cells. We have investigated the influence of aminoglycosides (amikacin, gentamicin, netilmicin and tobramycin), antibiotics with a marked concentration dependent killing effect, on the human neutrophil oxidative burst represented by the release of hydrogen peroxide. This study was performed using time-dependent cellular experiments and a cell-free system. In the cellular model, 2-h incubation with amikacin (ranging from 10 mg/l to 1 g/l), enhanced hydrogen peroxide release by stimulated human neutrophils. At higher concentrations (1 to 5 g/l), hydrogen peroxide production was decreased. No significant effects were observed with the other aminoglycosides at concentrations ranging from 10 mg/l to 2.5 g/l. The pro-oxidant activity of amikacin may be due to a cellular mechanism through oxidative metabolism of human neutrophils as demonstrated in the cell washing experiment, whereas the antioxidant activity observed for higher concentrations may be a result of a scavenging effect as demonstrated in the cell free system. The enhanced of hydrogen peroxide production observed for therapeutic concentrations of amikacin could be a beneficial effect for neutrophil bactericidal functions. PMID- 10091218 TI - Growth factor deprivation therapy of hormone insensitive prostate and breast cancers utilizing antisense oligonucleotides. AB - Antisense oligonucleotides (oligos) are artificial sequences of nucleotide bases which may be synthesized complementary to known regions within specific mRNAs. When these constructed oligos interact with protein encoding mRNA they may regulate expression of various growth factors and/or their receptors. Oligos directed against transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR), were employed: A) in vitro to affect the growth of hormone insensitive human derived PC-3 prostate cancer cells as well as the human derived UACC-893 breast cancer cell line; and B) in vivo to treat tumors established by these cell lines in athymic nude mice. The in vitro results for each oligo, and their combination, produced significant inhibition of both prostate and breast cell lines. In addition, the combination of oligos most efficiently diminished the immunohistochemical expression of both TGF-alpha and EGFR in PC-3 cells. Direct in vivo inoculation of oligos into established PC-3 or UACC-893 tumors in nude mice produced hemorrhagic necrosis within 2-3 days. Such therapy could represent a new tier of therapy for recurrent, hormone insensitive, tumors based upon the concept of growth factor deprivation. PMID- 10091219 TI - In vivo induced desensitization of beta-adrenoceptors in rat lung. Effect of nitrendipine. AB - The effect of nitrendipine on desensitization of beta-adrenoceptors induced by isoprenaline was investigated using rat lungs. Rats were treated with saline, isoprenaline, nitrendipine, or nitrendipine + isoprenaline. After 7 days of treatment, tracheas were isolated and the dissociation constant (Kb) for the propranolol-beta-receptor complex was determined. Lung parenchymal tissue was used to study the binding characteristics of beta-adrenoceptors. The Kb value for the propranolol-beta-receptor complex was found to be up to 6.4-fold higher in trachea isolated from isoprenaline-treated rats (32 +/- 5.4 nM) than from control rats (4.9 +/- 1.2 nM); the Kb value for trachea from isoprenaline + nitrendipine treated rats was 7.0 +/- 1.2 nM. A 31% reduction in the number of beta adrenoceptors as compared to those of the control group was observed in the isoprenaline-treated group while the number of the beta-adrenoceptors in the isoprenaline + nitrendipine-treated group was significantly increased as compared to that of the isoprenaline-treated group. PMID- 10091220 TI - Development of bone marrow erythroblastic islands in hypoxic rats with intact or damaged kidney tubules. AB - Keeping in mind the renal origin of erythropoietin (EPO), we designed our study in order to estimate the role of kidney damage in the development of bone marrow erythropoiesis in erythroblastic islands (EI). The experiment was performed comparing intact rats with untreated and gentamicin-pretreated rats (50 mg/kg/15 days) exposed to hypobaric pressure (42.55 kPa/6 h) to stimulate hypoxia. Blood samples were taken following a 2-week period. The study included an estimation of plasma EPO levels by RIA, the number of peripheral blood parameters and bone marrow EI (classes I to V/femur), the rate of erythroid differentiation into erythroblasts, and the rate of repeated participation of macrophages in new EI reconstruction. Plasma EPO increased to 52.88 mU/ml (p < 0.01) and 23.45 mU/ml at 0 h immediately following hypobaric exposure in untreated and gentamicin-treated rats, respectively, as compared to 14.25 mU/ml in intact animals. Bone marrow recovery patterns were markedly expressed in untreated hypoxic animals throughout the observed period. The rate of erythroid differentiation into erythroblasts in EI was increased (p < 0.01) while the number of maturing EI decreased (p < 0.01); increased reconstruction was observed in involuted EI. Less pronounced stimulation of erythropoiesis was observed in hypoxic gentamicin-treated rats. The direct impact of the hypoxic stimulus on the erythropoietic bone marrow tissue was considered significant for the erythropoietic response via activation of macrophages. These data support the hypothesis that EI central macrophages play an important role as local regulators of bone marrow erythropoiesis. PMID- 10091221 TI - Role of antioxidants in gastric mucosal damage induced by indomethacin in rats. AB - Reactive oxygen species play a role in the formation of gastric lesions induced by nonsteroidal antiinflammatory drugs. The present study was undertaken to determine whether endogenous antioxidants in gastric mucosa can protect it against the damaging effects of oxygen free radicals. This study examine oxygen free radical production (superoxide anions and hydrogen peroxide), gastric mucosa antioxidant defense mechanisms (glutathione, catalase, superoxide dismutase), the lesion-inducing effects of the generated oxygen free radicals (vascular permeability, lipid peroxidation) and gastric ulceration in rats treated orally with indomethacin at 10 mg/kg at 2 and 6 h after drug administration. Two hours after administration of the antiinflammatory drug, there was a sharp increase in production of oxygen free radicals in the gastric mucosa with no alteration in other parameters examined. Six hours after indomethacin administration the production of oxygen free radicals returned to basal levels, but there was a high degree of gastric ulceration and a significant increase in lipid peroxidation and vascular permeability together with decreases of 45% in glutathione concentration and 30% in catalase relative to the control group. These results suggest that like plasma, the gastric mucosa has an antioxidant capacity and only when this capacity is exhausted are the lesive effects of the oxygen free radicals manifested. PMID- 10091222 TI - Effect of methylcarbonylmethyl 2(S)-[4-(4-guanidinobenzoyloxy) phenyl] propionate methanesulfonate (TT-S24) on pancreatic secretion in rats. AB - The effect of methylcarbonylmethyl 2(S)-[4-(4-guanidinobenzoyloxy) phenyl] propionate methanesulfonate (TT-S24), a newly synthesized trypsin inhibitor, on exocrine pancreatic secretion was examined and compared with that of camostat in rats. Intraduodenal (i.d.) administration of TT-S24 and camostat resulted in an increase in volume, amylase concentration and amylase output of pancreatic juice. Although i.v. injection of TT-S24 and camostat (3 mg/kg) had no effect on the pancreatic juice volume, TT-S24 (i.v.) dose-dependently increased pancreatic juice volume under acetylcholine (10 micrograms/kg/min) infusion. In addition, the weight of pancreases from WBN rats was significantly increased by 28 day oral administration of TT-S24 (100 mg/kg) with a potency similar to that observed with camostat. PMID- 10091223 TI - The effect of topical dihydroergocristine on the intraocular pressure in alpha chymotrypsin-induced ocular hypertensive rabbits. AB - Having previously reported that topical dihydroergocristine dose-dependently reduces intraocular pressure in ocular normotensive rabbits with a maximum response and potency higher than those of timolol and pilocarpine, the aim of the present work was to assess the effect of this drug in alpha-chymotrypsin-induced ocular hypertensive rabbits. Intraocular pressure was measured with a pneumatonometer. The experiments examining the effects of dihydroergocristine on intraocular pressure were conducted in 10 albino rabbits in which ocular hypertension was induced by intracameral injection of alpha-chymotrypsin. Intraocular pressure responses to drug vehicle and 5 different doses of topical dihydroergocristine were studied in order to obtain a dose-response curve. Tonographies were also performed in ocular hypertensive rabbits 2 h after vehicle and dihydroergocristine instillation to ascertain the actions of this drug on aqueous humor dynamics. Topical dihydroergocristine was found to lower intraocular pressure in alpha-chymotrypsin-induced ocular hypertensive rabbits in a dose-related manner, with the ED50 of the concentration-response curve very similar to that previously obtained in ocular normotensive rabbits. Data from tonographic studies indicate that dihydroergocristine reduces intraocular pressure in this animal model for glaucoma by decreasing the aqueous humor inflow. Our findings suggest that topical dihydroergocristine may be useful in the treatment of ocular hypertension. PMID- 10091224 TI - Discovery and pharmacological evaluation of new platelet glycoprotein gpIIb/IIIa antagonists. PMID- 10091225 TI - [Science and practice at the 83rd Annual Congress of the German Society of Pathology: Pathology of the Gastrointestinal Tract. Progress reports from important areas in pathology. The 1999 best research results. Diagnostic courses. On to Jena!]. PMID- 10091226 TI - [Tissue fragment diagnosis in gynecopathology]. AB - Empirical knowledge, daily diagnostic efforts and scientific spirits are the prerequisites of theoretical and practical progress in gynecopathology. The current standards in this field have their root in the continuous interests of gynecologists educated and skilled in pathology. In Germany, however, there is no more the gynecologist, who is in charge for both the clinical and pathological diagnostic business. Also, it is no more a rule for gynecologists to pass through a fellowship in pathology during their specialization. This development leads to more distance between gynecology and pathology, which per se is a potential source of misunderstandings. One of the tasks of this introduction and subsequent articles is to describe controversial areas and to offer ways out of the conflicts. Yet, the master key for avoiding misunderstandings is the close interdisciplinary co-operation in the perioperative management of the patient. PMID- 10091227 TI - [Guidelines for preparation of uterine surgical specimen]. AB - Tumor classification, grading and staging of malignant tumors of the cervix and corpus uteri should be done according to the rules of the WHO fascicle of 1994 and the TNM manual of 1997, respectively. With these lines taking into account, the surgical pathology report will include the most important prognostic factors, which in part are also of therapeutic relevance, i.e. localization of the lesion, depth of invasion and distant tumor manifestation. Yet, gross inspection and preparation are the prerequisites of the quality of the histopathological statement. Accurate documentation of tumor extension, depth of invasion into the cervical stroma and/or the myometrium and distance to the resection lines at the vaginal cuff and the parametrium needs to be given in centimeters, first by eye, than controlled by histopathology. The tumor extension of cervical carcinomas should be given in three dimensions, including the depth of invasion into the cervical wall. It is also mandatory to document the number and size of lymph nodes with metastatic involvement compared to the total number of nodes which are discovered in parametral, pelvioperitoneal and paraaortal sites. Most of what has been outlined for the surgical pathology report of hysterectomy specimens is also pertinent to conisations, by whatever method these are performed (cold knife, laser or loop). For appropriate documentation of the localization of the lesion, horizontal expansion of the dysplastic lesion and recognition of microinvasion it is sufficient to dissect the conisation specimen clockwise and to cut the various paraffin blocks in serial sections. PMID- 10091228 TI - [Natural course of HPV infection. Usefulness of HPV analysis in cervix diagnosis]. AB - Cervical carcinomas and their precursors (cervical dysplasia, CIN1-3) are associated with human papillomavirus (HPV) infections. Epidemiological and in vitro-studies have shown that some of the genital HPV types, the high risk-types 16, 18, 31 etc., code for proteins (E6/E7) which strongly influence the cell cycle and genome stability. Progression from weak to severe dysplasia and to invasive cancer is associated with increasing expression of these viral oncogenes. Which additional cofactors contribute to progression of some dysplasias to carcinomas is still a matter of investigation. Recent results point to genetic predisposition (p53 polymorphism), cellular immune reaction, and cytokine expression. For HPV detection in cervical swabs and biopsies two highly sensitive and reliable systems (PCR, Hybrid Capture system) are available. Although classical histological methods are sufficient for the diagnosis of high grade lesions and invasive cancer, HPV testing might give valuable diagnostic and prognostic clues especially in cases of unclear cytology (ASCUS) or weak dysplasia. PMID- 10091229 TI - [Assessment of cervical dysplasia with DNA image cytometry]. AB - Dysplastic epithelia represent potentially precancerous conditions in which the risk of progression to cancer is unknown in the individual case. The positive predictive value of mild and moderate dysplasias of the uterine cervix is only about 13%. Using DNA image cytometry on restained, conventional Papsmears the cytometric equivalent of chromosomal aneuploidy can be detected as marker for neoplastic transformation of cells. The identification of DNA aneuploidy in dysplastic squamous epithelia can increase the predictive value for malignant transformation to over 90%. DNA aneuploidy qualifies squamous intraepithelial lesions as high grade (H-SIL) which have to be treated whereas lack of DNA aneuploidy characterizes low grade squamous intraepithelial lesions (L-SIL) which have only to be controlled. The methodology is meanwhile internationally standardized concerning performance and diagnostic interpretation. PMID- 10091230 TI - [Diagnosis and therapy of cervical squamous epithelial dysplasias]. AB - Diagnosis of cervical dysplasia is based on colposcopy, cytology and histology. In case of suspect cytology, the management (controls only, extended diagnosis by histology or therapy without additional histological control) is dependent on colposcopic findings. Biopsy or endocervical curettings are necessary in cases of suspect ectocervical findings or endocervical lesions, respectively. As a rule, HE staining is sufficient for histological diagnosis. Yet, additional prognostic information is obtained by HPV-analysis and DNA-cytometry. Grading of dysplasia should be done according to the most recent WHO/ISGYP criteria. The exact diagnosis as to the grading and extension of dysplasia is the prerequisite of an effective individually adjusted therapy. For ablative therapy, gynecologists have to focus their attention on modern organ preserving surgery strategies (loop excision). PMID- 10091231 TI - [Diagnosis and therapy of cervical squamous epithelial carcinomas]. AB - The clinical management of cervical carcinomas is solely based upon the FIGO staging system. Therefore clinical staging is crucial for primary therapy of cervical carcinomas. Accurate morphologic evaluation of the surgical specimens completes the clinical staging and determines postoperative procedures and the individual prognosis. The most important morphologic prognostic factors include stromal invasion, vascular space involvement, tumor volume and surgical margins (pelvic recurrence, metastasic dissemination, survival). The prognostic and therapeutic importance of tumor biological markers is presently controversial. Radical surgical therapy (Wertheim-Meigs surgery) and primary or adjuvant pelvic radiation are currently the basic therapeutic modalities for invasive cervical carcinomas. The role of chemotherapy still needs to be defined. A less radical therapeutic approach is performed for microinvasive cervical carcinomas depending on the extent of stromal invasion, the presence of vascular space involvement and the surgical margins. PMID- 10091232 TI - [Molecular and clinical endocrinology of the endometrium]. AB - The ovarian steroid hormones estradiol and progesterone exert their effect by interacting with their intracellular receptors, which, after ligand binding translocate to the nucleus and bind to the promoter regions of target genes. The consequence is a change in the transcription rate of the target genes, followed by a change in production of the corresponding proteins. Target genes of the sexual steroid hormones include cytokines and growth factors, among them CSF-1, TGF-beta and LIF. The rhythm and activity of steroidogenesis, receptor modulation and transcription are reflected by cycle-specific proliferation and differentiation processes in the endometrium. Quantitative and/or qualitative molecular endocrinology is of increasing interest for better definition of morphological changes, although, as yet, the pathological laboratory test is of much less practical consequence than a suspicious vaginal sonography. In spite of the high standard of ultrasound techniques, however, most cases with slightly increased endometrial thickness show histologically benign changes of the endometrium rather than endometrial precancer or cancer. This is especially true for perimenopausal women with no other clinical findings. Yet, the cancer risk is increased in women under tamoxifen therapy. Hence, as a rule, these cases, when endometrial thickness exceeds 5 mm, need a diagnostic biopsy or abrasio. PMID- 10091233 TI - [Algorithm of endometrial meta- and hyperplasia]. AB - As to to their frequency and variety, endometrial meta- and hyperplasias are the most impressive examples of the growth and differentiation potential of the Muellerian system and the inductive power of steroid hormones and related inter- and intracellular factors. Characteristic steroid reactions are the glandular hyperplasias, ciliated and squamous cell metaplasias in the case of hyperestrogenism, and the mucinous and clear cell meta- and hyperplasias in the case of gestagen excess. In 1994, the WHO established a new classification of endometrial hyperplasias. This classification takes into account the profound differences in cancer risk, and accordingly demands a clearcut distinction between simple and complex (steroid sensitive, almost always reversible) hyperplasias without atypia, and simple and complex (partial steroid resistant and potential progressive) hyperplasias with atypia. The conclusion drawn from clinical experience is, that the atypical endometrial hyperplasia--and this alone -is the precancerous lesion of the ordinary endometroid carcinoma. In contrast, it is still not clear which biological significance accounts to all the complex squamous, mucinous, clear cell and ciliated cell meta- and hyperplasias. Yet, it is good pathological and clinical practice, to upgrade any metaplastic lesion with nuclear atypia, and to remove the uterus as it is done in almost all atypical endometrial hyperplasias. PMID- 10091234 TI - [Algorithm of clinical aspects and pathology of endometrial carcinoma]. AB - The carcinoma of the endometrium is the most common malignancy seen in the female pelvic genital organs. Important risk factors are age and unopposed estrogen (both endogenous and exogenous). In comparison, the association of antiestrogens (e.g., tamoxifen) and endometrial cancer is rather small, as yet. Fortunately, survival is high because the majority of patients have in common the presence of a low grade, low stage carcinoma of the endometroid type which gives rise to vaginal bleeding and forces the patients to attend the gynecologist. Special screening studies (e.g. vaginal sonography) to evaluate the endometrium are not indicated in the asymptomatic patient without risk factors. Tumor type, grading, and--most importantly--the depth of myoinvasion and the extent of extrauterine disease are the prognostic indicators that allow differential treatment, and help to identify patients at high risk vs. low risk for recurrent disease. Investigations of growth fraction, ploidy, steroid receptors, K-ras or p53 may be a supplement for dissecting special subgroups, but do not influence the clinical regimen, as yet. Most patients with stage I cancer are cured by surgery alone. Patients successfully treated for endometrial cancer should enjoy the benefits of estrogen replacement therapy, since they do not bear a risk of increased recurrence of their disease. Radiation therapy will be given to patients with incomplete resection of pelvic disease and/or extensive lymphonodal involvement, especially paraaortal lymph node metastasis. As yet, there is no rationale for an adjuvant hormone-(gestagen-) or chemotherapy. An exception, however, is the (mostly palliative) treatment of recurrent disease. PMID- 10091235 TI - [Trophoblast lesions and trophoblast tumors]. AB - The clinico-pathologic characteristics and the histological/immunohistological differential diagnosis of villous trophoblastic lesions (complete, partial, and invasive hydatiform moles), gestational choriocarcinoma and trophoblastic tumors and pseudotumors of the placental site (placental-site trophoblastic tumor, exaggerated placental site reaction, placental site nodule) are reviewed in context with aspects of cytogenetics, epidemiology and molecular pathogenesis. PMID- 10091236 TI - [6th Baltic-German Symposium of Pathology in Palanga/Lithuania]. PMID- 10091237 TI - [Patient information: "Physicians in pathology: dedicated to life"]. PMID- 10091238 TI - How long to treat sinusitis? PMID- 10091239 TI - Is the body perfect? PMID- 10091240 TI - Dr. Altemeier requested the following review (human nutrition) PMID- 10091241 TI - A pediatrician's view. Commitment. PMID- 10091242 TI - A history of women in pediatrics. PMID- 10091243 TI - Issues of women in residency and early careers. PMID- 10091244 TI - Women in pediatric practice: trends and implications. PMID- 10091245 TI - Women in academic pediatrics. PMID- 10091246 TI - The future of women in pediatrics. PMID- 10091247 TI - Predicting protein decomposition: the case of aspartic-acid racemization kinetics. AB - The increase in proportion of the non-biological (D-) isomer of aspartic acid (Asp) relative to the L-isomer has been widely used in archaeology and geochemistry as a tool for dating. the method has proved controversial, particularly when used for bones. The non-linear kinetics of Asp racemization have prompted a number of suggestions as to the underlying mechanism(s) and have led to the use of mathematical transformations which linearize the increase in D Asp with respect to time. Using one example, a suggestion that the initial rapid phase of Asp racemization is due to a contribution from asparagine (Asn), we demonstrate how a simple model of the degradation and racemization of Asn can be used to predict the observed kinetics. A more complex model of peptide bound Asx (Asn + Asp) racemization, which occurs via the formation of a cyclic succinimide (Asu), can be used to correctly predict Asx racemization kinetics in proteins at high temperatures (95-140 degrees C). The model fails to predict racemization kinetics in dentine collagen at 37 degrees C. The reason for this is that Asu formation is highly conformation dependent and is predicted to occur extremely slowly in triple helical collagen. As conformation strongly influences the rate of Asu formation and hence Asx racemization, the use of extrapolation from high temperatures to estimate racemization kinetics of Asx in proteins below their denaturation temperature is called into question. In the case of archaeological bone, we argue that the D:L ratio of Asx reflects the proportion of non-helical to helical collagen, overlain by the effects of leaching of more soluble (and conformationally unconstrained) peptides. Thus, racemization kinetics in bone are potentially unpredictable, and the proposed use of Asx racemization to estimate the extent of DNA depurination in archaeological bones is challenged. PMID- 10091248 TI - Documenting the diet in ancient human populations through stable isotope analysis of hair. AB - Fundamental to the understanding of human history is the ability to make interpretations based on artefacts and other remains which are used to gather information about an ancient population. Sequestered in the organic matrices of these remains can be information, for example, concerning incidence of disease, genetic defects and diet. Stable isotopic compositions, especially those made on isolates of collagen from bones, have been used to help suggest principal dietary components. A significant problem in the use of collagen is its long-term stability, and the possibility of isotopic alteration during early diagenesis, or through contaminating condensation reactions. In this study, we suggest that a commonly overlooked material, human hair, may represent an ideal material to be used in addressing human diets of ancient civilizations. Through the analysis of the amino-acid composition of modern hair, as well as samples that were subjected to radiation (thus simulating ageing of the hair) and hair from humans that is up to 5200 years old, we have observed little in the way of chemical change. The principal amino acids observed in all of these samples are essentially identical in relative abundances and content. Dominating the compositions are serine, glutamic acid, threonine, glycine and leucine, respectively accounting for approximately 15%, 17%, 10%, 8% and 8% of the total hydrolysable amino acids. Even minor components (for example, alanine, valine, isoleucine) show similar constancy between the samples of different ages. This constancy clearly indicates minimal alteration of the amino-acid composition of the hair. Further, it would indicate that hair is well preserved and is amenable to isotopic analysis as a tool for distinguishing sources of nutrition. Based on this observation, we have isotopically characterized modern individuals for whom the diet has been documented. Both stable nitrogen and carbon isotope compositions were assessed, and together provide an indication of trophic status, and principal type (C3 or C4) of vegetation consumed. True vegans have nitrogen isotope compositions of about 7/1000 whereas humans consuming larger amounts of meat, eggs, or milk are more enriched in the heavy nitrogen isotope. We have also analysed large cross sections of modern humans from North America and Europe to provide an indication of the variability seen in a population (the supermarket diet). There is a wide diversity in both carbon and nitrogen isotope values based at least partially on the levels of seafood, corn-fed beef and grains in the diets. Following analysis of the ancient hair, we have observed similar trends in certain ancient populations. For example, the Coptics of Egypt (1000 BP) and Chinchorro of Chile (5000-800 BP) have diets of similar diversity to those observed in the modern group but were isotopically influenced by local nutritional sources. In other ancient hair (Egyptian Late Middle Kingdom mummies, ca. 4000 BP), we have observed a much more uniform isotopic signature, indicating a more constant diet. We have also recognized a primary vegetarian component in the diet of the Neolithic Ice Man of the Oetztaler Alps (5200 BP). In certain cases, it appears that sulphur isotopes may help to further constrain dietary interpretations, owing to the good preservation and sulphur content of hair. It appears that analysis of the often-overlooked hair in archaeological sites may represent a significant new approach for understanding ancient human communities. PMID- 10091249 TI - Preservation of key biomolecules in the fossil record: current knowledge and future challenges. AB - We have developed a model based on the analyses of modern and Pleistocene eggshells and mammalian bones which can be used to understand the preservation of amino acids and other important biomolecules such as DNA in fossil specimens. The model is based on the following series of diagenetic reactions and processes involving amino acids: the hydrolysis of proteins and the subsequent loss of hydrolysis products from the fossil matrix with increasing geologic age; the racemization of amino acids which produces totally racemized amino acids in 10(5) 10(6) years in most environments on the Earth; the introduction of contaminants into the fossil that lowers the enantiomeric (D:L) ratios produced via racemization; and the condensation reactions between amino acids, as well as other compounds with primary amino groups, and sugars which yield humic acid-like polymers. This model was used to evaluate whether useful amino acid and DNA sequence information is preserved in a variety of human, amber-entombed insect and dinosaur specimens. Most skeletal remains of evolutionary interest with respect to the origin of modern humans are unlikely to preserve useful biomolecular information although those from high latitude sites may be an exception. Amber-entombed insects contain well-preserved unracemized amino acids, apparently because of the anhydrous nature of the amber matrix, and thus may contain DNA fragments which have retained meaningful genetic information. Dinosaur specimens contain mainly exogenous amino acids, although traces of endogenous amino acids may be present in some cases. Future ancient biomolecule research which takes advantage of new methologies involving, for example, humic acid cleaving reagents and microchip-based DNA-protein detection and sequencing, along with investigations of very slow biomolecule diagenetic reactions such as the racemization of isoleucine at the beta-carbon, will lead to further enhancements of our understanding of biomolecule preservation in the fossil record. PMID- 10091250 TI - Early medieval cattle remains from a Scandinavian settlement in Dublin: genetic analysis and comparison with extant breeds. AB - A panel of cattle bones excavated from the 1000-year-old Viking Fishamble Street site in Dublin was assessed for the presence of surviving mitochondrial DNA (mtDNA). Eleven of these bones gave amplifiable mtDNA and a portion of the hypervariable control region was determined for each specimen. A comparative analysis was performed with control region sequences from five extant Nordic and Irish cattle breeds. The medieval population displayed similar levels of mtDNA diversity to modern European breeds. However, a number of novel mtDNA haplotypes were also detected in these bone samples. In addition, the presence of a putative ancestral sequence at high frequency in the medieval population supports an early post-domestication expansion of cattle in Europe. PMID- 10091251 TI - How microbial ancient DNA, found in association with human remains, can be interpreted. AB - The analysis of the DNA of ancient micro-organisms in archaeological and palaeontological human remains can contribute to the understanding of issues as different as the spreading of a new disease, a mummification process or the effect of diets on historical human populations. The quest for this type of DNA, however, can represent a particularly demanding task. This is mainly due to the abundance and diffusion of bacteria, fungi, yeasts, algae and protozoans in the most diverse environments of the present-day biosphere and the resulting difficulty in distinguishing between ancient and modern DNA. Nevertheless, at least under some special circumstances, by using rigorous protocols, which include an archaeometric survey of the specimens and evaluation of the palaeoecological consistency of the results of DNA sequence analysis, glimpses of the composition of the original microbial flora (e.g. colonic flora) can be caught in ancient human remains. Potentials and pitfalls of this research field are illustrated by the results of research works performed on prehistoric, pre Columbian and Renaissance human mummies. PMID- 10091252 TI - Freezer anthropology: new uses for old blood. AB - Archived blood fractions (plasma, settled red cells, white cells) have proved to be a rich and valuable source of DNA for human genetic studies. Large numbers of such samples were collected between 1960 and the present for protein and blood group studies, many of which are languishing in freezers or have already been discarded. More are discarded each year because the usefulness of these samples is not widely understood. Data from DNA derived from 10-35-year-old blood samples have been used to address the peopling of the New World and of the Pacific. Mitochondrial DNA haplotypes from studies using this source DNA support a single wave of migration into the New World (or a single source population for the New World), and that Mongolia was the likely source of the founding population. Data from Melanesia have shown that Polynesians are recent immigrants into the Pacific and did not arise from Melanesia. PMID- 10091253 TI - The molecular genetics of European ancestry. AB - In an earlier paper we proposed, on the basis of mitochondrial control region variation, that the bulk of modern European mitochondrial DNA(mtDNA) diversity had its roots in the European Upper Palaeolithic. Refining the mtDNA phylogeny and enlarging the sample size both within Europe and the Middle East still support this interpretation and indicate three separate phases of colonization: (i) the Early Upper Palaeolithic about 50,000 BP; (ii) the Late Upper Palaeolithic 11,000-14,000 BP; and (iii) the Neolithic from 8500 BP. PMID- 10091254 TI - Molecular genetic evidence for the human settlement of the Pacific: analysis of mitochondrial DNA, Y chromosome and HLA markers. AB - Present-day Pacific islanders are thought to be the descendants of Neolithic agriculturalists who expanded from island South-east Asia several thousand years ago. They speak languages belonging to the Austronesian language family, spoken today in an area spanning half of the circumference of the world, from Madagascar to Easter Island, and from Taiwan to New Zealand. To investigate the genetic affinities of the Austronesian-speaking peoples, we analysed mitochondrial DNA, HLA and Y-chromosome polymorphisms in individuals from eight geographical locations in Asia and the Pacific (China, Taiwan, Java, New Guinea highlands, New Guinea coast, Trobriand Islands, New Britain and Western Samoa). Our results show that the demographic expansion of the Austronesians has left a genetic footprint. However, there is no simple correlation between languages and genes in the Pacific. PMID- 10091256 TI - [Influenza and asthma]. AB - The relationship between infections of the respiratory tract and exacerbations of pulmonary symptoms in individuals with asthma is well established on clinical grounds. Patients having an acute attack of asthma often give a history of a "cold" before the onset of the exacerbation. The identification rate of viruses during exacerbations of asthma (10-30%) is much higher than the viral identification rate generally found during asymptomatic periods in asthmatics (3%). The mechanisms whereby upper respiratory viruses might induce or contribute to attacks of asthma are currently unknown: epithelial damage, increased cytokines releasability, mouth breathing.... Influenza vaccination is recommended in patients with chronic pulmonary diseases. However, bronchial hyperreactivity has been reported after influenza vaccination in asthmatics. Reactions to these vaccines may be due to non-immunogenic impurities, which are not present in the more recently developed subunit vaccines. In spite of the lack of double-blind studies between subunit and killed influenza virus vaccines, and because of the potential bad prognosis of influenza infection on airway obstruction, influenza vaccination should be recommended in asthmatics with stable respiratory function but influenza vaccination rate remains low. PMID- 10091255 TI - Analysis of ancient DNA from a prehistoric Amerindian cemetery. AB - The Norris Farms No. 36 cemetery in central Illinois has been the subject of considerable archaeological and genetic research. Both mitochondrial DNA (mtDNA) and nuclear DNA have been examined in this 700-year-old population. DNA preservation at the site was good, with about 70% of the samples producing mtDNA results and approximately 15% yielding nuclear DNA data. All four of the major Amerindian mtDNA haplogroups were found, in addition to a fifth haplogroup. Sequences of the first hypervariable region of the mtDNA control region revealed a high level of diversity in the Norris Farms population and confirmed that the fifth haplogroup associates with Mongolian sequences and hence is probably authentic. Other than a possible reduction in the number of rare mtDNA lineages in many populations, it does not appear as if European contact significantly altered patterns of Amerindian mtDNA variation, despite the large decrease in population size that occurred. For nuclear DNA analysis, a novel method for DNA based sex identification that uses nucleotide differences between the X and Y copies of the amelogenin gene was developed and applied successfully in approximately 20 individuals. Despite the well-known problems of poor DNA preservation and the ever-present possibility of contamination with modern DNA, genetic analysis of the Norris Farms No. 36 population demonstrates that ancient DNA can be a fruitful source of new insights into prehistoric populations. PMID- 10091257 TI - [Asthma in children below 5 years of age: diagnosis and treatment]. AB - Asthma is the most frequent chronic disease in pediatrics and the increase in its prevalence is a major public health problem. Diagnosis may be difficult in the young child, symptomatology most often occurring following a viral infection. It is important not to ignore a foreign body in the airways or fibrocystic disease and asthma remains, particularly in infants, a diagnosis of elimination. Misdiagnosis or insufficient treatment of asthma may risk the development of irreversible histological lesions and also could compromise pulmonary growth and the child's lung reserve. Spacer devices and nebulisers enable inhaled therapy to be administered to very young children. The value of early diagnosis is to institute appropriate treatment notably in severe asthma with inhaled corticosteroid therapy, the aim being to reduce remodelling lesions of the airways. The minimal effective dose should be defined to minimalize side-effects. The treatment of asthma is not restricted to pharmacotherapy: attempts should be made to reduce intercurrent viral infections, domestic pollution (including smoking) and allergenic concentrations. However, as for all chronic diseases, the clinician will encounter poor compliance. The work of education and support of health professionals is fundamental to the management of asthma. PMID- 10091258 TI - [Therapeutic use of N-acetylcysteine in acute lung diseases]. AB - Oxidants play a key role in disease processes, particularly in the detrimental mechanisms leading to tissue damage in certain forms of acute lung injury. A number of mediators contribute to the pathologic response in ARDS, SIRS or hyperoxia-induced pulmonary damage. One of the most important detrimental factors is the generation and activation of highly reactive oxygen species which are leading factors implicated in the process of tissue damage. N-acetylcysteine (NAC) is a free radical scavenger and might access the endothelial cell thus increasing intracellular glutathione (GSH) stores. Different studies have demonstrated that NAC might be a promising compound either for the prevention or the treatment of acute lung damages such as ARDS. However, the true beneficial effect so far reported in several clinical and experimental studies contrasts with some contradictory and intriguing aspects, probably because the significance of a direct in vivo antioxidative effect of this compound remains to be established in humans. Thus, the mode of action of NAC may not be the same in different pathologies and clinical situations. More research into the mechanisms of action of this unique xenobiotic substance may offer a clue for elucidating these controversies. PMID- 10091259 TI - [Physiopathology of sleep obstructive respiratory disorders. Experimental methods and practical applications]. AB - Recent progress in the physiology of the upper airways has led to significant advances in evaluating the dynamics of upper airway occlusion during sleep. Measuring the collapsibility of the upper airways and localizing the site of obstruction should theoretically lead to efficacious non-mechanical treatment and enable selection of patients susceptible of benefiting from surgical procedures. From a diagnostic point of view, fluctuations in the nasal pressure curve appear to give more precise information on ventilatory changes and their association with disrupted sleep pattern than conventional parameters such as thermistance signals or induction plethysmography. Again, from a pathophysiological point of view, little is known about the role or tissue inflammation and repeated upper airway trauma in the transition from simple snoring to sleep apnea syndrome. Current studies lead to the conclusion that the dilatroy muscles of the upper airways in the apneic subject are the target for adaptive trophic, immunohistochemical and metabolic phenomena in response to stimulation comparable to training against resistance. Although there is no evidence that sleep affects neuromuscular activity in apneic subjects, the disappearance of compensatory hyperactivity on awakening and the reduction of muscle contraction efficacy (transmission of the dilatory force to soft tissues) observed in patients may explain the greater instability of the upper airways characteristic of sleep apnea syndrome. PMID- 10091260 TI - [Pharyngeal muscles and sleep obstructive apnea syndrome]. AB - An analysis of the way the pharyngeal musculature modulates the caliber of the pharynx is important to better understand and treat obstructive sleep apnea syndromes. The caliber of the pharynx at the soft palate depends on the action of the tensor veli, the palatoglossus, the palatopharyngeus and the uvula muscles. At the ligual level, the action of the genioglossus and the geniohyoideus predominate. These different muscle groups contract in co-ordination before the diaphragm contracts. Their activity is diminished and disorganized during sleep. These muscles appears to have a histological composition adapted to short duration intense contractions making them vulnerable to fatigue. In apneic patients, these muscles are solicited constantly. Muscular lesions related to overwork have been suggested. The histological composition of these muscles is modified in apneic patients compared with non-apneic subjects (increased number of type IIa fibres), the expression of an adaptive process. The degree of adaptation varies depending of the pharyngeal level considered. Similar to their reflex stimulation, the response of these pharyngeal muscles to increased resistance is probably greater at the soft palate level. Greater solicitation of palatine muscles associated with their greater vulnerability to fatigue could explain why obstruction is particularly important at this level. A study of the mechanical and histological properties of the pharyngeal musculature is required for a better understanding of the occlusive mechanisms of the upper airways and must be undertaken before initiating therapeutic stimulation of these muscles. PMID- 10091261 TI - [Smoking among medical students in Casablanca]. AB - OBJECTIVES: Smoking is a real public health problem, even in the medical profession. Our work was aimed at determining the prevalence of smoking in medical students in Casablanca and assess their attitude towards this problem. MATERIALS AND METHODS: A questionnaire enquiry was carried out during the 1994 1995 university year. All medical students in Casablanca (2,640) were invited to participate the questionnaire but only 1,321 (50%) responded. RESULTS: Prevalence of occasional or regular smoking was 13%. It increased progressively from first year students (13%) to sixth year students (21.5%) and was significantly higher in male students (25.7% versus 3.2% in females). 53.8% of the smokers were trying to stop. Ex-smokers accounted for 10.3% of the total 76.3% of the smokers hoped they would not be smoking within five years although level was 90% in ex-smokers. 90.9% of the students admitted that smoking is dangerous to health, (76% of the first year students and 94% of the fifth and sixth year students). The respiratory risks of smoking were well understood. 73.6% of students thought that convincing others not to smoke is a responsibility of doctors, but only 31.6% would do this in the absence of disease linked to smoking. CONCLUSIONS: There has been a net fall in the prevalence of smoking since 1982 (34% at that time compared with 13% in 1994) and the dangers of tobacco are better understood. Medical students understand the problem better. Courses about the pathology of tobacco smoking since 1983 have certainly contributed. PMID- 10091262 TI - [Evolution of the management of lung diseases in general medicine in Bordeaux (1992-1995)]. AB - Lower respiratory tract infections (LRTI) are very often managed by General Practitioners (GPs). In France, the 1991 Lille Consensus Conference set out guidelines for the management of respiratory tract infections; in 1994, the Ministry of Health published Official Medical Recommendations (OMR) to be applied to seasonal respiratory infections. The aim of the study is to evaluate the impact of these OMR in 1995 on GPs' attitude when confronted with a community acquired pneumonia in a previously healthy 40-year-old adult, with no sign of complications. Sixty seven GPs took, part in the same study by questionnaire in 1992 and 1995; we observed an increase in the prescription of aminopenicillin without a beta-lactamase inhibitor (41% in 1992 vs 66% in 1995; p = 0.009), and a reduction in both the use of aminopenicillin with a beta-lactamase inhibitor (35% in 1992 vs 11% in 1995; p = 0.002) and the concomitant prescription of cortico steroids (43% in 1992 vs 14% vs 14% in 1995; p = 0.0009). Between 1992 and 1995, general practitioners in the Bordeaux region have changed their therapeutic choices in community-acquired pneumonia. In 1995, antibiotic prescriptions followed consensus guidelines more closely. PMID- 10091263 TI - [Cystic lymphangioma of the neck and mediastinum: are there acquired forms? Report of 37 cases]. AB - BACKGROUND: In 9 out of 10 cases, lymphangiomas are observed during the first years of life, generally located in the neck. Rare lymphangiomas have been reported in adults, usually in an intrathoracic localization, raising the hypothesis of an acquired origin. PATIENTS AND METHODS: A retrospective analysis of patients undergoing surgery for lymphanioma of the neck or mediastinum was conducted. Pathology reports, clinical data and medical imaging (CT) were reviewed and operative and post-operative findings were analyzed in order to determine whether the cases could be divided into congenital and non-congenital forms. RESULTS: Data were obtained on 37 patients (23 men and 14 women, mean age 45 years, range 8-77). Four lesions (11%) were located in the neck: 3 in children and one in an elderly subject (77 yrs). Thirty-three tumors (89%) were located in the mediastinum. In 5 cases, the tumor was located in the phrenic nodes of the anterior mediastinum. These lymphangiomas occurred in young adults, had a CT density less than liquid with enhancement after contrast injection, and had a malformative vascular component proven anatomically and histologically (hemolymphangioma). These elements favored a congenital orgin. In 28 cases (76.6%) the tumor involved nodes in the posterior or middle mediastinum. They occurred in older adults and were purely liquid with no vascular component. These lymphangiomas were undoubtedly acquired. CONCLUSION: In children, adolescents and young adults, lymphagiomas are found in the neck or anterior mediastinum and have a tissular component. These tumors should be considered as congenital lymphangiomas. In older adults, lymphangiomas are found in the posterior or middle mediastinum and are purely liquid cysts suggesting an acquired origin. PMID- 10091264 TI - [Respiratory complications of the vinorelbine-mitomycin combination]. AB - The respiratory toxicity of vinca alkaloids only appears when they are associated with mitomycin. Few reports have been noted with vinorelbine, the last molecule of this class. We report 4 cases of acute dyspnea induced by the association mitomycin-vinorelbin, The 4 patients were treated for lung cancer. At the end of the injection of vinorelbin appeared an acute bronchospasm. In 3 cases, the symptoms disappeared with broncho-dilatators and corticoids. The fourth patient needed an additional respiratory support. After the acute syndrome, a chronic respiratory insufficiency developed in three patients. Two patients required continuous oxygenotherapy. The pulmonary toxicity of the mitomyin-vinca alkaloids association is characterized by an acute dyspnea. The dyspnea appears within 2 hours after the end of the administration of vinorelbine. The frequent existence of airflow obstruction in patients with lung cancer exposes to high risk of severes incidents. These treatments must be stopped at onset of the first pulmonary symptom. The association of mitomycin with vinorelbine (as for all vinca alkaloids) in chemotherapy protocols for treatment of non-small-cell lung cancer should not be indicated because there is an increase of the toxicity without increase of efficiency. PMID- 10091265 TI - [Report of 2 cases of pleural recurrences of surgically treated bronchogenic carcinoids. Diagnostic and therapeutic problems]. AB - Recurrence after surgery for bronchial carcinoid tumors is very uncommon in cases of typical tumors and occasionally seen in cases of atypical tumors. We observed two cases of recurrence in an unusual location, the pleura. Somatostatin analog and MIBG scinigrams were useful for diagnosis. Treatment required surgical excision of the relapsing tumor, cytoreductive hepatic surgery or hepatic arterial chemoembolization for liver metastases, chemotherapy, interferon, radionuclide therapy, and somatostatin analogs for carcinoid syndrome. PMID- 10091266 TI - [Interstitial lung disease induced by timolol eye solution]. AB - Timolol maleate is a beta-blocker widely used in topical administration for open angle glaucoma. We report a case of interstitial pneumopathy which developed in a 58-year-old patient who was given timolol eyedrops (2 drops b.i.d. since 1986). The patient presented with cough and dyspnea and was found to have a restrictive disorder leading to hypoxemia (68 mmHg at rest and 51 mmHg during exercise). Bronchial lavage fluid had high lymphocyte (28%) and neutrophil (7%) counts. Transbronchial biopsies demonstrated moderate fibrous thickening of the interalveolar walls. Timolol eyedrops were stopped. Three months later, the patient was asymptomatic with normal lung function, chest x-ray and thoracic CT scan. PMID- 10091267 TI - [Weber-Rendu-Osler disease: pulmonary arterio-venous malformation with shunt disclosed after 5 occurrences of purulent meningococcal encephalitis]. AB - Hereditary hemorrhagic telangectasis or Weber-Rendu-Osler disease is associated with the presence of capillary malformations with pulmonary visceral shunts. These shunts are the cause of recurrent infections of the nervous system by loss of the anti-infectious lung filter. Hereditary hemorrhagic telangiectasis was diagnosed in a 68-year-old woman with a history of epistaxis, cutaneous telangectasis, purulent and pyogenic brain abscesses and meningitis. Outcome was favorable with antibiotic therapy. Ventilation as well as chest x-ray, brain scan and liver ultrasongraphy were normal. Blood gases showed a PO2 at 63 mmHg in ambient air and 62 mmHg with FiO2 = 1. There was no dyspnea or cyanosis nor any apparent polycythemia. Pulmonary angiography showed and arteriovenous malformation in the lower right lobe. Endovascular embolization was achieved with coils and N-butyl-cyano-acrylate glue which enabled angiographic occlusion and normalization of gas exchange: on ambient air the PaO2 = 71 mmHg and on FiO2 = 1, PaO2 was 359 mmHg. A true shunt was suspected on account of the association of hereditary hemorrhagic telangiectasis and recurrent meningitis. The diagnosis was suspected on blood gases alone. PMID- 10091268 TI - [Gorham disease of the rib with osteolysis followed by bone remodeling. Study with magnetic resonance imaging]. AB - Gorham disease, or massive osteolysis, generally presents as osteolysis of a girdle bone. We report the case of a young adult who presented a fracture followed by destruction of the third right rib, then by regrowth eight months later. PMID- 10091269 TI - [Alveolar microlithiasis with pleural calcification]. PMID- 10091270 TI - [Unusual diagnosis of post-traumatic hemothorax]. PMID- 10091271 TI - [Drug prescription protocol to improve prescription safety in thoracic oncology]. PMID- 10091272 TI - Exercise and immune function. Recent developments. AB - Comparison of immune function in athletes and nonathletes reveals that the adaptive immune system is largely unaffected by athletic endeavour. The innate immune system appears to respond differentially to the chronic stress of intensive exercise, with natural killer cell activity tending to be enhanced while neutrophil function is suppressed. However, even when significant changes in the level and functional activity of immune parameters have been observed in athletes, investigators have had little success in linking these to a higher incidence of infection and illness. Many components of the immune system exhibit change after prolonged heavy exertion. During this 'open window' of altered immunity (which may last between 3 and 72 hours, depending on the parameter measured), viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. However, no serious attempt has been made by investigators to demonstrate that athletes showing the most extreme post-exercise immunosuppression are those that contract an infection during the ensuing 1 to 2 weeks. This link must be established before the 'open window' theory can be wholly accepted. The influence of nutritional supplements, primarily zinc, vitamin C, glutamin and carbohydrate, on the acute immune response to prolonged exercise has been measured in endurance athletes. Vitamin C and glutamine have received much attention, but the data thus far are inconclusive. The most impressive results have been reported in the carbohydrate supplementation studies. Carbohydrate beverage ingestion has been associated with higher plasma glucose levels, an attenuated cortisol and growth hormone response, fewer perturbations in blood immune cell counts, lower granulocyte and monocyte phagocytosis and oxidative burst activity, and a diminished pro- and anti inflammatory cytokine response. It remains to be shown whether carbohydrate supplementation diminishes the frequency of infections in the recovery period after strenuous exercise. Studies on the influence of moderate exercise training on host protection and immune function have shown that near-daily brisk walking compared with inactivity reduced the number of sickness days by half over a 12- to 15-week period without change in resting immune function. Positive effects on immunosurveillance and host protection that come with moderate exercise training are probably related to a summation effect from acute positive changes that occur during each exercise bout. No convincing data exist that moderate exercise training is linked with improved T helper cell counts in patients with HIV, or enhanced immunity in elderly participants. PMID- 10091273 TI - Exercise metabolism and beta-blocker therapy. An update. AB - The rationale for the concurrent prescription of beta-blockers and programmes of exercise is that both medication and physical activity can improve the quality of life of patients with cardiovascular disease. Difficulties arise when drugs reduce either the physical ability or the motivation to exercise. This article focuses on the physiological limitations to prolonged aerobic exercise in patients receiving beta-blockers. Possible limiting factors to exercise while taking beta-blockers include reduction in heart rate and cardiac output, local alterations to blood flow, changes to muscle and liver glycogenolysis, and alterations to adipose and intra-muscular lipolysis. The disadvantages and advantages of nonselective and beta 1-selective drugs are discussed, as well as those of drugs that have beta 2-agonist properties. Particular emphasis is placed upon the beta-blocker-induced attenuation of the normal increase in fat oxidation during prolonged exercise. There are physiological advantages, especially for the physically active individual, in prescribing beta 1-selective rather than nonselective drugs in controlled release, rather than conventional release, form. Additionally, there may be further advantages in prescribing drugs which have partial agonist properties at beta 2 receptors. PMID- 10091275 TI - Physical training and exercise-related injuries. Surveillance, research and injury prevention in military populations. AB - Athletes and soldiers must both develop and maintain high levels of physical fitness for the physically demanding tasks they perform; however, the routine physical activity necessary to achieve and sustain fitness can result in training related injuries. This article reviews data from a systematic injury control programme developed by the US Army. Injury control requires 5 major steps: (i) surveillance to determine the size of the injury problem; (ii) studies to determine causes and risk factors for these injuries; (iii) studies to ascertain whether proposed interventions actually reduce injuries; (iv) implementation of effective interventions; and (v) monitoring to see whether interventions retain their effectiveness. Medical surveillance data from the US Army indicate that unintentional (accidental) injuries cause about 50% of deaths, 50% of disabilities, 30% of hospitalisations and 40 to 60% of outpatient visits. Epidemiological surveys show that the cumulative incidence of injuries (requiring an outpatient visit) in the 8 weeks of US Army basic training is about 25% for men and 55% for women; incidence rates for operational infantry, special forces and ranger units are about 10 to 12 injuries/100 soldier-months. Of the limited duty days accrued by trainees and infantry soldiers who were treated in outpatient clinics, 80 to 90% were the result of training-related injuries. US Army studies document a number of potentially modifiable risk factors for these injuries, which include high amounts of running, low levels of physical fitness, high and low levels of flexibility, sedentary lifestyle and tobacco use, amongst others. Studies directed at interventions showed that limiting running distance can reduce the risk for stress fractures, that the use of ankle braces can reduce the likelihood of ankle sprains during airborne operations and that the use of shock-absorbing insoles does not reduce stress fractures during training. The US Army continues to develop a comprehensive injury prevention programme encompassing surveillance, research, programme implementation and monitoring. The findings from this programme, and the general principles of injury control therein, have a wide application in civilian sports and exercise programmes. PMID- 10091274 TI - Dietary supplements and the promotion of muscle growth with resistance exercise. AB - Nutritional strategies of overfeeding, ingesting carbohydrate/protein before and after exercise, and dietary supplementation of various nutrients [e.g. protein, glutamine, branched-chain amino acid, creatine, leucine, beta-hydroxy beta-methyl butyrate (beta-HMB), chromium, vanadyl sulfate, boron, prasterone (dehydroepiandrosterone [DHEA]) and androstenedione] have been purported to promote gains in fat-free mass during resistance training. Most studies indicate that chromium, vanadyl sulfate and boron supplementation do not affect muscle growth. However, there is evidence that ingesting carbohydrate/protein prior to exercise may reduce catabolism during exercise and that ingesting carbohydrate/protein following resistance-exercise may promote a more anabolic hormonal profile. Furthermore, glutamine, creatine, leucine, and calcium beta-HMB may affect protein synthesis. Creatine and calcium beta-HMB supplementation during resistance training have been reported to increase fat-free mass in athletic and nonathletic populations. Prasterone supplementation has been reported to increase testosterone and fat-free mass in nontrained populations. However, results are equivocal, studies have yet to be conducted on athletes, and prasterone is considered a banned substance by some athletic organisations. This paper discusses rationale and effectiveness of these nutritional strategies in promoting lean tissue accretion during resistance training. PMID- 10091276 TI - Facial injuries in skiing. A retrospective study of 549 cases. AB - In the last 2 decades, reports of skiing injuries have shown an increasing number of skiers with severe trauma. This article provides an account of a retrospective study of 549 patients with 1155 facial injuries sustained while skiing who received treatment at the Department of Oral and Maxillofacial Surgery at the University Hospital in Innsbruck, Austria between 1991 and 1996. The study was based on a questionnaire answered by the patients and on case report forms. Most of the patients were male (65.2%) and were aged between 3 and 81 years (average 28.4 years). A simple fall while skiing was the main type of accident (45.9%), followed by collisions with other people (23.5%). Injuries were classified into 1 of 3 groups: (i) lesions of the soft tissue (32.2% of all injuries); (ii) dentoalveolar traumas (24.3%); and (iii) fractures of facial bones (43.5%). Lacerations and haematomas were the most frequent lesions in patients with injuries to the soft tissues. The group of patients with dentoalveolar trauma mainly presented with fractures of tooth crowns. Fractures involving the mandible and the zygomatic bone were predominant in patients in the third group. Concomitant injuries mainly included injuries to the brain and skull fractures. Treatment was ambulatory, or by admission and surgery. We did not observe an increase in the number of skiing accidents causing facial injury in the last 5 years. Facial injuries represented 4% of all skiing injuries, a lower proportion than in other sports. PMID- 10091277 TI - Management of lumbar injuries in athletes. AB - Lumbar spine pain is a common and disabling condition affecting an athlete's ability to train and compete. The athletic management team must take a cooperative approach to diagnosis and treatment. The presentation pattern and injury history may provide an early cue to diagnosis; information gained by the trainer or therapist at the time of injury is particularly important. The unique anatomy and biomechanics of the lumbar segments leads to certain injury patterns. Knowledge of the potential motion, muscle effectors of motion and mechanisms of injury allows for a highly specific diagnosis. A meticulous physical examination with particular attention to neurological findings should be used to confirm suspicions from the athlete's symptom pattern. Early conservative treatment should be initiated for all patients except those who are mechanically unstable or neurologically impaired. Aerobic and nonpainful sports-specific training may be continued under the care of the trainer or physical therapist. This will limit the loss of skill and endurance when normal activity is resumed. Diagnosis specific medical and physical therapy should supplement this training activity. A care team that carefully analyses the pain presentation, injury history and symptoms, and directs a diagnosis-specific treatment programme, should manage lumbar spine conditions in the athlete. PMID- 10091278 TI - [Pathological bone density in chronic inflammatory bowel diseases--prevalence and risk factors]. AB - INTRODUCTION: Osteopenia and osteoporosis are frequent but often underestimated complications in inflammatory bowel disease. In patients with IBD, several factors could contribute to osteopenia, but the pathogenetic mechanisms are still not completely understood. We carried out a prospective study to evaluate the prevalence and possible etiologic factors for osteopenia and subsequent osteoporosis in IBD-patients. METHODS: 140 patients with inflammatory bowel disease (Crohn's disease n = 125, ulcerative colitis n = 15) underwent clinical and spine radiological assessments. Lumbar bone mineral densities were measured by dual energy X-ray absorptiometry (DXA). Markers of bone formation and resorption and vitamin D were assessed in n = 95 patients. Patients were asked about medication, previous or actual intestinal stenosis, smoking and intestinal resection. A lactose-H2-breath test was undertaken if lactose intolerance was clinically suspected. RESULTS: Compared to age- and sex-matched healthy controls (Z-score), the prevalence of osteopenia (Z < -1) was 62%, while osteoporosis (Z < -2) occurred in 38%. The mean bone density of IBD-patients was osteopenic with no significant differences between Crohn's disease (Z = -1.24) and ulcerative colitis (Z = -1.25). Osteoporotic fractures were seen in three patients (2.1%). Crohn's disease patients with osteoporosis showed a significant lower body mass index (BMI) than patients with normal bone density. 52.9% of patients with manifest osteoporosis underwent systemic steroid treatment in the preceding year, but only 34% of those with normal bone density. Except hemoglobin, none of the biochemical markers showed a significant difference between osteoporosis, osteopenia and patients with normal bone density. CONCLUSION: The results show a high prevalence of osteopenia and osteoporosis in IBD. Since osteoporosis is often associated with low body mass index, multiple intestinal resections and previous systemic steroid treatment, we suggest a bone densitometry in these patients. Since etiology of osteoporosis in IBD is multifactorious and not completely understood, there is still no standard treatment. The effect of osteoanabolic and antiresorptive agents must be evaluated in further studies. PMID- 10091279 TI - [Endoscopic therapy of ischemia-type biliary lesions in patients following orthotopic liver transplantation]. AB - Ischemic-type biliary lesions (ITBL) mainly induce stenoses in liver transplants causing cholestasis thus endangering the allograft. ERC enables distinction of ITBL from other differential diagnosis. From 1988 to 1998, 1,026 liver transplantations had been carried out at our clinic. 2.4% (25 out of 1,026) of liver transplanted patients were afflicted from ITBL. 60% (15 out of 25) of patients were endoscopically treated by means of sphincterotomy and balloon dilation. Furthermore, some patients needed extraction of calculi (n = 3), bile duct sequester (n = 6) or stenting (n = 4), respectively. Three patients suffered from ITBL type 1 (= only extrahepatic lesions) and five other patients were afflicted from ITBL type 2 (= circumscript intrahepatic lesions). 90% of those patients revealed long-term benefit from endoscopic therapy (follow-up to seven years). Another 15 patients elicited ITBL type 3 (= multiple intra- and extrahepatic lesions). Therefrom, nine patients had to be retransplanted directly while eight others were assigned to endoscopic treatment. Follow-up investigations revealed that retransplantation could be avoided in 50% of ITBL patients by means of endoscopic therapy for at least three years. In contrast, only 27% of ITBL patients could survive for more than three years without endoscopic therapy. Endoscopic success depends on localization and severity of ITBL complications in the biliary tract of the liver allograft. Therefore, benefit of endoscopic therapy depends on proper diagnosis as early as possible guiding further therapeutic strategy. Conclusively, endoscopic success enables maintenance of liver function in ITBL afflicted liver grafts and avoids or at least, delays retransplantation. PMID- 10091280 TI - [Endoscopic therapy of Barrett esophagus--a supplement to drug and surgical options?]. AB - Within the last few years intestinal metaplasia at the gastroesophageal junction (Barrett's esophagus) has turned out to be a "shooting star" in the field of gastrointestinal diseases. The detection rate of Barrett's epithelium by the endoscopists and pathologists has raised dramatically as well as the incidence of the carcinoma at the gastroesophageal junction. Furthermore the "short Barrett" was discovered as a relevant risk factor for cancer development. To date ablation techniques with thermal devices, photodynamic techniques (PDT) and the mucosal resection (EMR) compete as local endoscopic treatment methods. However to date it is still in discussion whether in case of nondysplastic Barrett's esophagus endoscopic therapy is an "overtreatment" and an "undertreatment" in case of Barrett's with high-grade dysplasia or early cancer. The currently available data are discussed. PMID- 10091281 TI - [Ultrasound-controlled endoscopic papillotomy in pregnancy in severe biliary pancreatitis]. AB - A 24-years-old woman at eleventh weeks gestation was admitted to our hospital with severe acute pancreatitis. Based upon a history of cholecystolithiasis, laboratory findings of cholestasis and a critical clinical course an ultrasound guided endoscopic papillotomy was performed nine hours after admission. Sludge was removed from the common bile duct without fluoroscopic control. Following this procedure the patients condition improved continuously during typical conservative treatment of the acute pancreatitis. The laboratory findings returned to normal. An imminent abortion between the eighth and eleventh day of hospitalization could be avoided under conservative measures. Oral nutrition was resumed without complications, and the patient was discharged on the 15th day after admission being completely recovered. At 37th week's gestation she was delivered of a healthy girl. PMID- 10091282 TI - [Burns following magnetic resonance tomography study]. AB - Skin burns associated with magnetic resonance imaging (MRI) examinations have been published. We describe the case of a 54-year-old patient with third-degree burns after MRI of the abdomen and pelvis on a 1.5 T MR system. PMID- 10091283 TI - [Alcohol and body weight]. AB - Alcohol intake contributes to energy balance. Chronic and moderate alcohol consumption (i.e. 20-40 g/day) plus a high fat intake (i.e. > 40% of energy intake) favor a positive energy balance and thus weight gain. By contrast a high alcohol intake (i.e. > 20% of energy intake) may lead to malnutrition depending on the concomitant nutrient intake. It is evident that alcohol cannot be considered as an "empty" calorie. Energy wasting mechanisms, which have been proposed by some authors, are unlikely to contribute to energy balance in healthy subjects. Our present knowledge on the energetic value of alcohol mainly depend on physiologic data based on the measurements of energy and substrate balances. By contrast epidemiologic data on the effect of alcohol intake on body weight are contradictory. This is explained by the limitations of epidemiological studies as well as by the possible contributions of other life style-related factors. It is evident that many studies on the effect of alcohol on body weight are uncontrolled studies. It is surprising that although 100 years of research have gone in this area we still have no definite answer to the question. PMID- 10091285 TI - [Classification of chronic pancreatitis]. PMID- 10091284 TI - [Preferential COX-2 inhibition: its clinical relevance for gastrointestinal non steroidal anti-inflammatory rheumatic drug toxicity]. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. These drugs tend to cause significant side effects, however, including gastric and intestinal toxicity. The mechanism of action of NSAIDs is through their inhibition of the key enzyme of prostaglandin biosynthesis, the cyclooxygenase. Recently, two forms of cyclooxygenase have been found to exist: COX-1 and COX-2, the constitutive and inducible forms, respectively. COX-1 exists in the stomach, intestine, kidneys and platelets, while COX-2, the inducible form, is expressed during inflammation. The therapeutic effects of NSAIDs are largely the result of inhibition of the enzyme cyclooxygenase-2 (COX-2), whereas the toxic effects (e.g., gastrointestinal, renal and platelet effects) are primarily due to the inhibition of COX-1. Individual NSAIDs show different potencies against COX-1 compared with COX-2 and this explains the variations in the side effects of NSAIDs at their anti-inflammatory doses. Drugs with high potency against COX-2 and a better COX-2-/COX-1 activity ratio will have anti inflammatory activity with fewer gastrointestinal side effects. In contrast piroxicam and indomethacin, which drugs have a much higher potency against COX-1 than against COX-2, are amongst those with the highest gastrointestinal toxicity. Based on these findings, COX-2 seems to be an ideal target for the development of new anti-inflammatory drugs. Several compounds with preferential or specific COX 2 inhibiting properties have been synthesized and evaluated in pre-clinical and clinical studies i.e. Meloxicam, Celecoxib, MK-966, Flusolid and L-745, 337. The COX-2 selectivity of these novel NSAIDs relate well to their favorable gastrointestinal tolerability profile. Clinical trials have shown meloxicam and celecoxib to be as effective as currently available NSAIDs, but with an improved gastrointestinal tolerability profile. Further clinical trials and large-scale postmarketing surveillance programs are needed, however, to confirm the potential therapeutic benefits of these novel preferential or specific COX-2 inhibitors. PMID- 10091286 TI - [Milestones in the immunopathogenesis of endemic sprue]. PMID- 10091287 TI - [Regulated exocytosis: Ca(2+)-sensor in exocrine cells?]. PMID- 10091288 TI - [Venous diseases]. PMID- 10091289 TI - [Reconstruction of mediastinal veins in same side dialysis shunt]. AB - Centralvenous obstruction is a rare however typical lesion with patients on chronic hemodialysis. A still functional arteriovenous shunt in its run-in can cause serious disorder, especially painful congestion and an insufficient dialysis. Should the shunt be maintained, a run-off reconstruction is required. 13 patients were treated with a centralvenous obstruction combined with a complication of the shunt. In 8 patients the intervention was either impossible from the beginning or finally proved to be not successful after repeated recanalisations. 6 out of these patients underwent a transsternal reconstruction of their bypass (a total of 7 interventions). 2 patients died perioperatively, 2 patients died 1 year, respectively 1 1/2 years later with a still intact reconstruction, 2 patients are still alive. Their reconstruction has been working for two, respectively three years. The bypass material was large-calibrated e PTFE with external support. Compared to conventional indications the catheter techniques proved to be less effective in the treatment of central venous obstruction. One year after the first intervention only three out of seven shunts could still be used for the dialysis. The longest symptom-free period was 12 months. The operative reconstruction is indeed very effective but it implies considerable risks and effort. This method cannot be recommended to patients on chronic dialysis who are in a poor condition. PMID- 10091290 TI - [Therapy of deep leg vein thrombosis. When is surgical therapy indicated?]. AB - In spite of quite a few clinical trials the benefit of venous thrombectomy is seen controversially. The primary objectives of treating venous thrombosis are survival rate, prevention of pulmonary embolism and of postthrombotic syndrome. We report our experience with 47 patients who underwent venous thrombectomy. The mortality rate was 0%. We did not observe clinically relevant pulmonary embolism. After two years 90% of thrombectomised veins were patent. The mortality rates given in the literature of conservative treatment with heparin and following oral anticoagulation are 0.4 to 1.6%. Fibrinolysis shows mortality rates of 1 to 2.4, and thrombectomy of 3.8%, respectively. Venous thrombectomy is an effective treatment to prevent pulmonary embolism. In our own experience we saw no clinically significant pulmonary event. The danger of embolism rises with the proximity of the venous thrombus. Therefore those patients may have the greatest potential benefit from thrombectomy who present with a mobile inguinal thrombus or a thrombus in the iliac vein. So far there are no statistically sufficient data to support the indication of thrombectomy to prevent a postthrombotic syndrome. PMID- 10091291 TI - [Stent implantation after thrombectomy of pelvic veins. Indications, results]. AB - PURPOSE: Retrospective study on frequency of iliac venous stenoses that are cause (venous spur) or consequence (postoperative or postthrombotic) of iliofemoral thrombosis, and on the results of interventional treatment. METHODS: From 1990 through 1996, 76 patients were operated on for acute iliac vein thromboses. All patients had transfemoral venous thrombectomy with creation of an inguinal av fistula. Immediate results of thrombectomy were documented by intraoperative completion venogram. Since 1995 venous spurs eventually detected during thrombectomy were immediately treated by stent implantation. Before scheduled closure of the av-fistula at three months, cross-over arteriovenography was performed. Additional significant iliofemoral venous stenoses were also treated interventionally at this time. RESULTS: 42 hemodynamically significant iliofemoral venous stenoses were found in 38 (50%) patients. Intraoperative phlebography revealed left common iliac vein obstructions suggestive of venous spurs in 30 patients (49% of left-sided thromboses). At three months, five patients (7%) had postthrombotic iliac vein stenoses, and seven patients (9%) had postoperative common femoral vein stenoses. A total of 26 stents were implanted into 20 stenoses (eight spurs, all postthrombotic and postoperative stenoses). There was an acute re-occlusion due to a technical error during stent implantation. In all other patients, the venous lumen could be completely restored. Three of four re-stenoses (at 3, 4, 7, and 12 months) were successfully treated by another intervention. We observed one late failure at 60 months. Cumulative primary (secondary) five-year patency rate (Kaplan-Meier) is 72% (88%). CONCLUSION: For venous spurs as well as for postthrombotic or postoperative venous stenoses, stent implantation can be recommended as a simple, safe, and durable means to prevent rethrombosis. PMID- 10091292 TI - [Experiences with loco-regional fibrinolytic therapy of deep venous thrombosis with defined drainage management]. AB - From 1989 to September 1997 1184 patients with deep vein thrombosis were treated. 606 (51.2%) received a specific therapy with loco-regional lysis. The application of two cycles of 20 mg Alteplase within 8 hours prevailed in combination with 1000 IE heparin per hour. In absence or lack of therapeutical effect further cycles of 20 or 40 mg of Alteplase were given. In the time free from lysis the patients received 30,000 IE heparin/24 hours depending on the individual aPTT (1.5-2.5 times prolonged). We developed a special drainage-management using perforans-veins during the loco-regional lysis. Complete lysis resulted in nearly half of the cases and in another third there was a lysis of more than 50%. Complications were observed in 5.8% of the patients, 4% due to heparinization. Importantly no life-threatening bleeding like gastrointestinal or cerebral bleeding or pulmonary embolism occurred. According to our data we conclude that the loco-regional lytic effect tends to be better than using systemical lysis, the risks are minimized and patient monitoring and treatment is much simpler. PMID- 10091293 TI - [Secondary prevention after deep venous thrombosis. Low molecular weight heparin versus coumarin]. AB - In numerous clinical trials low molecular weight heparins (LMWHs) have proven to be highly efficacious and safe in preventing thromboembolic complications. There is also a strong evidence that for the prevention of recurrence after deep venous thrombosis LMWHs lead to results comparable to those of dose-adjusted coumarin: in a monocentric randomized prospective study 200 patients after conservatively or surgically treated deep vein thrombosis received either a fixed dose of LMWH (5000 U anti-Xa; Fragmin P forte) s.c. or dose-adjusted coumarin (Marcumar) p.o. during a period of 3-6 months. During a follow-up of 12 months there was no significant difference between both groups regarding recurrence of deep vein thrombosis but three major bleeding complications in the coumarin-group (none in the LMWH-group) occurred. PMID- 10091294 TI - [Vena cava filter--prevention of pulmonary embolism. Report of clinical experiences]. AB - Between 1982 and 1997 inferior vena cava filters were implanted in 182 patients. Indications were recurrent pulmonary embolism, massive embolism and prophylactic use prior to planned high-risk-operations upon patients with thromboembolic complications in shorter history. Kimray-Greenfield, Cardial and Vascor-systems were implanted. Mortality was 0, neither relevant bleedings, nor infections occurred. Vena-cava-filters prevented from re-embolism in 98%. During hospitalisation 3 cases of re-embolism (1.6%) were noticed due to incorrect filter-placement. One patient died (< 1%). Follow-up-examinations were performed in 74 cases 6 to 24 months after implantation. We discovered 8 cases (11%) of filter-migration, 3 cases (4%) of filter-kinking, one case of filter-perforation and one case of filter-shrut-fracture. All these patients remained without clinical sequelae. Cava-thrombosis was found in 2 patients 6 to 24 months after filter-insertion (2.7%). There was no sign of re-embolism in our longterm follow up. In our opinion the vena cava filter is an effective and safe method to prevent pulmonary re-embolism. Handling is quite easy and filter complications are low. In some elected cases prophylactic use of vena cava filters in high-risk patients may be indicated. PMID- 10091295 TI - [Value of the vena cava filter in treatment of deep venous thrombosis in the pelvis and leg]. AB - The indication of vena cava filter implantation is controversially discussed. A pure prophylactic indication is increasingly favoured, especially for temporary filter systems without any anamnestic pulmonary embolisms. On the basis of the available literature and our own results a critical analysis of this issue is given. Between 1994 and 1997, we inserted a total of 24 vena cava filters; 21 temporary and 3 permanent filters. In ten patients, the placement of the filter was indicated due to pulmonary embolism and a contra-indication to dose adjusted heparin therapy. Seven additional patients experienced a recurrent pulmonary embolism despite adequate heparin therapy. A prophylactic filter insertion was carried out in seven patients. The temporary vena cava filters were left in place between 7 to 38 days with an average of 19 days. Total implantation time of temporary filters was scheduled until complete mobilisation of the patients, generally in conjunction with an effective dosage of oral anticoagulants. No patient died in connection with the insertion of the filter and no further pulmonary embolisms occurred. One case of inferior vena cava thrombosis occurred in each group of temporary and permanent filters. In one third of the removed filter systems thrombi in the filter were found. Local infections of the catheter and introducer sets were observed in two patients. Moreover, in one case the strut of a temporary filter broke and subsequently dislocated 17 days after insertion. We conclude on the basis of these complication rates that until the results of randomised studies are available the usage of all filter systems should be limited to highly selected cases. PMID- 10091296 TI - [Reconstructive surgery of the cavo-ilio-femoral segment in acute occlusion]. AB - In-between 25 years 105 reconstructions of the cavoiliacal segment have been performed, for malignant disease 37, for fibrotic stenoses of the left common iliac vein 48, additionally in injury and hypoplasia of the caval or iliac veins and in case of thrombosed caval filters. In case of reconstructions of the iuxtarenal caval vein and renal veins (27) a direct suture with or without patch plasty was preferred. Reconstructions of the infrarenal caval vein have been performed by direct suture (16), by graft interposition (9) or bypass (2). Mainly reconstructions using deep veins as an autologous graft are preferred. Most operations have been performed in order to reconstruct the iliac veins (70). Endovascular procedures such as dilatation with or without stenting (35) offer an excellent palliation in tumour disease, however, results are poor in treatment of fibrotic stenoses of the left common iliac vein. Better results can be achieved by cross-over-bypasses (30), especially when using a superficial femoral vein graft. PMID- 10091297 TI - [Recurrent varicosity of the lesser saphenous vein. A 5-year follow-up]. AB - Between January 1st, 1992 and December 31st, 1996 we performed 1189 variectomies, 127 (11%) of these patients with recurrent varicosis. Only 5 (4%) of them exhibited an isolated perforator vein varicosis and 15 (1%) an isolated varicosis of lateral branches of the lesser saphenous vein. In 66 cases (52%) we noticed, as it was expected, a recurrent varicosis of the saphenous vein. The 41 patients (32%) with recurrent varicosis of the lesser saphenous vein were analysed exactly in detail. We used the classification described by Fischer. According to this we divided them up as follows. Type I: insufficiency of the lesser saphenous vein stump or from lateral branches of the lesser saphenous stump. Type II: recurrence by the femoro-popliteal vein. Type III: recurrence from the lateral branches vein. We obtained from type I: 27 patients (65%), from type II 6 patients and 8 patients (20%) from type III. The recurrences from the stump of the lesser saphenous vein dominated in male patients with 25 of 33; in female patients the recurrences from branches of the lesser saphenous vein with 4 of 8. The lesser saphenous vein was removed in 33 cases completely, and partly in 8 cases at the first operation. The ligation of the termination of the lesser saphenous vein in patients with a type I recurrence was done 16 times in fascial level and 8 times above the fascial level at the first operation. All the 27 type I patients were undergoing a subfascial ligation of the termination of the lesser saphenous vein at the second operation. We noticed the following complications: 2 haematomas, 2 lymphatic fistulas, 1 paraesthesia and 1 ilio-femoral venous thrombosis. After the recurrent operation we noticed no type I and no type II recurrence during follow-up, 17 out of the 26 patients examined again were satisfied. The value of the different investigations, indications, technical details, modifications and the results are discussed. CONCLUSIONS: The results demonstrate that most of the saphenous parvous vein stump recurrence would have been avoided by a sufficient ligation of the saphenous parvous stump at the first operation. It is obvious that an exact indication, a sophisticated operation technique and an experienced surgeon are necessary for successful therapy. PMID- 10091298 TI - [Bipolar electrocoagulation of red spider veins and telangiectasis of the face]. AB - The development of a patented bipolar "coagulation fork", applied in combination with a customized microprocessor-controlled high-frequency unit, constitutes a break-through in the treatment of very small varicose veins of less than 0.5 mm in diameter, commonly described as spider veins, that cannot be removed through sclerotherapy. The technique is quite simple and does not require any kind of anesthesia. It is also best suited to treat teleangiectases on the face. Follow up treatment is not required. PMID- 10091299 TI - [Vascular diseases in orthopedic practice]. AB - From 1.4.1995 to 30.3.1997 1861 patients had been treated in orthopedic practice. In 52 cases deep vein thrombosis was detected. We found severe varicosis in 169 legs. A complete occlusion of the arteria femoralis superficialis or arteria popliteal was found in 16 legs, an aneurysm of the femoral or popliteal artery was seen in 5 legs. PMID- 10091301 TI - [Thrombosed temporary vena cava filter]. AB - The application of temporary vena cava filters for the treatment of deep venous thrombosis of the lower extremity has become increasingly important in recent years. The filters are supposed to guarantee temporary protection from more extensive pulmonary embolism. Occlusion of the filter system by a larger embolus as well as vena cava thrombosis including the filter struts present major therapeutic problems. We report on one patient in whom the temporarily inserted filter was trapped in a large vena cava thrombus and had to be removed surgically by caval thrombectomy. Because of possible complications such as the above, the indication for insertion of temporary vena cava filters requires thorough consideration. Their duration of stay should be as short as possible and should be limited to the high risk phase, not exceeding ten days. PMID- 10091300 TI - [Evaluation of postoperative pain therapy with patient-controlled analgesia from the viewpoint of the patient and nursing staff]. AB - Patient-controlled analgesia has been proven to be an effective technique in postoperative pain management. The aim of our study was to evaluate PCA on general surgery wards. 311 patients and their nurses were questioned about their experiences in using PCA for postoperative pain management. Satisfaction with pain relief judged by both patients and nursing staff, incidence of negative side effects and technical problems were studied. The great majority of patients and nursing staff rated the quality of pain relief as being satisfactory. Incidence of negative side effects was extraordinarily low. There was no respiratory depression observed, technical problems hardly arose. Most of the patients coped very well with operating their PCA-pumps. We conclude that PCA is a safe and effective method in postoperative pain management on surgical wards. Under the condition of regular monitoring of pain intensity, of analgesic consumption, level of sedation and of side effects by trained medical and nursing staff, monitoring of respiration and vigilance is not necessary for the PCA regimen we used. PMID- 10091302 TI - [Minimally invasive concepts in esophageal surgery--thoracoscopic anastomosis. An animal experiment study]. AB - Based on animal trials the presented study describes two versions of thoracoscopic oesophageal anastomosis within the scope of abdomino-thoracoscopic oesophagectomy. This experimental approach is considered to provide a solution for the oncological problem to salvage the tumor bearing oesophagus. We describe the procedure of intrathoracic stapler anastomosis under thoracoscopic vision. By using a laparoscopic purse string suture clamp we were enabled to prepare the proximal oesophageal stump for anastomosis. A circular stapling instrument turned out to be very suitable for the thoracoscopic use. The final evaluation of the importance of minimally invasive surgery for the resection of oesophageal carcinomas should not be given until multicenter studies are performed. PMID- 10091303 TI - [Classification in trauma surgery (2)]. PMID- 10091304 TI - Clinical experiences with direct magnification mammography with the DIMA Plus M11. AB - OBJECTIVE: The evaluation of mammographies carried out by conventional technique (standard imaging and focal imaging with 1.9x magnification) should be compared with a direct magnification image (standard imaging with 1.7x magnification, focal imaging with 4x magnification and preparation imaging with 7x magnification) provided by the mammographic device DIMA Plus M11 of the company feinfocus Medizintechnik. MATERIAL AND METHODS: Out of over 1,000 mammographies (DIMA technique) 50 histologically proved cases were selected for evaluation. Within a three months period these cases underwent conventional standard mammography as well as 1.9x magnification and DIMA-mammographies. The second X ray was carried out when it was necessary for a pre-operative marking. RESULTS: When mammographies of mammaries, which were radiologically transparent and easily compressible, where taken by DIMA-technique, they showed a distinct advantage, especially in unclear micro-calcification cases, in comparison to the mammographies carried out by the conventional standard imaging. CONCLUSIONS: Direct magnification images carried out by DIMA Plus M11 provide a better breast cancer diagnostic. This refers in particular to focal images with 4x magnification and to digital mammography, which is yet being developed. PMID- 10091305 TI - [Placenta morphology and Doppler ultrasound of umbilical cord vessels in premature infants]. AB - OBJECTIVE: There is a raised morbidity and mortality in fetuses with pathological waveforms in the umbilical arteries. Less differentiation of the placental villi could (partly) explain this finding. MATERIALS AND METHODS: We examined a total of 51 placentas (28th to 35th week of gestation) as to a correlation between dopplersonographical findings in the umbilical arteries and placenta morphometry. RESULTS: In the groups with pathological waveforms there was not only a reduction in the weight of the placenta and child, but also less differentiation of the placental villi. The occurrence of so-called sprouts did not correlate with the dopplersonographical findings. CONCLUSIONS: The raised fetal morbidity and mortality in premature infants with pathological waveforms in the umbilical arteries can at least partly be explained less differentiation of the placental villi. We found no correlation with the occurrence of sprouts. PMID- 10091306 TI - [Pregnancy-induced gigantomastia--a disease picture of uncertain origin]. AB - OBJECTIVE: Pregnancy induced gigantomastia is a rare condition (1:100.000 pregnancies) of unknown etiology. Regarding this condition we would like to discuss the possibilities of antenatal treatment, management during pregnancy and treatment after delivery. RESULTS: In our histological and immunological investigations we did not find any facts that will point out any specific etiology of this condition. The pregnancy induced gigantomastia could not be influenced by any conservative management or medical treatment. CONCLUSION: Therefore we would recommend plastic reconstructive surgery from medical as well as cosmetic point of view. PMID- 10091307 TI - [Status of problems with administration of hormonal contraceptives]. AB - Following the application of oral hormonal contraceptives situations may occur which need fast clarification. In this report we discuss the practical aspects of forgetting to take hormonal contraceptives, the risk for birth defects, the time when to restart taking oral contraceptives after delivery and abortion, the indications for stopping the application, the taking of oral contraceptives under anticoagulant therapy, the behaviour during migraine, the raising need of ethinylestradiol in the case of epilepsy, the procedure in case of oligophrenia, the prevention of the rheumatoid arthritis as well as special questions in cases of diabetes mellitus and gestational diabetes. PMID- 10091308 TI - [Consultation per video-conferencing with regional hospitals: the MEDKOM project of the Hannover Medical University]. AB - Consultations between doctors are necessary tools for decisions in diagnosis and treatment of patients. The mainstay is a sound communication between the participants, using verbal and audio-visual means. Usually clinical findings and imaging results are included. Using video technology with ISDN (integrated services digital network), such consulting can be performed across any distance. The department of hematology and oncology of the Medical School Hanover has introduced such a system in 1989 for conferencing with 12 regional hospitals and two private practices. It is now a well recognized and established system being applied for 270 sessions and for 1100 Patients per year. It is an integrated part of the co-operation, also allows medical education and quality improvement. PMID- 10091309 TI - Family-centered care for HIV positive women. AB - Family-centered care means delivery of full scale primary and specialty care, including supportive services, to HIV infected individuals and their family members. In the South Bronx, New York, women are often the sole heads of households and decision makers of their families. For them and their children state-of-the-art care of HIV is delivered through pediatricians, internists, obstetrician-gynecologists, infectious disease-trained specialists, social workers, legal consultants, pharmacists etc. who work together at a central location. PMID- 10091310 TI - [Diagnostic and therapeutic concepts of HPV infection in HIV-positive women]. AB - Among HIV-seropositive women there is a high prevalence of anogenital human papillomavirus (HPV) infection. HPV-DNA is more frequent detected in cervicovaginal-lavage specimens from HIV-seropositive women as in those from HIV seronegative women. We and others suggest that HIV-infection increases the risk to have HPV-associated lesions of the lower female genital tract, especially the risk for developing a squamous intraepithelial lesion of the cervix. In this report we describe the current diagnostic and therapeutic strategies in HIV seropositive women with HPV-infection. The gynecological examination should be performed at six to twelve month intervals, including the colposcopy and the Pap smear test. We hope to improve the quality of our screening program by doing an additional HPV-test. At last we investigate the CD4+ T-lymphocyte counts because it is observed that women with low CD4+ cell counts (< 200/microliter) were more likely to have persistent HPV-infection as those with higher counts (> 500/microliter). The treatment method is dependent on the development of the HPV associated lesion and the clinical status of the HIV infected women. In cases with external warts local application of Condylox should be the first line treatment. Probably in about few months we could use other drugs like Wartec or Aldara in Germany. But the effectiveness of these drugs in HIV-positive women has to be proven yet. In the cause of persistence of external warts or recurrence of the disease the systemical application of Intron A or Roferon A is possible. The CO2-lasertreatment is performed under colposcopic guidance, especially in cases with multicentric condylomatous lesions. The treatment of cervical intraepithelial neoplasia (CIN) by CO2-laservaporisation or Loop Electrosurgical Excision Procedure (LEEP) is based on the clear colposcopic visualisation of the upper limit of the lesion. If CIN reaches the endocervix, being out of colposcopic view, and the squamocolumnar junction is localised in the endocervical canal conisation by laser or cold knife has to be performed. Before performing the treatment of CIN one should exclude multicentric cervical, vaginal and vulval intraepithelial neoplasia by colposcopy, because multicentric intraepithelial neoplasia of the lower female genital tract is more frequently than in HIV-seronegative women. Multicentric disease seems to be one cause of the high recurrence of HIV-seropositive women. However, higher levels of immunosuppression (CD4+ T-lymphocyte counts < 200/microliter) are also important determinants of recurrence of the disease. Therefore, an accurate short-term follow-up with colposcopy, Pap test and HPV test should be carried out after the treatment of HIV-seropositive women with low CD4+ counts. PMID- 10091311 TI - [Endocrine involvement in HIV infections]. AB - HIV associated endocrine abnormalities are usually only seen in patients with AIDS. They are probably not caused by the infection itself, but rather by secondary involvement of endocrine organs through opportunistic infections or metabolic disturbances. Thus, patients with the disease should be checked regularly for electrolyte imbalance, and special attention should be paid to the detection of early signs of thyroid or adrenal insufficiency, which might be mistaken for general symptoms of wasting disease and thus remain untreated. Several pharmacological agents used in HIV/AIDS may also cause endocrine deficiencies, which can be prevented by early initiation of specific replacement regimens. PMID- 10091312 TI - [Current position on the care of HIV-seropositive pregnancies]. AB - The reduction of vertical transmission rates in Germany to 5-7% is basically due to antiretroviral therapy during pregnancy with zidovudine and elective caesarean section after 37 weeks of gestation. Maternal versus fetal needs have to be considered carefully in respect to mode of delivery and antiretroviral therapy. Long term consequences for the fetus of antiretroviral therapy are not yet sufficiently known. PMID- 10091313 TI - [Antiretroviral therapy in childhood]. AB - The natural course of mostly perinatally acquired childhood HIV infection shows some special characteristics. Compared to adults the initial viral load is higher, persists for a longer period of time and without antiretroviral therapy up to 20% of infected children develop AIDS within the first year of life. It is therefore desirable to stop disease progression before an irreversible deterioration of the immune system has occurred by initiating early antiretroviral therapy. The choice of antiretroviral agents is difficult because data from adult studies cannot be directly applied to infants and data on antiretroviral therapy in pediatric patients are limited. The current national and international guidelines for antiretroviral therapy in perinatally acquired HIV infection are discussed. PMID- 10091314 TI - [HIV prevention for migrant prostitutes]. AB - A growing number of women from poor countries consider an engagement as sex workers in the wealthy industrialized countries as their only chance for making a decent living. This forces them into a variety of dependencies and obligations. They often accept high risks to their psychological and physical wellbeing. For these reasons migrant prostitutes have to be considered as an important target group for preventive measures, despite of an overall low HIV-prevalence among non drug-using female prostitutes in Western Europe. Coercive methods in public health care against prostitutes cannot be justified neither from an epidemiological point of view nor from the point of view of efficacy considering the high mobility of the target group. Street work in cooperation with native speakers combined with confidential and free of charge counselling and medical care has proved to be effective to reach migrant prostitutes also in Germany. PMID- 10091315 TI - [Companionship for women dying of AIDS]. AB - This report reflects the experience of accompanying HIV-infected women during the process of dying using their curriculi vitae as examples of different modes of dealing with fatal illness. The text contains paintings of past and contemporary art concerning death and eros and poetry as a form of therapy. PMID- 10091316 TI - Compostable packaging materials--test methods and limit values for biodegradation. AB - In order to classify packaging materials as capable of organic recovery according to the packaging regulation of the European Union, the intended materials must be tested for their compostability. An important prerequisite is the determination of biodegradability by standardized test methods. Details of the intended tests are not comprehensible without further knowledge of the problems of biodegradation testing. The test methods and the limit values used to evaluate the biodegradation results are presented and discussed against the background of established test methods and limit values for chemicals. Furthermore the problem of ecotoxicity tests in connection with compost quality is discussed and an overview of European test laboratories is given. PMID- 10091317 TI - Microbial degradation of polyurethane, polyester polyurethanes and polyether polyurethanes. AB - Polyurethane (PUR) is a polymer derived from the condensation of polyisocyanate and polyol and it is widely used as a base material in various industries. PUR, in particular, polyester PUR, is known to be vulnerable to microbial attack. Recently, environmental pollution by plastic wastes has become a serious issue and polyester PUR had attracted attention because of its biodegradability. There are many reports on the degradation of polyester PUR by microorganisms, especially by fungi. Microbial degradation of polyester PUR is thought to be mainly due to the hydrolysis of ester bonds by esterases. Recently, polyester-PUR degrading enzymes have been purified and their characteristics reported. Among them, a solid-polyester-PUR-degrading enzyme (PUR esterase) derived from Comamonas acidovorans TB-35 had unique characteristics. This enzyme has a hydrophobic PUR-surface-binding domain and a catalytic domain, and the surface binding domain was considered as being essential for PUR degradation. This hydrophobic surface-binding domain is also observed in other solid-polyester degrading enzymes such as poly(hydroxyalkanoate) (PHA) depolymerases. There was no significant homology between the amino acid sequence of PUR esterase and that of PHA depolymerases, except in the hydrophobic surface-binding region. Thus, PUR esterase and PHA depolymerase are probably different in terms of their evolutionary origin and it is possible that PUR esterases come to be classified as a new solid-polyester-degrading enzyme family. PMID- 10091318 TI - Regulation and cloning of microbial chitinase genes. AB - A range of chitinase genes from microorganisms have been cloned and the potential uses of these genetically manipulated organisms are being investigated by various researchers. Fungi and yeast are better producers of chitinase than bacteria. Since fungi grow at a slower rate, there have been efforts to clone the fungal chitinase genes into fast-growing bacteria. This review gives a brief survey of recent progress in the regulation and cloning of microbial chitinase genes. Emphasis is placed on the post-translational modification and localization of the recombinant protein in the host. Various amino acid domains are present in this protein. The mode of catalytic activity of the recombinant protein in comparison to the wild-type protein is discussed in the available literature. The different mechanisms involved in the regulation of chitinase genes from various microorganisms is discussed by the researchers. The scope of future research and conclusions yet to be obtained in this particular area are also outlined in this review. PMID- 10091320 TI - Biotransformation of citronellol by the basidiomycete Cystoderma carcharias in an aerated-membrane bioreactor. AB - The basidiomycete Cystoderma carcharias transformed citronellol into 3,7-dimethyl 1,6,7-octanetriol as the main product. 3,7-Dimethyl-6,7-epoxy-1-octanol was identified as important intermediary product of the biotransformation, and the allylic diols 2,6-dimethyl-2-octene-1,8-diol, 3,7-dimethyl-5-octene-1,7-diol and 3,7-dimethyl-7-octene-1,6-diol were found to be minor products. Microbial formation of rose oxide, a flavour-impact component, was observed for the first time. The formation of the main products was inhibited by 70% after addition of 0.1 mmol l-1 cytochrome monooxygenase inhibitors. Formation of 3,7-dimethyl-1,6,7 octanetriol was effective in a bioreactor with aeration over a coil of a hydrophobic microporous polypropene capillary membrane. Production rates of up to 150 mg l-1 day-1 were reached and led to a product concentration of 866 mg l-1 (conversion rate: 52%). The total loss of the added volatile substrate via the exhaust air was 4.5% when this aeration method was used. PMID- 10091321 TI - Optimization of agitation and aeration conditions for maximum virginiamycin production. AB - To maximize the productivity of virginiamycin, which is a commercially important antibiotic as an animal feed additive, an empirical approach was employed in the batch culture of Streptomyces virginiae. Here, the effects of dissolved oxygen (DO) concentration and agitation speed on the maximum cell concentration at the production phase, as well as on the productivity of virginiamycin, were investigated. To maintain the DO concentration in the fermentor at a certain level, either the agitation speed or the inlet oxygen concentration of the supply gas was manipulated. It was found that increasing the agitation speed had a positive effect on the antibiotic productivity independent of the DO concentration. The optimum DO concentration, agitation speed and addition of an autoregulator, virginiae butanolide C (VB-C), were determined to maximize virginiamycin productivity. The optimal strategy was to start the cultivation at 450 rpm and to continue until the DO concentration reached 80%. After reaching 80%, the DO concentration was maintained at this level by changing the agitation speed, up to a maximum of 800 rpm. The addition of an optimal amount of the autoregulator VB-C in an experiment resulted in the maximal production of virginiamycin M (399 mg/l), which was about 1.8-fold those obtained previously. PMID- 10091322 TI - The amylopullulanase of Bacillus sp. DSM 405. AB - The amylopullulanse produced by Bacillus sp. DSM 405 was purified to homogeneity. It exhibited dual activity, cleaving the alpha 1-4 bonds in starch, releasing a range of malto-oligosaccharides, and also cleaving the alpha 1-6 bonds in pullulan, releasing maltotriose as the sole end-product. The enzyme was a glycoprotein and had a relative molecular mass of 126,000 and an isoelectric point of 4.3. While the enzyme was optimally active on starch at pH 6.5 and at pH 6.0 on pullulan, activity on both substrates was maximal at 70 degrees C. Kinetic analyses of the enzyme in a system that contained both starch and pullulan as two competing substrates demonstrated the dual specificity of the enzyme. Chemical modification of the carboxyl groups within the active centre of the protein showed that one active site was responsible for hydrolysis of the alpha 1-4 and alpha 1-6 bonds in starch and pullulan respectively. This is the first comprehensive investigation of an amylopullulanse produced by an aerobic bacterium, showing a single active site responsible for both activities. PMID- 10091323 TI - N-glycosylation is involved in the sensitivity of Saccharomyces cerevisiae to HM 1 killer toxin secreted from Hansenula mrakii IFO 0895. AB - Saccharomyces cerevisiae rhk mutants were previously shown to have a phenotype that is resistant to HM-1 killer toxin secreted from Hansenula mrakii IFO 0895. The RHK1/ALG3 gene encodes a mannosyl-transferase that is involved in the synthesis of an oligosaccharide in protein N-glycosylation. Previously, this gene was cloned and shown to complement the rhk1 mutation. In this study, the RHK2 gene, which complements the rhk2 mutation, was cloned. The RHK2 gene was found to be identical to the essential gene STT3, which encodes a subunit of the oligosaccharyl-transferase complex. This complex transfers the core oligosaccharide to proteins. The rhk2 mutants showed supersensitivity to several drugs (Calcofluor White, caffeine and FK506), suggesting that these strains have cell-wall defects. Activity staining of invertase in an acrylamide gel indicated that it was underglycosylated. These results suggest that one or more mannoproteins are involved in the cytocidal process of HM-1. PMID- 10091324 TI - A variant of Saccharomyces cerevisiae pep4 strain with improved oligotrophic proliferation, cell survival and heterologous secretion of alpha-amylase. AB - A variant of Saccharomyces cerevisiae pep4 strain 20B12, with improved oligotrophic proliferation, cell survival and secretion of heterologous mouse alpha-amylase, is described. Previously we reported a procedure to enrich NI transformants that are not inhibited by cytotoxic expression of hepatitis B virus surface antigen in the secretion pathway of the protease-A-deficient (pep4) strain. To use the NI cells as a host for heterologous expression, we tried to amend the introduced pYAS/12S vector and obtain a host strain, NI-C, with stable NI phenotype and trp1 marker restored. Southern analysis of genomic DNA of NI-C suggested that the original pYAS/12S was abnormally rearranged and not completely corrected. Further assay showed that the viability and mitotic ability of the NI C strain were increased. While using the NI-C strain as host for plasmid transformation and heterologous expression of mouse alpha-amylase, we observed that transformed colonies grew more quickly and secreted more alpha-amylase than general yeast strains. A further test showed that the NI-C strain was able to use mouse alpha-amylase as a positive selection marker to form transformed colonies on nitrogen-starved plates that contain starch as the sole carbon source. The results imply that the NI-C variant is an improved pep4 strain that can be used for heterologous expression and for the development of new selective markers in the yeast transformation system. PMID- 10091326 TI - Cloning of the transketolase gene and the effect of its dosage on aromatic amino acid production in Corynebacterium glutamicum. AB - Transketolase is a key enzyme of the non-oxidative pentose phosphate pathway. The effect of its overexpression on aromatic amino acid production was investigated in Corynebacterium glutamicum, a typical amino-acid-producing organism. For this purpose, the transketolase gene of the organism was cloned on the basis of its ability to complement a C. glutamicum transketolase mutant with pleiotropically shikimic-acid-requiring, ribose- and gluconic-acid-negative phenotype. The gene was shown by deletion mapping and complementation analysis to be located in a 3.2 kb XhoI-SalI fragment of the genome. Amplification of the gene by use of low-, middle-, and high-copy-number vectors in a C. glutamicum strain resulted in overexpression of transketolase activities as well as a protein of approximately 83kDa in proportion to the copy numbers. Introduction of the plasmids into a tryptophan and lysine co-producer resulted in copy-dependent increases in tryptophan production along with concomitant decreases in lysine production. Furthermore, the presence of the gene in high copy numbers enabled tyrosine, phenylalanine and tryptophan producers to accumulate 5%-20% more aromatic amino acids. These results indicate that overexpressed transketolase activity operates to redirect the glycolytic intermediates toward the nonoxidative pentose phosphate pathway in vivo, thereby increasing the intracellular level of erythrose 4-phosphate, a precursor of aromatic biosynthesis, in the aromatic amino-acid-producing C. glutamicum strains. PMID- 10091325 TI - Cloning and overexpression in Escherichia coli of the gene encoding dihydroxyacetone kinase isoenzyme I from Schizosaccharomyces pombe, and its application to dihydroxyacetone phosphate production. AB - The gene dak1 encoding a dihydroxyacetone kinase (DHAK) isoenzyme I, one of two isoenzymes in the Schizosaccharomyces pombe IFO 0354 strain, was cloned and sequenced. The dak1 gene comprises 1743 bp and encodes a protein of 62,245 Da. The deduced amino acid sequence showed a similarity to a putative DHAK of Saccharomyces cerevisiae and DHAK of Citrobacter freundii. The dak1 gene was expressed at a high level in Escherichia coli, and the recombinant enzyme was purified to homogeneity and characterized. The acetone powder of recombinant E. coli cells was used to produce dihydroxyacetone phosphate. PMID- 10091327 TI - Utilization of phenoxyacetic acid, by strains using either the ortho or meta cleavage of catechol during phenol degradation, after conjugal transfer of tfdA, the gene encoding a 2,4-dichlorophenoxyacetic acid/2-oxoglutarate dioxygenase. AB - The degradation of recalcitrant pollutants in contaminated soils and waters could be facilitated by broadening the degradative capabilities of indigenous microbes by the conjugal transfer of catabolic genes. The feasibility of establishing bacterial populations that degrade phenoxyacetic acid by conjugal transfer of tfdA, the gene encoding 2,4-dichlorophenoxyacetic acid/2-oxoglutarate dioxygenase, to phenol-degrading strains of Pseudomonas and Ralstonia was examined. The mobilizable plasmid pKJS32 served as a vector for delivery of tfdA and the regulatory gene, tfdS. Transconjugant strains that degraded phenol by an ortho cleavage of catechol grew well on phenoxyacetic acid while those employing a meta cleavage could only grow on phenoxyacetic acid in the presence of benzoic acid or after a prolonged lag period and the appearance of mutants that had gained catechol 1,2-dioxygenase activities. Thus, an ortho cleavage of catechol was essential for degradation of phenoxyacetic acid, suggesting that a product of the ortho-cleavage pathway, probably cis, cis-muconic acid, is an inducer of tfdA gene expression. Establishment of phenoxyacetic-acid-degrading soil populations by conjugal transfer of tfdA would depend on the presence of phenol-degrading recipients employing an ortho cleavage of catechol. PMID- 10091328 TI - Cloning and characterization of an endo-beta-1,3(4)glucanase and an aspartic protease from Phaffia rhodozyma CBS 6938. AB - We describe the identification and expression cloning of two novel enzymes, a beta-glucanase and an aspartic protease, secreted from the basidiomycetous yeast Phaffia rhodozyma. A cDNA library from P. rhodozyma CBS 6938 was constructed, and full-length cDNA encoding an endo-1,3(4)-beta-glucanase (bg1) and an aspartic protease (pr1) were cloned by expression cloning in Saccharomyces cerevisiae W3124. The bg1 cDNA encodes a 424-residue precursor protein with a putative signal peptide. The pr1 cDNA encodes a 405-residue prepropolypeptide with an 81 residue leader peptide. The aspartic protease was purified and characterized. It has a molecular mass of 36 kDa, an isoelectric point of pH 7.5, a pH activity optimum at 4.0-6.0, and a temperature activity optimum around 40 degrees C. Both enzymes show only low sequence identity to other known enzymes. PMID- 10091329 TI - A murC gene from coryneform bacteria. AB - The upstream flanking region of the ftsQ and ftsZ genes of Brevibacterium flavum MJ233, which belongs to the coryneform bacteria, was amplified by the inverse polymerase chain reaction method and cloned in Escherichia coli. Complementation analysis of E. coli mutant with a defective cell-wall synthesis mechanism with the cloned fragment and its DNA sequencing indicated the presence of the murC gene, encoding UDP-N-acetylmuramate:L-alanine ligase involved in peptidoglycan synthesis, just upstream from the ftsQ gene. The B. flavum murC gene could encode a protein of 486 amino acid residues with a calculated molecular mass of 51 198 Da. A 50-kDa protein was synthesized by the B. flavum murC gene in an in vitro transcription/translation system using E. coli S30 lysate. These results indicate that the genes responsible for cell-wall synthesis and cell division are located as a cluster in B. flavum similar to the E. coli mra region. PMID- 10091330 TI - Bacterial growth in space flight: logistic growth curve parameters for Escherichia coli and Bacillus subtilis. AB - Previous investigations have reported that bacterial suspension cultures grow to higher stationary concentrations in space flight than on Earth; however, none of these investigations included extensive ground controls under varied inertial conditions. This study includes extensive controls and cell-growth data taken at several times during lag phase, log phase, and stationary phase of Escherichia coli and Bacillus subtilis. The Marquardt-Levenberg, least-squares fitting algorithm was used to calculate kinetic growth parameters from the logistic bacterial growth equations for space-flight and control growth curves. Space flight cultures grew to higher stationary-phase concentrations and had shorter lag-phase durations. Also, evidence was found for increased exponential growth rate in space. PMID- 10091332 TI - Influence of environmental factors on lipase production by Lactobacillus plantarum. AB - A strain of Lactobacillus plantarum, DSMZ 12028 (Deutsch Sammlung von Mikroorganismen und Zellkulturen), isolated from a Portuguese dry fermented sausage, "chourico", was found to produce true lipase, producing free fatty acids from triolein (olive oil). This enzymatic activity was found in whole cells, but was negligible in comparison to lipolytic activity in culture supernatant. Therefore, only extracellular activity was studied. The effect of pH, temperature and glucose concentration on extracellular lipase production was studied in continuously stirred tank reactors, the first time this technology has been used to study the production of this enzyme in lactobacilli. Maximum lipase production was achieved at a pH of 5.5 and 30 degrees C and was kept at a significant level over a wide range of dilution rates (0.05-0.4 h-1); the production of lipase was still significant for low pH values, temperature and glucose concentration, conditions that are close to the ones present during chourico ripening. The effect of glucose concentration was also studied in a batch system. The control of lipase production was found to be related both to glucose concentration in the medium and to the growth rate/dilution rate. Glucose concentration was found to be important for fast lipase production, although it did not influence the maximum lipase activity reached in a batch culture. PMID- 10091333 TI - Hydroxylamine oxidation and subsequent nitrous oxide production by the heterotrophic ammonia oxidizer Alcaligenes faecalis. AB - Nitrous oxide (N2O), a greenhouse gas, is emitted during autotrophic and heterotrophic ammonia oxidation. This emission may result from either coupling to aerobic denitrification, or it may be formed in the oxidation of hydroxylamine (NH2OH) to nitrite (NO2(-). Therefore, the N2O production during NH2OH oxidation was studied with Alcaligenes faecalis strain TUD. Continuous cultures of A. faecalis showed increased N2O production when supplemented with increasing NH2OH concentrations. 15N-labeling experiments showed that this N2O production was not due to aerobic denitrification of NO2(-). Addition of 15N-labeled NH2OH indicated that N2O was a direct by-product of NH2OH oxidation, which was subsequently reduced to N2. These observations are sustained by the fact that NO2(-) production was low (0.23 mM maximum) and did not increase significantly with increasing NH2OH concentration in the feed. The NH2OH-oxidizing capacity increased with increasing NH2OH concentrations. The apparent Vmax and K(m) were 31 nmol min-1 mg dry weight-1 and 1.5 mM respectively. The culture did not increase its growth yield and was not able to use NH2OH as the sole N source. A non-haem hydroxylamine oxidoreductase was partially purified from A. faecalis strain TUD. The enzyme could only use K3Fe(CN)6 as an electron acceptor and reacted with antibodies raised against the hydroxylamine oxidoreductase of Thiosphaera pantotropha. PMID- 10091334 TI - Aerobic 4-nitrophenol degradation by microorganisms fixed in a continuously working aerated solid-bed reactor. AB - Studies of microbial purification of a model waste water containing 4-nitrophenol were carried out in a continuously working aerobic solid-bed reactor. The main emphasis was on the dynamic behaviour of the system after a sudden change in cultivation conditions and on the steady state performance of the reactor as a function of the pollution load. A change from ammonium-free to ammonium containing medium hardly influenced the nitrophenol degradation. The reactor responded differently to an increase in pollutant load, which was brought about by increasing either the 4-nitrophenol content or the flow of the waste water. Up to a load of 270 mg l-1 h-1 the pollutant was stably and almost completely degraded. At a higher load, only a partial 4-nitrophenol degradation took place. A mathematical model was derived to describe the processes that occurred in the reactor. By segregation into two compartments--the aqueous phase and the biofilm- account was taken of the fact that the pollutant is carried into the biofilm by diffusion and is degraded there. The observed relations between the pollutant load, the pollutant concentration in the outlet of the reactor and the reactor performance agreed with the simulated process behaviour. As the model simulation showed, the incomplete pollutant degradation at a higher reactor load was caused by oxygen limitation. PMID- 10091335 TI - Ultrastructural cytochemical study of proteoglycans in the endometrium of pregnant mice using cationic dyes. AB - Decidualization in rodents is accompanied by remarkable modifications of both fibrillar and non-fibrillar components of the endometrial extracellular matrix. Biochemical studies have shown that the levels of synthesis of hyaluronic acid and sulfated glycosaminoglycans change during decidualization in rodents. As the rodent decidua has regions containing cells in different stages of decidual transformation, we decided to analyse, by an ultrastructural cytochemical technique, the distribution of proteoglycans (PGs) in each region of the decidua of mice on different days of pregnancy. Endometria of mice on days 4, 5 and 7 of pregnancy were processed for electron microscopy in the presence of safranin O, a cationic dye which preserves most of the tissue PGs. The endometrium of non pregnant mice was used as control. We observed evident differences in the arrangement and distribution of the network of PGs between non-pregnant and 4-day pregnant endometria, as well as between different regions of pregnant endometria. The possible relationship between these modifications and cell transformation that occurs during decidualization is discussed. PMID- 10091336 TI - Ultrastructural changes during desiccation of the anhydrobiotic nematode Ditylenchus dipsaci. AB - Ultrastructural changes during desiccation of the anhydrobiotic nematode Ditylenchus dipsaci were followed and quantified after preparation of material at different levels of hydration using freeze substitution techniques. Some shrinkage was caused by processing in the more hydrated specimens but the changes observed correspond to those observed in live nematodes by light microscopy, indicating that the technique is useful for following changes during desiccation. The overall pattern of changes was a rapid decrease in the magnitude of the measured parameter during the first 5 min of desiccation, followed by a slower rate of decrease upon further desiccation. This was observed in the cuticle, the lateral hypodermal cords and the muscle cells and is consistent with the pattern of water loss of the nematode. The contractile region of the muscle cells, however, proved an exception and the muscle fibres appear to resist shrinkage and packing until water loss becomes severe. The mitochondria swell and then shrink during desiccation, which may indicate disruption of the permeability of the mitochondrial membrane. A decrease in the thickness of the cortical zone was the most prominent change in the cuticle and this may be related to the permeability slump which occurs during the first 5 min of desiccation. PMID- 10091337 TI - Changes in three-dimensional architecture of microfilaments in cultured vascular smooth muscle cells during phenotypic modulation. AB - To investigate changes in the three-dimensional microfilament architecture of vascular smooth muscle cells (SMC) during the process of phenotypic modulation, rabbit aortic SMCs cultured under different conditions and at different time points were either labelled with fluorescein-conjugated probes to cytoskeletal and contractile proteins for observation by confocal laser scanning microscopy, or extracted with Triton X-100 for scanning electron microscopy. Densely seeded SMCs in primary culture, which maintain a contractile phenotype, display prominent linear myofilament bundles (stress fibres) that are present throughout the cytoplasm with alpha-actin filaments predominant in the central part and beta actin filaments in the periphery of the cell. Intermediate filaments form a meshed network interconnecting the stress fibres and linking directly to the nucleus. Moderately and sparsely seeded SMCs, which modulate toward the synthetic phenotype during the first 5 days of culture, undergo a gradual redistribution of intermediate filaments from the perinuclear region toward the peripheral cytoplasm and a partial disassembly of stress fibres in the central part of the upper cortex of the cytoplasm, with an obvious decrease in alpha-actin and myosin staining. These changes are reversed in moderately seeded SMCs by day 8 of culture when they have reached confluence. The results reveal two changes in microfilament architecture in SMCs as they undergo a change in phenotype: the redistribution of intermediate filaments probably due to an increase in synthetic organelles in the perinuclear area, and the partial disassembly of stress fibres which may reflect a degradation of contractile components. PMID- 10091338 TI - Possible involvement of transforming growth factor-beta 1 and transforming growth factor-beta receptor type II during luteinization in the marmoset ovary. AB - The expression of transforming growth factor-beta 1 (TGF-beta 1), and transforming growth factor-beta receptor type II (T beta R-II), were evaluated in periovulatory marmoset ovaries. Histochemical methods were used, in particular double-labelling techniques, in order to correlate growth factor/receptor expression with proliferation (Ki 67), apoptosis (TUNEL method) and luteinization (3 beta-hydroxysteroid dehydrogenase (3 beta-HSD)). The latter was used as a luteinization marker. Periovulatory ovaries are especially suited for studying all aspects since they typically consist of small non-luteinized follicles, large luteinizing follicles and corpora lutea accessoria (Clas), which have developed from large luteinizing follicles. TGF-beta 1 and T beta R-II expression was found in luteinizing theca cells of large periovulatory follicles and in all luteal cells of Clas. Non-luteinized theca cells, including those of small follicles were always devoid of any immunostaining. Granulosa cells of small follicles were immunopositive for T beta R-II. Large follicles with granulosa cell immunoreactivity of both antibodies coexisted with non-reactive follicles of comparable size. The highest activity of the luteal marker enzyme 3 beta-HSD was co-localized in the same cells that expressed TGF-beta 1 and T beta R-II. The double-labelling experiments revealed that TGF-beta 1 and T beta R-II expression is not correlated with proliferation or apoptosis of follicular cells. Our results indicate that TGF-beta 1 and T beta R-II participate in differentiation processes, i.e. luteinization, rather than proliferation. In particular, the dynamics of T beta R-II expression appear highly related to the process of luteinization. PMID- 10091339 TI - Lymphatic endothelium expresses PECAM-1. AB - The expression of adhesion molecules on the lymphatic endothelium of human small intestine and submandibular lymph node was studied immunohistochemically with the antibodies for selectin family and Ig superfamily members. In both small intestine and submandibular lymph node, lymphatic endothelium did not express intercellular adhesion molecule-1 and endothelial cell-selectin but expressed platelet-endothelial cell adhesion molecule-1 (PECAM-1). Though lymphatic vessels may not have a positive function in leukocyte rolling and adhesion, lymphatic endothelium may interact with leukocytes, with PECAM-1 playing a role. PMID- 10091340 TI - Detection of vascular dendritic cells accumulating calcified deposits in their cytoplasm. AB - The distribution of calcified microdeposits in non-atherosclerotic intima of the human aorta was studied by electron microscopy. Aortic specimens were obtained during aortic reconstruction and were embedded in Lowicryl resin. Non-stained ultrathin sections were analysed using an electron microscope equipped with an energy-dispersive X-ray microanalyser. Subsequent staining of these ultrastructural sections with lead citrate allowed us to view the tissue structures and allowed the precise location of calcified deposits in the intimal tissue to be determined. Calcium-containing microstructures were found in the extracellular matrix of the intima but, occasionally, calcium-containing microdeposits were also seen in the cytoplasm of intimal cells. Cisterns of a tubulovesicular system which is uniquely developed in cells from the dendritic cell family were detected in the calcium-containing intimal cells, which enabled these calcium-accumulating cells to be identified as a phenotype of vascular dendritic cells. These modified vascular dendritic cells might be the 'calcifying vascular cells' described previously by others. PMID- 10091341 TI - [Prognostic factors in pediatric myringoplasty. A review of 90 cases]. AB - Although tympanic membrane perforations continue to be a significant source of otologic morbidity in the pediatric population, myringoplasty in children still elicits debate. The records of 76 patients under 18 who underwent 90 myringoplasties at the 12 de Octubre University Hospital (Madrid, Spain) over a recent 8-year period were reviewed. The overall short-term surgical success rate was 64.8%. The overall success rate evaluated at least one year after surgery was 58%. The audiological threshold improved in 68% per cent of successful cases. Surprisingly, females had lower graft take rates than males. The outcome of surgery was unrelated to age at operation, duration, mechanism, size, and location of the perforation, or condition of the opposite ear. PMID- 10091342 TI - [Tympanosclerosis. I: proposed anatomical-surgical classification]. AB - Tyrnpanosclerosis continues to be a clinically and pathogenically controversial topic. The options for dealing with it range from a conservative approach using hearing aids to surgery. With a view to justifying our therapeutic criteria, 29 cases of tympanosclerosis, out of a total of 200 surgical operations for otorrhea, were reviewed. An anatormical-surgical classification was established for use in approaching specific therapy for each particular case. PMID- 10091343 TI - [Electrophysiological study of cochlear damage in early otosclerosis and after stapedial surgery]. AB - Otoesclerotic patients usually have neurosensorial hearing toss in addition to a predominantly conductive impairment, but there is no universally accepted explanation for this abnormality. The bone conduction threshold in tonal audiometry is accepted as a test of cochlear function. An early evaluation of damage to the cochlea arid acoustic nerve after surgery was made by studying 99 ears with BERA and latency/intensity curves to test cochlear function. We concluded that early damage was present. Postoperative cochlear damage was found in spite of successful surgery, but it was no greater than the damage present before surgery. PMID- 10091344 TI - [Antimicrobial therapy in chronic suppurative otitis media]. AB - A randomized study was made of 125 patients with chronic middle ear infection. The most frequently isolated microorganisms were: Pseudomonas aeruginosa, Staphylococcus aureus and Enterobacteriaceae. Ciprofloxacin is very active against the microorganisms usually isolated and it has been shown to provide effective therapy in ear infections. In order to study the effectiveness of ciprofloxacin in chronic otitis media, we selected four different treatment groups: oral ciprofloxacin (500 mg/12 h); 0.5 and 0.2% topical solutions of ciprofloxacin (3 drops/8 h), and oral ciprofloxacin plus 0.2% topical solution. Topical polymyxin and neomycin were used as controls. Topical ciprofloxacin (0.2%) was the most effective regimen of those tested for the treatment of chronic otitis media. PMID- 10091345 TI - [Rehabilitation of facial paralysis by temporal muscle flap and implantation of gold weights]. AB - Facial paralysis is a severe disability that often produces major ocular disorders, cosmetic deformities, and, in many cases, functional incapacity for something as characteristic of human beings as facial expression. For these reasons, it is necessary to correct this defect as completely as possible to produce the best physiological result. Of the many methods available for the repair of the lesion, most authors agree that direct repair of the nerve is the most reliable technique. When this is not feasible, the use of gold weights for the eyelid and a temporalis muscle flap for the mouth are two easily realized methods that are reversible and produce good esthetic and functional results. As a result, this is the technique of choice for this disorder and it has the added advantage of being compatible with other procedures. PMID- 10091346 TI - [Non-Hodgkin's lymphoma of the maxillary sinuses. Pathological clinical study and current status of the treatment]. AB - Primary non-Hodgkin lymphoma (NHL) of the maxillary sinus is an infrequent neoplasm that represents about 8% of all malignancies in this area. A review was made of 74 patients diagnosed as malignancy of the maxillary sinus in a 20-year period. Five cases of primary extraganglionar NHL of the maxillary sinus were found. We describe all the cases and their extension in detail. The clinical manifestations, treatment, and long-term survival of these patients are discussed. PMID- 10091347 TI - [Evaluation with acoustic rhinometry of surgical results in patients undergoing septoplasty]. AB - We used acoustic rhinometry to evaluate the surgical results of septoplasty in patients with nasal respiratory insufficiency caused by morphological abnormalities of the nasal septum. Acoustic rhinometry is a relatively new exploration method for the nasal cavity that yields objective spatial measurements. These measurements are the cross sections and volumes of the nasal cavity divided longitudinally into two regions, an anterior region up to 32 mm from the nasal orifices and the posterior region, up to 64 mm from the same point. We studied 45 patients with nasal respiratory insufficiency who had undergone septoplasty. Measurements were made before and after surgery. Our results show a clear increase in nasal sections and volumes after surgery. They confirm the benefits of acoustic rhinometry as a method for quantifying morphological abnormalities of the nasal cavity. PMID- 10091348 TI - [Olfaction assessment in daily practice]. AB - A simple examination system for the detection and follow-up of olfactory disorders is described. This model distinguishes levels of detection, variations in the characteristics of smells, recognition of smells, and the number of correct responses. A systematic procedure is described. PMID- 10091349 TI - [New indication for adenoidectomy-tonsillectomy in children: elimination of obstruction in obstructive sleep apnea syndrome]. AB - Obstructive sleep apnea syndrome (OSAS) in children produces serious organic consequences that affect pharyngeal breathing and functional development. The high rate of incidence of this problem is important. In children, the most frequent cause of OSAS is hypertrophy of the tonsils, adenoids, or both. We think that a new indication for pediatric adenoidectomy and tonsillectomy is pharyngeal breathing obstruction by hypertrophic lymphoid formations in the Waldeyer ring. In a statistical analysis of 180 children with OSAS who underwent tonsillectomy and adenoidectomy, the disappearance of most symptoms 7 months after surgery was significant. PMID- 10091350 TI - [Retrospective study of complications of surgery for laryngeal cancer]. AB - Surgery, alone or in combination with other therapeutic measures, is one of the main approaches to curing laryngeal cancer. The risk of complications is implicit in any surgical procedure. We describe our experience with general and local complications in surgery for laryngeal cancer and examine their relation to tumor extension and surgical technique. A review was made of a series of 431 patients who underwent surgery for laryngeal cancer over a 10-year period (1982-1991). Twenty-two patients (5.1%) had systemic complications, including upper gastrointestinal hemorrhage (n = 5), massive cervical hemorrhage (n = 5), and four renal failure. Minor complications were recorded in 77 cases (17.8%), predominantly pharyngocutaneous salivary fistula, which developed in 55 patients (13.8%). The incidence of local complications was significantly greater in patients with extensive local spread (T4). There were no differences among patients with regional spread. The surgical technique and type of pharyngoesophageal reconstruction played no role in the development of complications. Preoperative radiotherapy did not influence on the development of salivary fistulas. PMID- 10091351 TI - [Care for elderly patients at an ENT clinic. Descriptive study]. AB - We report the results of a descriptive one-year study of the disorders encountered in patients over 65 in an ENT clinic. Out of a total of 1,516 patients, 439 were over 65: 57.86% (n = 254) women and 42.14% (n = 185) men. Patients consulted mainly for ear disorders (n = 284, 61.21%). Cerumen obstruction accounted for 29.84% of all new patients. Chronic pharyngitis (n = 58) was the second most frequent complaint and affected 82.8% of women. Malignant tumors were present in 2.2% of new patients. PMID- 10091352 TI - [Thrombophlebitis of the lateral sinus. A more frequent complication than expected]. AB - At present, the frequency of intracranial complications of middle ear infections has decreased sharply as a result of the use of more effective antibiotics. We report two cases of lateral sinus thrombosis, in a 2-year-old male and a 14-year old male respectively, after middle ear infection that progressed to mastoiditis with osteitis. The severity of these complications underlines the importance of clinical awareness and early diagnosis by angiographic magnetic resonance imaging so that suitable treatment can be begun. PMID- 10091353 TI - [Granular cell tumor: an infrequent cause of dysphonia in childhood]. AB - Granular cell tumors (GCT) are rare and usually benign tumors whose histogenesis is debated. The skin, subcutaneous tissues, and mucosae of the head and neck are areas of predilection for GCT. Laryngeal involvement is uncommon, but may create diagnostic and therapeutic problems when it occurs. Laryngeal GCT are decidedly uncommon in children, only 17 cases having been reported in the literature. A case of GCT of the larynx in an 11-year-old girl is reported. The presenting symptom was hoarseness. The macroscopic tumor and hoarseness disappeared after chemotherapy (EVAIA) for Ewing sarcoma of the knee. PMID- 10091354 TI - [Primary laryngeal lymphoma]. AB - We report a new case of supraglottic primary laryngeal lymphoma. The tumor was a B-cell, non-Hodgkin lymphoma with good response to polychemotherapy and radiotherapy. Although the head and neck region is a frequent site of origin of extranodal non-Hodgkin lymphomas, laryngeal involvement is exceptional. Including this case, 88 primary laryngeal lymphomas have been reported in the literature. PMID- 10091355 TI - [Lingual abscess with atypical clinical presentation]. AB - Lingual abscesses have become extremely rare since the discovery of antibiotics, with only about 200 cases reported in the last 160 years. Diagnosis on the basis of clinical symptoms alone is quite difficult. Imaging studies are essential for the diagnosis of lingual abscesses and for their differentiation from related pathologies with similar clinical symptoms. We report a case of lingual abscess with otherwise unremarkable clinical findings that was diagnosed by CT scan. The etiology, pathophysiology, bacteriology, diagnosis, and treatment of these uncommon infections is discussed. PMID- 10091356 TI - [Thyroid teratomas in the adult]. AB - Thyroid teratomas are rare neoplasms in adults (only 19 cases have been reported in the world literature). We report the case of a 55-year-old woman with a paratracheal mass, paralysis of the recurrent nerve, dyspnea, and results of palpation suggestive of malignancy. Total thyroidectomy was performed and anatomopathological study disclosed a benign thyroid teratoma in adult. We discuss this case and review the literature on adult thyroid teratomas. PMID- 10091357 TI - [Dermoid cyst of the mouth floor]. AB - Dermoid cysts are congenital lesions deriving from the ectodermal differentiation of stem cells. They are uncommon in the floor of the mouth. We report a sublingual dermoid cyst in a 24-year-old male and review the literature. PMID- 10091359 TI - Development of the cetacean nasal skull. AB - The adaptation of cetaceans to aquatic life habits is reflected, in their nasal region, in three marked changes from the original relations found in land mammals. These changes include (1) the loss of the sense of smell, (2) translocation of the nostrils from the tip of the rostrum to the vertex of the head, and (3) elongation of the anterior head to form a rostrum protruding far towards anterior. The morphogenetic processes taking place during embryogenesis of the nasal skull play a decisive part in the development of all these changes. The lateral parts of the embryonic nasal capsule, encompassing the nasal passages, change their position from horizontal to vertical. At the same time, the structures of the original nasal floor (the solum nasi) are shifted in front of the nasal passages towards the rostrum. The structures of the original nasal roof (the tectum nasi) and of the nasal side wall (the paries nasi) are translocated behind the nasal passages towards the neurocranium. The medial nasal septum (the septum nasi) mostly loses its connection to the nasal passages and is produced into a point protruding far towards anterior. The transformed embryonic nasal skull of the Cetacea can be divided into three sections: 1. The median structures. These include the cartilaginous structures, viz., the rostrum nasi, the septum interorbitale and the spina mesethmoidalis, which are accompanied by the dermal bones, the vomer and the praemaxillare. In adult cetaceans the rostrum nasi is mostly preserved as a robust cartilage of the skull, which may possibly serve as a sound transmitting structure of the sonar system, or it may be responsible for the sensing of water streams and vibrations. 2. The posterior side wall structures. These include the following cartilaginous structures that are mostly heavily reduced or mutually fused: the cupula nasi anterior, the tectum nasi, the lamina cribrosa, the paries nasi, the commissura orbitonasalis, the cupula nasi posterior, the processus paraseptalis posterior, the crista semicircularis, the frontoturbinale, the ethmoturbinale I and the maxilloturbinale. The cartilaginous structures are largely accompanied by the dermal bone, the maxillare. Of these embryonic elements, very little is preserved in adult cetaceans. The cartilages of the cupula nasi anterior form the variable skeleton around the nostrils. In Physeter the tectum nasi forms a very long cartilaginous bar that passes through the whole giant anterior head of the sperm whale as a structure accompanying the left nasal passage. 3. The anterior side wall structures. These include the cartilaginous structures, viz., the cartilago ductus nasopalatini, the cartilago paraseptalis, the processus lateralis ventralis and the lamina transversalis anterior, accompanied by the dermal bones, the praemaxillare and the vomer. These structures participate in the formation of the robust rostrum of the cetacean skull, and they are partly preserved even in adults in the form of the isolated ossa pararostralia (the Meckelian ossicles). The comparison of morphogeny of the nasal skull has also made it possible to draw certain conclusions on the phylogeny and systematics of Cetacea. Already the earliest embryonic stages permit us to discern weighty transformations of the original nasal skull of land mammals. These transformations are common to all embryos examined. This fact indicates a common origin of all Cetacea, which thus form a single monophyletic order. However, later embryonic stages show some different modifications of the nasal capsule according to which at least three major groups can be distinguished within the order Cetacea, probably ranking as superfamilies: Balaenopteroidea, Physeteroidea and Delphinoidea. Our observations, being in full accordance with other morphological, and embryological, as well as molecular biological results, suggest that the division of the order Cetacea into two suborders, Mysticeti and Odontoceti, is no longer tenable. PMID- 10091358 TI - [Biopsy of the temporal artery. Experience with the use of a protocol at an ENT department]. AB - INTRODUCTION: Temporal artery (TA) biopsy is required for the evaluation of several clinical scenarios because of the therapeutic implications of a positive result. We describe the experience of our department, which is the center for this technique in our hospital. PATIENTS AND METHODS: A retrospective study was made of all TA biopsies performed in the Department of Otolaryngology, Hospital Sierrallana, from January 1995 to April 1997. RESULTS: Thirty-four biopsies of the TA artery were performed in 33 patients for possible temporal arteritis. Mean age was 76 years (range: 61-87 years). Twelve were male and 21 female. Twenty-two patients (66.6%) had recent onset cephalalgia, 11 (33.3%) polymyalgia rheumatica, 5 (15.1%) mandibular claudication, and 8 (24.2%) ocular symptoms. In 75.8% ESR was elevated. An abnormal TA exam was observed in 9 cases (27.3%), 6 of which had a positive biopsy. Only 1 of the 15 patients without local findings at the physical examination had a positive TA biopsy. No information on the physical exam was recorded for the other 2 patients with a positive biopsy. CONCLUSIONS: TA biopsy is a relatively easy surgical procedure with a very low rate of complications. An abnormal physical TA examination correlates with a positive histopathological study. PMID- 10091360 TI - [Extramedullary plasmocytoma of the larynx]. AB - Extramedullary plasmacytomata (EMP) are rare malignant neoplasms composed of plasma cells, 90 percent of which occur in the neck and head area, but generally representing only 1 percent of tumors of that location. The paper report a case of extramedullary plasmacytoma of the larynx, in a 62-year-old man. We also review the different malignant plasma cell dyscrasias, paying special attention to the EMP, given its predilection for the upper aerodigestive tract. PMID- 10091361 TI - [Diagnostic methods in parotid gland pathology]. AB - A check over the used techniques on salivary glands pathology, that is to say: anamnesis, inspection, palpation, laboratory tests, quantitative and qualitative sialometry, gammagram, single radiology, sialography, CAT, MRI, fine needle biopsy in tumorous and non tumorous pathology. It is seen the practical value of each one of these techniques and when they must be utilized. Nowadays are of great value the CAT and MRI. Under the anatomical pathology are of great importance fine needle biopsy for tumoral studies and Daniel's biopsy for Sjogren' syndrome. Regarding surgery to get an untimely biopsy is fundamental. PMID- 10091362 TI - [The rat's vomeronasal organ. Histochemical study with lectins]. AB - A histochemistry study by means of lectins of vomeronasal organ or Jacobson's organ was performed in 5 Wistar rats. Vomeronasal organ is localized at the antero-inferior level of the septum and present two kinds of epithelium, an olfactory one and other respiratory, on the medial and on the lateral part, respectively. Olfactory epithelium shows a great reactivity to WGA lectin, moderate to PNA and weck to Con-A and SBA. In the respiratory epithelium the reactivity is moderate to DBA, PNa, SBA and WGA lectins for goblet cells, instead the periciliary sheat of mucus is reactive to all lectins but DBA and LTA. PMID- 10091363 TI - [Herpetic pseudotumor laryngitis]. AB - The goal of this paper is to report an interesting case of laryngeal involvement by herpes virus, showing a morphological aspect very alike to an extense neoplasm of this region. Laryngeal involvement of herpes virus is a clinical infrequent entity, but as its wide onset forms range from a banal laryngitis until a severe airway obstruction, hoarseness or dysphagia, it seems mandatory an accurate differential diagnose to settle a treatment and the effective follow-up. PMID- 10091364 TI - [Abrikosoff's tumor of the soft palate. A case report]. AB - Abrikossoff's tumor or granular cell tumor is an infrequent benign neoplasm, accurately described by Abrikossoff in 1926. We report the case of a young man, 19-year-old, affected with an Abrikossoff's tumor, sitting on the soft palate. After the timely perusal of the subject, we emphasize the peculiarity of the palatine localisation as well the importance of anatomical pathology in order to get a correct diagnosis of these neoformations of soft's parts. PMID- 10091365 TI - [Wegener's granulomatosis: localization in the subglottic space]. AB - In the paper is presented a localized form of Wegener's granulomatosis. This entity being considered as incipient stage of the disease. Its better knowledge and consequent early diagnosis has contributed to increase the clinic pictures. We report one of these cases sitting on the subglottic space, in a 40-years-old woman, beginning with a serious dyspnea. Several clinic aspects of the disease are emphasized as well the immunologic procedures helping to the diagnosis and to day's classifications. Finally, the better prognosis of localized forms, because its excellent response to immunosuppresants, is stressed. PMID- 10091366 TI - Hemangiopericytoma and temporal bone. AB - Hemangiopericytoma is a vascular tumor arising from the pericyts. The tumor involves usually the muskuloskeletal system and the skin. A hemangiopericytoma of the temporal bone is an extremely rare lesion. This paper describes a case of hemangiopericytoma located in temporal bone, its radiologic diagnosis and its therapeutic options as well. PMID- 10091367 TI - [Endocranial invasion of inverted papilloma]. AB - Inverted papilloma (PI) is a benign neoplasm of nose and paranasal sinuses. IP's pathophysiology is characterized by its capacity to be locally destructive, its ability to grow rapidly and its tendency to recur. IP's association with carcinoma is about 13 percent of cases. The surgical treatment of IP has evolved over the years, with a progression toward more radical en bloc extirpation. The paper reports an inverted papilloma case of nasal cavities, with destruction of frontal sinus roof and intracranial extension aside frontal lobe displacement. PMID- 10091368 TI - [Syndromic hereditary deafness. Usher's syndrome. Oto-neurologic and genetic factors]. AB - Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by congenital bilateral sensorineural hearing loss and progressive loss of vision due to retinitis pigmentosa (RP). The prevalence of Usher syndrome is estimated to be 3-4.4 cases per 100.000 people. Several clinical types have been distinguished by age at onset, rate of progression, and severity of symptoms. Type I (USH1) is characterized by a congenital, severe-to-profound deafness and absent vestibular function. Type II (USH2) shows a congenital and moderate-to severe hearing loss and normal vestibular response. It is also suggested a third type (USH3), clinically similar to USH2, but with progressive hearing loss. Genetic heterogeneity of USH is quite extensive. Up to now, seven different loci responsible for the defect are known: 14q, 11q, 11p, 10q and 21q for USH1; 1q for USH2 and 3q for USH3. Moreover, there are USH1 and USH2 families that fail to show linkage to these candidate regions demonstrating that should exist other loci causing USH, although their ubications are unknown. To date, only two genes involved in the USH pathology are known, although together they are responsibles of about the 80% of total USH cases: myosin VIIA, an unconventional myosin, involved in the USH1b phenotype and a protein similar to the laminina, responsible for the USH2a phenotype. PMID- 10091369 TI - [Initial clinical experience with deep sclerectomy in ambulatory surgery in glaucoma]. AB - Deep sclerectomy is a non-perforating filtering operation used in surgical treatment of open angle glaucomas. The advantage of the operation is the creation of gradual filtration due to the thin trabecular Descement membrane which reduces markedly the risk of development of postoperative complications typical for perforating antiglaucomatous operations. The authors operated at the out-patient department 10 eyes of 8 patients (age 46-81 years). Indications for deep sclerectomy was seven times primary open angle glaucoma (POAG), once capsular glaucoma and twice normotensive glaucoma (NTG). In all eyes deep sclerectomy was indicated because of decompensation of the intraocular pressure with maximum tolerated therapy before surgery. None of the eyes were operated previously. The mean value of intraocular pressure before surgery was 25.1 +/- 6.5 mm Hg. From the results ensues that in nine operated eyes the intraocular pressure at the end of the 6-month follow-up period was compensated without supplementary therapy, only in one eye beta-blockers were prescribed one month after surgery. The cause of failure of filtration was the development of superficial adherence at the site of microperforatiion of the trabecular Descemet membrane which developed during operation. The mean intraocular pressure values at the end of the investigation period were 14.3 +/- 2.8 mm Hg. In two eyes haemorrhage into the anterior chamber was observed on the first day after surgery, the blood was absorbed within 24 hours. Hypotonia in two eyes was only transient and was not associated with a change in the depth of the anterior chamber or other complications. In none of the patients a decline of visual acuity was observed. In three operated eyes a change of refraction was necessary due to discontinuation of miotics after surgery. Deep sclerectomy is a delicate microsurgical technique which calls for experience and skill of the surgeon. The most complicated task is to prevent perforation of the trabecular Descemet membrane during surgery. Provided the surgical technique is perfect, it burdens the patient less than commonly performed perforating antiglaucomatous operations and it can be implemented in the out-patient department. PMID- 10091370 TI - [Use of computer-assisted corneal topography in ophthalmology]. AB - The authors give an account of the possible application of corneal computer topography in some diseases of the cornea and in particular in refraction surgery. PMID- 10091371 TI - [Comparison of hyperopic photorefractive keratectomy and LASIK in correction of hypermetropia with excimer laser]. AB - The aim of this work is to compare results of the correction of hyperopia by method of hyperopic photorefractive keratectomy (HPRK) with method of laser assisted keratomileusis known as LASIK. We evaluate group of 129 eyes operated by excimer laser Keracor 117 manufactured by Technolas company. 77 eyes underwent HPRK and 52 eyes hyperopic LASIK (HLASIK). The patients were divided to two groups, the first of which comprised 47 eyes with low hyperopia to +3.5 Dsph and the second 82 eyes with high hyperopia. Follow-up period was 12 months results were statistically evaluated by Student t-test. One year after treatment, in the first group was 62% eyes with hyperopia to +1.0 Dsph after HPRK and 70% after HLASIK. In the second group it was 32% and 44%, respectively. No statistically significant differences have been found between the two groups. In spite of that, we consider HLASIK method better than HPRK from the point of view of stability of results, occurrence of complications and estimated resulting refraction, especially in the eyes with low hyperopia. PMID- 10091372 TI - [Bimanual irrigation/aspiration]. AB - Bimanual irrigation/aspiration is a safe method for the removal of lenticular mass from the eye and can be used in some complicated cases. As it is a perfectly closed system, oscillation of the posterior capsule does not occur and this prevents prolapse of the vitreous body. If the pupil is narrow, the margin of the pupil can be shifted by means of the irrigation cannula and thus suction of the lenticular mass up to the equator is made possible. In subluxed lenses by gently pushing back the lenticular capsule its adherence to the aspiration cannula is prevented. It is relatively easy to clean the anterior lenticular capsule from epithelial cells by bimanual I/A. PMID- 10091373 TI - [Tonic pupil]. AB - Authors evaluated the group of 21 patients (22 eyes) with pupillotonia. There were 2 postraumatic pupillotonias, 1 bilateral pupillotonia with systematic polyneuropathy in alcoholism, 6 Adie's pupillotonias and 9 postviral pupillotonias. In 4 one-sided pupillotonias there were finded no traumatic, viral or neurological cause. 2 patients (2 eyes) with traumatic cause, 2 patients with Adie's pupillotonia and 9 patients with viral cause had indicated the marked subjective difficulties in the eyes with pupillotonia--blurred vision, cephalea. After local application of Pilocarpin in 0.05%-0.1% concentration, these patients were indicating the marked improvement of their subjective troubles of the eyes. PMID- 10091374 TI - [Laboratory study of the cytotoxicity of colored soft contact lenses]. AB - In the clinical practice we have met with the fact that some patients did not tolerate soft coloured contact lenses even when they used them for a short time. To find whether the cause is the composition of these lenses, mainly the adding of stain, he used the laboratory test to determine cytotoxicity, the test of dynamic observation of cytotoxicity where the cells cultured in vitro are the experimental object. On the basis of the results of this test commonly used for the determination of the cytotoxicity of implantation materials, he thinks that the cause of intolerance of coloured lenses is not their toxicity but other phenomena. An individual hypersensitivity or insufficient care of lenses (the influence of disinfectants) can be among these causes. PMID- 10091375 TI - [Evaluation of permanent sequelae of eye injuries in relation to the duration of work disability and degree of invalidism]. AB - The authors evaluated the sequelae of 200 eye injuries based on forensic attests during the investigation period from 1983-1997. The group comprised 166 men and 34 women, mean age 37.5 years, incl. 25 children under 18 years. They classified the injuries in-to groups with regard to their origin and mechanism. Attention was paid to evaluation of visual acuity at distance, the number of operations of the eyes and the authors classified the group with regard to ophthalmological diagnosis and complications. The mean period of hospitalization was 32.8 days, the mean period of work incapacity 117.7 days. In the whole group there were 75 monoculi, 6 bilaterally blind subjects, one quarter had 6/6 vision on both eyes. Almost half the injured subjects had a reduced work capacity, there were 66 partial invalids, 22 full invalids, 13 subjects had an altered work capacity. The discussion is focused on better collaboration of the ophthalmologist and physician assessing the work capacity in evaluation of permanent sequelae of eye injuries. PMID- 10091376 TI - [Neovascularization of the optic nerve disk]. PMID- 10091377 TI - [Czech national standards for visual tests]. PMID- 10091378 TI - A twenty-year period in mass screening for uterine cervical cancer in Fukushima Prefecture. AB - To explore the change in age distribution of patients with uterine cervical cancer and its precursors, we analyzed 2,168,923 women in a series of mass screening for uterine cervical cancer in Fukushima Prefecture. The first examination rate was not increased over a 20-year period. During the screening period, severe dysplasia was found in 693 women, carcinoma in situ in 672 women, microinvasive carcinoma in 517 women, and frank invasive carcinoma in 421 women. The numbers of patients with frank invasive carcinoma was decreased gradually in every age group, which might reflect the effectiveness of our mass screening project. Although the detection rates of severe dysplasia, carcinoma in situ and microinvasive carcinoma have not changed in patients groups over 40 years old, the detection rates were increased in patients under the age of 39. These results may reflect a recent tendency for cervical cancer to increase in young women. It is important, therefore, to increase the screening rate for young women to prevent the progression with advanced cervical cancer. PMID- 10091379 TI - Surface expression of complement regulatory proteins, decay-accelerating factor (DAF) and CD59, on cultured human endothelial cells. AB - To clarify the response of endothelial cells to complement, we studied not only the reaction of endothelial cells against complement lysis sensitivity (CLS) test, but also the expression of complement regulatory proteins by two-color flow cytometric analysis and backscattered scanning immunoelectron microscopic analysis using monoclonal antibodies to decay-accelerating factor (DAF) and/or CD59. Complement activation didn't lead to the cell death of human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs). In control, two-color flow cytometric analysis indicated that HAECs consisted of a single double-positive population for these proteins as well as HUVECs. Then, HUVECs and HAECs after the CLS test resulted in having same distribution by flow cytometry. Moreover, the microscopic analysis showed that DAF or CD59 was expressed with a diffuse distribution. However, DAF on HUVECs and CD59 on HAECs were present at the margin of cell surfaces more than at the other places. These findings suggest that endothelial cells have a defense mechanism for complement activation in vitro by the changes of expression of complement regulatory proteins on the membrane surface, and that the mechanism of HAECs to complement is the same as that of HUVECs. PMID- 10091381 TI - Immunohistochemical localization of endothelin-1/big endothelin-1 in normal liver, liver cirrhosis and hepatocellular carcinoma. AB - In order to clarify the characteristics of cellular localization of ET-1/big ET-1 in liver tissues, we carried out immunohistochemical study on 30 normal, 87 cirrhosis (LC) and 55 hepatocellular carcinoma (HCC) liver specimens using anti ET-1 antibody and anti-big ET-1 antibody and further performed in situ hybridization on 5 LC liver specimens. Positive immunostaining of hepatocytes of normal and LC livers, and tumor cells of HCC was obtained. The frequency of positive cells for ET-1 and big ET-1 of normal liver was very low. In contrast, LC hepatocytes were stained much more frequently for both ET-1 and big ET-1 than those of normal liver (P < 0.01). In the HCC livers hepatoma cells showed intermediate frequency of positive cells between normal and LC livers. Big ET-1, not ET-1, expression in HCC was significantly high compared with that of normal liver (P < 0.01). Specific signals for ET-mRNA were not detected in hepatocytes of LCs by in situ hybridization. ETs detected in hepatocytes by immunohistochemistry, therefore, seem not to have been synthesized locally. The origin of ETs is not clear but they might have been taken up from the circulation through ET receptors on hepatocytes. Although the clearance mechanism of ETs by ET-converting enzyme or other peptidases in liver has not been elucidated, the mechanisms seem to be absent or impaired in LC and/or HCC liver since the frequency and intensity of ET-positivity in the diseased hepatocytes are significantly high than those of normal liver. In addition, a disturbance of ET excretion into the bile may be also responsible for the ET storage. Elevation of serum ET levels in LC may be caused by disturbance of ET degradation and/or leakage of bile into the blood, as the ET is excreted through the biliary system. PMID- 10091380 TI - Antineutrophil cytoplasmic antibody in patients with antinuclear antibody positive chronic hepatitis C. AB - Hepatitis C viral (HCV) infection has been shown to lead to autoimmune phenomena. Antineutrophil cytoplasmic antibodies (ANCA) have been known to be present in several autoimmune liver diseases. This study aimed to evaluate the prevalence of ANCA in sera of patients with antinuclear antibody (ANA)-positive chronic hepatitis C (CH-C) and to characterize ANCA antigens by Western blot compared with HCV-negative autoimmune hepatitis (AIH). METHODS: Ninety sera obtained from 20 patients with ANA-positive CH-C, 20 patients with ANA-negative CH-C, 20 patients with AIH, 6 patients with primary screlosing cholangitis (PSC) and 24 healthy controls were tested using an indirect immunofluorescence assay, cell ELISA and Western blotting to detect ANCA. RESULTS: In the indirect immunofluorescence assay, ANCA was found in 60% (12/20) of patients with ANA positive CH-C, 100% (20/20) of patients with AIH and 33.3% (2/6) of patients with PSC, but in none of patients with ANA-negative CH-C (n = 20) or healthy controls (n = 24). The staining pattern observed in sera of these patients was a peculiar mixture of both cytoplasmic and perinuclear patterns. The mean ANCA titer by cell ELISA was significantly (p < 0.01) higher in patients with AIH compared with ANA positive or ANA-negative CH-C patients or healthy controls. However, no correlation was found between ANCA titers and ANA titers, serum alanine amino transferase (ALT) or IgG levels in either ANA-positive CH-C or AIH. Western blots of ANCA-positive sera from ANA-positive CH-C patients revealed two bands corresponding to molecular weights of 72 and 46 kDa and there was no differencies in ANCA antigens compared with that from AIH patients. CONCLUSIONS: We found an increased incidence of ANCA in ANA-positive CH-C patients. ANCA in ANA-positive CH-C patients is thought to be one of autoimmune phenomena lead by HCV infection because no difference was observed in the epitope of ANCA antigens between patients with CH-C and AIH. PMID- 10091382 TI - Strength distribution in the tibia. AB - Stress fracture of a tibia is rarely associated with osteoarthros of the knee joint (gonarthrosis), whereas the present authors experienced a case of tibial stress fracture with high level lateral flail. To make an analysis with the statics of an elastic body, the shape of the tibia was read from a roentgenogram with a digitizer. The bend of a tibia was expressed with curvature (the reciprocal with curvature radius); fracture was expected to occur where the curvature was large. From the analysis, the fracture had occurred near one of the maximums of the curvature when the knee side was fixed and a force was applied to the ankle side --walking situation, e.g. The analysis also has indicated that the tibia would be very weak when the ankle side was fixed--skiing situation, e.g. PMID- 10091383 TI - Two sister cases of autoimmune hepatitis. AB - Two sister cases of autoimmune hepatitis are described. Case 1 involved a 49-year old woman who suffered from bleeding gums and general fatigue. Her laboratory data showed a marked increase in transaminase levels, an elevated IgG level with titers 1:80 or more of both antinuclear and smooth muscle antibodies and thrombocytopenia. Histology of the biopsied liver revealed chronic active hepatitis with a moderate infiltration of mononuclear cells. A complication of idiopathic thrombocytopenic purpura was determined based on higher titers of PA IgG and a normal bone marrow findings. Case 2 involved a 54-year-old woman, an elder sister of case 1, who suffered from general fatigue with jaundice. Her laboratory data showed a severe damage of liver function and an elevated IgG level with positive antibodies to nuclear and smooth muscle antigen. Histology of the biopsied liver revealed chronic active hepatitis. Both patients were negative to markers of hepatotrophic agents. Under diagnosis of autoimmune hepatitis, they have been treated with prednisone followed by a significant clinical improvement. HLA types of two patients were Bw54-DR4 and DR4. Among 4 other siblings, the eldest sister suffered from rheumatoid arthritis. The occurrence of two sister cases of type-1 autoimmune hepatitis has rarely reported and the fact would support a role of enviromental factors besides genetic factors for the onset of this disease. PMID- 10091384 TI - Beyond the FAB classification for myelodysplastic syndromes. PMID- 10091385 TI - Bone marrow transplantation for severe aplastic anemia from HLA identical siblings. PMID- 10091387 TI - The myelodysplastic syndromes: predictive value of eight prognostic systems in 143 cases from a single institution. AB - BACKGROUND AND OBJECTIVE: Despite the fact that several prognostic systems for myelodysplastic syndromes (MDS) have been proposed, few studies have been designed to test their effectiveness in independent patient populations. The aim of this study was to compare the prognostic value of 8 previously described prognostic systems in a series of consecutive MDS patients observed at a single institution over a 10-year period. DESIGN AND METHODS: One hundred and forty three patients were diagnosed as having myelodysplastic syndrome (MDS) according to the French-American-British (FAB) criteria. They were studied retrospectively in order to assess the prognostic value of the FAB classification and 7 other prognostic systems. RESULTS: On the basis of data at diagnosis, all investigated systems effectively stratified patients into groups with different life expectancies and identified a subset of patients with poor clinical outcome. However, the systems had different outcomes concerning median survival of patients classified as low-risk, ranging from less than 3 years for the Mufti scoring system to more than 8 years for the FAB classification modified according to Rosati et al. Moreover, patient distribution into different risk categories was quite different with the different prognostic systems. INTERPRETATION AND CONCLUSIONS: When applied to our case series, some of the prognostic systems had a much lower prognostic value than in the patient population from which they derived. This evidence suggests that testing of prognostic systems in independent case series is necessary before using the systems in clinical practice. PMID- 10091386 TI - von Willebrand factor contained in a high purity FVIII concentrate (Fanhdi) binds to platelet glycoproteins and supports platelet adhesion to subendothelium under flow conditions. AB - BACKGROUND AND OBJECTIVE: There is evidence suggesting that von Willebrand factor (VWF) from high purity factor VIII concentrates could be of clinical use in the management of patients suffering from VWD. We analyzed structural and functional characteristics of VWF present in a high purity factor VIII concentrate VWFHPC (Fanhdi). The multimeric structure, the ability to bind to platelet GP Ib/IX or GP IIb/IIIa, and the capacity of VWFHPC to promote platelet adhesion on injured vessels were investigated and compared with that present in standard plasma cryoprecipitates [VWFCRYO]. DESIGN AND METHODS: Binding studies were carried out by incubating radiolabeled VWF and washed platelets, which were activated with either ristocetin (1 mg/mL; for GP Ib/IX), or thrombin (2.5 U/mL; for GP IIb/IIIa). Platelet adhesion was assessed in a perfusion system (shear rate = 800 s-1, 10 min) in which the source of VWF was added (at 0.4 or 0.8 U/mL VWF:Ag) to washed platelets and red cells suspended in a human albumin solution. The deposition of platelets onto the perfused subendothelial surface was morphometrically evaluated and expressed as percentage of surface coverage (%SC). RESULTS: The VWFHPC (152 Units VWF:RCof/mg protein; VWF:RCof/VWF:Ag = 0.97), lacked only a small proportion of high-molecular-weight multimers present in VWFCRYO. Binding affinities (Kd values, nM) of VWFHPC were similar to those of VWFCRYO (5.3 +/- 0.86 vs 5.2 +/- 0.95, for GP Ib/IX; and 11.6 +/- 2.7 vs 15.4 +/- 1.7 for GPIIb-IIIa). A slightly, though not significantly, higher binding capacity for these receptors (Bmax values, molecules/pit) was obtained for VWFHPC. The %SC in perfusions in the presence of albumin was < 10%. Addition of VWFHPC or VWFCRYO significantly increased the %SC, with values of 27.1 +/- 4.9 and 17.5 +/- 2.8%, respectively with 0.4 U/mL (p < 0.004 and p < 0.02 vs albumin); and 30.8 +/- 4.9% and 20.03 +/- 4.1%, respectively, at 0.8 U/mL (p < 0.001 and p < 0.02 vs albumin). INTERPRETATION AND CONCLUSIONS: Our data show that VWF present in the high purity FVIII concentrate Fanhdi retains the functional capacity to bind to GPs Ib/IX and IIb/IIIa and to promote platelet adhesion onto exposed subendothelium. PMID- 10091388 TI - Prognostic significance of bone marrow biopsy in essential thrombocythemia. AB - BACKGROUND AND OBJECTIVE: The diagnostic and prognostic value of bone marrow biopsy (BMB) has been widely investigated in patients with chronic myeloproliferative disorders (CMPD). The present study is based on a review of the results of routine BMBs taken from 93 essential thrombocythemia (ET) patients at the time of diagnosis. DESIGN AND METHODS: The common BMB histologic parameters and clinico-hematologic variables were considered for diagnostic and prognostic purposes. Clinico-pathologic correlations were looked for univariately. Moreover, the diagnostic significance of the histologic findings was tested by means of cluster analysis. Overall survival and event-free survival were considered as prognostic endpoints. RESULTS: There were no correlations between the clinic and pathologic findings, and none of the histologic and clinical parameters was predictive of survival or the occurrence of major clinical events. Cluster analysis of the BMB findings revealed two distinct morphologic patterns: one was clearly myeloproliferative; the other had somewhat dysplastic features. The event-free and overall survival rates in the latter group were significantly worse (p = 0.0377 and p = 0.0162 respectively), with major ischemic events accounting for most of the difference in event-free survival. INTERPRETATION AND CONCLUSIONS: These results have no clearcut counterpart in the literature, but we feel that dysplastic BMB findings could be included in the definition of ET prognostic scores in order to allow therapeutic strategies to be adapted to the level of risk. PMID- 10091389 TI - Weekly administration of 2-chlorodeoxyadenosine in patients with hairy-cell leukemia is effective and reduces infectious complications. AB - BACKGROUND AND OBJECTIVE: It has been widely demonstrated that one single 7-day course continuous infusion (c.i.) 2-chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily is dramatically effective in inducing high and prolonged complete remission (CR) rates in patients with hairy-cell leukemia (HCL). However, 2-CdA administration often results in severe neutropenia and lymphocytopenia both responsible for the infectious complications observed in these patients. We previously reported preliminary data regarding the effectiveness and toxicity of a modified protocol of 2-CdA administration (0.15 mg/kg 2 hours infusion once a week for 6 courses) in 25 HCL patients. This treatment schedule produced a similar overall response rate compared to standard 2-CdA regimen and appeared to be followed by a lower incidence of infectious episodes. In the present study we report response rate and toxicity of weekly 2CdA administration in a larger cohort of patients and with a longer follow-up. DESIGN AND METHODS: In a group of HCL patients with a pronounced decrease in neutrophils count (< 1 x 10(9)/L), we modified the standard protocol (0.1 mg/kg daily x 7 days c.i.) by administering 2 CdA at a dose of 0.15 mg/kg 2 hours infusion once a week for 6 courses. Thirty HCL patients, 24 males and 6 females with a median age of 56 years (range 37-76), entered into this protocol. Seventeen out of 30 patients were at diagnosis while the remaining 13 had been previously treated with alpha-interferon (alpha-IFN) (7), or 2-CdA (4) or deoxycoformycin (DCF) (2). RESULTS: Overall, 22/30 (73%) patients achieved CR and 8 (27%) partial remission (PR) with a median duration of response at the time of writing of 35 months, ranging from 6 to 58 months. Five patients (1 CR and 4 PR) have so far progressed. The treatment was very well tolerated. Five out of 30 patients (16%) developed severe neutropenia (neutrophils < 0.5 x 10(9)/L) and only in two of them we did register an infectious complication which required treatment with systemic antibiotics and granulocyte colony-stimulating factor (G-CSF). INTERPRETATION AND CONCLUSIONS: In conclusion, we confirm that weekly administration of 2-CdA at a dose of 0.15 mg/kg for 6 courses appears to be very effective in HCL inducing a high CR rate, similar to that observed with daily c.i. administration. CR durability and relapse/progression rates are also comparable to standard 2-CdA schedule. Moreover this new regimen seems to be safer in pancytopenic patients, markedly reducing life-threatening infectious complications. PMID- 10091390 TI - Bone marrow transplantation for severe aplastic anemia: the Barcelona Hospital Clinic experience. AB - BACKGROUND AND OBJECTIVE: The outcome of patients with severe aplastic anemia (SAA) has improved considerably over the last decades. Bone marrow transplantation (BMT) is the treatment of choice in young patients who have an HLA-identical sibling donor. This study analyzes the outcome and factors related to survival in patients with SAA receiving BMT in our institution. DESIGN AND METHODS: Between March 1978 and December 1996, 49 consecutive patients received an HLA-identical sibling marrow transplant for SAA. Median age was 21 years (range, 4 to 47) and 15 (31%) were women. Median interval from diagnosis to transplant was 2.6 months (range, 0.5 to 159). Between 1978 and 1982 all patients were conditioned with cyclophosphamide (CY) alone and received methotrexate (MTX) until day 102 as graft-versus-host disease (GvHD) prophylaxis. From 1983 most patients received CY and thoraco-abdominal irradiation (TAI) as the conditioning regimen and cyclosporin A (CSA) as GvHD prophylaxis. RESULTS: Survival probability at 10 years was 55 +/- 7% with a median follow-up for the surviving patients of 8.5 years. The incidences of graft failure, grade II to IV acute GvHD, and chronic GvHD were 21%, 39.5% and 31%, respectively. In multivariate analysis three factors adversely influenced survival: a) age > or = 30 years (p = 0.05); b) > or = 10 transfusion units pre-BMT (p = 0.008); and c) use of long course MTX for GvHD prophylaxis (p = 0.01). One case of squamous-cell carcinoma occurred in a TAI-treated patient 13 years post-transplantation. INTERPRETATION AND CONCLUSIONS: BMT is effective in young patients with SAA who have an HLA identical sibling donor, particularly if minimally transfused pre-transplant. The introduction of TAI and CSA to our preparative regimen has led to a remarkably increased survival. PMID- 10091391 TI - Large-volume leukapheresis in pediatric patients: pre-apheresis peripheral blood CD34+ cell count predicts progenitor cell yield. AB - BACKGROUND AND OBJECTIVE: In children it is very important to optimize PBPC harvesting and to reduce the number of leukaphereses per patient. The value of pre-apheresis peripheral blood CD34+ cell concentration as a predictor of PBPC yield was studied in 23 pediatric patients with hematologic and non-hematologic malignancies in order to optimize duration of PBPC collection. DESIGN AND METHODS: The patients underwent 25 stem-cell mobilization episodes with G-CSF alone and 40 large-volume leukapheresis procedures. Peripheral blood and harvested CD34+ cell concentrations were analyzed by means of flow cytometry. RESULTS: Using linear regression analysis, a highly significant correlation was found between the peripheral blood CD34+ cell count and the CD34+ cells/kg patient body weight collected on the apheresis day (r = 0.826, p = 0.0001). The results indicate that at least 1 x 10(6)/kg CD34+ cells can be harvested during one leukapheresis procedure in all patients if the pre-apheresis blood CD34+ cell count is > or = 30/microL and a CD34+ cell target of > or = 5 x 10(6)/kg is achieved in at least 80% of patients if this value is > or = 50 CD34+ cells/microL processing a median blood volume of 438.7 mL/kg (range, 207-560) over a median time of 232.5 minutes (range, 182-376). INTERPRETATION AND CONCLUSIONS: Our results suggest that the number of CD34+ cells harvested in a single large-volume leukapheresis can be predicted from the measurement of peripheral blood CD34+ cell concentration on the collection day. PMID- 10091392 TI - Treatment of multiple myeloma. AB - BACKGROUND AND OBJECTIVE: Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies. The standard treatment with intermittent courses of melphalan and prednisone (MP) was introduced more than 30 years ago and, since then there has been little improvement in event-free and overall survival (EFS & OS). The aim of this article is to review: 1) the role of initial chemotherapy (ChT), maintenance treatment with alpha-interferon and salvage ChT, 2) the results of high-dose therapy (HDT) followed by allogeneic or autologous stem cell transplantation (allo-SCT and auto-SCT), and 3) the most important supportive measures. EVIDENCE AND INFORMATION SOURCES: The authors of this review have been actively working and contributing with original investigations on the treatment of MM during the last 15 years. In addition, the most relevant articles and recent abstracts published in journals covered by the Science Citation Index and Medline are also reviewed. STATE OF THE ART AND PERSPECTIVES: The importance of avoiding ChT in asymptomatic patients (smoldering MM) is emphasized. The criteria and patterns of response are reviewed. MP is still the standard initial ChT with a response rate of 50-60% and an OS of 2-3 years. Combination ChT usually increases the response rate but does not significantly influence survival when compared with MP. Exposure to melphalan should be avoided in patients in whom HDT followed by auto-SCT is planned, in order to not preclude the stem cell collection. The median response duration to initial ChT is 18 months. Interferon maintenance usually prolongs response duration but in most studies does not significantly influence survival (a large meta-analysis by the Myeloma Trialists' Collaborative Group in Oxford is being finished). In alkylating-resistant patients, the best rescue regimens are VBAD or VAD. In patients already resistant to VBAD or VAD and in those in whom these treatments are not feasible we recommend a conservative approach with alternate day prednisone and pulse cyclophosphamide. While HDT followed by autotransplantation is not recommended for patients with resistant relapse, patients with primary refractory disease seem to benefit from early myeloablative therapy. Although results from large randomized trials are still pending in order to establish whether early HDT intensification followed by auto-SCT is superior to continuing standard ChT in responding patients, the favorable experience with autotransplantation of the French Myeloma Intergroup supports this approach. However, although the complete response rate is higher with intensive therapy, the median duration of response is relatively short (median, 16 to 36 months), with no survival plateau. There are several ongoing trials comparing conventional ChT with HDT/autoSCT in order to identify the patients who are likely to benefit from one or another approach. With allo-SCT there is a transplant-related mortality ranging from 30 to 50% and also a high relapse rate in patients achieving CR. However, 10 to 20% of patients undergoing allo-SCT are long-term survivors (> 5 years) with no evidence of disease and, consequently, probably cured. The use of allogeneic peripheral blood stem cells (PBSC) in order to speed the engraftment and also the use of partially T-cell depleted PBSC which can decrease the incidence of graft-versus-host disease are promising approaches. In the setting of allo-SCT, donor lymphocyte infusion is an encouraging strategy in order to treat or prevent relapses. Finally, important supportive measures such as the treatment of anemia with erythropoietin, the management of renal failure and the use of bisphosphonates are reviewed. PMID- 10091393 TI - Thrombophilia as a multigenic disease. AB - BACKGROUND AND OBJECTIVE: Venous thrombosis is a common disease annually affecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing genetic and/or environmental risk factors in thrombosis patients. Most of the genetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the protein C system. INFORMATION SOURCES: Published results in articles covered by the Medline database have been integrated with our original studies in the field of thrombophilia. STATE OF THE ART AND PERSPECTIVES: The risk of venous thrombosis is increased when the hemostatic balance between pro- and anti-coagulant forces is shifted in favor of coagulation. When this is caused by an inherited defect, the resulting hypercoagulable state is a lifelong risk factor for thrombosis. Resistance to activated protein C (APC resistance) is the most common inherited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which predicts the substitution of Arg506 with a Gln. Arg506 is one of three APC-cleavage sites and the mutation results in the loss of this APC-cleavage site. The mutation is only found in Caucasians but the prevalence of the mutant FV allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations, in areas with high incidence of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. The second most common inherited risk factor for thrombosis is a point mutation (G20210A) in the 3' untranslated region of the prothrombin gene. This mutation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or protein S. Such defects are present in less than 1% of healthy individuals and together they account for 5-10% of genetic defects found in patients with venous thrombosis. Owing to the high prevalence of inherited APC resistance (FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals with multiple defects have a highly increased risk of thrombosis. As a consequence, multiple defects are often found in patients with thrombosis. PMID- 10091394 TI - Management of human cytomegalovirus infection and disease after allogeneic bone marrow transplantation. AB - BACKGROUND AND OBJECTIVE: Human cytomegalovirus (HCMV) infection and disease remain a major cause of morbidity and mortality after bone marrow transplantation. HCMV disease, especially pneumonitis, may be treated with ganciclovir and immunoglobulin but even so the outcome is poor with mortality rates of 30-70%. It is therefore imperative to treat HCMV infection before it develops into disease. The aim of this article is to describe the main strategies used to prevent HCMV infection and to improve the survival after CMV disease in bone marrow transplant recipients. INFORMATION SOURCES: In the present review, we examined personal papers in this field and articles published in journals covered by the Science Citation Index and Medline. STATE OF THE ART: Major advances have been made in preventing HCMV infection and disease through two different approaches, both of which reduce HCMV induced morbidity and mortality: In pre emptive therapy, patients are given ganciclovir when HCMV infection is first identified and this is continued 3-4 months after transplantation; in prophylactic therapy ganciclovir is given to all patients at risk of HCMV disease from engraftment up to 3-4 months post transplantation. Each strategy has advantages and disadvantages and there is no evidence for the superiority of one over the other since the overall survival is the same and the incidence of death from HCMV disease is similar. PERSPECTIVES: The use of more sensitive tests such as HCMV PCR or antigenemia may improve the outcome but probably will not eradicate all HCMV disease. Future possible strategies could include adoptive transfer of CD8+ HCMV-specific cytotoxic T lymphocytes clones derived from the donor marrow or boosting donor or patient immunity using subunit anti-HCMV vaccines such as gB or pp65. PMID- 10091395 TI - Factor V Leiden and antibodies against phospholipids and protein S in a young woman with recurrent thromboses and abortion. AB - We describe the case of a 39-year-old woman who suffered two iliofemoral venous thromboses, a cerebral ischemic infarct and recurrent fetal loss. Initial studies showed high levels of antiphospholipid antibodies (APAs) and a moderate thrombocytopenia. After her second miscarriage, laboratory diagnosis revealed that the woman was heterozygous for the factor V Leiden mutation and had a functional protein S deficiency as well as anti-protein S and anti-beta 2 glycoprotein I antibodies. The impairment of the protein C pathway at various points could well explain the recurrent thromboses in the patient and supports the role of a disturbed protein C system in the pathophysiology of thrombosis in patients with APAs. PMID- 10091396 TI - Parvovirus infection in a child with acute lymphoblastic leukemia. PMID- 10091397 TI - Skin changes in POEMS syndrome. PMID- 10091398 TI - Existence of a hypercoagulability state prior to prosthetic hip or knee surgery. PMID- 10091399 TI - Cryptic insertion (15;17) in a case of acute promyelocytic leukemia detected by fluorescence in situ hybridization. PMID- 10091400 TI - C-->T mutation at -158 G gamma HPFH associated with 4 bp deletion (-225-222) in the promoter region of the A gamma gene in homozygous beta 0 39 nonsense thalassemia. PMID- 10091401 TI - Successful treatment of AA amyloidosis secondary to Hodgkin's disease with 4' iodo-4'-deoxydoxorubicin. PMID- 10091402 TI - Hepatitis C virus infection and mixed cryoglobulinemia in patients with lymphoproliferative diseases. PMID- 10091403 TI - Dysmetabolic iron overload syndrome. PMID- 10091404 TI - Gilbert's syndrome and jaundice in glucose-6-phosphate dehydrogenase deficient neonates. AB - BACKGROUND AND OBJECTIVE: The pathogenesis of the hyperbilirubinemia present in approximately 30% of neonates affected by glucose-6-phosphate dehydrogenase deficiency is an unsolved problem. We evaluated the effect of Gilbert's syndrome, the most common defect of bilirubin conjugation, on the hyperbilirubinemia of these neonates. DESIGN AND METHODS: One hundred and two neonates affected by glucose-6-phosphate dehydrogenase deficiency were enrolled in this study: 56 had hyperbilirubinemia and 46 had normal bilirubin levels. The analysis of the A(TA)nTAA motif in the promoter region of the UGT1A gene was performed by means of PCR, followed by separation on 6% denaturing polycrylamide gel. RESULTS: The frequency of the three different genotypes of the A(TA)nTAA motif was similar in the study and control groups. Our results demonstrated no difference in the percentage of homozygotes for the UGT1A (TA)7 variant associated with Gilbert's syndrome. INTERPRETATION AND CONCLUSIONS: These findings indicate that Gilbert's syndrome does not account for the hyperbilirubinemia occurring in some neonates with glucose-6-phosphate dehydrogenase deficiency. Furthermore our results suggest that hemolysis is not the major event in the pathogenesis of hyperbilirubinemia in these patients. PMID- 10091405 TI - Co-inherited Gilbert's syndrome: a factor determining hyperbilirubinemia in homozygous beta-thalassemia. AB - BACKGROUND AND OBJECTIVE: Patients with thalassemia major and intermedia show a marked variability of serum indirect bilirubin levels. In this paper we tested the hypothesis related to the variability of the glucuronidation bilirubin rate which depends on the configuration of the A(TA)nTAA motif of the UGT1*1 glucuronosyltransferase gene promoter. DESIGN AND METHODS: We studied the configuration of the A(TA)nTAA motif in 26 patients with thalassemia major and 34 with thalassemia intermedia. RESULTS: In patients with thalassemia major and in those with thalassemia intermedia significantly higher bilirubin levels were found in patients with the (TA)7/(TA)7 genotype, than in those with the (TA)7/(TA)6 or (TA)6/(TA)6 genotype. INTERPRETATION AND CONCLUSIONS: These results indicate that the (TA)7/(TA)7 genotype, the configuration found in patients with Gilbert's syndrome, is capable of modifying the clinical phenotype of homozygous beta-thalassemia. This is an example of the role played by co inherited modifying gene(s) on the extent of clinical heterogeneity of monogenic disorders. PMID- 10091406 TI - (TA)8 allele in the UGT1A1 gene promoter of a Caucasian with Gilbert's syndrome. AB - BACKGROUND AND OBJECTIVE: Gilbert's syndrome, a chronic non-hemolytic unconjugated hyperbilirubinemia, is caused by a reduction in the activity of hepatic bilirubin UDP-glucuronosyltransferase (UGT1A1). This reduction has been shown to be due to a polymorphism in the promoter region of the UGT1A1 gene. The presence of seven thymine adenine (TA) repeats reduces the efficiency of transcription of the UGT1A1 gene. To elucidate the genetic background of a patient affected by Gilbert's syndrome, we collected blood samples from family members for the analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene. DESIGN AND METHODS: Analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene was performed by PCR. Estimation of UGT1A1 promoter containing the variable (TA) repeats was performed by using a luciferase reporter system. RESULTS: Three different genotypes were identified due to the presence of (TA)6, (TA)7 and (TA)8 repeats. The production of luciferase decreases in inverse relation to the number of repeats. INTERPRETATION AND CONCLUSIONS: The (TA)7 polymorphism, associated with Gilbert syndrome, is the only allele found up to now in white populations, while two other variants (TA)5 and (TA)8 have been identified in black populations. We describe here the first case of a subject affected by Gilbert's syndrome who is heterozygous for the (TA)8 allele in the promoter region of the UGT1A1 gene. This polymorphism, as well as the (TA)7 one, is associated with an increased level of bilirubin and a significant reduction of transcription activity of the UGT1A1 gene. PMID- 10091407 TI - Molecular analysis of 1p32 genetic involvement in pediatric T-cell non-Hodgkin's lymphoma. AB - BACKGROUND AND OBJECTIVE: T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic T-cell non-Hodgkin's lymphoma (T-NHL) are closely related disorders, and distinguishing between the two may be difficult. Cytogenetic investigations of large NHL series reported different recurring chromosomal alterations. Among these, aberrations of chromosome 1p seem to be associated with T-cell differentiation, the region most frequently involved in breakpoints being band 1p32-36. Deletions and translocations involving the same chromosomal region are frequently observed in T-ALL, in which one of the most common genetic changes is the breakage of the TAL1 gene, mapped to the 1p32 chromosomal region. The objective of this study was to assess the possibility of TAL1 involvement also in T-NHL. DESIGN AND METHODS: A series of 17 pediatric T-NHL patients was molecularly characterized by microsatellite markers analysis and by TAL1 gene microdeletions. RESULTS: TAL1 gene rearrangement was found in one case, while loss of heterozygosity (LOH) and microsatellite instability (MI) was identified in another case. INTERPRETATION AND CONCLUSIONS: Overall our findings indicate that, differently from T-ALL, neither TAL1 gene involvement nor LOH or MI at 1p32 appear particularly relevant in the oncogenic process of T-NHL transformation. PMID- 10091408 TI - Fusarium infections in patients with severe aplastic anemia: review and implications for management. AB - BACKGROUND AND OBJECTIVE: The prognosis of severe fungal infections, such as fusarium infections, in patients with aplastic anemia is directly related to the recovery of bone marrow functions. In this study, in vitro anti-Fusarium activity of granulocytes was investigated, the case of disseminated infection in a child with very severe aplastic anemia is reported, and implications for management of such infective complications are discussed. DESIGN AND METHODS: The in vitro efficiency of PMNL from three untreated, normal blood donors and from two G-CSF treated WBC donors in contrasting the growth of the Fusarium sp strain isolated from the patient we present was measured by a 3H-glucose uptake inhibition assay and confirmed by microscopic examination. RESULTS: Basic growth inhibitory activity of unstimulated PMNL on Fusarium cells was significantly enhanced in the presence of GM-CSF in all three blood donors tested. In one of the two G-CSF treated donors, in vitro efficiency of PMNL in contrasting the growth of the fungus increased notably after G-CSF treatment. We report the case of a 3-year old girl with very severe aplastic anemia unresponsive to conventional immunosuppressant therapy who developed a disseminated fusarium infection. The child initially responded to liposomal amphotericin B and granulocyte transfusions from G-CSF stimulated donors. Subsequently she was given a cord blood stem cell transplantation but died of disseminated infection. INTERPRETATION AND CONCLUSIONS: Including the present case, there are only ten reports of invasive infections caused by the genus Fusarium in aplastic anemia patients and only two of the patients survived. In vitro data seem to suggest that in vivo treatment with rh-G-CSF could have a stimulatory effect on the anti Fusarium activity of neutrophils. Despite the efficacy of granulocyte transfusions by G-CSF-stimulated donors in the temporary control of fusarium infection, treatment of the underlying hematologic disease is required to cure the infection in patients with severe aplastic anemia. Granulocyte transfusions by G-CSF-stimulated donors while awaiting bone marrow recovery following the blood stem cell transplant should be considered. PMID- 10091409 TI - Detection of focal myeloma lesions by technetium-99m-sestaMIBI scintigraphy. AB - BACKGROUND AND OBJECTIVE: The tracer tachnetium-99m-2-methoxy-isobutyl-isonitrile (Tc99m-sestaMIBI) has recently been shown to concentrate in some neoplastic tissues, including myeloma. We investigated the diagnostic capacity and limits of this procedure in tracing focal myeloma lesions, and compared them with those of conventional radiological procedures (Xr). DESIGN AND METHODS: We studied 55 patients suffering from multiple myeloma (MM) or solitary plasmacytoma in different stages and clinical conditions, or from monoclonal gammopathy of undefined significance (MGUS), by whole body scans obtained 10 minutes after injection of 555 MBq of Tc99m-sestaMIBI. Scans were defined as normal (physiological uptake only), diffuse (presence of bone marrow uptake), or focal (localized areas of uptake), and were compared to conventional skeletal Xr. RESULTS: Thirty patients showed no focal areas of Tc99m-sestaMIBI uptake; this group consisted of 5 patients with MGUS, 6 with MM in stage IA and 2 in stage IIA, 11 patients studied after effective chemotherapy and 6 in early relapse. Twenty-five patients showed one or more spots of focal uptake: all of them had active disease (untreated, resistant or relapsing MM). In the setting of tracing focal lesions, Tc99m-sestaMIBI scans were concordant with the radiological examination in 38 patients and discordant in 17. Among the latter, in 4 cases Tc99m-sestaMIBI revealed focal lesions not detected by Xr, and in 13 cases lytic areas detected by Xr did not show Tc99m-sestaMIBI uptake. INTERPRETATION AND CONCLUSIONS: In untreated patients, the number of lesions revealed by Tc99m sestaMIBI was comparable to that shown by Xr, while in pretreated patients Tc99m sestaMIBI traced a number of lesions lower than that detected by Xr. The reason for this discrepancy is that Tc99m-sestaMIBI traces only active lesions. Tc99m sestaMIBI limitations in identifying focal lesions may derive from the dimension of the smallest traceable lesion (about one centimeter), and from the possibility that focal plasma cell localizations in collapsed bone may not be visualized due to inadequate vascularization. Tc99m-sestaMIBI scintigraphy is an interesting tool for diagnosing, staging and following up focal myeloma lesions, in the bone as well as in soft tissues. It is more specific than conventional Xr in identifying sites of active disease. PMID- 10091410 TI - Autologous blood stem cell transplantation for acute myeloblastic leukemia in first complete remission. Intensification therapy before transplantation does not prolong disease-free survival. AB - BACKGROUND AND OBJECTIVE: To compare the clinical results of two consecutive therapeutic protocols including autologous blood stem cell transplantation (ABSCT) for patients with de novo acute myeloblastic leukemia (AML) in first complete remission (CR1). DESIGN AND METHODS: Between November 1989 and January 1997, 50 patients with AML in CR1 underwent ABSCT using two consecutive protocols. In the first one (Group A, 25 patients) peripheral blood stem cells (PBSC) were collected after induction and consolidation chemotherapy courses, and ABSCT was performed immediately thereafter. In the subsequent 25 patients (Group B), PBSC were collected after consolidation alone, and a further chemotherapy course with intermediate dose cytarabine (Ara-C 1 g/m2/12 h x3 days) and mitoxantrone (12 mg/m2/d x3 days) was administered as early intensification. The conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) in every case. RESULTS: Hematopoietic engraftment was slightly quicker in Group B, with median times to reach 0.5 x 10(9) neutrophils/L and 20 x 10(9) platelets/L being 13 and 12 days in Group A and 12 and 11 days in Group B, respectively. There were three graft failures (8%) (2 in Group A and 1 in Group B) and three transplant-related deaths (8%) (2 in Group A and 1 in Group B). No significant differences were observed between the groups in terms of relapse (64% at 4-years in Group A and 81% in Group B). Likewise, the actuarial 4-year disease free survival (DFS) was not significantly different between the two groups (32% v 18%). INTERPRETATION AND CONCLUSIONS: Our study confirms that AML patients in CR1 receiving ABSCT have rapid engraftment with low mortality. However, autologous transplants with PBSC collected after consolidation chemotherapy were still associated with a high rate of relapse (RR). This RR was not apparently reduced by the administration of intermediate dose Ara-C before transplantation. PMID- 10091412 TI - Polymorphisms for the size of heterochromatic regions allow sex-independent quantification of post-BMT chimerism targeting metaphase and interphase cells. AB - BACKGROUND AND OBJECTIVE: Fully quantitative cytological techniques for the analysis of hemopoietic chimerism are very limited and largely restricted to sex chromosome detection after sex-mismatched bone marrow transplants (BMTs). The aim of the present investigation was to assess the usefulness of autosomal polymorphisms for the size of heterochromatic regions in the identification of donor and recipient cells and therefore in the quantification of the hemopoietic chimerism after sex-matched BMT. DESIGN AND METHODS: Hemopoietic chimerism was followed up in 3 transplanted patients targeting a polymorphism for the size of the pericentromeric heterochromatin (PCH) of chromosome 9, uncovered by restriction endonuclease (RE) in situ digestion (REISD) with the RE Sau3A, to differentiate donor and recipient cells on conventional bone marrow chromosome preparations. RESULTS: The polymorphism for the size of the PCH of chromosome 9 allowed differentiation of donor and recipient cells targeting both metaphase and interphase nuclei. The misidentification error for the polymorphism for the size of HPC of chromosome 9 was estimated as 1% for metaphases and 6-11% for interphases. The 3 cases studied showed complete chimerism in the first post-BMT sample analyzed, which was maintained in 2 of them. One patient relapsed and showed transient mixed chimerism. One month later, this patient achieved a second complete remission, showing complete chimerism again. In this patient, who received a sex-mismatched BMT, chimerism was also quantified by sex-chromosome identification using established methods, such as conventional cytogenetics and FISH, and the results obtained were similar to those rendered by Sau3A-REISD. INTERPRETATION AND CONCLUSIONS: The polymorphism for the size of the PCH of chromosome 9 uncovered by Sau3A-REISD allows accurate quantification of the hemopoietic chimerism after sex-matched BMT. PMID- 10091411 TI - Recombinant human granulocyte-macrophage colony-stimulating factor accelerates engraftment kinetics after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia. AB - BACKGROUND AND OBJECTIVE: The use of recombinant human granulocyte-macrophage stimulating factor (rhGM-CSF) has been shown to be well-tolerated and to reduce post-transplantation morbidity in adults undergoing HLA-identical allogeneic bone marrow transplantation (BMT). There is however, limited experience in children. DESIGN AND METHODS: We performed a prospective, comparative multicenter trial using rhGM-CSF after allogeneic BMT in children with acute lymphoblastic leukemia (ALL). The study comprised 24 patients with ALL who received rhGM-CSF and 22 patients with ALL who did not receive rhGM-CSF. There were no statistically significant differences in the demographic characteristics between the rhGM-CSF treated and untreated groups. rhGM-CSF was given at a dose of 10 micrograms/kg/day infusion over 4 hours from day +1 until +28 or until the absolute neutrophil count (ANC) was > or = 1 x 10(9)/L. All patients received HLA identical sibling marrow and cyclosporine alone for graft-versus-host disease (GvHD) prophylaxis. The number of cells infused was similar in both groups. A software program (Statview 4.0, Abacus Concept, Inc., Berkeley, CA, USA) was used for statistical analysis. RESULTS: The median of days to achieve ANC > or = 0.5 x 10(9)/L was shorter in the rhGM-CSF-treated patients (14 days vs 18.5 days; p < 0.0001). Patients who received rhGM-CSF had a lower incidence of grade III-IV mucositis. The duration of hospital stay was significantly shorter in patients who received rhGM-CSF (31 days vs 45 days; p < 0.005). No differences in GvHD severity, relapse or survival were observed. At the dose and schedule used in the present study, rhGM-CSF was well-tolerated and no side effects were observed. INTERPRETATIONS AND CONCLUSIONS: rhGM-CSF at a dose of 10 micrograms/kg/day in children with ALL undergoing allogeneic BMT is well tolerated, accelerates neutrophil and platelet engraftment, reduces the intensity and severity of mucositis and permits a more rapid discharge from hospital. PMID- 10091413 TI - Costs of high-dose salvage therapy and blood stem cell transplantation for resistant-relapsed malignant lymphomas in a southern Italian hospital. AB - BACKGROUND AND OBJECTIVE: Analysis of costs of high technological procedures such as peripheral blood stem cell (PBSC) autotransplantation in lymphomas are generally finalized at disclosing whether the improvement of survival in a subset of patients is cost effective and whether the cost of the procedure could be reduced. With the aim of revealing a possibility of reducing costs with respect to conditions of safety, we present our experience with PBSC autotransplantation in a particularly poor prognosis subset of patients with lymphoma. DESIGN AND METHODS: The expenses are analyzed for groups of cost and main resources necessary at unitary cost are considered separately. Groups of cost include various phases of the PBSC autotransplantation such as preparative procedures, execution of myeloablative therapy, reinfusion of CD34 cells, supportive therapy after reinfusion until discharge of the patient, general support for the management of patient. All costs are calculated according to 1997 prices and salaries and reported in dollars. The analysis was conducted on 21 patients with lymphoma resistant to other therapies treated by myeloablative therapy and PBSC autotransplantation in an hematologic unit in an open ward; the assistance was provided by staff not exclusively dedicated to bone marrow transplant procedures, with some help from a family member. RESULTS: The PBSC procedure, including all phases, costs from $17,761.9 to $18,259.9 depending on the type of myeloablative therapy employed; the mean cost was $18,092.6. The preparative phase with mobilization of CD34 cells, cryopreservation and reinfusion costed $3,538.7 (19.6% of the total cost); a major cost of this phase was cryopreservation and CD34 manipulation ($857.1). The second phase with myeloablative therapy and reinfusion of CD34 cells had a mean cost of $2,785.9 (15.4% of the total cost); a major cost of this phase was the hospitalization ($1,119.8). The third phase of patient's support after treatment had a total cost of $7,649 (42.3% of the cost of the total procedure) with the major cost being due to hospitalization ($2,571) calculated on a mean of 15 days after the reinfusion of CD-34. The last group of costs, including management support, accounted for $4,119 (22.7%) with a major cost being amortization of the structure ($1,600). The general cost for nurse's assistance to the patient was $1,355.1 (7.5%). INTERPRETATION AND CONCLUSIONS: A procedure of PBSC autotransplantation in resistant lymphoma is affordable without the strict precautions generally given in intensive care units. This provides a substantial reduction of expenses because of the low number of specifically trained staff members and the generally low cost of the necessary supplies. Before, however, proposing PBSC autotransplantation in most patients with resistant lymphoma, an evaluation of whether costs could be further reduced and whether the procedure has a cost benefit impact is needed. PMID- 10091414 TI - Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes. AB - BACKGROUND AND OBJECTIVE: Crigler-Najjar syndromes type I and II and Gilbert's syndrome are familial unconjugated hyperbilirubinemias caused by genetic lesions involving a single complex locus encoding for bilirubin-UDP glucuronosyltransferase which is involved in the detoxification of bilirubin by conjugation with glucuronic acid. Over the last few years a number of different mutations affecting this gene have been characterized. The aim of this work is to review the molecular pathology of Crigler-Najjar and Gilbert's syndromes, to discuss its impact on the clinical and genetic classification of these conditions, and on the diagnostic evaluation of clinical pictures associated with unconjugated hyperbilirubinemia. EVIDENCE AND INFORMATION SOURCES: The authors of the present review are involved in the clinical management of patients with familial unconjugated hyperbilirubinemia as well as in the characterization of its molecular bases. Evidence from journal articles covered by the Science Citation Index and Medline has been reviewed and collated with personal data and experience. STATE OF THE ART AND PERSPECTIVES: It has been known for many years that mild to severe deficiency of bilirubin UDP-glucuronosyltransferase in the liver is the cause of two types of familial unconjugated hyperbilirubinemia, Crigler-Najjar syndromes I and II, and Gilbert's syndrome. Since the characterization of the gene encoding for bilirubin UDP-glucuronosyltransferase, a number of mutations affecting the expression of this gene have been identified. These mutations can be classified into three groups: mutations which result in a reduced production of a normal enzyme; mutations which give rise to the synthesis of a structurally abnormal and dysfunctional enzyme; mutations which completely abolish the expression of the affected allele. The combination of mutations affecting the coding region of the gene and of promoter mutations which reduce the expression of the gene accounts for the wide clinical spectrum of familial unconjugated hyperbilirubinemias, ranging from the clinically negligible Gilbert's syndrome to the severe and often fatal Crigler-Najjar type I syndrome. A better understanding of the genetics of these conditions and the availability of molecular diagnosis will improve the diagnostic efficiency and afford better informed genetic counseling, not only for Crigler-Najjar and Gilbert's syndromes, but also for several acquired conditions characterized by unconjugated hyperbilirubinemia. PMID- 10091415 TI - Thrombopoietin: its role from early hematopoiesis to platelet production. AB - BACKGROUND AND OBJECTIVE: Thrombopoietin (TPO), also referred to as MpI ligand, is the most potent cytokine that physiologically regulates platelet production. With the availability of sufficient amounts of recombinant forms of the protein, the biological in vitro and in vivo activities of this cytokine have been extensively studied. The objective of this review is to summarize the published data focusing on TPO production and regulation and to discuss the pleiotropic biological action of this hormone. The review also highlights the results so far obtained in preclinical and clinical trials. EVIDENCE AND INFORMATION SOURCES: The material examined in this review includes data published by the author and articles or abstracts published in Journals covered by Medline. The author has contributed to the isolation of TPO, has been working in the field for several years and has contributed original papers on the TPO/MpI system in normal and pathologic situations. STATE OF THE ART: TPO is a hormone constitutively produced by the liver and kidneys. Plasma levels of TPO are regulated through receptor mediated uptake, internalization and catabolism. First thought to be a lineage dominant factor promoting megakaryocytopoiesis, several lines of evidence indicate that TPO has pleiotropic effects on hematopoiesis. In vitro studies show that TPO alone, or in combination with early acting cytokines, stimulates the proliferation and enhances the expansion of primitive CD34+ CD38- hematopoietic progenitor cells. In vivo studies with c-mpl- and TPO-null mice reveal that the molecule sustains the survival and proliferation of early committed progenitor cells of various type. Preclinical and clinical trials indicate that recombinant TPO molecules increase platelet counts and megakaryocyte numbers in normal or mildly thrombocytopenic states. However, no significant effects of TPO administration on platelet recovery have so far been reported in patients subjected to intensive chemotherapy regimens. Recombinant molecules appear to be safe to administer and very little toxicity is reported. TPO augments the number of erythroid and myeloid committed progenitor cells in marrow, and mobilized stem cells in peripheral blood. PERSPECTIVES: The potential clinical use of TPO is still unclear. With the increased knowledge of the multiple effects of TPO on hematopoiesis, it is expected that future carefully monitored clinical trials will provide more information regarding the eventual benefits of this cytokine in the treatment of thrombocytopenia. At present, one successful application of TPO appears to be its addition in cytokine cocktails used to expand hematopoietic stem cells ex vivo. PMID- 10091416 TI - Autologous and allogeneic transplantation with peripheral blood CD34+ cells: a pediatric experience. AB - BACKGROUND AND OBJECTIVE: Peripheral blood stem cells (PBSC) have replaced bone marrow (BM) as the primary form for autologous hematopoietic stem cell transplantation. Furthermore, the use of allogeneic PBSC transplantation is now rapidly expanding and several centers have adopted this procedure. A new strategy in the use of PBSC is positive selection of CD34+ hematopoietic progenitor (CD34+) cells, and indeed large-scale devices for the clinical exploitation of CD34+ cell selection are now commercially available. In the autologous setting, the primary advantage of using CD34+ selected PBSC is reduced tumor cell contamination during PBSC preparation. On the other hand, in the allogeneic setting, CD34+ selection methods are used to reduce the incidence and severity of GvHD. Initial trials of CD34+ selected PBSC transplants have mainly been performed in adult cancer patients, and experience with CD34+ selected PBSC transplantation in pediatric populations is still limited. The purpose of this review is to clarify the status of CD34+ selected PBSC transplantation in the pediatric population. EVIDENCE AND INFORMATION SOURCES: All authors of the present review work in the field of pediatric stem cell transplantation and in a stem cell processing laboratory, and have contributed to original papers published in peer-reviewed journals. The materials examined in the present review include articles and abstracts published in journals covered by the Science Citation Index and Medline. However, since there is still limited experience with CD34+ cell selection in pediatric populations, information on experience in adults will be discussed regarding the CD34+ cell-selection procedures and transplantation. Pediatric experience with transplants with CD34+ selected cells will be presented and discussed primarily based on our own experience. Specific problems related to PBSC mobilization and collection in children will also be discussed. STATE OF THE ART: A review of the literature shows that with current CD34+ selection methods, purity of the CD34+ cell fraction can range from 30% to 90%, and two to three logs of T-cell depletion can be achieved. Tumor cell contamination has not yet been fully evaluated. The clonogenic activity of progenitor cells after CD34+ selection from PB remains high. Transplantation of autologous selected CD34+ cells from PBSC gives prompt and stable engraftment. The long-term therapeutic efficacy should be evaluated with regard to tumor recurrence. Allogeneic CD34+ selected cells successfully engraft immunomyeloablated recipients though a mega-cell dose effect between HLA-matched pairs. The results of allogeneic CD34+ selected cell transplantation from HLA mismatched donors are, so far, not satisfactory because of the high rate of rejection, severe infectious complications and relapse of the disease. CD34+ selection may also be used as a target of gene therapy, as a source of dendritic cells for cancer immunotherapy and for the treatment of patients with autoimmune disease. PMID- 10091417 TI - Toluol/xylol-induced leukemia. PMID- 10091418 TI - Multiple myeloma with numerous intranuclear Russell bodies. PMID- 10091419 TI - Isolated hyperferritinemia with normal transferrin saturation and dysmetabolism, in the absence of the two known mutations in the HFE gene of hereditary hemochromatosis. PMID- 10091420 TI - The dysmetabolic iron overload syndrome is clinically and genetically distinct from HFE-related genetic hemochromatosis. PMID- 10091421 TI - Variation in the phenotypic expression of C282Y hemochromatosis in an Italian family. PMID- 10091422 TI - Pilot study of combined therapy with interferon-alpha, arabinosyl cytosine and all-trans retinoic acid in patients with chronic myeloid leukemia in the chronic phase. PMID- 10091423 TI - Reconstitution of alveolar macrophages from donor marrow in allogeneic BMT; a study of variable number tandem repeat regions by PCR analysis of bronchoalveolar lavage specimens. PMID- 10091424 TI - A phase-II study with idarubicin, etoposide and prednisone (IVPP), in patients with refractory or early relapsed intermediate or high grade non-Hodgkin's lymphoma. PMID- 10091425 TI - Genetic polymorphism of methylenetetrahydrofolate reductase and venous thromboembolism: a case-control study. PMID- 10091426 TI - Recombinant human tissue plasminogen activator without heparin is effective in the treatment of hepatic veno-occlusive disease. PMID- 10091427 TI - The future of managed care organization. AB - This paper analyzes the transformation of the central organization in the managed care system: the multiproduct, multimarket health plan. It examines vertical disintegration, the shift from ownership to contractual linkages between plans and provider organizations, and horizontal integration--the consolidation of erstwhile indemnity carriers, Blue Cross plans, health maintenance organizations (HMOs), and specialty networks. Health care consumers differ widely in their preferences and willingness to pay for particular products and network characteristics, while providers differ widely in their willingness to adopt particular organization and financing structures. This heterogeneity creates an enduring role for health plans that are diversified into multiple networks, benefit products, distribution channels, and geographic regions. Diversification now is driving health plans toward being national, full-service corporations and away from being local, single-product organizations linked to particular providers and selling to particular consumer niches. PMID- 10091428 TI - Focusing on the health care consumer. PMID- 10091429 TI - Health plans' strategic responses to a changing marketplace. PMID- 10091430 TI - Explaining the decline in health insurance coverage, 1979-1995. AB - The decline in health insurance coverage among workers from 1979 to 1995 can be accounted for almost entirely by the fact that per capita health care spending rose much more rapidly than personal income during this time period. We simulate health insurance coverage levels for 1996-2005 under alternative assumptions concerning the rate of growth of spending. We conclude that reduction in spending growth creates measurable increases in health insurance coverage for low-income workers and that the rapid increase in health care spending over the past fifteen years has created a large pool of low-income workers for whom health insurance is unaffordable. PMID- 10091431 TI - Challenges in securing access to care for children. AB - Congressional approval of Title XXI of the Social Security Act, which created the State Children's Health Insurance Program (CHIP), is a significant public effort to expand health insurance to children. Experience with the Medicaid program suggests that eligibility does not guarantee children's enrollment or their access to needed services. This paper develops an analytic framework and presents potential indicators to evaluate CHIP's performance and its impact on access, defined broadly to include access to health insurance and access to health services. It also presents options for moving beyond minimal monitoring to an evaluation strategy that would help to improve program outcomes. The policy considerations associated with such a strategy are also discussed. PMID- 10091432 TI - How will we know if CHIP is working? PMID- 10091433 TI - Behavioral health benefits in employer-sponsored health plans, 1997. AB - Data for 1997 show that three-quarters or more of employer-sponsored health plans continue to place greater restrictions on behavioral health coverage than on general medical coverage. The nature of these restrictions varies by plan type. Some improvement in the treatment of mental health/substance abuse (MH/SA) benefits in employer plans may be occurring, however. Comparisons with data from 1996 show that the proportion of plans with benefits for "alternative" types of MH/SA services, such as nonhospital residential care, has increased. Further, the proportion with special limitations on these benefits shows a modest decrease. PMID- 10091434 TI - Mental health/medical care cost offsets: opportunities for managed care. AB - Health services researchers have long observed that outpatient mental health treatment sometimes leads to a reduction in unnecessary or excessive general medical care expenditures. Such reductions, or cost offsets, have been found following mental health treatment of distressed elderly medical inpatients, some patients as they develop major medical illnesses, primary care outpatients with multiple unexplained somatic complaints, and nonelderly adults with alcoholism. In this paper we argue that managed care has an opportunity to capture these medical care cost savings by training utilization managers to make mental health services more accessible to patients whose excessive use of medical care is related to psychological factors. For financial reasons, such policies are most likely to develop within health care plans that integrate the financing and management of mental health and medical/surgical benefits. PMID- 10091435 TI - Capturing mental health cost offsets. PMID- 10091436 TI - Justifying mental health care costs. PMID- 10091437 TI - Modernizing the FDA: an incremental revolution. AB - The U.S. Food and Drug Administration (FDA) is responsible for protecting consumers from unsafe or ineffective drugs and medical devices. The agency's role is defined by a growing and increasingly complex set of statutes, which reflect Congress's desires, on the one hand, to prevent product hazards and, on the other, to expedite FDA review and approval of promising new medical technologies. Congress's latest attempt to calibrate regulation to achieve these goals, the 1997 Food and Drug Administration Modernization Act, endorses certain of the FDA's own innovations and changes in the agency's ways of doing business. PMID- 10091438 TI - Mixed signals: public policy and the future of health care R&D. AB - The incentives facing health care research and development (R&D) are influenced by the ambiguous signals sent by private and public insurance decisions affecting the use of, and payments for, existing technologies. Increasingly, that uncertainty is exacerbated by confusion over technologies' impact on health care costs, how costs are to be measured, and the social difficulty of determining medical "need" for purposes of insurance coverage. R&D executives appear to believe that "major" advances are more likely to win such coverage and thus to be profitable. The products that result, therefore, may make the current policy dilemma of cost containment versus service restriction more acute rather than less so. If the aim of policy is to cut costs, innovative remedies are necessary. PMID- 10091439 TI - Waiting in the wings: eligibility and enrollment in the State Children's Health Insurance Program. PMID- 10091440 TI - Raising the bar: the use of performance guarantees by the Pacific Business Group on Health. AB - In 1996 the Pacific Business Group on Health (PBGH) negotiated more than two dozen performance guarantees with thirteen of California's largest health maintenance organizations (HMOs) on behalf the seventeen large employers in its Negotiating Alliance. The negotiations put more than $8 million at risk for meeting performance targets with the goal of improving the performance of all health plans. Nearly $2 million, or 23 percent of the premium at risk, was refunded to the PBGH by the HMOs for missed targets. The majority of plans met their targets for satisfaction with the health plan and physicians, as well as cesarean section, mammography, Pap smear, and prenatal care rates. However, eight of the thirteen plans missed their targets for childhood immunizations, refunding 86 percent of the premium at risk. PMID- 10091441 TI - Camelot or common sense? The logic behind the UCSF/Stanford merger. AB - Many academic medical centers (AMCs) throughout the United States have established their own community-based integrated delivery systems by purchasing physician groups and hospitals. Other AMCs have merged with existing nonprofit community-based delivery systems. Still other AMCs have been sold to for-profit firms. The AMCs at Stanford and the University of California, San Francisco (UCSF), chose a different strategy: to merge with each other to respond to the unique characteristics of the Bay Area marketplace. PMID- 10091442 TI - UCSF/Stanford: building a 'prestige cartel'. PMID- 10091443 TI - Making report cards work. PMID- 10091444 TI - Academic health centers: exploring a financial paradox. PMID- 10091445 TI - The muscular Samaritan: the National Health Service Corps in the new century. PMID- 10091446 TI - Cost of tax-exempt health benefits in 1998. AB - The tax expenditure for health benefits is the amount of revenues that the federal government forgoes by exempting the following from the federal income and Social Security taxes: (1) employer health benefits contribution, (2) health spending under flexible spending plans, and (3) the tax deduction for health expenses. The health tax expenditure was $111.2 billion in 1998. This figure varied from $2,357 per family among those with annual incomes of $100,000 or more to $71 per family among those with annual incomes of less than $15,000. Families with incomes of $100,000 or more (10 percent of the population) accounted for 23.6 percent of all tax expenditures. PMID- 10091447 TI - The economic value of informal caregiving. AB - This study explores the current market value of the care provided by unpaid family members and friends to ill and disabled adults. Using large, national data sets we estimate that the national economic value of informal caregiving was $196 billion in 1997. This figure dwarfs national spending for formal home health care ($32 billion) and nursing home care ($83 billion). Estimates for five states also are presented. This study broadens the issue of informal caregiving from the micro level, where individual caregivers attempt to cope with the stresses and responsibilities of caregiving, to the macro level of the health care system, which must find more effective ways to support family caregivers. PMID- 10091448 TI - Financial incentives and drug spending in managed care. AB - This study estimates the impact of patient financial incentives on the use and cost of prescription drugs in the context of differing physician payment mechanisms. A large data set was developed that covers persons in managed care who pay varying levels of cost sharing and whose physicians are compensated under two different models: independent practice association (IPA)-model and network model health maintenance organizations (HMOs). Our results indicate that higher patient copayments for prescription drugs are associated with lower drug spending in IPA models (in which physicians are not at risk for drug costs) but have little effect in network models (in which physicians bear financial risk for all prescribing behavior). PMID- 10091449 TI - Who bears the burden of Medicaid drug copayment policies? AB - This DataWatch examines the impact of Medicaid prescription drug copayment policies in thirty-eight states using survey data from the 1992 Medicare Current Beneficiary Survey. Findings indicate that elderly and disabled Medicaid recipients who reside in states with copay provisions have significantly lower rates of drug use than their counterparts in states without copayments. After controlling for other factors, we find that the primary effect of copayments is to reduce the likelihood that Medicaid recipients fill any prescription during the year. This burden falls disproportionately on recipients in poor health. PMID- 10091450 TI - Why are workers uninsured? Employer-sponsored health insurance in 1997. AB - This study examines the number of workers in firms offering employee health plans, the number of workers eligible for such plans, and participation in employer-sponsored insurance. Data from the February 1997 Contingent Worker Supplement to the Current Population Survey indicate that 10.1 million workers are employed by firms offering insurance but are not eligible. Not all of these workers are eligible for coverage, most often because of hours of work. Our results indicate that 11.4 million workers rejected coverage when it was offered. Of those, 2.5 million workers were uninsured. Workers cited high cost of insurance most often as the primary factor for refusing coverage. PMID- 10091451 TI - Improving lives through information. PMID- 10091452 TI - How are safety-net providers faring under Medicaid managed care? PMID- 10091453 TI - Medicaid managed care in rural areas: a ten-state follow-up study. PMID- 10091454 TI - A maturing market for health information technology? PMID- 10091455 TI - Information technology: value to patients. PMID- 10091456 TI - Health information: a broader view. PMID- 10091457 TI - A new proposal for cooperation in HIT development. PMID- 10091459 TI - Need to measure absolute, not relative, access to care. PMID- 10091460 TI - Performance measures and batting averages. PMID- 10091461 TI - More on reform of the NHS. PMID- 10091462 TI - Bronchial asthma and the menstrual cycle. PMID- 10091463 TI - Management of interstitial lung disease: an audit at a university teaching hospital in Saudi Arabia. AB - To assess the management of interstitial lung disease (ILD) in relation to the published guidelines 122 consecutive cases were analyzed. Clinical features and non-invasive laboratory tests led to the diagnosis in nearly one sixth of the patients (16%), mainly CTD and a few miscellaneous disorders. In another sixth the diagnosis was reached by means of a transbronchial lung biopsy, particularly in sarcoidosis. Nearly a third had surgical lung biopsies, which were diagnostic in 98%. The diagnoses were reached in 82 patients (67%) and include: cryptogenic fibrosing alveolitis (20), sarcoidosis (16), connective tissue disease (17) and miscellaneous (29). The remaining third were undiagnosed, and this group had a higher mean age and was much less likely to receive immunosuppressive therapy than any group with a specific diagnosis. It is concluded that while physicians reached a specific diagnosis in most cases of ILD, commonly through a lung biopsy. A sizeable proportion (nearly a third), or remained undiagnosed and those were less likely to be treated and had a poorer prognosis. The availability of less invasive techniques should encourage physicians to obtain a biopsy since this is likely to lead to a more active approach to therapy. PMID- 10091464 TI - Bronchoalveolar lavage (BAL) in newly diagnosed patients with collagen vascular diseases. AB - Collagen vascular diseases (CVD) are commonly associated with interstitial lung diseases. Bronchoalveolar lavage (BAL) fluid analysis has important diagnostic value when considered in conjunction with other information. The present study was undertaken in newly diagnosed patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) at presentation to characterise BAL cellular constituents and elucidate the cellular picture in patients with and without pulmonary symptoms and in those with and without radiological (high resolution computed tomography) features of interstitial lung disease. All the patients were non-smokers and had not received any form of treatment for their diseases. The means of percentages of lymphocytes, neutrophils, and macrophages were 23.3%, 6.2%, 70.5% respectively. There was a significant BAL lymphocyte predominance in patients with pulmonary symptoms, and a lymphocyte and neutrophil predominance in those having radiological evidence of interstitial lung disease. PMID- 10091465 TI - Respiratory pressures in normal Indian subjects. AB - Regression equations for the prediction of maximum inspiratory pressures (MIP) in North Indian adults are reported, based on observations in 120 females and 153 males. Age and sex were the only significant predictor variables. MIP was significantly related to vital capacity, FEV1 and peak flow rate. The MIP observed in the present study are similar to those reported earlier in Caucasians and Chinese. The lower lung volumes and flow rates in Indians are not explained by differences in MIP. PMID- 10091466 TI - Biology of basophils and their role in allergic inflammation. AB - Chronic allergic inflammatory reactions involve the infiltration and participation of many different cell types. Although it has been evident for many years that tissue specific mast cells have a primary role in the early stages of these reactions, recent studies indicated that, in addition to mast cells response, a later reaction which selectively recruits the circulating lymphocytes, eosinophils and basophils to the site of inflammation, is the hallmark for the progression of allergic diseases. PMID- 10091467 TI - Formation of an aspergilloma in a patient with allergic bronchopulmonary aspergillosis on corticosteroid therapy. PMID- 10091468 TI - Acute respiratory distress syndrome following nitrogen dioxide exposure. AB - A young laborer was accidentally exposed to toxic nitrogen dioxide fumes following an accidental explosion at work place. He developed acute respiratory distress within few hours of exposure and manifested with severe hypoxemia and permeability edema. Assistance with mechanical ventilation and corticosteroid therapy could be instituted only after 24 hours of exposure. He had shown remarkable recovery and could be weaned off after seven days. At three weeks after discharge, his lung function tests were normal. PMID- 10091469 TI - Bochdalek hernia in adulthood: a case report and review of recent literature. AB - A 37-year-old Filipino woman presented with a post road-traffic accident fracture of dorsal spine 12. Chest radiograph revealed evidence of loops of small bowel in the left lung field. She admitted to symptoms of respiratory insufficiency since birth and treatment for tuberculosis in childhood. A pre-operative diagnosis of left traumatic diaphragmatic hernia was not confirmed at laparotomy which revealed typical left congenital Bochdalek hernia with smooth edges and herniation of small bowel and spleen into the left pleural cavity. Following reduction and repair of the hernia, the patient made an uneventful recovery. Chest radiograph remains normal till now, eight years post-operatively. PMID- 10091470 TI - Intrapericardial benign teratoma with unusual presentation. AB - Benign teratoma, also referred as dermoid cyst, do occur in the mediastinum. However, their intrapericardial location has been reported very occasionally. This case of intrapericardial benign solid teratoma is being presented because of its rarity and its unusual presentation as a case of empyema, with features of cardiac compression and pericardial effusion. PMID- 10091471 TI - Pneumothorax due to electrical burn. AB - A 25-year-old male developed early as well as delayed (15 days post burn) pneumothorax of right side following high voltage, 1100 KV, electrical burn of the right side of the chest wall. Diagnosis was established by clinical examination and chest x-ray. Intercostal tube drainage with underwater seal relieved the patient of pneumothorax. PMID- 10091472 TI - Community health nurses' knowledge of Lyme disease: implications for surveillance and community education. AB - A statewide assessment was conducted to determine the general knowledge and professional practices about Lyme disease (LD) of local health department nurses. The study sample included 226 nurses practicing in 80 health departments in Indiana. Data were collected using a self-administered questionnaire and analyzed using group independent t tests. Findings showed that nurses were most knowledgeable about personal protection against LD and least knowledgeable about symptoms, case definition, and reporting criteria. Nonbaccalaureate degreed nurses scored significantly higher on questions about LD than the baccalaureate or master's prepared nurses. Results point to the need for better dissemination of LD information among public health nurses, expanded LD education for the public, and further development of LD surveillance activities. PMID- 10091473 TI - Postpartum home visits: infant outcomes. AB - Early postpartum discharge of mothers and infants has increased as health care providers and payers attempt to control health care cost. Questions regarding patient safety have been raised. Literature supports the safety of early discharge when providers adhere to strict discharge guidelines and when clients comply with home follow-up. Previous studies calculated hospital readmission rates, but few examined other outcomes or characteristics. The purposes of this descriptive study were to examine outcome data for infant participants in a postpartum home visit program and to explore factors that may influence hospital readmissions for infants. Using an audit tool with established reliability and validity, a convenience sample of 199 infant medical records was reviewed for demographic information, characteristics, and outcomes. The hospital readmission rate for all infants within 3 weeks of discharge was comparable to other studies; however, the rate for only early discharge infants was higher than the rate reported in other studies. The study of postdelivery outcomes for infants provides additional insight into the issue of early discharge and may reflect the significance of postpartum follow-up care and education. PMID- 10091474 TI - An analysis of nurses' communications in a shelter setting. AB - The purpose of this study was to analyze written communications among nurses providing care to battered women and their children in a community shelter setting over a 1-year period of time. Interviews were conducted with the nurses to study the perceived effectiveness of the manual used to update daily shelter health operations, clients of concern, follow-up recommendations, or other ongoing issues. The unit of analysis was each entry recorded in the manual. The Communications Process Model guided the study (Budd, Thorp, & Donohew, 1967). Communications were transcribed and analyzed for categories of meaning from the data utilizing the Ethnograph software (Seidel & Clark, 1983). When content analysis was applied, 10 distinct categories emerged: (a) injury assessment, (b) acute condition assessment, (c) chronic condition assessment, (d) pregnancy assessment, (e) emergency assessment, (f) nursing care and procedures, (g) teaching and counseling, (h) community referrals and resources, (i) housekeeping, and (j) health program issues. From the categories, 3 primary themes were identified: nursing assessments, nursing interventions, and health program operations. The nurses were positive about using the manual for various communications. Nurses who consider working in shelter settings may find descriptions of the realities of practice and application of a working tool for communications useful. Shelter administrators and board members need to recognize the importance of having nurses on staff to address inevitable injuries and health concerns of battered women and their children. Researchers are encouraged to develop models that relate to care of clients and caregivers in this challenging practice setting. PMID- 10091475 TI - Poor women living with HIV: self-identified needs. AB - Women with HIV are a growing at-risk population in our communities. They are often poor members of minority groups who have responsibilities for dependent children and other family members. They may experience physiological, psychological, and social symptoms and have needs that are unique to them as women. The purpose of this study was to give women with HIV the opportunity to identify their needs. Using the Objects Content Test, 48 women attending HIV clinics in a midsouth city listed 349 needs: 32% psychosocial, 14% physical, 13% service and maintenance, and 11% financial and legal. It is important for nurses working with these women in the community to know how they perceive their own needs and issues to plan and provide effective health care programs for this growing group of clients. PMID- 10091476 TI - HIV infection in U.S. correctional systems: its effect on the community. AB - Increased rates of HIV infection and risk-taking behaviors among incarcerated men and women make the fight against HIV within the prison and jail systems an especially critical issue in community health. Overcrowded conditions impact on the rotation of inmates in and out of the correctional system. This revolving door phenomenon has implications for disease prevention and control within the community into which the inmates are released. As more people pass in and out of jails and prisons, more problems and diseases associated with incarceration pass into the community. The special needs of the prison population must be taken into consideration not only by nurses but also by all health care workers and correctional officials when planning and implementing control and prevention strategies. PMID- 10091477 TI - Recent studies of cutaneous nociception in atopic and non-atopic subjects. AB - Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco-cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema. Previous case-control studies of our research group with patients suffering from atopic eczema (AE) revealed significantly diminished itch perception after iontophoretic application of different doses of histamine as well as substance P (i.c. injected). Further experiments using acetylcholine (ACh, i.c.) clearly demonstrated that ACh elicits pruritus instead of pain in patients with AE. The first part of the present review deals with the results of our most recent case control studies on histamine-induced itch perception in atopics devoid of eczema as well as in patients with urticaria or psoriasis compared to atopics with or without manifest eczema. We demonstrated that both focal itch and perifocal alloknesis (i.e., itch elicited by a slight mechanical, otherwise non-itching stimulus) were significantly reduced in eczema-free atopics yet were normal in non-atopics suffering from urticaria or psoriasis. In further studies using ACh i.c. injected into the uninvolved skin of patients with AE, lichen ruber, psoriasis, type IV contact eczema, or non-specific nummular eczema (n = 10/each group), all the atopics and 6/10 psoriatics felt itch instead of burning pain, but none of the others did. Different doses of vasoactive intestinal peptide (VIP) i.c. applied to the controls and the atopics with or without eczema did not markedly increase the intensity of nociceptive sensations. However, ACh induced pain in the controls, pure pruritus in the atopics with acute eczema, and a 'mixture' of pain and itch in the atopics just free from eczema. Obviously, the quality of sensations evoked by ACh and VIP depends on the inflammatory or non inflammatory state of the atopic skin. In a placebo-controlled, double blind study on histamine-induced focal itch and alloknesis with healthy subjects (n = 15) using naltrexone (opioid receptor antagonist) and cetirizine (H1-blocking agent), naltrexone was found to significantly reduce both itching and alloknesis. Cetirizine reduced focal itch but failed to influence the alloknesis phenomenon. The wheal and flare reaction was suppressed only by cetirizine. These different effects point to a mainly CNS-based activity of naltrexone but a peripheral level effect of cetirizine. Due to long-lasting experience with group sport as a supporting adjuvant for inpatients with AE, we evaluated, by clinical, psychometric, and physiological studies, the therapeutic efficacy of controlled physical exercise in addition to otherwise equal anti-eczematous therapy for both voluntary participants and non-participants in sports by performing several case control studies, one followed-up to 6 months after the patients' discharge from the hospital. Regular moderate exercises neither deteriorated nor impeded the recovery from AE, ameliorated the participants' scratch controlling ability and significantly their depressed emotional mood. The non-participants failed to achieve these aims. Sweating-induced itch was inhibited in almost all participants if simple skin care (clearing by warm shower, ointment) and short term rest were used by informed patients. In conclusion, there are several indications that itching is elicited in individuals inclined to cutaneous atopy, regardless of their eczematous or just eczema-free state, by a different physiological pathway from that in non-atopic individuals. Therefore, antipruritic agents influencing the centrally altered nociception of atopics are needed and may be expected in near future. (ABSTRACT TRUNCATED) PMID- 10091478 TI - Current topics in diagnosis and treatment of tinea unguium in Japan. AB - The number of patients with tinea unguium accounts for 0.5% to 2% of the total number of outpatients in Japan. The diagnosis of tinea unguium can be relatively easily made on the basis of clinical symptoms and direct microscopic findings. However onychomycosis due to fungi other than dermatophytes should always be suspected if no dermatophytes are cultured despite positive findings in direct microscopy. In such cases, it is necessary to repeat cultures and conduct histopathological evaluation using PAS-staining technique or enzyme antibody technique. At present, oral administration of griseofulvin and terbinafine are the treatments covered by health insurance in Japan. In the future, however, other orally active antifungal drugs such as itraconazole and fluconazole will become available for use by in-patients who do not respond to griseofulvin. It is essential to patiently continue treatment even if oral therapy is impossible, because other therapies such as ODT therapy using topical antifugal agents and urea ointment or abrading affected nails as much as possible with a file or dental drill may be effective without oral therapy. PMID- 10091479 TI - The potential role of skin protein kinase C isoforms alpha and delta in mouse hair growth induced by diphencyprone-allergic contact dermatitis. AB - The levels of protein kinase C (PKC) isoforms alpha and delta in mouse hair growth induced by diphencyprone (DPCP)-allergic contact dermatitis (ACD) were studied. BALB/c mice were sensitized by 2% DPCP in acetone on one side of their shaved backs and rechallenged with 0.1% DPCP on the same side weekly for 2 weeks. The opposite side treated with acetone served as a control. Before each elicitation, mice were shaved again in order to observe the hair growth that followed. Enhancement of hair growth on DPCP treated skin was observed in 94% of mice after first elicitation and significant hair growth was shown in all mice after second elicitation. No remarkable hair growth was seen on the control side. Western immunoblot analysis revealed that the level of skin PKC alpha on the DPCP treated side was decreased at 2 and 4 days after sensitization and returned to the control level after first elicitation. At 5 days after the second elicitation, a higher level of PKC alpha was detected. The level of PKC delta remained at the control level and increased at 5 days after second elicitation. These results suggest that: 1) In the first week after sensitization, PKC alpha was down-regulated. This down-regulation may play a role in DPCP-ACD induced hair growth; 2) after the elicitation, PKC alpha was over-expressed and this over expression was roughly correlated with the enhancement of mouse hair growth, suggesting that over-expression of PKC alpha may also play a part in the proliferation of hair follicle cells; and 3) overexpression of PKC delta after second elicitation may have an inhibitory effect on hair growth that keeps hair growth in balance. PMID- 10091480 TI - Intraepidermal expression of basement membrane components in the lesional skin of a patient with dystrophic epidermolysis bullosa. AB - The patient was a 15-year-old male. Since birth, he had developed blistering and erosion of the skin. Biopsy skin specimen of the bullous lesions showed subepidermal blister formation. Electron microscopic examination revealed that tissue separation had occurred at the sublamina densa level. By indirect immunofluorescence using antibodies specific for alpha 6 integrin, laminin 5, type IV collagen, and type VII collagen, all of these basement membrane components were detected as coarse granular intracytoplasmic deposits only in the basal and suprabasal cells of the blister roof. In the non-blistered regions, these basement membrane components showed a linear pattern similar to that seen in normal skin. These findings suggest that intraepidermal expression of basement membrane components was closely related to the blister formation. The biological meaning of intraepidermal expression of basement membrane components were also discussed. PMID- 10091481 TI - Genital angiofibromas in tuberous sclerosis: two cases. AB - Cutaneous lesions are an important feature of tuberous sclerosis (TS). Facial angiofibromas usually begin to appear at the end of the first decade of life and are considered to occur in about 88% of adults with TS. They are only rarely reported on sites other than the face or front. In this paper, we report two patients with the complete syndrome of TS that had, in addition to classic facial lesions, multiple papules on the genital area. Histopathology confirmed the diagnosis of angiofibroma. One patient's lesions were misdiagnosed as genital warts and were so being treated before the correct diagnosis was made. Although we don't know the incidence of genital angiofibromas in TS patients, we believe that they might be underreported, because dermatologists generally don't look for them when they see these patients. PMID- 10091482 TI - Treatment of reticular erythematous mucinosis with a large dose of ultraviolet B radiation and steroid impregnated tape. AB - To date, there are no successful treatments for reticular erythematous mucinosis (REM) other than antimalarial drugs such as chloroquine; these have many adverse side effects and are prohibited for use in Japan. We report a case of REM improved by a large dose of ultraviolet B (UVB) radiation and a steroid impregnated tape. The large dose of UVB radiation improved the erythema after 5 weeks. Application of steroid impregnated tape to a lesion where a large dose of UVB had been given produced an additive clinical effect. UVB radiation and steroid impregnated tape are considered to be effective treatments for REM. PMID- 10091483 TI - Erythema dyschromicum perstans in early childhood. AB - Erythema dyschromicum perstans (EDP) is a rare disorder characterized by asymptomatic, slowly progressive, ash-gray macular pigmentation of the skin which usually occurs from age 5 through adult life. We have experienced two cases of EDP in children aged 2 and 3, both exceptionally younger than the previously reported cases. We therefore suggest that EDP should be included in the differential diagnosis of pigmentary disorders occurring at an early age. PMID- 10091484 TI - A case of edematous striae distensae in lupus nephritis. AB - A 17-year-old girl with systemic lupus erythematosus presented with painful edematous abdominal striae. She had been treated with systemic steroid for the systemic lupus erythematosus. At the time of presentation, she had abruptly gained 10 kg due to combined lupus nephritis. The histopathologic finding of the edematous striae distensae included dermal edema with separation of collagen fibers and small fragmented elastic fibers. Edematous striae distensae are uncommon but can develop from the combined effects of glucocorticoid and generalized edema. PMID- 10091485 TI - Subcutaneous emphysema with spontaneous pneumomediastinum and pneumothorax in adult dermatomyositis. AB - We describe a 32-year-old patient with adult dermatomyositis who developed dyspnea and worsening of pre-existing infarcted skin lesions of the fingers. Chest radiographs showed diffuse hazy reticulonodular infiltration in both lungs, subcutaneous emphysema, pneumomediastinum, and pneumothorax. The pulmonary symptoms and cutaneous lesions gradually improved with a high dose of prednisolone. Although subcutaneous emphysema and pneumomediastinum occur frequently in association with traumatic disruption of cutaneous and mucosal barriers and assisted ventilation, it has rarely been observed in patients with interstitial pneumonitis in connective tissue diseases. Although dermatomyositis and subcutaneous emphysema are all relatively well-known diseases to dermatologists, the occurrence of spontaneous pneumomediastinum and pneumothorax and subsequent subcutaneous emphysema in connective tissue diseases such as dermatomyositis is unfamiliar. We discuss the possible mechanisms of this condition. PMID- 10091486 TI - Eruptions induced by the ACE inhibitor, lisinopril. PMID- 10091487 TI - Removal of unexploded ordnance from patients: a 50-year military experience and current recommendations. AB - BACKGROUND: Retained unexploded ordnance in a patient presents the surgeon with unique emotional and technical challenges. This report is a compilation of data to determine management strategies for these potentially catastrophic injuries. METHODS: All identified military cases from World War II to the present were reviewed. Cases were reviewed for site of injury, type of munition, personnel and equipment precautions, and outcome. Interviews were conducted with available involved surgeons. RESULTS: Thirty-six patients were identified with retained ordnance. Four were moribund upon arrival and died before operation. All of the remaining 32 patients survived the removal of the unexploded ordnance. Thirteen injuries involved the trunk, 4 involved the head and neck, and 18 involved extremities. The majority of missiles (51%) were 40-mm projectiles. No incident was identified in which a round exploded during transportation, preparation, or removal. Explosive Ordnance Disposal assistance was available to the surgical team for all but one patient during and after the Vietnam War. Measures used to reduce the chance of premature explosion are discussed. CONCLUSIONS: Isolation of the operating room and protection of personnel and equipment are essential. Patients should be triaged in the delayed category, because most are not morbund on arrival and all patients operated on survived. Explosive Ordnance Disposal expertise should be used. Knowledge of and adherence to several basic principles will protect personnel and equipment while permitting optimal patient care. PMID- 10091488 TI - Stress and coping in male and female health care providers during the Persian Gulf War: the USNS Comfort hospital ship. AB - The development of the USNS Comfort hospital ship during the Persian Gulf War provided an opportunity to examine the relationship of gender to stress and coping in health care providers exposed to wartime stressors. Just before the outbreak of Operation Desert Storm, medical personnel (N = 250) rated the stressfulness of current wartime experiences and the helpfulness of stress reducing resources onboard ship in a combat theater. The responses of men and women were compared; to identify the dimensions of these responses, a principal factor analysis (orthogonal rotation) was performed. Generally, men and women ranked stressors and stress reducers similarly; women scored higher on the stress ratings. Two factors, similar for men and women, were identified in the stress ratings: fear of injury and trauma-related work demands. The dimensions of the stress reducers, however, were different for men and women. The findings support retrospective studies and suggest that different mechanisms of stress reduction may be operative even though men and women are performing the same activity. PMID- 10091489 TI - The mental health status of women in the Navy and Marine Corps: preliminary findings from the Perceptions of Wellness and Readiness Assessment. AB - The 1995 Perceptions of Wellness and Readiness Assessment was designed to provide baseline health and risk-factor information on the physical and mental health status of women in the U.S. Navy and Marine Corps and to make comparisons both within military subpopulations and with civilian populations. A population-based, multi-stage, cluster sample of 782 active duty Navy and Marine Corps women and men were administered a structured computerized telephone interview to make Diagnostic and Statistical Manual-III-R psychiatric diagnoses. Estimates were 40 and 21% for overall lifetime and 1-year prevalence of psychiatric disorders, respectively. Women had about five times the risk of experiencing post-traumatic stress disorder than men and about twice the risk of a major depressive episode. Of all personnel meeting diagnostic criteria for an active mental disorder, only 19% sought mental health care in the last year. Women generally sought treatment more readily than men. PMID- 10091490 TI - Urinary incontinence among female soldiers. AB - A self-administered questionnaire was developed to assess the prevalence of urinary incontinence among active duty female soldiers. The questionnaire also addressed basic demographic information, including height, age, weight, and the subjects' present and past military activities. Adaptive measures that the soldiers commonly used to continue exercising and perform their duties were also explored. Seven hundred thirteen questionnaires were handed out to female soldiers at Fort Lewis (Washington), Fort Benning (Georgia), and Fitzsimons Army Medical Center (Colorado) during preparation for physical fitness tests. Of the 563 soldiers (79%) who returned completed questionnaires, 31% indicated that they commonly experienced urinary incontinence during duty and/or training to the extent that it interfered with job performance, hygiene, or was socially embarrassing. Thus, urinary incontinence is a pervasive problem among female soldiers. PMID- 10091491 TI - Development of a pediatric critical care transport team: experience at a military medical center. AB - INTRODUCTION: A pediatric critical care transport program was initiated and organized at Naval Medical Center San Diego in January 1994. The primary goal of the program was to formally train military pediatric residents in the early stabilization and transport of the critically ill neonatal and pediatric patient. It was also felt that such a program would generate significant cost savings to the Department of Defense. We present the statistics, training protocol, and the cost savings. In addition, we surveyed previous residents who had been involved with this program to determine its perceived benefit. METHODS: In the first phase of this project, the pediatric critical care transport program database from January 1994 to December 1997 was reviewed. The number and types of transports were recorded. Next, we determined cost savings for the transport program for fiscal year 1996-1998 (the period for which fiscal data were available). In the second phase of this project, we sent surveys to the 23 graduating residents who had participated in the pediatric critical care transport program. The survey sought to determine the perceived value of the transport training experience and the degree to which that training is now being used. All investigators were blinded to the responses. Statistical analysis consisted of determining the percentage of each response. RESULTS: During the 4-year period reviewed, 404 transports were performed (198 neonatal and 206 pediatric). During fiscal year 1996-1998, there was a cost avoidance of $1,962 per transport. In the second phase, 91% of the surveys were returned and analyzed. The majority of residents were practicing in overseas or isolated communities. All respondents rated their experience in the pediatric critical care transport program as worthwhile and educational, and they complemented their training in the neonatal and pediatric intensive care units. Seventy-one percent of the respondents had transported a critically ill neonate or child to another facility within the last year. CONCLUSIONS: In summary, we report our experience with the development of a pediatric critical care transport program. The program was developed to provide military pediatric residents instruction and experience in the stabilization and transport of critically ill children. In addition, we were able to demonstrate a significant cost avoidance. PMID- 10091492 TI - Patients, diagnoses, and procedures in a military internal medicine clinic: comparison with civilian practices. AB - BACKGROUND: Our goal was to compare the demographic features, diagnoses, and procedures in civilian and military ambulatory internal medicine clinics. METHODS: One year (September 1996 to August 1997) of data from the Ambulatory Data System of the Adult Primary Care Clinic at Madigan Army Medical Center was extracted and compared with the most recent (1995) National Ambulatory Medical Care Survey. RESULTS: A total of 41,374 Madigan patient encounters were compared with civilian data from the National Ambulatory Medical Care Survey. The age distribution was similar, with military patients averaging 53.5 years of age and civilian patients averaging 54.5 years. Military patients were more likely to be female (71 vs. 60%) and were more ethnically diverse (military: 68% white, 17% African American, 7% Hispanic, 7% Asian American, and 1% Native American; civilian: 78% white, 10% African American, 6% Hispanic, 5.9% Asian American, and 0.3% Native American). There were similar rank orderings of the top 189 diagnostic groups seen in each setting (Spearman's rho = 0.87). There were also no differences in the type or rank order of procedures performed between military and civilian internists (p = 0.53). CONCLUSION: The practice content of military and civilian practices appears to be more similar than different. PMID- 10091493 TI - Skin and soft-tissue infections after injury in the ocean: culture methods and antibiotic therapy for marine bacteria. AB - Isolated organisms from two common Indo-Pacific marine animals (Echinometra mathaei urchins and Acanthaster planci sea stars) likely to cause puncture wounds to recreational beachcombers, diverse, or operational military forces during amphibious assaults demonstrate why practitioners should consider their first choice for potential antibiotic therapy differently from their usual favorite antibiotics. The effects of thiosulfate-citrate-bile-sucrose (TCBS) agar, varying salt concentrations in the standard media, and comparison of room temperature incubation versus use of the 30 degrees C (86 degrees F) incubator are reviewed. The yield of pathogenic marine bacteria is increased if TCBS agar is used and more than one temperature is used for incubation. A potentially significant human pathogen, Vibrio vulnificus, appears to be ubiquitous. PMID- 10091494 TI - Measuring cultural climate in a uniformed services medical center. AB - The purpose of this study was to determine the employee perceptions of the cultural climate at a large uniformed service medical center in the mid-Atlantic region of the United States. The analyses are based on the responses of 1,751 medical center employees, whose demographic characteristics were representative of the medical center population. Analyses indicate the existence of systematic perceptual differences between: (1) the medical center and Department of Defense personnel, and (2) the following cultural groups: (a) male and female personnel, (b) military and civilian personnel, and (c) majority and minority personnel. Recommendations are provided for future areas of research that need to be conducted with respect to the phenomenon of cultural diversity and the development of positive cultural climates within both the military and civilian medical settings. PMID- 10091495 TI - Staphylinid (rove) beetle dermatitis outbreak in the American southwest? AB - An outbreak of a blistering disease was reported in a military unit training in the Arizona desert during heavy rain and flooding. In a unit of 249 personnel, 33 presented with dermatologic complaints, and 4 met stringent diagnostic criteria for dermatitis linearis. A fifth patient presented with symptoms and signs of "Nairobi eye." Staphylinid (rove) beetles related to the paederids, which have been responsible for vesicular dermatitis outbreaks in other parts of the world but not previously in the United States, were collected at the site. Reports in the antique scientific literature document paederids in the area after periodic floods. These findings suggest that rove beetle dermatitis should be added to the differential diagnosis of vesicular dermatitis in western North America. PMID- 10091496 TI - Disturbances in plasma sodium in patients with war head injuries. AB - Polyuria with marked plasma sodium disturbance was present in 39 of 224 patients with isolated craniocerebral war injuries. Twenty-one of these 39 patients had hyponatremia (sodium level < 130 mmol/l) and polyuria. Eight of them (38%) died within 30 days after trauma. The remaining 18 patients developed classic diabetes insipidus syndrome, and 6 of them (33%) died of hypernatremia within 30 days after trauma. The mortality in both patients with hyponatremia and patients with diabetes insipidus was higher in those with greater disturbances of plasma sodium concentration with polyuria and those with lower Glasgow Coma Scale scores. PMID- 10091497 TI - The American College of Physicians' Resident Abstract Competition: success of U.S. military trainees. AB - Research is a central aspect of internal medicine (IM) training, and accreditation organizations require that residency programs show that their residents participate in scholarly activity. To better understand the research productivity and the quality of research conducted by military IM trainees, we reviewed the records of the American College of Physicians' Resident Abstract Competition from 1995 to 1997. This national competition is prestigious, blindly judged, and highly selective. We found that although military residents account for less than 2% of all U.S. and Canadian IM trainees, they author more than 11% of the abstracts selected for presentation (p < 0.001). We conclude that military IM residents are disproportionately represented compared with their civilian peers in an objective, national competitive forum. This is consistent with the higher scores on in-service examinations and higher board-certification pass rates for military IM residents. PMID- 10091498 TI - Barodontalgia: a review, and the influence of simulated diving on microleakage and on the retention of full cast crowns. AB - This paper reviews the causes of barodontalgia and reports on a study that indicates a possible cause of barodontalgia in the diver. In the study, extracted teeth had full cast crowns cemented with either a zinc phosphate, a glass ionomer, or a resin cement, and simulated diving to 30 m (3.0 atmospheres) was performed. During simulated diving, the teeth were pressure cycled 15 times to 3 atmospheres and microleakage was monitored. The force required to dislodge the crown was then tested; a significant difference was found between the zinc phosphate and the glass ionomer cement groups (p < 0.01). No difference was found between the resin cement groups. Microleakage was also detected in the zinc phosphate and glass ionomer cement groups and was found to occur sooner, and to a greater extent with zinc phosphate. No microleakage was detected in the resin cement experimental group. This study showed that the retention of full cast crowns to extracted teeth is reduced after pressure cycling and that microleakage does occur if the crowns are cemented with either zinc phosphate cement or glass ionomer cement. PMID- 10091499 TI - Focal rhabdomyolysis and brachial plexopathy: an association with heroin and chronic ethanol use. AB - A 22-year-old man presented with acute swelling of the left neck and associated weakness of the left arm upon awakening after having snorted heroin. He had consumed large amounts of ethanol regularly for 7 years. Serum creatine kinase was greater than 19,000 units/l. A diagnosis of focal rhabdomyolysis and left brachial plexopathy was made. Focal rhabdomyolysis with associated plexopathy is an uncommon but recognized complication of acute heroin use. Chronic ethanol use may have a "sensitizing" role in the pathogenesis of this syndrome. PMID- 10091500 TI - Splenic syndrome in sickle cell trait: four case presentations and a review of the literature. AB - Four cases of splenic infarction/sequestration in sickle cell trait (SCT) patients are presented. All four patients were undergoing moderate exercise at elevations ranging from 5,500 to 12,000 feet. The patients include two African American males, a Hispanic male, and a white female. All four presented with the acute onset of mid epigastric then left upper-quadrant pain, nausea, vomiting, and respiratory splinting. A review of the literature indicates that splenic infarction with SCT is not uncommon; however, not surprisingly, it is often initially misdiagnosed. This is the first report in the literature of a female with SCT incurring a splenic syndrome with exposure to terrestrial altitude. Although SCT is not a contraindication for moderate- or high-altitude activities, military physicians need to consider the diagnosis of splenic infarction early in any patient regardless of race or sex who presents with left upper-quadrant pain at altitudes above 5,000 feet. Prompt evacuation to sea level may hasten recovery and spare further splenic trauma. Although SCT should be considered a relatively benign entity, the literature also suggests a higher than average risk of sudden death in military recruits with SCT from exertional heat illness and rhabdomyolysis. PMID- 10091501 TI - Death from hyponatremia as a result of acute water intoxication in an Army basic trainee. AB - Several reports during the past 15 years have described hyponatremia as a result of excessive water intake by athletes during endurance races. The high rates of fluid consumption have been attributed to the desire of athletes to prevent heat injury. The military has adopted guidelines for programmed drinking to maintain performance and minimize the risk of heat casualties. As military personnel increase their fluid intake, their risk of hyponatremia as a result of water overload increases. A potentially life-threatening complication is acute water intoxication. We report the first known death of an Army basic trainee as a result of acute water intoxication. The misinterpretation of his symptoms as those of dehydration and heat injury led to continued efforts at oral hydration until catastrophic cerebral and pulmonary edema developed. PMID- 10091502 TI - The use of fluconazole as a local irrigant for nephrostomy tubes. AB - OBJECTIVES: Few data exist concerning the combined use of fluconazole systemically and as an irrigant for nephrostomy tubes in a patient with renal candidiasis. The patient described here presented with renal fungal balls obstructing the drainage of urine from her nephrostomy tubes. METHODS: Twelve months after chemoradiation for a stage IIB squamous cell carcinoma of the uterine cervix, a 35-year-old woman presented with renal obstruction necessitating insertion of ureteral stents. After 6 months of chemotherapy, the patient developed uremia. After nephrostomy tubes were placed, renal candidiasis was noted, and fluconazole was begun systemically. When the renal candidiasis failed to clear, nephrostomy tube irrigations were begun. RESULTS: Fourteen days of therapy with fluconazole resulted in the resolution of the uremia. The patient died 6 months later with her nephrostomy tubes in situ and without evidence of candidiasis in her urinary tract. CONCLUSIONS: The patient described was successfully treated without having to remove her nephrostomy tubes. Two other authors have reported the successful use of fluconazole irrigation to treat candidiasis in nephrostomy tubes that was unresponsive to systemic fluconazole. Before the appearance of these reports, the best results were obtained with removal of the catheter in renal candidiasis. PMID- 10091503 TI - [Neurosurgery using the Gamma Knife]. AB - Gamma Knife radiosurgery is a neurosurgical technique dedicated to treat a wide spectrum of intracranial pathologies. Radiosurgery is a method employing a single fraction of high dose ionizing radiation beams focused on the stereotactically defined intracranial target volume through the intact skull. This precise irradiation of intracranial volumes can necrotize the targeted cell mass--as in treatments of tumors and functional syndromes--or may induce certain biological effects in the target tissue-as in treatments of AVM's and epilepsy--without imposing a significant risk on the neighboring intact neural tissues. The clinical application of Gamma Knife includes a wide range of neurosurgical indications, such as treatments of arteriovenosus malformations, pituitary adenomas, craniopharyngiomas, meningiomas, vestibular schwannomas, gliomas, metastatic tumors, as well as functional neurosurgical syndromes, such as trigeminal neuralgia, extra-pyramidal dysfunctions, epilepsy, pain- and psychiatric syndromes. The clinical effect of irradiation is not immediate, it becomes detectable on follow up studies after a few months. The application of the technique is determined by the histological type, size and location of the pathology. Gamma Knife has evolved to become an established alternative to opened cranial surgery in certain cases with low morbidity and no mortality, offering a safe neurosurgical treatment for inoperable as well as operable lesions that carry significantly high surgical risk. In our review we present the technical and radiobiological principles, clinical indications, limitations and outcome results of this method. Our data are based on the practice and results of the Lars Leksell Center for Gamma Surgery, Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA (Director: Ladislau Steiner dr.). PMID- 10091504 TI - [Normal values of vertebral heights in a representative population survey in Hungary]. AB - The authors' aim was to derive Hungarian normal vertebral heights, height ratios and threshold values. The mean -3 SD of these ratios give them the threshold values for defining normal vertebraes. They examined the standardized vertebral morphometric measurements obtained in a cross-sectional population survey. Radiographs were taken according to standardized protocol and morphomeric measurements of anterior, central and posterior heights from thoracic 4 to lumbar 4 were made with a semiautomatic technique. The anterior, central, posterior I and posterior II height ratios were calculated for each vertebra. The mean and standard deviation of these ratios for each sex were derived using a statistical procedure to normalize the distribution. From the normally distributed vertebral height ratios the mean and standard deviation give us the threshold values for defining normal vertebraes. Anterior and central vertebral height ratios were smaller in males than females. The authors compared the ratios and threshold values in different European centers using the same method. The data confirm that vertebral height ratios vary between and within populations and the authors suggest that normal values for vertebral height ratios should be derived separately for males and females at each vertebral level. Having the normal values the knowledge of the Hungarian normal vertebral height ratios gives the possibility to carry on multicentre clinical, therapeutic and epidemiologic studies of vertebral deformity in Hungary. The authors suggest the widespread use of morphometry to evaluate vertebral osteoporosis because it can be done in every radiology unit, it is a cheap and easy method for measuring the bone mineral content. PMID- 10091505 TI - [Ret-protooncogene mutation, verified by molecular genetic methods, in a Hungarian MEN Type 2a family]. AB - Multiple endocrine neoplasia Type 2 (MEN2) is a hereditary tumour syndrome characterized by the association of medullary thyroid cancer, phaeochromocytoma and hyperparathyroidism. It is inherited as an autosomal dominant trait. During the past few years the cloning of the gene responsible for the syndrome, the ret protooncogene, made the molecular genetic diagnosis of the disease possible. In this study we demonstrate the results of the MEN2 mutation analysis performed in three members of a Hungarian MEN2A family. The mutation analysis was carried out according to the method of Dr. W. Hoppner's Laboratory (Hamburg) that is the main centre for MEN2 genetic diagnosis in Germany. Two Members of the family are affected, one suffered from both medullary thyroid cancer and phaeochromocytoma, the other (the first patient's daughter) had only medullary thyroid cancer. We found a ret exon 11 codon 634 mutation, that resulted in the change of TGC to TAC, a cysteine-tyrosine amino acid exchange. We found no mutation in the youngest member of the family. This result is of great clinical significance, because the carrier status of this individual can thus be excluded and, therefore, there is no need for prophylactic thyroidectomy and further clinical screening tests. As molecular genetic diagnosis of MEN2 becomes possible, the uncertain clinical examinations used for MEN2 diagnosis seems to be less important. PMID- 10091506 TI - [Retroperitoneal malignant fibrous histiocytoma]. AB - Authors review the case history and follow-up of a rare malignant fibrous histiocytoma patient, based on the relevant literary data. The tumor filled the retroperitoneum on the right side, in front of the right kidney. Intravenous urography and computer tomography revealed a 10 x 15 cm sized mass, suspect of being a kidney tumor. Upon surgery, the tumor was found to be a retroperitoneal malignant fibrous histiocytoma. In connection to the case, a brief review is given of the storiform type of malignant fibrous histiocytoma, regarding its etiological, clinical and pathological aspects, the difficulties in diagnosis, as well as the therapeutic possibilities. Authors regard their case worthy of publication because of the retroperitoneal location and significant size of the tumor, and because of the unproven diagnosis prior to surgery. Even after 4 years the patient is symptom- and complaint-free, and CT has revealed no metastases. PMID- 10091507 TI - [Quo vadis "suprema lex"?]. PMID- 10091508 TI - [Quo vadis "suprema lex?]. PMID- 10091510 TI - [Effect of ambulatory stress training on patients with chronic obstructive lung disease]. PMID- 10091511 TI - [Changes in specific airway resistance after powder inhalation of formoterol or salmeterol in moderate bronchial asthma]. AB - Formoterol and salmeterol are two long acting beta 2 agonists available for the treatment of asthma which show differences in onset of action. In a multicentre parallel group study, patients with moderate asthma were investigated by measuring the specific airway resistance (sRaw), a more sensitive parameter than FEV1. A total of 99 patients were randomised for open treatment with either 12 micrograms formoterol delivered via Turbohaler or 50 micrograms salmeterol via Diskus. The patients were between 18 and 66 years of age, had a medium FEV1 of 68.8% (+/- 17.8%) predicted and showed a medium reversibility of 28.8% (+/- 16.5%). The patients response to one inhalation of the study drug was investigated by sRaw measurements 2, 5, 10, 20 and 60 minutes after inhalation of the formulation. Additionally, FEV1 was measured. The results show a significant decrease in specific airway resistance of 29% within the first two minutes in patients who had received 12 micrograms formoterol via Turbohaler. However, patients on salmeterol showed no change (sRaw +/- 1%). This difference is statistically highly significant (p < 0.0001). Furthermore, in 49% of the patients treated with salmeterol an increase in sRaw was seen immediately after inhalation of the drug. This increase was +16.4% in an average of 2 minutes after inhalation. One hour after inhalation the differences between the groups were small and not significant neither between formoterol and salmeterol-treated patients nor within the salmeterol group. In the following week patients were treated with 12 micrograms formoterol Turbohaler b.i.d. or 50 micrograms salmeterol Diskus b.i.d., respectively. A further sRaw measurement was performed 11 +/- 1 hours after the last inhalation of the drug. The results for sRaw and FEV1 show no differences between both study drugs indicating a similar duration of action for both formoterol Turbohaler and Salmeterol Diskus in moderate asthma. No serious adverse events were reported. The adverse event profile observed in both study groups was comparable. Thus, this study shows once again that formoterol delivered via Turbohaler has a more rapid onset of bronchodilating action compared with salmeterol Diskus. Furthermore the inhalation of salmeterol via Diskus in one-half of the patients led to an increase in specific airway resistance within the first minutes after inhalation. It is worth discussing whether an unspecific reaction to the relatively large lactose particles which are components of the salmeterol Diskus formulation are responsible for this observation. PMID- 10091512 TI - [Relevance of deep venous thrombosis of the leg in patients with acute exacerbated COPD]. AB - BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with dyspnoea and, consequently, reduced mobility. Immobility is a recognised risk factor for deep venous thrombosis (DVT), but few data exist regarding the prevalence of DVT in acute exacerbation of COPD. Real-time B-mode ultrasonography (US) is a noninvasive screening-method for the diagnosis of DVT. We therefore used US to investigate the prevalence of DVT in patients with an acute exacerbation of COPD. METHODS: In a prospective cohort study 196 patients with COPD were studied (110 men, 86 female, age: 66.9 +/- 9.1 years, weight: 63.5 +/- 12.7 kg, forced expiratory volume in 1 second [FEV1]: 0.7 +/- 0.21, FEV1% of vital capacity [VC]: 37 +/- 6) in a respiratory intensive care unit on the day of admission. Patients with reduced mobility due to other diseases were excluded. All US were performed by one experienced person with a 5 MHz linear scanner. The veins of the lower extremity were subdivided into 3 segments: 1. The common femoral, 2. superficial femoral veins including the long saphenous vein and 3. the popliteal vein. RESULTS: In 21 of 196 COPD patients (10.7%) DVT were demonstrated; 18 of these were asymptomatic. Bilateral DVT were not found. In 6 patients additional diagnoses were obtained. There was no difference between patient with and without DVT with respect to age, hemoglobin, PO2, PCO2, pH, FEV1, VC or dyspnoea scale. CONCLUSIONS: DVT in the lower extremity, which was not detectable on clinical examination, was relatively common in patients with an acute exacerbation of COPD. All measured clinical variables (age, weight, dyspnoe scale, lung function, hemoglobin and hematocrit and blood gases) failed to predict patients more likely to have DVT. PMID- 10091513 TI - [Fibrosing alveolitis: retrospective overview, future prospects?]. PMID- 10091514 TI - [Smoking habits in German clinics with pulmonary specialization]. PMID- 10091515 TI - [Hospital admission for bronchial asthma: comparison between inpatient children and patients attending ambulatory asthma education]. AB - BACKGROUND: Asthma bronchiale is a chronic disease with increasing prevalence, increasing numbers of hospital admissions, and a growing mortality rate. Training courses for patients could reduce the number of in-patients, but it is still not clear what leads to an increase in admissions and whether all children have equal access to the special training courses offered. METHODS: In order to settle these questions, 40 in-patients with asthma (clinical group) were compared with a training group of 80 children of the same age, who participated in an out patients' training course for asthmatics held at Asthma-Zentrum Rhein-Main. During a retrospective examination clinical characteristics (therapy prior to admission, number of times of seeing a doctor before admission, number of days of absence from school) and socio-economic conditions (size of flat, level of education of parents, proportion of children from families of non-German origin), as well as environmental factors (parents' tobacco smoking) were determined. FINDINGS: As expected, significant disadvantages regarding clinical characteristics and socioeconomic data were recorded for the clinical group. Children in the clinical group less often got a regular prophylactic treatment before admission to hospital (43% vs. 80%). They were absent from school three times more often than children from the training group (6 days vs. 2 days); proportionally, their parents smoked twice as often (53% vs. 23%); frequently, the number of persons living in the flat exceeded the total number of rooms (43% vs. 23%), and only 61% had their own bedroom (vs. 81% in the training group). 40% of the children in the clinical group are from families of nationalities other than German vs. only 14% in the training group. Moreover, most parents of the children in the clinical group were undereducated or had no professional training at all, and rarely held university degrees. INTERPRETATION: The results show that the patients' profiles regarding therapy and socio-economic conditions differ substantially between in-patients and children from the training group at the Asthma-Zentrum. A major part of these patients in question had no access to or could not be reached by an ambulant training course for asthmatics. Especially socially and economically disadvantaged families, and families with little compliance must be informed more carefully and should be persuaded of the benefits of ambulant training courses for asthmatics. PMID- 10091517 TI - [Reduced passive smoking exposure of children--parental behavior, possibilities for change and determinants]. AB - So far there have been hardly any investigations as to under what conditions parents can avoid or reduce their children's exposure to passive smoking similarly, there has not been much investigation on physician's influence on parental behaviour. In an anonymous questionnaire given to 105 parents (only one parent), one half of the children were constantly exposed to smoke. In households with both parents smoking a very high level of exposure is to be expected due to behaviour and cigarette-consumption. The problem is aggravated by visitors and partners who also smoke. A lack of parents' awareness of passive smoking cannot be regarded as relevant. The main thing that puts a stop to changing this seems to be taking a decision and is also dependent on the amount of cigarette smoke. Only 46% of the participants reported to have been addressed by their physician on this subject. No negative reactions to this intervention on behalf of the physicians were reported in this survey. Instead, talking about it rather made the patient feel he had a bad conscience. Hence, the doctors' concern about a negative reaction does not seem to be justified. Structured intervention strategies which can be introduced in hospitals or in a physician's general practice should be developed and tested. PMID- 10091516 TI - [Ambulatory vs. inpatient intravenous antibiotic therapy in mucoviscidosis patients--a controlled study]. AB - METHODS: 14 patients with cystic fibrosis and chronic pulmonary pseudomonas infection received four courses of two-week intravenous antibiotic therapy at home and during hospitalisation over an 18-month period. Following a controlled, intra-individual cross-over design, two courses of home therapy were followed by two courses of hospital treatment or vice versa. Parameters for inflammation, lung function, and body mass index were obtained at the beginning and end of each intravenous antibiotic therapy. Health-related quality of life, i.e. physical, emotional, social and functional components as well as happiness and medical care, was assessed at the end of each course. RESULTS: There was a trend towards better reduction of infection (p = 0.20 for leukocyte reduction) and improvement of lung function (p = 0.20 for FEV1 improvement) with hospital intravenous antibiotic therapy, although the differences did not attain statistical significance. Quality of life during therapy was significantly higher with home therapy regarding social (p < 0.01), functional and emotional subscales and happiness (all p < 0.05). The necessity for professional help and support from family and/or partner was emphasised. Individual answers showed that home therapy has the advantage of self-determination and continuity of daily life. Parents and partners felt impaired by day and night intravenous therapy at home. CONCLUSION: From our data we conclude that home intravenous antibiotic therapy is a useful option for a selected subgroup of patients with cystic fibrosis, but professional support and family aid is important to gain an effect similar to hospital treatment. PMID- 10091518 TI - [Functional outcome and quality of life at least 6 months after pneumonectomy- effect of operation, adjuvant therapy, tumor stage, sex, type of pneumonia and recurrence]. AB - This study reports on the results of a checkup carried out on 38 patients subjected to an extended cancer aftercare examination at least 6 months after pneumectomy because of bronchial carcinoma, 12 of these patients receiving adjuvant chemotherapy and/or radiotherapy. Lung function data determined by body plethysmography were measured, as well as the quality of life, using the Karnofsky and Spitzer indices as well as QLQ-C30 of the EORTC. In addition, anamnestic data and postoperative ECG and blood gas analysis results were recorded. The most important findings concern restricted lung function due to pneumectomy, an IVC decrease by 33.3%, a drop in FEV1 by 27.3% and a reduction of the total lung capacity (TLC) by 14%. Moreover, a distinctly increased right heart load was seen in 23.4% of all patients. The quality of life tests revealed a slightly reduced quality of life in the external assessment indices according to Karnofsky (86 +/- 11%) and Spitzer (8.6 +/- 1.2). Self-assessment by QLQ-C30 of the EORTC, however, evidenced a clear reduction of the global quality of life (54.2 +/- 15.6) and role function, a moderate decrease of physical, emotional, cognitive and social functioning as well as a greatly increased incidence of the symptoms fatigue, dyspnea, sleep disturbances and pain after surgery. Adjuvant therapy applied in 12 patients had no significant influence, neither on lung function parameters nor on the quality of life. A more advanced tumour stage or a relapse, however, will adversely affect the quality of life. PMID- 10091519 TI - [Pulmonary diagnosis with model aerosols. II: Aerosol bolus dispersion--a marker for convection gas transport. Basic principles and initial clinical results]. PMID- 10091520 TI - [The additional efficacy of the nifedipine-diuretic combination depends on the potency of the drug administered first and not the sequence of administration. A double blind study in salt-sensitive black hypertensives]. AB - OBJECTIVE: To evaluate whether the additional antihypertensive efficacy of the nifedipine-thiazide combination depends on the sequence of drug administration and whether the natriuretic effect of thiazide persists when co-administered with nifedipine. METHODS: Double blind, randomised, crossover, placebo-controlled study, in 12 salt-sensitive hypertensive black patients (SSH). Evaluation of the antihypertensive (24 h ambulatory monitoring) and natriuretic effects of placebo (PL), of nifedipine-GITS (NIF, 30 mg/d) and of hydrochlorothiazide (HCTZ, 25 mg/d) given alone and in combination within two separate therapeutic sequences: PL-->NIF-->NIF + HCTZ and PL-->HCTZ-->HCTZ + NIF (1 month for each therapeutic regimen). RESULTS: NIF induced greater (p < 0.04) reduction of 24 h mean arterial pressure (MAP) (-15.9 +/- 1.9 mm Hg, v PL) than HCTZ (-9.0 +/- 1.3 mm Hg). The association of NIF to HCTZ induced a greater (p < 0.05) additional reduction of MAP-24 h (9.7 +/- 2.2 mm Hg) than that produced by the association of HCTZ to NIF (4.1 +/- 1.3 mm Hg). NIF alone and in combination did not modify the diuresis natriuresis observed with the previous treatment, whereas HCTZ alone and in combination always increased diuresis (by 25%) and natriuresis (by 53%). There was a significant negative correlation (r = -0.71, p < 0.001) between blood pressure (BP) reduction induced by the drug administered first (NIF or HCTZ) and the additional BP reduction obtained by the association of the second drug. CONCLUSIONS: In most of the SSH the NIF-GITS was more potent than HCTZ. NIF did not modify the diuretic-natriuretic effect of PL and of HCTZ. The greater potency of NIF may explain why in most patients the combination HCTZ to NIF induced a lower hypotensive effect than that of the association of NIF to HCTZ. Independently of the sequence of the drug administration, the lower the hypotensive effect of the drug administered first the greater the additional hypotensive effect that was observed by adding the second drug. PMID- 10091521 TI - [Isolated left anterior artery disease: angiographic features and clinical evolution of patients submitted to surgical myocardial revascularization or angioplasty]. AB - The option for revascularization and the choice of intervention in isolated left anterior descending artery disease may be controversial. We decided to study retrospectively a group of revascularized patients (PTCA or surgery), with previous isolated LAD disease, to evaluate the angiographic features of LAD lesion, its contribution to the persistence of symptoms after revascularization and also to compare the occurrence of cardiac events in the two subgroups (PTCA and surgery). We studied 87 patients (mean age 57 +/- 10 years) submitted to myocardial revascularization (68 PTCA; 19 surgery), whose clinical evolution was followed for a mean period of 49 +/- 10 months (cardiac events: death, myocardial infarction, angina, heart failure, PTCA, surgery). We evaluated in cineangiography angiographic features of LAD lesions (degree of stenosis, lesion length and diameter, ectasia, luminal irregularity, ulcerated plaque, eccentricity, thrombus, calcification, type of lesion). On comparing angiographic features, we noted coronary lesions were longer in operated patients (p < 0.05) and a tendency for more complex lesions in this group (p = 0.08). After revascularization, 65% of PTCA patients and 26% of operated patients maintained angina (p < 0.01). The frequency of events was significantly higher in patients submitted to PTCA (84%) due to the greater occurrence of angina (65%). Sixteen percent PTCA were redilated and 6% operated whereas 11% of the surgical group were reoperated, without statistical difference regarding reintervention between the two groups. In the PTCA group, the greater frequency of angina and the necessity of a new PTCA could reflect restenosis. The disappearance of angina in operated patients may reflect probable patency of coronary bypass. PMID- 10091522 TI - [Elective coronary angioplasty in acute coronary syndromes: early versus delayed treatment]. AB - BACKGROUND: In patients with acute coronary syndromes (ACS) the optimal time required to stabilize the patient before attempting coronary intervention (PTCA) is uncertain. The recent use of newer devices and antiplatelet drugs allowed earlier percutaneous intervention. OBJECTIVE: We examined the efficacy and safety of coronary angioplasty in patients with ACS according to the period of stabilization with medical therapy. METHODS: We included 83 patients, 15 female, 54 with unstable angina and 29 with non-ST elevation myocardial infarction. We studied the rate of complications related to the procedure, the duration of CCU and hospital stay according to the period of stabilization with medical therapy: < 48 hours (early PTCA) and > or = 48 hours (delayed PTCA). RESULTS: No significant differences were found between the two groups of patients with respect to success rate (92% in early PTCA vs 98% in delayed PTCA), stents implantation (74% vs 78%), use of abeiximab (42% vs 24%), abrupt closure during procedure (3% vs 2%), infarct related procedure (0% vs 7%), re-PTCA (5% vs 7%) and surgical revascularization (0% vs 2%). No deaths occurred, CCU stay (2.5 vs 6.7 days, p < 0.001) and hospital stay (4 vs 9.4 days, p = 0.001) were significantly shorter in the group of early PTCA. CONCLUSIONS: In the present group of patients with ACS, early coronary intervention was a safe procedure with a shorter CCU and hospital stay compared with deferred PTCA. PMID- 10091523 TI - [Thrombolysis in pulmonary embolism - initial experience]. AB - Pulmonary embolism (PE) is a clinical situation difficult to diagnose, at times of great clinical instability, above all when it is massive, which leads to difficulties in the approach and treatment of patients. The treatment has not had any major innovations in recent years, being conventional the use of heparin and more rarely embolectomy. Recently, some clinical trials have defended the use of thrombolytics. The objective of this paper is to present our experience, although the series is still small. From April 1996 to November 1997, 11 patients were admitted to our Cardiac Intensive Care Unit with the clinical suspicion of PE, 5 of which with great hemodynamic instability and suspicion of massive PE. The clinical presentation was sudden dyspnea and loss of consciousness in 2 patients, dyspnea and hypotension in 2 patients and shock and respiratory arrest in one case. Gasimetry revealed acute hypoxemia and hypocapnia in all cases, average partial blood pressure in O2 (pO2) of 59 mm Hg and CO2 (pCO2) of 19 mm Hg. ECC and thorax x-ray contributed to the diagnosis in 3 patients, transthoracic echocardiography was decisive for the diagnosis in 5 cases, with visualisation of the thrombus by transesophageal echocardiography in 3 patients. All patients were monitored by Swan-Ganz catheter, the average systolic pulmonary artery pressure (PAP) was 74 mm Hg. Thrombolysis with rTPA (10 mg bolus followed by 90 mg in perfusion in 2 hrs) was administered in 6 episodes in 5 patients. Only in the case of the patient in shock were other complications related to the use of thrombolytics namely high digestive hemorrhage. There was a clear clinical improvement in all cases with great relief of dyspnea reduction of cyanosis and jugular engurgitation. The patient in shock recovered systemic pressures and improved the hemodynamic state. A significant reduction in PAP was observed (average of 32.5 mm Hg). PE recurred in two cases: with one death and therapeutic thrombolytic was repeated in the other patient with good results. After discharge, all patients remained asymptomatic under oral anticoagulation. IN CONCLUSION: Despite this small series, the results favour the use of thrombolytics in PE with a clear clinical and hemodynamic improvement. PMID- 10091524 TI - [Importance of multiplane transesophageal echocardiography in the diagnosis of pulmonary embolism]. AB - Pulmonary thromboembolism (PTE) is a clinical entity difficult to diagnose, its setting is often confused with other pathological entities. The inexistence of isotopic techniques in most centres and the difficulty and delay in performing a pulmonary angiography leads transesophageal echocardiography (TEE) to be, a method of increasing importance for its diagnosis. From January 1996 to November 1997, echocardiographic evaluation was requested for 33 patients due to clinical suspicion of pulmonary thromboembolism. A transthoracic assessment was made previously in 21 patients (average ages 58.3 years, 52% males) which had signs of right overload (dilatation of the right cavities, anomalous movement of the intraventricular septum and pulmonary hypertension) a TEE was performed. The TEE was negative in 10 patients (TEEn) without evidence of thrombi in the trunk and main branches of the pulmonary artery (PA); there was one death on this group for repeated pulmonary microembolisms confirmed by necropsy. The TEE was positive in 11 patients (TEEp) with evidence of thrombi in the PA trunk in 3 patients, bilaterally in both branches in 3 patients and in the right branch in 5 patients. There were dilatations of the right cavities in all patients, paradoxal movement of the interventricular septum and bulging of the intra-auricular septum to the left atria. Foramen ovale was detected in 2 patients. The best visualisation of the PA was achieved in the intermediate planes between 30-70 degrees and between 90-130 degrees (plane for transverse slice of the right branch of the pulmonary artery). In 7 patients with TEEp, PTE was confirmed by CT-scan (visualisation of the thrombi in the trunk and main branches of the PA) and/or ventilation perfusion scintigraphy and/or pulmonary angiography. In three cases of massive pulmonary embolism in young patients, with severe pulmonary hypertension, thrombolysis was performed with rTPA, under TEE control before and after rTPA in one of the cases. In conclusion, transesophageal echocardiography is an easy technique to be performed in the case of clinical suspicion of PTE. The existence of a negative examination does not invalidate the existence of PTE since only the trunk and the main branches of the PA are accessible by this technique. The detection of thrombi at this level in patients with clinical suspicion of massive pulmonary embolism confirms the diagnosis and supports the indication of thrombolysis. PMID- 10091526 TI - [Case report of serious cardiac insufficiency complicated by syncope]. AB - The authors describe a case of a patient with congestive heart failure complicated by syncope, hypotension and a transitory state of vigil coma. The transthoracic and transesophageal echocardiogram showed a huge mass that occupied almost totally the right ventricle causing sever obstruction. The patient was submitted to surgery and a resection of the mass with reconstruction of the free right ventricle wall was done. The histopathology revealed to be a leiomyosarcoma. There was a previous history of an uterine surgery. PMID- 10091525 TI - [Cardiac involvement in metabolic diseases]. AB - OBJECTIVE: To evaluate cardiac involvement in children with metabolic disease in the out patient clinic of the Pediatric Cardiology Unit of Maria Pia Children's Hospital and their follow-up. MATERIAL AND METHODS: Twenty-nine medical records belonging to out patients with metabolic disease in consultation at our unit were reviewed. The following data from each record was analyzed: sex, metabolic disease diagnosis, age and motive for referral to a pediatric cardiology unit, cardiology diagnosis, therapy and evolution. RESULTS: Seventeen patients were boys and 12 girls. The average age of referral was 7.2 years (SD 4.8). The motives for referral were: screening for heart disease, 16; heart murmur, 7; congestive heart failure, 3; heart murmur and fatigue, 2; poor weight gain, 1. The following metabolic diagnoses were made: lysosomal diseases, 21; mitochondrial citopathies, 5; disorder of beta-oxidation of fatty acids, 2; carbohydrate deficient glycoprotein syndrome (CDG syndrome), 1. The cardiologic evaluation was normal in ten patients (4 with lysosomal disease, 4 with mitochondrial citopathy, one disorder of beta-oxidation of fatty acids, the CDG syndrome). Mitral and aortic valve lesions predominated in lysosomal diseases (12/21); myocardial involvement alone was present in two patients, and both myocardial and valvular lesions were present in three. Dilated cardiomyopathy was the presented manifestation in two patients-one with mitochondrial citopathy and one with a disorder of beta-oxidation of fatty acids. Three patients died and 26 remain out-patients. One patient was submitted to valve surgery. The average duration of follow-up was 21 months (SD 24). COMMENTS: Lysosomal diseases were the most representative in our patients, as described in the literature. Heart valve disease was the most frequent alteration. Indication for heart valve surgery is dependent on systemic involvement of the primary disease. All children with a metabolic disease with eventual heart involvement should be evaluated periodically by a cardiology unit. On the other hand, it is mandatory to screen a cardiomyopathy of unknown cause for a metabolic disease. The authors draw attention to the importance of infectious endocarditis prophylaxis in this group of patients. PMID- 10091528 TI - [HMG-CoA reductase inhibitors: a brief review of their pharmacological properties and clinical efficacy in cardiovascular disease]. AB - The results of recently published studies on primary and secondary prevention of coronary heart disease with HMG-CoA reductase inhibitors--statins--support their use in patients with primary hypercholesterolaemia or mixed hyperlipidaemia, with or without atherosclerotic vascular disease. From a pharmacological point of view, statins inhibit HMG-CoA reductase, reduce the endogenous synthesis of cholesterol and increase the apoB/apoE lipoprotein clearance from plasma. Recent studies confirm that HMG-CoA reductase inhibitors may also decrease hepatic production of VLDL and LDL-cholesterol. However, they have different pharmacokinetic properties and variable effectiveness with potential clinical implications. These drugs are generally well tolerated with a similar profile of adverse effects (gastrointestinal effects, hepatic dysfunction and myopathy). The knowledge of their pharmacodynamic and pharmacokinetic properties can lead to a rational use and greater understanding of their potential benefits. PMID- 10091529 TI - [Stress echocardiography with dobutamine. Analysis of a personal experience]. PMID- 10091530 TI - [Herbal remedies and nephrotoxicity]. AB - Numerous substances from vegetal origin used as herbal remedies can be nephrotoxic. This article summarizes several circumstances of development of acute or chronic renal failure in which the responsible agent has been identified after a thorough toxicologic study. The Chinese herbs nephropathy is extensively described, detailing not only the epidemiological and histological aspects but also the extrarenal and neoplastic complications recently reported. PMID- 10091531 TI - [Screening, prediction and prevention of type 1 diabetes. Role of the Belgian Diabetes Registry]. AB - Since 1989, all incident cases of type 1 diabetes mellitus and their first-degree relatives younger than 40 years are entered in the Belgian Diabetes Registry (BDR). The incidence of type 1 diabetes is 11.8/100,000 in subjects younger than 15 years and 8.9/100,000 in subjects aged 15 to 40 years. Before 15 years of age, the cases are evenly divided between males and females, whereas in the older group the male-to-female ratio is 1.7. The median duration of symptoms at diagnosis is 3 weeks in patients younger than 15 years versus 8 weeks in those aged 15 to 40 years. The data of the BDR suggest that type 1 diabetes may be more "aggressive" in children than in adults. Autoantibodies are detectable before and during the clinical onset of type 1 diabetes. Over 90% of patients with type 1 diabetes have at least one type of autoantibody directed to beta-cell antigens. However, the nature of biological markers present at clinical onset tends to vary with age. Detection of autoantibodies in first-degree relatives of patients allows to diagnose the disease at a preclinical stage and to evaluate relatively safe preventive interventions in high-risk subjects. Several international studies in this area have been started. PMID- 10091532 TI - [Decision analysis and initiation of an "empiric" therapy]. AB - For more than 25 years, quantitative approaches were applied to evaluate the outcome of diagnostic and therapeutic strategies. Decision analysis is but one quantitative approach that guides therapeutic decisions. It allows careful analysis of the therapeutic outcome taking into consideration the effects of medical treatment, quality of life and economic costs. The goal of this kind of approach is to choose the management with the greatest benefit for the patient through systematic and logic reduction of the diagnostic uncertainty. It uses a model represented by a decision tree that helps the clinician tot quantify the outcomes. Followed by sensitivity analysis, it may provide a robust basis for the final decision. PMID- 10091533 TI - [Anatomical-clinical conference: mediastinal mass]. AB - A 56 years-old man developed a pneumonia. An anterior mediastinal mass is fortuitly found on the chest X-ray and the patient is hospitalised for further investigations. Differential diagnosis of mediastinal masses is discussed. PMID- 10091534 TI - [Pulmonary embolism and anterior septal ischemia on the electrocardiogram: diagnostic trap. Two case reports]. AB - The authors reports two cases of pulmonary embolism which have, on ECG, an anteroseptal subepicardial ischemia which could indicate a coronary origin. The value and role of electrocardiographic findings in the diagnosis of pulmonary embolism are analysed. Once the diagnosis of pulmonary embolism has been established, the rest-ECG could allow the massive forms to be distinguished from the non-massive ones. The anteroseptal subepicardial ischemia pattern in the precordial leads is the most frequent sign of pulmonary embolism. This parameter is easy to obtain and reflects the severity of pulmonary embolism. PMID- 10091535 TI - [Capitation fixed payment for primary care: a possible alternative to the traditional fee-for-service--part 2]. PMID- 10091536 TI - [Overprescribing of antibiotics outside the hospital]. AB - Overprescription of antibiotics is evident in the community as well as in hospital, in veterinary practice or in agriculture. This leads to bacterial multiresistance and treatment failures. The limitation of this overprescription will not be obtained unless diagnostic, therapeutic and preventive guidelines are followed particularly in the management of the upper respiratory tract infections. PMID- 10091537 TI - [Has disinfection of endoscopes by automatic machines become obligatory?]. PMID- 10091538 TI - [Should we treat cirrhosis in hepatitis C carriers with antiviral agents?]. PMID- 10091539 TI - [Should antisecretory agents be prescribed before endoscopy in cases with symptoms suggestive of gastroesophageal reflux?]. PMID- 10091540 TI - [Is anti-reflux surgery the treatment of choice for long-term control of gastroesophageal reflux?]. PMID- 10091541 TI - [Specificity of local medical evaluation group in continuing medical education]. PMID- 10091542 TI - [Paul Govaerts (1889-1960), clinician and physiologist]. PMID- 10091544 TI - [Fever after returning from travel to a tropical zone: what infectious diseases should be considered?]. PMID- 10091543 TI - [Travel outside our frontiers: parasitic diseases not to be missed]. PMID- 10091545 TI - [Triple expansion diseases: a new mutational concept]. AB - The human genome, made of about 3 billion bases, encodes between 75 and 100,000 genes. However, most of the genome is made of non coding sequences, whose function is still unknown. When a base variation occurs in a DNA fragment, base change, deletion or insertion of one or several bases, a mutation or a polymorphism is generated depending whether this base change modifies or not the function of the encoded gene. In 1991, a new type of mutation has been discovered, namely the expansion beyond a critical length of a three-base repeat, called triplet. These anomalies due to genome instability are not rare and are now responsible for at least twelve diseases. It is expected that other diseases due to the same mechanism will be discovered in the near future. This article illustrates the concept of mutation by triplet expansion and presents 3 diseases frequently observed in Pediatrics: the fragile X syndrome, myotonic dystrophy and Friedreich's ataxia. PMID- 10091546 TI - [The pediatrician's role in the evaluation of a "dysmorphic" child]. PMID- 10091547 TI - [Autistic disorders: screening and early intervention]. PMID- 10091548 TI - [Dermatologic problems]. PMID- 10091549 TI - [Vision examination in young children. Experience of Grepa Nord (France)]. AB - Starting with the fact that the results in screening for visual deficiencies for pre-school children were not as good as he hoped, the author proposes a clinical and semiological approach and the acquisition of simple and efficient tests with can be made quickly and are not too expensive. The selected tests are the Daum's test, the Lang's stereotest, the Pigassou's test with the Scolatest, the Ishihara's Design Charts for Colour-Blindness for Unlettered Persons or the Babydalton. Addresses and reduced prices possible for packages. PMID- 10091550 TI - [Fundamental research and clinical research in medicine]. PMID- 10091551 TI - [Internet for physicians: a tool for today and tomorrow ]. AB - The Internet is becoming more and more part of our habits regarding documentation and communication, thus limiting the frontiers to only that of the language. As in many other fields, the Internet is also present in the medical domain. The Internet is accessible to all, providing a technology which is simple and ergonomic and furthermore less costly. A growing number of individuals are indeed offering information, and the multiplication and diversification of documentary thus resulting renders the quality often questionable and the search for information difficult. This article firstly presents the Internet services with examples in the medical domain and more particularly in paediatrics. It then identifies the problems related to the Internet and further details three tools useful to find medical information and to surf on the Internet: Medline, a bibliographical reference search tool (from the National Library of Medicine NLM); Medhunt, a search tool of the Health on the Net Foundation specialised in the health domain; and the HONcode, a code of ethics developed to homogenize medical information on the Internet. PMID- 10091552 TI - ["Medical audit" of physicians' attitudes on preventing osteoporosis. Rennaz group]. PMID- 10091554 TI - Nitric oxide: physiological roles, biosynthesis and medical uses. PMID- 10091555 TI - On human perfection. PMID- 10091556 TI - Fear: the great equalizer. PMID- 10091557 TI - Defusing the latex bomb. PMID- 10091558 TI - Labeling lapse. When the bottle doesn't contain what you think you're giving. PMID- 10091559 TI - Rising above 'soar' throats. Take a common-sense approach to assessing young adults with sore throats. PMID- 10091560 TI - Reflections on the NICU. A mother's perspective. PMID- 10091561 TI - Reflections on the NICU. A nurse's perspective. PMID- 10091562 TI - Using superficial cooling for pain relief. PMID- 10091563 TI - 106th Congress. Proposals could impact women's health. PMID- 10091564 TI - New directions in asthma management. PMID- 10091565 TI - Emergency! Crush injury. PMID- 10091566 TI - Periodontal disease. PMID- 10091567 TI - Sickle cell disease. Do you doubt your patient's pain? PMID- 10091568 TI - Medication compliance in adults with asthma. PMID- 10091569 TI - Evaluating the quality of COPD care. PMID- 10091570 TI - Fosphenytoin for seizure control. PMID- 10091571 TI - Making a legislative impact. PMID- 10091572 TI - Relic or resource? The Code for Nurses. PMID- 10091573 TI - Workplace violence. PMID- 10091574 TI - Health going up in smoke. How can you prevent it. PMID- 10091575 TI - Chronic fatigue syndrome. Do you know what it means? PMID- 10091576 TI - Manage pain proactively. PMID- 10091577 TI - Na,K-ATPase mRNA beta 1 expression in rat myocardium--effect of thyroid status. AB - The abundance of Na,K-ATPase and its alpha and beta subunit mRNAs is upregulated in cardiac and other target tissue by thyroid hormone (T3). Multiple Na,K-ATPase mRNA beta 1 species encoding an identical beta 1 polypeptide are expressed in the heart. The different mRNA beta 1 species result from utilization of two transcription start-sites in the first exon and multiple (five) poly(A) signals in the terminal exon of the beta 1 gene. In the present study we identify the mRNA beta 1 species that are expressed in rat ventricular myocardium under basal conditions, and determine whether they are differentially regulated by T3. mRNA beta 1 species were identified by 3'-RACE followed by DNA sequencing, and by Northern blotting using probes derived from different regions of rat cDNA beta 1. Five mRNA beta 1 species are expressed in rat heart: mRNA beta 1 species that are initiated at the first transcription start-site and end at the first, second and fifth poly(A) sites (resulting in mRNAs of 1630, 1810, and 2780 nucleotides), and mRNA beta 1 species initiated at the second transcription start-site and ending at the second and fifth poly(A) sites (resulting in mRNAs of 1500 and 2490 nucleotides); in order of increasing length, the five mRNAs constitute 0.04, 0.15, 0.38, 0.11 and 0.32 of total mRNA beta 1 content. In hypothyroid rats (induced by addition of propyl-thiouracil to the drinking water for 3 weeks), total mRNA beta 1 content decreased to 0.18 euthyroid levels, which was associated with a disproportionate 7.5-fold decrease in the abundance of the longest transcript (P < 0.05); transcripts initiating at the first transcription start-site and ending at the second poly(A) signal in hypothyroid hearts were 0.26 euthyroid levels (P < 0.05). Hyperthyroidism induced by injection of normal rats with three doses of 100 micrograms T3/100 g body weight every 48 h resulted in an overall approximately 2-fold increase in mRNA beta 1 content with no change in the fractional contribution of any of the mRNA beta 1 species. The results indicate a complex heterogeneity in the expression of mRNA beta 1 in myocardium. PMID- 10091578 TI - Identification of the reactive cysteine residue (Cys227) in human carbonyl reductase. AB - Carbonyl reductase is highly susceptible to inactivation by organomercurials suggesting the presence of a reactive cysteine residue in, or close to, the active site. This residue is also close to a site which binds glutathione. Structurally, carbonyl reductase belongs to the short-chain dehydrogenase/reductase family and contains five cysteine residues, none of which is conserved within the family. In order to identify the reactive residue and investigate its possible role in glutathione binding, alanine was substituted for each cysteine residue of human carbonyl reductase by site-directed mutagenesis. The mutant enzymes were expressed in Escherichia coli and purified to homogeneity. Four of the five mutants (C26A, C122A C150A and C226A) exhibited wild-type-like enzyme activity, although K(m) values of C226A for three structurally different substrates were increased threefold to 10-fold. The fifth mutant, C227A, showed a 10-15-fold decrease in kcat and a threefold to 40-fold increase in K(m), resulting in a 30-500-fold drop in kcat/K(m). NaCl (300 mM) increased the activity of C227A 16-fold, whereas the activity of the wild-type enzyme was only doubled. Substitution of serine rather than alanine for Cys227 similarly affected the kinetic constants with the exception that NaCl did not activate the enzyme. Both C227A and C227S mutants were insensitive to inactivation by 4-hydroxymercuribenzoate. Unlike the parent carbonyl compounds, the glutathione adducts of menadione and prostaglandin A1 were better substrates for the C227A and C227S mutants than the wild-type enzyme. Conversely, the binding of free glutathione to both mutants was reduced. Our findings indicate that Cys227 is the reactive residue and suggest that it is involved in the binding of both substrate and glutathione. PMID- 10091579 TI - Rapid purification of membrane extrinsic F1-domain of chloroplast ATP synthase in monodisperse form suitable for 3D-crystallization. AB - A new chromatographic procedure for purification of the membrane extrinsic F1 domain of chloroplast ATP synthase is presented. The purification is achieved by a single anion exchange chromatography step. Determination of the enzyme-bound nucleotides reveals only 1 mole of ADP per complex. The purified enzyme shows a latent Ca(2+)-dependent ATPase activity of 1.0 mumol.mg-1 min-1 and a Mg(2+) dependent activity of 4.4 mumol.mg-1 .min-1. Both activities are increased up to 8-10-fold after dithiothreitol activation. Analysis of the purified F1-complex by SDS/PAGE, silver staining and immunoblotting revealed that the preparation is uncontaminated by fragmented subunits or ribulose-1,5-bisphosphate carboxylase/oxygenase. Gel filtration experiments indicate that the preparation is homogenous and monodisperse. In order to determine the solubility minimum of the purified F1-complex the isoelectric point of the preparation was calculated from pH mapping on ion exchange columns. In agreement with calculations based on the amino acid sequence, a slightly acidic pI of 5.7 was found. Using ammonium sulphate as a precipitant the purified CF1-complex could be crystallized by MicroBatch. PMID- 10091580 TI - Screening of an intragenic second-site suppressor of purine-cytosine permease from Saccharomyces cerevisiae. Possible role of Ser272 in the base translocation process. AB - The purine-cytosine permease from Saccharomyces cerevisiae mediates the active transport through the plasma membrane of adenine, hypoxanthine, guanine and cytosine using the proton electrochemical potential difference as an energy source. Analysis of the activity of strains mutated in a hydrophilic segment (371 377) of the polypeptidic chain has shown the involvement of this segment in the maintenance of the active three-dimensional structure of the carrier. In an attempt to identify permease domains that could interact functionally and/or physically with this segment, we looked for second-site mutations that could suppress the effects of amino acid changes in this region. This paper describes a positive screen that has allowed the isolation of one suppressor from a permease mutant displaying the N374I change (fcy2-20 allele), a substitution that induces a dramatic decrease in the affinity of the carrier for adenine, cytosine and hypoxanthine. The second-site mutation corresponds to the replacement of the Ser272 residue by Leu. Its suppressive effect is shown to be a partial restoration of the binding of cytosine and hypoxanthine to the permease. To test whether this second-site mutation is specific for the fcy2-20 allele, two double mutants were constructed (Fcy2pT213I, S272L and Fcy2pS272L, N377G). Results obtained with these two double mutants showed that the suppressive effect of S272 L replacement was not specific for the original N374I change. To understand the general effect of this amino acid replacement for the three distinct double mutants, a strain overexpressing Fcy2pS272I, was constructed. Kinetic analysis of this strain showed that, by itself, the S272 L change induced an improvement in the base-binding step that could account for its global suppressive effect. Moreover, S272 L induced a decrease in the turnover of the permease, thus showing the involvement of S272 in the translocation process. Taking into account the topological model of the permease proposed here, this Ser residue is probably located in a transmembrane amphipathic alpha-helix (TM5). The location and the observed decrease in the turnover of the carrier observed with the S272 L change lead us to propose that S272 could be part of a hydrophilic pore involved in the translocation of the base and/or the proton. PMID- 10091581 TI - The Schizosaccharomyces pombe Pzh1 protein phosphatase regulates Na+ ion influx in a Trk1-independent fashion. AB - We have previously shown that fission yeast encodes a PPZ-like phosphatase, designated Pzhl, which is an important determinant of cation homeostasis. pzh1 delta mutants display increased tolerance to Na+ ions, but they are hypersensitive to KC1 [Balcells, L., Gomez, N., Casamayor, A., Clotet, J. & Arino, J. (1997) Eur. J. Biochem. 250, 476-483]. We have immunodetected Pzh1 in yeast extracts and found that this phosphatase is largely associated with particulate fractions. Cells defective in Pzh1 do not show altered efflux of Na+ or Li+ ions, but they accumulate these cations more slowly than wild-type cells. K+ ion content of pzh1 delta cells is about twice that of wild-type cells, and this can be explained by decreased efflux of K+. Therefore, Pzh1 may regulate both Na+ influx and K+ efflux in fission yeast. To test the possible relationship between K+ uptake, Na+ tolerance and Pzh1 function, we deleted the trk1+ gene, which encodes a putative high-affinity transporter of K+ ions. trkl delta mutants grew well even at relatively low concentrations of KCl and did not show significantly altered content or influx of K+ ions. However, they showed a Na(+) sensitive phenotype which was greatly intensified by deletion of the sod2+ gene (which encodes the major determinant for efflux of Na+ ions), and clearly ameliorated by deletion of the pzh1 phosphatase, as well as by moderate concentrations of KCl in the medium. These results suggest that Trk1 does not mediate the effect of Pzh1 on NaCl tolerance and that fission yeast contains efficient systems, other than Trk1, for uptake of K+ ions. PMID- 10091582 TI - Substrate-specific selenoprotein B of glycine reductase from Eubacterium acidaminophilum. Biochemical and molecular analysis. AB - The substrate-specific selenoprotein B of glycine reductase (PBglycine) from Eubacterium acidaminophilum was purified and characterized. The enzyme consisted of three different subunits with molecular masses of about 22 (alpha), 25 (beta) and 47 kDa (gamma), probably in an alpha 2 beta 2 gamma 2 composition. PBglycine purified from cells grown in the presence of [75Se]selenite was labeled in the 47 kDa subunit. The 22-kDa and 47-kDa subunits both reacted with fluorescein thiosemicarbazide, indicating the presence of a carbonyl compound. This carbonyl residue prevented N-terminal sequencing of the 22-kDa (alpha) subunit, but it could be removed for Edman degradation by incubation with o-phenylenediamine. A DNA fragment was isolated and sequenced which encoded beta and alpha subunits of PBglycine (grdE), followed by a gene encoding selenoprotein A (grdA2) and the gamma subunit of PBglycine (grdB2). The cloned DNA fragment represented a second GrdB-encoding gene slightly different from a previously identified partial grdBl containing fragment. Both grdB genes contained an in-frame UGA codon which confirmed the observed selenium content of the 47-kDa (gamma) subunit. Peptide sequence analyses suggest that grdE encodes a proprotein which is cleaved into the previously sequenced N-terminal 25-kDa (beta) subunit and a 22-kDa (alpha) subunit of PBglycine. Cleavage most probably occurred at an -Asn-Cys- site concomitantly with the generation of the blocking carbonyl moiety from cysteine at the alpha subunit. PMID- 10091583 TI - Stopped-flow studies of the binding of 2-n-heptyl-4-hydroxyquinoline-N-oxide to fumarate reductase of Escherichia coli. AB - We have studied the kinetics of binding of the menaquinol analog 2-n-heptyl-4 hydroxyquinoline-N-oxide (HOQNO) by fumarate reductase (FrdABCD) using the stopped-flow method. The results show that the fluorescence of HOQNO is quenched when HOQNO binds to FrdABCD. The observed quenching of HOQNO fluorescence has two phases and it can be best fitted to a double exponential equation. A two-step equilibrium model is applied to describe the binding process in which HOQNO associates with FrdABCD by a fast bimolecular step to form a loosely bound complex; this is subsequently converted into a tightly bound complex by a slow unimolecular step. The rates of the forward and the reverse reactions for the first equilibrium (k1 and k2) are determined to be k1 = (1.1 +/- 0.1) x 10(7) M 1.s-1, and k2 = 6.0 +/- 0.6 s-1, respectively. The dissociation constants of the first equilibrium (Kd1 = k2/k1) is calculated to be about 550 nM. The overall dissociation constant for the two-step equilibrium, Kd overall = Kd1/[1+ (1/Kd2)], is estimated to be < or = 7 nM. Comparison of the kinetic parameters of HOQNO binding by FrdABCD and by dimethyl sulfoxide reductase provides important information on menaquinol binding by these two enzymes. PMID- 10091584 TI - Localization of neutral N-linked carbohydrate chains in pig zona pellucida glycoprotein ZPC. AB - Zona pellucida, a transparent envelope surrounding the mammalian oocyte, plays important roles in fertilization and consists of three glycoproteins; ZPA, ZPB and ZPC. In pig, neutral complex-type N-linked chains obtained from a ZPB/ZPC mixture possess sperm-binding activity. We have recently reported that among neutral N-linked chains triantennary and tetraantennary chains have a sperm binding activity stronger than that of diantennary chains. Triantennary and tetraantennary chains are localized at the second of the three N-glycosylation sites of ZPB. In this study, we focused on the localization of neutral N-linked chains in ZPC. ZPB and ZPC can not be separated from each other unless the acidic N-acetyllactosamine regions of their carbohydrate chains are removed by endo-beta galactosidase digestion. A large part of the acidic N-linked chains becomes neutral by the digestion, but the main neutral N-linked chains are not susceptible to the enzyme. N-glycanase digestion indicated that ZPC has three N glycosylation sites. Three glycopeptides each containing one of the N glycosylation sites were obtained by tryptic digestion of ZPC and the N glycosylation sites were revealed as Asn124, Asn146 and Asn271. The carbohydrate structures of the neutral N-linked chains from each glycopeptide were characterized by two-dimensional sugar mapping analysis taking into consideration the structures of the main, intact neutral N-linked chains of ZPB/ZPC mixture reported previously. Triantennary and tetraantennary chains were found mainly at Asn271 of ZPC, whereas diantennary chains were present at all three N glycosylation sites. Thus, ZPC has tri-antennary and tetra-antennary chains as well as ZPB, but the localization of the chains is different from that in ZPB. PMID- 10091585 TI - Importance of individual activated protein C cleavage site regions in coagulation factor V for factor Va inactivation and for factor Xa activation. AB - Activated protein C (APC) cleavage of Factor Va (FVa) at residues R506 and R306 correlates with its inactivation. APC resistance and increased thrombotic risk are due to the mutation R506Q in Factor V (FV). To study the effects of individual cleavages in FVa by APC and the importance of regions near the cleavage sites, the following recombinant (r) human FVs were prepared and purified: wild-type, Q306-rFV, Q506-rFV, and Q306Q506-rFV. All had similar time courses for thrombin activation. Q506-rFVa was cleaved by APC at R306 and was moderately resistant to APC in plasma-clotting assays and in prothrombinase assays measuring FVa residual activity, in agreement with studies of purified plasma-derived Q506-FVa. Q306-rFVa was cleaved by APC at R506 and gave a low APC resistance ratio similar to Q506-rFVa in clotting assays, whereas unactivated Q306-rFV gave a near-normal APC-resistance ratio. When FVa residual activity was measured after long exposure to APC, Q306-rFVa was inactivated by only < or = 40% under conditions where Q506-rFVa was inactivated > 90%, supporting the hypothesis that efficient inactivation of normal FVa by APC requires cleavage at R306. In addition, the heavy chain of Q306-rFVa was cleaved at R506 much more rapidly than activity was lost, suggesting that FVa cleaved at only R506 is partially active. Under the same conditions, Q306Q506-rFVa lost no activity and was not cleaved by APC. Therefore, cleavage at either R506 or R306 appears essential for significant inactivation of FVa by APC. Modest loss of activity, probably due to cleavage at R679, was observed for the single site rFVa mutants, as evidenced by a second phase of inactivation. Q306Q506-rFVa had a low activity-to-antigen ratio of 0.50 0.77, possibly due to abnormal Factor Xa (FXa) binding. Furthermore, Q306Q506-rFV was very resistant to cleavage and activation by FXa. Q306Q506-rFV appeared to bind FXa and inhibit FXa's ability to activate normal FV. Thus, APC may downregulate FV/Va partly by impairing FXa-binding sites upon cleavage at R306 and R506. This study shows that R306 is the most important cleavage site for normal efficient inactivation of FVa by APC and supports other studies suggesting that regions near R306 and R506 provide FXa-binding sites and that FVa cleaved at only R506 retains partial activity. PMID- 10091586 TI - Role of lysine and tryptophan residues in the biological activity of toxin VII (Ts gamma) from the scorpion Tityus serrulatus. AB - Toxin VII (TsVII), also known as Ts gamma, is the most potent neurotoxin in the venom of the Brazilian scorpion Tityus serrulatus. It has been purified to homogeneity using a new fast and efficient method. Chemical modification of TsVII with the tryptophan-specific reagent o-nitrophenylsulfenyl chloride yielded three modified derivatives (residues Trp39, Trp50 and Trp54). Acetylation of TsVII mostly generated the monoacetylated Lys12 derivative. No side reactions were detected, as indicated by endoproteinase Lys-C peptide mapping, Edman degradation and electrospray mass spectrometry. Circular dichroism and fluorimetric measurements showed that none of the chemical modifications altered the overall structure of the derivatives. The acetylation of Lys12 or the sulfenylation of Trp39 or Trp54 led to a loss of both toxicity in mice and apparent binding affinity for rat brain and cockroach synaptosomal preparations. Sulfenylation of Trp50, however, moderately affected the toxicity of TsVII in mice and had almost no effect on its binding properties. A 3-dimensional model of TsVII was constructed by homology modeling. It suggests that the most reactive residues (Lys12 and Trp39 and Trp54) are all important in the functional disruption of neuronal sodium channels by TsVII, and are close to each other in the hydrophobic conserved region. PMID- 10091587 TI - Role of autocrine stimulation on the effects of cyclic AMP on protein and lipid phosphorylation in collagen-activated and thrombin-activated platelets. AB - We compared several responses in thrombin-stimulated and collagen (type I) stimulated platelets with and without forskolin and inhibitors of autocrine stimulation (IAS: an ADP-removing system of creatine phosphate/creatine phosphokinase, Arg-Gly-Asp-Ser peptide to prevent fibrinogen/fibronectin binding to GPIIb/IIIa, SQ 29.548 as a thromboxane A2 receptor antagonist, cyproheptadine as a serotonin receptor antagonist, BN 52021 as a platelet-activating factor receptor antagonist). The pattern of tyrosine-phosphorylated proteins, the phosphorylation of lipids in the polyphosphoinositide cycle and phosphorylation of pleckstrin (P47) were studied as markers for signal-transducing responses, exposure of CD62 (P-selectin) and CD63 (Glycoprotein 53), as well as secretion of ADP + ATP and beta-N-acetyl-glycosaminidase were studied as final activation responses. Clear differences between thrombin-stimulated and collagen-stimulated platelets were observed. First, practically all protein-tyrosine phosphorylation induced by thrombin was inhibited by IAS, while a partial inhibition was observed for collagen; the phosphorylation due to collagen alone was apparently stimulated by elevation of cAMP. Secondly, the other responses to thrombin were inhibited by increased levels of cAMP, independent of autocrine stimulation. In contrast, only the autocrine part of the collagen-induced responses was inhibited by elevation of cAMP. Thus, the inhibition by elevated cAMP seen in collagen-stimulated platelets seems to be due to removal of the G-protein-mediated activation from secreted autocrine stimulators either by IAS or forskolin. The remaining activity is a pure collagen effect which is not affected by elevated levels of cAMP. PMID- 10091588 TI - Allosteric modulation of BPTI interaction with human alpha- and zeta-thrombin. AB - In this study, thrombin interaction with the basic pancreatic trypsin inhibitor (BPTI) was investigated in the presence of different allosteric modulators of thrombin, that is the C-terminal hirudin peptide 54-65 (Hir54-65), a recombinant thrombomodulin form (TMEGF4-6) and Na+. BPTI binding to alpha-thrombin is positively linked to Na+. Under low sodium concentration (5 mM Na+) the BPTI affinity for alpha-thrombin was roughly threefold lower than in the presence of 150 mM sodium (Ki = 320 microM vs. 100 microM). The hirudin fragment, which binds to the fibrinogen recognition site (FRS) of thrombin, induced a progressive and saturable decrease (3.6-fold) of alpha-thrombin affinity for BPTI, whereas the thrombomodulin peptide, which binds to a more extended region of FRS, caused a 5.5-fold increase of the enzyme affinity for the inhibitor. The opposite effect exerted by Hir54-65 and TMEGF4-6 was also observed for BPTI interaction with zeta thrombin, in which the amidic bond between W148 and T149 is cleaved. However, in this case the effect by Hir54-65 and TMEGF4-6, although qualitatively similar to that observed with alpha-thrombin, had a smaller magnitude. Thrombin hydrolysis of Protein C was also differently affected by Hir54-65 and TMEGF4-6 peptides. While the latter enhanced the Protein C activation, the former caused a reduction of both alpha- and zeta-thrombin kcat/K(m)' for Protein C cleavage. These results showed that (a) Na+ facilitates BPTI interaction with thrombin; (b) Hir54-65 and TMEGF4-6, though sharing in part the same binding site at the thrombin FRS, can affect in opposite way thrombin's interaction with BPTI and Protein C; (c) such findings along with the results obtained with zeta-thrombin might be explained by admitting that the thermodynamic linkage between FRS and the critical W60-loop is also controlled by ligation and/or conformational state of the W148 insertion loop. PMID- 10091589 TI - Analysis of DNA cleavage by reverse gyrase from Sulfolobus shibatae B12. AB - Reverse gyrase is a type I-5' topoisomerase, which catalyzes a positive DNA supercoiling reaction in vitro. To ascertain how this reaction takes places, we looked at the DNA sequences recognized by reverse gyrase. We used linear DNA fragments of its preferred substrate, the viral SSV1 DNA, which has been shown to be positively supercoiled in vivo. The Sulfolobus shibatae B12 strain, an SSV1 virus host, was chosen for production of reverse gyrase. This naturally occurring system (SSV1 DNA-S. shibatae reverse gyrase) allowed us to determine which SSV1 DNA sequences are bound and cleaved by the enzyme with particularly high selectivity. We show that the presence of ATP decreases the number of cleaved complexes obtained whereas the non-hydrolyzable ATP analog adenosine 5'-[beta, gamma-imido]triphosphate increases it without changing the sequence specificity. PMID- 10091590 TI - Sequestration of dopamine D2 receptors depends on coexpression of G-protein coupled receptor kinases 2 or 5. AB - We examined the agonist-dependent sequestration/internalization of dopamine D2 receptor (the long form D2L and short form D2S), which were transiently expressed in COS-7 and HEK 293 cells with or without G-protein-coupled receptor kinases (GRK2 or GRK5). Sequestration was assessed quantitatively by loss of [3H] sulpiride-binding activity from the cell surface and by transfer of [3H] spiperone-binding activity from the membrane fraction to the light vesicle fraction in sucrose-density gradients. In COS-7 cells expressing D2 receptors alone, virtually no sequestration was observed with or without dopamine (< 4%). When GRK2 was coexpressed, 50% of D2S receptors and 36% of D2L receptors were sequestered by treatment with 10(-4) M dopamine for 2 h, whereas no sequestration was observed in cells expressing the dominant negative form of GRK2 (DN-GRK2). When GRK5 was coexpressed, 36% of D2S receptors were sequestered following the same treatment. The agonist-dependent and GRK2-dependent sequestration of D2S receptors was reduced markedly in the presence of hypertonic medium containing 0.45 M sucrose, suggesting that the sequestration follows the clathrin pathway. Internalization of D2S receptors was also assessed by immunofluorescence confocal microscopy. Translocation of D2 receptors from the cell membrane to intracellular vesicles was observed following the treatment with dopamine from HEK 293 cells only when GRK2 was coexpressed. D2S receptors expressed in HEK 293 cells were shown to be phosphorylated by GRK2 in an agonist-dependent manner. These results indicate that the sequestration of D2 receptors occurs only through a GRK mediated pathway. PMID- 10091591 TI - Purification, characterization and gene cloning of 6-hydroxynicotinate 3 monooxygenase from Pseudomonas fluorescens TN5. AB - 6-Hydroxynicotinate 3-monooxygenase, a membrane-bound, 42-kDa monomeric enzyme from Pseudomonas fluorescens TN5 was purified and characterized. The enzyme catalyzes the oxidative decarboxylation of 6-hydroxynicotinate and depends on O2, NADH and FAD with the holoenzyme containing 1 M of FAD per 1 M of enzyme. The isolated enzyme was used for the synthesis of 2,5-dihydroxypyridine, a precursor for the chemical synthesis of 5-aminolevulinic acid, which is applied as a plant growth hormone, a herbicide and in cancer therapy. A 1.8-kbp DNA fragment, which contains the ORF encoding 6-hydroxynicotinic acid 3-monooxygenase, was cloned, sequenced and expressed in Escherichia coli. The deduced 385 amino acid sequence of the cloned ORF is in agreement with the enzyme molecular mass, amino acid sequence of an internal peptide, contains a putative FAD-binding site and is homologous to similar flavoproteins such as salicylate 1-monoxygenase. PMID- 10091592 TI - Molecular characterization of the B' regulatory subunit gene family of Arabidopsis protein phosphatase 2A. AB - Type 2A serine/threonine protein phosphatases (PP2A) have been implicated as important mediators of a diverse array of reversible protein phosphorylation events in plants. We have identified a novel Arabidopsis gene (AtB' delta) which encodes a 55-kDa B' type regulatory subunit of PP2A. The protein encoded by this gene is 57-63% identical and 69-74% similar to the previously identified AtB' genes. The AtB' delta gene appears to be expressed in all Arabidopsis organs indicating its protein product has a basic housekeeping function in plant cells. Unlike certain mRNAs derived from the AtB' gamma gene, AtB' delta mRNAs do not fluctuate significantly in response to heat stress. Further analysis of cDNA sequences derived from the AtB' genes identified an alternatively spliced cDNA derived from AtB' gamma. This cDNA differs from the previously identified AtB' gamma cDNA by the absence of a 133-bp region in its 5' untranslated region. The missing 133-bp region appears to constitute an unspliced intron and its presence in the AtB' gamma gene was confirmed by PCR using Arabidopsis genomic DNA as a template. AtB' gamma mRNA containing the 133-bp intron accumulate in all Arabidopsis organs and their levels fluctuate differentially in response to heat stress. The 133-bp insert contains two short open reading frames and hence might serve as a translational control mechanism affecting AtB' gamma protein synthesis. Finally we show, using both the yeast two hybrid system and in vitro binding assays, that the B' subunit of Arabidopsis PP2A is able to associate with other PP2A subunits, supporting the notion that the B' protein serves as a regulator of PP2A activity in plants. PMID- 10091593 TI - Dynamic redistribution of STAT1 protein in IFN signaling visualized by GFP fusion proteins. AB - STAT proteins (signal transducers and activators of transcription) are a family of transcription factors which are used by many cytokines and cell growth factors for initiating gene expression. They are activated by tyrosine phosphorylation through the cytoplasmic domain of stimulated receptors. Upon phosphorylation STAT proteins dimerize, translocate to the nucleus and activate transcription by binding to specific recognition sites. Different cytokines activate different subsets of STATs and other signaling proteins. We have made use of green fluoresencent protein (GFP) fusion proteins to visualize the subcellular localization and trafficking of STAT1, STAT2 and p48 during interferon (IFN) stimulation and have analysed in detail STAT1-GFP trafficking in living cells. Analysis of GFP fusion proteins allowed the determination of time kinetics of subcellular trafficking in individual living cells. STAT1-GFP is indistinguishable from its wild-type protein displaying strong activity as transcriptional activator as well as the same time kinetics of transport to the nucleus and retreat to the cytoplasm. After prolonged exposure to IFN, STAT1-GFP is no longer retained in the nucleus and relocation to the cytoplasm is observed. Restimulation with the same type of IFN does not lead to repeated nuclear translocation of STAT1-GFP. STAT1 is not subject of inhibition, as restimulation with another type of IFN allows immediate reuse of previously activated STAT1 GFP. However, restimulation with the same type of IFN can be achieved when the primary stimulus is removed after a short induction period. This method of visualizing signal transduction reveals a considerable inhomogeneity with respect to the extent of STAT1-GFP shuttling within a clonal cell population, indicating that competence for full-blasted IFN response is restricted to a cellular subpopulation whereas other cells respond incompletely, retarded or not at all. PMID- 10091594 TI - Conformational aspects of HIV-1 integrase inhibition by a peptide derived from the enzyme central domain and by antibodies raised against this peptide. AB - Monospecific antibodies were raised against a synthetic peptide K159 (SQGVVESMNKELKKIIGQVRDQAEHLKTA) reproducing the segment 147-175 of HIV-1 integrase (IN). Synthesis of substituted and truncated analogs of K159 led us to identify the functional epitope reacting with antibodies within the C-terminal portion 163-175 of K159. Conformational studies combining secondary structure predictions, CD and NMR spectroscopy together with ELISA assays, showed that the greater is the propensity of the epitope for helix formation the higher is the recognition by anti-K159. Both the antibodies and the antigenic peptide K159 exhibited inhibitory activities against IN. In contrast, neither P159, a Pro containing analog of K159 that presents a kink around proline but with intact epitope conformation, nor the truncated analogs encompassing the epitope, were inhibitors of IN. While the activity of antibodies is restricted to recognition of the sole epitope portion, that of the antigenic K159 likely requires interactions of the peptide with the whole 147-175 segment in the protein [Sourgen F., Maroun, R.G., Frere, V., Bouziane, A., Auclair, C., Troalen, F. & Fermandjian, S. (1996) Eur. J. Biochem. 240, 765-773]. Actually, of all tested peptides only K159 was found to fulfill condition of minimal number of helical heptads to achieve the formation of a stable coiled-coil structure with the IN 147-175 segment. The binding of antibodies and of the antigenic peptide to this segment of IN hampers the binding of IN to its DNA substrates in filter-binding assays. This appears to be the main effect leading to inhibition of integration. Quantitative analysis of filter-binding assay curves indicates that two antibody molecules react with IN implying that the enzyme is dimeric within these experimental conditions. Together, present data provide an insight into the structure-function relationship for the 147-175 peptide domain of the enzyme. They also strongly suggest that the functional enzyme is dimeric. Results could help to assess models for binding of peptide fragments to IN and to develop stronger inhibitors. Moreover, K159 antibodies when expressed in vivo might exhibit useful inhibitory properties. PMID- 10091595 TI - Origin of the integrin-mediated signal transduction. Functional studies with cell cultures from the sponge Suberites domuncula. AB - Sponges (phylum Porifera) represent the phylogenetically oldest metazoan animals. Recently, from the marine sponge Geodia cydonium a first cDNA encoding a putative integrin receptor molecule was isolated. In the present study basic functional experiments have been conducted to test the hypothesis that in sponges integrin polypeptides also function as adhesion molecules and as outside-in signaling molecules. The sponge Suberites domuncula has been used for the experiments because from this sponge only has a cell culture been established. Here we report that aggregation factor (AF)-mediated cell-cell adhesion is blocked by the RGDS peptide which is known to interact with beta integrin. Both RGDS and AF were found to stimulate DNA synthesis within 24 h. The beta subunit of the integrin receptor was cloned from S. domuncula; the estimated 91-kDa molecule comprises the characteristic signatures. Evolutionary conservation of the beta integrin was assessed by comparison with corresponding beta integrin subunits from evolutionary higher metazoan taxa. Addition of RGDS or of AF to isolated cells of S. domuncula causes a rapid (within 1-2 min) increase in the intracellular Ca2+ concentration which is further augmented in the presence of Ca2+. Furthermore, incubation of the cells with RGDS or AF causes an activation of the GTP-binding protein Ras. In addition it is shown that after a prolonged incubation of the cells with RGDS and AF the expression of the genes coding for Ras and for calmodulin is upregulated. These results suggest that the integrin receptor functions in the sponge system not only as adhesion molecule but also as a molecule involved in outside-in signaling. PMID- 10091597 TI - Crystal structure of a hybrid between ribonuclease A and bovine seminal ribonuclease--the basic surface, at 2.0 A resolution. AB - A variant of bovine pancreatic ribonuclease A has been prepared with seven amino acid substitutions (Q55K, N62K, A64T, Y76K, S80R, E111G, N113K). These substitutions recreate in RNase A the basic surface found in bovine seminal RNase, a homologue of pancreatic RNase that diverged some 35 million years ago. Substitution of a portion of this basic surface (positions 55, 62, 64, 111 and 113) enhances the immunosuppressive activity of the RNase variant, activity found in native seminal RNase, while substitution of another portion (positions 76 and 80) attenuates the activity. Further, introduction of Gly at position 111 has been shown to increase the catalytic activity of RNase against double-stranded RNA. The variant and the wild-type (recombinant) protein were crystallized and their structures determined to a resolution of 2.0 A. Each of the mutated amino acids is seen in the electron density map. The main change observed in the mutant structure compared with the wild-type is the region encompassing residues 16-22, where the structure is more disordered. This loop is the region where the polypeptide chain of RNase A is cleaved by subtilisin to form RNase S, and undergoes conformational change to allow residues 1-20 of the RNase to swap between subunits in the covalent seminal RNase dimer. PMID- 10091596 TI - Protection of mice against a lethal influenza virus challenge after immunization with yeast-derived secreted influenza virus hemagglutinin. AB - The A/Victoria/3/75 (H3N2-subtype) hemagglutinin (HA) gene was engineered for expression in Pichia pastoris as a soluble secreted molecule. The HA cDNA lacking the C-terminal transmembrane anchor-coding sequence was fused to the Saccharomyces cerevisiae alpha-mating factor secretion signal and placed under control of the methanol-inducible P. pastoris alcohol oxidase 1 (AOX1) promoter. Growth of transformants on methanol-containing medium resulted in the secretion of recombinant non-cleaved soluble hemagglutinin (HA0s). Remarkably, the pH of the induction medium had an important effect on the expression level, the highest level being obtained at pH 8.0. The gel filtration profile and the reactivity against a panel of different HA-conformation specific monoclonal antibodies indicated that HA0s was monomeric. Analysis of the N-linked glycans revealed a typical P. pastoris type of glycosylation, consisting of glycans with 10-12 glycosyl residues. Mice immunized with purified soluble hemagglutinin (HA0s) showed complete protection against a challenge with 10 LD50 of mouse-adapted homologous virus (X47), whereas all control mice succumbed. Heterologous challenge with X31 virus [A/Aichi/2/68 (H3N2-subtype)], resulted in significantly higher survival rates in the immunized group compared with the control group. These results, together with the safety, reliability and economic potential of P. pastoris, as well as the flexibility and fast adaptation of the expression system may allow development of an effective recombinant influenza vaccine. PMID- 10091598 TI - Lipopolysaccharide stimulates HepG2 human hepatoma cells in the presence of lipopolysaccharide-binding protein via CD14. AB - Lipopolysaccharide (LPS)-binding protein (LBP), an opsonin for activation of macrophages by bacterial LPS, is synthesized in hepatocytes and is known to be an acute phase protein. Recently, cytokine-induced production of LBP was reported to increase 10-fold in hepatocytes isolated from LPS-treated rats, compared with those from normal rats. However, the mechanism by which the LPS treatment enhances the effect of cytokines remains to be clarified. In the present study, we examined whether LPS alone or an LPS/LBP complex directly stimulates the hepatocytes, leading to acceleration of the cytokine-induced LBP production. HepG2 cells (a human hepatoma cell line) were shown to express CD14, a glycosylphosphatidylinositol-anchored LPS receptor, by both RT/PCR and flow cytometric analyses. An LPS/LBP complex was an effective stimulator for LBP and CD14 production in HepG2 cells, but stimulation of the cells with either LPS or LBP alone did not significantly accelerate the production of these proteins. The findings were confirmed by semiquantitative RT/PCR analysis of mRNA levels of LBP and CD14 in HepG2 cells after stimulation with LPS alone and an LPS/LBP complex. In addition, two monoclonal antibodies (mAbs) to CD14 (3C10 and MEM-18) inhibited LPS/LBP-induced cellular responses of HepG2 cells. Furthermore, prestimulation of HepG2 cells with LPS/LBP augmented cytokine-induced production and gene expression of LBP and CD14. All these findings suggest that an LPS/LBP complex, but not free LPS, stimulates HepG2 cells via CD14 leading to increased basal and cytokine-induced LBP and CD14 production. PMID- 10091599 TI - The structure of an entire noncovalent immunoglobulin kappa light-chain dimer (Bence-Jones protein) reveals a weak and unusual constant domains association. AB - Monoclonal free light chains secreted in immunoproliferative disorders are frequently involved in renal complications, including a specific proximal tubule impairment, Fanconi's syndrome. The latter is characterized in most cases by intracellular crystallization including a light-chain variable-domain fragment which resists lysosomal proteases. Bence-Jones protein (BJP) DEL was isolated from a patient with myeloma-associated Fanconi's syndrome. The crystal structure of this human kappa immunoglobulin light-chain noncovalent dimer was determined using molecular replacement with the structure of molecule REI, as the variable domain, and that of BJP LOC as the constant domain. To our knowledge, DEL is the first complete kappa BJP structure described to date. The R-factor is 20.7% at 2.8 A resolution. The BJP DEL dimer was compared with other light-chain dimers and with Fab fragments with a kappa light chain. Although the domain-folding pattern was similar, the relative positions of the constant domains differed. BJP DEL showed a noncanonical quaternary structural arrangement which may be attributable to the poor CL-CL affinity and lack of an interchain disulfide bridge, combined with the conformational editing effect of the crystal-packing forces. Our results suggest that, in the absence of a disulfide bridge, most BJP CLs are probably mobile in solution. This may explain their high susceptibility to proteases and the absence of naturally occurring crystals for these dimers. Furthermore, these findings of an unusual quaternary structure of an immunoglobulin light-chain association extend our knowledge about the large and highly diverse structures of the immunoglobulin superfamily. PMID- 10091600 TI - The epidermal growth factor precursor. A calcium-binding, beta-hydroxyasparagine containing modular protein present on the surface of platelets. AB - Various human body fluids and secretions contain a soluble form of the epidermal growth factor (EGF) precursor. The EGF precursor molecule contains eight EGF modules in addition to EGF itself. Using monoclonal antibodies specific for the EGF modules 7 and 8, we have purified the soluble form of the EGF precursor from human urine to homogeneity. The protein was shown to have a molecular mass of about 160 kDa and the N-terminal sequence SAPNHWSXPE. EGF modules 2, 7 and 8 of the precursor have the consensus sequence for post-translational beta hydroxylation of Asp/Asn residues. We identified the presence of erythro-beta hydroxy-aspartic acid (Hya) in acid hydrolysates of the EGF precursor (2.4 M.M protein-1). As the DNA sequence encodes Asn in the corresponding position, the Hya represents erythro-beta-hydroxyasparagine (Hyn). The Hyn-containing modules have a consensus calcium-binding motif immediately N-terminal of the first Cys residue. The synthetic EGF module 2 (residues 356-395) of the EGF precursor was found to bind calcium with low affinity, Kd approximately 3.5 mM, i.e. similar to the affinity of other isolated calcium-binding EGF modules. EGF module 7, when part of the intact protein, was found to bind Ca2+ with a Kd approximately 0.2 microM, i.e. approximately 10(4)-fold higher than that of isolated EGF modules presumably due to the influence of neighboring modules. We have detected EGF precursor in platelet-rich plasma and demonstrated it to be associated to platelets. The platelets were found to have 30-160 EGF molecules each. PMID- 10091601 TI - Delta 9-fatty acid desaturase from arachidonic acid-producing fungus. Unique gene sequence and its heterologous expression in a fungus, Aspergillus. AB - Based on the sequence information for delta 9-desaturase genes (from rat, mouse and yeast), which are involved in the desaturation of palmitic acid and stearic acid to palmitoleic acid and oleic acid, respectively, the corresponding cDNA and genomic gene were cloned from the fungal strain, Mortierella alpina 1S-4, which industrially produces arachidonic acid. There was a cytochrome b5-like domain linked to the carboxyl terminus of this Mortierella desaturase, as also seen in the yeast delta 9-desaturase. The Mortierella delta 9-desaturase genomic gene had only one intron, in which a novel phenomenon was observed: there was a GC-end at the 5'-terminus instead of a GT-end that is, in general, found in introns of eukaryotic genes. The full-length cDNA clone was expressed under the control of an amyB promoter in a filamentous fungus, Aspergillus oryzae, resulting in drastic changes in the fatty acid composition in the transformant cells; the contents of palmitoleic acid (16:1) and oleic acid (18:1) increased significantly, with accompanying decreases in palmitic acid (16:0) and stearic acid (18:0). These changes were controlled by the addition of maltose as a carbon source to the medium. Also, the expression of the gene caused a significant change in the lipid composition in the Aspergillus transformant. Genomic Southern blot analysis of the transformant with the Mortierella delta 9-desaturase gene as a probe confirmed the integration of this gene into the genome of A. oryzae. PMID- 10091602 TI - Genetic and biochemical characterization of phosphofructokinase from the opportunistic pathogenic yeast Candida albicans. AB - We have used the two PFK genes of Saccharomyces cerevisiae encoding the alpha and beta-subunit of the enzyme phosphofructokinase (Pfk) as heterologous probes to isolate fragments of the respective genes from the dimorphic pathogenic fungus Candida albicans. The complete coding sequences were obtained by combining sequences of chromosomal fragments and fragments obtained by inverse polymerase chain reaction (PCR). The CaPFK1 and CaPFK2 comprise open reading frames of 2961 bp and 2838 bp, respectively, encoding Pfk subunits with deduced molecular masses of 109 kDa and 104 kDa. The genes presumably evolved by a duplication event from a prokaryotic type ancestor, followed by another duplication. Heterologous expression in S. cerevisiae revealed that each gene alone was able to complement the glucose-negative phenotype of a pfk1 pfk2 double mutant. In vitro Pfk activity in S. cerevisiae was not only obtained after coexpression of both genes, but also in conjunction with the respective complementary subunits from S. cerevisiae. This indicates the formation of functional hetero-oligomers consisting of C. albicans and S. cerevisiae Pfk subunits. In C. albicans, specific Pfk activity was shown to decrease twofold upon induction of hyphal growth. CaPfk cross-reacts with a polyclonal antiserum raised against ScPfk and displays similar allosteric properties, i.e. inhibition by ATP and activation by AMP and fructose 2,6-bisphosphate. PMID- 10091604 TI - Isolation and structural analysis of phosphorylated oligosaccharides obtained from Escherichia coli J-5 lipopolysaccharide. AB - The chemical structure of the phosphorylated lipopolysaccharide (LPS) of Escherichia coli J-5 was investigated because it is of biomedical interest in the context of septic shock, a syndrome often encountered in nosocomial infections with gram-negative pathogens. The successive de-O-acylation and de-N-acylation of J-5 LPS yielded phosphorylated oligosaccharides which represent the complete carbohydrate backbone. Five compounds were separated by high-performance anion exchange chromatography and analysed by one-dimensional and two-dimensional homonuclear and heteronuclear 1H-NMR, 13C-NMR and 31P-NMR spectroscopy. The main product was a nonasaccharide of the structure alpha-D-Glcp-(1-->3)-[alpha-D-GlcpN (1-->7)-alpha-L,D-Hepp-(1-->7)]-alpha-L,D-Hepp-(1-->3)-alpha -L, D-Hepp-4P-(1- >5)-[alpha-Kdop-(2-->4)]-alpha-Kdop-(2-- >6)-beta-D-GlcpN-4p- (1-->6)-alpha-D GlcN-1P wherein all sugars are present as D-pyranoses. Hep and Kdo represent L glycero-D-manno-heptose and 3-deoxy-D-manno-oct-2-ulosonic acid, respectively. In addition, two octasaccharides and two heptasaccharides were isolated that were partial structures of the nonasaccharide. In one octasaccharide the terminal alpha-D-GlcpN was missing and an additional phosphate group linked to O4 of the branched heptose was present, whereas in the other octasaccharide the side-chain Kdo was missing. In both heptasaccharides the side-chain alpha-D-GlcpN-(1-->7)-L alpha-D-Hepp-disaccharide was absent; they differed in their phosphate substitution. Whereas both heptasaccharides contained two phosphates in the lipid A backbone (beta-1,6-linked GlcpN-disaccharide at the reducing end) and one phosphate group at O4 of the first heptose, only one of them was additionally substituted with phosphate at O4 of the second heptose. PMID- 10091603 TI - Stimulation of premature retinoic acid synthesis in Xenopus embryos following premature expression of aldehyde dehydrogenase ALDH1. AB - In order for nuclear retinoic acid receptors to mediate retinoid signaling, the ligand retinoic acid must first be produced from its vitamin A precursor retinal. Biochemical studies have shown that retinal can be metabolized in vitro to retinoic acid by members of the aldehyde dehydrogenase enzyme family, including ALDH1. Here we describe the first direct evidence that ALDH1 plays a physiological role in retinoic acid synthesis by analysis of retinoid signaling in Xenopus embryos, which have plentiful stores of maternally derived retinal. The Xenopus ALDH1 gene was cloned and shown to be highly conserved with chick and mammalian homologs. Xenopus ALDH1 was not expressed at blastula and gastrula stages, but was expressed at the neurula stage. We used a retinoic acid bioassay to demonstrate that retinoic acid is normally undetectable in embryos from fertilization to the initial gastrula stage, but that a tremendous increase in retinoic acid occurs during neurulation when ALDH1 is first expressed. Overexpression of ALDH1 by injection of Xenopus embryos with mRNAs encoding the mouse, chick or Xenopus ALDH1 homologs induced high levels of retinoic acid detection during the blastula stage. Thus, premature expression of ALDH1 stimulates premature synthesis of retinoic acid. These findings reveal an important conserved role for ALDH1 in retinoic acid synthesis in vivo, and demonstrate that conversion of retinoids from the aldehyde form to the carboxylic acid form is a crucial regulatory step in retinoid signaling. PMID- 10091605 TI - The covalent attachment of polyamines to proteins in plant mitochondria. AB - Plant mitochondria from both potato and mung bean incorporated radioactivity into acid insoluble material when incubated with labelled polyamines (spermine, spermidine and putrescine). Extensive washing of mitochondrial precipitates with trichloroacetic acid and the excess of cold polyamine failed to remove bound radioactivity. Addition of nonradioactive polyamine stopped further incorporation of radioactivity but did not release radioactivity already bound. The radioactivity is incorporated into the membrane fraction. The labelling process has all the features of an enzymatic reaction: it is long lasting with distinctive kinetics peculiar to each polyamine, it is temperature dependent and is affected by N-ethylmaleimide. The latter inhibits the incorporation of putrescine but stimulates the incorporation of spermine and spermidine. Treatment of prelabelled mitochondria with pepsin releases bound radioactivity thus indicating protein to be the ligand for the attachment of polyamines. HPLC of mitochondrial hydrolysates revealed that the radioactivity bound to mitochondria is polyamines; traces of acetyl polyamines were also found in some samples. On autoradiograms of SDS/PAGE gels several radioactive bands of proteins were detected. Protein sequencing of labelled spots from a 2D gel gave a sequence which was 60% identical to catalase. We suggest that the attachment of polyamines to mitochondrial proteins occurs cotranslationally possibly via transglutaminases. PMID- 10091606 TI - The tricarboxylic acid cycle of Helicobacter pylori. AB - The composition and properties of the tricarboxylic acid cycle of the microaerophilic human pathogen Helicobacter pylori were investigated in situ and in cell extracts using [1H]- and [13C]-NMR spectroscopy and spectrophotometry. NMR spectroscopy assays enabled highly specific measurements of some enzyme activities, previously not possible using spectrophotometry, in in situ studies with H. pylori, thus providing the first accurate picture of the complete tricarboxylic acid cycle of the bacterium. The presence, cellular location and kinetic parameters of citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate oxidase, fumarate reductase, fumarase, malate dehydrogenase, and malate synthase activities in H. pylori are described. The absence of other enzyme activities of the cycle, including alpha-ketoglutarate dehydrogenase, succinyl-CoA synthetase, and succinate dehydrogenase also are shown. The H. pylori tricarboxylic acid cycle appears to be a noncyclic, branched pathway, characteristic of anaerobic metabolism, directed towards the production of succinate in the reductive dicarboxylic acid branch and alpha-ketoglutarate in the oxidative tricarboxylic acid branch. Both branches were metabolically linked by the presence of alpha-ketoglutarate oxidase activity. Under the growth conditions employed, H. pylori did not possess an operational glyoxylate bypass, owing to the absence of isocitrate lyase activity; nor a gamma-aminobutyrate shunt, owing to the absence of both gamma-aminobutyrate transaminase and succinic semialdehyde dehydrogenase activities. The catalytic and regulatory properties of the H. pylori tricarboxylic acid cycle enzymes are discussed by comparing their amino acid sequences with those of other, more extensively studied enzymes. PMID- 10091607 TI - Regulation of cyclooxygenase-2 expression in human mesangial cells- transcriptional inhibition by IL-13. AB - Activated mesangial cells may play an important part in glomerulonephritis. Cytokines can modulate the release of prostanoids by human mesangial cells (HMC). We have investigated the effects of pro-inflammatory stimuli on COX-2 expression in HMC and its potential modulation by interleukin (IL)-13. HMC released increased amounts of prostaglandin E2 (PGE2) after treatment with several combinations of IL-1 beta, tumor necrosis factor (TNF)-alpha and/or lipopolysaccharide. Increases in PGE2 correlated with the induction of COX-2 protein expression. The accumulation of PGE2 elicited by a combination of IL-1 beta/TNF-alpha correlated closely with the temporal pattern of COX-2 protein expression, which reflected the induction of COX-2 mRNA. IL-13 inhibited IL-1 beta/TNF-alpha-elicited PGE2 production, as well as COX-2 protein and mRNA expression in a concentration-dependent fashion. With 50 ng.mL-1 IL-13 these parameters were inhibited by 90, 80 and 84%, respectively. In HMC transfected with the 5' regulatory region of the COX-2 gene, IL-13 suppressed cytokine induced promoter activation. Our results suggest that COX-2 expression is a major target for IL-13-mediated abrogation of prostaglandin release by HMC and support that this process takes place by transcriptional inhibition of the COX-2 gene. PMID- 10091608 TI - Multiple binding sites in the growth factor receptor Xmrk mediate binding to p59fyn, GRB2 and Shc. AB - Melanoma formation in Xiphoporus is initiated by overexpression of the EGFR related receptor tyrosine kinase Xmrk (Xiphoporus melanoma receptor kinase). This receptor is activated in fish melanoma as well as in a melanoma-derived cell line (PSM) resulting in constitutive Xmrk-mediated mitogenic signaling. In order to define the underlying signaling pathway(s), triggered by the activated Xmrk receptor, we attempted to identify its physiological substrates. Examination of the Xmrk carboxyterminus for putative tyrosine autophosphorylation sites revealed the presence of potential binding motifs for GRB2 as well as for Shc. Binding of these adaptor proteins to the Xmrk receptor was detected in vitro and in cells expressing the mrk kinase. The GRB2 and Shc interactions with the receptor could be disrupted individually by phosphotyrosine peptides containing putative Xmrk autophosphorylation sites, indicating direct binding of both proteins. Recruitment of GRB2 by the constitutively activated Xmrk receptor led to strong MAP kinase activation in Xiphoporus melanoma cells. We also identified a high affinity binding site for src-kinases (pYEDL) in the Xmrk carboxyterminus. Competition experiments with phosphopeptides comprising this site confirmed that it is used for high-affinity binding of Xiphoporus fyn (Xfyn) to Xmrk in melanoma cells. Thus, Xmrk can initiate different signaling pathways by using multiple substrate-binding sites to trigger proliferation of pigment cells. PMID- 10091609 TI - Primary structure and biochemical characterization of yeast GTPase-activating proteins with substrate preference for the transport GTPase Ypt7p. AB - Small GTPases of the Ypt/Rab family are regulators of vesicular protein trafficking in exo-and endocytosis. GTPase-activating proteins (GAP) play an important role as down regulators of GTPases. We here report the molecular cloning of a novel GAP-encoding gene (GYP7, for GAP for Ypt7) by high expression from a Saccharomyces cerevisiae genomic library. The GYP7 gene encodes a hydrophilic protein with a molecular mass of 87 kDa. Comparison of its primary sequence with that of the three other known GAPs for transport GTPases, the yeast Gyp6 and Gyp1 proteins and the Rab3A-GAP from rat brain, shows similarity between the yeast GAPs only. Like GYP6 and GYP1, GYP7 is not essential for yeast cell viability. Gyp7p was able to most effectively accelerate the intrinsic GTPase activity of Ypt7p. It was also active, but to a lesser extent, on Ypt31p, Ypt32p and Ypt1p. Ypt6p, Sec4p and the human H-Ras protein did not serve as substrates. We also report the identification and cloning of a gene from the dimorphic yeast Yarrowia lipolytica that encodes a protein whose primary structure and biochemical activity are significantly related to those of Gyp7p from baker's yeast. PMID- 10091610 TI - Cerebral implantation in movement disorders: state of the art. PMID- 10091611 TI - The vulnerability of nigral neurons to Parkinson's disease is unrelated to their intrinsic capacity for dopamine synthesis: an in situ hybridization study. AB - The contribution of the dopamine-synthetic capacity of nigral neuronal subregions to their vulnerability to degeneration in idiopathic Parkinson's disease (IPD) was explored using semiquantitative in situ hybridization to study expression of mRNA encoding the rate-limiting dopamine synthetic enzyme, tyrosine hydroxylase (TH). Expression of mRNA, the structural protein, beta-tubulin, and the glycolytic enzyme, fructose-1,6, biphosphate aldolase (aldolase C) was studied in parallel in individual neurons of the substantia nigra pars compacta (SNc) in matched groups of IPD and control subjects. TH mRNA expression was found to be heterogeneously expressed in nigral neurons in control and IPD subjects. There was no significant difference in mean values for TH mRNA expression between control and IPD cases and none between nigral subregions, either in control subjects or in established IPD subjects in this study, but there was evidence for a selective upregulation of TH mRNA expression in non-melanized neurons in IPD. There was no relationship between TH mRNA expression disease duration or L-dopa dosage in the IPD group. Mean TH mRNA values for two additional 40-year-old control subjects fell within the range of values of the aged-control group. Aldolase C and beta-tubulin expression did not differ between control and IPD groups or between nigral subregions. These findings suggest that regulation of dopamine synthesis at the level of the cell body does not play a part in determining the pattern of nigral cell vulnerability in IPD. The heterogeneous pattern of TH synthesis was not age-dependent and may be of physiological significance in nigral function. There was no evidence for compensatory upregulation of TH synthesis in surviving melanized neurons in IPD but non melanized neurons may be involved in this process. Surviving nigral neurons in IPD appear to retain the capacity for normal aldolase C and beta-tubulin peptide synthesis. Long-term L-dopa treatment does not appear to compromise normal function of nigral dopaminergic neurons. PMID- 10091612 TI - Variations in the monoamine oxidase B (MAOB) gene are associated with Parkinson's disease. AB - The monoamine oxidase B gene (MAOB; Xp15.21-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of MAOB polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with PD and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with PD (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (GT) repeat alleles > or =188 base pairs in the intron 2 marker of the MAOB gene were significantly associated with PD (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with PD (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort. PMID- 10091613 TI - Lack of allelic association of dopamine D4 receptor gene polymorphisms with Parkinson's disease in a Chinese population. AB - Parkinson's disease (PD) is a neurodegenerative disease caused by a multitude of environmental, neurochemical, and genetic factors. The gene for human dopamine D4 receptor (DRD4) has been considered as a plausible candidate for the pathogenesis of PD. Different dopamine D4 receptor allelic forms have variable affinity toward certain neuroleptics such as clozapine, suggesting a role for dopamine D4 receptors in neurologic disorders. To test the hypothesis that the DRD4 polymorphism is associated with the susceptibility to Parkinson's disease, we have examined differences in allele frequencies of different DRD4 polymorphisms in 101 Chinese patients with PD and in 105 age-matched control subjects in Hong Kong. The DRD4 gene was analyzed by a non-radioactive polymerase chain reaction based Southern hybridization with chemiluminescence detection. The number of polymorphic 48 base pair tandem repeats in exon 3 was identified in each study subject. The DRD4 alleles with high frequencies in the control subjects are 4 repeat allele (72.4%), 2-repeat allele (21.4%), and 7-repeat allele (3.8%) which accounted for over 97% of the total alleles in the elderly Chinese population. The most prevalent genotype in the control subjects is the 4/4 (47.6%), followed by 4/2 (38.6), 4/7 (7.6%), and 2/2 (3.0%). None of the variable number tandem repeat polymorphism showed evidence for genetic association with Parkinson's disease. PMID- 10091614 TI - CYP2D6 polymorphism and Parkinson's disease susceptibility. AB - Following the recent identification of multiple novel mutations and alleles of the cytochrome P450 CYP2D6 gene which cause decreased, increased, or absent enzyme activity, we re-examined the controversial hypothesis of a role of the CYP2D6 polymorphism in Parkinson's disease (PD) susceptibility. For this purpose, a strategy based on PCR-SSCP and RFLP analyses allowing the detection of all known CYP2D6 alleles was performed in DNA from 109 patients with sporadic PD. This strategy was also applied to DNA from 68 members of PD families including 18 affected and 50 unaffected members. Seventeen mutations occurring alone or in various combination on 14 alleles of CYP2D6 have been identified in patients with sporadic PD. Moreover, 12 mutations and nine alleles of the gene have been characterized in members of PD families. No significant difference was observed when the distribution of mutations and alleles of CYP2D6 was compared between the PD patients and 514 control subjects previously analyzed using the same strategy. There was also no difference in the distribution of phenotypes predicted from genotypes between both groups. In addition, when the distribution of CYP2D6 genotypes was compared, no difference between affected and unaffected members of PD families was observed. These data indicate that CYP2D6 polymorphism is not a susceptibility factor to PD. PMID- 10091615 TI - Fatigue in patients with Parkinson's disease. AB - OBJECTIVE: To compare the prevalence of fatigue in patients with Parkinson's disease (PD) with that in healthy elderly people and to explore the suggestion that fatigue is an independent symptom of PD. DESIGN: Questionnaire survey. SETTING: Community-based population. PATIENTS AND CONTROL SUBJECTS: 233 patients derived from a prevalence study in the county of Rogaland, Norway and 100 healthy elderly people with the same age and sex distribution as the patients with PD. MAIN OUTCOME MEASURE: A score for fatigue was obtained by combining the results from the rating scale for low energy in the Nottingham Health Profile (NHP) with the results obtained from a 7-point scale devised to evaluate fatigue. RESULTS: 44.2% of the patients with PD and 18% of the healthy elderly control subjects reported fatigue. Fatigue was associated with depression, dementia, disease severity, disease duration, levodopa dose, and the use of sleeping pills. In a multivariate analysis, only depressive symptoms reached statistical significance. The prevalence of fatigue in patients with PD who were not depressed, demented, or had a sleeping disturbance was similar to that found in the total PD population. CONCLUSION: Fatigue is a common symptom in PD. Although fatigue correlated with depressive symptoms, patients with PD who did not have depression, dementia, or sleep disturbances also reported a high prevalence of this symptom. This supports the hypothesis that fatigue is an independent symptom of PD overlapping with, but not causally related to, the concurrence of depressive symptoms. PMID- 10091616 TI - Worsening of levodopa-induced dyskinesias by motor and mental tasks. AB - Ten patients who had Parkinson's disease with disabling dyskinesia were included in this study to evaluate the role of mental (mental calculation) and motor (flexion/extension of right fingers, flexion/extension of left fingers, flexion/extension of the neck, speaking aloud) tasks on the worsening of peak dose dyskinesia following administration of an effective single dose of apomorphine. Compared with the score at rest (1.3+/-0.3), a significant aggravation of the dyskinesia score was observed during speaking aloud (5.2+/ 1.1, p<0.05), movements of right (4.5+/-1.0, p<0.05) and left (3.7+/-0.8, p<0.05) fingers, movements of the neck (5.1+/-1.0, p<0.05), and mental calculation (3.1+/ 1.0, p<0.05). These results suggest that activation tasks such as "speaking aloud" could be used for objective assessment of dyskinesia severity. PMID- 10091617 TI - Selegiline-induced postural hypotension in Parkinson's disease: a longitudinal study on the effects of drug withdrawal. AB - OBJECTIVES: The United Kingdom Parkinson's Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinson's disease (PD) randomized to receive 10 mg selegiline per day and L-dopa compared with those taking L-dopa alone. Recently, we found that therapy with selegiline and L-dopa was associated with selective systolic orthostatic hypotension which was abolished by withdrawal of selegiline. This unwanted effect on postural blood pressure was not the result of underlying autonomic failure. The aims of this study were to confirm our previous findings in a separate cohort of patients and to determine the time course of the cardiovascular consequences of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension. METHODS: The cardiovascular responses to standing and head-up tilt were studied repeatedly in PD patients receiving selegiline and as the drug was withdrawn. RESULTS: Head-up tilt caused systolic orthostatic hypotension which was marked in six of 20 PD patients on selegiline, one of whom lost consciousness with unrecordable blood pressures. A lesser degree of orthostatic hypotension occurred with standing. Orthostatic hypotension was ameliorated 4 days after withdrawal of selegiline and totally abolished 7 days after discontinuation of the drug. Stopping selegiline also significantly reduced the supine systolic and diastolic blood pressures consistent with a previously undescribed supine pressor action. CONCLUSION: This study confirms our previous finding that selegiline in combination with L-dopa is associated with selective orthostatic hypotension. The possibilities that these cardiovascular findings might be the result of non-selective inhibition of monoamine oxidase or of amphetamine and metamphetamine are discussed. PMID- 10091618 TI - Reduction of Parkinsonian signs in patients with Parkinson's disease by dopaminergic versus anticholinergic single-dose challenges. AB - We investigated the effect of an anticholinergic (biperiden) and a dopamine agonist (apomorphine) on tremor, rigidity, and akinesia in patients with idiopathic Parkinson's disease. In a standardized, crossover study design 17 patients received single-dose challenges of 5 mg biperiden intravenously and a previously determined dose of apomorphine subcutaneously on 2 consecutive days. Resting (RT), postural (PT), and action tremor (AT) were assessed using spectral analysis of accelerometer data, and Unified Parkinson's Disease Rating Scale (UPDRS) scores for rigidity and akinesia were determined before and after administration of the study drug. Both single-dose challenges significantly reduced the amplitude of RT, PT, and AT, but only apomorphine significantly reduced UPDRS scores for rigidity and akinesia. In only one patient was tremor reduced by the dopamine agonist but not by the anticholinergic. We found that anticholinergic and dopaminergic agents are both effective in reducing tremor in IPD, and there was no evidence for a selective anticholinergic responsiveness of parkinsonian tremor. Akinesia and rigidity, on the other hand, were not improved by biperiden. We therefore conclude that dopaminergic substances are as effective as anticholinergics in patients with parkinsonian tremor and additionally improve other parkinsonian signs. PMID- 10091619 TI - Stereotactic posteroventral pallidotomy: clinical methods and results at 1-year follow up. AB - Twenty consecutive patients with idiopathic Parkinson's disease underwent stereotactic posteroventral pallidotomy. Schwab and England ADL scores in the "off" state were improved by 18% and in the "on" state the scores declined by 2%. Three patients also reported marked improvement in "off" state dystonia. One-year data are available on 12 patients who underwent evaluations according to the Core Assessment Program for Intracerebral Transplantation protocol preoperatively and at 3, 6, and 12 months after surgery. Significant improvements in Unified Parkinson's Disease Rating Scale sections II and III scores in the "off" state, composite "off" state scores of bradykinesia and rigidity, contralateral tremor in the "off" state, and contralateral dyskinesias were observed. Although there was reduction in the daily levodopa dose, this did not reach statistical significance. Major complications (15%) included hemiparesis (one of 20) and visual field cuts (two of 20); minor complications (45%) included mild cognitive dysfunction (four of 20), reading difficulty not related to visual disturbance (one of 20), and 5-10 lb weight gain (four of 20). PMID- 10091620 TI - Parkinsonism associated with Sjogren's syndrome: three cases and a review of the literature. AB - Sjogren's syndrome (SS) is a common multisystem autoimmune disorder. As with other autoimmune disorders such as systemic lupus erythematosus (SLE), SS has been associated with a wide range of neurologic abnormalities. Parkinsonism has been reported previously in five SS patients. We present three additional cases of SS with parkinsonism. PMID- 10091621 TI - Apomorphine and levodopa challenge in patients with a focal midbrain lesion. AB - Three patients who presented with parkinsonian signs resulting from a focal midbrain lesion are reported. In all patients parkinsonian features occurred acutely and improved following acute challenge with apomorphine but not with levodopa. Remission of parkinsonian signs occurred spontaneously to a different degree. Inconsistent clinical response following administration of levodopa has been well documented in patients with focal midbrain lesions associated with parkinsonian signs; however, the efficacy of apomorphine has not been tested before. Anatomic or etiologic features do not allow us to predict in which cases parkinsonian signs secondary to a midbrain lesion would respond to levodopa or to dopamine agonists. A trial with apomorphine is warranted in all such cases. PMID- 10091622 TI - A kinematic study of progressive apraxia with and without dementia. AB - BACKGROUND: Prehension is an ideationally simple, cued movement requiring proximal (transport) and distal (manipulation) limb control. Patients with this syndrome of progressive apraxia are unable to perform many activities of daily living that require prehension. There is little known about how this syndrome kinematically disrupts such movements or whether concurrent dementia might play a critical role. OBJECTIVES: Using prehension as a paradigm for an ideationally simple, cued functional movement, we sought to (1) characterize the kinematic features of progressive apraxia in general, and (2) contrast the kinematic differences between apraxic patients with and without dementia. METHODS: Eight patients with the syndrome of progressive apraxia (including five without dementia, one of whom had autopsy-confirmed corticobasal ganglionic degeneration, and three with dementia, one of whom had autopsy-confirmed Alzheimer's disease) were compared with eight age-matched normal control subjects on a prehension task using an Optotrak camera system. RESULTS: Compared with control subjects, apraxic subjects had slowed reaction time, slowed transport and manipulation kinematics, greater lateral deviation from the linear prehension trajectory, greater intermanual asymmetry, motor programming disturbances, and mild transport manipulation uncoupling. There were minor differences between the apraxia subgroups such as greater intermanual differences and impaired grip aperture velocity in the nondemented group, and overall slower movement in the demented group. CONCLUSIONS: There are major kinematic differences between apraxic and control subjects on a prehension task. The differences between clinical pathologic subgroups are more subtle, and the movement disorder itself rather than concurrent dementia is the greatest determinant of motor disability. PMID- 10091623 TI - Three-dimensional measurement of essential tremor. AB - A mechanical linkage device was used to measure the three-dimensional position of the fingertip during a postural task. Thirty patients with essential tremor were tested simultaneously with the device, uniaxial accelerometry, and clinical tremor measures. Eighteen patients were tested again 16+/-4 days later. The device accurately recorded the three-dimensional behavior of essential tremor. Measures from the device included mean three-dimensional velocity, mean three dimensional dispersion, and power of the three-dimensional acceleration. The logarithms of these measures were strongly correlated (r = .841-.984) with all clinical measures including self-reported tremor disability. The device measures were reliable within and between testing sessions (intraclass correlation coefficients = .971-.977). The performance of the device was superior to uniaxial accelerometry, most likely as a result of the three-dimensional nature of the measurements. We conclude that essential tremor can be validly and reliably quantified during a postural task providing the recording device records movement in three dimensions and the measurements are logarithmically transformed. PMID- 10091624 TI - Movement dysfunction following repetitive hand opening and closing: anatomical analysis in Owl monkeys. AB - Repetitive strain injuries are thought to result from biomechanical stress and tissue microtrauma. The purpose of this study was to investigate the presence of local inflammation, scarring or anatomical variations of the flexor tendons and the median and ulnar nerves in four Owl monkeys behaviorally trained at a repetitive motor or sensory task. Three monkeys were trained to repetitively open and close a handpiece. The two monkeys that used rapid, stereotypical hand squeezing developed a task-specific movement dysfunction (one in 5 weeks and one in 24 weeks). The third monkey used a variable shoulder-pulling strategy and did not develop movement problems. The fourth monkey served as a control subject for the repetitive motor movements, trained on a repetitive sensory task, and did not develop a task-specific movement dysfunction. On dissection and histologic staining, there were no signs of active inflammation in the median nerve, the ulnar nerve, or the flexor tendons in any of the monkeys. However, the monkey that developed movement problems after 5 weeks of repetitive hand squeezing had an anatomical restriction of the flexor profundus tendon on the fourth digit of the trained side and the third digit of the untrained side. Reorganization of the representation of the hand on the contralateral somatosensory cortex (area 3b) was noted in the two monkeys that developed motor control problems and in the monkey performing the repetitive sensory task. These findings suggest that repetitive, stereotypical motor behaviors can lead to motor control problems without local signs of tendon or nerve inflammation. Preexisting anatomical restrictions may modify the time course for the development of movement dysfunction under conditions of stressful repetition. This animal model may simulate clinical focal hand dystonia (or occupational hand cramps) which can develop in human subjects who perform prolonged, repetitive, stereotypical movements. PMID- 10091625 TI - Effect of muscle activity immediately after botulinum toxin injection for writer's cramp. AB - Animal and human studies have shown that nerve stimulation enhances some effects of botulinum toxin (btx A) injection. Voluntary muscle activity might work similarly and would focus the effect of an injection into the active muscles. We studied the effects of exercise immediately after btx A injection in eight patients with writer's cramp with established response to btx A over two injection cycles with a single-blinded, randomized, crossover design. Immediately after the first study injection, they were randomly assigned to write continuously for 30 min or have their hand and forearm immobilized for 30 min. Following the second injection, they were assigned the alternate condition. Patients were assessed just before each injection, and at 2 weeks, 6 weeks, and 3 months post-injection. Assessment included objective strength testing, self reported rating of benefit and weakness, and blinded evaluation of videotapes and writing samples of the patients writing a standard passage. Strength testing showed that the maximum weakness occurred at 2 weeks post-injection, but the benefit was maximum at 6 weeks post-injection. The "write" condition resulted in greater reduction in strength than the "rest" condition. Btx A treatment led to improvement in self-reported ratings, writer's cramp rating scale scores by blinded raters, and reduction in writing time, but the differences between the "write" and "rest" conditions were not significant. We conclude that voluntary muscle activity immediately after btx A injection leads to greater reduction in muscle strength. Our findings raise the possibility that voluntary muscle activation may allow reduction of btx A doses and favorably alter the balance of benefit and side effects of btx A injections. PMID- 10091626 TI - Intersubject variability and intrasubject reproducibility of the bereitschaftspotential. AB - We assessed the intersubject variability and intrasubject reproducibility of the bereitschaftspotential (BP). Twenty healthy volunteers performed extensions of their wrist in a self-paced manner every 5-10 seconds. A surface electromyography (EMG) electrode was attached to the wrist extensor group of the dominant hand to record at least 100 wrist movements, and electroencephalography electrodes were placed over the scalp. Trials were performed at baseline, 15 minutes, 4 hours, and 4 weeks. Measures derived from the BP included area 1 (-2000 to -650 msec), area 2 (-650-0 msec), total area (area 1 + area 2), amplitude at -650 msec, amplitude at peak negativity prior to EMG onset, and amplitude at 0 msec (trigger). Our findings revealed different variability/reproducibility depending on the particular BP measure being analyzed. Using intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC) as measures of intrasubject reproducibility, area 2, amplitude at peak negativity prior to EMG onset, and amplitude at 0 msec produced the best values. We conclude that in studies that attempt to quantify BP changes before and after an intervention in the same group of subjects, the most reproducible BP measures are those pertaining to the late BP component. PMID- 10091627 TI - Differential clinical and motor control function in a pair of monozygotic twins with Huntington's disease. AB - We report a pair of monozygotic Huntington's disease (HD) twins who, although sharing identical CAG repeat lengths, not only present with marked differences in clinical symptoms but also behavioral abilities as measured by our experimental procedures. Both HD twins and two healthy control subjects were tested twice over 2 years. Patient A was generally more impaired at a motor level, whereas Patient B showed greater attentional impairment; Patient B, however, showed more progressive deterioration. The control subjects' performance remained consistent over the 2-year interval. Patient A clinically had the more hyperkinetic hypotonic variant of the disease, whereas Patient B, who was the more impaired, presented with a more hypokinetic hypertonic (rigid) variant. The influences of epigenetic pre- and postnatal environmental factors should not be ignored. PMID- 10091628 TI - Riluzole therapy in Huntington's disease (HD). AB - We conducted a 6-week open-label trial of riluzole (50 mg twice a day) in eight subjects with Huntington's disease. Subjects were evaluated before riluzole treatment, on treatment, and off treatment with the chorea, dystonia, and total functional capacity (TFC) scores from the Unified Huntington's Disease Rating Scale and magnetic resonance spectroscopy measurements of occipital cortex and basal ganglia lactate levels. Adverse events and safety blood and urine tests were assessed throughout the study. All subjects completed the study and riluzole was well tolerated. The age was 45+/-10.2 years (mean +/- standard deviation) and the disease duration was 6.1+/-4.1 years. The chorea rating score improved by 35% on treatment (p = 0.013) and worsened after discontinuation of treatment (p = 0.026). There were no significant treatment effects on the dystonia or TFC scores. The baseline occipital and basal ganglia lactate levels were elevated in all subjects; there was a trend toward lower lactate/creatine ratios during riluzole treatment in the basal ganglia spectra but not in occipital cortex spectra. Additional clinical studies of riluzole for both symptomatic and neuroprotective benefit in Huntington's disease are warranted. PMID- 10091629 TI - Anatomic correlates of painful tonic spasms in multiple sclerosis. AB - Painful tonic spasms (PTS) are now regarded as a typical symptom of multiple sclerosis but pathologic or radiologic findings rarely have been described. We report clinical and magnetic resonance imaging records of five original cases. In all of them, lesions likely responsible for unilateral PTS involved the motor pathway at the level of the posterior limb of the internal capsule or the cerebral peduncle on the opposite side. Closeness of motor fibers seems to be the most important underlying anatomic factor because it enables involvement of a higher proportion of axons by a single demyelinating lesion and radial spread of ephaptic activation. In turn, preservation of the underlying pyramidal-spinal tract could make it easier for the pathologic discharge to reach the peripheral effectors and generate PTS. PMID- 10091631 TI - A family with an atonic variant of paroxysmal kinesigenic choreoathetosis and hypercalcitoninemia. AB - We report a family with an incompletely atonic variant of paroxysmal kinesigenic choreoathetosis (PKC). Three members of the family experienced attacks of muscle weakness which resembled the choreoathetotic attacks that occur in PKC in terms of their kinesigenicity and duration, clarity of consciousness during the attacks, good therapeutic response to low doses of phenytoin, and familial transmission, but differed from choreoathetotic attacks in PKC in that they were atonic. All three affected individuals were hypercalcitoninemic. PMID- 10091630 TI - A randomized, double-blind study of a skin patch of a dopaminergic agonist, piribedil, in Parkinson's disease. AB - This randomized, double-blind trial was designed to evaluate the efficacy of a transdermal system of piribedil on the motor symptoms of Parkinson's disease during 3 weeks of treatment administered to three different groups: placebo, one piribedil patch (1 PP), and two (2 PP) piribedil patches. Twenty-seven patients with idiopathic Parkinson's disease, treated with L-dopa but not sufficiently controlled, were included in this trial. The test treatment did not demonstrate any clinical efficacy on either the main end point (Unified Parkinson's Disease Rating Scale motor score) or the secondary end points (rigidity, bradykinesia, postural, and resting tremor scores). The main adverse events were nausea (11%), vomiting (7.4%), and malaise (7.4%) mainly observed in the placebo group (four of seven patients). The local acceptability of the transdermal system was good. Plasma piribedil concentrations at the end of treatment were 6.74+/-1.10 and 9.31+/-3.33 ng/mL in the 1 PP and 2 PP groups, respectively. These plasma levels could account for the lack of clinical efficacy, because a previous pharmacokinetics-PD study conducted in parkinsonian patients and treated with the intravenous route demonstrated that the critical limits of activity on tremor were between 10 and 30 ng/mL. PMID- 10091632 TI - Bilateral hemifacial spasm: a report of five cases and a literature review. AB - We describe five patients with bilateral hemifacial spasm evaluated in a Movement Disorders Clinic to illustrate the clinical characteristics and to draw attention to the differential diagnosis of this condition. All patients had unilateral onset followed by bilateral, asymmetric, and asynchronous facial contractions. The mean age of the patients (4 women and 1 man) was 70.6 years (range, 54-81 yrs), and the mean duration of symptoms was 17 years (range, 2-30 yrs). The facial twitching started in the left eyelid in all cases and the opposite side of the face began to twitch on the average 8.4 years (range, 0.2-15 yrs) later. Imaging studies revealed tortuous vertebrobasilar arteries in three patients. Four patients were successfully treated with botulinum toxin injections. Bilateral hemifacial spasm is a rare, peripherally induced disorder that must be differentiated from tics, dystonia including blepharospasm and other cranial dystonia, and other facial dyskinesias. Botulinum toxin injection appears to be the treatment of choice. PMID- 10091633 TI - A 32-year-old man with progressive spasticity and parkinsonism. PMID- 10091634 TI - Implantable venous access system for apomorphine infusion in complicated Parkinson's disease. PMID- 10091635 TI - Hemifacial spasm in Parkinson's disease. PMID- 10091637 TI - Brain stem cystic astrocytoma presenting with "pure" parkinsonism. PMID- 10091636 TI - Hemiparkinsonism-hemiatrophy with brain hemihypoplasia. PMID- 10091638 TI - Postoperative parkinsonian tremor in a patient with a frontal meningioma. PMID- 10091639 TI - Focal tremor following striatal infarct--a case report. PMID- 10091640 TI - Cortical tremor secondary to a frontal cortical lesion. PMID- 10091641 TI - Dystonia; a central nervous system presentation of Sjogren's syndrome. PMID- 10091642 TI - Shoulder girdle dyskinesia associated with a thalamic infarct. PMID- 10091643 TI - Risperidone is effective in severe hemichorea/hemiballismus. PMID- 10091644 TI - Acetazolamide-responsive periodic ataxia induced by amiodarone. PMID- 10091645 TI - Melatonin-induced withdrawal emergent dyskinesia and akathisia. PMID- 10091646 TI - Dopaminergic neurons degenerate by apoptosis in Parkinson's disease. PMID- 10091647 TI - Clinical assessment of olfactory dysfunction in Parkinson's disease. PMID- 10091648 TI - Drug-induced dystonia and dysphonia in Parkinson's disease. PMID- 10091649 TI - Structure and dynamics in solution of the complex of Lactobacillus casei dihydrofolate reductase with the new lipophilic antifolate drug trimetrexate. AB - We have determined the three-dimensional solution structure of the complex of Lactobacillus casei dihydrofolate reductase and the anticancer drug trimetrexate. Two thousand seventy distance, 345 dihedral angle, and 144 hydrogen bond restraints were obtained from analysis of multidimensional NMR spectra recorded for complexes containing 15N-labeled protein. Simulated annealing calculations produced a family of 22 structures fully consistent with the constraints. Several intermolecular protein-ligand NOEs were obtained by using a novel approach monitoring temperature effects of NOE signals resulting from dynamic processes in the bound ligand. At low temperature (5 degrees C) the trimethoxy ring of bound trimetrexate is flipping sufficiently slowly to give narrow signals in slow exchange, which give good NOE cross peaks. At higher temperature these broaden and their NOE cross peaks disappear thus allowing the signals in the lower temperature spectrum to be identified as NOEs involving ligand protons. The binding site for trimetrexate is well defined and this was compared with the binding sites in related complexes formed with methotrexate and trimethoprim. No major conformational differences were detected between the different complexes. The 2,4-diaminopyrimidine-containing moieties in the three drugs bind essentially in the same binding pocket and the remaining parts of their molecules adapt their conformations such that they can make effective van der Waals interactions with essentially the same set of hydrophobic amino acids, the side-chain orientations and local conformations of which are not greatly changed in the different complexes (similar chi1 and chi2 values). PMID- 10091650 TI - Solution assembly of the pseudo-high affinity and intermediate affinity interleukin-2 receptor complexes. AB - The high affinity interleukin-2 receptor is composed of three cell surface subunits, IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma. Functional forms of the IL-2 receptor exist, however, that enlist only two of the three subunits. On activated T-cells, the alpha- and beta-subunits combine as a preformed heterodimer (the pseudo-high affinity receptor) that serves to capture IL-2. On a subpopulation of natural killer cells, the beta- and gamma-subunits interact in a ligand-dependent manner to form the intermediate affinity receptor site. Previously, we have demonstrated the feasibility of employing coiled-coil molecular recognition for the solution assembly of a heteromeric IL-2 receptor complex. In that study, although the receptor was functional, the coiled-coil complex was a trimer rather than the desired heterodimer. We have now redesigned the hydrophobic heptad sequences of the coiled-coils to generate soluble forms of both the pseudo-high affinity and the intermediate affinity heterodimeric IL-2 receptors. The properties of these complexes were examined and their relevance to the physiological IL-2 receptor mechanism is discussed. PMID- 10091651 TI - Role of the lateral channel in catalase HPII of Escherichia coli. AB - The heme-containing catalase HPII of Escherichia coli consists of a homotetramer in which each subunit contains a core region with the highly conserved catalase tertiary structure, to which are appended N- and C-terminal extensions making it the largest known catalase. HPII does not bind NADPH, a cofactor often found in catalases. In HPII, residues 585-590 of the C-terminal extension protrude into the pocket corresponding to the NADPH binding site in the bovine liver catalase. Despite this difference, residues that define the NADPH pocket in the bovine enzyme appear to be well preserved in HPII. Only two residues that interact ionically with NADPH in the bovine enzyme (Asp212 and His304) differ in HPII (Glu270 and Glu362), but their mutation to the bovine sequence did not promote nucleotide binding. The active-site heme groups are deeply buried inside the molecular structure requiring the movement of substrate and products through long channels. One potential channel is about 30 A in length, approaches the heme active site laterally, and is structurally related to the branched channel associated with the NADPH binding pocket in catalases that bind the dinucleotide. In HPII, the upper branch of this channel is interrupted by the presence of Arg260 ionically bound to Glu270. When Arg260 is replaced by alanine, there is a threefold increase in the catalytic activity of the enzyme. Inhibitors of HPII, including azide, cyanide, various sulfhydryl reagents, and alkylhydroxylamine derivatives, are effective at lower concentration on the Ala260 mutant enzyme compared to the wild-type enzyme. The crystal structure of the Ala260 mutant variant of HPII, determined at 2.3 A resolution, revealed a number of local structural changes resulting in the opening of a second branch in the lateral channel, which appears to be used by inhibitors for access to the active site, either as an inlet channel for substrate or an exhaust channel for reaction products. PMID- 10091652 TI - The solution structure of a superpotent B-chain-shortened single-replacement insulin analogue. AB - This paper reports on an insulin analogue with 12.5-fold receptor affinity, the highest increase observed for a single replacement, and on its solution structure, determined by NMR spectroscopy. The analogue is [D-AlaB26]des-(B27 B30)-tetrapeptide-insulin-B26-amide. C-terminal truncation of the B-chain by four (or five) residues is known not to affect the functional properties of insulin, provided the new carboxylate charge is neutralized. As opposed to the dramatic increase in receptor affinity caused by the substitution of D-Ala for the wild type residue TyrB26 in the truncated molecule, this very substitution reduces it to only 18% of that of the wild-type hormone when the B-chain is present in full length. The insulin molecule in solution is visualized as an ensemble of conformers interrelated by a dynamic equilibrium. The question is whether the "active" conformation of the hormone, sought after in innumerable structure/function studies, is or is not included in the accessible conformational space, so that it could be adopted also in the absence of the receptor. If there were any chance for the active conformation, or at least a predisposed state to be populated to a detectable extent, this chance should be best in the case of a superpotent analogue. This was the motivation for the determination of the three-dimensional structure of [D-AlaB26]des-(B27-B30) tetrapeptide-insulin-B26-amide. However, neither the NMR data nor CD spectroscopic comparison of a number of related analogues provided a clue concerning structural features predisposing insulin to high receptor affinity. After the present study it seems more likely than before that insulin will adopt its active conformation only when exposed to the force field of the receptor surface. PMID- 10091653 TI - Physicochemical consequences of amino acid variations that contribute to fibril formation by immunoglobulin light chains. AB - The most common form of systemic amyloidosis originates from antibody light chains. The large number of amino acid variations that distinguish amyloidogenic from nonamyloidogenic light chain proteins has impeded our understanding of the structural basis of light-chain fibril formation. Moreover, even among the subset of human light chains that are amyloidogenic, many primary structure differences are found. We compared the thermodynamic stabilities of two recombinant kappa4 light-chain variable domains (V(L)s) derived from amyloidogenic light chains with a V(L) from a benign light chain. The amyloidogenic V(L)s were significantly less stable than the benign V(L). Furthermore, only the amyloidogenic V(L)s formed fibrils under native conditions in an in vitro fibril formation assay. We used site-directed mutagenesis to examine the consequences of individual amino acid substitutions found in the amyloidogenic V(L)s on stability and fibril formation capability. Both stabilizing and destabilizing mutations were found; however, only destabilizing mutations induced fibril formation in vitro. We found that fibril formation by the benign V(L) could be induced by low concentrations of a denaturant. This indicates that there are no structural or sequence-specific features of the benign V(L) that are incompatible with fibril formation, other than its greater stability. These studies demonstrate that the V(L) beta-domain structure is vulnerable to destabilizing mutations at a number of sites, including complementarity determining regions (CDRs), and that loss of variable domain stability is a major driving force in fibril formation. PMID- 10091654 TI - Mapping cyclic nucleotide-induced conformational changes in cyclicAMP receptor protein by a protein footprinting technique using different chemical proteases. AB - CyclicAMP receptor protein (CRP) regulates transcription of numerous genes in Escherichia coli. Both cAMP and cGMP bind CRP, but only cAMP induces conformational changes that dramatically increase the specific DNA binding activity of the protein. We have shown previously that our protein footprinting technique is sensitive enough to detect conformational changes in CRP by cAMP [Baichoo N, Heyduk T. 1997. Biochemistry 36:10830-10836]. In this work, conformational changes in CRP induced by cAMP and cGMP binding were mapped and quantitatively analyzed by protein footprinting using iron complexed to diethylenetriaminepentaacetic acid ([Fe-DTPA]2-), iron complexed to ethylenediaminediacetic acid ([Fe-EDDA]), iron complexed to desferrioxamine mesylate ([Fe-HDFO]+), and copper complexed to o-phenanthroline ([(OP)2Cu]+) as proteases. These chemical proteases differ in size, charge, and hydrophobicity. Binding of cAMP to CRP resulted in changes in susceptibility to cleavage by all four proteases. Cleavage by [Fe-EDDA] and [Fe-DTPA]2- of CRP-cAMP detected hypersensitivities in the DNA-binding F alpha-helix, the interdomain hinge, and the ends of the C alpha-helix, which is involved in intersubunit interactions. [Fe-EDDA] and [Fe-DTPA]2- also detected reductions in cleavage in the D and E alpha-helices, which are involved in DNA recognition. Cleavage by [Fe-HDFO]+ of CRP-cAMP detected hypersensitivities in beta-strand 8, the B alpha-helix, as well as in parts of the F and C alpha-helices. [Fe-HDFO]+ also detected protections from cleavage in beta-strands 4 to 5 and their intervening loop, beta-strand 7, which is part of the nucleotide binding pocket, as well as in the D and E alpha helices. Cleavage by [(OP)2Cu]+ of CRP-cAMP detected hypersensitivities in beta strands 9 and 11 as well as in the D and E alpha-helices. [(OP)2Cu]+ also detected protections in the C alpha-helix , the interdomain hinge, and beta strands 2-7. Binding of cGMP to CRP resulted in changes in susceptibility to cleavage only by [(OP)2Cu]+, which detected minor protections in beta-strands 3 7, the interdomain hinge, and the C alpha-helix. These results show that binding of cAMP causes structural changes in CRP in the nucleotide binding domain, the interdomain hinge, the DNA binding domain, and regions involved in intersubunit interaction. Structural changes induced by binding of cGMP appear to be very minor and confined to the nucleotide binding domain, the interdomain hinge, and regions involved in intersubunit interaction. Use of different cleaving agents in protein footprinting seems to give a more detailed picture of structural changes than the use of a single protease alone. PMID- 10091655 TI - Domain exchange experiments in duck delta-crystallins: functional and evolutionary implications. AB - Delta-crystallin, the major soluble protein component of the avian and reptilian eye lens, is homologous to the urea cycle enzyme argininosuccinate lyase (ASL). In duck lenses there are two delta crystallins, denoted delta1 and delta2. Duck delta2 is both a major structural protein of the lens and also the duck orthologue of ASL, an example of gene recruitment. Although 94% identical to delta2/ASL in the amino acid sequence, delta1 is enzymatically inactive. A series of hybrid proteins have been constructed to assess the role of each structural domain in the enzymatic mechanism. Five chimeras--221, 122, 121, 211, and 112, where the three numbers correspond to the three structural domains and the value of 1 or 2 represents the protein of origin, delta1 or delta2, respectively--were constructed and thermodynamically and kinetically analyzed. The kinetic analysis indicates that only domain 1 is crucial for restoring ASL activity to delta1 crystallin, and that amino acid substitutions in domain 2 may play a role in substrate binding. These results confirm the hypothesis that only one domain, domain 1, is responsible for the loss of catalytic activity in delta1. The thermodynamic characterization of human ASL (hASL) and duck delta1 and delta2 indicate that delta crystallins are slightly less stable than hASL, with the delta1 being the least stable. The deltaGs of unfolding are 57.25, 63.13, and 70.71 kcal mol(-1) for delta1, delta2, and hASL, respectively. This result was unexpected, and we speculate that delta crystallins have adapted to their structural role by adopting a slightly less stable conformation that might allow for enhanced protein-protein and protein-solvent interactions. PMID- 10091656 TI - Crystal structure of thymidylate synthase A from Bacillus subtilis. AB - Thymidylate synthase (TS) converts dUMP to dTMP by reductive methylation, where 5,10-methylenetetrahydrofolate is the source of both the methylene group and reducing equivalents. The mechanism of this reaction has been extensively studied, mainly using the enzyme from Escherichia coli. Bacillus subtilis contains two genes for TSs, ThyA and ThyB. The ThyB enzyme is very similar to other bacterial TSs, but the ThyA enzyme is quite different, both in sequence and activity. In ThyA TS, the active site histidine is replaced by valine. In addition, the B. subtilis enzyme has a 2.4-fold greater k(cat) than the E. coli enzyme. The structure of B. subtilis thymidylate synthase in a ternary complex with 5-fluoro-dUMP and 5,10-methylenetetrahydrofolate has been determined to 2.5 A resolution. Overall, the structure of B. subtilis TS (ThyA) is similar to that of the E. coli enzyme. However, there are significant differences in the structures of two loops, the dimer interface and the details of the active site. The effects of the replacement of histidine by valine and a serine to glutamine substitution in the active site area, and the addition of a loop over the carboxy terminus may account for the differences in k(cat) found between the two enzymes. PMID- 10091657 TI - Two well-defined motifs in the cAMP-dependent protein kinase inhibitor (PKIalpha) correlate with inhibitory and nuclear export function. AB - The heat stable inhibitor of cAMP-dependent protein kinase (PKIalpha) contains both a nuclear export signal (NES) and a high affinity inhibitory region that is essential for inhibition of the catalytic subunit of the kinase. These functions are sequentially independent. Two-dimensional NMR spectroscopy was performed on uniformly [15N]-labeled PKIalpha to examine its structure free in solution. Seventy out of 75 residues were identified, and examination of the CaH chemical shifts revealed two regions of upfield chemical shifts characteristic of alpha helices. When PKIalpha was fragmented into two functionally distinct peptides for study at higher concentrations, no significant alterations in chemical shifts or secondary structure were observed. The first ordered region, identified in PKIalpha (1-25), contains an alpha-helix from residues 1-13. This helix extends by one turn the helix observed in the crystal structure of a PKIalpha (5-24) peptide bound to the catalytic subunit. The second region of well-defined secondary structure, residues 35-47, overlaps with the nuclear export signal in the PKIalpha (26-75) fragment. This secondary structure consists of a helix with a hydrophobic face comprised of Leu37, Leu41, and Leu44, followed by a flexible turn containing Ile46. These four residues are critical for nuclear export function. The remainder of the protein in solution appears relatively unstructured, and this lack of structure surrounding a few essential and well defined signaling elements may be characteristic of a growing family of small regulatory proteins that interact with protein kinases. PMID- 10091658 TI - Energetics of solvent and ligand-induced conformational changes in alpha lactalbumin. AB - The energetics of structural changes in the holo and apo forms of a-lactalbumin and the transition between their native and denatured states induced by binding Ca2+ and Na+ have been studied by differential scanning and isothermal titration microcalorimetry and circular dichroism spectroscopy under various solvent conditions. Removal of Ca2+ from the protein enhances its sensitivity to pH and ionic conditions due to noncompensated negative charge-charge interactions at the cation binding site, which significantly reduces its overall stability. At neutral pH and low ionic strength, the native structure of apo-alpha-lactalbumin is stable below 14 C and undergoes a conformational change to a native-like molten globule intermediate at temperatures above 25 degrees C. The denaturation of either holo- or apo-alpha-lactalbumin is a highly cooperative process that is characterized by an enthalpy of similar magnitude when calculated at the same temperature. Measured by direct calorimetric titration, the enthalpy of Ca2+ binding to apo-LA at pH 7.5 is -7.1 kJ mol(-1) at 5.0 degrees C. which is essentially invariant to protonation effects. This small enthalpy effect infers that stabilization of alpha-lactalbumin by Ca2+ is primarily an entropy driven process, presumably arising from electrostatic interactions and the hydration effect. In contrast to the binding of calcium, the interaction of sodium with apo LA does not produce a noticeable heat effect and is characterized by its ionic nature rather than specific binding to the metal-binding site. Characterization of the conformational stability and ligand binding energetics of alpha lactalbumin as a function of solvent conditions furnishes significant insight regarding the molecular flexibility and regulatory mechanism mediated by this protein. PMID- 10091659 TI - Structure in the channel forming domain of colicin E1 bound to membranes: the 402 424 sequence. AB - To explore the structure of the pore-forming fragment of colicin E1 in membranes, a series of 23 consecutive single cysteine substitution mutants was prepared in the sequence 402-424. Each mutant was reacted with a sulfhydryl-specific reagent to generate a nitroxide labeled side chain, and the mobility of the side chain and its accessibility to collision with paramagnetic reagents was determined from the electron paramagnetic resonance spectrum. Individual values of these quantities were used to identify tertiary contact sites and the nature of the surrounding solvent, while their periodic dependence on sequence position was used to identify secondary structure. In solution, the data revealed a regular helix of 11 residues in the region 406-416, consistent with helix IV of the crystal structure. Upon binding to negatively charged membranes at pH 4.0, helix IV apparently grows to a length of 19 residues, extending from 402-420. One face of the helix is solvated by the lipid bilayer, and the other by an environment of a polar nature. Surprisingly, a conserved charged pair, D408-R409, is located on the lipid-exposed face. Evidence is presented to suggest a transmembrane orientation of this new helix, although other topographies may exist in equilibrium. PMID- 10091660 TI - Analysis of interactive packing of secondary structural elements in alpha/beta units in proteins. AB - An alpha-helix and a beta-strand are said to be interactively packed if at least one residue in each of the secondary structural elements loses 10% of its solvent accessible contact area on association with the other secondary structural element. An analysis of all such 5,975 nonidentical alpha/beta units in protein structures, defined at < or = 2.5 A resolution, shows that the interaxial distance between the alpha-helix and the beta-strand is linearly correlated with the residue-dependent function, log[(V/nda)/n-int], where V is the volume of amino acid residues in the packing interface, nda is the normalized difference in solvent accessible contact area of the residues in packed and unpacked secondary structural elements, and n-int is the number of residues in the packing interface. The beta-sheet unit (beta u), defined as a pair of adjacent parallel or antiparallel hydrogen-bonded beta-strands, packing with an alpha-helix shows a better correlation between the interaxial distance and log(V/nda) for the residues in the packing interface. This packing relationship is shown to be useful in the prediction of interaxial distances in alpha/beta units using the interacting residue information of equivalent alpha/beta units of homologous proteins. It is, therefore, of value in comparative modeling of protein structures. PMID- 10091661 TI - A survey of left-handed polyproline II helices. AB - Left-handed polyproline II helices (PPII) are contiguous elements of protein secondary structure in which the phi and psi angles of constituent residues are restricted to around -75 degrees and 145 degrees, respectively. They are important in structural proteins, in unfolded states and as ligands for signaling proteins. Here, we present a survey of 274 nonhomologous polypeptide chains from proteins of known structure for regions that form these structures. Such regions are rare, but the majority of proteins contain at least one PPII helix. Most PPII helices are shorter than five residues, although the longest found contained 12 amino acids. Proline predominates in PPII, but Gln and positively charged residues are also favored. The basis of Gln's prevalence is its ability to form an i, i + 1 side-chain to main-chain hydrogen bond with the backbone carbonyl oxygen of the proceeding residue; this helps to fix the psi angle of the Gln and the phi and psi of the proceeding residue in PPII conformations and explains why Gln is favored at the first position in a PPII helix. PPII helices are highly solvent exposed, which explains why apolar amino acids are disfavored despite preferring this region of phi/psi space when in isolation. PPII helices have perfect threefold rotational symmetry and within these structures we find significant correlation between the hydrophobicity of residues at i and i + 3; thus, PPII helices in globular proteins can be considered to be amphipathic. PMID- 10091662 TI - The mechanism of sugar phosphate isomerization by glucosamine 6-phosphate synthase. AB - Glucosamine 6-phosphate synthase converts fructose-6P into glucosamine-6P or glucose-6P depending on the presence or absence of glutamine. The isomerase activity is associated with a 40-kDa C-terminal domain, which has already been characterized crystallographically. Now the three-dimensional structures of the complexes with the reaction product glucose-6P and with the transition state analog 2-amino-2-deoxyglucitol-6P have been determined. Glucose-6P binds in a cyclic form whereas 2-amino-2-deoxyglucitol-6P is in an extended conformation. The information on ligand-protein interactions observed in the crystal structures together with the isotope exchange and site-directed mutagenesis data allow us to propose a mechanism of the isomerase activity of glucosamine-6P synthase. The sugar phosphate isomerization involves a ring opening step catalyzed by His504 and an enolization step with Glu488 catalyzing the hydrogen transfer from C1 to C2 of the substrate. The enediol intermediate is stabilized by a helix dipole and the epsilon-amino group of Lys603. Lys485 may play a role in deprotonating the hydroxyl O1 of the intermediate. PMID- 10091663 TI - Comparison of protein-protein interactions in serine protease-inhibitor and antibody-antigen complexes: implications for the protein docking problem. AB - The protein-protein interaction energy of 12 nonhomologous serine protease inhibitor and 15 antibody-antigen complexes is calculated using a molecular mechanics formalism and dissected in terms of the main-chain vs. side-chain contribution, nonrotameric side-chain contributions, and amino acid residue type involvement in the interface interaction. There are major differences in the interactions of the two types of protein-protein complex. Protease-inhibitor complexes interact predominantly through a main-chain-main-chain mechanism while antibody-antigen complexes interact predominantly through a side-chain-side-chain or a side-chain-main-chain mechanism. However, there is no simple correlation between the main-chain-main-chain interaction energy and the percentage of main chain surface area buried on binding. The interaction energy is equally effected by the presence of nonrotameric side-chain conformations, which constitute approximately 20% of the interaction energy. The ability to reproduce the interface interaction energy of the crystal structure if original side-chain conformations are removed from the calculation is much greater in the protease inhibitor complexes than the antibody-antigen complexes. The success of a rotameric model for protein-protein docking appears dependent on the extent of the main-chain-main-chain contribution to binding. Analysis of (1) residue type and (2) residue pair interactions at the interface show that antibody-antigen interactions are very restricted with over 70% of the antibody energy attributable to just six residue types (Tyr > Asp > Asn > Ser > Glu > Trp) in agreement with previous studies on residue propensity. However, it is found here that 50% of the antigen energy is attributable to just four residue types (Arg = Lys > Asn > Asp). On average just 12 residue pair interactions (6%) contribute over 40% of the favorable interaction energy in the antibody-antigen complexes, with charge-charge and charge/polar-tyrosine interactions being prominent. In contrast protease inhibitors use a diverse set of residue types and residue pair interactions. PMID- 10091664 TI - Functional insights from structural predictions: analysis of the Escherichia coli genome. AB - Fold assignments for proteins from the Escherichia coli genome are carried out using BASIC, a profile-profile alignment algorithm, recently tested on fold recognition benchmarks and on the Mycoplasma genitalium genome and PSI BLAST, the newest generation of the de facto standard in homology search algorithms. The fold assignments are followed by automated modeling and the resulting three dimensional models are analyzed for possible function prediction. Close to 30% of the proteins encoded in the E. coli genome can be recognized as homologous to a protein family with known structure. Most of these homologies (23% of the entire genome) can be recognized both by PSI BLAST and BASIC algorithms, but the latter recognizes an additional 260 homologies. Previous estimates suggested that only 10-15% of E. coli proteins can be characterized this way. This dramatic increase in the number of recognized homologies between E. coli proteins and structurally characterized protein families is partly due to the rapid increase of the database of known protein structures, but mostly it is due to the significant improvement in prediction algorithms. Knowing protein structure adds a new dimension to our understanding of its function and the predictions presented here can be used to predict function for uncharacterized proteins. Several examples, analyzed in more detail in this paper, include the DPS protein protecting DNA from oxidative damage (predicted to be homologous to ferritin with iron ion acting as a reducing agent) and the ahpC/tsa family of proteins, which provides resistance to various oxidating agents (predicted to be homologous to glutathione peroxidase). PMID- 10091665 TI - Trifluoroethanol-induced conformational transitions of proteins: insights gained from the differences between alpha-lactalbumin and ribonuclease A. AB - The trifluoroethanol (TFE)-induced structural changes of two proteins widely used in folding experiments, bovine alpha-lactalbumin, and bovine pancreatic ribonuclease A, have been investigated. The experiments were performed using circular dichroism spectroscopy in the far- and near-UV region to monitor changes in the secondary and tertiary structures, respectively, and dynamic light scattering to measure the hydrodynamic dimensions and the intermolecular interactions of the proteins in different conformational states. Both proteins behave rather differently under the influence of TFE: alpha-lactalbumin exhibits a molten globule state at low TFE concentrations before it reaches the so-called TFE state, whereas ribonuclease A is directly transformed into the TFE state at TFE concentrations above 40% (v/v). The properties of the TFE-induced states are compared with those of equilibrium and kinetic intermediate states known from previous work to rationalize the use of TFE in yielding information about the folding of proteins. Additionally, we report on the properties of TFE/water and TFE/buffer mixtures derived from dynamic light scattering investigations under conditions used in our experiments. PMID- 10091666 TI - Cloning, mutagenesis, and structural analysis of human pancreatic alpha-amylase expressed in Pichia pastoris. AB - Human pancreatic alpha-amylase (HPA) was expressed in the methylotrophic yeast Pichia pastoris and two mutants (D197A and D197N) of a completely conserved active site carboxylic acid were generated. All recombinant proteins were shown by electrospray ionization mass spectrometry (ESI-MS) to be glycosylated and the site of attachment was shown to be Asn461 by peptide mapping in conjunction with ESI-MS. Treatment of these proteins with endoglycosidase F demonstrated that they contained a single N-linked oligosaccharide and yielded a protein product with a single N-acetyl glucosamine (GlcNAc), which could be crystallized. Solution of the crystal structure to a resolution of 2.0 A confirmed the location of the glycosyl group as Asn461 and showed that the recombinant protein had essentially the same conformation as the native enzyme. The kinetic parameters of the glycosylated and deglycosylated wild-type proteins were the same while the k(cat)/Km values for D197A and D197N were 10(6)-10(7) times lower than the wild type enzyme. The decreased k(cat)/Km values for the mutants confirm that D197 plays a crucial role in the hydrolytic activity of HPA, presumably as the catalytic nucleophile. PMID- 10091667 TI - The Mycobacterium tuberculosis recA intein can be used in an ORFTRAP to select for open reading frames. AB - The DNA repair protein RecA of Mycobacterium tuberculosis contains an intein, a self-splicing protein element. We have employed this Mtu recA intein to create a selection system for successful intein splicing by inserting it into a kanamycin resistance gene so that functional antibiotic resistance can only be restored upon protein splicing. We then proceeded to develop an ORFTRAP, i.e., a selection system for the cloning of open reading frames (ORFs). The ORFTRAP exploits the self-splicing properties of inteins (which depend on full-length in-frame translation of a precursor protein) by allowing protein splicing to occur when DNA fragments encoding ORFs are inserted into the Mtu recA intein, whereas DNA fragments containing non-ORFs are selected against. Regions of the Mtu recA intein that tolerate the insertion of additional amino acids were identified by Bgl II linker scanning mutagenesis, and a respective construct was chosen as the ORFTRAP. To test the maximum insert size that could be cloned into ORFTRAP, DNA fragments of increasing length from the Listeria monocytogenes hly gene as well as a genomic library of Haemophilus influenzae were inserted and it was found that the longest permissive inserts were 425 bp and 251 bp, respectively. The H. influenzae ORFTRAP library also demonstrated the strength (strong selection power) and weakness (insertion of very small fragments) of the system. Further modifications should make the ORFTRAP useful for protein expression, epitope mapping, and antigen screening. PMID- 10091668 TI - Protein structure comparison using iterated double dynamic programming. AB - A protein structure comparison method is described that allows the generation of large populations of high-scoring alternate alignments. This was achieved by incorporating a random element into an iterative double dynamic programming algorithm. The maximum scores from repeated comparisons of a pair of structures converged on a value that was taken as the global maximum. This lay 15% over the score obtained from the single fixed (unrandomized) calculation. The effect of the gap penalty was observed through the shift of the alignment populations, characterized by their alignment length and root-mean-square deviation (RMSD). The best (lowest RMSD) values found in these populations provided a base-line against which other methods were compared. PMID- 10091670 TI - GRASS: a server for the graphical representation and analysis of structures. AB - GRASS (Graphical Representation and Analysis of Structures Server), a new web based server, is described. GRASS exploits many of the features of the GRASP program and is designed to provide interactive molecular graphics and quantitative analysis tools with a simple interface over the World-Wide Web. Using GRASS, it is now possible to view many surface features of biological macromolecules on either standard workstations used in macromolecular analysis or personal computers. The result is a World-Wide Web-based, platform-independent, easily used tool for macromolecular visualization and structure analysis. PMID- 10091669 TI - Covalent modification of Lys19 in the CTP binding site of cytidine 5' monophosphate N-acetylneuraminic acid synthetase. AB - Periodate oxidized CTP (oCTP) was used to investigate the importance of lysine residues in the CTP binding site of the cytidine 5'-monophosphate N acetylneuraminic acid (CMP-NeuAc) synthetase (EC 2.7.7.43) from Haemophilus ducreyi. The reaction of oCTP with the enzyme follows pseudo-first-order saturation kinetics, giving a maximum rate of inactivation of 0.6 min(-1) and a K(I) of 6.0 mM at pH 7.1. Mass spectrometric analysis of the modified enzyme provided data that was consistent with beta-elimination of triphosphate after the reaction of oCTP with the enzyme. A fully reduced enzyme-oCTP conjugate, retaining the triphosphate moiety, was obtained by inclusion of NaBH3CN in the reaction solution. The beta-elimination product of oCTP reacted several times more rapidly with the enzyme compared to equivalent concentrations of oCTP. This compound also formed a stable reduced morpholino adduct with CMP-NeuAc synthetase when the reaction was conducted in the presence of NaBH3CN, and was found to be a useful lysine modifying reagent. The substrate CTP was capable of protecting the enzyme to a large degree from inactivation by oCTP and its beta-elimination product. Lys19, a residue conserved in CMP-NeuAc synthetases, was identified as being labeled with the beta-elimination product of oCTP. PMID- 10091671 TI - Combinatorial codons: a computer program to approximate amino acid probabilities with biased nucleotide usage. AB - Using techniques from optimization theory, we have developed a computer program that approximates a desired probability distribution for amino acids by imposing a probability distribution on the four nucleotides in each of the three codon positions. These base probabilities allow for the generation of biased codons for use in mutational studies and in the design of biologically encoded libraries. The dependencies between codons in the genetic code often makes the exact generation of the desired probability distribution for amino acids impossible. Compromises are often necessary. The program, therefore, not only solves for the "optimal" approximation to the desired distribution (where the definition of "optimal" is influenced by several types of parameters entered by the user), but also solves for a number of "sub-optimal" solutions that are classified into families of similar solutions. A representative of each family is presented to the program user, who can then choose the type of approximation that is best for the intended application. The Combinatorial Codons program is available for use over the web from http://www.wi.mit.edu/kim/computing.html. PMID- 10091672 TI - Common structural features of MAPEG -- a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism. AB - A novel superfamily designated MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism), including members of widespread origin with diversified biological functions is defined according to enzymatic activities, sequence motifs, and structural properties. Two of the members are crucial for leukotriene biosynthesis, and three are cytoprotective exhibiting glutathione S transferase and peroxidase activities. Expression of the most recently recognized member is strongly induced by p53, and may therefore play a role in apoptosis or cancer development. In spite of the different biological functions, all six proteins demonstrate common structural characteristics typical of membrane proteins. In addition, homologues are identified in plants, fungi, and bacteria, demonstrating this superfamily to be generally occurring. PMID- 10091673 TI - Synthesis of potent and selective inhibitors of human plasma kallikrein. AB - The synthesis and in vitro enzyme inhibition profile of a series of novel trifluoromethylketone (TFMK) inhibitors of human plasma kallikrein (PK) are described. We have developed an efficient method for the construction of peptide TFMKs that provides the final product devoid of compromised stereochemical integrity. Many of these compounds are potent inhibitors of PK and exhibit reduced inhibition of tissue kallikrein (TK) and plasmin (HP). PMID- 10091674 TI - Structure-based design of COX-2 selectivity into flurbiprofen. AB - Comparative computer modeling of the X-ray crystal structures of cyclooxygenase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity into the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small alcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-1 and COX-2. The design hypothesis was tested by synthesis and biological assay of a series of flurbiprofen analogs, culminating in the discovery of several inhibitors having up to 78-fold selectivity for COX-2 over COX-1. PMID- 10091675 TI - Carbohydroxamido-oxazolidines: antibacterial agents that target lipid A biosynthesis. AB - A series of carbohydroxamido-oxazolidine inhibitors of UDP-3-O-[R-3 hydroxymyristoyl]-GlcNAc deacetylase, the enzyme responsible for the second step in lipid A biosynthesis, was identified. The most potent analog L-161,240 showed an IC50 = 30 nM in the DEACET assay and displayed an MIC of 1-3 microg/mL against wild-type E. coli. PMID- 10091676 TI - Synthesis and hybridization property of an oligonucleotide containing a 3 thioformacetal linked pentathymidylate. AB - A pentathymidylate fully substituted with 3'-thioformacetal intemucleotidic linkages was synthesized and subsequently incorporated into an oligonucleotide (ON) 15mer. Tm analysis was performed on the resulting ON hybridized with its complementary RNA. This duplex demonstrated slightly improved binding affinity relative to the control phosphate diester ON/RNA hybrid. PMID- 10091677 TI - Substituted furans as inhibitors of the PDE4 enzyme. AB - The synthesis and in vitro activity of a series of substituted furans as a novel structural class of PDE4 inhibitors is described. Comparison of emetic threshold with known PDE4 inhibitors is presented. PMID- 10091678 TI - Novel series of O-substituted 8-quinolines and 4-benzothiazoles as potent antagonists of the bradykinin B2 receptors. AB - The synthesis and the SAR study of novel O-substituted 8-quinolines and 4 benzothiazoles as highly potent non-peptide bradykinin B2 receptor antagonists are described. Several members of this series of antagonists efficiently inhibited the BK-induced vasoconstriction on different isolated organ preparations. PMID- 10091679 TI - New selective nonsteroidal aromatase inhibitors: synthesis and inhibitory activity of 2,3 or 5-(alpha-azolylbenzyl)-1H-indoles. AB - Six azolyl substituted indoles were synthesized and tested for their activity to inhibit two P450 enzymes: P450 arom and P450 17a. It was observed that the introduction of alpha-imidazolylbenzyl chain at carbon 3 or 5 on indole nucleus led to very active molecules. Compounds 22, 23 and especially 33 demonstrate very high potential against P450 arom. Under our assay conditions of high substrate concentration the IC50 are 0.057, 0.0785 and 0.041 microM, respectively. These compounds are moderate inhibitors against P450 17alpha. PMID- 10091680 TI - Quantitative analysis of the kinetics of phospholipase A2 using fast atom bombardment mass spectrometry. AB - Fast atom bombardment mass spectrometry that can directly analyze lysophospholipids was used to quantitatively determine the kinetics of phospholipase A2. This method is 1250 times more sensitive than the colorimetric assay. PMID- 10091681 TI - A "cephalosporin-like" cyclic depsipeptide: synthesis and reaction with beta lactam-recognizing enzymes. AB - The cyclic depsipeptide 8-carboxy-3-phenylacetamido-3,4-dihydro-2H-1-benzopyran-2 one, a cyclic analog of aryl phenaceturates with structural similarity to cephalosporins, has been synthesized as a potential substrate/inhibitor of B lactam-recognizing enzymes. It was found to be a tight-binding, poor substrate of class A beta-lactamases and an irreversible inhibitor of several DD-peptidases. PMID- 10091682 TI - Monocarboxylic-based phosphotyrosyl mimetics in the design of GRB2 SH2 domain inhibitors. AB - Three monocarboxylic-containing analogues, O-carboxymethyltyrosine (cmT, 5), 4 (carboxymethyl)phenylalanine (cmF, 6), and 4-(carboxydifluoromethyl)phenylalanine (F2cmF, 7) were utilized as phosphotyrosyl (pTyr) replacements in a high affinity B-bend mimicking platform, where they exhibited IC50 values of 2.5 microM, 65 microM and 28 microM, respectively, in a Grb2 SH2 domain Biacore binding assay. When a terminal N(alpha)-oxalyl axillary was utilized to enhance ligand interactions with a critical SH2 domain Arg67 residue (alphaA-helix), binding potencies increased from 4- to 10-fold, resulting in submicromolar affinity for cmF (IC50 = 0.6 microM) and low micromolar affinity for F2cmF (IC50 = 2 microM). Cell lysate binding studies also showed inhibition of cognate Grb2 binding to the p185erbB-2 phosphoprotein in the same rank order of potency as observed in the Biacore assay. These results indicate the potential value of cmF and F2cmF residues as pTyr mimetics for the study of Grb2 SH2 domains and suggest new strategies for improvements in inhibitor design. PMID- 10091683 TI - Periodinates: a new class of protein tyrosine phosphatase inhibitors. AB - A series of periodinates has been synthesized and tested as protein tyrosine phosphatase substrates. Their potency is comparable to or higher than that of vanadates but much lower than that of peroxovanadates. PMID- 10091684 TI - The LMC delta opioid recognition pharmacophore: comparison of SNC80 and oxymorphindole. AB - A recognition pharmacophore for the delta opioid receptor was developed de novo. Through the use of the pharmacophore and a novel four-point recognition model, major differences were observed between oxymorphindole and SNC80. This work suggests that these two classes of delta selective opioids do not bind to the delta opioid receptor in the same orientation. PMID- 10091685 TI - Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 3. Enhancing activity by imposing conformational restriction in the C-4" side chain. AB - The preparation and biological evaluation of a series of benzo[b]thiophene diamine thrombin inhibitors possessing conformationally restricted C-4" linkers are reported. Compared to the parent compounds 1a/b, the unsaturated derivatives 3a/b exhibited a modest twofold increase in thrombin inhibitory activity, while the more lipophilic carbocyclic ring containing analogs 4a/b affected an eightfold enhancement in potency. PMID- 10091686 TI - Synthesis and biological evaluation of cryptophycin analogs with substitution at C-6 (fragment C region). AB - Analogs of the antitumor agents cryptophycins 1 and 8 with dialkyl substitution at C-6 (fragment C) were synthesized and evaluated for in vitro cytotoxicity against human leukemia cells (CCRF-CEM). The activity of these analogs decreased as the size of the substituents at C-6 increased. The C-6 spirocylopropyl compound (2g) was highly potent in vitro and showed excellent antitumor activity in animal models. PMID- 10091687 TI - Synthesis and structure-activity relationships of a series of novel thiazoles as inhibitors of aminoacyl-tRNA synthetases. AB - A series of novel aminoacyl adenylate mimics has been prepared and evaluated for their inhibitory activity against aminoacyl-tRNA synthetases. Several of these thiazole derivatives displayed potent and selective enzyme activity against both Gram-positive and Gram-negative bacteria. PMID- 10091688 TI - Synthesis and biological evaluation of 1alpha,24-dihydroxy-25-nitrovitamin D3. AB - 1Alpha,24(R)Dihydroxy-25-nitrovitamin D3 1 and 1alpha,24(S)-dihydroxy-25 nitrovitamin D3 2 were synthesized using the palladium-catalyzed alkylative enyne cyclization reaction. Their biological properties were studied based on VDR binding affinity and HL-60 cell differentiation activity. PMID- 10091689 TI - Nucleosides and nucleotides. 183. Synthesis of 4'alpha-branched thymidines as a new type of antiviral agent. AB - A series of 4'alpha-branched thymidines was synthesized and evaluated as potential antiviral agents. 4'-Ethylthymidine (3), 4'-ethenylthymidine (5), and 4'-ethynylthymidine (6) exhibited potent anti-HSV-1 and anti-HIV-1 activities with no significant cytotoxicity. PMID- 10091690 TI - Modulation of multidrug resistance in tumor cells by taxinine derivatives. AB - Among a series of taxinine (1) and its designed derivatives (2-33), two taxoids (29 and 33) increased cellular accumulation of vincristine in multidrug-resistant tumor cells more potently than verapamil, while the activities of eight taxoids (11, 14-16, 22, and 30-32) were comparable with that of verapamil. These results reveal that some taxinine derivatives are good modifiers of multidrug resistance in tumor cells. PMID- 10091691 TI - Proof that the ACTVI genetic region of Streptomyces coelicolor A3(2) is involved in stereospecific pyran ring formation in the biosynthesis of actinorhodin. AB - Pyran ring formation in the biosynthesis of actinorhodin in Streptomyces coelicolor A3(2) was studied using the act cluster deficient strain, CH999, carrying pRM5-based plasmids harbouring combinations of the actVI genes. The strain, CH999/pIJ5660 (pRM5 + actVI-ORF1), produced a chiral intermediate, (S) DNPA, suggesting that the actVI-ORF1 product is a reductase determining the C-3 stereochemical centre. PMID- 10091692 TI - Synthesis and thromboxane A2 antagonistic activity activity of indane derivatives. AB - A new series of indane derivatives were prepared and evaluated for their thromboxane A2 (TXA2, 1) antagonistic activity. Among these compounds, 24a (Z 335) was found to be a potent TXA2 antagonist in oral administration. PMID- 10091693 TI - The synthesis and evaluation of temperature sensitive tubulin toxins. AB - The synthesis of several potent inhibitors of tubulin polymerization that exert their activities through interaction at the colchicine binding site is described. These agents were evaluated for their abilities to inhibit the polymerization of tubulin and the growth of neoplastic cell cultures. Additionally, the inhibition of tubulin polymerization activity of these agents was assessed over a temperature range of 30-45 degrees C to ascertain the effect of temperature on this activity. Several of the compounds possess significant inhibition of tubulin polymerization activity, and select compounds exhibit this activity in a temperature dependent manner. PMID- 10091694 TI - Symmetrical anhydride-type serine protease inhibitors: structure-activity relationship studies of human chymase inhibitors. AB - We prepared a potent and relatively selective human chymase inhibitor 9 (-), based on the study of SAR of a symmetrical anhydride-type serine protease inhibitor 1. Kinetic studies suggested that 9 (-) reacts with the Ser residue at the active site of the enzyme, forming a stable acyl enzyme complex. We also showed the importance of the tri-substituted beta-amino acid structure for the potent anti-enzymatic activity. PMID- 10091695 TI - On the relationship of OSW-1 to the cephalostatins. AB - Antineoplastic bis-steroidal (cephalostatin-type) analogues of the saponin OSW-1 were produced from a dihydroaglycone of OSW-1. The key aglycone 6H was obtained from 5alpha-androstan-3beta-ol-17-one in 8 steps (38% yield). The SAR of the aglycones, intermediates, and hybrid analogues provide insights regarding the proposed common role of C22-oxocarbenium ions in the bioactivity of both OSW-1 and cephalostatins. PMID- 10091696 TI - New lead compounds for brassinosteroid biosynthesis inhibitors. AB - The first brassinosteroid biosynthesis inhibitor is reported. Among newly synthesized triazole derivatives, 4-(4-chlorophenyl)-2-phenyl-3-(1,2,4 triazoyl)butan-2-ol (6) was found to inhibit the growth of cress seedlings, and this inhibition was recovered by the treatment of brassinolide, suggesting that compound 6 primarily inhibits brassinosteroid biosynthesis. PMID- 10091697 TI - Synthetic [5,5] trans-fused indane lactones as inhibitors of thrombin. AB - Synthesis of trans-fused lactones containing the indane nucleus has resulted in a series of potent acylating inhibitors of thrombin. As an example compound 11e has an apparent second order rate constant of 11 x 10(6) M(-1)sec(-1) for the inhibition of thrombin. The anticoagulant activity of these compounds is discussed. PMID- 10091698 TI - Automated parallel synthesis of a tetrahydroisoquinolin-based library: potential prolyl endopeptidase inhibitors. AB - Solution-phase automated parallel synthesis of a Tic-based library is described. This library comprising 2560 members, was obtained from the combination of 80 carboxylic acids and 32 amines and was screened against Tc80 protease, a parasitic prolyl endopeptidase secreted by Trypanosoma cruzi. Pyrrolidine derivatives proved the most potent inhibitors with IC50 values found in the low nanomolar range. PMID- 10091699 TI - Inhibition of herpes proteases and antiviral activity of 2-substituted thieno[2,3 d]oxazinones. AB - Cinnamyl derivatives of thieno[2,3-d]oxazinones are mechanism-based inhibitors of the HSV-2, VZV and CMV herpes proteases which demonstrate nanomolar potency. Compounds 5 and 28 inhibit protease processing in HSV-2 infected cells with a selectivity index of at least 30. PMID- 10091700 TI - Inhibition of human cytomegalovirus protease by enedione derivatives of thieno[2,3-d]oxazinones through a novel dual acylation/alkylation mechanism. AB - Enedione derivatives of thieno[2,3-d]oxazinones are nanomolar inhibitors of CMV protease which act through a novel dual acylation of the catalytic serine and alkylation of the protease cysteine 161 via a Michael addition to the enedione moiety of the inhibitor. PMID- 10091701 TI - Simplification of adenophostin A defines a minimal structure for potent glucopyranoside-based mimics of D-myo-inositol 1,4,5-trisphosphate. AB - The synthesis of 1-O-[(3S,4R)-3-hydroxytetrahydrofuran-4-yl]-alpha-D glucopyranosid e 3,4,3'-trisphosphate (7), a novel Ca2+ mobilising agonist at the Ins(1,4,5)P3 receptor, designed by excision of two motifs of adenophostin A is reported, defining a potential minimal structure for potent glucopyranoside-based agonists of Ins(1,4,5)P3 receptors. PMID- 10091702 TI - Cleavage of the cyclohexyl-subunit of rapamycin results in loss of immunosuppressive activity. AB - The cyclohexyl-subunit of rapamycin was cleaved by a sequence involving a Baeyer Villiger reaction and acid hydrolysis of the resulting lactone-acetal as key steps. Binding of this new rapamycin derivative to FKBP12 was only slightly reduced by this modification, whereas the loss of antiproliferative and immunosuppressive activity was dramatic. These findings indicate that part of the cyclohexyl-subunit of rapamycin could belong to its effector domain. PMID- 10091703 TI - The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold. AB - The Bradykinin B2 receptor antagonist HOE 140 (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D Tic-Oic-Arg) has been used as a template for the de novo design and synthesis of a small number of non-peptide lead compounds based on the 1,4-benzodiazepin-2-one framework. Two of the compounds have been found to exhibit moderate K(i) values of 8.9 and 9.2 microM at the human Bradykinin B2 receptor. PMID- 10091704 TI - Novel cytokine release inhibitors. Part IV: analogs of podocarpic acid. AB - Podocarpic acid derivatives as cytokine (IL-1beta) release inhibitors are discussed. PMID- 10091705 TI - Structure-activity relationships of a series of benzothiophene-derived NPY Y1 antagonists: optimization of the C-2 side chain. AB - A series of benzo[b]thiophene-derived NPY-1 receptor antagonists is described. Systematic modification of the C-2 substituent afforded a 1000-fold range in Y1 receptor affinity. Appropriate substitution at the ortho and para positions of the C-2 phenyl ether produced a synergistic effect on Y1 binding affinity, which led to the discovery of the most active ligands, 12t (K(i) = 15 nM), 12u (K(i) = 11 nM), and 12v (K(i) = 13 nM). PMID- 10091706 TI - Comparative molecular field analysis (CoMFA) models of phenylethanolamine N methyltransferase (PNMT) and the alpha2-adrenoceptor: the development of new, highly selective inhibitors of PNMT. AB - As a guide to the development of new and more selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) vs the alpha2-adrenoceptor, we have performed a comparative molecular field analysis (CoMFA) on a series of 80 benzylamine analogues. Using the models obtained, we have proposed a series of 3 trifluoromethyl-1,2,3,4-tetrahydroisoquinolines and predicted the activity of other analogues. PMID- 10091707 TI - A highly efficient preparation of neoglycoconjugate vaccines using subcarriers that bear clustered carbohydrate antigens. AB - A limited amount of spacer-equipped carbohydrate haptens was linked by reductive amination to a subcarrier, an oligopeptide containing 16 amino groups, to give a hapten-carrying subcarrier (HCS). It was then linked, via the remaining free amino groups, to chicken serum albumin (CSA) to give a cross-linked neoglycoconjugate bearing the haptens in the form of clusters. Alternatively, the same type of a glycoconjugate, but with higher conjugation efficiency, was obtained when HCS was treated successively with squaric acid diethyl ester and CSA. PMID- 10091709 TI - Leucine-phenylalanine dipeptide-based N-mesyloxysuccinimides: synthesis of all four stereoisomers and their assay against serine proteases. AB - The four stereoisomers of 3-(N-acetylleucylamino)-3-benzyl-1 [(methylsulfonyl)oxy]succinimid e have been prepared and shown to inhibit alpha chymotrypsin and human neutrophil elastase. The structural and stereochemical features that affect the potency and selectivity of inhibition are discussed. PMID- 10091708 TI - Potent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclization. AB - Backbone cyclization of urea-based somatostatin agonists resulted in novel, orally bioavailable agonists. Binding assays confirmed that the resulting conformationally constrained cyclic ureas retained the potency of their acyclic counterparts. SAR studies subsequently led to highly potent analogs, selective for receptor subtype 2, and having good oral bioavailability. PMID- 10091710 TI - Diamine preparation for synthesis of a water soluble Ni(II) salen complex. AB - A reliable and efficient synthesis of a Ni(II) salen complex useful in probing nucleic acid structure is described and illustrates a general approach for constructing cis diamines suitable for assembly into N2O2 Schiff base complexes. Two equivalents of an aryllithium reacted with 1,4-dimethylpiperazine-2,3-dione to form the symmetric alpha-dione. This material was then converted to its dioxime and reduced by TiCl4/NaBH4 to yield the meso-diamine. Condensation of the diamine and salicyladehyde, coordination of nickel and final methylation generated the desired water soluble and redox active complex. PMID- 10091711 TI - The synthesis and P388 cytotoxicity of mycalazol 11 and related 5-acyl-2 hydroxymethylpyrroles. AB - We report a general method for the synthesis of mycalazol 11 and some related 5 acyl-2-hydroxymethylpyrroles using a Stille coupling of 5-(tri-n butylstannyl)pyrrole-2-carboxaldehyde with an acid chloride as the key step. The newly prepared 5-acyl-2-hydroxymethylpyrroles 5-7, together with the 5 carboxamido-2-hydroxymethylpyrrole 10, have been assayed for in vitro cytotoxicity against the P388 murine leukemia cell line. PMID- 10091712 TI - Behavioral studies of the effects of moderate oligemic hypoxia caused by bilateral clamping of carotid arteries in mice. Impairment of spatial working memory. AB - The experiments carried out on Albino Swiss mice indicated that bilateral clamping of carotid arteries (BCCA) for 30 min caused no neuronal damage but produced an increase in GABA content in the hippocampus, striatum and frontal cortex. The behavioral studies have shown that BCCA did not influence the motor coordination, the spontaneous locomotor activity, the reactivity to pain and the cataleptic response to haloperidol of the mice. However, a significant increase in amphetamine-induced hyperactivity was observed after BCCA. In mice, BCCA did not impair long-term memory and spatial working memory, reflected by alternation behavior in the Y-maze. The same dose of scopolamine impaired the working memory in mice which underwent BCCA much more than sham-operated controls. Naftidrofuryl improved the working memory in mice subjected to BCCA as measured 48 h after the surgery. Pretreatment with naftidrofuryl protected the animals against the impairment of alternation behavior caused by scopolamine administration. PMID- 10091713 TI - Comparison of the effects of low and high concentrations of group I metabotropic receptor agonists on field potentials in the hippocampal CA1 region in vitro. AB - We compared the effects of low and high concentrations of the selective group I metabotropic glutamate receptor (mGluR) agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) and the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3 dicarboxylic acid ((1S,3R)-ACPD) on extracellularly recorded potentials which were evoked in the rat hippocampal CA1 region by stimulation of the Schaffer collateral/commissural pathway and on intracellularly recorded electrophysiological properties of CA1 neurons, in vitro. At low concentrations (2.5 and 5 microM) DHPG and (1S,3R)-ACPD increased while at high concentrations (20 and 50 microM) they decreased population spike amplitudes. Simultaneous recordings of population spikes in the CA1 cell layer and field excitatory postsynaptic potentials (fEPSPs) in stratum radiatum of the CA1 area revealed that the enhancement of the population spike amplitude is not associated with any change in the fEPSP slope, but the decrease in population spikes is accompanied with a decrease in the fEPSP slope, suggesting that at high concentrations both agents may attenuate excitatory synaptic transmission in CA1 cells. DHPG and (1S,3R)-ACPD had a number of direct excitatory effects on CA1 pyramidal cells like a concentration-dependent depolarization and an inhibition of the slow afterhyperpolarization, which in all probability underlay the increase in the amplitude of population spikes. At high concentrations, both mGluR agonists strongly depolarized CA1 cells indicating that depolarization block of cell discharges may underlay the reduction in the population spike amplitude. Furthermore, robust cell discharges induced by the strong depolarizations, activate several secondary processes which may significantly contribute to the action of high concentrations of DHPG and (1S,3R)-ACPD. Therefore, the effects of low and high concentrations of the studied mGluR agonists may involve different mechanisms, at low concentrations the effects can be directly related to the activation of postsynaptically localized group I mGluRs while at higher concentrations the contribution of indirect effects may predominate. PMID- 10091714 TI - N6-2-(4-aminophenyl)ethyladenosine (APNEA), a putative adenosine A3 receptor agonist, enhances methamphetamine-induced dopamine outflow in rat striatum. AB - In the present study, the effect of adenosine A3 receptor agonist, N6-2-(4 aminophenyl)ethyladenosine (APNEA), on methamphetamine (MTH)-induced dopamine (DA) release in rat striatum was evaluated using microdialysis in freely moving animals. MTH at a dose of 5 mg/kg injected 3-times every two hours produced massive overflow of DA and decline in the level of DOPAC (3,4 dihydroxyphenylacetic acid) and HVA (homovanillic acid). APNEA perfused locally to the striatum via microdialysis probe triggered opposite effects, at 75 microM it diminished MTH-induced DA overflow during first 2 h of the experiment (p<0.05), but potently enhanced it at higher 100 microM concentration for entire period of treatment (p<0.001). Concomitant release of glutamate in striatum was slightly decreased by MTH alone, and significantly diminished by coadministration of 100 M APNEA (p<0.001). The data indicate that activation of adenosine A3 receptor exerts rather toxic effect on DA neurons and exacerbates neurotoxicity of MTH. In addition, MTH-induced DA overflow does not seem to result from the increased release of striatal glutamate level. PMID- 10091715 TI - Effects of calcium ions and substances affecting Ca2+ -related mechanisms on histamine-evoked stimulation of cyclic AMP formation in chick pineal gland. AB - In avian central nervous system (CNS), and particularly in the pineal gland, histamine (HA) potently stimulates synthesis of cyclic AMP in intact tissue, and only weakly affects adenylyl cyclase activity in membrane preparation. In this work, we focussed on calcium (Ca2+) as a possible link in the mechanism through which HA affects cyclic AMP generation in the chick pineal. The problem was studied in two sets of experiments where the action of HA on the pineal cyclic AMP was tested: (1) in the incubation medium containing various compounds influencing Ca2+ influx and/or Ca2+ intracellular concentration/action (Ca2+ ionophore calcimycin, Ca2+ -channel agonist Bay-K 8644, Ca2+ -channels blockers: diltiazem, verapamil, nifedipine and omega-conotoxin-GVIA, CaCl2, EGTA in the absence of CaCl2 in the incubation medium, as well as calmodulin inhibitors: calmidazolium and W-7), and (2) in a CaCl2-free incubation medium yet containing different concentrations of BaCl2, CdCl2, CoCl2, MgCl2, and NiSO4. The results of the first series were mostly negative; an exception was the inhibiton of the HA evoked cyclic AMP formation observed in the presence of 5.2 and 10.4 mM CaCl2 In the second series of experiments, divalent cations (however with the exception of Mg2+, which was inactive at concentrations up to 15.6 mM) inhibited the HA-evoked cyclic AMP production, with the following rank order of potency: Cd2+ >> Co2+ >> Ni2+ > Ba2+. The inhibitory effect of CdCl2 was prevented by nifedipine. Taken together, the present data suggest that intracellular Ca2+ -related mechanisms are not of major importance in the HA action on cyclic AMP synthesis in the chick pineal. It could be suspected that the inhibition of the HA-driven cyclic AMP formation by high concentrations of Ca2+, and other divalent cations, probably resulted from their direct inhibitory interaction with the catalytic site of the pineal adenylyl cyclase. PMID- 10091716 TI - Effect of enflurane on selected neuropeptides and marker enzymes in rabbit brain. AB - The aim of this study was to evaluate the effect of 5-, 15-, and 60-min enflurane anesthesia on the levels of Met-enkephalin, Leu-enkephalin and neuropeptide Y in discrete areas of the rabbit brain. We also evaluated the effect of enflurane anesthesia on energetic, transport and catabolic processes by measuring the activities of succinate dehydrogenase, magnesium-dependent adenosine triphosphatase and acid phosphatase in the rabbit striatum and hypothalamus. Induction of anesthesia (5 min) decreased Met-enkephalin levels in the hypothalamus and striatum, and increased them in the hippocampus and mesencephalon. Induction of anesthesia increased Leu-enkephalin levels in all brain areas studied, except for the striatum, and increased neuropeptide Y content in the hippocampus. 15- and 60-min enflurane anesthesia increased Met enkephalin content in the hypothalamus and hippocampus. After 15- and 60-min anesthesia, and after cessation of anesthesia, Leu-enkephalin levels were increased in the hypothalamus and mesencephalon, and were decreased in the striatum and hippocampus. In the striatum, neuropeptide Y content was significantly decreased during anesthesia and after cessation of anesthesia. Histochemical analysis revealed that enflurane enhanced ATP production, catabolic processes, and the rates of exchange and transport of energetic substrates in the striatum and hypothalamus. In conclusion, enflurane affects the levels of Met, Leu-enkephalins and NPY in a manner depending on the duration of anesthesia and the brain structure. Compared with isoflurane , which was studied in our previous study enflurane produces stronger alterations in the activities of enzymatic marker in the rabbit brain. This suggests that enflurane may be less safe than isoflurane. PMID- 10091717 TI - Terikalant modifies the contractility and effective refractory period of heart muscle: comparative study in rats and guinea pigs. AB - The aim of the present study was to examine concentration-dependent effects of terikalant, a blocker of inwardly rectifying K+ currents (IK1), rapidly activated delayed rectifying currents (IKr) and transient outward currents (Ito), on the contractility and effective refractory period in rat and guinea pig isolated papillary muscles. The following parameters were measured: force of contraction (Fc), velocity of contraction (+dF/dt), velocity of relaxation (-dF/dt) and effective refractory period (ERP). ERP was measured indirectly, as the shortest interval between two stimuli S1-S2 inducing an increase in amplitude of force of contraction by at least 25% above baselin value. It has been found that terikalant exerted triphasic effect in the guinea pig preparation. First, a positive inotropic effect and a prolongation of ERP was observed at drug concentrations of 0.03, 0.1 and 0.3 microM. Then, a negative inotropic action was noted at drug concentration of 1 microM in comparison with the maximum positive inotropic action, without significant effect on ERP duration. Subsequently, a positive inotropic action at drug concentrations of 3 and 10 microM and significant prolongation of ERP were detected in comparison with the effects obtained at 1 microM concentration. In rat preparations, however, terikalant had no effect on the contractility and the duration of ERP in the concentration range from 0.03 to 1 microM. At 1 and 3 microM, a tendency to the negative inotropic action was observed, but the results were not significantly different as compared with the control value. At 10 microM, a significant positive inotropic action and prolongation of ERP duration occured, in comparison with the control values as well as the values obtained at terikalant concentration of 1 microM. These differences in the effects of terikalant in guinea pig and rat papillary muscles are probably due to the species differences, especially to a lack of functional IK current in rat heart. PMID- 10091718 TI - 1,4-Benzoxazin-3(4H)-one derivatives and related compounds as 5-HT1A and 5-HT2A receptor ligands; the effect of the terminal amide fragment on the 5-HT1A/5-HT2A affinity and functional activity. AB - A number of new 1-phenyl- (a), 1-(3-chlorophenyl)- (b) and 1-(2-methoxyphenyl)- (c) piperazine derivatives containing 1,4-benzoxazin-3(4H)-one (2-4), 2,4 benzoxazin-3-(4H)-one (5), 1,2-benzoxazolin-3-one (6) and 1,3-benzoxazolin-2,4 dione (7) were synthesized. Radioligand binding measurements showed that the majority of compounds had a distinct affinity for 5-HT1A (3a, 6a, 2-5b, 6c; Ki = 7.5-81 nM) and/or 5-HT2A (2b, 5-7a,b; Ki = 18-69 nM) receptors. Structure Activity Relationship (SAR) studies revealed structural features which seem to favour the binding to either or both of these two receptor subtypes. For evaluation of the functional in vivo profile of the most potent 5-HT1A (5b, 6b) and/or 5-HT2A (5-7b) ligands, the following tests were used: the 8-OH-DPAT induced lower lip retraction (LLR) and behavioral syndrome in rats--for 5-HT1A receptor antagonistic activity, and the (+/-)DOI-induced head twitches in mice and the (+/-)DOI-induced discriminative stimulus properties in rats--for 5-HT2A receptor antagonistic properties. The obtained results show that compounds 5b and 6c behave like potent 5-HT1A antagonists, whereas 5b, 6b and 7b demonstrate 5 HT2A receptor antagonistic properties. None of the in vivo tested compounds, given alone, mimicked 8-OH-DPAT activity in those tests. It seems that derivative 5b, which has an equipotent 5-HT1A and 5-HT2A affinity and antagonistic properties at both these receptors, is a promising potential psychotropic substance. PMID- 10091719 TI - Effect of linking bridge modifications on the 5-HT1A receptor activity of some 4 (omega-benzotriazol-1-yl)alkyl-1-(2-methoxy-phenyl)piperazines. AB - A new series of arylpiperazines with two (2a-4a) and four (2c-4c) methylene spacers was synthesized. Compounds 2a, 2c, 3c, 4a and 4c were found to be 5-HT1A ligands (Ki = 4-88 nM). The most promising compound, 2c, bound with the highest affinity (Ki = 4 nM) at 5-HT1A sites. The results of in vivo experiments showed that compounds 2a-4a were inactive, while 2c-4c revealed a distinct antagonistic activity towards postsynaptic 5-HT1A receptors. The pharmacological profile of the tested compounds was discussed in comparison with that of the three methylene analogs b, described earlier. PMID- 10091720 TI - Anxiolytic- and antidepressant-like effects of an antagonist at glycineB receptors. AB - L-701,324 [7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1H)-quinolone], a selective antagonist at glycineB receptors, was studied in behavioral tests used to predict a potential anxiolytic (conflict drinking test in rats, four-plate test in mice) and antidepressant (forced swimming test in rats and mice) activity. In the conflict drinking test in rats, L-701,324 (0.5 mg/kg, but not 0.25 and 1 mg/kg) increased the number of punished licks in a statistically significant manner. In the four-plate test in mice, L-701,324 (2 mg/kg, but no lower doses) significantly increased the number of punished crossings. In the forced swimming test in rats, L-701,324 (0.5 mg/kg) slightly, but statistically significantly, reduced the immobility time; the drug was inactive in doses of 0.25 and 1 mg/kg. In mice, L-701,324 administered only in the highest dose used (2 mg/kg) significantly shortened the immobility time. L-701,324 (given in doses higher then 2 mg/kg) induced motor impairment in animals. The above findings indicate that L-701,324 shows weak anxiolytic- and antidepressant-like activities in the animal models used. PMID- 10091721 TI - Effect of neurosteroids on glutamate binding sites and glutamate uptake in rat hippocampus. AB - Effects of some neurosteroids on the binding of [3H]-glutamate, [3H]-alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and [3H]-MK-801, as well as on the [3H]-glutamate uptake were examined in rat hippocampus. The following compounds were evaluated: (a) positive modulators of the GABA(A) receptor: 5alpha pregnan-3alpha-ol-20-one (allopregnanolone), 5alpha-pregnane-3alpha,21-diol-20 one (allotetrahydrodeoxycorticosterone), 5alpha-pregnan-3alpha-ol-11,20-dione (alphaxalone) and 5alpha-androstan-3alpha-ol-17-one (androsterone); (b) compounds showing GABA(A)-antagonistic and/or N-methyl-D-aspartic acid (NMDA)-agonistic properties: dehydroepiandrosterone sulfate and pregnenolone sulfate; (c) a substance which, apart from its GABA(A)-agonistic potency, has a NMDA antagonistic action: 5beta-pregnan-3alpha-ol-20-one. None of those neurosteroids tested at concentrations of 0.001-100 microM affected the binding of [3H] glutamate, [3H]-AMPA and [3H]-MK-801 or the glutamate uptake. The present study suggests that the previously reported inhibitory effects of neurosteroids on excitatory amino acid-induced seizures and neurotoxicity can be linked neither to the direct interaction of these compounds with the above binding sites on glutamate receptor complexes, nor to the glutamate uptake mechanism. PMID- 10091722 TI - Influence of bezafibrate on total antioxidant activity of serum and deformability of blood cells in hypercholesterolaemic patients. AB - Fourteen patients with hypercholesterolaemia were treated with bezafibrate (600 mg/day) for a month. Before and after the treatment some biochemical and physical parameters were investigated. Plasma cholesterol levels, elevated before treatment, significantly decreased after one month (p<0.001). Deformability of red blood cells increased significantly in this time (p<0.05). Total antioxidant status of serum decreased statistically significantly (p<0.01). It is concluded that the mechanism of action of bezafibrate is not connected with resistance to oxygen free radicals since the drug has no antioxidant activity. A main mechanism of action of bezafibrate seems to be lowering the cholesterol level. An increase in deformability of red blood cells may make some contribution to this mechanism. PMID- 10091723 TI - Strychnine-insensitive glycine/NMDA sites are altered in two stress models of depression. AB - Chronic severe stress (CSS) and chronic mild stress (CMS) affect the properties of [3H]5,7-dichlorokynurenic acid (5,7-DCKA) binding to strychnine-insensitive glycine/NMDA sites in the rat cerebral cortex. Specifically, CSS decreases, while CMS increases, the potency of glycine to displace [3H]5,7-DCKA binding to glycine/NMDA sites. Moreover, in both models, a reduction of the specific [3H]5,7 DCKA binding was observed. The present results demonstrate the involvement of the cortical NMDA receptor complex in the animal models of depression. PMID- 10091724 TI - Transforming growth factor-beta1: a useful tumor marker in patients with colorectal carcinoma? PMID- 10091725 TI - Pathologic prognostic factors in Barrett's associated adenocarcinoma: a follow-up study of 96 patients. AB - BACKGROUND: The objective of this study was to evaluate a variety of histologic features, some of which to our knowledge have never been evaluated in Barrett's associated adenocarcinoma (BAd) (such as Crohn's-like lymphoid reaction and peritumoral lymphoid response) in patients with and without preoperative neoadjuvant chemotherapy combined with radiotherapy (chemrad) to determine their prognostic significance in these two groups of patients. METHODS: Tumor sections from 96 patients (83 males and 13 females; mean age, 62 years) with resected BAd (61 with chemrad and 35 without chemrad) were evaluated for numerous histologic features such as pathologic stage according to the American Joint Committee on Cancer TNM staging system, peritumoral lymphoid infiltrate, Crohn's-like lymphoid reaction, and degree of post chemrad residual tumor and correlated with the preoperative chemrad status and with survival (mean follow-up, 23 months). RESULTS: By univariate analysis, older patient age (P = 0.02), higher pathologic stage (P = 0.02) (including depth of invasion and lymph node status), infiltrative growth pattern (P = 0.05), perineural invasion (P = 0.05), vascular invasion (P = 0.04), and the absence of a peritumoral lymphoid infiltrate (P = 0.04) were associated with shortened survival in the entire cohort and in patients without chemrad, with the exception of infiltrative growth pattern (P = 0.1 in the nonchemrad group only). Higher stage was the only feature associated with decreased survival in the chemrad group. Subcategorization of lymph nodes according to the number involved with metastases (fewer than four, four to seven, and greater than seven) had no further effect on prognosis. However, subcategorization of T1 tumors into Tla and T1b did influence prognosis in a negative manner. Using multivariate analysis, only older patient age (P = 0.005) and the absence of a peritumoral lymphoid infiltrate (P = 0.05) were statistically associated with poor survival independent of stage. In addition, perineural invasion (P = 0.07) showed a trend toward shortened survival in patients with this feature. Preoperative chemrad had no effect on survival in this retrospective nonrandomized cohort of patients. CONCLUSIONS: This study confirms the strong prognostic usefulness of the TNM staging system in patients with resected BAd, even in those patients who received preoperative chemrad. In addition, older patient age, the absence of a peritumoral lymphoid infiltrate, and possibly perineural invasion correlate with poor survival independent of pathologic stage in patients with these tumors. PMID- 10091726 TI - Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma. AB - BACKGROUND: The majority of advanced gastric carcinoma patients with serosal invasion die of peritoneal recurrence, even when a curative gastrectomy is performed, because peritoneal recurrence occurs due to intraperitoneal free tumor cells that detach from the serosal-invaded focus. In an attempt to prevent peritoneal recurrence, intraperitoneal hyperthermic chemoperfusion (IHCP) treatment was combined with aggressive surgery. METHODS: Between March 1987 and December 1996, 141 gastric carcinoma patients with macroscopic serosal invasion were allocated randomly to 2 groups. Seventy-one patients underwent IHCP combined with surgery (IHCP group) and the remaining 70 patients underwent surgery alone (control group). IHCP was performed just after gastric resection and alimentary tract reconstruction under general anesthesia along with systemic hyperthermia. RESULTS: Postoperative complications were reported in 2 of the 71 patients in the IHCP group and in 2 of the 70 patients in the control group. The peritoneal recurrence rate in the IHCP group was significantly decreased (P = 0.0000847) compared with that in the control group. The 2-year, 4-year, and 8-year survival rates for the IHCP group were 88%, 76%, and 62%, respectively, whereas those for the control group were 77%, 58%, and 49%, respectively. The IHCP group thus reaped a significant survival benefit (P = 0.0362) compared with the control group. CONCLUSIONS: Although this study was conducted randomly for a small number of patients, compared with the control group, the IHCP group had a high survival rate and better prognosis. PMID- 10091727 TI - 5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. AB - BACKGROUND: The objectives of the current study were: 1) to verify whether the addition of modulating low doses of interferon-2b (IFN) to 5-fluorouracil (5-FU) and levofolinic acid (1-FA) could improve clinical results in patients with advanced colorectal carcinoma; and 2) to evaluate the role of tumor burden and liver involvement as prognostic factors. METHODS: A total of 204 untreated patients were randomized to receive 1-FA at 100 mg/m2 and 5-FU at 375 mg/m2 for 5 consecutive days with or without IFN every 3 weeks. IFN was given subcutaneously at 3 MU/day for 7 days starting 2 days before chemotherapy administration. Patients were stratified according to the presence or absence of hepatic disease (H+ or H-) and to total tumor burden defined as "low" or "high" using an area of 10 cm2 as the cutoff value. Thus, four patient categories were obtained: Group 1: H+ > or = 10 cm2; Group 2: H+ < 10 cm2; Group 3: H- > or = 10 cm2; and Group 4: H < 10 cm2. RESULTS: No differences were observed in the objective response rate (23% for the combination of 1-FA and 5-FU vs. 24% for the 1-FA, 5-FU, and IFN regimen), median duration of response (11 months vs. 10 months), time to progression (5 months in both arms), and median survival (11 months vs. 12 months). A statistically significant improvement in response rate was observed in patients with limited liver involvement versus those with massive involvement independent of the chemotherapy arm (44% vs. 22%; P = 0.02). Overall survival also was improved in patients with limited liver disease (P = 0.0001) and in those without liver involvement (P = 0.004). Multivariate analysis confirmed these data and identified response and female gender as positive prognostic factors. Toxic side effects (mainly diarrhea, mucositis, and fever) were statistically more frequent in the IFN arm. CONCLUSIONS: The addition of low modulating doses of IFN to the regimen of 5-FU and I-FA failed to increase the response rate and survival of patients with advanced colorectal adenocarcinoma and significantly worsened toxicity. High tumor burden and the presence of liver involvement were confirmed prospectively as poor prognostic factors and should be taken in account in designing future Phase II or comparative trials. PMID- 10091728 TI - Amplified CDK2 and cdc2 activities in primary colorectal carcinoma. AB - BACKGROUND: Cyclins are overexpressed in various malignancies, including carcinoma of the colorectum, esophagus, lung, larynx, and breast. However, to the authors' knowledge, the protein levels and activities of cyclin-dependent kinases (CDKs), which are the functional cyclin partners in the cell cycle, have not been investigated previously. METHODS: Eight samples of cancer tissue and adjacent normal tissue were taken from 23 patients with Stage B2-C1 (AJCC/UICC Stage II III) colorectal carcinoma during curative resection. The protein levels of cyclin and CDKs were determined by Western blot analysis. The activities of CDKs were determined by the phosphorylation amount using specific substrates after immunoprecipitations. RESULTS: The protein expression of cyclin (D1, D3, E, and A) and CDKs (CDK4, CDK2, and cdc2) was higher in primary colorectal carcinoma tissue than in adjacent normal tissue. Whereas only 3 of 8 patients had increased CDK4 activity in cancer tissue, 8 of 8 and 7 of 8 patients had increased CDK2 and cdc2 activities, respectively, in cancer tissue compared with adjacent normal tissue. However, there were no positive correlations among the pathologic staging or differentiation status and the increased ratio of cyclin protein, CDK protein, or CDK activity. CONCLUSIONS: These results indicate that significant activation of S and M phases of the cell cycle occurs in primary colorectal carcinoma. PMID- 10091729 TI - Elevated serum levels of transforming growth factor-beta1 in patients with colorectal carcinoma: its association with tumor progression and its significant decrease after curative surgical resection. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) acts as a potent inhibitor of cell growth and tumor progression but loss of this negative regulation can contribute to tumor development. Some studies have reported an association between disease progression and TGF-beta1 expression in patients with colorectal carcinoma, but their results were not always consistent. METHODS: Serum levels of TGF-beta1 were measured using an enzyme-linked immunoadsorbent assay in 121 consecutive patients with colorectal carcinoma and compared with TGF beta1 serum levels in 31 healthy volunteers. Serum levels of TGF-beta1 also were measured in 50 patients who underwent curative surgical resection (part of the 121 preoperative patients) to compare their levels with preoperative serum levels of TGF-beta1. RESULTS: Serum levels of TGF-beta1 in patients with colorectal carcinoma (45+/-15 ng/mL) (mean+/-the standard deviation) were significantly higher than those in the healthy control group (32+/-4 ng/mL) (P = 0.001). Serum levels of TGF-beta1 increased with increasing tumor stage (P < 0.01). Serum levels of TGF-beta1 were correlated significantly with depth of tumor invasion, lymph node metastasis, distant metastasis, and serum levels of carcinoembryonic antigen (CEA). Serum levels of TGF-beta1 tended to increase with increasing CEA (correlation coefficient = 0.21; P < 0.05). The mean serum level of TGF-beta1 in patients with colorectal carcinoma before surgery (45+/-14 ng/mL) (n = 50) significantly decreased to 34+/-7 ng/mL, which was within the normal range (32+/ 4 ng/mL), after curative surgical resection of the tumor (P = 0.0000). Serum levels of TGF-beta1 after tumor resection decreased more significantly in patients with higher preoperative levels of TGF-beta1 (from 53+/-12 ng/mL to 36+/ 6 ng/mL) (n = 30). CONCLUSIONS: The results of the current study suggest that serum levels of TGF-beta1 in colorectal carcinoma patients may be associated with disease progression and may be used as a biomarker in the management of colorectal carcinoma patients. The authors believe further studies with a large number of patients for a longer follow-up period are necessary to conclude whether serum levels of TGF-beta1 carry significant clinical relevance. PMID- 10091730 TI - Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. AB - BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare neoplasm of vascular origin that occurs in the liver and other organs; its etiology is unknown. METHODS: The authors analyzed the clinicopathologic and immunohistochemical features of 137 patients with EHE of the liver in an attempt to identify features that might predict tumor behavior. To their knowledge, this article represents the largest series reported from one institution. RESULTS: Patients were ages 12 86 years; 84 (61%) were females and 53 (39%) were males. They presented with nonspecific symptoms such as right upper quadrant pain or weight loss. Macroscopically, the tumors usually were multiple. They typically were white, firm to hard, and ranged in size from 0.2-14 cm. Histologically, the tumors were comprised of dendritic and epithelioid cells that often contained vacuoles representing intracellular lumina. The stroma was fibrous, with myxohyaline areas. Immunohistochemically, all tumors were positive for at least one endothelial marker (factor VIII-related antigen [FVIII-RAg], CD34, and/or CD31). Treatment modalities included hepatic resection or transplantation. Although the metastatic rate in this series was 27%, the prognosis is considered much more favorable than that of other hepatic malignancies. Twenty-six patients (43%) survived > or = 5 years; 2 patients were alive and well at last follow-up after 23 and 27 years, respectively. Twenty-six of 60 patients (43%) died of their disease, 1 of whom died 28 years after discovery of her tumor. In an attempt to predict behavior of the tumor, several histologic parameters were evaluated using univariate analysis. No significant correlation was found with mitoses, Glisson's capsule infiltration, or nuclear atypia. High cellularity was significantly correlated with a poor clinical outcome (P = 0.00012), whereas the association with tumor necrosis approached significance (P = 0.057). CONCLUSIONS: EHE is a very rare clinical entity. The key to diagnosis is the demonstration of cells containing FVIII-RAg. The histology of the tumor, including nuclear pleomorphism and the mitotic count, are of no value in predicting clinical outcome. High cellularity most likely is the most significant parameter predicting an unfavorable prognosis in EHE because mitotic counts often are quite low in both low grade and aggressive tumors. Further studies are needed to identify the factors responsible for the apparent dissociation between the clinical behavior and biologic characteristics of this tumor. PMID- 10091731 TI - Analysis of paraaortic lymph node involvement in pancreatic carcinoma: a significant indication for surgery? AB - BACKGROUND: Lymph node status is a key prognostic factor for pancreatic carcinoma. The paraaortic lymph nodes are the highest level of lymph nodes that can be resected safely in the abdomen for pancreatic and other gastrointestinal tumors. The pattern of paraaortic lymph node involvement and its relation with other lymph node groups were analyzed and the significance of this information relative to surgical therapy examined. METHODS: Between 1974-1996, 99 patients with invasive ductal carcinoma of the pancreas underwent pancreatectomy at the study institution. The pattern of lymph node involvement, particularly paraaortic, was evaluated by careful pathologic review of extended lymphadenectomy specimens. RESULTS. Fifty-eight of 76 patients (76%) with carcinoma in the pancreatic head (Ph) and 19 of 23 patients (83%) with carcinoma of the pancreatic body and tail (Pbt) had lymph node involvement. Fourteen patients with Ph disease (18%) and 4 with Pbt disease (17%) had paraaortic lymph node involvement. Tumor size did not correlate with paraaortic lymph node involvement. A correlation was found between Group 13 (posterior pancreaticoduodenal lymph nodes), Group 14 (lymph nodes surrounding the superior mesenteric artery), and the paraaortic lymph nodes for Ph disease. All paraaortic lymph node metastases were located in the 16M region (the region between the celiac trunk and the inferior mesenteric artery). For patients with Pbt disease, the distribution of paraaortic lymph node metastases was the same as for those with Ph disease. Only 33% of cases of paraaortic lymph node metastases were suspected preoperatively or perioperatively. The longest survival for a patient with paraaortic lymph node metastases was 36 months and 17 months, respectively, for patients with Ph and Pbt disease. CONCLUSIONS: The paraaortic lymph nodes are frequent sites of metastasis from pancreatic carcinoma, and are difficult to evaluate preoperatively or perioperatively. This situation mandates paraaortic lymph node dissection, at least in the 16M region. PMID- 10091732 TI - Spontaneous apoptosis in laryngeal squamous cell carcinoma is independent of bcl 2 and bax protein expression. AB - BACKGROUND: bcl-2 and bax genes are known to be involved in the control of apoptotic cell death, an important mechanism of growth regulation that influences the biologic behavior of tumors. The aim of the current study was to investigate the relationship of bcl-2 and bax expression to the rate of spontaneous apoptosis in laryngeal carcinomas, and to assess its relations to clinicopathologic features of tumors. METHODS: Immunohistochemical analyses for bcl-2 and bax were performed on paraffin embedded tissue sections from 134 primary laryngeal squamous cell carcinomas. To visualize apoptotic cells, the nick end labeling method was used. The proliferative activity of tumors was analyzed by determination of mitotic indices. RESULTS: bcl-2 immunoreactivity was positively correlated with tumor grade (P < 0.00001), high T category (P < 0.02), metastatic involvement of cervical lymph nodes (P < 0.003), and supraglottic or subglottic location of primary tumors (P < 0.00005). An inverse relation was found between bcl-2 and bax expression (P < 0.004). The frequency of spontaneous apoptosis was closely associated with mitotic activity (P < 0.0004) but appeared to be unrelated to protein levels of bcl-2 or bax as well as to bcl-2:bax ratios. CONCLUSIONS: The results of this study point to the significance of cell proliferation as a major determinant of the rate of spontaneous apoptosis in laryngeal carcinomas. The bcl-2:bax expression ratio obviously does not affect the incidence of apoptosis, but it may be considered as a marker of disease progression and poor prognosis. PMID- 10091733 TI - Genetic changes in the spectrum of neuroendocrine lung tumors. AB - BACKGROUND: Recent classifications identify four categories of neuroendocrine (NE) tumors of the lung: low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC), and high grade large cell neuroendocrine carcinoma (LC NEC) and small cell lung carcinoma (SCLC). METHODS: The authors studied the molecular changes present in 59 archival NE tumors (10TCs, 11 ACs, 18 LNECs, and 20 SCLCs). Utilizing microdissection and polymerase chain reaction-based assays, the authors examined loss of heterozygosity (LOH) at ten chromosomal regions frequently deleted in lung tumors (3p, 5q, 11q, 13q, and 17p) and for mutations at the p53 and ras genes. RESULTS: With the exception of ras gene mutations, the majority of these changes frequently were present in carcinomas and were present at lower frequencies in carcinoids. LOH at one or more 3p regions was the most frequent change found in the carcinoids. A relatively high incidence of LOH at the MEN1 gene was common in all NE lung tumors. The incidence of LOH and p53 gene abnormalities progressively increased with increasing severity of tumor type. The patterns of p53 gene mutations were different between AC and high grade NE tumors. LOH at 5q21 was correlated with poor survival in the carcinoid group. CONCLUSIONS: Although NE lung tumors have varied etiologies, the results of the current study support the clinicopathologic concept that they represent a spectrum ranging from low grade TC to the highly malignant NE carcinomas. PMID- 10091734 TI - Extramedullary tumors of myeloid blasts in adults as a pattern of relapse following allogeneic bone marrow transplantation. AB - BACKGROUND: Extramedullary tumors of lymphoid and myeloid blasts outside the well defined sanctuaries following allogeneic bone marrow transplantation (allo-BMT) are rare. Little is known about the biology, treatment, and outcome of these tumors in this setting. METHODS: In this retrospective analysis, 134 consecutive patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who underwent allo-BMT at a single institution between 1990 and 1998 were reviewed. Five cases of isolated extramedullary myeloid sarcoma that occurred as patterns of recurrence following allo-BMT between 1990 and 1998 are reported. These patients were treated with radiotherapy, systemic chemotherapy, or a second allo BMT. Clinical outcome is compared with posttransplantation bone marrow relapses observed during the same period at the same institution. The literature on the clinical characteristics, currently available treatment, and outcome of posttransplantation myeloid sarcoma patients was reviewed. RESULTS: Excluding isolated skin and central nervous system recurrences, the frequency of extramedullary myeloid sarcoma encountered as a relapse pattern following allo BMT was determined to be 3.7% among patients with acute or chronic leukemia of myeloid origin. The survival of patients who were managed with radiotherapy and systemic chemotherapy was less than 4 months. A patient who underwent a second allo-BMT following local radiotherapy is alive and in complete remission more than 33 months after the diagnosis of myeloid sarcoma. The median survival of 17 patients with posttransplantation bone marrow relapse following allo-BMT was 2.2 months. When posttransplantation medullary recurrences are analyzed, patients with CML had a median survival of 12 months, with a significantly better 5-year survival rate than patients with AML (0 vs. 60%, P = 0.015; median survival, 12 months). CONCLUSIONS: The clinical outcomes of patients with recurrent isolated extramedullary myeloid sarcoma following allo-BMT are poor, as in any leukemic relapse, with the exception of patients with CML in this setting. PMID- 10091735 TI - Predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysis. AB - BACKGROUND: Management of patients with ductal carcinoma in situ (DCIS) is a dilemma, as mastectomy provides nearly a 100% cure rate but at the expense of physical and psychologic morbidity. It would be helpful if we could predict which patients with DCIS are at sufficiently high risk of local recurrence after conservative surgery (CS) alone to warrant postoperative radiotherapy (RT) and which patients are at sufficient risk of local recurrence after CS + RT to warrant mastectomy. The authors reviewed the published studies and identified the factors that may be predictive of local recurrence after management by mastectomy, CS alone, or CS + RT. METHODS: The authors examined patient, tumor, and treatment factors as potential predictors for local recurrence and estimated the risks of recurrence based on a review of published studies. They examined the effects of patient factors (age at diagnosis and family history), tumor factors (sub-type of DCIS, grade, tumor size, necrosis, and margins), and treatment (mastectomy, CS alone, and CS + RT). The 95% confidence intervals (CI) of the recurrence rates for each of the studies were calculated for subtype, grade, and necrosis, using the exact binomial; the summary recurrence rate and 95% CI for each treatment category were calculated by quantitative meta-analysis using the fixed and random effects models applied to proportions. RESULTS: Meta-analysis yielded a summary recurrence rate of 22.5% (95% CI = 16.9-28.2) for studies employing CS alone, 8.9% (95% CI = 6.8-11.0) for CS + RT, and 1.4% (95% CI = 0.7 2.1) for studies involving mastectomy alone. These summary figures indicate a clear and statistically significant separation, and therefore outcome, between the recurrence rates of each treatment category, despite the likelihood that the patients who underwent CS alone were likely to have had smaller, possibly low grade lesions with clear margins. The patients with risk factors of presence of necrosis, high grade cytologic features, or comedo subtype were found to derive the greatest improvement in local control with the addition of RT to CS. Local recurrence among patients treated by CS alone is approximately 20%, and one-half of the recurrences are invasive cancers. For most patients, RT reduces the risk of recurrence after CS alone by at least 50%. The differences in local recurrence between CS alone and CS + RT are most apparent for those patients with high grade tumors or DCIS with necrosis, or of the "comedo" subtype, or DCIS with close or positive surgical margins. CONCLUSIONS: The authors recommend that radiation be added to CS if patients with DCIS who also have the risk factors for local recurrence choose breast conservation over mastectomy. The patients who may be suitable for CS alone outside of a clinical trial may be those who have low grade lesions with little or no necrosis, and with clear surgical margins. Use of the summary statistics when discussing outcomes with patients may help the patient make treatment decisions. PMID- 10091736 TI - Male breast carcinoma: a review of 229 patients who presented to the Princess Margaret Hospital during 40 years: 1955-1996. AB - BACKGROUND: A single-institution review of clinical presentation, treatment, and outcome of male breast carcinoma was conducted. METHODS: Data obtained by chart review of 229 cases were analyzed with respect to clinical presentation, treatment choice, significant prognostic factors, and survival. The patients were analyzed both as a single cohort and as four cohorts grouped according to decade of diagnosis. RESULTS: Presentation occurred at a median age of 63 years, most often with a self-detected lump. Pathology consisted of subtypes similar to those of female breast carcinoma. The majority of tumors were larger than 2 cm in greatest dimension. Lymph node status, hormone receptors, and histologic and nuclear grade were underreported. Primary, adjuvant, and advanced disease treatment practices were reviewed over time. The 5-year disease free survival (DFS), overall survival (OS), and local control were 47%, 53%, and 91%, respectively. No difference in outcome by decade of diagnosis was observed. Negative lymph nodes and adjuvant hormone treatment predicted for better DFS and OS. Younger age and Stage 0 also predicted for better OS. CONCLUSIONS: Compared with data from female breast carcinoma patients, 5-year OS for this series was low; however, when these patients were separated by lymph node status, survival was similar for those with axillary lymph node metastases. Despite a change in standard primary surgical treatment and an increased use of chemotherapy and hormone therapy over the study period, no difference in outcome was observed among these males. In the absence of prospective, randomized clinical trials, collection of comprehensive data on the presentation and management of male breast carcinoma may help to optimize clinical care. PMID- 10091737 TI - Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. AB - BACKGROUND: A number of patients who have undergone adjuvant (CMF) chemotherapy for operative primary breast carcinoma have reported impaired cognitive function, sometimes even years after completion of therapy. The possible role of cytostatic treatment as a causative factor has scarcely been investigated. The objective of the current study was to examine the late effects on neuropsychologic functioning of CMF adjuvant chemotherapy given to patients with breast carcinoma. METHODS: Thirty-nine breast carcinoma patients who had been treated with adjuvant CMF (6 courses) followed (n = 20) by 3 years of tamoxifen 20 mg daily or not (n = 19) were examined with neuropsychologic tests and interviews. The control group consisted of 34 age-matched axillary lymph node negative breast carcinoma patients who received the same surgical and radiation therapy but no systemic adjuvant treatment. The CMF patients were examined a median of 1.9 years after the sixth CMF course, and the controls a median of 2.4 years after surgery of the primary tumor. RESULTS: Patients treated with CMF reported significantly more problems with concentration (31% vs. 6%, P = 0.007) and with memory (21% vs. 3%, P = 0.022) than the control patients. No relation was found between reported complaints and results on the neuropsychologic tests. Impairment in cognitive function was found in 28% of the patients treated with chemotherapy compared with 12% of the patients in the control group (odds ratio 6.4 [95% confidence interval 1.5-27.6] P = 0.013). Hormonal therapy had no influence on patients' self-reports of symptoms or cognitive function. Cognitive impairment following chemotherapy was noticed in a broad domain of functioning, including attention, mental flexibility, speed of information processing, visual memory, and motor function. CONCLUSIONS: Breast carcinoma patients treated with adjuvant CMF chemotherapy have a significantly higher risk of late cognitive impairment than breast carcinoma patients not treated with chemotherapy (OR 6.4). This cognitive impairment is unaffected by anxiety, depression, fatigue, and time since treatment, and not related to the self-reported complaints of cognitive dysfunction. PMID- 10091738 TI - Vascularity index as a novel parameter for the in vivo assessment of angiogenesis in patients with cervical carcinoma. AB - BACKGROUND: The importance of angiogenesis now is well recognized. Conventionally, tumor angiogenesis is assessed by determination of microvessel density (MVD) in the surgical specimen. This study examines tumor angiogenesis using power Doppler ultrasound and a quantitative image processing system. The authors hope to develop an in vivo and noninvasive method for quantitating tumor angiogenesis. METHODS: Thirty-five patients with FIGO Stage IB-IIA cervical carcinoma exhibiting visible cervical tumors by transvaginal ultrasound were included in this study. All patients underwent radical abdominal hysterectomy and pelvic lymph node dissection. Transvaginal power Doppler ultrasound was performed before surgery to search for blood flow signals from the tumor. The intratumoral vascularity index (VI) and resistance index (RI) were calculated. The VI was defined as the number of colored pixels divided by the number of total pixels in the defined tumor section. Maximal VI and minimal RI of a certain tumor were used for analysis. Clinical and pathologic data also were recorded. The MVD of the excised tumor was assessed immunohistochemically using a monoclonal antibody against CD34. RESULTS: Significantly higher VI values were noted in Stage II tumors compared with Stage 1 tumors (19.01+/-10.90% vs. 9.09+/-6.59%; P = 0.008), tumors invad-ing+/-50% of the cervical stroma compared with tumors invading < 50% of the cervical stroma (13.20+/-8.20% vs. 5.72+/-5.00%; P = 0.003), tumors with lymphovascular emboli compared with tumors without lymphovascular emboli (17.28+/ 8.26% vs. 6.98 +/- 5.09%; P = 0.001), and tumors with pelvic lymph node metastases compared with tumors without pelvic lymph node metastases (26.16+/ 7.88% vs. 8.00+/-4.95%; P = 0.021). None of the variables mentioned earlier showed a significant difference in terms of the RI values. No correlation was noted between intratumoral RI and VI in respective tumors (P = 0.53). Analysis of VI revealed linear regression with regard to tumor size (P < 0.001, correlation coefficient [r] = 0.586) and depth of stromal invasion (P = 0.002, r = 0.497). In addition, the MVD exhibited a linear relation with VI (P = 0.006, r = 0.454), tumor size (P = 0.005, r = 0.465), and depth of stromal invasion (P = 0.009, r = 0.436) using simple regression analysis. No correlation could be found between MVD and RI. CONCLUSIONS: In cervical carcinoma, intratumoral VI assessment by power Doppler ultrasound and quantitative image processing system showed better correlation with tumor stage, tumor size, and pathologic findings including depth of stromal invasion, lymphovascular emboli, and pelvic lymph node metastases than intratumoral RI. The in vivo indicator of angiogenic activity (VI) is well correlated with the conventional indicator of tumor angiogenic activity (MVD). Thus, VI could be a useful parameter for the in vivo assessment of global tumor angiogenesis. PMID- 10091739 TI - Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma. AB - BACKGROUND: Resistance to the potent growth inhibitory effects of transforming growth factor-beta (TGF-beta) is a characteristic of many malignancies. TGF-beta insensitivity has been attributed to alterations in the number and function of the TGF-beta receptors as well as disturbances of downstream signal transduction. Paradoxically, increased levels of TGF-beta ligand have been demonstrated in several types of malignant tumors. TGF-beta also may play a role in ovarian carcinogenesis; however, the nature of this interaction has yet to be defined completely. METHODS: To explore the potential role of TGF-beta-mediated autocrine and paracrine influences in epithelial ovarian carcinoma, mRNA expression levels of the three TGF-beta ligand isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) and the three TGF-beta receptors (TbetaR-I, T/betaR-II, and TbetaR-III) were examined by Northern blot analysis in both primary and recurrent ovarian carcinoma specimens. Immunohistochemical analysis was performed to localize expression of TbetaR-I and TbetaR-II, whereas the presence of genetic alterations in TbetaR-1 was examined through Southern blot analysis. RESULTS: Compared with normal ovarian tissue, both primary and recurrent ovarian carcinomas demonstrated significant overexpression of the TGF-beta1 and TGF-beta3 mRNA transcripts. TGF beta2 expression was detectable in 75% of primary and only 53% of recurrent tumor specimens. Alterations also were detected in TbetaR mRNA expression. Expression levels of TbetaR-III were significantly reduced in both primary and recurrent ovarian carcinomas. Furthermore, detectable levels of TbetaR-I and TbetaR-III mRNA transcripts were present in only 47% and 50% of recurrent ovarian tumors, respectively. Immunohistochemical staining demonstrated that TbetaR-I and TbetaR II expression localized to tumor cells; however, receptor staining in stromal tissue also was detected. Southern blot analysis of TbetaR-I did not reveal any major genetic changes to account for the absence of TbetaR-I expression. CONCLUSIONS: Alterations in expression of TGF-beta ligands and receptors consistently were greater in recurrent ovarian carcinomas compared with primary tumors, and may reflect a phenotype that promotes tumor recurrence or chemoresistance. Together, these data suggest that enhanced expression of TGF betaI and TGF-beta3, as well as the loss of expression of TbetaR-I and TbetaR III, contribute to ovarian carcinogenesis and/or tumor progression. PMID- 10091740 TI - Clear cell carcinoma has an expression pattern of cell cycle regulatory molecules that is unique among ovarian adenocarcinomas. AB - BACKGROUND: The purpose of this study was to identify biologic differences between ovarian clear cell carcinoma and other ovarian adenocarcinomas by comparing the expression of cell cycle regulatory molecules and by analyzing the survival of the patients. METHODS: In 51 cases of epithelial ovarian carcinoma, the expression of the cell proliferation marker Ki-67 and that of the cell cycle regulatory molecules p53, p16, p21, p27, cyclin E, and cyclin A was studied using immunohistochemical techniques. The correlations among clinical stage, histologic subtype, labeling index for Ki-67, and expression of these cell cycle regulators were examined statistically. Multivariate survival analysis was performed using these factors in the Cox proportional hazards model. RESULTS: Clear cell carcinoma revealed such trends as low expression of both p53 and cyclin A and significantly increased expression of both p21 and cyclin E (compared with the other histologic subtypes). In all ovarian carcinomas, a very strong positive correlation (correlation coefficient 0.79; P < 0.0001) between p53 positive staining and cyclin A positive staining and a weak positive correlation (correlation coefficient 0.47; P < 0.01) between p21 positive staining and cyclin E positive staining were recognized at the level of expression of cell cycle regulatory molecules. Clinical stage was the only independent predictive factor for the survival of the patients. CONCLUSIONS: Among ovarian adenocarcinomas, clear cell carcinoma exhibits a unique pattern of expression of cell cycle regulatory molecules, though in this study the survival of the patients did not correlate with histologic subtype, only with clinical stage. PMID- 10091741 TI - Late side effects unchanged 4-8 years after radiotherapy for prostate carcinoma: a comparison with age-matched controls. AB - BACKGROUND: The authors of this study previously evaluated pelvic irradiation induced late side effects in patients with localized prostatic carcinoma 4 years after external irradiation by administering a validated self-assessment questionnaire (QUFW94), and compared the results with those of age-matched controls. The current study was designed to evaluate prospectively the patients' problems 8 years after radiotherapy and to compare them with those reported by the same controls. METHODS: The questionnaire was sent out at a mean of 8 years (range, 72-104 months) after irradiation to 120 patients and 125 controls. For analysis of sexual function, the patient group was divided into two subgroups, one treated with radiotherapy only (RT) and one group treated with radiotherapy plus castration (RT+A). A value of >1 on a 0-10 scale indicated that the patient was having a problem. RESULTS: The mean age was 73 years for both patients and controls. No changes in urinary problems were seen between the 4-year and the 8 year follow-up in the 2 groups. Sixty percent and 54% of the patients (P = 0.096) and 24% and 31% of the controls (P = 0.988) reported urinary problems at the 4 year and 8-year follow-ups, respectively. No changes in gastrointestinal late side effects in the patient group were seen between the 4-year (65%) and the 8 year (62%) follow-ups (P = 0.490). However, there was a decrease in intestinal problems in the control group between the 4-year (12%) and the 8-year (9%) follow ups (P = 0.001). The sexual problems did not change during the two periods, in the patient groups or in the control groups. Fifty-six percent and 65% of the RT group (P = 0.052), 67% and 54 % of the RT + A group (P = 0.555), and 27% and 33 % of the control group (P = 0.243) indicated some kind of sexual problem at the 4 year and 8-year follow-ups, respectively. CONCLUSIONS: The amount of pelvic irradiation-induced urinary late side effects, intestinal late side effects, and sexual function, evaluated with a self-assessment questionnaire, did not change between 4 and 8 years after RT. The age-matched controls reported no change in urinary or sexual problems despite advanced age, but there was a reported decrease in intestinal problems. PMID- 10091742 TI - Impact of tumor size on the clinical outcomes of patients with Robson State I renal cell carcinoma. AB - BACKGROUND: In the TNM classification of renal cell carcinoma released in 1997, T1 tumors were defined as organ-confined tumors 7.0 cm or less in size, and T2 as those larger than 7.0 cm. The consideration of tumor size should be predicated on its prognostic value in predicting survival, because the goal of clinical staging is to separate patients into similar classes of survival based on the extent of disease at presentation. The authors examined the impact of tumor size on the clinical outcomes of patients with Robson Stage I disease to determine a size cutoff that would maximize the predictive value of the TNM staging system. METHODS: Between 1962 and 1995, 382 patients with renal cell carcinoma were treated at the Department of Urology at the Osaka Medical Center for Cancer and Cardiovascular Diseases in Osaka, Japan, and the TNM staging of 350 of those patients was recorded. Of 350 patients, 157 (45%) were at TNM Stage I, 47 (13%) at Stage II, 65 (19%) at Stage III, and 81 (23%) at Stage IV, according to the TNM stages defined in 1997. Robson Stage I includes TNM Stages I and II, and 204 patients in these stages were analyzed in this study. This study group included 146 men and 58 women with a mean age of 57.8 years (range, 26-84 years). The mean follow-up period was 5.4 years. RESULTS: The patient survival periods were not significantly different for those with TNM Stages I and II. This finding indicated that the tumor size cutoff of 7.0 cm was not useful in predicting the prognosis. The patients at TNM Stages I and II were then divided into two groups at each size cutoff, from 2.5 cm to 9.0 cm, at 0.5-cm intervals. The tumor size cutoff of 5.5 cm was most predictive of patient survival (P = 0.0121). None of other patient characteristics varied significantly between the two groups at this dichotomous point. Tumor size and microscopic intrarenal venous invasion, but not grade or infiltration pattern, were found in univariate and multivariate analyses to be significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. CONCLUSIONS: The current data indicate that the tumor size cutoff of 5.5 cm was most significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. The tumor size cutoff of 5.5 cm was also shown to be significant in univariate and multivariate analyses. PMID- 10091743 TI - Incidence of breast carcinoma in women with thyroid carcinoma. AB - BACKGROUND: Breast carcinoma and differentiated thyroid carcinoma(the most common endocrine malignancy) occur predominantly in women. An association between the two tumors has been suggested by some investigators, but the potential impact of treatment of one of these diseases on the development of the other remains unclear. The authors examined the relation between the occurrence of these two tumors. METHODS: There were 41,686 patients with breast carcinoma and 3662 with thyroid carcinoma who registered at The University of Texas M. D. Anderson Cancer Center between March 1944 and April 1997. Women who received both diagnoses since 1976 were identified and incidence rates and relative risks of secondary tumor development were calculated. Surveillance, Epidemiology and End Results (SEER) program data on the age-adjusted incidences of these diseases during the same time period were used for the expected incidences in the same population. RESULTS: Among 18,931 women with a diagnosis of breast carcinoma since 1976, 11 developed differentiated thyroid carcinoma > or = 2 years after the diagnosis of breast carcinoma. These breast carcinoma patients contributed 129,336 person years of follow-up; the observed incidence of thyroid carcinoma in this group was not different from that in a similar age group of women in the SEER database. Among 1013 women with a diagnosis of thyroid carcinoma since 1976, 24 developed breast carcinoma > or = 2 years after the diagnosis of thyroid carcinoma. These thyroid carcinoma patients contributed 8380 person-years of follow-up; the observed incidence of breast carcinoma in women ages 40-49 years was significantly higher than the expected incidence for women in the same age group in the SEER database. CONCLUSIONS: Breast carcinoma developing after thyroid carcinoma was diagnosed more frequently than expected in young adult women seen at the study institution since 1976. This potential association and plausible mechanisms of breast carcinoma development after thyroid carcinoma should be evaluated in larger cohorts of patients. PMID- 10091744 TI - The management of unicentric and multicentric Castleman's disease: a report of 16 cases and a review of the literature. AB - BACKGROUND: Castleman's disease (CD), or angiofollicular lymph node hyperplasia, creates both diagnostic and therapeutic dilemmas for most physicians. For patients with this rare and poorly understood disease, the optimal therapy is unknown. The authors report their experience during the years 1986-1997 with this uncommon clinicopathologic entity. METHODS: Sixteen patients with a histologic diagnosis of CD were identified in the pathology database. Unicentric disease was defined as a solitary mass. Multicentric disease compromised patients with widespread lymphadenectomy. Clinical, radiologic, and laboratory data were analyzed to evaluate treatment response. RESULTS: The study group consisted of 16 patients classified into 3 clinicopathologic groups: hyaline-vascular, plasma cell, and "mixed." Of those patients who underwent complete surgical excision of a unicentric hyaline-vascular CD mass (n = 8), all remain symptom free without clinical or radiographic recurrence. Two patients remain asymptomatic following partial resection or radiation therapy for an unresectable unicentric hyaline vascular CD mass. Two patients with multicentric hyaline-vascular CD are currently in complete remission following adjuvant therapy. Multicentric plasma cell CD was present in a single patient. This patient (who underwent surgical and systemic therapy) died of disease within 4 months of presentation. Three patients with unicentric hyaline-vascular/plasma cell-CD remain symptom free following either complete resection or observation. CONCLUSIONS: The authors recommend surgical resection for patients with the unicentric variant of CD. Surgical removal of a unicentric mass of hyaline-vascular or hyaline-vascular/plasma cell type is curative. Partial resection, radiotherapy, or observation alone may avoid the need for excessively aggressive therapy. Patients with multicentric disease, either hyaline-vascular or plasma cell type, do not benefit from surgical management and should be candidates for multimodality therapy, the nature of which has yet to be defined. PMID- 10091745 TI - p53 gene mutations and rearrangements in non-Hodgkin's lymphoma. AB - BACKGROUND: Alterations of the p53 gene have been associated with the progression of certain human malignancies. To establish further the correlation between p53 gene alterations and progression of non-Hodgkin's lymphomas (NHLs), the authors analyzed both mutations and rearrangements of the p53 gene in a cohort of 84 NHLs. METHODS: Eighty-four NHLs were analyzed for p53 gene alterations. Point mutations of exons 5-9 were studied by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), and DNA rearrangements were studied by Southern blot analysis. RESULTS. Point mutations and DNA rearrangements of the p53 gene were detected in 6 (7.2%) and 3 (3.6%) patients, respectively. All p53 gene abnormalities were found exclusively in B-cell NHLs. Taken together, patients with p53 gene alterations had poorer survival than other patients (P = 0.024). However, of the three patients with p53 gene rearrangements, the two who appeared to have one normal allele showed a relatively better response to chemotherapy and had longer survival (27 and 47 months). In contrast, the remaining patient who had rearranged bands much stronger than the germline, and thus appeared to have both alleles rearranged, was refractory to chemotherapy and had poorer survival (6 months). CONCLUSIONS: Patients with NHLs of intermediate and high grades who carried point mutations or rearrangements of p53 genes had worse outcomes than other patients. Patients with one abnormal p53 allele and one residual normal allele had a more favorable prognosis than those with two abnormal alleles. PMID- 10091746 TI - Extraskeletal Ewing's sarcoma. AB - BACKGROUND: Ewing's sarcoma usually is identified as a primary malignancy of bone affecting children and young adults. Extraskeletal Ewing's sarcoma is rare, and very few data are available addressing optimal surgical and oncologic treatment modalities. METHODS: The authors chose to review retrospectively 24 patients with extraskeletal Ewing's sarcoma treated at the study institution with modern multimodality therapies. Anatomic location, tumor size, patient age at diagnosis, stage of disease at the time of diagnosis, surgical margins, radiation dose, and the type and dose of chemotherapy were documented for every patient. Follow-up averaged 64 months for surviving patients. RESULTS: The overall 5-year survival rate was 61% and the disease free survival rate was 54%. A multivariate analysis found that younger age at the time of diagnosis was associated with improved 5 year survival and disease free survival (P = 0.008 and P = 0.005, respectively). Patients who underwent wide resection and less-than-wide resection had better overall survival (P = 0.001 and P = 0.015, respectively) and disease free survival (P = 0.002 and P = 0.024) compared with those who underwent no attempt at surgical resection. Patients who underwent a wide resection had an improved overall survival compared with those who underwent a less-than-wide resection (P = 0.045). The size of the lesion (P = 0.277) and the presence of metastatic disease at the time of diagnosis (P = 0.219) were not found to be significant prognostic factors. CONCLUSIONS: Age and surgical treatment were found to be important prognostic variables in the treatment of extraskeletal Ewing's sarcoma. No other variables, such as tumor size, tumor location, stage of disease, or radiation therapy, were found to improve survival. Surgical resection should be considered for all patients with extraskeletal Ewing's sarcoma. PMID- 10091747 TI - Military service of male survivors of childhood malignancies. AB - BACKGROUND: The objective of this study was to assess the eligibility for and the course of compulsory military service of childhood cancer survivors. METHODS: The medical, military recruitment, conscription, and military service data of male Finnish childhood cancer survivors were collected from manually filed records. Inclusion criteria were: survivors born 1977 or earlier, treated for a malignancy between birth and age 15 years, and followed by a pediatrician until at least age 18 years. The documents of 207 survivors from the Pediatric Clinics of Finnish University Hospitals were examined, and 130 of these survivors were considered eligible for military service. Demographic factors, the predictors of fitness for military service, factors associated with service interruption, the attained level of military training, and the health status of conscripts during service were evaluated. Comparisons were made with the Finnish male population of the same age and with conscripts serving at the corresponding time. RESULTS: Approximately 60% of studied survivors were enlisted. Positive predictors of fitness for service were year of birth of 1973 or later (odds ratio [OR], 3.2), height at call-up age of 170-174.9 cm (OR, 3.6), and the man's own positive opinion of his fitness for service (OR, 62.3). Negative predictors were age at diagnosis > or = 11 years (OR, 0.5), central nervous system radiotherapy (OR, 0.3), limb defects (OR, 0.02), and the group of sequelae concerning neurologic, cardiopulmonary, and gastrointestinal systems, or secondary malignancies (OR, 0.3). Survivors interrupted their service more often (20%) (P < 0.001). Leukemia survivors were less likely to interrupt their service (7%) compared with other survivors (P = 0.04). Factors associated with service interruption were: diagnosis (P = 0.04), the man's own opinion of his fitness for service (P = 0.013), surgery (P = 0.003), and height (P = 0.049), weight (P = 0.019), and body mass index (P = 0.035) at the beginning of military service. The attained level of military training was equal to that of controls. The survivors visited the garrison physician less frequently in total (mean, 5.9 times) (P < 0.001), visited because of infections as much as controls, and were off duty more (mean, 11.9 days) (P = 0.012) than controls. CONCLUSIONS: The current study found that childhood cancer survivors were less likely to meet the requirements set for military service in Finland. The causes of rejection usually were obvious, but approximately 30% were rejected merely on the basis of a former cancer diagnosis. However, enlisted survivors coped well with military service if their treatment sequelae were taken into consideration carefully at the time of enlistment. Vocational opportunities within the armed forces might be an appropriate career option even for survivors of childhood malignancies. PMID- 10091748 TI - The RNA component of telomerase as a marker of biologic potential and clinical outcome in childhood neuroblastic tumors. AB - BACKGROUND: Telomerase is a ribonucleoprotein enzyme associated with cellular immortality that may be useful in determining the biologic potential of a tumor. Neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN) are neuroblastic tumors (NTs) that exhibit a spectrum of histologic features and are often associated with unpredictable behavior and clinical outcome. METHODS: The authors investigated the expression of the RNA component of human telomerase (hTR) by in situ hybridization in 32 cases of NTs (including 24 NBs, 4 GNBs, and 4 GNs), using [35S]-UTP labeled single stranded sense and antisense RNA probes. Eight NBs were early stage, 12 NBs were advanced stage, and 4 NBs were Stage IVS, a widely metastatic variant associated with an excellent clinical prognosis. Four NBs had N-myc amplification. In addition, the authors compared a proliferation marker, MIB-1, with hTR expression in a subset of tumors. RESULTS: Thirty of 32 NTs expressed hTR, with expression varying from weak (1+) to intense (4+). Most advanced stage NBs (9 of 12) and only 2 of 8 early stage NBs had moderate to intense (2 to 4-) expression of hTR. The remaining early stage tumors (6 of 8) and 3 of 12 advanced stage NBs had absent or weak expression of hTR (0 to 1+). There was no disease progression in any of the patients with absent or weak expression of hTR. In contrast, 8 tumors (from 7 patients) with moderate to intense expression of hTR in the tumor sections had adverse clinical outcomes, including recurrence, persistent disease, or death. hTR expression in all the Stage IVS tumors was weak, despite the fact that the patients had widely metastatic disease at presentation. The mean hTR score of 3.1 for NBs associated with an adverse outcome (n = 8) was significantly different from the mean hTR score of 1.3 for NBs associated with a favorable outcome (n = 16), P < 0.001. hTR expression in the GNB/GNs was limited to the ganglion cells only; Schwann cells were negative for hTR expression. Stage IVS tumors, which are associated with an excellent outcome, had high MIB-1 but weak hTR expression, indicating that the latter may be a better discriminator of true biologic potential and that hTR levels do not always correlate with cell proliferation. CONCLUSIONS: Increased hTR expression may reflect the potential for aggressive behavior within the spectrum of NTs; conversely, down-regulation of hTR may be useful in identifying subsets with limited capacity for progression and a favorable prognosis. PMID- 10091750 TI - Serum CA 125 is of clinical value in the staging and follow-up of patients with non-Hodgkin's lymphoma: correlation with tumor parameters and disease activity. PMID- 10091751 TI - Immunohistochemical study of the expression of human chorionic gonadotropin-beta in oral squamous cell carcinoma. AB - BACKGROUND: Human chorionic gonadotropin (hCG) is a glycoprotein hormone comprised of two dissimilar subunits (alpha and beta) and normally is synthesized by trophoblastic tissue. Although hCG expression has been identified in a variety of neoplastic tissues, to the authors' knowledge no investigation has centered on tumors of oral origin. METHODS: Oral squamous cell carcinomas (OSCC) were studied in comparison with oral fibromas for the presence of hCGbeta using the avidin biotin-peroxidase complex immunohistochemical technique. RESULTS: hCGbeta immunoreactivity was identified in 29 of 45 OSCC (64%). The positively staining cells in each tumor specimen were few (range, 0.5-5%) and were scattered throughout the tumor. When tumors were classified according to grade, it was found that hCGbeta staining was positive in 5 of 15 well differentiated OSCC (33%), in 12 of 15 moderately differentiated OSCC (80%), and in 12 of 15 moderately to poorly differentiated OSCC (80%). hCGbeta immunoreactivity could not be demonstrated in any of the oral fibromas. CONCLUSIONS: The presence of hCGbeta positive tumor cells appears potentially to reflect a malignant behavior of OSCC. PMID- 10091749 TI - Childhood melanoma survival. AB - BACKGROUND: Melanoma in childhood is uncommon. Some believe that melanoma among children is associated with a better prognosis than among adults. METHODS: The authors reviewed their institutional experience with melanoma in 40 patients younger than 18 years treated between 1950 and 1984. All slides were reviewed by a single dermatopathologist who was blinded to clinical outcomes. Long term follow-up was available for all but three patients. RESULTS: There were 26 girls and 14 boys. The median age at diagnosis was 15 years (range, 3-17 years). Eleven patients (28%) were younger than 12 years. Fifteen patients (38%) had melanoma arise in a congenital nevus (2 had bathing trunk nevi. The most common site was the extremity (n = 23), followed by the trunk (n = 10) and the head and neck (n = 7). Seventeen patients (43%) initially were considered to have benign lesions, and 23 patients (57%) were diagnosed correctly with melanoma at initial presentation. Only 21 of 37 evaluable patients (57%) were alive at last follow-up with a median follow-up of 18 years (range, 2-48 years). Fifteen patients (41%) died of their disease, with a median survival of 12 months (range, 6-60 months). One patient died of breast carcinoma 14 years after treatment for melanoma. Disease free survival was 57% at 5 and 10 years. Of the 15 patients who died of disease, 12 were female (P = 0.09) and 10 had melanoma arising in a congenital nevus (P < 0.05). Five-year overall survival was 78% for patients who presented with localized disease (n = 23) and 30% for patients who presented with regional metastasis (n = 16, P < 0.001). There were no survivors among those who presented with systemic disease (n = 1). CONCLUSIONS: Children with melanoma are at significant risk of dying of their disease. Survival is similar to that seen among adults and depends on stage at presentation. The survival advantage observed for adult females is not seen among children. PMID- 10091752 TI - The quality of swallowing for patients with operable esophageal carcinoma: a randomized trial comparing surgery with radiotherapy. AB - BACKGROUND: Surgery is considered the standard treatment for operable esophageal carcinoma, although there is no compelling evidence that surgery can achieve better results than radiotherapy. There has previously been no direct randomized comparison of these two modalities with survival or disease specific outcome end points. METHODS: Ninety-nine patients with operable squamous cell carcinoma of the esophagus were randomly allocated to surgery or radiotherapy after stratification for tumor length (< or = or >5 cm). Those randomized to surgery underwent transthoracic esophagectomy with limited lymphadenectomy, whereas those in the radiotherapy arm received 50 gray in 28 fractions followed by a 15-gray boost to the primary tumor. Disease specific outcome was assessed for 4 subgroups: 1) disease specific symptoms, 2) physical symptoms, 3) ability to work, and 4) social/family interaction and global perception of disease specific outcome. The questionnaire was given prior to treatment and posttreatment at 3 month intervals for 1 year. Death was a secondary end point. RESULTS: There was an overall improvement in the quality of swallowing in both treatment arms after treatment and with the passage of time. The swallowing status was better in the surgery arm than in the radiotherapy arm at 6 months after treatment (P = 0.03, Fisher's exact test). Logistic regression analysis showed randomization arm (P = 0.035), time since treatment (P = 0.003), and pretreatment swallowing status to be significant determinants of posttreatment swallowing status. Surgery was twice as likely to result in improvement in swallowing than radiotherapy after correction for time and pretreatment swallowing status. Overall survival was better in the surgery arm than in the radiotherapy arm (P = 0.002, log rank test) (OR = 2.74 with 95% confidence intervals 1.51-4.98; P < 0.009, Cox proportional hazards model). CONCLUSIONS: Both surgery and radiotherapy can improve the quality of swallowing significantly for patients with operable esophageal carcinoma. Surgery is marginally superior to radiotherapy in improving the quality of swallowing. In this trial, survival in the surgery arm was significantly better than in the radiotherapy arm, although the small number of patients is a limitation. PMID- 10091753 TI - The prognostic significance of lymph node micrometastasis in patients with esophageal carcinoma. AB - BACKGROUND: Lymph node metastasis is a well known feature of poor prognosis in patients with esophageal adenocarcinoma and squamous cell carcinoma. However, a significant proportion of apparently lymph node negative patients die early of metastatic disease. The aim of this study was to determine the prevalence and prognostic significance of occult lymph node metastasis in patients with esophageal adenocarcinoma and squamous cell carcinoma. METHODS: Lymph node sections from esophagectomy specimens of 78 patients with lymph node negative esophageal carcinoma (49 patients with adenocarcinoma and 29 with squamous cell carcinoma) were cut serially, it toto, and immunostained with the cytokeratin antibody AE1/AE3 and evaluated for occult lymph node metastasis. The results were correlated with the clinical and pathologic features and with patient survival. RESULTS: Fifteen of 49 patients (31%) with adenocarcinoma and 5 of 29 patients (17%) with squamous cell carcinoma had occult lymph node metastasis detected by cytokeratin staining. In the adenocarcinoma patients, the presence of occult lymph node metastasis showed a significant correlation with increasing depth of invasion, but was not associated significantly with any other clinical or pathologic feature. In the squamous cell carcinoma patients, the presence of occult lymph node metastasis did not correlate significantly with any clinical or pathologic parameter, except that patients with occult lymph node metastasis were more likely to have received preoperative chemotherapy or radiation therapy. Occult lymph node metastasis did not correlate with poorer survival rates in patients with either adenocarcinoma (Cox proportional hazards ratio: 1.42; P - 0.46) or squamous cell carcinoma (Cox proportional hazards ratio: 0.86; P = 0.90). CONCLUSIONS: Occult lymph node metastasis is not an independent poor prognostic feature in esophageal adenocarcinoma or squamous cell carcinoma. Therefore, the authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostication of patients with these malignancies. PMID- 10091754 TI - Validation and simplification of Bethesda guidelines for identifying apparently sporadic forms of colorectal carcinoma with microsatellite instability. AB - BACKGROUND: Colorectal tumors with microsatellite instability (MSI) that do not comply with previously defined clinical criteria may be found in recently diagnosed hereditary nonpolyposis colorectal carcinoma families. Until recently, the indications for MSI testing were not clearly established. The objective of the current study was to validate the recently published Bethesda guidelines for MSI testing in a series of patients with apparently sporadic forms of colorectal carcinoma (CRC). METHODS: Sixty-two patients with so-called sporadic CRC were included in the current study. MSI was analyzed at seven poly(CA) repeat sequences and at one poly(A) locus. RESULTS: Nine of 62 patients (14.5%) had tumors exhibiting MSI at > or = 2 loci and 7 patients (11%) had MSI at > or = 3 loci. Patients with MSI positive tumors were younger (P < 0.05), and their tumors more frequently were right-sided (P < 0.02) and more often exhibited a mucinous component (P < 0.05). The Bethesda guidelines were positive in 18% (11 of 62) of patients. The sensitivity of these guidelines in identifying tumors with MSI at > or = 3 loci was 43% and the positive predictive value (PPV) was 27% (3 of 11 cases). Other variables were considered as alternative criteria to identify CRCs with MSI: age < 45 years and/or a right-sided tumor with a mucinous component. Using these 2 criteria alone, sensitivity increased to 85% and PPV to 46%. CONCLUSIONS: In this study group, the use of three clinical criteria as sole indicators for MSI testing in patients with apparently sporadic forms of CRC were significantly more discriminating compared with the Bethesda guidelines, in addition to being substantially easier. PMID- 10091755 TI - A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. AB - BACKGROUND: This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5 fluorouracil (5-FU)-based chemotherapy. METHODS: CPT-11 was given as a 90-minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5 22.6%). Among patients given a starting dose of 100 mg/m2, the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicities between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age > or = 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS: CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicities. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients. PMID- 10091756 TI - Markedly elevated cell turnover is characteristic of small, deeply invasive carcinomas of the colorectum. AB - BACKGROUND: Small, deeply invasive carcinomas invading the muscularis propria or deeper and measuring < or = 2 cm in greatest dimension (S-ADV) are rare in comparison with their larger counterparts (NS-ADV), and their clinicopathologic features are obscure. METHODS: S-ADV and NS-ADV cases as well as cases of submucosal carcinoma (SM-CA) were comparatively assessed for: 1) clinicopathologic findings; 2) Ki-67, mitotic, and apoptotic indices; 3) cathepsin G, p53, and bcl-2 immunoreactivities; and 4) c-Ki-ras mutations. RESULTS: S-ADV and SM-CA, which both are significantly smaller than NS-ADV, did not differ in size, but the frequency of moderately and poorly differentiated carcinoma elements at the leading edges was observed to be higher than in the central cores only in S-ADV, as was tumor "budding" of small clusters of undifferentiated carcinoma cells. The frequency of severe lymphatic involvement in S-ADV was as high as in NS-ADV, and significantly greater than in SM-CA. The Ki-67, mitotic, and apoptotic indices for S-ADV were significantly increased compared with those for NS-ADV and/or SM-CA. Expression of cathepsin G in S-ADV tumor and stromal cells was significantly decreased compared with NS-ADV and/or SM-CA cases. No significant differences in the expression of either p53 or bcl-2 or the incidence of c-Ki-ras mutations were observed among the three groups. CONCLUSIONS: S-ADV can be considered a distinct type of deeply invasive carcinoma, presenting with poor tumor differentiation at the leading edge, and with increased tumor cell proliferation despite its small size. PMID- 10091757 TI - The effect of preoperative radiation therapy on glucose utilization and cell kinetics in patients with primary rectal carcinoma. AB - BACKGROUND: Proliferating cells in neoplasms usually show rapid cell cycle times and high rates of glycolysis. Tumor glucose utilization (TuGluc), potential cell doubling time (Tpot), and the effect of radiotherapy (RT) were evaluated in patients with primary rectal carcinoma. METHODS: 2-[18F]-fluoro-2-deoxy-glucose (18F-FDG) was administered and dynamic positron emission tomography (PET) performed to determine TuGluc. Cell kinetics were measured with flow cytometry after labeling with iodo-deoxy-uridine. Two groups of patients were investigated prospectively: 1) those patients undergoing surgery only and 2) those patients undergoing surgery after receiving 30 gray of RT. Twenty consecutive patients with a cT3-NX-M0 tumor and age > 50 years were selected and randomized. One patient was excluded because of unexpected liver metastases and another had incomplete data. RESULTS: At baseline, the TuGluc for Group 1 was 222+/-104 nmol/mL/minute (mean +/- 1 standard deviation), and was 215+/-126 nmol/mL/minute for Group 2 (P > 0.8). After RT TuGluc decreased to 77+/-39 nmol/mL/minute (P = 0.008). Tpot was 3.4+/-1.2 days for Group 1 and 2.6+/-2.0 days for Group 2 at baseline (P > 0.2). Two weeks after RT, Tpot slowed to 5.7+/-3.6 days (P = 0.04). A weak negative correlation (correlation coefficient = -0.36) was found between TuGluc and Tpot. After RT, the proportion of labeled cells had not changed from baseline levels (P > 0.2), suggesting undisturbed proliferation, but the DNA synthesis time had increased. The significant decrease of TuGluc indicated cell loss. CONCLUSIONS: Tumor FDG uptake and cell kinetics are not correlated strongly in rectal carcinoma. Preoperative RT results in an overall loss of tumor cells (tumor reduction) and an increase in Tpot, although proliferation of the viable cell fraction is maintained. PMID- 10091758 TI - Measurement of serum levels of des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma by a revised enzyme immunoassay kit with increased sensitivity. AB - BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a useful tumor marker for hepatocellular carcinoma (HCC). The conventional enzyme immunoassay (EIA) kit for DCP lacks adequate sensitivity to detect small HCC. Thus, a revised EIA kit for DCP has been developed. In this revised DCP kit, the blank value has been reduced, making it now possible to obtain a normal value. The authors used this revised EIA kit for DCP with increased sensitivity and evaluated its usefulness as a tumor marker for HCC. METHODS: Serum DCP and alpha-fetoprotein (AFP) levels were determined in 60 patients with HCC, 60 with cirrhosis, 57 with chronic hepatitis, and 273 normal subjects. The cutoff value for the revised DCP kit was determined to be 40 mAU/mL, and the values for the conventional DCP kit and AFP were 100 mAU/mL (0.1 AU/mL) and 20 ng/mL, respectively. RESULTS: The mean DCP value was 17.5 mAU/mL in the normal subjects, and the detection limit was 10 mAU/mL for this revised DCP kit. The positivity rate for DCP in patients with HCC was 60% by the revised DCP kit, in contrast to 40% by the conventional DCP kit. The sensitivity, specificity, and accuracy of the revised kit were 60%, 92.3%, and 81.4%, respectively, whereas those of the conventional kit were 40%, 98.3%, and 78.5%. Thirty-five percent of HCC tumors smaller than 2 cm and 78.1% of those larger than 3 cm were positive for DCP by the revised kit. The corresponding figures were 20% and 56.3% with the conventional kit. Twelve (33.3%) of the 36 HCC patients who were negative for DCP by the conventional kit were positive by the revised kit. When the revised DCP kit was used in combination with AFP, 86.7% of the HCC patients and 78.3% of the patients with solitary HCC were positive for at least 1 of these markers. CONCLUSIONS: The revised DCP kit is more useful than the conventional DCP kit as a tumor marker for HCC and should be used in combination with AFP. PMID- 10091759 TI - Acquisition of glutamine synthetase expression in human hepatocarcinogenesis: relation to disease recurrence and possible regulation by ubiquitin-dependent proteolysis. AB - BACKGROUND: The authors previously reported increased ubiquitin (Ub) immunoreactivity in hepatocellular carcinomas (HCCs) and suggested a possible correlation between changes in ubiquitinated protein levels and multistep hepatocarcinogenesis. The current study was performed to identify one of these ubiquitinated proteins (42 kDa) and to analyze the clinical significance of its accumulation. METHODS: The protein was purified using two-dimensional gel electrophoresis and identified by amino acid sequence analysis. The authors studied the expression of this protein in 101 HCCs and 23 precancerous lesions by immunohistochemical methods and in 26 HCCs by immunoblot analysis. A survival analysis was performed on patients with advanced HCC using the Kaplan-Meier method with approximate chi-square statistics for the log rank test. RESULTS: The target protein for ubiquitination was identified as glutamine synthetase (GS). Accumulation of GS was found in 19 of 49 advanced HCCs (38.8%) by immunohistochemical methods and in 9 of 16 (56.3%) by immunoblot analysis, whereas the frequency was much lower in early HCCs (12.9% and 33.3%, respectively) and precancerous lesions (4.3% by immunostaining). In the Ub immunoblot analysis of strongly GS positive specimens, an intense 42-kDa ubiquitinated band was observed. Nine of 21 (42.9%) nodule-in-nodule type HCCs showed a GS positive, high-grade component within a GS negative, low-grade component, indicating the acquisition of GS expression during progression. Among 23 patients with a single advanced HCC nodule, the relapse free survival time was significantly shorter in the GS positive group than in the GS negative group. CONCLUSIONS: The results of this study demonstrate the acquisition of GS expression during hepatocarcinogenesis and the possible regulation of GS enzyme activity by a Ub-dependent proteolytic system. Moreover, GS might play a significant role in promoting the metastatic potential of HCC. PMID- 10091760 TI - Characterization of six cell lines established from human pancreatic adenocarcinomas. AB - BACKGROUND: Six human pancreatic carcinoma cell lines, designated as KMP-1 to KMP 6, were established and maintained in vitro for > 3 years. All were derived from pancreatic ductal adenocarcinomas. The six cell lines originated from either primary pancreatic tumors, metastatic liver tumors, or metastases to lymph nodes. METHODS: Each cell line was characterized by its morphology, doubling time, colony forming efficiency (CFE) on plastic dishes, tumorigenicity in nude mice, chromosomal analysis, and the amount of tumor markers secreted into the culture medium. Furthermore, mutations in the K-ras, p53, and p16/INK4a genes were analyzed. RESULTS: All cell lines grew as an adhering monolayer and were cultured in medium supplemented with 2% fetal bovine serum. The doubling time ranged from 16-70 hours, and the CFE ranged from 0.1-11%. Subcutaneous transplantation of these carcinoma cells into nude mice resulted in the formation of tumors. Chromosomal analysis showed that the modal numbers ranged from 43-124, and each karyotype was unique. Each cell line secreted detectable amounts of squamous cell carcinoma antigen, carcinoembryonic antigen, carbohydrate antigen 19-9, Dupan-II, and cytokeratin 19 fragment, respectively. Genetic alterations of the K-ras, p53, and p16 genes were detected in six, three, and five, respectively, of the six cell lines. CONCLUSIONS: The authors believe that these newly established pancreatic carcinoma cell lines will contribute to wide ranging studies regarding pancreatic carcinoma progression. PMID- 10091761 TI - Basaloid squamous cell carcinoma of the sinonasal tract. AB - BACKGROUND: Basaloid squamous cell carcinoma (BSCC) is a high grade, aggressive variant of squamous cell carcinoma with a predilection for the larynx, hypopharynx, tonsils, and base of the tongue. To the authors' knowledge, BSCC originating in the nasal cavity and paranasal sinuses rarely has been reported. METHODS: Fourteen cases of BSCC involving the nasal cavity and paranasal sinuses were identified in the files of the Otolaryngic-Head and Neck Pathology Tumor Registry of the Armed Forces Institute of Pathology from 1975-1997. Clinical records and follow-up were available in all cases. Paraffin blocks were available for histochemical and immunohistochemical studies in all cases. RESULTS: There were 7 females and 7 males, ages 32-86 years (median, 66.5 years; mean, 62 years). The patients presented primarily with a mass lesion and unilateral nasal obstruction. In nine patients the tumor was confined to the nasal cavity. In three patients the tumor involved the sinuses alone and in two patients the tumor involved the nasal cavity and paranasal sinuses. Histologically, the tumors were widely invasive with a variety of growth patterns, including lobular, solid, trabecular, cribriform, and fascicular. The neoplastic infiltrate included predominantly pleomorphic, basaloid-appearing cells with hyperchromatic nuclei, inconspicuous to prominent nucleoli, and a variable amount of eosinophilic to clear-appearing cytoplasm. Mitotic figures, including atypical forms, were readily apparent as was necrosis (individual cell and comedo-type). Foci of squamous differentiation were limited in extent but were found in all cases and included squamous whorls, individual cell keratinization, and intercellular bridges. Intraepithelial dysplasia, carcinoma in situ, or invasive squamous carcinoma was present in all cases. Other histologic features included intercellular stromal hyalinization and peripheral nuclear palisading. In two cases, neural-type rosettes were found. Immunoreactivity for a variety of epithelial markers including cytokeratin (AE1/AE3/LP34), CAM 5.2, 34betaE12, CK7, and epithelial membrane antigen was present in all cases. Variable reactivity was present with vimentin, actins (smooth muscle and muscle specific), neuron specific enolase, S-100 protein, glial fibrillary acidic protein, CK20, carcinoembryonic antigen, Leu7, and Ewing's marker. Chromogranin, synaptophysin, neurofibrillary protein, leukocyte common antigen, HMB-45, desmin, and Epstein Barr virus latent membrane protein were absent. Surgical resection was the treatment of choice. Eight patients had recurrent or persistent tumor and metastatic disease occurred in five patients. At last follow-up, 7 patients (50%) had died of disease with a median survival of 12 months from the time of diagnosis and 3 patients were alive with disease over periods ranging from 8 months-5 years. Of the 4 remaining patients, 2 were alive without disease at 1 month and 5 years, respectively, 1 patient was lost to follow-up with no evidence of tumor at 3 years, and 1 patient had died of unrelated causes with no evidence of disease. CONCLUSIONS: Sinonasal BSCC is a histologically distinct variant of squamous cell carcinoma with pathologic features and aggressive biologic behavior similar to BSCC localized to more common mucosal sites of the upper aerodigestive tract. PMID- 10091762 TI - Increasing dose intensity of cisplatin-etoposide in advanced nonsmall cell lung carcinoma: a phase III randomized trial of the Spanish Lung Cancer Group. AB - BACKGROUND: The authors designed this randomized, controlled trial to assess whether dose intensification of a cisplatin-etoposide combination (PE), achieved by shortening the interval between chemotherapy cycles, would improve response rate and survival. The maximum tolerated dose of PE was administered in either 3- or 4-week cycles to patients with advanced nonsmall cell lung carcinoma (NSCLC). METHODS: One hundred twenty-three patients were randomized into two groups. The dose-intense arm received cisplatin 35 mg/m2 and etoposide 200 mg/m2 on Days 1-3 every 4 weeks. The dose-dense arm received the same schedule every 3 weeks along with 5 microg/kg of recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) administered subcutaneously on Days 4-13. RESULTS: Patient characteristics were well balanced in both treatment arms. Fifty-four percent of patients were classified as Stage IIIB. A 32% increase in relative dose intensity was achieved in the dose-dense arm compared with the dose-intense arm. The response rates were 32% in the dose-intense arm and 27% in the dose-dense arm (P = 0.9). The median overall survival was higher in the dose-dense arm, 9 versus 7.2 months (P = 0.2). The main toxicity was myelosuppression, although the administration of GM-CSF significantly reduced the percentage of patients with Grade 4 granulocytopenia (53% vs. 78%). Fifty-four percent of the patients in the dose-intense arm and 35% of those in the dose-dense arm developed febrile neutropenia (P = 0.07). There were ten (8%) treatment-related deaths, three (4%) in the dose-intense arm and seven (12%) in the dose-dense arm (P = 0.3); three deaths in each arm were due to febrile neutropenia. CONCLUSIONS: The dose intensification achieved in the dose-dense PE regimen did not correlate with significant improvements in response rate or survival and cannot be recommended in the light of the diversity of new drug combinations available today. However, the use of rhGM-CSF significantly reduced the incidence of severe granulocytopenia. PMID- 10091763 TI - Five-year survivors with resected pN2 nonsmall cell lung carcinoma. AB - BACKGROUND: Some patients with resected pN2 lung carcinoma were long term survivors. To determine appropriate therapeutic modalities for the selected patients, the clinicopathologic characteristics of these patients were examined using the actual number of survivors rather than the cumulative survival rate because the cumulative survival rate occasionally is confounded due to patients with short follow-up periods. METHODS: Between 1981-1990, 178 patients with pN2 nonsmall cell lung carcinoma underwent complete resection with systemic lymph node dissection. The ratios of 5-year survivors to all patients in groups with several clinicopathologic factors were compared. RESULTS: Gender, the side that was operated on, location of the tumor, histologic type, or surgical procedure were not related to the ratio of 5-year survivors. However, T classification, skip metastasis, and the number of levels involved were associated with the ratio significantly. The authors also found that the location of the involved lymph node(s) affected the ratio. CONCLUSIONS: Even in the presence of pN2 disease, lung carcinoma patients with T1 tumors, skip metastasis, or single level mediastinal lymph node involvement, especially Level 4, Level 5, or Level 6 lymph nodes, had a relatively favorable prognosis and may be candidates for primary resection. PMID- 10091764 TI - Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. AB - BACKGROUND: This article reports on 241 patients each with pelvic Ewing sarcoma registered for studies in Germany, Austria, and the Netherlands from January 1, 1981, until January 31, 1994. One hundred sixty-four patients had localized disease and 87 had metastases at diagnosis (PMP). Eighty-four patients with localized disease were entered on protocol (PP) and 80 were followed (FP). METHODS: Statistics included an analysis of event free survival by the Kaplan Meier method and a Cox regression analysis of factors influencing prognosis. RESULTS: In the Kaplan-Meier analysis, on February 1, 1995, the event free survival (EFS) rate was 32% at 12 years for all patients, 54% for PP, 25% for FP, and 13% for PMP. Cox regression analysis showed that response to chemotherapy, initial metastases, and less intense therapy were significant prognostic factors. Among patients who had surgery for local control, the histologic response to chemotherapy was analyzed in the surgical specimen and had a significant influence on survival: EFS 69% for PP with good response compared with 47% (P = 0.11) for patients with poor response, and for FP 56% versus 13% (P = 0.002). All PP with small tumors had relapse free survival, compared with 69% of patients with medium-sized tumors and 36% of patients with tumors larger than 200 mL (P = 0.006). The initial tumor volume was a significant predictor of survival. CONCLUSIONS: Combined modality treatment has resulted in definitive improvement of prognosis for patients with localized pelvic Ewing sarcoma. However, the results for patients with metastases at diagnosis are still discouraging, and their treatment requires new approaches. Tumor load, responsiveness to chemotherapy, and adequate surgical margins are the major factors influencing the prognosis of patients with localized Ewing sarcoma of the pelvis. PMID- 10091765 TI - The surgical management of sacrococcygeal chordoma. AB - BACKGROUND: Complete excision of sacrococcygeal chordoma is necessary at initial surgery due to its poor sensitivity to radiotherapy and chemotherapy. However, due to the anatomic characteristics of this tumor, intralesional excision tends to be employed, resulting in local recurrences in many patients. METHODS: The clinical features and results of surgical treatment of 13 patients with sacrococcygeal chordoma who were treated at the Chiba Cancer Center and Chiba University beginning in 1972 were analyzed. RESULTS: Intralesional excision was performed in eight patients, marginal excision in two patients, and wide excision in three patients. Local recurrence was observed in six patients, with a high proportion occurring in the gluteal muscles attached to the sacrum (the gluteus maximus muscle and piriform muscle). Seven patients died of their disease and six patients were alive with no evidence of disease. The 5-year survival rate was 81.8% and the 10-year survival rate was 29.1%. CONCLUSIONS: It is highly possible that residual chordoma infiltrating the gluteal muscles accounts mainly for the local recurrences. Therefore, a precise preoperative assessment of the tumor infiltration into the gluteal muscles by magnetic resonance imaging is important for the prevention of local recurrence. For complete tumor removal, a radical wide posterior surgical margin of the gluteal muscles should be employed. A less radical anterior surgical margin is sufficient because there is a firm presacral fascia anterior to the sacrum. The appropriate surgical margin for the complete removal of the chordoma differs according to the location of the tumor and tissues involved. PMID- 10091766 TI - Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis--a pattern or an entity? A case report. AB - BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is prototypically represented by "undifferentiated" nasopharyngeal carcinoma, but it has also been described in many other anatomic locations, including the skin. In the last of these sites, primary LELC has been assumed in the past to show dermal adnexal differentiation. METHODS: The authors present a case wherein LELC of the skin (LELCS) instead appeared to be a morphologic manifestation of squamous carcinoma of the skin surface, as supported by the results of immunohistology and in situ hybridization. RESULTS: Like other examples of LELCS, it showed no evidence of integration of the Epstein-Barr viral genome, and its behavior was indolent. CONCLUSIONS: The heterogeneous nature of LELC as seen in different body sites is reviewed in this report, resulting in the conclusion that this tumor probably represents a morphologic pattern rather than a distinct clinicopathologic entity. PMID- 10091767 TI - Prognostic value of plasma prostate specific antigen after megestrol acetate treatment in patients with metastatic breast carcinoma. AB - BACKGROUND: Prostate specific antigen (PSA) is an established tumor marker of prostate adenocarcinoma that recently also was found in breast tumors. Minute amounts of PSA are found in female plasma. It is known from cell culture studies that PSA expression can be up-regulated by androgens and progestins but not estrogens. In this study, the authors examined whether plasma PSA in women with breast carcinoma changes after the therapeutic administration of the progestin megestrol acetate (MA) and whether these changes have any prognostic value. METHODS: Plasma PSA was measured by a highly sensitive immunofluorometric procedure that can measure within 1 ng/L of PSA. Serial plasma levels from women with metastatic breast carcinoma who received either MA (N = 52) or other treatments (N = 24) were evaluated. PSA changes in plasma were correlated with patient outcomes. RESULTS: The study found that approximately 50% of the patients receiving MA had a significant increase in their plasma PSA concentration after the treatment and that this increase was rapid (starting within 1 week) and dose dependent. PSA levels declined when treatment was withdrawn. Further comparisons with similar groups of patients receiving tamoxifen or doxorubicin have shown that the plasma PSA increases are specific to the MA treatment. The plasma PSA increases reflect the stimulation of the tumor by MA to produce PSA and the secretion of PSA into the general circulation. There is a statistically significant association between the plasma PSA changes after MA treatment and overall patient survival; patients with increased plasma PSA have an approximate threefold increase in their relative risk of death during the follow-up period. Multivariate analysis has shown that the increased risk of death in this group is associated, at least in part, with the frequent presence of distant metastasis. CONCLUSIONS: The measurement of plasma PSA after treatment with MA allows for patient classification into two groups. The group that did not demonstrate any changes in their plasma PSA level after MA treatment (approximately 50% of the patients) had a significantly better prognosis. The group that did demonstrate an increase in their plasma PSA level after MA treatment represented a subset of patients who may benefit more from MA withdrawal and the initiation of alternative regimens. However, these data need further confirmation with a larger pool of patients. PMID- 10091768 TI - Long term follow-up of women treated with 16-week, dose-intensive adjuvant chemotherapy for high risk breast carcinoma. AB - BACKGROUND: A Phase II study was performed evaluating the disease free and overall survival rates associated with a dose-intensive, 16-week, doxorubicin based adjuvant chemotherapy regimen in women with breast carcinoma and > or = 10 involved axillary lymph nodes. METHODS: Eligible patients underwent staging with computed tomography and bone scanning and were treated with a 16-week, dose intensive chemotherapy regimen, comprised of 8 2-week courses of cyclophosphamide, 100 mg/m2 orally, on Days 1-7; doxorubicin, 40 mg/m2 intravenously (i.v.), on Day 1; methotrexate, 100 mg/m2 i.v., on Day 1 with leucovorin rescue, 10 mg/m2, every 6 hours for 6 doses orally on Day 2; vincristine, 1 mg i.v. on Day 1; 5-fluorouracil (5-FU), 600 mg/m2 i.v., on Day 2 over 2 hours; and 5-FU, 300 mg/m2/day continuous i.v. on Days 8 and 9. Tamoxifen, 20 mg daily, was administered to patients with estrogen receptor positive tumors treated after October 1988. All patients were offered locoregional radiation therapy. RESULTS: Sixty-four women were treated on protocol. The median follow-up of 27 surviving patients was > 8 years at last follow-up. Three patients were lost to follow-up. The median time to progression was 54 months, the Kaplan-Meier estimate of event free survival at 5 years was 44% (95% confidence interval [CI], 31-56%), and the Kaplan-Meier estimate of overall survival at 5 years was 57% (95% CI, 44-69%). At 98 months the Kaplan-Meier estimate of freedom from recurrence was 31% (95% CI, 19-43%) and the Kaplan-Meier estimate of survival at 111 months was 36% (95% CI, 23-49%). CONCLUSIONS: Despite the use of dose intensive, doxorubicin-based, adjuvant chemotherapy, and intensive staging prior to study entry, the results of the current study are similar to those of previous reports for standard dose chemotherapy and appear inferior to those reported for high dose therapy. PMID- 10091769 TI - The current status of surgical staging of ovarian serous borderline tumors. AB - BACKGROUND: The purpose of the current study was to evaluate the current practice of surgical staging of ovarian serous borderline tumors. METHODS: Women with a diagnosis of ovarian serous borderline tumors whose pathology slides were sent to the M. D. Anderson Cancer Center for second-opinion diagnostic consultation between 1990-1996 were identified. The original pathology reports and M. D. Anderson Cancer Center consultation reports of 255 cases were reviewed for the frequencies of frozen-section analyses and staging biopsies, biopsy results, the specialty of the surgeon, and hospital type. RESULTS: The majority (78%) of ovarian borderline tumors primarily were encountered and staged by general obstetrician-gynecologists. Overall, 66% of patients had at least 1 staging biopsy performed. Approximately 12% of subjects underwent complete surgical staging, defined as having biopsy samples taken from pelvic and abdominal peritoneum, omentum, and retroperitoneal lymph nodes. Gynecologic oncologists performed complete staging in 50% of cases, obstetrician-gynecologists performed complete staging in 9% of cases, and general surgeons performed complete staging in 0% cases. The overall frequency of a positive staging biopsy was 37%. Approximately 47% (80 of 169) of patients who underwent biopsies were upstaged as a result of positive biopsies, - with 41% (70 of 169) having extrapelvic spread. CONCLUSIONS: Currently, surgical staging for women with ovarian serous borderline tumors remains inadequate, although a significant proportion of patients who undergo staging are noted to have extrapelvic spread. PMID- 10091770 TI - The management of inferior vena cava obstruction complicating metastatic germ cell tumors. AB - BACKGROUND: Inferior vena cava obstruction (IVCO) is a poorly characterized complication of metastatic germ cell tumor (GCT). The authors identified 31 cases to describe the clinical features, radiologic findings, complications, and treatment of this clinical entity. METHODS: Patients with GCT and IVCO were identified from case records of a GCT database. The records of 333 male patients with metastatic GCT (27% with seminoma and 73% with nonseminomatous GCTs) were screened for either clinical or computed tomography (CT) scan evidence of inferior vena cava compression or involvement. RESULTS: Thirty-one patients were identified (9.3% of patients with metastatic GCT). Common presenting symptoms were leg swelling and dilated abdominal wall veins. Approximately 29% of patients had thromboembolic complications and there was a single case of fatal pulmonary embolism. Nine patients had no clinical features at presentation but either had CT scan evidence of IVCO or developed symptoms during treatment. Right-sided testicular primary tumors were associated more frequently with IVCO compared with left-sided primary tumors (14% vs. 4% of cases of metastatic GCT, respectively). All patients had an abdominal mass measuring > 5 cm in maximum transverse dimension. CONCLUSIONS: The authors recommend careful clinical and radiologic evaluation for the presence of IVCO in cases of bulky metastatic GCT. A high index of suspicion must accompany the evaluation of a patient with a right-sided primary testicular tumor and a paracaval abdominal mass measuring > 5 cm in maximum transverse dimension. When IVCO is identified, prophylactic anticoagulation is recommended. PMID- 10091771 TI - Telomerase activity in patients with transitional cell carcinoma: a preliminary study. AB - BACKGROUND: Telomerase activity is not detectable in normal cells, and their telomers shorten until the chromosome is unable to replicate. Immortal cells have short but stable chromosomes and increased telomerase activity. Transitional cell carcinoma (TCC) has only a few useful markers of diagnostic or prognostic importance. The objective of this study was to determine whether there was a correlation between telomerase activity and the grade or stage of TCC, and whether the enzyme's activity could serve as a biochemical marker of this tumor. METHODS: The study included 29 patients with TCC. From each patient, samples of urine cells were obtained, and a cup biopsy was taken from an apparently normal area as well as from a part of the bladder tumor resected transurethrally. Control uroepithelial biopsies were taken from normal transitional cell sites from non-TCC patients. Biopsies or cells were subjected to either histologic examination or telomerase activity determination. RESULTS: Twenty-six of 29 (90%) of the tumor biopsies exhibited telomerase activity. Most of the cup biopsies were categorized as metaplastic or dysplastic, and 20 of 29 (69%) of these exhibited telomerase activity. Telomerase activity was found in 17 of 21 (81%) of the urine cells but in only 3 of 14 (21%) of control urine cells. All (10 of 10) of the uroepithelial biopsies taken from non-TCC patients did not show any telomerase activity. CONCLUSIONS: In this study, almost all tumor biopsies exhibited telomerase activity. The high incidence of telomerase activity found in cup biopsies of the malignant field uroepithelial cells from cup biopsies of TCC patients may suggest that telomerase could be activated early in carcinogenesis. A high incidence of telomerase activity was found in voided uroepithelial cells of TCC patients; however, no correlation between this activity and the histologic determination of grading and staging of the tumor was found. PMID- 10091772 TI - Final report on the University of California-San Francisco experience with bromodeoxyuridine labeling index as a prognostic factor for the survival of glioma patients. AB - BACKGROUND: At the University of California-San Francisco (UCSF), a labeling index (LI) based on in vivo administration of bromodeoxyuridine (BUdR) was routinely determined in tumors from patients with infiltrating gliomas for the 10 year period, 1984-1994. Considered an indicator of tumor proliferative potential, it was anticipated that the BUdR LI would aid in determining patient prognosis. The data have now matured, and a final report on the extensive UCSF experience is appropriate. METHODS: Patients were grouped separately based on tumor grade and whether LI was determined at the time of primary diagnosis or at recurrence. To assure data quality and consistent follow-up, only adult patients entered on clinical trials were included. Patients with primary Grade 2 gliomas could not be included because most of these patients did not enter clinical trials. Each patient LI was categorized as low (lowest quartile), moderate (between the 25th and 75th percentiles), or high (highest quartile). Statistical analyses included log rank and multivariate proportional hazards models. RESULTS: One hundred ninety patients with primary tumors (69 Grade 3, 121 Grade 4) and 149 patients with recurrent tumors (24 Grade 2, 37 Grade 3, and 88 Grade 4) were included. LI score was predictive of survival (P < or = 0.02 for univariate or multivariate analyses) in all but the primary Grade 4 patients. For that group, it was a significant predictor (P = 0.03) only among those surviving > or = 1.5 years. CONCLUSIONS: BUdR LI improved the predictability of long term patient outcome both initially and at the time of recurrence. Further research on measures of tumor proliferative potential as markers of outcome is warranted. PMID- 10091773 TI - Peritumoral brain edema associated with meningioma: influence of vascular endothelial growth factor expression and vascular blood supply. AB - BACKGROUND: The extent of peritumoral brain edema (PTBE) associated with meningiomas is very variable. Many causative factors have been investigated, but the mechanism of PTBE associated with meningioma has been unclear until now. Recently, the cerebral-pial blood supply and vascular endothelial growth factor (VEGF) have been implicated as causative factors of PTBE. METHODS: Seventy-three supratentorial meningiomas were investigated to identify factors, including type of arterial blood supply and VEGF expression, that may influence the development of meningioma-associated PTBE. The type of arterial blood supply was defined by the selective angiography. Paraffin embedded tumor sections were stained with monoclonal VEGF antibody by an immunoperoxidase method. The extent of PTBE was estimated by using preoperative magnetic resonance imaging as an edema index (EI). RESULTS: Forty-six meningiomas demonstrated PTBE, and the other 27 did not. Multiple regression analysis revealed close correlation between PTBE and type of arterial supply (P = 0.004), size of tumor (P = 0.021), vascular density (P = 0.028), and VEGF expression (P = 0.046). In meningiomas with cerebral-pial supply, the EI had increased significantly, just as VEGF was strongly expressed (P < 0.001). In contrast, meningiomas without a cerebral-pial supply developed little or no PTBE and less VEGF expression. CONCLUSIONS: The current results suggest that VEGF expression contributes to PTBE formation in meningioma only when a cerebral-pial blood supply exists. PMID- 10091774 TI - Surveillance of patients to detect recurrent thyroid carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate the utility of surveillance with annual whole-body iodine-131 (131I) scintigraphy for patients with recurrent thyroid carcinoma. METHODS: The records of patients with thyroid carcinoma were reviewed. The 76 patients included in this study had undergone thyroidectomy and postoperative 131I therapy, and had at least 1 negative whole-body 131I scintigraphy 1 year after 131I therapy. There were 59 females and 17 males (age range, 12-74 years). Surgery consisted of a total thyroidectomy for 84% of patients and a subtotal thyroidectomy for 16%. 131I was administered within 1 month of thyroidectomy and annually thereafter until complete ablation of remaining thyroid tissue occurred. Annual follow-up diagnostic whole-body 131I scintigraphy was performed at Years 1 and 2, and then every 3-5 years. Some patients also had scintigraphy performed in Years 3, 4, and 5. RESULTS: Patients received 1-4 annual administrations of 131I (median, 1). The administered activity per treatment was 30-211 mCi, and the total activity administered that was necessary to achieve complete ablation of functioning thyroid tissue ranged from 30 to 514 mCi (median, 100 mCi). The relapse free survival at both 5 and 10 years was 88%. By definition, all of these patients had a negative 131I scintigraphy at 1 year after their last therapeutic 131I administration. Seven patients had a positive 131I scintigraphy 1 year after the first negative scintigraphy. Two other patients had positive 131I images after 2 consecutive negative annual 131I scintigraphic studies. The predictive value for relapse free survival of 1 negative diagnostic 131I study of these patients was 91% (+/- 0.02), and for 2 consecutive annual negative 131I studies the value was 97% (+/- 0.02); these results were significantly different (P = 0.0197). A stepwise logistic regression analysis was performed in an effort to identify risk factors for disease recurrence after complete ablation. None of the variables assessed- age, gender, tumor histology, tumor size, vascular invasion, capsular invasion, surgical margin status, or lymph node status--was predictive of recurrence after complete ablation. CONCLUSIONS: A single negative 131I scintigraphic study after complete ablation has a lower predictive value for relapse free survival than do two consecutive annual negative studies. Annual 131I imaging is recommended for surveillance until 2 consecutive annual negative studies are obtained, after which repeat imaging at 3-5 years appears to be satisfactory. PMID- 10091775 TI - A phase II trial of cisplatin, methotrexate, levofolinic acid, and 5-fluorouracil in the treatment of patients with locally advanced, metastatic squamous cell carcinoma of the head and neck. AB - BACKGROUND: Induction chemotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) might improve survival with respect to radiation therapy alone. Furthermore, chemotherapy represents the only therapeutic option in metastatic head and neck carcinoma. METHODS: To improve further the results that could be obtained with an induction regimen of cisplatin (CDDP) plus 5-fluorouracil (5-FU), the authors treated 50 patients with locally advanced or metastatic SCCHN with a combination of CDDP 65 mg/m2 on Day 1, methotrexate 500 mg/m2 on Day 1, levofolinic acid 250 mg/m2 on Day 2, and 5-FU 800 mg/m2 on Day 2. Cycles were repeated every 2 weeks. The authors' aim was to increase the activity of CDDP plus 5-FU (PF) using a regimen that combined the three most active drugs in SCCHN and provided an adequate biochemical modulation of 5-FU, which was administered as an intravenous bolus infusion. RESULTS: Forty objective responses were observed among 50 evaluable patients (80%; 95% confidence interval [C.I.], 66-90%), including 7 complete responses (14%; 95% C.I., 5-27%), and 33 partial responses (66%; 95% C.I., 51-79%). Locoregional treatment, consisting of radiotherapy or surgery, was given at the end of chemotherapy. On completion of induction chemotherapy and locoregional treatment, 42 of 46 patients (91%) were rendered disease free. After a median follow-up of 20 months, the median duration of response was 10 months, the median failure free survival was 10 months, and the median overall survival was 21 months. The treatment was generally well tolerated. Grade 3-4 neutropenia occurred in 25 patients (50%), but it was febrile in only 3 patients. Nausea and vomiting were well managed with serotonin-3 blocking agents. Severe mucositis was seldom observed and easily manageable, and it never required hospitalization. CONCLUSIONS: The high level of activity, the manageable toxicity, and the noteworthy survival data of this regimen compare favorably with most of the drug combinations used worldwide to treat similar patient populations, with the additional advantage of significantly lower cost. PMID- 10091776 TI - Expression of thymidine phosphorylase and vascular endothelial cell growth factor in human head and neck squamous cell carcinoma and their different characteristics. AB - BACKGROUND: Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF). dThdPase is known to promote the development of new blood vessels, which are fundamental to tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a 34-42 kilodalton (kD) protein that induces both angiogenesis and vascular permeability. Proliferating cell nuclear antigen (PCNA) is a 36 kD nuclear protein, and its expression is associated with DNA synthesis and cell proliferation. METHODS: The authors investigated the correlations of dThdPase and VEGF with the growth of head and neck squamous cell carcinoma (HNSCC) in 95 patients by examining PCNA expression as a marker of tumor proliferation. They also retrospectively examined the expression of dThdPase in primary HNSCC and its association with angiogenesis and clinicopathologic findings. RESULTS: Microvessel count was significantly correlated with the expression of VEGF (P = 0.046) but not with dThdPase expression. The expression of PCNA was significantly correlated with dThdPase (P < 0.001) but not VEGF expression. A significant correlation was found between VEGF and dThdPase expression (P = 0.003). Neither dThdPase nor VEGF correlated with clinicopathologic findings, except for the correlation between tumor location and VEGF expression (P 0.020). CONCLUSIONS: These findings suggest that VEGF is involved in angiogenesis in HNSCC. dThdPase may have effects on tumor growth other than angiogenic activity in HNSCC. PMID- 10091777 TI - Hodgkin disease with subsequent transformation to CD30 positive non-hodgkin lymphoma in six patients. AB - BACKGROUND: Previous studies have indicated that some patients with Hodgkin disease have an aggressive clinical course. However, their characteristics have not been elucidated. METHODS: Six patients initially diagnosed as having Hodgkin disease with subsequent transformation to CD30 positive non-Hodgkin lymphoma were clinically and immunohistochemically studied. Ten patients with classic anaplastic large cell lymphoma (ALCL) and 19 patients with classic Hodgkin disease were studied for comparison by immunohistochemistry. RESULTS: Five patients, excluding one whom the authors recently encountered, had an aggressive clinical course and died within approximately 1 year after diagnosis; four of them were autopsied. Common histologic findings in the six patients included sheets of atypical mononuclear cells and sinusoidal infiltration of small numbers of these cells, as well as Reed-Sternberg cells or lacunar cells. Follow-up biopsies revealed histologic progression to ALCL in which sheets of atypical mononuclear or multinucleated cells spread throughout the lymph nodes. Immunohistochemically, epithelial membrane antigen, granzyme B, perforin, and pancadherin were expressed frequently in the six patients and in ALCL but were not expressed in Hodgkin disease. Latent membrane protein-1 (LMP-1) and Epstein Barr virus-encoded RNA (EBER-1) were totally negative in the six patients and in ALCL but were expressed frequently in Hodgkin disease. In contrast, LeuM1 (CD15) was expressed frequently in the six patients and in Hodgkin disease, whereas it was not expressed in ALCL. MT1 (CD43), UCHL-1 (CD45RO), and P80 were totally negative in the six patients and in Hodgkin disease, whereas they were expressed variably in ALCL. CONCLUSIONS: These results suggest that the six patients studied had intermediate phenotypes between ALCL and Hodgkin disease. The authors also suggest that patients with sheets of atypical mononuclear cells and sinusoidal infiltration of atypical mononuclear and multinucleated cells have an aggressive clinical course and should be treated with intensive chemotherapy. PMID- 10091779 TI - Treatment outcome of patients with brain metastases from malignant germ cell tumors. AB - BACKGROUND: Multiinstitutional experience with the management of cerebral metastases from malignant germ cell tumors (MGCT) is presented. METHODS: Clinical data regarding brain metastases from MGCT at diagnosis (Group 1 [56 patients]) or after cisplatin-based chemotherapy (Group 2 [83 patients]) were collected retrospectively. All patients in Group 1 received "conventional" cisplatin-based chemotherapy supplemented by cerebral radiotherapy (36 patients) and/or neurosurgery (10 patients). In the patients in Group 2 cerebral metastases were detected a median of 9 months after the initiation of chemotherapy. Thirty-five patients received chemotherapy, 59 patients received radiotherapy, and 25 patients underwent neurosurgery. RESULTS: The 5-year cause specific survival rate in Group 1 was 45% (95% confidence interval [CI], 31-59%). Neurosurgery and the absence of extracerebral, nonpulmonary visceral disease, but not cerebral radiotherapy, were independent predictors of good prognosis. The 5-year cause specific survival rate in Group 2 was 12% (95% CI, 4-20%), but was 39% among patients with an isolated brain recurrence (24 patients). Radiotherapy, but not chemotherapy, represented an independent predictor of good prognosis together with brain metastases at first recurrence and the absence of extracerebral recurrence. CONCLUSIONS: Among patients with brain metastases at the time of diagnosis of an MGCT, cisplatin-based chemotherapy resulted in a 5-year cause specific survival rate of 45%, with cerebral radiotherapy having limited impact. The 5-year cause specific survival rate for all patients with brain metastases after cisplatin-based chemotherapy was 12%, but increased to 39% in patients with an isolated brain recurrence. Cerebral radiotherapy (and neurosurgery) represent essential treatment modalities for patients in whom brain metastases are diagnosed after induction chemotherapy. PMID- 10091778 TI - An early phase II study of intratumoral P-32 chromic phosphate injection therapy for patients with refractory solid tumors and solitary metastases. AB - BACKGROUND: In this early Phase II study, the authors investigated the efficacy of intratumoral injection of P-32 chromic phosphate in 17 patients with refractory solid tumors or solitary metastases in terms of response rates and overall survival. METHODS: Seventeen patients (median age, 60 years) with either cytostatic drug-resistant tumors or tumors known to be primarily chemotherapy resistant were entered into the study. After sonographic determination of the tumor volume, P-32 chromic phosphate (74-555 MBq) was injected into the central part of the tumor under sonographic guidance. Follow-up investigations included serial scintigraphy, sonographic examinations, and hematologic studies. RESULTS: Injection of P-32 chromic phosphate into refractory tumors resulted in remarkable regression. The median survival of all patients was 13 months (range, 8-25 months). The response rate was 71% (12 patients). A complete remission was seen in 7 patients (41%), and the rate of partial remissions was 29% (5 patients). However, 5 patients (30%) did not respond to the treatment. In one patient thrombocytopenia was observed, but no other side effects were apparent. Important pathologic and anatomic changes within the tumor tissue were demonstrated in solitary liver metastases of gastrointestinal malignancies excised in second-look operations. In all cases examined, formation of a cyst within the area of central activity, surrounded by a centrifugal necrotic ring and a marginal fibrotic structure, was found. CONCLUSIONS: Lack of persistent systemic or local side effects, as well as noteworthy efficacy, are properties of this optimal regional treatment modality with P-32 chromic phosphate. This modality deserves consideration for further clinical trials. PMID- 10091781 TI - Magnetic resonance imaging to detect bone marrow metastases in the initial staging of small cell lung carcinoma and breast carcinoma. AB - BACKGROUND: Bone marrow is a common site of metastases in patients with small cell lung carcinoma (SCLC) and female breast carcinoma (FBC). Metastatic bone marrow involvement is found in approximately 50% of SCLC patients and up to 85% of FBC patients at autopsy. Initial staging procedures detect malignant bone marrow lesions in only 2-30% of patients with these tumors. This study was performed to assess whether MRI can improve the detection rate of bone marrow metastases in tumors with a high incidence of skeletal involvement. METHODS: Fifty-two patients with histologically verified SCLC (25 with limited stage disease and 27 with extensive stage disease) and 33 women with FBC were entered into a prospective study. The MRI protocol was comprised of coronal slices in the pelvic region and sagittal slices of the whole spine utilizing a T1-weighted spin echo sequence with a field of view of 50 cm. All patients underwent initial routine diagnostic staging procedures including bone scintigraphy, unilateral crest biopsy, and plain film radiography of suspicious skeletal areas. RESULTS: Only in two SCLC patients, MRI was positive in 25 cases. All SCLC patients with bone marrow lesions histologically verified, diagnosed by crest biopsy (six patients) or by bone scan (seven patients) had the correct diagnosis of metastases by MRI. In addition MRI revealed hypointense bone marrow foci in 14 cases. In contrast, 28 of 33 FBC patients examined during the initial staging procedure showed no evidence of bone marrow involvement. MRI was not superior compared with bone scintigraphy in FBC patients. CONCLUSIONS: The staging results obtained in SCLC and FBC patients are different, although both tumors have a high incidence of bone marrow metastases. It may be assumed that the biologic behavior of these tumors is reflected by the initial bone marrow involvement. Because of its superiority compared with biopsy and bone scan, the authors believe MRI should become an integral part of the initial staging procedures in patients with SCLC. When staging patients with FBC, MRI should be applied only in clinically indicated cases. PMID- 10091780 TI - Outcome of palliative urinary diversion in the treatment of advanced malignancies. AB - BACKGROUND: It is unclear whether palliative endourologic or percutaneous urinary diversion in the treatment of advanced cancer provides significant improvement in quality or duration of life. The purpose of this study was to evaluate survival and performance status after endourologic palliative urinary diversion in patients with advanced malignancy and to compare the results for different malignancies. METHODS: One hundred three patients with advanced malignancies underwent palliative urinary diversion (stent or nephrostomy) between 1986 and 1997. Ninety-two patients and 11 patients had bilateral and unilateral obstruction, respectively. Indications, complications, performance status after diversion, and survival for patients with different malignancies were identified and compared. A modified Karnofsky performance scale (KPS) was used for assessment of physical performance. A scale of 0-4 was used: 0) hospitalized until death; 1) bedridden at home, severe pain despite analgesia; 2) moderate disability, moderate pain despite analgesia; 3) mild disability, pain free with medication; and 4) normal. RESULTS: The mean age of patients was 68 years. The mean pre- and postoperative creatinine levels were 6 mg/dL and 3.3 mg/dL, respectively (P < 0.0001). The median survival and days of hospitalization were 112 and 45, respectively. The median postdiversion KPS score was 2 (range, 0-4), and 15% of patients never left the hospital. Overall, 51% required secondary percutaneous procedures, and 68.4% had complications (minor, 63%; major, 5.4%). CONCLUSIONS: Most patients with advanced cancers had poor performance status and survival after diversion. Eighty six percent had cancer-related symptoms despite the diversion. The average survival was 5 months, 50% of which was spent in the hospital. Primary endourologic procedures had a high failure rate, and additional procedures were required. PMID- 10091782 TI - Low p27 expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma. AB - BACKGROUND: p27, a cyclin-dependent kinase inhibitor, regulates progression from G1 to S phase. There have been a few clinical reports of low p27 expression associated with poor survival among patients with cancer; however, there have been no reports of such an association in cases of head and neck cancer. The authors investigated whether p27 expression in patients with oral tongue squamous cell carcinoma was associated with their prognosis. METHODS: Ninety-four patients with oral tongue squamous cell carcinoma were analyzed. The authors performed p27 immunohistochemistry on all patients and Western blot analysis on 19 available patients. Cox proportional hazards regression analysis that included gender, history of smoking and alcohol usage, presence of multiple primary cancers, stage, histologic grade, and p27 status was used to identify the multivariate predictive value of prognostic factors. RESULTS: Twenty-six patients had high p27 expression (> or =50% tumor cell nuclei positive), and 68 patients had low p27 expression (<50%) by immunohistochemistry. In those with low p27 expression, N(+) and advanced T (T3 or T4) were significantly higher than in those with high p27 expression (P = 0.02 and 0.04). The 5-year survival rate in the low p27 group was 44%, whereas that in the high p27 group was 68%, indicating a significant difference (P = 0.04). p27 expression was inferred from Western blot analysis, and an arbitrary quantity (<1, 1-5, or > or =5) from the ratio of tumor to normal tissue density was used to characterize, resulting in 8 (42%), 3 (16%), and 8 (42%) patients in the low (<1-fold), intermediate (1-5-fold), and high (> or =5 fold) groups, respectively. Results of immunohistochemical analysis for p27 were significantly correlated with those of Western blot analysis (P = 0.02). Multivariate analysis revealed that low intensity of p27 expression and advanced stage (Stage III or IV) were predictors of reduced survival (P = 0.02 and 0.001). CONCLUSIONS: Low p27 expression was associated with increasing lymph node metastasis and stage of tumor and resulted in a poor prognosis for patients with oral tongue squamous cell carcinoma. p27 is apparently a significant predictor of survival. PMID- 10091783 TI - Early diagnosis and treatment monitoring roles of tumor markers Cyfra 21-1 and TPS in oral squamous cell carcinoma. AB - BACKGROUND: Mucosal oral squamous cell carcinoma (SCC) accounts for 3-5% of all reported cancers, with a 5-year survival rate of approximately 50%. Unfortunately, current detection means are of no value in diagnosing lesions early enough for cure, especially when they recur after resection. Postoperative radiotherapy and/or covering the resection site with reconstructive flaps (regional or free vascularized) often makes early diagnosis an impossible task. METHODS: The authors examined the detection and treatment monitoring capacity of two relatively new tumor markers in the serum of SCC patients, comparing their levels with those in patients with other oral/perioral malignancies or benign oral tumors and with disease free, posttreatment SCC patients and healthy controls. RESULTS: Values of sensitivity, specificity, and positive and negative prediction for Cyfra 21-1 were 96%, 87%, 93%, and 53%, respectively, whereas those for tissue polypeptide specific antigen (TPS) were 69%, 87%, 93%, and 54%, respectively. Approximately 2-3 weeks after resection of the SCC lesion, Cyfra 21 1 and TPS levels were reduced by 47% (P < or = 0.003) and 36% (P < or = 0.041), respectively. Cyfra 21-1 levels in SCC patients were significantly greater than those of healthy patients by 73% (P < or = 0.0001), patients with benign tumors by 74% (P < or = 0.0003), and patients in disease remission by 66% (P < or = 0.0002). Similarly, the TPS levels of SCC patients were significantly greater than those of healthy patients by 59% (P < or = 0.0005), patients with benign tumors by 55% (P < or = 0.0001), and patients in disease remission by 59% (P < or = 0.0001). In two patients, a second, new SCC lesion was diagnosed within the follow-up period, with increased tumor markers noted concomitantly with the diagnosis. CONCLUSIONS: The accumulated data point to the suitability of the clinical usage of these two markers, especially Cyfra 21-1, in the early detection of oral SCC lesions (primary, recurrent, or secondary) as well as for treatment monitoring. These results may open new avenues for the diagnosis and follow-up of these patients and hopefully improve their treatment outcome. PMID- 10091784 TI - Inadequacy of computed tomography in assessing patients with esophageal carcinoma after induction chemoradiotherapy. AB - BACKGROUND: Induction chemoradiotherapy followed by surgery may improve survival of patients with esophageal carcinoma. Computed tomography (CT) has been used to evaluate the tumor response after completing induction chemoradiotherapy. The authors examined the ability of CT to evaluate the pathologic tumor response to induction therapy and to stage the tumor correctly. METHODS: Preinduction and postinduction chemoradiotherapy CT scans were reviewed retrospectively for 50 patients enrolled in a protocol of induction chemoradiotherapy followed by surgery. All studies were performed on third-generation or fourth-generation scanners. Radiographic response was determined using Eastern Cooperative Oncology Group solid tumor response criteria for bidimensional measurable disease. This was compared with the pathologic tumor response. CT-tumor (T) classification using the modified Tio scale was compared with the pathologic T classification. RESULTS: CT-T classification did not correlate with the pathologic stage (P = 0.09) or the pathologic tumor response (P = 0.22). The postinduction chemoradiotherapy CT accurately staged the T classification in 42% of patients but overstaged 36% of patients and understaged 20% of patients. CT had a sensitivity of 65%, a specificity of 33%, a positive predictive value of 58%, and a negative predictive value of 41% in evaluating the pathologic tumor response. CONCLUSIONS: CT is a poor diagnostic study tool for determining the pathologic tumor response or the pathologic disease stage after induction chemoradiotherapy in patients with esophageal carcinoma. PMID- 10091785 TI - Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma. AB - BACKGROUND: Urokinase-type plasminogen activator (uPA) plays an important role in the destruction of the extracellular matrix and basement membrane around cancer cells. In the current study, the authors investigated uPA expression in cancer cells and stromal cells in patients with gastric carcinoma. METHODS: uPA activity was determined by an enzymatic assay using synthetic substrate (S-2444) in tumor specimens obtained from 71 patients with gastric carcinoma and was compared with the results of immunohistochemical staining for uPA. RESULTS: Higher uPA activity was significantly associated with tumors with peritoneal metastases and tumors with deeper invasion into the gastric wall. Undifferentiated tumors showed significantly higher uPA activities compared with differentiated tumors. The 25 patients with high uPA activity (> or = 60 U/mg protein) had a lower survival rate than the 46 patients with low uPA activity (< 60 U/mg protein) (P < 0.05). uPA activity showed prognostic significance in patients with International Union Against Cancer Stage II and Stage III tumors (P < 0.05, respectively). There was no significant relation between immunohistochemical expression of uPA in cancer cells and uPA enzymatic activity. However, uPA expression in stromal cells significantly correlated with uPA activity in tumor tissues. The uPA expression in stromal cells also correlated with tumor histology and peritoneal metastases. CONCLUSIONS: These results suggest that uPA enzymatic activity is a prognostic factor in gastric carcinoma, and that uPA produced by stromal cells may regulate cancer cell invasion. PMID- 10091786 TI - The value of serum tissue polypeptide specific antigen in the diagnosis of hepatocellular carcinoma. AB - BACKGROUND: Tissue polypeptide specific antigen (TPS) recently was introduced as an indicator of cell proliferation in various tumors. The authors investigated the value of serum TPS as a complement to alpha-fetoprotein (AFP) in the detection of hepatocellular carcinoma (HCC) in Chinese patients. METHODS: Serum TPS and AFP levels were measured by monoclonal immunoradiometric assay in 85 subjects (52 males and 33 females): 26 with HCC, 30 with chronic hepatitis (CH), and 29 healthy controls. RESULTS: Patients with HCC had significantly higher TPS levels compared with healthy controls (P < 0.05). However, the difference between the HCC and CH groups was not significant (P = 0.18). The sensitivity and specificity of TPS were 73.1% and 71.2%, respectively, with a cutoff value of 164 U/L for HCC diagnosis. TPS had lower discriminatory power compared with AFP (72.1% vs. 79.2%). In addition, TPS had a much lower specificity compared with AFP (89.1%). Combining the cutoff values for serum TPS and AFP levels in a pessimistic prognostic rule increased the sensitivity by 11.6% from 69.2% using serum AFP levels alone, but reduced the diagnostic power by 3.7% to 75.5% due to an 18.9% decrease in specificity to 70.2%. CONCLUSIONS: Using TPS alone offers no advantage over AFP for the diagnosis of HCC in Chinese patients. In conjunction with AFP, TPS reduced the false-negative rate. However, the clinical utility of the combined prognostic rule is limited due to the poor discriminatory power of TPS for HCC and CH. Therefore, the use of serum TPS levels in the detection of HCC is not recommended. PMID- 10091787 TI - High grade surface osteosarcoma: a clinicopathologic study of 46 cases. AB - BACKGROUND: High grade surface osteosarcoma is a rare subtype of osteosarcoma arising on the surface of bone, accounting for only 8.9% of surface osteosarcomas at the study institution. METHODS: This study reviews 46 cases of high grade surface osteosarcoma, comprised of 13 cases from the Mayo Clinic files and 33 from the authors' files. Histologic features were reviewed in all cases, and radiographs were reviewed in 29 cases. RESULTS: There was a definite male predominance, and 70% of the patients were in the second and third decades of life. Forty-four of the 46 patients had lesions involving the long bones, the most common site being the midportion of the femur. Radiographically, the majority of lesions showed dense to moderate mineralization with a fluffy, immature appearance. Radiating spicules of bone perpendicular to the long axis of the bone, characteristic of periosteal osteosarcoma, were sparse. Histologic findings were identical to those of conventional osteosarcoma. Overall, survival at 5 years was 46.1%. Statistical analysis revealed that marginal excision was associated with an increased risk of local recurrence and that the patients with Broders Grade 3 tumors had a better prognosis than those with Grade 4 tumors. A good response to chemotherapy was associated with better clinical outcome. CONCLUSIONS: High grade surface osteosarcoma is a rare subtype of surface osteoscarcoma that has a prognosis similar to that of conventional osteosarcoma, in contrast to the more common type of osteosarcoma arising on the surface of bone. Wide excision and effective systemic chemotherapy are associated with better clinical results. PMID- 10091788 TI - Acute tumor lysis syndrome associated with concurrent biochemotherapy of metastatic melanoma: a case report and review of the literature. AB - BACKGROUND: Treatment of solid tumors rarely has been associated with tumor lysis syndrome. However, to the authors' knowledge the clinical scenario has not been reported previously in melanoma patients. METHODS: A patient with bulky metastatic melanoma was treated with concurrent biochemotherapy using interleukin 2, interferon-alpha, and a combination of cisplatin, vinblastine, and dacarbazine. RESULTS: Within 24 hours of the initiation of treatment, brisk tumor lysis occurred and led to a fatal outcome. CONCLUSIONS: Improvements in the treatment of solid tumors may increase the incidence of tumor lysis syndrome for tumors once believed to be marginally responsive. Oncologists should remain cognizant of this problem as more active regimens become available. PMID- 10091789 TI - Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study. AB - BACKGROUND: The objective of the current study was to evaluate the response rate, survival, and toxicity of treatment with cisplatin and high dose intravenous continuous infusion interleukin-2 (IL-2) with or without interferon-alpha-2a (IFN) in patients with metastatic melanoma. METHODS: One hundred and seventeen patients with metastatic melanoma randomly were assigned to receive cisplatin, 100 mg/m2, followed after a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days 17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration (Arm 2). In the absence of disease progression or undue toxicity, the cycle could be repeated on Day 29. Patients who responded after two cycles eventually could receive a third cycle. One hundred and one patients were evaluable for toxicity and efficacy. RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response (CR) and 5 patients (10%) achieved a partial response (PR) with a median response duration of 3.8 months for the CRs and 8.7 months for the PRs. On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9 and 33.1 months, respectively) and 11 patients (21%) a PR with a median response duration of 8.3 months. The median durations of overall survival were 10.4 months (range, 1.1 39.7+ months) and 10.9 months (range, 0.5-38.1+ months) for treatment Arms 1 and 2, respectively. The toxicity profile was consistent with the known side effects of this IL-2 intravenous regimen combined with cisplatin chemotherapy and IFN. Toxicity was more pronounced in treatment Arm 2 compared with treatment Arm 1. There were 2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within 28 days after completion of treatment. CONCLUSIONS: The observed overall response rates of 16% and 25% in treatment Arms 1 and 2, respectively, is lower than that expected with biochemotherapy; despite the fact that the objective of the trial was not to show any difference between the 2 treatment arms, our results indicate that the addition of IFN, at the dose and schedule used in this trial, fails to improve the activity of a cisplatin/IL-2 regimen significantly in patients with metastatic melanoma. Although response rates were relatively low, the median overall survival was nearly 1 year in both groups. PMID- 10091790 TI - Thin cutaneous malignant melanomas (< or =1.5 mm): identification of risk factors indicative of progression. AB - BACKGROUND: Although thin cutaneous melanomas generally have a favorable prognosis, in some cases they may undergo progression. The current study was undertaken to identify variables that may predict a more aggressive clinical outcome in these patients. In addition to classic clinicopathologic features, the authors tested the prognostic impact of three new morphometric quantitative parameters: 1) tumor thickness plus regression thickness (T+R), 2) percentage of skin thickness infiltrated by tumor cells (T/S ratio), and 3) percentage of skin thickness infiltrated by tumor cells and regression ([T+R]/S ratio). METHODS: The authors retrospectively evaluated 287 patients with invasive cutaneous melanoma < or = 1.5 mm in thickness. Disease free survival rates (Kaplan-Meier method) were compared by using the log rank test. A multivariate analysis (Cox proportional hazards model) was used to determine the independent effect of each variable on progression. Progression was defined as any documented cutaneous local and/or distant metastasis. RESULTS: Thirty-two of the 287 patients (11.1%) underwent disease progression. The overall 5-year and 10-year disease free survival rates were 89.3% and 84.6%, respectively. In the univariate analysis, the following factors were found to be significant predictors of progression: male gender (P = 0.01), acral-lentiginous histotype (P = 0.02), tumor thickness (P = 0.005), T+R (P = 0.001), T/S ratio > or = 50% (P = 0.03), (T+R)/S ratio > or = 50% (P = 0.006), vertical growth phase (P = 0.04), and absence of inflammatory response (P < 0.0001). Conversely, age, site, and Clark's level did not affect the risk of recurrences and/or metastases significantly. In the multivariate analysis, only T+R (P = 0.009) and inflammatory response (P < 0.0001) were found to be independent predictors of progression. Five-year disease free survival rates according to presence versus absence of inflammatory response were 93.4% and 63.8%, respectively (P < 0.0001). CONCLUSIONS: In the current study, peritumoral and intratumoral inflammatory infiltrate and T+R were found to be strong independent predictors of progression in thin cutaneous melanomas. PMID- 10091791 TI - Leiomyosarcoma of the inferior vena cava: prognosis and comparison with leiomyosarcoma of other anatomic sites. AB - BACKGROUND: Leiomyosarcoma of the inferior vena cava (IVC) is an uncommon tumor that many believe portends a poor prognosis compared with leiomyosarcoma with similar histology at other anatomic sites. Because of the limited international experience with this disease, the optimal management of these patients is unknown. METHODS: From October 1978 to January 1997, 14 patients with leiomyosarcoma of the IVC were treated at the University of California-Los Angeles Medical Center. Wide resection was attempted in all patients. The characteristics of each patient were documented and compared with those of patients with leiomyosarcoma of the stomach (n = 13), small intestine (n = 18), retroperitoneum (n = 19), and uterus (n = 10) who were treated during the same time period. RESULTS: Age, gender, tumor size, tumor grade, and lymph node status did not impact survival of patients with leiomyosarcoma of the IVC. Patients with positive surgical margins fared significantly worse (P < 0.03) compared with those who underwent complete resection. Radiation therapy diminished local recurrence and may improve median survival (6 months [n = 2] vs. 51 months [n = 12]) in this patient population. Patients who received combined chemotherapy and radiation lived longer than those who did not (P < 0.05). The 5-year cumulative survival rate (Kaplan-Meier method) was 53% for patients with leiomyosarcoma of the IVC, 47% for those with leiomyosarcoma of the stomach, 43% for those with leiomyosarcoma of the small intestine, 56% for those with leiomyosarcoma of the retroperitoneum, and 65% for those with leiomyosarcoma of the uterus. CONCLUSIONS: Despite having a tumor that originates from the IVC, patients with this tumor type can enjoy reasonably long term survival. It appears that these patients benefit from radiation therapy to control local disease. Survival of these patients is no worse than of patients with leiomyosarcomatous lesions of other origin. Aggressive surgical management combined with adjuvant therapy offers the best treatment for patients with leiomyosarcoma of the IVC. PMID- 10091792 TI - Trends in incidence and treatment for ductal carcinoma in situ in Hispanic, American Indian, and non-Hispanic white women in New Mexico, 1973-1994. AB - BACKGROUND: Incidence rates of ductal carcinoma in situ (DCIS) breast carcinoma and the use of breast-conserving surgery (BCS) for its treatment show substantial geographic and ethnic variations nationwide. To the authors' knowledge, few studies have investigated incidence rates and treatment patterns in Hispanics and American Indians. METHODS: The authors used data from the population-based New Mexico Tumor Registry to describe trends in DCIS incidence rates between 1973 1994 and investigate patient and physician characteristics related to BCS in a multiethnic population between 1985-1994. Multiple logistic regression was used to evaluate patient and physician factors related to receiving BCS. RESULTS: Incidence rates for DCIS in Hispanics were approximately 50% lower compared with non-Hispanic whites. American Indians had the lowest incidence rate. Beginning in 1985, incidence rates for Hispanics and non-Hispanic whites showed a 21% annual increase. Between 1990-1994, incidence rates in American Indians increased more than twofold. BCS increased 5.8% per year between 1985-1994, with 50% of Hispanic and non-Hispanic white patients treated with BCS in 1994. The strongest factor associated with receiving BCS was geographic location of treatment (P < 0.001). The odds of receiving BCS were 5.8 times higher in the northern third of the state compared with the southern third. No significant variation in BCS was found by ethnicity, rural/urban residency, socioeconomic status, or physician characteristics. CONCLUSIONS: Incidence rates for DCIS increased substantially in all three ethnic groups. The use of BCS was associated most strongly with the location of treatment, most likely reflecting differences in physician practices and treatment recommendations. Further research is needed to investigate the increasing incidence rates of DCIS and the determinants of BCS for the treatment of DCIS. PMID- 10091793 TI - A prospective, randomized Phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. AB - BACKGROUND: A prospective, multicenter, randomized, Phase III trial comparing the efficacy of combination chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) with a combination of vinorelbine and doxorubicin (NA) in the treatment of patients with advanced breast carcinoma was undertaken. METHODS: One hundred and seventy-seven patients who previously were untreated for recurrent or metastatic breast carcinoma were entered into the study; 7 patients could not be assessed. The final analysis relates to 85 patients who were treated with FAC and 85 patients who were treated with NA, of whom 21 (25%) and 44 (52%), respectively, had received prior adjuvant chemotherapy. RESULTS: The overall response rates were similar for the two treatments and were unaffected by prior exposure to adjuvant therapy; overall response rate (ORR) for FAC was 74% (95% confidence interval [95% CI], 65-83%), and the ORR for NA was 75% (95% CI, 66 84%). The activity of NA in patients with liver involvement was greater than that of FAC in terms of survival. Overall survivals were similar, with a median of 17.3 months for patients receiving FAC and 17.8 months for patients receiving NA. Severe toxicity was uncommon with World Health Organization Grade 3-4 neutropenia affecting only 7% of patients in each arm of the study. NA was associated with a higher incidence of mild to moderate constipation, neurotoxicity, and phlebitis, whereas FAC produced a slight excess of mild cardiotoxicity. CONCLUSIONS: The efficacy of these two regimens is very similar, although NA may be more active in a subset of patients with visceral metastatic disease, particularly liver involvement. It is clear that, in a direct comparison with an established three drug regimen, the newer two-drug combination of NA demonstrated equivalent activity with no significant excess of Grade 3-4 toxicity. PMID- 10091794 TI - Immunohistochemistry with pancytokeratins improves the sensitivity of sentinel lymph node biopsy in patients with breast carcinoma. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy is being investigated as a staging procedure for breast carcinoma. The authors evaluated whether immunohistochemical (IHC) analysis improves the sensitivity of this procedure. METHODS: Forty-four women with breast carcinoma were recruited for SLN biopsy. Preoperative lymphoscintigraphy was followed by intraoperative localization using a handheld gamma probe and blue dye. After SLN identification, an immediate complete axillary lymph node dissection was performed in all patients. All lymph nodes were subjected to routine histology (hematoxylin and eosin [H&E]) and IHC using antibody to cytokeratins. RESULTS: The SLN was identified in 41 of 43 patients (95%). Successful SLN identification was independent of biopsy technique (open surgical [95%] vs. fine-needle aspiration/core needle biopsy [96%]). Twelve of 41 patients (29%) had evidence of lymph node metastasis in the SLN by routine histology. Of the twenty-nine patients with H&E negative SLN, 3 were found to have metastasis by IHC for a conversion rate of 10%. Fifteen of 41 patients (37%) had evidence of metastasis in SLN. All 26 patients with H&E and IHC negative SLN had negative nonsentinel lymph nodes by routine histology and IHC (100% negative predictive value). All patients with tumors < 2 cm and micrometastasis to the SLN had no additional lymph node disease, in contrast to patients with lesions > 2 cm or patients with macrometastasis to the SLN (P = 0.007). CONCLUSIONS: These results confirm that SLN biopsy is extremely accurate for patients with breast carcinoma, even after open surgical biopsy. IHC analysis or serial sectioning of SLN improves the sensitivity of this staging technique. PMID- 10091795 TI - Compliance with consensus recommendations for the treatment of early stage breast carcinoma in elderly women. AB - BACKGROUND: The goal of this study was to assess variations with age in the management of breast carcinoma and to identify determinants of care received. METHODS: A stratified random sample was selected among women age > or = 50 newly diagnosed with lymph node negative breast carcinoma in Quebec in 1988, 1991, and 1993. Information was abstracted from medical charts. Predictors of definitive locoregional treatment (total mastectomy with lymph node dissection or breast conserving surgery with both axillary lymph node dissection and radiation therapy) were identified by multiple logistic regression analysis. RESULTS: Overall, 1174 patients age > or = 50 years with breast carcinoma were included. Women age > or = 70 years were much less likely to receive definitive locoregional treatment compared with women ages 50-69 years (48.7% vs. 83.5%; P < 0.0001). Older women were less likely to undergo surgery with breast preservation (76.7% vs. 86.3%; P < 0.0001), radiation therapy (54.7% vs. 90.5%; P < 0.0001), dissection of the axillary lymph nodes (55.6% vs. 86.3%; P < 0.0001), or chemotherapy (1.2% vs. 13.9%; P < 0.0001), but not treatment with tamoxifen (66.4% vs. 64.7%; P = 0.41). Adjusting for comorbidity and other characteristics related to the disease, the hospital, and the attending physician, age remained a strong determinant of the probability of receiving definitive locoregional treatment (odds ratio [OR], 0.14; 95% confidence interval [95% CI], 0.12-0.18 for women age > or = 70 years vs. women ages 50-69 years). The same association was observed when women who did not undergo lymph node dissection but who received systemic adjuvant treatment were considered to have received definitive therapy (OR, 0.13; 95% CI, 0.10-0.17) for women age > or = 70 years vs. women ages 50-69 years). CONCLUSIONS: Less aggressive patterns of care are provided to elderly breast carcinoma patients, independent of comorbidity. This could explain, at least in part, the sustained breast carcinoma mortality in this population. PMID- 10091796 TI - Psychologic distress in women with abnormal findings in mass mammography screening. AB - BACKGROUND: This study was conducted to explore the psychologic morbidity of women recalled for diagnostic assessment during population-based mammographic screening. METHODS: This study prospectively attempted to measure physical, social, and emotional well-being by the administration of a questionnaire before screening, at the time of recall; and 1 month later to women recalled and matched women with those not recalled. RESULTS: Of the 224 women who were recalled for further diagnostic assessment and their matches, complete follow-up was obtained on 182 pairs (81.3%). In contrast to those women not recalled, recalled women exhibited increased levels of concern at the time of recall. These levels had not decreased to the initial level after 1 month, even though breast carcinoma was not diagnosed. Similar negative short term effects also were evident in the areas of physical well-being, social functioning, and anxiety and insomnia levels, although these were not sustained. CONCLUSIONS: Women with normal results after mass mammographic breast screening experienced no increase in psychologic distress and a decrease in their concern regarding breast carcinoma. However, those women who were recalled to follow-up after abnormal findings experienced an increase in their level of concern regarding breast carcinoma and this concern was sustained, as determined by repeat questionnaire, 1 month after a negative result had been determined. PMID- 10091797 TI - A prospective comparison of stereotaxic fine-needle aspiration versus stereotaxic core needle biopsy for the diagnosis of mammographic abnormalities. AB - BACKGROUND: Confidence in a negative stereotaxic breast biopsy result allows for safe clinical and mammographic follow-up, whereas a positive or equivocal diagnosis leads to excision. Direct comparison of stereotaxic core needle biopsy (SCBX) and fine-needle aspiration (SFNA) is needed, and should be based on the use of appropriate current methods of practice, and address the indication of each for different types of mammographic lesions. METHODS: The diagnostic accuracy of SFNA, SCBX, and combined SFNA with SCBX performed at a community radiology practice were assessed for different mammographic lesions and levels of radiologic suspicion. Negative predictive values (NPVs) measured the confidence that a negative diagnosis (failure to identify atypia or malignancy) was benign and therefore suitable for follow-up. A benign outcome was accepted only after surgical excision or > or =24 months' follow-up of the lesion. Positive predictive values (PPVs) [final diagnoses at least atypical (A) or carcinoma (CA)] also were calculated. RESULTS: SFNA was performed for 495 lesions and was combined with SCBX for 252 of these. Nondiagnostic (SFNA, 2%; SCBX, 8%) and atypical (SFNA, 7%; SCBX, 3%) rates were low. The authors obtained 94% follow-up (81% > or = 24 months). NPVs were all SFNAs, 99%; SCBXs, 95% (corresponding SFNAs, 98%); and SFNA with SCBX, 99%. NPVs were 100% for masses, ill-defined densities, and architectural distortions. NPVs for microcalcifications (for low, moderate, and high suspicion) were all SFNAs, 97% (100, 95, and 75); SCBXs, 93% (94, 93, and 67), corresponding SFNAs, 96% (100, 94, 75); and SFNA with SCBX, 98% (100, 97, 75). All false-negative lesions were microcalcifications. Calcium was recognized in 98% of SFNA specimens and in 89% of SCBX specimens from microcalcifications. No calcium was identified in the histologic sections in 63% (5 of 8) SCBX false-negative specimens. PPVs(A) were atypical (SFNA, 46%; SCBX, 88%) and suspicious (SFNA, 93%). PPVs(CA) were SFNA carcinoma, 100%; SCBX in situ, 89%; and SCBX invasive, 100%. CONCLUSIONS: SFNA identified benign lesions more reliably for follow-up, particularly microcalcifications. Based on these results, the authors suggest 1) added SCBX if on-site SFNA assessment is nondiagnostic, atypical, or positive (and needs preoperative confirmation of invasion); 2) either SCBX or SFNA for masses, architectural distortions, and ill defined densities; 3) SFNA for microcalcifications, with SCBX added for moderately and highly suspicious lesions; and 4) surgical excision for all highly suspicious microcalcifications. PMID- 10091798 TI - p53 protein expression in squamous cell carcinoma of the vulva. AB - BACKGROUND: The objective of the study was to evaluate the pathogenetic and prognostic value of p53 protein expression in squamous cell carcinoma of the vulva. METHODS: The clinical data in charts of 167 patients with International Federation of Gynecology and Obstetrics (FIGO) Stages I-III primary tumors who were treated by surgery were reviewed. Samples from the primary tumor were immunostained for p53 protein. p53 overexpression was defined as immunoreactivity in > 5% of nuclei. RESULTS: p53 overexpression was observed in 92 tumors (55%). p53 overexpression did not correlate with age at diagnosis, FIGO stage, histologic grade, vessel invasion, tumor thickness, tumor greatest dimension, DNA ploidy, or inguinal lymph node metastasis. In the whole group a significantly reduced 5-year corrected survival was observed in patients with p53 overexpression compared with p53 negative patients (P = 0.04). In the different FIGO stages, disease-related survival was not influenced by p53 overexpression in 37 patients with Stage I disease (P = 0.60) or in 86 patients with Stage II disease (P = 0.96). In 44 patients with Stage III disease, p53 overexpression was significantly associated with poorer prognosis (P = 0.004). Independent prognostic factors for corrected survival in the entire group of 167 patients were: vascular invasion, groin metastasis, tumor greatest dimension, and p53 overexpression. In patients with FIGO Stage III disease p53 overexpression was not an independent prognostic factor. CONCLUSIONS: p53 protein overexpression appears to be involved in the pathogenesis of vulvar squamous cell carcinoma. p53 protein overexpression was significantly associated with disease-related survival. p53 prognostic impact was observed only in patients with advanced disease. PMID- 10091799 TI - The significance of squamous metaplasia in the development of low grade squamous intraepithelial lesions in young women. AB - BACKGROUND: The purpose of this study was to examine, prospectively, the presence and extent of cervical epithelial immaturity as well as the rate of squamous metaplastic activity as a risk for the development of low grade squamous intraepithelial lesions (LSIL). METHODS: The study was a nested case-control design that used subjects from an ongoing cohort study of human papillomavirus infection. Fifty-four sexually active young women who developed LSIL were matched for age and number of visits with 54 women who had never developed LSIL. The percent of cervical immaturity was interpreted from colpophotography using a computer-generated pixel count of delineated immature and total cervical areas. Activity of squamous metaplasia was interpreted as the percent change in the area of immaturity over a defined time period. Conditional logistic regression analysis examined risks for the development of LSIL. RESULTS: Baseline area of biologic immaturity was not a predictor of LSIL. However, women with the a high degree of metaplastic activity near the SIL event were more likely to develop LSIL (odds ratio = 3.01 [95% confidence interval, 1.3, 6.8] for every 10% unit change in area of immaturity). CONCLUSIONS: A rapid rate of metaplastic change within the transformation zone, rather than the initial area of biologic immaturity, is a significant risk factor for the development of LSIL. PMID- 10091800 TI - Phase II trial of intermediate dose methotrexate in combination with vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. AB - BACKGROUND: This study was undertaken to determine whether the use of intermediate dose methotrexate in combination with vinblastine, doxorubicin, and cisplatin as first-line therapy increases the proportion of major responders and overall survival in patients with unresectable or metastatic transitional cell carcinoma (TCC) of the urothelial tract. METHODS: Twenty-nine patients with histologically confirmed TCC received methotrexate at a dose of 1000 mg/m2 on Day 1 followed by leucovorin calcium rescue on Day 2 and vinblastine (3 mg/m2), doxorubicin (30 mg/m2), and cisplatin (70 mg/m2) (VAC) on Day 2. Therapy was recycled at 28-day intervals. RESULTS: Fourteen of 28 patients (50%; 95% confidence interval [CI], 31-69%) achieved a major response, including 6 pathologic or clinical complete responses (CR) and 8 partial responses (PR). Nine patients were rendered disease free after postchemotherapy surgical resection of residual disease (surgical CR), including five patients who had PR and four nonresponders to chemotherapy alone. Five of 18 patients with disease limited to lymph nodes attained CR, in contrast to only 1 of 10 patients with visceral metastatic disease. The median survival for the entire population was 13.6 months. CONCLUSIONS: The escalation of methotrexate to 1000 mg/m2 in combination with vinblastine, doxorubicin, and cisplatin did not result in a response proportion or median survival superior to that observed with standard dose M-VAC. As previously observed in a Phase II trial of M-VAC, only the attainment of CR was associated with prolongation of survival. PMID- 10091801 TI - Screening for metastatic malignant melanoma of the uvea revisited. AB - BACKGROUND: The purpose of the current study was to assess the value of routine imaging and liver function tests in detecting metastases from malignant melanoma of the uvea. METHODS: Forty-six consecutive patients diagnosed with metastatic uveal melanoma between 1985 and 1996 who had participated in a screening program that included annual liver function tests (LFT), chest X-ray, and abdominal ultrasonography (US) were eligible for this retrospective cohort study. Main outcome measures were the sensitivity of screening tests, presence of symptoms, recurrence free interval, and metastatic burden. RESULTS: Metastases were diagnosed in 74% of patients (95% confidence interval [95% CI], 59-86) at screening and in 26% (95% CI, 14-41) when the patient consulted a physician because of symptoms that developed before the next scheduled visit. Of all the patients, 59% (95% CI, 43-73) were asymptomatic, and 80% (95% CI, 66-91) had only hepatic metastases. The median recurrence free interval, greatest dimension of the largest metastasis, and metastatic burden of the two groups did not differ. US was diagnostic in 78% (95% CI, 64-89), at least 1 LFT test was abnormal in 70% of patients (95% CI, 54-82), and a chest X-ray was abnormal in 2% of patients (95% CI, 0-12). LFTs and US did not reveal hepatic metastases in 33% and 4% of patients, respectively. The sensitivity of individual LFTs ranged from 0.27 to 0.67, and their specificity from 0.90 to 0.96, with lactate dehydrogenase being the most sensitive LFT used. CONCLUSIONS: The authors believe that annual screening with LFTs and abdominal US will identify 59% of patients while they are still asymptomatic and that semiannual screening will detect >95% of such patients. Chest X-ray has a very low yield and is recommended only at baseline to exclude metastatic disease to the eye and if pulmonary symptoms develop. PMID- 10091802 TI - Topotecan treatment of adults with primary malignant glioma. The Brain Tumor Center at Duke. AB - BACKGROUND: Topotecan activity was evaluated for the treatment of malignant glioma. METHODS: Sixty-three patients with newly diagnosed (n = 25) or recurrent (n = 38) malignant glioma were treated with topotecan [AU: Please verify all dosages here and throughout text.]at a dose of 2.6 mg/m2 over a 72-hour period weekly. Recurrent tumors included glioblastoma multiforme (GBM) (n = 28) and anaplastic astrocytoma (AA) (n = 10). Newly diagnosed tumors included GBM (n = 14), AA (n = 8), and anaplastic oligodendroglioma (n = 3). RESULTS: Partial responses were observed in 2 of 14 evaluable patients with newly diagnosed GBM, 1 of 8 patients with newly diagnosed AA, 3 of 10 patients with recurrent AA, and none of 28 patients with recurrent GBM. Four patients with recurrent AA and 7 patients with recurrent GBM demonstrated stable disease (range, 8-52 weeks; median, 21 weeks). Toxicity was limited to infrequent National Cancer Institute Common Toxicity Criteria Grade 3 myelosuppression. CONCLUSIONS: These results suggest that topotecan has modest activity against malignant glioma and continued evaluation of its effectiveness may be warranted when alternative schedules or combination regimens are used. PMID- 10091803 TI - Osseous Hodgkin disease. AB - BACKGROUND: Hodgkin disease rarely presents as an osseous lesion, and the majority of patients are found at staging to have concurrent disease in lymph nodes. Many cases of osseous Hodgkin disease have been misdiagnosed on initial biopsy. METHODS: All cases of Hodgkin disease diagnosed by open bone biopsy at the Mayo Clinic were identified. These included patients with primary osseous tumors, those presenting with multiple sites of involvement (with osseous lesions), and those with recurrence in bone. Recut sections were subjected to immunohistochemical stains to confirm the diagnosis. Clinical data and follow-up information were obtained from patients' charts. RESULTS: Twenty-five patients (15 males and 10 females with an average age of 37 years) with osseous Hodgkin disease were identified during the years 1927-1996. Three patients had solitary, osseous tumors and two had primary, multifocal, osseous Hodgkin disease without involvement of nonosseous sites. Twelve patients who presented with lesions in osseous sites also had nonosseous tumors detected at staging, and 8 patients had recurrent Hodgkin disease that presented in bone. The majority of patients with primary and recurrent tumors presented only with bone pain; >50% of patients with concurrent osseous and nonosseous disease also had B-type symptoms. Nearly all lesions were in the axial and proximal appendicular skeleton. Radiographic features included osteosclerotic, osteolytic, and mixed lytic/sclerotic patterns. Cortical destruction, periosteal new bone formation, and soft tissue masses were present in 50% of cases. The histologic diagnosis of osseous Hodgkin disease occasionally was problematic; osteomyelitis was the most frequent misdiagnosis. Immunohistochemical stains revealed expression of CD15 and CD30 in neoplastic cells (which were negative for CD45 and B-cell and T-cell antigens) in all but two cases. Involved lymph nodes typically exhibited nodular sclerosis Hodgkin disease. Three patients with primary solitary osseous Hodgkin disease received radiation treatment only; at last follow-up 2 patients were alive at 22 months and 10 years, respectively. Patients with concurrent osseous and nonosseous tumors exhibited a 60% overall survival rate, but at last follow-up all 4 patients diagnosed after 1986 still were alive; those with Hodgkin disease that recurred as osseous lesions had a 60% survival rate at 8 years, but only 1 of the 5 patients diagnosed since 1984 had died of disease. CONCLUSIONS: Osseous Hodgkin disease typically presents with bone pain, and the majority of patients have concurrent nonosseous lesions detected at staging. Radiographic features of osseous Hodgkin disease vary but indicate an aggressive malignant process. The histologic diagnosis may be problematic; immunohistochemical stains aid in establishing the diagnosis of Hodgkin disease in bone. Survival of patients with osseous Hodgkin disease has been found to be good for the last 10 years. PMID- 10091804 TI - Phase I trial of paclitaxel, carboplatin, and topotecan with or without filgrastim (granulocyte-colony stimulating factor) in the treatment of patients with advanced, refractory cancer. AB - BACKGROUND: Topotecan is a new antineoplastic agent with a broad spectrum of activity. The purpose of this Phase I trial was to define the maximum tolerated dose of topotecan when added to the widely used combination of paclitaxel and carboplatin. METHODS: Patients with advanced cancer that was refractory or resistant to standard treatments were treated with paclitaxel, carboplatin, and topotecan; doses were escalated in sequential cohorts of patients. After definition of the maximum tolerated dose without cytokines, granulocyte-colony stimulating factor (G-CSF) was added and further dose escalation was attempted. RESULTS: The maximum tolerated doses were: paclitaxel, 135 mg/m2, as a 1-hour intravenous (i.v.) infusion on Day 1; carboplatin, area under the curve 5.0, on Day 1; and topotecan, 0.75 mg/m2, i.v. on Days 1, 2, and 3; the regimen was repeated every 21 days. Myelosuppression, particularly thrombocytopenia, was the dose-limiting toxicity with this three-drug combination. Nonhematologic toxicity was uncommon. The addition of G-CSF did not allow substantial dose escalation because thrombocytopenia was uneffected by this agent. Eleven of 25 patients had major responses to this combination, including 8 of 14 patients with previously treated small cell lung carcinoma. CONCLUSIONS: The combination of paclitaxel, carboplatin, and topotecan is feasible, although only relatively low doses of all three drugs can be tolerated due to myelosuppression. This regimen showed a high level of activity in these patients with refractory cancer, and merits further investigation. PMID- 10091805 TI - The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. AB - BACKGROUND: Fatigue is a major disease and treatment burden for cancer patients. Several scales have been created to measure fatigue, but many are long and difficult for very ill patients to complete, or they are not easy to translate for non-English speaking patients. The Brief Fatigue Inventory was developed for the rapid assessment of fatigue severity for use in both clinical screening and clinical trials. METHODS: The study enrolled 305 consecutive, consenting adult inpatients and outpatients with cancer who could understand and complete the self report measures used in the study. The same instruments also were administered to 290 community-dwelling adults to obtain a comparison sample. Research staff completed a form that indicated the primary site and stage of the cancer, rated the Eastern Cooperative Oncology Group performance status of the patient, described the characteristics of the pain, and described the current pain treatment being provided to the patients. RESULTS: The BFI was shown to be an internally stable (reliable) measure that tapped a single dimension, best interpreted as severity of fatigue. It correlated highly with similar fatigue measures. Greater than 98% of patients were able to complete it. A range of scores defining severe fatigue was identified. CONCLUSIONS: The BFI is a reliable instrument that allows for the rapid assessment of fatigue level in cancer patients and identifies those patients with severe fatigue. PMID- 10091806 TI - The concept of Tenju-gann, or "natural-end cancer". PMID- 10091807 TI - Primary staging and follow-up of high risk melanoma patients with whole-body 18F fluorodeoxyglucose positron emission tomography: results of a prospective study of 100 patients. PMID- 10091808 TI - Prediction of axillary lymph node involvement of women with invasive breast carcinoma: a multivariate analysis. PMID- 10091809 TI - Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy. A report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy. PMID- 10091810 TI - Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-Gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. PMID- 10091811 TI - Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-Gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. PMID- 10091812 TI - The greatest dimension of prostate carcinoma is a simple, inexpensive predictor of prostate specific antigen failure in radical prostatectomy specimens. PMID- 10091813 TI - Performance status and comorbidity in elderly cancer patients compared with young patients with neoplasia and elderly patients without neoplastic conditions. PMID- 10091814 TI - 50th anniversary historical article. Congenital heart disease. PMID- 10091815 TI - The effects of pravastatin on hospital admission in hypercholesterolemic middle aged men: West of Scotland Coronary Prevention Study. AB - OBJECTIVES: The purpose of the study was to assess the effect of lipid reduction with pravastatin on hospital admissions in middle-aged men with hypercholesterolemia in the West of Scotland Coronary Prevention Study. BACKGROUND: A prospective, randomized controlled trial was undertaken in primary care centers in the West of Scotland. METHODS: A total of 6,595 participants randomized to receive pravastatin 40 mg or placebo daily were followed up for a mean of 4.9 years (range 3.5 to 6.1 years). Analysis of hospital admissions was undertaken according to the "intention to treat" principle both for cardiovascular diseases and noncardiovascular diseases (including malignant neoplasms, psychiatric diagnoses, trauma and other causes). A secondary analysis of hospitalization in patients who were > or = 75% compliant was performed. RESULTS: During the trial, 2,198 (33%) of the 6,595 men were admitted to hospital on 4,333 occasions, of which 1,234 (28%) were for cardiovascular causes. Pravastatin reduced the number of subjects requiring hospital admission for cardiovascular causes by 21% (95% CI [confidence interval] 9 to 31, p = 0.0008) overall, and by 27% (95% CI 15 to 38) in compliant participants. The number of admissions per 1,000 subject-years for cardiovascular disease was reduced by 10.8 (95% CI 4 to 17.4, p = 0.0013) in all subjects, and by 15.6 (95% CI 8.3 to 23, p < 0.0001) in compliant participants. Pravastatin had no significant influence on hospital admission for any noncardiovascular diagnostic category. There were 13.4 fewer admissions per 1,000 subject-years for all causes in the pravastatin treated group (95% CI -0.4 to 27.3, p = 0.076). No significant difference in duration of hospital stay was found between the pravastatin and placebo patients in any diagnostic group. CONCLUSIONS: Pravastatin therapy reduced the burden of hospital admissions for cardiovascular disease, without any adverse effect on noncardiovascular hospitalization. PMID- 10091816 TI - Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the Studies of Left Ventricular Dysfunction. AB - OBJECTIVES: This analysis was performed to assess whether beta-adrenergic blocking agent use is associated with reduced mortality in the Studies of Left Ventricular Dysfunction (SOLVD) and to determine if this relationship is altered by angiotensin-converting enzyme (ACE) inhibitor use. BACKGROUND: The ability of beta-blockers to alter mortality in patients with asymptomatic left ventricular dysfunction is not well defined. Furthermore, the effect of beta-blocker use, in addition to an ACE inhibitor, on these patients has not been fully addressed. METHODS: This retrospective analysis evaluated the association of baseline beta blocker use with mortality in 4,223 mostly asymptomatic Prevention trial patients, and 2,567 symptomatic Treatment trial patients. RESULTS: The 1,015 (24%) Prevention trial patients and 197 (8%) Treatment trial patients receiving beta-blockers had fewer symptoms, higher ejection fractions and different use of medications than patients not receiving beta-blockers. On univariate analysis, beta-blocker use was associated with significantly lower mortality than nonuse in both trials. Moreover, a synergistic reduction in mortality with use of both a beta-blocker and enalapril was suggested in the Prevention trial. After adjusting for important prognostic variables with Cox multivariate analysis, the association of beta-adrenergic blocking agent use with reduced mortality remained significant for Prevention trial patients receiving enalapril. Lower rates of arrhythmic and pump failure death and risk of death or hospitalization for heart failure were observed. CONCLUSIONS: The combination of a beta-blocker and enalapril was associated with a synergistic reduction in the risk of death in the SOLVD Prevention trial. PMID- 10091817 TI - Tolerability and efficacy of carvedilol in patients with New York Heart Association class IV heart failure. AB - OBJECTIVES: The purpose of this study was to assess the tolerability and efficacy of carvedilol in patients with New York Heart Association (NYHA) functional class IV symptoms. BACKGROUND: Carvedilol, a nonselective beta-adrenergic blocking drug with alpha-adrenergic blocking and antioxidant properties, has been shown to improve left ventricular function and clinical outcome in patients with mild to moderate chronic heart failure. METHODS: We retrospectively analyzed the outcomes of 230 patients with heart failure treated with carvedilol who were stratified according to baseline functional class: 63 patients were NYHA class IV and 167 were NYHA class I, II or III. Carvedilol was commenced at 3.125 mg b.i.d. and titrated to 25 mg b.i.d. as tolerated. Patients with class IV symptoms were older (p = 0.03), had lower left ventricular fractional shortening (p < 0.001), had lower six-min walk distance (p < 0.001) and were receiving more heart failure medications at baseline compared with less symptomatic patients. RESULTS: Nonfatal adverse events while taking carvedilol occurred more frequently in class IV patients (43% vs. 24%, p < 0.0001), and more often resulted in permanent withdrawal of the drug (25% vs. 13%, p < 0.01). Thirty-seven (59%) patients who were NYHA class IV at baseline had improved by one or more functional class at 3 months, 8 (13%) were unchanged and 18 (29%) had deteriorated or died. Among the less symptomatic group, 62 (37%) patients had improved their NYHA status at 3 months, 73 (44%) were unchanged and 32 (19%) had deteriorated or died. The differences in symptomatic outcome at three months between the two groups were statistically significant (p = 0.001, chi-square analysis). Both groups demonstrated similar significant improvements in left ventricular dimensions and systolic function. CONCLUSIONS: Patients with chronic NYHA class IV heart failure are more likely to develop adverse events during initiation and dose titration when compared with less symptomatic patients but are more likely to show symptomatic improvement in the long term. We conclude that carvedilol is a useful adjunctive therapy for patients with NYHA class IV heart failure; however, they require close observation during initiation and titration of the drug. PMID- 10091818 TI - Endothelin B receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction. AB - OBJECTIVES: This study was designed to assess the functional importance of endothelin (ET)B receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ET(A) and ET(B) agonist, with ET-3, a selective ET(B) receptor agonist. BACKGROUND: Knowledge of the functional importance of ET(B) receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ET(A) and ET(B) receptors are required to fully prevent vasoconstriction to endogenously produced ET-1. METHODS: We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. RESULTS: Endothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean +/- SEM 100 +/- 3 to 105 +/- 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 +/- 142 to 2,055 +/- 164 dyn/s/cm(-5), p < 0.001) and a fall in cardiac index (2.44 +/- 0.21 to 2.22 +/- 0.20 liters/min/m , p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 +/- 6 to 105 +/- 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 +/- 210 to 1,918 +/- 245 dyn/s/cm(-5), p < 0.01) and a fall in cardiac index (2.66 +/- 0.28 to 2.42 +/- 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group. CONCLUSIONS: Both ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ET(B) receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD. PMID- 10091819 TI - Endothelin, the bad actor in the play: a marker or mediator of cardiovascular disease. PMID- 10091820 TI - Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure. AB - OBJECTIVES: We studied whether direct assessment of the hemodynamic response to exercise could improve the prognostic evaluation of patients with heart failure (HF) and identify those in whom the main cause of the reduced functional capacity is related to extracardiac factors. BACKGROUND: Peak exercise oxygen consumption (VO2) is one of the main prognostic variables in patients with HF, but it is influenced also by many extracardiac factors. METHODS: Bicycle cardiopulmonary exercise testing with hemodynamic monitoring was performed, in addition to clinical evaluation and radionuclide ventriculography, in 219 consecutive patients with chronic HF (left ventricular ejection fraction, 22 +/- 7%; peak VO2, 14.2 +/- 4.4 ml/kg/min). RESULTS: During a follow-up of 19 +/- 25 months, 32 patients died and 6 underwent urgent transplantation with a 71% cumulative major event-free 2-year survival. Peak exercise stroke work index (SWI) was the most powerful prognostic variable selected by Cox multivariate analysis, followed by serum sodium and left ventricular ejection fraction, for one-year survival, and peak VO2 and serum sodium for two-year survival. Two-year survival was 54% in the patients with peak exercise SWI < or = 30 g x m/m2 versus 91% in those with a SWI >30 g x m/m2 (p < 0.0001). A significant percentage of patients (41%) had a normal cardiac output response to exercise with an excellent two-year survival (87% vs. 58% in the others) despite a relatively low peak VO2 (15.1 +/- 4.7 ml/kg/min). CONCLUSIONS: Direct assessment of exercise hemodynamics in patients with HF provides additive independent prognostic information, compared to traditional noninvasive data. PMID- 10091821 TI - Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction. AB - OBJECTIVES: The purpose of this study was to evaluate the relationship of baseline pulse pressure and mean arterial pressure to mortality in patients with left ventricular dysfunction. BACKGROUND: Increased conduit vessel stiffness increases pulse pressure and pulsatile load, potentially contributing to adverse outcomes in patients with left ventricular dysfunction. METHODS: Pulse and mean arterial pressure were analyzed for their effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 6,781 patients randomized into the Studies of Left Ventricular Dysfunction trials. RESULTS: Pulse and mean arterial pressure were related positively to each other, age, ejection fraction and prevalence of diabetes and hypertension and inversely to prior myocardial infarction and beta adrenergic blocking agent use. Higher pulse pressure was associated with increased prevalence of female gender, greater calcium channel blocking agent, digoxin and diuretic use, lower heart rate and a higher rate of reported smoking history. Higher mean arterial pressure was associated with higher heart rate, lower calcium channel blocker and digoxin use and lower New York Heart Association functional class. Over a 61-month follow-up 1,582 deaths (1,397 cardiovascular) occurred. In a multivariate analysis adjusting for the above covariates and treatment assignment, higher pulse pressure remained an independent predictor of total and cardiovascular mortality (total mortality relative risk, 1.05 per 10 mm Hg increment; 95% confidence interval, 1.01 to 1.10; p = 0.02). Mean arterial pressure was inversely related to total and cardiovascular mortality (total mortality relative risk, 0.89; 95% confidence interval, 0.85 to 0.94; p <0.0001). CONCLUSIONS: One noninvasive blood pressure measurement provides two independent prognostic factors for survival. Increased conduit vessel stiffness, as assessed by pulse pressure, may contribute to increased mortality in patients with left ventricular dysfunction, independent of mean arterial pressure. PMID- 10091822 TI - Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance. AB - OBJECTIVES: The purpose of the study was to investigate if apoptosis occurs in skeletal muscle myocytes and its relation to exercise intolerance in patients with chronic heart failure (CHF). BACKGROUND: Intrinsic abnormalities of skeletal muscle frequently limit exercise tolerance in CHF patients. Recently, apoptosis has been detected in cardiac myocytes of patients with CHF, suggesting that apoptosis may contribute to the reduced contractile force. The presence and regulation of apoptosis in skeletal myocytes of patients with CHF remains to be defined. METHODS: Skeletal muscle biopsies (m. vastus lateralis) of 34 CHF patients (New York Heart Association functional class II-III) and eight age matched healthy control subjects were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling for the presence of apoptosis, and by immunohistochemistry and videodensitometrical quantification for inducible nitric oxide synthase (iNOS) and Bcl-2 expression. Maximal oxygen consumption (VO2max) was determined by ergospirometry. RESULTS: Apoptosis was detected in 16/34 (47%) patients with CHF and in none of the healthy subjects. Patients with apoptosis-positive skeletal muscle myocytes exhibited a significantly lower VO2max (12.0 +/- 3.7 vs. 18.2 +/- 4.4 ml/kg/min; p = 0.0005), a higher iNOS expression (6.8 +/- 3.6 vs. 3.7 +/- 2.6% iNOS-positive stained tissue area; p = 0.015) and a lower Bcl-2 expression (1.0 +/- 0.3 vs. 1.4 +/- 0.4% Bcl-2-positive tissue area; p = 0.03) as compared with patients with apoptosis-negative biopsies. CONCLUSIONS: These results indicate that apoptosis is frequently found in skeletal muscle obtained from CHF patients, which is associated with significant impairment of functional work capacity. In skeletal muscle of these patients, iNOS and Bcl-2 are possibly involved in the regulation of apoptosis. PMID- 10091823 TI - Amiodarone versus propafenone for conversion of chronic atrial fibrillation: results of a randomized, controlled study. AB - OBJECTIVES: The purpose of this study was to investigate the efficacy and safety of amiodarone and propafenone in the conversion of chronic atrial fibrillation in a prospective, randomized, placebo-controlled study. BACKGROUND: The effectiveness of amiodarone and propafenone in the treatment of patients with chronic atrial fibrillation has not been adequately studied. METHODS: One hundred one patients (48 men, mean age 64 +/- 9 years) with atrial fibrillation lasting >3 weeks participated in the study. Thirty-four patients received amiodarone (300 mg intravenously over 1 h, followed by 20 mg/kg over the next 24 h plus 600 mg orally, in three doses, for 1 week, then 400 mg/day orally, for three weeks), 32 received propafenone (2 mg/kg intravenously over 15 min, followed by 10 mg/kg over 24 h and then 450 mg/day orally, for one month) and the remaining 35 served as control subjects. All patients received digoxin and anticoagulant treatment as indicated (International Normalized Ratio 2 to 3). RESULTS: Conversion to sinus rhythm was achieved in 16 (47.05%) patients who received amiodarone, in 13 (40.62%) who received propafenone and in none of the control subjects (p < 0.001 for both groups vs. control subjects). Those who converted had smaller atria than those who did not and atrial fibrillation of shorter duration in both the amiodarone and propafenone groups. Treatment was discontinued in one patient of the propafenone group because of significant QRS widening. CONCLUSIONS: Amiodarone and propafenone appear to be safe and equally effective in the termination of chronic atrial fibrillation. Left atrial diameter and arrhythmia duration are independent predictors of conversion. PMID- 10091824 TI - The creation of linear contiguous lesions in the atria with an expandable loop catheter. AB - OBJECTIVES: This article describes a catheter system designed to create linear atrial lesions and identifies electrophysiologic markers that are associated with the creation of linear lesions. BACKGROUND: Atrial fibrillation (Afib) is the most common arrhythmia in humans and causes a significant morbidity. The success of surgical interventions has provided the impetus for the development of a catheter-based approach for the ablation of Afib. METHODS: We tested a catheter system with 24 4-mm ring electrodes that can create loops in the atria. The electrodes can be used to record electrical activity and deliver radiofrequency power for ablation. In 33 dogs, 82 linear lesions were generated using three power titration protocols: fixed levels, manual titration guided by local electrogram activity and temperature control. Bipolar activity was recorded from the 24 electrodes before, during and after lesion generation. Data were gathered regarding lesion contiguity, transmurality and dimensions; the changes in local electrical activity amplitude; the incidence rate of rapid impedance rises and desiccation or char formation; and rhythm outcomes. RESULTS: Catheter deployment usually requires <60 s. Linear lesions (12 to 16 cm in length and 6 +/- 2 mm wide) can be generated in 24 to 48 min without moving the catheter. Effective lesion formation can be predicted by a decrease of greater than 50% in the amplitude of bipolar recordings. Splitting or fragmentation of the electrogram and increasing pacing threshold (3.1 +/- 3.3 mV to 7.1 +/- 3.8 mV, p < 0.01) are indicative of effective lesion formation. Impedance rises and char formation occurred at 91 +/- 12 degrees C. Linear lesion creation does not result in the initiation of Afib. However, atrial flutter was recorded after the completion of the final lesion in 3/12 hearts. When using temperature control, no char was noted in the left atrium, whereas 8% of the right atrium burns had char. CONCLUSIONS: This adjustable loop catheter forces the atrial tissue to conform around the catheter and is capable of producing linear, contiguous lesions up to 16 cm long with minimal effort and radiation exposure. Pacing thresholds and electrogram amplitude and character are markers of effective lesion formation. Although Afib could not be induced after lesion set completion, sustained atrial flutter could be induced in 25% of the hearts. PMID- 10091825 TI - Utility of a single-stage isoproterenol tilt table test in adults: a randomized comparison with passive head-up tilt. AB - OBJECTIVES: This study was conducted to develop a time-efficient tilt table test. BACKGROUND: Current protocols of tilt table testing are quite time-consuming. This study was designed to assess the diagnostic value, tolerance and procedural time of a single-stage isoproterenol tilt table protocol. METHODS: A single-stage isoproterenol tilt table test was compared with the passive tilt table test. The study was prospectively designed in a randomized and crossover fashion. RESULTS: The study population consisted of 111 patients with a history of syncope (mean age 55 +/- 20 years). Of the total, 62 patients (56%; 95% confidence interval, 46% to 65%) had a positive vasovagal response during isoproterenol tilt table testing and 35 (32%; 23% to 41%) during passive tilt table testing (p = 0.002). The mean procedural times of the study population were 11.7 +/- 3.6 min and 36.9 +/- 13.3 min for isoproterenol and passive tilt table testing, respectively (p < 0.001). All patients tolerated single-stage isoproterenol testing. In the 23 control subjects (mean age 34 +/- 11 years), the apparent specificities were 91% (72% to 99%) and 83% (61% to 99%) for passive and single-stage tilt table testing, respectively. CONCLUSIONS: The single-stage isoproterenol tilt table test was more effective in inducing a positive vasovagal response in an adult population than the standard passive tilt table test, and it significantly reduced the procedural time. The increase in positive yield was associated with a moderate decrease in apparent specificity. These observations support the conclusion that single-stage tilt table testing could be a reasonable diagnostic option in patients undergoing syncope evaluation. PMID- 10091826 TI - Assessment of regional and global left ventricular function by reinjection T1-201 and rest Tc-99m sestamibi ECG-gated SPECT: comparison with three-dimensional magnetic resonance imaging. AB - OBJECTIVES: The purpose of this study was to test the ability of reinjection thallium-201 and rest technetium-99m sestamibi ECG (electrocardiographic)-gated SPECT (i.e., reinjection-g-SPECT [single-photon emission computed tomography] and MIBI-g-SPECT) to determine regional and global functional parameters. BACKGROUND: The ECG-gated perfusion SPECT was reported to provide accurate left ventricular ejection fraction (LVEF) using an automated algorithm. We hypothesized that other various functional data may be obtained using reinjection-g-SPECT and MIBI-g SPECT. METHODS: Reinjection-g-SPECT, MIBI-g-SPECT, and three-dimensional magnetic resonance imaging (3DMRI) were conducted in 20 patients with coronary artery disease. Regional wall motion (RWM) and wall thickening (RWT) were analyzed using semiquantitative visual scoring by each g-SPECT and 3DMRI. The left ventricular end-systolic and end-diastolic volumes (EDV, ESV) and LVEF estimated by reinjection- and MIBI-g-SPECT were compared with the results of 3DMRI. RESULTS: A high degree of agreement in RWM and RWT assessment was observed between each g SPECT and 3DMRI (kappa >.70, p < .001). The LVEF values by reinjection- and MIBI g-SPECT correlated and agreed well with those by 3DMRI (reinjection: r = .92, SEE = 5.9%, SD of differences = 5.7%; sestamibi: r = .94, SEE = 4.4%, SD of differences = 5.1%). The same also pertained to EDV (reinjection: r = .85, SEE = 18.7 ml, SD of differences = 18.4 ml; sestamibi: r = .92, SEE = 13.1 ml, SD of differences = 13.0 ml) and ESV (reinjection: r = .94, SEE = 10.3 ml, SD of differences = 10.3 ml; sestamibi: r = .97, SEE = 6.7 ml [p < .05 vs. reinjection by F test], SD of differences = 6.6 ml [p < .05 vs. reinjection by F test]). CONCLUSIONS: Reinjection- and MIBI-g-SPECT provide clinically satisfactory various functional data. These functional data in combination with the perfusion information will improve diagnostic and prognostic accuracy without an increase in cost or the radiation dose to the patients. PMID- 10091827 TI - Influence of a platelet GPIIb/IIIa receptor antagonist on myocardial hypoperfusion during rotational atherectomy as assessed by myocardial Tc-99m sestamibi scintigraphy. AB - OBJECTIVES: This study evaluated the effect of the glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist abciximab on myocardial hypoperfusion during percutaneous transluminal rotational atherectomy (PTRA). BACKGROUND: PTRA may cause transient ischemia and periprocedural myocardial injury. A platelet-dependent risk of non-Q wave infarctions after directional atherectomy has been described. The role of platelets for the incidence and severity of myocardial hypoperfusion during PTRA is unknown. METHODS: Seventy-five consecutive patients with complex lesions were studied using resting Tc-99m sestamibi single-photon emission computed tomography prior to PTRA, during, and 2 days after the procedure. The last 30 patients received periprocedural abciximab (group A) and their results were compared to the remaining 45 patients (group B). For semiquantitative analysis, myocardial perfusion in 24 left ventricular regions was expressed as percentage of maximal sestamibi uptake. RESULTS: Baseline characteristics did not differ between the groups. Transient perfusion defects were observed in 39/45 (87%) patients of group B, but only in 10/30 (33%) patients of group A (p < 0.001). Perfusion was significantly reduced during PTRA in 3.3 +/- 2.5 regions in group B compared to 1.4 +/- 2.5 regions in group A (p < 0.01). Perfusion in the region with maximal reduction during PTRA in groups B and A was 76 +/- 15% and 76 +/- 15% at baseline, decreased to 56 +/- 16% (p < 0.001) and 67 +/- 14%, respectively, during PTRA (p < 0.01 A vs. B), and returned to 76 +/- 15% and 80 +/- 13%, respectively, after PTRA. Nine patients in group B (20%) and two patients in group A (7%) had mild creatine kinase and/or troponin t elevations (p = 0.18). Patients with elevated enzymes had larger perfusion defects than did patients without myocardial injury (4.2 +/- 2.7 vs. 2.3 +/- 2.5 regions, p < 0.05). CONCLUSIONS: These data indicate that GPIIb/IIIa blockade reduces incidence, extent and severity of transient hypoperfusion during PTRA. Thus, platelet aggregation may play an important role for PTRA-induced hypoperfusion. PMID- 10091828 TI - Lipoprotein(a) and coronary thrombosis and restenosis after stent placement. AB - OBJECTIVES: The objective of this prospective study was to evaluate the relation between high lipoprotein(a) levels and thrombotic and restenotic events after coronary stent implantation. BACKGROUND: Lipoprotein(a) may promote atherogenesis, coronary thrombosis and restenosis after balloon angioplasty, but the clinical significance remains unclear. METHODS: The study included 2,223 consecutive patients with successful coronary stent placement. According to the serum level of lipoprotein(a), patients were divided in two groups: 457 patients of the highest quintile formed the high lipoprotein(a) group, and 1,766 patients of the lower four quintiles formed the low lipoprotein(a) group. Primary end points were the incidence of angiographic restenosis at six months and the event free survival at one year. Secondary end point was the incidence of angiographic stent occlusion. RESULTS: Early stent occlusion occurred in four of the 457 patients (0.9%) with high and 37 of the 1,766 patients (2.1%) with low lipoprotein(a) levels, odds ratio of 0.41 (95% confidence interval, 0.15 to 1.16). Angiographic restenosis occurred in 173 of the 523 lesions (33.2%) in the high lipoprotein(a) group and 636 of the 1,943 lesions (32.7%) in the low lipoprotein(a) group, odds ratio of 1.02 (0.83 to 1.25). The probability of event free survival was 73.0% in the high lipoprotein(a) group and 74.8% in the low lipoprotein(a) group (p = 0.45). On the basis of the findings in the low lipoprotein(a) group, the power of this study to detect a 25% increase in the incidence of restenosis and adverse events in the group with elevated lipoprotein(a) was 90% and 75%, respectively. CONCLUSIONS: Elevated lipoprotein(a) levels did not influence the one-year clinical and angiographic outcome after stent placement. Thrombotic events and measures of restenosis were not adversely affected by the presence of high lipoprotein(a) levels. PMID- 10091829 TI - Association of lipoprotein lipase gene polymorphisms with coronary artery disease. AB - OBJECTIVES: The purpose of this study was to test whether the HindIII (+) and PvuII (-) or (+) restriction enzyme-defined alleles are associated with angiographic coronary artery disease (CAD). BACKGROUND: Lipoprotein lipase (LPL) plays a central role in lipid metabolism, hydrolyzing triglyceride in chylomicrons and very low density lipoproteins. Polymorphic variants of the LPL gene are common and might affect risk of CAD. METHODS: Blood was drawn from 725 patients undergoing coronary angiography. Leukocyte deoxyribonucleic acid segments containing the genomic sites were amplified by the polymerase chain reaction and digested, and polymorphisms were identified after electrophoresis in 1.5% agarose gel. RESULTS: In no-CAD control subjects (n = 168), HindIII (-) and (+) allelic frequencies were 28.6% and 71.4%, and (-) and (+) alleles were carried by 44.0% and 86.9% of subjects, respectively. Control PvuII (-) and (+) allelic frequencies were 41.7% and 58.3%, and (-) and (+) alleles were carried by 64.3% and 81.0%, respectively. In CAD patients (>60% stenosis; n = 483), HindIII (+) allelic carriage was increased (93.8% of patients, odds ratio [OR] = 2.28, confidence interval [CI] 1.27 to 4.00). Also, PvuII (-) allelic carriage tended to be more frequent in CAD patients (OR = 1.33, CI 0.92 to 1.93). Adjusted for six CAD risk factors and the other polymorphism, HindIII (+) carriage was associated with an OR = 2.86, CI 1.50 to 5.42, p = 0.0014, and PvulI (-) carriage, OR = 1.42, CI 0.95 to 2.12, p = 0.09. The two polymorphisms were in strong linkage disequilibrium, and a haplotype association was suggested. CONCLUSIONS: The common LPL polymorphic allele, HindIII (+), is moderately associated with CAD, and the PvuII (-) allele is modestly associated (trend). Genetic variants of LPL deserve further evaluation as risk factors for CAD. PMID- 10091830 TI - Perioperative morbidity and mortality after transmyocardial laser revascularization: incidence and risk factors for adverse events. AB - OBJECTIVES: The purpose of this study was to describe the incidence and spectrum of perioperative cardiac and noncardiac morbidity and mortality after transmyocardial laser revascularization (TMR) and to identify predictors of these adverse clinical events. BACKGROUND: Clinical studies have demonstrated the efficacy of TMR for relieving angina pectoris, although no study to date has specifically addressed the associated perioperative morbidity and mortality. METHODS: Between October 1995 and August 1997, 34 consecutive patients with end stage coronary artery disease (CAD) underwent isolated TMR. The majority of patients (94%) had class III or IV angina pectoris, and two patients (6%) had unstable symptoms preoperatively. Patient records were reviewed for fatal and nonfatal adverse cardiac and noncardiac events. RESULTS: Perioperative death occurred in two patients (5.9%) due to cardiogenic shock complicating acute myocardial infarction. Perioperative cardiac morbidity occurred in 16 patients (47.1%); noncardiac morbidity was seen in 12 patients (35.3%). Preoperative unstable angina was the only variable predictive of perioperative death (p = 0.005). Cardiac (p = 0.005) and noncardiac (p < 0.001) morbidity rates were significantly higher for the initial 15 patients undergoing the procedure. Other predictors of perioperative complications included lack of postoperative treatment with a furosemide infusion (p < or = 0.04) and preoperative unstable angina (p = 0.05). CONCLUSIONS: Perioperative mortality in patients undergoing isolated TMR is low. Transmyocardial laser revascularization patients are at higher risk for adverse perioperative cardiac and noncardiac events, likely reflecting the lack of immediate benefit from the procedure in the setting of severe CAD. These patients merit vigilant surveillance for adverse events and aggressive medical management in the perioperative period. PMID- 10091831 TI - Is the development of myocardial tolerance to repeated ischemia in humans due to preconditioning or to collateral recruitment? AB - OBJECTIVES: The purpose of this study in patients with quantitatively determined, poorly developed coronary collaterals was to assess the contribution of ischemic as well as adenosine-induced preconditioning and of collateral recruitment to the development of tolerance against repetitive myocardial ischemia. BACKGROUND: The development of myocardial tolerance to repeated ischemia is nowadays interpreted to be due to biochemical adaptation (i.e., ischemic preconditioning). METHODS: In 30 patients undergoing percutaneous transluminal coronary angioplasty, myocardial adaptation to ischemia was measured using intracoronary (i.c.) electrocardiographic (ECG) ST segment elevation changes obtained from a 0.014-in. (0.036 cm) pressure guidewire positioned distal to the stenosis during three subsequent 2-min balloon occlusions. Simultaneously, an i.c. pressure-derived collateral flow index (CFI, no unit) was determined as the ratio between distal occlusive minus central venous pressure divided by the mean aortic minus central venous pressure. The study patients were divided into two groups according to the pretreatment with i.c. adenosine (2.4 mg/min for 10 min starting 20 min before the first occlusion, n = 15) or with normal saline (control group, n = 15). RESULTS: Collateral flow index at the first occlusion was not different between the groups (0.15 +/- 0.10 in the adenosine group and 0.13 +/- 0.11 in the control group, p = NS), and it increased significantly and similarly to 0.20 +/- 0.14 and to 0.19 +/- 0.10, respectively (p < 0.01) during the third occlusion. The i.c. ECG ST elevation (normalized for the QRS amplitude) was not different between the two groups at the first occlusion (0.25 +/- 0.13 in the adenosine group, 0.25 +/- 0.19 in the control group). It decreased significantly during subsequent coronary occlusions to 0.20 +/- 0.15 and to 0.17 +/- 0.13, respectively. There was a correlation between the change in CFI (first to third occlusion; deltaCFI) and the respective ST elevation shift (deltaST): deltaST = -0.02 to 0.78 x deltaCFI; r = 0.54, p = 0.02. CONCLUSIONS: Even in patients with few coronary collaterals, the myocardial adaptation to repetitive ischemia is closely related to collateral recruitment. Pharmacologic preconditioning using a treatment with i.c. adenosine before angioplasty does not occur. The variable responses of ECG signs of ischemic adaptation to collateral channel opening suggest that ischemic preconditioning is a relevant factor in the development of ischemic tolerance. PMID- 10091832 TI - Percutaneous transluminal coronary angioplasty as a model of ischemic preconditioning and preconditioning-mimetic drugs. PMID- 10091833 TI - Feasibility of direct discharge from the coronary/intermediate care unit after acute myocardial infarction. AB - OBJECTIVES: This investigation was designed to determine the feasibility and cost effectiveness of direct discharge from the coronary/intermediate care unit (CICU) in 497 consecutive patients with an acute myocardial infarction (AMI). BACKGROUND: Although patients with an AMI are traditionally treated in the CICU followed by a period on the medical ward, the latter phase can likely be incorporated within the CICU. METHODS: All patients were considered for direct discharge from the CICU with appropriate patient education. The 6-week postdischarge course was evaluated using a structured questionnaire by a telephone interview. RESULTS: There were 497 patients (men = 353; women = 144; age 63.5 +/- 0.6 years) in the study, with 29 in-hospital deaths and a further 11 deaths occurring within 6 weeks of discharge. The mode length of CICU stay was 4.0 days (mean 5.1 +/- 0.2 days): 1 to 2 (12%), 3 (19%), 4 (21%), 5 (14%), 6 to 7 (19%) and > or = 7 (15%) days, respectively with 87.2% discharged home directly. Of the 425 patients surveyed, 119 (28.0%) indicated that they had made unscheduled return visits (URV) to a hospital or physician's office: 10.6% to an emergency room, 9.4% to a physician's office and 8.0% readmitted to a hospital. Of these URV, only 14.3% occurred within 48 h of discharge. Compared to historical controls, the present management strategy resulted in a cost savings of Cdn. $4,044.01 per patient. CONCLUSIONS: Direct discharge from CICU is a feasible and safe strategy for the majority of patients that results in considerable savings. PMID- 10091834 TI - Early discharge after acute myocardial infarction: who and when? PMID- 10091835 TI - Impaired endothelial function following a meal rich in used cooking fat. AB - OBJECTIVES: The purpose of this study was to test the hypothesis that intake of used cooking fat is associated with impaired endothelial function. BACKGROUND: Diets containing high levels of lipid oxidation products may accelerate atherogenesis, but the effect on endothelial function is unknown. METHODS: Flow mediated endothelium-dependent dilation and glyceryl trinitrate-induced endothelium-independent dilation of the brachial artery were investigated in 10 men. Subjects had arterial studies before and 4 h after three test meals: 1) a meal (fat 64.4 g) rich in cooking fat that had been used for deep frying in a fast food restaurant; 2) the same meal (fat 64.4 g) rich in unused cooking fat, and 3) a corresponding low fat meal (fat 18.4 g) without added fat. RESULTS: Endothelium-dependent dilation decreased between fasting and postprandial studies after the used fat meal (5.9 +/- 2.3% vs. 0.8 +/- 2.2%, p = 0.0003), but there was no significant change after the unused fat meal (5.3 +/- 2.1% vs. 6.0 +/- 2.5%) or low fat meal (5.3 +/- 2.3% vs. 5.4 +/- 3.3%). There was no significant difference in endothelium-independent dilation after any of the meals. Plasma free fatty acid concentration did not change significantly during any of the meals. The level of postprandial hypertriglyceridemia was not associated with change in endothelial function. CONCLUSIONS: Ingestion of a meal rich in fat previously used for deep frying in a commercial fast food restaurant resulted in impaired arterial endothelial function. These findings suggest that intake of degradation products of heated fat contribute to endothelial dysfunction. PMID- 10091836 TI - Enhanced exercise-induced hyperkalemia in patients with syndrome X. AB - OBJECTIVES: The purpose of this study was to determine whether patients with syndrome X have altered potassium metabolism. BACKGROUND: Patients with syndrome X have angina pectoris and exercise induced ST segment depression on the electrocardiogram despite normal coronary angiograms. Increasing evidence suggests that myocardial ischemia is uncommon in these patients. Altered potassium metabolism causing interstitial potassium accumulation in the myocardium may be an alternative mechanism for chest pain and ST segment depression in syndrome X. METHODS: We compared the magnitude of exercise-induced hyperkalemia in 16 patients with syndrome X (12 female and four male, mean +/- SD age 53 +/- 6 years) and 15 matched healthy control subjects. The participants underwent a bicycle test at a fixed load of 75 W for 10 min, and blood samples were taken for analysis of potassium, catecholamines and lactate before, during and in the recovery period after exercise. In five patients with syndrome X, the test was repeated during alpha1 adrenoceptor blockade. RESULTS: Baseline concentrations of serum potassium, plasma catecholamines and plasma lactate were similar in patients and control subjects. The rate of exercise-induced increment of serum potassium was increased in the patients (70 +/- 29 vs. 30 +/- 21 micromol/liter/min in control subjects, p < 0.001). Six patients, who stopped before 10 min of exercise, showed very rapid increments in serum potassium concentration. Compared to the control subjects, patients also demonstrated larger increments in rate-pressure product, plasma norepinephrine and lactate concentrations during exercise. The rate of serum potassium increment correlated with the rate of plasma norepinephrine increment in the patients (r = 0.63, p < 0.02), but not in the control subjects (r = 0.01, p = 0.97). Blockade of alpha1 adrenoceptors decreased systolic blood pressure at baseline, but did not influence the increment of serum potassium, plasma catecholamines and lactate. CONCLUSIONS: Patients with syndrome X have enhanced exercise induced hyperkalemia in parallel with augmented increases of circulating norepinephrine and lactate. The prevailing mechanisms behind the abnormal potassium handling comprise sources distinct from alpha1-adrenoceptor activation. PMID- 10091837 TI - Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite. AB - OBJECTIVES: This study examined the effects of endotoxin on cardiac contractility in human myocardium. BACKGROUND: In animal myocardium, endotoxin and cytokine treatment led to enhanced inducible nitric oxide synthase (iNOS) expression and contractile dysfunction. Effects in human myocardium are unknown. METHODS: Left ventricular myocardial preparations from failing (n = 18) and nonfailing (n = 5) human hearts were incubated for 6 and 12 h in tyrode solution or in tyrode plus lipopolysaccharides (LPS), with LPS plus N(G)-mono-methyl-L-arginine (L-NMMA), with LPS plus hemoglobin or with LPS plus the superoxide scavenger 4,5-dihydroxy 1,3-benzene disulfonic acid (Tiron). Force of contraction in response to isoprenaline (0.001 to 3 micromol/liter) was determined in electrically stimulated muscle preparations. The iNOS mRNA expression was examined by in situ hybridization and by polymerase chain reaction. The cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay. RESULTS: Isoprenaline concentration dependently increased force of contraction. Six and 12 hours of LPS treatment of failing myocardium decreased maximum inotropic response to isoprenaline by 54% (p = 0.009) and by 69% (p = 0.0023), respectively. In nonfailing myocardium, 12 h of LPS treatment decreased maximum inotropic effect of isoprenaline by 66% (p < 0.001). The LPS effects were attenuated by L-NMMA, hemoglobin and also Tiron. The iNOS mRNA was expressed in all LPS-treated preparations but also in most control myocardial preparations. In situ hybridization revealed iNOS expression within cardiac myocytes. There was no increase in myocardial cGMP content in response to endotoxin. CONCLUSIONS: Endotoxin exposure of human myocardium leads to a depression of cardiac contractility, which is mediated by enhanced iNOS activity and release of nitric oxide (NO). Consecutive reaction of NO with superoxide and formation of peroxynitrite may contribute to the decrease in force of contraction. PMID- 10091838 TI - Perspectives on the role of new treatment strategies in hypertrophic obstructive cardiomyopathy. PMID- 10091839 TI - ACC expert consensus document on ethical coding and billing practices for cardiovascular medicine specialists. American College of Cardiology. PMID- 10091840 TI - Effect of a primary-care-based epilepsy specialist nurse service on quality of care from the patients' perspective: quasi-experimental evaluation. AB - Initiatives to improve epilepsy care have emphasized the role of specialist nurses. Formal evaluation of these initiatives are scarce. Further evaluative studies are required to ascertain the optimal means of providing epilepsy care. This study aimed to assess the effect of a primary-care-based epilepsy specialist nurse service on patients' reported health status, perceived quality of life, health care use, attitudes to health care, and provision of information. A quasi experimental follow-up questionnaire survey was sent to all 574 patients aged 16 years or over and receiving antiepileptic drugs for epilepsy, registered in 14 general practices in north-west Bristol. Patients in seven practices who received the new service (intervention patients) were compared with patients in seven practices who did not (control patients). Follow-up comparisons between intervention and control patients were adjusted for baseline differences. Response rates to the first, second and both surveys were 66.2%, 68.6% and 50.9%, respectively. Intervention patients were more likely than control patients to have discussed most epilepsy topics with general practitioners and/or hospital doctors. and were significantly more likely to have categorized general practitioner care as excellent (odds ratio (OR) 2.30, 95% confidence intervals (CI) 1.12-4.70). Intervention patients were significantly less likely than controls to have reported never missing taking their anti-epileptic drugs (OR 0.48, 95% CI0.24-0.94). There were no significant changes in measures of health status, use of other health care services, and perceived quality of life between intervention and control patients. This study provides evidence of an improvement, after 1 year, in communication and satisfaction but not health status resulting from the introduction of a primary-care-based epilepsy service. PMID- 10091841 TI - Adjunctive therapy in epilepsy: a cost-effectiveness comparison of two AEDs. AB - The objective of this study was to compare the relative cost-effectiveness of two AEDs by a prospective clinical audit. Patients starting on the adjunctive therapies lamotrigine and topiramate were recruited from the out-patient epilepsy clinics at Queen Square. Three interview were scheduled: baseline; three months follow-up and six months from baseline. Of the 81 patients recruited, a total of 73 patients completed all three interviews. An intention to treat analysis was performed on the data. Seizure severity and frequency were assessed using the National Hospital Seizure Severity Scale. Side-effects, adverse events and reasons for stopping medication were also recorded. At the third interview, a total of 47/73 (64%) were still on the prescribed adjunctive drug. Outcome was assessed by two methods: the > 50% seizure reduction cited in the literature and a more stringent assessment of patient 'satisfaction' which we defined operationally on clinical criteria. Using this definition, a total of 10/73 (14%) patients were 'satisfied'. The relative costs of starting patients on each of the two AEDs were calculated, both drug costs and the costs of adverse events (the latter were defined as events requiring urgent medical attention). The costs of the two drugs were compared. A number of methodological issues relating to cost comparison are discussed. Outcome and pharmaco-economic studies need to assess more than reduction in number of seizures. They should take into account variables important for quality of life including side-effects and adverse events. PMID- 10091842 TI - Willingness to pay: a feasible method for assessing treatment benefits in epilepsy? AB - Contingent valuation using willingness to pay (WTP) is one of the methods available for assessing the value of a new technology or treatment for a disease in monetary terms. Experience with this method is lacking in epilepsy. The objectives of this study were to assess the acceptability of the WTP method in epilepsy, the level of the responses, and to investigate its validity by comparison with other non-monetary preference measures. Among 397 patients with epilepsy responding to a comprehensive questionnaire, 82 were randomly selected for an interview. They were asked about their WTP for an imaginary new technology which could permanently cure their epilepsy. Fifty-nine patients participated and 57 completed the interview (32 women; mean age 44 years), the majority with well controlled epilepsy. The patients indicated a median WTP of Norwegian Kroner (NOK) 150,000 (USD 20,000; GBP 11,800), interquartile range NOK 50,000-350,000 (USD 6, 667-46, 667; GBP 3,937-27,559) for this cure. Non-response was low, indicating high acceptability of this method. There was little association between WTP and other preference measures; the Spearman rank correlation coefficient was -0.09 and -0.12 with time trade-off and standard gamble respectively, questioning the validity of this method. PMID- 10091843 TI - Patient readmission and support utilization following anterior temporal lobectomy. AB - The aim of this study was to examine factors precipitating patient readmission, following anterior temporal lobectomy (ATL) for refractory epilepsy. A second aim was to explore the use of hospital outpatient and community support services ('outpatient services') by this patient population. These aims served the more general goal of identifying patients most likely in need of services additional to those routinely provided by our Seizure Surgery Follow-up and Rehabilitation Programme. The medical records of 100 consecutive ATL patients were retrospectively examined for the incidence and diagnoses precipitating acute readmission, and the utilization of additional outpatient services. Twenty-one patients (21%) required readmission post-ATL, totalling 47 readmissions between them. Psychiatric diagnoses were the most prevalent (53%), including anxiety, depression and/or post-ictal psychosis. Epileptological diagnoses were the other main precipitant (28%). Additional outpatient services were predominantly utilized for ongoing psychological support. Of the 21 patients requiring readmission, 10(10%) also needed additional outpatient services. These patients were predominantly female or unemployed, in contrast to male or employed patients who tended to require readmission only. Seventeen patients (17%) were maintained within the community using additional outpatient services only. Characteristics of these patients included disrupted family dynamics, limited social networks, and/or a psychiatric history. These patients were also more frequently beyond the 24-month follow-up period of the programme. A profile of patients most in need of additional support services can be constructed to assist team planning of proactive management strategies for the rehabilitation phase of ATL. PMID- 10091844 TI - Outcome of pregnancies in epileptic women: a study in Saudi Arabia. AB - We studied the outcome of 79 pregnancies in 44 Saudi women who had epilepsy. Their mean age was 28+/-6.5 years and the number of pregnancies studied varied from one to six. Nineteen subjects had generalized seizures, 16 had partial seizures and nine were unclassified. The commonest drug prescribed was carbamazepine and the majority of the women (61%) were on monotherapy. The seizures were controlled in 53 pregnancies (67%). Spontaneous vertex deliveries were the commonest. The indications for intervention by lower segment Caesarean section, forceps or ventouse were foetal distress, pre-eclamptic toxaemia (PET), eclampsia, breech presentation and prolonged labour. The most frequent adverse outcome in the babies was low birth weight (<2.5 kg) in nine pregnancies. The frequency of congenital malformation was 2.5%. Low birth weight was associated with prematurity, PET, congenital malformation and polytherapy. Avoidance of polytherapy appears to be the most feasible intervention in reducing the frequency of low birth-weight children by epileptic mothers. PMID- 10091845 TI - Information exchange in an epilepsy forum on the World Wide Web. AB - The Partners Healthcare Epilepsy Service hosts an epilepsy 'Webforum'. In this paper, we describe our observations regarding who uses it, what kind of information is exchanged, how much misinformation is present and how we can better serve our patients. We examined a sample of 155 posts to the forum and 342 responses to those posts. The individual making the post and the type of questions were categorized. We also determined whether any information was objectively inaccurate. The principal users were care-givers (49%) and patients (34%). Eighty percent of the primary posts were questions. Answers were given largely by patients (38%) and care-givers (34%). The most commonly asked questions were about treatment options (31%) and the natural history of the illness (28%). In 20% of the questions, the user incidentally remarked that a health-care provider had not met their information needs. Six percent of the information was objectively inaccurate. The Web can serve as an effective means for the exchange of information between individuals with a common medical condition. We found that a small amount of misinformation is exchanged and that health-care providers are sometimes perceived as unable or unwilling to supply important health-related information. PMID- 10091846 TI - Readability of patient information leaflets on antiepileptic drugs in the UK. AB - The Audit Commission in the UK recommends that patient information leaflets (PILs) should be audited by health professionals using a formal readability test. However, no such study on antiepileptic drugs (AEDs) has been identified in a Medline search. The aim of this study was to audit the readability of PILs prepared for marketed proprietary AEDs in the UK. Twelve PILs were compared with six antiepileptic drug articles from medical journals and six headline articles from UK newspapers. The Gunning Fog index and the Flesch Reading Ease index were calculated for each PIL and article. The results of the Gunning Fog index and the Flesch Reading Ease score were compared using the Kruskal-Wallis non-parametric test. PILs were shown to have a statistically significant lower mean reading age than the medical articles and newspapers (P < 0.001). The Gunning Fog index and Flesch Reading Ease score showed that PILs had a mean reading age of 8.8 and mean readability score of 69, respectively. In conclusion, the PILs prepared for proprietary antiepileptic drugs in the UK are suitable for the reading age of the general adult population. PMID- 10091847 TI - Topiramate for intractable childhood epilepsy. AB - To better define the efficacy and tolerability of the new anticonvulsant topiramate in pediatric patients, the clinical courses of 49 children with intractable seizures were monitored during topiramate therapy. The 80% of children who had complex partial seizures experienced better seizure control with topiramate than the 20% who had generalized seizures. Efficacy was greatest with doses between 2.5 and 7.5 mg/kg/day. More than half the children on topiramate experienced adverse effects which could interfere with learning at school, but 20% demonstrated increased alertness or improved behavior. Topiramate is effective and may be considered as part of the treatment pathway for complex partial seizures in children, although careful monitoring of cognitive function is required. PMID- 10091848 TI - Clinical and EEG findings in complex partial status epilepticus with tiagabine. AB - A case of complex partial status epilepticus (CPSE) with high dose treatment of tiagabine (TGB) is reported. Seizure aggravation and CPSE developed after stepwise increase of TGB to a dose of 60 mg per day as add-on treatment to carbamazepine (CBZ) 1200 mg/day and vigabatrine (VGB) 1000 mg/day. The EEG during CPSE showed bilateral rhythmic slow activity. Clinical symptoms of CPSE and the EEG normalized after i.v. treatment with clonazepam. The literature and the possible mechanism of this paradoxical phenomenon are discussed. PMID- 10091849 TI - Possibilities of non-pharmacological conservative treatment of epilepsy. AB - This study set out to assess the effect of non-pharmacological conservative (NPC) interventions as alternatives to antiepileptic pharmacotherapy. A prospective follow-up cohort study was conducted in an outpatient seizure clinic of a referral center for epilepsy. Twenty-five patients (nine males, 16 females) aged 16-45, with at least two well-described epileptic seizures, were included who had rejected antiepileptic pharmacotherapy. Twelve had idiopathic generalized epilepsy, 11 had symptomatic or cryptogenic localization-related epilepsy, and two had epilepsy with generalized and focal signs. Twenty-three of the patients were followed for more than 2 years. The patients were treated with arrest after focal seizure onset (2 cases), sensory protection against reflex seizures (3 cases), avoidance of non-specific seizure-precipitating factors ('life hygiene', 16 cases), and/or miscellaneous interventions (8 cases). The main outcome measures were complete seizure control (more than 2 years) or sufficient improvement to continue with NPC treatment alone. Eight of the 23 patients were completely seizure free for more than 4 years, and three were sufficiently improved to continue NPC treatment without drugs. Trends were observed for patients with idiopathic generalized epilepsies with less than seven convulsive seizures, and with only one seizure type to respond better to NPC treatment. The duration of epilepsy, and the finding of generalized epileptiform discharge in the EEG had no influence on the outcome. Rational NPC treatments which are aimed at specific factors in the precipitation and development of epileptic seizures can be useful therapeutic alternatives for patients with milder forms of epilepsy. Apart from photosensitive patients, those most likely to profit are patients with idiopathic generalized epilepsy, a maximum of six generalized tonic clonic seizures which were precipitated by lack of sleep or excessive alcohol intake, and with no or rare concomitant absences. In such cases, NPC treatment may be as effective as pharmacotherapy and gives the patient a positive experience of regained self-control. PMID- 10091850 TI - Non-epileptic attack disorder (NEAD): a comprehensive review. AB - Non-epileptic attack disorder (NEAD) represents a well-recognized clinical problem with a reported incidence among individuals with a diagnosis of intractable epilepsy as high as 36%. A failure to identify this disorder may lead to certain risks for the patient including polypharmacy, anticonvulsant toxicity, hazardous intervention, social and economic demands and a lack of recognition or neglect of any underlying psychological distress. This review provides a description of NEAD in an historic and societal context and discusses the variety of terminology which has been applied to this psychophysiological phenomenon. Epidemiology and associated methodological limitations; and diagnostic and classification issues related to NEAD in comparison to epilepsy are considered. The problems of failure to recognize NEAD in comparison to epilepsy are considered. The problems of failure to recognize NEAD are outlined, and theoretical and empirical aetiological issues are discussed. PMID- 10091851 TI - Seizure-alert dogs--fact or fiction? AB - Anecdotal evidence suggests that some dogs may be able to sense the onset of seizures and other medical conditions in humans, although this has never been explored scientifically. There is, however, evidence that dogs can be specially trained to recognize specific changes preceding a seizure and give an overt signal enabling the dog to warn his/her owner. The introduction of the use of dogs to detect and accurately predict the onset of a seizure, giving sufficient time for a person to take control of the situation will have a dramatic impact on quality of life. Support Dogs, a registered charity which trains dogs to assist disabled people, has successfully trained several 'Seizure-alert dogs'. As training progressed, the dogs were able to provide overt signals to their owners within time periods varying from 15 to 45 minutes prior to a seizure occurring. Each dog had an accurate prediction time and, in each case, the owner's seizure frequency was reduced. PMID- 10091852 TI - Psychosocial and economic problems of parents of children with epilepsy. AB - The parents of children with epilepsy (PCE) face multiple psychosocial and economic problems that are often neglected. We undertook this study to ascertain these problems among the patients attending a tertiary referral center for epilepsy in India. A structured questionnaire was administrated to parents of 50 children aged between 5-10 years and having epilepsy for more than 1 year's duration. Some 52% of the children had partial epilepsy whilst the remaining had generalized epilepsy. The median seizure frequency was one per 6 months. The majority of the patients (86%) were living in villages. The family income was less than 1000 Rs per month (1 USD = 42 INR) for 66% of the patients. A decline in social activities, after the onset of epilepsy in their children, was reported by 80% of the parents. Daily routines were significantly affected in over 75% of the parents. Parents had been experiencing frustration (52%) and hopelessness (76%), whilst 60% were in financial difficulties. The most important item of expenditure was cost of drugs or cost of travel to hospital for 54% and 36% parents respectively. Impaired emotional status and poor social adaptation were co-related with the severity of epilepsy (frequent seizures/generalized seizures/attention disorder) and low economic status of the parents. These observations need to be borne in mind while organizing rehabilitation programs for epilepsy. PMID- 10091853 TI - Can the long-term prognosis of patients with seizures and structural brain lesions be improved by surgical treatment? PMID- 10091854 TI - Cadmium: a possible etiological factor in peripheral polyneuropathy. AB - Uncovering the exact cause of polyneuropathies seems to be impossible in up to 24% of the cases. Experimental studies have shown that cadmium (Cd), which is a well-known occupational and environmental hazard, can be a potent neurotoxicant for the peripheral nervous system. Moreover, Cd has a half-life of more than 15 years in humans. We hypothesize that older workers may be more susceptible to an increased Cd body burden, and may develop a peripheral polyneuropathy (PNP) over time. A blinded epidemiological survey was performed in 13 retired, long-term Cd exposed workers and 19 age-matched controls. Historical Cd biomonitoring data were available over the last two decades. A neurological clinical examination, nerve conduction studies, and needle EMG were performed, and a standardized questionnaire was given to evaluate polyneuropathy complaints. If two of the following four criteria, i.e. complaints of polyneuropathy, neurophysiological changes compatible with polyneuropathy, distal symmetrical areflexia, or distal symmetrical anesthesia for vibration sense, temperature or blunt-sharp discrimination were present, the diagnosis of PNP was made. Two (11%) of the control and seven (54%) of the retired Cd workers met the PNP criteria OR: 9.92 (95%CI 1.60-61.6), Fisher exact test p=0.015. The existence of a polyneuropathy was related to the level of the Cd body burden as reflected by urinary Cd multiple logistic regression p=0.016, OR=1.26, (95%CI, 1.04-1.51), but not to blood lead (p=0.352). Our findings favour the hypothesis of a promoting role of increased cadmium body burden in the development of PNP at older age. PMID- 10091855 TI - Effects of prenatal zidovudine treatment on learning and memory capacities of preweanling and young adult mice. AB - The present study analyzed the short and long-term effects of prenatal zidovudine (AZT) exposure on learning and memory capacities of CD-1 mice. Two tasks normally used in rodents were used, namely a passive avoidance step-through task and a Morris navigation task. AZT (0, 0.4, and 0.8 mg/ml) was administered via drinking water to pregnant CD-1 females from day 10 of gestation to delivery. Data on reproductive performance, such as gestation length, litter size, and pup mortality were collected. Avoidance learning in the offspring was tested on postnatal day (PND) 15, while spatial learning performances in the Morris water maze were obtained on PND 45. Retention of the passive avoidance response was mildly impaired in the offspring exposed to the 0.8 mg/ml AZT solution, whereas spatial learning on PND 45 was unaffected. PMID- 10091856 TI - The effect of 1,3-dinitrobenzene on the functioning of the auditory pathway in the rat. AB - 1,3-Dinitrobenzene (DNB) has previously been shown to be neuropathic, causing gliovascular lesioning in the rat brainstem, with the nuclei of the auditory pathway being particularly affected. Lesion severity was shown to be dependent on functional activity, which could be markedly decreased within one pathway by monaurally reducing sensory input. The aim of this study was to characterise the changes in electrophysiological and vascular function associated with this asymmetric lesioning. Depth electrodes located in the inferior colliculi were used to measure wave II and IV of the auditory evoked response (AER) and collicular blood flow. These were measured up to eight days after DNB exposure in rats, in which preexisting reduction in sensory input in one ear was achieved by tympanic membrane rupture. Significant increases of between 14-27 dB were seen in the mean stimulus level required to generate a 50% isoamplitude response for wave IV in the intact (ie vulnerable) pathway over days 1-8 post DNB. No significant changes in this response for the other AER waves were seen over the same recording period. Significant increases in blood flow were seen in the inferior colliculi up to 24 hours after the final dose of DNB. Differences in increased flow between the colliculi were also highly significant, with peak increases of 200% and 80% seen in the intact and protected sides respectively. This difference shows that DNB enhanced blood flow appears to reflect the severity of the DNB induced functional deficit. In both cases, disturbance to normal glial function in maintaining K+ homeostasis, may underlie the neurophysiological deficit and the increase in blood flow seen at the level of the inferior colliculi. These asymmetric functional changes were also parallelled by the differential lesion severity between the protected and unprotected pathways. Hence, protection against DNB glial lesion severity by reduction in sensory input, and consequently metabolic demand, is paralleled by the early vascular response and functional neuronal deficit seen over the eight day post DNB recording period. PMID- 10091857 TI - The naturally occurring food mycotoxin fumonisin B1 impairs myelin formation in aggregating brain cell culture. AB - The effects of subchronical applications of the mycotoxin Fumonisin B1 (FB1) were analyzed in vitro, using aggregating cell cultures of fetal rat telencephalon as a model. As cells in the aggregates developed from an immature state to a highly differentiated state, with synapse and compact myelin formation, it was possible to study the effects of FB1 at different developmental stages. The results showed that FB1 did not cause cell loss and it had no effects on neurons. However it decreased strongly the total content of myelin basic protein, the main constituent of the myelin sheath, during the myelination period (DIV 18-28). The loss of myelin was not accompanied by a loss of oligodendrocytes, the myelinating cells. However FB1 had effects on the maturation of oligodendrocytes, as revealed by a decrease in the expression of galactocerebroside, and on the compaction of myelin, as shown by a reduction of the expression of the mnyelin/oligodendrocyte glycoprotein MOG. The content of the cytoskeletal component glial fibrillary acidic protein (GFAP) was decreased in differentiated astrocytes, exclusively, while neurons were not affected by 40 microM of FB1 applied continuously for 10 days. In summary, FB1 selectively affected glial cells. In particular, FB1 delayed oligodendrocyte development and impaired myelin formation and deposition. PMID- 10091858 TI - Zidovudine [AZT] myotoxicity: quantitative separation of AZT effects on proliferation and differentiation of muscle cells in vitro. Lack of myotoxicity potentiation by retrovirus. AB - We compared quantitatively the myotoxicity of 3'-azido-2',3'-dideoxythymidine (AZT) against uninfected and ts1 retrovirus infected mouse skeletal muscle (ATCC CRL 1772) cells at different stages of maturation in vitro. The AZT half inhibitory concentration (IC50) for myoblast proliferation was determined for uninfected myoblasts and parallel cultures infected with ts1 virus. The AZT IC50 for muscle cell differentiation was determined in cultures where myoblasts were grown to confluence and then changed to the fusion medium to which AZT was added at increasing concentrations. Creatine kinase activity was used as a marker of muscle cell differentiation and was determined in homogenates after 7 days. Total cellular mitochondrial DNA was analyzed by Southern blotting. The estimated AZT IC50 for muscle cell proliferation (2-5 microM) was significantly less than the AZT IC50 for muscle cell differentiation (100 microM). Infection with ts1 retrovirus did not significantly shift the IC50 for either proliferation or differentiation of muscle cells. Toxic concentrations of AZT did not cause selective depletion of mitochondrial DNA. The myotoxic effects of AZT on myoblast proliferation and muscle cell differentiation in vitro were quantitatively different and were not changed by productive ts1 retrovirus infection of muscle cells. These results suggest that AZT may impair muscle fiber regeneration in the course of retrovirus associated myopathy. The mechanism of AZT myotoxicity was not explained by alterations in total mitochondrial DNA content. PMID- 10091859 TI - The influence of developmental period of lead exposure on long-term potentiation in the adult rat dentate gyrus in vivo. AB - Previous work has demonstrated an increase in the threshold for induction of long term potentiation (LTP) in the dentate gyrus of animals chronically exposed to lead (Pb) from birth (Gilbert et al., 1996). The present study sought to extend these findings by evaluating the developmental periods critical for Pb-induced impairment of LTP. Rats were exposed to Pb through maternal milk and/or the drinking water over different developmental intervals: 1) beginning just prior to birth and continuing throughout life (PL); 2) beginning just prior to birth and terminating at weaning (PW); or 3) continuously from the early post-weaning period throughout life (WL). Pregnant dams received 0.2% Pb-acetate in the drinking water on gestational day (GD)16, with male offspring switched to the same solution (PL group) or tap water (PW group) at weaning on postnatal day (PND)21. Postweaning exposure began on PND30 and continued throughout life. As adults (PND130-210), field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia, and an ascending series of stimulus trains was administered to induce LTP and to determine its threshold. The magnitude of population spike (PS) LTP was reduced relative to controls in animals exposed throughout life (PL) and in animals exposed after weaning (WL). No impairment in PS LTP was evident in animals removed from Pb at weaning and tested as adults (PW). Similarly, thresholds for induction of PS LTP were elevated relative to controls in the PL and WL groups, but were not affected by Pb exposure limited to the lactational period (PW). Reductions in the magnitude of LTP of the EPSP slope were evident in posttrain I/O functions in all Pb exposed groups, including the PW group. An elevated LTP threshold was evident in the EPSP slope measure in the continuously exposed group (PL) only. Thus Pb exposure restricted to the lactational period appeared less disruptive to adult LTP in the dentate gyrus than continuous exposure beginning around birth or weaning. However, EPSP slope LTP was impaired in animals exposed to Pb for as little as 30 days in the early postnatal period. An attenuated ability to support neuroplastic change in synaptic function may contribute to cognitive deficits associated with Pb-induced toxicity. PMID- 10091860 TI - Chronic developmental lead exposure and hippocampal long-term potentiation: biphasic dose-response relationship. AB - Developmental exposure to lead (Pb) has long been associated with reductions in intellectual function in children and behavioral impairments in animal models of learning and memory. We have used long-term potentiation (LTP) in the dentate gyrus of the Pb-exposed rats to determine the potential of a reduced capacity for synaptic plasticity to contribute to Pb-induced cognitive dysfunction. Previous work demonstrated that developmental exposure resulting in moderate blood concentrations of Pb increase the threshold for induction of long-term potentiation (LTP) in the dentate gyrus in vivo. These findings were also suggestive of reductions in LTP magnitude (Gilbert et al., 1996). The present study was designed to further examine the effects of Pb on LTP magnitude and to determine if lower blood Pb levels commonly encountered in children are also effective in impairing synaptic plasticity in this rodent model. Pregnant dams were exposed to control tap water or 0.1, 0.2, 0.5 or 1.0% Pb-acetate in the drinking water beginning just prior to parturition (gestational day 16, GD16). Male offspring were weaned at 21 days of age (PN21) to the same solution given their dams and continued on this regimen until testing. As adults, animals were anesthetized with urethane and stimulating and recording electrodes placed in the perforant path and dentate gyrus, respectively. Post-train I/O functions taken 1 hour after delivery of a series of six high frequency (400Hz) trains revealed a reduced capacity for LTP of the PS amplitude and EPSP slope in Pb-exposed animals in all but the 1.0% group, indicative of a biphasic dose-effect relationship. The 1.0% Pb exposure was clearly less effective than the lower exposure levels in reducing LTP magnitude, and did not differ significantly from control values. The mechanisms underlying the reduced efficacy of higher exposure levels of Pb to impair LTP are not clear. Blood (26-117 microg/dl) and brain (220-1812 ng/g tissue) concentrations of Pb were elevated as a function of increasing exposure (0.1%-1.0%) and cannot readily account for the lack of an effect in the 1.0% group on LTP. We have observed a similar profile in hippocampal glutamate release employing a similar range of exposure levels, i.e., reduction of glutamate release that is absent at higher concentrations of Pb in the drinking water (Lasley et al., 1998). These and previously reported data suggest that the ability of Pb to diminish presynaptic transmitter release contributes to a reduced capacity for LTP at lower exposure levels. The reversal of the effect of Pb on glutamate release that accompanies higher exposure levels may serve to compensate for the mechanism underlying the LTP impairment and form the basis for the biphasic dose-response pattern seen with chronic developmental exposure. PMID- 10091862 TI - Understanding the NIH review process: a brief guide to writing grant proposals in neurotoxicology. AB - During the past two years, the National Institutes of Health have made significant changes in the review process for investigator-initiated research grant applications in neurotoxicology. First, study sections that formerly dealt with toxicology and alcohol, respectively, have been merged. Neurotoxicology grant applications are now reviewed by ALTX-3, a study section in which the majority of members have expertise in the neuronal, biochemical or behavioral effects of alcohol, but usually not other neurotoxicants. Second, the NIH has instituted new review criteria, in which significance, approach, innovation, investigator expertise, and research environment must all be explicitly addressed by the reviews. In this article, past and present members of the ALTX-3 study section describe the NIH review process, with emphasis on how neurotoxicology applications are handled, and provide guidelines for preparing competitive applications. PMID- 10091861 TI - Glutathione depletion increases brain susceptibility to m-dinitrobenzene neurotoxicity. AB - To test the hypothesis that glutathione (GSH) status in brain tissue plays an important role in the selective neurotoxicity of m-dinitrobenzene (DNB), the sensitivity to intoxication of three groups of male F344 rats were studied and correlated with brain tissue GSH levels. In Group I were young 6-8 week old rats with normal GSH levels, and in Group II were rats of the same age whose brain GSH levels had been reduced by intracerebroventricular (i.c.v.) injections of L buthionine-[S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. In Group III were 6 month old rats that, as a result of normal aging, show GSH levels of 16-29% below those seen in younger animals. All three groups were subjected to a 1 to 4 dose schedule of dosing with DNB (7.5 mg/kg/day i.p.) and killed 1 day after the last dose of DNB. It was found that whereas Group I animals developed ataxia and brain stem lesions after 4 doses, Group III animals showed these changes after 3 doses, while Group II animals had brain stem lesions after only 2 doses of DNB. The timing of the onset of these changes correlated closely with the degree of reduction of brain tissue levels of GSH, this being greatest in those animals infused i.c.v. with BSO. This demonstration indicates that GSH status in brain tissue is likely to be an important factor in determining regional sensitivity to gliovascular damage from this agent. PMID- 10091863 TI - Computer-assisted three-dimensional reconstruction and motion analysis of living, crawling cells. AB - A computer-assisted three-dimensional dynamic image analysis system (3D-DIAS) has been developed for reconstructing and motion analyzing living, crawling cells. The system simultaneously reconstructs the cell surface, the nucleus and pseudopodia, both expanding and retracting. Although this system has been developed for single cell analysis, it can be used for the dynamic reconstruction and motion analysis of cells in early embryos, the human heart and any other cell, organ or object changing shape over time. Ongoing development of a dynamic analysis system with a confocal front-end, a high speed reconstruction system, a near-real time system and a virtual reality system are described. PMID- 10091864 TI - Towards a microMRI atlas of mouse development. AB - This study investigates the potential of microscopic Magnetic Resonance Imaging to obtain information for 3D digital atlases of mouse development using fixed samples. Fixed samples allow direct comparison with already published atlases and provide a testing ground for future in vivo efforts. 3D MR images of mouse embryos (dpc 6.5-16) illustrate that the necessary contrast and level of detail is available with this technique. Diffusion weighted imaging, diffusion tensor imaging, and multi-valued data sets are presented as examples of uniquely MR methods of obtaining anatomical information. MRI is performed non-invasively on the intact sample, leaving open the possibility of other manipulations (e.g. classical histology, immunohistochemistry, in situ hybridization, and in vitro growth for unfixed samples) after conducting the MRI experiment. PMID- 10091865 TI - In utero ultrasound backscatter microscopy of early stage mouse embryos. AB - A high resolution ultrasound imaging technique, ultrasound backscatter microscopy (UBM), has previously been shown to be useful for in utero imaging of mouse embryos, and for direct manipulation of mouse embryos through UBM-guided injections. UBM images from mouse embryos staged between 8.5 and 10.5 days of gestation are presented to demonstrate the range of anatomical structures which can be studied with this approach. Ultrasound contrast agents have been injected into the forebrain ventricle of 10.5 day embryos to characterize the resulting three-dimensional distribution of the injected agents. These studies provide important background data relevant to future use of this technique for in utero analysis of early brain and heart development, and for in utero manipulation of mouse embryos through UBM-guided injections. PMID- 10091866 TI - Magnetic resonance imaging of embryos: an Internet resource for the study of embryonic development. AB - The recent amassing of gene expression data to study development in mammals has led to an increased demand for access to human embryological data. The difficulty of obtaining well-preserved human embryos presents an important challenge to studying human development. The Multidimensional Human Embryo project is generating an image data set based on magnetic resonance microscopy of specimens from the highly respected Carnegie Collection of Human Embryos. The data are available from a web site to facilitate the work of clinicians, investigators, and students of human development. A consequence of the project will be to preserve a highly respected, yet impermanent, collection of human embryos and minimize the need for collecting new specimens. PMID- 10091867 TI - Use and evaluation of the World Wide Web as a tool to explore the human developmental anatomy center. AB - Since the origination of the Human Developmental Anatomy Center at the National Museum of Health and Medicine of the Armed Forces Institute of Pathology, efforts have been made to use electronic media to assist researchers wishing to use collections housed there. Earlier projects involved creating high-resolution images of the thousands of sections in the collections; later efforts involved creating three-dimensional models; later still, these images and models have been placed in a World Wide Web format for ease of distribution. This article assesses the utility of the project and anticipates future uses of the growing website. PMID- 10091868 TI - 3D computer modeling of human cardiogenesis. AB - We obtained digitized histological serial sections of three human embryos of different stages from the Armed Forces Institute of Pathology from which contours of cardiac structures were digitally traced. Traces were placed in register for the construction of wire frame models using Silicon Graphics Incorporated 3D computer modeling software (Alias/Wavefront) and for surface rendering to demonstrate internal and external developmental anatomy. The models allowed stage to-stage morphing and physical model construction using stereolithography. These innovations in embryo reconstruction not only facilitate medical education, they also serve as new tools for scientific investigation of cardiogenesis and congenital heart disease. PMID- 10091869 TI - The current status and future potential of fetal intervention: image is everything. AB - Fetal imaging is integral to the past, present, and future of fetal intervention. In the early history of fetal intervention, the role of prenatal ultrasound was primarily to identify a fetal lesion, provide a correct anatomic diagnosis, and exclude other anatomic defects. We now depend on ultrasound, and other imaging studies, not only to provide anatomic information, but to provide prognostic, physiologic and functional information prior to, during, and after surgery for optimal selection and management of fetal surgery patients. In the future improvements in imaging and non-invasive technology will drive further expansion of indications and therapeutic options for fetal intervention. PMID- 10091870 TI - The tobacco pandemic. PMID- 10091871 TI - Good news and not such good news. PMID- 10091872 TI - Dilemmas and realities in the laboratory diagnosis of tuberculosis in low income countries. PMID- 10091873 TI - Risk from tobacco and potentials for health gain. AB - Evidence that smoking tobacco harms health has accumulated over 200 years, but was largely ignored before 1950, when five case-control studies associated smoking with the development of lung cancer. The idea that it might cause the disease was greeted with scepticism, and it was nearly 10 years before it became generally accepted. By then there had been additional evidence from cohort studies, and known carcinogens had been identified in tobacco tars. Cigarette smoking has now been positively associated with some 40 causes of death and negatively associated with eight or nine. A few of the associations are due to confounding, but the great majority reflect causality. In several instances cigarette smoking increases the risk of death ten-fold, and altogether it doubles the annual risk of death at all ages combined, in both sexes. Tobacco smoke in the environment also has a small effect on the health of non-smokers, particularly in infancy and childhood, but also to some extent later in life. Nearly a quarter of all deaths in men and a tenth in women in industrialised countries in 1990 were attributed to smoking, giving a total of 1.8 million a year. In 20-30 years' time the total is estimated to rise to 10 million a year, with 7 million in low income countries, if smoking habits persist unchanged. PMID- 10091874 TI - Physicians can make a difference with smokers: evidence-based clinical approaches. Presentation given during the Symposium on Smoking Cessation at the 29th World Conference of the IUATLD/UICTMR and Global Congress on Lung Health, Bangkok, Thailand, 23-26 November 1998. International Union Against Tuberculosis and Lung Disease. AB - Tobacco use poses one of the greatest public health challenges globally. This paper reviews the role of the physician as a key figure in promoting tobacco control and prevention. The physician is in a prime position to assist patients to stop smoking because of the high rate of contact with the general public. His/her efforts can contribute towards stemming the projected increase in smoking prevalence and resulting mortality and morbidity from cigarette-related diseases. However, the doctor is not taking full advantage of this window of opportunity to identify smokers and provide stop smoking advice. Evidence of physicians' and general practitioners' success in advising patients to stop smoking is presented. In general, clinical trials have reported abstinence rates of 5% to 10% for brief advice, and 20% to 36% for more physician involvement in providing advice and counselling. Nicotine replacement therapies (gum and patch) and other pharmacological treatments are useful adjuncts to physicians' advice to quit. Three evidence-based approaches available for the physician to use are described: 'Smokescreen for the 1990s in Australia', 'Smoking Cessation Clinical Practice Guideline' in the USA, and 'Guidelines on Smoking Cessation for General Practitioners and Other Health Professionals' in Europe. The information and resources that we have produced in industrialised countries must be translated, made culturally appropriate and distributed to physicians around the world, particularly in low income countries, so that they can fulfil their vital function of assisting patients to stop smoking. PMID- 10091875 TI - Are low income countries targets of the tobacco industry? Plenary lecture given during the Conference on Global Lung Health and 1997 Annual Meeting of the International Union Against Tuberculosis and Lung Disease, Palais des Congres, Paris, France, 1-4 October 1997. AB - Estimations show that tobacco consumption is steadily increasing in low income countries already deprived of basic human needs, such as adequate food and water supplies and education. Among the many factors affecting this, the most significant is the aggressive marketing strategies of the tobacco industry. The tobacco industry operates by denying health evidence, sponsoring scientific research that diverts attention to other fields, investing heavily in promotion and advertising, interfering with national public health laws, forming joint ventures with national monopolies, and persuading governments on the risks of smuggling. Turkey, a tobacco-growing country, opened its markets to the multinational tobacco industry after 1984. This paper presents examples of the marketing strategies used by the tobacco industry in the last two decades, and shows the consequences for Turkey in the hope that this information can help other low income countries that are not yet targets of the invasion of the tobacco industry. PMID- 10091876 TI - Bioavailability of rifampicin, isoniazid and pyrazinamide in a triple drug formulation: comparison of plasma and urine kinetics. AB - SETTING: The present study assesses bioavailability indices for rifampicin, isoniazid and pyrazinamide when administered to healthy volunteers separately or in a fixed triple-drug formulation, Rifater 125 SCT. OBJECTIVE: To compare the pharmacokinetics of rifampicin, isoniazid and pyrazinamide based on their blood concentrations up to 12 hours with the proportions of the doses of the drugs and their metabolites excreted in urine up to 12 hours, and to assess the bioavailability indices for the free and fixed triple drug formulations. DESIGN: An open cross-over study was conducted in 18 healthy volunteers with normal hepatic and renal functions to whom the drug combinations were administered in free and fixed dose formulations a week apart, to the same subject. RESULTS: Concentrations of the three drugs/metabolites were assessed in blood and urine. The results indicated the absence of negative pharmacokinetic interactions between the drugs when administered in both the free and the new fixed triple drug formulation. CONCLUSION: Human bioavailability studies provide direct straightforward information, particularly when studying compounds such as rifampicin and other major anti-tuberculosis drugs. The results of the present study indicate that the pharmacokinetic properties of rifampicin, isoniazid and pyrazinamide as assessed after individual and combined administration do not change when combined in a single pharmaceutical preparation. The bioavailability indices calculated based on plasma concentrations and urinary levels for all three drugs compared well. PMID- 10091878 TI - Pharmacokinetics of pyrazinamide in children suffering from pulmonary tuberculosis. AB - SETTING: The Paediatric and Clinical Pharmacology unit of Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India. OBJECTIVE: The pharmacokinetics of the anti-tuberculosis drug pyrazinamide was evaluated in 10 children aged 6 to 12 years suffering from pulmonary tuberculosis. METHODS: Serial blood samples were collected at 0, 1, 2, 4, 6, 12 and 24 hours after administration of pyrazinamide in a dose of 35 mg/kg. Serum pyrazinamide levels were analysed by spectrophotometry. RESULTS: The serum concentrations of pyrazinamide were above the minimum inhibitory concentration of 20 microg/ml of pyrazinamide for Mycobacterium tuberculosis up to 6 hours after drug administration in all the patients, and up to 12 hours in six patients. The mean peak serum concentration of pyrazinamide was 41.2+/-11.8 microg/ml, and this was attained in (Tmax) 2.9+/-1.7 hours. The elimination half life was 10.9+/-4.5 hours, the volume of distribution 16.1+/-10.9 litres and clearance 20.2+/-16.3 ml/minute. The corresponding mean residence time was 19.9+/-14.6 hours. CONCLUSION: The serum pyrazinamide concentrations achieved with a dose of 35 mg/kg were above the minimum inhibitory concentration of pyrazinamide for M. tuberculosis for over 6 hours after drug administration. It appears that the absorption and the clearance of pyrazinamide is slower, the elimination half life longer and the volume of distribution higher in children compared with the reported values in the adult population. PMID- 10091877 TI - Assessment of a combined preparation of isoniazid, rifampicin and pyrazinamide (Rifater) in the initial phase of chemotherapy in three 6-month regimens for smear-positive pulmonary tuberculosis: a five-year follow-up report. AB - SETTING: Singapore Tuberculosis Service. OBJECTIVE: To assess the acceptability, efficacy and relapse rate of a combined formulation of three drugs--isoniazid, rifampicin and pyrazinamide (Rifater)--given in the initial phase of chemotherapy in three 6-month regimens (2SHRZ/4H3R3, 1SHRZ/5H3R3 and 2HRZ/4H3R3) under direct observation for all patients. DESIGN: A randomised, controlled, unblinded study comparing a group of patients treated with Rifater and another given the three component drugs as separate formulations. RESULTS: The 310 patients admitted to the study were divided into two groups of 155 patients. The frequency of side effects was similar in both groups. Of 271 patients with drug-sensitive strains who had completed treatment without interruption, sputum cultures converted in all patients. At the end of 5 years, there were 15 relapses: three (2.2%) in the separate drugs group and 12 (9.3%) in the Rifater group. Exclusion of two cases in the Rifater group, one with silicotuberculosis and another with no bacteriological confirmation of diagnosis, gave a relapse rate of 7.9% (P = 0.03 for the comparison of relapse rates in the two groups). CONCLUSION: A combined formulation of three drugs given daily in the initial phase of 6-month short course therapy, followed by intermittent treatment with isoniazid and rifampicin given three times a week under direct observation for all patients, appears to be less effective than treatment with the component drugs given as separate formulations. PMID- 10091879 TI - Microcolony detection in 7H11 thin layer culture is an alternative for rapid diagnosis of Mycobacterium tuberculosis infection. AB - SETTING: Radiometric technology and molecular biology are used in rapid diagnosis of tuberculosis in laboratories around the world. However, these technologies increase costs and are not available in laboratories where economic resources are limited. OBJECTIVE: To compare sensitivity and time for detection of positive cultures in a microcolony method, Middlebrook 7H11 thin layer agar plate (TL7H11), and a conventional culture, Lowenstein-Jensen (L-J). DESIGN: A total of 761 clinical samples were processed using acid-fast smear and culture on TL7H11 plates and L-J tubes. TL7H11 plates were checked microscopically for microcolony growth twice weekly for 4 weeks, and L-J tubes were checked once a week for 8 weeks. RESULTS: Overall positivity was 11.0%. More than 60% of the positive samples were detected within the first 10 days on TL7H11, and none on L-J. After 2 weeks, more than 80% were positive on TL7H11 compared to 10% on L-J. In paucibacillary samples, TL7H11 detected 2.18% and L-J 4.57% (P < 0.001). Microcolony morphology was 100% distinctive for Mycobacterium tuberculosis on TL7H11. The calculated cost of TL7H11 prepared in the laboratory was US$2.90 per unit. CONCLUSION: The TL7H11 method is an inexpensive, rapid and reliable alternative for diagnosing M. tuberculosis infection. It is therefore a valuable option for laboratories in low income countries. PMID- 10091880 TI - Drug susceptibility of Mycobacterium tuberculosis in a rural area of Bangladesh and its relevance to the national treatment regimens. AB - SETTING: Greater Mymensingh District, a rural area of Bangladesh, at the start of the National Tuberculosis Programme (NTP). OBJECTIVES: To determine the prevalence of initial and acquired drug resistance of Mycobacterium tuberculosis, and to assess the appropriateness of the NTP's standard regimens. DESIGN: Sampling of pre-treatment sputum from all newly registered smear-positive cases in five centres covering the area. Culture and susceptibility testing in a supra national reference laboratory. RESULTS: Initial resistance to isoniazid (H) was 5.4%, and to rifampicin (R) 0.5%. Acquired H and R resistance were 25.9% and 7.4%, respectively. Multidrug resistance (MDR) was observed in one new case only and in 5.6% of previously treated patients. Changing the present NTP indication for retreatment regimen to one month of previous H intake would increase coverage of H-resistant cases from 52% to 89%, adding 6% to drug costs. CONCLUSION: The prevalence of drug resistance is surprisingly low in Bangladesh, but could rise with improving economic conditions. The NTP regimens for smear-positive cases are appropriate, all the more so since the human immunodeficiency virus is virtually absent. Indications for the retreatment regimen should be extended to include all patients treated for at least one month with any drug. The NTP regimen for smear negative cases runs the risk of leading to MDR under present field conditions. PMID- 10091881 TI - Drug-resistant strains of Mycobacterium tuberculosis isolated in Russia. AB - SETTING: State Research Center for Applied Microbiology, Russian Research Institute of Phthisiopulmonology (Ministry of Health, Moscow). OBJECTIVE: To analyze drug-resistant clinical isolates of Mycobacterium tuberculosis obtained from patients referred to the institute from different parts of Russia, and to study the mechanisms of their rifampicin resistance. DESIGN: Fifty clinical isolates of M. tuberculosis were analysed. Polymerase chain reaction (PCR) and sequencing were used to study the mechanisms of rifampicin resistance in 25 isolates. RESULTS: Among cultures isolated from 50 patients, drug resistance was detected in 33. Most of the isolates were resistant to rifampicin (25 isolates), isoniazid (14 isolates), and streptomycin (seven isolates). Only 6% of the isolates were resistant to one drug, while 14% were resistant to two, 32% to three, 40% to four, and 8% to five drugs. Susceptible isolates were derived from 17 patients. The following point mutations and deletions in the rpoB locus, responsible for high level rifampicin resistance (more than 50 microg/ml in egg based medium), were detected: G-->A/395 (Arg-->Gln), C-->T/232 (His-->Tyr), C- >T/221 (Ser-->Leu), G-->T/202 (Asp-->Tyr), GA-->TT/202-203 (Asp-->Phe), deltaATGGACCAG/199-207 (Met, Asp, Gin), A-->T/91 (Met-->Leu), TG-->CC/227-228 (Leu-->Ser), GAG-->AGT/349-350-351 (Gln-->Ser), deltaGGG/354(Gly). CONCLUSION: A number of previously unrecognised genetic modifications in the rpoB region were found in rifampicin-resistant strains isolated from patients from different parts of Russia. PMID- 10091882 TI - Use of incentives to increase compliance for TB screening in a population of intravenous drug users. Vancouver Injection Drug Use Study Group. AB - SETTING: Intravenous drug users (IDUs) represent a high risk group for dual human immunodeficiency virus (HIV) and tuberculosis (TB) infection. Screening with TB skin testing has therefore been suggested in this group. Subjects' compliance for returning to have TB skin test results read is a major problem. In the setting of a needle exchange program we evaluated the role of financial incentives to increase compliance. METHODS: We evaluated the role of giving a small financial incentive of Can $5 to subjects if they returned to have their purified protein derivative (PPD) skin test read. IDUs who had previously been skin-tested were compared with IDUs drawn from a similar population who, prospectively, were offered a financial incentive. RESULTS: During the initial period 558 subjects were evaluated and no incentive was offered. During the second phase of the study 549 IDUs were assessed but were also offered Can $5 if they returned to have their skin test read. Use of incentives increased compliance from 43% to 78% (P = 0.001). During the same period three active cases of TB were also diagnosed. CONCLUSIONS: We suggest that use of financial incentives can increase the return of IDUs to have their skin tests read. Further studies are required to assess the efficacy of follow-up interventions, especially the use of isoniazid chemoprophylaxis. PMID- 10091883 TI - Altitude: a determinant for tuberculosis in Kenya? AB - OBJECTIVE: To determine to what extent tuberculosis incidence is associated with altitude. METHODS: Notification rates were obtained from all 41 districts in Kenya in the period 1988-1990; the mean altitude of each district was estimated. Data on indicators of socio-economic status such as literacy rate and infant mortality rate were obtained from the 1989 census, as well as data on other potential confounders such as urbanisation and median household size. RESULTS: The notification rate of new smear-positive tuberculosis was 32/100000 overall, varying between districts from 5 to 222/100000. Notification rates steeply reduced with increasing altitude (r = -0.71; 95% confidence interval [CI] -0.51 to -0.83). At altitudes of 1000 m or more the notification rates were less than 30% of those in districts at altitudes below 500 m, also after adjustment for confounding. CONCLUSION: Tuberculosis incidence in Kenya decreases strongly with increasing altitude. If the association is not due to unknown confounding factors, a range of potential biological explanations needs to be explored. PMID- 10091884 TI - Lymph node tuberculosis in the suburbs of Paris: 59 cases in adults not infected by the human immunodeficiency virus. AB - We report 59 cases of lymph node tuberculosis in adults not infected by the human immunodeficiency virus (HIV), observed over a period of 5 years in the North Eastern suburbs of Paris. There were 31 women and 28 men; 84.7% were aged under 44 years; 69.5% were not French, and 78% had exclusive lymph node tuberculosis. A superficial distribution was found in 52 cases and a deep pattern in 17 cases. Cervical and supraclavicular lymphadenopathies were the most common (64.4%). General symptoms were present in 63% of cases. The diagnosis was established by fine needle aspiration in 10 cases and by biopsy in 36 cases. Three cases of primary resistance to anti-tuberculosis therapy were described. Lymph node tuberculosis is still present in the Paris region, independently of HIV infection, probably due to poor social conditions. PMID- 10091885 TI - Innate resistance to tuberculosis: revisiting Max Lurie genetic experiments in rabbits. AB - Experimental inoculation of tubercle bacilli does not correspond to natural contagion. The classic and unique study published in the literature, performed by Max Lurie with inbred rabbit families to evaluate resistance and susceptibility to tuberculosis, closely simulated the natural mode of infection, reproducing the varying types of the disease as it occurs in man. Lurie observed that resistant families developed cavitary tuberculosis and susceptible families developed disseminated tuberculosis. The conclusions were based only on resistance to the progress of tuberculous infection due to cellular-mediated immunity. In this report we have made an additional analysis of this experiment, looking for the resistance to infection itself. PMID- 10091886 TI - Identification of Mycobacterium shimoidei by molecular techniques: case report and summary of the literature. AB - A 53-year-old woman from Melbourne, Australia, with squamous cell carcinoma of the oesophagus was shown by computed tomography (CT) scan to have a left apical cavity and inflammatory changes in the right lung consistent with aspiration. Acid-fast bacilli isolated from bronchial washings were identified biochemically first as Mycobacterium terrae, but later as M. shimoidei on the basis of 1) restriction fragment analysis and 2) sequencing of polymerase chain reaction (PCR) amplified 16S rDNA. Nine other descriptions of patients with M. shimoidei isolates were collated. The salient feature of isolates considered to be pathogenic was pulmonary cavitation. Most patients had underlying lung disease, including past tuberculosis or malignancy. Six of eight patients died of progressive respiratory illness, although the contribution of M. shimoidei was not always clear, and two patients improved. One patient with the acquired immune deficiency syndrome (AIDS) died with Salmonella enteritidis and M. shimoidei isolated from blood cultures. One isolate was regarded as a coloniser. There are insufficient clinical or sensitivity data on which to base recommendations for therapy, but a combination of ethambutol, rifabutin and pyrazinamide could be considered. PMID- 10091887 TI - How drug resistance emerges as a result of poor compliance. PMID- 10091888 TI - Loss of tuberculosis officers from a national tuberculosis programme: the Malawi experience, 1993-1997. PMID- 10091889 TI - The origins of DOTS. PMID- 10091890 TI - Gestational diabetes mellitus: growing consensus on management but not diagnosis. PMID- 10091891 TI - How should our public hospitals respond to increasing ethical challenges? AB - AIM: To explore the considerations and influences on decision making of doctors and managers when faced with ethical dilemmas. METHOD: Two hundred and eighty four doctors and managers responded to a mailed survey. The questionnaire probed the types of considerations that were salient in the ethical dilemmas faced by doctors and by managers, the support these groups received for reflection on these difficult decisions, the specific influences on their decision making and their perception of future ethical issues in the health sector. RESULTS: The study found that doctors and managers report encountering a similar frequency of ethical dilemmas in their work but apply significantly different considerations and influences in their decision making. They reported similar levels of support from their colleagues but differing levels of support from their managers and the Crown Health Enterprise overall. CONCLUSIONS: This study highlights various areas of dissonance between different stakeholders in the public health sector, in particular, between the manager representing the organisation's interest and the doctor representing the patients' interests. Policy makers, purchasers and providers need to consider the infrastructure required to support doctors and managers in their work. Above all, with more ethically challenging decisions ahead, there needs to be clarity over the decision-making role of the government, the health manager and the doctor. PMID- 10091892 TI - Women in general practice in New Zealand. AB - AIM: To investigate the role of women general practitioners (GPs) in New Zealand. METHOD: A five-page questionnaire was posted to 200 randomly selected women GPs from throughout New Zealand. One follow-up mailing was sent. RESULTS: A response rate of 79% was achieved. Twenty-four percent of women GPs work less than 5/10 but 46% earn less than $40000. Forty-eight percent of women GPs' partners also earn less than $40000. The most common reason for working part-time was parenting responsibilities. Eighty-seven percent are married or live with a partner, 77% have children, 48% have preschool-aged children. Only 15% have Membership of the RNZCGP and 57% are owner or partner in their practice. CONCLUSION: Women GPs suffer both professional and financial difficulties because of their dual motherhood/professional roles. PMID- 10091893 TI - The future of the immunisation schedule: recommendations of a workshop. AB - The Ministry of Health convened a workshop in June 1998 on the future of the immunisation schedule. Your comments are invited on the recommendations of the workshop. PRINCIPLES BEHIND THE SCHEDULE: Improve on-time immunisation coverage as the priority. Reaching the last 20% will cost at least as much as the first 80% and is vital to achieve the aims of the immunisation programme (disease elimination and improved control). Obtain regular secure coverage data, derived from a tracking system that ensures children are followed up. Assess compliance with early childhood centre immunisation checks at entry and improve if necessary. Establish an expert committee to advise on the immunisation schedule and policies. Keep the schedule as simple as possible. Accept that vaccines are not generic and future schedule recommendations may be vaccine-specific. Involve providers in the process of change. PROPOSED CHANGES: Move the second dose of measles-mumps-rubella vaccine from age 11 years to around five years. Consider moving the third visit from five to four months to achieve earlier protection against pertussis. Consider adding a fifth dose of pertussis vaccine. Change to acellular pertussis vaccine, once suitable vaccines are available. Change to inactivated polio vaccine, once suitable vaccines are available. Consider omitting the fourth dose of polio vaccine. Consider introducing an adult immunisation schedule with fewer adult tetanus-diphtheria boosters. PMID- 10091894 TI - Statins and PHARMAC. PMID- 10091895 TI - The Health and Disability Commissioner Act. PMID- 10091896 TI - Cervical screening. PMID- 10091897 TI - Ocular toxicity from ethambutol. PMID- 10091898 TI - Antimicrobial resistance. PMID- 10091899 TI - Psychological factors and chronic fatigue syndrome. PMID- 10091900 TI - Pseudomonas folliculitis from a spa pool in an immunocompromised patient. PMID- 10091901 TI - Complications of legal termination of pregnancy. PMID- 10091902 TI - Advice to health service managers. PMID- 10091903 TI - Booklet on abortion. PMID- 10091904 TI - If it isn't ADD then it must be Asperger's. Attention Deficit Disorder. PMID- 10091905 TI - Medicalisation of human conditions. PMID- 10091906 TI - New Zealand death certificates. PMID- 10091907 TI - Combining summaries of binary outcomes with those of continuous outcomes in a meta-analysis. AB - We present a methodology for combining trials some of which report continuous outcome measures and others binary outcomes created by a dichotomy of the continuous measurement. This was motivated by a series of controlled clinical trials investigating the effect of prophylactic use of oxytocics on postpartum blood loss during labor. Data were available in the form of summary statistics from published papers. The log-odds ratio is used as a common measure of treatment difference across all trials. We discuss the general applicability of this approach. PMID- 10091908 TI - Two-sample continual reassessment method. AB - We discuss an extension of the continual reassessment method (CRM) for use in phase I dose-finding studies. The extension enables the method to be applied to two groups of patients to determine the appropriate dose levels for each group. The method takes the specification of a simple relationship between the dose toxicity curves for the two groups and runs the CRM on the bivariate model using maximum likelihood. We prove consistency of the method under fairly weak conditions and provide several simulations to give an idea how the method works in practice. We also undertake an evaluation of its performance by considering three possible situations: The first is the two-sample CRM, which directly uses a working model for the relationship between the two groups, carrying out a single trial using this method; the second situation carries out single trials for each of the two groups separately using the original (one-sample) CRM. The third situation is the case where such heterogeneity is ignored and the two groups are pooled into a single group, again using the original (one-sample) CRM. Simulations are carried out under a large class of model misspecifications, both of the dose-toxicity relationships and of the functional form linking the groups, and are backed up by asymptotic results. Our conclusions match intuition: The first scheme gives the most favorable results when the two groups are different but share some features. When the groups are very different, the second scheme performs similarly to the first for finite sample sizes while having some advantages in terms of asymptotic efficiency. The third, as expected, gives the best results in the absence of patient heterogeneity. The two-sample method appears particularly advantageous when there may not be enough subjects in one of the subgroups for it to be feasible to carry out two trials. PMID- 10091909 TI - Complementary nonparametric analysis of covariance for logistic regression in a randomized clinical trial setting. AB - In the randomized clinical trial setting, controlling for covariates is expected to produce variance reduction for the treatment parameter estimate and to adjust for random imbalances of covariates between the treatment groups. However, for the logistic regression model, variance reduction is not obviously obtained. This can lead to concerns about the assumptions of the logistic model. We introduce a complementary nonparametric method for covariate adjustment. It provides results that are usually compatible with expectations for analysis of covariance. The only assumptions required are based on randomization and sampling arguments. The resulting treatment parameter is a (unconditional) population average log-odds ratio that has been adjusted for random imbalance of covariates. Data from a randomized clinical trial are used to compare results from the traditional maximum likelihood logistic method with those from the nonparametric logistic method. We examine treatment parameter estimates, corresponding standard errors, and significance levels in models with and without covariate adjustment. In addition, we discuss differences between unconditional population average treatment parameters and conditional subpopulation average treatment parameters. Additional features of the nonparametric method, including stratified (multicenter) and multivariate (multivisit) analyses, are illustrated. Extensions of this methodology to the proportional odds model are also made. PMID- 10091910 TI - Use of predictive probabilities in phase II and phase III clinical trials. AB - Predictive probability is particularly useful in aiding a decision-making process related to drug development. This is especially true for decisions occurring as the result of interim analyses of clinical trials. Examples of clinical trial applications of Bayesian predictive probability and the use of the beta-binomial distribution are described. PMID- 10091911 TI - Some results on combinations of two binary screening tests. AB - When two medical screening tests for a disease exist, it may be appealing to combine them to increase screening accuracy. Combination of two valid screening tests, where each independently has screening performance, can increase the overall disease screening performance. Some results are obtained when two binary screening tests are combined according to the Boolean Any+ strategy, as defined by Maguire (1). These results are useful and provide investigators of two screening tests a sense of what to expect of the performance of the two tests when combined. This then may be followed by a clinical trial that directly demonstrates the benefit of the combined test. PMID- 10091912 TI - New models for pharmacokinetic data based on a generalized Weibull distribution. AB - We consider the development of the concentration of a drug in the blood after single oral or intravenous administration. We introduce a new nonlinear model capable of describing concentration-time curves following intravenous administration. A similar model is proposed for oral data. Both models have four parameters, of which two regulate the shape of the curve and two determine the scale of the time and concentration axes. All the parameters are closely related to geometric properties of the curve. The scale parameters determine a point in the curve, and the shape parameters can be calculated by using numerical integration. The models can be used when the object of the analysis is to quantify the shape of a concentration-time curve. We discuss the usefulness of the models in bioequivalency trials, in clinical safety and efficacy trials, and in population pharmacokinetics. The models are applied to two previously presented data sets. To reduce the number of parameters, the shape parameters are assumed common for all individuals. Encouraging results are obtained. We also present a new four-parameter Michaelis-Menten model. PMID- 10091913 TI - Design and analysis issues for crossover designs in phase I clinical studies. AB - To assess the efficacy of potential new drugs in the initial phase of clinical research, one must use an efficient design that satisfies conditions to guarantee the safety of the subjects. For a parallel design, a two-period crossover design, two three-period crossover designs, and a Latin square design with three periods, we compared variances of estimators based on a mixed analysis of variance model. The proposed three-period crossover designs turned out to be only slightly less efficient than the Latin square design, which is not capable of satisfying the necessary safety conditions. The analysis of data from the crossover design poses several problems, including nonconstant variances for all observations and the possibility of carryover effects. To resolve these issues, we generalized the Box Cox transformations to the mixed model at hand and, using simulation, investigated the sensitivity of the analysis to the presence of (first-order) carryover effects. This showed that results from the model without carryover are reliable for only very small carryover effects. PMID- 10091914 TI - Evaluating overall significance levels in multifactor ANOVA. AB - Multifactor ANOVA procedures are commonly used by practitioners. A hierarchical process for testing the interaction effect(s) first, followed by tests for the main effects, is usually employed. Generally, no consideration is given to the overall type I error rate for these dependent (or conditional) tests. In this article, we formulate a method to evaluate the true overall significance levels for two-factor fixed-effect ANOVA models. Methods for evaluating conditional p values are discussed. We present the overall significance levels for several specific two-factor designs. We discuss upper bounds on the overall significance level and extensions of the computational methods to higher-order designs as well as applications to random-effect models and mixed models. PMID- 10091915 TI - Analysis of protein activity data by Gaussian stochastic process models. AB - The effects of certain chemical additives at maintaining a high level of activity in protein constructs during storage is investigated. We use a semiparametric regression technique to model the effects of the additives on protein activity. The model is extended to handle categorical explanatory variables. On the basis of the available data, the important factors are estimated to be buffer, detergent, protein concentration, and storage temperature. The relationships among protein activity and these factors appear to be moderately nonlinear with strong interaction effects. These features are revealed in a data-adaptive way by the semi parametric model, without explicit modeling of the nonlinearities or interactions. We use cross-validation to assess the fit of our model. The protein activity response appears to be extremely erratic. We recommend several sets of storage conditions and that further design points be chosen in regions around these estimated optima. PMID- 10091916 TI - Application of generalized estimating equations to a dental randomized clinical trial. AB - Longitudinal data present statistical problems of interest in clinical trials and epidemiologic studies. In this article, we consider a dental clinical trial in which the outcome measurements are taken on each subject at two follow-up times, and the primary interest is in the dependence of the outcome variable on covariates. The common data structure of these studies is the presence of an intraclass or serial correlation within primary sampling units or subjects. Recently generalized linear models have had extensions to methods for generalized estimating equations that take correlations within primary sampling units into account. We review and apply the Liang-Zeger methodology to a dental clinical trial. In this study, 109 adult male and female volunteers with pre-existing dental plaque were randomized to two mouth rinses (A and B) or a control mouth rinse with double blinding. The major research question in this analysis was: Are the two experimental mouth rinses more effective than the control mouth rinse in inhibiting the development of dental plaque? And if so, what is the effect of baseline plaque measurement? PMID- 10091917 TI - Pilot trial for the assessment of relative bioavailability in generic drug product development: statistical power. AB - In developing generic drug products, pilot trials are used for identifying successful test formulations to enter pivotal trials. In this study, we derive the power function based on the log-normal distribution and evaluate the effects of potential influential factors-the true test-reference ratio, intrasubject variability, and sample sizes-on the statistical power of a pilot trial to identify successful test formulations, defined as the probability that the test reference ratio estimate from a pilot trial falls within a predetermined acceptance range when the true ratio is acceptable. Of these influential factors, the test-reference ratio exhibits the largest impact on the statistical power of a pilot trial, followed by intrasubject variability, sample sizes of pivotal trials, and sample sizes of pilot trials. The sample sizes that are used in pilot trials (8-12 subjects) may be sufficient for test products with low intrasubject variability and true ratio close to 1 and may fall short otherwise. PMID- 10091918 TI - Problematic formulations of SAS PROC.MIXED models for repeated measurements. AB - The work reported in this article was undertaken to evaluate the utility of SAS PROC.MIXED for testing hypotheses concerning GROUP and TIME x GROUP effects in repeated measurements designs with drop-outs. If dropouts are not completely at random, covariate control over informative individual differences on which dropout data patterns depend is widely recognized to be important. However, the inclusion of baseline scores and time-in-study as between-subject covariates in an otherwise well formulated SAS PROC.MIXED model resulted in inadequate control over type I error in simulated data with or without drop-outs present. The inadequate model formulations and resulting deviant test sizes are presented here as a warning for others who might be guided by the same information sources to employ similar model specifications when analyzing data from actual clinical trials. It is important that the complete model specification be provided in detail when reporting applications of the general linear mixed-model procedure. A single random-coefficients model produced appropriate test sizes, but it provided inferior power when informative covariates were added in the attempt to adjust for dropouts. As an alternative, the incorporation of covariate controls in simpler two-stage endpoint or random regression analyses is documented to be effective in dealing with dropouts under specifiable conditions. PMID- 10091919 TI - Effect of solvent on the characteristics of pentamidine loaded microcapsule. AB - Biodegradable microcapsules of pentamidine/poly(L-lactide-co-D,L-lactide) were prepared by solvent evaporation technique using a mixture of organic solvents. The control batch of microcapsules was prepared using dichloromethane. The effect of solvent on the characteristics of pentamidine loaded microcapsules was examined by substituting up to 30% of dichloromethane with acetone, methanol, DMSO, ethyl acetate, and ethanol, respectively. No significant change in the surface morphology was observed when dichloromethane was substituted with 20% or less amount of other solvents. These microcapsules were all porous and spherical. However, the use of 30% DMSO or ethanol, along with dichloromethane, resulted in a mixture of elongated and spherical microcapsules. The efficiency of encapsulation of these two batches was also significantly higher than the other batches of microcapsules. The average particle size of the microcapsules prepared with 30% DMSO (165 microm) was significantly higher than the other batches (< 80 microm). A substitution of 10-30% dichloromethane with other listed organic solvents also showed a significant difference in the initial drug release. The drug release within the first twenty-four hours varied from 4 to 16%. The use of a second organic solvent, except ethanol, resulted in a significantly higher drug release during the second half of the dissolution study. The drug release continued more than 60 days. PMID- 10091920 TI - A study on hydroxyapatite formation on/in the hydroxyl groups-bearing nonionic hydrogels. AB - Using the biomimetic method, we formed a hydroxyapatite (HAp) layer on/in certain types of nonionic hydrogels that contain hydroxyl groups. The hydrogels used were poly(vinyl alcohol) (PVA), poly(2-hydroxyethyl methacrylate) (PHEMA), poly(glucosyloxyethyl methacrylate) (PGEMA), and agarose. Under an optical microscope, we observed a thin, continuous HAp layer on the top surface of the PVA, PHEMA, and PGEMA gels. On the other hand, we only observed an intermittent HAp layer on the surface of the agarose gel. The swelling ratio and the bound water content of these hydrogels were measured as an essential character in HAp formation. There was some relation among the HAp formation, the swelling ratios, and the bound water content. PMID- 10091921 TI - Fixation of femoral shaft osteotomy with an intramedullary composite rod: an experimental study on dogs with a two-year follow-up. AB - A novel composite material with an ultra-high strength and a low elastic modulus called carbon fibre-reinforced liquid crystalline polymer (LCP/CF) has been developed. An experimental diaphyseal osteotomy of the proximal femur in fourteen Beagle dogs was fixed with an intramedullary LCP/CF rod of 4.5 mm in diameter and 80 mm in length. The radiological follow-up intervals were 1, 3, 6, 12, 24, 52, and 104 weeks. Five dogs were killed at 1 year and three dogs at 2 years for histological studies; six dogs were retained for longer follow-up. Radiographs showed an uncomplicated healing of the diaphyseal osteotomy with an external callus formation in all dogs in 12 weeks. Histological analysis revealed a benign host tissue response with few inflammatory cells. Both bone and fibrous tissue were seen at the LCP/CF-host tissue interface. The cross-sectional cortical area of the operated femur was slightly greater than that of the control femur in the 2-year follow-up. LCP/CF showed promising properties for high-load applications. PMID- 10091922 TI - Preparation and characterization of nanoparticles bearing heparin or dextran covalently-linked to poly(methyl methacrylate). AB - Nanoparticles have been obtained directly in aqueous media, from amphiphilic copolymers synthesized by radical polymerization of methyl methacrylate (MMA) initiated by Ce(IV) ions in the presence of heparin or dextran. The reaction conditions under which the copolymers spontaneously formed nanoparticles depended on the type of polysaccharide and on the concentrations of the reagents. Fluorescent nanoparticles containing N-vinyl carbazole (NVC), covalently linked to PMMA, were also prepared by random copolymerization of MMA and NVC in similar polymerization systems. The non-fluorescent nanoparticle suspensions were stable for several months without using surfactant. The fluorescent particles were larger and less stable then the unlabelled ones. Since all the particles are monodisperse, and in the submicron range, they can be used as models of drug carriers; the covalently-linked fluorescent species allowing them to be followed in vivo. The average molecular weights of the PMMA blocks of the copolymers and of oxidized heparin and dextran were determined by viscometry and/or gel permeation chromatography. The antithrombic activity of oxidized heparin was measured. The results show that the polysaccharide chains were cleaved by Ce(IV) in aqueous nitric acid, resulting in formation of block copolymers made of one or two blocks of PMMA linked to the ends of one polysaccharide block. Taken together, the results suggest that the particles were organized with the polysaccharidic moieties on the surface of the particles and the more hydrophobic PMMA or P(MMA-co-NVC) in the core, in a brush-like structure. This should confer 'stealth' properties to such particles. PMID- 10091923 TI - In vitro evaluation of cytotoxicity of a naturally occurring cross-linking reagent for biological tissue fixation. AB - A recognized drawback of the currently available chemical cross-linking reagents used to fix bioprostheses is the potential toxic effects a recipient may be exposed to from the fixed tissues and/or the residues. It is, therefore, desirable to provide a cross-linking reagent which is of low cytotoxicity and may form stable and biocompatible cross-linked products. To achieve this goal, a naturally occurring cross-linking reagent -- genipin -- which has been used in herbal medicine and in the fabrication of food dyes, was used by our group to fix biological tissues. The study was to assess the cytotoxicity of genipin in vitro using 3T3 fibroblasts (BALB/3T3 C1A31-1-1). Glutaraldehyde, the most commonly used cross-linking reagent for tissue fixation, was used as a control. The cytotoxicity of the glutaraldehyde- and genipin-fixed tissues and their residues was also evaluated and compared. The observation in the light microscopic examination revealed that the cytotoxicity of genipin was significantly lower than that of glutaraldehyde. Additionally, the results obtained in the MTT assay implied that genipin was about 10000 times less cytotoxic than glutaraldehyde. Moreover, the colony forming assay suggested that the proliferative capacity of cells after exposure to genipin was approximately 5000 times greater than that after exposure to glutaraldehyde. It was noted that the cells seeded on the surface of the glutaraldehyde-fixed tissue were not able to survive. In contrast, the surface of the genipin-fixed tissue was found to be filled with 3T3 fibroblasts. Additionally, neocollagen fibrils made by these fibroblasts were observed on the genipin-fixed tissue. This fact suggested that the cellular compatibility of the genipin-fixed tissue was superior to its glutaraldehyde fixed counterpart. Also, the residues from the glutaraldehyde-fixed tissue markedly reduced the population of the cultured cells, while those released from the genipin-fixed tissue had no toxic effect on the seeded cells. In conclusion, as far as cytotoxicity is concerned, genipin is a promising cross-linking reagent for biological tissue fixation. PMID- 10091924 TI - Neovascularization effect of biodegradable gelatin microspheres incorporating basic fibroblast growth factor. AB - Biodegradable microspheres were prepared through glutaraldehyde cross-linking of gelatin without using any surfactants as a carrier matrix of basic fibroblast growth factor (bFGF). In the in vitro system, bFGF was sorbed to microspheres of acidic gelatin with an isoelectric point (IEP) of 5.0, but not to those of basic gelatin with an IEP of 9.0. The rate of bFGF sorption to the acidic gelatin microsphere in phosphate-buffered saline solution (pH 7.4) was smaller than that in water. Following incorporation of bFGF into the microspheres at 4 degrees C for 12 h, bFGF release from the bFGF-incorporating microspheres was studied. Approximately 30% of incorporated bFGF was released from the acidic gelatin microsphere within the initial 3 h, followed by no substantial release, whereas the basic gelatin microsphere released almost completely the incorporated bFGF within 1 day. It is likely that when basic bFGF molecules were immobilized to the acidic gelatin constituting microspheres through polyion complexation, they were not readily released under the in vitro nondegradation condition of gelatin. Incorporation of anionic carboxylmethyl cellulose (CMC) into the acidic gelatin microspheres reduced the amount of bFGF desorbed initially. This indicates that the initial burst is ascribed to free bFGF which is not ionically interacted with the acidic gelatin. CMC will function as a bFGF sorbent to suppress the initial leakage from the microspheres. When injected subcutaneously into the mouse back, bFGF-incorporating acidic gelatin microspheres were degraded over time and induced neovascularization around the injection site, in marked contrast to bFGF in the solution form. CMC incorporation slowed down the biodegradation and vascularization effect of bFGF-incorporating gelatin microspheres. It was concluded that the gelatin microsphere was a promising carrier matrix of bFGF to enhance the vascularization effect. PMID- 10091925 TI - Cytomimetic biomaterials. 3. Preparation and transport studies of an alginate/amphiphilic copolymer/polymerized phospholipid film. AB - The significance of molecular design methodologies based upon membrane-mimetic systems lies in the ability to engineer robust materials of varying geometry with a high degree of reproducibility and molecular control over surface order and chemistry. However, non-covalently associated assemblies, in and of themselves, are often insufficiently robust for many applications. We have previously reported the in situ polymerization of a single phospholipid monolayer on a self assembled film of octadecyltrichrolosilane (OTS) on glass, as well as the polymerization of phospholipids on an amphiphilic, dialkyl-containing terpolymer bound to a gold-coated silicon wafer. We now report the polymerization of a phospholipid monolayer assembly onto an alkylated hydrogel substrate with significant alteration in both surface chemistry and mass transport properties at the hydrogel-water interface. A general platform is thereby created for enhancing the control of either the local delivery of specific macromolecules or the immunoisolation barrier for many cell based therapies. PMID- 10091926 TI - A potential cell affinity sorbent: fibronectin carrying poly(EGDMA/HEMA) microbeads. AB - Both non-swellable and swellable poly(EGDMA/HEMA) microbeads were produced by suspension copolymerization. These microbeads were modified by immobilization of a spacer-arm (hexamethylene diamine, HMDA) and fibronectin. The optimal values for modifications were as follows: the sodium periodate concentration 1.0 mg ml( 1); the HMDA concentration 4 mg ml(-1); and the glutaraldehyde concentration 0.070 microg ml(-1). Adsorption of fibronectin onto the plain and periodate oxidized poly(EGDMA/HEMA) microbeads were very similar, and were 0.025-0.035 mg fibronectin per g polymer, respectively. Fibronectin immobilization on poly(EGDMA/HEMA) microbeads were studied at different temperature, time and pH using single protein solution containing different amount of proteins. The optimal values for immobilizations were as follows: the initial fibronectin concentration 0.1 mg ml; temperature + 25 degrees C; pH 7; the immobilization time 120 min. Both fibroblastic 3T3 and epithelial MDBK cells were attached to these unmodified and modified microbeads. The attachments of both 3T3 and MDBK cells, especially to the fibronectin-immobilized swellable microbeads, were very high. Almost 96% of the 3T3 cells available in the cell culture medium did attach to these microbeads (2345 +/- 98 cells per mg of polymer). PMID- 10091927 TI - Effect of cross-link density and hydrophilicity of PU on blood compatibility of hydrophobic PS/hydrophilic PU IPNs. AB - To investigate the effect of the hydrophilic and hydrophobic microdomain structure on blood compatibility, a series of interpenetrating polymer networks (IPNs) composed of hydrophilic polyurethane (PU) and hydrophobic polystyrene (PS) was prepared. One series was prepared with varying cross-link densities of each network, the other with varying hydrophilicity of the PU component. All PU/PS IPNs exhibited microphase-separated structures that had dispersed PS domains in the continuous PU matrix. The domain size decreased with decreasing the hydrophilicity of the PU component and increasing the cross-link density of each network. As the cross-link density and hydrophobicity of the PU component was increased, an inward shift of Tgs was observed, which was due to the decrease in phase separation between the hydrophobic PS component and hydrophilic PU component. In the in vitro platelet adhesion test, as the microdomain size of PU/PS IPN surface decreased, the number of adhered platelets on the PU/PS IPN surface was reduced and deformation of the adhered platelets decreased. It could be concluded that blood compatibility of PU/PS IPN was mainly affected by the degree of mixing between PU and PS component, which was reflected by the domain size of PS rich phase. PMID- 10091928 TI - Parameters affecting cellular adhesion to polylactide films. AB - Absorbable biomaterials have been recently incorporated into the field of tissue engineering. Little work has been performed, even with the clinically acceptable absorbables, concerning their tissue promoting capability or lack, thereof. Furthermore, the relative attractions of cells to these implants may be largely disguised by the presence of serum. This research involved the development of an adhesion assay to compare the adhesion behavior of two cell types to two different polylactides in a serum free environment. The results showed that the attachment behavior depends not only on the cell or the polymer but a combination of the two. PMID- 10091929 TI - The role of fibronectin in platelet adhesion to plasma preadsorbed polystyrene. AB - Platelet adhesion to synthetic surfaces that come in contact with blood is mediated by the adsorption of adhesive plasma proteins, especially fibrinogen. However, the roles of other adhesive proteins, such as fibronectin, vitronectin, and von Willebrand factor in platelet adhesion are not yet clear. In this study, the role of fibronectin in platelet adhesion to surfaces was assessed using three approaches. First, platelet adhesion was measured on Immulon I preadsorbed with fibronectin-depleted plasma or fibronectin-depleted plasma replenished with increasing amount of fibronectin. Under these conditions, fibronectin adsorbed from plasma did not have any effect on platelet adhesion, while fibrinogen played a major role in mediating platelet adhesion. Since fibronectin might play a role in platelet adhesion to surfaces which adsorb little or no fibrinogen, we also used two other strategies to assess the potential role of fibronectin. One was to use platelets treated with a platelet activation inhibitor, prostaglandin E1, which prevents the activation of platelet fibrinogen receptor GP IIb/IIIa. The adhesion of prostaglandin E1-treated platelets to Immulon I preadsorbed with plasma was greatly decreased compared to that of untreated platelets, but was increased by the addition of supernormal concentrations of fibronectin to the plasma. This suggests that GP Ic/IIa, rather than GP IIb/IIIa, might be the platelet receptor which is responsible for platelet adhesion to surface-bound fibronectin. Finally, we studied the effect of fibronectin on platelet adhesion to surfaces preadsorbed with fibronectin-depleted afibrinogenemic plasma. We found that fibronectin re-addition to fibronectin-depleted afibrinogenemic plasma increased platelet adhesion. However, our most important finding was that fibronectin seems to play little or no role in mediating platelet adhesion to polystyrene surfaces preadsorbed with normal plasma. PMID- 10091930 TI - Insulin release from islets of Langerhans entrapped in a poly(N isopropylacrylamide-co-acrylic acid) polymer gel. AB - A copolymer of N-isopropylacrylamide (98 mol% in feed) and acrylic acid, poly(N isopropylacrylamide-co-acrylic acid) (P(NIPAAm-co-AAc)), was prepared by free radical polymerization for development of a thermally reversible polymer to entrap islets of Langerhans for a refillable biohybrid artificial pancreas. A 5 wt% solution of the polymer in Hanks' balanced salt solution forms a gel at 37 degrees C that exhibits no syneresis. Diffusion of fluorescein isothiocyanate (FITC) dextrans having molecular weights of 4400 and 70000 were used to evaluate mass transport in the gel at 37 degrees C. Insulin secretion from islets in the polymer gel was also investigated in both static and dynamic systems. The polymer gel exhibited excellent diffusion of FITC dextran 4400 and FITC dextran 70000 with diffusion ratios, D/D0 (ratio of diffusion in the gel to diffusion in water), of 0.20+/-0.04 and 0.35+/-0.17, respectively. Human islets entrapped in the polymer gel showed prolonged insulin secretion in response to basal (5.5 mM) glucose concentration compared to free human islets. Rat islets showed prolonged insulin secretion in response to high (16.5 mM) glucose concentrations compared to free rat islets. Rat islets in the polymer gel maintained insulin secretion in response to the higher glucose concentration for over 26 days. Rat islets entrapped by the polymer also released higher quantities of insulin more rapidly in response to changes in concentrations of glucose and other stimulants than rat islets entrapped in an alginate control. These results suggest that this material would provide adequate diffusion for rapid insulin release in an application as a synthetic extracellular matrix for a biohybrid artificial pancreas. PMID- 10091932 TI - Cell interactions with perfluoropolyether-based network copolymers. AB - We have investigated the potential of several polymers based on perfluoropolyether (PFPE) macromonomers for use in biomaterial applications. Polymer networks were synthesised from the PFPE macromonomers of increasing chain length and the adhesion and proliferation of corneal, vascular and bone cells was evaluated on these polymers. The polymer surfaces were quite hydrophobic, having sessile air-water contact angles ranging between 96 and 125 degrees. However, these polymers supported the attachment and growth of bovine corneal epithelial and endothelial cells and fibroblasts at 60-100% of the rate of cell growth on the culture substratum, TCPS. Furthermore, the PFPE polymers supported the attachment and growth of vascular endothelial cells (from human umbilical artery) and human bone-derived cells over a 7 day period at an equal level to TCPS. The relationship between the macromonomer chain length (n = 1 to 4) and the ability of the resulting PFPE homopolymer to support the overgrowth of corneal epithelial tissue was also evaluated. The PFPE-containing polymers supported corneal epithelial tissue overgrowth, with the most effective having a performance equivalent to that of TCPS. In addition to these homopolymers, copolymers comprising of PFPE and N,N-dimethylaminoethyl methacrylate (DMAEMA) were also synthesised. Surprisingly, the addition of DMAEMA to the PFPE polymer network lead to a reduction in the growth and attachment of corneal epithelial cells and fibroblasts. These results indicate that PFPE-based materials show a potential for use in the development of biomaterials in the ocular, vascular and orthopaedic areas. PMID- 10091931 TI - The effect of polymeric chemistry on the expression of bone-related mRNAs and proteins by human bone-derived cells in vitro. AB - This study used human bone-derived cells (HBDC) grown on two defined polymeric substrata to examine the effect of substrata chemistry on the expression of mRNAs and proteins characteristic of the osteoblastic phenotype. The growth profile of cells grown on tissue culture polystyrene (TCP) was exponential whereas for those seeded on polyethyleneterephthalate (PET) there was a pronounced lag period before cellular multiplication. The temporal expression pattern of mRNAs in HBDC cultured on TCP was similar to that of cells on PET. On TCP, the levels of several mRNAs peaked at day 4, as cellular proliferation slowed. In contrast, the induction in mRNA levels in cells grown on PET corresponded to maximum mitotic activity. There appears to be sequential cascade in protein expression in cells grown on TCP with overlapping peaks of thrombospondin (Tsp), osteocalcin (OC) and osteopontin (OP) expression. In contrast, peak intracellular protein expression levels for Tsp, OC and OP did not overlap when cells were grown on PET. PMID- 10091933 TI - Transient adhesion of platelets in pump-oxygenator systems: influence of SMA and nitric oxide treatments. AB - We employed gamma scintigraphy to quantify the transient accumulations of platelets in pump-oxygenator systems employed in cardiopulmonary bypass (CPB). A flat sheet microporous polypropylene membrane oxygenator (Cobe Duo) was employed, with and without siloxane/caprolactone oligomer coating (SMA) (n = 8 each). The effect of nitric oxide gas infusion on platelet deposition was also evaluated for the uncoated Cobe Duo system (n = 10 each). Scintigraphic images of radiolabelled cells were obtained and converted to numbers of all platelets, labeled and unlabeled, adhering to the pump and oxygenator surfaces. These numbers were compared, by study group, for a 90-min period of normothermic CPB in the adult pig, employing standard prime and anticoagulation regimens. Platelets adhered in large numbers to control oxygenators, reaching maxima (> 20% of the circulating platelet mass) 30 min following institution of CPB, and decreasing for the duration of CPB. SMA treatment significantly decreased platelet adhesion following a 5-10-min transient accumulation period. Nitric oxide infusion significantly reduced platelet adhesion throughout the CPB period. Platelet accumulations on the high fluid shear centrifugal pump surfaces increased monotonically to maxima at about the same time as for the oxygenators, but did not decrease thereafter. Higher platelet surface densities were observed on the centrifugal pump surfaces than on the oxygenator surfaces. CPB with the untreated circuit tended to reduce circulating platelet counts vs theoretical values based on hemodilution alone. In contrast, SMA significantly increased the circulating platelet count versus the untreated control group. These results indicate that platelet adherence to the foreign surfaces of CPB equipment are influenced in characteristic ways by time and fluid shear. SMA treatment and nitric oxide infusion both reduce platelet adhesion to oxygenator surfaces. SMA treatment spares these cells for the circulation. PMID- 10091934 TI - Wear debris and cytokine production in the interface membrane of loosened prostheses. AB - In this study, thirty-nine patients were examined. All of them suffered from hip joint prostheses loosening and underwent revision surgery. Bioptic samples were collected at the interface between bone and implant either at the stem or cotyle level. Immunohistochemistry was performed to detect IL-1alpha, IL-1beta, IL-6 and TNF, cytokines that directly cause bone resorption and indirectly induce synthesis of other bone resorbing cytokines. Quantitative analysis of the positive cells and correlation with clinical data was performed. It resulted that there is a great variability in positive cells for cytokines according to the harvest site; anyway, cytokines tend to be higher in patients carrying a joint prosthesis with polyethylene acetabular component and it is associated with plastic wear particles, even though there is no direct correlation between wear amount and cytokine levels. There is a statistically significant negative correlation between metal wear and a cytokine (IL-6); cytokines levels do not depend on the implant time to failure and do not correlate with pain score. As expected, cytokines levels tend to be lower in subjects being treated with non steroidal antiinflammatory drugs. It can be concluded that plastic wear is the factor inducing the highest cytokine levels in the tissues around the prosthesis at the interface; cytokines that are an indicator of osteolysis risk. PMID- 10091935 TI - Angiogenic capacity and lung-colonizing potential in vivo is increased in weakly metastatic B16F1 cells and decreased in highly metastatic BL6 cells by phorbol esters. AB - The development of tumor metastasis is a multistep process. Key aspects of this process are the interaction of tumor cells with the extracellular matrix, digestion of, and motility through the basement membrane and the induction of angiogenesis. In this study, we analysed the effects of a low dose of TPA (12 tetradecanoylphorbol-13-acetate; 0.1 microM on angiogenesis, proteolytic activity and lung colonizing potential of both weakly metastatic B16F1 cells and highly metastatic BL6 murine melanoma cells. Our results demonstrated opposite effects of TPA in the two cell lines. TPA-treated B16F1 cells showed enhanced release of basic FGF (bFGF) and vascular endothelial growth factor (VEGF) and increased angiogenic capacity and lung colony formation in vivo. In contrast, TPA-treated BL6 cells demonstrated a dramatic reduction of angiogenic and gelatinolytic activity and metastatic capacity. However, both cell lines showed an induction of VEGF as well as bFGF expression by TPA treatment suggesting that in BL6 cells antagonistic factors, inhibiting the angiogenic and metastatic capacity, are induced by this treatment. PMID- 10091936 TI - Diminution of the development of experimental metastases produced by murine metastatic lines in essential fatty acid-deficient host mice. AB - In a previous study we found that the capacity for spontaneous metastases of tumors developed after subcutaneous transplantation of RSV-transformed Balb/c 3T3 cells was reduced in essential fatty acids (EFA)-deficient host animals. In the present study, we have extended our investigation by considering the requirement of EFA for the formation of lung colonies obtained by i.v. injection of two metastatic murine cell lines of different origin: (1) T3 cells, a highly metastatic cell line isolated from a fibrosarcoma, and (2) the F10 variant of B16 melanoma (B16-F10 cells). We found that EFA deficiency reduces the lung colonization of both T3 cells and B16-F10 cells without affecting the retention of tumor cells in the lung. NK cells did not seem to be involved in the diminution of lung colonization in EFA-deficient animals. Furthermore, by examining histologically the lung parenchyma at successive intervals after tumor cell injection, we found that, in comparison with control mice, EFA-deficient animals had fewer lung colonies and a prevalence of smaller microcolonies during the entire period of observation. This led us to conclude that the diminution in development of tumor colonies in the lungs of EFA-deficient host animals was related to a reduced growth rate of tumor cells at this site. PMID- 10091937 TI - Functional consequences of cyclin D1 overexpression in human mammary luminal epithelial cells. AB - The proliferation of eukaryotic cells is primarily regulated by a decision made during the G1 phase of the cell cycle as to remain in the cycle and divide, or to withdraw from the cycle and adopt a different cell fate. During this time, environmental signals, which regulate the synthesis of the G1 cyclins, are coupled to cell division. In this context, mammalian D-type cyclins have been shown to control progression through the G1 phase of the mammalian cell cycle. Specifically, cyclin D1 has been reported frequently to be amplified, over transcribed and overexpressed in human breast carcinomas. Although the effects of cyclin D1 overexpression have been examined in human breast carcinoma cell lines, the biological consequences of cyclin D1 expression in normal human mammary epithelial cells remain to be elucidated. In this study we have stably over expressed cyclin D1 in human mammary luminal epithelial cells in order to more directly address the role of cyclin D1 in cell cycle control and tumorigenesis of the human breast. Here, we demonstrate that the effect of cyclin D1 overexpression in these cells is to reduce their growth factor dependency, as well as shorten the duration of G1 and correspondingly reduce the mean generation time. Collectively, our data indicate that deregulation of cyclin D1 expression in human mammary epithelial cells can provide a growth advantage and hence contribute to the oncogenic potential of these cells. PMID- 10091939 TI - Expression and function of the high affinity alphaIIbbeta3 integrin in murine melanoma cells. AB - In resting platelets integrin alphaIIbbeta3 is constitutively expressed in an inactive state and it does not recognize soluble proteins. Platelet activation results in a conformational change of the low-affinity alphaIIbbeta3 to a high affinity state which then recognizes plasma fibrinogen. The ectopic expression of alphaIIbbeta3 integrin in rodent and human cells derived from solid tumors is well documented, although little is known about its affinity state in these tumor cells. In this study we analysed expression and function of high-affinity alphaIIbbeta3 in murine metastatic melanoma B16a cells by using a mAb that specifically recognizes high-affinity alphaIIbbeta3 (PAC-1). These tumor cells while in suspension bound PAC-1 and fibrinogen. Immunofluorescent studies of B16a cells indicated that high-affinity alphaIIbbeta3 is associated with the Golgi complex and the cell surface. Stimulation of B16a cells with a PKC-activator, 12(S)-HETE, induced translocation of the high-affinity integrin from an intracellular pool to the plasma membrane, which resulted in increased tumor cell adhesion to fibronectin. In addition to participating in 12(S)-HETE-stimulated adhesion of B16a cells, the high-affinity alphaIIbbeta3 integrin is also involved in tumor cell invasion through a reconstituted basement membrane. In conclusion, results from this study suggest that in non-megakaryocytic lineage B16a cells alphaIIbbeta3 is constitutively expressed in a high-affinity state, and that this conformation participates in tumor cell adhesion and invasion. PMID- 10091938 TI - Integrin alpha5beta1: a potent inhibitor of experimental lung metastasis. AB - The integrin alpha5beta1 seems to be the most relevant receptor of tumor cells for binding to fibronectin. Although numerous studies suggest a role of tumor cell fibronectin interaction in tumor metastasis, differential integrin expression on tumor cells has, however, not been correlated with metastatic capabilities. We addressed this question by transfection of the integrin alpha5beta1 cDNA into HT-29 human colon carcinoma cells which led to de novo expression of functional integrin alpha5beta1. Similar to other reports, expression of the integrin alpha5beta1 in HT-29 tumor cells exerted an inhibitory action on cell proliferation as indicated in our study by formation of fewer colonies in soft agar. The tumor growth inhibitory property of the integrin alpha5beta1 was also shown by reduction of subcutaneous xenograft growth in nude mice to approximately 50% of that of control transfectants. For the first time, we found that several clones of integrin alpha5 subunit transfectants displayed dramatically reduced formation of lung colonies and cutaneous metastasis after intravenous injection into nude mice. While most animals inoculated with control transfectant cells formed macroscopically visible lung colonies ranging from 12.6 +/- 2.6 to 22.0 +/- 6.6 (mean colony number +/- SEM), mice inoculated with HT-29 cell clones expressing the integrin alpha5beta1 were almost completely free of lung colonies (ranging from 0.0 +/- 0 to 0.2 +/- 0.1). Our results imply that integrin alpha5beta1 expression inhibits circulating tumor cells in pursuing late steps of the metastatic process as represented by the artificial metastasis (lung colonisation) model. PMID- 10091940 TI - Multiple effects of transfection with interleukin 2 and/or interferon gamma on the behavior of mouse T lymphoma cells. AB - We have previously reported that transfection of mouse interferon gamma (IFN gamma) in H-2Kk-positive BW variants (BW-Sp3) abolishes tumorigenicity and reduces metastatic capacity. To further increase the immunogenicity of BW-Sp3 cells, the gene for human interleukin 2 (huIL-2) was transfected in these cancer cells. Single BW-Sp3(huIL-2) and double BW-Sp3(huIL-2+IFN-gamma) transfectants were generated and their behavior was investigated as compared to parental and IFN-gamma-transfected BW-Sp3. Although expression of huIL-2 was equally effective as IFN-gamma in preventing tumor formation and reducing experimental metastasis, it did not confer protection to spontaneous metastases and even reversed the anti metastatic activity of IFN-gamma. Inoculation of the BW variants in immunocompromised mice revealed that expression of IL-2 activates both T cells and aspecific immune effectors. However, in immunocompromised mice a clear pro metastatic effect of IL-2 was recorded. Analysis of membrane antigens on the different variants showed a selective effect of huIL-2 on the expression of two surface antigens, i.e. L-selectin and metastatic T cell hybridoma antigen (MTH), which may contribute to metastasis. Hence upon expression of huIL-2 in T lymphoma variants, tumor outcome will depend on the balanced effects of the transfected cytokines on the immune response and the redirected effect on tumor progression. PMID- 10091941 TI - Alterative expression of the collagenase and adhesion molecules in the highly metastatic clones of human colonic cancer cell lines. AB - Human colonic carcinoma cell lines, KM12C, KM12SM and KM12L4, were previously established and their in vivo metastatic potentials have been well evaluated. The highly metastatic cell lines KM12SM and KM12L4 were derived from the parental low metastatic cell line KM12C in vivo. To evaluate the metastatic behavior of these cell lines in vitro, we examined colony formation on monolayers of the pulmonary arterial endothelial (CPAE) cells. On day 4, the highly metastatic cell lines showed an approximately 2-fold increase in number of colonies on CPAE cell monolayers relative to the parental KM12C cell line. To investigate what evidence is correlated with their metastatic and invasive abilities, Northern blot analysis and flow cytometry were performed in all cell lines. According to the results of Northern blot analysis, the levels of matrix metalloproteinase (MMP)-2 and c-met mRNA expression were increased in highly metastatic cell lines as compared with the parental cell line. We also examined the cell-surface expression of several adhesion molecules by flow cytometry. The levels of expression of sialyl Lewisa antigen (sLe(a)) in KM12SM and KM12L4 were twice higher than that in KM12C. However, the levels of expression of E-cadherin in KM12SM and KM12L4 were decreased to half that in KM12C. The alterative expression of the collagenase and adhesion molecules might contribute to their metastatic/invasive abilities of these cell lines both in vivo and in vitro. PMID- 10091942 TI - Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. AB - The DNA methylation status of the metastasis-associated S100A4 gene in S100A4 positive and -negative human colon adenocarcinoma cell lines was examined. Northern and Western blot analyses revealed that HT-29, SW480, SW620, WiDr and Colo201 cells expressed S100A4, whereas SW837, LoVo and DLD-1 cells expressed little S100A4. Using CpG methylation-sensitive and -insensitive restriction enzymes and PCR-based methylation assay, it was found that the S100A4 gene in HT 29, SW480, SW620, WiDr and Colo201 cells, but not in SW837, LoVo and DLD-1 cells, was hypomethylated and that the hypomethylation of the second intron was correlated well with the expression of S100A4. 5-Aza-2'-deoxycytidine, an inhibitor of the eukaryotic DNA methyltransferase, induced the expression of the S100A4 gene in SW837, LoVo and DLD-1 cells, while it showed no effect on the expression of the gene in WiDr cells. These results indicate that hypomethylation of the S100A4 gene results in the expression of the gene in colon adenocarcinoma cells. PMID- 10091943 TI - Use of tumor lines with selectable markers in assessing the effect on experimental metastases of combination chemotherapy with alkylating agents. AB - High-dose chemotherapy with a 3-day regimen of cyclophosphamide, cisplatin, and carmustine was used to treat mice bearing experimental lung metastases of mammary tumor cell lines with selectable markers (lines 66cl4 and 4TO7). Cloning of lung cells at various times after treatment revealed a rapid 3 to 4 log loss of clonogenic tumor cells, down to undetectable levels. However, after several weeks, clonogenic tumor cells reappeared in the lungs; few cures were obtained even when mice had a relatively low tumor burden when treated with chemotherapy. Splenocyte numbers and response to Concanavalin A indicated a transient immunosuppression. In one experiment, mice were treated with a second round of chemotherapy 3 weeks after the first. The number of clonogenic cells per lung again dropped, but regrowth of cells was rapid, and no cures were obtained. Inoculation of tumor-bearing mice s.c. after chemotherapy with lethally irradiated cells of the highly immunogenic tumor cell line 4TO7-IL-2 had little effect on the rate of reappearance of line 4TO7 in lungs, but subsequent growth of tumor cells in lungs was slowed. This model system can be used to test the efficacy of additional immunotherapy and chemotherapy regimens on minimal residual metastatic disease after high-dose chemotherapy, when remaining metastatic cells are apparently dormant. PMID- 10091944 TI - Interaction of glycated albumin-gold complexes with mouse brain microvascular endothelium. AB - The main objective of this study was to obtain new information about the structural aspects of the enhanced brain uptake of blood-borne glycated albumin observed recently by authors using quantitative, biochemical methodology. Bovine serum albumin glycated in vitro by progressive accumulation of advanced glycosylation end products complexed with colloidal gold (AGE-BSA-G) was used. Mice received a bolus injection of this complex into the common carotid artery and were killed after 3, 15, and 30 minutes. The samples of brain, heart muscles, and liver were processed for transmission electron microscopy. Control mice received injections of native BSA-G complexes. The results indicate the following. (1) Glycation of albumin molecules results in enhanced binding of AGE BSA-G complexes to the luminal surface of brain microvascular endothelium, which is most pronounced at the earliest times (3 minutes). At later time points, the concentration of circulating complexes decreases rapidly, and some adsorbed particles are endocytosed and internalized in endosomes or multivesicular bodies. Only a few gold particles were found (at 15 minutes) in perivascular neuropil, suggesting their negligible transvascular passage. (2) Presumably as a result of the competition of blood plasma albumin, BSA-G complexes were almost not adsorbed or internalized. (3) Circulating AGE-BSA-G complexes were phagocytosed rapidly in liver sinusoids, mainly by reticulo-endothelial cells. They also were endocytosed and transcytosed by heart capillary endothelia and by fenestrated endothelia of the brain circumventricular organs. The binding of AGE-BSA-G complexes suggests the presence of receptors for AGE on the surface of the brain microvascular endothelium. However, the presence of these receptors presumably is not sufficient for making the blood-brain barrier fully permeable for circulating complexes. PMID- 10091945 TI - CD56(NCAM) antigen in glandular epithelium of human thyroid: light microscopic and ultrastructural study. AB - CD56 antigen, an isoform of the neural cell adhesion molecule (NCAM) was previously found by us in human thyroid by APAAP immunohistochemistry in light microscopy on frozen tissue sections. In the current study, it was attempted to trace the antigen in question using another light microscopic immunohistochemical procedure and to validate the results at the ultrastructural level. For light microscopy, cryostat sections of 12 surgical samples of human thyroid were subjected to ABC (preformed avidin-biotin-peroxidase complex) method. For immunoelectron microscopy, immunoperoxidase reaction was carried out on prefixed, small thyroid tissue blocks. Following preliminary inspection of semithin sections, ultrathin sections were examined in the transmission electron microscope. ABC reaction revealed distinct specific CD56 staining of thyrocyte cell membranes. The staining was weak or absent in thyroid papillary carcinoma cells. The results were confirmed in semithin sections by indirect immunoperoxidase. The latter reaction in ultrathin sections at the ultrastructural level has shown that specific reaction product was confined to free and lateral surfaces of thyroid follicular cells. Endothelial cell membranes of thyroid capillary vessels were totally devoid of the reaction product. The reaction was weakly positive in thyroid follicular and papilllary carcinomas but absent from medullary carcinoma. PMID- 10091946 TI - Changes in expression of pRb, p16 and cyclin D1 in non-small cell lung cancer: an immunohistochemical study. AB - Aberrations in the pathway composed of p16, cyclin D1/CDK4,6 and pRb (pRb pathway) which controls the transition from G1 to S phase occur frequently in various types of tumors. In the present study we analyzed immunohistochemically the expression of pRb, p16 and cyclin D1 in 1 12 primary non-small cell lung carcinomas (NSCLC). Loss of expression of pRb and p16 proteins was demonstrated in 15/112 cases and 64/112 cases, respectively. Inverse expression of pRb and p16 proteins was observed in 61 cases and was statistically correlated with advanced stage of the disease (p=0.03). Overexpression of cyclin D1 was detected in 34 cases and was more frequently observed in stage I than in stage III of the disease (p=0.02). Concomitant overexpression of cyclin D1 and lack of p16 was observed in 57% of cyclin D1-positive tumors. In summary, 82 of 112 analyzed cases showed an aberrant expression of at least one of the investigated proteins. These results indicate that although pRb protein expression is altered only in a small percentage of NSCLCs, the pRb pathway is disrupted very frequently in this type of tumor. There were no statistically significant correlations between changes in protein expression and histological type of tumor, gender, smoking habits and occupation of patients. PMID- 10091947 TI - Flow cytometric evaluation of lymphocyte subpopulations in BALF of healthy smokers and nonsmokers. AB - The purpose of this work was to evaluate the normal lymphocyte phenotype in the bronchoalveolar lavage fluid (BALF). BAL was carried out in 12 untreated healthy nonsmoking volunteers and in 9 cigarette smokers. For the analysis of lymphocyte subsets by two-color flow cytometry, the monoclonal antibodies used were directed anti: CD3, CD4, CD8, CD16, CD19, D25, CD45, CD56 and anti HLA-DR. An increase in the total number of cells in BALF of smoking persons and increased proportion of macrophages was observed. The percentage of CD8+ lymphocytes was 1.7 times higher, whereas the proportions of CD4+ cells, and a CD4+/CD8+ ratio were lower 1.5 and 2.6 times, respectively, in the BALF of cigarette smoking persons when compared with nonsmoking volunteers. The changes did not depend on the age of the person. In conclusion, we suggest that the decreased CD4/CD8 ratio and the elevated CD8 T cell subset may be regarded as a potential risk factor associated with clinically asymptomatic lung cancer. Moreover, in the interpretation of BALF from patients with pulmonary diseases cell proportions of nonsmoking and of smoking persons should be compared with the respective controls. PMID- 10091948 TI - Effect of Spumol K on the ultrastructure of Aspergillus niger strains sensitive or resistant to toxic compounds of beet molasses. AB - Aspergillus niger strains sensitive and resistant to toxic compounds of beet molasses grown in the presence of Spumol K were the object of the present studies. The antifoamer used diminished the number of mitochondria in both groups of strains and caused the reduction of their cristae in the sensitive ones. The disturbances in the ultrastructure of nucleus and mitochondria appeared mostly in sensitive strains. On the other hand, Spumol K presence in resistant strains not only increased the number of deposits of electron dense material in mitochondria, vacuoles, cytoplasm and in nuclear envelope but also was responsible for multivesicular body formation. The differences also existed in the ultrastructure of the cell wall: in the sensitive strains treated with Spumol K, the cell wall was completely deprived of fibrillar component, only granular component was present. In the resistant strains, granular component dominated, although fibrillar one was still visible. The present studies suggest that antifoamer in resistant strains becomes inactivated in different cell compartments, therefore its toxicity is lower than in sensitive strains where defence mechanism, inactivating toxic substances, is weaker and toxicity stronger. PMID- 10091949 TI - Senescence vs. changes in nuclear DNA, protein and dry mass contents in leaf mesophyll of two species differing in occurrence of endomitotic polyploidy. AB - DNA and Naphtol yellow S-staining (F-NYS) protein contents were measured cytophotometrically using the Feulgen method in the nuclei of the mesophyll from the basal and apical zone of young and old leaves in two perennial monocotyledonous species: Rhoeo discolor and Clivia miniata, differing in presence or absence of DNA endoreplication. Dry mass content was determined interferometrically using an uniform field with large image shearing method. It has been shown that nuclei with 2C DNA and below 2C DNA content dominate in old leaves. The decrease in dry mass content of nuclei correlated with the decrease in NYS protein content. Parallelly a significant increase in NYS protein and DNA contents observed in chromocenters Rhoeo discolor was proportional to the increase in their dry mass. The decrease in nuclear DNA content in mesophyll of old leaves in endoreplicating species was the same as in non-edoreplicating one, however the senescence was more intensive in endoreplicating species. PMID- 10091950 TI - GA3 content in antheridia of Chara vulgaris at the proliferative stage and in spermiogenesis estimated by capillary electrophoresis. AB - In male sex organs of Chara vulgaris L., the gibberellic acid (GA3), was identified by capillary zone electrophoresis. The antheridia at cell division stage of antheridial filaments leading to formation of spermatids contain 0.09 microg GA3 per antheridium, i.e. 5.3 times more than antheridia at differentiation stage of spermatozoids (spermiogenesis). Spermiogenesis is not regulated by gibberellins. PMID- 10091951 TI - An examination of ALDH2 genotypes, alcohol metabolism and the flushing response in Native Americans. AB - OBJECTIVE: The study was designed to examine the relationship between aldehyde dehydrogenase (ALDH2) genotype and the flushing response in a population of Native Americans. METHOD: Objective measures of the flushing response were obtained by monitoring skin temperature, heart rate, blood pressure, as well as blood alcohol concentrations, in flushing and nonflushing Native Americans (n = 105) as well as in Oriental (n = 15) and white (n = 15) control subjects following a dose of alcohol (0.2 or 0.4 gm/kg). ALDH genotypes were determined via polymerase chain reaction followed by hybridization to 32P or biotin-labeled allele-specific oligonucleotide probes. RESULTS: There were no ALDH2 mutations detectable in Native Americans reporting the flushing response, nor any objective evidence of an Oriental-like response to alcohol. The rate of alcohol metabolism was shown to be the same among whites, Native flushers and Native nonflushers. CONCLUSIONS: The results demonstrate that the flushing reaction experienced by Native Americans appears to be milder and less unpleasant than the "Oriental" flushing reaction, with little effect on drinking frequency and amount. In addition, the flushing is not mediated by the ALDH2 mutation or elevated blood acetaldehyde. A critical analysis of the discrepancies in the literature regarding alcohol metabolism in Native Americans is provided. PMID- 10091953 TI - Differences in ethanol sensitivity and acute tolerance between UChA and UChB rats. AB - OBJECTIVE: In order to learn more about the genetic factors that determine the different responses to ethanol that contribute to the voluntary consumption of ethanol, this study examines the sensitivity to a nonnarcotic dose of ethanol (2.3 g/kg IP) of rats genetically selected for their low (UChA) and high (UChB) ethanol voluntary consumption. METHOD: Sensitivity was evaluated by studying both ethanol-induced (2.3 g/kg) motor impairment in a modified tilting-plane test and hypothermia. Blood ethanol concentration obtained after the ethanol dose and the correlation between ethanol sensitivity and voluntary ethanol consumption were also studied. RESULTS: Results obtained with both tests revealed that UChB rats were less sensitive to ethanol than UChA ones. The genetic difference in motor impairment appeared not to be the result of different blood ethanol levels. Furthermore, rats of both strains recovered motor activity when blood ethanol was at the highest level, indicating the development of acute tolerance. The acute tolerance appeared to develop in shorter time in UChB than in UChA rats. In contradistinction, time course of hypothermia was significantly related to that of blood ethanol. A significant correlation between motor impairment and ethanol voluntary consumption (p<.001) was obtained. CONCLUSIONS: The difference in motor impairment reported here might be related to differences between the strains in the ability to develop acute tolerance to ethanol. Acute tolerance development appears to be positively correlated to voluntary ethanol consumption by the rat. PMID- 10091952 TI - Alcohol dependence and conduct disorder among Navajo Indians. AB - OBJECTIVE: The purpose of this study is to examine the association between conduct disorder before age 15 and subsequent alcohol dependence, and to describe the lifetime prevalence of alcohol dependence among Navajo Indian women and men. METHOD: This was a case-control design which included both men (n = 735) and women (n = 351) and in which the Diagnostic Interview Schedule was used for the diagnosis of the lifetime history of alcohol dependence and conduct disorder. Alcohol dependent cases were selected from inpatient and outpatient treatment programs (204 men, 148 women). Whenever possible, controls were matched for age, sex and community of residence and were randomly selected and interviewed until a nonalcohol dependent individual was found. Among the men, there were 374 alcohol dependent controls and 157 nonalcohol dependent controls. Among the women, the figures were 60 and 143, respectively. When combined, the controls comprise samples of the adult male and female populations from which estimates of lifetime prevalence of alcohol dependence, and of the amount of alcohol dependence in the population attributable to conduct disorder, may be inferred. RESULTS: Conduct disorder is a risk factor for alcohol dependence among both men and women. Lifetime prevalence of alcohol dependence in this population is high (70.4% for men and 29.6% for women), but the amount of alcohol dependence in the population attributable to conduct disorder is low. On the other hand, among the alcohol dependent, those with conduct disorder had the most severe alcohol- and nonalcohol-related problems. CONCLUSIONS: The potential limitations of the study are those common to case-control designs, especially biased recall by cases. There are also potential sampling biases among the controls. It is shown that none of the potential biases invalidate the findings, which support the hypothesis that in this population conduct disorder is a risk for alcohol dependence. The implications for primary prevention of alcohol dependence are discussed. PMID- 10091954 TI - Effects of acamprosate on memory in healthy young subjects. AB - OBJECTIVE: Several studies have shown acamprosate (calciumacetylhomotaurinate) to increase abstinence rates in weaned alcoholics. Chronic alcoholics often suffer from cognitive deficits. Since acamprosate appears to interact with N-methyl-D aspartate (NMDA) receptors, a subclass of glutamate receptors playing an important role in learning and memory processes, this study was performed in order to investigate different cognitive functions during administration of acamprosate. METHOD: A randomized, double-blind, cross-over, placebo-controlled design, involving 12 healthy male volunteers was used. Acamprosate 2 g daily per os or placebo were administered for 7 days respectively, with a wash-out interval of 21 days between phases. Mood and different memory functions (i.e., working memory, delayed recall, recognition tasks) were assessed. RESULTS: It was shown that a dose of acamprosate 2 g/day for 7 days may produce an impairment in delayed free recall. Recognition tasks, short term working memory and mood were not altered. CONCLUSIONS: The present study supports the hypothesis that acamprosate impairs memory functions. This is in keeping with the concept of acamprosate acting as NMDA receptor antagonist. The limitations of the study are discussed. PMID- 10091956 TI - DSM-IV alcohol abuse: investigation in a sample of at-risk drinkers in the community. AB - OBJECTIVE: Although a category for alcohol abuse has been included in the major nomenclatures since DSM-III, many questions have been raised about the definitions and validity of this category. METHOD: We investigated DSM-IV alcohol abuse in 628 at-risk drinkers residing in households who never met criteria for DSM-IV alcohol dependence at the time of a baseline interview. Cross-sectional and prospective longitudinal information were used. RESULTS: Subjects most often met criteria for abuse with the single criterion, recurrent hazardous use (usually driving after drinking too much, on average 4.5 times per year). Younger and white subjects were more likely to receive the abuse diagnosis at baseline, as were drug users and those who drank five or more drinks per occasion frequently. Very few subjects received a diagnosis of DSM-IV alcohol dependence at follow-up, and those who did were equally likely to come from the abuse and non-abuse baseline groups. A current abuse diagnosis at baseline strongly and significantly predicted an abuse diagnosis at follow-up, although a past-only (remitted) abuse diagnosis at baseline was not clearly predictive of abuse at follow-up. CONCLUSIONS: The DSM-IV alcohol abuse category has some predictive validity. However, given the manner in which respondents met criteria for the disorder, its merits as a diagnostic category remain in question. Researchers should be cautious about combining alcohol dependence and abuse into the same category. PMID- 10091955 TI - The relationship of alcohol use to cocaine relapse in cocaine dependent patients in an aftercare study. AB - OBJECTIVE: To examine the relationship between alcohol use and cocaine relapse. METHOD: Ninety-eight cocaine-dependent male patients in aftercare were followed for 6 months following completion of an intensive outpatient rehabilitation program (IOP). Past and current alcohol dependence was assessed at entrance into aftercare, and drinking behavior prior to cocaine relapse and "near miss" episodes was assessed at 3- and 6-month follow-ups. Data on cocaine and alcohol use throughout the follow-up were also obtained. RESULTS: Patients who had never met criteria for alcohol dependence and those with current alcohol dependence had worse cocaine outcomes (cocaine use on 10% and 7% of the days in the follow-up, respectively) than those with past alcohol dependence (cocaine use on 3% of the days in the follow-up), although alcohol dependence status no longer predicted cocaine use outcomes when cocaine use in IOP was controlled. Alcohol use in 4 of the first 5 follow-up months significantly predicted cocaine relapse status in the next month after cocaine use in IOP and alcohol dependence diagnosis at baseline were controlled. Patients who experienced cocaine relapses were much more likely to report drinking before the onset of the episode than those who had "near misses," particularly on the day of the episode (40% vs. 6% at 3 months; 62% vs. 0% at 6 months). Alcohol did not appear to be a factor in the relapses of cocaine patients with no history of alcohol dependence, even though they did report drinking on 5% of the days in the follow-up. CONCLUSIONS: Relapse prevention efforts with cocaine abusers who have histories of alcohol dependence should include interventions designed to reduce drinking. PMID- 10091957 TI - The comparative validity of eleven alcoholism typologies. AB - OBJECTIVE: This study directly compared the clinical validity of 11 empirically defined alcoholism typologies to determine whether some typologies are clinically more valid than others. METHOD: A sample of 360 hospitalized alcoholic men were extensively evaluated at entry into the study and again 1 year later. Twenty three measures of clinical validity were employed; 15 were postdictive and 8 were predictive. Postdictive retrospective measures obtained at entry into the study included family history, age of onset and lifetime course characteristics associated with alcoholism severity, general psychopathology and psychosocial functioning. Predictive outcome measures drawn from information obtained during the 1-year follow-up included: abstinence, alcoholism severity and clinician ratings of outcome. The measures were subjected to various statistical analyses, including factor analysis. RESULTS: We found that all of the alcoholism typologies met at least 7 of the 23 a priori measures of clinical validity. The correlations between these conceptually and methodologically disparate typologies were often striking. Exploratory factor analysis, which explained 35% of the variance, suggested three possible underlying dimensions to account for the overlap among typologies: (1) age and its correlates, including age-of-alcoholism onset; (2) "pure" alcoholism versus psychiatrically heterogeneous alcoholism that encompassed antisocial personality disorder; and (3) current severity of psychiatric distress, impairment and dysfunction. CONCLUSIONS: No single method of subtyping alcoholics clearly emerged as superior. All demonstrated some degree of predictive and postdictive clinical validity. Most methods of subtyping correlated positively with each other at moderate, but typically significant, levels. PMID- 10091958 TI - A reliability and validity analysis of an alcohol-related harm scale for surveys. AB - OBJECTIVE: To test reliability and construct validity of an alcohol-related harm scale widely used in North American surveys. METHOD: Data base: three representative general population household telephone surveys in Ontario, Canada (1994: N = 2,022, response rate 63%; 1995: N = 994, response rate 63%; 1996: N = 2,721, response rate 64%). STATISTICAL ANALYSIS: psychometric analysis of internal consistency (Cronbach); Mokken scaling to test homogeneity of underlying construct; tests for construct validity by measuring associations with similar scales. RESULTS: The scale showed high internal consistency and homogeneity of the underlying construct. The correlations with the CAGE and ICD-10 criteria for dependence ranged between 0.5 and 0.7. CONCLUSIONS: The harm scale is measuring a unidimensional construct, but one which is not distinct from that measured by the CAGE or dependence criteria. PMID- 10091959 TI - Specific alcoholic beverages and physical and mental health among adolescents. AB - OBJECTIVE: This study investigated the longitudinal inter-relationships among the consumption of specific alcoholic beverages (beer, wine and distilled spirits), physical symptoms and psychological distress. Two causal processes were examined for each type of beverage: (1) the use of alcohol to cope with pre-existing psychological distress and physical symptoms; (2) the impairment effects of alcohol on subsequent physical and mental health. METHOD: Data were collected at three points in time (baseline, 3-year follow-up, 6-year follow-up) from a household sample of 1,270 youths who were ages 12, 15 and 18 at the baseline interview. RESULTS: Consumption of all three beverages increased through early adolescence and leveled off at ages 18 and 21, and males reported more beer use than females. Structural equation models showed that the use of all three alcoholic beverages contributed significantly to longitudinal increases in physical symptoms, but not to changes in psychological distress. In contrast, no evidence supported the coping hypothesis. Finally, there were no significant interaction effects involving beverage type, gender or age on physical symptoms. CONCLUSIONS: The results suggested that the physical impairment process operated similarly for beer, wine and distilled spirits, for males and females, and for adolescents of different ages. PMID- 10091960 TI - Stress-motivated drinking in collegiate and postcollegiate young adulthood: life course and gender patterns. AB - OBJECTIVE: This study examines stress-motivated drinking and its potential contribution to alcohol problems for young adults in college and subsequent postcollegiate contexts, specifically focusing on the simultaneous influences of life course stage and gender. METHOD: Data are drawn from a research project on health and well-being among multiple cohorts of college students and graduates from an undergraduate institution of higher education. Representative samples of students were surveyed in 1982 (n = 1,514), 1987 (n = 659) and 1991 (n = 926). Surveys were administered to graduates in 1987 (graduating classes of '79, '82 and '85; n = 860) and again in 1991 (graduating classes of '79, '82, '85 and '89; n = 1,151). Using this cross-sectional and longitudinal database, developmental aging effects are tested while checking for historical cohort and period effects. RESULTS: Stress-motivated drinking is somewhat more prevalent in the undergraduate years as are other drinking motivations, but stress-related reasons for drinking are relatively more prominent among motivations and relatively more problematic in terms of consumption levels and consequences in succeeding years after college. The prominence of stress-related drinking and its increased negative effects begin sooner for women than for men. CONCLUSION: Moving from college to stages of postcollegiate young adulthood is associated with substantial decreases in alcohol consumption and related problems. Drinking for stress-reduction, however, becomes increasingly prominent as the primary motivation for the drinking that does occur in postcollegiate life and this drinking motivation also becomes increasingly problematic in terms of negative consequences of alcohol use as each cohort ages. The problematic prominence of stress-motivated drinking is notable at earlier developmental points in this trajectory for women. PMID- 10091961 TI - Alcohol consumption among high school students in Barcelona, Spain. AB - OBJECTIVE: Since adolescents are a high-risk group for alcohol-related problems, this study was undertaken to gain insight into the prevalence of alcohol consumption among this population. METHOD: This study was carried out in the city of Barcelona using an anonymous questionnaire which included information about frequency and quantity of alcohol consumption. The sample population was composed of all the students from 13 to 20 years old who were attending high school during 1992-93 (n = 1,137) and 1994-95 (n = 1,094). The amount of alcohol consumption was calculated in alcohol units per week for 4 groups of different beverages (beer, wine, spirits and aperitifs) and also in grams per day. RESULTS: Lifetime prevalence of alcohol consumption was 92.5% in 1992-93 and 77.0% in 1994-95. Students who drank more frequently were older and male. In 1992-93, 8% of female students had an absolute alcohol intake beyond 24 g per day (risk consumption), which was the same percentage in 1994-95. Male students had a higher intake, although risk consumption rate (more than 40 g per day) was similar to that of females: 9% and 7.4% in 1992-93 and 1994-95, respectively. CONCLUSIONS: While changes in the prevalence of drinking are encouraging, the results of this study also show an increase in the quantity of alcohol consumed. PMID- 10091962 TI - The measurement of problem drinking in young adulthood. AB - OBJECTIVE: Researchers and clinicians have been struggling for more than 20 years to define problem drinking. This study focuses on young adults and aims to examine the construct validity of three dimensions of problem drinking and to empirically determine appropriate cutpoints for problem drinking along these dimensions. METHOD: A stratified sample of 1,269 young adults who reported drinking alcohol in the year prior to 1995 was used in these analyses. Respondents were originally interviewed in 1985 in middle schools in a southeastern U.S. county. RESULTS: Symptoms of dependency and drunkenness were relatively common in this sample, but adverse consequences were rare. Results of analyses using the Chi-squared Automatic Interaction Detector (CHAID) and the SUrvey DAta ANalysis (SUDAAN) software suggest that drunkenness and adverse consequences are the most significant predictors of problems in other areas of life. Symptoms of dependency were significant only in interaction with drunkenness, although the analyses were limited to only lifetime measures of dependency. Appropriate cutpoints, based on these analyses, appear to be (1) drunk at least six times in the past year, (2) four or more lifetime symptoms of dependency and (3) one or perhaps two or more adverse consequences in the past year. CONCLUSIONS: Results suggest that frequency of drunkenness may be the single best indicator of problem drinking among young adults and that adverse consequences may indicate a more serious form of problem drinking than do symptoms of dependency. In addition, appropriate cutpoints on these dimensions for young adults appear to be similar to those that have been used in studies of adolescents. Further study of both adolescents and young adults is suggested. PMID- 10091963 TI - The influence of parental drinking and closeness on adolescent drinking. AB - OBJECTIVE: This study examines the relationship of parental drinking and adolescent's closeness to parents to adolescent drinking behavior by focusing on three related issues: (1) the independent effects of parental drinking and closeness to parents on adolescent drinking, (2) the mediating role of closeness to parents for the effect of parental drinking, and (3) their interactive effects. METHOD: The issues were addressed with use of data from 378 respondents in a random-digit dialing sample of 625 male adolescents at age range 16 to 19 in the Buffalo area. Mother's and father's drinking and adolescent's closeness to mother and father were measured separately. Regression analyses were used to assess the effects of these measures on adolescent drinking regarding the three related issues. RESULTS: Only father's drinking has a direct effect on adolescent drinking. Although closeness to mother is a significant protection against adolescent drinking, mother's drinking has no effect on closeness to mother. In contrast, father's drinking has a significant effect on closeness to father, but closeness to father has no direct effect on adolescent drinking. Therefore, there is no mediating role of closeness to parents for the effect of parental drinking. Finally, there is an interaction between mother's drinking and closeness to mother, which indicates that adolescents whose mothers are heavy drinkers and who have low closeness to their mothers drink more heavily. CONCLUSIONS: Findings suggest that for the mother and the father there are different patterns of the relationship between parental drinking and closeness at work in explaining adolescent drinking. PMID- 10091964 TI - Telescoping of landmark events associated with drinking: a gender comparison. AB - OBJECTIVE: The literature suggests that women exhibit "telescoped" development of (i.e., faster progression to) alcoholism, with fewer years drinking than men. The purpose of this study was to use data gathered in the course of a large clinical trial to further examine this issue. METHOD: Subjects in this retrospective study were from a pool of 1,307 men and 419 women enrolled in Project MATCH, a multisite alcohol treatment matching study. MATCH subjects were recruited from both outpatient and aftercare settings over a 2-year period. Age-of-onset for landmark events in the development of alcoholism were determined from self-report and clinical interviews given at baseline entry into the study. Gender differences in age-of-onset variables were assessed within both outpatient and aftercare settings. Gender differences in progression times between successive landmarks were also examined. Differences were tested with both multivariate and univariate ANOVA techniques. RESULTS: Women generally began getting drunk regularly at a later average age than men (26.6 versus 22.7 years, p< or =.001), began experiencing their first drinking problems at a later average age than men (27.5 versus 25.0 years, p< or =.001) and exhibited loss of control over their drinking at a later average age than men (29.8 versus 27.2 years, p< or =.001). However, these gender differences were most pronounced for older individuals and attenuated for younger subjects. Women also progressed faster than men, on average, between first getting drunk regularly and first encountering drinking problems (0.9 versus 2.3 years, p< or =.001) and between first loss of drinking control and onset of worst drinking problems (5.5 versus 7.8 years, p< or =.001). Women also exhibited shorter average progression times between first getting drunk regularly and first seeking treatment (11.6 versus 15.8 years, p< or =.001), although this effect was negligible for younger subjects. CONCLUSIONS: Telescoping is a relatively robust phenomenon in treatment-seeking alcoholics and indicates that women are more likely to progress faster through the landmark events in the development of alcoholism than are men. PMID- 10091965 TI - Employee drinking practices and work performance. AB - OBJECTIVE: The purpose of this study was to examine the independent effects of a variety of drinking indicators on self-reported work performance. METHOD: Data from a cross-sectional mailed survey (response rate = 71%) of managers, supervisors and workers (N = 6,540) at 16 worksites were analyzed. Average daily volume was computed from frequency and usual quantity reports. Drinking on the job included drinking during any of six workday situations. The CAGE was used to indicate alcohol dependence. Employees were also asked how frequently they drank to get high or drunk. Work performance was measured through a series of questions about work problems during the prior year. The number of times respondents experienced work performance problems was regressed on the four drinking measures, and a variety of demographic characteristics, job characteristics and life circumstances that might also negatively affect work performance. RESULTS: The frequency of self-reported work performance problems increased, generally, with all four drinking measures. In a multivariate model that controlled for a number of demographics, job characteristics and life-situations, average daily volume was no longer significantly associated with work performance but the other three drinking measures were. Interestingly, although moderate-heavy and heavy drinkers reported more work performance problems than very light, light, or moderate drinkers, the lower-level-drinking employees, since they were more plentiful, accounted for a larger proportion of work performance problems than did the heavier drinking groups. CONCLUSIONS: Employers should develop clear policies limiting drinking on the job and, in addition to employee assistance programs for problem drinkers, should develop worksite educational interventions aimed at informing all employees about the relationship between drinking behaviors and work performance. PMID- 10091966 TI - Substance dependence and personality disorders: comorbidity and treatment outcome in an inpatient treatment population. AB - OBJECTIVE: Personality disorders (PDs) are common among patients with substance dependence, and antisocial PD in particular has been found to have a significant impact on treatment outcomes. Relatively little is known about other comorbid PDs, however. This study was designed to clarify the distribution of PDs among substance dependent patients and assess their role in treatment outcome. METHOD: PDs and substance use disorders were diagnosed for 252 (181 male) consecutively admitted substance dependent inpatients using structured clinical interviews. A subsample of these (n = 104) were also followed for 1 year to monitor treatment outcome and relapse. RESULTS: Fifty percent of the patients were diagnosed with one or more personality disorders, but no consistent relationships between drug of choice and PDs were found. The likelihood of relapse, however, increased significantly with the diagnosis of a PD. Only 6% of the patients who received more than one PD diagnosis were maintaining sobriety at the end of 1 year compared with 44% of those with no PD diagnoses. A preference for cocaine was also a significant predictor of relapse. CONCLUSIONS: The low participation rate for the treatment outcome study and other methodological limitations render the study results tentative. Nevertheless, the findings suggest that more attention should be given to Axis II disorders in substance dependence research and treatment. PMID- 10091967 TI - Conduct disorder, antisocial personality disorder and substance use disorders in schizophrenia and major affective disorders. AB - OBJECTIVE: To examine the relationships between childhood conduct disorder (CD), antisocial personality disorder (ASPD) and substance use disorders (substance abuse or substance dependence) in psychiatric patients with severe mental illness. METHOD: Substance use-related problems on screening instruments, lifetime and recent prevalence of substance use disorders, and family history of substance use disorder were evaluated in four groups of 293 patients with mainly schizophrenia-spectrum and major affective disorders: No ASPD/CD, CD Only, Adult ASPD Only, Full ASPD. RESULTS: Full ASPD was strongly related to all measures of substance use problems and disorders, as well as fathers' history of substance use disorder. The odds ratios for Full ASPD and substance use disorders ranged between 3.96 (lifetime cannabis use disorder) to 11.35 (recent cocaine use disorder). To a lesser extent, patients with CD Only or Adult ASPD Only were also at increased risk for having substance use disorders compared to the No ASPD/CD patients. CONCLUSIONS: Childhood CD and adult ASPD represent significant risk factors for substance use disorders in patients with schizophrenia-spectrum and major affective disorders. Considering other research indicating that CD and ASPD have a higher prevalence in patients with severe mental illness, the present findings suggest that CD and ASPD could reflect a common factor that independently increases patients' vulnerability to both psychiatric and substance use disorders. PMID- 10091968 TI - Findings of a pilot study of motivational interviewing with pregnant drinkers. AB - OBJECTIVE: Cost-effective interventions are needed for counseling pregnant drinkers, in order to reduce risk of fetal alcohol effects. METHOD: 42 pregnant women who reported alcohol consumption participated in this pilot study of motivational interviewing. Following a comprehensive alcohol use assessment, the participants were randomly assigned to receive either written information about the risks related to drinking during pregnancy or a one-hour motivational interview. The motivational interview was an empathic, client-centered, but directive session focusing on the health of the participants' unborn babies. RESULTS: At the end of a 2-month follow-up period, the 34 women (81%) who remained in the study showed a significant reduction in alcohol consumption and peak intoxication levels. Women who had reported the highest blood alcohol concentration (BAC) levels during early pregnancy showed a significantly greater reduction in their estimated BACs at follow-up (during later pregnancy) if assigned to the treatment rather than the control condition. CONCLUSIONS: Motivational interviewing shows promise as a specific intervention for initiating a reduction in drinking among pregnant women who are at greatest risk. Simpler assessment and advice may suffice for women with lower initial consumption levels. PMID- 10091969 TI - Modular control analysis of slipping enzymes. AB - A theory is developed that deals with the metabolic control exerted by enzymes that catalyze two or more, incompletely coupled reactions. The starting point is modular (top-down) metabolic control theory. Slipping enzymes are considered as modules with more than one independent flux. Control by the coupled reaction is distinguished quantitatively from control by the extent of slippage. This is achieved by appropriate linear transformation of fluxes or logarithms thereof. Different transformations are proposed and discussed. Our examples include free energy transducing proton pumps and the Na+, K+-ATPase. It is shown that control coefficients can be calculated on the basis of a description of slipping enzymes in terms of linear non-equilibrium thermodynamics. PMID- 10091970 TI - Active Brownian particles with energy depots modeling animal mobility. AB - In the model of active motion studied here, Brownian particles have the ability to take up energy from the environment to store it in an internal depot and to convert internal energy into kinetic energy. Considering also internal dissipation, we derive a simplified model of active biological motion. For the take-up of energy two different examples are discussed: (i) a spatially homogeneous supply of energy, and (ii) the supply of energy at spatially localized sources (food centers). The motion of the particles is described by a Langevin equation which includes an acceleration term resulting from the conversion of energy. Dependent on the energy sources, we found different forms of periodic motion (limit cycles), i.e. periodic motion between 'nest' and 'food'. An analytic approximation allows the description of the stationary motion and the calculation of critical parameters for the take-up of energy. Finally, we derive an analytic expression for the efficiency ratio of energy conversion, which considers the take-up of energy, compared to (internal and external) dissipation. PMID- 10091971 TI - Using genetic algorithms for the construction of phylogenetic trees: application to G-protein coupled receptor sequences. AB - Many different phylogenetic clustering techniques are used currently. One approach is to first determine the topology with a common clustering method and then calculate the branch lengths of the tree. If the resulting tree is not optimal exchanging tree branches can make some local changes in the tree topology. The whole process can be iterated until a satisfactory result has been obtained. The efficiency of this method fully depends on the initially generated tree. Although local changes are made, the optimal tree will never be found if the initial tree is poorly chosen. In this article, genetic algorithms are applied such that the optimal tree can be found even with a bad initial tree topology. This tree generating method is tested by comparing its results with the results of the FITCH program in the PHYLIP software package. Two simulated data sets and a real data set are used. PMID- 10091972 TI - Metabolism and the problem of its universalization. AB - Metabolism tends to be conceived either as an operationally closed network of production of components or as an autonomous apparatus of management of energy flows. Taking up some recent ideas that connect the concept of autonomy with thermodynamic requirements, we move further to defend the hypothesis that there must be a deep intertwinement between the relational-constructive logic of a basic biological system and the logic of its thermodynamic implementation. Hence, we propose that metabolism should be universally defined as the recursive self maintenance of controls upon the energy flows necessary for the physical realization of a component production system operationally closed. Finally, being critical with some claims of the so-called 'strong' artificial life approach, we try to show that present 'computational metabolisms' are necessarily different in their structure and functioning from any real metabolic system, due to the distinct type of causal relations and mechanisms which are respectively established in them. PMID- 10091973 TI - Fractal properties of DNA walks. AB - We describe two dimensional DNA walks, and analyze their fractal properties. We show results for the complete genome of S. cerevisiae. We find that the mean square deviation of the walks is superdifussive, corresponding to a fractal structure of dimension lower than two. Furthermore, the coding part of the genome seems to have smaller fractal dimension, and longer correlations, than noncoding parts. PMID- 10091974 TI - The mechanical advantages of DNA. AB - The elastic properties of DNA and the contractile activities of enzymes involved in transcription, translation and supercoiling may have contributed to the ability of early cells (protocells) to withstand turgor pressure. In the hypothesis proposed here, resistance to turgor resulted from (1) the elastic properties of DNA which was connected to the membrane by association with positively charged lipids and with membrane peptides, (2) the coupled transcription-translation-insertion of peptides into membrane--transertion--which connected membranes with phase-condensed DNA, and (3) the action of topoisomerases which supercoiled and shortened DNA. The existence of a negative feedback system is also proposed to explain how weakened regions of membrane were preferentially strengthened. It may prove possible to test this hypothesis by studying transertion using optical tweezers and by studying wall-less L-form bacteria. PMID- 10091975 TI - Modeling and simulation of gene regulation and metabolic pathways. PMID- 10091976 TI - Modified subtotal laryngectomy with cricohyoidoepiglottopexy--long term results in 81 patients. AB - BACKGROUND: Standard treatment of early glottic carcinoma is radiotherapy, but involvement of the anterior commissure leads to a reduced cure rate. We investigated retrospectively whether our modified subtotal laryngectomy had improved results for early glottic carcinomas involving the anterior commissure, without causing excessive disability to laryngeal functions. METHODS: Eighty-one patients with T1 or T2 glottic carcinoma involving the anterior commissure were reviewed. Follow-up was at least 3 years. Speech was assessed by subjective evaluation and a computer-assisted voice analysis device. RESULTS: Three-year overall survival rate and 3- and 5-year actuarial survival rates were, respectively, 90.1%, 95%, and 90.8%, with no difference between the different T stages involved (p > 0.46). The local recurrence rate was 7.4%. Speech recovered in all patients and was evaluated as satisfactory in 86% of cases. CONCLUSION: For early glottic carcinomas involving the anterior commissure, subtotal laryngectomies appear to be more effective than radiotherapy, and our modified technique simplifies the procedure. PMID- 10091977 TI - Factors influencing contralateral lymph node metastasis from oral carcinoma. AB - BACKGROUND: An ipsilateral neck dissection is mandatory during initial treatment stages II-IV oral carcinomas. However, no consensus exists whether or not to perform an elective contralateral neck dissection. METHODS: Five hundred thirteen consecutive cases of squamous cell carcinoma (269 tongue, 135 floor of the mouth, 44 inferior gingiva, 65 retromolar trigone) were reviewed. Tumor stages were: 69 T1, 227 T2, 217 T3-T4, 263 N0, 250 N1-N3. A total of 563 neck dissections were performed in 448 patients. Univariate and multivariate analysis of risk factors were performed using logistic regression. RESULTS: Two hundred twenty-three patients (49.8%) had positive nodes in the specimen (182 ipsilateral, 36 bilateral, 5 contralateral). Contralateral neck recurrences occurred in 38 cases (33 not submitted to a contralateral neck dissection initially). Multivariate logistic regression analysis demonstrated that clinical stage (p = .0001), tumor crossing midline (p = .0011), and floor of the mouth involvement (p = .0236) were the most important predictors of contralateral metastasis. CONCLUSION: The contralateral side of the neck is a common and potentially preventable site of recurrence in tumors of the oral cavity. The multivariate model obtained discriminates patients with low and high risk (more than 20%) of contralateral metastasis. The application of this mathematical model can be useful for the indication of contralateral neck dissections, because not all tumors crossing midline are associated to a high risk (stages I and II tumors not involving the floor of the mouth) and not all tumors not crossing midline are at low risk (stages III and IV tumors involving the floor of the mouth). PMID- 10091978 TI - Enhanced visualization of parathyroid tissue by infusion of a visible dye conjugated to an antiparathyroid antibody. AB - BACKGROUND: The antiparathyroid antibody BB5-G1 conjugated to cibacron blue, a blue dye, was intravenously infused to enhance parathyroid visualization. Previously, we demonstrated selective staining of human parathyroid implants in athymic nude mice after infusion of the conjugate. METHODS: Mice possessing implanted parathyroid tissue were randomized into the following: group I, infused with cibacron blue alone; group II, infused with the antibody/dye conjugate; and group III, infused with radiolabeled BB5-G1 alone. Implants were surgically explored. Three blinded observers ranked parathyroid visualization in the operative fields, and corresponding histologic sections were computer analyzed. RESULTS: Group II implants were easily visualized; groups I and III showed no staining. Group III showed high gamma counts. Subjective rankings and computer rankings correlated well (p < .05). Group II showed a higher mean staining intensity of 27.45 picogram protein product (PPP)/cell compared with 7.76 PPP/cell of group I (p = .002). CONCLUSION: Cibacron blue/BB5-G1 consistently enhances visualization of implanted parathyroid tissue. PMID- 10091979 TI - Management of stage II (T2N0M0) glottic carcinoma by radiotherapy and conservation surgery. AB - BACKGROUND: The best therapeutic approach for the treatment of stage II (T2N0M0) glottic carcinoma is controversial. METHODS: A retrospective tumor registry data retrieval of patients with stage II glottic carcinoma treated with curative intent at Washington University Medical Center-Barnes Hospital between January 1971 and December 1989 (surgery) and December 1995 (radiotherapy) was performed. RESULTS: Among 134 patients with stage II glottic carcinomas treated with curative intent and function preservation, there were 47 patients treated with low dose radiotherapy (median dose, 58.5 Gy at 1.5-1.8 Gy daily fractions), 16 patients with high dose radiotherapy (67.5-70 Gy) at higher daily fractionation doses (2-2.25 Gy), and 71 patients underwent conservation surgery. The overall local control rate was 85%. The overall salvage rate was 68%. The 5-year actuarial and disease specific survivals were 81.5% and 92%, respectively. Unaided phonation was achieved in 84.4% of the patients. An incidence of 10.4% regional metastases, 2.2% distant metastases, and 6% second primary tumors was documented. There were no statistical differences in local control, voice preservation, and 5-year actuarial and disease specific cure rates between conservation surgery and high dose radiation (p = .89). Low dose radiation had statistically lower local controls, 5-year survival, and voice preservation (p = .014). In advanced T2B disease, treating the ipsilateral neck nodes reduced regional metastases (p = .02). CONCLUSIONS: High dose and daily fractionation (70 Gy at 2 Gy daily fraction doses) radiation achieved results equivalent to those of conservation surgery in 5-year local control, survival, and voice preservation. In advanced T2B disease, treatment of the ipsilateral neck nodes by radiotherapy or functional neck dissection reduced regional metastases. PMID- 10091980 TI - T1 and T2 squamous cell carcinoma of the oral tongue: prognostic factors and the role of elective lymph node dissection. AB - BACKGROUND: The management of micrometastatic disease from squamous cell carcinoma (SCC) of the oral tongue remains controversial. This study describes prognostic factors in the disease and reviews the role of elective neck dissection (END). METHODS: A retrospective analysis of all patients undergoing definitive surgical treatment of T1 and T2 SCC of the oral tongue between 1956 and 1994 at the University of Alabama at Birmingham was performed. RESULTS: Patient, disease, and treatment variables were compiled for 169 patients. Multivariate analysis showed age (p = .02), sex (p = .02), disease differentiation (p = .0003), and palpable lymphadenopathy (p = .02) to be significant prognostic variables. Fifteen patients underwent END and 6 were shown to have micrometastatic disease (40.0%). There were no neck recurrences in these patients, but END was not shown to improve survival. CONCLUSIONS: The presence of poorly differentiated disease gave the worst prognosis in this population of patients with T1 and T2 SCC of the oral tongue. A high incidence of nodal micrometastatic disease and the absence of recurrent disease after END suggest that END is appropriate therapy for these patients. PMID- 10091981 TI - Postlaryngectomy pharyngocutaneous fistula: incidence, predisposing factors, and therapy. AB - BACKGROUND: Pharyngocutaneous fistula is the most common complication following total laryngectomy. The present study was designed to determine the incidence and predisposing factors and to describe the management of the complication. METHODS: The records of 246 consecutive patients who underwent total laryngectomy for squamous cell carcinoma were reviewed. We evaluated 23 factors potentially predisposing to fistula formation (age, sex, smoking and drinking habits, hypertension, diabetes, chronic bronchitis, chronic congestive heart failure, anesthesiologic risk, cholinesterase level, pre- and postoperative hemoglobin and albumin levels, previous treatment, previous tracheotomy, site of origin of the tumor, surgical procedure, concurrent neck dissection, suture material, status of surgical margins, clinical stage, and histologic grade) using the chi-squared test and logistic regression analysis. RESULTS: A pharyngocutaneous fistula developed in 16% of patients within a mean time of 11 days from surgery. Spontaneous closure with local wound care was achieved in 70% of cases. Ten patients required surgical closure by direct suture of the pharyngeal mucosa; a deltopectoral flap and a pectoralis major myocutaneous flap were used in one case each. The mean healing time was 39+/-46 days in the group of patients requiring surgical closure, compared with 19+/-12 days in the group in which spontaneous closure occurred. The definitive model of logistic regression analysis showed that pharyngolaryngectomy, chronic congestive heart failure, and postoperative hemoglobin level lower than 12.5 g/dL carried respectively a two-, five-, and ninefold increase in the risk of fistula development. The model, with a specificity of 81%, is fairly good in identifying patients with a low risk of fistula. CONCLUSIONS: The results observed in the group of patients under analysis corroborated the relevance of factors such as the extension of laryngectomy and postoperative hemoglobin level on fistula occurrence. However, chronic congestive heart failure, which is an expression of disturbance of the organism, emerged for the first time as an additional statistically significant risk factor for pharyngocutaneous fistula formation. Our experience confirmed that most fistulas can be successfully managed with conservative treatment. Except for the rare cases in which large defects are present, direct suture is appropriate when conservative treatment has failed. PMID- 10091982 TI - Laryngeal framework surgery for the management of aspiration. AB - BACKGROUND: During the past decade, laryngeal framework surgery has become the treatment of choice for the management of adductor paralysis of the vocal fold. The primary impetus for the use of this technique has been on the rehabilitation of voice. The purpose of this study was to ascertain the effectiveness of laryngeal framework surgery, including medialization laryngoplasty with silicone (MLS), with or without arytenoid adduction (AA), on eliminating aspiration, improving diet, and aiding in the subsequent decannulation of individuals with glottic insufficiency secondary to vocal fold palsy. METHODS: A retrospective chart review was performed on all patients initially seen with vocal cord paralysis who were treated with laryngeal framework surgery from June 1992 to April 1996. The study comprised 70 patients, including 31 women and 39 men, with a median age of 57 years. Clinical information was obtained regarding the etiology of the lesion, characteristics of the vocal cord deficit, history of aspiration, the presence of other neurologic deficits or concurrent pulmonary disease, treatment, and outcome. To determine the effectiveness of MLS, with or without AA, we assessed the final outcome regarding the presence and degree of aspiration, diet, history of aspiration pneumonia, and decannulation. RESULTS: Seventy patients underwent 77 MLS (three bilateral, four revisions), and 21 AA. Decreased aspiration was obtained in 96% of our patients. Seventy-five percent of those patients who had required a tracheotomy were decannulated. CONCLUSIONS: These results support the use of laryngeal framework surgery for the effective treatment of aspiration in selected patients initially seen with deficits of the glottic closure secondary to vocal fold paralysis or paresis. PMID- 10091983 TI - Tissue oxygen distribution in head and neck cancer patients. AB - BACKGROUND: The importance of hypoxia in limiting the sensitivity of tumor cells to ionizing radiation has long been known. METHODS: We evaluated the tissue oxygenation status with a polarographic needle electrode system in 37 patients with malignancies of the head and neck and correlated the pO2 of 25 patients with treatment outcome. RESULTS: Sixteen tumors contained areas of severe hypoxia, defined by pO2 values below 2.5 mm Hg. Tumor oxygenation parameters were not correlated with hemoglobin, age, and history of tobacco use. There were no subcutaneous PO2 values below 10 mm Hg (ie, no areas of moderate or severe hypoxia), whereas this degree of hypoxia was commonly found in the tumors. Though not statistically significant, hypoxic tumors showed trends for poorer treatment outcome. CONCLUSION: Our data demonstrate a great interindividual variability in the oxygenation of head and neck cancers and appears unassociated with clinical parameters. The method is capable of identifying patients with poorly oxygenated tumors, thereby providing important information for selecting patients who might need customized therapy designed to kill hypoxic tumor cells. Hypoxic tumors show a consistent trend for poor treatment outcome. PMID- 10091984 TI - Parapharyngeal space masses. PMID- 10091985 TI - Primary T-cell lymphoma of the thyroid. AB - BACKGROUND: The routine use of immunocytochemical analysis has led to the recognition that many thyroid neoplasms previously diagnosed as anaplastic or small cell carcinomas are actually lymphomas of the thyroid. The great majority are B-cell lymphomas which can be associated with Hashimoto's thyroiditis. In spite of this, thyroid lymphomas are still not commonly recognized as a significant part of thyroid differential diagnosis. METHODS: A rare case of a primary T-cell lymphoma of the thyroid gland is presented along with general clinical history and physical findings which should make the practitioner suspicious of a thyroid lymphoma. The usefulness of radiology scans and fine needle aspiration are discussed. RESULTS: Both prognosis and treatment options are very different for thyroid lymphomas and anaplastic carcinoma. CONCLUSIONS: Cyclophosphamide/adriamycin/vincristine/prednisolone chemotherapy/radiotherapy regimens have proven to be very effective for most thyroid lymphomas. PMID- 10091986 TI - Follicular dendritic cell tumor of the parapharyngeal region. AB - BACKGROUND: Follicular dendritic cell (FDC) tumors are rare. A majority of the reported cases were confined to the lymph nodes. We report a case of FDC tumor occurring in the parapharyngeal region in a 45-year-old woman. METHODS: Characteristic histopathologic features of the excised primary and recurrent parapharyngeal tumors in conjunction with immunohistochemistry and electron microscopy helped us to arrive at a diagnosis of FDC tumor. RESULTS: Histopathology of primary excision revealed a lobulated tumor with a suggestion of ill-defined whorls. The most striking feature was regular occurrence of aggregates of lymphocytes within the tumor, especially around the blood vessels. The anatomic location together with the histology indicated the possibilities of either a meningioma, a salivary gland tumor, or a nerve sheath tumor. Immunostains for cytokeratin (CK), S-100 protein, and smooth muscle actin (SMA) were negative. However, the tumor cells showed strong immunoreactivity for epithelial membrane antigen (EMA) and vimentin. A diagnosis of parapharyngeal meningioma appeared to be the closest possibility. One year later, the patient developed a recurrence at the same site. A reexcision showed an identical tumor with an additional feature of lymphatic embolization and angioinvasion. A review of the entire case with further immunoreactivity for CD21 and CD35 confirmed the diagnosis of FDC. CONCLUSIONS: Follicular dendritic cell tumor has distinctive morphologic features and immunohistochemical profile. It is also characterized by considerable potential for recurrences. PMID- 10091987 TI - Leiomyosarcoma of the parotid gland: a case report and review of the literature. AB - BACKGROUND: A primary leiomyosarcoma of the parotid gland has been reported only three times in the English literature. This type of tumor represents an extremely rare group of salivary gland neoplasm. METHODS: A 44 year old man was initially seen with a 5 cm right parotid mass which was resected with a total parotidectomy, preserving the facial nerve. The patient had no palpable cervical lymph nodes. RESULTS: The majority of the specimen was made up of a relatively well demarcated tumor 5 cm in diameter. The tumor was noted to contain moderate to poorly differentiated primary leiomyosarcoma of the parotid. CONCLUSIONS: A primary leiomyosarcoma of the parotid gland is an extremely rare existing entity. A review of the literature reveals that primary leiomyosarcoma and other sarcomas of the major salivary glands may share similar histogenesis and biologic behavior with their soft tissue counterparts. PMID- 10091988 TI - The use of granulocyte colony stimulating factor to promote wound healing in a neutropenic patient after head and neck surgery. AB - BACKGROUND: Neutropenia and neutrophil dysfunction, in association with a variety of diseases, has been shown to play a role in poor wound healing. Wound breakdown with fistula formation in patients undergoing total laryngectomy results in significant morbidity and increased hospital stay. Although malnutrition, prior radiation, diabetes, and other diseases are recognized as factors predisposing patients with head and neck cancer to developing fistulas, neutrophil dysfunction should also be considered. Granulocyte colony stimulating factor (G-CSF) has been used successfully to treat neutropenia and neutrophil dysfunction. METHODS: This study was conducted as a case report. RESULTS: We present the first report of a neutropenic head and neck cancer patient with a persistent wound of 6 months' duration who showed dramatic improvement after treatment with G-CSF. CONCLUSION: We conclude that G-CSF may represent a useful adjunct in patients with persistent wound healing problems and neutropenia despite adequate treatment by conventional means. Further clinical experience with G-CSF in patients with delayed healing is indicated. PMID- 10091989 TI - Nuclear and nucleolar localization of an African swine fever virus protein, I14L, that is similar to the herpes simplex virus-encoded virulence factor ICP34.5. AB - PCR analysis of the genomes of 18 different African swine fever virus (ASFV) isolates showed that the I14L open reading frame (ORF) was present as either a long form or short form in all of the isolates. Sequencing of the ORF from eight isolates confirmed that both forms of the ORF were well conserved. Antisera raised against the I14L protein identified the long form of the protein as a 21 kDa protein expressed late during ASFV infection. Immunofluorescent analysis of transiently expressed haemagglutinin-tagged forms of the I14L protein showed that the long form of the protein localized predominantly to the nucleus and within the nucleoli. In contrast, although the short form of the protein was also present predominantly in the nucleus, it did not localize to the nucleoli. Deletion of the N-terminal 14 amino acids from the long form of the I14L protein, which includes a high proportion of basic Arg/Lys residues, abolished the specific nucleolar localization of the protein, although the protein was still present in the nucleus. Addition of this 14 amino acid sequence to beta galactosidase or replacement of the N-terminal 14 amino acids of the I14L short form with those from the long form directed both of these modified proteins to the nucleolus. This indicates that this 14 amino acid sequence contains all the signals required for nucleolar localization. PMID- 10091990 TI - Distribution of B-cell epitopes on the pseudorabies virus glycoprotein B. AB - In order to map antigenically important regions of glycoprotein B (gB) of pseudorabies virus (PrV), a panel of recombinant fragments of gB expressed in E. coli and truncated fragments of gB generated by cleavage of purified native gB with trypsin and cyanogen bromide was analysed by using 26 monoclonal antibodies directed against gB. Three continuous epitopes were localized in the vicinity of the N terminus of gB, between amino acids (aa) 59 and 126. One continuous epitope mapped between residues 214 and 279. The residues involved in the assembly of eight discontinuous epitopes were located between aa 540 and 734. The constituents of two discontinuous epitopes were harboured in a segment encompassing aa 540-646. The clustering of continuous epitopes at the extreme N terminus of PrV gB and the locations of residues involved in the assembly of discontinuous epitopes of PrV gB are in good agreement with data on epitope locations in gB homologues from other herpesviruses. PMID- 10091991 TI - Kinetics of transcription of human cytomegalovirus chemokine receptor US28 in different cell types. AB - In permissive cells, human cytomegalovirus encodes the protein US28, a functional CC chemokine receptor. US28 polyadenylated mRNA could be detected by RT-PCR as early as 2 h post-infection. US28 mRNA appeared after major IE1 transcripts (UL123), but before transcripts of the early genes pp65 (UL83) and gB (UL55), and the late gene pp150 (UL32). This temporal appearance indicates that US28 is transcribed earlier than previously reported. Furthermore, US28 mRNA could be detected in semi- and non-permissive cells. PMID- 10091992 TI - Activation of cyclin A gene expression by the cyclin encoded by human herpesvirus 8. AB - Human herpesvirus-8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus, encodes a protein, referred to as HHV8-Vcyc, with sequence similarity to human G1 cyclins, in particular of the D type. HHV8-Vcyc is expressed in Kaposi's sarcoma and functional analysis suggests that it can activate cyclin-dependent kinases (cdk) and thereby trigger inactivation of the retinoblastoma protein (pRb), indicating that HHV8-Vcyc may contribute to the oncogenic potential of HHV-8. We show here that HHV8-Vcyc can activate transcription of the human cyclin A gene in quiescent cells, a property shared with known transforming oncogenes. Transcriptional activation by HHV8-Vcyc depends on an E2F-binding site in the cyclin A promoter, and cdk6 kinase activity is required. The ability of HHV8-Vcyc to activate cyclin A gene expression is shared by D-type cyclins and cyclin E. Unlike D-type cyclins, HHV8-Vcyc is unable to trigger phosphorylation of the pRb-related protein p107 and fails to induce dissociation of p107 from E2F. Unlike cyclin E, HHV8-Vcyc fails to interact physically with E2F complexes on the cyclin A promoter. These results provide additional evidence for the notion that the HHV-8-encoded cyclin differs in several properties from cellular G1 cyclins. PMID- 10091993 TI - Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) encodes a homologue of the Epstein-Barr virus bZip protein EB1. AB - Analysis of the recently completed genomic sequence of Kaposi's sarcoma associated herpesvirus (human herpesvirus-8) revealed that ORF 50 encodes a protein with homology to the Epstein-Barr virus (EBV) transcription factor R. In this report, we show that ORF K8, contiguous to ORF 50, is interrupted by two introns and that the spliced RNA is translated into a bZip protein that has homology to the EBV transcription factor EB1. The newly characterized K8 protein forms homodimers but does not heterodimerize with other members of the bZip protein family. PMID- 10091994 TI - Development of porcine adenovirus-3 as an expression vector. AB - Porcine adenovirus-3 (PAV-3) was developed as an expression vector using homologous recombination in Escherichia coli BJ 5183. As a prerequisite, the complete genome of PAV-3 was first introduced as a PacI restriction fragment into a bacterial plasmid. The plasmid, when PacI restricted and transfected into swine testicular cells, produces an infectious virus. The potential of this procedure was demonstrated by the construction of several PAV-3 recombinants. Part of the E3 region, which is nonessential for virus replication under cell culture conditions, was identified and deleted from the virus genome. The gene for glycoprotein D (gD) of pseudorabies virus (PRV), which elicits PRV-neutralizing antibodies in pigs, was cloned and expressed from the E3 region of PAV-3. A 50 kDa polypeptide was identified in recombinant PAV-3-infected cell lysates by immunoprecipitation assays using gD-specific monoclonal antibodies. In another experiment, a region between the right inverted terminal repeat and the promoter of the E4 region was used to clone and express the chloramphenicol acetyltransferase (CAT) gene under the control of SV40 immediate early promoter. CAT gene expression was observed irrespective of the orientation of the CAT gene. These results indicate that the helper-independent recombinant PAV-3 could be used as an expression vector and has potential as a recombinant vaccine vector in pigs. PMID- 10091995 TI - Neuronal and glial cell type-specific promoters within adenovirus recombinants restrict the expression of the apoptosis-inducing molecule Fas ligand to predetermined brain cell types, and abolish peripheral liver toxicity. AB - Gene therapy using Fas ligand (FasL) for treatment of tumours and protection of transplant rejection is hampered because of the systemic toxicity of FasL. In the present study, recombinant replication-defective adenovirus vectors (RAds) encoding FasL under the control of either the neuronal-specific neuronal-specific enolase (NSE) promoter or the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter have been constructed. The cell type-specific expression of FasL in both neurons and glial cells in primary cultures, and in neuronal and glial cell lines is demonstrated. Furthermore, transgene expression driven by the neuronal and glial promoter was not detected in fibroblastic or epithelial cell lines. Expression of FasL driven by a major immediate early human cytomegalovirus promoter (MIEhCMV) was, however, achieved in all cells tested. As a final test of the stringency of transgene-specific expression, the RAds were injected directly into the bloodstream of mice. The RAds encoding FasL under the control of the non cell type-specific MIEhCMV promoter induced acute generalized liver haemorrhage with hepatocyte apoptosis, while the RAds containing the NSE or GFAP promoter sequences were completely non-toxic. This demonstrates the specificity of transgene expression, enhanced safety during systemic administration, and tightly regulated control of transgene expression of highly cytotoxic gene products, encoded within transcriptionally targeted RAds. PMID- 10091996 TI - Concerted expression of BK virus large T- and small t-antigens strongly enhances oestrogen receptor-mediated transcription. AB - Previous studies have shown that the human polyomavirus BK (BKV) genome contains an oestrogen response element (ERE). This isolated element binds its cognate receptor in vitro and can mediate 17beta-oestradiol-induced gene expression when linked to a heterologous promoter. The roles of the ERE- and the AP-1-binding sites in oestrogen receptor-directed transcription from the complete BKV promoter/enhancer (Dunlop strain) have been examined and the effects of the general co-activator CBP and large T- and small t-antigens on oestrogen receptor mediated transcription have been investigated. A constitutive activated oestrogen receptor stimulated BKV promoter activity in HeLa cells. Mutations in either the ERE- or the AP-1-binding sites did not impair oestrogen receptor-induced activation of the BKV Dunlop promoter, while mutations in both binding motifs almost completely abolished oestrogen receptor-induced transcription. Simultaneous expression of large T- and small t-antigens strongly activated oestrogen receptor-mediated transcription. When expressed separately, only large T-antigen moderately stimulated oestrogen receptor-mediated transcription. The stimulatory effect of large T-antigen on the activity of the oestrogen receptor is probably indirect because no physical interaction between the two proteins was detected in a two-hybrid assay. Large T-antigen abrogated the synergistic effect on transcription between this nuclear receptor and the general co-activator CBP. The findings that the BKV early proteins amplify oestrogen receptor-mediated transcription may have important biological implications in individuals with raised oestrogen concentrations. PMID- 10091997 TI - Human papillomavirus type 16 variant lineages characterized by nucleotide sequence analysis of the E5 coding segment and the E2 hinge region. AB - We have previously examined 29 cervical cell isolates for human papillomavirus type 16 (HPV-16) sequence variations in the E6, L2 and L1 coding regions, and the long control region (LCR). Twenty-five of these isolates as well as 23 additional isolates are characterized here as we present the complete E5 coding segment and the E2 hinge region. Eight amino acid variations were observed in the E5 coding segment, 13 were identified in the E2 hinge region and 5 were observed in the overlapping E4 coding segment. These amino acid variations may be relevant to differences in biological functions and may result in altered humoral or cell mediated immune responses to HPV-16 variants. The characterization of sequence variation within high-risk HPV types might be important in the search for epidemiological correlates of cervical cancer risk. This work complements and extends HPV-16 genome sequence information from specific isolates previously reported by our group. PMID- 10091998 TI - Functional analysis of mutations conferring lamivudine resistance on hepatitis B virus. AB - Two patterns of mutation are commonly observed in the polymerase gene of lamivudine [(-)2'-deoxy-3'-thiacytidine]-resistant hepatitis B virus (HBV). The M539I substitution in the conserved YMDD motif occurs independently of other changes, whereas the M539V substitution is associated with an additional upstream change (L515M). These mutations were introduced into a common background and their effects on HBV DNA replication and lamivudine resistance studied. The L515M and M539V mutations provided only partial resistance while the M539I mutation conferred a high degree of lamivudine resistance. The combination of the L515M and M539V mutations gave an intermediate level of replication competence, compared with either mutation alone, and increased resistance to lamivudine. This probably accounts for these two mutations always being observed together. The M539I mutation reduced replication competence. PMID- 10091999 TI - A cellular protein which binds hepatitis B virus but not hepatitis B surface antigen. AB - The envelope of hepatitis B virus (HBV) consists of three related proteins known as the large (L), middle (M) and small (S) hepatitis B surface antigens (HBsAg). L-HBsAg has a 108-119 amino acid extension at the N terminus compared with M HBsAg and contains the preS1 sequence of the HBV envelope. Previous research has identified this region as the likely virus attachment protein which is thought to interact with the cellular receptor for the virus. However, as the receptor has still not been identified unequivocally, we used the preS1 region of L-HBsAg to screen a human liver cDNA library by the yeast two-hybrid system. Several positive clones were isolated which encoded cellular proteins that interacted with the HBV preS1 protein. The specificity was examined in an independent manner in experiments in which baculovirus-derived glutathione S-transferase (GST)-preS1 was incubated with 35S-labelled protein expressed by in vitro translation from the positive clones. The intensity of the interactions using this alternative approach mirrored those observed in the yeast two-hybrid system and two proteins (an unidentified protein and a mitochondrial protein) were selected for further study. The specificity of the binding reaction between the preS1 protein and these two proteins was further confirmed in a competition assay; HBV purified from serum, but not purified HBsAg, was able to compete with preS1 and thus block GST-preS1 binding to the unidentified protein but not to the mitochondrial protein. The unidentified protein was then expressed as a fusion protein with GST and this was able to bind HBV virions in a direct manner. PMID- 10092000 TI - Hepadnavirus evolution and molecular strategy of adaptation in a new host. AB - In order to elucidate the mechanisms of hepadnavirus evolution in vivo and to trace the fate of known quasispecies in a single animal during the acute phase of infection, a woodchuck (Marmota monax) was infected with the hepadnavirus woodchuck hepatitis B virus (WHV). Woodchuck 197 (W197) was injected intravenously with pooled sera collected from a chronic carrier that had been infected originally with a molecular clone of known genome sequence (WHV7). Viral genome variants from both the inoculum and the follow-up sera from W197 were characterized for the presence of quasispecies related to the WHV7 sequence. Interestingly, WHV7-related genomes were predominant 6 weeks post-infection (p.i.), whereas a highly heterogeneous virus population was present in the first viraemic serum (4 weeks p.i.). Using WHV7 as the prototype, the variability of the Pol and PreS/S regions in the first 11 weeks p.i. has been calculated. The sequence population in serum collected 6 weeks p.i. was highly homogeneous, with a mean variability of 0.36% in the region analysed. Mean variability values ranging from 0.82% to 1.61% were found in quasispecies from the other sera. The presence of possible selective pressure was analysed by means of the non synonymous versus synonymous variation ratio (dn/d5). We found that the dn/d5 values were stable for the S ORF (ranging from 2.6 to 3.0), whereas a wider range was observed for the Pol ORF (from 1.4 to 3.0). Furthermore, from the analysis of the variability of the codon positions for the two overlapping ORFs it was found that, in most cases, non-synonymous mutations at position 1 of the Pol ORF (position 3 of the S ORF) corresponded to synonymous variation in the S (Pol) ORF, indicating independent evolution of the encoded proteins. PMID- 10092001 TI - Infection of apheresis cells by parvovirus B19. AB - Parvovirus B19 is the only member of the Parvoviridae family known to cause disease in humans. Owing to the high level of cell tropism the virus can only replicate in proliferating and differentiating erythroid precursor cells, which are present in human bone marrow and foetal liver. As human bone marrow is very difficult to obtain, an alternative in vitro system for the propagation of B19 virus has been developed, based on the application of mobilized haemapoietic progenitor (apheresis) cells. These cells are routinely harvested from cancer patients after treatment with recombinant human granulocyte/macrophage colony stimulating factor. Replication of parvovirus B19 in vitro is possible in these cells after stimulation with erythropoietin. Therefore, this system is an easily, accessible alternative to the use of human bone marrow in parvovirus B19 infection assays. PMID- 10092002 TI - Susceptibility of TT virus to interferon therapy. AB - TT virus (TTV) is a newly identified single-stranded DNA virus. We retrospectively analysed serum samples from sixteen patients, infected with both hepatitis C virus (HCV) and TTV, and who had been treated with interferon. An elevated serum alanine aminotransferase level after interferon was associated with persistence of HCV (abnormal in five of seven patients with persistence of HCV compared with normal in all nine patients who showed eradication of HCV) irrespective of persistence of TTV. Comparison of partial viral DNA nucleotide sequences and phylogenetic analysis showed that viral strains that had a high identity to the prototype virus were more resistant to interferon than those showing low nucleotide sequence identity. Although we observed no liver cell injury caused by persistent TTV infection, the mechanism(s) of TTV resistance to interferon should be further investigated for a better understanding of viral diseases and establishment of therapy. PMID- 10092003 TI - Relationships between simian and human enteroviruses. AB - Partial sequences from two genomic regions of simian enteroviruses were analysed and their relatedness to other picornaviruses was compared. Of the 18 simian viruses included in the analysis, sequences were obtained from eleven strains for at least one genomic region. In the 5' non-coding region, SV6, SV19, SV26, SV35, SV43 and SV46 (simian viruses) and BA13 (baboon virus) clearly grouped together with human enteroviruses, whereas SV4, SV28 and SA4 (South African isolate) were more distantly related. In the 3D RNA polymerase-coding region, SV26, SV35, SV43 and SV46 could be clearly identified as enteroviruses and fell into the previously defined cluster A, which contains such human viruses as coxsackievirus A16 and enterovirus 71. However, although SV6 and BA13 were also enterovirus like, they did not belong to any known genetic cluster of human enteroviruses. Moreover, while SV18 could be recognized as a picornavirus, it did not directly group with members of the genus Enterovirus. PMID- 10092004 TI - Molecular evolution of swine vesicular disease virus. AB - Phylogenetic analysis was used to examine the evolutionary relationships within a group of coxsackie B viruses that contained representatives of the major serotypes of this group and 45 isolates of swine vesicular disease virus (SVDV) from Asia and Europe. Separate analyses of sequence data from two regions of the viral genomes encoding the VP1 and 3BC genes both revealed that the SVDV belonged to a single monophyletic group which could be clearly distinguished from all other sampled coxsackieviruses. Regression analysis revealed that within the SVDV clade at least 80% of the synonymous variation in evolutionary divergence between isolates was explained by time, indicating the existence of an approximate molecular clock. Calibration of this clock according to synonymous substitutions per year indicated the date of occurrence of a common ancestor for the SVDV clade to be between 1945 and 1965. PMID- 10092006 TI - Demonstration of bovine CD8+ T-cell responses to foot-and-mouth disease virus. AB - The aim of this study was to investigate the importance of cellular immunity in foot-and-mouth disease in cattle, in particular to determine whether a CD8+ T cell response could be detected, as these cells may play a role in both immunity and virus persistence. As attempts to characterize classical cytotoxic T cells had yielded non-reproducible results, largely due to high backgrounds in control cultures, a proliferation assay was developed that was demonstrated to detect antigen-specific, MHC class I-restricted bovine CD8+ cells responding to foot-and mouth disease virus (FMDV). Proliferative CD8+ T-cell responses were detected consistently from 10 to 14 days following infection with FMDV and typically lasted 3-4 weeks. The role of CD8+ T cells in control of the disease, in particular their relevance for the establishment of persistence, may now be investigated. PMID- 10092005 TI - Avian encephalomyelitis virus is a picornavirus and is most closely related to hepatitis A virus. AB - The complete RNA genome of avian encephalomyelitis virus (AEV) has been molecularly cloned and sequenced. This revealed AEV to be a member of the Picornaviridae and consequently it is the first avian picornavirus for which the genome has been sequenced. Excluding the poly(A) tail the genome comprises 7032 nucleotides, which is shorter than that of any mammalian picornavirus sequenced to date. An open reading frame commencing at nucleotide 495 and terminating at position 6896 (6402 nucleotides) potentially encodes a polyprotein of 2134 amino acids. The polyprotein sequence has 39% overall amino acid identity with hepatitis A virus (HAV; genus Hepatovirus), compared to 19 to 21% for viruses from the other five picornavirus genera. Eleven cleavage products were predicted. The highest identity (49%) with HAV was in the P1 region, encoding the capsid proteins. The 5' and 3' untranslated regions (UTRs) comprise 494 and 136 nucleotides, respectively. The 5' UTR is the shortest of any picornavirus sequenced to date and, unlike HAV, it does not contain a long polypyrimidine tract. PMID- 10092007 TI - Evidence of partial protection against foot-and-mouth disease in cattle immunized with a recombinant adenovirus vector expressing the precursor polypeptide (P1) of foot-and-mouth disease virus capsid proteins. AB - A recombinant live vector vaccine was produced by insertion of cDNA encoding the structural proteins (P1) of foot-and-mouth disease virus (FMDV) into a replication-competent human adenovirus type 5 vaccine strain (Ad5 wt). Groups of cattle (n = 3) were immunized twice, by the subcutaneous and/or intranasal routes, with either the Ad5 wt vaccine or with the recombinant FMDV Ad5-P1 vaccine. All animals were challenged by intranasal instillation of FMDV 4 weeks after the second immunizations. In the absence of a detectable antibody response to FMDV, significant protection against viral challenge was seen in all of the animals immunized twice by the subcutaneous route with the recombinant vaccine. The observed partial protection against clinical disease was not associated with a reduction in titre of persistent FMDV infections in the oropharynx of challenged cattle. PMID- 10092008 TI - A hepatitis E virus variant from the United States: molecular characterization and transmission in cynomolgus macaques. AB - The partial sequence of a hepatitis E virus (HEV-US1) isolated from a patient in the United States (US), suffering from acute viral hepatitis with no known risk factors for acquiring HEV, has been reported. These sequences were significantly different from previously characterized HEV isolates, alluding to the existence of a distinct human variant. In this paper, we report the near full-length sequences of HEV-US1 and a second US isolate (HEV-US2). HEV-US2 was identified in a US patient suffering from acute viral hepatitis. These sequences verify the presence of a new HEV strain in North America and provide information as to the degree of variability between variants. The HEV-US nucleotide sequences are 92% identical to each other and only 74% identical to the Burmese and Mexican strains. Amino acid and phylogenetic analyses also demonstrate that the US isolates are genetically distinct, suggesting the presence of three genotypes of HEV. Serum from the second US patient induced hepatitis following inoculation into a cynomolgus macaque. Within 2-4 weeks, HEV-US2 RNA was detectable in both the serum and faecal material coinciding with elevated serum alanine transaminase levels. Infection resolved as antibody titres increased 8 weeks post-inoculation. PMID- 10092009 TI - Genetic diversity of equine arteritis virus. AB - Equine arteritis viruses (EAV) from Europe and America were compared by phylogenetic analysis of 43 isolates obtained over four decades. An additional 22 virus sequences were retrieved from GenBank. Fragments of the glycoprotein G(L) and the replicase genes were amplified by RT-PCR, prior to sequencing and construction of phylogenetic trees. The trees revealed many distinctive lineages, consistent with prolonged diversification within geographically separated host populations. Two large groups and five subgroups were distinguished. Group I consisted mainly of viruses from North America, whilst group II consisted mainly of European isolates. In most instances, where the geographic origin of the viruses appeared to be at variance with the phylogenetically predicted relationships, the horses from which the viruses were recovered had been transported between Europe and America or vice versa. Analysis of the replicase gene revealed similar phylogenetic relationships although not all of the groups were as clearly defined. Virus strains CH1 (Switzerland, 1964) and S1 (Sweden, 1989) represented separate 'outgroups' based on analysis of both genomic regions. The results of this study confirm the value of the G(L) gene of EAV for estimating virus genetic diversity and as a useful tool for tracing routes by which EAV is spread. In addition, computer-assisted predictions of antigenic sites on the G(L) protein revealed considerable variability among the isolates, especially with respect to regions associated with neutralization domains. PMID- 10092011 TI - Differences between hepatitis C virus 5' untranslated region quasispecies in serum and liver. AB - It is unclear whether the sequence populations of hepatitis C virus (HCV) quasispecies in the liver and in serum are different, as a variety of studies on this subject provide conflicting results. In the current study, the populations of HCV 5' untranslated region (5' UTR) sequences in paired serum and liver samples from six patients with chronic hepatitis were analysed. Liver-derived, negative-strand viral RNA was amplified with a highly strand-specific Tth-based assay, and extensive measures, including accounting for template copy number, were undertaken to lower the risk of sporadic artefactual polymorphism. Amplified sequences were compared by single-strand conformation polymorphism analysis and by direct sequencing of identified differences. In four patients, liver samples were found to contain variants within the quasispecies which were not found in serum or negative-strand viral RNA, while in the remaining two patients, low virus titre prevented a reliable quasispecies analysis. These results suggest the presence in the same individual of HCV variants differing in the 5' UTR and possibly replicating with different kinetics. PMID- 10092010 TI - Characterization and mutational analysis of the helicase and NTPase activities of hepatitis C virus full-length NS3 protein. AB - The non-structural protein 3 (NS3) of hepatitis C virus (HCV) possesses three activities which are likely to be essential for virus replication; a serine protease located in the N terminus and helicase and NTPase activities located in the C terminus. Sequence analysis of the helicase/NTPase domain has identified motifs indicative of the DEAD-box family of helicases. Here we present the characterization of the helicase and NTPase activities of full-length NS3, expressed as a His-tagged fusion protein in E. coli, and make comparisons with published data of NS3 helicase domain alone. The helicase and NTPase activities of full-length NS3 have been demonstrated and we have characterized the effects of amino acid substitutions on conserved motifs of NS3 helicase. Helicase and NTPase activities were dependent on Mg2+ and ATP and inhibited by monovalent cations. NS3 was able to hydrolyse all four NTPs and dNTPs to drive DNA duplex unwinding but with differing abilities. NTPase activity was stimulated by all polynucleotides tested, with poly(U) having the greatest effect. Mutational analysis of conserved motifs of NS3 helicase showed all conserved residues to be required for optimal activity. These results are in accord with a recently proposed model for NS3 helicase activity. PMID- 10092012 TI - Variation of hepatitis C virus following serial transmission: multiple mechanisms of diversification of the hypervariable region and evidence for convergent genome evolution. AB - We have studied the evolution of hepatitis C virus (HCV) from a common source following serial transmission from contaminated batches of anti-D immunoglobulin. Six secondary recipients were each infected with virus from identifiable primary recipients of HCV-contaminated anti-D immunoglobulin. Phylogenetic analysis of virus E1/E2 gene sequences [including the hypervariable region (HVR)] and part of NS5B confirmed their common origin, but failed to reproduce the known epidemiological relationships between pairs of viruses, probably because of the frequent occurrence of convergent substitutions at both synonymous and nonsynonymous sites. There was no evidence that the rate at which the HCV genome evolves is affected by transmission events. Three different mechanisms appear to have been involved in generating variation of the hypervariable region; nucleotide substitution, insertion/deletion of nucleotide triplets at the E1/E2 boundary and insertion of a duplicated segment replacing almost the entire HVR. These observations have important implications for the phylogenetic analysis of HCV sequences from epidemiologically linked isolates. PMID- 10092013 TI - Immunogenicity of variable regions of hepatitis C virus proteins: selection and modification of peptide epitopes to assess hepatitis C virus genotypes by ELISA. AB - The immunogenicity of variable regions of hepatitis C virus (HCV) proteins was studied by ELISA by using 543 synthetic peptides from 120 variable regions and 90 sera from HCV-infected patients. Some regions from certain genotypes were less immunogenic, or even non-immunogenic, compared with their equivalents in other genotypes. However, the mean recognition of all peptides from genotypes 1a, 1b and 3 by sera infected with genotypes 1a, 1b and 3, respectively, showed no significant differences, suggesting a similar overall immunogenicity of variable regions from these genotypes. Proteins NS4a, NS4b and NS5a were found to be the most immunogenic. Recognition of individual peptides by the sera of infected patients showed that the humoral response against HCV is patient-dependent. The work shows that 15-mer peptides may encompass several B-cell epitopes. These epitopes may lie in slightly different positions in different genotypes. Thirty one percent of the 543 peptides were recognized by some of the 35 healthy donors. This may be a reflection of the large number of antigens to which they had been exposed, but it may also reflect a strategy of HCV to respond to immune pressure. After selection and modification, a set of 40 peptides was used to assess genotypes 1a, 1b, 1, 2 and 3 in the sera of HCV-infected patients, with sensitivities of 34.1, 48.5, 68.8, 58.3 and 48.9% and specificities of 100, 99.1, 97.1, 99.5 and 99%, respectively. The overall sensitivity and specificity for the assessment of genotypes 1, 2 and 3 were 64 and 98%, respectively. PMID- 10092014 TI - Geographic distribution and evolution of Sindbis virus in Australia. AB - The molecular epidemiology and evolution of Sindbis (SIN) virus in Australia was examined. Several SIN virus strains isolated from other countries were also included in the analysis. Two regions of the virus genome were sequenced including a 418 bp region of the E2 gene and a 484 bp region containing part of the junction region and the 5' end of the C gene. Analysis of the nucleotide and deduced amino acid sequence data from 40 SIN virus isolates clearly separated the Paleoarctic/Ethiopian and Oriental/Australian genetic types of SIN virus. Examination of the Australian strains showed a temporal rather than geographic relationship. This is consistent with the virus having migratory birds as the major vertebrate host, as it allows for movement of virus over vast areas of the continent over a relatively short period of time. The results suggest that the virus is being periodically redistributed over the continent from an enzootic focus of evolving SIN virus. However, SIN virus strains isolated from mosquitoes collected in the south-west of Australia appear to represent a new SIN virus lineage, which is distinct from the Paleoarctic/Ethiopian and Oriental/Australian lineages. Given the widespread geographic dispersal of the Paleoarctic/Ethiopian and Oriental/Australian lineages, it is surprising that the South-west genetic type is so restricted in its area of circulation. Nucleotide sequence data from the C gene of the prototype strain of the alphavirus Whataroa were also determined. This virus was found to be genetically distinct from the SIN virus isolates included in the present study; however, it is clearly SIN-like and appears to have evolved from a SIN-like ancestral virus. PMID- 10092015 TI - Amino acid substitutions in a conserved region in the stalk of the Newcastle disease virus HN glycoprotein spike impair its neuraminidase activity in the globular domain. AB - The ectodomain of the paramyxovirus haemagglutinin-neuraminidase (HN) glycoprotein spike can be divided into two regions: a membrane-proximal, stalk like structure and a terminal globular domain. The latter contains all the antibody recognition sites of the protein, as well as its receptor recognition and neuraminidase (NA) active sites. These two activities of the protein can be separated by monoclonal antibody functional inhibition studies and mutations in the globular domain. Herein, we show that mutation of several conserved residues in the stalk of the Newcastle disease virus HN protein markedly decrease its NA activity without a significant effect on receptor recognition. Thus, mutations in the stalk, distant from the NA active site in the globular domain, can also separate attachment and NA. These results add to an increasing body of evidence that the NA activity of this protein is dependent on an intact stalk structure. PMID- 10092016 TI - Long terminal repeat sequences of equine infectious anaemia virus are a major determinant of cell tropism. AB - The Wyoming strain of equine infectious anaemia virus (EIAV) is a highly virulent field strain that replicates to high titre in vitro only in primary equine monocyte-derived macrophages. In contrast, Wyoming-derived fibroblast-adapted EIAV strains (Malmquist virus) replicate in primary foetal equine kidney and equine dermis cells as well as in the cell lines FEA and Cf2Th. Wyoming and Malmquist viruses differ extensively both in long terminal repeat (LTR) and envelope region sequences. We have compared the promoter activities of the Wyoming LTR with those of LTRs derived from fibroblast-adapted viruses by examining their abilities to drive a luciferase reporter gene as well as by construction of infectious molecular clones differing only in LTR sequence. Our results indicate that LTR sequences are a major restriction for growth of the Wyoming strain of EIAV in fibroblasts. PMID- 10092017 TI - Vaccination with experimental feline immunodeficiency virus vaccines, based on autologous infected cells, elicits enhancement of homologous challenge infection. AB - Cats were vaccinated with fixed autologous feline immunodeficiency virus (FIV) infected cells in order to present viral proteins to the immune system of individual cats in an MHC-matched fashion. Upon vaccination, a humoral response against Gag was induced. Furthermore, virus-neutralizing antibodies were detected in a Crandell feline kidney cell-based neutralization assay, but not in a neutralization assay based on primary peripheral blood mononuclear cells. Despite the induction of these FIV-specific responses, vaccinated cats were not protected. Instead, accelerated virus replication was found, an observation similar to what previous experiments using other vaccine candidates have shown. Here, the results of the present study are discussed in the light of enhancement of lentivirus infections as a complicating factor in lentivirus vaccine development. PMID- 10092018 TI - Secretion of beta-chemokines by bronchoalveolar lavage cells during primary infection of macaques inoculated with attenuated nef-deleted or pathogenic simian immunodeficiency virus strain mac251. AB - Primary infection of macaques with simian immunodeficiency virus (SIV) as a model of human immunodeficiency virus (HIV) infection represents a unique opportunity to investigate early lentivirus-host interactions. In order to gain insight into immunopathogenic events taking place in the lung during lentiviral infection, we analysed lymphocyte expansion in the lung and chemokine secretion by mononuclear cells obtained by bronchoalveolar lavage (BALMCs) during primary infection by a pathogenic and a non-pathogenic SIV. Two groups of cynomolgus macaques were inoculated intravenously with a fully pathogenic isolate of SIVmac251 or with an attenuated, nef-deleted, molecular clone of SIVmac251. Spontaneous MIP-1alpha, MIP-1beta and RANTES production was assessed by ELISA in supernatants of short term cultured BALMCs. Kinetics of haematological, virological and immunological parameters were investigated simultaneously. All 11 inoculated animals became infected. Monkeys inoculated with the nef-deleted SIV clone exhibited a significantly reduced plasma virus load and a less pronounced accumulation of lymphocytes in the lung compared to monkeys infected with the pathogenic SIVmac251 isolate. Compared to pre-infection levels, we observed an increase in the levels of RANTES, MIP1-alpha and MIP1-beta production in the two groups of monkeys, by the time of peak viraemia. Strikingly, a greater enhancement of RANTES and MIP-1alpha production was detected in monkeys infected with the attenuated virus. Given the potential influence of beta-chemokines on the immune response and virus replication, such results suggest that RANTES, MIP1-alpha and MIP1-beta could contribute to the singular features of the immune response elicited during infection of macaques with an attenuated SIV. PMID- 10092019 TI - Translational effects of peptide antagonists of Tat protein of human immunodeficiency virus type 1. AB - The Tat (trans-activator of transcription) regulatory protein of human immunodeficiency virus (HIV-1) acts by interacting with the TAR RNA domain of nascent viral transcripts and with cellular proteins to increase viral transcription. In Jurkat-derived HCLE-D36 cells, which are stably transfected with the chloramphenicol acetyltransferase (CAT) reporter gene expressed from the TAR-encoding long terminal repeat (LTR) of HIV-1, CAT protein expression is dependent on Tat. The Tat9-K-biotin peptide antagonist of Tat binds specifically to TAR RNA and competes with Tat for binding. In the cellular expression system, Tat9-K-biotin reduces Tat-dependent CAT expression. However, while the Tat antagonist greatly reduces CAT protein production and polysome association of CAT mRNA, it has little effect on CAT mRNA levels, suggesting that the antagonist works at the post-transcriptional level. PMID- 10092020 TI - Characterization of the 25K FP gene of the baculovirus Bombyx mori nucleopolyhedrovirus: implications for post-mortem host degradation. AB - Mutagenesis experiments on the baculovirus Bombyx mori nucleopolyhedrovirus (BmNPV) using 5-bromo-2'-deoxyuridine generated five mutants with a 'few polyhedra' (FP) phenotype. Sequence analysis of the 25K gene homologue of the BmNPV FP mutants revealed nucleotide substitutions in the coding region. Rescue experiments indicated that the FP phenotype of the BmNPV mutants resulted from mutations in the 25K coding region. Effects of infection by these FP mutants were analysed following injection of the viruses into silkworm (B. mori) larvae. Compared to infection with wild-type virus, infection with each FP mutant resulted in reduced host degradation (liquefaction). The degree to which liquefaction was blocked corresponded to the degree of functional disruption of the 25K gene product and to the extent to which polyhedron production was reduced. Electron microscopy revealed that (1) polyhedron production was reduced, (2) very few virions were occluded and those that were lacked envelopes, and (3) the basal lamina of fat-body tissue was not destroyed by infection and accumulations of virions occurred along the membrane. Typical NPV-induced liquefaction was observed following infection with a polyhedrin deletion mutant, indicating that host degradation was not related to polyhedron production. These results suggest that (1) the 25K gene product is involved in the host degradation process caused by virus infection and (2) the FP phenotype is an indirect result of disruption of the 25K gene; activation or suppression of a specific host or viral gene related to tissue degradation and polyhedron formation may be involved. PMID- 10092021 TI - Nucleotide sequences and taxonomy of satsuma dwarf virus. AB - The nucleotide sequences of genomic RNA1 (6795 nt) and RNA2 (5345 nt) of satsuma dwarf virus (SDV), a tentative member of the genus Nepovirus, were determined. The deduced genome organization of SDV showed similarities to the organization in como-, faba- and nepoviruses. There is extensive amino acid sequence similarity in the N-terminal regions of the proteins encoded by RNA1 and RNA2, as reported previously only for tomato ringspot nepovirus. However, unlike definitive nepoviruses, which have a single coat protein, SDV has two coat proteins. SDV RNA2 does not contain the long (> 1300 nt) 3' non-coding region characteristic of some nepoviruses. Phylogenetic analysis of SDV RNA polymerase placed SDV apart from como-, faba- and nepoviruses. These unique features suggest that SDV is distinct from the Comovirus, Fabavirus and Nepovirus genera, and needs to be separated into a new genus, probably within the family Comoviridae. PMID- 10092022 TI - Proteolytic processing of tomato ringspot nepovirus 3C-like protease precursors: definition of the domains for the VPg, protease and putative RNA-dependent RNA polymerase. AB - Tomato ringspot nepovirus (TomRSV) RNA-1 encodes a putative NTP-binding protein (NTB), a putative viral genome-linked protein (VPg), a putative RNA-dependent RNA polymerase (Pol) and a serine-like protease (Pro), which have been suggested to be involved in viral RNA replication. Proteolytic processing of protease precursors containing these proteins was studied in Escherichia coli and in vitro. The TomRSV protease could cleave the precursor proteins and release the predicted mature proteins or intermediate precursors. Although processing was detected at all three predicted cleavage sites (NTB-VPg, VPg-Pro and Pro-Pol), processing at the VPg-Pro cleavage site was inefficient, resulting in accumulation of the VPg-Pro intermediate precursor in E. coli and in vitro. In addition, the presence of the VPg sequence in the precursor resulted in increased cleavage at the Pro-Pol cleavage site in E. coli and in vitro. Direct N-terminal sequencing of the genomic RNA-linked VPg, of the mature protease purified from E. coli extracts and of radiolabelled mature polymerase purified from in vitro translation products revealed the sequences of the NTB-VPg, VPg-Pro and Pro-Pol dipeptide cleavage sites to be Q/S, Q/G and Q/S, respectively. In vitro processing at the NTB-VPg and Pro-Pol cleavage sites was not detected upon mutation or deletion of the conserved glutamine at the -1 position of the cleavage site. These results are discussed in light of the cleavage site specificity of the TomRSV protease. PMID- 10092023 TI - The complete genome sequence of the major component of a mild citrus tristeza virus isolate. AB - The genome of the Spanish mild isolate T385 of citrus tristeza virus (CTV) was completely sequenced and compared with the genomes of the severe isolates T36 (Florida), VT (Israel) and SY568 (California). The genome of T385 was 19,259 nt in length, 37 nt shorter than the genome of T36, and 33 and 10 nt longer than those of VT and SY568, respectively, but their organization was identical. T385 had mean nucleotide identities of 81.3, 89.3 and 94% with T36, VT and SY568, respectively. The 3' UTR had over 97% identity in all isolates, whereas the 5' UTR of T385 had 67% identity with VT, 66.3% with SY568 and only 42.5% with T36. In the coding regions, the nucleotide differences between T385 and VT were evenly distributed along the genome (around 90% identity); this was not observed between T385 and the other isolates. T385 and T36 had nucleotide identities around 90% in the eight 3'-terminal ORFs of the genome, but only 72.3% in ORF 1a, a divergence pattern similar to that reported previously for T36 and VT. T385 and SY568 had nucleotide identities close to 90% in the 5'- and 3'-terminal regions of the genome, whereas the central region had over 99% identity. Our data suggest that the central region in the SY568 genome results from RNA recombination between two CTV genomes, one of which was almost identical to T385. PMID- 10092024 TI - New defective RNAs from citrus tristeza virus: evidence for a replicase-driven template switching mechanism in their generation. AB - Defective RNAs (D-RNAs) ranging in size from 1968 to 2759 nt were detected in four citrus tristeza virus (CTV) isolates by hybridization of electroblotted dsRNAs with two probes specific for the 5'- and 3'-terminal genomic regions. The RNAs that hybridized with both probes were eluted, cloned and sequenced. Comparison with the sequences of the corresponding genomic regions of the helper virus showed, in all cases, over 99% nucleotide identity and direct repeats of 4 5 nt flanking or in the vicinity of the junction sites. The presence of the repeats from two separate genome locations suggests a replicase-driven template switching mechanism for the generation of these CTV D-RNAs. Two of the CTV isolates that differed greatly in their pathogenicity contained an identical D RNA, suggesting that it is unlikely that this D-RNA is involved in symptom modulation, which may be caused by another factor. PMID- 10092025 TI - A study of the application sharing capabilities in telemedicine. AB - The main aim of this study was to find out if the image format (TIFF or JPEG) influenced the time delay for transferring radiological images by the application sharing tool of a desktop videoconferencing system. The second task of the study was to define a procedure that optimized the time delay to load and remotely visualize the images. The results were achieved by applying a test procedure called 'benchmark protocol'. The videoconferencing system used for the test was Intel ProShare 200 v2.0. The image transfer was performed by a BRI ISDN connection. We showed that the image format had no significant influence on the time delay. We presented an optimal procedure for image transfer. Furthermore, store and forward procedures with simple file transfer were shown to be inferior to the use of application sharing. For radiological image transfer we recommend to use lossless file formats and application sharing with the image already loaded in because this method achieves the lowest time delays. PMID- 10092026 TI - Rapid algorithms for the construction of cerebral blood flow and oxygen utilization images with oxygen-15 and dynamic positron emission tomography. AB - Two rapid estimation algorithms for construction of cerebral blood flow (CBF) and oxygen utilization (CMRO) images with dynamic positron emission tomography (PET) are presented. These algorithms are based on the linear least squares (LLS) and generalized linear least squares (GLLS) methodologies. Using the conventional two compartmental model and multiple tracer studies, we derived a linear relationship for brain tissue activity to arterial blood activity, time-integrated arterial blood activity and time-integrated brain tissue activity. The LLS technique is computationally efficient as no regression analysis is required, while GLLS is used to refine the estimates obtained from LLS. A comparative study using non linear least squares regression (NLS) revealed excellent correlation between the new algorithms for various noise levels expected in clinical applications. A sensitivity analysis was performed to examine reliability and identifiability of the parameter estimates. In view of the results, LLS and GLLS provide rapid and reliable estimates of CBF and CMRO when applied to dynamic PET data. These algorithms are particularly suitable for pixel-by-pixel construction of high resolution and highly accurate PET functional images. PMID- 10092027 TI - Application of high-order boundary elements to the electrocardiographic inverse problem. AB - Eight-noded quadrilateral boundary elements are applied to the electrocardiographic inverse problem as an example for high-order boundary elements. It is shown that the choice of the shape functions used for approximation of the potentials has a remarkable influence on the solution obtained if the number of electrodes is smaller than the number of primary source points (under-determined equation system). Three different formulations are investigated considering a concentric spheres problem where an analytic solution is available: (a) the isoparametric formulation; (b) the quasi-first-order formulation; and (c) the pseudo-subparametric formulation as a new method. In a second step the pseudo-subparametric formulation (which provided the best results in the test problem) is applied to real word data. The transmembrane potential pattern of a 40 years old female suffering from severe heart failure and ventricular tachycardia after large anterior wall myocardial infarction is reconstructed for one time instant. Furthermore, an algorithm for the calculation of the transfer matrix is presented which avoids restrictions to the boundary element mesh caused by the placement of the electrodes. PMID- 10092028 TI - An object-oriented Monte Carlo simulator for 3D cylindrical positron tomographs. AB - Monte Carlo simulation is a very powerful tool in understanding performances of positron tomographs as well as in assessing image reconstruction algorithms and their implementations. We present an object-oriented Monte Carlo simulator developed for 3D positron tomography. Results from phantom simulation studies including absorption and scattering of the photons in the field-of-view are presented. Scatter fractions determined from these studies are in good agreement with measured scatter fractions published in the literature. Limitations and future prospects are discussed. PMID- 10092029 TI - Design of optimal two-sample bolus injection tests for measuring low plasma clearance rates. AB - The bolus injection technique is widely used for assessing plasma clearance rates of substances and is based on multiexponential data analysis of multiple concentration measurements. This approach can be simplified to a monoexponential description with only two measurements if intercompartmental mixing occurs at a much faster rate than elimination, i.e. with low plasma clearance rates. In this context initial transients must be ignored because the first measurement time instant affects the accuracy of clearance estimates if mixing is still incomplete. Moreover, measurement noise affects estimation precision which can be optimized by suitable choice of the sampling schedule and of the injected test dose. The aim of this study is to design two-sample bolus injection tests for measuring low plasma clearance rates with preassigned precision and with minimum amount of injected test substance. This paper provides equations for evaluating whether plasma clearance is sufficiently low to allow a monoexponential description of the plasma disappearance curve and for choosing the first sampling time instant. Closed form equations are proposed for determining the optimal test dose and the second sampling time. Result are derived for a particular heteroscedastic measurement noise description, and the problem of robustness with respect to interpatient variability of kinetic parameters is addressed. PMID- 10092030 TI - Development of a 3-D measurement and evaluation system for facial forms with a liquid crystal range finder. AB - A 3-D measurement and evaluation system for facial forms was developed with a liquid crystal range finder (LCRF). Its mechanical resolution was approximately/= 0.4 mm, and it was capable of measuring >30000 points from the entire facial surface in one second. An original program was developed to identify facial landmarks using not only linear distances, but also 3D-curvatures and discriminant analysis of the RGB data. With this program, the 3-D identification of anthropometrical points became possible with high accuracy. Due to the rapidity of the measuring apparatus and morphological evaluation system, it became possible to analyze the facial forms of infants such as cleft lip patients three dimensionally, without any sedation. Therefore, 97 normal infants (mean: 4.3 months of age) were measured and analyzed with this system. A cleft lip infant was measured and compared with the normal infants before and after cleft lip surgery, and the improved points and remaining problems were clearly recognized. PMID- 10092031 TI - Simple and powerful visual stimulus generator. AB - We describe a cheap, simple, portable and efficient approach to visual stimulation for neurophysiology which does not need any special hardware equipment. The method based on an animation technique uses the FLI autodesk animator format. This form of the animation is replayed by a special program ('player') providing synchronisation pulses toward recording system via parallel port. The 'player is running on an IBM compatible personal computer under MS-DOS operation system and stimulus is displayed on a VGA computer monitor. Various stimuli created with this technique for visual evoked potentials (VEPs) are presented. PMID- 10092032 TI - A methodology for simulating biological systems using Microsoft Excel. AB - The objective of this present study was to develop a simple, easily understood methodology for solving biologically based models using a Microsoft Excel spreadsheet. The method involves the use of in-cell formulas in which Rows and Columns of new data are generated from data typed into the spreadsheet, but does not require any programming skills or use of the macro language. The approach involves entering the key parameter values into the spreadsheet and conducting the simulation by solving a set of equations based on these parameter values. The examples used in this paper are firstly, a simple voltage clamp simulation in which initial parameter values are used to calculate a system in steady state. The second example is a current clamp simulation where steady state is not reached and the solution of the equations for each time increment is used as the input for the next time increment in the simulation. The calculations are based on the Hodgkin Huxley mathematical equations that describe the voltage dependence of ion channel behavior. The problems and flexibility of the method are briefly discussed. The methodology developed in this present study should help novice modelers to create simple simulations without the need to learn a programming language or purchase expensive software. PMID- 10092033 TI - A software implementation for detailed volume conductor modelling in electrophysiology using finite difference method. AB - There is an evolving need for new information available by employing patient tailored anatomically accurate computer models of the electrical properties of the human body. Because construction of a computer model can be difficult and laborious to perform sufficiently well, devised models have varied greatly in the level of anatomical accuracy incorporated in them. This has restricted the validity of conducted simulations. In the present study, a versatile software package was developed to transform anatomic voxel data into accurate finite difference method volume conductor models conveniently and in a short time. The package includes components for model construction, simulation, visualisation and detailed analysis of simulation output based on volume conductor theory. Due to the methods developed, models can comprise more anatomical details than the prior computer models. Several models have been constructed, for example, a highly detailed 3-D anatomically accurate computer model of the human thorax as a volume conductor utilising the US National Library of Medicine's (NLM) Visible Human Man (VHM) digital anatomy data. Based on the validation runs the developed software package is readily applicable in analysis of a wide range of bioelectric field problems. PMID- 10092034 TI - Comparison of haemorrheological parameters and blood pressure in various breeds of dog. AB - Relationships between blood pressure and haemorrheological factors were examined in three groups of dogs characterised by different levels of blood pressure. The groups used were sight hounds (high pressure), retrievers (low pressure) and a mixed group with intermediate pressure. The three groups had different levels of haematocrit and blood viscosity at both high and low shear rates, with the sight hounds showing the highest and retrievers showing the lowest levels for each of the parameters. The plasma viscosities did not differ significantly between the groups. Blood pressure and blood viscosity or haematocrit were not correlated within dog groups, but when the dog groups were considered together, significant positive correlations existed between pressure and viscosity and pressure and haematocrit. PMID- 10092035 TI - Temporomandibular ankylosis in the cat: a review of seven cases. AB - Ankylosis of the temporomandibular joint (TMJ) in the cat is an unusual complication of traumatic lesions involving articular (true ankylosis) or periarticular structures (false ankylosis). Seven cats with true ankylosis of the TMJ (four cases unilateral and three cases bilateral), of which previous trauma had been documented in five cases, were referred to the authors' clinic between September 1991 and October 1996. Radiographic assessment was performed in all cases, using dorsoventral and oblique projections. Five subjects underwent arthroplastic excision of the TMJ and, in the remaining two cases, stretching of the jaws was performed under general anaesthesia. The surgical outcome was satisfactory in all but one case, where partially decreased joint mobility was observed (follow-up time one to five years), but in the two cases where non surgical treatment was carried out, recurrence of TMJ ankylosis was observed (follow-up time two to five months). In the authors' experience, surgery represents the treatment of choice for TMJ ankylosis in cats. Additional mandibular symphysiotomy can confirm the radiological findings in unilateral cases. PMID- 10092036 TI - Owner perception of the care of long-term phenobarbital-treated epileptic dogs. AB - A study was undertaken to evaluate owners' perception of the effect that epilepsy and long-term phenobarbital therapy had on the quality of pet and owner lifestyle. Selected owners who participated in a prospective, longitudinal clinical epilepsy study were sent a questionnaire at the end of the two-year study. Inclusion criteria were dogs with a history of seizures without previous medical attention or therapy by any veterinarian before enrolment, subsequent determination of seizure aetiology using a standardised diagnostic protocol and treatment with phenobarbital for a minimum period of six months. A relatively equal distribution of the respondents' dogs had a determined (secondary, 47 per cent) or undetermined (primary, 53 per cent) seizure aetiology, and the vast majority of owners agreed that they would choose to treat their epileptic pet again rather than opt for other alternatives. Most owners disagreed that their pet was leading a poor quality of life after the start of phenobarbital therapy. A significant negative correlation existed between an owner's perception of the pet's quality of life and the amount of work required to care for the pet during the two-year study period. This study demonstrates that many owners are willing to care for epileptic dogs on long-term phenobarbital treatment, regardless of the underlying cause. PMID- 10092037 TI - Resolution of paraneoplastic alopecia following surgical removal of a pancreatic carcinoma in a cat. AB - A 13-year-old female neutered domestic longhaired cat was presented with a five month history of progressive weight loss and bilaterally symmetrical alopecia of the ventrum, limbs and perineum. The alopecic skin had a shiny appearance and hair in the non-alopecic areas was easily epilated. Fine needle aspirate cytology of a palpable cranial abdominal mass revealed it to be of epithelial or glandular origin. A pancreatic mass was excised by left pancreatectomy during exploratory laparotomy, and histopathology and skin biopsies confirmed a diagnosis of pancreatic carcinoma with concurrent paraneoplastic alopecia. No evidence of metastases was found on liver and lymph node biopsies. At re-examination 10 weeks after surgery, the hair had fully regrown. Skin signs recurred after 18 weeks and metastatic spread of the tumour was confirmed on postmortem examination. This case confirms that paraneoplastic alopecia associated with internal malignancies is a potentially reversible process if the internal neoplasm is excised. PMID- 10092038 TI - Feline granulocytic ehrlichiosis--a report of a new clinical entity and characterisation of the infectious agent. AB - A 14-month-old shorthaired cat was presented to the Animal Hospital in Skara, Sweden, with a two-day history of lethargy, anorexia and tachypnoea. Clinical examination and laboratory investigations revealed fever, dehydration, tick infestation, neutrophilia with left shift, lymphopenia, hyperglycaemia and intracytoplasmic neutrophilic Ehrlichia inclusions. After treatment with intravenous doxycycline and lactated Ringer's solution the temperature returned to normal. Oral treatment with doxycycline continued for 20 days. The ehrlichiosis diagnosis was confirmed by serology, polymerase chain reaction and DNA sequencing. No relapse was observed during the eight-month follow-up period. The granulocytotropic Ehrlichia strain found in the cat was later characterised by analysis of the 16S rRNA gene sequence which showed 100 per cent identity to DNA sequences found in Swedish canine and equine granulocytotropic Ehrlichia strains. This is, to the best of the authors' knowledge, the first reported case of granulocytic ehrlichiosis in a cat. PMID- 10092039 TI - Intestinal haemorrhage associated with colonic vascular ectasia (angiodysplasia) in a dog. AB - An eight-year-old, sexually intact, male, 37 kg crossbred dog was referred for investigation of two acute episodes of intestinal bleeding and severe anaemia within a five-month period. There was no evidence of coagulopathy or underlying systemic disease. Technetium-labelled red blood cell scintigraphy suggested the colon as the site of bleeding. Colonoscopy identified a focal area of dilated and tortuous mucosal blood vessels. Histopathology of the resected colon revealed vascular ectasia (angiodysplasia). At nine months post-resection, the dog remained healthy and free of any overt intestinal haemorrhage. PMID- 10092040 TI - Lipid storage myopathy in a cocker spaniel. AB - A six-year-old male cocker spaniel was presented to the Veterinary Medical Teaching Hospital, University of Florida, with a three-week history of generalised weakness and myalgia. Electrodiagnostic evaluation, cerebrospinal fluid analysis and thoracolumbar myelography were unremarkable. Biopsies from vastus lateralis and triceps muscles revealed numerous large lipid droplets within type 1 fibres and to a lesser degree within type 2 fibres. The resting plasma lactate was mildly increased and there was elevated urinary excretion of lactic, pyruvic and acetoacetic acids, increased urinary excretion of carnitine esters, and increased plasma alanine. This pattern of metabolite excretion is consistent with an, as yet undefined, block in oxidative metabolism. PMID- 10092041 TI - Congress '99: what's new in the treatment of lymphoma? PMID- 10092042 TI - Analysing hippocampal function in transgenic mice: an ethological perspective. AB - Advances in molecular genetics and technology have led to the dawn of a new era for neuroscience: manipulation of single genes now makes it possible to dissect the complexities of neurobiological phenotypes and to understand many of the intricacies of brain and behaviour, even in mammals. The phenotypical analysis of these mutant animals is complicated because the potential outcome of gene manipulation is difficult to predict. While behavioural analysis should form an integral part of any multidisciplinary research programme investigating the phenotypical effects of single genes on hippocampal function, it is crucial that the behavioural tests are designed and conducted appropriately. Approaches that take species-specific behavioural characteristics into account and use ethological methods could be the most useful for interpreting these behavioural findings and understanding the biological mechanisms of brain function. PMID- 10092043 TI - Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. AB - The emergence of a new generation of stereological techniques for counting objects in histological sections has prompted a debate about whether or not these methods are better than previously available techniques when they are used to make estimates of the total numbers of neurons and synapses in a neural structure. During this debate, the concepts of an unbiased estimate and that of a precise estimate have often been confused. A full understanding of the distinction between these two separate aspects of an estimate is required in order to be able to appreciate the virtues of these new counting methods and to apply them correctly. This review intends to make the fundamental issues of this debate more clear, and describes (1) the fundamental differences between the newer design-based counting techniques and previously available assumption-based techniques, and (2) the distinction between an unbiased estimate and a precise estimate. PMID- 10092044 TI - Molecular murder. PMID- 10092045 TI - Feeding and body-weight regulation by hypothalamic neuropeptides--mediation of the actions of leptin. AB - Neuropeptides are essential for the regulation of appetite and body weight within the hypothalamus. The understanding of the neuropeptide regulation of energy homeostasis has been greatly advanced by the recent discovery of leptin, the protein product of the obese gene (ob). Significant new insights into the relationship between peripheral adiposity signals and their impact on the hypothalamic neuropeptide signaling circuitry have provided some crucial missing links in the negative-feedback regulation of appetite and body weight. The neuropeptide Y orexigenic network is a final common pathway for this signaling cascade and, along with feeding-inhibitory neuropeptides such as melanocortin, corticotropin-releasing factor and glucagon-like peptide 1, it is a major target through which leptin exerts a regulatory tonic restraint on body adiposity. PMID- 10092046 TI - Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders. AB - Cholinergic neurons originating in the basal forebrain innervate all cortical areas and participate in the gating of cortical information processing. Aberrations in the excitability of cortical cholinergic inputs fundamentally alter the processing of sensory stimuli and higher processes, thereby advancing the development of major neuropsychiatric disorders. Cortical cholinergic deafferentation has been considered to be a major neuropathological variable that contributes to the development of age- and dementia-associated impairments in cognition. Conversely, it has been suggested that increases in the excitability of cortical cholinergic inputs mediate the abnormal cognitive processes that escalate into psychotic symptoms and contribute to addictive-drug-seeking behavior, anxiety and phobia. Abnormal regulation of the excitability of cortical cholinergic afferents represents a 'final common pathway' that mediates the manifestation of major neuropsychiatric disorders. PMID- 10092047 TI - Auditory cortical plasticity: a comparison with other sensory systems. AB - The auditory cortex has a crucial role in higher cognitive functions, including the perception of speech, music and auditory space. Cortical plasticity, as in other sensory systems, is used in the fine tuning of the auditory system for these higher functions. Auditory cortical plasticity can also be demonstrated after lesions of the cochlea and it appears to participate in generating tinnitus. Early musical training leads to an expansion in the representation of complex harmonic sounds in the auditory cortex. Similarly, the early phonetic environment has a strong influence on speech development and, presumably, on the cortical organization of speech. In auditory spatial perception, the spectral cues generated by the head and outer ears vary between individuals and have to be calibrated by learning, which most probably takes place at the cortical level. The neural mechanisms of plasticity are likely to be the same across all cortical regions. It should be useful, therefore, to relate some of the findings and hypotheses about auditory cortical plasticity to previous studies of other sensory systems. PMID- 10092048 TI - Multiple genes for neuropeptides and their receptors: co-evolution and physiology. AB - It is now well established that neuropeptide receptors, which are present throughout the CNS and in peripheral tissues, frequently exist in a variety of different forms (called subtypes), each of which is encoded by a distinct gene. With the recent identification of new neuropeptide genes, it has become clear that families of neuropeptides also occur, which raises the possibility that specific peptide ligands activate particular receptor subtypes preferentially. This article reviews some of the recent advances in the neuropeptide field and provides evidence in support of three ideas: (1) that different receptor subtypes for a given ligand can be distinguished physiologically; (2) that neuropeptide genes probably arose before the corresponding receptor genes; and (3) that, despite the current wealth of information on neuropeptides and neuropeptide receptors, several new members are likely to be discovered before the beginning of the next millennium. PMID- 10092049 TI - Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function. AB - The application of caged-Ca2+ compounds to the study of Ca2+-dependent exocytosis has begun to reveal kinetic intermediates in this important process. The time course of exocytosis varies greatly among different cell and vesicle types, even in response to Ca2+ 'jumps' of identical amplitude. The kinetics of the binding of Ca2+ to the putative Ca2+ sensor for exocytosis also vary. Theoretical analysis reveals that the kinetic diversity of exocytotic and Ca2+-binding reactions has distinct roles in determining the probability of exocytosis occurring. It is proposed that both of these reactions are optimized for the secretory function of specific cell types and that the exocytotic reaction includes vesicle translocation in addition to the fusion of vesicles with the plasma membrane. PMID- 10092050 TI - Salicylate-induced kidney mitochondrial permeability transition is prevented by cyclosporin A. AB - The effect of salicylate, the active metabolite of aspirin (acetyl salicylic acid) in the presence of Ca2+ and phosphate on mitochondrial permeability transition (MPT) was studied. MPT is often associated with opening of a Ca2+ induced pore. The opening of this pore leads to swelling, loss of mitochondrial membrane potential and release of accumulated Ca2+. In freshly isolated rat kidney mitochondria, salicylate (400 microM) in the presence of 20 nmol Ca2+/mg protein and 0.1 mM phosphate induced swelling, loss of mitochondrial membrane potential and release of accumulated Ca2+. All these changes were eliminated when cyclosporin A (1 microM), (a pore inhibitory agent) was included in the incubation medium. Unlike salicylate, unhydrolyzed aspirin (400 microM) induced these changes slightly. We concluded that salicylate acts as an activator of Ca2+ and phosphate in promoting the opening of kidney inner mitochondrial membrane pore. As a result a great consideration should be given to its toxicological effect. PMID- 10092051 TI - Apoptotic photoreceptor cell death induced by quinolone phototoxicity in mice. AB - We examined retinal degeneration induced by phototoxicity of quinolone antibacterial agents. Albino Balb/c and pigmented DBA/2 mice fasted overnight were given a single oral administration of ciprofloxacin (CPFX), levofloxacin (LVFX), enoxacin (ENX), lomefloxacin (LFLX) or sparfloxacin (SPFX), followed by ultraviolet-A (UVA) irradiation at 1.5 mW/cm2 for 4 h (21.6 J/cm2). At 24 h after quinolone administration, the mice were sacrificed, and the eyes were then histologically examined. ENX or LFLX at 200 or 400 mg/kg or SPFX at 50 or 100 mg/kg plus UVA induced retinal degeneration in Balb/c mice, whereas no histological change was observed in the eyes of DBA/2 mice. CPFX and LVFX at 800 mg/kg plus UVA had no effect on the eyes in either Balb/c or DBA/2 mice. Agarose gel electrophoresis showed that chromosomal DNA extracted from the eyes of Balb/c mice was fragmented in the SPFX 100 mg/kg group, but not in the LVFX 800 mg/kg group. In the electron microscopic examination, swelling of mitochondria and disruption of the cytoplasm were observed in the photoreceptor inner segment (PIS) at 2 h, and disarrangement of lamellar disks in the outer segment (POS) and condensed chromatin in photoreceptor cell nuclei in the outer nuclear layer (ONL) were observed at 4 h after 100 mg/kg SPFX administration to Balb/c mice. These results suggest that quinolone plus UVA irradiation induces retinal degeneration in albino Balb/c mice, but not in DBA/2 mice, and this degeneration is associated with apoptotic photoreceptor cell death. PMID- 10092052 TI - Effect of environmental pollutants on the production of pro-inflammatory cytokines by normal human dermal keratinocytes. AB - The effect of the environmental pollutants, diesel exhaust particles (DEP) and formaldehyde (FA), on the production of pro-inflammatory cytokines (interleukin (IL)-1alpha, IL-1beta, tumor necrosis factor (TNF)-alpha and IL-8) by normal human dermal keratinocytes (hKCs) was investigated. Normal hKCs were incubated with various concentrations of DEP (0.4, 0.8, 4, or 20 microg/ml) or FA (0.25, 0.5, 1, or 5 microg/ml), and cytokine production was then determined by enzyme linked immunosorbent assay (ELISA). DEP (20 microg/ml) induced IL-1beta production without altering cell growth. The increased production of IL-1beta induced by this concentration of DEP was further enhanced by the presence of phorbol 12-myristate 13-acetate (PMA), although PMA alone did not affect the levels of IL-1beta. IL-8 production was also increased by DEP (0.4 and 0.8 microg/ml), which is consistent with the results that these concentrations of DEP increased the number of cells significantly after 72 h incubation. Although FA alone did not stimulate the production of IL-1beta or IL-8 by keratinocytes, FA (0.5 microg/ml and 5 microg/ml) significantly increased IL-8 and IL-1beta production, respectively, in cells stimulated with PMA. IL-1alpha production was not modulated by FA or DEP even in the presence of PMA. TNF-alpha was produced by unstimulated keratinocytes at barely detectable levels after 48 h incubation. Although basal levels of TNF-alpha in the culture supernatants were increased after stimulation with PMA, neither pollutant alone nor combination with PMA affected the levels of TNF-alpha. These in vitro findings suggest that environmental pollutants may act as modulating factors of cutaneous inflammation by affecting the ability of keratinocytes to release pro-inflammatory cytokines. PMID- 10092053 TI - Modulation of halobenzene-induced hepatotoxicity by DT-diaphorase modulators, butylated hydroxyanisole and dicoumarol: evidence for possible involvement of quinone metabolites in the toxicity of halobenzenes. AB - Recent metabolic studies have demonstrated the importance of reactive intermediates like quinones or semiquinone radicals in the covalent binding of halobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobenzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-electron reduction of the quinone intermediates by DT-diaphorase is considered to be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisole (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dicoumarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BB (2.5 or 3.5 mmol/kg, i.p.) or 1,2,4-TCB (0.75 or 1.5 mmol/kg, i.p.). Dietary BHA markedly suppressed the hepatotoxicity caused by both BB and 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BB at different times after the end of dietary BHA exposure, the degree of the protection against the hepatotoxicity appears to correlate to the extent of the induction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment failed to protect against carbon tetrachloride-induced hepatotoxicity. These results seem to provide evidence for the involvement of the quinone metabolites in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity. PMID- 10092054 TI - Contribution of aerosols generated during mixing and loading of pesticides to operator inhalation exposure. AB - The occupational exposure resulting from the application of crop protection agents continues to be of great interest for the purposes of identifying hazards or determining safer chemical handling methods. The purpose of the present study was to identify the potential respirator exposure of a mixer/loader to chlorothalonil, with the mixing and loading operation as the only source of aerosols (particles <13 microm diameter). Three worst-case mixing/loading scenarios were simulated in the lab: (1) a spill of undiluted chlorothalonil formulation onto a dry, horizontal metal surface; (2) a spill of undiluted chlorothalonil formulation onto a rapidly rotating shaft; and (3) pouring undiluted chlorothalonil formulation into a container of water. Aerosol generation from these scenarios was compared to that resulting from atomizing dilute chlorothalonil through hydraulic nozzles. Aerosols were captured with a cascade impactor, and quantified by gas chromatography. Results indicated that simulated spill scenarios generated aerosol concentrations between 2.1 and 5.3 ng/l, which were in the same order of magnitude as, and only marginally higher than, the detection threshold (1.7 ng/l) and background levels (2.2 ng/l). In comparison, atomization of dilute chlorothalonil through a hollow cone and flat fan nozzles resulted in airborne concentrations of 354 and 96 ng/l, respectively, related to the atomization characteristics of these nozzles. Measurement of the dimensions of the aerosol cloud indicated that aerosols resulting from a spill amounted to approximately 10(-5)% of the spilled chlorothalonil. It was estimated that a male worker respiring 29 l/min would inhale approximately 0.32-0.78 ng of chlorothalonil during a typical 30 s spill, assuming a 1% transfer efficiency between the spill site and the mixer/loader. These estimates were between 10000 and 480000 times less than literature data for respiratory exposure of chlorothalonil by applicators and harvesters, suggesting that inhalation of aerosols from mixing and loading represents a minor component of overall exposure. PMID- 10092055 TI - Pretreatment of male BALB/c mice with beta-ionone potentiates thioacetamide induced hepatotoxicity. AB - A possible role of metabolic activation by cytochrome P450 (P450) in thioacetamide-induced hepatotoxicity was investigated in male BALB/c mice. The mice were pretreated with the P450 inducer, beta-ionone, subcutaneously at 600 mg/kg, 72 and 48 h prior to an intraperitoneal administration of either 100 or 200 mg/kg of thioacetamide. The elevated activities of serum alanine aminotransferase and serum aspartate aminotransferase by thioacetamide were greatly potentiated by the pretreatment with beta-ionone. Moreover, the potentiation of thioacetamide-induced hepatotoxicity was also observed in the histopathological examination of livers. The hepatic necrosis by thioacetamide was potentiated when mice were pretreated with beta-ionone. In liver microsomes, the activities of P450 2B-specific pentoxyresorufin O-depentylase and benzyloxyresorufin O-debenzylase were significantly induced by the treatment with beta-ionone. Beta-ionone also induced other P450-associated monooxygenases. Because the pretreatment with beta-ionone was not hepatotoxic at the dose inducing P450s. our present results suggest that beta-ionone may be a useful model inducer of P450 enzyme(s) in studying toxic mechanism of certain chemicals which require metabolic activation by P450s in mice. PMID- 10092056 TI - A comparison of the effects of verocytotoxin-1 on primary human renal cell cultures. AB - Infection with verocytotoxin-producing Escherichia coli causes haemolytic uraemic syndrome (HUS). Verocytotoxin-1 (VT1) is cytopathic to renal microvascular endothelial cells in culture, supporting the hypothesis that the vasculopathy of HUS is caused directly by the toxic action of VT1 on cells. We provide evidence that VT1 inhibits protein synthesis in primary cultures of glomerular epithelial cells (GE), cortical tubular epithelial cells (CTE) and mesangial cells (MC). Using 100 pg/ml of VT1 we saw a decrease in protein synthesis to 14.3+/-1.9% in vero cells (a primate cell line), 1.7+/-0.3% in GE, 0.9+/-0.4% in CTE and 74.8+/ 1.3% in MC at 24 h. The human renal epithelial cells are at least as sensitive as vero cells to the protein synthesis inhibitory effects of VT1 if not more so. Cell viability decreased in all cultures as measured by MTT reduction, neutral red incorporation and lactate dehydrogenase release and followed the same pattern of susceptibility as for protein synthesis inhibition. However, unlike vero cells, death occurred without DNA fragmentation. Cell sensitivity was greatest in cells which bound more VT1. PMID- 10092057 TI - Disposition of lantadene A, the pentacyclic triterpenoid hepatotoxin, orally administered to guinea pigs. AB - Lantadene A (LA) administered orally to guinea pigs elicited cholestasis. LA could not be detected in liver, bile, gall bladder, blood and urine. LA and its biotransformation product reduced lantadene A (RLA) could be detected in caecum, large intestine, and faeces. In vitro incubation of LA with liver homogenates under aerobic and anaerobic conditions did not elicit its biotransformation to RLA. On the other hand, in vitro incubation of LA with guinea pig caecal and large intestinal contents under anaerobic conditions elicited conversion of LA to RLA. This is the first report of the biotransformation of LA in the animal system. PMID- 10092059 TI - Effect of age on vanadium nephrotoxicity in rats. AB - The present study was designed to assess potential age dependent differences of vanadium nephrotoxicity in the rat following parenteral administration of vanadate. Young (22 days) and adult (62 days) male Sprague-Dawley rats received i.p. injections of sodium orthovanadate at 10 mg/kg/day for 8 consecutive days. Two additional groups of control rats received i.p. injections of 0.9% saline during the same period. Significant age-differences were found in most of the parameters used as indicators of nephrotoxicity in young and adult rats, with adverse renal effects being more severe with age. Vanadium-induced morphologic changes in the kidney were also more pronounced with age. These findings agree with a higher renal concentration of vanadium in the group of adult rats treated with vanadate than in the vanadate-untreated group. The current results can be of concern if in the future, vanadium compounds can be administered in the treatment of diabetic patients. PMID- 10092058 TI - The plant ribosome inactivating protein saporin induces micronucleus formation in peripheral human lymphocytes in vitro. AB - Saporin belongs to the family of plant enzymes known as ribosome inactivating proteins (RIPs) for their property to depurinate the major rRNA, thus leading to inactivation of ribosomes. In this work we analyzed the genotoxic effects of saporin, purified from root cultures of Saponaria officinalis, by evaluating micronucleus formation and by the quantitative determination of cytosolic histone associated DNA fragments. Saporin induces micronuclei formation in cultured human lymphocytes in a dose dependent manner; treated lymphocytes show a decrease in cell viability and a concomitant increase in the apoptotic response evidenced by the appearance of cytosolic oligonucleosomes. On the other hand saporin treatment failed to induce sister-chromatid exchange (SCE) at any of the doses tested. PMID- 10092060 TI - Metabolism of methyl tert-butyl ether and other gasoline ethers in mouse liver microsomes lacking cytochrome P450 2E1. AB - To reduce the production of pollutants in motor vehicle exhaust, methyl tert butyl ether (MTBE) and other ethers such as ethyl tert-butyl ether (ETBE) and tert-amyl methyl ether (TAME) are added to gasoline as oxygenates for more complete combustion. Metabolism of these gasoline ethers is catalyzed by cytochrome P450 (P450) enzymes. P450 2E1, which metabolizes diethyl ether, was suggested to be an enzyme involved. The present study used 2E1 knock-out mice (2E1-/-) to assess the contribution of 2E1 to the metabolism of MTBE, ETBE and TAME. Liver microsomes prepared from the 2E1 knock-out mice lacked 2E1 activity (assayed as N-nitrosodimethylamine demethylation), but were still active in metabolizing all three gasoline ethers. The levels of ether-metabolizing activity (nmol/min per mg) in the liver microsomes from 7 week old female 2E1 knock-out mice were 0.54+/-0.17 for MTBE, 0.51+/-0.24 for ETBE and 1.14+/-0.25 for TAME at a 1 mM substrate concentration. These activity levels were not significantly different from those of the sex- and age-matched C57BL/6N and 129/Sv mice, which are the parental lineage strains of the 2E1 knock-out mice and are both 2E1+/+. Our results clearly demonstrate that 2E1 plays a negligible role in the metabolism of MTBE, ETBE and TAME in mouse livers. PMID- 10092061 TI - Differential expression of key cell cycle genes (p16/cyclin D1/pRb) in head and neck squamous carcinomas. AB - Cyclin D1, p16, and Rb are key genes that play critical roles in the control of G1/S cell cycle progression and cellular homeostasis. To assess the differential expression of these genes in the biologic evaluation of head and neck squamous carcinoma (HNSC), we analyzed their protein expression in 11 cell lines and 46 primary tumors by Western blotting and correlated the results with clinicopathologic factors. In all cell lines, reciprocal expression between p16 and cyclin-D1 and Rb proteins was noted; p16 protein was detected in one (9%) cell line that lacked Rb and cyclin D1 and was absent in 10 of the cell lines (91%) that expressed both cyclin D1 and Rb proteins. Similar, albeit less striking, results were obtained in primary tumors: 30 tumors (65%) lacked p16 expression, and 33 tumors (72%) and 38 tumors (83%) expressed Rb and cyclin D1 proteins, respectively. p16 and Rb proteins were inversely expressed in 72% of tumors and in all cell lines. Except for gender and age, no significant correlation between protein expression and the clinicopathologic factors was found. Our results indicate that (1) loss of the p16 protein may constitute an early event in the development of these HNSC, (2) the reciprocal expression of p16 and Rb suggests a tight regulatory interaction between these genes in HNSC tumorigenesis, and (3) alteration in at least one of these genes might be required for HNSC development and progression. PMID- 10092062 TI - Expression of CD40/CD40 ligand and Bcl-2 family proteins in labial salivary glands of patients with Sjogren's syndrome. AB - Lymphocytes infiltrating the salivary glands of patients with Sjogren's syndrome (SS) are activated and resist apoptosis. We determined the role of interactions between CD40 and CD40 ligand (CD40L) in these infiltrating lymphocytes on B-cell differentiation and expression of Bcl-2 family proteins. Ten human T-cell leukemia/lymphoma virus-I (HTLV-I)-seronegative and eight HTLV-I-seropositive SS patients were examined in the present study. Immunohistochemistry was performed to examine the expression of CD3, CD20, PCA-1, CD40, CD40L, Bcl-2, Bax, and Bcl-x on T and B lymphocytes infiltrating labial salivary glands of SS patients. We also examined the expression of CD40 and CD40L on peripheral blood lymphocytes of the same patients by using flow cytometry. CD40L was not expressed on peripheral blood lymphocytes of SS patients. Peripheral blood B cells but not T cells expressed CD40. In contrast, >50% of mononuclear cells, including T and B cells infiltrating the glands, expressed CD40. In addition, a clear expression of CD40L in both infiltrating T cells and B cells, and that of PCA-1, was also demonstrated. Surprisingly, the expression of Bcl-2 and Bcl-x was colocalized with that of CD40 determined by mirror section technique. Bcl-x was also abundantly expressed on infiltrating mononuclear cells, but, Bax expression was relatively less than that of Bcl-2 or Bcl-x. The expression of the above molecules was not different between HTLV-I-seronegative and HTLV-I-seropositive SS patients. Our results indicate that CD40/CD40L pathways could be augmented in salivary glands of SS patients, inducing B-cell differentiation to PCA-1 + plasma cells. Immunohistochemical analysis also suggests that signaling through CD40 by means of CD40L increases the expression of Bcl-2 as well as Bcl-x in infiltrating lymphocytes, providing the resistance against apoptosis. Our findings were commonly observed in SS patients irrespective of HTLV-I seropositivity. PMID- 10092063 TI - MDR1 gene expression in primary and advanced breast cancer. AB - P-glycoprotein (Pgp)-associated multidrug resistance (MDR) is related to intrinsic and acquired cross resistance to anthracyclines, vinca alkaloids, and other antineoplastic antibiotics. Expression of MDR1 is widely considered to play an important role in conferring resistance to adjuvant chemotherapy in women with breast tumor cells in women with disseminated disease, although data supporting this view is, at best, conflicting. The expression of MDR1 gene and its gene product, P-glycoprotein, was investigated in primary and advanced breast cancers (both previously untreated and previously treated on specific treatment protocols) to assess the role of P-glycoprotein in determining responsiveness to adjuvant chemotherapy. Expression was assessed by immunohistochemistry, reverse transcription-PCR (RT-PCR), Northern Blot and Western Blot. MDR1 mRNA was detected in 40% of the breast cancers tested by RT-PCR with 40 cycles of PCR amplification. When reducing the PCR amplification cycles to 28, the MDR1 gene expression signal disappeared from breast cancers of the highest expressers; however, known MDR1 positive control normal tissues, such as adrenal, kidney, and liver continued to show an expression product. Western and Northern blots failed to demonstrate the MDR1 gene product, P-glycoprotein, in these breast cancers. In contrast, physiologic levels of P-glycoprotein was clearly detected in normal adrenal, kidney, and liver by these techniques. Immunohistochemistry confirmed that breast carcinoma cells lacked P-glycoprotein expression; however, interstitial mononuclear cells, morphologically consistent with lymphocytes or macrophages did show immunostaining in some of these breast tumors. MDR1 gene expression identified by RT-PCR was not correlated either with response to paclitaxel therapy (29 patients able to be evaluated, p = 0.34, Fisher Exact Test) or overall survival (32 breast cancer patients with clinical follow-up information, p = 0.336, log rank). In conclusion, P-glycoprotein was not expressed in breast carcinoma cells at significant levels, although it was expressed in stomal lymphocytes or macrophages. These results suggest that P glycoprotein does not play a significant role in multidrug resistance of breast cancer. PMID- 10092064 TI - Differential tissular expression and localization of type IV collagen alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) chains and their mRNA in normal breast and in benign and malignant breast tumors. AB - Type IV collagen, the major component of basement membrane (BM), is composed of six genetically distinct alpha chains. We investigated the cellular regulation and origin of these alpha(IV) chains in normal and neoplastic breast tissues by immunohistochemistry by using alpha(IV) chain-specific antibodies and by in situ hybridization. In normal breast, alpha1(IV) and alpha2(IV) chains were stained in all BM, whereas alpha5(IV) and alpha6(IV) chains were restrictively localized in a linear pattern in the BM of the mammary gland. Similar immunostaining profiles were observed in benign breast tumors and in the intraductal components of invasive ductal carcinoma. However, in invasive ductal carcinoma, alpha1(IV) and alpha2(1V) chains were discontinuously or negatively stained in the cancer cell nests, and the assembly of alpha5(IV) and alpha6(IV) chains into the BM was completely inhibited. Coexpression of alpha5(IV) and alpha6(IV) chains was related to the localization of alpha-smooth muscle actin (alpha-SMA)-positive myoepithelial cells. By in situ hybridization, in fibroadenoma and invasive ductal carcinoma, the signals for alpha1(IV) and alpha2(IV) mRNA were abundant in stromal cells. However, the signals for alpha5(IV) and alpha6(IV) mRNA were not seen in any of these cells. In contrast, in intraductal papilloma, coexpression of alpha1 (IV)/alpha2(IV) mRNA and alpha5(IV)/alpha6(IV) mRNA was identified in epithelial cells. The results indicate that the mammary gland forms a second network of BM composed of alpha5(IV)/alpha6(IV) chains, in addition to the classic network of alpha1(IV)/alpha2(IV) chains. The expression of type IV collagen alpha chains seems to be differentially regulated by the epithelial myoepithelial interaction and to be associated with the invasive potential of breast cancer. PMID- 10092065 TI - Developmental abnormalities of glycosylphosphatidylinositol-anchor-deficient embryos revealed by Cre/loxP system. AB - One mode used to link membrane proteins to a cell membrane is by means of a special glycolipid anchor termed glycosylphosphatidylinositol (GPI). Pig-a, an X linked gene, is involved in the first step of GPI-anchor biosynthesis. Disruption of this gene causes cessation of GPI biosynthesis on the endoplasmic reticulum, thereby leading to the absence of GPI-anchored proteins on the cell surface. We have previously reported that mice with high chimerism was never obtained from Pig-a disrupted ES cells, suggesting that GPI-anchored protein(s) may have important roles for mouse development such that the absence of GPI-anchored proteins causes a lethal effect to mice. In this study, this lethal effect has been investigated by using a conditional approach to "knockout" the Pig-a gene. For this, mice harboring a Pig-a gene flanked by two loxP sites (Pig-aflox) were mated with hCMV-Cre transgenic mice, which express Cre recombinase before implantation. The allele disruptions were identified by PCR analysis of embryo yolk sac DNA. Embryos harboring a complete disruption of Pig-a gene ceased to develop beyond the ninth day of gestation. Female embryos in which one Pig-a allele was disrupted by Cre such that only half of the cells in the embryo proper did not express GPI-anchored proteins due to random X inactivation developed until 19 days post coitum (dpc), but showed abnormal phenotypes such as insufficient closure of neural tube and cleft palate. These data further highlight the importance of GPI-anchored proteins during mouse embryonic development. PMID- 10092066 TI - Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin. AB - Although the gene responsible for multiple endocrine neoplasia, type 1 (MEN1) has been identified recently, the function of its gene product, menin, is not known. To examine menin's biological role, we created an N-terminal tagged fusion protein to follow the distribution of menin in the cell. In all cell lines tested, menin was found both in the nucleus and the cytoplasm, but its localization was dependent on the phase of the cell cycle; during a nondividing phase, menin was found in the nucleus; during and immediately after cell division, it was found in the cytoplasm. To confirm the cellular localization seen with the N-terminal tagged protein, we developed and purified peptide specific antibodies. One of these antibodies (NCI 624), which recognizes a domain (aa 383-395) of menin, was used in immunofluorescence studies to corroborate the N-terminal tagging results. Further confirmation of menin localization was obtained in a pituitary tumor cell line derived from a familial MEN1 patient, which contained a mixed cell population with either none, or one functional copy of the MEN1 gene. Our results indicate that menin functions principally as a nuclear protein but may be found in the cytoplasm during cell division. PMID- 10092067 TI - Duplications of DNA sequences between loci D20S478 and D20S206 at 20q11.2 and between loci D20S902 and D20S480 at 20q13.2 mark new tumor genes in papillary renal cell carcinoma. AB - Trisomy of chromosome 20 is associated with the progression of papillary renal cell carcinomas (RCC). To define the gene loci, we have analyzed 40 tumors by applying 18 polymorphic microsatellite markers. An allelic imbalance at all informative loci was seen in 14 cases. Partial duplications of chromosome 20 in 14 tumors delineated four nonsyntenic regions: region A at chromosome 20p12-p13, regions B and C at chromosome 20q11.2, and region D at chromosome 20q13.2. Region B was bracketed by loci D20S206 and D20S478, both mapped to 54 cM and both excluded. The smallest overlapping duplication at region D was scaled down to the region between loci D20S480 and D29S902 marking approximately 100-kb genomic sequences. Allelic duplication in papillary RCC was confirmed by fluorescence in situ hybridisation analysis by using BAC clones 441o14 and 354n14 positive for the flanking loci at region B. Altogether 70% of papillary RCC showed genetic changes at least at one of the four regions, but coalteration of two or more regions was seen in most cases. PMID- 10092068 TI - Blockade of CD28/CTLA4-B7 pathway prevented autoantibody-related diseases but not lung disease in MRL/lpr mice. AB - We studied the role of CD28/CTLA4 costimulatory T-cell activation pathway on the pathogenesis of MRL/lpr mice. Administration of CTLA4IgG from day 0 significantly inhibited autoantibody production such as anti-double-stranded DNA antibody and rheumatoid factor. In addition, end-organ diseases in kidney, salivary gland, and liver were significantly improved. Improvement of pathologic findings coincided with a significant improvement in survival. At 350 days of age, 90% of mice treated with CTLA4IgG from day 0 were still alive, compared with none of mice treated with hIgG. As expected, activation of conventional T cells was significantly inhibited after CTLA4IgG treatment. However, lung disease that was characterized by perivascular accumulation and interstitial infiltration of lymphocytes and macrophages was not inhibited. Even after CTLA4IgG treatment from day 0, pathologic findings of lung disease were not improved. Additionally, the expression of activation markers such as B7-1, B7-2, CD71, ICAM1, and LFA1 on Mac1+ fraction in both spleen and lung and the concentration of TNFalpha in bronchoalveolar lavage fluid were not significantly suppressed. These results demonstrated that lung disease was independent of the CD28/CTLA4-B7 pathway. Thus, this study emphasizes the differential dependence of the CD28/CTLA4-B7 pathway in development of diseases in MRL/lpr mice. PMID- 10092069 TI - Culture characterization of differentiated high endothelial venule cells from human tonsils. AB - High endothelial venules (HEV) are specialized vessels that support abundant lymphocyte emigration from peripheral blood into secondary lymphoid organs. HEV endothelial cells (HEVEC) exhibit particular structural and functional features, including secretion of the HEV-specific extracellular matrix protein hevin and an array of uniquely glycosylated counter-receptors for L-selectin expressed on lymphocytes. These ligands are collectively called the peripheral lymph node addressin (PNAd), originally defined by the monoclonal antibody MECA-79. PNAd expression was used to purify HEVEC by positive immunoselection from enzyme digested human tonsils after negative immunoselection for other cells. Purified HEVEC maintained secretion of hevin and homogenous expression of intercellular adhesion molecule (ICAM)-1 (CD54), ICAM-2 (CD102), and CD31, at high levels following 8 days in culture. Expression of functional PNAd was maintained during the first 4 to 5 days of culture but decreased gradually and disappeared on day 8, while the expression of CD34 remained strong. However, the CD34 glycoform shifted toward the in situ phenotype of flat-walled vessels, suggesting that the observed loss of L-selectin binding determinants and MECA-79 antigen was due to down-regulation of the glycosyl- and sulfo-transferases essential for their expression. Our rapid and reproducible method to establish HEVEC cultures provides a useful mechanistic tool for identification of the factors that induce and maintain the HEV phenotype, as well as a source for isolation of HEV-specific genes. PMID- 10092070 TI - Fluorescence melting curve analysis for the detection of the bcl-1/JH translocation in mantle cell lymphoma. AB - PCR amplification and product analysis for the detection of chromosomal translocations such as bcl-1/JH have traditionally been performed as a two-step process with separate amplification and product detection. PCR product detection has generally entailed gel electrophoresis, hybridization, or sequencing for confirmation of assay specificity. By using a microvolume fluorimeter integrated with a thermal cycler and the PCR compatible double-stranded DNA (dsDNA) binding dye SYBR Green I, we simultaneously amplified and detected bcl-1/JH translocation products by using rapid cycle PCR and fluorescence melting curve analysis. We analyzed DNA from 25 cases of lymphoproliferative disorders comprising 12 previously documented bcl-1/JH-positive mantle cell lymphomas, and 13 reactive lymphadenopathies. The samples were coded and analyzed in a blind manner for the presence of bcl-1/JH translocations by fluorescence melting curve analysis. The results of fluorescence analysis were compared with those of conventional PCR and gel electrophoresis. All of the 12 cases (100%) previously determined to be bcl 1/JH positive by conventional PCR analysis showed a characteristic sharp decrease in fluorescence at about 86 degrees C by melting curve analysis. For easier visualization of melting temperatures (Tm), fluorescence melting peaks were obtained by plotting the negative derivative of fluorescence over temperature ( dF/dT) versus temperature (T). Dilutional assays revealed that fluorescence melting curve analysis was more sensitive than conventional PCR and agarose gel electrophoresis with ultraviolet transillumination by as much as 40-fold. Our results indicate that nucleic acid amplification integrated with fluorescence melting curve analysis is a simple, reliable, sensitive, and rapid method for the detection of bcl-1/JH translocations. The feasibility of specific PCR product detection without electrophoresis or expensive fluorescently labeled probes makes this methodology attractive for studies in molecular pathology. PMID- 10092071 TI - Sequencing analysis of RNA and DNA of exons 1 through 11 shows p53 gene alterations to be present in almost 100% of head and neck squamous cell cancers. AB - Data on p53 alterations in human cancers are mainly based on studies restricted to the core domain (exons 5-9), because mutations outside this region are assumed to be rare. To test this assumption, we studied 25 consecutive patients with primary, untreated head and neck squamous cell carcinoma (HNSCC) with a p53 mutation analysis strategy that consists of sequencing all 11 p53 exons and the complete p53 mRNA. With this method, we encountered p53 mutations in 91% of patients; 33% of these were located outside the core domain. Overexpression of the p53 protein was assessed with staining with antibody Bp 53-12-1. Protein overexpression was found in 64%. In one case, p53 overexpression occurred without p53 gene mutations. Analysis of tumor tissue from two autopsied patients with multiple lesions in the head and neck and at distant sites allowed analysis of the clonal relationship of the different tumor foci. In one patient, the head and neck lesion had a mutation different from the one observed at the distant sites, suggesting two different primary tumors, one of them leading to widespread metastastic disease. In all lesions from the second patient, the same mutation was found, suggesting one primary that had metastatized. It appears that sequencing of all exons of the p53 gene is vital for assessment of the real incidence of p53 mutations in HNSCC, because 33% of all mutations are located outside the core domain, leading to a mutation frequency of almost 100% in HNSCC. In 96% of cases, either presence or absence of p53 protein expression could be explained by the type of p53 gene mutation. When only analyzing the p53 core domain, the incidence of p53 mutations in HNSCC is underestimated. PMID- 10092072 TI - Histologic, hematologic, and biochemical characteristics of apo E-deficient mice: effects of dietary cholesterol and phytosterols. AB - In this study, we examined the effects of a "Western-type" diet containing 9% (w/w) fat and 0.15% (w/w) cholesterol, in the presence or absence of 2% (w/w) phytosterol mixture over an 18-week period in apolipoprotein E-deficient mice. Addition of phytosterols to the high cholesterol diet was associated with normalization of the depressed hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity (from 22.3+/-6.3 to 55.4+/-19.9 pmol/mg protein/minutes, p < 0.05). This finding was associated with a significant decrease in plasma and hepatic cholesterol concentrations compared with animals fed the high cholesterol diet without phytosterols (33.3+/-5.0 versus 19.2+/-6.2 pmol/mg protein, p < 0.05). The activities of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase were comparable between the two groups of mice. Urinalyses and hematologic data were comparable between the two groups except for significantly lower platelet counts in the phytosterol-treated animals (681.6+/-118.9 versus 857.1+/-185.4 x10(9)/L, p < 0.05). The phytosterol-treated animals had significantly (p < 0.05) less fragile erythrocytes when exposed to 0.08, 0.07, or 0.05 M NaCl compared with cholesterol-fed mice. The consumption of the Western-type diet was associated with the development of xanthomatous skin lesions in 33% of the cholesterol-fed animals, but in none of the phytosterol-treated animals. Histologic examination revealed oil red O-negative vacuolation in liver and kidney parenchymal cells of the cholesterol-fed group, but not in the phytosterol treated mice. Arrested spermatogenesis and atrophy of seminiferous tubules were observed, to a variable extent, in both groups of animals. We conclude that addition of the phytosterol mixture (2% w/w) to a Western-type diet in apolipoprotein E-deficient mice significantly decreases plasma and hepatic cholesterol concentrations, increases hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, and prevents cutaneous xanthomatosis and vacuolation in the parenchymal cells of kidneys and livers. PMID- 10092073 TI - Detection of hepatitis C virus RNA in more than 20-year-old paraffin-embedded liver tissue. PMID- 10092074 TI - The essential role of phorbol ester-sensitive protein kinase C isoforms in activation-induced cell death of Th1 cells. AB - Th1 and Th2 cells, which were induced from naive T cells of TCR-transgenic mice, showed differential sensitivity to activation-induced cell death (AICD) triggered by stimulation with anti-CD3 monoclonal antibody. The Th1 cells showed more rapid AICD than Th2 cells. This accelerated AICD of Th1 cells was strongly blocked by protein kinase C (PKC) inhibitors (H-7 or GF 109203X). Moreover, long-term treatment of Th1 cells with phorbol 12-myristate 13-acetate (PMA) caused the abrogation of anti-CD3-induced AICD in parallel with the disappearance of PMA sensitive PKC isoforms such as PKC alpha, gamma, epsilon and theta. Therefore, it was clearly demonstrated that PMA-sensitive PKC isoforms are essential for AICD of Th1 cells. The different susceptibility to AICD between Th1 and Th2 cells was not due to their differential expression levels of PMA-sensitive PKC isoforms but appeared to be due to their differential requirement for PMA-sensitive isoforms in the up-regulation of Fas ligand which is involved in suicide killing of activated Th1 cells. PMID- 10092075 TI - IgG transport across trophoblast-derived BeWo cells: a model system to study IgG transport in the placenta. AB - In primates, prenatal transfer of IgG from mother to offspring occurs predominantly across the placenta. Although a number of Fcgamma-receptors and IgG binding proteins have been detected in human placental tissue, an involvement of any of these receptors in IgG transport across the syncytiotrophoblast remains to be demonstrated. Therefore, we investigated the mechanism of IgG transcytosis in trophoblast-derived BeWo cells. BeWo cells were not only found to express the MHC class I-related IgG Fc receptor, human FcRn, but also specifically bound fluorescein isothiocyanate (FITC)-labeled human IgG (FITC-hIgG) at the apical surface at mildly acidic pH. The cells preferentially transcytosed FITC-hIgG from the apical to the basolateral side when compared to the fluid-phase marker FITC dextran and to FITC-hIgG transcytosis in the opposite direction. However, endocytosis of FITC-hIgG at the apical plasma membrane at physiological pH required the continuous presence of FITC-hIgG at concentrations similar to those present in the maternal circulation. These results suggest a mechanism by which IgG is internalized by BeWo cells via fluid-phase endocytosis. Tight binding of IgG to hFcRn may then occur in acidic endosomes, followed by selective sorting into the transcytotic pathway. Thus, the main function of this receptor is to prevent entry of IgG into the degradative pathway in lysosomes. PMID- 10092076 TI - Apoptosis-resistant T cells have a deficiency in NF-kappaB-mediated induction of Fas ligand transcription. AB - Apoptosis induced through the TCR in CD4+ T cells is mostly mediated by the inducible expression of Fas ligand (FasL) as a primary event leading to the commitment to death. To gain a better understanding of the transcriptional events that regulate this expression, we took advantage of our previously described mutant Jurkat cells. These cells are deficient in FasL expression and apoptosis induced upon TCR triggering, although their cytokine (IL-2 and IFN-gamma) production is normal. Here we show that both a FasL- and a consensus NF-kappaB reporter construct are inefficiently induced in these cells compared to wild-type cells. In addition, we demonstrate that the inducible transcriptional activity of the FasL reporter is abolished by specific inhibitors of NF-kappaB activation. Thus, we could trace the deficit of the mutant cells to an inefficient NF-kappaB activation, evidencing a relevant role for NF-kappaB in the regulation of FasL expression in activated T cells. Furthermore, our results suggest that the induction of FasL versus cytokine gene expression is differentially sensitive to NF-kappaB deprivation. PMID- 10092077 TI - Cloning of murine NKG2A, B and C: second family of C-type lectin receptors on murine NK cells. AB - Multiple NK cell receptors for MHC class I have been identified. They include killer inhibitory receptors and CD94/NKG2 heterodimers in humans and the Ly49 family in mice. Here we report the cloning of murine NKG2A, B and C. The deduced amino acid sequence of mouse NKG2A contains only one consensus cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM). NKG2A from B6 and BALB/c mice differ by six amino acid residues in the extracellular domain. Murine NKG2B, like its human conterpart, appears to be a splice variant of NKG2A and lacks a large portion of the stalk region. Murine NKG2C lacks an ITIM in its cytoplasmic domain, a feature shared by human and rat NKG2C. However, unlike the human counterpart, the transmembrane domain of mouse NKG2C does not contain a charged amino acid residue. Mouse NKG2A mRNA was detected in IL-2-activated NK cells and spleen cells but not in other tissues. The NKG2A gene was localized on the distal portion of chromosome 6 where the NK complex has been located. These results further extend the repertoire of C-type lectin receptors on murine NK cells. PMID- 10092078 TI - Presentation of the Leishmania antigen LACK by infected macrophages is dependent upon the virulence of the phagocytosed parasites. AB - We have previously demonstrated that murine macrophages (Mphi) infected with Leishmania promastigotes, in contrast to Mphi infected with the amastigote stage of these parasites, are able to present the Leishmania antigen LACK (Leishmania homologue of receptors for activated C kinase) to specific, I-Ad-restricted T cell hybrids and to the T cell clone 9.1-2. These T cells react with the LACK (158-173) peptide, which is immunodominant in BALB/c mice. Here, we show that the level of stimulation of the LACK-specific T cell hybridoma OD12 by promastigote infected Mphi is clearly dependent upon the differentiation state of the internalized parasites. Thus, shortly after infection with log-phase or stationary-phase promastigotes of L. major or of L. amazonensis, Mphi strongly activated OD12. The activity was transient and rapidly lost. However, under the same conditions, activation of OD12 by Mphi infected with metacyclic promastigotes of L. major or of L. amazonensis was barely detectable. At the extreme, Mphi infected with amastigotes were incapable to stimulate OD12. Thus, the presentation of LACK by infected Mphi correlates with the degree of virulence of the phagocytosed parasites, the less virulent being the best for the generation/expression of LACK (158-173)-I-Ad complexes. While the intracellular killing of the parasites appears to be an important condition for the presentation of LACK, it is not the only requisite. The partial or total destruction of intracellular L. amazonensis amastigotes does not allow the presentation of LACK to OD12. A preferential interaction of LACK (158-173) with recycling rather than newly synthesized MHC class II molecules does not explain the transient presentation of LACK by Mphi infected with log-phase or stationary phase promastigotes because brefeldin A strongly inhibited the presentation of LACK to OD12. Taken together, these results suggest that virulent stages of Leishmania, namely metacyclics and amastigotes, have evolved strategies to avoid or minimize their recognition by CD4+ T lymphocytes. PMID- 10092079 TI - TNF accelerates the onset but does not alter the incidence and severity of myelin basic protein-induced experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) induction in TNF gene-targeted mice has resulted in conflicting reports in part due to the strong association of TNF with the MHC locus. To define the participation of TNF in EAE development, we back-crossed TNF-deficient mice (H-2b) into the SJL/J strain and directly compared them to H-2b congenic SJL or inbred SJL/J mice. Induction of EAE with myelin basic protein (MBP) revealed that H-2b congenic SJL mice are fully susceptible, indicating that the H-2b haplotype does not affect disease susceptibility. Using H-2b congenic SJL mice we show here that TNF deficiency modifies the normal course of EAE by considerably delaying the onset for approximately 5 days, suggesting that TNF is required for the normal initiation of MBP-induced EAE. However, TNF-deficient mice eventually developed severe EAE with perivascular inflammation and primary demyelination similar to wild-type controls, indicating that TNF is not essential during these processes. Taken together, these results indicate that although TNF is not required for the progression of MBP-induced EAE, it contributes positively by advancing the onset of disease. PMID- 10092080 TI - Characterization of type II intracellular IL-1 receptor antagonist (IL-1ra3): a depot IL-1ra. AB - Three molecular forms of the IL-1 receptor antagonist (IL-1ra) have been identified and cloned. Secreted IL-1ra (sIL-1ra or IL-1ra1) contains a classical leader peptide giving a released mature protein. Two intracellular isoforms, icIL 1ra type I (IL-1ra2) and icIL-1ra type II (IL-1ra3), have no leader sequence, thus predicting that these proteins remain intracellular. In an effort to define its biological role, we structurally and functionally characterized IL-1ra3. Endogenous immunoreactive IL-1ra3 was detected in a variety of inflammatory cells and tissues. We used a gene transfer strategy to explore the possible intracellular functions of IL-1ra3 (and IL-1ra2) and the cell-associated agonist IL-1alpha. The intracellular IL-1ra3 isoform, as well as IL-1ra2, does not block the action of exogenous and endogenous IL-1 under these conditions. Intact IL 1ra3 was released from the cells killed by NK effectors. The intracellular isoforms may represent a reservoir of IL-1ra, released upon cell death, whose function is to limit the pro-inflammatory action of cell debris. PMID- 10092081 TI - CD28 induces cell cycle progression by IL-2-independent down-regulation of p27kip1 expression in human peripheral T lymphocytes. AB - CD28 is the primary T cell costimulatory receptor, and upon ligation with its ligands, it enhances T cell proliferation and IL-2 synthesis. In this study we examined the role of CD28 in the initial proliferative response and cell cycle entry of T lymphocytes. Stimulation through CD3 alone resulted in a poor proliferative response, while in the presence of CD28 costimulation a strong increase in the number of cells in S-phase could be detected after 48 h of stimulation. CD28 costimulation enhanced expression of cyclin D3 and induced down regulation of p27kip1 expression. Cross-linking CD28 was much more effective in inducing cyclin D3 expression and in down-regulating p27kip1 expression than addition of IL-2. Blocking experiments, using antibodies that neutralize IL-2 or the IL-2 receptor, showed that the effects induced by CD28 are independent of endogenous IL-2. Moreover, using a variety of immunosuppressants that interfere with IL-2 signaling pathways, we were able to show that IL-2 is not required for cell cycle entry induced by CD28 costimulation. From these experiments it can be concluded that CD28 and IL-2 use different signaling pathways for down-regulation of p27kip1 expression. We hypothesize that costimulation through CD28 is responsible for initial cell cycle entry of T lymphocytes, while IL-2, which is produced after costimulation, might be involved in sustaining proliferation. PMID- 10092082 TI - Selectin and Lewis(x) are required as co-receptors in antibody-dependent cell mediated cytotoxicity of human eosinophils to Schistosoma mansoni schistosomula. AB - Killing of Schistosoma mansoni larvae by human eosinophils via antibody-dependent cell-mediated cytotoxicity (ADCC) mechanisms requires adherence between effector cells and parasite targets. The role of adhesion molecules in this mechanism was investigated using blocking monoclonal antibodies (mAb) and soluble ligands. We show that, along with the Mac-1 alpha chain, interactions between selectins and LewisX-related structures, both expressed by eosinophils and parasite targets, play a critical part in the antibody-dependent cytotoxic function of eosinophils. To further elucidate the interactions between adhesion molecules and eosinophil Fc receptors, ADCC was performed with IgG1 or IgA mAb. We found that mAb directed against Mac-1 alpha chain or against LewisX could significantly inhibit the IgG1 , but not IgA cytotoxicity. This result might be explained, at least in part, by the inhibitory effect of these mAb on the release by eosinophils of eosinophil cationic protein, one of the major mediators involved in target killing. Taken together, these results suggest novel interactions between Fc receptors and selectins and LewisX-related structures which might act as co-receptors for eosinophil-mediated cytotoxicity. PMID- 10092083 TI - ICAM-1 co-stimulation has differential effects on the activation of CD4+ and CD8+ T cells. AB - T cells play a central role in the initiation, maintenance and regulation of the immune response. Effector responses of T cells are controlled by complex combinations of lymphokines and adhesion/co-stimulatory molecule signals. To isolate the effects of the adhesion/co-stimulatory molecule ICAM-1, we have stimulated purified murine CD4+ and CD8+ T cells with plate-bound anti-CD3 in the presence or absence of plate-bound soluble ICAM-1. In this report, we demonstrate that the co-immobilization of soluble ICAM-1 and anti-CD3 leads to a much greater increase in IL-2 production by CD8+ T cells than CD4+ T cells. The ICAM-1-induced enhancement we observed has differential sensitivity to LFA-1 blockade, depending on the T cell subsets and cytokine evaluated. These effects may play an important role in the generation and modulation of immune responses. PMID- 10092084 TI - Control of C3b and C5b deposition by CD46 (membrane cofactor protein) after alternative but not classical complement activation. AB - C3b and C5b deposition following complement activation, and its regulation by CD46 were studied using xenogenic Chinese hamster ovary (CHO) cells as targets and cytofluorometry. Following activation of the alternative pathway, an initial low level of C3b deposition was observed on CHO cell surfaces after a lag time of approximately 4 min. This was followed by a secondary high level of C3b deposition with a slower rate. C3b deposition was maximal within 15 min. When CD46 was expressed (B2 isoform), the kinetics of C3b deposition were essentially unchanged, but the onset of the secondary high C3b deposition was fully prevented. C5b deposition was also observed on CHO but not on CHO.CD46 cells following activation of the alternative pathway. Activation of the classical pathway on CHO and CHO.CD46 cells, using factor B-depleted human serum and anti CHO antibodies, resulted in almost identical single-peak C3b deposition profiles. Accordingly, no regulation of C5b deposition by CD46 was evident following activation of the classical pathway. These data indicate that CD46 prevents the C3b deposition amplification loop mediated by the alternative C3 convertase and, consequently, inhibits the formation of the alternative C5 convertase. But CD46 prevents neither the spontaneous tick-over C3b deposition leading to the formation of the alternative C3 convertase nor the formation of the functional classical C3 and C5 convertases. PMID- 10092085 TI - SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation. AB - CD45 is an alternatively spliced membrane phosphatase required for T cell activation. Exons 4, 5 and 6 can be included or skipped from spliced mRNA resulting in several protein isoforms that include or exclude epitopes referred to as RA, RB or RC, respectively. T cells reciprocally express CD45RA or CD45RO (lacking all three exons), corresponding to naive versus memory T cells. Overexpression of the alternative splicing regulators, SF2 or SWAP, induces skipping of CD45 exon 4 in transfected COS cells. We show here that the arginine/serine-rich domain of SWAP and the RNA recognition motifs of SF2 are required for skipping of CD45 exon 4. Unlike SWAP, SF2 specifically regulated alternative splicing of CD45 exon 4, having no effect on a non-regulated exon of CD45 (exon 9). Like SF2 and SWAP, the SR proteins SC35, SRp40 and SRp75, but not SRp55 also induced CD45 exon 4 skipping. In contrast, antisense inhibition of SRp55 induced exon 4 skipping. SF2 and SRp55 proteins were not detectable or expressed at a very low level in freshly isolated CD45RA+ and CD45RO+ T cells. Activation of CD45RA+ T cells shifted CD45 expression from CD45RA to CD45RO, and induced a large increase in expression of both SF2 and SRp55. Thus, SF2 at least in part determines splicing of CD45 exon 4 during T cell activation. SRp55, SR protein phosphorylation, or other splicing factors likely regulate CD45 splicing in CD45RO+ memory T cells. The different SR proteins expressed by memory and activated T cells emphasize the different phenotypes of these cell types that both express CD45RO. PMID- 10092087 TI - Distinction between processing of normal and mutant complement C3 within human skin fibroblasts. AB - Inherited C3 deficiency may result from mutations in the C3 gene affecting transcription or translation (type I deficiency). We described a type II C3 deficiency caused by a mutation yielding an abnormal non-secreted C3. The post translational processing of mutant and normal C3 was analyzed in fibroblasts grown from skin biopsies. Mutant C3 is located mainly in the endoplasmic reticulum (ER), whereas normal C3 is seen evenly distributed throughout the cytoplasm. Most of the mutant C3 is degraded within the cell, and only a small fraction (around 8%) is secreted after 20 h chase. Processing of C3 at 19 degrees C was reduced in normal fibroblasts but completely blocked in mutant fibroblasts. ATP depletion blocked processing of normal proC3 to C3. In contrast, the mutant proC3 was partly degraded in ATP-depleted cells, yet its complete degradation and secretion were blocked. Intracellular degradation of the mutant C3 was not inhibited by NH4Cl, thus excluding cleavage within lysosomes. These results demonstrate that the type II mutant C3 studied here is retained in the ER probably by a quality contol machinery that identifies abnormal protein folding. Consequently, it is destined to undergo a two-step intracellular degradation; an initial ATP-independent step followed by an ATP-dependent step. PMID- 10092086 TI - CTLA4 ligation attenuates AP-1, NFAT and NF-kappaB activity in activated T cells. AB - CTLA4 is currently viewed as a late-appearing T cell surface receptor which is able to inhibit the proliferation of activated T cells. We sought to identify how CTLA4 ligation exerts these anti-proliferative effects by studying its influence on the activities of the relevant nuclear transcription factors AP-1, NFAT and NF kappaB. We found that cross-linking CTLA4 on activated T cells completely blocks AP-1 and NFAT transcription factor activity before any effects on T cell proliferation can be observed, with NF-kappaB activity affected to a lesser degree. The suppression of AP-1 and NFAT transcriptional activity correlates with reduced levels of AP-1 and NFAT DNA binding as early as 10 h after T cell activation, prior to detectable up-regulation of CTLA4 on the T cell surface. Additionally, inhibitory effects on T cell proliferation only occurred when CTLA4 molecules were ligated in proximity to signaling TCR complexes, and inhibition of transcription factor DNA binding and activity was observed in the absence of CD28 stimulation. CTLA4 can thus act early during T cell activation to reduce the activity of several key nuclear transcription factors important for continued T cell proliferation and differentiation. PMID- 10092088 TI - Cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibits CD28-induced IkappaBalpha degradation and RelA activation. AB - Purified CD4+ cells from the spleens of C57BL/6 mice were stimulated with anti CD3, anti-CD28 and anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibodies. The results show that CTLA-4 stimulation inhibits IL-2 production induced by CD3-CD28 co-stimulation. Since CD3-CD28 co-stimulation induces IkappaBalpha degradation and consequently activates RelA, an NFkappaB family member relevant for the induction of IL-2 mRNA transcription, we tested whether the inhibitory effect of CTLA-4 stimulation interferes with this mechanism. CD3 CD28 co-stimulation was found to induce a drastic decrease in cytoplasmic IkappaBalpha and increase in nuclear RelA. CTLA-4 stimulation abrogates this effect of co-stimulation by increasing the level of cytoplasmic IkappaBalpha and decreasing the nuclear RelA level and DNA-binding activity. In conclusion, our results indicate that the inhibitory effect of CTLA-4 engagement on cytokine production correlates with prevention of IkappaBalpha degradation and inhibition of RelA nuclear translocation. PMID- 10092089 TI - Enhancement of human IL-4 activity by soluble IL-4 receptors in vitro. AB - The recombinant form of the extracellular domain of the IL-4 receptor (sIL-4R) is a potential candidate to neutralize IL-4; however, murine sIL-4R displayed both antagonistic and agonistic activity in vivo. Here we show that human recombinant sIL-4R induced the formation of complexed IL-4 in supernatants of activated T cells in a dose-dependent manner as measured by newly developed enzyme-linked immunosorbent assays. These IL-4/sIL-4R complexes liberated free IL-4 even after prolonged culturing. In contrast, in the absence of exogenously added sIL-4R, free IL-4 was rapidly consumed or proteolytically degraded in cultures of activated T cells. Thus, no IL-4 bioactivity could be determined in supernatants of T cells activated in the presence of IL-4 for 6 days. In contrast, the same cultures carried out in the presence of sIL-4R showed marked IL-4 bioactivity. While low concentrations of sIL-4R enhanced IL-4-driven inhibiton of IFN-gamma production by activated T cells, higher concentrations neutralized IL-4. Together, human sIL-4R, besides its activity as an antagonist to IL-4, also possesses protective and agonistic functions for IL-4, which may be relevant for clinical studies aiming to neutralize IL-4 in vivo. PMID- 10092090 TI - Induction of the Igkappa 3' enhancer by distinct pathways can be inhibited by cross-linking of the CD40 receptor. AB - Upon treatment with lipopolysaccharide (LPS), primary B cells proliferate and differentiate into plasma cells with concomitant up-regulation of immunoglobulin (Ig) gene expression. Here we examine the role of the Igkappa 3' enhancer in this process using a kappa3'-enhancer-driven beta-globin reporter gene in transgenic mice. We find that LPS treatment up-regulates kappa3' enhancer activity as a function of differentiation rather than proliferation, since proliferation only (induced by cross-linking of CD40) is insufficient to activate the element, whilst differentiation with only limited proliferation (LPS + transforming growth factor-beta) does allow activation to occur. The Igkappa 3' enhancer is also induced by cross-linking of surface Ig and this signal can synergize with LPS activation, suggesting that distinct activation pathways are used. Nevertheless, both of these pathways can be inhibited by co-cross-linking of CD40. Thus Ig enhancers in the heavy and light chain loci are differentially regulated in response to CD40. PMID- 10092091 TI - NF-kappaB regulates Fas/APO-1/CD95- and TCR- mediated apoptosis of T lymphocytes. AB - The maintenance of lymphocyte homeostasis by apoptosis is a critical regulatory mechanism in the normal immune system. The transcription factor NF-kappaB has been shown to play a role in protecting cells against death mediated by TNF We show here that NF-kappaB also has a role in regulating Fas/APO-1/CD95-mediated death, a major pathway of peripheral T cell death. Transfection of Jurkat cells with the NF-kappaB subunits p50 and p65 confers resistance against Fas-mediated apoptosis. Reciprocally, inhibition of NF-kappaB activation by a soluble peptide inhibitor or a dominant form of the NF-kappaB inhibitor, IkappaB, makes the cells more susceptible to Fas-mediated apoptosis. Furthermore, inhibition of NF-kappaB activation by a soluble peptide inhibitor rendered a T cell hybridoma more susceptible to TCR-mediated apoptosis. Correspondingly, transfection of p50 and p65 provided considerable protection from TCR-mediated apoptosis. These observations were corroborated by studies on Fas-mediated death in primary T cells. Concanavalin A-activated cycling T cell blasts from mice that are transgenic for the dominant IkappaB molecule have increased sensitivity to Fas mediated apoptosis, associated with a down-regulation of NF-kappaB complexes in the nucleus. In addition, blocking TNF, itself a positive regulator of NF-kappaB, with neutralizing antibodies renders the cells more susceptible to anti-Fas mediated apoptosis. In summary, our results provide compelling evidence that NF kappaB protects against Fas-mediated death and is likely to be an important regulator of T cell homeostasis and tolerance. PMID- 10092092 TI - Requirement of PEST domain tyrosine phosphatase PEP in B cell antigen receptor induced growth arrest and apoptosis. AB - Signaling events leading to B cell growth or apoptosis are beginning to be unravelled, but detailed information is still lacking. To identify signaling molecules involved in B cell antigen receptor (BCR)-initiated pathways, we used the immature B cell line, WEHI-231, to investigate protein tyrosine phosphatases (PTP) whose expression was modulated by BCR ligation. Among the PTP cloned by reverse transcription-PCR, mRNA expression of the proline-, glutamic acid-, serine- and threonine-rich (PEST) domain phosphatase (PEP) was selectively elevated 3.1-fold within 3 h after anti-IgM antibody stimulation. In contrast, expression of another PEST domain phosphatase, PTP-PEST, was unaffected. Western blot analysis revealed that 71% of PEP was located in the cytosolic fraction, while 29% was in the membrane fraction. To examine the direct contribution made by PEP to BCR-initiated signal transduction, we transfected an antisense PEP cDNA into WEHI-231 cells. Two stable clones were established in which PEP expression was reduced by 34% and 47%, respectively. Strikingly, BCR-mediated inhibition of DNA synthesis was significantly rescued in the clones, and G1 phase cell cycle arrest and apoptosis were almost completely ablated. Considered collectively, these results indicate that PEP is a positive, crucial regulator in determining B cell fate triggered by BCR engagement. PMID- 10092093 TI - Mechanisms of IL-8-induced Ca2+ signaling in human neutrophil granulocytes. AB - Interleukin-8 (IL-8) plays an important role in the activation of neutrophil granulocytes. Although intracellular Ca2+ signals are essential in this process, they have not been studied in great detail so far. Here, we have measured IL-8 induced Ca2+ signals in single human neutrophil granulocytes using the Ca2+ indicator dye FURA-2 AM and we have investigated the signal transduction that leads to these Ca2+ signals with various pharmacological tools. Our results indicate that IL-8-induced Ca2+ signals consist of at least two components. An initial fast component was followed by a smaller and more persistent one. The initial Ca2+ signal was independent of extracellular Ca2+. It required the activation of phospholipase C via a pertussis toxin sensitive G-protein and was due to activation of IP3 receptor-coupled Ca2+ release channels. The late phase of the Ca2+ signal was suppressed when extracellular Ca2+ was removed suggesting that it was generated by Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels. This Ca2+ influx may prolong IL-8-induced Ca2+ signals during granulocyte activation. PMID- 10092094 TI - Class II antigen processing defects in two H2d mouse cell lines are caused by point mutations in the H2-DMa gene. AB - The molecular nature of the defect in two mouse antigen processing-defective cell lines was examined. Both mutants were derived from the A20 (BALB/c, H2d) B cell line, and both were found to have defects in the H2-DMa gene. Mutant 3A5 exhibits severely reduced amounts of H2-DMa message, and no detectable DMalpha protein. cDNA sequence revealed a C-->T transition at nucleotide 118, introducing a premature stop codon in exon 2 of the H2-DMa gene. In contrast, mutant 2A2 exhibits reduced but detectable levels of H2-DMa message and DMalpha protein only after treatment with IL-4, which induces the expression of both the H2-DMa and the H2-DMb genes in B cells. In this mutant the cDNA sequence revealed a missense mutation in exon 3 resulting in the conversion of a conserved proline residue in the Ig-like domain to serine. Stable transfection with full-length H2-DMa cDNA reconstitutes the antigen processing capacity of both mutants, as demonstrated by the ability to present native antigen to T cell clones, and by restored class II SDS stability. PMID- 10092095 TI - A tumor necrosis factor-induced model of human primary demyelinating diseases develops in immunodeficient mice. AB - We have reported previously that in the central nervous system (CNS) local expression of tumor necrosis factor (TNF) transgenes can trigger the development of oligodendrocyte apoptosis, primary inflammatory demyelination and neurological dysfunction, accompanied by lymphocyte and macrophage infiltration into the CNS. To distinguish between the local effects of transgene-encoded TNF and the potential encephalitogenic effects of immune infiltrates upon CNS disease pathogenesis, we have backcrossed Tg6074 TNF-transgenic mice to mice deficient in CD4, beta2-microglobulin (beta2m), immunoglobulin mu chain (Igmu) or recombination activation gene-1 (Rag-1). TNF was capable of triggering undiminished primary demyelination in all of the immunodeficient mice, in the presence of activated cells of the macrophage/microglial lineage. We conclude that TNF is sufficient to induce primary inflammatory demyelination and neurological deficits even in the absence of adaptive immunity. PMID- 10092096 TI - Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. AB - Dietary lectins, present in beans and other edible plant products, pose a potential threat to consumers due to their capacity to induce histamine release from basophils. In this study, we analyzed the capacity of 16 common, in particular dietary, lectins to induce human basophils to secrete IL-4 and IL-13, the key promoters of Th2 responses and IgE synthesis. Several of the lectins, especially concanavalin A, lentil lectin, phytohemagglutinin, Pisum sativum agglutinin and Sambucus nigra agglutinin, triggered basophils to release IL-4 at concentrations of up to 1 ng/10(6) basophils. Lectins with high IL-4-inducing capacity also stimulated the release of IL-13 and histamine. Lectin-induced IL-4 and IL-13 release reached a maximum after 4-6 h and more than 18 h, respectively. Affinoblotting revealed that lectins with the capacity to induce mediator release bind to IgE, suggesting IgE binding as initial step of signal generation. In conclusion, several dietary lectins can trigger human basophils to release IL-4 and IL-13. Since lectins can enter the circulation after oral uptake, they might play a role in inducing the so-called early IL-4 required to switch the immune response towards a Th2 response and type I allergy. PMID- 10092097 TI - The transcriptional regulator Rel is essential for antigen receptor-mediated stimulation of mature T cells but dispensable for positive and negative selection of thymocytes and T cell apoptosis. AB - The family of Rel/NF-kappaB transcription factors is a crucial regulator of various cellular responses. Using Rel-deficient (c-rel-/-) mice crossed with T cell receptor (TCR)-transgenic mice we show that Rel is neither required for positive selection of major histocompatibility complex (MHC)-restricted T cells nor for deletion of thymocytes bearing autoreactive antigen receptors. Our studies also demonstrate that Rel is dispensable for T lymphocyte apoptosis. Rel is, however, essential for antigen-induced activation of mature T cells and its absence exacerbates the anergic state. These results indicate that thymocytes and mature T cells differ in their requirement for Rel in mediating TCR-induced responses. PMID- 10092098 TI - Functional Fc epsilonRI engagement by a second secretory IgE isoform detected in humans. AB - We have recently reported that besides the most abundant form epsilonS1, there exists another human secretory epsilon H chain isoform, epsilonS2, resulting from alternative splicing in the epsilonCH4 exon. Using a specific antibody targeted to the epsilonS2-specific C-terminal tailpiece, we now show that this second secretory IgE isoform (IgE-S2) is constitutively co-expressed with the classical secretory IgE-S1 by human myeloma cells. The epsilonS2 variant was also detected in tonsils and in the serum of three non-atopic donors, but was absent in the vast majority of sera of both atopic and non-atopic individuals tested, indicating rare serum expression. IgE-S2 is capable of binding to cells expressing Fc epsilonRI, the high-affinity receptor for IgE. Analysis of intracellular tyrosine phosphorylation signal, degranulation, and rate of receptor internalization suggest a quantitatively lower response by IgE-S2 compared to IgE-S1. The modest differences observed do not appear to overall affect the degranulation competency of IgE-S2, but suggest that the unique structure of the epsilonS2 tailpiece can exert an effect on the interaction with the alpha chain of Fc epsilonRI. PMID- 10092099 TI - Resolution of experimental and tick-borne Borrelia burgdorferi infection in mice by passive, but not active immunization using recombinant OspC. AB - Vaccination with outer surface protein A (OspA) of Borrelia burgdorferi prevents subsequent infection and disease in both laboratory animals and humans with high efficacy. OspA-based immunity, however, does not affect established infection due to the loss of OspA expression in the vertebrate host. We show here that repeated passive transfer of mouse and/or rabbit immune sera to recombinant GST-OspC fusion protein resulted in a dose-dependent resolution (1) of fully established arthritis and carditis as well as infection in needle-challenged C.B-17 SCID and (2) of infection in both experimentally and tick-infected BALB/c mice. Unexpectedly, active immunization of disease-susceptible AKR/N mice with GST-OspC only led to prevention but not resolution of disease and infection, in spite of high serum titers of OspC-specific Ab and the expression of ospC in tissue derived spirochetes. The data suggest that the efficacy of OspC antibody-mediated immunity depends on the immunological history of the recipient and/or environment dependent regulation of OspC surface expression by spirochetes in vivo. The results encourage further attempts to develop therapeutic vaccination protocols against Lyme disease. PMID- 10092100 TI - Curative treatment of experimental autoimmune thyroiditis by in vivo administration of plasmid DNA coding for interleukin-10. AB - The autoimmune response in experimental autoimmune thyroiditis (EAT) is characterized by a lymphocyte infiltration of the thyroid gland and by the appearance of circulating autoantibodies to thyroglobulin (Tg). Cytokines play a crucial role in the immunoregulation and pathology of EAT. Systemic administration of IL-10 has curative effects on EAT, but requires high doses and iterative injections due to the rapid turnover of this molecule. We have designed an original in vivo gene transfer using a mixture of liposomes and poly-L-Lysine that greatly enhanced the transfection yield, and induced a fast and long-lasting expression of IL-10 on mouse thyroid follicular cells (TFC). IL-10 expression on TFC of mice wit EAT dramatically wipe out the lymphocytic infiltration in the thyroids. A significant diminution in the proliferative anti-Tg T cell response was observed, along with a trend towards a Th2 response characterized by decreased production of IFN-gamma and by increased anti-Tg IgG1/IgG2a Ab ratios. In conclusion, local IL-10 gene therapy using non-viral vectors is a novel and promising approach for the treatment of thyroid autoimmune disorders. PMID- 10092101 TI - Recombinant adenovirus is an efficient and non-perturbing genetic vector for human dendritic cells. AB - Recombinant adenoviral vectors have promise for human gene therapy because of efficient transgene expression in nondividing primary cell types. Dendritic cells (DC) have potential as adjuvants for immune therapy, since they are specialized to capture antigens to form MHC-peptide complexes, migrate to T cell areas in the lymph node, and activate T cells including CD4+ helpers and CD8+ cytotoxic T lymphocytes (CTL). We show that several current chemical and physical transfection methods allow < 2 % of DC to express reporter genes but that recombinant adenoviruses, encoding the reporter genes green fluorescent protein and LacZ, efficiently transfect monocyte-derived human DC. Immature DC, generated with IL-4 and GM-CSF, are transfected to 95% efficiency, while mature DC show reduced transfection (50%) and gene expression. Adenovirus-transfected, immature DC exhibit several critical functions. The DC can differentiate in the presence of lipopolysaccharide or a monocyte-conditioned medium to express the surface markers of mature, T cell stimulatory DC including CD25, CD83, and high levels of CD86 and HLA-DR. Transfected DC can also secrete high levels of IL-12 and are potent inducers of T cell growth. Transgene expression in DC is stable for at least 6 days in the presence of the DC survival factor, TRANCE. Therefore adenoviral infection does not perturb the maturation and function of DC. The efficiency of adenoviral-mediated gene transfer prompts the evaluation of this vector in studies of DC biology, including the expression of antigens for active immune therapy. PMID- 10092102 TI - Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes. AB - We recently evidenced a dramatic enrichment for T cells reactive against Epstein Barr virus (EBV) within inflamed joints of two rheumatoid arthritis patients. To assess the generality of this phenomenon and its relevance to autoimmunity, we studied the responses of CD8 T cells from patients with either acute or chronic inflammatory diseases (rheumatoid arthritis: n = 18, ankylosing spondylitis: n = 5, psoriatic arthritis: n = 4, Reiter's syndrome: n = 3, arthrosis: n = 2, uveitis: n = 2, multiple sclerosis: n = 2, encephalitis: n = 1) against viral proteins derived from EBV and another common herpes virus, human cytomegalovirus (CMV). T cell responses against EBV and/or CMV epitopes were frequently observed within CD8 T cells derived from chronic inflammatory lesions, irrespective of their location (knee, eye, brain) and autoimmune features. In most cases, CD8 T cells derived from affected organs yielded stronger anti-viral T cell responses than CD8 T cells derived from patients' PBL, even in chronic inflammatory diseases devoid of autoimmune features or induced by defined bacterial agents. Taken together, these results suggest that the presence of virus-specific T cells within inflamed lesions of patients suffering from autoimmune diseases is a general phenomenon associated with chronic inflammation rather than the initiating cause of the autoimmune process. Since this phenomenon was sometimes associated with long-term T repertoire biases within inflamed lesions, the physiopathological significance of T cell clonal expansions found in a recurrent fashion within chronically inflamed autoimmune lesions should be interpreted with caution. PMID- 10092103 TI - DNA immunization confers systemic, but not mucosal, protection against enteroinvasive bacteria. AB - Naked plasmid DNA (pRc/Y-hsp60) with a cytomegalovirus promoter and a sequence encoding Yersinia enterocolitica 60-kDa heat shock protein (Y-HSP60) was used for vaccination. After intramuscular injection of pRc/Y-hsp60, Y-hsp60 mRNA could be detected by reverse transcription-PCR in muscle, liver and spleen. A single immunization with pRc/Y-hsp60 induced significant Y-HSP60-specific T cell responses after 1 week. IFN-gamma production by spleen cells upon stimulation with Y-HSP60 was strictly dependent on the presence of CD4+ T cells, indicating the generation of a Th1 response upon DNA immunization. DNA immunization in addition induced strong Y-HSP60-specific IgG2a, weak IgG1, but not IgA antibodies. Immunization of BALB/c and C57BL/6 mice with pRc/Y-hsp60 conferred protection against disseminated Y. enterocolitica infection in spleen, but not at the site of mucosal entry, the Peyer's patches. Furthermore, pRc/Y-hsp60 vaccination did not induce cross-protection against related pathogens. Vaccination of beta2-microglobulin- and H2-I-Abeta-deficient mice was not protective, suggesting that both CD4+ and CD8+ T cells are required for protective immunity induced by DNA vaccination. PMID- 10092104 TI - Isolation and characterization of natural human IgG with a morphine-like activity. AB - Although naturally occurring antibodies have been associated with numerous biological activities, their functional relevance is still a matter of debate. The presence of natural autoantibodies towards immune-related molecules such as cytokines and antibodies suggests a physiological immunomodulatory role. The neuroendocrine opioid system participates in the immune homeostasis. We report here the presence of antibodies with an agonist-like activity towards the human mu-type opioid receptor within a normal human IgG pool. Starting from an IgG pool, autoantibodies were affinity purified using Chinese hamster ovary cells expressing the human mu-opioid receptor. Their specificity was assessed by cytofluorometry and pharmacological analyses. The potency of these antibodies to recognize the mu-opioid receptor was similar to mu-opioid selective agonists. Furthermore, the functional opioid-like activity of the anti-opioid receptor IgG was demonstrated by their ability to inhibit adenylate cyclase activity by a Gi/o protein-mediated mechanism as indicated by abrogation of the effect by either opioid antagonist or pertussis toxin. Five IgG pools, each from four unrelated healthy blood donors, and single IgG preparations from six other donors were prepared. Antibodies directed against the mu-opioid receptor were found in all IgG samples. PMID- 10092105 TI - M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1. AB - Transforming growth factor-beta1 (TGF-beta1) is a critical cytokine for cell proliferation and differentiation. It is secreted by many cells in a latent pro form (LTGF-beta1) from which biologically active TGF-beta1 is released by an in vivo mechanism that is not known. Here we show that the mannose-6 phosphate/insulin-like growth factor II-receptor (M6P/IGFII-R), which binds LTGF beta1, complexes with urokinase (plasminogen activator)-receptor (uPA-R) on the surface of human monocytes and directly binds plasminogen (Plg). Plasmin generated from Plg in the complex mediates release of TGF-beta1 when M6P/IGFII-R is associated with uPA-R. Thus, this interaction of M6P/IGFII-R and uPA-R suggests a potential mechanism for the generation of TGF-beta1 by cells. PMID- 10092106 TI - The murine homologue of the human NKp46, a triggering receptor involved in the induction of natural cytotoxicity. AB - The NKp46 molecule has been proposed to play the role of triggering receptor in the natural cytotoxicity mediated by human NK cells. In this study we have identified the gene encoding the murine NKp46 homologue that we termed MAR-1. The MAR-1 gene is localized on chromosome 7 that is synthenic to the human chromosome 19 where the NKp46 gene is located. MAR-1 encodes a type I transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily that, like human NKp46, is characterized by two C2-type Ig-like domains, a transmembrane portion containing a positively charged residue and a cytoplasmic tail lacking the immunoreceptor tyrosine-based activation motif (ITAM). The MAR-1 protein is expressed on the surface of cell transfectants and displays a molecular mass of approximately 46 kDa similar to that of its human counterpart. Semiquantitative RT-PCR analysis showed that MAR-1, similar to the human NKp46, is selectively expressed by NK cells. The MAR-1 protein displays 58 % identity with the human NKp46 receptor. This high homology together with the presence of a charged amino acid (Arg) in the transmembrane portion suggest that MAR-1 may associate at the cell membrane into a multimeric complex with ITAM containing polypeptides. PMID- 10092107 TI - Airway exposure to bacterial superantigen (SEB) induces lymphocyte-dependent airway inflammation associated with increased airway responsiveness--a model for non-allergic asthma. AB - Although immunological consequences of systemic superantigen administration have been extensively studied, the effects of local mucosal exposure to superantigens are not well defined. The purpose of this study was to delineate the type of immune response triggered by superantigen exposure to the airway mucosa in mice. In dose-response experiments we determined a low dose of staphylococcal enterotoxin B (SEB) that triggered an inflammatory response characterized by mucosal and airway recruitment of lymphocytes, eosinophils and neutrophils together with elevated levels of IL-4, but not IFN-gamma, in bronchoalveolar lavage (BAL) fluids. TCR Vbeta analysis revealed that superantigen-responsive and -non-responsive T cells were equally recruited into the airways. SEB markedly enhanced the frequency of TNF-alpha-positive BAL macrophages as well as the amount of TNF-alpha in BAL fluids. These responses were associated with the development of increased airway responsiveness (AR) in SEB-treated mice. This effect occurred in an antibody-independent fashion. Furthermore, this type of response was observed in IgE-high responder BALB/c as well as in IgE low/intermediate responder C57BL/6 mice. The development of increased AR was CD4+ T cell dependent as shown by transfer experiments into BALB/c nu/nu mice. These results suggest that the local immune response following mucosal superantigen administration triggers a unique inflammatory response in the airways resembling many features of "intrinsic asthma". PMID- 10092108 TI - TGF-beta-independent induction of immunogenicity by decorin gene transfer in human malignant glioma cells. AB - Ectopic expression of the proteoglycan, decorin, abrogates the growth of experimental C6 gliomas in the rat. Since gliomas release large amounts of transforming growth factor-beta (TGF-beta) and since decorin is a TGF-beta antagonist, decorin gene transfer-mediated abrogation of glioma growth in vivo may involve enhanced immunogenicity of the tumor cells. Here, we report that human glioma cells stimulate alloreactive immune responses when engineered to express decorin whereas parental glioma cells are non-immunogenic in vitro. The alloreactive immune response is mediated by CD8+ and CD4+ T cells as well as by NK cells. The immunosuppression exerted by parental or mock-transfected glioma cells is mediated by soluble factors and can in part be mimicked by exogenous TGF beta. However, neutralizing anti-TGF-beta antibodies do not reverse glioma mediated immunosuppression, suggesting that decorin abrogates glioma-induced immune cell inhibition by interfering with the activity of other, so far unidentified glioma-secreted mediators. We conclude that enhanced immunogenicity may mediate the antineoplastic effects of decorin gene therapy for malignant glioma but that factors other than TGF-beta may be responsible for glioma-induced immunosuppression. PMID- 10092109 TI - Interferon-beta mediates stromal cell rescue of T cells from apoptosis. AB - The resolution of immune responses is characterized by extensive apoptosis of activated T cells. However, to generate and maintain immunological memory, some antigen-specific T cells must survive and revert to a resting G0/G1 state. Cytokines that bind to the common gamma chain of the IL-2 receptor promote the survival of T cell blasts, but also induce proliferation. In contrast, soluble factors secreted by stromal cells induce Tcell survival in a resting G0/G1 state. We now report that interferon-beta is the principal mediator of stromal cell mediated Tcell rescue from apoptosis. Interferon-alpha and -beta promote the reversion of blast Tcells to a resting G0/G1 configuration with all the characteristic features of stromal cell rescue; such as high Bcl-XL expression and low Bcl-2. Type I interferons and stromal cells stimulate apparently identical signaling pathways, leading to STAT-1 activation. We also show that this mechanism may play a fundamental role in the persistence of T cells at sites of chronic inflammation; suggesting that chronic inflammation is an aberrant consequence of immunological memory. PMID- 10092110 TI - Characterization of CD4+ T cells in mouse bone marrow. I. Increased activated/memory phenotype and altered TCR Vbeta repertoire. AB - A significant proportion of memory B cells home to bone marrow (BM) which is a major site of anamnestic antibody responses in mice. We hypothesized that memory T cells likewise accumulate in BM perhaps to provide help for antibody production, and that the compartment of CD4+ T cells in BM of unimmunized mice would be enriched for memory phenotype cells that might have been activated by environmental antigens. The phenotype of activated/memory CD4+ lymphocytes has been defined as CD44hi CD45RBlo CD62L-. Conversely, the phenotype of immunologically naive cells is CD44lo CD45RBhi CD62L+. Flow cytrometric analysis of tissue from normal, adult C57BL/6 mice identified 1-2 % CD3+CD4+ cells in BM. Up to 40 % of CD3+CD4+ cells in the BM expressed the activated/memory phenotype compared with < or = 10% in the spleen and lymph nodes. Analysis of TCR Vbeta repertoire revealed that expression of Vbeta3 and Vbeta7 genes was increased as much as fourfold in BM compared to the periphery; most of this increase was within the CD44hi T cells. The accumulation of activated/memory T cells and clonotypic expansion(s) was not seen in the BM of germ-free mice, indicating that it reflects the history of the animal's exposure to antigens. Finally, immunization of mice which express a transgenic T cell receptor specific for ovalbumin peptide resulted in appearance of antigen-specific T cells with activated/memory phenotype in the BM. PMID- 10092111 TI - Nomenclature of immunoglobulin A and other proteins of the mucosal immune system. IUIS/WHO Subcommittee on IgA Nomenclature. AB - The predominant immunoglobulin found in exocrine secretions of humans and most other mammals is secretory IgA, a polymeric form of IgA containing an additional glycoprotein chain designated "secretory component." In this article recommended abbreviations are proposed for the following forms of human IgA and other proteins of related interest: secretory IgA, secretory IgM, secretory component, polymeric immunoglobulin receptor, polymeric IgA, monomeric IgA, IgA subclass 1, IgA subclass 2, A2 allotype marker 1, and A2 allotype marker 2. PMID- 10092112 TI - Regulation of cytosolic phospholipase A2 in rat endometrial stromal cells: the role of epidermal growth factor. AB - The effect of epidermal growth factor on the levels of cytosolic phospholipase A2 mRNA and protein in cultured rat endometrial stromal cells isolated from uteri sensitized for the decidual cell reaction was examined. Treatment with epidermal growth factor increased the steady-state cytosolic phospholipase A2 mRNA and protein levels as demonstrated by Northern and Western blot analyses, respectively. Immunocytochemical analysis demonstrated an increase of cytosolic phospholipase A2 protein in most cells, as opposed to a small subpopulation of cells in culture. These results show that epidermal growth factor causes an increase in steady-state cytosolic phospholipase A2 mRNA and protein levels in rat endometrial stromal cells from uteri sensitized for the decidual cell reaction. Epidermal growth factor receptor ligands may regulate cytosolic phospholipase A2 and thus prostaglandin production in the endometrial stromal cells during implantation. PMID- 10092113 TI - Strain dependency of TGFbeta1 function during embryogenesis. AB - There is incomplete penetrance to Tgfb1 knockout phenotypes. About 50% of Tgfb1 homozygous mutant (Tgfb1-/-) and 25% of Tgfb1 heterozygous (Tgfb1+/-) embryos die during embryogenesis. In a mixed NIH/Ola x C57BL/6J/Ola x 129 background partial embryonic lethality of the Tgfb1-/-embryos occurs due to defective yolk sac vasculopoiesis and/or hematopoiesis. We show here that on a predominantly CF-1 genetic background, lack of TGFbeta1 causes a pre-morula lethality in about 50% of the null embryos. This partial lethality is not reversed by transfer of Tgfb1 /- embryos to Tgfb1-/+ hosts. The extent of embryonic lethality in Tgfb1-/- embryos ranges in a background dependent manner from 20% to 100%. Based on these and other studies it is clear that TGFbeta1 acts at two distinct phases of embryogenesis: pre-implantation development and yolk sac vasculogenesis/hematopoiesis. The susceptibility for the pre-implantation lethality depends on a small number of genetic modifiers since a small number of backcrosses onto the high susceptibility strain C57BL/6 leads to complete penetrance of the lethality. PMID- 10092114 TI - Expression of insulin-like growth factor binding protein-4, insulin-like growth factor-I receptor, and insulin-like growth factor-I in the mouse uterus throughout the estrous cycle. AB - Recent evidence suggests that a regulated insulin-like growth factor (IGF) system mediates the effects of estrogen, promoting the proliferation and differentiation of specific uterine cell types throughout the estrous cycle and during gestation in the rodent. Previous studies have shown that IGFs are differentially expressed in the mouse uterus during the periimplantation period. In the current study, we examined the expression of IGF binding protein-4 (IGFBP-4), IGF-I receptor (IGF IR), and IGF-I in the mouse uterus throughout the estrous cycle. Ligand blot analysis was conducted on uterine homogenates using [125I]IGF-I. IGFBP-4 was detected in all uterine homogenates, varying in intensity throughout the estrous cycle. In situ hybridization studies at metestrus and diestrus demonstrated an intense IGFBP-4 mRNA signal in antimesometrial stromal cells between the luminal epithelium and the myometrium, but at proestrus and estrus, no IGFBP-4 signal was detected. No IGF-I mRNA was detected at any stage of the estrous cycle by in situ hybridization. However, by RT-PCR analysis, IGF-I mRNA was detected at all stages of the estrous cycle. RT-PCR analysis also showed IGF-IR mRNA throughout the estrous cycle. Using immunohistochemistry, IGF-IR immunostaining was detected throughout the estrous cycle and on days 2-7 of gestation, but was restricted to the glandular epithelium. These results suggest that uterine IGFBP-4 expression may not be dependent on uterine IGF-I expression. They also suggest that IGFBP-4 may play a role in uterine physiology independent of the inhibition of IGF-I action, and that IGF-IR is constitutively expressed in the mouse uterus. PMID- 10092115 TI - DNA-protein interactions in the CCAAT box region of the murine lactate dehydrogenase C promoter. AB - Electrophoretic Mobility (EMSA), using oligonucleotides containing CCAAT box sequences from the murine Idhc promoter show the presence of CCAAT binding proteins in nuclear extracts from liver and testis. In a liver extract, a single shifted band is seen. However, in the testis extract, two shifts are observed, one of which may be due to a testis specific isoform of CCAAT binding factor (CBF). Southwestern analysis with an oligonucleotide probe containing these sequences reveals the presence of a protein of approximately 120 kD in the testis extract. In the liver extract, a 70-kD protein binds the probe. An antibody against HeLa CBF causes a supershift in testis nuclear extract. PMID- 10092116 TI - Coordinate action of Wt1 and a modifier gene supports embryonic survival in the oviduct. AB - The Wt1 gene, originally identified as a tumor suppressor gene associated with Wilms' tumors, encodes a zinc finger containing transcription factor expressed during gonadal and kidney development. Although Wt1 appears to be required for gonadal and kidney development, no reproductive defects were observed in outbred females heterozygous for a targeted mutation in Wt1. In contrast, no litters were obtained from Wt1 +/- females on a strain 129/Sv inbred genetic background. Ovaries were smaller in Wt1 +/- 129/Sv mice and produced fewer ova, but transplanted Wt1 +/- ovaries from 129/Sv females were able to support successful pregnancies. The inability of Wt1 +/- 129/Sv females to produce successful implantations after ovulation and fertilization appeared to be due to the failure of one-cell embryos to undergo mitosis, such that they were lost in the oviduct before reaching the uterus. Approximately 50% of Wt1 +/- females generated from a backcross of Wt1 +/- 129/Sv:C57BI/6 F1 hybrids to 129/Sv were fertile, indicating the presence of a Wt1 modifier gene that affects survival of the preimplantation embryo. Neither levels of WT1 protein nor the ratio of WT1 spice forms were significantly altered in Wt1 +/- reproductive organs, suggesting that this modifier effect acts downstream of WT1. Wt1 is therefore among a small subset of genes required for survival of the pre-implantation embryo, and appears to function non-autonomously. PMID- 10092117 TI - Comparison of ES cell fate in sandwiched aggregates and co-cultured aggregates during blastocyst formation by monitored GFP expression. AB - Markers and the means to detect them are required to monitor the fate of living cells. However, few suitable markers for living cells were known until a green fluorescent protein (GFP) was discovered. We have established mouse embryonic stem (ES) cell lines that express mutant GFP under the chicken beta-actin (CAG) promoter. Using these cell lines, we were able to follow the migration of ES cells during blastocyst formation both in sandwiching and coculture methods, even if only a single ES cell was used. Furthermore, the contribution of ES cells to the inner cell mass (ICM) was easily estimated at the blastocyst stage. We compared sandwiching with coculture aggregation relative to the contribution of the ES cell in the ICM, and the results indicated that there was no difference in the ratios of chimeric embryos having ICM contributed from cultured ES cells. Furthermore, an aggregated single ES cell was able to contribute three or four cells to the ICM at the blastocyst stage. Thus we conclude that one, instead of two, embryos is enough to make aggregation with ES cells, and a single ES cell attached to an embryo is enough to produce germline chimeras. Moreover, we could clearly observe single cell fate during blastocyst formation. This suggests that our established cell line can be used for monitoring single cell fate in vivo. In addition, we have shown that up to five doses of 30 sec of UV irradiation using GFP filters have no effect on the embryonic development. PMID- 10092118 TI - The Hsp70 homolog gene, Hsc70t, is expressed under translational control during mouse spermiogenesis. AB - Hsc70t is a member of the Hsp70 family of genes and is constitutively expressed after meiosis in mouse spermatogenesis. Immunohistochemistry and in situ hybridization techniques were used to examine the precise localization of the Hsc70t product during the various stages of spermatogenesis. A rabbit antiserum raised againstthe mouse Hsc70t-lacZ fusion protein detected the Hsc70t protein in the late spermatid-enriched fraction after two-dimensional Western blot analyses. On histological sections, the protein appears in the cytoplasm of spermatids as they progress from step 9 to the final step of spermatogenesis. An antisense RNA probe generated from the 3' untranslated region of Hsc70t cDNA detected Hsc70t mRNA in late round spermatids from step 7 onward with the signal disappearing in spermatids at step 15. Thus, Hsc70t mRNA first appears after meiosis in haploid cells but is not translated effectively until these cells progress to the transcriptionally inactive stage which coincides with chromatin condensation. These results establish that the synthesis of Hsc70t protein is under strict translational control. PMID- 10092119 TI - Tlk, a novel evolutionarily conserved murine serine threonine kinase, encodes multiple testis transcripts. AB - Hypothesizing that genes important in meiotic processes in mammals might have evolutionarily conserved counterparts in lower organisms, we used the yeast IME2 meiotic gene (serine threonine kinase) as a probe for screening a mouse testis cDNA library. This screening resulted in identification of a novel putative serine threonine kinase. Although it did not exhibit significant homology to IME2, it did show significant sequence homology to the Tousled kinase in Arabidopsis. Tousled is associated with various differentiative processes including differentiation of the reproductive organs. The new murine gene was designated accordingly Tlk (Tousled like kinase). Tousled like kinase sequences have been reported to occur in C. elegans and in the human. Positive hybridization signals obtained in zooblot analysis suggest evolutionary conservation of Tlk throughout the phylogenetic ladder. Four distinct Tlk transcripts were detected in mouse testis, at least one of which is testis specific. Northern and in situ hybridization analyses revealed that in normal testis, Tlk is expressed predominantly in pachytene spermatocytes and in round spermatids. Transcripts differ from one another in their 3' untranslated region, resulting from use of different polyadenylation sites, and in the length of their 5' region. Within the coding region, three of the putative peptides share the kinase and C-terminal domains but differ in their N-terminal domain, suggesting that the latter may be involved in the regulation of Tlk's function. We conclude that although Tlk might have an essential role in all tissues, these kinases are likely to take part in the complex array of phosphorylations involved in regulating spermatogenesis. PMID- 10092120 TI - Timing of DNA integration, transgenic mosaicism, and pronuclear microinjection. AB - Selection of transgenic embryos prior to embryo transfer is a means to increase the efficiency of transgenic livestock production. Among transgenic reporters, cytoplasmic expression of green fluorescent protein (GFP) has features that make it ideal for transgenic embryo selection. The primary objective of this study was to assess cytoplasmic expression of a specially designed GFP reporter as a tool for transgenic bovine embryo selection. A second objective was to evaluate this reporter for studying transgenic mosaicism related to timing of integration of pronuclear microinjected DNA. Transgenic embryos produced by pronuclear injection showed a discrete pattern of GFP expression with clusters at 25, 50, and 100% of blastomeres expressing GFP. This pattern of mosaicism is interpreted to indicate that the integration of microinjected DNA occurred, not only at the pronuclear stage, but also in the subsequent cell divisions. Among the GFP-positive transgenic embryos, only in 21% did all the blastomeres show the green fluorescence. Using the fraction of positive blastomeres within an embryo, the timing of integration of microinjected DNA was estimated. The frequency of nonmosaic embryos expressing GFP is consistent with published germline transmission success rates of transgenic cattle derived from pronuclear microinjected embryos. These results indicate the possible application of GFP as a marker of transgenic embryos and graphically illustrate underlying complexities in DNA integration in embryos subjected to pronuclear microinjection. PMID- 10092121 TI - High-level expressing YAC vector for transgenic animal bioreactors. AB - The position effect is one major problem in the production of transgenic animals as mammary gland bioreactors. In the present study, we introduced the human growth hormone (hGH) gene into 210-kb human alpha-lactalbumin position independent YAC vectors using homologous recombination and produced transgenic rats via microinjection of YAC DNA into rat embryos. The efficiency of producing transgenic rats with the YAC vector DNA was the same as that using plasmid constructs. All analyzed transgenic rats had one copy of the transgene and produced milk containing a high level of hGH (0.25-8.9 mg/ml). In transgenic rats with the YAC vector in which the human alpha-lactalbumin gene was replaced with the hGH gene, tissue specificity of hGH mRNA was the same as that of the endogenous rat alpha-lactalbumin gene. Thus, the 210-kb human alpha-lactalbumin YAC is a useful vector for high-level expression of foreign genes in the milk of transgenic animals. PMID- 10092122 TI - Potential of fetal germ cells for nuclear transfer in cattle. AB - The developmental potential of bovine fetal germ cells was evaluated using nuclear transfer. Male and female germ cells at three stages of fetal development from 50- to 57-, 65- to 76- or 95- to 105-day-old fetuses were fused to enucleated oocytes 2 to 4 hr prior to activation with 7% ethanol (5 min) followed by 5 hr culture in 10 microg/ml cycloheximide and 5 microg/ml cytochalasin B. The in vitro development of nuclear transfer embryos derived from germ cells was compared with those derived from embryonic cells (blastomeres from day 5 or day 6 embryos). Blastocyst rate (38%) obtained with germ cells from 50- to 57-day-old fetuses tended to be higher than when using germ cells from 65- to 76- or 95- to 105-day-old fetuses (23% and 20%, respectively). Within each stage of fetal development, the proportion of blastocysts derived from male germ cells tended to be higher than that obtained with female germ cells, but due to the high variation between individual fetuses this difference was not significant. With the post activation procedure used in this study, germ cells from 50- to 57-day old fetuses supported the development of nuclear transfer embryos to the blastocyst stage significantly (P<0.05) better than nuclei of embryonic cells (38% vs. 3%). After transfer of blastocysts derived from germ cells of 50-to 57- and 65- to 76-day fetuses, respectively, 45% (5/11) and 50% (3/6) recipients were pregnant on day 30. The corresponding pregnancy rates on day 90 were 36% (4/11) and 17%(1/6). One live male calf was delivered by cesarean section at day 277 of gestation. Our results show that nuclei of bovine fetal germ cells may successfully be reprogrammed to support full-term development of nuclear transfer embryos. PMID- 10092123 TI - Changes in poly(A) tail length of maternal transcripts during in vitro maturation of bovine oocytes and their relation with developmental competence. AB - Molecules of mRNA are stored in the oocyte cytoplasm in order to be used during the initial phases of embryonic development. The storage takes place during oocyte growth and the extent of poly(A) tail at the 3' end of the transcripts has emerged as an important regulatory element for determining their stability. The objective of the present study was to analyse changes in polyadenylation levels of mRNA transcripts, stored in bovine oocytes, during in vitro maturation and their possible relation with developmental competence. Oocyte developmental competence was predicted on the basis of the morphological appearance of their originating ovary as previously established (Gandolfi et al. 1997a. Theriogenology 48:1153-1160) and were divided into groups H (high competence) and L (low competence). The length of the poly(A) tail of the following genes, beta actin (beta-Act), connexin 43, glucose transporter type 1, heat shock protein 70, oct-4, plakophilin, pyruvate dehydrogenase phosphatase (PDP), and RNA poly(A) polymerase, was determined at the germinal vesicle (GV) and metaphase II (MII) stage. The results indicated that the poly(A) tail of all genes except for beta Act and PDP, is shorter after in vitro maturation (IVM) in both groups. Moreover, group L oocytes showed a shorter poly(A) tail than group H oocytes in all genes except for beta-Act and PDP, both at GV and MII stage. We conclude that most of the examined transcripts follow the default deadenylation pattern described during oocyte maturation in other species and that a shorter poly(A) tail is correlated with low developmental competence. PMID- 10092124 TI - Structural and biochemical features of fractionated spermatid manchettes and sperm axonemes of the azh/azh mutant mouse. AB - The tubulin-containing axoneme and manchette develop consecutively during mammalian spermiogenesis. The nature of their molecular components and developmental sequence are not completely known. The azh/azh (for abnormal sperm headshape) mouse mutant is an ideal model for analyzing tubulin isotypes and microtubule-associated proteins of the manchette and axoneme in light of a potential role of the manchette in the shaping of the sperm head and formation of the tail. We have searched for possible differences in tubulin isotype variants in fractionated manchettes and axonemes of wildtype and azh/azh mutant mice using isotype-specific tubulin antibodies as immunoprobes. Manchettes from wild-type and azh/azh mutant mouse spermatids were fractionated from spermatogenic stage specific seminiferous tubules and axonemes were isolated from epididymal sperm. We have found that: (1) Fractionated manchettes of azh/azh mutants are longer than in wild-type mice; (2) Manchette and sperm tail axonemes display a remarkable variety of posttranslationally modified tubulins (acetylated, glutamylated, tyrosinated, alpha-3/7 tubulins). Acetylated tubulin was more abundant in manchette than in axonemes; (3) An acidic 62 kDa protein was identified as the main component of the perinuclear ring of the manchette in wild type and azh/azh mice; (4) Bending and looping of the mid piece of the tail of azh/azh sperm, accompanied by a dislocation of the connecting piece from head attachment sites, were visualized by phase-contrast, immunofluorescence and transmission electron microscopy in about 35% of spermatids/sperm; and (5) A lasso-like tail configuration was predominant in epididymal sperm of azh/azh mutants. We speculate that spermatid and sperm tail abnormalities in the azh/azh mutant could reflect structural and/or assembly deficiencies of peri-axonemal proteins responsible for maintaining a stiffened tail during spermiogenesis and sperm maturation. PMID- 10092125 TI - Simple histochemical stain for acrosomes on sperm from several species. AB - The acrosome reaction is an exocytotic process that enables a sperm to penetrate the zona pellucida and fertilize an egg. The process involves the fenestration and vesiculation of the sperm plasma membrane and outer acrosomal membrane releasing the acro somal contents. Many different methods have been devel oped to detect the acrosomal status of sperm. These techniques are sometimes complicated, costly, and can be used on only a few species. The aim of this study was to develop an efficient and inexpensive method to assess the acrosomal status of sperm from a variety of species. We prepared and fixed sperm from humans, cattle, swine, rabbits, guinea pigs, and mice and stained them with Coomassie G250. The acrosomes were stained intensely blue in color. Following capacitation, some sperm were incubated for 1 hr with 10 microM calcium ionophore A23187 to induce the acrosome reaction. They were also stained with Coomassie G-250. Ionophore treated sperm lacked Coomassie staining over the acrosomal region. Differential interference contrast (DIC), bright field microscopy or Pisum sativum agglutinin staining confirmed that the acrosomes of sperm from these species were reacted in response to calcium ionophore treatment and the acrosome reaction frequencies matched results with Coomassie staining. These results demonstrate that the acrosomal status of mammalian sperm from several species can be determined easily and reliably using this simple Coomassie Blue G-250 staining method. PMID- 10092126 TI - Jumping translocation at 11q23 with MLL gene rearrangement and interstitial telomeric sequences. AB - myeloid leukemia of acute myeloid leukemia (AML) M5a showing a jumping translocation with a breakpoint at 11q23. Fluorescence in situ hybridization (FISH) demonstrated triplication of the MLL gene and the presence of interstitial telomeric sequences, supporting the role of repetitive sequences in the mechanism of jumping translocations. Southern blot analysis of the MLL breakpoint cluster region showed the presence of an MLL gene rearrangement. Jumping translocation with MLL gene rearrangement is a previously unreported phenomenon in leukemia cytogenetics. PMID- 10092127 TI - Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization. AB - By means of comparative genomic hybridization (CGH), we screened 58 primary gastric cancers for changes in copy number of DNA sequences. We detected frequent losses on Ip32-33 (21%), 3p21-23 (22%), 5q14-22 (36%), 6q16 (26%), 9p21-24 (22%), 16q (21%), 17p13 (48%), 18q11-21(33%), and 19(40%). Gains were most often noted at I p36 (22%), 8p22-23 (24%), 8q23-24 (29%), 11q12-13 (24%), 16p(21%), 20p (38%), 20q (45%), Xp21-22(38%), and Xq21-23 (43%), with high-level amplifications at 6p21(2%),7q31(10%), 8p22-23(5%), 8q23-24 (7%), 11q13(4%), 12p12-13(4%), 17q21(2%), 19q12-13(2%), and 20q13(2%). High-level amplification at 8p22-23 has never been reported in any other cancer type and its frequency was as high as that reported for the MYC, MET, and KRAS genes. We narrowed down the smallest common amplicon to 8p23.1 by reverse-painting FISH to prophase chromosomes. Southern blot analysis using one EST marker (D38736) clearly demonstrated that amplification of this exon-like sequence had occurred in all three tumors in which amplifications at 8p22-23 had been detected by CGH. Our data provide evidence for several, previously undescribed, genomic aberrations that are characteristic of gastric cancers. PMID- 10092128 TI - Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases. AB - We have analyzed 26 tumors from 12 patients with metastatic colorectal adenocarcinoma by comparative genomic hybridization (CGH). Primary tumors and their lymph node metastases from five Dukes' C patients as well as primary tumors and their liver metastases from seven Dukes' D patients were used to assess the extent of genetic differences between primary and secondary colorectal carcinomas from the same patients, to calculate the degree of clonal divergence and genetic heterogeneity in metastatic colorectal cancer, and to determine the differences in genetic imbalances between Dukes' C and D stage tumors. We show that the same genetic aberrations were frequently found in the primary tumors and their metastases. However, metastases often contained genetic aberrations not found in the corresponding primary tumors. The comparison of Dukes' stages C and D revealed genetic aberrations common to both. However, reduced copy number of chromosome arm 17p (5/5 vs. 0/7; P = 0.001) was significantly associated with Dukes' stage C and lymph node metastases, while increased copy number of chromosome arms 6p (6/7 vs. 0/5; P = 0.007) and 17q (5/7 vs. 0/5; P = 0.027) was associated more with Dukes' stage D and liver metastases. Our results established a repertoire of chromosomal alterations associated with metastatic colorectal cancer and suggest that Dukes' C (lymph node metastasis) tumors are not always simply an earlier stage of Dukes' D (liver metastasis) tumors and, thus, in some instances at least, they are distinct forms of the disease. PMID- 10092129 TI - Molecular cytogenetic delineation of the breakpoint at 18q21.1 in low-grade B cell lymphoma of mucosa-associated lymphoid tissue. AB - Extranodal malignant non-Hodgkin lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma) represents a subtype of B-cell lymphoid malignancies with distinct clinicopathological features and is often associated with a favorable prognosis. Recent cytogenetic studies have revealed that t(11;18)(q21;q21) is a characteristic chromosomal aberration in low-grade B-cell MALT-type lymphoma. In the present study, we employed florescence in situ hybridization analysis using contiguous YAC clones mapped to the 18q21.1 region to identify a YAC clone, y789F3, encompassing the breakpoint of t(11;18)(q21;q21) in a MALT lymphoma. PI artificial chromosome (PAC) contigs constructed on this YAC clone were used to analyze the breakpoint region. PAC clone 264m4 was observed on normal chromosome 18 and on der(18), and PAC clone 879n 10 on normal chromosome 18 and on der(II), confirming that the breakpoint is located between these two PAC clones. We also found that a region of approximately 500 kb between the two PAC clones was deleted. These results indicate that the locus between PAC clones 264m4 and 879n 10 at 18q21.1 involved in t(11;18) translocation or associated deletion plays an important role in the development of MALT lymphoma. PMID- 10092130 TI - Analysis of PTEN mutations and deletions in B-cell non-Hodgkin's lymphomas. AB - The PTEN gene is involved in 10q23 deletions in several types of cancer, including glioma, melanoma, endometrial and prostate carcinomas. The PTEN gene product is a dual-specificity phosphatase with putative tumor suppressor function. Deletions and rearrangements of 10q22-25 have been reported in approximately 5%-10% of non-Hodgkin's lymphomas (NHLs), raising the possibility of PTEN involvement in these tumors. In order to address this question, we analyzed a panel of NHLs (n = 74) representative of the main histologic subtypes for mutations and homozygous deletions of PTEN. We report somatic coding/splice site mutations in 20% (2 of 10) of Burkitt's lymphoma cell lines and in 3% (2 of 64) of primary NHL cases analyzed. No homozygous deletions were found in these tumors. Interestingly, this study showed that cytogenetically characterized NHL cases (n = 6) with 10q22-q25 abnormalities displayed neither biallelic deletions nor mutations of PTEN. These results suggest that a tumor suppressor gene distinct from PTEN may be involved in 10q deletions in this subgroup of NHL cases. PMID- 10092131 TI - Hypermethylation of the p16/CDKN2A/MTSI gene and loss of protein expression is associated with nonfunctional pituitary adenomas but not somatotrophinomas. AB - The cyclin-dependent kinase inhibitor 2A/multiple tumor suppressor gene 1 (CDKN2A/MTS//p16) plays an important role in the control of progression from G to S-phase of the cell cycle through the inhibition of CDK4-mediated RBI phosphorylation. In this study we investigated 46 nonfunctional pituitary tumors and 21 somatotrophinomas for aberrant methylation of the CpG island contained within the CDKN2A gene as an alternative mechanism of gene silencing. We demonstrate methylation in 32/46 (70%) of nonfunctioning tumors, in contrast to 2/21 (9.5%) somatotrophinomas and 0/15 histologically normal postmortem pituitaries. Methylation in noninvasive and invasive nonfunctional tumors was approximately equal at 15/20 (75%) and 17/26 (65%), respectively. Immunohistochemical analysis showed an absence of CDKN2A protein in 25/32 (78%) methylated nonfunctioning tumors, demonstrating a highly significant overall correlation (P = 0.00007) between hypermethylation of the gene and absence of the p 16 protein. The association between hypermethylation and absence of CDKN2A protein remained when the cohort of nonfunctional tumors was further subdivided into noninvasive 12/15 (80%; P = 0.004) and invasive 13/17 (76%; P = 0.01), suggesting this to be an early event in pituitary tumorigenesis. In contrast, a single invasive methylated somatotrophinoma failed to express the CDKN2A protein. These data show that hypermethylation of the CpG island within exon 1, but not exon 2, of the CDKN2A gene is frequently associated with loss of protein expression in nonfunctional pituitary tumors, but not somatotrophinomas, suggesting different tumorigenic pathways. PMID- 10092133 TI - Frequent allelic loss at the TOC locus on 17q25.1 in primary breast cancers. AB - Sporadic breast cancers often show allelic losses on the long arm of chromosome 17. Since the BRCA1 gene lies at 17q21.1 and the TOC locus, associated with esophageal cancer, lies at 17q25.1, either gene could be the target of those losses. We examined both loci in 178 primary breast cancers, using microsatellite markers covering the relevant regions of 17q, and observed allelic losses in 97 tumors (55%). Losses were most frequent at markers around the TOC locus (48% at D7S1839 and 43% at D17S1603), where we identified a distinct commonly deleted region within a I -cM interval. Another larger, separate commonly deleted region including the BRCA1 gene was also identified, which exhibited 45% of allelic loss (at D17S934). Allelic loss on 17q was more frequent in tumors of the solid tubular histologic type (P = 0.0129) and in estrogen-negative and progesterone negative tumors (P = 0.0281 and 0.0196, respectively). The results indicated that BRCA1 and TOC are independent targets of allelic loss on 17q in primary breast cancers, and that inactivation of the TOC locus in particular may play an important role in the genesis of sporadic breast tumors. PMID- 10092132 TI - Comparative genomic hybridization of squamous cell carcinoma of the esophagus: the possible involvement of the DPI gene in the 13q34 amplicon. AB - We investigated copy number aberrations in 29 primary tumors and 12 cell lines of esophageal squamous cell carcinoma (ESC) using comparative genomic hybridization. In the primary tumors, the most common sites of copy number gains were 3q26.3-27 (45%), 8q24 (41%), 5p15 (38%), Xq27-28 (38%), 14q32 (31%), 11q13 (28%), and 20q13.3 (28%). High-level gains (HLGs) indicative of gene amplifications were identified at 11q13 in two cases, and in one case each at 2q33-34, 3q25-29, 5p15.1-15.2, 7q21-22, 11p11.2, 12p11.2-12, and 13q34. Recurrent losses were observed only at 9p13(17.2%). In the 12 ESC cell lines, the most common sites of HLGs were 5p15.1-15.3 (four cases), 11q13 (four cases), 8q24.1-24.2 (three cases), 20q13.2-13.3 (three cases), 3q26.3 (two cases), and 7p15-22 (two cases). Less frequent HLGs (one case each) were observed at 2p16-22, 3q25, 7p12-14, 7q21 22, 9q34, 10q21, 11p11.2, 14q13-14, 14q31-32, 15q22-26, and 17p11.2. Chromosomes and chromosome arms that showed frequent losses in the cultured lines were 18q (58%), 4 (50%), 9p (50%), and 3p (42%). These findings provide evidence for a number of previously unknown genomic aberrations in ESC, suggesting target regions for positional cloning of genes relevant to carcinogenesis in the esophagus. In particular, we identified a significant amplification of the DPI gene (TFDPI), a transcription factor that forms heterodimers with E2FI, in the single primary tumor that exhibited HLG at 13q34. PMID- 10092134 TI - High-resolution deletion mapping of chromosome arm 1p in pancreatic cancer identifies a major consensus region at 1p35. AB - Chromosomal arm 1p has long been suspected, on the basis of loss of heterozygosity (LOH) and other data, to harbor a tumor suppressor gene important in pancreatic carcinomas and other tumors. We constructed a high-resolution map of LOH at I p in a panel of pancreatic adenocarcinomas. Using 44 markers, we identified LOH on I p in 49% of 43 cancers. Breakpoints in 1p were identified in 15 of the carcinomas and could be used to ascertain consensus patterns. We found a major consensus region of LOH at 1p35 between loci D1S233 and D1S247. This region participates in the majority of LOH events on 1 p in pancreatic cancer. These data provide a roadmap for further regional mapping, homozygous deletion searches, comparison to LOH patterns seen in other tumor types, and prioritization of studies using candidate genes. PMID- 10092135 TI - Studies of bovine enterovirus structure by ultraviolet resonance Raman spectroscopy. AB - The structural comparison of bovine enterovirus MZ468 strain before and after the heat treatment was studied by ultraviolet resonance Raman (UVRR) spectra excited at both 235 and 251 nm. The difference between full, heated full and purified empty particles, which were expected as an in vitro model of uncoating, were demonstrated. At 235 nm excitation, the Raman bands of the capsid protein dominated in all the UVRR spectra. The UVRR spectra of the empty particles exhibited non-homogenious broadening for tryptophan W3 band and W7 Fermi doublet bands, which were characteristics of hydrophobic environment, when compared with those of the full particles. The results indicates that some Trp indole rings of the full particles were packaged inside the viral capsids and not strained by virion assembly. On the other hand, the Raman bands assigned to guanine residues of the single stranded-RNA genome were enhanced strongly in the 251-nm excited UVRR spectrum. The spectral differences between the packaged (full particles) and the unpackaged virions (heated full particles) indicates that some guanine residues had strong hydrogen bonds in the full particles. PMID- 10092136 TI - Generation of infectious genome of bovine adenovirus type 3 by homologous recombination in bacteria. AB - The widely used technique of generating adenovirus vectors by homologous recombination in mammalian cells is usually not very efficient. This communication describes a simple method of generating a plasmid containing the full-length genome of an adenovirus by homologous recombination in bacteria. Following transfection of a suitable mammalian cell line with the full-length adenovirus genome, infectious virus progeny could easily be generated. Using this technique the generation of adenovirus recombinants would be efficient and straightforward. PMID- 10092137 TI - Purification of full-length enterovirus cDNA by solid phase hybridization capture facilitates amplification of complete genomes. AB - The aim of the study was to develop a method for the selective purification of full-length enterovirus single strand (ss) cDNA for subsequent amplification of complete enterovirus genomes by long distance PCR. As a model system we have used the prototype strain of echovirus 5 (EV5). Due to inefficient first strand cDNA synthesis using EV5 RNA as template, only a few molecules of EV5 sscDNA were completely reverse transcribed and no amplification products were observed when long distance polymerase chain reaction (LD-PCR) was used for amplification of complete EV5 genomes. To purify the complete EV5 cDNA present, an oligonucleotide, derived from the conserved 5' end of an enterovirus genome, was immobilized on paramagnetic beads and complete EV5 sscDNA was captured and purified from the less than full-length cDNAs. LD-PCR using the purified EV5 cDNA resulted in amplification of complete EV5 genomes. Transfection of the EV5 RNA transcribed from these uncloned amplicons resulted in production of replicating viruses. This demonstrates that solid phase hybridization capture of sscDNA is an efficient method that can be used for enrichment and purification of full-length enterovirus sscDNAs. PMID- 10092138 TI - Characterization of primary cell cultures as potential target cells for analysis of bovine cytotoxic T lymphocytes. AB - In domestic animal species, assessment of cell-mediated immune responses to virus infection is hampered by the requirement for class I MHC compatibility between target and effector cells. Additional complicating factors can include an inability to infect target cells in vitro, or virus-induced lysis of infected target cells. One way to circumvent these problems is to use virus-mediated gene transfer to deliver individual viral genes to autologous primary target cells. Several primary bovine cell cultures were assessed as potential target cells for cytotoxic T lymphocyte (CTL) assays by measuring their levels of class I MHC expression and susceptibilities to retroviral gene delivery. High levels in both class I MHC expression and susceptibility to gene delivery were seen in adherent cell cultures isolated from peripheral blood (PBAC). PBAC, which arose as an outgrowth of adherent peripheral blood mononuclear cell cultures, had morphology, protein expression patterns, and response to functional assays characteristic of high endothelial cells. Expression of viral vector-delivered genes in PBAC cells was confirmed with a recombinant retrovirus carrying the green fluorescent protein (GFP) gene. The use of vector-mediated delivery of viral genes to bovine high endothelial cells is a promising method for assessment of cell-mediated immunity in cattle. PMID- 10092139 TI - Detection of Epstein-Barr virus EBER sequence in post-transplant lymphoma patients with DNA dendrimers. AB - The EBER RNAs are the most numerous viral transcripts in latently infected lymphocytes in healthy individuals and also in the tumor cells of Epstein Barr virus (EBV)-associated malignancies. A rise in EBV load in peripheral blood has been associated with the onset of post-transplant lymphoproliferative disease (PTLD) in immunocompromised patients. Treatment of PTLD with adoptive immunotherapy has made the rapid and accurate determination of EBV load essential. The relationship between EBV load and other EBV-associated malignancies, like Hodgkin's disease or AIDS-associated lymphoma, is unknown. In order to define viral load based on the number of EBV-infected cells in the peripheral blood, we developed a method which combines cellular dilution of peripheral blood mononuclear cells with the direct detection of EBER-1 RNA with DNA dendrimers. DNA dendrimers are large scaffolds of DNA which give at least a 500 1000-fold increase in detection of membrane bound nucleic acid over oilgonucleotide probes. The use of a novel class of these nucleic acid superstructures is described as a specific probe for EBER-1 detection. When two PTLD patients were analyzed for viral load with DNA dendrimers, at least one in 250000 peripheral blood mononuclear cells were shown to be infected with EBV. PMID- 10092140 TI - Optimization of in situ cellular ELISA performed on influenza A virus-infected monolayers for screening of antiviral agents. AB - Viral susceptibility testing has been traditionally performed by the plaque reduction assay (PRA) which is laborious, time consuming, relatively expensive, and requires subjective input by the reader. An in situ cellular enzyme-linked immunosorbent assay (ELISA) has been developed with the potential to overcome many of the limitations of PRA and has been applied to a variety of viruses. This study establishes the specific conditions necessary for susceptibility testing of influenza A virus to antiviral agents such as amount of inoculum size, duration of incubation, fixative type, and cell number; factors which are critical to the performance of the in situ cellular ELISA. In situ cellular ELISA was found to correlate strongly with the plaque assay (PA) (R2 = 0.997, P < 0.002). Both assays were applied to test the susceptibility of influenza A virus to a new antiviral emulsion agent and yielded comparable data. The optimized in situ cellular ELISA can serve as a reliable assay for the rapid screening of large numbers of antiviral agents. PMID- 10092141 TI - Recovery and detection of enterovirus, hepatitis A virus and Norwalk virus in hardshell clams (Mercenaria mercenaria) by RT-PCR methods. AB - A method for recovery of enteric viruses from hardshell clams (Mercenaria mercenaria) has been developed and evaluated. Seeded 50-g samples of clam tissue homogenates were processed by adsorption elution precipitation, two fluorocarbon extractions and PEG precipitation. Clam concentrates were assayed by infectivity and by RT-PCR after guanidinium isothiocyanate (GIT) extraction and/or an indirect immunomagnetic capture (IC) of the virus using paramagnetic beads. GIT extraction removed PCR inhibitors and allowed a reliable RT-PCR detection of viral RNA. The detection sensitivity of GIT extraction-RT-PCR was < 1 PFU of poliovirus 1, < 10 PFU of HAV and 1-11 PCRU of Norwalk virus. IC was very effective for additional concentration and purification of enteric viruses from clam concentrates removing most RT-PCR inhibitors. The sensitivity of this method was comparable to the GIT extraction and the sample volume tolerance for PCR was increased about 10-fold. Both methods gave similar efficiency for virus detection in samples seeded with low virus levels. The procedure developed in this study is effective for enteric viruses detection in hardshell clams by RT-PCR. PMID- 10092142 TI - Purification of E. coli-expressed HIS-tagged hepatitis B core antigen by Ni2+ chelate affinity chromatography. AB - Hepatitis B virus is a major cause of human liver disease. In the case of chronic infection the virus can lead to liver cancer and cirrhosis. The virion consists of an outer envelope containing lipids of the endoplasmic reticulum and virally encoded surface proteins. This lipoprotein shell encloses the nucleocapsid or core antigen (HBcAg), which contains the viral genome. The capsid consists of dimers of a 183-residue protein, which can be divided into an assembly (residues 1-149) and a protamin-like domain (residues 150-183), responsible for polymerization into particles and RNA packaging, respectively. Upon expression of the core gene in bacteria the products are assembled into capsids resembling those of wild type particles. A purification protocol was developed for unpolymerised (dimeric) and polymerized HBcAg by fusion of six histidine residues to a C-terminal deletion mutant of the core protein allowing the isolation of the respective antigens after denaturing Ni2+-chelate affinity chromatography and renaturing dialysis. The possible incorporation of E. coli proteins during the assembly process and the inclusion of nucleic acids can be avoided. The method might be an attractive alternative to common purification protocols of hybrid virus-like particles (VLPs) for vaccine use. PMID- 10092143 TI - Determination of antibodies to TT virus (TTV) and application to blood donors and patients with post-transfusion non-A to G hepatitis in Japan. AB - Recently, a nonenveloped single-stranded DNA virus named TT virus (TTV) has been reported in association with non-A to G post-transfusion as well as sporadic acute and chronic liver disease. A method was developed for the detection of antibody to TTV (anti-TTV) by means of immune precipitation and detection of TTV DNA by the polymerase chain reaction. The test serum was incubated with TTV, recovered from feces of a carrier, and after incubation, the formed immune complexes were precipitated with goat antiserum to human IgG. TTV DNA was sought for by the polymerase chain reaction in both precipitate and supernatant. The detection of TTV DNA in the precipitate, but not in the supernatant, was considered to represent anti-TTV in the test serum. Of the 44 healthy blood donors in Japan, anti-TTV was detected in one of the six (17%) with TTV DNA and 11 of the 38 (29%) without TTV DNA. In the two patients with post-transfusion non A to G hepatitis, free anti-TTV developed as they cleared TTV in serum. Anti-TTV complexed with TTV in serum, detectable by precipitating sera with goat anti human IgG and testing for TTV DNA, elicited while the patients had elevated alanine transaminase levels. The determination of anti-TTV would be useful for detecting resolved infection in surveys for exposure to TTV in the general population, and for establishing the mechanism of liver injury associated with TTV infection. PMID- 10092144 TI - Susceptibility of human and non-human cell lines to HCV infection as determined by the centrifugation-facilitated method. AB - The centrifugation-facilitated inoculation method was used to test 51 human and non-human cell lines for ability to support HCV replication. As determined by nested RT-PCR, one fifth of the cell lines tested were virus positive 15 days post inoculation suggesting that the centrifugation-facilitated inoculation is an efficient method for cell infection with HCV. However, virus production by infected cultures remained of low grade, thus showing that the unknown factors which limit HCV replication in vitro are not overcome by the procedure. PMID- 10092145 TI - An immunochemical focus assay to quantify replication competent and defective viruses involved in murine acquired immunodeficiency syndrome. AB - Murine acquired immunodeficiency syndrome is a lymphoproliferative disease with a concurrently developing immunodeficiency. The disease is induced after injection of supernatant of a chronically infected cell line that releases a mixture of two replication competent virus classes and a replication incompetent virus species responsible for pathogenicity. An immunochemical detection assay for virus infected foci on cell monolayers has been developed. This assay allows quantification of all three types of virus. PMID- 10092146 TI - Apoptosis: its relevance to carcinogenesis and anti-tumour drug sensitivity. PMID- 10092147 TI - Characterization of chromosome 8 aberrations in the prostate cancer cell line LNCaP-FGC and sublines. AB - In two androgen-dependent (FGC and P70) and two androgen-independent (LNO and R) sublines of the prostate cancer model LNCaP numerical and structural aberrations of chromosome 8 were investigated in detail. The techniques used were whole chromosome paint (WCP) and fluorescence in situ hybridization (FISH) with three cosmid probes mapping to different parts of the p-arm (D8S7 (8p23.3), LPL (8p22) and PLAT (8p11.1)). By WCP all four cell lines showed four copies of chromosome 8 in most cells. However, FISH demonstrated that in all sublines deletions in the 8p region were present. The majority of both FGC and P70 had two copies of cosmids D8S7 and LPL. The cosmid PLAT showed a broader distribution (1-4 copies), especially in P70. Compared with FGC and P70, both LNO and R showed a larger number of copies (3 or 4) of all three cosmid loci. It is discussed that this difference is probably the result of nondisjunction as a reaction to loss of other sequences on 8p, possibly the tumor suppressor gene (TSG) mapping to 8p21. The fact that both sublines LNO and R are androgen-independent raises the possibility of a link between TSG loss on 8p and androgen independence. PMID- 10092148 TI - Transient tenascin enhancement is an early event after androgen ablation in rat prostate. AB - Tenascin (tenascin-C), a mesenchymal glycoprotein, is expressed in many tissue remodeling processes. We evaluated tenascin expression during androgen deprivation-related involution of the rat prostate. At set intervals following castration and subsequent testosterone repletion, prostates were removed in 30 adult rats. Each prostate was immunostained with a polyclonal antiserum against rat tenascin and keratin antibodies specifically directed against exocrine basal cells and luminal cells in the prostate glandular structure. Morphologic impressions were semiquantatively evaluated using a computer-assisted image analysis system. Rat prostates showed a transient increase in the periglandular tenascin expression directly following castration that reached a maximum at day 3. At day 6, tenascin expression was similar to control prostates. This was accompanied by a decrease of cells in the luminal cell layer. The weakest tenascin immunoreactivity was noted on day 14 after androgen withdrawal. This process was reversed by androgen repletion. This study shows that in the rat prostate tenascin expression may be androgen dependent and that during androgen deprivation-related involution tenascin expression is probably associated with tissue remodeling by stromal-epithelial interactions. PMID- 10092149 TI - The cytostatic effect of 9-cis-retinoic acid, tretinoin, and isotretinoin on three different human bladder cancer cell lines in vitro. AB - Retinoids have been shown to have activity in both preclinical and clinical bladder cancer studies but their exact role in its treatment and prevention remains obscure. In this study cytostatic activity of a novel 9-cis-retinoic acid (9-cis-RA) was compared with two other retinoids: tretinoin and isotretinoin, in three different bladder cancer cell lines: RT4 (well differentiated), 5637 (moderately differentiated) and T24 (poorly differentiated). The three retinoids were incubated at concentrations of 0.3, 3 and 30 microg/ml with bladder cancer cells in microtitre plates for 3 and 6 days. The cytostatic effect was estimated by using luminometric measuring of ATP activity of viable cells in suspension. Compared with the older retinoids, tretinoin and isotretinoin, the highest concentration of 9-cis-RA had a cytostatic efficacy in all three bladder cancer cell lines tested. A clear dose response relationship was observed in isotretinoin-treated cultures after 6 days and in all 9-cis-RA-treated cultures. Tretinoin was either ineffective or had a stimulating effect on poorly differentiated tumour cells. To conclude, isotretinoin and 9-cis-RA had a cytostatic effect on human bladder cancer cells in vitro. However, the possibility of stimulating cancer growth at small doses, at least with tretinoin, and toxicity at high doses must be considered when planning clinical trials. PMID- 10092150 TI - Prostate specific membrane antigen (PSM) is expressed in various human tissues: implication for the use of PSM reverse transcription polymerase chain reaction to detect hematogenous prostate cancer spread. AB - Detection of prostate-specific membrane antigen (PSM)-mRNA expression in blood samples using reverse transcription polymerase chain reaction (RT-PCR) is discussed as a new diagnostic marker of circulating micrometastases in prostate cancer patients. We applied the RT-PCR technique to different human tissues and obtained positive signals for PSM transcripts in human genital and multiple extra genital tissue sites. The cDNAs were prepared from different human tissues and prostatic cell lines. RT-PCR and nested RT-PCR for PSM was performed with primers derived from the published PSM cDNA. The RT-PCR fragments obtained were cloned and showed 100% sequence homology to PSM. Southern blot hybridization with labeled probes was used to confirm the specificity of the amplicons. In addition to the known PSM expression in the human brain, PSM-mRNA was detected in cDNA isolated from human testis, epididymis and seminal vesicles and in the PC-3 prostatic cancer cell line. Furthermore, we found PSM-mRNA in heart, liver, lung, kidney, spleen, and thyroid gland. The results indicate that PSM expression is not restricted to the prostate gland, but represents a more general component of genital and extra-genital human tissues. This must be considered when RT-PCR and nested RT-PCR screening for PSM expression is performed as a diagnostic measure in blood from prostate cancer patients. PMID- 10092151 TI - Obstructive nephropathy: an update of the experimental research. AB - Ureteral obstruction (UO) is one of the most common problems confronting the urologist. Although large amounts of animal and clinical research have been done, the pathophysiologic mechanisms accompanying UO are not fully elucidated. Most of our knowledge on UO has been derived from experimental studies in a variety of animal models. Both antenatal and postnatal UO models have been developed mainly by ligation of the ureter or by burying the ureter into the psoas muscle. Most experimental studies have focused on short-term complete ureteral obstruction. The long-term effects of partial ureteral obstruction have been less intensively studied. It is now clear that obstructive nephropathy is not a simple result of mechanical impairment to urine flow but a complex syndrome resulting in alterations of both glomerular hemodynamics and tubular function caused by the interaction of a variety of vasoactive factors and cytokines that are activated in response to UO. Leukocyte infiltration appears to play an important role in obstructive nephropathy suggesting that UO also has an immunological component. Growth factors such as platelet-derived growth factor, transforming growth factor beta, epidermal growth factor and insulin-like growth factor I may all play a role in the development and progression of fibrotic and sclerotic changes in the obstructed kidney. At present, the selection of patients with congenital hydronephrosis for operative treatment is controversial. Studies in animals and patients have shown that partial unilateral UO does not always cause a loss of renal function or progression in urinary tract dilation during long-term follow up. The implications of UO continue to raise many questions and further work is necessary to achieve a better understanding of the pathogenesis in obstructive nephropathy. PMID- 10092152 TI - Ureteral growth in animal models with increased renal excretion of urine. AB - The influence of increased functional load on the macroscopical and histological appearance of the ureter was investigated. Sixty rats were divided into five groups: (1) sucrose-fed rats with non-osmotic polyuria; (2) diabetic rats with osmotic polyuria; (3) uninephrectomized rats; (4) sham-operated control rats; and (5) control rats. The 24-hour urinary volume was measured on days 7, 14 and 21. Growth of the kidney, ureter and bladder was investigated and the histological appearance of the ureter was further evaluated. Diabetic and sucrose-fed rats had comparable polyuria with a seven-fold increase in urinary output. The urinary volume for the remaining kidney was doubled in uninephrectomized rats. After 3 weeks, diabetic rats had increased weight of the kidney, ureter and bladder, sucrose-fed rats had increased weight of the bladder, whereas uninephrectomized rats had increased weight of the kidney and ureter. The cross-sectional area (CSA) of the ureter wall from control rats increased from the proximal to the distal portion. The size of the whole ureter from diabetic rats was dramatically increased, the CSA of the wall of the distal ureter portion being four times that of the controls. The CSA of the ureter wall from sucrose-fed rats was increased only in the distal portion, whereas the ureter from uninephrectomized rats was increased only in the proximal portion. The results demonstrate the importance of differentiating between different portions of the rat ureter when examining histological sections of this organ. Moreover, polyuria per se is shown to induce growth of the bladder and of the adjacent distal part of the ureter, whereas uninephrectomy and diabetes caused growth of the kidney and the upper parts of the ureter, in addition to the growth induced by polyuria. PMID- 10092153 TI - Screening for mutations in candidate genes for hypospadias. AB - Hypospadias. a condition with a frontally placed urethral orifice on the penis, is the most common malformation in males. During fetal development several components are necessary for normal male genital development. Testosterone and dihydrotestosterone act via the androgen receptor but a defective receptor function results in different degrees of genital malformations. Testosterone 5alpha-reductase converts testosterone to dihydrotestosterone, which is crucial for normal differentiation, and a total lack of this enzyme results, in syndromes with hypospadias. The Wilms' tumour 1 (WT1) gene is expressed in the fetal gonad and genital malformations can occur due to WT1 gene mutations. These genes are therefore strong candidate genes for hypospadias. We have analysed 35 boys with hypopadias and one girl diagnosed as with complete androgen insensitivity syndrome, using exon by exon polymerase chain reaction (PCR) amplification of the AR, WTI and 5alpha-reductase genes and screened for point mutations and performed subsequent DNA sequencing. No mutations in any of these genes were found in the 26 patients with isolated hypospadias. Two patients with severe hypospadias with cryptorchidism were found to carry mutations in the androgen receptor gene. Also the girl with clinically diagnosed complete androgen insensitivity was found to be homozygous for a splice mutation in the 5alpha-reductase gene. In summary, mutations in the WT1, AR and 5alpha-reductase genes are not common causes of isolated hypospadias. PMID- 10092154 TI - Role of inter-alpha-inhibitor and its related proteins in urolithiasis. Purification of an inter-alpha-inhibitor related protein from the bovine kidney. AB - Urine contains several macromolecules that inhibit calcium oxalate (CaOx) crystallization. Among them is bikunin, the light chain of most of the inter alpha-inhibitor (IalphaI) family of glycoproteins. This study aimed to verify whether bikunin and other members of the IalphaI family are synthesized in the kidneys or derived exclusively from the plasma. Proteins extracted from homogenized bovine kidney were applied successively to three chromatographic steps on DEAE-Sephacel, Sephacryl S-300, and Mono Q column. The inhibitory activity was assayed using a CaOx crystallization system. The presence of IalphaI related proteins was determined by electrophoresis and Western blotting. The results showed that kidney extract contained a 125-kDa protein that cross-reacted with anti-IalphaI antibodies. This protein inhibited CaOx crystallization efficiently. According to its molecular weight and immunoreaction with anti IalphaI antibody, the 125-kDa protein could be pre-alpha-inhibitor. The latter is known to encompass a heavy chain and bikunin, which may explain its inhibitory activity against CaOx crystallization. Consequently, we hypothesize that kidneys may produce some IalphaI-related proteins that are involved in the inhibition of stone formation. PMID- 10092156 TI - Inhibitory effect of bikunin on calcium oxalate crystallization in vitro and urinary bikunin decrease in renal stone formers. AB - Two proteins of 17 and 24 kDa, respectively, which were immunologically related to bikunin, were purified from urine of healthy men, using in the last step a trypsin CNBr-sepharose affinity column. These proteins strongly inhibited calcium oxalate (CaOx) crystallization in two in vitro models. In the first model, the presence of 8 microg/ml protein in a medium containing 0.76 mM CaCl2 (with 45Ca) and 0.76 mM ammonium oxalate inhibited the crystallization process by 80%, as estimated by supernatant radioactivity after 60 min of incubation. A similar inhibition was observed in the second turbidimetric model, where the CaOx crystallization kinetics were followed for 10 min at 620 nm in a medium containing 4 mM CaCl2 and 0.5 mM Na2Ox. These proteins were used as standard protein for the development of an enzyme-linked immunosorbent assay (ELISA) in urine. Mean (+/-SEM) urinary bikunin concentration in 18 healthy subjects was 5.01 +/- 0.91 microg/ml. This was a concentration range of strong inhibitory activity in vitro. Bikunin values were nearly 50% lower (2.54 +/- 0.42 microg/ml, P=0.007) in 31 CaOx renal stone formers (having weddelite crystals in their first morning urine) than in the healthy volunteers. A correlation was found between urinary bikunin and alpha-1 microglobulin concentrations in the control group (y=0.73x + 1.09, r2=0.8) while no such correlation existed in the lithiasis group. In conclusion, bikunin exerts a strong inhibitory action of CaOx crystallization in vitro. Its involvement in urinary CaOx crystallization of stone formers is highly probable, based on the significant decrease in its urinary concentration in the majority of stone formers studied. PMID- 10092155 TI - Role of inter-alpha-inhibitor and its related proteins in experimentally induced calcium oxalate urolithiasis. Localization of proteins and expression of bikunin gene in the rat kidney. AB - Our earlier studies indicated that members of the inter-alpha-inhibitor (IalphaI) family of glycoproteins may play an important role in urolithiasis. Indeed bikunin, the light chain of IalphaI is a potent inhibitor of calcium oxalate crystallization. In order to understand this role, the distribution of IalphaI and its related proteins, as well as the expression of bikunin, were studied in normal and nephrolithic rats. In normal rats, IalphaI immunoreactivity was located mainly in proximal tubules. However, in nephrolithic rats, in addition to proximal tubules, the staining was intensively extended to tubules in the corticomedullary junction. Furthermore, by using polymerase chain reaction technique, we demonstrated that gene encoding for bikunin was activated in kidneys of nephrolithic rats. We have previously demonstrated increased staining for osteopontin in association with calcium oxalate crystal deposition in rat kidneys. Others have shown an increase in osteopontin production by renal epithelial cells on exposure to calcium oxalate crystals. Based on these observations we conclude that kidney cells possess an auto-defense system against calcium oxalate crystallization and stone formation in which members of the IalphaI family may be closely involved. PMID- 10092157 TI - Effect of cola consumption on urinary biochemical and physicochemical risk factors associated with calcium oxalate urolithiasis. AB - Since stone formers are advised to increase their intake of fluid, the present study was undertaken to determine the effect of cola beverage consumption on calcium oxalate kidney stone risk factors. Fourteen males and 31 females provided 24-h urines before and after an acute load of cola. Relative supersaturations, activity products and empirical risk indices, ratios and quotients were calculated from urinary biochemical data to assess calcium oxalate crystal and stone formation risk. Several risk factors changed unfavourably following consumption of cola. In males, oxalate excretion, the Tiselius risk index and modified activity product increased significantly (P < 0.05). In females, oxalate excretion increased significantly while magnesium excretion and pH decreased significantly (P < 0.05). Scanning electron microscopy showed that urines obtained from both sexes after cola consumption supported calcium oxalate crystallization to a greater extent than the control urines. It is concluded that consumption of cola causes unfavourable changes in the risk factors associated with calcium oxalate stone formation and that therefore patients should possibly avoid this soft drink in their efforts to increase their fluid intake. PMID- 10092158 TI - COX-1, COX-2: so what? AB - The discovery of the second isoform of cycloxygenase has led to a rapid expansion in basic science, pharmacology and clinical data. With the completion of phase II studies of the new COX-2 specific inhibitors this review examines some of the implications of the new data. PMID- 10092159 TI - Treatment adherence in juvenile rheumatoid arthritis--a review. AB - Adherence to long-term complex treatment in children with Juvenile Rheumatoid Arthritis (JRA) is a major problem. This article reviews psychosocial factors that compromise treatment adherence and discusses ways to improve long-term adherence. Child-centred information, therapy management, behaviour modification, and parental monitoring are described as adherence facilitating strategies for clinical and non-clinical settings. Finally, the implications for further practice and research are discussed. PMID- 10092160 TI - Weight-bearing physical activity, calcium intake, systemic glucocorticoids, chronic inflammation, and body constitution as determinants of lumbar and femoral bone mineral in juvenile chronic arthritis. AB - The associations between the lumbar and femoral bone mineral and several body constitutional, lifestyle, and disease related variables were studied in 111 children with juvenile chronic arthritis (JCA) by factor and multiple linear regression analyses. In addition to the measurement of bone mineral density (BMD), bone width and bone mineral volumetric density (BMDvol) were determined by dual-x-ray absorptiometry (DXA). Factor analysis of 13 explanatory variables yielded six non-correlating factors, named as body size, physical activity, calcium intake, glucocorticoids, disease duration, and disease activity. These six factors were used as new variables to explain BMD, BMDvol, and bone width by multiple linear regression analyses. These showed body size, physical activity, and calcium intake as significant positive and disease activity and glucocorticoids as significant negative determinants of BMD in JCA. The analyses revealed also considerable differences in the relationships between factors and BM Dvol or bone width. PMID- 10092161 TI - Clinical and biological characteristics of immunopathological disease-related erythema nodosum in children. AB - We report a series of 22 children with idiopathic, drug unrelated erythema nodosum (EN) admitted to our Department. In 5 of them an history of streptococcal pharyngitis was referred; the remaining patients came to us with a diagnosis of "EN of unknown origin". Acute phase reactants, immunoglobulins, stool alpha1 antitrypsin, ANA, anti dsDNA antibodies and ANCA assay, chest roentgenogram, tuberculin test, and ophthalmologic assessment were performed in all patients. Etiologic diagnosis was made in 16 patients: Streptococcal pharyngitis (5 cases), chronic inflammatory bowel disease, IBD (3 cases), Behcet syndrome (2 cases), Yersinia enteritis (2 cases), infectious mononucleosis, atypical mycobacterial infection, immunodeficiency related infection, and SLE-like syndrome due to C4 deficiency (1 case each). We found oral/scrotal aphthae in 3 cases, gastrointestinal symptoms in 5 cases, arthritis in 3 cases. Acute phase reactants were positive in 16 patients without correlation to the underlying disease. Conversely, the increased alpha1 antitrypsin stool excretion and IgA serum concentration seemed to represent helpful indicators of IBD and Behcet syndrome, respectively. Proinflammatory cytokine pattern showed increased IL6 serum concentrations both in infectious and in non infectious disease-related EN, whereas a minor involvement of TNF was found in these patients. PMID- 10092162 TI - The prognosis and outcome of patients referred to an outpatient clinic for rheumatic diseases characterized by the presence of antinuclear antibodies (ANA). AB - To evaluate if patients with symptoms related to the musculoskeletal system, characterized by the presence of ANA, are prone to develop SLE or other specific rheumatic diseases, a follow-up study was started to investigate all patients who for the first time visited the outpatient clinic of the Department of Rheumatology in the period from 1983 to 1986 and who had detectable ANA. Patients with anti-dsDNA antibodies were excluded from evaluation. In total 65 patients could be included in the study, with a mean duration of follow-up of 9.3 years (range 2-16 years). During follow-up a specific rheumatic diagnosis could be established in 38 patients, on 75% of the patients within 2 years of follow-up, and in 90% within 5 years. Five patients developed a non-rheumatic disease. For the remaining 22 patients, diagnosis was not conclusive. These patients without a conclusive diagnosis had a mild clinical picture, which remained stable during follow-up. In conclusion 58% of patients presented with rheumatic symptoms and detectable ANA developed an overt rheumatic disease, usually within the first 5 years of follow-up. PMID- 10092163 TI - Prevalence of mutilans-like hand deformities in patients with seropositive rheumatoid arthritis. A prospective 20-year study. AB - This study examined radiographically the prevalence of arthritis mutilans hand deformities in an inception cohort of 68 rheumatoid arthritis (RA) patients. Hand deformities of 103 RF-positive RA patients were evaluated after 8 years, 83 patients after 15 years and 68 patients 20 years after entry. The grade of destruction in the hand joints was assessed by the Larsen method and Larsen scores of 0-50 were determined for both PIP (+IP) and MCP joints. At the end point, 3 patients had Larsen scores > or =40 for both PIP and MCP joints. These three patients had severe resorption in most of the finger joints, but did not demonstrate classical opera-glass hand. The prevalence of mutilans-like hand deformities with RA was 3/68 (4.4%) in a prospective 20-year study. PMID- 10092164 TI - Hypothalamo-pituitary-adrenal axis and growth hormone axis in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic disease and is associated with cytokines (IL-1, IL-6, TNF-alpha) production. There is little information on hypothalamo pituitary-adrenal (HPA) axis and growth hormone (GH) axis in the patients with RA. We have, therefore, investigated these systems in twenty patients with confirmed RA. Ten of the patients had active and 10 patients remitted RA. Serum cortisol, ACTH and GH levels were measured in the basal state and after insulin induced hypoglycaemia. Cortisol, adrenocorticotropic hormone (ACTH) and GH responses were impaired in 65%, 85% and 30% of the patients, respectively. The basal and peak hormone levels were similar between the patients with active RA and the patients in remission. These findings indicate that there is an impairment in HPA and GH axis in patients with active and remitted RA. The site of this impairment is probably hypothalamus and/or pituitary gland. PMID- 10092165 TI - Muscle relaxation training and quality of life in rheumatoid arthritis. A randomized controlled clinical trial. AB - The purpose of the study was to investigate the effects of supervised muscle relaxation training in individuals with rheumatoid arthritis (RA). Sixty-eight participants were allocated at random either to a muscle relaxation training group or to a control group. Every participant was evaluated for health-related quality of life, muscle function, pain, and disease activity. The training group exercised 30 minutes, twice a week for 10 weeks, while no intervention was made in the control group. The results indicated improvements in the training group regarding self-care according to the Arthritis Impact Measurement Scales 2, and in recreation and pastimes according to the Sickness Impact Profile-RA (p < 0.05) directly after the intervention. Mobility and arm function (p < 0.01) according to the Arthritis Impact Measurement Scales 2, and muscle function of the lower limbs (p < 0.05) were improved after six months. No improvements remained after twelve months. It thus seems that 10 weeks' relaxation training might have some short-term influence in individuals with RA. PMID- 10092166 TI - Successful pregnancy and delivery in a case of systemic lupus erythematosus treated with immunoadsorption therapy and cyclosporin A. AB - A 32-year-old woman diagnosed as systemic lupus erythematosus (SLE) became pregnant. During pregnancy she was treated with a daily dosage of prednisolone 15 mg. However, because the exanthema became worse, she was hospitalized on January 14, 1997 in order to receive immunoadsorption therapy. Before delivery we implemented the immunoadsorption therapy twice and cyclosporin A (CsA) was administered simultaneously. She gave birth in her 37th week. The baby weighed 2260 g at the time of delivery and had no deformities. The mother also had no side effects. The success of pregnancy and childbirth in our case, without any side effects, shows the possibility that the combination of CsA and immunoadsorption therapy may be considered safe to control a pregnancy complicated by SLE. PMID- 10092167 TI - Dermatomyositis associated with rapidly progressive fatal interstitial pneumonitis and pneumomediastinum. AB - We describe two cases of dermatomyositis (DM), which subsequently developed into rapidly progressive fatal interstitial pneumonitis and pneumomediastinum during steroid therapy. Both cases showed the classical cutaneous manifestations of DM, but the muscular symptoms were absent or mild. Both rapidly progressive interstitial pneumonitis and pneumomediastinum can occur in DM showing less inflammatory changes in the muscles. Patients with this form should be treated with extreme caution. PMID- 10092168 TI - An overlap syndrome with features of atypical Cogan syndrome and Wegener's granulomatosis. AB - A 48 year old women developed serous otitis, scleritis, myalgia, vertigo, polyneuropathy, crescentic glomerulonephritis, general cerebral dysrythmia, hilar adenopathy, and retroorbital granulomatous inflammation. Pulmonary manifestations were absent and antibodies against neutrophilic cytoplasmic antigens (ANCA) could not be detected. The clinical picture was classified as an overlap syndrome with features of both atypical Cogan syndrome and Wegener's granulomatosis. The patient responded to treatment with high dose corticosteroids and pulse cyclophosphamide. PMID- 10092169 TI - Complexity and expression of the glutamine synthetase multigene family in the amphidiploid crop Brassica napus. AB - In the amphidiploid genome of oilseed rape (Brassica napus) the diploid ancestral genomes of B. campestris and B. oleracea have been merged. As a result of this crossing event, all gene loci, gene families, or multigene families of the A and C genome types encoding a certain protein are now combined in one plant genome. In the case of the multigene family for glutamine synthetase, the key enzyme of nitrogen assimilation, six different cDNA sequences were isolated from leaf and root specific libraries. One sequence pair (BnGSL1/BnGSL2) was characterized by the presence of amino-terminal transit peptides, a typical feature of all nuclear encoded chloroplast proteins. Two other cDNA pairs (BnGSR1-1/BnGSR1-2 and BnGSR2 1/BnGSR2-2) with very high homology between each other were found in a root specific cDNA library and represent protein subunits for cytosolic glutamine synthetase isoforms. Comparative PCR amplifications of genomic DNA isolated from B. napus, B. campestris and B. oleracea followed by sequence-specific restriction analyses of the PCR products permitted the assignment of the cDNA sequences to either the A genome type (BnGSL1/BnGSR1-1/BnGSR2-1) or the C genome type (BnGSL2/BnGSR1-2/BnGSR2-2). Consequently, the ancestral GS genes of B. campestris and B. oleracea are expressed simultaneously in oilseed rape. This result was also confirmed by RFLP (restriction fragment length polymorphism) analysis of RT PCR products. In addition, the different GS genes showed tissue specific expression patterns which are correlated with the state of development of the plant material. Especially for the GS genes encoding the cytosolic GS isoform BnGSR2, a marked increase of expression could be observed after the onset of leaf senescence. PMID- 10092170 TI - High-efficiency Agrobacterium-mediated transformation of Norway spruce (Picea abies) and loblolly pine (Pinus taeda). AB - Agrobacterium-mediated gene transfer is the method of choice for many plant biotechnology laboratories; however, large-scale use of this organism in conifer transformation has been limited by difficult propagation of explant material, selection efficiencies and low transformation frequency. We have analyzed co cultivation conditions and different disarmed strains of Agrobacterium to improve transformation. Additional copies of virulence genes were added to three common disarmed strains. These extra virulence genes included either a constitutively active virG or extra copies of virG and virB, both from pTiBo542. In experiments with Norway spruce, we increased transformation efficiencies 1000-fold from initial experiments where little or no transient expression was detected. Over 100 transformed lines expressing the marker gene beta-glucuronidase (GUS) were generated from rapidly dividing embryogenic suspension-cultured cells co cultivated with Agrobacterium. GUS activity was used to monitor transient expression and to further test lines selected on kanamycin-containing medium. In loblolly pine, transient expression increased 10-fold utilizing modified Agrobacterium strains. Agrobacterium-mediated gene transfer is a useful technique for large-scale generation of transgenic Norway spruce and may prove useful for other conifer species. PMID- 10092171 TI - IFG, a gypsy-like retrotransposon in Pinus (Pinaceae), has an extensive history in pines. AB - A 1 kb EcoRI restriction fragment cloned from a band visible in an agarose gel of Pinus lambertiana (sugar pine) genomic DNA is present in both subgenera of Pinus with at least 10(4) copies/genome. A full-length copy of this repeated element recovered from a P. radiata (Monterey pine) genomic DNA library was found to possess all of the sequence features associated with gypsy-like retrotransposons. This report describes the biology and history of the IFG (Institute of Forest Genetics) family of retrotransposons. The characterized IFG7 is 5937 bp long. Immediately interior to its 5' and 3' long terminal repeats are sequences consistent with primer binding sites for reverse transcription of the RNA genome. Presumptive gene products associated with retrotransposition appear to be coded in a single reading frame and are in the same order as the gypsy-like retrotransposons and retroviruses. The 1.0 kb EcoRI fragment of IFG elements codes for the 3' half of IFG's reverse transcriptase and the entire RNase H domain. Southern blot analysis suggests IFG was present in Pinaceae before its division into its modern genera. Sequence analysis of IFG 1.0 kb RI fragments and southern analysis also suggest that IFG continued to evolve in Pinus with restriction fragment length polymorphism (RFLP) subfamilies appearing early in the history of each subgenus often correlating with subdivisions of Pinus. Features shared with other plant retrotransposons are also discussed. PMID- 10092172 TI - Identification of genes specifically expressed in cauliflower reproductive meristems. Molecular characterization of BoREM1. AB - Using the meristems of the cauliflower curd as a source of tissue and a series of subtractive hybridizations and amplification reactions, we have constructed a cDNA library highly enriched in cDNAs expressed in reproductive meristems. The analysis of a sample of 250 clones from this library identified 22 cDNA clones corresponding to genes specifically expressed in these cauliflower meristems. Apart from two clones that corresponded to APETALA1, and two other ones showing similarity to different aminoacyl-tRNA synthetases, the remaining clones showed no similarity to any sequence in the databases and may correspond to novel genes. One of these clones, BoREM1, was further characterized and found to correspond to a gene encoding a protein with features of regulatory proteins that follows a expression pattern very similar to the LEAFY transcripts. PMID- 10092173 TI - Down-regulation of cinnamyl alcohol dehydrogenase in transgenic alfalfa (Medicago sativa L.) and the effect on lignin composition and digestibility. AB - To improve the digestibility of the forage crop alfalfa (Medicago sativa L.), cinnamyl alcohol dehydrogenase (CAD), which catalyses the last step in the biosynthesis of the lignin monomers, was down-regulated by using an antisense approach. A subset of six transgenic lines with reduced CAD activity and control lines were analysed when grown in the greenhouse and in the field. The down regulation of the CAD enzyme was associated with a red coloration of the stem. The lignin quantity remained unchanged, but the lignin composition, as determined by thioacidolysis, was altered. The highest reduction of CAD activity was associated with a lower syringyl/guaiacyl (S/G) ratio and a lower S+G yield, mainly because of a decreased amount of S units. An increase in in situ disappearance of dry matter and of cell wall residue was detected in one of the transgenic lines grown in the greenhouse, and for two of the lines grown in the field the rate of disappearance of dry matter slightly improved. Furthermore, these two lines had a higher solubility in alkali as shown by the lower yield of saponified residue. This study opens perspectives for improving forage crop digestibility by the modulation of enzymes involved in lignin biosynthesis. PMID- 10092174 TI - Identification of cytosolic Mg2+-dependent soluble inorganic pyrophosphatases in potato and phylogenetic analysis. AB - Using polyclonal antibodies raised against a previously cloned potato Mg2+ dependent soluble inorganic pyrophosphatase (ppa1 gene) [8], a second gene, called ppa2, could be isolated. A single locus homologous to ppa2 was mapped on potato chromosomes, unlinked to the two loci identified for ppa1. From a phylogenetic and structural point of view, the PPA1 and PPA2 polypeptides are more closely related to prokaryotic than to eukaryotic Mg2+-dependent soluble inorganic pyrophosphatases (soluble PPases). Subcellular localization by immunogold electron microscopy, using sections from leaf parenchyma cells, showed that PPA and PPA2 are localized to the cytosol. Based on these observations, the likely phylogenetic origin and the physiological significance of the cytosolic soluble pyrophosphatases are discussed. PMID- 10092175 TI - cDNA and genomic cloning of sugar beet V-type H+-ATPase subunit A and c isoforms: evidence for coordinate expression during plant development and coordinate induction in response to high salinity. AB - The plant V-type H+-ATPase (V-ATPase) does not only serve basic housekeeping functions but is also involved in stress-induced NaCl sequestration during salinity stress. To address the question whether the same isoforms conferring housekeeping functions are equally involved in the response to high salinity, we have isolated cDNA clones for subunits A and c, as representing the peripheral V1 complex and the membrane-integral V0 complex, respectively, from the halotolerant sugar beet (Beta vulgaris L., diploid variety). RNA blot analysis with gene specific probes revealed a coordinate expression of the cloned subunit A and c isoforms during plant development and in response to high salinity. Also, in rapidly dividing suspension-cultured cells with 10-fold increased transcript amounts as compared to young leaf tissue, the ratio of transcripts for both genes was similar to the ratio found for transcripts in leaves of different age. We have then isolated partial genomic clones (BVA/70 for Beta V-ATPase 70 kDa subunit; BVA/16-1 for Beta V-ATPase 16 kDa subunit), including the promoter regions. Transcription start mapping revealed long 5'-UTR leader sequences (230 and 172 bases, respectively) for both genes. Both promoters contain putative G box motifs in similar distance to the TATA boxes. For a quantitative comparison of relative promoter strength, the BVA/70 and BVA/16-1 promoters linked to the luciferase reporter gene (LUC) were delivered to sugar beet suspension-cultured cells by particle bombardment. The BVA/16-1 promoter showed a 1.7-fold higher activity as compared with the BVA/70 promoter. Salt treatment induced an increase of BVA/70 (+70%) and BVA/16-1 (+57%) promoter activities, concomitant with increased transcript amounts. The following sequences have been deposited at the EMBL database X98767: Beta vulgaris V-ATPase subunit A, cDNA clone; X98851, B. vulgaris V-ATPase subunit c isoform 1, cDNA clone; Y11038, B. vulgaris V-ATPase subunit A, partial genomic clone; Y11037, B. vulgaris V-ATPase subunit c isoform 1, partial genomic clone. PMID- 10092176 TI - Expression of tobacco class II catalase gene activates the endogenous homologous gene and is associated with disease resistance in transgenic potato plants. AB - We have previously shown that healthy potato plants respond poorly to salicylic acid (SA) for activating disease resistance against the late blight fungal pathogen Phytophthora infestans. However, SA is essential for the establishment of potato systemic acquired resistance (SAR) against P. infestans after treatment with the fungal elicitor arachidonic acid (AA). To understand the molecular mechanisms through which AA induces SA-dependent SAR in potato, we have recently studied the expression of potato class II catalase (Cat2St) in comparison with its tobacco homologue, Cat2Nt, which has previously been shown to bind SA. In the present study, we show that tobacco Cat2Nt is expressed at high levels and accounts for almost half of total SA-binding activity detected in tobacco leaves. In contrast, potato Cat2St is not expressed in healthy leaves, which is associated with the low SA responsiveness of potato plants for activation of disease resistance mechanisms. Upon treatment with AA, expression of potato Cat2St is induced not only in AA-treated leaves, but also in the upper untreated parts of the plants, concomitant with the establishment of SA-dependent SAR to P. infestans. Moreover, expression of the tobacco Cat2Nt gene in transgenic potato plants leads to constitutive expression of the endogenous potato Cat2St gene and is associated with enhanced resistance to P. infestans. These results collectively indicate that plant SA-binding class II catalases may play an important role in the development of disease resistance, possibly by serving as biological targets of SA. PMID- 10092177 TI - Apoptosis in developing anthers and the role of ABA in this process during androgenesis in Hordeum vulgare L. AB - Intra-nucleosomal cleavage of DNA into fragments of about 200 bp was demonstrated to occur in developing anthers, in which microspores had developed into the mid late to late uni-nucleate stage in situ, i.e. at the verge of mitosis. The same was observed, but to a much larger extent, if these anthers were pre-treated by a hyper-osmotic shock. Pretreatment of anthers before the actual culture of microspores was required for optimal androgenesis of microspores. The use of the TUNEL reaction, which specifically labels 3' ends of DNA breaks, after intra nucleosomal cleavage of DNA, revealed that DNA fragmentation mainly occurred in the loculus wall cells, tapetum cells and filament cells. TUNEL staining was absent or infrequently observed in the microspores of developing anthers in situ. Electron microscopy studies showed condensed chromatin in nuclei of loculus wall cells in the developing anthers. These observations at the chromatin and DNA level are known characteristics of programmed cell death, also known as apoptosis. Features of apoptosis were infrequently found in microspores from freshly isolated mature anthers. However, most tapetum cells had disappeared in these anthers and the remaining cell structures showed loss of cellular content. The viability of microspores in pre-treated anthers was comparable to those in freshly isolated anthers and almost four times higher than in anthers from control experiments. This observation was correlated with three to four times less microspores showing TUNEL staining and a two times higher level of ABA in the anther plus medium samples than in controls. Addition of ABA to the controls enhanced the viability and lowered the occurrence of apoptosis linked characteristics in the microspores. These data suggest that pre-treatment is effective in stimulating androgenesis because it leads to an increase in ABA levels which protects microspores from dying by apoptosis. PMID- 10092178 TI - Structure of two maize phytase genes and their spatio-temporal expression during seedling development. AB - Up to 80% of Zea mays L. grain phosphorus is stored in the form of phytin in the embryo. Our objective is to determine the control of phytin mobilization during germination and seedling growth. A maize phytase cDNA, phy S11, has been previously characterized (Maugenest et al., Biochem J 322: 511-517, 1997). In the present work, phy S11 was used to screen a maize genomic library and two distinct genes, PHYT I and PHYT II, were isolated and sequenced. The transcribed sequences of these two genes presented a strong homology whereas the untranscribed upstream and downstream sequences appeared very different. Northern blot analysis and in situ hybridization showed a high accumulation of phytase mRNA at the early steps of germination in the coleorhiza, radicle cortex and coleoptile parenchyma. Phytase expression was also detected at a lower extent in the scutellum. In adult plants, northern blot analyses revealed low but significant levels of phytase mRNA in the roots. In situ hybridizations on root cross-sections localized phytase mRNA in rhizodermis, endodermis and pericycle layers. Immunolocalization analysis showed phytase accumulation at the same sites as its mRNA. A RT-PCR approach was used in an attempt to discriminate between the transcripts from each gene in the different situations. These experiments indicate that both genes are expressed during germination, whereas only PHYT I is expressed in adult roots. This suggests that signals responsible for phytase gene expression in roots are different from those responsible for gene expression during germination. PMID- 10092179 TI - Characterization and functional analysis of Arabidopsis TFIIA reveal that the evolutionarily unconserved region of the large subunit has a transcription activation domain. AB - TFIIA has initially been identified as a component of transcription initiation complex of RNA polymerase II. Its role in transcription has been controversial. In this paper, we report the characterization and functional analysis of both the Arabidopsis TFIIA large and small subunits. Sequence analysis revealed that Arabidopsis TFIIA is structurally more related to animal than to yeast counterparts. Arabidopsis has at least two genes for the large subunit and one for the small subunit. Both types of genes are constitutively transcribed in various plant organs. The proteins encoded by the cDNA interact each other in yeast 2-hybrid system. Only the N-terminal part of the large subunit is necessary for the interaction with the small subunit. Recombinant Arabidopsis TFIIA polypeptides bind to TBP-DNA complex in gel shift assays. The large subunit of TFIIA can stimulate transcription in yeast and in plant cells when fused to a DNA binding domain binding to cis sequences upstream of a minimal promoter. This trans-activating activity is localized to a 35 amino acid segment within the evolutionarily unconserved central region. PMID- 10092180 TI - Coordinate modulation of maize sulfate permease and ATP sulfurylase mRNAs in response to variations in sulfur nutritional status: stereospecific down regulation by L-cysteine. AB - To gain insight into the regulatory mechanisms and the signals responsible for the adaptation of higher plants to conditions of varying sulfate availability, we have isolated from a sulfate-deprived root library maize cDNAs encoding sulfate permease (ZmST1) and ATP sulfurylase (ZmAS1), the two earliest components of the sulfur assimilation pathway. The levels of ZmST1 and ZmAS1 transcripts concomitantly increased in both roots and shoots of seedlings grown under sulfate deprived conditions, and rapidly decreased when the external sulfate supply was restored. This coordinate response, which was not observed under conditions of limiting nitrate or phosphate, correlated with the depletion of glutathione, rather than sulfate stores. However, drastically reducing glutathione levels through treatment with buthionine sulfoximine, a specific inhibitor of gamma glutamyl cysteine synthetase, did not provide an adequate stimulus for the up regulation of either sulfate permease or ATP sulfurylase messengers. Indeed, L cysteine, but not D-cysteine, effectively down-regulated both transcripts when supplied to sulfur-deficient seedlings under conditions of blocked glutathione synthesis. Altogether, these data provide evidence for the coordinate regulation of sulfur assimilation mRNAs in higher plants and for the glutathione-independent involvement of cysteine as a stereospecific pretranslational modulator of the expression of sulfur status-responsive genes. PMID- 10092181 TI - Regulation by biotic and abiotic stress of a wheat germin gene encoding oxalate oxidase, a H2O2-producing enzyme. AB - Germins and germin-like proteins (GLPs) constitute a ubiquitous family of plant proteins that seem to be involved in many developmental and stress-related processes. Wheat germin has been extensively studied at the biochemical level: it is found in the apoplast and the cytoplasm of germinating embryo cells and it has oxalate oxidase activity (EC 1.2.3.4). Germin synthesis can also be induced in adult wheat leaves by auxins and by a fungal pathogen but it remains to be determined whether the same gene is involved in developmental, hormonal and stress response. In this work, we have studied the expression of one of the wheat germin genes, named gf-2.8, in wheat as well as in transgenic tobacco plants transformed with either this intact gene or constructs with GUS driven by its promoter. This has allowed us to demonstrate that expression of this single gene is both developmentally and pathogen-regulated. In addition, we show that expression of the wheat gf-2.8 germin gene is also stimulated by some abiotic stresses, especially the heavy metal ions Cd2+, Cu2+ and Co2+. Several chemicals involved in stress signal transduction pathways were also tested: only polyamines were shown to stimulate expression of this gene. Because regulation of the wheat gf-2.8 germin gene is complex and because its product results in developmental and stress-related release of hydrogen peroxide in the apoplast, it is likely that it plays an important role in several aspects of plant growth and defence mechanisms. PMID- 10092182 TI - A strong constitutive positive element is essential for the ammonium-regulated expression of a soybean gene encoding cytosolic glutamine synthetase. AB - In order to identify important promoter elements controlling the ammonium regulated expression of the soybean gene GS15 encoding cytosolic glutamine synthetase, a series of 5' promoter deletions were fused to the GUS reporter gene. To allow the detection of positive and negative regulatory elements, a series of 3' deletions were fused to a -90 CaMV 35S promoter fragment placed upstream of the GUS gene. Both types of construct were introduced into Lotus corniculatus plants and soybean roots via Agrobacterium rhizogenes-mediated transformation. Both spectrophotometric enzymatic analysis and histochemical localization of GUS activity in roots, root nodules and shoots of transgenic plants revealed that a strong constitutive positive element (SCPE) of 400 bp, located in the promoter distal region is indispensable for the ammonium-regulated expression of GS15. Interestingly, this SCPE was able to direct constitutive expression in both a legume and non-legume background to a level similar to that driven by the CaMV 35S full-length promoter. In addition, results showed that separate proximal elements, located in the first 727 bp relative to the transcription start site, are essential for root- and root nodule-specific expression. This proximal region contains an AAAGAT and two TATTTAT consensus sequences characteristic of nodulin or nodule-enhanced gene promoters. A putative silencer region containing the same TATTTAT consensus sequence was identified between the SCPE and the organ-specific elements. The presence of positive, negative and organ-specific elements together with the three TATTTAT consensus sequences within the promoter strongly suggest that these multiple promoter fragments act in a cooperative manner, depending on the spatial conformation of the DNA for trans-acting factor accessibility. PMID- 10092183 TI - A novel flower-specific Arabidopsis gene related to both pathogen-induced and developmentally regulated plant beta-1,3-glucanase genes. AB - Beta-1,3-glucanases are usually associated with plant defense responses, although some are also developmentally or hormonally regulated. We characterized two Arabidopsis genes linked in a tandem array, BG4 and BG5, encoding putative novel isoforms of beta-1,3-glucanase. The deduced polypeptides, BG4 and BG5, were highly similar to each other (89% amino acid identity) but only moderately related (32 to 41% amino acid identity) to the different categories of previously characterized beta-1,3-glucanases, suggesting that BG4 and BG5 may represent a novel class of beta-1,3-glucanases in plants. Neither of the genes was responsive to pathogen or SA induction in contrast to the previously identified Arabidopsis beta-1,3-glucanases, nor could we detect any developmental or hormonally induced expression in the vegetative parts of the plants. Both RNA blot and in situ hybridization data demonstrated that the BG4 gene was specifically expressed in the style and septum of the ovary, suggesting that the corresponding protein is involved in the reproductive process of the plant. PMID- 10092184 TI - Differential expression of genes encoding the light-dependent and light independent enzymes for protochlorophyllide reduction during development in loblolly pine. AB - The expression patterns of the two distinct subfamilies of genes (designated porA and porB) encoding the light-dependent NADPH:protochlorophyllide oxidoreductases (PORs) in loblolly pine (Pinus taeda L.) were examined. Transcripts arising from both gene subfamilies were shown to be present at high levels in the cotyledons of dark-grown pine seedlings and to a lesser extent in their stems. Exposure of dark-grown seedlings to light resulted in increased levels of both porA and porB transcripts, as well as increased levels of mRNAs encoding other photosynthesis related gene products, suggesting that they are under a common mode of regulation. Relative levels of the porA and porB transcripts were similar in seedling cotyledons and primary needles of two-month-old pine trees, whereas only porB transcripts were present at a significant level in mature secondary needles of two-year-old trees. Immunoblot analysis showed that the 37 kDa PORA protein was most abundant in dark-grown tissues, decreased dramatically upon exposure to light, but could still be detected at low levels in light-grown seedlings. In comparison, levels of the 38 kDa PORB protein were not significantly changed upon transfer of dark-grown tissues to light. While both PORA and PORB were detected in cotyledons and primary needles, only PORB could be detected in mature needles. Transcripts derived from the three plastid genes, chlL, chlN, and chlB, encoding subunits of the light-independent protochlorophyllide reductase were detected in the cotyledons and stems of dark-grown seedlings, and in mature needles. The highest levels of chlL, chlN, and chlB transcripts were detected within the top one-third of the stem and decreased gradually towards the stem/root transition zone. Correspondingly, the highest levels of light-independent chlorophyll formation took place near the top of the hypocotyl. A similar pattern of expression was observed for other photosynthesis-related gene products, including porA and porB. Our results suggest that many aspects of the light-dependent, tissue-specific and developmental regulation of POR expression first described in angiosperms were already established in the less evolutionarily advanced gymnosperms. However, unlike angiosperms, light is not the dominant regulatory factor controlling porA expression in these species. PMID- 10092186 TI - Male gametic cell-specific expression of H2A and H3 histone genes. AB - Formation of the generative cell in flowering plants initiates the male spermatogenesis pathway which eventually culminates in the process of double fertilization. Little is known about the molecular mechanisms operative in the generative cell. Here, we report the isolation and characterization of cDNA clones encoding generative cell-specific histones, gcH2A and gcH3. In situ hybridization analysis revealed that both genes are activated after formation of the generative cell and accumulation of transcripts increases progressively during generative cell maturation. These results suggest that gcH2A and gcH3 mRNAs are products of transcriptional activation of the generative cell nucleus and thus provide the first evidence for male germ line cell-specific gene expression in flowering plants. PMID- 10092185 TI - Higher plant tyrosine-specific protein phosphatases (PTPs) contain novel amino terminal domains: expression during embryogenesis. AB - Sequences encoding proteins with homology to protein tyrosine phosphatases have been identified in Arabidopsis, soybean and pea. Each contains a predicted catalytic domain containing sequence motifs characteristic of tyrosine-specific protein phosphatases (PTPs) which play an important role in signal transduction in other eukaryotes and are distinct from dual-specificity, cdc25 or low molecular-weight protein tyrosine phosphatases. Their identity as PTPs was confirmed by characterising the soybean PTP expressed as a recombinant His-tagged fusion protein. The enzyme had phosphatase activity towards p nitrophenolphosphate (pNPP) and phosphotyrosine, but did not hydrolyse phosphoserine or phosphothreonine at a measureable rate. Phosphotyrosine containing peptides also served as substrates, with Km values in the micromolar range. Activity was abolished by inhibitors specific for tyrosine phosphatases (vanadate, dephostatin) but was unaffected by inhibitors of serine/threonine protein phosphatases (fluoride, cantharidin, metal-chelating agents). Gel filtration chromatography showed that the recombinant enzyme was a monomer. The Arabidopsis PTP sequence was isolated both as a genomic clone and as a partial EST, whereas the pea and soybean sequences were isolated as cDNAs. Southern analysis suggested a single gene in Arabidopsis and a small gene family in pea and soybean. In pea, PTP transcripts were present in embryos, and decreased in level with development; transcripts were also detectable in other tissues. The plant PTPs all contain a similar N-terminal domain which shows no similarity to any known protein sequence. This domain may be involved in PTP functions unique to plants. PMID- 10092187 TI - Seed-specific expression patterns and regulation by ABI3 of an unusual late embryogenesis-abundant gene in sunflower. AB - We cloned the genomic sequences that correspond to a previously described group 1 late embryogenesis-abundant (Lea) cDNA from sunflower: Ha ds10. The Ha ds10 G1 gene had structural and gene-expression features that depart from those of other group 1 Lea genes. An intron was present at a conserved position but showed a much larger size (1024 bp). Transcription from the Ha ds10 G1 promoter was strictly seed-specific and it originated from at least two close initiation sites. The mRNAs accumulated from stages of embryogenesis that preceded seed desiccation. Ha ds10 G1 mRNA accumulation was moderately induced, by exogenous abscisic acid treatments, in immature seeds but not induced in seedlings. We observed unprecedented changes in Lea mRNA localization associated with seed desiccation: the homogeneous tissue distribution of Ha ds10 G1 mRNAs, which was characteristic of immature embryos, evolved later in embryogenesis to an asymmetric distribution within the cotyledons, with preferential mRNA accumulation in the cells of the palisade parenchyma and provascular bundles. We also showed that, in sunflower embryos, the Ha ds10 G1 promoter could be transiently activated by the Arabidopsis ABI3 transcription factor. We discuss the significance of these results regarding hypotheses of regulation and function of plant genes from the same family. PMID- 10092188 TI - Isolation and characterization of mRNAs differentially expressed during ripening of wild strawberry (Fragaria vesca L.) fruits. AB - Wild strawberry (Fragaria vesca L.) is an attractive model system for studying ripening in non-climacteric fruit, because of its small diploid genome, its short reproductive cycle, and its capacity for transformation. We have isolated eight ripening-induced cDNAs from this species after differential screening of a cDNA library. The predicted polypeptides of seven of the clones exhibit similarity to database protein sequences, including acyl carrier protein, caffeoyl-CoA 3-O methyltransferase, sesquiterpene cyclase, major latex protein, cystathionine gamma-synthase, dehydrin and an auxin-induced gene. A ninth cDNA clone that was constitutively expressed is predicted to encode a metallothionein-like protein. None of these proteins appear to be directly related to events generally associated with ripening such as cell wall metabolism or the accumulation of sugars and pigments, rather, their putative functions are indicative of the wide range of processes upregulated during fruit ripening. PMID- 10092189 TI - Beauveriolides, specific inhibitors of lipid droplet formation in mouse macrophages, produced by Beauveria sp. FO-6979. AB - Beauveria sp. FO-6979, a soil isolate, was found to produce inhibitors of lipid droplet formation in mouse peritoneal macrophages. A new compound beauveriolide III was isolated along with a known compound beauveriolide I from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography, silica gel column chromatography and preparative HPLC. Beauveriolides I and III caused a reduction in the number and size of cytosolic lipid droplets in macrophages at 10 microM without any cytotoxic effect on macrophages. PMID- 10092190 TI - Structure elucidation of fungal beauveriolide III, a novel inhibitor of lipid droplet formation in mouse macrophages. AB - The structure of fungal beauveriolide III, an inhibitor of lipid droplet formation in mouse macrophages, was elucidated to be cyclo-[(3S,4S)-3-hydroxy-4 methyloctanoyl-L-phenylalanyl-L-alanyl- D-allo-isoleucyl] by spectral analyses and chemical degradation. PMID- 10092191 TI - Brasilicardin A, a new terpenoid antibiotic from pathogenic Nocardia brasiliensis: fermentation, isolation and biological activity. AB - A novel tricyclic diterpenoid antibiotic, brasilicardin A, was isolated from the culture broth of Nocardia brasiliensis IFM 0406. The antibiotic exhibited immunosuppressive activity in a mouse mixed lymphocyte reaction (MLR) assay system and its IC50 value was 0.057 microg/ml. Although the inhibitory activity of cyclosporin A (CyA) against IL-2 production was confirmed in the MLR assay system, brasilicardin A did not have the activity. The results of in vitro toxicity testing of brasilicardin A against various human cell lines were compared with those of CyA. PMID- 10092192 TI - IC202A, a new siderophore with immunosuppressive activity produced by Streptoalloteichus sp. 1454-19. I. Taxonomy, fermentation, isolation and biological activity. AB - IC202A, a new immunosuppressive compound, was isolated from the culture filtrate of Streptoalloteichus sp. 1454-19. It showed a suppressive effect on mixed lymphocyte culture reaction with an IC50 value of 3.6 microg/ml and mitogen induced lymphocyte blastogenesis in vitro. PMID- 10092193 TI - IC202A, a new siderophore with immunosuppressive activity produced by Streptoalloteichus sp. 1454-19. II. Physico-chemical properties and structure elucidation. AB - IC202A (1) was isolated from the culture filtrate of Streptoalloteichus sp. 1454 19. The structure of 1 was determined by spectral analysis including a variety of two-dimentional NMR and FAB-MS experiments. IC202A is a ferrioxamine-related compound containing a butylidene N-oxide function. PMID- 10092194 TI - Zelkovamycin, a new cyclic peptide antibiotic from Streptomyces sp. K96-0670. I. Production, isolation and biological properties. AB - A new antibiotic termed zelkovamycin was isolated from the fermentation broth of Streptomyces sp. K96-0670 by solvent extraction, ODS column chromatography and preparative HPLC. Zelkovamycin showed antibacterial activity against Xanthomonas oryzae, Acholeplasma laidlawii, Pyricularia oryzae and Staphylococcus aureus. PMID- 10092195 TI - Zelkovamycin, a new cyclic peptide antibiotic from Streptomyces sp. K96-0670. II. Structure elucidation. AB - The structure of antibiotic zelkovamycin was elucidated as a cyclic peptide comprising glycyl, 2-aminobutanoyl, 2-amino-2-butenoyl, N-methyl glycyl, alanyl, 1,3-thiazoyl, 7-methoxytryptophanyl and 2-methyldehydrothreonyl residues. The sequence of the amino acids was established by spectroscopic studies including 1H 1H COSY, 13C-1H COSY, 13C-1H HMQC, 13C-1H HMBC, 15N-1H HMQC and 15N-1H HMBC NMR experiments. PMID- 10092196 TI - Growth and production kinetics of a teicoplanin producing strain of Actinoplanes teichomyceticus. AB - The growth and production kinetics of a teicoplanin producing strain of Actinoplanes teichomyceticus (ATCC 31121) was investigated during batch cultivations on defined media. The growth was characterised by two exponential growth phases (EGPs), with a higher specific growth rate in the first than in the second phase. Also the specific rate of formation of teicoplanin was significantly lower in the second phase than in the first phase. This two-phased growth pattern was suggested to be caused by inhibition of growth by teicoplanin accumulated. Furthermore high concentrations of ammonia or phosphate reduced both the specific growth rate in the first EGP and the total production of teicoplanin. PMID- 10092197 TI - Immunosuppressant deoxyspergualin-induced inhibition of cell proliferation is accompanied with an enhanced reduction of tetrazolium salt. AB - Deoxyspergualin (DSG) has both antitumor and immunosuppressive activities. We explored the mechanism of DSG activities using an aqueous soluble analogue, methyldeoxyspergualin (MeDSG) for in vitro culture studies. It is known that DSG has inhibitory effects on cell proliferation, and we also observed that MeDSG inhibited [3H]-thymidine incorporation by rapidly dividing murine T cell hybridomas. However, when tetrazolium (MTT) colorimetric assay was adopted to evaluate its inhibitory effects on cell proliferation, MeDSG induced an enhanced MTT reduction. When we examined whether these results were applicable to the actively dividing cells of other origins than T cells, similar effects were seen with Raji cells, J774.1 cells and NIH3T3 cells. N-30, another analogue which was capable of suppressing anti-SRBC antibody production in vivo, also induced inhibition of cell growth and an enhanced MTT reduction. In contrast, the analogue which failed to prevent the antibody production, neither enhanced MTT reduction nor inhibited cell proliferation. Our results demonstrated that the ability to generate MTT formazan in dividing cells is a common property among, DSG analogue with the immunosuppressive and antiproliferative activities. PMID- 10092198 TI - Studies on time-kill kinetics of different classes of antibiotics against veterinary pathogenic bacteria including Pasteurella, Actinobacillus and Escherichia coli. AB - A systematic analysis of the bacteriostatic/bactericidal effect of several antibiotics used in veterinary medicine was carried out by time-kill kinetic analysis using P. haemolytica, P. multocida, A. pleuropneumoniae, and E. coli. The antibiotics tested were enrofloxacin, danofloxacin, erythromycin, tilmicosin, penicillin G, ceftiofur and tetracycline. Unexpectedly, the antibiotics well characterized as bacteriostatic agents against human pathogens such as tetracycline and macrolides, showed bactericidal activity against P. haemolytica and A. pleuropneumoniae. In contrast, tetracycline and erythromycin were bacteriostatic and tilmicosin was bactericidal against P. multocida. In addition, P. multocida was killed by fluoroquinolones at a slower rate than the other bacteria. Spectrum analysis revealed that ceftiofur and tilmicosin were good substrates of the universal efflux pump, AcrA/B, but penicillin and tetracycline were not. The fluoroquinolones were modest substrates for AcrA/B. PMID- 10092199 TI - Isolation and structure of a new antibiotic viridomycin F produced by Streptomyces sp. K96-0188. PMID- 10092200 TI - Inhibitory effect of antimicrobial agents on alginate production in Pseudomonas aeruginosa. PMID- 10092201 TI - New derivatives of tylosin. IV. Dihydro and tetrahydro desmycosin oximes. PMID- 10092202 TI - Effects of erythromycin and its derivatives on interleukin-8 release by human bronchial epithelial cell line BEAS-2B cells. PMID- 10092203 TI - CDK9 (PITALRE): a multifunctional cdc2-related kinase. AB - CDK9 is a cdc2-related kinase protein. Previously named PITALRE, this protein is a serine-threonine kinase involved in many physiological processes. Unlike most of the cdc2-like kinases, its activity is not cell cycle-regulated. CDK9 acts preferentially in processes different from cell-cycle regulation, such as differentiation. Its cyclin partners, cyclins of T family, recently have been isolated. CDK9 immunoprecipitates with several unidentified polypeptides that may regulate its kinase activity. CDK9 has been shown to associate with the HIV-Tat protein, suggesting a possible involvement in AIDS. CDK9 recently was shown to be responsible for the kinase activity associated with the TAK complex and with the P-TEFb complex, suggesting activity also in the transcription process. PMID- 10092204 TI - Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists. AB - Neuropeptides, including mammalian bombesin-like peptides, act as potent cellular growth factors and have been implicated in a variety of normal and abnormal processes, including development, inflammation, and malignant transformation. These signaling peptides exert their characteristic effects on cellular processes by binding to specific G protein-coupled receptors (GPCR) on the surface of their target cells. Typically, the binding of a neuropeptide to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades is an important early response to neuropeptides. An emerging theme in signal transduction is that these agonists also induce rapid and coordinate tyrosine phosphorylation of cellular proteins including the nonreceptor tyrosine kinase p125fak and the adaptor proteins p130cas and paxillin. This tyrosine phosphorylation pathway depends on the integrity of the actin cytoskeleton and requires functional Rho. The purpose of this article is to review recent advances in unraveling the pathways that play a role in transducing mitogenic and migratory responses induced by G protein-coupled neuropeptide receptor agonists. PMID- 10092205 TI - Integration of the central death pathway in cellular decision-making. PMID- 10092206 TI - Molecular genetics of the germinal center reaction. PMID- 10092207 TI - Physiological signals and oncogenesis mediated through Crk family adapter proteins. AB - The viral Crk oncogene (v-Crk) is known to induce sarcomas in chicken and its cellular homologs c-Crk I, c-Crk II, and Crk-like (CRKL) have been implicated in many signal transduction events. These include cell differentiation, cell migration, and the induced nonresponsiveness of T-cells to stimulation of the T cell receptor (TCR), a state known as anergy. CRKL is also the most prominent substrate of the Bcr-Abl oncoprotein which causes human chronic myelogenous leukemias (CML). The modular composition of the Crk family adapters which largely consist of Src homology (SH2 and SH3) domains has prompted an intensive search for physiological and pathological upstream and downstream signalling partners which selectively bind to these adapters. Upstream proteins include various receptors and large multisite docking proteins, while several protein kinases and guanine nucleotide release proteins (GNRPs) have been suggested to function downstream of c-Crk and CRKL. Most Crk/CRKL SH2- and SH3-binding proteins contain several docking sites with considerable sequence similarity. Thus the binding requirements of Crk/CRKL SH2 and SH3 domains are now well defined, providing a basis for the design of small inhibitory molecules to block the function of these adapter proteins. The enzymatic cascades activated through Crk family adapters are only partially known, but stress kinases (SAPKs/JNKs) and the GTPase Rap1, as well as the B-Raf isoform of the Raf protein kinases, are affected in some systems. Several yet unidentified, highly selective Crk interacting proteins detectable in specific cell types remain to be studied. More detailed analyses of the enzymatic activities triggered through Crk-type adapters will also be crucial to fully define the signalling pathways controlled by this protein family. PMID- 10092208 TI - Long-term expression of differentiated functions in hepatocytes cultured in three dimensional collagen matrix. AB - Hepatocytes entrapped in collagen gel and cultured in serum-free conditions survived longer than cells cultured on plastic (5 days vs. 3 weeks), showed fewer signs of early cell senescence (no increase in c-fos oncoprotein expression), and maintained the expression of differentiated hepatic metabolic functions over a longer period of time. Cells cultured in collagen gels retained their ability to respond to hormones. The insulin-stimulated glycogen synthesis rate remained fairly constant during 18 days in culture (between 5.4 +/- 0.37 and 9 +/- 2.7 nmol glucose/h/microg DNA). Collagen-cultured hepatocytes recovered glycogen stores to levels similar to those found in liver, or in hepatocytes isolated from fed rats. Urea synthesis from ammonia remained stable for more than 2 weeks (average value, 23 +/- 4 nmol urea/h/microg DNA). The rate of albumin synthesis in collagen-entrapped cells was maintained above the day-1 level during 18 days in culture. Cells showed high levels of glutathione (GSH) (1,278 +/- 152 pmol/microg DNA). Biotransformation activities CYP4501A1, CYP4502A2, CYP4502B1, and CYP4503A1 remained fairly stable in collagen-cultured hepatocytes. CYP4502E1 and CYP4502C11 decreased but were still measurable after 18 days. After 4 days in culture, GST activity returned to levels observed in isolated hepatocytes. In contrast with plastic cultures, cells responded to CYP450 inducers (methylcholanthrene for CYP4501A1, CYP4501A2, and glutathione-transferase, and ethanol for CYP4502E1) for more than 2 weeks. CYP4501A1, CYP4501A2, and glutathione-transferase A2 (GST A2) induction was preceded by an increase in specific mRNA, while the effects on CYP4502E1 seemed to be at a posttranslational level. Analysis of the expression of relevant hepatic genes by reverse Northern and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that culturing hepatocytes in collagen gels results in a sustained higher expression of key liver transcription factor genes DBP, C/EBP-alpha and beta, and HNF-1 and -4, as well as specific liver enzyme genes (phosphoenol pyryvate carboxykinase, and carbamoylphosphate-synthetase I). PMID- 10092209 TI - Regulation of the collagenase-3 receptor and its role in intracellular ligand processing in rat osteoblastic cells. AB - We have previously described a specific, saturable receptor for rat collagenase-3 in the rat osteosarcoma cell line, UMR 106-01. Binding of rat collagenase-3 to this receptor is coupled to the internalization and eventual degradation of the enzyme and correlates with observed extracellular levels of the enzyme. In this study we have shown that decreased binding, internalization, and degradation of 125I-rat collagenase-3 were observed in cells after 24 h of parathyroid hormone treatment; these activities returned to control values after 48 h and were increased substantially (twice control levels) after 96 h of treatment with the hormone. Subcellular fractionation studies to identify the route of uptake and degradation of collagenase-3 localized intracellular accumulation of 125I-rat collagenase-3 initially in Golgi-associated lysosomes and later in secondary lysosomes. Maximal lysosomal accumulation of the radiolabel and stimulation of general lysosomal activity occurred after 72 h of parathyroid hormone treatment. Preventing fusion of endosomes with lysosomes (by temperature shift, colchicine, or monensin) resulted in no internalized 125I-collagenase-3 in either lysosomal fraction. Treatment of UMR cells with the above agents or ammonium chloride decreased excretion of 125I-labeled degradation products of collagenase-3. These experiments demonstrated that degradation of collagenase-3 required receptor mediated endocytosis and sequential processing by endosomes and lysosomes. Thus, parathyroid hormone regulates the expression and synthesis of collagenase-3 as well as the abundance and functioning of the collagenase-3 receptor and the intracellular degradation of its ligand. The coordinate changes in the secretion of collagenase-3 and expression of the receptor determine the net abundance of the enzyme in the extracellular space. PMID- 10092210 TI - In vivo evaluation of hsp27 as an inhibitor of actin polymerization: hsp27 limits actin stress fiber and focal adhesion formation after heat shock. AB - The role of hsp27 as an inhibitor of actin polymerization was considered in the context of the actin cytoskeleton and its relationship with focal adhesion formation. The aim of this study was to evaluate the potential effects of hsp27 on focal adhesion formation as a relevant biological consequence of actin stress fiber formation. When hsp27 was overexpressed in stably transfected cells, cell attachment was delayed and recovery of disrupted stress fibers and focal adhesions was limited. In ROS 17/2.8 cells, heat shock caused the reversible disruption of stress fibers and focal adhesions. The loss of stress fibers and focal adhesions was associated with reduced phosphotyrosine on the focal adhesion kinase (FAK). Microinjection of recombinant 6-His hsp27 and phosphorylated 6-His hsp27 was used to demonstrate that nonphosphorylated hsp27 prevented the recovery of stress fibers and focal adhesions. These results provide in vivo evidence that hsp27 acts as an inhibitor of actin polymerization that can alter cellular interactions with extracellular environments by perturbation of stress fibers, and subsequently focal adhesions. PMID- 10092211 TI - Metabolic depletion inhibits the uptake of nontransferrin-bound iron by K562 cells. AB - The effect of metabolic inhibitors on nontransferrin bound iron transport by K562 cells was investigated. Incubation with 1 microM rotenone, 10 microM antimycin, or 0.5 mM 2,4-dinitrophenol effectively reduced ATP levels by approximately 50%. Both the rate and extent of Fe+3 uptake were impaired in ATP-depleted cells, which display a reduced Vmax for uptake. K562 cell ferrireductase activity was also lowered by metabolic inhibitors, suggesting that the apparent energy requirements for transport reside in the reduction of Fe+3 to Fe+2. However, ATP depletion was found to inhibit the rate and extent of Fe+2 uptake as well. Thus, the transbilayer passage of Fe+2 and/or Fe+3 appears to be an energy-requiring process. These features possibly reflect properties of the transport mechanism associated with a recently identified K562 cell transport protein, called SFT for "Stimulator of Fe Transport," since exogenous expression of its activity is also affected by ATP depletion. PMID- 10092212 TI - Differential regulation of the clusterin gene by Ha-ras and c-myc oncogenes and during apoptosis. AB - Clusterin (ApoJ) is an extracellular glycoprotein expressed during processes of tissue differentiation and regression that involve programmed cell death (apoptosis). Increased clusterin expression has also been found in tumors, however, the mechanism underlying this induction is not known. Apoptotic processes in tumors could be responsible for clusterin gene activation. Alternatively, oncogenic mutations could modulate signal transduction, thereby inducing the gene. We examined the response of the rat clusterin gene to two oncogenes, Ha-ras and c-myc, in transfected Rat1 fibroblasts. While c-myc overexpression did not modify clusterin gene activity, the Ha-ras oncogene produced a seven to tenfold repression of clusterin mRNA; this down-regulation was also observed in the presence of c-myc. Since no induction of the clusterin gene was observed by the two oncogenes, we tested the alternative mechanism involving apoptosis. Growth factor withdrawal induced apoptosis, as shown by DNA degradation and micronuclei formation in the floating cells. Concomittantly we observed a three to tenfold increase in the amount of clusterin mRNA in the adhering cells of Rat1 and the c-myc transformed cell lines, and a weaker induction in the Ha-ras transformed cell line. On the basis of our results, we suggest that clusterin gene induction in the vital cells is produced by signaling molecules that are generated by the apoptotic cells. We conclude that apoptotic processes, not oncogenic mutations, are responsible for increased clusterin expression in tumors. PMID- 10092213 TI - Expression of HSP27 results in increased sensitivity to tumor necrosis factor, etoposide, and H2O2 in an oxidative stress-resistant cell line. AB - The role of HSP27 in cell growth and resistance to stress was investigated using murine fibrosarcoma L929 cells (normally devoid of constitutively expressed small HSPs) and human osteoblast-like SaOS-2 cells stably transfected with a human hsp27 expression vector. Our data showed that our L929 cells were more resistant to oxidative stress than generally observed for this line. Production of HSP27 in these cells led to a marked decrease in growth rate associated with a series of phenotypical changes, including cell spreading, cellular and nuclear hypertrophy, development of an irregular outline, and a tremendous accumulation of actin stress fibers. By contrast, none of these changes was observable in SaOS-2/hsp27 transfectants overexpressing the protein product. Together, these observations are consistent with a cause-to-effect cascade relationship between increased (or induced) HSP27 expression, changes in cytoskeletal organization, and decreased growth. On the other hand, whereas the transfection of the hsp27 gene increased the cell resistance to heat in both cell lines, only in SaOS-2 cells was this associated with protection to the cytotoxic action of tumor necrosis factor-alpha (TNF-alpha) and etoposide. Unexpectedly, L929/hsp27 transfectants exhibited an increased sensitivity to both agents and also to H2O2. These data thus imply that different mechanisms are involved in the cell resistance to heat shock and to the cytotoxic action of TNF-alpha, etoposide, and H2O2. They also plead against the simple view that overexpression of a phosphorylatable HSP27 would necessarily be beneficial in terms of increased cell resistance to any type of stress. Our data further indicate that the role of HSP27 in cellular resistance to stress and in cell proliferation involves different targets and that the ultimate result of its interference with these processes depends on the intracellular context in which the protein is expressed. PMID- 10092214 TI - Enterocytic differentiation of the human Caco-2 cell line correlates with alterations in integrin signaling. AB - We previously reported that the enterocytic differentiation of human colonic Caco 2 cells correlated with down-regulation of fibronectin (FN) and laminin (LN), two extracellular matrix components interacting with cell surface integrin receptors. We now investigated whether Caco-2 cell differentiation was associated with alterations in integrin signaling with special interest in the expression and activity of focal adhesion kinase (FAK) and mitogen-activated protein (MAP) kinase. The differentiation of Caco-2 cells was associated with: 1) down regulation of beta1 integrin expression at the mRNA and protein levels; 2) increased FAK expression together with decreased FAK autophosphorylation; 3) decreased FAK's ability to associate with PI3-kinase and pp60c-src; and 4) increased MAP kinase expression along with decreased MAP activity. In addition, we show that FAK and MAP kinase belong to distinct integrin signaling pathways and that both pathways remain functional during Caco-2 cell differentiation since the coating of differentiating cells on FN and LN but not on polylysine increased the tyrosine phosphorylation of FAK and of its endogenous substrate paxillin, and stimulated MAP kinase activity. In conclusion, our results provide evidence that FAK and MAP kinase, two signaling molecules activated independently by beta1 integrins in Caco-2 cells, undergo alterations of both expression and activity during the enterocytic differentiation of this cell line. PMID- 10092215 TI - Growth factor regulation of the amylase promoter in a differentiating salivary acinar cell line. AB - Salivary glands contain two major epithelial cell types: acinar cells which produce the primary salivary secretion, including amylase, and ductal cells which reabsorb electrolytes but also secrete kallikrein. Here we investigated salivary acinar cell differentiation in vitro using the activity of the salivary amylase and tissue kallikrein promoters as markers of acinar cell and ductal cell differentiation, respectively. Each of the promoter sequences was cloned into a replication-deficient adenoviral vector containing the luciferase reporter gene. Previous studies showed that a human submandibular gland cell line (HSG) differentiated into acinar cells when cultured on a reconstituted basement membrane matrix (Matrigel). The luciferase activity of the amylase promoter vector (AdAMY-luc) was low in HSG cells cultured on plastic, where they grow as an epithelial monolayer. The promoter activity increased approximately tenfold when HSG cells were cultured on Matrigel and developed an acinar phenotype. Under the same conditions, the luciferase activity of the kallikrein promoter (AdKALL luc) was not induced. Because HSG cells demonstrate acinar cell morphology, but not amylase gene expression, when cultured on laminin-1, certain soluble components of Matrigel were tested for their ability to induce the amylase promoter during in vitro differentiation of acinar cells. We find that epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), which are present in the basement membrane, and hepatocyte growth factor (HGF) increase activity of the amylase promoter. Other basement membrane-derived growth factors such as TGF-beta, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PGDF), as well as tumor necrosis factor (TNF-alpha), keratinocyte growth factor (KGH), nerve growth factor (NGF) and interferon gamma (IFN-gamma) were inactive. This system will be further exploited to study the mechanisms by which extracellular matrix molecules and growth factors regulate salivary acinar cell differentiation. PMID- 10092216 TI - Isolation and characterization of a cDNA clone encoding a novel peptide (OSF) that enhances osteoclast formation and bone resorption. AB - Using an expression cloning approach, we identified and cloned a novel intracellular protein produced by osteoclasts that indirectly induces osteoclast formation and bone resorption, termed OSF. Conditioned media from 293 cells transiently transfected with the 0.9 kb OSF cDNA clone stimulated osteoclast-like cell formation in both human and murine marrow cultures in the presence or absence 10(-9) M 1,25-dihydroxyvitamin D3. In addition, conditioned media from 293 cells transfected with the OSF cDNA clone enhanced the stimulatory effects of 1,25-(OH)2D3 on bone resorption in the fetal rat long bone assay. In situ hybridization studies using antisense oligomers showed expression of OSF mRNA in highly purified osteoclast-like cells from human giant cell tumors of the bone. Northern blot analysis demonstrated ubiquitous expression of a 1.3 kb mRNA that encodes OSF in multiple human tissues. Sequence analysis showed the OSF cDNA encoded a 28 kD peptide that contains a c-Src homology 3 domain (SH3) and ankyrin repeats, suggesting that it was not a secreted protein, but that it was potentially involved in cell signaling. Consistent with these data, immunoblot analysis using rabbit antisera against recombinant OSF demonstrated OSF expression in cell lysates but not in the culture media. Furthermore, recombinant OSF had a high affinity for c-Src, an important regulator of osteoclast activity. Taken together, these data suggest that OSF is a novel intracellular protein that indirectly enhances osteoclast formation and osteoclastic bone resorption through the cellular signal transduction cascade, possibly through its interactions with c-Src or other Src-related proteins. PMID- 10092217 TI - Intracellular targeting of the endoplasmic reticulum/nuclear envelope by retrograde transport may determine cell hypersensitivity to verotoxin via globotriaosyl ceramide fatty acid isoform traffic. AB - The pentameric B subunit of verotoxin (VT) mediates the attachment to cell surface globotriaosyl ceramide (Gb3) to facilitate receptor-mediated endocytosis of the toxin. In highly toxin-sensitive tumor cells, the holotoxin and VT1 B subunit is targeted intracellularly to elements of the endoplasmic reticulum (ER)/nuclear membrane. In less sensitive cells, the toxin is targeted to components of the Golgi apparatus. We have studied two cell systems: the induced VT hypersensitivity of human astrocytoma cell lines cultured in the presence of sodium butyrate (compared to sodium propionate and capronate) and the increased VT sensitivity of multiple drug-resistant mutants as compared to parental human ovarian carcinoma cells. In both cases, a difference in the intracellular retrograde transport of the receptor-bound internalized toxin to the ER/nuclear envelope, as opposed to the Golgi, correlated with a >1,000-fold increase in cell sensitivity to VT. This change in intracellular routing may be due to sorting of Gb3 fatty acid isoforms, since nuclear targeting was found in turn to correlate with the preferential synthesis of Gb3 containing shorter chain (primarily C16) fatty acid species. We propose that the isoform-dependent traffic of Gb3 from the cell surface to the ER/nuclear membrane provides a new signal transduction pathway for Gb3 binding proteins. PMID- 10092218 TI - The concentration-dependent membrane activity of cecropin A PMID- 10092219 TI - Phase separation scenario for manganese oxides and related materials AB - Recent computational studies of models for manganese oxides have revealed a rich phase diagram, which was not anticipated in early calculations in this context performed in the 1950s and 1960s. In particular, the transition between the antiferromagnetic insulator state of the hole-undoped limit and the ferromagnetic metal at finite hole density was found to occur through a mixed-phase process. When extended Coulomb interactions are included, a microscopically charged inhomogeneous state should be stabilized. These phase separation tendencies, also present at low electronic densities, influence the properties of the ferromagnetic region by increasing charge fluctuations. Experimental data reviewed here by applying several techniques for manganites and other materials are consistent with this scenario. Similarities with results previously discussed in the context of cuprates are clear from this analysis, although the phase segregation tendencies in manganites appear stronger. PMID- 10092220 TI - Replication of apparent nonlinear seismic response with linear wave propagation models AB - It is necessary to understand ground-motion amplification by sediment, defined as the ratio of ground motions at sediment sites to those at rock sites, to predict seismic loadings for earthquake engineering. At sediment sites, observed weak motion amplifications from magnitude 3 to 4 aftershocks of the 1994 Northridge earthquake were twice as large as magnitude 6.7 mainshock amplifications. Amplitude-dependent (nonlinear) amplification by sediment is one explanation. However, earthquake simulations with empirical impulse responses and elastic finite-difference calculations with weakly heterogeneous, random three dimensional (3D) crustal velocity variations show that linear wave propagation can explain observed (apparently nonlinear) sediment responses. Random 3D velocity variations also reproduce the observed log-normal dispersion of peak ground motions. Deterministic wave propagation models are not adequate to quantify the scaling and dispersion of near-source ground motions. PMID- 10092221 TI - Unconditional security of quantum key distribution over arbitrarily long distances AB - Quantum key distribution is widely thought to offer unconditional security in communication between two users. Unfortunately, a widely accepted proof of its security in the presence of source, device, and channel noises has been missing. This long-standing problem is solved here by showing that, given fault-tolerant quantum computers, quantum key distribution over an arbitrarily long distance of a realistic noisy channel can be made unconditionally secure. The proof is reduced from a noisy quantum scheme to a noiseless quantum scheme and then from a noiseless quantum scheme to a noiseless classical scheme, which can then be tackled by classical probability theory. PMID- 10092222 TI - The effect of spin splitting on the metallic behavior of a two-dimensional system AB - Experiments on a constant-density two-dimensional hole system in a gallium arsenide quantum well revealed that the metallic behavior observed in the zero magnetic-field temperature dependence of the resistivity depends on the symmetry of the confinement potential and the resulting spin splitting of the valence band. PMID- 10092223 TI - Chain walking: A new strategy to control polymer topology AB - Ethylene pressure has been used to control the competition between isomerization (chain walking) and monomer insertion processes for ethylene coordination polymerization catalyzed by a palladium-alpha-diimine catalyst. The topology of the polyethylene varies from linear with moderate branching to "hyperbranched" structures. Although the overall branching number and the distribution of short chain branching change very slightly, the architecture or topology of the polyethylene changes from linear polyethylene with moderate branches at high ethylene pressures to a hyperbranched polyethylene at low pressures. PMID- 10092224 TI - Hydrogen peroxide on the surface of Europa. AB - Spatially resolved infrared and ultraviolet wavelength spectra of Europa's leading, anti-jovian quadrant observed from the Galileo spacecraft show absorption features resulting from hydrogen peroxide. Comparisons with laboratory measurements indicate surface hydrogen peroxide concentrations of about 0.13 percent, by number, relative to water ice. The inferred abundance is consistent with radiolytic production of hydrogen peroxide by intense energetic particle bombardment and demonstrates that Europa's surface chemistry is dominated by radiolysis. PMID- 10092225 TI - Arctic ozone loss due to denitrification AB - Measurements from the winter of 1994-95 indicating removal of total reactive nitrogen from the Arctic stratosphere by particle sedimentation were used to constrain a microphysical model. The model suggests that denitrification is caused predominantly by nitric acid trihydrate particles in small number densities. The denitrification is shown to increase Arctic ozone loss substantially. Sensitivity studies indicate that the Arctic stratosphere is currently at a threshold of denitrification. This implies that future stratospheric cooling, induced by an increase in the anthropogenic carbon dioxide burden, is likely to enhance denitrification and to delay until late in the next century the return of Arctic stratospheric ozone to preindustrial values. PMID- 10092227 TI - Polarimetric constraints on the optical afterglow emission from GRB 990123 AB - Polarization of the optical emission from GRB 990123 was measured on 24.17 January 1999 universal time with the Nordic Optical Telescope. An upper limit of 2.3% on the linear polarization was found. Accurate polarization measurements provide important clues to the blast wave geometry and magnetic field structure of gamma-ray bursts (GRBs). The lack of detectable polarization for GRB 990123 indicates that the optical afterglow was produced by a blast wave of unknown geometry with an insignificant coherent magnetic field or by a beamed outflow at high Lorentz factor seen at a small viewing angle. Such a collimated jet would help solve the problem of energy release in this exceptionally luminous cosmological burst. PMID- 10092226 TI - Decay of the GRB 990123 optical afterglow: implications for the fireball model AB - Broad-band (ultraviolet to near-infrared) observations of the intense gamma ray burst GRB 990123 started approximately 8.5 hours after the event and continued until 18 February 1999. When combined with other data, in particular from the Robotic Telescope and Transient Source Experiment (ROTSE) and the Hubble Space Telescope (HST), evidence emerges for a smoothly declining light curve, suggesting some color dependence that could be related to a cooling break passing the ultraviolet-optical band at about 1 day after the high-energy event. The steeper decline rate seen after 1.5 to 2 days may be evidence for a collimated jet pointing toward the observer. PMID- 10092228 TI - Spectroscopic limits on the distance and energy release of GRB 990123 AB - An optical spectrum of the afterglow from the unusually bright gamma-ray burst GRB 990123 obtained on 24.25 January 1999 universal time showed an absorption system at a redshift of z = 1.600. The absence of a hydrogen Lyman alpha forest sets an upper limit of z < 2.17, whereas ultraviolet photometry indicates an upper limit of z < 2.05. The probability of intersecting an absorption system as strong as the one observed along a random line of sight out to this z is at most a few percent, implying that GRB 990123 was probably at z = 1. 600. Currently favored cosmological parameters imply that an isotropic energy release equivalent to the rest mass of 1.8 neutron stars (4.5 x 10(54) erg) was emitted in gamma rays. Nonisotropic emission, such as intrinsic beaming, may resolve this energy problem. PMID- 10092229 TI - A simple predictive model for the structure of the oceanic pycnocline AB - A simple theory for the large-scale oceanic circulation is developed, relating pycnocline depth, Northern Hemisphere sinking, and low-latitude upwelling to pycnocline diffusivity and Southern Ocean winds and eddies. The results show that Southern Ocean processes help maintain the global ocean structure and that pycnocline diffusion controls low-latitude upwelling. PMID- 10092230 TI - Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. AB - Transforming growth factor-beta (TGF-beta) signaling is mediated by a complex of type I (TBRI) and type II (TBRII) receptors. The type III receptor (TBRIII) lacks a recognizable signaling domain and has no clearly defined role in TGF-beta signaling. Cardiac endothelial cells that undergo epithelial-mesenchymal transformation express TBRIII, and here TBRIII-specific antisera were found to inhibit mesenchyme formation and migration in atrioventricular cushion explants. Misexpression of TBRIII in nontransforming ventricular endothelial cells conferred transformation in response to TGF-beta2. These results support a model where TBRIII localizes transformation in the heart and plays an essential, nonredundant role in TGF-beta signaling. PMID- 10092231 TI - Inhibition of myosin light chain kinase by p21-activated kinase. AB - p21-activated kinases (PAKs) are implicated in the cytoskeletal changes induced by the Rho family of guanosine triphosphatases. Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin II that are regulated by myosin light chain kinase (MLCK)-mediated phosphorylation of the regulatory myosin light chain (MLC). p21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity. MLCK activity and MLC phosphorylation were decreased, and cell spreading was inhibited in baby hamster kidney-21 and HeLa cells expressing constitutively active PAK1. These data indicate that MLCK is a target for PAKs and that PAKs may regulate cytoskeletal dynamics by decreasing MLCK activity and MLC phosphorylation. PMID- 10092232 TI - Imaging protein kinase Calpha activation in cells. AB - Spatially resolved fluorescence resonance energy transfer (FRET) measured by fluorescence lifetime imaging microscopy (FLIM), provides a method for tracing the catalytic activity of fluorescently tagged proteins inside live cell cultures and enables determination of the functional state of proteins in fixed cells and tissues. Here, a dynamic marker of protein kinase Calpha (PKCalpha) activation is identified and exploited. Activation of PKCalpha is detected through the binding of fluorescently tagged phosphorylation site-specific antibodies; the consequent FRET is measured through the donor fluorophore on PKCalpha by FLIM. This approach enabled the imaging of PKCalpha activation in live and fixed cultured cells and was also applied to pathological samples. PMID- 10092233 TI - Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A. AB - Dysregulation of Wnt-beta-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies. The adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3beta form a Wnt-regulated signaling complex that mediates the phosphorylation-dependent degradation of beta catenin. A protein phosphatase 2A (PP2A) regulatory subunit, B56, interacted with APC in the yeast two-hybrid system. Expression of B56 reduced the abundance of beta-catenin and inhibited transcription of beta-catenin target genes in mammalian cells and Xenopus embryo explants. The B56-dependent decrease in beta catenin was blocked by oncogenic mutations in beta-catenin or APC, and by proteasome inhibitors. B56 may direct PP2A to dephosphorylate specific components of the APC-dependent signaling complex and thereby inhibit Wnt signaling. PMID- 10092234 TI - Role of the S. typhimurium actin-binding protein SipA in bacterial internalization. AB - Entry of the bacterium Salmonella typhimurium into host cells requires membrane ruffling and rearrangement of the actin cytoskeleton. Here, it is shown that the bacterial protein SipA plays a critical role in this process. SipA binds directly to actin, decreases its critical concentration, and inhibits depolymerization of actin filaments. These activities result in the spatial localization and more pronounced outward extension of the Salmonella-induced membrane ruffles, thereby facilitating bacterial uptake. PMID- 10092235 TI - Regulation of keystone predation by small changes in ocean temperature AB - Key species interactions that are sensitive to temperature may act as leverage points through which small changes in climate could generate large changes in natural communities. Field and laboratory experiments showed that a slight decrease in water temperature dramatically reduced the effects of a keystone predator, the sea star Pisaster ochraceus, on its principal prey. Ongoing changes in patterns of cold water upwelling, associated with El Nino events and longer term geophysical changes, may thus have far-reaching impacts on the composition and diversity of these rocky intertidal communities. PMID- 10092236 TI - A cytotoxic ribonuclease targeting specific transfer RNA anticodons. AB - The carboxyl-terminal domain of colicin E5 was shown to inhibit protein synthesis of Escherichia coli. Its target, as revealed through in vivo and in vitro experiments, was not ribosomes as in the case of E3, but the transfer RNAs (tRNAs) for Tyr, His, Asn, and Asp, which contain a modified base, queuine, at the wobble position of each anticodon. The E5 carboxyl-terminal domain hydrolyzed these tRNAs just on the 3' side of this nucleotide. Tight correlation was observed between the toxicity of E5 and the cleavage of intracellular tRNAs of this group, implying that these tRNAs are the primary targets of colicin E5. PMID- 10092237 TI - Artificial corneas. PMID- 10092238 TI - The World Bank. PMID- 10092239 TI - NICE: a panacea for the NHS? PMID- 10092240 TI - The evidence for beta blockers in heart failure. PMID- 10092241 TI - The physical consequences of depressive illness. PMID- 10092242 TI - Reflux "increases risk of adenocarcinoma of oesophagus" PMID- 10092243 TI - Statins being prescribed for those "least in need". PMID- 10092244 TI - In brief PMID- 10092245 TI - US women asked to pay for epidurals in advance. PMID- 10092246 TI - "Thrifty gene" identified in manitoba indians PMID- 10092247 TI - Deaths from nvCJD rise sharply PMID- 10092248 TI - FDA proposes measuring antibiotics in feed PMID- 10092249 TI - American trade union aims to recruit more doctors. PMID- 10092250 TI - Japan tackles dioxin levels. PMID- 10092251 TI - All GPs to be required to have defence cover. PMID- 10092252 TI - GPs face escalating litigation. PMID- 10092253 TI - Drug trial investigators asked to declare financial interests. PMID- 10092254 TI - UK juniors to be surveyed over action on pay PMID- 10092255 TI - Upper age limit should be raised for cancer screening PMID- 10092256 TI - Government sets out vision for clinical governance PMID- 10092257 TI - Germany: doctors' training to change PMID- 10092258 TI - New curriculum at the Charite/ virchow medical school in berlin PMID- 10092259 TI - Eradication of Helicobacter pylori in functional dyspepsia: randomised double blind placebo controlled trial with 12 months' follow up. The Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group. AB - OBJECTIVES: To determine whether eradication of Helicobacter pylori relieves the symptoms of functional dyspepsia. DESIGN: Multicentre randomised double blind placebo controlled trial. SUBJECTS: 278 patients infected with H pylori who had functional dyspepsia. SETTING: Predominantly secondary care centres in Australia, New Zealand, and Europe. INTERVENTION: Patients randomised to receive omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily or placebo for 7 days. Patients were followed up for 12 months. MAIN OUTCOME MEASURES: Symptom status (assessed by diary cards) and presence of H pylori (assessed by gastric biopsies and 13C-urea breath testing using urea labelled with carbon-13). RESULTS: H pylori was eradicated in 113 patients (85%) in the treatment group and 6 patients (4%) in the placebo group. At 12 months follow up there was no significant difference between the proportion of patients treated successfully by intention to treat in the eradication arm (24%, 95% confidence interval 17% to 32%) and the proportion of patients treated successfully by intention to treat in the placebo group (22%, 15% to 30%). Changes in symptom scores and quality of life did not significantly differ between the treatment and placebo groups. When the groups were combined, there was a significant association between treatment success and chronic gastritis score at 12 months; 41/127 (32%) patients with no or mild gastritis were successfully treated compared with 21/123 (17%) patients with persistent gastritis (P=0. 008). CONCLUSION: No convincing evidence was found that eradication of H pylori relieves the symptoms of functional dyspepsia 12 months after treatment. PMID- 10092260 TI - Systematic review of day hospital care for elderly people. The Day Hospital Group. AB - OBJECTIVE: To examine the effectiveness of day hospital attendance in prolonging independent living for elderly people. DESIGN: Systematic review of 12 controlled clinical trials (available by January 1997) comparing day hospital care with comprehensive care (five trials), domiciliary care (four trials), or no comprehensive care (three trials). SUBJECTS: 2867 elderly people. MAIN OUTCOME MEASURES: Death, institutionalisation, disability, global "poor outcome," and use of resources. RESULTS: Overall, there was no significant difference between day hospitals and alternative services for death, disability, or use of resources. However, compared with subjects receiving no comprehensive care, patients attending day hospitals had a lower odds of death or "poor" outcome (0.72, 95% confidence interval 0.53 to 0.99; P<0.05) and functional deterioration (0.61, 0.38 to 0.97; P<0.05). The day hospital group showed trends towards reductions in hospital bed use and placement in institutional care. Eight trials reported treatment costs, six of which reported that day hospital attendance was more expensive than other care, although only two analyses took into account cost of long term care. CONCLUSIONS: Day hospital care seems to be an effective service for elderly people who need rehabilitation but may have no clear advantage over other comprehensive care. Methodological problems limit these conclusions, and further randomised trials are justifiable. PMID- 10092261 TI - Paralytic poliomyelitis associated with live oral poliomyelitis vaccine in child with HIV infection in Zimbabwe: case report. AB - OBJECTIVE: To describe a complication of oral vaccination with live, attenuated poliomyelitis virus in a child infected with HIV. DESIGN: Case report. SETTING: Teaching hospital in Harare, Zimbabwe. SUBJECTS: A boy of 41/2 years and his mother. MAIN OUTCOME MEASURES: Results of clinical and laboratory investigations. RESULTS: Two weeks after receiving the second dose of oral poliomyelitis vaccine during national immunisation days the child developed paralysis of the right leg. He had a high titre of antibodies against poliovirus type 2, as well as antibodies against HIV-1, a low CD4 count, a ratio of CD4 to CD8 count of 0.47, and hypergammaglobulinaemia. He did not have any antibodies against diphtheria, tetanus, or poliovirus types 1 and 3, although he had been given diphtheria, tetanus, and pertussis and oral polio vaccines during his first year and a booster of the diphtheria, tetanus, and pertussis vaccine at 24 months. He had no clinical symptoms of AIDS, but his mother had AIDS and tuberculosis. CONCLUSION: Paralytic poliomyelitis in this child with HIV infection was caused by poliovirus type 2 after oral poliomyelitis vaccine. PMID- 10092262 TI - Postcodes as useful markers of social class: population based study in 26 000 British households. PMID- 10092263 TI - Transient hemiparesis with topiramate. PMID- 10092264 TI - Lifetime prevalence, characteristics, and associated problems of non-consensual sex in men: cross sectional survey. AB - OBJECTIVE: To identify the lifetime prevalence of non-consensual sexual experiences in men, the relationship between such experiences as a child and as an adult, associated psychological and behavioural problems, and help received. DESIGN: Cross sectional survey. SETTING: England. SUBJECTS: 2474 men (mean age 46 years) attending one of 18 general practices. MAIN OUTCOME MEASURES: Experiences of non-consensual and consensual sex before and after the age of 16 years-that is, as a child and adult respectively-psychological problems experienced for more than 2 weeks at any one time, use of alcohol (CAGE questionnaire), self harm, and help received. RESULTS: 2474 of 3142 men (79%) agreed to participate; 71/2468 (standardised rate 2.89%, 95% confidence interval 2.21% to 3.56%) reported non consensual sexual experiences as adults, 128/2423 (5.35%, 4.39% to 6.31%) reported non-consensual sexual experiences as children, and 185/2406 (7.66%, 6.54% to 8.77%) reported consensual sexual experiences as children that are illegal under English law. Independent predictors of non-consensual sex as adults were reporting male sexual partners (odds ratio 6.0, 2.6 to 13.5), non-consensual sex in childhood (4.2, 2.1 to 8.6), age (0.98, 0.96 to 0.99), and sex of interviewer (2.0, 1.2 to 3.5). Non-consensual sexual experiences were associated with a greater prevalence of psychological problems, alcohol misuse, and self harm. These sexual experiences were also significant predictors of help received from mental health professionals. CONCLUSION: Almost 3% of men in England report non-consensual sexual experiences as adults. Medical professionals need to be aware of the range of psychological difficulties in men who have had such experiences. They also need to be aware of the relationship between sexual experiences in childhood and adulthood in men. PMID- 10092265 TI - Towards primary care groups: joining up care in London-establishing the North Southwark Primary Care Group. PMID- 10092266 TI - Science, medicine, and the future. Antivascular therapy: a new approach to cancer treatment. PMID- 10092267 TI - Lesson of the week: Turner's syndrome mosaicism in patients with a normal blood lymphocyte karyotype. PMID- 10092268 TI - ABC of labour care: assessment of mother and fetus in labour. PMID- 10092269 TI - The dawn of medical science in russia PMID- 10092271 TI - The World Bank and world health: changing sides. PMID- 10092270 TI - Changing perceptions in osteoporosis. PMID- 10092272 TI - Control of house dust mite in managing asthma. Effectiveness of measures depends on stage of asthma. PMID- 10092273 TI - More thoughts prompted by the Bristol case. Damned if you do and damned if you don't? PMID- 10092274 TI - Fear of hypercapnia is leading to inadequate oxygen treatment. PMID- 10092275 TI - Having practice pharmacists is not only way of reducing prescribing costs. PMID- 10092276 TI - Thalassaemia among Asians in Britain. Thalassaemia Society is working to improve awareness. PMID- 10092277 TI - Costs incurred by one severely ill Jehovah's Witness could run one unit in Africa for one year. PMID- 10092278 TI - How do two meta-analyses of similar data reach opposite conclusions? PMID- 10092279 TI - Management of drug budgets. Neurologists do not have confidence in Glasgow's method of managing drugs budget. PMID- 10092280 TI - Patients who are eligible but not randomised should be included as additional comparative arm in study. PMID- 10092281 TI - Patients' understanding of randomised controlled trials depends on their education. PMID- 10092282 TI - Review on bladder cancer. New rather than old TNM staging system should have been used. PMID- 10092284 TI - Robert harvard davis PMID- 10092283 TI - Use of health services by children. Study does not rule out effect of social class. PMID- 10092285 TI - LMCs should be recognised in health bill PMID- 10092286 TI - Medicine in the english middle ages PMID- 10092287 TI - Dementia reconsidered: the person comes first PMID- 10092288 TI - The cochrane library 1998 issue 4 PMID- 10092289 TI - Clinical governance: making it happen PMID- 10092290 TI - Screening stories PMID- 10092292 TI - Where there's will, there's a way PMID- 10092291 TI - Website of the week PMID- 10092293 TI - Spin doctor PMID- 10092295 TI - Day hospitals are no better than other comprehensive elderly care PMID- 10092294 TI - Eradicating helicobacter pylori does not relieve dyspepsia PMID- 10092297 TI - Postcodes can be useful indicators of social class PMID- 10092296 TI - Poliomyelitis may occur in children with HIV after poliomyelitis vaccination PMID- 10092298 TI - Almost 3% of men report non-consensual sexual experiences as adults PMID- 10092299 TI - Should prophylaxis against osteoporotic fractures ignore bone mineral density? PMID- 10092300 TI - Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. AB - BACKGROUND & AIMS: The aim of this study was to evaluate the role of known colorectal adenoma and carcinoma susceptibility genes and to locate a novel susceptibility gene in an Ashkenazi family (SM1311) with dominantly inherited predisposition to colorectal adenomas and carcinomas. METHODS: Clinicopathologic and family history data were collected. Genetic linkage and mutational analyses were used to investigate the genetic basis of the family's disease. RESULTS: Affected members of SM1311 develop multiple tubular, villous, tubulovillous, and/or serrated colorectal adenomas throughout the large bowel, and some develop colon carcinoma. There are no extracolonic features clearly associated with disease in SM1311. We have shown that the family's phenotype does not result from APC mutations (including the I1307K variant) or from genetic changes in the other known genes that predispose to colon cancer. Using genetic linkage analysis, supplemented by allele loss in tumors, we have provided evidence for a new colorectal cancer susceptibility gene, CRAC1 (colorectal adenoma and carcinoma), mapping to chromosome 15q14-q22. CONCLUSIONS: We provide evidence for a novel colorectal adenoma and carcinoma susceptibility gene on chromosome 15q14-q22. Further studies are needed to confirm this localization and to evaluate the contribution of CRAC1 to this disease. PMID- 10092301 TI - Paramyxovirus infections in childhood and subsequent inflammatory bowel disease. AB - BACKGROUND & AIMS: Measles virus has been implicated in the etiology of both inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis. Subacute sclerosing panencephalitis (SSPE) is caused by atypical measles infection. This study investigated the patterns of infection that are risks for SSPE, early infection and a close temporal relationship between measles and another infection, as potential risks for IBD. METHODS: The data are from 7019 members of a nationally representative 1970 British Cohort Study. The ages of five childhood infections were recorded before onset of IBD symptoms. Diagnoses of IBD and insulin-dependent diabetes mellitus (IDDM), as a control disease, were identified by age 26 years. RESULTS: Mumps infection before age 2 years was a risk for ulcerative colitis (odds ratio, 25.12; 95% confidence interval, 6. 35 99.36). Measles and mumps infections in the same year of life were significantly associated with ulcerative colitis and Crohn's disease, with odds ratios of 7.47 (2.42-23.06) and 4.27 (1.24-14.46), but not with IDDM. These relationships are independent of each other as well as sex, social class at birth, household crowding in childhood, and family history of IBD. CONCLUSIONS: Atypical paramyxovirus infections in childhood may be risk factors for later IBD. PMID- 10092302 TI - Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults. AB - BACKGROUND & AIMS: Oral immunization with Helicobacter pylori urease can cure Helicobacter infection in animals. As a step toward therapeutic immunization in humans, the safety and immunogenicity of oral immunization with recombinant H. pylori urease were tested in H. pylori-infected adults. METHODS: Twenty-six H. pylori-infected volunteers were randomized in a double-blind study to four weekly oral doses of 180, 60, or 20 mg of urease with 5 microg heat-labile enterotoxin of Escherichia coli (LT), LT alone, or placebo. Side effects and immune responses were evaluated weekly after immunization, and gastric biopsy specimens were obtained after 1 month and 6 months for histology and quantitative cultures. RESULTS: Diarrhea was noted in 16 of 24 (66%) of the volunteers who completed the study. Antiurease serum immunoglobulin A titers increased 1. 58-fold +/- 0.37 fold and 3.66-fold +/- 1.5-fold (mean +/- SEM) after immunization with 60 and 180 mg urease, respectively, whereas no change occurred in the placebo +/- LT groups (P = 0.005). Circulating antiurease immunoglobulin A-producing cells increased in volunteers exposed to urease compared with placebo (38.9 +/- 13. 6/10(6) vs. 5.4 +/- 3.1; P = 0.018). Eradication of H. pylori infection was not observed, but urease immunization induced a significant decrease in gastric H. pylori density. CONCLUSIONS: H. pylori urease with LT is well tolerated and immunogenic in H. pylori-infected individuals. An improved vaccine formulation may induce curative immunity. PMID- 10092303 TI - Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice. AB - BACKGROUND & AIMS: Hypochlorhydria is associated with an increased risk of gastric cancer. We have studied the effect of pharmacologically induced hypochlorhydria on the gastric juice ascorbate/nitrite ratio, which regulates the synthesis of potentially carcinogenic N-nitroso compounds. METHODS: Saliva, gastric juice, and serum from 20 healthy volunteers (9 positive for Helicobacter pylori), with a mean age of 30 years (range, 20-47 years), were analyzed for nitrite, ascorbic acid, and total vitamin C before and for 2 hours after ingestion of 2 mmol [corrected] nitrate (nitrate content of a standard salad meal). This was repeated after 4 weeks of treatment with omeprazole, 40 mg daily. RESULTS: Before omeprazole treatment, the nitrate meal lowered gastric ascorbic acid levels from 3.8 to 0.9 microg/mL (P < 0.05) and increased median salivary nitrite levels from 44 to 262 micromol/L (P < 0.001); gastric nitrite concentration remained undetected in 10 subjects. Omeprazole increased median fasting gastric nitrite levels from 0 to 13 micromol/L (P = 0.001) and decreased fasting gastric ascorbic acid levels from 3.8 to 0.7 microg/mL (P < 0.001). With omeprazole treatment, gastric nitrite levels after the nitrate meal were markedly increased at 154 micromol/L (range, 49-384 micromol/L; P < 0.001). In H. pylori infected subjects, omeprazole also decreased total vitamin C levels in both gastric juice and serum. CONCLUSIONS: Omeprazole and dietary nitrate independently decrease the ascorbate/nitrite ratio. This may lead to an increased risk of gastric cancer. PMID- 10092304 TI - Geographic distribution of vacA allelic types of Helicobacter pylori. AB - BACKGROUND & AIMS: Distinct allelic types of Helicobacter pylori vacA have been defined. The geographic distribution of vacA alleles and cagA was assessed in this study. METHODS: A total of 735 cultures from patients in 24 countries were analyzed by polymerase chain reaction and reverse hybridization on a line probe assay (LiPA). RESULTS: In 124 (16.9%) of the 735 cultures, multiple vacA genotypes were detected, permitting analysis of 611 strains. In Europe, a distribution gradient of s1 subtypes was observed. In northern and eastern Europe, 89% were subtype s1a. s1a and s1b were equally present in France and Italy, whereas in Spain and Portugal 89% of strains were subtype s1b. s1a and s1b were approximately equally prevalent in North America. In Central and South America, virtually all s1 strains were subtype s1b. Subtype s1c was observed in 77% of the s1 isolates from East Asia. m1 and m2a have equal presence, except on the Iberian peninsula and in Central and South America, where m1 (86.2%) is more prevalent than m2 (13.8%). Subtype m2b was found exclusively among East Asian s1c strains. In all parts of the world, vacA s1/cagA-positive genotypes were associated with peptic ulcer disease (P < 0.001). CONCLUSIONS: These data indicate a geographic distribution of H. pylori genotypes and aid in understanding the relationship of H. pylori with disease. PMID- 10092305 TI - Epidermal growth factor and transforming growth factor alpha down-regulate human gastric lipase gene expression. AB - BACKGROUND & AIMS: It was recently reported that human gastric lipase (HGL) activity is modulated by epidermal growth factor (EGF). The aims of this study were to establish the cellular localization of HGL, to assess the correlation between HGL messenger RNA (mRNA) and protein levels, and to establish the molecular mechanism of action of EGF and its homologue transforming growth factor alpha (TGF-alpha) on HGL expression. METHODS: Cellular localization of HGL was determined by immunohistochemistry using a polyclonal antibody. Enzymic determinations, Western blotting, and Northern hybridization were used to analyze expression of HGL mRNA, protein, lipase activity, and the p42/p44(mapk) activation status. RESULTS: HGL was localized in the secretory granules of gastric chief cells as early as 13 weeks. A close parallelism was found between the variations of mRNA, protein, and enzymic activity. EGF and/or TGF-alpha down regulated HGL mRNA levels and decreased enzymic activity. The role of the mitogen activated protein kinase cascade in the regulation of HGL expression was highlighted by the use of MAP kinase kinase-1/2 inhibitor PD98059, which blunted both the activation of p42/p44(mapk) and the down-regulation of HGL mRNA induced by EGF and/or TGF-alpha. CONCLUSIONS: The expression of HGL is regulated at the mRNA level, and the down-regulatory action of EGF and/or TGF-alpha on HGL involves the stimulation of p42/p44(mapk) cascade. PMID- 10092306 TI - Transcriptional regulation of pig lactase-phlorizin hydrolase: involvement of HNF 1 and FREACs. AB - BACKGROUND & AIMS: One-kilobase sequence of the upstream fragment of the pig lactase-phlorizin hydrolase gene has been shown to control small intestinal specific expression and postweaning decline of lactase-phlorizin hydrolase in transgenic mice. The aim of this study was to identify the regulatory DNA elements and transcription factors controlling lactase-phlorizin hydrolase expression. METHODS: The activity of different lactase-phlorizin hydrolase promoter fragments was investigated by transfection experiments using Caco-2 cells. Electrophoretic mobility shift assays and supershift analyses were used to characterize the interaction between intestinal transcription factors and the identified regulatory elements. RESULTS: Functional analysis revealed three previously undescribed regulatory regions in the lactase-phlorizin hydrolase promoter: a putative enhancer between -894 and -798 binding hepatocyte nuclear factor (HNF)-1 at position -894 to -880; a repressor-binding element between -278 to -264 to which an HNF-3-like factor is able to bind; and an element between 178 to -164 that binds an activating transcription factor. CONCLUSIONS: Identification of three new regulatory regions and HNF-1 and HNF-3-like transcription factor as players in the regulation of lactase-phlorizin hydrolase gene transcription has an impact on the understanding of the molecular mechanisms behind age-dependent, tissue-specific, differentiation-dependent, and regional regulation of expression in the intestine. PMID- 10092307 TI - Inhibition of cytoplasmic phospholipase A2 expression by glucocorticoids in rat intestinal epithelial cells. AB - BACKGROUND & AIMS: Glucocorticoids are the most potent and widely accepted anti inflammatory agents in the treatment of pathological conditions of the gastrointestinal tract in part by inhibiting the synthesis of proinflammatory prostanoids and leukotrienes. Multiple forms of phospholipase A2 may be associated with the production of these metabolites; this study focused on the molecular mechanism(s) by which glucocorticoids control expression of the arachidonyl-selective, cytosolic phospholipase A2 (cPLA2) in intestinal cells. METHODS: Northern analysis, a transcriptional assay, and enzymatic evaluation were used to access expression of the cPLA2 gene in rat small intestinal epithelial and mouse fibroblast cell lines treated with dexamethasone. RESULTS: Basal cPLA2 messenger RNA (mRNA) expression was repressed 75% in the presence of dexamethasone with a concomitant decrease in enzymatic activity. Nuclear runoff assays showed a marked decline in de novo cPLA2 RNA synthesis, implicating a transcriptional mechanism associated with the dexamethasone-mediated suppression of cPLA2. Induced expression of cPLA2 mRNA by several proinflammatory cytokines was blocked by cotreatment with dexamethasone. CONCLUSIONS: Glucocorticoids are capable of markedly altering basal and cytokine-stimulated cPLA2 gene expression in intestinal epithelial cells, leading to a reduction in arachidonate pools in these cells. Dexamethasone-dependent inhibition occurs through a direct reduction of de novo cPLA2 gene transcription. PMID- 10092308 TI - Role of the proteasome in rat indomethacin-induced gastropathy. AB - BACKGROUND & AIMS: Intercellular adhesion molecule (ICAM)-dependent adhesion of circulating neutrophils to microvascular endothelial cells is thought to be critical in causing indomethacin (nonsteroidal anti-inflammatory drug [NSAID]) induced gastropathy. Indomethacin stimulates tumor necrosis factor (TNF)-alpha expression, which may enhance adhesiveness of gastric capillaries for neutrophils by activating ICAM expression on endothelial cells. Stimulation of ICAM expression is mediated by activation of the transcription factor NF-kappaB. Because activation of NF-kappaB requires proteolytic degradation of IkappaB by the ubiquitin-proteasome pathway of intracellular proteolysis, treatment with proteasome inhibitors was evaluated for efficacy in preventing NSAID gastropathy. METHODS: The effect of proteasome inhibitors on gastric injury caused by oral indomethacin was measured, along with their effects on gastric mucosal permeability measured by the blood to lumen EDTA clearance. Gastric ICAM expression was measured in vivo using infusion of a labeled rat ICAM antibody. RESULTS: Proteasome inhibitors prevented NSAID gastropathy if administered from 0 to 12 hours before indomethacin. Equivalent efficacy was observed with intravenous and oral administration of proteasome inhibitors. There was a strong correlation between the potency of proteasome inhibitors in preventing NSAID gastropathy and their potency in inhibiting intracellular proteolysis or their anti-inflammatory potency. All three classes of proteasome inhibitors, peptide boronates, aldehydes, and the mechanistically different lactacystin, prevented NSAID gastropathy. Proteasome inhibitor treatment also abolished the increase in gastric mucosal permeability and the increase in gastric endothelial ICAM expression induced by indomethacin. CONCLUSIONS: Indomethacin-induced gastric injury and increased ICAM expression are inhibited by inhibition of the proteasome. PMID- 10092309 TI - VCAM-1 and ICAM-1 mediate leukocyte-endothelial cell adhesion in rat experimental colitis. AB - BACKGROUND & AIMS: The molecular mechanisms responsible for leukocyte recruitment in experimental colitis are poorly understood. The aims of this study were to measure expression of endothelial intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) and to determine their role in leukocyte recruitment in experimental colitis. METHODS: Rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis and control rats were studied 1, 7, or 21 days after treatment. ICAM-1 and VCAM-1 expressions were measured by the double radiolabeled antibody technique. Leukocyte-endothelial cell interactions were determined in colonic venules by fluorescence intravital microscopy. Therapeutic effects of treatment with anti-VCAM-1 antibodies were also assessed. RESULTS: Colonic endothelial ICAM-1 was constitutively expressed and did not increase in colitic animals. In contrast, constitutive expression of VCAM-1 was low but markedly increased (6-fold) 1 and 7 days after induction of colitis. Increased colonic expression of VCAM-1 paralleled macroscopic damage score, myeloperoxidase activity, and increased leukocyte adhesion in colonic venules. The latter was significantly decreased by immunoneutralization of ICAM-1 and completely abrogated by immunoneutralization of VCAM-1. Long-term administration of anti VCAM-1 antibody resulted in significant attenuation of colitis. CONCLUSIONS: Induction of colitis in rats by TNBS is followed by up-regulation of endothelial VCAM-1. VCAM-1 and constitutive ICAM-1 are major determinants of leukocyte recruitment to the inflamed intestine. PMID- 10092310 TI - Inflammatory modulation of calcium-activated potassium channels in canine colonic circular smooth muscle cells. AB - BACKGROUND & AIMS: The characteristics of colonic circular smooth muscle slow waves are altered during inflammation. The aim of this study was to examine whether inflammation modulates the open-state probability of Ca2+-activated K+ (KCa) channels in these cells to contribute to these alterations. METHODS: The experiments were performed on freshly dissociated single smooth muscle cells from the canine colon using standard patch clamp methods. Inflammation was induced by mucosal exposure to ethanol and acetic acid. RESULTS: Inflammation decreased the open-state probability of large-conductance KCa (BK) channels in the cell attached and excised inside-out configurations. The voltage sensitivity of the channels was also reduced during inflammation. Inflammation had no significant effect on the large, medium, and small conductances or the unitary current levels of channel openings. However, it decreased the maximum number of simultaneous channel openings. The channels were Ca2+-dependent and were blocked by tetraethylammonium and charybdotoxin in normal and inflamed cells. CONCLUSIONS: Inflammation decreases the open-state probability of BK channels. This may partially reverse the decrease in duration and amplitude of slow waves and depolarization of membrane potential seen in inflammation. PMID- 10092311 TI - Risk factors for acquisition of hepatitis C virus infection in blood donors: results of a case-control study. AB - BACKGROUND & AIMS: Few studies have explored risk factors predicting hepatitis C virus (HCV) infection in blood donors; their results are contradictory. The aim of this study was to evaluate the association between HCV infection and various risk factors in Canadian volunteer blood donors. METHODS: Four transfusion centers were involved in this case-control study. A total of 267 confirmed anti HCV-positive blood donors were interviewed along with 1068 seronegative blood donors matched for sex, age, donation site, and date. Information was collected using a structured telephone interview. The main outcome measures were odds ratios (ORs) and 95% confidence intervals (CIs) for various risk factors from univariate and multivariate analyses using conditional logistic regression. RESULTS: By univariate analysis, 23 variables were associated with anti-HCV positivity. In the final multivariate analysis, only 5 factors remained independently predictive of HCV infection: previous intravenous drug use (OR, 127.5; 95% CI, 26.0-625.0), having lived in a prison or juvenile detention center (56.1; 11.4-275.7), previous blood transfusion (10.5; 4.7-23.2), sexual contact with an intravenous drug user (6.9; 3.1-15.2), and tattooing (5.7; 2.5-13). CONCLUSIONS: Most blood donors acquire infection by percutaneous exposure to contaminated blood. A role for sexual transmission is suggested by this study. PMID- 10092312 TI - Postcholecystectomy pain syndrome: pathophysiology of abdominal pain in sphincter of Oddi type III. AB - BACKGROUND & AIMS: Persistent abdominal pain occurs in many patients after cholecystectomy, some of whom are described as having sphincter of Oddi dysfunction (SOD). Pain in SOD type III is thought to be of biliary origin with little objective data, and treatment is often unsatisfactory. Chronic abdominal pain without a biological disease marker is similar to irritable bowel syndrome, in which many patients exhibit visceral hyperalgesia. This study tested the hypothesis that duodenal-specific visceral afferent sensitivity exists in patients with SOD type III. METHODS: Eleven patients with chronic abdominal pain after cholecystectomy and 10 controls underwent duodenal and rectal barostat studies to evaluate visceral pain perception measured with a visual analog scale. All subjects underwent psychological testing. RESULTS: Patients with SOD type III exhibited duodenal but not rectal hyperalgesia compared with controls. There were no differences in duodenal compliance between the groups. Duodenal distention reproduced symptoms in all but 1 patient. Patients showed high levels of somatization, depression, obsessive-compulsive behavior, and anxiety. CONCLUSIONS: Patients with SOD type III exhibited duodenal-specific visceral hyperalgesia, and duodenal distention reproduced symptoms in all but 1 patient. Abdominal pain in these patients may not originate exclusively from the biliary tree. PMID- 10092313 TI - Hepatic arterial flow volume and reserve in patients with cirrhosis: use of intra arterial Doppler and adenosine infusion. AB - BACKGROUND & AIMS: In cirrhosis, liver blood flow becomes increasingly dependent on the hepatic artery. The aim of this study was to investigate hepatic arterial blood flow volume and resistance and hepatic arterial flow reserve in relation to liver function and systemic hemodynamic alterations in patients with cirrhosis. METHODS: In 38 patients with cirrhosis, liver function, cardiac output, and systemic vascular resistance were studied, and hepatic arterial blood flow velocity, flow volume, and pulsatility index at baseline and during intra arterial administration of adenosine (2-40 microg. min-1. kg body wt-1) were assessed by angiography combined with intravascular Doppler flowmetry. RESULTS: Hepatic arterial flow velocity was 21 +/- 11, 31 +/- 17, and 41 +/- 27 cm/s; flow volume was 266 +/- 246, 342 +/- 289, and 417 +/- 220 mL/min; and pulsatility index was 2.2 +/- 0.7, 1.7 +/- 0.6, and 1.5 +/- 0.5 in Child-Pugh classes A, B, and C, respectively (differences not statistically significant). Adenosine induced changes in these parameters were more marked in Child-Pugh class A (68 +/ 15 cm/s, 1246 +/- 486 mL/min, and -1.14 +/- 0.5) than in class C (45 +/- 23, P < 0.05; 704 +/- 492, P = 0.02; and -0.58 +/- 0.38, P < 0.05). Using analysis of variance, cardiac index, systemic vascular resistance, and ascites, but not Child Pugh class, were related to baseline values and adenosine-induced changes. CONCLUSIONS: Adenosine is a potent dilator of the hepatic artery in humans. The data suggest that hepatic arterial blood flow and adenosine-dependent flow reserve in patients with cirrhosis are under systemic hemodynamic or neurohormonal control. PMID- 10092314 TI - Comparative effects of oxygen supplementation on theophylline and acetaminophen clearance in human cirrhosis. AB - BACKGROUND & AIMS: Sinusoidal capillarization in cirrhosis may impair the transfer of oxygen into hepatocytes; this may contribute to impaired oxidative drug metabolism. The aim of this study was to test this hypothesis by comparing the effects of oxygen supplementation in cirrhotic patients on the clearance of theophylline, which is dependent on hepatic oxidative metabolism, with its effect on the clearance of acetaminophen, which is reliant on hepatic conjugation reactions. METHODS: Ten cirrhotic patients awaiting liver transplant and 5 control subjects were studied. Oral acetaminophen (1000 mg) and intravenous theophylline (3 mg/kg) were administered simultaneously on two separate occasions, 7 days apart. Subjects were randomized to breathe either room air or oxygen via face mask at 12 L/min for 9 hours of blood sampling. RESULTS: Theophylline and acetaminophen clearances were significantly reduced by a mean of 54% and 50%, respectively, in cirrhotic patients compared with controls. Oxygen supplementation improved plasma theophylline clearance in cirrhotic patients by a mean of 34% (P = 0. 001), whereas acetaminophen clearance remained unchanged. CONCLUSIONS: These findings indicate that, in cirrhosis, impaired hepatocyte oxygenation contributes to reduced oxidative drug metabolism and that oxidative drug metabolism can be improved by oxygen supplementation. PMID- 10092315 TI - Involvement of p38MAPK in the regulation of proteolysis by liver cell hydration. AB - BACKGROUND & AIMS: Liver cell hydration is a major determinant of proteolysis control; however, the underlying mechanisms are unknown. METHODS: The role of mitogen-activated protein kinases for proteolysis control was studied in perfused rat liver. RESULTS: Hyposmolarity led to a rapid activation of Erk-2 and p38(MAPK), but not of c-Jun-N-terminal kinase 1. Likewise, isosmotic cell swelling induced by insulin, ethanol, or glutamine/glycine activated p38(MAPK). Inhibition of hyposmotic Erk activation by pertussis or cholera toxin, erbstatin, or genistein had no effect on the swelling-induced inhibition of proteolysis. Likewise, wortmannin, rapamycin, and okadaic acid were ineffective, but proteolysis recovery from hyposmotic inhibition was okadaic acid sensitive. SB203580, an inhibitor of p38(MAPK), abolished both the antiproteolytic effect of hyposmotic cell swelling and the hyposmolarity-induced inhibition of autophagic vacuole formation. Also, the antiproteolytic effect of isotonic cell swelling induced by ethanol, glutamine/glycine, or insulin was abolished by SB203580, but not the swelling potency of these agents. SB203580 had no effect on the cell hydration-independent control of proteolysis exerted by NH4Cl, asparagine, or phenylalanine. CONCLUSIONS: The data suggest an important role of p38(MAPK) in the regulation of autophagic proteolysis by cell volume in liver. PMID- 10092316 TI - A recombinant bovine gallbladder mucin polypeptide binds biliary lipids and accelerates cholesterol crystal appearance time. AB - BACKGROUND & AIMS: Mucin has a central role in the pathogenesis of cholesterol gallstones, in part because of its ability to bind biliary lipids and accelerate cholesterol crystal appearance time. Previous studies have localized these properties to nonglycosylated mucin domains, and we have recently shown that these domains contain a series of 127-amino acid, cysteine-rich repeats. The aim of this study was to express a recombinant mucin polypeptide containing these repeats and investigate its lipid-binding and pronucleating properties. METHODS: A recombinant mucin polypeptide was expressed as a glutathione S-transferase fusion protein in Escherichia coli, purified by affinity chromatography, and compared with native bovine gallbladder mucin in lipid-binding and cholesterol crystal appearance time assays. RESULTS: The recombinant mucin polypeptide bound a hydrophobic fluorescent probe and cholesterol in a concentration-dependent manner. It accelerated the appearance of cholesterol crystals from lithogenic model bile, an effect that was both time and concentration dependent. CONCLUSIONS: The cysteine-rich repeats in the recombinant mucin polypeptide correspond to the protease-sensitive hydrophobic domains identified in earlier biochemical studies. Further delineation of the lipid-binding site(s) in these repeats will provide new insights into the mechanism of cholesterol crystal nucleation and stone growth. PMID- 10092317 TI - Involvement of Rab4 in regulated exocytosis of rat pancreatic acini. AB - BACKGROUND & AIMS: Rab4, a Ras-related small guanosine triphosphate (GTP)-binding protein, has been suggested to participate in exocytosis. The function of Rab4 in regulated exocytosis of pancreatic acini was examined in this study. METHODS: Subcellular localization of Rab4 was determined by Western blotting and immunohistochemistry. The Rab4 function in regulated exocytosis was examined by introducing Rab4 hypervariable carboxy-terminal domain peptide (Rab4 peptide) and anti-Rab4 antibody into streptolysin O-permeabilized acini. The regulation of Rab4 by cholecystokinin (CCK) and 12-O-tetradecanoyl-phorbol 13-acetate (TPA) was investigated by examining their effects on [32P]GTP binding rate into the Rab4 immunoprecipitates. The participation of protein kinase C in the Rab4 regulation by CCK was confirmed by calphostin C pretreatment of acini. RESULTS: Rab4 was localized on zymogen granule membranes. Both Rab4 peptide and anti-Rab4 antibody enhanced calcium-stimulated amylase release from streptolysin O-permeabilized acini, suggesting the inhibitory role of Rab4 in exocytosis. CCK and TPA increased GTP binding to Rab4. Calphostin C attenuated the stimulatory effect of CCK on GTP binding to Rab4. CONCLUSIONS: Rab4 negatively modulates regulated exocytosis of pancreatic acini and is controlled by CCK through a protein kinase C pathway. PMID- 10092318 TI - Evolution of acute cytomegalovirus gastritis to chronic gastrointestinal dysmotility in a nonimmunocompromised adult. AB - A 30-year-old nonimmunocompromised woman developed chronic gastrointestinal dysmotility as a consequence of acute cytomegalovirus infection. The acute nature of the infection was documented by high immunoglobulin M antibody titer to cytomegalovirus (CMV); the chronicity of the infection was shown by persistence of CMV in biopsy specimens of her gastrointestinal tract over a 21/2-year period. Gastrointestinal dysmotility was confirmed by delayed emptying on gastric nuclear scintigraphy, by retrograde propagation of migrating myoelectric complexes on small intestinal manometry, and by presence of tachygastria on cutaneous electrogastrography. The patient's nausea, vomiting, abdominal pain, and early satiety resolved after a short course of treatment with leuprolide acetate but returned after medication was discontinued. Her symptoms persisted despite clearance of CMV from the gastrointestinal tract after a course of treatment with ganciclovir. These observations show that acute CMV infection can cause gastrointestinal dysmotility in nonimmunocompromised individuals and that the disturbance in gastrointestinal motor function may persist for years after viral infection of the gastrointestinal tract has been eradicated. PMID- 10092319 TI - Mitochondrial neurogastrointestinal encephalomyopathy: manometric and diagnostic features. PMID- 10092320 TI - Emerging roles of purinergic signaling in gastrointestinal epithelial secretion and hepatobiliary function. PMID- 10092321 TI - Pseudo-obstruction: current approaches. PMID- 10092322 TI - Early virus infections and inflammatory bowel disease: back to the drawing board? PMID- 10092323 TI - Working towards a Helicobacter pylori vaccine. PMID- 10092324 TI - Less degradation, more shock, please. PMID- 10092325 TI - Sphincter of Oddi dysfunction type III: another manifestation of visceral hyperalgesia? PMID- 10092326 TI - Is antibody testing for inflammatory bowel disease clinically useful? PMID- 10092327 TI - Chemoprevention of colon cancer: have you had your multivitamin today? PMID- 10092328 TI - Taking control of fecal incontinence: early results of an artificial sphincter device. PMID- 10092329 TI - New insights into the pathogenesis of rumination: what's coming up next. PMID- 10092330 TI - Omeprazole test and 24-hour esophageal pH monitoring in diagnosing GERD. PMID- 10092331 TI - Postsurgical recurrence in Crohn's disease. PMID- 10092332 TI - It's time to bring the best and brightest back to gastroenterology. PMID- 10092333 TI - Glutathione S-transferase as a major autoantigen in anti-SLA-positive autoimmune hepatitis. PMID- 10092334 TI - Helicobacter sp. are not detectable in bile from German patients with biliary disease. PMID- 10092335 TI - Octreotide for therapy of chylous ascites in yellow nail syndrome. PMID- 10092336 TI - AIDS and mental health -- part II. PMID- 10092337 TI - Social ties and health. PMID- 10092338 TI - The psychiatric cost of immigration. PMID- 10092339 TI - Child-rearing and behavior, East and West. PMID- 10092340 TI - What is the role of glutamate in schizophrenia? PMID- 10092341 TI - Applicants for sex change. PMID- 10092342 TI - Predicting suicides and other deaths. PMID- 10092343 TI - Effect of sentence length on the production of linguistic stress by left- and right-hemisphere-damaged patients. AB - An acoustical/perceptual study of phonemic stress (e.g., HOTdog vs. hot DOG) was conducted to evaluate the effect of sentence length on stress production after brain damage. Productions of phonemic stress pairs were elicited in sentence contexts of increasing length from eight left-hemisphere-damaged nonfluent (LHD NFL), fluent LHD-FL), right-hemisphere-damaged (RHD), and normal speakers (n = 32). Tape recordings of subjects' productions were presented to naive listeners for perceptual identification of stress placement. Acoustic analysis focused on fundamental frequency, duration, and intensity of the initial and final syllables as well as pause duration between syllables. Perceptual tests indicated that regardless of sentence length, all brain-damaged groups exhibited an impairment in the production of linguistic stress when compared to normals. The LHD-NFL group experienced the greatest difficulty in signaling stress contrasts, followed in order by the LHD-FL and RHD groups. In medium-length sentences, the LHD-FL group's performance was degraded by comparison to short-length sentences. Acoustic analysis showed that pause duration was the strongest predictor of phonemic stress for all groups. Acoustic profiles of the RHD group were similar qualitatively to those of normals, but differed quantitatively in terms of magnitude of effect associated with shifts in stress patterns. Findings are brought to bear on the nature of the stress production deficit after unilateral brain damage, the role of the right hemisphere in linguistic prosody, and the concept of "subtle phonetic deficit" in fluent aphasia. PMID- 10092344 TI - Phonemic vowel length contrasts in cerebellar disorders. AB - Apraxia of speech and Broca's aphasia both affect voice onset time (VOT) whereas phonemic vowel length distinctions seem to be preserved. Assuming a close cooperation of anterior perisylvian language zones and the cerebellum with respect to speech timing, a similar profile of segment durations must be expected in ataxic dysarthria. In order to test this hypothesis, patients with cerebellar atrophy or cerebellar ischemia were asked to produce sentence utterances including either one of the German lexial items "Rate" (/ra:t(h)e/, 'installment'), "Ratte" (/rat(h)e/, 'rat'), "Gram" (/gra:m/, 'grief'), "Gramm" (/gram/, 'gramm'), "Taten" (/t(h)atn/, 'actions'), or "Daten" (/datn/, 'data'). At the acoustic signal, the duration of the target vowels /a/ and /a:/ as well as the VOT of the word-initial alveolar stops /d/ and /t/ were determined. In addition, a master tape comprising the target words from patients and controls in randomized order was played to three listeners for perceptual evaluation. In accordance with a previous study, first, the cerebellar subjects presented with a reduced categorical separation of the VOT of voiced and unvoiced stop consonants. Second, vowel length distinctions were only compromised in case of the minimal pair "Gram"/"Gramm." In contrast to "Rate"/"Ratte", production of the former lexical items requires coordination of several orofacial structures. Disruption of vowel length contrasts would, thus, depend upon the complexity of the underlying articulatory pattern. PMID- 10092345 TI - Individual differences in the hemispheric specialization of dual route variables. AB - The dual route model suggests that reading of letter strings can occur through both a lexical and a nonlexical route. Hemispheric specialization of these routes has also been posited, suggesting that the left hemisphere has both lexical and nonlexical routes while the right hemisphere has only a lexical route. However, some recent data conflict with this hemispheric dual route model, suggesting that both hemispheres may have access to both routes. The purpose of the present study was to investigate individual differences in the hemispheric specialization of these routes and to determine whether these group differences in their specialization might explain conflicts in the literature. The effect of four individual difference factors was explored: handedness, biological sex, menstrual stage (i.e., fluctuations in estrogen), and self-rated degree of masculinity (i.e., sexual attribution). We looked at the interaction of these individual differences with the following dual route variables: (i) string length, (ii) word frequency, (iii) regularity of grapheme-phoneme correspondences of words, and (iv) the interaction of frequency and regularity using a bilateral lexical decision task. We observed that sex, menstrual stage, and masculinity each affected hemispheric specialization of the dual route variables, but did so in different ways. We posit that both hemispheres have orthographical (lexical) access as well as phonological (nonlexical) access to words. Further, we suggest that the presence of phonological processing in the right hemisphere depends on available resources and the strategies used, which are subject to individual differences. PMID- 10092346 TI - The critical role of group studies in neuropsychology: comprehension regularities in Broca's aphasia. AB - We reexamine the empirical record of the comprehension abilities of Broca's aphasic patients. We establish clear, commonly accepted, selection criteria and obtain a pool of results. We then subject these results to a detailed statistical analysis and show that these patients comprehend certain canonical sentences (actives, subject relatives, and clefts with agentive predicates) at above-chance levels, whereas comprehension of sentences that contain deviations from canonicity (passives, object-gap relatives, and clefts) is distinct and is at chance. That the latter is the case, and patients indeed guess at such structures, we show by comparing the distribution of individual results in passive comprehension to that of a model for such guessing-an analogous series of tosses of an unbiased coin. The two distributions are virtually identical. We conclude that the group's performance is stable, and well-delineated, despite intersubject variation whose source is now identified. This means that certain comprehension tests may not always be used for the diagnosis of individual patients, but they do characterize the group. It also means that group studies are not just a valid option in neuropsychology; they are a must, since demonstrations like ours indiciate very clearly that single-case studies may be misleading. As we show, the findings from any one patient, without the context of a group, may give a distorted picture of the pathological reality. Our conclusions thus promote studies of groups of brain-damaged patients as a central tool for the investigation of brain/behavior relations. PMID- 10092347 TI - Stabilization of Metal Nanoparticles in Aqueous Medium by Polyethyleneoxide Polyethyleneimine Block Copolymers. AB - The branched polyethyleneoxide-polyethyleneimine (PEO)n-b-PEI block copolymers are synthesized and fractionated. The (PEO)n-b-PEI block copolymers are found to be able to form micelles in aqueous solution after addition of certain metal compounds (H2PtCl6, Na2PtCl4, RhCl3). The degree of copolymer polydispersity seems to play an important role in metal nanoparticle stabilization. Comparison of diblock and branched copolymers shows that as a rule branched block copolymers are the better stabilizing systems for metal nanoparticles. In the case of micelle formation due to interaction with metal compounds, fine control on colloid morphology can be provided, which leads to very uniform particles. Variation of different parameters (such as concentration, pH, type of reducing agent) affects the nanoparticle morphology as well. Copyright 1999 Academic Press. PMID- 10092348 TI - Some Thermodynamic Data on Copper-Chitin and Copper-Chitosan Biopolymer Interactions. AB - Chitin and chitosan are good removers of cations from aqueous solution and wastewater. The interactive effect of cation with both biopolymers in aqueous medium was studied by the batch method at 298 +/- 1 K. The results were fitted to the modified Langmuir equation. The same adsorption was followed by calorimetric titration. In this process, 50.0 mg of each polymer was suspended in 19.0 cm3 of bidistilled water at 298.15 +/- 0.02 K, maintained under mechanical turbine stirring. The titration was performed by adding increments of 10 uL of 0.10 mol dm-3 Cu(NO3)2 aqueous solution to the system. The resulting isotherm was also adjusted to a modified Langmuir equation. From the thermal effects K and DeltaH values were determined, enabling the calculation of DeltaG and DeltaS for the interaction of copper cations with chitin and chitosan, giving the enthalpic values of -19.85 +/- 0.34 and -41.27 +/- 1.57 kJ mol-1, respectively. The spontaneity of this interaction is shown from DeltaG values of -35.9 +/- 0.1 and 36.8 +/- 0.1 kJ mol-1, which are followed by DeltaS values of +54 and of -15 J mol-1 K-1, respectively. The complexation is probably associated with the lack of order of the chitin polymeric chain or with the freedom of water molecules initially bonded to cations. The copper ion is coordinated to the pendant groups of the polymeric chain to form stable complexes. Copyright 1999 Academic Press. PMID- 10092349 TI - Preparation and Characterization of Carbonated Barium Hydroxyapatites. AB - Carbonated barium hydroxyapatite (Ba10(PO4)6(OH)2-2x(CO3)x, X = 0.30-0.57, BaHAP) particles with different Ba/P molar ratios were prepared by a wet method. CO2-3 ions were incorporated into OH- sites of a BaHAP lattice during the preparation at high solution pH. The obtained BaHAP particles were well crystallized and showed a high thermostability. On elevating the mixing temperature of H3PO4 and Ba(OH)2 solutions, the mean particle size of BaHAP particles decreased and their specific surface area increased. The amount of CO2 adsorbed irreversibly on BaHAP particles increased with an increase of their Ba/P molar ratio. Copyright 1999 Academic Press. PMID- 10092350 TI - Surface Complexation Modeling of Yb(III) and Cs(I) Sorption on Silica. AB - A surface complexation model is used to describe sorption of ytterbium and cesium on the silica surface. The constant capacitance model gives the description of the solid-solution interface chosen for this work. The first step in the modeling consists of extracting the surface acidity constants. The result is: The second step consists of the extraction of surface complexation constants for both ytterbium and cesium. The sorption of the cations is represented as follows: for the ytterbium sorption, for the cesium sorption, In the case of cesium, the sorption of sodium is competitive and has to be considered: Copyright 1999 Academic Press. PMID- 10092351 TI - Porous Silica Particles Prepared from Silicon Tetrachloride Using Ultrasonic Spray Method. AB - Silica particles having the median diameter of 1 to 3 um were prepared from silicon tetrachloride vapor by a reaction with water droplets using the ultrasonic spray method. The particle sizes of silicas were controlled by changing the composition of silicon tetrachloride and water. These silica particles had microporous structures from nitrogen and water adsorption measurements. The microporous and mesoporous particles were prepared from the reaction of water droplets including sodium and potassium carbonates with silicon tetrachloride vapor. Copyright 1999 Academic Press. PMID- 10092352 TI - An Experimental Study on the Relationship between the Physical Properties of CTAB/Hexanol/Water Reverse Micelles and ZrO2-Y2O3 Nanoparticles Prepared. AB - Based on the studies of their physical properties such as aqueous solution uptake, electric conductivity, and microstructure, CTAB/hexanol/water reverse micelles (CTAB, cetyltrimethyl ammonium bromide) were used to prepare ZrO2-Y2O3 nanoparticles. The relationship between the micelle microstructure and size, morphology, and aggregate properties of particles prepared was also investigated. It has been found that with high CTAB concentration ([CTAB] > 0.8 mol/l), the reverse micelles can solubilize a sufficient amount of aqueous solution with high metallic ion concentration ( approximately 1.0 mol/L), while the microstructure of the reverse micelles keeps unchanged. The most important factor affecting the size and shape of reverse micelles was found to be the water content w0 (w0, molar ratio of water to surfactant used). When both the CTAB concentration and the w0 values are low, the diameters of reverse micelles are below 20 nm, and the ZrO2-Y2O3 particles prepared are also very small. However, the powders obtained were found to form a lot of aggregates after drying and calcination. High CTAB concentration, high w0 value, and high metallic ion concentration in the aqueous phase for high powder productivity were found to be the suitable compositions of reverse micelles for preparing high-quality ZrO2-Y2O3 nanoparticles. Under these conditions, the reverse micelles are still spherical in shape even the reverse micellar system is nearly saturated with aqueous solutions. These reverse micelles were found to have a diameter of between 60 and 150 nm and the ZrO2-Y2O3 particles prepared therefrom range from 30 to 70 nm with spherical shape and not easy to form aggregates. Copyright 1999 Academic Press. PMID- 10092353 TI - Comparing Electrostatic and Nonelectrostatic Surface Complexation Modeling of the Sorption of Lanthanum on Hematite. AB - The sorption of lanthanum on hematite is studied in experiments for three different surface loading ratios. The experiments consist of following the evolution of the amount of cation sorbed on surface with pH, and as well as measuring the number of protons released during sorption for the three different surface loading conditions. The sorption edge shifts to high pH, and the number of protons released during sorption increases, when the surface loading increases. Three different surface complexation models (SCMs), with three different electrostatic descriptions of the interface, are used to fit the experimental sorption curves. The stoichiometries proposed by the models are compared with the measurement of the protons released. Descriptions of the interface are given by the diffuse layer model (DLM), the constant capacitance model (CCM), and a nonelectrostatic model (NEM). If the fit quality is comparable for the three models, only the electrostatic models are able to account for the dependence of stoichiometry on surface loading. On the other hand, the NEM gives the same stoichiometry, with the same number of protons released, when surface loading conditions change. This is not in agreement with experiment observations. The stoichiometries, confirmed by an independent experiment, and the value of the surface constants obtained are the same, error aside, for DLM and CCM for the three different surface loading ratios. The NEM gives different values, even if the fit quality is comparable. Copyright 1999 Academic Press. PMID- 10092354 TI - Colloidal Fouling of Ultrafiltration Membranes: Impact of Aggregate Structure and Size. AB - A close coupling between the structure and size of hematite flocs formed in suspension and the permeability of the cake that accumulates on ultrafiltration membranes is observed. Specific resistances of cakes formed from flocs generated under diffusion-limited aggregation conditions are at least an order of magnitude lower than those of cakes formed from flocs generated under reaction-limited aggregation conditions. Similar effects are observed whether the aggregation regime is controlled by salt concentration, pH, or added organic anions. This dramatic difference in cake resistance is considered to arise from the size and fractal properties of the hematite assemblages. The ease of fluid flow through these assemblages will be influenced both by the fractal dimension of the aggregates and by their size relative to primary particle size (since, for fractal aggregates, porosity increases as the size of the aggregate increases). The size and strength of aggregates are also important determinants of the relative effects of permeation drag, shear-induced diffusion, and inertial lift and result, in the studies reported here, in relatively similar rates of particle deposition for both rapidly and slowly formed aggregates. The results presented here suggest that control of cake permeability (and mass) via control of aggregate size and structure is an area with scope for further development though the nature and extent of compaction effects in modifying the fractal properties of aggregates generated in suspension requires attention. Copyright 1999 Academic Press. PMID- 10092355 TI - Drug-Cyclodextrin Association Constants Determined by Surface Tension and Surface Pressure Measurements. AB - The complexation reaction between the amphiphilic peptide antibiotic polymyxin B and naturally occurring cyclodextrins, used as potential drug carriers, was quantitatively evaluated from surface tension measurements at various drug concentrations. The association constant, Ka, of polymyxin B:beta-cyclodextrin inclusion complex formation of 1:1 stoichiometry was determined from the change in the drug interfacial activity upon the addition of beta-cyclodextrin at the excess solution concentration (10(-3) M). The obtained Ka value is discussed in terms of molecular matching of the host cyclodextrin cavity and the guest drug molecule. Copyright 1999 Academic Press. PMID- 10092356 TI - Drug-Cyclodextrin Association Constants Determined by Surface Tension and Surface Pressure Measurements. AB - The compression of water-insoluble drug monolayers spread on the aqueous subphase containing cyclodextrins (CD) led to a shift of surface pressure (pi)-area (A) isotherms toward smaller molecular areas with respect to the pi-A isotherms on the pure water subphase. The displacement of the compression isotherm obtained for the retinol spread on the beta-CD containing aqueous subphase was used to quantify the depletion process and to determine the drug-CD association constants. The proposed method appeared to be sensitive enough to account for extremely low amounts of sequestered drug molecules. The obtained values of the association constants Ka ranged from about 1.4.10(-2) to 36 m2/mol. The magnitudes of these constants are discussed in terms of drug bioavailability and of the stoichiometry of retinol-beta-cyclodextrin inclusion complex which was shown to have a 1:1 correspondence. Copyright 1999 Academic Press. PMID- 10092357 TI - Microstructure and Viscosity of Aggregating Colloids under Strong Shearing Force. AB - Disaggregation under strong shearing force is simulated for an aggregating colloid based on a sticky particle model which can describe the disaggregating and aggregating kinetics, the deformation, and the rupture of clusters with a minimum number of parameters. For a 2-dimensional system, the viscosity and coordination number of the model colloid are calculated at each time step, and the changes of microstructure with shear flow are observed directly by displaying the configuration of particles onto a monitor. The viscosity depends on both area fraction and shear rate, but coordination number depends only on shear rate. Furthermore, the viscosity and coordination number at steady state are independent of the initial state of particles, which indicates that the disaggregation and aggregation are mutually reversible. Copyright 1999 Academic Press. PMID- 10092358 TI - Membrane Potential of Composite Bipolar Membrane in Ethanol-Water Solutions: The Role of the Membrane Interface. AB - The membrane potential across a composite bipolar membrane (CBM) composed of a cation-exchange membrane with an anion-exchange membrane is theoretically and experimentally analyzed for LiCl ethanol-water solutions. The theoretical approach is based on an extension of the Donnan equilibrium and the Nernst-Planck equation of monopolar charged membranes for the case of two ion-exchange layers by considering the effect of electrolyte ion pairing in the external solution. The experimental results show that the effective membrane charge densities of the two ion-exchange layers will become smaller than those which are separately estimated for each layer. We have introduced a contact factor, zeta, into the theoretical approach to clarify this phenomenon in this study, and the theoretical predictions were in good agreement with the experimental data. The membrane potential measurements show that CBM has the characteristics of a bipolar membrane and can significantly contribute to a better electrochemical characterization of the CBMs. Copyright 1999 Academic Press. PMID- 10092359 TI - Adsorption of Dimers at Surfaces. AB - A model for the adsorption of dimers at a surface is presented. The model is based on a generalization of the Ono-Kondo lattice theory. The densities of dimer molecules that are parallel to the surface, x parallel, and perpendicular to the surface, x perpendicular, are calculated. It is shown that symmetric dimer molecules adsorb preferentially parallel to the surface at all densities. The model also predicts that the Gibbs adsorption is negative for small interaction energies between dimers and the surface. Copyright 1999 Academic Press. PMID- 10092360 TI - A Study on the Surface Silanol Groups Developed by Hydrothermal and Acid Treatment of Faujasite Type Zeolites. AB - The surface silanol groups on faujasite type zeolites, which were formed by hydrothermal and acid treatments and considered to be lattice defect, were characterized. IR measurements of silanol groups were made in situ and thermogravimetic analysis was conducted under vacuum so as to quantify their content. It was thus possible to quantify separately the concentration of silanol groups forming hydroxy nests and the concentration of terminal silanol groups present on the secondary pores and crystal external surfaces. As the evacuation temperature increased, silanol groups forming hydroxy nests were found to decrease as a result of dehydroxylation condensation. The number of terminal silanol groups on the secondary pores and external surface remained virtually unchanged. The concentration of terminal silanol groups agreed well with the value calculated according to the proposed destruction model of the zeolite framework. This justified the model that there remained the double 6-ring structure on the secondary pore surfaces after the sodalite cage was collapsed as a result of the treatments. The effect of silanol groups forming hydroxy nests on the zeolite surface polarity was examined by measuring immersional heats in various solvents. It turned out that the extremely localized silanol groups forming hydroxy nests in the framework were linked via hydrogen bond to each other and showed nonpolar behavior. Copyright 1999 Academic Press. PMID- 10092361 TI - Homogeneous Precipitation of Uniform alpha-Fe2O3 Particles from Iron Salts Solutions in the Presence of Urea. AB - Uniform alpha-Fe2O3 particles within the nanometer range (100-300 nm) have been obtained by precipitation of iron (III) perchlorate in the presence of urea. Different morphology, from spheres to ellipsoidal particles with axial ratio up to approximately 10, was obtained by adding to the initial solution increasing amounts of phosphate anions up to 7 x 10(-3) M. The main targets of this work are the reduction in particle size and precipitation time and the increase of the particles axial ratio, keeping a narrow particle size distribution, in comparison to other methods previously developed to obtain homogenous alpha-Fe2O3 particles. A detailed analysis of the reaction products and a systematic study of the influence of the different precipitation conditions on the characteristics of the resulting particles have been carried out. Finally, some information on the formation mechanism of the ellipsoidal hematite particles in the iron (III) salt urea-phosphate system is also given. Copyright 1999 Academic Press. PMID- 10092362 TI - Surface and Texture Characterization of Alumina-Supported Manganese Oxide Catalysts and Their Formate Precursors. AB - Alumina-supported manganese oxide catalysts as well as the parent formates were characterized my means of FTIR spectroscopy and nitrogen physisorption. Two different manganese formate solutions are used for the impregnation of alumina (4.8 and 8.0 mass%). The infrared bands in the high frequency region (OH stretches) indicate that the manganese complexes formed in the solutions are deposited gradually at the basic and acid surface OH groups. Part of the basic OH groups are neutralized with HCOOH (pH 5-5.2). The neutral OH groups remain unchanged during the impregnation. The nitrogen physisorption shows that the initial mesoporous character of the gamma-Al2O3 structure does not change during impregnation. The rFHH values which characterized the adsorbent-adsorbate interaction forces depend on the concentration of the impregnating solutions, i.e., on the type of the manganese complexes deposited on alumina surfaces. On the basis of the analysis of the pore size distribution curves the distribution of the supported formate and oxide phases is discussed. Copyright 1999 Academic Press. PMID- 10092363 TI - Small-Angle Scattering and Electron Microscopy Investigation of Nanotubules Made from a Perfluoroalkylated Glucophospholipid. AB - Anionic glucophospholipids were recently reported as a new family of tubule forming lipids. We report here investigations on the structure of nanotubules made from a glucophospholipid with a mixed fluorocarbon-hydrocarbon hydrophobe, using freeze fracture and cryo-transmission electron microscopy (TEM) and X-ray and neutron small angle scattering (SAXS, SANS). The hollow and regularly shaped tubules are very thin: they have an external radius of 140 A and an internal radius of 35 A on the average. Their 105 A-thick wall appears to consist in three bilayers in which the glucophospholipid molecules are probably in a tilted and/or interdigitated configuration. Upon heating these nanotubes convert reversibly into vesicles; transformation is complete at 60 degrees C. Copyright 1999 Academic Press. PMID- 10092364 TI - Electroosmotic Flows Created by Surface Defects in Capillary Electrophoresis. AB - We compute the electroosmotic flow in nonuniformly charged planar and cylindrical capillaries for the limit of low-Reynolds-number flows and thin Debye layers. Analytical formulae for the velocity field are provided for the general case of an arbitrary surface inhomogeneity but we also focus on various specific defect geometries. Many important features can be obtained from the simple lubrication approximation. The pressure jump induced by the presence of such surface defects is calculated and the possible occurrence of recirculating flows is discussed, as are effects of the flow perturbations on dispersion in capillary electrophoresis. Copyright 1999 Academic Press. PMID- 10092365 TI - alpha-Alumina-H2O Interface Analysis by Electroacoustic Measurements. AB - In this work an electroacoustic technique was used to characterize the dispersing behavior of alumina in water with or without the addition of an anionic polyelectrolyte as dispersant. Electroacoustic measurements enabled the zeta potential and particle size distribution to be noted; additionally, the in situ measure of the conductivity allows the ionic strength to be simultaneously determined. In this way the pH or dispersant contribution to powder stabilization has been evaluated. With this technique important colloidal parameters such as the isoelectric point and particle size distribution at various solution or powder conditions (alumina vol%, pH, dispersant wt%, milling time) can be measured and the minimum amount of dispersant (Duramax D3021) required to cover completely the powder can be easily estimated. Copyright 1999 Academic Press. PMID- 10092366 TI - Effects of Carboxylic Acids on Calcite Formation in the Presence of Mg2+ Ions. AB - The effects of seven carboxylic acids on calcite formation in the presence of Mg2+ ions, whose molar concentration ratio Mg2+/Ca2+ = 0.5 exclusively induced aragonite precipitation in the absence of carboxylic acids, were studied using a double diffusion technique. The presence of carboxylic acids, acrylic acid, maleic acid, tartaric acid, malonic acid, malic acid, succinic acid, and citric acid in the gel medium favored the formation of magnesian calcite relative to the amount of the additives. Induction time and the positions of the first precipitation were measured to analyze the behavior of crystallization based on the equivalency rule. The formation of magnesian calcite was also studied with the help of Avrami's equation (solid-state model for transformation). The results of applying this equation suggested that aragonite transformed into calcite through a solid-to-solid process. The formation of magnesian calcite was interpreted as the following process: aragonite nuclei, formed owing to Mg2+ ions at the initial stage of CaCO3 crystallization, transformed into calcite nuclei through a solid-to-solid process while their growth was inhibited by the adsorption of carboxylic acids. The magnesian calcite crystals grew on crystal seeds of calcite formed from aragonite nuclei. Copyright 1999 Academic Press. PMID- 10092367 TI - Interfacial Wave Motions Due to Marangoni Instability. AB - In annular containers, traveling periodic wavetrains are generated in liquid layers due to the surface adsorption and subsequent liquid absorption of a miscible surface-active substance. First, localized nucleation of shock-wave-like disturbances are generated by the Marangoni effect. Then, these disturbances yield to surface-wave trains with three-dimensional features which travel through the annular container or to stationary source-and-sink states. To illustrate these phenomena we provide shadowgraph pictures of the waves, space-time diagrams showing the wave evolution and wave modulation, mean frequency of wavetrains as a function of the wave mode, surface deformation, peak-to-trough wave amplitudes, wave sources and sinks, and the time evolution of the estimated Marangoni number. Copyright 1999 Academic Press. PMID- 10092368 TI - Interactions in Calcium Oxalate Hydrate/Surfactant Systems. AB - Phase transformation of calcium oxalate dihydrate (COD) into the thermodynamically stable monohydrate (COM) in anionic (sodium dodecyl sulfate (SDS)) and cationic (dodecylammonium chloride) surfactant solutions has been studied. Both surfactants inhibit, but do not stop transformation from COD to COM due to their preferential adsorption at different crystal faces. SDS acts as a stronger transformation inhibitor. The general shape of adsorption isotherms of both surfactants at the solid/liquid interface is of two-plateau-type, but differences in the adsorption behavior exist. They originate from different ionic and molecular structures of crystal surfaces and interactions between surfactant headgroups and solid surface. Copyright 1999 Academic Press. PMID- 10092369 TI - Electrorheological Effects in Lecithin Organogels with Water and Glycerol. AB - The effect of an external electric field on ternary mixtures consisting of lecithin, n-decane, and small amounts of polar additives (water or glycerol) has been studied by oscillating rheology, polarizing microscopy, and electric birefringence. It is shown that an electric field that is applied induces a so called electrorheological (ER) effect, i.e., an increase in the viscosity and dynamic shear moduli of all the examined mixtures. The ER effect is absent in solutions of nonoverlapping micelles. The electric field causes the formation of fiber-like structures in the interelectrode gap. The ER effect becomes evident at a critical field of about 40 and 100 V/mm for water- and glycerol-containing organogels, respectively. In the latter case, a region of the reproducible and stable ER effect is extended up to 1700 V/mm, which is 3-4 times greater than that observed in the jelly-like phases with water. The buildup, as followed from birefringent measurements, includes fast and slow processes. Those correspond to both the local motions of parts of micellar chains and the restructuring of the whole network under the action of an external electric field. The ER response depends on the molar ratio of the polar additives to lecithin. Diagrams describing the behavior of ternary mixtures under the electric field have been constructed. They differ for water- and glycerol-containing organogels. The dependence of the stable ER effects on the molar ratio of glycerol to lecithin has a maximum in the vicinity of the phase separation of the homogeneous organogel, whereas for water-containing systems there is a gradual increase up to and including mixtures with the solid precipitate. A new rheological regime has been first established for solutions of polymer-like micelles. This feature is the square-root scaling of the dynamic moduli with the frequency. Such a scaling is inherent in polymers. A possible mechanism is considered, basing on the ordering of cylindrical micelles under the action of an external electric field. Copyright 1999 Academic Press. PMID- 10092370 TI - Calculation of the BET Compatible Surface Area from Any Type I Isotherms Measured below the Critical Temperature. AB - It may occur in practice that the nitrogen isotherm should be measured at 77 K only in order to determine the Brunauer-Emmett-Teller (BET) specific surface area [as(N2, 77)]. This fact has given cause for an elaborate method to calculate the value of as(N2, 77) from Type I isotherms measured on any adsorbents at any temperature. Since Type I isotherms are measured most often in practice the proposed method makes it possible to calculate the value of as(N2, 77) from isotherms of adsorptives which are the actual topics of the investigations. Thus, in these cases the determination of nitrogen isotherms at 77 K can be omitted. The proposed method is based on the Toth (T) equation and on its modified and extended forms. In these equations are present the parameters chim, chio, and t with the following physical meanings: chim and chio are integral constants originating from the Gibbs equation integrated between definite limits of pressure and coverage and t is a parameter characterizing the heterogeneity of the adsorbents. The parameters chim and chio assure the thermodynamic consistence of these relationships. It is proven that the parameters (chim)1/t and (chio)1/t depend only on the structure of adsorbents (micro-, mezoporous, or smooth surfaces). These parameters, calculated from Type I isotherms measured under the critical temperature of the adsorptives, are the bases of the calculation of the BET compatible surface areas. Copyright 1999 Academic Press. PMID- 10092371 TI - Separation of the First Adsorbed Layer from Others and Calculation of the BET Compatible Surface Area from Type II Isotherms. AB - In the previous paper it has been proven that a BET compatible specific surface area, asc(N2, 77), can be calculated from any Type I isotherm measured below the critical temperature. In this paper it is proven that the same calculation can be performed from any Type II isotherms if the isotherm has a pure monolayer domain. In order to distinguish the mono- and multilayer adsorption the relative free energy of the surface as a function of the adsorbed amount, pir(ns), and the functions psi(pr) and psi(ns) are applied, both defined by the differential expression (ns/pr)(dpr/dns). When the multilayer adsorption becomes the dominant process then the function pir(ns) has a point of inflexion and functions psi(pr) and psi(ns) have maximum values. It has been demonstrated that in most of the Type II isotherms the mono- and multilayer domains can be separated, so the monolayer component isotherm can be calculated by the T (Toth) equation. Therefore, it is possible to calculate the BET compatible specific surface area discussed in detail in the previous paper. It has also been proven that there are Type II isotherms which describe only multilayer adsorption; i.e., the functions psi(pr) and psi(ns) do not have maximum values. In these cases the Harkins-Jura equation should be applied. Copyright 1999 Academic Press. PMID- 10092372 TI - The Effect of Polymer Substrate Surface Basicity on the Adsorption of a Cationic Polyacrylamide. AB - The adsorption of a cationic polyacrylamide onto polytetrafluoroethylene, bisphenol-A based epoxy resins, and acrylate substrates was characterized with X ray photoelectron spectroscopy (XPS) and dynamic contact angle measurement in water. Surface acidity-basicity was quantified via dynamic contact angle measurement in water, ethylene glycol, and diiodomethane. The epoxy resins exhibited intermediate surface basicity and adsorbed the most polyelectrolyte, suggesting that specific substrate-adsorbate acid-base interactions govern adsorption of the cationic polyacrylamide onto surfaces of low to intermediate basicity. In general polar interactions appear to dominate the adsorption process. Advancing contact angle measurements have yielded quantitative fractional surface coverage information for polymer-on-polymer adsorption comparable to that obtained via XPS. Copyright 1999 Academic Press. PMID- 10092373 TI - Adsorptive Deformation of Organo-Substituted Laminar Silicates. AB - Deformations of organo-substituted laminar silicates (Pyzhevsk montmorillonite and synthetic fluorohectorite) upon water, hexane, and benzene vapor sorption have been studied. To solve this problem a dilatometer was used. Its main part was a line differential transformer, the core of which was connected to the sorbent by means of a rod. Any changes of the sorbent height caused a change in the core position in the transformer, which influenced the signal recorded from its secondary winding. The calibrated dilatometer was located in a liquid thermostat with a given temperature and was connected with the measurement unit (frequency meter, voltmeter, generator). Montmorillonite and synthetic fluorohectorite were modified by cetylpyridinium bromide and used in the form of tablets. As a result of the sample preparation conditions, the modified clay silicates swelled isotropically. These results were compared with the adsorption isotherms obtained gravimetrically. High sensitivity of the dilatometric method to the structural changes of the organo-substituted laminar silicates has been shown. The dilatometer used allowed the measurement of absolute deformations in the range 1 x 10(-4) to 3 mm. Copyright 1999 Academic Press. PMID- 10092374 TI - Trajectory Analysis and Collision Efficiency during Microbubble Flotation. AB - The hydrodynamic interaction between a rising bubble and a sedimenting particle during microbubble flotation is considered. The effects of attractive van der Waals forces and attractive or repulsive electrostatic forces are included. A mathematical model is presented which is used to perform a trajectory analysis and to calculate collision efficiencies between the bubble and particle. It is shown that collision efficiencies and the nature of the bubble-particle interactions are strongly dependent on the relative strengths of the van der Waals and electrostatic forces and on the lengthscales over which these forces act. It is demonstrated that optimal operating conditions can be suggested to achieve efficient microbubble flotation by correctly accounting for the interaction of van der Waals, electrostatic, and hydrodynamic forces. Copyright 1999 Academic Press. PMID- 10092375 TI - Electrical Conductivity of a Concentrated Suspension of Spherical Colloidal Particles. AB - A general expression for the electrical conductivity of a concentrated suspension of spherical colloidal particles is obtained for the case where the particle zeta potential is low and the overlapping of the electrical double layers of adjacent particles is negligible by using Kuwabara's cell model. It is shown how the conductivity of a concentrated suspension depends on the particle volume fraction, the zeta potential zeta, and the reduced particle radius kappaa (kappa = Debye-Huckel parameter and a = particle radius). It is also found that the obtained conductivity formula tends to Maxwell's formula for two different extreme cases: (i) when the particles are uncharged (zeta = 0) and (ii) when the electrical double layers around the particles are infinitesimally thin (kappaa - > infinity). That is, in the latter limiting case (kappaa --> infinity), the conductivity becomes independent of the zeta potential, just as in the case of dilute suspensions. Copyright 1999 Academic Press. PMID- 10092376 TI - Colloid Vibration Potential in a Concentrated Suspension of Spherical Colloidal Particles. AB - A relation between the dynamic electrophoretic mobility of spherical colloidal particles in a concentrated suspension and the colloid vibration potential (CVP) generated in the suspension by a sound wave is obtained from the analogy with the corresponding Onsager relation between electrophoretic mobility and sedimentation potential in concentrated suspensions previously derived on the basis of Kuwabara's cell model. The obtained expression for CVP is applicable to the case where the particle zeta potential is low, the particle relative permittivity is very small, and the overlapping of the electrical double layers of adjacent particles is negligible. It is found that CVP shows much stronger dependence on the particle volume fraction φ than predicted from the φ dependence of the dynamic electrophoretic mobility. It is also suggested that the same relation holds between the electrokinetic sonic amplitude of a concentrated suspension of spherical colloidal particles and the dynamic electrophoretic mobility. Copyright 1999 Academic Press. PMID- 10092377 TI - 1H NMR Self-Diffusion Study of Morphology and Structure of Polyvinyl Alcohol Cryogels. AB - The multicomponent self-diffusion of the polyvinyl alcohol (PVA) cryogels prepared by a freezing-thawing treatment of aqueous and water-DMSO solutions of PVA has been studied with the NMR FT-PGSE method. The temperature dependencies of the self-diffusion coefficients, Ds, for the PVA chains have a maximum at 45 degrees C due to the syneresis of cryogels. They are quite different from the monotonous increase of Ds for the aqueous solutions of PVA. Evaluated apparent activation energies, Ea, of the self-diffusion for the PVA chains in the PVA solutions and cryogels in D2O are practically the same and equal 22-24 kJ/mol below the crucial point. The proton spin-lattice relaxation times, T1, of the PVA chain also coincide with one another for solutions and cryogels. This means that molecular packing in cryogels depends mainly on the dimensions of the ice and polymer microcrystallites formed by freezing the solution. Above the crucial point polymer compartments become firmer, and the chain mobility somewhat reduces. The strength of cryogels also increases along with growing the DMSO contents and decreases by the BSA addition. For estimation of the cryogel morphology, effects of the restricted diffusion of both the water and PVA in a q space have been taken into account. By the introduction of DMSO to cryogels the solvent filled pores become smaller, and channels become much shorter. The diameter of the PVA filaments is similar to those for all the cryogels, but the length of filaments with D2O is twice that for cryogels with a mixed solvent. Entrapment of BSA in the cryogel matrix by preparation leads to the increase of an average diameter of the water filled pores and destroys molecular packing the cryogel. Copyright 1999 Academic Press. PMID- 10092378 TI - Stability of Emulsions Containing Both Sodium Caseinate and Tween 20. AB - The creaming and rheology of oil-in-water emulsions (30 vol% n-tetradecane, pH 6.8) stabilized by a mixture of commercial sodium caseinate and the non-ionic emulsifier polyoxyethylene sorbitan monolaurate (Tween 20) has been investigated at 21 degrees C. The presence of sufficient Tween 20 to displace most of the protein from the emulsion droplet surface leads to greatly enhanced emulsion creaming (and strongly non-Newtonian rheology) which is indicative of depletion flocculation by nonadsorbed surface-active material (protein and emulsifier). In emulsions containing a constant amount of surface-active material, the replacement of a very small fraction of Tween 20 by caseinate in a stable pure Tween 20 emulsion leads to enhanced creaming for a small fraction of the droplets, and this fraction increases with increasing replacement of emulsifier by protein. This behavior is probably due to depletion flocculation, although an alternative bridging mechanism is also a possibility. The overall stability of these sets of emulsions can be represented in terms of a global stability diagram containing regions of bridging flocculation and coalescence (low content of surface-active material), stability (intermediate content), and depletion flocculation (high content). Copyright 1999 Academic Press. PMID- 10092379 TI - Synthesis of Iron Oxide Nanoparticles Used as MRI Contrast Agents: A Parametric Study. AB - Colloidal iron oxides play an important role as magnetic resonance imaging (MRI) contrast agents. The superparamagnetic particles actually used are constituted by solid cores (diameter of 5-15 nm), generally coated by a thick polysaccharidic layer (hydrodynamic radii of 30-100 nm), and formulated by direct coprecipitation of iron salts in the presence of polymeric material. To better control the synthesis, we attempted to formulate new stable uncoated superparamagnetic nanoparticles. Colloids were generated by coprecipitation of an aqueous solution of iron salts and tetramethylammonium hydroxide (TMAOH) solution. The influence of parameters such as media composition, iron media, injection fluxes, Fe and TMAOH concentrations, temperature, and oxygen on size, magnetic and magnetic resonance relaxometric properties, and colloidal stability of particles were evaluated. We have determined the relative importance of these parameters as well as the optimal conditions for obtaining uncoated stable particles with an average size of 5 nm and interesting relaxivities. The interpretation of the observed limits takes into account diffusibilities of reactants and product, feeding rates of reactants, and surface properties of nanoparticles. A model of synthesis, related to spontaneous emulsification of suspensions, is proposed. Copyright 1999 Academic Press. PMID- 10092380 TI - Dynamics and Morphology of Holes in Dewetting of Thin Films. AB - The formation and growth of holes in apolar nonslipping Newtonian thin films subjected to long-range Lifshitz-van der Waals forces are investigated based directly on numerical solutions of the thin-film equation. The nonphysical divergences of the hydrodynamic model and of the van der Waals force at the three phase contact line are removed by inclusion of the short-range Born repulsion. Three distinct regimes of the hole growth after its appearance are identified: (1) a short, unsteady phase in which the dynamic contact angle and velocity change rapidly, followed by (2) a long, quasi-steady phase with slow logarithmic changes, and finally (3) a hindered phase in which rims of the neighboring holes overlap and lead to formation of equilibrium drops. The cross section of the rim surrounding a growing hole is noncircular and asymmetric, with higher slopes near the contact line. A slight depression is created ahead of the moving rim, but the regions of the film away from the rim remain undisturbed. For very viscous (e.g., polymeric) liquids displaying small contact angles, a nonlinear regime of hole growth (radius ~ timeq, with the exponent q approximately 0.7-0.9) is obtained for realistic time scales. Copyright 1999 Academic Press. PMID- 10092381 TI - Surface Aggregation of Candida albicans on Glass in the Absence and Presence of Adhering Streptococcus gordonii in a Parallel-Plate Flow Chamber: A Surface Thermodynamical Analysis Based on Acid-Base Interactions. AB - Adhesive interactions between yeasts and bacteria are important in the maintenance of infectious mixed biofilms on natural and biomaterial surfaces in the human body. In this study, the extended DLVO (Derjaguin-Landau-Verwey Overbeek) approach has been applied to explain adhesive interactions between C. albicans ATCC 10261 and S. gordonii NCTC 7869 adhering on glass. Contact angles with different liquids and the zeta potentials of both the yeasts and bacteria were determined and their adhesive interactions were measured in a parallel-plate flow chamber.Streptococci were first allowed to adhere to the bottom glass plate of the flow chamber to different seeding densities, and subsequently deposition of yeasts was monitored with an image analysis system, yielding the degree of initial surface aggregation of the adhering yeasts and their spatial arrangement in a stationary end point. Irrespective of growth temperature, the yeast cells appeared uncharged in TNMC buffer, but yeasts grown at 37 degrees C were intrinsically more hydrophilic and had an increased electron-donating character than cells grown at 30 degrees C. All yeasts showed surface aggregation due to attractive Lifshitz-van der Waals forces. In addition, acid-base interactions between yeasts, yeasts and the glass substratum, and yeasts and the streptococci were attractive for yeasts grown at 30 degrees C, but yeasts grown at 37 degrees C only had favorable acid-base interactions with the bacteria, explaining the positive relationship between the surface coverage of the glass by streptococci and the surface aggregation of the yeasts. Copyright 1999 Academic Press. PMID- 10092382 TI - Ionic Diffusivity, Electrical Conductivity, Membrane and Thermoelectric Potentials in Colloids and Granular Porous Media: A Unified Model. AB - Ionic diffusivity, electrical conductivity, membrane and thermoelectric potentials in isotropic and homogeneous colloidal suspensions, and granular porous media saturated by a binary symmetric 1:1 electrolyte are four interrelated phenomena. The microstructure and the surface properties of the solid grains-water interface influence directly these properties. The ionic diffusivities (and the electrical conductivity, respectively) in colloids and porous media have contributions from diffusion (and electromigration, respectively) through the bulk solution occupying the pores, together with electromigration occurring at the grains-water interface in the electrical double layer. Surface diffusion in porous materials has no contribution from concentration gradients along the grains-water interface. Instead, surface diffusion is envisioned as a purely electromigration process due to the membrane potential. The tortuosities of the transport of anions and cations are equal to the bulk tortuosity of the pore space only at high ionic strength. As the ionic strength decreases, the dominant paths for transport of the ion corresponding to the counterion of the electrical double layer shift from the pore space to the solid grains-water interface. Because anions and cations do not move independently, the membrane potential created by the charge polarization alters the velocity of the anions and influences the mutual diffusivity coefficient of the salt in the porous material. An electric potential of thermal origin is also produced in nonisothermal conditions. The ionic contributions to the electrical conductivity are based on a differential effective medium approach. These ionic contributions to the electrical conductivity are used to derive the ionic diffusivities and the membrane and thermoelectric potentials. The influence of the temperature and the presence, in the pore space, of a second immiscible and nonwetting phase is also considered in this model. Porosity is shown to affect the membrane potential. Several predictions of the model are checked with success by comparing the model to a set of experimental data previously published. Copyright 1999 Academic Press. PMID- 10092383 TI - A Fifth OH-Stretching Band in IR Spectra of Kaolinites. AB - Transmission infrared spectra of different kaolinites were studied by curve fitting. These spectra generally exhibit four hydroxyl stretching bands. In this article we show that a fifth OH band (already identified in Raman and photoacoustic IR spectra of kaolinites) is also observed in transmission IR spectra of hydrothermal and authigenic kaolinites, which have a high degree of crystallinity. This additional band is weak or undetectable for kaolinites with a low degree of crystallinity. Copyright 1999 Academic Press. PMID- 10092384 TI - Structural Change in Dextran: Mechanism of Insolubilization by Adsorption on the Air-Liquid Interface. AB - To clarify the insolubilization mechanism of water-soluble dextran, the association of dextran in water was studied by dynamic light scattering measurements and a surface chemical approach. Dynamic light scattering measurements indicated that insolubilization of dextran is accompanied by a structural change in dextran. Surface tension data for dextran molecules revealed a structural change in dextran molecules at the air-liquid interface. These results suggest that insolubilization of dextran molecules occurred through an adsorption process at the air-liquid interface. Insolubilization of dextran molecules can be reduced by inhibition of this structural change in dextran molecules. The presence of boron as an impurity was found to trigger precipitation based on inductively coupled plasma mass spectrometry measurements and precipitation tests. Copyright 1999 Academic Press. PMID- 10092385 TI - Surface Electrical Properties of Barium Sulfate Modified by Adsorption of Poly alpha, beta Aspartic Acid. AB - The surface electrical properties of precipitated barium sulfate in aqueous solution have been probed in the presence and absence of synthetic poly alpha, beta aspartic acid. The effect of cation type, ion concentration, and pH on the electrokinetic properties of barite with and without adsorbed polyaspartic acid has been analyzed to afford insights into the mechanism by which polyaspartic acid acts as an inhibitor of barium sulfate precipitation. In addition, vibrational spectroscopy has been employed to monitor bond changes within polyaspartic acid molecules adsorbed on precipitated barium sulfate. These studies have indicated that the surface electrical charge of "pure" barite differs significantly from that of barite precipitated in the presence of calcium ions. Moreover, the presence of the cations Ca2+ and Mg2+ in the suspending liquor has a marked influence of the measured electrokinetic properties. The infrared spectral studies strongly suggest that polyaspartic acid is bound to the barite via the backbone nitrogen atoms. This proposal in conjunction with the electrokinetic and adsorption data has allowed a tentative model of barium sulfate inhibition to be proposed; viz, calcium ions are needed to complex with the polyaspartic acid, first, to reduce the molecules electrical charge in order to promote adsorption onto a charged surface; second, to induce a conformational change in the molecule in order to allow optimal anchoring via the backbone nitrogen atoms; and, third, to reduce the solubility of the molecule in order to increase its surface activity. Copyright 1999 Academic Press. PMID- 10092386 TI - Formation of Ultrathin Films at the Solid-Liquid Interface Studied by In Situ Ellipsometry. AB - Ellipsometric investigations of self-assembled monolayers (SAMs) of alkylsiloxanes on native silicon substrates and of organothiols on gold substrates were performed under in situ conditions with the substrate in direct contact with the adsorbate solution. Specially designed liquid cells matched for different incidence angles were used to carry out measurements in a range of organic solvents with different refractive indices as the ambient medium. The observed shifts in the ellipsometric phase angles Delta upon monolayer formation were found to depend very sensitively on the incidence angle and the refractive indices of the adsorbate film and the ambient solvent, from which a rather simple method for determining the refractive index of the adsorbate film, based on a variation of the ambient refractive index, was derived. Time-resolved in situ measurements of SAM formation in different solvents and onto different substrates yielded accurate kinetic information on the monolayer growth process and revealed hitherto unknown strong solvent effects on the growth rate. Copyright 1999 Academic Press. PMID- 10092387 TI - Self-assembled Monolayers of Two Aromatic Disulfides and a Diselenide on Polycrystalline Silver Films: An Investigation by SERS and XPS. AB - Self-assembled monolayers of diphenyldisufide (DDS), naphthalenedisulfide (NDS), and diphenyldiselenide (DDSe) on polycrystalline silver films have been investigated by surface enhanced Raman spectroscopy (SERS) and X-ray photoelectron spectroscopy (XPS). DDS adsorbs on Ag through a homolytic cleavage of the S-S bond and resultant thiolate at the surface decomposes upon prolonged exposure to air. The geometry of the molecule is such that the benzene ring is almost horizontal to the surface. The Raman spectrum has been assigned in the light of ab-initio molecular orbital calculations. In DDSe, the Se-Se bond is retained upon adsorption and the molecule sticks up. In contrast, NDS is highly reactive on the microscopically rough surface so that a stable monolayer could not be prepared. A temperature dependent Raman study of the DDS monolayer shows the absence of any reorientation at the surface as one would expect from the adsorption geometry. XPS study complements the SERS data and shows the presence of Ag2S on an NDS exposed surface. Copyright 1999 Academic Press. PMID- 10092388 TI - Infrared Emission Spectroscopic Study of the Dehydroxylation via Surface Silanol Groups of Synthetic and Natural Beidellite. AB - The structural changes of synthetic and natural beidellites during dehydroxylation have been studied using infrared emission spectroscopy of the OH stretching and bending regions. The OH-stretching region is characterized by two OH-stretching modes around 3600-3615 cm-1 and around 3650 cm-1. These bands strongly decrease in intensity upon dehydroxylation up to 600 degrees C for the natural beidellite and 700-750 degrees C for the synthetic ones. The differences in bandwidth, intensity, and dehydroxylation behavior are interpreted as due to differences in crystallinity with crystallinity increasing in the order natural beidellite < synthetic beidellite BSK3 < synthetic beidellite E498. Above 400 degrees C a new band attributed to silanol groups becomes visible in all samples due to transfer of the hydroxyls from the octahedral layer to the siloxane layer before they are lost. The broad band around 3300-3400 cm-1 is assigned to both H bonding in H2O and H-bonding to Si-O-Al linkages. The presence of two different OH groups is also reflected in the OH-bending modes around 875-895 cm-1 and 915 925 cm-1 and in the OH-libration modes around 780 and 800-820 cm-1. These bands show a decrease in intensity upon heating and dehydroxylation of the clay structure. Here again the same order can be observed for the disappearance of the bands as for the OH-stretching region. Copyright 1999 Academic Press. PMID- 10092389 TI - Assembly of Electroactive Ordered Multilayer Films of Cobalt Phthalocyanine Tetrasulfonate and Polycations. AB - Films with alternating layers of the anion cobalt phthalocyanine tetrasulfonate (CoIIPcTS4-) and cationic polydimethyldiallylammonium chloride (PDDA) were prepared by electrostatic layer-by-layer adsorption. Quartz crystal microbalance and optical studies demonstrated formation of smooth ultrathin films with a linear increase in thickness with the number of deposition steps. Films containing 1, 2, 3, 4, and 5 bilayers of CoIIPcTS4-/PDDA on a gold electrode gave reversible, reproducible steady state cyclic voltammetry for the CoII/CoI redox couple with midpoint potential at -0.28 V vs a saturated calomel reference electrode. Voltammetry was controlled predominantly by charge transport processes in the film, even for films containing only a bilayer of PDDA/CoIIPcTS4-. The peak reduction current increased with the number of layers and showed a tendency to saturation after a deposition of 4-5 bilayers. Copyright 1999 Academic Press. PMID- 10092390 TI - Effect of the Interface Component on Current-voltage Curves of a Composite Bipolar Membrane for Water and Methanol Solutions. AB - The current-voltage curves of a composite bipolar membrane (CBM) were experimentally measured by varying the interface component between cation- and anion-exchange membranes for water and methanol solutions. In each solution system, 0.05 mol/l LiCl was used as the electrolyte. The interface component was varied by pasting the polymers or installing the thin membranes in the intermediate region of the CBM. The measured results show that the functional groups of the polymers and thin membranes enhanced the water and methanol splitting effect. This phenomenon can be explained by the protonation deprotonation reactions occurring between these functional groups and the water or methanol molecules in the intermediate region of the CBM. The effect of transition metal compounds existing in the intermediate region of the CBM was also experimentally examined in this study. It was found that the effect of transition metal compounds on water or methanol splitting was not obvious. Copyright 1999 Academic Press. PMID- 10092391 TI - Preparation of Polymer Particles Coated with Hydroxyapatite. AB - Polymer particles coated with hydroxyapatite were prepared by treating Pd0 immobilized polystyrene-co-acrylic acid particles in aqueous CaCl2 and NaH2PO2 solutions. Hydroxyapatite coating took place at neutral to alkaline pH conditions, and the homogeneous growth of the hydroxyapatite layer on the surface of polymer particles was observed at relatively low temperature (30-50 degrees C). The thickness of the hydroxyapatite layer increased with reaction time. Copyright 1999 Academic Press. PMID- 10092392 TI - Interdiffusion in Polymer Film by Ellipsometry. AB - The long-time approximation for the time-dependence concentration of solvent into film is derived. The interdiffusion coefficients for different temperatures and the different polystyrene molecular weights were calculated by using asymptotic formulae and time-dependence concentrations of solvent into polymer films. The apparent activation energies of interdiffusion were estimated. Copyright 1999 Academic Press. PMID- 10092393 TI - Dynamics of Micelles of Polyethyleneoxide-Polypropyleneoxide-Polyethyleneoxide Block Copolymers in Aqueous Solutions. AB - The dynamics of the micelles of five triblock poly(ethyleneoxide) poly(propyleneoxide)-poly(ethyleneoxide) copolymers, the Pluronics P104 (EO27PO61EO27), P84 (EO19PO43EO19), P65 (EO18PO29EO18), P85 (EO26PO40EO26), and P103 (EO17PO60EO17), have been investigated using two chemical relaxation methods: the temperature-jump and the ultrasonic relaxation (absorption). In the frequency range investigated (0.5-50 MHz), the ultrasonic absorption spectra (absorption vs frequency plots) consisted in tails of relaxation curves, indicating characteristic times much longer than 0.3 us for the exchange of copolymers between micelles and intermicellar solution. Absorption measurements at a fixed frequency yielded the critical micellization temperature of the solutions. The temperature-jump results obtained in this study together with those from a previous one for the copolymers L64 (EO13PO30EO13) and PF80 (EO73PO27EO73) (B. Michels et al., Langmuir 13, 3111, 1997) showed that the relaxation time associated with the formation/breakup of micelles becomes longer upon increasing copolymer molecular weight at constant composition. This time also increased when decreasing the length of the hydrophilic block at fixed hydrophobic block length or increasing the length of the hydrophobic block at fixed hydrophilic block length, similar to conventional surfactants. The dynamics of block copolymers micelles in aqueous solution are discussed. Copyright 1999 Academic Press. PMID- 10092394 TI - Novel Method for Preparation of a Nanosized Gold Catalyst Supported on TiO2. AB - A TiO2 surface was readily modified with nanosized gold particles prepared by the thermal relaxation technique. Adsorption of the gold particles was very rapid, and the adsorbed gold particles distributed independently. By the two-step calcination of the modified TiO2, the nanosized gold particles were immobilized on the TiO2 surface without size growth or coagulation. The supported gold particles showed low-temperature catalytic activity on CO oxidation. The preprepared nanosized gold particles interacted with TiO2. Copyright 1999 Academic Press. PMID- 10092395 TI - Adsorption of Bovine Serum Albumin and Lysozyme on Hydrophobic Calcium Hydroxyapatites. AB - The adsorption of bovine serum albumin (BSA) and lysozyme (LSZ) to oleyl phosphate(OP)-grafted calcium hydroxyapatite (OP-CaHAP) with different degrees of hydrophobicity, ranging the number of surface oleyl group per unit nm2 (nO) from 0 to 2.60, was investigated. The pronounced effects of the hydrophobic moiety of adsorbent on protein adsorption were observed. The saturated amount of adsorbed BSA (ns) was increased up to nO = 0.6 by an enlargement of hydrophobic interaction between hydrophobic CaHAP particle and proteins. However, ns decreased at nO >/= 1.3 by increasing the electrostatic repulsive force between negatively charged BSA and OP-CaHAP particles. On the other hand, the ns value of LSZ was continuously increased up to nO = 2.0 and saturated by increasing either the hydrophobic interaction or the electrostatic attraction of positively charged LSZ and negatively charged OP-grafted CaHAPs. The BSA adsorption experiment revealed that the effect of positively charged adsorption sites on the exposed ac or bc crystal faces (C-sites) of the CaHAPs is screened by the OP-groups grafted on their particle surfaces. Copyright 1999 Academic Press. PMID- 10092396 TI - Critical Phenomena in the Clouding Behavior of Nonionic Surfactants Induced by Additives. AB - Effects of anionic surfactants, hydrotropes, and electrolytes on the cloud point of Triton X-100 have been studied over six decades of additives concentrations. A comprehensive look at all the data reveals significant new learnings. While anionic surfactants and hydrotropes affect the cloud point of non-ionics at ultra low (monomeric) concentrations, electrolytes exhibit a minimum critical concentration above which they cast their effect. This suggests that the former work by modifying the surface charge of non-ionic micelles (i.e., by affecting the solute), whereas the latter work by modifying the properties of the bulk medium. Above their respective critical concentrations, salting-out electrolytes decrease the cloud point while salting-in electrolytes increase it, the trends being linear with additive concentration in either case. The magnitude of the effect of anionic surfactants and hydrotropes increases gradually with increasing concentration till their respective cmc's are reached and then there is a sharp rise in the cloud point. Copyright 1999 Academic Press. PMID- 10092397 TI - MMT: science and policy. PMID- 10092398 TI - Transport and control of manganese ions in the central nervous system. PMID- 10092399 TI - Neurotoxic effects of low level exposure to manganese in human populations. PMID- 10092400 TI - Inhalation health risk assessment of MMT. PMID- 10092401 TI - Manganese homeostasis in the CNS. PMID- 10092402 TI - Long-term ambient ozone concentration and the incidence of asthma in nonsmoking adults: the AHSMOG Study. AB - We conducted a prospective study of a cohort of 3091 nonsmokers, ages 27 to 87 years, to evaluate the association between long-term ambient ozone exposure and development of adult-onset asthma. Over a 15-year period, 3.2% of males and 4.3% of females reported new doctor diagnoses of asthma. For males, we observed a significant relationship between report of doctor diagnosis of asthma and 20-year mean 8-h average ambient ozone concentration (relative risk (RR)=2.09 for a 27 ppb increase in ozone concentration, 95% CI=1.03 to 4.16). We observed no such relationship for females. Other variables significantly related to development of asthma were a history of ever-smoking for males (RR=2.37, 95% CI=1.13 to 4.81), and for females, number of years worked with a smoker (RR=1.21 for a 7-year increment, 95% CI=1.04 to 1.39), age (RR=0.61 for a 16-year increment, 95% CI=0.44 to 0.84), and a history of childhood pneumonia or bronchitis (RR=2.96, 95% CI=1.68 to 5.03). Addition of other pollutants (PM10, SO4, NO2, and SO2) to the models did not diminish the relationship between ozone and asthma for males. These data suggest that long-term exposure to ambient ozone is associated with development of asthma in adult males. PMID- 10092403 TI - Genotoxicity of fumes from heated cooking oils produced in Taiwan. AB - Epidemiologic investigations of lung cancer among Taiwanese nonsmoking women have found that exposure to fumes from cooking oils may be an important risk factor. Fume samples from three different commercial cooking oils (lard, soybean, and peanut oils) often used in Taiwan for preparing Chinese meals were collected for genotoxicity analysis in SOS chromotest and sister chromatid exchange (SCE) assays. The induction factors of the SOS chromotest in Escherichia coli PQ 37 were dependent on the concentrations of lard and soybean cooking oil extracts without S9 mix. In addition, when CHO-K1 cells were exposed to condensates of cooking oil fumes for 12 h, SCEs showed a dose-related increase in extracts of lard and soybean oil fumes. This result provides experimental evidence and is in accordance with the findings of epidemiologic studies that women exposed to the emitted fumes of cooking oils are at an increase risk of contracting lung cancer. PMID- 10092404 TI - Genotoxicity of drinking water from Chao Lake. AB - Genotoxic activity appears to originate primarily from reactions of chlorine with humic substances in the source waters. Comparisons of extracts of settled versus chlorinated water have confirmed that chlorinating during water treatment produces mutagenic activity in the mutagenicity tests. Present work on XAD-2 extracts of raw, chlorinated (treated), and settled water from the Chao Lake region of China has involved a battery of mutagenicity assays for various genetic endpoints: the Salmonella test, the sister-chromatid exchange (SCE) induction in Chinese hamster lung (CHL) cells, and the micronucleus (MN) induction in the peripheral blood erythrocytes of silver carp. Extracts of raw and treated water but not the settled water are mutagenic in the Salmonella assay. On the other hand, extracts of three water samples show activity in the SCE and MN assays, especially the raw and treated water. These data show that contamination and chlorinating contribute mutagens to drinking water and suggest that the mammalian assays may be more sensitive for detecting mutagenicity in aquatic environment than the Salmonella test. PMID- 10092405 TI - Identification of a chemical marker of environmental exposure to formaldehyde. AB - Formaldehyde (F) binds human serum albumin (HSA) covalently, giving rise to a molecular adduct F-HSA having the F as hapten. The humoral immune response to the adduct provides a biological marker of F exposure. In order to titrate serum anti F-HSA antibodies, a new indirect competitive enzyme immunoassay (displacement assay) was developed. Two groups of about 90 heterogeneous healthy subjects were examined using two in vitro conjugated F-HSA adducts with different ratios between F and HSA (5:1 and 10:1). Contingency table analysis showed a greater sensitivity (97%) and specificity (92%) of the test with the 10:1 F-HSA adduct than with the 5:1. Data examination using multivariate analysis of variance revealed that in both groups the smoking variable significantly explains (P<0.01) the values of the F exposure marker. A significant association with immunological response was obtained only in male smokers, using 5:1 F-HSA adduct, while with 10:1 ratio, a good association in male and female smokers was found. Results confirm that the immunological assay developed (displacement assay) could be a useful method for evaluating F exposure, especially for public health monitoring on a large scale. PMID- 10092406 TI - Biomarkers of exposure to organophosphorous insecticides among farmers' families in rural El Salvador: factors associated with exposure. AB - Most studies of the health effects of pesticides have concentrated on occupational exposure. Little is known about community environmental exposure to agricultural pesticides. The purpose of this study was to investigate nonoccupational pesticide exposure among farmers' families in rural El Salvador, a country known for intensive use of extremely toxic compounds. The study population included all residents 8 years and older living in five agricultural communities in El Salvador. Current exposure to organophosphate insecticides (OPs) was established through analysis of urine samples for alkyl phosphate metabolites of OPs. Nearly half of 358 analyzed samples had detectable levels of OP metabolities. Of subjects not performing agricultural fieldwork, 30% nonetheless excreted detectable levels of metabolities. Similar rates held for children and adults. The best independent predictors for an individual's excretion of OP metabolites were (a) performing fieldwork during the past 2 weeks, (b) the head household farmer's application of OPs during the past 2 years, and (c) the household mother reporting use of OPs in the home or yard. The latter factors were significantly associated with metabolite excretion regardless of whether the individual had done fieldwork. The results of this study support the hypothesis that a large proportion of rural Salvadorans, including children, is exposed to pesticides through environmental as well as occupational routes. PMID- 10092407 TI - Field measurement of dermal soil loadings in occupational and recreational activities. AB - Risks associated with dermal exposure to contaminated soil are not well characterized, but nevertheless must be estimated to define endpoints for remedial strategies. Among the parameters contributing to the uncertainty of these estimates is soil adherence to skin. Pre- and postactivity soil loadings have been obtained from hands, forearms, lower legs, faces, and/or feet of volunteers engaged in various occupational and recreational activities. These data are distinguished from other sources of estimates of soil adherence by the manner of their collection. Soil loads were obtained directly from multiple body parts before and after uncontrived exposure scenarios. Data presented for the first time here supplement prior results and roughly double the available data base. This expanded data base provides a useful perspective on types of behavior likely to lead to soil contact falling within general classes of activity (e.g., background, low, moderate, or high contact). Prior conclusions supported by the additional data include the following: (1) post-activity loadings are typically higher than preactivity levels, demonstrating that exposure is episodic; (2) hand loadings are dependent upon class of activity; (3) hand loadings generally provide conservative estimates of loadings on nonhand body parts within activity classes; and (4) hand loadings do not provide conservative estimates of nonhand loadings across activity classes. Finally quantitative estimates of relative loads on unclothed nonhand body parts are presented. PMID- 10092408 TI - Acute health effects associated with nonoccupational pesticide exposure in rural El Salvador. AB - Little is known about the health effects of nonoccupational pesticide exposure in agricultural communities of poor countries. Therefore, this study investigated acute symptoms associated with nonoccupational exposure to organophosphate insecticides (OPs) in rural El Salvador, a region known for intensive pesticide use. In the five communities studied, 2-week prevalences of several acute symptoms were associated with living with a farmer who had recently applied methyl parathion. These included cramps in limbs (odds ratio 2.1, 95% confidence interval 1.2-3.7), chest pressure (OR 2.3, 95% CI 1.3-4.0), change in defecation (OR 2.3, 95% CI 1.3-4.1), feeling dazed (OR 2.4, 95% CI 1.3-4.4), and eyes tearing (OR 2.5, 95% CI 1. 4-4.5). Associations were found regardless of whether the individuals reporting the symptoms had themselves performed field labor. These results suggest that living in areas where pesticides are used on crops may represent an environmental health concern, especially for children. PMID- 10092409 TI - Selection effects on an estimation of long-term changes in pulmonary function. AB - To reveal the association of initial pulmonary function level with subsequent mortality and participation in a follow-up reexamination, a prospective cohort study was performed. Female residents in a volcanic area of southern Kyushu, Japan, were followed up for their vital status and the pulmonary function 15 years after they received the first pulmonary function test. A cohort of 512 Japanese female residents who were examined for pulmonary function as indicated by forced expiratory volume and forced expiratory volume in one second was measured in a baseline examination in 1980. After 15 years, 35 females were lost to follow-up. Of the remaining 477 females, 340 and 137 females provided good and poor levels of pulmonary function tests (PFT) at baseline, respectively. Mortality by 1995 in the poor PFT group was significantly higher than that in the good PFT group (33.6% vs 9.4%). The mortality differences were still highly significant when the 35 lost cases were included as all alive. Among the 399 survivors, the nonparticipation rate in the reexamination in 1995 was significantly higher in the poor PFT group than that in the good PFT group (80.2% vs 69.5%). The results of the present study, a longitudinal study of pulmonary function, provide evidence of selection effects due to death or failure to participate in a subsequent reexamination. PMID- 10092410 TI - Characteristics of pesticide use in a pesticide applicator cohort: the Agricultural Health Study. AB - Data on recent and historic pesticide use, pesticide application methods, and farm characteristics were collected from 35,879 restricted-use pesticide applicators in the first 2 years of the Agricultural Health Study, a prospective study of a large cohort of private and commercial licensed pesticide applicators that is being conducted in Iowa and North Carolina. (In Iowa, applicators are actually "certified," while in North Carolina they are "licensed"; for ease of reference the term license will be used for both states in this paper.) Commercial applicators (studied in Iowa only) apply pesticides more days per year than private applicators in either state. When the types of pesticides being used by different groups are compared using the Spearman coefficient of determination (r2), we find that Iowa private and Iowa commercial applicators tend to use the same type of pesticides (r2=0.88). White and nonwhite private applicators tended to use the same type of pesticides (North Carolina r2=0.89), as did male and female private applicators (Iowa r2=0.85 and North Carolina r2=0.84). There was less similarity (r2=0. 50) between the types of pesticides being used by Iowa and North Carolina private applicators. A greater portion of Iowa private applicators use personal protective equipment than do North Carolina private applicators, and pesticide application methods varied by state. This heterogeneity in potential exposures to pesticides between states should be useful for subsequent epidemiologic analyses using internal comparison groups. PMID- 10092411 TI - Characteristics of persons who self-reported a high pesticide exposure event in the Agricultural Health Study. AB - Characteristics of persons who report high pesticide exposure events (HPEE) were studied in a large cohort of licensed pesticide applicators from Iowa and North Carolina who enrolled in the Agricultural Health Study between December 1993 and December 1995. Fourteen percent reported having "an incident or experience while using any pesticide which caused an unusually high personal exposure. " After taking into account total number of applications made and education, females (OR=0.76), applicators from NC (OR=0.65), and privately licensed applicators (OR=0.65) were less likely to have reported an HPEE. Work practices more common among both private and commercial applicators with an HPEE included delay in changing clothing or washing after pesticide application, mixing pesticide application clothing with the family wash, washing up inside the house after application, applying pesticides within 50 yards of their well, and storing pesticides in the home. Job characteristics more common among those with an HPEE included self-repair of application equipment and first pesticide use more than 10 years in the past. These job characteristics explained much of the difference in reported HPEE between males and females, but not between IA and NC subjects or between commercial or private applicators. PMID- 10092413 TI - Foreword PMID- 10092412 TI - Evaluation of biomarkers of environmental exposures: urinary haloacetic acids associated with ingestion of chlorinated drinking water. AB - A study was conducted to determine if DCAA and TCAA urinary excretion rates are valid biomarkers of chronic ingestion exposure to these disinfection by-products of chlorination of drinking water. Entire first morning urine voids, time-of visit urine samples, and tap water samples were collected from 47 female subjects. In addition, a 48-h recall questionnaire was administered to determine the amounts and types of liquids ingested by each subject as well as other exposures that could lead to DCAA and TCAA urinary excretion. The TCAA excretion rate for the first morning urine samples was significantly correlated with the estimated 48-h TCAA ingestion exposure for 25 subjects whose ingestion exposures primarily occurred at home, while the DCAA excretion rate was not correlated with the DCAA ingestion exposure. Thus, urinary TCAA appears to be a valid biomarker of chronic ingestion exposure to TCAA from chlorinated water, while urinary DCAA is not. It is proposed that the difference in the biological half-lives between these two compounds is the rationale for this finding. The biological half-life of TCAA is longer than successive exposure intervals; thus TCAA accumulates until it reaches a steady state. The half-life of DCAA is shorter than successive exposure intervals; thus DCAA is almost completely metabolized following an exposure and is eliminated from the body. This study suggests that biological half-life, exposure interval, and sample collection interval should be considered in selecting biomarkers and designing studies to validate them. PMID- 10092414 TI - Key environmental human health issues in the Great Lakes and St. Lawrence River basins. AB - In May 1997, Health Conference '97-Great Lakes/St. Lawrence, an international conference on the effects of the environment on human health in the Great Lakes and St. Lawrence River basins, was held in Montreal, Quebec, Canada. This was the third international conference on this topic sponsored by agencies in the United States and Canada. More than 120 platform and poster presentations were given by scientists of different disciplines from the Great Lakes region and elsewhere. The presentations represented the most current research findings on the effects of the Great Lakes environment on human health. The reports covered environmental contaminant levels of persistent toxic substances (PTSs), routes and pathways of exposure, exposure assessment and human tissue levels of PTSs, human health outcomes, risk communication and assessment, and approaches to scientific collaboration. Reports indicate that levels of contaminants in the Great Lakes and St. Lawrence River basins have generally declined since the 1970s, although certain contaminants have plateaued or slightly increased. The findings include elevated body burden levels of contaminants in persons who consume large amounts of some Great Lakes sport fish, developmental deficits and neurologic problems in children of some fish-consuming parents, nervous system dysfunction in adults, and disturbances in reproductive parameters. The findings underscore the need for better public health intervention strategies. PMID- 10092415 TI - Paternal Lake Ontario fish consumption and risk of conception delay, New York State Angler Cohort. AB - The aquatic ecosystems of the Great Lakes are contaminated with a variety of compounds, some of which are considered reproductive toxicants. Few studies of paternal fish consumption and reproductive endpoints have been undertaken and serve as the impetus for study. Standardized telephone interviews were conducted with 2445 female members of the New York State Angler Cohort (82% response) to update reproductive profiles and to ascertain specific information on time-to pregnancy (TTP). The study sample includes women with a known TTP and paternal fish consumption data (n=785). Conception delay was defined as more than 12 cycles of unprotected intercourse to achieve pregnancy. Paternal fish consumption was assessed by three measures: frequency of Lake Ontario sport fish meals in 1991, numbers of years eating fish, and estimated PCB exposure from fish consumption. Adjusted ORs for number of fish meals, based on logistic regression, ranged from 0.69 to 0.80; from 0.61 to 0.82 for number of years eating fish; and from 0.44 to 1.14 for quartiles of estimated PCB exposure from fish consumption. All confidence intervals included one. These findings suggest that, based on paternal self-reports, Lake Ontario fish consumption does not increase the risk of conception delay. PMID- 10092416 TI - Body burden levels of dioxin, furans, and PCBs among frequent consumers of Great Lakes sport fish. The Great Lakes Consortium. AB - Dioxins, furans, and polychlorinated biphenyls (PCBs) are toxic, persist in the environment, and bioaccumulate to concentrations that can be harmful to humans. Sport anglers may be exposed to these residues via consumption of contaminated Great Lakes (GL) fish. The Health Departments of five GL states, Wisconsin, Michigan, Ohio, Illinois, and Indiana, formed a consortium to study body burden levels of chemical residues in fish consumers of Lakes Michigan, Huron, and Erie. In Fall 1993, a telephone survey was administered to sport angler households to obtain fish consumption habits and demographics. A blood sample was obtained from a portion of the study subjects. One hundred serum samples were analyzed for 8 dioxin, 10 furan, and 4 coplanar PCB congeners. Multiple linear regression was conducted to assess the predictability of the following covariates: GL sport fish species, age, BMI, gender, years sport fish consumed, and lake. Of the 100 subjects, there were 58 men; 35 consumed sport fish from Lake Michigan, 29 from Lake Huron, and 36 from Lake Erie. The overall average number of GL sport fish meals consumed in the previous 12 months was 43. Lake Erie male and female consumers, on average, ate more GL sport fish, a mean of 57 and 42 meals, respectively, than men and women from the other two lake subgroups. Median total dioxin toxic equivalents (TEq), total furan TEq, and total coplanar PCB TEq were higher among all men than all women (P=0.0001). Lake trout, salmon, age, BMI, and gender were significant regression predictors of log(total coplanar PCBs). Lake trout, age, gender, and lake were significant regression predictors of log(total furans). Age was the only significant predictor of total dioxin levels. PMID- 10092417 TI - Serum PCB and DDE levels of frequent Great Lakes sport fish consumers-a first look. The Great Lakes Consortium. AB - Great Lakes (GL) sport fish consumption is a potential human exposure route for polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE). Because of fish tissue contamination, frequent consumers of Great Lakes sport caught fish (GLSCF) may be at risk for PCB and DDE accumulation. To examine this problem, the Health Departments of Wisconsin, Illinois, Indiana, Ohio, and Michigan formed a health assessment consortium. Participants were contacted by telephone to complete a detailed demographic and fish consumption survey. Frequent and infrequent GLSCF consumers were identified, and a participant subset was then asked to donate blood for PCB and DDE analysis. Analysis of variance (ANOVA) was done to study exposure group mean differences, while correlation and regression analyses were performed to examine relationships between demographic characteristics, GLSCF consumption, PCB, and DDE body burdens. A total of 4206 individuals participated in the study. Of these, 2542 were habitual GLSCF consumers (mean greater than 35 meals/year males; greater than 27 meals/year females), while 1664 did not eat GLSCF. A subset of 538 participants donated blood and included 439 frequent and 99 infrequent GLSCF consumers. PCB levels were significantly higher in the group of GLSCF consumers (geometric mean: 4.8 ppb males, 2.1 ppb females) when compared to their referents (geometric mean: 1.5 ppb males, 0.9 ppb females), while DDE levels were also higher for GLSCF consumers. PCB and DDE body burdens varied by exposure group, gender, and great lake (Michigan, Huron, Erie). PCB and DDE levels were significantly correlated to age, body mass index, and sport fish and Great Lakes sport fish consumption histories. Regression analysis identified years of consuming sport caught fish as the most robust predictor of PCBs (r2=25%), while age was the best predictor of DDE levels (r2=21%). This study corroborated previous findings relating frequent GLSCF consumption to a higher body burden for PCBs and DDE. PMID- 10092418 TI - Are PCBs the major neurotoxicant in Great Lakes salmon? AB - Epidemiological studies have demonstrated an association between consumption, by women, of contaminated Great Lakes salmon and deficits in cognitive performance in the children of these women. Although significant statistical associations between polychlorinated biphenyl (PCB) body burdens and these negative outcomes suggest that PCBs may be responsible, the fetus and neonate are also exposed to other fish-borne neurotoxicants. In this manuscript we present data from two developmental studies that support the hypothesis that PCBs may serve either as a marker for other contaminants that are responsible for the observed effects, or that other contaminants present in the fish interact synergistically with the PCBs to produce the observed neurotoxicity. In the first study we demonstrated that exposure of rats to diets containing lyophilized Great Lakes salmon, resulting in exposure to as little as 13.9 micrograms/(kg small middle dotday) of total PCBs, induced significant reductions in regional brain dopamine (DA) concentrations. In the second study, we demonstrated that exposure of rats to the ortho-substituted PCB congener (2,4,2', 4'-tetrachloro- biphenyl) at 1, 10 or 20 mg/(kg small middle dotday) also induced significant reductions in DA concentrations in the same brain regions although only at the two highest doses levels at least 100-fold higher than seen in the first study. On the basis of these developmental neurochemical studies we suggest that the reported cognitive deficits in children exposed in utero and during lactation to fish-borne contaminants may be due either to contaminants other than PCBs or to complex interactions between PCBs and other neurotoxicants present in the fish. PMID- 10092419 TI - Motor function in aging Great Lakes fisheaters. AB - Exposure to contaminants in Great Lakes fish has been linked to impaired neuropsychological functioning in children, but neurological function of exposed adults has not been evaluated. This report describes a cross-sectional analysis of the effects of PCB/DDE exposure from contaminated fish on fine motor function in older adults. The subjects were 50-90-year-old Michigan residents who were members of a previously established study cohort. Fisheaters ate 24 lbs or more of sport-caught Lake Michigan fish/year at the time they were originally recruited in 1980-1982. Age- and sex-matched non-fisheaters ate 6 or fewer lbs/year. Outcome measures were scores on the Static Motor Steadiness Test (SMST) and Grooved Pegboard Test (GPT). PCB/DDE exposure was determined through serum analyses performed at the time of recruitment into the present study in 1993 1995. Because of the high correlation between serum PCB and DDE levels in this sample (Spearman r=0.64, P<0.0001), the effects of the two contaminants were assessed jointly using a single derived exposure variable=Low=both PCB and DDE at or below the medians of their respective distributions, intermediate=PCB and/or DDE in the third quartile, and high=PCB and/or DDE in the upper quartile. In unadjusted analyses, high exposure to PCBs/DDE was associated with significantly poorer performance on the GPT (P=0.03). However, in the multiple regression model, age and gender emerged as the most significant factors affecting GPT scores, and exposure to PCB/DDE was not significant. Performance on the SMST was not related to PCB/DDE exposure in initial unadjusted analyses, but performance with the dominant hand was marginally (P=0.052) associated with exposure in the final model. Scores on the SMST improved slightly as PCB/DDE exposure increased. A similar trend was not observed for the nondominant hand (P=0.46). These findings suggest that PCB/DDE exposure from Great Lakes fish has not significantly impaired hand steadiness or visual-motor coordination in this sample of older adults. PMID- 10092420 TI - Exploratory assessment of fish consumption among Asian-origin sportfishers on the St. Lawrence river in the montreal region. AB - An exploratory survey was undertaken in the fall 1995 open-water fishing season with nine Bangladeshi and nine Vietnamese-origin sportfishers. Survey methodology and techniques of dietary and fish intake assessment were adapted to the cultural values and second language of each community. A 70-item instrument assessing sportfishing practices and fish consumption habits was administered by dietitians in participants' homes. Two 24-h diet recalls (aided by photographs taken by the participants) and a fish consumption calendar permitted the assessment of fish intake in the overall dietary context. A fish frequency item addressed consumption of locally available fish species (both sport and market fish) as well as imported frozen or dried species. Annually, Bangladeshi fishers consumed 46.8+/-25.6 sportfish meals, and Vietnamese fishers ate 40. 7+/-35.1 meals. In contrast, Bangladeshis reported greater annual consumption of imported, frozen nonsportfish (76.0+/-40.9 meals), and the Vietnamese ate more ocean than freshwater fish (45.1+/-34.4 ocean fish meals). Fish constituted approximately 19% of all protein foods eaten among the Bangladeshi fishers and 10% in the Vietnamese sample. Plasma and erythrocyte eicosapentanoic acid (EPA):arachidonic acid (AA) ratios supported findings from the fish frequency question showing that the two groups of Asian-origin fishers eat differing quantities of different fish species and that Asian-origin sportfishers-particularly the Bangladeshis-eat fish overall more frequently and in greater variety and quantity than francophone Quebecers; species selection appears to be both culturally motivated and influenced by the availability of St. Lawrence sportfish. PMID- 10092421 TI - Reliability and relative validity of fish consumption data obtained in an exposure assessment study among Montreal-area sportfishers. AB - A two-season exercise was undertaken in 29 high-level sportfish consumers to evaluate the reliability and accuracy of study instruments. Fishers were invited to participate after completing the main study interview (Time 1) in fall 1995 or winter 1996. Over a 4-week period, they provided a nonconsecutive 7-day weighed food record, kept a fish consumption calendar, and responded to a shortened version of the Time 1 instrument at the end of this period (Time 2). A second blood sample (at Time 2) was analyzed for whole blood mercury (Hg) and the omega 3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) in plasma and erythrocytes. Identical questions were compared in the Time 1 and Time 2 instruments. Reported sportfish consumption assessed by the different instruments was subjected to nutrient analysis. Three estimates of exposure to the target substances were derived from the dietary intake estimates and correlated with their respective Time 2 plasma (EPA, DHA) or blood (Hg) values, and with a kinetically derived interval-specific plasma/blood uptake value. Remarkable similarities were observed for the data derived from like questions in the Time 1 and 2 questionnaires in both seasons. However, frank discrepancies between some portion size estimates and measured values may signal cause for concern. The strongest correlations between the Time 2 plasma DHA and EPA, and blood Hg, and the three exposure indices emerged between estimates of retrospective DHA intake and DHA fish calendar values and their corresponding Time 2 plasma levels, and for Hg estimated both retrospectively and from the fish consumption calendar and correlated with Time 2 blood Hg, especially in the winter 1996 dataset. Overall, the results suggest that the main study instrument provides a reliable and relatively accurate indication of sportfishers' fishing practices, species selection, and sportfish consumption habits. PMID- 10092422 TI - Assessment of prenatal exposure to PCBs from maternal consumption of Great Lakes fish: an analysis of PCB pattern and concentration. AB - The current study was designed to assess the pattern and concentration of prenatal PCB exposure in the newborns of women who consumed Great Lakes fish. We compared the pattern and concentration of umbilical cord blood PCBs of 145 women who reported never having consumed Great Lakes fish to 134 women who reported consuming at least 40 PCB-equivalent fish lbs of Great Lakes fish in their lifetime (Lonky et al., 1996). Although the average levels of total PCBs in cord blood were exceedingly low (approximately 1.0 ppb), the data clearly indicated that both the proportion (mol%) and the absolute concentration (ppb) of the most heavily chlorinated and persistent PCB homologues (homologues C17-C19) were markedly elevated in the cord blood of fish eaters. This effect grew markedly as a function of the total PCBs detected in the sample. Moreover, the concentration of the most heavily chlorinated PCB homologues was significantly dependent on how recently the fish were consumed relative to pregnancy. The order of highly chlorinated PCB concentration was consumed fish throughout pregnancy > consumed fish up until pregnancy > stopped consuming fish in 1984 > never consumed Lake Ontario fish. In contrast, PCB homologues of light (Cl1-Cl3) or moderate (Cl4 Cl6) chlorination were unrelated to fish consumption. Analysis of the relationship between the PCB homologues in cord blood and their homologues in breast milk provided further converging evidence of these findings. While PCB homologues of light (Cl1-Cl3) or moderate (Cl4-Cl6) chlorination did not correlate with their breast milk homologues, the most persistent and heavily chlorinated PCB homologues (Cl7-Cl9) were significantly and positively correlated with breast milk levels. These data indicate that the most heavily chlorinated PCBs provide valid and reliable exposure information in a lean medium such as cord blood. We conclude that maternal consumption of Great Lakes fish increases the risk of prenatal exposure to the most heavily chlorinated PCB homologues. PMID- 10092423 TI - Local fish consumption and serum PCB concentrations among Mohawk men at Akwesasne. AB - A study was conducted to assess local fish consumption patterns and their relationship to concentrations of total polychlorinated biphenyls (PCBs) in the serum of Mohawk men residing near three hazardous waste sites. From 1992 to 1995, 139 men were interviewed and donated a 20-ml venous blood sample. The results indicated that the men ate a mean of 21.2 local fish meals during the past year, compared with annual means of 27.7 meals 1-2 years before and 88.6 meals more than 2 years before (P<0.001 for test of trend). This change is probably a consequence of advisories issued against the consumption of local fish, since 97% of the men were aware of the advisories and two-thirds had changed their behavior as a result. Multiple regression analysis revealed that serum PCB levels increased with age (beta=0.036, P<0.001) and local fish consumption (beta=0.088, P=0.006). The data suggest that local fish consumption has contributed to body burdens in this population and that the advisories have been effective in modifying local fish consumption habits. PMID- 10092424 TI - Immune functions in the Fisher rat fed beluga whale (Delphinapterus leucas) blubber from the contaminated St. Lawrence estuary. AB - In order to assess the immunotoxic potential of food naturally contaminated with PCBs and other organohalogens, Fisher rats were fed a diet in which the lipids originated from the blubber of either a highly polluted St. Lawrence beluga or a relatively uncontaminated Arctic beluga. After a period of 2 months, different immune functions were evaluated, including lymphoblastic transformation, natural killer cell activity, plaque-forming cells, phagocytosis, oxidative burst, and immunophenotyping. For all assays, rats fed a St. Lawrence beluga blubber diet or a mixture of Arctic and St. Lawrence beluga blubber diet were not different from control rats fed a diet containing Arctic beluga blubber. These results are inconsistent with the well-known immunosuppressive effects of organochlorines in numerous species and with the lesions suggestive of organochlorine-related immunosuppression that are observed in St. Lawrence belugas. The lack of observable immunotoxic effects in rats fed contaminated beluga blubber might be explained by antagonistic effects in the organohalogen mixture, by a response specific to the rat, by a strain-related lack of sensitivity to organochlorines, or by insufficient dose due to the shortness of the exposure period or the route of exposure. PMID- 10092425 TI - Behavioral impairment produced by low-level postnatal PCB exposure in monkeys. AB - The preponderance of evidence in humans suggests that polychlorinated biphenyl (PCB)-induced behavioral deficits result from prenatal exposure rather than exposure through breast milk, although a recent study reported lower psychomotor scores during infancy associated with PCB concentration in breast milk. In the current study, monkeys were dosed from birth to 20 weeks of age with a PCB congener mixture representative of the PCBs found in human breast milk. Blood and fat levels of PCB-exposed monkeys at the end of the dosing period were within the range observed in the general human population, while levels in control monkeys were below averages observed in humans in industrialized countries. Behavioral assessment on a series of tasks was performed when monkeys were between 2.5 and 5.0 years of age. Robust deficits were observed on spatial delayed alternation, fixed interval, and differential reinforcement of low rate performance. No group differences were observed for the number of errors on a series of nonspatial and spatial discrimination reversal tasks. Behavioral deficits included retarded learning, perseverative behavior, and inability to inhibit inappropriate responding. These results have implications for the potential contribution of exposure to PCBs through breast milk to behavioral impairment. PMID- 10092426 TI - Effects of waterborne exposure to 4-nonylphenol and nonylphenol ethoxylate on secondary sex characteristics and gonads of fathead minnows (Pimephales promelas). AB - Fathead minnows were exposed to 4-nonylphenol (NP) or nonylphenol ethoxylate (NPEO) to determine the effects of these weak estrogen agonists on secondary sex characteristics and gonads of sexually mature males and females during 42-day continuous-flow exposures. Neither NP nor NPEO caused statistically significant effects on tubercles or fatpad size at the concentrations tested. Exposure to 1. 1 or 3.4 micrograms NP/L caused changes in the number and size of Sertoli cells and germ cell syncytia. Necrotic aggregates of various stages of germ cells in the spermatogenic sequence were observed in the testes of males exposed to NP. Electron microscopy of the testes of NP-exposed males revealed the presence of phagocytic cells in the lumina of seminiferous tubules. The cytoplasm of some Sertoli cells was distended with myelin figures and necrotic spermatozoa. No significant effects on the stages of follicular development were observed in females exposed to NP. There were no differences in the gonads or secondary sex characteristics of males or females exposed to 5.5 micrograms NPEO/L, the greatest concentration studied. The histologic responses observed are sensitive indicators of waterborne exposure to NP at environmentally relevant concentrations, but not as sensitive as induction of plasma vitellogenin. The secondary sex characteristics were not affected by concentrations of NP or NPEO as great as 3.4 or 5.5 micrograms/L, respectively. Histologic responses occurred at concentrations that were less than the final chronic value based on survival and approximately the same as those required to cause effects on egg production. The histologic effects caused by NP were similar to, but not exactly the same as those caused by exposure of fathead minnows to 17 beta-estradiol. PMID- 10092427 TI - Blood PCB, p,p'-DDE, and mirex levels in Great Lakes fish and waterfowl consumers in two Ontario communities. AB - PCB, p,p'-DDE, and mirex levels were examined in blood plasma samples of 232 anglers from Cornwall and Mississauga, Ontario, in a pilot study to establish the feasibility and suitability of using a cohort of Ontario fish license holders for large-scale health studies. Great Lakes fish, waterfowl, and ocean fish consumption were examined as predictors of contaminant levels using regression analysis, with adjustment for age, gender, and community. Levels of Great Lakes fish and waterfowl consumption and contaminant levels were generally low in comparison with those observed in other Great Lakes studies. However, even within these low levels, Great Lakes fish consumption was associated with increased blood plasma PCB levels in men and mirex levels in both men and women. Waterfowl consumption was associated with higher plasma PCB (men and women), DDE (men only), and mirex levels (men and Cornwall women), and requires further exploration. We conclude that other study designs are required (to identify high consumers) for carrying out studies of health effects associated with high levels of Great Lakes fish and waterfowl consumption. PMID- 10092428 TI - Fish consumption and contaminant exposure among Montreal-area sportfishers: pilot study. AB - A 1995 pilot study assessed sport fish consumption and contaminant exposure among Montreal-area residents fishing the frozen St. Lawrence River. Interviews conducted among 223 ice fishers met on-site were used to create an index of estimated exposure to fish-borne contaminants. A second-stage assessment of sport fish consumption and tissue contaminant burdens included 25 interviewees at the highest level of estimated contaminant exposure (of 38, or 66% of those solicited) and 15 low-exposure fishers (of 41, or 37% of those solicited). High level fisher-consumers reported eating 0. 92+/-0.99 sport fish meals/week during the previous 3 weeks compared to 0.38+/-0.21 (P<0.05) for the low-level group. Based on the product of consumption frequency times mass of sport fish meals consumed, high-level consumers ate a mean of 18.3 kg of sport fish annually versus 3.3 kg for the low-level consumers. Tissue contaminant assessments showed significant (P<0.05) groupwise differences: 0-1 cm hair mercury (median 0.73 microgram/g for the high versus 0.23 microgram/g for the low group), lipid adjusted plasma PCB congeners (Aroclor 1260: median 0.77 microgram/g versus 0.47 microgram/g), and lipid-adjusted plasma DDE (median 0.35 microgram/g versus 0.26 microgram/g). No participant had a hair mercury or plasma DDE concentration above Health Canada recommendations but 2/25 high-level participants (8%) had plasma Aroclor 1260 concentrations above recommended limits. The results of this pilot study suggest that a small number of Montreal-area sportfishers consume their catch as often as three times weekly and that those consuming sport fish frequently have significantly higher tissue levels of mercury, PCBs, and DDE than do infrequent consumers. On the other hand, compared to other groups in Quebec, such as the Inuit or commercial fishers on the North Shore of the Gulf of St. Lawrence, Montreal-area sportfishers eat less fish and have lower tissue concentrations of fish-related contaminants. PMID- 10092429 TI - Contaminant exposure in Montrealers of Asian origin fishing the St. Lawrence River: exploratory assessment. AB - Fishing and fish consumption are widely practiced among members of certain ethnocultural groups. Informal assessment led us to ascribe high levels of consumption of locally caught sportfish to Montrealers of Asian origin and to hypothesize that their choices of species and fish organs differ from those of the majority group. An exploratory assessment of contaminant bioindicators reflective of St. Lawrence River fish consumption was conducted in late 1995 among nine Vietnamese and nine Bangladeshi Montreal sportfishers identified by community contacts. Vietnamese participants, six men and three women, were 27-70 (median 36) years of age and had immigrated to Canada 3-20 (median 7) years earlier. In contrast, the nine Bangladeshi males aged 28-41 (median 34) years had been in Canada for 2-13 (median 4) years. Bio-indicator concentrations among Bangladeshi and Vietnamese participants are compared to those found for majority community Montreal-area high-level consumers recruited on the St. Lawrence River during winter 1995. All results are presented as the median and 90th percentile. Hair mercury concentrations were higher for both Vietnamese (1.2, 4.6 microgram/g) and Bangladeshis (1.1, 2.3 microgram/g) than for majority-community sportfishers (0.7, 1.9 microgram/g). Certain organochlorine levels, specifically total PCB (estimated by plasma Aroclor 1260), p,p'-DDT, p,p'-DDE, and B-BHC, were highest in the Bangladeshis compared to Vietnamese and to majority-community sportfishers. In contrast, plasma levels of other pesticides were low in all three groups, including mirex, chlordane, and cis-nonachlor. A correlation between plasma p,p'-DDT levels and recency of arrival in Canada was found for the Bangladeshis. These data suggest a distinct pattern of tissue organochlorines, which we postulate relates to exposure prior to arrival in Canada and perhaps to the ongoing consumption of foods (other than St. Lawrence River sportfish) specific to these groups. PMID- 10092430 TI - Relation of Lake Ontario fish consumption, lifetime lactation, and parity to breast milk polychlorobiphenyl and pesticide concentrations. AB - Lactating female members and spouses of male members of the New York State Angler Cohort who agreed to provide breast milk samples were the subjects of this study. Questionnaires were provided to participants focusing on Lake Ontario fish consumption, reproductive history, and lactation history. Milk samples were analyzed for 77 polychlorinated biphenyls (PCB) congeners, 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (DDE), a metabolite of dichlorodiphenyltrichloroethane (DDT), hexachlorobenzene (HCB), and 1,1a,2,2,3,3a, 4,5,5,5a,5b,6 dodecachlorooctahydro-1,3, 4-methano-1H-cyclobuta[cd]pentalene (Mirex). The percentage of samples with quantifiable levels, above the limit of detection (LOD), varied among the individual congeners from 10 to 100%. Nine PCB congeners (designated by their IUPAC No.) and DDE were found in all of the 100 samples analyzed. These include the following, in decreasing order of concentration: DDE>153>138>180>118>187>188>177>200. Total PCB concentrations were estimated by taking the sum of the concentrations of all PCB congeners (up to 77 congeners) above their respective LOD in a given sample. PCB concentrations increased with increasing concentration of milk lipid. Lipid adjusted PCB concentrations increased as a function of maternal age. PCB congener profiles in milk favored the higher chlorinated congeners, with the four highest congeners having 5 to 7 chlorine atoms. Fish eaters had a significantly higher level of several major PCB congeners with congeners 153 and 138 being 1.36 and 1.34 times higher, respectively. PCB and DDE concentrations, expressed on a lipid basis, varied inversely with parity. The total number of months of lifetime lactation varied inversely with the total PCB concentration in breast milk. A similar relationship was evident for DDE. These data are of use for risk assessment in estimating the relative exposure to these environmental contaminants in breast fed infants whose mothers consumed contaminated Lake Ontario fish. PMID- 10092431 TI - Evaluation of the contamination of marine algae (Seaweed) from the St. Lawrence River and likely to be consumed by humans. AB - The goal of the study was to assess the contamination of marine algae (seaweeds) growing in the St. Lawrence River estuary and Gulf of St. Lawrence and to evaluate the risks to human health from the consumption of these algae. Algae were collected by hand at low tide. A total of 10 sites on the north and south shores of the St. Lawrence as well as in Baie des Chaleurs were sampled. The most frequently collected species of algae were Fucus vesiculosus, Ascophyllum nodosum, Laminaria longicruris, Palmaria palmata, Ulva lactuca, and Fucus distichus. Alga samples were analyzed for metals (As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, and Zn), iodine, and organochlorines. A risk assessment was performed using risk factors (e.g., RfD of the U.S. EPA, ADI of Health Canada, etc.). In general, concentrations in St. Lawrence algae were not very high. This was especially true for mercury and the organochlorines, concentrations of which were very low or below detection limits. Consequently, health risks associated with these compounds in St. Lawrence algae were very low. Iodine concentration, on the other hand, could be of concern with regard to human health. Regular consumption of algae, especially of Laminaria sp., could result in levels of iodine sufficient to cause thyroid problems. For regular consumers, it would be preferable to choose species with low iodine concentrations, such as U. lactuca and P. palmata, in order to prevent potential problems. Furthermore, it would also be important to assess whether preparation for consumption or cooking affects the iodine content of algae. Algae consumption may also have beneficial health effects. Scientific literature has shown that it is a good source of fiber and vitamins, especially vitamin B12. PMID- 10092432 TI - Sport-caught fish consumption and conception delay in licensed Michigan anglers. AB - Between 1993 and 1995, we surveyed 4931 licensed anglers aged 17-34 years residing in 10 Michigan counties bordering a Great Lake. Responses were received from 1443 anglers and 844 of their partners. Lifetime sport-caught fish consumption was estimated as the number of sport-caught fish meals consumed in the previous 12 months times years since 1970 in which sport-caught fish were consumed. Analysis was restricted to currently married couples (n=626). Lifetime sport-caught fish consumption was categorized in men as 0 (14%); 1-114 (27%); 115 270 (30%); 271-1127 (29%) meals; and in women as 0 (28%); 1-54 (26%); 55-138 (27%); fand 139-1127 (19%) meals, respectively. Conception delay (ever having failed to conceive after 12 months of trying) was reported by 13% of both men and women. Among men, the unadjusted odds ratios (OR) for conception delay were 1.2, 1.3, and 2.0 across the three increasing levels of sport-caught fish consumption compared to none (trend test P=0.06). After adjustment for age, race, region of Michigan, household income, educational attainment, smoking, alcohol consumption, and partner's sport fish consumption, the OR for conception delay in men were 1.4, 1.8, and 2.8, respectively. In women, unadjusted OR for conception delay were 0.9, 1.0, and 1.4 with increasing sport-caught fish consumption (trend test P=0.35). With the same covariates and the sport-caught fish consumption of the woman's partner included in the model, the OR were 0.8, 0.8, and 1.0, respectively. These data suggest a modest association, in men only, of sport caught fish consumption with risk of conception delay. PMID- 10092433 TI - Assessing environmental exposure to PCBs among Mohawks at Akwesasne through the use of geostatistical methods. AB - The Mohawk Nation at Akwesasne is a Native American community located along the St. Lawrence River in New York State, Ontario, and Quebec. One component of a multiphase human health study was to assess the impact of different pathways of human exposure resulting from the off-site migration of polychlorinated biphenyl (PCB) contamination in this area. This paper illustrates how mapped residential information and environmental sampling data can be united to assist in exposure assessment for epidemiologic studies using geographic information system (GIS) technology and statistical methods. A proportional sampling scheme was developed to collect 119 surface soils. Using a method of cross validation, the average estimated error can be computed and the best estimator can be selected. Seven spatial methods were examined to estimate surface soil PCB concentrations; the lowest relative mean error was 0.42% for Inverse 3 nearest neighbor weighted according to the inverse distance, and the highest relative mean error was 4.4% for Voronoi polygons. Residual plots indicated that all methods performed well except near some of the sampling points that formed the outer boundaries of the sampling distribution. PMID- 10092434 TI - Exposure assessment: serum levels of TCDD in Seveso, Italy. AB - Accurate exposure assessment is an important step in both risk assessment and epidemiologic studies involving potential human exposure to environmental toxicants. Various methods have been used to assess human exposure. These methods include models based on one's temporal and spatial nearness to the source, environmental levels of toxicant, and biological measures. We believe that the latter measure is the "gold standard." In this article we present the serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in residents of the contaminated zones in Seveso, Italy, in 1976, and delineate these data by age and gender. Some of these serum levels are among the highest ever reported and thus this population serves as a benchmark for comparison of human exposure and potential adverse health effects. One such potential population is that population consuming potentially contaminated fish. PMID- 10092435 TI - PCB congener patterns in rats consuming diets containing Great Lakes salmon: analysis of fish, diets, and adipose tissue. AB - As part of a multidisciplinary toxicological investigation into Great Lakes contaminants, chinook salmon were collected from Lake Huron (LH) and Lake Ontario (LO) and incorporated (as lyophilized fillets) into standard rat diets as 20 or 100% of the protein complement (5 or 20%, w/w diet-LH5, LH20, LO5, and LO20 diets). Final PCB concentrations in the experiment ranged from 3.15 ng/g in the control diet to 1080 ng/g in the high-dose (20%) LO diet, with maximal estimated daily consumption by the rats of 82microg PCBs/kg body wt in the LO20 dietary group. Seventeen PCB congeners, PCB 85, 99, 101, 105, 110, 118, 128, 129, 132, 138, 149, 153, 170, 177, 180, 187, and 199, occurred at >/=3.0% of the total PCBs in the fish with no major site differences. Cumulatively, these 17 congeners accounted for up to 75% of the total PCBs in the fish compared to 44 and 54% in two commercial Aroclors, 1254 and 1260, respectively. PCB 77 was the major "dioxin-like" congener in the fish, followed by PCB 126 and then PCB 169. All major dietary congeners bioaccumulated in the adipose tissue of the rats with the exception of PCB congeners 101, 110, 132, and 149. The group of 17 major congeners accounted for up to 71% of the total PCBs in adipose tissue samples collected from the rats following up to 19 weeks of diet ingestion. Of the coplanar PCB congeners, PCB 77 appeared to bioaccumulate to a lesser extent compared to PCBs 126 and 169. When comparing PCBs in the rat adipose tissue to PCB congeners in Canadian breast milk, PCBs 44, 49, 74, and 137 tended to occur in higher amounts in the human samples (contributing together 18.4 vs. 1.4% of the total PCB concentration), whereas PCB 129 occurred at higher levels in the rats (3.4 vs. 0.3% of the total PCB concentration, respectively). Although adipose tissue from the rats fed diets containing Great Lakes salmon had up to two orders of magnitude higher concentrations of PCBs compared to average human values, with the exception of some lower chlorinated congeners, similar major congeners tended to be present in both the rats in the present study and humans. PMID- 10092436 TI - Consumption of freshwater fish in Kahnawake: risks and benefits. AB - Kahnawake is a Mohawk community located on the south shore of the Saint Lawrence River near Montreal. A comprehensive study was conducted in 1996-1997 to address the local concern regarding health risks of contaminant exposure associated with freshwater fish consumption. Forty-two participants, including most of the identified active fishermen (n=33), were interviewed. Walleye, perch, bullhead, and smallmouth bass were the species most consumed. Average daily intake of locally caught fish was 23 g/day. Nutrient and contaminant levels of locally collected fish were analyzed. Fish were good sources of protein, polyunsaturated fatty acids (particularly omega-3 fatty acids), calcium, zinc, and iron. Levels of cadmium, lead, arsenic, polychlorinated biphenyls (PCBs), and other chlorinated pesticides were at least 10 times lower than the guideline levels. Mercury levels of some predatory fish exceeded the guideline of 0.5 microgram/g. Average daily intakes of all contaminants were below the guideline levels by a factor of 10 except for mercury. Average mercury intake rate was about one-third that of the guideline level (200 micrograms/week). Contrary to residents' perception, Kahnawake fish were not particularly contaminated. In view of the nutritional as well as cultural benefits, fishing and fish consumption may be promoted. PMID- 10092437 TI - Communicating their individual results to participants in an environmental exposure study: insights from clinical ethics. AB - The objective of this study was to formulate a framework for determining what information to communicate to individual subjects of a study measuring biomarkers of exposure, consistent with the principles of ethical clinical and research practice. Methods consisted of review of the scope of environmental exposure studies, including the use of biomarker measurement in clinical medicine and environmental research and the relevant principles of clinical ethics and research practice. An exposure biomarker study is designed to elucidate constitutional, behavioral, and environmental determinants of tissue concentrations of exogenous substances. Of itself, it is not designed to measure risk relations, those being the relation between biomarker levels and health outcomes. In many settings, measured tissue biomarker concentrations fall below those known or reasonably predicted to cause disease. Ethical clinical and research practice, aiming to maximize autonomy and beneficence and to minimize harm, requires that study findings concerning the determinants of exposure be communicated to study participants. In addition, investigators should reference clinical action levels beyond which individual biomarker results are routinely communicated to participants. When biomarkers have no known relation to risk, or when levels fall below action levels, it may be preferable not to communicate individual results, if this arrangement has been formalized at the time of informed consent. PMID- 10092438 TI - Proposed model of the relationship of risk information seeking and processing to the development of preventive behaviors. AB - We articulate a model that focuses on characteristics of individuals that might predispose them to seek and process information about health in different ways. Specifically, the model proposes that seven factors-(1) individual characteristics, (2) perceived hazard characteristics, (3) affective response to the risk, (4) felt social pressures to possess relevant information, (5) information sufficiency, (6) one's personal capacity to learn, (7) beliefs about the usefulness of information in various channels-will influence the extent to which a person will seek out this risk information in both routine and nonroutine channels and the extent to which he or she will spend time and effort analyzing the risk information critically. By adapting and synthesizing aspects of Eagly and Chaiken's Heuristic-Systematic Model and Ajzen's Theory of Planned Behavior, we also expect that people who engage in more effortful information seeking and processing are more likely to develop risk-related cognitions, attitudes, and behaviors that are more stable (i.e., less changeable or volatile) over time. Since most forms of health information campaigns attempt to get people to adopt habitual or lifestyle changes, factors leading to the stability or volatility of those behavioral changes are essential concerns. PMID- 10092439 TI - Public health implications. PMID- 10092440 TI - Morphological and functional alterations of human erythrocytes induced by SiO2 particles: An electron microscopy and dielectric spectroscopy study. AB - The interaction of aerosil particles with human erythrocytes was investigated by electron microscopy methods complemented with hemolysis and radio wave dielectric spectroscopy to elucidate the extent of morphological and functional modification induced by aerosil surface. Scanning electron microscopy and freeze-fracturing techniques were used to follow morphological and ultrastructural modifications and hemolysis tests and radio wave dielectric spectroscopy to monitor the membrane damage. All experimental results indicate that there is an effect depending on both silica concentration and incubation time. Our results are in good agreement with an interaction model based on membrane protein denaturation due to the electrostatic attraction between (-SiO-) groups at the silica surface and proteins embedded in the membrane. The process is time-limited and reaches saturation after about 20 min. The extent of the damage is determined mainly by the ratio between cell and aerosil surface, that is, aerosil concentration. Limited damage is observed, especially when little aerosil surface per cell is available. Conversely, strong membrane damage is obtained when aerosil surface is considerable. In any case, due to the high surface/volume of aerosil particles used in our experiments we obtained considerable membrane damage with small weight concentrations. PMID- 10092441 TI - In utero methylmercury exposure differentially affects the activities of selenoenzymes in the fetal mouse brain. AB - Pregnant ICR mice were subcutaneously injected with 0,5, or 3x3 mg Hg/kg of methylmercury (MeHg) on days 12,13, and 14(G12-14) of gestation and were sacrificed on G17. Activity of selenoenzymes, including glutathione peroxidase (GPx) and 5'- or 5-iodothyronine deiodinases (5'-DI, 5-DI), was determined in fetal brain and placenta. MeHg did not affect the concentration of Se in these tissues, while it significantly inhibited the activity of GPx in the fetal brain and placenta, but not in the maternal brain. Although the levels of thyroid hormones in the maternal and fetal plasma were not affected by MeHg, 5-DI decreased and 5'-DI increased in the fetal brain, as if they had responded to hypothyroidism. Because the level of T4 in the fetal plasma was not affected by MeHg, these changes in enzymatic activities may result in a harmful excess of T3 in the fetal brain. In addition, 5-DI activity was increased in the placenta of MeHg-treated mice. These effects of prenatal MeHg exposure on fetal and placental DIs differed from those of dietary-induced Se deficiency, where the activities of DIs were decreased or not affected. Further evaluation of the effect of MeHg on selenoenzymes, especially 5-DIs, is warranted. PMID- 10092442 TI - Assessment of Pb, Cd, Cu, and Zn exposures of 6- to 10-year-old children in Mumbai. AB - Population exposures to toxic trace metals are of great concern due to their nonbiodegradable nature and long biological half-lives for elimination from the body. Response to a toxic metal varies with age group; children are more sensitive and hence more at risk than others. The present study was therefore undertaken on 6- to 10-year-old children residing in various localities of Greater Mumbai and Thane. Blood samples from 566 children residing in 13 locations in Mumbai along with 410 air particulate samples and 64 "duplicate diet" samples were collected for this study. Levels of Pb, Cd, Cu, and Zn in these samples were estimated by differential pulse anodic stripping voltammetric technique. Intake of Pb, Cd, Cu, and Zn for 6- to 10-year-old children through ingestion and inhalation pathways have also been assessed. A correlation coefficient of 0.88 is observed between air lead and blood lead. It is also seen that every microgram increase in the Pb concentration in air (m-3) results in 3.56 microg increase in the blood Pb concentration (dl-1) in children. Similar correlation, however, was not observed in cases of Cd, Cu, and Zn. PMID- 10092443 TI - Cadmium uptake and defense mechanism in insect cells. AB - The uptake of cadmium and the defense mechanism against this heavy metal were studied in the Aedes albopictus C6/36 cell line. The internalization of cadmium was a very quick process and exhibited saturation kinetics over the metal concentration gradient (1.37 to 131 micromol/L). Cd toxicity and influx were both shown to be temperature dependent. The uptake was not influenced by a 2, 4 dinitrophenol pretreatment but was significantly decreased by the Ca2+ antagonist verapamil. These data suggest that cadmium is readily taken up through mediated transport, not requiring metabolic energy. A considerable amount of the metal passes through the Ca2+ channels, but probably (an)other transporting molecule(s) also play(s) an important role in the uptake process. The remarkable, nonsigmoid viability pattern of Cd-treated cultures suggests that CdCl2 concentrations above 33 micromol/L induce a cellular defense system. This phenomenon went together with increased protein synthesis. We found a major induction of a group consisting of 71-, 75-, and 78-kDa proteins, probably belonging to the HSP70 family, as similar proteins were induced by heat shock. A slight induction of a 120-kDa protein also occurred. At the highest Cd concentrations 98-, 108-, and 110-kDa proteins were induced. These data suggest that heat shock proteins may play an important role in the Aedes cell protection against Cd insult. PMID- 10092444 TI - Neurobehavioral and respiratory findings in jet engine repair workers: A comparison of exposed and unexposed volunteers. AB - Workers repairing jet engines had respiratory, rheumatic, and neurobehavioral symptoms. They had welded and ground stainless steel parts using hard metal tools and cleaned metal with chlorinated and fluorinated organic solvents. We compared 154 workers and 112 unexposed subjects, all volunteers of similar ages and with similar educational levels, for abnormalities on chest radiographs, spirometric measurements, and questionnaires. Also appraised were performance of reaction time, balance, blink reflex latency, color discrimination, Culture Fair, vocabulary, slotted pegboard, trail making A and B, profile of mood states (POMS), and frequencies of 35 symptoms. Compared to unexposed subjects, workers had significantly more respiratory symptoms but no differences in pulmonary function. They had significantly prolonged simple and choice reaction time (P<0.0001), and abnormal balance with eyes open and eyes closed (P<0. 0001), and abnormal color discrimination. Blink reflex latency was abnormal in both exposed workers and in local unexposed compared to other reference groups. Focus of the inquiry on lung disease helped ensure that for neurobehavioral tests confounding factors were minimal and known biases were small. We tentatively attribute the neurobehavioral impairments and increased symptom frequencies to chlorinated solvent exposure. Excessive respiratory symptoms are attributed to welding stainless steel combined with cigarette smoking. Specifically, manganese exposure may have affected the respiratory and the central nervous systems. PMID- 10092445 TI - Environment, health, and gender in Latin America: trends and research issues. AB - Over the past several decades, Latin America underwent rapid urbanization, a demographic shift led by women. Women now make up almost half of the economically active population and the feminization of urban poverty is being reported as well. The majority of men and women now work in unregulated, unorganized "informal" and nontraditional industries and services lacking occupational and environmental regulations. There is a marked paucity of health studies examining possible hazardous exposures, especially where gender-based social etiologies are concerned. This is true even in concentrated industries such as manufacturing assembly plants and in potentially hazardous occupations in mining and nontraditional agricultural exports, for which data from other disciplines are available and raise serious concerns. The need to ensure enough jobs at sufficient levels of income to alleviate poverty will remain a major challenge at the turn of the century and the environmental health implications of doing so could be far-reaching. What data are available and, more strikingly, the paucity of published epidemiologic studies warrant deep concern and support calls for urgent, multidisciplinary research into the health effects of the combined, multiple assaults of hazardous industrial waste, inadequate water and sewage treatment, and occupational exposures. Given the complex and varied work roles of women, the information reviewed also points to the need to conduct such research in the region within a social-etiologic framework of gender analysis. PMID- 10092446 TI - Research management in the Great Lakes and St. Lawrence River basins: challenges and opportunities. AB - Research management in the Great Lakes and St. Lawrence River basins is both challenging and filled with opportunities. From the perspective of public health practice, research management is more than just research managers managing discrete programs; it requires everyone involved in the process to become active participants, including researchers, communities, potential interest groups, policymakers, and other stakeholders. Agencies, organizations, and individuals responsible for managing research and resources in the Great Lakes and St. Lawrence River basins are facing problems of decreased research funding, data gaps, and research quality. Managers of research and resources in the basins face many challenges as they address these problems. They are challenged with strengthening the link between research and management in the face of decreasing resources and increasing expectations of results and findings while extending those results and findings to public health practice. A number of actions and activities have been proposed that can lead to better management of constrained programs, pooled resources, partnerships, targeted priorities, and improved effectiveness. With guidance and assistance from the International Joint Commission (IJC), research managers in the Great Lakes and St. Lawrence River basins who have initiated and maintained traditional research programs based on sound science are now adopting different and innovative management strategies. The research community must be proactive in articulating the role of science in bridging the gaps in knowledge between public health practice and regulatory programs. Supported by a firm foundation of credible science, critical assessment, and public service, basin research managers are recognizing the need to move outside the comfort zone and extend to areas previously unwelcomed or uncomfortable. PMID- 10092447 TI - Comparison of PCB congeners and pesticide levels between serum and milk from lactating women. AB - Samples of blood and milk were obtained from lactating women participating in the New York State Angler study. A total of seven women gave one blood and one milk sample at time intervals between blood and milk collection different for each woman. The time between samples varied from 3 to 318 days. One subject provided a second milk sample 219 days after the first milk sample. The samples were analyzed for 69 PCB congeners, DDE (a metabolite of DDT), Mirex, and hexachlorobenzene (HCB). Lipid content was determined by gravimetric analysis. The congener profiles in serum and milk were similar for each individual but different among all subjects. The sum of the concentrations of the congeners present above the limit of detection was used to estimate the total PCB concentration that was in the range of 2.6 to 5.8 ng/g of serum and 3.5 to 14.1 ng/g of milk. The ratio of serum to milk concentrations varied from 0.18 to 1.66 with a mean of 0.65+/-0.49 showing no consistency among individuals prior to adjusting the data for lipid content. The total PCB levels normalized for lipid content were 320-728 ng/g of serum lipid and 239-428 ng/g of milk lipid. The range of the lipid adjusted serum/milk ratio was 1.1 to 2.8 and the mean+/-SD serum/milk ratio was 1.9+/-0.5. The ranges of lipid adjusted serum concentration of DDE, HCB, and Mirex were 95 to 591, 8 to 48, and 3 to 29 ng/g lipid, respectively. The ranges of lipid adjusted milk concentration of DDE, HCB, and Mirex were 90 to 577, 11 to 22, and 1 to 10 ng/g lipid, respectively. For DDE, HCB, and Mirex, the means of the individual lipid adjusted serum to milk ratios were 1.5+/-0.7, 2.5+/-1.5, and 5. 3+/-4.6, respectively. Considerable differences were found among lipid adjusted concentrations of these environmental pollutants in serum and milk samples from the same individual. This suggests that body burden estimates in lactating women using different matrices may not be equivalent even when lipid adjusted values are used. PMID- 10092448 TI - Absence of nonresponse bias in a study of sport-caught Great Lakes fish consumption and conception failure. AB - INTRODUCTION: We have reported that men's lifetime sport-caught Great Lakes fish consumption was associated with lifetime prevalence of conception delay or failure. Those cross-sectional data were based on responses to a postal questionnaire. The present study was conducted to evaluate whether nonresponse bias could explain the cross-sectional findings. METHODS: We conducted telephone interviews with 230 men and 38 women who did not respond to the original survey, and compared these individuals to the original responders with respect to key demographic, behavioral, and reproductive characteristics. RESULTS: Nonresponders were approximately 1.5 years older at interview, were more likely to be Caucasian, and reported higher incomes than responders. Among men, nonresponders had fished fewer days in the past year (12% reported no fishing, compared to 4. 3% of responders). Almost one half of nonresponders reported no fish consumption in the past year, compared to one quarter of responders. Nonresponders were more likely than responders to have ever conceived a live-born child, had more children, and were less likely to intend to have additional children in the next 5 years. Among both responders and nonresponders there was an increased prevalence of a period of conception failure among men who reported consuming greater quantities of sport-caught Great Lakes fish. DISCUSSION: Our study provides support for the cross-sectional analyses presented previously, insofar as nonresponse bias is unlikely to have a major role in the observed association. PMID- 10092450 TI - 26th international congress on occupational health (ICOH2000) PMID- 10092449 TI - Effect of clofibrate, a peroxisome proliferator, in sea bass (Dicentrarchus labrax), a marine fish. AB - The effects of 35 or 70 mg/kg clofibrate on some peroxisomal, mitochondrial, and microsomal enzymes (markers of peroxisome proliferation) in liver, gill, and kidney of sea bass following 2 weeks i.p. treatment have been studied. Induction of lauric acid hydroxylase, UDP-glucuronyl transferase, palmitoyl-CoA oxidase, carnitine-palmitoyl-transferase, p-nitrophenylacetate hydrolase, and benzaldehyde and propionaldehyde dehydrogenase activities was not observed in any case. The clofibrate administration at the dose of 70 mg/kg induced in the liver the glutathione S-tranferase and reduced epoxide hydrolase activities. These results demonstrate that a marine fish species, such as sea bass, is refractory to peroxisome proliferation. PMID- 10092451 TI - Isolation of chloroform-resistant mutants of filamentous phage: localization in models of phage structure. AB - Interaction of fd or M13 filamentous phage with a chloroform/water interface induces morphological change, contracting the filaments sequentially into shortened rods (I-forms), and then into spheroidal particles (S-forms). To further investigate this phage contraction, 34 and 26 chloroform-resistant isolates of fd and M13, respectively, were selected after chloroform treatment of wild-type phages at pH 8. 2 and 4 degrees C. DNA sequencing of gene VIII of the 34 fd isolates revealed five different mutants: these were D5H, M28L, V31L, I37T, and S50T. All 26 M13 isolates were I37T. These mutants exhibited variable sensitivity to chloroform, but all contracted much more slowly than wild-type phage during treatment at 4 degrees C. They all contracted like wild-type phage at 37 degrees C. Site-directed mutagenesis showed that the indicated single mutations carried the chloroform resistance. In structural models of the phage, the D5H locus is on the outside and the S50T locus is on the inside. The M28L and I37T loci are buried in a mostly hydrophobic region in the middle. Although these four mutants are spread out radially, they are localized in the axial direction into a thin disk in the model. The last mutant locus, V31L, is out of this disk, but this locus is proximal to the M28L and I37T loci and also in contact with the surface via a deep hydrophobic hole or depression. These five mutants, their locations, and their variable affects on contraction suggest that chloroform induced contraction involves a specific mechanism rather than a generalized solvent-induced denaturation and that the critical structural changes occur in a localized level in the phage. These results add weight to suggestions that the sequential contraction of filaments-->I-forms-->S-forms mimic corresponding steps in phage penetration, and, in the reverse order, for phage assembly. PMID- 10092453 TI - Inventory, assembly and analysis of Bacillus subtilis ABC transport systems. AB - We have undertaken the inventory and assembly of the ATP binding cassette (ABC) transporter systems in the complete genome of Bacillus subtilis. We combined the identification of the three protein partners that compose an ABC transporter (nucleotide-binding domain, NBD; membrane spanning domain, MSD; and solute binding protein, SBP) with constraints on the genetic organization. This strategy allowed the identification of 86 NBDs in 78 proteins, 103 MSD proteins and 37 SBPs. The analysis of transcriptional units allows the reconstruction of 59 ABC transporters, which include at least one NBD and one MSD. A particular class of five dimeric ATPases was not associated to MSD partners and is assumed to be involved either in macrolide resistance or regulation of translation elongation. In addition, we have detected five genes encoding ATPases without any gene coding for MSD protein in their neighborhood and 11 operons that encode only the membrane and solute-binding proteins. On the bases of similarities, three ATP binding proteins are proposed to energize ten incomplete systems, suggesting that one ATPase may be recruited by more than one transporter. Finally, we estimate that the B. subtilis genome encodes for at least 78 ABC transporters that have been split in 38 importers and 40 extruders. The ABC systems have been further classified into 11 sub-families according to the tree obtained from the NBDs and the clustering of the MSDs and the SBPs. Comparisons with Escherichia coli show that the extruders are over-represented in B. subtilis, corresponding to an expansion of the sub-families of antibiotic and drug resistance systems. PMID- 10092452 TI - Lack of evolutionary stasis during alternating replication of an arbovirus in insect and mammalian cells. AB - The evolution of vesicular stomatitis virus (VSV) in a constant environment, consisting of either mammalian or insect cells, has been compared to the evolution of the same viral population in changing environments consisting in alternating passages in mammalian and insect cells. Fitness increases were observed in all cases. An initial fitness loss of VSV passaged in insect cells was noted when fitness was measured in BHK-21 cells, but this effect could be attributed to a difference of temperature during VSV replication at 37 degrees C in BHK-21 cells. Sequencing of nucleotides 1-4717 at the 3' end of the VSV genome (N, P, M and G genes) showed that at passage 80 the number of mutations accumulated during alternated passages (seven mutations) is similar or larger than that observed in populations evolving in a constant environment (two to four mutations). Our results indicate that insect and mammalian cells can constitute similar environments for viral replication. Thus, the slow rates of evolution observed in natural populations of arboviruses are not necessarily due to the need for the virus to compromise between adaptation to both arthropod and vertebrate cell types. PMID- 10092454 TI - Differential binding of the Escherichia coli HU, homodimeric forms and heterodimeric form to linear, gapped and cruciform DNA. AB - We have shown recently that the relative abundance of the three dimeric forms (alpha2, alphabeta and beta2) of the HU protein from Escherichia coli varies during growth and in response to environmental changes. Using gel retardation assays we have compared the DNA binding properties of the three dimers with different DNA substrates. The determination of their DNA binding parameters shows that the relative affinities of HUalphabeta and HUalpha2 are comparable. Both recognize, with a high degree of affinity under stringent conditions, cruciform structures or DNA molecules with a nick or a gap, whereas they bind to linear DNA only at low salt. DNA containing a gap of two nucleotides is in fact the substrate recognized with the highest degree of affinity by these two forms under all conditions. Conversely, HUbeta2 binds very poorly to duplex DNA and shows a much lower affinity for nicked or gapped DNAs. However, HUbeta2 binds to cruciform DNA structures almost as well as HUalphabeta and HUalpha2. This almost exclusive binding of HUbeta2 to a unique substrate is surprising in regards of the quasi identity, in the three forms, of the flexible arms considered as the DNA-binding domains of the three forms of HU. Cruciform DNA may stabilize HUbeta2 structure which could be structurally defective. PMID- 10092455 TI - Detection of anticodon nuclease residues involved in tRNALys cleavage specificity. AB - The tRNALys-specific anticodon nuclease exists in latent form in Escherichia coli strains containing the optional prr locus. The latency is a result of a masking interaction between the anticodon nuclease core-polypeptide PrrC and the Type IC DNA restriction-modification enzyme EcoprrI. Activation of the latent enzyme by phage T4-infection elicits cleavage of tRNALys 5' to the wobble base, yielding 5' OH and 2', 3'-cyclic phosphate termini. The N-proximal half of PrrC has been implicated with (A/G) TPase and EcoprrI interfacing activities. Therefore, residues involved in recognition and cleavage of tRNALys were searched for at the C-half. Random mutagenesis of the low-G+C portion encoding PrrC residues 200-313 was performed, followed by selection for loss of anticodon nuclease-dependent lethality and production of full-sized PrrC-like protein. This process yielded a cluster of missense mutations mapping to a region highly conserved between PrrC and two putative Neisseria meningitidis MC58 homologues. This cluster included two adjacent members that relaxed the inherent enzyme's cleavage specificity. We also describe another mode of relaxed specificity, due to mere overexpression of PrrC. This mode was shared by wild-type PrrC and the other mutant alleles. The additional substrates recognised under the promiscuous conditions had, in general, anticodons resembling that of tRNALys. Taken together, the data suggest that the anticodon of tRNALys harbours anticodon nuclease identity elements and implicates a conserved region in PrrC in their recognition. PMID- 10092456 TI - The functional cycle and regulation of the Thermus thermophilus DnaK chaperone system. AB - The Escherichia coli DnaK (DnaKEco) chaperone cycle is tightly regulated by the cochaperones DnaJ, which stimulates ATP hydrolysis, and GrpE, which acts as a nucleotide exchange factor. The Thermus thermophilus DnaK (DnaKTth) system additionally comprises the DnaK-DnaJ assembly factor (DafATth) that is mediating formation of a 300 kDa DnaKTth. DnaJTth.DafATth complex.A model peptide derived from the tumor suppressor protein p53 was used to dissect the regulation of the individual kinetic key steps of the DnaKTth nucleotide/chaperone cycle. As with DnaKEco the DnaKTth.ATP complex binds substrates with reduced affinity and large exchange rates compared to the DnaKTth.ADP.Pi state. In contrast to DnaKEco, ADP Pi release is slow compared to the rate of hydrolysis, reversing the balance of the two functional nucleotide states. Whereas GrpETth stimulates nucleotide release from DnaKTth, DnaJTth does not accelerate ATP hydrolysis under various experimental conditions. However, it exerts influence on the interaction of DnaKTth with substrates: in the presence of DafATth, DnaJTth inhibits substrate binding, and substrate already bound to DnaKTth is displaced by DnaJTth and DafATth, indicating competitive binding of DnaJTth/DafATth and substrate. It thus appears that the DnaKTth. DnaJTth.DafATth complex as isolated from T. thermophilus does not represent the active species in the DnaKTth chaperone cycle. Isothermal titration calorimetry showed that the ternary complex of DnaKTth, DnaJTth and DafATth is assembling with high affinity, whereas binary complexes of DnaKTth and DnaJTth or DafATth were not detectable, indicating highly synergistic formation of the 300 kDa DnaKTth. DnaJTth.DafATth complex. Based on these results, a model describing the DnaKTth chaperone cycle and its regulation by cochaperones is proposed where DnaKTth. DnaJTth.DafATth constitutes the resting state, and a DnaKTth. substrate.DnaJTth complex is the active chaperone species. The novel factor DafATth that mediates interaction of DnaKTth with DnaJTth would thus serve as a "template" to stabilise the ternary DnaKTth.DafATth.DnaJTth complex until it is replaced by substrate proteins under heat shock conditions. PMID- 10092457 TI - Cavity defects in the procapsid of bacteriophage P22 and the mechanism of capsid maturation. AB - Bacteriophage P22 belongs to a family of double-stranded DNA viruses that share common morphogenetic features like DNA packaging into a procapsid precursor and maturation. Maturation involves cooperative expansion of the procapsid shell with concomitant lattice stabilization. The expansion is thought to be mediated by movement of two coat protein domains around a hinge. The metastable conformation of subunit within the procapsid lattice is considered to constitute a late folding intermediate. In order to understand the mechanism of expansion it is necessary to characterize the interactions stabilizing procapsid and mature capsid lattices, respectively. We employ pressure dissociation to compare subunit packing within the procapsid and expanded lattice. Procapsid shells contain larger cavities than the expanded shells, presumably due to polypeptide packing defects. These defects contribute to the metastable nature of the procapsid lattice and are cured during expansion. Improved packing contributes to the increased stability of the expanded shell. Comparison of two temperature sensitive folding (tsf) mutants of coat protein (T294I and W48Q) with wild-type coat revealed that both mutations markedly destabilized the procapsid shell and yet had little effect on relative stability of the monomeric subunit. Thus, the regions affected by these packing defects constitute subunit interfaces of the procapsid shell. The larger activation volume of pressure dissociation observed for both T294I and W48Q indicates that the decreased stability of these particles is due to increase of cavity defects. These defects in the procapsid lattice are cured upon expansion suggesting that the intersubunit contacts affected by tsf mutations are absent or rearranged in the mature shell. The energetics of the in vitro expansion reaction also suggests that entropic stabilization contributes to the large free energy barrier for expansion. PMID- 10092458 TI - Probing the physical basis for trp repressor-operator recognition. AB - The bacterial repressor protein, trp repressor, is one of the best studied transcriptional regulatory proteins in terms of function, structure, dynamics and stability. Despite these significant advances, the structural and energetic basis for the specific recognition of its operator sites by trp repressor remains poorly understood. In fact, recognition in this system is controled by the binding of the co-repressor ligand, l-tryptophan, as well as by conformational and dynamic properties of the operator targets, DNA sequence-dependent control of the oligomerization properties of the repressor, water-mediated interactions, and specific interactions involving the peptide backbone and phosphate moieties. Moreover, only one direct contact between the protein and the DNA is evident from the crystallographically determined structure of the complex. In an attempt to better define how the various sequence elements in the operator target contribute to this complex control of affinity and cooperativity of trp repressor binding, we have studied the binding of trp repressor to a series of mutated operator targets using fluorescence anisotropy, which provides very high quality data allowing fairly precise estimations of the affinities involved. We conclude from these studies that even on very small (25 bp) targets, the repressor binds slightly cooperatively, populating a 2:1 dimer/DNA complex, and then at higher concentrations a third dimer is bound with significantly lower affinity, revealing an inherent asymmetry in the trpEDCBA-derived target. Investigation of the basis for the asymmetry implicates the identity of the second base in the so called structural half-site GNACT, which apparently influences the switch between tandem and simple binding. Mutation of the C or the T bases in the structural half-site abolishes all specificity in binding, and alteration of the single direct contact, the G of the structural half-site, or the central TTAA significantly lowers the affinity of the dimer for its site, without modifying the apparent cooperativity. Finally, we note that the order of affinity is conserved in the absence of the co-repressor, and moreover, it is in all cases significantly higher than that observed for holo-repressor binding to non specific DNA, indicating that one cannot simply equate apo-repressor and non specific binding. PMID- 10092459 TI - Crystal structures of phenylalanyl-tRNA synthetase complexed with phenylalanine and a phenylalanyl-adenylate analogue. AB - The crystal structures of Thermus thermophilus phenylalanyl-tRNA synthetase (PheRS) complexed with phenylalanine and phenylalaninyl-adenylate (PheOH-AMP), the synthetic analogue of phenylalanyl-adenylate, have been determined at 2.7A and 2.5A resolution, respectively. Both Phe and PheOH-AMP are engulfed in the active site cleft of the catalytic alpha-subunit of PheRS, and neither makes contact with the PheRS beta-subunit. The conformations and binding of Phe are almost identical in both complexes. The recognition of Phe by PheRS is achieved through a mixture of multiple van der Waals interactions and hydrogen bonds. The side-chain of the Phe substrate is sandwiched between the hydrophobic side-chains of Phealpha258 and Phealpha260 on one side, and the main-chain atoms of the two adjacent beta-strands on the other. The side-chains of Valalpha261 and Alaalpha314 form the back wall of the amino acid binding pocket. In addition, PheRS residues (Trpalpha149, Seralpha180, Hisalpha178, Argalpha204, Glnalpha218, and Glualpha220) form a total of seven hydrogen bonds with the main-chain atoms of Phe. The conformation of PheOH-AMP and the network of interactions of its AMP moiety with PheRS are reminiscent of the other class II synthetases. The structural similarity between PheRS and histidyl-tRNA synthetase extends to the amino acid binding site, which is normally unique for each enzyme. The complex structures suggest that the PheRS beta-subunit may affect the first step of the reaction (formation of phenylalanyl-adenylate) through the metal-mediated conserved alpha/beta-subunit interface. The modeling of tyrosine in the active site of PheRS revealed no apparent close contacts between tyrosine and the PheRS residues. This result implies that the proofreading mechanism against activated tyrosine, rather than direct recognition, may play the major role in the PheRS specificity. PMID- 10092460 TI - Functionally important correlated motions in the single-stranded DNA-binding protein encoded by filamentous phage Pf3. AB - To elucidate the interplay between different parts of dimeric single-stranded DNA binding proteins we have studied the correlated motions in the protein encoded by filamentous phage Pf3 via the combined use of 15N-NMR relaxation experiments, molecular dynamics simulations and essential dynamics calculations. These studies provide insight into the mechanism underlying the protein-DNA binding reaction. The most important motions can be described by a few essential modes. Most outstanding is the correlated symmetric motion of the DNA-binding wings, which are far apart in the structure. This motion determines the access of DNA to the DNA-binding domain. A correlation between the motion of the DNA-binding wing and the complex loop is indicated to play a role in the cooperative binding of the protein to DNA. These motions are in the nanosecond regime in correspondence with the 15N-NMR relaxation experiments. PMID- 10092461 TI - Crystallographic structures of bovine copper-zinc superoxide dismutase reveal asymmetry in two subunits: functionally important three and five coordinate copper sites captured in the same crystal. AB - A key feature of the generally accepted catalytic mechanism of CuZn superoxide dismutase (CuZnSOD) is the breakage of the imidazolate bridge between copper and zinc and the loss of a coordinated water molecule from copper on reduction from Cu(II) to Cu(I). Crystal structures exist for the enzyme from a number of sources in the oxidised, five coordinate copper form. For the reduced form two structures from different sources have been determined only recently but provide contradictory results. We present crystal structures of bovine CuZnSOD (BSOD) in two different space groups. The structure of the P212121 form (pBSOD), at 1.65 A resolution clearly shows one subunit with Cu in the five coordinate, oxidised form, and the other with Cu in the three coordinate form expected for the reduced state. This mixed state of pBSOD is confirmed by XANES data of these crystals. The pBSOD structure has thus captured each subunit in one of the two oxidation state conformations and thus provides direct crystallographic evidence for the superoxide dismutase mechanism involving the breakage of the imidazole bridge between Cu and Zn. A shift in the position of copper in subunit A poises the catalytic centre to undergo the first stage of catalysis via dissociation of Cu from His61 with a concomittant movement of the coordinated water molecule towards His61, which rotates by approximately 20 degrees, enabling it to form a hydrogen bond to the water molecule. The Cu-Zn separation in the reduced site is increased by approximately 0.5 A. In contrast the 2.3 A resolution structure in space group C2221 (cBSOD) shows both of the Cu atoms to be in the five coordinate, oxidised form but in this space group the whole of subunit A is significantly more disordered than subunit B. An examination of published structures of "oxidised" SODs, shows a trend towards longer Cu-Zn and Cu-His61 separations in subunit A, which together with the structures reported here indicate a potential functional asymmetry between the subunits of CuZnSODs. We also suggest that the increased separation between Cu and Zn is a precursor to breakage of His61. PMID- 10092462 TI - Solution structure of the transactivation domain of ATF-2 comprising a zinc finger-like subdomain and a flexible subdomain. AB - Activating transcription factor-2 (ATF-2) is a transcription factor that binds to cAMP response element (CRE). ATF-2 contains two functional domains, an N-terminal transactivation domain and a C-terminal DNA-binding domain. The DNA-binding domain contains the basic leucine zipper (bZip) motif. Here, the three dimensional structure of the transactivation domain of ATF-2 has been determined by NMR. The transactivation domain consists of two subdomains: the structure of an N-terminal half (N-subdomain) is well determined, while a C-terminal half (C subdomain) takes a highly flexible and disordered structure. The architecture of the N-subdomain is very similar to that of the well-known zinc finger motif found in DNA-binding domains, consisting of an antiparallel beta-sheet and an alpha helix. The zinc atom is tetrahedrally coordinated to two cysteine residues and two histidine residues. Amino acids that form the hydrophobic core in all of the DNA-binding zinc fingers are well conserved in the N-subdomain of the transactivation domain, whereas some amino acids that are responsible for binding to the phosphate backbone of DNA in the DNA-binding zinc fingers are substituted with other amino acids. The flexible C-subdomain, which contains two threonine residues that the stress-activated protein kinases phosphorylate, is likely to undergo a conformational change by specific binding to a target protein. PMID- 10092463 TI - The cellulose-binding domains from Cellulomonas fimi beta-1, 4-glucanase CenC bind nitroxide spin-labeled cellooligosaccharides in multiple orientations. AB - The N-terminal cellulose-binding domains CBDN1 and CBDN2 from Cellulomonas fimi cellulase CenC each adopt a jelly-roll beta-sandwich structure with a cleft into which amorphous cellulose and soluble cellooligosaccharides bind. To determine the orientation of the sugar chain within these binding clefts, the association of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl) spin-labeled derivatives of cellotriose and cellotetraose with isolated CBDN1 and CBDN2 was studied using heteronuclear 1H-15N NMR spectroscopy. Quantitative binding measurements indicate that the TEMPO moiety does not significantly perturb the affinity of the cellooligo-saccharide derivatives for the CBDs. The paramagnetic enhancements of the amide 1HN longitudinal (DeltaR1) and transverse (DeltaR2) relaxation rates were measured by comparing the effects of TEMPO-cellotetraose in its nitroxide (oxidized) and hydroxylamine (reduced) forms on the two CBDs. The bound spin label affects most significantly the relaxation rates of amides located at both ends of the sugar-binding cleft of each CBD. Similar results are observed with TEMPO-cellotriose bound to CBDN1. This demonstrates that the TEMPO-labeled cellooligosaccharides, and by inference strands of amorphous cellulose, can associate with CBDN1 and CBDN2 in either orientation across their beta-sheet binding clefts. The ratio of the association constants for binding in each of these two orientations is estimated to be within a factor of five to tenfold. This finding is consistent with the approximate symmetry of the hydrogen-bonding groups on both the cellooligosaccharides and the residues forming the binding clefts of the CenC CBDs. PMID- 10092464 TI - Exploring the kinetic requirements for enhancement of protein folding rates in the GroEL cavity. AB - The chaperonin system, GroEL and GroES of Escherichia coli enable certain proteins to fold under conditions when spontaneous folding is prohibitively slow as to compete with other non-productive channels such as aggregation. We investigated the plausible mechanisms of GroEL-mediated folding using simple lattice models. In particular, we have investigated protein folding in a confined environment, such as those offered by the GroEL, to decipher whether rate and yield enhancement can occur when the substrate protein is allowed to fold within the cavity of the chaperonins. The GroEL cavity is modeled as a cubic box and a simple bead model is used to represent the substrate chain. We consider three distinct characteristic of the confining environment. First, the cavity is taken to be a passive Anfinsen cage in which the walls merely reduce the available conformation space. We find that at temperatures when the native conformation is stable, the folding rate is retarded in the Anfinsen cage. We then assumed that the interior of the wall is hydrophobic. In this case the folding times exhibit a complex behavior. When the strength of the interaction between the polypeptide chain and the cavity is too strong or too weak we find that the rates of folding are retarded compared to spontaneous folding. There is an optimum range of the interaction strength that enhances the rates. Thus, above this value there is an inverse correlation between the folding rates and the strength of the substrate cavity interactions. The optimal hydrophobic walls essentially pull the kinetically trapped states which leads to a smoother the energy landscape. It is known that upon addition of ATP and GroES the interior cavity of GroEL offers a hydrophilic-like environment to the substrate protein. In order to mimic this within the context of the dynamic Anfinsen cage model, we allow for changes in the hydrophobicity of the walls of the cavity. The duration for which the walls remain hydrophobic during one cycle of ATP hydrolysis is allowed to vary. These calculations show that frequent cycling of the wall hydrophobicity can dramatically reduce the folding times and increase the yield as well under non permissive conditions. Examination of the structures of the substrate proteins before and after the change in hydrophobicity indicates that there is global unfolding involved. In addition, it is found that a fraction of the molecules kinetically partition to the native state in accordabce with the iterative annealing mechanism. Thus, frequent "unfoldase" activity of chaperonins leading to global unfolding of the polypeptide chain results in enhancement of the folding rates and yield of the folded protein. We suggest that chaperonin efficiency can be greatly enhanced if the cycling time is reduced. The calculations are used to interpret a few experiments on chaperonin-mediated protein folding. PMID- 10092465 TI - Comparison of SH3 and SH2 domain dynamics when expressed alone or in an SH(3+2) construct: the role of protein dynamics in functional regulation. AB - Protein dynamics play an important role in protein function and regulation of enzymatic activity. To determine how additional interactions with surrounding structure affects local protein dynamics, we have used hydrogen exchange and mass spectrometry to investigate the SH2 and SH3 domains of the protein tyrosine kinase Hck. Exchange rates of isolated Hck SH3 and SH2 domains were compared with rates for the same domains when part of a larger SH(3+2) construct. Increased deuterium incorporation was observed for the SH3 domain in the joint construct, particularly near the SH2 interface and the short sequence that connects SH3 to SH2, implying greater flexibility of SH3 when it is part of SH(3+2). Slow cooperative unfolding of the SH3 domain occurred at the same rate in isolated SH3 as in the SH(3+2) construct, suggesting a functional significance for this unfolding. The SH2 domain displayed relatively smaller changes in flexibility when part of the SH(3+2) construct. These results suggest that the domains influence each other. Further, our results imply a link between functional regulation and structural dynamics of SH3 and SH2 domains. PMID- 10092466 TI - Exploring structures in protein folding funnels with free energy functionals: the denatured ensemble. AB - We discuss the formulation of free energy functionals that describe the formation of structure in partially folded proteins. These free energy functionals take into account the inhomogeneous nature of contact energies, chain entropy and cooperative contributions reflecting the many body character of some folding forces like hydrophobicity, but do not directly account for non-native contacts because they assume the validity of the minimal frustration principle. We show how the free energy functionals can be used to interpret experiments on partially folded proteins that probe the fractional occupancy of specific local structures. In particular, we study the hydrogen protection factors in lysozyme studied in transient experiments by Gladwin and Evans and by Nash and Jonas using equilibrium pressure denaturation and the NMR order parameters measured by Dobson and Kim for the homologous protein alpha-lactalbumin. PMID- 10092467 TI - Exploring structures in protein folding funnels with free energy functionals: the transition state ensemble. AB - We use free energy functionals that account for the partial ordering of residues in the transition state ensemble to characterize the free energy surfaces for fast folding proteins. We concentrate on chymotrypsin inhibitor and lambda repressor. We show how the explicit cooperativity that can arise from many body forces, such as side-chain ordering or hydrophobic surface burial, determines the crossover from folding with a large delocalized nucleus and the specific small classical nucleus of the type envisioned in nucleation growth scenarios. We compare the structural correlations present in the transition state ensemble obtained from free energy functionals with those inferred from experiment using extrathermodynamic free energy relations for folding time obtained via protein engineering kinetics experiments. We also use the free energy functionals to examine both the size of barriers and multidimensional representations of the free energy profiles in order to address the question of appropriate reaction coordinates for folding. PMID- 10092468 TI - Alignment and structure prediction of divergent protein families: periplasmic and outer membrane proteins of bacterial efflux pumps. AB - Broad-specificity efflux pumps have been implicated in multidrug-resistant strains of Pseudomonas aeruginosa and other Gram-negative bacteria. Most Gram negative pumps of clinical relevance have three components, an inner membrane transporter, an outer membrane channel protein, and a periplasmic protein, which together coordinate efflux from the cytoplasmic membrane across the outer membrane through an unknown mechanism. The periplasmic efflux proteins (PEPs) and outer membrane efflux proteins (OEPs) are not obviously related to proteins of known structure, and understanding the structure and function of these proteins has been hindered by the difficulty of obtaining reasonable multiple alignments. We present a general strategy for the alignment and structure prediction of protein families with low mutual sequence similarity using the PEP and OEP families as detailed examples. Gibbs sampling, hidden Markov models, and other analysis techniques were used to locate motifs, generate multiple alignments, and assign PEP or OEP function to hypothetical proteins in several species. We also developed an automated procedure which combines multiple alignments with structure prediction algorithms in order to identify conserved structural features in protein families. This process was used to identify a probable alpha helical hairpin in the PEP family and was applied to the detection of transmembrane beta-strands in OEPs. We also show that all OEPs contain a large tandem duplication, and demonstrate that the OEP family is unlikely to adopt a porin fold, in contrast to previous predictions. PMID- 10092469 TI - An Examination of the Joint Effects of Affective Experiences and Job Beliefs on Job Satisfaction and Variations in Affective Experiences over Time. AB - This study investigated the joint influences of episodic levels of pleasant mood at work and beliefs about one's job on judgments of job satisfaction, as well as examining the prediction of the patterns of affective states over time. Twenty four managerial workers completed a diary during work hours which required them to report their mood state at four different times during the workday. The diaries were completed for 16 workdays. At a separate time they completed a measure of overall satisfaction, a Valence-Instrumentality-Expectancy (VIE) measure of beliefs about the job and two dispositional variables, dispositional happiness and affect intensity. Results showed that average levels of pleasant mood over the 16 days and VIE beliefs about the job made significant and independent contributions to the prediction of overall job satisfaction and did so over and above the contribution of dispositional happiness. Results also indicated that individual differences in affective intensity predicted the variability of pleasant mood over time as well as mean levels of mood activation. Finally, spectral analyses applied to the series of mood observations showed that the variability over time in the series of mood observations showed two definite cycles, one corresponding to a daily cycle and one corresponding to a two-period oscillation in mood. Results are discussed in terms of the joint influences of affective experiences and job beliefs on job attitudes and the importance of studying affect over time independent of job satisfaction. Copyright 1999 Academic Press. PMID- 10092470 TI - On the Social Psychology of Agency Relationships: Lay Theories of Motivation Overemphasize Extrinsic Incentives. AB - Three laboratory studies and one field study show that people generally hold lay theories which contain an extrinsic incentives bias-people predict that others are more motivated than themselves by extrinsic incentives (job security, pay) and less motivated by intrinsic incentives (learning new things). The extrinsic incentives bias can be separated from a self-serving bias and it provides an empirical counterexample to the traditional actor-observer effect in social psychology (although its theoretical explanation is similar). This kind of bias may hinder organizations from organizing because people who act as principals may use improper lay theories to offer inappropriate deals to agents. Copyright 1999 Academic Press. PMID- 10092471 TI - Testing the Compatibility Test: How Instructions, Accountability, and Anticipated Regret Affect Prechoice Screening of Options. AB - Subjects screened a set of jobs, retaining those for which they wished to apply and rejecting those that were no longer under consideration. In Experiment 1, subjects who indicated the jobs for which they would apply/not apply screened out fewer jobs than those with instructions to reject/not reject or those with instructions simply to screen (control). There were no differences between the reject and control conditions. Experiment 2 used a design similar to that of Experiment 1, but subjects were made accountable for their screening judgments. The reject-apply discrepancy remained, but the accountability manipulation made the subjects more stringent in their screening compared to those who were not accountable for their judgments. In Experiment 3, subjects were told to consider either the regret resulting from retaining a bad option (regret bad) or the regret from rejecting a good option (regret good). Subjects in the regret bad condition rejected more jobs than did subjects in the regret good condition, but not more than subjects in the control condition. As predicted by image theory, the normal screening process appears to be to screen out the bad options rather than screen in the good options. This is demonstrated by screening in the control condition being similar to screening under the reject instructions (Experiment 1) and under regret bad instructions (Experiment 3), since these conditions were shown to focus attention on the bad options. Copyright 1999 Academic Press. PMID- 10092472 TI - Studies on a haemolymph lectin isolated from Rhodnius prolixus and its interaction with Trypanosoma rangeli. AB - We demonstrated that in Rhodnius prolixus haemocyte monolayers, both Trypanosoma cruzi and Trypanosoma rangeli are capable of inducing haemocyte/parasite clump formation. We also purified, by one-step affinity chromatography, a haemolymph galactoside-binding lectin from R. prolixus which we believe could play an important role in the development of T. rangeli in the haemocoel of the insect vector. This lectin markedly enhanced the activation of clump formation by T. rangeli in R. prolixus haemocyte monolayers, with an increase in clump size and haemocyte aggregation. The haemolymph lectin also significantly affected the motilitity and survival of T. rangeli culture short forms, but not the long forms, when they were incubated in vitro. This molecule is also one of the few described in insects with agglutination activity independent of calcium ions. The partial N-terminal amino acid sequence of this lectin demonstrated similarity to a bacterial xylulose kinase and in preliminary experiments the purified haemolymph lectin phosphorylated a tyrosine kinase substrate in a dose-dependent manner. The possible role of this haemolymph lectin in the life cycle of T. rangeli is discussed. PMID- 10092473 TI - Haemobartonellosis in squirrel monkeys (Saimiri sciureus): antagonism between Haemobartonella sp. and experimental Plasmodium falciparum malaria. AB - A hemotropic parasite of the genus Haemo bartonella (rickettsial parasite of the Family Anaplasmataceae) is responsible for latent asymptomatic infection in colony-born Saimiri monkeys. Indeed, many of these animals develop a patent Haemobartonella infection following splenectomy. Such patent parasitism is characterized by an intense Haemobartonella parasitemia which peaks between days 12 and 14 after removal of the spleen and then decreases to become undetectable between days 25 and 30. During the resolving phase of parasitemia, a moderate anemia associated with monocytosis and erythrophagocytosis is observed. In certain Saimiri monkeys, Haemobartonella parasitemia remains latent following removal of the spleen. This indicates that the spleen plays a role but is not necessary to maintain latent Haemobartonella parasitism. It also suggests the existence of heterogeneity in the host immune reactivity to the parasite. Latent or patent haemobartonellosis might raise a problem when Saimiri monkeys are used as experimental hosts of Plasmodium falciparum asexual blood stages, as already noticed with "rodent malaria." Thus we investigated the relationship between Haemobartonella and P. falci parum in splenectomized monkeys. When animals harboring latent Haemobartonella sp. were infected with P. falciparum, the former remained latent and exerted no influence on the course of the P. falciparum parasitemia. In constrast, when P. falciparum was initiated in animals which were in the process of developing patent haemobarto nellosis, the course of the former was protracted and either the animal resisted longer, or it self-cleared the P. falciparum infection. Conversely, patent haemobartonellosis was delayed when splenectomy was performed at different times after initiation of P. falciparum infection in intact monkeys. Our results do not allow us to draw conclusions as to the mechanism(s) of the antagonism between the two parasites, but they emphasize the need to monitor the presence of Haemobartonella when splenectomized Saimiri monkeys are used as experimentals hosts for P. falciparum parasitism. PMID- 10092474 TI - Trypanosoma rangeli: discrimination from Trypanosoma cruzi based on a variable domain from the large subunit ribosomal RNA gene. AB - 306-314. Three synthetic oligonucleotides corresponding to sequences within the D7a divergent domain of the large subunit ribosomal RNA gene have been used to amplify the total DNA of Trypanosoma rangeli and Trypanosoma cruzi, two morphologically similar protozoa with overlapping geographical distribution and hosts. The two organisms may be distinguished by the electrophoretic mobilities of their respective amplification products. For T. rangeli a 210-bp product was obtained. The presence of this fragment was confirmed in 14 T. rangeli strains. For T. cruzi two possible amplification products were originated: a 265-bp DNA fragment for strains typed as lineage 1 and a 250-bp fragment for lineage 2 strains. Eleven unidentified trypanosome stocks, recently isolated from Amazonian vectors, could be discriminated using the proposed assay. The potential field application of multiplex PCR was further demonstrated by identification of the two parasite species in samples containing intestinal tract and feces of triatomines. In the present study we have also amplified the D7a domain of several trypanosomatids employing primers complementary to the conserved flanking regions. Size and sequence polymorphisms were observed, indicating that this region could also be explored as a target for specific detection of other members of the Trypanosomatidae family. PMID- 10092475 TI - Hymenolepis diminuta: glucose and glycogen gradients in the adult tapeworm. AB - Adult (20-day-old) Hymenolepis diminuta were cut into 12 pieces of equal length, and the individual pieces of the tapeworm's strobila were analyzed. There was a continuous gradient of decreasing concentrations of glucose (mM) and decreasing levels of glycogen (microgram/mg wt) in the strobila. The ethanol extracts of the individual pieces of strobila contained four compounds tentatively identified as disaccharides; the distributions of these compounds were different from those of glucose and glycogen. The distributions of glucose, glycogen, and the "disaccharides" changed when tapeworms were incubated for 1 h in saline or glucose. When compared, on a per-weight basis, to the most posterior sections of the strobila, the anterior sections absorbed more glucose and incorporated more glucose into glycogen. There was a continuous gradient of decreasing values along the tapeworm's strobila of the Vmax for glucose uptake, while the Kt values for glucose uptake changed only slightly. The data indicate that glucose and glycogen metabolism are most active in the anterior part of the tapeworm's strobila where new proglottids are produced and the initial stages of organogenesis occur. PMID- 10092476 TI - Trypanosoma brucei: killing of bloodstream forms in vitro and in vivo by the cysteine proteinase inhibitor Z-phe-ala-CHN2. AB - Cysteine proteinases were tested for their suitability as targets for chemotherapy of sleeping sickness using the peptidyl inhibitor Z-Phe-Ala diazomethyl ketone (Z-Phe-Ala-CHN2). In vitro, the inhibitory concentration of Z Phe-Ala-CHN;2 required to reduce the growth rate by 50% was 400 times lower for culture-adapted bloodstream forms of Trypanosoma brucei than for a mouse myeloma cell line. At an inhibitor concentration of 10;M the parasites were lysed within 48 h of incubation. Parasitemia of mice infected with T. brucei decreased to undetectable levels for 3 days following treatment with 250 mg/kg Z-Phe-Ala-CHN2 on days 3 to 6 after infection. Although parasitemia returned thereafter to control levels, infected mice treated with the inhibitor survived approximately twice as long as those treated with placebo. Z-Phe-Ala-CHN2 inhibited proteinolysis in lysosomes in vitro and almost completely blocked cysteine proteinase activity in vivo. The results demonstrate the importance of cysteine proteinase activity for survival of T. brucei and suggest that such activity is an appropriate target for antitrypanosomal chemotherapy. PMID- 10092478 TI - Developmental regulation of proline transport in Leishmania donovani. AB - Leishmania donovani are the causative agents of kala azar in humans. These organisms cycle between the proline-rich environment of the sand fly vector (extracellular promastigotes) and the sugar-rich condition in the mammalian host (intracellular amastigotes). Parasites have adapted to these extreme changes in proline concentrations: promastigotes utilize proline as a carbon source, whereas amastigotes utilize sugars and fatty acids. Previous studies have suggested that promastigotes and amastigotes express distinct proline transporters. However, the information available on these transporters is limited. In this work, proline transport was investigated in axenic L. donovani cultures. Three transport systems were identified: cation-dependent and -independent proline transporters in promastigotes (systems A and B, respectively) and a single cation-independent transporter in amastigotes (system C). Systems A and C have broad specificity to almost all amino acids and obtain optimum activity at acidic pH ranges (pH 6 and 5, respectively). System B is more specific to proline, as it is inhibited by only five amino acids. Temperature response analyses indicated that the transporters of both promastigotes and amastigotes perform best at 37 degrees C. The activity of system A during parasite differentiation was assessed. The transport activity of system A disappeared 3 days after promastigotes were induced to differentiate into amastigotes. In these cells, elevated temperature and acidic pH each suppressed the activity of system A. When amastigotes were induced to differentiate back into promastigotes, system A resumed its activity 24 h after differentiation was initiated. In conclusion, L. donovani obtain proline transport systems that are stage specific, regulated by both pH and temperature. This paper constitutes the first investigation of amino acid transport in axenic L. donovani. PMID- 10092477 TI - Failure of highly immunogenic filarial proteins to provide host-protective immunity. AB - In areas that are endemic for lymphatic filariasis, there are individuals who are parasite free and who appear not to have experienced symptoms attributable to filarial infection. These "putatively immune" individuals may recognize immunogens that could be important in host protection. We have immunoscreened expression libraries expressing epitopes encoded by filarial open reading frames and have identified three antigens that are differentially recognized by the two polar clinical groups-endemic normals and asymptomatic microfilaremics. Pre immunization of susceptible hosts (Meriones unguiculatus) with these antigens revealed that none was able to elicit consistent host protective immunity. Our data are consistent with Waksman's conjecture that highly immunogenic antigens of parasite origin may be inappropriate candidates for prophylactic immunization. PMID- 10092479 TI - Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei brucei. AB - Trypanosoma brucei brucei is a causative agent of bovine trypanosomiasis (nagana), a disease of considerable economic significance in much of Africa. Here we report investigations on the effects of various irreversible cysteine proteinase inhibitors, including vinyl sulfones (VS), peptidyl chloromethylketones (CMK), diazomethylketones, and fluoromethyl ketones, on the major lysosomal cysteine proteinase (trypanopain-Tb) of T. b. brucei and on in vitro-cultured bloodstream forms of the parasite. Many of the tested inhibitors were trypanocidal at low micromolar concentrations. Methylpiperazine urea-Phe homoPhe-VS was the most effective trypanocidal agent, killing 50% of test populations at a work ing concentration of 0.11 microM, while carbobenzoxy-Phe Phe-CMK was the most trypanocidal of the methylketones with an IC50 of 3.6 microM. Labelling of live and lysed T. b. brucei with biotinylated inhibitor derivatives suggests that trypanopain-Tb is the likely intracellular target for these inhibitors. Kinetic analysis of the inhibition of purified trypanopain-Tb by the inhibitors showed that most had kass values in the 10(6) M-1 s-1 range. We conclude that cysteine proteinase inhibitors have potential as trypanocidal agents and that a major target of these compounds is the lysosomal enzyme trypanopain-Tb. PMID- 10092480 TI - 16S rDNA phylogeny and ultrastructural characterization of Wolbachia intracellular bacteria of the filarial nematodes Brugia malayi, B. pahangi, and Wuchereria bancrofti. PMID- 10092481 TI - Plasmodium gallinaceum: a novel morphology of malaria ookinetes in the midgut of the mosquito vector. AB - Malaria ookinetes invade midgut epithelial cells of the mosquito vector from the bloodmeal in the lumen of the mosquito midgut, but the cellular interactions of ookinetes with the mosquito vector remain poorly described. We describe here a novel morphology of Plasmodium gallinaceum ookinetes in which the central portion of the ookinete is an elongated narrow tube or stalk joining the anterior and posterior portions of the parasite. We propose that the previously undescribed stalkform ookinete may be an adaptation to facilitate parasite locomotion through the cytoplasm of mosquito midgut epithelial cells. PMID- 10092482 TI - Plasmodium falciparum: assignment of microsatellite markers to chromosomes by PFG PCR. PMID- 10092483 TI - Purification of active cysteine proteases by affinity chromatography with attached E-64 inhibitor. AB - Cysteine proteases are implicated in many regulatory and degradative processes in animal and plant cells. Many of the proteases are strongly inhibited by an irreversible inhibitor, trans-(epoxysuccinyl)-l-leucylamino-4-guanidinobutane (E 64) from Aspergillus japonicus. Here we report a method for purification of cysteine proteases by affinity chromatography on E-64. Attachment of the inhibitor to thiopropyl Sepharose through its epoxy group resulted in the loss of its irreversible activity but did not affect the specificity of interaction or its capability to bind cysteine proteases. Papain that served as a model cysteine protease was fully active after elution. We also provide evidence for purification of active proteases from a mixture of extracellular fluid of Botrytis cinerea- and Trichoderma harzianum-inoculated bean plants. Since the proteases are eluted with urea after the column is washed with 1 M NaCl, this procedure may provide highly efficient purification. PMID- 10092484 TI - Expression and characterization of recombinant mast cell tryptase. AB - Tryptase, a serine protease, is the major protein component in mast cells. In an animal model of asthma, tryptase has been established as an important mediator of inflammation and late airway responses induced by antigen challenge. Human tryptase is notable for its tetrameric structure, requirement of heparin for stability, and resistance to endogenous inhibitors. Human protryptase was expressed as a recombinant protein in Pichia pastoris. The recombinant protein consisted of two forms of protryptase, one containing the entire propeptide and the other containing only the Val-Gly dipeptide at its amino terminus. Isolation of active recombinant tryptase required a two column purification protocol and included a heparin- and dipeptidyl peptidase I-dependent activation step. Purified recombinant tryptase migrated as a tetramer on a gel filtration column and displayed kinetic parameters identical to those of a native tryptase obtained from HMC-1 cells, a human mast cell line. Recombinant and HMC-1 tryptase exhibited comparable sensitivities to an array of protein and low-molecular weight inhibitors, including one that is highly specific for tryptase (APC-1167). Similarly, the recombinant enzyme cleaved both alpha- and beta-chains of fibrinogen to generate fibrinogen fragments indistinguishable from those generated by HMC-1-derived tryptase. Thus, recombinant tryptase expressed in P. pastoris displays physical and enzymatic properties essentially identical to the native enzyme. This system provides a cost-effective and easy to manipulate expression system that will enable the functional characterization of this unique enzyme. PMID- 10092485 TI - Overexpression and purification of an immunologically reactive His-BIV capsid fusion protein. AB - The gene of the capsid protein of bovine immunodeficiency virus (BIV) was linked to a sequence encoding for six histidines and expressed as the (His)6 p26 capsid fusion protein. The fusion protein was strongly expressed as both soluble and insoluble forms after induction by isopropylthio-beta-d-galactoside. Purification was based on interaction of the hexa-histidine polypeptide with metal ions. Expression could represent 11% of the total protein in Escherichia coli, allowing more than 20 mg of highly purified protein to be obtained per liter of bacterial culture. The (His)6 p26 capsid fusion protein purified by immobilized metal affinity chromatography reacted specifically in Western blot with sera from cattle experimentally infected by BIV, as well as with two monoclonal antibodies directed against different epitopes of the Gag protein. The ease of expression, purification, and specificity of this fusion protein should permit a thorough study of prevalence of BIV infection in large-scale serological studies of field samples. PMID- 10092486 TI - Expression and purification of human calbindin D28k. AB - Calbindin D28k is a protein abundant in the mammalian central nervous system and in epithelial tissue involved in Ca2+ transport. Human calbindin D28k was cloned into a Pet3a vector and expressed in Escherichia coli. The protein was purified in three steps: (i) heat precipitation of bacterial proteins, (ii) ion-exchange chromatography on a DEAE-cellulose column in the presence of calcium, and (iii) ion-exchange chromatography on a DEAE-Sephacel column in the presence of EDTA. The protein was then supplemented with calcium and dialyzed against neutral water. The final yield was 20-50 mg of pure, homogeneous calcium-loaded calbindin D28k per liter of bacterial culture. The identity and purity of the protein were confirmed by immunoblotting, SDS-polyacrylamide gel electrophoresis, and agarose gel electrophoresis in the absence and presence of calcium and 1H NMR spectroscopy. The entire expression and purification protocol takes only 3 days and is easy to scale up and down. It was designed to minimize degradation and deamidation. PMID- 10092487 TI - Expression and characterization of the extracellular domain of guanylyl cyclase C from a baculovirus and Sf21 insect cells. AB - Guanylyl cyclase (GC)-C, a single-transmembrane receptor protein for heat-stable enterotoxin, guanylin, and uroguanylin, and its N-terminal extracellular domain were prepared at a high level of expression from a system constructed of Sf21 insect cells and recombinant baculovirus. The recombinant GC-C, containing the complete sequence, retained its binding affinity to heat-stable enterotoxin with a KD value (6.2 x 10(-10) M) and cyclase catalytic activity at a level similar to those of GC-C expressed in mammalian cell lines, such as COS-7. The N-terminal extracellular domain was prepared in a form which contained the hexahistidine tail at its C-terminus and was purified as a homogenous protein by Con A and Ni chelating affinity chromatography from the culture medium of the insect cells. The purified N-terminal extracellular domain of GC-C exhibited the high (KD = 4 x 10(-10) M) and low (KD = 7 x 10(-8) M) affinity sites in binding to heat-stable enterotoxin. These results clearly indicate that the N-terminal extracellular domain of GC-C possesses the same biochemical characteristics as the complete GC C protein even in the membrane-free form. Moreover, the extracellular domain is able to form an oligomer in a ligand-dependent manner, suggesting that the N terminal extracellular domains interact with one another in binding to ligands. PMID- 10092488 TI - Purification and characterization of a metalloprotease from Chryseobacterium indologenes Ix9a and determination of the amino acid specificity with electrospray mass spectrometry. AB - The heat-stable protease from Chryseobacterium indologenes Ix9a was purified to homogeneity using immobilized metal affinity chromatography. The enzyme was characterized as a metalloprotease with an approximate relative molecular mass of 24,000, a pH optimum of 6.5, and a high temperature optimum (50 degrees C). The metal chelator EDTA and the Zn2+-specific chelator 1,10-phenanthroline were identified as inhibitors and atomic absorption analysis showed that the enzyme contained Ca2+ and Zn2+. The activity of the apoenzyme could be restored with Ca2+, Zn2+, Mg2+, and Co2+. Phosphoramidon and Gly-d-Phe did not inhibit Chryseobacterium indologenes Ix9a protease. Heat inactivation did not follow first order kinetics, but showed biphasic inactivation curves. The protease has a Km of 0.813 microg. ml-1 for casein as substrate. Amino acid analysis showed that the protease contains a high amount of small amino acids like glycine, alanine, and serine, but a low concentration of methionine and no cysteine at all. Electrospray mass spectrometry of proteolysis fragments formed when insulin B chain was hydrolyzed showed cleavage at the amino terminal of leucine, tyrosine, and phenylalanine. A hydrophobic amino acid at the carboxyl donating side seems to increase the rate of reaction. PMID- 10092489 TI - Differences in the expression and localization of human melanotransferrin in lepidopteran and dipteran insect cell lines. AB - The ability of several lepidopteran and dipteran insect cell lines to express human melanotransferrin (p97), a glycosyl phosphatidylinositol (GPI)-anchored, iron-binding sialoglycoprotein, was assessed. Spodoptera frugiperda-derived (Sf9) cell lines, transformed with the p97 gene under control of a baculovirus immediate-early promoter, were able to constitutively express the protein and correctly attach it to the outer cell membrane via a GPI anchor as demonstrated by PI-PLC treatment. In contrast, stable constitutive expression could not be demonstrated with cell lines derived from either Drosophila melanogaster (Kc1 or SL2) or Lymantria dispar (Ld652Y) despite the observation that p97 could be detected in transient expression assays. This may indicate that the long-term expression and accumulation of p97 is inhibitory to Drosophila cells, possibly due to improper localization of the protein and resultant competition for cellular iron. In stably transformed Sf9 cells, p97 was expressed on the cell at a maximal level of 0.18 microg/10(6) cells and was secreted at a maximal rate of 9.03 ng/10(6) cells/h. This level was comparable to the amount expressed with the baculovirus system (0.37 microg/10(6) cells and 31.2 ng/10(6) cells/h) and transformed CHO cells (0.88 microg/10(6) cells and 7.8 ng/10(6) cells/h). Deletion of the GPI cleavage/attachment site resulted in an eightfold increase in the secretion rate of p97, when compared to the intact construct suggesting that the rate-limiting step involves processing of the GPI anchor. PMID- 10092490 TI - Streamlined procedure for the production of normal and altered versions of recombinant human proinsulin. AB - A method for the simplified, reproducible production of both normal and altered versions of human proinsulin has been developed. A polyhistidine/proinsulin fusion protein was expressed using a prokaryotic expression system and partially purified by affinity chromatography. Disulfide bonds within the polypeptide were formed prior to removal of the affinity tag. The proinsulin cleaved from the fusion protein was then subjected to a final purification step of semipreparative reversed-phase high-performance liquid chromatography. Integrity of both the normal and mutant proinsulins was confirmed by peptide mapping and mass spectrometry. The different versions of proinsulin will be used to map those residues of the substrate used in cleavage site recognition by members of the furin/PC family of converting enzymes. PMID- 10092491 TI - Spinach holo-acyl carrier protein: overproduction and phosphopantetheinylation in Escherichia coli BL21(DE3), in vitro acylation, and enzymatic desaturation of histidine-tagged isoform I. AB - Spinach ACP isoform I was overexpressed in Escherichia coli BL21(DE3) using a gene synthesized from codons associated with high-level expression in E. coli. The synthetic gene has extensive changes in codon usage (23 of 77 total codons) relative to that of the originally synthesized plant gene (P. D. Beremand et al., 1987, Arch. Biochem. Biophys. 256, 90-100). After expression of the new synthetic gene, purified ACP and ACP-His6 were obtained in yields of up to 70 mg L-1 of culture medium, compared to approximately 1-6 mg L-1 of purified ACP obtained from the gene composed of predicted spinach codons. In either shaken flask or fermentation culture, approximately 15% conversion to holo-ACP or holo-ACP-His6 was obtained regardless of the level of protein expression. However, coexpression of ACP-His6 with E. coli holo-ACP synthase in E. coli BL21(DE3) during pH- and dissolved O2-controlled fermentation routinely yielded greater than 95% conversion to holo-ACP-His6. Electrospray ionization mass spectrometric analysis of the purified recombinant ACPs revealed that the amino terminal Met was efficiently removed, but only if the bacterial cell lysates were prepared in the absence of EDTA. This observation is consistent with the inhibition of endogenous Met-aminopeptidase by removal of catalytically essential Co(II) and introduces the importance of considering the catalytic properties of host enzymes providing ad hoc posttranslational modification of recombinant proteins. Stearoyl-ACP-His6 was shown to be indistinguishable from stearoyl-ACP as a substrate for enzymatic acylation and desaturation. In combination, these studies provide a coordinated scheme to produce and characterize quantities of acyl-ACPs sufficient to support expanded biophysical and structural studies. PMID- 10092492 TI - High-level expression of Rhizopus niveus lipase in the yeast Saccharomyces cerevisiae and structural properties of the expressed enzyme. AB - Rhizopus niveus lipase (RNL) has a unique structure consisting of two noncovalently bound polypeptides (A-chain and B-chain). To improve this enzyme's properties by protein engineering, we have developed a new expression system for the production of recombinant lipase in the yeast Saccharomyces cerevisiae. For the present study, we developed a more efficient expression system using the strain ND-12B and the multicopy-type plasmid pJDB219. We purified two types of recombinant lipases, each to a single peak by gel-filtration HPLC, although they were found to be heterogeneous by SDS-PAGE. Analysis of reversed-phase HPLC, N terminal amino acid sequence, and sugar content showed that the difference between the two types of lipases was due mainly to their sugar content (high or low mannose type). Moreover, there were two species within each type of lipase. One kind was processed to the A-chain and B-chain as in the native lipase, while the other remained unprocessed. Although these yeast-purified lipases contained several posttranslational modifications and different glycosylations, their secondary structures were the same as those of the native lipase as measured by circular dichroism spectra and determination of disulfide bonding. This suggests that protein folding of the recombinant lipase occurred correctly in yeast. PMID- 10092493 TI - Escherichia coli skp chaperone coexpression improves solubility and phage display of single-chain antibody fragments. AB - Expression of single-chain antibody fragments (scAb)in the periplasm of Escherichia coli often results in low soluble product yield and cell lysis. We have increased scAb solubility and prevented cell culture lysis by coexpressing the E. coli Skp chaperone gene. A mutant Skp cistron was linked to a bacteriophage T7 gene 10 translational initiation region and placed either downstream of a scAb gene within an isopropyl beta-d-thiogalactopyranoside inducible expression cassette or on a separate colE1-compatible arabinose inducible vector. Increases in scAb solubility reflected the amount of coexpressed Skp. A bacteriophage display vector that was also engineered to coexpress Skp permitted display of a virtually undisplayable scAb and should prove useful in expanding library sizes. PMID- 10092494 TI - Purification and stabilization of a monomeric isocitrate dehydrogenase from Corynebacterium glutamicum. AB - Monomeric isocitrate dehydrogenase was expressed in Corynebacterium glutamicum cells harboring pEK-icdES1, a plasmid carrying the gene for the enzyme. Two- to three-fold higher expression levels of the recombinant enzyme were observed in such cells when grown in fermentors, compared to those grown in shaker incubators. The enzyme was purified to homogeneity by ammonium sulfate fractionation, Sephadex G-150 gel filtration, FPLC Mono Q anion-exchange chromatography, and affinity gel chromatography. Approximately 4 mg of 98% pure recombinant enzyme was obtained per liter of bacterial culture. Our results also include optimum buffer conditions for purification and storage of the enzyme. PMID- 10092495 TI - The expression of recombinant large myelin-associated glycoprotein cytoplasmic domain and the purification of native myelin-associated glycoprotein from rat brain and peripheral nerve. AB - The myelin-associated glycoprotein (MAG) is a transmembrane protein of the immunoglobulin superfamily existing as two isoforms (L-MAG and S-MAG) that are differentially expressed by myelinating glial cells of the central and peripheral nervous systems, where MAG represents 1 and 0.1% of the total myelin proteins, respectively. The polypeptide chains of the two isoforms differ only by the carboxy terminus of their respective cytoplasmic domains, which most probably determine the isoform-specific functions. Here, we describe the expression of the L-MAG cytoplasmic domain as a GST fusion protein. The recombinant protein was used to raise polyclonal antibodies against the L-MAG-specific carboxy terminus and against the region of the MAG cytoplasmic domain common to both S-MAG and L MAG. These antibodies, which function in dot blotting, Western blotting, and immunoprecipitation, were used to immunopurify native MAG from both rat brain and peripheral nerves in quantities and purity sufficient for the realization of most biochemical and functional studies. The antibodies and the recombinant and native MAG proteins provide much needed tools for the study of the common and isoform specific properties and functions of L-MAG and S-MAG. PMID- 10092496 TI - Optimization of the production of a honeybee odorant-binding protein by Pichia pastoris. AB - A honeybee putative general odorant-binding protein ASP2 has been expressed in the methylotrophic yeast Pichia pastoris. It was secreted into the buffered minimal medium using either the alpha-factor preprosequence with and without the Glu-Ala-Glu-Ala spacer peptide of Saccharomyces cerevisiae or its native signal peptide. Whereas ASP2 secreted using the alpha-factor preprosequence with the spacer peptide showed N-terminal heterogeneity, the recombinant protein using the two other secretion peptides was correctly processed. Mass spectrometry showed that the protein secreted using the natural peptide sequence had a mass of 13,695.1 Da, in perfect agreement with the measured molecular mass of the native protein. These data showed a native-like processing and the three disulfide bridges formation confirmed by sulfhydryl titration analysis. After dialysis, the recombinant protein was purified by one-step anion-exchange chromatography in a highly pure form. The final expression yield after 7-day fermentation was approximately 150 mg/liter. To our knowledge, this is the first report of the use of a natural insect leader sequence for secretion with correct processing in P. pastoris. The overproduction of recombinant ASP2 should allow ligand binding and mutational analysis to understand the relationships between structure and biological function of the protein. PMID- 10092497 TI - Expression and one-step purification of a fully active polyhistidine-tagged cytochrome bc1 complex from Rhodobacter sphaeroides. AB - The fbcB and fbcC genes encoding cytochromes b and c1 of the bc1 complex were extended with a segment to encode a polyhistidine tag linked to their C-terminal sequence allowing a one-step affinity purification of the complex. Constructions were made in vitro in a pUC-derived background using PCR amplification. The modified fbc operons were transferred to a pRK derivative plasmid, and this was used to transform the fbc- strain of Rhodobacter sphaeroides, BC17. The transformants showed normal rates of growth. Chromatophores prepared from these cells showed kinetics of turnover of the bc1 complex on flash activation which were essentially the same as those from wild-type strains, and analysis of the cytochrome complement and spectral and thermodynamic properties by redox potentiometry showed no marked difference from the wild type. Chromatophores were solubilized and mixed with Ni-NTA-Sepharose resin. A modification of the standard elution protocol in which histidine replaced imidazole increased the activity 20 fold. Imidazole modified the redox properties of heme c1, suggesting ligand displacement and inactivation when this reagent is used at high concentration. The purified enzyme contained all four subunits in an active dimeric complex. This construction provides a facile method for preparation of wild-type or mutant bc1 complex, for spectroscopy and structural studies. PMID- 10092498 TI - Production, purification, and luminometric analysis of recombinant Saccharomyces cerevisiae MET3 adenosine triphosphate sulfurylase expressed in Escherichia coli. AB - ATP sulfurylase cDNA from MET3 on chromosome X of Saccharomyces cerevisiae was amplified and cloned, and recombinant ATP sulfurylase was expressed in Escherichia coli. The synthesis of ATP sulfurylase was directed by an expression system that employs the regulatory genes of the luminous bacterium Vibrio fischeri. A soluble, biologically active form was purified to electrophoretic homogeneity from lysates of recombinant E. coli by ammonium sulfate fractionation, ion-exchange chromatography, and gel filtration. The specific activity of the purified enzyme was estimated to 140 U/mg. The apparent molecular mass of the recombinant enzyme was determined by gel filtration to be 470 kDa, which indicates that the active enzyme is an octamer of identical subunits (the molecular mass of a single subunit is 59.3 kDa). The ATP sulfurylase activity was monitored in real time by a very sensitive bioluminometric method. PMID- 10092499 TI - Removal of N-terminal polyhistidine tags from recombinant proteins using engineered aminopeptidases. AB - We have developed a specific and efficient method for complete removal of polyhistidine purification tags (HisTags) from the N-termini of target proteins. The method is based on the use of the aminopeptidase dipeptidyl peptidase I (DPPI), either alone or in combination with glutamine cyclotransferase (GCT) and pyroglutamyl aminopeptidase (PGAP). In both cases, the HisTag is cleaved off by DPPI, which catalyzes a stepwise excision of a wide range of dipeptides from the N-terminus of a peptide chain. Some sequences, however, are resistant to DPPI cleavage and a number of mature proteins have nonsubstrate N-termini which protects them against digestion. For such proteins, HisTags composed of an even number of residues can be cleaved off by treatment with DPPI alone. When the target protein is unprotected against DPPI, a blocking group is generated enzymatically from a glutamine residue inserted between the HisTag and the target protein. A protein with a HisTag-Gln extension is incubated with both DPPI and GCT. As above, the polyhistidine sequence is cleaved off by DPPI, but when the glutamine residue appears in the N-terminus, it is immediately converted into a pyroglutamyl residue by an excess of GCT and further DPPI digestion is prevented. The desired sequence is finally obtained by excision of the pyroglutamyl residue with PGAP. All the enzymes employed can bind to immobilized metal affinity chromatography (IMAC) matrices, and in this paper we demonstrate a simple and highly effective process combining IMAC purification of His-tagged proteins, our aminopeptidase-based method for specific excision of HisTags and use of subtractive IMAC for removing processing enzymes. Typical recoveries were 75-90% for the enzymatic processing and subtractive IMAC. The integrated process holds promises for use in large-scale production of pharmaceutical proteins because of a simple overall design, use of robust and inexpensive matrices, and use of enzymes of either recombinant or plant origin. PMID- 10092500 TI - Electrospray ionization mass spectrometry: a promising new technique in the study of protein/DNA noncovalent complexes. AB - With the emergence of electrospray ionization mass spectrometry (ESI-MS), mass spectrometry is no longer restricted to the study of small, stable molecules, but has become a viable technique to study large biomolecules as well as noncovalent biomolecular complexes. ESI-MS has been used to study noncovalent interactions involving proteins with metals, ligands, peptides, oligonucleotides, and other proteins. An area where ESI-MS holds significant promise is in the study of protein/DNA interactions. The most common technique employed to study protein/DNA interactions is the electrophoretic gel mobility shift assay (EMSA). Although this technique has and will continue to provide excellent results, ESI-MS has shown the ability to provide detailed results not easily obtainable by EMSA. In this review I will discuss some of the protein/DNA noncovalent interactions that have been measured using ESI-MS, and contrast the results obtained by ESI-MS to those obtained by EMSA. PMID- 10092501 TI - Detection of various epitopes of murine osteopontin by monoclonal antibodies. AB - We immunized rats with recombinant murine osteopontin protein and obtained four monoclonal antibodies recognizing distinct epitopes of murine osteopontin. OPN1.2 recognized the amino-terminal half of OPN, while OPN2.2, OPN2.3, and OPN3.1 recognized the carboxy-terminal half of OPN. The epitope recognized by OPN2.2 was destroyed by further cleavage of the carboxy half of OPN. The epitope recognized by OPN2.3 was located in the amino-terminal end of the carboxy half of OPN, whereas that recognized by OPN3.1 was located in the carboxy-terminal end of the carboxy half of OPN. OPN1.2 and OPN2.2 recognized thrombin-cleaved osteopontin, whereas thrombin-cleaved osteopontin was not recognized by OPN2.3 and OPN3.1. Thus, these monoclonal antibodies will be useful in structure/function studies of the role of osteopontin in murine models of disease. PMID- 10092502 TI - Role of Suc1 in the activation of the cyclosome by protein kinase Cdk1/cyclin B. AB - A large complex, called the cyclosome or anaphase-promoting complex, has specific and regulated protein-ubiquitin ligase activity that targets mitotic regulators (such as cyclin B) for degradation at the end of mitosis. In early embryonic cell cycles the cyclosome is inactive in the interphase, but is subsequently converted by protein kinase Cdk1/cyclin B to an active, phosphorylated form, in a process that includes an initial lag period. This time lag may be important to prevent premature self-inactivation of Cdk1/cyclin B before the end of mitosis. We have previously observed that the phosphorylated form of the cyclosome binds to Suc1, a protein that associates with Cdk1 and with phosphate-containing compounds. We now report that low, physiological concentrations of Suc1 stimulate the activation of the interphase form of the cyclosome by the protein kinase. When Suc1 was present from the beginning of the incubation together with protein kinase Cdk1/cyclin B, activation of the cyclosome took place with the normal lag kinetics. However, when interphase cyclosome was first incubated with protein kinase Cdk1/cyclin B without Suc1, the subsequent addition of Suc1 caused a rapid burst of cyclosome activation and the lag was completely abolished. These findings are consistent with the interpretation that following initial slow phosphorylations of the cyclosome by the protein kinase, Suc1 accelerates multiple phosphorylations that culminate in the full activation of the cyclosome. In support of this interpretation, we find that Suc1 stimulates the phosphorylation of several proteins in the preparation of interphase cyclosome and that the effect of Suc1 on phosphorylation was augmented by prior incubation of interphase cyclosome with protein kinase Cdk1/cyclin B. PMID- 10092503 TI - A radicicol-related macrocyclic nonaketide compound, antibiotic LL-Z1640-2, inhibits the JNK/p38 pathways in signal-specific manner. AB - Macrocyclic nonaketide compounds, radicicol and its two analogues, 87-250904-F1 and LL-Z1640-2, have various biological activities. Here we show that these compounds inhibit signal-dependent transcriptional activation with different specificity with distinct mechanism. Although all three compounds inhibited PMA induced AP-1 transcriptional activity in cell-based reporter assay, these compounds exhibited differential effects in separate transcriptional reporter assays for NF-kappaB and glucocorticoid receptor. Next we found that one of these compounds, LL-Z1640-2, was a signal-specific inhibitor of the JNK/p38 pathways. In contrast to LL-Z1640-2, radicicol and 87-250904-F1 did not inhibit JNK/p38 activation. Recently, radicicol was reported as an inhibitor of activated-Ras induced ERK activation. These results indicated that radicicol and LL-Z1640-2 showed distinct specificity to various MAP kinase pathways despite their structural similarity. Furthermore, LL-Z-1640-2 inhibited anisomycin-induced but not TNF-induced JNK/p38 activation, indicating that the inhibition mechanism is signal-specific. PMID- 10092504 TI - Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A. AB - Mutations in the novel gene, EPM2A, have been shown recently to cause the progressive myoclonus epilepsy of Lafora type. EPM2A is predicted to encode a putative protein-tyrosine phosphatase but its specific role in normal brain function and in the Lafora disease is not known. As a first step towards understanding the cellular function of EPM2A in an animal model, we have isolated cDNA clones for mouse EPM2A and analyzed its expression. Sequence analyses of the mouse cDNA clones revealed a complete ORF that supports the 5' coding sequence predicted for human EPM2A from the genomic sequence. When compared to EPM2A, the mouse homologue, named Epm2a, shows 86% identity at the nucleotide level and 88% identity and 93% similarity at the amino acid level. Similar to the human counterpart, Epm2a showed ubiquitous expression in Northern with a major transcript size of 3.5 kb. We have mapped the Epm2a to the proximal region of mouse chromosome 10 which is the syntenic region for human chromosome band, 6q24. Our results suggest that EPM2A is highly conserved in mammals and might have a conserved function. PMID- 10092505 TI - Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages. AB - We have cloned the full-length cDNA for the human ATP binding cassette transporter 1 (hABC1). The 6603-bp open reading frame encodes a polypeptide of 2201 amino acids resulting in a deduced molecular weight of 220 kDa. The hABC1 cDNA is highly homologous (62%) to the human rim ABC transporter (ABCR). hABC1 is expressed in a variety of human tissues with highest expression levels found in placenta, liver, lung, adrenal glands, and fetal tissues. We demonstrate that the hABC1 expression is induced during differentiation of human monocytes into macrophages in vitro. In macrophages, both the hABC1 mRNA and protein expression are upregulated in the presence of acetylated low-density lipoprotein (AcLDL). The AcLDL-induced increase in hABC1 expression is reversed by cholesterol depletion mediated by the addition of high-density lipoprotein (HDL3). Our data, demonstrating sterol-dependent regulation of hABC1 in human monocytes/macrophages, suggest a novel role for this transporter molecule in membrane lipid transport. PMID- 10092506 TI - Structural and functional characterization of the Drosophila glycogen phosphorylase gene. AB - We identified a P element insertional mutant of the Drosophila glycogen phosphorylase (DGPH) gene. Glycogen phosphorylase protein concentration and enzyme activity are decreased while glycogen content is increased in flies homozygous for the mutant allele. The DGPH gene has been cloned and sequenced; its open reading frame codes for a protein of 844 amino acids with a predicted molecular mass of 97 kDa. Comparison of the conceptual amino acid sequence of the Drosophila glycogen phosphorylase with glycogen phosphorylase sequences from other organisms shows a high degree of homology to mammalian enzymes. All the residues of the allosteric effector binding sites, the active site, and the site of phosphorylation are exactly conserved, but some of the residues of the glycogen storage site are not. PMID- 10092507 TI - Characterization and purification of carbohydrate response element-binding protein of the rat L-type pyruvate kinase gene promoter. AB - The L-III transcriptional regulatory element of the rat pyruvate kinase L gene is located between -170 and -150 base pairs upstream of the hepatocyte-specific transcription initiation site. As the L-III element is not only necessary for cell type-specific expression but also for transcriptional stimulation by carbohydrates, it is also referred to as a carbohydrate-response element. Electrophoretic mobility shift assays using rat liver nuclear extract showed that L-III element-binding protein (L-IIIBP) was observed as multiple bands. These bands disappeared when the nuclear extract was preincubated at 60 degrees C for 5 min and were competed with unlabeled L-III oligonucleotide but not with unlabeled adenovirus major late promoter E box oligonucleotide. In addition, these bands were not affected in the presence of antiserum against upstream stimulating factor (USF). Thus, we conclude that L-IIIBP is different from USF. Then, heat labile L-IIIBP was purified from rat liver nuclear extracts. Purified L-IIIBP exhibited two bands on sodium dodecyl sulfate/polyacrylamide gel electrophoresis by silver staining. Ultraviolet crosslinking experiment showed that both bands had binding activity to the L-III oligonucleotide. PMID- 10092508 TI - Cloning and expression of a novel lysophospholipase which structurally resembles lecithin cholesterol acyltransferase. AB - Lecithin cholesterol acyltransferase (LCAT) is the key enzyme in the esterification of plasma cholesterol and in the reverse cholesterol transport on high-density lipoprotein (HDL). We have found a novel LCAT-related gene among differentially expressed cDNA fragments between two types of foam cells derived from THP-1 cells, which are different in cholesterol efflux ability, using a subtractive PCR technique. The deduced 412-amino-acid sequence has 49% amino acid sequence similarity with human LCAT. In contrast to the liver-specific expression of LCAT, mRNA expression of the gene was observed mainly in peripheral tissues including kidney, placenta, pancreas, testis, spleen, heart, and skeletal muscle. The protein exists in human plasma and is probably associated with HDL. Moreover, we discovered that the recombinant protein hydrolyzed lysophosphatidylcholine (lysoPC), a proatherogenic lipid, to glycerophosphorylcholine and a free fatty acid. We have therefore named this novel enzyme LCAT-like lysophospholipase (LLPL), through which a new catabolic pathway for lysoPC on lipoproteins could be elucidated. PMID- 10092509 TI - Cyclic ADP-ribose-dependent Ca2+ release is modulated by free [Ca2+] in the scallop sarcoplasmic reticulum. AB - Cyclic ADP-ribose (cADPR) elicits calcium-induced calcium release (CICR) in a variety of cell types. We studied the effect of cADPR on Ca2+ release in muscle cells by incubating SR vesicles from scallop (Pecten jacobaeus) adductor muscle in the presence of the Ca2+ tracer fluo-3. Exposure of SR to cADPR (20 microM) produced Ca2+ release, which was a function of free [Ca2+] in a range between about 150 and 1000 nM, indicating an involvement of ryanodine-sensitive Ca2+ channels. This Ca2+ release was not significantly enhanced by calmodulin (7 micrograms/ml), but it was enhanced by equimolar addition of noncyclic ADPR. Also, the Ca2+ release elicited by cADPR/ADPR was a function of free [Ca2+] in a range between about 150 and 3000 nM, over which Ca2+ was inhibitory. cADPR self inactivation was observed at low free [Ca2+] (about 150 nM), but it tended to disappear upon [Ca2+] elevation (about 250 nM). Caffeine or ryanodine induced a Ca2+ release which was ruthenium red (2.5 microM) sensitive at low [Ca2+]. However, the Ca2+ release induced by either ryanodine or cADPR was no longer ruthenium red sensitive when free [Ca2+] was increased. Based on these data, a model is proposed for Ca2+ signaling in muscle cells, where a steady-state cADPR level would trigger Ca2+ release when free [Ca2+] does reach a threshold slightly above its resting level, hence producing cascade RyR recruitment along SR cisternae from initial Ca2+ signaling sites. PMID- 10092510 TI - Association and dissociation of the calcium-binding domains of calpain by Ca2+. AB - The calmodulin-like domain of calpain is important for the association of the calpain large and small subunits. We expressed the calmodulin-like domains of the large subunits of rabbit mu- and m-calpains and their small subunits in E. coli and purified them to homogeneity. Unlike the full-length subunits, the calmodulin like domains are soluble in buffer containing Ca2+. We performed gel filtration chromatography of the purified proteins and found that all three calmodulin-like domains exist as homodimers in the absence of Ca2+ and dissociate into monomers upon the addition of Ca2+. PMID- 10092511 TI - Characterization of TFG in mus musculus and Caenorhabditis elegans. AB - TFG was discovered as a fusion partner of NTRK1 in human papillary thyroid carcinoma. We assembled the mouse TFG cDNA from EST sequences and 5' end RACE product, identified full coding length TFG EST clones in pig (c17b07) and Schistosoma mansoni (SMNAS62), and analyzed the genomic structure of TFG in Caenorhabditis elegans (Y63D3A). The protein sequences of mouse, pig, and S. mansoni TFG are highly homologous to human TFG. The C. elegans sequence has diverged, but its predicted secondary structure is remarkably conserved. Human, mouse, and C. elegans TFG contain a putative trimeric N-terminal coiled-coil domain, glycosylation, myristylation, and phosphorylation sites, and SH2- and SH3 binding motifs. The SH2-binding motif is absent in C. elegans TFG. The expression of TFG does not vary among 7, 11, 15, and 19 day mouse embryonal stages. In situ hybridization with a TFG probe in 10, 5-day whole mouse embryos showed preferential staining of the limb buds, branchial arches, nasal processes, and brain, and weak staining of the primitive spinal cord and dorsal root ganglia. PMID- 10092512 TI - Bystander macrophages silence transgene expression driven by the retroviral long terminal repeat. AB - The Moloney murine leukemia virus (MLV)-based retroviral vector has been widely used for transfer of exogenous genes to various organs and tissues. Although the long terminal repeat (LTR) of MLV allows for transgene expression in a wide range of cell type, its activity is often silenced in vivo. In reporter macrophages transduced with a MLV-based retroviral vector, activity of the LTR was transiently and reversibly suppressed following stimulation by lipopolysaccharide (LPS). When unstimulated reporter macrophages were co-cultured with LPS stimulated, untransduced macrophages, the LTR activity was similarly depressed. Activity of the LTR in retrovirus-transduced, mesangial cells was also down regulated when co-cultured with activated macrophages. This suppressive effect was reproduced by cross-feeding with culture media conditioned by activated macrophages. LPS-stimulated macrophages abundantly expressed cytokines including IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor beta1 (TGF-beta1). When externally added, TNF-alpha and/or TGF-beta1, but not IL 1beta, depressed activity of the LTR in reporter macrophages and reporter mesangial cells. These results raise a possibility that expression of transgenes driven by the MLV-LTR may be silenced in vivo when the retrovirally-transduced cells are co-localized with activated macrophages. PMID- 10092513 TI - Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. AB - We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al., Biochem. Biophys. Res. Commun. 221, 286-289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans. PMID- 10092514 TI - Alternative initiation of translation accounts for a 67/45 kDa dimorphism of the human estrogen receptor ERalpha. AB - The estrogen receptor protein, in the nuclear receptor superfamily, carries two transactivator domains designated AF1 and AF2. The activity of AF2, localized in the carboxy-terminal region, is ligand-dependent, whereas AF1 (amino-terminal) seems to be activated via the MAPKkinase pathway. Uterine and mammary cells exhibiting large amounts of ERalpha were the first estrogen target organs demonstrated. The response intensity in these tissues is related to the affinity of the receptor and to the number of sites occupied by its ligand. Certain physiological and pharmacological phenomena of estrogen resistance associated with a truncated form of ERalpha (deleted in the AF1 domain) would seem however to challenge this assertion. The 45 kDa truncated form is unable to induce cell proliferation but can still increase the expression of certain genes. In this work we suggest that this 45 kDa ERalpha form may originate from differential regulation of translation of the mRNA encoding the ERalpha. In vitro translation studies and transient expression in COS-7 cells in vivo demonstrated a mechanism of translation regulation that produced from a given mRNA either the wild type ER 67 kDa form or the AF1 deleted ER 45 kDa isoform. Bicistronic vectors were used to demonstrate that the 45 kDa protein originates from translation initiation at AUG 174 induced by an internal ribosome entry. PMID- 10092515 TI - Chronic ethanol consumption disrupts complexation between EGF receptor and phospholipase C-gamma1: relevance to impaired hepatocyte proliferation. AB - We have previously shown that chronic ethanol consumption inhibits liver regeneration by impairing EGF receptor (EGFR)-operated phospholipase C-gamma1 (PLC-gamma1) activation and resultant intracellular Ca2+ signalling. Activation of PLC-gamma1 by EGFR requires the EGFR to bind to PLC-gamma1 after its translocation from cytosol to cytoskeleton. In order to understand the mechanism by which ethanol impairs PLC-gamma1 activation, we examined the effect of alcohol on interactions between EGFR and PLC-gamma1. In cultured hepatocytes from control rats, EGF rapidly induced tyrosine phosphorylation of both the EGFR and of PLC gamma1. EGF also stimulated PLC-gamma1 translocation from cytosol to a cytoskeletal compartment where PLC-gamma1 interacted with EGFR. In hepatocytes from rats fed ethanol for 16 weeks, the above reactions were substantially inhibited. Tyrphostin AG1478, an EGFR-specific tyrosine kinase inhibitor, mimicked the effects of chronic ethanol on EGFR phosphorylation, PLC-gamma1 translocation and interactions between EGFR and PLC-gamma1 in the cytoskeleton. Further, tyrphostin AG1478 also inhibited EGF-induced DNA synthesis. These results indicate that ethanol impairs EGFR-operated [Ca2+]i signaling by disrupting the interactions between EGFR and PLC-gamma1. PMID- 10092516 TI - H-Ras is a negative regulator of alpha3beta1 integrin expression in ECV304 endothelial cells. AB - We have examined the role of Ras in integrin expression in ECV304 endothelial cells. Among the integrins examined in stable ECV304 transfectants expressing dominant active H-Ras (DAR-ECV), expression of alpha3beta1 integrin showed a prominent reduction in all the DAR-ECV clones when compared to the parental ECV304 cells. This implies that H-Ras negatively regulates the expression of alpha3beta1 integrin in ECV304 cells. When treated with inhibitors of the Ras downstream pathway (LY294002, PD98059, SB203580), the expression of alpha3beta1 integrin was up-regulated most significantly by LY294002, suggesting that among the downstream pathways of Ras, phosphatidylinositol 3-kinase is a major determinant. With the application of blocking antibody to alpha3beta1 integrin (2 - 2 x 10(4) nM), migration of ECV304 cells was enhanced to maximal (18%) at 20 nM. These results suggest that migration of endothelial cells could be modulated by H-Ras via alteration of the expression levels of alpha3beta1 integrin. PMID- 10092518 TI - A Bacillus-specific factor is needed to trigger the stress-activated phosphatase/kinase cascade of sigmaB induction. AB - The general stress regulon of Bacillus subtilis is controlled by the transcription factor sigmaB. Environmental stress activates sigmaB via a phosphatase/kinase cascade that triggers sigmaB's release from an anti sigma factor complex. To determine if the members of the phosphatase/kinase cascade are sufficient to detect environmental stress and activate sigmaB, we expressed sigmaB and its regulators in E. coli. In E. coli, as in B. subtilis, the intact collection of regulators silenced sigmaB, while allowing sigmaB to be active if the cascade's most upstream negative regulator was deleted. The regulators could not, however, activate sigmaB in response to ethanol treatment or heat shock. In other experiments, the GroEL and DnaK chaperones, known to be important in controlling stress sigma factors in E. coli, were found to be unimportant for sigmaB activity in B. subtilis. The findings argue that stress induction of sigmaB requires novel factors that are B. subtilis specific. PMID- 10092517 TI - Identification of NEDD8-conjugation site in human cullin-2. AB - NEDD8 is a novel ubiquitin-like protein that has been shown to conjugate to nuclear proteins in a manner analogous to ubiquitination and sentrinization. Recently, human cullin-4A was reported to be conjugated by a single molecule of NEDD8. Here, we show that human cullin-2 is also conjugated by a single molecule of the NEDD8. The C-terminal 171-amino-acid residues in human cullin-2 are sufficient for NEDD8-conjugation. In addition, the equivalent C-terminal fragments of other cullins have been shown to be conjugated by NEDD8. Mapping of the NEDD8-conjugation site revealed that Lys-689 in human cullin-2 is conjugated by NEDD8. Interestingly, the Lys residue at position 689 in cullin-2 is conserved in all cullin family members, including human cullin-1, -2, -3, -4A, -4B, and -5 and yeast cullin (Cdc53), suggesting the possibility that other cullin family members are conjugated by NEDD8/Rub1 at a Lys residue of equivalent position. PMID- 10092519 TI - Characterization of a novel Ras-binding protein Ce-FLI-1 comprising leucine-rich repeats and gelsolin-like domains. AB - Ras proteins are conserved from yeasts to mammals and implicated in regulation of the actin cytoskeleton. The flightless-1 (fli-1) gene of Drosophila melanogaster and its homologs in Caenorhabditis elegans and humans encode proteins (FLI-1) comprising a fusion of a leucine-rich repeats (LRRs) domain and a gelsolin-like domain. This LRRs domain is highly homologous to those of three proteins involved in Ras-mediated signaling; Saccharomyces cerevisiae adenylyl cyclase, C. elegans SUR-8, and mammalian RSP-1. Here we report that the LRRs domain of C. elegans FLI 1 (Ce-FLI-1) associates directly with Ras (Kd = 11 nM) and, when overexpressed, suppresses the heat shock sensitive phenotype of yeast cells bearing the activated RAS2 gene (RAS2(Val-19)). Further, the gelsolin-like domain of Ce-FLI-1 is shown to possess a Ca2+-independent G-actin-binding activity as well as F actin-binding and -severing activities. FLI-1 may be involved in regulation of the actin cytoskeleton through Ras. PMID- 10092520 TI - Cloning, sequencing, and expression of an Escherichia coli acid phosphatase/phytase gene (appA2) isolated from pig colon. AB - Bacterial strains were isolated from the pig colon to screen for phytase and acid phosphatase activities. Among 93 colonies, Colony 88 had the highest activities for both enzymes and was identified as an Escherichia coli strain. Using primers derived from the E. coli pH 2.5 acid phosphatase appA sequence (Dassa et al. (1990), J. Bacteriol. 172, 5497-5500), we cloned a 1482 bp DNA fragment from the isolate. In spite of 95% homology between the sequenced gene and the appA, 7 amino acids were different in their deduced polypeptides. To characterize the properties and functions of the encoded protein, we expressed the coding region of the isolated DNA fragment and appA in Pichia pastoris, respectively, as r appA2 and r-appA. The recombinant protein r-appA2, like r-appA and the r-phyA phytase expressed in Aspergillus niger, was able to hydrolyze phosphorus from sodium phytate and p-nitrophenyl phosphate. However, there were distinct differences in their pH profiles, Km and Vmax for the substrates, specific activities of the purified enzymes, and abilities to release phytate phosphorus in soybean meal. In conclusion, the DNA fragment isolated from E. coli in pig colon seems to encode for a new acid phosphatase/phytase and is designated as E. coli appA2. PMID- 10092521 TI - Uncompetitive inhibition of superoxide generation by a synthetic peptide corresponding to a predicted NADPH binding site in gp91-phox, a component of the phagocyte respiratory oxidase. AB - The large subunit of cytochrome b558, gp91-phox, is believed to play a key role in superoxide generation in neutrophils by accepting electrons from NADPH and donating them to molecular oxygen. We found that a peptide corresponding to a predicted NADPH binding site in gp91-phox inhibited superoxide generation in a cell-free system consisting of neutrophil membrane and cytosol. Minimum essential sequence for the inhibition was KSVWYK, which corresponded to residues 420-425 (IC50 = 30 microM). Unlike other peptides known to inhibit the reaction, this peptide was effective even when added to the system after activation or to activated membrane from stimulated neutrophils. Furthermore, the peptide inhibited superoxide generation in a membrane system activated without cytosol. Kinetic analysis revealed that the peptide inhibited the reaction uncompetitively. These results suggest that the peptide combines with the activated cytochrome b558-NADPH complex and thereby inhibits electron transfer from NADPH to molecular oxygen. PMID- 10092522 TI - The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein tyrosine kinase. AB - Hematopoietic cell kinase (Hck) is a member of the Src-family of protein tyrosine kinases. We have found that upon enzymatic activation of Hck by the heavy metal mercuric chloride, there was a rapid increase in the levels of tyrosine phosphorylation of several proteins including the proto-oncogene p120(Cbl). Fibroblasts that are transformed with an activated allele of Hck exhibit constitutive Cbl phosphorylation. Upon Fcgamma receptor activation, a more physiologically relevant extracellular signal, Cbl is tyrosine phosphorylated and the Src-family selective inhibitor, PP1, can prevent this phosphorylation on Cbl. Hck phosphorylates Cbl in vitro and the interaction between Cbl and Hck is direct, requiring Hck's unique, SH3 and SH2 domains for optimal binding. Using a novel estrogen-regulated chimera of Hck we have shown a hormone-dependent association between Hck and Cbl in murine fibroblasts. This work suggests that Cbl serves as a key mediator of Hck induced signalling in hematopoietic cells. PMID- 10092523 TI - Molecular and functional study of AQY1 from Saccharomyces cerevisiae: role of the C-terminal domain. AB - The yeast YPR192w gene, which encodes a protein (Aqy1p) with strong homology to aquaporins (AQPs), was cloned from nine S. cerevisiae strains. The osmotic water permeability coefficient (Pf) of X. laevis oocytes expressing the gene cloned from the Sigma1278b strain (AQY1-1) was 5.7 times higher than the Pf of oocytes expressing the gene cloned from other strains (AQY1-2). Aqy1-1p, initially cloned without its C-terminus (Aqy1-1DeltaCp), mediated an approximately 3 times higher water permeability than the full-length protein. This corresponds to a 3-fold higher protein density in the oocyte plasma membrane, as shown by freeze-fracture electron microscopy. Pf measurements in yeast spheroplasts confirmed the presence of functional water channels in Sigma1278b and a pharmacological study indicated that this strain contains at least a second functional aquaporin. PMID- 10092524 TI - Rapid induction of NF-kappaB binding during liver cell isolation and culture: inhibition by L-NAME indicates a role for nitric oxide synthase. AB - This study is the first to demonstrate activation of NF-kappaB binding just 10 minutes into the commonly employed hepatocyte isolation procedure. It is further reported that the anti-oxidant Trolox can prevent the induction of NF-kappaB during the well established hepatocyte isolation procedure but not during their subsequent culture. However both phases of NF-kappaB activation are inhibited by L-NAME intimating a role for NO production, via nitric oxide synthase. These findings demonstrate that at least 2 different signal transduction pathways are operative during hepatocyte isolation and culture. Thus further studies employing Trolox and L-NAME will help delineate how each pathway contributes to the generalised loss of liver function commonly observed in vitro. PMID- 10092525 TI - Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: activation of c-Jun N-terminal kinase prior to the transcription factors AP-1 and NFkappaB. AB - Benzyl isothiocyanate (BIT), a microconstituent found in cruciferous vegetables, is known to be a potent inducer of the detoxification enzyme, NAD(P)H: quinone reductase (QR). QR catalyzes a two-electron transfer to a wide variety of redox cycling species, including quinones, transforming them into dihydrodiols, thereby preventing the mutation of DNA and reducing cancer risk. The upstream signaling mechanisms that lead to the induction of QR remain unclear. The 5' promoter region of the human QR gene contains the cis-acting AP-1 and NFkappaB transcription factor binding sites. When HT29 human colon cells were exposed to 25microM benzyl isothiocyanate, AP-1 binding increased, beginning at 3 hours and increasing until 16 hours. NFkappaB binding also increased, reaching a maximum at around 6 hours. We also found that c-Jun N-terminal kinase (JNK), which phosphorylates c-Jun, a component of AP-1, was activated 9-fold over controls, beginning at 60 minutes. The temporal sequence of these events supports the idea that JNK is involved in the induction of QR and that this is an initial event preceding an increase in transcription factor binding and subsequent QR activity. PMID- 10092526 TI - Multiple alternative transcripts of the human homologue of the mouse TRAD/R51H3/RAD51D gene, a member of the rec A/RAD51 gene family. AB - Yeast RAD51, a homologue of Escherichia coli recA, plays a crucial role in mitotic and/or meiotic recombination and in the repair of double-strand DNA breaks. We have identified unique multiple alternative transcripts of a human TRAD/R51H3/RAD51D gene, a member of the recA/RAD51 gene family. One of the transcripts encoded a 328-amino-acid protein with 83.0% overall amino acid identity and 98. 2% similarity with the mouse TRAD gene and had two nucleotide binding consensus sequences, motif A and motif B, conserved among members of this family. Other transcripts encoded truncated proteins with a partial N-terminal region of the orthologue or short proteins lacking internal sequences which contain nucleotide binding motifs. Northern blot analysis revealed that multiple transcripts of the human TRAD gene were expressed in various tissues and their distribution was not ubiquitous. PMID- 10092527 TI - Altered levels of primary antioxidant enzymes in progeria skin fibroblasts. AB - Free radicals are involved in the aging process. In this study, the profile of primary antioxidant enzymes that scavenge reactive oxygen species (ROS) was examined for the first time in human skin fibroblasts from progeria, a premature aging disease. Altered levels of antioxidant enzymes were found in progeria cells. Basal levels of MnSOD were decreased in progeria cells as well as a blunted induction in response to chronic stress. This change may contribute to the accelerated aging process in progeria cells. In contrast, the levels of CuZnSOD showed no progeria-related change. Two H2O2 removing enzymes demonstrated a significant reduction in progeria cells: only 50% of normal CAT activity and 30% of normal GPX activity can be detected in progeria cells. This diminished H2O2 removing capacity in progeria cells may lead to an imbalance of intracellular ROS and therefore may play an important role in the development of progeria. PMID- 10092528 TI - The influence of SV40 immortalization of human fibroblasts on p53-dependent radiation responses. AB - The simian virus 40 large tumor antigen (SV40 Tag) has been ascribed many functions critical to viral propagation, including binding to the mammalian tumor suppressor p53. Recent studies have demonstrated that SV40-transformed murine cells have functional p53. The status of p53 in SV40-immortalized human cells, however, has not been characterized. We have found that in response to ionizing radiation, p53-dependent p21 transactivation activity is present, albeit reduced, in SV40-immortalized cells and that this activity can be further reduced with either dominant negative p53 expression or higher SV40 Tag expression. Furthermore, overexpression of p53 in SV40-immortalized ataxia-telangiectasia (A T) cells restores p53-dependent p21 induction to typical A-T levels. All SV40 immortalized cell lines exhibited an absence of G1 arrest. Moreover, all SV40 immortalized cell lines exhibited increased apoptosis relative to primary cells in response to ionizing radiation, suggesting that SV40 immortalization results in a unique phenotype with regard to DNA damage responses. PMID- 10092529 TI - Tissue distribution of placenta-type 6-phosphofructo- 2-kinase/fructose-2,6 bisphosphatase. AB - Several isozymes of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase have been characterized from mammalian tissues and, based on tissue origin, they are classified as liver, skeletal muscle, heart, testis, and placenta isozymes. In this paper, we examined the tissue distribution of placenta-type isozyme in rat tissues at the levels of transcription and translation. Analysis by Northern blotting showed that placenta, brain, testis, liver, kidney, and skeletal muscle expressed mRNA of placenta-type isozyme. Western blot analysis of fractions from POROS-HQ column chromatography of extracts from various rat tissues showed that proteins of placenta-type isozyme are expressed in placenta, brain, testis, liver, spleen, heart and lung, but not in kidney and skeletal muscle. An immunohistochemical study showed that, in liver, placenta-type isozyme is localized in Kupffer cells. These results indicate that isozymes of this particular enzyme may occur in particular cell types within each tissue. PMID- 10092530 TI - Angiogenin is involved in morphological changes and angiogenesis in the ovary. AB - Angiogenin is a potent angiogenic factor secreted by cultured tumor cells and is found in various normal organs and tissues. The ovary is one of the adult organs in which angiogenesis normally occurs during the female reproductive cycle. In this study, we examined whether angiogenin protein is localized and if angiogenin mRNA is expressed in the normal bovine ovary by immunohistochemistry using polyclonal rabbit anti-bovine angiogenin IgG and by in situ hybridization using bovine angiogenin probe, respectively. The localization and mRNA expression of angiogenin in the ovarian follicle and in the corpus luteum were different in their developmental stages. The intensities of immunoreactivities and angiogenin transcripts in the follicle increased from the primordial to the tertiary (or Graafian) follicle. The early corpus luteum contained strong immunoreactivities and mRNA expression of angiogenin but these intensities weakened during regression. The results suggest that angiogenin is involved in morphological changes and angiogenesis in the ovary. PMID- 10092531 TI - Differentially expressed genes in activin-induced apoptotic LNCaP cells. AB - Gene transcripts differentially expressed in activin-induced human prostatic LNCaP apoptotic cells have been discovered by an improved subtractive hybridization method, uracil-DNA subtraction assay (USA), which involves digestion with uracil-DNA glycosylase and mung-bean nuclease. Among the five up regulated and seven down-regulated genes, we have identified six known (>95% homology and similar size; p16, p53, Siva, RHAMM, Pax2, and eIF-4a1), three homologues (>95% homology but different size; myosin, a helicase motif, and a kinase motif), and three novel genes (no homology). In addition, anti-sense knock out of a resulting novel kinase-like gene was found to abolish the apoptotic DNA fragmentation in activin-treated LNCaP cells. These findings indicate a new potential mechanism in DNA fragmentation of activin-induced cell-cycle arresting and apoptosis. PMID- 10092532 TI - An additional exon of stress-inducible heat shock protein 70 gene (HSP70-1). AB - The HSP70-1 gene, reportedly a single exon, encodes a major stress-inducible 72 kDa heat shock protein (HSP70). We recently demonstrated that patients with major depression had a 162-base pair (bp)-deletion in the 5'-flanking sequence of HSP70 1 mRNA in their peripheral blood mononuclear cells. Present study has been conducted to clarify how this short mRNA is generated, and demonstrated that a novel 385 bp sequence is located 1.1 kb upstream from the HSP70-1 gene of normal subjects. Except for the 162 bp deletion, it is compatible with part of the 5' flanking sequence of the HSP70-1 gene, and contains another exon of 358 bp (exon 1) that may be connected to the 3'-terminus (exon 3) of the conventional HSP70-1 gene. Alternative transcription of exons 1 and 3 may cause the short mRNA. It is concluded that HSP70-1 gene is constituted of three exons and may cause alternative splicing. PMID- 10092533 TI - Expression of the human hepatocyte growth factor cDNA in primary cultures of rat hepatocytes. AB - Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are primary mitogens for hepatocytes in culture. hepatocytes express the HGF-receptor MET but not HGF itself. To investigate the influence of autocrine HGF expression on the proliferative potential of hepatocytes, primary cultures were submitted to retrovirus-mediated transduction of the human hgf (huHGF) cDNA. Expression of the transduced cDNA revealed a minimum 2-fold increase in HGF-mRNA, whereas expression of the Escherichia coli beta-galactosidase gene remained even. Estimation of huHGF copy numbers showed there was a minimum 4-fold increase, suggesting an increase in the population of transduced cells. Immunoprecipitation of excreted huHGF and growth bioassays proofed that HGF was present and functional. HGF is excreted into the medium and therefore, by diffusion, available to transduced and non-transduced cells. The increase in huHGF transduced cells suggests that the autocrine pathway as opposed to the paracrine pathway, which are both present at the same time, confers a growth advantage to these cells. PMID- 10092534 TI - Molecular cloning of a novel 130-kDa cytoplasmic protein, Ankhzn, containing Ankyrin repeats hooked to a zinc finger motif. AB - A novel gene was trapped in mouse embryonic stem cells with a promoterless gene trap vector. Fused transcripts were isolated from the embryos by rapid amplification of cDNA ends, which were used for full-length cDNA cloning. The protein predicted from the cDNA consisting of 7143 nucleotides comprises 1184 amino acids, which was confirmed by in vitro transcription/translation assaying. An antibody against the synthesized peptide reacted with an approximate 130-kDa protein on SDS-PAGE. A search of available databases revealed that this protein is a novel protein composed of 17 ankyrin repeats hooked to a zinc finger motif, which we named Ankhzn. Ankhzn was observed on the endosomal membrane on immunoelectron microscopic analysis. Ankhzn belongs to a new subgroup of double zinc finger proteins which may be involved in vesicle or protein transport. Ankhzn mRNA and its protein were expressed ubiquitously from embryonic day 10.5 to adulthood. PMID- 10092535 TI - Acceleration of adhesion of cancer cells and neutrophils to endothelial cells in the absence of de novo protein synthesis: possible implication for involvement of hydroxyl radicals. AB - The adhesion of colon cancer cells (colo201) and neutrophils to endothelial cells which had been briefly exposed to either hypoxanthine/xanthine oxidase, or hydrogen peroxide, or peroxynitrite was analyzed in the absence of de novo protein synthesis. Such treatments accelerated the adhesions of both colo201 cells and neutrophils to endothelial cells. These effects were blocked by SOD/catalase or EDTA. The results provided evidence that hydroxyl radicals affect the cell surface of endothelial cells and accelerate cell adhesion. PMID- 10092536 TI - Presence of bleomycin-detectable free iron in the alveolar system of preterm infants. AB - Chronic lung disease (CLD) is a major cause of long term morbidity in preterm infants. Reactive oxygen species (ROS) play an important role in the pathogenesis of CLD. We show that a high percentage (63 to 83%) of the investigated bronchoalveolar secretions (BAS) of neonates contain bleomycin-detectable free iron concentrations (0. 04-0.124 nmol/micrograms SC, median range). Beside the presence of redox-active iron several iron-binding proteins like transferrin, ferritin and lactoferrin were determined in BAS. Comparison of protein distribution within the first three days of life showed slight differences between the group of preterm infants who developed CLD and the neonates who recovered from RDS. Because of the existence of free iron we suggest a higher risk of hydroxyl radical formation in the alveolar space. In an artificial system with addition of iron and hydrogen peroxide we were able to demonstrate OH radical production in BAS by electron paramagnetic resonance (EPR). OH-radical formation by H2O2 and iron in buffer solution was slightly enhanced in the presence of BAS, indicating the absence of OH-radical-scavengers in BAS. PMID- 10092537 TI - Reverse motion of organelles with myosin molecules along bundles of the actin filaments in a Characean internodal cell. AB - We have visualized bundles of the actin filaments of a Characean internodal cell and investigated the sliding motion of organelles with myosin on the bundles. The investigation revealed that a power spectrum of the sliding velocity time series of the organelle has two remarkable peaks near 4 and 7.5 Hz. This suggests that myosin molecules attached to the organelle not independently but cooperatively produce the sliding force. Moreover, we have found that some organelles move in the opposite direction of their sliding motion for several hundred milliseconds along the bundles. The fluctuation analysis of that motion showed that a power spectrum profile of the reverse velocity time series almost agreed with that of the sliding velocity time series. This result suggests that the dynamics of the reverse motion is the same as that of the sliding motion. PMID- 10092538 TI - A mitochondrial DNA mutation cosegregates with the pathophysiological U wave. AB - In a family with long QT syndrome (LQT2), some individuals who did not harbor the HERG mutation had a prolonged QTU interval on electrocardiograms after exercise. It may be determined or modified by other gene(s) or factor(s). The sequence analysis of mtDNA in these individuals of this family showed a candidate pathogenic mutation at 3394 in the ND1 gene. The cybrids (mutation at 3394) showed significantly reduced NADH-CoQ reductase (complex I) activity and O2 consumption to normal levels. These inhibitory effects on respiratory function may result in the depletion of ATP and could possibly produce an increase in Ca2+ concentration in cytosol, and it may lead to the prolongation of the QTU intervals on electrocardiograms. Therefore, we stated that the 3394 mutation in the ND1 gene is pathogenic and could be the cause of prolongation of the QTU intervals or modification of the phenotypes of not only congenital but also so called "acquired drug-induced long QT syndrome." PMID- 10092539 TI - Signaling transduction pathway of angiotensin II in human mesangial cells: mediation of focal adhesion and GTPase activating proteins. AB - Human mesangial cells (HMCs) respond to angiotensin II stimulation, which modulates their physiological activities, i.e., contraction and proliferation. It has been revealed that focal adhesion kinase (FAK) and paxillin participate in the angiotensin II-mediated signaling and cytoskeletal rearrangements at focal adhesion. We investigated the influences of cell adhesion upon angiotensin II effects in HMCs. In adherent cells, both FAK and paxillin were tyrosine phosphorylated by angiotensin II, while the cell detachment completely inhibited the tyrosine phosphorylation of paxillin. Activation of p44/42 mitogen-activated protein (MAP) kinase by angiotensin II was accentuated in suspended cells. Moreover, p190, a member of Rho GTPase activating protein (GAP), and RasGAP were coprecipitated with paxillin in adherent cells and angiotensin II stimulation reduced the formation of paxillin-p190 and paxillin-RasGAP complexes. These results suggest that the formation of focal adhesion complexes accelerated by accumulation of mesangial matrices may inhibit the proliferation of HMCs by modulating MAP kinase activity and be related to mesangial cell depletion. PMID- 10092540 TI - Synergistic inhibition of carboxypeptidase A by zinc ion and imidazole. AB - Zinc ion in solution yields a 560-fold enhancement in the kinetic inhibition of carboxypeptidase A by the simple heterocycle imidazole, behavior attributed to formation of a ternary complex of the three species. However, the effect is partially negated by formation of less-inhibitory Zn2+(C3H4N2)2-4 coordination complexes, providing for the enzyme an anomalous profile of catalytic rate versus imidazole concentration. PMID- 10092544 TI - HLA-G: a new opening for HLA. PMID- 10092541 TI - Oxidative stress in newborn infants with and without asphyxia as measured by plasma antioxidants and free fatty acids. AB - A rapid perfusion of oxygen in infants at birth may cause an increase of oxidative stress. To assess this possibility, we measured levels of blood plasma antioxidants and free fatty acids in 20 normal infants at 0, 1, 3, and 5 days after birth. Plasma levels of the most reactive antioxidant, ascorbic acid, decreased daily to equilibrium values at days 3 and 5. Percentages of oxidized form of coenzyme Q-10 (%CoQ-10) in total coenzyme Q, another good marker of oxidative stress, in infants (25-31%) were significantly higher than those in healthy young adults (4.5%). Plasma levels of total free fatty acids (FFA) in normal infants were highest at day 1 and decreased rapidly thereafter. The content of polyunsaturated fatty acids (PUFA) in total FFA was lowest at day 1 and then increased. Since PUFA are susceptible to oxidation, these changes in FFA composition suggest that oxidative stress is most evident at the initial day of neonatal life. Furthermore, it appears that mono-unsaturated fatty acids such as oleic and palmitoleic acids increase in response to the oxidative loss of PUFA. Similar changes in plasma antioxidants, FFA levels, and FFA compositions were observed in 9 infants with asphyxia. Values of %CoQ-10 in infants with asphyxia were significantly greater than those in normal infants, suggesting that infants with asphyxia have elevated oxidative stress. PMID- 10092545 TI - The immunotolerance role of HLA-G. AB - HLA-G is a non-classical MHC class I molecule involved in immune tolerance. We present our results concerning the effects of HLA-G on the cellular immune response, where it impairs both NK and T cell functions. We describe the NK inhibitory properties of HLA-G ex vivo, demonstrating its role in materno-fetal tolerance, which is supported by our in vitro studies using membrane-bound HLA-G1 and HLA-G2-transfected cells and a full-length soluble HLA-G molecule. We also report how HLA-G interacts at the T cell level, here exemplified by its inhibitory effect on both T cell allogeneic proliferative and Ag-specific CTL responses. PMID- 10092546 TI - Natural killer cell-mediated recognition of human trophoblast. AB - Large numbers of natural killer cells are present within the maternal decidua close to the extravillous trophoblast cells. Most of these natural killer cells express high levels of inhibitory NK receptors (KIR) specific for HLA class I molecules. Since trophoblast cells only express HLA-C and HLA-G, the KIR expressed by decidual NK cells can only recognize these HLA class I molecules in order to avoid NK-mediated rejection of fetal tissues. We show that HLA-C recognition by decidual NK cells can be mediated by p58, LIR-1 and (indirectly) by CD94/NKG2A receptors. On the other hand, HLA-G recognition is not only mediated by LIR-1 and (indirectly) by CD94/NKG2A but also by a newly identified receptor termed p49. The p49 receptor, unlike the other KIR, appears to be selectively expressed by decidual NK cells. PMID- 10092547 TI - How do NK cells sense the expression of HLA-G class Ib molecules? AB - The nature of NK cell receptors involved in recognition of HLA-G1 has remained an unclear issue; we herein review this topic based on our experience. We found no evidence that well characterized p58 and p70 KIRs may interact with HLA-G1. By contrast, our data support that NK recognition of cells expressing HLA-G1 involves at least two non-overlapping receptor-ligand systems: (1) the direct engagement of the ILT2 (LIR1) receptor by HLA-G1; and (2) the interaction of CD94/NKG2A and CD94/NKG2C receptors with the non-classical class I molecule HLA E, co-expressed on the surface upon binding to a nonamer (VMAPRTLFL) from the HLA G leader sequence. PMID- 10092548 TI - HLA-G expression: immune privilege for tumour cells? AB - The non-classical class I antigen HLA-G has been shown to play a role in foeto maternal tolerance. It interacts with inhibitory receptors to down-regulate natural killer and T cell cytotoxic functions. We here report our investigations on HLA-G expression in melanoma cells and its implication in the induction of immune tolerance to tumours. We provide the first evidence that both malignant human melanoma cell lines and ex vivo biopsies can exhibit high levels of HLA-G transcription with differential HLA-G isoform transcription and protein expression patterns. We further demonstrated that melanoma cells that express HLA G inhibit NK cytolysis. We thus propose that HLA-G expression may impede the elimination of malignant cells by anti-tumour immune effector cells, constituting a newly described mechanism by which tumour cells may evade immunosurveillance. PMID- 10092549 TI - HLA-G and HLA-C at the feto-maternal interface: lessons learned from pathogenic viruses. AB - Immunoevasive viruses which effect antigen presentation by class I major histocompatibility complex (MHC) molecules have helped to broaden our understanding of the intracellular transport and processing of HLA-G and HLA-C in the placenta. Cellular infection with herpes simplex virus (HSV) and human cytomegalovirus (HCMV) are each associated with the downregulation of surface expression of HLA-A and -B, albeit by remarkably distinct mechanisms. Investigations on the effects of HSV and HCMV infection on HLA-G and HLA-C in the trophoblast have revealed both hypothesized similarities and surprising differences between trophoblast and classical class I products. PMID- 10092550 TI - The role of peptide presentation in the physiological function of HLA-G. AB - The HLA-G gene gives rise to six differently spliced mRNAs. The membrane bound HLA-G1 molecule containing all three extracellular domains presents peptides that follow motif requirements similar to those of classical HLA class I molecules. This isoform is also capable of inhibiting Natural Killer (NK) cells, but is only efficiently transported to the cell surface when peptides are provided in the endoplasmic reticulum. In the absence of sufficient peptide supply to the ER a small molecule of 18-kDa is transported to the cell surface in HLA-G transfectants of LCL721.221 cells. HLA-G transfectants with impaired ER peptide supply are nevertheless protected from NK lysis. PMID- 10092551 TI - The regulation of HLA class I expression: is HLA-G the odd one out? AB - The expression of HLA-G in extravillous cytotrophoblast cells coincides with a general lack of classical MHC class I expression in this tissue. This differential expression of HLA-G and classical HLA class I molecules in trophoblasts suggests a tight transcriptional control. Transactivation of classical MHC class I genes is mediated by two groups of juxtaposed cis -acting elements which can be viewed as regulatory modules. The most up-stream module consists of the enhancer A and ISRE, and mediates the constitutive and cytokine induced expression. The recently identified S-X-Y module is important in the constitutive and CIITA mediated transactivation. Both modules are divergent in HLA-G rendering this gene unresponsive to NF-kappaB, IRF-1, and CIITA mediated induction pathways. However, other known regulatory sequences that could contribute to the tissue-specific expression of HLA-G have so far not been identified in the proximal promoter region (-1500 bp) and in the first five intronic sequences. This implies a unique regulation of HLA-G transcription. Here, the transcriptional control of HLA-G and classical class I molecules in trophoblast cells are discussed. PMID- 10092552 TI - The measurement of health related quality of life. PMID- 10092553 TI - Identification and treatment of patients with atrial fibrillation in primary care. PMID- 10092554 TI - Stamps in cardiology. Phonocardiography. PMID- 10092555 TI - New British recommendations for prevention of coronary heart disease in clinical practice. PMID- 10092556 TI - Potential interests of heart rate lowering drugs. PMID- 10092557 TI - Determinants of an impaired quality of life five years after coronary artery bypass surgery. AB - OBJECTIVE: To identify determinants of an inferior quality of life (QoL) five years after coronary artery bypass grafting (CABG). SETTING: University hospital. PARTICIPANTS: Patients from western Sweden who underwent CABG between 1988 and 1991. MAIN OUTCOME MEASURES: Questionnaires for evaluating QoL before CABG and five years after operation. Three different instruments were used: the Nottingham health profile (NHP), the psychological general wellbeing index (PGWI), and the physical activity score (PAS). RESULTS: 2121 patients underwent CABG, of whom 310 died during five years' follow up. Information on QoL after five years was available in 1431 survivors (79%). There were three independent predictors for an inferior QoL with all three instruments: female sex, a history of diabetes mellitus, and a history of chronic obstructive pulmonary disease. Multivariate analysis showed that a poor preoperative QoL was a strong independent predictor for an impaired QoL five years after CABG. An impaired QoL was also predicted by previous disease. CONCLUSIONS: Female sex, an impaired QoL before surgery, and other diseases such as diabetes mellitus are independent predictors for an impaired QoL after CABG in survivors five years after operation. PMID- 10092558 TI - Prospective study of health related quality of life before and after coronary artery bypass grafting: outcome at five years. AB - OBJECTIVE: To determine the long term health related quality of life of coronary artery bypass graft patients, to look at changes between one and five years after surgery, and to examine the ability of preoperative variables to predict longer term outcome. DESIGN: Nottingham health profile (NHP) was used to assess patients at five years compared to results obtained at one year. PATIENTS: 100 male patients aged < 60 years at time of surgery; 77 had three vessel disease and 84 received three or more saphenous vein grafts. RESULTS: In comparing the five year results with those at one year, lower mean scores, indicating slight improvements, were seen in the NHP dimensions of pain, sleep, social isolation, and emotional reactions, whereas signs of deterioration were noted in the physical mobility and energy scores. Chest pain was experienced by 34 of 84 patients at five years compared with 17 of 89 patients at one year. The proportion of patients who were unrestricted in their activities ranged from 61 70% at five years compared with 82-88% at one year. Absence of dyspnoea before surgery, indicating relatively good left ventricular function, was a predictor of good outcome at both one and five years. CONCLUSIONS: Evidence of deterioration in physical function is compatible with expected decline in graft patency; specific rather than generic measures were most sensitive to this change. PMID- 10092559 TI - Unilateral pulmonary oedema complicating supine bicycle exercise echocardiography. PMID- 10092560 TI - Quality of life four years after acute myocardial infarction: short form 36 scores compared with a normal population. AB - OBJECTIVES: To assess the impact of myocardial infarction on quality of life in four year survivors compared to data from "community norms", and to determine factors associated with a poor quality of life. DESIGN: Cohort study based on the Nottingham heart attack register. SETTING: Two district general hospitals serving a defined urban/rural population. SUBJECTS: All patients admitted with acute myocardial infarction during 1992 and alive at a median of four years. MAIN OUTCOME MEASURES: Short form 36 (SF 36) domain and overall scores. RESULTS: Of 900 patients with an acute myocardial infarction in 1992, there were 476 patients alive and capable of responding to a questionnaire in 1997. The response rate was 424 (89. 1%). Compared to age and sex adjusted normative data, patients aged under 65 years exhibited impairment in all eight domains, the largest differences being in physical functioning (mean difference 20 points), role physical (mean difference 23 points), and general health (mean difference 19 points). In patients over 65 years mean domain scores were similar to community norms. Multiple regression analysis revealed that impaired quality of life was closely associated with inability to return to work through ill health, a need for coronary revascularisation, the use of anxiolytics, hypnotics or inhalers, the need for two or more angina drugs, a frequency of chest pain one or more times per week, and a Rose dyspnoea score of >/= 2. CONCLUSIONS: The SF 36 provides valuable additional information for the practising clinician. Compared to community norms the greatest impact on quality of life is seen in patients of working age. Impaired quality of life was reported by patients unfit for work, those with angina and dyspnoea, patients with coexistent lung disease, and those with anxiety and sleep disturbances. Improving quality of life after myocardial infarction remains a challenge for physicians. PMID- 10092561 TI - Changes in cardiorespiratory fitness, psychological wellbeing, quality of life, and vocational status following a 12 month cardiac exercise rehabilitation programme. AB - OBJECTIVE: To examine and evaluate improvements in cardiorespiratory fitness, psychological wellbeing, quality of life, and vocational status in postmyocardial infarction patients during and after a comprehensive 12 month exercise rehabilitation programme. SUBJECTS: The sample population comprised 124 patients with a clinical diagnosis of myocardial infarction (122 men and two women). INTERVENTIONS: 62 patients were randomly allocated to a regular weekly aerobic training programme, three times a week for 12 months, and compared with 62 matched controls who did not receive any formal exercise training. A five year follow up questionnaire/interview was subsequently conducted on this population to determine selected vocational/lifestyle changes. RESULTS: Significant improvements in cardiorespiratory fitness (p < 0.01-0.001), psychological profiles (p < 0.05-0.001), and quality of life scores (p < 0.001) were recorded in the treatment population when compared with their matched controls. Although there were no significant differences in mortality, a larger percentage of the regular exercisers resumed full time employment and they returned to work earlier than the controls. Controls took lighter jobs, lost more time from work, and suffered more non-fatal reinfarctions (p < 0.05-0.01). CONCLUSIONS: Regularly supervised and prolonged aerobic exercise training improves cardiorespiratory fitness, psychological status, and quality of life. The trained population also had a reduction in morbidity following myocardial infarction, and significant improvement in vocational status over a five year follow up period. PMID- 10092562 TI - Priority points and cardiac events while waiting for coronary bypass surgery. AB - OBJECTIVE: To assess the risk of important cardiac events while waiting for coronary artery bypass surgery (CABG) in relation to the New Zealand priority scoring system; to compare clinical characteristics of patients referred for CABG in New Zealand with those in Ontario, Canada; and to compare the New Zealand priority scoring system for CABG with the previously validated Ontario urgency score. DESIGN: Analysis of outcomes in a consecutive case series of patients referred for CABG. SETTING: University hospital. PATIENTS: All 324 patients from Christchurch Hospital wait listed for isolated CABG between 1 January 1994 and 31 December 1995. MAIN OUTCOME MEASURES: Death, myocardial infarction, and unstable angina while waiting for CABG; waiting time to surgery. RESULTS: Clinical characteristics at referral were very similar, but median waiting time was longer in New Zealand than in a large Canadian case series (212 days v 17 days). While waiting for elective CABG, 44% (114/257) of New Zealand patients had cardiac events: death 4% (13/257), non-fatal myocardial infarction 6% (16/257), readmission with unstable angina 34% (87/257). Priority scores did not predict cardiac events while waiting for CABG. Indeed, death or non-fatal myocardial infarction occurred in 4% (3/76) and 8% (6/76), respectively, of those with priority scores < 35. These people are no longer eligible for publicly funded surgery in New Zealand. CONCLUSIONS: Very long waiting times for CABG are associated with frequent cardiac events, at considerable cost to both patients and health care providers. Priority scores may facilitate comparison between countries but such scores did not predict clinical events while waiting. PMID- 10092563 TI - Role of risk factors for major coronary heart disease events with increasing length of follow up. AB - BACKGROUND: It has been suggested that the predictive value of certain risk factors for coronary heart disease (CHD) measured at one point in time diminishes with increasing length of follow up. DESIGNS AND METHODS: The relation was examined between a wide range of risk factors and the risk of major CHD events over 15 years' total (cumulative) follow up and for three separate five year periods (0-5.0, 5.1-10.0, and 10.1-15.0 years) in men with and without diagnosed CHD in a large prospective study of 7735 men aged 40-59 years. SETTING: General practices in 24 towns in the UK. RESULTS: The cumulative CHD event rate for all men was 9.4/1000 person-years for the 15 years of follow up. In men with no recall of a diagnosis of CHD, the established risk factors-serum total cholesterol, high density lipoprotein cholesterol, systolic and diastolic blood pressure, physical activity, body mass index (BMI), alcohol intake, diabetes mellitus, parental history, and evidence of CHD on chest pain questionnaire or on ECG-were predictive of CHD events occurring in the three specific periods after baseline measurement. Blood pressure (systolic and diastolic) was still predictive of events occurring 10.1-15.0 years later with some attenuation in the relative risk associated with systolic blood pressure. The risks associated with blood glucose and serum insulin concentration, factors measured with greater imprecision, attenuated with longer follow up and were not predictive of events occurring 10. 1-15.0 years later. In men with recall of diagnosed CHD, the absolute risk was very high (38.8/1000 person-years); only cigarette smoking, BMI, total cholesterol, and serum insulin were predictive of CHD events occurring 10.1-15.0 years later. CONCLUSION: In men without recall of diagnosed CHD most major risk factors measured in middle age predict risk of CHD events occurring in up to 15 years of follow up, both cumulatively and in the three separate five year periods. Risk factors measured at one point in time in middle age may be regarded as reliable indicators for long term prognosis of major CHD events on a group basis, despite the changes that may take place in these risk factors in some individuals during prolonged follow up. PMID- 10092564 TI - Contribution of modern cardiovascular treatment and risk factor changes to the decline in coronary heart disease mortality in Scotland between 1975 and 1994. AB - OBJECTIVE: To estimate the fall in coronary heart disease (CHD) mortality in Scotland attributable to medical and surgical treatments, and risk factor changes, between 1975 and 1994. DESIGN: A cohort model combining effectiveness data from meta-analyses with information on treatment uptake in all patient categories in Scotland. SETTING AND PATIENTS: The whole Scottish population of 5.1 million, including all patients with recognised CHD. INTERVENTIONS: All cardiological, medical, and surgical treatments, and all risk factor changes between 1975 and 1994. Data were obtained from epidemiological surveys, routine National Health Service sources, and local audits. MAIN OUTCOME MEASURES: Deaths from CHD in 1975 and 1994. RESULTS: There were 15 234 deaths from CHD in 1994, 6205 fewer deaths than expected if there had been no decline from 1975 mortality rates. In 1994, the total number of deaths prevented or postponed by all treatments and risk factor reductions was estimated at 6747 (minimum 4790, maximum 10 695). Forty per cent of this benefit was attributed to treatments (initial treatments for acute myocardial infarction 10%, treatments for hypertension 9%, for secondary prevention 8%, for heart failure 8%, aspirin for angina 2%, coronary artery bypass grafting surgery 2%, and angioplasty 0.1%). Fifty one per cent of the reduction in deaths was attributed to measurable risk factor reductions (smoking 36%, cholesterol 6%, secular fall in blood pressure 6%, and changes in deprivation 3%). Other, unquantified factors apparently accounted for the remaining 9%. These proportions remained relatively consistent across a wide range of assumptions and estimates in a sensitivity analysis. CONCLUSIONS: Medical treatments and risk factor changes apparently prevented or postponed about 6750 coronary deaths in Scotland in 1994. Modest gains from individual treatments produced a large cumulative survival benefit. Reductions in major risk factors explained about half the fall in coronary mortality, emphasising the importance and future potential of prevention strategies. PMID- 10092565 TI - Management of non-cardiac chest pain: from research to clinical practice. AB - BACKGROUND: Non-cardiac chest pain assessed by cardiologists in their outpatient clinics or by coronary angiography usually has a poor symptomatic functional and psychological outcome. Randomised trials have shown the effectiveness of specialist psychological treatment with those who have persistent symptoms, but such treatment is not always acceptable to patients and may not be feasible in routine clinical settings. OBJECTIVES: To describe a sample of patients referred to cardiac outpatient clinics from primary care in a single health district who were consecutively reassured by cardiologists that there was not a cardiac cause for their presenting symptom of chest pain. DESIGN: Systematic recording of referral and medical information of patients consecutively reassured by cardiologists. Reassessment in research clinic six weeks later (with a view to inclusion in a randomised trial of psychological treatment, which has been separately reported) and followed up at six months. SETTING: A cardiac clinic in a teaching hospital providing a district service to patients referred from primary care. PATIENTS: 133 patients from the Oxfordshire district presenting with chest pain and consecutively reassured that there was no cardiac cause during the recruitment period; 69 had normal coronary angiograms and 64 were reassured without angiography. INTERVENTION: A subgroup (n = 56) with persistent disabling chest pain at six weeks were invited to take part in a randomised controlled trial of cognitive behavioural treatment. MAIN OUTCOME MEASURES: Standardised interview and self report measures of chest pain, other physical symptoms, mood and anxiety, everyday activities, and beliefs about the cause of symptoms at six week assessment; repeat of self report measures at six months. RESULTS: Patients had a good outcome at six weeks, but most had persistent, clinically significant symptoms and distress. Some found the six week assessment and discussion useful. The psychological treatment was helpful to most of those recruited to the treatment trial, but a minority (15%) of those treated appeared to need more intensive and individual collaborative management. Patients reassured following angiography were compared with those reassured without invasive investigation. They had longer histories of chest pain, more often reported breathlessness on exertion, and were more likely to have previously been diagnosed as having angina, treated with antianginal medication, and admitted to hospital as emergencies. CONCLUSION: These findings suggest a need for "stepped" aftercare, with management tailored according to clinical need. This may range from simple reassurance and explanation in the cardiac clinic to more intensive individual psychological treatment of associated underlying and often enduring psychological problems. Simple ways in which the cardiologist might improve care to patients with non-cardiac chest pain are suggested, and the need for access to specialist psychological treatment discussed. PMID- 10092566 TI - Coronary artery stenting in unstable angina pectoris: a comparison with stable angina pectoris. AB - OBJECTIVE: To compare early complication rates in unselected cases of coronary artery stenting in patients with stable v unstable angina. SETTING: Tertiary referral centre. PATIENTS: 390 patients with stable angina pectoris (SAP) and 306 with unstable angina (UAP). Patients treated for acute myocardial infarction (primary angioplasty) or cardiogenic shock were excluded. INTERVENTIONS: 268 coronary stents were attempted in 211 patients (30.3%). Stents used included AVE (63%), Freedom (14%), NIR (7%), Palmaz-Schatz (5%), JO (5%), and Multilink (4%). Intravascular ultrasound was not used in any of the cases. All stented patients were treated with ticlopidine and aspirin together with periprocedural unfractionated heparin. RESULTS: 123 stents were successfully deployed in 99 SAP patients v 132 stents in 103 UAP patients. Failed deployment occurred with nine stents in SAP patients, v four in UAP patients (NS). Stent thrombosis occurred in four SAP patients and 11 UAP patients. Multivariate analysis showed no relation between stent thrombosis and clinical presentation (SAP v UAP), age, sex, target vessel, stent length, or make of stent. Stent thrombosis was associated with small vessel size (p < 0.001) and bailout stenting (p = 0.01) compared with elective stenting and stenting for suboptimal PTCA, with strong trends toward smaller stent diameter (p = 0.052) and number of stents deployed (p = 0.06). Most stent thromboses occurred in vessels < 3 mm diameter. CONCLUSIONS: Coronary artery stenting in unstable angina is safe in vessels >/= 3 mm diameter, with comparable initial success and stent thrombosis rates to stenting in stable angina. PMID- 10092567 TI - The functional significance of chronotropic incompetence during dobutamine stress test. AB - OBJECTIVE: To investigate the functional significance of chronotropic incompetence during dobutamine stress echocardiography. PATIENTS AND METHODS: The functional significance of chronotropic incompetence was evaluated during dobutamine stress echocardiography in 512 patients without beta blocker treatment who underwent dobutamine stress echocardiography (up to 40 microg/kg/min) and completed the protocol or reached the target heart rate. Mean (SD) age was 60 (12) years (313 men, 199 women). Chronotropic incompetence was defined as failure to achieve 85% of the maximum exercise heart rate predicted for age and sex (220 age in men; 200 - age in women) at maximum dobutamine dose. RESULTS: Chronotropic incompetence occurred in 196 patients (38%). Affected patients were significantly younger, more likely to be men (both p << 0.001) and smokers (p < 0.05), had a higher prevalence of previous myocardial infarction (p < 0.005) and resting wall motion abnormalities (p < 0. 05), and had a lower resting heart rate (p << 0.001) and systolic blood pressure (p << 0.001) than patients without chronotropic incompetence, but there was no difference in the overall prevalence of ischaemia and significant coronary artery disease. By multivariate analysis, independent predictors of chronotropic incompetence were a lower resting heart rate (p << 0.001), younger age (p << 0.001), and male sex (p << 0.001). CONCLUSIONS: The relations among sex, age, and chronotropic incompetence show the need to titrate the dobutamine dose using specific data based on age and sex related heart rate responses to dobutamine rather than to an exercise stress test. Obtaining specific heart rate criteria is necessary to determine whether chronotropic incompetence represents a real failure to achieve a normal response or is the result of applying an inappropriate gold standard. PMID- 10092568 TI - Effect of repetitive episodes of exercise induced myocardial ischaemia on left ventricular function in patients with chronic stable angina: evidence for cumulative stunning or ischaemic preconditioning? AB - BACKGROUND: Myocardial stunning is known to occur following a single episode of effort angina in patients with coronary artery disease. The effect on left ventricular (LV) function of repeated episodes of ischaemia is unknown. OBJECTIVES: To investigate the effects of repeated episodes of exercise induced ischaemia on LV function in patients with chronic stable angina. METHODS: Patients with significant coronary artery disease and normal LV function underwent two episodes of symptom limited treadmill exercise separated by three different time intervals: either 30 minutes (group A, n = 14); 60 minutes (group B, n = 14); or 240 minutes (group C, n = 14). Quantitative stress echocardiography was performed at repeated intervals between the two exercises and for 240 minutes following the second test. RESULTS: For all groups there was no difference between the degree of ischaemia judged by maximal ST depression during the two tests. All episodes of exercise induced ischaemia produced prolonged abnormalities of LV systolic and diastolic function despite rapid normalisation of haemodynamic and ECG changes. In group A (30 minutes) these abnormalities were less pronounced after the second test than after the first, while in group B (60 minutes) they were more severe and long lasting. In group C (240 minutes) the two tests produced similar abnormalities of LV function. CONCLUSIONS: Prolonged abnormalities of LV function occurred following exercise induced ischaemia with a time course consistent with myocardial stunning. The severity and degree of LV dysfunction caused by a further episode of ischaemia appear to be dependent on the time interval between ischaemic episodes. PMID- 10092569 TI - Arterial thromboembolism in patients with sick sinus syndrome: prediction from pacing mode, atrial fibrillation, and echocardiographic findings. AB - OBJECTIVE: To evaluate whether thromboembolism in sick sinus syndrome can be predicted by pacing mode, atrial fibrillation, or echocardiographic findings. METHODS: Patients were randomised to single chamber atrial (n = 110) or ventricular (n = 115) pacing. They were divided into subgroups with and without brady-tachy syndrome at time of randomisation. The occurrence of atrial fibrillation and thromboembolism during follow up were investigated and compared with echocardiographic findings. RESULTS: The annual risk of thromboembolism was 5.8% in patients with brady-tachy syndrome randomised to ventricular pacing, 3.2% in patients without brady-tachy syndrome randomised to ventricular pacing, 3% in patients with brady-tachy syndrome randomised to atrial pacing, and 1.5% in patients without brady-tachy syndrome randomised to atrial pacing. In atrial paced patients without brady-tachy syndrome at randomisation and without atrial fibrillation during follow up, the annual risk of thromboembolism was 1.4%. Left atrial size measured by M mode echocardiography was of no value in predicting thromboembolism. CONCLUSIONS: Arterial thromboembolism in patients with sick sinus syndrome is very common and is associated primarily with brady-tachy syndrome at randomisation and with ventricular pacing. The risk of thromboembolism is small in atrial paced patients in whom atrial fibrillation has never been documented. PMID- 10092570 TI - Early detection of anthracycline induced cardiotoxicity in asymptomatic patients with normal left ventricular systolic function: autonomic versus echocardiographic variables. AB - OBJECTIVE: To investigate left ventricular dysfunction in patients who had been treated with anthracycline based chemotherapy. METHODS: Autonomic function was compared with left ventricular diastolic function in 20 asymptomatic women with normal systolic function (left ventricular ejection fraction (LVEF) > 0.50) treated for breast cancer with high dose anthracycline based chemotherapy, and 20 age matched healthy controls. Left ventricular diastolic function was assessed echocardiographically by measuring the early peak flow velocity to atrial peak flow velocity ratio, isovolumic relaxation time, and deceleration time. Heart rate variability analysis was assessed for time domain and frequency domain parameters. RESULTS: The mean (SD) age of the patients was 45 (7) years and the mean LVEF was 0.59 (0.06). The time interval after the end of chemotherapy was 29 (27) months. One or more diastolic variables were abnormal in 50% of the patients. Heart rate variability was abnormal in 85% of patients. Mean values of both time domain and frequency domain parameters were decreased (p < 0.05), in particular the parasympathetic indices. CONCLUSIONS: Autonomic impairment occurs in a large proportion of asymptomatic patients with normal systolic left ventricular function after high dose anthracycline based chemotherapy. In particular, heart rate variability analysis may be a sensitive tool to identify the first signs of cardiotoxicity in these patients. PMID- 10092572 TI - Images in cardiology Acute myocardial infarct from paradoxical embolism in a case of massive pulmonary thromboembolism. PMID- 10092571 TI - Spontaneous late improvement of myocardial viability in the chronic infarct zone is possible, depending on persistent TIMI 3 flow and a low grade stenosis of the infarct artery. AB - OBJECTIVE: In the chronic phase of myocardial infarction, the relation between myocardial recovery and infarct related artery status remains unclear. The spontaneous changes in rest-redistribution thallium defect size were prospectively studied over six months in 52 patients with chronic Q wave myocardial infarction. DESIGN: Changes in rest thallium defect size, thallium uptake in the infarct area, and radionuclide left ventricular ejection fraction were compared to the quantitative coronary angiogram data. Two groups of patients were considered: patients with a percentage of stenosis below 100% (group 1, n = 31); and patients with an occluded artery (group 2, n = 21). RESULTS: In the overall population, the mean (SD) defect size decreased from 28.2 (17.2)% to 24.9 (19.3)% of the whole myocardium (p = 0.01), while, in this area, the thallium uptake increased from 62.9 (13.7)% to 66. 9 (15.6)% (p < 0.001). At the time of inclusion, the defect size, thallium uptake, and ejection fraction were similar in both groups. In group 1 patients only, the reduction in defect size correlated with the improvement in ejection fraction (r = 0.41, p = 0.02) and was related to the percentage of coronary artery stenosis. TIMI 3 patients reduced the defect size while other patients increased this defect (-5.1 (7.0)% v +11.0 (14.4)%, p < 0.001). In contrast, no significant relations were found in group 2 patients. CONCLUSION: Late spontaneous recovery in thallium defect can occur in patients with a patent infarct related artery, depending on the TIMI flow grade and a low grade stenosis of the infarct related artery, and is associated with functional improvement. PMID- 10092573 TI - Implantable loop recorder: evaluation of unexplained syncope. PMID- 10092574 TI - Recurrence of thymoma presenting as a superior vena cava syndrome. PMID- 10092575 TI - Platelet IIb/IIIa antagonists followed by delayed stent implantation. A new treatment for vein graft lesions containing massive thrombus. AB - The percutaneous treatment of saphenous vein graft lesions containing angiographically massive thrombus is associated with a high risk of distal embolisation and no-reflow. The optimal management for these lesions remains unclear and a challenge to the interventional cardiologist. Five cases are described in whom the risks of percutaneous angioplasty were felt to be excessive owing to a high thrombus load. Each case was treated with a bolus and infusion of abciximab (ReoPro; Eli Lilly-a platelet glycoprotein IIb/IIIa receptor antagonist) at least 24 hours before further angiography. Repeat angiography of the culprit vein graft, following treatment with abciximab alone, demonstrated a major reduction in the thrombus score and the presence of TIMI 3 flow in each case. Immediately following repeat angiography, angioplasty with stent insertion was performed successfully with no distal embolisation or no-reflow phenomenon. This staged approach, with abciximab used alone to reduce thrombus load, is a new treatment for vein graft lesions containing massive thrombus. PMID- 10092576 TI - Transcatheter closure of a mid-muscular ventricular septal defect with an amplatzer VSD occluder device. AB - A 5 year old girl with a haemodynamically significant mid-muscular ventricular septal defect (VSD) had successful transcatheter closure using the Amplatzer VSD occluder. This device passes through a small diameter sheath and can be easily retrieved or repositioned. These properties may make it a suitable device for closure of large mid-muscular defects in small children. PMID- 10092577 TI - Diagnostic utility of metabolic exercise testing in a patient with cardiovascular disease. AB - Disproportionate exercise limitation in patients with cardiovascular disease is a common problem faced by clinical cardiologists and other physicians. Symptoms may be attributed to psychological factors or hypothetical pathophysiological mechanisms that are difficult to confirm clinically. This case report describes how the use of metabolic exercise testing in a 28 year old woman with morphologically and haemodynamically mild hypertrophic cardiomyopathy and severe exercise limitation led to the diagnosis of an alternative cause for the patient's symptoms, namely a primary disturbance of the mitochondrial respiratory chain probably caused by a nuclear encoded gene defect. PMID- 10092578 TI - Dilated cardiomyopathy in thyrotoxicosis. PMID- 10092579 TI - Non-surgical CHOP cures right ventricular outflow obstruction. PMID- 10092580 TI - Isolated unruptured aneurysm of the right sinus of Valsalva causing right ventricular outflow obstruction. PMID- 10092581 TI - Images in cardiology Coronary artery spasm. PMID- 10092582 TI - Phosphoinositide 3-kinases and their FYVE domain-containing effectors as regulators of vacuolar/lysosomal membrane trafficking pathways. PMID- 10092583 TI - A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. AB - We have cloned human protein kinase Bgamma (PKBgamma) and found that it contains two regulatory phosphorylation sites, Thr305 and Ser472, which correspond to Thr308 and Ser473 of PKBalpha. Thus it differs significantly from the previously published rat PKBgamma. We have also isolated a similar clone from a mouse cDNA library. In human tissues, PKBgamma is widely expressed as two transcripts. A mutational analysis of the two regulatory sites of human PKBgamma showed that phosphorylation of both sites, occurring in a phosphoinositide 3-kinase-dependent manner, is required for full activity. Our results suggest that the two phosphorylation sites act in concert to produce full activation of PKBgamma, similar to PKBalpha. This contrasts with rat PKBgamma, which is thought to be regulated by 3-phosphoinositide-dependent protein kinase 1 alone. PMID- 10092584 TI - TAKs, thylakoid membrane protein kinases associated with energy transduction. AB - The phosphorylation of proteins within the eukaryotic photosynthetic membrane is thought to regulate a number of photosynthetic processes in land plants and algae. Both light quality and intensity influence protein kinase activity via the levels of reductants produced by the thylakoid electron transport chain. We have isolated a family of proteins called TAKs, Arabidopsis thylakoid membrane threonine kinases that phosphorylate the light harvesting complex proteins. TAK activity is enhanced by reductant and is associated with the photosynthetic reaction center II and the cytochrome b6f complex. TAKs are encoded by a gene family that has striking similarity to transforming growth factor beta receptors of metazoans. Thus thylakoid protein phosphorylation may be regulated by a cascade of reductant-controlled membrane-bound protein kinases. PMID- 10092585 TI - Direct interaction of Alzheimer's disease-related presenilin 1 with armadillo protein p0071. AB - Alzheimer's disease-related presenilins are thought to be involved in Notch signaling during embryonic development and/or cellular differentiation. Proteins mediating the cellular functions of the presenilins are still unknown. We utilized the yeast two-hybrid system to identify an interacting armadillo protein, termed p0071, that binds specifically to the hydrophilic loop of presenilin 1. In vivo, the presenilins constitutively undergo proteolytic processing, forming two stable fragments. Here, we show that the C-terminal fragment of presenilin 1 directly binds to p0071. Nine out of 10 armadillo repeats in p0071 are essential for mediating this interaction. Since armadillo proteins, like beta-catenin and APC, are known to participate in cellular signaling, p0071 may function as a mediator of presenilin 1 in signaling events. PMID- 10092586 TI - The N-terminal CUB-epidermal growth factor module pair of human complement protease C1r binds Ca2+ with high affinity and mediates Ca2+-dependent interaction with C1s. AB - The Ca2+-dependent interaction between complement serine proteases C1r and C1s is mediated by their alpha regions, encompassing the major part of their N-terminal CUB-EGF-CUB (where EGF is epidermal growth factor) module array. In order to define the boundaries of the C1r domain(s) responsible for Ca2+ binding and Ca2+ dependent interaction with C1s and to assess the contribution of individual modules to these functions, the CUB, EGF, and CUB-EGF fragments were expressed in eucaryotic systems or synthesized chemically. Gel filtration studies, as well as measurements of intrinsic Tyr fluorescence, provided evidence that the CUB-EGF pair adopts a more compact conformation in the presence of Ca2+. Ca2+-dependent interaction of intact C1r with C1s was studied using surface plasmon resonance spectroscopy, yielding KD values of 10.9-29.7 nM. The C1r CUB-EGF pair bound immobilized C1s with a higher KD (1.5-1.8 microM), which decreased to 31.4 nM when CUB-EGF was used as the immobilized ligand and C1s was free. Half-maximal binding was obtained at comparable Ca2+ concentrations ranging from 5 microM with intact C1r to 10-16 microM for C1ralpha and CUB-EGF. The isolated CUB and EGF fragments or a CUB + EGF mixture did not bind C1s. These data demonstrate that the C1r CUB-EGF module pair (residues 1-175) is the minimal segment required for high affinity Ca2+ binding and Ca2+-dependent interaction with C1s and indicate that Ca2+ binding induces a more compact folding of the CUB-EGF pair. PMID- 10092587 TI - DNA contacts stimulate catalysis by a poxvirus topoisomerase. AB - Eukaryotic type 1B topoisomerases act by forming covalent enzyme-DNA intermediates that transiently nick DNA and thereby release DNA supercoils. Here we present a study of the topoisomerase encoded by the pathogenic poxvirus molluscum contagiosum. Our studies of DNA sites favored for catalysis reveal a larger recognition site than the 5'-(T/C)CCTT-3' sequence previously identified for poxvirus topoisomerases. Separate assays of initial DNA binding and covalent complex formation revealed that different DNA sequences were important for each reaction step. The location of the protein-DNA contacts was mapped by analyzing mutant sites and inosine-substituted DNAs. Some of the bases flanking the 5' (T/C)CCTT-3' sequence were selectively important for covalent complex formation but not initial DNA binding. Interactions important for catalysis were probed with 5'-bridging phosphorothiolates at the site of strand cleavage, which permitted covalent complex formation but prevented subsequent religation. Kinetic studies revealed that the flanking sequences that promoted recovery of covalent complexes increased initial cleavage instead of inhibiting resealing of the nicked intermediate. These data 1) indicate that previously unidentified DNA contacts can accelerate a step between initial binding and covalent complex formation and 2) help specify models for conformational changes promoting catalysis. PMID- 10092588 TI - Thrombin, a survival factor for cultured myoblasts. AB - Three members of the family of protease-activated receptors (PARs), PARs-1, -3 and -4, have been identified as thrombin receptors. PAR-1 is expressed by primary myoblast cultures, and expression is repressed once myoblasts fuse to form myotubes. The current study was undertaken to investigate the hypothesis that thrombin inhibits myoblast fusion. Primary rodent myoblast cultures were deprived of serum to promote myoblast fusion and then cultured in the presence or absence of thrombin. Thrombin inhibited myoblast fusion, but another notable effect was observed; 50% of control cells were apoptotic within 24 h of serum deprivation, whereas less than 15% of thrombin-treated cells showed signs of apoptosis. Proteolysis was required for the effect of thrombin, but no other serine protease tested mimicked the action of thrombin. Neither a PAR-1- nor a PAR-4-activating peptide inhibited apoptosis or fusion, and myoblast cultures were negative for PAR-3 expression. Myoblasts exposed to thrombin for 1 h and then changed to medium without thrombin accumulated apoptosis inhibitory activity in their medium over the subsequent 20 h. Thus the protective action of thrombin appears to be effected through cleavage of an unidentified thrombin receptor, leading to secretion of a downstream apoptosis inhibitory factor. These results demonstrate that thrombin functions as a survival factor for myoblasts and is likely to play an important role in muscle development and repair. PMID- 10092589 TI - Barley BLZ2, a seed-specific bZIP protein that interacts with BLZ1 in vivo and activates transcription from the GCN4-like motif of B-hordein promoters in barley endosperm. AB - A barley endosperm cDNA, encoding a DNA-binding protein of the bZIP class of transcription factors, BLZ2, has been characterized. The Blz2 mRNA expression is restricted to the endosperm, where it precedes that of the hordein genes. BLZ2, expressed in bacteria, binds specifically to the GCN4-like motif (GLM; 5' GTGAGTCAT-3') in a 43-base pair oligonucleotide derived from the promoter region of a Hor-2 gene (B1-hordein). This oligonucleotide also includes the prolamin box (PB; 5'-TGTAAAG-3'). Binding by BLZ2 is prevented when the GLM is mutated to 5' GTGctTCtc-3' but not when mutations affect the PB. The BLZ2 protein is a potent transcriptional activator in a yeast two-hybrid system where it dimerizes with BLZ1, a barley bZIP protein encoded by the ubiquitously expressed Blz1 gene. Transient expression experiments in co-bombarded developing barley endosperms demonstrate that BLZ2 transactivates transcription from the GLM of the Hor-2 gene promoter and that this activation is also partially dependent on the presence of an intact PB. A drastic decrease in GUS activity is observed in co-bombarded barley endosperms when using as effectors equimolar mixtures of Blz2 and Blz1 in antisense constructs. These results strongly implicate the endosperm-specific BLZ2 protein from barley, either as a homodimer or as a heterodimer with BLZ1, as an important transcriptional activator of seed storage protein genes containing the GLM in their promoters. PMID- 10092590 TI - Metallothionein is part of a zinc-scavenging mechanism for cell survival under conditions of extreme zinc deprivation. AB - Metallothionein (MT) is a small cysteine-rich protein thought to play a critical role in cellular detoxification of inorganic species by sequestering metal ions that are present in elevated concentrations. We demonstrate here that metallothionein can play an important role at the other end of the homeostatic spectrum by scavenging an essential metal in a mouse fibroblast cell line that has been cultured under conditions of extreme zinc deprivation (LZA-LTK-). These cells unexpectedly produce constitutively high levels of metallothionein mRNA; however, the MT protein accumulates only when high concentrations of zinc are provided in the media. Until this MT pool is saturated, no measurable zinc remains in the external media. In this case, zinc deprivation leads to amplification of the MT gene locus in the LZA-LTK- cell line. Furthermore, the intracellular zinc levels in the fully adapted cells remain at the normal level of 0.4 fmol zinc/cell, even when extracellular zinc concentration is decreased by 2 orders of magnitude relative to normal media. PMID- 10092591 TI - Importance of the carboxyl terminus in the folding and function of alpha hemolysin of Staphylococcus aureus. AB - The physical state of two model mutants of alpha-hemolysin (alphaHL), alphaHL(1 289), a carboxyl-terminal deletion mutant (CDM), and alphaHL(1-331), a carboxyl terminal extension mutant (CEM), were examined in detail to identify the role of the carboxyl terminus in the folding and function of native alphaHL. Denatured alphaHL can be refolded efficiently with nearly total recovery of its activity upon restoration of nondenaturing conditions. Various biophysical and biochemical studies on the three proteins have revealed the importance of an intact carboxyl terminus in the folding of alphaHL. The CDM exhibits a marked increase in susceptibility to proteases as compared with alphaHL. alphaHL and CEM exhibit similar fluorescence emission maxima, and that of the CDM is red-shifted by 9 nm, which indicates a greater solvent exposure of the tryptophan residues of the CDM. In addition, the CDM binds 8-anilino-1-naphthalene sulfonic acid (ANS) and increases its fluorescence intensity significantly unlike alphaHL and CEM, which show marginal binding. The circular dichroism studies point that the CDM possesses significant secondary structure, but its tertiary structure is greatly diminished as compared with alphaHL. These data show that the CDM has several of the features that characterize a molten globule state. Experiments with freshly translated mutants, using coupled in vitro transcription and translation, have further supported our observations that deletion at the carboxyl terminus leads to major structural perturbations in the water-soluble form of alphaHL. The studies demonstrate a critical role of the carboxyl terminus of alphaHL in attaining the native folded state. PMID- 10092592 TI - Acrolein causes inhibitor kappaB-independent decreases in nuclear factor kappaB activation in human lung adenocarcinoma (A549) cells. AB - Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in various situations. In the present study, the effects of sublethal doses of acrolein on nuclear factor kappaB (NF-kappaB) activation in A549 human lung adenocarcinoma cells were investigated. Immediately following a 30-min exposure to 45 fmol of acrolein/cell, glutathione (GSH) and DNA synthesis and NF-kappaB binding were reduced by more than 80%. All parameters returned to normal or supranormal levels by 8 h post-treatment. Pretreatment with acrolein completely blocked 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced activation of NF-kappaB. Cells treated for 1 h with 1 mM diethyl maleate (DEM) showed a 34 and 53% decrease in GSH and DNA synthesis, respectively. DEM also reduced NF kappaB activation by 64% at 2 h post-treatment, with recovery to within 22% of control at 8 h. Both acrolein and DEM decreased NF-kappaB function approximately 50% at 2 h after treatment with TPA, as shown by a secreted alkaline phosphatase reporter assay. GSH returned to control levels by 8 h after DEM treatment, but proliferation remained significantly depressed for 24 h. Interestingly, DEM caused a profound decrease in NF-kappaB binding, even at doses as low as 0.125 mM that had little effect on GSH. Neither acrolein nor DEM had any effect on the levels of phosphorylated or nonphosphorylated inhibitor kappaB-alpha (IkappaB alpha). Furthermore, acrolein decreased NF-kappaB activation in cells depleted of IkappaB-alpha by TPA stimulation in the presence of cycloheximide, demonstrating that the decrease in NF-kappaB activation was not the result of increased binding by the inhibitory protein. This conclusion was further supported by the finding that acrolein modified NF-kappaB in the cytosol prior to chemical dissociation from IkappaB with detergent. Together, these data support the conclusion that the inhibition of NF-kappaB activation by acrolein and DEM is IkappaB-independent. The mechanism appears to be related to direct modification of thiol groups in the NF-kappaB subunits. PMID- 10092593 TI - The absence of a direct correlation between the loss of [D-Ala2, MePhe4,Gly5 ol]Enkephalin inhibition of adenylyl cyclase activity and agonist-induced mu opioid receptor phosphorylation. AB - Chronic activation of the mu-opioid receptor (MOR1TAG) results in the loss of agonist response that has been attributed to desensitization and down-regulation of the receptor. It has been suggested that opioid receptor phosphorylation is the mechanism by which this desensitization and down-regulation occurs. When MOR1TAG was stably expressed in both neuroblastoma neuro2A and human embryonic kidney HEK293 cells, the opioid agonist [D-Ala2,MePhe4, Gly5-ol]enkephalin (DAMGO) induced a time- and concentration-dependent phosphorylation of the receptor, in both cell lines, that could be reversed by the antagonist naloxone. Protein kinase C can phosphorylate the receptor, but is not involved in DAMGO induced MOR1TAG phosphorylation. The rapid rate of receptor phosphorylation, occurring within minutes, did not correlate with the rate of the loss of agonist mediated inhibition of adenylyl cyclase, which occurs in hours. This lack of correlation between receptor phosphorylation and the loss of response was further demonstrated when receptor phosphorylation was increased by either calyculin A or overexpression of the G-protein receptor kinases. Calyculin A increased the magnitude of MOR1TAG phosphorylation without altering the DAMGO-induced loss of the adenylyl cyclase response. Similarly, when mu- and delta-opioid (DOR1TAG) receptors were expressed in the same system, overexpression of beta-adrenergic receptor kinase 2 elevated agonist-induced phosphorylation for both receptors. However, in the same cell lines under the same conditions, overexpression of beta adrenergic receptor kinase 2 and beta-arrestin 2 accelerated the rate of DPDPE- but not DAMGO-induced receptor desensitization. Thus, these data show that phosphorylation of MOR1TAG is not an obligatory event for the DAMGO-induced loss in the adenylyl cyclase regulation by the receptor. PMID- 10092594 TI - Identification of peroxisomal acyl-CoA thioesterases in yeast and humans. AB - A computer-based screen of the Saccharomyces cerevisiae genome identified YJR019C as a candidate oleate-induced gene. YJR019C mRNA levels were increased significantly during growth on fatty acids, suggesting that it may play a role in fatty acid metabolism. The YJR019C product is highly similar to tesB, a bacterial acyl-CoA thioesterase, and carries a tripeptide sequence, alanine-lysine phenylalanineCOOH, that closely resembles the consensus sequence for type-1 peroxisomal targeting signals. YJR019C directed green fluorescence protein to peroxisomes, and biochemical studies revealed that YJR019C is an abundant component of purified yeast peroxisomes. Disruption of the YJR019C gene caused a significant decrease in total cellular thioesterase activity, and recombinant YJR019C was found to exhibit intrinsic acyl-CoA thioesterase activity of 6 units/mg. YJR019C also shared significant sequence similarity with hTE, a human thioesterase that was previously identified because of its interaction with human immunodeficiency virus-Nef in the yeast two-hybrid assay. We report here that hTE is also a peroxisomal protein, demonstrating that thioesterase activity is a conserved feature of peroxisomes. We propose that YJR019C and hTE be renamed as yeast and human PTE1 to reflect the fact that they encode peroxisomal thioesterases. The physical segregation of yeast and human PTE1 from the cytosolic fatty acid synthase suggests that these enzymes are unlikely to play a role in formation of fatty acids. Instead, the observation that PTE1 contributes to growth on fatty acids implicates this thioesterase in fatty acid oxidation. PMID- 10092595 TI - The pleckstrin homology domain of protein kinase D interacts preferentially with the eta isoform of protein kinase C. AB - The results presented here demonstrate that protein kinase D (PKD) and PKCeta transiently coexpressed in COS-7 cells form complexes that can be immunoprecipitated from cell lysates using specific antisera to PKD or PKCeta. The presence of PKCeta in PKD immune complexes was initially detected by in vitro kinase assays which reveal the presence of an 80-kDa phosphorylated band in addition to the 110-kDa band corresponding to autophosphorylated PKD. The association between PKD and PKCeta was further verified by Western blot analysis and peptide phosphorylation assays that exploited the distinct substrate specificity between PKCs and PKD. By the same criteria, PKD formed complexes only very weakly with PKCepsilon, and did not bind PKCzeta. When PKCeta was coexpressed with PKD mutants containing either complete or partial deletions of the PH domain, both PKCeta immunoreactivity and PKC activity in PKD immunoprecipitates were sharply reduced. In contrast, deletion of an amino terminal portion of the molecule, either cysteine-rich region, or the entire cysteine-rich domain did not interfere with the association of PKD with PKCeta. Furthermore, a glutathione S-transferase-PKDPH fusion protein bound preferentially to PKCeta. These results indicate that the PKD PH domain can discriminate between closely related structures of a single enzyme family, e.g. novel PKCs epsilon and eta, thereby revealing a previously undetected degree of specificity among protein-protein interactions mediated by PH domains. PMID- 10092596 TI - A mechanistic study of self-inactivation of the peroxidase activity in prostaglandin H synthase-1. AB - Prostaglandin H synthase (PGHS) is a self-activating and self-inactivating enzyme. Both the peroxidase and cyclooxygenase activities have a limited number of catalytic turnovers. Sequential stopped-flow measurements were used to analyze the kinetics of PGHS-1 peroxidase self-inactivation during reaction with several different hydroperoxides. The inactivation followed single exponential kinetics, with a first-order rate constant of 0.2-0.5 s-1 at 24 degrees C. This rate was independent of the peroxide species and concentration used, strongly suggesting that the self-inactivation process originates after formation of Compound I and probably with Intermediate II, which contains an oxyferryl heme and a tyrosyl radical. Kinetic scan and rapid scan experiments were used to monitor the heme changes during the inactivation process. The results from both experiments converged to a simple, linear, two-step mechanism in which Intermediate II is first converted in a faster step (0.5-2 s-1) to a new compound, Intermediate III, which undergoes a subsequent slower (0.01-0.05 s-1) transition to a terminal species. Rapid-quench and high pressure liquid chromatography analysis indicated that Intermediate III likely retains an intact heme group that is not covalently linked with the PGHS-1 protein. PMID- 10092597 TI - Distinct roles for Galphai2, Galphai3, and Gbeta gamma in modulation offorskolin- or Gs-mediated cAMP accumulation and calcium mobilization by dopamine D2S receptors. AB - Previous studies have shown that a single G protein-coupled receptor can regulate different effector systems by signaling through multiple subtypes of heterotrimeric G proteins. In LD2S fibroblast cells, the dopamine D2S receptor couples to pertussis toxin (PTX)-sensitive Gi/Go proteins to inhibit forskolin- or prostaglandin E1-stimulated cAMP production and to stimulate calcium mobilization. To analyze the role of distinct Galphai/o protein subtypes, LD2S cells were stably transfected with a series of PTX-insensitive Galphai/o protein Cys --> Ser point mutants and assayed for D2S receptor signaling after PTX treatment. The level of expression of the transfected Galpha mutant subunits was similar to the endogenous level of the most abundant Galphai/o proteins (Galphao, Galphai3). D2S receptor-mediated inhibition of forskolin-stimulated cAMP production was retained only in clones expressing mutant Galphai2. In contrast, the D2S receptor utilized Galphai3 to inhibit PGE1-induced (Gs-coupled) enhancement of cAMP production. Following stable or transient transfection, no single or pair set of mutant Galphai/o subtypes rescued the D2S-mediated calcium response following PTX pretreatment. On the other hand, in LD2S cells stably transfected with GRK-CT, a receptor kinase fragment that specifically antagonizes Gbeta gamma subunit activity, D2S receptor-mediated calcium mobilization was blocked. The observed specificity of Galphai2 and Galphai3 for different states of adenylyl cyclase activation suggests a higher level of specificity for interaction of Galphai subunits with forskolin- versus Gs-activated states of adenylyl cyclase than has been previously appreciated. PMID- 10092598 TI - Prolyl tripeptidyl peptidase from Porphyromonas gingivalis. A novel enzyme with possible pathological implications for the development of periodontitis. AB - Porphyromonas gingivalis possesses a complex proteolytic system, which is essential for both its growth and evasion of host defense mechanisms. In this report we characterized, both at a protein and genomic level, a novel peptidase of this system with prolyl tripeptidyl peptidase activity. The enzyme was purified to homogeneity, and its enzymatic activity and biochemical properties were investigated. The amino acid sequence at the amino terminus and of internal peptide fragments enabled identification of the gene encoding this enzyme, which we refer to as PtpA for prolyl tripeptidyl peptidase A. The gene encodes an 82 kDa protein, which contains a GWSYGG motif, characteristic for members of the S9 prolyl oligopeptidase family of serine proteases. However, it does not share any structural similarity to other tripeptidyl peptidases, which belong to the subtilisin family. The production of prolyl tripeptidyl peptidase may contribute to the pathogenesis of periodontal tissue destruction through the mutual interaction of this enzyme, host and bacterial collagenases, and dipeptidyl peptidases in the degradation of collagen during the course of infection. PMID- 10092599 TI - Intermediate length Rieske iron-sulfur protein is present and functionally active in the cytochrome bc1 complex of Saccharomyces cerevisiae. AB - To investigate the relationship between post-translational processing of the Rieske iron-sulfur protein of Saccharomyces cerevisiae and its assembly into the mitochondrial cytochrome bc1 complex we used iron-sulfur proteins in which the presequences had been changed by site-directed mutagenesis of the cloned iron sulfur protein gene, so that the recognition sites for the matrix processing peptidase or the mitochondrial intermediate peptidase (MIP) had been destroyed. When yeast strain JPJ1, in which the gene for the iron-sulfur protein is deleted, was transformed with these constructs on a single copy expression vector, mitochondrial membranes and bc1 complexes isolated from these strains accumulated intermediate length iron-sulfur proteins in vivo. The cytochrome bc1 complex activities of these membranes and bc1 complexes indicate that intermediate iron sulfur protein (i-ISP) has full activity when compared with that of mature sized iron-sulfur protein (m-ISP). Therefore the iron-sulfur cluster must have been inserted before processing of i-ISP to m-ISP by MIP. When iron-sulfur protein is imported into mitochondria in vitro, i-ISP interacts with components of the bc1 complex before it is processed to m-ISP. These results establish that the iron sulfur cluster is inserted into the apoprotein before MIP cleaves off the second part of the presequence and that this second processing step takes place after i ISP has been assembled into the bc1 complex. PMID- 10092600 TI - Protein kinase C mu is negatively regulated by 14-3-3 signal transduction proteins. AB - Recent studies have documented direct interaction between 14-3-3 proteins and key molecules in signal transduction pathways like Ras, Cbl, and protein kinases. In T cells, the 14-3-3tau isoform has been shown to associate with protein kinase C theta and to negatively regulate interleukin-2 secretion. Here we present data that 14-3-3tau interacts with protein kinase C mu (PKCmu), a subtype that differs from other PKC members in structure and activation mechanisms. Specific interaction of PKCmu and 14-3-3tau can be shown in the T cell line Jurkat by immunocoprecipitiation and by pulldown assays of either endogenous or overexpressed proteins using PKCmu-specific antibodies and GST-14-3-3 fusion proteins, respectively. Using PKCmu deletion mutants, the 14-3-3tau binding region is mapped within the regulatory C1 domain. Binding of 14-3-3tau to PKCmu is significantly enhanced upon phorbol ester stimulation of PKCmu kinase activity in Jurkat cells and occurs via a Cbl-like serine containing consensus motif. However, 14-3-3tau is not a substrate of PKCmu. In contrast 14-3-3tau strongly down-regulates PKCmu kinase activity in vitro. Moreover, overexpression of 14-3 3tau significantly reduced phorbol ester induced activation of PKCmu kinase activity in intact cells. We therefore conclude that 14-3-3tau is a negative regulator of PKCmu in T cells. PMID- 10092601 TI - A heptad motif of leucine residues found in membrane proteins can drive self assembly of artificial transmembrane segments. AB - Specific interactions between alpha-helical transmembrane segments are important for folding and/or oligomerization of membrane proteins. Previously, we have shown that most transmembrane helix-helix interfaces of a set of crystallized membrane proteins are structurally equivalent to soluble leucine zipper interaction domains. To establish a simplified model of these membrane-spanning leucine zippers, we studied the homophilic interactions of artificial transmembrane segments using different experimental approaches. Importantly, an oligoleucine, but not an oligoalanine, se- quence efficiently self-assembled in membranes as well as in detergent solution. Self-assembly was maintained when a leucine zipper type of heptad motif consisting of leucine residues was grafted onto an alanine host sequence. Analysis of point mutants or of a random sequence confirmed that the heptad motif of leucines mediates self-recognition of our artificial transmembrane segments. Further, a data base search identified degenerate versions of this leucine motif within transmembrane segments of a variety of functionally different proteins. For several of these natural transmembrane segments, self-interaction was experimentally verified. These results support various lines of previously reported evidence where these transmembrane segments were implicated in the oligomeric assembly of the corresponding proteins. PMID- 10092602 TI - Expression cloning of mouse cDNA of CMP-NeuAc:Lactosylceramide alpha2,3 sialyltransferase, an enzyme that initiates the synthesis of gangliosides. AB - Expression cloning of a cDNA for the alpha2,3-sialyltransferase (GM3 synthase) (EC 2.4.99.-) gene was performed using a GM3-lacking mouse fibroblast line L cell and anti-GM3 monoclonal antibody. Plasmids from a cDNA library generated with poly(A)+ RNA of a mouse fibrosarcoma line CMS5j and pdl3027 (polyoma T antigen) were co-transfected into L cells. The isolated cDNA clone pM3T-7 predicted a type II membrane protein with 13 amino acids of cytoplasmic domain, 17 amino acids of transmembrane region, and a large catalytic domain with 329 amino acids. Introduction of the cDNA clone into L cells resulted in the neo-synthesis of GM3 and high activity of alpha2,3-sialyltransferase. Among glycosphingolipids, only lactosylceramide showed significant activity as an acceptor, indicating that this gene product is a sialyltransferase specific for the synthesis of GM3. An amino acid sequence deduced from the cloned cDNA showed the typical sialyl motif with common features among alpha2,3-sialyltransferases. Among various mouse tissues, brain, liver, and testis showed relatively high expression of a 2.3-kilobase mRNA, whereas all tissues, more or less, expressed this gene. PMID- 10092603 TI - Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin. AB - Helicobacter pylori secretes a cytotoxin (VacA) that induces the formation of large vacuoles originating from late endocytic vesicles in sensitive mammalian cells. Although evidence is accumulating that VacA is an A-B toxin, distinct A and B fragments have not been identified. To localize the putative catalytic A fragment, we transfected HeLa cells with plasmids encoding truncated forms of VacA fused to green fluorescence protein. By analyzing truncated VacA fragments for intracellular vacuolating activity, we reduced the minimal functional domain to the amino-terminal 422 residues of VacA, which is less than one-half of the full-length protein (953 amino acids). VacA is frequently isolated as a proteolytically nicked protein of two fragments that remain noncovalently associated and retain vacuolating activity. Neither the amino-terminal 311 residue fragment (p33) nor the carboxyl-terminal 642 residue fragment (p70) of proteolytically nicked VacA are able to induce cellular vacuolation by themselves. However, co-transfection of HeLa cells with separate plasmids expressing both p33 and p70 resulted in vacuolated cells. Further analysis revealed that a minimal fragment comprising just residues 312-478 functionally complemented p33. Collectively, our results suggest a novel molecular architecture for VacA, with cytosolic localization of both fragments of nicked toxin required to mediate intracellular vacuolating activity. PMID- 10092604 TI - Ubiquinol:cytochrome c oxidoreductase. Effects of inhibitors on reverse electron transfer from the iron-sulfur protein to cytochrome b. AB - The effects of inhibitors on the reduction of the bis-heme cytochrome b of ubiquinol: cytochrome c oxidoreductase (complex III, bc1 complex) has been studied in bovine heart submitochondrial particles (SMP) when cytochrome b was reduced by NADH and succinate via the ubiquinone (Q) pool or by ascorbate plus N,N,N', N'-tetramethyl-p-phenylenediamine via cytochrome c1 and the iron-sulfur protein of complex III (ISP). The inhibitors used were antimycin (an N-side inhibitor), beta-methoxyacrylate derivatives, stigmatellin (P-side inhibitors), and ethoxyformic anhydride, which modifies essential histidyl residues in ISP. In agreement with our previous findings, the following results were obtained: (i) When ISP/cytochrome c1 were prereduced or SMP were treated with a P-side inhibitor, the high potential heme bH was fully and rapidly reduced by NADH or succinate, whereas the low potential heme bL was only partially reduced. (ii) Reverse electron transfer from ISP/c1 to cytochrome b was inhibited more by antimycin than by the P-side inhibitors. This reverse electron transfer was unaffected when, instead of normal SMP, Q-extracted SMP containing 200-fold less Q (0. 06 mol Q/mol cytochrome b or c1) were used. (iii) The cytochrome b reduced by reverse electron transfer through the leak of a P-side inhibitor was rapidly oxidized upon subsequent addition of antimycin. This antimycin-induced reoxidation did not happen when Q-extracted SMP were used. The implications of these results on the path of electrons in complex III, on oxidant-induced extra cytochrome b reduction, and on the inhibition of forward electron transfer to cytochrome b by a P-side plus an N-side inhibitor have been discussed. PMID- 10092605 TI - Biochemical characterization of CD1d expression in the absence of beta2 microglobulin. AB - CD1d is a major histocompatibility complex class I-like molecule that exhibits a distinct antigen processing pathway that functions in the presentation of hydrophobic antigens to T cells. CD1d has been previously shown to be expressed on the cell surface of human intestinal epithelial cell lines in vivo and a transfected cell line in vitro independently of beta2-microglobulin (beta2m). To define the relationship between CD1d and beta2m and characterize the biochemical structure of CD1d in the absence of beta2m, we have used a newly generated series of CD1d transfectants and CD1d-specific antibodies. These studies show that in the absence of beta2m, CD1d is expressed on the cell surface as a 45-kDa glycoprotein that is sensitive to endoglycosidase-H and is reduced to 37-kDa after N-glycanase digestion. In contrast, in the presence of beta2m, CD1d is expressed on the cell surface as a 48-kDa endoglycosidase-H-resistant glycoprotein. Pulse-chase metabolic labeling studies demonstrate that acquisition of endoglycosidase-H resistance of CD1d is observed in the presence of beta2m but not in the absence of beta2m even after a 24-h chase period. Thus, CD1d is able to be transported to the cell surface independently of beta2m; however, in the absence of beta2m, the glycosylation pattern of CD1d is altered and consistent with an immature glycoprotein. PMID- 10092606 TI - Regulation of I-branched poly-N-acetyllactosamine synthesis. Concerted actions by I-extension enzyme, I-branching enzyme, and beta1,4-galactosyltransferase I. AB - I-branched poly-N-acetyllactosamine is a unique carbohydrate composed of N acetyllactosamine branches attached to linear poly-N-acetyllactosamine, which is synthesized by I-branching beta1, 6-N-acetylglucosaminyltransferase. I-branched poly-N-acetyllactosamine can carry bivalent functional oligosaccharides such as sialyl Lewisx, which provide much better carbohydrate ligands than monovalent functional oligosaccharides. In the present study, we first demonstrate that I branching beta1, 6-N-acetylglucosaminyltransferase cloned from human PA-1 embryonic carcinoma cells transfers beta1,6-linked GlcNAc preferentially to galactosyl residues of N-acetyllactosamine close to nonreducing terminals. We then demonstrate that among various beta1, 4-galactosyltransferases (beta4Gal Ts), beta4Gal-TI is most efficient in adding a galactose to linear and branched poly-N-acetyllactosamines. When a beta1,6-GlcNAc branched poly-N acetyllactosamine was incubated with a mixture of beta4Gal-TI and i-extension beta1,3-N-acetylglucosaminyltransferase, the major product was the oligosaccharide with one N-acetyllactosamine extension on the linear Galbeta1- >4GlcNAcbeta1-->3 side chain. Only a minor product contained galactosylated I branch without N-acetyllactosamine extension. This finding was explained by the fact that beta4Gal-TI adds a galactose poorly to beta1,6-GlcNAc attached to linear poly-N-acetyllactosamines, while beta1, 3-N-acetylglucosaminyltransferase and beta4Gal-TI efficiently add N-acetyllactosamine to linear poly-N acetyllactosamines. Together, these results strongly suggest that galactosylation of I-branch is a rate-limiting step in I-branched poly-N-acetyllactosamine synthesis, allowing poly-N-acetyllactosamine extension mostly along the linear poly-N-acetyllactosamine side chain. These findings are entirely consistent with previous findings that poly-N-acetyllactosamines in human erythrocytes, PA-1 embryonic carcinoma cells, and rabbit erythrocytes contain multiple, short I branches. PMID- 10092607 TI - Calcium-dependent regulation of cytochrome c gene expression in skeletal muscle cells. Identification of a protein kinase c-dependent pathway. AB - Mitochondrial biogenesis can occur rapidly in mammalian skeletal muscle subjected to a variety of physiological conditions. However, the intracellular signal(s) involved in regulating this process remain unknown. Using nuclearly encoded cytochrome c, we show that its expression in muscle cells is increased by changes in cytosolic Ca2+ using the ionophore A23187. Treatment of myotubes with A23187 increased cytochrome c mRNA expression up to 1.7-fold. Transfection experiments using promoter-chloramphenicol acetyltransferase constructs revealed that this increase could be transcriptionally mediated since A23187 increased chloramphenicol acetyltransferase activity by 2.5-fold. This increase was not changed by KN62, an inhibitor of Ca2+/calmodulin-dependent kinases II and IV, and it was not modified by overexpression of protein kinase A and cAMP response element-binding protein, demonstrating that the A23187 effect was not mediated through Ca2+/calmodulin-dependent kinase- or protein kinase A-dependent pathways. However, treatment of myotubes with staurosporine or 12-O-tetradecanoylphorbol-13 acetate reduced the effect of A23187 on cytochrome c transactivation by 40-50%. Coexpression of the Ca2+-sensitive protein kinase C isoforms alpha and betaII, but not the Ca2+-insensitive delta isoform, exaggerated the A23187-mediated response. The short-term effect of A23187 was mediated in part by mitogen activated protein kinase (extracellular signal-regulated kinases 1 and 2) since its activation peaked 2 h after A23187 treatment, and cytochrome c transactivation was reduced by PD98089, a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor. These results demonstrate the existence of a Ca2+-sensitive, protein kinase C-dependent pathway involved in cytochrome c expression and implicate Ca2+ as a signal in the up regulation of nuclear genes encoding mitochondrial proteins. PMID- 10092608 TI - Cloning, expression, and properties of a nonneuronal secreted acetylcholinesterase from the parasitic nematode Nippostrongylus brasiliensis. AB - We have isolated a full-length cDNA encoding an acetylcholinesterase secreted by the nematode parasite Nippostrongylus brasiliensis. The predicted protein is truncated in comparison with acetylcholinesterases from other organisms such that the carboxyl terminus aligns closely to the end of the catalytic domain of the vertebrate enzymes. The residues in the catalytic triad are conserved, as are the six cysteines which form the three intramolecular disulfide bonds. Three of the fourteen aromatic residues which line the active site gorge in the Torpedo enzyme are substituted by nonaromatic residues, corresponding to Tyr-70 (Thr), Trp-279 (Asn), and Phe-288 (Met). High level expression was obtained via secretion from Pichia pastoris. The purified enzyme behaved as a monomeric hydrophilic species. Although of invertebrate origin and possessing the above substitutions in the active site gorge residues, the enzyme efficiently hydrolyzed acetylthiocholine and showed minimal activity against butyrylthiocholine. It displayed excess substrate inhibition with acetylthiocholine at concentrations over 2. 5 mM and was highly sensitive to both active site and "peripheral" site inhibitors. Northern blot analysis indicated a progressive increase in mRNA for AChE B in parasites isolated from 6 days postinfection. PMID- 10092609 TI - Insect immunity. Isolation from the lepidopteran Heliothis virescens of a novel insect defensin with potent antifungal activity. AB - Lepidoptera have been reported to produce several antibacterial peptides in response to septic injury. However, in marked contrast to other insect groups, no inducible antifungal molecules had been described so far in this insect order. Surprisingly, also cysteine-rich antimicrobial peptides, which predominate in the antimicrobial defense of other insects, had not been discovered in Lepidoptera. Here we report the isolation from the hemolymph of immune induced larvae of the lepidopteran Heliothis virescens of a cysteine-rich molecule with exclusive antifungal activity. We have fully characterized this antifungal molecule, which has significant homology with the insect defensins, a large family of antibacterial peptides directed against Gram-positive strains. Interestingly, the novel peptide shows also similarities with the antifungal peptide drosomycin from Drosophila. Thus, Lepidoptera appear to have built their humoral immune response against bacteria on cecropins and attacins. In addition, we report that Lepidoptera have conferred antifungal properties to the well conserved structure of antibacterial insect defensins through amino acid replacements. PMID- 10092610 TI - Testis expression of hormone-sensitive lipase is conferred by a specific promoter that contains four regions binding testicular nuclear proteins. AB - The testicular isoform of hormone-sensitive lipase (HSLtes) is encoded by a testis-specific exon and 9 exons common to the testis and adipocyte isoforms. In mouse, HSLtes mRNA appeared during spermiogenesis in round spermatids. Two constructs containing 1.4 and 0.5 kilobase pairs (kb) of the human HSLtes gene 5' flanking region cloned upstream of the chloramphenicol acetyltransferase gene were microinjected into mouse oocytes. Analyses of enzyme activity in male and female transgenic mice showed that 0.5 kb of the HSLtes promoter was sufficient to direct expression only in testis. Cell transfection experiments showed that CREMtau, a testis-specific transcriptional activator, does not transactivate the HSLtes promoter. Using gel retardation assays, four testis-specific binding regions (TSBR) were identified using testis and liver nuclear extracts. The testis-specific protein binding on TSBR4 was selectively competed by a probe containing a SRY/Sox protein DNA recognition site. Sox5 and Sox6 which are expressed in post-meiotic germ cells bound TSBR4. Mutation of the AACAAAG motif in TSBR4 abolished the binding. Moreover, binding of the high mobility group domain of Sox5 induced a bend within TSBR4. Together, our results showed that 0.5 kb of the human HSLtes promoter bind Sox proteins and contain cis-acting elements essential for the testis specificity of HSL. PMID- 10092611 TI - Identification of initiation sites for DNA replication in the human dnmt1 (DNA methyltransferase) locus. AB - Vertebrates have developed multiple mechanisms to coordinate the replication of epigenetic and genetic information. Dnmt1 encodes the maintenance enzyme DNA methyltransferase, which is responsible for propagating the DNA methylation pattern and the epigenetic information that it encodes during replication. Direct sequence analysis and bisulfite mapping of the 5' region of DNA-methyltransferase 1 (dnmt1) have indicated the presence of many sequence elements associated with previously characterized origins of DNA replication. This study tests the hypothesis that the dnmt1 region containing these elements is an origin of replication in human cells. First, we demonstrate that a vector containing this dnmt1 sequence is able to support autonomous replication when transfected into HeLa cells. Second, using a gel retardation assay, we show that it contains a site for binding of origin-rich sequences binding activity, a recently purified replication protein. Finally, using competitive polymerase chain reaction, we show that replication initiates in this region in vivo. Based on these lines of evidence, we propose that initiation sites for DNA replication are located between the first intron and exon 7 of the human dnmt1 locus. PMID- 10092613 TI - Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. AB - Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) has been implicated as a negative regulator of insulin signaling. Prior studies have indicated that this negative regulation by protein kinase C involves the mitogen activated protein kinase and phosphorylation of serine 612 in IRS-1. In the present studies, the negative regulation by platelet-derived growth factor (PDGF) was compared with that induced by endothelin-1, an activator of protein kinase C. In contrast to endothelin-1, the inhibitory effects of PDGF did not require mitogen-activated protein kinase or the phosphorylation of serine 612. Instead, three other serines in the phosphorylation domain of IRS-1 (serines 632, 662, and 731) were required for the negative regulation by PDGF. In addition, the PDGF activated serine/threonine kinase called Akt was found to inhibit insulin signaling. Moreover, this inhibition required the same IRS-1 serine residues as the inhibition by PDGF. Finally, the negative regulatory effects of PDGF and Akt were inhibited by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), one of the downstream targets of Akt. These studies implicate the phosphatidylinositol 3-kinase/Akt kinase cascade as an additional negative regulatory pathway for the insulin signaling cascade. PMID- 10092612 TI - Limited role of ceramide in lipopolysaccharide-mediated mitogen-activated protein kinase activation, transcription factor induction, and cytokine release. AB - The involvement of ceramide in lipopolysaccharide-mediated activation of mouse macrophages was studied. Lipopolysaccharide, cell-permeable ceramide analogs, and bacterial sphingomyelinase led to phosphorylation of the extracellular signal regulated kinases, c-Jun NH2-terminal kinases, and p38 kinase and induced AP-1 DNA binding in C3H/OuJ (Lpsn) but not in C3H/HeJ (Lpsd) macrophages. Lipopolysaccharide and ceramide mimetics showed distinct kinetics of mitogen activated protein kinase phosphorylation and AP-1 induction and activated AP-1 complexes with different subunit compositions. Lipopolysaccharide-activated AP-1 consisted of c-Fos, Jun-B, Jun-D, and c-Jun, while C2-ceramide induced Jun-D and c-Jun only. Lipopolysaccharide and, less potently, C2-ceramide or sphingomyelinase, stimulated AP-1-dependent reporter gene transcription in RAW 264.7 cells. Unlike lipopolysaccharide, C2-ceramide failed to activate NF-kappaB and did not induce production of tumor necrosis factor or interleukin-6. The lipopolysaccharide antagonist, Rhodobacter sphae-roides diphosphoryl lipid A, inhibited lipopolysaccharide activation of NF-kappaB and AP-1 but did not block C2-ceramide-induced AP-1. Pretreatment of C3H/OuJ macrophages with C2-ceramide greatly diminished AP-1 induction following subsequent C2-ceramide stimulation. However, lipopolysaccharide-induced transcription factor activation and cytokine release were not influenced. In contrast, lipopolysaccharide pretreatment inhibited both lipopolysaccharide- and C2-ceramide-mediated responses. Thus, ceramide partially mimics lipopolysaccharide in activating the mitogen-activated protein kinases and AP-1 but not in mediating NF-kappaB induction or cytokine production, suggesting a limited role in lipopolysaccharide signaling. PMID- 10092614 TI - The flavin environment in old yellow enzyme. An evaluation of insights from spectroscopic and artificial flavin studies. AB - Spectroscopic and chemical modification studies of modified flavins bound to old yellow enzyme have led to predictions about the flavin environment of this enzyme. These studies analyzed solvent accessibility and hydrogen bonding patterns of particular flavin atoms, in addition to suggesting amino acid residues that are in close proximity to those atoms. Here, these studies are evaluated in the light of the crystal structure of old yellow enzyme to reveal that the spectroscopic and modified flavin results are generally consistent with the crystal structure. This highlights the fact that these are useful methods for studying flavin binding site structure. Although several of the inferred properties of the flavin environment are not consistent with the crystal structure, these discrepancies occurred in cases where an incorrect choice was made from among multiple plausible explanations for an experimental result. We conclude that modified flavin studies are powerful probes of flavin environment; however, it is risky to specify details of interactions, especially because of uncertainties due to induced charge delocalization in the flavin. PMID- 10092615 TI - Putidaredoxin-cytochrome p450cam interaction. Spin state of the heme iron modulates putidaredoxin structure. AB - During the monooxygenase reaction catalyzed by cytochrome P450cam (P450cam), a ternary complex of P450cam, reduced putidaredoxin, and d-camphor is formed as an obligatory reaction intermediate. When ligands such as CO, NO, and O2 bind to the heme iron of P450cam in the intermediate complex, the EPR spectrum of reduced putidaredoxin with a characteristic signal at 346 millitesla at 77 K changed into a spectrum having a new signal at 348 millitesla. The experiment with O2 was carried out by employing a mutant P450cam with Asp251 --> Asn or Gly where the rate of electron transfer from putidaredoxin to oxyferrous P450cam is considerably reduced. Such a ligand-induced EPR spectral change of putidaredoxin was also shown in situ in Pseudomonas putida. Mutations introduced into the neighborhood of the iron-sulfur cluster of putidaredoxin revealed that a Ser44 - > Gly mutation mimicked the ligand-induced spectral change of putidaredoxin. Arg109 and Arg112, which are in the putative putidaredoxin binding site of P450cam, were essential for the spectral changes of putidaredoxin in the complex. These results indicate that a change in the P450cam active site that is the consequence of an altered spin state is transmitted to putidaredoxin within the ternary complex and produces a conformational change of the 2Fe-2S active center. PMID- 10092616 TI - Tumor necrosis factor-alpha, sphingomyelinase, and ceramide inhibit store operated calcium entry in thyroid FRTL-5 cells. AB - Tumor necrosis factor alpha (TNF-alpha) is a potent inhibitor of proliferation in several cell types, including thyroid FRTL-5 cells. As intracellular free calcium ([Ca2+]i) is a major signal in activating proliferation, we investigated the effect of TNF-alpha on calcium fluxes in FRTL-5 cells. TNF-alpha per se did not modulate resting [Ca2+]i. However, preincubation (10 min) of the cells with 1-100 ng/ml TNF-alpha decreased the thapsigargin (Tg)-evoked store-operated calcium entry in a concentration-dependent manner. TNF-alpha did not inhibit the mobilization of sequestered calcium. To investigate whether the effect of TNF alpha on calcium entry was mediated via the sphingomyelinase pathway, the cells were pretreated with sphingomyelinase (SMase) prior to stimulation with Tg. SMase inhibited the Tg-evoked calcium entry in a concentration-dependent manner. Furthermore, an inhibition of calcium entry was obtained after preincubation of the cells with the membrane-permeable C2-ceramide and C6-ceramide analogues. The inactive ceramides dihydro-C2 and dihydro-C6 showed only marginal effects. Neither SMase, C2-ceramide, nor C6-ceramide affected the release of sequestered calcium. C2- and C6-ceramide also decreased the ATP-evoked calcium entry, without affecting the release of sequestered calcium. The effect of TNF-alpha and SMase was inhibited by the kinase inhibitor staurosporin and by the protein kinase C (PKC) inhibitor calphostin C but not by down-regulation of PKC. However, we were unable to measure a significant activation of PKC using TNF-alpha or C6-ceramide. The effect of TNF-alpha was not mediated via activation of either c-Jun N terminal kinase or p38 kinase. We were unable to detect an increase in the ceramide (or sphingosine) content of the cells after stimulation with TNF-alpha for up to 30 min. Thus, one mechanism of action of TNF-alpha, SMase, and ceramide on thyroid FRTL-5 cells is to inhibit calcium entry. PMID- 10092617 TI - HSP27 multimerization mediated by phosphorylation-sensitive intermolecular interactions at the amino terminus. AB - Distinct biochemical activities have been reported for small and large molecular complexes of heat shock protein 27 (HSP27), respectively. Using glycerol gradient ultracentrifugation and chemical cross-linking, we show here that Chinese hamster HSP27 is expressed in cells as homotypic multimers ranging from dimers up to 700 kDa oligomers. Treatments with arsenite, which induces phosphorylation on Ser15 and Ser90, provoked a major change in the size distribution of the complexes that shifted from oligomers to dimers. Ser90 phosphorylation was sufficient and necessary for causing this change in structure. Dimer formation was severely inhibited by replacing Ser90 with Ala90 but not by replacing Ser15 with Ala15. Using the yeast two-hybrid system, two domains were identified that were responsible for HSP27 intermolecular interactions. One domain was insensitive to phosphorylation and corresponded to the C-terminal alpha-crystallin domain. The other domain was sensitive to serine 90 phosphorylation and was located in the N terminal region of the protein. Fusion of this N-terminal domain to firefly luciferase conferred luciferase with the capacity to form multimers that dissociated into monomers upon phosphorylation. A deletion within this domain of residues Arg5-Tyr23, which contains a WDPF motif found in most proteins of the small heat shock protein family, yielded a protein that forms only phosphorylation-insensitive dimers. We propose that HSP27 forms stable dimers through the alpha-crystallin domain. These dimers further multimerize through intermolecular interactions mediated by the phosphorylation-sensitive N-terminal domain. PMID- 10092618 TI - Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene. AB - A T --> G mutation at position 8993 in human mitochondrial DNA is associated with the syndrome neuropathy, ataxia, and retinitis pigmentosa and with a maternally inherited form of Leigh's syndrome. The mutation substitutes an arginine for a leucine at amino acid position 156 in ATPase 6, a component of the F0 portion of the mitochondrial ATP synthase complex. Fibroblasts harboring high levels of the T8993G mutation have decreased ATP synthesis activity, but do not display any growth defect under standard culture conditions. Combining the notions that cells with respiratory chain defects grow poorly in medium containing galactose as the major carbon source, and that resistance to oligomycin, a mitochondrial inhibitor, is associated with mutations in the ATPase 6 gene in the same transmembrane domain where the T8993G amino acid substitution is located, we created selective culture conditions using galactose and oligomycin that elicited a pathological phenotype in T8993G cells and that allowed for the rapid selection of wild-type over T8993G mutant cells. We then generated cytoplasmic hybrid clones containing heteroplasmic levels of the T8993G mutation, and showed that selection in galactose-oligomycin caused a significant increase in the fraction of wild-type molecules (from 16 to 28%) in these cells. PMID- 10092619 TI - Amyloid beta peptides do not form peptide-derived free radicals spontaneously, but can enhance metal-catalyzed oxidation of hydroxylamines to nitroxides. AB - Amyloid beta (Abeta) peptides play an important role in the pathogenesis of Alzheimer's disease. Free radical generation by Abeta peptides was suggested to be a key mechanism of their neurotoxicity. Reports that neurotoxic free radicals derived from Abeta-(1-40) and Abeta-(25-35) peptides react with the spin trap N tert-butyl-alpha-phenylnitrone (PBN) to form a PBN/.Abeta peptide radical adduct with a specific triplet ESR signal assert that the peptide itself was the source of free radicals. We now report that three Abeta peptides, Abeta-(1-40), Abeta (25-35), and Abeta-(40-1), do not yield radical adducts with PBN from the Oklahoma Medical Research Foundation (OMRF). In contrast to OMRF PBN, incubation of Sigma PBN in phosphate buffer without Abeta peptides produced a three-line ESR spectrum. It was shown that this nitroxide is di-tert-butylnitroxide and is formed in the Sigma PBN solution as a result of transition metal-catalyzed auto oxidation of the respective hydroxylamine present as an impurity in the Sigma PBN. Under some conditions, incubation of PBN from Sigma with Abeta-(1-40) or Abeta-(25-35) can stimulate the formation of di-tert-butylnitroxide. It was shown that Abeta peptides enhanced oxidation of cyclic hydroxylamine 1-hydroxy-4-oxo 2,2,6, 6-tetramethylpiperidine (TEMPONE-H), which was strongly inhibited by the treatment of phosphate buffer with Chelex-100. It was shown that ferric and cupric ions are effective oxidants of TEMPONE-H. The data obtained allow us to conclude that under some conditions toxic Abeta peptides Abeta-(1-40) and Abeta (25-35) enhance metal-catalyzed oxidation of hydroxylamine derivatives, but do not spontaneously form peptide-derived free radicals. PMID- 10092620 TI - Cellular responses to excess phospholipid. AB - Phosphatidylcholine (PtdCho) is the major membrane phospholipid in mammalian cells, and its synthesis is controlled by the activity of CDP:phosphocholine cytidylyltransferase (CCT). Enforced CCT expression accelerated the rate of PtdCho synthesis. However, the amount of cellular PtdCho did not increase as a result of the turnover of both the choline and glycerol components of PtdCho. Metabolic labeling experiments demonstrated that cells compensated for elevated CCT activity by the degradation of PtdCho to glycerophosphocholine (GPC). Phospholipase D-mediated PtdCho hydrolysis and phosphocholine formation were unaffected. Most of the GPC produced in response to excess phospholipid production was secreted into the medium. Cells also degraded the excess membrane PtdCho to GPC when phospholipid formation was increased by exposure to exogenous lysophosphatidylcholine or lysophosphatidylethanolamine. The replacement of the acyl moiety at the 1-position of PtdCho with a non-hydrolyzable alkyl moiety prevented degradation to GPC. Accumulation of alkylacyl-PtdCho was associated with the inhibition of cell proliferation, demonstrating that alternative pathways of degradation will not substitute. GPC formation was blocked by bromoenol lactone, implicating the calcium-independent phospholipase A2 as a key participant in the response to excess phospholipid. Owing to the fact that PtdCho is biosynthetically converted to PtdEtn, excess PtdCho resulted in overproduction and exit of GPE as well as GPC. Thus, general membrane phospholipid homeostasis is achieved by a balance between the opposing activities of CCT and phospholipase A2. PMID- 10092621 TI - A region in IVS5 of the human cardiac L-type calcium channel is required for the use-dependent block by phenylalkylamines and benzothiazepines. AB - Mutations in motif IVS5 and IVS6 of the human cardiac calcium channel were made using homologous residues from the rat brain sodium channel 2a. [3H]PN200-110 and allosteric binding assays revealed that the dihydropyridine and benzothiazepine receptor sites maintained normal coupling in the chimeric mutant channels. Whole cell voltage clamp recording from Xenopus oocytes showed a dramatically slowed inactivation and a complete loss of use-dependent block for mutations in the cytoplasmic connecting link to IVS5 (HHT-5371) and in IVS5 transmembrane segment (HHT-5411) with both diltiazem and verapamil. However, the use-dependent block by isradipine was retained by these two mutants. For mutants HHT-5411 and HHT-5371, the residual current appeared associated with a loss of voltage dependence in the rate of inactivation indicating a destabilization of the inactivated state. Furthermore, both HHT-5371 and -5411 recovered from inactivation significantly faster after drug block than that of the wild type channel. Our data demonstrate that accelerated recovery of HHT-5371 and HHT-5411 decreased accumulation of these channels in inactivation during pulse trains and suggest a close link between inactivation gating of the channel and use-dependent block by phenylalkylamines and benzothiazepines and provide evidence of a role for the transmembrane and cytoplasmic regions of IVS5 in the use-dependent block by diltiazem and verapamil. PMID- 10092622 TI - A single amino acid change (substitution of glutamate 3 with alanine) in the N terminal region of rat liver carnitine palmitoyltransferase I abolishes malonyl CoA inhibition and high affinity binding. AB - We have recently shown by deletion mutation analysis that the conserved first 18 N-terminal amino acid residues of rat liver carnitine palmitoyltransferase I (L CPTI) are essential for malonyl-CoA inhibition and binding (Shi, J., Zhu, H., Arvidson, D. N. , Cregg, J. M., and Woldegiorgis, G. (1998) Biochemistry 37, 11033-11038). To identify specific residue(s) involved in malonyl-CoA binding and inhibition of L-CPTI, we constructed two more deletion mutants, Delta12 and Delta6, and three substitution mutations within the conserved first six amino acid residues. Mutant L-CPTI, lacking either the first six N-terminal amino acid residues or with a change of glutamic acid 3 to alanine, was expressed at steady state levels similar to wild type and had near wild type catalytic activity. However, malonyl-CoA inhibition of these mutant enzymes was reduced 100-fold, and high affinity malonyl-CoA binding was lost. A mutant L-CPTI with a change of histidine 5 to alanine caused only partial loss of malonyl-CoA inhibition, whereas a mutant L-CPTI with a change of glutamine 6 to alanine had wild type properties. These results demonstrate that glutamic acid 3 and histidine 5 are necessary for malonyl-CoA binding and inhibition of L-CPTI by malonyl-CoA but are not required for catalysis. PMID- 10092623 TI - Nitric oxide-induced S-glutathionylation and inactivation of glyceraldehyde-3 phosphate dehydrogenase. AB - S-Nitrosylation of protein thiol groups by nitric oxide (NO) is a widely recognized protein modification. In this study we show that nitrosonium tetrafluoroborate (BF4NO), a NO+ donor, modified the thiol groups of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by S-nitrosylation and caused enzyme inhibition. The resultant protein-S-nitrosothiol was found to be unstable and to decompose spontaneously, thereby restoring enzyme activity. In contrast, the NO-releasing compound S-nitrosoglutathione (GSNO) promoted S glutathionylation of a thiol group of GAPDH both in vitro and under cellular conditions. The GSH-mixed protein disulfide formed led to a permanent enzyme inhibition, but upon dithiothreitol addition a functional active GAPDH was recovered. This S-glutathionylation is specific for GSNO because GSH itself was unable to produce protein-mixed disulfides. During cellular nitrosative stress, the production of intracellular GSNO might channel signaling responses to form protein-mixed disulfide that can regulate intracellular function. PMID- 10092624 TI - Cooperative binding of Smad proteins to two adjacent DNA elements in the plasminogen activator inhibitor-1 promoter mediates transforming growth factor beta-induced smad-dependent transcriptional activation. AB - Transforming growth factor beta (TGFbeta) activates transcription of the plasminogen activator inhibitor type-1 (PAI-1) gene through a major TGFbeta responsive region (-740 and -647) in the PAI-1 promoter. This process requires the Smad family of signaling molecules. Upon phosphorylation by the TGFbeta receptors, Smad2 and Smad3 homoligomerize and heteroligomerize with Smad4, translocate to the nucleus and activate transcription of TGFbeta responsive genes. Smad3 and Smad4 have been shown to bind to various sites in the PAI-1 promoter. To determine the number of Smad-binding sites within the 94-base pair major TGFbeta-responsive region and the mechanism of Smad-mediated transactivation, we systematically mapped the Smad-binding sites and show that Smad4 and Smad3 bind cooperatively to two adjacent DNA elements in this region. Both elements were required for TGFbeta-induced, Smad3- and Smad4-dependent activation of PAI-1 transcription. Contrary to previous reports, transactivation of the PAI-1 promoter was mediated by the amino- but not carboxyl-terminal domains of the Smads. Furthermore, oligomerization of Smad3 markedly enhanced its binding to the two binding sites. Finally, a Smad4 mutation identified in a human pancreatic carcinoma that inactivates Smad4 signaling abolished Smad4 DNA binding activity, hence preventing transactivation of TGFbeta-responsive genes. These results underscore the importance of the Smad4 DNA binding activity in controlling cell growth and carcinogenesis. PMID- 10092625 TI - Physiological consequence of disruption of the VMA1 gene in the riboflavin overproducer Ashbya gossypii. AB - The vacuolar ATPase subunit A structural gene VMA1 of the biotechnologically important riboflavin overproducer Ashbya gossypii was cloned and disrupted to prevent riboflavin retention in the vacuolar compartment and to redirect the riboflavin flux into the medium. Cloning was achieved by polymerase chain reaction using oligonucleotide primers derived form conserved sequences of the Vma1 proteins from yeast and filamentous fungi. The deduced polypeptide comprises 617 amino acids with a calculated molecular mass of 67.8 kDa. The deduced amino acid sequence is highly similar to that of the catalytic subunits of Saccharomyces cerevisiae (67 kDa), Candida tropicalis (67 kDa), and Neurospora crassa (67 kDa) with 89, 87, and 60% identity, respectively, and shows about 25% identity to the beta-subunit of the FoF1-ATPase of S. cerevisiae and Schizosaccharomyces pombe. In contrast to S. cerevisiae, however, where disruption of the VMA1 gene was conditionally lethal, and to N. crassa, where viable disruptants could not be isolated, disruption of the VMA1 gene in A. gossypii did not cause a lethal phenotype. Disruption of the AgVMA1 gene led to complete excretion of riboflavin into the medium instead of retention in the vacuolar compartment, as observed in the wild type. PMID- 10092626 TI - Specific androgen receptor activation by an artificial coactivator. AB - Transcription activation of steroid receptors, such as the androgen receptor (AR), is mediated by coactivators, which bridge the receptor to the preinitiation complex. To develop a tool for studying the role of the AR in normal development and disease, we constructed artificial coactivators consisting of the transcription activation domains of VP16 or p65/RelA and the AR hinge and ligand binding domain (ARLBD), which has been shown to interact with the AR N-terminal domain. The artificial VP16-ARLBD and ARLBD-p65 coactivators interacted with the AR N terminus and wild-type AR in an androgen-dependent and androgen-specific manner. VP16-ARLBD and ARLBD-p65 enhanced the AR transactivity up to 4- and 13 fold, respectively, without affecting the expression of the AR protein. The coactivators did not enhance the transcription activity of the progesterone receptor (PR) or the glucocorticoid receptor (GR), showing their specificity for the AR. In addition, to construct PR- and GR-specific coactivators, the VP16 activation domain was fused to the PR and GR hinge/ligand-binding domain. Although VP16-PRLBD and VP16-GRLBD interacted with the C-terminal portion of steroid receptor coactivator-1, they did not enhance the transcription activity of their receptor. The presented strategy of directing activation domains or other protein activities into the DNA-bound AR complex provides a novel means of manipulating AR function in vitro and in vivo. PMID- 10092627 TI - Cef1p is a component of the Prp19p-associated complex and essential for pre-mRNA splicing. AB - The Prp19p protein of the budding yeast Saccharomyces cerevisiae is an essential splicing factor and is associated with the spliceosome during the splicing reaction. We have previously shown that Prp19p is not tightly associated with small nuclear ribonucleoprotein particles but is associated with a protein complex consisting of at least eight protein components. By sequencing components of the affinity-purified complex, we have identified Cef1p as a component of the Prp19p-associated complex, Ntc85p. Cef1p could directly interact with Prp19p and was required for pre-mRNA splicing both in vivo and in vitro. The c-Myb DNA binding motif at the amino terminus of Cef1p was required for cellular growth but not for interaction of Cef1p with Prp19p or Cef1p self-interaction. We have identified a small region of 30 amino acid residues near the carboxyl terminus required for both cell viability and protein-protein interactions. Cef1p was associated with the spliceosome in the same manner as Prp19p, i.e. concomitant with or immediately after dissociation of U4. The anti-Cef1p antibody inhibited binding to the spliceosome of Cef1p, Prp19p, and at least three other components of the Prp19p-associated complex, suggesting that the Prp19p-associated complex is likely associated with the spliceosome and functions as an integral complex. PMID- 10092628 TI - Discovery of a regulatory motif that controls the exposure of specific upstream cyclin-dependent kinase sites that determine both conformation and growth suppressing activity of pRb. AB - The conformation and activity of pRb, the product of the retinoblastoma susceptibility gene, is dependent on the phosphorylation status of one or more of its 16 potential cyclin-dependent kinase (cdk) sites. However, it is not clear whether the phosphorylation status of one or more of these sites contributes to the determination of the various conformations and activity of pRb. Moreover, whether and how the conformation of pRb may regulate the phosphorylation of the cdk sites is also unclear. In the process of analyzing the function and regulation of pRb, we uncovered the existence of an unusual structural motif, m89 (amino acids 880-900), the mutation of which confers upon pRb a hypophosphorylated conformation. Mutation of this structural domain activates, rather than inactivates, the growth suppressor function of pRb. In order to understand the effect of the mutation of m89 on the phosphorylation of cdk sites, we identified all the cdk sites (Thr-356, Ser-807/Ser-811, and Thr821) the phosphorylation of which drastically modify the conformation of pRb. Mutation of each of these four sites alone or in combinations results in the different conformations of pRb, the migration pattern of which, on SDS-polyacrylamide gel electrophoresis, resembles various in vivo hypophosphorylated forms. Each of these hypophosphorylated forms of pRb has enhanced growth suppressing activity relative to the wild type. Our data revealed that the m89 structural motif controls the exposure of the cdk sites Ser-807/Ser-811 in vitro and in vivo. Moreover, the m89 mutant has enhanced growth suppressing activity, similar to a mutant with alanine substitutions at Ser-807/Ser-811. Our recent finding, that the m89 region is part of a structural domain, p5, conserved antigenically and functionally between pRb and p53, suggests that the evolutionarily conserved p5 domain may play a role in the coordinated regulation of the activity of these two tumor suppressors, under certain growth conditions. PMID- 10092629 TI - RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. AB - RNA transcripts encoding the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor (5-HT2CR) undergo adenosine-to-inosine RNA editing events at up to five specific sites. Compared with rat brain, human brain samples expressed higher levels of RNA transcripts encoding the amino acids valine-serine-valine (5-HT2C-VSV) and valine-glycine-valine (5-HT2C-VGV) at positions 156, 158, and 160, respectively. Agonist stimulation of the nonedited human receptor (5-HT2C-INI) and the edited 5 HT2C-VSV and 5-HT2C-VGV receptor variants stably expressed in NIH-3T3 fibroblasts demonstrated that serotonergic agonists were less potent at the edited receptors. Competition binding experiments revealed a guanine nucleotide-sensitive serotonin high affinity state only for the 5-HT2C-INI receptor; the loss of high affinity agonist binding to the edited receptor demonstrates that RNA editing generates unique 5-HT2CRs that couple less efficiently to G proteins. This reduced G protein coupling for the edited isoforms is primarily due to silencing of the constitutive activity of the nonedited 5-HT2CR. The distinctions in agonist potency and constitutive activity suggest that different edited 5-HT2CRs exhibit distinct responses to serotonergic ligands and further imply that RNA editing represents a novel mechanism for controlling physiological signaling at serotonergic synapses. PMID- 10092630 TI - Induction of the soxRS regulon of Escherichia coli by superoxide. AB - The soxRS regulon orchestrates a multifaceted defense against oxidative stress, by inducing the transcription of approximately 15 genes. The induction of this regulon by redox agents, known to mediate O-2 production, led to the view that O 2 is one signal to which it responds. However, redox cycling agents deplete cellular reductants while producing O-2, and one may question whether the regulon responds to the depletion of some cytoplasmic reductant or to O-2, or both. We demonstrate that raising [O-2] by mutational deletion of superoxide dismutases and/or by addition of paraquat, both under aerobic conditions, causes induction of a member of the soxRS regulon and that a mutational defect in soxRS eliminates that induction. This establishes that O-2, directly or indirectly, can cause induction of this defensive regulon. PMID- 10092631 TI - Probing the unfolding pathway of alpha1-antitrypsin. AB - Protein misfolding plays a role in the pathogenesis of many diseases. alpha1 Antitrypsin misfolding leads to the accumulation of long chain polymers within the hepatocyte, reducing its plasma concentration and predisposing the patient to emphysema and liver disease. In order to understand the misfolding process, it is necessary to examine the folding of alpha1-antitrypsin through the different structures involved in this process. In this study we have used a novel technique in which unique cysteine residues were introduced at various positions into alpha1-antitrypsin and fluorescently labeled with N, N'-dimethyl-N-(iodoacetyl) N'-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)ethylenediamine. The fluorescence properties of each protein were studied in the native state and as a function of guanidine hydrochloride-mediated unfolding. The studies found that alpha1 antitrypsin unfolded through a series of intermediate structures. From the position of the fluorescence probes, the fluorescence quenching data, and the molecular modeling, we show that unfolding of alpha1-antitrypsin occurs via disruption of the A and C beta-sheets followed by the B beta-sheet. The implications of these data on both alpha1-antitrypsin function and polymerization are discussed. PMID- 10092632 TI - Nitric oxide regulation of gene transcription via soluble guanylate cyclase and type I cGMP-dependent protein kinase. AB - Nitric oxide (NO) regulates the expression of multiple genes but in most cases its precise mechanism of action is unclear. We used baby hamster kidney (BHK) cells, which have very low soluble guanylate cyclase and cGMP-dependent protein kinase (G-kinase) activity, and CS-54 arterial smooth muscle cells, which express these two enzymes, to study NO regulation of the human fos promoter. The NO releasing agent Deta-NONOate (ethanamine-2,2'-(hydroxynitrosohydrazone)bis-) had no effect on a chloramphenicol acetyltransferase (CAT) reporter gene under control of the fos promoter in BHK cells transfected with an empty vector or in cells transfected with a G-kinase Ibeta expression vector. In BHK cells transfected with expression vectors for guanylate cyclase, Deta-NONOate markedly increased the intracellular cGMP concentration and caused a small (2-fold) increase in CAT activity; the increased CAT activity appeared to be from cGMP activation of cAMP-dependent protein kinase. In BHK cells co-transfected with guanylate cyclase and G-kinase expression vectors, CAT activity was increased 5 fold in the absence of Deta-NONOate and 7-fold in the presence of Deta-NONOate. Stimulation of CAT activity in the absence of Deta-NONOate appeared to be largely from endogenous NO since we found that: (i) BHK cells produced high amounts of NO; (ii) CAT activity was partially inhibited by a NO synthase inhibitor; and (iii) the inhibition by the NO synthase inhibitor was reversed by exogenous NO. In CS-54 cells, we found that NO increased fos promoter activity and that the increase was prevented by a guanylate cyclase inhibitor. In summary, we found that NO activates the fos promoter by a guanylate cyclase- and G-kinase-dependent mechanism. PMID- 10092633 TI - Transient and steady-state kinetics of the oxidation of substituted benzoic acid hydrazides by myeloperoxidase. AB - Myeloperoxidase is the most abundant protein in neutrophils and catalyzes the production of hypochlorous acid. This potent oxidant plays a central role in microbial killing and inflammatory tissue damage. 4-Aminobenzoic acid hydrazide (ABAH) is a mechanism-based inhibitor of myeloperoxidase that is oxidized to radical intermediates that cause enzyme inactivation. We have investigated the mechanism by which benzoic acid hydrazides (BAH) are oxidized by myeloperoxidase, and we have determined the features that enable them to inactivate the enzyme. BAHs readily reduced compound I of myeloperoxidase. The rate constants for these reactions ranged from 1 to 3 x 10(6) M-1 s-1 (15 degrees C, pH 7.0) and were relatively insensitive to the substituents on the aromatic ring. Rate constants for reduction of compound II varied between 6.5 x 10(5) M-1 s-1 for ABAH and 1.3 x 10(3) M-1 s-1 for 4-nitrobenzoic acid hydrazide (15 degrees C, pH 7.0). Reduction of both compound I and compound II by BAHs adhered to the Hammett rule, and there were significant correlations with Brown-Okamoto substituent constants. This indicates that the rates of these reactions were simply determined by the ease of oxidation of the substrates and that the incipient free radical carried a positive charge. ABAH was oxidized by myeloperoxidase without added hydrogen peroxide because it underwent auto-oxidation. Although BAHs generally reacted rapidly with compound II, they should be poor peroxidase substrates because the free radicals formed during peroxidation converted myeloperoxidase to compound III. We found that the reduction of ferric myeloperoxidase by BAH radicals was strongly influenced by Hansch's hydrophobicity constants. BAHs containing more hydrophilic substituents were more effective at converting the enzyme to compound III. This implies that BAH radicals must hydrogen bond to residues in the distal heme pocket before they can reduce the ferric enzyme. Inactivation of myeloperoxidase by BAHs was related to how readily they were oxidized, but there was no correlation with their rate constants for reduction of compounds I or II. We propose that BAHs destroy the heme prosthetic groups of the enzyme by reducing a ferrous myeloperoxidase-hydrogen peroxide complex. PMID- 10092634 TI - Pseudomonas aeruginosa exoenzyme S, a double ADP-ribosyltransferase, resembles vertebrate mono-ADP-ribosyltransferases. AB - Previous data indicated that Pseudomonas aeruginosa exoenzyme S (ExoS) ADP ribosylated Ras at multiple sites. One site appeared to be Arg41, but the second site could not be localized. In this study, the sites of ADP-ribosylation of c-Ha Ras by ExoS were directly determined. Under saturating conditions, ExoS ADP ribosylated Ras to a stoichiometry of 2 mol of ADP-ribose incorporated per mol of Ras. Nucleotide occupancy did not influence the stoichiometry or velocity of ADP ribosylation of Ras by ExoS. Edman degradation and mass spectrometry of V8 protease generated peptides of ADP-ribosylated Ras identified the sites of ADP ribosylation to be Arg41 and Arg128. ExoS ADP-ribosylated the double mutant, RasR41K,R128K, to a stoichiometry of 1 mol of ADP-ribose incorporated per mol of Ras, which indicated that Ras possessed an alternative site of ADP-ribosylation. The alternative site of ADP-ribosylation on Ras was identified as Arg135, which was on the same alpha-helix as Arg128. Arg41 and Arg128 are located within two different secondary structure motifs, beta-sheet and alpha-helix, respectively, and are spatially separated within the three-dimensional structure of Ras. The fact that ExoS could ADP-ribosylate a target protein at multiple sites, along with earlier observations that ExoS could ADP-ribosylate numerous target proteins, were properties that have been attributed to several vertebrate ADP ribosyltransferases. This prompted a detailed alignment study which showed that the catalytic domain of ExoS possessed considerably more primary amino acid homology with the vertebrate mono-ADP-ribosyltransferases than the bacterial ADP ribosyltransferases. These data are consistent with the hypothesis that ExoS may represent an evolutionary link between bacterial and vertebrate mono-ADP ribosyltransferases. PMID- 10092635 TI - Chinese hamster ovary cells require the coexpression of microsomal triglyceride transfer protein and cholesterol 7alpha-hydroxylase for the assembly and secretion of apolipoprotein B-containing lipoproteins. AB - Due to the absence of microsomal triglyceride transfer protein (MTP), Chinese hamster ovary (CHO) cells lack the ability to translocate apoB into the lumen of the endoplasmic reticulum, causing apoB to be rapidly degraded by an N-acetyl leucyl-leucyl-norleucinal-inhibitable process. The goal of this study was to examine if expression of MTP, whose genetic deletion is responsible for the human recessive disorder abetalipoproteinemia, would recapitulate the lipoprotein assembly pathway in CHO cells. Unexpectedly, expression of MTP mRNA and protein in CHO cells did not allow apoB-containing lipoproteins to be assembled and secreted by CHO cells expressing apoB53. Although expression of MTP in cells allowed apoB to completely enter the endoplasmic reticulum, it was degraded by a proteolytic process that was inhibited by dithiothreitol (1 mM) and chloroquine (100 microM), but resistant to N-acetyl-leucyl-leucyl-norleucinal. In marked contrast, coexpression of the liver-specific gene product cholesterol 7alpha hydroxylase with MTP resulted in levels of MTP lipid transfer activity that were similar to those in mouse liver and allowed intact apoB53 to be secreted as a lipoprotein particle. These data suggest that, although MTP-facilitated lipid transport is not required for apoB translocation, it is required for the secretion of apoB-containing lipoproteins. We propose that, in CHO cells, MTP plays two roles in the assembly and secretion of apoB-containing lipoproteins: 1) it acts as a chaperone that facilitates apoB53 translocation, and 2) its lipid transfer activity allows apoB-containing lipoproteins to be assembled and secreted. Our results suggest that the phenotype of the cell (e.g. expression of cholesterol 7alpha-hydroxylase by the liver) may profoundly influence the metabolic relationships determining how apoB is processed into lipoproteins and/or degraded. PMID- 10092636 TI - Molecular cloning of a major mRNA species in murine 3T3 adipocyte lineage. differentiation-dependent expression, regulation, and identification as semicarbazide-sensitive amine oxidase. AB - In an effort to identify novel mRNAs modulated during the course of adipose conversion, we have used a simplified differential display technique and have isolated a cDNA encoding an amine oxidase tremendously expressed in the adipocyte, the semicarbazide-sensitive amine oxidase (SSAO). The predicted amino acid sequence (765 amino acids) is likely to be the homologue of the human placental amine oxidase and of the partially known sequence of the rat adipocyte membrane amine oxidase. SSAO mRNAs are present in several tissues, but strikingly, the highest levels of gene expression are found in adipose tissue and aorta. Enzyme transcript levels are barely detectable in preadipocytes but are induced several hundred-fold during the adipocyte differentiation of 3T3-L1 or 3T3-F442A cells and of rat precursor primary cultures. These changes in transcript levels parallel a sharp increase in SSAO enzyme activity. The biochemical properties of the SSAO present in 3T3-L1 or 3T3-F442A adipocytes closely resemble the features of the SSAO activity previously described in white and brown adipose tissues. Interestingly, SSAO mRNA levels and enzyme activity drop in response to effectors of the cAMP pathway and to the cytokine tumor necrosis factor-alpha, indicating that two major signaling molecules of adipose tissue development and metabolism can control SSAO function. Moreover, the expression of SSAO transcripts and activity are clearly down-regulated in white adipose tissue from obese Zucker rats. Because of its known stimulatory effect on glucose transport, its biochemical properties and its pattern of expression and regulation, SSAO could play an important role in the regulation of adipocyte homeostasis. PMID- 10092637 TI - Different foci for the regulation of the activity of the KefB and KefC glutathione-gated K+ efflux systems. AB - KefB and KefC are glutathione-gated K+ efflux systems in Escherichia coli, and the proteins exhibit strong similarity at the level of both primary sequence and domain organization. The proteins are maintained closed by glutathione and are activated by binding of adducts formed between glutathione and electrophiles. By construction of equivalent mutations in each protein, this study has analyzed the control over inactive state of the proteins. A UV-induced mutation in KefB, L75S, causes rapid spontaneous K+ efflux but has only a minor effect on K+ efflux via KefC. Similarly amino acid substitutions that cause increased spontaneous activity in KefC have only small effects in KefB. Exchange of an eight amino acid region from KefC (HALESDIE) with the equivalent sequence from KefB (HELETAID) has identified a role for a group of acidic residues in controlling KefC activity. The mutations HELETAID and L74S in KefC act synergistically, and the activity of the resultant protein resembles that of KefB. We conclude that, despite the high degree of sequence similarity, KefB and KefC exhibit different sensitivities to the same site-specific mutations. PMID- 10092638 TI - Phosphorylation and regulation of choline kinase from Saccharomyces cerevisiae by protein kinase A. AB - The CKI1-encoded choline kinase (ATP:choline phosphotransferase, EC 2.7.1.32) from Saccharomyces cerevisiae was phosphorylated in vivo on multiple serine residues. Activation of protein kinase A activity in vivo resulted in a transient increase in the phosphorylation of choline kinase. This phosphorylation was accompanied by a stimulation in choline kinase activity. In vitro, protein kinase A phosphorylated choline kinase on a serine residue with a stoichiometry (0.44 mol of phosphate/mol of choline kinase) consistent with one phosphorylation site/choline kinase subunit. The major phosphopeptide derived from the enzyme phosphorylated in vitro by protein kinase A was common to one of the major phosphopeptides derived from the enzyme phosphorylated in vivo. Protein kinase A activity was dose- and time-dependent and dependent on the concentrations of ATP (Km 2.1 microM) and choline kinase (Km 0.12 microM). Phosphorylation of choline kinase with protein kinase A resulted in a stimulation (1.9-fold) in choline kinase activity whereas alkaline phosphatase treatment of choline kinase resulted in a 60% decrease in choline kinase activity. The mechanism of the protein kinase A-mediated stimulation in choline kinase activity involved an increase in the apparent Vmax values with respect to ATP (2.6-fold) and choline (2.7-fold). Overall, the results reported here were consistent with the conclusion that choline kinase was regulated by protein kinase A phosphorylation. PMID- 10092639 TI - Tumor necrosis factor-alpha mediates both apoptotic cell death and cell proliferation in a human hematopoietic cell line dependent on mitotic activity and receptor subtype expression. AB - The TF-1 human erythroleukemic cell line exhibits opposing physiological responses toward tumor necrosis factor-alpha (TNF) treatment, dependent upon the mitotic state of the cells. Mitotically active cells in log growth respond to TNF by rapidly undergoing apoptosis whereas TNF exposure stimulates cellular proliferation in mitotically quiescent cells. The concentration-dependent TNF induced apoptosis was monitored by cellular metabolic activity and confirmed by both DNA epifluorescence and DNA fragmentation. Moreover, these responses could be detected by measuring extracellular acidification activity, enabling rapid prediction (within approximately 1.5 h of TNF treatment) of the fate of the cell in response to TNF. Growth factor resupplementation of quiescent cells, resulting in reactivation of cell cycling, altered TNF action from a proliferative stimulus to an apoptotic signal. Expression levels of the type II TNF receptor subtype (p75TNFR) were found to correlate with sensitivity to TNF-induced apoptosis. Pretreatment of log growth TF-1 cells with a neutralizing anti-p75TNFR monoclonal antibody inhibited TNF-induced apoptosis by greater than 80%. Studies utilizing TNF receptor subtype-specific TNF mutants and neutralizing antisera implicated p75TNFR in TNF-dependent apoptotic signaling. These data show a bifunctional physiological role for TNF in TF-1 cells that is dependent on mitotic activity and controlled by the p75TNFR. PMID- 10092640 TI - A kinetic mechanism for the polymerization of alpha1-antitrypsin. AB - The mutation in the Z deficiency variant of alpha1-antitrypsin perturbs the structure of the protein to allow a unique intermolecular linkage. These loop sheet polymers are retained within the endoplasmic reticulum of hepatocytes to form inclusions that are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. The process of polymer formation has been investigated here by intrinsic tryptophan fluorescence, fluorescence polarization, circular dichroic spectra and extrinsic fluorescence with 8-anilino 1-naphthalenesulfonic acid and tetramethylrhodamine-5-iodoacetamide. These biophysical techniques have demonstrated that alpha1-antitrypsin polymerization is a two-stage process and have allowed the calculation of rates for both of these steps. The initial fast phase is unimolecular and likely to represent temperature-induced protein unfolding, while the slow phase is bimolecular and associated with loop-sheet interaction and polymer formation. The naturally occurring Z, S, and I variants and recombinant site-directed reactive loop and shutter domain mutants of alpha1-antitrypsin were used to demonstrate the close association between protein stability and rate of alpha1-antitrypsin polymerization. Taken together, these data allow us to propose a kinetic mechanism for alpha1-antitrypsin polymer formation that involves the generation of an unstable intermediate, which can form polymers or generate latent protein. PMID- 10092641 TI - Differential mechanisms of retinoid transfer from cellular retinol binding proteins types I and II to phospholipid membranes. AB - Cellular retinol-binding proteins types I and II (CRBP-I and CRBP-II) are known to differentially facilitate retinoid metabolism by several membrane-associated enzymes. The mechanism of ligand transfer to phospholipid small unilamellar vesicles was compared in order to determine whether differences in ligand trafficking properties could underlie these functional differences. Unidirectional transfer of retinol from the CRBPs to membranes was monitored by following the increase in intrinsic protein fluorescence that occurs upon ligand dissociation. The results showed that ligand transfer of retinol from CRBP-I was >5-fold faster than transfer from CRBP-II. For both proteins, transfer of the other naturally occurring retinoid, retinaldehyde, was 4-5-fold faster than transfer of retinol. Rates of ligand transfer from CRBP-I to small unilamellar vesicles increased with increasing concentration of acceptor membrane and with the incorporation of the anionic lipids cardiolipin or phosphatidylserine into membranes. In contrast, transfer from CRBP-II was unaffected by either membrane concentration or composition. Preincubation of anionic vesicles with CRBP-I was able to prevent cytochrome c, a peripheral membrane protein, from binding, whereas CRBP-II was ineffective. In addition, monolayer exclusion experiments demonstrated differences in the rate and magnitude of the CRBP interactions with phospholipid membranes. These results suggest that the mechanisms of ligand transfer from CRBP-I and CRBP-II to membranes are markedly different as follows: transfer from CRBP-I may involve and require effective collisional interactions with membranes, whereas a diffusional process primarily mediates transfer from CRBP-II. These differences may help account for their distinct functional roles in the modulation of intracellular retinoid metabolism. PMID- 10092642 TI - Motile properties of the kinesin-related Cin8p spindle motor extracted from Saccharomyces cerevisiae cells. AB - We have developed microtubule binding and motility assays for Cin8p, a kinesin related mitotic spindle motor protein from Saccharomyces cerevisiae. The methods examine Cin8p rapidly purified from crude yeast cell extracts. We created a recombinant form of CIN8 that fused the biotin carrying polypeptide from yeast pyruvate carboxylase to the carboxyl terminus of Cin8p. This form was biotinated in yeast cells and provided Cin8p activity in vivo. Avidin-coated glass surfaces were used to specifically bind biotinated Cin8p from crude extracts. Microtubules bound to the Cin8p-coated surfaces and moved at 3.4 +/- 0.5 micrometer/min in the presence of ATP. Force production by Cin8p was directed toward the plus ends of microtubules. A mutation affecting the microtubule-binding site within the motor domain (cin8-F467A) decreased Cin8p's ability to bind microtubules to the glass surface by >10-fold, but reduced gliding velocity by only 35%. The cin8-3 mutant form, affecting the alpha2 helix of the motor domain, caused a moderate defect in microtubule binding, but motility was severely affected. cin8-F467A cells, but not cin8-3 cells, were greatly impaired in bipolar spindle forming ability. We conclude that microtubule binding by Cin8p is more important than motility for proper spindle formation. PMID- 10092643 TI - Mechanism of superoxide generation by neuronal nitric-oxide synthase. AB - Neuronal nitric-oxide synthase (NOS I) in the absence of L-arginine has previously been shown to generate superoxide (O-2) (Pou, S., Pou, W. S., Bredt, D. S., Snyder, S. H., and Rosen, G. M. (1992) J. Biol. Chem. 267, 24173-24176). In the presence of L-arginine, NOS I produces nitric oxide (NO.). Yet the competition between O2 and L-arginine for electrons, and by implication formation of O-2, has until recently remained undefined. Herein, we investigated this relationship, observing O-2 generation even at saturating levels of L-arginine. Of interest was the finding that the frequently used NOS inhibitor NG-monomethyl L-arginine enhanced O-2 production in the presence of L-arginine because this antagonist attenuated NO. formation. Whereas diphenyliodonium chloride inhibited O-2, blockers of heme such as NaCN, 1-phenylimidazole, and imidazole likewise prevented the formation of O-2 at concentrations that inhibited NO. formation from L-arginine. Taken together these data demonstrate that NOS I generates O-2 and the formation of this free radical occurs at the heme domain. PMID- 10092644 TI - Subunit interface selectivity of the alpha-neurotoxins for the nicotinic acetylcholine receptor. AB - Peptide toxins selective for particular subunit interfaces of the nicotinic acetylcholine receptor have proven invaluable in assigning candidate residues located in the two binding sites and for determining probable orientations of the bound peptide. We report here on a short alpha-neurotoxin from Naja mossambica mossambica (NmmI) that, similar to other alpha-neurotoxins, binds with high affinity to alphagamma and alphadelta subunit interfaces (KD approximately 100 pM) but binds with markedly reduced affinity to the alphaepsilon interface (KD approximately 100 nM). By constructing chimeras composed of portions of the gamma and epsilon subunits and coexpressing them with wild type alpha, beta, and delta subunits in HEK 293 cells, we identify a region of the subunit sequence responsible for the difference in affinity. Within this region, gammaPro-175 and gammaGlu-176 confer high affinity, whereas Thr and Ala, found at homologous positions in epsilon, confer low affinity. To identify an interaction between gammaGlu-176 and residues in NmmI, we have examined cationic residues in the central loop of the toxin and measured binding of mutant toxin-receptor combinations. The data show strong pairwise interactions or coupling between gammaGlu-176 and Lys-27 of NmmI and progressively weaker interactions with Arg-33 and Arg-36 in loop II of this three-loop toxin. Thus, loop II of NmmI, and in particular the face of this loop closest to loop III, appears to come into close apposition with Glu-176 of the gamma subunit surface of the binding site interface. PMID- 10092645 TI - Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5 dibromophenyl)propenamide]. AB - In a systematic effort to design potent inhibitors of the anti-apoptotic tyrosine kinase BTK (Bruton's tyrosine kinase) as anti-leukemic agents with apoptosis promoting and chemosensitizing properties, we have constructed a three dimensional homology model of the BTK kinase domain. Our modeling studies revealed a distinct rectangular binding pocket near the hinge region of the BTK kinase domain with Leu460, Tyr476, Arg525, and Asp539 residues occupying the corners of the rectangle. The dimensions of this rectangle are approximately 18 x 8 x 9 x 17 A, and the thickness of the pocket is approximately 7 A. Advanced docking procedures were employed for the rational design of leflunomide metabolite (LFM) analogs with a high likelihood to bind favorably to the catalytic site within the kinase domain of BTK. The lead compound LFM-A13, for which we calculated a Ki value of 1.4 microM, inhibited human BTK in vitro with an IC50 value of 17.2 +/- 0.8 microM. Similarly, LFM-A13 inhibited recombinant BTK expressed in a baculovirus expression vector system with an IC50 value of 2.5 microM. The energetically favorable position of LFM-A13 in the binding pocket is such that its aromatic ring is close to Tyr476, and its substituent group is sandwiched between residues Arg525 and Asp539. In addition, LFM-A13 is capable of favorable hydrogen bonding interactions with BTK via Asp539 and Arg525 residues. Besides its remarkable potency in BTK kinase assays, LFM-A13 was also discovered to be a highly specific inhibitor of BTK. Even at concentrations as high as 100 micrograms/ml (approximately 278 microM), this novel inhibitor did not affect the enzymatic activity of other protein tyrosine kinases, including JAK1, JAK3, HCK, epidermal growth factor receptor kinase, and insulin receptor kinase. In accordance with the anti-apoptotic function of BTK, treatment of BTK+ B-lineage leukemic cells with LFM-A13 enhanced their sensitivity to ceramide- or vincristine-induced apoptosis. To our knowledge, LFM-A13 is the first BTK specific tyrosine kinase inhibitor and the first anti-leukemic agent targeting BTK. PMID- 10092646 TI - Identification of substrate binding site of cyclin-dependent kinase 5. AB - Cyclin-dependent kinase 5 (CDK5), unlike other CDKs, is active only in neuronal cells where its neuron-specific activator p35 is present. However, it phosphorylates serines/threonines in S/TPXK/R-type motifs like other CDKs. The tail portion of neurofilament-H contains more than 50 KSP repeats, and CDK5 has been shown to phosphorylate S/T specifically only in KS/TPXK motifs, indicating highly specific interactions in substrate recognition. CDKs have been shown to have a high preference for a basic residue (lysine or arginine) as the n+3 residue, n being the location in the primary sequence of a phosphoacceptor serine or threonine. Because of the lack of a crystal structure of a CDK-substrate complex, the structural basis for this specific interaction is unknown. We have used site-directed mutagenesis ("charged to alanine") and molecular modeling techniques to probe the recognition interactions for substrate peptide (PKTPKKAKKL) derived from histone H1 docked in the active site of CDK5. The experimental data and computer simulations suggest that Asp86 and Asp91 are key residues that interact with the lysines at positions n+2 and/or n+3 of the substrates. PMID- 10092647 TI - Human pancreatic islets express mRNA species encoding two distinct catalytically active isoforms of group VI phospholipase A2 (iPLA2) that arise from an exon skipping mechanism of alternative splicing of the transcript from the iPLA2 gene on chromosome 22q13.1. AB - An 85-kDa Group VI phospholipase A2 enzyme (iPLA2) that does not require Ca2+ for catalysis has recently been cloned from three rodent species. A homologous 88-kDa enzyme has been cloned from human B-lymphocyte lines that contains a 54-amino acid insert not present in the rodent enzymes, but human cells have not previously been observed to express catalytically active iPLA2 isoforms other than the 88-kDa protein. We have cloned cDNA species that encode two distinct iPLA2 isoforms from human pancreatic islet RNA and a human insulinoma cDNA library. One isoform is an 85-kDa protein (short isoform of human iPLA2 (SH iPLA2)) and the other an 88-kDa protein (long isoform of human iPLA2 (LH-iPLA2)). Transcripts encoding both isoforms are also observed in human promonocytic U937 cells. Recombinant SH-iPLA2 and LH-iPLA2 are both catalytically active in the absence of Ca2+ and inhibited by a bromoenol lactone suicide substrate, but LH iPLA2 is activated by ATP, whereas SH-iPLA2 is not. The human iPLA2 gene has been found to reside on chromosome 22 in region q13.1 and to contain 16 exons represented in the LH-iPLA2 transcript. Exon 8 is not represented in the SH-iPLA2 transcript, indicating that it arises by an exon-skipping mechanism of alternative splicing. The amino acid sequence encoded by exon 8 of the human iPLA2 gene is proline-rich and shares a consensus motif of PX5PX8HHPX12NX4Q with the proline-rich middle linker domains of the Smad proteins DAF-3 and Smad4. Expression of mRNA species encoding two active iPLA2 isoforms with distinguishable catalytic properties in two different types of human cells demonstrated here may have regulatory or functional implications about the roles of products of the iPLA2 gene in cell biologic processes. PMID- 10092648 TI - Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. AB - The chemokine receptor CCR5 is the major coreceptor for R5 human immunodeficiency virus type-1 strains. We mapped the epitope specificities of 18 CCR5 monoclonal antibodies (mAbs) to identify domains of CCR5 required for chemokine binding, gp120 binding, and for inducing conformational changes in Env that lead to membrane fusion. We identified mAbs that bound to N-terminal epitopes, extracellular loop 2 (ECL2) epitopes, and multidomain (MD) epitopes composed of more than one single extracellular domain. N-terminal mAbs recognized specific residues that span the first 13 amino acids of CCR5, while nearly all ECL2 mAbs recognized residues Tyr-184 to Phe-189. In addition, all MD epitopes involved ECL2, including at least residues Lys-171 and Glu-172. We found that ECL2 specific mAbs were more efficient than NH2- or MD-antibodies in blocking RANTES or MIP-1beta binding. By contrast, N-terminal mAbs blocked gp120-CCR5 binding more effectively than ECL2 mAbs. Surprisingly, ECL2 mAbs were more potent inhibitors of viral infection than N-terminal mAbs. Thus, the ability to block virus infection did not correlate with the ability to block gp120 binding. Together, these results imply that chemokines and Env bind to distinct but overlapping sites in CCR5, and suggest that the N-terminal domain of CCR5 is more important for gp120 binding while the extracellular loops are more important for inducing conformational changes in Env that lead to membrane fusion and virus infection. Measurements of individual antibody affinities coupled with kinetic analysis of equilibrium binding states also suggested that there are multiple conformational states of CCR5. A previously described mAb, 2D7, was unique in its ability to effectively block both chemokine and Env binding as well as coreceptor activity. 2D7 bound to a unique antigenic determinant in the first half of ECL2 and recognized a far greater proportion of cell surface CCR5 molecules than the other mAbs examined. Thus, the epitope recognized by 2D7 may represent a particularly attractive target for CCR5 antagonists. PMID- 10092649 TI - The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. AB - Niemann-Pick C disease (NP-C) is a neurovisceral lysosomal storage disorder. A variety of studies have highlighted defective sterol trafficking from lysosomes in NP-C cells. However, the heterogeneous nature of additional accumulating metabolites suggests that the cellular lesion may involve a more generalized block in retrograde lysosomal trafficking. Immunocytochemical studies in fibroblasts reveal that the NPC1 gene product resides in a novel set of lysosome associated membrane protein-2 (LAMP2)(+)/mannose 6-phosphate receptor(-) vesicles that can be distinguished from cholesterol-enriched LAMP2(+) lysosomes. Drugs that block sterol transport out of lysosomes also redistribute NPC1 to cholesterol-laden lysosomes. Sterol relocation from lysosomes in cultured human fibroblasts can be blocked at 21 degrees C, consistent with vesicle-mediated transfer. These findings suggest that NPC1(+) vesicles may transiently interact with lysosomes to facilitate sterol relocation. Independent of defective sterol trafficking, NP-C fibroblasts are also deficient in vesicle-mediated clearance of endocytosed [14C]sucrose. Compartmental modeling of the observed [14C]sucrose clearance data targets the trafficking defect caused by mutations in NPC1 to an endocytic compartment proximal to lysosomes. Low density lipoprotein uptake by normal cells retards retrograde transport of [14C]sucrose through this same kinetic compartment, further suggesting that it may contain the sterol-sensing NPC1 protein. We conclude that a distinctive organelle containing NPC1 mediates retrograde lysosomal transport of endocytosed cargo that is not restricted to sterol. PMID- 10092650 TI - Fibromodulin-null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendon. AB - Fibromodulin is a member of a family of connective tissue glycoproteins/proteoglycans containing leucine-rich repeat motifs. Several members of this gene family bind to fibrillar collagens and are believed to function in the assembly of the collagen network in connective tissues. Here we show that mice lacking a functional fibromodulin gene exhibit an altered morphological phenotype in tail tendon with fewer and abnormal collagen fiber bundles. In fibromodulin-null animals virtually all collagen fiber bundles are disorganized and have an abnormal morphology. Also 10-20% of the bundles in heterozygous mice are similar to the abnormal bundles in fibromodulin-null tail tendon. Ultrastructural analysis of Achilles tendon from fibromodulin-null mice show collagen fibrils with irregular and rough outlines in cross-section. Morphometric analysis show that fibromodulin-null mice have on the average thinner fibrils than wild type animals as a result of a larger preponderance of very thin fibrils in an overall similar range of fibril diameters. Protein and RNA analyses show an approximately 4-fold increase in the content of lumican in fibromodulin-null as compared with wild type tail tendon, despite a decrease in lumican mRNA. These results demonstrate a role for fibromodulin in collagen fibrillogenesis and suggest that the orchestrated action of several leucine-rich repeat glycoproteins/proteoglycans influence the architecture of collagen matrices. PMID- 10092651 TI - Antiidiotypic antibody recognizes an amiloride binding domain within the alpha subunit of the epithelial Na+ channel. AB - We previously raised an antibody (RA6.3) by an antiidiotypic approach which was designed to be directed against an amiloride binding domain on the epithelial Na+ channel (ENaC). This antibody mimicked amiloride in that it inhibited transepithelial Na+ transport across A6 cell monolayers. RA6.3 recognized a 72 kDa polypeptide in A6 epithelia treated with tunicamycin, consistent with the size of nonglycosylated Xenopus laevis alphaENaC. RA6.3 specifically recognized an amiloride binding domain within the alpha-subunit of mouse and bovine ENaC. The deduced amino acid sequence of RA6.3 was used to generate a three-dimensional model structure of the antibody. The combining site of RA6.3 was epitope mapped using a novel computer-based strategy. Organic residues that potentially interact with the RA6.3 combining site were identified by data base screening using the program LUDI. Selected residues docked to the antibody in a manner corresponding to the ordered linear array of amino acid residues within an amiloride binding domain on the alpha-subunit of ENaC. A synthetic peptide spanning this domain inhibited the binding of RA6.3 to alphaENaC. This analysis provided a novel approach to develop models of antibody-antigen interaction as well as a molecular perspective of RA6.3 binding to an amiloride binding domain within alphaENaC. PMID- 10092652 TI - E-cadherin mediates aggregation-dependent survival of prostate and mammary epithelial cells through the retinoblastoma cell cycle control pathway. AB - E-cadherin and the retinoblastoma tumor suppressor (Rb) are traditionally associated with diverse regulatory aspects of cell growth and differentiation. However, we have discovered new evidence, which suggests that these proteins are functionally linked in a physiologic pathway required for cell survival and programmed cell death. Pharmacological activation of protein kinase C (PKC) or inducible overexpression and activation of the alpha isozyme of PKC (PKCalpha) resulted in approximately 60% apoptosis of mammary and prostate epithelial cells. Interestingly, the surviving cells had undergone dramatic aggregation concurrent with increased E-cadherin expression. When aggregation was inhibited by the addition of an E-cadherin-blocking antibody, apoptosis increased synergistically. We hypothesized that survival of the aggregated population was associated with contact-inhibited growth and that apoptosis might result from aberrant growth regulatory signals in non-aggregated, cycling cells. This hypothesis was confirmed by experiments that demonstrated that E-cadherin-dependent aggregation resulted in Rb-mediated G1 arrest and survival. Immunoblot analysis and flow cytometry revealed that hypophosphorylated Rb was present in non-aggregated, S phase cultures concurrent with synergistic cell death. We have also determined that the loss of membrane E-cadherin and subsequent hypophosphorylation of Rb in luminal epithelial cells preceded apoptosis induced by castration. These findings provide compelling evidence that suggests that E-cadherin-mediated aggregation results in Rb activation and G1 arrest that is critical for survival of prostate and mammary epithelial cells. These data also indicate that Rb can initiate a fatal growth signal conflict in non-aggregated, cycling cells when the protein is hypophosphorylated as these epithelial cells enter S phase. PMID- 10092653 TI - A structure-function study of the C2 domain of cytosolic phospholipase A2. Identification of essential calcium ligands and hydrophobic membrane binding residues. AB - The C2 domain of cytosolic phospholipase A2 (cPLA2) is involved in the Ca2+ dependent membrane binding of this protein. To identify protein residues in the C2 domain of cPLA2 essential for its Ca2+ and membrane binding, we selectively mutated Ca2+ ligands and putative membrane-binding residues of cPLA2 and measured the effects of mutations on its enzyme activity, membrane binding affinity, and monolayer penetration. The mutations of five Ca2+ ligands (D40N, D43N, N65A, D93N, N95A) show differential effects on the membrane binding and activation of cPLA2, indicating that two calcium ions bound to the C2 domain have differential roles. The mutations of hydrophobic residues (F35A, M38A, L39A, Y96A, Y97A, M98A) in the calcium binding loops show that the membrane binding of cPLA2 is largely driven by hydrophobic interactions resulting from the penetration of these residues into the hydrophobic core of the membrane. Leu39 and Val97 are fully inserted into the membrane, whereas Phe35 and Tyr96 are partially inserted. Finally, the mutations of four cationic residues in a beta-strand (R57E/K58E/R59E/R61E) have modest and negligible effects on the binding of cPLA2 to zwitterionic and anionic membranes, respectively, indicating that they are not directly involved in membrane binding. In conjunction with our previous study on the C2 domain of protein kinase C-alpha (Medkova, M., and Cho, W. (1998) J. Biol. Chem. 273, 17544-17552), these results demonstrate that C2 domains are not only a membrane docking unit but also a module that triggers membrane penetration of protein and that individual Ca2+ ions bound to the calcium binding loops play differential roles in the membrane binding and activation of their parent proteins. PMID- 10092654 TI - Urate synthesis in the blood-sucking insect rhodnius prolixus. Stimulation by hemin is mediated by protein kinase C. AB - Hemin is a catalyst of the formation of reactive oxygen species. We proposed that hematophagous insects are exposed to intense oxidative stress because of hemoglobin hydrolysis in their midgut (Petretsky, M. D., Ribeiro, J. M. C., Atella, G. C., Masuda, H., and Oliveira, P. L. (1995) J. Biol. Chem. 270, 10893 10896). We have shown that hemin stimulates urate synthesis in the blood-sucking insect Rhodnius prolixus (Graca-Souza, A. V., Petretsky, J. H., Demasi, M., Bechara, E. J. H., and Oliveira, P. L. (1997) Free Radical Biol. Med. 22, 209 214). Once released by fat body cells, urate accumulates in the hemolymph, where this radical scavenger constitutes an important defense against blood-feeding derived oxidative stress. Incubation of Rhodnius fat bodies with okadaic acid raises the level of urate synthesis, suggesting that urate production can be controlled by protein phosphorylation/dephosphorylation. Urate synthesis is stimulated by dibutyryl cAMP and inhibited by N(2((p-bromocinnamil)amino)ethyl)-5 isoquinolinesulfonamide (H-89), an inhibitor of protein kinase A, as well as activated by the protein kinase C activator phorbol 12-myristate 13-acetate. In the presence of hemin, however, inhibition of urate synthesis by H-89 does not occur, suggesting that the hemin stimulatory effect is not mediated by protein kinase A. Calphostin C completely inhibits the hemin-induced urate production, suggesting that the triggering of urate antioxidant response depends on protein kinase C activation. This conclusion is reinforced by the observation that in fat bodies exposed to hemin, both protein kinase C activity and phosphorylation of specific endogenous polypeptides are significantly increased. PMID- 10092655 TI - Effect of cold shock on lipid A biosynthesis in Escherichia coli. Induction At 12 degrees C of an acyltransferase specific for palmitoleoyl-acyl carrier protein. AB - Palmitoleate is not present in lipid A isolated from Escherichia coli grown at 30 degrees C or higher, but it comprises approximately 11% of the fatty acyl chains of lipid A in cells grown at 12 degrees C. The appearance of palmitoleate at 12 degrees C is accompanied by a decline in laurate from approximately 18% to approximately 5.5%. We now report that wild-type E. coli shifted from 30 degrees C to 12 degrees C acquire a novel palmitoleoyl-acyl carrier protein (ACP) dependent acyltransferase that acts on the key lipid A precursor Kdo2-lipid IVA. The palmitoleoyl transferase is induced more than 30-fold upon cold shock, as judged by assaying extracts of cells shifted to 12 degrees C. The induced activity is maximal after 2 h of cold shock, and then gradually declines but does not disappear. Strains harboring an insertion mutation in the lpxL(htrB) gene, which encodes the enzyme that normally transfers laurate from lauroyl-ACP to Kdo2 lipid IVA (Clementz, T., Bednarski, J. J., and Raetz, C. R. H. (1996) J. Biol. Chem. 271, 12095-12102) are not defective in the cold-induced palmitoleoyl transferase. Recently, a gene displaying 54% identity and 73% similarity at the protein level to lpxL was found in the genome of E. coli. This lpxL homologue, designated lpxP, encodes the cold shock-induced palmitoleoyl transferase. Extracts of cells containing lpxP on the multicopy plasmid pSK57 exhibit a 10 fold increase in the specific activity of the cold-induced palmitoleoyl transferase compared with cells lacking the plasmid. The elevated specific activity of the palmitoleoyl transferase under conditions of cold shock is attributed to greatly increased levels of lpxP mRNA. The replacement of laurate with palmitoleate in lipid A may reflect the desirability of maintaining the optimal outer membrane fluidity at 12 degrees C. PMID- 10092656 TI - Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens. AB - Interferon signaling is mediated by STATs and interferon regulatory factor (IRF) families of transcription factors. Ten distinct IRFs have been described and most are expressed in a variety of cells except for interferon consensus sequence binding protein (ICSBP) and lymphoid-specific IRF/Pip that are thought to be exclusively expressed in lymphoid cells. We show here for the first time that ICSBP is constitutively and inducibly expressed in the mouse lens. In contrast to lymphoid cells with exclusive expression of ICSBP in the nucleus, ICSBP is present in both the cytoplasm and nucleus of the lens cell. However, ICSBP in the nucleus is of lower apparent molecular weight. We further show that the ICSBP promoter is constitutively bound by lens nuclear factors and that its activation requires binding of additional factors including STAT1. Furthermore, transcriptional activation of ICSBP gene by interferon gamma is accompanied by selective nuclear localization of ICSBP in proliferating epithelial cells but not in the nuclei of nondividing cells in the lens fiber compartment. Constitutive and inducible expression of ICSBP in the ocular lens and differential regulation of its subcellular localization in the developing lens suggest that ICSBP may have nonimmunity related functions and that the commonly held view that it is lymphoid-specific be modified. PMID- 10092657 TI - Cardiac hypertrophic and developmental regulation of the beta-tubulin multigene family. AB - Increased microtubule density, through viscous loading of active myofilaments, causes contractile dysfunction of hypertrophied and failing pressure-overloaded myocardium, which is normalized by microtubule depolymerization. We have found this to be based on augmented tubulin synthesis and microtubule stability. We show here that increased tubulin synthesis is accounted for by marked transcriptional up-regulation of the beta1- and beta2-tubulin isoforms, that hypertrophic regulation of these genes recapitulates their developmental regulation, and that the greater proportion of beta1-tubulin protein may have a causative role in the microtubule stabilization found in cardiac hypertrophy. PMID- 10092658 TI - Multiple DNA binding activities of the novel site-specific recombinase, Piv, from Moraxella lacunata. AB - The recombinase, Piv, is essential for site-specific DNA inversion of the type IV pilin DNA segment in Moraxella lacunata and Moraxella bovis. Piv shows significant homology with the transposases of the IS110/IS492 family of insertion elements, but, surprisingly, Piv contains none of the conserved amino acid motifs of the lambda Int or Hin/Res families of site-specific recombinases. Therefore, Piv may mediate site-specific recombination by a novel mechanism. To begin to determine how Piv may assemble a synaptic nucleoprotein structure for DNA cleavage and strand exchange, we have characterized the interaction of Piv with the DNA inversion region of M. lacunata. Gel shift and nuclease/chemical protection assays, competition and dissociation rate analyses, and cooperativity studies indicate that Piv binds two distinct recognition sequences. One recognition sequence, found at multiple sites within and outside of the invertible segment, is bound by Piv protomers with high affinity. The second recognition sequence is located at the recombination cross-over sites at the ends of the invertible element; Piv interacts with this sequence as an oligomer with apparent low affinity. A model is proposed for the role of the different Piv binding sites of the M. lacunata inversion region in the formation of an active synaptosome. PMID- 10092659 TI - Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-kappaB-mediated transcription. AB - Virus infections, the majority of which are rhinovirus infections, are the major cause of asthma exacerbations. Treatment is unsatisfactory, and the pathogenesis unclear. Lower airway lymphocyte and eosinophil recruitment and activation are strongly implicated, but the mechanisms regulating these processes are unknown. Intercellular adhesion molecule-1 (ICAM-1) has a central role in inflammatory cell recruitment to the airways in asthma and is the cellular receptor for 90% of rhinoviruses. We hypothesized that rhinovirus infection of lower airway epithelium might induce ICAM-1 expression, promoting both inflammatory cell infiltration and rhinovirus infection. We therefore investigated the effect of rhinovirus infection on respiratory epithelial cell ICAM-1 expression and regulation to identify new targets for treatment of virus-induced asthma exacerbations. We observed that rhinovirus infection of primary bronchial epithelial cells and the A549 respiratory epithelial cell line increased ICAM-1 cell surface expression over 12- and 3-fold, respectively. We then investigated the mechanisms of this induction in A549 cells and observed rhinovirus-induction of ICAM-1 promoter activity and ICAM-1 mRNA transcription. Rhinovirus induction of ICAM-1 promoter activity was critically dependent upon up-regulation of NF kappaB proteins binding to the -187/-178 NF-kappaB binding site on the ICAM-1 promoter. The principal components of the rhinovirus-induced binding proteins were NF-kappaB p65 homo- or heterodimers. These studies identify ICAM-1 and NF kappaB as new targets for the development of therapeutic interventions for virus induced asthma exacerbations. PMID- 10092660 TI - Role of the second extracellular loop of human C3a receptor in agonist binding and receptor function. AB - The C3a anaphylatoxin receptor (C3aR) is a G protein-coupled receptor with an unusually large second extracellular loop (e2 loop, approximately 172 amino acids). To determine the function of this unique structure, chimeric and deletion mutants were prepared and analyzed in transfected RBL-2H3 cells. Whereas replacement of the C3aR N-terminal segment with that from the human C5a receptor had minimal effect on C3a binding, substitution of the e2 loop with a smaller e2 loop from the C5a receptor (C5aR) abolished binding of 125I-C3a and C3a stimulated calcium mobilization. However, as much as 65% of the e2 loop sequence (amino acids 198-308) may be removed without affecting C3a binding or calcium responses. The e2 loop sequences adjacent to the transmembrane domains contain multiple aspartate residues and are found to play an important role in C3a binding based on deletion mutagenesis. Replacement of five aspartate residues in the e2 loop with lysyl residues significantly compromised both the binding and functional capabilities of the C3a receptor mediated by intact C3a or by two C3a analog peptides. These data suggest a two-site C3a-C3aR interaction model similar to that established for C5a/C5aR. The anionic residues near the N and C termini of the C3aR e2 loop constitute a non-effector secondary interaction site with cationic residues in the C-terminal helical region of C3a, whereas the C3a C terminal sequence LGLAR engages the primary effector site in C3aR. PMID- 10092661 TI - The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation. Involvement of STAT3. AB - Cell type-specific responses to the leukemia inhibitory factor (LIF)/interleukin 6 cytokine family are mediated by dimerization of the LIF receptor alpha-chain (LIFRalpha) with the signal transducer gp130 or of two gp130 molecules followed by activation of the JAK/STAT and Ras/mitogen-activated protein kinase cascades. In order to dissect the contribution of gp130 and LIFRalpha individually, chimeric molecules consisting of the extracellular domain of the granulocyte colony stimulating factor receptor (GCSF-R) and various mutant forms of the cytoplasmic domains of gp130 or LIFRalpha were expressed in embryonic stem (ES) cells to test for suppression of differentiation, or in a factor-dependent plasma cytoma cell line to assess for induction of proliferation. Carboxyl-terminal domains downstream of the phosphatase (SHP2)-binding sites were dispensable for mitogen-activated protein kinase activation and the transduction of proliferative signals. Moreover, carboxyl-terminal truncation mutants which lacked intact Box 3 homology domains showed decreased STAT3 activation, failed to induce Hck kinase activity and suppress ES cell differentiation. Moreover, STAT3 antisense oligonucleotides impaired LIF-dependent inhibition of differentiation. Substitution of the tyrosine residue within the Box 3 region of the GSCF-R abolished receptor-mediated suppression of differentiation without affecting the transduction of proliferative signals. Thus, distinct cytoplasmic domains within the LIFRalpha, gp130, and GCSF-R transduce proliferative and differentiation suppressing signals. PMID- 10092662 TI - Expression and characterization of a DNase I-Fc fusion enzyme. AB - Recombinant human deoxyribonuclease I (DNase I) is an important clinical agent that is inhaled into the airways where it degrades DNA to lower molecular weight fragments, thus reducing the viscoelasticity of sputum and improving the lung function of cystic fibrosis patients. To investigate DNases with potentially improved properties, we constructed a molecular fusion of human DNase I with the hinge and Fc region of human IgG1 heavy chain, creating a DNase I-Fc fusion protein. Infection of Sf9 insect cells with recombinant baculovirus resulted in the expression and secretion of the DNase I-Fc fusion protein. The fusion protein was purified from the culture medium using protein A affinity chromatography followed by desalting by gel filtration and was characterized by amino-terminal sequence, amino acid composition, and a variety of enzyme-linked immunosorbent assays (ELISA) and activity assays. The purified fusion contains DNase I, as determined by a DNase I ELISA and an actin-binding ELISA, and an intact antibody Fc region, which was quantified by an Fc ELISA, in a 2:1 stoichiometric ratio, respectively. The dimeric DNase I-Fc fusion was functionally active in enzymatic DNA digestion assays, albeit about 10-fold less than monomeric DNase I. Cleavage of the DNase I-Fc fusion by papain resulted in a specific activity comparable to the monomeric enzyme. Salt was inhibitory for wild type monomeric DNase I but actually enhanced the activity of the dimeric DNase I-Fc fusion. The DNase I-Fc fusion protein was also less Ca2+-dependent than DNase I itself. These results are consistent with a higher affinity of the dimeric fusion protein to DNA than monomeric DNase I. The engineered DNase I-Fc fusion protein described herein has properties that may have clinical benefits. PMID- 10092663 TI - The ADP-ribosylation factor (ARF)-related GTPase ARF-related protein binds to the ARF-specific guanine nucleotide exchange factor cytohesin and inhibits the ARF dependent activation of phospholipase D. AB - ADP-ribosylation factor-related protein (ARP) is a membrane-associated GTPase with remote similarity to the family of ADP-ribosylation factors (ARF). In a yeast two-hybrid screen designed to identify proteins interacting with ARP, we isolated a partial cDNA of the ARF-specific guanine nucleotide exchange factor mSec7-1/cytohesin encoding its N terminus and most of the Sec7 domain (codons 1 200). ARP and ARP-Q79L (GTPase-negative ARP) exhibited a higher affinity to mSec7 1-(1-200) than ARP-T31N (nucleotide exchange-defective ARP) in the two-hybrid assay. Similarly, full-length [35S]mSec7-1/cytohesin was specifically adsorbed to glutathione-Sepharose loaded with glutathione S-transferase (GST)-ARP-Q79L, GST ARP, or GST-ARP-T31N, the latter exhibiting the lowest binding affinity. Overexpression of ARP-Q79L, but not of ARP-T31N, in COS-7 cells reduced the fluorescence from co-expressed green fluorescent protein fused with mSec7 1/cytohesin or mSec7-2/ARNO in plasma membranes as detected by deconvolution microscopy. Recombinant ARP and ARP-Q79L, but not ARP-T31N, inhibited the phospholipase D (PLD) activity stimulated by mSec7-2/ARNO and ARF in a system of isolated membranes. Furthermore, transfection of HEK-293 cells with ARP or ARP Q79L, but not ARP-T31N, inhibited the muscarinic acetylcholine receptor-3 induced PLD stimulation and translocation of ARF from cytosol to membranes. These data suggest that the GTP-bound form of ARP specifically binds mSec7-1/cytohesin, and that ARP may be involved in a pathway inhibiting the ARF-controlled activity of PLD. PMID- 10092664 TI - A disulfide-bridged mutant of natriuretic peptide receptor-A displays constitutive activity. Role of receptor dimerization in signal transduction. AB - Natriuretic peptide receptor-A (NPR-A), a particulate guanylyl cyclase receptor, is composed of an extracellular domain (ECD) with a ligand binding site, a transmembrane spanning, a kinase homology domain (KHD), and a guanylyl cyclase domain. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), the natural agonists, bind and activate the receptor leading to cyclic GMP production. This receptor has been reported to be spontaneously dimeric or oligomeric. In response to agonists, the KHD-mediated guanylate cyclase repression is removed, and it is assumed that ATP binds to the KHD. Since NPR-A displays a pair of juxtamembrane cysteines separated by 8 residues, we hypothesized that the removal of one of those cysteines would leave the other unpaired and reactive, thus susceptible to form an interchain disulfide bridge and to favor the dimeric interactions. Here we show that NPR-AC423S mutant, expressed mainly as a covalent dimer, increases the affinity of pBNP for this receptor by enhancing a high affinity binding component. Dimerization primarily depends on ECD since a secreted NPR-A C423S soluble ectodomain (ECDC423S) also documents a covalent dimer. ANP binding to the unmutated ECD yields up to 80-fold affinity loss as compared with the membrane receptor. However, the ECD C423S mutation restores a high binding affinity. Furthermore, C423S mutation leads to cellular constitutive activation (20-40-fold) of basal catalytic production of cyclic GMP by the full-length mutant. In vitro particulate guanylyl cyclase assays demonstrate that NPR-AC423S displays an increased sensitivity to ATP treatment alone and that the effect of ANP + ATP joint treatment is cumulative instead of synergistic. Finally, the cellular and particulate guanylyl cyclase assays indicate that the receptor is desensitized to agonist stimulation. We conclude the following: 1) dimers are functional units of NPR-A guanylyl cyclase activation; and 2) agonists are inducing dimeric contact of the juxtamembranous region leading to the removal of the KHD-mediated guanylyl cyclase repression, hence allowing catalytic activation. PMID- 10092665 TI - Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy. AB - Activation of beta-adrenoreceptors induces cardiomyocyte hypertrophy. In the present study, we examined isoproterenol-evoked intracellular signal transduction pathways leading to activation of extracellular signal-regulated kinases (ERKs) and cardiomyocyte hypertrophy. Inhibitors for cAMP and protein kinase A (PKA) abolished isoproterenol-evoked ERK activation, suggesting that Gs protein is involved in the activation. Inhibition of Gi protein by pertussis toxin, however, also suppressed isoproterenol-induced ERK activation. Overexpression of the Gbetagamma subunit binding domain of the beta-adrenoreceptor kinase 1 and of COOH terminal Src kinase, which inhibit functions of Gbetagamma and the Src family tyrosine kinases, respectively, also inhibited isoproterenol-induced ERK activation. Overexpression of dominant-negative mutants of Ras and Raf-1 kinase and of the beta-adrenoreceptor mutant that lacks phosphorylation sites by PKA abolished isoproterenol-stimulated ERK activation. The isoproterenol-induced increase in protein synthesis was also suppressed by inhibitors for PKA, Gi, tyrosine kinases, or Ras. These results suggest that isoproterenol induces ERK activation and cardiomyocyte hypertrophy through two different G proteins, Gs and Gi. cAMP-dependent PKA activation through Gs may phosphorylate the beta adrenoreceptor, leading to coupling of the receptor from Gs to Gi. Activation of Gi activates ERKs through Gbetagamma, Src family tyrosine kinases, Ras, and Raf-1 kinase. PMID- 10092666 TI - Definition of a consensus transportin-specific nucleocytoplasmic transport signal. AB - The low cytoplasmic and high nuclear concentration of the GTP-bound form of Ran provides directionality for both nuclear protein import and export. Both import and export factors bind RanGTP directly, yet this interaction produces opposite effects; in the former case, RanGTP binding induces nuclear cargo release, whereas in the latter, RanGTP binding induces nuclear cargo assembly. Therefore, nuclear import and export receptors and their protein recognition sites are predicted to be distinct. Nevertheless, the approximately 38-amino acid M9 sequence present in heterogeneous nuclear ribonucleoprotein A1 has been reported to serve as both a nuclear localization signal and a nuclear export signal, even though only one protein, the nuclear import factor transportin, has been shown to bind M9 directly. We have used a combination of mutational randomization followed by selection for transportin binding to exhaustively define amino acids in M9 that are critical for transportin binding in vivo. As expected, the resultant approximately 12-amino acid transportin-binding consensus sequence is also predictive of nuclear localization signal activity. Surprisingly, however, this extensive mutational analysis failed to dissect M9 nuclear localization signal and nuclear export signal function. Nevertheless, transportin appears unlikely to be the M9 export receptor, as RanGTP can be shown to block M9 binding by transportin not only in vitro, but also in the nucleus in vivo. This analysis therefore predicts the existence of a nuclear export receptor distinct from transportin that nevertheless shares a common protein-binding site on heterogeneous nuclear ribonucleoprotein A1. PMID- 10092667 TI - Altered expression profile of the surface glycopeptidolipids in drug-resistant clinical isolates of Mycobacterium avium complex. AB - Members of the Mycobacterium avium complex are the most frequently encountered opportunistic bacterial pathogens among patients in the advanced stage of AIDS. Two clinical isolates of the same strain, numbers 397 and 417, were obtained from an AIDS patient with disseminated M. avium complex infection before and after treatment with a regimen of clarithromycin and ethambutol. To identify the biochemical consequence of drug treatment, the expression and chemical composition of their major cell wall constituents, the arabinogalactan, lipoarabinomannan, and the surface glycopeptidolipids (GPL), were critically examined. Through thin layer chromatography, mass spectrometry, and chemical analysis, it was found that the GPL expression profiles differ significantly in that several apolar GPLs were overexpressed in the clinically resistant 417 isolate at the expense of the serotype 1 polar GPL, which was the single predominant band in the ethambutol-susceptible 397 isolate. Thus, instead of additional rhamnosylation on the 6-deoxytalose (6-dTal) appendage to give the serotype 1-specific disaccharide hapten, the accumulation of this nonextended apolar GPL probably provided more precursor substrate available for further nonsaccharide substitutions including a higher degree of O-methylation to give 3 O-Me-6-dTal and the unusual 4-O-sulfation on 6-dTal. Further data showed that this alteration effectively neutralized ethambutol, which is known to inhibit arabinan synthesis. Thus, in contrast with derived Emb-resistant mutants of Mycobacterium smegmatis or Mycobacterium tuberculosis, which are devoid of a surface GPL layer, the lipoarabinomannan from resistant 417 isolate grown in the presence of this drug was not apparently truncated. PMID- 10092668 TI - The catalytic mechanism of a pyrimidine dimer-specific glycosylase (pdg)/abasic lyase, Chlorella virus-pdg. AB - The repair of UV light-induced cyclobutane pyrimidine dimers can proceed via the base excision repair pathway, in which the initial step is catalyzed by DNA glycosylase/abasic (AP) lyases. The prototypical enzyme studied for this pathway is endonuclease V from the bacteriophage T4 (T4 bacteriophage pyrimidine dimer glycosylase (T4-pdg)). The first homologue for T4-pdg has been found in a strain of Chlorella virus (strain Paramecium bursaria Chlorella virus-1), which contains a gene that predicts an amino acid sequence homology of 41% with T4-pdg. Because both the structure and critical catalytic residues are known for T4-pdg, homology modeling of the Chlorella virus pyrimidine dimer glycosylase (cv-pdg) predicted that a conserved glutamic acid residue (Glu-23) would be important for catalysis at pyrimidine dimers and abasic sites. Site-directed mutations were constructed at Glu-23 to assess the necessity of a negatively charged residue at that position (Gln-23) and the importance of the length of the negatively charged side chain (Asp-23). E23Q lost glycosylase activity completely but retained low levels of AP lyase activity. In contrast, E23D retained near wild type glycosylase and AP lyase activities on cis-syn dimers but completely lost its activity on the trans-syn II dimer, which is very efficiently cleaved by the wild type cv-pdg. As has been shown for other glyscosylases, the wild type cv-pdg catalyzes the cleavage at dimers or AP sites via formation of an imino intermediate, as evidenced by the ability of the enzyme to be covalently trapped on substrate DNA when the reactions are carried out in the presence of a strong reducing agent; in contrast, E23D was very poorly trapped on cis-syn dimers but was readily trapped on DNA containing AP sites. It is proposed that Glu-23 protonates the sugar ring, so that the imino intermediate can be formed. PMID- 10092669 TI - Unique DNA binding specificity of the binuclear zinc AlcR activator of the ethanol utilization pathway in Aspergillus nidulans. AB - AlcR is the transcriptional activator in Aspergillus nidulans, necessary for the induction of the alc gene cluster. It belongs to the Zn2Cys6 zinc cluster protein family, but contains some striking differences compared with other proteins of this group. In this report, we show that no dimerization element is present in the entire AlcR protein which occurs in solution as a monomer and binds also to its cognate sites as a monomer. Another important feature of AlcR is its unique specificity for single sites occurring naturally as inverted or direct repeats and sharing a common motif, 5'-(T/A)GCGG-3'. Like most other Zn2Cys6 proteins, AlcR contacts directly with the CGG triplet and, in addition, the upstream adjacent guanine is required for high affinity binding. We also establish that the flanking regions outside the core play an essential role in tight binding. From our in vitro analysis, we propose an optimal AlcR-binding site which is 5' PuNGCGG-AT rich 3'. PMID- 10092670 TI - Cloning, expression, and substrate specificity of MeCPA, a zinc carboxypeptidase that is secreted into infected tissues by the fungal entomopathogen Metarhizium anisopliae. AB - To date zinc carboxypeptidases have only been found in animals and actinomycete bacteria. A cDNA clone (MeCPA) for a novel fungal (Metarhizium anisopliae) carboxypeptidase (MeCPA) was obtained by using reverse transcription differential display polymerase chain reaction to identify pathogenicity genes. MeCPA resembles pancreatic carboxypeptidases in being synthesized as a precursor species (418 amino acids) containing a large amino-terminal fragment (99 amino acids). The mature (secreted) form of MeCPA shows closest amino acid identity to human carboxypeptidases A1 (35%) and A2 (37%). MeCPA was expressed in an insect cell line yielding an enzyme with dual A1 + A2 specificity for branched aliphatic and aromatic COOH-terminal amino acids. However, in contrast to the very broad spectrum A + B-type bacterial enzymes, MeCPA lacks B-type activity against charged amino acids. This is predictable as key catalytic residues determining the specificity of MeCPA are conserved with those of mammalian A-type carboxypeptidases. Thus, in evolutionary terms the fungal enzyme is an intermediate between the divergence of A and B forms and the differentiation of the A form into A1 and A2 isoforms. Ultrastructural immunocytochemistry of infected host (Manduca sexta) cuticle demonstrated that MeCPA participates with the concurrently produced endoproteases in procuring nutrients; an equivalent function to digestive pancreatic enzymes. PMID- 10092671 TI - Suboptimal cross-linking of antigen receptor induces Syk-dependent activation of p70S6 kinase through protein kinase C and phosphoinositol 3-kinase. AB - Ligation of the B cell antigen receptor (BCR) induces a cascade of signaling pathways that lead to clonal expansion, differentiation, or abortive activation induced apoptosis of B lymphocytes. BCR-mediated cross-linking induces the rapid phosphorylation of protein tyrosine kinases. However, the pathways leading to the activation of downstream serine/threonine kinases such as mitogen-activated protein kinase, p90(Rsk), and p70S6 kinase (p70(S6k)) that mediate reorganization of the actin cytoskeleton, cell cycle progression, gene transcription, and protein synthesis have not been delineated. We recently demonstrated that cross linking of BCR leads to activation of p70(S6k) in B lymphocytes. In this report, we demonstrate that multiple protein tyrosine kinase-dependent signal transduction pathways induced by BCR lead to the activation of p70(S6k). These distinct pathways exhibit different thresholds with respect to the extent of receptor cross-linking required for their activation. Activation of p70(S6k) by suboptimal doses of anti-Ig is Syk-dependent and is mediated by protein kinase C and phosphoinositol 3-kinase. Moreover, the activation of p70(S6k) results in phosphorylation of S6 protein which is important for ribosomal protein synthesis and may be coupled to BCR-induced protein and DNA synthesis in primary murine B cells. PMID- 10092672 TI - Identification of two amino acids in activin A that are important for biological activity and binding to the activin type II receptors. AB - Activins are members of the transforming growth factor-beta family of growth and differentiation factors. In this paper, we report the results of a structure function analysis of activin A. The primary targets for directed mutagenesis were charged, individual amino acids located in accessible domains of the protein, concentrating on those that differ from transforming growth factor-beta2, the x ray crystal structure of which is known. Based on the activities of the recombinant activin mutants in two bioassays, 4 out of 39 mutant proteins (D27K, K102A, K102E, and K102R) produced in a vaccinia virus system were selected for further investigation. After production in insect cells and purification of these four mutants to homogeneity, they were studied in bioassays and in cross-linking experiments involving transfected receptor combinations. Mutant D27K has a 2-fold higher specific bio-activity and binding affinity to an ActRIIA/ALK-4 activin receptor complex than wild type activin, whereas mutant K102E had no detectable biological activity and did not bind to any of the activin receptors. Mutant K102R and wild type activin bound to all the activin receptor combinations tested and were equipotent in bioassays. Our results with the Lys-102 mutants indicate that the positive charge of amino acid 102 is important for biological activity and type II receptor binding of activins. PMID- 10092673 TI - Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappaB. AB - The role of insulin-like growth factor 1 (IGF-1) for the treatment of neurodegenerative disorders, such as Alzheimer's disease, has recently gained attention. The present study demonstrates that IGF-1 promotes the survival of rat primary cerebellar neurons and of immortalized hypothalamic rat GT1-7 cells after challenge with oxidative stress induced by hydrogen peroxide (H2O2). Neuroprotective concentrations of IGF-1 specifically induce the transcriptional activity and the DNA binding activity of nuclear factor kappaB (NF-kappaB), a transcription factor that has been suggested to play a neuroprotective role. This induction is associated with increased nuclear translocation of the p65 subunit of NF-kappaB and with degradation of the NF-kappaB inhibitory protein IkappaBalpha. IGF-1-mediated protection of GT1-7 cells against oxidative challenges was mimicked by overexpression of the NF-kappaB subunit c-Rel. Partial inhibition of NF-kappaB baseline activity by overexpression of a dominant negative IkappaBalpha mutant enhanced the toxicity of H2O2 in GT1-7 cells. The pathway by which IGF-1 promotes neuronal survival and activation of NF-kappaB involves the phosphoinositol (PI) 3-kinase, because both effects of IGF-1 are blocked by LY294002 and wortmannin, two specific PI 3-kinase inhibitors. Taken together, our results provide evidence for a novel molecular link between IGF-1 mediated neuroprotection and induction of NF-kappaB that is dependent on the PI 3 kinase pathway. PMID- 10092674 TI - Photorhabdus luminescens W-14 insecticidal activity consists of at least two similar but distinct proteins. Purification and characterization of toxin A and toxin B. AB - Both the bacterium Photorhabdus luminescens alone and its symbiotic Photorhabdus nematode complex are known to be highly pathogenic to insects. The nature of the insecticidal activity of Photorhabdus bacteria was investigated for its potential application as an insect control agent. It was found that in the fermentation broth of P. luminescens strain W-14, at least two proteins, toxin A and toxin B, independently contributed to the oral insecticidal activity against Southern corn rootworm. Purified toxin A and toxin B exhibited single bands on native polyacrylamide gel electrophoresis and two peptides of 208 and 63 kDa on SDS polyacrylamide gel electrophoresis. The native molecular weight of both the toxin A and toxin B was determined to be approximately 860 kDa, suggesting that they are tetrameric. NH2-terminal amino acid sequencing and Western analysis using monospecific antibodies to each toxin demonstrated that the two toxins were distinct but homologous. The oral potency (LD50) of toxin A and toxin B against Southern corn rootworm larvae was determined to be similar to that observed with highly potent Bt toxins against lepidopteran pests. In addition, it was found that the two peptides present in toxin B could be processed in vitro from a 281 kDa protoxin by endogenous P. luminescens proteases. Proteolytic processing was shown to enhance insecticidal activity. PMID- 10092675 TI - Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. AB - Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major component of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD, but their pathogenic mechanism is not understood. Here we show that both wild type and mutant alpha-synuclein form insoluble fibrillar aggregates with antiparallel beta-sheet structure upon incubation at physiological temperature in vitro. Importantly, aggregate formation is accelerated by both PD-linked mutations. Under the experimental conditions, the lag time for the formation of precipitable aggregates is about 280 h for the wild type protein, 180 h for the A30P mutant, and only 100 h for the A53T mutant protein. These data suggest that the formation of alpha-synuclein aggregates could be a critical step in PD pathogenesis, which is accelerated by the PD-linked mutations. PMID- 10092676 TI - Hic-5, a paxillin homologue, binds to the protein-tyrosine phosphatase PEST (PTP PEST) through its LIM 3 domain. AB - The Hic-5 protein is encoded by a transforming growth factor-beta1- and hydrogen peroxide-inducible gene, hic-5, and has striking similarity to paxillin, especially in their C-terminal LIM domains. Like paxillin, Hic-5 is localized in focal adhesion plaques in association with focal adhesion kinase in cultured fibroblasts. We carried out yeast two-hybrid screening to identify cellular factors that form a complex with Hic-5 using its LIM domains as a bait, and we identified a cytoplasmic tyrosine phosphatase (PTP-PEST) as one of the partners of Hic-5. These two proteins are associated in mammalian cells. From in vitro binding experiments using deletion and point mutations, it was demonstrated that the essential domain in Hic-5 for the binding was LIM 3. As for PTP-PEST, one of the five proline-rich sequences found on PTP-PEST, Pro-2, was identified as the binding site for Hic-5 in in vitro binding assays. Paxillin also binds to the Pro 2 domain of PTP-PEST. In conclusion, Hic-5 may participate in the regulation of signaling cascade through its interaction with distinct tyrosine kinases and phosphatases. PMID- 10092677 TI - Selective perturbation of early endosome and/or trans-Golgi network pH but not lysosome pH by dose-dependent expression of influenza M2 protein. AB - Many sorting stations along the biosynthetic and endocytic pathways are acidified, suggesting a role for pH regulation in protein traffic. However, the function of acidification in individual compartments has been difficult to examine because global pH perturbants affect all acidified organelles in the cell and also have numerous side effects. To circumvent this problem, we have developed a method to selectively perturb the pH of a subset of acidified compartments. We infected HeLa cells with a recombinant adenovirus encoding influenza virus M2 protein (an acid-activated ion channel that dissipates proton gradients across membranes) and measured the effects on various steps in protein transport. At low multiplicity of infection (m.o.i.), delivery of influenza hemagglutinin from the trans-Golgi network to the cell surface was blocked, but there was almost no effect on the rate of recycling of internalized transferrin. At higher m.o.i., transferrin recycling was inhibited, suggesting increased accumulation of M2 in endosomes. Interestingly, even at the higher m.o.i., M2 expression had no effect on lysosome morphology or on EGF degradation, suggesting that lysosomal pH was not compromised by M2 expression. However, delivery of newly synthesized cathepsin D to lysosomes was slowed in cells expressing active M2, suggesting that acidification of the TGN and endosomes is important for efficient delivery of lysosomal hydrolases. Fluorescence labeling using a pH sensitive dye confirmed the reversible effect of M2 on the pH of a subset of acidified compartments in the cell. The ability to dissect the role of acidification in individual steps of a complex pathway should be useful for numerous other studies on protein processing and transport. PMID- 10092678 TI - The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation. AB - We have isolated a human cDNA for the signaling adapter molecule FRS-2/suc1 associated neurotrophic factor target and shown that it is tyrosine phosphorylated in response to nerve growth factor (NGF) stimulation. Importantly, we demonstrate that the phosphotyrosine binding domain of FRS-2 directly binds the Trk receptors at the same phosphotyrosine residue that binds the signaling adapter Shc, suggesting a model in which competitive binding between FRS-2 and Shc regulates differentiation versus proliferation. Consistent with this model, FRS-2 binds Grb-2, Crk, the SH2 domain containing tyrosine phosphatase SH-PTP-2, the cyclin-dependent kinase substrate p13(suc1), and the Src homology 3 (SH3) domain of Src, providing a functional link between TrkA, cell cycle, and multiple NGF signaling effectors. Importantly, overexpression of FRS-2 in cells expressing an NGF nonresponsive TrkA receptor mutant reconstitutes the ability of NGF to stop cell cycle progression and to stimulate neuronal differentiation. PMID- 10092679 TI - Identification and characterization of a protein destruction signal in the encephalomyocarditis virus 3C protease. AB - The amino acid sequence LLVRGRTLVV, which is probably located in a strand-turn strand structure, has been identified as a protein destruction signal in the rapidly degraded encephalomyocarditis virus 3C protease. Mutations within this sequence reduced the susceptibility of the 3C protease toward ubiquitination and degradation in rabbit reticulocyte lysate. This signal is transferable, since poliovirus 3C protease, which is a poor ubiquitin-mediated proteolytic system substrate, was found to be ubiquitinated and degraded when the signal sequence was either generated at an internal location in the protein or fused to the N terminus. An evaluation of the behavior of 3C protease proteins containing mutations in the signal region indicates that considerable variability in the primary structure is tolerated, although the conservation of certain features appears to be required for signal function. Two E3 ubiquitin-protein ligases that recognize the encephalomyocarditis virus 3C protease as a substrate were also partially purified. One of these was identified as the previously described E3alpha, and this was shown to require the destruction signal sequence to catalyze efficiently the ubiquitination of the 3C protease. The other is a Ubc5 dependent E3 that appears to recognize a different, unidentified feature of the 3C protease. PMID- 10092680 TI - A high molecular weight intermediate filament-associated protein in BHK-21 cells is nestin, a type VI intermediate filament protein. Limited co-assembly in vitro to form heteropolymers with type III vimentin and type IV alpha-internexin. AB - BHK-21 fibroblasts contain type III vimentin/desmin intermediate filament (IF) proteins that typically co-isolate and co-cycle in in vitro experiments with certain high molecular weight proteins. Here, we report purification of one of these and demonstrate that it is in fact the type VI IF protein nestin. Nestin is expressed in several fibroblastic but not epithelioid cell lines. We show that nestin forms homodimers and homotetramers but does not form IF by itself in vitro. In mixtures, nestin preferentially co-assembles with purified vimentin or the type IV IF protein alpha-internexin to form heterodimer coiled-coil molecules. These molecules may co-assemble into 10 nm IF provided that the total amount of nestin does not exceed about 25%. However, nestin does not dimerize with types I/II keratin IF chains. The bulk of the nestin protein consists of a long carboxyl-terminal tail composed of various highly charged peptide repeats. By analogy with the larger neurofilament chains, we postulate that these sequences serve as cross-bridgers or spacers between IF and/or other cytoskeletal constituents. In this way, we propose that direct incorporation of modest amounts of nestin into the backbone of cytoplasmic types III and IV IFs affords a simple yet flexible method for the regulation of their dynamic supramolecular organization and function in cells. PMID- 10092681 TI - Extracellular matrix-dependent activation of syndecan-1 expression in keratinocyte growth factor-treated keratinocytes. AB - Syndecan-1 is a major heparan sulfate proteoglycan of the epidermis. Its expression is strongly induced in migrating and proliferating keratinocytes during wound healing and, on the other hand, diminished or lost in invasive squamous cell carcinoma. We have recently found in the syndecan-1 gene an enhancer (fibroblast growth factor-inducible response element (FiRE)) that activates gene expression in wound edge keratinocytes (Jaakkola, P., Kontusaari, S., Kauppi, T., Maatta, A., and Jalkanen, M. (1998) FASEB J. 12, 959-969). Now, we demonstrate that the activation of this enhancer by keratinocyte growth factor (KGF) is modulated by the components of the extracellular matrix (ECM). MCA-3D mouse immortal keratinocytes growing on fibrillar collagen failed to activate FiRE and subsequently to induce syndecan-1 in response to KGF. The same cells growing on fibronectin or laminin, however, increased FiRE-dependent reporter gene expression upon KGF treatment. The inhibition of the KGF induction by collagen appears to be specific for signaling to FiRE, as the increase in cell proliferation by KGF was not affected. The effect was selective to KGF, as EGF induction was independent on ECM composition. Changes in the transcription factor binding were not involved in the differential activation of FiRE, as the levels and composition of the AP-1 complexes were unchanged. However, application of anisomycin, an activator of Jun amino-terminal kinase, resulted in a lower response in cells growing on collagen compared with fibronectin. These results indicate that the composition of ECM and availability of growth factors can play a role in the epidermal regulation of syndecan-1 expression and that FiRE is a novel target for gene regulation by the extracellular matrix. PMID- 10092682 TI - RGS7 and RGS8 differentially accelerate G protein-mediated modulation of K+ currents. AB - The recently discovered family of RGS (regulators of G protein signaling) proteins acts as GTPase activating proteins which bind to alpha subunits of heterotrimeric G proteins. We previously showed that a brain-specific RGS, RGS8 speeds up the activation and deactivation kinetics of the G protein-coupled inward rectifier K+ channel (GIRK) upon receptor stimulation (Saitoh, O., Kubo, Y., Miyatani, Y., Asano, T., and Nakata, H. (1997) Nature 390, 525-529). Here we report the isolation of a full-length rat cDNA of another brain-specific RGS, RGS7. In situ hybridization study revealed that RGS7 mRNA is predominantly expressed in Golgi cells within granule cell layer of cerebellar cortex. We observed that RGS7 recombinant protein binds preferentially to Galphao, Galphai3, and Galphaz. When co-expressed with GIRK1/2 in Xenopus oocytes, RGS7 and RGS8 differentially accelerate G protein-mediated modulation of GIRK. RGS7 clearly accelerated activation of GIRK current similarly with RGS8 but the acceleration effect of deactivation was significantly weaker than that of RGS8. These acceleration properties of RGS proteins may play important roles in the rapid regulation of neuronal excitability and the cellular responses to short-lived stimulations. PMID- 10092683 TI - Identification and characterization of a protein destruction signal in the encephalomyocarditis virus 3C protease AB - The amino acid sequence LLVRGRTLVV, which is probably located in a strand-turn strand structure, has been identified as a protein destruction signal in the rapidly degraded encephalomyocarditis virus 3C protease. Mutations within this sequence reduced the susceptibility of the 3C protease toward ubiquitination and degradation in rabbit reticulocyte lysate. This signal is transferable, since poliovirus 3C protease, which is a poor ubiquitin-mediated proteolytic system substrate, was found to be ubiquitinated and degraded when the signal sequence was either generated at an internal location in the protein or fused to the N terminus. An evaluation of the behavior of 3C protease proteins containing mutations in the signal region indicates that considerable variability in the primary structure is tolerated, although the conservation of certain features appears to be required for signal function. Two E3 ubiquitin-protein ligases that recognize the encephalomyocarditis virus 3C protease as a substrate were also partially purified. One of these was identified as the previously described E3alpha, and this was shown to require the destruction signal sequence to catalyze efficiently the ubiquitination of the 3C protease. The other is a Ubc5 dependent E3 that appears to recognize a different, unidentified feature of the 3C protease. PMID- 10092684 TI - Vascularity in asthmatic airways: relation to inhaled steroid dose. PMID- 10092685 TI - Sex differences and sleep apnoea. PMID- 10092686 TI - Pulmonary and critical care medicine: a peculiarly American hybrid? PMID- 10092687 TI - EUROSCOP, ISOLDE and the Copenhagen city lung study. PMID- 10092688 TI - Vascularity in asthmatic airways: relation to inhaled steroid dose. AB - BACKGROUND: There is an increase in vascularity in the asthmatic airway. Although inhaled corticosteroids (ICS) are an effective anti-inflammatory treatment in asthma, there are few data on any effects on structural changes. METHODS: Endobronchial biopsy specimens from seven asthmatic subjects not receiving ICS and 15 receiving 200-1500 microg/day beclomethasone dipropionate (BDP) were immunohistochemically stained with an anti-collagen type IV antibody to outline the endothelial basement membrane of the vessels. These were compared with biopsy tissue from 11 non-asthmatic controls (four atopic and seven non-atopic). RESULTS: There was a significant increase in the density of vessels (number of vessels/mm2 of lamina propria) in the asthmatic subjects not on ICS compared with non-asthmatic controls (mean 485 (interquartile range (IQR) 390-597) versus 329 (IQR 248-376) vessels/mm2, p<0.05; 95% CI for the difference 48 to 286). There was no significant difference between asthmatic subjects on ICS and those not on ICS or control subjects in the number of vessels/mm2 (mean 421 (IQR 281-534)). However, patients who received >/=800 microg/day BDP tended to have a reduced number of vessels/mm2 compared with patients not on ICS and those receiving /=45 years from the same cohort. RESULTS: Deaths from asthma were associated with a history of clinically severe asthma (OR 6.29 (95% CI 1.84 to 21.52)), chest pain (OR 3.78 (95% CI 1.06 to 13.5)), biochemical or haematological abnormalities at admission (OR 4.12 (95% CI 1.36 to 12.49)), prescription of ipratropium bromide (OR 4.04 (95% CI 1.47 to 11.13)), and failure to prescribe inhaled steroids on discharge (OR 3.45 (95% CI 1.35 to 9.10)). Deaths from chronic obstructive pulmonary disease (COPD) were associated with lower peak expiratory flow rates (OR 2.56 (95% CI 1.52 to 4.35) for each 50 l/min change), a history of smoking (OR 5.03 (95% CI 1.17 to 21.58)), prescription of ipratropium bromide (OR 7.75 (95% CI 2.21 to 27.14)), and failure to prescribe inhaled steroids on discharge (OR 3.33 (95% CI 0.95 to 11.10)). Cardiovascular deaths were more common among those prescribed ipratropium bromide on discharge (OR 3.55 (95% CI 1.05 to 11.94)) and less likely in those admitted after an upper respiratory tract infection (OR 0.21 (95% CI 0.05 to 0.95)). Treatment with ipratropium bromide at discharge was associated with an increased risk of death from asthma even after adjusting for peak flow, COPD and cardiovascular co morbidity, ever having smoked, and age at onset of asthma. CONCLUSIONS: Prescription of inhaled steroids on discharge is important even for those patients with co-existent COPD and asthma. Treatment with ipratropium at discharge is associated with increased risk of death from asthma even after adjustment for a range of markers of COPD. These results need to be tested in larger studies. PMID- 10092691 TI - Early use of inhaled nedocromil sodium in children following an acute episode of asthma. AB - BACKGROUND: Current guidelines on the treatment of childhood asthma recommend the introduction of an anti-inflammatory drug in children who have persistent symptoms and require regular treatment with a bronchodilator. The efficacy and safety of inhaled nedocromil sodium (Tilade Mint aerosol) administered using a Fisonair spacer at a dose of 4 mg three times daily was compared with placebo in the treatment of asthmatic children aged 6-12 years who are symptomatic and recovering from an acute exacerbation of asthma. METHODS: A group comparative, double blind, placebo controlled trial was performed in children who were recovering from an acute episode of asthma following treatment in the emergency department of the hospital or in children referred from their general practitioner following a wheezing episode and documented evidence of at least two previous episodes of wheezing. A two week baseline period on existing bronchodilator treatment was followed by a 12 week treatment period on either nedocromil sodium (2 mg/puff) or placebo. Both treatments were administered using a Fisonair spacer at a dose of two puffs three times daily. Changes from baseline values in daytime asthma and night time asthma symptom scores, usage of rescue bronchodilators, mean peak expiratory flow (PEF) recorded twice daily on diary cards, patients' opinion of treatment, and withdrawals due to treatment failure were measured during the primary treatment period (last six weeks of treatment). RESULTS: One hundred and forty two children aged 6-12 years entered the baseline period. Sixty three were withdrawn due to failure to meet the entry criteria (18) or the criteria for asthma symptom severity (15) or reversibility (9), because they developed uncontrolled asthma (2), because they took disallowed treatment (2), or for other non-trial related reasons (17). Seventy nine patients (46 boys) of mean age 8. 8 years entered the treatment period. There were significant differences in the changes from baseline values during the last six weeks of treatment in favour of nedocromil sodium compared with placebo in the primary variables of daytime asthma and night time asthma, morning and evening PEF, and the usage of rescue inhaled bronchodilators; 53% of patients reported nedocromil sodium to be very or moderately effective compared with 44% placebo. Improvement in asthma symptoms, PEF, and reduction in use of rescue bronchodilators did not reach statistical significance until after six weeks of treatment. Twenty two patients were withdrawn or dropped out during the treatment phase, 12 due to uncontrolled asthma or persistence of asthma symptoms, four due to suspected adverse drug reactions (nedocromil sodium 3 (headaches 2, angio-oedema/urticaria 1), placebo 1(persistent cough)), and six due to non-treatment related reasons. Seventy one adverse events were reported by 27 patients in the nedocromil group and 75 by 30 patients in the placebo group. CONCLUSIONS: Asthma symptoms, use of bronchodilators, and lung function can be improved significantly in children recovering from an acute exacerbation of asthma or wheeze and currently receiving treatment with bronchodilators alone by the addition of inhaled nedocromil sodium at a dose of 4 mg three times daily administered using a Fisonair holding chamber. PMID- 10092692 TI - Effect of inhaled corticosteroids on bronchial responsiveness in patients with "corticosteroid naive" mild asthma: a meta-analysis. AB - BACKGROUND: Inhaled corticosteroids are the most efficacious anti-inflammatory drugs in asthma. International guidelines also advocate the early introduction of inhaled corticosteroids in corticosteroid naive patients. A study was undertaken to assess the effects of inhaled corticosteroids on bronchial hyperresponsiveness in patients with corticosteroid naive asthma by conventional meta-analysis. METHODS: A Medline search of papers published between January 1966 and June 1998 was performed and 11 papers were selected in which the patients had no history of treatment with inhaled or oral corticosteroids. Bronchial responsiveness to bronchoconstricting agents was considered as the main outcome parameter. Doubling doses (DD) of histamine or methacholine were calculated. RESULTS: The total effect size of inhaled corticosteroids (average daily dose 1000 microg) versus placebo in the 11 studies was +1.16 DD (95% confidence interval (CI) +0.76 to +1.57). When only the eight short term studies (2-8 weeks) were analysed the effect size of the bronchoconstricting agent was +0.91 DD (95% CI +0.65 to +1.16). No relationship was found between the dose of inhaled corticosteroid used and the effect on bronchial responsiveness. CONCLUSION: This meta-analysis in patients with corticosteroid naive asthma indicates that, on average, high doses of inhaled corticosteroids decrease bronchial hyperresponsiveness in 2-8 weeks. It remains unclear whether there is a dose-response relationship between inhaled corticosteroids and effect on bronchial hyperresponsiveness. PMID- 10092693 TI - Neck soft tissue and fat distribution: comparison between normal men and women by magnetic resonance imaging. AB - BACKGROUND: Obesity and increased neck circumference are risk factors for the obstructive sleep apnoea/hypopnoea syndrome (SAHS). SAHS is more common in men than in women, despite the fact that women have higher rates of obesity and greater overall body fat. One factor in this apparently paradoxical sex distribution may be the differing patterns of fat deposition adjacent to the upper airway in men and women. A study was therefore undertaken to compare neck fat deposition in normal men and women. METHODS: Using T1 weighted magnetic resonance imaging, the fat and tissue volumes in the necks of 10 non-obese men and 10 women matched for age (men mean (SE) 36 (3) years, women 37 (3) years, p = 0.7), body mass index (both 25 (0. 6) kg/m2, p>0.9), and Epworth Sleepiness Score (both 5 (1), p = 0.9) were assessed; all denied symptoms of SAHS. RESULTS: Total neck soft tissue volume was greater in men (1295 (62) vs 928 (45) cm3, p<0. 001), but the volume of fat did not differ between the sexes (291 (29) vs 273 (18) cm3, p = 0.6). The only regions impinging on the pharynx which showed a larger absolute volume of fat in men (3.2 (0. 7) vs 1.1 (0.3) cm3, p = 0.01) and also a greater proportion of neck fat in men (1.3 (0.3)% vs 0.4 (0.1)%, p = 0.03) were the anterior segments inside the mandible at the palatal level. CONCLUSIONS: There are differences in neck fat deposition between the sexes which, together with the greater overall soft tissue loading on the airway in men, may be factors in the sex distribution of SAHS. PMID- 10092694 TI - Comparison of two new methods for the measurement of lung volumes with two standard methods. AB - BACKGROUND: The two most commonly used methods for the measurement of lung volumes are helium dilution and body plethysmography. Two methods have been developed which are both easier and less time consuming to perform. Mathematical modelling uses complex calculations from the flow-volume loop to derive total lung capacity (TLC), and the nitrogen balance technique uses nitrogen from the atmosphere to calculate lung volume in a similar way to helium dilution. This study was designed to compare the two new methods with the two standard methods. METHODS: Sixty one subjects were studied, 23 with normal lung function, 17 with restrictive airway disease, and 21 with obstructive ventilatory defects. Each subject underwent repeated measurements of TLC by each of the four methods in random order. Reproducible values were obtained for each method according to BTS/ARTP guidelines. Bland-Altman plots were constructed for comparisons between the methods and paired t tests were used to assess differences in means. RESULTS: Bland-Altman plots showed that the differences between body plethysmography and helium dilution fell into clinically acceptable ranges (agreement limits +/-0.9 l). The agreement between mathematical modelling or the nitrogen balance technique and helium dilution or body plethysmography was poor (+/-1.8-3.4 l), especially for subjects with airflow obstruction. CONCLUSIONS: Neither of the new methods agrees sufficiently with standard methods to be useful in a clinical setting. PMID- 10092695 TI - Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer. AB - BACKGROUND: Resection is the treatment of choice for lung cancer, but may cause impaired cardiopulmonary function with an adverse effect on quality of life. Few studies have considered the effects of thoracotomy alone on lung function, and whether the operation itself can impair subsequent exercise capacity. METHODS: Patients being considered for lung resection (n = 106) underwent full static and dynamic pulmonary function testing which was repeated 3-6 months after surgery (n = 53). RESULTS: Thoracotomy alone (n = 13) produced a reduction in forced expiratory volume in one second (FEV1; mean (SE) 2.10 (0.16) versus 1.87 (0.15) l; p<0.05). Wedge resection (n = 13) produced a non-significant reduction in total lung capacity (TLC) only. Lobectomy (n = 14) reduced forced vital capacity (FVC), TLC, and carbon monoxide transfer factor but exercise capacity was unchanged. Only pneumonectomy (n = 13) reduced exercise capacity by 28% (PVO2 23.9 (1.5) versus 17.2 (1.7) ml/min/kg; difference (95% CI) 6.72 (3.15 to 10.28); p<0.01) and three patients changed from a cardiac limitation to exercise before pneumonectomy to pulmonary limitation afterwards. CONCLUSIONS: Neither thoracotomy alone nor limited lung resection has a significant effect on exercise capacity. Only pneumonectomy is associated with impaired exercise performance, and then perhaps not as much as might be expected. PMID- 10092696 TI - Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis. AB - BACKGROUND: The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. To gain a better understanding of this process the expression by these cells of cell surface activation markers, co stimulatory molecules, and adhesion molecules was analysed. METHODS: CD4+ and CD8+ T lymphocytes from peripheral blood (PBL) or bronchoalveolar lavage (BAL) fluid, as well as paired peripheral blood monocytes and alveolar macrophages from 27 patients with sarcoidosis were analysed by flow cytometry. RESULTS: CD26, CD54, CD69, CD95, and gp240 were all overexpressed in T cells from BAL fluid compared with those from PBL in both the CD4+ and CD8+ subsets, while CD57 was overexpressed only in BAL CD4+ cells. In contrast, CD28 tended to be underexpressed in the BAL T cells. Monocyte/macrophage markers included CD11a, CD11b, CD11c, CD14, CD16, CD54, CD71, CD80 and CD86 and HLA class II. CD11a expression in alveolar macrophages (and peripheral blood monocytes) was increased in patients with active disease and correlated positively with the percentage of BAL lymphocytes. Expression of CD80 in macrophages correlated with the BAL CD4/CD8 ratio. CONCLUSIONS: Our data indicate substantial activation of both CD4+ and CD8+ lung T cells in sarcoidosis. There were also increased numbers of BAL lymphocytes whose phenotypic characteristics have earlier been associated with clonally expanded, replicatively senescent cells of the Th1 type. PMID- 10092697 TI - Silica dust and lung cancer in the German stone, quarrying, and ceramics industries: results of a case-control study. AB - BACKGROUND: A work force based case-control study of lung cancer was performed in non-silicotic subjects exposed to crystalline silica to investigate the association between silica dust and lung cancer excluding the influence of silicosis. METHODS: Two hundred and forty seven patients with lung cancer and 795 control subjects were enrolled, all of whom had been employed in the German stone, quarrying, or ceramics industries. Smoking was used as a matching criterion. Exposure to silica was quantified by measurements, if available, or otherwise by industrial hygienists. Several indices (peak, average and cumulative exposure) were used to analyse the relationship between the level of exposure and risk of lung cancer as odds ratios (OR). RESULTS: The risk of lung cancer is associated with the year of and age at first exposure to silica, duration of exposure, and latency. All odds ratios were adjusted for these factors. Considering the peak exposure, the OR for workers exposed to high levels (>/=0.15 mg/m3 respirable silica dust which is the current occupational threshold value for Germany) compared with those exposed to low levels (<0.15 mg/m3) was 0.85 (95% CI 0.58 to 1. 25). For the time weighted average exposure the OR was 0.91 (95% CI 0.57 to 1.46). The OR for the cumulative exposure was 1.02 (95% CI 0. 67 to 1.55). No increase in risk was evident with increasing exposure. CONCLUSIONS: This study shows no association between exposure to crystalline silica and lung cancer. The exclusion of subjects with silicosis may have led to dilution with respect to the level of exposure and therefore reduced the power to detect a small risk. Alternatively, the risk of getting lung cancer may be restricted to subjects with silicosis and is not directly linked to silica dust. PMID- 10092698 TI - Pseudo-steroid resistant asthma. AB - BACKGROUND: Steroid resistant asthma (SRA) represents a small subgroup of those patients who have asthma and who are difficult to manage. Two patients with apparent SRA are described, and 12 additional cases who were admitted to the same hospital are reviewed. METHODS: The subjects were selected from a tertiary hospital setting by review of all asthma patients admitted over a two year period. Subjects were defined as those who failed to respond to high doses of bronchodilators and oral glucocorticosteroids, as judged by subjective assessment, audible wheeze on examination, and serial peak flow measurements. RESULTS: In 11 of the 14 patients identified there was little to substantiate the diagnosis of severe or steroid resistant asthma apart from symptoms and upper respiratory wheeze. Useful tests to differentiate this group of patients from those with severe asthma appear to be: the inability to perform reproducible forced expiratory manoeuvres, normal airway resistance, and a concentration of histamine causing a 20% fall in the forced expiratory volume (FEV1) being within the range for normal subjects (PC20). Of the 14 subjects, four were health care staff and two reported childhood sexual abuse. CONCLUSION: Such patients are important to identify as they require supportive treatment which should not consist of high doses of glucocorticosteroids and beta2 adrenergic agonists. Diagnoses other than asthma, such as gastro-oesophageal reflux, hyperventilation, vocal cord dysfunction and sleep apnoea, should be sought as these may be a cause of glucocorticosteroid treatment failure and pseudo-SRA, and may respond to alternative treatment. PMID- 10092699 TI - Health effects of passive smoking-10: Summary of effects of parental smoking on the respiratory health of children and implications for research. AB - BACKGROUND: Two recent reviews have assessed the effect of parental smoking on respiratory disease in children. METHODS: The results of the systematic quantitative review published as a series in Thorax are summarised and brought up to date by considering papers appearing on Embase or Medline up to June 1998. The findings are compared with those of the review published recently by the Californian Environmental Protection Agency (EPA). Areas requiring further research are identified. RESULTS: Overall there is a very consistent picture with odds ratios for respiratory illnesses and symptoms and middle ear disease of between 1.2 and 1.6 for either parent smoking, the odds usually being higher in pre-school than in school aged children. For sudden infant death syndrome the odds ratio for maternal smoking is about 2. Significant effects from paternal smoking suggest a role for postnatal exposure to environmental tobacco smoke. Recent publications do not lead us to alter the conclusions of our earlier reviews. While essentially narrative rather than systematic and quantitative, the findings of the Californian EPA review are broadly similar. In addition they have reviewed studies of the effects of environmental tobacco smoke on children with cystic fibrosis and conclude from the limited evidence that there is a strong case for a relationship between parental smoking and admissions to hospital. They also review data from adults of the effects of acute exposure to environmental tobacco smoke under laboratory conditions which suggest acute effects on spirometric parameters rather than on bronchial hyperresponsiveness. It seems likely that such effects are also present in children. CONCLUSIONS: Substantial benefits to children would arise if parents stopped smoking after birth, even if the mother smoked during pregnancy. Policies need to be developed which reduce smoking amongst parents and protect infants and young children from exposure to environmental tobacco smoke. The weight of evidence is such that new prevalence studies are no longer justified. What are needed are studies which allow comparison of the effects of critical periods of exposure to cigarette smoke, particularly in utero, early infancy, and later childhood. Where longitudinal studies are carried out they should be analysed to look at the way in which changes in exposure are related to changes in outcome. Better still would be studies demonstrating reversibility of adverse effects, especially in asthmatic subjects or children with cystic fibrosis. PMID- 10092701 TI - Effective immunosuppressive therapy in a patient with primary pulmonary hypertension. AB - The case history is described of a young woman who presented with primary pulmonary hypertension and non-specific inflammatory signs. The patient received prolonged immunosuppressive treatment with low dose methotrexate and prednisone without any vasodilator agent. After one year the pulmonary artery pressure fell from a mean value of 47 mm Hg to 30 mm Hg and there was a corresponding clinical response. This case suggests that, in patients with pulmonary hypertension of unknown origin, immunopathogenetic factors should be sought in order to consider the utility of immunosuppressive therapy. PMID- 10092700 TI - Ethical and clinical issues in the use of home non-invasive mechanical ventilation for the palliation of breathlessness in motor neurone disease. PMID- 10092702 TI - Lecture notes on respiratory medicine. 5th edition PMID- 10092703 TI - Introduction PMID- 10092704 TI - Radiation therapy for benign central nervous system disease. AB - The most common indication for the use of radiation therapy in the treatment of benign central nervous system disease is for the treatment of benign brain tumors, such as meningioma, pituitary adenoma, acoustic neuroma, arteriovenous malformation, and craniopharyngioma. Other less common benign intracranial tumors treated with radiation include chordoma, pilocytic astrocytoma, pineocytoma, choroid-plexus papilloma, hemangioblastoma, and temporal bone chemodectomas. Benign conditions, such as histiocytosis X, trigeminal neuralgia, and epilepsy, are also amenable to radiation treatment. There have also been reports of radiosurgery being used for the treatment of movement disorders and psychiatric disturbances, such as obsessive-compulsive and anxiety disorders. For benign brain tumors, radiation therapy as either primary or adjuvant therapy plays an integral role in improving local control. In the treatment of trigeminal neuralgia, epilepsy, tremor, and some psychiatric disturbances, radiosurgery may help ameliorate or eliminate some symptoms. Patients with benign central nervous system disease are expected to live a long time. As such, treatment should be highly conformal and based on three-dimensional planning using magnetic resonance imaging, computed tomography, or both. It is critical that damage to normal brain be minimized. PMID- 10092705 TI - Radiation therapy to prevent coronary artery restenosis. AB - The problem of restenosis after coronary angioplasty remains a major limiting factor of the procedure. Intracoronary stenting has led to a modest reduction in the frequency of this event. In the early 1990s, the effectiveness of ionizing radiation combined with balloon angioplasty and stenting was first convincingly demonstrated in animal models of restenosis. Small feasibility studies and two randomized trials have, in general, supported the promise of these initial preclinical studies in the prevention of restenosis. Much remains to be learned about the application of radiation for this therapy. This article reviews the current status of preclinical and clinical investigation of this therapy. PMID- 10092706 TI - Radiation therapy to prevent stenosis of peripheral vascular accesses. AB - Postangioplasty vascular restenosis is a major clinical problem. There has been an upsurge in interest in the use of postangioplasty endovascular brachytherapy in preventing vascular restenosis. Much of the work in this field is being driven by the interventional cardiology community, and there has been a tendency to use a one-size-fits-all approach. This article reviews the application of vascular radiation therapy to prevent postangioplasty dialysis access restenosis. We identify the key features of dialysis accesses that distinguish them from other clinical situations of postangioplasty restenosis. The implications for interventional radiation therapy in this setting are discussed at length, including the need for a centering device, the issues involved in isotope selection, and the advantages offered by external-beam radiation therapy. PMID- 10092707 TI - Radiation therapy for age-related macular degeneration. AB - Neovascular age-related macular degeneration is the most common cause of severe irreversible blindness in the Western world in people older than age 50. Laser photocoagulation is the only proven treatment for this disease; however, fewer than 20% of patients are eligible for this treatment because the majority of choroidal neovascularization membranes are not visible by ophthalmoscopy or angiography. In addition, many patients elect not to undergo this treatment because laser treatment of subfoveal neovascular membranes results in immediate and permanent central visual loss. Several treatments are under investigation, including external-beam radiation therapy. There are multiple publications of early trials using radiation therapy, but to date there is only one randomized published study. This article reviews these trials and summarizes the status of radiation therapy as a treatment for macular degeneration. PMID- 10092708 TI - Radiation therapy for heterotopic ossification. AB - Heterotopic ossification is a common complication after bone and joint surgery. If the disease progresses, it may cause pain and disability, eventually defeating the purpose of surgery in the first place. Today, prophylactic treatment is indicated after surgery. Both nonsteroidal antiinflammatory drugs and radiation therapy are effective. Radiation therapy is associated with fewer side effects and is preferred. Single-dose postoperative irradiation has been found to be as effective as fractionated radiation therapy. PMID- 10092709 TI - Radiation treatment of benign mesenchymal disease. AB - The benign mesenchymal diseases, for which radiation is often quite effective in halting progression or achieving complete and permanent resolution, include neoplastic and nonneoplastic processes (eg, giant cell tumor of bone to keloid). Radiation oncologists have been reluctant to employ radiation in the management of patients with benign disease for several reasons: (1) the small but nonzero risk of late appearance of radiation-induced malignant tumors; (2) were radiation subsequently required to be employed in the same region of the body for treatment of a separate and independent neoplasm, the radiation dose might have to be reduced to an ineffective level; and (3) nonmalignant tissue changes that might appear at quite remote times and complicate healing of surgical wounds. Currently a liberalization of the use of radiation is in progress because of the clinical seriousness of many benign processes for which radiation yields a major therapeutic benefit. This reassessment of radiation oncology in the United States has been stimulated by the much wider application of radiation for patients with a wide spectrum of benign diseases in several European countries. This article considers the major indications and the expected outcomes from radiation treatment of benign mesenchymal diseases. For benign neoplasms that are locally progressive, the radiation dose is usually in the range 50 to 60 Gy administered at 1.8 to 2.0 Gy/fraction, five fractions per week. The response is characteristically quite slow, and the long-term local control probability is high (80%). Further, the response probability is not sensitive to lesion size, in contrast to malignant tumors of the mesenchymal tissues. For the nonneoplastic processes managed in some instances by radiation, the doses recommended are usually in the range of 6 to 12 Gy as single-dose or 20 to 25 Gy as fractionated dose irradiation. The efficacy of such treatment tends to be equal to or less than that noted for the benign neoplastic diseases. PMID- 10092710 TI - Radiation therapy for benign disease of the orbit. AB - Benign diseases of the orbit can cause significant impairment of visual function through direct effects on the eye or supporting orbital tissues. Persistent moderate-to-severe inflammatory symptoms, diplopia, and visual loss may prompt therapeutic intervention. Low doses of external-beam irradiation (20 Gy in 2-Gy fractions) have an efficacy equivalent to corticosteroid medications in the treatment of both Graves' ophthalmopathy and orbital pseudotumor, with response rates of 50% to 80%. Appropriate patient selection, coordination with other medical subspecialties, and careful treatment planning are important in maximizing benefit from radiation therapy. In the case of Graves' ophthalmopathy, quantitative assessment of orbital disease severity and thyroid status as well as attainment of cross-sectional imaging should be performed before treatment. Patients whose thyroid disease is controlled but who have moderate-to-severe active orbital involvement can be offered orbital radiation therapy with a high likelihood of response. Stability of disease is generally obtained within 6 months; surgical correction of residual abnormalities may be required. For orbital pseudotumor, attainment of histological material before treatment is important in excluding benign or malignant systemic diseases, including malignant lymphoma. Genotypic abnormalities may exist in patients with reactive lymphoid hyperplasia, some of whom ultimately develop systemic lymphoma. Within the dose range recommended for treatment of Graves' ophthalmopathy and pseudotumor, late radiation effects on the retina or optic nerve should be nonexistent. Adequate lens shielding is required, however, to prevent cataract formation. This may require individualized treatment planning with computed tomography at the time of simulation. Pterygia recurrence after bare sclera excision occurs in at least 30% of cases, usually within 6 months of surgery. Radiation of the surgical bed using a strontium-90 source, beginning within 24 hours postoperatively, reduces the risk of recurrence substantially. Late scleral complications have been associated with large single-fraction treatments. To achieve maximal efficacy with minimal complications, fractionated treatment should be given by radiation oncologists experienced with the technique using sources calibrated by the National Bureau of Standards. PMID- 10092711 TI - Endovascular brachytherapy for peripheral vascular disease. AB - The most common cause of morbidity and mortality in the United States is vascular disease, which afflicts a wide spectrum of organs such as the heart (cardiovascular system), brain (cerebrovascular system), kidney (renal system), liver (hepatic system), and extremities (peripheral vascular system). The most common pathology of vascular diseases is occlusion. Percutaneous Transluminal Angioplasty (PTA) is currently the most common nonsurgical treatment for obstructive arteries. Unfortunately, the long-term effectiveness of PTA is limited by a high restenosis rate. Efforts to reduce post-PTA restenosis, including laser, mechanical atherectomy, intravascular stenting, and pharmacologic agents, have not been successful. With recent advances in the pathogenesis of restenosis, we have learned that the major problem is the intimal hyperplastic reaction in response to vessel injury. Encouraging animal data in the use of various radiotherapeutic approaches to prevent restenosis has led to a large number of multi-national, multicenter, randomized trials on coronary vascular systems. Because early results have been in favor of radiation therapy, and because the basic process of restenosis is similar for coronary and noncoronary vascular systems, many investigators extend the application of radiotherapy to the prevention of restenosis in peripheral vascular systems. However, the clinical scenarios are much different for peripheral vascular systems than for the coronary vascular system. This article discusses the current views of the pathophysiology of restenosis, major clinical trials, and perspectives on future studies. Experimental studies on animal models have documented the profound effects of endovascular brachytherapy in reducing restenosis caused by angioplasty and stenting. Early results of clinical trials are encouraging and confirm these positive results. Long-term follow-up data are needed to show that radiation does prevent, not merely delay, restenosis; Several areas of opportunity exist for both basic science research and clinical studies to enhance our knowledge of the pathophysiology. This would optimize the treatment strategy, maximizing the benefits and minimizing late complications. PMID- 10092712 TI - The molecular and cellular biologic basis for the radiation treatment of benign proliferative diseases. AB - Since its discovery, radiation has been used to treat numerous ailments, including many benign conditions. The most susceptible disorders have included keloids, heterotopic bone formation, and, most recently, vascular restenosis. These disorders are proliferative in nature and fall under the category of excessive wound healing or scar formation after trauma. In addition, radiation has been used for its immunosuppressive quality, eg, in organ transplantation to suppress graft rejection and in the treatment of autoimmune diseases. In this article, we have chosen keloids as an archetype for radiation use with benign conditions; the radiation inhibition of vascular restenosis will be used as a prototype to explore a paradigm for the molecular and cellular basis of radiation treatment for selected benign disorders. Vascular restenosis is currently one of the new frontiers of radiation therapy and offers opportunities to explore the role of inflammatory or immune cell responses in benign conditions that lead to excessive fibrogenesis and require treatment. The pathophysiology of surgical wound healing has not been avidly studied in the radiobiologic laboratory setting. However, the paradigm we propose for the effectiveness of radiation treatment for benign conditions is based on the model offered by Clark. He describes three phases of molecular and cellular events in which an inflammatory phase precedes the fibrogenic phase, occurs within hours of injury, and continues for weeks. We postulate that the radiosensitive targets within the vascular milieu are the monocyte/macrophages that would otherwise act as the trigger for the induced cytokine cascade, leading to the myofibroblast being recruited from a quiescent to a proliferative phase, resulting in fibrogenesis. PMID- 10092713 TI - Cincinnati Prehospital Stroke Scale: reproducibility and validity. AB - STUDY OBJECTIVE: The Cincinnati Prehospital Stroke Scale (CPSS) is a 3-item scale based on a simplification of the National Institutes of Health (NIH) Stroke Scale. When performed by a physician, it has a high sensitivity and specificity in identifying patients with stroke who are candidates for thrombolysis. The objective of this study was to validate and verify the reproducibility of the CPSS when used by prehospital providers. METHODS: The CPSS was performed and scored by a physician certified in the use of the NIH Stroke Scale (gold standard). Simultaneously, a group of 4 paramedics and EMTs scored the same patient. RESULTS: A total of 860 scales were completed on a convenience sample of 171 patients from the emergency department and neurology inpatient service. Of these patients, 49 had a diagnosis of stroke or transient ischemic attack. High reproducibility was observed among prehospital providers for total score (intraclass correlation coefficient [rI],.89; 95% confidence interval [CI],.87 to.92) and for each scale item: arm weakness, speech, and facial droop (.91,.84, and.75, respectively). There was excellent intraclass correlation between the physician and the prehospital providers for total score (rI,.92; 95% CI,.89 to.93) and for the specific items of the scale (.91,.87, and.78, respectively). Observation by the physician of an abnormality in any 1 of the 3 stroke scale items had a sensitivity of 66% and specificity of 87% in identifying a stroke patient. The sensitivity was 88% for identification of patients with anterior circulation strokes. CONCLUSION: The CPSS has excellent reproducibility among prehospital personnel and physicians. It has good validity in identifying patients with stroke who are candidates for thrombolytic therapy, especially those with anterior circulation stroke. PMID- 10092714 TI - Cardioversion of paroxysmal atrial fibrillation in the emergency department. AB - STUDY OBJECTIVE: Patients presenting to the emergency department with acute atrial fibrillation are traditionally admitted to hospital. The objective of this study was to review the success and safety of ED cardioversion and discharge of patients with acute atrial fibrillation. METHODS: This health records survey included a cohort sample of consecutive patients presenting with acute atrial fibrillation to the ED of a university-affiliated tertiary hospital. Patients who were in unstable condition on presentation, who had a complicating cardiac diagnosis, or those with other medical or surgical conditions requiring admission were excluded from the study analysis. Patient visit information was entered into a database that included demographics and clinical presentation, investigations, ED therapy, complications, consultations, disposition, and follow up. Patient visits were then categorized into the following groups: no ED intervention, spontaneous resolution, heart rate control, attempted chemical cardioversion, or electrical cardioversion. The data were analyzed using descriptive methods. RESULTS: Of the 289 eligible patients seen during an 18-month period, 62% (180) underwent attempted chemical cardioversion with a 50% success rate and 28% (80) had attempted electrical cardioversion with a 89% success rate. Ninety-three percent of electrical cardioversions were performed by emergency physicians. There was an overall 6% (19) complication rate, 95% of which were regarded as minor. One patient had a complication caused by a rate control medication, which necessitated hospital admission. Ninety-seven percent (280) of the patients were discharged home directly from the ED. CONCLUSION: Cardioversion and immediate discharge of patients who present to the ED with acute atrial fibrillation appears to be both safe and effective. This management approach should be prospectively evaluated in multiple settings. PMID- 10092715 TI - Pediatric telephone triage protocols: standardized decisionmaking or a false sense of security? AB - STUDY OBJECTIVE: To determine whether implementation of a set of standardized pediatric telephone triage protocols results in consistent triage dispositions when applied by different operators. METHODS: A descriptive study with interrater comparisons was performed. Telephone interviews simulated the setting of a triage station in a university hospital-based pediatric emergency department. A mock parent presented 15 standardized respiratory cases in random order to 12 pediatric ED nurses. Nurses assigned patients' complaints to severity categories using 9 respiratory complaint protocols extracted from a commercially available pediatric telephone triage tool. Protocol selection and severity endpoints were recorded. Interobserver agreement among nurses was analyzed by the kappa statistic. Comparisons of operator characteristics and triage results were carried out by ANOVA. RESULTS: Interrater agreement in triage disposition among nurses was poor (kappa,.11; 95% confidence interval,.02 to.20). Protocol selection varied; the group used a mean of 3 different disposition-generating protocols per case. Disposition also varied, with up to 4 different severity endpoints per protocol in a given case. A post-hoc comparison of the mean disposition severity between nurses did not reach significance at an adjusted level (P =.04). Fifty-eight percent of the nurses felt confined by the protocols, and 42% admitted to at least 1 intentional deviation from them. CONCLUSION: It may not simply be assumed that the use of protocols will standardize care. This is particularly important in the case of triage, with current trends toward medical decisionmaking by less skilled providers with diminishing patient contact. Although triage protocols may be useful to guide clinical thinking, their consistency must be validated before they may be safely disseminated for general use. PMID- 10092716 TI - A randomized clinical trial of dermal anesthesia by iontophoresis for peripheral intravenous catheter placement in children. AB - STUDY OBJECTIVE: To assess the efficacy of dermal anesthesia by lidocaine iontophoresis in children undergoing peripheral intravenous (PIV) catheter placement in the emergency department. METHODS: A double-blind, randomized, clinical trial was conducted at a tertiary children's hospital ED. Alert children 7 years or older requiring nonemergency PIV were eligible. Patients in the lidocaine group received 1 mL of 2% lidocaine with 1:100,000 epinephrine over a potential PIV site by iontophoresis. The control group received 1 mL of.9% saline solution with 1:100,000 epinephrine. After PIV placement, patients ranked the procedural pain using a visual analog scale. Complications were noted by visual inspection or telephone follow-up. RESULTS: During a 6-month period, 22 patients were assigned to the lidocaine group and 25 to the control group. There was no significant difference in age, sex, or ethnic background between the 2 study groups, and mean application time was 12.0 minutes. The median pain score was.5 in the lidocaine group compared with 4 in the control group (P =.0002; 95% confidence interval [CI] 1 to 5). No significant immediate or delayed complications were observed. CONCLUSION: Lidocaine iontophoresis provides effective dermal anesthesia for children older than 7 years of undergoing nonemergency PIV placement in the ED. PMID- 10092717 TI - Effect of magnesium hydroxide administration on iron absorption after a supratherapeutic dose of ferrous sulfate in human volunteers: a randomized controlled trial. AB - STUDY OBJECTIVE: Animal models have demonstrated that administration of magnesium hydroxide (MgOH) decreases serum iron levels after an iron overdose. We designed this study to determine the effect of MgOH administration on iron absorption and adverse effects after a supratherapeutic dose of ferrous sulfate in healthy male volunteers. METHODS: We conducted a prospective, unblinded, randomized trial involving 16 healthy, fasting men. All subjects ingested a 10-mg/kg dose of elemental iron in the form of ferrous sulfate. One-half hour after the iron dose, the 8 subjects in the experimental group were given 5 mg of MgOH for every 1 mg of ingested elemental iron. Serum iron levels were obtained at baseline and at each subsequent hour for 6 or 7 hours. Serum magnesium levels were obtained at baseline, after 3 hours, and after 6 hours. Side effects were recorded hourly. Serum iron levels between groups were compared by repeated-measures ANOVA and ANCOVA. The 95% confidence intervals (CIs) for the difference in serum iron levels between groups at each time point and for the difference in peak serum iron level between groups were calculated. RESULTS: Baseline mean serum iron levels did not differ between the 2 groups (P =.28). There were no statistical differences between groups (P =.20). Mean serum iron levels at each time point and peak serum iron levels did not differ significantly between groups. The mean peak serum iron level was 300.8 micrograms/dL in the control group and 272.5 micrograms/dL in the experimental group. CONCLUSION: Administration of MgOH does not affect iron absorption in humans after a supratherapeutic dose of iron when the ratio of MgOH to elemental iron is 5:1. PMID- 10092719 TI - Modeling the occurrence of cardiac arrest as a poisson process. AB - STUDY OBJECTIVE: A statistical model for the occurrence of cardiac arrest has not been described in the literature. Independent events occurring along the time axis may constitute a Poisson process, described by the Poisson and exponential probability distributions. This statistical model defines the probability distribution of events occurring within time intervals and enables construction of confidence intervals for the mean rate. Moreover, the probability that 2 or more events will occur close in time can be estimated from knowledge of the mean rate. We investigated whether the occurrence of cardiac arrests constitutes a Poisson process. METHODS: Time and date for cardiac arrests requiring CPR out of hospital (county population, 155,000) or in hospital (850 beds) during 5 years were analyzed. Goodness of fit was assessed by comparing the observed weekly counts of cardiac arrests and the observed time intervals between such events with the values predicted from the model. RESULTS: The Poisson parameter estimates (mean weekly rates) for out-of-hospital and in-hospital cardiac arrest were 2.02 and 1.09 events per week, respectively. There was close agreement between observed and predicted values, indicating an adequate model fit. CONCLUSION: Occurrence of cardiac arrest along the time axis constitutes a Poisson process and may be adequately modeled by the Poisson and exponential distributions. The model provides information about the nature of these events and allows for probability calculations based on the mean rate of events. Examples of such calculations are given. PMID- 10092718 TI - Heating oil company responses to inquiries concerning carbon monoxide toxicity. AB - STUDY OBJECTIVE: Carbon monoxide (CO) is the leading cause of poisoning fatalities in the United States. We conducted a survey to sample the quality of the information available to the public from Connecticut heating oil distributors regarding these risks. METHODS: An observational, cross-sectional telephone survey of oil distributors in Connecticut was conducted, using a scripted set of questions regarding CO poisoning risk from oil-burning furnaces. We first asked whether such a risk existed and then elicited explanations for confirmation or denial of that risk. We then inquired as to the proper response to a home CO detector alarm. Of 282 calls made, responses were obtained from 91 distributors. Reasons for lack of response included incorrect phone listings, duplicate listings, and unwillingness of the person answering to respond to the questions asked. RESULTS: Nearly one fourth of distributors responding (23%) denied any risk of CO poisoning from oil burners, 43% of these claiming that the odor would provide protective warning before toxic exposure; another 33% stated that CO is a risk only with gas heaters. Of the 77% who confirmed the possibility of CO toxicity, half (49%) minimized the risk, also invoking a "warning odor." In case of CO alarm, only 14% of responders recommended turning off the furnace until the source is found. Five percent did not recommend having ambient CO levels checked at the time of the alarm. CONCLUSION: Heating oil companies in Connecticut do not uniformly provide correct information regarding CO risks. In our survey a majority of distributors responding offered misplaced "reassurance." As such, they are a potential area for public health intervention and an untapped resource for educating the public on these risks. PMID- 10092720 TI - Use of a handheld, battery-operated chemistry analyzer for evaluation of heat related symptoms in the backcountry of Grand Canyon National Park: a brief report. AB - STUDY OBJECTIVES: To test the feasibility of using handheld, battery-operated chemical analyzers by EMS personnel in a wilderness environment to aid in the diagnosis and management of heat illness. METHODS: During the summer of 1996, 3 portable clinical analyzers (i-STAT Corp, Princeton, NJ) were kept at different locations along the main hiking trail into the Grand Canyon. An operational protocol was designed for field use, and Park Service EMS personnel used the instruments at their discretion, primarily to determine serum sodium concentration and identify cases of hyponatremia. Data were collected on all EMS encounters. This study reviews our experience with the instruments. RESULTS: The i-STAT analyzer was used for 64 patients in the backcountry; of these uses, at least 22 were in the field and the remainder in backcountry ranger stations. Eight error messages were recorded in 6 patients. Subsequently, all but 1 had a successful determination. Among patients evacuated for further evaluation and care, serum sodium values were highly consistent with later analysis using standard laboratory equipment. The instrument was used in 31 (48%) of 64 of patients evaluated and released for self-treatment and self-evacuation, and 31 (36%) of 87 of patients evacuated by EMS personnel from the canyon. Nine cases of hyponatremia were confirmed in the field, allowing appropriate intervention. CONCLUSION: Portable clinical analyzers can reliably be used in a hot wilderness environment. In our application, it allowed identification of exercise-associated hyponatremia, an important cause of serious heat illness during endurance exercise in a hot environment. The results helped make treatment and disposition decisions. PMID- 10092721 TI - Emergency medical services outcomes project I (EMSOP I): prioritizing conditions for outcomes research. AB - Over the past several years, out-of-hospital EMS have come under increased scrutiny regarding the value of the range of EMS as currently provided. We used frequency data and expert opinion to rank-order EMS conditions for children and adults based on their potential value for the study of effectiveness of EMS care. Relief of discomfort was the outcome parameter EMS professionals identified as having the most potential impact for the majority of children and adults in the top quartile conditions. Future work from this project will identify appropriate severity and outcome measures that can be used to study these priority conditions. The results from the first year of this project will assist those interested in EMS outcomes research to focus their efforts. Furthermore, the results suggest that nonmortality out-come measures, such as relief of discomfort, may be important parameters in determining EMS effectiveness. PMID- 10092722 TI - Number needed to treat (NNT). AB - Because decisions regarding therapy are so common in clinical practice, the application of number needed to treat (NNT) is one of the most important evidence based medicine skills to be acquired. NNT provides a clinically useful "yardstick" of the effort required to have a beneficial outcome or prevent a bad outcome with a therapy. A brief overview of the concept, derivation, and application of NNT is presented. PMID- 10092723 TI - Methodologic standards for the development of clinical decision rules in emergency medicine. AB - The purpose of this review is to present a guide to help readers critically appraise the methodologic quality of an article or articles describing a clinical decision rule. This guide will also be useful to clinical researchers who wish to answer 1 or more questions detailed in this article. We consider the 6 major stages in the development and testing of a new clinical decision rule and discuss a number of standards within each stage. We use examples from emergency medicine and, in particular, examples from our own research on clinical decisions rules for radiography in trauma. PMID- 10092724 TI - The Emergency Medicine Foundation: 25 years of advancing education and research. PMID- 10092725 TI - Early stroke diagnosis saves time. PMID- 10092726 TI - Early metabolic acidosis and coma after acetaminophen ingestion. AB - Metabolic acidosis and coma may develop in patients who experience severe hepatic injury after acetaminophen poisoning. The onset of acidosis and coma soon after acetaminophen overdose, but preceding manifest hepatic injury, contrasts with the typical course of poisoning. This pattern has been reported in a limited number of cases. Coingestions and the rare occurrence of these findings after an overdose have engendered controversy as to whether acetaminophen alone is the cause of early coma and acidosis. We describe 4 separate overdoses among 3 patients who arrived at the emergency department comatose with a metabolic acidosis soon after ingesting large amounts of acetaminophen without evidence of toxic liver injury. Our cases support the view that early metabolic acidosis with coma does indeed occur after acetaminophen poisoning, independent of hepatic failure or its complications. PMID- 10092727 TI - Serotonin syndrome in a child after a single dose of fluvoxamine. AB - Serotonin syndrome, a potentially fatal iatrogenic complication of psychopharmacologic therapy, is most commonly reported with combinations of serotonergic medications. Serotonin syndrome is characterized by alterations in cognition, behavior, autonomic, and central nervous system function as a result of increased postsynaptic serotonin receptor agonism. We present the first reported case of serotonin syndrome after a single dose of fluvoxamine in a pediatric patient after ingestion of a single supratherapeutic dose of fluvoxamine. PMID- 10092728 TI - Localized tetanus in a child. AB - The majority of physicians in practice today in developed countries have never seen a case of tetanus. The last pediatric case reported in Canada occurred in 1992. We present the case of a child who had localized tetanus despite previous partial immunization. PMID- 10092730 TI - National highway traffic safety administration (NHTSA) notes. PMID- 10092729 TI - Cultivating conscience: learning to make end-of-life decisions in the emergency department. PMID- 10092731 TI - Gone fishing. PMID- 10092732 TI - Cardiac troponin T as predictor of complications. PMID- 10092734 TI - gamma-Hydroxybutyrate intoxication and overdose. PMID- 10092736 TI - Emergency medicine in Namibia. PMID- 10092739 TI - Empiric chest radiographs in febrile children with leukocytosis. PMID- 10092740 TI - An evaluation of the incidence of work-related asthma in the United States. AB - The objective of the study was to estimate the incidences of physician-diagnosed cases of work-related asthma (WRA) in Michigan and the entire United States. The statewide surveillance system for WRA in Michigan receives reports primarily from three sources: physicians, hospital discharge data, and worker's compensation claims. Knowledge of the overlap in reports from these sources was used in conjunction with capture-recapture methods to estimate the total number of diagnosed cases of WRA, and incidence rates were calculated using the estimated number of civilian employees in Michigan as the population at risk. For the entire United States, the product of a national incidence rate for asthma among adults and estimates of the proportion that is work-related was used. A total of 933 cases of WRA were reported to the Michigan surveillance program during 1988 1995, of which 904 were reported by at least one of the three main sources and equaled an average incidence of 27 cases/10(6)/year. This estimate was less than the range of estimates 58 to 204 cases/10(6)/year in Michigan arrived at using the capture-recapture methods. The national estimates of WRA ranged from 63 to 441 cases/10(6)/year. The authors' indirect estimates are closer to estimates from Canada, Sweden, and Finland than most existing direct estimates in the United States, but probably still underestimates the magnitude of WRA incidence because of the limitations of physician recognition of the work-relatedness of asthma among adults. PMID- 10092741 TI - Back supports and back injuries: a second visit with the Home Depot cohort study data on low-back injuries. AB - The back support has been controversial as a means of reducing injuries to the lower back. Diverse issues bear on the interpretation of data obtained in a major epidemiologic investigation of the utility of back supports in the retail-trade home improvement industry. These concerns are focused on alternate explanations for the changes in injury rates observed over the six-year study period, on individual and group factors other than the use of the back support that might have contributed to reducing the risk of injury, and on related methodologic issues. Each issue is addressed with specific reference to how it might affect the analyses and the conclusion that the supports showed a protective effect. PMID- 10092742 TI - Particulate matter, sulfur dioxide, and pulmonary function in never-smoking adults in Chongqing, China. AB - Chongquing is one of the most polluted cities in China. To study the respiratory health effects of air pollution for this city, the authors monitored the ambient levels of particulate matter (PM2.5) and sulfur dioxide (SO2) in urban and suburban areas and performed pulmonary function testing on 1,075 adults 35 to 60 years of age who had never smoked and did not use coal stoves for cooking or heating. The mean concentration of SO2 in the urban areas (213 micrograms/m3) was twice as high as that in suburban areas (103 micrograms/m3). Mean PM2.5 levels were high in both urban (143 micrograms/m3) and suburban (139 micrograms/m3) areas. A generalized additive model was used to estimate the differences between the two areas in FEV1, FVC, and FEV1/FVC%, with adjustment for potential confounding factors, including sex, age, height, education, passive smoking, and occupational exposures to dust, gas, or fumes. Estimated differences in FEV1 between the urban and suburban areas were 199 mL (SE = 50 mL) for men and 87 mL (SE = 30 mL) for women, both statistically significant. When the men and women were pooled, the estimated difference in FEV1 was 126 mL (SE = 27 mL). Similar trends were observed for FVC and FEV1/FVC%. After exclusion of 104 subjects with histories of occupational exposures to dust, gas, or fumes, the estimated difference was some-what smaller than that of the total samples. However, the effects on FEV1 and FEV1/FVC% remained significant for both men and women. PMID- 10092743 TI - Socio-medical intervention in occupational health: benzenism in Brazil. AB - This review describes the authors' experience with 2,000 cases of benzene poisoning reported between 1983 and 1995 in Cubatao, an industrial section of Sao Paulo, Brazil, investigated through the integration of epidemiology and clinical research. Conflicting economic interests were reflected in disputes about medical criteria for evaluation of poisoned workers, about proper means of conducting workplace hygiene evaluations, about benzene exposure standards, and about compensation for chronic bone-marrow damage. PMID- 10092744 TI - Surveillance and occupational health. AB - This report explains the basics of two important uses of surveillance data: determining the magnitude of a specific occupational health or injury problem and examining temporal trends to determine whether the problem is increasing or decreasing. Types of data available for the purpose and some of their strengths and weaknesses are described. The utility of surveillance data is illustrated with examples from surveillance of acute injuries, musculoskeletal disorders, lead overexposures, and hazard surveillance data sets. Increasingly, surveillance systems may be used to evaluate the effectiveness of interventions. Surveillance is most important in times of rapid change in the economy and when resources for prevention may be limited. Both conditions are common in the world today. PMID- 10092745 TI - International agency efforts to protect workers and the environment. AB - Every year 335,000 workers die in occupational accidents and altogether 1.1 million fatalities are caused by work-related factors. Some 250 million nonfatal accidents causing absence from work are aggravated by permanent disabilities, reduced capacity of life and work, and economic losses amounting to 4% of gross national product. The role of the International Labour Office (ILO) in promoting social justice is based on ethical principles and demonstrated by the ILO's standard-setting work, information exchange, and proposed Global Program on Occupational Safety, Health and the Environment, Ethical and policy dimensions of the ILO's practices are targeted to a participatory process aimed at better legislation and enforcement, as well as trained and well-informed specialists to modify work environments and cultures to eliminate or reduce the problems and suffering. The ILO's key present and new activities and outputs, such as the new 4th edition of the Encyclopedia on Occupational Health and Safety, are described. A better system of collaboration and networking in occupational safety and health is still needed. PMID- 10092746 TI - Managing the ecosystem to improve human health: integrated approaches to safe drinking water. AB - The ecosystem approach to human health is a holistic concept of health for both humans and the environment in which they live. This approach requires a holistic management of all facets of the ecosystem, be they physical, biologic, or indeed human-such as culture, economy, and developmental needs. This paradigm may at first glance seem theoretical and difficult to put into practice in everyday field research. However, using basic human needs, such as water and sanitation, as entry points illustrates how ecosystem health can indeed prove a powerful tool for sustainable development, promoting both human well-being and sustainable ecosystems. The authors describe the efforts of international agencies, particularly the International Development Research Centre (IDRC), to promote household safe drinking water security in developing countries. Essential to the success of these endeavors are strong partnerships with communities, research institutions, and donor agencies. The roles of these players are delineated. An important feature of IDRC projects, which is critical to their success, is the establishment of a simple, community-based water-quality monitoring program that the people can maintain with the limited resources available to them. The process and outcomes of past IDRC projects are presented and ongoing efforts are described. PMID- 10092747 TI - Innovative intersectoral approach reduces blood leads levels of children and workers in Romania. AB - With the support of the U.S. Agency for International Development (USAID), an intersectoral approach involving the community, governmental and nongovernmental agencies, and the management of the local copper smelting plant succeeded in reducing the blood lead levels of plant workers and of young children living in the vicinity of a copper smelter, Zlatna, Romania. Specifics of the collaborative effort, which attracted enthusiastic responses from all participants, are provided. PMID- 10092748 TI - The local impact of globalization: worker health and safety in Mexico's sugar industry. AB - With the opening of its economy to international trade, the government of Mexico privatized many of its productive holdings, including the state-owned sugar industry. Sugar cane and mill workers had played an important role in the armed struggles of the revolutionary period (1910-1917). Organized into a militant labor union, they had become staunch supporters of the new government in the following decades. Furthermore, in the early years of industrialization, the sugar industry was very important for the Mexican economy, and the union played an active role in the political arena. Since the privatization of the sugar mills, the sugar workers have experienced a dramatic reorganization of the work process, and industry-union relationships are being reshaped. This paper offers an analysis of the impact of the privatization on workers' health and safety. Since the economic and social changes in the work process have a direct impact on the community as a whole, the study also explores these effects. PMID- 10092749 TI - Global corporate policies and international "double standards" in occupational and environmental health. PMID- 10092750 TI - People centered science and globalization: putting the public back into public health policy. PMID- 10092751 TI - Age-related ultramorphologic sperm abnormalities among salvage workers from the Chernobyl nuclear power plant. PMID- 10092753 TI - More on the Ottawa knee rules. PMID- 10092754 TI - Worst headache and subarachnoid hemorrhage. PMID- 10092755 TI - Melatonin after night shift work. PMID- 10092756 TI - Tetanus among injecting-drug users. PMID- 10092759 TI - Cutting edge: negative selection of immature thymocytes by a few peptide-MHC complexes: differential sensitivity of immature and mature T cells. AB - We quantitated the number of peptide-class II MHC complexes required to affect the deletion or activation of 3A9 TCR transgenic thymocytes. Deletion of immature double positive thymocytes was very sensitive, taking place with approximately three peptide-MHC complexes per APC. However, the activation of mature CD4+ thymocytes required 100-fold more complexes per APC. Therefore, a "biochemical margin of safety" exists at the level of the APC. To be activated, autoreactive T cells in peripheral lymphoid tissues require a relatively high level of peptide MHC complexes. PMID- 10092760 TI - Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein. AB - During somatic hypermutation of Ig V genes, mismatched nucleotide substitutions become candidates for removal by the DNA mismatch repair pathway. Previous studies have shown that V genes from mice deficient for the MSH2 and PMS2 mismatch repair proteins have frequencies of mutation that are comparable with those from wild-type (wt) mice; however, the pattern of mutation is altered. Because the absence of MSH2 and PMS2 produced different mutational spectra, we examined the role of another protein involved in mismatch repair, MLH1, on the frequency and pattern of hypermutation. MLH1-deficient mice were immunized with oxazolone Ag, and splenic B cells were analyzed for mutations in their V kappa Ox1 light chain genes. Although the frequency of mutation in MLH1-deficient mice was twofold lower than in wt mice, the pattern of mutation in Mlh1-/- clones was similar to wt clones. These findings suggest that the MLH1 protein has no direct effect on the mutational spectrum. PMID- 10092761 TI - Modulation of the humoral immune response by antibody-mediated antigen targeting to complement receptors and Fc receptors. AB - During an ongoing immune response, immune complexes, composed of Ag, complement factors, and Igs, are formed that can interact with complement receptors (CRs) and IgG Fc receptors (Fc gamma R). The role of CR1/2 and Fc gamma R in the regulation of the immune response was investigated using OVA that was chemically conjugated to whole IgG of the rat anti-mouse CR1/2 mAb 7G6. FACS analysis using the murine B cell lymphoma IIA1.6 confirmed that the 7G6-OVA conjugate recognized CR1/2. Incubating IIA1.6 cells with 7G6-OVA triggered tyrosine phosphorylation and Ag presentation to OVA-specific T cells in vitro. Immunizing mice with 7G6 OVA at a minimal dose of 1 microgram i.p. per mouse markedly enhanced the anti OVA Ig response, which was primarily of the IgG1 isotype subclass. The 7G6-OVA did not enhance the anti-OVA response in CR1/2-deficient mice. OVA coupled to an isotype control Ab induced a considerably lower anti-OVA response compared with that induced by OVA alone, suggesting inhibition by interaction between the Fc part of the Ab and the inhibitory Fc gamma RIIb on B cells. This findings was supported by the observation that IIA1.6 cells which were incubated with 7G6-OVA lost the ability to present Ag upon transfection with Fc gamma RIIb. In sum, 7G6 conjugated OVA, resembling a natural immune complex, induces an enhanced anti-OVA immune response that involves at least CR1/2-mediated stimulation and that may be partially suppressed by Fc gamma RIIb. PMID- 10092762 TI - Chronic modulation of the TCR repertoire in the lymphoid periphery. AB - Using TCR V beta 5 transgenic mice as a model system, we demonstrate that the induction of peripheral tolerance can mold the TCR repertoire throughout adult life. In these mice, three distinct populations of peripheral T cells are affected by chronic selective events in the lymphoid periphery. First, CD4+V beta 5+ T cells are deleted in the lymphoid periphery by superantigens encoded by mouse mammary tumor viruses-8 and -9 in an MHC class II-dependent manner. Second, mature CD8+V beta 5+ T cells transit through a CD8lowV beta 5low deletional intermediate during tolerance induction by a process that depends upon neither mouse mammary tumor virus-encoded superantigens nor MHC class II expression. Third, a population of CD4-CD8-V beta 5+ T cells arises in the lymphoid periphery in an age-dependent manner. We analyzed the TCR V alpha repertoire of each of these cellular compartments in both V beta 5 transgenic and nontransgenic C57BL/6 mice as a function of age. This analysis revealed age-related changes in the expression of V alpha families among different cellular compartments, highlighting the dynamic state of the peripheral immune repertoire. Our work indicates that the chronic processes maintaining peripheral T cell tolerance can dramatically shape the available TCR repertoire. PMID- 10092763 TI - In vivo and in vitro activation of T cells after administration of Ag-negative heat shock proteins. AB - Heat shock proteins (HSP) Hsp70 and gp96 prime class I-restricted cytotoxic T cells against Ags present in the cells from which they were isolated. The immunization capacity of HSPs is believed to rely on their ability to bind antigenic peptides. In this study, we employed the well-established OVA and beta galactosidase (beta-gal) antigenic model systems. We show that in vitro long-term established OVA and beta-gal-specific CTL clones release TNF-alpha and IFN-gamma when incubated with Ag-negative Hsp70 and gp96. In the absence of antigenic peptides, HSP-mediated secretion of TNF-alpha and IFN-gamma requires cell contact of the APC with the T cell but is not MHC-I restricted. Moreover, Hsp70 molecules purified from Ag-negative tissue, e.g., negative for antigenic peptide, are able to activate T cells in vivo, leading to significant higher frequencies in OVA specific CD8+ T cells. In unprimed animals, these T cells lyse OVA-transfected cell lines and produce TNF-alpha and IFN-gamma after Ag stimulus. Taken together our data show that, besides the well-established HSP/peptide-specific CTL induction and activation, a second mechanism exists by which Hsp70 and gp96 molecules activate T cells in vivo and in vitro. PMID- 10092764 TI - Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotoxicity. AB - Here we investigate the activation of and a possible role for the hematopoietic Rac1 exchange factor, Vav, in the signaling mechanisms leading to NK cell mediated cytotoxicity. Our data show that direct contact of NK cells with a panel of sensitive tumor targets leads to a rapid and transient tyrosine phosphorylation of Vav and to its association with tyrosine-phosphorylated Syk. Vav tyrosine phosphorylation is also observed following the activation of NK cells through the low-affinity Fc receptor for IgG (Fc gamma RIII). In addition, we demonstrate that both direct and Ab-mediated NK cell binding to target cells result in the activation of nucleotide exchange on endogenous Rac1. Furthermore, Vav antisense oligodeoxynucleotide treatment leads to an impairment of NK cytotoxicity, with Fc gamma RIII-mediated killing being more sensitive to the abrogation of Vav expression. These results provide new insight into the signaling pathways leading to cytotoxic effector function and define a role for Vav in the activation of NK cell-mediated killing. PMID- 10092765 TI - Reciprocal expression in CD4 or CD8 subsets of different members of the V alpha 11 gene family correlates with sequence polymorphism. AB - Previous staining studies with TCR V alpha 11-specific mAbs showed that V alpha 11.1/11.2 (AV11S1 and S2) expression was selectively favored in the CD4+ peripheral T cell population. As this phenomenon was essentially independent of the MHC haplotype, it was suggested that AV11S1 and S2 TCRs exert a preference for recognition of class II MHC molecules. The V alpha segment of the TCR alpha chain is suggested to have a primary role in shaping the T cell repertoire due to selection for class I or II molecules acting through the complementarity determining regions (CDR) 1 alpha and CDR2 alpha residues. We have analyzed the repertoire of V alpha 11 family members expressed in C57BL/6 mice and have identified a new member of this family; AV11S8. We show that, whereas AV11S1 and S2 are more frequent in CD4+ cells, AV11S3 and S8 are more frequent in CD8+ cells. The sequences in the CDR1 alpha and CDR2 alpha correlate with differential expression in CD4+ or CD8+ cells, a phenomenon that is also observed in BALB/c mice. With no apparent restriction in TCR J alpha usage or CDR3 alpha length in C57BL/6, these findings support the idea of V alpha-dependent T cell repertoire selection through preferential recognition of MHC class I or class II molecules. PMID- 10092766 TI - Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide. AB - Tetracyclines (doxycycline and minocycline) augmented (one- to twofold) the PGE2 production in human osteoarthritis-affected cartilage (in the presence or absence of cytokines and endotoxin) in ex vivo conditions. Similarly, bovine chondrocytes stimulated with LPS showed (one- to fivefold) an increase in PGE2 accumulation in the presence of doxycycline. This effect was observed at drug concentrations that did not affect nitric oxide (NO) production. In murine macrophages (RAW 264.7) stimulated with LPS, tetracyclines inhibited NO release and increased PGE2 production. Tetracycline(s) and L-N-monomethylarginine (L-NMMA) (NO synthase inhibitor) showed an additive effect on inhibition of NO and PGE2 accumulation, thereby uncoupling the effects of tetracyclines on NO and PGE2 production. The enhancement of PGE2 production in RAW 264.7 cells by tetracyclines was accompanied by the accumulation of both cyclooxygenase (COX)-2 mRNA and cytosolic COX-2 protein. In contrast to tetracyclines, L-NMMA at low concentrations (< or = 100 microM) inhibited the spontaneous release of No in osteoarthritis-affected explants and LPS-stimulated macrophages but had no significant effect on the PGE2 production. At higher concentrations, L-NMMA (500 microM) inhibited NO release but augmented PGE2 production. This study indicates a novel mechanism of action of tetracyclines to augment the expression of COX-2 and PGE2 production, an effect that is independent of endogenous concentration of NO. PMID- 10092767 TI - Differential roles of N- and C-terminal immunoreceptor tyrosine-based inhibition motifs during inhibition of cell activation by killer cell inhibitory receptors. AB - Killer cell inhibitory receptors (KIRs) inhibit NK and T cell cytotoxicity when recognizing MHC class I molecules on target cells. They possess two tandem intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs) that, when phosphorylated, each bind to the two Src homology 2 domain-bearing protein tyrosine phosphatases SHP-1 and SHP-2 in vitro. Using chimeric receptors having an intact intracytoplasmic KIR domain bearing both ITIMs (N + C-KIR), a deleted domain containing the N-terminal ITIM only (N-KIR), or a deleted domain containing the C-terminal ITIM only (C-KIR), we examined the respective contributions of the two ITIMs in the inhibition of cell activation in two experimental models (a rat mast cell and a mouse B cell line) that have been widely used to analyze KIR functions. We found that the two KIR ITIMs play distinct roles. When coaggregated with immunoreceptor tyrosine-based activation motif-bearing receptors such as high-affinity IgE receptors or B cell receptors, the N + C-KIR and the N-KIR chimeras, but not the C-KIR chimera, inhibited mast cell and B cell activation, became tyrosyl-phosphorylated, and recruited phosphatases in vivo. The N + C-KIR chimera recruited SHP-1 as expected, but also SHP-2. Surprisingly, the N-KIR chimera failed to recruit SHP-1; however, it did recruit SHP-2. Consequently, the N-terminal ITIM is sufficient to recruit SHP-2 and to inhibit cell activation, whereas the N-terminal and the C-terminal ITIMs are both necessary to recruit SHP-1. The two KIR ITIMs, therefore, are neither mandatory for inhibition nor redundant. Rather than simply amplifying inhibitory signals, they differentially contribute to the recruitment of distinct phosphatases that may cooperate to inhibit cell activation. PMID- 10092768 TI - The Jun kinase cascade is responsible for activating the CD28 response element of the IL-2 promoter: proof of cross-talk with the I kappa B kinase cascade. AB - Costimulation of TCR/CD3 and CD28 receptors leads to activation of the Jun kinase (JNK) cascade, which plays a key role in T cell activation, including activation of the IL-2 promoter. We demonstrate that the JNK cascade plays a central role in the activation of the CD28 response element (CD28RE) in the IL-2 promoter. This response element is linked to an activating protein-1 (AP-1) site, which functions synergistically with the CD28RE. The role of the JNK cascade in the activation of this composite element is twofold: 1) activation of the AP-1 site through transcriptional activation of c-Jun, and 2) activation of the CD28RE through selective cross-talk with I kappa B kinase-beta (IKK beta). Dominant negative versions of JNK kinase, c-Jun, and IKK beta interfered In CD3- plus CD28 induced CD28RE/AP-1 luciferase activity in Jurkat cells. In contrast, the dominant-active JNK kinase kinase, MEKK1, induced CD28RE/AP-1 luciferase activity, in parallel with induction of c-Jun and c-Rel binding to this combined promoter site. Dominant-active MEKK1 also induced transfected IKK beta, but not IKK alpha, activity. In contrast to the JNK cascade, the extracellular signal regulated kinase (ERK) cascade did not exert an affect on the CD28RE/AP-1 site, but did contribute to activation of the distal NF-AT/AP-1 site. PMID- 10092769 TI - Early membrane rupture events during neutrophil-mediated antibody-dependent tumor cell cytolysis. AB - Although cell-mediated cytolysis is a fundamental immune effector response, its mechanism remains poorly understood at the cellular level. In this report, we image for the first time transient ruptures, as inferred by cytoplasmic marker release, in tumor cell membranes during Ab-dependent cellular cytolysis. The cytosol of IgG-opsonized YAC tumor cells was labeled with tetra-methylrhodamine diacetate followed by the formation of tumor cell-neutrophil conjugates. We hypothesized that tumor cell cytolysis proceeds via a series of discrete membrane rupture/resealing events that contribute to marker release. To test this hypothesis, we occluded the fluorescence image of the labeled tumor cells by passing an opaque disk into a field-conjugated plane between the light source and the sample. Multiple small bursts of fluorescent label release from tumor cells could be detected using a photomultiplier tube. Similarly, multiple fluorescent plumes were observed at various sites around the perimeter of a target. These findings support a multihit model of target cytolysis and suggest that cytolytic release is not focused at specific sites. Cytolytic bursts were generally observed at 20-s intervals, which match the previously described reduced nicotinamide-adenine dinucleotide phosphate and superoxide release oscillation periods for neutrophils; we speculate that metabolic oscillations of the effector cell drive the membrane damage of the target. PMID- 10092770 TI - Expression of functional selectin ligands on Th cells is differentially regulated by IL-12 and IL-4. AB - Immune responses may be qualitatively distinct depending on whether Th1 or Th2 cells predominate at the site of Ag exposure. T cell subset-specific expression of ligands for vascular selectins may underlie the distinct patterns of recruitment of Th1 or Th2 cells to peripheral inflammatory sites. Here we examine the regulation of selectin ligand expression during murine T helper cell differentiation. Large numbers of Th1 cells interacted with E- and P-selectin under defined flow conditions, while few Th2 and no naive T cells interacted. Th1 cells also expressed more fucosyltransferase VII mRNA than naive or Th2 cells. IL 12 induced expression of P-selectin ligands on Ag-activated naive T cells, even in the presence of IL-4, and on established Th2 cells restimulated in the presence of IL-12 and IFN-gamma. In contrast, Ag stimulation alone induced only E selectin ligand. Interestingly, restimulation of established Th2 cells in the presence of IL-12 and IFN-gamma induced expression of P-selectin ligands but not E-selectin ligands; IFN-gamma alone did not enhance expression of either selectin ligand. In summary, functional P- and E-selectin ligands are expressed on most Th1 cells, few Th2 cells, but not naive T cells. Furthermore, selectin ligand expression is regulated by the cytokine milieu during T cell differentiation. IL 12 induces P-selectin ligand, while IL-4 plays a dominant role in down-regulating E-selectin ligand. PMID- 10092771 TI - Development of CD8+ effector T cells is differentially regulated by IL-18 and IL 12. AB - We investigated the effects of IL-18 on the development of CD8+ effector T cells in DBA/2 anti-BDF1 whole spleen cell MLC and compared the results with those of IL-12. Addition of IL-18 to the MLC resulted in a twofold increase in CD8/CD4 ratios compared with the control cultures when cells were expanded in IL-2 containing medium following MLC. Purified CD8+ T cells recovered from the IL-18 stimulated MLC produced 20- to 30-fold more IFN-gamma after secondary stimulation with C57BL/6 spleen cells or anti-CD3 mAb, and exhibited strong allospecific CTL activity. Neither IL-18 nor IL-18-supplemented culture supernatants from DBA/2 anti-BDF1 MLC induced type I CD8+ effector T cells when purified CD8+ T cells were used as responder cells in primary MLC. Furthermore, CD4+ T cell depletion from the responder cells abrogated the IL-18-induced increase in secondary IFN gamma production by CD8+ T cells, suggesting that IL-18-induced type I effector CD8+ T cell development was CD4+ T cell dependent. In marked contrast, adding IL 12 to primary MLC decreased CD8/CD4 ratios by 50% and suppressed secondary IFN gamma production and CTL activity by CD8+ T cells regardless of concentration, whereas Th1 development was promoted by IL-12. Moreover, both IL-12 and IL-18 efficiently induced type I CD8+ effector T cells in C57BL/6 anti-BDF1 MLC. These findings show that IL-18 plays an important role in the generation of type I CD8+ effector T cells, and further suggest that functional maturation of CD8+ T cells is differentially regulated by IL-18 and IL-12. PMID- 10092772 TI - Human 60-kDa heat-shock protein: a danger signal to the innate immune system. AB - Mammalian 60-kDa heat-shock protein (hsp60) is a key target of T cell and Ab responses in chronic inflammation or atherosclerosis. We show in this study that human hsp60 is also an Ag recognized by cells of the innate immune system, such as macrophages. Both mouse and human macrophages respond to contact with exogenous human hsp60 with rapid release of TNF-alpha; mouse macrophages in addition produce nitric oxide. The proinflammatory macrophage response is hsp60 dose dependent and similar in kinetics and extent to LPS stimulation. Human hsp60 was found to synergize with IFN-gamma in its proinflammatory activity. Finally, human hsp60 induces gene expression of the Th1-promoting cytokines IL-12 and IL 15. These findings identify autologous hsp60 as a danger signal for the innate immune system, with important implications for a role of local hsp60 expression/release in chronic Th1-dependent tissue inflammation. PMID- 10092773 TI - Negative regulation of myeloid cell proliferation and function by the SH2 domain containing tyrosine phosphatase-1. AB - The SH2 domain containing tyrosine phosphatase SHP-1 has been implicated in the regulation of a multiplicity of signaling pathways involved in hemopoietic cell growth, differentiation, and activation. A pivotal contribution of SHP-1 in the modulation of myeloid cell signaling cascades has been revealed by the demonstration that SHP-1 gene mutation is responsible for the overexpansion and inappropriate activation of myelomonocytic populations in motheaten mice. To investigate the role of SHP-1 in regulation of myeloid leukocytes, an HA epitope tagged dominant negative (interfering) SHP-1 (SHP-1C453S) was expressed in the myelo-monocytic cell line U937 using the pcDNA3 vector. Overexpression of this protein in SHP-1C453S transfectants was demonstrated by Western blot analysis and by detection of decreased specific activity. Growth, proliferation, and IL-3 induced proliferative responses were substantially increased in the SHP-1C453S overexpressing cells relative to those in control cells. The results of cell cycle analysis also revealed that the proportion of cells overexpressing SHP 1C453S in S phase was greater than that of control cells. The SHP-1C453S expressing cells also displayed diminished rates of apoptosis as detected by flow cytometric analysis of propidium iodide-stained cells and terminal deoxynucleotidyltransferase-mediated fluorescein-dUTP nick end-labeling assay. While motility and phagocytosis were not affected by SHP-1C453S overexpression, adhesion and the oxidative burst in response to PMA were enhanced in the SHP 1C453S compared with those in the vector alone transfectants. Taken together, these results suggest that SHP-1 exerts an important negative regulatory influence on cell proliferation and activation while promoting spontaneous cell death in myeloid cells. PMID- 10092774 TI - Final maturation of dendritic cells is associated with impaired responsiveness to IFN-gamma and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. AB - Activation of immature CD83- dendritic cells (DC) in peripheral tissues induces their maturation and migration to lymph nodes. Activated DC become potent stimulators of Th cells and efficient inducers of Th1- and Th2-type cytokine production. This study analyzes the ability of human monocyte-derived CD1a+ DC at different stages of IL-1 beta and TNF-alpha-induced maturation to produce the major Th1-driving factor IL-12. DC at the early stages of maturation (2 and 4 h) produced elevated amounts of IL-12 p70 during interaction with CD40 ligand bearing Th cells or, after stimulation with the T cell-replacing factors, soluble CD40 ligand and IFN-gamma. The ability to produce IL-12 was strongly down regulated at later time points, 12 h after the induction of DC maturation, and in fully mature CD83+ cells, at 48 h. In contrast, the ability of mature DC to produce IL-6 was preserved or even enhanced, indicating their intact responsiveness to CD40 triggering. A reduced IL-12-producing capacity of mature DC resulted mainly from their impaired responsiveness to IFN-gamma, a cofactor in CD40-induced IL-12 p70 production. This correlated with reduced expression of IFN gamma R (CD119) by mature DC. In addition, while immature DC produced IL-12 and IL-6 after stimulation with LPS or Staphylococcus aureus Cowan I strain, mature DC became unresponsive to these bacterial stimuli. Together with the previously described ability of IL-10 and PGE2 to stably down-regulate the ability to produce IL-12 in maturing, but not in fully mature, DC, the current data indicate a general resistance of mature DC to IL-12-modulating factors. PMID- 10092775 TI - Evidence for distinct intracellular signaling pathways in CD34+ progenitor to dendritic cell differentiation from a human cell line model. AB - Intracellular signals that mediate differentiation of pluripotent hemopoietic progenitors to dendritic cells (DC) are largely undefined. We have previously shown that protein kinase C (PKC) activation (with phorbol ester (PMA) alone) specifically induces differentiation of primary human CD34+ hemopoietic progenitor cells (HPC) to mature DC. We now find that cytokine-driven (granulocyte-macrophage CSF and TNF-alpha) CD34+ HPC-->DC differentiation is preferentially blocked by inhibitors of PKC activation. To further identify intracellular signals and downstream events important in CD34+ HPC-->DC differentiation we have characterized a human leukemic cell line model of this process. The CD34+ myelomonocytic cell line KG1 differentiates into dendritic like cells in response to granulocyte-macrophage CSF plus TNF-alpha, or PMA (with or without the calcium ionophore ionomycin, or TNF-alpha), with different stimuli mediating different aspects of the process. Phenotypic DC characteristics of KG1 dendritic-like cells include morphology (loosely adherent cells with long neurite processes), MHC I+/MHC IIbright/CD83+/CD86+/CD14- surface Ag expression, and RelB and DC-CK1 gene expression. Functional DC characteristics include fluid phase macromolecule uptake (FITC-dextran) and activation of resting T cells. Comparison of KG1 to the PMA-unresponsive subline KG1a reveals differences in expression of TNF receptors 1 and 2; PKC isoforms alpha, beta I, beta II, and mu; and RelB, suggesting that these components/pathways are important for DC differentiation. Together, these findings demonstrate that cytokine or phorbol ester stimulation of KG1 is a model of human CD34+ HPC to DC differentiation and suggest that specific intracellular signaling pathways mediate specific events in DC lineage commitment. PMID- 10092776 TI - Recruitment of pleckstrin and phosphoinositide 3-kinase gamma into the cell membranes, and their association with G beta gamma after activation of NK cells with chemokines. AB - The role of phosphoinositide 3 kinases (PI 3-K) in chemokine-induced NK cell chemotaxis was investigated. Pretreatment of NK cells with wortmannin inhibits the in vitro chemotaxis of NK cells induced by lymphotactin, monocyte chemoattractant protein-1, RANTES, IFN-inducible protein-10, or stromal-derived factor-1 alpha. Introduction of inhibitory Abs to PI 3-K gamma but not to PI 3-K alpha into streptolysin O-permeabilized NK cells also inhibits chemokine-induced NK cell chemotaxis. Biochemical analysis showed that within 2-3 min of activating NK cells, pleckstrin is recruited into NK cell membranes, whereas PI 3-K gamma associates with these membranes 5 min after stimulation with RANTES. Recruited PI 3-K gamma generates phosphatidylinositol 3,4,5 trisphosphate, an activity that is inhibited upon pretreatment of NK cells with wortmannin. Further analysis showed that a ternary complex containing the beta gamma dimer of G protein, pleckstrin, and PI 3-K gamma is formed in NK cell membranes after activation with RANTES. The recruitment of pleckstrin and PI 3-K gamma into NK cell membranes is only partially inhibited by pertussis toxin, suggesting that the majority of these molecules form a complex with pertussis toxin-insensitive G proteins. Our results may have application for the migration of NK cells toward the sites of inflammation. PMID- 10092777 TI - Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. AB - The effects of inflammatory cytokines on naive T cells have been studied using MHC protein/peptide complexes on microspheres, thus avoiding the use of APCs whose functions may be affected by the cytokines. IL-1, but not IL-12, increased proliferation of CD4+ T cells in response to Ag and IL-2, which is consistent with effects on in vivo priming of CD4+ cells. In contrast, proliferation of CD8+ T cells to Ag and IL-2 required IL-12, and IL-12 replaced adjuvant in stimulating an in vivo response to peptide. These results support a model in which distinct inflammatory cytokines act directly on naive CD4+ and CD8+ T cells to provide a third signal, along with Ag and IL-2, to optimally activate differentiation and clonal expansion. PMID- 10092778 TI - Phagosomes are fully competent antigen-processing organelles that mediate the formation of peptide:class II MHC complexes. AB - During the processing of particulate Ags, it is unclear whether peptide:class II MHC (MHC-II) complexes are formed within phagosomes or within endocytic compartments that receive Ag fragments from phagosomes. Murine macrophages were pulsed with latex beads conjugated with OVA. Flow or Western blot analysis of isolated phagosomes showed extensive acquisition of MHC-II, H-2M, and invariant chain within 30 min, with concurrent degradation of OVA. T hybridoma responses to isolated subcellular fractions demonstrated OVA (323-339):I-Ad complexes in phagosomes and plasma membrane but not within dense late endocytic compartments. Furthermore, when two physically separable sets of phagosomes were present within the same cells, OVA(323-339):I-Ad complexes were demonstrated in latex-OVA phagosomes but not in phagosomes containing latex beads conjugated with another protein. This implies that these complexes were formed specifically within phagosomes and were not formed elsewhere and subsequently transported to phagosomes. In addition, peptide:MHC-II complexes were shown to traffic from phagosomes to the cell surface. In conclusion, phagosomes are fully competent to process Ags and generate peptide:MHC-II complexes that are transported to the cell surface and presented to T cells. PMID- 10092779 TI - Fas-mediated suicide of tumor-reactive T cells following activation by specific tumor: selective rescue by caspase inhibition. AB - CD8+ T lymphocytes that specifically recognize tumor cells can be isolated and expanded ex vivo. While the lytic properties of these cells have been well described, their fate upon encounter with cognate tumor is not known. We performed reverse 51Cr release assays in which the lymphocyte effectors rather than the tumor cell targets were radioactively labeled. We found that melanoma tumor cells caused the apoptotic death of tumor-specific T cells only upon specific MHC class I-restricted recognition. This death was entirely blockable by the addition of an Ab directed against the Fas death receptor (APO-1, CD95). Contrary to the prevailing view that tumor cells cause the death of anti-tumor T cells by expressing Fas ligand (FasL), our data suggested that FasL was instead expressed by T lymphocytes upon activation. While the tumor cells did not express FasL by any measure (including RT-PCR), functional FasL (as well as FasL mRNA) was consistently found on activated anti-tumor T cells. We could successfully block the activation-induced cell death with z-VAD-fmk, a tripeptide inhibitor of IL-1 beta-converting enzyme homologues, or with anti-Fas mAbs. Most importantly, these interventions did not inhibit T cell recognition as measured by IFN-gamma release, nor did they adversely affect the specific lysis of tumor cell targets. These results imply that Fas-mediated activation-induced cell death could be a limiting factor in the in vivo efficacy of adoptive transfer of class I restricted CD8+ T cells and provide a means of potentially enhancing their growth in vitro as well as their function in vivo. PMID- 10092780 TI - IL-2-dependent expression of genes involved in cytoskeleton organization, oncogene regulation, and transcriptional control. AB - IL-2 induces growth, differentiation, and/or apoptosis of lymphoid cells. To study further the molecular basis of IL-2 function, we used a cDNA subtraction approach involving a cell line grown in IL-2 or IL-4. From the corresponding library, 66 nonredundant sequences were characterized; 16 of them encode identified proteins. The kinetics of in vitro expression of 8 selected sequences, the functions of which could be associated with IL-2-induced T cell activation/differentiation, was investigated using an IL-2-dependent T cell line. IL-2 increased the expression of cytoskeleton proteins (alpha-tubulin), oncogene regulating proteins (CCCTC-binding factor, Jun inhibitor factor-1), and transcription factors (E2F-4, cyclic AMP-responsive element-binding protein, zhx 1). IL-2 also regulated the expression of genes coding for multifunctional proteins, e.g., beta-catenin and nucleolin. These results were verified using Con A-induced T cell blasts stimulated or not by IL-2. The in vivo expression of four of these genes was also analyzed in spleen and lymph node cells of IL-2-deficient and MRL/lpr mice, which both have high numbers of activated cells, but the latter have intact IL-2 expression. The expression of beta-catenin, CCCTC-binding factor, Jun inhibitor factor-1, and nucleolin was significantly higher in MRL/lpr animals. A similar analysis of thymocytes from IL-2-/- and IL-2+/- mice demonstrated the same expression patterns of the 4 sequences in these strains. The expression of the IL-2-induced genes described herein is similar to the regulatory pattern of IL-2R alpha. Taken together, our data provide additional evidence for the pleiotropic action of IL-2 in the periphery and IL-2 independence of molecular processes involved in thymocyte differentiation. PMID- 10092781 TI - Dissociation between IFN-alpha-induced anti-viral and growth signaling pathways. AB - The ability of IFN-alpha to induce an anti-viral state in a wide variety of cell types as well as to inhibit cellular growth has long been appreciated. It is less clear, however, whether both these effects lie downstream of a common signaling pathway. In this study we have taken advantage of an atypical human myeloma cell line (KAS-6/1) displaying a dramatic proliferative response to IFN-alpha in an effort to resolve the signaling requirements for IFN-alpha-induced anti-viral and growth regulatory effects. Thus, we have analyzed the ability of IFN-alpha to induce a number of known receptor-initiated events in this cell line and have compared these responses with those exhibited by a cell lineage- and maturation stage-matched myeloma cell line (ANBL-6) that displays typical IFN-alpha responsiveness. Despite the widely contrasting effects of IFN-alpha on cellular proliferation, IFN-alpha was shown to be comparable in its ability to induce the expression of early response genes as well as induce resistance to viral infection in both cell lines. By contrast, the effects of IFN-alpha on the activation of mitogen-activated protein kinase (MAPK) were strikingly distinct. Finally, although inhibition of MEK and MAPK activation had no effect on the induction of the anti-viral response, it completely blocked IFN-alpha-stimulated proliferation of the KAS-6/1 cells. In summary, our analysis of the role of the MAPK and anti-viral signaling pathways using these two cell lines suggests that the anti-viral and growth regulatory effects of IFN-alpha display a differential requirement for activation of the MAPK pathway. PMID- 10092782 TI - Differential responses to CD40 ligation among Burkitt lymphoma lines that are uniformly responsive to Epstein-Barr virus latent membrane protein 1. AB - Ligation of CD40 on the surface of B cells induces multiple phenotypic effects, many of which are mimicked by the EBV latent membrane protein 1 (LMP1) through its interaction with downstream components of the CD40 signaling pathway. Because the effects of LMP1 have been most closely studied in human Burkitt Lymphoma (BL) cell lines retaining a tumor biopsy-like phenotype in vitro, we have examined the response of a panel of such lines to CD40 ligation. Two distinct patterns of response were observed that were unrelated to the surface level of CD40 or to the EBV genome status of the lines. Following exposure to either CD40-specific mAbs or the soluble trimeric ligand (sCD40L), high responder (HR) lines showed rapid aggregation, activation of NF-kappa B, up-regulation of cell surface markers ICAM 1/CD54 and Fas/CD95, and growth inhibition. Aggregation was seen at lower doses than those required to elicit the other effects. By contrast, low responder (LR) lines showed no detectable response to CD40 mAbs, while their responses to sCD40L were limited to activation of NF-kappa B and up-regulation of CD95 only. However, in transfection experiments, LMP1 uniformly induced the full spectrum of phenotypic effects in both HR and LR lines. We conclude that some BL cell lines show a highly restricted response to CD40 ligation but remain fully susceptible to LMP1. PMID- 10092783 TI - IL-2-mediated cell cycle progression and inhibition of apoptosis does not require NF-kappa B or activating protein-1 activation in primary human T cells. AB - The IL-2 growth hormone is the major growth factor of activated T lymphocytes during a developing immune response. IL-2 is required not only for cell cycle progression but also to protect Ag-activated T cells from programmed cell death. In several cell types, activation of NF-kappa B and/or activating protein-1 (AP 1) has been demonstrated to be extremely important in blocking apoptosis. To determine whether either or both of these transcription factors are involved in cell survival or cell cycle progression in response to IL-2, primary human T cells responsive to the growth factor were analyzed for NF-kappa B and AP-1 activation. The current study clearly demonstrates that IL-2 does not induce I kappa B alpha degradation or NF-kappa B activation in primary human T cells that respond to IL-2 by entering the cell cycle and avoiding apoptosis. Similarly, IL 2 neither activates JNK nor increases AP-1 binding activity to a consensus o tetradecanoylphorbol 13-acetate (TPA) response element. On the other hand, the growth factor does induce the activation of STAT3 and STAT5 in these cells, as has been previously demonstrated. These data show that neither NF-kappa B nor AP 1 activation is required for IL-2-mediated survival or cell cycle progression in activated primary human T cells. PMID- 10092784 TI - Regulation of lymphotoxin production by the p21ras-raf-MEK-ERK cascade in PHA/PMA stimulated Jurkat cells. AB - Although the production of lymphotoxin (LT) from activated Th1 lymphocytes has been reported extensively, the intracellular signaling mechanisms that regulate this T cell function remain totally undefined. We have examined whether the p21ras-raf-1-mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) kinase (MEK)-ERK cascade plays a role in regulating the production of LT, because the activity of these signaling molecules is up regulated in activated T lymphocytes. Transfection of Jurkat leukemic T cells with a dominant negative mutant of p21ras (ras17N or ras15A), raf-1 (raf 1-130), or ERK1 (Erk1-K71R) resulted in the suppression of the mitogen/phorbol ester stimulated production/secretion of LT. This suppression was accompanied by a parallel inhibition of mitogen-stimulated ERK activation. The selective antagonist of MEK1 activation, PD98059, also attenuated the mitogen-stimulated or anti-CD3 Ab and phorbol ester-stimulated production of LT from Jurkat cells or peripheral blood T lymphocytes. This study provides, for the first time, direct evidence that the p21ras-raf-MEK-ERK cascade plays a vital role in regulating the production of LT. PMID- 10092785 TI - Differential activation of c-Jun NH2-terminal kinase and p38 pathways during FTY720-induced apoptosis of T lymphocytes that is suppressed by the extracellular signal-regulated kinase pathway. AB - FTY720 is a novel immunosuppressive drug derived from a metabolite from Isaria sinclairii that is known to induce apoptosis of rat splenic T cells. In this study, we examined the intracellular signaling pathway triggered by FTY720. Treatment of human Jurkat T lymphocytes with FTY720-induced apoptosis characterized by DNA fragmentation. The same treatment induced activation of protein kinases such as c-Jun NH2-terminal kinase (JNK), p38/CSBP (CSAID-binding protein), and a novel 36-kDa myelin basic protein (MBP) kinase, but not extracellular signal-regulated kinase (ERK). Pretreatment of Jurkat cells with DEVD-CHO blocked FTY720-induced DNA fragmentation as well as the activation of p38/CSBP. However, DEVD-CHO treatment failed to inhibit FTY720-induced activation of JNK and the 36-kDa MBP kinase. We have also demonstrated that activation of the ERK signaling pathway completely suppressed the FTY720-induced apoptotic process including activation of caspase 3 and activation of JNK and the 36-kDa MBP kinase. Furthermore, transient expression of constitutively active mitogen activated protein kinase/ERK kinase (MEK) protected the cells from FTY720-induced cell death. The effect of MEK was canceled by coexpression of a mitogen-activated protein kinase phosphatase, CL100. These results indicate that JNK and p38 pathways are differentially regulated during FTY720-induced apoptosis and that activation of ERK pathway alone is sufficient to cancel the FTY720-induced death signal. PMID- 10092786 TI - Postthymic development of CD28-CD8+ T cell subset: age-associated expansion and shift from memory to naive phenotype. AB - During human aging, one of the major changes in the T cell repertoire is a dramatic expansion of T cells with the atypical CD28-CD8+ phenotype. In this study, we show that this increase is a consequence not only of an expansion in the CD28-CD8+ population but also of a decrease in the number of CD28+CD8+ T cells. The decrease in circulating CD28+CD8+ T cells is dramatically accelerated after the age of 50 and is not accompanied by an equivalent reduction in the CD28+CD8+ subset. Our findings confirm that aging leads to an accumulation of CD45RO+ T cells within the CD28+CD8+ subset as previously observed. Surprisingly, we found an increase in CD45RA+ expression with age in the CD28-CD8+ subset. Immune-phenotyping for activation markers, measurement of telomere DNA content, and cytokine production analysis indicate that the large majority of CD28-CD8+ T cells are Ag-experienced, despite their CD45RA+ phenotype. Our study further demonstrates that the poor proliferative response displayed by CD28-CD8+ T cells is not a consequence of telomere shortening. Also, analysis of cytokine production at the single cell level revealed that the proportions of IFN-gamma +, IL-4+, and IL-10+ T cells are considerably higher among the CD28-CD8+ than the CD28+CD8+ subset. In summary, these data explain the presence of CD45RA+ T cells in the elderly, shed light on the phylogenetic origin of CD28-CD8+ T cells, and suggest a role for these cells in the immune senescence process. PMID- 10092787 TI - Suppressive immunization with DNA encoding a self-peptide prevents autoimmune disease: modulation of T cell costimulation. AB - Usually we rely on vaccination to promote an immune response to a pathogenic microbe. In this study, we demonstrate a suppressive from of vaccination, with DNA encoding a minigene for residues 139-151 of myelin proteolipid protein (PLP139-151), a pathogenic self-Ag. This suppressive vaccination attenuates a prototypic autoimmune disease, experimental autoimmune encephalomyelitis, which presents clinically with paralysis. Proliferative responses and production of the Th1 cytokines, IL-2 and IFN-gamma, were reduced in T cells responsive to PLP139 151. In the brains of mice that were successfully vaccinated, mRNA for IL-2, IL 15, and IFN-gamma were reduced. A mechanism underlying the reduction in severity and incidence of paralytic autoimmune disease and the reduction in Th1 cytokines involves altered costimulation of T cells; loading of APCs with DNA encoding PLP139-151 reduced the capacity of a T cell line reactive to PLP139-151 to proliferate even in the presence of exogenous CD28 costimulation. DNA immunization with the myelin minigene for PLP-altered expression of B7.1 (CD80), and B7.2 (CD86) on APCs in the spleen. Suppressive immunization against self-Ags encoded by DNA may be exploited to treat autoimmune diseases. PMID- 10092788 TI - B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation. AB - In aged mice the population of mature peripheral B cells is maintained despite a severalfold decrease in the population of bone marrow B cell progenitors. The analysis of the rate of accumulation of 5'-bromo-2-deoxyuridine (BrdU)-labeled splenic B cells in mice fed BrdU for 8 days to 8 wk demonstrated a severalfold increase in the half-life of mature B cells in aged mice. Consistent with a role for decreased B cell turnover in maintaining the mature B cell population of aged mice, several findings indicate that fewer newly generated B cells enter the spleen from the bone marrow in aged vs young adult mice. These include 1) a fourfold decrease in the population of relatively immature splenic B cells, defined as cells that express high levels of heat-stable Ag and accumulate BrdU within 8 wk of labeling; and 2) an equivalent decrease in the population of bone marrow cells representative of later stages of B cell maturation (sIgD-sIgM(int high)). Surprisingly, despite a four- to sixfold decrease in pre-B cells, the population of least mature bone marrow B cells (IgD-sIgM(very low)) remains intact. Because this population accumulates BrdU-labeled cells more slowly in aged mice than in younger mice, and bone marrow B cells at more mature developmental stages are diminished, it appears that in aged mice B cell development beyond the sIgM(very low) stage may be retarded and that cells, therefore, accumulate within this population. PMID- 10092789 TI - Enumeration of antigen-presenting cells in mice infected with Sendai virus. AB - Substantial progress has been made in understanding Ag presentation to T cells; however, relatively little is known about the location and frequency of cells presenting viral Ags during a viral infection. Here, we took advantage of a highly sensitive system using lacZ-inducible T cell hybridomas to enumerate APCs during the course of respiratory Sendai virus infection in mice. Using lacZ inducible T cell hybridomas specific for the immunodominant hemagglutinin neuraminidase HN421-436/I-Ab and nucleoprotein NP324-332/Kb epitopes, we detected APCs in draining mediastinal lymph nodes (MLNs), in cervical lymph nodes, and also in the spleen. HN421-436/I-Ab- and NP324-332/Kb-presenting cells were readily detectable between days 3 and 9 postinfection, with more APCs present in the MLN than in the cervical lymph nodes. Interestingly, no infectious virus was detected in lymphoid tissue beyond day 6, suggesting that a depot of noninfectious viral Ag survives, in some form, for 2-3 days after viral clearance. Fractionation of the MLN demonstrated that APC frequency was enriched in dendritic cells and macrophages but depleted in the B cell population, suggesting that B cells do not form a large population of APCs during the primary response to this virus. PMID- 10092790 TI - Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. AB - Peroxynitrite (ONOO-) is a potent oxidizing and nitrating agent produced by the reaction of nitric oxide with superoxide. It readily nitrates phenolic compounds such as tyrosine residues in proteins, and it has been demonstrated that nitration of tyrosine residues in proteins inhibits their phosphorylation. During immune responses, tyrosine phosphorylation of key substrates by protein tyrosine kinases is the earliest of the intracellular signaling pathways following activation through the TCR complex. This work was aimed to evaluate the effects of ONOO- on lymphocyte tyrosine phosphorylation, proliferation, and survival. Additionally, we studied the generation of nitrating species in vivo and in vitro during immune activation. Our results demonstrate that ONOO-, through nitration of tyrosine residues, is able to inhibit activation-induced protein tyrosine phosphorylation in purified lymphocytes and prime them to undergo apoptotic cell death after PHA- or CD3-mediated activation but not upon phorbol ester-mediated stimulation. We also provide evidence indicating that peroxynitrite is produced during in vitro immune activation, mainly by cells of the monocyte/macrophage lineage. Furthermore, immunohistochemical studies demonstrate the in vivo generation of nitrating species in human lymph nodes undergoing mild to strong immune activation. Our results point to a physiological role for ONOO- as a down modulator of immune responses and also as key mediator in cellular and tissue injury associated with chronic activation of the immune system. PMID- 10092791 TI - T cell repertoire alterations of vascularized xenografts. AB - The role of T cells in the rejection of vascularized xenografts has been little explored. Because of the high potential diversity of xenoantigens, it has been suggested that xenotransplantation could induce a strong cellular response that could contribute to delayed rejection. Alternatively, alterations in molecular interactions could impair the T cell response. Because the analysis of TCR repertoire in vivo indirectly reflects the nature and the magnitude of T cell xenorecognition, we took advantage of the possibility of obtaining long term survival of hamster heart xenografts in rat recipients treated with a combination of cobra venom factor and cyclosporin A (CsA), to analyze T cell infiltration and, for the first time, V beta TCR usage, at the complementarity-determining region 3 level, in accommodated and rejected xenografts, compared with allografts. After withdrawal of CsA (on day 40), the analysis of V beta family expression and corresponding complementarity-determining region 3 lengths in rejected xenografts revealed a Gaussian pattern, in contrast to a much more restricted pattern in rejected allografts (p = 0.002), suggesting that, after withdrawal of CsA, all the underrepresented T cell clones are rapidly expanded in xenografts. These results correlate with the rapid kinetics of rejection (4 +/- 1 days), the high number of T cells, the rapid expression of markers of activation (IL-2 receptor alpha-chain and class II receptor), and the strong deposit of IgG Abs in rejected xenografts. Taken together, these results suggest that the intensity and diversity of the T cell response to xenografts could be stronger than the response to allografts in vivo. PMID- 10092792 TI - Effect of fever-like whole-body hyperthermia on lymphocyte spectrin distribution, protein kinase C activity, and uropod formation. AB - Regional inflammation and systemic fever are hallmarks of host immune responses to pathogenic stimuli. Although the thermal element of fever is thought to enhance the activity of immune effector cells, it is unclear what the precise role of increased body temperatures is on the activation state and effector functions of lymphocytes. We report here that mild, fever-like whole body hyperthermia (WBH) treatment of mice results in a distinct increase in the numbers of tissue lymphocytes with polarized spectrin cytoskeletons and uropods, as visualized in situ. WBH also induces a coincident reorganization of protein kinase C (PKC) isozymes and increased PKC activity within T cells. These hyperthermia-induced cellular alterations are nearly identical with the previously described effects of Ag- and mitogen-induced activation on lymphocyte spectrin and PKC. Immunoprecipitation studies combined with dual staining and protein overlay assays confirmed the association of PKC beta and PKC theta with spectrin following its reorganization. The receptor for activated C kinase-1 was also found to associate with the spectrin-based cytoskeleton. Furthermore, all these molecules (spectrin, PKC beta, PKC theta, and receptor for activated C kinase-1) cotranslocate to the uropod. Enhanced intracellular spectrin phosphorylation upon WBH treatment of lymphocytes was also found and could be blocked by the PKC inhibitor bisindolylmaleimide I (GF109203X). These data suggest that the thermal element of fever, as mimicked by these studies, can modulate critical steps in the signal transduction pathways necessary for effective lymphocyte activation and function. Further work is needed to determine the cellular target(s) that transduces the signaling pathway(s) induced by hyperthermia. PMID- 10092793 TI - Fine specificity and MHC restriction of trinitrophenyl-specific CTL. AB - In this study, the fine specificity and MHC restriction of a CTL response specific to the trinitrophenyl (TNP) hapten was analyzed. Based on the structure of peptide/Kb complexes and ternary TCR/Ag/MHC complexes, four TNP peptides, two octamers, and two nonamers were chosen for eliciting anti-TNP CTL responses. Hapten was conjugated at position 4 in the octamers and at position 5 in the nonamers, positions which should allow engagement of the hapten by TCRs. Potent CTL activity for each of the TNP peptides was obtained that was highly hapten specific; however, there were considerable differences in the extent of cross reactivity with other TNP peptides, with the octamers generating more cross reactive CTL than the nonamers. MHC restriction analysis suggested that anti hapten responses were less dependent on MHC recognition than anti-peptide responses. This was evidenced by the relative ease of detecting cross-reactivity to haptenated peptides presented by allo-MHC and by the relative insensitivity of anti-hapten vs anti-peptide CTL to mutations in the Kb molecule at potential TCR interaction sites. One potential explanation for this insensitivity to MHC mutation was the finding that the anti-hapten response appeared to be of higher avidity, since a > 100-fold difference in the amount of Ag required to sensitize target cells was found between these two types of Ags. PMID- 10092794 TI - Overexpression of protein kinase C isoforms protects RAW 264.7 macrophages from nitric oxide-induced apoptosis: involvement of c-Jun N-terminal kinase/stress activated protein kinase, p38 kinase, and CPP-32 protease pathways. AB - Nitric oxide (NO) induces apoptotic cell death in murine RAW 264.7 macrophages. To elucidate the inhibitory effects of protein kinase C (PKC) on NO-induced apoptosis, we generated clones of RAW 264.7 cells that overexpress one of the PKC isoforms and explored the possible interactions between PKC and three structurally related mitogen-activated protein (MAP) kinases in NO actions. Treatment of RAW 264.7 cells with sodium nitroprusside (SNP), a NO-generating agent, activated both c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinase, but did not activate extracellular signal-regulated kinase (ERK)-1 and ERK-2. In addition, SNP-induced apoptosis was slightly blocked by the selective p38 kinase inhibitor (SB203580) but not by the MAP/ERK1 kinase inhibitor (PD098059). PKC transfectants (PKC-beta II, -delta, and -eta) showed substantial protection from cell death induced by the exposure to NO donors such as SNP and S-nitrosoglutathione (GSNO). In contrast, in RAW 264.7 parent or in empty vector-transformed cells, these NO donors induced internucleosomal DNA cleavage. Moreover, overexpression of PKC isoforms significantly suppressed SNP induced JNK/SAPK and p38 kinase activation, but did not affect ERK-1 and -2. We also explored the involvement of CPP32-like protease in the NO-induced apoptosis. Inhibition of CPP32-like protease prevented apoptosis in RAW 264.7 parent cells. In addition, SNP dramatically activated CPP32 in the parent or in empty vector transformed cells, while slightly activated CPP32 in PKC transfectants. Therefore, we conclude that PKC protects NO-induced apoptotic cell death, presumably nullifying the NO-mediated activation of JNK/SAPK, p38 kinase, and CPP32-like protease in RAW 264.7 macrophages. PMID- 10092795 TI - Normal development in porcine thymus grafts and specific tolerance of human T cells to porcine donor MHC. AB - The induction of T cell tolerance is likely to play an essential role in successful xenotransplantation in humans. In this study, we show that porcine thymus grafts in immunodeficient mice support normal development of polyclonal, functional human T cells. These T cells were specifically tolerant to MHC Ags of the porcine thymus donor and responded to nondonor porcine xenoantigens and alloantigens. Exogenous IL-2 did not abolish tolerance, suggesting central clonal deletion rather than anergy as the likely tolerance mechanism. Our study suggests that the thymic transplantation approach to achieving tolerance with restoration of immunocompetence may be applicable to xenotransplantation of pig tissues to humans. PMID- 10092796 TI - Presentation of antigens internalized through the B cell receptor requires newly synthesized MHC class II molecules. AB - Exogenous Ags taken up from the fluid phase can be presented by both newly synthesized and recycling MHC class II molecules. However, the presentation of Ags internalized through the B cell receptor (BCR) has not been characterized with respect to whether the class II molecules with which they become associated are newly synthesized or recycling. We show that the presentation of Ag taken up by the BCR requires protein synthesis in splenic B cells and in B lymphoma cells. Using B cells transfected with full-length I-Ak molecules or molecules truncated in cytoplasmic domains of their alpha- or beta-chains, we further show that when an Ag is internalized by the BCR, the cytoplasmic tails of class II molecules differentially control the presentation of antigenic peptides to specific T cells depending upon the importance of proteolytic processing in the production of that peptide. Integrity of the cytoplasmic tail of the I-Ak beta-chain is required for the presentation of the hen egg lysozyme determinant (46-61) following BCR internalization, but that dependence is not seen for the (34-45) determinant derived from the same protein. The tail of the beta-chain is also of importance for the dissociation of invariant chain fragments from class II molecules. Our results demonstrate that Ags internalized through the BCR are targeted to compartments containing newly synthesized class II molecules and that the tails of class II beta-chains control the loading of determinants produced after extensive Ag processing. PMID- 10092798 TI - Toward a role of dendritic cells in the germinal center reaction: triggering of B cell proliferation and isotype switching. AB - We have reported previously that in vitro generated dendritic cells (DC) can directly regulate B cell responses. Recently, germinal center DC (GCDC) were identified within B cell follicles. Due to their particular localization, we have tested in the present study whether GCDC could contribute to key events characteristic of the GC reaction. Our present results demonstrate that 1) ex vivo GCDC induce a dramatic GC B cell expansion upon CD40 and IL-2 activation and drive plasma cell differentiation, 2) this property is shared by GCDC and blood DC, but not by Langerhans cells, 3) IL-12 production by GCDC is critical in GC B cell expansion and differentiation, and 4) importantly, GCDC also induce IL-10 independent isotype switching toward IgG1. These observations support the novel concept that GCDC directly contribute to the germinal center reaction. PMID- 10092797 TI - CD86 (B7-2) can function to drive MHC-restricted antigen-specific CTL responses in vivo. AB - Activation of T cells requires both TCR-specific ligation by direct contact with peptide Ag-MHC complexes and coligation of the B7 family of ligands through CD28/CTLA-4 on the T cell surface. We recently reported that coadministration of CD86 cDNA along with DNA encoding HIV-1 Ags i.m. dramatically increased Ag specific CTL responses. We investigated whether the bone marrow-derived professional APCs or muscle cells were responsible for the enhancement of CTL responses following CD86 coadministration. Accordingly, we analyzed CTL induction in bone marrow chimeras. These chimeras are capable of generating functional viral-specific CTLs against vaccinia virus and therefore represent a useful model system to study APC/T cell function in vivo. In vaccinated chimeras, we observed that only CD86 + Ag + MHC class I results in 1) detectable CTLs following in vitro restimulation, 2) detectable direct CTLs, 3) enhanced IFN-gamma production in an Ag-specific manner, and 4) dramatic tissue invasion of T cells. These results support that CD86 plays a central role in CTL induction in vivo, enabling non-bone marrow-derived cells to prime CTLs, a property previously associated solely with bone marrow-derived APCs. PMID- 10092800 TI - Polymerization of IgA and IgM: roles of Cys309/Cys414 and the secretory tailpiece. AB - We have investigated how the secretory tailpiece (tp), Cys414 and the amino acids flanking Cys414 or Cys309 are involved in regulating the different polymerization of IgM and IgA to pentamers and dimers/monomers, respectively. Whereas changing the tp of IgM to that of IgA has little effect on IgM polymerization, introducing the mu tp to IgA leads to the formation of larger than wild-type IgA polymers, including pentamers and hexamer. This shows that the secretory tp can differentially regulate polymerization depending on the heavy chain context. Cys414, which is engaged in intermonomeric disulfide bonds in IgM, is not crucial for the difference in IgM and IgA polymerization; IgM with a C414S mutation forms more large polymers than IgA. Also, IgA with IgM-like mutations in the five amino acids flanking Cys309, which is homologous to Cys414, oligomerize similarly as IgA wild type. Thus, IgA appears to have an inherent tendency to form monomers and dimers that is partially regulated by the tp, while the Cys309 region has only a minor effect. We also show that complement activation by IgM is sensitive to alterations in the polymeric structure, while IgA is inactive in classical complement activation even for polymers such as pentamers and hexamers. PMID- 10092799 TI - Induction of Ig somatic hypermutation and class switching in a human monoclonal IgM+ IgD+ B cell line in vitro: definition of the requirements and modalities of hypermutation. AB - Partly because of the lack of a suitable in vitro model, the trigger(s) and the mechanism(s) of somatic hypermutation in Ig genes are largely unknown. We have analyzed the hypermutation potential of human CL-01 lymphocytes, our monoclonal model of germinal center B cell differentiation. These cells are surface IgM+ IgD+ and, in the absence of T cells, switch to IgG, IgA, and IgE in response to CD40:CD40 ligand engagement and exposure to appropriate cytokines. We show here that CL-01 cells can be induced to effectively mutate the expressed VHDJH-C mu, VHDJH-C delta, VHDJH-C gamma, VHDJH-C alpha, VHDJH-C epsilon, and V lambda J lambda-C lambda transcripts before and after Ig class switching in a stepwise fashion. In these cells, induction of somatic mutations required cross-linking of the surface receptor for Ag and T cell contact through CD40:CD40 ligand and CD80: CD28 coengagement. The induced mutations showed intrinsic features of Ig V(D)J hypermutation in that they comprised 110 base substitutions (97 in the heavy chain and 13 in the lambda-chain) and only 2 deletions and targeted V(D)J, virtually sparing CH and C lambda. These mutations were more abundant in secondary VHDJH-C gamma than primary VHDJH-C mu transcripts and in V(D)J-C than V lambda J lambda-C lambda transcripts. These mutations were also associated with coding DNA strand polarity and showed an overall rate of 2.42 x 10(-4) base changes/cell division in VHDJH-CH transcripts. Transitions were favored over transversions, and G nucleotides were preferentially targeted, mainly in the context of AG dinucleotides. Thus, in CL-01 cells, Ig somatic hypermutation is readily inducible by stimuli different from those required for class switching and displays discrete base substitution modalities. PMID- 10092801 TI - Impaired fetal thymocyte development after efficient adenovirus-mediated inhibition of NF-kappa B activation. AB - We introduce a new experimental system combining adenovirus-mediated gene transfer and fetal thymic organ culture (FTOC). This system allowed us to efficiently express in developing thymocytes a mutant form of the NF-kappa B inhibitor I kappa B alpha (mut-I kappa B) and to study the maturation defects occurring when NF-kappa B activation is inhibited during fetal development. Fetal thymocytes infected with adenovirus containing mut-I kappa B were found to develop normally until the CD44-CD25+, CD4-CD8- double-negative stage, while production of more mature double-positive and single-positive populations was strongly decreased. Proliferation, as measured by the percentage of cells in cycle appeared normal, as did rearrangement and expression of the TCR beta-chain. However, apoptosis was much higher in FTOC infected with adenovirus containing mut-I kappa B than in FTOC infected with a control virus. Taken together, these results suggest that NF-kappa B plays a crucial role in ensuring the differentiation and survival of thymocytes in the early stages of their development. PMID- 10092802 TI - Sodium dodecyl sulfate stability of HLA-DR1 complexes correlates with burial of hydrophobic residues in pocket 1. AB - Certain class II MHC-peptide complexes are resistant to SDS-induced dissociation. This property, which has been used as an in vivo as well as an in vitro peptide binding assay, is not understood at the molecular level. Here we have investigated the mechanistic basis of SDS stability of HLA-DR1 complexes by using a biosensor-based assay and SDS-PAGE with a combination of wild-type and mutant HLA-DR1 and variants of hemagglutinin peptide HA306-318. Experiments with wild type DR1 along with previously published results establish that the SDS-stable complexes are formed only when the hydrophobic pocket 1 (P1) is occupied by a bulky aromatic (Trp, Phe, Tyr) or an aliphatic residue (Met, Ile, Val, Leu). To further explore whether the SDS sensitivity is primarily due to the exposed hydrophobic regions, we mutated residue beta Gly86 at the bottom of P1 to tyrosine, presumably reducing the depth of the pocket and the exposure of hydrophobic residues and increasing the contacts between subunits. In direct contrast to wild-type DR1, the peptide-free mutant DR1 exists as an alpha/beta heterodimer in SDS. Moreover, the presence of a smaller hydrophobic residue, such as alanine, as P1 anchor with no contribution from any other anchor is sufficient to enhance the SDS stability of the mutant complexes, demonstrating that the basis of SDS resistance may be localized to P1 interactions. The good correlation between SDS sensitivity and the exposure of hydrophobic residues provides a biochemical rationale for the use of this assay to investigate the maturation of class II molecules and the longevity of the complexes. PMID- 10092803 TI - A conserved sequence block in the murine and human TCR J alpha region: assessment of regulatory function in vivo. AB - Temporal control of rearrangement at the TCR alpha/delta locus is crucial for development of the gamma delta and alpha beta T cell lineages. Because the TCR delta locus is embedded within the alpha locus, rearrangement of any V alpha-J alpha excises the delta locus, precluding expression of a functional gamma delta TCR. Approximately 100 kb spanning the C delta-C alpha region has been sequenced from both human and mouse, and comparison has revealed an unexpectedly high degree of conservation between the two. Of interest in terms of regulation, several highly conserved sequence blocks (> 90% over > 50 bp) were identified that did not correspond to known regulatory elements such as the TCR alpha and delta enhancers or to coding regions. One of these blocks lying between J alpha 4 and J alpha 3, which appears to be conserved in other vertebrates, has been shown to augment TCR alpha enhancer function in vitro and differentially bind factors from nuclear extracts. To further assess a plausible regulatory role for this element, we have created mice in which this conserved sequence block is either deleted or replaced with a neomycin resistance gene driven by the phosphoglycerate kinase promoter (pgk-neor). Deletion of this conserved sequence block in vivo did have a local effect on J alpha usage, echoing the in vitro data. However, its replacement with pgk-neor had a much more dramatic, long range effect, perhaps underscoring the importance of maintaining overall structure at this locus. PMID- 10092804 TI - Two constituents of the initiation complex of the mannan-binding lectin activation pathway of complement are encoded by a single structural gene. AB - Mannan-binding lectin (MBL) forms a multimolecular complex with at least two MBL associated serine proteases, MASP-1 and MASP-2. This complex initiates the MBL pathway of complement activation by binding to carbohydrate structures present on bacteria, yeast, and viruses. MASP-1 and MASP-2 are composed of modular structural motifs similar to those of the C1q-associated serine proteases C1r and C1s. Another protein of 19 kDa with the same N-terminal sequence as the 76-kDa MASP-2 protein is consistently detected as part of the MBL/MASP complex. In this study, we present the primary structure of this novel MBL-associated plasma protein of 19 kDa, MAp19, and demonstrate that MAp19 and MASP-2 are encoded by two different mRNA species generated by alternative splicing/polyadenylation from one structural gene. PMID- 10092805 TI - Differential regulation of 4E-BP1 and 4E-BP2, two repressors of translation initiation, during human myeloid cell differentiation. AB - Human myeloid differentiation is accompanied by a decrease in cell proliferation. Because the translation rate is an important determinant of cell proliferation, we have investigated translation initiation during human myeloid cell differentiation using the HL-60 promyelocytic leukemia cell line and the U-937 monoblastic cell line. A decrease in the translation rate is observed when the cells are induced to differentiate along the monocytic/macrophage pathway or along the granulocytic pathway. The inhibition in protein synthesis correlates with specific regulation of two repressors of translation initiation, 4E-BP1 and 4E-BP2. Induction of HL-60 and U-937 cell differentiation into monocytes/macrophages by IFN-gamma or PMA results in a dephosphorylation and consequent activation of 4E-BP1. Dephosphorylation of 4E-BP1 was also observed when U-937 cells were induced to differentiate into monocytes/macrophages following treatment with retinoic acid or DMSO. In contrast, treatment of HL-60 cells with retinoic acid or DMSO, which results in a granulocytic differentiation of these cells, decreases 4E-BP1 amount without affecting its phosphorylation and strongly increases 4E-BP2 amount. Taken together, these data provide evidence for differential regulation of the translational machinery during human myeloid differentiation, specific to the monocytic/macrophage pathway or to the granulocytic pathway. PMID- 10092806 TI - A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. AB - The regulation of monocyte function and the inhibition of TNF-alpha production during bacterial sepsis are critical in attenuating adverse host responses to endotoxemia. To study the function of a novel receptor tyrosine kinase, mer, that is expressed in monocytes, we generated mice (merkd) that lack the signaling tyrosine kinase domain. Upon LPS challenge, merkd animals died of endotoxic shock (15/17, 88.2%), whereas control wild-type mice survived (1/15, 6.7% died). Susceptible merkd mice exhibited edema, leukocyte infiltration, and signs of endotoxic shock that correlated with higher levels of TNF-alpha found in the serum of merkd mice as compared with wild-type control animals. Death due to LPS induced endotoxic shock in merkd mice was blocked by administration of anti-TNF alpha Ab, suggesting that overproduction of this cytokine was principally responsible for the heightened suseptibility. The increase in TNF-alpha production appeared to be the result of a substantial increase in the LPS dependent activation of NF-kappa B nuclear translocation resulting in greater TNF alpha production by macrophages from merkd mice. Thus, Mer receptor tyrosine kinase signaling participates in a novel inhibitory pathway in macrophages important for regulating TNF-alpha secretion and attenuating endotoxic shock. PMID- 10092807 TI - Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. AB - TNF and lymphotoxin-alpha (LT alpha) may act at various stages of the host response to Mycobacterium tuberculosis. To dissect the effects of TNF independent of LT alpha, we have used C57BL/6 mice with a disruption of the TNF gene alone (TNF-/-). Twenty-one days following aerosol M. tuberculosis infection there was a marked increase in the number of organisms in the lungs of TNF-/- mice, and by 28 35 days all animals had succumbed, with widespread dissemination of M. tuberculosis. In comparison with the localized granulomas containing activated macrophages and T cells in lungs and livers of C57BL/6 wild-type (wt) mice, cellular infiltrates in TNF-/- mice were poorly formed, with extensive regions of necrosis and neutrophilic infiltration of the alveoli. Phenotypic analysis of lung homogenates demonstrated similar numbers of CD4+ and CD8+ T cells in TNF-/- and wt mice, but in TNF-deficient mice the lymphocytes were restricted to perivascular and peribronchial areas rather than colocated with macrophages in granulomas. T cells from TNF-/- mice retained proliferative and cytokine responses to purified protein derivative, and delayed-type hypersensitivity to purified protein derivative was demonstrable. Macrophages within the lungs of TNF /- and wt mice showed similar levels of MHC class II and inducible nitric oxide synthase expression, and levels of serum nitrite were comparable. Thus, the enhanced susceptibility of TNF-/- is not compensated for by the presence of LT alpha, and the critical role of TNF is not in the activation of T cells and macrophages but in the local organization of granulomas. PMID- 10092808 TI - Inhibition of inducible nitric oxide synthase exacerbates chronic cerebral toxoplasmosis in Toxoplasma gondii-susceptible C57BL/6 mice but does not reactivate the latent disease in T. gondii-resistant BALB/c mice. AB - Infection of C57BL/6 mice with Toxoplasma gondii leads to progressive and ultimately fatal chronic Toxoplasma encephalitis (TE). Genetic deletion or inhibition of inducible nitric oxide synthase (iNOS) from the beginning of infection increased the number of T. gondii cysts in the brain and markedly reduced the time-to-death in this mouse strain. In the present study, we addressed whether iNOS also contributes to the control of intracerebral parasites in a clinically stable latent infection that develops in T. gondii-resistant BALB/c mice after resolution of the acute phase of TE. iNOS was expressed in the inflammatory cerebral infiltrates of latently infected BALB/c mice, but the number of iNOS+ cells was significantly lower than in the brains of chronically infected T. gondii-susceptible C57BL/6 mice. In BALB/c mice with latent TE (> 30 days of infection), treatment with the iNOS inhibitors L-N6-iminoethyl-lysine or L-nitroarginine-methylester for < or = 40 days did not result in an increase of the intracerebral parasitic load and a reactivation of the disease, despite the presence of iNOS-suppressive inhibitor levels in the brain. However, L nitroarginine-methylester treatment had remarkably toxic effects and induced a severe wasting syndrome with high mortality. In contrast to BALB/c mice, L-N6 iminoethyl-lysine treatment rapidly exacerbated the already established chronic TE of C57BL/6 mice. Thus, the containment of latent toxoplasms in T. gondii resistant BALB/c mice is independent of iNOS, whereas the temporary control of intracerebral parasites in T. gondii-susceptible C57BL/6 mice with chronic TE requires iNOS activity. PMID- 10092809 TI - Modulation of endocytosis in nuclear factor IL-6(-/-) macrophages is responsible for a high susceptibility to intracellular bacterial infection. AB - Activated macrophages kill bacteria, a function known to depend on the expression of NF-IL-6. Here, it is demonstrated that the attenuated Brucella abortus vaccine strain 19 replicates much better in NF-IL-6-/- than in NF-IL-6(+/+) and NF-IL 6(+/+)-activated murine macrophages and at levels comparable to those observed in normal macrophages infected with the pathogenic strain 2308. The role of NF-IL-6 in the inhibition of intracellular bacterial replication is related to its control of endocytosis and membrane fusion between endosomes and Brucella containing phagosomes. Addition of the granulocyte-CSF (G-CSF), whose induction is impaired in NF-IL-6(-/-) macrophages, restores both endocytosis and the morphology of endosomes, together with bactericidal activity. Regulation of membrane traffic in endocytosis by G-CSF whose expression is controlled by NF-IL 6 may explain how a host cell can control intracellular bacterial replication. PMID- 10092810 TI - Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. AB - Certain cytokines activate the hypothalamic-pituitary-adrenal axis for glucocorticoid release, and these hormones can protect against cytokine-mediated pathologies. However, endogenous activation of such a pathway has not been established during infections. A prominent glucocorticoid response peaks 36 h following murine CMV (MCMV) infection, coincident with circulating levels of the cytokines IL-12, IFN-gamma, TNF, and IL-6, and dependent on IL-6 for maximal release. These studies examined functions of the hormone induction. Mice rendered glucocorticoid deficient by adrenalectomy were more susceptible than intact mice to MCMV-induced lethality, and the increased sensitivity was reversed by hormone replacement. Lack of endogenous glucocorticoids resulted in increases in IL-12, IFN-gamma, TNF, and IL-6 production, as well as in mRNA expression for a wider range of cytokines, also including IL-1 alpha and IL-1 beta. Viral burdens did not increase, and actually decreased, in the livers of glucocorticoid-deficient mice. TNF, but not IFN-gamma, was required for increased lethality in the absence of endogenous hormone. These results conclusively demonstrate the importance of induced endogenous glucocorticoids in protection against life-threatening effects resulting from infection-elicited cytokine responses. Taken together with the dependence on induced IL-6, they document existence of an immune system hypothalamic-pituitary-adrenal axis pathway for regulating endogenous responses to viral infections. PMID- 10092811 TI - Identification of a second major tumor-specific antigen recognized by CTLs on mouse mastocytoma P815. AB - Murine mastocytoma P815 induces CTL responses against at least four distinct Ags (AB, C, D, and E). Recent studies have shown that the main component of the CTL response against the P815 tumor is targeted against Ags P815AB and P815E. The gene P1A has been well characterized. It encodes the P815AB Ag in the form of a nonameric peptide containing two epitopes, P815A and P815B, which are recognized by different CTLs. Here, we report the identification of the P815E Ag. Using a cDNA library derived from tumor P815, we identified the gene coding for P815E. We also characterized the antigenic peptide that anti-P815E CTLs recognize on the MHC class I molecule H-2Kd. The P815E Ag results from a mutation within an ubiquitously expressed gene encoding methionine sulfoxide reductase, an enzyme that is believed to be important in the protection of proteins against the by products of aerobic metabolism. Surprisingly, immunizing mice i.p. with syngeneic tumor cells (L1210) that were constructed to express B7-1 and P815E did not induce resistance against live P815, even though a strong anti-P815E CTL response was observed with splenocytes from immunized animals. PMID- 10092812 TI - Differential sensitivity of distinct Chlamydia trachomatis isolates to IFN-gamma mediated inhibition. AB - Resistance to the mouse pneumonitis (MoPn) strain of Chlamydia trachomatis has been mapped to MHC class II-restricted, IL-12-dependent CD4+ T cells that secrete a type 1 profile of proinflammatory cytokines, which includes IFN-gamma and TNF alpha. The relative contribution of IFN-gamma is controversial, however, due to variation in results presented by different laboratories. To determine whether C. trachomatis strain differences contributed to this apparent conflict, the relative resistance of IFN-gamma-deficient mice to murine and human strains of C. trachomatis was compared. All human serovars were much more sensitive to the direct inhibitory actions of IFN-gamma than the MoPn strain. Furthermore, genital clearance of human serovar D in the C57BL/6 mouse was mediated by class II independent mechanisms that probably involved local production of IFN-gamma by cells of the innate immune system. TNF-alpha also contributed indirectly to host resistance against all strains tested. The differential susceptibility of distinct C. trachomatis strains to effector cytokines such as IFN-gamma could not have been predicted by interstrain biologic variation or by the profile of cytokines stimulated during infection. These findings indicate that strain variation should be considered in situations where related isolates of a given parasite produce conflicting data in models of infection and immunity. They also suggest that stimulation of mucosal IFN-gamma activity is a relevant goal for a human chlamydial vaccine. PMID- 10092813 TI - The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells. AB - Recruitment of activated T cells to mucosal surfaces, such as the airway epithelium, is important in host defense and for the development of inflammatory diseases at these sites. We therefore asked whether the CXC chemokines IFN induced protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN inducible T-cell alpha-chemoattractant (I-TAC), which specifically chemoattract activated T cells by signaling through the chemokine receptor CXCR3, were inducible in respiratory epithelial cells. The effects of proinflammatory cytokines, including IFN-gamma (Th1-type cytokine), Th2-type cytokines (IL-4, IL 10, and IL-13), and dexamethasone were studied in normal human bronchial epithelial cells (NHBEC) and in two human respiratory epithelial cell lines, A549 and BEAS-2B. We found that IFN-gamma, but not TNF-alpha or IL-1 beta, strongly induced IP-10, Mig, and I-TAC mRNA accumulation mainly in NHBEC and that TNF alpha and IL-1 beta synergized with IFN-gamma induction in all three cell types. High levels of IP-10 protein (> 800 ng/ml) were detected in supernatants of IFN gamma/TNF-alpha-stimulated NHBEC. Neither dexamethasone nor Th2 cytokines modulated IP-10, Mig, or I-TAC expression. Since IFN-gamma is up-regulated in tuberculosis (TB), using in situ hybridization we studied the expression of IP-10 in the airways of TB patients and found that IP-10 mRNA was expressed in the bronchial epithelium. In addition, IP-10-positive cells obtained by bronchoalveolar lavage were significantly increased in TB patients compared with normal controls. These results show that activated bronchial epithelium is an important source of IP-10, Mig, and I-TAC, which may, in pulmonary diseases such as TB (in which IFN-gamma is highly expressed) play an important role in the recruitment of activated T cells. PMID- 10092814 TI - Nasopharyngeal-associated lymphoreticular tissue (NALT) immunity: fimbriae specific Th1 and Th2 cell-regulated IgA responses for the inhibition of bacterial attachment to epithelial cells and subsequent inflammatory cytokine production. AB - To investigate the antibacterial activity of mucosal Th1 and Th2 immune responses induced nasally and orally, mice were immunized with mucosal vaccine containing fimbrial protein of Porphyromonas gingivalis, a causative agent for a destructive chronic inflammation in the periodontium, and cholera toxin (CT) as mucosal adjuvant. Nasal vaccine containing low doses of fimbriae (10 micrograms) and CT (1 microgram) induced Ag-specific Th1/Th2-type response in CD4+ T cells in mucosal effector tissues, including nasal passage and submandibular glands, which accounted for the generation of Ag-specific IgA-producing cells. In contrast, oral immunization required higher amounts of fimbriae and CT for the induction of Ag-specific IgA responses. Fimbriae-specific IgA mAbs generated from submandibular glands of nasally immunized mice inhibited P. gingivalis attachment to and reduced subsequent inflammatory cytokine production from epithelial cells. These findings suggest that nasal vaccination is an effective immunization regimen for the induction of Ag-specific Th1 and Th2 cell-driven IgA immune responses that possess the ability to inhibit bacterial attachment to epithelial cells and subsequent inflammatory cytokine production. PMID- 10092815 TI - Assessment of immunogenicity of human Melan-A peptide analogues in HLA-A*0201/Kb transgenic mice. AB - Previous studies have shown that substitution of single amino acid residues in human Melan-A immunodominant peptides Melan-A27-35 and Melan-A26-35 greatly improved their binding and the stability of peptide/HLA-A*0201 complexes. In particular, one Melan-A peptide analogue was more efficient in the generation of Melan-A peptide-specific and melanoma-reactive CTL than its parental peptide in vitro from human PBL. In this study, we analyzed the in vivo immunogenicity of Melan-A natural peptides and their analogues in HLA-A*0201/Kb transgenic mice. We found that two human Melan-A natural peptides, Melan-A26-35 and Melan-A27-35, were relatively weak immunogens, whereas several Melan-A peptide analogues were potent immunogens for in vivo CTL priming. In addition, induced Melan-A peptide specific mouse CTL cross-recognized natural Melan-A peptides and their analogues. More interestingly, these mouse CTL were also able to lyse human melanoma cell lines in vitro in a HLA-A*0201-restricted, Melan-A-specific manner. Our results indicate that the HLA-A*0201/Kb transgenic mouse is a useful animal model to perform preclinical testing of potential cancer vaccines, and that Melan-A peptide analogues are attractive candidates for melanoma immunotherapy. PMID- 10092816 TI - Successful adoptive immunotherapy of murine poorly immunogenic tumor with specific effector cells generated from gene-modified tumor-primed lymph node cells. AB - We previously reported that cytokine gene transfer into weakly immunogenic tumor cells could enhance the generation of precursor cells of tumor-reactive T cells and subsequently augment antitumor efficacy of adoptive immunotherapy. We investigated whether such potent antitumor effector T cells could be generated from mice bearing poorly immunogenic tumors. In contrast to similarly modified weakly immunogenic tumors, MCA102 cells, which are chemically induced poorly immunogenic fibrosarcoma cells transfected with cDNA for IL-2, IL-4, IL-6, IFN gamma, failed to augment the host immune reaction. Because priming of antitumor effector T cells in vivo requires two important signals provided by tumor associated Ags and costimulatory molecules, these tumor cells were cotransfected with a B7-1 cDNA. Transfection of both IFN-gamma and B7-1 (MCA102/B7-1/IFN-gamma) resulted in regression of s.c. tumors, while tumor transfected with other combinations of cytokine and B7-1 showed progressive growth. Cotransfection of IFN-gamma and B7-1 into other poorly immunogenic tumor B16 and LLC cells also resulted in the regression of s.c. tumors. Cells derived from lymph nodes draining MCA102/B7-1/IFN-gamma tumors showed potent antitumor efficacy, eradicating established pulmonary metastases, but this effect was not seen with parental tumors. This mechanism of enhanced antitumor efficacy was further investigated, and T cells with down-regulated L-selectin expression, which constituted all the in vivo antitumor reactivity, were significantly increased in lymph nodes draining MCA102/B7-1/IFN-gamma tumors. These T cells developed into potent antitumor effector cells after in vitro activation with anti-CD3/IL-2. The strategy presented here may provide a basis for developing potent immunotherapy for human cancers. PMID- 10092817 TI - C1qRP is a heavily O-glycosylated cell surface protein involved in the regulation of phagocytic activity. AB - C1q, mannose-binding lectin (MBL), and pulmonary surfactant protein A (SPA) interact with human monocytes and macrophages, resulting in the enhancement of phagocytosis of suboptimally opsonized targets. mAbs that recognize a cell surface molecule of 126,000 Mr, designated C1qRP, have been shown to inhibit C1q- and MBL-mediated enhancement of phagocytosis. Similar inhibition of the SPA mediated enhancement of phagocytosis by these mAbs now suggests that C1qRP is a common component of a receptor for these macromolecules. Ligation of human monocytes with immobilized R3, a IgM mAb recognizing C1qRP, also triggers enhanced phagocytic capacity of these cells in the absence of ligand, verifying the direct involvement of this polypeptide in the regulation of phagocytosis. While the cDNA for C1qRP encodes a 631 amino acid membrane protein, Chinese hamster ovary cells transfected with the cDNA of the C1qRP coding region express a surface glycoprotein with the identical 126,000 Mr in SDS-PAGE as the native C1qRP. Use of glycosylation inhibitors, cleavage of the mature C1qRP with specific glycosidases, and in vitro translation of C1qRP cDNA demonstrated that both posttranslational glycosylation and the nature of the amino acid sequence of the protein contribute to the difference between its predicted m.w. and its migration on SDS-PAGE. These results verify that the cDNA cloned codes for the mature C1qRP, that C1qRP contains a relatively high degree of O-linked glycoslyation, and that C1qRP cross-linked directly by monoclonal anti-C1qRP or engaged as a result of cell surface ligation of SPA, as well as C1q and MBL, enhances phagocytosis. PMID- 10092818 TI - Modulation of formyl peptide receptor expression by IL-10 in human monocytes and neutrophils. AB - IL-10, originally described as a cytokine synthesis inhibitory factor, is secreted by a number of cells of the immune system, including monocytes and T cells. Although IL-10 is being assigned as an immunosuppressive cytokine, our study showed that FMLP-R mRNA was rapidly up-regulated by exposure of monocytes to graded concentrations of this cytokine, with maximal (three- to fourfold) stimulation with 10 ng/ml. The effect was rapid, being observable as early as 1 h of treatment with IL-10, maximal between 2 and 4 h, and still evident after 24 h and was associated with an increase of receptor expression on the cell surface as assessed by flow cytometry analysis. Pretreatment of monocytes with actinomycin D completely abrogated the effect of IL-10, suggesting a transcriptional regulation. Moreover, IL-10-treated monocytes showed a significantly enhanced functional responsiveness to FMLP with enhanced (three- to fourfold) chemotaxis and augmented (twofold) intracellular calcium mobilization. In polymorphonuclear neutrophils (PMN), IL-10 also mediated a twofold augmentation of FMLP-R expression. In parallel experiments, we observed that IL-10 could differentially modulate other chemotactic receptors. Hence, we observed that IL-10 augmented two to threefold platelet-activating factor receptor (PAF-R) expression, whereas it had no significant effect on the fifth component of complement (C5a) receptor (C5a-R) expression. Collectively, our results demonstrate that IL-10 may play an important role in inflammatory process through modulation of chemotactic receptor expression. PMID- 10092819 TI - Paradoxical preservation of a lipopolysaccharide response in C3H/HeJ macrophages: induction of matrix metalloproteinase-9. AB - C3H/HeJ mice carry a mutant allele (Lpsd) of a recently identified gene whose normal allele (Lpsn) confers responsiveness to bacterial LPS in C3H/HeN and most other mouse strains. Recently we reported differential display analysis of matched macrophage-derived cell lines from C3H/HeJ and C3H/HeN mice under LPS free conditions. Of the approximately 12,000 transcripts evaluated, 4 were differentially expressed. One transcript represented secretory leukocyte protease inhibitor. In this study, we report another differentially expressed transcript, mouse matrix metalloprotease-9 (MMP-9). Like secretory leukocyte protease inhibitor, MMP-9 was expressed constitutively in the Lpsd macrophage cell line and not in the Lpsn cell line. Similarly, two additional macrophage cell lines that respond readily to LPS by producing nitric oxide and TNF expressed no MMP-9 under LPS-free conditions. However, in all four cell lines, LPS induced MMP-9 or augmented its expression. In primary macrophages, concentrations of LPS in the ng/ml range augmented the expression of MMP-9 mRNA. Paradoxically, macrophages from Lpsd mice expressed more MMP-9 transcripts than macrophages from Lpsn mice. In contrast, the induction of TNF in response to LPS was much more pronounced in Lpsn macrophages. The present findings with MMP-9 suggest that homozygosity at Lpsd does not so much prevent a response to LPS as dysregulate it, resulting in the suppression of some LPS signaling pathways and the preservation of others. PMID- 10092820 TI - Soluble Fas ligand is chemotactic for human neutrophilic polymorphonuclear leukocytes. AB - It has been recently shown that Fas ligand (FasL) expression on islet beta grafts results in neutrophilic infiltration and graft rejection. In this study, we show that human recombinant soluble FasL is endowed with potent chemotactic properties toward human neutrophilic polymorphonuclear leukocytes (neutrophils) at concentrations incapable of inducing cell apoptosis. Furthermore, neutrophils exposed to soluble FasL did not display detectable change of intracellular Ca2+ and did not undergo superoxide production or exocytosis of primary and secondary granules. Our results show that FasL is a potent chemoattractant for human neutrophils without evoking their secretory responses. This finding suggests a novel proinflammatory function for this ligand and may help to clarify the mechanism governing FasL-mediated graft rejection, thereby offering rational bases for controlling and modulating FasL-based immunotherapies. PMID- 10092821 TI - IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. AB - Adenosine is a potent endogenous anti-inflammatory agent released by cells in metabolically unfavorable conditions, such as hypoxia or ischemia. Adenosine modulates different functional activities in macrophages. Some of these activities are believed to be induced through the uptake of adenosine into the macrophages, while others are due to the interaction with specific cell surface receptors. In murine bone marrow-derived macrophages, the use of different radioligands for adenosine receptors suggests the presence of A2B and A3 adenosine receptor subtypes. The presence of A2B receptors was confirmed by flow cytometry using specific Abs. The A2B receptor is functional in murine macrophages, as indicated by the fact that agonists of A2B receptors, but not agonists for A1, A2A, or A3, lead to an increase in cAMP levels. IFN-gamma up regulates the surface protein and gene expression of the A2B adenosine receptor by induction of de novo synthesis. The up-regulation of A2B receptors correlates with an increase in cAMP production in macrophages treated with adenosine receptor agonist. The stimulation of A2B receptors by adenosine or its analogues inhibits the IFN-gamma-induced expression of MHC class II genes and also the IFN gamma-induced expression of nitric oxide synthase and of proinflammatory cytokines. Therefore, the up-regulation of the A2B adenosine receptor expression induced by IFN-gamma could be a feedback mechanism for macrophage deactivation. PMID- 10092822 TI - Dynamic association of L-selectin with the lymphocyte cytoskeletal matrix. AB - L-selectin mediates lymphocyte extravasation into lymphoid tissues through binding to sialomucin-like receptors on the surface of high endothelial venules (HEV). This study examines the biochemical basis and regulation of interactions between L-selectin, an integral transmembrane protein, and the lymphocyte cytoskeleton. Using a detergent-based extraction procedure, constitutive associations between L-selectin and the insoluble cytoskeletal matrix could not be detected. However, engagement of the L-selectin lectin domain by Abs or by glycosylation-dependent cell adhesion molecule-1, an HEV-derived ligand for L selectin, rapidly triggered redistribution of L-selectin to the detergent insoluble cytoskeleton. L-selectin attachment to the cytoskeleton was not prevented by inhibitors of actin/microtubule polymerization (cytochalasin B, colchicine, or nocodozole) or serine/threonine and tyrosine kinase activity (staurosporine, calphostin C, or genistein), although L-selectin-mediated adhesion of human PBL was markedly suppressed by these agents. Exposure of human PBL or murine pre-B transfectants expressing full-length human L-selectin to fever-range hyperthermia also markedly increased L-selectin association with the cytoskeleton, directly correlating with enhanced L-selectin-mediated adhesion. In contrast, a deletion mutant of L-selectin lacking the COOH-terminal 11 amino acids failed to associate with the cytoskeletal matrix in response to Ab cross linking or hyperthermia stimulation and did not support adhesion to HEV. These studies, when taken together with the previously demonstrated interaction between the L-selectin cytoplasmic domain and the cytoskeletal linker protein alpha actinin, strongly implicate the actin-based cytoskeleton in dynamically controlling L-selectin adhesion. PMID- 10092823 TI - Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. AB - Gene therapy is a promising new approach in the treatment of rheumatoid arthritis. Gene delivery to diseased joints offers the prospect of achieving high, local concentrations of a therapeutic gene product in a sustained manner, while minimizing exposure of nontarget organs. We report that a single administration of a modified adenovirus encoding the Epstein-Barr-derived homologue of IL-10 can suppress the development of disease for extended periods of time when injected locally within the periarticular tissue surrounding the ankle joints of mice with collagen type II-induced arthritis. Furthermore, we show that injection of an adenoviral vector carrying the IL-10 gene into a single paw can suppress development of arthritis in other, noninjected paws of the same individual. The systemic protection resulting from local gene therapy occurred in the absence of detectable levels of viral IL-10 in the serum. Circulating Ab levels to heterologous collagen were unaffected; however, treatment with viral IL 10 significantly suppressed the development of Abs to autologous mouse type II collagen. Thus, the treatment of a single joint by local delivery of the vIL-10 gene may protect multiple joints of the same individual while avoiding deleterious side effects often associated with systemic therapy. PMID- 10092824 TI - Endotoxin fails to induce IFN-gamma in endotoxin-tolerant mice: deficiencies in both IL-12 heterodimer production and IL-12 responsiveness. AB - Mice exposed to sublethal endotoxemia develop short-term endotoxin tolerance, a state characterized by decreased monokine production and enhanced protection against endotoxic lethality. We confirmed that TNF-alpha production is markedly impaired in endotoxin-tolerant mice and additionally found 2- to 6-fold decreases in serum IFN-gamma in these animals following endotoxin challenge. The IFN-gamma deficiency of endotoxin tolerance correlated with 8-fold decreases in the bioactive p40/p35 heterodimeric form of IL-12. In contrast, total circulating IL 12 p40 was reduced by only 30-50%. Endotoxin-tolerant mice were less responsive to IL-12 than control mice, as evidenced by 3-fold lower levels of IFN-gamma inducible in vivo when rIL-12 was administered at the time of endotoxin challenge. Similarly, spleen cell cultures of endotoxin-tolerant mice produced 3 fold less IFN-gamma in the presence of optimal concentrations of both IL-12 and IL-18. Finally, levels of IL-12R beta 2 subunit mRNA and the percent composition of NK lymphocytes in the spleen were both decreased in endotoxin-tolerant mice relative to controls. We conclude that endotoxin-tolerant mice are profoundly impaired in their ability to produce IFN-gamma in response to endotoxin and that this is associated with acquired defects in both the production of circulating IL 12 heterodimer response and the response to IL-12 by NK cells. PMID- 10092825 TI - Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. AB - Phagocyte recognition, uptake, and nonphlogistic degradation of neutrophils and other leukocytes undergoing apoptosis promote the resolution of inflammation. This study assessed the effects of anti-inflammatory glucocorticoids on this leukocyte clearance mechanism. Pretreatment of "semimature" 5-day human monocyte derived macrophages (M phi) for 24 h with methylprednisolone, dexamethasone, and hydrocortisone, but not the nonglucocorticoid steroids aldosterone, estradiol, and progesterone, potentiated phagocytosis of apoptotic neutrophils. These effects were specific in that the potentiated phagocytosis of apoptotic neutrophils was completely blocked by the glucocorticoid receptor antagonist RU38486, and glucocorticoids did not promote 5-day M phi ingestion of opsonized erythrocytes. Similar glucocorticoid-mediated potentiation was observed with 5 day M phi uptake of alternative apoptotic "targets" (eosinophils and Jurkat T cells) and in uptake of apoptotic neutrophils by alternative phagocytes (human glomerular mesangial cells and murine M phi elicited into the peritoneum or derived from bone marrow). Importantly, methylprednisolone-mediated enhancement of the uptake of apoptotic neutrophils did not trigger the release of the chemokines IL-8 and monocyte chemoattractant protein-1. Furthermore, longer-term potentiation by methylprednisolone was observed in maturing human monocyte derived M phi, with greater increases in 5-day M phi uptake of apoptotic cells being observed the earlier glucocorticoids were added during monocyte maturation into M phi. We conclude that potentiation of nonphlogistic clearance of apoptotic leukocytes by phagocytes is a hitherto unrecognized property of glucocorticoids that has potential implications for therapies aimed at promoting the resolution of inflammatory diseases. PMID- 10092826 TI - Amplification of the antibody response by C3b complexed to antigen through an ester link. AB - Complement C3 has been described as playing an important role in the cell mediated immune response. C3b has the capacity to covalently bind Ag and then to stimulate in vitro Ag presentation to T lymphocytes. To verify this observation in vivo, we prepared and purified covalent human C3b-Ag complexes using lysozyme (HEL) as Ag. The characterization of these HEL-C3b complexes indicates that they are representative of those susceptible to be generated in physiological conditions. Mice were immunized with 0.1 to 0.6 microgram of either free HEL, HEL + C3b, HEL-C3b, or HEL + CFA. Response was assessed after two i.p. injections by quantification of specific Ab production. Immunization with either HEL-C3b complexes or HEL + CFA leads to anti-HEL IgG production whereas free HEL or HEL + C3b was ineffective. Either HEL-C3b or HEL + CFA immunizations led to a similar Ig subclass patterns, including IgG1, IgG2a, IgA, and IgM. Our experiments provide the first evidence for modulation of specific Ab response by C3b when it is bound to Ag through a physiological-like link. Taken together with previous data concerning Ab response following recombinant HEL-C3d immunization, cellular events such as processing of C3b-Ag by APC and recognition by T lymphocytes, this present result underlines the importance of C3b and its fragments in stimulation of the immune system, through the multiplicity and complementarity of its interactions. PMID- 10092827 TI - Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury. AB - Inflammatory lung injury is probably regulated by the balance between proteases and protease inhibitors together with oxidants and antioxidants, and proinflammatory and anti-inflammatory cytokines. Rat tissue inhibitor of metalloprotease-2 (TIMP-2) and secreted leukoprotease inhibitor (SLPI) were cloned, expressed, and shown to be up-regulated at the levels of mRNA and protein during lung inflammation in rats induced by deposition of IgG immune complexes. Using immunoaffinity techniques, endogenous TIMP-2 in the inflamed lung was shown to exist as a complex with 72- and 92-kDa metalloproteinases (MMP-2 and MMP-9). In inflamed lung both TIMP-2 and SLPI appeared to exist as enzyme inhibitor complexes. Lung expression of both TIMP-2 and SLPI appeared to involve endothelial and epithelial cells as well as macrophages. To assess how these endogenous inhibitors might affect the lung inflammatory response, animals were treated with polyclonal rabbit Abs to rat TIMP-2 or SLPI. This intervention resulted in significant intensification of lung injury (as revealed by extravascular leak of albumin) and substantially increased neutrophil accumulation, as determined by cell content in bronchoalveolar lavage (BAL) fluids. These events were correlated with increased levels of C5a-related chemotactic activity in BAL fluids, while BAL levels of TNF-alpha and chemokines were not affected by treatment with anti-TIMP-2 or anti-SLPI. The data suggest that endogenous TIMP-2 and SLPI dynamically regulate the intensity of lung inflammatory injury, doing so at least in part by affecting the generation of the inflammatory mediator, C5a. PMID- 10092828 TI - Elimination of the immunogenicity of therapeutic antibodies. AB - The immunogenicity of therapeutic Abs limits their long-term use. The processes of complementarity-determining region grafting, resurfacing, and hyperchimerization diminish mAb immunogenicity by reducing the number of foreign residues. However, this does not prevent anti-idiotypic and anti-allotypic responses following repeated administration of cell-binding Abs. Classical studies have demonstrated that monomeric human IgG is profoundly tolerogenic in a number of species. If cell-binding Abs could be converted into monomeric non-cell binding tolerogens, then it should be possible to pretolerize patients to the therapeutic cell-binding form. We demonstrate that non-cell-binding minimal mutants of the anti-CD52 Ab CAMPATH-1H lose immunogenicity and can tolerize to the "wild-type" Ab in CD52-expressing transgenic mice. This finding could have utility in the long-term administration of therapeutic proteins to humans. PMID- 10092829 TI - Implication of TNF receptor-I-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation in growth of AIDS-associated Kaposi's sarcoma cells: a possible role of a novel death domain protein MADD in TNF-alpha-induced ERK1/2 activation in Kaposi's sarcoma cells. AB - TNF-alpha is a key pathogenic mediator of infectious and inflammatory diseases. HIV infection stimulates and dysregulates the immune system, leading to abnormal production of TNF-alpha. Despite its cytotoxic effect on some tumor cell lines, TNF-alpha functions as a growth stimulator for Kaposi's sarcoma (KS), a common malignancy in HIV-infected patients. However, signaling pathways linked to TNF alpha-induced mitogenic responses are not well understood. We found that extracellular signal-regulated kinases 1 and 2 (ERK1/2) in KS cells were significantly activated by TNF-alpha through tyrosine/threonine phosphorylation. Using neutralizing anti-TNFR-I and TNFR-II mAbs, we have now obtained evidence that TNF-alpha-induced KS cell growth and ERK1/2 activation are mediated exclusively by TNFR-I, not by TNFR-II. A selective inhibitor for ERK1/2 activator kinases, PD98059, profoundly inhibited not only the activation of ERK1/2, but also the TNF-alpha-induced KS cell proliferation. We therefore propose that the TNFR-I-ERK1/2 pathway plays a pivotal role in transmitting to KS cells the mitogenic signals of TNF-alpha. TNFR-I possesses no intrinsic kinase activity, suggesting that TNFR-I-associated proteins may provide a link between TNFR-I and ERK1/2 activation. We found that actinomycin D treatment of KS cells selectively abolished expression of mitogen-activated protein kinase-activating death domain protein (MADD), a novel TNFR-I-associated death domain protein. TNF-alpha failed to induce ERK1/2 activation in the actinomycin D-treated cells. MADD may couple TNFR-I with the ERK1/2 signaling pathway required for KS cell proliferation. PMID- 10092830 TI - Clonal dominance patterns of CD8 T cells in relation to disease progression in HIV-infected children. AB - CD8 T cells are important mediators of cellular immune responses as evidenced by clonal expansions in the CD8 TCR V beta repertoire during primary HIV infection in adults. This study investigated the CD8 TCR V beta repertoire by complementarity-determining region 3 length analysis using multiplex PCR in purified peripheral blood CD8 T cells of 22 HIV-infected children (age range was 0.75-15 yr, mean was 8.2 +/- 4.1 yr). Evidence of clonal dominance in one or more V beta families was obtained in 15 of 22 children. The patterns of clonal dominance were designated as major, minor, single, and none to indicate the involvement of three or more, two, one, or no V beta families, respectively. A pattern of major or minor clonal dominance was observed in 12 children (group 1), whereas 10 children had single or no clonal dominance (group 2). In comparison with group 2, the children in group 1 had a higher percentage of CD4 cells (28.3 +/- 11.6 vs 8.6 +/- 4.8, p < 0.001); a higher stimulation index in lymphoproliferative responses to Candida (92.0 +/- 59.5 vs 12.3 +/- 14.4, p = 0.002), tetanus (76.3 +/- 51.2 vs 11.2 +/- 12.7, p = 0.002), and alloantigens (178.3 +/- 298.9 vs 32.9 +/- 35.2, p < 0.001); and a lower percentage of CD8+HLA DR+CD38+ cells (37.4 +/- 13.1 vs 54.6 +/- 14.2, p < 0.01). The number of dominant CD8 T cell clones was significantly correlated with the percentage of CD4 T cells (r = 0.669, p < 0.001) but not with plasma HIV RNA. Compared with group 1, patients in group 2 had a 4.8 times greater probability of having < 15% CD4 cells. These findings indicate that CD8 clonal dominance in HIV-infected children reflects robustness of immune responses, regardless of time since infection and virus load. PMID- 10092831 TI - Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes. AB - The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele. PMID- 10092832 TI - EBV gene expression not altered in rheumatoid synovia despite the presence of EBV antigen-specific T cell clones. AB - T cells infiltrating the rheumatoid arthritis (RA) joint are oligoclonal, implicating an Ag-driven process, but the putative joint-specific Ags remain elusive. Here we examine expression of selected EBV genes in RA synovia and find no abnormal expression in RA. DNA of CMV and EBV was detectable by PCR in the synovial tissue of RA. RNA of several latent and lytic EBV genes was also detectable. However, there were no differences in EBV gene expression in synovial tissues or peripheral blood when comparing RA with osteoarthritis, Gulf War syndrome, and other disease controls. RA synovia with highly expanded CD8 T cell clones reactive with defined EBV peptide Ags presented by HLA class I alleles lacked evidence of abnormal mRNA expression for the relevant EBV Ag (BZLF1) or lacked amplifiable mRNA (BMLF1). Thus, local production of EBV Ags in synovial tissues may not be the cause of the accumulation of T cell clones specific for these Ags. Instead, APCs loaded with processed EBV peptides may migrate to the synovium. Alternatively, EBV-specific T cells clones may be generated in other tissues and then migrate to synovia, perhaps due to cross-reactive joint-specific Ags or because of expression of homing receptors. PMID- 10092833 TI - Colitis-inducing potency of CD4+ T cells in immunodeficient, adoptive hosts depends on their state of activation, IL-12 responsiveness, and CD45RB surface phenotype. AB - We studied the induction, severity and rate of progression of inflammatory bowel disease (IBD) induced in SCID mice by the adoptive transfer of low numbers of the following purified BALB/c CD4+ T cell subsets: 1) unfractionated, peripheral, small (resting), or large (activated) CD4+ T cells; 2) fractionated, peripheral, small, or large, CD45RBhigh or CD45RBlow CD4+ T cells; and 3) peripheral IL-12 unresponsive CD4+ T cells from STAT-4-deficient mice. The adoptive transfer into SCID host of comparable numbers of CD4+ T cells was used to assess the colitis inducing potency of these subsets. Small CD45RBhigh CD4+ T lymphocytes and activated CD4+ T blasts induced early (6-12 wk posttransfer) and severe disease, while small resting and unfractionated CD4+ T cells or CD45RBlow T lymphocytes induced a late-onset disease 12-16 wk posttransfer. SCID mice transplanted with STAT-4-/- CD4+ T cells showed a late-onset IBD manifest > 20 wk posttransfer. In SCID mice with IBD transplanted with IL-12-responsive CD4+ T cells, the colonic lamina propria CD4+ T cells showed a mucosa-seeking memory/effector CD45RBlow Th1 phenotype abundantly producing IFN-gamma and TNF-alpha. In SCID mice transplanted with IL-12-unresponsive STAT-4-/- CD4+ T cells, the colonic lamina propria, mesenteric lymph node, and splenic CD4+ T cells produced very little IFN-gamma but abundant levels of TNF-alpha. The histopathologic appearance of colitis in all transplanted SCID mice was similar. These data indicate that CD45RBhigh and CD45RBlow, IL-12-responsive and IL-12-unresponsive CD4+ T lymphocytes and lymphoblasts have IBD-inducing potential though of varying potency. PMID- 10092834 TI - Differential effects of CD40 ligand/trimer stimulation on the ability of dendritic cells to replicate and transmit HIV infection: evidence for CC chemokine-dependent and -independent mechanisms. AB - The role of exogenous stimulation of CD40 by CD40 ligand (CD40L) in dendritic cell (DC) maturation, CC-chemokine production, and CCR5 receptor expression was examined using a soluble trimeric CD40L agonist protein (CD40LT). Stimulation of monocyte-derived DCs with CD40LT enhanced the production of the CC-chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES and diminished surface expression of CCR5. Based on these findings, the functional role of CD40LT stimulation on the ability of DCs to replicate and transmit HIV viral infection was studied. The addition of CD40LT to cocultures of naive CD4+ T cells and autologous DCs (T/DC) infected with the macrophage-tropic isolate, HIVBaL, caused a striking reduction in reverse transcriptase (RT) activity after 10 and 14 days of culture. The addition of a mixture of Abs against CC-chemokines abrogated the decrease in RT activity, demonstrating that the inhibitory effect mediated by CD40LT was CC-chemokine-dependent. In contrast, the presence of CD40LT in T/DC cocultures infected with the T cell-tropic isolate, HIV IIIB, caused an increase in RT activity that was CC-chemokine-independent. Of note, CD40LT stimulation also inhibited RT activity in cultures containing macrophage tropic virus (HIVBaL)-infected DC only. However, in contrast to the results seen in the T/DC cocultures, CD40LT stimulation inhibited RT activity in cultures of DCs alone in a CC-chemokine-independent manner. Together, these results show that CD40LT stimulation of DCs suppresses HIV replication and transmission to CD4+ T cells by two potentially different mechanisms. PMID- 10092835 TI - Kinetics of the changes of lymphocyte subsets defined by cytokine production at single cell level during highly active antiretroviral therapy for HIV-1 infection. AB - The effects of highly active antiretroviral therapy on cytokine imbalances associated with HIV-1 infection have not been characterized. Using single cell analysis by flow cytometry, we show that a significant recovery in the frequency of IL-2-producing cells was only observed in patients with a sustained control of viral replication and that the overexpanded CD8 T cell population of CD28- IFN gamma + cells was not significantly reduced after 1 yr of effective therapy. Moreover, a detrimental role of IL-4 is suggested by the association between an enhanced proportion of IL-4-producing cells within the CD4 and particularly the CD8 subset and viral load rebound. Finally, the kinetics of changes of cell subsets assessed for simultaneous production of different cytokines supports the view that cell reconstitution during highly active antiretroviral therapy is initially due to redistribution of terminally differentiated cells, followed by peripheral expansion of less differentiated ones and a late progressive increase of the proportion of functionally defined naive/memory precursor lymphocytes. These data bring new support for the role of cytokine imbalances in AIDS pathogenesis and may be relevant for the definition of immunointervention targets. PMID- 10092836 TI - Molecular and functional analysis of a conserved CTL epitope in HIV-1 p24 recognized from a long-term nonprogressor: constraints on immune escape associated with targeting a sequence essential for viral replication. AB - It has been hypothesized that sequence variation within CTL epitopes leading to immune escape plays a role in the progression of HIV-1 infection. Only very limited data exist that address the influence of biologic characteristics of CTL epitopes on the emergence of immune escape variants and the efficiency of suppression HIV-1 by CTL. In this report, we studied the effects of HIV-1 CTL epitope sequence variation on HIV-1 replication. The highly conserved HLA-B14 restricted CTL epitope DRFYKTLRAE in HIV-1 p24 was examined, which had been defined as the immunodominant CTL epitope in a long-term nonprogressing individual. We generated a set of viral mutants on an HX10 background differing by a single conservative or nonconservative amino acid substitution at each of the P1 to P9 amino acid residues of the epitope. All of the nonconservative amino acid substitutions abolished viral infectivity and only 5 of 10 conservative changes yielded replication-competent virus. Recognition of these epitope sequence variants by CTL was tested using synthetic peptides. All mutations that abrogated CTL recognition strongly impaired viral replication, and all replication-competent viral variants were recognized by CTL, although some variants with a lower efficiency. Our data indicate that this CTL epitope is located within a viral sequence essential for viral replication. Targeting CTL epitopes within functionally important regions of the HIV-1 genome could limit the chance of immune evasion. PMID- 10092837 TI - Protein kinase C delta. AB - The protein kinase C (PKC) family consists of 11 isoenzymes that, due to structural and enzymatic differences, can be subdivided into three groups: The Ca(2+)-dependent, diacylglycerol (DAG)-activated cPKCs (conventional PKCs: alpha, beta 1, beta 2, gamma); the Ca(2+)-independent, DAG-activated nPKCs (novel PKCs: delta, epsilon, eta, theta, mu), and the Ca(2+)-dependent, DAG non-responsive aPKCs (atypical PKCs: zeta, lambda/iota). PKC mu is a novel PKC, but with some special structural and enzymatic properties. PMID- 10092838 TI - Point mutations in the guanine phosphoribosyltransferase from Giardia lamblia modulate pyrophosphate binding and enzyme catalysis. AB - Guanine phosphoribosyltransferase (GPRTase) from Giardia lamblia, an enzyme required for guanine salvage and necessary for the survival of this parasitic protozoan, has been kinetically characterized. Phosphoribosyltransfer proceeds through an ordered sequential mechanism common to many related purine phosphoribosyltransferases (PRTases) with alpha-D-5-phosphoribosyl-1 pyrophosphate (PRPP) binding to the enzyme first and guanosine monophosphate (GMP) dissociating last. The enzyme is a highly unique purine PRTase, recognizing only guanine as its purine substrate (K(m) = 16.4 microM) but not hypoxanthine (K(m) > 200 microM) nor xanthine (no reaction). It also catalyzes both the forward (kcat = 76.7 s-1) and reverse (kcat = 5.8.s-1) reactions at significantly higher rates than all the other purine PRTases described to date. However, the relative catalytic efficiencies favor the forward reaction, which can be attributed to an unusually high K(m) for pyrophosphate (PPi) (323.9 microM) in the reverse reaction, comparable only with the high K(m) for PPi (165.5 microM) in Tritrichomonas foetus HGXPRTase-catalyzed reverse reaction. As the latter case was due to the substitution of threonine for a highly conserved lysine residue in the PPi-binding loop [Munagala et al. (1998) Biochemistry 37, 4045-4051], we identified a corresponding threonine residue in G. lamblia GPRTase at position 70 by sequence alignment, and then generated a T70K mutant of the enzyme. The mutant displays a 6.7-fold lower K(m) for PPi with a twofold increase in the K(m) for PRPP. Further attempts to improve PPi binding led to the construction of a T70K/A72G double mutant, which displays an even lower K(m) of 7.9 microM for PPi. However, mutations of the nearby Gly71 to Glu, Arg, or Ala completely inactivate the GPRTase, suggesting the requirement of flexibility in the putative PPi binding loop for enzyme catalysis, which is apparently maintained by the glycine residue. We have thus tentatively identified the PPi-binding loop in G. lamblia GPRTase, and attributed the relatively higher catalytic efficiency in the forward reaction to the unusual loop structure for poor PPi binding in the reverse reaction. PMID- 10092839 TI - Biosynthesis of indole-3-acetic acid in Azospirillum brasilense. Insights from quantum chemistry. AB - Quantum chemical methods AM1 and PM3 and chromatographic methods were used to qualitatively characterize pathways of bacterial production of indole-3-acetic acid (IAA). The standard free energy changes (delta G(o)'sum) for the synthesis of tryptophan (Trp) from chorismic acid via anthranilic acid and indole were calculated, as were those for several possible pathways for the synthesis of IAA from Trp, namely via indole-3-acetamide (IAM), indole-3-pyruvic acid (IPyA), and indole-3-acetonitrile (IAN). The delta G(o)'sum for Trp synthesis from chorismic acid was -402 (-434) kJ.mol-1 (values in parentheses were calculated by PM3). The delta G(o)'sum for IAA synthesis from Trp were -565 (-548) kJ.mol-1 for the IAN pathway, -481 (-506) kJ.mol-1 for the IAM pathway, and -289 (-306) kJ.mol-1 for the IPyA pathway. By HPLC analysis, the possibility was assessed that indole, anthranilic acid, and Trp might be utilized as precursors for IAA synthesis by Azospirillum brasilense strain Sp 245. The results indicate that there is a high motive force for Trp synthesis from chorismic acid and for IAA synthesis from Trp, and make it unlikely that anthranilic acid and indole act as the precursors to IAA in a Trp-independent pathway. PMID- 10092840 TI - Kinetic characterization of Aspergillus niger N400 endopolygalacturonases I, II and C. AB - Endopolygalacturonases I, II and C isolated from recombinant Aspergillus niger strains were characterized with respect to pH optimum, activity on polygalacturonic acid and mode of action and kinetics on oligogalacturonates of different chain length (n = 3-7). Apparent Vmax values using polygalacturonate as a substrate at the pH optimum, pH 4.1, were calculated as 13.8 mukat.mg-1, 36.5 mukat.mg-1 and 415 nkat.mg-1 for endopolygalacturonases I, II and C, respectively. K(m) values were < 0.15 mg.mL-1 for all three enzymes. Product progression analysis using polygalacturonate as a substrate revealed a random cleavage pattern for all three enzymes and suggested processive behavior for endopolygalacturonases I and C. This result was confirmed by analysis of the mode of action using oligogalacturonates. Processivity was observed when the degree of polymerization of the substrate exceeded 5 or 6 for endopolygalacturonase I and endopolygalacturonase C, respectively. The bond-cleavage frequencies obtained for the hydrolysis of the oligogalacturonates were used to assess subsite maps. The maps indicate that the minimum number of subsites is seven for all three enzymes. Using pectins of various degrees of esterification, it was shown that endopolygalacturonase II is the most sensitive to the presence of methyl esters. Like endopolygalacturonase II, endopolygalacturonases I, C and E, which was also included in this part of the study, preferred the non-esterified pectate. Additional differences in substrate specificity were revealed by analysis of the reaction products of hydrolysis of a mixture of pectate lyase-generated delta 4,5 unsaturated oligogalacturonates of degree of polymerization 4-8. Whereas endopolygalacturonase I showed a strong preference for generating the delta 4,5 unsaturated dimer, with endopolygalacturonase II the delta 4,5-unsaturated trimer accumulated, indicating further differences in substrate specificity. For endopolygalacturonases C and E both the delta 4,5-unsaturated dimer and trimer were observed, although in different ratios. PMID- 10092841 TI - Probing the role of C-1 ester group in Naja naja phospholipase A2-phospholipid interactions using butanetriol-containing phosphatidylcholine analogues. AB - To understand the role of the ester moiety of the sn-1 acyl chain in phospholipase A2-glycerophospholipid interactions, we introduced an additional methylene residue between the glycerol C1 and C2 carbon atoms of phosphatidylcholines, and then studied the kinetics of hydrolysis and the binding of such butanetriol-containing phospholipids with Naja naja phospholipase A2. Hydrolysis was monitored by using phospholipids containing a NBD-labelled sn-2 acyl chain and binding was ascertained by measuring the protein tryptophan fluorescence. The hydrolysis of butanetriol-containing phospholipids was invariably slower than that of the glycerol-containing phospholipids. In addition, the enzyme binding with the substrate was markedly decreased upon replacing the glycerol residue with the 1,3,4-butanetriol moiety in phosphatidylcholines. These results have been interpreted to suggest that the sn 1 ester group in glycerophospholipids could play an important role in phospholipase A2-phospholipid interactions. PMID- 10092842 TI - Characterization of thermostable RecA protein and analysis of its interaction with single-stranded DNA. AB - Thermostable RecA protein (ttRecA) from Thermus thermophilus HB8 showed strand exchange activity at 65 degrees C but not at 37 degrees C, although nucleoprotein complex was observed at both temperatures. ttRecA showed single-stranded DNA (ssDNA)-dependent ATPase activity, and its activity was maximal at 65 degrees C. The kinetic parameters, K(m) and kcat, for adenosine triphosphate (ATP) hydrolysis with poly(dT) were 1.4 mM and 0.60 s-1 at 65 degrees C, and 0.34 mM and 0.28 s-1 at 37 degrees C, respectively. Substrate cooperativity was observed at both temperatures, and the Hill coefficient was about 2. At 65 degrees C, all tested ssDNAs were able to stimulate the ATPase activity. The order of ATPase stimulation was: poly(dC) > poly(dT) > M13 ssDNA > poly(dA). Double-stranded DNAs (dsDNA), poly(dT).poly(dA) and M13 dsDNA, were unable to activate the enzyme at 65 degrees C. At 37 degrees C, however, not only dsDNAs but also poly(dA) and M13 ssDNA showed poor stimulating ability. At 25 degrees C, poly(dA) and M13 ssDNA gave circular dichroism (CD) peaks at around 192 nm, which reflect a particular structure of DNA. The conformation was changed by an upshift of temperature or binding to Escherichia coli RecA protein (ecRecA), but not to ttRecA. The dissociation constant between ecRecA and poly(dA) was estimated to be 44 microM at 25 degrees C by the change in the CD. These observations suggest that the capability to modify the conformation of ssDNA may be different between ttRecA and ecRecA. The specific structure of ssDNA was altered by heat or binding of ecRecA. After this alteration, ttRecA and ecRecA can express their activities at each physiological temperature. PMID- 10092843 TI - Pre-steady-state kinetics of the reactions of [NiFe]-hydrogenase from Chromatium vinosum with H2 and CO. AB - Results are presented of the first rapid-mixing/rapid-freezing studies with a [NiFe]-hydrogenase. The enzyme from Chromatium vinosum was used. In particular the reactions of active enzyme with H2 and CO were monitored. The conversion from fully reduced, active hydrogenase (Nia-SR state) to the Nia-C* state was completed in less than 8 ms, a rate consistent with the H2-evolution activity of the enzyme. The reaction of CO with fully reduced enzyme was followed from 8 to 200 ms. The Nia-SR state did not react with CO. It was discovered, contrary to expectations, that the Nia-C* state did not react with CO when reactions were performed in the dark. When H2 was replaced by CO, a Nia-C* EPR signal appeared within 11 ms; this was also the case when H2 was replaced by Ar. With CO, however, the Nia-C* state decayed within 40 ms, due to the generation of the Nia S.CO state (the EPR-silent state of the enzyme with bound CO). The Nia-C* state, induced after 11 ms by replacing H2 by CO in the dark, could be converted, in the frozen enzyme, into the EPR-detectable state with CO bound to nickel (Nia*.CO) by illumination at 30 K (evoking the Nia-L* state), followed by dark adaptation at 200 K. This can be explained by assuming that the Nia-C* state represents a formally trivalent state of nickel, which is unable to bind CO, whereas nickel in the Nia-L* and the Nia*.CO states is formally monovalent. PMID- 10092844 TI - Kinetic study on the dimer-tetramer interconversion of glycogen phosphorylase a. AB - Kinetic theory of dissociating enzyme systems has been applied to a study of the dimer-tetramer interconversion of glycogen phosphorylase a. All kinetic constants for the dissociating-associating reaction of phosphorylase a have been determined. The results indicate that (a) the presence of glucose-1-phosphate has no influence on either the rate of dissociation or the rate of association, and hence does not shift the dimer-tetramer equilibrium of phosphorylase a; (b) the binding og glycogen to the enzyme decreases the association rate of the dimer to form the tetramer, but has no effect on the dissociation rate of the tetramer; (c) both the dimeric and tetrameric form of phosphorylase a can bind glycogen, but the tetrameric form has a lower affinity for glycogen and is catalytically inactive. PMID- 10092845 TI - Homologous plasminogen N-terminal and plasminogen-related gene A and B peptides. Characterization of cDNAs and recombinant fusion proteins. AB - The cDNA corresponding to exons 2-4 of the processed human plasminogen (Pgn) gene, encoding the N-terminal peptide domain (NTP), has been cloned, expressed in Escherichia coli as a recombinant protein (r-NTP) containing a hexahistidine tag, and refolded to the native structure that contains two internal cystine bridges. RNA expression of the two Pgn-related genes, PRG A and PRG B, that potentially encode 9-kDa polypeptides having extensive similarity to the NTP has been investigated. Using RNA-based PCR with liver RNA as template, we demonstrate that PRG A encodes a detectable mRNA species. PRG A and PRG B have been found to be transcribed in the liver and yield virtually identical mRNAs. Neither of the PRGs are expressed in a variety of other normal tissues, as determined by Northern blot analysis. Factor-Xa digestion of the tagged r-NTP yields cleavage products which indicates that the expressed r-NTP domain of Pgn is endowed with a flexible conformation. Recombinant PRG B protein (r-PRG B) fused to a hexahistidine tag was purified and analyzed for structural integrity. Preliminary 1H-NMR spectroscopic data for r-NTP and r-PRG B indicate relatively fast amide 1H-2H exchange in 2H2O and close conformational characteristics for the two homologous polypeptides. Far ultraviolet-CD spectra for r-NTP and r-PRG B at pH 7.0 indicate similar defined secondary structure content for both domains, with 13-17% alpha helix and 24-27% antiparallel beta-sheet. The fact that two transcriptionally active genes encode almost identical polypeptides supports the hypothesis that the Pgn NTP, together with the putative polypeptides encoded by the PRGs, may serve an important function, such as controlling the conformation of Pgn and thus its susceptibility to tissue activators. PMID- 10092846 TI - Oxidative polymerization of ribonuclease A by lignin peroxidase from Phanerochaete chrysosporium. Role of veratryl alcohol in polymer oxidation. AB - The mechanism of lignin peroxidase (LiP) was examined using bovine pancreatic ribonuclease A (RNase) as a polymeric lignin model substrate. SDS/PAGE analysis demonstrates that an RNase dimer is the major product of the LiP-catalyzed oxidation of this protein. Fluorescence spectroscopy and amino acid analyses indicate that RNase dimer formation is due to the LiP-catalyzed oxidation of Tyr residues to Tyr radicals, followed by intermolecular radical coupling. The LiP catalyzed polymerization of RNase in strictly dependent on the presence of veratryl alcohol (VA). In the presence of 100 microM H2O2, relatively low concentrations of RNase and VA, together but not individually, can protect LiP from H2O2 inactivation. The presence of RNase strongly inhibits VA oxidation to veratraldehyde by LiP; whereas the presence of VA does not inhibit RNase oxidation by LiP. Stopped-flow and rapid-scan spectroscopy demonstrate that the reduction of LiP compound I (LiPI) to the native enzyme by RNase occurs via two single-electron steps. At pH 3.0, the reduction of LiPI by RNase obeys second order kinetics with a rate constant of 4.7 x 10(4) M-1.s-1, compared to the second-order VA oxidation rate constant of 3.7 x 10(5) M-1.s-1. The reduction of LiP compound II (LiPII) by RNase also follows second-order kinetics with a rate constant of 1.1 x 10(4) M-1.s-1, compared to the first-order rate constant for LiPII reduction by VA. When the reductions of LiPI and LiPIi are conducted in the presence of both VA and RNase, the rate constants are essentially identical to those obtained with VA alone. These results suggest that VA is oxidized by LiP to its cation radical which, while still in its binding site, oxidizes RNase. PMID- 10092847 TI - Transcriptional activity and regulatory protein binding of metal-responsive elements of the human metallothionein-IIA gene. AB - Multiple copies of a cis-acting DNA element, metal-responsive element (MRE) are required for heavy metal-induced transcriptional activation of mammalian metallothionein genes. To approach the regulatory mechanism mediated by these multiple elements, we studied the properties of seven MREs located upstream of the human metallothionein-IIA (hMT-IIA) gene in detail. Transfection assays of reporter gene constructs each containing one of these MREs as the promoter element revealed that only four MREs can mediate zinc response. With respect to the distribution of active MREs over the promoter region, the hMT-IIA gene is largely different from the mouse metallothionein-I gene, suggesting that MRE arrangement is not an important factor for metal regulation. Experiments using various model promoters showed that multiple MRE copies act highly synergistically, supporting the biological significance of the multiplicity. Only the four active MREs efficiently bound the purified transcription factor human MTF-1, and MRE mutants defective in binding this protein lost the ability to support zinc-induced reporter gene expression, strongly suggesting that the direct interaction between human MTF-1 and a set of the selected MREs plays the major role in heavy metal regulation. In protein/DNA binding reactions in vitro, the purified human MTF-1 was activated by zinc but not by other metallothionein inducing heavy metals, supporting the idea that zinc is the direct modulator of human MTF-1. PMID- 10092848 TI - Acceleration of Ca2+ ionophore-induced arachidonic acid liberation by thrombin without the proteolytic action toward the receptor in human platelets. AB - We investigated the regulation of arachidonic acid liberation catalyzed by group IV cytosolic phospholipase A2 (cPLA2) in human platelets upon stimulation with thrombin through interaction with protease-activated receptor-1 (PAR-1) or glycoprotein Ib. Leupeptin, a protease inhibitor, completely inhibited thrombin induced arachidonic acid liberation and Ca2+ mobilization, with inhibition of its protease activity. However, preincubation with thrombin in the presence of leupeptin potentiated Ca2+ ionophore-induced arachidonic acid liberation. The preincubation did not affect the intracellular Ca2+ level or cPLA2 activity in response to ionomycin. Human leukocyte elastase, which cleaves glycoprotein Ib, did not inhibit the enhancement of arachidonic acid liberation by thrombin in the presence of leupeptin. However, the effect of thrombin with leupeptin was abolished by a peptide corresponding to residues 54-65 of hirudin (hirudin peptide), which impairs the binding of thrombin to PAR-1. Furthermore, Phe-Pro Arg chloromethyl ketone (PPACK)-thrombin, which binds to platelets but has no protease activity, also enhanced Ca2+ ionophore-induced arachidonic acid liberation. In contrast, trypsin with leupeptin did not mimic the effect of thrombin with leupeptin, and furthermore trypsin-induced arachidonic acid liberation was insensitive to hirudin peptide. On the basis of the present results, we suggest that thrombin may accelerate cPLA2-catalyzed arachidonic acid liberation through non-proteolytic action toward PAR-1 but not toward glycoprotein Ib in co-operation with the proteolytic action leading to Ca2+ mobilization. PMID- 10092849 TI - Biochemical characterization and solution structure of nitrous oxide reductase from Alcaligenes xylosoxidans (NCIMB 11015). AB - Nitrous oxide reductase (N2OR) is the terminal enzyme involved in denitrification by microbes. No three-dimensional structural information has been published for this enzyme. We have isolated and characterised N2OR from Alcaligenes xylosoxidans (AxN2OR) as a homodimer of M(r) 134,000 containing seven to eight copper atoms per dimer. Comparison of sequence and compositional data with other N2ORs suggests that AxN2OR is typical and can be expected to have similar domain folding and subunit structure to other members of this family of enzymes. We present synchrotron X-ray-scattering data, analysed using a model-independent method for shape restoration, which gave a approximately 20 A resolution structure of the enzyme in solution, providing a glimpse of the structure of any N2OR and shedding light on the molecular architecture of the molecule. The specific activity of AxN2OR was approximately 6 mumol of N2O reduced.min-1. (mg of protein)-1; N2OR activity showed both base and temperature activation. The visible spectrum exhibited an absorption maximum at 550 nm with a shoulder at 635 nm. On oxidation with K3Fe(CN)6, the absorption maximum shifted to 540 nm and a new shoulder at 480 nm appeared. Reduction under anaerobic conditions resulted in the formation of an inactive blue form of the enzyme with a broad absorption maximum at 650 nm. As isolated, the enzyme shows an almost featureless EPR spectrum, which changes on oxidation to give an almost completely resolved seven line hyperfine signal in the gII region, g = 2.18, with AII = 40 G, consistent with the enzyme being partially reduced as isolated. Both the optical and EPR spectra of the oxidized enzyme are characteristic of the presence of a CuA centre. PMID- 10092850 TI - Molecular cloning of cDNAs of mouse peptidylarginine deiminase type I, type III and type IV, and the expression pattern of type I in mouse. AB - Peptidylarginine deiminases (PADs), a group of post-translational enzymes, catalyze the conversion of protein-bound arginine residues to citrulline residues in a calcium ion-dependent manner and are widely distributed in various organs of vertebrates. Although the existence of four isoforms of PAD (types I, II, III, and IV) is reported in rodents, the relative functions of the isoforms with respect to their colocation in the tissues have yet to be explored. In this study, we cloned the full-length cDNA encoding mouse PAD type I by screening a uterine cDNA library and using the RACE method. This cDNA consists of an open reading frame of 1989 bases encoding 662 amino acids (73,823 Da), a 5' untranslated region of 127 bases and a 3'-untranslated region of 1639 bases. Comparative reverse transcription-PCR and Northern-blot analyses detected PAD type I mRNA only in the epidermis and uterus. Administration of estrogen to adult ovariectomized mice increased the content of PAD type I mRNA in the uterus, providing evidence that its expression is under the control of the sex steroid hormone. We also cloned the full-length cDNAs of mouse PAD type III and type IV by the reverse transcription-PCR and RACE methods. The primary structure of PAD type III contains 664 amino acids (75,098 Da) deduced from the coding region of 1995 bases, and the primary structure of PAD type IV consists of 666 amino acids (74,475 Da) deduced from the coding region of 2001 bases. Comparison of the deduced amino acid sequences of all four isoforms of PAD showed about 50% identity with each other, the 3' regions being highly homologous compared with the 5' regions. PMID- 10092851 TI - Cloning and expression of the human p8, a nuclear protein with mitogenic activity. AB - We have previously identified a new rat mRNA, provisionally named p8, which showed a strong, but transient, induction in the pancreas in response to acute pancreatitis. We report here the cloning and sequencing of the human p8 cDNA. The human p8 polypeptide is 82 amino acids long and shows an overall identity of 74% with the rat counterpart. The complete structure of the p8 gene was also established. The p8 gene comprises three exons separated by two introns and the gene was mapped to chromosome 16. Analysis of the p8 primary structure suggested the presence of a bipartite motif of nuclear targeting, indicating that p8 may function within the nucleus. This presumption has been confirmed by transfection of COS-7 cells with the p8 cDNA followed by immunostaining with specific antibodies. p8 mRNA expression is induced in some, but not all, cells by serum starvation and ceramide. To analyze the p8 function, we stably transfected HeLa cells with a p8 expression plasmid, and measured their growth and their sensitivity to apoptosis. Response to TNF alpha and staurosporine-induced apoptosis was not modified by p8 expression. However, cells expressing p8 grew significantly more rapidly. PMID- 10092852 TI - Structural organization and expression of the mouse gene for Pur-1, a highly conserved homolog of the human MAZ gene. AB - We have characterized the genomic structure and expression of the mouse gene for Pur-1. The cloned Pur-1 gene spans a 5-kb region encompassing the promoter, five exons, four introns and the 3'-untranslated region. All exon-intron junction sequences conform to the GT/AG rule. The promoter region has typical features of a housekeeping gene: a high G + C content (77.5%); a high frequency of CpG dinucleotides, in particular within the region 0.5 kb upstream of the site of initiation of translation; and the absence of canonical TATA and CAAT boxes. S1 nuclease protection assay demonstrated the presence of multiple sites for initiation of transcription around a site 108 nucleotides upstream of the ATG codon. Comparison of Pur-1 with the human gene for MAZ (Myc-associated zinc finger protein) revealed a striking homology of both their nucleotide and deduced protein sequences, an identical genomic organization and high similarity in promoter architecture and mRNA expression pattern. Sequence analysis of the 5' flanking region of Pur-1 revealed numerous potential binding sites for transcription factors Sp1, AP-2 and Pur-1/MAZ itself. An element required for basal Pur-1 expression was mapped from nucleotide -258 to +43. This region also mediated stimulation of basal transcription by ectopically expressed MAZ protein. We conclude that the Pur-1 gene is the murine homolog of human MAZ and, like it, belongs to the family of housekeeping genes. PMID- 10092853 TI - Comparisons of flux control exerted by mitochondrial outer-membrane carnitine palmitoyltransferase over ketogenesis in hepatocytes and mitochondria isolated from suckling or adult rats. AB - The primary aim of this paper was to calculate and report flux control coefficients for mitochondrial outer-membrane carnitine palmitoyltransferase (CPT I) over hepatic ketogenesis because its role in controlling this pathway during the neonatal period is of academic importance and immediate clinical relevance. Using hepatocytes isolated from suckling rats as our model system, we measured CPT I activity and carbon flux from palmitate to ketone bodies and to CO2 in the absence and presence of a range of concentrations of etomoxir. (This is converted in situ to etomoxir-CoA which is a specific inhibitor of the enzyme.) From these data we calculated the individual flux control coefficients for CPT I over ketogenesis, CO2 production and total carbon flux (0.51 +/- 0.03; -1.30 +/- 0.26; 0.55 +/- 0.07, respectively) and compared them with equivalent coefficients calculated by similar analyses [Drynan, L., Quant, P.A. & Zammit, V.A. (1996) Biochem. J. 317, 791-795] in hepatocytes isolated from adult rats (0.85 +/- 0.20; 0.23 +/- 0.06; 1.06 +/- 0.29). CPT I exerts significantly less control over ketogenesis in hepatocytes isolated from suckling rats than those from adult rats. In the suckling systems the flux control coefficients for CPT I over ketogenesis specifically and over total carbon flux (< 0.6) are not consistent with the enzyme being rate-limiting. Broadly similar results were obtained and conclusions drawn by reanalysis of previous data {from experiments in mitochondria isolated from suckling or adult rats [Krauss, S., Lascelles, C.V., Zammit, V.A. & Quant, P.A. (1996) Biochem. J. 319, 427-433]} using a different approach of control analysis, although it is not strictly valid to compare flux control coefficients from different systems. Our overall conclusion is that flux control coefficients for CPT I over oxidative fluxes from palmitate (or palmitoyl CoA) differ markedly according to (a) the metabolic state, (b) the stage of development, (c) the specific pathway studied and (d) the model system. PMID- 10092854 TI - Solution structure of a lipid transfer protein extracted from rice seeds. Comparison with homologous proteins. AB - Nuclear magnetic resonance (NMR) spectroscopy was used to determine the three dimensional structure of rice nonspecific lipid transfer protein (ns-LTP), a 91 amino acid residue protein belonging to the broad family of plant ns-LTP. Sequence specific assignment was obtained for all but three HN backbone 1H resonances and for more than 95% of the 1H side-chain resonances using a combination of 1H 2D NOESY; TOCSY and COSY experiments at 293 K. The structure was calculated on the basis of four disulfide bridge restraints, 1259 distance constraints derived from 1H-1H Overhauser effects, 72 phi angle restraints and 32 hydrogen-bond restraints. The final solution structure involves four helices (H1: Cys3-Arg18, H2: Ala25-Ala37, H3: Thr41-Ala54 and H4: Ala66-Cys73) followed by a long C-terminal tail (T) with no observable regular structure. N-capping residues (Thr2, Ser24, Thr40), whose side-chain oxygen atoms are involved in hydrogen bonds with i + 3 amide proton additionally stabilize the N termini of the first three helices. The fourth helix involving Pro residues display a mixture of alpha and 3(10) conformation. The rms deviation of 14 final structures with respect to the average structure is 1.14 +/- 0.16 A for all heavy atoms (C, N, O and S) and 0.72 +/- 0.01 A for the backbone atoms. The global fold of rice ns-LTP is close to the previously published structures of wheat, barley and maize ns-LTPs exhibiting nearly identical pattern of the numerous sequence specific interactions. As reported previously for different four-helix topology proteins, hydrophobic, hydrogen bonding and electrostatic mechanisms of fold stabilization were found for the rice ns-LTP. The sequential alignment of 36 ns-LTP primary structures strongly suggests that there is a uniform pattern of specific long range interactions (in terms of sequence), which stabilize the fold of all plant ns-LTPs. PMID- 10092855 TI - The cytochrome bc1 complex from Rhodovulum sulfidophilum is a dimer with six quinones per monomer and an additional 6-kDa component. AB - A highly active, large-scale preparation of cytochrome bc1 complex has been obtained from the photosynthetic purple bacterium Rhodovulum (Rhv.) sulfidophilum. It has been characterized using mass spectrometry, quinone and lipid analysis as well as inhibitor binding. About 35 mg of pure complex can be obtained from 1 g of membrane protein. EPR spectroscopy and optical titrations have been used to obtain the redox midpoint potentials of the cofactors. The Em value of 310 mV for the Rieske protein is the most positive midpoint potential for this protein in a bc1 complex so far. The bc1 complex from Rhv. sulfidophilum is very stable and consists of three subunits and a 6-kDa polypeptide. The complex appears as a dimer in solution and contains six quinone molecules per monomer which are tightly bound. EPR spectroscopy shows that the Q(o) site is highly occupied. High detergent concentrations convert the complex into an inactive, monomeric form that has lost the Rieske protein as well as the quinones and the 6-kDa component. PMID- 10092856 TI - Cloning, sequencing and functional expression of a cDNA encoding porcine pancreatic preprocarboxypeptidase A1. AB - A full-length cDNA clone coding for porcine pancreatic preprocarboxypeptidase A1 (prePCPA1) was isolated from a cDNA library. The open reading frame (ORF) of the nucleotide sequence was 1260 nt in length and encoded a protein of 419 amino acids (aa). The cDNA included a short signal peptide of 16 aa and a 94 aa-long activation segment. The calculated molecular mass of the mature proenzyme was 45561 Da, in accordance with that of the purified porcine pancreatic PCPA1. The deduced aa sequence of the corresponding enzyme differed from that predicted by the three-dimensional structure by 40 aa, and showed 85% identity and 55% identity to that of procarboxypeptidases A1 and A2, respectively. Moreover the sequence was identical to that of several independent cDNA clones, suggesting that it is the major transcribed gene. No evidence for a second variant was observed in the cDNA library and PCPA2 is apparently absent from the porcine pancreas. The cDNA was expressed in Saccharomyces cerevisiae under the control of the yeast triose phosphate isomerase promoter. The signal peptide of the PCPA protein efficiently directed its secretion into the culture medium (1.5 mg.L-1) as a protein of the predicted size. The recombinant proenzyme was analyzed by immunological and enzymological methods. Its activation behavior was comparable with that of the native form and led to a 35-kDa active enzyme. PMID- 10092857 TI - Comparisons of genomic structures and chromosomal locations of the mouse aldose reductase and aldose reductase-like genes. AB - Aldose reductase (AR), best known as the first enzyme in the polyol pathway of sugar metabolism, has been implicated in a wide variety of physiological functions and in the etiology of diabetic complications. We have determined the structures and chromosomal locations of the mouse AR gene (Aldor1) and of two genes highly homologous to Aldor1: the fibroblast growth factor regulated protein gene (Fgfrp) and the androgen regulated vas deferens protein gene (Avdp). The number of introns and their locations in the mouse Aldor1 gene are identical to those of rat and human AR genes and also to those of Fgfrp and Avdp. Mouse Aldor1 gene was found to be located near the Cald1 (Caldesmon) and Ptn (Pleiotropin) loci at the proximal end of chromosome 6. The closely related genes Fgfrp and Avdp were also mapped in this region of the chromosome, suggesting that these three genes may have arisen by a gene duplication event. PMID- 10092858 TI - Enzymatic properties of mouse 25-hydroxyvitamin D3 1 alpha-hydroxylase expressed in Escherichia coli. AB - Renal 25-hydroxyvitamin D3 1 alpha-hydroxylase cDNA cloned from the kidneys of mice lacking the vitamin D receptor was expressed in Escherichia coli JM109. As expected, the bacterially-expressed enzyme catalyzes the 1 alpha-hydroxylation of 25-hydroxyvitamin D3 with a Michaelis constant, K(m), value of 2.7 microM. Unexpectedly, the enzyme also hydroxylates the 1 alpha-position of 24,25 dihydroxyvitamin D3 with a K(m) of 1.3 microM, and a fourfold higher Vmax/K(m) compared with the 25-hydroxyvitamin D3 hydroxylase activity, suggesting that 24,25-dihydroxyvitamin D3 is a better substrate than 25-hydroxyvitamin D3 for 1 alpha-hydroxylase. In addition, the enzyme showed 1 alpha-hydroxylase activity toward 24-oxo-25-hydroxyvitamin D3. However, it showed only slight activity towards 23,25-dihydroxyvitamin D3 and 24-oxo-23,25-dihydroxyvitamin D3, and no detectable activity towards vitamin D3 and 24,25,26,27-tetranor-23-hydroxyvitamin D3. These results suggest that the 25-hydroxyl group of vitamin D3 is essential for the 1 alpha-hydroxylase activity and the 24-hydroxyl group enhances the activity, but the 23-hydroxyl group greatly reduced the activity. Another remarkable finding is that living recombinant E. coli cells can convert the substrates into the 1 alpha-hydroxylated products, suggesting the presence of a redox partner of 1 alpha-hydroxylase in E. coli cells. PMID- 10092859 TI - The interaction of coenzyme Q with phosphatidylethanolamine membranes. AB - Coenzyme Q (CoQ) is a component of the mitochondrial respiratory chain which carries out additional membrane functions, such as acting as an antioxidant. The location of CoQ in the membrane and the interaction with the phospholipid bilayer is still a subject of debate. The interaction of CoQ in the oxidized (ubiquinone 10) and reduced (ubiquinol-10) state with membrane model systems of 1,2 dielaidoyl-sn-glycero-3-phosphoethanolamine (Ela2Gro-P-Etn) has been studied by means of differential scanning calorimetry (DSC), 31P-nuclear magnetic resonance (31P-NMR) and small angle X-ray diffraction (SAXD). Ubiquinone-10 did not visibly affect the lamellar gel to lamellar liquid-crystalline phase transition of Ela2Gro-P-Etn, but it clearly perturbed the multicomponent lamellar liquid crystalline to lamellar gel phase transition of the phospholipid. The perturbation of both transitions was more effective in the presence of ubiquinol 10. A location of CoQ forming head to head aggregates in the center of the Ela2Gro-P-Etn bilayer with the polar rings protruding toward the phospholipid acyl chains is suggested. The formation of such aggregates are compatible with the strong hexagonal HII phase promotion ability found for CoQ. This ability was evidenced by the shifting of the lamellar to hexagonal HII phase transition to lower temperatures and by the appearance of the characteristic hexagonal HII 31P NMR resonance and SAXD pattern at temperatures at which the pure Ela2Gro-P-Etn is still organized in extended bilayer structures. The influence of CoQ on the thermotropic properties and phase behavior of Ela2Gro-P-Etn is discussed in relation to the role of CoQ in the membrane. PMID- 10092860 TI - The cyclic structure of microcin J25, a 21-residue peptide antibiotic from Escherichia coli. AB - Microcin J25 (MccJ25) is the single representative of the immunity group J of the microcin group of peptide antibiotics produced by Enterobacteriaceae. It induces bacterial filamentation in susceptible cells in a non-SOS-dependent pathway [R. A. Salomon and R. Farias (1992) J. Bacteriol. 174, 7428-7435]. MccJ25 was purified to homogeneity from the growth medium of a microcin-overproducing Escherichia coli strain by reverse-phase HPLC. Based on amino acid composition and absolute configuration determination, liquid secondary ion and electrospray mass spectrometry, extensive two-dimensional NMR, enzymatic and chemical degradations studies, the structure of MccJ25 was elucidated as a 21-residue peptide, cyclo(-Val1-Gly-Ile-Gly-Thr- Pro-Ile-Ser-Phe-Tyr-Gly-Gly-Gly-Ala-Gly-His Val-Pro-Glu-Tyr-Phe21- ). Although MccJ25 showed high resistance to most of endoproteases, linearization by thermolysin occurred from cleavage at the Phe21 Val1 bond and led to a single peptide, MccJ25-L. While MccJ25 exhibited remarkable antibiotic activity towards Salmonella newport and several E. coli strains (minimal inhibitory concentrations ranging between 0.01 and 0.2 microgram.mL-1), the thermolysin-linearized microcin showed a dramatic decrease of the activity, indicating that the cyclic structure is essential for the MccJ25 biological properties. As MccJ25 is ribosomally synthesized as a larger peptide precursor endowed with an N-terminal extremity, the present study shows that removal of this extension and head-tail cyclization of the resulting propeptide are the only post-translational modifications involved in the maturation of MccJ25, that appears as the first cyclic microcin. PMID- 10092861 TI - Expression and regulation of 6-phosphofructo-2-kinase/fructose- 2,6 bisphosphatase isozymes in white adipose tissue. AB - The aim of this work was to identify the 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase (PFK-2/FBPase-2) isozyme(s) present in white adipose tissue. Ion exchange chromatography of PFK-2 from rat epididymal fat pads yielded an elution pattern compatible with the presence of both the L (liver) and M (muscle) isozymes. This was consistent with a study of the phosphorylation of the purified adipose tissue enzyme by cAMP-dependent protein kinase, by specific labelling of the preparation with [2-32P]fructose 2,6-bisphosphate and by reaction with antibodies. Characterization of the PFK-2/FBPase-2 mRNAs showed that mature adipocytes express the mRNA that codes for the L isozyme and the two mRNAs that code for the M isozyme. Preadipocytes expressed mRNA that codes for the M isozyme. Incubation of rat epididymal fat pads with adrenaline stimulated glycolysis but decreased fructose 2,6-bisphosphate concentrations without significant inactivation of PFK-2. These results support previous findings showing that fructose 2,6-bisphosphate is not involved in the adrenaline-induced stimulation of glycolysis in white adipose tissue. PMID- 10092862 TI - Non-viral neuronal gene delivery mediated by the HC fragment of tetanus toxin. AB - Many inherited neurological diseases and cancers could potentially benefit from efficient targeted gene delivery to neurons of the central nervous system. The nontoxic fragment C (HC) of tetanus toxin retains the specific nerve cell binding and transport properties of tetanus holotoxin. The HC fragment has previously been used to promote the uptake of attached proteins such as horseradish peroxidase, beta-galactosidase and superoxide dismutase into neuronal cells in vitro and in vivo. We report the use of purified recombinant HC fragment produced in yeast and covalently bound to polylysine [poly(K)] to enable binding of DNA. We demonstrate that when used to transfect cells, this construct results in nonviral gene delivery and marker gene expression in vitro in N18 RE 105 cells (a neuroblastoma x glioma mouse/rat hybrid cell line) and F98 (a glioma cell line). Transfection was dependent on HC and was neuronal cell type specific. HC may prove a useful targeting ligand for future neuronal gene therapy. PMID- 10092864 TI - Mimicry of beta II'-turns of proteins in cyclic pentapeptides with one and without D-amino acids. AB - The solution structure of eight cyclic pentapeptides has been determined by two dimensional 1H-NMR spectroscopy combined with spectra simulations and restrained molecular dynamic simulations. Six of the cyclic pentapeptides were derived from the C-terminal cholecystokinin fragment CCK-4 enlarged with Asp1 resulting in the sequence (Asp-Trp-Met-Asp-Phe), one L-amino acid after the other was substituted by its D-analog. In addition, two peptides, including an all-L-amino-acid containing cyclic pentapeptide, cyclo(Asp-Phe-Lys-Ala-Thr) and cyclo(Asp-Phe-Lys Ala-D-Thr) were investigated. All D-amino-acid-containing peptides show beta II' turn conformations with the D-amino acid in the i + 1 position, excepting the D aspartic-acid-containing peptides. These two peptides are characterized by the lack of beta-turns at pH values less than 4, suggesting that D-aspartic acid in the full-protonized state avoids the formation of beta-turns in these compounds. At pH values greater than 5, a conformational change into the beta II'-turn conformation was also observed for these peptides. Conformations without beta turns are expected for cyclic all-L pentapeptides, but both cyclo(Asp-Phe-Lys-Ala Thr) and the D-Thr analog cyclo(Asp-Phe-Lys-Ala-D-Thr) exhibit beta II'-turn conformations around Thr-Asp and D-Thr-Asp. Thus cyclic all-L pentapeptides and those with one D-amino acid are able to form similar structures preferably with a beta II'-turn. The beta-turn formation in cyclic pentapeptides containing a D aspartic acid is dependent on the ionization state. The relevance of the work to the design of beta'-turn mimetics is discussed. PMID- 10092863 TI - Donor substrate specificity of recombinant human blood group A, B and hybrid A/B glycosyltransferases expressed in Escherichia coli. AB - The human blood group A and B glycosyltransferases catalyze the transfer of GalNAc and Gal, to the (O)H-precursor structure Fuc alpha (1-2)Gal beta-OR to form the blood group A and B antigens, respectively. Changing four amino acids (176, 235, 266 and 268) alters the specificity from an A to a B glycosyltransferase. A series of hybrid blood group A/B glycosyltransferases were produced by interchanging these four amino acids in synthetic genes coding for soluble forms of the enzymes and expressed in Escherichia coli. The purified hybrid glycosyltransferases were characterized by two-substrate enzyme kinetic analysis using both UDP-GalNAc and UDP-Gal donor substrates. The A and B glycosyltransferases were screened with other donor substrates and found to also utilize the unnatural donors UDP-GlcNAc and UDP-Glc, respectively. The kinetic data demonstrate the importance of a single amino acid (266) in determining the A vs. B donor specificity. PMID- 10092865 TI - Sequence, heterologous expression and functional characterization of tryparedoxin1 from Crithidia fasciculata. AB - Tryparedoxin (TXN) has recently been discovered as a constituent of the complex peroxidase system in the trypanosomatid Crithidia fasciculata [Nogoceke et al. (1997) Biol. Chem. 378, 827-836] where it catalyzes the reduction of a peroxiredoxin-type peroxidase by trypanothione. Here we report on the full-length DNA sequence of the TXN previously isolated from C. fasciculata (TXN1). The deduced amino acid sequence comprises 147 residues and matches with all the peptide sequences of fragments obtained from TXN1. It shares a characteristic sequence motif YFSAxWCPPCR with some thioredoxin-related proteins of unknown function. This motif is homologous with the CXXC motif, which characterizes the thioredoxin superfamily of proteins and is known to catalyze disulfide reductions. Sequence conservations between TXNs and the typical thioredoxins are restricted to the intimate environment of the CXXC motif and three more remote residues presumed to contribute to the folding pattern of the thioredoxin-type proteins. The TXNs thus form a distinct molecular clade within the thioredoxin superfamily. TXN1 was expressed in Escherichia coli BL21 (DE3)pLysS as a C terminally extended and His-tagged protein, isolated by chelate chromatography and characterized functionally. The recombinant product exhibited a kinetic pattern identical with, and kinetic parameters similar to those of the authentic enzyme in the trypanothione/peroxiredoxin oxidoreductase assay. The recombinant TXN1 can therefore be considered a valuable tool for the screening of specific inhibitors as potential trypanocidal agents. PMID- 10092866 TI - The mitochondrial adenine nucleotide translocator from Dictyostelium discoideum. Functional characterization and DNA sequencing. AB - The mitochondrial adenine nucleotide translocator (ANT) catalyses the exchange of ATP and ADP between the mitochondria and the cytosol. We have cloned and sequenced the gene encoding the Dictyostelium discoideum ANT (DdANT) and analysed its transcriptional regulation. The single copy D. discoideum ant gene encodes a protein of 309 amino acid residues with a predicted molecular mass of 33,469 Da and a pI of 9.85. These values are comparable to those of ANTs from mammals, insects and fungi. The long N-terminal extension characteristic of plant ANT is absent in DdANT. The protein coding region of the D. discoideum ant gene is interrupted by three introns. Polyclonal antibodies directed against the beef heart mitochondrial ANT or its C-terminal peptide recognized the D. discoideum protein. Northern blot analysis revealed that the expression of the D. discoideum ant gene decreased rapidly during the first hours of multicellular development but the amount of protein remained stable throughout differentiation. PMID- 10092867 TI - Pertussis toxin-sensitive and insensitive intracellular signalling pathways in undifferentiated 3T3-L1 cells stimulated by insulin converge with phosphatidylinositol 3-kinase upstream of the Ras mitogen-activated protein kinase cascade. AB - We have previously reported that pertussis toxin (PTX)-sensitive GTP binding protein (G-protein) and phosphatidylinositol 3-kinase (PI 3-K) are involved in adipocyte differentiation of 3T3-L1 cells induced by insulin/dexamethasone/methylisobutyl xanthine. The aim of this study was to examine the effect of PTX on the tyrosine kinase cascade stimulated by insulin acting through insulin-like growth factor-I (IGF-I) receptors in undifferentiated 3T3-L1 cells. A high level of mitogen-activated protein kinase (MAPK) activation was sustained for up to 4 h after insulin treatment, and mobility shifted and tyrosine phosphorylated MAPK was also detected. MAPK kinase activity measured by the incorporation of 32P into kinase-negative recombinant MAPK was enhanced by insulin treatment. We previously discovered that insulin activates Ras and that this is mediated by wortmannin-sensitive PI 3-K. Tyrosine-phosphorylation of IRS 1 and Shc also occurred in response to insulin. Subsequently, we investigated the effects of PTX on the activation of these proteins by insulin. Interestingly, treating 3T3-L1 cells with PTX attenuates the activation by insulin of both the Ras-MAPK cascade and PI 3-K. In contrast, neither tyrosine-phosphorylation of IRS 1 and Shc nor the interaction between IRS-1 and PI 3-K is sensitive to PTX. However, activation of the Ras-MAPK cascade and tyrosine-phosphorylation of Shc by epidermal growth factor are insensitive to PTX. These results indicate that there is another pathway which regulates PI 3-K and Ras-MAPK, independent of the pathway mediated by IGF-I receptor kinase. These findings suggest that in 3T3-L1 fibroblasts, PTX-sensitive G-proteins cross-talk with the Ras-MAPK pathway via PI 3-K by insulin acting via IGF-I receptors. PMID- 10092868 TI - Probing the function of the conserved tryptophan in the flexible loop of the Yersinia protein-tyrosine phosphatase. AB - The involvement of the strictly conserved Trp354 residue in the catalysis of the Yersinia protein tyrosine phosphatase (PTPase) has been investigated by site directed mutagenesis and kinetic studies. Crystallographic structural data have revealed that Trp354 interacts with the active site Arg409 and is located at one of the hinge positions of the flexible surface loop (WpD loop) which also harbors the general acid/base (Asp356) essential for catalysis [Schubert, H. L., Fauman, E. B., Stuckey, J. A., Dixon, J. E. & Saper, M. A. (1995) Protein Sci. 4, 1904 1913]. Two mutants were constructed and expressed that contained the Trp354-->Phe and Trp354-->Ala substitutions. The K(m) of the W354F and W354A mutants were not significantly different from that of the wild-type. However, a major decrease in the affinity for oxyanions was observed for the mutants, which is consistent with Trp354 playing a role in aligning Arg409 for oxyanion binding. In addition replacement of Trp354 with Phe or Ala caused a decrease in kcat of 200-fold and 480-fold, respectively, and impaired the ability of the mutant enzymes to stabilize the negative charge in the leaving group at the transition state. In fact, the W354F and W354A mutants exhibited catalytic efficiency and leaving group dependency similar to those observed for the general acid-deficient PTPase D356N. These results indicate that Trp354 is an important residue that keeps the WpD loop in a catalytically competent conformation and positions the general acid/base Asp356 in the correct orientation for proton transfer. PMID- 10092869 TI - Studies on the formation and stability of a complex between Streptomyces proteinaceous metalloprotease inhibitor and thermolysin. AB - The effects of certain physicochemical parameters on the formation and stability of a complex between Streptomyces proteinaceous metalloprotease inhibitor (SMPI) and thermolysin were investigated. SMPI had its lowest Ki value at a pH of around 6.5 (similar to the pH dependence of the kcat/K(m) of thermolysin catalysis), reflecting the splitting mechanism of the SMPI inhibition of thermolysin. This Ki increased with an increase in pressure, and in (Ki-1) was almost linear with respect to pressure. The volume of the reaction (delta Vcomp), which is the volume change accompanying enzyme-inhibitor complex formation, was calculated as +8.1 +/- 0.3 mL.mol-1, which has a sign opposite to delta Vcomp for neutral peptide inhibitors and acyl-peptide substrates. The temperature dependence of Ki 1 gave the reaction enthalpy (delta Hcomp) and reaction entropy (delta Scomp) of the complex formation as 34.6 +/- 1.4 kJ.mol-1 and 298 +/- 5 J.mol-1.K-1, respectively. These positive reaction volumes and reaction entropies were related to the electrostatic interactions and ionic strength dependence of Ki which corresponded to the key ionic interaction during complex formation. Complex formation with SMPI stabilized thermolysin against pressure perturbation as observed by the changes in the Trp fluorescence of thermolysin with increasing pressure. Thermal stability, however, was affected very little by complex formation with SMPI. Phosphoramidon, Cbz-Phe-Gly-NH2 and Cbz-Phe also positively affected the pressure-tolerance of thermolysin, in the following order: Cbz-Gly Phe-NH2 < Cbz-Phe << phosphoramidon. The third compound exhibited stabilizing effects comparable with those of SMPI, which suggests that the interaction between SMPI and thermolysin was localized to the reactive site. PMID- 10092870 TI - Purification of a new intestinal anti-proliferative factor from normal human small intestine. AB - Previous studies suggest that intestinal cell proliferation may be controlled by endogenous mitosis inhibitors. We describe here the isolation of a protein named intestinal anti-proliferative factor (IAF) from human small intestine. Successive DEAE anion exchange, isoelectric focusing and gel filtration chromatographies led to a purified anti-proliferative protein fraction used to produce antibodies. Using these antibodies as affinity chromatography ligand, IAF was purified from human small intestine cytosolic fraction. IAF was a potent inhibitor of adenocarcinoma colon cells (HT-29 D4 line) DNA synthesis and proliferation with 50% inhibition observed at picomolar concentrations. Analyzed on SDS/PAGE under reducing conditions, this protein migrates with an apparent molecular mass of 120 kDa and amino acid sequence of two internal peptides displays no homology with another listed protein. Cell cycle studies showed that the growth inhibitory effect was maximal between mid G1 and early S phases. Moreover, flow cytometry studies demonstrated that IAF inhibited the progression of HT-29 D4 cells from G1 to S phase. Northern blot analysis using a dipeptidyl peptidase i.v. probe revealed that the growth arrest mediated by IAF was not linked to differentiation processes. By Western blotting with polyclonal antibodies against IAF, we found that this protein was not detected in differentiated colonic carcinoma. Our results suggest that IAF might regulate intestinal cell proliferation. PMID- 10092871 TI - N-glycan structures of matrix metalloproteinase-1 derived from human fibroblasts and from HT-1080 fibrosarcoma cells. AB - Matrix metalloproteinase-1 (MMP-1) is a collagenolytic metalloproteinase capable of cleaving native triple-helical forms of several collagen subtypes, as well as a number of non-collagenous substrates. The role of MMP-1 in various diseases affecting the connective tissue is well characterized. MMP-1 is secreted as both glycosylated and unglycosylated species, and the two forms have been shown to be identical with respect to substrate specificity, specific activity and inhibitory profile. No function for the glycan moiety of the enzyme has been ascribed to date. In the present study, we report on the detailed characterization of MMP-1 derived oligosaccharides. Using strategies based on sequential exoglycosidase digestion combined with matrix-assisted laser desorption ionization-time of flight MS and electrospray tandem MS, we have characterized the N-glycan structures of MMP-1, derived from human dermal fibroblasts and from the HT-1080 fibrosarcoma cell line. MMP-1 derived from fibroblasts was found to carry mainly alpha 2,3-sialylated complex-type diantennary glycans. On the other hand, HT-1080 cells produce MMP-1 that has a heterogeneous glycosylation pattern, comprising diantennary glycans carrying Lewis X, LacdiNAc, sialylated LacdiNAc and GalNAc beta 1,4 (Fuc alpha 1,3)GlcNAc (LacdiNAc analogue of Lewis X) as terminal elements. We also show that, of the two potential glycosylation sites in the MMP 1 sequence, only Asn120 is used. PMID- 10092872 TI - Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site. AB - P-glycoprotein is a plasma membrane protein of mammalian cells that confers multidrug resistance by acting as a broad-specificity, ATP-dependent efflux transporter of diverse lipophilic neutral or cationic compounds. Previously, we identified two positively cooperative drug-binding sites of P-glycoprotein involved in transport [Shapiro, A. B. & Ling, V. (1997) Eur. J. Biochem. 250, 130 137]. The H site is selective for Hoechst 33342 and colchicine. The R site is selective for rhodamine 123 and anthracyclines. Substrate binding to one site stimulates transport by the other. In this paper, we show that prazosin and progesterone stimulate the transport of both Hoechst 33342 and rhodamine 123. Rhodamine 123 and prazosin (or progesterone) in combination stimulate Hoechst 33342 transport in an additive manner. In contrast, Hoechst 33342 and either prazosin or progesterone interfere with each other, so that the stimulatory effect of the combination on rhodamine 123 transport is less than that of each individually. Non-P-glycoprotein-specific effects of prazosin on membrane fluidity and permeability were excluded. These results indicate the existence of a third drug-binding site on P-glycoprotein with a positive allosteric effect on drug transport by the H and R sites. This allosteric site appears to be one of the sites of photoaffinity labeling of P-glycoprotein by [125I]iodoarylazidoprazosin [Safa, A. R., Agresti, M., Bryk, D. & Tamai, I. (1994) Biochemistry 33, 256-265] and is likely not to be capable of drug transport. PMID- 10092873 TI - ATP and phosphate reciprocally affect subunit association of human recombinant High Km 5'-nucleotidase. Role for the C-terminal polyglutamic acid tract in subunit association and catalytic activity. AB - IMP-specific, High Km 5'-nucleotidase (EC 3.1.3.5) is an ubiquitous enzyme, the activity of which is highly regulated by substrate, ATP, and inorganic phosphate. The cDNA encoding this enzyme has recently been cloned and found to contain a unique stretch of nine glutamic and four aspartic acid residues at the C terminus. To study the effects of this acidic tail, and of ATP and inorganic phosphate on enzyme function, we generated several structural modifications of the 5'-nucleotidase cDNA, expressed the corresponding proteins in Escherichia coli and compared their molecular and kinetic properties. As with the enzyme purified from human placenta, all recombinant proteins were activated by ATP and inhibited by inorganic phosphate. Although the S0.5-values were higher, the specific activities of the purified protein variants (except that truncated at the C-terminus) were similar. The molecular mass of the full-length enzyme subunit has been estimated at 57.3 kDa and the molecular mass of the native protein, as determined by gel-filtration chromatography, was estimated to be 195 kDa. Increasing the concentration of NaCl to 0.3 M promoted oligomerization of the protein and the formation of aggregates of 332 kDa. ATP induced further oligomerization to 715 kDa, while inorganic phosphate reduced the estimated molecular mass to 226 kDa. In contrast to the truncation of 30 amino acids at the N-terminus, which did not alter enzyme properties, the removal of the polyglutamic/aspartic acid tail of 13 residues at the C-terminus caused profound kinetic and structural changes, including a 29-fold decrease in specific activity and a significant increase in the sensitivity to inhibition by inorganic phosphate in the presence of AMP. Structurally, there was a dramatic loss of the ability to form oligomers at physiological salt concentration which was only partially restored by the addition of NaCl or ATP. These data suggest an important function of the polyglutamic acid tract in the process of association and dissociation of 5'-nucleotidase subunits. PMID- 10092874 TI - Distinct regions specify the nuclear membrane targeting of emerin, the responsible protein for Emery-Dreifuss muscular dystrophy. AB - Emery-Dreifuss muscular dystrophy is a neuromuscular disorder that has three characteristics: (a) early contracture of the elbows, Achilles tendons and postcervical muscles; (b) slowly progressive wasting and weakness of skeletal muscle; and (c) cardiomyopathy with severe conduction block. The responsible gene for the X-linked recessive form of this disease encodes an inner nuclear membrane protein named emerin. Although emerin is absent in tissues from patients with this disorder, it remains obscure why the loss of this widely expressed protein affects selectively skeletal muscle, heart and joints. As the first step to address this question, we examined the molecular regions of emerin that are essential for nuclear membrane targeting and stability of the protein. We found that the C-terminal hydrophobic region was necessary, but not sufficient, for nuclear membrane anchoring and stability of the protein. In the absence of this transmembrane domain, the upstream nucleoplasmic domain showed no firm association with the nuclear rim, but showed the tendency to accumulate at the nucleolus-like structures. Furthermore, proper targeting of emerin to the nuclear membrane required the latter half of the nucleoplasmic domain. These characteristics are distinct from those of lamina-associated polypeptide 2. Our findings indicate that emerin has distinct interactions with the inner nuclear membrane components that may be required for the stability and function of rigorously moving nuclei in tissues such as skeletal muscle, heart and joints. PMID- 10092875 TI - Chemotaxin-dependent translocation of immunoreactive ADP-ribosyltransferase-1 to the surface of human neutrophil polymorphs. AB - mRNA from human polymorphonuclear neutrophil leucocytes (PMNs) was probed with cDNA encoding human skeletal muscle arginine-specific ADP-ribosyltransferase (ART1). A single 2.6-kb transcript was identified, which was similar in size to that observed in human skeletal muscle RNA. An 872-bp cDNA fragment, corresponding to the amino acid sequence of the processed human skeletal muscle enzyme, was generated by reverse transcription-PCR amplification of RNA from human PMNs, and was found to be identical to the ART1 cDNA derived from human skeletal muscle. ART1 was expressed as a fusion protein with glutathione S transferase (GST) in insect cells, and antibodies were raised against the fusion protein in a rabbit. Following removal of GST immunoreactivity by immunoprecipitation, these antibodies were used to measure the abundance of immunoreactive ART1 on the surface of PMNs. Exposure of PMNs to formyl-Met-Leu Phe (FMLP) was followed by a rapid increase in the abundance of cell surface ART1 (T1/2 = 1.9 min), and the concentration of FMLP for half-maximum response was 28.6 nM. Similar responses were observed after exposure of the cells to platelet activating factor or interleukin-8, and we conclude that some of the effects of these chemotaxins are mediated by translocation of an intracellular pool of ART1 to its site of catalytic activity on the outer aspect of the plasma membrane. PMID- 10092876 TI - A Kazal-type trypsin inhibitor from the protochordate Ciona intestinalis. AB - A trypsin inhibitor from Ciona intestinalis, present throughout the animal, was purified by ion-exchange chromatography followed by four HPLC steps. By MS the molecular mass of the native form was determined to be 6675 Da. The N-terminal amino acid sequence was determined by protein sequencing, but appeared to be partial because the theoretical molecular mass of the protein was 1101 Da too low. Thermolysin treatment gave rise to several fragments each containing a single disulphide bridge. By sequence analysis and MS intramolecular disulphide bridges could unequivocally be assigned to connect the pairs Cys4-Cys37, Cys8 Cys30 and Cys16-Cys51. The structure of the inhibitor is homologous to Kazal-type trypsin inhibitors. The inhibitor constant, KI, for trypsin inhibition was 0.05 nM whereas chymotrypsin and elastase were not inhibited. To reveal the complete sequence the cDNA encoding the trypsin inhibitor was isolated. This cDNA of 454 bp predicts a protein of 82 amino acid residues including a 20 amino acid signal peptide. Moreover, the cDNA predicts a C-terminal extension of 11 amino acids compared to the part identified by protein sequencing. The molecular mass calculated for this predicted protein is in accordance with the measured value. This C-terminal sequence is unusual for Kazal-type trypsin inhibitors and has apparently been lost early in evolution. The high degree of conservation around the active site strongly supports the importance of the Kazal-type inhibitors. PMID- 10092877 TI - An intrinsic curvature towards the minor groove in the cAMP-responsive element DNA found by combined NMR and molecular modelling studies. AB - The cAMP-responsive element (CRE, 5'-TGACGTCA-3') is essential to the transcriptional function of numerous gene promoters in eukaryotic cells. We carried out NMR restrained molecular mechanics studies using two different force fields (Flex and "AMBER94") on a hexadecanucleotide d(GAGATGACGTCATCTC) containing CRE. Results indicated that free CRE is a B-DNA that is intrinsically curved towards the minor groove. To our knowledge, NMR restraints have not previously been useful in accounting for a global DNA curvature. In order to validate the bend in CRE, we applied a new strategy in which DNA structures displaying different curvatures were generated and then compared with NMR data. Conformations of CRE curved towards the minor groove provided the best agreement with NMR data. Our results contrast with previous results obtained from NMR restrained modelling and gel methods; these suggested conformations that were straight or curved towards the major groove, respectively. The curve in free CRE is spread along the DNA helix: several kinks are repeated in phase within the helical turn, although they are centred mainly on CpG in between the TGA half sites, thus slightly increasing their spacing within the major groove. Comparison with the crystal structure of CRE complexed to general control protein 4 showed that the curve orientation is reversed from the minor to the major groove upon protein binding, due to a helix distortion concentrated mainly on CpG. PMID- 10092878 TI - Structural analysis of a novel putative capsular polysaccharide from Pseudomonas (Burkholderia) caryophylli strain 2151. AB - A novel putative capsular polysaccharide consisting of D-Glcp and D-Fruf in the molar ratio of 1:1 was isolated as minor constituent from the lipopolysaccharide (LPS) fraction of Pseudomonas (Burkholderia) caryophylli. Its structure was determined, using mainly one- and two-dimensional NMR spectroscopy, as: -->6) alpha-D-Glcp-(1-->1)-beta-D-Fruf-(2-->. PMID- 10092879 TI - Activation of a cGMP-stimulated cAMP phosphodiesterase by protein kinase C in a liver Golgi-endosomal fraction. AB - The ability of Ca2+/phospholipid-dependent protein kinase (protein kinase C, PKC) to stimulate cAMP phosphodiesterase (PDE) activity in a liver Golgi-endosomal (GE) fraction was examined in vivo and in a cell-free system. Injection into rats of 4 beta-phorbol 12-myristate 13-acetate, a known activator of PKC, caused a rapid and marked increase in PKC activity (+325% at 10 min) in the GE fraction, along with an increase in the abundance of the PKC alpha-isoform as seen on Western immunoblots. Concurrently, 4 beta-phorbol 12-myristate 13-acetate treatment caused a time-dependent increase in cAMP PDE activity in the GE fraction (96% at 30 min). Addition of the catalytic subunit of protein kinase A (PKA) to GE fractions from control and 4 beta-phorbol 12-myristate 13-acetate treated rats led to a comparable increase (130-150%) in PDE activity, suggesting that PKA is probably not involved in the in-vivo effect of 4 beta-phorbol 12 myristate 13-acetate. In contrast, addition of purified PKC increased (twofold) PDE activity in GE fractions from control rats but affected only slightly the activity in GE fractions from 4 beta-phorbol 12-myristate 13-acetate-treated rats. About 50% of the Triton-X-100-solubilized cAMP PDE activity in the GE fraction was immunoprecipitated with an anti-PDE3 antibody. On DEAE-Sephacel chromatography, three peaks of PDE were sequentially eluted: one early peak, which was stimulated by cGMP and inhibited by erythro-9 (2-hydroxy-3-nonyl) adenine (EHNA); a selective inhibitor of type 2 PDEs; and two retarded peaks of activity, which were potently inhibited by cGMP and cilostamide, an inhibitor of type 3 PDEs. Further characterization of peak I by HPLC resolved a major peak which was activated (threefold) by 5 microM cGMP and inhibited (87%) by 25 microM EHNA, and a minor peak which was insensitive to EHNA and cilostamide. 4 beta Phorbol 12-myristate 13-acetate treatment caused a selective increase (2.5-fold) in the activity associated with DEAE-Sephacel peak I, without changing the K(m) value. These results suggest that PKC selectively activates a PDE2, cGMP stimulated isoform in the GE fraction. PMID- 10092880 TI - The rainbow trout Oncorhynchus mykiss interleukin-1 beta gene has a differ organization to mammals and undergoes incomplete splicing. AB - The rainbow trout interleukin (IL)-1 beta gene consists of six exons/five introns, in contrast to mammals which have seven exons/six introns. The missing exon appears to be at the 5' end of the gene, probably equivalent to exon 1 or 2 of mammals. Fewer and smaller introns make the trout IL-1 beta only half the size of mammalian IL-1 beta genes. Highest homology (> 60% amino acid similarity) is seen between exon 5 of trout and exon 6 of mammals. Reverse transcription-PCR analysis revealed two additional incompletely spliced variants of the trout IL-1 beta gene, containing intron 5 or introns 4 and 5. All three transcripts are detectable in gill, kidney, liver and spleen tissue from bacterially challenged fish but only the fully spliced transcript is detectable in blood. Northern blot analysis revealed that the latter transcript is also induced following stimulation of kidney leucocytes with lipopolysaccharide for 4 h. A second inducible transcript is also detected but is larger (approximately 3 kb) than any of the above, suggesting that it could be from a second gene. Southern blot analysis also suggests at least two copies of the IL-1 beta gene or genes related to the 3' end of the IL-1 beta sequence, are present in trout. PMID- 10092881 TI - Molecular cloning, cell localization and binding affinity to DNA replication proteins of the p36/LACK protective antigen from Leishmania infantum. AB - The p36/LACK antigen from Leishmania, an analogue of the receptor for activated protein kinase C (PKC), induces high levels of protection against parasite infection in the BALB/c mouse model. This protection is more than twice as high as that elicited by major parasite antigens such as soluble Leishmania antigen or the main surface protease gp63. We have cloned and purified p36/LACK from Leishmania infantum, the causative agent of visceral leishmaniasis in Europe. This protein belongs to the large family of WD 40 repeat proteins confined to eukaryotes and involved in numerous regulatory functions. Differential solubilization and immunofluorescence experiments indicate that p36/LACK is present close to the kinetoplast disc in the cell cytoplasm, probably bound to multiprotein complexes but not to membrane structures. These complexes probably also include cytoplasm PKC isoforms. The use of a genetically-encoded peptide library indicates that p36/LACK binds sequences present in several proteins involved in DNA replication and RNA synthesis. The recognition and binding sequences present in vacuolar proteins and at the beta-chain of major histocompatability complex (MHC) class II suggest the involvement of this regulatory protein in the early mechanisms triggering the protective immune response of the host against the parasite infection. PMID- 10092882 TI - Recombinant domain IV of perlecan binds to nidogens, laminin-nidogen complex, fibronectin, fibulin-2 and heparin. AB - Domain IV of mouse perlecan, which consists of 14 immunoglobulin superfamily (IG) modules, was prepared from recombinant human cell culture medium in the form of two fragments, IV-1 (IG2-9, 100 kDa) and IV-2 (IG10-15, 66 kDa). Both fragments bound to a heparin column, being eluted at ionic strengths either below (IV-2) or above (IV-1) physiological level, and could thus be readily purified. Electron microscopy demonstrated an elongated shape (20-25 nm), and folding into a native structure was indicated by immunological assay and CD spectroscopy. Solid-phase and surface plasmon resonance assays demonstrated strong binding of fragment IV-1 to fibronectin, nidogen-1, nidogen-2 and the laminin-1-nidogen-1 complex, with Kd values in the range 4-17 nM. The latter binding apparently occurs through nidogen 1, as shown by the formation of ternary complexes. Only moderate binding was observed for fibulin-2 and collagen IV and none for fibulin-1 and BM-40. Fragment IV-2 showed a more restricted pattern of binding, with only weaker binding to fibronectin and fibulin-2. None of these activities could be demonstrated for recombinant fragments corresponding to the N-terminal perlecan domains I to III. This indicates a special role for domain IV in the integration of perlecan into basement membranes and other extracellular structures via protein-protein interactions. PMID- 10092883 TI - Acidic pH as a physiological regulator of human cathepsin L activity. AB - Human cysteine protease cathepsin L was inactivated at acid pH by a first-order process. The inactivation rate decreased with increasing concentrations of a small synthetic substrate, suggesting that substrates stabilize the active conformation. The substrate-independent inactivation rate constant increased with organic solvent content of the buffer, consistent with internal hydrophobic interactions, disrupted by the organic solvent, also stabilizing the enzyme. Circular dichroism showed that the inactivation is accompanied by large structural changes, a decrease in alpha-helix content being especially pronounced. The high activation energy of the reaction at pH 3.0 (200 kJ.mol-1) supported such a major conformational change occurring. The acid inactivation of cathepsin L was irreversible, consistent with the propeptide being needed for proper folding of the enzyme. Aspartic protease cathepsin D was shown to cleave denatured, but not active cathepsin L, suggesting a potential mechanism for in vivo regulation and turnover of cathepsin L inside lysosomes. PMID- 10092884 TI - Agmatine modulates polyamine content in hepatocytes by inducing spermidine/spermine acetyltransferase. AB - Agmatine has been proposed as the physiological ligand for the imidazoline receptors. It is not known whether it is also involved in the homoeostasis of intracellular polyamine content. To show whether this is the case, we have studied the effect of agmatine on rat liver cells, under both periportal and perivenous conditions. It is shown that agmatine modulates intracellular polyamine content through its effect on the synthesis of the limiting enzyme of the interconversion pathway, spermidine/spermine acetyltransferase (SSAT). Increased SSAT activity is accompanied by depletion of spermidine and spermine, and accumulation of putrescine and N1-acetylspermidine. Immunoblotting with a specific polyclonal antiserum confirms the induction. At the same time S adenosylmethionine decarboxylase activity is significantly increased, while ornithine decarboxylase (ODC) activity and the rate of spermidine uptake are reduced. This is not due to an effect on ODC antizyme, which is not significantly changed. All these modifications are observed in HTC cells also, where they are accompanied by a decrease in proliferation rate. SSAT is also induced by low oxygen tension which mimics perivenous conditions. The effect is synergic with that promoted by agmatine. PMID- 10092885 TI - Site-directed mutagenesis of proline 204 in the 'hinge' region of yeast phosphoglycerate kinase. AB - Site-specific mutants have been produced in order to investigate the role of proline 204 in the 'hinge' region of yeast phosphoglycerate kinase (PGK). This totally conserved proline has been shown to be the only cis-proline in the high resolution crystal structures of yeast, B. stearothermophilus, T. brucei and T. maritima PGK, and may therefore have a role in the independent folding of the two domains or in the 'hinge' bending of the molecule during catalysis. The residue was replaced by a histidine (Pro204His) and a phenylalanine (Pro204Phe), and the resulting proteins characterised by differential scanning calorimetry (DSC), circular dichroism (CD), tryptophan fluorescence emission and kinetic analysis. Although the secondary and tertiary structure of the Pro204His protein is generally similar to that of the wild-type enzyme as assessed by CD, the enzyme is less stable to heat and guanidinium chloride denaturation than the wild-type. In the denaturation experiments two transitions were observed for both the wild type and the Pro204His mutant, as have been previously reported for yeast PGK [Missiakas, D., Betton, J.M., Minard, P. & Yon, J.M. (1990) Biochemistry 29, 8683 8689]. The first transition is accompanied by an increase in fluorescence intensity leading to a hyperfluorescent state, followed by the second, corresponding to a decrease in fluorescence intensity. However, for the Pro204His mutant, the first transition proceeded at lower concentrations of guanidinium chloride and the second transition proceeded to the same extent as for the wild type protein, suggesting that sequence-distant interactions are more rapidly disrupted in this mutant enzyme than in the wild-type enzyme, while sequence local interactions are disrupted in a similar way. The Michaelis constants (K(m)) for both 3-phospho-D-glycerate and ATP are increased only by three or fourfold, which confirms that, as expected, the substrate binding sites are largely unaffected by the mutation. However, the turnover and efficiency of the Pro204His mutant is severely impaired, indicating that the mechanism of 'hinge' bending is hindered. The Pro204Phe enzyme was shown to be significantly less well folded than the wild-type and Pro204His enzymes, with considerable loss of both secondary and tertiary structure. It is proposed that the proline residue at 204 in the 'hinge' region of PGK plays a role in the stability and catalytic mechanism of the enzyme. PMID- 10092886 TI - A novel egg-derived tyrosine phosphatase, EDTP, that participates in the embryogenesis of Sarcophaga peregrina (flesh fly). AB - We have previously reported that cathepsin L mRNA is present in unfertilized eggs of Sarcophaga peregrina (flesh fly) as a maternal mRNA, which suggests that cathepsin L is required for embryogenesis. Now we have identified an egg protein, with a molecular mass of 100 kDa, that is extremely susceptible to cathepsin L digestion and which disappears rapidly as the embryos develop. We purified this protein to homogeneity, cloned its cDNA, and found that it contained a consensus sequence for the active site of tyrosine phosphatase. In fact this protein showed tyrosine phosphatase activity, indicating that it is a novel tyrosine phosphatase. The expression and subsequent disappearance of this protein, which we have named egg-derived tyrosine phosphatase (EDTP), may be indispensable for embryogenesis of Sarcophaga. PMID- 10092887 TI - The cell surface expression level of the human interleukin-5 receptor alpha subunit determines the agonistic/antagonistic balance of the human interleukin-5 E13Q mutein. AB - The human interleukin-5 (IL-5) receptor consists of an alpha-chain that specifically binds the ligand with intermediate affinity, and a beta c-chain, that associates with the IL-5/IL-5R alpha complex, leading to a high-affinity, signal transducing receptor complex. Structure-function studies showed that modification of the putative beta c-chain binding site in IL-5 (E13Q mutein) converted the molecule into an antagonist. However, analysis of the effect of this mutant IL-5 on COS-1 cells transfected with both receptor subunits, did not show reduced interaction with the beta c subunit [Tavernier, J., Tuypens, T., Verhee, A., Plaetinck, G., Devos, R., Van der Heyden, J., Guisez, Y. & Oefner, C. (1995) Proc. Natl Acad. Sci. USA 89, 7041-7045]. To gain more insight into the mechanism of IL-5 antagonism by E13Q, we tested its biological activity on two FDC-P1 subclones that express clearly different numbers of alpha-subunits yet an almost constant number of murine beta c-subunits. Here we show that E13Q has a biological activity comparable to wild-type IL-5 only when a high number of alpha chains is present on the cells. Confirming the critical role of the IL5R alpha cell-surface expression level, treatment with suboptimal doses of a neutralising anti-IL-5R alpha antibody results in reduced activity of the mutant but not of wild-type IL-5. PMID- 10092888 TI - The effects of crossing porcine renal artery ostia with various endovascular stents. AB - OBJECTIVES: To compare the effects of crossing renal artery ostia with various stents. METHODS: The renal artery ostia of 24 large white pigs were covered with a Wallstent (nine ostia), a Palmaz stent (nine ostia) and a Memotherm stent (13 ostia). After an interval of 6-15 weeks, aortography, renal pressure and blood samples were performed and the pigs then sacrificed for histological examination. RESULTS: Histological examination revealed an organised collagen matrix with endothelial cells covering the struts in contact with the aorta. This occurred with all stents but was most organised with the Wallstent. This matrix did not involve the renal artery ostia crossed by Wallstents, but in one Palmaz stent and in 12/13 Memotherm stents, a disorganised acellular matrix caused partial ostial occlusion. There was no mean fall in renal artery pressure but traces were damped in 8/13 cases of partial occlusion. There was a rise in serum creatinine in two cases using the Palmaz stent. CONCLUSIONS: Covering renal arteries with the Wallstent appears to be safe in the short-term. Placement of stents with larger struts across renal arteries will require imaging methods, such as intravascular ultrasound (IVUS) to ensure that the ostia are not obstructed. PMID- 10092889 TI - Acute renal impairment due to a primary aortocaval fistula is normalised after a successful operation. AB - OBJECTIVES: To study renal function in patients with aortocaval fistula, before and after surgery. DESIGN: Retrospective study. MATERIAL AND METHODS: During the last 22 years nine male patients (median age 67, age range 50-72) with spontaneous aortocaval fistula in combination with AAA were operated upon. This constitutes 4% of the patients with ruptured AAA and 1.5% of all patients with AAA. RESULTS: A preoperative diagnosis of aortocaval fistula was established in three of the nine cases. The medium duration of symptoms prior to surgery was 5 days (range 4 h-14 days). The fistula was combined with an extravasating ruptured AAA in only three patients. Seven of the patients had acute renal insufficiency, with creatinine levels of in median 292 mumol (IQR 218-342). Creatinine declined to 172 mumol/l (IQR 170-313) on the fifth postoperative day in uncomplicated cases and to 86 mumol at discharge. One patient died due to multi-organ failure, whereas the other left hospital well and alive with normal renal function. CONCLUSION: Acute preoperative renal insufficiency due to an aortocaval fistula in patients with AAA is often due to venous congestion, and is normalised after successful surgery. PMID- 10092890 TI - Prospective randomised trial of distal arteriovenous fistula as an adjunct to femoro-infrapopliteal PTFE bypass. AB - OBJECTIVES: To compare graft patency and limb salvage rate following femoro infrapopliteal bypass using ePTFE grafts with and without the addition of adjuvant arterio-venous fistula. DESIGN: A prospectively randomised controlled trial. MATERIALS: Patients referred to two teaching hospital vascular surgery units in the U.K. for the treatment of critical limb ischaemia. METHODS: Eighty seven patients (M:F; 2.3:1) undergoing 89 femoro-intrapopliteal bypass operations with ePTFE grafts for critical limb ischaemia were randomly allocated to have AVF included in the operative procedure (n = 48) or to a control group without AVF (n = 41). An interposition vein-cuff was incorporated at the distal anastomosis in all patients. RESULTS: The cumulative rates of primary patency and limb salvage at 1-year after operation for patients with AVF were 55.2% and 54.1% compared to 53.4% and 43.2%, respectively, for the control group. The differences between the AVF and control groups did not reach statistical significance, in terms of either graft patency or limb salvage, at any stage after operation (Log-Rank test). CONCLUSIONS: AVF confers no additional significant clinical advantage over interposition vein cuff in patients having femoro-infrapopliteal bypass with ePTFE grants for critical limb ischaemia. PMID- 10092891 TI - Endovascular abdominal aortic aneurysm repair with percutaneous transfemoral prostheses deployment under local anaesthesia. Initial experience with a new, simple-to-use tubular and bifurcated device in the first 27 cases. AB - BACKGROUND: Modification of endografts are required to simplify and improve the safety of the endovascular management of abdominal aortic aneurysms (AAA). OBJECTIVES: The aim of this study is to evaluate the efficacy of a new custom made, tubular and bifurcated device. MATERIALS AND METHODS: The graft consisted of a continuous, self-expanding, stainless steel, Z-stent structure, covered with a thin wall PTFE tube. Bifurcated grafts were constructed in vivo from three PTFE tubes with a continuous Z-stent structure. Twenty-seven high risk patients with a mean age of 74 (62-86) years and AAA, mean diameter 5.9 cm, were treated in the last 26 months. Tube grafts were deployed in 13 aortic and one iliac cases, bifurcated grafts in nine cases and aorto-uni-iliac grafts with femorofemoral bypass in four cases. Grafts were deployed percutaneously under local anaesthesia. Patients were followed with contrast CT periodically. RESULTS: All grafts were deployed. There were no open conversions or other major complications. There were nine proximal and one distal postoperative endoleak. Four sealed spontaneously, three were treated successfully with endovascular techniques and three are under surveillance. In the 7 (2-23) months follow-up, one patient died due to heart failure 3 months post-procedure. CONCLUSIONS: Local anaesthesia and percutaneous graft introduction simplify and improve the efficacy of the procedure. Continuous aortic graft support provides stability and reduces the risk of migration. PTFE is a flexible, low-profile material for use in endovascular stent-grafts. The bifurcation concept used offers a simple technique for bifurcated grafts. PMID- 10092892 TI - Mortality in ruptured abdominal aortic aneurysms. The Finnvasc Study Group. AB - OBJECTIVE: To assess mortality related to rupture of abdominal aortic aneurysm (RAAA). DESIGN: A 4-year cross-sectional study based on a nationwide vascular registry Finnvasc and national cause-of-death registry (Statistics Finland). MATERIALS AND METHODS: A total of 454 operations for RAAA among 11,747 surgical vascular reconstructions recorded in the Finnvasc registry and 1004 deaths due to RAAA during the same period based on Statistics Finland. RESULTS: The operative mortality rate was 49% based on the Finnvasc registry and 54% based on Statistics Finland. With all RAAA deaths at hospitals included, total hospital mortality was 68%. No association existed between hospital volume of RAAA operations and surgical mortality, although an inverse association did exist between hospital volume of RAAA operations and all RAAA deaths in the hospital (p = 0.01). The case fatality for RAAA in Finland was 80%. CONCLUSIONS: RAAA surgical mortality calculations for RAAA, based on a vascular registry, underestimate the true rate because some cases with fatal outcome tend to escape registration. Because surgical mortality rates may also be skewed by patient selection, total hospital RAAA mortality thus represents the results of RAAA treatment more accurately. PMID- 10092893 TI - Complications in carotid endarterectomy are predicted by qualifying symptoms and preoperative CT findings. AB - OBJECTIVES: To relate the 30-day perioperative rate of stroke or death in carotid endarterectomy (CEA) to preoperative qualifying symptoms and to the presence of cerebral infarction (CI) demonstrated on computed tomography (CT). DESIGN: Retrospective clinical study. MATERIAL AND METHODS: Two hundred and seventy-two consecutive CEAs for symptomatic stenosis in 262 patients were analysed. RESULTS: The total complication rate was 5.9%. Patients with retinal symptoms (n = 81) had no complications, TIA patients (n = 76) had 6.6% (p < 0.001). Patients qualifying with minor stroke (n = 113) had complications in 9.7% (N.S. compared to TIA patients). Patients qualifying with cortical symptoms had a significantly higher complication rate compared to those with retinal (8.4% vs. 0%, p = 0.004). The presence of a preoperative CT-verified infarction resulted in a higher risk for stroke or death (9.8% vs 2.8%, p = 0.008). Within the subgroup presenting with minor stroke, the presence of CI resulted in stroke or death in 13.9%. In patients without CI the corresponding figure was 2.4% (p = 0.017). CONCLUSION: The qualifying symptoms and the presence of CI visualized by CT influence the complication rate in CEA. When evaluating risk and comparing outcome, these parameters should be included in reporting standards. PMID- 10092894 TI - Volume flow estimation by colour duplex. AB - OBJECTIVE: To assess the accuracy of volume blood flow using a digitised colour duplex scanner. DESIGN: Observer-blinded experimental study. MATERIALS AND METHODS: Method comparison was performed with linear regression analysis of 89 paired observations in 11 anaesthetised pigs. A Siemens Sonoline Elegra ultrasound system was used for transcutaneous volume flow estimation using invasive transit time flowmetry by Cardiomed as a reference. RESULTS: For the individual measurement we found a standard error of the estimate (SEE) of 22 ml/min. For the regression line, however, the SEE was only 0.2 ml/min. CONCLUSIONS: Digitised colour-duplex sonography has a volume flow measurement error that is too high for single measurements in the individual patient for the method to be useful in clinical decision making, but sufficient for examinations of groups and comparison of groups. PMID- 10092895 TI - Peripheral blood flow rates and microvascular responses to orthostatic pressure changes in claudicants before and after revascularisation. AB - OBJECTIVES: To study the effect of arterial reconstruction for occlusive atherosclerotic disease with intermittent claudication on blood flow rate during rest and on microvascular responses to orthostatic pressure changes in the pulp skin of the first toe where arteriovenous anastomoses are numerous. MATERIAL: Eleven patients with Fontaine IIa claudication (ankle blood pressure index > 0.30) before and 7 (range: 2-11) months after intervention. METHODS: Blood flow rate was measured by the heat washout method with the toe at heart level and after passive lowering to 50 cm below this level using a Clark type electrode with thermostatically controlled cap that was fixed to the pulp of the first toe by adhesive tape. RESULTS: At heart level, blood flow rate was lower in claudicants before reconstruction as compared to a group of previously published control subjects (p = 0.0076, Wilcoxon), blood flow rate increased in claudicants from before to after intervention (p = 0.0128), and postoperative blood flow rate was like that of normals (N.S.). Before surgery, blood flow rate in claudicants increased in median with a factor of 1.79 during lowering (p < 0.0051). CONCLUSIONS: The disturbance of the microcirculatory responses to orthostatically induced pressure changes in claudicants reverted towards normal after arterial reconstruction. PMID- 10092896 TI - Duplex-derived evidence of reflux after varicose vein surgery: neoreflux or neovascularisation? AB - BACKGROUND: Recurrent varicose veins remain a problem in surgical practice despite improvements to the preoperative investigation of, and surgery for varicose veins. Neovascularisation accounts for some cases of recurrence within a few years of surgery, but other factors relating to disease progression must also play a part. We investigated whether new venous reflux (neoreflux) could occur in the early postoperative period (within 6 weeks) following successful varicose vein surgery. METHODS: Eighteen-month prospective observational study in the dedicated vascular surgery unit of a university teaching hospital. Forty-six patients, with primary saphenofemoral junction reflux, awaiting varicose vein surgery were chosen consecutively from the waiting list. All saphenofemoral surgery was performed in a standardised fashion. Assessments were performed prior to, at 6 weeks and at 1 year after surgery. Duplex ultrasound was used to identify and locate sites of reflux. RESULTS: Neoreflux was present at the 6-week postoperative scan in nine limbs after varicose vein surgery (19.6%), and resolved in 55.6% of patients within 1 year. Neovascularisation was noted in two limbs at the 1-year scan. CONCLUSION: New sites of reflux, which may resolve spontaneously, occur in the early postoperative period despite adequate varicose vein surgery. It is our hypothesis that this is a manifestation of the effect of altered venous haemodynamics in a system of susceptible veins. PMID- 10092897 TI - A policy of quality control assessment helps to reduce the risk of intraoperative stroke during carotid endarterectomy. AB - OBJECTIVES: A pilot study in our unit suggested that a combination of transcranial Doppler (TCD) plus completion angioscopy reduced incidence of intra operative stroke (i.e. patients recovering from anaesthesia with a new deficit) during carotid endarterectomy (CEA). The aim of the current study was to see whether routine implementation of this policy was both feasible and associated with a continued reduction in the rate of intraoperative stroke (IOS). MATERIALS AND METHODS: Prospective study in 252 consecutive patients undergoing carotid endarterectomy between March 1995 and December 1996. RESULTS: Continuous TCD monitoring was possible in 229 patients (91%), while 238 patients (94%) underwent angioscopic examination. Overall, angioscopy identified an intimal flap requiring correction in six patients (2.5%), whilst intraluminal thrombus was removed in a further six patients (2.5%). No patient in this series recovered from anaesthesia with an IOS, but the rate of postoperative stroke was 2.8%. CONCLUSIONS: Our policy of TCD plus angioscopy has continued to contribute towards a sustained reduction in the risk of IOS following CEA, but requires access to reliable equipment and technical support. However, a policy of intraoperative quality control assessment may not necessarily alter the rate of postoperative stroke. PMID- 10092898 TI - Gastric emptying after elective abdominal aortic aneurysm surgery: the case for early postoperative enteral feeding. AB - OBJECTIVE: To assess gastric emptying with a view to early postoperative enteral nutrition after elective abdominal aortic aneurysm (AAA) surgery. METHODS: The paracetamol absorption test was used to assess gastric emptying in 13 consecutive patients at 6, 18 and 32 h following elective AAA surgery. All patients received postoperative analgesia with marcaine given via an epidural catheter during the first 48 postoperative hours. Normal emptying was defined as an area under the plasma paracetamol concentration curve at 60 min (AUC-60) of > 600 mg/min/l. RESULTS: The median time to normal gastric emptying was 18 +/- 7.7 h. One patient (7.6%) had normal emptying at 6 h, nine (69%) at 18 h and 12 (92%) at 32 h. The nasogastric tubes were removed at a median of 3.2 days after surgery, and enteral feeding was commenced on day 4. CONCLUSIONS: Gastric emptying was normal 18 h post-AAA surgery as assessed by the paracetamol absorption test. In view of the importance of maintaining an intact gastrointestinal mucosa, enteral nutrition may be commenced on the second postoperative day. PMID- 10092899 TI - The association between laser Doppler reactive hyperaemia curves and the distribution of peripheral arterial disease. AB - OBJECTIVES: To determine whether postocclusive laser Doppler fluxmetry (LDF) curves can be related to the arteriographic distribution of disease. DESIGN: Prospective study. MATERIALS: Sixty-nine patients with symptomatic peripheral ischaemia and 15 healthy subjects. METHODS: Laser Doppler fluxmetry (LDF) was monitored on the dorsum of the symptomatic foot following 2 min of arterial occlusion at the ankle. During reperfusion three patterns of LDF were identified (types I-III). All patients subsequently underwent arteriography which was reported independent of LDF results. The distribution of disease, particularly patency of below-knee vessels, was related to the type of LDF curve observed during reactive hyperaemia. RESULTS: Type I curves were observed in all healthy subjects and 75% of patients with a single arterial lesion. Type II curves were found in 78% of patients with multiple lesions above the knee. The presence of either a type I or II curve was associated with a continuous vessel from knee to ankle (positive predictive value 83%, p < 0.01), whilst type III curve was associated with discontinuous infrapopliteal run-off (positive predictive value 86%, p < 0.01). CONCLUSIONS: This pilot study suggests that post-occlusive LDF curves may identify the distribution of arterial disease and may be useful in the non-invasive management of peripheral ischaemia. PMID- 10092900 TI - Management of coexisting coronary artery and asymptomatic carotid artery disease: report of a series of patients treated with coronary bypass alone. AB - BACKGROUND: A retrospective chart review of 94 patients with asymptomatic high grade carotid stenosis undergoing coronary bypass (and valve replacement in some cases) was performed to determine whether significant carotid lesions can be safely ignored in patients undergoing cardiac surgical procedures. These operations were performed during a 2-year period. PATIENTS AND METHODS: There were 55 men and 39 women, with an age range of 37-89 years. Seventy-one patients had unilateral high-grade carotid stenosis, 17 patients had bilateral high-grade lesions, and six patients had unilateral high-grade stenosis and contralateral occlusion. Associated medical problems were recorded and short-term follow-up was obtained. RESULTS: There was one perioperative stroke and no deaths in this group of patients. CONCLUSIONS: Although these data indicate that high-grade carotid stenoses may be safely ignored during cardiac surgical procedures, a multicentre prospective randomized trial is needed to determine the appropriate treatment of the patient with coexisting carotid and coronary artery disease. PMID- 10092901 TI - Thoracoabdominal aortic surgery with special reference to spinal cord protection and perfusion techniques. "Second Nordic Workshop-group". PMID- 10092902 TI - A method for reinforcing an aortic-graft anastomosis by a strip of Dacron. PMID- 10092903 TI - Stent-graft treatment of iatrogenic iliac artery perforations: report of three cases. PMID- 10092904 TI - Rupture of an iliac artery pseudo-aneurysm into a ureter. PMID- 10092905 TI - Ischaemic sciatic neuropathy: a complication of endovascular repair of abdominal aortic aneurysm. PMID- 10092906 TI - Type IV thoraco-abdominal aortic aneurysm complicated by an aorto-enteric fistula due to previous infrarenal aortic graft. PMID- 10092907 TI - Computerised carotid plaque characterisation. PMID- 10092908 TI - Hypercoagulable states. PMID- 10092909 TI - Vein graft surveillance. PMID- 10092910 TI - Aortic aneurysms. PMID- 10092911 TI - Carotid duplex. PMID- 10092912 TI - Idiopathic thrombocytopenic purpura in adults. PMID- 10092913 TI - Hyperbaric oxygen for carbon monoxide poisoning. PMID- 10092914 TI - Educating medical students about cancer. PMID- 10092915 TI - The treatment of hepatitis C. PMID- 10092916 TI - Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial. AB - OBJECTIVE: To assess neurological sequelae in patients with all grades of carbon monoxide (CO) poisoning after treatment with hyperbaric oxygen (HBO) and normobaric oxygen (NBO). DESIGN: Randomised controlled double-blind trial, including an extended series of neuropsychological tests and sham treatments in a multiplace hyperbaric chamber for patients treated with NBO. SETTING: The multiplace hyperbaric chamber at the Alfred Hospital, a university-attached quarternary referral centre in Melbourne providing the only hyperbaric service in the State of Victoria. PATIENTS: All patients referred with CO poisoning between 1 September 1993 and 30 December 1995, irrespective of severity of poisoning. Pregnant women, children, burns victims and those refusing consent were excluded. INTERVENTION: Daily 100-minute treatments with 100% oxygen in a hyperbaric chamber--60 minutes at 2.8 atmospheres absolute for the HBO group and at 1.0 atmosphere absolute for the NBO group--for three days (or for six days for patients who were clinically abnormal or had poor neuropsychological outcome after three treatments). Both groups received continuous high flow oxygen between treatments. MAIN OUTCOME MEASURES: Neuropsychological performance at completion of treatment, and at one month where possible. RESULTS: More patients in the HBO group required additional treatments (28% v. 15%, P = 0.01 for all patients; 35% v. 13%, P = 0.001 for severely poisoned patients). HBO patients had a worse outcome in the learning test at completion of treatment (P = 0.01 for all patients; P = 0.005 for severely poisoned patients) and a greater number of abnormal test results at completion of treatment (P = 0.02 for all patients; P = 0.008 for severely poisoned patients). A greater percentage of severely poisoned patients in the HBO group had a poor outcome at completion of treatment (P = 0.03). Delayed neurological sequelae were restricted to HBO patients (P = 0.03). No outcome measure was worse in the NBO group. CONCLUSION: In this trial, in which both groups received high doses of oxygen, HBO therapy did not benefit, and may have worsened, the outcome. We cannot recommend its use in CO poisoning. PMID- 10092917 TI - Antenatal hospitalisations in New South Wales, 1995-96. AB - OBJECTIVES: To provide a population-based estimate of the prevalence of antenatal hospitalisations and to determine the reasons for admission. DESIGN: Descriptive study. Data sources were primarily the New South Wales inpatient Statistics Collection (ISC) and also the linked population-based New South Wales Midwives Data Collection. SETTING AND PATIENTS: All women resident in New South Wales (NSW) admitted to public and private hospitals in NSW for pregnancy complications from 1 July 1995 to 30 June 1996. MAIN OUTCOME MEASURE: Antenatal hospitalisations for pregnancy complications per 100 confinements. RESULTS: There were a total of 25,710 antenatal non-delivery admissions in NSW hospitals among 86,263 confinements, yielding a ratio of 30 antenatal admissions per 100 confinements (21 per 100 excluding day-stay admissions). Women without private health insurance, Aboriginal women and women under the age of 20 had significantly higher rates of antenatal admissions. The principal admitting diagnoses were hypertension (17.6%), threatened preterm labour (14.1%), antepartum haemorrhage (14.0%), threatened labour (after 37 weeks' gestation) (11.1%) and excessive vomiting in pregnancy (9.4%). A majority (58%) of antenatal admissions (including admissions to day-stay facilities) were for one day. CONCLUSIONS: Significant pregnancy-related morbidity, as measured by high ratios of antenatal admissions, is evident in NSW. Sociodemographic factors and health service management protocols appear to account for some of the variability in antenatal admissions. PMID- 10092918 TI - The diagnosis of idiopathic thrombocytopenic purpura in adults: does bone marrow biopsy have a place? AB - OBJECTIVE: To assess the value of routine bone marrow biopsy (BMB) in adult patients less than 65 years of age with suspected idiopathic thrombocytopenic purpura (ITP). DESIGN: Retrospective analysis. Data were collected from hospital medical records and laboratory results. SETTING: Large tertiary-level metropolitan teaching hospital, Victoria. PARTICIPANTS: Sixty-six patients who had undergone BMB for investigation of isolated thrombocytopenia between January 1992 and May 1997, according to defined eligibility criteria. RESULTS: Sixty-one of the 66 patients had BMB findings consistent with ITP (i.e., normal or increased numbers of megakaryocytes and other haemopoietic lineages normal). Three of these patients' biopsies incidentally showed reduced or absent iron stores. In the remaining five patients, BMB in four showed mild hypocellularity and the subsequent course in these patients was consistent with chronic ITP. The fifth patient had neutrophil hypersegmentation and giant band cells on BMB, the cause of which was unclear. The subsequent course in this patient has also been consistent with chronic ITP. CONCLUSIONS: Our data suggest that the routine performance of BMB for the diagnosis of ITP is not useful, provided that a thorough clinical history and physical examination are undertaken and that the blood count and peripheral blood smear show no abnormalities apart from thrombocytopenia. PMID- 10092919 TI - An adverse reaction to the herbal medication milk thistle (Silybum marianum). Adverse Drug Reactions Advisory Committee. PMID- 10092920 TI - The force of numbers: why hepatitis C is spreading among Australian injecting drug users while HIV is not. PMID- 10092921 TI - Confidentiality and the courts. AB - There is a general belief that, once in the witness box, doctors are compelled to reveal confidential information about their patients if asked by counsel. Where no issue of public interest is involved, a medical witness should ask the court to rule in its inherent discretion that the information sought is confidential and privileged. PMID- 10092922 TI - A survey of cancer curricula in Australian and New Zealand medical schools in 1997. Oncology Education Committee of the Australian Cancer Society. AB - OBJECTIVE: To assess teaching about cancer in medical schools in Australia and New Zealand. DESIGN AND SETTING: Postal survey of all 12 Australian and New Zealand medical schools in 1997. PARTICIPANTS: The Dean (or a nominee) of each medical school and the representative of each university on the Oncology Education Committee (OEC) of the Australian Cancer Society. OUTCOME MEASURES: Curriculum content, clinical placements and forms of teaching and assessment related to cancer; presence and composition of cancer curriculum planning, and assessment groups. RESULTS: 22 responses were received from 10 medical schools (from nine Deans or nominees and 13 OEC representatives). Implementation of cancer teaching and overall course structure varied considerably between schools. Nine of these 10 schools had a "cancer planning group", and four were using problem-based learning. Only five schools could readily provide detailed curriculum maps. Courses covered most areas of basic and clinical sciences outlined in the ACS ideal curriculum; chemotherapy and palliative care were taught in all courses, but other subjects were covered less often (e.g., clinical staging, radiation oncology and pain management were taught in nine schools, critical evaluation of medical literature in seven, and economic evaluation in five). Teaching on cancer in clinical placements also varied considerably (e.g., one school devoted no time to palliative care). DISCUSSION: There has been some improvement in delivery of cancer education in medical schools since 1993, but considerable variation in teaching practice and implementation remains. Difficulty in determining details of course content led directly to difficulty in assessing the quality of teaching about cancer. PMID- 10092923 TI - Pancreatic disease. PMID- 10092924 TI - Effect of contamination of Sydney drinking water on hospital primary care presentations. PMID- 10092925 TI - Increase in Campylobacter gastroenteritis coinciding with Melbourne gas restrictions. PMID- 10092926 TI - Positron emission tomography in assessing response to neoadjuvant chemotherapy for non-small-cell lung cancer. PMID- 10092927 TI - Surgery and the randomised controlled trial: past, present and future. PMID- 10092928 TI - Self-reported diabetes and distribution of HbA1c in a population-based sample in Victoria. PMID- 10092929 TI - Psychological morbidity and quality of life in Australian women with early-stage breast cancer: a cross-sectional survey. PMID- 10092930 TI - Should smoking be an indication for lipid-lowering therapy? PMID- 10092931 TI - Drugs for hypertension. PMID- 10092932 TI - The ability of polyethylene glycol conjugated bovine hemoglobin (PEG-Hb) to adequately deliver oxygen in both exchange transfusion and top-loaded rat models. AB - The purpose of this study was to determine whether a six gram percent (g%) solution of the hemoglobin based oxygen carrier, polyethylene glycol conjugated bovine hemoglobin (PEG-Hb) could adequately deliver oxygen in both partial exchange transfusion and top-loaded rat models. This study measured tissue oxygen tension, circulatory retention and cardiovascular effects following both 30% exchange transfusion and 20 to 25 mL/kg top-loaded infusions of PEG-Hb. Oxygen delivery to rat tissues was determined using an oxygen dependent phosphorescence quenching method (Oxyspot). Telemetric intravascular blood pressure probes monitored heart rate and mean arterial pressure. In both models, six g% PEG-Hb (P50-15 torr) was shown to oxygenate tissue better than stroma-free bovine Hb (P50-26 torr), cross-linked bovine Hb (P50-48 torr) or simple plasma expanders. The mean circulatory half life of PEG-Hb was 15.0 +/- 2.3 hours and 17.4 +/- 1.6 hours for exchange transfusion and 25 mL/kg top-loaded rat models, respectively. Mean arterial pressure (MAP) in PEG-Hb treated rats was insignificantly different from sham controls undergoing a 30% exchange transfusion or following a top loaded infusion. In conclusion, the PEG conjugated form of bovine Hb with its relatively long vascular persistence may possess characteristics that facilitate tissue oxygenation in the rat. PMID- 10092933 TI - Determination of endogenous porphyrins and the maximal HpD tumor/normal skin ratio in SKH-1 hairless mice by light induced fluorescence spectroscopy. AB - The treatment of skin tumors is an application of photochemotherapy (PCT) which involves an initial administration of a photosensitizer (PS) followed by irradiation with a light beam that causes the PS to produce cytotoxic oxygen species within the tumors. As the PS is also present in normal skin, it is necessary to know how it is distributed between the two tissues. In this study, we have used SKH-1 hairless mice bearing papillomas or carcinomas chemically induced. The biodistribution of hematoporphyrin derivative (HpD) and the tissue autofluorescence measurements were studied by light induced fluorescence spectroscopy. The tumor and normal autofluorescence spectra measured on control mice with papillomas or carcinomas had a very similar shape. However, the principal endogenous porphyrin peak at about 630 nm showed a fluorescence signal amplitude 2 (for papilloma) and 1.5 (for carcinoma)-fold higher than the one found for the normal skin. Moreover, the fluorescence intensity of carcinoma spectrum is 1.4-fold lower than the one of papilloma spectrum at 630 nm. The tissue autofluorescence can be used to distinguish tumor from normal skin and benign from malignant tumor. This difference in fluorescence intensity at 630 nm was directly related to the concentration of endogenous porphyrins in the tumor. Fluorescence intensity ratios between tumor and normal skin were measured 4, 8, 24, 48, 72 and 96 hours after intraperitoneal injection of HpD (5 mg/kg body weight). The best tumor/normal skin ratio was 6.2 for HpD and the time required to reach this ratio was 48 h. HpD showed a moderate selectivity since the ratio was higher than 1 during the four first days. Photodynamic therapy with the same dose of HpD used in this biodistribution study must also be carried out to verify that the maximal tumor/skin ratio corresponds to the maximal efficiency of HpD. PMID- 10092934 TI - pH-dependent secondary conformation of the peptide hormone leptin in different buffer solutions. AB - The secondary structure of leptin in each different pH buffer solution (pH 5.35, 6.75, 7.58 and 8.45) was first determined by attenuated total reflection (ATR)/Fourier transform infrared (FT-IR) spectrometer with second-derivative, Fourier self-deconvolution and band curve-fitting methods to quantitatively estimate the secondary structure of leptin. The results indicate that pH induced more stretching vibration of CH2 and bending vibration of C-H and/or symmetric stretching of carboxylate of leptin structure in higher pH buffer solution than in lower pH buffer solution. Moreover, the band area of amide I for leptin in the higher pH buffer solution markedly enlarged, suggesting the amide I contour of leptin was very sensitive to pH to alter the secondary conformation of leptin structure. The structural component and composition of amide I band for leptin in both pH 6.75 and pH 7.58 buffer solutions were similar and had 50-52% helical structure including alpha-helix at 1654 cm-1 and 3(10)-helical structure at 1659 1667 cm-1 and 1640 cm-1. Although the secondary structure of leptin in pH 5.35 and 8.45 buffer solutions were also similar, a different structural information was obtained. PMID- 10092935 TI - Comparison of resuscitation with diaspirin crosslinked hemoglobin (DCLHb) vs fresh blood in a rat burn shock model. AB - Diaspirin crosslinked hemoglobin (DCLHb; Baxter Healthcare Corp, Deerfield, IL) is hemoglobin-based oxygen carrier which, in our laboratory, improved hemodynamic parameters in a rat burn shock model. Our objective was to compare the effects on hemodynamic parameters and metabolic acidosis of resuscitation with different doses of fresh blood (FB) vs DCLHb. Male Wistar rats (200 to 250 g), surgically prepared for an acute study, were randomly assigned to one of five treatment groups. (n = 8): I. SHAM (not burned, not resuscitated), II. DCLHb 2 ml/kg/% Total Body Surface Area (TBSA) burn and 2 ml/kg/% TBSA burn of Lactated Ringers (LR), III. DCLHb 1 ml/kg/% TBSA burn and 1 ml/kg/% TBSA burn of LR IV. FB 2 ml/kg/% TBSA burn and 2 ml/kg/% TBSA burn of LR V. FB 1 ml/kg/% TBSA burn and 1 ml/kg/% TBSA burn of LR After placement of indwelling catheters, the following baseline hemodynamic values were obtained mean arterial pressure (MAP), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR) and base excess (BE). The animals were immediately intravenously resuscitated after receiving a 30% scald burn and were followed for 6 hours. Resuscitation was based on the Parkland formula. Blood was obtained from donor male Wistar rats. The animals were euthanized at 6 hours. MAP remained within normal range in all groups. The SVR, CO, SV and BE were normalized earlier in the LR-DCLHb groups when compared to the LR-FB groups (p < 0.05). Early resuscitation with DCLHb is superior to FB in improving hemodynamics in this model. There appears to be a direct relationship between dose and effect with the use of DCLHb. DCLHb could be useful in decreasing resuscitation fluid requirements in acute burns without compromising general tissue perfusion. PMID- 10092936 TI - Intravenous infusion ascitic fluid during hemodialysis: a study of 108 treatments in 13 uremic cases. AB - Nephrogenic ascites is a clinical diagnosis defined as persistent ascites in an uremic patient without evidence for a causative underlying disease. It imperils the patient's life with intradialytic hypotension, however there is no effective therapy other than renal transplantation so far. In 13 cases, 108 treatments with i.v. ascites infusion were performed with hemofilter alone or combined with plasmafilter during hemodialysis over past 7-years. The ascitic fluid was filtrated and dialyzed before it was intravenously infused into the blood compartment of the hemofilter. There were a mean of 8.38 treatments per patient in a period of 56 days and 3,275.9 +/- 1,359.5 ml of ascitic fluid were removed per treatment. The patients' appetite and physical ability were considerably improved and the intradialytic hypotensions disappeared immediately following the initiation of ascitic fluid infusions. In this study, one patient was transplanted successfully. The longest interval without ascitic fluid infusion was 127 days. Main side effect was light pyrogenic reaction, which was presented in 12.96% of the total treatments. It is concluded that this method permits to continue hemodialysis, improves the nutritional condition and prolongs the lifespan by conserving and reusing the ascites protein. PMID- 10092937 TI - Haemoglobin (Erythrogen)-enhanced post-thaw growth of cryopreserved cells. AB - Supplementation of semi-solid R2 culture medium with a commercial bovine haemoglobin (Hb) solution (Erythrogen) at 1:50-1:500 (v:v), had beneficial effects on the growth, following cryopreservation, of cells of the Indica rice, Oryza sativa cv. Pusa Basmati 1. The mean absorbance, as assessed by triphenyl tetrazolium chloride reduction, of rice cells at 8 d post-thawing, was increased by up to 60% (P < 0.05), compared to cells recovered in the absence of Hb. Erythrogen (1:50-1:500 v:v) promoted an increase in biomass, of up to 25% over control (P < 0.05), at 24 d post-thawing. Cell suspensions, re-established by transfer to liquid medium of cells initially thawed and cultured with Erythrogen for 24 d, exhibited increased (up to 2-fold) growth rates over a subsequent 20-d period, compared to cells recovered without Hb. PMID- 10092938 TI - Evaluation of commercial and purified Pluronic F-68 in a human blood neutrophil bioassay. AB - The effects have been studied of commercial grade Pluronic F-68 or its purified fractions, prepared by passage through silica gel resin (SGR) or by supercritical fluid fractionation (SFF), on human polymorphonuclear leucocyte (PMNL) chemiluminescence in vitro. The mean (+/- s.d., n = 3) total chemiluminescence following stimulation of neutrophils with phorbol 12-myristate 13-acetate in saline controls, was 190 +/- 3 mV x min. Commercial Pluronic inhibited chemiluminescence by a maximum of 26% (P < 0.05), whilst, in contrast, Pluronic F 68 fractions prepared by SGR or SFF stimulated chemiluminescence by up to 53% over control (P < 0.05). The total chemiluminescence with Pluronic F-68 prepared by SFF followed by SGR was not significantly different to that produced by saline (0.9% w/v NaCl). These results reinforce previous suggestions that trace impurities in commercial preparations of the Pluronic F-68 are responsible for reported adverse biological effects. PMID- 10092939 TI - National blood program in Korea. AB - Transfusion requirements for red cells and platelets have been completely fulfilled by voluntary donations since 1980 in Korea. However, Korea imports 300,000 liters of plasma each year to produce plasma fractionation products. Korean Red Cross Blood Center supplies 96 percent of blood consumed in Korea. The remaining 4 percent is supplied by 95 hospital blood centers. Measures to supply safer blood, to achieve national self-sufficiency of plasma, and to improve quality assurance are under way. PMID- 10092940 TI - Novel substrates of yeast alcohol dehydrogenase--4. Allyl alcohol and ethylene glycol. AB - In the present work, we have determined the steady-state kinetic constants for yeast alcohol dehydrogenase-catalyzed oxidation of allyl alcohol (H2C = CH.CH2OH) and ethylene glycol (HOCH2.CH2OH) with NAD+, at pH 8.0; also, a kinetic mechanism for the former reaction was determined at the same pH. In addition, it was found that acrolein is a potent inhibitor of yeast alcohol dehydrogenase. PMID- 10092941 TI - Characterization and partial purification of CD34+ progenitor cell ecto phosphatidic acid phosphohydrolase. AB - Phosphatidic acid and its hydrolysis product, diacylglycerol, play potentially vital roles as extracellular messengers in numerous cellular systems and may play a key role in regulating hematopoiesis. In this study, we describe an ecto phosphatidic acid phosphohydrolase that potentially regulates cellular responses to phosphatidic acid on bone marrow derived human hematopoietic progenitors. We partially purified hematopoietic progenitor ecto-PAPase using a novel in-gel phosphatase assay and then characterized the enzyme on phenotypically defined subpopulations of hematopoietic CD34+ progenitors isolated by flow cytometry. The most pronounced PAPase activity was confined to uncommitted CD34+/CD38+ hematopoietic progenitors, which lacked the expression of other lineage associated antigens. We conclude that hematopoietic progenitor cells at various stages of maturation possess a potent ecto-PAPase, an enzyme well positioned to regulate progenitor cell growth and differentiation induced by phosphatidic acid and related lipids. PMID- 10092942 TI - Pressure effects on proteolysis catalysed by calpain. AB - The effects of pressure on mu and m-calpain stability and specific activity have been examined. Activity and stability of these neutral calcium-dependent heterodimeric proteinases were studied using an in-house built bioreactor allowing on-line spectrophotometric monitoring with retention of pressure. Both isozymes were founded to be rather baro-sensitive with t1/2 at 1500 bar of 6 min and 11 min for mu and m-calpain respectively. Activity measurements under pressure showed a biphasic behavior for both proteinases with a slight activation for pressure up to 500 bar and 750 bar for m and mu-calpain respectively. Activation volume changes indicated that the proteolytic reaction was alternatively favored and disfavored by pressure due to catalytic step activation associated with enzyme-substrate binding step being continuously inhibited by pressure. Furthermore, autoproteolysis of calpain, a calcium dependent phenomenon was inhibited by application of pressure indicating that pressure inhibition of proteolytic activity could also be due to Ca2(+)-binding decrease under pressure. Implication of these results with catalytic mechanism of these heterodimeric proteinases is also discussed. PMID- 10092943 TI - Cloning of the genomic sequence encoding a processed adenylate kinase 2 pseudogene. AB - A chromosomal DNA sequence harboring a processed AK2B pseudogene was isolated from a human genomic library. It was a variant of the AK2B gene sequence including several point mutations, deletions, and insertions. The nucleotide sequence of the ORF of the AK2B pseudogene predicted a truncated form of the AK2B mutant suggesting that the processed pseudogene is nonfunctional. A repetitive sequence, AAAAGAGAG, found in the 5' and 3' flanking regions of the pseudogene and the poly(A) tract in the 3' end junction suggest that a mRNA of AK2B may have been converted to the processed pseudogene by retrotransposition events. Previously, it was suggested that an adenylate kinase (AK) 2 related gene on chromosome 2, confirmed by Southern analysis using somatic cell hybrid cell lines, may be a processed pseudogene. It is proposed that the processed pseudogene isolated in this study may be the AK2 related nonfunctional gene localized on human chromosomes 2. PMID- 10092944 TI - Comparison of kinetic properties of amine oxidases from sainfoin and lentil and immunochemical characterization of copper/quinoprotein amine oxidases. AB - Kinetic properties of novel amine oxidase isolated from sainfoin (Onobrychis viciifolia) were compared to those of typical plant amine oxidase (EC 1.4.3.6) from lentil (Lens culinaris). The amine oxidase from sainfoin was active toward substrates, such as 1,5-diaminopentane (cadaverine) with K(m) of 0.09 mM and 1,4 diaminobutane (putrescine) with K(m) of 0.24 mM. The maximum rate of oxidation for cadaverine at saturating concentration was 2.7 fold higher than that of putrescine. The amine oxidase from lentil had the maximum rate for putrescine comparable to the rate of sainfoin amine oxidase with the same substrate. Both amine oxidases, like other plant Cu-amine oxidases, were inhibited by substrate analogs (1,5-diamino-3-pentanone, 1,4-diamino-2-butanone and aminoguanidine), Cu2+ chelating agents (diethyltriamine, 1,10-phenanthroline, 8-hydroxyquinoline, 2,2'-bipyridyl, imidazole, sodium cyanide and sodium azide), some alkaloids (L lobeline and cinchonine), some lathyrogens (beta-aminopropionitrile and aminoacetonitrile) and other inhibitors (benzamide oxime, acetone oxime, hydroxylamine and pargyline). Tested by Ouchterlony's double diffusion in agarose gel, polyclonal antibodies against the amine oxidase from sainfoin, pea and grass pea cross-reacted with amine oxidases from several other Fabaceae and from barley (Hordeum vulgare) of Poaceae, while amine oxidase from the filamentous fungus Aspergillus niger did not cross-react at all. However, using Western blotting after SDS-PAGE with rabbit polyclonal antibodies against the amine oxidase from Aspergillus niger, some degree of similarity of plant amine oxidases from sainfoin, pea, field pea, grass pea, fenugreek, common melilot, white sweetclover and Vicia panonica with the A. niger amine oxidase was confirmed. PMID- 10092945 TI - Factors influencing the levels of fatty acid synthase complex activity in fowl. AB - There is a notable discrepancy between the FAS (fatty acid synthase) activity of four types of fowl (egg chicken, meat chicken, egg duck, and meat duck) with distinctively different body fat levels. There is a 14.8 fold difference per unit body weight between the maximum and minimum FAS activities. The three major factors affecting this discrepancy are liver weight per unit body weight, which is 2.3 times greater in meat ducks than in egg chickens, the amount of FAS protein per gram of liver, which is 1.85 times greater in meat ducks than in egg chickens, and the FAS specific activity in meat ducks, which is 3.5 times greater in meat ducks than in egg chickens. Within the same species of egg chickens, the abdomen fat per kg of body weight at 470 days after egg production is 66 times greater than 90 days before egg production and the liver FAS activity is increased 9.6 fold. The 9.6 fold FAS activity increase resulted from an increase in the specific activity, since the liver weight per kilogram of body weight remained constant at approx. 20 grams and the FAS weight per gram of liver also remained constant at approx. 4.5 mg. This shows that the control of the basic FAS activity level which is closely related to the level of body fat does not mainly arise from genetic control. For the same kind of fowl, the control of the basic FAS activity level occurs after gene expression. It is suggested that control may be imposed in the folding phase when new peptides give rise to functional proteins. PMID- 10092946 TI - Effects of ethanol ingestion on sperm monosaccharides and fertility. AB - Chronic alcohol abuse is often associated with reproductive disorders. Sperm monosaccharides play an indispensable role in sperm-egg interactions and fertilization. Ethanol (3 g/kg body weight as 25%, v/v) was given by gastric intubation twice daily for 30 days while in another group, rats which had been treated with ethanol were withdrawn from treatment for a further period of 30 days, in order to assess the reversibility of the ethanol-induced effects. Epididymal ethanol content, sperm monosaccharides and the fertility of ethanol treated and ethanol withdrawn rats were assessed. Ethanol ingestion caused a significant decrease in sperm monosaccharides suggesting defective glycosylation of sperm surface proteins. Sperm monosaccharides and fertility were returned to normal following the withdrawal of ethanol. Ethanol-induced changes in sperm monosaccharides may be one of the reasons for the reduced fertility of ethanol treated rats. PMID- 10092947 TI - Relationship between the physicochemical parameters and biological activity of sulfosuccinic acid ester surfactants. AB - The effect of 11 sulfosuccinic acid ester surfactants on the abiotrophic developmental forms of the asexual spores of Plasmopara halstedii was determined. The strength and the selectivity of the effect was separated by the spectral mapping technique and the relationship between the biological activities and physico-chemical parameters of anionic surfactants was elucidated by stepwise regression analysis. It was established that the plasmalemma of cell wall less zoospores showed the highest and the resting zoosporangia the lowest average sensitivity toward the surfactants. The biological efficacy of surfactants was highly different the di-n-octyl ester being the most effective. Calculations proved that both the strength and selectivity of the biological activity mainly depends on the lipophilicity of the molecule and, to a lesser extent, on the electronic parameters. PMID- 10092948 TI - Zinc-induced damage to carp (Cyprinus carpio L.) erythrocytes in vitro. AB - Fish erythrocytes were used to elucidate the effect of zinc ions on the cell antioxidant defence system. It was detected that an increase of the Zn2+ concentration (0.01-1 mM) leads to a marked decrease (p < 0.05) in the catalase and the glutathione peroxidase activities. We observed a loss of 14-39% activity of glutathione peroxidase, and 16-20% diminution for catalase. No significant changes were found in case of the superoxide dismutase. Incubation of red blood cells with zinc brought about a decrease of the erythrocyte thiol group content. Treatment of carp erythrocytes with zinc ions also resulted in enhanced hemolysis and in the induction of significant (p < 0.001) changes in the intracellular glucose level. The increase of glucose concentration in the erythrocytes was correlated with increased concentration of metal in the incubation medium. It was proposed that Zn could affect transport systems across the red blood cells and therefore increased the permeability of the membranes to small molecules (e.g. hexose), and led to hemolysis. Zinc ions could act as a potential cell toxicant, leading to disturbances in functions of the antioxidant defence system and to alterations in the erythrocyte membrane properties. PMID- 10092949 TI - Electron paramagnetic resonance studies of membrane fluidity in ozone-treated erythrocytes and liposomes. AB - Doxyl stearate spin probes which differed in the attachment of the nitroxide free radical to the fatty acid have been used to study membrane fluidity in ozone treated bovine erythrocytes and liposomes. Analysis of EPR spectra of spin labels incorporated into lipid bilayer of the erythrocyte membranes indicates an increase in the mobility and decrease in the order of membrane lipids. In isolated erythrocyte membranes (ghosts) the most significant changes were observed for 16-doxylstearic acid. In intact erythrocytes statistically significant were differences for 5-doxylstearic acid. The effect of ozone on liposomes prepared from a lipid extract of erythrocyte lipids was marked in the membrane microenvironment sampled by all spin probes. Ozone apparently leads to alterations of membrane dynamics and structure but does not cause increased rigidity of the membrane. PMID- 10092950 TI - Presence and comparison of angiotensin converting enzyme in commercial cell culture sera. AB - This study was conducted to determine the presence of the angiotensin converting enzyme in commercial sera used in cell culture medium. The aim of the research was to bring the presence of proteinases (angiotensin converting enzyme) to cell culture users' knowledge and to give some data for solving problems about the development of peptides as useful drugs. The enzymes, purified from foetal bovine, adult bovine, foetal equine, adult equine, and human sera, showed molecular weights of about 170 kDa. Captopril and lisinopril inhibited enzyme activities at nanomolar concentrations. The enzymes were able to hydrolyze, with different efficiency, angiotensin I, bradykinin and epidermal mitosis inhibiting pentapeptide. The heat inactivation of commercial sera at 56 degrees C for 30 min showed a reduction of ACE activity of about 35-80%. Therefore, the presence of ACE activity in commercial sera can influence the activity of biological peptides tested on cell lines cultured "in vitro." PMID- 10092951 TI - The polarization model in bacterial photosynthesis. AB - The widely accepted model of reaction center /RC/ functioning is proved to come into contradiction with some recent data. In particular, it cannot explain why only a minor part of electronic excitations (approximately 10%) escapes from excited RC special pairs back to antenna BChls. Therefore we believe that the model must be substantially modernized. In 1981 we developed a new model/1,2/. We suggested a femtosecond state to precede primary e-transfer reaction due to reorientation of water molecule dipole in the electric field of excited RC dimer. This mechanism is responsible for energy trapping before the primary e-transport occurs. During last years his mechanism got support from various experimental works. Now this polarization model claims to fit all reliable experimental data at least in bacterial photosynthesis. PMID- 10092952 TI - Preferential accumulation of muscle type acylphosphatase in the nucleus during differentiation. AB - In a previous paper we observed a direct involvement of acylphosphatase in differentiation, associated with enhanced levels of the enzyme in the cell. We have here investigated the subcellular localization of the two known acylphosphatase isoforms during this process. We show that in C2C12 myoblast cells, muscle type acylphosphatase accumulates in the nucleus during differentiation. The same pattern of accumulation is observed also in K562 erythroleukemia cells, although at a lower extent: this fact indicates that this phenomenon is not restricted to muscular cells but rather it could be of general importance in the differentiative process. The common type acylphosphatase, showing an 8-fold increase in the cytoplasm during differentiation, does not accumulate in the nucleus, suggesting distinct roles of the two isoenzymes in this process. PMID- 10092953 TI - Steroid sulfatase activity in leukocytes: a comparative study in 45,X; 46,Xi(Xq) and carriers of steroid sulfatase deficiency. AB - The enzyme steroid sulfatase (STS) hydrolyses 3-beta-hydroxysteroid sulfates. The female-male STS activity ratio is 1.04-1.7:1 in several cell lines in adults and reaches 2:1 in prepubertal subjects. In fibroblasts, STS values in X-chromosome abnormalities show a partial positive correlation according to the number of X chromosomes. X-linked ichthyosis (XLI) carriers, with only one copy of the STS gene, present lower STS levels than normal controls. This study analyzes the STS activity in leukocytes of 46,Xi(Xq); 45,X; XLI carriers and normal controls using 7-[3H]-dehydroepiandrosterone sulfate as substrate. X-monosomy (1.07 +/- 0.18 pmol/mg protein/h), Xq isochromosome (1.02 +/- 0.12 pmol/mg protein/h) and normal females (1.03 +/- 0.11 pmol/mg protein/h) had similar STS values (p > 0.05). XLI carriers and males showed the lowest STS levels (0.34 +/- 0.04 pmol/mg protein/h, p < 0.001 and 0.82 +/- 0.14 pmol/mg protein/h, p < 0.05, respectively). Female male STS activity ratio in leukocytes was 1.3:1. These data indicate that a complex mechanism regulates the STS expression depending on each type of cell line. PMID- 10092954 TI - Differential regulation of protooncogene c-myc expression in rat ventral prostate after castration. AB - To evaluate the possibility that the protooncogene c-myc plays a role in ventral prostate, the effects of castration have been investigated at a beginning of a period by Northern blot hybridization and the levels of c-myc mRNA were also compared with mRNA of androgen-regulated genes, C1 and TRPM-2. Levels of c-myc mRNA in ventral prostate increased with maximal stimulation reached at 6 hours (early induction) and 48 hours (late induction) after castration, respectively. The level of C1 mRNA did not change and TRPM-2 was not detected at early induction of c-myc mRNA after castration. The level of early induction of c-myc mRNA after castration was increased in ventral prostate treated with cycloheximide, but it was almost reduced by actinomycin-D pretreatment. Administration of androgen at the time of castration prevented early induction of c-myc mRNA. These results suggest that protooncogene c-myc is differentially regulated in ventral prostate after castration. PMID- 10092955 TI - Thymoquinone protects against carbon tetrachloride hepatotoxicity in mice via an antioxidant mechanism. AB - Thymoquinone (TQ) is the major active component of the volatile oil of Nigella sativa seeds. The effects of TQ on carbon tetrachloride (CCl4)-induced hepatotoxicity was investigated in male Swiss albino mice. Carbon tetrachloride (20 microliters/Kg, i.p.) injected into mice, induced damage to liver cells and was followed by the increase in serum alanine aminotransferase (ALT) activity after 24 h. Oral administration of TQ in a single dose (100 mg/Kg) resulted in significant (p < 0.001) protection against the hepatotoxic effects of CCl4. TQ was tested as a substrate for mice hepatic DT-diaphorase in the presence of NADH. TQ appears to undergo reduction to dihydrothymoquinone (DHTQ). Reduction rates as a function of protein (liver homogenate) and substrate (TQ) concentrations are reported. An apparent K(m) of 0.1 mM and an apparent Vmax of 74 mumol/min/g liver were measured. TQ and DHTQ inhibited the in vitro non-enzymatic lipid peroxidation in liver homogenate (induced by Fe(3+)-ascorbate) in a dose dependent manner. In this in vitro model DHTQ was more potent in comparison with TQ and butylated hydroxytoluene (BHT). The IC50 for DHTQ, TQ and BHT were found to be 0.34, 0.87 and 0.58 microM respectively. The data suggest that the in vivo protective action of TQ against CCl4-induced hepatotoxicity may be mediated through the combined antioxidant properties of TQ and its metabolite DHTQ. PMID- 10092956 TI - Once daily aminoglycoside therapy. Is it less toxic than multiple daily doses and how should it be monitored? AB - After 50 years of clinical experience with the aminoglycoside agents, there is continuing debate over the most appropriate administration regimen for these drugs. In recent years, once daily administration has been used increasingly, in the hope of both improving efficacy and reducing toxicity. At least 30 controlled clinical trials have compared once versus conventional multiple daily administration. Efficacy was assessed in some, but not all, studies using clinical and/or bacteriological cure. Toxicity was generally determined using rather nonsensitive end-points such as measurement of serum creatinine for nephrotoxicity and clinically detectable hearing loss for ototoxicity. The results of individual clinical trials and subsequent meta-analyses have been variable. However, 5 of 9 meta-analyses found clinical efficacy to be significantly better with once daily administration, and in 3 of the 9 there were significantly less nephrotoxicity with once daily administration. The results were not significant for ototoxicity in any of the meta-analyses. There is debate about how therapeutic drug monitoring should be performed, and whether it is still required with once daily administration. Previous experience with the aminoglycosides, especially in patients with impaired drug clearance caused by renal impairment, suggests that monitoring is still prudent. Results from the once daily administration trials appear to support this. Various methods of monitoring and dose adjustment have been proposed. The most common is to measure a 24-hour trough concentration and to adjust the dose to maintain the trough concentration below a value of 2, 1 or 0.5 mg/L. However, this method allows for greater total aminoglycoside exposure than has been permitted with conventional dosages, increasing the likelihood of toxicity in patients with impaired aminoglycoside clearance. Other methods measure drug concentrations at a time point or points within the dose interval (when the concentration is still measurable), and adjust the dose according to concentration-time curve nomograms or to a target area under the concentration-time curve. This allows the use of higher doses in those with high drug clearance. Furthermore, in patients with impaired clearance, drug exposure is limited to the same extent as, or less than, that with conventional multiple daily administration. To date no controlled trials have compared methods of dose-individualisation. In summary, in addition to a slight overall improvement in efficacy, once daily administration has resulted in a small reduction in nephrotoxicity. In the studies using more sensitive measures of toxicity, the differences in toxicity were greater, strengthening the case for once daily administration. Therapeutic drug monitoring is probably required with once daily administration. Methods which use mid-dosage interval concentrations to gauge drug exposure would seem to be preferable over trough concentration measurement. PMID- 10092957 TI - Clinical pharmacokinetics of docetaxel. AB - Docetaxel (Taxotere), a semi-synthetic analog of paclitaxel (Taxol), is a promoter of microtubule polymerization leading to cell cycle arrest at G2/M, apoptosis and cytotoxicity. Docetaxel has significant activity in breast, non small-cell lung, ovarian and head and neck cancers. Docetaxel has undergone phase I study in a number of schedules, including different infusion durations and various treatment cycles. Doses studied in adults have ranged from 5 to 145 mg/m2 and those in children from 55 to 235 mg/m2. The most frequently used regimen in adults is 100 mg/m2 every 3 weeks. A 1-hour infusion every 3 weeks has been favoured in phase II and III studies, and the disposition of docetaxel after such treatment is best described by a 3 compartment model with alpha, beta and gamma half-lives of 4.5 minutes, 38.3 minutes and 12.2 hours, respectively. The disposition of docetaxel appears to be linear, the area under the plasma concentration-time curve (AUC) increasing proportionately with dose. Docetaxel is widely distributed in tissues with a mean volume of distribution of 74 L/m2 after 100 mg/m2, every 3 weeks. The mean total body clearance after this schedule is approximately 22 L/h/m2, principally because of hepatic metabolism by the cytochrome P450 (CYP)3A4 system and biliary excretion into the faeces. Renal excretion is minimal (< 5%). Docetaxel is > 90% bound in plasma. Population pharmacokinetic studies of docetaxel have demonstrated that clearance is significantly decreased with age, decreased body surface area, increased concentrations of alpha 1-acid glycoproteinand albumin. Importantly, patients with elevated plasma levels of bilirubin and/or transaminases have a 12 to 27% decrease in docetaxel clearance and should receive reduced doses. Although docetaxel is metabolised by CYP3A4, phase I combination studies have not shown major evidence of significant interaction between docetaxel and other drugs metabolised by the same pathway. Nevertheless, care should be taken with the use of known CYP3A4 inhibitors such as erythromycin, ketoconazole and cyclosporin. Conversely, increased doses may be required for patients receiving therapy known to induce this cytochrome (e.g. anticonvulsants). Perliminary data suggest the erythromycin breath test, an indicator of CYP3A4 function, is a predictor of toxicity after treatment with docetaxel. Such methodologies may eventually enable clinicians to individualise doses of docetaxel for patients with cancer. PMID- 10092958 TI - Clinical pharmacokinetics of meloxicam. A cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug. AB - Meloxicam [4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine -3 carboxamide-1, 1-dioxide] is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class which shows preferential inhibition of cyclo-oxygenase-2. Meloxicam has a plasma half-life of approximately 20 hours, making it convenient for once daily administration. Meloxicam is eliminated after biotransformation to 4 pharmacologically inactive metabolites, which are excreted in urine and faeces. Meloxicam and its metabolites bind extensively to plasma albumin. Substantial concentrations of meloxicam are attained in synovial fluid, the proposed site of action in chronic inflammatory arthropathies. Neither moderate renal nor hepatic insufficiency significantly alter the pharmacokinetics of meloxicam. Dosage adjustment is not required in the elderly. Drug-drug interaction studies are available for some commonly co-prescribed medications. Concentration-dependent therapeutic and toxicological effects have yet to be extensively elucidated for this NSAID. PMID- 10092959 TI - Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. AB - Cidofovir and adefovir are members of a new class of antiviral compounds. They are acyclic phosphonate analogues of deoxynucleoside monophosphates. Both compounds undergo intracellular activation to form diphosphates that are potent inhibitors of viral DNA polymerases. Cidofovir has broad spectrum antiviral activity against herpesviruses, papillomaviruses and poxviruses, whereas adefovir has potent activity against retroviruses and certain DNA viruses, including herpesviruses and hepadnaviruses. Intravenous cidofovir is approved for treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir and adefovir are dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of both drugs are independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and both drugs are cleared by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (< 10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir and adefovir from serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For both drugs, > 90% of an intravenous dose is recovered unchanged in the urine over 24 hours. Metabolism does not contribute significantly to the total clearance of either drug. Concomitant oral probenecid decreases both the renal clearance of cidofovir and the incidence of nephrotoxicity, presumably by blocking its active tubular secretion. This is the basis of the clinical use of concomitant probenecid as a nephroprotectant during cidofovir therapy. Subcutaneous administration produces exposure equivalent to that following intravenous administration. Drug interaction studies with cidofovir are ongoing, but there is no evidence of an interaction between zidovudine and either cidofovir or adefovir. Clearance of cidofovir in patients with renal impairment showed a linear relationship to creatinine clearance. The low oral bioavailability of adefovir has led to the development of an oral prodrug, adefovir dipivoxil, currently in development for the treatment of HIV and hepatitis B infections. PMID- 10092960 TI - Interchangeability and predictive performance of empirical tolerance models. AB - Models of tolerance are commonly derived on empirical grounds, because of lack of knowledge about the mechanism of tolerance or because of the difficulty of appropriately simplifying complex physiological processes. The present study was performed to evaluate the interchangeability of tolerance models used in the literature and to address some determinants for selection of an appropriate design and data analysis strategy. Seven models were chosen (noncompetitive antagonist model, partial agonist model, reverse agonist model, direct moderator model, indirect moderator model, pool model and adaptive pool model) along with their corresponding parameter estimates, representing a wide range of empirical models. The performance of the models on various data sets was evaluated. Data were simulated from each original model and were further analysed by the other models. The effect-time course of each and every data set could be described well by at least 2 different empirical tolerance models, but no model could describe all the data sets adequately. However, all models could adequately describe at least 2 different data sets. This indicates that, without additional knowledge or assumptions, it is unlikely that reliable mechanistic information can be deduced from the mere fact that 1 (or more) of these models can describe the data. Generally, data expressing only limited tolerance can be described by a wide variety of models, whereas few models will be appropriate for data characterised by extensive tolerance. The models that gave an adequate description of a data set were selected for further study that investigated their predictive capacity based on the parameters previously determined. Predictions were made for 4 different administration schemes. The selected models gave similar predictions for the extended designs of 3 data sets for which the original study designs characterised tolerance well. For the other 4 data sets, the selected models gave disparate predictions, although the models described the original data set well. Thus, the predictive capability of a model was linked to the original study design, whereas the correlation between predictive performance and the type of model was weak or absent. Based on the results, factors of importance for the design and evaluation of studies of tolerance were identified and discussed. PMID- 10092961 TI - Diagnosis of Chlamydia trachomatis and Neisseria gonorrhoeae. Genitourinary infections in males by the Amplicor PCR assay of urine. AB - The Amplicor CT/NG polymerase chain reaction (PCR) test on urine specimens from males was prospectively evaluated against established specimens and laboratory methods for diagnosing Chlamydia trachomatis and Neisseria gonorrhoeae genitourinary infections, in patients from a remote region of Western Australia. Seventy-three males who were tested for both C. trachomatis and N. gonorrhoeae by both conventional methodology and Amplicor PCR on urine were enrolled in the study. Established testing comprised enzyme immunoassay/immunofluorescence antigen testing (EIA/IF) for C. trachomatis and microscopy and/or culture for N. gonorrhoeae on urethral swabs. Positive test results were confirmed using a set of criteria that included supplemental PCR testing and clinical history. Overall, 13.7% of patients were resolved as positive for C. trachomatis and 52.1% as positive for N. gonorrhoeae. The sensitivity and specificity of the Amplicor CT/NG PCR on male urine specimens for C. trachomatis were 80.0% (8/10) and 95.2% (60/63), compared with 60.0% (6/10) and 100.0% (63/63) for EIA/IF on urethral swabs. For N. gonorrhoeae, the sensitivity and specificity of the Amplicor CT/NG PCR on male urine specimens were both 100% (38/38 and 35/35, respectively) compared with 86.8% (33/38) and 100% (35/35) for microscopy and/or culture on urethral swabs. The results of this study indicate that the Amplicor CT/NG multiplex PCR test for C. trachomatis and N. gonorrhoeae performed on urine in males provides a highly sensitive, specific, and robust method for the diagnosis of both C. trachomatis and N. gonorrhoeae, for the early detection of both symptomatic and asymptomatic infected individuals. PMID- 10092962 TI - Measurement of measles virus-specific neutralizing antibodies: evaluation of the syncytium inhibition assay in comparison with the plaque reduction neutralization test. AB - Plaque reduction neutralization (PRN) is the "gold-standard" for the measurement of measles-specific neutralizing antibodies. However, it is a complicated assay and tends to be operator-dependent. It has been suggested that the simpler syncytium inhibition assay (SIA) can give results comparable to the PRN test. We compared these two assays using 594 serum or plasma samples obtained from children at various times after natural infection, primary measles immunization, and measles revaccination. The results of the two assays correlated well overall (r = .86; p < 0.0001). The strain of challenge virus (wild-type versus vaccine strain) did not significantly influence SIA titers and the assay performed equally well with serum and plasma. PRN titers > or = 120 and > 800 are thought to indicate protection against clinical illness and infection respectively. The equivalent SIA cut-off values using 125 plaque-forming units as the challenge inoculum were > or = 16 and > 128 respectively. At low PRN titers (< 200), the correlation between PRN and SIA values was reasonable (r = 0.60; p < 0.001) when a challenge inoculum of 12.5 plaque-forming units was used. At the lowest PRN titers (< 100), 15% of the samples gave divergent results. These data confirm the utility of the SIA in the determination of measles-specific neutralizing antibodies when antibody titers are high. However, the PRN assay remains the test of choice when maximum sensitivity at low titers is required. PMID- 10092963 TI - Improved sensitivity of reverse transcriptase polymerase chain reaction for hepatitis C virus using random hexamer primers. AB - The use of specific primers and random primers for the detection of hepatitis C virus RNA by reverse transcriptase-polymerase chain reaction was compared. The cDNA obtained from using both methods was amplified by the same protocol. Of the 30 plasma specimens tested, 6 (20%) were hepatitis C virus RNA-positive using specific primers and 19 (63%) were positive using random primers, demonstrating that the use of random hexamer-primed reverse transcriptase-polymerase chain reaction significantly improves the sensitivity (p < 0.01). PMID- 10092964 TI - Laboratory diagnosis of Pneumocystis carinii infections by PCR directed to genes encoding for mitochondrial 5S and 28S ribosomal RNA. AB - PCR with 5S mitochondrial ribosomal RNA (5S) target is a sensitive and specific assay for the detection of Pneumocystis carinii in clinical specimens from the respiratory tract. We developed an oligonucleotide probe directed to a 200 bp amplicon generated by fungal-specific universal primers that anneals with sequences specific for P. carinii in the 28S ribosomal RNA gene (28S). Of 50 archived bronchoalveolar lavage 1(BAL) specimens, 46 of 50 samples (92% agreement) gave the same result (23 positive, 23 negative) by PCR directed to the 5S and 28S assays. Results of calcofluor white staining of BAL smears on slides indicated agreement with the molecular results in 43 of 46 (93.5%) assays. PCR detection of P. carinii by amplification of 28S ribosomal gene target by fungal specific primers and an organism-specific probe provides an alternate genomic target for the laboratory diagnosis of this organism. PMID- 10092965 TI - Single PCR and nested PCR with a mimic molecule for detection of Mycobacterium avium subsp. paratuberculosis. AB - Mycobacterium avium subsp. paratuberculosis is the causative agent of Johne's disease in ruminants. The current methods for detection of M. avium subsp. paratuberculosis are slow and insensitive. We report the use of a polymerase chain reaction (PCR) based on IS900 to confirm growth of M. avium subsp. paratuberculosis in primary bacterial cultures from bovine tissue and fecal samples. The use of PCR on single colonies reduced the time for analysis by 2 months compared with conventional methods. We also report the development of a nested PCR based on IS900 and the development of a positive internal control molecule, a so-called mimic. The system was tested with spiked tissue samples, and the sensitivity was estimated to 10 CFU per sample. Seventeen tissue samples, previously found M. avium subsp. paratuberculosis positive by microbiological culture, were analyzed by nested PCR and the efficiency of the PCR was checked by co-amplification of the mimic. Absence of the mimic amplicon indicated inhibition of the amplification. Ten of the samples were positive and five were negative, as judged from the presence or absence of the IS900 PCR product. Two negative samples could not be judged because of inhibition revealed by mimic molecules. It was concluded that the nested PCR, together with the mimic, could be a useful tool in screening tissue materials. PMID- 10092966 TI - Multicenter evaluation of two commercial amplification kits (Amplicor, Roche and LCx, Abbott) for direct detection of Mycobacterium tuberculosis in pulmonary and extrapulmonary specimens. AB - Direct detection of Mycobacterium tuberculosis was performed in parallel with the Amplicor M. tuberculosis test (Roche Diagnostic System, USA) and the LCx M. tuberculosis (Abbott Diagnostic Division, USA) on 697 samples, collected from 481 patients, in three different Italian laboratories. Though both systems are licensed only for pulmonary specimens, 113 extrapulmonary specimens (represented mainly by pleural fluids, cerebrospinal fluids and urines) were included in the study. Amplification results were compared with acid-fast microscopy, culture, and identification of isolates. Final clinical diagnosis was used to resolve discrepant results. M. tuberculosis was detected in 105 specimens by both assays, whereas 561 were agreeing negatives; 21 and 6 of the remaining true-positive samples scored positive with LCx only and with Amplicor only, respectively. There were three false-positives with LCx and one false-positive with Amplicor. The diagnostic sensitivity of both methods was significantly better when only respiratory specimens were considered (78% versus 59% in nonrespiratory samples with Amplicor, and 88% versus 65% with LCx). Our data reveal a significantly better sensitivity of the LCx (p = 0.026) and a slight better specificity of the Amplicor assay. It is noteworthy that 16 of the 21 Amplicor-negative specimens in which LCx detected M. tuberculosis were culture negative, thus suggesting that the higher diagnostic sensitivity of the latter assay is attributable to its better analytical sensitivity. However, the majority of such samples originated from patients under antimicrobial treatment, which makes uncertain the clinical significance of such increased sensitivity. Considering true-positive for LCx and true-negative for Amplicor, the 16 culture-negative/LCx-positive/Amplicor negative specimens resulted true-positives after the resolution of discrepancies, the final overall sensitivity and specificity values of the LCx assay were not significantly different from the ones of the Amplicor assay. PMID- 10092967 TI - Spectrum and antimicrobial activity of alexomycin (PNU-82, 127), a peptide compound projected for use in animal health. AB - Alexomycin (PNU-82, 127) is a thiopeptide antimicrobial complex intended for veterinary practice that belongs to a series of cyclic peptides produced by Streptomyces arginensis. MICs against selected routine and fastidious clinical isolates of animal and human origin were determined by broth microdilution or agar dilution reference methods. Alexomycin was active against Gram-positive pathogens such as oxacillin-susceptible and -resistant Staphylococcus aureus and coagulase-negative staphylococci (260 strains; MIC90, 0.5 microgram/mL), as well as Enterococcus species (95 strains; MIC90, 0.25 to 0.5 microgram/mL), and generally inactive against Gram-negative aerobes. Alexomycin had more potent activity against Streptococcus bovis (MIC90, 0.12 microgram/mL), S. agalactiae (MIC90, 0.12 microgram/mL), Corynebacterium species (MIC90, 0.06-0.12 microgram/mL), and Listeria monocytogenes (MIC90, 0.5 microgram/mL). Alexomycin activity was limited against Bacillus species (MIC90, 1 microgram/mL), Neisseria meningiditis (MIC90, 2 micrograms/mL), Haemophilus influenzae (MIC90, 8 micrograms/mL), Moraxella catarrhalis (MIC90, 16 micrograms/mL), and Campylobacter jejuni (MIC90, 32 micrograms/mL). This thiopeptide complex was also found to be stable at low concentrations (0.015-32 micrograms/mL) in Mueller Hinton broth for up to 24 h, possesses static antimicrobial activity and did not produce resistant mutants after multiple passages at subinhibitory drug concentrations. Alexomycin seems to have potential for use as a feed additive to increase feed efficiency and promote growth in poultry and swine as well as other applications against Gram-positive pathogens. PMID- 10092968 TI - Natural antibiotic susceptibility of Escherichia coli, Shigella, E. vulneris, and E. hermannii strains. AB - The natural antibiotic susceptibility of 139 Escherichia coli strains (including 18 enterohemorrhagic E. coli), 73 Shigella strains (S. sonnei (n = 37), S. flexneri (n = 29), S. boydii (n = 6), S. dysenteriae (n = 1)), 23 E. vulneris, and 20 E. hermannii strains toward 71 antibiotics was examined. MICs were determined using a microdilution procedure. All examined taxa were naturally sensitive/intermediate toward tetracyclines, aminoglycosides, some penicillins (amoxycillin/clavulanate, ampicillin/sulbactam, piperacillin [with and without tazobactam], mezlocillin, azlocillin), cephalosporins, carbapenems, monobactams, quinolones, trimethoprim, cotrimoxazole, and chloramphenicol and were naturally resistant/intermediate toward benzylpenicillin, oxacillin, macrolides, lincosamides, glycopeptides, rifampicin, and fusidic acid. No differences in natural antibiotic susceptibility were seen between enterohemorrhagic and other E. coli strains. Likewise, with one exception, no significant differences in natural antibiotic susceptibility were seen either among the Shigella subgroups or between Shigella and E. coli. The natural population of S. flexneri was slightly more susceptible to chloramphenicol than the natural populations of other taxa within the Shigella-E. coli complex. E. vulneris and E. hermannii showed susceptibility patterns to many antibiotics similar to Shigella and E. coli, but there were other antibiotics toward which there were significant differences in natural susceptibility. E. vulneris and E. hermannii were less susceptible to nitrofurantoin and slightly more susceptible to several aminoglycosides than E. coli and Shigella. E. hermannii was the only species that was naturally resistant/intermediate to ticarcillin and amoxycillin (DIN standard). The addition of clavulanic acid to the latter resulted in a decrease of seven twofold dilution steps (E. vulneris: four twofold dilution steps, E. coli/Shigella: two twofold dilution steps) of the MICs of the natural population. With the exception of cefoperazone and cefepime, E. hermannii was more susceptible to cephalosporins than strains of the other species. E. vulneris was the species most susceptible to ticarcillin and the only species that was highly resistant to fosfomycin (MIC > 256 micrograms/mL). The antibiotic susceptibility to fosfomycin was also unique for E. hermannii (MIC 32-128 micrograms/mL), whereas the natural populations of E. coli and Shigella showed lower MIC values. The data of this study represent an assessment of the natural susceptibility of strains of Escherichia spp. and Shigella subgroups to a wide range of antibiotics. These databases can be used for the validation of antibiotic susceptibility test results of Escherichia spp. and shigellae. The conformity of the natural antibiotic susceptibility test results not only among the Shigella subgroups but also between Shigella and E. coli support the status of Shigella as a subgroup of the species E. coli. PMID- 10092969 TI - Evaluation of a rapid slide agglutination test for identification of Staphylococcus aureus. AB - This study compared the Staph Latex Kit (Remel) with two other rapid agglutination tests (Staphaurex Plus (Murex) and Staphyloslide (Becton Dickinson Microbiological Systems)) and the tube coagulase test. The Staph Latex Kit, Staphaurex Plus, Staphyloslide, and Tube Coagulase correctly identified 98.4%, 100%, 99.5%, and 99.5%, of 191 staphylococcal isolates, respectively. PMID- 10092970 TI - Streptococcus anginosus (milleri) septicemia: interest in systematically searching for parenchymatous abscesses. PMID- 10092971 TI - Changes in physiological parameters and feeding behaviour of Atlantic salmon Salmo salar infected with sea lice Lepeophtheirus salmonis. AB - Atlantic salmon Salmo salar L. artificially infected with salmon lice Lepeophtheirus salmonis (Kroyer 1837) recovered from detrimental physiological changes and skin damage induced by preadult lice as the parasites matured. Growth rates of Atlantic salmon remained unaffected by lice infection, but food consumption decreased with increasing feeding and movement of the lice prior to and post-mating, correlating with the appearance of head erosions and detrimental changes in physiological integrity. Food consumption of the fish increased as the lice moulted to the adult stage and gravid female lice settled in a posterior location on the fish, subsequently reducing the impact of infection and allowing recovery of the skin damage. However, the impact of preadults was limited, as the decrease in food consumption of fish at 21 d post-infection had no effect on either the specific growth rate or condition factor of the fish. Furthermore, the intensity of lice infections at each of the sample days was not correlated with food consumption, specific growth rate or any of the haematological or physiological parameters measured, either before or after infection, indicating that lice intensity was independent of social dominance/subordinance. This work has provided the first evidence that infected fish can recover from the detrimental changes caused by lice infection, even when they are still infected with lice. If fish can survive the preadult stage of lice, then the mortal impact of lice infections is greatly reduced. PMID- 10092972 TI - Different prevalences of Renibacterium salmoninarum detected by ELISA in Alaskan chinook salmon Oncorhynchus tshawytscha spawned from freshwater and seawater. AB - Soluble antigen of Renibacterium salmoninarum (Rs) was detected by a polyclonal enzyme-linked immunosorbent assay (ELISA) at significantly higher prevalences in adult chinook salmon Oncorhynchus tshawytscha that matured in freshwater than in the same cohort of fish spawned after maturation in seawater. The cumulative results were consistent during 4 yr of comparison at the Little Port Walter Hatchery on Baranof Island, Alaska, USA. Possible causes for this difference are discussed. Maturation of chinook salmon broodstock in seawater has become a practical strategy at this hatchery to reduce the prevalence of Rs-positive parent fish and the numbers of culled eggs. PMID- 10092973 TI - Relative virulence of three isolates of Piscirickettsia salmonis for coho salmon Oncorhynchus kisutch. AB - Piscirickettsia salmonis was first recognized as the cause of mortality among pen reared coho salmon Oncorhynchus kisutch in Chile. Since the initial isolation of this intracellular Gram-negative bacterium in 1989, similar organisms have been described from several areas of the world, but the associated outbreaks were not reported to be as serious as those that occurred in Chile. To determine if this was due to differences in virulence among isolates of P. salmonis, we conducted an experiment comparing isolates from Chile, British Columbia, Canada, and Norway (LF-89, ATL-4-91 and NOR-92, respectively). For each of the isolates, 3 replicates of 30 coho salmon were injected intraperitoneally with each of 3 concentrations of the bacterium. Negative control fish were injected with MEM-10. Mortalities were collected daily for 41 d post-injection. Piscirickettsiosis was observed in fish injected with each of the 3 isolates, and for each isolate, cumulative mortality was directly related to the concentration of bacterial cells administered. The LF-89 isolate was the most virulent, with losses reaching 97% in the 3 replicates injected with 10(5.0) TCID50, 91% in the replicates injected with 10(4.0) TCID50, and 57% in the fish injected with 10(3.0) TCID50. The ATL-4 91 isolate caused losses of 92% in the 3 replicates injected with 10(5.0) TCID50, 76% in the fish injected with 10(4.0) TCID50, and 32% in those injected with 10(3.0) TCID50. The NOR-92 isolate was the least virulent, causing 41% mortality in the replicates injected with 10(4.6) TCID50. At 41 d post-injection, 6% of the fish injected with 10(3.6) TCID50 NOR-92 had died. Mortality was only 2% in the fish injected with 10(2.6) TCID50 NOR-92, which was the same as the negative control group. Because the group injected with the highest concentration (10(4.6) TCID50) of NOR-92 was still experiencing mortality at 41 d, it was held for an additional 46 d. At 87 d post-injection, the cumulative mortality in this group had reached 70%. These differences in virulence among the isolates were statistically significant (p < 0.0001), and are important for the management of affected stocks of fish. PMID- 10092974 TI - Phylogenetic analysis of Piscirickettsia salmonis by 16S, internal transcribed spacer (ITS) and 23S ribosomal DNA sequencing. AB - Piscirickettsia salmonis, the etiologic agent of piscirickettsiosis, is a systemic disease of salmonid fish. Variations in virulence and mortality have been observed during epizootics at different geographical regions and in laboratory experiments with isolates from these different locations. This raises the possibility that biogeographical patterns of genetic variation might be a significant factor with this disease. To assess the genetic variability the 16S ribosomal DNA, the internal transcribed spacer (ITS) and the 23S ribosomal DNA of isolates from 3 different hosts and 3 geographic origins were amplified using the polymerase chain reaction (PCR). Results of this analysis confirm that P. salmonis is a member of the gamma subgroup of the Proteobacteria and show that the isolates form a tight monophyletic cluster with 16S rDNA similarities ranging from 99.7 to 98.5%. The ITS regions were 309 base pairs (bp), did not contain tRNA genes, and varied between isolates (95.2 to 99.7% similarity). Two-thirds of the 23S rRNA gene was sequenced from 5 of the isolates, yielding similarities ranging from 97.9 to 99.8%. Phylogenetic trees were constructed based on the 16S rDNA, ITS and 23S rDNA sequence data and compared. The trees were topologically similar, suggesting that the 3 types of molecules provided similar phylogenetic information. Five of the isolates are closely related (> 99.4% 16S rDNA similarity, 99.1% to 99.7% ITS and 99.3 to 99.8% 23S rDNA similarities). The sequence of one Chilean isolate, EM-90, was unique, with 16S rDNA similarities to the other isolates ranging from 98.5 to 98.9%, the ITS from 95.2 to 96.9% and the 23S rDNA from 97.6 to 98.5%. PMID- 10092975 TI - Further observations on the epidemiology and spread of epizootic haematopoietic necrosis virus (EHNV) in farmed rainbow trout Oncorhynchus mykiss in southeastern Australia and a recommended sampling strategy for surveillance. AB - Epizootic haematopoietic necrosis virus (EHNV) is an iridovirus confined to Australia and is known only from rainbow trout Oncorhynchus mykiss and redfin perch Perca fluviatilis. Outbreaks of disease caused by EHNV in trout populations have invariably been of low severity, affecting only 0+ post-hatchery phase fingerlings < 125 mm in length. To date the virus has been demonstrated in very few live in-contact fish, and anti-EHNV antibodies have not been found in survivors of outbreaks, suggesting low infectivity but high case fatality rates in trout. During an on-going study on an endemically infected farm (Farm A) in the Murrumbidgee River catchment of southeastern New South Wales, EHNV infection was demonstrated in 4 to 6 wk old trout fingerlings in the hatchery as well as in 1+ to 2+ grower fish. During a separate investigation of mortalities in 1+ to 2+ trout on Farm B in the Shoalhaven River catchment in southeastern New South Wales, EHNV infection was demonstrated in both fingerlings and adult fish in association with nocardiosis. A 0.7% prevalence of antibodies against EHNV was detected by ELISA in the serum of grower fish at this time, providing the first evidence that EHNV might not kill all infected trout. EHNV infection on Farm B occurred after transfer of fingerlings from Farm C in the Murrumbidgee river catchment. When investigated, there were no obvious signs of diseases on Farm C. 'Routine' mortalities were collected over 10 d on Farm C and EHNV was detected in 2.1% of 190 fish. Tracing investigations of sources of supply of fingerlings to Farm B also led to investigation of Farm D in Victoria, where the prevalence of anti-EHNV antibodies in 3+ to 4+ fish was 1.3%. The results of this study indicate that EHNV may be found in trout in all age classes, need not be associated with clinically detectable disease in the population, can be transferred with shipments of live fish, can be detected in a small proportion of 'routine' mortalities and may be associated with specific antibodies in a small proportion of older fish. Sampling to detect EHNV for certification purposes should be based on examination of 'routine' mortalities rather than random samples of live fish. Antigen-capture ELISA can be used as a cost effective screening test to detect EHNV on a farm provided that sampling rates conform with statistical principles. PMID- 10092976 TI - Isolation of infectious salmon anemia virus (ISAV) from Atlantic salmon in New Brunswick, Canada. AB - Infectious salmon anemia virus (ISAV) was isolated at a marine grow-out site in New Brunswick, Canada, from Atlantic salmon Salmo salar which experienced mortalities due to hemorrhagic kidney syndrome (HKS). Of 20 fish sampled in this study, 14 showed histologically various degrees of interstitial hemorrhaging, tubular epithelial degeneration and necrosis, and tubular casts in the posterior kidney, typical of HKS. Posterior kidney and spleen homogenates produced a cytopathic effect on chinook salmon embryo (CHSE-214) cells 10 to 14 d after inoculation. Pleomorphic virus particles in the size range 80 to 120 nm were seen by electron microscopy. The virus was confirmed as ISAV using reverse transcriptase-polymerase chain reaction (RT-PCR). This is a systematic diagnostic study of the isolation of ISAV on the North American continent and the first description of the growth of ISAV on the CHSE-214 cell line. PMID- 10092977 TI - Genomic relationships of the North American isolate of infectious salmon anemia virus (ISAV) to the Norwegian strain of ISAV. AB - Nucleotide and deduced amino acid sequences were determined for a 436 bp reverse transcriptase-polymerase chain reaction (RT-PCR) cDNA fragment from genome segment 8 and a 1151 bp RT-PCR cDNA fragment from genome segment 2 of the North American isolate of infectious salmon anemia virus (ISAV) and compared to the published sequences of Norwegian isolates of ISAV. The North American ISAV isolate exhibited 82.9% identity with the Sotra 92/93 ISAV isolate from Norway in the partial cDNA sequence of genome segment 2, which encodes a polymerase component protein (PB1). The North American ISAV exhibited 88 and 89% identity with 2 partial cDNA sequences of genome segment 8 (nonstructural, NS, gene) reported for the Glesvaer/2/90 isolate from Norway. The North American ISAV exhibited 96.6% similarity with the Sotra 92/93 ISAV isolate from Norway in the deduced amino acid sequences of the PB1 protein. The deduced amino acid sequence of the protein encoded in the partial cDNA fragment of open reading frame (ORF) 1 of genome segment 8 of the North American ISAV exhibited only 71.2 and 66.7% similarity with the 2 sequences of the Norwegian Glesvaer/2/90 isolate. However, the North American ISAV isolate exhibited 96.2 and 87.2% similarity with the 2 sequences of the Norwegian Glesvaer/2/90 isolate in the deduced amino acid sequences of the protein encoded in the partial cDNA of ORF 2. Comparison of these partial cDNA nucleotide and deduced amino acid sequences confirmed that the North American isolate is ISAV. However, the differences observed in these genomic sequences suggest that the North American isolate may represent a distinct genomic variant from the previously described Norwegian strains. PMID- 10092978 TI - First identification of infectious salmon anaemia virus in North America with haemorrhagic kidney syndrome. AB - Haemorrhagic kidney syndrome (HKS), a serious disease affecting Atlantic salmon on the east coast of Canada, was determined to be caused by infectious salmon anaemia virus (ISAV) through the isolation of the pathogen on the SHK-1 (salmon head kidney) cell line and confirmation by ISAV-specific immunofluorescent antibody test (IFAT) and reverse transcriptase polymerase chain reaction (RT PCR). In addition, the defining histopathology of HKS could be reproduced following the injection of material that rendered challenged fish ISAV-positive by cell culture in the absence of any other detectable pathogen. Preliminary nucleotide sequence comparison does not suggest any direct epidemiological connection between the Canadian and Norwegian isolates. PMID- 10092979 TI - Virus susceptibility of the fish cell line SAF-1 derived from gilt-head seabream. AB - The recently reported SAF-1 cell line from fins of gilt-head seabream was evaluated for susceptibility to lymphocystis disease virus (LDV) and to several salmonid fish viruses, such as infectious haematopoietic necrosis virus (IHNV), viral haemorrhagic septicemia virus (VHSV) and several strains of infectious pancreatic necrosis virus (IPNV). LDV, VHSV and IHNV replicated well in the cultured fin cells as demonstrated by cell lysis and increases in viral titer. The potential use of this cell line to detect viruses from fish marine species is discussed. PMID- 10092980 TI - Small subunit rRNA gene sequences of Aeromonas salmonicida subsp. smithia and Haemophilus piscium reveal pronounced similarities with A. salmonicida subsp. salmonicida. AB - The small subunit ribosomal RNA (SSU rRNA) encoding genes from reference strains of Aeromonas salmonicida subsp. smithia and Haemophilus piscium were amplified by polymerase chain reaction and cloned into Escherichia coli cells. Almost the entire SSU rRNA gene sequence (1505 nucleotides) from both organisms was determined. These DNA sequences were compared with those previously described from A. salmonicida subsp. salmonicida, subsp. achromogenes and subsp. masoucida. This genetic analysis revealed that A. salmonicida subsp. smithia and H. piscium showed 99.4 and 99.6% SSU rRNA gene sequence identity, respectively, with A. salmonicida subsp. salmonicida. PMID- 10092982 TI - Neurone-specific enolase and N-acetyl-aspartate as potential peripheral markers of ischaemic stroke. AB - BACKGROUND: After stroke, brain-specific proteins (including neurone-specific enolase) leak into the blood. The question addressed in the present study was whether N-acetyl-aspartate (amino acid derivative localized in cerebral neurones) could also serve as a peripheral marker of ischaemic damage. N-acetyl-aspartate levels were determined in the blood of stroke patients and related to clinical outcome, volume of infarction and to serum neurone-specific enolase. METHODS: Blood samples from 19 patients (seven women, 12 men, mean age of 73 years, range 56-88 years) were collected during the first 4 days after stroke and analysed for neurone-specific enolase (radioimmunoassay) and/or N-acetyl-aspartate (mass spectrometry). Clinical outcome was assessed using the Glasgow Outcome Score, and volume of infarction was calculated using computerized tomography (CT). Control values of N-acetyl-aspartate, determined in six female and nine male volunteers (mean age 47.4 years; range 28-73 years) were 0.26 +/- 0.02 mumol L-1. RESULTS: The increase in serum N-acetyl-aspartate was highly significant (P < 0.0001) within the first 24 h and at 72 h after stroke and correlated (P < 0.05) with volume of infarction only in patients with a bad prognosis (Glasgow Outcome Score < 5). Serum N-acetyl-aspartate at 24 h and neurone-specific enolase at 72 h were negatively correlated, suggesting that more N-acetyl-aspartate reaches the blood when brain tissue is less irreversibly affected. CONCLUSION: Serum N-acetyl aspartate appears to be an early peripheral marker of ischaemically affected brain neurones, and the ratio of N-acetyl-aspartate to a protein marker, such as NSE, may serve as an index of irreversibility. PMID- 10092981 TI - The effects of iloprost infusion on microcirculation is independent of nitric oxide metabolites and endothelin-1 in chronic peripheral ischaemia. AB - BACKGROUND: Endothelial vascular tone modulators are thought to be involved in aetiopathogenesis of systemic sclerosis (SS) and of peripheral artery occlusive disease (PAOD). Iloprost, a prostacyclin (PGI2) analogue, induces clinical benefit in patients suffering from peripheral ischaemia. This study was performed to investigate the effect of this drug on endothelial function in vivo to elucidate the role of vascular tone modulators. METHODS: Fourteen PAOD and 15 SS patients were treated for 24 and 10 days respectively. On the first day, before and after therapy, nitric oxide metabolites (NO2-/NO3-) and endothelin-1 (ET-1) plasma concentrations were detected; moreover, the endothelium-dependent vasodilatation in response to artificial ischaemia was evaluated by means of an echo-Doppler device. RESULTS: The echo-Doppler evaluation showed that the percentage of arterial reactive dilatation was not modified by placebo or by iloprost, and that the increase in blood velocity flow lasted for a significant longer time after drug infusion (226.79 +/- 17.49 vs. 310.71 +/- 36.32 s; P > 0.04). NO2-/NO3- and ET-1 plasma concentration were higher in patients than in control subjects (P < 0.004). After 6 h of iloprost infusion, no significant modifications were detected. CONCLUSION: This study provides evidence that iloprost enhances the microvascular functional capacity and clinical benefit for patients. The effects of the drug seem to be independently or not directly correlated with its interactions with vascular tone modulators such as NO2-/NO3- or ET-1. PMID- 10092983 TI - Beta-blockers reduce the release and synthesis of endothelin-1 in human endothelial cells. AB - BACKGROUND: Endothelins play an important role in cardiovascular diseases, and clinical trials have shown a reduction in endothelin levels after long-term treatment of chronic heart failure with beta-adrenergic antagonists. It is not known, however, whether this effect is caused by haemodynamic changes associated with the use of beta-adrenergic antagonists or by direct interaction of beta blockers with human endothelial cells. The aim of this study was to determine whether beta-adrenergic antagonists have an influence on endothelin-1 (ET-1) synthesis and release in human endothelial cells. METHODS: Pretreatment of cultured endothelial cells from human umbilical veins (HUVECs) with different concentrations of the non-selective beta-blocker propranolol, the beta 1-blocker metoprolol and the beta 1-blocker and beta 2-agonist celiprolol (all 10(-7)-10( 4) mol L-1) was found to reduce ET-1 production. This ET-1-reducing effect was even more pronounced in thrombin-stimulated cells (10(-5) mol L-1 of propranolol, metoprolol and celiprolol: 19% +/- 5.8%, 25% +/- 4% and 37% +/- 5.2% respectively). RESULTS: Quantitative reverse transcriptase polymerase chain reaction and Northern blotting confirmed an inhibitory effect of the beta-blocker on biosynthesis. Furthermore, the ET-1-reducing effect of propranolol, metoprolol and celiprolol was not due to a compensatory increase in prostacyclin and was not reversible by N-nitro-L-arginine. CONCLUSION: The effect of beta-adrenergic antagonists on ET-1 production of the endothelium may at least partially explain the efficacy of beta-blockers in the treatment of diseases such as advanced heart failure, essential hypertension as well as acute coronary syndromes. PMID- 10092984 TI - Lipid and lipoprotein analysis of cats with lipoprotein lipase deficiency. AB - BACKGROUND: We have previously described a colony of domestic cats with a naturally occurring mutation in the lipoprotein lipase (LPL) gene. We have now further characterized cats homozygous for LPL deficiency (LPL -/-, homozygotes), and have contrasted these with heterozygotes (LPL +/-) and normal cats (LPL +/+). MATERIALS AND METHODS: Density gradient ultracentrifugation with subsequent lipid analysis, agarose and polyacrylamide gel electrophoresis was used to examine detailed liproprotein differences between the genotypes. Oral fat loading studies and breast milk fatty acid analysis were also performed to further characterize the phenotypic expression of LPL deficiency in this model system. RESULTS: Several lipid abnormalities associated with homozygosity for LPL deficiency were evident. Triglyceride-rich lipoprotein-triglycerides (TRL-TG) and cholesterol (TRL-C) were higher (TRL-TG 2.09 +/- 1.14 vs. 0.15 +/- 0.04 mmol L-1, P < 0.001; TRL-C 0.42 +/- 0.30 vs. 0.11 +/- 0.16 mmol L-1, P < 0.05) in male -/- than in male +/+ cats, as was HDL-cholesterol (HDL-C, 1.75 +/- 0.24 vs. 1.41 +/- 0.14 mmol L-1, P < 0.05). LDL-C levels were lower in homozygous cats than in control cats, similar to what is seen in human LPL deficiency. Oral fat loading studies revealed that homozygous cats have a marked reduced ability to clear plasma TGs in terms of peak time (7 h vs. 3 h), peak height (9.36 vs. 1.1 mmol L-1), area under the TG clearance curve (AUC, 280.3 vs. 2.2 h mmol L-1) and time to return to baseline. Fasting lipid and lipoprotein levels were not significantly different between heterozygous and normal cats. However, oral fat loading in heterozygotes revealed an intermediate phenotype (peak of 2.35 mmol L-1 at 5 h, AUC 13.1 h mmol L-1), highlighting the impaired TG clearance in these animals. CONCLUSION: Thus, LPL deficiency in the cat results in a lipid and lipoprotein phenotype that predominantly parallels human LPL deficiency, further validating the use of these animals in studies on the pathobiology of LPL. PMID- 10092985 TI - The effect of circulating non-esterified fatty acids on the entero-insular axis. AB - BACKGROUND: Circulating non-esterified fatty acids (NEFAs) have been causally associated with impairment of glucose metabolism, although their effect on the entero-insular axis, either in obesity or health, is unknown. MATERIALS AND METHODS: Glucose, insulin, glucagon-like peptide-1 (7-36 amide) (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to 100 g of carbohydrate in 400 mL water were evaluated during simultaneous modulation of circulating non-esterified fatty acids (NEFAs). A total of 10,000 units of heparin (to increase serum NEFAs) and 500 mg of acipimox (2 h before oral carbohydrate ingestion to reduce serum NEFAs) were administered to seven obese [mean +/- SEM: age 40 +/- 3.7 years; body mass index (BMI) 38.9 +/- 2.1 kg m-2] and seven lean (age 39.6 +/- 3.6 years; BMI 22.4 +/- 0.4 kg m-2) women. RESULTS: Higher fasting levels and post-heparin total integrated NEFAs (P < 0.05) and glycerol (P < 0.05) responses were seen in the obese than in the lean group. Incremental integrated GLP-1 responses to oral carbohydrate post-heparin in lean (P < 0.01) and obese (P < 0.05) subjects were significantly lower than after acipimox. Total integrated GIP (P < 0.05) and glucose (P < 0.01) responses were higher post heparin than after acipimox in obese subjects only. CONCLUSION: The inverse relationship in GIP and GLP-1 responses in the obese group after modulation of NEFAs indicates that reciprocal changes between these two hormones may exist to ensure constancy of B-cell stimulation. Our results suggest that in obese subjects compensatory secretion of GIP was incomplete and could not prevent impairment in glucose tolerance after heparin-induced rise in NEFAs. These results may be important in understanding the role of the insulinotropic hormones in carbohydrate metabolism characterized by high NEFA levels such as obesity and diabetes mellitus. PMID- 10092986 TI - The effects of ABT-229 and octreotide on interdigestive small bowel motility, bacterial overgrowth and bacterial translocation in rats. AB - BACKGROUND: Interdigestive small bowel motility has a regulatory function on the microflora of the upper small bowel. Here we investigate the effects of ABT-229 and octreotide on morphine-induced dysmotility, the accompanying bacterial overgrowth and bacterial translocation. METHODS: Rats were fitted with jejunal myoelectrodes and a subcutaneous cannula for continuous infusion of saline or morphine. Fasting motility was measured for 6 h on four occasions: one control measurement (day 0) and three measurements on consecutive days (days 1-3) while receiving saline alone (group A), morphine alone (group B), saline + ABT-229 (group C), morphine + ABT-229 (group D), saline + octreotide (group E) or morphine + octreotide (group F). Samples from the mesenteric lymph node complex (MLN), liver, spleen, duodenum and ileum were taken for quantitative microbial culturing on day 4. RESULTS: Neither ABT-229 nor octreotide increased the number of propagated activity fronts during saline infusion. During morphine-induced dysmotility, ABT-229 induced more propagated activity fronts in group D (13.4, 9.8 and 8.8 per 6 h) than in group B (7.0, 4.5, 3.8 per 6 h) on days 1, 2 and 3 (P < 0.05 for all days) Octreotide did not induce more propagated activity fronts. Disruption of small bowel motility by morphine led to bacterial overgrowth in the duodenum. ABT-229 and octreotide did not reduce the bacterial growth levels. The total incidence of bacterial translocation was significantly higher in the morphine-treated animals than in the saline-treated animals. Neither ABT-229 nor octreotide reduced the bacterial translocation incidence. The number of propagated activity fronts on day 3 and duodenal bacterial growth correlated significantly in groups A, E and F. CONCLUSIONS: ABT-229, but not octreotide, reduced morphine induced dysmotility. Small bowel bacterial overgrowth and bacterial translocation were not prevented. Fasting small bowel motility has a regulatory function on the intestinal microflora of the upper small bowel. PMID- 10092987 TI - Characterization of antigens from the human exocrine pancreatic tissue (Pag) relevant as target antigens for autoantibodies in Crohn's disease. AB - BACKGROUND: The present study was performed to analyse the immunological properties of the autoantigens recognized by autoantibodies against exocrine pancreas (PAb), which have been described in Crohn's disease. METHODS: Autoantibodies were detected by indirect immunofluorescence. Inhibition studies were performed by preincubating tissue sections with various glycoproteins and the different fractions obtained in fractioned salt precipitation of pancreas homogenate with ammonium sulphate. Immunoblotting of human pancreas homogenate was conducted using PAb-positive sera. RESULTS: In size exclusion chromatography, the molecular weight of the pancreas autoantigen (PAg) was determined as > 800 kD. In the fractionated salt precipitation, the autoantigen could be detected in fractions I (0-25% ammonium sulphate) and III (50-90% ammonium sulphate). In immunoblotting, a number of protein bands were observed (at 16, 18, 19, 24, 27, 29, 31 and 34 kD), and the binding pattern showed little variation between individual patients. CONCLUSIONS: The protein that is recognized by PAb appears to be a large protein complex consisting of several subunits which exhibit reactivity to PAb. PMID- 10092988 TI - Pancreatic autoantibodies in Crohn's disease. PMID- 10092989 TI - Lack of interleukin 10 regulation of antigen presentation-associated molecules expressed on colonic epithelial cells. AB - BACKGROUND: Colonic epithelial cells may behave as antigen-presenting cells. Interleukin 10 (IL-10) is known to play a major role in the intestinal immune system; however, it remains to be determined whether human intestinal epithelial cells express IL-10 receptor, and whether this cytokine modulates their expression of antigen presentation-associated molecules. METHODS: The binding of biotinylated IL-10 was studied in SW 1116, HT-29 and T84 human colonic epithelial cell lines and freshly isolated normal colonic epithelial cells. Reverse transcription-polymerase chain reaction was also performed to detect IL-10 receptor mRNA. The effect of IL-10 on antigen presentation associated molecules was assessed by flow cytometry. RESULTS: Biotinylated IL-10 bound to SW 1116, HT 29, T84, and normal colonic epithelial cells. IL-10 receptor mRNA was detected in SW 1116 and normal epithelial cells. SW 1116 and HT-29 cells expressed MHC class I and ICAM-1, but not CD80, and SW 1116 constitutively expressed HLA-DR. Interferon-gamma up-regulated HLA-DR and ICAM-1 expression on both cells, whereas lipopolysaccharide increased ICAM-1 expression only on SW 1116. IL-10 failed to modulate these antigens, even after stimulation by lipopolysaccharide or interferon-gamma. Moreover, these molecules decreased IL-10 binding in both lines. CONCLUSION: The presence of IL-10 receptor on intestinal epithelial cells suggest that IL-10 may play a role in mucosal physiology, however its effect on the immune response remains to be determined. PMID- 10092990 TI - Relationship of Helicobacter pylori CagA(+) status to gastric juice vitamin C levels. AB - BACKGROUND: To date it is not known whether gastric juice vitamin C levels are influenced by Helicobacter pylori CagA(+) strains. The aim of the present study, therefore, was to study the impact of H. pylori CagA status on gastric juice vitamin C levels. MATERIALS AND METHODS: We studied 30 H. pylori(+) patients, and the results were compared with 10 endoscopically and histologically normal H. pylori(-) subjects (control group) who were similar to the H. pylori(+) group in terms of age and sex. In all patients, gastric juice vitamin C levels were determined and the severity of gastritis was graded on a scale of 0 (absent) to 3 (severe). CagA was determined by immunoblotting the sera from patients against H. pylori antigens. RESULTS: Among 30 H. pylori(+) patients, 20 were CagA(+) and 10 CagA(-). In the entire group of H. pylori(+) patients, the median gastric juice vitamin C levels (mg L-1) were 16.35 (range 3.5-33.6) and were significantly lower (P < 0.001) than in the control group of H. pylori(-) patients [35.5 (23.1 50.2)]. In addition, in the entire group of H. pylori(+) patients there was a highly significant (P < 0.0001) inverse correlation between the gastritis activity score and the gastric juice vitamin C levels. In the group of H. pylori CagA(+) patients, the median levels of gastric juice vitamin C were 13.8 (3.5 31.2) and were significantly lower than the corresponding levels in both the H. pylori CagA(-) group [24.8 (22-33.6), P < 0.01] and the H. pylori(-) control group [35.5 (23.1-50.2), P < 0.001], the last groups being similar. Furthermore, the gastritis activity median score in the H. pylori CagA(+) group [2 (1-3)] was significantly higher (P < 0.05) than in the H. pylori CagA(-) group [1 (1-2)]. CONCLUSION: These data indicate that infection with CagA(+) H. pylori strains significantly lowers the gastric juice vitamin C levels in comparison with CagA( ) H. pylori strains, which might have a significant impact on gastric carcinogenesis. PMID- 10092991 TI - Direct in vivo gene transfer to healing rat patellar ligament by intra-arterial delivery of haemagglutinating virus of Japan liposomes. AB - BACKGROUND: Manipulation of ligament healing has been a major focus of orthopaedic research. In recent years, gene transfer to healing ligament appears to be a feasible method for manipulating the healing process. In this study, we investigated the feasibility of gene transfer to healing rat patellar ligament by intra-arterial delivery. METHODS: An attempt was made to transfer a reporter gene (Escherichia coli, beta-galactosidase gene) to healing rat patellar ligament using the haemagglutinating virus of Japan (HVJ) liposome-mediated gene transfer method. Three days after cutting the patellar tendons of 25 14-week-old male Wistar rats, HVJ-liposome complexes containing beta-galactosidase (beta-gal) cDNA were injected into the femoral artery of 15 Wistar rats as the experimental group. HVJ liposomes without DNA were injected into the femoral artery of 10 Wistar rats as the control group. Three rats from the experimental group and two control rats were killed 3, 7, 14, 28 and 56 days after the injection. RESULTS: After X-gal staining, the rate of transfection in the experimental group (mean +/ SEM) was found to be 12.1% +/- 0.590%, 8.7% +/- 0.217%, 10.2% +/- 0.227%, 3.2% +/- 0.247% and 0.7% +/- 0.060% at post-injection days 3, 7, 14, 28 and 56 respectively. In control sections the number of blue-stained cells were very few at any point. CONCLUSION: We succeeded in introducing a reporter gene into healing rat patellar ligament by infra-arterial delivery of HVJ-liposome complexes. This method appears to have the potential to be applicable for soft tissue healing studies and also healing studies of other tissues and organs. PMID- 10092992 TI - Management of renal cell carcinoma in von Hippel-Lindau disease. AB - BACKGROUND: An evaluation of nephron-sparing surgery (NSS) or radical nephrectomy (RN) for treating renal cell carcinoma (RCC) in patients with von Hippel-Lindau disease (VHL) was carried out. METHODS: Between 1976 and 1997, 10 patients with RCC from four VHL families, of whom seven were from one family, were studied by clinical and histopathological examination. Before 1991, three patients were treated using RN, and thereafter five patients were treated using NSS. Two patients were not operated on. RESULTS: RCCs in our patients showed a slow growth rate (on average 0.3 cm year-1), and asymptomatic patients presented with tumours of low-grade malignancy. In all patients, tumours were surrounded by a fibrous pseudocapsule. In 5 out of 17 tumours, pseudocapsular invasion was observed, and three of these five tumours broke through the pseudocapsule. To date, these patients have not shown a less favourable outcome than those without pseudocapsular involvement by tumour growth. Multicentricity of RCC was relatively low (4.6 lesions per kidney). In two of the three RN patients, only a single satellite lesion, in the direct vicinity of a RCC, was found in one kidney. Six tumours (1.8-5.5 cm) were enucleated by NSS. During a mean follow-up of 30 months, renal function in these patients was well preserved. CONCLUSIONS: In our patients, RCCs grew slowly, were of low grade, had a dense fibrous pseudocapsule and were thus good candidates for NSS. PMID- 10092993 TI - Induction of rat uncoupling protein-2 gene treated with tumour necrosis factor alpha in vivo. AB - BACKGROUND: The cytokine tumour necrosis factor (TNF) alpha has been reported to induce metabolic abnormalities such as anorexia and thermogenesis. To investigate functional modulators of uncoupling protein-2 (UCP2) gene expression, we examined the effects of TNF-alpha on UCP2 mRNA expression in rats. METHODS: Mature male Wistar King A (WKA) rats at 10-11 weeks of age were treated with recombinant human TNF-alpha at a dose of 0.6 nmol 100 g-1 body weight by intraperitoneal administration. RESULTS: TNF-alpha treatment induced an increase in UCP2 mRNA expression in broadly distributed tissues including brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle, and an elevation of ob gene mRNA expression in WAT. After the TNF-alpha treatment, an increase in plasma leptin concentration occurred in an ob gene-dependent manner, accompanied by an anorectic effect. CONCLUSION: The present results provide evidence for a new regulatory loop involving TNF-alpha and UCP2, and add novel insights into the regulatory mechanisms of energy homeostasis. PMID- 10092994 TI - Pulmonary surfactant protein A binds to Cryptococcus neoformans without promoting phagocytosis. AB - BACKGROUND: Evidence is accumulating that the alveolar collecting surfactant protein A (SP-A) plays an important role in the first line of defence against infiltrating pathogenic micro-organisms and viruses. The ability of SP-A to facilitate the binding and uptake of acapsular Cryptococcus neoformans by monocyte-derived macrophages, human alveolar macrophages, monocytes and polymorphonuclear leucocytes was investigated. MATERIALS AND METHODS: Binding, competition and phagocytosis experiments were performed using a flow cytometry technique. RESULTS: SP-A bound to both the acapsular and the encapsulated form of C. neoformans in a concentration-dependent manner. SP-A showed a threefold better binding to the acapsular yeast: this binding was partly calcium dependent and could be inhibited by mannose (ID50 = 3 mmol L-1) and glucose (ID50 = 2.1 mmol L 1) but not by galactose (ID50 = 391 mmol L-1). SP-A did not function as an opsonin in phagocytosis of acapsular C. neoformans for any of the phagocytes studied. CONCLUSION: Our results indicate that SP-A binds in a concentration dependent manner to both encapsulated and acapsular C. neoformans. Despite SP-A binding to the acapsular C. neoformans, phagocytosis by various phagocytes was not enhanced. PMID- 10092995 TI - Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor-alpha release by cultured smooth muscle cells. AB - BACKGROUND: Inflammatory related cardiovascular disease, i.e. cardiac allograft rejection, myocarditis, septic shock, are accompanied by cytokine production, which stimulates the expression of inducible nitric oxide (iNOS). MATERIALS AND METHODS: The aim of the present study was to examine whether anti-inflammatory doses of acetylsalicylic acid (aspirin) could regulate iNOS protein expression in bovine vascular smooth muscle cells (BVSMCs) in culture. RESULTS: Interleukin 1 beta (IL-1 beta, 0.03 U mL-1) induced nitric oxide release by BVSMCs. Aspirin inhibited nitric oxide release from IL-1 beta-stimulated BVSMCs in a dose dependent manner. In addition, aspirin significantly inhibited iNOS protein expression in BVSMCs and reduced the translocation of the nuclear factor-kappa B (NF-kappa B). Furthermore, aspirin and the blockade of NO generation by BVSMCs reduced the production of tumour necrosis factor alpha (TNF-alpha) by these cells. CONCLUSION: High doses of aspirin inhibited iNOS protein expression in BVSMCs and decreased NF-kappa B mobilization. The inhibition of iNOS expression by aspirin was further associated with a reduced ability of BVSMCs to produce TNF alpha. This study could provide new mechanisms of action for aspirin in the treatment of the inflammation-related cardiovascular diseases. PMID- 10092996 TI - Plasma homocysteine concentration related to diet, endothelial function and mononuclear cell gene expression among male hyperlipidaemic smokers. AB - BACKGROUND: Elevated plasma concentration of homocysteine is an independent risk factor for development of cardiovascular diseases. MATERIALS AND METHODS: We evaluated potential links between homocysteine and atherothrombogenesis by relating the plasma concentration of homocysteine to (i) dietary antioxidants and omega-3 fatty acids (and determined influence of intervention with antioxidants or omega-3 fatty acids); (ii) markers of endothelial cell function; and (iii) peripheral blood mononuclear cell mRNA levels. RESULTS: We observed an inverse relationship between the plasma homocysteine concentration and dietary intake of vegetables, vitamin C and beta-carotene and between homocysteine and the serum concentration of folate, vitamin B12 and omega-3 fatty acids. Intervention with antioxidants or omega-3 fatty acids did not affect plasma homocysteine concentration. The plasma levels of cysteinylglycine and vitamin B12 correlated positively with circulating E-selectin and VCAM-1, respectively, whereas folate in serum and blood correlated negatively with P-selectin. A negative correlation was found between the concentrations of homocysteine and von Willebrand factor. Negative and positive correlations were found between plasma homocysteine and the mononuclear cell mRNA levels of peroxisome proliferator activated receptor delta (PPAR delta) and c-myc respectively. A negative correlation was also found between plasma homocysteine and mononuclear cell mRNA levels of the proteoglycan serglycin. Homocysteine was not correlated with serum activity of glutathione peroxidase or with the mRNA level of glutathione peroxidase in mononuclear cells. CONCLUSION: The plasma homocysteine level was negatively correlated with dietary intake of vegetables, including vitamins C and E, and serum omega-3 fatty acids, whereas supplementation with antioxidants or omega-3 fatty acids did not affect plasma homocysteine concentration. Homocysteine was not associated with circulating adhesion molecules or increased procoagulant activity, but homocysteine may alter mononuclear cell gene expression. Cysteine showed no significant correlation with these parameters. PMID- 10092997 TI - Atrial natriuretic peptide increases albuminuria in type I diabetic patients: evidence for blockade of tubular protein reabsorption. AB - BACKGROUND: It has been suggested that atrial natriuretic peptide (ANP) contributes to the glomerular hyperfiltration of diabetes mellitus. Infusion of ANP increases the urinary excretion of albumin in patients with type I diabetes mellitus (IDDM). Although the increased albuminuria is attributed to a rise in glomerular pressure, alterations in tubular protein handling might be involved. PATIENTS AND METHODS: We have studied the effects of ANP in nine microalbuminuric IDDM patients. After obtaining baseline parameters, ANP was infused over a 1-h period (bolus 0.05 microgram kg-1, infusion rate 0.01 microgram kg-1 min-1). Renal haemodynamics, sodium and water clearance and tubular protein handling were studied. RESULTS: The glomerular filtration rate (GFR) increased from 116.4 +/- 8.9 to 128.3 +/- 8.8 mL min-1 1.73 m-2, whereas the effective renal plasma flow (ERPF) decreased from 534.3 +/- 44.3 to 484.9 +/- 33.3 mL min-1 1.73 m-2 (P < 0.05). As a result, the filtration fraction was significantly higher during infusion of ANP. ANP attenuated proximal tubular sodium reabsorption. Urinary albumin excretion rose from 87.57 +/- 21.03 to 291.40 +/- 67.86 micrograms min-1 (P < 0.01). Changes in the urinary excretion of beta 2-microglobulin and free kappa light chains were more marked, the excretion of beta 2-microglobulin increasing from 0.28 +/- 0.21 to 51.87 +/- 10.51 micrograms min-1 (P < 0.01), and of free kappa-light chains from 4.73 +/- 1.74 to 46.14 +/- 6.19 micrograms min-1 (P < 0.01). CONCLUSIONS: The observed rise in albuminuria during infusion of ANP does not simply reflect a change in glomerular pressure, but might at least partly result from an attenuation of tubular protein reabsorption. PMID- 10092998 TI - Cholesteryl ester transfer protein gene effect on CETP activity and plasma high density lipoprotein in European populations. The EARS Group. AB - BACKGROUND: Variation at the cholesteryl ester transfer protein (CETP) gene locus has been implicated in determining the levels and activity of CETP, apoAI and high-density lipoprotein (HDL) plasma concentration and the risk of developing coronary artery disease. STUDY DESIGN: The effects of two common polymorphisms of CETP, TaqIB in intron 1 and isoleucine 405 to valine (I405-->V) in exon 14, were examined in a sample of 822 men age 18-28 years from 11 countries in Europe who had participated in a study (the European Atherosclerosis Research Study II) of the offspring of myocardial infarction sufferers before the age of 55 years and age-matched control subjects. RESULTS: The frequency of the rare TaqIB allele (B2) and the rare V405 allele was 0.44 and 0.28 respectively and was the same in different regions of Europe. There was a moderate linkage disequilibrium between the two polymorphisms in all the regions (D' = +0.31, P < 0.001), explained by the preferential association between the two common alleles, B1 and I405. There was a statistically significant association of the rare alleles for both the polymorphisms with lower activity of CETP (P < 0.001), 11.2% lower for the TaqIB and 7.0% lower for the I405-->V polymorphism. The TaqIB polymorphism explained 9.1% (P < 0.001) and I405-->V explained 3.7% (P < 0.001) of the variance in CETP activity, and in combination these genotypes explained 12.0% of the variance (P < 0.001). Overall, subjects whose fathers had had an early coronary heart disease had 2.4% higher plasma CETP activity than those without such family history, which became statistically significant when adjusted for the effect of the genotypes (P = 0.015), but the significance disappeared after adjustment for the effect of lipids. There was a statistically significant effect of the TaqIB polymorphism on both plasma HDL cholesterol and apoAI level (P < 0.001), with those homozygous for the rare B2 allele having the highest level. Those individuals homozygous for the rare V405 allele had the highest HDL and apoAI levels, although these effects only reached statistical significance for HDL (P < 0.03). CONCLUSION: These results suggest that the TaqIB and I405-->V polymorphisms represent two independent functional variations in the CETP gene that may affect the activity of CETP and thus plasma levels of HDL. PMID- 10093000 TI - Distribution of diacylglycerols among plasma lipoproteins in control subjects and in patients with non-insulin-dependent diabetes. AB - BACKGROUND: Diacylglycerols (DAGs), which are well-known components of insect lipophorins, have been recently recognized as a major glyceride of human high density lipoprotein (HDL). Moreover, DAGs are good substrates for hepatic lipase and for the phospholipid transfer protein (PLTP). The present work was undertaken to determine the lipoprotein concentrations of DAGs, in control subjects, in non insulin-dependent diabetic (NIDD) patients and in patients with severe hypertriglyceridaemia. MATERIALS AND METHODS: Lipoproteins were isolated from 11 control subjects, 17 diabetic patients and three hypertriglyceridaemic patients, using a combination of ultracentrifugation and precipitation. After lipid extraction, DAGs were separated by thin-layer chromatography and quantified by a glyceride assay. RESULTS: DAGs were detectable in all lipoprotein fractions of the three groups of subjects. Total DAGs were correlated with total triglycerides (TGs) and even more strikingly with very low-density lipoprotein triglycerides. Although the majority of DAG was recovered in apo B-containing lipoproteins, the proportion of DAG with respect to TG was most elevated in HDL. CONCLUSION: These findings indicate that DAGs are probably formed from TG during lipolysis and that they can be transported to HDL through the action of PLTP. This raises the question whether DAG might act as an inhibitor of phospholipid transfer by competition for binding to PLTP. PMID- 10092999 TI - Effects of dietary fatty acids and vitamin E levels in HL-60 cell proliferation. AB - BACKGROUND: Fatty acids have shown to be both modulators and messengers of signals triggered at the level of cell membranes. There is, however, controversy about the role of fatty acids in cell proliferation kinetics, and it is still unknown whether cell proliferation can be regulated by fatty acid dietary intake in humans. Our objective was to investigate whether feasible changes in the human dietary food intake that induce significant changes in lipids, fatty acids and the oxidative state were able to influence proliferation kinetics of the leukaemia cell line HL-60. MATERIALS AND METHODS: Healthy men and women were subjected to four consecutive dietary periods with increasing degree of unsaturation: saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), n-6 polyunsaturated fatty acids (n-6 PUFAs), n-3 polyunsaturated fatty acids (n-3 PUFAs). Plasma lipids and oxidation parameters were controlled during each period. Serum from each subject in the four dietary periods was incubated for 3 days with the leukaemia cell line, HL-60 (250 x 10(3) cell mL-1), to study cell proliferation. RESULTS: In men, an n-3 polyunsaturated fatty acid-enriched diet showed a significant inhibition of DNA duplication with respect to a saturated enriched diet, but the effect is not sufficient in blocking cell proliferation. However, as expected, the in vitro addition of fatty acids to HL-60 cells significantly halted proliferation. In addition, the HL-60 growth ratio was shown to be inversely correlated with plasma vitamin E (P = 0.0004) and oleic acid in phospholipids (P = 0.01) in plasma of the individuals in the dietary intervention study. CONCLUSIONS: Our results demonstrate that changes in serum fatty acid composition obtained with dietary changes, without extreme variations of the regular diets of a free-living population, cannot block HL-60 cell proliferation. PMID- 10093001 TI - Leptin levels in smokers and long-term users of nicotine gum. AB - BACKGROUND: The aim of this study was to examine the effects of cigarette smoking and other forms of long-term nicotine consumption on circulating leptin levels as well as the relationship between leptin levels and insulin sensitivity, measured with the euglycaemic hyperinsulinaemic clamp, in healthy middle-aged men. STUDY DESIGN: Samples from 73 subjects were analysed: 23 non-smokers, 31 smokers and 19 long-term nicotine gum chewers (NGCs) with similar ranges of age, body mass index (BMI) and per cent body fat. RESULTS: Leptin levels were higher in NGCs and smokers than in the non-smoking matched control subjects. Smoking cessation for 8 weeks further increased the leptin levels, probably due to the concomitant increase in body fat (mean +/- SD, 2.2 +/- 1.8 kg). Acute administration of one dose of nicotine nasal spray or smoking one cigarette did not significantly change the circulating leptin levels during the following 60 min. Plasma leptin concentrations were positively correlated with the proportion of body fat and negatively correlated with the degree of insulin sensitivity in each of the three subject groups. In a stepwise multiple linear regression analysis, plasma leptin concentrations were significantly correlated with the proportion of body fat, degree of insulin sensitivity and smoking status. CONCLUSION: These data show that long-term use of nicotine is associated with elevated circulating leptin levels. The increased leptin levels may be an important reason for the lower body weight in smokers. The results of this study also support the view that leptin is directly or indirectly related to insulin sensitivity in men. PMID- 10093002 TI - Effects of spiroglumide, a gastrin receptor antagonist, on acid secretion in humans. AB - BACKGROUND: A gastrin receptor antagonist, CR2194 (spiroglumide), was used to explore the physiological role of gastrin in regulating gastric acid secretion in humans. MATERIALS AND METHODS: The effect of CR2194 on inhibition of gastrin stimulated acid output was evaluated in a four-period crossover study. Each subject received intravenous doses of 1, 2.5 or 7.5 mg kg-1 h-1 CR2194 or saline (control) followed by graded increasing doses of gastrin (6.4-800 pmol kg-1 h-1). Secondly, the effect of CR2194 on meal-stimulated intragastric acidity was evaluated by infusing either saline (control) or CR2194 (7.5 mg kg-1 h-1) before and after food ingestion. RESULTS: Acid secretion was dose-dependently inhibited by CR2194. With CR2194, acidity was significantly reduced in the pre-meal and post-prandial period (P < 0.01 and 0.002 respectively), and the integrated gastrin response was augmented to 8.0 +/- 1.4 ng mL-1 240 min compared with 1.5 +/- 0.8 ng mL-1 240 min in the control experiment (P < 0.01). Finally, acid secretion in response to sham feeding was significantly reduced: 15.9 +/- 0.9 mmol 90 min-1 in the control experiment compared with 2.8 +/- 0.9 mmol 90 min-1 during CR2194 infusion (P < 0.05). CONCLUSION: Gastrin receptor blockade with CR2194 alters gastric acid secretion in response to food ingestion or to sham feeding. The results support a physiological role for gastrin in regulating acid secretion in humans. PMID- 10093003 TI - The sensitivity of the lactulose/rhamnose gut permeability test. AB - BACKGROUND: The lactulose/rhamnose (L/R) intestinal permeability test is widely used. However, different quantities and proportions of lactulose and rhamnose are used. The aim of this study was to determine whether a low dosage of lactulose is able to discriminate between normal and increased permeability. MATERIALS AND METHODS: Two groups of 10 healthy subjects were studied. In group 1, three different iso-osmolar test solutions were administered on 3 days. The solutions consisted of 10 g of L with 1 g of R, 5 g of L with 0.5 g of R and 1 g of L with 0.1 g of R in 65 mL of water. Group 2 ingested these solutions 1 h after ingestion of 750 mg of chenodeoxycholeic acid (CDCA), which is known to increase permeability. The urinary L/R ratio was determined using high-performance liquid chromatography. Data are presented as medians (range). RESULTS: In group 1, no differences were observed between the three solutions. In Group 2, there was a significant difference (P = 0.045) between the three solutions. The L/R ratios were 0.0079 (0.0024-0.0152) (1L to 0.1R), 0.0138 (0.0066-0.0192) (5L to 0.5R) and 0.0144 (0.0074-0.0374) (10L to 1R). The L/R ratio differed significantly between Groups 1 and 2 (P < 0.001) using the 5L to 0.5R and 10L to 1R solutions respectively. CONCLUSION: If the permeability is increased, the urinary L/R ratio depends on the quantity of lactulose and rhamnose administered in equal proportion. 5L to 0.5R is sufficient to discriminate between a normal and a moderately increased permeability. PMID- 10093004 TI - Cell death by overload of the elastin-laminin receptor on human activated lymphocytes: protection by lactose and melibiose. AB - BACKGROUND: Activated human lymphocytes were shown to express the elastin-laminin receptor in vitro and also in vivo in atherosclerotic plaques. In the presence of the agonist, elastin peptides, this receptor was shown to mediate an increased cell proliferation and an increased synthesis and excretion of an elastase-type serine endopeptidase. In this study, we investigated the variation of the above reaction as a function of agonist concentration. MATERIALS AND METHODS: Human lymphocytes were obtained by tonsillectomy and cultured in the presence of phytohaemagglutinin and elastin peptides. Cell viability was evaluated by vital dye exclusion. Elastase and cathepsin G activities were determined in culture supernates and cell lysates using synthetic substrates. Apoptotic cells were identified by the TUNEL method and by electron microscopy. RESULTS: At increasing concentrations of elastin peptides, a dose-dependent increase in cell death was observed. Up to 100 micrograms mL-1 elastin peptides and an increasing fraction of lymphocytes were found permeable to trypan blue, and a large proportion was in apoptosis. Elastin peptide-induced cell death was inhibited by 1 microgram mL-1 lactose and melibiose. CONCLUSION: We describe here cell death of human activated lymphocytes expressing the elastin-laminin receptor in the presence of increasing concentrations of elastin peptides, agonists of the receptor. The mechanism of cell death appears to be related to the triggering of the release of elastase and free radicals mediated by the elastin-laminin receptor. Antagonists of this receptor, lactose and melibiose, protected the lymphocytes from the receptor mediated cell death. PMID- 10093005 TI - T-cell receptor gene usage in patients with fibrosing alveolitis and control subjects. AB - BACKGROUND: Fibrosing alveolitis is characterized by inflammation, fibrosis and increased numbers of activated CD4+ T-cells in the lower respiratory tract. The aims of this study were to compare the T-cell antigen receptor repertoire in the lungs of subjects with fibrosing alveolitis systemic sclerosis (FASSc) with cryptogenic fibrosing alveolitis (CFA) and normal control subjects, to determine whether FASSc is driven by a specific T-cell trigger and is determined by a T cell driven immune response, and to assess the clonality of CD4+ and CD8+ TcR usage in subjects with FASSc. MATERIALS AND METHODS: We used reverse transcription polymerase chain reaction with specific V alpha- and V beta-chain primers to identify the TcR gene usage in biopsy material, bronchoalveolar lavage fluid or peripheral blood from our subjects. RESULTS: We found individual specific restriction of V alpha- and V beta-chain usage in lung biopsies from patients and control subjects. To establish whether this was due to expression bias in the CD4+ or CD8+ T-cells and was restricted to the lung, the alpha beta-T cell receptor chain usage was assessed in T-cell subsets separated from the lungs of patients with fibrosing alveolitis and was compared with that of the peripheral blood. There was no consistent difference in the expression of any variable family chain among the population studied, although there was a significant difference between lung and peripheral blood lymphocyte V beta families in CD8+ T-cells (P = 0.0007). CONCLUSION: We conclude that there is individual TcR V alpha- and V beta-expression bias in subjects with fibrosing alveolitis. PMID- 10093006 TI - Whole-blood cultures: a valid and reliable tool for studying cytokines in exercise. PMID- 10093007 TI - CAD-prevention--a perspective. PMID- 10093008 TI - [Prevention of coronary heart disease--"evidence-based medicine" of antilipemic therapy]. AB - A considerable number of large scale clinical trials provide clear evidence that cholesterol lowering is one of the most important risk-reduction strategies for secondary and primary prevention of coronary artery disease. Unlike the older studies with fibrates, the most recent trials of cholesterol-lowering therapies with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have clearly shown that their use can reduce coronary artery disease and total mortality as well as the need for expensive hospitalization and revascularization procedures. Studies such as the Scandinavian Simvastatin Survival Study (4S), the West of Scotland Coronary Prevention Study (WOS), the Cholesterol and Recurrent Events (CARE) trial and most recently the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) as well as numerous other investigations, have established that decreasing elevated levels of low-density lipoprotein (LDL) cholesterol will result in a reduction in risk of coronary artery disease. In addition, HMG-CoA reductase inhibition reduces the risk for cerebral ischemia. Recent data indicate that less than half of patients with coronary artery disease receive cholesterol-lowering therapy, and few meet the LDL-cholesterol goal. Therefore clinicians treating coronary artery disease need to emphasize secondary prevention and recognize the key role of cholesterol-lowering therapy. The challenge for clinicians is to apply the important lessons learned from these clinical trials to an "evidence-based" patient care. PMID- 10093009 TI - [Laboratory diagnosis in preventive cardiology]. AB - In recent years a large number of coronary artery disease risk factors were discovered. The knowledge of these factors improves the estimate of the coronary artery disease (CAD) risk--however it still remains to be only an "estimate". A perfect prediction of an upcoming CAD event is not possible, despite all high score laboratory technology. Therefore the use of specialized laboratory procedures should be applied carefully. Knowing the blood levels of cholesterol, triglycerides, HDL- and LDL-cholesterol and Lp(a) can be sufficient for many therapeutical decisions. Severe dyslipidemia, familial CAD and CAD without any obvious reasons demand a more specialized work-up, however, risk stratification factors such as family history, clinical history (CAD, hypertension, diabetes mellitus, smoker) and genetics are crucial, apart from the above mentioned laboratory values. Purely on the basis of the lipidologic baseline concentrations we can't give well based recommendations for the treatment of individual patients. Currently there are expert systems available which allow a risk estimate once important laboratory values (LDL cholesterol, HDL cholesterol, Triglycerides) as well as clinical data (blood pressure, family history, clinical history) are available. This system can be accessed by internet under "http:/(/)www.chd-taskforce.com". PMID- 10093010 TI - [Mechanisms of plaque stabilization]. AB - Numerous angiographic control regression studies have demonstrated that aggressive reduction of plasma cholesterol significantly reduces the incidence of clinical overt cardiovascular complications, but has almost no effect on the angiographically determined luminal diameter of the coronary arteries. These, as well as other morphological and molecular studies have led to a new paradigm of coronary heart disease, i.e. clinical prognosis is not mainly determined by the extent of a single stenosis but by the number and biological nature of atherosclerotic plaque. Accordingly, stable plaques can be differentiated from instable or vulnerable plaques. The vulnerable or instable plaque is characterized by a large lipid-rich core with surrounding inflammation and a thin friable overlying fibrous cap susceptible to rupture or fissuring and thereby a high risk of thrombus formation. Rupture and thrombus formation can cause an acute coronary syndrome, such as unstable angina or myocardial infarction. There is increasing clinical and experimental evidence that statins do not only lower plasma cholesterol, but might also have direct effects on the vessel wall, possibly explaining early benefits in cardiovascular complications. Reduction of plasma cholesterol by lipid lowering therapy has been shown to significantly improve paradoxic vasoconstriction of cardiac vessels, a phenomenon indicating endothelial dysfunction. In addition, lipid lowering therapy can result in a diminution of the lipid-rich core, a reduction of inflammatory cells within the plaques, decreased macrophage activation as well as foam cell formation and events related to thickening of the fibrous cap. A clinical prospective should be to better clinically morphologically characterize the vulnerability of plaques in order to therapeutically and preventively reduced specific events leading to acute coronary syndromes, such as unstable angina or myocardial infarction. PMID- 10093011 TI - Role of intravascular ultrasound imaging in identifying vulnerable plaques. AB - A plaque that has a large lipid core and a thin fibrous cap may undergo rupture. Once it ruptures, it may lead to thrombus formation and subsequent vessel occlusion. To identify unstable plaques before they rupture is essential for clinical management and patient's prognosis. Intravascular ultrasound (IVUS) opens a new window for the assessment of plaque morphology to identify vulnerable plaques and plaque rupture. We examined 144 patients with angina and ischemic ECG changes using IVUS. Ruptured plaques, characterized by a plaque cavity and a tear on the thin fibrous cap, were identified in 31 patients (group A) of which 23/31 (74%) clinically presented as unstable angina. Plaque rupture was confirmed by injecting contrast medium filling the plaque cavity during IVUS examination. Of the patients without plaque rupture (group B, n = 108), only 19 (18%) had unstable angina. No significant differences between the 2 groups were found concerning the vessel and plaque areas (p > 0.05). The percent stenosis in group A (56.2 +/- 16.5%) was significantly lower than in group B (67.9 +/- 13.4%) (p < 0.001). Area of the plaque cavity in group A (4.1 +/- 3.2 mm2) was significantly larger than the echolucent zone in group B (1.32 +/- 0.79 mm2) (p < 0.001). The plaque cavity/plaque ratio in group A (38.5 +/- 17.1%) was larger than the echolucent area/plaque ratio in group B (11.2 +/- 8.9%) (p < 0.001). The thickness of the fibrous cap in group A (0.47 +/- 0.20 mm) was significantly thinner than that (0.96 +/- 0.94 mm) in group B (p < 0.001). CONCLUSIONS: Plaques seem to be prone to rupture when the echolucent area is larger than 1 mm2, the echolucent area/plaque ratio greater than 20% and the fibrous cap thinner than 0.7 mm. IVUS has the capacity of identifying plaque rupture and vulnerable plaques. This may have potential influence on patients management and therapy. PMID- 10093012 TI - [Therapy with CSE inhibitors--more than lipid lowering?]. AB - An elevated plasma cholesterol concentration is an established risk factor for coronary heart disease. Dietary and drug interventions with fibrate, nicotinic acid and colestyramine have resulted in a decreased rate of major coronary events but failed to decrease mortality. Studies using the more potent lipid lowering statins have shown remarkable results in primary (WOSCOPS, AFCAPS, TexCAPS) and secondary prevention (4S, CARE, LIPID). The use of these drugs reduced the risk for coronary events as well as the need for interventions. Furthermore, improvement of angina has been shown in several studies. In high-risk patients coronary heart disease associated mortality and overall mortality was reduced. Lowering of cholesterol was shown to be effective in women, older people and diabetics. Lipid lowering improves prognosis after heart transplant and could be an alternative to PTCA. Furthermore it was also shown that cholesterol lowering reduces the incidence of stroke. New mechanisms are discussed to explain the rapid onset of clinical improvement. Among these are: influences on inflammatory processes in the plaque, on vascular smooth muscle activity, on coagulation and on endothelial dysfunction. PMID- 10093013 TI - Lipid lowering and beyond: results from the CARE study on lipoproteins and inflammation. Cholesterol and Recurrent Events. AB - The plasma LDL concentration in firmly established as a cause of coronary heart disease. However, the efficacy of LDL lowering may reach a limit when it is brought well below average during treatment. The Cholesterol and Recurrent Events (CARE) trial compared pravastatin and placebo in patients who had experienced myocardial infarction who had average concentrations of total cholesterol < 240 mg/dl (baseline mean 209 mg/dl) and LDL cholesterol (LDL) 115 to 174 mg/dl (mean 139 mg/dl). Pravastatin reduced coronary death or recurrent myocardial infarction by 24%. In multivariate analysis, the LDL concentration achieved during follow-up was a significant predictor of the coronary event rate. The relationship was nonlinear since the coronary event rate declined as LDL decreased during follow up from 174 to approximately 125 mg/dl, but no further decline was seen in the LDL range from 125 to 71 mg/dl. A major ongoing effort in the CARE trial concerns the identification of non-LDL mediated mechanisms of coronary events. Chronic low grade inflammation has recently been identified as an important new risk factor for coronary artery disease. Two markers of inflammation, C-reactive protein (CRP) and serum amyloid A (SAA), were measured in patients in the CARE trial who suffered a recurrent myocardial infarction or coronary death and in those who did not have these recurrent events. Levels of both inflammatory markers were significantly higher among post-myocardial infarction patients who subsequently developed recurrent coronary events. This association was significant in the patients who were treated with placebo but not in those in the pravastatin group. In conclusion, attaining an LDL of < 125 mg/dl may be sufficient treatment of LDL concentrations, removing the adverse effect of LDL on coronary events. These findings also raise the possibility that the efficacy of pravastatin may partly result from anti-inflammatory as well as lipid lowering properties. PMID- 10093014 TI - [Plaque stabilization by LDL apheresis?]. AB - Vulnerable lipid-rich plaques are often the cause of atherothrombotic events leading to unstable angina and/or to acute myocardial infarction. Consequent long term LDL-lowering by drugs as shown by the most important intervention studies lead to plaque stabilization as shown by the significant reduction of myocardial reinfarction. First studies in patients undergoing regular extracorporeal LDL elimination indicate, that clinical events might be reduced much earlier as by drug therapy alone: A more than 60% reduction of LDL at weekly intervals is obviously associated with an early regression of lipid-rich vascular lesions. LDL apheresis, mainly by HELP and by double filtration reduces the shear-stress of the flowing blood on vulnerable plaques either by its effect on plasmaviscosity and/or on the vasomotoric reserve thus leading to a lower peripheral arterial resistance. Furthermore oxidized LDL, which might counteract plaque stabilisation by its inflammatory effects are effectively eliminated by LDL-apheresis. The affinity of different LDL-apheresis procedures to coagulation factors normalizes hypercoagulatory states thus avoiding atherothrombotic events at the site of vulnerable or erosive plaques. PMID- 10093015 TI - [Endothelial dysfunction--assessment of current status and approaches to therapy]. AB - The vascular endothelium is the inner lining of all blood vessels and serves as an important autocrine and paracrine organ, that regulates vascular wall functions. Because of its strategic location between the circulating blood and the vascular wall, the endothelium interacts with cellular and neurohumoral mediators, thus controlling vascular contractile state and cellular composition. The vascular endothelium maintains vascular homeostasis by modulating blood vessel tone, by regulating local cellular growth and extracellular matrix deposition and by controlling hemostatic as well as inflammatory responses. One of the best characterized and most important substances released from the endothelium is nitric oxide (NO). NO is a soluble gas which is continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutively expressed nitric oxide synthase. The most important stimuli represent physical factors such as shear stress and pulsatile stretching of the vessel wall as well as circulating and locally released vasoactive substances. The endothelium can be seen as a biosensor, reacting to a large variety of stimuli and therefore maintaining adequate NO release. A large number of risk factors for atherosclerosis including hypercholesterolemia, systemic hypertension, smoking and diabetes have been associated with impaired endothelial NO-mediated vasodilation. "Endothelial dysfunction" is an early marker of atherosclerosis and may be closely related to the disease process. In acute coronary syndromes dysfunctional endothelium may trigger the devastating event of plaque rupture by promoting adhesion of leukocytes, vasoconstriction, activation of platelets and thrombos formation. Atherosclerotic blood vessels are further characterized by activation through zytokines and expression of cellular adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and endothelial-leukocyte adhesion molecule-1 (E Selectin). After adhesion to the endothelium mononuclear cells migrate to the subendothelial space to take up oxidized LDL, thus transforming into foam cells, a hall mark of early atherosclerotic lesions. A number of conditions including infection with Chlamydia pneumoniae may cause continuous activation of the endothelium and inflammation of the vessel wall. Continuous endothelial dysfunction and activation, caused by risk factors and infection, represent the basis for atherogenesis and acute coronary syndromes. PMID- 10093017 TI - Episodes of care: theoretical frameworks versus current operational realities. AB - BACKGROUND: Fundamental changes in the structure of the health care industry have stimulated the need for improved definitions of output and for better methods of organizing utilization data into appropriate units. Although the "episode of care" concept has existed since the 1960s, its recognition as integral to the management of health care cost and utilization is relatively recent. Conceptually, episodes of care represent a meaningful unit of analysis for assessing the full range of primary and specialty services provided in treating a particular health problem. Proprietary episode software grouper products are currently being used by health care organizations for the purposes of provider profiling, clinical benchmarking, disease management, and quality measurement. DESCRIPTION OF EPISODE GROUPER SOFTWARE PRODUCTS: Four episode grouper products are described that use a computerized approach for developing episodes of care from administrative data. They are compared on several characteristics, including purpose, case-mix adjustment, comprehensiveness, and clinical flexibility. Their differences in episode construction, such as how the start points and endpoints of an episode are defined, are also delineated. CONCLUSIONS: Episode groupers are critical to the analysis of health care delivery, since they focus on the entire process of care. Although all the groupers reviewed have many strengths, much developmental work still needs to occur in order to standardize the measurement and operationalization of episodes of care as units of analysis. Furthermore, until the data sources used are more valid and reliable, they will at best remain gross screening measures of quality. PMID- 10093016 TI - [Significance of silent myocardial ischemia for identification and optimal therapy of patients with latent coronary heart disease. Is there a marker for prognostic indication for PTCA?]. AB - Although percutaneous transluminal coronary angioplasty (PTCA) improves the symptomatic status and exercise capacity of patients with coronary artery disease and stale or unstable angina pectoris, a beneficial effect on long-term prognosis has not been convincingly demonstrated so far. In totally asymptomatic patients with coronary artery disease, however, decision to undertake PTCA is greatly influenced by prognostic considerations. Usually, detection of silent myocardial ischemia in non-invasive examinations (exercise stress testing, ambulatory electrocardiographic monitoring) precedes the angiographic diagnosis of coronary artery disease in these patients. PMID- 10093018 TI - The accuracy of hospital reports of organ donation eligibility, requests, and consent: a cross-validation study. AB - BACKGROUND: Many states require hospitals to complete a form for each patient who dies, reporting the patient's organ and tissue donation eligibility status, whether a request was made, and the outcome of the request. A study was conducted to determine the accuracy of state-required forms in documenting organ eligibility and procurement activities. METHODS: Four Level 1 trauma hospitals in northeast Ohio were sampled by using a weekly review of all deaths. Detailed chart reviews were conducted on a total of 2,270 deaths occurring during a six month period in 1997, interviews with health care providers and staff members at organ procurement organizations were held, and records of the local Ohio Department of Health (ODH) were reviewed. Agreement between these data sources and the ODH form were compared to evaluate whether the ODH form correctly documented patients' eligibility status, occurrence of a donation request, and donation request outcome. Descriptive statistics and sensitivity and specificity analyses were completed. RESULTS: The quality of the information provided through these forms was variable. Problems included missing, inaccurate, and contradictory data. State reporting forms overrepresented the size of the organ donor pool by about four times, and requests for donation and consent to donation were inaccurately reported. Hospital form completion rates ranged from 12% to 82.6%. CONCLUSIONS: Basing the evaluation of hospital or statewide organ procurement performance on summary information provided by these forms would lead to an inaccurate picture of organ procurement activities in the state. PMID- 10093019 TI - The utility of decision support, clinical guidelines, and financial incentives as tools to achieve improved clinical performance. AB - BACKGROUND: Whether one seeks to reduce inappropriate utilization of resources, improve diagnostic accuracy, increase utilization of effective therapies, or reduce the incidence of complications, the key to change is physician involvement in change. Unfortunately, a simple approach to the problem of inducing change in physician behavior is not available. COMPREHENSIVE CLINICAL GUIDELINES: There is a generally accepted view that expert, best-practice guidelines will improve clinical performance. However, there may be a bias to report positive results and a lack of careful analysis of guideline usage in routine practice in a "postmarketing" study akin to that seen in the pharmaceutical industry. FINANCIAL INCENTIVES: Systems that allow the reliable assessment of quality of outcomes, efficiency of resource utilization, and accurate assessment of the risks associated with the care of given patient populations must be widely available before deciding whether an incentive-based system for providing the full range of medical care is feasible. DECISION SUPPORT: Decision support focuses on providing information, ideally at the "point of service" and in the context of a particular clinical situation. Rules are self-imposed by physicians and are therefore much more likely to be adopted. CONCLUSION: As health care becomes corporatized, with increasing numbers of physicians employed by large organizations with the capacity to provide detailed information on the nature and quality of clinical care, it is possible that properly constructed guidelines, appropriate financial incentives, and robust forms of decision support will lead to a physician-led, process improvement approach to more rational and affordable health care. PMID- 10093020 TI - Physicians taking the lead to improve patient care. AB - BACKGROUND: "Quality: putting clinicians in the Cockpit"--a conference about producing measurable, clinically important improvement in the quality and cost of health care--was sponsored by the Institute for Clinical Systems Integration, based in Minneapolis, and the Institute for Healthcare Improvement, in Boston. More than 200 persons, including clinicians engaged in clinical improvement activities, medical directors, medical group administrators, and quality improvement staff and researchers, attended the Minneapolis meeting, held October 1-3, 1997. PHYSICIANS AS LEADERS: According to James Reinertsen, MD, who described the strategies that physician leaders can use, the leader's main role is to "establish an environment in which quality can thrive" by removing obstacles to quality improvement. DATA: IMPROVING CESAREAN SECTION RATES: Robert DeMott, MD, reported an initiative conducted in a region in which physicians had strongly held beliefs and long-held approaches to obstetric care. DATA LEADS TO DECISION SUPPORT TOOLS FOR CARDIAC CARE: William Nugent, MD, described the impact of the Northern New England Cardiovascular Disease Study Group, a voluntary regional initiative to improve outcomes in patients undergoing coronary bypass grafting. EVIDENCE-BASED IMPROVEMENT--THE GROUP HEALTH EXPERIENCE: Michael Stuart, MD, commented on Group Health's efforts to develop clinical guidelines so that clinical decisions are based on the best available evidence. SHARING INFORMATION IN A COMPETITIVE ENVIRONMENT: Gordon Mosser, MD, and Donald Berwick, MD, discussed the challenges clinicians face in sharing information in a competitive environment. In a session on making sense of information, Paul Batalden, MD, noted, "There is lots of information; if it were only clear who to send it to for the improvement of health care." PMID- 10093021 TI - How to design and implement your children's services outcomes management program: a practical training institute for child welfare, behavioral health, and substance abuse services. AB - During the two-day conference, attendees met in groups to discuss the information provided and concerns or problems they were having regarding outcomes within their own organizations. Subjects addressed included current and future outcomes measurement requirements, determination of good outcomes measures for behavioral health care organizations, effective collection of outcomes data, and use of outcomes data to improve services. Throughout the conference sessions, attendees were reminded to use the outcomes measures and their results to manage and change; include all the pertinent (internal and external) players that will help with the measurement process; define a specific strategy to follow; and keep data collection simple (if people aren't able to collect the data, then collection won't occur). PMID- 10093022 TI - Bone poroelasticity. AB - Poroelasticity is a well-developed theory for the interaction of fluid and solid phases of a fluid-saturated porous medium. It is widely used in geomechanics and has been applied to bone by many authors in the last 30 years. The purpose of this work is, first, to review the literature related to the application of poroelasticity to the interstitial bone fluid and, second, to describe the specific physical and modeling considerations that establish poroelasticity as an effective and useful model for deformation-driven bone fluid movement in bone tissue. The application of poroelasticity to bone differs from its application to soft tissues in two important ways. First, the deformations of bone are small while those of soft tissues are generally large. Second, the bulk modulus of the mineralized bone matrix is about six times stiffer than that of the fluid in the pores while the bulk moduli of the soft tissue matrix and the pore water are almost the same. Poroelasticity and electrokinetics can be used to explain strain generated potentials in wet bone. It is noted that strain-generated potentials can be used as an effective tool in the experimental study of local bone fluid flow, and that the knowledge of this technique will contribute to the answers of a number of questions concerning bone mineralization, osteocyte nutrition and the bone mechanosensory system. PMID- 10093023 TI - The conflicting requirements of laxity and conformity in total knee replacement. AB - Bearing surfaces of total condylar knees which are designed with a high degree of conformity to produce low stresses in the polyethylene tibial insert may be overconstrained. This study determines femoral and tibial bearing surface geometries which will induce the least destructive fatigue mechanisms in the polyethylene whilst conserving the laxity of the natural knee. Sixteen knee designs were generated by varying four parameters systematically to cover the range of contemporary knee designs. The parameters were the femoral frontal radius (30 or 70 mm), the difference between the femoral and tibial frontal radii (2 or 10 mm), the tibial sagittal radius (56 or 80 mm) and the posterior-distal transition angle (-8 or -20 degrees), which is the angle at which the small posterior arc of the sagittal profile transfers to the larger distal arc. Rigid body analyses determined the anterior-posterior and rotational motions as well as the contact points during the stance phase of gait for the different designs. In addition, a damage function which accumulated the fluctuating maximum shear stresses was used to predict the susceptibility to delamination wear of the polyethylene (damage score). This study predicted that of the 16 designs, the knee with a frontal radius of 70 mm, a difference in femoral and tibial frontal radii of 2 mm, a tibial sagittal radius of 80 mm and a posterior distal transition angle of -20 degrees would satisfy the conflicting needs of both resistance to delamination wear and natural kinematics. PMID- 10093024 TI - Effects of wave reflection timing on left ventricular mechanics. AB - The aim of this study was to evaluate how the timing of the pressure pulse produced by peripheral reflection affects the left ventricle (stroke volume, ventricular work, coronary driving pressure). Ten isolated perfused rabbit hearts were attached to rubber tubes of different lengths (0.5, 0.8 and 1 m) connected to a hydraulic resistance. The different lengths produced reflections at different times and the reflected pulse returned to the ventricle in early (at 84 ms), middle (at 134 ms) and late systole (at 168 ms) for the three tubes, respectively. The loading parameters (ventricular filling pressure and hydraulic resistance) were not changed during the procedure. Ventricular and aortic pressure and aortic flow were monitored continuously and recorded; cardiac cycle was fixed at 800 ms. An operator-independent procedure was used to calculate instantaneous and total systolic external work, mean diastolic aorto-ventricular pressure difference and ventricular stroke volume. RESULTS: The mean value of stroke volume for the three different length rubber tubes was 320 +/- 71, 348 +/- 77 and 368 +/- 87 microliters, respectively. The mean value of total external work was 20.3 +/- 8.3, 22.5 +/- 8.8 and 24.2 +/- 9.6 mJ, respectively. The mean aortoventricular pressure difference was 40 +/- 12, 46 +/- 13, 50 +/- 14 mmHg, respectively (1 mmHg = 133 Pa). The differences between the parameters measured in the three conditions were statistically significant (p < 0.05). A reduction of reflection timing, reduces, on a pure mechanical basis, cardiac output and external ventricular work and has a negative effect on coronary driving pressure. PMID- 10093025 TI - Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. AB - A new quantitative tissue differentiation theory which relates the local tissue formation in a fracture gap to the local stress and strain is presented. Our hypothesis proposes that the amounts of strain and hydrostatic pressure along existing calcified surfaces in the fracture callus determine the differentiation of the callus tissue. The study compares the local strains and stresses in the callus as calculated from a finite element model with histological findings from an animal fracture model. The hypothesis predicts intramembranous bone formation for strains smaller approximately +/- 5% and hydrostatic pressures smaller than +/- 0.15 MPa. Endochondral ossification is associated with compressive pressures larger than about -0.15 MPa and strains smaller than +/- 15%. All other conditions seemed to lead to connective tissue or fibrous cartilage. The hypothesis enables a better understanding of the complex tissue differentiation seen in histological images and the mechanical conditions for healing delayed healing or nonunions. PMID- 10093026 TI - Leg stiffness primarily depends on ankle stiffness during human hopping. AB - When humans hop in place or run forward, they adjust leg stiffness to accommodate changes in stride frequency or surface stiffness. The goal of the present study was to determine the mechanisms by which humans adjust leg stiffness during hopping in place. Five subjects hopped in place at 2.2 Hz while we collected force platform and kinematic data. Each subject completed trials in which they hopped to whatever height they chose ("preferred height hopping") and trials in which they hopped as high as possible ("maximum height hopping"). Leg stiffness was approximately twice as great for maximum height hopping as for preferred height hopping. Ankle torsional stiffness was 1.9-times greater while knee torsional stiffness was 1.7-times greater in maximum height hopping than in preferred height hopping. We used a computer simulation to examine the sensitivity of leg stiffness to the observed changes in ankle and knee stiffness. Our model consisted of four segments (foot, shank, thigh, head-arms-trunk) interconnected by three torsional springs (ankle, knee, hip). In the model, increasing ankle stiffness by 1.9-fold, as observed in the subjects, caused leg stiffness to increase by 2.0-fold. Increasing knee stiffness by 1.7-fold had virtually no effect on leg stiffness. Thus, we conclude that the primary mechanism for leg stiffness adjustment is the adjustment of ankle stiffness. PMID- 10093027 TI - The effect of surface roughness on the stress adaptation of trabecular architecture around a cylindrical implant. AB - The effect of implant-bone bonding and the effect of implant surface roughness on bone remodeling near the bone-implant interface were studied by using a surface remodeling theory and the boundary element method. The study has shown that implant attachment plays an important role in bone remodeling near the implant. It has been observed in animal experiments and in clinical situations that the remodeled trabecular bone architecture around a cylindrical implant could vary, on one hand, from a hub surrounding the implant with a set of external spokes to, on the other hand, a hubless situation in which a set of spokes attach directly to the implant. It is shown here that the difference in these structures may be attributed to differences in implant attachment. The results show that the bone with perfect bonding or roller boundary condition without a gap remodeled to a hubless spoke trabecular bone architecture. On the other hand, the roller boundary condition with a specified gap yielded a spoke trabecular architecture with a hub or ring surrounding the implant. These quantitative results mirror the experimental and clinical observations. It is concluded that the hub is a consequence of the gap and not a consequence of the lack of friction between the implant and the bone. PMID- 10093028 TI - Time-resolved X-ray diffraction from tendon collagen during creep using synchrotron radiation. AB - In order to understand the molecular mechanism of relaxation phenomena in collagenous tissue, time-resolved, small-angle X-ray diffraction measurements were performed on bovine Achilles tendon collagen under creep. A tension-induced increase in the 67 nm period (D-period) was observed, and the strain in the D period, epsilon D, was found to be almost proportional to the external force per unit cross-sectional area (average stress) of the specimen. With an increase in epsilon D, a change in the ratio of intensities of the third-order reflection peak of the D-period to that of the second-order peak was also observed. The increase in epsilon D was decomposed into three elementary processes of D-period deformation, which are presented on the basis of the Hodge-Petruska model: (1) molecular elongation, (2) increase in gap region, and (3) relative slippage of lateral adjoining molecules. Up to 8 MPa of average stress, the contribution to epsilon D originated mostly from only mode (1). At more than 10 MPa of average stress, modes (2) and (3) also contributed to fibril elongation. For epsilon D by molecular elongation (mode (1)), the time dependence of the D-period change in the immediate response region is a sharply shaped step function, while the contribution to epsilon D by molecular rearranging modes gives a slight creep nature at the immediate response region in the time dependence of epsilon D. Because this creep nature is observed at the immediate response, it is related qualitatively to the KWW function in a stress-relaxation modulus of collagenous tissue observed in an immediate response region (Sasaki et al. (1993). Journal of Biomechanics 26, 1369-1376). The elementary process of KWW-type relaxation is concluded to be related to the tension-induced molecular rearrangement within a D period. PMID- 10093029 TI - Surface friction in near-vertex head and neck impact increases risk of injury. AB - A computational head-neck model was developed to test the hypothesis that increases in friction between the head and impact surface will increase head and neck injury risk during near-axial impact. The model consisted of rigid vertebrae interconnected by assemblies of nonlinear springs and dashpots, and a finite element shell model of the skull. For frictionless impact surfaces, the model reproduced the kinematics and kinetics observed in near-axial impacts to cadaveric head-neck specimens. Increases in the coefficient of friction between the head and impact surface over a range from 0.0 to 1.0 resulted in increases of up to 40, 113, 9.8, and 43% in peak post-buckled resultant neck forces, peak moment at the occiput-C1 joint, peak resultant head accelerations, and HIC values, respectively. The most dramatic increases in injury-predicting quantities occurred for COF increases from 0.0 to 0.2, while further COF increases above 0.5 generally produced only nominal changes. These data suggest that safety equipment and impact environments which minimize the friction between the head and impact surface may reduce the risk of head and neck injury in near-vertex head impact. PMID- 10093031 TI - Quantitative anatomy of the lumbar musculature. AB - This paper describes the anatomy of the musculature crossing the lumbar spine in a standardized form to provide data generally suitable for static biomechanical analyses of muscle and spinal forces. The muscular anatomy from several sources was quantified and transformed to the mean bony anatomy of four young healthy adults measured from standing stereo-radiographs. The origins, insertions and physiological cross-sectional area (PCSA) of 180 muscle slips which act on the lumbar spine are given relative to the bony anatomy defined by the locations of 12 thoracic and five lumbar vertebrae, and the sacrum, and the shape and positions of the 24 ribs. The broad oblique abdominal muscles are each represented by six vectors and an appropriate proportion of the total PCSA was assigned to each to represent the muscle biomechanics. PMID- 10093030 TI - The role of the lamellar interface during torsional yielding of human cortical bone. AB - Fragility fractures are a result of alterations in bone quantity, tissue properties, applied loads, or a combination of these factors. The current study addresses the contribution of cortical bone tissue properties to skeletal fragility by characterizing the shear damage accumulation processes which occur during torsional yielding in normal bone. Samples of human femoral cortical bone were loaded in torsion and damaged at a post-yield twist level. The number of microcracks within osteons, interstitial tissue, and along cement lines were assessed using basic fuchsin staining. Damage density measures (number of cracks/mm2) were correlated with stiffness degradation and changes in relaxation. Damaged samples exhibited a wide variation in total microcrack density, ranging from 1.1 to 43.3 cracks/mm2 with a mean density of 19.7 +/- 9.8 cracks/mm2. Lamellar interface cracks comprised more than 75% of the total damage, indicating that the lamellar interface is weak in shear and is a principal site of shear damage accumulation. Damage density was positively correlated with secant stiffness degradation, but only explained 22% of the variability in degradation. In contrast, damage density was uncorrelated with the changes in relaxation, indicating that a simple crack counting measure such as microcrack density was not an appropriate measure of relaxation degradation. Finally, a nonuniform microcrack density distribution was observed, suggesting that internal shear stresses were redistributed within the torsion samples during post-yield loading. The results suggested that the lamellar interface in human cortical bone plays an important role in torsional yielding by keeping cracks physically isolated from each other and delaying microcrack coalescence in order to postpone the inevitable formation of the fatal crack. PMID- 10093032 TI - Discrete wavelet transform: a tool in smoothing kinematic data. AB - Motion analysis systems typically introduce noise to the displacement data recorded. Butterworth digital filters have been used to smooth the displacement data in order to obtain smoothed velocities and accelerations. However, this technique does not yield satisfactory results, especially when dealing with complex kinematic motions that occupy the low- and high-frequency bands. The use of the discrete wavelet transform, as an alternative to digital filters, is presented in this paper. The transform passes the original signal through two complementary low- and high-pass FIR filters and decomposes the signal into an approximation function and a detail function. Further decomposition of the signal results in transforming the signal into a hierarchy set of orthogonal approximation and detail functions. A reverse process is employed to perfectly reconstruct the signal (inverse transform) back from its approximation and detail functions. The discrete wavelet transform was applied to the displacement data recorded by Pezzack et al., 1977. The smoothed displacement data were twice differentiated and compared to Pezzack et al.'s acceleration data in order to choose the most appropriate filter coefficients and decomposition level on the basis of maximizing the percentage of retained energy (PRE) and minimizing the root mean square error (RMSE). Daubechies wavelet of the fourth order (Db4) at the second decomposition level showed better results than both the biorthogonal and Coiflet wavelets (PRE = 97.5%, RMSE = 4.7 rad s-2). The Db4 wavelet was then used to compress complex displacement data obtained from a noisy mathematically generated function. Results clearly indicate superiority of this new smoothing approach over traditional filters. PMID- 10093033 TI - Accuracy of cancellous bone volume fraction measured by micro-CT scanning. AB - Volume fraction, the single most important parameter in describing trabecular microstructure, can easily be calculated from three-dimensional reconstructions of micro-CT images. This study sought to quantify the accuracy of this measurement. One hundred and sixty human cancellous bone specimens which covered a large range of volume fraction (9.8-39.8%) were produced. The specimens were micro-CT scanned, and the volume fraction based on Archimedes' principle was determined as a reference. After scanning, all micro-CT data were segmented using individual thresholds determined by the scanner supplied algorithm (method I). A significant deviation of volume fraction from method I was found: both the y intercept and the slope of the regression line were significantly different from those of the Archimedes-based volume fraction (p < 0.001). New individual thresholds were determined based on a calibration of volume fraction to the Archimedes-based volume fractions (method II). The mean thresholds of the two methods were applied to segment 20 randomly selected specimens. The results showed that volume fraction using the mean threshold of method I was underestimated by 4% (p = 0.001), whereas the mean threshold of method II yielded accurate values. The precision of the measurement was excellent. Our data show that care must be taken when applying thresholds in generating 3-D data, and that a fixed threshold may be used to obtain reliable volume fraction data. This fixed threshold may be determined from the Archimedes-based volume fraction of a subgroup of specimens. The threshold may vary between different materials, and so it should be determined whenever a study series is performed. PMID- 10093034 TI - Quantitation of T-cell receptor frequencies by competitive PCR: generation and evaluation of novel TCR subfamily and clone specific competitors. AB - T cell receptor (TCR) V gene usage has been used to characterize the immune response to bacteria, viruses, allografts, self antigens, tumor antigens, and superantigens. Sensitive methods to detect changes in the frequency of TCR subfamilies or clonotypes might be useful in evaluating the efficacy of vaccines against infectious agents, immunotherapy treatments for cancer patients, or the status of autoimmune diseases. Two HLA-A2 restricted CTL clones expressing BV17 were isolated from a tumor infiltrating lymphocytes (TIL) culture of a patient with metastatic melanoma. One clone recognized the MART-1(27-35) peptide and the other clone recognized the gp100(209-217) peptide. The frequency of each of these CTL clones in an expanding TIL culture was measured using a novel competitive RT PCR (cRT-PCR) strategy. cRT-PCR uses a single primer pair to amplify template cDNA simultaneously with a modified DNA competitor molecule. A rapid two-step PCR technique followed by a single cloning step was used to generate a TCR BV17 subfamily specific competitor or competitors specific for the MART-1(27-35) reactive CTL clone (CO-41) and the gp100(209-217) reactive CTL clone (CO-4). Each competitor contained a segment of the TCR BC region that served as an internal reference standard. Using the BV17 competitor we were able to accurately and reproducibly measure cDNA templates at a frequency as low as 1/100,000 using cDNA samples of known TCRBV subfamily composition. This competitor was used to monitor the frequency of BV17 expressing T cells in the TIL and PMBC of a patient with metastatic melanoma. We determined that the frequency of BV17 expressing T cells increased from 4.5% of the culture on day 35 to 60.7% of the culture on day 58. Expansion of the BV17 subfamily was due predominantly to the expansion of the CO 4 clone. This method can be used to meaningfully quantify the precursor frequency of T cell mRNA in prepared samples via TCR subfamily or TCR sequence specific primers. PMID- 10093035 TI - THF-gamma 2-mediated reduction of pulmonary metastases and augmentation of immunocompetence in C57BL/6 mice bearing B16-melanoma. AB - Immunotherapy with the immunomodulating thymic humoral factor-gamma 2 (THF-gamma 2) octapeptide, combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy, will be used for enhancing host immune response to arrest pulmonary metastases of a B16-F10.9 melanoma tumor. In this experimental model of pulmonary metastasis, the highly metastatic B16-F10.9 melanoma tumor cells (2 x 10(5)) were inoculated into the footpad of mice to form a primary tumor. The tumor-bearing leg was surgically removed on reaching the size of 5.5 mm, which resulted in the appearance of metastases in the lungs of the animals. After tumor excision, mice were treated intraperitoneally with a single dose of BCNU (20 or 35 mg/kg) followed by a series of intraperitoneal THF-gamma 2 injections (1 microgram/0.5 ml/injection). Relative to untreated mice and those receiving chemotherapy alone, the antitumor action of the combined THF-gamma 2 chemoimmunotherapy protocol was significantly augmented according to the following in vivo parameters: (a) decreased postsurgical spontaneous metastatic burden; (b) prolonged survival time; (c) increased resistance to tumor cell challenge; and (d) massive infiltration of lymphocytes, polymorphonuclear cells, and macrophages in the lung tissue. The THF-gamma 2 immunotherapy also prevented a decrease in lymphocyte reactivity, otherwise induced by the tumor/BCNU chemotherapy. THF-gamma 2 immunotherapy resulted in restoration of the response to Lipopolysaccharide mitogenic stimulation and the allogeneic response. Our data suggest that postoperative THF-gamma 2 immunotherapy could be a valuable adjunct to anticancer chemotherapy as a treatment for metastatic arrest of melanoma tumor. PMID- 10093036 TI - Intrathecal administration of an anti-ganglioside antibody results in specific accumulation within meningeal neoplastic xenografts in nude rats. AB - Intrathecal (i.t.) administration of monoclonal antibodies (MAbs) represents a new therapeutic approach for the treatment of leptomeningeal (LM) cancer, which is presently rapidly fatal. In this study, we quantitated the accumulation of an intrathecally administered anti-ganglioside GD2 MAb (3F8) within leptomeningeal neoplastic xenografts of GD2 positive melanoma and neuroblastoma in nude rats by measuring concentrations of radiolabeled and unmodified MAbs and by immunohistochemistry. Intrathecal administration of 125I-3F8 resulted in area under the tissue concentration versus time curve (AUC) values in SK-MEL-1 melanoma xenografts (53.1 microCi*h/g) that were 14-fold greater than in corresponding blood (3.9 microCi*h/g), whereas i.t. administration of a control nonspecific MAb resulted in AUC values in tumors (7.1 microCi*h/g) that were less than those in blood (9.5 microCi*h/g). Administration of acetazolamide and furosemide, which slow the clearance of IgG MAb from rat cerebrospinal fluid resulted in a fivefold increase in AUC of 125I-3F8 in melanoma (262.9 microCi*h/g). The highest concentration of 125I-MAb in tumor after i.t. administration was seen at the first sampling time of 2 h, and this fell to 50% of maximum values at 8-16 h. Pharmacokinetic analysis of unmodified MAb demonstrated retention of MAb within the LM space of animals with tumor. The concentration of MAb 3F8 appearing in serum after i.t. administration was 10-fold lower in animals with melanoma xenografts than in those without tumor implants. Radiation dose estimates after intraventricular administration of radiolabeled MAb indicated delivery to tumor of 1,870 rad/mCi of 125I-3F8 but only 40 rad/mCi of 125I-labeled control MAb. These results indicate that anti-ganglioside MAbs and other MAbs directed to tumor-associated antigens are excellent candidates for i.t. treatment of appropriate leptomeningeal cancers in humans. PMID- 10093037 TI - Coinfusion of irradiated splenocytes with low titer tumor-infiltrating lymphocytes augments antitumor efficacy in adoptive immunotherapy. AB - We hypothesized that adoptively increasing the density of antigen-presenting cells (APCs) at a tumor site would improve tumor-infiltrating lymphocyte (TIL) in vivo antitumor efficacy. Irradiated splenocytes were used as crude APCs. Alone, they did not have in vitro antitumor activity nor did they augment TIL efficacy in vitro. Pulmonary metastases were established by intravenous (i.v.) injection of 5 x 10(5) MC-38 tumor into irradiated C57B1/6 mice (500 cGy). After 3 days, MC 38 TIL (0.1, 0.5, and 1 x 10(6) cells) +/- irradiated splenocytes (5,000 cGy) as APCs were administered intravenously (0.25, 0.5, and 1 x 10(6) cells) to each group (n = 5/group). Interleukin-2 (60,000 IU) was injected intraperitoneally three times daily for 3 days. Mice were sacrificed 9 days later and metastases elaborated in blinded fashion. A titer of 1 x 10(6) TIL, completely eradicated pulmonary metastases. In two consecutive experiments, when increasing titers of irradiated splenocytes were coinfused with a constant titer of TIL that did not completely eradicate pulmonary metastases, a moderate reduction in pulmonary metastases was observed. The contribution of splenocytes to an improvement in TIL antitumor efficacy was not altered when irradiated splenocytes derived from mice bearing 10-day subcutaneous MC-38 tumors were used. The coinfusion of nonirradiated splenocytes did not improve TIL antitumor in vivo activity. Activated B cells (expressing ICAM-1, B7.1, and B7.2) had no effect on in vitro tumor lysis and did not augment in vivo TIL efficacy. The results show a modest but statistically significant improvement in adoptive immunotherapy antitumor efficacy with fewer TIL by coinfusion of irradiated splenocytes. Further studies to characterize the active potential APC cell subpopulation and to clarify the mechanism(s) responsible for in vivo augmentation of TIL antitumor efficacy are in progress. PMID- 10093038 TI - Gene gun-mediated IL-12 gene therapy induces antitumor effects in the absence of toxicity: a direct comparison with systemic IL-12 protein therapy. AB - Using three murine tumor models, we compared the antitumor efficacy and certain physiological effects of an in vivo interleukin-12 (IL-12) gene therapy protocol and a systemic IL-12 protein therapy protocol. An IL-12 cDNA gene construct was administered in situ into skin tissue via gene gun delivery, and recombinant IL 12 protein was administered subcutaneously at a dose of 1 microgram/mouse/treatment. Both treatment regimes induced a comparable level of regression of established intradermal MethA sarcomas. In B16 melanoma and P815 mastocytoma models, antitumor efficacy of IL-12 protein therapy appeared to be slightly higher than that of IL-12 gene therapy; however, the protein therapy protocol in this comparative study resulted in a high level of mortality of mice. It was also demonstrated that IL-12 gene therapy, in contrast to the IL-12 protein therapy, was not associated with weight loss, splenomegaly, increased Ly6 antigen expression in the spleen, or visible signs of toxicity, such as fur ruffling and lethargy. Moreover, serum levels of interferon-gamma (IFN-gamma) induced in response to IL-12 gene therapy were 300-1000 times lower than those induced by the systemic IL-12 protein administration. Together, these results suggest that gene gunmediated in vivo delivery of IL-12 cDNA may be considered as a safer alternative to IL-12 protein therapy for certain human cancers. PMID- 10093039 TI - Regimens with or without interferon-alpha as treatment for metastatic melanoma and renal cell carcinoma: an overview of randomized trials. AB - The effect of interferon-alpha (IFN-alpha) as single agent or in combination in the treatment of metastatic malignant melanoma (MM) or of advanced renal cell carcinoma (RCC) has been widely explored in phase II trials. To evaluate the net benefit of IFN-alpha therapy in these diseases, we performed a meta-analysis comprising all available randomized trials comparing regimens with or without IFN alpha. Data were obtained from the Medline data base, and from the data bases at the National Cancer Institute, Schering-Plough, and Hoffmann-La Roche. A total of six published and five unpublished studies on metastatic MM, as well as six published and two unpublished studies on advanced RCC, comprising altogether 1,164 and 525 patients, respectively, fulfilled our criteria. In MM, the overall response rate for the IFN-alpha-containing regimens was 24% (range, 10-46%), compared with 17% (range, 5-30%) for those without IFN-alpha. In RCC, the overall response rate for IFN-alpha-containing regimens was 14% (range, 4-33%), and 8% (range, 3-27%) for those without IFN-alpha. A meta-analysis showed that regimens including IFN-alpha improved response rates compared with regimens without IFN alpha. The pooled odds ratio (OR) for improved response with IFN-alpha in metastatic MM was 0.65 [95% confidence interval (CI) 0.48 to 0.87], and in advanced RCC the OR was 0.47 (95% CI 0.26-0.85). In five metastatic MM trials and three RCC trials, enough data on survival were reported to estimate a pooled 1 year OR for survival. The pooled OR for improved survival with IFN-alpha was 0.69 (95% CI 0.50-0.94), and 0.46 (95% CI 0.28-0.75), respectively. The data on both metastatic MM and advanced RCC indicate that better response rates and prolonged survival can be achieved with regimens including IFN-alpha. The clinical relevance of these findings will be discussed. PMID- 10093040 TI - A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. AB - Mutations in the ras genes occur in 20% of all human cancers. These genes, in turn, produce mutated proteins that are unique to cancer cells, rendering them distinguishable from normal cells by the immune system. Thus, mutated Ras proteins may form potential targets for immune therapy. We conducted a phase I/pilot clinical trial in patients with advanced cancers to test the toxicity and the ability to induce an immune response by vaccination with 13-mer mutated Ras peptides reflecting codon 12 mutations. These peptides corresponded to each of the patient's own tumor Ras mutation. Patients were vaccinated monthly x3 subcutaneously with the specific Ras peptide along with Detox adjuvant (RiBi ImmunoChem Research, Inc., Hamilton, MT, U.S.A.) at one of five different peptide dose levels (100, 500, 1,000, 1,500, and 5,000 micrograms). Three out of 10 evaluable patients generated a mutant Ras specific CD4+ and/or CD8+ T-cell immune response. The CD8+ cytotoxic cells specific for Gly to Val mutation at codon 12 were capable of lysing an HLA-A2-matched tumor cell line carrying the corresponding mutant but not the wild-type ras gene. The treatment has been well tolerated with no evidence of serious acute or delayed systemic side effects on any of the five dose levels. We demonstrated that we can generate in cancer patients specific T-lymphocyte responses that detect single amino acid differences in Ras oncoproteins. Neither the immune responses nor the minor side effects seen were found to be dose dependent. This approach may provide a unique opportunity for generating a tumor-directed therapy. Also, in vitro stimulation of these cells with the corresponding peptide generated specific T-cell lines that could be used for adoptive immune therapy. PMID- 10093041 TI - Recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and autologous melanoma vaccine mediate tumor regression in patients with metastatic melanoma. AB - In mice, significant immunoprotection was achieved using B16 melanoma cells transfected with granulocyte-macrophage colony-stimulating factor (GM-CSF) as vaccines (Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993;90:3539-43). The aim of this study is to test the hypothesis that recombinant human GM-CSF (rhGM-CSF) injected with autologous melanoma vaccine may result in tumor rejection in melanoma patients. Twenty stage IV melanoma patients were treated as outpatients with multiple cycles of autologous melanoma vaccine and bacillus Calmette-Guerin (BCG) plus rhGM-CSF injection in the vaccine sites. Two patients (10%) showed a complete response, with one patient showing resolution of subcutaneous, hepatic, and splenic metastases. In the second patient, buccal, subcutaneous, pulmonary, paraaortic, hepatic, splenic, and retroperitoneal metastases regressed completely. Two patients (10%) showed partial response, with regression of a paraaortic metastasis in one patient. In the second patient, there was shrinkage (> 75%) of a large hepatic lesion. One patient has been rendered free of disease after resection of a single pulmonary metastatic nodule. Three patients (15%) had stable disease during treatment but subsequently developed progression of disease. In 12 patients (60%), the disease progressed. Side effects were minimal. In a separate pilot study, 15 stage IV melanoma patients were also treated with autologous melanoma vaccine with BCG but not with rhGM-CSF; none responded. The fact that four patients showed objective responses to active specific immunotherapy with rhGM-CSF demonstrates that melanoma patients bearing a significant tumor burden may respond specifically to their autologous melanoma. PMID- 10093042 TI - Treatment of chronic myelogenous leukemia with interleukin-2: a phase II study in 21 patients. AB - We designed a phase II study to assess the activity of recombinant interleukin-2 (rIL-2) in patients with chronic myelogenous leukemia (CML). Study population included 11 patients in the chronic phase of CML (6 in hematologic remission and 5 with active disease), 6 patients in the accelerated phase, and 4 in blastic phase of CML. Patients received three 5-day cycles administrated every other week. rIL-2 was given as intravenous bolus infusions of 8 x 10(6) IU/m2 three times a day during cycle 1 and twice a day during cycles 2 and 3. Response to rIL 2 was assessed on day 45. No hematologic response was achieved in the patients with evaluable disease. One patient in hematologic remission with rIL-2 achieved a major response (from 72% to 9% Ph+ metaphases), and two patients had some degree of reduction of Ph+ metaphases. Responses were short-lived (< 6 months), but two of these three patients achieved a new cytogenetic response with interferon given post-rIL-2. A significant immune activation was achieved with rIL-2 including a marked increase in CD3+/CD25+ cells, CD56+ cells, and in natural killer/lymphokine activated killer cell cytotoxic activity. These results confirm preclinical studies, which showed that IL-2 has antileukemic activity in CML. However, the responses observed were short lived and restricted to a subgroup of patients with low disease burden. This invites further studies testing its impact in situations of minimal disease or in combination with other cytokines. PMID- 10093043 TI - Ophthalmologic evaluation in patients undergoing immunization with melanoma associated antigens. PMID- 10093044 TI - Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: I. Regional hemodynamics and myocyte remodeling. AB - A chronic pressure overload animal model was created in young guinea pigs by surgical constriction of the descending thoracic aorta. Hemodynamics, echocardiography and myocyte size characterization demonstrated compensated pressure overloaded left ventricular (LV) hypertrophy at 4 weeks (4 wk), and congestive left heart failure 6 months (6 mo) after aortic constriction. Compared to age-matched sham-surgery control groups, the cell length and length/width ratio of isolated LV myocytes were significantly increased at 6 mo but not at 4 wk. LV myocyte lengthening was statistically correlated to an increase in LV chamber dimension and diastolic wall stress at 6 mo. These data demonstrate that myocyte lengthening occurs in mechanical overload-induced congestive heart failure, contributes to LV chamber dilatation, and is associated with increased end-diastolic wall stress. Myocytes of the other three chambers remained morphometrically normal at 4 wk. Hypertrophy of left atrial (LA) and right ventricular and atrial myocytes was evident at 6 mo. Increases in both cell length and cross-sectional area contributed significantly to the hypertrophy in the three chambers. More than 85% of LV myocytes were binucleate and the binucleation remained unchanged in the sham-surgery group from the tested 4 wk to 6 mo time point. LV hypertrophy and failure showed no significant effects on the binucleation of LV myocytes. By contrast, over 96% of LA myocytes were mononucleate. The mononucleate percent of LA myocytes was not appreciably altered during either normal growth or hypertrophy induced by secondary hemodynamic overload due to LV failure. PMID- 10093045 TI - Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: II. Cytoskeletal remodeling. AB - The cytoskeleton is a major regulator of cell shape. To explore potential mechanisms for maladaptation of cardiac myocyte shape in pressure overload induced congestive heart failure, the abundance and organization of major intra- and extra-myofibrillar cytoskeleton of cardiac myocytes were examined with western blotting and confocal microscopy in guinea pigs with chronic aortic stenosis. It was found that: (1) the amount and distribution of alpha-actinin and myomesin remained unchanged at both the compensated hypertrophy and the congestive heart failure stages; (2) loss of titin was associated with myocyte lengthening in heart failure; (3) desmin protein and filaments in LV myocytes increased progressively with mechanical overload cardiac hypertrophy and subsequent heart failure; (4) a newly developed and validated quantitative confocal microscopic approach disclosed that the microtubule density in isolated LV myocytes increased by 21% at 4 weeks and by 48% 6 months after aortic constriction; (5) at the heart failure stage, microtubule density in LV myocytes showed a statistically significant inverse correlation to the LV maximum +dP/dt and a direct correlation to LV myocyte lengthening; (6) the increased microtubule density in LV myocytes in this model was not due to an increase in total tubulin; and (7) microtubule density in left atrial and right ventricular myocytes also increased when they underwent hypertrophy secondary to left heart failure. These results suggest that the down-regulation of titin and up-regulation of microtubule and desmin filaments may contribute to myocyte lengthening and malfunction in pressure overload congestive heart failure. PMID- 10093046 TI - Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: III. Intercalated disc remodeling. AB - The intercalated disc is an extremely important specialised structure of cardiac muscle. Intercalated disc alterations have been implicated in ischemic and dilated cardiomyopathy. With a chronic aortic stenosis guinea pig model, we demonstrated in the current study substantial intercalated disc remodeling during the progression of compensated left ventricular (LV) hypertrophy to congestive left heart failure. For the first time, we reported that although the abundance of beta-catenin and vinculin remained unchanged as shown by quantitative Western blotting, the normal distribution of beta-catenin and vinculin at intercalated disc sites was relocated into the cell body in a large fraction of LV myocytes. gamma-Catenin did not show a compensatory up-regulation at the intercalated disc sites where beta-catenin concentration was reduced. Both abundance and distribution of the transmembrane protein N-cadherin remained unchanged in this model. While co-labeled N-cadherin remained unchanged, quantitative confocal microscopy shows that the amount of connexin43 per LV myocyte decreased by 37% at the congestive heart failure stage but not at the compensated hypertrophy stage. No compensatory upregulation of connexin45 was evident when connexin43 was decreased in failing LV myocytes. The relocation of beta-catenin and vinculin away from intercalated discs in failing myocytes may impair the mechanical linkage between N-cadherin and thin filaments and adversely affect myocyte shape. Loss of connexin43 in LV myocytes may impair electrical coupling of adjacent myocytes. PMID- 10093047 TI - Redox regulation of signal transduction in cardiac and smooth muscle. AB - In addition to the well-known property of reactive oxygen species (ROS) to cause non-specific cellular damage, the potential role of ROS in regulation of signal transduction has been recognized. Studies of vascular smooth muscle cells strongly suggest that ROS are required for cell growth signaling. The IP3-induced Ca2+ release from vascular smooth muscle can be selectively stimulated by ROS which may enhance signal transduction for muscle contraction and gene expression. The subunit-subunit contact within the ryanodine receptor complex, as well as intermolecular interactions between the ryanodine receptor and triadin, are redox sensitive, suggesting that ROS may regulate cardiac muscle Ca(2+)-signaling events. The biochemistry of ROS and thiol regulation may allow for specific interactions between ROS and target molecules during redox regulation. PMID- 10093048 TI - Effects of U50488 and bremazocine on [Ca2+]i and cAMP in naive and tolerant rat ventricular myocytes: evidence of kappa opioid receptor multiplicity in the heart. AB - To explore the existence of multiplicity of kappa receptor in the heart, two series of experiments were performed. In the first we studied the antagonistic actions of nor-BNI, a selective kappa 1 antagonist, and quadazocine, a preferential kappa 2 antagonist, against the effects of U50488, a selective kappa 1 agonist, and bremazocine, a universal agonist preferentially binding to kappa 2 receptor, on the electrically stimulated [Ca2+]i transient and forskolin stimulated cAMP accumulation in the rat ventricular myocyte. In the second series of experiments, we determined and compared the effects of above two kappa receptor agonists in the ventricular myocytes made insensitive to kappa 1 and kappa 2 agonists by prior exposure to the respective agonists. At the concentration range of 3 x 10(-6)-3 x 10(-5) M, both U50488 and bremazocine dose dependently inhibited the [Ca2+]i transient induced by electrical stimulation. The inhibitory effects of U50488 and bremazocine were antagonized by nor-BNI and quadazocine. The antagonistic actions of nor-BNI were significantly greater against the effects of U50488, but smaller against the effects of bremazocine than those of quadazocine. At 1 x 10(-6)-5 x 10(-5) M, both U50488 and bremazocine dose-dependently and significantly inhibited the forskolin-induced cAMP accumulation. The inhibitory effect of 30 microM U50488 on cAMP accumulation was significantly attenuated by 5 microM nor-BNI, but not by quadazocine at the same concentration; whereas the effect of 30 microM bremazocine was significantly blocked by 5 microM quadazocine, but not by nor-BNI at the same concentration. The inhibitory effect of 30 microM U50488 on electrically stimulated [Ca2+]i was abolished by preincubation of myocytes with 10(-6) M U50488 for 24 h, but not with 10(-6) M bremazocine for h; whereas the inhibitory effect of 30 microM bremazocine on electrically stimulated [Ca2+]i transient was significantly attenuated after incubation of the myocyte with 10(-6) M bremazocine for 24 h, but not with 10(-6) M U50488 for 24 h. The observations indicate the existence of kappa receptor subtypes in the rat heart. PMID- 10093049 TI - Interactions at the NH2-terminal interface of cardiac troponin I modulate myofilament activation. AB - Cardiac troponin I (cTnI) is an essential element in activation of myofilaments by Ca2+ binding to cardiac troponin C (cTnC). Yet, its role in transduction of the Ca2+ binding signal to cardiac troponin T (cTnT) and tropomyosin-actin remain poorly understood. We have recently discovered that regions of cTnI C-terminal to a previously defined inhibitory peptide are essential for full inhibitory activity and Ca(2+)-sensitivity of cardiac myofilaments (Rarick et al., 1997). However, apart from its role in structural binding to cTnC, there is little knowledge concerning the role of the N-terminus of cTnI in the activation and regulation of cardiac myofilaments. To address this question, we generated wild type mouse cardiac TnI (WT-cTnI; 211 residues) and two N-terminal deletion mutants of mouse cTnI, cTnI54-211 (missing 53 residues), and cTnI80-211 (missing 79 residues). The cTnI54-211 mutant retained the ability to bind to cTnT, but lost the ability to bind to cTnC, whereas the cTnI80-211 mutant lost the ability to bind to cTnT, but bound weakly to cTnC. Both mutants bound to F-actin. In the absence of Ca2+, cTnI54-211 was able to inhibit the unregulated MgATPase activity of myofibrils lacking endogenous cTnI-cTnC to the same extent as WT-cTnI, whereas cTnI80-211 had some impairment of its inhibitory capability. Reconstitution with cTnI54-211/cTnC complex did not restore Ca(2+)-activation of myofibrillar MgATPase activity at all, however, the cTnI80-211/cTnC complex restored Ca(2+) activation to nearly 50% of that obtained with WT-cTnI/cTnC. These data provide the first evidence of a significant function of a cTnT-binding domain on cTnI. They also indicate that the structural cTnC binding site on cTnI is required for Ca(2+)-dependent activation of cardiac myofilaments, and that cTnT binding to the N-terminus of cTnI is a negative regulator of activation. PMID- 10093050 TI - Hypoxia-reoxygenation and polyunsaturated fatty acids modulate adrenergic functions in cultured cardiomyocytes. AB - The polyunsaturated fatty acids (PUFAs) of the omega 3 series are known to modulate adrenergic functions in ventricular myocytes. This study evaluated the influence of hypoxia duration and PUFA composition on the ability of cultured rat cardiomyocytes in producing alpha- and beta-adrenergic messengers (IPs and cAMP). After hypoxia (1.5, 2.5 or 3.5 h) followed by reoxygenation (1h). IP and cAMP production was induced by phenylephrine or isoproterenol stimulation, respectively. Hypoxia did not affect the basal level of messenger production in unstimulated cells, but decreased the cAMP production elicited by isoproterenol stimulation (up to 50%). The decrease in IP production after phenylephrine stimulation was observed only after long-term hypoxia duration close to irreversible cellular damages. The use of modified culture media supplemented with either arachidonic acid (AA) or docosahexaenoic acid (DHA) induced cardiomyocytes displaying either an arachidonic acid membrane profile (35% AA and 2% DHA in the phospholipids) or a docosahexaenoic acid membrane profile (15% AA and 20% DHA). These modifications did not alter the basal level of either messenger production in unstimulated cells nor the IP released after alpha adrenergic stimulation. Conversely, the decrease in cAMP production was significantly more pronounced in docosahexaenoic acid-enriched cells than in arachidonic acid-enriched cells. This study suggests that hypoxia alters the beta adrenergic messenger production, and that the alpha-system may balance the depression of the beta-system. The depression of the beta-adrenergic function induced by the incorporation of docosahexaenoic acid in membrane phospholipids may contribute to the beneficial effect of this fatty acid in the reperfused heart. PMID- 10093051 TI - Endothelin-1 gene suppression by shear stress: pharmacological evaluation of the role of tyrosine kinase, intracellular calcium, cytoskeleton, and mechanosensitive channels. AB - Physiological fluid shear stress regulates endothelin-1 (ET-1) gene expression in endothelial cells by inducing an early transient upregulation followed by a sustained suppression, at times greater than 2 h in duration. We evaluated the mechanism of ET-1 mRNA downregulation in confluent monolayers of bovine aortic endothelial (BAE) cells by applying a 6 h steady laminar shear stress of magnitude 20 dyn/cm2. Inhibition of tyrosine kinases using herbimycin A (875 nM) abolished the shear-induced decrease in ET-1 mRNA expression. Similarly, chelation of intracellular calcium ([Ca2+]i) with quin 2-AM (10 microM) blocked the suppression of ET-1 mRNA by shear. To examine the role of the endothelial cytoskeleton in the response to flow, cytochalasin D was used to disrupt F-actin microfilaments. This treatment induced cell retraction and detachment under flow, whereas stabilization of F-actin with phalloidin (1 microM) did not affect shear induced ET-1 downregulation. In contrast, disruption of the microtubule network with nocodazole (10 micrograms/ml) completely prevented, while microtubule stabilization with taxol (10 microM) did not affect the suppression of ET-1 mRNA by flow. To determine the possible contributions of mechanosensitive channels, barium (1 mM BaCl2), was added to confluent BAE monolayers in a low-sulfate/low phosphate modified medium and was noted to abrogate the downregulation of ET-1 gene expression and to attenuate the shear-induced increase in cytoplasmic free calcium concentration. Tetraethylammonium (3 mM TEA) partially inhibited the suppression of ET-1 mRNA by shear; in contrast, gadolinium (10 microM GdCl3), an inhibitor of the stretch-activated cation channel ISA, had no effect. Membrane depolarization by elevated extracellular potassium ([K+]o) also attenuated the suppression of ET-1 mRNA by flow at [K+]o = 70 mM and completely inhibited it at [K+]o = 135 mM. In summary, the steady-state downregulation of ET-1 mRNA by physiological levels of fluid shear stress shares signaling features with the morphological and cytoskeletal response to shear stress. These include requirement for intracellular calcium, tyrosine kinase activity, an intact microtubule network, and independence from a Gd(3+)-sensitive ISA. Unlike shear induced changes in cell morphology and the actin cytoskeleton, the shear-induced decrease in ET-1 mRNA level is blocked by cell depolarization and by Ba2+, a blocker of the shear-activated IKS which also decreases shear-induced cytoplasmic calcium increase. PMID- 10093052 TI - Effect of aging on myocardial adenosine production, adenosine uptake and adenosine kinase activity in rats. AB - Adenosine levels present in the interstitial fluid and coronary effluent of the aged heart exceed those of the young adult heart. The present study investigated mechanisms in the Fischer 344 rat heart which may be responsible for the observed differences. (1) Total production of adenosine was determined in isolated perfused hearts by measuring coronary effluent adenosine content while inhibiting adenosine deamination and rephosphorylation with erythrohydroxy-nonyladenosine (EHNA) and iodotubercidin (ITC), respectively. Total adenosine production was similar in both young (3-4 month) and aged (20-21 month) hearts at 31.8 +/- 6.6 and 38.4 +/- 3.3 nmol/min/g dry wt, respectively. However, stimulation with the beta-adrenergic agent, isoproterenol, elicited a significantly greater increase in adenosine production in the young vs. aged heart. (2) Adenosine transport was evaluated in isolated perfused hearts by determining 14C uptake by the myocardium after 20 min of 14C-adenosine perfusion. Adenosine uptake in the agent-free heart was found to be decreased 17 to 25% in aged compared to young adult hearts. (3) Adenosine transport characteristics were determined with nitrobenzylthioinosine saturation-binding studies in ventricular membrane preparations. The Bmax values were significantly lower in aged than young adult hearts (140.2 +/- 1.5 fmol/mg and 191.9 +/- 2.3 fmol/mg in aged and young hearts, respectively) indicating a decreased number of transporter sites in the aged heart. However, the values for Kd were decreased with aging, suggesting an increase in the affinity of the transporter for adenosine in the aged vs. young adult heart. (4) The activities and kinetics of adenosine kinase were determined in homogenates of aged and young adult ventricular myocardium. No statistical difference was found between the two activities. Taken together these results suggest that increased interstitial adenosine levels in the aged heart result from decreased uptake of adenosine by the ventricular myocardium. PMID- 10093053 TI - Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling. AB - In the fetus and neonate, beta-adrenoceptor stimulation fails to produce physiological desensitization. The current study explores the mechanisms underlying the response pattern in neonatal rats. Homologous cardiac beta adrenergic desensitization caused by isoproterenol treatment in vivo was demonstrable in adult rats by the immediate (2h) and specific loss of the ability of isoproterenol, but not glucagon, to stimulate adenylyl cyclase in vitro. Homologous desensitization was absent when the same treatment was given to neonates. By 12 h post-treatment, the adults showed heterologous desensitization (loss of the response to glucagon), an effect which was once again absent in the immature rats. The absence of desensitization in neonates did not reflect a deficiency in the activity or subcellular distribution of beta ARK1, the enzyme that initiates the phosphorylation and consequent desensitization of beta adrenoceptors. On the other hand, neonates showed relatively poor receptor-Gs transduction as assessed by the GTP-induced shift in receptor ligand binding. Repeated isoproterenol treatment of adult rats led to uncoupling of receptor-G protein transduction but the same treatment in neonates enhanced transduction. Furthermore, neonatal sympathectomy with 6-OHDA interfered with the ontogenetic rise in beta-adrenoceptor-Gs interactions. These results indicate that the maintenance of agonist responses in the face of neonatal adrenergic stimulation does not reflect simply an absence of the ability to elicit homologous or heterologous desensitization but rather represents an active regulatory mechanism in which neural input exerts a positive trophic role at the level of G-protein function. PMID- 10093054 TI - Physical association between recombinant cardiac ATP-sensitive K+ channel subunits Kir6.2 and SUR2A. AB - The inwardly-rectifying K+ channel Kir6.2 serves as a common pore-forming core in various ATP-sensitive K+ (KATP) channels, and it is through assembly with sulfonylurea-receptor (SUR) isoforms, which are ATP-binding cassette (ABC) proteins, that tissue-specific channel phenotypes can be generated. In this regard, Kir6.2 has been shown to physically associate with SUR1 to form the pancreatic KATP channel. While cardiac KATP channel activity can be reconstituted by coexpression of Kir6.2 with a distinct SUR isoform, SUR2A, no direct proof has been provided for physical association between these two proteins. Therefore, we tested, by a coimmunoprecipitation procedure in conjunction with an amino terminal Kir6.2-antibody, physical association between recombinant Kir6.2 and SUR2A. From a mixture of Kir6.2 and SUR2A in vitro-translated proteins, the Kir6.2-specific antibody coimmunoprecipitated 38-kDa and 140-kDa proteins corresponding to Kir6.2 and SUR2A, respectively. In the absence of Kir6.2, SUR2A was not precipitated by the anti-Kir6.2 antibody, indicating that the antibody recognized SUR2A only when SUR2A formed a complex with Kir6.2. A Kir6.2 deletion mutant lacking 37 amino acids from the carboxyterminus still coimmunoprecipitated with SUR2A, indicating that the distal carboxy-terminus of Kir6.2 is unnecessary for subunit association. Kir6.2 mutants lacking more proximal carboxy-terminus regions, including the M2 transmembrane domain, failed to immunoprecipitate SUR2A, suggesting that the proximal carboxyterminus together with the M2 domain are required for channel assembly. These deletion constructs supported cellular distribution of Kir6.2. Thus, the present study provides direct evidence for physical association between Kir6.2 and SUR2A, essentially reconstituting the cardiac KATP channel in vitro. The demonstration of complex formation between Kir6.2 and SUR2A indicates that the structural basis for channel function may rely on direct physical interaction of the two subunits. PMID- 10093055 TI - Ischemia-stimulated glucose uptake does not require catecholamines in rat heart. AB - The authors tested the hypothesis that ischemia stimulates glucose uptake in rat heart independent of the insulin signaling pathway and independent of endogenous catecholamines. Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing [2-3H]glucose (5 mmol/l, 0.05 muCi/ml) and Na-oleate (0.4 mmol/l) with or without the phosphatidylinositol 3-kinase inhibitor wortmannin (3 mumol/l). Insulin (1 mU/ml) was added to the perfusate in the middle of the experiments or the hearts were subjected to 30 min of low-flow ischemia (75% reduction in coronary flow) followed by 15 min of reperfusion. In a separate group, hearts were subjected to ischemia and reperfusion in the presence of propranolol (10 mumol/l) plus phentolamine (10 mumol/l). Cardiac power was stable but decreased (-75%) during ischemia. Both insulin and ischemia increased glucose uptake (P < 0.01). Glucose uptake returned to pre-ischemic values during reperfusion. Wortmannin completely inhibited insulin-stimulated glucose uptake and glycogen synthesis, but did not affect the ischemia-stimulated glucose uptake or glycogen resynthesis during reperfusion. Full adrenergic blockade did not abolish the ischemia-stimulated glucose uptake. The authors conclude that: (1) insulin and ischemia increase glucose uptake through different mechanisms; (2) ischemia-stimulated glucose uptake is not catecholamine mediated: and (3) glycogen resynthesis during reperfusion is independent of PI3-K. PMID- 10093056 TI - Differential effects of angiotensin II receptor blockade on pressure-induced left ventricular hypertrophy and fibrosis in rats. AB - The effects of the angiotensin II receptor type 1 (AT1) antagonist losartan on pressure overload-induced left ventricular (LV) hypertrophy were studied in female Sprague-Dawley rats. Starting on the day of surgery, losartan (L, 12 mg/kg/day) was administered as continuous intraperitoneal infusion for 2 weeks by using alzet mini-osmotic-pumps (model 2002). This dose of losartan shifted the in vivo dose-response curve of the angiotensin II-induced elevation of left ventricular systolic pressure (LVSP) to the right. Pressure overload was achieved by placing a band around the aortic arch. This caused an aortic stenosis (AS) with an outer diameter of 1.0 mm. The hemodynamic effects were measured in the intact, anesthetized rats (n = 15). The hearts were excised, and the weights of the left (LV) and right ventricle (RV) were determined. Some of these hearts (n = 7) were perfused with collagenase to obtain isolated cardiac myocytes for the measurement of cell volume. Other hearts (n = 8) were examined for morphological changes. In the animals with AS, LVSP was markedly elevated. Furthermore, LV weight and LV myocyte cell volume were increased in this group, while RV weight and RV myocyte cell volume remained stable in all the groups. L had no significant effect on the AS-induced increase in LVSP and cell size parameters, nor on the weight gain of the LV. Histological analysis revealed that the AS induced enlargement of the mean myocyte diameter was not affected by L. The interstitial collagen fraction was increased in the AS rats and became normalized by L. These data suggest that the renin-angiotensin system might not be involved in the development of pressure-induced cardiac hypertrophy within the time-frame of these experiments, but that it does play a major role in the genesis of the interstitial fibrosis which is a typical feature of this pathophysiological condition. PMID- 10093057 TI - Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. AB - The beneficial effects of angiotensin-converting enzyme inhibitors on ameliorating cardiac fibrosis have been partially attributed to their ability to prevent the degradation of kinins. The potential role of bradykinin and the related signaling molecule nitric oxide (NO) in modulating extracellular matrix (ECM) production was examined in primary cultures of adult rat cardiac fibroblasts. Treatment of fibroblasts with 5 nM bradykinin for 24 h led to a reduction in steady-state mRNA levels for fibronectin (34 +/- 7%) and collagens type I (19 +/- 8%) and type III (48 +/- 4%), as determined by Northern blot analysis. The NO synthase inhibitor L-NAME attenuated the reduction observed in fibronectin and collagen mRNA levels in response to bradykinin. The NO donor DETA NONOate (100 microM) mimicked the effects of bradykinin on ECM mRNA levels. Protein levels of soluble fibronectin, assessed in conditioned medium by ELISA, were decreased by 14 +/- 4% and 21 +/- 4% after 48 h treatment with 1 microM bradykinin and 100 microM DETA NONOate, respectively. Bradykinin stimulated intracellular cGMP accumulation 73.7 +/- 10.3% after 10 min of treatment. Cell proliferation rates at 48 h were unaffected by bradykinin, but were reduced by 26 +/- 12% by 100 microM DETA NONOate. These data indicate that bradykinin downregulates ECM protein production in cardiac fibroblasts and suggest that NO and the related signaling molecule cGMP may play an important role in mediating this response. PMID- 10093058 TI - Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. AB - Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury. These effects are due in large part to endothelial dysfunction leading to an upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. The proteasome inhibitor, PS-519, has been shown to attenuate leukocyte endothelial cell interactions. We tested the effects of PS-519 on neutrophil mediated cardiac dysfunction in ischemia/reperfusion. This study examines the effects of PS-519 in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of PS-519 (0.01, 0.1, 0.3, 1.0 mg/kg) to I/R hearts perfused with PMNs improved coronary flow, and preserved left ventricular developed pressure (LVDP) and + dP/dt max as indices of cardiac contractile function. At 1.0 mg/kg, PS-519 treated hearts exhibited a final LVDP of 98 +/- 3% of initial compared to 52 +/- 8% in I/R hearts receiving only vehicle (P < 0.001). In addition, PS-519 significantly reduced PMN accumulation in the ischemic myocardium from 25.1 +/- 2.1 PMNs/mm2 in untreated hearts to 7.3 PMNs/mm2, and attenuated P-selectin surface expression on coronary vascular endothelium from 7.1 +/- 0.3% to 1.4 +/- 0.2% (P < 0.01). These results provide evidence that PS-519 is a potent and effective cardioprotective agent that inhibits P-selectin leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion. PMID- 10093059 TI - mRNA levels of myogenic regulatory factors in rat slow and fast muscles regenerating from notexin-induced necrosis. AB - The transcript levels of the myogenic regulatory factors (myoD, myf5, myogenin and MRF4) were measured by RT PCR in rat soleus (slow) and EDL (fast) muscles which were regenerating from notexin-induced necrosis. Some muscle fibers in the EDL were more resistant to the toxin, therefore the necrosis and the dominance of myoblasts were delayed for two days in EDL compared to soleus. In spite of this shift in time-course of necrosis, both types of muscle presented roughly similar, although variable, changes in the expression pattern of MRF mRNA levels. For both muscles, the myoD mRNA was upregulated on the first day after administration of the toxin, whereas concomitantly myf-5 mRNA disappeared but showed a substantial increase in later stages of regeneration. In contrast, the mRNA levels of the late MRFs myogenin and MRF4 decreased on day one only in the soleus, then increased on day three in both types of muscle. Meanwhile in EDL the level of MRF4 mRNA remained relatively normal. Four weeks after administration of the toxin the mRNA levels for each of the MRFs returned to nearly control levels. This shows that in spite of the different time course of the necrosis and regeneration, also documented by the microscopical morphology and the skeletal actin mRNA levels of the muscles, the level of MRF transcripts changed according to a quite predictable pattern; the upregulation corresponded to myoblast activation and the downregulation to the reinnervation. PMID- 10093060 TI - Myotonic ADR-MDX mutant mice show less severe muscular dystrophy than MDX mice. AB - In Duchenne muscular dystrophy (DMD) and its murine model, the dystrophic mouse (MDX), the skeletal musculature lacks dystrophin. The presumed function of this cytoskeletal protein is to protect the sarcolemma against mechanical stress during muscle activity. To test this hypothesis in vivo, we bred a double mutant mouse that combines two genetic defects: the dystrophin-deficiency of the MDX mouse and the Cl- channel myotonia of the arrested development of righting response (ADR) mouse. We hypothesized that high mechanical muscle activity would aggravate muscular dystrophy in double mutant ADR-MDX mice. On the contrary, ADR MDX mice showed fewer signs of muscle fiber necrosis and fibrosis than MDX mice at all ages. Plasma creatine kinase levels were slightly increased in ADR-MDX, but significantly lower when compared to MDX mice. Sections of ADR-MDX muscle showed a uniform pattern of oxidative muscle fibers. Similar findings have been obtained in dystrophin-positive ADR mice, they result from a complete fiber-type IIB to IIA transformation in myotonic muscle. Our results suggest that small, oxidative fibers of myotonic mice are less sensitive to dystrophin deficiency. Therefore, ADR-MDX mice develop less severe muscular dystrophy than MDX mice do, although their muscles are continually stressed. The new ADR-MDX double mutant mouse is the first animal model combining both a dystrophinopathy and a channelopathy. The results presented here give new insights into the pathomechanism of muscular dystrophy and may be helpful for the therapeutic management of DMD. PMID- 10093061 TI - Mutual interference of myotonia and muscular dystrophy in the mouse: a study on ADR-MDX double mutants. AB - For Duchenne muscular dystrophy (DMD, dystrophin deficiency) and Thomsen/Becker myotonia (muscular chloride channel deficiency) genetically homologous mouse models are available, the dystrophin-deficient MDX mouse and the myotonic ADR mouse. Whereas the latter shows more severe symptoms than human myotonia patients, the MDX mouse, in contrast to DMD patients, is only mildly affected. We have introduced, by appropriate breeding, the defect leading to myotonia (Clc1 null mutation, adr allele) into MDX mice, thus creating ADR-MDX double mutants. The expectation was that, due to mechanical stress during myotonic cramps, the ADR status should symptomatically aggravate the muscle fibre necrosis caused by the dystrophin deficiency. The overall symptoms of the double mutants were dominated by myotonia. Weight reduction and premature death rate were higher in ADR-MDX than in ADR mice. Sarcolemmal ruptures as indicated by influx into muscle fibres of serum globulins and injected Evans blue were found with great inter individual variation in MDX and in ADR-MDX muscles. Affected fibres were found mainly in large groups in MDX but single or in small clusters in ADR-MDX leg muscles. The symptoms of myotonia (aftercontractions, shift towards oxidative fibres) were less pronounced in ADR-MDX than in ADR muscles. Conversely, numbers of damaged fibres as well as the percentage of central nuclei (an indicator of fibre regeneration) were significantly lower in ADR-MDX than in MDX skeletal muscles. Thus it appears that, at the level of the muscle fibre, myotonia and muscular dystrophy attenuate each other. PMID- 10093062 TI - Juvenile myasthenia gravis with prepubertal onset. AB - Juvenile myasthenia gravis (JMG) with prepubertal onset is an uncommon disease. We studied 19 patients with age at onset ranging from 1.5 to 9.2 years and compared their clinical characteristics and response to therapy with 114 cases with MG onset after the prepubertal age, up to 20 years. Neither sex prevalence nor autoimmune diseases other than MG were found in younger patients. Although ocular myasthenia was more frequent than in later-onset JMG, children with generalized symptoms were often severely affected and respiratory involvement was present in 8/19 patients. Anti-acetylcholine receptor antibodies were detected at a lower rate and, in contrast with results in older patients, seronegativity was more frequent among children with generalized disease. Three out of six patients with onset before the age of five showed spontaneous remission. Nine prepubertal patients underwent thymectomy and, as most of them also received immunosuppressive therapy, the influence of surgery on disease outcome remains unclear; in no case was thymoma found. This is in contrast to the good results after thymectomy and the presence of thymoma in the later-onset group. Eleven patients in the prepubertal series were treated with immunosuppressive therapy. At the end of follow-up, most patients were in good condition. The frequency of immunosuppressive therapy and the rate of good therapeutic results did not differ from those observed in older patients. PMID- 10093063 TI - Clinical heterogeneity associated with mitochondrial DNA depletion in muscle. AB - We studied 10 patients with a variable degree of mtDNA depletion in muscle. Seven patients showed a clear-cut myopathic pattern, while the three remaining had brain involvement. There was no relationship between age at onset and relative mtDNA copy number in muscle, but we found an apparent correlation between clinical severity and degree of muscle mtDNA depletion. Muscle morphology showed that mtDNA depletion was associated with mitochondrial proliferation and cytochrome c oxidase negative fibers. Biochemical studies revealed single or combined defects of mtDNA-dependent respiratory chain complexes. Our data indicate that patients with mtDNA depletion may have a more variable age at onset and clinical evolution and wider phenotype than previously thought. The diagnosis of this condition, so far regarded as rare, may have been overlooked to some extent. PMID- 10093064 TI - Muscle pain as a prominent feature of facioscapulohumeral muscular dystrophy (FSHD): four illustrative case reports. AB - Clinical studies of facioscapulohumeral muscular dystrophy (FSHD) rarely report muscle pain as a significant feature of the condition. We report four adult patients with FSHD in whom muscle pain was a presenting complaint and remains their most disabling symptom. These four patients were investigated using a pain questionnaire and diary. Inflammatory and metabolic causes of muscle pain were sought by muscle biopsy and a range of biochemical investigations. All patients reported between three and seven different pains of varying site and nature. None of the group had more than one painfree day per month and all complained of disturbed sleep. While some pains could potentially be attributed to postural problems, others were clearly myalgic in nature, though most often not specifically exercise-related. These myalgic pains could be particularly difficult to control. Results of metabolic investigations and muscle biopsy revealed no clue to the pathogenesis of these pains and there was no evidence for any exceptional inflammatory response. We believe that pain in FSHD is an under reported but significant symptom and that further work is necessary to determine its prevalence, understand its cause and provide effective treatment. PMID- 10093065 TI - Scapulothoracic arthrodesis for patients with facioscapulohumeral muscular dystrophy. AB - Ten scapulothoracic arthrodesis procedures were performed in six patients with facioscapulohumeral muscular dystrophy in order to improve considerably restricted activities of daily living. Four of these procedures were bilateral. The duration of follow-up ranged from 28 to 120 months. All patients reported improved function in activities of daily living. Active shoulder abduction was improved by an average of 44 degrees, and active flexion increased by 56 degrees. There was no deterioration in improved upper limb function with time. Complications included pneumothorax, atelectasis, pleural effusion and re exploration for a segment of retained drain. PMID- 10093066 TI - Cardiac transplantation in a Duchenne muscular dystrophy carrier. AB - We report here for the first time the case of a symptomatic DMD carrier, who had a heart transplant for a severe dilated cardiomyopathy. Dystrophin immunohistochemistry, western blot and analysis of X-chromosome inactivation on leucocytes, and skeletal and cardiac muscle biopsies on the explanted heart were performed. The patient was a heterozygote for exons 50-52 deletion in the dystrophin gene. The number of dystrophin-deficient fibres in the heart was much higher than in skeletal muscle. On the other hand, the explanted heart showed a non-skewed pattern of X-chromosome inactivation, as in leukocytes and skeletal muscle. The adverse cardiac course may be explained by the absence of regeneration among cardiomyocytes. PMID- 10093067 TI - 3rd workshop of the European CMT consortium: 54th ENMC International Workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28-30 November 1997, Naarden, The Netherlands. PMID- 10093068 TI - Can alpha-immunotherapy succeed where other systemic modalities have failed? PMID- 10093069 TI - Simultaneous assessment of myocardial viability and function for the detection of hibernating myocardium using ECG-gated 99Tcm-tetrofosmin emission tomography: a comparison with 201Tl emission tomography combined with cine magnetic resonance imaging. AB - The aims of this study were to evaluate the simultaneous assessment of myocardial viability and function for the detection of hibernating myocardium using ECG gated 99Tcm-tetrofosmin single photon emission tomography (SPET), and to compare the technique with 201Tl SPET in combination with cine magnetic resonance imaging (MRI). Fifteen patients aged 41-70 years with impaired left ventricular function (mean LVEF 23.4 +/- 8.1%) and three-vessel coronary artery disease were studied before and after coronary artery bypass grafting (CABG). The following investigations were performed within the 3 months before surgery: stress/redistribution and separate-day rest 201Tl SPET with early and late imaging, stress and ECG-gated rest 99Tcm-tetrofosmin SPET, and resting cine MRI. Between 3 and 6 months post-surgery, stress/redistribution 201Tl SPET and cine MRI were repeated. Tracer uptake in nine segments of the left ventricle was graded visually and by quantitative analysis. Myocardial motion and thickening were graded visually from cine MRI and from gated 99Tcm-tetrofosmin SPET images. Segments were defined as hibernating pre-operatively if tracer uptake was moderately reduced or better but myocardial motion was severely hypokinetic or worse. The accuracy of pre-operative assessment was assessed by comparison with post-operative function assessed by MRI. The sensitivity and specificity for the prediction of functional improvement were 69% and 60% for late rest 201Tl uptake combined with MRI; 58% and 62% for rest 99Tcm-tetrofosmin uptake combined with MRI; and 62% and 45% when gated 99Tcm-tetrofosmin SPET was used to assess both tracer uptake and wall motion. In 21 of 135 segments, contractile function could not be assessed by gated 99Tcm-tetrofosmin SPET because of inadequate tracer uptake; function was improved in 5 (25%) of these segments after CABG. In conclusion, the combined assessment of viability and function using ECG-gated 99Tcm-tetrofosmin SPET is feasible and it allows the assessment of hibernating myocardium with similar accuracy to the combination of ungated 99Tcm-tetrofosmin SPET with MRI. Where tracer uptake is too poor for assessment of function, there is a low incidence of myocardial hibernation. However, ECG-gated 99Tcm tetrofosmin SPET is not superior to 201Tl SPET combined with cine MRI in the identification of hibernation. PMID- 10093070 TI - A new non-invasive test for the detection of compartment syndromes. AB - Chronic exertional compartment syndrome (CECS) is currently diagnosed using invasive pressure measurements. We report the use of 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) scintigraphy as a new non-invasive method of diagnosis. Forty-six patients with suspected chronic compartment syndrome underwent graded treadmill exercise to reproduce the presenting symptoms. At peak exercise, 300 MBq of 99Tcm-MIBI were injected intravenously. Subsequent cross-sectional imaging provided by emission tomography demonstrated regional abnormalities in muscle perfusion in the calf. A repeat study was performed at rest the following day. All patients in whom there was a strong clinical suspicion of CECS were considered for invasive pressure measurements. Statistical analysis of the results for investigation of CECS using 99Tcm-MIBI versus pressure studies gave P = 0.06. A comparison of 99Tcm-MIBI versus outcome gave P < 0.0001. The sensitivity was 80% and the specificity 97% for 99Tcm-MIBI studies based on outcome. The positive predictive value was 89% and the negative predictive value 94%. Thus 99Tcm-MIBI can detect compartment syndromes with good positive and negative predictive values. It is relatively simple, cheap and less invasive than pressure measurements. This technique shows promise in the diagnosis of CECS. PMID- 10093071 TI - How to interpret differing cerebral blood flow patterns estimated with 99Tcm HMPAO and 99Tcm-ECD SPET in a healthy population. AB - Two radiopharmaceuticals, 99Tcm-hexamethyl propylene amine oxime (99Tcm-HMPAO) and 99Tcm-ethyl cysteinate dimer (99Tcm-ECD), are currently used to determine cerebral blood flow. 99Tcm-ECD is, by virtue of its greater stability, superseding 99Tcm-HMPAO for routine examinations. Since the clinical assessment of 99Tcm-ECD images is usually based on experience with 99Tcm-HMPAO, we used both radiopharmaceuticals to compare regional cerebral blood flow in the same individuals. Eleven healthy subjects aged 67.1 +/- 6.3 years (mean +/- S.D.) underwent 99Tcm-ECD followed by 99Tcm-HMPAO single photon emission tomography. Cerebral blood flow was quantified in cortical and central regions of interest (basal ganglia, ventricles, white matter) in relation to cerebellar uptake. The intra-subject comparison of cerebral blood flow in the cortical areas revealed higher levels of perfusion in the posterior parietal, parieto-occipital and temporo-occipital areas using 99Tcm-ECD. In contrast to the cortical areas, cerebral blood flow in the central areas was greater using 99Tcm-HMPAO, especially in the centrum semiovale, basal ganglia, frontal white matter and frontal horns. This difference in cerebral blood flow when imaging healthy individuals with 99Tcm-ECD and 99Tcm-HMPAO should be taken into account in clinical practice when changing from one radiopharmaceutical to the other. PMID- 10093072 TI - Evaluation of algorithms for the registration of 99Tcm-HMPAO brain SPET studies. AB - Five functions of merit were used for the registration of 99Tcm-HMPAO brain SPET studies. The correlation coefficient (COR), the stochastic sign change (SSC), the standard deviation of ratios (SDR), the sum of the absolute differences (SAD) and a new function based on a local correlation coefficient (LOC) were tested in the registration of photic neuroactivation (ACT), epilepsy (EPL) and Wada (WAD) SPET studies. The comparison included simulated and real studies. The translation error in registration was 0.1 +/- 0.1 pixels (mean +/- S.D.) for all functions of merit for the complete set of simulated studies (10 runs for each ACT, EPL and WAD). For rotation, LOC yielded the best results with a mean error of 0.3 +/- 0.2 degree and a maximum error of 0.6 degree. Slightly higher errors were found with SAD (0.4 +/- 0.2 degree, maximum 1.0 degree) and COR (0.5 +/- 1.0 degree, maximum 1.0 degree). The highest errors were found with SDR (0.8 +/- 1.0 degree, maximum 4.8 degrees) and SSC (0.8 +/- 1.1 degrees, maximum 4.7 degrees). The results obtained from five real studies of ACT, of EPL and of WAD were in agreement with the findings from the simulated studies, thus confirming the robustness of LOC, SAD and COR for the registration of 99Tcm-HMPAO brain SPET studies. PMID- 10093073 TI - Prone SPET scintimammography. AB - Prone single photon emission tomography (SPET) was performed in 24 patients with suspected primary or recurrent breast cancer to determine if this technique offers more accurate imaging than that obtained from planar scintimammography. All patients were imaged on a specially designed couch with two cushion inserts. The first insert was lined with lead and was used to perform prone lateral planar scintimammography 5 min after the injection of 740 MBq 99Tcm-MIBI. The second insert did not contain lead and was used to perform a prone SPET acquisition for 30 min immediately after planar imaging. The results of both studies were read independently and there was agreement between the two techniques in 23 cases (96%). All cases of cancer proven on histology were found on planar imaging, but a 4-mm ductal cancer was missed on prone SPET. This was thought to be due to activity from this medial cancer being obscured by the star artefact produced by back-projection reconstruction from activity in the heart. There were two false positive studies with both techniques. However, prone SPET enabled better localization and characterization of breast cancers than planar imaging. Prone SPET imaging of the breast produces results similar to prone lateral imaging and may be used instead of planar imaging if a reduced total acquisition time is desirable. Care must be taken when reading scans in the presence of small tumours near the heart when back-projection reconstruction techniques are used. PMID- 10093075 TI - Positron emission tomography using 18F-fluorodeoxyglucose in advanced stages of malignant melanoma: a comparison of ultrasonographic and radiological methods of diagnosis. AB - The diagnostic and therapeutic impact and the cost-effectiveness of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) will depend on the role for which the tests are used. In 68 patients with advanced malignant melanoma, original sets of FDG-PET images from various institutes were compared with findings obtained by ultrasonography, conventional radiology, computed tomography (CT) and magnetic resonance imaging. In 22 patients, all examinations were undertaken within 2 weeks and strategies of staging were analysed. In 46 patients, only some of these examinations were performed within this time period, and comparison of methods was restricted to the examined organs. The occurrence of metastasis, without specifying the number of foci, was detected by either conventional staging with CT or by PET in 20 of 22 patients. None of these patients were up- or down-staged by FDG-PET compared with CT staging. In the 68 patients as a whole, FDG-PET detected fewer pulmonary and hepatic metastases and fewer cerebral foci, but more lymph node and bone metastases than conventional radiology or CT. For the detection of lymph node or skeletal metastases, false positive FDG-PET findings were taken into account when compared with follow-up data. In advanced melanoma, FDG-PET did not influence the pattern of subsequent diagnostic testing. Thus, indications for FDG-PET include pre-metastatic melanoma, localized lymph node metastases and monitoring of the response to treatment. PMID- 10093074 TI - Visualization of functional improvement by 123I-IMP lung SPET after thromboendarterectomy for chronic pulmonary embolism. AB - We report on six patients with chronic pulmonary embolism who underwent 123I-IMP and 99Tcm-MAA lung SPET before and after thromboendarterectomy. 123I-IMP lung SPET can assess the viability of lung parenchyma, because it is a non-particulate agent that accumulates in the endothelial membranes of pulmonary capillaries. Chronic pulmonary thromboembolism accompanied by pulmonary hypertension has a poor prognosis that may be improved only by thromboendarterectomy. We compared 123I-IMP and 99Tcm-MAA lung SPET in terms of functional improvement after such surgery. After thromboendarterectomy, all six patients were functionally improved, according to the criteria of the New York Heart Association. The pre- and post-surgery percentage of vascular obstruction did not differ significantly with 99Tcm-MAA lung SPET (44.8 +/- 11.2% and 32.5 +/- 15.6% pre- and post surgery, respectively). In contrast, 123I-IMP lung SPET revealed a significant pre- versus post-surgery difference (15.5 +/- 9.5% and 3.3 +/- 5.9% pre- and post surgery, respectively). 123I-IMP lung SPET could be useful for evaluating thromboendarterectomy because pulmonary parenchymal viability owing to arterial microvasculature can be estimated. PMID- 10093077 TI - Deadtime correction in measurement of fractional renal accumulation of 99Tcm MAG3. AB - Fractional renal accumulation of a radiotracer is often used to measure renal function with camera-based methods. We evaluated the effect of deadtime count loss on the calculation of fractional renal accumulation of 99Tcm mercaptoacetyltriglycine (99Tcm-MAG3). In 15 patients, dynamic renal scintigraphy was performed after the injection of 250 MBq of 99Tcm-MAG3. A reference source was placed on the periphery of the field of view of the gamma camera to monitor the loss of counts in dynamic imaging. The activity in the syringe was also counted with the camera to measure the injected dose, and the deadtime count loss in the syringe was computed from the observed count rate and deadtime in imaging a point source. Fractional renal accumulation, the ratio of renal accumulation on dynamic imaging to the injected dose, was assessed with and without correction for deadtime loss. Fractional renal accumulation was over-estimated by 4.1% with no deadtime correction, when the value after correction for loss in both syringe counts and dynamic imaging was used as a standard. It was underestimated by 4.0% with correction for syringe counts only. The results suggest that correction for count loss only in measuring the injected dose does not lead to a significant improvement in the accuracy of estimating renal function with camera-based methods. PMID- 10093076 TI - Predictive value of 99Tcm-DTPA captopril scintigraphy in patients with a solitary kidney and reduced kidney function. AB - The aim of this study was to determine if the qualitative 99Tcm-DTPA captopril radionuclide test (CRT) can help predict the acute detrimental effect of angiotensin-converting enzyme (ACE) inhibitors on renal function in hypertensive patients with solitary kidneys and chronic renal failure. Between 1991 and 1996, eight consecutive patients (6 males, 2 females) aged 27-73 years (mean 49.8 years) with known chronic renal failure and a solitary kidney referred for ACE treatment were included. 99Tcm-DTPA renography was performed at baseline and 1 h after the administration of 25 mg captopril within 1 week of each other. The CRT was performed in accordance with the criteria of the Working Party on the Diagnostic Criteria of Renovascular Hypertension with Captopril Renography. A beneficial or detrimental effect of subsequent ACE inhibitor treatment on renal function was determined by long-term follow-up (> or = 2 years). The CRT accurately predicted outcome in all eight patients subsequently treated with ACE inhibitors. In conclusion, our results suggest a role for qualitative 99Tcm-DTPA CRT in the prediction of renal function in patients with a solitary kidney and chronic renal failure subsequently treated with ACE inhibitors. PMID- 10093078 TI - Body surface area correction in single-sample methods of glomerular filtration rate estimation. AB - Single-sample methods of estimating glomerular filtration rate (GFR) are used routinely, in a number of institutions, to calculate values of total plasma clearance (TPC), which are then converted to GFR. Adjustment of the final estimate for body surface area (BSA) is not adequate to allow adult equations to be used in children and work has been undertaken to seek an age-independent technique. The aim of this study was to evaluate the ability of an alternative method of correcting for BSA, of scaling the plasma sample activity, to achieve an age-independent solution. The accuracy of the scaled TPC values was compared with a monoexponential analysis as the 'gold' standard. Data from 60 patients were analysed using 16 single-sample models. Patients were chosen so that 10 could be allocated to each of six categories involving three age groups (0-3 years, 4-17 years and 18+ years) and two classes of TPC (< 40 and > 40 ml.min-1). Adjustment of the plasma activity gave more accurate results than correction of the final estimate in 87% of the categories for 15 of the models. This improvement was particularly apparent in the case of adult equations applied to child data, which gave results similar to those obtained using child equations, indicating that they can be used with equal accuracy. PMID- 10093079 TI - Experiences in setting up the first centralized radiopharmacy in Spain. AB - The centralized radiopharmacy set up in Spain by the Cetir Medical Group allows optimal use of radiopharmaceuticals and complies with laws (Directive 89/343/EEC and Royal Decree 479/1993/Spain) governing their use. More than 220,000 individual patient doses have been supplied since the unit was established in November 1995. In this paper, we describe the infrastructure of the centralized radiopharmacy, including the operations and procedures involved, and how we believe we have achieved our original objectives. PMID- 10093080 TI - Preparation and properties of 99Tcm-exametazime using stannous ion augmentation of fractionated cold kits. AB - Fractionation of 99Tcm-exametazime enables several patients doses to be prepared from one vial. To overcome the disadvantages of storage at -70 degrees C, storage at higher temperatures was investigated with replacement of stannous ions before use. Kits were fractionated using a nitrogen-purged 0.9% w/v sodium chloride injection, sub-dispensed into five nitrogen-filled vials in an aseptic environment and stored at -20 degrees C. Under these conditions, exametazime vials failed quality control in approximately 1 week. However, the addition of stannous pyrophosphate solution (10 micrograms Sn(II) in 0.1 ml, prepared by aseptic dilution of a red blood cell labelling kit) immediately before 99Tcm pertechnetate produced 90.1 +/- 1.6% (n = 8) lipophilic complex with a normal rate of decomposition. Biodistribution studies of this product in mice compared with the full kit showed identical brain and other organ uptakes. This product was used for cerebral imaging in patients with 90.5 +/- 3.3% lipophilic complex (n = 647) at approximately 3 min and produced excellent clinical results. It is concluded that stannous ion augmentation ('reboot') using approved Sn(II) pyrophosphate kits is a viable option for institutions with facilities for aseptic preparation of fractionated exametazime kits, enabling substantial cost savings. Other advantages include removal of restrictions on generator eluate and 'rejuvenation' of expired kits. PMID- 10093081 TI - Indoor air pollution and the respiratory health of children. AB - Children spend much of their time indoors, yet relatively little attention is paid to the effects of indoor air pollution owing to the difficulties of obtaining information about it. The most important single element is probably environmental tobacco smoke (passive smoking), which causes respiratory illness and impairment of lung function. Oxides of nitrogen, mostly derived from gas cookers, may cause symptoms in some children. House dust mites affect children with allergic asthma, but are very difficult to remove from the indoor environment. Indoor mould growth seems to be associated with ill-health, but it is not entirely clear whether this is attributable to exposure to the spores. Formaldehyde is emitted by some materials in buildings and furniture; it may affect children's respiratory health, but the information is rather sparse. VOCs are produced by a range of human activities; their significance for health is not known. More work is needed to ascertain the short-term and long-term effects of exposure to indoor air pollutants. PMID- 10093082 TI - Health effects of urban outdoor air pollution in children. Current epidemiological data. PMID- 10093083 TI - Air pollution and respiratory disease in children: what is the clinically relevant impact? AB - Acute exposure to air pollution is associated with increased respiratory symptoms and decreases in lung function in children. Most of the respiratory symptoms are nonspecific and not severe. However, lower respiratory symptoms and extra use of bronchodilators may be increased by about one third with exposure to peak levels of ozone in children with asthma. Sensitivity to air pollution does not seem to be determined by the severity of preexisting asthma and there is no indication that new cases of asthma are induced by ozone exposure. However, hospital and outpatient admissions for children with preexisting asthma may be increased in the range of 20% with acute exposure to ambient ozone peaks and possibly with increased sulfur dioxide. This indicates a significant impact of acute effects of air pollution on respiratory health in children, and an increase in the use of medical resources which will vary with the local exposure level and duration. Chronic exposure to increased levels of respirable particles, SO2 and NO2 are associated with up to threefold increases in nonspecific respiratory symptoms such as chronic cough, but not with asthma. Exposure to high traffic flow has been found to lead to significant increases in respiratory symptoms, while no clear effect on the inception of asthma has been documented. Although these symptoms are usually not severe, they will contribute to an increased use of pediatric health care facilities. It appears unlikely that long-term exposure to pollutants or irritants is responsible for the secular increase in asthma and allergy observed in Western countries. Whether exposure to car traffic is a significant risk factor for acute asthma or its inception remains to be clarified. PMID- 10093084 TI - Lung function testing in infants. AB - During recent years, there has been rapid development in the availability and application of pulmonary function tests in infants and young children. Whereas original methods were based on adaptations of classical techniques, over the past decade there has been an increasing trend towards developing less complex techniques specifically for use in infants and young children. Interpretation of these measurements requires a knowledge of respiratory physiology, and may be confounded by an unstable end expiratory level, compliant chest wall, dominance of the upper airways, difficulty in achieving flow limitation in healthy infants, and the variability of respiratory, lung or airway resistance which increases the difficulty of assessing the significance of changes in resistance as a result of treatment or challenge. Nevertheless, with care, the assessment of respiratory function during infancy and early childhood can increase knowledge of the growth and development of the respiratory system, and our understanding of the patho physiological processes underlying respiratory diseases in early life. They also have the potential to provide valuable objective outcome measures in the quest for effective preventive and therapeutic strategies in respiratory medicine. PMID- 10093085 TI - Lung function testing in preschool children. PMID- 10093086 TI - Respiratory function testing in early childhood: where have we come from and where are we going? AB - After an initially slow beginning, we are currently witnessing something of a revolution in the field of respiratory function testing during early childhood, both with respect to the number of techniques available and the applications to which they are being put. There is now an urgent need for international, collaborative efforts to develop more objective, standardized methods of assessment (including improved, properly validated equipment and software) and reliable reference data for this age group. This would improve our understanding of exactly what these tests are measuring, and facilitate the development of effective therapeutic and preventive strategies to minimize suffering from respiratory illness not only during early childhood but, hopefully, throughout life. PMID- 10093087 TI - Diagnosis and diagnostic approaches in interstitial lung disease. PMID- 10093088 TI - Interstitial lung disease in children: an overview. PMID- 10093089 TI - Asthma epidemiology: clues and puzzles. PMID- 10093090 TI - Role of allergens in the natural history of childhood asthma. AB - This review article deals with the role of allergens in the natural history of asthma. Several studies clearly demonstrate a strong relationship between allergen exposure, especially mite-allergen exposure, and risk of sensitization. Those studies have led to the proposed threshold equal to 2 micrograms/g dust. However, more recent evidence shows that there is no threshold for sensitization, especially in children born to atopic parents. As far as occurrence of asthma is concerned, geographical comparisons of asthma prevalence across Europe, Australia or in other populations with contrasted exposure to mite allergens do show such a relationship. The latter is not exemplified in studies performed within the same geographical area, probably because the exposure categories are not contrasted enough. Finally, asthma severity in mite sensitive asthmatics is partly modulated by allergen exposure but repeated exposure to low amounts of allergen can trigger disease activity. In conclusion, allergen exposure is involved at each step of the natural history of asthma. Even low doses can play a significant role. Thus avoidance methods, in order to be efficient in primary and secondary prevention, should lead to a drastic decrease in allergenic exposure. PMID- 10093091 TI - Regional differences in prevalence and risks of respiratory diseases in children. PMID- 10093092 TI - Non-invasive biomarkers of asthma. AB - Several non-invasive biomarkers of inflammation in asthma such as exhaled NO and eosinophil numbers in induced sputum have been developed. Their usefulness in experimental asthma models has been validated but there is less experience in their use in clinical practice. Because specific cooperation may be needed from the patient in producing samples from the airways for assay of biomarkers, younger children may not be suitable. Specific experience in these age groups is required. There remains a need to examine these biomarkers in patients from the mild asymptomatic to the more symptomatic difficult asthmatic in longitudinal studies. Is it useful to monitor these biomarkers as a response to treatment rather than the more conventional measures of symptoms and lung function measurements for prevention of exacerbations and long-term reduction in lung function? Answers to such issues will be crucial in adopting the routine measurement of certain biomarkers from the airways in the assessment of asthma severity and control. PMID- 10093093 TI - Bronchial asthma in infants and children. The German experience. PMID- 10093094 TI - Bronchial asthma in children: clinical and epidemiologic approach in different Portuguese speaking countries. AB - BACKGROUND: Geographical differences in asthma prevalence are currently accepted, but evidence is sparse due to the lack of multicentre studies using the same protocol. OBJECTIVES: To compare the prevalence of asthma and atopy among schoolchildren from Portuguese speaking countries (ISAAC and Portuguese Study) and evaluate some environmental variables, such as house dust mite exposure. MATERIAL AND METHODS: Significant random samples of schoolchildren studied with standard validated methods--questionnaires, skin prick tests, methacholine bronchial challenge tests; dust bed sampling for analysis of mite antigens. RESULTS: In the ISAAC study, in the 13-14 year-old age group, statistical significant differences were found, with higher wheezing prevalence in Brazil than in Portugal (two-fold). In the Portuguese Study, atopy prevalence ranged between 6.0 and 11.9% in Sal and S. Vicente (Cape Verde), up to 48.6 and 54.1% in Macau and Madeira. Active asthma had the higher values in Madeira (14.6%), and the lower in Macau (1.3%). Cape Verde had intermediate asthma prevalence (10.6 and 7.0%). The bronchial challenge test was positive in 25, 66 and 70% of asthmatic children from Sal, S. Vicente and Madeira respectively. Significant HDM antigen concentrations (Der p1) were found in Cape Verde and Madeira. CONCLUSIONS: There are significant variations in asthma and atopy prevalence between these pediatric populations. The reasons remain under discussion, but genetics linked to race, seem to play a central role, modulated by environmental and lifestyle variables. PMID- 10093095 TI - Mechanisms of hypersecretion in acute asthma, proposed cause of death, and novel therapy. AB - Neutrophil chemoattractants cause neutrophil-dependent goblet cell degranulation in guinea pig and human airways through a novel mechanism involving close contact between neutrophils and goblet cells, mediated by neutrophil elastase. The chemoattractant plays various roles in the response: It causes neutrophil recruitment and mobilizes elastase to the surface of the neutrophil. In addition, it induces surface expression of adhesion molecules, which allow the neutrophil to interact with the goblet cell surface, resulting in goblet cell secretion. PMID- 10093096 TI - Chest CT-scan in children: main applications and advantages. PMID- 10093097 TI - Mediastinal and thoracic MRI in children. PMID- 10093098 TI - The recent evolution of pulmonary imaging in the fetus and neonate. PMID- 10093099 TI - Laryngotracheal stenosis. New perspectives. PMID- 10093100 TI - Current approach of primary tracheal dyskinesia. PMID- 10093101 TI - Compression of the trachea in children. PMID- 10093103 TI - Management of chronic sinusitis in children with cystic fibrosis. PMID- 10093102 TI - Laryngotracheal manifestations of gastroesophageal reflux in children. AB - Gastroesophageal reflux is generally a benign condition, which resolves spontaneously, and which is usually manifested by digestive signs. More recently, laryngotracheal conditions such as laryngospasm, laryngomalacia and recurrent laryngitis, have been ascribed to gastroesophageal reflux. However, there is not a single common mechanism linking these two pathologies and different theories are postulated. Diagnosis of gastroesophageal reflux is based essentially on prolonged pH monitoring, where a negative result unfortunately cannot rule out reflux responsibility. Thus, in the end, in the face of a sufficient body of evidence, it is the effectiveness of the anti-reflux treatment which will make it possible to establish a link between gastroesophageal reflux and the laryngotracheal manifestations observed. PMID- 10093104 TI - Towards improved aerosol devices for the young child. PMID- 10093105 TI - Aerosol delivery to children: what to use, how to choose. AB - Careful in vitro assessment of aerosol delivery devices using realistic breathing patterns can be advantageous in choosing an efficient and efficacious delivery system for infants and children. These modeling investigations become more important in assessing delivery to the very young patient, more so if the treatment is not as successful as anticipated. The choices in devices to use for inhalant therapy are increasing and physicians and patients should have a good understanding of the functional differences between them. PMID- 10093106 TI - Therapeutic strategies for treatment of CF based on knowledge of CFTR. AB - CF is one of the first diseases where it is now possible to take an entirely "bottom-up" approach and attempt to develop molecular therapeutics based on fundamental properties of the gene and gene product which cause the disease. As I have tried to illustrate this is a task of enormous magnitude and although significant progress is being made, it is reasonable to expect that considerable time may be required for a satisfactory outcome to be achieved. PMID- 10093107 TI - Pulmonary arteriovenous shunting and pulmonary artery hypertension in children with liver disease. PMID- 10093108 TI - Pulmonary manifestations of rheumatic diseases. AB - The pulmonary manifestations of rheumatic diseases can vary substantially, both in severity and mechanism of injury. There is still relatively little experience with these conditions in the pediatric age group. Perhaps tissue diagnosis will help elucidate the pathophysiology involved and allow for the development of more specific treatment protocols. PMID- 10093109 TI - Immunological aspects of bronchopulmonary disease in cystic fibrosis. PMID- 10093110 TI - Etiology of CF: knowns and unknowns. AB - It is still difficult to rationalize many of the features of CF with mutations in a single gene coding for a protein with one well-established function. The central question to be resolved is whether there are additional functions of CFTR to be discovered which better explain the poorly understood aspects of the molecular pathophysiology. Alternatively, each of the steps between primary chloride channel dysfunction and the different pathological processes must be elucidated. PMID- 10093111 TI - Childhood asthma: outcome after 20 years. PMID- 10093112 TI - Role of neutral endopeptidase and angiotensin converting enzyme in asthma. PMID- 10093113 TI - Current approaches in tracheal surgery. PMID- 10093114 TI - Current surgical treatment for pleural empyema in children. PMID- 10093115 TI - Mixed viral-bacterial pulmonary infections in children. PMID- 10093116 TI - Chemokines and chemokine receptors in allergic diseases. PMID- 10093117 TI - Therapy of allergic pulmonary diseases with anti-IgE antibodies. A review. PMID- 10093118 TI - Inhibition of allergic inflammation in the lung by plasmid DNA allergen immunization. AB - The nature of the immune response (Th1/Th2) in mice to protein antigens or allergens was compared to that of immunization with pDNA encoding the same antigens. pDNA immunization induced a Th1 response and no IgE antibodies whereas the proteins induced a Th2 response and IgE antibodies. Furthermore, the pDNA induced Th1 response dominated over the protein elicited Th2 response in a secondary immune response. In particular, a preexisting Th2 response (as is the case in allergic patients) did not prevent a new Th1 response to an allergen-pDNA booster injection. The major reason why pDNA immunization induced a Th1 response to allergens was the presence of immunostimulatory non-coding DNA sequences (ISS) in the plasmid constructs having a CpG motif. These ISS caused antigen presenting cells to secrete INF-alpha, INF-beta and IL-12, all cytokines that induce naive T cells to differentiate into CD4+ Th1 cells and CD8+ Tc1 cells. Passive transfer of both Th1 and Tc1 cells from pDNA immunized mice into naive mice inhibited a Th2 response and IgE antibody formation to a subsequent injection of allergen in alum. pDNA immunization or ISS-oligonucleotide injection prior to allergen challenge reduced both immediate type airway sensitivity and late phase allergen induced eosinophil filtration of the lung. Allergen-pDNA immunization may provide a novel type of immunotherapy for the treatment of allergic diseases in man. Since only small amounts of allergen are secreted by the allergen-pDNA transformed cells, allergen-pDNA immunotherapy will unlikely carry the risk of the anaphylactic reactions that are associated with classical allergen injection immunotherapy. PMID- 10093119 TI - Bronchoalveolar lavage of newborn infants. AB - NB-BAL is a very useful technique for investigating respiratory disorders of newborn infants. It is safe and easy to perform even in the sickest infants receiving mechanical ventilation. Information about the cellular and molecular processes that may be important in the pathogenesis of neonatal respiratory disorders may be obtained especially since serial BAL is possible. PMID- 10093120 TI - Interventional bronchoscopy. PMID- 10093121 TI - Pediatric bronchoscopy in the 21st century: challenges and opportunities. PMID- 10093122 TI - Directly observed therapy for tuberculosis in children. AB - DOT is an important part of the treatment strategies for tuberculosis in children. It is highly effective, relatively inexpensive, and is the only way to ensure that the child is adequately treated. Although the public health ramifications of inadequate treatment of tuberculosis in children are not as severe as those for inadequate treatment in adults, the personal health consequences of nonadherence in children can be disastrous. In countries with adequate resources, DOT should be considered the standard of care for children with tuberculosis disease. The goal for the world should be to treat every child with tuberculosis with DOT. PMID- 10093123 TI - The immune responses in tuberculosis: role for pathogenesis, diagnosis and prevention. PMID- 10093124 TI - Tuberculosis in children: where do we go now? PMID- 10093125 TI - The role of viral and atypical bacterial pathogens in asthma pathogenesis. AB - The recent development of PCR for the diagnosis of respiratory viral infections has permitted studies revealing the importance of virus infections in acute exacerbations of asthma. Several studies implicate rhinovirus as the major virus type in mild and severe wheezing illness in children of all age groups, but particularly over 1 year of age. Rhinoviruses have been shown to replicate in the lower airway, suggesting that virus induced asthma exacerbations result from direct inoculation, spread of the virus from the upper to the lower airway. The importance of RS virus infection in bronchiolitis and wheezing in infants has been reaffirmed. Recent studies using PCR to detect C pneumoniae, suggests a high prevalence of chronic infection in asthmatic children, and that the immune response to this organism may play a pathological role in asthma. These studies now require confirmation with larger carefully controlled studies. PMID- 10093126 TI - Community-acquired pneumonia: diagnosis and treatment. AB - Community-acquired pneumonia remains a common and serious illness, which affects children of all age groups. The spectrum of causative organisms is wide and it differs according to the age of patients. Therefore, age is a good predictor of the cause of pneumonia. Because of the nonspecificity, of clinical and radiological findings and the limitations of diagnostic tests for identifying the etiologic pathogen, initial therapy is inevitably empiric. PMID- 10093127 TI - Antibiotic therapy of childhood pneumonia. AB - Antibiotic therapy of childhood pneumonia must be based on various factors. Among them, clinical skills, diagnostic studies, knowledge of possible etiologic agents and their in-vitro susceptibility, and avoidance of antibiotic overuse are of greatest importance. The challenge of selective treatment is the reality in developed countries. The equation of pneumonia with antibiotic therapy can no longer be accepted as absolute. If antibiotic therapy is indicated, a new macrolide is usually the drug of choice. PMID- 10093128 TI - Allergic diseases and pediatric allergology in Portugal. PMID- 10093129 TI - Food allergies in Spain: causal allergens and diagnostic strategies. AB - A correct diagnosis of food allergy in the child is based on a careful medical history, together with the demonstration of specific IgE for the involved foods. However, before establishing an elimination diet, the "food-symptoms" relationship must be proven through a controlled challenge test. PMID- 10093130 TI - Parietaria allergy in children. AB - Parietaria, a grassy plant belonging to the Urticaceae family which is commonly found in urban environments, tends to grow on fences, walls and soils with a high content in nitrogen. Since 1983 the Xarxa Aerobiologica de Catalunya (Catalonian Aerobiological Network) has been using Hirst and Court sensors to monitor the daily concentrations of its pollen with respect to the weather conditions (wind, rain, temperature) in various sites in Catalonia and the Balearic Islands. This pollen is present practically all year round in our area, mainly during cold, rainy and seaside areas. Studies at a pediatric level are scarce and this is why we reviewed our data in this field. The study included a total of 12,650 case histories of first time attendances to our Pediatric Allergology Unit; 449 children showed sensitivity to Parietal pollen. Exclusive sensitivity to Parietaria in this age group of 1 and 15 years olds tended to be very low. However, we observed that after initial preferential sensitization to domestic allergens, Parietal pollen became the most frequent cause of sensitivity as the patients grew older. Although rhinoconjunctival manifestations predominate, at least at a pediatric level, the implication of Parietal pollen as a cause of bronchial asthma cannot be ignored. PMID- 10093131 TI - Allergy to house dust mite and snails: a model of cross-reaction between food and inhalant allergens with a clinical impact. AB - A knowledge of cross-reactions between different allergens can facilitate the diagnosis of allergy. IgE cross-reactivity has been identified between house dust mite and snails. While most patients have mild symptoms, asthma and/or anaphylaxis may occur with these and other cross-reacting foods. It may be worthwhile to include measurement of IgE to some edible invertebrate animals in asthmatics, e.g. in mite allergic asthmatic patients who eat snails. PMID- 10093132 TI - Peanut hypersensitivity in children. AB - Peanut is the major allergen in the United States. It is increasing in importance in Europe and has become the principal food allergen affecting children over the age of three years, once hypersensitivity to eggs has resolved. We report 132 pediatric cases of peanut hypersensitivity, confirmed by food challenge. The study group included 86 boys and 46 girls aged between 6 months and 15 years. More than half the children with peanut hypersensitivity were diagnosed before the age of three. The most common symptom was atopic dermatitis (43.1% of cases). The other symptoms observed were hoarseness (34.8%), asthma attacks (13.6%), anaphylaxis (6%), gastrointestinal symptoms (1.5%) and oral syndrome (0.7%). All patients had positive skin prick tests, with a mean wheal diameter of 8 mm (range: 2 to 25 mm). Wheal diameter was significantly smaller in the youngest children (mean 4.5 mm for children under the age of 1 year, p < 0.01). Specific IgE concentration was below 0.75 IU/ml in 16 cases (14.3%), the mean for the entire group being 30.9 IU/ml (range: 0.75 to 100 IU/ml). Food challenges were not performed in three of the eight children with a history of anaphylaxis. Labial food challenge (LFC) was positive in 85 cases (64.8%). An oral food challenge (OFC) was carried out for 45 children (34.3%) and the mean reactive dose was 850 mg (range: 1 mg to 7g). LFC with peanut oil was positive in 2 cases of 50 tested (4%) and 17 of 63 children (29.9%) tested by OFC were also found to be sensitized to peanut oil. Half the children were also hypersensitive to other foods, as demonstrated by oral challenge (53.7%) or sensitized to airborne allergens (62.8%). Hypersensitivity in the very youngest children raises questions about how sensitization occurs. Diagnosis was confirmed by food challenge. Peanut products are very difficult to eliminate from the diet because of inadequate labeling of food products. An ELISA test, available in a number of countries, can be used to detect the allergen. PMID- 10093133 TI - Particularities of pollen allergies in Greece. AB - Pollen allergy is a significant clinical problem in older Greek children causing approximately 25% of respiratory allergic disease in children of mean age 10 years. This is due to climatic conditions that favor rich and long pollinic seasons more so in Central and Southern Greece as well as the Greek islands. Similarities are evident between Greece and other Mediterranean countries, especially Southern Italy and Spain. Most prevalent allergenic plants with known clinical significance are grasses, Olea europaea and Parietaria species. The pollen grains of these plants can reach high atmospheric concentrations if the weather conditions are favorable, causing severe clinical symptoms of rhinoconjunctivitis and/or asthma. Preseasonal and coseasonal drug administration as well as immunotherapy are used in the management of children with pollinosis. More aerobiologic and allergen identification studies at a local level are needed to fully evaluate the type and specific characteristics of pollen allergens in Greece. Furthermore, additional epidemiologic studies in children are necessary to fully appreciate the magnitude of the problem and the natural outcome. PMID- 10093134 TI - Specific childhood allergic diseases in southern Europe: synthesis and conclusions. PMID- 10093135 TI - Functional pulmonary surfactant deficiency and neonatal respiratory disorders. AB - The pathophysiology of functional deficiency of pulmonary surfactant in the neonatal respiratory disorders represented by MAS, hemorrhagic lung edema and ARDS was discussed. The removal of inhibitor(s) is the cardinal procedure for MAS and the lavage with surfactant solution seems to be promising. In case of replacement therapy, we should consider using a different dose compared to the one used in RDS due to lung immaturity, in order to optimize results. PMID- 10093136 TI - New tools in ventilatory support: high frequency ventilation, nitric oxide, tracheal gas insufflation, non-invasive ventilation. AB - Protection of the lungs against ventilator-induced lung injury is becoming one of the main concerns in pediatric and neonatal intensive care. High frequency ventilation using a constant distending pressure with small variations during respiratory cycles allows adequate recruitment. High frequency oscillation is the most promising HFV mode especially in premature neonates but clinical studies are contradictory. Nitric oxide, an inhaled gas with specific pulmonary vasodilating effects, has become a powerful tool in the treatment of pulmonary arterial hypertension alone or in combination with HFO, but studies have failed to show improvement in survival in neonates as well as in children with ARDS. Tracheal gas insufflation, in addition to conventional ventilation, by washing dead space during exhalation, improves gas exchange while lowering tidal volume. It is however still experimental. Maintenance of spontaneous ventilation during conventional ventilation improves gas exchange, hemodynamic functions, mobilization, active coughing, and avoids prolonged muscle weakness. Non invasive modes of ventilation like BiPAP have certain indications in pediatrics but need to become more familiar to the pediatric intensivist. PMID- 10093137 TI - Liquid ventilation: background and clinical trials. PMID- 10093138 TI - New modes of ventilation: a non-aggression pact. PMID- 10093139 TI - Advances in management of sleep apnea syndromes in infants and children. PMID- 10093140 TI - Larynx and neonatal apneas. AB - This paper summarizes current knowledge on laryngeal dynamics during neonatal apneas, including mechanisms potentially involved in mixed/obstructive apneas at the laryngeal level, and recent personal data on active glottic closure throughout spontaneous central apneas (either isolated or in periodic breathing) observed in preterm lambs. It is suggested that this is reminiscent of the basic respiratory pattern in vertebrates alternating periods of lung ventilation with periods of breath-holding with the exchanger full of gas. Moreover, this unique ovine model of spontaneous neonatal apneas and periodic breathing offers new opportunity for studying candidate treatments of neonatal apneas. PMID- 10093141 TI - Cellular and molecular mechanisms responsible for the pathogenesis of primary pulmonary hypertension. PMID- 10093142 TI - Imaging of lung vascularization and perfusion in children. AB - Imaging techniques to evaluate lung perfusion are continuously evolving. Chest film is still the first step. Spiral CT has revolutionized chest imaging in children, MRI is still progressing and thanks to it, multiplanar abilities will probably take a great importance in the future. The accessibility of the machine is still a limiting factor. Angiography is now restricted to interventional procedures. PMID- 10093143 TI - New developments in the pathogenesis and treatment of neonatal pulmonary hypertension. PMID- 10093144 TI - The role of pulmonary inflammation in the development of pulmonary hypertension in newborn with meconium aspiration syndrome (MAS). AB - 1. There was no clear correlation between the tracheal aspirate cytokines and the elevation of pulmonary arterial pressure in newborn piglets with MAS. The use of dexamethasone significantly suppressed tracheal aspirate cytokines but did not significantly alter pulmonary arterial pressure. Dexamethasone significantly increased the cardiac stroke volume and blood pressure. 2. Early dexamethasone therapy (< 12 hrs) for one week in infants with MAS significantly improved pulmonary ventilation and facilitated weaning from mechanical ventilation. 3. The mechanisms for the improvement in cardiopulmonary status following early dexamethasone therapy in MAS remain unclear. An overall improvement in cardiac hemodynamics, along with a significant decrease in lung inflammation may be responsible for the improvement. PMID- 10093145 TI - Corticosteroids and chronic lung disease in extremely immature infants: a dilemma. AB - What is the balance of benefits and risks of dexamethasone in extremely immature infants? The answer remains unclear. We feel that the risks of "early" treatment outweigh the benefits, because many infants who would not develop CLD will be treated. Treatment between day 7 and day 14 seems more appropriate to us, as it focuses on infants with a high risk of developing CLD. However, the lungs may be already somewhat damaged when starting treatment, whose expected benefit is a shortened duration of mechanical ventilation and a decreased incidence of CLD. The risks for growth and brain development are not clearly assessed. Both 7-day courses and pulse therapy are effective, but no comparison of these 2 schedules has been published. We therefore do not know whether pulse therapy provides the same benefits as 7-day courses with fewer risks for growth or cardiomyopathy. PMID- 10093146 TI - Strategy for the prevention and treatment of chronic lung disease of the premature infant. AB - Based on the analyses of approximately 1,000 infants with CLD, this condition was classified into 7 types according to the preceding illnesses and the chest X-ray appearance. The profile of inflammatory enzymes, cytokines and chemical mediators supported the relevance of the classification. Since different insults to the lung with different onsets exhibit the different spectra of the disease, appropriate strategies adapted to each type of CLD should be pursued. For types I and II prophylactic administration of exogenous surfactant, early enough to prevent the oxygen toxicity and barotrauma, is important. RDS can be diagnosed by the stable microbubble rating on gastric aspirates within several minutes of birth. The application of milder modes of ventilation such as HFOV started at birth should also be remembered. The recommended strategies for type IV and V are the care of the very low birth weight infant in the fully humidified incubator with careful fluid administration to prevent symptomatic PDA, and early detection and treatment of infection by screening with sensitive methods such as the APR score. However, the most difficult problem is to identify the correct strategy for type III and III', because these types of CLD can only be prevented by the complete eradication of intrauterine infection. PMID- 10093147 TI - Infant asthma in Tunisia. AB - Asthma is a frequent often unrecognized disease. The aim of this study was to assess the clinical and evolutive characteristics of this disorder in a population of Tunisian hospitalized infants. This is a retrospective study of infants less than 30 months of age, presenting at least 3 episodes of wheezing dyspnea. Our results showed that asthmatic infants accounted for 43% of total asthmatic children. The onset of respiratory symptoms was at the age of 6.9 (5.2) months. The disease began by acute bronchiolitis in 90% of cases. The first asthma attack was severe in 17% of cases. Atopic eczema was found in 15% of cases. A positive family history of allergic disease was noticed by 60% of the patients, 48% of them being asthma. Skin prick tests were positive in 27% of cases and the most frequently identified allergens were dust mites. Among 175 infants treated during more than 24 months, 27% of cases are still symptomatic. Twenty-eight patients have moderate or severe asthma. Atopic family history, positive skin pricks test and acute attack precedents were predictive factors of an unfavorable evolution. It will be necessary to identify as early as possible infants who are genetically predisposed to develop atopy and asthma so that preventive measures can be instituted. PMID- 10093148 TI - Follow-up of childhood asthma in Morocco. PMID- 10093149 TI - Role of allergic factors in childhood asthma in Morocco. PMID- 10093150 TI - Treatment of childhood asthma in Algeria. PMID- 10093151 TI - Profile of the asthmatic child in Lebanon. PMID- 10093152 TI - [Testing the osmotic-diffusion properties for the membranous dressing Bioprocess]. AB - In order to determine of the osmotic-diffusive properties of membranous dressing Bioprocess, which is a microfibrous network of homogeneous cellulose produced in biosynthesis by Acetobacter, the hydraulic permeability (Lp), reflection (sigma) and diffusive permeability (omega) coefficients were measured. The values of these coefficients showed that this membrane possess a low selectivity. This amount it easy permeable for solvent (water) as well as for solutions (aqueous solutions of glucose, sucrose, ethanol, NaCl or KCl). Thus, it attend a demands make for polymeric materials used in therapy of scald and ulceration. PMID- 10093153 TI - [Calculation of the concentration Rayleigh number for isothermal transport processes across a polymeric membrane by a method for measuring diffusion flux in three component non-electrolytic solutions]. AB - A method of determination critical value of concentration Rayleigh Number ((Rci)lim.) in isothermal membrane transport processes of three component non electrolyte solutions was worked out. The method based on the derived in the paper equation, which include membrane transport coefficients (hydraulic permeability, reflection and diffusive permeability coefficients), solution parameters (viscosity coefficient, density and diffusion coefficient in solution). In order to experimental verification of these method the transport coefficients of symmetric flat polymeric membrane, parameters of solutions and diffusive flux for glucose solution in 0.2 mole/l aqueous ethanol solution were determined. Experiments were carried out by osmotic-diffusive single-membrane double-cell system. One cell in all experiments was filled with pure water while the other with the examined solutions. The experimental critical value of concentration Rayleigh Number (RCi)lim. = 1799 is comparable with theoretical critical value of thermal Rayleigh Number (TT)lim. = 1707. PMID- 10093154 TI - [Gravity-osmotic pressure effect for flat polymeric membranes and three-component non-electrolyte solutions]. AB - In this paper the classification of the gravitational effects in a passive transmembrane transport is presented. Among these effects there are the flux (flux graviosmotic effect, flux gravidiffusive, current gravielectric effect) and force (pressure graviosmotic effect, pressure gravidiffusive effect, voltage gravielectric effect) gravitational effects. The pressure graviosmotic effect model equation in a single-membrane system is elaborated. In this system the flat, microporous and symmetric polymeric membrane (Nephrophan) positioned horizontally separated water and binary (aqueous glucose) or ternary (glucose-0.2 mole/l) aqueous ethanol) non-electrolyte solutions. The calculations of pressure graviosmotic effects for two (A and B) configurations of the single-membrane system were elaborated. In configuration A solution was placed in compartment below membrane and in configuration B--above membrane. These calculated results are interpreted in terms of the convective instability that increases the diffusive permeability coefficient of complex: boundary layer/membrane/boundary layer. PMID- 10093155 TI - Cellulose materials modified by antiseptics and their antimicrobial properties. AB - Adsorption properties of dressing cellulose materials with respect to surfactant antiseptics were studied. These antiseptics are a complex of the copolymer of N vinylpyrrolidone and crotonic acid with dimethylbenzylalkylammonium chloride (a synthetic polymer with a wide spectrum of antimicrobial effect) and its low molecular weight analogue (dimethylbenzylalkylammonium chloride). It was established that cellulose materials reversibly adsorb mentioned surfactant antiseptics depending on their concentration in the initial solutions. Maximum release of surfactant antiseptics is achieved at solutions at pH = 7.0. Microbiological tests of cellulose materials modified by antiseptics have shown that they exhibit antimicrobial activity. These results can be used in medical practice in clinics for imparting antimicrobial properties to dressing materials. PMID- 10093156 TI - [Reconstruction of the diaphragm in extensive congenital diaphragmatic hernia]. AB - Congenital diaphragmatic hernia presents a wide spectrum of anatomical variants ranging from small defects to a complete absence of the hemidiaphragm. The surgical correction of this congenital anomaly consists of restoring the continuity of the diaphragmatic barrier after the herniated viscera has been replaced into the abdominal cavity. In some babies primary repair of the diaphragm is not possible due to a significant extent of a defect. In these cases prosthetic diaphragm reconstruction must be carried out. In this paper the pathophysiological aspects of reconstruction of the diaphragm in babies affected by congenital diaphragmatic hernia are discussed. The various methods of diaphragmatic repair including use of prosthetic materials, muscle flaps and autogenous graft are reviewed. The results of experimental studies in animals comparing nonabsorbable and absorbable materials and muscle flaps as a diaphragmatic patch are presented. In view of the fact that the modern neonatal intensive medicine allows more babies with an extensive diaphragmatic defect to survive, the use of various reconstructive techniques will be without doubt play a more important role in their surgical management. PMID- 10093157 TI - [Use of the BIOGRAN preparation in surgical treatment of periodontal disease]. AB - Biogran is bioglass which thanks to its osteoinductive and osteoconductive properties has found application in rebuilding of bone defects caused by a periodontal illness. In the work the properties of the material and the possibilities of clinical application in periodontology are described. Our own experiences resulting from its application in treatment of 83 bone pockets are also presented. PMID- 10093158 TI - [The influence of orthosilicon acid on traumatic edema of the skin. Introduction]. AB - In the Ward of Children Surgery of the local Hospital 35 children from 0 to 15 years old with burn wounds of skin of different degrees have been treated. In surface, medium-deep and deep wounds regression of oedema, reddening and inflammatory reaction were observed already from 2nd day of treatment. Suppuration of wounds was not observed. It was observed that orthosilicon acid has anti-edematous and cooling (reduces pain) effect, quickens epidermization and shortens the time of appearing of granulation in deep burns. We think that orthosilicon acid is preparation worth further clinical testing of its usage in skin illnesses. PMID- 10093159 TI - Improving the measurement and use of tobacco control "inputs". PMID- 10093160 TI - Cigarette testing methods, product design, and labelling: time to clean up the "negative baggage". PMID- 10093162 TI - Senegal: now you see it, now you don't--PM's April fool's joke on Clinton. PMID- 10093161 TI - Impact of a gallery of posters on quitting smoking. PMID- 10093163 TI - How to make the US State Department's tobacco directive work for you: Senegal's case. PMID- 10093164 TI - EU/UK: ad ban busting plan. PMID- 10093165 TI - Alaska: trampling tobacco. PMID- 10093166 TI - State laws on youth access to tobacco in the United States: measuring their extensiveness with a new rating system. AB - OBJECTIVE: To develop and implement a rating system evaluating the extensiveness of state laws restricting youth access to tobacco. DESIGN: State laws on youth access to tobacco were analysed and assigned ratings on nine items. Six items addressed specific tobacco-control provisions, and three related to enforcement provisions. For each item, a target was specified reflecting public health objectives. Achieving the target resulted in a rating of +4 points; for three items, a rating of +5 was possible if the target was exceeded. Criteria for lower ratings were established for situations when the target was not met. SETTING: United States. RESULTS: State scores (sum of the ratings across all nine items) ranged from 0-18 in 1993, 2-21 in 1994, and 1-21 in 1995 and 1996, out of a possible total of 39. The average score across states was 7.2 in 1993, 7.9 in 1994, 8.2 in 1995, and 9.0 in 1996. The overall mean rating (per item) was 0.80 in 1993, 0.88 in 1994, 0.91 in 1995, and 1.00 in 1996, on a scale where 4.0 indicates that the target goals (per item) were met. From 1993 to 1996, scores increased for 20 states, decreased for one state, and remained unchanged for the others. The number of states for which state preemption of local tobacco regulation was a factor doubled from 10 states in 1993 to 20 states in 1996. CONCLUSIONS: Although all states have laws addressing youth access to tobacco, this analysis reveals that, as of the end of 1996, the progress towards meeting health policy targets is slow, and state legislation that preempts local tobacco regulation is becoming more common. PMID- 10093167 TI - Gender and ethnic differences in young adolescents' sources of cigarettes. AB - OBJECTIVE: To identify the sources used by young adolescents to obtain cigarettes. DESIGN: In early 1994 a survey assessing usual sources of cigarettes and characteristics of the respondents was administered in homeroom classes. SETTING: A large urban, predominantly African American school system. SUBJECTS: A population-based sample of 6967 seventh graders averaging 13 years of age. MAIN OUTCOME MEASURE: Reports of usual sources of cigarettes. RESULTS: At this age level, young smokers were more likely to get cigarettes from friends (31.2%) than buy them in stores (14.3%). However, the odds of purchasing varied for different groups of children. Regular smokers were much more likely (48.3%) to have purchased cigarettes than experimental smokers (9.6%), p < 0.001. Girls were less likely to have bought their cigarettes than boys (p < 0.001), and black smokers were less likely to have purchased cigarettes than white children (p < 0.001). Results suggested that family members who smoke may constitute a more important source of tobacco products than previously recognised, particularly for young girls. CONCLUSIONS: In this middle-school sample, peers provided the major point of cigarette distribution. However, even at this age, direct purchase was not uncommon. Sources of cigarettes varied significantly with gender, ethnicity, and smoking rate. PMID- 10093168 TI - Influence of physician and patient gender on provision of smoking cessation advice in general practice. AB - OBJECTIVE: To examine the association between physician and patient gender and physicians' self-reported likelihood of providing smoking cessation advice to smokers using hypothetical case scenarios in primary care. DESIGN: Cross sectional analysis of a self-administered questionnaire. SUBJECTS: National random sample of Australian general practitioners (GPs). MAIN OUTCOME MEASURES: Self-reported likelihood of advising hypothetical male and female smokers to stop smoking during a consultation for ear-syringing ("opportunistic" approach) or a dedicated preventive health "check up". RESULTS: 855 GPs returned questionnaires (67% response rate). Significantly more respondents indicated they would be "highly likely" to initiate an opportunistic discussion about smoking with a male smoker (47.8% (95% confidence intervals (CI) = 44.5 to 51.2)) than a female smoker (36.3% (95% CI = 33.1 to 39.5]). Older, male GPs were less likely to adopt an opportunistic approach to smoking cessation for patients of either sex. Respondents were more likely to recommend that a male patient return for a specific preventive health check up. Furthermore, in the context of a health check up, a greater proportion in total of respondents indicated they would be "highly likely" to discuss smoking with a man (86.9%, 95% CI = 84.5 to 89.0) than a female smoker (82.5%, 95% CI = 79.8 to 84.9). CONCLUSIONS: As measured by physician self-report, the likelihood of advising smokers to quit during primary care consultations in Australia appears to be influenced by gender bias. Gender sensitive strategies to support cessation activities are recommended. PMID- 10093169 TI - Does over-the-counter nicotine replacement therapy improve smokers' life expectancy? AB - OBJECTIVE: To determine the public health benefits of making nicotine replacement therapy available without prescription, in terms of number of quitters and life expectancy. DESIGN: A decision-analytic model was developed to compare the policy of over-the-counter (OTC) availability of nicotine replacement therapy with that of prescription ([symbol: see text]) availability for the adult smoking population in the United States. MAIN OUTCOME MEASURES: Long-term (six-month) quit rates, life expectancy, and smoking attributable mortality (SAM) rates. RESULTS: OTC availability of nicotine replacement therapy would result in 91,151 additional successful quitters over a six-month period, and a cumulative total of approximately 1.7 million additional quitters over 25 years. All-cause SAM would decrease by 348 deaths per year and 2940 deaths per year at six months and five years, respectively. Relative to [symbol: see text] nicotine replacement therapy availability, OTC availability would result in an average gain in life expectancy across the entire adult smoking population of 0.196 years per smoker. In sensitivity analyses, the benefits of OTC availability were evident across a wide range of changes in baseline parameters. CONCLUSIONS: Compared with [symbol: see text] availability of nicotine replacement therapy, OTC availability would result in more successful quitters, fewer smoking-attributable deaths, and increased life expectancy for current smokers. PMID- 10093170 TI - Filter ventilation and nicotine content of tobacco in cigarettes from Canada, the United Kingdom, and the United States. AB - OBJECTIVES: The purpose was to determine filter ventilation and the nicotine content of tobacco and their contribution to machine-smoked yields of cigarettes from the United States, Canada, and the United Kingdom. METHODS: Ninety-two brands of cigarettes (32 American, 23 Canadian, and 37 British brands) were purchased at retail outlets in State College, Pennsylvania, United States, Toronto, Canada, and London, United Kingdom. A FIDUS FDT filter ventilation tester measured the percentage air-dilution from filter vents. High-pressure, liquid chromatography was used to measure the nicotine content of tobacco. Regression techniques were used to examine the contributions of tobacco nicotine content and filter ventilation to machine-smoked yields of tar, nicotine, and carbon monoxide (CO). RESULTS: Ninety-four per cent of the American brands, 91% of the Canadian brands, and 79% of British brands were ventilated. The total nicotine content of tobacco and percent nicotine (by weight of tobacco) averaged 10.2 mg (standard error of the mean (SEM) 0.25, range: 7.2 to 13.4) and 1.5% (SEM 0.03, range 1.2 to 2) in the United States, 13.5 mg (SEM 0.49, range: 8.0 to 18.3) and 1.8% (SEM 0.06, range: 1.0 to 2.4) in Canada, 12.5 mg (SEM 0.33, range: 9 to 17.5) and 1.7% (SEM 0.04, range: 1.3 to 2.4) in the United Kingdom. Multiple regression analyses showed that ventilation was by far the largest factor influencing machine-smoked yields of tar, nicotine, and CO. CONCLUSION: Filter ventilation appears to be the predominant method for reducing machine-smoked yields of tar, nicotine, and CO in three countries. However, some brands contain about twice as much nicotine (total content or percent nicotine) as do others, indicating that tobacco types or blends and tobacco castings can be used to manipulate nicotine content and nicotine delivery of cigarettes. PMID- 10093171 TI - Predictors of crop diversification: a survey of tobacco farmers in North Carolina (USA). AB - OBJECTIVE: To assess the attitudes and behaviours of North Carolina tobacco farmers around crop diversification. DESIGN: Cross-sectional telephone survey. PARTICIPANTS: Active tobacco farmers in 14 North Carolina counties (n = 1236), interviewed between January and April 1997 (91% response rate). OUTCOME MEASURES: Interest in, experience with, and perceived barriers to diversification. RESULTS: Most farmers (95%) grew/raised a commodity other than tobacco (mean = 2.8). A total of 60% of farmers expressed interest in trying other on-farm activities to supplement their tobacco and 60% reported taking action in the past year around supplementation. Younger age and college education were positively associated with interest. College education, off-farm income, and larger farm size were associated with the number of actions taken. For perceived external barriers to diversification, use of tobacco, percent income from tobacco, lack of college education, and younger age were most strongly associated with the number of barriers. For internal barriers (personal factors), percent income from tobacco, use of tobacco, and lack of college education were most strongly associated with the number of barriers. CONCLUSIONS: Most farmers were involved in diverse operations and expressed interest in continuing to diversify, although the breadth of diversification was narrow. Farmers noted many barriers to diversifying. If conventional production and marketing techniques are employed for non-tobacco alternatives, these alternatives may not provide the sustainable profitability that tobacco has afforded. Competition from foreign tobacco growers is the primary threat to the future of American growers and tobacco dependent communities. PMID- 10093172 TI - Patterns of smoking in Bulgaria. AB - BACKGROUND: Although the rate of smoking-related deaths in Bulgaria is still relatively low, in international terms, it has been rising rapidly. This is likely to become worse in the future as Bulgaria faces growing pressure from transnational tobacco companies. There is, however, little information on patterns of smoking, which is necessary for development of effective policies to tackle tobacco consumption. OBJECTIVE: To describe the pattern of smoking in Bulgaria and its relationship with sociodemographic factors. DESIGN: Multivariate analysis of data on patterns of tobacco consumption from a multi-stage nationwide survey of 1550 adults. SETTING: Bulgaria, in 1997. MAIN OUTCOME MEASURE: Prevalence of current cigarette smoking. RESULTS: 38.4% of men and 16.7% of women smoke. Smoking rates are strongly associated with age, with 58% of men and 30% of women aged 30-39 smoking whereas only 5% of men aged 70 years and older and almost no women of this age smoke. Smoking is more common in cities, among those who are widowed or divorced, or who do not own their home. There is no clear association with household income or, for men, with education, although there is a suggestion that smoking may be more common among more highly educated women. CONCLUSIONS: The observed pattern of smoking indicates the need for a robust policy to tackle smoking in Bulgaria, especially among the young in large cities, informed by a better understanding of why smoking rates vary among different groups. PMID- 10093173 TI - Recognition of cigarette brand names and logos by primary schoolchildren in Ankara, Turkey. AB - OBJECTIVE: To assess the smoking behaviour of primary schoolchildren and their ability to recognise brand names and logos of widely advertised cigarettes, compared with other commercial products intended for children. DESIGN: Cross sectional survey in classroom settings using a questionnaire designed to measure attitudes towards smoking and the recognition of brand names and logos for 16 food, beverage, cigarette, and toothpaste products. SETTING: Ankara, Turkey. SUBJECTS: 1093 children (54.6% boys, 44.4% girls) aged 7-13 years (mean = 10, SD = 1), from grades 2-5. The student sample was taken from three primary schools- one school in each of three residential districts representing high, middle, and low income populations. MAIN OUTCOME MEASURES: Prevalence of ever-smoking, recognition of brand names and logos. RESULTS: Prevalence of ever-smoking was 11.7% overall (13.9% among boys and 9.1% among girls; p < 0.05). Children aged eight years or less had a higher prevalence of ever-smoking (19.6%) than older children (p < 0.002). Ever-smoking prevalence did not differ significantly across the three school districts. Ever-smoking prevalence was higher among children with at least one parent who smoked (15.3%) than among those whose parents did not (4.8%) (p < 0.001). Brand recognition rates ranged from 58.1% for Chee-tos (a food product) to 95.2% for Samsun (a Turkish cigarette brand). Recognition rates for cigarette brand names and logos were 95.2% and 80.8%, respectively, for Samsun; 84.0% and 90.5%, respectively, for Camel; and 92.1% and 69.5%, respectively, for Marlboro. The Camel logo and the Samsun and Marlboro brand names were the most highly recognised of all product logos and brand names tested. CONCLUSIONS: The high recognition of cigarette brand names and logos is most likely the result of tobacco advertising and promotion. Our results indicate the need to implement comprehensive tobacco control measures in Turkey. PMID- 10093174 TI - The tobacco scandal: where is the outrage? PMID- 10093175 TI - Tobacco control advocates must demand high-quality media campaigns: the California experience. AB - OBJECTIVE: To document efforts on the part of public officials in California to soften the media campaign's attack on the tobacco industry and to analyse strategies to counter those efforts on the part of tobacco control advocates. METHODS: Data were gathered from interviews with programme participants, direct observation, written materials, and media stories. In addition, internal documents were released by the state's Department of Health Services in response to requests made under the California Public Records Act by Americans for Nonsmokers' Rights. Finally, a draft of the paper was circulated to 11 key players for their comments. RESULTS: In 1988 california voters enacted Proposition 99, an initiative that raised the tobacco tax by $0.25 and allocated 20% of the revenues to anti-tobacco education. A media campaign, which was part of the education programme, directly attacked the tobacco industry, exposing the media campaign to politically based efforts to shut it down or soften it. Through use of outsider strategies such as advertising, press conferences, and public meetings, programme advocates were able to counter the efforts to soften the campaign. CONCLUSION: Anti-tobacco media campaigns that expose industry manipulation are a key component of an effective tobacco control programme. The effectiveness of these campaigns, however, makes them a target for elimination by the tobacco industry. The experience from California demonstrates the need for continuing, aggressive intervention by nongovernmental organisations in order to maintain the quality of anti-tobacco media campaigns. PMID- 10093177 TI - Patient perceptions: an important contributor to how physicians approach tobacco cessation. PMID- 10093178 TI - Quality in quantity: in support of consistent, physician-delivered smoking intervention. PMID- 10093179 TI - Consolidation in the tobacco industry. PMID- 10093176 TI - Psychosocial factors related to adolescent smoking: a critical review of the literature. AB - OBJECTIVE: To extend the analysis of psychosocial risk factors for smoking presented in the United States surgeon general's 1994 report on smoking and health, and to propose a theoretical frame of reference for understanding the development of smoking. DATA SOURCES: General Science Index, Medline, PsycLIT, Sociofile, Sociological Abstracts, and Smoking and Health. Holdings of the Addiction Research Foundation of Ontario Library as well as the authors' personal files. STUDY SELECTION: Reviewed literature focused on studies that examined the association of sociodemographic, environmental, behavioural, and personal variables with smoking. DATA SYNTHESIS: Adolescent smoking was associated with age, ethnicity, family structure, parental socioeconomic status, personal income, parental smoking, parental attitudes, sibling smoking, peer smoking, peer attitudes and norms, family environment, attachment to family and friends, school factors, risk behaviours, lifestyle, stress, depression/distress, self-esteem, attitudes, and health concerns. It is unclear whether adolescent smoking is related to other psychosocial variables. CONCLUSIONS: Attempts should be made to use common definitions of outcome and predictor variables. Analyses should include multivariate and bivariate models, with some attempt in the multivariate models to test specific hypotheses. Future research should be theory driven and consider the range of possible factors, such as social, personal, economic, environmental, biological, and physiological influences, that may influence smoking behaviour. The apparent inconsistencies in relationships between parental socioeconomic status and adolescent disposable income need to be resolved as does the underlying constructs for which socioeconomic status is a proxy. PMID- 10093180 TI - Strategic marketing of cigarettes to young people in Sri Lanka: "go ahead--I want to see you smoke it now". PMID- 10093181 TI - Y-1 papers, white paper, Chinese mortality, BC ingredient disclosure, SRNT, PANNA, foundation watch, plus youth shoplifting. PMID- 10093182 TI - Smoking in movies remained high in 1997. PMID- 10093183 TI - Smoking: rates and attitudes among health services staff in central Sydney, Australia. PMID- 10093184 TI - "Zero tolerance" for student smokers. PMID- 10093185 TI - Managed care and approaches to tobacco control. PMID- 10093186 TI - "One sure way to break the cycle". PMID- 10093187 TI - Challenges and opportunities for tobacco control: the Robert Wood Johnson Foundation agenda. PMID- 10093188 TI - Results from the first annual survey on addressing tobacco in managed care. PMID- 10093189 TI - Overview of the Agency for Health Care Policy and Research guideline. PMID- 10093190 TI - Dissemination of the Agency for Health Care Policy and Research guideline. PMID- 10093191 TI - Changing practice patterns as a result of implementing the Agency for Health Care Policy and Research guideline in 20 primary care clinics. PMID- 10093192 TI - Building effective strategies to decrease tobacco use in a health maintenance organisation: Group Health Cooperative of Puget Sound. PMID- 10093193 TI - Forming community coalitions: "smoking stinks". PMID- 10093194 TI - Anti-tobacco media campaign for young people. PMID- 10093195 TI - Using multiple interventions to make an impact in the community. PMID- 10093196 TI - An overview of tobacco measures. PMID- 10093197 TI - Waking the health plan giant: Group Health Cooperative stops counting sheep and starts counting key tobacco indicators. AB - Implementing a comprehensive approach to decreasing tobacco use in a large health plan requires hard work and commitment on the part of many individuals. We found that major organisational change can be accomplished and sustained. Keys to our success included our decision to remove access barriers to our cessation programmes (including cost); obtaining top leadership buy-in; identifying accountable individuals who owned responsibility for change; measuring key processes and outcomes; and finally keeping at it tenaciously through multiple cycles of improvement. PMID- 10093198 TI - Smoking as a vital sign: a work in progress. PMID- 10093199 TI - Smoking out the incentives for tobacco control in managed care settings. PMID- 10093200 TI - Percutaneous ethanol injection in treatment of benign nonfunctional and hyperfunctional thyroid nodules. AB - In recent years a new method of treatment of thyroid disorders, percutaneous ethanol injection (PEI), has been successfully used as an alternative to surgery for the management of benign nodules. In this study 103 females and 5 males (34.4 +/- 11.3 yrs) with nonfunctional cystic (23) or solid (38) nodules, and also 47 with hyperfunctional solid nodules, were treated with single or repeated ethanol injections. In all patients, the cytological studies, ultrasound evaluation and the levels of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin or thyroids-stimulating hormone (TSH) before and after ethanol administration, were determined. The patients were followed up for 12-36 months. The size of the benign nonfunctional nodules was totally reduced in 49.9% of cases with solid and in 60.9% of patients with cystic nodules. Hyperthyroidism was cured in 91.5% of patients. The PEI procedure was connected with a few significant complications only, in relation to the localization of nodules. It was cheap, possible on an outpatient basis, easy to perform and acceptable to patients. Since the cost of thyroidectomy is high and the complication rate significant, PEI is a suitable substitute treatment especially for some patients with small toxic benign nodules of the thyroid gland. PMID- 10093201 TI - Evaluation of killing, superoxide anion and nitric oxide production by Leishmania infantum-infected dog monocytes. AB - Protozoa of the genus Leishmania infect reticuloendothelial cells of several mammalian species, including dogs, in which they often give rise to a chronic, not self-healing visceral disease. The parasitocidal mechanism of peripheral blood monocytes towards Leishmania in the dog has not been investigated in detail. Consequently, Leishmania infantum-infected monocyte cultures of healthy dogs were evaluated using the following parameters: (1) phagocytosis and killing capacities; (2) oxidative burst, in terms of superoxide anion (O2-) release, and (3) nitric oxide (NO) activity, in terms of nitrite (NO2-) production in the presence or absence of the NO synthase inhibitor NG-monomethyl-L-arginine (NGMMLA). Parallel experiments were performed on monocytes stimulated with supernatants of concanavalin A-activated PBMC and on unstimulated monocytes. The amount of IFN-gamma in PBMC supernatants used for monocyte activation was determined by a biological assay on a canine Madin Darby cell line. Results demonstrated that phagocytosis, killing capacity and O2- production significantly increased in monocytes stimulated with supernatants, in comparison with unstimulated cells. A positive correlation was observed between the killing capacity, the O2- production and the amount of IFN-gamma in PBMC supernatants employed for monocyte activation. No significant differences were observed in NO production between unstimulated and stimulated cultures, or between the same cultures with and without NGMMLA. Finally, the killing percentage was similar in the presence or absence of NGMMLA, suggesting that in this experimental model peripheral blood dog monocytes lack NO-mediated killing. PMID- 10093202 TI - Ultrastructure of spermatozoa correlated with phylogenetic relationship between Heteropneustes fossilis and Rana tigrina. AB - A study using transmission electron microscopy (TEM) of the spermatozoa of Rana tigrina and Heteropneustes fossilis in all phases of the annual reproductive cycle revealed that there was a phylogenetic relationship between them. The spermatozoa of H. fossilis appeared horseshoe-shaped, somewhat oval or wedge shaped at the anterior end and broader at the posterior end. The horseshoe-shaped spermatozoan nucleus was observed during spermiogenesis of R. tigrina but later changed into a finger shape at maturity. The posterior end of the nuclei of mature spermatozoa of R. tigrina was blunt. The extremely dense homogenized nucleus was capped with an acrosomal vesicle in both species suggesting a definite phylogenetic inter-relationship between them. PMID- 10093203 TI - Isolation of an osmotolerant ale strain of Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae (ale strain) grown in batch culture to stationary phase was tested for its tolerance to heat (50 degrees C for 5 min), hydrogen peroxide (0.3 M) and salt (growth in 1.5 M sodium chloride/YPD medium). Yeast cells which have been exposed previously to heat shock are more tolerant to hydrogen peroxide and high salt concentrations (1.5 M NaCl) than the controls. Their fermentative activity as judged by glucose consumption and their viability, as judged by cell number and density have higher levels when compared with cells not previously exposed to heat shock. Experimental conditions facilitated the isolation of S. cerevisiae ale strain, which was tolerant to heat, and other agents such as hydrogen peroxide and sodium chloride. PMID- 10093204 TI - The physiological properties of human red cells as derived from kinetic osmotic volume changes. AB - Volume changes were originally used for studying the dynamic properties of glucose transport in red cells. As an extension it has been found possible to examine the interplay of three functional proteins evolved for the physiological role of human erythrocytes in transporting carbon dioxide and bicarbonate. The proteins chiefly concerned in this investigation were the cytoplasmic carbonic anhydrase and the two membrane transporting proteins, namely the band 3 anion exchanger and the unique bicarbonate transporter, which are distinct from the anion exchanger. The rates of anion membrane transport measured and the volume changes may be more than two orders of magnitude faster than those which regulate cationic movement in red cells, but this may only be an adaptation for the physiological role of red cells. The new concepts derived from the studies and their possible wider applications to physiological mechanisms are briefly discussed. PMID- 10093205 TI - Semantic and phonological information flow in the production lexicon. AB - When speakers produce words, lexical access proceeds through semantic and phonological levels of processing. If phonological processing begins based on partial semantic information, processing is cascaded; otherwise, it is discrete. In standard models of lexical access, semantically processed words exert phonological effects only if processing is cascaded. In 3 experiments, speakers named pictures of objects with homophone names (ball), while auditory distractor words were heard beginning 150 ms prior to picture onset. Distractors speeded picture naming (compared with controls) only when related to the nondepicted meaning of the picture (e.g., dance), exhibiting an early phonological effect, thereby supporting the cascaded prediction. Distractors slowed picture naming when categorically (e.g., frisbee) related to the depicted picture meaning, but not when associatively (e.g., game) related to it. An interactive activation model is presented. PMID- 10093206 TI - Semantic and phonological codes interact in single word production. AB - The relationship between semantic-syntactic and phonological levels in speaking was investigated using a picture naming procedure with simultaneously presented visual or auditory distractor words. Previous results with auditory distractors have been used to support the independent stage model (e.g., H. Schriefers, A. S. Meyer, & W. J. M. Levelt, 1990), whereas results with visual distractors have been used to support an interactive view (e.g., P.A. Starreveld & W. La Heij, 1996b). Experiment 1 demonstrated that with auditory distractors, semantic effects preceded phonological effects, whereas the reverse pattern held for visual distractors. Experiment 2 indicated that the results for visual distractors followed the auditory pattern when distractor presentation time was limited. Experiment 3 demonstrated an interaction between phonological and semantic relatedness of distractors for auditory presentation, supporting an interactive account of lexical access in speaking. PMID- 10093207 TI - Time course of word identification and semantic integration in spoken language. AB - The minimum duration signal necessary to identify a set of spoken words was established by the gating technique; most words could be identified before their acoustic offset. Gated words were used as congruous and incongruous sentence completions, and isolation points established in the gating experiment were compared with the time course of semantic integration evident in event-related brain potentials. Differential N400 responses to contextually appropriate and inappropriate words were observed about 200 ms before the isolation point. Semantic processing was evident before the acoustic signal was sufficient to identify the words uniquely. Results indicate that semantic integration can begin to operate with only partial, incomplete information about word identity. Influences of semantic constraint, word frequency, and rate of presentation are described. PMID- 10093208 TI - Amount of reward has opposite effects on the discounting of delayed and probabilistic outcomes. AB - Previous research has shown that the value of large future rewards is discounted less steeply than is the value of small future rewards. These experiments extended this line of research to probabilistic rewards. Two experiments replicated the standard findings for delayed rewards but demonstrated that amount has an opposite effect on the discounting of probabilistic rewards. That is, large probabilistic amounts were discounted at the same or higher rates than small amounts. Although amount had opposite effects on the discounting of delayed and probabilistic rewards, nevertheless, the same form of mathematical function accurately described discounting of both types of reward. The findings suggest that fundamentally similar, but not identical, processes are involved in decision making regarding delayed and probabilistic rewards. The implications of these findings for impulsivity and self-control are discussed. PMID- 10093209 TI - Think before you speak: pauses, memory search, and trace redintegration processes in verbal memory span. AB - Immediate memory span and speed of memory search were assessed for words and nonwords of short and long spoken duration. Memory span was substantially greater for words than for nonwords and for short than for long items, though speed of memory search was unaffected by either length or lexicality. An analysis of the temporal pattern of responses in the memory span task indicated that inter-item pauses were longer between nonwords than words but that these pause durations were unaffected by item length. A model of verbal short-term memory span is described in which trace selection from a short-term store and the redintegration (restoration) of degraded phonological traces both occur in the pauses between saying successive items. Both trace selection and trace redintegration appear to play important roles in accounting for individual differences in memory span. PMID- 10093210 TI - Quantitative determination of E5880 in rat plasma by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. AB - A simple and sensitive method is described for the determination of E5880 in rat plasma. The method is based on high-performance liquid chromatography/electrospray ionization mass spectrometry, using deuterated E5880 as an internal standard. Selected reaction monitoring is employed for selectivity and sensitivity, this in turn enables quantification in a short period of time (within 7 minutes) over the extended range of 0.1-1000 ng/ml with acceptable precision and accuracy. The method demonstrated to be suitable for the quantitative analysis of E5880 in rat plasma. The pharmacokinetic profile of E5880 after a single intravenous administration of E5880 was elucidated. PMID- 10093211 TI - Matrix optimization for matrix-assisted laser desorption/ionization mass spectrometry of oligosaccharides from human milk. AB - Neutral and acidic oligosaccharides from human milk were analyzed by matrix assisted laser desorption/ionization mass spectrometry (MALDI/MS). These experiments require suitable matrices; their selection and particularly their preparation protocols must be optimized. Important criteria are sensitivity, reproducibility, tolerance against impurities and resolution over a wide mass range. For analytical investigations of these oligosaccharides, containing labile fucosylated and sialylated components, another property of a matrix becomes a significant factor, namely the influence on ion stability and the extent of (metastable) fragmentation. The experience gained with the MALDI/MS of neutral and acidic oligosaccharides is summarized taking into account different intentions of measurement and typical problems, such as impurities after enzymatic treatment. For a rapid screening of an oligosaccharide sample, superior results were obtained with a new preparation technique using 5-chloro-2 mercaptobenzothiazole (CMBT) as the first layer for 2,5-dihydroxybenzoic acid. For structural analysis by post-source decay, CMBT as the first layer for 3 aminoquinoline is a favoured preparation protocol, because extensive fragmentation is achieved. For acidic oligosaccharides, a special preparation protocol makes it possible to determine the number of sialic acids by inducing highly effective cationization. Matrix-assisted laser desorption/ionization mass spectrometry; matrices; oligosaccharides; post-source decay. PMID- 10093212 TI - Sample purification and preparation technique based on nano-scale reversed-phase columns for the sensitive analysis of complex peptide mixtures by matrix-assisted laser desorption/ionization mass spectrometry. AB - A simple reversed-phase nano-column purification and sample preparation technique is described, which markedly improves the mass spectrometric analysis of complex and contaminated peptide mixtures by matrix-assisted laser desorption/ionization (MALDI). The method is simple, fast and utilizes only low-cost disposables. After loading the sample on the column and a subsequent washing step, the analyte molecules are eluted with 50-100 nl of matrix solution directly on to the MALDI/MS target. The washing step ensures removal of a wide range of contaminants. The small bed volume of the column allows efficient sample concentration and the elution process yields very small sample spots. This simplifies the analysis and minimizes discrimination effects due to sample heterogeneity, because the desorption/ionization laser simultaneously irradiates a large portion of the sample. Taken together, these features of the method significantly improve the sensitivity for MALDI/MS analysis of contaminated peptide samples compared with the commonly used sample preparation procedures. This is demonstrated with in-gel tryptic digests of proteins from human brain that were separated by 2D gel electrophoresis. Furthermore, it is shown that with this method 2,5-dihydroxybenzoic acid (DHB) acts as an efficient matrix for peptide mapping. Both detection sensitivity and sequence coverage are comparable to those obtained with the currently preferred matrix alpha-cyano-4 hydroxycinnamic acid (CHCA). The higher stability of peptide ions generated with DHB compared with CHCA is advantageous when analyzing fragile sample molecules. Therefore, the method described here is also of interest for the use of Fourier transform ion cyclotron resonance (FT-ICR) or ion-trap mass analyzers. PMID- 10093213 TI - Conformations of protonated gas-phase bradykinin ions: evidence for intramolecular hydrogen bonding. AB - The post-source decay of bradykinin, Lys1-bradykinin, des-Arg1-bradykinin, des Arg9-bradykinin and [D-Phe7]-bradykinin [M + H]+ ions was examined in order to assertain the influence of secondary structure on peptide ion dissociation. Fragment ions corresponding to the elimination of H2O and HN=C=NH are observed in the product ion mass spectra of Lys1-bradykinin and des-Arg1-bradykinin but not in the spectra of bradykinin or des-Arg9-bradykinin. Cleavage reactions at the Phe-Ser and/or Ser-Pro bonds are observed for all peptide [M + H]+ ions with the exception of des-Arg9-bradykinin. The product ions arising from the processes described above are rationalized in terms of the intramolecular solvation of the protonated guanidino groups of the arginines. The strongest intramolecular interaction appears to be a proton bridge between the guanidino groups of the N- and C-terminal arginines in bradykinin. In addition, increased abundances of fragment ions in the vicinity of Ser-Pro may be attributed to intramolecular solvation of the protonated C-terminal guanidino group by the Ser-Pro portion of the molecule. This self-solvation of the ionizing proton leads to a gas-phase peptide conformation that is supported by solution-phase NMR studies at elevated temperatures and in non-polar solvents but which is different from the conformation in polar solvents. PMID- 10093214 TI - The Drosophila virilis alcohol dehydrogenase catalytic residues are conserved. PMID- 10093215 TI - A novel approach to phylogeny reconstruction from protein sequences. AB - The reliable reconstruction of tree topology from a set of homologous sequences is one of the main goals in the study of molecular evolution. If consistent estimators of distances from a multiple sequence alignment are known, the distance method is attractive because the tree reconstruction is consistent. To obtain a distance estimate d, the observed proportion of differences p (p distance) is usually "corrected" for multiple and back substitutions by means of a functional relationship d = f(p). In this paper the conditions under which this correction of p-distances will not alter the selection of the tree topology are specified. When these conditions are not fulfilled the selection of the tree topology may depend on the correction function applied. A novel method which includes estimates of distances not only between sequence pairs, but between triplets, quadruplets, etc., is proposed to strengthen the proper selection of correction function and tree topology. A "super" tree that includes all tree topologies as special cases is introduced. PMID- 10093216 TI - Estimation of the transition/transversion rate bias and species sampling. AB - The transition/transversion (ti/tv) rate ratios are estimated by pairwise sequence comparison and joint likelihood analysis using mitochondrial cytochrome b genes of 28 primate species, representing both the Strepsirrhini (lemurs and lories) and the Anthropoidea (monkeys, apes, and humans). Pairwise comparison reveals a strong negative correlation between estimates of the ti/tv ratio and the sequence distance, even when both are corrected for multiple substitutions. The maximum-likelihood estimate of the ti/tv ratio changes with the species included in the analysis. The ti/tv bias within the lemuriform taxa is found to be as strong as in the anthropoids, in contradiction to an earlier study which sampled only one lemuriform. Simulations show the surprising result that both the pairwise correction method and the joint likelihood analysis tend to overcorrect for multiple substitutions and overestimate the ti/tv ratio, especially at low sequence divergence. The bias, however, is not large enough to account for the observed patterns. Nucleotide frequency biases, variation of substitution rates among sites, and different evolutionary dynamics at the three codon positions can be ruled out as possible causes. The likelihood-ratio test suggests that the ti/tv rate ratios may be variable among evolutionary lineages. Without any biological evidence for such a variation, however, we are left with no plausible explanations for the observed patterns other than a possible saturation effect due to the unrealistic nature of the model assumed. PMID- 10093217 TI - Compositional bias may affect both DNA-based and protein-based phylogenetic reconstructions. AB - It is now well-established that compositional bias in DNA sequences can adversely affect phylogenetic analysis based on those sequences. Phylogenetic analyses based on protein sequences are generally considered to be more reliable than those derived from the corresponding DNA sequences because it is believed that the use of encoded protein sequences circumvents the problems caused by nucleotide compositional biases in the DNA sequences. There exists, however, a correlation between AT/GC bias at the nucleotide level and content of AT- and GC rich codons and their corresponding amino acids. Consequently, protein sequences can also be affected secondarily by nucleotide compositional bias. Here, we report that DNA bias not only may affect phylogenetic analysis based on DNA sequences, but also drives a protein bias which may affect analyses based on protein sequences. We present a striking example where common phylogenetic tools fail to recover the correct tree from complete animal mitochondrial protein coding sequences. The data set is very extensive, containing several thousand sites per sequence, and the incorrect phylogenetic trees are statistically very well supported. Additionally, neither the use of the LogDet/paralinear transform nor removal of positions in the protein alignment with AT- or GC-rich codons allowed recovery of the correct tree. Two taxa with a large compositional bias continually group together in these analyses, despite a lack of close biological relatedness. We conclude that even protein-based phylogenetic trees may be misleading, and we advise caution in phylogenetic reconstruction using protein sequences, especially those that are compositionally biased. PMID- 10093218 TI - Novel predicted RNA-binding domains associated with the translation machinery. AB - Two previously undetected domains were identified in a variety of RNA-binding proteins, particularly RNA-modifying enzymes, using methods for sequence profile analysis. A small domain consisting of 60-65 amino acid residues was detected in the ribosomal protein S4, two families of pseudouridine synthases, a novel family of predicted RNA methylases, a yeast protein containing a pseudouridine synthetase and a deaminase domain, bacterial tyrosyl-tRNA synthetases, and a number of uncharacterized, small proteins that may be involved in translation regulation. Another novel domain, designated PUA domain, after PseudoUridine synthase and Archaeosine transglycosylase, was detected in archaeal and eukaryotic pseudouridine synthases, archaeal archaeosine synthases, a family of predicted ATPases that may be involved in RNA modification, a family of predicted archaeal and bacterial rRNA methylases. Additionally, the PUA domain was detected in a family of eukaryotic proteins that also contain a domain homologous to the translation initiation factor eIF1/SUI1; these proteins may comprise a novel type of translation factors. Unexpectedly, the PUA domain was detected also in bacterial and yeast glutamate kinases; this is compatible with the demonstrated role of these enzymes in the regulation of the expression of other genes. We propose that the S4 domain and the PUA domain bind RNA molecules with complex folded structures, adding to the growing collection of nucleic acid-binding domains associated with DNA and RNA modification enzymes. The evolution of the translation machinery components containing the S4, PUA, and SUI1 domains must have included several events of lateral gene transfer and gene loss as well as lineage-specific domain fusions. PMID- 10093219 TI - Plant mitochondrial RNA editing. AB - RNA editing affects messenger RNAs and transfer RNAs in plant mitochondria by site-specific exchange of cytidine and uridine bases in both seed and nonseed plants. Distribution of the phenomenon among bryophytes has been unclear since RNA editing has been detected in some but not all liverworts and mosses. A more detailed understanding of RNA editing in plants required extended data sets for taxa and sequences investigated. Toward this aim an internal region of the mitochondrial nad5 gene (1104 nt) was analyzed in a large collection of bryophytes and green algae (Charles). The genomic nad5 sequences predict editing in 30 mosses, 2 hornworts, and 7 simple thalloid and leafy liverworts (Jungermanniidae). No editing is, however, required in seven species of the complex thalloid liverworts (Marchantiidae) and the algae. RNA editing among the Jungermanniidae, on the other hand, reaches frequencies of up to 6% of codons being modified. Predictability of RNA editing from the genomic sequences was confirmed by cDNA analysis in the mosses Schistostega pennata and Rhodobryum roseum, the hornworts Anthoceros husnotii and A. punctatus, and the liverworts Metzgeria conjugata and Moerckia flotoviana. All C-to-U nucleotide exchanges predicted to reestablish conserved codons were confirmed. Editing in the hornworts includes the removal of genomic stop codons by frequent reverse U-to-C edits. Expectedly, no RNA editing events were identified by cDNA analysis in the marchantiid liverworts Ricciocarpos natans, Corsinia coriandra, and Lunularia cruciata. The findings are discussed in relation to models on the phylogeny of land plants. PMID- 10093220 TI - Evolution of microsatellites in the yeast Saccharomyces cerevisiae: role of length and number of repeated units. AB - The observed and expected frequencies of occurrence of microsatellites in the yeast Saccharomyces cerevisiae were investigated. In all cases, the observed frequencies exceeded the expected ones. In contrast to predictions by Messier et al. (1996), there is no critical number of repeats beyond which the observed frequencies of microsatellites significantly exceed the frequencies expected in a random DNA sequence of the same size. Rather, the degree of deviation from expectation was found to be dependent on the length of the microsatellite. That is, a fourfold concatemeric repeat of 3 bp was found to deviate from expectation as much as three-fold concatemeric repeat of 4 bp. These findings suggest that microsatellites evolve through strand-slippage events, rather than recombination events. This, in turn, suggests that the chances of erroneous hybridizations leading to strand-slippage are length dependent. PMID- 10093221 TI - Genomic organization around the centromeric end of the HLA class I region: large scale sequence analysis. AB - We previously sequenced two regions around the centromeric end of HLA class I and the boundary between class I and class III. In this paper we analyze the two regions of about 385 kb and confirm, giving a new line of evidence, that the following two pairs of the genomic segments were duplicated in evolution: (i) a 43-kb genomic segment including the HLA-B gene showing the highest polymorphism among the classical HLA class I loci (class Ia) and a 40-kb segment including the HLA-C locus showing the lowest polymorphism and (ii) a 52-kb segment including the MIC (MHC class I chain related gene) B and a 35-kb segment including MICA. We also found that repetitive elements such as SINEs, LINEs, and LTRs occupy as much as 47% of nucleotides in this 385-kb region. This unusually high content of repetitive elements indicates that repeat-mediated rearrangements have frequently occurred in the evolutionary history of the HLA class Ia region. Analysis of LINE compositions within the two pairs of duplicated segments revealed that (i) LINEs in these regions had been dispersed prior to both the duplication of the HLA-B and -C loci and the duplication of the MICB and MICA loci, and (ii) the divergence of the HLA-B and -C loci occurred prior to the duplication of the MICA and MICB loci. To find novel genes responsible for HLA class I-associated or other diseases, we performed computer analysis applying GenScan and GRAIL to GenBank's dbEST. As a result, at least five as yet uncharacterized genes were newly mapped on the HLA class I centromeric region studied. These novel genes should be analyzed further to determine their relationships to diseases associated with this region. PMID- 10093222 TI - A mariner-like transposable element in the insect parasite nematode Heterorhabditis bacteriophora. AB - For the first time, mariner elements were found in insect parasitic nematodes. Full-length elements were isolated from the rhabditid Heterorhabditis bacteriophora. They were 1279 bp long, flanked by two 30-bp inverted repeats, and were able to encode a putative 358-amino acid transposase. These elements were present in about 30 copies in the H. bacteriophora genome, but their distribution among closely related Heterorhabditis and Steinernema genera was patchy. DNA and encoded peptide sequences of H. bacteriophora mariners showed greater similarity to the mariner of the coleopteran Carpelimus sp. than to the mariners of the rhabditid Caenorhabditis elegans. The possibility of horizontal transfer was investigated by examination of a host for Heterorhabditis nematodes, a beetle of the Phyllophaga sp. Mariner elements were found in this insect, but they were not very similar to the H. bacteriophora elements. Finally, the H. bacteriophora mariners formed a group with those of invertebrates, suggesting vertical transmission from a common ancestor. PMID- 10093223 TI - A group I intron in the 18S ribosomal DNA from the parasitic fungus Isaria japonica. AB - The nucleotide sequence of the 18S rDNA coding gene in the ascomycetes parasitic fungus Isaria japonica contains a group I intron with a length of 379 nucleotides. The identification of the DNA sequence as a group I intron is based on its sequence homology to other fungal group I introns. Its group I intron contained the highly conserved sequence elements P, Q, R, and S found in other group I introns. Surprisingly, the intron sequence of I. japonica is more similar to that of Ustilago maydis than to the one found in Sclerotinia sclerotiorum. This is in contrast to the sequence identity found on the neighboring rDNA. This is an interesting finding and suggests a horizontal transfer of group I intron sequences. PMID- 10093224 TI - Evolution of chitin-binding proteins in invertebrates. AB - Analysis of a group of invertebrate proteins, including chitinases and peritrophic matrix proteins, reveals the presence of chitin-binding domains that share significant amino acid sequence similarity. The data suggest that these domains evolved from a common ancestor which may be a protein containing a single chitin-binding domain. The duplication and transposition of this chitin-binding domain may have contributed to the functional diversification of chitin-binding proteins. Sequence comparisons indicated that invertebrate and plant chitin binding domains do not share significant amino acid sequence similarity, suggesting that they are not coancestral. However, both the invertebrate and the plant chitin-binding domains are cysteine-rich and have several highly conserved aromatic residues. In plants, cysteines have been elucidated in maintaining protein folding and aromatic amino acids in interacting with saccharides [Wright HT, Sanddrasegaram G, Wright CS (1991) J Mol Evol 33:283-294]. It is likely that these residues perform similar functions in invertebrates. We propose that the invertebrate and the plant chitin-binding domains share similar mechanisms for folding and saccharide binding and that they evolved by convergent evolution. Furthermore, we propose that the disulfide bonds and aromatic residues are hallmarks for saccharide-binding proteins. PMID- 10093225 TI - Partial sequence of the mitochondrial genome of Littorina saxatilis: relevance to gastropod phylogenetics. AB - A 8022 base pair fragment from the mitochondrial DNA of the prosobranch gastropod Littorina saxatilis has been sequenced and shown to contain the complete genes for 12 transfer RNAs and five protein genes (CoII, ATPase 6, ATPase 8, ND1, ND6), two partial protein genes (CoI and cyt b), and two ribosomal RNAs (small and large subunits). The order of these constituent genes differs from those of other molluscan mitochondrial gene arrangements. Only a single rearrangement involving a block of protein coding genes and three tRNA translocations are necessary to produce identical gene orders between L. saxatilis and K. tunicata. However, only one gene boundary is shared between the L. saxatilis gene order and that of the pulmonate gastropod Cepaea nemoralis. This extends the observation that there is little conservation of mitochrondrial gene order amongst the Mollusca and suggests that radical mitochondrial DNA gene rearrangement has occurred on the branch leading to the pulmonates. PMID- 10093226 TI - Inclusion of cetaceans within the order Artiodactyla based on phylogenetic analysis of pancreatic ribonuclease genes. AB - Mammalian secretory ribonucleases (RNases 1) form a family of extensively studied homologous proteins that were already used for phylogenetic analyses at the protein sequence level previously. In this paper we report the determination of six ribonuclease gene sequences of Artiodactyla and two of Cetacea. These sequences have been used with ruminant homologues in phylogenetic analyses that supported a group including hippopotamus and toothed whales, a group of ruminant pancreatic and brain-type ribonucleases, and a group of tylopod sequences containing the Arabian camel pancreatic ribonuclease gene and Arabian and Bactrian camel and alpaca RNase 1 genes of unknown function. In all analyses the pig was the first diverging artiodactyl. This DNA-based tree is compatible to published trees derived from a number of other genes. The differences to those trees obtained with ribonuclease protein sequences can be explained by the influence of convergence of pancreatic RNases from hippopotamus, camel, and ruminants and by taking into account the information from third codon positions in the DNA-based analyses. The evolution of sequence features of ribonucleases such as the distribution of positively charged amino acids and of potential glycosylation sites is described with regard to increased double-stranded RNA cleavage that is observed in several cetacean and artiodactyl RNases which may have no role in ruminant or ruminant-like digestion. PMID- 10093227 TI - Multiple substitutions affect the phylogenetic utility of cytochrome b and 12S rDNA data: examining a rapid radiation in leporid (Lagomorpha) evolution. AB - Partial sequences of two mitochondrial genes, the 12S ribosomal gene (739 bp) and the cytochrome b gene (672 bp), were analyzed in hopes of reconstructing the evolutionary relationships of 11 leporid species, representative of seven genera. However, partial cytochrome b sequences were of little phylogenetic value in this study. A suite of pairwise comparisons between taxa revealed that at the intergeneric level, the cytochrome b gene is saturated at synonymous coding positions due to multiple substitution events. Furthermore, variation at the nonsynonymous positions is limited, rendering the cytochrome b gene of little phylogenetic value for assessing the relationships between leporid genera. If the cytochrome b data are analyzed without accounting for these two classes of nucleotides (i.e., synonymous and nonsynonymous sites), one may incorrectly conclude that signal exists in the cytochrome b data. The mitochondrial 12S rRNA gene, on the other hand, has not experienced excessive saturation at either stem or loop positions. Phylogenies reconstructed from the 12S rDNA data support hypotheses based on fossil evidence that African rock rabbits (Pronolagus) are outside of the main leporid stock and that leporids experienced a rapid radiation. However, the molecular data suggest that this radiation event occurred in the mid-Miocene several millions of years earlier than the Pleistocene dates suggested by paleontological evidence. PMID- 10093228 TI - A translocated mitochondrial cytochrome b pseudogene in voles (Rodentia: Microtus) AB - A full-length cytochrome b pseudogene was found in rodents; it has apparently been translocated from a mitochondrion to the nuclear genome in the subfamily Arvicolinae. The pseudogene (psi cytb) differed from its mitochondrial counterpart at 201 of 1143 sites (17.6%) and by four indels. Cumulative evidence suggests that the pseudogene has been translocated to the nucleus. Phylogenetic reconstruction indicates that the pseudogene arose before the diversification of M. arvalis/M. rossiaemeridionalis from M. oeconomus, but after the divergence of the peromyscine/sigmodontine/ arvicoline clades some approximately 10 MYA. Published rates of divergence between mitochondrial genes and their nuclear pseudogenes suggest that the translocation of this mitochondrial gene to the nuclear genome occurred some 6 MYA, in agreement with the phylogenetic evidence. PMID- 10093229 TI - Effects of Burkholderia pseudomallei and other Burkholderia species on eukaryotic cells in tissue culture. AB - Burkholderia pseudomallei causes melioidosis, a serious and often fatal bacterial infection. B. pseudomallei can behave as a facultatively intracellular organism and this ability may be important in the pathogenesis of both acute and chronic infection. The uptake of B. pseudomallei and other Burkholderia spp. by cells in tissue culture was examined by electron microscopy. B. pseudomallei can invade cultured cell lines including phagocytic lines such as RAW264, J774 and U937, and non-phagocytic lines such as CaCO-2, Hep2, HeLa, L929, McCoy, Vero and CHO. Uptake was followed by the intracellular multiplication of B. pseudomallei and the induction of cell fusion and multinucleate giant cell formation. Similar effects were produced by B. mallei and B. thailandensis. PMID- 10093230 TI - Improving the success of culturing Helicobacter pylori from gastric biopsies. AB - Factors influencing the successful isolation of Helicobacter pylori from human gastric biopsies were studied. Within 24 h, each of the gastric biopsies was inoculated onto chocolate blood agar media and incubated for up to 2 weeks. Among 63 (70%) culture positive cases in 90 patients, 58 (64%) cases were culture positive for both specimens, while five (6%) cases were culture positive in only one biopsy. Of the 63 positive cultures, 51 H. pylori strains (81%) grew on both media with and without antibiotics. Eight strains (13%) grew only on medium without antibiotics, while four isolates (6%) were obtained only from medium with antibiotics. These results support the previous histological observation of patchy colonization of H. pylori in the stomach. The success rate for culture of H. pylori from gastric biopsies increased when two biopsies were taken and inoculated on chocolate blood agar media with and without antibiotics. PMID- 10093231 TI - AH7, a non-polyenic antifungal antibiotic produced by a new strain of Streptosporangium roseum. AB - An antibiotic (AH7) produced by Streptosporangium roseum strain 214 was investigated. This compound was extracted with chloroform from the filtrate culture and purified using thin-layer chromatography and high pressure liquid chromatography procedures. The antibiotic strongly inhibited the growth of several strains of fungi and bacteria known to be plant and human pathogens. This compound differed from all other antibiotics known to be synthesized by Streptosporangium spp. Some of its chemical and physical properties resembled those of maytansines produced by Nocardia but the antibiotic AH7 has only antibacterial and antitumoral activities. PMID- 10093232 TI - Space flight micro-fungi after 27 years storage in water and in continuous culture. AB - Four species of micro-fungi were selected for study in the National Aeronautics and Space Administration (NASA) Apollo Microbial Ecology Evaluation Device (MEED) mycology experiments. Trichophyton terrestre, Rhodotorula rubra, Saccharomyces cerevisiae and Chaetomium globosum were selected from a series of preflight test fungi for the MEED mycology studies during the 2 years prior to the actual flight (Volz, 1971a, 1972b). Conidia of T. terrestre, ascospores of C. globosum and yeast cells of R. rubra and S. cerevisiae were suspended in sterile distilled water and loaded into wet and dry cuvettes for exposure to specific space flight parameters according to the filters built into the space flight hardware (Volz, 1971b). Living cells were found in the original inocula and phenotype water storage after 27 years. Colony cells were also examined after 27 years of continuous culture. PMID- 10093233 TI - Address by the president of the Alaska Federation of Natives. PMID- 10093234 TI - Address by the president of the Inuit Circumpolar Conference. PMID- 10093235 TI - Traditional healing among Alaska Natives. PMID- 10093236 TI - History of tobacco and the Inuit. PMID- 10093237 TI - Circumpolar health: science and health--what is missing? PMID- 10093238 TI - Maintaining public health into the 21st century: the impact of poverty, privatization, and politics. PMID- 10093239 TI - Keeping women and children last: America's war on the poor. PMID- 10093240 TI - Investigating cancer clusters. AB - A cluster is a mini-epidemic of a rare disease. Clusters may give clues to the etiology of disease, or may signal a hazardous exposure. Unfortunately, cluster investigations seldom are conclusive, for several reasons. Statistically significant clusters can occur by chance. The probability of finding chance cancer clusters is calculated for the 200 Alaska Native villages. The problem of selection bias is explained, and other limitations of epidemiology are described. A logical, stepwise protocol for investigating cancer clusters is presented. PMID- 10093241 TI - Ethical issues in community health research: implications for First Nations and circumpolar indigenous peoples. AB - Current changes in research relationships include a re-examination of the ethical contracts made between researchers, individuals, and Aboriginal communities. New guidelines for research have been written by First Nations and circumpolar indigenous peoples' organizations. This paper discusses these guidelines, using case examples to illustrate the ethical, methodological, and political problems in the conduct of community-based health research. PMID- 10093242 TI - Developing a Code of Research Ethics for research with a Native community in Canada: a report from the Kahnawake Schools Diabetes Prevention Project. AB - This paper describes the background and evolution of a Code of Research Ethics that was developed for a primary diabetes prevention project in the Native Mohawk community of Kahnawake in Canada. Embodying the principles of participatory research, this code was written by the researchers in conjunction with the community in the first year of the three-year project. The code ensures that the community is a full partner for the entire research process. For this project a Community Advisory Board is representative of the community. PMID- 10093243 TI - The ethics of informed consent among storyteller cultures. AB - The protection of the rights of people from research risks is a primary reason for obtaining informed consent from a potential volunteer. The procedure followed in the United States utilizes a standardized ethical code. Its basic principles are set forth in the Belmont Report, which serves as the basis for the regulations regarding informed consent contained in 45 CFR 46, The Protection of Human Subjects. However, this standardized approach may be inappropriate for use with peoples who have a different ethical perspective or moral outlook on life. This paper presents an alternative approach to the issue of informed consent of people to be participants in research. The ethic is examined as a narrative consisting of a dialogue between the inquirer and the participant in the research process. A story evolves that is the ethic, and this involves a dynamic, ongoing process that continues for the duration of the inquiry. These issues are addressed from a philosophical and an applied perspective. The applicability of this approach to research and interventions among indigenous northern peoples is discussed. PMID- 10093244 TI - Experience of aboriginal health interpreters in mediation of conflicting values in end-of-life decision making. AB - This paper examines the experience of Aboriginal medical interpreters working with terminally ill patients, family members, and care providers, and serving as mediators when cultural values and decision frameworks are in conflict. The discussion is based on a qualitative analysis of interaction in 12 patient encounters which were observed and for which transcripts were made of the discourse and interaction. Each case involved intervention by a professional interpreter. Interaction involved the signing of advance directives or other consent agreements in situations in which Aboriginal patients were terminally ill. Analysis will focus on the cultural dimension of value conflict situations, particularly in relation to issues of individual autonomy and biomedical emphasis on truth-telling in the communication of terminal prognosis. PMID- 10093245 TI - The Tyrolean Iceman and excavated human remains as sources of information about the past, the present, and the future. AB - The 5,200-year-old mummy of the so-called "Iceman" found in the Tyrolean Alps in September 1991 has not only provided unique information about the European Stone Age, but has also supported disciplines of glaciology and paleoclimatology, contributed to medical history, age-at-death determination, and plastic surgery. The Iceman is the oldest known case of medical tattooing. Since the body is unique, new noninvasive methods had to be developed to investigate it. Stereolithographic skull models were produced to study the skull. Age determination was partly based on computer tomography. These methods may even be used for present or future medical or forensic practice. Furthermore, a collection of identified skulls from a charnel house in Austria, dating from about 1780 AD to 1990 AD, has been used for testing and developing osteological methods, though the inclusion of the skulls in the charnel house is formally classified a second burial. These skulls have been studied by permission from the local Catholic church. Careful respect for the ancestors is crucial in both these and other cases. In return, access to the remains of ancestors provides information which may shed light upon the past, the present, and even help survival in the future. PMID- 10093246 TI - Value orientation of the Copper Inuit. AB - Primary health services in the Canadian Arctic are predominantly provided by nurses whose cultural backgrounds differ from that of their clientele. As in other areas, this diversity can result in misunderstanding and conflict between the health care providers and their clients. Greater understanding of the client culture is necessary in order to identify areas in which conflict exists and to plan culturally appropriate health programs and initiatives. This study defines and describes the value orientation profile of some Copper Inuit living in the hamlet of Coppermine (Kugluktuk), Northwest Territories. Data were collected through interviews, using a modification of the Kluckhohn value orientation questionnaire. Data analysis using t-test analysis of the overall value orientations indicated a distinct value orientation profile. PMID- 10093247 TI - Traditional healing and allopathic medicine: issues at the interface. AB - There is increasing interest in Native traditional healers and the possibility of their working in some form of relationship with the allopathic medical system. It represents a resurgence of effort in an area of great potential benefit to the Native community, but is rife with issues that could destroy the effort at any number of stages in the process. Issues related to professional and institutional responsibility, the power of medicalization, physical and philosophical interactions of the systems of healing, measures of effectiveness, issues of reimbursement, and many more must be dealt with in an intentional and thorough manner if the process is to be successful. PMID- 10093248 TI - The illness known as "twisted mouth" among the Nehinaw (Cree). AB - This paper is based on interviews with two individuals who talked about their experiences with a condition known as "twisted mouth." While the biomedical label of Bell's palsy is often applied to such cases, the appropriateness of this label is not explored here. Rather, the focus is on how Nehinaw (Cree) cultural understandings frame the experience of and response to illness, even when biomedical practitioners were consulted. The interviews were carried out by the first author using the Nehinaw language as much as possible. Subtle linguistic clues within the interviews point to the pervasiveness of Nehinaw cultural understandings. PMID- 10093249 TI - Appropriate training for northern physicians. AB - It remains difficult to find appropriately trained physicians to work in isolated northern areas. Urban-based family medicine programs have not been able to provide appropriate training. The Northern Family Medicine Education (NorFam) Program of Memorial University of Newfoundland was created to fill this need. This paper reviews the NorFam Program and discusses current practice locations and the relevance of the program as reported by its graduates. From 1993 to 1995, the NorFam Program trained 14 residents. The residents participate in a variety of educational and training activities--all chosen to be as relevant to northern practice as possible. When the graduates were surveyed, nine had remained in northern/remote or rural practice and three were doing further medical training. All respondents reported that the NorFam Program gave them more relevant training for northern practice than they would have received in an urban-based family medicine program. PMID- 10093250 TI - Educating medical students for Alaska. AB - Because Alaska does not have its own medical school, it has become part of WAMI (Washington, Alaska, Montana, Idaho), an educational agreement with the University of Washington School of Medicine (UWSM). Each year, 10 Alaskans are accepted into the entering class of UWSM and spend their first year at the University of Alaska Anchorage (UAA). UWSM third- and fourth-year medical students can obtain some of their clinical experience in Alaska. To meet the needs of Alaska, students are chosen based on academic and personal records, as well as the likelihood of their returning to Alaska for practice. To this end, over the last seven years 30% of accepted students have come from rural communities and 10% are Alaska Natives. The curriculum for the first year includes several sessions dedicated to Alaska health problems, cross-cultural issues, and Alaska's unique rural health care delivery system. Students do two preceptorships--one with a private primary care physician and one with a physician at the Alaska Native Medical Center. Additionally, students have the option to spend a week at a rural site to learn about the community's health care system. An Alaska track is being developed whereby an Alaskan UWSM student can do most of the third year in state via clerkships in family medicine, obstetrics/gynecology, psychiatry, internal medicine, and pediatrics. All UWSM students at the end of their first year can elect to participate for one month in the R/UOP (Rural/Underserved Opportunities Program), which includes several Alaska sites. The overall goals of these approaches are to educate UWSM students, especially Alaskans, about the state's health needs and health care system and to encourage UWSM graduates to practice in the state. PMID- 10093251 TI - Medical teaching program in a rural northern hospital. AB - Canada has a population of over 100,000 Aboriginal people who live in remote northern communities. Their culture and health care needs differ substantially from those of Canadian urban and rural non-Aboriginal populations. The health care delivery system is largely based on primary care nurses supported by family physicians. In Canada there is a dearth of training opportunities for medical practitioners interested in such a northern practice. The University of Toronto Sioux Lookout Program is based in the Sioux Lookout Zone Hospital, the busiest Aboriginal hospital in Canada. The program trains family practice residents, pediatric residents, and medical students from the University of Toronto, as well as graduate nurses preparing for northern primary care practice. Training focuses on exposure to Aboriginal culture and health care problems particular to our patient population. Enhanced understanding of northern Aboriginal life and improved recruitment of health care professionals are important goals of the teaching program. PMID- 10093252 TI - Premedical program effective in increasing admissions to health professional schools. AB - The Special Premedical Studies Program (SPSP) has been successful in preparing Aboriginal students in Canada for admission to medicine, dentistry, medical rehabilitation, and pharmacy at the University of Manitoba. The success rate for admission to these faculties is 20%. There is a higher failure rate in the basic years of medical/dental education, but remediation has been 100% successful. Failure rates in the clinical years do not differ from those of the mainstream population. Grade point averages and MCAT scores are given less weight in the special consideration category of application at the University of Manitoba. SPSP students can and do apply to this category. The higher rate of first unsuccessful attempt in the basic years of medical education specifically can be attributed to a variety of factors, including reading skills. Although the numbers are small, we show that there is a correlation between the comprehension score of the Nelson Denny test and the verbal score of MCAT. But there was no difference on the average between verbal score in MCAT and pass/fail in basic medical years. Students who scored above the 80th percentile on the comprehension portion of the Nelson-Denny test were successful in their first attempt at examinations in medical school. PMID- 10093253 TI - Health promotion partnerships: service and education addressing the health needs of vulnerable groups. AB - This paper describes partnerships between service and education that can assist in meeting the health care needs of vulnerable population groups. Baccalaureate nursing students learn about population-based nursing practice as a means of addressing health needs. Each semester, groups of 8-10 senior students work with a community agency serving a population at risk. Students assess health needs and plan, implement, and evaluate a health promotion intervention with the population and the agency. Emphasis is placed on designing culturally appropriate interventions that are accomplished in partnership with the agency and population. Projects which illustrate the generalizability of this approach will be discussed. Such experiences reduce barriers that separate education from practice. Community agencies benefit as health needs that might not otherwise be met are addressed. PMID- 10093254 TI - Using the evaluation of the Dalhousie Outpost Nursing Program for responsive social action. AB - The Dalhousie Outpost Nursing Program is designed specifically to prepare registered nurses to provide primary health care in northern Canadian Aboriginal communities where there are no resident physicians. In 1993, the program was extensively evaluated, using a responsive participatory approach that is consistent with the direction of health care in Canada. The evaluation documented the effectiveness of the program and permitted diverse views to be expressed. Most importantly, the evaluation enabled the voice of Aboriginal people living in northern communities to be heard. Dalhousie School of Nursing has used the evaluation results to provide some direction for program planning in the context of Canadian health reform. PMID- 10093255 TI - Continuing medical education for community health aides/practitioners. PMID- 10093256 TI - Use of objective structured clinical examinations (OSCEs) in training and evaluating community health aides. AB - Community Health Aides (CHAs) provide village-based health services throughout Alaska. The Objective Structured Clinical Examination (OSCE) was developed approximately 20 years ago in Scotland in an effort to make exams more valid, reliable, and practical. OSCEs have been used by medical schools to assess more objectively a variety of clinical skills; this structured examination format is being used during the four four-week basic training sessions for CHAs to assess clinical competency in both common problem and critical skills. The OSCE consists of multiple-timed stations where each CHA is presented with the same situation and evaluated using a check list of predetermined detailed evaluation criteria. In the regular clinical setting CHAs demonstrate skills managing a variety of medical problems; the OSCE setting presents each examinee with an identical, controlled, simulated situation in which only particular skills are evaluated. The testing stations are designed to evaluate a variety of clinical skills: history-taking, physical exam, making assessments, developing plans, using the CHA manual, documentation, reporting, laboratory and procedure techniques, and emergency skills. PMID- 10093257 TI - Family pattern and family care in Greenland. AB - Information on household and family patterns from the 1993-94 Health Interview Survey in Greenland is described. The average size of households is 3.5, and almost three-fourths of the Greenlandic population live in families with children. The pattern of these families with children covers a variety of single parent families (6% of the total Greenlandic population), nuclear families (42%), extended families (14%), and other types of families (11%). PMID- 10093258 TI - Rankin Inlet Birthing Project: outcome of primipara deliveries. AB - Within the Rankin Inlet Birthing Project, primipara (first baby) prenatals were not offered midwifery-assisted, elective delivery because of the unknown outcome of an untried pelvis. No data of primipara outcomes of Canadian northern populations have been published to allow comparisons. Over 36% of the Rankin Inlet Birthing Project prenatal population were primipara. A review of primipara outcomes from November 1993 to December 1995 indicated that 19 (38.7%) of 49 primipara deliveries were complicated. However, 13 (68.4%) of the 19 were anticipated to be complicated and would have been referred to hospital for delivery. A complication was defined as anything which could not have been managed by midwives in an isolated community health center, e.g., pregnancy induced hypertension, labor induction by artificial means, fourth degree tears, anything other than a spontaneous vaginal delivery, or any newborn requiring more than a minimum of resuscitative measures. PMID- 10093259 TI - Evaluation of a midwifery birthing center in the Canadian north. AB - An evaluation of a midwife-operated community birthing center was conducted to identify whether it would be safe, cost-effective, and psychologically and socially satisfying for Inuit women in one community in the Northwest Territories. Two nurse-midwives provided antenatal and postnatal care to all pregnant women and delivered those designated as 'low risk' for complications. Another community similar in size but with no community birthing was used for comparison of the three indices. Data were gathered on reproductive histories and pregnancy risk profiles of all women giving birth in a one-year period. The financial costs were calculated for those women transferred out to hospital for delivery and compared with those who stayed in the community. Pregnant women and their partners in both communities, health staff, and community members were interviewed for their feelings and concerns about the birthing services. Preliminary findings suggest that with experienced midwives community births are safe. A minimum of 25 births is required in the community for this project to be cost effective. The women who had their infants in the community expressed satisfaction for a number of reasons. PMID- 10093260 TI - Indications for transfer for childbirth in Inuit women at the Innuulisivik Maternity. AB - The Innuulisivik Maternity is a northern-based service in Povungnituk, Quebec, which serves the Inuit women of the Hudson Coast. Although most women stay in the North for childbirth, others are transferred south. This paper will describe the experience of the Innuulisivik Maternity, which uses committee-based risk assessment for transfer decisions. Data for the three-year period 1989-1991 were examined. Descriptive statistics were used to compare the observed differences in the distribution of several variables according to birthplace. Data were available for 411 women. Three hundred fifty (85.2%) of the births occurred at Innuulisivik: 44 (10.7%) women were transferred and 17 (4.1%) were nursing station births. In 80% of transfers, clinical conditions were identified which in themselves usually require transfer. Premature labor was prevalent in the transfer group. The data demonstrate that risk scoring by consensus is a viable option for northern birthing units. Finally, logistical and cultural factors should be included for meaningful risk assessment in the North. PMID- 10093261 TI - Incidence of ectopic pregnancy and sexually transmitted disease in the Canadian Central Arctic. AB - A retrospective review of all medical evacuations from 1987-1994 of women in the Keewatin District of the Canadian Central Arctic was undertaken to determine the incidence of ectopic pregnancy. The incidence of N. gonorrhoeae and C. trachomatis as major risk factors for ectopic pregnancy was also determined. The average annual incidence of ectopic pregnancy in the Keewatin over the study period was 178/100,000 women age 15-44 years, or 9.6/1,000 reported pregnancies; for Southern Canada the corresponding average annual incidence is 118.3/100,000 women age 15-44 years, or 15.7/1,000 reported pregnancies. The high general fertility rate in the Keewatin (189/1,000 population) accounts for the difference in ectopic pregnancy rates expressed per population versus per pregnancy. The average annual incidence of gonorrhea and chlamydia infection were 1,444 and 3,695/100,000 population, respectively; these rates were 27- and 22-fold higher than those seen in the general Canadian population. The incidence of chlamydia was particularly high (16,194/100,000) in women age 15-24 years. Despite the high incidence of gonorrhea and chlamydia in the Keewatin, the rate of ectopic pregnancy expressed per 1,000 pregnancies is comparable to that seen in Southern Canada. Possible differences between populations in the determinants of tubal damage, including time from exposure to infection to pregnancy, host immunity and bacterial virulence, may account for this observation. PMID- 10093262 TI - Iron-deficiency anemia in Nunavik: pregnancy and infancy. AB - PURPOSE: This paper documents the problem of iron-deficiency anemia in the Inuit region of Nunavik, in Northern Quebec, particularly among pregnant women and infants. It also addresses the issue of Helicobacter pylori gastritis as a possible cause of anemia in this population. METHOD: Data on anemia in pregnancy are from routinely collected prenatal records. Data on anemia in infants are drawn from blood samples collected for a study on the impact of environmental contaminants. Helicobacter serologies were done on cord-blood specimens from 100 consecutive births screened for contaminant exposure. For comparison, serologies were done on a series of cord-blood specimens from 99 births in Southern Quebec. RESULTS: By term, 40% of pregnant women in Nunavik are anemic (Hgb < 115 g/L). Of infants aged 9-14 months, 58% are anemic (Hgb < 110 g/L), and among the remaining 42%, over half have depleted iron stores. Twenty-seven percent of the Nunavik sample had positive or equivocal Helicobacter serologies. In the comparison group, 10% were positive or equivocal. PMID- 10093263 TI - Disease pattern in children living in the Arctic: visits to a general practitioner by 0- to 14-year-old children living in Nuuk, Greenland. PMID- 10093264 TI - Ecology and children's health conditions the far eastern region of Russia. PMID- 10093265 TI - Prematurity in Greenland. PMID- 10093266 TI - Baby-bottle tooth decay: are we on the right track? AB - The baby-bottle tooth decay (BBTD) risk factor literature was critically assessed for strength of evidence, and the prevention literature for the identification of which risk factors are being addressed. "Inappropriate" feeding practices (non nutritive sucking, prolonged bottle/breast feeding, nap-time feeding) are believed to cause BBTD. The association of these practices with BBTD is inconsistent and the strength of association varies greatly. These practices increase exposure to lactose, a cariogenic carbohydrate, but the current causation model fails to explain why the majority of children with these risk factors do not develop BBTD. The association of BBTD with low socioeconomic status is stronger and more consistent. Prevention has focused almost exclusively on education directed at changing the postnatal feeding practices despite the fact that teeth begin formation in utero. Prenatal deficiencies of calcium and vitamin D can lead to enamel defects, and enamel defects in turn predispose teeth to caries. Baby-bottle tooth decay is especially prevalent in Aboriginal people, for whom studies have consistently reported diets deficient in vitamin D and calcium. BBTD may be a consequence of the poor socioeconomic conditions and malnutrition. Perhaps more attention should be given to primary prevention. PMID- 10093267 TI - Awareness of periodontal disease in a group of northern Canadian children. AB - Periodontal disease destroys the supporting structures of the teeth. The clinical signs start early in childhood as inflammation of the gingival tissues; if uncontrolled, it becomes the major cause of loss of teeth in adult life. The purpose of this survey was to determine the understanding that a group of 10- to 15-year-olds living in the Inuvialuit, Gwich'in, and Sahtu Districts of the Northwest Territories have regarding the recognition and prevention of periodontal-gingival disease. A total of 953 students, with a median age of 12.5 years, completed the survey. The data, which included rural and urban centers as well as rural and remote regions, were analyzed using the chi-square method. Ethnic and gender differences are reported. Results indicate that girls have a better awareness of good oral health. Non-Native children have a somewhat better understanding regarding the recognition and prevention of periodontal disease. Both Native and non-Native groups share uncertainties with respect to the rationale and reasons behind the disease process. Educators of oral health prevention should incorporate into their programs preventive measures that take into consideration Native culture and traditions. PMID- 10093268 TI - Dental caries knowledge in a group of Northwest Territories children. AB - A total of 953 children in schools in communities in the Northwest Territories was surveyed to determine their attitudes and knowledge about dental decay. A questionnaire was answered by these Native and non-Native children in the Northwest Territories. The median age of the children was 12.5 years. The girls tended to brush their teeth more frequently and consumed less sugared sweets between meals. More of the girls and in particular the Native girls knew about "nursing" caries. The Native students more often than not went for dental treatment when it was necessary. The Native students brushed their teeth less frequently and often learned to brush their teeth on their own. The consumption of sugared sweets between meals was greater in the Native sample. The knowledge level of the factors that affect dental decay rates was lower in the Native group, but was not extremely high in either group. These children should receive more information on oral health practices and be given an opportunity to improve their oral health knowledge. PMID- 10093269 TI - Food mail: the Canadian alternative to food stamps. AB - PURPOSE: To describe the impact of a selective transportation subsidy on food costs in isolated communities in Northern Canada, and the government's proposal to refine the "food mail" program to promote better nutrition. METHOD: The cost of various components of a Northern Food Basket has been monitored since 1990. An assessment of the probable impact and acceptability of program refinements was made through surveys of merchants and health and social service providers and focus group sessions. Decisions expected following consultations with stakeholders in March and April 1996 are also described. RESULTS: Costs of nutritious perishable food have been reduced in the Northwest Territories, and consumption of these foods in the Baffin region doubled within three years. Program refinements were proposed, with the objective of increasing intakes of calcium, folacin, and vitamin A, reducing dependency on convenience perishable foods, and reducing the cost of a healthy diet. PMID- 10093270 TI - Food affordability in air stage communities. AB - In 1991 and 1992, changes were made to the rate structure and eligibility requirements of the Northern Air Stage Program. To determine the effect of these changes on the affordability of a nutritious diet, food price surveys were conducted in 20 isolated communities, staging points, and selected southern cities and used to cost a 46-item Northern Nutritious Food Basket (NFB), which meets the nutrient requirements of a reference family of four. Food affordability was calculated as the percentage of "after-shelter" social assistance income required to purchase the NFB. In the Northwest Territories (NWT), from 100% to 123% of income was required in Air Stage communities in 1990-1991 and from 86% to 125% in 1993. In the provinces, from 65% to 83% of income was needed in 1990-1991 and from 56% to 98% in 1993. In Kangiqsujuaq and Nain, the amount of "after shelter" income needed increased by as much as 6% and 15%, respectively. Changes to the Northern Air Stage Program reduced the cost of perishable foods and improved the affordability of a nutritious diet in the NWT. Affordability is also affected by social assistance income. In most isolated communities, families would still find it difficult to afford a nutritious diet. PMID- 10093271 TI - Infant nutrition program effectively prevents iron-deficiency anemia in a First Nations community. AB - Iron-deficiency anemia (IDA) has received relatively little attention in Canada, with no national public health initiatives even among high-risk infants. IDA has a high prevalence in First Nations children and has been shown to cause developmental delay. This study is a before/after prevalence survey studying the effect of a public health intervention, conducted on a First Nations reserve off the central coast of British Columbia (BC). We screened for IDA one cohort of infants born January 1993 to August 1994 and between the ages of 6 and 24 months. Twenty-five of a possible 37 infants were screened. We found 13 (52%) of the 25 had anemia, with a hemoglobin less than 100 g/L. The average hemoglobin was 98.9 +/- 19.2 g/L. The subsequent implementation of an infant nutrition program focused on educating parents and encouraging the use of iron-fortified formula for nonbreast-fed infants. In the year following program implementation, the cohort of infants born between September 1994 and September 1995 were screened for IDA when they were between the ages of 6 and 15 months. Twenty-four of 27 infants participated. Only one infant was anemic with a hemoglobin less than 100 g/L. The average hemoglobin was 116.6 +/- 11.6 g/L. The increase in the average hemoglobin and the decrease in the prevalence of anemia were both highly significant (p < .01). We judged our intervention to be very effective and would recommend similar programs for other First Nations communities. PMID- 10093272 TI - Nutrition of Chukotka Native children. AB - We estimated nutrient and food intakes of adolescents aged 14 to 17 who inhabit the coastal and tundra zones of the Chukotka Autonomous Region, Russia, and developed approaches to improving their diet. We reassessed the dietary intakes of Native (n = 162) and non-Native (n = 155) adolescents of both sexes. We found that mean energy and nutrient intakes (protein, fat, carbohydrates) among schoolchildren were similar in different ethnic and sex groups. The diet of the subjects studied is high in sugar (18-19% of energy) and has an unfavorable fat composition, with saturated fatty acids (SFAs) contributing 14-15% of energy, and polyunsaturated fatty acids (PUFAs) contributing 5-6% of energy. Our results demonstrate that the children's diet approaches that of "Western society" to a greater extent than that of adults. A program on nutrition based on the national government project "Children of the North" has been developed at the Institute of Internal Medicine in collaboration with the Chukotka Sanitary and Epidemiology Supervision Services. This program includes the list of food products recommended for children. Some ecological factors and ethnic idiosyncrasies are considered. PMID- 10093273 TI - Food consumption patterns of Inuit women. AB - To evaluate nutrient intake and food consumption patterns of Inuit women of child bearing age, a 24-hour diet recall and general health and food frequency questionnaire was administered to 688 Inuit women aged 15-44 in six isolated communities. Data were analyzed using the 1991 Canadian Nutrient File. Mean intakes of essential nutrients were expressed as percentages of Health Canada's 1990 Recommended Nutrient Intakes (RNI). Chi-square tests were used to determine relationships between categorical variables. Folacin intake ranged from 49% to 95% of the RNI in most communities (median = 76%) and was only 37% of the RNI for pregnant and 54% for lactating women. Mean calcium intake for pregnant and lactating women averaged 55% and 47% of the RNI, respectively. Average vitamin A intakes ranged from 26% to 87% of the RNI (median = 65%), with intake for pregnant Inuit women and lactating women 79% and 54% of the RNI, respectively. Country food was the major source of protein and iron, and store foods the major source of calories, calcium, folacin, and vitamin A. Low intakes of folacin, calcium, and vitamin A, especially among pregnant and lactating women, place Inuit women of childbearing age at risk. Women on social assistance are nutritionally vulnerable. PMID- 10093274 TI - Preliminary assessment of nutrients in daily diets of a sample of Belcher Island Inuit adults. AB - In order to describe daily food patterns and nutrient intakes of adults in the Inuit community of Sanikiluaq, 48 adults (young and older men and women, 12 per group, randomly selected from all individuals within their age and sex group) provided two 24-hour recalls of food consumption, once each in two seasons (February/March, October/November). The most frequent Inuit foods were reindeer, seal, and arctic char, while the most frequent market foods were tea, sugar, and bannock. On average 799 grams of Inuit food were consumed per day, providing 47% of daily energy and 65-92% of daily protein, iron, zinc, phosphorus, thiamin, riboflavin, and niacin. Inuit foods are primary sources of many nutrients for the Belcher Island Inuit. PMID- 10093275 TI - Ooligan grease: a traditional food fat of western Canada and Alaska. AB - First Nations Peoples prepare ooligan grease by ripening several tons of the small fish, Thaleichthys pacificus, and rendering the fish oil. Eighteen samples from different family preparations of five cultural areas were analyzed for a spectrum of nutrients, organochlorines, and heavy metals. Ooligan grease was found to be a rich source of retinol (2444 +/- 1198 RE/100 g) and n-3 fatty acids, but had less vitamin A compared to fat of raw fish. There was a 10-fold increase in n-3 fatty acids in grease compared to raw fish fat, which may be attributed to microbial conversion of other fatty acids to DHA. Whole fish were good sources of Ca, Fe, and Zn; heavy metals were below guideline levels in grease. Chlorinated pesticides and PCB increased from north to south locations in British Columbia, with mean levels being 110 ng/g lipid of total chlorinated pesticides and 30 ng/g lipid of PCB. These levels are below regulation limits established by Health Canada. It is concluded that ooligan grease is a superior food fat and safe for human consumption. PMID- 10093276 TI - Sources of bias in estimates of calcium and vitamin A intakes of indigenous peoples in the Northwest Territories, Canada. AB - Calcium and vitamin A have consistently been reported as nutrients at risk among northern indigenous peoples in Canada. Using a data set recently collected in the Sahtu region of Denendeh, Northwest Territories, potential sources of bias and their effect on estimates of dietary intake are investigated. Calcium and vitamin A intakes appear to be underestimated to differing extents and for differing reasons specific to each nutrient. Underestimation of calcium intake may affect a large portion of the dietary records and is most likely due to insufficient probing for methods of food preparation during dietary interviews. Underestimation of vitamin A intake appears to affect a smaller proportion of the food records and be related to the difficulty of recording the occurrence of rare and seasonal events. In both cases, more precise nutrient composition data are needed to reflect nutrient content of traditional food as consumed. PMID- 10093277 TI - Benefits of traditional food in Dene/Metis communities. AB - Data collected in 16 Dene/Metis communities are used to illustrate the many nutritional, economic, and sociocultural benefits associated with the harvest and consumption of traditional food by indigenous peoples. These include exceptional nutrient composition, absence of industrial processing that changes quality and taste properties, taste preference, reasonable cost compared to market food, quality of the time spent on the land, increased physical activity, sharing of the harvest within the community, opportunity to practice spirituality, and encouragement for children to discover the natural environment. The importance of traditional food to the health of individuals and communities can be directly related to the nutritional value of the food itself, the physical activity associated with its procurement, and its role in mediating positive health determinants such as self-efficacy and locus of control. PMID- 10093278 TI - Communication about health and the risk effect of eating traditional food. AB - Like other populations, the Arctic population has to deal with the fact that specialized information made available to them through environmental and medical research is often difficult to grasp. Not only are the data complicated, they are also often misconstrued through media distortion. Communication is more than just information. Experience with communication gained during a 1990s international autopsy study in Greenland will be presented. The study looked at the possible protective effect against atherosclerosis due to the special fatty acid composition in the traditional food and also the effect of exposure of the local people to heavy metal and organochlorine. "When I eat traditional food, I know who I am" (Inuk). PMID- 10093279 TI - Review of food-borne diseases in Nunavik. PMID- 10093280 TI - Primer on food-borne pathogens for subsistence food handlers. AB - Subsistence food preparations may lead to human illnesses caused by pathogenic bacteria and viruses. Little is known about the incidence of food-borne illnesses other than botulism in circumpolar indigenous populations. Lack of documentation for other pathogens may be related to the sparsely populated communities involved, limited laboratory analysis, and non-lethality to healthy individuals. This overview covers the major food-borne pathogens, their sources, transmission, growth parameters, and prevention. Examples of indigenous peoples' food preparations that may be susceptible to pathogenic bacterial growth and toxin formation are described. PMID- 10093281 TI - C. Earl Albrecht and the struggle against tuberculosis in Alaska. AB - This paper outlines the contributions of C. Earl Albrecht in tuberculosis control in Alaska during his term as Territorial Commissioner of Health from 1945 to 1956. Tuberculosis, called the "Scourge of Alaska," had spread by the end of World War II to every corner of Alaska, with especially devastating effects on the Alaska Natives. When Dr. Albrecht became commissioner, the epidemic was at its peak. With an obvious zest for battle, he organized a campaign on many fronts, with initial emphasis on case-finding, establishing a tuberculosis register, and making available hospital beds both for orthopedic and pulmonary tuberculosis. Later, BCG vaccination, ambulatory chemotherapy, and chemoprophylaxis were added to the battle plan. The results were strikingly successful. He became an eloquent spokesman and advocate for health in both Juneau and Washington, and was successful in obtaining greatly increased territorial and federal appropriations, not to mention surplus military buildings, ships, and supplies. He was also notably effective in bringing together into a functional team such diverse agencies as the U.S. Public Health Service, the Bureau of Indian Affairs, the Territorial Department of Health, and various voluntary health organizations. PMID- 10093282 TI - Tuberculosis: finding a community solution. AB - The Tuberculosis Surveillance Project set out to gain community and health care worker support for and participation in the development and implementation of a tuberculosis control program which would address the high incidence of tuberculosis in Innu and Inuit communities in Labrador. The underlying principle of this project is that a tuberculosis control program must have the support of both the communities and the health care workers if it is to succeed. A three person tuberculosis steering committee, with representation from the Innu Nation, the Labrador Inuit Association, and the Labrador Health Services Board, supervised initial tuberculosis data collection and analysis and workshop planning. Community Health Representatives, community physicians, and community nurses participated in a workshop to develop a tuberculosis protocol for the region. In addition, community tuberculosis control strategies were developed in workshops in each community in an effort to ensure community and health care worker support for the protocol and tuberculosis control in its broadest sense. This project illustrates how partnerships between communities and health care workers can be achieved. Future tuberculosis incidence rates will be used to evaluate the effectiveness of the partnership. PMID- 10093283 TI - The dispersal of the 1918 influenza virus on the Seward Peninsula, Alaska: an ethnohistoric reconstruction. AB - This paper considers the spread of the 1918 influenza virus as it occurred among Inupiat communities on Alaska's Seward Peninsula. Documented historical sources concerning the epidemic among the Native communities are scarce and contain limited information. In contrast, oral histories of the event provide not only information about community mortality rates, but they also corroborate the few written documents that discuss the epidemic. Additionally, it has been found that the dispersal of the virus on the peninsula can only be accurately reconstructed with the aid of oral testimony. Data useful to both anthropologists and epidemiologists can be derived from this approach to historical analysis. PMID- 10093284 TI - Respiratory tract infections in Greenlandic children: a prospective cohort study. AB - Respiratory tract infections in children, measured in terms of both morbidity and mortality, represent a major health problem in Greenland. In particular, otitis media is highly prevalent, and is characterized by early onset and a high degree of chronicity. There is, however, little knowledge about the epidemiology of respiratory tract infections in Greenland. In the spring of 1996, a prospective study of such infections in infants and children was initiated in Sisimiut, West Greenland. The main objectives of the study are to describe the epidemiology of respiratory tract infections in children under four years of age, to estimate the impact of these diseases on short- and long-term morbidity, and to identify risk factors for transmission and clinical severity. An open cohort of children in Sisimiut will be formed, including all resident children below three years of age at the beginning of the study, as well as all children born in the following two year period: in total approximately 600 children. During two years, these children will be followed closely, including registration of episodes of respiratory tract infections. Furthermore, growth will be measured and microbiological samples obtained. PMID- 10093285 TI - RSV-associated hospitalizations in Alaska Native infants. AB - PURPOSE: Retrospective reviews for 1986-1992 suggested that Alaska Native children experience high rates of respiratory syncytial virus (RSV)-associated hospitalization; however, the epidemiology of RSV infections has been poorly characterized. METHODS: A prospective hospital-based surveillance study was undertaken to determine rates of RSV-associated hospitalization in Alaska Native children < 36 months from the Yukon-Kuskokwim Delta. RESULTS: During the first study year, October 1993 to September 1994, there were 40 RSV cases (hospitalization rate, 53/1,000 infants < 1 year of age); however, during the second year, October 1994 to September 1995, there were 251 RSV cases (hospitalization rate, 294/1,000 infants). An unusually high proportion, 12%, of RSV cases were < 1 month of age. Disease severity was higher for children with a history of prematurity, heart, or lung disease (p = .001, X2 analysis). Of 255 cell cultures during 1994-1995, 190 were RSV-positive, 11 were positive for influenza, 4 for adenovirus, and 1 for parainfluenza. This study demonstrates wide seasonal variation in a population with an extremely high RSV hospitalization rate; increased disease severity associated with young age and pre-existing medical conditions; and co-circulation of RSV with other viruses. PMID- 10093286 TI - Pneumococcal carriage in an Alaskan drug-using population. AB - This study examined the prevalence of pneumococcal carriage rates in an Alaskan drug-using population. Data collection included: (a) The Risk Behavior Assessment, (b) a supplemental smoking questionnaire, and (c) collection and culture of nasal/oropharyngeal specimens for isolation of Streptococcus pneumoniae. The overall carriage rate for S. pneumoniae was 13%. Of seven smoking variables, only hashish smoking within the prior six-month period was significantly associated with pneumococcal carriage. Other carriage indicators in the literature were nonsignificant. Results of the logistic regression indicate that the risk factors for carriage were (a) smoking hashish within the last six months, (b) receiving income from public assistance, and (c) receiving income from a family member or friend. PMID- 10093287 TI - The prevalence of otitis media with effusion among Inuit children. AB - PURPOSE: Studies over the past 30 years have shown a decline in the prevalence of chronic otitis media in some parts of the Arctic, presumably largely due to more prompt treatment, preventing acute infections from becoming chronic. In contrast, some researchers have suggested that the prevalence of otitis media with effusion has increased. The purpose of this study was to determine the prevalence of otitis media with effusion among children aged 6-17 years in Sanikiluaq, an Inuit community in the Keewatin District of the Northwest Territories. METHODS: A cohort of 126 children at the local community school was examined and assessed by otoscopy, audiometry, and impedance testing. RESULTS: Four percent of children were found to have otitis media with effusion causing significant hearing loss. An additional 17% had otitis media with effusion, with minimal or no detectable hearing loss. Thus, the prevalence of otitis media with effusion in Sanikiluaq school-age children is 4% to 21%. There are few previously published data with which to compare these findings. In the past, otitis media with effusion was infrequently reported among the Inuit. Therefore, our results may suggest an increasing prevalence over the past several decades. If these results are representative of other communities, otitis media with effusion is a significant health problem among the Inuit. PMID- 10093288 TI - The management of ear disease: guidelines for Aboriginal health care programs. AB - Middle ear disease represents a continuing burden of illness for children of circumpolar regions. Uncertainty in management has been shown to create a barrier to timely and adequate treatment. Consistent intervention strategies were sought for the management of middle ear disease in children of the central Canadian Arctic. The current literature was reviewed using MEDLINE. A consensus document was established in consultation with specialists in community medicine, infectious disease, otolaryngology, pediatrics, and community-based care providers. Definitive recommendations and supportive algorithms have been established for management of middle ear disease in Inuit children. PMID- 10093289 TI - Overview of viral hepatitis. AB - Viral hepatitis is a general term that is reserved for infections of the liver caused by one of at least six distinct hepatitis viruses, designated hepatitis virus A, B, C, D, E, and G/GB. The human hepatitis viruses are a group of diverse pathogens that share an ability to cause inflammation and necrosis of the liver. The most notable sign of this disease is jaundice, an orange-yellow discoloration of the scleroproteins of the skin and conjunctivae caused by the deposition of bilirubin in the blood resulting from faulty excretion of bile pigment by damaged hepatocytes. PMID- 10093290 TI - HIV and hepatitis B surveillance in First Nations alcohol and drug treatment centers in British Columbia, Canada. AB - Data have been lacking on the prevalence of HIV and hepatitis B (HB) infections in the North American Indian population in Canada. In January 1992, surveillance was introduced into two residential First Nations alcohol and drug treatment centers in British Columbia as part of an AIDS/STD education program. Male and female clients were given the option of participating and submitting serum for testing of HIV, HBsAg, and anti-HBc. As of December 31, 1995, 1,165 Native persons had been tested. There were four positive HIV results--two males and two females--a rate of 3.5/1,000. This compares with an expected rate of 4/1,000 for a British Columbia population not selected for specific risk factors. Similarly, the rate of HB carriage is low at 0.3%, compared to a provincial population rate of 0.5%. Evidence of past hepatitis B infection is 11.3%, double the rate of a British Columbia blood donor population. This study is ongoing. PMID- 10093291 TI - Immunogenicity of a combined hepatitis B and Haemophilus influenzae type b conjugate vaccine in Alaska Native infants. AB - Hepatitis B and Haemophilus influenzae b (Hib), prevalent diseases in Alaska Native infants, have been reduced 95% following universal vaccination. Therefore, we were interested in studying a new combined Hib and hepatitis B vaccine in this population. METHOD: Healthy Alaska Native infants free from Hib and hepatitis B exposure were randomized into four groups, three with different lots of bivalent Hib and hepatitis B vaccine, and one with Hib and hepatitis B monovalent controls. The Hib component had 7.5 micrograms of polyribosylribitol phosphate polysaccharide (PRP) bound to 125 micrograms of Neisseria meningitidis outer membrane protein complex (OMP); the hepatitis B component was 5 micrograms of recombinant hepatitis B surface antigen. The vaccines were given at 2 months, 4 months, and 12-15 months of age. RESULTS: There were no differences in the responses to the bivalent compared to the monovalent controls except for a lower Hib anti-PRP level at 12-15 months in the bivalent recipients; this did not persist after the booster. CONCLUSION: A combined Hib and hepatitis B vaccine appears immunogenic. The recommended schedule for the Hib component (PRP-OMP) of 2 months, 4 months, and 12-15 months appears to promote an optimal response to the hepatitis B component as well. PMID- 10093292 TI - Helicobacter pylori in a Chukotka Native male population. AB - Helicobacter pylori (HP) is a widespread human pathogen closely associated with gastroduodenal diseases. Thirty-four males from one of the settlements of coastal Chukotka (72% of total adult male population, mean age 31.6 years) underwent upper endoscopy, and HP was examined histologically in antral biopsies (Giemsa stain). Histology revealed normal mucosa in 16%, antral superficial gastritis in 29%, and atrophic gastritis in 55%. HP was found in 40% of histological specimens of normal mucosa, in 100% of superficial gastritis, and in 77% of atrophic gastritis. Correlation was found between the degree of bacterial contamination and both the activity of gastritis and grade of mononuclear infiltration. Data indicate a high prevalence of HP among Chukotka Natives (77%) which may partly explain the significant frequency of antral gastritis in this population. PMID- 10093293 TI - Cardiovascular risk factors in the adolescent population of Chukotka. AB - Representative samples of adolescents of both sexes, aged 15-17, who were residents of coastal and tundra Chukotka settlements (325 subjects) have been examined. The survey was conducted according to methods based on WHO recommendations. The program included a questionnaire, two measurements of arterial blood pressure, anthropometry, and assessment of blood lipid levels. The prevalence of smoking in boys was 40%; in girls, 19%. High systolic BP occurred more often in newly arrived boys (25%). Hypercholesterolemia was minimal in Chukotka Natives (5%), as was hypertriglyceridemia. The prevalence of low HDL cholesterol was highest (48%) in Native boys. Lipid disorders in Chukotka Native children obviously result from an unbalanced diet. High levels of arterial blood pressure in non-Native adolescents of Chukotka are probably caused by stress on the adaptation system under severe conditions in the North. PMID- 10093294 TI - Regional variation in cardiovascular risk factors and ischemic heart disease mortality in Greenland. AB - In a random sample of 264 indigenous Greenlanders, behavioral and biochemical risk factors for cardiovascular disease were compared between the capital, Nuuk, and the rest of the country ("the Coast") while the whole sample was compared with Denmark. In Nuuk consumption of marine food averaged 23 meals per month, compared with 38 on the Coast. N6/N3 ratio was higher in Nuuk but HDL concentrations were similar. There were fewer current smokers in Nuuk, but the prevalence of hypertension and mortality from ischemic heart disease (IHD) were similar. IHD mortality is lower in Greenland than in Denmark (352 and 434 per 100,000). This is in agreement with the dietary differences, and with the low N6/N3 ratio and the high HDL concentration in Greenland, but opposed to a high proportion of smokers and a high prevalence of hypertension in Greenland compared with Denmark. IHD mortality is apparently decreasing in Greenland concurrently with a Westernization of the lifestyle. This paradox may be due to the fact that societal changes are recent, and the situation may change in the future. PMID- 10093295 TI - Arterial calcification as a marker for atherosclerosis in three Arctic populations. AB - Accumulation of calcification in the arterial wall in the course of the atherogenic process is considered to be a manifestation of advanced atherosclerosis. In this study of autopsy specimens from Alaska non-Natives, Alaska Natives, and Greenland Natives, comparisons were made of the prevalence and extent of arterial calcification with that of all raised (advanced) lesions in the thoracic aorta, abdominal aorta, right coronary artery, and left anterior descending coronary artery, to determine the degree to which calcified lesions track the development of advanced lesions. Calcification was determined quantitatively from radiograph images of the fixed specimens; advanced lesion data on these specimens were available from prior studies. Findings show that the prevalence and extent of calcified lesions closely follows the pattern of prevalence and extent of advanced lesions among the groups. We conclude that calcification is a good marker for comparisons of the prevalence and may also provide a good measure of the extent of atherosclerosis in these populations. PMID- 10093296 TI - Left ventricular hypertrophy in northern and Siberian populations. AB - Characteristics of left ventricular hypertrophy (LVH) were investigated in random samples of the Chukotka coastal Native population (131 males) and in the urban Novosibirsk population (627 males) aged 30-59. Standard epidemiological methods employing electrocardiography (EKG) and echocardiography (EchoCG) were used. The frequency of EKG-LVH in the urban population was about six percent. The prevalence of LVH in Chukotka was more than twice as high as in Novosibirsk, as determined by both EKG and EchoCG criteria. About half of EchoCG-LVH cases in Natives and one-fifth of those in the city population could not be explained by conventional reasons. Advanced family surveys in Novosibirsk established the fact that myocardial hypertrophy exhibits a family aggregation in first-degree relatives of normotensive probands affected by LVH. The data demonstrate an inherited predisposition for LVH and suggest the need for molecular-genetic analysis. PMID- 10093297 TI - Increase in leukotrienes in the coronary circulation by cooling: a study in the anesthetized dog. AB - Pentobarbital-anesthetized dogs were instrumented for hemodynamic measurements and cooled by heat exchange tubes. Through a catheter in the coronary sinus, blood samples were obtained and plasma leukotrienes measured using a high pressure liquid chromatography technique. Hemodynamic function was significantly reduced during cooling, and during subsequent rewarming hemodynamic function was only partly restored. Leukotriene C4 and B4 were significantly increased at a body core temperature of 31 degrees C and 25 degrees C during cooling but not during rewarming (28 degrees C) and after rewarming (37 degrees C). This indicates that during decreasing body temperature elevated leukotriene levels may increase vascular permeability, inflammation, and vasoactivity and counteract temperature-dependent decrease in these functions. Disturbed microcirculation may thus diminish cardiac recovery during rewarming. PMID- 10093298 TI - The Alaska Native Naming Test: assessing speech loss in Alaska Natives after injury or stroke. PMID- 10093299 TI - Effects of dietary seal oil on fat metabolism. AB - In the 1970s, Bang and Dyerberg demonstrated that a high intake of n-3 acids in Greenland protected against ischemic heart disease. This started the interest in fish oil as a preventive component in cardiac disease. The fatty acid composition in Greenlandic diet is quite different from the one in the Danish diet, being lower in saturated fatty acids and polyunsaturated fatty acids (PUFAs) and higher in monounsatured fatty acids (MUFAs). During the last decade, evidence has suggested that the MUFA (18:1) is not a neutral dietary component but has a positive effect of its own. This paper reports on a current project undertaken to study the effect of marine MUFAs and PUFAs on atherosclerosis-related parameters and to evaluate their possible synergistic effect in the prevention of atherosclerosis. The project has recently started, so at the moment results cannot be presented. The study will be carried out as an intervention study on 50 healthy volunteers. Capsules of Greenlandic halibut oil (rich in MUFAs) and "Biomarin" (rich in n-3 PUFAs) will be tested against seal oil. PMID- 10093300 TI - Dietary fat and disease patterns in Chukotka Native adults. AB - It is well documented that dietary patterns have been changing for northern indigenous peoples as they adapt to a contemporary lifestyle. Recent dietary research among Chukotka Native adults showed a higher intake of saturated fatty acids (15% of energy) and sugar, and lower content of polyunsaturated fatty acids (5%) compared with our previous studies. We showed a higher percentage of dietary fat from animal fats (31%) and meat products (28%) than from seafoods and fish, which provide only 11% of daily fat intake. Increasing use of marketed foods and decreasing consumption of traditional foods among Chukotka Native adults contribute to more frequent cases of overweight, diabetes mellitus, and cancer. Dietary recommendations with an emphasis on traditional eating patterns should be considered for promotion of a healthy diet in Chukotka inhabitants. Promoting local foods of high biological value and establishing educational nutrition programs are of great importance. PMID- 10093301 TI - Chlamydia pneumoniae antibodies associated with altered serum lipid profile. AB - Chronic Chlamydia pneumoniae infection has been associated with atherosclerosis by seroepidemiological studies. Further, acute bacterial infections are known to influence lipid metabolism. To clarify the possible pathogenetic mechanisms of this association, we studied serum lipids and the C. pneumoniae IgG antibody titers of 1,053 males who participated in the reindeer herders health survey in Northern Finland in 1986-1989. The mean age of the study group was 47 years (range 20-87). When comparing nonsmoking C. pneumoniae antibody-positive (IgG > or = 32) subjects to those with no antibodies, the age-adjusted mean concentration of triglycerides was increased (1.34 vs. 1.04 mmol/l; p = 0.03) and high-density lipoprotein (HDL) was decreased (1.24 vs. 1.35 mmol/l; p < 0.001). HDL:total cholesterol ratio was also decreased (0.20 vs. 0.23; p = 0.01). In smokers changes were very similar, but not statistically significant. Thus, C. pneumoniae antibodies seem to correlate with an altered serum lipid profile considered to increase the risk of atherosclerosis. This finding supports the proposal that infections, in this case C. pneumoniae infection, may play a role in the pathogenesis of atherosclerosis. PMID- 10093302 TI - Diabetes mellitus in the First Nations population of British Columbia, Canada. AB - This study is the continuation of diabetes mellitus surveillance in the First Nations population of British Columbia. In 1990, the authors reported on a 1987 study of 348 cases of diabetes mellitus in the on-reserve residents of 104 communities. That study showed that the overall prevalence of diabetes appeared to be lower than in the non-Native population and was one of the lowest for the First Nations in Canada. The surveillance was repeated in 1992 and in 1995. In 1992, results were obtained for 60 communities. The overall rate was 2.0% compared to 1.2% in 1987. For diabetics aged 35+, the overall rate was 5.9% compared to 4.5% in 1987. In 1995, the overall rate was 2.2%, and for those aged 35+ it was 6.3%. The First Nation rates continue to be low but have increased considerably from 1987. The higher rates are found in the coastal and southern areas of the province. A North-South gradient has been noted elsewhere in Canada with the lowest rates in the North. This has been attributed to acculturation, including the adoption of a non-traditional diet and a more sedentary lifestyle. It is not clear otherwise why the coastal communities are affected to this extent. In spite of low rates overall, those in the north-eastern interior region of the province have steadily and significantly increased over the period of the study. A significant proportion of First Nations diabetics are reliant on insulin for blood sugar control, and higher rates of mortality from diabetes and cardiovascular disease suggest that complication rates may be excessive in this population. Diabetes remains a significant health challenge for the First Nations in British Columbia. PMID- 10093303 TI - Prevalence of diabetes mellitus and obesity in the Keewatin District of the Canadian Arctic. AB - Through a medical chart review, the prevalence of diagnosed diabetes mellitus in Inuit of the Keewatin District of the Canadian Northwest Territories was determined to be 0.27%. All cases were in adults, and no cases of gestational diabetes were noted. The prevalence and pattern of obesity were determined from measurements of body mass index (BMI), skinfold thickness, and waist-hip ratio obtained during the 1990-91 Keewatin Health Assessment Study. Thirty-one percent of 414 randomly identified adults (29% of men, 37% of women) were overweight (BMI > 27). Central fat patterning was more prevalent in women and less prevalent in men from the Keewatin compared to the general Canadian population. Comparison of skinfold thickness values to published measurements obtained from earlier arctic surveys supports the hypothesis that changes in diet and activity levels associated with urbanization have resulted in increased obesity in the Inuit. PMID- 10093304 TI - Glucose tolerance and insulin-resistance syndrome among St. Lawrence Island Eskimos. AB - OBJECTIVES: Non-insulin-dependent diabetes mellitus (NIDDM) prevalence in Alaska Natives is rising but remains lower than the U.S. average. We conducted a screening study for diabetes mellitus and cardiovascular disease in a remote Yup'ik Eskimo community in Alaska. RESEARCH DESIGN AND METHODS: The study population included Siberian Yup'ik Eskimo residents of Gambell, Alaska, > or = age 40 years who underwent a 2 h 75 gm oral glucose tolerance test interpreted by WHO criteria. Other measurements included fasting serum insulin and lipid levels, bioimpedance body fat %, body-mass-index (BMI), waist-to-hip ratio (WHR), and blood pressure. RESULTS: Of 114 eligible subjects, 65 (57%) participated. These subjects had lower mean systolic or diastolic blood pressure, lower triglyceride, and higher mean HDL cholesterol levels compared to a similarly aged U.S. all races sample. The mean fasting insulin level of 50.9 pmol/L appeared low given the high mean BMI (27.2). Six subjects had NIDDM (9%, 95% CI 2%-16%) and eight had impaired glucose tolerance (IGT) (12%, 95% CI 4%-20%). Compared to normoglycemic subjects, diabetic subjects were more frequently female (83% vs 53%) and had higher mean systolic BP (138 mm Hg vs 117 mm Hg) than normoglycemic subjects. We used multiple regression to analyze associations between fasting insulin and either blood pressure or serum lipids, while adjusting for % body fat, WHR, age, sex, and antihypertensive medication use. Fasting insulin was significantly related to both diastolic blood pressure (p = .0430) and fasting serum triglyceride (p = .0182) but not to systolic BP, total cholesterol, or LDL and HDL subfractions. CONCLUSIONS: Although NIDDM prevalence was not high compared to non-Native U.S. residents, elements of the insulin-resistance syndrome exist in this subarctic population. PMID- 10093305 TI - Gestational diabetes and subsequent development of NIDDM in aboriginal women of northwestern Ontario. AB - OBJECTIVES: To determine (1) the risk of development of non-insulin-dependent diabetes mellitus (NIDDM) in women with a previous history of gestational diabetes mellitus (GDM), (2) the average duration between diagnoses of GDM and NIDDM, (3) various modes of presentation, and (4) adequacy of follow-up post diagnosis of GDM. METHODS: A retrospective chart review of women diagnosed with GDM in the Sioux Lookout Zone between 1985-1995. There were 4,211 pregnancies and 332 women with a diagnosis of GDM. Sixty-one charts were randomly selected. Both GDM and NIDDM were defined according to World Health Organization standards. RESULTS: Seventy percent of the women with GDM went on to develop NIDDM. The average duration between diagnosis of GDM and diagnosis of NIDDM was three years. Greater than 70% of the women developed NIDDM within four years post diagnosis of GDM. The majority presented with asymptomatic hyperglycemia (88%); 3% presented with acidosis; 6% presented with symptoms of polydipsia and polyuria; and 3% presented with abnormal weight gain. Specific physician-requested follow-up after six weeks postpartum occurred in only 38% of the cases. However six-week follow up occurred in 41%, a yearly follow-up occurred in 61% of the women, and 81% of the women had some sort of follow-up post diagnosis of GDM. CONCLUSIONS: The risk of developing NIDDM after GDM is very high in Aboriginal women of the Sioux Lookout Zone. There is an urgent need for a structured follow-up program for this group of high-risk women. Furthermore, the offspring of these pregnancies should be a focus for follow-up and preventive programs. PMID- 10093306 TI - Pregnancy outcome in aboriginal women with NIDDM in the Sioux Lookout Zone. AB - PURPOSE: To review the pregnancy outcomes of Aboriginal women with non-insulin dependent diabetes mellitus (NIDDM) in the Sioux Lookout Zone of Northwestern Ontario, Canada. METHOD: Retrospective chart review of deliveries of all women with a confirmed diagnosis of NIDDM was carried out between 1989 and 1992. RESULTS: During this period, 26 infants were born to 19 women with the diagnosis of NIDDM. Mean birth weight was 4,075 grams, with an average gestational age at delivery of 38 weeks. Three newborns required cesarean delivery, one required forceps, and one a vacuum extraction. There were four cases of shoulder dystocia. There were one stillbirth, one maternal death, and two cases of congenital heart disease. Ten newborns had neonatal jaundice and only two had neonatal hypoglycemia. These results suggest there is significant risk associated with NIDDM in pregnancy. PMID- 10093308 TI - The Kahnawake Schools Diabetes Prevention Project: community participation in a diabetes primary prevention research project. PMID- 10093307 TI - The Sioux Lookout Diabetes Program: diabetes prevention and management in northwestern Ontario. AB - Clinically, non-insulin-dependent diabetes mellitus (NIDDM) in the First Nations population of the Sioux Lookout Zone (SLZ), Northwestern Ontario, represents a very different entity than that found in the general Canadian population. Here, its prevalence reaches upwards of 17% (over the age of 10) and children as young as five years of age have been diagnosed. Diabetic ketoacidosis is frequently found, and clients with blood glucose levels of 50 mmol/L or more have remained asymptomatic. Prevention and management of NIDDM in the SLZ must reflect this reality, as well as those of geographic remoteness; community-specific needs; and cultural, in addition to personal, relevance. Over the past five years, the Sioux Lookout Diabetes Program has been developing innovative services and resources to address these needs. Traveling foot-care and diabetes education programs, Community Health Representative training programs, a youth camp, school programs, grocery store labeling programs, and culturally relevant education manuals are a few such initiatives. Visions for the future include the development of a network of community-based diabetes workers to address more completely prevention and management needs on an ongoing basis and the development of stress management workshops for First Nations clients. With our current programming, these new initiatives, and an aggressive early screening program, we hope to stem the imminent onslaught of amputations, heart attacks, renal failure, and blindness. PMID- 10093310 TI - The cost-effectiveness of a retinal photography screening program for preventing diabetic retinopathy in the First Nations diabetic population in British Columbia, Canada. AB - Seven-field stereo retinal photography is both 100% sensitive and specific for diagnosing diabetic retinopathy and is the standard for evaluating the severity of retinopathy both for clinical and epidemiological studies. It is also very useful for follow-up of diabetics and eventual treatment of complicated cases with laser and other treatment modalities. If the 450 First Nations diabetic cases that were surveyed in 1992 in British Columbia, Canada, were to receive an annual assessment by an ophthalmologist, the cost is estimated at $164,000 (Canadian). This amount includes travel, hotel, and meal costs of patients traveling to the ophthalmic centers in their areas and the fee for specialist services. Alternately, retinal photography screening is estimated to cost $61,000. This amount includes photo-technician labor, travel costs to the community, hotel and meal costs, ophthalmologist interpretation of the photographs, and annualized capital maintenance costs. In the first year, the cost of vehicle purchase with accessories and a camera with accessories is estimated at $61,000, with an estimated four-year lifespan of equipment. Maintenance and insurance, including vehicle fuel, will cost $12,256 annually. A retinal photography program could travel to the diabetic patient, and nearly 100% of First Nations diabetic patients could receive this service annually. This program could be highly effective in preventing blindness in First Nations diabetic patients in British Columbia through early intervention in diabetic retinopathy. PMID- 10093309 TI - Preventing NIDDM among aboriginal people: is exercise the answer? Description of a pilot project using exercise to prevent gestational diabetes. AB - Rates of diabetes and its complications have reached epidemic proportions among North American Aboriginal peoples. This appears largely due to changes in diet and activity levels associated with a shift away from traditional lifestyles. Since exercise has been shown to be effective in preventing non-insulin-dependent diabetes mellitus (NIDDM), Aboriginal communities may be able to reduce their rates of the disease by incorporating exercise programs into their public health programs. We describe a pilot project in Saskatoon, Saskatchewan, whose ultimate purpose is to evaluate the effect of exercise in preventing gestational diabetes. If successful, this would reduce the risk of developing NIDDM for both women and their offspring. PMID- 10093311 TI - Seasonal variation of serum TSH and thyroid hormones in males living in subarctic environmental conditions. AB - To evaluate the seasonal influence upon thyroid hormone dynamics, we took blood samples every two months during a period of 14 months from 20 healthy males living in Northern Finland (69-70 degrees N), where the mean daily temperature ranges from a winter minimum of -40 degrees C to a summer maximum of 2 degrees C, while the photoperiod changes from a polar night of 6 days in winter to a polar day of 45 days in summer. The subjects were allowed free choice of diet, exercise, and outdoor exposure. Serum free T3 levels were lower in February than in August (3.9 vs. 4.4 pmol/l, p < 0.05) and TSH levels higher in December than during other months (2.1 vs. 1.5-1.7 mU/l, p < 0.05). Serum total and free T4 and total T3 levels were unchanged. Serum free T3 correlated significantly to the mean outdoor temperature of the preceding month. Serum TSH did not show any correlation with the mean temperature of the month or with free T3. Low serum free T3 in winter suggests that the disposal of thyroid hormones is accelerated in cold as described in the Polar T3 Syndrome. Elevations in serum TSH are not accounted for by changes in circulating thyroid hormones, suggesting that other influences, such as photoperiod, may mediate this fluctuation. PMID- 10093312 TI - Seasonal variation of the amino acid, L-tryptophan, in interior Alaska. AB - The seasonal pattern of L-tryptophan was studied in a Fairbanks, Alaska, population that was unadapted to the extreme light variations of the North. Previously, this population was shown to exhibit seasonal behavior effects such as increases in fatigue and sleep duration, as well as endocrine effects such as increases in melatonin levels and phase shifting. Caloric and macronutrient intake have been reported to vary seasonally in humans, thereby potentially influencing the plasma levels of L-tryptophan, which is a precursor of serotonin and melatonin. Plasma levels of L-tryptophan from volunteers, whose average duration of stay in Alaska was eight months, were determined by automated amino acid analysis. Prominent results included finding increased levels in the winter at several different diurnal time points. These findings support hypotheses which relate underlying physiological adaptations to the North to the increased incidence of behavioral disorders such as depression and alcoholism. PMID- 10093313 TI - Cancer trends from 1972-1991 for Registered Indians living on Manitoba Reserves. AB - BACKGROUND: The objectives of this study were to determine if the incidence of and mortality from cancer have increased between 1972-1991, and to describe the distribution of cancer sites and survival for Registered Indians living on reserves. METHODS: Cancer cases and deaths on-reserve were obtained from the provincial cancer registry, using a postal code match. Treaty Status was verified using a population registry kept by Health Canada. Population figures on-reserve were obtained from the federal Department of Indian Affairs. RESULTS: The average annual number of cases and deaths increased by 64% and 122%, respectively, between 1972-76 and 1987-91 (NS). The age and sex standardized incidence and mortality rates increased by 7% and 50% (NS). Males had a 1.1 times higher incidence and 1.4 times higher death rate than females. The entire excess male incidence and mortality occurs after age 50. Females have 1.1 to 6.2 times the incidence and mortality between ages 20-49. CONCLUSIONS: Cancer incidence and mortality appear to be increasing on-reserve. The distribution of leading sites and pattern of survival are similar to that of the rest of the population, with the exception of a higher proportion of cases and mortality caused by cervical and gallbladder cancer in females and kidney cancer in both sexes. The lung cancer rate is increasing in women and is the leading cause of cancer mortality for both sexes. It is likely that these trends will continue for some time unless there is reduction in the high rate of smoking, dietary change, and implementation of more widespread and effective Pap screening on-reserves. PMID- 10093314 TI - Development and implementation of a breast and cervical cancer screening program in urban and rural Alaska. AB - Early detection of breast and cervical cancers represents the single best strategy to effect the reduction of associated morbidity and mortality. The State of Alaska identified a need to establish a service delivery system which would assure the availability of breast and cervical cancer screening services for women who are low income, under- and uninsured, and from racial/ethnic minorities. In March 1995 the Alaska Breast and Cervical Cancer Early Detection Program (AK-BCCEDP) began funding breast and cervical cancer screening services through the Centers for Disease Control and Prevention, National Breast and Cervical Cancer Early Detection Program. The purpose of AK-BCCEDP is to establish a comprehensive service delivery strategy which includes screening, tracking, referral, follow-up, public education, quality assurance, surveillance, coalition building/partnering, and evaluation. During the first year of services (March 1, 1995, to February 29, 1996) 651 women were screened for breast and cervical cancer. Higher than expected numbers of breast cancer were detected. Of the 651 women screened, four were diagnosed with invasive breast cancer and three were diagnosed with high-grade squamous intraepithelial lesions. PMID- 10093315 TI - Follow-up of a decentralized colposcopy program for the investigation and management of cervical intraepithelial neoplasia in the central Canadian Arctic. AB - Cervical intraepithelial neoplasia (CIN) is the second leading cause of cancer in Canadian Inuit women, and the incidence ratio in this population is 3.1 times the Canadian average. In 1993 a program was developed in a regional northern health center (Churchill) to provide colposcopy and loop electrosurgery for women in the Keewatin District of the central Canadian Arctic. Data collected prospectively over the following 2.5 years are presented. One hundred and forty-six women were seen in 341 visits. Indication for referral included CIN I on Pap smear (54.1%), CIN II (34.9%), CIN III (9.6%), and carcinoma of the cervix (1.4%). Large loop excision of the transformation zone was performed at a rate of 9.7 procedures per 100 patient visits. Estimated travel cost-savings attributable to this northern program are $299,200 (Canadian). Use of portable colposcopy in patients' home communities is presently being considered in order to provide enhanced accessibility and further cost-effectiveness. PMID- 10093316 TI - Management of hereditary non-polyposis colon cancer in a northern rural setting: a progress report. PMID- 10093318 TI - Common mental disorders among patients in primary health care in Greenland. AB - Studies from all over the world have shown that well defined mental disorders are common in all general health care settings and that marked disability is associated with common mental disorders, more so than with chronic physical disorders without psychological disturbances. A majority of mental disorders are unrecognized and do not get appropriate treatment. No such study has been made in Greenland, but there are many indications that mental health is threatened and needs more attention. A two-stage study of common mental disorders among patients in the primary health service in Greenland is planned to take place from September 1996 to 1998. The research plan is presented as an invitation to replicate the study in other circumpolar areas. PMID- 10093317 TI - Hepatitis B and hepatocellular carcinoma in Eskimo/Inuit population. AB - Hepatitis B virus (HBV) is major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. Serologic surveys performed in the 1970s and 1980s have demonstrated that Alaskan Eskimos, Canadian Inuit, and Greenland Inuit have very high prevalence rates of HBV. In Alaska, a high incidence of HCC in Eskimos, especially males, has been reported. Alaska Natives chronically infected with HBV have a relative risk of HCC of 148 compared to Alaska Natives who are not chronically infected. In Canada the incidence of HCC is six times more frequent in elderly Inuit than in Canadians in general. However, an elevated rate of HCC has not been found in Greenland. Primary prevention programs to prevent HCC by vaccination against HBV are being conducted in Alaska, Canada, and Greenland. In addition, in Alaska a program to detect HCC earlier by screening persons chronically infected with HBV, using semiannual alpha-fetoprotein testing, has resulted in detecting over 60% of HCC early enough for surgical resection. PMID- 10093319 TI - Psycho-physiological mechanisms of adaptation of rotation personnel in Arctic regions. AB - Transit workers (240 oil industry workers, aged 19-50) living in the European part of Russia and flying to work in the northern regions of West Siberia (Tyumen district) were observed. Psychological status was determined by the method of Taylor. Biological rhythms, chemical control of ventilation, oxygen (O2) and carbon dioxide (CO2) consumption, body temperature, and hormone-metabolic data were assessed. The analysis of illness for the Nadymgazprom Enterprise was carried out in accordance with the medical charts. One may notice a certain cyclic recurrence of the adaptation process. Thus, the first stage of vigorous rearrangement of the psycho-physiological regulation system is followed by a period of relative stability, the result of initiation of compensatory processes. Compensation mechanisms, however, may become disabled, triggering development of a disadaptive state. Results of these scientific investigations were used to introduce new transit work regimens at Nadymgazprom Enterprise. PMID- 10093320 TI - The investigation of stress in resource-dependent communities: the effect of rapid socioeconomic changes on mental health service use. AB - Drawing on census data and psychiatric hospital records, this paper examines the impact of rapid socioeconomic change on the mental health of residents in Northwestern Ontario resource-dependent communities. This research investigates whether residents in economically growing and declining communities experience more mental distress and use more psychiatric services than people in stable communities. Findings show socio-demographic change is associated with significant differences in psychiatric hospital utilization between different types of communities, with bust communities illustrating the highest rates (5.5/1,000). Furthermore, acute stress symptoms are reported much more frequently in bust and boom communities than in stable communities. Results of multiple regression analysis indicate that decreasing household income level also contributes to increasing rates of mental health service utilization. PMID- 10093321 TI - The effect of an alcohol ban on the number of alcohol-related hospital visits in Barrow, Alaska. AB - PURPOSE: This study was conducted to examine the impact of a change in local alcohol laws on alcohol-related hospital usage. Heavy alcohol consumption and its complications are major health problems in the Arctic. For many years, the sale of alcohol in Barrow was illegal, i.e., "damp" status. In October 1994, the residents of Barrow voted to make both the sale and importation of alcohol illegal, i.e., "dry" status. METHODS: The Public Health Service Hospital in Barrow is the only physician-staffed health care facility for 4,000 residents in Barrow, as well as for five of its seven outlying, dry villages (approximately 2,000 more residents). We retrospectively studied the number of alcohol-related outpatient visits to our hospital from November 1993 through October 1994 (the damp year), and from November 1994 through October 1995 (the dry year). The data used were from the emergency visit log in our outpatient department. RESULTS: We found a 76.5% to 93.2% decrease in alcohol-related outpatient visits when comparing corresponding months during the dry year to those during the damp year. The average overall decrease in alcohol-related outpatient visits was 84.7%. These results were highly significant with a p-value of 0.0022. We conclude that the prohibition of alcohol in remote areas can be an effective method in reducing the amount of alcohol-related health problems and can help make a healthier community. PMID- 10093322 TI - Clinical and social aspects of alcoholism among the Nenetz population. PMID- 10093323 TI - Alcohol consumption among Alaskan drug users. AB - This study investigated predictors of alcohol consumption among drug users not currently in treatment in Anchorage, Alaska. Data were collected from 114 female and 269 male drug users via structured interviews. Alcohol consumption was defined as estimated number of drinks consumed in the last 30 days. Results revealed a high proportion consuming alcohol within the last 48 hours and 30 days (73% and 96%, respectively). Stepwise multiple regression revealed that five variables, accounting for 9% of the variance, were significantly related to alcohol consumption. Positively related were greater perceived risk of getting AIDS; obtaining income from spouse, family, or friend; living on the streets or in a shelter; or living in a hotel or boarding house. Negatively related was having an education level greater than high school. For those participants who reported having sex during the last 30 days, two variables were positively related to alcohol consumption and accounted for 17% of the variance: number of times used alcohol with sex and frequency of sex without a condom. In addition to identifying several demographic variables that are significantly related to alcohol consumption, the results document the relationship between alcohol consumption and unsafe sexual practices. PMID- 10093324 TI - Flushing response and its role in alcohol disease in Siberian populations. AB - The characteristics of alcohol-induced flushing response were studied in some Siberian Native populations (Chukchi, Eskimo, Jakuts, Udege, and Nanaian). Flushing peculiarities were estimated and the interrelationship with drinking patterns, the ethanol patch test (EPT), and somatic disorders were analyzed. Frequency of flushing response varied from 9.0% to 66.7%, and was more often apparent among females. Only the Nanaian demonstrated typical flushing, which did not allow them to consume high doses of alcohol. In the rest of the populations flushing was "atypical," i.e., appearing sometimes after high doses of alcohol but not interrupting alcohol drinking, and not associated with a positive EPT. Direct genotyping in DNA samples of Chukotka Natives did not reveal atypical allele aldehyde dehydrogenase (AIDH 2/2). Frequencies of alcohol problems, alcohol dependence symptoms, and somatic disorders (arterial hypertension, silent ischemia, diffuse liver lesions, and noncalculous cholecystitis) were higher among atypical flushers compared to nonflushers (p < 0.05-0.01). The mechanism of the observed atypical flushing response is unknown. We speculate on its hereditary nature, since flushing alcoholics, compared to nonflushers, reported that their parents had flushing responses significantly more often. Further studies are required. PMID- 10093325 TI - Alcohol, drugs, and family violence: perceptions of high school students in southwest Alaska. AB - Many programs have attempted to address alcohol and drug use and family violence as issues of public health. This paper examines the degree to which high school students in Southwest Alaska identify these issues as problems in their communities. Qualitative and quantitative data come from a 1995 survey of children in grades 9 to 12 in four villages, one town, and one boarding school in Alaska. Alcohol policies differ in rural Alaska, with "dry" communities banning alcohol possession, "damp" communities allowing alcohol possession but not sale, and "wet" communities permitting purchase and importation of alcohol. Although the majority of all students believe alcohol and drugs are problems in their communities, only 45% of town students and 22% of village students report too much family violence in their communities. Qualitative data indicate that alcohol and drugs are of concern to young people. One female student, when asked if she would be a successful person, responded "Yes, because I look at my drunk relatives and tell myself, that will never happen to me." PMID- 10093326 TI - Unmet treatment needs of drug users in Alaska: correlates and societal costs. AB - This study assessed the unmet treatment needs of drug users in Anchorage, Alaska. It revealed that almost half of the drug users who desire treatment cannot secure it, largely for external reasons. The primary barrier to treatment was lack of availability of treatment slots, followed by excessive treatment costs and restrictive admission criteria. Unlike other studies, this investigation did not suggest that members of ethnic minority groups, women, and parenting women were disproportionately disadvantaged with regard to ability to secure treatment. However, substance abusers who also met criteria for a co-morbid psychiatric diagnosis other than substance abuse or dependence had more difficulty than their non-co-morbid peers in finding available treatment slots. Social, legal, and medical costs incurred by unsuccessful treatment seekers are outlined and suggest significant cost, as well as perpetuation of intergenerational cycles of violence and substance use. PMID- 10093327 TI - Cocaine smokers and injection drug users in Alaska: what distinguishes Native Americans from non-Native Americans? AB - Demographic and behavioral characteristics were modeled for distinguishing Native American drug users from non-Native American drug users in Anchorage, Alaska. Data were collected using a structured interview administered to participants (n = 1,091) who smoked cocaine, injected drugs, or both. Multivariate analyses were performed using logistic regression modeling. Four characteristics distinguish Native Americans (n = 223) from non-Native Americans (n = 868). Native Americans were more likely to have used marijuana at an earlier age and to have less than high school education; they were less likely to have ever used heroin and cocaine together, and to have used a condom during sex. Results are useful for administering interventions, data collection, and targeting hidden populations. PMID- 10093328 TI - The development of a culture-based substance abuse treatment program in the Kuskokwim Delta, Alaska. AB - This paper describes the development of a substance abuse program for three remote Western Alaska villages with strong traditional cultures. Although the impact of substance abuse is known to be substantial in the Kuskokwim Delta, intervention and treatment services have not been universally accepted by the traditional Yup'ik and Cup'ik communities. The reason may be that services do not accommodate the cultural values of the people they are intended to serve. The Chemical Misuse Treatment and Recovery Services (CMTRS) program was designed to address this issue. The paper will describe the demographics and cultural characteristics of the people of the three villages participating in the program, describe how traditional Yup'ik and Cup'ik values were incorporated into the program, and discuss some of the early data on the acceptance and use of the program services. PMID- 10093329 TI - Methodological issues in evaluating a culture-based substance abuse treatment program in the Kuskokwim Delta, Alaska. AB - This paper presents a rationale for using videotape records in evaluation research. Although videotaping is commonly used in ethnographic and sociometric analysis, the evaluation literature does not show the application of these recording techniques to program evaluations. The authors outline a model for exploring the effectiveness of video in qualitative program evaluation. PMID- 10093330 TI - New approaches to smoking prevention in the north. AB - Morbidity and mortality rates of noncommunicable diseases (NCD) are very high in Siberia. The prevalence of NCD risk factors is also very high, smoking being one of the most widespread risk factors. Prevention and cessation of smoking may improve the health of the population. Within the framework of the WHO MONICA (Monitoring Cardiovascular Diseases) project, we have conducted three population surveys in Novosibirsk within a 10-year period (1984-1995) to show trends of cardiovascular diseases and their risk factors. We also conducted similar surveys in some Siberian regions. Economic crisis and social stress greatly affect the health of the population, and new methods and approaches to disease prevention are needed. As participants in the WHO CINDI program (Countrywide Integrated Program for Disease Prevention), we started our work to reduce and control the main NCD risk factors. Smoking being widespread in Siberia, we started an anti smoking campaign in Novosibirsk as participants in the international "QUIT & WIN" campaign in 1994. In 1995 we arranged a similar contest at the local level in the city; and now in May 1996 we are again taking part in the QUIT & WIN campaign. PMID- 10093331 TI - Education on health risks of smoking in Magadan, Russia. AB - PURPOSE: The purpose of this project was to educate young Russians on the health risks of smoking. METHOD: The American Cancer Society, Alaska Division, sponsored a project to deliver its teaching modules on the health risks of tobacco use to first- through third-graders in Magadan, Russia. Starting with a $4,400 (U.S.) contribution designated for this purpose, a young teacher, Irina Alishova, was contacted in Magadan in 1993. She translated the modules of the American Cancer Society oriented to the first- to the third-grade level. Irina also made contact with the Magadan school system, specifically the principal of Middle School Number 29, Alla Vakulyuk. Principal Vakulyuk encouraged the project and worked with the other schools in the Magadan school system. RESULTS: Throughout the 1993 94 school year, nearly all of the first- and second-grade classes and a portion of the third-grade classes received and participated in the 50-minute teaching module. An American representative for the American Cancer Society observed one of the classes and noted thoughtful and enthusiastic participation by the schoolchildren. PMID- 10093332 TI - Accidental deaths and suicides among Alaska Natives, 1979-1994. PMID- 10093333 TI - Preventing deaths in Alaska's commercial fishing industry. AB - BACKGROUND AND PURPOSE: The arctic and sub-arctic waters of Alaska provide a very hazardous work setting, with special hazards posed by great distances, seasonal darkness, cold waters, high winds, brief fishing seasons, and icing. Our intent is to reduce the remarkably high occupational fatality rate (200/100,000/year in 1991-1992) among Alaska's commercial fishing workers. Over 90% of these deaths have been due to drowning or drowning plus hypothermia, primarily associated with vessel capsizings and sinkings. METHODS: Comprehensive surveillance for commercial fishing occupational fatalities was established during 1991 in Alaska. During 1990 through 1994, the U.S. Commercial Fishing Industry Vessel Safety Act of 1988 required the implementation of comprehensive prevention measures for all fishing vessels in offshore cold waters, including immersion suits and other personal flotation devices, survival craft (life rafts), emergency position indicating radio beacons, and crew training in emergency response and first aid. Parallel to this, voluntary training efforts by nonprofit organizations have greatly increased. RESULTS: During 1990-1994, drowning was the leading cause of occupational death in Alaska. During this period, 117 fishers died, 101 of them from drowning or drowning/hypothermia. During 1991-1994, there was a substantial decrease in Alaskan commercial fishing-related deaths, from 34 in 1991 to 35 in 1992, 22 in 1993, and 10 in 1994. While man-overboard drownings and some other categories of deaths (falls, fires) have continued to occur, the most marked progress has been in vessel-related events. CONCLUSION: Specific measures tailored to prevent drowning in vessel capsizings and sinkings in Alaska's commercial fishing industry have been very successful so far. Additional efforts must be made to reduce the frequency of vessel events and to prevent man overboard events and drownings associated with them. PMID- 10093334 TI - Occupational aviation deaths in Alaska, 1990-1995. AB - PURPOSE: In Alaska, aviation was the leading cause of work-related death in 1995 and the second leading cause for the period 1990-95. A descriptive study of aviation crashes was completed to characterize occupational aviation crashes and fatalities in Alaska. METHODS: Aviation-related incidents were abstracted from the Alaska Occupational Injury Surveillance System and National Transportation Safety Board preliminary reports. RESULTS: Records for a total of 1065 aviation crashes were abstracted. There were 285 aviation-related fatalities (8.5/100,000/yr) for all Alaskans; 135 (47%) of the fatalities (7.3/100,000/yr for Alaskan workers) were occupationally related. Helicopters accounted for 55 (17%) of the total occupational aviation crashes and 14 (10%) of the fatalities. The most common phase of flight cited in all crashes was takeoff (59 [18%]) and landing (136 [41%]); in contrast, only 9 (13%) of the fatal crashes occurred during takeoff and landing combined. In fatal crashes, the cruise phase (27 [38%]), followed by maneuvering (16 [23%]), were the most frequent phases of flight cited. Thirty-one percent (n = 22) of aircraft involved in fatal occupational incidents were not completely destroyed, allowing for potential survivors. Shoulder harnesses and helmet use, improved cockpit design, and energy absorbing seats could reduce aviation-related injury and death. PMID- 10093335 TI - Effective injury prevention using surveillance data: helicopter logging, Alaska, 1992-1995. AB - BACKGROUND AND PURPOSE: To reduce the fatality rate in helicopter sling-load logging in Alaska. These operations--on rugged terrain, due to environmental restrictions and economics--are an emerging technology application worldwide. During 1992 and 1993, crashes during these operations in Alaska resulted in multiple fatalities. METHODS: During 1992, comprehensive surveillance for these events was established, combining electronic media and interagency notification with active investigation to identify preventable risk factors. These data were applied in mid-1993 by an interagency working group, which included representatives of the Alaska Department of Health and Social Services, Alaska Department of Labor, Federal Aviation Administration, National Transportation, Safety Board, U.S. Coast Guard, Occupational Safety and Health Administration, U.S. Forest Service, and National Institute for Occupational Safety and Health. In response to surveillance data, consensus safety recommendations were developed. Working closely with industry, immediate improvements were made in worker training, work/rest cycles, and oversight. Surveillance results are being used to evaluate the effectiveness of interventions. On March 1-2, 1995, an international workshop was convened in Ketchikan, Alaska, to involve industry and government agencies in planning for durable prevention in this industry. RESULTS: In Alaska between January 1, 1992, and June 30, 1993, there were 6 helicopter crashes, with 9 fatal (4 in pilots) and 10 severe nonfatal injuries, out of only 25 helicopters flying in helicopter logging operations. Alaska logging helicopters thus had the extraordinarily high annual crash rate of 16% and a catastrophic pilot fatality rate of 5,000/100,000/year. Investigation revealed that all crashes involved improper operational and/or maintenance practices. Since these recommendations were implemented in July 1993, there have been no additional helicopter logging fatalities in Alaska through 1995. The 1995 meeting resulted in further recommendations, including more vigorous oversight; development of rigorous voluntary industry standards for equipment, maintenance, and training; exclusive use of multi-engine rotocraft; and more vigorous controls on alcohol and drug use in this industry. PMID- 10093336 TI - Urban encroachment on the wilderness: moose-vehicle collisions in Anchorage, Alaska, 1991-1995. AB - BACKGROUND: Moose have successfully adapted to urban sprawl in Anchorage, Alaska, using greenbelt areas for shelter, forage, and protection. However, the proximity of moose to people poses unique hazards: a collision with a moose may cause significant injury and vehicle damage. METHODS: Moose-vehicle collisions were identified using Municipality of Anchorage records. Completeness of reporting was assessed from Alaska Department of Fish and Game records. RESULTS: The moose vehicle collision rate increased significantly from 38 to 49.2/100,000/yr during the study period (p = .005, x2 = 7.795). Of 519 reported moose-auto collisions, 120 (23%) resulted in injury to 158 people, with no human fatalities. Most collisions (291 or 56%) occurred between 1800 and 0200 hours; 411 (79%) occurred after dark; 154 (30%) occurred during December and January; and slick road conditions were identified in 280 (54%) incidents. Incidents occurred primarily near greenbelt areas. CONCLUSIONS: Moose-vehicle collisions often occur at night, on unlighted, slick road surfaces. Moose-vehicle collisions may be prevented by: reducing speed limits around green-belt areas, brighter vehicle headlights, placement of street lights in known moose areas, underpasses for wildlife at known crossings, and snow removal to reduce berm height in known moose areas. PMID- 10093337 TI - Man and polar bear in Svalbard: a solvable ecological conflict? AB - The objective of this study is twofold. First, it is to assess the nature and magnitude of the polar bear-human conflict with respect to injuries to man and bear. Second, a major concern has been to minimize injurious interactions in order to safeguard the people who live and work in the Arctic, and, at the same time, secure the future of the polar bear in one of the last relatively unspoiled habitats on earth for big carnivores. From 1971 to 1995, approximately 80 bears were involved in serious bear-human interactions. Of these, 77 bears were killed and 3 escaped after having injured people. During the same period, 10 people were injured, 4 of them fatally, in 7 separate interactions, each involving a single bear. None of the victims carried an appropriate firearm. The circumstances leading up to the confrontations give strong reasons for supposing that the majority of the attacks were predatory in nature. Seven of the injured, including the four who were killed, sustained bites to the head and neck. Correct use of firearms could probably have prevented all the fatalities. However, the keeping and use of firearms caused two accidental deaths in the same period. We conclude that alertness, the absence of attractants (food, garbage), and appropriate bear repellents to secure field camps are important items in preventing conflicts and should always be available. However, as a last but indispensable resort, a firearm (rifle or shotgun) carried by an experienced user is the only safe precaution for avoiding injuries in polar bear country. Killing a bear on the rare occasions when humans are in danger presents no threat to the bear population. With regard to physical injury to people, the problem is a minor one. Bears have a dual impact on everyday life in the Svalbard settlements. While there is some anxiety related to the presence of bears, the polar bear is a source of breathtaking adventure highly valued by both residents and visitors. PMID- 10093338 TI - Social and cultural impacts of environmental change on aboriginal Peoples in Canada. AB - Environmental change, often the result of Western industrial development, has had a major impact on Canadian Aboriginal people. Even when there are no provable direct health effects, Aboriginal peoples' holistic concepts of health, balance, and harmony, and the interrelatedness of health and environment lead them to regard social and cultural effects as health effects. This paper explores the links between environmental change and the social and cultural and, hence, health effects these changes produce. It is argued that factors such as Aboriginal holistic concepts of environment and health, perceptions of risk, and difficulties in communication contribute to these social and cultural effects and their subsequent health effects-effects which frequently present a greater problem in Canadian Aboriginal communities than do the direct health effects of environmental change. PMID- 10093339 TI - Cultural environmental health risk perception in the Canadian north. AB - This paper examines perceptions of various sources of environmental health risk in one Aboriginal community in Northern Canada to better understand how community members view those risks. The central question addressed is whether there is a pattern of perception, or form of cultural rationality, that informs risk perception generally, or are health risk perceptions created in an ad hoc manner, depending on local circumstances. A case study approach, involving both ethnographic and survey methods, was employed in three aboriginal communities in Quebec, Saskatchewan, and Manitoba. This paper reports on one of those communities. Distinct cultural patterns of perception were found: a pattern that recognizes contingencies and conditions that produce dangerous circumstances--a pattern that is open to new forms of knowledge and sensitive to uncertainty. PMID- 10093340 TI - Points of view: Inuit women's perceptions of pollution. AB - Inuit women's perceptions of health risks from potential contamination in the arctic food chain were investigated in 1995 through in-depth interviews with 47 women in a Canadian arctic community. This number represents 34% of the eligible participants in the population of the research community. Many of these Inuit women suggest that pollution can appear in a variety of forms, from drug and alcohol consumption to visible air and water contaminants to possible invisible contaminants in arctic wildlife. Concepts of pollution--starting with the individual body and extending to the body politic--are influenced by a complex of sociocultural factors arising from historical and contemporary community life. PMID- 10093341 TI - Persistent organic compounds in women residing in the Russian Arctic. AB - Within the framework of a joint Russian-Norwegian project on human health assessment under the eight-nation Arctic Monitoring and Assessment Program, a study of persistent organic compounds was conducted in 42 non-indigenous women who delivered in the hospitals of Norilsk and Salekhard during February and March 1995. Samples of venous blood, breast milk, umbilical cord blood, and placental tissue were collected. The concentration of organochlorines (chlorinated pesticides and polychlorinated biphenyls) was estimated by high-resolution gas chromatography, and levels of polycyclic aromatic hydrocarbons were determined by high-performance liquid chromatography with a fluorescence detector. The results obtained are related to, first, the global transport of organochlorine contaminants not used in Arctic, and second, the level of local food consumption, especially freshwater fish, smoked and dried. A comparison of the results of this study with the data of the Inuit Health Survey was made. This has shown that the discrepancy between Canadian and Russian data may be explained by differing dietary factors. PMID- 10093342 TI - Cultural concerns regarding contaminants in Alaskan local foods. AB - Indigenous people of Alaska, who depend in many ways on foods which they obtain locally by hunting, fishing, and gathering, have raised concerns about the changing quality of their foods in light of confirmation of the long-range transport of global pollutants. A review of a variety of parallel research efforts has shown little consistency in practice, no clear evaluation of exposure levels through dietary surveys on a broad scale, and no comprehensive educational effort to inform the general public of the changing levels of pollutants in local foods. Nor has there been adequate communication regarding the source of the contamination, whether natural contaminants or anthropogenic pollution. Alaska Native cultural issues that contribute to the risk perception of a health problem inherent in eating a traditional diet that is showing signs of increasing levels of pollution, no matter how small, must be considered in any recommendations regarding locally obtained foods and in public health efforts. Recommended cross cultural communication methods should be employed in dealing with topics of high community concern. PMID- 10093343 TI - A database for environmental contaminants in traditional food in northern Canada. AB - The potential health effects of environmental contaminants in traditional food on indigenous peoples in Northern Canada have been a growing concern. We have conducted an extensive literature review on contaminant levels in Northern Canada through searches of commercial, private, and government databases for the years 1986-1995, including MEDLine, Agricola, Biological Abstracts, Current Contents, Applied Science and Technology, Biosis, CABCD, Aquatic Sciences and Fisheries Abstracts, CRIS/ICAR, and the Northern Aquatic Food Chain Contaminant Database. More than 20,000 data items were identified in over 50 published articles, unpublished data, government reports, and review articles. Ranges of levels of 13 contaminants in major traditional food groups collected from four geographical regions (Yukon, MacKenzie, Keewatin, Baffin and Northern Quebec) were calculated. Exposure levels, particularly according to different dietary patterns, were estimated and discussed in relation to guideline levels. PMID- 10093344 TI - A public health perspective on the evaluation of subsistence food safety. AB - Persistent organic compounds and trace metals are found in the arctic food chain, generating concerns about the safety of subsistence food consumption. One approach for evaluating subsistence food safety is a process used extensively in regulating environmental clean-up and pollution standards. This process, regulatory risk assessment, is substantially different from approaches used in public health risk assessment. Limitations to the use of regulatory risk assessment in assessing public health threats from environmental exposures in the diet include a narrow scope, a lack of incorporation of the nutritional and health benefits of subsistence foods, and the overestimation of risks because of the incorporation of worst-case assumptions in the absence of scientific information. Sound public health policy recognizes that attempts to err on the side of safety for one exposure by recommending reduced consumption of a selected food may inadvertently err on the side of harm by reducing a coexisting exposure of potentially great health benefit. The following discussion should serve as a useful background for future multidisciplinary discussions on the safety of subsistence foods in the Arctic. PMID- 10093345 TI - Twenty years of trace metal analyses of marine mammals in Alaska: evaluation and summation. AB - The compilation of existing data on contaminants in the marine food chain is essential in addressing concerns regarding the magnitude of potential human exposures and in the evaluation of subsistence food safety. This paper presents a summary of studies on trace metals in tissues of Alaska marine mammals from the 1970s to the present, along with derived mean tissue trace metal concentrations. The derived mean can serve as a norm against which future monitoring results may be compared, and may be used to estimate human exposure to trace metals through the consumption of marine mammals. Additionally, the variation among studies in the reported mean tissue concentrations has been described through a derived standard deviation. Sufficient analytical and methodological details were available to derive means and standard deviations for tissues in bearded seal, bowhead whale, beluga whale, fur seal, harbor seal, Pacific walrus, and ringed seal. A high concordance between trace metal values reported in tissues (i.e., liver, kidney, muscle) was observed despite significant differences in reported sampling and analytical methodologies. Consistent with other reviews of trace metal concentrations in marine species, the standard deviation of tissue metal concentrations was generally < or = 100% of the reported mean. Significant gaps in available information remain, particularly for muscle tissues and for methylmercury, despite the considerable efforts to monitor marine mammal species in Alaska. PMID- 10093346 TI - Levels of heavy metals in women residing in the Russian Arctic. AB - Within the framework of the joint Russian-Norwegian project on human health assessment of the Arctic Monitoring and Assessment Program, a study on heavy metals was conducted in 42 nonindigenous women who delivered in the hospitals of Norilsk and Salekhard during February-March 1995. Samples of venous blood, breast milk, umbilical cord blood, and placental tissue were collected. The concentration of lead, cadmium, and nickel in these tissues and fluids was estimated by flameless atomic absorption spectrophotometry (AAS). Total mercury concentration was measured by cold vapor AAS. The results obtained are determined, first, by the level of local food consumption, especially fish and reindeer meat; second, by smoking habits; and, third, by industrial pollution of ambient air, fresh water, and snow cover. A comparison of the results of this study with those of the Inuit Health Survey has shown that the difference between the Canadian and Russian data can be explained by factors of differing diet and differing levels of industrial pollution. Where a similar contaminant concentration in human tissues occurred, as in a smoking habit, no differences in the levels of a pollutant such as cadmium were revealed. PMID- 10093347 TI - Northern exposure: further analysis of the results of the Canadian aboriginal methylmercury program. AB - An initial overall analysis of the Canadian First Nations and Inuit data on methylmercury (MeHg) levels in 38,571 Canadian Aboriginal people has been completed. Patterns of exposure and their relationship to socio-cultural issues and traditional lifestyles are now being further analyzed, especially in the light of the continuing concern regarding the significance of exposure among northern and arctic populations. A mean of 29.8 micrograms/l mercury in blood or blood equivalent, with a range of 1-225.7 micrograms/l, was found among Inuit in the Northwest Territories (NWT). Significant differences in South-North exposure and West-East exposure in NWT are discussed, as are the relationships between exposure of northern residents and development activities further south, and problems of risk management in the context of traditional arctic lifestyles. It is suggested that many of the differences are due to the greater consumption of traditional food in the North. However, with the levels found and current state of knowledge, this should not be seen as a reason to change lifestyles--a change which carries its own negative consequences. PMID- 10093348 TI - Communication of risks: organization of a methylmercury campaign in the Cree communities of James Bay, Northern Quebec, Canada. AB - In the James Bay region of Canada, with the advent of extensive hydroelectric development, methylmercury contamination of fish has become a serious problem, having a direct impact on the Cree way of living. In 1982, the Cree Board of Health and Social Services of James Bay implemented a methylmercury exposure surveillance program in all Cree communities. Since that time, it has developed several educational tools on methylmercury contamination, including posters, pamphlets, and a video. In 1993 and 1994, Cree leaders, Community Health Representatives, medical staff, and other selected band members were consulted to identify the needs of the population regarding information on mercury. All questions and comments were listed, and a summary was sent to those consulted to double check the type of information required by the population. This led to the preparation of a brochure on mercury in a question and answer format, as well as creation of posters. The brochure and the posters were published in French, English and Cree and distributed in each community. A radio message was broadcast in all communities, and individual and group meetings were also held. Cree involvement in the mercury information program has been essential to its success. PMID- 10093349 TI - Risk perception related to depletion of the ozone layer and UV-B radiation in the arctic. AB - Increase in UV-B radiation, due to stratospheric ozone depletion, is an environmental threat to arctic ecosystems and the health of their inhabitants. The aims of this longitudinal study are to provide basic population risk perception data related to UV-B and ozone depletion, and to compare the UV-B risk perception over time and with risk perception related to other objects and occurrences. A survey questionnaire, calling for a total of 118 judgments, measures risk perception, worries, and anticipated consequences. In the 1996 study, 143 persons completed the questionnaire, 34 of whom belong to the indigenous Sami population. Risk perception and the possibility of protecting oneself against 13 risks were measured on 7-point scales. The mean risk rating for depletion of the ozone layer and UV-B radiation was moderate to high. The possibility of protection was rated relatively low. Women, the youngest, and respondents in the North were most worried and perceived the highest risks. The Sami respondents are less worried and perceive a lower risk, a realistic short term evaluation due to their protection by pigment in the skin and their clothing habits. PMID- 10093350 TI - Arctic snow crab-related lung disease. PMID- 10093352 TI - The use of ethnic identifiers in epidemiologic research. AB - This paper attempts to identify issues surrounding the use of ethnic identifiers in epidemiologic research, with specific reference to First Nations and Inuit populations. Current controversies are examined and the rationale for diverging views explored, based on currently available literature and interviews with stakeholders. Examples of identifiers presently in use and data based on these identifiers are presented. Using illustrations from currently available data, the paper explores the hypothesis that ethnicity is often a proxy measure for other variables, such as socioeconomic status or environmental factors, and as such may lead to an unfocused public health response which fails to recognize the true risk factors for disease. PMID- 10093351 TI - Determining the feasibility of the Canadian First Nations and Inuit regional (longitudinal) health surveys. AB - The general framework recommended for the First Nations Regional Health Surveys can be summarized as follows: 1. Currently committed funding from Health Canada and Human Resources Development Canada should be used to develop a framework of regional cohort studies for First Nations and Inuit people in the 10 provinces to generate information on community health and the well-being of children. Indian and Northern Affairs should consider participating on an equal basis in this initiative, as long as program dollars are not compromised, in order to assist First Nations and Inuit communities in the documentation of socioeconomic conditions associated with health and the well-being of children. Representatives of these departments should work together with Metis representatives to secure funding for a similar initiative for Metis people in the provinces. 2. National First Nations and Inuit organizations and the major funding departments should be invited to appoint members to First Nations and Inuit National Steering Committees. These Committees will be responsible for the general supervision of the development of the regional cohort studies for their respective communities. 3. Regional (usually provincial) First Nations and Inuit political organizations should be invited to submit letters of intent indicating their interest in developing the longitudinal survey on behalf of all communities in their respective regions. 4. Regional organizations should be asked to propose a research group with which they wish to collaborate in the development of the survey. Research groups should be approved by the national steering committees. 5. National steering committees should appoint a "core questions research group" that will be responsible for the development of comparative "core questions" for the longitudinal surveys. 6. A national Aboriginal technical committee should be established consisting of members of the "core question" research group and one member from all other research groups involved in the longitudinal surveys. 7. National steering committees should approve grants to each regional organization/research group to develop and implement the survey. 8. This initiative should be developed at a pace which is suitable to Aboriginal organizations and communities. It is likely that the first wave of the survey in 1996 will be restricted to several pilot projects in different parts of the country. Other regions and communities may not be ready to participate until 1998. PMID- 10093353 TI - Social and cultural factors as determinants of self-rated health in Greenland. AB - In 1993-94, a countrywide health interview survey was performed in 38 towns and villages throughout Greenland. Information was collected on self-rated health and self-reported disease, social and cultural factors, lifestyle, and living conditions. A total of 1,580 adult Greenlanders and 148 Danes was interviewed (57% of the sample). Respondents were classified according to ethnic self identification and job category, but these customary classifications were not satisfactory. An alternative classification according to exposure to traditional Greenlandic hunting culture and Danish culture during childhood was tested. The population fell into three subgroups, each with its own socioeconomic, ethnic, and occupational pattern, and with different health and health behavior. The new classification has distinct advantages as a supplement to the usual classification according to ethnicity and job category. The aim of the present paper is to present a comprehensive health interview survey from Greenland and to discuss some considerations regarding sociocultural classification of the population. PMID- 10093354 TI - The role of hunting in a socioeconomic classification for Greenland. AB - The socioeconomic classification used in Western societies is not directly applicable to Greenland where other factors, such as success as a hunter, participation in community life, and raising children, also convey status and must be included in a status coding. In the 1993 Greenland Health Interview Survey the participants' hunting activities were estimated through a number of questions. Nineteen percent of male Greenlanders classified themselves as hunters when asked about their primary occupation, but in another question an additional 10% stated that they relied on hunting for a living. When asked about their job, hunters were confused as to whether hunting was considered a job by the researchers. This uncertainty may explain the difference between the two questions regarding classification of individuals as hunters. For future research it is necessary to develop a socioeconomic status classification which is culturally sensitive and suited to contemporary Greenlandic society. PMID- 10093355 TI - A health profile of the Inuit of Nunavik: report of the Sante Quebec Health Survey (1992). AB - This general survey of health and well-being aimed primarily to provide a comprehensive insight into the health and social situation in Nunavik, with a view to setting up prevention and intervention programs more properly adapted to the needs of the Inuit of Nunavik. The data gathered through the use of questionnaires were combined with the anthropometric and biological readings of some 1,567 Inuit of all ages to generate the survey findings. In essence, the report demonstrated that, as the current Inuit lifestyle, save for the consumption of traditional foods, was setting the stage for the development of several types of illness previously absent from Nunavik, behavioral changes were warranted. Although the Inuit reported few problems of a physical nature, mental health issues appeared challenging. The prevalence of psychological distress, suicidal thoughts, and parasuicides was of sufficient import to justify direct, concerted, and immediate action. PMID- 10093356 TI - Post-Soviet Russian indigenous health: the Sami people of the Kola Peninsula. AB - As part of health care cooperation in the Barents Euroarctic Region, a group of indigenous physicians from Norway and Russia, together with the author, became acquainted with the health situation and present health service of the indigenous population of the Kola Peninsula in Russia--the Sami people. The Sami Development Centre SEG from Tana, Norway, is coordinating the project. Dr. Marina Dubovtseva visited Norwegian and Finnish Samiland in December 1995 and January 1996, and Dr. Ole Mathis Hetta and the author visited Lovozero in March 1996, looking through health care institutions as well as interviewing health care professionals and local people. PMID- 10093357 TI - Well-being among Greenlandic students. AB - PURPOSE: To describe and gain more knowledge of self-perceived health status and behavior among schoolchildren in Greenland, in order to provide a basis for future actions in health promotion. METHOD: Self-administered questionnaires were mailed to students through their schools. Students aged 11 to 17 years in public school were included. The survey covered most of Greenland, and approximately 4,700 students participated. RESULTS: The results focus on three age groups: 11-, 13- and 15-year-olds. The number of students in each age group were: 11 years: 542, 13 years: 548, and 15 years: 413. Perceived health: 56% of the 11-year-olds felt "very healthy", as did 36% of the 13-year-olds and 25% of the 15-year-olds, with no significant differences by gender. The child who feels healthy is more likely to be a happy child, is more likely to feel self-confident, and is less likely to feel lonely. Feeling healthy is also strongly associated with avoiding health risks like smoking, drinking alcohol, and using drugs. CONCLUSION: Feeling healthy was strongly associated with avoiding health risks. Therefore, it is important to encourage good health and build up young peoples' self-confidence. PMID- 10093358 TI - Youth risk behavior survey: the Alaskan perspective. AB - The Youth Risk Behavior Survey (YRBS) is a national school-based survey used to monitor health risk behaviors that contribute to the leading causes of mortality, morbidity, and social problems among youth and adults in the United States. Both high school and middle school surveys were administered to a representative group of Alaska high school and middle school students for the first time in 1995. Surveys were administered in a confidential and anonymous manner, taking care to assure student privacy. A total of 1,634 high school students and 1,265 middle school students completed surveys. The survey revealed that, for the most part, Alaska students are similar to U.S. students. Among high school students, 23.2% of boys and 15.4% of girls seldom or never used seat belts; 36.4% of boys and 36.5% of girls had smoked cigarettes in the previous 30 days; 23.5% of boys and 6.7% of girls had used smokeless tobacco in the previous 30 days; 48.7% of boys and 48.0% of girls reported having had sexual intercourse at least once; 23.7% of boys and 59.5% of girls were trying to lose weight; and 77.9% of boys and 65.6% of girls had exercised vigorously on three of the previous seven days. The middle school survey was somewhat different than the high school survey, so that results are not directly comparable. Nonetheless, the data indicate that high-risk behaviors, such as tobacco use, drug use, and early sexual intercourse, do occur at the middle school level. The survey also showed that Alaska teens have desirable health behaviors as well, such as frequent exercise and eating fruits and vegetables. The 1995 Alaska YRBS was the first time that representative data on Alaska students were collected on a statewide basis. The YRBS provides Alaska with baseline data that can be compared to national data. PMID- 10093359 TI - Developing and conducting a health risk behavior survey among school-aged students. AB - PURPOSE: To conduct a survey in the school setting which inquires about health risk behaviors among students in grades 7-12. METHOD: The survey was designed by the National Centers for Disease Control and Prevention (CDC), in conjunction with many federal and state agencies, to monitor behaviors in the following six areas: unintentional and intentional injuries, tobacco use, alcohol and drug use, sexual behaviors, dietary behaviors, and physical activity. Surveys are administered at the national and state levels and can be optionally administered by local school districts. The standard survey instrument allows for comparisons of national, state, and, where appropriate, local data. Computer software allows for the selection of a random sample and when a sufficient response rate is achieved, survey results can be generalized to the entire sampling frame. Standard software packages can be used for analysis of the data. RESULTS: The Youth Risk Behavior Survey developed by the CDC provides a useful and practical tool to monitor health risk behaviors in adolescent populations. This type of instrument may prove useful to public health professionals in other countries. PMID- 10093360 TI - A comparison of demographic characteristics of selected year 2000 health objectives for the United States, using behavioral risk factor surveillance system data for Alaska. AB - PURPOSE: The Behavioral Risk Factor Surveillance System (BRFSS) is a nationally developed and state-administered telephone survey which monitors the health behaviors and practices of adults aged 18 and older. One use of the survey is to monitor progress towards some of the Year 2000 Health Objectives for the United States. METHOD: Alaska has been conducting BRFSS monthly since January 1991, collecting approximately 128 interviews each month, for a yearly yield of approximately 1,530. Survey design allows for the aggregation of data over several years to accumulate sufficient sample size to look at health behaviors in subgroups of interest. We look at progress towards Year 2000 objectives for Alaska by various demographic characteristics: age, gender, education, employment, and geographic region. RESULTS: Survey data such as BRFSS can be used to monitor health behaviors and practices in a population in a cost-efficient and systematic manner. PMID- 10093361 TI - Alaska Native community assessment: health care services, knowledge of health issues, and health education. AB - This project gathered information from 32 Alaska Native communities in Bristol Bay, located in southwestern Alaska, regarding use of health care services and knowledge of health care issues. It also educated residents about health care and their role in improving health status, enabling participants to feel that their involvement in planning health care services is important. In conjunction with the University of Washington Community Development Program and the Alaska Center for Rural Health, a household survey was developed. A coordinator in each community was trained, and packets of surveys and health education materials were delivered to each household or post-office box. Completed surveys were returned, confidentially, to the village clinic. An English/Yup'ik cassette tape explaining the project was also available. Results were analyzed by the University of Washington. The findings were determined to be accurate with a 95% confidence level. Of surveys delivered to households, there was a 66% return rate and an overall return rate of 45%. PMID- 10093362 TI - Integrated primary care. AB - The delivery of medical and health-related services tends to be compartmentalized and fragmented. If the goal is health and if an important part in achieving that goal is increasing the ability of the person, family, and community to care for themselves while providing cost-effective care, then it is imperative to integrate efforts across community and primary care arenas. The Southcentral Foundation is an Alaska Native organization focused on the delivery of community and primary care activities that continues to work at the challenges of integration and coordination. This paper discusses some of the efforts to date and hopes for the future. PMID- 10093363 TI - Quality development in health care in Greenland: facing unlikely odds. AB - Health care in Greenland is historically founded on a fully tax-based system financed in large part by the Danish state. Administratively, the system was until 1992 under the Danish health authorities, with a concomitant lack of clarity concerning lines of communication in quality issues. Because of the enormous distance and communications problems, the individual districts were and continue to be run with a great deal of autonomy; and to this time the level of centralized data sources concerning qualitative aspects of the health care sector are extremely sparse. An attempt is being made to introduce a state-of-the-art centralized data collection and analysis function, with all that that entails in terms of system and personnel development. This system is described as a project, using an analysis of the official waiting-list database as a case study. The establishment and administration of the system is described. A cross-sectional analysis of the database is presented, illustrating issues of validity and reliability, as well as specifying the areas of system and personnel development necessary to make this system functional. The author's perception of the generalized implications of the lessons learned to date is presented. PMID- 10093364 TI - The potential for Ontario region's health information system to facilitate case management, program planning, and evaluation and to promote enhanced First Nations' control of health services. AB - The Ontario Region of Medical Services Branch, Health Canada, comprises approximately 63,000 First Nations people living on-reserve in four geographical areas: Sioux Lookout, Moose Factory, Thunder Bay, and Southern Ontario. As of April 1996, 35% of the 126 First Nations communities in Ontario Region have either assumed control of the delivery of health services or are in the process of transfer negotiations with the federal government. Another 14% have entered into Integrated Community-based Health Services Agreements with the federal government, which is an intermediate step that could culminate in a complete transfer agreement. In order to provide First Nations with an epidemiological database for effective program planning and evaluation, Medical Services Branch, Ontario Region, has worked in partnership with First Nations during the past two and one-half years to develop a comprehensive, computerized Health Information System (HIS). HIS will provide First Nations with a significant degree of autonomy from the Medical Services Branch structure, with regard to access to health information for case management, program planning and evaluation, and the establishment of their own program priorities at the community level. With access to the HIS, First Nations will eventually be able to re-profile available resource in response to their own identified community health priorities. PMID- 10093365 TI - Designing a home health care system for Alaska Natives in Anchorage. AB - PURPOSE: To design a health care program that allows Alaska Natives to receive culturally appropriate health services in their homes, thus avoiding the trauma of institutionalization and significantly increasing the quality of the patient's life during the course of the treated illness. METHOD: Utilizing the culturally appropriate sensitivity that is found within Tribal Health Corporations, Southcentral Foundation is designing a federally based community health care model to bring health support services into the patient's home. Health Aides and Community Health Representatives play an important role in extending this model into an urban community setting. The cost of care is significantly reduced, as it is more cost-effective to keep patients in their own home environments rather than in institutions. RESULTS: Major outcomes for patients are increased cultural sensitivity to their needs, personal comfort, dignity, and care in their own home surroundings. Outcomes for the federal care system are significant savings and more efficient personalized health care. PMID- 10093366 TI - The recruiting of staff for the health system in Greenland. AB - Challenges in health service delivery in circumpolar countries include rapid turnover of professional personnel, maintaining quality care, and development of appropriate structure of the health care system. Recruitment and retention of personnel dedicated to indigenous health care and work in small communities is an ongoing issue. Strategies such as decentralized education, student programs, financial incentives, cross-cultural training, consultant networks, and community initiatives have all been applied to varying degrees. As the problem is similar across circumpolar countries, this roundtable will be an opportunity to explore new incentives and approaches to recruitment and retention from several countries. PMID- 10093367 TI - Telemedicine: have technological advances improved health care to remote Antarctic populations? AB - Telemedicine has been used in remote areas for decades. In recent years the information superhighway has been a catalyst for the rapid growth of telemedicine; development of new technologies; and proliferation of subspecialties, journals and abstracts, and centers for telemedicine law. It has further promoted conferences of clinicians and managers planning telemedicine to advance remote health care, as well as the generation of revenue from business opportunities. This "rediscovered" telemedicine is seen by many as the answer to the unavailability of professional health care in geographically isolated areas. Failures of some well established networks and the high costs of establishing and running others have stimulated calls for thorough evaluations to be made, especially of the use of appropriate technology rather than the latest and most sophisticated. I review here 50 years of telemedicine in Antarctica and make an assessment of its role in the improvement of health care services. PMID- 10093368 TI - Telemedicine in Greenland: the case for and against implementation. AB - Greenland has a population of approximately 55,000 spread over an enormous stretch of coast. Conditions for patient transport are often hostile due to weather and the availability of materials. The health clinics on the coast are wholly dependent on the ability to transport in cases of serious illness or injury, as no manpower or facilities for intensive treatment or care exist outside of populated centers. A large proportion of the population lives far away from the centers, and due to their closeness to nature, these people have a high incidence of injuries. For these reasons, installation of the highest possible level of technological knowledge transfer seems highly appropriate. However, technology proficiency on the part of health personnel in the outlying areas is low; indeed, the level of reading skills is not satisfactory in all cases. There is furthermore a significant language barrier. The case for telemedicine in this setting is clear in technical terms, but murky at best in the manpower sense. The final argument will be financial means, which must be found by savings in other settings, e.g., evacuations and treatment in distant settings. A current effort to increase the information base to support decision making in this sphere is presented. PMID- 10093369 TI - Preliminary experience with an orthopedic teleradiology service at the Alaska Native Medical Center. AB - The orthopedic service at the Alaska Native Medical Center (ANMC) in Anchorage provides comprehensive orthopedic care to 103,000 Native or "First Nation" peoples in the state of Alaska. From its base at ANMC, a 140-bed general hospital, the service provides outpatient services, inpatient services including surgery, and telephone consultation services to 10 regional medical centers, 15 subregional clinics, and 20 village health centers distributed over a wide geographical area. These outlying centers are staffed by 108 full- and part-time primary care physicians, 74 primary care advanced practice nurses or physicians assistants, and 456 Community Health Aides. In providing telephone consultation service, the current version of "radio clinic," a frequent challenge arises in interpretation of verbal descriptions of x-ray findings. Our primary care clinicians, while highly trained, cannot be expected to interpret x-rays at the same level as a specialist. Discrepancies occur in communicating radiographic detail. This can result in either delayed or unnecessary transfer of patients, inappropriate travel to regional medical centers or home villages, or simply suboptimal medical care. Fortunately, computer technology has evolved to a point at which quality x-ray images can be transmitted relatively inexpensively. This paper will describe our preliminary experience with such a system. PMID- 10093370 TI - Enhancing diagnostic ultrasound programs utilizing wide-area image management technology. AB - Diagnostic ultrasound in remote sites is limited by attendant delay in interpretation and reporting. Technology advances were incorporated in an ultrasound program based in Churchill, Manitoba, and designed to meet the needs of the Central Canadian Arctic. Still-frame ultrasound images are digitized via a sonographer's picture archiving and communications system (PACS) workstation, and as they are collected they are transmitted over a dial-up Internet protocol network in Dicom 3.0 format to a tertiary care center. Received images are routed to a physician's PACS workstation, where they can be reviewed prior to the patient leaving the remote clinic. The impact of existing technology on a northern ultrasound program is discussed. The implications of technology enhancement are reviewed, with specific reference to remote low bandwidth sites. PMID- 10093371 TI - Instrumentation available for remote diagnosis and consultation in eye care. AB - It is feasible to transmit digital images captured via a biomicroscope using currently available instrumentation, hardware, software, and communication technology. To demonstrate this point, commercially available digital imaging equipment was obtained and installed in the eye clinic at the Kanakanak Hospital. Interactive agreements were established with sites having compatible equipment. High-quality digital images were transmitted between the involved sites in Alaska, Arizona, and California. Images of sufficient quality and resolution for remote consultation and diagnosis were transmitted both to and from the clinic site in Dillingham. This demonstrates that the instrumentation currently exists for rapid sharing of digital images coupled with direct, real-time communication. PMID- 10093372 TI - Delivery of physiotherapy services to some First Nations communities in Manitoba. AB - PURPOSE: This program was instituted to extend physiotherapy services to communities without road access to traditional rehabilitation services. METHODS: Physiotherapy consulting services are provided on a monthly basis to communities involved in the program. Service is based in the communities' nursing stations and includes four components: direct care to clients, preventive care, professional resources, and education. RESULTS: Physiotherapy services can be effectively provided in isolated settings by an outreach program using experienced therapists based in a central location. PMID- 10093373 TI - The role of cost analysis in deciding whether to provide laparoscopic cholecystectomy in remote communities. AB - To review the role of cost analysis in deciding whether to provide laparoscopic cholecystectomy in a remote community, cholecystectomies for Baffin Region residents were reviewed. Actual cost was calculated using known travel costs, per diem costs, and length of stay (LOS) data. Laparoscopic cost was estimated using LOS and conversion data from the literature. Between 1992 and 1995, 72 patients from the Baffin Region had a cholecystectomy, 61 in Iqaluit and 11 in Montreal. Fifty-seven and five, respectively, were suitable candidates for laparoscopic surgery. LOS was 5.6 days in Iqaluit and 3.5 in Montreal. Annual cost was $167,465 (Canadian). Comparable laparoscopic cholecystectomy cost is $45,411, an annual saving of $122,054. Even after equipment depreciation, laparoscopy provides a calculated saving of over $100,000 a year. However, even maximal decrease in bed utilization is less than 0.5 bed per day. Such small decreases do not allow staffing reduction and, thus, most of the projected savings cannot be realized in practice. Therefore, neither costs nor savings can play a supportive role in a decision to provide laparoscopic cholecystectomy in remote communities. This decision would have to be based on other considerations. PMID- 10093374 TI - The Wenger Eskimo Anthropological Database: a valuable research tool. AB - The goal of the Wenger Eskimo Database Project is to develop a full-text database of early and primary written ethnographic sources in English on Inuit/Eskimo peoples and to make it available on CD-ROM, both to northern residents and to students and researchers dealing with northern topics. This paper describes the database, sets out a brief history of its growth, and describes recent developments, including the addition of new materials and a Windows format. The paper includes a demonstration of how the database may be used for health-related research. The database is available free of charge to nonprofit institutions that are willing to meet some simple, basic requirements. PMID- 10093375 TI - Up-to-date studies of the Siberian population: international programs of the Institute of Internal Medicine. AB - The worsening of the health status of northern populations is a matter of concern to scientists in many countries. International collaboration aimed at using international experience in the field of circumpolar health may speed up the research, making it more effective for solving problems of medical science and public health in the North. PMID- 10093376 TI - Russian Academy of Medical Sciences (RAMS), Siberian Branch, activity in solving the medical problems of Russian Circumpolar regions. AB - RAMS, Siberian Branch, has been actively participating for the last 25 years in elaboration and realization of numerous scientifically applied programs aimed at improving diagnosis, treatment, and prophylaxis of the most widespread diseases among the Native and newcoming populations of the Russian Far North (Taimyr, Yakutia, and Chukotka). The medical researchers of different RAMS, Siberian Branch, institutes, based on long-term investigations, have obtained a number of largely new data on etiology, pathogenesis, and epidemiology of cardiovascular, infectious, and cancer disease; diabetes; alcohol addiction; trauma; etc., and have developed practical recommendations for public health institutions on improvement of people's health. PMID- 10093377 TI - Self-determination: the panacea for Canadian aboriginal people with disabilities? AB - Equal access and participation issues are at the forefront of the current disability advocacy movement. Disabled people worldwide are demanding a change in attitudes and policies reflecting their inherent right as citizens to full participation in society. The inequalities faced by the Canadian Aboriginal community with disabilities are magnified by unique socioeconomic, political, environmental, and cultural barriers. The current rate of disability in the Canadian Aboriginal population (31%) is double the national rate. The existing system available to Aboriginal people with special needs has often resulted in an unaccountable and ineffective web of service delivery. This paper documents various aspects of the existing structure of service delivery and the potential barriers to independent living for adults with disabilities living in remote First Nations communities in Northern Manitoba, Canada. Possible advantages and drawbacks to service provision in health transfer from the federal government to First Nation control are explored. PMID- 10093378 TI - Genetic polymorphism of CYP1A1 and CYP2D6 in the Tundra Nentsi population of Siberia. AB - The purpose of this study was to establish the frequencies of CYP1A1 and CYP2D6 polymorphic genotypes in the Tundra Nentsi population, which is a small indigenous northern people living in Siberia and belonging to the Northern Mongoloid race. The frequencies of Ile/Ile, Ile/Val, and Val/Val genotypes in the Tundra Nentsi population, as determined by means of the allele-specific PCR, were 50.8%, 39.2%, and 10%, respectively. Thus, the Val allele frequency in Tundra Nentsi appeared to be as high (29.5%) as in the Japanese population (25%) reported elsewhere. Those frequencies in the reference group of Siberian Caucasians were in good agreement with the data reported elsewhere for other Caucasians, although the Val allele frequency observed in Siberia inhabitants (5.7%) was somewhat higher than those frequencies obtained for other Caucasian populations. By means of PCR followed by specific-site digestion with MvaI endonuclease, we analysed the frequencies of CYP2D6B allele in the Tundra Nentsi population. The frequencies of 2D6wt/2D6wt and 2D6wt/B in the group of 120 Nentsi were 84.2% and 15.8%, respectively, with no subject possessing the 2D6B/2D6B genotype. The group of Siberian Caucasians represented those frequencies as 67.7%, 27.1%, and 5.2%, respectively. In total, the frequency of CYP2D6B allele in the Tundra Nentsi population was half that in Caucasians (8.3% vs. 19%). Taken together, our data indicate that the frequencies of CYP2D6B and Val allele of CYP1A1 in Tundra Nentsi population are different from those obtained for Caucasians. We also found similarities in the CYP1A1 mutation frequencies in the Tundra Nentsi and Japanese populations. PMID- 10093379 TI - Standard versus modified bio-electrical impedance analysis on reactance measurements. AB - The purpose of this investigation was to compare score consistency of the observed reactance measurements for total body composition bio-electrical impedance analysis (BIA), using standard and modified electrode placement procedures. Subjects were 80 military males (19-56 years) who volunteered from Elmendorf Air Force Base, Anchorage, Alaska. The RJL Systems Spectrum Lightweight Instrument was used. RJL's rules were followed for standard procedure, and the proximal electrode sites were changed for the modified procedure. The hand and foot proximal electrodes were placed in the center of the antecubital space and popliteal fossa, respectively. The study used a four-faceted crossed, random effects design. The object of measurement was person, and facets of generalization were day, occasion, and trial. Data were analyzed independently for each electrode placement procedure. The analysis revealed: 1) person contributed the largest source of systematic variance, as expected, and 2) person x day interaction accounted for the significant percentage of unwanted measurement error for both electrode placement procedures. The relative and absolute coefficients of the G-studies (80 persons x 2 days x 2 occasions x 3 trials) were 0.86 for standard and 0.83 for modified. The D-studies (111, 211, 311, and 511) revealed relative and absolute coefficients which ranged from 0.75 to 0.94 for standard, 0.67 to 0.91 for relative, and 0.67 to 0.90 absolute for modified. The G-coefficients (G study and D studies) for reactance measurements showed the standard electrode placement procedure produced more consistent scores than the modified proximal electrode placement procedure. In conclusion, generalizability analysis on reactance scores demonstrated the standard electrode placement procedure still to be superior over the modified electrode placement procedure. PMID- 10093380 TI - Heat balance at -5 degrees C after cold water immersion. AB - Two different possible behaviors at -5 degrees C after cold water immersion were studied. A test subject wearing winter clothing walked (5 km/h) on a treadmill for 45 minutes at -5 degrees C and at a wind velocity of 3 m/s with dry clothing, immediately after a thorough immersion in 5 degrees C water, or after immersion and wringing, freezing, and beating of the clothing (to remove ice). A marked heat debt (ca. 1000 kJ) was measured at the end of the cold water immersion. Attempts to dry the clothing caused an additional heat debt of ca. 300 kJ. After 45 minutes walking, the difference in heat depth between the treatments was nearly the same as before the exercise. The difference in clothing weight was only 0.9 kg between the two treatments after walking. Beating frozen clothing items could remove ice corresponding to only 0.7% of the wet weight of the clothing. Results suggest that after cold water immersion in winter, the undressing procedure could not be recommended. Instead, after initially removing boots, mittens, and hat, the subject should start walking. The water accumulated in boots and mittens should be poured out when necessary. PMID- 10093381 TI - The hydration status of backpackers at high altitude. AB - The purpose of the descriptive study was to determine the hydration status of recreational backpackers (n = 201) hiking at altitudes between 7,500 and 14,000 feet. Urine specific gravity was used to document the level of hydration of each subject entering or leaving the Bridger-Teton Wilderness. Demographic, risk, and knowledge factors were also obtained from the sample. Both pre-hike and post-hike subjects were dehydrated; pre-hike mean specific gravity was 1.018, and the post hike mean was 1.023, showing a significant difference (t = -4.671, p < 0.0000). A small subset group (n = 10) entered both pre- and post-hike data and the findings were similar to the large group, showing a significant increase in specific gravity post-hike (t = -4.881, p < 0.0009). Interestingly, 24% (n = 130) of the post-hike males presented with hematuria. PMID- 10093382 TI - Trans-Antarctic expedition: the second 100 days. AB - On July 27, 1989, six men and 39 sled dogs embarked on the first trans-Antarctic dog, sled, and ski crossing. Data sheets were developed and a review of their day by-day reports was carried out. The period of time covered is November 3, 1989, to February 10, 1990. Miles traveled were recorded for each day and varied from no progress to 31 miles for a single day. A running account of the total miles traveled was also maintained in relationship to the number of days traveled. Radio contact was maintained when conditions permitted. They were able to make calls home and as far away as Paris, France. The time traveled was summarized where recorded and weather conditions particularly were reviewed and maintained. Land conditions, visibility, and cloud formations were discussed. The average temperature varied from -8 degrees C to -48 degrees C (-54 degrees F). Wind conditions and land locations were recorded, as were difficulties encountered on each day. High-calorie foods were eaten. One dog ate as many as 12,000 calories per day. Following a review of appropriate topics, a summary of the conditions is given. PMID- 10093383 TI - [30 years experience in articular fractures of the calcaneus bone]. AB - Results of 150 (123 in males, 27 in females) articular fractures of the calcaneus treated by various methods over period of 30 years have been evaluated. Mean age of the patients was 43 years. Minimum follow-up was 18 months. An analysis of the material indicates the need for reduction in every case. Westhues method is suitable for tongue type fracture, joint depression type should be managed by Palmer's method. Best results have been achieved after K-wire fixation of the reduced fracture and early mobilization. In fractures with no displacement or with a minor one functional treatment led to good results also. Unreduced fractures gave poor results; pain below lateral ankle was produced by compression of peroneal tendons with deformed calcaneus. Seventy per cent of the results were rated good, 15% fair and 15% poor. PMID- 10093384 TI - [Massive allogenic bone grafts in reconstructive surgery after local resection of malignant bone tumor]. AB - A series of 11 patients (5 females, 6 males) aged 11 to 43 years (mean 19.5 years) with primary malignant bone tumor is presented. MRI and CT served to determine the exact tumor invasion within soft tissues and medullar cavity. Prior to the surgery IIB stage (Enneking) was established in all cases. Chemotherapy was used in 7 cases, radiotherapy in 1. Local excision of the tumor was followed by implantation of massive frozen bone graft. Fixation was achieved with intramedullary nails, screws, AO plates or Martin external fixator. Follow-up ranged from 2 years 4 months to 5 years 2 months (mean 3 years 6 months). Adjuvant pre- and post-operative chemotherapy allowed for limb salvage and excision procedure with massive allograft to fill the defect. One patient died due to dissemination of the neoplastic disease, remaining 10 are alive with no symptoms of metastases. Stable osteosynthesis allows for early axial weight bearing and fast rehabilitation of the limb. PMID- 10093385 TI - [Hip joint deformity caused by osteochondrosis in the course of treatment of congenital dysplasia of the hip]. AB - A series of 73 patients with avascular necrosis complicating surgical or nonsurgical treatment for congenital hip dysplasia is presented. The femoral head, neck and subcapital growth plate has been damaged in all cases. A-P radiographs of proximal femur revealed three types of growth disturbances: lateral, medial and total one. Localization of growth plate damage determined the type of growth disturbances. Mutual features for all types were: shortening of the femoral neck and growth disproportion between femoral head and greater trochanter. In 43 hips the greater trochanter grew over the femoral head and constituted the most proximal part of the femur (trochanter altus). Growth disturbances of the acetabulum coexisted (primary and secondary acetabular dysplasia). Radiological parameters of deformed hips have been compared with normal values. PMID- 10093387 TI - [The assessment of changes of the plate growth in Blount disease by MRI]. AB - The changes within growth plates around the knee in Blount disease have been analyzed with MRI in 4 patients with late onset tibia vara. Extensive changes were found in both tibial and femoral growth plate. General widening of the plate, invagination into metaphysis and high intensity irregularities of the shape were observed. Lateral aspect of both physes was involved to higher degree. Our study supports mechanical etiology of the late onset tibia vara. In our opinion long lasting distraction stress on the lateral aspect of the knee due to the varus deformity might be responsible for the changes observed in MRI. PMID- 10093386 TI - [Radiography assessment of the hip joint after the implantation of cementless ceramic cup and metal cup]. AB - Radiographic assessment of the hip joint and clinical results after implantation of cementless Mittelmeier ceramic cup and metal Parchofer-Munch cup are presented. Material included 151 hips (56 ceramic cups and 95 metal cups). A-P radiograph and Engh criteria served for radiological assessment of the cup. Vertical, horizontal and angular migration as well as radiolucency in three De Lee zones were evaluated on postoperative and follow-up radiographs. Vertical migration and increased radiolucency within III De Lee zone were the most frequent findings. All types of migration and increased radiolucency in De Lee zones were observed more often after ceramic cup implantation. PMID- 10093388 TI - [The method of computer-assisted orthopedic surgery based on two-dimensional fluoroscopy: the principles of action]. AB - Surgical instruments play a major role in orthopedic surgery; usually they are controlled visually at the operation. In certain situations additional device to control instrument is needed. The aim of this paper is to present theoretical foundations, create prototype and give initial assessment of computer assisted orthopedic surgery system. Two-dimensional fluoroscopy was the base for system functioning. Lab tests and first applications in the operating room are presented. Precision of the system found allows for its use in orthopedic surgery with television monitoring. PMID- 10093389 TI - [Rotatory instability of the ankle: an experimental investigation of tibio fibular syndesmosis function]. AB - The influence of sectioning of different parts of tibiofibular syndesmosis on stability of the ankle in 10 anatomical preparations is presented. Sectioning of the anterior tibiofibular ligament increased rotational potential of the talus from 0.3 degree to 2.8 degrees. Sectioning of the tibiofibular syndesmosis allowed for further increase of rotation from 1.8 degrees to 4.9 degrees. PMID- 10093390 TI - [The results of treatment of posterior shoulder dislocation]. AB - The paper reports results of treatment for 5 posterior dislocations of the shoulder in 4 patients. Closed reduction was successful in 2 cases (2 days and 14 days after injury). Spontaneous reduction after removal of the Desault plaster cast 3 weeks after injury was observed in one case. Two patients with inveterate dislocation have been operated on. The defect within humeral head was filled with an allogenic bone graft in one patient and by lesser tuberosity transposition in another. Modified Constant score was used for clinical evaluation at the follow up ranging from 5.5 months to 56 months (mean 30.4 months). Two excellent and one good result were achieved in conservatively treated cases. After surgery one result was rated poor (allograft case) and one good (lesser tuberosity transposition). PMID- 10093391 TI - [The influence of antibiotic content in CMWI bone cement on its bacteriostatic and mechanical properties]. AB - The influence of antibiotic content in CMW1 bone cement on its bacteriostatic and mechanical properties has been investigated. It was found that antibiotics (beta lactams, II and III generation cefalosporins) preserved their bacteriostatic properties within bone cement. No significant impact of antibiotic content within CMW1 on its mechanical properties has been demonstrated. PMID- 10093392 TI - [Long-term results of surgical treatment of lumbar discopathy in children and adolescents]. AB - Long-term results of surgical treatment of lumbar discopathy in 29 patients with 5 years follow-up (14 girls, 15 boys) operated at the age of 13-18 years in Neurosurgery Department, Medical University in Bialystok between 1970 and 1993. Ten years follow-up was available in 26 patients (14 girls, 12 boys) operated between 1970 and 1988. Over period of 10 years 64.3% girls and 16.7% boys preserved recommended diet, 92.8% and 8.3% boys continued muscle strengthening exercises. Cigarette smoking abandoned 100% girls and none of the boys. Ten years after surgical treatment for lumbar discopathy excellent results were found in 85.7% females and 50% males. PMID- 10093393 TI - [Surgical treatment of congenital cleft foot]. AB - Results of surgical treatment for congenital cleft foot in 3 patients (5 foot) are reported. Two foot were classified type IIIA, 1--IIIB and 2--IVB according to Blauth and Borisch. Mean age of the patients at the surgery was 97 months, mean follow-up was 39 months. Wedge resection of the metatarsals with screw fixation was followed by performing skin syndactyly in all patients. No complications occurred, all patients wear commercial shoes and are satisfied with the result of surgery. PMID- 10093394 TI - [The three-staged evolution of the post-traumatic algodystrophy]. AB - Algodystrophy is considered to develop in three consecutive stages: acute, dystrophic and atrophic. However, there is little evidence documenting this staging in large series of patients. In order to verify the natural history of this condition 30 patients with post-traumatic algodystrophy were observed during one year in prospective controlled fashion. Twenty-three females and 7 males of mean age 60 years were included in the study. All patients, except one, were in stage I of the disease with mean duration of 2,7 months. Fracture of the distal radius was the most frequent predisposing factor. The patients were reassessed at 6 and 13 month after initial diagnosis. A group of 64 patients with algodystrophy subjected to the treatment was also reviewed in search for three-stage evolution of the condition. Of 30 non-treated patients 27 completed the study. Three patients were subjected to the treatment due to persistence or worsening of symptoms. In 26 patients (87%) most of symptoms withdrew at 13 months. In 1 patient some features at final assessment were suggestive of stage II of the disease. Of the 64 treated patients, 2 had developed stage II and in 4 condition persisted at the same stage 12 months. The study suggests that progressive, three staged course of algodystrophy occurs less frequently than it was earlier suspected. In most cases the condition resolves spontaneously. PMID- 10093395 TI - [Results of treatment of unilateral sacralization of transverse process of the fifth lumbar vertebrae]. AB - Pathology and symptomatology of unilateral sacralization of transverse process of the fifth lumbar vertebrae articulating with sacral and iliac bone is presented. Five patients (4 females, 1 male) aged 27-42 are reported. Symptoms included spinal pain, radicular pain, L4/L5 disc prolapse, and lumbar scoliosis. Patients were operated on: resection of the transverse process has been done in all cases, discectomy in 2 cases. Good results were found at the mean follow-up of 3 years. Author's experience supports idea of early surgical intervention in described condition. PMID- 10093396 TI - [One-stage treatment of chronic osteomyelitis with pedicled osteocutaneous flap: a case report]. AB - One-stage treatment for chronic osteomyelitis and soft tissue defect with pedicled fibular osteomuscle flap is reported. The treatment has been applied in 42 years old male with unstable angina pectoris and many years history of left tibia osteomyelitis. Primary wound closure, good bone healing after 8 months and remodeling of the tibia after 1 year has been achieved. Follow-up at 20 months did not reveal recurrence of osteomyelitis. Pedicled and free vascularized grafts use in treatment for chronic osteomyelitis has been discussed. PMID- 10093397 TI - [A rare case of tuberculosis of the spine]. AB - A case of rare form of tuberculosis of the spine localized within arches and articular processes complicated by neurological deficits is presented. Diagnostic difficulties, surgical treatment and postoperative management resulting in complete resolution of the disease is described. PMID- 10093398 TI - [Obituary on Professor Adrzej Tokarowski, MD, PhD (1934-1998)]. PMID- 10093399 TI - [Obituary on Professor Donat Tylman, MD, PhD (1930-1998)]. PMID- 10093400 TI - [The bone and joint decade 2000-2010]. PMID- 10093401 TI - [Results of Bankart arthroplasty procedure in the treatment of recurrent dislocation of the shoulder]. AB - The Bankart procedure is considered to be the common treatment for anterior instability of the shoulder but despite its popularity there have been no studies on the long-term outcome of this method. Results in 16 patients (14 males, 2 females, aged 19-35) treated with Bankart procedure are presented. Assessment of the results was based on postoperative clinical examination and a questionnaire (filled by a patient) inclusive of history of instability, level of pain, ability of the patient to function at home, at work and during sports. No instability has been found after the operation. Mean restriction of external rotation was 15 degrees, no other movement restriction occurred. Good clinical results were achieved in all cases, majority of patients admit high level of satisfaction. PMID- 10093402 TI - [Transplantation of the greater omentum and complication]. AB - A series of 13 patients (12 males, 1 female, aged 5-57) operated between 1990 and 1997 is presented. In 12 cases the greater omentum was used to cover tissue defect within upper extremity, in 1 case--lower extremity. Complications at donor site and within extremity were assessed in two groups (group I--5 cases of free omentum graft, group II--8 cases of pedicled omentum graft). Two acceptor site complications (flap necrosis and osteomyelitis) and no donor site complications were observed in group I. In group II 2 similar donor site complications occurred but 5 patients from this group complained of strong abdominal pain due to excessively short pedicle of the graft and 1 case of abdominal hernia occurred. The complications have been analyzed, means for prevention discussed. PMID- 10093403 TI - [Radiological assessment of the hip after Mittelmeier and Parhofer- Monch stem implantation]. AB - Radiological assessment and results after cementless stems implantation at Mittelmeier (Autophor 900 and 900S) and Parhofer-Monch total hip replacement are presented. Engh criteria were used to assess implantation of the stem on a-p radiograph. Vertical migration, presence of ossifications around the tip of the stem within medullar cavity and radiolucency in 7 Gruen zones were evaluated. The investigation revealed that vertical migration, presence of ossifications around the tip of the stem within medullar cavity and radiolucency around the stem were more frequent after implantation of stems with no microporous surface and Autophor 900 type stems. Radiolucency appeared mainly within IV and VII Gruen zone. PMID- 10093404 TI - [The application of autologous and fresh frozen allogenous bone grafts in uncemented total hip replacement using Parhofer-Monch endoprosthesis]. AB - An attempt to classify the use of autogenous and fresh frozen allogenous bone grafts in uncemented primary and revision total hip replacement using Parhofer Monch endoprosthesis is presented. Bone graft type and acceptor site have been analyzed in 102 patients (89 females, 13 males, mean age 51.1 years, range 20-74 years). Idiopathic and dysplastic hip oateoarthrosis constituted majority of diagnoses in this series. In only 4 primary replacements and in all 6 revision replacements frozen allogenous bone grafts were used. The study revealed, that autogenous bone grafts are used most frequently. The roof and bottom of the acetabulum is usual acceptor site. Dysplastic hip osteoarthrosis cases are most demanding in this regard. Revision arthroplasties require great amount of fresh frozen allogenic bone grafts. PMID- 10093405 TI - [Clinical significance of arthroscopic synovial biopsy in the diagnosis of knee synovitis]. AB - Eighty-two patients (49 females and 33 males, mean age 38.2 years) underwent arthroscopic synovial biopsy in the course of treatment for chronic knee synovitis. After histopatological analysis of the samples Fritz et al. criteria were used for their classification. In 16 cases of specific synovitis clinical diagnosis was always confirmed by histopathology. In 66 patients with nonspecific synovitis lymphoplasmatic and serofibrous type prevailed. In 8 cases with dominant non-specific synovitis histological features of specific synovitis have been also found and correct clinical diagnosis has been established. Arthroscopic synovial biopsy increases diagnostic potential in the synovitis of unclear etiology. PMID- 10093406 TI - [The ultrasonographic assessment of the knee extensors in patients with anterior knee pain syndrome]. AB - Sonographic assessment of the extensors of the knee in patients with anterior knee pain syndrome and in control group is presented. Both groups were similar in respect of age and sex. The assessment was done according to Heckmatt. Resting transverse sizes of rectus, intermedius, vastus lateralis and vastus medialis were related to their sizes during isotonic contracture under load. Statistical analysis has been done with Mann-Whitney test. Statistically significant weakening of rectus femoris, intermedius (p < 0.00001) and vastus medialis (p < 0.01) have been found in anterior knee patients. These might explain patellar malalignement in this group. PMID- 10093407 TI - [The methods of treatment for comminuted intra-articular fractures of the tibia in the materials of Department of Orthopedic Injuries at the Military Special Hospital in Lublin]. AB - Twenty-one patients (9 males, 12 females) aged 14-73 years (mean 46 years) with proximal tibia fracture were treated between 1993 and 1995. Surgery was performed in 12 recent cases and in 3 inveterate ones. Non-surgical treatment was used in 5 recent fractures and 1 inveterate. Follow-up ranged from 0.5 to 6 years. "L" plate, "T" plate, spongious screws, Kirchner wires were used for fixation. Lateral condyle depression used to be elevated and supported by bone graft harvested from the iliac crest. Functional treatment or 4 weeks plaster cast immobilization was used postoperatively. In majority of cases pain free knee joint with flexion over 90 degrees was found 3 months after surgery. All patients returned to work. There were 7 excellent results and 5 good ones according to Rasmussen criteria. PMID- 10093408 TI - [The influence of operative methods on biomechanics of tibio-fibular syndesmosis]. AB - Ten cadaver anatomical preparations of the ankle served to assess selected parameters of movement within this joint. Measurements were done in uninjured joint and after transfixation with tension wiring band, staples and screws. Wiring band provided better biomechanical results than screws or staples. PMID- 10093409 TI - [Algorithm in low back pain management in adults]. AB - Currently recommended management for low back pain in adults is presented. The algorithm consists of two phases. In a patient presenting acute low back pain with no previous history thorough clinical evaluation (phase I) should aim at exclusion of cauda equina syndrome, fracture, neoplasm, infection, progressive neurological deficit, or chronic pain syndrome. If none of these condition is responsible for low back pain 4-6 weeks therapy depending on the severity of symptoms should be commenced. Then clinical reevaluation is indicated and if pain persists patient should be referred to a specialist (phase II). Previous diagnosis and treatment should be reviewed critically; if found appropriate the treatment might be repeated during phase II. Primary sources of low back pain as herniated nucleus pulposus, unremitting low back pain (segmental instability), spondylolysis, isthmic spondylolisthesis degenerative spondylolisthesis with spinal stenosis should be identified and appropriate treatment (surgical or conservative) undertaken. Patient education is an important component of phase II. In general, phase II of the algorithm aims at returning the patient to full psychophysical activity and at prevention of low back pain recurrence. PMID- 10093410 TI - [Results of surgical treatment for the intervertebral disc protrusion within thoracic spine]. AB - Results of surgical treatment for intervertebral disc protrusion within thoracic spine in 4 cases are presented. Protrusion had caused spinal compression resulting in neurological impairment (plegia). There were 3 females and 1 male, all in their forties or fifties. Two cases are presented in details, with radiological investigations included. Lateral approach was used at surgery. Neurological deficits subsided completely in all cases. Follow-up ranged from 1 15 years, mean 8 years. PMID- 10093411 TI - [Complex tissue reconstruction of the arm with free vascularized fibular graft with skin island]. AB - Results of treatment for postraumatic bone and soft tissue defects within the arm in 3 patients (1 female, 2 males aged 20-30 years (mean 25 years), are presented. In both male patients osteomyelitis and irreversible radial nerve lesion was present. Stage 1 included radical excision of inflamed tissues. When the inflammation ceased reconstructive treatment has been initiated. Tendon transposition has been performed to restore writ and fingers extension. After several months free vascularized fibular graft (11-17 cm in length) was used to reconstruct bone and soft tissues of the arm. Zespol fixator has been used in two cases. Marginal skin island necrosis has been noted twice. Screw tract infection or lack of bony union in proximal end of the graft required re-operation. Bony union has been observed already in the 3rd month postoperatively but final incorporation and hypertrophy of the graft occurred after 6-26 months, (mean 14 months). In all cases final results were rated as excellent. PMID- 10093412 TI - [Isolated traumatic rupture of the subscapular tendon]. AB - Clinical appearance of isolated traumatic rupture of the subscapularis tendon confirmed with sonography, double contrast CT and intraoperatively in two patients has been presented. The mechanism of the injury--forceful external rotation and hyperextension of the arm, increased passive external rotation and positive "lifft of test" may lead to the correct diagnosis. PMID- 10093413 TI - [An attempt to treat loosening of the total hip endoprosthesis in Paget disease with Aredia]. AB - A case history of Paget's disease around the hip is presented from 1977 (intraoperative diagnosis) to 1998. Primary Weller THR as well as revision PM replacement in 1990 failed due to loosening. The use of bisodium pamidronian (Aredia, Ciba-Geigy) allowed for loosening arrest (remission of pain, preservation of extremity length, no further radiological changes) for 4 years. Aredia was well tolerated, side effects were transient and did not required therapy. PMID- 10093414 TI - [Giant cell tumor of the patella]. AB - A case of 26 years old patient with primary giant cell tumor of the patella treated with patellectomy and patellar ligament plasty with vascular prosthesis is presented. After 12 months follow-up no metastases or local recurrence is noted. The function of the extremity is sufficient for activities of daily living. PMID- 10093415 TI - [Congenital posterior and posteromedial bowing of the tibia and fibula]. AB - Five children with congenital posteromedial bowing of the tibia and fibula and 1 child with posterior bowing of the tibia and fibula have been followed-up. At the final examination age of the patients ranged from 6 months of 16 years (mean 69 months). In most of the cases the angulation had a tendency to decrease, shortening of the tibia remained constant. Pseudoarthrosis appeared in one of the children in 4th month of life at distal tibial diaphysis/metaphysis junction but healed spontaneously in 13 months time. PMID- 10093416 TI - Photodynamic stimulation causes sustained increase in intracellular calcium concentration in cells of small cell lung carcinoma. AB - Photodynamic agents, due to their selective uptake by tumor cells and photon dependent selective activation, have immense implications for cancer treatment. The present study provided direct evidence that the photon activation of chloro aluminum phthalocyanine sulphonate (A1PcS4) in the presence of extracellular Ca2+ caused a rapid increase followed by a sustained increase in intracellular concentration of calcium ion ([Ca2+]i) in a small cell lung carcinoma (SCLC) cell line, SBC-3. The [Ca2+]i increase by photodynamic stimulation was completely inhibited by the removal of extracellular Ca2+ and reintroduction of extracellular Ca2+ immediately led to a rapid elevation of [Ca2+]i. However, the increase was not inhibited by application of Ni2+, nifedipine, or SK&F 96365, a receptor-mediated and voltage-dependent Ca2+ entry blocker. The photosensitizer A1PcS4 alone or light alone (4 min) had no effect on [Ca2+]i. Cytotoxicity examination by trypan blue exclusion test, however, suggested photodynamic stimulation-induced cell injury which was observed in both the presence and the absence of extracellular Ca2+. These results indicate that [Ca2+]i increase may not be mandatory for photodynamic stimulation-induced cell injury. Whether [Ca2+]i increase can accelerate, at least in part, cell death under the physiological condition, whether the mechanism(s) of cell death can be different in the presence and the absence of extracellular Ca2+, and whether [Ca2+]i increase can be totally unrelated to cell death await further work. PMID- 10093417 TI - A single-tube RT-PCR method for the detection of Borna disease viral genomic RNA. AB - For detecting Borna disease virus (BDV) genomic stranded RNA, single-tube reverse transcription-polymerase chain reaction (St RT-PCR) was developed to equal the sensitivity of RT-nested PCR but with reduced risk of contamination. BDV-genomic stranded RNA was synthesized in vitro using plasmid cDNA of BDV p24 region as a template and RNA was also extracted from BDV-persistently infected MDCK (MDCK/BDV) cells. Both RNAs were amplified by St RT-PCR in which a single round of RT and a single round of PCR were performed in the same tube. Ten copies of synthesized RNA could be amplified by St RT-PCR, indicating that St RT-PCR method is as sensitive as the ordinary RT-nested PCR method. Furthermore, this method was applied to quantify the exact copy number of genomic RNA in MDCK/BDV cells. Signals were obtained from the samples containing more than 1 pg total cellular RNA. From the results, approximately 100 copies of BDV genomic RNA exist in one MDCK/BDV cell. BDV genomic RNA from the in vivo RNA samples using St RT-PCR, indicating this method is applicable for the epidemiological study of BDV without contamination. PMID- 10093418 TI - An antibody induction method in mice for the potency assays of diphtheria and tetanus components in combined vaccines. AB - Eleven batches of Adsorbed Diphtheria-Tetanus (DT) vaccines and thirteen batches of Adsorbed Diphtheria-Pertussis-Tetanus (DTP) vaccines were tested for the potency of diphtheria and tetanus components by an Antibody Induction Method (AIM) developed in mice. The potency results obtained were found comparable and did not show any statistically significant difference with those obtained by WHO recommended lethal challenge tests for diphtheria in guinea pigs and for tetanus in mice. AIM in mice is more economical as both diphtheria and tetanus components of combined vaccine can be tested in the same experiment and the procedure also eliminates the use of guinea pigs required in the lethal challenge/conventional tests. The data obtained while testing tetanus component by the conventional antibody induction (IP) method in guinea pigs suggests that minimum requirements laid down in i.p. is too low which may be fixed as at least 3 out of 9 guinea pig sera and should contain > or = 4 units of tetanus antitoxin per ml. PMID- 10093419 TI - Neonatal sepsis in hospital born babies. AB - Incidence of neonatal sepsis in a study carried out among hospital born babies was found to be 5.3 per cent significantly high (10.9%) amongst low birth weight compared to (3.1%) normal birth weight babies. Sepsis related mortality also exceeded significantly in low birth weight babies. Positive cultures were obtained in 36.7 per cent of babies with sepsis. The organisms identified were Staphylococcus pyogenes (40%), E. coli (27.5%), Klebsiella spp. (15%), Staphylococcus epidermidis (10%) and Enterobacter spp. (7.5%). Gram negative bacilli predominated in early onset (< 72 hrs. of life) and gram positive cocci in late onset. Mortality with early onset culture positive neonatal sepsis was significantly high compared to late onset. The bacterial isolates obtained were found to be resistant to routinely used antibiotics (penicillin, ampicillin and gentamycin). Third generation cephalosporins and aminoglycosides (netilmycin) were found to be effective in treatment of neonatal sepsis. PMID- 10093420 TI - Periodic syphilis profile in a New Delhi hospital. AB - The study reports the prevalence of syphilis determined at intervals of ten years amongst attendees of the Sexually Transmitted Diseases Centre (STD), in New Delhi, from 1954, to 1994. It was observed that the number of STD cases increased by about eight times in 1984 as compared to 1954. The prevalence of STDs had risen from 5.5 per cent in 1964 to 14.7 per cent in 1994. However, the syphilis load has been decreasing since 1974. Childhood syphilis has decreased from 12.6 per cent in 1954 to 0.5 per cent in 1994. However in adult males it increased from 62.3 per cent in 1954 to 80.4 per cent in 1984. Cardiovascular syphilis was last reported in 1954. The prevalence of syphilis was approximately three times higher in males than in females. PMID- 10093421 TI - Isolation of nalidixic acid resistant Campylobacters from cases of paediatric diarrhoea in Chennai. AB - A short term investigation on the Campylobacter enteritis among children under 10 years of age was carried out in Chennai. The study revealed an isolation rate of 11 per cent in 100 patients suffering from acute diarrhoea comprising C. jejuni (8%) and C. coli. (3%). Among the two culture methods used, the candle jar method was found to be superior to plastic bag incubation system in recovering campylobacters on charcoal cefeperazone deoxycholate agar. While all the isolates were sensitive to ciprofloxacin, all of them exhibited resistance to nalidixic acid. PMID- 10093422 TI - Screening for chlamydial infections in women with pelvic inflammatory diseases. AB - One hundred female patients clinically diagnosed as pelvic inflammatory disease (PID) were studied for the presence of chlamydial infection by cytology and antigen detection. Cervical smears stained by Giemsa revealed inclusion bodies, only in 3 percent of cases. While using Immunocomb Enzyme Immunoassay (EIA) test, antigen was detected in 13% of cases, thereby showing that antigen detection is a better method than cell cytology. A significant correlation with the low socioeconomic status and younger age group was seen in patients showing presence of Chlamydia trachomatis antigen. PMID- 10093423 TI - Evaluation of efficacy of Dettol-H in hospital use. AB - A study was conducted at Safdarjang Hospital, New Delhi, to elucidate the bactericidal effect of a new disinfectant having benzalkonium chloride (40%) + disodium edetate (1.5%) and commercially available as Dettol-H, in comparison with that of a disinfectant already in-use in this hospital and having chlorhexidine gluconate (7.5%) + cetrimide (15%) + isopropyl alcohol (commercially available as Alpilon). The modified Capacity test of Kelsey-Sykes and In-use test of Kelsey-Maurer were carried out using control strains and random gram positive and gram negative bacterial isolates from clinical specimens. The two disinfectant solutions were analysed at three dilutions viz. weak, recommended and strong. From the study it could be inferred that both Dettol-H and Alpilon were equally effective in recommended and strong dilutions against the organisms tested. Weak dilutions were not effective in both and hence Dettol-H and Alpilon are effective only if used in prescribed concentrations. PMID- 10093424 TI - A study of current trends in enteric fever. AB - The results of a study based on 68 cases of blood culture proven enteric fever are presented. Sensitivity to chloramphenicol, ampicillin and cotrimoxazole was found to be 55.88, 54.41, 38.23% respectively. Common clinical features were fever, vomiting, pain abdomen and cough in both the groups. There was no difference in complications in chloramphenicol sensitive against resistant cases. Of the chloramphenicol sensitive cases, 21.05% were resistant to cefotaxime. All cases were sensitive to ciprofloxacin. More than half the cases were sensitive to chloramphenicol and ampicillin. PMID- 10093425 TI - Multiple tubercular ulcer perforation of ileum in an AIDS patient: case report. AB - Intestinal perforation is an extremely uncommon complication of Mycobacterium tuberculosis (MTB) infection. We report a case of HIV infection in a male injecting drug user (IDU) with intestinal tuberculosis complicated with multiple ileal perforations at the Regional Institute of Medical Sciences Hospital, Imphal, Manipur. The emergency surgical therapy supported by antitubercular drugs (ATT) and parenteral nutrition saved the life of this patient who presented in a critical state of shock. The patient manifested with extrapulmonary tuberculosis, which is one of the criteria of AIDS. The authors stress the possibility that in future, tubercular complication till now considered atypical, may become more frequent. PMID- 10093426 TI - Susceptibility status of malaria vectors to insecticides in India. AB - The use of chemical insecticides for control of malaria vector populations continues to be the mainstay of malaria control strategy in India. Monitoring vector susceptibility to chemical insecticides is an important activity under the National Malaria Eradication Programme to ensure judicious and effective use of chemical Insecticides. 72 entomological zones were established under NMEP in 1977 for undertaking entomological studies in the malaria problematic areas. These zones have been generating insecticide susceptibility data in respect of the various malaria vectors. In this paper the insecticide susceptibility data, in respect of major vectors of malaria as on 1997, is presented. PMID- 10093427 TI - Preventing dengue/dengue haemorrhagic fever outbreaks in the National Capital Territory of Delhi--the role of entomological surveillance. AB - Outbreaks of Dengue/Dengue Haemorrhagic Fever have been occurring in the National Capital Territory (NCT) Delhi from time to time. A massive outbreak of Dengue/DHF causing considerable mortality occurred in 1996 in the NCT, Delhi. Since this outbreak regular entomological surveillance has been instituted, for timely preventive action against Dengue/DHF. The Central Cross Checking Organisation (CCO) of the National Malaria Eradication Programme cross-checks Aedes surveillance activities in Delhi. In this paper we present our experiences in entomological surveillance in relation Dengue, to share them with other workers in this field. PMID- 10093428 TI - "Handigodu disease: A disease of unknown etiology"--revisited. PMID- 10093429 TI - A study on the prevalence of Toxocora spp eggs at public places in Andhra Pradesh. PMID- 10093430 TI - A note on first isolation of Japanese encephalitis virus from Culex infula Theobald (Diptera:Culicidae). PMID- 10093431 TI - Hymenolepis diminuta infestation in a child. PMID- 10093432 TI - A comparative study of immunisation status of children in West Bengal. PMID- 10093433 TI - Process indicators for malaria control. AB - Malaria Control efforts are existing in India since antiquity. Organised malaria control interventions were initiated in 1953 by launching of National Malaria Control Programme (NMCP) which was soon converted to eradication in 1958. The initial success achieved was short-lived as malaria resurged in sixties. In 1977, Modified Plan of Operations was launched and the malaria decreased to 2-3 million cases in 1984 and was maintained at the same level. In 1994, after large scale epidemics were experienced, deaths due to malaria increased. WHO recommended a process-based approach to malaria control involving community with decentralized planning in the Global Malaria Control Strategy. Decentralised requires redefining the role and responsibilities at each level of implementation. To facilitate this and monitor the implementation of malaria control detailed process indicators have been developed. PMID- 10093434 TI - [Need for more careful alternative to sympathectomy. Complications following surgery for palmar sweating are more common than previously thought]. PMID- 10093435 TI - [Mammographic screening fulfills the requirements of health control]. PMID- 10093436 TI - [Integrity of young abortion applicants is overestimated]. PMID- 10093437 TI - [Let the general practitioners go! Offer them other agreements as an alternative to the monopoly of county councils!]. PMID- 10093438 TI - [Do the responsible persons believe that problems disappear when a special hospital will be closed?]. PMID- 10093439 TI - [Liquor-filled chocolate's response to police alcohol tests]]. PMID- 10093440 TI - [Surgery provides symptomatic relief in skeletal metastases]. AB - The skeleton is the third most common site of metastasis, after the lungs and the liver. Although metastasis to bone is associated with considerable morbidity, it is seldom the direct cause of death. Orthopaedic treatment of imminent or existing pathological fractures has been associated with a dismal outcome until recently, when the treatment principles of trauma surgery and arthroplasty began to be applied in cases of skeletal metastasis. The article consists in a report of 141 patients with symptoms of skeletal metastasis to the pelvis or extremities, where the indication for surgery was pathological fracture in 85 per cent of cases, the femur being the commonest site, followed by the humerus. A third of the patients had breast cancer. Median survival was six months in the series as a whole. At follow-up after one week, four months, and one year, outcome was rated as good or very good by 98, 99 and 100 per cent of the patients, respectively. PMID- 10093441 TI - [Rohypnol should be classified as a narcotic]. AB - Flunitrazepam, widely known by its trade names (e.g. Rohypnol), may cause severe violence, especially in combination with alcohol. Flunitrazepam abusers become cold-blooded, ruthless and violent, and do not remember their violence. Reputedly it is supplied to professional hit-men and enforcers by their bosses to promote ruthless efficacy. One case report describes how a young man, intoxicated with flunitrazepam and involved in causing serious knife and gunshot wounds and taking hostages, felt so invincible that he openly challenged the police, threatening them with an assault rifle, but was himself shot. Flunitrazepam may exert pharmacological effects on GABA-ergic systems, thus lowering serotonin levels. The impulsive execution of violent crimes and suicide attempts in which a violent method (hanging, shooting, self-stabbing) has been used are associated with the presence of low serotonin levels. It is therefore recommended that flunitrazepam should be classified as a controlled substance in Sweden as it is elsewhere. PMID- 10093442 TI - [Brain damage caused by hypotensive anesthesia? Both the anesthetic technique and the anesthetic agent must be chosen with care]. AB - During the fifty years since hypotensive anaesthesia, induced hypotension to minimise intraoperative blood loss, became an established routine, there have been few reports of associated cerebral complications. However, evidence of disturbed cerebral function among patients undergoing orthognathic surgery under induced hypotension was obtained in a recent study where the level of adenylate kinase activity in cerebrospinal fluid was used as a highly sensitive biochemical marker of brain cell injury. Moreover, psychometric tests revealed persistent postoperative mental deterioration. The underlying cause of brain cell injury seems to be complex, and as in all likelihood it is not hypotension per se that is responsible, the effect of the anaesthetic agents used (isoflurane and propofol) has to be considered. It was also noted that hypotension did not improve the clinical outcome of orthognathic surgery, as compared with comparable operations performed under normotension. PMID- 10093443 TI - [Does prehospital hypertonic infusion therapy improve the survival of trauma patients?]. AB - In cases of hypovolaemic shock and trauma, hypertonic saline (HS) resuscitation is beneficial as it results in rapid and efficient fluid redistribution from interstitial and cellular sources to the intravascular compartment. The ensuing haemodilution and reduction in blood viscosity improves venous return and increases preload, while afterload is simultaneously reduced due to the vasodilatory effects of HS. All these changes promote increased cardiac output and improve haemodynamic stability. HS seems to exert a moderate negative inotropic effect on cardiac function. A fluid replacement regimen based on both hypertonic and hyperoncotic fluid components seems to be the most advantageous approach, due to its better maintenance of haemodynamic stability and better restitution of nutritional blood flow. Experimental findings support the use of the colloid, dextran, in combination with HS, due to its beneficial effects on leucocyte-endothelial cell interactions, and thus on microvascular blood flow. As compared with standard fluid regimens, HS without the colloid, dextran, has not been shown to improve survival rates, whereas HS in combination with dextran may be a superior alternative. In specific categories of trauma patients, (e.g., those with head injuries), HS treatment seems clearly advantageous. Registration of HS solutions is currently under way in several countries. PMID- 10093444 TI - [Amnioinfusion or not during labor? Better documentation and more trials can answer the question]. AB - Intrapartal amnio-infusion has been described as a means of reducing the risk of fetal distress, as well as the Caesarean section rate among cases of oligohydramnios accompanied by CTG (cardiotocography) signs of cord compression. Among cases complicated by the presence of thick, meconium-stained amniotic fluid, dilution by amino-infusion has been shown to reduce the prevalence of meconium below the vocal cords, and of meconium aspiration syndrome in the newborn. A questionnaire concerning experience of the method, answered by 98% (61/62) of delivery wards in the country, showed Swedish obstetricians to be generally in favour of the procedure which they considered beneficial. However, as many of the wards had had very few cases, obstetricians answering the questionnaire felt that there was a need of guidelines and better prospective clinical studies. PMID- 10093445 TI - [More efficient care and satisfied personnel when pediatric psychiatric clinic became an outpatient clinic]. PMID- 10093446 TI - [Closure of pediatric clinics resulted in worsened care in county hospitals]. PMID- 10093447 TI - [HELLP syndrome is a life-threatening pregnancy complication. A specific coagulation factor therapy is now possible]. PMID- 10093448 TI - [Find latent mistakes instead of scapegoats. A new perspective on work with patients' safety in America]. PMID- 10093449 TI - [Grief, pain, life and happiness characterize the final period. Being a relative gives a hard-earned experience]. PMID- 10093450 TI - [Surprising ability to handle bad news. A study of how cancer patients create hope]. AB - The article discusses findings in a study where malignant glioma patients were serially interviewed to determine how they constructed new perceptions of reality when confronted with the diagnosis. Although most of the patients were aware that the tumour posed a grave threat, they were also able to find refuge and hope by using various cognitive strategies. The process, that draws on various resources (the body, supportive relationships, cognitive schemata, and information processing), is discussed in relation to adjacent psychoanalytic theory, and is regarded as an expression of the 'intermediate area' of mental life, which is proposed as theoretical point of reference in discussing How to tell cancer patients. PMID- 10093451 TI - [Posthumous diagnosis for Jane Austen]. PMID- 10093452 TI - [When is cardiopulmonary resuscitation medically futile? Prognostic instruments can make difficult decisions easier]. PMID- 10093453 TI - [The National Board of Health and Welfare on mammographic screening: mortality analysis requires completely different methods]. PMID- 10093454 TI - Dose-related effects of single focal irradiation in the medial temporal lobe structures in rats--magnetic resonance imaging and histological study. AB - The dose-related effects of single focal irradiation on the medial temporal lobe in rats were investigated by sequential magnetic resonance imaging and histological examination. Irradiation of 200 Gy as a maximum dose using 4 mm collimators with a gamma unit created an area of necrosis consistently at the target site within 2 weeks after irradiation. Irradiation of 100 Gy caused necrosis within 10 weeks, and 75 Gy caused necrosis within one year. Irradiation of less than 50 Gy did not induce necrosis consistently, although a restricted area of necrosis was created in the medial temporal structures including the intraparenchymal portion of the optic tract. 75 Gy may be the optimum dose for creating necrosis consistently in the medial temporal lobe structures. However, careful dose planning considering both dose-time and dose-volume relationships in necrosis development is necessary to avoid injury to vulnerable neural structures such as the optic tract when applying radiosurgical techniques to treat functional brain disorders in medial temporal lobe structures such as temporal lobe epilepsy. PMID- 10093455 TI - Intraoperative ultrasonography evaluation of posterior vertebral wall displacement in thoracolumbar fractures. AB - Intraoperative ultrasonography (IOUS) was used to evaluate the location and compressive effects of intraspinal fragments in thoracolumbar fractures and the efficacy of reduction maneuvers in patients operated on for isolated or attached intraspinal fragments or for global posterior wall disruption. Dynamic IOUS was used to evaluate the effects of traction and lordosis. Fifty-eight patients were evaluated using a 7.5 MHz ultrasound probe, including 27 treated by impaction, 19 by removal of apparently isolated fragments, and 12 by traction followed by lordosis for global posterior wall disruption. IOUS had limitations and problems caused by split fragments and residual pedicular attachments that can compromise intraoperative maneuvers. The risk of secondary displacement of isolated fragments treated by impaction was very high. In particular, the pinching effect produced by T-shaped fractures was commonly responsible for secondary displacement. IOUS evaluation of canal clearance after fragment removal was satisfactory, but did not provide quantitative data. IOUS was easier to perform and apparently more reliable than intraoperative myelography. The dynamic IOUS data suggest that, except for severely tilted fragments that are completely free or remain attached to a pedicle, residual discal attachments significantly influence the likelihood of successful reduction. PMID- 10093456 TI - Cerebral metabolism of the remote area after epilepsy surgery. AB - To clarify whether epilepsy surgery improves cerebral metabolism, pre- and postoperative positron emission tomography (PET) scans were performed, with special reference to hypometabolism outside the resected epileptogenic zones in nine patients (8 males, 1 female) with medically intractable complex partial seizures and multiple hypometabolic zones. Seven patients underwent unilateral anterior temporal lobectomy, one patient underwent selective amygdalohippocampectomy, and one patient underwent parieto-occipital cortical resection and anterior temporal lobectomy. PET scans were obtained at least 6 months after surgery. Eight patients became seizure-free, and one patient had fewer than three seizures per year. Four patients showed improved glucose metabolism in the formerly hypometabolic zones, which were remote to the surgical site and ipsilateral to the epileptogenic foci. Five patients, who showed bilateral temporal hypometabolism preoperatively, had contralateral temporal hypometabolism after surgery. The relative glucose uptake in four of these patients showed increased metabolism of the adjacent lobes ipsilateral to the surgical site. The lobes that showed increased glucose metabolism after surgery were mostly frontal. Hypometabolism is reversible in the ipsilateral remote area, and may be caused by inhibition via the intercortical pathway. Contralateral temporal hypometabolic zones that persist after surgery may be caused by a different mechanism, and neither indicate the presence of seizure foci nor affect the seizure outcome. PMID- 10093457 TI - Bilateral vertebral artery occlusion following cervical spine trauma--case report. AB - A 41-year-old female presented with a rare case of bilateral vertebral artery occlusion following C5-6 cervical spine subluxation after a fall of 30 feet. Digital subtraction angiography showed occlusion of the bilateral vertebral arteries. Unlocking of the facet joint, posterior wiring with iliac crest grafting, and anterior fusion were performed. The patient died on the 3rd day after the operation. This type of injury has a grim prognosis with less than a third of the patients achieving a good outcome. PMID- 10093458 TI - Abrupt exacerbation of acute subdural hematoma mimicking benign acute epidural hematoma on computed tomography--case report. AB - A 75-year-old male was hit by a car, when riding a bicycle. The diagnosis of acute epidural hematoma was made based on computed tomography (CT) findings of lentiform hematoma in the left temporal region. On admission he had only moderate occipitalgia and amnesia of the accident, so conservative therapy was administered. Thirty-three hours later, he suddenly developed severe headache, vomiting, and anisocoria just after a positional change. CT revealed typical acute subdural hematoma (ASDH), which was confirmed by emergent decompressive craniectomy. He was vegetative postoperatively and died of pneumonia one month later. Emergent surgical exploration is recommended for this type of ASDH even if the symptoms are mild due to aged atrophic brain. PMID- 10093459 TI - Post-traumatic pituitary apoplexy--two case reports. AB - A 60-year-old female and a 66-year-old male presented with post-traumatic pituitary apoplexy associated with clinically asymptomatic pituitary macroadenoma manifesting as severe visual disturbance that had not developed immediately after the head injury. Skull radiography showed a unilateral linear occipital fracture. Magnetic resonance imaging revealed pituitary tumor with dumbbell-shaped suprasellar extension and fresh intratumoral hemorrhage. Transsphenoidal surgery was performed in the first patient, and the visual disturbance subsided. Decompressive craniectomy was performed in the second patient to treat brain contusion and part of the tumor was removed to decompress the optic nerves. The mechanism of post-traumatic pituitary apoplexy may occur as follows. The intrasellar part of the tumor is fixed by the bony structure forming the sella, and the suprasellar part is free to move, so a rotational force acting on the occipital region on one side will create a shearing strain between the intra- and suprasellar part of the tumor, resulting in pituitary apoplexy. Recovery of visual function, no matter how severely impaired, can be expected if an emergency operation is performed to decompress the optic nerves. Transsphenoidal surgery is the most advantageous procedure, as even partial removal of the tumor may be adequate to decompress the optic nerves in the acute stage. Staged transsphenoidal surgery is indicated to achieve total removal later. PMID- 10093460 TI - Surgical treatment of internal carotid artery anterior wall aneurysm with extravasation during angiography--case report. AB - A 54-year-old female presented subarachnoid hemorrhage from an aneurysm arising from the anterior (dorsal) wall of the internal carotid artery (ICA). During four vessel angiography, an extravasated saccular pooling of contrast medium emerged in the suprasellar area unrelated to any arterial branch. The saccular pooling was visualized in the arterial phase and cleared in the venophase during every contrast medium injection. We suspected that the extravasated pooling was surrounded by hard clot but communicated with the artery. Direct surgery was performed but major premature bleeding occurred during the microsurgical procedure. After temporary clipping, an opening of the anterior (dorsal) wall of the ICA was found without apparent aneurysm wall. The vessel wall was sutured with nylon thread. The total occlusion time of the ICA was about 50 minutes. Follow-up angiography demonstrated good patency of the ICA. About 2 years after the operation, the patient was able to walk with a stick and to communicate freely through speech, although left hemiparesis and left homonymous hemianopsia persisted. The outcome suggests our treatment strategy was not optimal, but suture of the ICA wall is one of the therapeutic choices when premature rupture occurs in the operation. PMID- 10093461 TI - Hemangioblastoma mimicking tentorial meningioma: preoperative embolization of the meningeal arterial blood supply--case report. AB - A 72-year-old male presented with a primary hemangioblastoma of the posterior fossa with unusual dural attachment and meningeal arterial blood supply from the external carotid artery and marginal tentorial artery. Preoperative embolization facilitated complete resection of the tumor with no resultant neurological deficit. Hemangioblastoma must be included in the differential diagnosis of tumors with dural involvement. Preoperative embolization is very useful in such tumors. PMID- 10093462 TI - Primary intracranial squamous cell carcinoma--case report. AB - A 50-year-old female presented with primary intracranial squamous cell carcinoma (SCC) at the right cerebellopontine angle manifesting as right facial nerve paresis. She had undergone gross total removal of a right cerebellopontine angle epidermoid cyst 10 years before and had done well until recently. Magnetic resonance imaging showed a heterogeneous tumor with markedly enhanced irregular margin. Subtotal removal of the tumor was achieved. Histological examination showed moderately differentiated SCC. After surgery, she underwent chemotherapy and gamma radiosurgery. She is now well 5 years after the diagnosis of SCC. PMID- 10093463 TI - Cylindrical or T-shaped silicone rubber stents for microanastomosis--technical note. AB - The ostium of the recipient artery and the orifice of the donor artery must be clearly visualized for the establishment of microvascular anastomosis. Specially designed colored flexible cylindrical or T-shaped silicone rubber stents were made in various sizes (400 or 500 microns diameter and 5 mm length) and applied to bypass surgery in patients with occlusive cerebrovascular disease such as moyamoya disease and internal carotid artery occlusion. The colored flexible stents facilitated confirmation of the ostium of the artery even in patients with moyamoya disease and allowed precise microvascular anastomosis without problems caused by the stent. PMID- 10093465 TI - Integration of mental and physical health concerns. PMID- 10093464 TI - Special report of Brain Tumor Registry of Japan (1969-1990). PMID- 10093466 TI - Psychiatry and primary care: two cultures divided by a common cause. AB - Traditional problems between primary care physicians and psychiatrists have persisted, including inability to understand each other, disrespect, mutual distrust, and competition. Unfortunately, although these two medical specialties, which both use a whole-person approach to the patient, should be pulling together, they are often pulling apart. PMID- 10093467 TI - The primary care-mental health interface. AB - Although no comprehensive and generally accepted description of the interface exists, understanding of the differing models of care can set the stage for collaboration. It then becomes important to ensure that partners in this discussion share the same language. Only then can misunderstandings be avoided. PMID- 10093468 TI - The mental health provider's view. AB - What do we want from primary care physicians to make their care of our patients better and our jobs less difficult? We want reasonable access to primary care services, effective communication, reduction in excessive practice interference, and flexible collaboration. PMID- 10093469 TI - The primary care provider's view. AB - To take advantage of the services of mental health professionals, primary care physicians must improve their flexibility, communication, and teamwork. All parties must be willing to surrender a measure of autonomy and control, but the result is worth the effort. PMID- 10093470 TI - The integrated system's view. AB - Truly integrated systems in public sector settings have been few, and most of us are operating in uncharted waters. However, we can embark on this new effort with some eagerness and confidence that collaboration will contribute significantly to the care of our mutual patients. PMID- 10093471 TI - The carved-out system's view. AB - Rarely do issues of mental health care in medical settings and the medical care of severely and persistently mentally ill patients treated in public mental health get addressed. The best approach to ensure that care is integrated is to reduce obstacles to reimbursement. In particular, carved-out systems should ask questions that highlight areas for change. PMID- 10093472 TI - Gatekeeping and authorization. AB - Managed care techniques first used in the private sector are increasingly being applied to control costs in the public sector. When the system places the burden of recognizing, diagnosing, and even treating mental illness on the primary care physician, however, a number of problems can result. PMID- 10093473 TI - Confidentiality. AB - Collaboration is easily hampered by real or perceived differences in confidentiality that prevent two critical providers from communicating openly. However, increased communication can be a two-edged sword. Sensitive and confidential information can reach individuals who may not be directly involved in patient care. PMID- 10093474 TI - Finding opportunities at the interface. AB - Integration at the primary care-mental health interface in public systems provides the opportunity to return to values that for several decades have been pushed into the background: preventive (including rehabilitative) and population based care. PMID- 10093475 TI - [Professor Anna Dubowska-Inglot]. PMID- 10093476 TI - [The importance of angiogenesis in tumor growth dynamics]. AB - The interactions between tumor cells and cellular compartments of direct environment, including soluble ECM factors, in the mechanisms of cancer progressive growth are discussed. Experimental data showing the role of increased apoptotic index even with unchanged proliferation rate in achieving the tumor "dormant state" are presented. The role of various molecules and factors involved in the process of tumor angiogenesis and their value as diagnostic and prognostic markers in cancer patients is discussed. The new antitumor therapeutical strategies based on an antiangiogenic activity of new potential agents are reviewed. PMID- 10093477 TI - [Angiogenesis in brain neoplasms--biological and clinical aspects]. AB - Solid tumors are dependent on angiogenesis for sustained growth, therefore anti angiogenic treatment is a potential antineoplastic therapy. Glioblastoma multiforme has been considered a suitable candidate for such treatment. This review summarizes the fundamentals of angiogenic process in glioblastoma multiforme and in other types of brain tumors for which they represent a potential for anti-angiogenic therapy. PMID- 10093478 TI - [The adenoid as lymphoid tissue]. AB - The adenoid is part of the mucosa-associated lymphoid tissue and is organized in distinct compartments. The lymphoid follicles and the interfollicular zone are areas of B lymphocytes and of T lymphocytes, respectively. The adenoid may thus function both as an immunologic inductive and effector organ. PMID- 10093479 TI - [The role of proteolytic enzymes in apoptosis]. AB - The literature review dealing with participation of proteolytic enzymes in initiation and execution of apoptosis was done. Cysteine proteases with Asp-X cleavage specificity, called caspases, play the main role in this process. The other proteases such calpains and proteasomes take also part in apoptosis. The proteases degrade proteins of cytoskeleton and structural proteins of nucleus, they also activate proendonucleases. PMID- 10093480 TI - [The role of nitric oxide in normal and pathologic immunologic reactions]. AB - Nitric oxide is intercellular messenger that performs a number of important functions, including neurotransmission, vasodilation, inhibition of platelet aggregation and modulation of leukocyte adhesion. The paper presents a new aspects of NO synthesis regulation by bacterial products and cytokines. Problems concerning the role of NO in antimicrobial/antitumor resistance and pathomechanisms of autoimmune diseases are also discussed. PMID- 10093481 TI - [Serotonin--structure, activity and clinical significance]. AB - In the article we discuss the role of serotonin in maintaining homeostasis paying special attention to the endocrinological aspect of the matter. It has been proved that it contributes to hypothalamus and hypophysis secretion regulation and interferes with paracrine activity in digestive and reproductive system. It is also an important constituent of platelets and takes part in aggregation and coagulation. It is known to be an atherogenic factor and to act as a growth stimulator for blood cells. It can be produced in exceed amounts by neoplasm or be released by activated thrombocytes during stress or coagulation. The influence of this hormone on the most of regulation mechanisms seems obvious. Presence of many different receptors as well as their number in all the structures of mammalian body makes it possible to use a range of agonists and antagonists in research concerning psychiatric diseases (e.g. bulimia, anorexia, depression), Alzheimer disease, migraine, hypertension, carcinoid related syndrome, multiple endocrine neoplasms and pre-menstrual syndrome. The promising results enable to use some of the modifiers in their clinical treatment though more research is needed for fully satisfactory effects. PMID- 10093482 TI - [Interferons: Clinical applications in hematology]. PMID- 10093483 TI - [Understanding and treating levodopa-induced dyskinesias]. PMID- 10093484 TI - [Surveillance of the common food toxin infections (CFTI) in the Sousse area. A nine-year retrospective study]. PMID- 10093485 TI - [Treatment of pelvic disruption by external fixation. Report of 13 cases]. PMID- 10093486 TI - [The diabetic's mouth]. PMID- 10093487 TI - [Penetrating keratoplasty. Analysis and indications in corneal disease. Review of a series of 132 cases over 8 years]. PMID- 10093488 TI - [Functional and social-professional impact of rheumatoid arthritis in Tunisia]. PMID- 10093489 TI - [Role of urinary cytology in the diagnosis and followup of bladder tumors. Review of 200 cases]. PMID- 10093490 TI - [Hodgkin's disease associated with a Kaposi's sarcoma and tuberculosis of hematopoietic organs]. PMID- 10093491 TI - Acute respiratory infection, Afghanistan. PMID- 10093492 TI - Meningococcal meningitis, Sudan. PMID- 10093493 TI - Progress towards the global elimination of neonatal tetanus, 1990-1998. PMID- 10093495 TI - Automated and integrated system for high-throughput DNA genotyping directly from blood. AB - An automated and integrated system for DNA typing directly from blood samples has been developed. The multiplexed eight-array system is based on capillary microfluidics and capillary array electrophoresis. Three short-tandem-repeat loci, vWA, THO1, and TPOX, are coamplified simultaneously in a fused-silica capillary by a hot-air thermocycler. Blood is directly used as the sample for polymerase chain reaction (PCR) without any pretreatment. Modifications of standard protocols are necessary for direct PCR from blood. A programmable syringe pump plus a set of multiplexed liquid nitrogen freeze/thaw switching valves are employed for liquid handling in the fluid distribution network. The system fully integrates sample loading, PCR, addition of an absolute standard, on line injection of sample and standards, separation and detection. The genotypes from blood samples can be clearly identified in eight parallel channels when the electropherograms are compared with that of the standard allelic ladder by itself. Regeneration and cleaning of the entire system prior to subsequent runs are also integrated into the instrument. The instrumentation is compatible with future expansion to hundreds of capillaries to achieve even higher throughput. PMID- 10093496 TI - A flow injection renewable surface technique for cell-based drug discovery functional assays. AB - A novel flow injection-renewable surface (FI-RS) technique is introduced for the execution of automated pharmacology-based assays on living cells. Cells are attached to microcarrier beads, which serve as the disposable and renewable surface with which the assay is performed. The feasibility of this FI-RS technique is demonstrated by performing a functional assay using Chinese hamster ovary cells transfected with the rat muscarinic receptor (M1). The intracellular calcium elevation resulting from the agonist-receptor interaction is measured via a calcium-sensitive fluorescent probe (fura-2) and a fluorescence microscope photometry system. The FI apparatus allows reproducible and precise control of the concentration gradient of chosen muscarinic receptor agonists (carbachol, acetylcholine, pilocarpine) delivered to cells attached to microcarrier beads. The RS methodology eliminates problems associated with diminishing biological response vis-a-vis traditional functional assays that are performed repetitively on the same group of cells. Using this technique, reproducible responses are measured and pharmacologic parameters quantified that compare favorably to literature values. In addition, the use of the FI-RS functional assay as an analytical method for discrimination of agonists based on kinetic parameters is proposed. PMID- 10093497 TI - Interactions of HIV-1 TAR RNA with Tat-derived peptides discriminated by on-line acoustic wave detector. AB - The human immunodeficiency virus type I is strongly regulated at the transcriptional level through the interaction of an 86-amino acid protein (Tat) with a viral messenger RNA transcript. Accordingly, the binding of this protein and other cellular factors to the RNA has constituted a significant target for the development of anti-HIV drugs. In the present work, we describe the detection of the binding of two Tat-derived peptides, of 12 and 40 amino acids in length, with chemically synthesized RNA by an acoustic wave sensor. Immobilization of the nucleic acid to the sensor surface, which was incorporated in an on-line system, was effected using the biotin-neutravidin interaction. As expected, the changes in series resonance frequency and motional resistance for the two peptides indicate reversible interactions in both cases that can be further characterized by the calculation of kinetic off-rates. Of particular interest is the nature of the two frequency-based signals, which are in opposite directions for the two peptides. These results together with those obtained for the surface interactions of neutravidin and biotinylated RNA confirm that the thickness shear mode sensor, mass-response model involving the well-known Sauerbrey expression is invalid when applied to operation in liquids. PMID- 10093499 TI - Angiotensin II receptors-antagonists, molecular biology, and signal transduction. AB - The renin-angiotensin-aldosterone system (RAAS) plays an important role in both the short-term and long-term regulation of arterial blood pressure, and fluid and electrolyte balance. The RAAS is a dual hormone system, serving as both a circulating and a local tissue hormone system (i.e., local mediator) as well as neurotransmitter or neuromediator functions in CNS. Control of blood pressure by the RAAS is exerted through multiple actions of angiotensin II, a small peptide which is a potent vasoconstrictor hormone implicated in the genesis and maintenance of hypertension. Hypertension is a primary risk factor associated with cardiovascular, cerebral and renal vascular disease. One of the approaches to the treatment of hypertension, which may be considered as a major scientific advancement, involves the use of drugs affecting the RAAS. Pharmacological interruption of the RAAS was initially employed in the late 1970s with the advent of the angiotensin converting enzyme (ACE) inhibitor, captopril. ACE inhibitors have since gained widespread use in the treatment of mild to moderate hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy. As the roles of the RAAS in the pathophysiology of several diseases was explored, so did the realization of the importance of inhibiting the actions of angiotensin II. Although ACE inhibitors are well tolerated, they are also involved in the activation of bradykinin, enkephalins, and other biologically active peptides. These actions result in adverse effects such as cough, increased bronchial reactivity, and angioedema. Thus, the goal of achieving a more specific blockade of the effects of angiotensin II than is possible with ACE inhibition. The introduction of the nonpeptide angiotensin II receptor antagonist losartan in 1995 marked the achievement of this objective and has opened new vistas in understanding and controlling the additional biological effects of angiotensin II. Complementary investigations into the cloning and sequencing of angiotensin II receptors have demonstrated the existence of a family of angiotensin II receptor subtypes. Two major types of angiotensin II receptors have been identified in humans. The type 1 receptor (AT1) mediates most known effects of angiotensin II. The type 2 receptor (AT2), for which no precise function was known in the past, has gained importance recently and new mechanisms of intracellular signalling have been proposed. This review presents recent advances in angiotensin II receptor pharmacology, molecular biology, and signal transduction, with particular reference to the AT1 receptor. Excellent reviews have appeared recently on this subject. PMID- 10093498 TI - Kinetics and thermodynamics of free flavins and the flavin-based redox active site within glucose oxidase dissolved in solution or sequestered within a sol-gel derived glass. AB - We report on the steady-state and time-resolved fluorescence from the redox active site flavine adenine dinucleotides (FADs) that are bound to glucose oxidase (GOx) when this enzyme is dissolved in aqueous solution or sequestered within a sol-gel-derived glass. To the best of our knowledge, this represents the first report on the actual dynamics of an enzyme active site when the enzyme is part of a sol-gel-derived glass. The results from these experiments show that the "free" FAD intramolecular folding/unfolding kinetics are slowed 3-10-fold within the glass vs solution. The intramolecular exciplex formation event (i.e., excited state FAD residue folding/unfolding) is completely arrested for the GOx-bound FAD if the enzyme is sequestered within a glass in the absence of glucose. This is significantly different from the behavior of GOx dissolved in solution. However, despite this difference in behavior, the GOx molecules that are sequestered within the glasses continue to function somewhat like GOx dissolved in aqueous solution if they are challenged with glucose. We also found that the GOx molecules do not leach from the glass and they exhibit rotational mobility that is only 2-fold less than GOx dissolved in aqueous solution at 20 degrees C. In aqueous solution or within these glasses, the enzyme pocket that hosts the FAD redox sites opens up by 25-30% when GOx is challenged with glucose. Finally, we present preliminary analytical results for film-based sol-gel-derived biosensors that contain GOx, L-amino acid oxidase or cholesterol oxidase wherein the intrinsic FAD fluorescence produces the analytical signal. PMID- 10093500 TI - Stress and water balance: the roles of ANP, AVP and isatin. AB - Stress is often associated with water retention and its resolution with diuresis. The biological systems for the control of stress and water balance are very closely related. Corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) are co-localised in the hypothalamus and often act synergistically. Atrial natriuretic peptide (ANP) can exert a feedback control on the hypothalamic/pituitary/adrenal axis. ANP has been shown to be anxiolytic, whereas AVP may be anxiogenic. AVP and ANP levels have been found to be abnormal in a range of stress disorders and psychiatric illnesses. Isatin is an endogenous anxiogenic factor which is also a potent inhibitor of the ANP receptor. It may provide a link between the function of monoamines during stress, and the control of water balance by ANP. PMID- 10093501 TI - Rapid sexing of bovine preimplantation embryos using polymerase chain reaction: production of calves with predetermined sex under field conditions. AB - Two to four blastomere size biopsies were obtained from each 6-day-old embryo of zebu and crossbred cattle for sex determination. The sex of the embryos was determined with a set of bovine Y-chromosome specific primer pairs by using polymerase chain reaction. Thirty two biopsied embryos after their sex was determined, when transferred fresh to synchronized recipients, resulted in 56.2% pregnancy rate. Sixteen healthy calves were born at full term, while 2 heifers aborted at mid-term from fresh embryo transfer. Simultaneously, 44 biopsied embryos which were kept frozen, were thawed at a later date and transferred to the previously synchronized recipients, thereby leading to 24 pregnancies (54.5%). Twenty-three healthy calves were born at full term, while 1 heifer aborted at mid-term from frozen-thawed embryo transfer. The pregnancy rates from both fresh and frozen-thawed biopsied embryos were comparable with that of controls (P > 0.05). Except for a single misidentification of a male calf as a female by our PCR assay (2.6%), the phenotypic sex of all the live born calves as well as the aborted fetuses was correctly matched with the PCR detection. PMID- 10093502 TI - Expression and stable germline transmission of neomycin-resistance gene in transgenic mice. AB - Transgenic mice were produced to study the expression of amino-3' glycosyl phosphotransferase gene (neomycin resistance gene) in the embryonic fibroblast cells. A 1.9 Kb linear fragment of neomycin resistance gene under the control of pPGK promoter was microinjected into the pronucleus of mouse embryos. Out of 64 potential founders born, 5 were identified to be transgenic by the polymerase chain reaction (PCR) and southern hybridization. Multiple mice from first and second generation from two transgenic founders (N-10 and N-32) were analysed to determine the germline transmission. It was found to be 24.6 and 71.4% in first and second generation respectively. Results were also further confirmed by RT PCR, sequencing and in vitro bioassays. PMID- 10093503 TI - Effect of hyoscine butylbromide and atropine on heart rate during nocturnal sleep. AB - This is a single blind crossover study designed to test the effects of hyoscine butylbromide (HBB), an anticholinergic which does not cross the blood brain barrier (BBB), on the temporal changes in heart rate during nocturnal sleep. The effects were compared with atropine sulphate which is known to cross the BBB. Ten healthy male volunteers slept in the JIPMER sleep disorders laboratory for three nights and received either saline, atropine sulphate (0.4 mg, i.v.) or HBB (10 mg, i.v.) just prior to sleep onset. All night polysomnography recording was done to monitor heart rate during the specific stages of sleep. The normal physiological fall in heart rate is blunted by both drugs during slow wave sleep whereas only HBB prevented the fall in rapid eye movement sleep. Therefore, HBB may be a better choice as pre-anaesthetic medication for patients with cardiac abnormalities since it does not alter heart rate during both slow wave sleep and rapid eye movement sleep. PMID- 10093504 TI - Effect of exercise on transplanted extensor digitorum longus muscle in Sprague Dawley rats. AB - Effect of exercise has been studied on intact and transplanted extensor digitorum longus (EDL) muscle in rats. Majority of muscle fibres hypertrophied and a few showed hyperplasia in intact and transplanted EDL muscle after exercise. The weight, dimensions and diameter of muscle fibres increased, while total muscle area, number of muscle fibres and the number and diameter of nuclei decreased after exercise in all the experimental groups. The DNA, RNA and protein contents were however increased after exercise. PMID- 10093505 TI - Regeneration following orthotopic transplantation of entire plantaris muscle in Sprague Dawley rats. AB - Regeneration of rat plantaris muscle has been studied without predeneration. The original muscle fibres were completely degenerated within one week, but were completely regenerated at the end of experiment. The weight of regenerate showed 51% recovery. The breadth, length and total area of muscle and number of muscle fibres was less by 42, 37, 26 and 29% respectively, compared to control muscle at the end of experiment. The diameter of regenerated fibres was almost normalized at the end of experiment. The number and diameter of nuclei in the regenerate was more than that of control which coincides with the increase in DNA and RNA contents. The protein contents after an initial loss started increasing and continued to do so till the end of the experiment. The better regeneration of the plantaris muscle seems to be due to the presence of supporting gastrocnemius muscle. PMID- 10093506 TI - Role of bone marrow and thymus secretory protein in maintaining immune homeostasis and haemopoiesis in control and malnourished mice. AB - Injection of Salmonella typhi 'H' antigen was observed to produce a differential effect on bone marrow and thymus secretory profile depending upon the nutritional status of the host. The paracrine effect of Thy F1 (thymus fraction 1) was more significant (P < 0.01) than the autocrine effect of BIM (Bone marrow immunomodulator) in malnourished mice. BIM moreover, also had a paracrine effect on thymus irrespective of the nutritional status of the host. An improvement in neutrophil population (P < 0.01) and phagocytic myeloperoxidase activity (P < 0.01) was observed in BIM treated malnourished immuno-suppressed mice, whereas no appreciable change was observed by Thy F1. However, Thy F1 irrespective of the nutritional status of the host improved large lymphocyte population in circulation (P < 0.01). These findings indicate that both bone marrow and thymus play a major role in haemopoietic microenvironment of BDF (basal diet fed) control and malnourished mice. PMID- 10093507 TI - Effect of short-term treatment of eugenol on the seminal vesicles of adult albino rats. AB - The structure and biochemical content of adult albino rat seminal vesicles, were studied, after administration of two different doses of eugenol for 10 days (0.2 and 0.3 mg/kg/day, i.m.). Marked decreases in the concentrations of nucleic acids, fructose and total protein as well as RNA/DNA ratio (61%) and protein/DNA ratio (27%) were observed. A remarkable increase in phospholipid concentration was noted with a corresponding decrease in neutral lipids. Histologically, eugenol treated animals showed degeneration of the secretory columnar cells and well developed myofibrillar connective tissues when compared to control animals. PMID- 10093508 TI - Purification and characterization of phospholipase C of Salmonella gallinarum. AB - Phospholipase C was isolated from an outbreak strain of Salmonella gallinarum with ciprofloxacin extraction, dialysis, gel filtration, ion exchange chromatography and chromatofocussing. Purified phospholipase C (mol wt. 65 KDa; isoelectric point, pI 3.5) was resistant to pasteurization, stomach enzyme (pepsin), bacterial protease and lipase but lost its activity on trypsin and chymotrypsin treatment. It was sensitive to pH > or = 8.0. It was haemolytic, embryotoxic, enterohaemorrhagic, lethal to birds, cytotoxic to Vero and MDBK cells, dermonecrotoxic in rabbit and antigenically active protein. Antisera raised against purified phospholipase C neutralized its all biological activities and agglutinated the producer Salmonella strains. Serologically it was proved similar to phospholipase C of Klebsiella pneumoniae and S. weltevreden. Fluorescent antibody technique (FAT) was standardized to detect phospholipase producer strains. PMID- 10093509 TI - Development and characterization of monoclonal antibodies to foot and mouth disease virus type 'C'. AB - Five fusion experiments were conducted with spleen cells from Balb/c mice immunized with purified 146S antigen of foot and mouth disease virus type 'C' (vaccine strain). Monoclones (31) thus developed were isotyped as IgM (3), IgG1 (6), IgG2a (5), IgG2b (3) and IgG3 (14). Eleven clones isotyped as IgM, IgG2a and IgG2b showed neutralizing activity in virus neutralization and plaque reduction tests. Six of the neutralizing clones precipitated 146S virus in Ouchterlony reaction. On the basis of location of MAb reactive epitopes in relation to intact virus (146S), 12S particles and VP1 in ELISA test, the clones were classified as Class II (6), Class III (11) and Class IV (14). These clones may be useful for purposes of antigen detection from field isolates and for estimation of antibody titres in vaccinated animals. PMID- 10093510 TI - Precocious recrudescence of seminal vesicle and testis in catfish, Clarias batrachus (Linn.), subjected to a long photoperiod regime. AB - The catfish C. batrachus were exposed to a long photoperiod of 14 hr light during resting--early preparatory (December-February) phases of the reproductive cycle. At 70-day sampling, both the seminal vesicle (SV) and testis registered marked stimulatory effects in comparisons to control fish maintained under approximately 10.55 L:13.45D as shown by the increased size and weight. In both the SV and testis, concentrations of total proteins, fructose, hexosamines, and sialic acid were significantly high compared to those of the control fish indicating increased activities of the organs. Serum levels of gonadotropin-II, testosterone, and estradiol-17 beta were significantly high in the long photoperiod group. The results show that exposure to long photoperiod can stimulate early development of both the SV and testis by activating the pituitary -gonadal axis. PMID- 10093511 TI - Effect of vitamin B6 on lenses of diabetic rats. AB - Vitamin B6 is essential for the metabolism of fat, carbohydrate and protein. In this study the effect of vitamin B6 on diabetes induced impairments in rat lenses was investigated. Although macroscopic examination revealed no opacification of rat lenses in any groups, uncontrolled induced diabetes caused significant decreases in lens glutathione and increases in lens protein nonenzymatic glycosylation and blood glucose. Administration of vitamin B6 did not inhibit these diabetes induced alterations significantly. SDS-polyacrylamide gel electrophoresis revealed some significant differences in some protein bands between groups. PMID- 10093512 TI - Effect of drugs influencing central serotonergic mechanisms on pentazocine induced catalepsy in mice. AB - Cataleptic effect of pentazocine in mice was affected by pretreatment with dexfenfluramine, fluoxetine, buspirone, p-chlorophenylalanine, cyproheptadine, mianserin, cisapride, ondansetron, pindolol and propranolol. The results suggest that drugs which influence the activity of central serotonergic systems do modulate pentazocine-induced catalepsy in mice. PMID- 10093513 TI - Synthesis and anti-HIV activity of some non-nucleoside 2,3-disubstituted quinazoline derivatives (Part-V). AB - Several [2-phenyl-4(3H)-oxo-3-quinazolinylamino]-N-substituted- arylacetamides (1a-j) have been synthesized and tested at the National Cancer Institute, Bethesda, Maryland, USA, for their anti-HIV activity against susceptible human host cells (CEM cell line) over a wide range of concentrations (6.35 x 10(-8) to 2.00 x 10(-4) M). The highest protection observed is 45.67%. The structures of these compounds have been established on the basis of elemental analysis and spectral data. PMID- 10093514 TI - Controlled introduction of selenium into Chlorella cells. AB - Selenium (Se) is an important element in the antioxidant system of the human body, and Chlorella, well-known for its therapeutic effects, is the ideal carrier to offer it in the wanted organic form. The kinetics of Se absorption by growing algal cells and its distribution in the cells are studied using radioactive 75Se labelled solutions. There is a rapid Se absorption within the first few minutes at the cell surfaces where it is irreversibly fixed and cannot be absorbed by the human body. In the final state, reached after 24-48 hr, about 40% of the total fixed Se is inside the cells in the wanted organic-bound form. PMID- 10093515 TI - Human chemokines: role in lymphocyte trafficking. PMID- 10093516 TI - Viruses and human cancer. AB - Several kinds of viruses cause cancer in humans, accounting for 10-20% of cancer worldwide. Human cancer viruses include human papillomavirus, hepatitis B virus, Epstein-Barr virus, human T cell lymphotropic virus, and Kaposi's sarcoma associated herpesvirus. Cancer viruses alter the machinery of the infected cell to promote their own survival and growth. In the process, they interfere with normal cellular control mechanisms, leading to abnormal growth, genetic alterations and malignancy. Studies of virus replication and neoplastic cell transformation are revealing mechanisms by which these viruses cause human cancer. PMID- 10093517 TI - Carcinogenic metals. PMID- 10093518 TI - The applause of dentistry. PMID- 10093519 TI - Restorative and periodontal considerations of short clinical crowns. AB - The purpose of this review was to examine the periodontal and restorative factors related to restoring teeth with short clinical crowns. Modes of therapy are usually combined to meet the biologic, restorative, and esthetic requirements imposed by short clinical crowns. The complications presented by teeth with short clinical crowns demand a comprehensive treatment plan and proper sequencing of therapy to ensure a satisfactory result. Visualization of the desired result is a prerequisite of successful therapy. Short clinical crowns present many problems to the restorative dentist. Restorations should have proper form, function, and esthetics while promoting the maintenance of tissue health in the surrounding areas. However, adequate tooth structure for achieving these goals may not always be available. While it is difficult to precisely define minimum crown length, this study offers guidelines for defining a short clinical crown and suggests procedures for achieving a predictable result without compromising the periodontium. The consequences of placing a restoration on a tooth with insufficient crown length are discussed and various treatment methods are reviewed. PMID- 10093520 TI - Vertical ridge augmentation: surgical protocol and retrospective evaluation of 48 consecutively inserted implants. AB - The aim of this retrospective study was to evaluate the predictability of obtaining a vertical ridge augmentation around dental implants, strictly following a surgical protocol. Fourteen partially and four fully edentulous patients were treated between July 1993 and November 1995. Forty-eight consecutive implants were placed so that the circumference of the upper part of the cover screw was exposed from 2 to 7 mm. In addition to bone chips, autogenous bone grafts harvested with a bone-filtering aspirator were placed around the exposed threads and completely covered with a barrier membrane. Flaps were coronally displaced to cover the regenerative materials. Three of the 22 membranes became exposed prematurely and were removed immediately. The remaining 19 membranes stayed in place for a 12-month healing period until the second-stage surgery. In these 19 cases, where the membrane remained completely covered by the soft tissue, all of the available space underneath the membrane was filled with regenerative tissue. In eight cases a histologic biopsy was performed. Histologic analysis demonstrated vital bone with regularly formed bone cells; in three cases the most coronal part (approximately 1 mm) of the regenerative tissue was connective tissue, and the remaining tissue was bone. This retrospective analysis showed that when the clinical protocol was accurately followed, the possibility of clinical complication was reduced and the results for achieving vertical ridge augmentation around implants were predictable. PMID- 10093521 TI - Guided tissue regeneration versus coronally repositioned flap in the treatment of recession with double papillae. AB - Twenty buccogingival recessions (3 mm deep) in twenty patients were selected and divided into two groups. Periodontal parameters were recorded (recession reduction, probing depth, clinical attachment level, and keratinized tissue width), and both groups were treated with regenerative therapy using a resorbable polylactic acid membrane. The test group was treated using the double papilla flap procedure, and the control group was treated using the coronally repositioned flap procedure. The results obtained at a 1-year follow-up were comparable between the test and control groups for recession reduction, probing depth, and clinical attachment level, although the test group obtained a very large amount of keratinized gingiva (+74.7%) compared to the control group. PMID- 10093522 TI - Yttrium-partially stabilized zirconium dioxide posts: an approach to restoring coronally compromised nonvital teeth. AB - In the pursuit of esthetic restorations for nonvital teeth, the introduction of a tooth-colored intraradicular post system is described. Conventional metallic posts can corrode and may cause inflammatory reactions and discoloration of the periodontium. Zirconium dioxide is a chemically stable ceramic with physical and optical properties that make it an ideal choice for the construction of esthetic, life-like restorations. The purpose of this study was to describe the composition, properties, and practical applications of zirconia posts in clinical practice. PMID- 10093523 TI - Surgical reconstruction of the interdental papilla. AB - The traditional goal of disease elimination in the anterior region opens the interproximal spaces, causing flattening or cratering of the interdental papilla. Today's patients increasingly demand esthetic results in addition to periodontal treatment, and recent advances in periodontal plastic surgery have enhanced the periodontist's ability to address these concerns. Three case reports demonstrate a proposed surgical technique for the reconstruction of collapsed interdental papillae using a connective tissue graft under the buccal and palatal flaps. PMID- 10093524 TI - Oral tissue reactions to suture materials. AB - Tissue reactions to natural and synthetic braided and monofilament suture materials in gingiva and oral mucosa were studied. A total of 138 sutures made of four commonly used materials were placed in the edentulous ridges and vestibular mucosa of eight beagle dogs. Biopsy specimens including the suture loop and surrounding tissues were obtained after 3, 7, and 14 days and processed for histologic analysis. The inflammatory reaction was more rapid and intense than the reaction that has been reported after suture placement in skin. Bacterial invasion of the suture track was a common sequela regardless of the material used, but it was particularly prominent for silk. The formation of a perisutural epithelial sleeve was well under way at 3 days and in some instances included the entire suture track within 7 days. Connective tissue reactions consisted of several well-defined, concentric perisutural zones. At 14 days, these zones were partly replaced by granulation tissue surrounded by a fibrous capsule. The synthetic monofilament suture elicited a mild inflammatory tissue response. The results showed that sutures placed in gingiva and oral mucosa produce a prolonged tissue response that is most likely a result of the continual influx of microbial contamination along the suture channel, which may be a lesser problem when sutures are placed in other surgical compartments. The results indicate that chromic gut sutures are rapidly and unpredictably absorbed when used in an environment characterized by moisture and infectious potential. PMID- 10093525 TI - Molar root furcation: morphometric and morphologic analysis. AB - The objective of the present study was a morphometric and morphologic analysis of maxillary and mandibular first and second molars using three different techniques. Measurements of 207 maxillary molars (105 first and 102 second molars) and 207 mandibular molars (110 first and 97 second molars) were measured; root length, radicular trunk length (RTL), mesiodistal and buccolingual diameters (BLD) at the cementoenamel junction, inter-radicular angle (IRA) width, and furcal roof area (FRA) were recorded. No significant statistical correlations were found for most of these measurements, the only exception being the relationship between IRA/FRA, IRA/BLD in maxillary molars, and IRA/RTL in the maxillary first molar. Morphologic examination was carried out by stereo microscopy, light microscopy of undecalcified sections, and scanning electron microscopy. All of these techniques showed the complexity of the furcation area with a large number of anatomic irregularities and plaque-retentive structures that could hamper adequate cleaning during periodontal treatment. PMID- 10093526 TI - New attachment achieved by guided tissue regeneration using a bioresorbable polylactic acid membrane in dogs. AB - Created periodontal defects in dogs were randomly assigned for experimental (Guidor bioresorbable membranes) or control (conventional therapy) treatment. The results showed that the new connective tissue attachment was significantly greater in test sites than in controls. This new attachment averaged 2.79 +/- 0.74 mm and 1.47 +/- 0.20 mm at test and control sites, respectively (P < 0.05). Epithelial downgrowth was also reduced in the test sites (P < 0.05). No differences in bone response were found. The bioresorbable barrier was effective in blocking gingival epithelial downgrowth and connective tissue proliferation, promoting new attachment according to the principles of guided tissue regeneration. PMID- 10093527 TI - The importance of fimbriae in the virulence and ecology of some oral bacteria. AB - Cumulative evidence indicates that bacterial adherence to mucosal and tooth surfaces as well as bacterial coaggregation are essential steps for colonization of various oral bacterial species. Bacterial fimbriae have been shown to play an important role in the interaction between bacteria and host cells or among bacterial cells. The properties of fimbriae from selected species of oral bacteria are discussed in terms of virulence traits and ecological significance. Among others, Porphyromonas gingivalis fimbriae have been most extensively studied. The fimbrial structure is composed of 41-kDa fimbrillin proteins. DNA sequencing of the fimbrillin gene (fimA) from nine strains of P. gingivalis suggests intraspecies variation in the structure of fimA, while retaining common immunochemical specificities. P. gingivalis fimbriae exhibit a wide variety of biological activities including immunogenicity, binding to various host proteins, stimulation of cytokine production and promotion of bone resorption, Actinobacillus actinomycetemcomitans also possesses fimbriae; however, little is known concerning their chemical, genetical, and biological properties. Fimbriae of Prevotella intermedia are shown to induce hemagglutination reaction, while those of Prevotella loescheii are found to cause coaggregation with other bacteria, i.e., Actinomyces viscosus and sanguis streptococci. Fimbriae from gram positive oral bacteria such as oral Actinomyces and sanguis streptococci are described. These fimbriae may participate in coaggregation, binding to saliva coated hydroxyapatite or glycoprotein of the surface layer of oral epithelial cells. Taken together, fimbriae are key components in cell-to-surface and cell-to cell adherence of oral bacteria and pathogenesis of some oral and systemic diseases. PMID- 10093528 TI - Induction of secretory and serum antibody responses following oral administration of antigen with bioadhesive degradable starch microparticles. AB - Bioadhesive degradable starch microparticles were used to deliver antigen and immunoglobulin A (IgA)-enhancing cytokines to the oral mucosa. Degradable starch microparticle immunization groups consisted of rats dosed topically at the sublingual epithelium of the oral cavity, by subcutaneous injection in the vicinity of the major salivary glands or by oral intubation with degradable starch microparticles containing dinitrophenyl-bovine serum albumin +/- IL-5/IL-6 +/- penetration enhancer (alpha-lysophosphatidylcholine). Dinitrophenyl-bovine serum albumin was also adsorbed onto alum for salivary gland vicinity injection and administered to the oral cavity in soluble form. Animals were subjected to 3 immunization cycles, and sequential samples were assayed by radioimmunoassay for salivary IgA, tear IgA and serum IgG anti-dinitrophenyl antibodies after secondary and tertiary immunization. Salivary IgA responses were highest in degradable starch microparticle groups receiving penetration enhancer at 71 days post-secondary immunization and continued in one degradable starch microparticle((oral cavity) and two injected (salivary gland vicinity) groups for up to 88 days post-tertiary immunization. Long-term tear responses were also observed in degradable starch microparticle groups receiving penetration enhancer, but they dissipated before the salivary gland-alum responses following tertiary immunization. Serum IgG responses were most pronounced in salivary gland groups, but long-term low level responses were detectable in oral cavity groups receiving degradable starch microparticle formulations with penetration enhancer. Inclusion of IL-5 and IL-6 in oral cavity-delivered degradable starch microparticle formulations consistently enhanced tear IgA while only upregulating salivary IgA antibody responses at early time points post immunization. IL-5 and IL-6 did not enhance serum IgG antibodies in any group. These data indicate that bioadhesive degradable starch microparticles can be used as a vehicle to deliver antigen and cytokine signals to the oral cavity and, when delivered in combination with a penetration enhancer, can potentiate long-term salivary IgA responses. PMID- 10093529 TI - Antigenic components of Actinobacillus actinomycetemcomitans lipopolysaccharide recognized by sera from patients with localized juvenile periodontitis. AB - The dominant antigen of Actinobacillus actinomycetemcomitans recognized by high titer sera from patients with localized juvenile periodontitis is the serotype antigen located in the O-side chains of lipopolysaccharide. Whether such sera contain antibodies reactive with other epitopes in lipopolysaccharide, as is the case for patients with rapidly progressive periodontitis, remains unknown. We prepared and characterized by gas liquid chromatography lipopolysaccharide, lipid A, core carbohydrate with no or few O-side chains (core) and high-molecular-mass carbohydrate-rich in O-side chains (oligosaccharide) from A. actinomyce temcomitans ATCC 43718 (serotype b, Y4). Using enzyme-linked immunosorbent assay (ELISA), sera from 36 patients with localized juvenile periodontitis were surveyed using whole-cell sonicate as plate antigen. The seven highest titer sera were selected for further study. Specific IgG antibody binding was observed to intact lipopolysaccharide and to all the lipopolysaccharide fractions. The mean titers were highest for intact lipopolysaccharide (138.8 ELISA units), and lipid A (122 ELISA units), followed by the core fraction (81 ELISA units) and the oligosaccharide fraction (69.5 ELISA units). ELISA inhibition revealed that the core fraction at a concentration of 10 micrograms/test well inhibited antibody binding to A. actinomycetemcomitans lipopolysaccharide by a mean value of 56.7%. To further characterize antibody binding to the core fraction, ELISA inhibition was performed using as inhibitor the core carbohydrate fraction of the Re mutant of Salmonella minnesota, which is known to contain only alpha-keto-3 deoxyoctonate residues and phosphate. This fraction at 10 micrograms/test well inhibited binding of antibodies from 6 of 7 test sera with a mean value of 49.2%. Thus, sera from patients with localized juvenile periodontitis contain antibodies that bind to the O-side chains of lipopolysaccharide, as has been previously reported, but they also contain antibodies that bind to lipid A and to lipopolysaccharide core polysaccharide epitopes, specifically to alpha-keto-3 deoxyoctonate moieties. The humoral immune response to A. actinomycetemcomitans in patients with localized juvenile periodontitis is more complex than previously reported and is very similar to that of patients with rapidly progressive periodontitis. PMID- 10093530 TI - Variable serum immunoglobulin G immune response to genetically distinct Eikenella corrodens strains coexisting in the human oral cavity. AB - This study examined the variable serum immunoglobulin G (IgG) levels to genetically distinct autologous Eikenella corrodens strains by enzyme-linked immunosorbent assay (ELISA). Twenty subjects, including 10 adult periodontitis patients, 5 juvenile periodontitis patients and 5 periodontally healthy subjects were examined. Each subject was colonized by 2-8 genetically distinct E. corrodens strains. The serum IgG levels to autologous E. corrodens within individuals were significantly different in 7 adult periodontitis patients, 4 juvenile periodontitis patients and a periodontally healthy subject. Poor correlation was found in diseased subjects between serum IgG levels to autologous strains and to reference strains ATCC 23834 or FDC 373. Four adult periodontitis patients and two juvenile periodontitis patients exhibited significant serum IgG levels to autologous E. corrodens strains (two standard deviations above the mean for periodontally healthy subjects); two of these six diseased subjects exhibited low serum IgG levels to reference strains and would have been classified as low immune responders if only reference strains had been used in ELISA. This study showed the importance of using autologous E. corrodens strains in the assessment of serum IgG immune responses to this organism. PMID- 10093531 TI - Rapid evaluation of serum and gingival crevicular fluid immunoglobulin G subclass antibody levels in patients with early-onset periodontitis using checkerboard immunoblotting. AB - A method was developed to evaluate the presence of immunoglobulin G (IgG) subclass (1-4) antibody to Actinobacillus actinomycetemcomitans, serotype b (strain Y4) in patients with early-onset periodontitis on a single nitrocellulose membrane. Sera from 30 early-onset periodontitis patients and gingival crevicular fluid samples from 2 patients were collected and tested with four different preparations of A. actinomycetemcomitans (Y4). The principle steps of the assay are: a) binding of the bacterial antigen (Y4) and the anti-human IgG antibody (capture antibody) in parallel lanes on nitrocellulose membranes; b) incubation of known concentrations of the IgG subclasses 1, 2, 3 and 4, as well as a dilution of serum and/or gingival crevicular fluid from patients in lanes perpendicular to the antigen lanes; c) incubation of the membranes with the corresponding peroxidase conjugated anti-human IgG subclass secondary antibody; d) detection of positive signals by enhanced chemiluminescence. The blots were evaluated by visual comparison to a series of blots containing known concentrations of IgG subclasses. The method was used to rapidly screen a relatively large number of patient sera and gingival crevicular fluid samples for IgG subclasses in a cost-effective assay. The predominant IgG subclass found in early-onset periodontitis was IgG2. PMID- 10093532 TI - Interleukin-6 production by human monocytes treated with granulocyte-macrophage colony-stimulating factor in the presence of lipopolysaccharide of oral microorganisms. AB - This study focused on the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and lipopolysaccharide of the putative periodontal pathogens Porphyromonas gingivalis or Fusobacterium nucleatum on IL-6 production by THP-1 cells (a human monocytic cell line). Resting THP-1 cells were alternatively treated with GM-CSF (50 IU/ml) and lipopolysaccharide of P. gingivalis or F. nucleatum, in varying concentrations for varying time periods. IL-6 production in supernatant fluids of treated cells was evaluated by an enzyme-linked immunosorbent assay (ELISA) and a reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate gene expression. Untreated THP-1 cells did not produce IL-6 as determined by ELISA. RT-PCR also failed to detect IL-6 mRNA in untreated THP-1 cells, indicating that IL-6 was not constitutively produced. After stimulation of THP-1 cells with lipopolysaccharide of F. nucleatum or P. gingivalis, IL-6 was produced, peaking at 4 h (200-300 pg/ml) and thereafter sharply declining by 8 h. When GM-CSF was added together with lipopolysaccharide of P. gingivalis or F. nucleatum, there was a synergistic quantitative increase in production of IL-6 as measured by ELISA as compared with lipopolysaccharide alone. IL-6 mRNA was detected by RT-PCR, 15 min after stimulation with lipopolysaccharide of either P. gingivalis or F. nucleatum. GM-CSF supplementation with lipopolysaccharide of P. gingivalis shortened the transcription of IL-6 mRNA to 5 min, a shift which was not observed with lipopolysaccharide of F. nucleatum, possibly indicating a different mechanism of initiation of transcription. Production of IL-6 by GM-CSF-treated THP-1 cells in the presence of lipopolysaccharide of oral microorganisms may provide a model for studying the role of macrophages in acute and chronic periodontal diseases, including the clinical periodontal exacerbation as observed in chemotherapy patients receiving GM-CSF for bone marrow recovery. PMID- 10093533 TI - The relationship between salivary histatin levels and oral yeast carriage. AB - Candida species are common commensal inhabitants of the oral cavity. Human saliva contains antifungal proteins called histatins. We tested the hypothesis that oral yeast status is related to salivary histatin levels. Thirty subjects were divided into two groups based on the presence (n = 15) or absence (n = 15) of yeast on oral mucosa surfaces. Unstimulated and stimulated submandibular and sublingual and parotid saliva was collected from each subject. Salivary flow rates were measured and histatin concentrations were determined in the stimulated saliva samples. The yeast colony positive group showed lower median unstimulated parotid saliva flow rates as well as lower median concentrations of total histatins in submandibular and sublingual saliva. There was a negative correlation between yeast colony-forming units and unstimulated parotid saliva flow rates and between yeast colony-forming units and submandibular and sublingual saliva histatin concentration and secretion. The results suggest that oral yeast status may be influenced by unstimulated parotid saliva flow rates and by submandibular and sublingual histatin concentration and secretion. PMID- 10093534 TI - Ribotype diversity of Actinomyces with similar intraoral tropism but different types of N-acetyl-beta-D-galactosamine binding specificity. AB - Sixty-three isolates of Actinomyces naeslundii genospecies 1 and 2 and Actinomyces odontolyticus from three subjects clustered into 22 ribotypes. Unique ribotypes were found in the subjects and within individual tissue sites (bucca, tooth and tongue). A odontolyticus ribotypes shared tongue-specific binding properties, while those of genospecies 1 and 2 from buccal and tooth surfaces shared different types of N-acetyl-beta-D-galactosamine binding specificity. PMID- 10093535 TI - Current classification of the oral streptococci. AB - The classification of the oral streptococci has long remained a difficult area of streptococcal taxonomy. This article reviews the current classification of these bacteria into four species groups, and each group is described in detail. The often confusing changes that have taken place in the classification, identification and nomenclature of the member species are reviewed against a historical background of gradually improving techniques and approaches, leading towards a natural classification based primarily on genotypic evidence. Identification schemes currently in use employing biochemical tests are also reviewed, together with alternative molecular approaches. PMID- 10093536 TI - Effect of low-molecular-weight chitosans on the adhesive properties of oral streptococci. AB - It was previously shown that a low-molecular-weight chitosan and its derivatives N-carboxymethyl chitosan and imidazolyl chitosan inhibit Streptococcus mutans adsorption to hydroxyapatite. The ability of the same molecules to interfere with adhesive properties of other oral streptococci (Streptococcus sanguis, Streptococcus gordonii, Streptococcus constellatus, Streptococcus anginosus, Streptococcus intermedius, Streptococcus oralis, Streptococcus salivarius, Streptococcus vestibularis) was tested. When saliva-coated or -uncoated hydroxyapatite beads were treated with N-carboxymethyl chitosan, a reduction varying from 60% to 98% depending on strains was observed. Low-molecular-weight chitosans and imidazolyl chitosan did not have any effect. Growth in N carboxymethyl chitosan-supplemented medium (final concentrations ranging from 20 to 500 micrograms.ml-1) caused a dose related reduction in the adsorption of all strains to hydroxyapatite and in their affinity towards xylene. No effect was observed with low-molecular-weight chitosans and imidazolyl chitosan. In contrast to what observed with S. mutans, the three polysaccharides did not affect detachment from hydroxyapatite beads and adherence to cheek epithelial cells of the other streptococci. These results suggest that low-molecular-weight chitosans and/or imidazolyl chitosan, selectively affecting S. mutans adsorption to hydroxyapatite, may be very interesting as potential anti-dental caries agents. PMID- 10093537 TI - Active cytomegalovirus infection in human periodontitis. AB - This study used the reverse transcription polymerase chain reaction method to determine mRNA transcription of subgingival human cytomegalovirus (HCMV) in six adult and three localized juvenile periodontitis patients. The oligonucleotide primers targeted the major capsid protein gene to determine active HCMV infection. HCMV major capsid protein transcript was detected in deep periodontal pockets of two adult and two localized juvenile periodontitis patients but not in any shallow periodontal sites. The findings suggest that active HCMV replication can occur in periodontal sites. Further studies are necessary to establish whether periodontal reactivation of HCMV correlates with the initiation or progression of destructive periodontal disease. PMID- 10093538 TI - Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in young Chinese adults. AB - The aim of this study was to determine the presence or absence of Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in young Chinese adults and to examine the A. actinomycetemcomitans isolates from positive subjects with regard to the serotype distribution, presence of the leukotoxin gene lktA and the promoter for the leukotoxin operon as well as the incidence of phage Aa phi 23. Sixty subjects, working in a knitting factory in the Province of Guangzhou, People's Republic of China, were investigated. Subgingival microbial samples were taken from both upper first molars. They were cultured both anaerobically and in 5% CO2. P. gingivalis was found in 33 subjects. On average, it constituted 7% of the total anaerobic cultivable counts. A. actinomycetemcomitans was detected in 37 subjects of which seven yielded counts > 10(5). Twenty-one subjects were positive for both organisms. A. actinomycetemcomitans serotype a was found in 9 subjects, serotype c was found in 23 and serotype e in 5. A. actinomycetemcomitans serotypes b and d were not detected in any subjects. Presence of the leukotoxin gene lktA was demonstrated for all A. actinomycetemcomitans isolates; however, none of the A. actinomycetemcomitans strains from the present study had a deletion in the promoter region of the leukotoxin operon. The results of this investigation show a high frequency of the putative periodontal pathogens P. gingivalis and A. actinomycetemcomitans and corroborate the concept that there is variation in virulence and pathogenic potential among isolates from different subjects. PMID- 10093539 TI - Detection of clonotypic changes of T cells after stimulation with Porphyromonas gingivalis. AB - The aim of this study was to investigate whether Porphyromonas gingivalis stimulation would induce a selective activation and expansion of a limited T-cell receptor V beta repertoire or T-cell clonotype. Using samples from patients with chronic inflammatory periodontal diseases, we examined TCRBV gene usage and T cell clonotypes of peripheral blood mononuclear cells incubated in the presence or absence of P. gingivalis outer membrane through a combination of reverse transcription polymerase chain reaction (RT-PCR) and subsequent single strand conformation polymorphism (SSCP) analysis. There was no difference in the mean expression for most BV families with or without P. gingivalis outer membrane in the culture. However, in individual cases, a few BV gene families did become overexpressed or underexpressed following stimulation, although a consistent pattern did not emerge. SSCP analysis showed that several new distinct bands appeared after stimulation, indicating distinct clonal accumulations, although the number of distinct bands decreased in most cases. These data suggest that clonotypic change occurred following stimulation with P. gingivalis outer membrane. Furthermore, the possibility of superantigen stimulation by P. gingivalis is unlikely to be due to the small change in BV gene usage and clonal T-cell accumulations with P. gingivalis outer membrane stimulation, as evidenced by SSCP. Thus, RT-PCR and SSCP analysis is useful in evaluating the host response to periodontopathic antigens. PMID- 10093540 TI - Immunochemical detection of CD14 on human gingival fibroblasts in vitro. AB - The activation of monocytes and macrophages induced by lipopolysaccharide has been shown to contribute to the binding of lipopolysaccharide and lipopolysaccharide-binding protein complex to the cell surface CD14 molecule. To clarify the mechanism of the lipopolysaccharide-induced modulation of the function of gingival fibroblasts, we investigated the effect of anti-CD14 on interleukin 6 (IL-6) production on human gingival fibroblasts in vitro. Immunochemical staining revealed weak positivity for CD14 on fibroblasts from healthy gingiva, while strong positivity for CD14 was found on fibroblasts from inflamed gingiva. Western blot profiles of the fibroblasts and monocytes showed a CD14-positive reaction at 55 kDa. Fluorescein isothiocyanate-conjugated Escherichia coli lipopolysaccharide bound to fibroblasts more strongly in the presence of 10% fetal bovine serum than without serum. This binding, as well as IL-6 production, was blocked by anti-CD14 monoclonal antibody. The results showed that CD14 was present on human gingival fibroblasts, which suggests that lipopolysaccharide modulation of gingival fibroblast function depends on CD14. PMID- 10093541 TI - Characterization of lymphocyte subpopulations in periapical lesions by flow cytometry. AB - The mechanisms by which the bacterial root-canal infection leads to periapical bone destruction (cysts or granulomas) are not yet well understood. Previous works have shown elements of an active immune response in the lesions. In the present study, flow cytometry was used to improve the characterization of immune cells. Semiquantitative immunohistochemical analysis showed the presence of plasma cells, macrophages and B and T cells. The simultaneous use of several antibodies in flow cytometry allowed a more precise phenotype of the lymphocytes. The cysts displayed an abundance of B lymphocytes at the same time as a relative scarcity of CD8+ cells. CD4+ lymphocytes were the dominant lymphocyte population in most cases. A small number of gamma delta T lymphocytes and natural killer cells was found. These preliminary results show that flow cytometry may be used to characterize immune cells from inflamed tissue and opens the possibility for further functional studies. PMID- 10093542 TI - Distribution of interleukin-2 receptor alpha-chain and cells expressing major histocompatibility complex class II antigen in chronic human periapical lesions. AB - In situ distribution of CD2+ T-lymphocytes, CD4+ and CD8+ T-cell subsets, CD14+ macrophages, interleukin-2 receptor alpha-chain (IL-2R alpha) and class II major histocompatibility complex antigen (major histocompatibility complex class II, HLA-DR) expressing cells were determined in 14 chronic human periapical granulomas by immunohistochemical method using monoclonal antibodies. CD2+ lymphocytes were rather evenly distributed within the classical granulation tissue and comprised 55% of the mononuclear cells. Macrophages were distributed all over the periapical area, but their proportion was much less than that of T lymphocytes. Both small, lymphocyte-like mononuclear cells and larger mononuclear cells resembling macrophages displayed mild to strong circumferential staining with the anti-HLA-DR antibody. The majority of lymphocytes expressed IL-2R alpha indicating the activated state of T cells within the lesion. PMID- 10093543 TI - Defining form and position. PMID- 10093544 TI - Selecting the appropriate core material for immediate post and core buildup. PMID- 10093545 TI - Geometric considerations in anterior dental aesthetics: restorative principles. AB - While aesthetics is traditionally regarded as an artistic concept, quantifiable scientific principles are used in its development. Dental aesthetics are governed by mathematical parameters that, when applied by the clinician and laboratory technician, can achieve restorations with a unique aesthetic appearance. These geometric laws should not be viewed as immutable, but as useful guidelines for the fabrication sequence. This article demonstrates a series of geometric principles for the anterior maxillary dentition that can be utilized in the development of aesthetic restorations. PMID- 10093547 TI - Incorporating advanced procedures in a conventional practice. PMID- 10093548 TI - Pseudo realignment of maxillary anterior teeth with all-ceramic components. PMID- 10093546 TI - Utilization of advanced metal-ceramic technology: clinical and laboratory procedures for a lower-fusing porcelain. AB - Metal-ceramic restorations remain the most widely accepted type of indirect restorative modality, and have been applied successfully for years. Recent advances in material science have resulted in the development of a new class of metal-ceramic materials that have been termed lower-fusing ceramics. Following proper procedures for preparation and metal framework design, these metal-ceramic porcelains achieve the aesthetics normally demonstrated by conventional all ceramic restorations. This article provides an overview of the clinical and laboratory processes utilizing these materials and is illustrated by two case presentations. PMID- 10093549 TI - Dental injuries as a result of air bag deployment. PMID- 10093550 TI - Replacement of a mutilated maxillary incisor with a single implant restoration: a staged treatment. PMID- 10093551 TI - Direct posterior composite resin restorations: current concepts for the technique. AB - Due to the development of sound clinical procedures and evolution of advanced restorative materials, composite resins are being used with increasing frequency for direct posterior applications. When the clinical protocol for the use of composite resin is performed properly, this material can be utilized with success and predictability. This article presents the advantages and limitations of this restorative modality. It also reviews the characteristics of contemporary composite resin materials and demonstrates the treatment protocol that is utilized to achieve aesthetic restorations in the posterior segment. PMID- 10093552 TI - Intraoral camera systems and the contemporary dental practice. PMID- 10093553 TI - Working hard--or hardly working! PMID- 10093554 TI - SONICSYS approx: an innovative addition to the restorative continuum. AB - When cost and aesthetics form part of the treatment decision process, patients with Class II defects are invariably directed toward direct restorative options. Due to the mechanical stresses generated by polymerization shrinkage, direct composite resin restorations can be ineffective treatment modalities. One addition to the restorative continuum utilizes shaped, sonically driven, diamond coated preparation tips to adjust the cavity form to fit presized ceramic inlay restorations. This article introduces techniques that allow proper contacts and contour to be achieved utilizing this addition to the restorative continuum. PMID- 10093555 TI - Endodontic canal preparation: advances in rotary instrumentation. PMID- 10093556 TI - Single-tooth replacement in the aesthetic zone with immediate provisionalization: fourteen consecutive case reports. AB - The concept of osseointegration has been the subject of numerous investigations since it was originally introduced by Branemark. Researchers have attempted to further define and modify the surgical protocol for implant therapy, and have altered the length of healing, implant design, and the time of fixture placement in attempts to improve the efficacy and predictability of this restorative modality. This article demonstrates the use of an immediate placement procedure for restoring single teeth in the aesthetic zone, focusing on the maintenance of the hard and soft tissues in the region. PMID- 10093557 TI - Team implantology: a holistic approach. PMID- 10093558 TI - The interproximal height of bone: a guidepost to predictable aesthetic strategies and soft tissue contours in anterior tooth replacement. AB - Enhanced aesthetic objectives can be achieved with precision and predictability due to recent advances in restorative materials and procedures. Although these developments have expanded the therapeutic options available to practitioners and their patients, anterior hard and soft tissue deformities in the aesthetic zone continue to represent a significant technical challenge to the reconstructive team. The objective of this article is to present diagnostic and prognostic criteria that emphasize the osseous-gingival relationship as a means to achieve predictable aesthetic results in the anterior segment with conventional or implant-supported restorations. PMID- 10093559 TI - Internal bleaching with 10% carbamide peroxide in vitro. AB - This in vitro study assessed the efficacy of 10% carbamide peroxide to internally bleach discolored teeth. Following pulp removal, 38 tooth crowns were stained with erythrocytes and bleached 3 times over 14 days using either 10% carbamide peroxide or 30% H2O2 and sodium perborate. The pulp chambers were subsequently filled, and the tooth crowns stored for 3 months. The shades of the crowns were measured using reflectance spectroscopy prior to and at several time points following bleaching. Using statistical analysis, the authors determined that both materials significantly improved the shade of the crowns, and that 10% carbamide peroxide could be utilized clinically to internally bleach nonvital discolored teeth. PMID- 10093560 TI - Aesthetic implant restorations in partially edentulous patients: a technical note. PMID- 10093561 TI - Infrared thermographic analysis of temperature rise on implant surfaces: a pilot study on abutment preparation. PMID- 10093562 TI - We've got their attention! PMID- 10093563 TI - Transferring emergence profile created from the provisional to the definitive restoration. AB - One primary objective for implant therapy is the achievement of an aesthetic result, and this is significantly dependent upon the condition of the peri implant soft tissue and the implant emergence profile. The requisite for the configuration of the definitive crown is formulated by the provisional restoration, which transfers the position of the implant and the peri-implant soft tissue to the model utilized in the fabrication process. This article demonstrates the use of a provisionalization stage to precisely replicate the peri-implant tissue in the definitive restoration. PMID- 10093564 TI - An advancement in the delivery of local anesthesia. PMID- 10093565 TI - Lateralization of the inferior alveolar nerve with simultaneous implant placement: surgical techniques. AB - In the event of moderate to severe mandibular bone resorption posterior to the mental foramen, repositioning of the inferior alveolar nerve provides a greater amount of available bone for implant placement and reduces the risk of nerve injury. While neural paresthesia may initially occur, this altered sensation generally resolves spontaneously. Alveolar nerve repositioning may be possible in cases in which other procedures cannot be performed due to the extent of atrophy of the posterior mandibular alveolar crest. This article presents the surgical technique to achieve this objective. PMID- 10093566 TI - Soft tissue retraction with osseointegrated implants. PMID- 10093567 TI - Gingival-colored porcelain for implant-supported prostheses in the aesthetic zone. AB - Success in implant dentistry has evolved to include aesthetic excellence as well as functional longevity. Site development for optimal aesthetics is generally accomplished by surgical augmentation of hard and soft tissues. The results of osseous or gingival enhancement procedures are not always ideal, however, and some patients are unwilling to undergo additional surgical treatment. Use of tissue-colored porcelain is a nonsurgical option of hard and soft tissue replacement that provides lip support, restores symmetrical gingival architecture, and replaces lost papillae. The resulting prostheses can achieve or exceed the aesthetic expectations of these patients. PMID- 10093568 TI - Improved communication benefits provided by intraoral camera systems. PMID- 10093569 TI - [Benign proximal esophageal stenosis--mostly a complication of gastroesophageal reflux disease]. AB - BACKGROUND AND OBJECTIVE: Benign stenoses can occur anywhere in the oesophagus, but are most common in its distal part as a result of gastro-oesophageal reflux (GOR). It was the aim of this study to evaluate retrospectively the causes and incidence of benign stenosis of the proximal oesophagus (SPR) as well as its endoscopic and drug treatment. PATIENTS AND METHODS: Between December 1989 and December 1997 a total of 17,413 patients were referred to the authors' hospital for oesophago-gastroduodenoscopy, 1024 of them (6%) for clarification of heartburn, regurgitation and/or dysphagia. 53 of these patients (5%) were found to have benign stenosis of the oesophagus requiring bougie dilatation, located in the lower third in 29 (55%), in the middle third in six (11%) and in the upper third in 18 (34%) patients. Causes of stenosis in the upper third were peptic stricture in nine (50%), heterotopic gastric mucosa in three (17%), caustic corrosion in three (17%), post-radiation in two (11%), and the result of web formation in one (6%). Endoscopic bougie dilatation was performed in all these patients, those with GOR additionally receiving 40 mg omeprazole daily. RESULTS: In those patients with nonpeptic benign stenosis/stricture lasting improvement of symptoms was achieved with one to three dilatation. But those with GOR needed a mean of 13 dilatations during a follow-up period averaging 61 months. Barrett's oesophagus (replacement of squamous by columnar epithelium) was found in five patients. No case of dysplasia was discovered. Laparoscopic fundoplication was performed in one woman in whom bougie dilatation had failed. Remission was maintained, as needed, by bougie and omeprazole in eight patients. CONCLUSION: In benign stenosis of the upper oesophagus endoscopic dilatation is the treatment of choice. In cases of peptic aetiology the administration of proton pump inhibitors is the optimal adjuvant method. PMID- 10093570 TI - [Parotid swelling with night sweat, fever and weight loss symptoms. A rare differential diagnosis]. AB - HISTORY AND CLINICAL FINDINGS: A 29-year-old patient complained of recurrent swelling of the eyelids and cheeks, fever, diffuse headaches, night sweat and weight loss (8 kg during 8 weeks). Both parotid glands showed swelling which were solid, plain and non-painful to pressure. Palpation did not reveal enlarged lymph nodes. There were no other pathological findings except for anisocoria and disturbed motoric function of the right eye's pupil. INVESTIGATIONS: Laboratory findings, chest X-ray, abdominal sonography and ilium crest biopsy showed no signs of lymphoma or other tumour. MRT showed enlarged parotid glands and hypointensity of a few small (up to 2 cm) areas. Because of these findings Heerfordt syndrome with involvement of the third cranial nerve and the lacrimal glands was suspected and verified by parotid biopsy. TREATMENT AND COURSE: Under corticosteroid therapy started with 80 mg/d symptoms rapidly ceased. Therapy was continued for one year. 8 months after therapy had been stopped the patient had no complaints and investigations showed no signs of recurrence nor pulmonary or any other organ manifestation. CONCLUSION: If swelling of the parotid glands with night sweat, fever and weight loss occur, parotid biopsy should be performed early to exclude malignancy. With parotid gland biopsy also diagnosis of other diseases which have similar signs, such as Sjogren syndrome and parotid gland sarcoidosis, can be established early. PMID- 10093571 TI - [Kikuchi-Fusimoto disease: the differential diagnosis of cervical lymphadenitis with recurrent attacks of fever]. AB - HISTORY AND CLINICAL FINDINGS: A 49-year-old, otherwise healthy woman had recurrent fever and lymphadenopathy with leukopenia for nineteen years. Her symptoms prompted successless antibiotic therapy and extensive evaluations of fever of unknown origin. At admission there were several enlarged cervical lymph nodes and subfebrile temperatures. INVESTIGATIONS: Neither laboratory findings nor imaging did show an infectious, rheumatologic or hematologic cause of her symptoms. Histopathological examination of an lymph node biopsy revealed histiocytic, necrotizing lymphadenitis (Kikuchi-Fusimoto disease) as the underlying disease. TREATMENT AND COURSE: After spontaneous resolution without specific therapy the patient is now symptomless and well 9 months after diagnosis. CONCLUSION: Kikuchi-Fusimoto disease is a cause of benign and usually self-limiting lymphadenopathy. Clinicians and pathologists should be aware of this uncommon differential diagnosis since early histologic recognition will minimize potentially and unnecessary evaluations and treatments. PMID- 10093572 TI - [The therapy of the parkinsonian syndrome]. PMID- 10093573 TI - [Telomerase--its potential and limits for clinical applicability]. PMID- 10093574 TI - [Drug development in oncology. Its status and outlook with special consideration of the position of Germany]. PMID- 10093575 TI - [Helicobacter pylori screening in a general practice]. AB - BACKGROUND AND OBJECTIVE: The significance of Helicobacter pylori (Hp) infection in asymptomatic persons is largely unknown. This prospective study was undertaken to evaluate the diagnostic and, if appropriate, therapeutic relevance of a noninvasive screening for Hp. In addition, the practicality and validity of a simple serological test on whole blood was elucidated. PATIENTS AND METHODS: 100 consecutive patients (29 males, 71 females, median age 46 [18-79] years) of a general medical practice, seen in November of 1997, were included. Three patients had to be subsequently excluded, because they had been treated for Hp infection. All patients were given a standard interview after which a serological whole blood test (BM-Test Helicobacter pylori; Boehringer Mannheim) and a 13C-urea breath test were performed as noninvasive reference. Endoscopy of the upper gastrointestinal tract was offered if the serology and/or the breath test were gative. RESULTS: The Hp prevalence was 40%, rising significantly with age. The rapid serology test, when related to the breath test, had a negative and positive predictive value of < 80%. 44 of the 47 patients with a positive serological or breath test agreed to endoscopy. Eleven of them had a clinically significant abnormality macroscopically or histologically: four of them were found to have an Hp infection. CONCLUSIONS: Asymptomatic Hp-positive persons frequently have clinically abnormal findings in the upper gastrointestinal tract. These data point to the need for a large multi-centre study with cost-effect analysis to evaluate a noninvasive Hp screening test in nonsymptomatic persons as a public health measure. The 13C-urea breath test would be suitable as such a screening method. PMID- 10093576 TI - [A long-term organic brain syndrome and brain stem symptoms in an undiagnosed dialysis-associated encephalopathy]. AB - HISTORY AND CLINICAL FINDINGS: A 73-year-old woman in renal failure for the past 22 years had been on haemodialysis for 16 years. Because of hyperphosphataemia and peptic ulcers she had been on aluminium-containing antacids with a total intake over time of about 8 kg "pure" aluminium. Over the past 11 years she had biphasic symptoms of death anxieties and depression. She also had amnesic aphasia and some extrapyramidal symptoms as well as generalized convulsive seizures and recurrent falls. INVESTIGATIONS: Cranial computed tomography merely revealed signs of a microangiopathy and an age-related decrease in brain volume. The EEG showed intermittent changes while the CSF and ECG were unremarkable. There was no benzodiazepine or ethanol in the blood. TREATMENT AND COURSE: After excluding stroke with secondary epilepsy, uraemic encephalopathy was assumed to be the cause of the severe organic psychiatric syndrome. In the last few days before her death the patient had disturbance of consciousness and of breathing. She died during grotesque tossing movements, thought to be due to a brain stem stroke. Autopsy revealed high-grade myocardial hypertrophy caused by the hypertension, contracted kidney of vascular cause, hyperplasia of the parathyroid and calcification of the renal parenchyma as a sign of secondary parathyroidism. The CNS showed severe dialysis-associated encephalopathy with characteristic argyrophilic, aluminium-induced lysosomal intracytoplasmic inclusions in the choroid plexus epithelium, cortical glia and numerous neuron populations. Laser microprobe mass analysis (LAMMA) confirmed manifold increase in subcellular aluminium content, especially in the neuronal cytoplasm, also demonstrated by atom absorption spectrometry. Additional distinct deposition of beta A4-amyloid, typical of Alzheimer's disease, was probably age-related rather than associated with the dialysis and the aluminium uptake. CONCLUSION: Dialysis-associated encephalopathy must be taken into account as a possible cause of aetiologically uncertain neuropsychiatric symptoms in patients on chronic haemodialysis. PMID- 10093578 TI - [Mitochondrial medicine: human chromosome 25 and mitochondrial diseases]. PMID- 10093577 TI - [Metastatic breast carcinoma with neuroendocrine differentiation--its combined therapy with tamoxifen and the somatostatin analog octreotide]. AB - HISTORY AND ADMISSION FINDINGS: A 75-year-old woman with histologically confirmed liver metastases from an undiagnosed primary tumor was admitted for further diagnosis and treatment. She had no symptoms and was in a very good general condition. The physical examination was unremarkable. INVESTIGATIONS: The liver enzymes GOT and GPT were slightly elevated. The carcinoembryonic antigen (CEA) and the erythrocyte sedimentation rate (ESR) were markedly raised. Repeat analysis of the liver biopsies revealed a carcinoma with neuroendocrine differentiation (carcinoid). TREATMENT AND COURSE: Chemoembolization of the advanced liver metastases was undertaken. Subsequently the breast tumor was resected. Histological analysis revealed a mammary carcinoma with neuroendocrine differentiation. Postoperative radiotherapy to the breast was instituted and she was started on tamoxifen (30 mg daily). But despite repeat chemoembolization the liver metastases continued to grow. Administration of octreotide, a somatostatin analogue, was begun (200 micrograms twice daily). There were no side effects; the tumor markers showed definite reduction and scintigraphy demonstrated almost complete regression. Computed tomography indicated a dissociated response of the liver metastases to the treatment (some got smaller, one had grown and several new ones had appeared). CONCLUSION: Combined tamoxifen and octreotide treatment of a metastasizing carcinoma of the breast with neuroendocrine differentiation may give effective palliation. PMID- 10093579 TI - [The diagnosis of the parkinsonian syndrome]. PMID- 10093580 TI - [Selective denervation with the botulinum toxin as a therapeutic principle in the gastrointestinal tract]. PMID- 10093581 TI - Clinical manifestations of Parkinson's disease. AB - Although the clinical manifestations of PD remain similar to those described by Parkinson in the nineteenth century, knowledge of associated findings has increased dramatically. The ability to characterize the myriad of findings associated with PD enables clinicians to care better for patients with PD. Knowledge of the associated symptoms as well as the cardinal manifestations allows clinicians to target treatment to specific symptoms and thereby improve the quality of life of those affected with PD. PMID- 10093582 TI - Differential diagnosis of Parkinson's disease. AB - The differential diagnosis of PD includes other neurodegenerative disorders; hereditary disorders; and symptomatic causes, such as structural lesions, infections, metabolic abnormalities, hydrocephalus, and drugs or toxins. A good history of symptom evaluation, drug use, and family illness is just as essential as a careful neurologic examination when evaluating a patient with parkinsonism. Although there is no definitive diagnostic test for PD at this time, tests to rule out other causes should be considered and then treatment started. PMID- 10093583 TI - Progressive supranuclear palsy. AB - Richardson observed an unusual clinical syndrome in the 1950s, which he later designated progressive supranuclear palsy (PSP). Over the past 25 years, although knowledge of this disorder has gradually improved, its cause is still unknown, pathogenesis is unclear, and there is still no definitive treatment for this disorder. This article reviews the epidemiology, clinical features, diagnostic criteria, neuropathology, neuroimaging, and treatment of PSP. PMID- 10093584 TI - Multiple system atrophy. AB - MSA is a complex disorder, with regard to its pathology and cause as well as its clinical diagnosis and treatment. Although a number of clinical treatments may improve quality of life for these patients, given the widespread pathology present, symptomatic treatment, particularly that involving neurotransmitter replacement, is likely to remain difficult. Truly effective treatment for these patients is likely to depend on an understanding of the underlying pathogenic mechanisms and methods to halt or reverse disease progression. A firm understanding of the classification of these disorders is the first step to understanding the relevant pathogenic mechanisms. The finding of intracytoplasmic glial inclusion bodies provides a compelling piece of evidence that SND, OPCA, and SDS do, in fact, belong to one nosologic entity. These inclusions do not seem to be present in familial cases of OPCA; thus, they may provide a means to improve diagnostic specificity as well as sensitivity. With the ability to define clearly the entity of MSA, an understanding of the pathophysiology can be developed along with other degenerative neurologic diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. PMID- 10093585 TI - Management of early Parkinson's disease. AB - The two major questions in the treatment of early PD are (1) Does selegiline slow neuronal loss and delay the progression of clinical disability? and (2) Should dopamine agonists be used as initial symptomatic therapy in early disease rather than levodopa/PDI to reduce long-term disability and delay the onset of motor fluctuations and dyskinesia? Selegiline affords neuroprotection for dopamine neurons in cell culture systems and the results of several clinical trials are consistent with the hypothesis that it is neuroprotective in Parkinson's disease. Several clinical trials have found that initial symptomatic therapy with dopamine agonist to which levodopa/carbidopa is later added when needed leads to a lower incidence of long-term motor complications. These strategies are now being tested in prospective, randomized, blinded trials, many of which include PET or SPECT scans to assess the rate of dopamine neuron loss. These trials will provide more definitive answers to guide the early medial management of Parkinson's disease in the future. PMID- 10093586 TI - Dopamine agonists. AB - Dopamine agonists have been used in the treatment of Parkinson's disease (PD) since the mid 1970s. With the approval of two new agents in 1997, the number available in the United States is up to four; bromocriptine, pergolide, pramipexole, ropinirole. These agents differ in dopamine receptor affinities and chemical structure, which, in turn, may possibly result in differences in efficacy tolerability and safety. Dopamine have historically been used in combination with levodopa in patients with advanced PD, but indicators are now expanding. With is expansion comes increasing controversy. This article reviews dopamine receptor pharmacology and the results of the clinical trials that have used for agonists available in the United States as well as a discussion of three minor agonists. PMID- 10093588 TI - Managing late complications of Parkinson's disease. AB - Treatment of parkinsonism becomes more difficult as the disease progresses, and results from increasing neuronal degeneration, side effects from antiparkinsonian medications, or most often, a combination of each. Neurodegenerative parkinson symptoms may result from substantia nigra destruction, or from other areas in the nervous system. These include the cortex (cognitive and psychiatric disorders), brainstem (bulbar abnormalities), intermediolateral cell column (autonomic disturbances), among others. Medication side effects produce motor fluctuations, dyskinesias, delirium, hallucinations, psychosis, orthostatic hypotension, sleep disorders, and a host of other well-recognized complications. This article is divided into sections concerning motor fluctuations, gait difficulty bulbar disturbances, autonomic disturbances, sleep disorders, cognitive disorders, and psychiatric disorders, and is an attempt to provide the reader with strategies for treating common complications in the advanced Parkinson's disease patient. PMID- 10093587 TI - Monoamine oxidase and catechol-O-methyltransferase inhibitors. AB - Despite advances in the treatment of PD, there remain significant unmet therapeutic needs. This is particularly true at the later stages of the disease when dopaminergic therapy is complicated by motor fluctuations and dyskinesias. Inhibition of dopamine metabolism is a valuable adjunct to exogenous dopaminergic replacement. Inhibitors of MAO-B have been used to treat early and advanced PD for a number of years. Although controversy remains, existing evidence still raises the possibility that MAO-B inhibition may confer a protective effect in PD, delaying the progression of the underlying pathology. More recently, clinically useful inhibitors of COMT have become available. These medications largely act peripherally to increase the pool of available dopamine precursor and prolong the duration of effect of L-dopa. They are indicated primarily for control of motor fluctuations. PMID- 10093589 TI - Surgical options in Parkinson's disease. AB - Surgical treatments for Parkinson's disease (PD) have again become important adjuncts of care in these patients. We have learned much from the thousands of lesions performed historically, and are now advancing the entire field of movement disorder surgery to new levels of sophistication and understanding. The last 5 years have seen more precise and reliable lesioning and the arrival of multiple sites of intervention afforded by recent developments in deep brain stimulators. Because patients typically derive significant benefit in their quality of life from these procedures, while undergoing little risk, the surgical options should be carefully considered for selected PD patients. PMID- 10093590 TI - Nonpharmacologic management strategies. AB - Nonpharmacologic management strategies for Parkinson's disease should focus on educating the patient and family, empowering them to take control over the disease through physical, occupational and speech therapy, exercise, and good nutrition. An educated understanding of psycho-social resources will enable the patient and family to develop strategies to cope with life style changes encountered in the successful management of Parkinson's disease. PMID- 10093591 TI - Neuroprotective therapies. AB - Though effective symptomatic therapies for Parkinson's disease exist, currently no treatment is proven to slow the progression of the underlying disease. Our growing understanding of the mechanisms of neuronal models, however, offers hope that neuroprotective strategies will soon be a standard part of the treatment of PD. Current approaches to the development of neuroprotective strategies are based on the hypothesized roles of oxidative stress and excitotoxicity in the degenerative process. In this article, we review evidence in support of these hypotheses as well as attempts to achieve neuroprotection in PD based on these and other mechanisms. PMID- 10093592 TI - Novel drugs for Parkinson's disease. AB - Treatment options in PD have expanded remarkably in the past several years. Three new drugs were approved for use in the United States just within the 9 months preceding the preparation of this article. Several new compounds are in the pipeline. Nevertheless, the unmet needs of PD patients are readily apparent in any busy clinical practice. These needs can be posed as three deceivingly simple questions: 1. When and how should L-dopa be started? Despite the fact that L-dopa remains the mainstay of PD therapy after 30 years' time, lacking is a fundamental understanding of proper usage and avoidance of long-term complications. 2. What can be done about cognitive decline and dementia in PD? The current answer is nothing. Efforts are just beginning to fill this large void in knowledge and provide adequate treatment for this disabling problem. 3. How can PD be prevented? This question cannot be answered because the cause of PD remains uncertain. The dearth of substantive information available on this topic is evidenced in this article. The bulk of text appears under the heading Symptomatic Treatments, whereas only a few speculative comments can be offered under the heading Preventive Treatments. The paramount need for expanded resources and dedicated efforts to identify the causes and devise preventions must be met if advances in the treatment of PD are to be made in the twenty-first century. PMID- 10093593 TI - Restorative gene therapy approaches to Parkinson's disease. AB - Perhaps one of the most exciting developments in brain research of the past decade is the advent of genetic intervention in human neurologic disease. Although there are a variety of gene transfer approaches, none of which has been perfected, gene therapy is now science fact and no longer science fiction. As technology progresses, some vectors will prove more effective for certain disease categories than others; it is too early to predict definitively which vector would be most effective for therapy in Parkinson's disease and other movement disorders. Nonetheless, it is likely that within the next year or two a gene therapy trial will be instituted in human patients with Parkinson's disease. The potential for an impact on the symptoms and progression of this disease is significant. Clinicians may be on the threshold of a new era of intervention for Parkinson's disease and other neurologic diseases, based on bypassing traditional but less selective drug-extracellular receptor interactions and instead focusing on genetic modulation of specific intracellular processes. The continuing development of small incremental changes of new dopamine agonists and pharmacologic agents will likely pale in comparison to the specificity of intracellular genetic manipulation. PMID- 10093594 TI - [Discontinuing protease inhibitor treatment of HIV-1 patients for intolerance. Longitudinal study of 309 patients]. AB - OBJECTIVES: Determine the frequency and nature of interruptions in HIV-1 protease inhibitor treatment in HIV-infected patients. PATIENTS AND METHODS: A longitudinal study included patients treated with antiretroviral protocols including at least one antiprotease and followed from 1 March 1996 through 1 March 1998. RESULTS: Among the 309 patients followed for the duration of the study, 137 (44.3%) interrupted their antiprotease treatment at least once. Withdrawal was warranted by therapeutic failure in 49.6% of the cases and by drug intolerance in 45.4%. Drug intolerance concerned 37%, 36.7%, 5.7% and 2.9% of the patients taking ritonavir, indinavir, nelfinavir and saquinavir respectively (p < 106). Multivariate analysis demonstrated that saquinavir was significantly associated with better tolerance and with efficacy at least as good as ritonavir or indinavir. The most frequent cause for interrupting treatment were digestive disorders for ritonavir (20% of the treated patients) and lithiasic manifestations for indinavir (9.4%). The ritonavir-hepatitis C association appeared to predispose to drug-induced perturbed liver tests. CONCLUSION: Drug intolerance is a frequent cause of treatment interruption. Therapeutic success in HIV infection requires improved efficacy but also better tolerated antiretorviral drugs, particularly antiretroviral drugs. PMID- 10093595 TI - [Community-acquired bacterial meningitis in the Loire-Atlantic region: evolution of pneumococcal and meningococcal sensitivity to penicillin]. AB - OBJECTIVES: An epidemiological study of community-acquired bacterial meningitis was conducted in Loire-Atlantique in subjects aged over 1 month. Risk factors and changes in pneumococcal and meningococcal susceptibility to betalactams were analyzed. PATIENTS AND METHODS: All cases of proven or presumed bacterial meningitis registered by Loire-Atlantic bacteriology laboratories between May 1995 and April 1998 were analyzed. RESULTS: One hundred two cases were registered (annual incidence: 3.12 cases per 100,000 inhabitants). In children (33 cases) the main germs were meningococci (51%), pneumococci (24%) and Haemophilus influenzae (6%). In adults (69 cases), pneumococci (49%), meningococci (14%) and Listeria (4%) predominated. An underlying disease was noted 44% of the cases. Mortality was 17.6%. Sequellae were observed in 9.5%. Some degree of penicillin resistance was observed in 45% of the pneumococcal strains and in 50% of the meningococcal strains. Half of the pneumococcal strains were also resistant to third generation cephalosporins (C3G). No risk factor was significantly related to resistant strains. Susceptibility to antibiotics was not correlated with mortality for either pneumococcal or meningococcal strains, but sequellae were more frequent after meningitis caused by resistant pneumococci. CONCLUSION: For cases of community-acquired meningococcal meningitis diagnosed in 1999, it would be advisable to prescribe a combination C3G-vancomycin regimen as the first line empirical treatment while waiting for results of susceptibility tests. Certain guidelines proposed by the February 1996 consensus conference on community acquired purulent meningitis would thus need to be amended. PMID- 10093596 TI - [Severe forms of rubella encephalitis: arguments for a better vaccination policy]. AB - BACKGROUND: Two cases of rubella encephalitis in young adults are reported. CASES REPORTS: 2 patients, 19 and 16-year-old, presented with severe encephalitis. One required mechanical ventilation. Neither were vaccinated against rubella. MRI scan of the brain was normal. The diagnosis was confirmed by serology. Good recovery was noted in both patients. DISCUSSION: Both cases of rubella encephalitis occurring in young adults illustrate the severity of this rare disease. As already shown in Finland, improvement with the French vaccination policy should lead to the prevention of rubella encephalitis. PMID- 10093597 TI - [Pulmonary nocardiosis with fatal outcome, complicating bronchiectasis]. PMID- 10093598 TI - [Malaria and pulmonary tuberculosis: a booster effect of malaria on tuberculosis?]. PMID- 10093599 TI - [Chemoprophylaxis and persistent infection]. PMID- 10093600 TI - [Discontinuation of antiretroviral treatment containing a protease inhibitor. Failure and tolerance]. PMID- 10093601 TI - [Systemic antibiotic therapy in current practice: ENT and lower respiratory tract infections]. PMID- 10093602 TI - [Antibiotic therapy in ENT and respiratory tract infections: emergency recommendations]. PMID- 10093603 TI - [Immunologic reconstruction after antiretroviral treatment]. AB - DATA FAVORING IMMUNE RECONSTITUTION: Multiple drug therapies for HIV infection have enabled a major reduction in the viral load, higher CD4 counts, and a lower incidence of opportunistic infections and tumor formations, and subsequently lower hospitalization rates and mortality. TWO STAGES OF CD4 RECONSTITUTION: In HIV-positive patients with advanced stage disease treated with a protease inhibitor associated with 2 nucleoside analog reverse transcriptase inhibitors and followed prospectively, it has been observed that CD4 counts rise considerably, with a rapid increase during the first 2 months followed by a slower but still positive slope over a period of 18 months. Discordant results have however also been observed suggesting an ineffective anti-viral effect or a retarded immune reconstitution. SEVERAL MECHANISMS: The lymphocyte amplification observed during the early phase corresponds to re-circulation of CD4 and CD8 lymphocytes which had been sequestered in lymphoid organs; most of these CD4 lymphocytes are memory cells. A second phase corresponds to a more moderate and progressive rise in naive CD4 cells which originate from an unknown source. This biphasic reconstitution of CD4 lymphocytes is associated with a correction of the chronic lymphocyte overactivation. PARTIAL IMMUNE RECONSTITUTION: With treatment, the capacity to respond to known antigens reappears. This restored capacity is secondary to the amplification of CD4 memory cells and appears prior to the expansion phase of naive cells. The response remains moderate and is only observed against antigens from microorganisms highly prevalent during advanced stage infection. PMID- 10093604 TI - [Bartonella infection in humans]. AB - BARTONELLA BACILLIFORMIS: Among the 3 species of Bartonella known to be human pathogens, B. bacilliformis causes Carriun's disease, which manifests an acute phase (Oroya fever) and a chronic phase marked by benign skin eruption with wart like macules of vascular origin. Until 1993, B. bacilliformis was considered to be the only species in Bartonella genus. In 1993, species formally in the Rochalimaea genus were designated as Bartonella species. BARTONELLA QUINTANA: This species causes trench fever. It is also the causal agent in cases of bacillary angiomatosis, septicemia, endocarditis with negative blood cultures, and chronic nodal infections, particularly in immunosuppressed patients. Trench fever is transmitted by body lice and is becoming more prevalent, particularly in the homeless. BARTONELLA HENSELAE: This agent causes bacillary angiomatosis, visceral peliosis, septicemia, endocarditis and cat-scratch disease. Transmitted by cats, and perhaps by lice, cat-scratch disease is one of the most frequent zoonoses. OTHER SPECIES: The spectrum of Bartonella infections has continued to widen these last 5 years. The role of B. elizabethae and C. clarridgeiae as human pathogens remains to be defined [abstract corrected] PMID- 10093605 TI - [Tropheryma whippelii, an emerging intracellular pathogen causing Whipple disease]. AB - CLINICAL DIAGNOSIS: Whipple's disease is a diffuse disease with a wide variety of clinical manifestations. Differential diagnoses include chronic enteritis, chronic joint disease, chronic meningoencephalitis and prolonged fever with weight loss, chronic uveitis and endocarditis with negative blood culture. MOLECULAR DIAGNOSIS: Histologically the characteristic lesions contain PAS positive inclusions. PCR of RNAr gene 16S in fresh tissue identifies Tropheryma whippelii and confirms bacteriological diagnosis. AN EMERGING PATHOGEN: Tropheryma whippelii is a recently identified pathogen highly difficult to culture. Since its discovery, it has been a model of emerging pathogens. Clinical observation, microscope studies, molecular and cellular biology, and bacteriology have all contributed to its recent isolation which should lead to the development of indirect diagnostic techniques [abstract corrected] PMID- 10093606 TI - [Current microbiologic problems. Pulmonary infection by Streptococcus pneumoniae. Current physiopathological aspects]. AB - STILL A SERIOUS DISEASE: Despite advances in antibiotic therapy, and despite the emergence of beta-lactam-resistant strains, mortality of pneumococcal pneumonia has remained relatively unchanged. The pathogenicity of a pneumococcal strain results from an interaction between a specific host with its own capacity to "resist or yield" to the multiple virulence factors intrinsic to each S. pneumoniae strain. ROLE OF THE CAPSULE: The capsule is the pneumococci's principal arm of resistance against the host's defense systems. There is a wide variability depending on the capsule serotype. Inversely, the capsule plays no role in triggering the inflammatory reaction which is secondary to substances released from the bacterial wall such as teichoic acid and peptidoglycan. HOST RESPONSE: The molecular mechanisms of cellular activation and induction of proinflammatory cytokines triggered by S. pneumoniae follow similar pathways which are different from those for endotoxin triggered by Gram negative bacteria. PERSPECTIVES: A better understanding of the clinical expression, distinguishing simple nasopharyngeal carriage from bacterial pneumonia should lead to the design of new therapeutic agents which will reduce the capacity of certain S. pneumoniae strains to invade the host and trigger deleterious inflammatory reactions. PMID- 10093607 TI - [Current microbiological problems. Antibiotic resistance and therapeutic problems raised by Pseudomonas aeruginosa]. AB - RESISTANCE: Pseudomonas aeruginosa is characterized by its low intrinsic susceptibility to many antibiotics and its capacity to acquire additional resistance mechanisms to usually active drugs. Some beta-lactam resistance mechanisms are well known (penicillinase production, cephalosporinase overproduction) and others have been recently identified, such as active efflux systems, which confer coresistance to quinolones, and new beta-lactamases which are limited to a few countries (extended-spectrum beta-lactamases, imipenemase). Ceftazidime remains the most active beta-lactam agent. ACTIVE DRUGS: Among aminoglycosides, amikacin and isepamicin are the most frequently active drugs. The use of fluoroquinolones is limited by a high incidence of acquired resistance. The percentage of resistant strains is highly variable according to countries, hospitals and wards. CLINICAL PRACTICE: Therapy, usually based on a beta-lactam-aminoglycoside combination, will be empirical at first, according to local epidemiological factors, site of infection and previously administered antibiotics, then re-evaluated according to susceptibility results. PMID- 10093608 TI - [The aftercare of radiotherapy patients. The Radiation Protection Commission, the Federal Ministry for the Environment, Nature Protection and Reactor Safety]. PMID- 10093609 TI - Low hemoglobin is associated with increased serum levels of vascular endothelial growth factor (VEGF) in cancer patients. Does anemia stimulate angiogenesis? AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell specific mitogen with strong angiogenic activity. Expression of VEGF may therefore be an indicator for the angiogenic potential and biological aggressiveness of a tumor. Recently, measurement of the VEGF-protein in sera has become available. We report results of serum-VEGF in an unselected group of patients with cancer with special emphasis on a possible role of anemia. PATIENTS AND METHODS: Between August 1997 and January 1998, serum-levels of VEGF were determined in a total number of 54 consecutive patients with previously untreated, non-metastatic carcinomas at the Department of Radiotherapy at the Martin-Luther University Halle-Wittenberg. The age ranged from 35 through 89 years with a median age of 67 years. All patients had locoregional confined disease without evidence of hematogenous metastases. Tumor sites were gynecological cancers in 22, head and neck in 14, gastrointestinal in 13, lung in 4 and prostate in 1 case. Forty-four patients had squamous carcinomas and 10 adenocarcinomas. Prior to treatment, routine laboratory work-up was done including measurement of serum-vascular endothelial growth factor (VEGF). The pretreatment hemoglobin ranged from 8.9 through 15.6 g/dl with a median of 13 g/dl. VEGF was measured with a quantitative sandwich enzyme immunoassay technique. RESULTS: The serum levels of VEGF in 40 patients with benign diseases ranged from 57 through 891 pg/ml with a mean of 267 +/- 170 pg/ml. In the investigated 54 cancer patients, VEGF ranged from 62 through 2,609 pg/ml with a mean of 614 +/- 551 pg/ml. Age, UICC/FIGO-stage, T- or N-category, primary tumor site, grade and histologic type had no significant impact on VEGF-serum levels. There was, however, an association between hemoglobin level and serum-VEGF with an increased mean serum-VEGF in 26 patients with a low hemoglobin (< 13 g/dl) as compared to 28 patients with a hemoglobin > 13 g/dl (805 +/- 656 vs 438 +/- 360, p = 0.016, 2-sided t-test). CONCLUSIONS: With regard to the recently established correlation between anemia and intratumoral hypoxia, the increased serum-VEGF levels in patients with low hemoglobin may be explained via hypoxia-induced VEGF secretion. This would suggest that anemia may stimulate angiogenesis via hypoxia. The hypothesis, however, requires further investigation and might have important therapeutical impact. PMID- 10093610 TI - Concomitant radiochemotherapy with 5-FU and cisplatin for invasive bladder cancer. Acute toxicity and first results. AB - PURPOSE: To evaluate acute toxicity and efficacy of simultaneous radiochemotherapy for invasive urothelial cancer of the bladder. PATIENTS AND METHODS: From September 1993 to July 1997, 61 patients with invasive bladder cancer were treated with a transurethral resection (TURB) followed by radiochemotherapy (RCT). Twenty-five received a combination of 5-FU and cisplatin. The prescribed doses were 600 mg/m2 5-FU daily as continuous infusion over 5 days each in the 1st and 5th treatment week and 20 mg/m2 cisplatin daily at the same days as a short infusion. The pelvis was irradiated with 54 Gy, the bladder with 59.4 Gy and the paraaortic nodes in 7 cases with 45 Gy, respectively. Six to 8 weeks after RCT a second TURB was performed for reasons of restaging. RESULTS: Twenty out of 25 patients received at least 80% of the prescribed chemotherapy, in 13 cases the full dose could be given. Gastrointestinal toxicity of Grade I and II occurred in 10 cases, 1 patient developed severe diarrhea (Grade VI). After the 1st course of chemotherapy 7 patients had leuko- or thrombopenia of Grade III. One patient had a leucopenia of Grade IV. After the 2nd course 4 patients developed Grade III leuko- and thrombopenia, 1 of Grade IV. Two Grade II anemia were found. All more severe toxicities and necessary dose reductions were related to radiation of the paraaortic nodes. No life threatening infections, bleedings or cardiotoxicity was found. Restaging TURBs resulted in 22 complete remissions, 1 patient had a de novo-carcinoma (Tis) at this time, 2 were non-responders (8%). After a median follow-up of 38 months 20 patients are alive (80%). CONCLUSIONS: 1. If irradiation of paraaortic nodes is necessary, 5-FU should not be applied, because the gastrointestinal toxicity is too extensive. In all other cases side effects are tolerable and can be managed by supportive care. 2. The first results are promising and should be evaluated in a prospective study. PMID- 10093612 TI - Radiotherapy for intracranial and spinal ependymomas. A retrospective analysis. AB - BACKGROUND: The low incidence of ependymomas results in limited treatment experience. While standard therapy consists of surgery and postoperative radiotherapy, irradiation techniques are still subject to discussion. We report the experience from Munster over the last 35 years. PATIENTS AND METHODS: Since 1961, 25 evaluable patients with ependymoma were irradiated in Munster: 17 intracranial and 8 spinal tumors. Fourteen of 25 patients underwent subtotal resection. Fifteen of 25 patients were treated by local irradiation, 10 of 25 with large-field techniques (whole-brain/cranio-spinal irradiation) and an additional tumor boost. The median tumor dose amounted to 50 Gy (16 to 65 Gy). Sites of recurrence were analyzed and correlated with the irradiated region. RESULTS: Twelve recurrences were observed. Six of 12 could be exactly related to the irradiation portals and were found well inside the local or boost fields. The remaining 6 tumors also recurred locally; whether they were in-field or field margin recurrences was not to be discerned by the imaging available at the time. No out-field recurrences or spinal seeding were observed. For 8 of 17 locally irradiated patients with intracranial ependymomas, 5 local recurrences were recorded. In 9 of 17 patients receiving whole-brain or cranio-spinal irradiation, 6 local recurrences were found. Two of 8 spinal tumors recurred locally. CONCLUSIONS: All tumors recurred within the former tumor bed. In the remaining cranio-spinal axis no recurrences or metastases were found. Similar results are reported from current literature. The value of large-field techniques (whole brain/spinal irradiation) is to be questioned. Modern methods like IORT or stereotactic radiotherapy might be able to deliver a higher tumor dose without increasing toxicity. PMID- 10093611 TI - [Angiosarcoma of the right atrium: local control via low radiation doses and razoxane. A case report]. AB - BACKGROUND: Angiosarcomas of the heart are rare neoplasms bearing an unfavorable prognosis. In recent series, the median survival is about 5 months. The response to radiation therapy is uncertain. CASE REPORT: A 65-year-old copper smith with an angiosarcoma of the right atrium and metastases of the liver received a partial resection of the primary tumor in January 1992. This was followed by a polychemotherapy including ifosfamide, epirubicin and dacarbacin (DTIC). In April 1992, after 5 cycles of this treatment a large regrowth of the primary and multiple pulmonary metastases were observed. After a 4-day pretreatment with the radiosensitizer razoxane, the large tumor of the right heart was irradiated with 25 MV photons of a linear accelerator. Single doses of 200 cGy were given via parallel opposed fields. The total radiation dose at the tumor was 30 Gy. Concomitantly, razoxane was given at a dose of 125 mg twice daily during the radiation days until the end of the radiotherapy. The treatment was well tolerated and the patient went into a subtotal remission. Chest X-rays from September 1992 revealed a progression of the metastases in the lung and the liver, the recurrent tumor of the right atrium remained in a subtotal remission. The patient was retreated with ifosfamide, epirubicin and DTIC. No substantial remission of the metastases occurred and the patient died at the end of January 1993. At autopsy, the recurrent primary and the lung metastases within the region of the former radiation field remained locally controlled. CONCLUSION: Reviewing the literature and considering this case, irradiation seems to be a valid treatment option for the local control of cardiac angiosarcomas. The combination of radiotherapy with razoxane eventually allows a considerable reduction of the radiation dose. PMID- 10093613 TI - [The effect of adjuvant radiotherapy on the mental health of female patients with a breast-conserving operated breast carcinoma]. AB - BACKGROUND: In literature there are only few informations about the influence of postoperative irradiation on the psychological health of breast cancer patients treated by breast-conserving surgery. However, psychological distress and anxiety related to irradiation are often observed. Purpose of our study was the evaluation of the influence of radiotherapy-induced distress in these patients. PATIENTS AND METHODS: Between October 1995 and June 1996 in 48 breast cancer patients (31 to 76 years old) treated by breast-conserving surgery adjuvant irradiation with or without systemic therapy was applied. On the first and the last day of radiotherapy they were given a questionnaire (Table 1) which was designed together with psychologists. Covering different situations related to radiotherapy the construction of items are determined by factors with possible influence on psychological distress and perception with regard to irradiation. RESULTS: Most of the women (92%) stated to be well informed about the irradiation and tried to obtain further information about this treatment (83%). 56% tried not to think about radiotherapy and/or to distract themselves (81%). 40% were anxious about the fact to undergo irradiation. In the end of treatment 77% reported to have been anxious only initially or never; only 19% were anxious almost or most of the time. 35% were worried about the expected cosmetic alterations of their breast; only 30% observed acute cosmetic changes. With regard to situation related distress all patients (100%) stated that the communication with the medical staff made it easier to stand the irradiation treatment. CONCLUSIONS: In spite of theoretical considerations our results are explorative in character. However, following statements seem to be important: 1. A large requirement exists to get information about radiotherapy. 2. The patients experience irradiation treatment more positive than initially expected by themselves. 3. With regard to radiotherapy anxiety is reduced during the course of treatment. Here the psychosocial care of the medical staff is an important support for reduction of anxiety. PMID- 10093614 TI - [Radiotherapy of the elderly patient. Radiotherapy tolerance and results in older patients]. AB - BACKGROUND: Despite a growing number of elderly patients receiving radiation therapy little is known about side effects and outcome of irradiation in this section of the population. METHODS: In a review article epidemiologic data, aspects of radiation-biology as well as side effects and outcome of radiation therapy of elderly patients are discussed. RESULTS: Cancer incidence rises with age (Figure 1) and is exceeding 3.5% for males older than 85 years. With a life expectancy of more than 4 years, curative therapy is indicated even at this age. Furthermore several retrospective studies indicate that local control and disease Specific survival after radiation therapy of elderly patients is comparable with that of younger persons (Tables 3 and 4). The exception contains elderly patients with Grade-III to IV gliomas or with rectal carcinoma who show a reduced survival which is perhaps caused by less aggressive combined treatment (tumor resection). Although some biological and molecular data indicate a rise in radiation sensitivity with growing age like the reduction of the capacity of some DNA repair enzymes, there is no convincing evidence in animal studies or in retrospective clinical studies that radiation therapy is generally less well tolerated by older individuals (Tables 1 and 2). Some age-depending differences in organ toxicities are described in 3 large studies, which evaluate the data of patients who were enrolled in different EORTC-trials: Older patients suffer more of functional mucositis in case of radiation therapy to the head and neck, they have an increased weight loss and a higher frequency of late esophageal damage when irradiated in the thorax, and they show a higher prevalence of sexual dysfunction when treated with radiation therapy to the pelvis. On the other hand younger patients suffer more from acute toxicity like skin damage, nausea, and deterioration of the performance status during pelvic radiotherapy. When discussing the dose intensity of radiation therapy concomitant disease which leads to extensive atherosclerotic vessel damage should be kept in mind. Old patients should be monitored closely during therapy, since the loss of electrolytes or fluid is often not very well tolerated. CONCLUSION: The indication to radiation therapy of elderly cancer patients should take into account their performance status as well as the extent and the severity of comorbidity. Age per se is seldom a contraindication for radiation therapy. Regarding the available data in literature there is no indication for a dose reduction in radiation therapy only because of age, especially in the curative setting. PMID- 10093615 TI - [CT densitometry for the grading of subcutaneous fibrosis after the photon neutron therapy of malignant salivary gland tumors]. AB - BACKGROUND: To evaluate alternative treatment regimen e.g. neutron therapy determination of treatment efficacy as well as side effects is important. Sensitivity of computed tomography (CT) in detecting changes of connective tissue after neutron therapy was examined. PATIENTS AND METHODS: In the course of their follow-up period (median 45 months) 12 patients with malignant salivary gland tumors who had postoperatively received neutron (1/12) or photon/neutron therapy (11/12) were examined by means of CT densitometry on 3 representative scans in the area of radiotherapy. In 3 ROI (regions of interest) in subcutaneous fatty tissue the density at the irradiated and the non-irradiated side was determined according to Hounsfield units (HU) and the average density was calculated. The average density of both sides was compared and correlated with the clinical grade of fibrosis according to LENT SOMA. RESULTS: All CT measurements (216 ROI, 18 ROI per patient) showed higher density levels on the irradiated side than on the non irradiated side. The average density on the irradiated side was -57.7 +/- 4.7 HU and on the non-irradiated side -69.4 +/- 5.8 HU (p = 0.002). In 3/12 patients a clinical fibrosis was not seen; however, the relative density measured on the irradiated and non-irradiated side deviated by up to 8%. This could have been caused by minimal changes not being noticed by either patient and examiner. In patients with determined fibrosis Grade 1 (8/12) the relative density deviation was 4 to 39%. In 1/12 patients with determined fibrosis Grade 2 the relative density deviation was 50% (Figures 1a and 1b). Fibrosis Grade 3 and 4 did not occur (Table 1). CONCLUSIONS: Fibrosis is correlated with an increasing value of HU of the tissue density in CT. With the described method it is possible to graduate radiation induced subcutaneous fibrosis in correlation to the clinical fibrosis grade according to LENT SOMA. In the patients we examined subcutaneous fibroses after photon/neutron therapy were moderate. Especially in characterising subclinical or slight changes of connective tissue after radiotherapy computed tomography is of value. PMID- 10093616 TI - [Postoperative radiotherapy in curatively resected non-small-cell bronchial carcinoma]. PMID- 10093618 TI - Sun safety knowledge and behaviour: new data on which to build. PMID- 10093619 TI - Canadian National Survey on Sun Exposure & Protective Behaviours: methods. AB - This article describes the methods used for the 1996 Canadian National Survey on Sun Exposure & Protective Behaviours. A 55-item random-digit-dialling telephone household survey of people 15 years of age or more was completed in 1996. Items assessed were daily sun exposure and protective behaviours, as well as other sun related behaviours and attitudes. Data were collected regarding sun-related behaviours during leisure, work time and winter holidays, as well as for children 12 years of age or less (as reported by parents). To test for an effect on the survey response rate, a letter of introduction was sent to 40% of the households. The survey response rate was 69% (4023 successfully completed surveys out of 5847 households included in the sample). The response rate achieved in the subset that received the introductory letter was 75%. This survey is the first to establish national population estimates for sun exposure and protective behaviours in Canada. PMID- 10093620 TI - Canadian National Survey on Sun Exposure & Protective Behaviours: adults at leisure. AB - OBJECTIVE: To describe the prevalence of sun exposure and protective behaviours during leisure time among Canadian adults 25 years of age or more. DESIGN: A random-digit-dialling telephone household survey of 4023 people 15 years of age or more was completed; 3449 adults 25 years of age or more responded to questions about sun exposure and protective behaviours from June to August 1996. RESULTS: Many of the adults (51%) reported getting 30 minutes to 2 hours of daily sun exposure, and 26% reported getting more than 2 hours. Half (50%) reported having one or more sunburns during the study period; 21% said they actively spent time suntanning. Less than half reported taking adequate protective actions. Women, light-complexioned and adults 65 years or more were more likely than men, medium- or dark-complexioned adults and adults in younger groups to protect themselves. Nearly two-thirds (63%) of the adults said they forgot to take protective actions, 47% felt it was inconvenient to do so, and 29% were not concerned about sun exposure. DISCUSSION: Canadian adults, especially younger men, are exposed to significant amounts of sun during summer leisure time, but they do not always protect themselves adequately. Interventions should emphasize and facilitate convenient, effective sun protection strategies. PMID- 10093621 TI - Canadian National Survey on Sun Exposure & Protective Behaviours: youth at leisure. AB - OBJECTIVE: To describe the prevalence of sun exposure and protective behaviours during leisure time among Canadian youth 15 to 24 years of age. DESIGN: A random digit-dialling telephone household survey of 4023 people 15 years of age or more was completed in 1996; 574 youth responded to questions about their sun exposure and protective behaviours from June to August 1996. RESULTS: Half of the youth (51%) reported 30 minutes to 2 hours of daily sun exposure, and 36% reported more than 2 hours. A large proportion (68%) reported sunburns. The prevalence of sun protective actions ranged from 38% for wearing a hat to 26% for both seeking shade and avoiding the sun between 11 am and 4 pm. There were sex differences in sun-related behaviours among youth. DISCUSSION: The large proportion of Canadian youth who reported sun exposure and the small proportion who reported taking protective actions suggest the need for primary prevention. Interventions should address sex differences and focus on multiple methods of protection. PMID- 10093622 TI - Canadian National Survey on Sun Exposure & Protective Behaviours: parents' reports on children. AB - OBJECTIVE: To describe the prevalence of sun exposure and protective behaviours among Canadian children 12 years of age or less, as reported by their parents. DESIGN: A random-digit-dialling telephone household survey of 4023 people 15 years of age or more was completed in 1996; 1051 parents responded to questions about their children's sun-related behaviours from June to August 1996. RESULTS: Most children (89%) had 30 minutes or more of daily sun exposure, and many of them (45%) had sunburns. The prevalence of sun protective actions ranged from 36% for avoiding the sun to 76% for using sunscreen. Parental reports on sun protection for children 5 years of age or less differed significantly from reports for children 6 to 12 years old. DISCUSSION: High levels of sun exposure among Canadian children suggests the need for protection. Use of multiple methods of sun protection should be emphasized to parents, school personnel, recreation staff and child-care workers. PMID- 10093623 TI - Workshop report: research, policy and program planning on sun protective behaviours. PMID- 10093624 TI - Sun safety behaviours of alpine skiers and snowboarders in the western United States. AB - Skin cancer is epidemic. Sun safety behaviours of skiers and snowboarders have not been investigated despite prolonged exposure at high altitudes. A sample of 156 adult alpine skiers and snowboarders at 14 high-altitude ski resorts in the western United States were interviewed during 1996-97 to ascertain their sun protective actions and exposure. Few of the adults said they received any messages over their entire lifespan regarding sun safety while skiing or snowboarding. Sun protective behaviour was variable: it was negatively associated with being male, younger, a snowboarder, exposed to prevention messages, and being in cold, windy and cloudy weather, and positively related to chair-lift elevation, skin sun sensitivity and prior sunburning while skiing or snowboarding. Prevention programs should target the young, males, novices and snowboarders, and advocate protection throughout the season and during inclement weather. PMID- 10093625 TI - Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast Cancer Disease Site Group and the Provincial Systemic Treatment Disease Site Group. AB - GUIDELINE QUESTION: How effective is epirubicin compared with doxorubicin in the treatment of metastatic breast cancer? OBJECTIVE: To make recommendations about the use of epirubicin, particularly compared with doxorubicin, in women with metastatic breast cancer. OUTCOMES: Outcomes of interest are response rate, survival and toxicity. PERSPECTIVE (VALUES): Evidence was reviewed and summarized by a member of the Provincial Systemic Treatment Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. Drafts of the practice guideline were reviewed and discussed by the Breast Cancer DSG of the Cancer Care Ontario Practice Guidelines Initiative. The 2 DSGs comprise medical oncologists, radiation oncologists, surgeons, epidemiologists, pathologists, nurses, pharmacists, a medical sociologist and a community representative. QUALITY OF EVIDENCE: Thirteen randomized controlled trials (11 published reports and 2 reports in abstract form) were reviewed that compared epirubicin and doxorubicin at equal doses, epirubicin at a higher dose than that of doxorubicin, and epirubicin at escalating doses. BENEFITS: No significant differences were observed in response rate or median survival in the 7 trials comparing equal doses of epirubicin and doxorubicin or in the 3 trials comparing epirubicin at a higher dose than that of doxorubicin. An increased response rate was observed with higher doses of epirubicin in the 3 trials that compared escalating doses; no difference in survival was observed. HARMS: Compared with doxorubicin, epirubicin was associated with less nausea and vomiting (risk ratio [RR] 0.76; 95% confidence interval [CI] 0.63 to 0.92; p = 0.0048), less neutropenia (RR 0.52; 95% CI 0.35 to 0.78; p = 0.0017) and less cardiotoxicity (RR 0.43; 95% CI 0.24 to 0.77; p = 0.0044), including a trend toward fewer episodes of congestive heart failure (RR 0.38; 95% CI 0.14 to 1.04; p = 0.059). PRACTICE GUIDELINE: For the treatment of metastatic breast cancer in which the goal of treatment is palliation, epirubicin (at doses equivalent to doxorubicin) has been shown to be equally efficacious and less toxic than doxorubicin. Doxorubicin, however, is an acceptable alternative. CLINICAL PRACTICE GUIDELINE DATE: Oct. 2, 1997. PMID- 10093626 TI - The long-awaited drop in prostate cancer mortality: what does it mean? PMID- 10093627 TI - The need to invest in health services research. PMID- 10093628 TI - Quebec prostate cancer mortality dropped in 1996. AB - OBJECTIVE: To monitor incidence and mortality rates of prostate cancer in the province of Quebec. DESIGN: Population-based incidence and mortality trends. SETTING: Entire population of the province of Quebec between 1979 and 1996. MAIN OUTCOME MEASURES: Age-standardized incidence rates and mortality for prostate cancer. RESULTS: Prostate cancer mortality increased regularly until 1989, were stable between 1989 and 1995 and dropped in 1996 by 15%. Incidence rates increased steadily from 1989 until 1993 by an average of 9% per year. CONCLUSION: The rise in incidence is due to the increasing use of prostate specific antigen as a screening test for prostate cancer. The reasons for the reduction in prostate cancer mortality are unknown but are likely to reflect improved treatment modalities. PMID- 10093629 TI - How interested is the public in genetic testing for colon cancer susceptibility? Report of a cross-sectional population survey. AB - OBJECTIVE: To assess the public's interest in genetic testing for colon cancer susceptibility, to determine whether provision of information about the accuracy of the test or the population risk of inheriting the colon cancer gene influences interest, to determine the reasons for wanting to be tested and to identify the factors related to interest in testing. DESIGN: A cross-sectional random digit dialing telephone survey of 501 adults. SETTING: Ontario. MAIN OUTCOME MEASURES: Proportion of the public interested in genetic testing; reasons for interest in testing. RESULTS: Of the sample, 39.9% (95% confidence interval [CI] 35.5 to 44.3) stated that they would be very interested in taking a simple blood test if a positive result suggested they had an 80% chance of getting colon cancer sometime during their lifetime. When it was suggested that the test might be accurate only 90% of the time, 33.1% of the sample (95% CI 28.7 to 37.5) still said they would be very interested in testing. When informed that less than 1% of the population inherits the gene for colon cancer, the proportion of the sample stating they would still be very interested in genetic testing fell to 19.2% (95% CI 14.8 to 23.6). The main reasons given for wanting genetic testing were to take preventive action, for peace of mind and curiosity. For respondents who remained interested in testing after being given information about the population risk of inheriting the gene, 2 factors were identified by logistic regression analysis as being independently related to interest: worry about cancer and perceived risk of getting colon cancer. CONCLUSIONS: If the public's interest in testing for colon cancer susceptibility has any influence on its eventual request to be tested, then demand for genetic testing may be considerable once such tests become widely available and known to the public. This study reveals that the public's interest in genetic testing is substantial, although modifiable by the provision of information about the population risk of inheriting a colon cancer gene. This finding suggests that genetic researchers and others should be careful to provide the population risk of inheriting cancer genes when discussing the discovery of these genes with the media. Furthermore, public health educators will need to ensure that information aids include material on familial risk criteria, genetic counselling and genetic testing, as well as on the implications of genetic testing, the general population risk of developing colon cancer and the general population risk of carrying the colon cancer gene. This information should also be provided to those who seek assessment, to health care professionals and to the public. PMID- 10093630 TI - Health services research in breast cancer: background paper for a Canadian Breast Cancer Research Initiative workshop. AB - OBJECTIVE: To describe a systematic review of breast cancer health services research that was conducted to guide a Canadian Breast Cancer Research Initiative workshop. DESIGN: A literature review of major citation databases was conducted. The National Cancer Institute of Canada Framework for Cancer Control was adopted to classify articles by theme area and by type of health services research. RESULTS: The majority of the studies focused on screening for breast cancer and were descriptive studies on accessibility. Relatively few studies examined quality and outcomes of breast cancer services or interventions to improve such services. Furthermore, few health services research studies examined the areas of supportive care or palliation. CONCLUSIONS: The results help to identify the gaps in the Canadian and international research in this area. The material from the review was used as background for a workshop to support the work of the Canadian Breast Cancer Research Initiative Task Force on Health Services Research. PMID- 10093631 TI - Use of granulocyte colony-stimulating factor (G-CSF) in patients receiving myelosuppressive chemotherapy for the treatment of cancer. Provincial Systemic Treatment Disease Site Group. AB - GUIDELINE QUESTIONS: 1) Does G-CSF reduce the incidence of important adverse clinical outcomes due to infections in patients with cancer treated with myelosuppressive therapy? 2) Does G-CSF allow maintenance of the chemotherapy dose with the goal of improving survival? OBJECTIVE: To evaluate the evidence for the role of G-CSF in patients receiving myelosuppressive chemotherapy for the treatment of cancer. OUTCOMES: Clinical outcomes reflecting events that may affect quality of life and/or resource utilization (e.g., rates and duration of hospitalization, antibiotic use); outcomes reflecting the effect of treatment on infection rates, tumour response and survival and those related to the biological effect of G-CSF. PERSPECTIVE (VALUES): Evidence was selected, reviewed and synthesized by members of the Provincial Systemic Treatment Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. Drafts of this document have been circulated and reviewed by members of the Systemic Treatment DSG. The DSG comprises medical oncologists, pharmacists, supportive care personnel and administrators. Evaluation by clinicians was considered in the final practice guideline. Community representatives did not participate in the development of this report but will in future reports. Guidelines approval does require participation by community representatives. QUALITY OF EVIDENCE: Two published guidelines and an update of one guideline were identified. Ten eligible randomized controlled trials published in English were included. BENEFITS: A meta analysis of data from 8 trials showed that the odds of experiencing febrile neutropenia with G-CSF were significantly reduced (odds ratio 0.38; 95% confidence interval [CI] 0.27 to 0.52; p < 0.00001). G-CSF reduced the risk of febrile neutropenia by 34% (risk ratio 0.66; 95% CI 0.51 to 0.86; p = 0.0015). The use of G-CSF was associated with a significant reduction in antibiotic usage and days spent in hospital in 2 trials and had no effect in the other 4 in which it was measured. Five trials reported no difference in overall median survival, with 2 small trials detecting a significant increase related to G-CSF. However, further research is necessary to confirm these results. HARMS: The toxic effects of G-CSF are relatively mild. The most consistent clinical symptom attributed to G-CSF is bone pain, reported in incidence rates ranging from 20% to 50% in 3 trials. Except for one case, reported bone pain was mild. PRACTICE GUIDELINE: In cancer patients receiving myelosuppressive chemotherapy, granulocyte colony stimulating factor (G-CSF) may be beneficial for some patients. If a reduction in the number of febrile neutropenic episodes, or in the duration of such episodes, is expected to improve quality of life, then G-CSF is a reasonable treatment option for selected patients. A clear justification for the use of G-CSF should be stated. If the objective of using G-CSF is to maintain dose intensity of antitumour agents, then G-CSF can be recommended where reduction in dose intensity has been shown in randomized controlled trials to reduce survival or disease-free survival. Although the evidence is weaker, the Systemic Treatment DSG would support the practice endorsed by other guidelines (American Society of Clinical Oncology, Ontario Drug Benefit Plan) and would recommend G-CSF for patients receiving potentially curative chemotherapy: i) as primary prophylaxis; that is, where dose reductions below a specified level are required because of a known high risk of febrile neutropenia, or ii) as secondary prophylaxis in patients receiving chemotherapy of established efficacy who have suffered a prior serious episode of febrile neutropenia due to the same chemotherapy regimen. The exact cut-off for dose reductions is unknown at this time and ought to be left to the judgement of the clinician. In general, the use of G-CSF for dose reductions lower than 20% is not recommended. (ABSTRACT TRUNCATED) PMID- 10093633 TI - Developing a cervical screening information system. PMID- 10093632 TI - Best supportive care. PMID- 10093634 TI - Socioeconomic status and cancer incidence and survival. PMID- 10093635 TI - Psychological distress associated with organized breast cancer screening. AB - Regular breast cancer screening with the use of mammography for asymptomatic women is the most effective method for the early detection of breast cancer. Although the health and economic implications of breast cancer screening have received a great deal of attention, the psychological consequences of attending a breast screening program that includes mammography have been largely ignored. This article briefly reviews 10 studies that have examined the psychological distress associated with organized breast cancer screening. Anxiety appears to be the most prevalent consequence of mammography and seems to affect certain subgroups, with the most significant effects being among those women requiring further investigation because of abnormal results. The results of these studies, the research methods used and future directions in this area are discussed. PMID- 10093636 TI - Challenges of developing a cervical screening information system: the Ontario pilot project. AB - OBJECTIVE: To create a cervical screening information and reporting system in 2 geographic areas of Ontario. DESIGN: A pilot project involving access to, and linkage of, cervical screening-related cytology, colposcopy and histopathology records for women in the study areas, followed by development and production of woman-specific and aggregate reports. SETTING: Hospital cytology and pathology departments, colposcopy clinics, private cytology laboratories, and the provincial cancer agency (Cancer Care Ontario, formerly the Ontario Cancer Treatment and Research Foundation). MAIN OUTCOME MEASURES: Access to required records; data quality (i.e., standardization, completeness, accuracy); quality of record linkage; utility of reports to evaluators, data sources and physicians. RESULTS: The pilot project was not completed because of a number of major challenges, including multiple data sources requiring separate investigation and negotiations for access; variations in reporting terminology and coding; incompatibility or lack of computer systems; incompleteness of identifiers for record linkage; variation in legislation permitting data access and sharing and in its interpretation; and major financial, resource and time requirements. CONCLUSIONS: Although sufficient will and resources can overcome technical obstacles, changes in legislation will be required to overcome other challenges. Strong links with all sectors involved in cervical screening and attention to changes in the health care system are essential. PMID- 10093637 TI - Quality-of-life information and clinical practice: the oncologist's perspective. AB - OBJECTIVE: To collect information from a group of Canadian oncologists about their perspectives on quality of life (QOL) and QOL information. DESIGN: A self administered questionnaire (MD-QOL) containing 75 items with a 4-point Likert categorical response scale was administered by mail using Dillman survey methodology to all staff oncologists at a single institution. SETTING: A large Canadian cancer care centre (Princess Margaret Hospital, Toronto). MAIN OUTCOME MEASURES: Oncologists' knowledge, attitude, current behaviour and intended willingness to use QOL information. RESULTS: Of 67 eligible respondents 54 replied (80% response rate). In all, 74% felt that QOL can be quantified, and 95% felt that it gives information distinct from performance status measures. A total of 87% felt that published QOL data are useful for individual patient care, but 69% indicated that, at present, they would be more likely to base their recommendations on personal experience rather than on published literature. Of the respondents, 57% felt that decisions were made more difficult when QOL issues are considered. CONCLUSIONS: The surveyed oncologists support the relevance and importance of QOL information. Data from this study were used to develop a predictive model to assess oncologists' willingness to use QOL information; the model is being tested in other studies. PMID- 10093638 TI - Association between socioeconomic status and cancer incidence in Toronto, Ontario: possible confounding of cancer mortality by incidence and survival. AB - OBJECTIVE: To observe the association between socioeconomic status (SES) and cancer incidence in a cohort of Canadians. DESIGN: Cases of primary malignant cancer (83,666) that arose in metropolitan Toronto, Ont., from 1986 to 1993 were ascertained by the Ontario Cancer Registry and linked by residence at the time of diagnosis to a census-based measure of SES. Socioeconomic quintile areas were then compared by cancer incidence. RESULTS: Significant associations between SES and cancer incidence in the hypothesized direction--greater incidence in low income areas--were observed for 15 of 23 cancer sites. CONCLUSIONS: These findings, together with the recently observed consistent pattern of significant associations between SES and cancer survival in the United States and the equally consistent pattern of nonsignificant associations in Canada, support the notion that differences in cancer incidence alone explain the observed cancer mortality differentials by SES in Canada. The cancer mortality differential by SES observed in the United States is probably a function of differences in both incidence and length of survival, whereas in Canada such mortality differentials are more likely to be merely a function of differences in incidence by SES. This pattern of associations primarily implicates differences in the 2 health care systems; specifically, the more egalitarian access to preventive, investigative and therapeutic services available in the single-payer Canadian system. PMID- 10093640 TI - Metastasis Research Society VII International Congress (Part I). 7-10 October 1998, San Diego, CA, USA. AB - The first part of the congress, which mainly dealt with fundamental aspects of cancer invasion and metastasis showed how we have progressed in the understanding of the processes involved in both. It also became clear that there are several interesting targets for chemical intervention, particularly the inhibition of angiogenesis (according to the ideas of Folkman) which now seems to be a promising direction in which to push the fight against tumor growth, be it primary tumors or metastases. PMID- 10093641 TI - Metastasis Research Society VII International Congress (Part II). 7-10 October 1998, San Diego, CA, USA. AB - The Metastasis Research Society (MRS) has held its International Congress every two years since 1986, and alternates between European and North American meeting venues. The next MRS International Congress will be held in London, UK in the year 2000, and will be hosted by the current MRS President, Dr. Suzanne Eccles (Institute of Cancer Research, Sutton, UK). Dr. Eccles took over from the out going President, Dr. William Stetler-Stevenson (National Institutes of Health, Bethesda, MD, USA), at the San Diego meeting. Information on joining the Metastasis Research Society, which includes a subscription to the Society's journal, Clinical and Experimental Metastasis, can be obtained from Dr. Eccles (suzan@icr.ac.uk) or from the newly-elected Secretary/Treasurer Dr. Danny Welch (Hershey, PA, USA; drw9@psu.edu). The meeting was organized by Darwin Medical Communications Ltd (Gill Heaton, Oxford, UK), who have placed the full program on the meeting web site (http:@www.sparks.co.uk/mrs). It is envisaged that full abstracts of all the presentations will be placed on the Metastasis Research Society web site, which is currently under construction. Corporate sponsors for the San Diego meeting included Agouron Pharmaceuticals, Becton Dickinson & Co, Zeneca Pharma SA, Schering AG, AntiCancer Inc, Oncogene Research Products, Daiichi Seiyaku Co Ltd and Novartis Pharma AG. PMID- 10093642 TI - Effects on skeletal muscle fibres of diabetes and Ginkgo biloba extract treatment. AB - Combined cytophotometric and morphometric analysis of muscle fibre properties and myosin heavy chain electrophoresis were performed on extensor digitorum longus and soleus muscles from healthy rats and rats with streptozotocin-induced diabetes. Moreover, the protective effect of Ginkgo biloba extract, a potent oxygen radical scavenger, on diabetic muscles was investigated. Changes in fibre type-related enzyme activities, fibre type distribution, fibre cross areas and myosin isoforms were found. In muscles of diabetic rats, a metabolic shift was measured mainly in fibres with oxidative metabolism. Fast-oxidative glycolytic fibres showed a shift to more glycolytic metabolism and about a third transformed into fast-glycolytic fibres. Slow-oxidative fibres became more oxidative. Fibre atrophy was measured in diabetic muscles dependent on fibre type and muscle. Different fibre types atrophied to a different degree. Therefore, a decreased area percentage of slow fibres and an increased area percentage of fast fibres of the whole muscle cross section in both muscles were found. This is supported by reduced slow and increased fast myosin heavy chain isoforms. These alterations of diabetic muscle fibres could be due to less motion of diabetic rats and diabetic neuropathy. After treatment with Ginkgo biloba extract, enzyme activities were increased mainly in oxidative fibres of diabetic muscles, which was interpreted as protective effect. Generally, the soleus muscle with predominant oxidative metabolism was more vulnerable to diabetic alterations and Ginkgo biloba extract treatment than the extensor digitorum longus muscle with predominant glycolytic metabolism. PMID- 10093643 TI - Innervation of the fibro-elastic type of the penis: an immunohistochemical study in the male pig. AB - The occurrence and colocalization of several biologically active neuropeptides, catecholamine-, acetylcholine- or nitric oxide-synthesizing enzymes-tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (D beta H), choline acetyl transferase (ChAT) and nitric oxide synthase (NOS I), respectively, as well as the vesicular acetylcholine transporter (VAChT) were investigated in the penile glans (GP), corpus and crura (CP), as well as in the retractor penis muscle (RPM) of juvenile and adult boars. Immunohistochemistry revealed that nerves immunoreactive (IR) to TH, D beta H, vasoactive intestinal polypeptide (VIP) and somatostatin (SOM) were the most numerous, followed (in decreasing order of density) by nerves IR to NOS, neuropeptide Y (NPY), substance P (SP), calcitonin gene-related peptide (CGRP), galanin (GAL), Leu5-enkephalin (LENK) and ChAT/VAChT. The CP contained the largest number of nerve fibres followed by the RPM, GP and corpus. Enzyme/peptide-containing nerves were associated with both the vascular and non-vascular penile structures. However, differences existed for their density and intrapenile distribution. Nerve terminals IR for different combinations of VIP, GAL or SOM were more frequent than those IR for NOS or CGRP in the non-vascular penile structures while the vasculature and the RPM received a prominent TH/D beta H-, VIP-, SOM- or NOS-IR nerve input. The present data indicate that the porcine penis receives nerve fibres that exhibit diverse chemical codes and that differences in the chemical coding of the nerve fibres may depend on their penile target-structure. PMID- 10093644 TI - Distribution of apoptosis-related proteins in the quail ovary during folliculogenesis: BCL-2, BAX and CPP32. AB - It is suggested that follicular apoptosis is driven by the status of the BCL-2: BAX rheostat, and that CPP32 is a key effector of granulosa cell death. In the present study, we have immunohistochemically localized two BCL-2 family members, BCL-2 and BAX, and one caspase, CPP32, in the quail ovary during folliculogenesis. BCL-2 was predominantly found in the granulosa cells of developing follicles. BAX was detected in some follicular cells of atretic follicles, and in the nucleus of some prelampbrush oocytes. Expression of CPP32 was detected in leukocytes and in follicular cells of atretic follicles. Immunostaining was also found in interstitial cells, in surface epithelial and vascular endothelial cells, and in some thecal cells of post-ovulatory follicles. In the granulosa cells of non-growing and small prehierarchal follicles, a weak immunostaining was observed. We can conclude that in the avian ovary, BAX and CPP32 are involved in atresia. The present results support the BCL-2: BAX rheostat hypothesis. PMID- 10093645 TI - Zonal variation in the distribution of an alpha 1-acid glycoprotein glycoform receptor in human adrenal cortex. AB - Using a histochemical technique with three different alpha 1-acid glycoprotein glycoform one glycoform specific receptor has been identified in human adrenal cortex. The receptor is associated to alpha 1-acid glycoprotein glycoform B and alpha 1-acid glycoprotein glycoform C. The glycoform specific receptor was located in the cytoplasm of glomerulosa and outer fasciculata cells. The intensity of the reaction product decreased in the fasciculata, and no staining was seen in inner fasciculata and reticularis. Inhibition with the simple sugars, mannose and GlcNAc confirmed a lectin-like reaction. The binding activity was dependent on the presence of calcium ions and not on thiol reagents. Thus the lectin-like receptor may belong to the C-type lectin family. Using an antibody to alpha 1-acid glycoprotein the presence of alpha 1-acid glycoprotein was observed in the same location as the glycoform specific receptor. The binding of alpha 1 acid glycoprotein glycoform B and alpha 1-acid glycoprotein glycoform C to the glycoform specific receptor is inhibited by the steroid hormones cortisone, aldosterone, estradiol and progesterone but not by testosterone. The pronounced changes in the distribution of AGP and its glycoform receptors during cell differentiation in the adrenal cortex suggest that AGP and its complementary lectins belong to the group of lectins which control differentiation and spatial position. PMID- 10093646 TI - [Oxygen transport in septic patients]. PMID- 10093647 TI - [Oxygen delivery in sepsis. After 10 years more questions than answers]. AB - Object of this review is to present the physiological principles, diagnostic techniques and therapeutic options that are related to modifications of oxygen delivery in sepsis. Despite intense research activities in this area, many topics regarding oxygen transport and oxygen consumption in sepsis are still not clear. For example, the often discussed shift of the critical value of oxygen delivery to higher values in sepsis has not been proven, yet. Beside an impaired regional perfusion also disturbances in the cellular oxygen utilization may be responsible for organ failure in sepsis. Until now, it was not shown, whether the increase of oxygen delivery to supranormal levels reduces mortality in septic patients. It is also unknown, which catecholamine and which infusion solution is suitable for the treatment of septic patients. In future further research is necessary to solve the problems associated with sepsis therapy. PMID- 10093648 TI - [Postoperative nausea and vomiting following stabismus surgery in children. Inhalation anesthesia with sevoflurane-nitrous oxide in comparison with intravenous anesthesia with propofol-remifentanil]. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is still one of the major problems in strabismus surgery, especially in children. In recent years many studies have been published, suggesting that choosing propofol as the anaesthetic agent may help to reduce the high incidence of PONV in children undergoing strabismus surgery. Experience with remifentanil in children is still very limited and little is known, whether propofol in combination with this new short acting opioid is also superior regarding PONV in squint surgery compared to sevoflurane/N2O. Additionally, little is known, whether the type of operation or the muscle which is operated on has any influence with respect to PONV. METHODS: Following sample size estimation, ethics committee approval and parents informed consent in a prospective, randomised, observer-blind study 105 ASA I and II children aged 3-8 years scheduled for elective strabismus surgery were assigned into one of the following groups: Group TIVA (propofol/remifentanil, n = 53): anaesthesia was induced by remifentanil 0.5 microgram kg-1 min-1 over 2 min (loading phase), followed by 3 mg kg-1 propofol along with 30% O2 in air. After endotracheal intubation anaesthesia was maintained initially with remifentanil 0.25 microgram kg-1 min-1 and propofol 10 mg kg-1 h-1 by constant infusion. In the course of the operation the infusions of the anaesthetics were adjusted to the decreasing need for anaesthesia. Group VOLATIL (sevoflurane/N2O, n = 52): anaesthesia was induced by inhalation of sevoflurane along with 50% O2 in N2O. After endotracheal intubation anaesthesia was maintained with sevoflurane 1.0-1.5 MAC along with 30% O2 in N2O and in the course of the operation the administration of the inhaled anaesthetics was adjusted correspondingly. Preoperatively collected data included gender, age, weight and history of PONV. Intraoperatively collected data consisted of data belonging to routine monitoring (heart rate, blood pressure, peripheral oxygen saturation and temperature) as well as the duration of the operation and anaesthesia and specific data regarding the operation (including the number and type of muscles as well as the kind of operation). Data collected within the first 24 hours postoperatively in the recovery room and on the ward by blinded observers included any PONV events as well as the antiemetics and analgesics applied. RESULTS: Vomiting was observed less frequently in the TIVA-group than in the VOLATIL-group (21 of 53 vs. 32 of 52, p = 0.03) within the first 24 hours postoperatively. Posterior fixation suture ("faden-operation") compared to other operations was followed rather frequently by nausea and vomiting (30 of 44 and 33 of 44, respectively), whereas recessions were rarely associated with nausea and vomiting (12 of 35 and 9 of 35, respectively). CONCLUSIONS: TIVA with propofol/remifentanil proved to be a suitable form of anaesthesia for children in this setting. Propofol showed advantages over sevoflurane/N2O with respect to PONV after squint surgery in children also when applied in the combination with remifentanil. TIVA with propofol/remifentanil may therefore be one way to reduce the high incidence of PONV in this setting, bearing in mind, that PONV is not only influenced by the regimen of the general anaesthesia but rather by the combination of many other factors, in particular the type of operation. PMID- 10093649 TI - [Gamma-hydroxybutyrate for treatment of alcohol withdrawal syndrome in intensive care patients. A comparison between with two symptom-oriented therapeutic concepts]. AB - Seeing as gamma-hydroxybutyrate (GHB) and benzodiazepines interact with the GABA transmitter system, we investigated whether GHB can replace the conventional therapy, which uses benzodiazepines in the treatment of alcohol withdrawal syndrome in ICU settings. METHODS: 42 chronic alcoholics were included in this prospective and randomized study. Following the development of alcohol withdrawal syndrome, the patients were randomly allocated to the GHB or to the flunitrazepam group. In addition to this, clonidine was administered in order to treat autonomic signs of withdrawal. In cases were hallucinations occurred, haloperidol was administered. RESULTS: There was no significant difference in the efficacy of treatment used in the duration of mechanical ventilation and intensive care unit stay between groups. The patients in the GHB-group required significantly higher dosages of haloperidol and significantly lower dosages of clonidine. 14 out of 21 patients from the GHB-group developed hypernatriaemia and 15 out of 21 developed a metabolic alkalosis. CONCLUSIONS: Symptoms of the autonomic nervous system were more effectively prevented by GHB as evident in the lower dosage requirement of clonidine. However, GHB may not sufficiently block the hyperactivity of the dopaminergic system or may have an hallucinogenic effect itself. This may be evident from the higher dosages of haloperidol which were necessary. Due to the latter fact, the administration of GHB cannot be recommended in all patients suffering from AWS in ICU settings. PMID- 10093650 TI - [History of the development of intensive care medicine. Contemporary considerations. 3. Structural development of operative intensive care medicine. Part I]. PMID- 10093651 TI - [Ambulatory anesthesia: which preoperative screening tests are required]. AB - The volume of preoperative screening investigations for outpatient anaesthesia ranges from few, selectively ordered investigations to extensive routine diagnostic procedures. It seem appropriate to reevaluate benefit and efficacy of routine preoperative assessment programs. The purpose of preoperative diagnostic is to assess the risk of anaesthesia and surgery for the patient. As shown by a number of studies, preoperative screening investigations seldom disclose new pathological findings of clinical relevance. Abnormal laboratory results in otherwise healthy patients rarely alter the anaesthetic management of the patient and are not related to perioperative complications. Extensive use of costly diagnostic procedures considerably increases health care budgets. A more selective approach to order preoperative investigations promises considerable savings. To achieve costeffective evaluation an efficient organisation of properative assessment must be established to avoid costly delay and on day-of surgery-cancellations. There is no medicolegal obligation to perform routine diagnostic testing. The anaesthetist must be sufficiently informed in time to assess the perioperative risk of the patient and to alter anaesthetic management as necessary. According to the presented studies a clinical history and a through physical examination represent an effective method of screening for the presence of disease. Careful medical history evaluation and physical examination can avoid extensive investigations in apparently healthy individuals and the latter should only be ordered if indicated. PMID- 10093652 TI - [Can sevoflurane in everyday clinical use accelerate the timing of discharge. Commentary and reply on the paper of K. Hahnenkamp et al. Anaesthesist (1998) 47:335-338]. PMID- 10093653 TI - [Protection with heat and moisture exchange filter or a resterilizable filter from virus transmission]. PMID- 10093654 TI - [Spinal area regional anesthesia. Use of ADP antagonists or administration of direct thrombin inhibitors]. PMID- 10093655 TI - [Anesthesia in lung volume reduction]. PMID- 10093656 TI - [Anesthesia for geriatric patients. Pathophysiologic considerations]. PMID- 10093657 TI - [Intestinal complications of thrombotic microangiopathy in the adult. 4 cases and review of the literature]. AB - We report four cases of adult thrombotic microangiopathy associating diarrhea with severe ischemic colitis. In one case, the intestinal complications was severe and diffuse ischemic colitis, in two cases an inaugural colonic perforation requiring colectomy and in the last case a massive mesenteric infarct. In three cases, histologic examination showed vessel occlusion with microthrombi. Despite treatment with plasma exchange and plasma infusion, death ensued in two cases. Principally described in childhood thrombotic microangiopathy, intestinal complications occur exceptionally in adult thrombotic microangiopathy and are associated with a poor prognosis. Inaugural ischemic colitis revealing an adult thrombotic microangiopathy is also uncommon and thrombotic microangiopathy could be evoked in all patients presenting acute ischemic colitis. PMID- 10093658 TI - [The birth of the Medical Society of Hospitals of Paris]. PMID- 10093659 TI - [The clinical diagnosis in medicine]. AB - A physician's activity is not limited to, but does start at diagnosis. An accurate diagnosis requires collection of pertinent clinical information through history taking and physical examination and selection and organization of the observed symptoms to develop a diagnostic hypothesis to be confirmed or refuted. The prerequisites are adequate knowledge, a good patient-physician relationship and technical qualification. Learning to make a diagnosis is an individual endeavor. Teaching requires a good analysis of the diagnostic process and possible errors to design anatomoclinical conferences or diagnostic exercises. Experience can be transmitted directly; the 19th century clinical lessons are an excellent example. Progress in medical diagnosis is largely linked to advances in fundamental sciences and investigation techniques, but for the most difficult cases, clinical analysis remains the cornerstone of diagnosis. PMID- 10093660 TI - [Guillain-Barre syndrome: from the original description to the modern concepts]. AB - Since the original report, acute paralysis and albuminocytologic dissociation have remained hallmarks of the Guillain-Barre syndrome but the initially described favorable outcome with complete motor recovery is not always observed. Guillain-Barre syndrome can be complicated by early respiratory distress, dysautonomia and late functional impairment. The conduction block induced by acute demyelination accounts for the spontaneous neurological improvement. On the other hand, early axonal damage or sustained demyelination can be responsible for residual deficit. The cause and mechanism of the disease still remain unclear. For these patients, general care is essential and should be provided in appropriate hospital units. Today, specific treatment consists of either plasma exchange or high-dose intravenous immunoglobulins; the choice depends on their respective contraindications. PMID- 10093662 TI - [The observation of Mongin and collaborators]. PMID- 10093661 TI - [From Thibierge-Weissenbach syndrome (1910) to anti-centromere antibodies (1980). Clinical and biological features of scleroderma]. AB - G. Thibierge and M.R.J. Weissenbach reported during the 1st July 1910 session of the Hospital Medical Society the first case report of what was later called in 1964 in the English literature a CRST syndrome. This patient had progressive systemic sclerosis (PSS) with Raynaud's phenomenon, recurrent cutaneous calcinosis and face and trunk telangiectasiae. Since this first description, progressive systemic sclerosis has been split in various subtypes according to the extent of cutaneous and visceral involvement. Preliminary classification criteria have been edicted by the American College of Rheumatology (ACR) in 1980. Various antinuclear autoantibodies have been associated with the prognosis of the different subtypes of PSS: anticentromere antibodies are detected in 50% of patients with CREST syndrome which has a better vital prognosis than diffuse scleroderma. This later form is associated with either anti-Scl 70 (topoisomerase I) antibodies (20 to 30%) or anti-RNA polymerase III (20%). PMID- 10093663 TI - [Giant aneurysm of the inter-atrial septum]. AB - We report the case of a large atrial septal aneurysm and a review of the literature. Atrial septal aneurysm is found in 1-8% of normal subjects. Its prevalence is higher among patients with ischemic stroke. Transesophageal echocardiography is an optimal tool for the diagnosis of atrial septal aneurysm. The clinical course may be complicated by arterial embolism, but mechanical complications may also occur, as in this case. Due to the lack of general agreement, treatment options should be discussed on an individual basis for patients with atrial septal aneurysm. PMID- 10093664 TI - [Idiopathic aneurysm of the pulmonary artery trunk. Report of a case]. AB - Aneurysms of the aorta are frequent and treatment is well known, correlated with a statistical risk of rupture. Pulmonary artery aneurysms are less frequent. They may occur in connection with other conditions (infection, cardiopathy, notably pulmonary artery hypertension, endovascular trauma) or much more exceptionally regarded as idiopathic. Chest x-ray, CT-scan and digitalized pulmonary angiography and echocardiography give the diagnosis and help evaluate extension and localization. We report the case of a 72-year-old woman who developed idiopathic aneurysm of the left pulmonary artery which was discovered fortuitously. Because of the stability of the lesion and the lack of any worsening factor, we decided not to operate this high-risk patient. After 3 years, no complication has been observed and the CT-scan shows no evolution. In case of proximal idiopathic aneurysm of the pulmonary artery, the indication of surgery should be discussed. PMID- 10093665 TI - [Apheresis for Byler syndrome in pregnancy: tolerance and effectiveness]. AB - We report the first known case of a successful pregnancy in a 22-year-old white woman suffering from hepatic Byler's syndrome, a familial fibrogenic cholestasis observed in children and usually leading to death during adolescence or to liver transplantation. A first pregnancy was unsuccessful with intrauterine death. Medical surveillance of the second pregnancy was reinforced due to major cholestasis and itching sensation. Plasmapheresis was employed weekly from the 19th week of gestation. Within 2 weeks of treatment onset, plasma alkaline phosphatase levels returned to normal; pruritus completely disappeared after the second session. Delivery was decided at 33 weeks gestation with uterine section. The female baby weighed 2,090 g and outcome was excellent. This is the first reported case of Byler's syndrome with successful pregnancy. We underline the efficacy and safety of apheresis in this very particular disease. PMID- 10093666 TI - [Management of severe head injuries in the early stage. Recommendations]. PMID- 10093667 TI - [How to describe and evaluate the clinical gravity of a head injury in order to define a therapeutic strategy at a given moment?]. PMID- 10093668 TI - [What are the treatment modalities of severe head injuries in the prehospital phase?]. PMID- 10093669 TI - [What is the strategy to follow for carrying out examinations of diagnostic imaging?]. PMID- 10093670 TI - [What are the indications for neurosurgery in the early stage of head injury?]. PMID- 10093671 TI - [What are the indications and modalities for mechanical ventilation?]. PMID- 10093672 TI - [What are the indications and what are the modalities of sedation and curarization except for the specific treatment of intracranial hypertension?]. PMID- 10093674 TI - [What are the criteria for treating intracranial hypertension?]. PMID- 10093673 TI - [What are the indications and modalities of different monitoring techniques?]. PMID- 10093675 TI - [What are the indications and modalities of medical treatments for intracranial hypertension from severe head injuries?]. PMID- 10093676 TI - [What is the strategy for management of a multiple trauma patient with a severe head injury?]. PMID- 10093677 TI - [What is the role of prophylactic anticonvulsant treatment after head injury?]. PMID- 10093678 TI - [Must we avoid hyperthermia? Using what modalities? Indications and modalities of therapeutic hypothermia]. PMID- 10093679 TI - Services, costs and appropriate outcomes in end of life care. PMID- 10093680 TI - Research in low-income countries. PMID- 10093681 TI - p53-oriented cancer therapies: current progress. AB - Nearly twenty years after the initial discovery of p53, we are now in an ideal position to exploit our vast knowledge of p53 biology in the creation of novel cancer therapies. Disruption of p53 function through mutation, or other means, occurs very frequently in human cancer. Loss of p53 function has been linked with unfavourable prognosis in a large number of tumour types, as indicated by more aggressive tumours, early metastasis and decreased survival rates. Many different avenues of research have converged upon p53 to highlight this protein as being one of the foremost cellular responders to stress, in particular to DNA damage. Huge advances have been made in understanding the complex role p53 plays in the regulation of apoptosis and cell cycle arrest. This review is not meant to be a comprehensive description of p53 biology, but rather serves to highlight current progress in the development of p53-oriented cancer therapies. These may be categorised into three basic strategies: gene replacement therapy using wild-type p53, restoration of p53 function by other means and, finally, targeting of the p53 dysfunction itself. Rapid progress is expected to be made regarding the identification of conventional pharmaceutical agents which either work in a p53 independent manner or act preferentially in p53 defective cells. Gene replacement therapy with wild-type p53 also holds considerable potential for obtaining clinically relevant results quickly. The other forms of cancer therapies based around p53 are much further behind in the developmental process, but may prove to more efficacious in the long run, especially in terms of specificity. As with many other fields, the innovation of successful p53-oriented cancer therapies is only limited by our understanding of p53 biology and the creative use of such knowledge. PMID- 10093682 TI - Advanced soft tissue sarcoma: how many more trials with anthracyclines and ifosfamide? PMID- 10093683 TI - Prolonged neoadjuvant treatment in locally advanced tumours: a novel concept based on biological considerations. AB - BACKGROUND: Neoadjuvant chemotherapy is increasingly applied in patients with locally advanced cancers of many tumour types. Usually three cycles of chemotherapy are administered to reduce the tumour size prior to local therapy, and another three cycles thereafter. The chemotherapy certainly contributes to the improved outcome of this approach. However, biological factors within the primary tumour have been neglected, while they might also contribute to the eradication of micrometastases. We believe that the neoadjuvant strategy can be improved by optimally exploiting certain biological factors inherent to the primary tumour. In a group of patients with locally advanced breast cancer (LABC) we studied this concept. Recently we described the clinical results of this phase II study in patients with LABC treated with neoadjuvant chemotherapy plus granulocyte-macrophage colony-stimulating factor (GM-CSF). A remarkable good response and survival was seen. In contrast to other studies we applied six cycles of neoadjuvant treatment in stead of a sandwich approach consisting of three cycles before and three cycles after local therapy, leaving the primary tumour and draining lymph nodes in situ for a prolonged period. In addition, GM CSF was administered as a haematopoietic growth factor in stead of granulocyte colony-stimulating factor (G-CSF) as GM-CSF has also immuno-stimulating properties. Our findings definitely warrant further exploration of prolonged neoadjuvant systemic treatment in combination with GM-CSF in other high risk primary tumours. HYPOTHESES: The promising results of our study may be attributable to two potential biological phenomena. Firstly, the conservation of the tumour and its draining lymph nodes may prove to be an essential part of this approach, with particular emphasis on the activation of tumour specific cytotoxic T cells. Secondly, circulating angiogenesis inhibitors originating from the primary tumour may enhance the effect of chemotherapy on micrometastases. PMID- 10093684 TI - Use of resources and costs of palliative care with parenteral fluids and analgesics in the home setting for patients with end-stage cancer. AB - BACKGROUND: In 1992 a home care technology project was started in which infusion therapy in the home setting was made available for patients with end-stage cancer. Beside aspects of feasibility and quality of life the resource utilization and costs of this transition was studied. PATIENTS AND METHODS: We conducted a cost evaluation study, to determine the actual cost of managing patients with endstage cancer who require parenteral administration of fluid or analgesics in the home setting. A total of 128 patients were prospectively followed, with a detailed analysis of some aspects in a sample of 24 patients. RESULTS: The cost for each patient was found to be between $250.00 and $300.00 per day, half of which are for hospital charges, even with this active home care technology program. One-third of the costs can be attributed to primary health care activities, in particular those of the district nurses. A hypothetical control group (n = 25) was constructed based on current practice and chart review. Patients in this group would have cost around $750.00 per day. With a median treatment period of 16 days this means a saving of $8000.00 per patient. CONCLUSION: Our data suggest that significant savings can be obtained by implementing programs transferring palliative care technology to the home setting. PMID- 10093685 TI - Acute lymphoblastic leukemia in India: an analysis of prognostic factors using a single treatment regimen. AB - BACKGROUND: In the past, treatment results in Indian children with ALL have been poor, primarily due to inadequate chemotherapy and supportive care, but perhaps reflecting differences from Western countries in the pattern of subtypes. In an attempt to improve survival, we have used a more intensive treatment protocol, MCP841, and examined prognostic factors. PATIENTS AND METHODS: Five hundred thirty previously untreated patients < 25 years of age with ALL were entered on study at the Tata Memorial Hospital, Mumbai. Treatment consisted of three successive induction cycles, consolidation and six maintenance cycles. CNS prophylactic therapy consisted of cranial irradiation (2000 cGy) for patients above two years and high-dose cytarabine for patients less than two years. The total treatment duration was two years. RESULTS: Most patients had hepatosplenomegaly (80%) and or lymphadenopathy (79%) and 21% were of T-cell immunophenotype, but very few (1.3%) had CNS disease. CR was achieved in 484 (91.3%) patients and 145 (29.9%) patients relapsed. There were 36 induction deaths and 49 remission deaths, but the toxic death rate was significantly lower after 1990. In patients treated since 1990, three risk groups could be discerned: 1) WBC < 60,000 per mm3 and no lymphadenopathy (77% event-free survival (EFS) at five years): 2) WBC < 60,000 per mm3 with lymphadenopathy (53% EFS) or, WBC > 60,000 per mm3 and Hb 6 gm/dl or above (48% EFS): and 3) WBC > 60,000 per mm3 and Hb below 6 gm dl (16% EFS). In a multivariate model, only WBC, Hb and lymphadenopathy were significantly associated with EFS (P < 0.01). CONCLUSIONS: The CR and EFS rates achieved represent a significant improvement over previous results at this institution. Bulky extramedullary disease was an important risk factor in this series, but age and WBC alone inadequately defined risk groups, suggesting that prognostic factors may vary in different world regions. PMID- 10093686 TI - Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia. Eastern Cooperative Oncology Group (E1490). AB - PURPOSE: Considerable morbidity and mortality and costs occur during induction therapy for acute myeloid leukemia (AML). Colony-stimulating factors (CSFs) can shorten neutropenia, and may lower costs. We performed a cost-minimization analysis of granulocyte macrophage colony stimulating factor (GM-CSF) for AML patients > 55 to 70 years of age during an Eastern Cooperative Oncology Group Study. PATIENTS AND METHODS: Clinical data were from a randomized double-blind phase III trial of 117 AML patients. Estimates of costs were from financial accounts from seven participating institutions. Costs were reported from the third party payor perspective. Analyses were conducted utilizing a decision analytic model. The primary source of event probabilities was in-hospital care with or without an active infection. Sensitivity analyses were also reported. RESULTS: When compared to AML patients who received placebo. GM-CSF patients had fewer grade 4-5 infections (9.6% versus 36.2%, P = 0.002) and grade 3-5 infections (52% versus 70%. P = 0.07) and $2.310 in savings. Sensitivity analyses indicated that similar cost estimates applied over a range of clinical and economic assumptions. CONCLUSIONS: This analysis can serve as a template for cooperative group cost analyses. Cooperation on study methodologies may allow for results that are relevant to both clinicians and policy makers. PMID- 10093687 TI - Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia: a German multicenter phase II study. AB - PURPOSE: Fludarabine has been reported to be the most effective single-agent in previously treated chronic lymphocytic leukaemia (CLL). Based on the in vitro synergism of fludarabine with anthracyclines and on results showing a higher efficacy of CHOP against COP we attempted to improve treatment results with a combination of fludarabine and an anthracycline. PATIENTS AND METHODS: The aim of the multicenter study was to evaluate the rate and duration of remissions and investigate the toxic and immunosuppressive effects of fludarabine and epirubicin in the treatment of CLL in Binet stages B and C as first-line therapy or in first relapse. Thirty-eight patients were treated with fludarabine 25 mg/m2 on days 1-5 and epirubicin 25 mg/m2 on days 4 and 5. RESULTS: The overall response rate (OR) was 82% (95% confidence interval (95% CI): 66%-92%) with a CR rate of 32% (95% CI: 18%-49%). For the 25 previously untreated patients the OR was 92% (95% CI: 74%-99%) including 40% CRs (95% CI: 21%-61%). Granulocytopenia grade 3 occurred in 23% of all evaluable cycles, and grade 4 in 17%. The median remission duration was 19 months (range 6-37 months). CONCLUSION: The results show that the combination of fludarabine and epirubicin is tolerable and highly effective in the treatment of CLL. With the addition of epirubicin to fludarabine, it appears possible to achieve a higher response rate and a more rapid response, especially of nodal manifestations. This regimen can be administered in an outpatient facility except for the first cycle because of the risk of a tumour lysis. The possible benefit of the combination presented here in the treatment of CLL in comparison to single-agent fludarabine treatment is presently under study in a prospective randomized multicenter study. PMID- 10093688 TI - Hodgkin's disease in 35 patients with HIV infection: an experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in combination with antiretroviral therapy and primary use of G-CSF. AB - BACKGROUND: The optimal therapeutic approach for patients with Hodgkin's disease and human immunodeficiency virus infection (HD-HIV) is unknown. In an attempt to improve the results previously obtained with EBV (epirubicin, bleomycin and vinblastine) without G-CSF (Cancer 1994; 73: 437-44), in January 1993 we started a trial using chemotherapy (CT) consisting of EBV plus prednisone (EBVP), concomitant antiretroviral therapy (zidovudine, AZT or dideoxinosyne, DDI), and G CSF. PATIENTS AND METHODS: Up to August, 1997, 35 (30 M/5 F) consecutive previously untreated patients (median age 34, range 21-53 years) with HD-HIV were enrolled in the European Intergroup Study HD-HIV. Their median performance status was 1 (range 1-3). At diagnosis of HD, 26% of the patients had AIDS, 90% had B symptoms at HD presentation and 83% had advanced-stage HD. Patients received E 70 mg/m2 i.v. on day 1, B 10 mg/m2 i.v. on day 1, V 6 mg/m2 i.v. on day 1 and P 40 mg/m2 p.o. from day 1 to day 5 (EBVP). Courses were repeated every 21 days for six cycles. AZT (250 mg x 2/day), or DDI (200 or 300 mg x 2/day) if AZT had been previously used, were given orally from the beginning of CT. G-CSF was given at the dose of 5 mcg/kg/day s.c. from day 6 to day 20 in all cycles. RESULTS: An overall response rate of 91% was observed. There were 74% complete responses (CR) and 17% partial responses (PR). Toxicity was moderate, with grade 3-4 leukopenia and thrombocytopenia in 10 (32%) and three (10%) patients, respectively. The median number of administered cycles was 6 (range 3-6). Twenty-three of 35 patients received AZT and nine patients received DDI. Three (8%) patients had opportunistic infections (OI) during or immediately after CT. The median CD4+ cell count was 219/mm3 (6-812) at HD diagnosis and 220/mm3 (2-619) after the end of combined therapy, and these numbers remained unchanged. Ten of 26 (38%) patients who achieved CR relapsed. Twenty-three patients died of HD progression alone or in association with OI, being the cause of death in 48% and 9% of patients respectively. The median survival was 16 months, with a survival rate of 32% and a disease-free survival of 53% at 36 months. CONCLUSIONS: The combined antineoplastic and antiretroviral treatment is feasible, but HD in HIV setting is associated with a more adverse prognosis than in the general population. Although the CR rate obtained was satisfactory, the relapse rate was high. Furthermore, comparison of the results of our two consecutive prospective studies demonstrated no overall improvement in the current trial with respect to the CR rate and survival. PMID- 10093689 TI - Breast cancer screening by mammography in Norway. Is it cost-effective? AB - BACKGROUND: Mammography screening is a promising method for improving prognosis in breast cancer. PATIENTS AND METHODS: In this economic analysis, data from the Norwegian Mammography Project (NMP), the National Health Administration (NMA) and the Norwegian Medical Association (NMA) were employed in a model for cost effectiveness analysis. According to the annual report of the NMP for 1996, 60,147 women aged 50-69 years had been invited to a two-yearly mammographic screening programme 46,329 (77%) had been screened and 337 (0.7%) breast cancers had been revealed. The use of breast conserving surgery (BCS) was in this study estimated raised by 17% due to screening, the breast cancer mortality decreased by 30% and the number of life years saved per prevented breast cancer death was calculated 15 years. RESULTS: The cost per woman screened was calculated 75.4 Pounds, the cost per cancer detected 10.365 Pounds and the cost per life year (LY) saved 8.561 Pounds. A raised frequency of BCS, diagnosis and adjuvant chemotherapy brought two years forward, follow-up costs and costs/savings due to prevented breast cancer deaths were all included in the analysis. A sensitivity analysis documented mammography screening cost-effective in Norway when four to nine years are gained per prevented breast cancer death. CONCLUSION: Mammography screening in Norway looks cost-effective. Time has come to encourage national screening programmes. PMID- 10093690 TI - Docetaxel in the community setting: an analysis of 377 breast cancer patients treated with docetaxel (Taxotere) in the UK. UK Study Group. AB - BACKGROUND: Given as first- or second-line chemotherapy docetaxel appears to have great potential in advanced breast cancer. PATIENTS AND METHODS: Three hundred and seventy-seven locally advanced or metastatic breast cancer patients received docetaxel (Taxotere) as part of a named patient programme under the care of 108 oncologists from 61 cancer units across the UK. The recommended starting dose was 100 mg/m2, but patients at higher risk of toxicity started at 75 mg/m2. All patients received corticosteroid premedication. The modal number of prior chemotherapy regimens was 2 (range 1-7). 342 patients (91%) had at least one prior anthracycline-based regimen. RESULTS: Response was graded according to the managing clinician's best judgement without formal criteria. The overall response rate (ORR) was 46% among the 331 evaluable patients. 46% among the 299 patients who were anthracycline resistant and 35% among the 82 patients who were anthracycline refractory (progressive disease being the best response obtained to the most recent anthracycline containing regimen). One hundred and ninety-three patients started at the full dose of 100 mg/m2 with an ORR of 55% and 129 started at 75 mg m2 with an ORR of 33%. In October 1997, some two years after the programme had started, 26 of 377 patients were still alive, although no complete remissions have lasted to this date. Kaplan-Meier survival analysis yielded a median survival of 194 days (95% CI: 178-218 days). Haematological parameters were checked before each course of docetaxel and additionally as clinically indicated. The safety data confirmed that docetaxel has a manageable, predictable side effect profile; 29 of 377 (7.7%) patients were hospitalised as a result of neutropenic sepsis. CONCLUSIONS: The results of this named patient programme over a two year timespan confirm that docetaxel is an effective chemotherapy option in patients with locally advanced and/or metastatic breast cancer, including an 'anthracycline refractory' population. PMID- 10093691 TI - Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: a multicenter phase II trial. Greek Breast Cancer Cooperative Group. AB - PURPOSE: The activity of the docetaxel-gemcitabine combination in women with disease progression after initial chemotherapy for metastatic breast cancer (MBC) was investigated in a multicenter phase II study. PATIENTS AND METHODS: Fifty-two patients with metastatic breast cancer who had disease relapse or progression after completion of an anthracycline-based front-line regimen were treated with gemcitabine 900 mg/m2 on day 1 and day 8 and docetaxel 100 mg/m2 on day 8. G-CSF 150 mucg/m2/d s.c. was given from day 9 to day 16 and the treatment was repeated every three weeks. The patients' median age was 57 years and the performance status (WHO) was 0 for 26, 1 for 20 and 2 for 6 patients. The treatment was second-line for 27 (52%) and > or = third-line for 25 (48%) patients. All patients were evaluable for response and toxicity. RESULTS: Complete response occurred in seven (14%) patients and partial response in 21 (40%) for an overall response rate of 54% (95% confidence interval (95% CI): 40%-67%). Fifteen (29%) patients had stable disease and nine (17%) progressive disease. Of 25 patients previously treated with taxanes. 11 (44%) responded (1 CR, 10 PR). Interestingly, in four patients with disease progression while receiving docetaxel or paclitaxel monotherapy, the docetaxel + gemcitabine combination achieved partial responses. Responses were observed at all metastatic sites (local disease 62%, lymph nodes 58%, skin 44%, lung 47% and liver 36%) with a median duration of response of 3.6 months (range 1-16) and a median time to disease progression of eight months (range 2-18.5). Grade 3 neutropenia developed in 10 (19%) and grade 4 in five (10%) patients. Neutropenia was associated with infection in four patients without toxic deaths. Grade 3 thrombocytopenia developed in nine (17%) patients and grade 4 in two (4%). Non-hematologic toxicity was usually mild. CONCLUSION: The docetaxel-gemcitabine combination is an active and well tolerated salvage treatment in patients with MBC. Previous treatment with taxanes does not preclude a good clinical response to this regimen. PMID- 10093692 TI - Weekly gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase II study. AB - BACKGROUND: The combination of gemcitabine and cisplatin has proven effective in the treatment of advanced non-small-cell lung cancer (NSCLC). However, the optimal schedule for administration of the two drugs has not yet been determined. In this study we evaluated the activity and toxicity of a weekly gemcitabine and cisplatin schedule. PATIENTS AND METHODS: Thirty-six untreated patients with stage IIIB IV NSCLC entered the study. Treatment consisted of gemcitabine 1000 mg/m2 i.v. and cisplatin 35 mg/m2 i.v., both given weekly on day 1,8, and 15, followed by one week of rest. RESULTS: Ninety-seven courses (273 weekly administrations) were delivered. The median dose-intensity was 612 mg/m2 per week for gemcitabine (82%) and 21 mg/m2 per week for cisplatin (80%). All 36 of the patients were evaluable for toxicity, and 30 for response. Partial remissions were observed in 12 patients, for an overall response rate of 40% (95% confidence interval (95% CI): 22.5%-57.5%). Most of the partial remissions were seen in IIIB patients (54% of the stage IIIB and 22% of the stage IV patients responded). According to the intent-to-treat principle, the response rate was 33.3% (12 of 36 patients). The median response duration was 9.9 months (range 4-23) and the median survival time 11.8 months (range 1-24). World Health Organization (WHO) grade 3-4 myelotoxicity was: thrombocytopenia in nine patients (25%), neutropenia in six (16.6%) and anemia in six (16.6%); there was very little additional major toxicity. CONCLUSIONS: This regimen appears to be active and to have a favourable toxicity profile. PMID- 10093693 TI - A phase I study of docetaxel and 5-fluorouracil in patients with advanced solid malignancies. AB - PURPOSE: This study was undertaken to evaluate the feasibility of administering docetaxel (Taxotere; Rhone-Poulenc-Rorer) as a one-hour intravenous (i.v.) infusion on day 1 combined with 5-fluorouracil (5-FU) as a bolus i.v. injection for five (days 1-5) or three (days 1-3) consecutive days every four weeks. PATIENTS AND METHODS: Thirty-seven patients with advanced solid malignancies were treated with 115 total courses involving seven dose levels of the two regimens of docetaxel and 5-FU (docetaxel/5-FU [mg/m2]/mg/m2/d]). In an effort to reduce fluid retention and hypersensitivity phenomena related to docetaxel, patients received premedication with dexamethasone 8 mg orally twice daily for three consecutive days beginning 24 hours before treatment. RESULTS: Severe (grade 4) neutropenia lasting longer than seven days with or without fever and/or severe mucositis, precluded further dose escalation above docetaxel 60 mg/m2 on day 1 and 5-FU 300 mg/m2/day administered on days 1-5 every four weeks. The rates of these toxic effects were also unacceptably high above docetaxel 60 mg/m2 on day 1 and 5-FU 300 mg/m2/day administered on days 1-3 every four weeks. Nine patients experienced various manifestations of fluid-retention that were potentially related to study drugs. However, neither treatment delay nor discontinuation of treatment was required. Nausea, vomiting, diarrhea, and fatigue, were mild to modest in severity and occurred infrequently (< 10% of courses). Two patients with metastatic breast cancer experienced complete responses and a partial response occurred in a patient with metastatic non-small-cell lung cancer. CONCLUSION: Based on the results of this study, the regimen of docetaxel 60 mg/m2 on day 1 followed by 5-FU 300 mg/m2/d i.v. for three or five days every four weeks is well tolerated and these doses are recommended for further evaluations. The feasibility of administering docetaxel 60 mg/m2 followed by 5-FU 300 mg/m2 for three or five days every four weeks and the preliminary antitumor activity noted indicate that further disease-directed studies of docetaxel and 5-FU are warranted in patients with relevant solid malignancies. PMID- 10093694 TI - Epstein-Barr virus related hemophagocytic syndrome in a T-cell rich B-cell lymphoma. AB - We report the case of a 30-year-old woman who presented with an EBV related hemophagocytic syndrome. After a few months she developed a T-cell rich B-cell non-Hodgkin's lymphoma with liver involvement. Serological data demonstrated a reactivation of the EBV infection. Tumor progression with liver involvement occurred during treatment with conventional chemotherapy. Tumor reduction and disappearance of all masses was seen after starting high-dose sequential chemotherapy, followed by an autologous peripheral blood progenitor transplantation LMP-1 could be amplified in the tumor material by PCR technology, but no LMP-1 expression could be found in the few malignant B-cells with Reed Sternberg morphology. Sequence analysis of the carboxy terminal of the LMP-1 region revealed the naturally occurring 30 bp deletion variant of the LMP-1 with multiple point mutations within the NF kb region. Since LMP-1 was not expressed in the malignant tumor cells, no evidence could be found, that EBV participated in the tumorigenesis of this case. PMID- 10093695 TI - Phase II trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma. AB - PURPOSE: An earlier phase II trial of paclitaxel in patients with metastatic nasopharyngeal carcinoma (NPC) demonstrated a response rate of 22%. Hence we proceeded to study the combination of paclitaxel and carboplatin in these patients. PATIENTS AND METHODS: The 21-day regimen was as follows: i.v. paclitaxel 175 mg/m2 over three hours preceded by standard premedications, followed by i.v. carboplatin dosed at AUC of six infused over one hour. Only chemotherapy-naive patients with histological diagnoses of undifferentiated carcinoma of the nasopharynx, systemic metastases and radiologically measurable lesions were eligible. RESULTS: Thirty-two patients were accrued to this study. Twenty patients (62%) had at least two sites of metastasis. The main grade 3-4 toxicity was neutropenia (31%). Nine patients (28%) developed neutropenic sepsis, which caused the demise of one of them. Twenty-four patients (75%) responded to treatment, with one (3%) attaining a complete response. The median time to progression of disease was seven months and the median survival was 12 months. At one year, 52% of the patients were alive. CONCLUSIONS: The combination of paclitaxel and carboplatin is an active regimen in NPC. Its convenience of administration and good tolerability make it an attractive alternative regimen to consider for patients with metastatic disease. PMID- 10093696 TI - Prognostic value of cerebrospinal fluid cytology in pediatric medulloblastoma. Swiss Pediatric Oncology Group. AB - BACKGROUND: Although the demonstration of leptomeningeal dissemination is the most important predictor of poor outcome in children with medulloblastoma, there is lack of consensus on the prognostic value of a positive cerebrospinal fluid (CSF) cytology (i.e., stage M1). PATIENTS AND METHODS: Eighty-six pediatric medulloblastoma patients treated in Switzerland between 1972-1991 were retrospectively studied regarding the influence of M-stage on prognosis. 39 were M0, 13 M1, 15 Mx, 17 M2, and 2 M3. RESULTS: Five- and 10-year overall survival rates were 76% and 54% for M0, 68% and 50% for Mx, 36% and 25% for M1, and 22% and 22% for M2-3 (P < 0.001), respectively. No significant survival differences were observed between M1 and M2-3 patients. Among 26 patients with only postoperative CSF cytologies, seven were positive. Their outcome was similar to that of six preoperatively staged M1 and significantly different from that of M0 patients (P = 0.001). In 14 patients both pre- and postoperative CSF cytology was performed. Total agreement was observed between the pre- and postoperative results (six positive and eight negative). Among the 19 M2-3 patients CSF cytology was positive in eight, negative in five, and unknown in six. CONCLUSIONS: A positive CSF cytology either pre- or postoperatively predicts for a poor outcome, similar to that observed in stage M2-3 patients. A postoperative cytology is likely to be concordant with cytologic results obtained preoperatively, and seems to have the same prognostic significance. A negative cytology, however, does not exclude a more advanced stage. PMID- 10093697 TI - Hepatocellular carcinoma in a patient with Gaucher disease on enzyme supplementation therapy. PMID- 10093698 TI - Cost comparison between PAV and ICE treatment with peripheral blood progenitor cells (PBPC) reinfusion in small-cell lung cancer (SCLC) PMID- 10093699 TI - A specific approval procedure for prescribing albumin: impact on consumption in a cancer treatment institution. PMID- 10093700 TI - Colworth Medal lecture. Detection, repair and signalling of DNA double-strand breaks. PMID- 10093701 TI - Hopkins Memorial Medal lecture. Pleasant surprises en route from the biochemistry of collagen to attempts at gene therapy. PMID- 10093702 TI - Single molecule enzyme kinetics: application to myosin ATPases. PMID- 10093703 TI - The structure of bovine mitochondrial F1-ATPase: an example of rotary catalysis. AB - There is now compelling evidence in support of a rotary catalytic mechanism in F1 ATPase, and, by extension, in the intact ATP synthase. Although models have been proposed to explain how protein translocation in F0 results in rotation of the gamma-subunit relative to the alpha 3/beta 3 assembly in F1 [22], these are still speculative. It seems likely that a satisfactory explanation of this mechanism will ultimately depend on structural information on the intact ATP synthase. PMID- 10093704 TI - Visualizing enzyme intermediates using fast diffraction and reaction trapping methods: isocitrate dehydrogenase. PMID- 10093705 TI - DNA gyrase as a drug target. PMID- 10093706 TI - Dihydropteroate synthase: an old drug target revisited. PMID- 10093707 TI - Mechanistic diversity of beta-lactamases. PMID- 10093708 TI - Protein antibiotics and their inhibitors. PMID- 10093709 TI - The maternal, fetal and postnatal somatotrophic axes in intrauterine growth retardation. AB - Both the maternal and fetal somatotrophic axes are closely linked to fetal substrate supply. Nutritional insults at critical stages of fetal development may lead to permanent reprogramming of the relationships between these factors. The consequences of reprogramming during fetal life may be harmful to metabolic, endocrine and cardiovascular homoeostatic mechanisms in postnatal life. The exact mechanisms that lead to reprogramming during fetal life need thorough investigation before effective strategies to deal with this problem can be devised. PMID- 10093710 TI - Glucocorticoids and fetal programming. PMID- 10093711 TI - The Cre/loxP system--a versatile tool to study glucocorticoid signalling in mice. PMID- 10093712 TI - Development effects of thyroid hormone: the role of deiodinases in regulatory control. PMID- 10093713 TI - Intrauterine programming of hypertension: the role of the renin-angiotensin system. AB - From experiments with prenatal undernutrition in the rat, it is clear that fetal exposure to glucocorticoids of maternal origin is a key first step in the programming of hypertension and perhaps coronary heart disease. The chain of events leading from glucocorticoid action in the fetal tissues to hypertension in adulthood involves the development of hypersensitivity to glucocorticoids in adult life (Scheme 1). This has the effect of activating the RAS through induction of key genes such as ACE, which, in turn, may increase sensitivity of the blood vessels to the actions of ANGII. Another consequence of prenatal undernutrition, which may or may not involve glucocorticoids, is the abnormal development of the kidney [35]. Impaired nephrogenesis must surely have an impact upon lifelong renal function and cardiovascular control. Progress has been made in demonstrating that hypertension can be prenatally programmed through maternal dietary manipulation and some of the putative mechanisms involved have been identified. The priorities in this field of research must now be to clarify the role of maternal diet as a programming stimulus in order to generate an effective series of public health guidelines for pregnant women. Although the identification of metabolic mechanisms might suggest possible pharmacological interventions in early life as a means of reducing cardiovascular risk in adult life [49], it will always be more desirable to optimize maternal diet. PMID- 10093714 TI - Programming of hepatic and peripheral tissue insulin sensitivity by maternal protein restriction. AB - In recent years a great deal of research effort has been directed towards understanding the molecular basis of the relationship between markers of fetal and early growth retardation and the subsequent development of Type 2 diabetes. A lot of this work has focused on the maternal low protein rat model. Like many animal models, it does not perfectly represent the human situation and frank diabetes has not yet been produced. However, this model has yielded much information on potential mechanisms by which changes in insulin sensitivity can occur and has helped in understanding the role of the molecular machinery involved in the signalling of the metabolic actions of insulin. PMID- 10093715 TI - Maternal nutrition and endocrine programming of fetal adipose tissue development. PMID- 10093716 TI - Properties of the hyaluronan synthase from group A Streptococcus pyogenes. PMID- 10093717 TI - Mammalian hyaluronan synthases: investigation of functional relationships in vivo. PMID- 10093718 TI - The structure and regulation of hyaluronan-binding proteins. PMID- 10093719 TI - The conformations of hyaluronan in aqueous solution: comparison of theory and experiment. PMID- 10093720 TI - New approaches to the investigation of hyaluronan networks. PMID- 10093721 TI - Hyaluronan in joint cavitation. PMID- 10093722 TI - Receptor for hyaluronan-mediated motility (RHAMM), a hyaladherin that regulates cell responses to growth factors. PMID- 10093723 TI - The chondrocyte pericellular matrix: a model for hyaluronan-mediated cell-matrix interactions. PMID- 10093724 TI - Diversity in the signalling and regulation of G-protein-coupled receptors. PMID- 10093725 TI - Regulatory mechanisms of alpha 1B-adrenergic receptor function. PMID- 10093727 TI - Heterologous mammalian expression systems for investigating the properties of metabotropic glutamate receptors. PMID- 10093726 TI - Promiscuity and fidelity in receptor-G-protein coupling: cell cycle-dependent coupling of the vasopressin V1 receptor. PMID- 10093729 TI - Mechanisms of action of anti-psychotic drugs. PMID- 10093728 TI - Evidence that a novel metabotropic glutamate receptor mediates the induction of long-term potentiation at CA1 synapses in the hippocampus. PMID- 10093730 TI - Flavocytochromes: structures and implications for electron transfer. PMID- 10093731 TI - Flavocytochromes: transceivers and relays in biological electron transfer. PMID- 10093732 TI - Flavocytochrome P-450 BM3: a paradigm for the analysis of electron transfer and its control in the P-450s. PMID- 10093733 TI - Electron transfer in trimethylamine dehydrogenase and electron-transferring flavoprotein. PMID- 10093734 TI - Methylamine dehydrogenase: structure and function of electron transfer complexes. PMID- 10093735 TI - Electron transfer and coupled processes in protein film voltammetry. PMID- 10093736 TI - Generation and function of the soluble interleukin-6 receptor. PMID- 10093738 TI - Interleukin-6 receptor shedding: a possible role for members of the ADAM family. PMID- 10093737 TI - Characterization of the tumour necrosis factor alpha-converting enzyme, TACE/ADAM17. PMID- 10093739 TI - Angiotensin-converting enzyme and the amyloid precursor protein secretases. PMID- 10093740 TI - Proteolytic processing and degradation of Alzheimer's disease relevant proteins. PMID- 10093741 TI - Mechanisms controlling the shedding of transmembrane molecules. PMID- 10093742 TI - Proteinase-activated receptors: a growing family of heptahelical receptors for thrombin, trypsin and tryptase. PMID- 10093743 TI - Role for ADAM-family proteinases as membrane protein secretases. PMID- 10093744 TI - Live control of the living cell. PMID- 10093745 TI - Design of gene circuitry by natural selection: analysis of the lactose catabolic system in Escherichia coli. PMID- 10093746 TI - Theoretical studies on how ATP supply meets ATP demand. PMID- 10093747 TI - New insights into metabolic pathway optimization by analogy with industrial manufacturing processes. PMID- 10093748 TI - Enzyme kinetics from a metabolic perspective. PMID- 10093749 TI - Modelling lipid metabolism in plants: a slippery problem? PMID- 10093750 TI - Modelling metabolism in vivo: approaches using NMR. PMID- 10093751 TI - The structural design of glycolysis: an evolutionary approach. PMID- 10093752 TI - Importance of oestrogen, xenoestrogen and phytoestrogen metabolism in breast cancer risk. PMID- 10093753 TI - Metabolism of oestrogens and phytoestrogens: role of the gut microflora. PMID- 10093754 TI - Phytoestrogens in human biomatrices including breast milk. PMID- 10093755 TI - 4-hydroxylation of oestrogens as a marker for mammary tumours. PMID- 10093756 TI - Regulation of steroid sulphatase and oestradiol 17 beta-hydroxysteroid dehydrogenase in breast cancer. PMID- 10093757 TI - Analysis of structure-activity relationships with biosensors. PMID- 10093758 TI - Biosensors: past, present and future. PMID- 10093759 TI - BIACORE: an affinity biosensor system for characterization of biomolecular interactions. PMID- 10093760 TI - Cholera toxin and GM1: a model membrane study with IAsys. PMID- 10093761 TI - Molecularly imprinted polymers in chemical and biological sensing. PMID- 10093762 TI - The challenge of health care delivery to the elderly patient with cardiovascular disease. Demographic, epidemiologic, fiscal, and health policy implications. AB - Old age as our society is experiencing it is a new phenomenon. Never before in history have societies of developed countries enjoyed such longevity of life. In the next several decades the United States will face an unparalleled increase in the absolute number of elderly persons in our population. How will health care professionals, policy-makers, and society in general face the mammoth task of providing quality cardiovascular care for the elderly in an environment of limited financial resources? This article discusses the demographic, fiscal, and health policy implications of our aging society with particular emphasis on existing and anticipated impediments to the delivery of cardiovascular care to this rapidly expanding segment of our population. PMID- 10093763 TI - Cardiovascular pharmacology of aging. AB - Despite the relative paucity of drug trials in the old and especially the very old (> 85 years), some general principles of pharmacology in the aging patient can be taken from available data and clinical experience. The pharmacokinetic changes most consistently seen with aging occur in the volume of distribution, clearance, and half-life of a drug. Renal drug clearance is consistently diminished with aging. Hepatic metabolism is more variably affected, and in contrast to renal clearance, no reliable formula exists to estimate hepatic drug clearance. Pharmacodynamic changes, although present, are less well studied or described in the elderly. Drug interactions and adverse drug reactions increase with increasing numbers of medications prescribed and represent a complex interplay of age, underlying disease, and number and types of medications. The clinical caveats that apply to drug prescription in the very old include reduced starting doses with slow incremental increases; elimination of unnecessary medications; and anticipating and monitoring for drug interactions and ADRs, especially when prescribing warfarin, digoxin, and amiodarone. Future studies that look at the aging patient in the presence of effects of age, physiology, gender, comorbid illness, and multiple drug therapies may help evolve a new set of paradigms for geriatric drug prescribing. PMID- 10093764 TI - Cardiovascular consequences of the aging process. AB - There are many challenges in the study of the normal age-associated changes that occur in the cardiovascular system, the most important of which is the fact that cardiovascular disease is so common in the elderly. In animal models and healthy humans, three age-associated changes with increasing age include (1) impaired left ventricular diastolic filling, (2) reduction in the adrenergic responsiveness to catecholamines, and (3) an increase in arterial stiffness. These changes likely are influenced by the increasingly sedentary lifestyle in the elderly. These age-associated changes also influence the manifestations of cardiovascular disease in the elderly and the response to therapy. PMID- 10093765 TI - Aging and cardiovascular disease. Use of subclinical measurements. AB - This article examines the use of subclinical measurements in cardiovascular disease in the elderly. In the past 10 years, the development of new technology to measure subclinical disease has provided the opportunity to evaluate the prevalence of subclinical disease, the risk factors for subclinical disease, and the risk for clinical disease given the presence or absence of subclinical disease. PMID- 10093766 TI - Promises and perils of managed care for older patients with cardiac disease. AB - Managed care for elderly patients with cardiovascular disease will likely become more widespread because it has the propensity to provide comprehensive care while controlling costs. The issues of comorbidity and the changes of aging per se become increasingly important with increasing age and emphasize the need to use the basic principles of clinical decision making in the management of elderly patients, rather than focusing exclusively on a specific acute problem. Currently, there is great turmoil in the managed care market for the elderly with multiple models being tried with highly variable degrees of success from both the financial and patient satisfaction perspective. Physician leadership can be a critical element in resolving many of the dilemmas. PMID- 10093767 TI - Hypertension in the elderly. AB - The decade of the 1990s has clarified the perspective on treating hypertension in the elderly and provided a wealth of evidence to assist in the treatment of elevated blood pressure in older persons. Despite this wealth of information, important questions remain about treatment of hypertension in the elderly. PMID- 10093768 TI - Coronary heart disease. Stable and unstable syndromes. AB - CHD in the elderly population will continue to be a source of major concern because of the increasing costs entailed and uncertainties about how the widespread array of diagnostic and therapeutic interventions, often expensive and sometimes hazardous, should be applied. Financial, political, and health policy decisions will continue to occupy much attention, but it is likely that philosophic considerations about aging and death, both from the individual and the societal perspective, will be of paramount importance of deciding how the substantial resources available to the elderly will be used. Randomized, controlled trials are unlikely to play a major role in resolution of management dilemmas in the elderly because of the extraordinary heterogeneity in this population. Registries (databases) involving carefully prospectively collected key variables are likely to be a more effective approach. Critical characterization of complications of procedures, adverse drug reactions, and collection of follow-up data on functional status are among the critical questions, and these can be answered by registry studies. Algorithms and clinical rules developed in younger cohorts are not directly transferable to the elderly cardiovascular patients, further emphasizing the need for prospectively collected, syndrome-specific data. Treatments convincingly demonstrated to reduce mortality in absolute terms more in the elderly than in the young are underused. The heterogeneity of aging emphasizes the wide variability in patients' ability to withstand the stress of procedures and complications of disease and makes clear the need to consider physiologic reserve and biologic age rather than chronology. With better characterization of biologic age and physiologic reserve, more precise estimates of outcomes of therapies and interventions can be made, and patients can be given better information and with their families have more realistic expectations. Better-informed decisions will result. Biologic age will be multifactorial, involving cognitive, emotional, physical, and nutritional attributes as well as specific organ function (lung, kidney, liver) because no single feature can characterize the total elderly patient. The concept of competing risks among the cardiovascular disease being treated, comorbidity, risks of study, and life expectancy will evolve because even the most successful therapy will have limited effect on longevity in the very old. Although important research at the cellular and molecular level will characterize and provide better understanding of the aging process, it is not likely that this basic information will be immediately useful in the management of the large number of elderly patients with major cardiovascular disease. Preventive measures, including physical exercise, mental stimulation, avoidance of depression, good nutrition, and abstinence from tobacco use, are useful approaches to postpone or ameliorate the consequences of aging and allow patients to tolerate cardiovascular diseases better when they become manifest. PMID- 10093769 TI - Heart failure. AB - Heart failure is predominantly a disorder of older adults, and to a large extent the epidemiology of heart failure reflects the convergence of age-related changes in the cardiovascular system and the rising prevalence of age-related cardiovascular diseases. The diagnosis of heart failure in the elderly is often difficult because of the presence of atypical symptomatology and comorbid conditions. Similarly, optimal treatment frequently poses a therapeutic challenge because of the high prevalence of confounding medical, behavioral, psychosocial, and economic factors. In addition, there is a paucity of data on the pharmacotherapy of heart failure in the very elderly (over age 80), and in the large proportion of older patients with heart failure and preserved left ventricular systolic function. Despite these difficulties, a number of therapeutic options, including ACE inhibitors, digoxin, and possibly beta blockers and angiotensin receptor antagonists, have been shown to favorably affect the clinical course of heart failure in elderly patients. In addition, several studies have documented the efficacy of multidisciplinary heart failure disease management programs for reducing hospital admission rates, improving quality of life, and decreasing cost of care. At present, the three greatest challenges in managing older heart failure patients are: (1) to more effectively implement proven treatments, such as ACE inhibitors, disease management systems, and antihypertensive therapy; (2) to develop effective therapies for the treatment of diastolic heart failure; and (3) to develop more effective means for heart failure prevention. It is hoped that future studies will address each of these critically important issues. PMID- 10093770 TI - Valvular disease in the elderly. AB - As the incidence of valvular disease in the elderly is increasing, understanding of its pathogenesis and natural progression as well as surgical approaches and device technologies are improving. Future studies are needed to develop medical interventions that slow or halt the degenerative valvular processes associated with aging. In addition, mechanical approaches with lower operative risks should be explored and the search should continue for a valve substitute that is durable, hemodynamically efficient, easy to implant, and does not require anticoagulation. Hopefully, future intervention trials will include quality of life assessments such as symptoms, functional capacity and perceptions of well being. At present, the degenerative valvular processes must be followed closely by the clinician, and individual management decisions for the elderly based on the type and severity of valve disease, comorbid medical conditions, and the risks and benefits of intervention, along with patient preferences, rather than on the chronologic age of the patient. It is becoming clear that both survival and quality of life outcomes can improve by consideration of surgery at the onset of indications, before further deterioration eliminates the opportunity to provide benefit for the elderly patient with valvular disease. PMID- 10093771 TI - Hypertrophic and restrictive cardiomyopathies in the elderly. AB - Congestive heart failure (CHF) increases with age, but most CHF in the elderly is due to diastolic dysfunction with preserved systolic function. The etiology, pathophysiology, diagnosis, natural history, and treatment of hypertrophic and restrictive cardiomyopathies in the elderly are discussed as a paradigm for CHF with normal systolic function. Hypertrophic obstructive and hypertensive hypertrophic cardiomyopathies are compared and contrasted. As an example of a restrictive cardiomyopathy, the various types of amyloidosis and their clinical import in older patients are covered. PMID- 10093772 TI - Atrial fibrillation in the elderly. AB - Atrial fibrillation is the most common sustained arrhythmia seen in clinical practice. Although it occurs in any age patients, its frequency increases with age and is very common in the elderly. Atrial fibrillation causes substantial symptoms and morbidity and is an important cause of thromboembolism and stroke. The two approaches for therapy in those patients with intermittent or persistent atrial fibrillation are (1) maintenance of sinus rhythm with an antiarrhythmic drug or nonpharmacologic therapy, and (2) maintenance of atrial fibrillation with rate control. At the present time there are no data about the best approach and therapy must therefore be individualized. PMID- 10093773 TI - Ventricular arrhythmias, electrophysiologic studies, and devices. AB - Because of the high incidence of heart disease in the elderly, ventricular tachyarrhythmias are not infrequent. Determining the nature and extent of the underlying heart disease and identifying precipitating causes is required prior to instituting long-term therapy. Recent studies suggest that for hemodynamically unstable ventricular tachyarrhythmias, mortality is lower with the implantable cardioverter-defibrillator compared with pharmacologic therapy. This benefit is likely to be more modest in the elderly because of competing cardiac and noncardiac causes of death. For similar reasons, the favorable results reported with the prophylactic use of the implantable cardioverter-defibrillator are likely to be attenuated in the elderly. PMID- 10093774 TI - Assessment of cardiovascular risks and overall risks for noncardiac surgery. AB - Appropriate care of the elderly patient requires a concerted multi-disciplinary approach before, during, and after surgery to optimize functional outcomes, with the principal focus placed on improving quality of life and strategies for risk reduction. Perioperative physicians must be able to assess the biologic, not the chronologic, age of geriatric patients and their capacity for independent function. Physicians need to understand alterations in the physiology of elderly patients attributable to the normal aging process as well as the prevalence of concurrent pathologic conditions that necessitate special precautions. Maintaining autonomy and function as a result of an acute surgical intervention may be the most important outcome to the elderly patient. Most of the data available and guidelines promulgated do not specifically address the elderly population. It is important to collect data prospectively and use sophisticated methods for analyses to develop better management algorithms for these (often complicated) clinical issues in the elderly. PMID- 10093775 TI - Cardiovascular surgery in the elderly. AB - The elderly segment of the population is increasing rapidly, and surgeons are more frequently being requested to operate on this group of patients. A number of reports suggest that elderly patients have a significantly higher incidence of operative mortality and 30-day hospital mortality as compared with younger patients. Elderly patients also had a significantly higher increased incidence of complications, such as renal failure, prolonged ventilation, and incidence of strokes and postoperative cardiac arrest. Regarding coronary artery disease, elderly patients are more acutely sick on admission, are more likely to have triple-vessel disease, more likely have comorbid disease, and are usually less likely to receive an internal mammary artery graft. The presence of valvular disorders with concomitant coronary disease (especially mitral ischemic related valve disease) increases operative time, morbidity, and mortality. Efforts must continue to be made to gather data on outcomes of cardiac surgery in the elderly. Consideration must be given to modify the operative approach that minimizes cardiopulmonary bypass time, mitigates the multisystem organ injury associated with cardiopulmonary bypass, and decreases the likelihood of embolization from the ascending aorta. Future efforts must be made to develop measures to decrease the complications rate identified in elderly patients. PMID- 10093776 TI - Cardiac rehabilitation and preventive cardiology in the elderly. AB - This article reviews data demonstrating the benefits of cardiac rehabilitation and exercise training programs in the elderly. Other risk factor interventions, including cessation of smoking, treatment of diabetes, and lipid therapy, are very beneficial for the elderly with coronary heart disease or strong risk of coronary heart disease. Also briefly reviewed are current data suggesting the benefits of antioxidant vitamins, and folic acid to reduce levels of homocysteine for the primary and secondary prevention of coronary heart disease in the elderly. PMID- 10093777 TI - [Epilepsy and autonomic diseases]. AB - This review article focuses on the functional anatomy of the central autonomic nervous system and the autonomic symptoms and dysfunctions occurring with epileptogenic activity involving areas of the central autonomic nervous system. Clinical experiences have demonstrated a close relation between epileptic and central autonomic activity. Autonomic symptoms are frequent signs of epileptic seizures and may cause dysfunctions in almost every organ system. Cardiorespiratory dysfunction has been described interictually. The increased frequency of sudden unexplained death in epilepsy patients may be related to disturbances in cardiac autonomic control. In contrast, electrical vagal stimulation reduces epileptogenic activity by influencing the central autonomic nervous system. PMID- 10093778 TI - [Postpartum dysphoric syndrome. Psychopathology, diagnosis and etiology]. AB - About half of newly delivered mothers suffer a transient phase of emotional lability or sadness a few days after parturition around the 2nd and 5th day after delivery. The transitory psychopathology of the postpartum blues is similar to premenstrual tension, whose main symptom is irritability. The essence of the postpartum blues is not depression, but a sudden, fleeting and unexpected mood change with anxiousness, low spirits, tearfulness, confusion, poor concentration and forgetfulness. The aetiology of this disorder is unknown. It is well known that oestrogens and progesterone modify catecholamine concentration and the density of adrenergic, noradrenergic und dopaminergic receptors in the limbic structures of the central nervous system. But most of the neurochemical studies have not distinguished between postpartum blues and other forms of depression found in women and occurring postpartum. Those research groups who defined a group with a dysphoric peak in the early puerperium could not find a significant correlation between sex hormone levels, neurobiochemical data, and postpartum mood changes. PMID- 10093779 TI - [Frontal lobe dementia. Clinical-pathologic case reports]. AB - Frontal lobe dementia (FLD) is characterised clinically by personality changes and a progressive speech disorder finally leading to mutism. In the course of the disease also other neurological syndromes may occur such as parkinsonism, a partial Kluver-Bucy-syndrome or a degeneration of motoneurons (FLD + MND). The latter leads to death within about three years. The clinical diagnosis of FLD is supported by functional (SPECT) and morphological (CT, MRI) investigations. From 1988 to 1997, 9 cases of FLD (6 female, 3 male) were clinically diagnosed at our department of Gerontology, LNK Linz. In two of these cases the clinical diagnosis was confirmed histopathologically. Characteristically, all except one patients showed a presenile beginning of the disease. The clinical course was slowly progressive with a mean duration of about 10 years. Special attention was given to additional signs and symptoms of motor neuron disease, parkinsonism and hyperorality. Six patients suffered from FLD + MND; parkinsonism (rigid-akinetic type) and a partial Kluver-Bucy-syndrome were diagnosed in 5 cases each. In histopathological investigations the incidence of FLD seems to increase. This type of dementia should be considered as an important diagnosis differential of presenile dementia-syndromes. PMID- 10093780 TI - [Predictors of response to phase prophylactics (mood stabilizers) in bipolar affective disorders]. AB - Since the introduction of lithium ions in the acute treatment and in the prophylaxis of bipolar disorders the antiepileptic drugs valproate and carbamazepine have been in use for several years as mood stabilizers. In a number of open and controlled clinical studies predictors of response for the single drugs were investigated. These studies indicated that valproate was a predictor of good response in mixed (dysphoric) mania and bipolar rapid cycling. Moreover, valproate has a better response than lithium in secondary mania (organic origin) and atypical mania (episode sequence: depression-mania-euthymia rather than mania depression-euthymia). The preferential efficacy in the spectrum of bipolar disorders of the new antiepileptic drugs lamotrigine and gabapentin must be analysed in more detail in future studies. PMID- 10093782 TI - [Tympanoplasty today: facts, hypotheses and controversies]. PMID- 10093781 TI - [The reliability of stroke scales. The german version of NIHSS, ESS and Rankin scales]. AB - Aim of the study was the translation of three frequently used stroke scales ("National Institutes of Health Stroke Scale" NIHSS, "European Stroke Scale" ESS and "Rankin Scale") into German and the analysis of the interrater reliability of the respective German versions. The translation process followed the protocol of the Medical Outcomes Trust (Boston) and included two independent forward, one backward translation and a consensus conference for the German versions. Interrater reliability was assessed using the weighted kappa statistic. For this study 43 patients with an ischemic stroke determined by computed tomography or magnetic resonance imaging were recruited from two university hospitals. Excluded were patients with an intracerebral hemorrhage or TIA. The interrater reliability of the three German versions was substantial to excellent. Mean Kappa for the NIHSS was 0.80, for the ESS 0.79 and 0.76 for the Rankin Scale using simple weights in the analysis. Additional analysis revealed the influence of preselected weights on the results of the kappa statistic. The use of German versions of frequently used stroke scales can reduce bias that is introduced by different levels of knowledge of the English language and thus improve the standardised assessment of neurological deficits in stroke. PMID- 10093783 TI - [Possibilities and limits of Doppler ultrasound in the area of the head-neck]. AB - Sonography has provided an important addition to the tools available for the diagnosis of the soft tissues in the head and neck region. The ENT surgeon himself is able to examine pathological formations by this quick, non-invasive and, last but not least, less expensive method. Due to the high resolution of the procedure the chance of detecting even small changes is increased and the exactness of diagnosis of pathological lymph nodes of the neck has been significantly improved compared to palpation alone. Ultrasound has replaced the sialographic procedures in the field of diagnostic evaluation of salivary gland disease in the daily practice except for special indications. After inauguration of color Doppler sonography non-invasive evaluation of vascular stenosis of the large cervical vessels concerning their hemodynamic effects has become possible. This issue is important for the differential diagnosis of otoneurological diseases such as sudden hearing loss, vertigo and tinnitus. Additionally, the extent of perfusion of space-occupying lesions can be easily examined, and therefore the risk of mass bleeding can be preoperatively assessed by this method without harm to the patient. Especially carotid body tumors may be diagnosed with high accuracy by the evidence of significant diffuse perfusion of the lesion. In several studies the specificity of the assessment of cervical lymph node disease could be increased by examination of resistance indices. However, other authors have shown inconsistent results in differentiation of benign and malignant lumps; therefore, final judgment does not seem to be possible yet. Use of echo-contrast agents to enhance the ultrasound signal seems to be a promising approach for future developments in color Doppler imaging. PMID- 10093784 TI - [Guidelines of the German Society of Otorhinolaryngology, Head and Neck Surgery. Tinnitus. German Society of Otorhinolaryngology]. PMID- 10093785 TI - [Immunoglobulin subclass defects in patients with therapy refractor chronic rhinosinusitis]. AB - In the present study 220 patients suffering from recurrent rhinosinusitis and not responding to antibiotic treatment were evaluated for a defect in IgG immunoglobulin subclasses. Twenty-one of these patients were found to have an antibody deficiency. These included deficiencies of IgG-2 (n = 10), IgG-1 (n = 6), IgG-3 (n = 1) and IgG-4 (n = 1). A common variable immune disease was diagnosed in three patients that was characterized by an additional defect in the IgG main class. However, an IgG subclass deficiency can only be ascertained by an immunological evaluation. The significance of a deficiency can be identified by a reaction to vaccination using (for example) protein or polysaccharide antigens. Treatment consists of antibiotics, intravenous immunoglobulins and long-term follow-up. Endonasal microsurgery should only be performed in cases that do not respond to conservative treatment. It is particularly necessary to observe these patients because a deficiency of immunoglobulin subclass in certain cases is the first sign of an immunological impairment that can advance to a severe immunodeficiency and predispose to the development of malignancy. PMID- 10093786 TI - [Modification of bacterial growth by alloplastic bone substitutes]. AB - BACKGROUND: To determine the applicability of alloplastic materials as bone substitutes it is now standard procedure to test materials for possible toxic effects and to study their behavior in animal models and cell cultures. This is especially important with respect to middle ear implants that can be put at risk by recurrent infections and require additional testing in a bacterially contaminated environment. MATERIALS AND METHODS: In the present study ionomeric cement (V-O CEM), bioactive glass ceramic and hydroxyapatite were subjected to contamination with S. aureus, E. coli, Pr. mirabilis, Ps. aeruginosa and Enterococci using agar diffusion and microbial suspension tests and examined for their antibacterial activity. A special feature of V-O CEM that had to be considered was that it could be implanted in two physical states (as a viscous substance and a fully hardened material). RESULTS: The agar diffusion test showed that an antibacterial effect of freshly mixed V-O CEM was demonstrable for up to 60 min. In the microbial suspension test growth of E. coli was found to be promoted after 48-h incubation by V-O CEM set for 1 h. S. aureus exhibited a depressed growth, while Pseudomonas cultures demonstrated cell death after 48 h. V-O CEM set for 24 h and 7 days, respectively, exerted a similar though less pronounced effect. Using the microbial suspension test, a comparison was also made of the antibacterial activities of 24-h V-O CEM, bioactive glass ceramic and hydroxyapatite against cultures of S. aureus, Pseudomonas and E. coli. The inhibitory effect of hydroxyapatite on the growth of S. aureus was found to persist beyond the 48-h incubation period. There was slight growth of E. coli in the presence of bioactive glass ceramic after 48 h, whereas hydroxyapatite produced inhibition of microbial growth. V-O CEM inhibited the growth of Pseudomonas, unlike bioactive glass ceramic and hydroxyapatite, which transiently promoted bacterial growth. DISCUSSION AND CONCLUSIONS: Our findings showed that V O CEM, bioactive glass ceramic and hydroxyapatite exhibited material-dependent bacterial colonization and thus resembled polymeric bone substitutes (susceptible to invasion by S. epidermidis) and metals (sensitive to S. aureus). In general, users of bone substitutes should conduct preclinical tests in order to obtain advance information on the properties of possible replacement material. Since there can be varying interactions between the materials studied and bacterial growth, material-specific effects on bacterial growth should be investigated. While it is recognized that in vitro studies are an inadequate simulation of the clinical situation, they still provide some insight into the likely behavior of a bone substitutes in human sites. PMID- 10093787 TI - [Detection of serum concentration of carbohydrate-deficient transferrin (CDT) in patients with head-neck carcinomas]. AB - It is now well known that chronic alcohol abuse is an important factor for developing head and neck squamous cell carcinoma (HNSCC). While hospitalized, these patients are at great risk for developing an unexpected alcohol-withdrawal syndrome. Compared to common markers of alcohol abuse, carbohydrate-deficient transferrin (CDT) has been found to be more sensitive and specific. It is therefore very useful for detecting alcoholism and controlling compliance of alcohol withdrawal. We analyzed the serum concentrations of CDT, liver enzymes and mean corpuscular volume in 49 male patients with HNSCC. Elevated CDT levels were found in more than 25% of patients who earlier denied a history of chronic alcohol abuse. Over one-third of these patients developed an alcohol-withdrawal syndrome. These findings demonstrated that analysis of elevated CDT serum levels was a valuable method for detecting chronic alcohol abuse and recognizing patients at risk for developing an alcohol-withdrawal syndrome post-operatively. PMID- 10093788 TI - [Distant metastasis of squamous epithelial carcinomas of the upper aerodigestive tract. The effect of clinical tumor parameters and course of illness]. AB - Screening for distant metastases from head and neck tumors is still controversial. In the present study, the records of 1087 patients with newly diagnosed squamous cell carcinomas of the upper aerodigestive tract were reviewed retrospectively to determine clinical factors influencing the incidence and location of distant metastases. Overall, 130 patients (12.0%) developed clinical evidence of metastatic disease, 17 of whom (1.6%) had metastases at the time of initial presentation. The rate of distant metastases significantly increased with the initial stage of tumors (P < 0.00001) and the occurrence of local and/or regional recurrences (P < 0.00001) or of second primaries below the clavicles (P < 0.0005). The locations of primary cancers as well as histopathologic grading were not independent risk factors for the development of distant metastases. They mainly reflected different frequency distributions of stages. The lungs, liver and bones were the most common sites of metastatic disease, being involved in 68.5%, 23.8% and 20.0% of cases, respectively. Our findings show that at the time of initial presentation chest X-ray alone appears to be sufficient to exclude distant metastases from tumors classified as T1-3 NO. Further screening comprising abdominal ultrasound, bone scanning and/or CT scans of the thorax is particularly indicated for patients with advanced-stage disease, local and/or regional recurrences and second primaries below the clavicles. However, the individual decisions should consider whether the detection of distant metastases will significantly affect clinical management. PMID- 10093789 TI - [Haptic form discrimination. Group comparison of children with normal speech development and former speech development disordered patients]. AB - The importance of the neurobiological basis of developmental language disorders includes somatosensory modalities. Twenty-five children were diagnosed as having specific language-impairment at preschool age. All were examined with regard to their manual haptic form discrimination without visual control at a mean age of 8.7 years +/- 7.1 months. This study group was compared to age- and gender matched normal children of equal non-verbal intelligence (control group). Haptic discrimination was measured with the Seguin formboard on which the children were required to place ten geometrical forms in appropriate holes. Both groups differed significantly in their mean quantitative performances in favor of the control group (P < 0.05). The difference in their mean performance and their mean discrimination times did not reach statistical significance. All results were not age-dependent. The control group on average performed significantly better with their left hands than the study group (P < 0.05). Qualitative analysis revealed a significant difference in haptic discrimination of the pointed forms and was probably caused by inadequate exploration procedures and/or cognitive representation deficits. The results of the children with previous developmental language disorders were interpreted as an expression of an impaired cerebral maturation. PMID- 10093790 TI - [Unusual intra-extracranial extension of meningioma of the lateral skull base]. AB - Extracranial meningiomas are rare tumors of the lateral skull base. A 37-year-old woman presented with tinnitus und progressive hearing loss of her right ear. A painful mass lesion was also palpable in her mandibular angle. CT and MRI scans revealed an intracranial mass with extension to the lateral skull base. These findings suggested the occurrence of a paraganglioma or meningioma. In a two stage surgical procedure tumor was extirpated without functional impairment to the patient. Histology of the excised lesion demonstrated an endotheliomatous meningioma. Since an extracranial meningioma can present as a mass lesion of the lateral skull base, CT and MRI scans are essential in preoperative surgical planning. PMID- 10093791 TI - [Parapharyngeal tumor. Ganglioneuroma of the right sympathetic trunk]. PMID- 10093792 TI - [Puncture tracheotomy versus conventional tracheostomy. An interdisciplinary discussion]. PMID- 10093793 TI - Intracerebroventricular injection of capsaicin or substance P provokes the micturition reflex in the rat. AB - Acute intracerebroventricular injection of 25 micrograms capsaicin or 40 micrograms substance P in isotonic saline elicited approximately similar effects on the micturition reflex, but capsaicin had twice as much effect as substance P. This effect is specific, since acute intracerebroventricular injection of isotonic saline did not produce the micturition reflex. It can be hypothesized that capsaicin and substance P may act on the brain micturition centers directly or by mediation of neuropeptides such as tachykinins, but other hypotheses are also made. PMID- 10093794 TI - The therapeutic potential of Aloe Vera in tumor-bearing rats. AB - Aloe Vera has been claimed to contain several important therapeutic properties, including anticancer effects. The effect of Aloe Vera administration was studied on a pleural tumor in rat. Growth of Yoshida AH-130 ascite hepatoma cells injected (2 x 10(5) in 0.1 ml) into pleura of male inbred Fisher rats was evaluated at different times (7th and 14th days). Data show that the use of Aloe Vera proved a therapeutic method, and that the present experimental model could be useful in the study of other therapeutics treatments in vivo. PMID- 10093795 TI - Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients. AB - Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects proved in experimental models and healthy volunteers. This study reports the results of a 4-week, randomized, double-blind, placebo-controlled trial investigating the effects of policosanol on platelet aggregation in type II hypercholesterolemic patients. Patients started or continued on a step-one cholesterol-lowering therapy for 4 weeks and those with total cholesterol > 5.0 mmol/L despite dietary conditions were randomized to receive under double-blind conditions placebo or policosanol (10 mg/day) for 30 days. Both groups were similar at randomization. Effects of policosanol on platelet aggregation induced by arachidonic acid (3.2 mM), collagen (0.5-1 microgram/ml) and ADP (0.5-1 uM) were determined at baseline and after 30 days of treatment. Policosanol significantly reduced platelet aggregation induced by arachidonic acid and collagen, meanwhile it only inhibited significantly the platelet aggregation induced by the lowest doses of ADP (0.5 uM). No adverse events occurred during the trial. Only one patient (placebo) discontinued from the study because of arthralgia. PMID- 10093796 TI - Intraarticular injection of sodium hyaluronate plus steroid versus steroid in adhesive capsulitis of the shoulder. AB - To determine the efficacy of a combined treatment--namely hyaluronan and corticosteroid injection plus physical exercises in the management of established idiopathic capsulitis of the shoulder--30 consecutive subjects with adhesive capsulitis were selected for the study. The diagnosis of adhesive capsulitis was established on the basis of a clinical history of spontaneous shoulder pain, shoulder examination showing passive limitation in conformity with capsular pattern, cervical examination excluding significant dysfunction of this area, plain radiographs excluding other significant shoulder diseases, or sonographic examination showing capsule shrinkage in affected joint. The patients were randomly allocated to receive intraarticular injections of sodium hyaluronate (20 mg) plus steroid (20 mg triamcinolone acetonide) and physiotherapy or intraarticular injections of steroid (20 mg triamcinolone acetonide) alone and physiotherapy. The intraarticular injections were performed at 15-day intervals in the first month and then monthly for 6 months. Physiotherapy was performed for 4-12 weeks. The results indicate an improvement of pain and joint motion after 6 months in all patients, especially in the patients treated with sodium hyaluronate. Intraarticular hyaluronan combined with triamcinolone acetonide and shoulder exercises may improve adhesive capsulitis. This drug possibly acts on shoulder tissue retraction by means of its influence on osmotic pressure and synovial fluid volume control. PMID- 10093797 TI - Effect of atropine on ciliary beat in human upper respiratory tract epithelial cells. AB - The mucociliary apparatus is a fundamental element among the defensive mechanisms of the airways. In man, average ciliary beat frequency (CBF) has been reported to be between 600 and 1,000 beats/min and does not vary significantly at different sites along the respiratory tract. Ciliary function is altered by numerous factors, including temperature, pH, cigarette smoke, drugs, and alcohol. The aim of the present study was to evaluate whether intravenous (i.v.) infusion of atropine alters CBF. We studied nine patients (six females and three males, mean age 42.9 years) with otosclerosis, a nonrespiratory disease. All patients were scheduled for surgical stapedectomy. In all patients, nasal brushing was performed before and 20 min following i.v. injection of 0.5 mg atropine sulphate. The cellular samples, maintained viable in tissue medium, were observed under a microscope and filmed. A quantitative evaluation of ciliary activity was obtained by playing the film back in slow motion. The mean CBF value prior to atropine infusion in the nine patients studied was 588.12 (+/- 53.29 SD) beats/min. After infusion of atropine, mean CBF was 442.33 (+/- 52.82 SD) beats/min. The mean percentage drop in CBF following atropine infusion was 24.79% (t = 5.82, p < 0.001). Our data show a drop in in vitro CBF following atropine infusion which, presumably, reflects a fall in the in vivo efficacy of mucociliary transport. Atropine treatment determined a loss in CBF that was inversely correlated with increasing age. PMID- 10093798 TI - Treatment of tibial bone defects with the Ilizarov circular external fixator in high-velocity gunshot wounds. AB - One of the applications for circular external fixators is the treatment of large bone defects which may be difficult to manage with conventional methods. Successful results have been reported with the use of circular external fixators, particularly in the treatment of infected tibial pseudoarthroses and those with bone loss. In this study, a total of 43 cases with tibial bone defects (18 infected) as a result of high-velocity gun-shot injuries were treated with circular external fixators between January 1, 1988 and December 31, 1995. The mean follow-up period was 50 months (range: 28-98 months) after the removal of the Ilizarov device. Satisfactory union was obtained in 40 cases without any major complication or additional surgical intervention, in spite of the large and in some cases infected defects. We conclude that this is a safe method for the treatment of infected or noninfected tibial bone defects. PMID- 10093799 TI - Open reduction and internal fixation of acetabular fractures. AB - Between 1982 and 1995, 84 patients with displaced acetabular fractures underwent open reduction and internal fixation in our institution. The mean follow-up was 5.5 years with a minimum of 2 years. There were 33 simple and 51 complex fractures according to the classification of Judet and Letournels. Reduction after operation was anatomical in 49% of the patients, satisfactory in 24%, and unsatisfactory in 27%. Using Merle d'Aubigne's scale, the clinical results were excellent in 39% of the patients, good in 29%, fair in 8%, and poor in 24%. Factors of statistical significance associated with a poor clinical outcome were T-shaped fractures, unsatisfactory reduction (> 3 mm residual displacement), age > 40 years and development of avascular necrosis. Acetabular surgery is demanding, and a high rate of complications can be expected. Trauma centres should designate a group of surgeons who will consistently treat these fractures in order to obtain more experience and better results. PMID- 10093800 TI - Effects of aggressive early rehabilitation on the outcome of anterior cruciate ligament reconstruction with multi-strand semitendinosus tendon. AB - To evaluate the effects of aggressive early rehabilitation on the clinical outcome of anterior cruciate ligament reconstruction using semitendinosus (and gracilis) tendon, 103 of 110 consecutive patients who underwent ACL reconstruction using multistrand semitendinosus tendon (ST) or the central one third of patellar tendon with bony attachments (BTB) were analyzed prospectively. Subjectively, the Lysholm score was not different among the groups. The Lachman test indicated a trend of less negative grade in the ST men's group than that in the BTB men's group. On the patellofemoral grinding test, only women patients of both groups showed pain, with less positive crepitation in the ST group than in the BTB group. KT measurements at manual maximum showed more patients with more than 5 mm differences in the ST group than in the BTB group. The results of this study suggest that aggressive early rehabilitation after the ACL reconstruction using the semitendinosus (and gracilis) tendon has more risk of residual laxity than with the BTB. PMID- 10093801 TI - The role of fibular length and the width of the ankle mortise in post-traumatic osteoarthrosis after malleolar fracture. AB - We assessed the role of fibular length and the width of the ankle mortise as risk factors in the occurrence of post-traumatic osteoarthritis of the ankle joint by comparison of radiographs of the affected and unaffected sides. A shortened fibular malleolus (P < 0.01), a wide ankle mortise (P < 0.01) and Weber type B fracture (P < 0.01) were significantly associated with the development of osteoarthrosis but an elongated fibular (P > 0.05) and a narrowing of the ankle mortise (P > 0.07) were not. PMID- 10093802 TI - Modified Bankart procedure for recurrent anterior dislocation and subluxation of the shoulder in athletes. AB - Thirty-four athletes (34 shoulders) with recurrent anterior glenohumeral instability were treated with a modified Bankart procedure, using a T-shaped capsular incision in the anterior capsule. The inferior flap was advanced medially and/or superiorly and rigidly fixed at the point of the Bankart lesion by a small cancellous screw and a spike-washer. The superior flap was advanced inferiority and sutured over the inferior flap. Twenty-five athletes (median age: 22) were evaluated over a mean period of follow-up of 65 months. The clinical results were graded, according to Rowe, as 22 (88%) excellent, 3 (12%) good, and none as fair or poor. The mean postoperative range of movement was 92 degrees of external rotation in 90 degrees of abduction. Elevation and internal rotation was symmetrical with the opposite side. Twenty-four patients returned to active sport, 22 at their previous level. This modified Bankart procedure is an effective treatment for athletes with recurrent anterior glenohumeral instability. PMID- 10093803 TI - Results of the Bosworth method for unstable fractures of the distal clavicle. AB - Eleven consecutive Neer's type II unstable fractures of the distal third of the clavicle were treated by open reduction and internal fixation, using a temporary Bosworth-type screw. In all cases, fracture healing occurred within 10 weeks. Shoulder function was restored to the pre-injury level. A Bosworth-type screw fixation is a relatively easy and safe technique of open reduction and internal fixation of type II fractures of the distal third of the clavicle. PMID- 10093804 TI - The effect of using a tourniquet on the intensity of postoperative pain in forearm fractures. A randomized study in 32 surgically treated patients. AB - We have analysed the relationship between the intensity of postoperative pain and the use of a pneumatic tourniquet in procedures for operative fixation of fractures of the forearm. Thirty-two patients were divided randomly into two groups as a control (NT) and tourniquet (T). The pain scores in the NT group were significantly lower. Patients over the age of 30 had notably more pain than those younger after the use of a tourniquet. Avoidance of the tourniquet gave better postoperative analgesia in male patients and in those with comminuted fractures. When a tourniquet was used the best results were obtained if it was kept inflated for less than one hour. PMID- 10093805 TI - Predicting the outcome of adductor tenotomy. AB - This study reviewed 57 hips in 30 children (18 girls and 12 boys) with cerebral palsy who had undergone an adductor tenotomy alone or in combination with an anterior obturator neurectomy (23 hips). Results were evaluated by the Reimers migration percentage (MP). The hips were split into three groups: group A (12 hips) a preoperative MP of less than 20%, group B (25 hips) between 20 and 40%, and group C (20 hips) more than 40%. The mean age at the time of surgery was 6 years and 1 month (range: 2.5-13 years). The mean period of review was 6 years and 3 months (2-20 years). The results were considered as "good" when radiographs at the longest follow-up showed a decrease of > 10% of the MP, as "bad" when they showed an increase of > 10%, and as "stable" when the MPs varied less than 10%. At the latest review of group A, 11 were stable (92%) and 1 was bad. In group B, 12 were stable (48%), 7 were good (28%), and 6 were bad (24%). In group C, 7 were stable (35%), and 13 were bad (65%). The preoperative migration percentage provided to be the only predictor of outcome. Age at the time of surgery had no constant significant effect on the outcome, neither had the addition of an anterior neurectomy. PMID- 10093806 TI - Coating titanium implants with bioglass and with hydroxyapatite. A comparative study in sheep. AB - This study compares the osteointegration of titanium implants coated with bioglass (Biovetro GSB formula) and with hydroxyapatite (HAP). Twenty-four bioglass-coated and 24 HAP-coated cylinders were implanted in the femoral diaphyses of sheep, and examined after 2, 4, 6, 8, 12, and 16 weeks. The HAP coating gave a stronger and earlier fixation to the bone than did bioglass. Bioglass formed a tissue interface which showed a macrophage reaction with little new bone formation activity. In contrast, HPA, showed intense new bone formation, with highly mineralised osseous trabeculae in the neighbourhood of the interface. PMID- 10093807 TI - Osteonecrosis of the hip in sickle-cell disease associated with tuberculous arthritis. A review of 15 cases. AB - We report a study of 15 cases of tuberculous hips with sickle-cell disease who presented during 1991-1993. Although the osteonecrosis was long-standing, biopsy was nearly always required to reveal the more recent tuberculous infection. Management consisted of 6 months of anti-tuberculous chemotherapy with appropriate palliative surgery 5-8 weeks after the start of drug treatment. The operative techniques which we used are described. The results were good both post operatively, and in 12 patients followed-up at an average of 3 years. We recommend this combined management for the treatment of secondary tuberculous infections of hips previously damaged by sickle-cell disease. PMID- 10093809 TI - Fractures of the posteromedial process of the talus. A report of two cases. AB - The authors present two cases of fractures of posteromedial process of talus. One was treated conservatively and the other by excision. The appearances of the CT scans, the therapeutic options and the mechanisms of injury are discussed. PMID- 10093808 TI - Simultaneous bilateral total knee arthroplasty in a single procedure. AB - Eighty-eight consecutive patients undergoing total knee arthroplasty (TKA) were reviewed retrospectively and divided into two groups. Group I (64 patients) had both knees replaced simultaneously by one team in a single procedure while Group II (24 patients) had 2 operations staged about 7 days apart. The blood loss, operative time, knee functional score, period of hospitalisation and complications were documented in order to compare the 2 groups. Performing simultaneous bilateral TKA (Group I) did not increase the incidence of operative or post-operative complications. Equally, the functional score and mean intra- and post-operative blood loss were not influenced. The operative time and duration of hospitalisation were significantly shorter in Group I than in Group II. On the basis of the results of this study, it appears that simultaneous bilateral TKA is beneficial. PMID- 10093810 TI - Pathological fracture of a lumbar vertebra caused by rheumatoid arthritis--a case report. AB - We describe a case of rheumatoid arthritis (RA) with collapse of the L3 lumbar vertebra for which surgery was performed. The pathogenesis of lumbar lesions affected by RA is discussed and the literature reviewed. PMID- 10093811 TI - Chondrodiatasis in a patient with spondyloepimetaphyseal dysplasia using the Ilizarov technique: successful correction of an angular deformity with ensuing ossification of a large metaphyseal lesion. A case report. AB - Distraction through the physis (chondrodiatasis) is a controversial technique with unpredictable results. However, it has been used in the past for the lengthening and correction of angular deformities of long bones. We report the case of an 11-year-old patient with spondyloepimetaphyseal dysplasia (SEMD) who presented with a severe recurvatum deformity of the left proximal tibia secondary to collapse of the tibial plateau into a large metaphyseal cystic lesion. Using the chondrodiatasis technique with a percutaneously applied Ilizarov circular frame, we were able to correct this deformity. Surprisingly, healing and ossification of the metaphyseal lesion was simultaneously observed at the end of the treatment, a finding which, to the best of our knowledge, has not been previously reported. PMID- 10093812 TI - Multiple disc herniations in spondyloepiphyseal dysplasia tarda. A case report. AB - Spondyloepiphyseal dysplasia (SED) tarda is a group of inherited dysplasias in which the spine and the epiphyses of long bones are affected from late childhood. A 19-year-old male was diagnosed as SED tarda. He had a thoracic and then lumbar disc herniations which were separated by a 4-year interval. Surgical excision was performed for each disc herniation. This is the first case report of multiple disc herniations in SED. PMID- 10093813 TI - [Cervical spondylolisthesis in skeletal fluorosis. A case report]. AB - The authors report an uncommon complication in cervical skeletal fluorosis. It is a cervical spondylolisthesis at C5-C6 level complicated by a radiculomyelopathy described in a man living in an endemic area for fluorosis. After 3 years, a spontaneous stabilization of the cervical spine with a posterior calcification of the supraspinal and interspinal ligaments has caused an improvement of the neurological symptomatology. PMID- 10093814 TI - Growth factors in bone. AB - Bone contains several growth factors, including bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-beta), insulin-like growth factors I and II (IGF-I and IGF-II), platelet derived growth factor (PDGF) and basic and acidic fibroblast growth factor (bFGF and aFGF). Spatial and temporal variations in the expression and secretion of the various growth factors have been demonstrated in osteoblastic cultures and in various experimental and clinical in vivo models, including fracture healing in humans. Local application of various growth factors influences proliferation, differentiation and protein synthesis in osteoblastic cultures and bone formation in different animal models, including experimental fractures and skeletal defects. The BMPs are the only growth factors known to provoke bone formation heterotopically by making undifferentiated mesenchymal cells differentiate into osteoblasts (osteoinduction). BMPs and other growth factors, soon to become commercially available for clinical use, need a delivery system for their sustained release, as the factors are otherwise rapidly absorbed. Some existing systems inhibit bone formation by inducing chronic inflammation or physically by unresorbed carrier obstructing bone formation. New delivery systems are being investigated. PMID- 10093815 TI - The orthopaedic aspects of multiple epiphyseal dysplasia. AB - Five cases of multiple epiphyseal dysplasia (MED) were treated from 1985-1996 at the Orthopaedics and Trauma Department of SSK Izmir Educational Hospital. Four patients were female and one was male. The pedigrees of the first two female patients had the same features of inter-related marriages. The patients have been followed up for 5.5-11 years (average of 7.5 years). Surgical operations were mostly required in the lower limbs. Problems in the hips required adductor myotomy, the Soutter procedure, total hip replacement, and pertrochanteric extension osteotomy. Management of the knees required supracondylar shortening and extension osteotomy of the femur, high tibial extension osteotomy, debridement of the knee joint with removal of osteophytes, ogleotomy of the patellar lengthening of the knee flexors and posterior capsulotomy. Interphalangeal arthrodesis for hammer toes, extension osteotomy of the head of the first metatarsals, and Kellers operation were carried out in the foot. In the upper limb decompression and anterior transposition of the ulnar nerve, debridement of the elbow joint, extension and valgus osteotomy of the distal radius, and extension osteotomy of the head of the first metacarpal were required. PMID- 10093816 TI - A neurophysiological approach to brainstem reflexes. Blink reflex. AB - The blink reflex (BR) is a generalised phenomenon in mammals. Its teleological protective eye function is perhaps the reason why the BR can be provoked by a multitude of stimuli. As corneal and glabellar reflexes, BR has an inveterate use in the neurological exploration. Some of its physiopathological aspects were discussed more than 100 years ago, and soon half a century will have passed since the first electrophysiological study was published. This review focuses on the BR elicited by the electrical stimulation of the trigeminal supraorbital nerve, a controlled and reliable model in clinical neurophysiology. The electrically elicited BR is an exteroceptive-nociceptive reflex recorded on the orbicularis oculi muscle and formed by three components: the two principal ones, R1 and R2, of well-known characteristics, and a third, R3, of increasing interest, to which there is wide mention. The trigeminal afferent limb reaches the facial efferent one by means of a long and quite complex central pathway located at the brainstem bulbopontine level. The anatomical substrate and criteria of the rich topographical lesional semiology of the BR are established. The importance of the suprasegmental influences upon the reflex, coming mainly from the cerebral cortex and basal ganglia, as well as the impairment caused by their damage, will be emphasised. Special attention is paid to the relationship between the reflex and the dopaminergic system, and the consequences of its derangement. The methods of habituation and suppression-recovery of the BR are extensively and critically reviewed. These methods measure its excitability and serve in practice for the pathophysiological study of numerous diseases. The relationship of the BR with the spontaneous blinking is considered, and the existence of a primary inhibitory reflex on levator palpebrae muscles, previous to the active reflex response of the orbicularis, is proposed. The electrophysiological characteristics of the glabellar reflex, the corneal reflex, the acoustic, photic and somatosensory provoked BR, the ontogeny, and some of the common factors influencing the reflex, such as sleep, are also discussed. The strategic position of the neural structures of the BR, in an area involved in the gating of the various sensory motor systems and the relative ease to its evaluation with common methodology used in clinical neurophysiology, makes the BR an essential tool for the diagnosis and pathophysiological insight into an important number of human neurological disorders. PMID- 10093817 TI - Simplified projection of EEG dipole sources onto human brain anatomy. AB - This study was aimed at determining an easy way to project dipole modelling results onto brain anatomy. This simplified projection is based on the estimation of the mean location of the centre of the dipole sphere according to internal brain landmarks. The mean values for the centre location were calculated from ten epileptic patients. To define the axes of the dipole model frame on the patient's magnetic resonance image (MRI), markers were pasted at some electrode positions during the acquisition. An estimation was then made of the mean position of the model centre from the bicommissural line (anterior commissure-posterior commissure [AC-PC]), and a simple transformation to pass from the model cartesian coordinates to the anatomical correlates either in the subject MRI or in the Talairach atlas. These data were then tested in four additional subjects in whom no markers had been placed during the MRI acquisition. On average, the horizontal plane of the sphere model was pitched up 1.9 degrees +/- 1.8 only with respect to the AC-PC horizontal plane, which allowed the projection of dipoles directly onto the Talairach atlas, without pitch. The mean sphere centre was located 7.4 +/- 4.2 mm above the bicommissural line, and 8.2 +/- 1 mm in front of the posterior commissure. In the four additional subjects, projections on MRI and atlas indicated the same anatomical regions and showed high congruence with the physiology or the pathology. This simplified way we report herein has proved to give reliable results. We believe that this method will be useful as a first approximation to project dipole coordinated onto MRI data; moreover, when MRI is unavailable, our results show that dipole modelling results can be superimposed onto atlas slices provided that they are represented according to the AC-PC plane. PMID- 10093818 TI - [Event-related desynchronization and synchronization. Reactivity of electrocortical rhythms in relation to the planning and execution of voluntary movement]. AB - Cortical electroencephalographic rhythms reactivity may be quantified using event related desynchronization (ERD) and synchronization (ERS) methods. We therefore studied cortical activation occurring during programming and performance of voluntary movement in healthy subjects. EEG power evolution within the reactive frequency bands (mu and beta central rhythms) was averaged before, during and after a minimum of 50 self-paced flexions of the thumb. Recordings in 18 normal adults showed that ERD (decrease in power) of mu rhythm started 2,000 ms before movement onset, while ERD of beta rhythm started 1,500 ms before movement onset. Early ERD of mu and beta rhythms were located over the contralateral central region covering primary motor cortex. They were followed by bilateral ERD occurring over ipsilateral and contralateral central regions during performance of the movement. At the end of the movement, an ERS (increase in power) of beta rhythm occurred. These results suggest that programming of voluntary movement induces early activation in contralateral sensorimotor areas, while performance of the movement induces bilateral activation in sensorimotor areas. ERS of beta rhythm occurring at the end of the movement could correspond to inactivation of motor areas activated by movement. Based on EEG activity, ERD and ERS prove to be useful methods to analyze cortical activation during programming and performance of voluntary movements with good spatial and temporal resolution. PMID- 10093819 TI - [Event-related desynchronization and Parkinson disease. Importance in the analysis of the phase of preparation for movement]. AB - This study was aimed at determining the spatiotemporal distribution of event related desynchronization (ERD) during self-paced voluntary movement in order to establish the interest of this method for the analysis of movement programming in Parkinson's disease. Desynchronization of mu rhythm was recorded 2 s before to 0.5 s after right then left self-paced voluntary wrist flexions from 11 leads covering the primary sensorimotor cortex (central), supplementary motor area (frontocentral) and parietal cortex (parietocentral). Recordings were obtained from ten control subjects, ten patients treated for Parkinson's disease (bilateral symptoms) and 20 patients presenting with right or left hemiparkinsonism before and after chronic administration of L-dopa. In the control group, ERD started over the contralateral primary sensorimotor cortex 1,750 ms before movement and was bilateral just before performance of the movement. In both treated and de novo Parkinson's disease groups, decrease in ERD latency (1,000 to 1,250 ms before movement) was only observed when movements were performed with the akinetic hand and corresponded to a decrease in motor cortical activity. This confirmed that programming of movement is affected in Parkinson's disease. Earlier ERD with central ipsilateral distribution were also observed, suggesting that other cortical areas might be activated to compensate for dysfunction of movement programming and to increase the level of cortical activity required for performance of the movement. The administration of L-dopa to de novo hemiparkinsonians patients resulted in increased ERD latency over contralateral and ipsilateral central areas. As in the treated Parkinson's disease group, frontocentral ERD could also be recorded. L-dopa would thus partially restore the affected motor programmation and modulate cortical activation in both supplementary motor area and primary motor cortex, the later receiving more afferences from basal ganglia. PMID- 10093820 TI - Headache in children with centrotemporal spikes. AB - The aim of the study was to evaluate the long-term evolution of headache associated with rolandic centrotemporal spikes (CTS). The patient group consisted of a group of 32 children who suffered from headache and presented CTS at electroencephalogram (EEG). As the control group, we selected 52 sex- and age matched children with headache without any EEG abnormalities. During a follow-up of 5 years none of them showed epileptic seizures. The number of headache attacks decreased in the majority of patients, as in the controls. A good correlation could be identified between CTS and the number of headaches attacks both at baseline (r = 0.58, P < 0.001) and at follow-up (r = 0.64, P < 0.001). In four children (12.5%), the frequency of headache attacks increased and this increase was associated with a higher frequency of CTS. In two patients, a change in the EEG pattern was observed during follow-up, with a 'migration' of the epileptiform complex from central to parietooccipital leads. In conclusion, these findings confirm that CTS are not pathognomonic of centrotemporal epilepsy and that evolution of CTS and headache in children are statistically related. PMID- 10093821 TI - [Epilepsy in 1997-1998]. PMID- 10093822 TI - [Peripheral electrodiagnosis in 1998]. PMID- 10093823 TI - The role of pRb2/p130 protein in diagnosing lung carcinoma on fine needle aspiration biopsies. AB - The retinoblastoma gene family is composed of three members: the retinoblastoma gene, one of the most studied tumor suppressor genes, and two related genes: p107 and pRb2/p130. These proteins are also known as the pocket proteins due to a unique structural and functional domain composed of subdomains A and B separated by a spacer region that is highly conserved among each of the proteins. These proteins exhibit unique growth suppressive properties that are cell type specific, suggesting that although the pocket proteins may complement each other, they are not fully functionally redundant. With the development of antibodies recognizing these three proteins it is now possible to detect expression in formalin-embedded specimens. Recent studies on 235 lung cancers, using immunohistochemical techniques, suggested an independent role for Rb2/p130 in the development and/or progression of human lung carcinoma. We found a statistically significant inverse relationship between the histological grading (degree of malignant potential) and the expression of pRb/p105, p107 and pRb2/p130 in squamous cell carcinomas, meaning that an increase in grading resulted in a significant decrease in protein expression. This phenomenon was particularly evident for pRb2/p130 (p < .0001) which had the highest percentage of undetectable levels in all the specimens examined and the tightest inverse correlation (p value) with both the histological grading and PCNA expression in the most aggressive tumor types, suggesting an important role for pRb2/p130 in the pathogenesis and progression of certain lung cancers. We further explored the expression of pRb2/p130 protein in routine archival FNAB cytological material from 30 Patients with lung cancer using immunocytochemical techniques, comparing protein expression with tumor type. Two pathologists evaluated the staining pattern and scored the percentage of positive cells. Of the 30 neoplasms, 27 displayed a positive staining for pRb2/p130. In particular, we detected pRb2/p130 in 9 (100%) squamous carcinomas, 11 (84%) adenocarcinomas, 5 (100%) BAC, and 2 (66%) SCC. The percentage of positive nuclei varied in different tumors with the highest expression level in adenocarcinomas. Immunocytochemistry represents a sensitive method for detection of pRb2/p130 expression in cytological or archival specimens, and the level of detection seems to be comparable to paraffin sections. Therefore, this methodology could be used in the preoperative evaluation of routine cytological specimens in order to improve the diagnostic and prognostic evaluation of lung cancer patients. PMID- 10093824 TI - Human glioblastoma differentiation is modulated by growth environment. PMID- 10093825 TI - Lymph node revealing solution: a rapid method for the fixation of cystectomy specimens. AB - The objective of this study was to describe the use of the lymph node revealing solution (LNRS) for rapid fixation of total cystectomy specimens, and to compare it with formalin fixation. LNRS is a mixture of 95% ethanol, diethyl ether, glacial acetic acid and buffered formalin (65:20:5:10 v/v) prepared under a fume hood. Sixteen consecutive cystectomy specimens were fixed for two hours either in LNRS or in buffered formalin. Representative sections were embedded in paraffin, sectioned and stained with H&E, periodic acid Schiff, alcian-blue, and immunostained for cytokeratins 20, high and low molecular weight cytokeratins, prostatic specific antigen, Factor VIII related antigen, s-100 protein, and protein kinase C isoenzymes. Results showed that the tissues were well fixed after 2 hours in LNRS, and were not fixed after 2 hours in formalin. Processing and sectioning of the paraffin blocks of the LNRS fixed tissue was excellent; it was impossible in the sections fixed for 2 hours in formalin. All the stains were excellent after LNRS fixation. We conclude that fixation of cystectomy specimens in LNRS requires only two hours and results in excellent stained slides. It is therefore recommended for cystectomy specimens. PMID- 10093826 TI - Existence of junction-like structures in large B-cell non-Hodgkin's lymphomas. An ultrastructural study. AB - The purpose of this work is to study the presence of cell junction-like structures in large B-cell lymphomas. The ultrastructural study, based on 20 cases of this entity proved by immunohistochemistry and flow cytometry, demonstrated four types of junction-like devices easily found between tumor cells. Several explanations are offered about the possible nature of such structures, including the possibility of them being the result of adhesion phenomena. It should also be emphasized that they can potentially complicate the differential diagnosis of those neoplasms. We should, therefore, be careful in rejecting an ultrastructural diagnosis of large B-cell lymphoma based only on the presence of junction-like structures. PMID- 10093827 TI - The role of persisting infections in the pathogenesis of pulmonary emphysema. Electron microscopy reveals a probable bacterial colonization of the alveolar space and the bronchioles. AB - Lung volume reduction surgery (LVRS) yields resection specimens from patients with advanced pulmonary emphysema. Regarding the development of lung function parameters, recent results obtained by light microscopy revealed an unfavorable prognosis in patients with remarkable inflammation, particularly in the bronchioli. Tissue from ten patients (alpha1-antitrypsin level in the normal range) was furthermore investigated by electron microscopy. Scanning electron microscopy shows 0.4-0.6 micron spherical bodies variably densely arranged in the whole alveolar space and in the bronchioles of all patients. These bodies are mostly seen on the microvilli of type II pneumocytes. An immunological reaction with activation of macrophages and granulocytes occurs simultaneously. Macrophages show cytoplasmic extensions to the spherical bodies, which exhibit a cellular membrane but no cellular wall. This favors the diagnosis of bacterial colonization of the alveolar space and the bronchioles by mycoplasmas or L-forms of other bacteria. As patients undergoing lung volume reduction surgery are under optimal medical treatment and without any infection clinically, these findings appear to be relevant for the pathogenesis and/or progression of pulmonary emphysema. PMID- 10093829 TI - Atypical decubital fibroplasia associated with bizarre parosteal osteochondromatous proliferation (Nora's reaction). AB - We describe recurring bizarre parosteal osteochondromatous proliferation (Nora's reaction) associated with atypical decubital fibroplasia in the region of the greater trochanter of the femur in a 52-year-old man. We hypothesize that these two recently introduced entities may represent two forms of tissue response to injury (ischemia) inducing proliferative reaction of bone and cartilage in the vicinity of periosteum, and necroses with hyperplastic granulation tissue and myxoid stroma in the subcutaneous tissues. PMID- 10093828 TI - A case report of gastric carcinosarcoma with rhabdomyosarcomatous and neuroendocrinal differentiation. AB - We report herein an unusual gastric carcinosarcoma with rhabdomyosarcomatous and neuroendocrinal differentiation in a 63-year-old Japanese male. The tumor was a pedunculated large polypoid tumor (7 x 6.5 x 3.5 cm) located in the pylorus. Histologically, it invaded to the subserosa and was composed of both adenocarcinomatous and sarcomatous components. Adenocarcinomatous foci generally showed tubular to solid patterns and occupied the parts facing the gastric lumen, while the sarcomatous components showed a generally irregular and solid arrangement. There were transitions between the sarcomatous and carcinoma elements. In addition, carcinoma cells with a cord-like or trabecular arrangement similar to that seen in endocrine carcinoma expressed chromogranin A, and were mainly observed in an intermediate area between the adenocarcinomatous and sarcomatous foci. The sarcomatous areas were mainly composed of spindle cells and occasionally contained a sarcomatous component showing rhabdomyosarcomatous differentiation. This is an interesting case to consider how the variety of cell type appeared in such a type of tumor in the stomach. PMID- 10093830 TI - Wilms' tumor in the adult--report of a case and review of the literature. AB - Wilms' tumor is rare in adults. Its histology, grading and staging are identical to those in children. Investigators agree on a combined modality approach in the treatment of adult Wilms' tumor (AWT), but differ on how aggressive it should be. Some advocate adopting the current pediatric protocols which take into account tumor stage and grade. Others recommend using advanced disease regimens for all stages and grades. We report on an 18 year-old male with stage IV favorable histology Wilms' tumor. The patient underwent radical nephrectomy and received postoperative radiotherapy with intensive four-drug chemotherapy. He had one relapse after 12 months which was successfully treated with chemotherapy and radiotherapy. He remains in remission without relapses 36 months after the initial diagnosis. The genetics of Wilms' tumor has been well studied in children but is practically unknown in adults; karyotype and molecular genetic studies in this case were normal. PMID- 10093831 TI - Inflammatory pseudotumour of the liver--evidence for malignant transformation. AB - A case of inflammatory pseudotumour of the liver is reported, and evidence is presented for its subsequent evolution into malignant non-Hodgkin's lymphoma. Such postulated malignant transformation challenges the assumption that hepatic inflammatory tumours are entirely benign lesions. PMID- 10093832 TI - Neoplastic thrombotic endocarditis of the tricuspid valve in a patient with carcinoma of the thyroid. Report of a case. AB - A rare case of neoplastic thrombotic endocarditis of the tricuspid valve in a patient with poorly differentiated follicular carcinoma of the thyroid is described. Although some previous reports documented extension of the follicular thyroid carcinoma into the great veins of the neck to the right cardiac chambers, this seems to be the first report of a neoplastic thrombotic lesion of the tricuspid valve in a patient with thyroid carcinoma. In our institute, where about 2,500 autopsies are performed yearly, and about 600 valvular lesions are discovered, such a lesion was never detected. In patients with carcinoma, a neoplastic thrombotic endocarditis may be a source of microembolic neoplastic spread leading to a possible pulmonary colonisation. PMID- 10093833 TI - Laryngeal liposarcoma: report of a case. AB - Laryngeal and hypopharyngeal liposarcomas are fairly rare tumors, with only 30 convincing cases reported to date. These tumors usually arise in the supraglottic area, and only two cases have been reported to affect the true vocal cord. They behave in an indolent fashion with multiple local recurrences and only rarely cause the patient's death. Our case highlights the natural history of this entity. A 62-year-old man presented because of air-way obstruction. A CT scan discovered a large 5 cm polypoid mass in the right aryepiglottic fold. The patient had already undergone three previous operations for the same reason in another clinic, with histopathological diagnoses of fibrovascular polyps. In the last recurrence, only a careful search for lipoblasts in the surgical specimen allowed us to identify this lesion as a low-grade well-differentiated liposarcoma. Complete resection was impossible in this case, despite total laryngectomy. PMID- 10093834 TI - [Contrast optimization in CT angiography]. AB - This paper compares different contrast injection techniques for optimizing vessel contrast in CT angiography (CTA). The optimal vessel contrast shall be defined as constant strong enhancement confined to the scanning interval. This "plateau enhancement" guarantees high-quality CTA images and should therefore be approximated during every CTA examination by an appropriate contrast injection protocol. With well-established injection techniques such as the standard bolus technique (constant uniphasic contrast bolus for all patients) or adjustment of the scan delay, considerable individual differences in the arterial enhancement can be observed, and a nondiagnostic examination or an inefficient use of contrast agent might be the result in a particular patient. Therefore, two sophisticated mathematical models have recently been developed for analyzing the individual enhancement characteristics. These models can be exploited to predict the arterial enhancement for any given intravenous contrast bolus in any patient and to optimize the contrast bolus in order to approach the ideal "plateau enhancement." These techniques have to prove their effectiveness in larger clinical series. PMID- 10093835 TI - [Contrast-enhanced 3D MR-angiography of the thorax, abdomen and lower extremities]. AB - Contrast-enhanced 3D MR angiography permits comprehensive assessment of the arterial system in the chest, abdomen und lower extremities. The method combines intravenous bolus application of a non-nephrotoxic, paramagnetic, extracellular contrast agent with the acquisition of a fast 3D data set. High contrast between the vascular lumen and surrounding tissues, inherent three-dimensionality and the ability to collect image data in the chest and abdomen under apnea conditions all contribute to excellent image quality. Contrast-enhanced 3D MRA is being employed in many centers throughout the world for the evaluation of various arterial pathologies. This review provides a technical overview and critically discusses the clinical applications in the chest, abdomen and lower extremities based upon the available literature and several clinical examples. PMID- 10093836 TI - [Management of abdominal aortic and peripheral aneurysm using stent grafts]. AB - The implantation of stent grafts is a relatively new method for the treatment of aneurysms of the aorta or peripheral aneurysms. Before the implantation precise measurements are mandatory to obtain the necessary information about the aneurysm. The numerous contraindications must be observed strictly to successfully exclude the aneurysmal sac. The stent graft is inserted via a percutaneous puncture or, in the case of an aortic graft, through a surgical arteriotomy. After the implantation rigorous follow-up is mandatory to detect complications such as leaks or thrombi: Spiral CT angiography is the method of choice. Some of the complications require secondary interventions such as the implantation of additional stent grafts. The results are encouraging, with a secondary exclusion rate of the aneurysm of up to more than 95%; however, long term results are not available. PMID- 10093837 TI - [Endovascular brachytherapy for the prevention of recurrence after PTA]. AB - PURPOSE: Recurrent stenosis after PTA is caused by intimal hyperplasia and constrictive arterial remodeling. In experimental and first clinical studies, ionizing radiation has demonstrated its potential to control excessive intimal proliferation. We wanted to evaluate the safety, feasibility and efficacy of endoluminal irradiation after PTA and/or stent implantation. MATERIAL AND METHODS: From September 1996, 24 patients (24 lesions) who had a stenosis or occlusion measuring more than 5 cm in length in the superficial femoral artery or a restenosis after PTA underwent endoluminal irradiation. An isodose of 14 Gy was applied to the vessel wall using an Ir-192-HDR afterloading unit. The radiation was tolerated well; the additional time needed for the procedure was 30-45 min. RESULTS: In a mean follow-up time of 15 months we found a cumulative patency rate of 60%. No side effects were observed. CONCLUSION: Endovascular brachytherapy is a safe and brief procedure. In our selection of patients, a patency rate of approx. 40% after 1 year has to be expected. Thus, these first results are promising, although first published studies of endoluminal irradiation in peripheral vessels with stent implantation showed higher patency rates. No randomized data are currently available. We conclude that endovascular irradiation should be performed together with stent implantation in long lesions or recurrent stenosis after PTA, in order to control not only excessive intimal proliferation but also constrictive arterial remodeling. PMID- 10093838 TI - [Interventional treatment of arteriosclerotic carotid stenosis]. AB - PURPOSE: Angioplasty and stent placement of atherosclerotic internal carotid artery stenosis (ICA) are evaluated based on own experiences with the method and reports of other groups and are compared with vascular surgery. METHODS: ICA stenoses of more than 70% were treated by angioplasty and stent placement mainly using the Wallstent. The patients had follow-up examinations with an angiogram after 6 months and colour-coded duplex ultrasound at regular intervals. RESULTS: In 633 patients 799 ICA stenoses were treated, 70% of them were symptomatic and 30% asymptomatic. In 99% of the patients the stenoses could be removed with a reduction of the degree of stenosis from 82% to 12%. Transient neurological deficits occurred in 5% and permanent deficits in 2.7% of the patients with decreasing incidence over the years. Five-year patency was 91.6%. CONCLUSION: Endoluminal treatment of atherosclerotic ICA stenosis is an efficient procedure which can be applied in patients, in whom carotid surgery is indicated, but also in cases with an increased operative risk or inoperability from technical or medical reasons. PMID- 10093839 TI - [Percutaneous revascularization of renal artery stenosis. Balloon angioplasty vs. stent implantation]. AB - Renal artery stenosis (RAS) is the most common cause of secondary hypertension, with a prevalence of about 1% in the general population of people with hypertension. Severe arterial stenosis may also lead to impairment of excretory renal function. In experienced hands renal artery revascularization with or without stent implantation may be a safe and effective treatment in patients with sustained hypertension resistant to intensive antihypertensive treatment. Conventional balloon angioplasty of non-ostial RAS caused by fibromuscular dysplasia with a high technical and functional success rate may be the treatment of choice. However, there is continuous discussion concerning the utility of balloon angioplasty and renal stenting, respectively, in patients with atherosclerotic disease. At the time being, there are 3 randomized European trials ongoing to analyze the benefit of medical treatment versus percutaneous intervention. Several prospective studies dealing with renal artery stenting in ostial RAS found that the implantation of endoprostheses leads to much better morphologic longterm results as compared to those of balloon angioplasty alone and may be a safe and effective alternative to surgery. In addition, the functional results suggest that stent implantation in patients with mild or severe renal dysfunction may slow progression of renal failure and, thus delay the need for renal replacement therapy. It is to note that renal artery stenting does not impede any further surgical intervention. However, prior to any interventional treatment the indication of an eventual catheter procedure in patients with RAS should be discussed between experienced nephrologists and interventionalists based on clinical, functional and duplexsonographic data. PMID- 10093840 TI - [PTA vs. stent in femoro-popliteal obstruction]. AB - PURPOSE: To evaluate whether primary stenting is superior to balloon angioplasty (PTA) alone in the treatment of femoropopliteal obstructive disease. MATERIALS AND METHODS: Sixty-two patients, 24 female and 38 male, mean age 67 years (39-87) years, were randomized to PTA alone (n = 37) or balloon angioplasty followed by implantation of Palmaz stents (n = 33). Follow-up included clinical assessment, ankle-brachial index (ABI), color duplex ultrasound at 1, 3, 6 and 12 months after intervention and intravenous angiography at 6 or 12 months. RESULTS: We had four cases of primary PTA failures (10.8%) and no early (< 30 days) thrombosis compared to one primary stent failure (3.0%) and three early thromboses (9.0%) in the stent group. Cumulative primary angiographic patency rates (life-table analysis) for PTA alone were 82% and 72% (6 and 12 months, respectively) compared to 81% and 60% for primary stent placement. The secondary angiographic patency were 97% and 88% for PTA and 88% and 72% for stent implantation, respectively. However, there was no significant difference in patency rates. CONCLUSIONS: Despite fewer primary technical failures, mid-term angiographic and clinical patency were not improved by primary stent placement compared to PTA alone. PMID- 10093841 TI - [Fluid-attenuated-inversion-recovery (FLAIR) imaging in the diagnosis of cerebral gliomas and metastases]. AB - This study demonstrates the value of a fast fluid-attenuated inversion-recovery (FLAIR) technique in the assessment of cerebral gliomas and metastases. Thirty five patients with cerebral gliomas and 12 patients with a total of 39 cerebral metastases were examined by T2/proton density-weighted fast spin echo, fast FLAIR with and without contrast medium and contrast-enhanced T1-weighted spin echo using identical slice parameters. The images were evaluated using quantitative and qualitative criteria. Quantitative criteria were tumor-to-background and tumor-to-cerebrospinal fluid contrast and contrast-to-noise. The qualitative evaluation was performed as a multireader analysis concerning lesion detection, lesion delineation and image artifacts. In the qualitative evaluation, all readers found fast FLAIR to be superior to fast spin echo in the exact delineation of cerebral tumors (P < 0.001) and the delineation of enhancing and non-enhancing tumor parts. Fast FLAIR was superior in the delineation of cortically located and small lesions but was limited in lesions adjacent to the ventricles. Fast FLAIR provided significantly better tumor-to-CSF contrast and tumor-to-CSF contrast-to-noise (P < 0.001). The tumor-to-background contrast and tumor-to-background contrast-to-noise of the fast FLAIR images were lower than that of T2-weighted spin-echo images but were significantly increased after the application of contrast medium. FLAIR images had a more image artifacts, but these influenced the image interpretation in only two patients. Signal hyperintensities at the ventricular border were present in 92% of the patients. These are common findings in fast FLAIR and should be included in image interpretation. PMID- 10093842 TI - [Space occupying lesion in the basis of the skull]. PMID- 10093843 TI - [Heart diseases in thoracic radiographic images. 2]. PMID- 10093844 TI - [Cortical lesions in progressive supranuclear palsy (Steele-Richardson-Olszewski disease)]. AB - Histopathological changes seen in progressive supranuclear palsy (Steele Richardson-Olszewski disease) have been thought to be located in subcortical nuclei. However, abundant neurofibrillary tangles have been found recently in several neocortical areas. Their morphology and ultrastructure, regional and laminar distributions, as well as antigenic and biochemical properties make them clearly different from the neurofibrillary tangles observed in Alzheimer's disease and aging. Tau positive fibrillary accumulation in the nevroglia has also been seen in the cortex. The topographical distribution of the lesions is rather stereotyped, but some uncommon distributions (such as pallido-luysonigral) have been identified. Factorial analysis has shown that cortical and subcortical lesions are independent; pedonculopontine nucleus could play a role in the cortical diffusion of the lesions. PMID- 10093845 TI - [Arguments in favor of the early treatment of Parkinson's disease with L-Dopa]. PMID- 10093846 TI - [Arguments in favor of early treatment of Parkinson's disease with dopaminergic agonists]. PMID- 10093847 TI - [Controversial issues concerning the initial treatment of Parkinson's disease: L Dopa or dopaminergic agonists?]. PMID- 10093848 TI - [Unique medullary neurosarcoidosis]. PMID- 10093849 TI - [Cortical thrombophlebitis and developmental venous anomalies]. AB - Abnormal intracranial venous drainage called cerebral venous angioma is usually asymptomatic. Hemorrhages and seizures may however occur. The malformation may rarely be revealed by thrombosis. We report the case of a 25-year-old right handed woman who developed cortical thrombophlebitis subsequent to developmental venous anomalies. After a course of anticoagulant therapy, outcome was good, demonstrating that anticoagulant therapy may be indicated in spite of the high risk of hemorrhage. PMID- 10093850 TI - [Cortical heterotopias: animal models and human disease]. AB - Cortical heterotopia is defined as the misplacement of a group of neurons displaced to a precise localization in the neocortex and results from perturbed migration along the glial guide, either because of glial destruction or molecular anomalies. Heterotopic neurons are rarely dispersed but are rather grouped in nodules or bands. Heterotopic masses may lie in an ependymal or subcortical localization depending on whether they result from lack of migration or an arrested migration. Heterotopias can also occur in intra-cortical or extra cortical localizations. The cause of heterotopia remains to be elucidated. Two genes situated on chromosome X have been implicated but non-genetic forms attributable to antenatal ischemia or toxic aggression during fetal development have also been observed. The presence of heterotopia is usually associated with epilepsy and sometimes with mental retardation. Seizures may be initiated within the heterotopic region then propagate via long projections to the neocortex which may also be malformed. PMID- 10093851 TI - Quality assurance of secondary prevention--a solution to better implementation of guidelines. PMID- 10093852 TI - The significance of oral health and dental treatment for the postoperative outcome of heart valve surgery. AB - The objective of this study was to evaluate the significance of preoperative dental treatment for the development of complications in the form of infections during the first postoperative weeks after heart valve surgery. In one group of patients (n = 149), oral health was examined and dental treatment performed 3-6 months prior to heart valve surgery. In a second group (n = 104), oral health was examined postoperatively and these patients did not receive any dental treatment before surgery. Infections were recorded for all patients during the first three weeks after surgery and correlated to the dental status at the time of surgery. Sepsis or endocarditis occurred in 5.4% of the first group and in 1.9% of the second group. Freedom from all infections for the two groups was 55% and 56%, respectively. The results did not reveal any significant differences between the groups regarding patients' oral health at the primary oral examination. The frequencies of postoperative complications such as focal infections, fever and increased CRP were also found to be similar for both groups. The combined scores of complications were 2.1% and 1.8%, respectively. Data from the present study do not support the suggestion that dental intervention will decrease the rate of early complications following heart valve surgery. PMID- 10093853 TI - Multifactorial evaluation of a program for lifestyle behavior change in rehabilitation and secondary prevention of coronary artery disease. AB - A comprehensive, multifactorial lifestyle behavior change program was developed for rehabilitation and secondary prevention of subjects with coronary artery disease. The purpose of the present report is to describe this intervention model and to analyze results achieved in a first group of consecutive participants. Main inclusion criteria for the 292 subjects were a recent history of acute myocardial infarction, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty. The program commenced with a 4-week residential stay, with the focus on health education and the achievement of behavior change in major lifestyle areas. During the year of follow-up a systematic maintenance program included regular contact with a nurse. Morbidity and mortality was low. Self-reported quality of life improved and there were significant improvements in blood lipids, exercise capacity and body mass index. There were also significant changes both in psychological variables such as Type A behavior, anger, hostility, and in major lifestyle areas such as stress reactions, diet, exercise and smoking. These changes compared favorably with data from relevant samples from the Swedish normal population. This program had a considerable effect on a number of important factors for rehabilitation and secondary prevention of coronary artery disease. PMID- 10093854 TI - Diagnosis of acute myocardial infarction in patients with chronic left bundle branch block. Standard 12-lead ECG compared to dynamic vectorcardiography. AB - Standard 12-lead electrocardiogram (ECG) criteria were evaluated and compared with dynamic vectorcardiography for diagnosing acute myocardial infarction in 33 patients with chronic left bundle-branch block. In 14 patients a clinical diagnosis of acute myocardial infarction was made, but it was found that none of the seven most promising ECG criteria suggested in the literature could alone or in combination diagnose acute myocardial infarction. QRS vector difference evolution showed the same kind of pattern as that for patients with narrow QRS complex. By using a predefined specific pattern, a diagnostic accuracy of 79% was achieved. The results indicate that dynamic vectorcardiography is a better tool for diagnosing and monitoring acute myocardial infarction in patients with left bundle-branch block than standard 12-lead ECGs taken on admission and after 12-24 h. PMID- 10093855 TI - Intraoperative assessement of coronary flow and coronary vascular resistance during coronary bypass surgery. AB - The measurement of coronary graft flow rates is a well-established method of assessing graft function intraoperatively. In order further to understand the dynamics of graft function, the resistance to the flow was considered a desirable measurement intraoperatively. The coronary vascular resistance (CVR) was estimated by applying the Poiseuille-Hagen equation. The CVR was estimated at zero cardiac work (during cardioplegic arrest) using fixed perfusion flow rates and estimating the pressures produced. After going off cardiopulmonary bypass (CPB), the bypass graft flow (F) was estimated by a standard ultrasound Doppler technique. The perfusion pressure over the perfused coronary graft was then determined and the CVR in the working heart ascertained. The CVR was studied in 178 vein grafts in 59 patients undergoing coronary bypass surgery. The mean CVR in the cardioplegic heart (c-CVR) varied from 0.81 to 2.3 mmHg/ml/min for various coronary artery diameters and was significantly higher in small diameter arteries compared with larger arteries (p < 0.0002). Consequently significant high flows were found in the large vessels compared with the smaller ones (p < 0.0001). The mean c-CVR during cardioplegia of 1.57 +/- 0.06 increased significantly to 1.75 +/- 0.07 mmHg/ml/min after the procedure (p-CVR) and was attributed to the dynamic resistance of the working heart. The post-CPB graft flow was significantly and negatively correlated to the c-CVR of the arrested heart. The measurement of coronary vascular resistance reveals coronary beds at potential high risk for inadequate perfusion. Such areas are usually fed by small vessels with low flows. The working heart, in turn, increases the coronary resistance following cardioplegia during the surgical procedure. PMID- 10093856 TI - Adenosquamous carcinoma of the lung. Surgical results compared with squamous cell and adenocarcinoma. AB - The outcome of surgery for adenosquamous carcinoma of the lung in 39 patients treated in 1982-1996 was compared with results in squamous cell carcinoma and adenocarcinoma. Adenosquamous carcinoma comprised only 4.2% of all 914 resected primary lung cancers. The cumulative 5-year postoperative survival rate was 22.6% for the adenosquamous tumours. Comparison of survival curves with those for squamous cell carcinoma and adenocarcinoma indicated non-significant differences. The incidence of lymph-node metastasis was significantly higher in the patients with adenosquamous carcinoma than in the other patient groups. PMID- 10093857 TI - Monocusp valve in right ventricular outflow tract. AB - Sixty patients aged 5 days-10.3 years (mean 2.9 years) received monocusp valve implants in the right ventricular outflow tract in corrective surgery for congenital heart disease. The free edge of the monocusp valve was attached to the posterior wall of the new pulmonary tract to cover the entire root of the pulmonary tract when the monocusp valve closed. Follow-up was 3.8 (0-11.5) years. Early mortality was 8.3% (5/60) and late mortality 3.6% (2/55). Monocusp valve regurgitation developed in all patients. Moderate or severe valve failure was found in 30 patients at median 1.4, mean 2.2 (0.2-6.8) years postoperatively. Repeat surgery was performed in seven cases because of monocusp failure. It is emphasized that monocusps potentially give short-term reduction of pulmonary regurgitation when used for right ventricular outflow tract reconstruction. Only long-term follow-up can disclose whether all patients with a monocusp valve will require repeat surgery. PMID- 10093858 TI - Time-trends in thrombolytics: women are catching up. AB - Reports on gender differences in the management of acute coronary syndromes indicate that women do not receive as much active treatment as men. Other conflicting findings have also been published. To investigate whether previously reported gender differences in the treatment of acute myocardial infarction (AMI) still persist, we included all patients admitted to our coronary care unit (CCU) in 1984-1995, and discharged with a diagnosis of AMI, in a retrospective study. A total of 1991 female admissions was compared with 4067 male admissions. The time span was divided into two-year periods comprising approximately 1000 patients each. During one period, 1988 to 1989, women received significantly less thrombolytic therapy which, however, could reflect that women admitted with AMI were older than men. Analysis of time-trends showed a significant increase in the use of thrombolytic treatment in women and elderly men. In clinical praxis there has been a gender-gap in acute treatment of AMI, but age-dependent or not, this is now no longer apparent. PMID- 10093859 TI - Tetralogy of Fallot. A population-based study of epidemiology, associated malformations and survival in western Denmark 1984-1992. AB - The study describes the epidemiology and mortality of tetralogy of Fallot (TOF) in a population-based study in Western Denmark. Ninety-two infants with TOF were born during 1984-1992. Prevalence was 3.01 per 10,000 livebirths. Karyotype anomalies were present in 12 (13%) and extracardiac malformations in 16 (17%) of the infants. Down syndrome, cleft palate, cleft lip and palate and combined skeletal, gastrointestinal and renal lesions (VACTERL association) were prevalent. Twenty-four infants died (26% of total), 13 (54%) of the deaths occurring during the first year of life. Mortality was significantly increased in infants with extracardiac malformations (50% vs 19%, p < 0.05). Eighteen deaths (75% of total deaths) occurred before corrective surgery and 7 of these deaths were sudden. Extracardiac malformation(s) in infants with TOF is a significant risk factor for death. The study stresses the importance of population-based studies for the assessment of mortality from congenital heart malformations. Overall mortality may be very different from mortality related to cardiac surgery. PMID- 10093860 TI - Multiple endocrine neoplastic-associated thymic carcinoid tumour in close relatives: octreotide scan as a new diagnostic and follow-up modality. Two case reports. AB - Thymic carcinoid tumours constitute less than 1% of all carcinoids, and differ markedly from true thymomas in natural history, morphology, prognosis and therapeutic options. New clinical and diagnostic modalities are described in two brothers with thymic carcinoid associated with multiple endocrine neoplasia syndrome. Octreotide scintigraphy proved useful for diagnosis and follow-up, and somatostatin receptor positivity may provide new prospects for treatment of non resectable or recurrent tumour. PMID- 10093861 TI - Right-sided hiatal hernia of the oesophagus. AB - At chest radiography performed for recurrent pneumonia in a 3-month-old boy, an air-fluid level in the right cardiophrenic angle was found and initially perceived as a lung abscess. Upper gastrointestinal tract radiographs, however, revealed a congenital diaphragmatic hernia, which was successfully repaired. PMID- 10093862 TI - Treatment of a large congenital coronary fistula with coil embolization. AB - A 77-year-old woman suffering from progressive dyspnea and chest pain for 2 1/2 years was admitted to hospital. There were no ECG changes at exercise test and a dobutamine stress echocardiography was normal. At catheterization, right-sided pressures were within normal limits. Coronary angiography revealed a congenital coronary fistula, 3-4 mm in diameter, from the left anterior descending artery to the proximal pulmonary artery. There was no significant rise in blood oxygen saturation in the pulmonary artery. Transcatheter coil embolization was performed in the distal part of the tortuous fistula. Flow ceased within minutes, demonstrating the feasibility and efficacy of this technique for treating large fistulas. PMID- 10093863 TI - Placebo-controlled studies in schizophrenia--ethical and scientific perspectives: an overview of conference proceedings. AB - Much controversy has surrounded the issue of whether clinical trials of new antipsychotic medications for the treatment of schizophrenia ought to include a placebo control group. On 18 September 1997, the authors co-chaired a symposium at the University of Toronto devoted to elucidating the issues relevant to this debate. Speakers with expertise in the areas of schizophrenia research, clinical trials methodology, medical ethics and informed consent presented their perspectives. This paper aims to summarize the major scientific and ethical issues raised during the symposium. PMID- 10093864 TI - Placebo-controlled trials: when are they needed? AB - Randomized controlled trials require that patients be assigned to either receive the medication under investigation or to a control condition. It is not necessary that the control arm of the trial involve a placebo; it may consist of a different drug or conventional treatment. However, this can lead to serious problems in interpretation if the trial concludes that there is no statistically significant difference between the groups. In studies where a placebo arm was not used, it is extremely difficult to determine if this lack of a difference was due to equal effectiveness of the treatments, or was the result of a Type II error; i.e., erroneously concluding that there was no difference when one, in fact, existed. This may have been due to poor design or execution of the trial, or to low power resulting from an insufficient number of subjects in the study. The need for placebo controls can be minimized if there is assurance that the trial is well-designed and executed, and this may require external review of studies, especially those which are not peer-reviewed. If a placebo arm is deemed necessary, then it may be necessary to ensure that certain condition are met. These would include (1) setting very high requirements for informed consent; (2) an external group that monitors the prevalence of adverse reactions; (3) requiring that attending physicians not enroll their own patients into a trial; (4) not paying physicians on the basis of the subjects completing the trial; (5) having a time limit for patients remaining in the placebo condition; and (6) using only drug-free or drug-resistant patients. Further, alternatives to strict randomization schemes, such as 'play the winner' strategies, should be explored further. PMID- 10093865 TI - Placebo-controlled trials in schizophrenia: are they ethical? Are they necessary? AB - The current controversy as to the proper role of the placebo control in the evaluation of new treatments for schizophrenia requires an analysis that is sensitive to both ethical and scientific issues. Clinical equipoise, widely regarded as the moral foundation of the randomized controlled trial (RCT), requires the use of best available treatment as the control in RCT. Scientific criticisms of the use of an active control are examined and none present an insuperable barrier to the use of an active control. Indeed, scrutiny of the most recent argument for the use of placebo controls, 'assay sensitivity', suggests that the use of placebo may be the cause of the problem pointed to. Scientific, regulatory, ethical and legal advantages of the use of an active control are described. While the use of a placebo control may be acceptable in carefully defined circumstances, in most cases the use of an active control in schizophrenia research is ethically and scientifically preferable. PMID- 10093866 TI - Sense and nonsense: an essay on schizophrenia research ethics. AB - In this essay, the authors select topics from the current debate on the ethics of schizophrenia research. Accepting competent and voluntary informed consent as essential for most projects, the authors discuss the relation of diagnosis to decisional capacity, the respective roles of psychosis and cognitive impairments in decisional capacity, and whether impairments in capacity can be remediated. The roles of investigator, external agent, patient subject, and family or surrogate in the informed consent process are reviewed. A lack of understanding of the treatment of persons with schizophrenia has distorted and inflamed public discussion of issues such as 'withholding treatment'. A standard, based in common sense, is proposed: for viewing protocols; for allowing autonomy and altruism despite diagnostic class; and, for a meaningful discussion of what is meant by and what should be done about 'risk without direct benefit' protocols. PMID- 10093868 TI - Season of birth and schizophrenia: a systematic review and meta-analysis of data from the Southern Hemisphere. AB - AIMS: Data from the Northern Hemisphere support an excess of winter-spring births of individuals who later develop schizophrenia when compared with the general population. The data from the Southern Hemisphere have been less consistent. This paper will present a systematic review and meta-analysis of relevant data from the Southern Hemisphere. METHODS: To identify relevant studies we searched electronic databases, reviewed citations from target publications and wrote letters to published authors in the field. The counts for observed and expected births were assessed in four planned comparisons. In the absence of significant heterogeneity, the data were combined using Mantel-Haenzel odds ratio in a fixed effect model. RESULTS: Twelve studies were identified. Published and unpublished data from eight of these were able to be included in the analyses. For the two seasonal comparisons (n = 20,017), small but non-significant excesses were found in the first comparison (winter versus other seasons; OR = 1.04, 0.99-1.08) and for the second comparison (winter and spring versus other seasons; OR = 1.03, 0.99-1.07). For the two quarterly comparisons (n = 14,799), there was a small but non-significant excess found in the third comparison (third quarter versus other quarters; OR = 1.03, 0.98-1.09), and a small but non-significant deficit in the fourth comparison (third and fourth quarter versus other quarters OR = 0.99, 0.95 1.04). CONCLUSIONS: Assuming that season of birth acts as a proxy marker for fluctuating non-genetic risk-modifying factors for schizophrenia, this review suggests that in the Southern Hemisphere these factors may be weaker, less prevalent, less regular, and/or may be modified by other confounding or modifying variables. PMID- 10093869 TI - Psychotic illness after prenatal exposure to the 1953 Dutch Flood Disaster. AB - We tested the hypothesis that maternal stress during pregnancy increases the risk of non-affective psychosis for the child. The concept of non-affective psychosis includes the ICD categories schizophrenic disorder, paranoid state and other non organic psychosis. Data from the Dutch Psychiatric Registry were examined for an effect of the Flood Disaster of 1 February 1953. On this day, a gale caused a flood in the South-west of The Netherlands and 1835 people perished. Our study concerned the 19 villages where mortality exceeded 0.25%. The risk of non affective psychosis for the cohort born in the period February-October 1953 was compared to the risks for the cohorts born in the corresponding periods of the previous and subsequent 2 years. The relative risk of non-affective psychosis for those exposed during gestation was 1.8 [95% Confidence Interval (CI): 0.9-3.5]. Thus, our study failed to demonstrate a significant association between prenatal exposure to maternal stress and risk of non-affective psychosis. The possible explanations for this finding are discussed. PMID- 10093870 TI - Correlates of insight and insight change in schizophrenia. AB - Various theories have been proposed to account for poor insight in schizophrenia. This study examined the relationships between insight, mood, schizophrenic symptoms and cognitive functioning. The relationship between longitudinal changes in insight and changes in symptoms and mood was also investigated. One-hundred patients with DSM-III-R schizophrenia, recently recovered from a relapse of their illness, were rated on the Insight and Treatment Attitudes Questionnaire (ITAQ), the Positive and Negative Syndrome Scale (PANSS), the Montgomery Asberg Depression Rating Scale (MADRS), the Rivermead Behavioural Memory Test and tests of current and premorbid IQ. A random sample of 53 were then given an educational package (video and booklets) designed to improve their insight. Follow-up ratings on the ITAQ, PANSS and MADRS were subsequently obtained. At baseline, better insight was significantly correlated with lower mood and fewer positive symptoms. It was not related to cognitive functioning. Improvement in insight at follow up was related to worsening of mood, but not to change in positive symptoms. The results are consistent with the concept that poor insight, at least in part, results from the psychotic disease process itself. In addition, they suggest that poor insight may protect against depression in the early stages of recovery from schizophrenia. PMID- 10093871 TI - How do early stages of information processing influence social skills in patients with schizophrenia? AB - Persons with schizophrenia show deficits across a broad range of cognitive domains, and their social skill deficits are thought, to some extent, to be caused by cognitive dysfunction. In this study, we attempted to replicate the correlation between the early stages of information processing and non-verbal skills. Subjects for the study included 22 men and six women who met DSM-IV criteria for the diagnosis of schizophrenia. All subjects were attending a rehabilitation program at the day-treatment centers of their hospitals. Social skills were assessed using a structured role-play test. The Degraded-Continuous Performance Test (CPT) and Span of Apprehension Test (SPAN) were used. Non-verbal skills were significantly correlated with CPT-False Alarm Rate (the rate of commission errors of all trials) in multiple regression analysis, but the receiving-processing skills did not have any relation to CPT or SPAN score. Non verbal skills may be related to early information-processing deficiency, especially the response-inhibiting system. Receiving and processing skills may be related to later stages of information processing, or may reflect not only 'molecular' stages of information processing (less complex and less integration task in a continuum of complexity of cognitive processes) but also other factors such as social learning. PMID- 10093872 TI - Event-related potentials in schizophrenic patients during a degraded stimulus version of the visual continuous performance task. AB - Previous studies of the auditory P300 event-related potential (ERP) have reported smaller amplitudes in chronic schizophrenics but similar consistencies have not been observed with visual P300s. This study examined P300s in symptomatically stable, medicated, chronic schizophrenics (n = 14) and normal controls (n = 14) performing a visual continuous performance task utilizing degraded stimuli to burden encoding processes. Performance analysis found slower response times, fewer target detections and more false alarms in patients than in controls. Analysis of ERPs showed P300 amplitudes of schizophrenics to be significantly smaller than those of controls and, unlike controls, schizophrenics failed to exhibit significant target vs. non-target P300 amplitude differences. Discriminant analysis indicated target and non-target midline (Fz, Cz, Pz) P300 amplitudes together correctly classified all patients and controls. Exploratory topographic analysis indicated that P300 amplitudes were not asymmetrical in patients, as has been observed with auditory P300s, and, unlike the performance measures, the P300s did not correlate with the patient's positive or negative symptom ratings. The implications of these findings are described in relation to attentional disturbances and trait versus state issues in schizophrenics. PMID- 10093873 TI - [Contrast media-enhanced duplex ultrasonography of liver tumors]. AB - The differentiation of focal liver processes is a daily clinical problem. A new option in addition to magnetic resonance tomography has been created with the development of new stable sonographic contrast agents. In this paper, Levovist was studied as a sonographic contrast agent in the detection of specific tumour perfusion patterns. All focal liver processes were proven by cytology or histology. In 19 of 22 cases there was a pathological diagnosis. In 5 of 7 haemangiomas a feeding vessel was visualised. In 3 focal nodular hyperplasias intense intratumoural enhancement was visible shortly after injection. In 2 cases of hepatocellular carcinomas tumoural neovascularisations were visualised which were not seen before the injection of Levovist. The new sonographic contrast agents provide better differentiation of specific perfusion patterns of liver tumours than normal duplex sonography. PMID- 10093874 TI - [Epidemiological analysis of accidental falls by the elderly in Zurich and Geneva]. AB - The purpose of the study was to determine the prevalence rate of fallers (PRF%) and fall-related consequences among the elderly according to age, gender and setting. Data derive from a cross-sectional study on dementia, depression and handicaps among the elderly, carried out between 1995 and 1996. Elderly people aged 65 and over living in Zurich or Geneva were considered eligible for the study. By means of the Canberra Interview for the Elderly, 921 subjects' and/or informants' interviews were completed. The subjects were classified as a faller if the subject and/or informant reported a fall in the year prior to the interview. Overall PRF% amounted to 27.8% and was higher to a statistically significant degree among females (30.9%) than males (22.5%). Gender difference in PRF was found only among the non-institutionalized elderly. Age-specific PRF increased significantly with the age of the elderly. However, this increase was observed only among male subjects. 143 subjects (PRF 17.1%) have fallen once and 101 (PRF 9.9%) two or more times. Females showed a substantially higher propensity to recurrent falls (age-adjusted OR 1.86; 95% confidence interval 1.11 3.10). While the risk of suffering two or more falls increased with age, it did not increase among one-time fallers. Residents of nursing homes had significantly higher risk of falling as compared with home-dwelling subjects (age-adjusted OR 2.46; 95% confidence interval 1.04-5.78). Every second fall caused fall-related consequences. 9.1% of all falls led to fall-related fracture. The risk of suffering fall-related consequences depended on neither age nor gender. One third of fallers reported fear of further falling. Falls among the elderly occur often and contribute substantially to morbidity. PMID- 10093875 TI - [Quality standards for hospital hygiene in intermediate and large hospitals in Switzerland: a recommended concept]. AB - The incidence of nosocomial infections is one of the most important quality indicators in health care. It increases the economical burden, augments morbidity, lengthens hospital stay, and is associated with a high mortality rate. Infection control programs are designed to minimize such adverse events. An effective infection control program can reduce the incidence of nosocomial infections by over 30%. It is regarded as among the most cost-efficient medical interventions available in modern public health. The national law for health insurance (KVG) makes quality in health care also a legal issue. This law enforces quality assurance on a scientific basis. In Switzerland there are no national guidelines to define the nature and extent of infection control in health care institutions as in many other European countries. In the United States quality standards are part of accreditation of any health care institution. Evaluating scientific evidence and international experience this article provides the rationale for a quality standard for infection control in Swiss hospitals. It features three general rules and five elements of structural quality. The recommendations are: (1) Every hospital must have a system to control nosocomial infection in patients, care givers and visitors. (2) This program consists of defined elements of structural quality. (3) The program is permanently being improved in its quality. The basic elements are: (1) infection control committee, (2) infection control team, (3) guidelines, (4) surveillance, (5) infrastructure. The feasability and impact of this standard has to be evaluated. PMID- 10093876 TI - [Hereditary or acquired angioedema caused by functional deficiency of C1 inhibitor--a still unfamiliar disease picture]. AB - Hereditary angioneurotic oedema or hereditary angiooedema (HAE) and acquired angiooedema (AAE) are disorders of the C1-inhibitor (C1-INH) protein, caused by the lack, dysfunction or exhaustion of the C1-INH molecule. Inadequate function of C1-INH results in inappropriate control of various enzymes of the fibrinolytic, complement and kinin systems as well as of factor XII, being the initial enzyme of the kinin and contact coagulation systems. As C1-INH functional deficiency is rare and the clinical manifestation little known, even nowadays the most feared complication of the deficiency may evolve: death from acute airway obstruction. Patients deficient in C1-INH function whose clinical manifestations are misinterpreted as allergic angiooedema are most at risk for fatal laryngeal oedema. The therapy of allergic and C1-INH-related angiooedema is fundamentally different. The background for the hereditary form of inadequate C1-INH function is a gene defect. The predominant primary underlying disease of the acquired form of the deficiency (AAE) is a lymphoproliferative process. PMID- 10093877 TI - [Unusual lymphedema of the upper extremity]. PMID- 10093878 TI - [Medical ethics guidelines for definition and diagnosis of death with reference to organ transplantation]. PMID- 10093879 TI - [Use of snake venom proteins in medicine]. AB - Snakes feed exclusively on freshly killed prey animals which, following their immobilization, have to be swallowed whole. Venomous snakes effect prey immobilization by injection of their venom. Snake venoms are highly concentrated, complex mixtures of individual proteins which, either as enzymes, enzyme effectors or blocking ligands, acting as single agents or in synergistic conjunction with other venom components, modify vital structures of the prey organism to destroy their biological function. Predominantly neurotoxic venoms paralyze respiratory activity by pre- or postsynaptic blockade of neuromuscular transmission. Predominantly haemocytotoxic snake venoms contain components which interact with proteins of the haemostasis, kallikrein or complement system, causing blood volume loss, hypotension or intravascular coagulation which finally lead to circulatory failure. Several isolated snake venom proteins with a known mode of action have found practical application as pharmaceutical agents, diagnostic reagents or preparative tools in the field of haemostaseology, neurobiology and complement research. PMID- 10093880 TI - [Tuberculin testing of hospital personnel: large investment with little impact]. AB - Guidelines for the control and prevention of nosocomial tuberculosis include recommendations for surveillance of hospital employees with tuberculin skin tests (TST). We analysed a 2 1/2-year period of tuberculin skin testing at Kantonsspital St. Gallen, an 850-bed hospital in eastern Switzerland with 2000 employees and 21,000 admissions yearly. Tuberculosis cases among employees are reported for a 10-year period. TST were performed on engagement, if no recent positive result was available. A new TST was read in 717 (58%) of 1241 persons starting employment during the study period. In 261 workers in contact with 23 sputum smear positive tuberculosis patients, 180 (69%) follow-up TST were performed. Of a total of 37 increases in TST, 20 (54%) were retrospectively attributed to other causes than a recent infection with M. tuberculosis (vaccination with BCG, booster phenomenon, doubts concerning the previous test result). Of the remaining 17 TST converters, 5 finally completed a full course of preventive chemotherapy. With a total workload of 547 hours for this result, half a year's working hours were necessary to prevent one case of active tuberculosis. Over a 10-year period, 4 out of 9 active tuberculosis cases in employees were likely to be nosocomially acquired, but none was diagnosed thanks to TST surveillance. We conclude that surveillance with TST is time consuming, but has little impact on the tuberculosis situation in hospital employees. Alternative strategies to this unsatisfactory system are discussed. PMID- 10093881 TI - [Professional practice and theoretical orientation of women and men psychiatrists]. AB - RESEARCH QUESTIONS: Differences between male and female psychiatrists in their careers, professional and clinical activities, and clinical orientations, in general and in contrasted settings for the practice of psychiatry. METHODS: Survey by mailed questionnaire to psychiatrists working in private practice or in institutions. RESULTS: Male and female psychiatrists share some similar characteristics (age, many interests, etc.). However, female psychiatrists differ from male psychiatrists in numerous respects: more frequently engaged in private practice, shorter work-weeks, less diversification of clinical activities, more frequent reference to a psychological model. In women occupying hierarchic positions, these differences disappear, whilst they are maintained in private practice for those using the psychological model. The differences can be interpreted in part in terms of gender-specific socialization, but their origin could mainly arise from the existence of different systems of gender-based constraints in the management of professional and personal, or family, spheres. CONCLUSIONS: Adjusting the training period and working conditions in institutions could facilitate career diversification for both male and female psychiatrists. PMID- 10093882 TI - ["Burned out" testicular tumor: a rare form of germ cell neoplasias]. AB - Burned-out tumour of the testis is a rare form of a germ-cell malignancy of testicular localisation which can regress or disappear. This is a rare form of germ-cell neoplasm. We report on 2 patients with such a tumour. The histological findings, on clinical manifestations, on difficult differential diagnosis from primary retroperitoneal germ-cell tumour, therapy, and outcome of this malignancy are discussed. In the absence of palpable testicular tumour the symptomatology is due to metastasis. Burned-out tumour of the testis must be considered in a patient with retroperitoneal lymph node involvement and histology of "germ-cell tumour". In these patients sonography of scrotal contents may be useful to identify intratesticular abnormalities. These are often the site of the primary tumour. If burned-out tumour of the testis is suspected, the indication for surgery is given. If the frozen section is not "normal testicular tissue", orchiectomy should be performed. The metastasis is treated according to the histology and clinical stage of the tumour. It is important to distinguish burned out tumour of the testis from true extragonadal germ-cell tumours. Primary removal of the testicular tumour is necessary because of the high rate of persistent testicular malignancy, which may be as much as 50% despite systemic chemotherapy. PMID- 10093883 TI - [Lactose malabsorption and eating yogurt]. PMID- 10093884 TI - [Grandparents in gerontology: timid stepmothers?]. PMID- 10093885 TI - [Women and their retirement: adaptation as a dynamic assessment process]. AB - With this study we try to fill the gap in our knowledge about the retirement process for women. This study indicates that women assess their retirement in many different ways, both before their retirement (initial appraisal) and after it (tertiary appraisal). At the first interview before retirement almost half of the (63) women showed a positive appraisal, while 2.5 year after retirement almost 60% (of 51 women) showed a positive appraisal. We also notice an important diversity in the way they deal with the situation. Mostly problem-oriented and cognitive coping categories were used. The positive connection between the problem oriented coping on the one hand, and on the other hand a positive tertiary appraisal and positive changes in the appraisal underlines the efficacy of the problem-oriented coping. We found an important individual dynamic: almost half of the examined women (22 of 51) assesses their retirement differently during the retirement transition period. From an agogic point of view it is therefore important to pay attention to these individual trajectory changes. PMID- 10093886 TI - [Memory strategies in the elderly]. AB - The frequency and preference of memory strategies were investigated in a group of independently living older adults (N = 111, 45-85 year) who were interested in memory training because of subjective and objective memory problems. Mokken scale analysis identified, besides the use of 'no strategy', four strategy scales, viz. encoding, retrieval, general, and external strategies. These five scales allowed for a differentiated analysis of strategy use. Frequency judgments showed that external strategies were used most frequently, followed by retrieval strategies. Encoding strategies were used least often. Reports on the preference of strategies in specific situations showed that subjects reported to use specific strategies in the majority of situations, although here too external strategies were used most generally. Strategy reports were more related to psychological variables (mental speed, primary memory ability, need for cognition and memory complaints) than to demographic characteristics (age, educational level and sex). The explained variances, however, were low which suggests substantial individual differences in use and preference of memory strategies. PMID- 10093887 TI - [Grandparents: their experience of the relationship with the oldest grand-child and their psychological well-being]. AB - The aim of the present study was to investigate the relationship between the satisfaction with, perceived responsibilities in, and the meaning of the relationship with the oldest grandchild, on the one hand, and the level of psychological well-being measured with the six-dimensional scale of Ryff, on the other hand. Questionnaires came from 255 Flemish retired grandparents with a mean age of 64.6 years. The relationship with the oldest grandchild was generally experienced as positive. Nearly all the grandparents agreed with items about satisfaction drawn from the relationship with the grandchild, about feeling responsible for helping him or her and about experiencing oneself as a valued elder. In general, grandparents reported well-being on all six dimensions. The experience of the relationship with the grandchild was found to be a unique additional predictor of well-being, even when background variables as grandparent's age, subjective health, financial situation and marital status were first brought into the step-wise regression-analyses. These variables explained 5 to 8% of the variance in the dimensions of well-being and 7% of the variance in the total well-being. The experience of the relationship with the oldest grandchild explained an additional 6 to 7% of the variance. PMID- 10093888 TI - [Determinants of insomnia in relatively healthy elderly. A literature review]. AB - A review is presented based on the findings resulting from interview and questionnaire research concerning factors that determine insomnia in relatively healthy elderly. The investigated factors include modes of living, sleep wishes and personality aspects. During the period 1988-1997 18 published reports were found. Based on the findings it is difficult to claim that elderly persons with insomnia are characterized by inappropriate modes of living. There were, however, some (inconsistent) indications that tea consumption, smoking and lack of exercise predicted insomnia. There were also scarce indications for less realistic sleep expectations in bad than in good sleepers. More bad sleepers perceived their sleep as uncontrollable and unpredictable than than good sleepers. Bad sleepers had significantly higher scores for anxiety, neuroticism and depression than good sleepers. Anxiety as well as depression correlated positively with insomnia and negatively with sleep duration. Depression, anxiety or neuroticism often were better predictors of insomnia than health indicators such as perceived health and number of prescribed drugs. The findings suggest that insomnia in relatively healthy elderly is more tightly associated with psychological factors than with modes of living or health indicators. This has some consequences for therapy. In addition to advice concerning modes of living and sleep hygiene, one has to be alert for the possible presence of depression or anxiety. In that case depression or anxiety has to be treated, pharmacologically or nonpharmacologically. PMID- 10093889 TI - A rationale for targeting antithrombotic therapy at the vessel wall: improved antithrombotic effect and decreased risk of bleeding. AB - Intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) or vascular surgical procedures remains a significant problem despite current antithrombotic therapy. The use of the current antithrombotic drugs, namely heparin + chronic aspirin (ASA) +/- oral anticoagulants, is based upon the assumptions that: i) heparin blocks thrombin generation and/or accelerates thrombin inhibition by antithrombin III (ATIII); ii) aspirin acetylates platelet cyclooxygenase, thereby preventing thromboxane A2 (TxA2) synthesis; and iii) oral anticoagulants reduce the availability of vitamin K-dependent procoagulants, thereby reducing the risk of thrombus formation. Albeit beneficial, this approach has a number of shortcomings and limitations: i) when thrombin binds to an injured vessel wall, it becomes resistant to inhibition by heparin/ATIII; thus, surface-bound thrombin remains active, stimulating further thrombus formation, smooth muscle cell proliferation and subsequent hyperplasia; ii) while TxA2 inhibition reduces platelet reactivity, platelets are able to respond to multiple stimuli generated at the time of, or after, vessel wall injury; and iii) heparin, aspirin and the oral anticoagulants all render the patient hemostatically defective and at risk of bleeding. Recent studies suggest that alternate therapeutic approaches can inhibit thrombogenesis more effectively at the time of injury, thereby not only inhibiting hyperplasia more effectively than the currently used drugs, but also reducing (or eliminating) the need for long-term therapy. For example, we suggest that the heparin cofactor II (HCII) catalysts, dermatan sulfate and Intimatan, inhibit surface-bound thrombin more effectively than heparin/ATIII, thereby inhibiting intimal hyperplasia effectively. Their effects are achieved when the drug is given only at the time of injury; i.e. with no further antithrombotic therapy. Other studies indicate that injured vessel wall thrombogenicity can be reduced by pretreatment with Persantine (dipyridamole) or with certain fatty acid supplements which either increase vessel wall cAMP and/or 13HODE synthesis. These increases are associated with decreased vessel wall thrombogenicity, which, in turn, is associated with decreased intimal hyperplasia. Such results suggest that vessel wall repair is achieved more effectively by targeting antithrombotic drugs directly at the vessel wall thrombogenicity per se rather than indirectly by altering the circulating blood cells and systemic coagulant system. PMID- 10093890 TI - [Anti-integrins--new platelet function inhibitors for therapy and prevention of acute coronary syndrome]. AB - Acute occlusion of a large coronary artery by a platelet thrombus is a life threatening event. Intravasal thrombus generation in most cases is caused by a disturbed interaction between platelets and the vessel wall, with accompanying platelet hyperreactivity, local adhesion to the vessel wall, activation and aggregate formation after binding of soluble fibrinogen to the activated GP IIb/IIIa-receptor. Conventional antiplatelet agents, such as aspirin or ticlopidine/clopidogrel, inhibit uncontrolled local agonist-induced signal transduction within the platelet by interfering with the thromboxane A2 and ADP pathway, respectively. This results in an activation of the platelet GP IIb/IIIa receptor and, finally, in a reduced capacity of fibrinogen binding. Antiintegrins inhibit cell-cell and cell-matrix interactions. Antagonists of the platelet integrin alpha IIB/beta 3 (GP IIb/IIIa) (eg. Abciximab, Eptifibatide, Tirofiban) inhibit platelet adhesion and aggregation via their RGD (KGD) binding sequence, resulting in reduced fibrinogen binding. The significance of inhibition of other RGD-containing adhesion molecules (von Willebrand Factor, Vitronectin) with respect to the clinical efficacy of these compounds is stil under debate. GP IIb/IIIa-antagonists are the most effective inhibitors of platelet function and in high doses, may cause complete inhibition of platelet aggregation and maximum prolongation of bleeding time. The clinical efficacy of GP IIb/IIIa-antagonists for acute percutaneous coronary interventions and in the management of the acute coronary syndrome is established. Whether Abciximab and low-molecular weight intravenous compunds (Eptifibatide, Tirofiban, Lamifiban) are equipotent, remains to be demonstrated by controlled comparative studies. Orally active low-molecular weight compounds (Sibrafiban, Xemilofiban and others) are currently undergoing clinical trials. Whether these substances are superior to oral aspirin and/or clopidogrel in long-term prevention of acute arterial vessel occlusions remains to be determined. PMID- 10093891 TI - Effect of ticlopidine on streptokinase-induced thrombolysis in rats. AB - Using our original assay system we found that ticlopidine (TP, 30 mg/kg i.v.) had produced a prompt thrombolysis of preformed clots in extracorporeal circulation of anaesthetized rats. In contrast with ticlopidine streptokinase (SK, 30,000 U/kg i.v.) proved thrombogenic for an initial period of 10-30 min, followed only later by the expected thrombolytic action. In ticlopidine pretreated rats the thrombogenic effect of streptokinase was eliminated, and its thrombolytic potency intensified. This is the first experimental support for a conception that a combined therapy with ticlopidine and streptokinase may restrict the "early hazard" associated with streptokinase therapy. PMID- 10093892 TI - [Specific COX-2 inhibitors: prospects of therapy with new analgesic and anti inflammatory substances]. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, thereby suppressing the synthesis of proinflammatory prostaglandins. The identification and molecular-biological characterization of an inducible COX isoform (COX-2) in inflammatory cells led to the hypothesis that a selective inhibition of COX-2 would result in relief of inflammation and pain without causing the COX-1-dependent side effects (gastrointestinal ulceration, platelet dysfunction, kidney damage) of conventional NSAIDs. On the basis of data obtained in several laboratories by means of the "human whole blood assay" there is now convincing evidence that none of the currently available NSAIDs is a selective COX-2 inhibitor. Meanwhile, the specific COX-2 inhibitors celecoxib and rofecoxib are being tested worldwide in phase III clinical trials on patients with rheumatoid arthritis and osteoarthritis. However, the simple concept of COX-2 being an exclusively proinflammatory inducible enzyme cannot be upheld any longer. In addition, COX-2 is expressed constitutively in brain, spinal cord and kidney, as well as in numerous other organs. In the present review the perspectives and possible risks of specific COX-2 inhibitors are discussed, as well as additional indications for their implementation (e.g. colon cancer). PMID- 10093893 TI - Increased plasma, serum and urinary 8-epi-prostaglandin F2 alpha in heterozygous hypercholesterolemia. AB - Oxidation injury results in foam cell formation, which is known to be a central mechanism in atherogenesis. We investigated in this study whether 8-epi prostaglandin (PG) F2 alpha, an in vivo indicator of oxidative stress, is elevated in hyperlipoproteinemia. The isoprostane 8-epi-PGF2 alpha levels in plasma, serum and urine were determined in 123 patients (67 m, 56 f; 17-60 years) suffering from familial heterozygous hypercholesterolemia (FH). A group of 99 normocholesterolemic adults (51 m, 48 f; 20-63 years) served as controls. Plasma, serum and urine levels of 8-epi-PGF2 alpha were significantly (p < 0.01) higher in the FH group. Smokers showed elevated 8-epi-PGF2 alpha levels; however, no correlation was observed to hypertension, age and sex. Successful dietary and drug treatment of FH patients resulted in a significant decrease in 8-epi-PGF2 alpha levels in plasma, serum and urine. These findings indicate that FH is associated with increased oxidation injury, which is beneficially influenced by successful dietary and/or drug treatment. PMID- 10093894 TI - Expression of CKS1At in Arabidopsis thaliana indicates a role for the protein in both the mitotic and the endoreduplication cycle. AB - Although endoreduplication is common in plants, little is known about the mechanisms regulating this process. Here, we report the patterns of endoreduplication at the cellular level in the shoot apex of Arabidopsis thaliana L. Heynh. plants grown under short-day conditions. We show that polyploidy is developmentally established in the pith, maturing leaves, and stipules. To investigate the role of the cell cycle genes CDC2aAt, CDC2bAt, CYCB1;1, and CKS1At in the process of endoreduplication, in-situ hybridizations were performed on the vegetative shoot apices. Expression of CDC2aAt, CDC2bAt, and CYCB1;1 was restricted to mitotically dividing cells. In contrast, CKS1At expression was present in both mitotic and endoreduplicating tissues. Our data indicate that CDC2aAt, CDC2bAt, and CYCB1;1 only operate during mitotic divisions, whereas CKS1At may play a role in both the mitotic and endoreduplication cycle. PMID- 10093900 TI - Analysis of phloem protein patterns from different organs of Cucurbita maxima Duch. by matrix-assisted laser desorption/ionization time of flight mass spectroscopy combined with sodium dodecyl sulfate polyacrylamide gel electrophoresis. AB - Sieve tubes mediate the long-distance transport of nutrients and signals between source and sink organs of plants. To detect mobile phloem proteins that are differentially distributed in source and sink organs of Cucurbita maxima, we used both one-dimensional gel electrophoresis (SDS-PAGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Both techniques revealed that phloem protein patterns depend on the sampling site: whilst several proteins were consistently observed in all phloem samples studied others appeared to occur in a organ-specific manner. For a characterization and identification of distinct phloem polypeptides, two approaches were chosen. First, protein bands resolved by SDS-PAGE were eluted from the polyacrylamide gel and the masses of the proteins were then determined by MALDI-TOF MS. Second, proteins resolved by SDS-PAGE were subjected to proteolytic degradation and the resulting peptides were analyzed by MALDI-TOF MS: the masses of the proteolytic peptides were used for a database search. By the latter approach, three mobile phloem compounds were identified as the phloem-specific protein PP2 (D.E. Bostwick et al., 1992, The Plant Cell 4, 1539-1548) a chymotrypsin and an aspartic proteinase inhibitor. None of the other polypeptides studied corresponded to any of the protein sequences present in the database. Furthermore, MALDI-TOF MS analyses indicated that some of the mobile phloem proteins occur in a covalently modified form and that the extent of the modification depends upon the plant organ. PMID- 10093901 TI - Characterisation of an Arabidopsis thaliana cDNA encoding a novel thylakoid lumen protein imported by the delta pH-dependent pathway. AB - An Arabidopsis thaliana (L.) Heynh. cDNA encoding a novel 16-kDa protein (P16) of the chloroplast thylakoid lumen has been characterised. The function of the protein is unknown but it shares some sequence similarity with alpha allophycocyanins. P16 is synthesised with a bipartite, lumen-targeting presequence, and import experiments demonstrated that this protein follows the delta pH-dependent pathway. Analysis of the thylakoid transfer peptide revealed two unusual features. Firstly, the key targeting determinant is predicted to be a twin-arginine followed by a highly hydrophobic residue two residues later, rather than at the third position as in most transfer peptides. Secondly, the C-terminal domain of the transfer peptide contains multiple charged residues which may help to prevent mistargeting by the Sec-type protein translocase. PMID- 10093902 TI - Osmoregulation and water balance in the springhare (Pedetes capensis). AB - Springhares are large rodents that live in arid and semi-arid regions of Africa. We deprived springhares of water for periods of up to 7 days to determine what physiological adaptations. If any, enable them to survive in and regions without drinking. During water deprivation, springhares lost up to 30% body weight and produced a mean maximum urine concentration of 2548 mosmol kg-1 with a maximum of 3076 mosmol kg-1 in an individual animal. Haematocrit and plasma sodium and potassium concentrations were well regulated throughout water deprivation at 47.5 +/- 3.8% and 132.6 +/- 7.4 mmol l-1 and 3.5 +/- 0.7 mmol l-1, respectively, while plasma osmolality increased slightly from 293 +/- 12.5 mosmol kg-1 to 324 +/- 7.3 mosmol kg-1. Springhares thus appeared to be good osmoregulators and were able to maintain plasma volume during 7 days of water deprivation. In addition to the production of a relatively concentrated urine, water loss was limited by the lowered solute load and faecal water loss achieved by a reduction in food consumption and by the production of very dry faeces. These abilities, together with a favourable burrow microclimate and nocturnal activity pattern, enable them to survive in arid regions. PMID- 10093903 TI - The energetic cost of arousal from torpor in the marsupial Sminthopsis macroura: benefits of summer ambient temperature cycles. AB - The costs of arousal from induced torpor were measured in the striped-faced dunnart (Sminthopsis macroura, ca. 25 g) under two experimental ambient temperature cycles. The sinusoidal-type temperature cycles were designed to evaluate the effects of passive, ambient temperature heating during arousal from torpor in these insectivorous marsupials. It was hypothesised that diel ambient temperature cycles may offer significant energy savings during arousal in animals that employ daily torpor in summer as a response to unpredictable food availability. The cost of arousal in animal in which passive, exogenous heating occurred was significantly lower than that in animals not exposed to an ambient temperature cycle. The total cost of all three phases of torpor (entry maintenance and arousal) was almost halved when animals were exposed to an ambient heating cycle from 15 degrees C to 25 degrees C over a 24-h period. In all animals, irrespective of the experimental ambient temperature cycle employed, the minimum torpor body temperature was 17-18 degrees C. The body temperature (Tb) of animals exposed to exogenous heating increased from the torpor Tb minimum to a mean value of 22.59 degrees C before endogenous heat production commenced. This relatively small increase in Tb of ca. 5 degrees C through 'free' passive heating was sufficient to account for the significant ca. three-fold decrease in the cost of arousal and may represent an important energetic aid to free-ranging animals. PMID- 10093904 TI - Comparative metabolism, thermoregulation and morphology in two populations of vlei rats (Otomys irroratus). AB - The Hogsback (32 degrees 33S 26 degrees 57E) and Alice (32 degrees 47S 26 degrees 50E), Eastern Cape, South Africa, are separated by only 24 km but by 1000 m in altitude and fall into different climatic regions. Thermal responses (energy expenditure and body temperature) to ambient temperature were measured in a population of vlei rats (Otomys irroratus) from each of the two localities. We predicted that animals from the colder Hogsback would show differences in their thermal physiology and morphology consistent with better cold-resistance. Basal metabolic rates of the Hogsback population were slightly, but not significantly, higher than the Alice population (23.9 J g-1 h-1 vs 22.3 J g-1 h-1), but the slope of the regression between energy expenditure and ambient temperature below the thermal neutral zone was significantly lower (-1.28 vs -1.60). Body temperature, although quite variable in both populations, was not significantly influenced by ambient temperature in the Hogsback population, whereas that of Alice animals was. Fur length was longer and relative size of the ears and tail was smaller in the Hogsback population, which probably accounted for the slightly lower minimum thermal conductance (1.79 J g-1 h-1 degree C-1 vs 1.91 J g-1 h-1 degree C-1) in the Hogsback population. Vlei rats from the two sites also have different karyotypes that correlate with climate but there is insufficient evidence at present to suggest that the different karyotypes and the physiological parameters measured are adaptive. PMID- 10093905 TI - Energetic cost of hovering flight in nectar-feeding bats (Phyllostomidae: Glossophaginae) and its scaling in moths, birds and bats. AB - Three groups of specialist nectar-feeders covering a continuous size range from insects, birds and bats have evolved the ability for hovering flight. Among birds and bats these groups generally comprise small species, suggesting a relationship between hovering ability and size. In this study we established the scaling relationship of hovering power with body mass for nectar-feeding glossophagine bats (Phyllostomidae). Employing both standard and fast-response respirometry, we determined rates of gas exchange in Hylonycteris underwoodi (7 g) and Choeronycteris mexicana (13-18 g) during hover-feeding flights at an artificial flower that served as a respirometric mask to estimate metabolic power input. The O2 uptake rate (VO2) in ml g-1 h-1 (and derived power input) was 27.3 (1.12 W or 160 W kg-1) in 7-g Hylonycteris and 27.3 (2.63 W or 160 W kg-1) in 16.5-g Choeronycteris and thus consistent with measurements in 11.9-g Glossophaga soricina (158 W kg-1, Winter 1998). VO2 at the onset of hovering was also used to estimate power during forward flight, because after a transition from level forward to hovering flight gas exchange rates initially still reflect forward flight rates. VO2 during short hovering events (< 1.5 s) was 19.0 ml g-1 h-1 (1.8 W) in 16-g Choeronycteris, which was not significantly different from a previous, indirect estimate of the cost of level forward flight (2.1 W, Winter and von Helversen 1998). Our estimates suggest that power input during hovering flight Ph(W) increased with body mass M (kg) within 13-18-g Choeronycteris (n = 4) as Ph = 3544 (+/- 2057 SE) M1.76 (+/- 0.21 SE) and between different glossophagine bat species (n = 3) as Ph = 128 (+/- 2.4 SE) M0.95 (+/- 0.034 SE). The slopes of three scaling functions for flight power (hovering, level forward flight at intermediate speed and submaximal flight power) indicate that: 1. The relationship between flight power to flight speed may change with body mass in the 6-30-g bats from a J- towards a U-shaped curve. 2. A metabolic constraint (hovering flight power equal maximal flight power) may influence the upper size limit of 30-35 g for this group of flower specialists. Mass-specific power input (W kg-1) during hovering flight appeared constant with regard to body size (for the mass ranges considered), but differed significantly (P < 0.001) between groups. Group means were 393 W kg-1 (sphingid moths), 261 W kg-1 (hummingbirds) and 159 W kg-1 (glossophagine bats). Thus, glossophagine bats expend the least metabolic power per unit of body mass supported during hovering flight. At a metabolic power input of 1.1 W a glossophagine bat can generate the lift forces necessary for balancing 7 g against gravitation, whereas a hummingbird can support 4 g and a sphingid moth only 3 g of body mass with the same amount of metabolic energy. These differences in power input were not fully explained by differences in induced power output estimated from Rankine-Froude momentum-jet theory. PMID- 10093906 TI - Plasma leptin decreases during lactation in insectivorous bats. AB - We previously demonstrated high leptin levels during late pregnancy in little brown bats (Myotis lucifugus). We now extend these observations to a second species, the big brown bat (Eptesicus fuscus), and also report that leptin increases after the first trimester of pregnancy. Leptin decreased to baseline 1 week following parturition, with a half-time decay of 2 days. During lactation, leptin was significantly correlated with body mass in E. fuscus, but not in M. lucifugus. No circadian pattern of leptin was observed in M. lucifugus. The decrease in post-partum leptin in bats may be partly explained by loss of putative placental leptin. The continued decrease may reflect depletion of body fat during this energy demanding period, at least in Eptesicus. Changes in leptin during lactation appeared to be independent of circadian effects and time of sampling. Our study provides additional evidence that leptin increases during pregnancy and declines during lactation in a free-ranging mammal, supporting the hypothesis that leptin plays important but yet undetermined roles in reproduction. PMID- 10093907 TI - Energetics of offspring production: a comparison of a marsupial (Monodelphis domestica) and a eutherian (Mesocricetus auratus). AB - This study compares the energetic cost of reproduction during gestation and lactation of a eutherian, the golden hamster (Mesocricetus auratus), and a similar-sized (60,120 g) marsupial, the gray short-tailed opossum (Monodelphis domestica). Food consumption was monitored in 20 reproductively active (RA) opossums and 16 RA hamsters from conception to weaning at equivalent intervals in 19 non-reproductive (NR) opossums and 21 NR hamsters, all maintained within their zone of thermoneutrality (30 degrees C). Total energy assimilated from conception to weaning [opossums: 1261.3 +/- 28.0 Kcal (1 Kcal = 4.1868 J) and hamsters: 1647.5 +/- 60.6 Kcal] was positively correlated with litter size and mass per young in both species. Maternal mass-specific assimilated energy was significantly greater in hamsters than in opossums during gestation (P < 0.001), but not during lactation or from conception to weaning (P > 0.05). Efficiency of offspring production (energy stored in young/incremental energy in RA females) was higher in hamsters than in opossums and, in both species, it was higher during lactation than in gestation. The energetic cost of reproduction (per young per day) was higher in hamsters than in opossums. The marsupial mode of reproduction, as seen in opossums, yields young at lower cost but requires a longer reproductive period than is the case for a similar-sized eutherian. PMID- 10093908 TI - Effects of temperature and photoperiod on thermogenesis in plateau pikas (Ochotona curzoniae) and root voles (Microtus oeconomus). AB - We examined the effects of temperature and photoperiod on metabolic thermogenesis and the thermogenic characteristics of brown adipose tissue in plateau pikas (Ochotona curzoniae) and root voles (Microtus oeconomus), the dominant species of small mammals in the alpine meadow ecosystems on the Qinghai-Tibetan Plateau. Pikas and voles were acclimated in the following groups: (1) Long day-warm temperature (16L:8D, 23 degrees C) (2) Long day-cold temperature (16L:8D, 5 degrees C), (3) short day-warm temperature (8L:16D, 23 degrees C), and (4) short day-cold temperature (8L:16D, 5 degrees C). Both temperature and photoperiod were important environmental cues for changes in thermogenesis for both species. Low temperature and short photoperiod induced increases in metabolic rate, nonshivering thermogenesis (NST), mitochondrial protein contents of brown adipose tissue, and cytochrome C oxidase activity of brown adipose tissue mitochondria in both species. Plateau pikas were more sensitive to cold (79% of the total NST response) than to short photoperiod (21%), while root voles were more sensitive to short photoperiod (60% of the total NST response) than to cold (40%), although cold clearly enhanced thermogenesis. Their thermogenic characteristics correlated with their preferred habitats: plateau pikas are found mainly in more exposed microhabitats in open sunny meadow, while root voles live in more sheltered microhabitats in relatively closed shrub. Our results also showed that temperature and photoperiod combined induce thermogenic adjustments in both species in seasonal acclimatization in their alpine meadow macrohabitat. PMID- 10093909 TI - Analysis of the fluorescence anisotropy of labelled membranes submitted to a shear stress. AB - Human erythrocyte membranes are elastic and undergo a deformation under shear stress. The phenomenon has been analysed by recording the fluorescence anisotropy of labelled isolated membranes. A model has been developed which assumes an orientation correlation function of a molecular probe incorporated in an elongated membrane. This model has been successfully used to analyse quantitatively data obtained with (1-trimethylamino)-(1,6-diphenyl)-1,3,5 hexatriene (TMA-DPH) and 6-(9-anthroyloxy)-stearic acid (6-AS). In agreement with the model, the effect of the membrane deformation is opposite for these two probes, which corroborates the concept that the alteration of the fluorescence anisotropy reflects mainly the deformation of the membrane and not the rotational freedom of the molecular probe. PMID- 10093910 TI - Effect of liquid-nitrogen and formalin-based conservation in the in vitro measurement of laser-induced fluorescence from peripheral vascular tissue. AB - In order to investigate the effects of conservation in liquid nitrogen and formalin on peripheral vascular tissue (abdominal aortic, femoral, flank, ham, fibular and tibial artery tissue), laser-induced fluorescence spectra have been recorded during the exposure of these tissues to helium-cadmium and argon ion radiation. The spectral distribution of tissue fluorescence allows the development of simple algorithms based on the intensity difference in order to discriminate the tissue samples when they are fresh and after they have been stored for 24 and 28 h in liquid nitrogen or formalin. PMID- 10093911 TI - Simulations on the selectivity of 5-aminolaevulinic acid-induced fluorescence in vivo. AB - The knowledge of the exact time course of a photosensitizer in tumour and surrounding host tissue is fundamental for effective photodynamic therapy (PDT) and fluorescence-based diagnosis. In this study the time course of porphyrin fluorescence following topical application of 5-aminolaevulinic acid (ALA) using different formulations, concentrations and incubation times has been measured in amelanotic melanomas (A-Mel-3) (n = 54) grown in transparent dorsal skinfold chambers of Syrian golden hamsters and in human basal cell carcinomas (BCCs) (n = 40) in vivo. To simulate the accumulation of ALA-induced protoporphyrin IX (Pp IX), a three-compartment model has been developed and rate constants have been determined. The kinetics of both the A-Mel-3 tumours and the BCCs show a significantly higher fluorescence intensity in tumour as compared to normal surrounding host tissue. Maximal fluorescence intensity in A-Mel-3 tumours as a percentage of the reference standard used occurs 150 min post incubation (p.i.) using a 1, 3 or 10% (vol.) ALA solution buffered to pH 7.4 and 1 h incubation time. After a 4 h incubation time maximal fluorescence intensity in tumour is measured shortly p.i. A concentration of 10% ALA does not increase the fluorescence intensity as compared to 3% ALA following 4 h incubation, but either 3 or 10% ALA yields a significantly higher fluorescence after 4 h incubation time as compared to 1 h. The fluorescence intensity following an 8 h incubation reaches its maximum directly p.i. for all concentrations and then decreases exponentially. The fluorescence intensity in the surrounding host tissue shows no statistically significant difference regarding concentration or incubation time. At least during the first hour p.i., the fluorescence intensity measured in the surrounding tissue is lower as compared to that in the tumour in all groups. 24 h after topical application hardly any fluorescence is detectable in tumour or surrounding host tissue in all experimental groups. Incubating human BCCs with a 20% ALA cream (water-in-oil emulsion) or a 20% ALA gel (containing 40% dimethyl sulfoxide) for approximately 2 h yields a similar fluorescence intensity directly after incubation for either cream or gel. However, while yielding a maximum 120 min p.i. with cream, the fluorescence intensity increases for a longer time (about 2-3 h p.i.) and up to higher values using the gel formulation. In surrounding normal skin, cream as well as gel formulation yields a similar fluorescence intensity directly after incubation. Afterwards the fluorescence intensity decreases slowly using the cream whereas a further increase of the fluorescence intensity is measured in the normal skin with a maximum 240 min p.i. using the gel formulation. The results of the proposed three-compartment model indicate that the observed selectivity of accumulated porphyrins following topical application of ALA is mainly governed by an increased ALA penetration of the stratum corneum of the skin, an accelerated ALA uptake into the cell and a higher porphyrin formation in tumour as compared to normal skin tissue, but not by a reduced ferrocheletase activity. PMID- 10093912 TI - Differential effect of phototherapy on the activities of human natural killer cells and cytotoxic T cells. AB - Exposure to ultraviolet B (UV-B) light is recognized to induce suppression of certain immune responses, particularly delayed hypersensitivity. However, its effect on cytotoxic T lymphocyte (CTL) activity, of major importance in the resistance to viruses and tumours, has not been assessed to the same extent. In this study five normal subjects, seropositive for herpes simplex virus (HSV), underwent a standard course of broadband UV-B therapy, as used in the treatment of psoriasis. They received whole-body irradiation thrice weekly for four weeks with incremental doses dependent on skin type. Blood samples were taken immediately before, at two time points during, and at the end of the therapy. An HSV-specific CTL assay was performed using autologous B cells transformed with Epstein-Barr virus as targets. No consistent modulation in CTL activity was obtained as a result of the therapy. The CTLs were separated into CD4 and CD8 subsets by positive selection and, again, no effect of irradiation on CTL activity within each of these two populations was observed. In contrast, the natural killer (NK) cell activity, assessed by the lysis of K562 cells, was significantly reduced at the first time point after the initiation of the phototherapy in all five subjects, and it continued to decline as the treatment progressed. Thus a differential effect of UV-B exposure on cytotoxic activity has been demonstrated: the HSV-specific CTL response is unchanged, while the NK response is suppressed. PMID- 10093913 TI - Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation-induced pigmentation. AB - We have studied the effect of a plasmin inhibitor, trans-4 aminomethylcyclohexanecarboxylic acid (trans-AMCHA), on skin pigmentation induced by ultraviolet (UV) exposure in Weiser-Maples guinea pigs. When guinea pigs are exposed to UV radiation (840 mJ cm-2), skin pigmentation is clearly observed from seven days after exposure and continued to increase to 29 days. Post-exposure applications of 2 and 3% solutions of trans-AMCHA to the exposed regions prevent or inhibit the pigmentation process. When the skin is removed and stained by the Fontana-Masson method, melanin content in the basal layer of UV-exposed epidermis is significantly reduced in the regions to which 2 and 3% trans-AMCHA solutions have been applied, compared with the vehicle control. As plasmin is known to contribute to the release of arachidonic acid (AA) and the production of prostaglandins (PGs), we have examined the effects of trans-AMCHA on AA-induced pigmentation in guinea pig skin. Topical application of trans-AMCHA causes a dose dependent decrease in AA-induced pigmentation. These results suggest that trans AMCHA reduces melanocyte tyrosinase activity by suppressing the production of PGs, UV-induced melanogens, through the suppression of the UV-induced increase in epidermal plasmin activity. PMID- 10093914 TI - Fluorescence and quenching comparative studies of halophilic and bovine glutamate dehydrogenase. AB - Fluorescence techniques have been used to study the structural characteristics of many proteins. The halophilic enzyme NADP-glutamate dehydrogenase from Haloferax mediterranei is found to be a hexameric enzyme composed of identical subunits. Fluorescence spectra of native and denatured halophilic and bovine glutamate dehydrogenase (h-GDH and b-GDH) have been analysed. Native h-GDH presents the maximum emission at 338 nm, whereas for b-GDH the maximum appears at 332 nm. The denaturation process is accompanied by an exposure to the solvent of the tryptophan residues, as manifested by the red shift of the emission maximum in both cases. The unfolding of h-GDH is a gradual process, which is accompanied by a loss in enzyme activity. Fluorescence quenching by external quenchers, KI and acrylamide, has also been carried out. The tryptophan residues in the protein are more exposed to the solvent in h-GDH than in b-GDH. The total amount of tryptophan residues is nearly the same for both enzymes. PMID- 10093915 TI - Photostability and thermal stability of indocyanine green. AB - The photo-fading of the S0-S1 absorption band of the infrared dye indocyanine green sodium iodide (ICG-NaI) has been studied by cw laser excitation to the S1 band. Monomeric solutions in water, heavy water, aqueous sodium azide, human plasma, methanol and dimethyl sulfoxide (DMSO) as well as J-aggregated solutions in H2O and D2O have been investigated. A leucoform of indocyanine green seems to be formed by photodegradation. The degradation slows down with exposure time. The initial degradation yield, phi D,0, is determined. In monomeric and dimeric water, heavy water and sodium azide solutions the initial photostability is of the order of phi D.0 approximately 10(-3), in the organic solvents methanol and DMSO it is of the order of phi D.0 approximately 10(-5), and in human plasma it is phi D.0 approximately 2 x 10(-6). J-aggregates at high concentration are very stable. The thermal stability of the ICG-NaI solutions at room temperature in the dark is compared with their photostability. The thermal degradation time of monomeric and dimeric ICG-NaI in water, heavy water and sodium azide solutions is t(th) approximately 10 days, while no thermal degradation is observed for ICG-NaI J-aggregates and ICG-NaI in methanol, DMSO and human plasma. PMID- 10093916 TI - Visible radiation effects on flavocytochrome b2 in dilute aqueous solution: a steady-state and laser flash photolysis study. AB - Irradiation of flavocytochrome b2 by visible radiation at 450 nm in dilute aqueous solution is found to have a devastating effect not only on its activity but also on the important flavin mononucleotide (FMN) constituents. The active site and the substrate binding site are also found to be largely modified on exposure to visible radiation. This has a telling effect on the constituent aromatic amino acids, tryptophan and tyrosine, and therefore justifies the role of FMN as a very potent photosensitizer. Partial unfolding of the irradiated enzyme molecule is also observed. Damage is much greater in deaerated conditions, which indicates that molecular oxygen plays a protecting role in this particular system. The inactivation is mediated through rapid electron transfer from tryptophan and tyrosine to excited flavin, forming flavin semiquinone and tryptophanyl and tyrosinyl radicals, which in turn cause permanent damage at the molecular level. PMID- 10093917 TI - Bilirubin photoisomerization products in serum and urine from a Crigler-Najjar type I patient treated by phototherapy. AB - The relative compositions of the photoisomers of bilirubin-1X alpha (4Z, 15Z bilirubin) in serum and urine of a patient with Crigler-Najjar type I syndrome treated by phototherapy are reported. High-performance liquid chromatography analysis reveals the presence of high serum levels of the configurational bilirubin photoisomer (4Z,15E-bilirubin) before the beginning of phototherapy (between 12 and 16% of the total bilirubin). The configurational photoisomer value increases during phototherapy with blue fluorescent lamps up to a photoequilibrium of about 25%, similar to that obtained in a bilirubin solution in vitro irradiated by the same lamps. This evidence suggests an inefficient serum excretion of the 4Z,15E-bilirubin. Indeed, its average half-life in serum of the Crigler-Najjar patient is found to be about 8 h. No detectable traces of the bilirubin structural isomer, lumirubin, are found in the serum. On the other hand, lumirubin represents the dominant bilirubin isomer excreted in the urine, as both 15Z and 15E configurations. Smaller amounts of 4Z,15E-bilirubin, 4E,15Z bilirubin and native 4Z,15Z-bilirubin are observed in urine. The presence in urine of 4Z,15Z-bilirubin is probably due to a fast reversion of the configurational photoisomers to their native form. The half-life of the configurational photoisomers in urine kept at 38 degrees C is found to be of the order of a few minutes. Our study indicates that in Crigler-Najjar type I patients, mechanisms exist to excrete all bilirubin photoisomers. The lumirubin pathway seems to contribute markedly to bilirubin excretion in the urine, as occurs in jaundiced babies under phototherapy. However, the contribution of configurational isomers cannot be neglected. PMID- 10093918 TI - Interaction of bis(1-anilino-8-naphthalenesulfonate) with yeast hexokinase: a steady-state fluorescence study. AB - Bis(1-analino-8-naphthalenesulfonate) (bis-ANS) is a useful probe for hydrophobic areas on protein molecules and it has been proposed that it has a general affinity for the nucleotide binding site(s). There appear to be two different classes of binding sites for bis-ANS on hexokinase and these can be tentatively assigned as primary and secondary binding sites. The rate of binding of bis-ANS at the primary binding site is fast, whereas binding at secondary site(s) is slow. The slow increase in the fluorescence intensity on binding with bis-ANS is not due to conformational change in the enzyme, which may lead to the increase in the quantum yield of the bound dye. Circular dichroism measurements indicate that there is no significant change in the secondary structure on binding with this probe. In the presence of saturating amounts of glucose, the increase in fluorescence intensity due to binding at the secondary binding site(s) is significantly lowered. This indicates that glucose-induced conformational change has been sensed by this probe. From kinetic studies, it has been observed that bis-ANS is an effective competitive inhibitor of yeast hexokinase with respect to ATP. The stoichiometry of binding of this fluorescent probe is about one per subunit at the primary site both in the presence and absence of glucose, and the dissociation constant of bis-ANS is unaffected by glucose. It is possible to decrease significantly the amount of fluorescence intensity at the primary site by nucleotides. These results indicate that bis-ANS interacts at the site where nucleotide interacts. Energy transfer experiments indicate the proximity of some tryptophan(s) and bound bis-ANS molecule(s). PMID- 10093919 TI - Neurotoxicity of tetraphenylporphinesulfonate (TPPS4) and a hematoporphyrin derivative (Photosan) in organotypic cultures of chick embryonic dorsal root ganglia. AB - The neurotoxic effect of tetraphenylporphinesulfonate (TPPS4) and a hematoporphyrin derivative (HPD, Photosan) has been studied in organotypic cultures of chick dorsal root ganglia maintained in a semi-solid culture medium. The changes in two characteristics of neurite outgrowth, the mean radial length of neurites growing out from the ganglia and the area of neurite outgrowths, are used as parameters to evaluate the toxic effect. The porphyrins are tested over the concentration range 10-160 micrograms ml-1. TPPS4 is slightly more toxic than the HPD Photosan. The median inhibitory concentration (IC50) for TPPS4 is 45-50 micrograms ml-1 and for the HPD Photosan 50-60 micrograms ml-1, respectively. Nevertheless, the toxicity of the two drugs is relatively low compared to that of commonly used anticancer drugs, such as cisplatin or taxol. PMID- 10093920 TI - Photosensitization of Staphylococcus aureus with malachite green isothiocyanate: inactivation efficiency and spectroscopic analysis. AB - The potential of malachite green isothiocyanate as a photosensitizer for the inactivation of bacteria has been evaluated. Samples of Staphylococcus aureus are treated with the dye and exposed to continuous-wave red light from a filtered xenon lamp. Reduction in cell viability is seen to increase with radiation dose, whilst non-photosensitized samples are largely unaffected with exposure. The mechanism of photosensitization and the subsequent inactivation is addressed. UV Vis and Fourier-transform infrared absorption spectrometry have been applied to this biological system, revealing the rapid hydrolysis of the isothiocyanate group of the dye and the transition to the colourless carbinol base when in solution. On binding to Staphylococcus aureus via a complexation mechanism, the dye is seen to be stabilized in its cationic form. Involvement of the excited triplet state of the photosensitizer is suggested and identification of reduced dye photoproducts is made following irradiation. PMID- 10093921 TI - Mutagenicity and dark toxicity of the second-generation photosensitizer bacteriochlorin a. AB - Bacteriochlorin a (BCA) is an effective second-generation photosensitizer both in vitro and in vivo. BCA has a high molecular absorption coefficient (32,000 M-1 cm 1) at 760 nm. At this wavelength tissue penetration of light is almost optimal and melanin absorption is relatively low. BCA is preferentially retained in a number of tumour model systems and is rapidly cleared from non-cancerous tissues, thus inducing no or minor skin photosensitivity. Mutagenicity of BCA has been tested using the Salmonella typhimurium strains TA97, TA98, TA100, TA102 and TA104. In all tester strains used, BCA induces, in the dark, a minute increase in the number of revertants. No linear correlation between the number of revertants and the BCA dose is observed. Incubation of isolated rat hepatocytes with BCA, in the dark, does not result in increased cell death as measured by leakage of cytosolic lactate dehydrogenase. A convenient bioassay to test possible genotoxicity in vivo is the established Somatic Mutation and Recombination Test (SMART) on Drosophila melanogaster. Bacteriochlorin was tested for induction of loss of heterozygosity in the white/white+ eye mosaic assay, which predominantly measures homologous mitotic recombination in somatic cells of Drosophila after treatment of larval stages. BCA did not induce loss of heterozygosity above the level of the incorporated controls, with or without illumination. Based on these results, obtained in prokaryotic and eukaryotic cells and in vivo, we are inclined to conclude that the dark toxicity and mutagenic properties of BCA, as measured by the applied bioassays, are negligible. PMID- 10093922 TI - The mechanism of "Fenton-like" reactions and their importance for biological systems. A biologist's view. PMID- 10093923 TI - Free radicals as a result of dioxygen metabolism. PMID- 10093924 TI - Biological chemistry of copper-zinc superoxide dismutase and its link to amyotrophic lateral sclerosis. PMID- 10093925 TI - DNA damage mediated by metal ions with special reference to copper and iron. PMID- 10093926 TI - Radical migration through the DNA helix: chemistry at a distance. PMID- 10093927 TI - Involvement of metal ions in lipid peroxidation: biological implications. PMID- 10093928 TI - Formation of methemoglobin and free radicals in erythrocytes. PMID- 10093929 TI - Role of free radicals and metal ions in the pathogenesis of Alzheimer's disease. PMID- 10093930 TI - Metal binding and radical generation of proteins in human neurological diseases and aging. PMID- 10093931 TI - Thiyl radicals in biochemically important thiols in the presence of metal ions. PMID- 10093932 TI - Methylmercury-induced generation of free radicals: biological implications. PMID- 10093933 TI - Role of free radicals in metal-induced carcinogenesis. PMID- 10093934 TI - pH-dependent organocobalt sources for active radical species: a new type of anticancer agents. PMID- 10093935 TI - Detection of chromatin-associated hydroxyl radicals generated by DNA-bound metal compounds and antitumor antibiotics. PMID- 10093936 TI - Nitric oxide (NO): formation and biological roles in mammalian systems. PMID- 10093937 TI - Chemistry of peroxynitrite and its relevance to biological systems. PMID- 10093938 TI - Novel nitric oxide-liberating heme proteins from the saliva of bloodsucking insects. AB - The spectroscopic (UV-visible, IR, RR, MCD, Mossbauer, EPR), crystallographic, kinetic, and redox investigations that have been carried out on model hemes, hemoglobin, myoglobin, cytochrome a3 of cytochrome oxidase, horseradish peroxidase, prostaglandin H synthase, cytochromes P450, chloroperoxidase, and so forth have shown us the unique properties of heme-NO centers, as summarized above. However, in none of these cases is the Fe(III)NO complex of any known physiological importance. The nitrophorins of R. prolixus [59] (and Cimex lectularius [80]) are thus far unique in this respect. It is likely that further investigations of the roles of NO in biological systems will discover additional interesting involvements of heme proteins in these roles. PMID- 10093939 TI - Nitrogen monoxide-related disease and nitrogen monoxide scavengers as potential drugs. PMID- 10093940 TI - Therapeutics of nitric oxide modulation. PMID- 10093941 TI - Childhood immunizations and type 1 diabetes: summary of an Institute for Vaccine Safety Workshop. The Institute for Vaccine Safety Diabetes Workshop Panel. PMID- 10093942 TI - Immunoprophylaxis with palivizumab, a humanized respiratory syncytial virus monoclonal antibody, for prevention of respiratory syncytial virus infection in high risk infants: a consensus opinion. PMID- 10093943 TI - Predictors of physician compliance with a published guideline on management of febrile infants. AB - BACKGROUND: Previous studies have demonstrated clinicians' poor compliance with published management strategies and protocols, but the reasons why physicians often choose to vary their management of the febrile infant from published guidelines are poorly understood. OBJECTIVE: We conducted a study of physicians to learn more about the issues that influence their decisions in the management of febrile infants. METHODS: A survey study of pediatricians, emergency physicians and family physicians randomly selected from a list of licensed physicians in the United States. Chi square and Kruskal-Wallis tests were used to measure differences in responses by specialty. Odds ratios from logistic regression were used to measure differences in compliance with a recently published guideline. RESULTS: We received 193 completed surveys from pediatricians, 177 from emergency physicians and 104 from family physicians. After controlling for other variables, odds for compliance with a recently published guideline were higher for pediatricians [odds ratio (OR) = 9.13] and emergency physicians (OR = 2.5) than for family physicians (P < 0.001). Factors associated with decreased odds of compliance included more years since graduation from medical school (OR = 0.93), a higher proportion of office visits by children < 1 year of age (OR = 0.97) and increased comfort diagnosing serious bacterial illness (OR = 0.35). Factors associated with increased odds of compliance included a higher perceived likelihood of serious bacterial illness in febrile infants (OR = 1.01) and better reported knowledge of the recently published guideline (OR = 2.01). CONCLUSIONS: We found that specialty as well as other factors were associated with physician compliance with a recently published guideline. This information may facilitate guideline development and implementation by providing a better understanding of what motivates physicians in their clinical decision making. PMID- 10093944 TI - Management of otitis media among children in a large health insurance plan. AB - BACKGROUND: Otitis media is one of the most common office diagnoses among children in the US and the leading reason for the use of antimicrobials in pediatric practice. We undertook this study to characterize medical and surgical management of otitis media. METHODS: Using claims data from a large New England health insurer, we identified all children <10 years of age who had one or more episodes of acute otitis media between July, 1995, and June, 1996, and examined patterns of treatment for this condition. RESULTS: Study subjects (n = 22,004) averaged 2.9 physician office visits for management of otitis media; among children <2 years of age, one-fourth had 6 or more such visits. Amoxicillin was prescribed as initial therapy in more than one-half (56.6%) of all episodes of acute otitis media, followed by cephalosporins (18.3%), trimethoprim sulfamethoxazole (12.3%), macrolides (6.4%) and amoxicillin-clavulanate (6.0%). Over multiple episodes, however, use of amoxicillin declined by about 50%. Antimicrobial prophylaxis was received by 7.3% of all study subjects for a mean of 61.3 days; the incidence of breakthrough episodes of acute otitis media during prophylaxis varied according to the antimicrobial used (13.9, 12.3 and 19.5% for amoxicillin, trimethoprim-sulfamethoxazole and sulfisoxazole, respectively). Surgical procedures related to otitis media were performed on 3.8% of all study subjects, including 4.6% of children <2 years of age. CONCLUSIONS: The health care burden of otitis media is large, particularly in the first 2 years of life. PMID- 10093945 TI - A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group. AB - BACKGROUND: Despite concerns about safety in children, fluoroquinolone antibiotics have become the treatment of choice in patients with multidrug resistant typhoid fever in Vietnam. However, quinolone-resistant strains of Salmonella typhi have recently been reported from Vietnam; and if quinolone resistance becomes established, alternative oral treatment options will be needed. OBJECTIVE: Cefixime, an orally administered third generation cephalosporin, was compared with ofloxacin for the treatment of uncomplicated typhoid fever in children. METHODS: In an open trial children with suspected typhoid fever were randomized to receive either ofloxacin (10 mg/kg/day in two divided doses) for 5 days or cefixime (20 mg/kg/day in two divided doses) for 7 days. RESULTS: S. typhi was isolated from 82 patients (44 in the cefixime group, 38 in the ofloxacin group) and 70 (85%) of the isolates were multidrug-resistant. Median (95% confidence interval, range) fever clearance times were 4.4 (4 to 5.2, 0.2 to 9.9) days for ofloxacin recipients and 8.5 (4.2 to 9, 1.8 to 15.2) days for cefixime-treated patients (P < 0.0001). There were 11 treatment failures (10 acute and one relapse) in the cefixime group and 1 acute treatment failure in the ofloxacin group (mean difference, 22%; 95% confidence interval, 9 to 36%). CONCLUSION: Short course treatment with cefixime may provide a useful alternative treatment in cases of uncomplicated typhoid fever in children, but it is less effective than short course treatment with ofloxacin. PMID- 10093946 TI - Prevalence of antibodies to astrovirus types 1 and 3 in children and adolescents in Norfolk, Virginia. AB - OBJECTIVE: To determine the prevalence of antibody to human astrovirus types 1 (HAstV-1) and 3 (HAstV-3) in children. METHODS: Sera from children hospitalized in Norfolk, VA, for noninfectious conditions were collected for a 1-month period every 6 months from 1993 to 1996 and tested by enzyme immunoassay for antibody to HAstV-1 and HAstV-3 with the use of baculovirus-expressed recombinant capsid proteins as antigens. RESULTS: The seroprevalence of 393 infants and children to HAstV-1 decreased from 67% in infants <3 months of age to 7% by 6 to 8 months of age, consistent with loss of transplacental antibodies. Children acquired HAstV-1 antibody with a peak prevalence of 94% at 6 to 9 years of age (P < 0.001). Antibodies to HAstV-3 exhibited a lower prevalence, with 26% positive at <3 months, 0% at 6 to 11 months and 42% by 6 to 9 years of age. HAstV-1 seroprevalence in children O to 2 months of age decreased from 89% in November, 1993, to 40% in November, 1996 (P = 0.009). CONCLUSIONS: Astrovirus type-specific antibody prevalence can be measured by baculovirus-expressed capsid antigens in an enzyme immunoassay. Children developed antibody to HAstV-1 (94%) and to HAstV 3 (42%) by 6 to 9 years of age indicating frequent exposure to these enteric viruses in infancy and early childhood. PMID- 10093947 TI - Emergence and spread of a new clone of M type 1 group A Streptococcus coincident with the increase in invasive diseases in Japan. AB - BACKGROUND: In Japan invasive group A streptococcal infections such as sepsis and toxic shock syndrome (TSS) have increased since 1992. As is the case in the United States and Europe, M1 serotype is predominant among the isolates from Japanese patients. METHODS: By restriction enzyme digestion and pulsed field gel electrophoresis, we investigated the whole genomic DNA profiles of 95 M type 1 group A streptococcal strains isolated from patients with serious diseases including sepsis, toxic shock syndrome, necrotizing fasciitis and nonsuppurative complications and with uncomplicated pharyngitis during 1979 through 1996 in Japan. RESULTS: The genome profiles among 8 of 10 isolates from patients with serious diseases in 1979 through 1991 were all the same and were shared by the profiles of the 35 of 48 isolates from patients with uncomplicated pharyngitis in 1982 through 1991. All 18 strains isolated from patients with invasive diseases in 1992 to 1996 had a unique profile, which was shared by the profiles of 18 of 19 isolates from uncomplicated pharyngitis during the same period. This genomic profile was distinct from the predominant or any other profiles before 1992, and it was found to be a new clone. CONCLUSIONS: The emergence and spread of this new clone of M type 1 Streptococcus after 1991 may be associated with the increase in invasive streptococcal infections that occurred during the same period in Japan. Genomic profiles as well as serotypes of streptococcal isolates are important for the epidemiology of clinical relevance in streptococcal diseases. PMID- 10093948 TI - Low risk of bacteremia in febrile children with recognizable viral syndromes. AB - BACKGROUND: Previous studies of occult bacteremia in febrile children have excluded patients with recognizable viral syndromes (RVS). There is little information in the literature regarding the rate of bacteremia in febrile children with RVS. OBJECTIVE: To determine the rate of bacteremia in children 3 to 36 months of age with fever and RVS. METHODS: We performed a retrospective analysis of all patients 3 to 36 months of age with a temperature > or =39 degrees C seen during a 5 1/2-year period in the Emergency Department of a tertiary care pediatric hospital. From this group those with a discharge diagnosis of croup, varicella, bronchiolitis or stomatitis and no apparent concomitant bacterial infection were considered to have an RVS. The rate of bacteremia was determined for those subjects with RVS who had blood cultures. RESULTS: Of 21,216 patients 3 to 36 months of age with a temperature > or =39 degrees C, 1347 (6%) were diagnosed with an RVS. Blood cultures were obtained in 876 (65%) of RVS patients. Of patients who had blood cultures, true pathogens were found in only 2 of 876 (0.2%) subjects with RVS [95% confidence interval (CI) 0.01, 0.8%]. The rate of bacteremia was 1 of 411 (0.2%) for subjects with bronchiolitis, O of 249 (0%) for subjects with croup, O of 123 (0%) for subjects with stomatitis and 1 of 93 (1.1%) for subjects with varicella. CONCLUSIONS: Highly febrile children 3 to 36 months of age with uncomplicated croup, bronchiolitis, varicella or stomatitis have a very low rate of bacteremia and need not have blood drawn for culture. PMID- 10093949 TI - Evaluation of screening for hepatitis B surface antigen during pregnancy in a population with a high prevalence of hepatitis B surface antigen positive/hepatitis B e antigen-negative carriers. AB - BACKGROUND: Universal hepatitis B vaccination in infancy was implemented in Israel in 1992. The program consists of active vaccination at birth and at 1 and 6 months of age, without hepatitis B surface antigen (HBsAg) screening during pregnancy. Infants of HBsAg carrier mothers do not receive specific hepatitis B immunoglobulin in addition to vaccine at birth. The recently arrived Jewish immigrants from Ethiopia are the group with the highest rate of HBsAg carriage (approximately 10%) in Israel. AIM: The objective of this study was to evaluate whether the present policy is effective against perinatal HBV transmission from mothers of Ethiopian origin to their infants. METHODS: The study group included 411 Israeli born children, offspring of mothers of Ethiopian origin. All infants were fully vaccinated starting at birth. Sera were collected from the children at the age of 9 to 36 months and from their mothers. Tests for HBsAg, antibodies to HBsAg (anti-HBs) and antibodies to hepatitis B core antigen (anti-HBc) were performed. RESULTS: Eighty-nine percent of the children had detectable anti-HBs, including 82.2% with protective anti-HBs concentrations (> or =10 mIU/ ml). Although 24 mothers (6.2%) were HBsAg carriers, none of the children was HBsAg positive. Seven of 394 infants (1.7%) tested positive for anti-HBc. This test became negative in 5 of 6 who were followed for 12 months. The percentage of infants with protective anti-HBs concentrations decreased significantly from 91.4% at 9 to 12 months to 70.1% at 31 to 36 months of age. The mother's infection status was not associated with the infant's response to vaccine. Calculation based on the above data suggests that screening for HBsAg in pregnancy in that group is not cost-effective. CONCLUSIONS: Our results suggest that the Israeli vaccination program against HBV infection is effective, even in a high risk population, and additional measures are not cost-effective. PMID- 10093950 TI - Timing and effectiveness of requirements for a second dose of measles vaccine. AB - OBJECTIVE: Previous measles elimination goals have failed in the United States despite high coverage of schoolchildren with a single dose of measles vaccine. Since 1989 advisory groups have recommended that schoolchildren receive a second dose of measles vaccine as part of a revised strategy to eliminate measles from the US. States have responded by phasing in requirements for a second dose of measles vaccine at school entry for various age groups at primary school entrance, secondary school entrance or both. The purpose of this analysis was to evaluate the effectiveness of the requirements for a second dose of measles vaccine and to determine whether a primary or secondary school entrance requirement was more effective in lowering measles incidence. METHODS: Using national surveillance data we examined the influence of state requirements for the second dose of measles vaccine on measles incidence from 1993 through 1995. RESULTS: Overall measles incidence was lower in states that had a requirement for a second dose of measles vaccine at either primary school entrance [relative risk (RR) = 0.35; 95% confidence interval, 0.25 to 0.49] or secondary school entrance (RR = 0.38; 95% confidence interval 0.29 to 0.50), compared with states without a second dose requirement. Incidence was lowest in states that required a second dose of measles vaccine at both primary and secondary school entrance (RR = 0.22; 95% confidence interval, 0.13 to 0.37). CONCLUSIONS: Our findings demonstrate that a requirement for a second dose of measles vaccine at either primary or secondary school entrance is effective in lowering measles incidence, with a greater reduction occurring in states where the second dose is required for both age groups. PMID- 10093951 TI - An epidemic of a pertussis-like illness caused by Chlamydia pneumoniae. AB - BACKGROUND: Between June and July, 1994, we encountered an epidemic of a pertussis-like illness in adolescents in a junior high school located in a rural area of Japan. The purposes of this study were to record the clinical manifestations and to identify an etiology. PATIENTS AND METHODS: We interviewed patients and parents and we performed physical examinations on patients with cough during the epidemic. The chest radiographs were also reviewed by us. To identify an etiology we performed culture and serologic studies for a variety of bacteria, Mycoplasma, chlamydiae and viruses. Polymerase chain reaction (PCR) for Chlamydia pneumoniae was carried out on throat swab specimens. RESULTS: Of a total of 230 students 136 (59%) had severe cough illnesses. One developed pneumonia, 9 had bronchitis and the remaining 126 (93%) presented upper respiratory tract infections (URI). The mean duration of cough in cases with URI was 17.4 days and that in cases with bronchitis and pneumonia was 30.4 days. Serology and/or cultures for Bordetella pertussis, Bordetella parapertussis, Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia psittaci or viruses were negative. Detection of C. pneumoniae infection was carried out in 46 patients with pneumonia, bronchitis or URI by serology and PCR. The patient with pneumonia, 7 of 7 patients with bronchitis and 32 (84%) of 38 patients with URI were documented to be infected by C. pneumoniae either by serology, PCR or both tests. CONCLUSION: An epidemic of a pertussis-like illness in a junior high school population was caused by C. pneumoniae. PMID- 10093952 TI - Prevalence of Bartonella henselae immunoglobulin G antibodies in Singaporean cats. AB - BACKGROUND: Bartonella henselae causes several clinical diseases in humans. The most common infection is the classical cat-scratch disease (CSD) occurring in immunocompetent and immunocompromised children exposed to newly acquired kittens. This is the first study of B. henselae infection in Singaporean cat population. METHODS: Indirect fluorescent antibody tests were carried out on cat sera obtained from 80 cat blood samples. RESULTS: Of the cats studied in this project 47.5% tested seropositive, with high IgG titers (> or =1024) in 31 of 38 seropositive cats, 60.5% of which were males. CONCLUSIONS: Males cats had higher rates of infection than female cats. Serologic studies of cats in different parts of the United States have indicated that the prevalence of IgG antibody to B. henselae in cats is highest in regions with warm, humid climates and lowest in areas with cool, dry climates. The indirect fluorescent antibody test data for B. henselae infection in Singapore cats support this contention. PMID- 10093953 TI - Prevention of perinatal group B streptococcal infections. PMID- 10093954 TI - Viridans streptococcal infections in patients with neutropenia. PMID- 10093955 TI - Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). PMID- 10093956 TI - Vitamins and the regulation of the immune response. PMID- 10093957 TI - Clostridial bacteremia in the non-infant pediatric population: a report of two cases and review of the literature. PMID- 10093958 TI - Interstitial keratitis in a five-year-old. PMID- 10093959 TI - Failure of prediction of peak serum vancomycin concentrations from trough values in neonates. PMID- 10093960 TI - Cytokine analysis of middle ear effusions during acute otitis media: significant reduction in tumor necrosis factor alpha concentrations correlates with bacterial eradication. PMID- 10093961 TI - Time to development of acute otitis media during an upper respiratory tract infection in children. PMID- 10093962 TI - Brain abscess associated with neonatal listeriosis. PMID- 10093963 TI - Parvovirus B19 infection complicated by peripheral facial palsy and parotitis with intraparotid lymphadenitis. PMID- 10093964 TI - Nocardia asteroides septic arthritis in a healthy child. PMID- 10093965 TI - Risks of human immunodeficiency virus transmission from artificial insemination from an infected donor. PMID- 10093966 TI - Possible mechanisms through which dietary pectin influences fibrin network architecture in hypercholesterolaemic subjects. AB - It is suspected that not only fibrinogen concentration but also the quality of fibrin networks may contribute to cardiovascular risk. Evidence is accumulating that a "prudent" diet may protect against diseases associated with raised clotting factors. The effect of diet on fibrinogen is, however, still controversial. In a previous study performed in our laboratory, it was shown that dietary pectin influences fibrin network architecture in hypercholesterolaemic men without causing any changes in fibrinogen concentration. To elucidate the possible mechanisms, it was necessary to study the possibility that pectin may itself have indirect effects on fibrin network architecture. Pectin is fermented in the gastrointestinal tract to acetate, propionate, and butyrate. In humans, only acetate reaches the circulation beyond the liver. This investigation primarily examined the possibility that pectin may, through acetate, influence fibrin network architecture in vivo. The effects of pectin and acetate supplementation in hypercholesterolaemic subjects were compared. Furthermore, this study also aimed at describing the possible in vitro effects of acetate on fibrin network architecture. Two groups of 10 male hyperlipidaemic volunteers each received a pectin (15 g/day) or acetate (6.8 g/day) supplement for 4 weeks. Acetate supplementation did not cause a significant change in plasma fibrinogen levels. As in the pectin group, significant differences were found in the characteristics of fibrin networks developed in plasma after 4 weeks of acetate supplementation. Fibrin networks were more permeable (from 213+/-76 to 307+/-81 x 10(11) cm2), had lower tensile strength (from 23+/-3 to 32+/-9% compaction), and were more lyseable (from 252+/-11 to 130+/-15 minutes). These results strongly suggest that the effect of pectin on network architecture could partially be mediated by acetate. Progressive amounts of acetate were used in vitro to investigate the possibility that acetate may be directly responsible for changes that occurred in fibrin network architecture in the plasma medium. Results indicated that acetate influenced fibrin network architecture directly. From the results, it seems highly possible that acetate may be responsible in part for the beneficial effects of pectin supplementation in vivo. It is evident that pectin or acetate supplementation can be useful during the treatment or prevention of some clinical manifestations, especially those associated with raised total cholesterol and possibly also plasma fibrinogen. PMID- 10093967 TI - Two multiplex PCR-based DNA assays for the thrombosis risk factors prothrombin G20210A and coagulation factor V G1691A polymorphisms. AB - Two coagulation factor polymorphisms, G1691A in the factor V gene and G20210A in the prothrombin gene, are currently the most common known genetic risk factors for venous thrombosis in caucasian populations. Experimental conditions that permit simultaneous determination of these two polymorphisms using PCR-based DNA assays with the restriction enzyme, Hind III, were developed. Moreover, novel PCR based DNA assays were established using primers that introduce specific cleavage sequences which then permit the simultaneous determination of these polymorphisms using Sac I restriction digestion analysis. Multiplex PCR-based DNA assays were used to analyze a family with a history of venous thrombosis in which these polymorphisms were both present and the results confirm the interesting variability of these genetic risk factors among family members who are symptomatic. PMID- 10093968 TI - Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers. AB - Cigarette smoking is a well-known risk factor for atherosclerotic disorders. Several authors have suggested that platelet aggregability is important in smoking-induced vascular injury. When platelet-rich plasma is stirred at 37 degrees C in the absence of chemical stimulants, small aggregates of platelets may be formed, but it was difficult to detect small aggregates by conventional aggregometer using optical density. Recent technological advances have made it possible to detect small aggregates by using a newly developed assay system that employs laser light scattering. In the present study, we attempted to measure platelet aggregation by this method, using laser light scattering in 54 nonsmoking healthy males and 51 healthy male habitual smokers who were age matched. In smokers, blood was obtained after 10 hours of smoking abstinence. No significant difference in platelet aggregation was induced by 1 microM or 5 microM of ADP between smokers and nonsmokers. In smokers, plasma fibrinogen levels and the number of small aggregates formed in the absence of chemical stimulants was significantly higher than in nonsmokers. Small aggregates formed in the absence of stimulants correlated positively with the concentrations of von Willebrand factor (vWF) antigen (r=0.2654, p<0.01) and of fibrinogen (r=0.2834, p<0.01). The formation of these small aggregates was inhibited by monoclonal antibody against GPIIb/IIIa blocking fibrinogen binding to GPIIb/IIIa but not inhibited at all by monoclonal antibody against GPIb blocking vWF binding to GPIb. From these results, enhanced platelet aggregability in smokers was confirmed, and it was suggested that GPIIb/IIIa is concerned in platelet spontaneous aggregation, although vWF may not directly influence on the platelet spontaneous aggregation. Since the mechanism of spontaneous aggregation and the effect of increased spontaneous aggregability on the progression of atherosclerosis remains unclear, further study was considered necessary. PMID- 10093969 TI - Two-step spreading mode of human glioma cells on fibrin monomer: interaction of alpha(v)beta3 with the substratum followed by interaction of alpha5beta1 with endogenous cellular fibronectin secreted in the extracellular matrix. AB - Glioma cells, a human astrocyte-derived glioma cell line, were found to spread on immobilized fibrin monomer but not on fibrinogen. As a synthetic RGD-containing peptide GRGDSP blocked the spreading of glioma cells on fibrin monomer concentration-dependently, the spreading was thought to be mediated by their cell surface receptors. In fact, both the beta1- and beta3-integrins were located at 3 hours of incubation in the cytoplasmic areas and at 24 hours in the peripheral areas as well, although their distribution profiles were not necessarily identical with each other by immunohistochemical studies. By cytometry analysis utilizing respective monoclonal antibodies against alpha5- and alpha v-integrins, we were able to show expression of alpha5 (alpha5beta1) but not alpha v on the surface of glioma cells at 24 hours of incubation on immobilized fibrin monomer. A 50-kDa transmembrane protein designated as integrin-associated protein (IAP) known to be closely associated with the beta3-integrin was also located in the cytoplasmic and apical areas of spreading glioma cells, but its specific antibody B6H12 failed to inhibit the spreading. Thus, the IAP-dependent involvement of beta3-integrin may not be predominantly involved in the glioma cell spreading on fibrin monomer. As an anti-alpha v beta3 antibody LM 609 inhibited the spreading of glioma cells partially at approximately 35%, the spreading seems to proceed in a two-step mode, i.e., via alpha vbeta3 with its ligand exposed in fibrin monomer, and then via alpha5beta1 with endogenous cellular fibronectin secreted from the glioma cells themselves. In fact, the cellular fibronectin was clearly visualized by confocal microscopic observation. Thus, upon contact with fibrin in clots formed at traumatized areas in the brain, for example, glioma cells may have a chance to adhere to and spread via alpha v beta3 with fibrin monomer and then via alpha5beta1 with endogenous cellular fibronectin in the extracellular matrices. PMID- 10093970 TI - Suppression of protein kinase C is associated with inhibition of PYK2 tyrosine phosphorylation and enhancement of PYK2 interaction with Src in thrombin activated platelets. AB - Blood platelets have recently been shown to express PYK2, a nonreceptor tyrosine kinase belonging to the FAK gene family. In this study, we examined the involvement of protein kinase C (PKC) in PYK2-related responses in human platelets. While PYK2 tyrosine phosphorylation induced by thrombin was inhibited by preincubation of platelets with PKC inhibitors, staurosporine and Ro31-8220, PYK2 association with Src was markedly enhanced under the same conditions. Platelet intracellular Ca2+ mobilization induced by thrombin was hardly inhibited by these PKC inhibitors. p130Cas is a docking protein that associates with FAK or PYK2 through the SH3 domain. Although we identified p130Cas in platelets for the first time, this docking protein failed to interact with PYK2. These results suggest that PKC activation (but not Ca2+ mobilization) is involved in PYK2 tyrosine phosphorylation and that PYK2 associates with Src without PYK2 tyrosine phosphorylation or p130Cas involvement in platelets. PMID- 10093971 TI - Support for non-competitive trials. PMID- 10093972 TI - Detection of cervical intraepithelial neoplasia in developing countries. PMID- 10093973 TI - Management of cervical intraepithelial neoplasia. PMID- 10093974 TI - Air pollution and asthma: the dog that doesn't always bark. PMID- 10093975 TI - Treatment of IgA nephropathy. PMID- 10093976 TI - Preoperative fasting. PMID- 10093977 TI - Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. AB - BACKGROUND: The efficacy of highly active antiretroviral therapy (HAART) in suppression of HIV-1 is well documented. We investigated virological and clinical outcomes of HAART in routine practice. METHODS: We analysed prospective data from the Swiss HIV Cohort Study on suppression of viral load and progression to AIDS or death in 2674 outpatients (median age 36 years, 27.3% women) who started HAART in 1995-98. Viral rebound was defined as two consecutive HIV-1-RNA measurements of more than 400 copies/mL. We analysed separately outcomes in patients with a history of antiretroviral treatment and in treatment-naive patients. FINDINGS: An estimated 90.7% of treatment-naive patients reached undetectable viral load (<400 copies/mL) by 12 months. Among pretreated patients, estimates ranged from 70.3% treated with one new drug to 78.7% on three new drugs. 2 years after reaching undetectable concentrations, an estimated 20.1% of treatment-naive patients and 35.7-40.1% of pretreated patients had viral rebound. At 30 months, an estimated 6.6% (95% CI 4.6-8.6) of patients who had maintained undetectable concentrations, 9.0% (5.5-12.5) who had viral rebound, and 20.1% (15.3-24.9) who had never reached undetectable concentrations developed AIDS or died. Compared with patients who maintained undetectable viral load, the adjusted relative hazard of AIDS or death was 1.00 (0.66-1.55) for patients with viral rebound, and 2.40 (1.72-3.33) for patients who failed to reach undetectable concentrations. INTERPRETATION: The rate of virological failure of HAART was high among these patients, but the probability of clinical progression was low even in patients with viral rebound. PMID- 10093978 TI - Visual inspection with acetic acid for cervical-cancer screening: test qualities in a primary-care setting. University of Zimbabwe/JHPIEGO Cervical Cancer Project. AB - BACKGROUND: Naked-eye visual inspection of the cervix with acetic-acid wash (VIA), or cervicoscopy, is an alternative to cytology in screening for cervical cancer in poorly resourced locations. We tested the sensitivity, specificity, and predictive value of VIA done by nurse-midwives in a less-developed country. METHODS: Women were screened by six trained nurse-midwives in a two-phase, cross sectional study at 15 primary-care clinics in Zimbabwe. VIA and Pap smears were done concurrently, and their sensitivity and specificity compared. Colposcopy, with biopsy as indicated, was used as the reference test to allow a direct comparison of the test unaffected by verification bias. FINDINGS: 10934 women were screened. In phase II, 2148 (97.5%) of the 2203 participants for whom there was a screening result also had a reference test result. Also in phase II, VIA was more sensitive but less specific than cytology. Sensitivity (95% CI) was 76.7% (70.3-82.3) for VIA and 44.3% (37.3-51.4) for cytology. Specificity was 64.1% (61.9-66.2) for VIA and 90.6% (89.2-91.9) for cytology. INTERPRETATION: The high sensitivity of VIA shows that the test could be valuable in detection of precancerous lesions of the cervix. However, there are costs to the patient and system costs associated with high numbers of false-positive results, so attention should be given to improving the specificity of VIA. PMID- 10093979 TI - Effects of ambient air pollution on upper and lower respiratory symptoms and peak expiratory flow in children. AB - BACKGROUND: Previous epidemiological studies have shown acute effects of increased amounts of ambient air pollution on the prevalence of respiratory symptoms in children with respiratory disorders. We investigated whether children with bronchial hyperresponsiveness (BHR) and relatively high serum concentrations of total IgE (>60 kU/L, the median value) are susceptible to air pollution. METHODS: We collected data from children during three winters (1992-95) in rural and urban areas of the Netherlands. Lower respiratory symptoms (wheeze, attacks of wheezing, shortness of breath), upper respiratory symptoms (sore throat, runny or blocked nose), and peak expiratory flow were recorded daily for 3 months. The acute effects of airborne particulate matter with a diameter of less than 10 microm, black smoke, sulphur dioxide, and nitrogen dioxide were estimated by logistic regression. FINDINGS: 459 (73%) of 632 children had complete data. Of these, 26% had BHR and relatively high (above median) serum total IgE, 36% had no BHR and total IgE of 60 kU/L or less, 15% had BHR and total IgE of 60 kU/L or less, and 23% had a total IgE of more than 60 kU/L but no BHR. In children with BHR and relatively high serum total IgE the prevalence of lower respiratory symptoms increased significantly by between 32% and 139% for each 100 microm/m3 increase in particulate matter, and between 16% and 131% for each 40 microm/m3 increase in black smoke, SO2, or NO2. Decrease in peak expiratory flow of more than 10% in that group was more common with increased airborne particulate matter and black smoke. There were no consistent positive or negative associations between increased air pollution and prevalence of respiratory symptoms or decrease in peak expiratory flow in the other three groups of children. INTERPRETATION: Children with BHR and relatively high concentrations of serum total IgE are susceptible to air pollution. Although our odds ratios were rather low (range 1.16-2.39) the overall effect of air pollution on public health is likely to be substantial since these odds ratios refer to large numbers of people. PMID- 10093980 TI - Mortality after all major types of osteoporotic fracture in men and women: an observational study. AB - BACKGROUND: Mortality increases after hip fractures in women and more so in men. Little is known, however, about mortality after other fractures. We investigated the mortality associated with all fracture types in elderly women and men. METHODS: We did a 5-year prospective cohort study in the semi-urban city of Dubbo, Australia, of all residents aged 60 years and older (2413 women and 1898 men). Low-trauma osteoporotic fractures that occurred between 1989 and 1994, confirmed by radiography and personal interview, were classified as proximal femur, vertebral, and groupings of other major and minor fractures. We calculated standardised mortality rates from death certificates for people with fractures compared with the Dubbo population. FINDINGS: 356 women and 137 men had low trauma fractures. In women and men, mortality was increased in the first year after all major fractures. In women, age-standardised mortality ratios were 2.18 (95% CI 2.03-2.32) for proximal femur, 1.66 (1.51-1.80) for vertebral, 1.92 (1.70 2.14) for other major, and 0.75 (0.66-0.84) for minor fractures. In men, these ratios were 3.17 (2.90-3.44) for proximal femur, 2.38 (2.17-2.59) for vertebral, 2.22 (1.91-2.52) for other major, and 1.45 (1.25-1.65) for minor fractures. There were excess deaths (excluding minor fractures in women) in all age-groups. INTERPRETATION: All major fractures were associated with increased mortality, especially in men. The loss of potential years of life in the younger age-group shows that preventative strategies for fracture should not focus on older patients at the expense of younger women and of men. PMID- 10093981 TI - Corticosteroids in IgA nephropathy: a randomised controlled trial. AB - BACKGROUND: IgA nephropathy is progressive in most cases and has no established therapy. In this randomised trial, we assessed the efficacy and safety of a 6 month course of steroids in this disorder. METHODS: Between July, 1987, and September, 1995, we enrolled 86 consecutive patients from seven renal units in Italy. Eligible patients had biopsy-proven IgA nephropathy, urine protein excretion of 1.0-3.5 g daily, and plasma creatinine concentrations of 133 micromol/L (1.5 mg/dL) or less. Patients were randomly assigned either supportive therapy alone or steroid treatment (intravenous methylprednisolone 1 g per day for 3 consecutive days at the beginning of months 1, 3, and 5, plus oral prednisone 0.5 mg/kg on alternate days for 6 months). The primary endpoint was deterioration in renal function defined as a 50% or 100% increase in plasma creatinine concentration from baseline. Analyses were by intention to treat. FINDINGS: Nine of 43 patients in the steroid group and 14 of 43 in the control group reached the primary endpoint (a 50% increase in plasma creatinine) by year 5 of follow-up (p<0.048). Factors influencing renal survival were vascular sclerosis (relative risk for 1-point increase in score 1.53, p=0.0347), female sex (0.22, p=0.0163), and steroid therapy (0.41, p=0.0439). All 43 patients assigned steroids completed the treatment without experiencing any important side effects. INTERPRETATION: A 6-month course of steroid treatment protected against deterioration in renal function in IgA nephropathy with no notable adverse effects during follow-up. An increase in urinary protein excretion could be a marker indicating the need for a second course of steroid therapy. PMID- 10093982 TI - Risk factors for sudden unexpected death in epilepsy: a case-control study. AB - BACKGROUND: Sudden unexpected death is substantially more common in people with epilepsy than in the general population. Our objective was to investigate the association between some clinical variables and sudden unexpected death in epilepsy (SUDEP) to identify risk factors. METHODS: This nested case-control study was based on a cohort of people aged between 15 and 70 years, who, during 1980-89, had been admitted to and discharged with a diagnosis of epilepsy from any hospital in the county of Stockholm. The study population was followed up through the National Cause of Death Register until Dec 31, 1991. Cases were individuals who had died, with a diagnosis of epilepsy registered on the death certificate, and who after review of medical and necropsy records were found to meet our SUDEP criteria. Three control participants, who were living epilepsy patients matched for age and sex, were selected from the same cohort for each case. All medical records were examined. Clinical data were collected and analysed on a predesigned protocol. FINDINGS: 57 SUDEP cases were included, of whom 91% had undergone necropsy. The relative risk of SUDEP increased with number of seizures per year. The estimated relative risk was 10.16 (95% CI 2.94-35.18) in patients with more than 50 seizures per year, compared with those with up to two seizures per year. The risk of SUDEP increased with increasing number of antiepileptic drugs taken concomitantly--9.89 (3.20-30.60) for three antiepileptic drugs compared with monotherapy. Other major risk factors were early-onset versus late-onset epilepsy (7.72 [2.13-27.96]), and frequent changes of antiepileptic drug dosage compared with unchanged dosage (6.08 [1.99-18.56]). The association between SUDEP risk and early onset, and SUDEP risk and seizure frequency, was weaker for female than for male patients, whereas frequent dose changes showed a stronger association in female patients. INTERPRETATION: Our data suggest that SUDEP is a seizure-related event, although the pathophysiological substrate that predisposes individuals to SUDEP may be established at an early age, and there may be some sex differences. Improvement of seizure control and possibly the avoidance of polytherapy may be ways to reduce the risk of SUDEP. PMID- 10093983 TI - A perianal ulcer. PMID- 10093984 TI - Detection of doping with human growth hormone. PMID- 10093985 TI - Beta2-adrenoceptor gene polymorphism, body weight, and physical activity. PMID- 10093986 TI - Common polymorphisms of beta1-adrenoceptor: identification and rapid screening assay. PMID- 10093987 TI - Absence of brain Dp140 isoform and cognitive impairment in Becker muscular dystrophy. PMID- 10093988 TI - Genetic variation of CYP2A6, smoking, and risk of cancer. PMID- 10093989 TI - Appearance of IMP-1 metallo-beta-lactamase in Europe. PMID- 10093990 TI - Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. PMID- 10093991 TI - Lung epithelial damage at low concentrations of ambient ozone. PMID- 10093992 TI - Riboflavine and severe lactic acidosis. PMID- 10093993 TI - Coughing reflex induced by electrostimulation of the trachea: a pilot study. PMID- 10093994 TI - Aggressive interventionists find comfort in New Orleans. PMID- 10093995 TI - Lesley Fallowfield: blending psychology with science. PMID- 10093997 TI - Cross-culture communication needed. PMID- 10093996 TI - Royal commission divided over reform of long-term UK care. PMID- 10093998 TI - Colonic toxicity from pancreatins: a contemporary safety issue. PMID- 10093999 TI - Evidence-based interventions and comprehensive treatment. PMID- 10094000 TI - Cultural basis for differences between US and French clinical recommendations for women at increased risk of breast and ovarian cancer. PMID- 10094001 TI - Physicians for Human Rights documents systematic abuse against ethnic Albanian physicians and patients. PMID- 10094002 TI - Japan: prisoners wait for rights. PMID- 10094003 TI - Labour rights are human rights. PMID- 10094004 TI - Lifetime risk of developing coronary heart disease. PMID- 10094005 TI - Lifetime risk of developing coronary heart disease. PMID- 10094006 TI - Lifetime risk of developing coronary heart disease. PMID- 10094007 TI - Laxatives and the Ice Man. PMID- 10094008 TI - Laxatives and the Ice Man. PMID- 10094009 TI - Trandolapril and human diabetic neuropathy. PMID- 10094010 TI - Trandolapril and human diabetic neuropathy. PMID- 10094011 TI - Prevention of falls in elderly people. PMID- 10094012 TI - Prevention of falls in elderly people. PMID- 10094013 TI - 5-HT2A gene promoter polymorphism and anorexia nervosa. PMID- 10094014 TI - Multicentre clinical trials. PMID- 10094015 TI - Multicentre clinical trials. PMID- 10094016 TI - Drop-outs in tamoxifen prevention trials. PMID- 10094017 TI - Needle-exchange programmes are not the answer. PMID- 10094018 TI - The horrors of Ashworth: misdiagnosis. PMID- 10094019 TI - Geographical inequalities in provision of general practitioners in England and Wales. PMID- 10094020 TI - Low-molecular-weight heparin and thromboembolism in pregnancy. PMID- 10094021 TI - The acronym TTV. Transfusion transmitted virus. PMID- 10094025 TI - Talking shop. Tomorrow's doctors: caring more, curing less? PMID- 10094022 TI - Reproductive health. PMID- 10094026 TI - The Nobel chronicles. 1945: Sir Alexander Fleming (1881-1955); Sir Ernst Boris Chain (1906-79); and Baron Howard Walter Florey (1898-1968) PMID- 10094027 TI - Sketches from The Lancet. Antisepsis. PMID- 10094028 TI - WHO steps closer to its responsibilities. PMID- 10094030 TI - Britain sought to speed-up sequencing efforts. PMID- 10094029 TI - Human Genome Project aims to finish 'working draft' next year. PMID- 10094031 TI - WHO's bioethics code likely to stir debate. PMID- 10094032 TI - India falls into line over patents legislation. PMID- 10094033 TI - Call for a lighter regulatory burden on NIH researchers. PMID- 10094034 TI - US quest for AIDS vaccine appoints a leader. PMID- 10094035 TI - European archive for mouse mutants is set to open at last. PMID- 10094036 TI - Words go missing in cyberspace. PMID- 10094037 TI - Words go missing in cyberspace. PMID- 10094038 TI - Lessons from Iraq on bioweapons. PMID- 10094039 TI - Telomeres. Ageing hard or hardly ageing? PMID- 10094040 TI - Neolithic genetic engineering. PMID- 10094041 TI - Biotechnology. A new-for-old urinary bladder. PMID- 10094042 TI - Transcriptional regulation. Modification by nuclear export? PMID- 10094043 TI - Colour categories in a stone-age tribe. PMID- 10094044 TI - Sublimation from icy jets as a probe of the interstellar volatile content of comets. AB - Comets are some of the most primitive bodies left over from the Solar System's early history. They may preserve both interstellar material and material from the proto-solar nebula, and so studies of their volatile components can provide clues about the evolution of gases and ices, as a collapsing molecular cloud transforms into a mature planetary system. Previous observations of emission from rotational transitions in molecules have averaged over large areas of the inner coma, and therefore include both molecules that sublimed from the nucleus and those that result from subsequent chemical processes in the coma Here we present high resolution observations of emission from the molecules HNC, DCN and HDO associated with comet Hale-Bopp. Our data reveal arc-like structures-icy jets offset from (but close to) the nucleus. The measured abundance ratios on 1-3" scales are substantially different from those on larger scales, and cannot be accounted for by models of chemical processes in the coma; they are, however, similar to the values observed in the cores of dense interstellar clouds and young stellar objects. We therefore propose that sublimation from millimetre sized icy grains ejected from the nucleus provides access to relatively unaltered volatiles. The D/H ratios inferred from our data suggest that, by mass, Hale-Bopp (and by inference the outer regions of the early solar nebula) consists of > or =15-40% of largely unprocessed interstellar material. PMID- 10094045 TI - The limits of selection during maize domestication. AB - The domestication of all major crop plants occurred during a brief period in human history about 10,000 years ago. During this time, ancient agriculturalists selected seed of preferred forms and culled out seed of undesirable types to produce each subsequent generation. Consequently, favoured alleles at genes controlling traits of interest increased in frequency, ultimately reaching fixation. When selection is strong, domestication has the potential to drastically reduce genetic diversity in a crop. To understand the impact of selection during maize domestication, we examined nucleotide polymorphism in teosinte branched1, a gene involved in maize evolution. Here we show that the effects of selection were limited to the gene's regulatory region and cannot be detected in the protein-coding region. Although selection was apparently strong, high rates of recombination and a prolonged domestication period probably limited its effects. Our results help to explain why maize is such a variable crop. They also suggest that maize domestication required hundreds of years, and confirm previous evidence that maize was domesticated from Balsas teosinte of southwestern Mexico. PMID- 10094046 TI - Gaze direction controls response gain in primary visual-cortex neurons. AB - To localize objects in space, the brain needs to combine information about the position of the stimulus on the retinae with information about the location of the eyes in their orbits. Interaction between these two types of information occurs in several cortical areas, but the role of the primary visual cortex (area V1) in this process has remained unclear. Here we show that, for half the cells recorded in area V1 of behaving monkeys, the classically described visual responses are strongly modulated by gaze direction. Specifically, we find that selectivity for horizontal retinal disparity-the difference in the position of a stimulus on each retina which relates to relative object distance-and for stimulus orientation may be present at a given gaze direction, but be absent or poorly expressed at another direction. Shifts in preferred disparity also occurred in several neurons. These neural changes were most often present at the beginning of the visual response, suggesting a feedforward gain control by eye position signals. Cortical neural processes for encoding information about the three-dimensional position of a stimulus in space therefore start as early as area V1. PMID- 10094047 TI - brinker is a target of Dpp in Drosophila that negatively regulates Dpp-dependent genes. AB - Growth and patterning of the Drosophila wing is controlled in part by the long range organizing activities of the Decapentaplegic protein (Dpp). Dpp is synthesized by cells that line the anterior side of the anterior/posterior compartment border of the wing imaginal disc. From this source, Dpp is thought to generate a concentration gradient that patterns both anterior and posterior compartments. Among the gene targets that it regulates are optomotor blind (omb), spalt (sal), and daughters against dpp (dad). We report here the molecular cloning of brinker (brk), and show that brk expression is repressed by dpp. brk encodes, a protein that negatively regulates Dpp-dependent genes. Expression of brk in Xenopus embryos indicates that brk can also repress the targets of a vertebrate homologue of Dpp, bone morphogenetic protein 4 (BMP-4). The evolutionary conservation of Brk function underscores the importance of its negative role in proportioning Dpp activity. PMID- 10094048 TI - A new protease required for cell-cycle progression in yeast. AB - In eukaryotes, protein function can be modulated by ligation to ubiquitin or to ubiquitin-like proteins (Ubl proteins). The vertebrate Ubl protein SUMO-1 is only 18% identical to ubiquitin but is 48% identical to the yeast protein Smt3. Both SUMO-1 and Smt3 are ligated to cellular proteins, and protein conjugation to SUMO 1/Smt3 is involved in many physiological processes. It remained unknown, however, whether deconjugation of SUMO-1/Smt3 from proteins is also essential. Here we describe a yeast Ubl-specific protease, Ulp1, which cleaves proteins from Smt3 and SUMO-1 but not from ubiquitin. Ulp1 is unrelated to any known deubiquitinating enzyme but shows distant similarity to certain viral proteases, indicating the existence of a widely conserved protease fold. Proteins related to Ulp1 are present in many organisms, including several human pathogens. The pattern of Smt3-coupled proteins in yeast changes markedly throughout the cell cycle, and specific conjugates accumulate in ulp1 mutants. Ulp1 has several functions, including an essential role in the G2/M phase of the cell cycle. PMID- 10094049 TI - The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. AB - Interleukin-1 (IL-1) is a proinflammatory cytokine that has several effects in the inflammation process. When it binds to its cell-surface receptor, IL-1 initiates a signalling cascade that leads to activation of the transcription factor NF-kappaB and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-kappaB-inducing kinase (NIK) and I kappaB kinases (IKKs). However, the molecular mechanism by which NIK is activated is not understood. Here we show that the MAPKK kinase TAK1 acts upstream of NIK in the IL-1-activated signalling pathway and that TAK1 associates with TRAF6 during IL-1 signalling. Stimulation of TAK1 causes activation of NF-kappaB, which is blocked by dominant-negative mutants of NIK, and an inactive TAK1 mutant prevents activation of NF-kappaB that is mediated by IL-1 but not by NIK. Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway. PMID- 10094051 TI - New skilled nursing facility payment scheme boosts Medicare risk. AB - Medicare's cost-based reimbursement method for skilled nursing facility care has been replaced with a prospective payment system that includes a case-mix adjustment based on resource utilization groups. The changeover will reduce Medicare payments for most skilled nursing facilities. The financial risk of operating these facilities will be far greater if state Medicaid programs that reimburse nursing facilities on a cost basis follow Medicare's lead. PMID- 10094050 TI - NF-AT activation requires suppression of Crm1-dependent export by calcineurin. AB - Nuclear import of the NF-AT transcription factors during T-cell activation requires the calcium-activated phosphatase calcineurin, which unmasks nuclear location signals on NF-AT. We show here that the nuclear import of NF-ATs is not sufficient to activate NF-AT target genes, as NF-ATs are subject to a futile cycling across the nuclear envelope owing to engagement with the exportin protein Crm1. Calcineurin suppresses this futile cycling by a non-catalytic mechanism involving the masking of nuclear export signals on NF-AT targeted by Crm1. This clustering of binding sites for calcineurin and Crml on NF-AT establishes an inherent competition between these molecules that imparts exquisite calcium sensitivity to the shuttling dynamics of the NF-AT transcription factors. Such a balance between nuclear import and export may regulate the action of other transcription factors. PMID- 10094052 TI - Managing risk in a risky world. AB - A successful firm knows that its success depends on its knowledge of risk: what it knows and how quickly it can learn new approaches. The popularity of capitation managed care plans is in doubt in many areas, because the rate of innovation in risk adjustment is very slow. Managed care firms fear that implementation of severity adjustments by Medicare in the year 2000 could slash their Medicare rates. Methods to predict insurance risk must be retooled to prevent "cream skimming" discrimination against the sick, reduce stinting (undercare), and reward quality providers. Risk cannot be eliminated, but it can be prospectively analyzed, assessed, and hedged. In the coming world we must convi nce all concerned parties to spread the risks. Payers must take on some risk by paying for the research and development of valid and reliable severity adjustment systems, and they must pay a higher capitated amount for high-cost patients. A new mixed payment system of pure capitation plus prospective payment for high-risk high-cost patients will create a more equitable marketplace. If a health maintenance organization (HMO) does a great high-quality job of treating diabetes, acquired immunodeficiency syndrome (AIDS), or heart disease, it could advertise this fact and not be harmed financially by the resulting influx of high cost patients. PMID- 10094053 TI - Specialty contact capitation. AB - Contact capitation is an emerging new payment method for risk contracts that aligns incentives among physicians, protects individual physicians from their colleagues' less efficient practice patterns, and allows physicians to share in the rewards of their own clinical effectiveness. Contact capitation is working in a variety of settings and developing a track record as a payment method to help ailing independent physician associations, physician-hospital organizations, health plans, and other risk-bearing entities. PMID- 10094054 TI - Consolidation in the health care sector. AB - This article discusses trends in health care sector consolidations. Attention is given to the reasons behind consolidation efforts and consolidation failures and the potential impact of consolidations on physicians, patients, and the transformation of health care delivery. PMID- 10094055 TI - Nonprofit to for-profit hospital transactions: all roads lead to the attorney general's office. AB - As more and more hospitals travel the route from nonprofit to for-profit status, state attorneys general are increasingly playing the role of "traffic cop" along this rough and often contentious road. A better understanding of the attorney general's office and greater rapport with its officers is the "order of the day" for officers and directors looking to orchestrate such a transition. PMID- 10094056 TI - MSO development: progress versus pitfalls. AB - Physicians and hospitals are rapidly organizing integrated systems to compete more successfully in the new health care business arena. The preferred parent structure has been the management services organization (MSO). Notable factors have produced significant progress or pitfalls. Success is driven by the thoughtfulness of planning, the depth of management, and the quality of care. PMID- 10094057 TI - The new health care consumer. AB - Every seven seconds, a baby boomer turns 50. These 77 million aging revolutionaries will transform health care with their nontraditional expectations and their willingness to "vote" with their discretionary dollars. Toss in the increasing popularity of alternative medicine and the trend toward direct commerce between consumers and providers, and you have the recipe for what health care will look like in the 21st century. It will be unlike anything seen before. PMID- 10094058 TI - Using microcomputers to improve capital decision making. AB - Health care organizations have traditionally selected capital projects based on subjective measures such as medical staff priority, accreditation criteria, and regulations. In some cases, basic qualitative measures, such as payback period or profitability indices, have been used. The expected reduction in available capital that will result from changes in Medicare reimbursement and from managed care, as well as increased competition, will require health care decision makers to adopt more sophisticated methods of capital project evaluation in the future if they expect their organizations to remain viable. This article demonstrates, through the use of microcomputers and commonly used spreadsheet software, that the capital selection decision process can be improved and the optimal combination of projects, from a financial perspective, selected. PMID- 10094059 TI - Alternative method of funding hospital capital expenditures. AB - This article presents a model that demonstrates how a hospital can form a strategic partnership with a vendor to use the vendor's previous knowledge, experience, and strategic alliances to fund capital expenditures and implement cost savings programs for the hospital, with no capital outlay or risk to the hospital. The vendor assumes full financial risk for the success of the program. In exchange for the vendor's full risk, the hospital shares in the savings with the vendor. PMID- 10094060 TI - Let's merge competitive and regulatory strategies to achieve cost containment. AB - Whether market-driven or government-driven approaches should be used to curtail future health care expenditures has become the debate of the decade on Capitol Hill and in state legislatures. After examining both the competitive and the regulatory models to constrain health care costs, it is argued that to achieve an effective and efficient health care system, a properly structured market-driven approach should be blended with a minimal number of safety and soundness regulations. To successfully implement such a half-competitive, half-regulatory system in the United States, it will be necessary, for example, to empower thirdparty payers and providers to negotiate prices without direct government involvement; to modify enormous regional differences in use rates and health care costs for various treatments with more rigid treatment protocols that are promulgated by the managed care plans; to minimize administrative-type expenditures that have no visible, beneficial effect in improving quality patient care; and to curtail the supply of underutilized health care resources as another means to constrain health care expenditures. These strategies would have significant political, social, economic, and patient care implications for the United States but might result in our health care cost dilemma appearing to the public as finally being "under control." PMID- 10094061 TI - An investigation of social and class differences in very-low birth weight outcomes: a continuing public health concern. AB - The objective of this study was to examine the relationship of nonmedical factors, including socioeconomic status, social class, education, race, and social support, to low birth weight. In a case-control study of all resident very low-birth-weight births between December 1, 1989, and March 31, 1991, mothers completed an extensive survey related to their experience of pregnancy, including prenatal and postnatal care. Cases were defined as very-low-birth-weight (VLBW) infants and were matched to moderately-low-birth-weight and normal-birth-weight infants in race, age, and maternal residence. The hypothesis that social and class factors are more predictive of low birth weight than medical factors alone for women without chronic health problems was supported. Although the degree of the association varies depending on birth weight outcome, race even though addressed through matching--continued to play an important role in birth outcomes. A comparison of logistic model performance with and without the inclusion of social factors indicated the importance these variables play in prediction of birth outcomes. This is one of the few studies undertaken that explicitly investigates impact of patient factors on medical care. PMID- 10094062 TI - A design model for computer-based guideline implementation based on information management services. AB - Clinical practice guidelines must be implemented effectively if they are to influence the behavior of clinicians. The authors describe a model for computer based guideline implementation that identifies eight information management services needed to integrate guideline-based decision support with clinical workflow. Recommendation services determine appropriate activities in specific clinical circumstances. Documentation services involve data capture. Registration services integrate demographic and administrative data. Explanation services enhance the credibility of automated recommendations by providing supportive evidence and rating the quality of evidence. Calculation services measure time intervals, suggest medication dosages, and perform other computational tasks. Communication services employ standards for information transfer and provide data security. Effective presentation services facilitate understanding of complex data, clarify trends, and format written materials (including prescriptions) for patients. Aggregation services associate outcomes with specific guideline interventions. The authors provide examples of the eight services that make up the model from five evidence-based practice parameters developed by the American Academy of Pediatrics. PMID- 10094063 TI - Computer-based guideline implementation systems: a systematic review of functionality and effectiveness. AB - In this systematic review, the authors analyze the functionality provided by recent computer-based guideline implementation systems and characterize the effectiveness of the systems. Twenty-five studies published between 1992 and January 1998 were identified. Articles were included if the authors indicated an intent to implement guideline recommendations for clinicians and if the effectiveness of the system was evaluated. Provision of eight information management services and effects on guideline adherence, documentation, user satisfaction, and patient outcome were noted. All systems provided patient specific recommendations. In 19, recommendations were available concurrently with care. Explanation services were described for nine systems. Nine systems allowed interactive documentation, and 17 produced paper-based output. Communication services were present most often in systems integrated with electronic medical records. Registration, calculation, and aggregation services were infrequently reported. There were 10 controlled trials (9 randomized) and 10 time-series correlational studies. Guideline adherence improved in 14 of 18 systems in which it was measured. Documentation improved in 4 of 4 studies. PMID- 10094064 TI - Measuring the effects of reminders for outpatient influenza immunizations at the point of clinical opportunity. AB - OBJECTIVE: To evaluate the influence of computer-based reminders about influenza vaccination on the behavior of individual clinicians at each clinical opportunity. DESIGN: The authors conducted a prospective study of clinicians' influenza vaccination behavior over four years. Approximately one half of the clinicians in an internal medicine clinic used a computer-based patient record system (CPR users) that generated computer-based reminders. The other clinicians used traditional paper records (PR users). MEASUREMENTS: Each nonacute visit by a patient eligible for an influenza vaccination was considered an opportunity for intervention. Patients who had contraindications for vaccination were excluded. Compliance with the guideline was defined as documentation that a clinician ordered the vaccine, counseled the patient about the vaccine, offered the vaccine to a patient who declined it, or verified that the patient had received the vaccine elsewhere. The authors calculated the proportion of opportunities on which each clinician documented action in the CPR and PR user groups. RESULTS: The CPR and PR user groups had different baseline compliance rates (40.1 and 27.9 per cent, respectively; P<0.05). Both rates remained stable during a two-year baseline period (P = 0.34 and P = 0.47, respectively). The compliance rates in the CPR user group increased 78 per cent from baseline (P<0.001), whereas the rates for the PR user group did not change significantly (P = 0.18). CONCLUSIONS: Clinicians who used a CPR with reminders had higher rates of documentation of compliance with influenza-vaccination guidelines than did those who used a paper record. Measurements of individual clinician behavior at the point of each clinical opportunity can provide precise evaluation of interventions that are designed to improve compliance with guidelines. PMID- 10094065 TI - Driving toward guiding principles: a goal for privacy, confidentiality, and security of health information. AB - As health care moves from paper to electronic data collection, providing easier access and dissemination of health information, the development of guiding privacy, confidentiality, and security principles is necessary to help balance the protection of patients' privacy interests against appropriate information access. A comparative review and analysis was done, based on a compilation of privacy, confidentiality, and security principles from many sources. Principles derived from ten identified sources were compared with each of the compiled principles to assess support level, uniformity, and inconsistencies. Of 28 compiled principles, 23 were supported by at least 50 percent of the sources. Technology could address at least 12 of the principles. Notable consistencies among the principles could provide a basis for consensus for further legislative and organizational work. It is imperative that all participants in our health care system work actively toward a viable resolution of this information privacy debate. PMID- 10094066 TI - The limited use of digital ink in the private-sector primary care physician's office. AB - Two of the greatest obstacles to the implementation of the standardized electronic medical record are physician and staff acceptance and the development of a complete standardized medical vocabulary. Physicians have found the familiar desktop computer environment cumbersome in the examination room and the coding and hierarchic structure of existing vocabulary inadequate. The author recommends the use of digital ink, the graphic form of the pen computer, in telephone messaging and as a supplement in the examination room encounter note. A key concept in this paper is that the development of a standard electronic medical record cannot occur without the thorough evaluation of the office environment and physicians' concerns. This approach reveals a role for digital ink in telephone messaging and as a supplement to the encounter note. It is hoped that the utilization of digital ink will foster greater physician participation in the development of the electronic medical record. PMID- 10094067 TI - A reliability study for evaluating information extraction from radiology reports. AB - GOAL: To assess the reliability of a reference standard for an information extraction task. SETTING: Twenty-four physician raters from two sites and two specialties judged whether clinical conditions were present based on reading chest radiograph reports. METHODS: Variance components, generalizability (reliability) coefficients, and the number of expert raters needed to generate a reliable reference standard were estimated. RESULTS: Per-rater reliability averaged across conditions was 0.80 (95% CI, 0.79-0.81). Reliability for the nine individual conditions varied from 0.67 to 0.97, with central line presence and pneumothorax the most reliable, and pleural effusion (excluding CHF) and pneumonia the least reliable. One to two raters were needed to achieve a reliability of 0.70, and six raters, on average, were required to achieve a reliability of 0.95. This was far more reliable than a previously published per rater reliability of 0.19 for a more complex task. Differences between sites were attributable to changes to the condition definitions. CONCLUSION: In these evaluations, physician raters were able to judge very reliably the presence of clinical conditions based on text reports. Once the reliability of a specific rater is confirmed, it would be possible for that rater to create a reference standard reliable enough to assess aggregate measures on a system. Six raters would be needed to create a reference standard sufficient to assess a system on a case-by-case basis. These results should help evaluators design future information extraction studies for natural language processors and other knowledge-based systems. PMID- 10094068 TI - Units of measure in clinical information systems. AB - The authors surveyed existing standard codes for units of measures, such as ISO 2955, ANSI X3.50, and Health Level 7's ISO+. Because these standards specify only the character representation of units, the authors developed a semantic model for units based on dimensional analysis. Through this model, conversion between units and calculations with dimensioned quantities become as simple as calculating with numbers. All atomic symbols for prefixes and units are defined in one small table. Huge permutated conversion tables are not required. This method is also simple enough to be widely implementable in today's information systems. To promote the application of the method the authors provide an open-source implementation of this method in JAVA. All existing code standards for units, however, are incomplete for practical use and require substantial changes to correct their many ambiguities. The authors therefore developed a code for units that is much more complete and free from ambiguities. PMID- 10094069 TI - A model for enhancing Internet medical document retrieval with "medical core metadata". AB - OBJECTIVE: Finding documents on the World Wide Web relevant to a specific medical information need can be difficult. The goal of this work is to define a set of document content description tags, or metadata encodings, that can be used to promote disciplined search access to Internet medical documents. DESIGN: The authors based their approach on a proposed metadata standard, the Dublin Core Metadata Element Set, which has recently been submitted to the Internet Engineering Task Force. Their model also incorporates the National Library of Medicine's Medical Subject Headings (MeSH) vocabulary and MEDLINE-type content descriptions. RESULTS: The model defines a medical core metadata set that can be used to describe the metadata for a wide variety of Internet documents. CONCLUSIONS: The authors propose that their medical core metadata set be used to assign metadata to medical documents to facilitate document retrieval by Internet search engines. PMID- 10094070 TI - General practice registration networks in the Netherlands: a brief report. AB - In the Netherlands, several general practice registrations exist. Groups of general practitioners register elements of patient care according to agreed-upon criteria, and these data are collected in a central database. By means of a questionnaire the authors interviewed the managers of all nine computerized registration networks extensively about the possibilities and limitations of their registration. In addition, respondents answered some questions with data from the central database of their network. Various items are collected by nearly all the registration networks, while other items are collected by only one network. Answering questions with data from the central database turned out to be difficult. Organization and manpower are the main obstacles. PMID- 10094071 TI - Toward a measured approach to medical informatics. PMID- 10094072 TI - Highlights of 1998, Harbingers of 1999. PMID- 10094073 TI - The Women's Health Initiative: recruitment complete--looking back and looking forward. PMID- 10094074 TI - Keeping the surfing patient from drowning? PMID- 10094075 TI - Observations from the CDC: using health communications research to reduce birth defects. PMID- 10094076 TI - Patient education: relief for back pain. PMID- 10094077 TI - Toward optimal health: the experts respond to 'my aching back'. Interview by Jodi Godfrey Meisler. PMID- 10094078 TI - Fat: can't live with it, can't live without it part II. PMID- 10094079 TI - Teaching clinician-patient communication in the treatment of breast diseases. AB - In 1998, some 179,000 women in the United States were newly diagnosed with breast cancer, and 48,500 women died from it. Early detection by mammography, physical examination, and breast self-examination improves survival rates and can decrease mortality. The clinician's level of comfort with discussing education and prevention with patients can influence patients' adherence to preventive measures. Improved clinician-patient interpersonal communication has a demonstrated positive impact on adherence and health outcomes. We developed and pilot tested a core curriculum on breast health aimed at primary care community physicians and resident house staff. The goal was to improve interpersonal communication between clinician and patient. Two groups of participants attended either a week-long or a 2-week-long training program consisting of four components: a brief demonstration of an interview and breast examination, interviews and breast examinations with a standardized patient, and two separate workshops of varying length. This pilot program had a significant impact on clinician behavior and knowledge. We recommend further investigation of this area with larger sample sizes. PMID- 10094080 TI - Women's shoe wear: an orthopaedist's advice. PMID- 10094081 TI - Office of Research on Women's Health Seminar Series--Part I. Finding the answers on hormone replacement therapy. PMID- 10094082 TI - Prevention and medical management of unwanted pregnancy: the physician's role. PMID- 10094083 TI - Moderate alcohol consumption and bone density among postmenopausal women. AB - Chronic alcohol abuse is associated with low bone density and high risk of fracture. However, moderate alcohol consumption may help to maintain bone density in postmenopausal women by increasing endogenous estrogens or by promoting secretion of calcitonin. We conducted a prospective study among a sample of 188 white postmenopausal women (ages 50-74) from the Nurses' Health Study who participated in a health examination between 1993 and 1995 that included bone density assessments of the lumbar spine and proximal femur. Long-term alcohol intake was calculated as the average of the 1980 and 1990 measures from a food frequency questionnaire. Women who consumed 75 g or more of alcohol per week had significantly higher bone densities at the lumbar spine compared with non drinking women (0.951 vs. 0.849 g/cm2, p = 0.002) after adjusting for age, body mass index (kg/m2), age at menopause, use of postmenopausal estrogens, and smoking status. Further adjustment for physical activity and daily intakes of calcium, vitamin D, protein, and caffeine did not alter the results. We also observed a linear increase in spinal bone density over increasing categories of alcohol intake (p = 0.002), suggesting that alcohol intakes of less than 75 g/week may also be of benefit. This positive association was observed among both current users and never users of postmenopausal estrogens. In contrast to the lumbar spine, femoral bone density was not higher among drinkers compared with nondrinkers, although density did increase among drinkers with increasing level of alcohol consumption. Further research is needed to determine whether moderate alcohol consumption can help to protect against spinal fractures in postmenopausal women. This finding must also be evaluated within a larger scope of the risks and benefits of alcohol on heart disease, breast cancer, and hip fractures. PMID- 10094084 TI - Symptom patterns of premenstrual dysphoric disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders-IV. AB - Premenstrual dysphoric disorder was included in an appendix of DSM-III-R (revised third edition of the Diagnostic and Statistical Manual of Mental Disorders) and DSM-IV to facilitate systematic research. Items contained in its set of research criteria were considered tentative. Only one previous study of premenstrual symptoms specifically addressed symptoms of premenstrual dysphoric disorder, and it did not use DSM-IV criteria. In the present study, prospectively measured symptoms of 99 women were analyzed using exploratory principal components analysis with orthogonal rotation on all 24 items derived from the 11 symptoms listed in DSM-IV. Variation was found across phases of cycle and groups, with five factors predominating: (1) anger/irritability, (2) depressed mood, (3) anxiety/tension, (4) decreased energy and interest with physical symptoms, and (5) eating problems. PMID- 10094085 TI - Childhood origins of depression: evidence from native and nonnative women in Alaska and the Russian Far East. AB - Explanations for depression usually implicate contemporaneous stressors, although biologic predispositions and childhood violence may also serve as precursors. This study evaluates the relative influence of contemporaneous stressors and both intrafamilial and interethnic violence experienced in childhood. Logistic regression is applied to data collected from a random sample of 355 women aged 20 89 in 1993 who lived in Chukotka and Kamchatka in the Russian Far East and in the Aleutians and the Northwest Alaskan Native Association region of Alaska. Although two contemporaneous stressors influence the likelihood of depression, intrafamilial violence experienced in childhood and, for natives of both Alaska and the Russian Far East, childhood emotional abuse by nonnatives exhibit dramatically more important effects that do not decay with time. These findings point to a violence-induced biologic mechanism for depression in adulthood. They also warrant interventions that extend their focus to the subtle forms of emotional violence that members of one ethnic group may inflict on another and to the social power relationships that may give these forms of violence a lifelong impact. PMID- 10094086 TI - U.S. women physicians' assessment of the quality of healthcare they receive. AB - Surveys of women's perceptions of quality and satisfaction with healthcare are widely administered and reported, yet no similar studies of women physicians' perceptions have been conducted. We analyzed related data from the Women Physicians' Health Study, a nationally representative sample of 4501 U.S. women physicians. Among U.S. women physicians, 39% thought the healthcare they personally received was excellent, 37% considered it to be very good, 19% good, 4% fair, and 1% judged their healthcare to be poor quality. Physicians may be especially rigorous judges of healthcare quality, and their assessment of the healthcare they receive is generally positive, an encouraging finding. However, as physicians are highly qualified to assess and potentially obtain high-quality healthcare and as they generally did not judge the care they received to be excellent, the findings also suggest that there are opportunities for improvements in the quality of women's healthcare. PMID- 10094087 TI - Compliance with Papanicolaou smear screening following tubal ligation in women with cervical cancer. AB - To evaluate patient compliance with Papanicolaou (Pap) smear screening after tubal ligation compared with other methods of birth control in patients who develop cervical cancer, a retrospective review of 262 women with cervical cancer diagnosed at age < or = 70 years was undertaken at the Albert Einstein College of Medicine from January 1987 to December 1995. Demographic data, stage of the disease, histologic type, history of smoking, history of sexually transmitted disease (STD), and birth control use were recorded. The Pap screening history was obtained from all the patients. Women who had a bilateral tubal ligation (BTL) were compared with those who did not have this form of birth control. The date and result of their last Pap test prior to their diagnosis of cervical cancer was noted. Two hundred fourteen women with cervical cancer were evaluable. The clinical stage, mean age, history of smoking, and history of STD were similar for both groups. Gravidity among the BTL group was higher than in the non-BTL group (p < 0.01). Forty-eight (22.4%) women had a previous BTL. Twenty-seven of these 48 patients (56.3%) did not have a Pap smear within 3 years prior to the diagnosis of cervical cancer. Of the 166 patients, 61 (36.7%) did not have a Pap test within 3 years (p < 0.05). Fourteen women (29.2%) in the tubal ligation group never returned for a Pap test following the BTL. An average of 6.2+/-5.9 years elapsed since the last Pap test in the BTL group, with 4.0+/-5.1 years in the nontubal ligation group (p < 0.05). There was a correlation between the number of years since BTL (14.2+/-7.7) to the number of years since the last Pap test (6.2+/-5.9) (p < 0.05). Women who have had a BTL should be considered high risk because of poor screening compliance. A Pap test every 3 years is not adequate in this high-risk population group. We advocate improved counseling regarding the importance of continued annual Pap screening for women who are considering tubal ligation. PMID- 10094088 TI - Maintenance of weight loss using taste and smell sensations. AB - The mechanism responsible for matching the intake and expenditure of nutrients in order to maintain body weight is not fully understood. Seven females learned to terminate the act of eating when the pleasantness of flavor of food subsided during a meal. By the end of 1 month, significant weight loss took place in the study group compared with the baseline weight (p < 0.01) and was maintained throughout the study period of 1 year. Focusing on the changes in oronasal sensory signals during a meal could facilitate weight maintenance. PMID- 10094089 TI - Habitual physical activity and menopausal symptoms: a case-control study. AB - A case-control study design was used to examine whether habitual physical activity prior to the final menstrual period (FMP) was associated with reduced risk of vasomotor and other symptoms during the perimenopausal period. Both cases and controls were identified through a screening interview with randomly selected women members, ages 48-52, of a large health maintenance organization. Cases (n = 82) were defined as women 3-12 months past their FMP who reported regularly having hot flashes or night sweats at least once a day or night during the 3 months following their FMP. Controls (n = 89) were of the same biologic age with respect to the FMP but reported vasomotor symptoms less than once a week during the reference time period. Neither cases nor controls had a history of hormone replacement therapy (HRT), hysterectomy, or bilateral oophorectomy. Case-control status, habitual physical activity (including recreational, housework, child care, and occupational activity), and psychological and somatic symptoms were assessed by self-report. Participation in vigorous recreational activity during the year prior to the FMP was not associated with reduced risk of frequent vasomotor symptoms after the FMP (odds ratio [OR] = 1.03 for a 50-unit increase in activity score, 95% confidence interval [CI] = 0.97-1.1). This lack of relationship was observed in all domains of activity. Factors that were associated with decreased risk included higher body mass index (BMI) (weight in kg/(height in meters)2) (OR = 0.95 per 1 unit increase in BMI, 95% CI = 0.90 1.00) and higher education (having a college degree relative to less education) (OR = 0.56, 95% CI = 0.40-0.80). Physical activity was also unassociated with reduced risk of psychologic distress, depressive feelings, or somatic symptoms, but, relative to controls, having vasomotor symptoms (being a case) was strongly associated with increased risk of experiencing those symptoms (OR ranging from 1.83 for psychologic distress to 2.84 for depressive feelings). These findings suggest that regular physical activity before the FMP may not reduce the likelihood of experiencing symptoms during the perimenopause, although the small sample size may limit the inferences that can be drawn. PMID- 10094090 TI - WebWatch--women's health. Hair, skin, and nails. PMID- 10094091 TI - Women's Health LiteratureWatch. PMID- 10094092 TI - From preadipocyte to adipocyte: differentiation-directed signals of insulin from the cell surface to the nucleus. AB - An alarming rise in obesity, and the accompanying threat of type 2 diabetes mellitus and cardiovascular disease, have attracted worldwide attention. The pathogenic mechanism(s) underlying obesity remains obscure. However, new cellular and molecular insights about the development of adipose tissue, with respect to adipocyte number (hyperplasia) and size (hypertrophy), are occurring at a rapid pace. Specialized fibroblasts (preadipocytes) committed to the adipocyte lineage are present throughout life. Primary cell culture systems and immortalized cell line models of preadipocytes have advanced the study of adipocyte differentiation (adipogenesis). Differentiation-inducing cues are able to trigger a complex network of intracellular signaling pathways in the preadipocyte, allowing signals from cell-surface receptors to reach nuclear transcription factors that regulate the genetic program of adipocyte differentiation. The extracellular matrix environment of the preadipocyte, known to modulate adipogenesis, may act by altering some of these signaling events. PMID- 10094093 TI - Acidosis and tissue hypoxia in the critically ill: how to measure it and what does it mean. AB - We routinely monitor blood gases to determine the adequacy of ventilation and the presence of acid-base abnormalities. Changes in the blood are easily assessed, but of more importance is the abnormality at tissue level. Defects in acid-base homoeostasis have major effects on protein function, thus affecting tissue and organ performance. We concentrate on the changes seen in critically ill patients with acidosis because they form a large portion of the workload of the average intensive care unit. In addition, such patients have significant morbidity and mortality. The development of acidemia in the critically ill is often attributed to reductions in oxygen utilization, which in the past has generally been regarded as dysregulation of tissue blood supply. Resulting tissue hypoperfusion leads to anaerobic metabolism and lactic acidosis. Carbon dioxide production increases as anaerobically produced hydrogen ions are buffered by extracellular bicarbonate. The effectiveness of tissue perfusion is the target of much research, and in this review we outline factors that affect tissue acid-base status, techniques to measure tissue acid-base status, and explore the relationship between tissue acidosis and hypoxia in the critically ill. However, things are not always as simple as they may first appear. PMID- 10094094 TI - Benign prostatic hyperplasia: an overview. PMID- 10094095 TI - Hypertension in the elderly with coexisting benign prostatic hyperplasia. AB - The treatment of hypertension in the elderly can be safely achieved with low-dose diuretic therapy. Men with prostatism may benefit from peripheral alpha-blocking drugs. However, drugs such as doxazosin or terazosin may further lower blood pressure and at times may be associated with orthostatic hypotension, especially if diuretics are given concomitantly. Tamsulosin achieves relaxation of the smooth muscle of the prostate, as do terazosin and doxazosin, but without provoking changes in blood pressure, especially orthostatic hypotension. There appears to be no adverse interaction with any other antihypertensive medication or with low-dose diuretics. To manage such patients with hypertension and prostatism, hydrochlorothiazide 6.25 to 12.5 mg/day and tamsulosin 0.4 mg/day would be an adequate combination. Low-dose diuretics have been shown to be effective in both isolated systolic hypertension as well as fixed diastolic hypertension in the elderly. If other antihypertensives need to be added, then a low dose of a long-acting calcium-entry blocker, a central alpha-agonist (a transdermal clonidine for better compliance), an angiotensin-converting enzyme inhibitor (if renal vascular disease has been ruled out), or an angiotensin II receptor blocker, e.g., losartan or valsartan, should be considered. PMID- 10094096 TI - Alpha-adrenergic blocking drugs in the management of benign prostatic hyperplasia: interactions with antihypertensive therapy. AB - Management of benign prostatic hyperplasia (BPH) is often complicated by concomitant hypertension, a life-threatening condition that must be managed optimally. Many of the alpha blockers used to treat BPH also decrease blood pressure, and terazosin and doxazosin have been shown to have significant cardiovascular side effects, such as asthenia/fatigue, postural hypotension, and dizziness when used to treat BPH patients. Furthermore, these drugs are not first line therapies for hypertension, and the majority of hypertensive BPH patients will be receiving other antihypertensive agents. Therefore, it is possible that the introduction of these drugs will affect blood pressure control, at least temporarily, with possible adverse effects. In contrast, the selective alpha1A blocker tamsulosin does not appear to have significant cardiovascular side effects and produces minimal blood pressure reductions. Therefore, urologists can choose either to use alpha blockers to treat both hypertension and BPH or to treat BPH using alpha blockers that do not interact with antihypertensive therapy. This review focuses on the alpha blockers currently being used to treat BPH, their effects on the cardiovascular system, and their interaction with antihypertensive drugs. PMID- 10094097 TI - Alpha-adrenoceptor antagonists in neurogenic lower urinary tract dysfunction. AB - Lower urinary tract dysfunction is common in patients with a variety of neurological diseases, and may lead to debilitating symptoms and serious complications. Any treatment that can reduce these symptoms or complications is welcome. In many trials, alpha-adrenoceptor antagonists (alpha blockers) have been evaluated as treatment for neurogenic lower urinary tract dysfunction; however, these have generally been small and often nonrandomized, uncontrolled studies. Existing evidence suggests that alpha blockers may have a small but useful effect in the facilitation of storage and emptying, and in the prevention of autonomic dysreflexia. Better understanding of lower urinary tract physiology and larger clinical trials with longer follow-up will hopefully clarify the role of alpha blockers in the future. PMID- 10094098 TI - New concepts in tissue specificity for prostate cancer and benign prostatic hyperplasia. AB - Of the hundreds of species of mammals, all of which have prostate glands, only humans and dogs are known to suffer from benign prostatic hyperplasia (BPH) and prostate carcinoma. In humans, prostate carcinoma is common, yet carcinomas of other sex accessory tissues are rare. In addition, different anatomic regions within the prostate gland have very different rates of BPH and carcinoma. In this article, we explore ideas and potential mechanisms relating to these paradoxical findings that may help explain the species, organ, and zone specificity of BPH and prostate cancer. We present an evolutionary argument that attempts to relate a high-fat diet, with its potential for generating oxidative DNA damage, to the species selectivity of prostate cancer. In addition, we outline an argument based on our preliminary studies indicating that chronic inflammation and the associated increase in cell turnover in the setting of increased oxidative stress may help to account for the organ selectivity of genitourinary carcinomas. PMID- 10094099 TI - Effects of the menstrual cycle on excess postexercise oxygen consumption in healthy young women. AB - The effects of the menstrual cycle on excess postexercise oxygen consumption (EPOC) were studied in seven healthy young women aged 18 to 20 years. EPOC, resting metabolic rate (RMR), and energy expenditure during exercise (EEDE) in the fasting state were measured in the follicular and luteal phases. On the experimental days, subjects exercised for 60 minutes on a bicycle ergometer at an intensity of 60% maximal oxygen consumption (VO2max) followed by rest for 6 hours. The EPOC and RMR were significantly higher (P < .05) and the postexercise respiratory exchange ratio (RER) was significantly lower (P < .05) in the luteal phase versus the follicular phase, whereas differences in the EEDE and basal and exercise RER were negligible in both phases. Fat oxidation during the experimental period was significantly greater in the luteal phase (P < .05). These results suggest that exercise in the luteal phase results in greater postexercise energy expenditure and fat utilization than in the follicular phase. PMID- 10094100 TI - Thermogenic effect of slight hyperglycemia during a lipid infusion. AB - Resistance to the glucoregulatory action of insulin is a common finding in obesity and may affect thermogenesis. In 13 healthy subjects, we studied the influence of acute insulin resistance induced by a lipid infusion on thermogenesis without any glucose load (n = 4) or during a euglycemic hyperinsulinemic clamp (n = 5) and an oral glucose tolerance test (OGTT, n = 8). When substrates were not administered at the same time, the energy cost of storage was significantly (P < .05) lower for lipids (3.9%+/-0.9%) than for glucose (11.9%+/-0.5% during the clamp and 14.9%+/-4.0% during the OGTT, NS). The lipid infusion decreased glucose storage during the clamp (control, 3.99+/-0.40 mg x kg(-1) x min(-1); lipid infusion, 0.92+/-0.39; P < .05) but increased it during the OGTT (control, 1.76+/-0.22 mg x kg(-1) x min(-1); lipid infusion, 2.94+/-0.27; P < .05). Infused lipids were stored more (clamp, 3.31+/-0.16; OGTT, 2.65+/-0.11 mg x kg(-1) x min(-1); P < .01) and oxidized less (clamp, 0.64+/ 0.21; OGTT, 1.02+/-0.09 mg x kg(-1) x min(-1); P < .05) during the clamp than during the OGTT. When lipids were infused, the energy cost of substrate storage was lower during the clamp versus the OGTT (clamp, 3.2%+/-0.8%; OGTT, 7.3%+/ 1.0%; P < .05). This effect was attributed to a lipid-induced impairment of glucose tolerance, which overcomes the inhibitory effect of lipid infusion on glucose storage observed in euglycemia. A slight elevation of plasma glucose in response to a lipid infusion impairs thermogenesis by redirecting the storage of substrates from lipids to glucose, which has a higher energy cost. PMID- 10094101 TI - Apolipoprotein E affects serial changes in total and low-density lipoprotein cholesterol in adolescent girls: Project HeartBeat! AB - Apolipoprotein E (apo E) polymorphism is a genetic determinant of lipid and lipoprotein levels and the risk for coronary heart disease. The extent to which serial patterns of change in total cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations varied by apo E genotype was therefore investigated in 247 Caucasian girls aged 8 to 14 at baseline who were participating in Project HeartBeat!, a mixed longitudinal study of cardiovascular disease (CVD) risk factor development in children. Plasma lipid concentrations were determined for each participant three times per year (every 4 months) for up to 4 years from October 1991 through August 1995. Mean total cholesterol values for individuals with epsilon2/3, epsilon3/3, and epsilon3/4 genotypes were 141.7, 161.6, and 165.9 mg/dL, respectively (P < .001). Corresponding LDL-C values for individuals with epsilon2/3, epsilon3/3, and epsilon3/4 genotypes were 74.6, 94.8, and 98.7 mg/dL, respectively (P < .001). The results of longitudinal modeling indicated that age trajectories for total cholesterol and LDL-C varied significantly by apo E genotype. Individuals with epsilon3/3 and epsilon3/4 genotypes exhibited similar patterns of change in total cholesterol and LDL-C from ages 8 to 18, while individuals with the epsilon2/3 genotype demonstrated a significantly different pattern of change (age2 x genotype interaction, P < .05). For example, individuals with the epsilon2/3 genotype showed a slight increase in total cholesterol from approximately 141 to 146 mg/dL from ages 8 to 10; total cholesterol then decreased monotonically from ages 10 to 18 from 146 to 115 mg/dL. The apo E effect on total cholesterol and LDL-C and their change during adolescence is strong and may be modified by factors affecting growth, maturation, and reproductive function. PMID- 10094102 TI - Intralipid infusion combined with propranolol administration has favorable metabolic effects in elderly malnourished cancer patients. AB - Previous studies have shown that an elevated basal metabolic rate (BMR) is present in elderly malnourished cancer patients. A possible dysfunction of the autonomic nervous system needs to be demonstrated. In aged weight-losing cancer patients (n = 40), aged non-weight-losing cancer patients (n = 30), and aged weight-losing noncancer patients (n = 18), the baseline BMR and heart rate variability were studied. Aged weight-losing cancer patients (n = 40) underwent bioimpedance analysis, ambulatory electrocardiographic monitoring with analysis of heart rate variability, and determination of the BMR. Then, the patients received infusion of Intralipid (Pharmacia, Uppsala, Sweden) without and with propranolol (6 days of 40 mg twice daily) administration. At baseline, a simple correlation between the BMR and the low-frequency component (LF) (r = .42, P < .006) and LF to high-frequency (HF) ratio (r = .51, P < .001) was found. After propranolol administration, the percent decline in the BMR was significantly correlated with the percent decline in the LF (r = .39, P < .01) and LF/HF ratio (r = .53, P < .001). The percent decline in the BMR was not correlated with the HF (r = .13, P < .34) or the plasma noradrenaline concentration (r = .21, P < .20) at any time. With regard to the BMR and substrate oxidation, 6-day propranolol administration plus Intralipid infusion produced the strongest decline in the BMR. This study demonstrates that autonomic nervous system dysfunction occurs and is responsible for the elevated BMR in elderly cancer patients, propranolol administration rectifies the autonomic dysfunction, and Intralipid infusion combined with propranolol administration is useful for enhancing the daily caloric intake without a strong increase in energy expenditure. PMID- 10094103 TI - Renin-angiotensin-aldosterone system in primary hyperparathyroidism before and after surgery. AB - Twenty consecutive unselected patients with proven primary hyperparathyroidism (PH), 26 essential hypertensive (EH) patients, and 13 normotensives were studied. Blood pressure (BP) and, under constant salt intake, plasma renin activity (PRA), parathyroid hormone (PTH), urinary and plasma sodium, potassium, aldosterone (ALD), creatinine, total calcium, and phosphate were measured. Patients with PH were also studied 1 and 6 months after successful surgery. In patients with PH, systolic and diastolic BP was significantly lower (P < .001) than in EH patients and higher (P < .005) than in controls. Eight patients with PH (40%) had BP levels greater than 140/90 mm Hg. PTH and plasma and urinary calcium in patients with PH were significantly (P < .01) higher than in controls, while PRA, ALD, phosphate, potassium, and sodium were superimposable in the three groups. PTH in patients with PH was weakly correlated with PRA (positively) and with plasma potassium (negatively) and was not associated with ALD, calcium, sodium, and BP levels. Surgery was followed by a significant reduction (P < .01) in PTH, calcium, and urinary phosphate and an increase (P < .02) in plasma phosphate, potassium, and sodium, whereas PRA, ALD, urinary potassium and sodium, and BP showed no change. In hypertensive patients with PH, PTH, PRA, and plasma and urinary ALD, calcium, and sodium did not differ from the values in normotensive PH patients, and variations in these humoral parameters after surgery were comparable in the two groups. In conclusion, our results show that hypertension is frequently associated with PH. However, the present data raise doubts about the assumption of a renin-mediated causal relationship between hyperparathyroidism and high BP. Indeed, as a unique finding in favor of the hypothesis of a stimulating role of PTH in renin secretion, we observed only a weak relation between PTH and PRA. Thus, unknown and/or unassessed factors related to parathyroid disease cannot be ruled out to explain the hypertension observed in some patients with PH. PMID- 10094104 TI - Differences in postprandial concentrations of very-low-density lipoprotein and chylomicron remnants between normotriglyceridemic and hypertriglyceridemic men with and without coronary heart disease. AB - It has been suggested that the postprandial elevation of plasma triglycerides is more closely linked to coronary heart disease (CHD) than the fasting triglyceride level. However, the postprandial situation is complex, as hepatogenous triglyceride-rich lipoprotein (TRL) particles (apolipoprotein [apo]B-100 and very low-density lipoprotein [VLDL]) are mixed in the blood with apoB-48-containing lipoproteins secreted from the intestine. To analyze the relative proportion of liver-derived and intestinal apoB-containing TRL in subjects with and without CHD, we performed standardized oral fat-loading tests in young survivors of myocardial infarction, a large proportion of whom are hypertriglyceridemic (HTG), as well as sex- and population-matched healthy control subjects. A special effort was made to recruit healthy HTG subjects as controls for the HTG patients. Fasting plasma triglycerides (3.74+/-1.35 v3.01+/-0.83, NS), low-density lipoprotein (LDL) cholesterol, and VLDL lipids, and apoB-100 and apoB-48 content at Svedberg flotation rate (Sf) 60-400, Sf 20-60, and Sf 12-20 did not differ between HTG patients (n = 10) and HTG controls (n = 14). Normotriglyceridemic (NTG) patients (n = 15) had higher fasting plasma triglycerides (1.44+/-0.39 v 0.98+/-0.33 mmol/L, P < .05) and LDL cholesterol (4.07+/-0.71 v 3.43+/-0.64, P < .05) than NTG controls (n = 34). The triglyceride elevation was accounted for by a higher level of small VLDL (apoB-100 in the Sf 20-60 fraction, 52+/-17 v29+/-20 mg/L, P < .05). HTG patients responded with clearly elevated plasma triglycerides in the late postprandial phase, ie, 7, 8, and 9 hours after fat intake. Essentially, this was explained by a retention of large VLDL particles, since HTG patients exhibited no major differences in apoB-48 concentrations in the Sf > 400, Sf 60-400, and Sf 20-60 fractions but showed marked differences in the level of apoB-100 at Sf 60-400 (large VLDL) 9 hours after fat intake when compared with HTG controls (101+/-13 v 57+/-5 mg/L, P < .01). NTG patients were characterized by a more rapid increase of large VLDL in the early postprandial state, ie, 3 hours after fat intake, with a mean increase from baseline to 3 hours of 24.1+/ 6.7 mg/L for NTG patients and 11.8+/-2.0 mg/L for controls (P < .05). ApoB-48 levels were also slightly higher, but all TRL parameters returned to baseline within 9 hours after fat intake. In conclusion, elevated triglyceride levels in the postprandial state in CHD patients are explained to a large extent by the accumulation of endogenous TRL. This suggests that the postprandial dyslipidemia encountered in CHD is more dependent on a failure of regulation of endogenous TRL versus the exogenous TRL species. PMID- 10094105 TI - Gender difference in the response of growth hormone (GH)-deficient adults to GH therapy. AB - While individual hypopituitary patients undoubtedly benefit from growth hormone (GH) therapy, there is considerable variability in the response to treatment. Given the expense, possible lack of benefit, and potential risks associated with long-term therapy, we sought to identify characteristics potentially associated with a favorable response to GH replacement. Twelve GH-deficient adults (seven men and five women aged 35.4+/-2.5 years, mean +/- SEM) participated in a 12 month open study of GH replacement (0.125 IU/kg/wk for 4 weeks and 0.25 IU/kg/wk thereafter) designed to examine the impact of GH on body composition, lipid profile, and psychological well-being. Using bioelectrical impedance analysis (BIA), there was a reduction in body fat (BF) and an increase in lean body mass (LBM) and total body water (TBW) (P < .05) following 12 months of GH treatment. In addition, there was a significant improvement in psychological well-being as indicated by a decrease in the Nottingham Health Profile (NHP) score (P < .05) and a decrease in both total cholesterol (P = .005) and low-density lipoprotein (LDL) cholesterol (P < .03). GH therapy was associated with an increase in fasting plasma glucose (P = .008) and hemoglobin A1c (HbA1c (P = .06). When analyzed by gender, the beneficial effect of GH was greater in men versus women for the increment in insulin-like growth factor-1 ([IGF-1] 375+/-59 v 148+/-73 microg/L, mean +/- SEM), increase in LBM (6.8+/-2.5 v -0.06+/-1.6 kg), reduction in BF (5.6+/-1.6 v 1.0+/-1.9 kg), and increase in TBW (5.0+/-1.6 v 0.14+/-1.29 L) (P < .05). HbA1c increased significantly in women (P < .05). The beneficial effect of GH tended to be greatest in those with the most significant abnormality in baseline values (P < .05). The duration of hypopituitarism showed an indirect correlation with the change in total cholesterol (P < .005). Baseline IGF-1 levels correlated directly with changes in TBW (P < .05). These data indicate that men with GH deficiency appear more responsive to GH therapy than women with respect to the increase in IGF-1 levels and improvement in body composition. In general, patients with the most significant abnormality in baseline values, the highest IGF-1 levels, and the shortest duration of hypopituitarism respond best. With long-term GH therapy, careful monitoring of glucose tolerance is indicated. PMID- 10094106 TI - High-affinity growth hormone (GH)-binding protein (GHBP), body fat mass, and insulin-like growth factor-binding protein-3 predict the GHBP response to GH therapy in adult GH deficiency syndrome. AB - The study objective was to investigate which baseline factors can accurately predict plasma high-affinity growth hormone (GH)-binding protein (GHBP) levels after GH replacement therapy in patients with GH deficiency (GHD). The study group consisted of 36 GHD patients (22 men and 14 women; mean age, 43.1 years; (range, 21 to 60) known to have adult-onset GHD for many years (range, 4 to 22). They were randomly divided into a GH-treated group (n = 19) and a placebo group (n = 17). Body composition (assessed by bioelectrical impendance analysis [BIA]), plasma GHBP (fast protein liquid chromatography [FPLC] size-exclusion gel chromatography), insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 ([IGFBP-3] radioimmunoassays) were measured before and after 6 months. A stepwise multiple linear regression analysis with the plasma GHBP level after 6 months as the dependent variable was used to unravel significant explanatory (or predictor) variables. In contrast to placebo therapy, GH replacement therapy increased the mean plasma levels of IGF-I and IGFBP-3 to the normal range, whereas a small but statistically significant increase in plasma GHBP was observed. The combination of baseline plasma GHBP, body fat mass, and IGFBP-3 predicts posttreatment GHBP levels accurately (adjusted R2 = .97), indicating that baseline variables such as age, gender, fat-free mass, and IGF-I have no contribution. Furthermore, reliability analysis showed that the observed and predicted values for GHBP fit a strict parallel model. These findings indicate that the variations in body fat mass and IGFBP-3 among adult GHD subjects explain the reported variable response of GHBP to GH replacement therapy. PMID- 10094107 TI - Long-term exposure of isolated rat islets of Langerhans to supraphysiologic glucose concentrations decreases insulin mRNA levels. AB - Chronic hyperglycemia has been postulated to contribute to beta-cell dysfunction in type 2 diabetic patients. A deleterious effect of prolonged exposure to high glucose concentrations on insulin gene expression has been demonstrated in insulin-secreting cell lines. This study was designed to investigate in isolated rat islets the effects of long-term exposure to supraphysiologic glucose concentrations on insulin, GLUT2, and glucokinase gene expression. The acute effects of glucose on gene expression were investigated by culturing rat islets in 2.8 or 16.7 mmol/L glucose for 24 hours. Insulin, GLUT2, and glucokinase mRNA levels were assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). As expected, glucose acutely increased relative insulin and GLUT2 mRNA levels by 2.8- +/- 0.5-fold (n = 5, P < .005) and 1.8- +/- 0.3-fold (n = 5, P < .05), respectively, but had no effect on glucokinase gene expression (1.1- +/- 0.1-fold increase, n = 4, NS). These results validate the use of semiquantitative RT-PCR to detect changes in gene expression in rat islets. Islets were then cultured in 5.6 or 16.7 mmol/L glucose for 2, 4, or 6 weeks. Relative insulin mRNA levels were higher in islets cultured in high glucose after 2 weeks (1.8+/-0.1 v 1.0+/-0.1, n = 4, P < .05), identical after 4 weeks (0.9+/ 0.1 v 1.00+/-0.2, n = 4, NS), and significantly lower after 6 weeks (0.6+/-0.1 v 1.0+/-0.2, n = 6, P < .05). Relative GLUT2 mRNA levels were higher in islets cultured in high glucose after 2 weeks (1.7+/-0.2 v 1.0+/-0.2, n = 3, P < .05) and then identical in both groups after 4 weeks (1.0+/-0.1 v 1.0+/-0.1, n = 3, NS) and 6 weeks (1.0+/-0.2 v 1.0+/-0.1, n = 6, NS). Relative glucokinase mRNA levels were identical under both culture conditions at 2 (1.4+/-0.4 v 1.0+/-0.2, n = 3, NS), 4 (0.8+/-0.5 v 1.0+/-0.3, n = 3, NS), and 6 (0.9+/-0.2 v 1.0+/-0.1, n = 6, NS) weeks. These results indicate that a 6-week exposure of rat islets to supraphysiologic glucose concentrations decreases insulin mRNA levels without affecting GLUT2 and glucokinase gene expression. We conclude that the phenomenon of glucose toxicity decreasing insulin gene expression is not restricted to transformed cells, and might provide insight into the mechanisms by which chronic hyperglycemia adversely affects beta-cell function. PMID- 10094108 TI - Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients. AB - Cytokines have been implicated in the pathogenesis of the euthyroid sick syndrome. Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor alpha (rTNF) and melphalan in patients with melanoma or sarcoma is accompanied by high systemic TNF levels. We examined the prolonged effects (7 days) of ILP on thyroid hormone metabolism with respect to induction and recovery of the euthyroid sick syndrome in six cancer patients. After ILP, when the limb is reconnected to the systemic circulation, leakage of residual rTNF resulted in systemic peak levels at 10 minutes postperfusion followed by a parallel increase in plasma interleukin-6 (IL-6) and cortisol, with maximum levels at 4 hours (P < .05). A rapid decrease was observed at 5 minutes for plasma triiodothyronine (T3), reverse T3 (rT3), thyroxine (T4), and thyroxine-binding globulin (TBG) (P < .05), whereas free T4 (FT4) and T3-uptake showed a sharp increase, with peak levels at 5 minutes (P < .05). T3, T4, and TBG levels remained low until 24 hours after ILP In contrast, rT3 increased above pretreatment values to maximum levels at 24 hours (P < .05). Plasma thyrotropin (TSH) showed an initial decrease at 4 hours postperfusion (P < .05) but exceeded pretreatment values from day 1 to day 7 (by +94%+/-43% to +155%+/-66%, P < .05), preceding the recovery of T4 and T3 levels. T3 and rT3 returned to initial values at day 4. T4 and TBG levels recovered at day 2. T4 exceeded basal values at days 5 to 7 (P < .05). It is concluded that ILP with rTNF induces a euthyroid sick syndrome either directly or indirectly through other mediators such as IL-6 or cortisol. The recovery from this euthyroid sick syndrome is, at least in part, TSH-dependent, since the prolonged elevation of TSH values preceded and persisted during the normalization of T3 and the elevation of T4 levels. This biphasic pattern of induction of and recovery from the euthyroid sick syndrome may be a general feature of nonthyroidal disease. The euthyroid sick syndrome should be interpreted not only in relation to the presence of nonthyroidal diseases but also in relation to the recovery from these diseases. PMID- 10094109 TI - Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis but does not cause dyslipidemia in conscious normal rats. AB - Type 2 diabetes mellitus and obesity are characterized by fasting hyperinsulinemia, insulin resistance with respect to glucose metabolism, elevated plasma free fatty acid (FFA) levels, hypertriglyceridemia, and decreased high density lipoprotein (HDL) cholesterol. An association between hyperinsulinemia and dyslipidemia has been suggested, but the causality of the relationship remains uncertain. Therefore, we infused eight 12-week-old male catheterized conscious normal rats with insulin (1 mU/min) for 7 days while maintaining euglycemia using a modification of the glucose clamp technique. Control rats (n = 8) received vehicle infusion. Baseline FFAs were 1.07+/-0.13 mmol/L, decreased to 0.57+/-0.10 (P < .05) upon initiation of the insulin infusion, and gradually increased to 0.95+/-0.12 by day 7 (P = NS vbaseline). On day 7 after a 6-hour fast, plasma insulin, glucose, and FFA levels in control and chronically hyperinsulinemic rats were 32+/-5 versus 116+/-21 mU/L (P < .005), 122+/-4 versus 129+/-8 mg/dL (P = NS), and 1.13+/-0.18 versus 0.95+/-0.12 mmol/L (P = NS); total plasma triglyceride and cholesterol levels were 78+/-7 versus 66+/-9 mg/dL (P = NS) and 50+/-3 versus 47+/-2 mg/dL (P = NS), respectively. Very-low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL2 and HDL3 subfractions of plasma triglyceride and cholesterol were similar in control and hyperinsulinemic rats. Plasma FFA correlated positively with total (r = .61, P < .005) triglycerides. On day 7 after an 8-hour fast, hyperinsulinemic-euglycemic clamps with 3-3H-glucose infusion were performed in all rats. Chronically hyperinsulinemic rats showed peripheral insulin resistance (glucose uptake, 15.8+/-0.8 v 19.3+/-1.4 mg/kg x min, P < .02) but normal suppression of hepatic glucose production (HGP) compared with control rats (4.3+/-1.0 v 5.6+/-1.4 mg/kg x min, P = NS). De novo tissue lipogenesis (3-3H-glucose incorporation into lipids) was increased in chronically hyperinsulinemic versus control rats (0.90+/-0.10 v 0.44+/-0.08 mg/kg x min, P < .005). In conclusion, chronic physiologic hyperinsulinemia (1) causes insulin resistance with regard to the suppression of plasma FFA levels and increases lipogenesis; (2) induces peripheral but not hepatic insulin resistance with respect to glucose metabolism; and (3) does not cause an elevation in VLDL triglyceride or a reduction in HDL-cholesterol. PMID- 10094110 TI - Effect of glucose on the plasma concentration and urinary excretion of uridine and purine bases. AB - To examine whether glucose increases the plasma concentration of purine bases and uridine, 75 g glucose was administered orally to eight healthy subjects and two patients with hyperuricemia. The plasma concentration of uridine increased by 21%, 25%, and 20% 30, 60, and 90 minutes after administration of glucose, respectively. However, urinary excretion of uridine was not affected, nor were the plasma concentrations and urinary excretion of purine bases (hypoxanthine, xanthine, and uric acid). These results suggest that the glucose-induced increase in plasma uridine was not concomitant with adenosine triphosphate (ATP) consumption-induced purine degradation, but instead was ascribable to a uridine diphosphate (UDP)-glucose consumption-induced pyrimidine degradation (UDP-glucose ->UDP-->uridine monophosphate [UMP]-->uridine). PMID- 10094111 TI - Corticotropin-induced reduction of plasma lipoprotein(a) concentrations in healthy individuals and hemodialysis patients: relation to apolipoprotein(a) size polymorphism. AB - Lipoprotein(a) [Lp(a)], a strong independent cardiovascular risk factor, consists of the unique apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein particle. Apo(a) contains a widely differing number of the plasminogen-like kringle IV, a size polymorphism that is codominantly inherited. In addition to powerful genetic control, renal failure is known to influence the plasma Lp(a) concentration. There is still a lot to be learned about the mode and site of catabolism of Lp(a), and there is no readily applicable Lp(a)-lowering treatment available. Therefore, it was of interest to study further the Lp(a) lowering effect of corticotropin (ACTH) that has been demonstrated in small studies. The main purpose of the present study was to investigate the influence of ACTH on different apo(a) isoforms. Short-term treatment with ACTH decreased the plasma Lp(a) concentration in all 26 study participants. The two study groups (12 healthy individuals and 14 hemodialysis patients) responded similarly, with a median decrease in plasma Lp(a) of 39% and 49%, respectively. In subjects with two clearly separable apo(a) bands, apo(a) phenotyping and densitometric scanning of the bands before and after treatment with ACTH revealed a change in the proportion of apo(a) isoforms, ie, a shift toward the isoform with lower molecular weight. This was observed in seven of nine investigated subjects (four of five healthy individuals and three of four hemodialysis patients). PMID- 10094112 TI - Metabolic abnormalities in the genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty rat can be prevented and reversed by alpha-glucosidase inhibitor. AB - The recently developed Otsuka Long-Evans Tokushima Fatty (OLETF) rat is known to develop insulinopenic diabetes after a prolonged period in a condition resembling non-insulin-dependent diabetes mellitus (NIDDM). We examined the effect of pharmacological intervention with a potent intestinal alpha-glucosidase inhibitor, acarbose, on the metabolic and histopathologic changes in this rat model. The first two groups of rats received an acarbose-rich diet (150 mg/100 g normal chow) from 12 weeks of age (ie, before the onset of diabetes) or from 28 weeks of age (ie, after the onset of diabetes), while a third group received the acarbose-rich diet for the initial 16 weeks only (from 12 to 28 weeks of age). A control group received standard rat chow. Acarbose-fed rats gained less weight or lost weight despite increased food intake when switched to the acarbose-rich diet. Acarbose also reduced visceral adipose depots and fasting triglyceride (TG), glucose, and insulin levels. At the end of the study at 72 weeks, the pancreatic wet weight and insulin content were significantly higher in the treated groups versus control rats. The morphological changes observed in control rats, such as atrophy of the pancreas and reduced number and size of islets, were not present in acarbose-treated rats. Rats fed acarbose from 12 to 28 weeks of age gradually gained weight after switching to standard chow, and hyperinsulinemia, hyperglycemia, and hyperlipidemia appeared (in that order). The pancreatic insulin content in these rats was significantly higher and the visceral adipose depot was significantly smaller than in control rats. Our study demonstrates that acarbose prevented and reversed the metabolic derangement and histopathological changes in genetically diabetic rats. Moreover, treatment with acarbose even for a short period produced a marked delay in the development of insulin insensitivity and frank diabetes. PMID- 10094113 TI - Relationship of visceral adipose tissue to metabolic risk factors for coronary heart disease: is there a contribution of subcutaneous fat cell hypertrophy? AB - Visceral adipose tissue (VAT) accumulation is an important correlate of the metabolic complications found in obese patients. The aim of this study was to evaluate the respective contribution of VAT deposition versus subcutaneous abdominal or femoral fat cell hypertrophy as correlates of the metabolic risk profile in 69 men and 65 premenopausal women (aged 35+/-5 years) with a wide range of fatness (body mass index, 18 to 57 kg/m2). In both genders, VAT accumulation was positively correlated with fasting plasma insulin, triglyceride (TG), and low-density lipoprotein (LDL)-apolipoprotein B (apo B) levels and the cholesterol (CHOL)/high-density lipoprotein (HDL)-CHOL ratio (.24 < or = r < or = .71, P < .05). A similar pattern of positive relationships was found between subcutaneous abdominal fat cell weight and metabolic risk variables in men and women (.33 < or = r < or = .60, P < .01). Positive associations were also observed in women between femoral fat cell weight and fasting plasma insulin, TG, and CHOL levels and the CHOL/HDL-CHOL ratio (.29 < or = r < or = .42, P < .05). However, only plasma TG concentrations and the CHOL/HDL-CHOL ratio were positively correlated with femoral fat cell weight in men (r = .30, P < .05). To better investigate the relationships between the metabolic risk profile and hypertrophic subcutaneous obesity, individuals with small versus large subcutaneous abdominal adipocytes were matched according to VAT accumulation. Men with large abdominal fat cells displayed higher plasma TG and LDL-apo B levels compared with men characterized by small abdominal adipocytes (P < .05). Stepwise multiple regression analyses showed that subcutaneous abdominal fat cell weight was the best independent variable predicting plasma TG and LDL-apo B levels in men. No significant difference was found in the metabolic profile of subjects displaying small versus large femoral adipocytes. Taken together, these results suggest that for a given VAT deposition, the presence of hypertrophied subcutaneous abdominal adipocytes in men appears to be associated with further deterioration in the metabolic risk profile. On the other hand, the hypertrophy of femoral adipocytes does not further alter the metabolic complications generally related to obesity in both men and women. PMID- 10094114 TI - Campestanol (24-methyl-5alpha-cholestan-3beta-ol) absorption and distribution in New Zealand White rabbits: effect of dietary sitostanol. AB - Campestanol (24-methyl-5alpha-cholestan-3beta-ol) is a naturally occurring plant stanol, structurally similar to cholesterol (5-cholesten-3beta-ol) and widely distributed in vegetable oils consumed in human diets. We measured the absorption and turnover of campestanol by the plasma dual-isotope ratio method and mathematical analysis of specific activity versus time decay curves after simultaneous oral and intravenous pulse-labeling with [3alpha-3H]- and [23-14C] labeled campestanol, respectively, in New Zealand White (NZW) rabbits: six fed chow and six fed chow with 125 mg/d campestanol and 175 mg/d sitostanol (24-ethyl 5alpha-cholestan-3beta-ol). Plasma concentrations increased insignificantly from 0.08+/-0.01 to 0.09+/-0.01 mg/dL with dietary stanols. The percent campestanol absorption measured by the plasma dual-isotope ratio method after the rabbits were fasted for 6 hours yielded the percent absorption in the absence of competing intestinal sterols and stanols and declined insignificantly from 11.6%+/-3.5% in controls to 8.1%+/-3.7% in the treated rabbit groups. In contrast, the turnover, which measured actual absorption averaged over 24 hours, increased from 0.12+/-0.05 to 0.37+/-0.05 mg/d (P < .05) with campestanol and sitostanol added to the diet. However, the actual percent absorption declined from 3% to 0.3% of dietary intake with the campestanol and sitostanol-enriched diet. Campestanol pool sizes, although remaining small, increased slightly from 1.1+/-0.4 to 2.5+/-1.5 mg. The removal constant (KA) from pool A (MA) did not change significantly with added dietary campestanol and sitostanol (KA= -0.040+/ 0.005 v -0.037+/-0.007 d(-1)). The results demonstrate small campestanol plasma concentrations and body pools even when the rabbits consumed substantial amounts because (1) intestinal absorption was limited and (2) was further reduced by competing dietary sitostanol, and (3) campestanol was removed rapidly from the body. Thus, campestanol, which shares the same basic structure and intestinal absorption pathway with cholesterol, does not accumulate when fed, and may be incorporated into the diet to block cholesterol absorption. PMID- 10094116 TI - Does paracentesis of ascites influence measurements of bone mineral or body composition by dual-energy x-ray absorptiometry? AB - Measurements of bone mineral content (BMO) and density (BMD) by dual-energy x-ray absorptiometry (DXA) may be affected by changes in soft tissue overlying bone. Furthermore, the accuracy error for body composition determined by DXA may be high in the trunk region due to the complex bone geometry. Our objective was to evaluate the impact of paracentesis on measurements of bone mineral and body composition by DXA. DXA (Norland XR-36; Norland, Fort Atkinson, WI) scans were performed in six patients with cirrhosis of the liver before and after treatment of ascites by paracentesis. There were no significant differences in the spinal BMC (change [delta] = 0.04%) and BMD (delta = -0.9%) (P > .05), nor in total body BMC ([TBBMC] delta = 1.9%) and BMD ([TBBMD] delta = 0.4%) (P > .05). The median volume of ascites drained (6.8 L; range, 1.6 to 14.7) was not significantly different from the median change in total (5.8 kg; range, 2.0 to 16.1) or trunk lean tissue mass ([LTM] 5.8 kg; range, 1.9 to 11.9) (P > .05). The changes in body weight correlated with the changes in trunk LTM (r = .93, standard error of the estimate [SEE] = 1.8 kg, P = .007). Total and regional fat mass were not changed significantly by the paracentesis. We conclude that measurements of total body and spinal bone mineral by DXA are unaffected by large changes in the soft tissue composition and height of the trunk. Furthermore, the change in body composition induced by ascites drainage was accurately determined as a change in total body and trunk LTM on a group level. PMID- 10094115 TI - Urinary excretion of apolipoprotein(a) fragments in type 1 diabetes mellitus patients. AB - High levels of plasma lipoprotein(a) [Lp(a)] represent an independent risk factor for cardiovascular morbidity; however, Lp(a) has not yet been identified as a risk factor for type 1 diabetic patients. Results from the limited number of available studies on plasma Lp(a) levels in relation to renal function in type 1 diabetes mellitus are inconclusive. We hypothesized that only type 1 diabetes mellitus patients with impaired renal function show increased plasma Lp(a) levels, due to decreased urinary apolipoprotein(a) [apo(a)] excretion. We therefore measured urinary apo(a) levels in 52 type 1 diabetes mellitus patients and 52 matched controls, and related the urinary apo(a) concentration to the plasma Lp(a) level, kidney function, and metabolic control. Our findings indicate that patients with incipient diabetic nephropathy as evidenced by microalbuminuria (20 to 200 microg/min) exhibit significantly higher plasma Lp(a) levels (median, 15.6 mg/dL) in comparison to normoalbuminuric patients (median, 10.3 mg/dL) and healthy controls (median, 12.0 mg/dL). Urinary apo(a) normalized to creatinine excretion was significantly elevated in both normoalbuminuric (median, 22.3 microg/dL) and microalbuminuric type 1 diabetic patients (median, 29.1 microg/dL) compared with healthy subjects (median, 16.0 microg/dL) and correlated significantly with Lp(a) plasma levels in both patient and control groups (P < .003). No correlation existed between the Lp(a) plasma level or urinary apo(a) concentration and metabolic control in type 1 diabetes mellitus patients. From these studies, we conclude that urinary apo(a) excretion is significantly increased in type 1 diabetic patients and correlates with plasma Lp(a) levels, and only type 1 diabetic patients with microalbuminuria have higher plasma levels of Lp(a) compared with patients with normoalbuminuria and healthy controls. PMID- 10094117 TI - Age-related changes in sex hormones affect the sex difference in serum leptin independently of changes in body fat. AB - Serum leptin concentrations are highly correlated with body fatness, but there is considerable variability among individuals after adjusting for differences in body fatness. Theoretically, sex hormone levels may influence serum leptin, since the levels are higher in women than in men independently of body fat. Increasing old age is associated with decreases in serum sex hormone concentrations and changes in body fatness that may independently alter serum leptin concentrations. In a cross-sectional sample of 106 men and 166 women aged 62 to 98 years, serum leptin adjusted for total body fat had a significant positive association with age in men and a nonsignificant negative association with age in women. Serum testosterone had a significant negative association with serum leptin in men after adjusting for total body fat, the fasting insulin resistance index (FIRI), and sex hormone-binding globulin (SHBG). In a longitudinal sample of 22 elderly men and 52 women, serum leptin levels increased significantly over a 14-year period in men, but not in women. Increases in serum leptin were significantly associated with decreases in serum testosterone but not with changes in the body mass index (BMI) in men. In contrast, changes in leptin were associated with changes in the BMI but not with changes in serum estrone in women. These results suggest that differences among men and changes with age in serum leptin are associated with circulating levels of testosterone. Elderly men become progressively "hyperleptinemic" with age regardless of changes in body fatness, possibly due to decreasing testosterone levels. PMID- 10094118 TI - Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide. AB - The incretins glucose-dependent insulinotropic polypeptide (GIP1-42) and truncated forms of glucagon-like peptide-1 (GLP-1) are hormones released from the gut in response to ingested nutrients, which act on the pancreas to potentiate glucose-induced insulin secretion. These hormones are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV ([DPIV] CD26). This study describes the effect on glucose tolerance and insulin secretion of inhibiting endogenous DPIV in the rat using Ile-thiazolidide, a specific DPIV inhibitor. High performance liquid chromatography (HPLC) analysis of plasma following in vivo administration of 125I-labeled peptides showed that inhibition of DPIV by about 70% prevented the degradation of 90.0% of injected 125I-GLP-17-36 after 5 minutes, while only 13.4% remained unhydrolyzed in rats not treated with the DPIV inhibiting agent after only 2 minutes. Ile-thiazolidide treatment also increased the circulating half-life of intact GLP-17-36 released in response to intraduodenal (ID) glucose (as measured by N-terminal specific radioimmunoassay [RIA]). In addition, inhibition of DPIV in vivo resulted in an earlier increase and peak of plasma insulin and a more rapid clearance of blood glucose in response to ID glucose challenge. When considered with the HPLC data, these results suggest that the altered insulin profile is an incretin-mediated response. DPIV inhibition resulting in improved glucose tolerance may have therapeutic potential for the management of type 2 diabetes mellitus. PMID- 10094119 TI - Reduced cortisol potentiates the exercise-induced increase in corticotropin to a greater extent in trained compared with untrained men. AB - We examined the effect of acute exercise and reduced cortisol on pituitary and adrenal responsiveness and the impact of reduced plasma cortisol on maximal oxygen consumption (VO2max) in eight trained (T) and eight untrained (UT) males. Subjects completed two graded maximal exercise tests (GXT), each preceded by either overnight metyrapone (MET) or placebo (PLA) administration. Blood samples were collected before and after GXT. With PLA, resting corticotropin (ACTH) levels were higher in T versus UT men; however, cortisol and 11-deoxycortisol were similar between groups. Following GXT on PLA, cortisol was unchanged but 11 deoxycortisol increased in both groups; however, ACTH increased only in UT men. For both groups, cortisol, 11-deoxycortisol, and ACTH were different post-GXT with MET versus PLA. Furthermore, following GXT with MET, the ACTH response was greater in T versus UT subjects. VO2max was not altered by MET in either group. We conclude that (1) at rest, only ACTH levels differed between T and UT men; (2) individually, the GXT and MET provide a similar ACTH response in UT but not in T subjects; (3) when GXT and MET are superimposed, they provide a stronger stimulus to pituitary and adrenal reserve than either test alone; (4) the combination of MET and GXT elicits a greater ACTH response in T compared with UT men; and (5) an acute reduction in plasma cortisol does not alter VO2max. PMID- 10094120 TI - Hypothalamic-pituitary-adrenal axis and sympathetic nervous system activities in Pima Indians and Caucasians. AB - It has been proposed that both hypercortisolism and low sympathetic nervous system (SNS) activity contribute to obesity. Because glucocorticoids inhibit SNS activity, we hypothesized that hypercortisolism and low SNS activity may be found in association in Pima Indians, a population with a high prevalence of obesity. We therefore measured indices of hypothalamic-pituitary-adrenal (HPA) axis and SNS activities in 39 nondiabetic men, 20 Pimas (age, 30+/-5 years; weight, 94+/ 26 kg; 35%+/-8% body fat [mean +/- SD]) and 19 Caucasians (33+/-9 years, 91+/-23 kg, 28%+/-11% body fat). HPA axis activity was assessed by measurements of morning fasting plasma corticotropin (ACTH) and cortisol concentrations and 24 hour urinary free cortisol (UFC) excretion. SNS activity was assessed as muscle sympathetic nerve activity (MSNA) by microneurography and by measurement of catecholamines (fasting plasma concentration and 24-hour urinary excretion). Plasma ACTH and cortisol and UFC were similar in Pimas and Caucasians. MSNA was positively correlated with percent body fat (r = .49, P = .002) and was lower in Pimas compared with Caucasians after adjustment for percent body fat (24+/-9 v 31+/-10 bursts/min, P = .04). We conclude that Pima Indians, a population with a high prevalence of obesity, have lower SNS activity but normal HPA axis activity compared with Caucasians. PMID- 10094122 TI - The blood vessel, linchpin of diabetic lesions. AB - The morbidity and mortality associated with diabetes mellitus are essentially related to the vascular lesions that develop over time in this condition. Both the macrocirculation and microcirculation are involved, and as a consequence, vital organs such as the brain, retina, heart, and kidney and the limbs become damaged. Because microalbuminuria represents the earliest and probably most sensitive indication of endothelial dysfunction in diabetes mellitus, the results of pharmacologic intervention with angiotensin-converting enzyme inhibitors, which treat glomerular hypertension were the first indication of potential beneficial effects in reducing diabetic nephroplasty. The nature of endothelial dysfunction related to diabetes is probably not homogeneous, since microcirculation networks are affected at different periods and with variable intensity. This appears to be the case for the aorta, the heart, segments of the digestive tract, the skin, and the skeletal muscle, the largest consumer of insulin. Although the aorta and large arteries contain a small portion of the total blood volume, their distribution of blood flow (pulse pressure) to peripheral organs may affect endothelial function in the microcirculation. Changes in the structure of conduit arteries, partly responsible for the alteration in compliance characteristics, could well be related to the way these arteries are fed by the vasa vasorum system. This report describes a new in vitro approach to examine capillary permeability in normal and alloxan-induced diabetic rabbits. Preliminary results indicate that the size of terminal arterioles of the vasa vasorum (increased diameter) and the capillary permeability to albumin (markedly enhanced) in this specialized network are profoundly affected in the thoracic aorta obtained from diabetic animals. Albumin extravasation into the interstitial fluid compartment of the aorta is likely to lead to structural and physicochemical changes: in fact, removal of interstitial macromolecules via lymphatic drainage is poor in the blood vessel wall of large arteries. This experimental approach is likely to be useful in the exploration of medications affecting the structure and function of conduit vessels. PMID- 10094121 TI - Biliary cholesterol and bile acid excretion do not increase in hamsters fed cereal-based diets containing cholesterol. AB - The major compensatory responses to increased cholesterol consumption are decreased cholesterol synthesis and increased cholesterol excretion through the bile either as free cholesterol or bile acids. The objective of this study was to test the hypothesis that biliary cholesterol excretion is increased in hamsters fed low levels of cholesterol reflecting normal human intake. The hypothesis was based on observations that hamsters generally resist changes in bile acid synthesis when fed large amounts of cholesterol; therefore, increased biliary cholesterol excretion represents a potentially significant pathway for elimination of excess cholesterol in this species. Hamsters were fed modified NIH 07 cereal-based diets containing 0.02%, 0.03%, and 0.05% cholesterol (0.04, 0.06, and 0.10 mg cholesterol/kcal, respectively). The primary response to increasing amounts of dietary cholesterol was downregulation of whole-body cholesterol synthesis, reduced from 3.93+/-0.14 micromol x d(-1) x 100 g(-1) body weight in hamsters fed 0.02% cholesterol to 0.52+/-0.14 micromol x d(-1) x 100 g(-1) in the 0.05% cholesterol group. Biliary cholesterol excretion was also slightly reduced in hamsters fed 0.05% cholesterol, whereas bile acid excretion was not altered by dietary cholesterol. Despite a pronounced downregulation of whole-body cholesterol synthesis, liver and plasma cholesterol concentrations increased in hamsters fed 0.05% cholesterol. The data indicate that increased biliary cholesterol excretion is not a major compensatory route of cholesterol excretion in hamsters consuming cholesterol. Furthermore, cholesterol added to the diet at 0.05% appears to be the approximate threshold at which compensatory mechanisms can prevent increases in liver and plasma cholesterol in male Syrian hamsters. Consequently, this species may be an appropriate animal model for "hyperresponding" individuals in the human population. PMID- 10094123 TI - A selective imaging of tinnitus. AB - We selectively imaged the neural correlates of tinnitus, by contrasting a condition with no phantom auditory sensation with a condition during which tinnitus is present, using a rare form of tinnitus elicited by eye movements. Using positron emission tomography (PET), we demonstrate that phantom auditory sensation increases regional cerebral blood flow bilaterally in temporo-parietal association auditory areas but not in the primary auditory cortex. These results confirm that conscious perception does not necessarily require activation in primary areas and suggest that the perceptual qualities of tinnitus, e.g. intensity, frequency and spatial localization, are represented in temporo parietal regions. Activation in these regions is compatible with cortical processing of ascending auditory messages generated at subcortical levels. PMID- 10094124 TI - Human cortical gustatory areas: a review of functional neuroimaging data. AB - In an effort to define human cortical gustatory areas we reviewed functional neuroimaging data for which coordinates standardized in Talairach proportional space were available. We observed a wide distribution of peaks within the insula and parietal and frontal opercula, suggesting multiple gustatory regions within this cortical area. Multiple peaks also emerged in the orbitofrontal cortex. However, only two peaks, both in the right hemisphere, were observed in the caudolateral orbitofrontal cortex, the region likely homologous to the secondary taste area described in monkeys. Overall significantly more peaks originated from the right hemisphere suggesting asymmetrical cortical representation of taste favoring the right hemisphere. PMID- 10094125 TI - OMP gene deletion causes an elevation in behavioral threshold sensitivity. AB - To characterize the behavioral consequences of OMP gene deletion on odor processing we assessed the ability of OMP-null animals to acquire an air vs odor discrimination for five odorants, and determined whether OMP-null animals differed from controls in their threshold sensitivity to the odorant propanol. On average, control and OMP-null animals did not differ in the number of testing sessions needed to achieve criterion performance on each discrimination problem (2.04 vs 1.68, respectively; t=0.83, p=0.41). However, null animals were significantly less sensitive to the odorant propanol (3.01 x 10(-8) vs 1.06 x 10( 5), respectively; t=4.09, p=0.015). These in vivo behavioral results provide support for the hypothesis that OMP plays a modulatory role in the odor detection/signal transduction process. PMID- 10094126 TI - Early visual processing during binocular rivalry studied with visual evoked potentials. AB - Visual evoked potentials (VEPs) were recorded to probes presented to the dominant and suppressed eyes in a binocular rivalry paradigm. Probes presented to the suppressed eye interrupted the current dominance phase and produced a P300-like deflection (400-700 ms). Probes delivered to the dominant eye increased the duration of the current dominance phase. VEPs to these probes included an endogenous component that overlapped the early exogenous components. The early endogenous component (rivalry-related potential, RRP) started as early as 70 ms and had a broad centroparietooccipital distribution. PMID- 10094127 TI - GAT-1 developmental expression in the rat cerebellar cortex: basket and pinceau formation. AB - In view of the key role exerted by neurotransmitter transporters in the synaptic transmission, the expression of GABA transporter GAT-1 was analysed during cerebellar development, when relevant processes of synapse maturation take place. GAT-1-immunoreactive (IR) structures started to be detected on PD 8-9, at the low molecular and Purkinje cell layer, coincident with the onset of functional inhibitory synapses on Purkinje neurons. By PD 18, GAT-1-IR structures completely ensheathed the Purkinje cell somata thus outlining the characteristic perisomatic formation, whereas GAT-1 wrapping on the axon initial segment started to be detected only at PD 15, and the mature form of the pinceau was fully developed from PD 23 on. These results, when compared with the functional maturation of the GABAergic input to Purkinje cells, indicate that GAT-1 may play a significant role in the differentiation of basket interneuron-Purkinje cell circuit. PMID- 10094128 TI - Endothelin stimulates nitric oxide-dependent cyclic GMP formation in rat cerebellar astroglia. AB - Endothelins (ETs) elicit a diversity of cellular responses in cultured astrocytes that suggest an important role of these peptides in glial cell function. Stimulation of astroglial ET receptors induces phosphoinositide (PI) hydrolysis and intracellular calcium mobilization, but little is known about the signalling events that occur downstream of this system. Here we show that in rat cerebellar astroglia in culture ETs produce a receptor-mediated stimulation of cyclic GMP (cGMP) formation that is rapid and totally dependent on nitric oxide synthase (NOS) activity. The effect is blocked by an inhibitor of PI phospholipase C, compound U73122, and by depletion of intracellular calcium stores with thapsygargin. These results indicate that calcium released by inositol trisphosphate is responsible for NOS activation and subsequent cGMP formation. PMID- 10094129 TI - cAMP potentiates beta-amyloid-induced nitric oxide release from microglia. AB - The beta-amyloid peptide (Abeta) has been known to activate microglia and to induce release of nitric oxide (NO). In this study, we examined the effect of cAMP on Abeta-induced microglial activation using cultured rat brain microglia. Dibutyryl-cAMP (dbcAMP) and 3-isobutyl-1-methylxanthine (IBMX) significantly potentiated Abeta(25-35)- or Abeta(1-42)-induced NO release in a dose-dependent manner. The increase in NO release was due to the increased expression of inducible nitric oxide synthase (iNOS). However, forskolin, an adenylate cyclase activator, weakly increased NO release at 10-50 microM but caused a decrease at 100 microM. These results suggest that increase in intracellular cAMP could potentiate microglial activation induced by Abeta. PMID- 10094130 TI - Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). AB - Metabolic hypofunction is a common finding in a number of neurodegenerative diseases, including Alzheimer's disease (AD). The strong linkage between the amyloid precursor protein (APP) and AD led us to examine whether over-expression of this protein in CNS-type cells had an effect on mitochondria. We found abnormal morphology in mitochondria of the neuroectodermal progeny of P19 cells stably transfected with human APP751. In addition, the mitochondria of APP transfected clones had a decreased mitochondrial membrane potential. These changes were independent of Abeta toxicity and distinct from complex I inhibition. Our results have important implications for the earliest events in the pathophysiology of AD and, by extrapolation, for intervention therapies. PMID- 10094131 TI - Ginkgo biloba extract (EGb 761) protects Na,K-ATPase activity during cerebral ischemia in mice. AB - Neuroprotective drugs such as Ginkgo biloba extract (EGb 761) could prevent the ischemia-induced impairment of the Na,K-ATPase activity. In this study, Na,K ATPase activity and expression, contents in fatty acids and malondialdehyde, an index of lipoperoxidation, were compared in the ipsilateral (ischemic) and the contralateral (unlesioned) cortices after 1 h of unilateral focal cortices cerebral ischemia in the mouse. EGb 761 (110 mg/kg) was administered daily to half of the animals for 10 days before ischemia. Ischemia significantly reduced Na,K-ATPase activity by about 40% and increased malondialdehyde content; EGb 761 pretreatment abolished these effects. The free radical scavenger properties of EGb 761 are a potential mechanism by which Na,K-ATPase injury and lipoperoxidation are prevented. PMID- 10094132 TI - Chemokine receptor mRNA expression at the in vitro blood-brain barrier during HIV infection. AB - Viral entry through the blood-brain barrier (BBB) has not been fully defined and identification of coreceptors that can facilitate this phenomenon is crucial in understanding disease progression. Using a RNAse protection assay to examine chemokine receptor families simultaneously, we analyzed the total RNA of in vitro BBB cultures treated with purified preparations of HIV gp120, gp41, TAT proteins and TNF-alpha. HIV tat protein affected CCRI and CCR3 mRNA expression whereas the other viral by-products had no effect. Interestingly, TNF-alpha was able to induce CCR1, CCR3 as well as CXCR1, CXCR2, CXCR4 receptors and Burkitt's lymphoma receptor BLR2. These results suggest that HIV-induced molecules can manipulate the surface receptor expression of the BBB to allow for their preferential entry into brain. PMID- 10094133 TI - No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population. AB - The serotonin hypothesis in schizophrenia had regained interest with the superior efficacy of clozapine in the refractory schizophrenic patients. Among the serotonin receptors, the serotonin 2A (5HT2A) receptor subtype is the most widely studied. Previous studies on the association between a silent mutation polymorphism of the 5HT2A gene (102T/C) and schizophrenia or clozapine response have yielded conflicting findings. Therefore, we investigated whether these genetic variants of the 5HT2A receptor are associated with schizophrenia or with response to clozapine treatment in a Chinese population. Ninety-seven schizophrenic patients and 101 control subjects were included in the study. The receptor variants were found at similar frequencies in schizophrenic patients and healthy control subjects. Also, we did not find the variants to influence the response to clozapine in schizophrenic patients. We suggest that the assessment method of clozapine response and the ethnicity may influence the result. PMID- 10094134 TI - Kynurenine aminotransferase I (KATI) isoform gene expression in the rat brain: an in situ hybridization study. AB - Kynurenine aminotransferase I (KATI) converts kynurenine into kynurenic acid (KYNA), a broadspectrum antagonist at ionotropic excitatory amino acid receptors. The main interest in KYNA centers on its potential neuroprotective action in physiological and pathological conditions. We show here by in situ hybridization that KATI mRNA is widely expressed throughout the adult rat brain. A strong autoradiographic signal was detected in the hippocampus, piriform cortex, and choroid plexus. Microscopic evaluation suggested that KATI mRNA was expressed not only in astrocytes but also in hippocampal neurons and in choroid plexus epithelial cells. Neuronal expression of KATI mRNA was further confirmed by RT PCR and in a model of transient cerebral ischemia. The expression pattern of the mitochondrial form (mKATI) of the enzyme was almost comparable to that of KATI. The major difference was observed in the choroid plexus where mKATI mRNA signal was very low. PMID- 10094135 TI - Synaptosomal glutamate release induced by the fraction Bc2 from the venom of the sea anemone Bunodosoma caissarum. AB - The effect of a fraction (Bc2) from the venom of the sea anemone Bunodosoma caissarum on [3H]glutamate release from rat cortical synaptosomes was investigated. Bc2 (2-20 microg/ml) provoked massive glutamate release without causing synaptosome disruption. Glutamate release stimulated by Bc2 was independent of extracellular Ca2+ and of voltage-sensitive Na+ channels, and it was completely abolished by the addition of sphingomyelin. No definitive evidence about the mechanism underlying the stimulatory effect of Bc2 is available as yet. However, a direct interaction with the exocytotic machinery cannot be ruled out. PMID- 10094136 TI - In vivo metabolism of nociceptin/orphanin FQ in rat hippocampus. AB - The in vivo metabolism of the newly identified endogenous ligand for the ORL1 receptor, the opioid-like peptide nociceptin (orphanin FQ) in rat hippocampus was studied using size-exclusion chromatography linked to electrospray ionization mass spectrometry. The results show that nociceptin is metabolized step-wise in vivo into fragments (1-13) and (14-17) as well as (1-9) and (10-13), respectively. Interestingly, the (1-13) and (1-9) fragments have the same C terminus, Arg-Ala-Lys, suggesting that this is a motif recognized by an enzyme which fragments the peptide in two consecutive steps. Injection of the (1-13) fragment into rat hippocampus had no effect on spatial learning or motor function under conditions where nociceptin is active, showing that this metabolic conversion reduces affinity for the ORL-1-receptor. PMID- 10094137 TI - Enhanced acetylcholine release in striatum after chronic amphetamine is NMDA dependent. AB - Behavioral sensitization to chronic amphetamine develops in parallel with an enhancement of amphetamine-stimulated efflux of acetylcholine (ACh) in striatum. The present study investigated the role of NMDA receptors in the latter phenomenon. Rats were treated with either saline (1.0 ml/kg, i.p.) or amphetamine (4.0 mg/kg, i.p., b.i.d.) for 12 days followed by a withdrawal period of 2-3 weeks. In vivo microdialysis was employed to measure striatal ACh efflux. Amphetamine challenge (4.0 mg/kg, i.p.) evoked a significant increase in striatal ACh efflux in rats withdrawn from chronic amphetamine while having no significant effect on ACh efflux in saline-pretreated rats. Inclusion of the NMDA receptor antagonist (+/-)-2-amino-5-phoshonopentanoic acid (APV; 100 microM) in the perfusion solution blocked the amphetamine-induced increase in striatal ACh efflux observed in amphetamine-pretreated rats. In saline-pretreated animals, the presence of APV had no apparent effect on the profile of striatal ACh efflux following amphetamine challenge. Thus, the stimulatory effect of amphetamine challenge on striatal ACh efflux that selectively is observed in animals withdrawn from chronic amphetamine is dependent upon NMDA receptor activation. PMID- 10094138 TI - Effect of neostigmine on the hippocampal noradrenaline release: role of cholinergic receptors. AB - The effect of the cholinesterase inhibitor neostigmine on hippocampal noradrenaline (NA) release was studied using in vivo microdialysis. Local application of neostigmine significantly increased the release of NA. The effect was potentiated by coperfusion of the nicotinic antagonist mecamylamine but was completely blocked by the muscarinic antagonist atropine. The neostigmine-evoked NA release was not affected by the M2-selective muscarinic antagonist gallamine but was completely blocked by the M1-selective muscarinic antagonist pirenzepine. While muscarinic antagonists had no effect on the resting release of NA, mecamylamine increased it. Our data indicate that acetylcholine can stimulate the hippocampal NA release via M1 muscarinic receptors and that a population of nicotinic receptors mediate inhibitory tone on hippocampal NA release. The fact that neostigmine is able to enhance both cholinergic and noradrenergic neurotransmission may help to understand the beneficial effect of cholinesterase inhibitors in Alzheimer's disease. PMID- 10094139 TI - Spinal cord ischemia reduces mu-opioid receptors in rats: correlation with morphine insensitivity. AB - The present study examined the effects of spinal cord ischemia on the expression of mu-opioid receptors in rat dorsal spinal cord and the effects of intrathecal (i.t.) morphine on the acute mechanical allodynia that developed after spinal ischemia. The mechanical allodynia was not significantly alleviated by up to 10 microg i.t. morphine, a dose which caused strong antinociception in the tail flick test. Immunohistochemical staining demonstrated that the level of mu-opioid receptor expression in the dorsal horn of spinal cord segments receiving input from the allodynic skin was markedly reduced 2 days after ischemia, when the rats were allodynic. The results indicate that spinal cord ischemia reduces the expression of mu-opioid receptors in rat dorsal horn, which may be one of the underlying mechanisms of morphine insensitivity for treating acute allodynia after spinal ischemia. PMID- 10094140 TI - Grape polyphenols protect neurodegenerative changes induced by chronic ethanol administration. AB - Increased oxidative stress in the brain due to chronic ethanol consumption is known to result in a number of neurodegenerative changes. This study was designed to test whether dietary supplementation of grape polyphenols (GP) can offer protection to the neurodegenerative changes resulting from chronic ethanol consumption. Sprague-Dawley rats were fed a Leiber-DeCarli liquid diet with ethanol or isocaloric amount of maltose, and with or without GP for 2 months. Chronic ethanol caused significant decreases in synaptosomal Na,K-ATPase (20.5%) and dopamine uptake (22.8%) activities compared with pair-fed controls. Although GP alone did not alter activities of these membrane-bound proteins, GP supplementation was able to completely protect the decrease in synaptic protein function elicited by chronic ethanol consumption. PMID- 10094141 TI - Differential alcohol modulation of GABA(A) and NMDA receptors. AB - NMDA and GABA(A) receptors are believed to be important CNS targets of alcohol action. In mouse hippocampal neurons, n-alcohols from ethanol to dodecanol enhanced GABA-activated ion current, whereas higher alcohols had no effect. Alcohols below pentanol affected NMDA receptors more potently than GABA(A) receptors. Increasing alcohol carbon chain length produced a greater average change in apparent binding energy and potency for modulation of GABA(A) than of NMDA receptor-channels, with the result that alcohols above pentanol affected GABA(A) receptors more potently than NMDA receptors. The anesthetic potency of n alcohols in rats more closely reflected NMDA receptor modulatory potency for lower alcohols and GABA(A) receptor modulatory potency for higher alcohols. The results suggest that there may be fundamental differences in the sites through which alcohols affect NMDA and GABA(A) receptor function. PMID- 10094143 TI - Recombinant tissue plasminogen activator reduces infarct size after reversible thread occlusion of middle cerebral artery in mice. AB - It has been suggested that tissue plasminogen activator (tPA), which is widely used for the thrombolytic treatment of stroke, exhibits neurotoxic side effects. To test this hypothesis, mice exposed to 90 min nonthrombotic middle cerebral artery thread occlusion were treated with 10 mg/kg recombinant tPA (rt-PA) at 15 min after the onset of vascular occlusion. Measurements of blood flow, infarct volume, brain swelling and neurological performance revealed faster recirculation and a significant reduction of ischemic injury in rt-PA-treated animals. These data are at variance with previous reports on tPA neurotoxicity and demonstrate, on the contrary, that tPA protects the brain even after non-thrombotic vascular occlusion. PMID- 10094142 TI - Tolerance develops to the inhibitory effect of orphanin FQ on morphine-induced antinociception in the rat. AB - Recent studies that intracerebroventricular (i.c.v.) administration of orphanin FQ (OFQ) blocks opioid-induced antinociception in a variety of animal models of pain. In the present study, we sought to investigate the inhibitory effect of OFQ on morphine-induced antinociception using the hot plate test in rats and to examine whether tolerance develops to the anti-opioid effect of the peptide. Microinjection of OFQ (50nmol, i.c.v.) significantly attenuated the antinociceptive effect of morphine without affecting baseline hot plate latencies, suggesting that modification of morphine-induced antinociception can be achieved via activation of the ORL-1 receptor by OFQ with no apparent mu opioid receptor blockade or interference with basal nociceptive responses. Chronic treatment with OFQ (50 nmol/day for 5 days) produced a complete loss of the inhibitory effect of the peptide indicating that tolerance developed to the anti-opioid effect of OFQ. Taken together, these results indicate that neuronal plasticity may occur following chronic use of OFQ as is evident for the other opioid agonists. PMID- 10094144 TI - C-terminal fragment of Alzheimer's amyloid precursor protein inhibits sodium/calcium exchanger activity in SK-N-SH cell. AB - Numerous lines of evidence suggest that some of the neurotoxicity associated with Alzheimer's disease (AD) is due to proteolytic fragments of the amyloid precursor protein (APP). Most research has focused on the amyloid beta peptide (Abeta). However, the possible role of other cleaved products of APP is less clear. We have previously shown that a recombinant carboxy-terminal 105 amino acid fragment (CT 105) of APP induced strong non-selective inward currents and also showed neurotoxicity in PC 12 cells and primary cortical neurons and blocked later phase of long term potentiation (LTP) in rat hippocampus in vivo. In this study, we investigated the effects of CT 105 on Na+-Ca2+ exchanger activity in SK-N-SH human neuroblastoma, in the presence of ouabain and monensin, which are considered to drive Na+-Ca2+ exchanger in the reverse mode. CT 105 inhibited the activity of this exchanger in SK-N-SH cells by approximately 50%. PMID- 10094145 TI - Neural features of recovery from CNS injury revealed by PET in human brain. AB - Dysfunction of the brain occurring after local brain injury often improves clinically; however, the reason for this improvement has not been scientifically clarified. We used a new technique for imaging phosphoinositide turnover, carbon 11-labeled diacylglycerol-positron emission tomography, to observe the process of recovery from injury in human brain. Patients with local brain injury exhibited radioactive spots located in the association areas distant from the lesion, while normal controls did not exhibit such spots. These findings indicated one of possible features of the neural recovery from the central nervous system injury, which appears to play a role in modulation of synaptic transmission in the intact brain. Conventionally, attention has been directed primarily to areas surrounding brain injury, such as the penumbra; however, the present study suggests that initiation of reorganization of neural connections occurs in remote cortex. PMID- 10094146 TI - Decay of cortical pre-attentive sound discrimination in middle-age. AB - Ageing effects on pre-attentive cortical detection of sound change, as indexed by magnetic mismatch negativity (MMNm), were disclosed with whole-head magnetoencephalography (MEG). Seventy healthy subjects (aged 17-82 years) were presented with a sequence of homogeneous standard tones and occasional deviants of shorter duration. The MMNm elicited by the shorter tones was diminished in amplitude (r = -0.42, p < 0.001) and increased in latency in the hemisphere ipsilateral to the ear stimulated (r = 0.38, p < 0.01), these effects being significant even in middle-aged subjects. The results suggest that pre-attentive comparison of incoming stimuli to a short-lived sensory memory trace in the central auditory system is impaired, and delayed in the ipsilateral hemisphere, already by the middle-age. PMID- 10094147 TI - Beta-amyloid levels predict cholinesterase activity in human cerebrospinal fluid. AB - There is increasing evidence suggesting that beta-amyloid (Abeta) has a direct influence on cholinergic activity. In particular, Abeta has been shown to induce the expression of acetylcholinesterase in the brains of CT-100-expressing transgenic mice and in cell culture experiments. These data indicate a link exists between Abeta production and acetylcholinesterase expression in the human CNS. To test this hypothesis, Abeta levels and cholinesterase activity were measured in 110 human CSF samples. Abeta levels were found to have a significant and positive correlation with cholinesterase activity. This correlation was particularly strong in individuals > 50 years of age. These data support the hypothesis that Abeta can effect cholinergic activity and that this effect may be enhanced in the elderly. PMID- 10094148 TI - Improved recovery after spinal cord trauma in ICAM-1 and P-selectin knockout mice. AB - Traumatic spinal cord injury is followed by infiltration of leukocytes, influenced by endothelial adhesion molecules such as ICAM-1 and P-selectin. In order to evaluate the pathogenetical role of these molecules, wild-type mice and mice lacking ICAM-1 and P-selectin were subjected to an experimental spinal cord compression of two degrees of severity. Hind limb motor function decreased after injury in all animals but the groups of injured ICAM-1/P-selectin knockout animals had a better functional outcome during the entire observation period of 14 days. This difference was statistically significant on day 1. Our results indicate that adhesion molecules influence the functional outcome after spinal cord injury in a negative way and may be a target for future therapy of neurotrauma. PMID- 10094149 TI - When a rubber hand 'feels' what the real hand cannot. AB - We examined a patient who was clinically much better at reporting tactile stimulation when he could see his stimulated hand. Experimentally, we found that he had difficulty detecting taps accompanied by a salient (but not predictive) light located directly above his concealed hand. However, his performance was dramatically improved if the light was attached to a rubber hand situated in line with the patient's hidden hand. Previous studies have suggested that tactile sensitivity can be improved by nearby visual stimulation. However, our effect shows that crossmodal sensory facilitation does not only depend upon simple spatial proximity alone. Rather, a simultaneous visual event dramatically improves perception of touch specifically when it is attributed to the perceiver's stimulated limb. PMID- 10094150 TI - Atypical temporal lobe language representation: MEG and intraoperative stimulation mapping correlation. AB - Functional brain imaging techniques hold many promises as the methods of choice for identifying areas involved in the execution of language functions. The success of any of these techniques in fulfilling this goal depends upon their ability to produce maps of activated areas that overlap with those obtained through standard invasive procedures such as electrocortical stimulation. This need is particularly acute in cases where active areas are found outside of traditionally defined language areas. In the present report we present two patients who underwent mapping of receptive language areas preoperatively through magnetoencephalography (MEG) and intraoperatively through electrocortical stimulation. Language areas identified by both methods were located in temporoparietal regions as well as in less traditional regions (anterior portion of the superior temporal gyrus and basal temporal cortex). Importantly there was a perfect overlap between the two sets of maps. This clearly demonstrates the validity of MEG-derived maps for identifying cortical areas critically involved in receptive language functions. PMID- 10094151 TI - The popout in some conjunction searches is due to perceptual grouping. AB - The target in a visual search task usually pops out if it can be distinguished from its background on the basis of only one visual feature but not if the target represents a conjunction of two or more features. However, several recent reports suggest that in certain cases, search targets defined by a conjunction of two features also pop out. We have reinvestigated three pairs of such features to determine whether the popout in these cases can be attributed to perceptual grouping. We find that that in all three cases, popout no longer occurs when perceptual grouping is degraded, suggesting that the popout is the result of perceptual grouping and not of novel mechanism/s of conjunction search. PMID- 10094152 TI - Long-term retention of classical eyeblink conditioning in amnesia. AB - The retention of classical eyeblink conditioning was investigated in amnesic patients 10 days and 2 months after original learning. During reacquisition, the first CR occurred earlier and the CR frequencies during the first 10 trials were higher than in the baseline session. The overall CR rates increased significantly across sessions during both acquisition and extinction. The amnesics did not differ from matched controls on any of these effects, although they did not recall previous conditioning sessions and did not become fully aware of CS-US contingencies. The smaller number of electrodermal responses to the CS tone during extinction in the amnesics may relate to their lack of insight into the change in the reinforcement schedule. PMID- 10094153 TI - Intracerebroventricular injection of lipopolysaccharide increases plasma leptin levels. AB - Leptin regulates adiposity by reducing caloric intake and increasing energy expenditure. Because loss of body weight is common during infectious, neoplastic, and autoimmune diseases of the central nervous system, we examined whether an injection of lipopolysaccharide (LPS) into the lateral cerebral ventricle increases circulating leptin levels in fasted mice. Centrally injected LPS (100 ng) induced a two-fold elevation in plasma leptin 6, 12, and 18 h post-injection. Peripheral injection of the same dose of LPS did not affect leptin secretion. This suggests that inflammatory stimuli localized in the CNS are sufficient to induce leptin secretion in the periphery. The induction of leptin by inflammatory stimuli in the brain may be part of a feed-back loop that contributes to anorexia and cachexia in many CNS-oriented diseases. PMID- 10094154 TI - Evidence for regulation of vasopressin gene transcription by the NMDA receptor. AB - We investigated the effects of dizocilpine maleate (MK-801), an NMDA receptor antagonist, on arginine vasopressin heterogeneous nuclear RNA expression in the supraoptic nucleus in the rat hypothalamus. MK-801 treatment completely blocked the osmotic stimulus-induced increase in AVP hnRNA expression, but had no effect on basal AVP hnRNA expression in the SON. These observations indicate that the NMDA receptor is essential for regulation of AVP gene transcription in response to osmotic stimulation, but has no effect on steady-state AVP gene transcription. PMID- 10094155 TI - Neuroprotective effects of Gly-Pro-Glu, the N-terminal tripeptide of IGF-1, in the hippocampus in vitro. AB - Insulin-like growth factor 1 (IGF-1) plays a critical role in CNS development. IGF-1 can block neuronal apoptosis in vitro and in vivo. IGF-1 is thought to be cleaved into des-N-(1-3)-IGF-1 and an amino terminal glycine-proline-glutamate (GPE tripeptide). Here we report a neuroprotective role for GPE tripeptide, with enhanced survival of the CA1-2 hippocampal neurons following an excitotoxic insult in vitro. Binding and displacement studies suggest uniquely distributed sites of action within the rat including the hippocampal CA1-2, pyriform cortex, amygdala, choroid plexus, blood vessels and to a lesser extent in the cortical regions. A similar pattern of binding was seen in the human. This finding could lead to new strategies to reduce neuronal death after injury and in disease. PMID- 10094156 TI - Auditory-vocal cholinergic pathway in zebra finch brain. AB - The two main song control nuclei in the zebra finch forebrain, the higher vocal center (HVC) and the robust nucleus of the archistriatum (RA), receive cholinergic innervation from the ventral paleostriatum (VP) of the basal forebrain which may play a key role in song learning. By injecting two kinds of neuroanatomical tracers, we found that a topographically segregated pathway from nucleus ovoidalis (Ov) and nucleus dorsomedialis posterior thalami (DMP) to VP and further to RA and HVC. Ov is known as a major relay in the main ascending auditory pathway. The results suggest that cholinergic neurons in the VP which are responsible for song learning are regulated by auditory information from the Ov. PMID- 10094157 TI - Light-dependent suppression of the vestibulo-ocular reflex during development. AB - In the fish Oreochromis mossambicus, light conditions affect the development of the roll-induced vestibuloocular reflex (rVOR). During development under continous light-dark conditions the rVOR amplitude, which is the maximum eye movement during a complete 360 degrees lateral roll, shows a secondary drop after a first peak at stage 17 by 64% (36.3 degrees at stage 17; 13.0 degrees at stage 20). This drop was shifted by 2 stages to older postembryonal stages and was 33% (29.2 degrees at stage 20; 19.5 degrees at stage 22) less pronounced in animals which were exposed to complete darkness for several days. Because the period of rVOR diminution is sensitive to light conditions, it is likely that outgrowing visual projection fibres reorganize the neuronal network underlying visual vestibular behavior thus transiently suppressing the rVOR. PMID- 10094158 TI - Brain energy stores in C57BL/6 mice after C. parvum injection. AB - Activation of the immune system has been associated with the development of fatigue of unknown cause. We were interested in brain energy stores (e.g., phosphocreatine (PCr) and creatine kinase) after immune activation to investigate whether this system was altered. In this model, fatigue (defined as > 50% reduction in spontaneous running) was induced in C57BL/6 mice after a single injection of Corynebacterium parvum antigen. Maximal fatigue (about 86% reduction on day 10 post injection) was associated with reduced (about 29%) brain PCr/gamma ATP and increased creatine kinase levels (approximately 31%), suggesting an active process of brain ATP depletion and replenishment. These findings need to be further delineated to establish the relationship between immune activation, reduced brain energy pools and fatigue. PMID- 10094159 TI - The fusiform face area is selective for faces not animals. AB - To test whether the human fusiform face area (FFA) responds not only to faces but to anything human or animate, we used fMRI to measure the response of the FFA to six new stimulus categories. The strongest responses were to stimuli containing faces: human faces (2.0% signal increase from fixation baseline) and human heads (1.7%), with weaker but still strong responses to whole humans (1.5%) and animal heads (1.3%). Responses to whole animals (1.0%) and human bodies without heads (1.0%) were significantly stronger than responses to inanimate objects (0.7%), but responses to animal bodies without heads (0.8%) were not. These results demonstrate that the FFA is selective for faces, not for animals. PMID- 10094160 TI - Stimulus inversion and the responses of face and object-sensitive cortical areas. AB - Behavioral and neuropsychological studies suggest that upright and inverted face stimuli are processed by computationally and anatomically distinct systems. Specifically, inverted faces seem to be addressed by general object perception systems, avoiding face-specific processes. We tested this model by examining the fMRI signal response of a functionally defined fusiform face area and bilateral object-responsive cortical areas during the perception of upright and inverted stimuli (faces and cars). While inversion of face stimuli had no effect upon the magnitude of responses in the fusiform face area, inverted faces evoked greater neural responses compared to upright faces within object regions. This finding supports the assertion that object areas are involved to a greater degree in the perception of inverted vs upright faces. PMID- 10094161 TI - The functional anatomy of the McCollough contingent colour after-effect. AB - We report two functional magnetic resonance imaging (fMRI) experiments which reveal a cortical network activated when perceiving coloured grids, and experiencing the McCollough effect (ME). Our results show that perception of red black and green-black grids activate the right fusiform gyrus (area V4) plus the left and right lingual gyri, right striate cortex (V1) and left insula. The ME activated the left anterior fusiform gyrus as well as the ventrolateral prefrontal cortex, and in common with colour perception, the left insula. These data confirm the critical role of the fusiform gyrus in actual and illusory colour perception as well as revealing localized frontal cortical activation associated with the ME, which would suggest that a 'top-down' mechanism is implicated in this illusion. PMID- 10094162 TI - DOTS and drug resistance: a silver lining to a darkening cloud. PMID- 10094163 TI - Low levels of drug resistance amidst rapidly increasing tuberculosis and human immunodeficiency virus co-epidemics in Botswana. AB - SETTING: Botswana, southern Africa, where the tuberculosis (TB) case rate increased by 120% from 1989 to 1996 in spite of a decade of implementation of the directly observed therapy, short-course (DOTS) strategy. OBJECTIVE: To determine prevalence of and risk factors for drug-resistant tuberculosis in an epidemic setting. DESIGN: Systematic national random survey of newly diagnosed pulmonary TB and all patients with TB requiring retreatment during 1995-1996. Interviews were conducted, human immunodeficiency virus (HIV) testing was offered, and drug susceptibility testing was performed for isoniazid, rifampicin, streptomycin and ethambutol. RESULTS: Resistance to at least one drug was identified in 16 (3.7%) new cases and 18 (14.9%) retreatment cases. One (0.2%) new and seven (5.8%) retreatment cases had resistance to at least both isoniazid and rifampicin (multidrug-resistant TB). Retreatment cases with multidrug-resistant TB were significantly more likely to have worked in the mines in South Africa than were cases with fully susceptible isolates (6/7 [85.7%] versus 32/ 103 [31.1%], odds ratio 13.3, 95% confidence interval 1.5-311.0, P = 0.007). Of 240 patients tested for HIV, 117 (48.8%) were positive; prevalence was similar among new and retreatment cases, and was not a risk factor for drug resistance in either group. CONCLUSION: During the HIV and TB co-epidemics in sub-Saharan Africa, DOTS may help to control drug-resistant TB. However, the TB case rate can be expected to continue to climb in spite of the implementation of the DOTS strategy. PMID- 10094164 TI - Risk factors for tuberculosis in patients with AIDS in London: a case-control study. AB - OBJECTIVE: To identify risk factors for the acquired immune-deficiency syndrome (AIDS) associated with tuberculosis, in patients with AIDS attending 11 of the largest human immunodeficiency virus (HIV)/AIDS Units in London. DESIGN: Case control study nested in a retrospective cohort of 2048 HIV-1 positive patients. Cases were defined as patients with a definitive diagnosis of tuberculosis, and controls as patients with AIDS and without tuberculosis during follow-up. RESULTS: Of 627 patients diagnosed with AIDS, 121 had a definitive diagnosis of tuberculosis. Significant risk factors for tuberculosis in the univariate analysis were sex, ethnicity, age, HIV exposure category and hospital attended, and in the multiple regression analysis ethnicity, age and hospital attended. African ethnicity was the strongest risk factor for tuberculosis (adjusted odds ratio [AOR] 5.9, 95% confidence interval 3.4-10.2). The risk of tuberculosis was higher in the younger age groups (test for trend P < 0.001). The hospital associated risk of tuberculosis was more heterogeneous in the non-African group, and non-Africans attending Hospital 1 had an increased risk of tuberculosis which was statistically significant. CONCLUSIONS: The risk factors for AIDS-associated tuberculosis in London are sub-Saharan African origin, younger age group, and, among the non-Africans only, attending one hospital in east London. Different transmission patterns and mechanisms for the development of tuberculosis may operate in different settings depending on the background risk of tuberculous infection. Screening for tuberculosis infection and disease among HIV-positive individuals in London is important for the provision of preventive or curative therapy, and prophylaxis policies need to be designed in accordance with the transmission patterns and mechanisms of disease. PMID- 10094165 TI - Incidence of tuberculosis in a community of Senegalese immigrants in Northern Italy. AB - SETTING: Tuberculosis is the world's foremost cause of death from a single infectious agent among adults. Although morbidity and mortality rates are highest in low income countries, industrialized countries have also faced a recent resurgence of the tuberculosis epidemic. In Europe and the United States increasing tuberculosis incidence rates are observed, particularly among persons with the human immunodeficiency virus infection and immigrants from highly endemic countries. OBJECTIVE: To measure the incidence of tuberculosis in a retrospective cohort of Senegalese immigrants in a closed community. DESIGN: During 1991, 721 of 794 (91%) community residents were actively screened using the tuberculin skin test and chest X-ray. In 1995 the out-patient clinical charts and the tuberculosis notification registers were reviewed to determine tuberculosis incidence. RESULTS AND CONCLUSION: A total of 328 subjects (45.4% of those screened) was retrospectively followed for a cumulative period of 10 147 months. Ten cases of active tuberculosis were detected. The annual incidence rate for tuberculosis was 11.8/1000, compared to 15.1/ 100 000 in the general population. Tuberculosis incidence was similar in subjects with a positive (12.3/1000), compared to a negative baseline tuberculin test (12.5/1000). Tuberculosis incidence is very high, and recent infections might account for a substantial proportion of cases among immigrants living in closed communities. PMID- 10094166 TI - Tuberculin reactivity in a pediatric population with high BCG vaccination coverage. AB - SETTING: The tuberculin skin test (TST) is often included in diagnostic algorithms for tuberculosis (TB) in children. TST interpretation, however, may be complicated by prior Bacillus Calmette-Guerin (BCG) vaccination. We assessed the prevalence of and risk factors for positive TST reactions in children 3 to 60 months of age in Botswana, a country with high TB rates and BCG coverage of over 90%. METHODS: A multi-stage cluster survey was conducted in one rural and three urban districts. Data collected included demographic characteristics, nutritional indices, vaccination status, and prior TB exposure. Mantoux TSTs were administered and induration measured at 48-72 hours. RESULTS: Of 821 children identified, 783 had TSTs placed and read. Of the 759 children with vaccination cards, 755 (99.5%) had received BCG vaccine. Seventy-nine per cent of children had 0 mm induration, 7% had > or =10 mm induration ('positive' TST), and 2% had > or =15 mm. A positive TST was associated with reported contact with any person with active TB (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.02-3.6), or a mother (OR 5.1; 95% CI 2.1-12.4) or aunt (OR 5.3; 95% CI 2.0-14.0) with active TB. TSTs > or =5 mm (but not > or =10 mm) were associated with presence of a BCG scar. Positive reactions were not associated with age, time since BCG vaccination, clinical signs or symptoms of TB, nutritional status, crowding, or recent measles or polio immunization. CONCLUSION: The TST remains useful in identifying children with tuberculous infection in this setting of high TB prevalence and extensive BCG coverage. PMID- 10094167 TI - Prevalence and factors associated with tuberculosis infection among new school entrants, New York City, 1991-1993. AB - SETTING: New York City public (or state-run) and private schools-elementary and secondary. OBJECTIVE: To describe the prevalence and determine factors associated with positive tuberculin skin tests (TSTs) in school children. DESIGN: Mandatory TST surveys among cohorts of new school entrants for the 1991, 1992 and 1993 school years, of whom birthplace was known for 81%. A positive tuberculin skin test defined as > or =10 mm induration. RESULTS: Of the 298506 new school entrants, 2.1% (6326) were tuberculin test positive. The proportion that was tuberculin test positive was 0.5% (931/199 728) among US-born and 9.2% (3794/41 346) among foreign-born students. Foreign-born (FB) students with a history of BCG vaccination were much more likely to have a positive tuberculin test than US born students (13.6% vs. 0.5%, odds ratio [OR] = 33.6, 95% confidence interval [CI] 31.7, 35.6), and were more likely to have a positive tuberculin test than FB students with no history of BCG (13.6% vs. 4.4%, OR = 3.4, 95% CI 2.5, 4.6). Older age was independently associated with tuberculin test positivity, except among foreign-born BCG-vaccinated children, in whom the youngest were more likely to have a positive tuberculin test. CONCLUSIONS: Even in the midst of a tuberculosis resurgence such as that experienced by New York City, where tuberculosis cases nearly tripled from 1978 to 1992, the risk of tuberculosis infection among school children remained quite low. Given the reduced predictive value of the tuberculin test among low risk children and the effects of BCG vaccination, many children (especially younger children) with positive tuberculin test results are probably not infected with Mycobacterium tuberculosis. To reduce unnecessary evaluation and treatment, routine tuberculin tests should be administered only to high risk groups such as older children from countries with high rates of tuberculosis. PMID- 10094168 TI - Replacement of streptomycin by ethambutol in the intensive phase of tuberculosis treatment: no effect on compliance. AB - SETTING: Seven tuberculosis clinics in the National Tuberculosis Programme of Madagascar. OBJECTIVE: To compare the treatment efficacy and tolerance of regimens including either streptomycin or ethambutol for patient compliance during initial treatment of smear-positive tuberculosis. DESIGN: The 1023 patients included in the study were randomly divided into two treatment groups one to receive streptomycin (S), isoniazid (H), rifampicin (R) and pyrazinamide (Z) (SHRZ), and the other to receive EHRZ, where streptomycin was replaced by ethambutol (E). During the 2-month intensive phase, drug delivery was completely supervised. The same 6-month continuation regimen was then given in both groups. Follow-up consisted of a clinical and bacteriological examination at the end of the second, fifth and eighth months. RESULTS: There was no significant difference between the two regimens as regards compliance with treatment, the number of patients lost or who died, or for bacteriological response during the intensive phase. EHRZ was better tolerated. During the continuation phase, the results of the two groups remained comparable, but treatment failures occurred earlier in the patients who had received streptomycin. CONCLUSION: Patient compliance was not better with streptomycin. The ethambutol-containing regimen was as efficient as the other, and better tolerated. There is no argument for preferring streptomycin in the intensive phase of treatment of smear-positive tuberculosis. PMID- 10094169 TI - Prednisolone: a beneficial and safe adjunct to antituberculosis treatment? A randomized controlled trial. AB - SETTING: A referral centre for thoracic diseases in Izmir, Turkey, 1992-1995. OBJECTIVE: To appraise the adjunctive role of prednisolone (PN) in pulmonary tuberculosis (PTB) with toxic reactions. DESIGN: After excluding other febrile causes, and 2 weeks of four/five-drug antituberculosis therapy insufficient to resolve toxic reactions, 178 human immunodeficiency virus (HIV) negative patients with advanced PTB causing persistent high-grade fever (> or =38 degrees C), weight loss (> or =2 kg/week) and/or low serum albumin levels (<3 g/dL) were randomly allocated to receive either a 12-month course of antituberculosis treatment using four first-line drugs and PN (20 mg b.i.d. IV/IM initially, decreasing over 40 days) (91 patients-PN group), or 12 months of antituberculosis treatment only (87 patients-CO group). Twice-weekly sputum bacillary count, temperature recorded every 6 hours, weekly weight, serial albumin level and liver function measurements and chest roentgenograms were used to assess the effects of PN on PTB. RESULTS: Temperature decreased from 39.1+/-0.9 degrees C to 37.9+/-0.7 degrees C (P = 0.0030) within the first 72 (+/-9) hours in those patients on PN treatment, whereas a gradual decline occurred over 22 (+/-3) days in the CO group. In the PN group, patients' weight increased from 49.7+/-4.8 kg to 56.9+/ 8.3 kg, compared to 47.1 +/- 6.4 kg to 51.31+/-5.9 kg in the CO group (P = 0.0022). Increases in serum albumin levels in the PN and CO groups were from 2.26+/-0.8 g/dL to 3.32+/-0.6 g/dL and from 2.31+/-0.5 g/dL to 2.90+/-0.7 g/dL, respectively (P = 0.0035). The radiographic regression and drop in bacillary count were more rapid, and the hospital stay shorter (53.4+/-3.1 days vs 71.3+/ 5.6 days) in the PN group, although there were no differences in the acid-fast bacilli conversion rates. There were no detrimental side effects and relapses attributable to PN during the 1-3 year follow-up, even in 18 cases with drug resistance. CONCLUSION: Prednosolone is a beneficial and safe adjunct to 12-month antituberculosis treatment in advanced PTB causing toxic reactions, provided that close clinical, radiographic and bacillary monitoring is exercised. PMID- 10094170 TI - Quality control of smear microscopy for acid-fast bacilli: the case for blinded re-reading. AB - SETTING: Quality control of sputum smear microscopy, which is essential for ensuring correct tuberculosis (TB) diagnosis, is often performed through the unblinded rereading of all positive slides and a sample of negative slides. OBJECTIVE: To assess misclassification error introduced by knowledge of prior results. METHODS: The Southern Vietnam Regional TB Laboratory prepared three gold standard sets of 750 slides: an unblinded set, an unblinded set in which 13% of negative slides were replaced by weakly positive slides purposefully mislabelled as negative, and a blinded set. Six provincial technicians who normally perform district quality control each reread 125 slides from each set. RESULTS: In the three sets only one negative slide was misread as positive. In the unblinded set (referent), 2.9% (9/311) positive slides were misread as negative, compared with 18.7% (57/305) in the blinded set (prevalence ratio [PR] = 6.5; 95% confidence interval [CI] 3.3-12.8; P < 0.001), and 11.3% (33/293) in the unblinded set with mislabelled slides (PR = 3.9; 95%CI 1.9-8.0; P < 0.001). CONCLUSIONS: False negative error was more common than false-positive error. Knowledge of prior reading influences re-reading. Blinded re-reading of systematically selected slides would appear preferable, although this method requires high levels of proficiency among quality control technicians. PMID- 10094171 TI - The validity of acid-fast smears of gastric aspirates as an indicator of pulmonary tuberculosis. AB - SETTING: A tuberculosis referral hospital in Canada. OBJECTIVE: To determine the validity of acid-fast (AFB) smears of gastric aspirates (GA) in the diagnosis of pulmonary tuberculosis, and to assess the prevalence of nontuberculous mycobacteria (NTM) in GA isolates from such patients. DESIGN: A retrospective case review of our experience with AFB smears (Kinyoun) and cultures of GA and sputum over a 3-year period. RESULTS: From 1994 to 1996 inclusive, 1155 GA were performed in 889 patients. Mycobacteria were cultured from 109 (9%) GA. Thirteen of these were positive on smear (sensitivity 19%). All GA that were positive on smear were culture positive for Mycobacterium tuberculosis. There were no false positive smears (specificity 100%). The sensitivity and specificity of the sputum smear were 45% and 99%, respectively. Of the 96 culture positive, smear negative GA, 54 grew M. tuberculosis and 42 grew an NTM. Of 13 patients who had sputum and GA studied coincidentally, and in whom the sputum was both smear and culture positive, the GA culture was positive in 13 and the smear was positive in eight (66%). CONCLUSION: AFB smear of GA is a relatively insensitive but highly specific indicator of pulmonary tuberculosis warranting institution of antituberculosis treatment. Gastric AFB smear positivity appears to reflect a high bacillary burden within the respiratory tract. PMID- 10094173 TI - A survey of prescribing patterns for tuberculosis treatment amongst doctors in a Bolivian city. AB - SETTING: A sample survey of knowledge about prescribing tuberculosis treatment among private physicians in the city of Santa Cruz, Bolivia. OBJECTIVES: To study the anti-tuberculosis regimens prescribed by private physicians and to assess the number of tuberculosis patients treated by them. DESIGN: Questionnaire survey of a random sample of 401 private physicians in Santa Cruz. RESULTS: Of the 401 physicians, 165 (41%) could not be located or did not want to participate. Among the 236 completed questionnaires, 137 physicians (58%) stated that they did not see patients with tuberculosis, 16 (7%) referred them to other centres and 83 (35%) treated them in their practice. Among 80 prescribed regimens that could be evaluated there were 58 different regimens: 17 (21%) followed the National Tuberculosis Control Programme's standard regimen, but overall 35 regimens (60%) were incorrect-18 regimens (31%) were non-curative and 17 (29%) could not be recommended. Frequent errors were the prescription of medications not available in the market (7%) or not included in the national regimen (34%), the prescription of insufficient medications (9%), or of only one in the continuation phase (16%), or for too short (9%), or too long (12%) a period. Eighty physicians estimated that they attended in their practice an average total of 404 patients with tuberculosis per month. CONCLUSIONS: A significant number of physicians in private practice did not adhere to the standard norms for prescribing anti tuberculosis treatment. This study also suggests that in the city of Santa Cruz, Bolivia, there is a not insignificant number of patients with tuberculosis treated outside the National Tuberculosis Control Programme. PMID- 10094172 TI - Mycobacterium kansasii infection in a Paris suburb: comparison of disease presentation and outcome according to human immunodeficiency virus status. Groupe dEtude Des Mycobacteries de la Seine-Saint-Denis. AB - SETTING: Department of Seine-Saint-Denis, France. OBJECTIVE: To compare the presentation and outcome of Mycobacterium kansasii infections according to human immunodeficiency virus (HIV) status. DESIGN: Retrospective analysis of all the medical charts of adults meeting the diagnostic criteria of the American Thoracic Society for M. kansasii infection between 1991 and 1995. RESULTS: Between 1991 and 1995, 35 cases (23 HIV-[6%] and 12 HIV+ [34%]) were found, giving an annual incidence of 0.5/100000. The following particularities were common to both groups: 1) frequency and prominence of respiratory and general symptoms, 2) rarity of clinically apparent extra-thoracic involvement, 3) bacteriological confirmation mostly obtained with respiratory tract specimens, 4) favourable bacteriological outcome, and 5) low mortality attributable to the mycobacterial infection. The most striking differences concerned chest radiography: HIV- patients had apical cavitated and nodular lesions, while HIV+ patients exhibited a variety of other patterns, including alveolar infiltrates, miliary lesions and/or thoracic lymphadenopathy. CONCLUSION: Apart from pulmonary radiographic differences, presentation and short-term outcome of M. kansasii infections were similar in HIV+ and HIV-patients. PMID- 10094174 TI - High compliance in an ambulatory tuberculosis treatment programme in a rural community of Uganda. AB - The increasing numbers of clinical tuberculosis in Uganda, mainly due to the human immunodeficiency virus (HIV) epidemic, means that it is no longer possible to hospitalise all TB patients, and the feasibility of ambulatory treatment needs to be assessed. A successful ambulatory TB treatment programme has been implemented in Rakai district. An annual cohort analysis for the period 1992-1996 showed that high completion rates were achieved. Of a total of 1659 TB patients, 92% of those surviving completed the prescribed treatment. Reasons for this high completion rate included: treating patients at one health unit, treating patients near their homes, training and supervision of health workers, and progressive use of short-course chemotherapy. PMID- 10094175 TI - Multidrug-resistant tuberculosis caused by 'W'-related strains in three immunocompetent foreign-born patients. PMID- 10094176 TI - Tuberculosis in New York City. PMID- 10094177 TI - Genic amplification test in the diagnosis of mammary and disseminated tuberculosis. PMID- 10094178 TI - The coronary artery as a living organ. PMID- 10094179 TI - Flow-dependent vasodilation in the coronary circulation: alterations in diseased states. AB - Flow-dependent vasodilation has been recognized to play an important role in the perfusion of the myocardium and the occurrence of myocardial ischaemia. In the past few years, the role of the endothelium in the regulation of coronary artery dimensions has gained a lot of attraction. Changes in coronary artery size are caused through the contraction and relaxation of the smooth musculature within the vessel wall. Vasoactive substances released from the endothelium play a crucial role in the regulation of vessel size and coronary vasomotor tone. During physiologic exercise, normal coronary arteries dilate, whereas stenotic arteries constrict. This abnormal behaviour of the stenotic artery has been associated with the occurrence of myocardial ischaemia, and has been thought to be either due to: endothelial dysfunction with reduced release or production of the endothelial derived relaxant factor (EDRF); an increased sympathetic stimulation during exercise; enhanced platelet aggregation with release of thromboxane A2 and serotonin; and/or a passive collapse of the disease-free vessel segment within the stenosis when blood-flow velocity increases during exercise. Thus, a diseased coronary endothelium may have a dramatic effect on the function of the coronary arteries, and may cause or contribute to the occurrence of myocardial ischaemia under high-demand situations, e.g. physical exercise or mental stress. Changes in flow-dependent vasodilation have been described in various disease states, e.g. hypercholesterolaemia, hypertension, diabetes mellitus, but also in valvular heart disease, heart failure and transplantation. Most of these alterations are due to functional changes of the endothelium, but vascular remodelling of the coronary arteries with thickening of the intima and an enlargement of the artery may affect these functional changes importantly. PMID- 10094180 TI - Functional assessment of collaterals in the human coronary circulation. AB - The coronary collateral circulation is an alternative source of blood supply to a myocardial area jeopardized by the failure of the stenotic or occluded vessel to provide enough blood flow to this region. Until recently, only qualitative or semiqualitative methods have been available for the assessment of the coronary collateral circulation in humans, such as the patient's history of walk-through angina pectoris, the registration of intracoronary ECG signs for myocardial ischaemia or angina pectoris during coronary occlusion, or coronary angiographic classification (score 0-3) of collaterals. Studies of coronary wedge pressure measurements distal of a balloon-occluded coronary artery and the recent advent of ultrathin pressure and Doppler angioplasty guidewires have made it possible to obtain pressure or flow velocity data in remote vascular areas and, thus, to calculate functional variables for coronary collateral flow. Those coronary occlusive pressure- and flow velocity-derived parameters express collateral flow as a fraction of antegrade coronary flow during vessel patency of the collateral receiving vessel. They are both interchangeable, and they have been validated in comparison to 'traditional' methods and against each other. The possibility of accurately measuring coronary collateral flow indices in humans undergoing coronary balloon angioplasty opens areas of investigation of the pathogenesis, pathophysiology and therapeutic promotion of the collateral circulation previously reserved for exclusively experimental studies. The purpose of this article is to review several clinically available methods for the functional characterization of the coronary collateral circulation. PMID- 10094181 TI - Blood flow assessment with intravascular ultrasound catheters: the ideal tool for simultaneous assessment of the coronary haemodynamics and vessel wall? AB - We present the potentials of a novel method of intracoronary flow visualization and quantification that is based on conventional intravascular ultrasound (IVUS) imaging catheters. The quantification of flow is obtained from analysis of the rate of decorrelation of digitized radiofrequency ultrasound echo signals. Flow information is superimposed on the IVUS image using a colour scale. Integration of the blood velocity components normal to the scan plane permits calculation of the volume flow. Validation using IVUS and electromagnetic (EM) flowmeter recordings were obtained in vivo from instrumented pigs. IVUS flow (IVUS(f)) compared favourably to EM flow (EM(f)): IVUS(f)=1.0 EM(f)+5.72 cc/min, r2=0.98. Clinical results for the first five patients investigated are reported. A Doppler wire was used to measure the flow in four coronary arteries and one renal artery in baseline and hyperaemia conditions. IVUS flow and derived coronary flow reserve (CFR) demonstrated a very good agreement with the data derived from the combination of quantitative angiography and velocity when measured with the Doppler wire (DOP(f)): IVUS(f)=1.01 DOP(f)-20 cc/min, r2=0.90 and IVUS(cfr)=1.03 DOP(cfr)-0.03, r2=0.93. This demonstrates that simultaneous morphological and physiological assessment of coronary or peripheral arteries with one IVUS catheter is feasible. This method should be very useful for the evaluation of intermediate coronary stenoses or the results of revascularization procedures. PMID- 10094182 TI - Positron emission tomography to assess the haemodynamics of the coronary circulation. AB - Positron emission tomography (PET) allows the non-invasive measurement of absolute myocardial blood flow (ml/min/g of myocardium) in man. This has made possible the measurement of myocardial blood flow and the coronary vasodilator reserve (an index of the ability of the coronary microcirculation to dilate) in healthy volunteers to establish the normal values and ranges of these parameters. This technique allows the assessment of the functional significance of epicardial coronary stenoses as well as the investigation of the function of the coronary microcirculation in patients with and without coronary artery disease. PMID- 10094183 TI - Shear stress in atherosclerosis, and vascular remodelling. AB - Shear stress plays a role in lipid accumulation in primary atherosclerosis and vascular remodelling. We will present applications of a new technique, which enables to quantify shear stress in 3D vessel reconstructions. The method is based on 3D IVUS reconstructions of blood vessels either obtained by IVUS pull back (external iliac artery) or by a combination of angiography and IVUS (curved coronary artery). Distribution of wall thickness of a curved human right coronary artery was such that low wall thickness occurred where shear stress was high, and wall thickness was high where shear stress was low. Consequently, an inverse relationship between shear stress and wall thickness was detected. Although vascular remodelling after PTA in external iliac arteries of atherosclerotic Yucatan pigs was predicted both by acute gain and decrements in shear stress, the decrement in shear stress appeared a better predictor. In conclusion, shear stress appears to play a role in primary atherosclerosis and vascular remodelling after PTA. PMID- 10094184 TI - Measurement of flow velocity in the coronary circulation: requirements and pitfalls. AB - The introduction of Doppler guide wires has allowed the wide-spread use of Doppler technology in the catheterization laboratory for coronary diagnostics and pathophysiological studies. Doppler-ultrasound-derived measurement of coronary flow velocity serves as a substitute for true volumetric flow measurement. To produce reliable and reproducible flow velocity data, the whole Doppler spectrum should be evaluated. Special attention should be paid to the velocity distribution within the spectrum. A spectral display with strong signals in the high velocity range and a sharply defined envelope are markers for a good positioning of the Doppler wire. Additional security for the optimal positioning can give the recently developed tracking indicator. For reliable CFR determination using average peak velocity at rest and during hyperaemia, changes of the shape of the velocity profile and of the cross-sectional vessel area, as well as the position of the Doppler guide wire, have to be taken into account, otherwise the CFR will be underestimated. To eliminate cross-sectional area changes, the vessel should be pretreated with nitroglycerin. PMID- 10094185 TI - New strategy for multi-colour fluorescence in situ hybridisation: COBRA: COmbined Binary RAtio labelling. AB - Multicolour in situ hybridisation (MFISH) is increasingly applied to karyotyping and detection of chromosomal abnormalities. So far 27 colour analyses have been described using fluorescently labelled chromosome painting probes in a so-called combinatorial approach. In this paper a new strategy is presented to use efficiently the currently available number of spectrally separated fluorophores in order to increase the multiplicity of MFISH. We introduce the principle of COBRA (COmbined Binary RAtio labelling), which is based on the simultaneous use of combinatorial labelling and ratio labelling. Human chromosome painting in 24 colours is accomplished using four fluorophores only. Three fluorophores are used pair wise for ratio labelling of a set of 12 chromosome painting probes. The second set of 12 probes is labelled identically but is also given a binary label (fourth fluorophore). The COBRA method is demonstrated on normal human chromosomes and on a lymphoma (JVM) cell line, using probes enzymatically labelled with fluorescein, lissamine and cy5 as primary fluorophores, and diethylaminocoumarin (DEAC), a blue dye, as combinatorial fourth label to demonstrate incorporated digoxigenin. In addition, the principle was tested using chemical labelling. The first set of 12 painting probes was therefore labelled by ULS (Universal Linkage System), using DEAC, cy3 and cy5 as primary labels, and the second set was labelled similarly, but also contained a digoxigenin-ULS label, which was indirectly stained with fluorescein. Subsequently, a mathematical analysis is presented and methods are indicated for achieving an MFISH multiplicity of 48, 96 or even higher using existing technology. PMID- 10094186 TI - An integrated map of chromosome 18 CAG trinucleotide repeat loci. AB - Expansions of trinucleotide CAG repeats have been demonstrated in at least eight neurodegenerative disorders, and suggested to occur in several others, including bipolar disorder and schizophrenia. Chromosome 18 loci have been implicated in bipolar disorder pedigrees by linkage analysis. To address this putative link between chromosome 18 CAG trinucleotide repeats and neuropsychiatric illness, we have screened a chromosome 18 cosmid library (LL18NCO2" AD") and identified 14 novel candidate loci. Characterisation of these loci involved repeat flank sequencing, estimation of polymorphism frequency and mapping using FISH as well as radiation hybrid panels. These mapped trinucleotide loci will be useful in the investigation of chromosome 18 in neurodegenerative or psychiatric conditions, and will serve to integrate physical and radiation hybrid maps of chromosome 18. PMID- 10094187 TI - Novel mutations in Rsk-2, the gene for Coffin-Lowry syndrome (CLS). AB - Coffin-Lowry syndrome (CLS) is an X-linked disorder characterized by facial dysmorphism, digit abnormalities and severe psychomotor retardation. CLS had previously been mapped to Xp22.2. Recently, mutations in the ribosomal S6 kinase (Rsk-2) gene were shown to be associated with CLS. We have tested five unrelated individuals with CLS for mutations in nine exons of Rsk-2 using Single Strand Conformation Polymorphism (SSCP) analysis. Two patients had the same missense mutation (C340T), which causes an arginine to tryptophan change (R114W). This mutation falls just outside the N-terminal ATP-binding site in a highly conserved region of the protein and may lead to structural changes since tryptophan has an aromatic side chain whereas arginine is a 5 carbon basic amino acid. The third patient also had a missense mutation (G2186A) resulting in an arginine to glutamine change (R729Q). The fourth patient had a 2bp deletion (AG) of bases 451 and 452. This creates a frameshift that results in a stop codon 25 amino acids downstream, thereby producing a truncated protein. This deletion also falls within the highly conserved amino-catalytic domain of the protein. The fifth patient has a nonsense mutation (C2065T) which results in a premature stop codon, thereby producing a truncated protein. These mutations further confirm Rsk-2 as the gene involved in CLS and may help in understanding the structure and function of the protein. PMID- 10094188 TI - Mutations within or upstream of the basic helix-loop-helix domain of the TWIST gene are specific to Saethre-Chotzen syndrome. AB - Saethre-Chotzen syndrome (ACS III) is an autosomal dominant craniosynostosis syndrome recently ascribed to mutations in the TWIST gene, a basic helix-loop helix (b-HLH) transcription factor regulating head mesenchyme cell development during cranial neural tube formation in mouse. Studying a series of 22 unrelated ACS III patients, we have found TWIST mutations in 16/22 cases. Interestingly, these mutations consistently involved the b-HLH domain of the protein. Indeed, mutant genotypes included frameshift deletions/insertions, nonsense and missense mutations, either truncating or disrupting the b-HLH motif of the protein. This observation gives additional support to the view that most ACS III cases result from loss-of-function mutations at the TWIST locus. The P250R recurrent FGFR 3 mutation was found in 2/22 cases presenting mild clinical manifestations of the disease but 4/22 cases failed to harbour TWIST or FGFR 3 mutations. Clinical re examination of patients carrying TWIST mutations failed to reveal correlations between the mutant genotype and severity of the phenotype. Finally, since no TWIST mutations were detected in 40 cases of isolated coronal craniosynostosis, the present study suggests that TWIST mutations are specific to Saethre-Chotzen syndrome. PMID- 10094189 TI - Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. AB - Sanfilippo B syndrome (mucopolysaccharidosis IIIB, MPS IIIB) is caused by a deficiency of alpha-N-acetylglucosaminidase, a lysosomal enzyme involved in the degradation of heparan sulphate. Accumulation of the substrate in lysosomes leads to degeneration of the central nervous system with progressive dementia often combined with hyperactivity and aggressive behaviour. Age of onset and rate of progression vary considerably, whilst diagnosis is often delayed due to the absence of the pronounced skeletal changes observed in other mucopolysaccharidoses. Cloning of the gene and cDNA encoding alpha-N acetylglucosaminidase enabled a study of the molecular basis of this syndrome. We were able to identify 31 mutations, 25 of them novel, and two polymorphisms in the 40 patients mostly of Australasian and Dutch origin included in this study. The observed allellic heterogeneity reflects the wide spectrum of clinical phenotypes reported for MPS IIIB patients. The majority of changes are missense mutations; also four nonsense and nine frameshift mutations caused by insertions or deletions were identified. Only five mutations were found in more than one patient and the observed frequencies are well below those observed for the common mutations in MPS IIIA. R643C and R297X each account for around 20% of MPS IIIB alleles in the Dutch patient group, whilst R297X, P521L, R565W and R626X each have a frequency of about 6% in Australasian patients. R643C seems to be a Dutch MPS IIIB allele and clearly confers the attenuated phenotype. One region of the gene shows a higher concentration of mutations, probably reflecting the instability of this area which contains a direct repeat. Several arginine residues seem to be 'hot-spots' for mutations, being affected by two or three individual base pair exchanges. PMID- 10094190 TI - Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene. AB - We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNASer(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities. PMID- 10094191 TI - Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene. AB - Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes. PMID- 10094192 TI - Spectrum of mutations in fucosidosis. AB - Fucosidosis is a lysosomal storage disorder characterised by progressive psychomotor deterioration, angiokeratoma and growth retardation. It is due to deficient alpha-l-fucosidase activity leading to accumulation of fucose containing glycolipids and glycoproteins in various tissues. Fucosidosis is extremely rare with less than 100 patients reported worldwide, although the disease occurs at a higher rate in Italy, in the Hispanic-American population of New Mexico and Colorado, and in Cuba. We present here a review study of the mutational spectrum of fucosidosis. Exon by exon mutation analysis of FUCA1, the structural gene of alpha-l-fucosidase, has identified the mutation(s) in nearly all fucosidosis patients investigated. The spectrum of the 22 mutations detected to date includes four missense mutations, 17 nonsense mutations consisting of seven stop codon mutations, six small deletions, two large deletions, one duplication, one small insertion and one splice site mutation. All these mutations lead to nearly absent enzymatic activity and severely reduced cross reacting immunomaterial. The observed clinical variability is, therefore, not due to the nature of the fucosidosis mutation, but to secondary unknown factors. PMID- 10094193 TI - Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome. AB - The nail patella syndrome (NPS1) is an autosomal dominant disorder characterised by dysplasia of the finger nails and skeletal abnormalities. NPS1 has been mapped to 9q34, to a 1 cM interval between D9S315 and the adenylate kinase gene (AK1). We have mapped the breakpoints within the candidate NPS1 region in two unrelated patients with balanced translocations. One patient [46,XY,t(1;9)(q32.1;q34)] was detected during a systematic survey of old cytogenetic files in Denmark and southern Sweden. The other patient [46,XY,t(9;17)(q34.1;q25)] was reported previously. D9S315 and AK1 were used to isolate YACs, from which endclones were used to isolate PACs. Two overlapping PAC clones span the 9q34 breakpoints in both patients, suggesting that NPS1 is caused by haploinsufficiency due to truncation or otherwise inactivation of a gene at or in the vicinity of the breakpoints. PMID- 10094194 TI - Lamellar ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus. AB - Lamellar ichthyosis (LI) is an autosomal recessive genodermatosis which has been shown to be both clinically and genetically heterogeneous. Keratinocyte transglutaminase (or transglutaminase 1: TGM1) has been demonstrated to be the disease-causing gene in some families, whilst in others, a second unidentified LI gene was mapped to chromosome 2q33-35 (ICR2B locus). In this study, we present a physical map that encompasses the ICR2B locus, including the mapping of new microsatellite markers. Based on this new map, genotyping additional families highly suggests a reduction in size of the candidate interval. The final interval is covered by a single yeast artificial chromosome (937-H-3) which is 2.2Mb in length. Fine mapping of potential candidate transcripts was also focused on this region. PMID- 10094195 TI - Full results of the genome-wide scan which localises a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. AB - Three hundred million individuals are at risk of infection by schistosomes, and thousands die each year of severe hepatic disease. Previous studies have shown that the intensity of infection by Schistosoma mansoni in a Brazilian population is controlled by a major gene, denoted as SM1. We report here the full results of a genome-wide search that was performed on this population to localise SM1. Two hundred and forty-six microsatellites were used for the primary map, and only one region in 5q31-q33 provided significant evidence of linkage. SM1 was subsequently mapped to this region, which contains several genes encoding cytokines or cytokine receptors which are involved in protection against schistosomes. Three additional regions, 1p22.2, 7q36 and 21q22-22-qter, yielded promising, although not significant, lod-score values. These regions contain candidate genes encoding cytokines or molecules relevant to anti-schistosome immunity. PMID- 10094196 TI - First International SNP Meeting at Skokloster, Sweden, August 1998. Enthusiasm mixed with scepticism about single-nucleotide polymorphism markers for dissecting complex disorders. PMID- 10094197 TI - Nontargeted stable integration of recombinant adeno-associated virus into human leukemia and lymphoma cell lines as evaluated by fluorescence in situ hybridization. AB - A number of studies on human epithelial cells of varying origin have demonstrated integration of recombinant adeno-associated virus (AAV) vectors into a variety of chromosomes compared with the site-specific integration on chromosome 19 predominantly observed for wild-type (wt) AAV. We have constructed a recombinant AAV (rAAV) vector and tested the integration into hematopoietic cells, using the human acute myeloid leukemia cell line AML5 and the human non-Hodgkin's lymphoma cell line OCI-LY18 as targets. The integration sites were visualized by fluorescence in situ hybridization (FISH). Positive signals were observed for chromosomes 1, 2, 3, 8, 14, 15, 19, and Y. The majority of cells demonstrated integration into one specific site. A minority showed simultaneous integration into more than one chromosome. The frequency of observed integrations was not uniformly distributed among chromosomes; for instance, in AML5 chromosome 2 seemed to be favored. Colony-derived AML5 clones bore unique integration patterns indicating successful transduction of clonogenic progenitor cells with high proliferative potential. The integration was stable and observed for more than 12 months after transduction. FISH has been shown to be a powerful tool for detailed analyses of rAAV integration patterns and can be used to evaluate targets and transduction conditions. PMID- 10094198 TI - Targeting retroviral vectors to CD34-expressing cells: binding to CD34 does not catalyze virus-cell fusion. AB - We have attempted to engineer murine leukemia virus (MuLV)-based retroviral vectors to specifically transduce cells expressing human CD34, an antigen present on the surface of undifferentiated hematopoietic stem cells. A number of chimeric ecotropic MuLV envelope (Env) proteins were constructed that contained anti-CD34 single-chain antibody variable fragments (scFvs). The scFv-Env proteins were generated either by replacing the receptor-binding domain of Env with the scFv or by inserting the scFv into the N terminus of the Env protein. Only chimeric Env proteins with scFv insertions between amino acids 6 and 7 were incorporated into viral particles, and coexpression of native MuLV Env did not rescue incorporation defective proteins. In addition, the efficiency of incorporation varied with the specific anti-CD34 scFv that was used. Retroviral vectors containing the scFv-Env proteins bound to CD34+ cells and transduced NIH 3T3 cells expressing human CD34 (3T3-CD34 cells) at approximately twice the efficiency of the parental NIH 3T3 cells. However, the introduction of the mutation D84K, which prevents binding to the ecotropic MuLV receptor mcat-1, prevented transduction of both NIH 3T3 and 3T3-CD34 cells. Complementation cell-cell fusion assays [Zhao et al. (1997). J. Virol. 71, 6967-6972] in 3T3-CD34 cells revealed that although the scFv-Env proteins could contribute postbinding entry functions when bound to mcat-1, they were unable to do so when bound to CD34. Taken together, these data suggest that although the interaction with CD34 effectively increased the concentration of virus on 3T3-CD34 cells, entry could occur only through an interaction with mcat 1; CD34 alone was not capable of triggering the appropriate postbinding changes that lead to viral entry. PMID- 10094199 TI - Efficient discrimination between different densities of target antigen by tetracycline-regulatable T bodies. AB - Engineered T cells expressing chimeric T cell receptors (chTCRs) are of interest for cancer gene therapy but many "cancer antigens" are thought to be unsuitable targets because they are expressed at low levels on normal tissues. We therefore sought to determine whether engineered T cells expressing variable surface densities of a high-affinity chTCR could discriminate different concentrations of the targeted antigen. We plotted the relationship between chTCR density and the concentration of target antigen using Jurkat T cells expressing a hapten-binding chTCR whose expression could be modulated by tetracycline. Our analysis reveals that there is a dynamic equilibrium between cell surface density of the chTCR and the antigen density that optimally triggers T cell activation. At a fixed density of target antigen, optimal T cell activation can be achieved only within a certain range of chTCR densities, while excessive TCR signaling triggers apoptosis of the engineered T cells. Our results show that T cells can be engineered to discriminate different antigen densities and that the T cell response to a fixed concentration of antigen can be optimized by tuning the cell surface density of TCRs. PMID- 10094200 TI - Tissue-engineered human bioartificial muscles expressing a foreign recombinant protein for gene therapy. AB - Murine skeletal muscle cells transduced with foreign genes and tissue engineered in vitro into bioartificial muscles (BAMs) are capable of long-term delivery of soluble growth factors when implanted into syngeneic mice (Vandenburgh et al., 1996b). With the goal of developing a therapeutic cell-based protein delivery system for humans, similar genetic tissue-engineering techniques were designed for human skeletal muscle stem cells. Stem cell myoblasts were isolated, cloned, and expanded in vitro from biopsied healthy adult (mean age, 42 +/- 2 years), and elderly congestive heart failure patient (mean age, 76 +/- 1 years) skeletal muscle. Total cell yield varied widely between biopsies (50 to 672 per 100 mg of tissue, N = 10), but was not significantly different between the two patient groups. Percent myoblasts per biopsy (73 +/- 6%), number of myoblast doublings prior to senescence in vitro (37 +/- 2), and myoblast doubling time (27 +/- 1 hr) were also not significantly different between the two patient groups. Fusion kinetics of the myoblasts were similar for the two groups after 20-22 doublings (74 +/- 2% myoblast fusion) when the biopsy samples had been expanded to 1 to 2 billion muscle cells, a number acceptable for human gene therapy use. The myoblasts from the two groups could be equally transduced ex vivo with replication-deficient retroviral expression vectors to secrete 0.5 to 2 microg of a foreign protein (recombinant human growth hormone, rhGH)/10(6) cells/day, and tissue engineered into human BAMs containing parallel arrays of differentiated, postmitotic myofibers. This work suggests that autologous human skeletal myoblasts from a potential patient population can be isolated, genetically modified to secrete foreign proteins, and tissue engineered into implantable living protein secretory devices for therapeutic use. PMID- 10094201 TI - Targeting the replication of adenoviral gene therapy vectors to lung cancer cells: the importance of the adenoviral E1b-55kD gene. AB - It has been proposed that an adenovirus with the E1b-55kD gene deleted has a selective advantage in replicating in cancer cells that have mutations in the p53 gene (Bischoff et al., 1996). We have explored this hypothesis in several lung cancer cell lines, and evaluated potential mechanisms that might regulate the replication of Ad338, an E1b-55kD-deleted virus, with the objective of developing a rational approach for targeting gene therapy to lung tumors. Our data show that Ad338 replicates poorly in three lung cancer cell lines with various p53 mutations (H441, H446, and Calu1), yet this virus replicates to a high level in a lung cancer cell line with wild-type p53 (A549) and in a normal lung fibroblast line (IMR90). Viral DNA replication, expression of viral proteins, and shutoff of host cell proteins were not important variables in limiting the replication of the E1b-55kD-deleted virus. However, the cell lines resistant to host cell protein shutoff were also the most resistant to the cytopathic effect induced by mutant and wild-type virus and the only cells to survive for 8 days following infection. The E1b-55kD protein clearly has an important role in viral replication beyond its interaction with p53. Thus, an E1b-55kD-deleted virus cannot be used to specifically target viral replication to p53-mutated lung cancer cells. PMID- 10094202 TI - Two independent molecular pathways for recombinant adeno-associated virus genome conversion occur after UV-C and E4orf6 augmentation of transduction. AB - Numerous environmental influences have been demonstrated to enhance recombinant adeno-associated virus (rAAV) transduction. Such findings are the foundation of developing new and innovative strategies to improve the efficiency of rAAV as a gene therapy vector. Several of these environmental factors included genotoxic stresses such as UV and y irradiation as well as certain adenoviral gene products such as E4orf6. The mechanisms by which these environmental stimuli increase rAAV transduction are only partially understood but have been suggested to involve both endocytosis and uptake of virus to the nucleus, as well as conversion of single-stranded DNA viral genomes to double-stranded expressible forms. Two molecular intermediates of rAAV genomes, which have been demonstrated to correlate with transgene expression and/or the persistence of rAAV, include both replication form (Rf) monomers and dimers as well as circular intermediates. In the present study, we demonstrate that augmentation of rAAV transduction by UV irradiation and the adenoviral protein E4orf6 correlates with distinct increases in either circular or replication form intermediates, respectively. UV irradiation of primary fibroblasts at 15 J/m2 resulted in a 15-fold induction of head-to-tail circular intermediates, with minimal induction of replication form rAAV genomes. In contrast, E4orf6-augmented rAAV transduction was correlated with the formation of replication form intermediates, with no alteration in the abundance of circular intermediates. These findings demonstrate that rAAV transduction can occur through two independent molecular pathways that convert single-stranded AAV genomes to expressible forms of DNA. PMID- 10094203 TI - Delivery of an adenovirus vector in a calcium phosphate coprecipitate enhances the therapeutic index of gene transfer to airway epithelia. AB - Gene transfer could provide a novel treatment for cystic fibrosis. However, current vectors, including recombinant adenoviruses, are relatively inefficient at gene transfer to airway epithelia. We have found that delivering adenovirus in a calcium phosphate coprecipitate (Ad:CaPi coprecipitates) enhanced the efficiency of gene transfer to airway epithelia in vitro and in vivo. However, the potential for injury to the epithelium was not evaluated. In NIH 3T3 cells treated with Ad:CaPi coprecipitates, we found that a 30-min exposure, which was sufficient for maximal transgene expression, produced no toxicity; whereas some other transfection reagents induced significant toxicity. Moreover, when Ad:CaPi coprecipitates were applied to the apical surface of differentiated airway epithelia in vitro, they did not reduce transepithelial resistance, even after prolonged incubation. Delivery of Ad:CaPi coprecipitates to mouse lung induced an inflammatory response, but it was not substantially different from that following administration of adenovirus alone. Thus, Ad:CaPi coprecipitates significantly enhance gene transfer to differentiated human airway epithelia in vitro and to mouse lung in vivo without increasing toxicity or the inflammatory response. Thus, CaPi coprecipitates may enhance the therapeutic index of adenovirus-based gene transfer vectors. PMID- 10094204 TI - High-efficiency transfer of cystic fibrosis transmembrane conductance regulator cDNA into cystic fibrosis airway cells in culture using lactosylated polylysine as a vector. AB - To find more efficient vectors for the transfer of CFTR cDNA, lactosylated polylysine was explored for transfer into airway epithelial cells in primary culture. The efficacy and high efficiency of transfection were shown by several criteria: expression of both mRNA and protein for CFTR and the functional correction of the Cl- channel activity. Using specific combinations of agents to enhance the transfection, an efficiency of 90% was obtained as detected by in situ hybridization with digoxigenin-labeled probes generated against exon 14 of CFTR. The highest efficiency was observed by adding E5CA peptide (10 microg) and 5% glycerol to the transfection mixture. The degree of transfection could be controlled by the enhancing agents, thus modulating the efficiency of transfection. The highest level of transfection efficiency is equivalent to that reported for viral vectors. None of the agents or their combinations in the concentrations used were cytotoxic to the primary cells. Antibody pAb3145 was used to detect the expression of the CFTR protein in the cells. When an N terminal GFP-CFTR fusion gene was used to transfect the CF cells a functional correction of the CFTR Cl- channel was detected by patch-clamp electrophysiology. The high efficiency of CFTR gene transfer with lactosylated polylysine leads to the conclusion that lactosylated polylysine is a promising vector to transfer the CFTR gene into human airway cells in culture. PMID- 10094205 TI - Induction of anti-tumor immunity elicited by tumor cells expressing a murine LFA 3 analog via a recombinant vaccinia virus. AB - T cell activation requires binding of the T cell receptor to the major histocompatibility molecule-peptide complex in the presence of adhesion and/or costimulatory molecules such as B7-1 (CD80), B7-2 (CD86), ICAM-1 (CD54), and LFA 3 [corrected]. The major ligand of CD2 is CD48, the murine analog of human leukocyte function-associated antigen 3 (LFA-3). To determine the effect of LFA-3 expression on the immunogenicity of tumor cells, we constructed a recombinant vaccinia virus containing the murine LFA-3 gene (designated rV-LFA-3). rV-LFA-3 was shown to be functional in vitro in terms of expression of LFA-3, T cell proliferation, adhesion, and cytotoxicity. Subcutaneous inoculation of rV-LFA-3 infected murine colon adenocarcinoma tumor cells (MC38) into immunocompetent syngeneic C57BL/6 mice resulted in complete lack of tumor growth. Inoculation of MC38 cells infected with equal doses of control wild-type vaccinia virus resulted in tumor growth in all animals. In addition, partial immunological protection was demonstrated against subsequent challenge with uninfected parental tumor cells up to 56 days after vaccination with rV-LFA-3-infected cells. Anti-tumor memory was also demonstrated by using gamma-irradiated MC38 cells and cells from another carcinoma model (CT26). These studies demonstrate that expression of LFA-3 via a poxvirus vector can be used to induce anti-tumor immunity. PMID- 10094206 TI - No discrepancy between in vivo gene marking efficiency assessed in peripheral blood populations compared with bone marrow progenitors or CD34+ cells. AB - Reports of 1- to 2-log higher gene transfer levels in purified CD34+ cells or marrow CFU compared with levels in mature circulating blood cells after transplantation of retrovirally transduced primitive human hematopoietic cells have resulted in concern that transduced progenitors do not contribute proportionally to ongoing hematopoiesis (Kohn et al., 1995; Brenner, 1996). To study the issue in a relevant large animal, we analyzed samples of mature blood cells, marrow CD34-enriched cells and marrow CD34-depleted cells, and marrow CFU from a cohort of 11 rhesus transplanted with retrovirally transduced cells and followed for up to 5.5 years. They were transplanted with CD34-enriched bone marrow (BM) or G-CSF/SCF-mobilized peripheral blood (PB) cells transduced with vectors containing either neo, human glucocerebrosidase, or murine adenosine deaminase genes. There were no significant differences between the levels of vector sequences found in BM CD34+ cells, BM CD34- cells, PB granulocytes, or PB mononuclear cells (MNCs) in any animal. In four animals transplanted with SCF/G CSF-primed BM cells and analyzed 3-6 months posttransplantation, the percentage of CFU containing the neo vector appeared to be 1 log higher than the representation of marked cells in the PB of these animals, but this discrepancy did not persist at time points greater than 6 months posttransplantation. The level of CFU marking was no higher than PB granulocyte or MNC marking at any time points in the other animals. Low levels of mature gene-modified cells probably reflect poor transduction of repopulating stem cells, not a block in differentiation or specific immune rejection of mature cells. This study represents the longest follow-up of primates transplanted with transduced hematopoietic cells, and it is encouraging that the levels of vector-containing cells appear stable for up to 5 years. PMID- 10094207 TI - Evaluation of adeno-associated virus-mediated gene transfer into the rat retina by clinical fluorescence photography. AB - The purpose of this study was to evaluate recombinant adeno-associated virus (AAV) as an in vivo gene transfer vector for the retina and to explore the possibility of monitoring the expression of green fluorescent protein (GFP) using a noninvasive method. Rats were injected subretinally with rAAV-gfp or rAAV-lacZ. Strong expression of the reporter gene in a circular area surrounding the injection site was observed in retinal whole mounts and tissue sections. Higher magnification revealed that cells demonstrating high levels of green fluorescence were hexagonal in shape, indicating they were retinal pigment epithelium (RPE) cells. Histological observation of retinal sections demonstrated that recombinant AAV specifically transduced RPE cells. Ten animals were injected with rAAV-gfp for longitudinal studies and the fluorescence was monitored by retinal fluorescence photography. The GFP signal was detected in 100% of the animals as early as 2 weeks postinjection and remained present throughout the experimental period of 4 months. After 2 weeks, a gradual increase in the number of transduced cells occurred before reaching maximal levels of GFP expression at 8 weeks. This was followed by a small decrease over 4 weeks before reaching stable expression at 16 weeks. Our results demonstrated that rAAV efficiently transduces rat RPE cells and that retinal fluorescence photography is suitable for monitoring GFP expression. By using this noninvasive technique, we demonstrated that repetitive measurements of GFP expression in vivo in the rAAV-gfp-transduced retina are possible. This study demonstrated that retinal fluorescence photography is a potent tool for studying AAV-mediated gene delivery in the retina. PMID- 10094208 TI - Thymidine kinase-deleted vaccinia virus expressing purine nucleoside phosphorylase as a vector for tumor-directed gene therapy. AB - Tumor-directed gene therapy faces many obstacles. Lack of tissue targeting and low in vivo transduction efficiency represent some of the limitations for a successful therapeutic outcome. A thymidine kinase-deleted mutant vaccinia virus has been shown in marker studies to replicate selectively in tumor tissue in animal models. Purine nucleoside phosphorylase (PNP), from E. coli, converts the nontoxic prodrug 6-methylpurine deoxyriboside (6-MPDR) to the toxic purine 6 methylpurine. In this study, we investigated the cytotoxic properties of PNP, expressed by an optimized synthetic early/late promoter in a vaccinia virus (vMPPNP). In vitro cytotoxicity of psoralen-inactivated vMPPNP (1 microg of psoralen, 4 min of LWUV [365 nm]) at the maximum tolerated dose (MTD) of 6-MPDR (80 microM) reduced cell viability by day 3 to 1.7%. At an MOI of 0.002, replication-competent vMPPNP and 6-MPDR (80 microM) caused reduction of cell viability to 19.8% within 4 days. Furthermore, there was complete abrogation of viral replication after intracellular conversion of prodrug into the active toxin. The potency of such a system was similar among all histologies tested. Finally, the cytotoxic efficacy has been shown to be more rapid and complete than that of cytosine deaminase (CD), a more established enzyme/prodrug system. When virus was delivered intraperitoneally into athymic mice with hepatic metastases, followed by administration of prodrug, there was a significant prolongation of survival and a 30% cure rate. In summary, owing to its tumor-targeting capabilities, high transduction efficiency, and high gene expression, a vaccinia virus expressing PNP could prove to be a potent and valuable vector for tumor targeted gene therapy. PMID- 10094209 TI - Safe and effective regulation of hematocrit by gene gun administration of an erythropoietin-encoding DNA plasmid. AB - This work examines the effect of delivering a DNA plasmid encoding murine erythropoietin (pVRmEpo) to BALB/c mice by gene gun. Whereas intramuscular injection elicits a rise in hematocrit persisting >8 months, intradermal delivery triggers the dose-dependent secretion of biologically active erythropoietin (Epo) for approximately 1 month. Repeated administration of pVRmEpo by gene gun elicits a stable increase in hematocrit. The source of the Epo produced following gene gun delivery was analyzed by periodically grafting the site of injection onto naive recipients. Results indicate that both stationary cells (presumably keratinocytes) and migratory (presumably dendritic) cells were transfected and secreted biologically active Epo in vivo. Gene gun administration of plasmid DNA appears to be safe, and provides an additional strategy for achieving the regulated secretion of an exogenous gene product. PMID- 10094210 TI - Gene transfer into fetal baboon hematopoietic progenitor cells. AB - We studied hematopoietic progenitors from fetal baboon blood, marrow, and liver at four time points (125, 140, 160, and 175 days) during the third trimester (gestation approximately 180 days) to determine if fetal baboons might be an appropriate model for in utero gene therapy of hematopoietic stem cells (HSCs). Cells were studied for expression of CD34, CD33, CD38, and HLA-DR, for progenitor content in colony-forming cell assays, and for susceptibility of CD34+ progenitors to retrovirus-mediated gene transfer. Throughout the third trimester, the frequency of CD34+ progenitors in blood and marrow appears to remain unchanged at approximately 0.6 and 5.0%, respectively. In liver, progenitors progressively decrease to undetectable levels by day 175. The proportion of fetal baboon bone marrow and liver CD34+ cells expressing CD38 and HLA-DR appears to increase with increasing fetal age, similar to changes reported for human cord blood CD34+ cells. In fetal baboon blood the proportion of CD34+ cells expressing CD33 appears to decrease with increasing gestational age, also similar to changes reported for human cord blood cells. Progenitors from human cord blood and baboon fetal tissues were similarly susceptible to transduction by the gibbon ape leukemia pseudotyped retroviral vector LAPSN(PG13) containing the genes for human placental alkaline phosphatase (AP) and the bacterial neomycin phosphotransferase (neo). Fetal baboon and human hematopoietic progenitor cells undergo similar phenotypic changes during the third trimester of fetal development and are similarly susceptible to retrovirus-mediated gene transfer. The fetal baboon may be a model in which approaches to mobilization and gene transfer into fetal HSCs can be studied. PMID- 10094212 TI - Gene Therapy Advisory Committee. Report on the potential use of gene therapy in utero. Health Departments of the United Kingdom, November 1998. PMID- 10094211 TI - Increased bax expression is associated with cell death induced by ganciclovir in a herpes thymidine kinase gene-expressing glioma cell line. AB - The herpes simplex virus thymidine kinase gene (HSV-tk) was stably transfected into rat C6 glioma cells (C6tk) in order to characterize the mechanisms underlying cell toxicity induced in vitro by the guanosine analog ganciclovir (GCV). The results demonstrate the efficiency of the HSV-tk/GCV system in ablating most of the tumoral cells within 7 to 8 days of treatment with 20 mivroM GCV; however, a few cells still survive. C6tk cells arrest in the S phase of the cell cycle after 2 days of drug treatment before undergoing cell death. Microscopic analysis reveals dying cells with ultrastructural characteristics consistent with apoptosis; we cannot rule out, however, that necrotic cell death may also be occurring. The cytotoxicity induced by GCV is not associated with changes in the expression of p53 protein, suggesting that cell cycle arrest and cell death may occur through a p53-independent pathway. C6tk cells constitutively express Bcl-xL and Bax proteins; when exposed to GCV, Bcl-xL levels do not change but Bax accumulation is rapidly induced. These findings suggest that the balance between Bcl-xL and Bax proteins may be of importance in determining the sensitivity of tumoral cells to GCV. PMID- 10094213 TI - Inhaled corticosteroid therapy in asthma: a balancing act. PMID- 10094214 TI - Changing prevalence of allergic rhinitis and asthma. AB - OBJECTIVE: This review will enable the reader to discuss prevalence, risk factors, and prognosis of allergic rhinitis and asthma. DATA SOURCES: MEDLINE (PubMed) search using the terms allergic rhinitis, asthma, prevalence, risk factors. STUDY SELECTION: Human studies published in the English language since 1978, especially studies of relatively large populations in the United States, Great Britain, Australia, and New Zealand, with cross referencing to earlier relevant studies. RESULTS: Current prevalence of allergic rhinitis at 16 years of age in cohorts of British children born in 1958 and 1970 increased from 12% in the earlier cohort to 23% and in the later cohort. Local surveys of allergic rhinitis at approximately 18 years of age in the United States in 1962 to 1965 disclosed prevalence of 15% to 28%, while the national survey of 1976 to 1980 disclosed a prevalence of 26%. Thus, it is uncertain whether prevalence of allergic rhinitis has changed in the United States based on these limited data. Data from several sources indicate worldwide increases in prevalence of asthma. Annual Health Interview surveys indicate increases in prevalence of asthma in the United States from 3.1% in 1980 to 5.4% in 1994, but prevalence among impoverished inner city children has been much higher. Combined prevalence of diagnosed and undiagnosed asthma among inner city children has been 26% and 27% at 9 to 12 years of age in Detroit and San Diego. Positive family history and allergy are important risk factors for allergic rhinitis and asthma. Prognosis is guarded; allergic rhinitis resolves in only 10% to 20% of children within 10 years, and at least 25% of young adults who have had asthma during early childhood are symptomatic as adults. CONCLUSION: Increases in prevalence remain unexplained, but avoidance of recognized allergens should reduce the prevalence of allergic rhinitis and asthma. PMID- 10094215 TI - Markedly high eosinophilia and an elevated serum IL-5 level in an infant with cow milk allergy. AB - BACKGROUND: Interleukin-5 (IL-5) promotes the production and function of eosinophils, and an increase in the serum soluble CD23 (sCD23) level is suggestive of enhanced type-2 helper T-cell activity. The secretion of a large amount of the proinflammatory cytokine, tumor necrosis factor alpha (TNF-a), has been reported to alter the intestinal barrier capacity. OBJECTIVE: To determine whether or not distinct profiles of cytokine production were involved in the marked peripheral eosinophilia of as high as 20,000/mm3 and the gastrointestinal symptoms seen in an infant with cow milk allergy. METHODS: The levels of IL-5, sCD23, and TNF-alpha in serum and the culture supernatants of mononuclear cells were compared with those in infants with anaphylaxis to cow milk and nonallergic infants. RESULTS: Interleukin-5 was detected in the serum (19 pg/mL) but became undetectable after 2 weeks on a milk-free diet together with clinical remission. A kinetic decrease in the serum sCD23 level was also observed during the administration of a milk-free diet with improvement of the eosinophilia in 2 months. The TNF-alpha produced in vitro after stimulation with cow milk protein was not different from in controls. CONCLUSION: It seems likely that the allergic inflammation due to cow milk can induce marked eosinophilia with an associated increase in IL-5 production. PMID- 10094216 TI - Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. AB - BACKGROUND: The current stepwise approach to pharmacotherapy in the treatment of asthma includes the initiation of an inhaled corticosteroid with the addition of a long-acting inhaled bronchodilator if low dose inhaled corticosteroid fails to control asthma symptoms. OBJECTIVE: To determine whether initiation of salmeterol and fluticasone propionate treatment together improves asthma control greater than initiation of monotherapy with the individual agents alone with no additional safety risk in patients with asthma who had not previously been treated with inhaled corticosteroids. METHODS: A total of 136 male and female patients at least 12 years of age with asthma [forced expiratory volume in 1 second (FEV) between 50% and 80% of predicted] were randomized to twice daily salmeterol 42 microg, fluticasone propionate 88 microg, fluticasone propionate 220 microg, salmeterol 42 microg plus fluticasone propionate 88 microg, salmeterol 42 microg plus fluticasone propionate 220 microg, or placebo for 4 weeks. RESULTS: Patients treated with salmeterol combined with fluticasone propionate had improvements over baseline in FEV at endpoint that were at least twice as great (0.6 to 0.7 L) as improvements in patients treated with salmeterol (0.3 L) or fluticasone propionate alone (0.3 L) (P < .05). Patient-rated data (peak expiratory flow, asthma symptom scores, percent of days with no asthma symptoms) confirmed greater (P < .05) mean change from baseline improvements after combined treatment compared with fluticasone propionate alone. No clinically significant differences were noted between treatment groups in any safety measurement. CONCLUSION: Initiation of maintenance therapy with salmeterol and fluticasone propionate in patients with asthma treated with short-acting beta2-agonists alone provides greater improvements in pulmonary function and symptom control than initiation of maintenance therapy with fluticasone propionate alone. PMID- 10094217 TI - Reduction in health care resource utilization associated with extended-release theophylline. AB - BACKGROUND: People with airway disease are high utilizers of health care resources. Few studies document the value of alternative therapies in reducing utilization. Studies examining theophylline, which demonstrate reduction in resource utilization, have been primarily of short duration in hospitalized settings with small samples. OBJECTIVE: The purpose of this study was to examine the role of oral extended-release theophylline in reducing health care utilization over an extended period of time when added to existing inhaler therapy for ambulatory patients with airway disease. METHODS: We used a retrospective, pretest/posttest design in examining the 1990-1993 South Carolina Medicaid database to compare health care utilization of 455 ambulatory patients for 4 months before and 6 months after extended-release theophylline was added to their treatment regimen. We assessed the following three outcomes: inhaler use, physician office visits, and emergency department visits, all measured in units/person/month. RESULTS: Our sample consisted of patients taking beta2 agonist only (n = 393), steroid only (n = 25), and beta2-agonist plus steroid (n = 37). Inhaler use and physician office visits declined significantly among beta2 agonist users, as well as within the entire sample. Initiation of extended release theophylline therapy was associated with a 30% decline in utilization of inhaler and physician office visits, influenced mostly by the decline with the beta2-agonist group. CONCLUSION: The results of this effectiveness study using an administrative claims database are consistent with the published randomized clinical trials that document the value of extended-release theophylline when added to existing inhaler therapy. PMID- 10094218 TI - Diskus and diskhaler: efficacy and safety of fluticasone propionate via two dry powder inhalers in subjects with mild-to-moderate persistent asthma. AB - BACKGROUND: Fluticasone propionate is a topically active glucocorticoid with potent antiinflammatory activity in the treatment of asthma. OBJECTIVE: This study evaluated the safety and efficacy of fluticasone propionate administered via the Diskus and Diskhaler powder delivery devices in subjects with mild-to moderate asthma. METHODS: Fluticasone propionate (500 microg twice daily) or placebo was administered via the Diskus and Diskhaler to 213 adolescent and adult asthma subjects in a randomized, double-blind, double-dummy, parallel-group study for 12 weeks. Subjects were stratified according to baseline therapy of inhaled corticosteroids or beta2-agonists alone. Subjects were dropped from the study if they met predefined criteria for lack of efficacy. RESULTS: Fluticasone propionate improved pulmonary function both in subjects previously treated with inhaled corticosteroids or beta2-agonists alone. At endpoint, fluticasone propionate significantly improved forced expiratory volume in 1 second (P < .001), morning and evening peak expiratory flow (P < .001), and asthma symptom scores (P < or = .016), and significantly reduced nighttime awakenings (P = .016; Diskhaler group only) and rescue albuterol use (P < .001). Overall, efficacy measurements for the Diskus and Diskhaler were similar. More placebo-treated subjects (34%) withdrew from the study due to lack of efficacy than subjects in the Diskus (5%) or Diskhaler (5%) groups. The incidence and severity of adverse events were similar across groups. Measurement of plasma fluticasone propionate and cortisol concentrations showed no apparent influence of device on systemic exposure. CONCLUSION: Fluticasone propionate powder, administered via the Diskus or Diskhaler inhalation devices, was well tolerated and effective in the treatment of mild-to-moderate persistent asthma. PMID- 10094219 TI - Patient dropouts before completion of optimal dose, multiple allergen immunotherapy. AB - BACKGROUND: Many patients don't complete the recommended 3 to 5-year course of immunotherapy. Why? OBJECTIVE: Determine the percentage of our patients receiving optimal dose, multiple-allergen immunotherapy from 1982 to 1996 who discontinued their immunotherapy prior to completion of the recommended 3 to 5-year immunotherapy protocol. Second, assess the reasons for these premature dropouts. Third, determine any differences related to the clinic location where injections are given. DESIGN AND METHODS: The medical records of patients who dropped out of our immunotherapy program before 3 years were analyzed by the author. SUMMARY OF RESULTS: Our dropout rate before 3 years was 12%. The five commonest reasons for early dropout were concurrent medical problems, noncompliance, change of residence, inconvenience, and allergic reactions. The systemic reaction rate for the 3-year dropout group was 1.00% compared with 0.9% for our overall study group. Eighty-eight percent of the systemic reactions were mild. About 1% of our immunotherapy patients quit early due to allergic reactions secondary to immunotherapy. CONCLUSIONS: The dropout rate for our optimal-dose patients is similar to/that reported previously by Tinkelman who apparently used a lower than optimal maintenance dose. (2) Many of our dropouts were predictable and avoidable. Few patients quit early due to allergic reactions secondary to our immunotherapy program. PMID- 10094220 TI - Trends in asthma mortality in young people in southern Brazil. AB - BACKGROUND: Mortality from asthma increased and is now declining in some countries, but little is known about these trends in South America. OBJECTIVE: We aimed to assess trends in mortality from asthma in southern Brazil in children and young adults. METHODS: Death certificates of 425 people in the state of Rio Grande do Sul aged between 5 and 39 years in whom asthma was reported to be the underlying cause of death during the period 1970 to 1992 were reviewed. Population data were available in 10-year age groups. Testing for trends in mortality rates was conducted using linear and log-linear regression procedures. RESULTS: Asthma mortality rates in the age groups 5 to 19 and 20 to 39 years ranged between 0.04 and 0.39/100,000 and 0.28 to 0.75/100,000, respectively, and were nonuniformly distributed over the study period. The mean annual increase in rate in 5- to 19-year olds was +0.01 (95% CI 0.003 to 0.016), an average annual percentage increase of +6.8% (95% CI 3% to 11%), with a total increase of 352% between 1970 and 1992. This increase was not due to a shift in labeling from bronchitis to asthma. In the 20 to 39-year age group, asthma and bronchitis mortality rates showed no trend to increase or decrease. CONCLUSIONS: Asthma mortality in southern Brazil is low, but rose significantly between 1970 and 1992 in the 5 to 19-year age group. This trend differs from that found in other states of Brazil and several other Latin American countries. Reasons for this difference remain unclear. PMID- 10094221 TI - Selective enhancement of production of IgE, IgG4, and Th2-cell cytokine during the rebound phenomenon in atopic dermatitis and prevention by suplatast tosilate. AB - BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disease, which is commonly treated with topical steroids. It is, however, associated with rebound after therapy has been discontinued. OBJECTIVE: This study was designed to elucidate the mechanisms of the rebound phenomenon, and to test the effect of an oral anti-allergic medication, suplatast tosilate, on atopic dermatitis. METHODS: This is a randomized, placebo controlled study. Patients with atopic dermatitis who had been treated with strong steroid ointment (dexamethasone valerate) for several years were divided into two groups. One group (the control group, n = 15) was treated with a non-steroid anti-inflammatory ointment (bufexamac ointment), while the other group (the suplatast tosilate group, n = 17) was treated with the anti-allergic medications, suplatast tosilate and bufexamac ointment. In each group, in vitro production of immunoglobulins and cytokines before and after 2 weeks of treatment was measured. RESULTS: In the control group, 15 of the 15 patients experienced rebound and mean production of IgE, IgG4, IL-4, IL-5, IL-10, and IL-13 was enhanced after 2 weeks. In contrast, only 2 of the 17 patients in the suplatast tosilate group experienced rebound. There was no enhancement of production of immunoglobulins and cytokines after 2 weeks of treatment. CONCLUSION: Enhanced production of the Th2-cell cytokines, which selectively induces IgE and IgG4 production, may be involved in the pathogenesis of the rebound phenomenon, and that suplatast tosilate may prevent the rebound phenomenon by down-regulating the production of these cytokines. PMID- 10094222 TI - National guidelines needed to manage rhinitis and prevent complications. AB - OBJECTIVES: Rhinitis is an extremely common disease worldwide and nasal allergies are one of the major causes of the condition. Allergic rhinitis not only produces a range of nasal and non-nasal symptoms, but it has been closely associated with other chronic airways diseases, such as asthma and sinusitis. This review was undertaken to evaluate the relationship of allergic rhinitis to these diseases and to provide support for proposing national guidelines for managing rhinitis. DATA SOURCES: Relevant studies in English were searched for using MEDLINE, bibliographies from obtained articles, and consultation with experts. STUDY SELECTION: All major studies related to the epidemiology and effects of allergic rhinitis and the relationship between allergic rhinitis and asthma, sinusitis, and other airways diseases were reviewed. DATA SYNTHESIS: There is substantial scientific and clinical evidence that allergic rhinitis frequently coexists with asthma, and sinusitis and may be a predisposing factor for both. In addition, a number of studies have demonstrated that nasal inflammation and obstruction directly affect pulmonary function and clinical symptoms of asthma. Finally, it has been clearly demonstrated that treating allergic rhinitis with antihistamines, nasal corticosteroids, immunotherapy, and allergen avoidance have a significant, positive effect on lung function and asthma symptomology. CONCLUSIONS: The prevalence of allergic rhinitis, asthma, and sinusitis are increasing. Asthma and sinusitis can be debilitating conditions. Asthma alone can be life threatening and costly to treat. The timely and optimal treatment of allergic rhinitis may help prevent these conditions or, at least, prevent them from worsening. Consequently, there is an immediate need to establish national, evidence-based, practice guidelines to assist primary care physicians in diagnosing and managing rhinitis and in evaluating and managing rhinitis and in evaluating and managing allergic rhinitis coexisting with other airways diseases. PMID- 10094223 TI - Effect of two different types of vacuum cleaners on airborne Fel d 1 levels. AB - BACKGROUND: Vacuum cleaners may increase the level of airborne allergens by leakage through the cleaners or by disturbance of floor dust by the exhaust air produced. OBJECTIVE: The aim of this study was to evaluate the short-term effect of vacuum cleaning with two different types of cleaners on airborne cat allergen analyzed by a biologic and by an immunochemical test. METHODS: Ten homes with cats were cleaned in random order with a 1-week interval by a traditional canister type vacuum cleaner (T) and a semi-stationary vacuum cleaner (S) that conducts the air to the exterior through a valve in the wall. Airborne particles were collected by air sampling for 2 hours and cat allergen, Fel d 1, was quantified biologically by basophil histamine release test (HR test) and immunochemically by enzyme linked immunosorbent assay (ELISA). RESULTS: Using the S resulted in smaller amounts of airborne cat allergen than the T (mean 2.1 ng/m3 air (range .8 to 12.5) versus 5.2 ng/m3 (1.3 to 13.3), P < .002 measured by ELISA). Results from ELISA and HR test correlated well (r = .91, P < .001). CONCLUSIONS: The use of S with exhaust to the outside of the dwelling gave rise to less airborne low particle size allergen during the cleaning procedure than a T method. The basophil histamine release test could be a valid alternative method to establish allergen content in environmental samples especially in allergen systems with no available monoclonal antibodies. PMID- 10094224 TI - Thorax high resolution computerized tomography findings in asthmatic children with unusual clinical manifestations. AB - BACKGROUND: It has been consistently observed in high resolution computerized tomography (HRCT) scans that asthmatic patients manifest more abnormalities related to airways remodeling than do normal subjects. OBJECTIVE: To find the underlying abnormalities in the lungs of asthmatic children with unusual manifestations. METHOD: Asthmatic children not responding as expected to inhaled steroid therapy with or without localized permanent or temporary recurrent auscultation findings (rales) were evaluated with chest radiographs and HRCT scans. Bronchoscopy was performed on the ones with localized rales. RESULTS: The sample consisted of 16 asthmatic children (6 girls and 10 boys, mean age = 7.75+/ 4.43 years). Chest radiograph abnormality rate was 44% and the thorax HRCT scan abnormality rate was 75% (56% fibrotic retractions, 38% atelectasis, 19% bronchiectasis, and 19% bronchial wall thickening). Two patients with localized permanent rales and with right middle lobe (RML) atelectasis in HRCT scan underwent bronchoscopy which revealed RML syndrome due to mucus plugging in one and lymph node pressure in the other. In one patient with localized temporary recurrent rales and major bronchiectasis in HRCT scan, bronchoscopy revealed bronchitis. The patient with RML syndrome due to mucus plugging required lobectomy. CONCLUSION: We conclude with this experience that thorax HRCT scanning may be a helpful adjunct in the evaluation of an asthmatic children with atypical clinical findings. PMID- 10094225 TI - High performance medical image processing in client/server-environments. AB - As 3D scanning devices like computer tomography (CT) or magnetic resonance imaging (MRI) become more widespread, there is also an increasing need for powerful computers that can handle the enormous amounts of data with acceptable response times. We describe an approach to parallelize some of the more frequently used image processing operators on distributed memory architectures. It is desirable to make such specialized machines accessible on a network, in order to save costs by sharing resources. We present a client/server approach that is specifically tailored to the interactive work with volume data. Our image processing server implements a volume visualization method that allows the user to assess the segmentation of anatomical structures. We can enhance the presentation by combining the volume visualizations on a viewing station with additional graphical elements, which can be manipulated in real-time. The methods presented were verified on two applications for different domains. PMID- 10094226 TI - Spatial positioning of an hip stem solid model within the CT data set of the host bone. AB - A new protocol is proposed which allows the spatial registration of a prosthetic hip stem solid model with the CT data set of the host bone collected pre operatively using a limited number of reference landmarks taken from post operative images. Although based on well know algorithms, such as the Single Value Decomposition, this method opens new possibilities to the three-dimensional modelling of operated bones. In a preliminary experiment based on a synthetic human femur replica the proposed protocol achieved a global accuracy of 1.53 mm (root mean square error of the centre location of ten control sections) using only six CT post-operative slices. This methodology allows an accurate three dimensional modelling of operated bone which have been implanted with high density metallic devices which produce relevant artefacts in post-operative CT images. PMID- 10094227 TI - Using 'off the shelf', computer programs to mine additional insights from published data: diurnal variation in potency of ACTH stimulation of cortisol secretion revealed. AB - We describe the use of available computer programs to mine additional insights from published data. Graphs from four studies of ACTH and cortisol plasma levels collected throughout the 24 h day in humans were scanned into digital form and the data points extracted. To investigate the magnitude of ACTH stimulation of cortisol secretion across the 24 h, Monte Carlo methods were used to fit the parameters of a computer model of the ACTH-adrenal axis to the extracted data. ACTH was found to have a greater effect on cortisol secretion during the peaks of the cycle than at the nadir. This finding could not be explained by previously published dose response curves of ACTH effect. This implies that other modulators influence the effect of ACTH on the adrenal. This study also demonstrates how available computer programs can be used to examine models of physiologic regulation using data already available in the literature. PMID- 10094228 TI - Applying wavelet-transform on Internet-based radiologic brain images. AB - Wavelet-transform compression creates high-quality images of small file size by tuning its compression ratio between 10:1 and 80:1. We applied the wavelet-based compression technique to radiologic brain images on the Internet for image display purposes. Wavelet transform compression reduces file size up to 50%. Wavelet transform compression offers the advantage of retaining complete color information in digital images and faster Internet transmission than traditional Joint Photography Experts Group (JPEG) files of equivalent file size. The application of wavelet-based compression technique decreases storage requirements for images on Internet servers. PMID- 10094229 TI - EasyBound--a user-friendly approach to nonlinear regression analysis of binding data. AB - The introduction of non-linear regression analysis of data from pharmacological experiments has provided an enormous advantage in making it possible to analyze raw data without any mathematical transformation. However, the disadvantage has been the lack of computer programs with simple user interfaces and the ability to easily handle large amounts of data. With the aim to develop a light-weight and still powerful program we have written an application called EasyBound which is designed to be used with Microsoft Excel and hence takes advantage of the abilities of the spreadsheet application to handle large amounts of data. Focus has been on creating an easy-to-understand user interface. There are commercial programs available, but they tend to be very complex and difficult to grasp for inexperienced users. EasyBound displays original data, calculated results and graphs on the same sheet/page. The program fully implements the most powerful algorithms for non-linear regression analysis, giving results that are more accurate than using built-in iterative analysis functions of the spreadsheet application without compromising ease of use. PMID- 10094230 TI - Structure of the standardized computerized 24-h diet recall interview used as reference method in the 22 centers participating in the EPIC project. European Prospective Investigation into Cancer and Nutrition. AB - A computerized 24-h diet recall interview program (EPIC-SOFT) was developed for use in a large European multi-center study, namely the European Prospective Investigation into Cancer and Nutrition (EPIC). This program, which was adapted for each participating country and translated into nine languages, was developed to standardize interviews between the 22 EPIC centers. Common rules were pre entered into the system to describe, quantify and probe approximately 1500-2200 foods and 150-350 recipes. Common methods used to classify and export the EPIC SOFT dietary data facilitate their exchange, comparison and analysis. So far, EPIC-SOFT is the only available computerized 24-h diet recall system developed to provide comparable food consumption data between several European countries. PMID- 10094231 TI - Using semantic constraints to help verify the completeness of a computer-based clinical guideline for childhood immunization. AB - The paper describes Commander, a prototype computer program designed to help verify the completeness of a computer-based clinical practice guideline built using if then rules. It also describes the application of Commander to a guideline for childhood immunization. Commander is designed to help identify incomplete rule sets, where there are clinically meaningful conditions to which the guideline does not respond. To allow this, the user defines semantic constraints, in the form of if-then statements, which indicate combinations of conditions which are not meaningful. In an iterative process, Commander takes the guideline rules, together with an increasingly refined set of constraints and helps focus in on any combinations of conditions to which the guideline does not respond. When applied to the clinical guideline for childhood immunization, Commander was able to dramatically reduce the number of potential combinations of conditions for consideration and also identified several areas of incompleteness in the rules. PMID- 10094232 TI - Residual analysis in random regressions using SAS and S-PLUS. AB - A program package RRAP: Random Regression Residual Analysis Program using SAS [1] and S-PLUS [2] is available for performing random regression residual analysis. The PROCEDURE MIXED from SAS is used for statistical inference. Both elementary level and individual-level residuals are used. The S-PLUS programs provide: (1) a transformation to orthogonalize the elementary-level correlated residuals for standard regression residual analyses; and (2) several statistics and plots for checking model assumptions, assessing model fitting and detecting outlying individuals. RRRAP starts with a SAS Macro RRRAPMAC on the data followed by a S PLUS Program DoRRRAP on a UNIX system. PMID- 10094233 TI - Electrophysiological evidence for an inverse benzodiazepine receptor agonist in panic disorder. AB - Inverse agonists of the GABA(A) receptor clearly decrease the amplitudes of the spontaneous EEG in the beta-frequency range. Therefore, we tested the hypothesis that panic patients exhibit a reduction of the EEG's spectral power in the beta frequency band. Ten unmedicated patients with panic disorder and agoraphobia according to DSM-III-R criteria and 10 matched controls were investigated under baseline conditions, after hyperventilation and 30 min after hyperventilation. EEG recordings from the position Pz and Cz were performed under eyes closed conditions. At baseline conditions the patients suffering from panic disorder depicted a reduced beta-power reaching statistically significance for lead position Pz. Immediately after hyperventilation for both channels we observed a decreased beta-power. After hyperventilation we observed the same situation as under baseline conditions. Taken together, our results point to the view that in panic disorder an endogenous inverse agonist of the GABA(A)-benzodiazepine receptor could be hypothesized. PMID- 10094234 TI - Neuropsychological function and cerebral glucose utilization in isolated memory impairment and Alzheimer's disease. AB - We hypothesized that 20 patients with isolated memory impairment (IMI) would demonstrate [18F]-2-fluoro-2-deoxy-D-glucose utilization and a progression of neuropsychological symptoms consistent with Alzheimer's disease (AD). IMI subjects performed similarly to AD in recall and verbal fluency, but comparable to normal subjects in other areas of cognitive functioning. A positron emission tomography (PET) diagnostic index based on parietal Z-scores categorized IMI patients into normal and abnormal metabolic patterns. Ten of the original 20 IMI patients (50%) reflected PET AD abnormalities. Clinical information was available for IMI patients at three-year follow-up. Ten (50%) had converted to AD, three were found to have pseudodementia and the seven remained IMI. Of the 10 IMI patients with an originally normal PET index, three (30%) were diagnosed with AD at three years. Of the 10 with an abnormal index originally, seven (70%) converted to AD. The finding that memory deficit in IMI was as pronounced as that in AD patients is consistent with the notion that memory is an initial symptom of AD. A substantial number of the IMI patients reflected regional hypometabolism similar to AD, suggesting that IMI is likely an early stage in progressive dementia. A large percentage of IMI patients converted clinically to AD within three years of initial study, though we observed impaired memory functioning well before a clinical diagnosis of AD could be made. In addition to potential clinical utility, IMI and PET represent an opportunity to study dementia in relation to brain chemistry at a time when brain pathology is in the process of development. PMID- 10094235 TI - Serotonin and learned helplessness: a regional study of 5-HT1A, 5-HT2A receptors and the serotonin transport site in rat brain. AB - Serotonin (5-HT) plays a central role in the neurochemistry of the learned helplessness animal model of depression. Using quantitative autoradiography, we measured the density of 5-HT1A and 5-HT2A receptors and of 5-HT transport sites in medial prefrontal cortex, dorsal hippocampus, septum, hypothalamus, and amygdala in learned helpless rats, and in rats that were nonhelpless after inescapable stress, as well as in shuttlebox-tested and nonhandled controls. We found no changes in 5-HT1A receptor density among the groups in any region studied. In dorsal hippocampus, 5-HT2A receptor density was decreased in nonhelpless rats, while in amygdala 5-HT2A receptor density was decreased in both groups of stressed rats, whether helpless or nonhelpless. In the hypothalamus 5 HT2A receptor density, was decreased in helpless rats as compared to controls. In medial prefrontal cortex, the serotonin transport sites showed decreased density in helpless rats as compared to controls but not to nonhelpless rats. These findings further highlight the complexity of regional 5-HT effects in the learned helplessness animal model. PMID- 10094236 TI - Two year follow-up of atypical depression. AB - The symptom cluster of Atypical Depression (AD) has been characterized based on its presentation and selective response to pharmcological treatments, while relatively little is known about the outcome of these patients after treatment trials. The present study was undertaken to assess the long term outcome of 40 patients after a controlled treatment trial of fluoxetine vs phenelzine. Twenty five of these subjects were interviewed approximately two years after completion of the initial trial. They reported a high frequency of symptom recurrence, but generally little symptomatic or social impairment between episodes. Eighteen subjects were taking antidepressants at follow-up. A higher frequency of depressive episodes was recorded during the times when off antidepressant medications. Overall outcome was rated as moderate or good in the majority of subjects. These results suggest that AD presents from similarities with other subtypes of depression, with high rates of symptomatic recurrence and lasting response to chronic antidepressant treatment. Conversely, social functioning and overall outcome appear more favorable in AD. PMID- 10094237 TI - Temperament and character inventory (TCI) and depression. AB - Although several studies have assessed the relationships between the temperament dimensions of the Cloninger model of personality and depression, little is known about the role played by the character dimensions proposed by the seven-factor model of Cloninger in depression. In this study, the relationships between the Temperament and Character Inventory (TCI) and depression were examined in a sample of 40 major depressive patients and 40 healthy controls. Depressed patients exhibit higher harm avoidance and self-transcendence scores as well as lower self-directedness and cooperativeness scores as compared to healthy controls. However, the three other dimensions do not differ between depressive patients and controls. Among the depressive group, harm avoidance, self directedness and cooperativeness dimensions are related to the severity of depression as assessed by the Hamilton scale. This study confirms the state dependence of the harm avoidance dimension and suggests a relationship between the character dimensions of the Cloninger model and depression. PMID- 10094238 TI - Assessment of parent-of-origin effect in families unlineally affected with panic disorder-agoraphobia. PMID- 10094239 TI - Brain N-acetyl aspartate concentrations measured by H MRS are reduced in adult male rats subjected to perinatal stress: preliminary observations and hypothetical implications for neurodevelopmental disorders. AB - The present study was undertaken to determine if the concentration of brain N acetyl-aspartate (NAA), a putative neuronal marker, is reduced in adult rats subjected to stress during the perinatal period. As the prenatal stressor, pregnant rats were subjected to restraint stress for one hour twice daily from days 14-21 of gestation; stressed offspring were reared by normal dams and studied as adults. As the postnatal stressor, normal pups were reared by prenatally 'stressed' dams and studied as adults. As compared to non-stressed controls (n=6), NAA concentrations were significantly reduced 21 and 25% in left frontal cortex from the prenatal (n=4) and postnatal (n=6) stress groups. respectively. The data suggest that in perinatally stressed adult offspring permanent neuronal damage or loss has occurred. While no direct causal associations between perinatal stress and the developmental of particular disorders can be inferred from these limited data, the effects of perinatal stress on subsequent brain neuropathology are reviewed. particularly in relation to NAA. For hypothesis-generating purposes, the possible relevance of stress and NAA to the neurodevelopmental hypothesis of schizophrenia is discussed in greater detail. PMID- 10094240 TI - Depressive comorbidity of panic, social phobic, and obsessive-compulsive disorders re-examined: is there a bipolar II connection? AB - Utilizing the DSM-III-R schema, we have investigated lifetime comorbidity between panic disorder with or without agoraphobia (PD), social phobia (SP) and obsessive compulsive disorder (OCD) on the one hand, and mood disorder on the other. Compared with PD, the results for SP and OCD showed significantly higher numbers of comorbid anxiety and mood disorders. In addition, SP and OCD were significantly more likely to cooccur with each other than with PD. The complexity of these comorbid patterns is underscored by the finding of significantly higher numbers of anxiety disorders in those with lifetime comorbidity with bipolar (especially bipolar II) disorder. We conclude that the comorbidity between anxiety and mood disorders - conventionally conceived as the relationship between anxiety and unipolar depressive states -- might very well extend into the domain of bipolar spectrum disorders in a subset of these disorders. Among the latter, the spontaneous or antidepressant-induced switches into brief disinhibited (hypomanic) behavior can be conceptualized to lie on a dimensional continuum with the temperamental inhibition (or constraint) underlying the anxiety disorders under discussion. These findings and theoretical considerations have important therapeutic implications. PMID- 10094241 TI - A psychiatric 12-year follow-up of adult patients with neurofibromatosis type 1. AB - The impact of neurofibromatosis type 1 (NF1) on psychiatric symptoms and diagnoses, personality variables and self evaluation was studied in a 12 year follow-up of patients with NF 1 in the city of Goteborg, Sweden. 48 living adult patients with NF1 were re-evaluated in 1990 in a 12 year long time follow up study. The patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders. The following scales were used; the Comprehensive Psychopathological Rating Scale (CPRS), the Karolinska Scales of Personality inventory (KSP) and the Self-Evaluation Scale (SES). A significant psychopathology was found in the NFI patients, p <0.001. One third of the patients were affected by a psychiatric disease, 21% by dysthymia. There was no significant progress in psychiatric symptoms in the follow up period. The personality profile disclosed a heightened self-esteem. The chronic stigmatizing character of NF1 may be the reason for the increased psychopathology found. PMID- 10094242 TI - Worsening of delusional depression after sleep deprivation: case reports. AB - Five patients (three bipolars and two unipolars) affected by a major depressive episode with psychotic features were treated with total sleep deprivation (TSD) without concurrent psychotropic medication. After TSD we observed a worsening in psychotic as well as in depressive symptoms as rated on the Dimension of Delusional Experience Rating Scale and on Hamilton Rating Scale for Depression, respectively. TSD is known to markedly enhance the activity of brain monoaminergic pathways. Given the interaction between brain serotonergic and dopaminergic systems in delusional depression, it is possible that an enhancement in dopaminergic activity may be responsible of the symptomatological worsening in delusional depressives observed after TSD. PMID- 10094243 TI - Epinephrine-induced panic attacks and hyperventilation. AB - To assess the effects of epinephrine on ventilation in patients with panic disorder and in social phobics, analyses were performed on pooled data from two previous infusion studies. Throughout the infusion, changes in transcutaneous PCO2 (tcPCO2), subjective anxiety, heart rate and blood pressure were recorded continuously. Twenty-nine patients received epinephrine, ten patients received placebo. Thirteen patients (45%) had a panic attack during epinephrine. The fall in tcPCO2 and the cardiovascular response was greater in panicking patients than patients who did not panic. Although the fall in tcPCO2 associated with panic was not substantial and did not indicate clinically significant acute hyperventilation, it appears to be a sensitive index for epinephrine-induced panic. The fall in tcPCO2 was predicted rather by the frequency of occurrence of anxiety-related somatic symptoms than by the fear of these symptoms. These findings further reduce a role for fear of bodily sensations in epinephrine induced panic attacks and favor a biological sensitivity to sympathetic stimulation. PMID- 10094244 TI - Evaluation of the potential immunotoxicity of bromodichloromethane in rats and mice. AB - In the past two decades, concern has been expressed over the potential carcinogenicity of disinfection by-products (DBPs) found in chlorinated drinking water. More recently, research efforts have expanded to include noncancer endpoints as well. The objective of the present studies was to evaluate the potential of bromodichloromethane (BDCM), one of the most prevalent DBPs, to adversely affect immune function in mice and rats following drinking water or gavage exposure. Antigen-specific immunity was assessed as the antibody response to sheep erythrocytes; responses to T- and B-cell mitogens were evaluated as a non-antigen-specific measure of the proliferative potential of splenic and mesenteric lymph node lymphocytes. In consideration of an exposure route relevant to humans, C57BL/6 mice received 0.05, 0.25, or 0.5 g BDCM/L and F344 rats received 0.07 or 0.7 g BDCM/L via drinking water. In order to evaluate the effects of higher doses, animals were administered 50, 125, or 250 mg BDCM/kg/d (mice) or 75, 150, or 300 mg BDCM/kg/d (rats) via gavage. Under the conditions of these studies, no significant adverse effects on immune function were observed in mice. Despite some changes that were observed in non-antigen-specific immunity in rats, these experiments suggest that the immune system is not a sensitive target organ for BDCM toxicity. PMID- 10094245 TI - Aroclor 1242 inhalation and ingestion by Sprague-Dawley rats. AB - PCBs have been considered to be almost nonvolatile and insoluble in water. However, recent studies have shown the importance of their slight solubility in water and capability to enter the atmosphere and disperse throughout the global environment. This preliminary study was designed to measure uptake and observe any physiological changes in Sprague-Dawley rats. The PCB product Aroclor 1242 is the major pollutant of the Hudson River, NY, and New Bedford Harbor, MA. The rats were exposed for 30 d to 0.9 microg/m3 via inhalation and 0.436 microg/g (ppm) in the food. The inhalation of PCBs gave a greater PCB uptake than ingestion. Both routes of administration caused significant serum thyroid hormone elevations. Histopathologic changes were observed in the urinary bladder, thymus, and the thyroid after both exposure regiments. Rearing and ambulation were significantly decreased in both exposure regiments in an open field behavior test. PMID- 10094246 TI - Coal fly ash- and copper smelter dust-induced modulation of ex vivo production of tumor necrosis factor-alpha by murine macrophages: effects of metals and overload. AB - The objective of this study was to assess the effect of two arsenic-containing particles, coal fly ash (FA) and copper smelter dust (CU), on lung integrity and on the ex vivo release of tumor necrosis factor alpha (TNF-alpha) by alveolar phagocytes. Particle effects were compared in nonoverload condition on the basis of a low but identical volume load and arsenic content intratracheally instilled in the mouse lung (273 nl/mouse and 186 ng arsenic/mouse; FAL and CUL groups). Other mice received 600 ng arsenic/mouse in amounts of particles leading to different volume loads (FAH and CUH groups: 880 and 273 nl/mouse, respectively). Animals were sacrificed at 1, 6, 30, or 120 d (FAL and CUL groups) or at 6 and 120 d posttreatment (FAH and CUH groups). Biochemical markers and inflammatory cell number and type were analyzed in bronchoalveolar lavage, ex vivo TNF-alpha production by alveolar phagocytes was assessed, and measurement of arsenic lung content and histopathological examinations were performed. Our results show that coal fly ash and copper smelter dust bear distinct inflammatory properties. At the end of the observation period (d 120), the high CU dose (CUH) produced a fibrotic reaction whereas the high dose of FA particles (FAH) generated a delayed and persistent lung inflammatory reaction associated with lymphoid noduli. Marked differences in TNF-alpha production were observed within the CU and FA groups. CU particles, conceivably through their metal content, decreased TNF-alpha production by alveolar phagocytes. Due to their low arsenic content, considerably higher FA particle doses needed to be administered to produce an inhibition of TNF-alpha production. Since high doses of FA (FAH) caused an overload condition, our results do not allow us to decide whether FA-mediated TNF-alpha reduction is due to the load administered or to the metallic content. PMID- 10094247 TI - Pancreatic cancer mortality and total hardness levels in Taiwan's drinking water. AB - The possible association between the risk of pancreatic cancer mortality and hardness levels in drinking water from municipal supplies was investigated in a matched case-control study in Taiwan. All eligible pancreatic cancer deaths (883 cases) of Taiwan residents from 1990 through 1994 were compared with deaths from other causes (883 controls), and the hardness levels of the drinking water used by these residents were determined. Data on water hardness throughout Taiwan was collected from Taiwan Water Supply Corporation (TWSC). The control group consisted of people who died from other causes and were pair matched to the cancer cases by sex, year of birth, and year of death. The results show that there is a 39 % excess risk of mortality from pancreatic cancer in relation to the use of soft water. Trend analyses showed an increasing odds ratio for pancreatic cancer with decreasing levels of hardness in drinking water. This is an important finding for the Taiwan water industry and human health. PMID- 10094248 TI - Unilateral pallidotomy for advanced Parkinson's disease. PMID- 10094249 TI - Attention and executive deficits in Alzheimer's disease. A critical review. AB - In this review we summarize the progress that has been made in the research on attentional and executive deficits in Alzheimer's disease. Like memory, attention is now recognized as consisting of subtypes that differ in their function and anatomical basis. We base our review upon a classification of three subtypes of attention: selective, sustained and divided. This model derives from lesion studies, animal electrophysiological recordings and functional imaging. We examine how these subcomponents of attention can be reconciled with neuropsychological models of attentional control, particularly the Supervisory Attentional System and the Central Executive System of Shallice and Baddeley, respectively. We also discuss the relationship of attention to the concept of executive function. Current evidence suggests that after an initial amnesic stage in Alzheimer's disease, attention is the first non-memory domain to be affected, before deficits in language and visuospatial functions. This is consistent with the possibility that difficulties with activities of daily living, which occur in even mildly demented patients, may be related to attentional deficits. It appears that divided attention and aspects of selective attention, such as set-shifting and response selection, are particularly vulnerable while sustained attention is relatively preserved in the early stages. The phenomenon of cognitive slowing in Alzheimer's disease and normal ageing emphasizes the need to discriminate quantitative changes in attention dysfunction from qualitative changes which may be specifically related to the disease process. The neuropathological basis of these attentional deficits remains unsettled, with two competing hypotheses: spread of pathology from the medial temporal to basal forebrain structures versus corticocortical tract disconnection. Finally we discuss the difficulties of comparing evidence across studies and look at the implications for the design of future studies and future directions that may be fruitful in the research on attention in Alzheimer's disease. PMID- 10094250 TI - Relationship of lesion location to clinical outcome following microelectrode guided pallidotomy for Parkinson's disease. AB - The purpose of this study was to examine the relationship between lesion location and clinical outcome following globus pallidus internus (GPi) pallidotomy for advanced Parkinson's disease. Thirty-three patients were prospectively studied with extensive neurological examinations before and at 6 and 12 months following microelectrode-guided pallidotomy. Lesion location was characterized using volumetric MRI. The position of lesions within the posteroventral region of the GPi was measured, from anteromedial to posterolateral along an axis parallel to the internal capsule. To relate lesion position to clinical outcome, hierarchical multiple regression analysis was used. The variance in outcome measures that was related to preoperative scores and lesion volume was first calculated, and then the remaining variance attributable to lesion location was determined. Lesion location along the anteromedial-to-posterolateral axis within the GPi influenced the variance in total score on the Unified Parkinson's Disease Rating Scale in the postoperative 'off' period, and in 'on' period dyskinesia scores. Within the posteroventral GPi, anteromedial lesions were associated with greater improvement in 'off' period contralateral rigidity and 'on' period dyskinesia, whereas more centrally located lesions correlated with better postoperative scores of contralateral akinesia and postural instability/gait disturbance. Improvement in contralateral tremor was weakly related to lesion location, being greater with posterolateral lesions. We conclude that improvement in specific motor signs in Parkinson's disease following pallidotomy is related to lesion position within the posteroventral GPi. These findings are consistent with the known segregated but parallel organization of specific motor circuits in the basal ganglia, and may explain the variability in clinical outcome after pallidotomy and therefore have important therapeutic implications. PMID- 10094251 TI - Reassessment of unilateral pallidotomy in Parkinson's disease. A 2-year follow-up study. AB - Unilateral pallidotomy has gained popularity in treating the motor symptoms of Parkinson's disease. We present the results of a 2-year post-pallidotomy follow up study. Using the Unified Parkinson's Disease Rating Scale (UPDRS), the Goetz dyskinesia scale and the Purdue Pegboard Test (PPBT), we evaluated 20 patients at regular intervals both off and on medications for 2 years post-pallidotomy. There were no significant changes in the dosages of antiparkinsonian medications from 3 months pre-pallidotomy to 2 years post-pallidotomy. On the side contralateral to the operation, the improvements were preserved in 'on'-state dyskinesia (83% reduction from pre-pallidotomy to 2 years post-pallidotomy, P < 0.001) and 'off' state tremor (90% reduction from pre-pallidotomy to 2 years post-pallidotomy, P = 0.005). There were no statistically significant differences between pre pallidotomy scores and those at 2 years post-pallidotomy in ipsilateral dyskinesia, axial dyskinesia, 'off'- or 'on'-state PPBT, 'off'-state Activities of Daily Living (ADL) and 'off'-state gait and postural stability. After 2 years, the 'on'-state ADL scores worsened by 75%, compared with pre-pallidotomy (P = 0.005). We conclude that 2 years after pallidotomy, the improvements in dyskinesia and tremor on the side contralateral to pallidotomy are preserved, while the initial improvements in most other deficits disappear, either because of progression of pathology or loss of the early efficacy achieved by surgery. PMID- 10094252 TI - Clinicopathological features of Churg-Strauss syndrome-associated neuropathy. AB - We assessed the clinicopathological features of 28 patients with peripheral neuropathy associated with Churg-Strauss syndrome. Initial symptoms attributable to neuropathy were acute painful dysaesthesiae and oedema in the dysaesthetic portion of the distal limbs. Sensory and motor involvement mostly showed a pattern of mononeuritis multiplex in the initial phase, progressing into asymmetrical polyneuropathy, restricted to the limbs. Parallel loss of myelinated and unmyelinated fibres due to axonal degeneration was evident as decreased or absent amplitudes of sensory nerve action potentials and compound muscle action potentials, indicating acute massive axonal loss. Epineurial necrotizing vasculitis was seen in 54% of cases; infiltrates consisted mainly of CD8-positive suppressor/cytotoxic and CD4-positive helper T lymphocytes. Eosinophils were present in infiltrates, but in smaller numbers than lymphocytes. CD20-positive B lymphocytes were seen only occasionally. Deposits of IgG, C3d, IgE and major basic protein were scarce. The mean follow-up period was 4.2 years, with a range of 8 months to 10 years. Fatal outcome was seen only in a single patient, indicating a good survival rate. The patients who responded well to the initial corticosteroid therapy within 4 weeks regained self-controlled functional status in longterm follow-up (modified Rankin score was < or = 2), while those not responding well to the initial corticosteroid therapy led a dependent existence (P < 0.01). In addition the patients with poor functional outcomes had significantly more systemic organ damage caused by vasculitis (P < 0.05). Necrotizing vasculitis mediated by cytotoxic T cells, leading to ischaemic changes, appears to be a major cause of Churg-Strauss syndrome-associated neuropathy. The initial clinical course and the extent of systemic vasculitic lesions may influence the long-term functional prognosis. PMID- 10094253 TI - Does withdrawal of different antiepileptic drugs have different effects on seizure recurrence? Further results from the MRC Antiepileptic Drug Withdrawal Study. AB - One thousand and thirteen patients, in remission of epilepsy for at least 2 years, were randomized to continued therapy or slow withdrawal over 6 months and were followed up for a median period of 5 years. At the time of randomization 83% of patients were receiving monotherapy with carbamazepine (237 patients), phenobarbitone/primidone (72 patients), phenytoin (184 patients) or valproate (228 patients) in low doses, and plasma levels were below the usual optimal range. The most important factor determining seizure recurrence was continued therapy, which was the case for barbiturates, phenytoin and valproate. There was no significant difference for patients taking carbamazepine at randomization, because of a low rate of recurrence in those withdrawing treatment. The difference between carbamazepine and other drugs was not explained by differences in covariate prognostic factors. There was no evidence that withdrawal of phenobarbitone was associated with withdrawal seizures. These data provide unique evidence for the effectiveness of standard antiepileptic drugs as monotherapy. The results for carbamazepine may be open to a number of interpretations. PMID- 10094255 TI - Coherent cortical and muscle discharge in cortical myoclonus. AB - There is increasing evidence in man that the cortical drive to motor neurons is rhythmic. This oscillatory drive may be exaggerated in patients with cortical myoclonus. Spectral analysis of surface bipolar EEG and EMG activity was performed in eight such patients. Only three cases had evidence of giant cortical evoked potentials or a cortical correlate on back-averaging at the time of study. In six subjects, significant coherence between contralateral and vertex EEG and EMG was observed in ranges similar to that previously reported for normal subjects (15-30 and 30-60 Hz). Three out of these six subjects also had significant coherence at higher frequencies (up to 175 Hz). All eight patients had a correlate in the cumulant density estimate between EEG and contralateral EMG. EMG lagged EEG by about 14, 25 and 35 ms for the muscles of the forearm, hand and foot, respectively. These delays were estimated from the slope of the phase curves and the timing of the peaks in the cumulant density estimates, and are appropriate for conduction in fast pyramidal pathways. The results provide clear evidence of a cortical drive synchronizing muscle discharge over a broad range of frequencies in patients with cortical myoclonus. Fourier analysis is a promising technique in the diagnosis and investigation of such patients. PMID- 10094254 TI - The distribution of ganglioside-like moieties in peripheral nerves. AB - GM1 ganglioside has been implicated as a target of immune attack in some diseases of the peripheral nervous system. Anti-GM1 ganglioside antibodies are associated with certain acquired immune-mediated neuropathies. It is not clear how anti-GM1 antibodies cause nerve dysfunction and injury; however, sodium and/or potassium ion channel dysfunction at the node of Ranvier has been implicated. To gain insight into the pathogenesis of these neuropathies, we examined the distribution of GM1 ganglioside and Gal(beta1-3)GalNAc moieties in nerve fibres and their relationship to voltage-gated sodium and potassium (Kv1.1, 1.5) channels at the nodes of Ranvier in peripheral nerves from human, rat and dystrophic mice. Gal(beta1-3)GalNAc moieties were localized via the binding of cholera toxin and peanut agglutinin. As a control for the specificity of these findings, we compared the distribution of GM1 moieties to that of the ganglioside GT1b. Our study provides definitive evidence for the presence of Gal(beta1-3)GalNAc bearing moieties on the axolemmal surface of mature myelinated fibres and on Schwann cells. Gal(beta1-3)GalNAc binding sites did not have an obligatory co localization with voltage-gated sodium channels or the potassium ion channels Kv1.1 and Kv1.5 and are thus not likely carried by these ion channels. In contrast with Gal(beta1-3)GalNAc, GT1b-like moieties are restricted to the axolemma. PMID- 10094256 TI - Neurological complications of neurofibromatosis type 1 in adulthood. AB - Neurofibromatosis type 1 (NF1) is a genetic disease with a wide range of neurological manifestations. To examine these, and to evaluate neurological morbidity in adulthood of patients with NF1, we studied a hospital-based series of 158 patients that included 138 adult patients aged >18 years and 20 children. NF1 evaluation included a multidisciplinary clinical and a clinically oriented radiological investigation. Neurological events occurring during childhood (in both children and adults of the series) and adulthood were recorded. One or several neurological manifestations have been observed in 55% of patients (adults and children) (n = 87). These included: headache (28 patients); hydrocephalus (7); epilepsy (5); lacunar stroke (1); white matter disease (1); intraspinal neurofibroma (3); facial palsy (1); radiculopathy (5); and polyneuropathy (2). Tumours included: optic pathway tumours (20); meningioma (2); cerebral glioma (3); and malignant peripheral nerve sheath tumours (6). Life-threatening complications were observed in five adults and included four malignant peripheral nerve sheath tumours and one meningioma. Pain was the leading symptom in 11 adults and was related to malignant peripheral nerve sheath tumours, complications of intraspinal neurofibromas, subcutaneous neurofibromas and peripheral nerve neurofibromas. NF1 in adults was not associated with other disabling or life-threatening neurological complications. Symptomatic optic pathway tumours, cerebral gliomas, symptomatic aqueductal stenosis and spinal compression due to intraspinal NF were observed exclusively during childhood. In this series, the predominant neurological features of adults with NF1 were chronic pain and malignant peripheral nerve sheath tumours. PMID- 10094257 TI - A PET study of sequential finger movements of varying length in patients with Parkinson's disease. AB - To study the difficulty that patients with Parkinson's disease have in performing long sequential movements, we used H2(15)O PET to assess the regional cerebral blood flow (rCBF) associated with the performance of simple repetitive movements, well-learned sequential finger movements of varying length and self-selected movements. Sequential finger movements in the Parkinson's disease patients were associated with an activation pattern similar to that found in normal subjects, but Parkinson's disease patients showed relative overactivity in the precuneus, premotor and parietal cortices. Increasing the complexity of movements resulted in increased rCBF in the premotor and parietal cortices of normal subjects; the Parkinson's disease patients showed greater increases in these same regions and had additional significant increases in the anterior supplementary motor area (SMA)/cingulate. Performance of self-selected movements induced significant activation of the anterior SMA/cingulate in normal subjects but not in Parkinson's disease patients. We conclude that in Parkinson's disease patients more cortical areas are recruited to perform sequential finger movements; this may be the result of increasing corticocortical activity to compensate for striatal dysfunction. PMID- 10094258 TI - The neural consequences of conflict between intention and the senses. AB - Normal sensorimotor states involve integration of intention, action and sensory feedback. An example is the congruence between motor intention and sensory experience (both proprioceptive and visual) when we move a limb through space. Such goal-directed action necessitates a mechanism that monitors sensorimotor inputs to ensure that motor outputs are congruent with current intentions. Monitoring in this sense is usually implicit and automatic but becomes conscious whenever there is a mismatch between expected and realized sensorimotor states. To investigate how the latter type of monitoring is achieved we conducted three fully factorial functional neuroimaging experiments using PET measures of relative regional cerebral blood flow with healthy volunteers. In the first experiment subjects were asked to perform Luria's bimanual co-ordination task which involves either in-phase (conditions 1 and 3) or out-of-phase (conditions 2 and 4) bimanual movements (factor one), while looking towards their left hand. In half of the conditions (conditions 3 and 4) a mirror was used that altered visual feedback (factor two) by replacing their left hand with the mirror image of their right hand. Hence (in the critical condition 4) subjects saw in-phase movements despite performing out-of-phase movements. This mismatch between intention, proprioception and visual feedback engendered cognitive conflict. The main effect of out-of-phase movements was associated with increased neural activity in posterior parietal cortex (PPC) bilaterally [Brodmann area (BA) 40, extending into BA 7] and dorsolateral prefrontal cortex (DLPFC) bilaterally (BA 9/46). The main effect of the mirror showed increased neural activity in right DLPFC (BA 9/ 46) and right superior PPC (BA 7) only. Analysis of the critical interaction revealed that the mismatch condition led to a specific activation in the right DLPFC alone (BA 9/46). Study 2, using an identical experimental set-up but manipulating visual feedback from the right hand (instead of the left), subsequently demonstrated that this right DLPFC activation was independent of the hand attended. Finally, study 3 removed the motor intentional component by moving the subjects' hand passively, thus engendering a mismatch between proprioception and vision only. Activation in the right lateral prefrontal cortex was now more ventral than in studies 1 or 2 (BA 44/45). A direct comparison of studies 1 and 3 (which both manipulated visual feedback from the left hand) confirmed that a ventral right lateral prefrontal region is primarily activated by discrepancies between signals from sensory systems, while a more dorsal area in right lateral prefrontal cortex is activated when actions must be maintained in the face of a conflict between intention and sensory outcome. PMID- 10094259 TI - Absolute quantification of brain metabolites by proton magnetic resonance spectroscopy in normal-appearing white matter of multiple sclerosis patients. AB - The aim of this research was to obtain an absolute quantification of the N-acetyl aspartate, choline, creatine and phosphocreatine levels in normal-appearing white matter by means of 1H magnetic resonance spectroscopy in a group of multiple sclerosis patients (27 with the relapsing-remitting form and 13 with the secondary progressive form). These values were compared with those of a group of 12 age-matched healthy control subjects. A significant decrease in the N-acetyl aspartate concentration was found in normal-appearing white matter of frontal and parietal brain areas in multiple sclerosis patients compared with the same areas in control subjects. This reduction was more evident in progressive patients. The decrease in the N-acetyl-aspartate concentration in normal-appearing white matter significantly correlated with the Expanded Disability Status and the lesional load. No significant change was found in the concentration of creatine or choline. This finding concurs with previous evidence of heterogeneity in the multiple sclerosis pathological process which is not confined to the lesions and involves not only myelin, but also axons, even in white matter which appears normal on MRI. PMID- 10094260 TI - Heterogeneity of T-cell receptor usage in experimental autoimmune neuritis in the Lewis rat. AB - In experimental autoimmune neuritis (EAN), T-cell receptor (TCR) variable (V) region gene usage by neuritogenic T cells has been reported to be clonally restricted at the RNA level. This study was designed to verify TCR usage by neuritogenic T cells at the protein level. We generated two monoclonal antibodies (mAbs) 7H4 and 8G8 specific for a Vbeta4/Valpha11 associated idiotype expressed by the majority of neuritogenic cells of P2-specific T-cell lines. The remaining neuritogenic P2-specific T cells either exhibited a dominant usage of the TCR Vbeta13 chain recognized by the recently generated mAbs 17D5 and 18B1 or showed diverse Vbeta usage. Treatment of adoptive-transfer (AT)-EAN or of EAN actively induced with the neuritogenic P2 peptide by mAbs 7H4 and 8G8 led to a partial, but significant, reduction of clinical disease. Treatment with Vbeta13-specific mAb 17D5 had no clear effect on active EAN. Our data show that at least three different TCR are used by P2-specific pathogenic T cells in EAN, an animal model for human inflammatory neuropathies. PMID- 10094261 TI - Memories are made of this: the effects of time on stored visual knowledge in a case of visual agnosia. AB - We report the effects of the passage of time on the longterm visual knowledge for objects in a patient with visual agnosia (H.J.A.). The naming of real objects was found to have improved, although this was not associated with any change in H.J.A.'s basic perceptual abilities which were stable over a 16-year period. The improvement in object naming was attributed to better use of non-contour-based visual information (such as surface detail and depth cues). In addition, we demonstrate a deterioration in H.J.A.'s long-term memory for the visual properties of objects, and argue that this has occurred as a result of his having impaired perceptual input. The deterioration was only apparent in drawing from memory and in the verbal descriptions of items; with forced-choice testing, H.J.A. operated at ceiling; we propose that current tests of visual imagery may not be sufficiently sensitive to detect subtle impairments of visual memory. Our findings can be taken to indicate that perceptual and memorial processes are not functionally independent, but are linked in an interactive manner. PMID- 10094262 TI - Language outcome following multiple subpial transection for Landau-Kleffner syndrome. AB - Landau-Kleffner syndrome is an acquired epileptic aphasia occurring in normal children who lose previously acquired speech and language abilities. Although some children recover some of these abilities, many children with Landau-Kleffner syndrome have significant language impairments that persist. Multiple subpial transection is a surgical technique that has been proposed as an appropriate treatment for Landau-Kleffner syndrome in that it is designed to eliminate the capacity of cortical tissue to generate seizures or subclinical epileptiform activity, while preserving the cortical functions subserved by that tissue. We report on the speech and language outcome of 14 children who underwent multiple subpial transection for treatment of Landau-Kleffner syndrome. Eleven children demonstrated significant postoperative improvement on measures of receptive or expressive vocabulary. Results indicate that early diagnosis and treatment optimize outcome, and that gains in language function are most likely to be seen years, rather than months, after surgery. Since an appropriate control group was not available, and that the best predictor of postoperative improvements in language function was that of length of time since surgery, these data might best be used as a benchmark against other Landau-Kleffner syndrome outcome studies. We conclude that multiple subpial transection may be useful in allowing for a restoration of speech and language abilities in children diagnosed with Landau Kleffner syndrome. PMID- 10094263 TI - Impaired modulation of quadriceps tendon jerk reflex during spastic gait: differences between spinal and cerebral lesions. AB - In healthy subjects, functionally appropriate modulation of short latency leg muscle reflexes occurs during gait. This modulation has been ascribed, in part, to changes in presynaptic inhibition of Ia afferents. The changes in modulation of quadriceps tendon jerk reflexes during gait of healthy subjects were compared with those of hemi- or paraparetic spastic patients. The spasticity was due to unilateral cerebral infarction or traumatic spinal cord injury, respectively. The modulation of the quadriceps femoris tendon jerk reflex at 16 phases of the step cycle was studied. The reflex responses obtained during treadmill walking were compared with control values obtained during gait-mimicking standing postures with corresponding levels of voluntary muscle contraction and knee angles. In healthy subjects the size of the reflexes was profoundly modulated and was generally depressed throughout the step cycle. In patients with spinal lesion the reflex depression during gait was almost removed and was associated with weak or no modulation during the step cycle. In patients with cerebral lesion there was less depression of the reflex size associated with a reduced reflex modulation on the affected side compared with healthy subjects. On the 'unaffected' side of these patients reflex modulation was similar to that of healthy subjects, but the reflex size during gait was not significantly different from standing control values. These observations suggest that the mechanisms responsible for the depression of reflex size and the modulation normally seen during gait in healthy subjects are impaired to different extents in spasticity of spinal or cerebral origin, possibly due to the unilateral preservation of fibre tracts in hemiparesis. PMID- 10094264 TI - Colorectal cancer screening: an overview of available methods and current recommendations. AB - BACKGROUND: Screening asymptomatic persons for colorectal cancer may decrease the incidence and mortality of this disease. METHODS: The MEDLINE database was used to identify articles addressing the rationale for colorectal cancer screening, methods used and their effectiveness, and current recommendations. RESULTS: Methods of screening for colorectal cancer include flexible sigmoidoscopy, fecal occult blood tests, barium enema, and colonoscopy. The method used and the frequency of screening are determined by assessing an individual's risk of having colorectal cancer. CONCLUSIONS: Colorectal cancer is a common malignancy in the United States, is curable when detected at an early stage, and is potentially preventable. The acceptance of colorectal cancer screening by patients and physicians has been suboptimal. while there remains little debate about the potential for screening to reduce mortality from colorectal cancer, debate continues about the cost-effectiveness of colorectal cancer screening when applied to the general population. PMID- 10094265 TI - Aging and sensory senescence. AB - BACKGROUND: The aging process typically is associated with decline in function for the various senses. A decline in sensory ability may simulate an intellectual decline that is not present. Sensory decline can lead to depression, social isolation, and even to hallucinations. METHODS: I reviewed the medical literature via computer, focusing on recent findings. RESULTS: Sensory changes with aging are common yet often go unrecognized and untreated. Declines in sensory function often reflect the combined effect of age-related changes in both the sensory organ and the central nervous system processing of sensory information. Combinations of defects in several sensory modalities are often found in the older individual. CONCLUSIONS: Correct diagnosis is important for management so that correctable causes of sensory decline are not overlooked. PMID- 10094266 TI - Human pulmonary dirofilariasis: review of the literature. AB - BACKGROUND: The dog heartworm Dirofilaria immitis is known to cause solitary pulmonary nodules in humans. Human pulmonary dirofilariasis (HPD) is more prevalent along the coastal regions of the United States, especially along the Mississippi River Valley. Diagnosis is generally made by surgical resection, since HPD is often preoperatively presumed to be lung cancer. METHODS: I searched for relevant clinical articles and case reports on HPD, using MEDLINE and the Index Medicus. I carefully reviewed each article for information regarding HPD. RESULTS: Of the 37 cases reviewed, 29 (78.4%) were in the southern and southeastern states. The youngest patient was a 33-year-old woman, and the oldest was a 79-year-old man (mean age, 57.3 years). This literature review found that 43.2% were symptomatic, 51.4% were asymptomatic, and 5.4% were not recorded. Solitary lesions were found in 89.7%, with a mean diameter of 1.9 cm. CONCLUSION: Based on the available literature and epidemiologic data, HPD should be considered in the differential diagnosis of pulmonary nodules in the appropriate clinical and geographic setting. PMID- 10094267 TI - Demographic changes in tuberculosis: high risk groups. AB - We conducted a statistical analysis of all verifiable tuberculosis (TB) cases in Tennessee from 1990 through 1996 to determine the demographic changes in TB. We studied variables, including age, sex, race, site of the disease, and possible impact of known risk factors such as human immunodeficiency virus (HIV) infection, homelessness, foreign birth, and residency in extended care facility. The percentage increase in all such categories, except in the nursing home population, had a statistically significant increase. Unlike national epidemiologic findings, foreign-born TB comprised less than 1% of the total cases. Association of HIV as a co-infection increased from 16 (2.7%) in 1990 to 41 (8.1%) in 1996. These findings will have significant impact on TB control measures and the clinical practice of TB cases in Tennessee and other areas of the southeastern US. PMID- 10094268 TI - Purulent pericarditis misdiagnosed as septic shock. AB - BACKGROUND: Septic shock is common, with approximately 200,000 cases recognized annually. This syndrome is so well characterized that when a patient is febrile and in shock, septic shock may be diagnosed without regard to alternative possibilities. Purulent pericarditis is a relatively rare disorder in which fever and hypotension are common. Classic signs and symptoms, such as chest pain, pericardial friction rub, pulsus paradoxus, and elevation of jugular venous pressure, are seen in only 50%. METHODS: In this report, we describe four patients in whom purulent pericarditis and pericardial tamponade was initially misdiagnosed as septic shock. During a 3-month period, three men and one woman (mean age, 44.5 years) came to Kern Medical Center with purulent pericarditis and pericardial tamponade. These cases represented 13% of patients admitted with a diagnosis of septic shock. RESULTS: All patients were bacteremic, and the classic findings of pericardial tamponade were absent or relatively subtle. Hemodynamic findings of elevated systemic vascular resistance, low cardiac output, and normal pulmonary artery occlusion pressure were critical to the diagnosis. CONCLUSIONS: Consideration of purulent pericarditis is important in cases diagnosed as septic shock. Clinicians should be aware that patients with purulent pericarditis may not exhibit classic signs and symptoms, and a high index of suspicion is necessary for appropriate management. PMID- 10094269 TI - Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases. AB - BACKGROUND: We sought to determine the relationship among radiographic findings, clinical presentation, and diagnostic testing of pulmonary blastomycosis. METHODS: We reviewed the medical records of 100 consecutive patients with pulmonary blastomycosis. RESULTS: Air-space infiltrates were the usual radiographic finding of pulmonary blastomycosis. Mass-like infiltrates were associated more with chronic than acute presentations. Air-space and mass-like infiltrate were predominately involved in the upper lobes. Sputum analysis made the initial diagnosis of blastomycosis most often. Acute and chronic presentations were not different between immunosuppressed patients and the remainder of the patients. In addition, infiltrates on chest radiographs in immunosuppressed patients were similar to the other patients. CONCLUSIONS: In an endemic area, pulmonary blastomycosis should be considered for any pulmonary infiltrate, especially in the upper lobes. Sputum analysis in most cases aids in the diagnosis, but bronchoscopy and/or tissue biopsy should be considered if the suspicion of blastomycosis is high and sputum analysis is inconclusive, negative, or not possible. Follow-up with chest radiographs after antifungal therapy is reasonable until complete resolution or fibrotic changes in patients with pulmonary blastomycosis. PMID- 10094270 TI - Comparison of internal medicine, pediatric, and medicine/pediatrics applicants and factors influencing career choices. AB - BACKGROUND: A reemergence of medical students choosing primary care is occurring, with medicine/pediatrics as an increasingly popular option. We compared applicants to pediatrics, medicine, and medicine/pediatrics and the factors that influence career choice. METHODS: We designed a survey to gather objective data and information shown to influence career choices. Applicants interviewing in our three primary care programs completed the survey. RESULTS: Pediatric applicants were more likely to be women and to choose their career in the 2nd year of medical school. Medicine/Pediatrics applicants had the highest interest in practicing primary care and in pursuing an academic career. However, they had the smallest number of role models. The average education debt was the same. CONCLUSION: Differences in applicants applying to primary care programs may be used to target particular applicants and to counsel medical students on career choice. PMID- 10094271 TI - Prostate cancer screening in primary care. AB - BACKGROUND: Little is known about the actual frequency with which men have prostate screening in primary care settings, nor are the determinants of screening understood. METHODS: We examined the records of 50 consecutive primary care office visits by men aged 50 or older. Men were asked to complete a brief questionnaire outlining their previous use of prostate screening services and the factors that influenced screening. RESULTS: Screening in the previous year with digital rectal examination (DRE) and prostate specific antigen (PSA) was reported by 46% and 30% of respondents, respectively. Most respondents (86%) had heard of prostate screening and most (78%) believed it was effective. The only factor predictive of screening with DRE in multivariate analysis was a doctor's discussion of screening (odds ratio, 4.8). Two factors were predictive of PSA screening--knowing someone who had prostate cancer (odds ratio, 12.8) and advancing age (odds ratio [per year], 1.1). CONCLUSIONS: Many men are not having annual prostate screening. Men who were older, who reported knowing someone with prostate cancer, and whose doctors discussed screening, were more likely to have been screened in the past year. PMID- 10094272 TI - Study of condom integrity after brief exposure to over-the-counter vaginal preparations. AB - BACKGROUND: Latex condoms are used as contraceptives and as preventives against sexually transmitted diseases. Latex rapidly and significantly deteriorates when exposed to pure mineral oil and vegetable oil. We wanted to determine if short exposures to readily available over-the-counter (OTC) intravaginal preparations could affect latex condom integrity. METHODS: We compared the mean burst time of test latex condoms, which had 5-minute exposure to various OTC vaginal products, with the mean burst time of control (unexposed) condoms during pressurized air inflation. RESULTS: Baby oil reduced the mean burst time from nearly a minute to just over 11 seconds. One intravaginal moisturizer and two intravaginal antifungal preparations also adversely affected latex condom integrity. Products that weakened latex condoms contained either mineral oil or vegetable oil. CONCLUSIONS: Women who rely on latex condoms should exercise caution if using OTC vaginal products containing either mineral oil or vegetable oil. Such products apparently can decrease condom strength and potentially jeopardize efficacy. PMID- 10094273 TI - "One-stop" surgery: implications for anesthesiologists of an expedited pediatric surgical process. AB - BACKGROUND: "One-stop surgery" (OSS) allows pediatric patients to undergo initial surgical evaluation, anesthesia, surgery, and discharge home, on the same day. METHODS: Patients referred for umbilical hernia repair, circumcision, or central venous catheter removal completed a screening questionnaire, after which they were scheduled for initial surgical and anesthesia evaluation if eligible and had surgery if indicated on the same day. RESULTS: Three patients had comorbidity precluding OSS, two patients refused indicated surgery, two patients did not require surgery, and 12 patients did not keep their appointment. Eighty patients had surgery without complications. Average total time was significantly shorter for OSS than non-OSS for circumcision (120 vs 142 min) and umbilical hernia repair (139 vs 165 min) but similar for catheter removal (100 vs 109 min). All families were satisfied with OSS. CONCLUSIONS: One-stop surgery appears to be a safe, efficient, and convenient alternative to the traditional process for patients and their families. PMID- 10094274 TI - Postoperative pulmonary edema. AB - BACKGROUND: Noncardiogenic pulmonary edema may be caused by upper airway obstruction due to laryngospasm after general anesthesia. This syndrome of "negative pressure pulmonary edema" is apparently well known among anesthesiologists but not by other medical specialists. METHODS: We reviewed the cases of seven patients who had acute pulmonary edema postoperatively. RESULTS: There was no evidence of fluid overload or occult cardiac disease, but upper airway obstruction was the most common etiology. Each patient responded quickly to therapy without complications. CONCLUSIONS: Of the seven patients with noncardiogenic postoperative pulmonary edema, at least three cases were associated with documented laryngospasm causing upper airway obstruction. This phenomenon has been reported infrequently in the medical literature and may be underdiagnosed. Immediate recognition and treatment of this syndrome are important. The prognosis for complete recovery is excellent. PMID- 10094275 TI - Traumatic L5-S1 spondylolisthesis. AB - We report a case of traumatic spondylolisthesis in a 31-year-old man struck by a steel I-beam. Although most reported traumatic spondylolisthesis cases are from low-energy trauma, this was a high-energy trauma case. The initial examination revealed no signs of cauda equina syndrome, and the patient's spinal injury was primarily capsuloligamentous. We present this rare case, with a review of pertinent literature and treatment mechanisms for traumatic spondylolisthesis. PMID- 10094277 TI - Anesthetic management of a patient with tetra-amelia. AB - The case presented is that of a parturient with tetra-amelia, the congenital absence or near absence of all limbs. The difficulties encountered with monitoring and venous access due to absence of extremities illustrate the necessity for a detailed management plan with emphasis on early intervention. The reasons for the high incidence of operative delivery are outlined. PMID- 10094276 TI - Basal cell carcinoma with lung metastasis diagnosed by fine-needle aspiration biopsy. AB - Basal cell carcinoma of the skin is one of the most common types of cancer. Its natural history is one of local recurrence rather than metastatic spread. Certain histologic features and primary tumor size seem to be risk factors for metastases. The diagnosis of metastatic disease imparts a poor prognosis with a short median survival. Treatment is usually in the form of systemic chemotherapy with cisplatin-based combination described as most active agent. PMID- 10094278 TI - Seminal vesicle abscess due to tuberculosis: role of tissue culture in making the diagnosis. AB - Abscess formation involving the seminal vesicle occurs rarely. We report a case of seminal vesicle abscess due to tuberculosis. Urine and fluid cultures and histologic examination of the prostate were negative for mycobacteria. The cause of the abscess was confirmed only after tissue cultures were done. PMID- 10094279 TI - Heterotopic pregnancy: discovery of ectopic pregnancy after elective abortion. AB - We report a case of combined intrauterine and tubal pregnancy in a 23-year-old woman. The patient came to the emergency department complaining of lower abdominal pain after having had an elective abortion 2 weeks earlier. Her physician had done pelvic ultrasonography, noting an intrauterine pregnancy before the abortion. Our working diagnosis in the emergency department was retained products of conception versus postabortion endometritis. Pelvic ultrasonography in the emergency department revealed an ectopic pregnancy without evidence of retained products of conception, and the patient had a right salpingotomy with removal of the ectopic fetus without complications. PMID- 10094280 TI - Near fatal acute respiratory distress syndrome in a patient with human ehrlichiosis. AB - Human ehrlichiosis is not a common cause of acute respiratory distress syndrome (ARDS). Physicians should be aware of this life-threatening but treatable entity. Progression to ARDS may be related to delay in diagnosis and treatment. Fever, leukopenia, thrombocytopenia, and a history of tick exposure in an endemic area during the spring and summer months should alert the physician to the possibility of human ehrlichiosis, since a definitive diagnosis requires serologic testing that may take weeks to confirm. We describe a case of ARDS resulting from human ehrlichiosis. A unique feature in our case was that despite the early use of doxycycline, the patient had near fatal ARDS that responded dramatically to high doses of steroids. PMID- 10094281 TI - Ehrlichiosis with severe pulmonary manifestations despite early treatment. AB - It is generally thought that if patients with ehrlichiosis are treated promptly, life-threatening illness can be avoided. We report a patient who sought medical attention 1 day after the onset of symptoms, was immediately given doxycycline, and still had serious illness with generalized edema, pulmonary infiltrates, acute respiratory distress syndrome, and noncardiogenic pulmonary edema, while receiving replacement intravenous fluids. This case alerts physicians to the serious end of the disease spectrum that can occur even though patients are given prompt, appropriate drug treatment at the onset of illness. Further studies are needed to clearly define the mechanisms involved in pulmonary complications and generalized edema, including noncardiogenic pulmonary edema, in patients with ehrlichiosis. PMID- 10094282 TI - Midline posterior cervical cystic hygroma. AB - Cystic hygromas are among the most common congenital neck masses. They have a predilection for the left posterior triangle and manifest early in life. Although various locations of cystic hygromas are found in the literature, we believe our case of a 9-month-old girl represents the first reported occurrence of a posterior cervical midline cystic hygroma. PMID- 10094283 TI - Evidence for a dose-response relationship between occupational noise and blood pressure. AB - In this study, we investigated the role of occupational noise exposure and blood pressure among workers at 2 plants. A noise-exposed plant (plant 1, > or = 89 dBA) and a less-noise-exposed plant (plant 2, < or = 83 dBA) were chosen. Exposure was based on department-wide average noise measures; on the basis of job location and adjusting for layoffs during their employment at the plant, a cumulative time-weighted average noise level was calculated for each worker. The study population comprised 329 males in plant 1 and 314 males in plant 2. Their ages ranged from 40 to 63 y (mean ages = 49.6 and 48.7, respectively), and they had worked at least 15 y at the plant. The clinical examination was administered prior to the workday and measured height, weight, pulse, and blood pressure. In addition, we noted medical and personal-habits histories, including alcohol intake and cigarette smoking patterns. We used a questionnaire to determine in depth occupation, military history, noisy hobbies, and family history of hypertension. When individuals who took blood-pressure medication were removed from the analysis, t tests for differences in average blood pressure between plants showed a mean systolic blood pressure of 123.3 mm Hg in plant 1 versus 120.8 mm Hg in plant 2 (p = .06) and a mean diastolic blood pressure of 80.3 mm Hg versus 77.8 mm Hg in Plant 1 and 2, respectively (p = .014). On the basis of data from the combined plants, multivariate analysis revealed that age, body mass index, cumulative noise exposure, current use of blood pressure medications, and alcohol intake were significant predictors for systolic blood pressure. Cumulative noise exposure was a significant predictor of diastolic blood pressure in plant 1 but not in plant 2, possibly reflecting a threshold effect. PMID- 10094284 TI - Association of benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid (BPDE-DNA) adduct level with aging in male smokers and nonsmokers. AB - We used our new flow cytometric method to measure benzo[a]pyrene-diolepoxide deoxyribonucleic acid adduct levels in peripheral lymphocytes from healthy male smokers and nonsmokers. Smokers who had pack-years of 20 or more had significantly higher mean benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels than nonsmokers. In smokers, the adduct levels were correlated significantly with age, years of smoking, and pack-years, whereas daily tobacco consumption was not correlated with adduct levels. We also found a positive relationship between age and benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels in nonsmokers. Passive exposure to tobacco smoke was not associated with adduct levels. The results of our study indicate that benzo[a]pyrene-diol epoxide-deoxyribonucleic acid adduct levels may be closely related to aging and that tobacco smoking-as well as other environmental factors-may play a role in the benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct formation. PMID- 10094285 TI - Time course of sensory eye irritation in humans exposed to N-butanol and 1 octene. AB - In this study, we investigated the time course effect of sensory eye irritation in 16 subjects exposed (i.e., eye only) to n-butanol and 1-octene. Half the subjects were exposed to n-butanol, and the remaining subjects were exposed to 1 octene. Each subject was studied on 5 different days; during each day each subject was exposed in three runs (i.e., run 1, run 2, and run 3) to a constant concentration of either n-butanol or 1-octene. We performed run 1 and run 3, both of which lasted 15 min each, to evaluate persistence in "sensitization." We performed run 2, which lasted 60 min, to study the time course of sensory irritation. Ratings of ocular irritation intensity were obtained continuously during all three runs. The exposure concentrations for n-butanol were 0 mg/m3, 300 mg/m3, 900 mg/m3, and 3 000 mg/m3, and the exposure concentrations for 1 octene were 0 mg/m3, 6 000 mg/m3, 10 400 mg/m3, and 18 000 mg/m3. During run 2, we observed a slight increase in perceived eye irritation intensity for the lower concentrations of 1-octene and for all exposure concentrations of n-butanol. However, the threshold for irritation was clearly exceeded for only the 1-octene 10 400-mg/m3 and 18 000-mg/m3 exposures. During these two exposures, the response increased 10-fold following 20-40 min of exposure during run 2, after which the response remained constant. We investigated the existence of persistence in "sensitization" by comparing intensity of responses between run 1 and run 3. Persistence in "sensitization" was apparent for only the 1-octene exposure. PMID- 10094286 TI - Personal exposure to fine particles in children correlates closely with ambient fine particles. AB - To investigate the validity of ambient fine-particle concentrations as a measure of exposure in epidemiological time-series studies, we established the association between personal and ambient concentrations, within subjects, over time. We conducted repeated measurements of personal and ambient fine-particle concentrations in 13 children who lived in Wageningen, The Netherlands. For each child separately, we related personal exposures to ambient concentrations in a regression analysis. The median Pearson's correlation coefficient was 0.86. Personal fine-particle concentrations were also highly correlated with ambient particulate matter (i.e., < or = 10-microm) concentrations (median Pearson's correlation coefficient = .75). Personal fine-particle concentrations were typically approximately 11 microg/m3 higher than ambient concentrations. We excluded measurements of children who were exposed to environmental tobacco smoke, and the difference was only 5 microg/m3. The findings of high correlations between personal fine-particle concentrations and both ambient fine-particle concentrations and particulate matter (i.e., < or = 10-microm) found in this group of children provide support for investigators to use ambient particulate matter concentrations to measure exposure to fine-particle concentrations in epidemiological time-series studies. PMID- 10094287 TI - Health effects of chronic high exposure to hexachlorobenzene in a general population sample. AB - Hexachlorobenzene, an organochlorine compound that accumulates in humans, is widespread throughout the environment. In this study, we describe the health status of inhabitants of a rural village that surrounds an electrochemical factory characterized by high levels of hexachlorobenzene in the air. During 1994, we conducted a cross-sectional study of 1 800 inhabitants in the south of Catalonia, Spain, who were older than 14 y of age. We obtained information on lifestyles and occupational and medical histories via questionnaire. Self reported health outcomes were validated against clinical records and cancer registry data. Serum levels of hexachlorobenzene were very high in males who worked in the electrochemical factory (geometric mean = 54.6 ng/ml in randomized participants). Levels were lower among subjects who had never worked in the electrochemical factory (females, 14.9 ng/ml; males, 9.0 ng/ml). Levels of other organochlorine compounds (i.e., beta-hexachlorocy-clohexane, 2,2-bis[p chlorophenyl]-1,1-dichloroethylene) were in the same range found in other communities. Perceived health, prevalence of self-reported common chronic conditions, and porphyria cutanea tarda, thyroid pathology, Parkinson's disease, cancer, and reproductive outcomes were within the ranges observed in other studies. Employment in the plant, however, was associated with having any of the a priori selected health outcomes that were potentially related to exposure to hexachlorobenzene (odds ratio for cancer prevalence = 1.9; 95% confidence interval = 0.5, 7.6). Our population of workers and nonworkers had the highest levels of hexachlorobenzene ever described. The results suggest that exposure to hexachlorobenzene did not affect the general health status of the this population, but it was associated with specific health effects of the most highly exposed subjects. PMID- 10094288 TI - Serial levels of serum organochlorines during pregnancy and postpartum. AB - In utero exposure to dichlorodiphenyldichloroethene and polychlorinated biphenyls, within the range found in the general U.S. population, may produce detectable effects in offspring. To design studies of the effects of in utero organochlorine exposure, we obtained data on the relationship between gestational and perinatal maternal levels in females on several occasions. We studied 67 pregnant women in the United States who agreed to have their blood drawn once during each trimester and once postpartum. We examined the Pearson correlation coefficient between the natural logarithm of levels (microg/g serum lipid). The correlation, r, among levels in the first and third trimester was .86 and .77 for dichlorodiphenyldichloroethene and for polychlorinated biphenyls. Correlations among levels determined at other times (i.e., second trimester and postpartum) were similar. On the basis of these results, we suggest that in studies of the effects of in utero or perinatal exposure to the aforementioned compounds, the time when specimens are collected is not critical. PMID- 10094289 TI - Formaldehyde exposure levels and serum antibodies to formaldehyde-human serum albumin of Korean medical students. AB - In our study, we estimated formaldehyde exposure levels of Korean medical students during their cadaver dissection practice hours. In addition, we examined the prevalence rates of formaldehyde-specific immunoglobulin E or immunoglobulin G antibodies and compared the results with the symptoms the students experienced as a result of formaldehyde exposure. There were 167 Korean medical students (i.e., subjects) aged 23.8+/-2.5 y (mean+/-standard deviation) and a control group of 67 premedical students aged 20.1+/-2.8 y (mean+/-standard deviation). Concentrations of formaldehyde in the cadaver dissection practice laboratory ranged from 0.194 to 11.245 mg/m3 (3.736+/-3.478 mg/m3 [mean+/-standard deviation]). Students reported by self-administered questionnaires that eye soreness (92.8%) and lacrimation (74.9%) were the most common symptoms they experienced during the laboratory sessions. One (0.6%) of the 167 medical students had a history of wheezing during dissection. Fourteen (8.4%) had specific immunoglobulin G antibody, but none had specific immunoglobulin E antibody. These results suggest that (a) Korean medical students are exposed to formaldehyde at a relatively high levels in their dissection practice hours, (b) specific immunoglobulin G is not related to adverse eye or respiratory symptoms, and (c) specific immunoglobulin E is rarely induced as a result of exposure to formaldehyde. PMID- 10094290 TI - Effects of smoking and Japanese cedar pollinosis on lymphocyte subpopulations. AB - Approximately 10-30% of the Japanese population suffer from Japanese cedar (Cryptomeria japonica) pollinosis in the spring. To date, the effects of this pollinosis on lymphocyte subpopulations have not been examined epidemiologically. To examine the effects of smoking and Japanese cedar pollinosis on lymphocyte subpopulations, we used flow cytometry to measure CD4+ and CD8+ T-lymphocyte subpopulations, natural-killer cell subpopulations, B(CD19+) lymphocytes, and total lymphocytes in 61 smokers and 51 nonsmokers. Some of these individuals had histories of pollinosis during November 1993-an off-season for Japanese cedar pollination. Our findings suggested that (a) CD4+ T-lymphocyte subpopulations (i.e., CD4+CD29+, CD4+CD45RA+, and CD4+ CD45RO+ cells) together with total CD4+ T, total T, and total lymphocytes, were increased by the effects of smoking; (b) CD8dim+CD11a+T, and CD8+CD11bt, and CD57+CD16+ natural killer cells, together with total CD8+CD11 a+ T and total CD8+ T lymphocytes, were increased by the effects of pollinosis on smokers, even though no lymphocyte subpopulations were increased by only the pollinosis effects; (c) CD4+CD29+T and CD8dimCD11a+ T lymphocytes were increased by the effects of smoking on pollinosis, and (d) CD4+CD29+ T and CD4+CD45RO+ T lymphocytes, CD8dim+CD11 a+ T, and CD8+CD11b+ T lymphocytes and CD57+CD16+ natural killer cells, together with total CD4+ T, total T (CD3+), total CD8+CD11a+, total CD8+ T, and total lymphocytes, were increased by the combined effects of smoking and pollinosis. PMID- 10094291 TI - Levels of dichloro-dyphenyl-trichloroethane (DDT) metabolites in maternal milk and their determinant factors. AB - To document the levels and the determinants of dichloro-dyphenyl-trichloroethane (DDT) metabolites in maternal milk, we conducted a cohort study of 50 adult females who lived in Mexico City. We measured social and dietary characteristics via interview. Levels of DDT metabolites were determined by gas-liquid chromatography. The mean values (lipid milk basis) were 0.162 ppm p,p'-DDT; 0.138 ppm o,p'-DDT; and 0.594 ppm 2,2(bis)p-chlorophyenyl-1-1-dichloroethylene (DDE). The main determinants of DDT metabolites were maternal age, lifetime lactation, history of living in an agricultural area, and consumption of salted meat and fish. We estimated that 6.0% of the breast-fed babies had daily intakes of DDT above the level of 0.005 mg/kg d recommended by the World Health Organization/Food and Agriculture Organization of the United Nations (WHO/FAO). Health-outcomes research among children is needed, and investigators should design or adjust current surveillance programs. PMID- 10094292 TI - Effects of particulate and gaseous air pollution on cardiorespiratory hospitalizations. AB - We obtained data on daily numbers of admissions to hospital in Toronto, Canada, from 1980 to 1994 for respiratory, cardiac, cerebral vascular, and peripheral vascular diseases. We then linked the data to daily measures of particulate mass less than 10 microns in aerodynamic diameter (PM10), particulate mass less than 2.5 microns in aerodynamic diameter (PM2.5), and particulate mass between 2.5 and 10 microns in aerodynamic diameter (PM10-2.5), ozone, carbon monoxide, nitrogen dioxide, and sulfur dioxide. Air pollution was only associated weakly with hospitalization for cerebral vascular and peripheral vascular diseases. We controlled for temporal trends and climatic factors, and we found that increases of 10 microg/m3 in PM10, PM2.5, and PM10-2.5 were associated with 1.9%, 3.3%, and 2.9% respective increase in respiratory and cardiac hospital admissions. We further controlled for gaseous pollutants, and the percentages were reduced to 0.50%, 0.75%, and 0.77%, respectively. Of the 7.72 excess daily hospital admissions in Toronto attributable to the atmospheric pollution mix, 11.8% resulted from PM2.5, 8.2% to PM10-2.5, 17% to carbon monoxide, 40.4% to nitrogen dioxide, 2.8% to sulfur dioxide, and 19.8% to ozone. PMID- 10094294 TI - The value of the blind review process: is blindness best? PMID- 10094293 TI - Possible teratogenic effects of intrauterine exposure to chlorpyrifos (Dursban) PMID- 10094295 TI - Acute confusion indicators: risk factors and prevalence using MDS data. AB - Long-term care (LTC) Minimum Data Set (MDS) data from a Midwestern state were analyzed to validate whether components of a conceptual model developed from findings in acute care identified acute confusion risk variables in LTC. The prevalence of probable acute confusion in this sample was 13.98% (n = 324). Using a cross-sectional design, both univariate and unconditional stepwise logistic regression analyses were accomplished with presence or absence of probable acute confusion as the outcome variable (N = 2,318). Variables significantly related to acute confusion by univariate analysis were included in the logistic regression analysis. Inadequate fluid intake was the first variable to enter the stepwise equation and was highly significant (OR 3.40, 95% CI 2.99-3.81, p < .0001). Other significant variables included a diagnosis of dementia or a fall in the last 30 days. Implications for nursing practice, education and research are discussed. PMID- 10094296 TI - Professional nursing support for culturally diverse family members of critically ill adults. AB - Family members' perceptions of professional support expected of critical care nurses were examined for differences related to cultural affiliation using the "Professional Support Questionnaire for Critical Care Nurses Working with Family Members" (PSQ). The PSQ was administered face-to-face to family members waiting to visit a critically ill relative admitted to the intensive care unit. ANOVA and post hoc tests were computed to compare 90 family members' expectations for professional nursing support during a relative's critical illness across three cultural groups-African American, Hispanic, and White. There were significant differences in family members' responses on certain PSQ items across cultural groups. Despite these differences, family members' expectations of professional support from critical care nurses were generally universal-suggesting equitable care, dignity, and respect should be universal values. There is a need for critical care nurses to develop interventions that respect some cultural uniqueness as well as address the universal needs of family members coping with the ICU admission of a critically ill family member. PMID- 10094297 TI - AHCPR clinical practice guideline on surgical pain management: adoption and outcomes. AB - Pain management practices and short-term patient outcomes in nine acute care hospitals in Milwaukee, Wisconsin, were studied at two points in time. One-and-a half years after the Agency for Health Care Policy and Research's (AHCPR) Clinical Practice Guideline on Acute Pain Management was published, data from 330 adult surgical patients were collected (Time I). These data were contrasted with data from 373 adult surgical patients collected 2 years later (Time II). There were significant increases in the percentage of patients who reported being taught how to report pain using a pain rating scale and about setting a pain goal preoperatively; in the percentage of patient hospital records with at least one documented numeric pain rating; and in the percentage of patients who received analgesics by intravenous administration. However, pain management practices continued to differ from recommendations in the AHCPR guideline. No significant improvement was noted in the short-term outcomes of patient-rated pain or patient satisfaction with pain management. Availability of well-published guidelines alone may be insufficient to ensure comprehensive adoption of guidelines that are multidimensional in nature and to obtain improvements in patient outcome. PMID- 10094298 TI - Developmental intervention for preterm infants diagnosed with periventricular leukomalacia. AB - Preterm infants with periventricular leukomalacia (PVL) were evaluated to determine whether multi-sensory stimulation is safe and to assess whether it improved neurobehavior and neurodevelopment. Thirty preterm infants with documented PVL were randomly assigned to control (n= 15) or experimental (Group E) (n= 15) groups at 33 weeks post-conceptional age. Group E infants received 15 minutes of auditory, tactile, visual, and vestibular (ATVV) intervention twice a day, five days a week, for four weeks during hospitalization. Repeated measures ANOVA demonstrated that Group E infants experienced significant increases in heart and respiratory rate and a 0.72% drop in hemoglobin saturation, coinciding with a significant behavioral state shift from sleep to alertness during intervention. No differences were identified in neurobehavioral function and neurodevelopment, indicating that Group E suffered no injury. Group E had an average hospital stay nine days shorter than that of controls, with the associated cost savings of $213,840. The earlier hospital discharge indicates that ATVV intervention promotes alertness without compromising physiologic status in vulnerable infants. PMID- 10094299 TI - Correlation of anthropometry with CT in Mexican-American women. AB - Measurement of regional fat has commonly been accomplished by extrapolation from anthropometric measures. Recent studies of White and Black women have demonstrated differences in intra-abdominal fat, using computerized tomographic (CT) techniques. These same estimates were computed for 48 Mexican American women who were undergoing CT for diagnostic purposes. Waist-hip ratios, waist-thigh ratios, and sagittal diameter index were also calculated. Four (7mm) CT slices between L-4 and L - 5 were analyzed with imaging software. The volume of both subcutaneous and visceral fat was estimated. Like other minority women, Mexican American women had less intra-abdominal fat than subcutaneous fat, which is important because of the association of excess intra-abdominal fat with cardiovascular risk. Intra-abdominal fat volume was significantly predicted by only one variable, sagittal abdominal diameter, while subcutaneous fat volume was predicted by hip and thigh circumferences. PMID- 10094300 TI - Medical and ecological factors in estimating motor outcomes of preschool children. AB - The twofold purpose of this study was to compare motor function in preschool children born with varying degrees of medical risk and to determine the independent contribution to motor function of three domains of ecological influence. One hundred and eighty-four 4-year-old children and their mothers participated. Three predictor sets, proximal, distal, and child, and four motor outcomes were measured by multiple methods. Children born prematurely scored lower on all dimensions of motor function. Prematurity complications had a different effect on motor function. Hierarchical regression models explained 16 40% of motor score variance. Results are discussed in relation to heterogeneity of prematurity and ecological influences on motor outcomes. PMID- 10094301 TI - Mediation effect of social support between ethnic attachment and loneliness in older Korean immigrants. AB - The purpose of the study was to investigate the mediating effect of two types of social support (emotional and tangible support) between ethnic attachment and loneliness in older Korean immigrants. Emotional and tangible social support had three components; network size, network composition, and satisfaction with network members. The sample consisted of 174 older Korean immigrants who lived in a metropolitan area. Telephone interviews were used to collect data using translated Korean versions of the Revised UCLA Loneliness Scale, Ethnic Attachment Questionnaire, and the Revised Social Support Questionnaire. Emotional and tangible social support network size and satisfaction mediated the effect of ethnic attachment on loneliness. Older Koreans who had stronger ethnic attachment had more emotional and tangible supports, were more satisfied with their supports, and had a lower level of loneliness. Emotional and tangible social network composition did not serve as mediators in this study. PMID- 10094302 TI - Interviewing children. AB - The focus in health-related research on children has shifted from seeking information about children to seeking information directly from them. Children, even as young as three years old, can give graphic descriptions and have excellent recall of experiences related to adverse events, such as illness and hospitalization. Children use scripts as the primary means of anticipating, comprehending, and re-creating real-life experience. The content, timing, number, and structure of interviews will influence the completeness, accuracy, and consistency of children's recall of events. Although at times conflicting, the findings from recent scholarship on children's narrative competence will assist researchers to select the interviewing strategies most likely to yield faithful representations of experience. PMID- 10094303 TI - The role of overlapping U1 and U11 5' splice site sequences in a negative regulator of splicing. AB - Splicing of Rous sarcoma virus RNA is regulated in part by a cis-acting intronic RNA element called the negative regulator of splicing (NRS). An NRS mutant affecting nt 916-923 disrupts U11 snRNP binding and reduces NRS activity (Gontarek et al., 1993, Genes & Dev 7:1926-1936). However, we observed that a U15' splice site-like sequence, which overlapped the U11 site, was also disrupted by this mutation. To determine whether the U1 or the U11 site was essential for NRS activity, we analyzed twelve additional mutants involving nt 915-926. All mutations that disrupted the potential base pairing between U1 snRNA and the NRS reduced NRS activity, including single point mutations at nt 915, 916, and 919. The point mutation at nt 919 was partially suppressed by a compensatory base change mutation in U1 snRNA. In contrast, a mutation which strengthened the potential base pairing between the U1 site and the NRS increased NRS activity. Surprisingly, mutations that specifically targeted the U115' splice site consensus sequence increased the levels of unspliced RNA, suggesting U11 binding plays an antagonistic role to NRS activity. We propose that U1 snRNP binding to the NRS inhibits splicing and is regulated by U11 snRNP binding to the overlapping sequence. Competition between U1 and U11 snRNPs would result in the appropriate balance of spliced to unspliced RNAs for optimal viral replication. Further, a virus mutated in the U1/U11 region of the NRS was found to have delayed replication. PMID- 10094304 TI - Polypyrimidine-tract binding protein (PTB) is necessary, but not sufficient, for efficient internal initiation of translation of human rhinovirus-2 RNA. AB - Initiation of translation of the animal picornavirus RNAs is via a mechanism of direct internal ribosome entry, which requires a substantial segment of the viral 5'-untranslated region, generally known as the IRES (for "internal ribosome entry site"). Because, however, translation of the RNAs of members of the enterovirus, and more especially, the rhinovirus subgroups of the Picornaviridae is restricted in the reticulocyte lysate system, but is greatly stimulated by the addition of HeLa cell extracts, the implication is that, in these cases, internal initiation also requires cellular trans-acting factors that are more abundant in HeLa cell extracts than in rabbit reticulocytes. This was used as the basis of a functional assay for the purification of the HeLa cell factors required for translation dependent on the human rhinovirus-2 (HRV) IRES. There are two such HeLa cell factors separable by ion-exchange chromatography, each of which is individually active in the assay, although their combined effect is synergistic. One of these activities is shown to be polypyrimidine-tract binding protein (PTB) on the grounds that (1) the activity copurifies to homogeneity with PTB and (2) recombinant PTB expressed in Escherichia coli stimulates HRV IRES-dependent translation with a specific activity similar to that of the purified HeLa cell factor. Furthermore, it is shown that recombinant PTB also stimulates the translation of RNAs bearing the poliovirus type 1 (Mahoney) IRES. PMID- 10094305 TI - The identification and characterization of a novel splicing protein, Isy1p, of Saccharomyces cerevisiae. AB - We have identified a novel splicing factor, Isy1p, through two-hybrid screens for interacting proteins involved in nuclear pre-mRNA splicing. Isy1p was tagged and demonstrated to be part of the splicing machinery, associated with spliceosomes throughout the splicing reactions. At least a portion of the Isy1 protein population is associated with snRNAs; low levels of U5 and U6 snRNAs are coimmunoprecipitated specifically with Isy1p. When the ISY1 gene was knocked out, no defect in vegetative growth was observed. Using a sensitive in vivo splicing assay, however, we observed lower splicing efficiency in the isy1 null mutant compared to wild-type, indicating that Isy1 p is important in the optimization of splicing. PMID- 10094306 TI - Sensitivity of splice sites to antisense oligonucleotides in vivo. AB - A series of HeLa cell lines which stably express beta-globin pre-mRNAs carrying point mutations at nt 654, 705, or 745 of intron 2 has been developed. The mutations generate aberrant 5' splice sites and activate a common 3' cryptic splice site upstream leading to aberrantly spliced beta-globin mRNA. Antisense oligonucleotides, which in vivo blocked aberrant splice sites and restored correct splicing of the pre-mRNA, revealed major differences in the sensitivity of these sites to antisense probes. Although the targeted pre-mRNAs differed only by single point mutations, the effective concentrations of the oligonucleotides required for correction of splicing varied up to 750-fold. The differences among the aberrant 5' splice sites affected sensitivity of both the 5' and 3' splice sites; in particular, sensitivity of both splice sites was severely reduced by modification of the aberrant 5' splice sites to the consensus sequence. These results suggest large differences in splicing of very similar pre-mRNAs in vivo. They also indicate that antisense oligonucleotides may provide useful tools for studying the interactions of splicing machinery with pre-mRNA. PMID- 10094307 TI - Exonic splicing enhancers contribute to the use of both 3' and 5' splice site usage of rat beta-tropomyosin pre-mRNA. AB - The rat beta-tropomyosin gene encodes two tissue-specific isoforms that contain the internal, mutually exclusive exons 6 (nonmuscle/smooth muscle) and 7 (skeletal muscle). We previously demonstrated that the 3' splice site of exon 6 can be activated by introducing a 9-nt polyuridine tract at its 3' splice site, or by strengthening the 5' splice site to a U1 consensus binding site, or by joining exon 6 to the downstream common exon 8. Examination of sequences within exons 6 and 8 revealed the presence of two purine-rich motifs in exon 6 and three purine-rich motifs in exon 8 that could potentially represent exonic splicing enhancers (ESEs). In this report we carried out substitution mutagenesis of these elements and show that some of them play a critical role in the splice site usage of exon 6 in vitro and in vivo. Using UV crosslinking, we have identified SF2/ASF as one of the cellular factors that binds to these motifs. Furthermore, we show that substrates that have mutated ESEs are blocked prior to A-complex formation, supporting a role for SF2/ASF binding to the ESEs during the commitment step in splicing. Using pre-mRNA substrates containing exons 5 through 8, we show that the ESEs within exon 6 also play a role in cooperation between the 3' and 5' splice sites flanking this exon. The splicing of exon 6 to 8 (i.e., 5' splice site usage of exon 6) was enhanced with pre-mRNAs containing either the polyuridine tract in the 3' splice site or consensus sequence in the 5' splice site around exon 6. We show that the ESEs in exon 6 are required for this effect. However, the ESEs are not required when both the polyuridine and consensus splice site sequences around exon 6 were present in the same pre-mRNA. These results support and extend the exon-definition hypothesis and demonstrate that sequences at the 3' splice site can facilitate use of a downstream 5' splice site. In addition, the data support the hypothesis that ESEs can compensate for weak splice sites, such as those found in alternatively spliced exons, thereby providing a target for regulation. PMID- 10094308 TI - Structural alterations of the tRNA(m1G37)methyltransferase from Salmonella typhimurium affect tRNA substrate specificity. AB - In Salmonella typhimurium, the tRNA(m1G37)methyltransferase (the product of the trmD gene) catalyzes the formation of m1G37, which is present adjacent and 3' of the anticodon (position 37) in seven tRNA species, two of which are tRNA(Pro)CGG and tRN(Pro)GGG. These two tRNA species also exist as +1 frameshift suppressor sufA6 and sufB2, respectively, both having an extra G in the anticodon loop next to and 3' of m1G37. The wild-type form of the tRNA(m1G37)methyltransferase efficiently methylates these mutant tRNAs. We have characterized one class of mutant forms of the tRNA(m1G37)methyltransferase that does not methylate the sufA6 tRNA and thereby induce extensive frameshifting resulting in a nonviable cell. Accordingly, pseudorevertants of strains containing such a mutated trmD allele in conjunction with the sufA6 allele had reduced frameshifting activity caused by either a 9-nt duplication in the sufA6tRNA or a deletion of its structural gene, or by an increased level of m1G37 in the sufA6tRNA. However, the sufB2 tRNA as well as the wild-type counterparts of these two tRNAs are efficiently methylated by this class of structural altered tRNA(m1G37)methyltransferase. Two other mutations (trmD3, trmD10) were found to reduce the methylation of all potential tRNA substrates and therefore primarily affect the catalytic activity of the enzyme. We conclude that all mutations except two (trmD3 and trmD10) do not primarily affect the catalytic activity, but rather the substrate specificity of the tRNA, because, unlike the wild-type form of the enzyme, they recognize and methylate the wild-type but not an altered form of a tRNA. Moreover, we show that the TrmD peptide is present in catalytic excess in the cell. PMID- 10094309 TI - Cloning and characterization of a mammalian pseudouridine synthase. AB - This report describes the cloning and characterization of a pseudouridine (psi) synthase from mouse that we have named mouse pseudouridine synthase 1 (mpus1p). The cDNA is approximately 1.5 kb and when used as a probe on a Northern blot of mouse RNA from tissues and cultured cells, several bands were detected. The open reading frame is 393 amino acids and has 35% identity over its length with yeast psi synthase 1 (pus1p). The recombinant protein was expressed in Escherichia coli and the purified protein converted specific uridines to psi in a number of tRNA substrates. The positions modified in stoichiometric amounts in vitro were 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA. A human cDNA was also cloned and the smaller open reading frame (348 amino acids) was 92% identical over its length with mpus1p but is shorter by 45 amino acids at the amino terminus. The expressed recombinant human protein has no activity on any of the tRNA substrates, most probably the result of the truncated open reading frame. PMID- 10094310 TI - The cis acting sequences responsible for the differential decay of the unstable MFA2 and stable PGK1 transcripts in yeast include the context of the translational start codon. AB - A general pathway of mRNA turnover has been described for yeast in which the 3' poly(A) tail is first deadenylated to an oligo(A) length, leading to decapping and subsequent 5'-3' exonucleolytic decay. The unstable MFA2 mRNA and the stable PGK1 mRNAs both decay through this pathway, albeit at different rates of deadenylation and decapping. To determine the regions of the mRNAs that are responsible for these differences, we examined the decay of chimeric mRNAs derived from the 5' untranslated, coding, and 3' untranslated regions of these two mRNAs. These experiments have led to the identification of the features of these mRNAs that lead to their different stabilities. The MFA2 mRNA is unstable solely because its 3' UTR promotes the rates of deadenylation and decapping; all other features of this mRNA are neutral with respect to mRNA decay rates. The PGK1 mRNA is stable because the sequence context of the PGK1 translation start codon and the coding region function together to stabilize the transcript, whereas the PGK13' UTR is neutral with respect to decay. Importantly, changes in the PGK1 start codon context that destabilized the transcript also reduced its translational efficiency. This observation suggests that the nature of the translation initiation complex modulates the rates of mRNA decapping and decay. PMID- 10094311 TI - An engineered class I transfer RNA with a class II tertiary fold. AB - Structure-based engineering of the tertiary fold of Escherichia coli tRNA(Gln)2 has enabled conversion of this transfer RNA to a class II structure while retaining recognition properties of a class I glutamine tRNA. The new tRNA possesses the 20-nt variable stem-loop of Thermus thermophilus tRNA(Ser). Enlargement of the D-loop appears essential to maintaining a stable tertiary structure in this species, while rearrangement of a base triple in the augmented D-stem is critical for efficient glutaminylation. These data provide new insight into structural determinants distinguishing the class I and class II tRNA folds, and demonstrate a marked sensitivity of glutaminyl-tRNA synthetase to alteration of tRNA tertiary structure. PMID- 10094312 TI - Packaging and replication regulation revealed by chimeric genome segments of double-stranded RNA bacteriophage phi6. AB - Bacteriophage phi6 has a double-stranded RNA genome composed of three linear segments, L, M, and S. The innermost particle in the virion of phi6, like in the other dsRNA viruses, is an RNA-dependent RNA polymerase complex, which carries out all the functions needed for the replication of the viral genome. Empty polymerase complexes can package the single-stranded copies of the viral genome segments, replicate the packaged segments into double-stranded form (minus strand synthesis), and then produce new plus strands (transcripts) from the double stranded RNA templates. The three viral genomic segments contain unique packaging signals at their 5' ends, and minus strand synthesis initiation is dependent on the sequence at the 3' end. Here we have constructed chimeric segments that have the packaging signal from one segment and the minus strand synthesis initiation signal from another segment. Using purified recombinant polymerase complexes and single-stranded/chimeric and original RNA segments, we have analyzed the packaging and replication regulation operating in in vitro conditions. We show that the 5' end of the L genome segment in single-stranded form is needed to switch from the packaging to the minus strand synthesis and the same sequence is required in double-stranded form to switch on plus strand synthesis. In addition we have constructed deletions to the M segment to analyze the possible regulatory role of the internal noncoding area of this segment. PMID- 10094313 TI - Nop58p is a common component of the box C+D snoRNPs that is required for snoRNA stability. AB - Eukaryotic nucleoli contain a large family of box C+D small nucleolar RNA (snoRNA) species, all of which are associated with a common protein Nop1p/fibrillarin. Nop58p was identified in a screen for synthetic lethality with Nop1p and shown to be an essential nucleolar protein. Here we report that a Protein A-tagged version of Nop58p coprecipitates all tested box C+D snoRNAs and that genetic depletion of Nop58p leads to the loss of all tested box C+D snoRNAs. The box H+ACA class of snoRNAs are not coprecipitated with Nop58p, and are not codepleted. The yeast box C+D snoRNAs include two species, U3 and U14, that are required for the early cleavages in pre-rRNA processing. Consistent with this, Nop58p depletion leads to a strong inhibition of pre-rRNA processing and 18S rRNA synthesis. Unexpectedly, depletion of Nop58p leads to the accumulation of 3' extended forms of U3 and U24, showing that the protein is also involved in snoRNA synthesis. Nop58p is the second common component of the box C+D snoRNPs to be identified and the first to be shown to be required for the stability and for the synthesis of these snoRNAs. PMID- 10094315 TI - Socialization patterns are key to the transmission dynamics of tuberculosis. PMID- 10094316 TI - TB: the return of the phage. A review of fifty years of mycobacteriophage research. AB - The first mycobacteriophage was isolated in 1947, and since that time over 250 of these viruses have been identified. Phages have made a significant contribution to our knowledge of mycobacteria over the past fifty years, and following the development of typing techniques in the 1960s and 1970s they were widely used in epidemiological studies of tuberculosis. Unfortunately, attempts to use lytic phages therapeutically during tuberculosis infection have so far failed to elicit cure in experimentally infected animals. During the past decade phages have become important in molecular studies of mycobacteria, both in terms of studying phage biology and as tools in recombinant DNA technology, thus facilitating the investigation of mycobacterial pathogenesis. Today their potential as diagnostics reagents is also being realised with the development of exciting new techniques for rapid bacterial detection and drug susceptibility testing. This review outlines the history of these remarkable organisms, from their discovery fifty years ago to the current developments in rapid diagnostic techniques. PMID- 10094314 TI - The splicing factors 9G8 and SRp20 transactivate splicing through different and specific enhancers. AB - The activity of the SR protein family of splicing factors in constitutive or alternative splicing requires direct interactions with the pre-mRNA substrate. Thus it is important to define the high affinity targets of the various SR species and to evaluate their ability to discriminate between defined RNA targets. We have analyzed the binding specificity of the 30-kDa SR protein 9G8, which contains a zinc knuckle in addition to the RNA binding domain (RBD). Using a SELEX approach, we demonstrate that 9G8 selects RNA sequences formed by GAC triplets, whereas a mutated zinc knuckle variant selects different RNA sequences, centered around a (A/U)C(A/U)(A/U)C motif, indicating that the zinc knuckle is involved in the RNA recognition specificity of 9G8. In contrast, SC35 selects sequences composed of pyrimidine or purine-rich motifs. Analyses of RNA-protein interactions with purified recombinant 30-kDa SR proteins or in nuclear extracts, by means of UV crosslinking and immunoprecipitation, demonstrate that 9G8, SC35, and ASF/SF2 recognize their specific RNA targets with high specificity. Interestingly, the RNA sequences selected by the mutated zinc knuckle 9G8 variant are efficiently recognized by SRp20, in agreement with the fact that the RBD of 9G8 and SRp20 are similar. Finally, we demonstrate the ability of 9G8 and of its zinc knuckle variant, or SRp20, to act as efficient splicing transactivators through their specific RNA targets. Our results provide the first evidence for cooperation between an RBD and a zinc knuckle in defining the specificity of an RNA binding domain. PMID- 10094317 TI - Measuring morbidity in adult asthmatics. AB - SETTING: Whereas prevalence studies usually involve a general population sample, morbidity studies often involve the evaluation of factors that affect asthma severity within an asthmatic population. OBJECTIVE: To review methods of measuring morbidity in adult asthmatics, and to assess the appropriateness of the available methods in a variety of research contexts. FINDINGS: As in prevalence studies, symptoms are the cornerstone of studies of asthma morbidity. These may be supplemented by physiological measures including daily peak flow measurement, but bronchial hyper-responsiveness (BHR) testing is usually impractical, and there is no simple relationship between current asthma severity and current levels of BHR in individuals. Health service and medication usage are often taken as measures of asthma morbidity, but they may be inappropriate in studies in which increased contact with the health services is an intended or unintended effect of participation. Measures of quality of life can be a useful complement to more 'objective' methods. CONCLUSIONS: In studies of morbidity in adult asthmatics, the emphasis should be on using 'appropriate methodology', and methods that may be appropriate in one context may be completely inappropriate in another. PMID- 10094318 TI - Incidence rate of adult-onset asthma in relation to age, sex, atopy and smoking: a Swedish population-based study of 15813 adults. AB - SETTING: Our knowledge about asthma incidence in an adult population is limited. The aim of the present investigation was to estimate the incidence rate of adult onset asthma in relation to age, sex, atopy and smoking in a random population sample. METHODS: A random sample of 20000 subjects 20 to 50 years of age was investigated using a short respiratory questionnaire. It was answered by 15813 persons. Adult-onset asthma was defined as a positive response to 'physician diagnosed' asthma from 16 years of age. Subjects were also asked to report the year of asthma diagnosis, and also, when relevant, the year of smoke-start and smoke-stop. Incidence rates of adult-onset asthma and incidence rate ratios (IRR) were calculated. RESULTS: The incidence rate of adult-onset asthma among females was 1.3 cases/1000 person-years compared with 1.0/1000 person-years for males (IRR 1.3, 95% confidence interval [CI] 1.0-1.6). The incidence rate was high (3.0/1000 person-years) among females aged 16-20 years. There was a strong association between the incidence rate of adult-onset asthma and hay fever, atopic dermatitis and family history of atopy. Compared with never-smokers, the IRR for female smokers was 1.6 (95% CI 1.1-2.2), while for male smokers it was unity. Both male and female ex-smokers had moderately increased rate ratios, of 1.5 and 1.1, respectively. CONCLUSIONS: In this retrospective study, reported atopic symptoms and family history of atopy were strongly associated with incidence of adult-onset asthma. Tobacco smoking may be associated with an increased incidence rate of adult-onset asthma, especially among women. PMID- 10094319 TI - Acute severe asthma in Trinidad and Tobago. AB - SETTING: Accident and emergency department, General Hospital, Port of Spain, Trinidad and Tobago. OBJECTIVE: To measure the occurrence and clinical management of acute severe asthma. DESIGN: Data collected prospectively for consecutive attendees with asthma over a period of 3 months. RESULTS: Asthma accounted for 8.8% of attendances. Treatment for the acute attack included nebulised salbutamol in 1031 (85%) and nebulised atrovent in 769 (63%). Systemic corticosteroids were given to 623 (51%) patients. Only 247 (20%) had planned follow-up arrangements recorded. Usual maintenance treatment included inhaled salbutamol in 767 (63%) and inhaled corticosteroid in 286 (24%). Inhaled corticosteroids were more often used by patients aged > or =15 years or who had had previous hospital admissions for asthma. CONCLUSION: The survey identified deficiencies in the clinical management of acute asthma attacks and in longterm asthma care. Caribbean guidelines for asthma care have subsequently been published, and follow-up surveys should be carried out to evaluate their implementation. PMID- 10094320 TI - Transmission of tuberculosis between people of different ages in The Netherlands: an analysis using DNA fingerprinting. AB - SETTING: In the period 1950 to 1980 the risk of tuberculous infection in the Netherlands declined more steeply than tuberculosis incidence. This study aimed at determining whether this might be explained by preferential transmission within age groups. METHODS: Using restriction fragment length polymorphism (RFLP) typing on all Mycobacterium tuberculosis isolates in the Netherlands from 1993 to 1996, clusters with identical fingerprints were identified. The correlation between the ages of people in clusters of two Dutch patients was determined. RESULTS: The mean difference in age between the two people, in 81 clusters of two, was 13.9 years, while the mean age difference between all possible pairs of individuals in this data set was 25.5 years. Fisher's intraclass correlation coefficient was 0.62 (95% confidence interval [CI] 0.46-0.74). CONCLUSION: It is concluded that sources of tuberculosis may preferentially transmit infection to people close to their own age. As the average age of cases has increased in the period 1950-1980, sources may have become less likely to infect children in whom the risk of infection has been measured. The annual risk of infection measured in children and young adults in countries with low levels of tuberculosis may not apply to older members of the population. PMID- 10094321 TI - Outbreak of multiple drug-resistant tuberculosis in Lisbon: detection by restriction fragment length polymorphism analysis. AB - SETTING: Multidrug-resistant tuberculosis (MDR-TB) mainly among human immunodeficiency virus (HIV) seropositive patients in Lisbon hospitals in 1996 1997. OBJECTIVE: Detection of transmission of MDR-TB strains and epidemic outbreaks in several hospital units in the city of Lisbon, including a prison hospital. DESIGN: Use of restriction fragment length polymorphism (RFLP) to fingerprint isolates of Mycobacterium tuberculosis resistant to isoniazid, rifampicin, and one other drug. RESULTS: A total of 43 MDR-TB strains were typed. Sixty-seven per cent of the patients were HIV positive, 12% were HIV negative, and the remainder had unknown HIV status. About 88% of the isolates were grouped in three genetically similar clusters, suggesting possible recent transmission. A predominant cluster (cluster A), corresponding to 72% of the cases, was found, 45% of which came from the prison hospital. Strains from this cluster were resistant to isoniazid, rifampicin, streptomycin, and sometimes ethambutol. A retrospective epidemiological investigation was conducted with respect to all patients in cluster A, and epidemiological links were established between them. CONCLUSION: Our results suggest recent transmission of MDR-TB, mainly in HIV positive patients, in Lisbon hospitals. Moreover, the predominant MDR-TB clustered strains were not confined to HIV-infected individuals, as they were also isolated in some immunocompetent patients. PMID- 10094322 TI - Phase II trial of recombinant interferon-alpha2b in patients with advanced intractable multidrug-resistant pulmonary tuberculosis: long-term follow-up. AB - SETTING: Multidrug-resistant tuberculosis patients without human immunodeficiency virus (HIV) infection, with Mycobacterium tuberculosis resistant to almost all of the available drugs. OBJECTIVE: Limited phase II trial with recombinant interferon-alpha2b in five chronic multidrug-resistant tuberculosis patients. METHODS: Three million units of r-IFN-alpha2b were administered subcutaneously every week for 12 weeks. Before and after treatment, and during a 30-month follow up period, the patients underwent clinical and radiological examination, together with bacteriological, immunological and routine laboratory testing. RESULTS: Two of the five patients became long-term sputum smear and culture negative after r IFN-alpha2b therapy; one of the patients showed clinical improvement and negative smear after therapy, but remained culture positive. The other two patients showed no response. CONCLUSION: The results of this trial suggest that r-IFN-alpha2b should be evaluated further in multidrug-resistant tuberculosis in prospective controlled trials. PMID- 10094323 TI - The prevalence of Mycobacterium tuberculosis drug resistance in New Caledonia, 1995-1996. AB - SETTING: Study of the susceptibility to anti-tuberculosis drugs of Mycobacterium tuberculosis strains isolated in New Caledonia, a French South Pacific Territory, where tuberculosis continues to be a public health problem. OBJECTIVE: To assess the stability of this susceptibility in order to justify both non-systematic susceptibility testing and the implementation of simplified chemotherapy regimens. METHODS: Over a period of nearly 2 years (1995-1996), every new case of tuberculosis confirmed by the laboratory was included in the study. A total of 105 strains were tested against five anti-tuberculosis drugs: isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin. RESULTS: No primary drug resistance was detected for the main drugs. One strain with acquired resistance to isoniazid and streptomycin was isolated from one of the 12 patients suffering a relapse of the disease. CONCLUSIONS: The results of this exhaustive study justify the non-systematic approach to susceptibility testing for new patients. However, for strains isolated from patients suffering from relapse or therapeutic failure, or who belong to a high risk population, drug susceptibility testing should be performed. This kind of management will aid in the detection of possible isoniazid and streptomycin resistance, thus avoiding the selection and possible emergence of strains resistant to rifampicin. The results of the study argue for the use of a fixed dose regimen using triple combination tablets of isoniazid, rifampicin and pyrazinamide (HRZ) for 2 months, followed by dual drug therapy (HR) for 4 months. PMID- 10094324 TI - Control of tuberculosis in Uganda: a tale of two districts. AB - SETTING: Rakai and Mbarara districts, south-western Uganda. OBJECTIVE: To compare compliance and other treatment outcomes with tuberculosis (TB) treatment for Rakai and Mbarara districts, and to elucidate factors associated with the disparity. DESIGN: A retrospective cohort analysis of tuberculosis treatment outcomes for the period 1992-1996. Predictors for compliance were examined for 1995 using univariate and multivariate methods. RESULTS: Of the surviving patients, 57% finished treatment in Mbarara compared to 92% in Rakai. Enhanced compliance on univariate analysis was associated with being smear positive; previous TB treatment; use of short-course chemotherapy; return for repeat smear; no change of health unit; no change of district; registration in Rakai; and not being hospitalised. On multivariate analysis, being smear positive, previous TB treatment, hospitalisation and registration site were not significant. The highest risk for default was unit change after the intensive phase of treatment, with an adjusted odds ratio of 17.53. The highest differences in the two districts were for the hospitalisation and unit change rates, with corresponding odds ratios of 52 and 0.06. CONCLUSIONS: Initial hospitalisation of TB patients is not necessary for subsequent completion of treatment. Use of one health unit for both the intensive and continuation phase of treatment may improve compliance. PMID- 10094325 TI - Evaluation of the MycoDot test in patients with suspected tuberculosis in a field setting in Tanzania. AB - SETTING: Rapid, simple and inexpensive methods are needed to improve the diagnosis of tuberculosis in low-income countries. The MycoDot test has these characteristics. OBJECTIVE: To assess the utility of the MycoDot test in screening patients with suspected tuberculosis. DESIGN: Ambulatory patients presenting with symptoms of pulmonary tuberculosis were evaluated by physical examination and sputum acid-fast bacilli (AFB) microscopy. Separately, the MycoDot test was performed on whole blood. Patients with AFB-negative smears were treated with a 10-day course of erythromycin. Those remaining symptomatic had a chest radiograph. All sputum specimens were cultured for mycobacteria. Patients with culture-negative tuberculosis and those without a tuberculosis diagnosis were reassessed at 2 months. RESULTS: Among the 241 patients who were evaluated, the MycoDot test was positive in 26% of patients with AFB-positive/culture positive tuberculosis, 7% with AFB-negative/culture-positive tuberculosis, 7% with culture-negative tuberculosis, 19% treated for tuberculosis who did not meet study case definitions, and 16% without tuberculosis. Twenty four patients did not complete the assessment. Test sensitivity was 16%, specificity 84% and positive predictive value 45%. Sensitivity was highest (41%) in AFB-positive/HIV negative patients and lowest (3%) in AFB-negative/HIV-positive patients. CONCLUSION: The MycoDot test is not useful for the diagnosis of tuberculosis in sub-Saharan African countries, especially where HIV infection is prevalent. PMID- 10094326 TI - The immune response to Mycobacterium tuberculosis in HIV-infected and uninfected adults in Uganda: application of a whole blood cytokine assay in an epidemiological study. AB - SETTING: Out-patient clinic, Entebbe, Uganda. BACKGROUND: It has been proposed that 'type 1' cytokines are essential in protective immunity to Mycobacterium tuberculosis and that suppression of 'type 1' or a switch to a 'type 2' profile is deleterious. We employed a simple assay to examine whether the dependence of the immunological responses to mycobacterial antigens on a range of explanatory factors could be determined in a population where tuberculosis is endemic. OBJECTIVE: To determine the relationship between the tuberculin skin test response and cytokine profile, and the effect of human immunodeficiency virus (HIV) infection. DESIGN: A cross-sectional study of 97 Ugandan adults (22 HIV positive, 75 HIV-negative). Whole blood was stimulated in vitro using mycobacterial antigens (purified protein derivative [PPD] and culture filtrate proteins [CFP]). 'Type 1' cytokines (gamma interferon [IFN-gamma] and interleukin 2 [IL-2]), 'type 2' cytokines (IL-5 and IL-10) and tumour necrosis factor alpha (TNF-alpha) were measured in culture supernatants. RESULTS: Among HIV-negative subjects, a positive tuberculin skin test was associated with type 1 or mixed (type 1 + type 2) cytokine production, but a positive IFN-gamma response also occurred in a proportion of tuberculin skin test negative subjects (36% for PPD, 17% for CFP). In association with HIV infection, IFN-gamma responses to mycobacterial antigens were profoundly impaired (odds ratio [OR] 0.10 for PPD, 0.06 for CFP, P< or =0.001), but production of IL-2, IL-5 and TNF-alpha was relatively sustained, and IL-10 increased or sustained (OR 3.97 for PPD, P = 0.01, 1.14 for CFP, P = 0.99). CONCLUSION: The type 1/type 2 cytokine balance was not defined by the tuberculin skin test response, and may have a closer relation to protective immunity. IFN-gamma production was strikingly impaired in association with HIV infection, while production of type 2 cytokines was sustained or increased. Use of a simple assay allowed a large sample of subjects to be examined, producing epidemiologically meaningful results. PMID- 10094327 TI - Tuberculosis vaccination versus isoniazid preventive therapy: a decision analysis to determine the preferred strategy of tuberculosis prevention in HIV-infected adults in the developing world. AB - SETTING: The developing world. OBJECTIVE: To compare the strategy of TB vaccination with that of tuberculin skin-testing in conjunction with isoniazid (INH) in preventing tuberculosis in HIV-infected persons. For any clinical scenarios in which immunization would be more effective than INH preventive therapy, to determine the minimum necessary vaccine safety and effectiveness required. DESIGN: Decision analysis. A hypothetical cohort of 10000 HIV-infected persons, 65% of whom were tuberculin positive, living in the developing world, was studied. Probability estimates were based on BCG vaccine for the baseline analysis, and it was assumed that the vaccine cannot protect if given after infection. RESULTS: Under the probability estimates and assumptions of the analysis, tuberculin skin testing/INH preventive therapy would prevent 458 more cases of TB and 45 more deaths due to TB than TB vaccination. One- and two-way sensitivity analyses revealed no thresholds at which TB vaccination would be the preferred strategy. Vaccine safety did not impact the outcome of the analysis. Three-way sensitivity analysis revealed that if the prevalence of anergy were 35% and the risk of progression to active TB among anergic persons 12.2 cases per 100 person-years, a vaccine would have to be at least 87% effective to be preferred over INH preventive therapy. CONCLUSIONS: Under the conditions of the analysis, which did not account for cost or logistics, tuberculin skin testing/INH preventive therapy would be more effective than TB vaccination in preventing TB among HIV-infected persons. The hypothesized TB vaccine would prevent more TB than INH preventive therapy only in areas where the prevalence of anergy and risk of active TB if anergic were high, and vaccine effectiveness exceeded 87%. PMID- 10094328 TI - The effects of BCG immunization and human immunodeficiency virus infection on dual skin test reactions to purified protein derivative and Mycobacterium avium sensitin among adults in Zambia. AB - SETTING: University hospital in Lusaka, Zambia. OBJECTIVE: To determine the effects of childhood bacille Calmette-Guerin (BCG) immunization and human immunodeficiency virus (HIV) infection on dual skin test reactions to purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS) in a developing country. DESIGN: Descriptive cross-sectional study. RESULTS: Dual skin testing was performed on 112 adults, 58 HIV-positive and 54 HIV-negative. Forty-seven (42%) of 112 had PPD reactions > or =10 mm and 52 (46%) had MAS reactions > or =10 mm. PPD reactions > or =10 mm were present in 30 (63%) of 48 BCG-positive subjects compared to 17 (27%) of 64 BCG-negative subjects (P<0.001). Nineteen (33%) of 58 PPD or MAS skin test positive subjects were PPD dominant, 15 (26%) were MAS dominant, and 24 (41%) were non-dominant. MAS dominant and non-dominant reactions were significantly reduced in HIV-positive subjects, and non-dominant reactions were increased in BCG-positive subjects. CONCLUSIONS: Childhood BCG immunization is associated with PPD reactions > or =10 mm among adults. Reduced PPD reaction rates in HIV-positive adults appear to be due to a loss of BCG induced PPD reactivity. Prior infection with M. avium complex is detectable in a significant proportion of adults in a developing country. PMID- 10094329 TI - Outcome of tuberculous meningitis at 6 and 12 months: a multiple regression analysis. AB - OBJECTIVE: There are few studies on the long-term outcome of tuberculous meningitis (TBM) employing multivariate analysis. The present study was undertaken to evaluate the outcome predictors of TBM at 6 and 12 months. METHOD: Those patients with TBM who could be sequentially followed up for 6 and 12 months were included in this prospective, hospital-based study. The outcome was defined at 6 and 12 months by Barthel Index (BI) score into complete (BI = 20), partial (BI = 12-19) and poor (BI<12). Death was included in the 'poor recovery' group for statistical analysis. A number of clinical, laboratory and radiological parameters were evaluated by multiple regression analysis. RESULTS: Fifty-eight patients with TBM aged between 1 and 64 years (mean 25.6 years), 18 of whom were females and 17 children below 12 years, were included in the study. Fifty-eight patients were followed up for 6 months and 56 for 12 months. At 6 months' follow up 37 patients had complete recovery, three partial, six poor and 12 had died. At 12 months, 40 patients had complete recovery, one partial and three poor. The best set of parameters predicting outcome at 6 and 12 months included stage of TBM, Glasgow coma scale (GCS) and brain infarction. CONCLUSION: This study highlights the importance of stage of meningitis, GCS and infarction in predicting the long term outcome of tuberculous meningitis. PMID- 10094330 TI - Tuberculosis in immigrants. PMID- 10094331 TI - Drug-resistant tuberculosis in chronic excretors in Casablanca, Morocco. PMID- 10094332 TI - Noninvasive surgery for epilepsy: the era of image guidance. PMID- 10094333 TI - Assessing effective transvascular particle delivery to the brain parenchyma: a challenge to neuroradiology. PMID- 10094334 TI - The carotid artery through a keyhole. PMID- 10094335 TI - Technical advances and clinical progress in carotid diagnosis. PMID- 10094336 TI - There is no simple answer to a rare complication of inferior petrosal sinus sampling. PMID- 10094337 TI - Value of diffusion-weighted imaging and apparent diffusion coefficient in recent cerebral infarctions: a correlative study with contrast-enhanced T1-weighted imaging. AB - BACKGROUND AND PURPOSE: The clinical usefulness and the time course of diffusion weighted imaging and apparent diffusion coefficient (ADC) in acute and subacute cerebral infarction have not yet been established, although it is known that contrast-enhanced T1-weighted spin-echo imaging can detect a subacute infarct. Our aim was to study which imaging technique is useful in detecting recent infarcts, and whether an increase in ADC or a decrease in signal intensity on diffusion-weighted images is correlated with enhancement on T1-weighted spin-echo images. METHODS: Forty-one infarctions with a duration of 9 hours to 27 days were studied in 29 patients. The ADC and signal intensity on diffusion-weighted images were compared with the contrast-enhancement ratio (CER) on T1-weighted spin-echo images (CER = signal intensity after contrast injection/signal intensity before contrast injection). RESULTS: ADC was linearly correlated with CER, and signal intensity on diffusion-weighted images was inversely correlated with CER. The correlation between ADC and age of the infarct in the subacute phase was weak. CONCLUSION: Diffusion-weighted and contrast-enhanced T1-weighted spin-echo images complement each other in detecting subacute infarcts. Neovascularization and disruption of the blood-brain barrier in infarcts can be important in increasing ADC in subacute infarcts. PMID- 10094338 TI - Localization of the first and second somatosensory areas in the human cerebral cortex with functional MR imaging. AB - BACKGROUND AND PURPOSE: Our objective was to map by means of a conventional mid field (1.0 T) MR imaging system the somatosensory areas activated by unilateral tactile stimulation of the hand, with particular attention to the areas of the ipsilateral hemisphere. METHODS: Single-shot echo-planar T2*-weighted imaging sequences were performed in 12 healthy volunteers to acquire 10 contiguous 7-mm thick sections parallel to the coronal and axial planes during tactile stimulation of the hand. The stimulation paradigm consisted of brushing the subjects' palm and fingers with a rough sponge at a frequency of about 1 Hz. RESULTS: Stimulation provoked a signal increase (about 2% to 5%) that temporally corresponded to the stimulus in several cortical regions of both hemispheres. Contralaterally, activation foci were in the anterior parietal cortex in an area presumably corresponding to the hand representation zone of the first somatosensory cortex, in the posterior parietal cortex, and in the parietal opercular cortex forming the upper bank of the sylvian sulcus and probably corresponding to the second somatosensory cortex. Activation foci were also observed in the frontal cortex. Ipsilaterally, activated areas were in regions of the posterior parietal and opercular cortices roughly symmetrical to those activated in the contralateral hemisphere. The same activation pattern was observed in all subjects. CONCLUSION: The activated areas of the somatosensory cortex described in the present study corresponded to those reported in other studies with magnetoelectroencephalography, positron emission tomography, and higher-field functional MR imaging. An additional area of activation in the ipsilateral parietal operculum, unnoticed in other functional MR imaging studies, was also observed. PMID- 10094339 TI - A quantitative MR study of the hippocampal formation, the amygdala, and the temporal horn of the lateral ventricle in healthy subjects 40 to 90 years of age. AB - BACKGROUND AND PURPOSE: Several investigators have defined normal age-specific values for the medial temporal lobe structures in neurologically normal elderly subjects, but, to our knowledge, no one has reported those values for a large sample of healthy volunteers. The purpose of our study was to define normal age specific values for the hippocampal formation, the amygdala, and the temporal horn of the lateral ventricle by age group, ranging from 40 to 90 years, in order to generate a guideline for the quantitative MR diagnosis and differential diagnosis for early Alzheimer disease. METHODS: MR-based volumetric measurements of the hippocampal formation, the amygdala, and the temporal horn, standardized by total intracranial volume, were obtained from oblique coronal and sagittal T1 weighted MR images in 619 healthy volunteers and two cadaveric specimens. RESULTS: Differences in standardized volumes of the hippocampal formation, the amygdala, and the temporal horn were significant among the 61- to 70-year-old, 71 to 80-year-old, and 81- to 90-year-old groups, and were not significant between the 40- to 50-year-old and 51- to 60-year-old groups. We found no significant differences in side or sex among the age groups for any of the structures. CONCLUSION: Differences in the mean value and in the 95% normal range of standardized volumes of the hippocampal formation, the amygdala, and the temporal horn correspond to differences in age among healthy subjects; therefore, age should be considered a factor in correlative research, especially in that involving patients in the early stages of Alzheimer disease. PMID- 10094340 TI - Early and delayed MR and PET changes after selective temporomesial radiosurgery in mesial temporal lobe epilepsy. AB - We report a patient with medically refractory mesial temporal lobe epilepsy treated by gamma knife radiosurgery. In lieu of a microsurgical procedure, an entorhinoamygdalohippocampectomy was performed with a gamma knife and low marginal doses (25 Gy). The clinical and imaging studies, including CT, MR imaging, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and long term follow-up MR examinations, are reported. The patient has been seizure-free since the day of treatment, with no clinical complications. MR studies accurately depicted the effect on the target structures and the transient secondary changes around them. FDG-PET scans showed decreased metabolism after gamma knife surgery throughout the anteromesial part of the epileptogenic temporal lobe. This metabolic decrease was reversible in the lateral temporal cortex. Our case suggests that gamma knife surgery is a promising tool for use as a minimally invasive approach to the treatment of epilepsy. PMID- 10094341 TI - A physiological barrier distal to the anatomic blood-brain barrier in a model of transvascular delivery. AB - BACKGROUND AND PURPOSE: Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the brain. The apparent global delivery of viral-sized iron oxide particles to the rat brain after BBB opening as seen on MR images was compared with the cellular and subcellular location and distribution of the particles. METHODS: Two dextran coated superparamagnetic monocrystalline iron oxide nanoparticle contrast agents, MION and Feridex, were administered intraarterially in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB with hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the brain was evaluated first with MR imaging then by histochemical analysis and electron microscopy to assess perivascular and intracellular distribution. RESULTS: After BBB opening, MR images showed enhancement throughout the disrupted hemisphere for both Feridex and MION. Feridex histochemical staining was found in capillaries of the disrupted hemisphere. Electron microscopy showed that the Feridex particles passed the capillary endothelial cells but did not cross beyond the basement membrane. In contrast, after MION delivery, iron histochemistry was detected within cell bodies in the disrupted hemisphere, and the electron-dense MION core was detected intracellularly and extracellularly in the neuropil. CONCLUSION: MR images showing homogeneous delivery to the brain at the macroscopic level did not indicate delivery at the microscopic level. These data support the presence of a physiological barrier at the basal lamina, analogous to the podocyte in the kidney, distal to the anatomic (tight junction) BBB, which may limit the distribution of some proteins and viral particles after transvascular delivery to the brain. PMID- 10094342 TI - Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis. AB - BACKGROUND AND PURPOSE: Ultrasmall particles of iron oxide (USPIO) constitute a contrast agent that accumulates in cells from the mononuclear phagocytic system. In the CNS they may accumulate in phagocytic cells such as macrophages. The goal of this study was to compare USPIO-enhanced MR images with conventional T2 weighted images and gadolinium-enhanced T1-weighted images in a model of experimental autoimmune encephalomyelitis (EAE). METHODS: Nine rats with EAE and four control rats were imaged at 4.7 T and 1.5 T with conventional T1- and T2 weighted sequences, gadolinium-enhanced T1-weighted sequences, and T2-weighted sequences obtained 24 hours after intravenous injection of a USPIO contrast agent, AMI-227. Histologic examination was performed with hematoxylin-eosin stain, Perls' stain for iron, and ED1 immunohistochemistry for macrophages. RESULTS: USPIO-enhanced images showed a high sensitivity (8/9) for detecting EAE lesions, whereas poor sensitivity was obtained with T2-weighted images (1/9) and gadolinium-enhanced T1-weighted images (0/9). All the MR findings in the control rats were negative. Histologic examination revealed the presence of macrophages at the site where abnormalities were seen on USPIO-enhanced images. CONCLUSION: The high sensitivity of USPIO for macrophage activity relative to other imaging techniques is explained by the histologic findings of numerous perivascular cell infiltrates, including macrophages, in EAE. This work supports the possibility of intracellular USPIO transport to the CNS by monocytes/macrophages, which may have future implications for imaging of human inflammatory diseases. PMID- 10094343 TI - Evaluation of cerebral aneurysms with high-resolution MR angiography using a section-interpolation technique: correlation with digital subtraction angiography. AB - BACKGROUND AND PURPOSE: The objective was to evaluate the results of high resolution, fast-speed, section-interpolation MR angiography and digital subtraction angiography (DSA), thereby examining the potential use of a primary noninvasive screening test for intracranial aneurysms. METHODS: The images were obtained in 39 cerebral aneurysmal lesions from 30 patients with a time-of-flight MR angiographic technique using a 1.5-T superconducting MR system. The total image volume was divided into four slabs, with 48 partitions each. To save time, only 24 phase-encoded steps were measured and interpolated to 48. The parameters used included 30/6.4 (TR/TE), a flip angle of 25 degrees , a 160x512 matrix, a field of view of 150x200, 7 minutes 42 seconds of scan time, an effective thickness of 0.7 mm, and an entire thickness of 102.2 mm. Maximum intensity projection was used for the image analysis, and a multiplanar reconstruction technique was used for patients with intracranial aneurysms. RESULTS: Among 39 intracranial aneurysmal lesions in 30 patients, 21 were ruptured and 18 were unruptured. Twelve lesions were less than 2 mm in size, 12 were 3 to 5 mm, 12 were 6 to 9 mm, and three were larger than 10 mm. At initial examinations, 38 of 39 aneurysmal lesions were detected by both MR angiography and DSA, with 97% sensitivity. In confirming aneurysms in neck and parent vessels, multiplanar reconstruction was successful in detecting all 39 aneurysms, whereas MR angiography was successful in detecting 27 (69%) and DSA was successful in detecting 32 (82%) of the lesions. CONCLUSION: High-resolution MR angiography with a section-interpolation technique showed equal results to those of DSA for the detection of intracranial aneurysms and may be used as a primary noninvasive screening test. In the evaluation of aneurysms in neck and parent vessels, the concurrent use of MR angiography and multiplanar reconstruction was far superior to the use of either MR angiography or DSA alone. PMID- 10094344 TI - In vitro and in vivo comparison of three MR measurement methods for calculating vascular shear stress in the internal carotid artery. AB - BACKGROUND AND PURPOSE: Vascular abnormalities, such as atherosclerosis and the growth and rupture of cerebral aneurysms, result from a derangement in tissue metabolism and injury that are, in part, regulated by hemodynamic stress. The purpose of this study was to establish the feasibility and accuracy of determining wall shear rate in the internal carotid artery from phase-contrast MR data. METHODS: Three algorithms were used to generate shear rate estimates from both ungated and cardiac-gated 2D phase-contrast data. These algorithms were linear extrapolation (LE), linear estimation with correction for wall position (LE*), and quadratic extrapolation (QE). In vitro experiments were conducted by using a phantom under conditions of both nonpulsatile and pulsatile flow. The findings from five healthy volunteers were also studied. MR imaging-derived shear rates were compared with values calculated by solving the fluid flow equations. RESULTS: Findings of in vitro constant-flow experiments indicated that at one or two excitations, QE has the advantage of good accuracy and low variance. Results of in vitro pulsatile flow experiments showed that neither LE* nor QE differed significantly from the predicted value of wall shear stress, despite errors of 17% and 22%, respectively. In vivo data showed that QE did not differ significantly from the predicted value, whereas LE and LE* did. The percentages of errors for QE, LE, and LE* in vivo measurements were 98.5%, 28.5%, and 36.1%, respectively. The average residual of QE was low because the residuals were both above and below baseline whereas, on average, LE* tended to be a more biased overestimator of the shear rate in volunteers. The average and peak wall shear force in five volunteers was approximately 8.10 dyne/cm2 and 13.2 dyne/cm2, respectively. CONCLUSION: Our findings show that LE consistently underestimates the shear rate. Although LE* and QE may be used to estimate shear rate, errors of up to 36% should be expected because of variance above and below the true value for individual measurements. PMID- 10094345 TI - Twinkling artifact on intracerebral color Doppler sonography. AB - Transcranial Doppler sonography shows potential as a noninvasive technique for long-term follow-up of treated intracranial saccular aneurysms. This technical note describes a color Doppler artifact related to microcoil architecture that might represent a potential pitfall in transcranial Doppler sonographic evaluation of aneurysmal cavity thrombosis, since it may be wrongly interpreted as residual flow or aneurysmal cavity recanalization. PMID- 10094346 TI - Cerebral veins: comparative study of CT venography with intraarterial digital subtraction angiography. AB - BACKGROUND AND PURPOSE: Our objective was to compare the reliability of CT venography with intraarterial digital subtraction angiography (DSA) in imaging cerebral venous anatomy and pathology. METHODS: In 25 consecutive patients, 426 venous structures were determined as present, partially present, or absent by three observers evaluating CT multiplanar reformatted (MPR) and maximum intensity projection (MIP) images. These results were compared with the results from intraarterial DSA and, in a second step, with the results of an intraobserver consensus. In addition, pathologic conditions were described. RESULTS: Using DSA as the standard of reference, MPR images had an overall sensitivity of 95% (specificity, 19%) and MIP images a sensitivity of 80% (specificity, 44%) in depicting the cerebral venous anatomy. On the basis of an intraobserver consensus including DSA, MPR, and MIP images (415 vessels present), the sensitivity/specificity was 95%/91% for MPR, 90%/100% for DSA, and 79%/91% for MIP images. MPR images were superior to DSA images in showing the cavernous sinus, the inferior sagittal sinus, and the basal vein of Rosenthal. Venous occlusive diseases were correctly recognized on both MPR and MIP images. Only DSA images provided reliable information of invasion of a sinus by an adjacent meningioma. CONCLUSION: CT venography proved to be a reliable method to depict the cerebral venous structures. MPR images were superior to MIP images. PMID- 10094347 TI - Cerebellar infarct caused by spontaneous thrombosis of a developmental venous anomaly of the posterior fossa. AB - Spontaneous thrombosis of a posterior fossa developmental venous anomaly (DVA) caused a nonhemorrhagic cerebellar infarct in a 31-year-old man who also harbored a midbrain cavernous angioma. DVA thrombosis was well depicted on CT and MR studies and was proved at angiography by the demonstration of an endoluminal clot. PMID- 10094348 TI - Vasa vasorum: another cause of the carotid string sign. AB - BACKGROUND AND PURPOSE: Our purpose was to describe a variant of the carotid string sign that may be associated with a completely occluded vessel and to consider possible pathophysiological mechanisms for this observation. METHODS: Carotid angiography was performed in three patients with suspected carotid stenosis and in a fourth with carotid dissection. Surgery was performed in one of the patients with carotid stenosis. RESULTS: On all angiograms, instead of a single linear or curvilinear contrast "string," either single or multiple serpiginous channels were seen. In one case, such a channel was seen emanating from below the origin of an occluded internal carotid stump, reconstituting the distal portion of the vessel. Surgery revealed a completely occluded lumen with a small intramural vessel bypassing the obstruction. CONCLUSION: We propose that these channels are either atherosclerotically induced neovessels connecting bridging vasa vasorum or recanalized luminal thrombus. We review the literature associated with this subject. PMID- 10094349 TI - Use of three-dimensional MR angiography for tracking a contrast bolus in the carotid artery. AB - Contrast-bolus tracking in the carotid bifurcation was accomplished using an MR angiographic technique with a 3D turbo field-echo readout (TR/TE = 6/3, flip angle = 50 degrees) modified by a keyhole scheme. Optimal visibility of the contrast bolus was achieved by digital subtraction from a reference volume. This technique reliably time-resolves the carotid arteries from the jugular veins. PMID- 10094350 TI - A new sonographic technique for assessing carotid artery disease: extended-field of-view imaging. AB - We describe a new sonographic technique, extended-field-of-view imaging, and its clinical application for carotid artery disease. The technique identifies identical structures on two successive images for position registration to make a panoramic image in real time without position sensors. In 39 of 41 subjects, this technique provided high-quality panoramic images that could not be obtained with conventional real-time sonography, and made findings in the carotid artery more interpretable. PMID- 10094351 TI - A persistent pharyngohyostapedial artery: embryologic implications. AB - A 3-year-old child was examined because of otorrhagia. CT scans showed an unusual vessel, confirmed by angiography, related to a persistent pharyngohyostapedial artery. This embryonic persistent artery associated with the normal internal carotid artery would explain the "duplication" aspect of the internal carotid artery. PMID- 10094352 TI - Spontaneous CSF otorrhea caused by abnormal development of the facial nerve canal. AB - In two patients with surgically proved CSF fistula through the facial nerve canal, MR and CT examinations showed smooth enlargement of the geniculate fossa with CSF signal. In the clinical setting of CSF otorrhea or rhinorrhea, the presence of an enlarged labyrinthine facial nerve canal and enlarged geniculate fossa on CT scans and CSF intensity on MR images strongly suggests a CSF fistula through the facial nerve canal. PMID- 10094353 TI - Ramsay Hunt syndrome associated with brain stem enhancement. AB - Postcontrast T1-weighted MR images in a patient with Ramsay Hunt syndrome showed an enhancing lesion in the region of the nucleus of the pontine facial nerve and abnormal enhancement of the intrameatal, labyrinthine, and tympanic facial nerve segments and of the geniculate ganglion, as well as enhancement of the vestibulocochlear nerve and parts of the membranous labyrinth. This enhancement most probably resulted from a primary neuritis of the intrameatal nerve trunks of the seventh and eighth cranial nerves. PMID- 10094354 TI - CT and MR findings of Michel anomaly: inner ear aplasia. AB - In 1863, Michel described a condition characterized by a total absence of differentiated inner ear structures associated with other skull base anomalies, including an abnormal course of the facial nerve and jugular veins. Michel aplasia clearly differs from Michel dysplasia, in which arrest of embryologic development occurs later. Recently, the role of otic capsule formation on mesenchymal differentiation was reported as well as the impact of the genetic deletion of the homeobox gene on the development of the ear, cranial nerves, and hindbrain. We report two patients with a total absence of inner ear structures bilaterally, illustrating the characteristic appearance of Michel aplasia and associated skull base anomalies. PMID- 10094355 TI - Orbital dirofilariasis: MR findings. AB - Dirofilariasis is a helminthic zoonosis occurring in many parts of the world. We report the findings in a 61-year-old woman who had painless right exophthalmos caused by orbital dirofilariasis. A vivid worm was embedded inside an inflammatory nodule in the right orbit. On T1-weighted MR images, the parasite was visible as a discrete, low-intensity, tubular signal in the center of the nodule surrounded by contrast-enhancing inflammatory tissue. PMID- 10094356 TI - Mucocele involving the anterior clinoid process: MR and CT findings. AB - We report two patients with surgically proved mucoceles involving the anterior clinoid process. One patient had a mucocele of an Onodi cell and the other had a mucocele isolated to the anterior clinoid process. The MR signal was increased on both T1- and T2-weighted images in the first patient but was isointense on both sequences in the second patient, a finding that resulted in misdiagnosis. The developmental and anatomic features, as well as the diagnostic pitfalls, are discussed. PMID- 10094357 TI - In vitro models of intracranial arteriovenous fistulas for the evaluation of new endovascular treatment materials. AB - BACKGROUND AND PURPOSE: The purpose of this study was to create and test an in vitro model of intracranial arteriovenous fistulas (AVFs) that simulates the geometry of human vasculature and allows realistic testing of devices used in endovascular therapy. METHODS: The models were derived from corrosion casts of the main cervicocranial arteries and veins obtained from two nonfixed human specimens. Wax copies of the casts were produced and combined to create complex models simulating various types of intracranial AVFs. Wax assemblies were embedded with liquid silicone solidified into transparent blocks containing, after wax evacuation, hollow reproductions of the original vascular trees. The models were connected to a pulsatile pump and their compatibility with various imaging techniques and endovascular treatment materials was evaluated. RESULTS: The models were compatible with digital subtraction angiography, CT, MR imaging, and transcranial Doppler sonography. They provided a realistic endovascular environment for the simulation of interventional neuroradiologic procedures. CONCLUSION: Anatomically accurate and reproducible in vitro models of intracranial AVFs provide a valuable method for evaluating new endovascular treatment materials and for teaching purposes. PMID- 10094358 TI - Risk of clot formation in femoral arterial sheaths maintained overnight for neuroangiographic procedures. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the presence of blood clots in femoral arterial sheaths maintained after cerebral angiography and the effect of heparinized saline on clot formation. METHODS: Twenty-three sheaths were evaluated in 18 patients. Sheaths were maintained for 14 to 80 hours (average, 33 hours; median, 24 hours). After the sheaths were removed, they were vigorously flushed with 60 mL of normal saline and the number and size of clots found in each sheath were recorded. Additionally, patients' age, catheter size, presence of heparin, amount of time the sheath was kept in the artery, and patients' coagulation status were recorded. RESULTS: Clots were found in 17 (74%) of the 23 sheaths. Ten catheters had continuous heparin drip, of which seven (70%) sustained clots. Of the 13 sheaths without heparin, 10 sustained clots (77%). The difference was not statistically significant. The average number of clots was 2.2, and the maximal length of clots ranged from 0.5 to 105 mm. No thromboembolic complications associated with sheath placement were encountered in our patient population. CONCLUSION: Blood clots are present in the vast majority of intraarterial sheaths maintained after cerebral angiography. These clots constitute a risk of thromboembolic complications in the event of repeat angiography. Sheath exchange should be considered before obtaining repeat cerebral angiograms. PMID- 10094359 TI - Radiation dose to patients and personnel during intraoperative digital subtraction angiography. AB - BACKGROUND AND PURPOSE: The use of intraoperative angiography to assess the results of neurovascular surgery is increasing. The purpose of this study was to measure the radiation dose to patients and personnel during intraoperative angiography and to determine the effect of experience. METHODS: Fifty consecutive intraoperative angiographic studies were performed during aneurysmal clipping or arteriovenous malformation resection from June 1993 to December 1993 and another 50 from December 1994 to June 1995. Data collected prospectively included fluoroscopy time, digital angiography time, number of views, and amount of time the radiologist spent in the room. Student's t-test was used to assess statistical significance. Effective doses were calculated from radiation exposure measurements using adult thoracic and head phantoms. RESULTS: The overall median examination required 5.2 minutes of fluoroscopy, 55 minutes of operating room use, 40 seconds of digital angiographic series time, and four views and runs. The mean room time and the number of views and runs increased in the second group of patients. A trend toward reduced fluoroscopy time was noted. Calculated effective doses for median values were as follows: patient, 76.7 millirems (mrems); radiologist, 0.028 mrems; radiology technologist, 0.044 mrems; and anesthesiologist, 0.016 mrems. CONCLUSION: Intraoperative angiography is performed with a reasonable radiation dose to the patient and personnel. The number of angiographic views and the radiologist's time in the room increase with experience. PMID- 10094361 TI - Endovascular treatment of ruptured, peripheral cerebral aneurysms: parent artery occlusion with short Guglielmi detachable coils. AB - We report two cases of distal cerebral aneurysms that were treated by parent artery occlusion with short Guglielmi detachable coils (GDCs). One patient had a presumed mycotic aneurysm of the distal left posterior cerebral artery, and the other had a partially clipped aneurysm of the distal right anterior inferior cerebellar artery that had hemorrhaged. Short GDCs allow controlled, accurate occlusion of the parent artery at the aneurysmal neck. PMID- 10094360 TI - Venous subarachnoid hemorrhage after inferior petrosal sinus sampling for adrenocorticotropic hormone. AB - Neurologic complications associated with inferior petrosal sinus sampling for adrenocorticotropic hormone in the diagnosis of Cushing syndrome are rare. Previously reported complications include brain stem infarction and pontine hemorrhage. We report a case of venous subarachnoid hemorrhage with subsequent acute obstructive hydrocephalus occurring during inferior petrosal sinus sampling for Cushing syndrome. PMID- 10094362 TI - Normal development of the pituitary gland: assessment with three-dimensional MR volumetry. AB - BACKGROUND AND PURPOSE: Currently available data on pituitary volume have been based on indirect methods of measurement and are mostly limited to adult populations. The purpose of this study was to determine the normal development of pituitary volume by means of direct measurements made on thin-section 3D MR acquisitions. METHODS: The volume of the normal pituitary gland in children and adolescents was measured by using 3D MR sequences with a section thickness of 0.6 to 0.75 mm. The clinical study group consisted of 199 pediatric patients with clinically normal pituitary function and no abnormal findings on routine MR studies. The volume of the posterior pituitary was also measured in all the subjects. RESULTS: A phantom study revealed measurement errors within 25%. In the clinical study, the measured pituitary volumes showed a growth spurt during puberty, which was more prominent in girls. Posterior pituitary volumes showed gradual growth without such a spurt. Among 5- to 9-year-olds, the posterior pituitary volumes were significantly larger for boys than for girls. CONCLUSION: Normal development of the pituitary gland and posterior pituitary was determined by means of 3D MR volumetry. With this technique, we found a gender difference in the volume of the posterior pituitary. PMID- 10094363 TI - Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method. AB - BACKGROUND AND PURPOSE: Our purpose was to determine the characteristic MR features of early-onset (before age 2 years) versus late-onset (after age 2 years) globoid cell leukodystrophy (GLD). METHODS: Thirty-four brain MR images in 22 patients with GLD were reviewed. A severity score (0 to 32), based on a point system derived from the location and extent of disease and the presence of focal and/or global atrophy, was calculated for each examination. RESULTS: Of the 22 patients, three were asymptomatic and 19 were symptomatic. Ten patients had early onset disease, whereas nine had late-onset disease. MR images of all patients showed abnormalities. In the early-onset group (n = 10; mean maximum MR score, 8.1; range, 3-18), 90% had pyramidal tract involvement, 80% had cerebellar white matter involvement, 70% had deep gray matter involvement, 60% had posterior corpus callosal involvement, 50% had parietooccipital white matter involvement, and 40% had cerebral atrophy. Serial MR imaging in four of these patients revealed progressive disease. In the late-onset group (n = 9; mean maximum MR score, 5.6; range, 4-10), 100% had pyramidal tract involvement, 100% had parietooccipital white matter involvement, 89% had posterior corpus callosal involvement, and none had cerebellar white matter involvement, deep gray matter involvement, or cerebral atrophy. Serial MR imaging in one patient with late onset GLD did not reveal any change. A spectrum of findings was observed in the three patients who were asymptomatic. CONCLUSION: Cerebellar white matter and deep gray matter involvement are present only in early-onset GLD. Pyramidal tract involvement is a characteristic finding in both early- and late-onset GLD. This scoring method for brain MR observations will assist in the objective assessment of the impact of hematopoietic stem cell transplantation in patients with GLD. PMID- 10094364 TI - MR imaging findings in children with merosin-deficient congenital muscular dystrophy. AB - BACKGROUND AND PURPOSE: Our purpose was to determine the brain MR imaging characteristics of merosin-deficient congenital muscular dystrophy in children. METHODS: We reviewed the MR imaging findings of the brain in three children with known merosin-deficient congenital muscular dystrophy to determine the presence of any cerebral or cerebellar abnormalities of development or abnormalities of the white matter. RESULTS: In all three patients, there was normal formation of the cerebrum, the cerebellum, and no evidence of neuronal migration anomalies. All three patients had abnormal white matter in the cerebrum, with sparing of the corpus callosum, internal capsule, cerebellum, and brain stem. CONCLUSION: MR imaging of the brain in children with merosin-deficient congenital muscular dystrophy reveals a consistent pattern of white matter abnormality. We postulate that disruption of the blood-brain barrier associated with merosin deficiency leads to increased water content, resulting in abnormal white matter signal intensity. PMID- 10094365 TI - Helical CT angiography: dynamic cerebrovascular imaging in children. AB - BACKGROUND AND PURPOSE: The purpose of this study was to assess the feasibility of helical CT cerebrovascular imaging (CTCVI) in children and to make initial comparisons with MR angiography and digital subtraction angiography (DSA). METHODS: Twenty-six patients, ages 3 days to 17 years, were examined with CTCVI. Patients were scanned with 1-mm collimation and 2:1 pitch 30 seconds after the initiation of a hand injection of 2 mL/kg nonionic contrast material (320 mg/dL iodine) with a maximum dose that did not exceed 80 mL (minimum volume, 5 mL in a 2.5-kg infant). Reconstructions were done using maximum intensity projection and integral rendering algorithms. Four patients had CTCVI, MR angiography, and DSA (42 vessels studied) and nine patients had CTCVI and DSA (136 vessels studied). Scores of 1 (not present) to 3 (present in continuity to the first bifurcation) were assigned independently by two radiologists to 32 vessels in each correlated case for each available technique. RESULTS: There were no technical failures. CTCVI depicted 18 thrombosed dural sinuses, three vascular malformations, one intracranial aneurysm, and four tumors. Ninety-five percent of the vessels seen with DSA were also seen with CTCVI. CTCVI identified all vessels seen on MR angiography. CONCLUSION: Helical CTCVI is an effective technique for assessing the intracranial circulation in children. In this initial comparison, CTCVI showed more vascular detail than MR angiography, and had fewer technical limitations. PMID- 10094366 TI - The relationship between cerebral infarction and angiographic characteristics in childhood moyamoya disease. AB - BACKGROUND AND PURPOSE: In childhood-onset moyamoya disease, the angiographic disease process of stenoocclusive lesions is progressive, and cerebral infarctions often develop as a result of ischemia. Our purpose was to determine how the severity of stenoocclusive lesions in the anterior and posterior circulations affects the distribution of cerebral infarction in patients with childhood-onset moyamoya disease. METHODS: In 69 patients with childhood-onset moyamoya disease, angiograms were reviewed for stenoocclusive lesions, and CT scans, MR images, or both were reviewed for the sites and extent of cerebral infarction. The relationship between the angiographic and CT/MR findings was examined. RESULTS: The prevalence and degree of stenoocclusive lesions of the posterior cerebral artery (PCA) significantly correlated with the extent of lesions around the terminal portion of the internal carotid artery (ICA). The prevalence of infarction significantly correlated with the degree of stenoocclusive changes of both the ICA and PCA. Infarctions tended to be distributed in the anterior borderzone in less-advanced cases, while in more advanced cases lesions were additionally found posteriorly in the territory of the middle cerebral artery, the posterior borderzone, and the PCA territory. CONCLUSION: Our results indicate that progressive changes of the anterior and posterior circulations are associated with the distribution of cerebral infarction, culminating in a patchily disseminated or honeycomb pattern of infarction on CT and MR studies in late stages of the disease. PMID- 10094367 TI - Subcutaneous sacrococcygeal myxopapillary ependymoma. AB - We report a case of myxopapillary ependymoma presenting as a primary tumor of the subcutaneous tissue in the sacrococcygeal region. The mass was large, well encapsulated, lobulated, and multiseptated, with varying signal intensity on T1- and T2-weighted MR images caused by hemorrhagic necrosis, blood degradation products, and calcification. Only a small viable portion enhanced after administration of contrast material. Multiple lobules formed from fibrous septa and dystrophic calcification also characterize this tumor. PMID- 10094368 TI - Dural arteriovenous fistula of the cervical spine presenting with subarachnoid hemorrhage. AB - We describe a case of dural arteriovenous fistula (DAVF) presenting with subarachnoid hemorrhage (SAH). The diagnosis of DAVF was based on spinal angiography. A review of the literature revealed that five of 13 previously reported DAVFs of the cervical spine were accompanied by SAH. SAH has not been observed in DAVFs involving other segments of the spinal canal. PMID- 10094369 TI - Exposure of medical personnel to methylmethacrylate vapor during percutaneous vertebroplasty. AB - The occupational exposure to methylmethacrylate (MMA) vapor during percutaneous vertebroplasty was determined. During five vertebroplasty procedures, air sampling pumps were attached to medical personnel. MMA vapor levels in the samples were then quantified using gas chromatography. The samples collected yielded MMA vapor levels of less than five parts per million (ppm). The MMA vapor concentrations measured were well below the recommended maximum exposure of 100 ppm over the course of an 8-hour workday. PMID- 10094370 TI - MR of the spine in the presence of metallic bullet fragments: is the benefit worth the risk? PMID- 10094371 TI - Charles George Drake, neurosurgeon. PMID- 10094372 TI - Structure, function and clinical significance of transferrin receptors. AB - Iron plays an essential role in a spectrum of metabolic processes. Cellular iron uptake is facilitated by transferrin receptor (TfR)-mediated endocytosis. In recent years more insight has been obtained in TfR physiology and the regulation of cellular iron homeostasis. The synthesis of TfR and the iron storage protein ferritin is regulated reciprocally at the post-transcriptional level according to the cellular iron status. As a result of externalization of TfR during the endocytic cycle, a soluble form of TfR can be detected in serum. The serum TfR (sTfR) level is closely related to erythroid TfR turnover and the prime determinants of the sTfR concentration are cellular iron demands and erythroid proliferation rate. In the absence of a hyperplastic erythropoiesis the sTfR level is a sensitive parameter of early tissue iron deficiency. The entire spectrum of body iron status can be assessed by measurement of serum ferritin and sTfR levels, with ferritin as marker of tissue iron stores and sTfR as index of tissue iron needs. The sTfR may be a promising tool to detect iron deficiency in inflammatory states and in the anaemia of chronic disease as its concentration is, in contrast to ferritin levels, not influenced by the acute phase response. Determination of sTfR levels may also improve assessment of body iron stores during pregnancy and in neonates. Finally, the sTfR may be a useful parameter to monitor erythropoiesis in various clinical settings, for instance in the prediction of the haematological response to erythropoietin treatment. However, standardization of the sTfR assay, with definition of reference and pathological ranges, is necessary for the definitive introduction of the sTfR as major parameter of iron metabolism. PMID- 10094373 TI - Cardiac troponin I and troponin T: recent players in the field of myocardial markers. AB - The troponin (Tn) complex consists of three subunits referred to as TnT, TnI and TnC. Myocardium contains TnT and TnI isoforms which are not present in skeletal muscles and which can be separated from the muscular isoforms by immunological techniques. Using commercially available immunoassays, clinical laboratories are able to determine cardiac TnT and TnI (cTnT and cTnI) quickly and reliably as classical cardiac markers. After acute myocardial infarction, cTnT and cTnI concentrations start to increase in serum in a rather similar way than CK-MB, but return to normal after longer periods of time (approximately one week). Because of their excellent cardiac specificity, Tn subunits appear ideally suited for the differential diagnosis of myocardial and muscular damage, for example in noncardiac surgery patients, in patients with muscular trauma or with chronic muscular diseases, or after intense physical exercise. cTnT and cTnI may also be used for detecting evidence of minor myocardial damage: therefore they have found new clinical applications, in particular risk stratification in patients with unstable angina. In spite of the possible reexpression of cTnT in human skeletal muscles, and of the lack of standardization of cTnI assays, Tn subunits are not far to meet the criteria of ideal markers for acute myocardial injury. Only an insufficient sensitivity in the first hours following the acute coronary syndroms requiries to maintain an early myocardial marker in the cardiac panel for routine laboratory testing. PMID- 10094374 TI - Determination of free apolipoprotein(a) in serum by immunoassay and its significance for risk assessment in patients with coronary artery disease. AB - This paper describes a new enzyme-linked ligand sorbent assay (ELLSA) to quantify free apolipoprotein(a) (apo(a)). The new test immobilizes free apo(a) utilizing a specific peptide that carries the amino acid sequence of a non-covalent apo(a) binding site on apoB3375-3405 (ligand-peptide). The ligand-peptide coupled to Sepharose was used in affinity chromatography to separate free apo(a) from whole serum. Isolated free apo(a) consisted of full length apo(a) and smaller apo(a). Additionally, free apo(a) levels determined by ELLSA as well as by electroimmunodiffusion correlated moderately well. Significantly increased serum concentrations of free apo(a) were found in coronary artery disease. The mean value of free apo(a) was three times higher in patients than in controls while the lipoprotein(a) (Lpla)) concentration was doubled. Utilizing receiver operating characteristic diagrams, it was shown that the free apo(a)-ELLSA had a better diagnostic test performance in atherosclerotic risk assessment than the Lp(a)-test: specificity free apo(a)-ELLSA 0.77, Lp(a)-test 0.81 [with (a:a) enzyme immunoassay (EIA)] to 0.83 [with (a:B)-EIA]; sensitivity free apo(a)-ELLSA 0.57, Lp(a)-test 0.36 to 0.40. In conclusion, the new free apo(a)-ELLSA allows for the specific quantification of free apo(a). This provides an interesting indicator for atherosclerotic risk assessment. PMID- 10094375 TI - Fecal tumor necrosis factor alpha, eosinophil cationic protein and IgE levels in infants with cow's milk allergy and gastrointestinal manifestations. AB - Infants with atopic eczema exhibit a specific fecal protein pattern after oral challenge with cow's milk, characterized by an increase in both eosinophil cationic protein (ECP) and tumor necrosis factor (TNF)alpha. The aim of our study was to determine the pattern of these proteins in allergic infants with intestinal manifestations. TNFalpha, ECP and immunoglobulin E (IgE) were measured in stools from 13 infants with intestinal symptoms and 10 healthy infants. The allergic infants underwent two stool collections, one before a cow's milk challenge and the other after the challenge, either at the onset of clinical manifestations (n=6) or 15 days after the challenge if no clinical manifestations occurred (n=7). Baseline TNFalpha, ECP and IgE levels were low in all infants. The concentration of TNFalpha increased after the challenge in infants positive to challenge (p<0.05) but not in those negative to challenge. ECP and IgE levels remained low after the challenge in all the allergic infants. These data confirm that fecal TNFalpha and ECP levels indicate various reaction types of food allergy and that different immunologic disturbances lead to atopic eczema or intestinal symptoms during food allergy. Fecal protein pattern can thus be a useful tool in diagnosing food allergy in infants with intestinal manifestations. PMID- 10094376 TI - Detection of GB virus C/hepatitis G virus RNA by reverse-transcription polymerase chain reaction. AB - Recently, a novel RNA virus, designated GB virus C or hepatitis G virus (GBV C/HGV) has been identified which may possibly be associated with human hepatitis. In this study, the nucleotide sequences of the partial nonstructural 5 (NS5) gene of GBV-C/HGV derived from sera of eight Chinese patients were determined. The overall degree of nucleotide conservation and the existence of regional highly conserved sequences make this part of the genome suitable for the development of diagnostic reagents. On the basis of sequence analysis, two sets of oligonucleotide primers were designed to establish a nested polymerase chain reaction (PCR) for detection of GBV-C/HGV RNA. The efficacy of three PCR methods (first, one stage PCR, second, nested PCR with primers from the NS5 region designed according to the prototype sequence and the third, our newly developed PCR) was compared in 133 Chinese patients with liver disease. The positive rates of these three methods were 8.3%, 11.3% and 18.0% respectively. The specificity of our PCR detecting system was verified by sequencing and restriction fragment length polymorphism (RFLP). In conclusion, because of the heterogeneity and geographic distribution character of GBV-C/HGV, it is necessary to assess the sequence variation among Chinese patients infected with GBV-C/HGV. This may allow to identify GBV-C/HGV RNA with high sensitivity and specificity. PMID- 10094377 TI - Development of capillary electrophoresis as an alternative to high resolution agarose electrophoresis for the diagnosis of multiple sclerosis. AB - The presence of oligoclonal bands in cerebrospinal fluid (CSF) is used as a diagnostic indicator of multiple sclerosis (MS). These bands, gamma-globulins thought to result from a restricted antibody response directed against autoantigens or viral antigens, are consistent with CSF-specific immunoglobulin synthesis when observed in the spinal fluid and not in the serum. Current methodology commonly involves electrophoresing concentrated CSF with high resolution agarose gel electrophoresis (HRAGE) followed by protein staining in order to visualize the oligoclonal bands. Capillary zone electrophoresis (CZE) was evaluated as an alternative method. Separation of CSF and serum proteins from 54 patients in a bare silica capillary containing a high pH borate buffer allowed for resolution of the five major zones including the gamma-region and showed a 90% concordance with the results from HRAGE banding studies. Since a simple borate buffer did not provide adequate resolution of the oligoclonal bands in the gamma-region, the separation buffer was augmented with polyethylene glycol (PEG) which provided a significant enhancement in resolution of proteins in this region (24 patient study). In addition to obtaining banding information from electropherograms obtained with these separation conditions, it was feasible to calculate a CSF Index which compared favorably with the results from nephelometry. Finally, we show that zwitterionic additives such as O phosphorylethanolamine may further enhance resolution and that capallary electrophoresis (CE) may allow oligoclonal banding information to be obtained directly from CSF without concentration. PMID- 10094378 TI - Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathological parameters. AB - Ninety-eight patients with histologically confirmed ovarian tumors (77 primary ovarian carcinomas of stages T1 to T3 according to the postoperative histopathological classification pTNM classification, 14 ovarian metastases of various origins and seven benign ovarian tumors) were investigated with regard to the concentration of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in membrane extracts of tumors. The results were correlated with the clinical course and with histopathological findings. With more advanced stage of primary ovarian carcinomas, there was a highly significant rise in the membrane concentrations of both uPA and PAI-1. However, increasing dedifferentiation of the tumors correlated only with uPA, but not with PAI-1. There was no correlation between the number of steroid receptors for estradiol and progesterone and the content of uPA or PAI-1 in the primary ovarian carcinomas. In the 14 ovarian metastases of different origins incluced in the study, the contents of uPA and PAI-1 were comparable to those of primary ovarian carcinomas. Compared with the malignant ovarian tumors, the median uPA and PAI-1 concentrations in the membrane fraction were 2.5-6 fold lower (highly significant) in the group of seven benign tumors. A cut-off value of 4.8ng/mg pellet protein for a prognostically favorable (< 4.8) or unfavorable course (> 4.8) could be determined for uPA (p = 0.0392) but not for PAI-1 on the basis of the Kaplan and Meier survival curves in the malignant primary ovarian carcinomas. PMID- 10094379 TI - Intracellular and extracellular, ionized and total magnesium in pre-eclampsia and uncomplicated pregnancy. AB - Magnesium (Mg) and calcium (CA) concentrations in women with pre-eclampsia, women with an uncomplicated pregnancy and non-pregnant women were compared. Ionized serum magnesium and calcium concentrations and intracellular magnesium concentrations were measured in 15 pregnant women with severe pre-eclampsia, 34 uncomplicated pregnant women early, at midterm and preterm in their pregnancy and 24 non-pregnant women. The ionized calcium concentration did not chance during normal pregnancy or during pre-eclampsia relative to non-pregnant women. In contrast, elevated total and ionized magnesium serum concentrations were found in women with severe pre-eclampsia (total Mg = 0.85+/-0.11 mM, ionized Mg = 0.61+/ 0.06 mM) relative to uncomplicated pregnant women (total Mg = 0.72+/-0.06 mM, ionized Mg = 0.53+/-0.03 mM). Total magnesium in pre-eclamptic women were similar to non-pregnant women. Intracellular ionized and total magnesium concentrations in mononuclear blood cells and erythrocytes were similar in pre-eclamptic women and women with uncomplicated pregnancy. Serum magnesium concentrations are elevated in severe pre-eclamptic women relative to women with uncomplicated pregnancy and are related to birth weight and gestational age at delivery. There may be a causal relationship since magnesium is involved in blood pressure regulation through an intracellular inhibition of NO synthase in endothelial cells. PMID- 10094380 TI - Phospholipases A2 in gastric juice of Helicobacter pylori--positive and negative individuals. AB - Gastric juice is known to have phospholipase A2 catalytic activity. Helicobacter pylori (H. pylori) has been reported to produce phospholipase A2, which is believed to hydrolyse the protective layer of gastric mucosal phospholipids and to promote mucosal damage. The current study aimed at identifying secretory phospholipase A2 subtypes (pancreatic group I phospholipase A2 and synovial-type group II phospholipase A2) in gastric juice and their relation to the presence of H. pylori in gastric mucosal biopsies in the same individuals. Gastric juice was collected from 29 individuals during gastroscopy. Biopsies were taken from the antrum and body of the stomach to determine the H. pylori status. We found catalytically active phospholipase A2 and both group I and group II phospholipases A2 in the gastric juice samples. The catalytic activity and the mass concentrations of group I and group II phospholipases A2 correlated significantly with the pH value in gastric juice. The gastric juice of H. pylori positive individuals did not contain higher amounts of phospholipases A2 than the juice of H. pylori negative individuals. Rather, the mass concentration of group II phospholipase A2 in gastric juice seemed to be somewhat lower in individuals with H. pylori infection than in uninfected individuals. The results of the current study show that both group I and group II phospholipases A2 are present in gastric juice. The main sources of phospholipases A2 in gastric juice are probably other than H. pylori. PMID- 10094381 TI - Appropriateness of physicians' requests of laboratory examinations in primary health care: an over- and under-ulilisation study. AB - The aim of this work is to study the appropriateness of the laboratory measurement for quantities that may be conditioned by the result of another quantity, estimating the proportions of inappropriate requests due to over- or under-utilisation. We refer to over-utilisation when a quantity was requested and measured when it was not needed, and we refer to under-utilisation when a quantity was not requested and not measured when it was needed. In our centre, the laboratory staff together with the primary health care physicians of the region designed a new laboratory request form. This request form incorporated an agreed requesting protocol for the most common diagnoses in primary health care. Protocols included, according to each case, one or several of 11 pairs of quantities depending on each case. Second quantity in each pair was measured or not, conditional on the result of the first quantity of the pair, the age, the sex and the diagnosis corresponding to the requested protocol. Following recommendations from scientific societies, we decided what should be the results of the first quantity in the pair so to measure the second quantity in the pair. When recommendations were not available, we reviewed the data contained in the laboratory information system, and we established as non-conditioning values, the levels of the first quantities that were associated with the results of second quantities within their reference intervals in 99.95% of cases. The study was done retrospectively using 46091 old laboratory request forms received in our laboratory over two years. Among the 46091 request forms, the first quantities included in the present forms that incorporate agreed requesting protocols were requested 66434 times. The 66434 corresponding second quantities were measured and should not have been measured in 14225 cases (21.4%) and were not measured and should have been measured in 16137 cases (24.3%). Using the request forms according to the conditioning protocols changes the number of quantities by a mean of 0.66 in every request form. This change would have increased the number of quantities measured by 0.04 quantities per form, but would also have improved the appropriate use of the laboratory. PMID- 10094382 TI - Effect of the hemoglobin-based oxygen carrier HBOC-201 on laboratory instrumentation: cobas integra, chiron blood gas analyzer 840, Sysmex SE-9000 and BCT. AB - As part of a clinical trial, we evaluated the effects of the hemoglobin-based oxygen-carrier (HBOC) HBOC-201 (an ultrapurified, stroma-free bovine hemoglobin product, Biopure, Cambridge, MA, USA) on our routine clinical chemistry analyzer (Cobas Integra, F. Hoffmann-La Roche Ltd, Basel, Switzerland ), blood gas analyzer (Chiron 840, Chiron Diagnostics Corporation, East Walpole, MA, USA), routine hemocytometry analyzer (Sysmex SE-9000, TOA Medical Electronics Co Ltd., Kobe, Japan), hemostasis analyzer (BCT, Dade-Behring, Marburg, Germany) and bloodbanking system (Dia-Med-ID Micro Typing System, DiaMed AG, Cressier, Switzerland). The maximum tested concentration of HBOC-201 was 65 g/l. Of the 27 routine clinical chemistry tests challenged with HBOC-201, bilirubin-direct, creatine kinase MB-fraction (CK-MB), creatine kinase (CK), gamma glutamyltransferase (GGT), magnesium and uric acid were influenced by even low concentrations of HBOC-201. These tests were excluded from use on the plasma of patients treated with HBOC-201. Since the non-availability of the cardiac marker CK-MB may lead to problems in acute situations, we introduced the qualitative Trop T-test (Boehringer Mannheim), which was not influenced. The applicability of another nine tests was limited by the concentration of the HBOC-201 in the patients' plasma. No interference of HBOC-201 in routine hemocytometry, hemostasis-analysis and red-blood cell agglutination detection (blood-bank tests) was observed. Although immediate patient-care was not compromised, routine use of hemoglobin-based oxygen carriers will have a strong impact on logistical management. The development of robust laboratory tests free from the interference of the pigmented oxygen carriers should therefore precede its introduction into routine transfusion medicine. PMID- 10094383 TI - Current system of undergraduate and postgraduate education in clinical chemistry in Croatia. AB - We present here a specific model of education and practice in clinical chemistry that is almost exclusively based on the medical biochemists academically educated at the Faculty of Pharmacy and Biochemistry. This model has been successfully used for 35 years in Croatian Health Care System. Undergraduate education in clinical chemistry consists of four years of specific university education which provides for all requirements to maintain the high quality of our profession. Postgraduate education leading to more specific scientific and professional expertise is further regulated by the laws issued by The Ministry of Health and The Ministry of Science and Technology. At present there is a compulsory programme of lifelong continuing education recognised by Croatian Chamber of Medical Biochemists. PMID- 10094384 TI - The effects of fasting on blood antioxidant potential and malondialdehyde levels. PMID- 10094385 TI - Biological variation in lipoprotein(a) PMID- 10094386 TI - CK2, a protein kinase of the next millennium. AB - Protein kinase CK2 is a ubiquitous eukaryotic protein kinase composed of two catalytic subunits, alpha and/or alpha', and two regulatory subunits, beta. In order to define similarities and dissimilarities between the alpha and alpha' catalytic subunits, which might account for their particular cellular functions, different forms of the enzyme were expressed in Sf9 cells and their properties determined. Both catalytic subunits were expressed separately, and also along with the regulatory beta subunit, in order to obtain free alpha and alpha', as well as alpha2beta2 and alpha'2beta2 forms. Our results confirm that the beta subunit acts to stabilize the alpha and alpha' subunits and also influences the substrate specificity and kinetic properties of the enzyme. Although significant differences between the specificities of holoenzymes alpha2beta2 and alpha'2beta2 as determined using a number of substrates were not detected, autophosphorylation studies on alpha2beta2 and alpha'2beta2 revealed significant differences in this property. The regulatory subunit beta was phosphorylated less rapidly by the alpha' subunit than by the alpha subunit, and the extent of phosphorylation of beta by alpha was also greater than that of beta by alpha'. It was also noted that the thermo-stability and the extent of its activation by NaCl were greater for alpha2beta2 than for alpha'2beta2. These different properties may relate to distinct functions of the two form of CK2. PMID- 10094387 TI - A multifunctional network of basic residues confers unique properties to protein kinase CK2. AB - Protein kinase CK2 is characterized by a number of features, including substrate specificity, inhibition by polyanionic compounds and intrasteric down-regulation by its beta-subunit, which denote a special aptitude to interact with negatively charged ligands. This situation may reflect the presence in CK2 catalytic subunits of several basic residues that are not conserved in the majority of other protein kinases. Some of these residues, notably K49 in the 'Gly rich loop', K74, K75, K76, K77, K79, R80, K83 in the 'Lys rich segment' and R191, R195, K198 in the 'p+1 loop', have been shown by mutational studies to be implicated to various extents and with distinct roles in substrate recognition, inhibition by heparin and by pseudosubstrate and instrasteric regulation. Molecular modelization based on crystallographic data provide a rationale for the biochemical observations, showing that several of these basic residues are clustered around the active site where they make contact with individual acidic residues of the peptide substrate. They can also mediate the effect of polyanionic inhibitors (e.g. heparin) and of regulatory elements present in the beta-subunit, in the N terminal segment of the catalytic subunit and possibly in other proteins interacting with CK2. Our data also disclose a unique mode of binding of the phosphoacceptor substrate which bridges across the catalytic cleft making contacts with both the lower and upper lobes of CK2. PMID- 10094388 TI - Intermolecular contact sites in protein kinase CK2. AB - Chemical crosslinking and analysis of CNBr-digested fusion products by immunoblotting with sequence-specific antibodies identifies an interaction between positions 55-70 of subunit beta (beta55-70) and 65-80 of subunit alpha (alpha65-80). This has been supported by crosslinking of subunits with peptides alpha65-80 and beta55-70, by binding of subunits to immobilized peptides, and by the hindrance of coprecipitation with peptide-raised antibodies (anti-alpha65-80; anti-beta55-70). Functionally, beta55-70 is a negative regulatory region for the kinase activity of subunit alpha. The opposite, stimulatory property of subunit beta has been assigned to its C-terminal part. Subdivision of peptide beta155 181, that has stimulatory effect, into overlapping peptides and assaying for alpha binding and binding competition revealed a tight physical contact at beta162-175. This region, however, is non-stimulatory indicating binding a necessary but not sufficient quality for stimulation. A contact might exist to regions surrounding C147 and/or C220 at subunit alpha as indicated by crosslinking and peptide competition. The crosslinking data also confirm a beta beta contact in CK2 holoenzyme. Effects by non-ionic detergents show hydrophobic interactions to play an important role in catalytic activity adjustment. PMID- 10094389 TI - Binding of polylysine to protein kinase CK2, measured by Surface Plasmon Resonance. AB - The interaction between protein kinase CK2 and polylysine has been studied by Surface Plasmon Resonance (SPR). The binding process has a very low energy of activation, it is irreversible, and too slow as to explain the enzyme activity stimulation as a direct consequence of the polylysine binding. The polylysine interaction with a peptide substrate and with casein are faster, and in agreement with a substrate-mediated mechanism of activity stimulation. After several hours of incubation, the binding of polylysine to CK2 produces the loss of enzymatic activity. PMID- 10094390 TI - Functional analysis of CK2beta-derived synthetic fragments. AB - Synthetic peptides reproducing the amino and carboxyl terminal region of CK2beta subunit have been analyzed for their ability to mimic different properties of full length beta subunit. Peptide beta[1-77], containing both the autophosphorylation site and the down-regulatory domain 55-64, is readily phosphorylated by alpha subunit whose activity is concomitantly inhibited. Such inhibition is accompanied by a weak interaction detectable by BIAcore sensograms but not by far Western blots, and is not reversed by polylysine which conversely overcome inhibition of calmodulin phosphorylation by full length beta subunit. A strong interaction with alpha is observed with beta[155-215] but not with its shorter derivative beta[170-215] as judged from far Western blotting and sucrose gradient ultracentrifugation analysis. Both peptides, however, affect the regular interaction between alpha and beta subunits altering the autophosphorylation pattern and responsiveness to salt. beta[155-215], unlike beta[170-215] tends to aggregate more readily than full length beta subunit. This behaviour which is reminiscent of the homodimerization of full length beta subunit, would indicate that tight self-association of beta[155-215] crucially depends on residues in the 155-170 sequence. Failure of beta[1-77] fragment to mediate responsiveness to polybasic peptides and accentuated self-association propensity of beta[155-215] suggest that other structural elements between the sequences 1-77 and 155-215 are required in order to confer optimal functionality to the beta subunit. PMID- 10094391 TI - Dissecting subdomains involved in multiple functions of the CK2beta subunit. AB - We have characterized several subdomains of the beta subunit of protein kinase CK2. The N-terminal half of the protein exhibits a pseudo-substrate segment in tandem with a polyamine binding domain responsible for the activation of the kinase by these polybasic compounds. Study of the chemical features of this polyamine binding site showed that polyamine analogs exhibiting the highest affinity for CK2 are the best CK2 activators. Mutational analysis disclosed that glutamic residues lying in the polyacidic region of the CK2beta subunit are involved in the interaction with polyamine molecules and allowed the delineation of an autonomous binding domain. Furthermore, this regulatory domain was shown to mediate the association of CK2 with plasma membrane. The C-terminal domain of the CK2beta subunit plays a role in the oligomerization of the kinase since it was observed that a truncated form of this subunit lacking its 33-last amino acids was incompetent for the assembly of polymeric forms of CK2. Altogether, our results support the notion that the beta subunit of CK2 is a modular protein made by the association of interdependent domains that are involved in its multiple functions. PMID- 10094392 TI - Interactions of protein kinase CK2beta subunit within the holoenzyme and with other proteins. AB - Protein kinase CK2 is a ubiquitous, highly conserved protein kinase with a tetrameric alpha2beta2 structure. For the formation of this tetrameric complex a beta-alpha dimer seems to be a prerequisite. Using the two-hybrid system and a series of CK2beta deletion mutants, we mapped domains involved in alpha-beta and beta-beta interactions. We also detected an intramolecular beta interaction within the amino acid stretch 132-165. Using CK2beta as a bait in a two-hybrid library screening several new putative cellular partners have been identified, among them the S6 kinase p90rsk, the putative tumor suppressor protein Doc-1, the Fas-associated protein FAF1, the mitochondrial translational initiation factor 2 and propionyl CoA carboxylase beta subunit. PMID- 10094393 TI - CK2alpha loci in the human genome: structure and transcriptional activity. AB - Two CK2alpha loci are present in the human genome. First, locus 20p13, that contains the CK2alpha coding gene. It spans around 70 kb, is composed of 13 exons and shows homology to the respective gene in the nematode Caenorhabditis elegans. The translation start site is located in the second exon, the stop codon in exon 13. Two transcription start sites were identified, the further 5' located site defines position 1 of the gene, the second site is located at position 50, respectively. The promoter region shows characteristics of a so-called house keeping gene: A high GC content, lack of a TATA-box and presence of several GC boxes. By reporter gene assays, the promoter region of the CK2alpha gene could be located between position -256 and 144 relative to the first transcription start site. In the 3' noncoding region of the CK2alpha gene, six polyadenylation signals were identified. As indicated by Northern blot analysis and by comparison with expressed sequence tags from the EMBL databank, the most 3' located, active polyadenylation signal seems to be the fourth defining the end of the CK2alpha gene. The second CK2alpha locus is at 11p15. It contains a processed pseudogene, which shows all typical features of a processed sequence, such as absence of introns, short poly-A tail and direct flanking repeats. Interestingly, it contains a complete open reading frame and has potential promoter elements in its 5' region. Nevertheless, no promoter activity could be detected in reporter gene assays. PMID- 10094394 TI - Murine protein kinase CK2: gene and oncogene. AB - Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with a wide range of substrates, many of which are involved in cell cycle regulation. CK2 activity is elevated in a variety of human tumors and we have used a transgenic mouse model to demonstrate that dysregulated expression of CK2 can induce lymphoma. Thus, CK2 fulfills the definition of an oncogene: A mutated, dysregulated, or mis-expressed gene that contributes to cancer in a dominant fashion. CK2 cooperates in transforming cells with other lymphoid oncogenes such as myc and tal-1, and here we show cooperativity with loss of the tumor suppressor gene p53. To understand more about the physiological and pathological role of CK2, we are cloning the murine CK2alpha' cDNA and gene. CK2alpha' will be used to generate transgenic and knockout mice and the regulatory elements for gene expression will be analyzed. PMID- 10094395 TI - Interactions of protein kinase CK2 subunits. AB - Several approaches have been used to study the interactions of the subunits of protein kinase CK2. The inactive mutant of CK2alpha that has Asp 156 mutated to Ala (CK2alphaA156) is able to bind the CK2beta subunit and to compete effectively in this binding with wild-type subunits alpha and alpha'. The interaction between CK2alphaA156 and CK2beta was also demonstrated by transfection of epitope-tagged cDNA constructs into COS-7 cells. Immunoprecipitation of epitope-tagged CK2alphaA156 coprecipitated the beta subunit and vice-versa. The assay of the CK2 activity of the extracts obtained from cells transiently transfected with these different subunits yielded some surprising results: The CK2 specific phosphorylating activity of these cells transfected with the inactive CK2alphaA156 was considerably higher than the control cells transfected with vectors alone. Assays of the immunoprecipitated CK2alphaA156 expressed in these cells, however, demonstrated that the mutant was indeed inactive. It can be concluded that transfection of the inactive CK2alphaA156 affects the endogenous activity of CK2. Transfection experiments with CK2alpha and beta subunits and CK2alphaA156 were also used to confirm the interaction of CK2 with the general CDK inhibitor p21WAF1/CIP1 co-transfected into these cells. Finally a search in the SwissProt databank for proteins with properties similar to those derived from the amino acid composition of CK2beta indicated that CK2beta is related to protein phosphatase 2A and to other phosphatases as well as to a subunit of some ion-transport ATPases. PMID- 10094396 TI - Mutations in the C-terminal domain of topoisomerase II affect meiotic function and interaction with the casein kinase 2 beta subunit. AB - Topoisomerase II is a major target of the protein kinase casein kinase 2 (PK CK2) in vivo. All major phosphorylation acceptor sites in the yeast enzyme are found in the C-terminal 350aa. The acceptor sites are generally clustered such that there is more than one modified Ser or Thr within a short peptide. Mutagenesis of the predicted acceptor sites have confirmed that five of the eight predicted sites are targeted in vitro and in vivo by PK CK2. Mutation to nonphosphorylatable, neutral residues provokes at most a 10% increase in mitotic doubling time. Truncation of the enzyme leaves the enzyme catalytically active, but slightly lengthens the doubling time during mitotic growth and impedes progress through meiosis. Since this could reflect the loss of interaction with an important ligand, we have examined whether the C-terminal domain of the yeast enzyme mediates interaction with the regulatory beta subunit of PK CK2, which was previously reported to bind topoisomerase II. We find that point mutation of the phospho-acceptor sites does not abrogate the interaction with a small region of PK CK2beta, while truncation at aa1276 or aa1236 does. The site of interaction within PK CK2beta does not coincide with the highly negatively charged spermine binding site. PMID- 10094397 TI - Association of protein kinase CK2 with eukaryotic translation initiation factor eIF-2 and with grp94/endoplasmin. AB - Protein kinase CK2 forms complexes with some protein substrates what may be relevant for the physiological control of this protein kinase. In previous studies in rat liver cytosol we had detected that the trimeric form of eukaryotic translation initiation factor 2 (eIF-2) co-eluted with protein kinase CK2. We have now observed that the ratio between eIF-2 and cytosolic CK2 contents in testis, liver and brain is quite similar, being eIF-2 levels about 5-fold higher than those of CK2. Furthermore eIF-2 was present in liver samples immunoprecipitated with anti-CK2alpha/alpha' antibodies, confirming the existence of complexes containing both proteins. Nonetheless, these complexes would represent only a fraction of total cytosolic CK2 and eIF-2. We had also observed that rat liver membrane glycoproteins obtained through chromatography on wheat germ lectin-Sepharose contain CK2 activity which copurifies with grp94/endoplasmin. We have now confirmed that this activity was due to the presence of protein kinase CK2 as evidenced by immunodetection with antibodies against CK2alpha/alpha'. The fractions enriched in grp94/endoplasmin and CK2 also contained another 55-kDa polypeptide (p55) phosphorylated by CK2 which has been identified as calreticulin by N-terminal sequencing. Calreticulin and grp94/endoplasmin could be partially resolved from CK2 by chromatography on heparin-agarose and almost completely on ConA-Sepharose. However, phosphorylation of immunoprecipitated grp94/endoplasmin was enhanced by its preincubation with purified CK2 prior to immunoprecipitation, what confirms the easy reassociation between these proteins. The association of protein kinase CK2 with eIF-2 and with grp94/endoplasmin may serve to locate the enzyme in the cellular machinery involved in protein synthesis and folding, and reinforces the possible involvement of CK2 in these processes. PMID- 10094398 TI - Searching interaction partners of protein kinase CK2beta subunit by two-hybrid screening. AB - To date, the intracellular regulation of protein kinase CK2 is unknown. However it was observed that the enzyme associates with several intracellular proteins and the formation of such molecular complexes may represent a mechanism for the control of CK2 activity. Using the Interaction Trap system in yeast, with the CK2beta as a bait, we looked for CK2 partners. We present the identification of new potential partners of CK2beta and it is hoped that their classification will help in understanding the physiological roles and the regulation of CK2 in the cell. PMID- 10094400 TI - BTF3 is a potential new substrate of protein kinase CK2. AB - BTF3, initially discovered as a factor required for transcription inititation of RNA polymerase II, is expressed in two isoforms, termed a and b. BTF3b, the transcriptionally inactive isoform, was identified as an interaction partner of protein kinase CK2 subunit beta employing the interaction trap system for screening ofa HeLa cDNA fusion library. We report here on the interaction between the other isoform, BTF3a, and protein kinase CK2. The complete cDNA of BTF3a was cloned by RT-PCR and used for analysis in the two-hybrid system with a three reporter yeast strain. Interaction of BTF3a with CK2 subunits alpha, alpha' or beta was detectable by one of three reporters, whereas the CK2beta - BTF3a interaction was activating two reporters. It was also shown that BTF3a is phosphorylated in vitro by the alpha2beta2 holoenzyme, but not by alpha or alpha' alone, indicating the requirement of beta for substrate recognition. Immunoprecipitations of GST-fused BTF3a carried out in vitro resulted in co precipitation of beta. Similarly, GST-BTF3a, but not GST alone isolated with glutathione agarose beads from buffer containing recombinant CK2 subunits was found complexed with alpha and beta, likely representing alpha2beta2 holoenzyme. The data show a weak, nevertheless specific interaction of protein kinase CK2 via subunit beta with the putative transcription factor BTF3a in vitro and in vivo, and a role of BTF3a as a potential new substrate for CK2. PMID- 10094399 TI - Protein kinase CK2 interacts with a multi-protein binding domain of p53. AB - p53 is one of the most powerful negative regulators of growth. To manage this in an efficient way it has to interact with a set of different cellular proteins. Most contacts with the cellular environment occur in the N- or the C-terminal domain of the protein. Since we previously found that p53 binds to the regulatory beta-subunit of CK2 we now analyzed N- and C-terminal domains of p53 separately for the binding of protein kinase CK2, an enzyme which seems to have a certain importance for proliferation processes. With different overlay assays we could map the binding domain of protein kinase CK2 to a sequence between amino acids 325-344, a region which coincides with the interaction domain of some other p53 binding proteins. We also found that the regulatory beta-subunit of protein kinase CK2 binds independent of the catalytic alpha-subunit to this C-terminal domain of p53. PMID- 10094401 TI - Protein kinase CK2alpha may induce gene expression but unlikely acts directly as a DNA-binding transcription-activating factor. AB - The gene-inducing property ofCK2alpha, a Ser/Thr protein kinase that appears normally to be complexed to a CK2beta protein controlling activity and substrate selectivity, has been unclear. We show here that CK2alpha induces in human JEG-3 cells the expression of Aromatase, an estrogen-synthesis key enzyme, which is regulated at transcriptional level. Electrophoretic mobility shift assays indicate that CK2alpha binds to the Aromatase gene promoter. To test for CK2alpha's transactivating ability as a DNA-binding protein, a CK2alpha binding site was cloned in front of indicator genes. The constructs were used to transform a yeast-based one-hybrid system. Overexpression of activation-domain fused CK2alpha in this system, i.e., CK2alpha in its native configuration, failed to activate the transcription machinery. The data indicate CK2alpha to affect gene expression at the level of transcription via an indirect as yet unknown mechanism rather than directly as a DNA-binding transcription-activating protein. PMID- 10094402 TI - Role of protein kinase CK2 in phosphorylation nucleosomal proteins in relation to transcriptional activity. AB - Protein kinase CK2 undergoes rapid translocation to nuclear matrix and nucleosomes on androgenic stimulation of growth in prostatic epithelial cells. Further, CK2 appears to be regulated differentially in the transcriptionally active and inactive nucleosomes. We have investigated the role of CK2 in phosphorylation of nucleosome-associated proteins in the transcriptionally active and inactive nucleosomes that were isolated from ventral prostate subjected to different androgenic status in vivo. Proteins associated with these nucleosomes were phosphorylated via the intrinsic protein kinase activity, using [gamma 32P]ATP in the absence and presence of GTP. Several proteins appear to be potential substrates for CK2 associated with the nucleosomes. Among them are proteins that are differentially associated with the transcriptionally active and inactive nucleosomes. Phosphorylation of several of these proteins is modulated depending not only on their sites of association (i.e., active vs. inactive nucleosomes) but also on the state of transcriptional activity. Differential phosphorylation of specific proteins by CK2 associated with the active and inactive nucleosomes may be pertinent to the process of transcription regulation. PMID- 10094403 TI - A review of progress towards elucidating the role of protein kinase CK2 in polymerase III transcription: regulation of the TATA binding protein. AB - We have investigated the molecular basis of the requirement for protein kinase CK2 in nuclear transcription in Saccharomyces cerevisiae. In vivo and in vitro analysis has demonstrated that CK2 is required for efficient transcription of the tRNA and 55 rRNA genes by RNA polymerase III. This suggests that a component of the pol III transcription machinery is regulated by CK2. We tested this possibility by a biochemical complementation approach in which components of the pol III transcription machinery from wild type cells were tested for their ability to rescue transcription in extract from a conditionally CK2-deficient mutant. We found that pol III transcription initiation factor IIIB (TFIIIB) fully restores transcription in CK2-deficient extract. Further in vitro studies revealed that TFIIIB must be phosphorylated to be active, that a single subunit of wild type TFIIIB, the TATA binding protein (TBP), is efficiently phosphorylated by CK2, and that recombinant TBP and a limiting amount of CK2 rescues transcription in CK2-deficient extract. We conclude that TBP is the physiological target of CK2 among the components of the pol III transcription machinery. The implications of this result are discussed in the context of previous data concerning the regulation of TFIIIB. PMID- 10094404 TI - The binding of the alpha subunit of protein kinase CK2 and RAP74 subunit of TFIIF to protein-coding genes in living cells is DRB sensitive. AB - In a previous report, we documented that a major portion of the nuclear protein kinase CK2alpha (CK2alpha) subunit does not form heterooligomeric structures with the beta subunit, but it binds tightly to nuclear structures in an epithelial Chironomus cell line. We report here that the CK2alpha, but not beta, subunit is co-localized with productively transcribing RNA polymerase II (pol II) on polytene chromosomes of Chironomus salivary gland cells. Likewise, the RAP74 subunit ofTFIIF, a potential substrate for CK2, is co-localized with pol II. The occupancies of chromosomes with the CK2alpha and RAP74 subunits are sensitive to DRB, an inhibitor of pol II-based transcription and the activity of CK2 and pol II carboxyl-terminal kinases. DRB alters the chromosomal distribution of the CK2alpha and RAP74 subunits: there is a time-dependent clearance from the chromosomes of CK2alpha and RAP74 subunits, which coincides in time the completion and release of preinitiated transcripts after addition of DRB. The results suggest that both the CK2alpha and RAP74 subunits travel with the elongating pol II molecules along the DNA template during the entire transcription cycle. No detectable re-association of CK2alpha and RAP74 with the promoters takes, however, place after the completion of the preinitiated transcripts in the presence of DRB. In contrast, the binding of hypophosporylated pol II and TFIIH to the active gene loci is not abolished by the DRB regimen. Our data are consistent with the possibility that in living Chironomus salivary gland cells, DRB interferes with the recruitment of TFIIF, but not of TFIIH, to the promoter by interference with the activity of the CK2alpha subunit enzyme and phosphorylation of RAP74 and thereby DRB blocks transcription initiation. PMID- 10094405 TI - Transcriptional regulation of the S. cerevisiae ENA1 gene by casein kinase II. AB - The regulatory subunit of S. cerevisiae casein kinase II (CKII) is encoded of two genes, CKB1 and CKB2. Strains harboring deletions of either or both genes exhibit specific sensitivity to high concentrations of Na+ or Li+. Na+ tolerance in S. cerevisiae is mediated primarily by transcriptional induction of ENA1, which encodes the plasma membrane sodium pump, and by conversion of the potassium uptake system to a higher affinity form that discriminates more efficiently against Na+. To determine whether reduced ENA1 expression plays a role in the salt sensitivity of ckb mutants, we integrated an ENA1-lacZ reporter gene into isogenic wild-type, ckb1, ckb2, and ckb1 ckb2 strains and monitored beta galactosidase activity at different salt concentrations. In all three mutants transcription from the ENA1 promoter remained salt-inducible, but both basal and salt-induced expression was depressed approximately 3- to 4-fold. The degree of reduction in ENA1 expression was comparable to that observed in an isogenic strain carrying a null mutation in protein phosphatase 2B (calcineurin), which is also required for salt tolerance. These results suggest that reduced expression ofENA1 contributes to the salt sensitivity of ckb strains. Consistent with this conclusion, overexpression of ENA1 from a heterologous promoter (GAL1) completely suppressed the salt sensitivity of ckb mutants. Induction of ENA1 expression by alkaline pH is also depressed in ckb mutants, but unlike calcineurin mutants, ckb strains are not growth inhibited by alkaline pH. PMID- 10094406 TI - A role for casein kinase II phosphorylation in the regulation of IRF-1 transcriptional activity. AB - The Interferon Regulatory Factors (IRFS) play an important role in the transcriptional control of growth regulatory and immunoregulatory genes. The inducibility and availability of IRF-1 and IRF-2 are influenced by external stimuli, such as virus infection or interferon treatment. In the present study, we sought to examine the potential modulatory role of phosphorylation on IRF-1 transcriptional activity. During the purification of IRF recombinant proteins, a kinase activity copurified with IRF-1 (and IRF-2) from baculovirus infected Sf9 insect cell extracts, but not from E. coli extracts. The kinase activity was also identified in Jurkat T cells, specifically interacted with IRF proteins in GST affinity chromatography, and phosphorylated IRF-1 with high specificity in vitro. Using an in gel kinase assay with recombinant IRF-1 as substrate, two molecular weight forms of the kinase (43 and 38 kDa) were identified. Biochemical criteria identified the kinase activity as the alpha catalytic subunit of casein kinase II (CKII). Furthermore, far western analysis of protein-protein interactions demonstrated that casein kinase II directly interacted with IRF-1 protein. Deletion mutation analysis of IRF-1 revealed that IRF-1 was phosphorylated at two clustered sites, one located between amino acids 138-150, the other in the C terminal acidic activation domain between amino acids 219-231. Cotransfection studies comparing wild type and point mutated forms of IRF-1 demonstrated that mutations of the four phosphoaceptor residues in the C-terminal transactivation domain, significantly decreased transactivation by IRF-1, indicating that casein kinase II may be involved in the regulation of IRF-1 function. Strikingly, the casein kinase II clusters in IRF-1 resemble the sites identified in the C terminal PEST domain of IkappaBalpha. The present experiments, together with previously published studies with IkappaBalpha, c-Jun and other proteins, indicate a broad role for casein kinase II phosphorylation in the regulation of transcription factor activity. PMID- 10094407 TI - A structural model for elongation factor 1 (EF-1) and phosphorylation by protein kinase CKII. AB - EF-1alpha binds aminoacyl-tRNA to the ribosome with the hydrolysis of GTP; the betagammadelta complex facilitates the exchange of GDP for GTP to initiate another round of elongation. To examine the subunit structure of EF-1 and phosphorylation by protein kinase CKII, recombinant beta, gamma, and delta subunits from rabbit were expressed in E. coli and the subunits were reconstituted into partial and complete complexes and analyzed by gel filtration. To determine the availability of the beta and delta subunits for phosphorylation by CKII, the subunits and the reconstituted complexes were examined as substrates for CKII. Formation of the nucleotide exchange complex increased the rate of phosphorylation of the beta subunit and reduced the Km, while addition of alpha to beta or the betagammacomplex inhibited phosphorylation by CKII. However, alpha had little effect on phosphorylation of delta. Thus, the beta and delta subunits in EF-1 were differentially phosphorylated by CKII, in that phosphorylation of beta was altered by association with other subunits, while the site on delta was always available for phosphorylation by CKII. From the availability of the subunits for phosphorylation by CKII and the composition of the reconstituted partial and complete complexes, a model for the subunit structure of EF-1 consisting of(alpha2betagamma2delta)2 is proposed and discussed. PMID- 10094408 TI - Protein kinase CK2-dependent regulation of p53 function: evidence that the phosphorylation status of the serine 386 (CK2) site of p53 is constitutive and stable. AB - The p53 tumour suppressor protein is regulated by several mechanisms including multisite phosphorylation. One of the protein kinases which has an established role in regulating p53 function is the protein kinase CK2. The regulation by CK2 occurs both through interaction of p53 with CK2 itself (the regulatory beta subunit) and phosphorylation at the penultimate residue of p53, serine 386 (murine p53). Strikingly, this phosphorylation event controls several independent functions of p53 including site-specific DNA binding, strand renaturation, transcriptional repression and the anti-proliferative function of p53. However, CK2 is a constitutively-active enzyme and therefore the mechanism by which the phosphorylation of p53 at serine 386 is itself regulated, or indeed the question as to whether phosphorylation of this site is regulated at all, remains unresolved. In this paper we provide evidence that serine 386 is highly resistant to dephosphorylation in cultured cells, even though this site can be dephosphorylated in vitro by recombinant protein phosphatase 1. These data suggest that, once phosphorylated at the CK2 site, a p53 molecule remains in this modified form throughout its lifespan. To address the issue of whether the level of serine 386 phosphorylation may be regulated through controlling the subcellular compartmentalisation of p53 and CK2, we examined the subcellular localisation of p53 and CK2alpha in C57MG cells and Rat-1 fibroblasts by immunofluorescence staining. Both proteins were present in the cytoplasm and enriched in the nucleus, with minor variations in the intensity of subcellular location over the course of the cell cycle. Similarly, activation of p53 by UV irradiation or DNA damage-inducing drugs had no effect on either the localisation or levels of CK2alpha, even although significant nuclear p53 accumulation was observed. A striking observation arising from these studies was the intense staining of CK2alpha with the centrosomes, suggesting a potentially important role for this kinase in microtubule formation and/or chromosomal segregation. PMID- 10094409 TI - Distribution of CK2, its substrate MAP1B and phosphatases in neuronal cells. AB - Neuronal morphogenesis depends on the organization of cytoskeletal elements among which microtubules play a very important role. The organization of microtubules is controlled by the presence of microtubule-associated proteins (MAPs), the activity of which is modulated by phosphorylation and dephosphorylation. One of these MAPs is MAP1B, which is very abundant within growing axons of developing neurons where it is found phosphorylated by several protein kinases including CK2. The expression of MAP1B is notably decreased after neuronal maturation in parallel with a change in the localization of the protein, which becomes largely concentrated in neuronal cell bodies and dendrites. Interestingly, MAP1B remains highly phosphorylated at sites targeted by protein kinase CK2 in mature neurons. We have analyzed the expression and localization of CK2 catalytic subunits along neuronal development. CK2alpha subunit appears early during development whereas CK2alpha' subunit appears within mature neurons at the time of dendrite maturation and synaptogenesis, in parallel with the change in the localization of MAP1B. CK2alpha subunit is found associated with microtubule preparations obtained from either grey matter or white matter from adult bovine brain, whereas CK2alpha' subunit is highly enriched in microtubules obtained from grey matter. These results lend support to the hypothesis that CK2alpha' subunit is concentrated in neuronal cell bodies and dendrites, where it associates with microtubules, thus contributing to the increased phosphorylation of MAP1B in this localization in mature neurons. PMID- 10094410 TI - CK2alpha-protein phosphatase 2A molecular complex: possible interaction with the MAP kinase pathway. AB - Despite its wide range of known substrates, the signaling function of protein kinase CK2 is still enigmatic. Mounting evidence suggests that CK2alpha, the catalytic subunit of holoenzymic CK2, may exist free of its usual regulatory partner CK2beta, raising the possibility that 'free' CK2alpha has regulation and function distinct from those of the holoenzyme. We previously reported that CK2alpha could bind to the core dimer of protein phosphatase 2A, and indirectly cause down-regulation of the PP2A substrate MEK1, possibly via activation of PP2A and/or targeting of PP2A to some element of the Ras/Raf/MEK pathway. Here, these results are confirmed and extended. By using transfection experiments and immune kinase assays, we show that endogenous PP2Ac and CK2beta are the only major substrates associating with epitope-tagged CK2alpha, and that expression of activated Raf results in disruption of the CK2alpha-PP2A association. Such disruption might be a necessary step for maximal activation of the MAP kinase pathway by Raf. In keeping with this idea, overexpression ofCK2alpha dose dependently inhibits the mitogen-induced activation of cotransfected, epitope tagged MAP kinase. We suggest that the CK2beta free form of CK2alpha is both a target and a regulator of Raf/MAPK signaling. PMID- 10094411 TI - Expression and regulation of protein kinase CK2 during the cell cycle. AB - There are indications from genetic, biochemical and cell biological studies that protein kinase CK2 (formerly casein kinase II) has a variety of functions at different stages in the cell cycle. To further characterize CK2 and its potential roles during cell cycle progression, one of the objectives of this study was to systematically examine the expression of all three subunits of CK2 at different stages in the cell cycle. To achieve this objective, we examined levels of CK2alpha, CK2alpha' and CK2beta on immunoblots as well as CK2 activity in samples prepared from: (i) elutriated populations of MANCA (Burkitt lymphoma) cells, (ii) serum-stimulated GL30-92/R (primary human fibroblasts) cells and (iii) drug arrested chicken bursal lymphoma BK3A cells. On immunoblots, we observed a significant and co-ordinate increase in the expression of CK2alpha and CK2alpha' following serum stimulation of quiescent human fibroblasts. By comparison, no major fluctuations in CK2 activity were detected during any other stages during the cell cycle. Furthermore, we did not observe any dramatic differences between the relative levels of CK2alpha to CK2alpha' during different stages in the cell cycle. However, we observed a significant increase in the amount of CK2beta relative to CK2alpha in cells arrested with nocodazole. We also examined the activity of CK2 in extracts or in immunoprecipitates prepared from drug-arrested cells. Of particular interest is the observation that the activity of CK2 is not changed in nocodazole-arrested cells. Since CK2 is maximally phosphorylated in these cells, this result suggests that the phosphorylation of CK2 by p34cdc2 does not affect the catalytic activity of CK2. However, the activity of CK2 was increased by incubation with p34cdc2 in vitro. Since this activation was independent of ATP we speculate that p34cdc2 may have an associated factor that stimulates CK2 activity. Collectively, the observations that relative levels of CK2beta increase in mitotic cells, that CK2alpha and CK2beta are phosphorylated in mitotic cells and that p34cdc2 affects CK2 activity in vitro suggest that CK2 does have regulatory functions associated with cell division. PMID- 10094412 TI - Identification of proteins that associate with protein kinase CK2. AB - In order to aid in an understanding of the cellular functions of protein kinase CK2, a search for interacting proteins was carried out using a 32P-labeled CK2 overlay method. Several proteins were found to associate with CK2 by this assay; among them, one protein of 110 kDa appeared to be the most prominent one. The possible association of CK2 with p110 was suggested by experiments involving the co-immunoprecipitation using anti-CK2 antibodies. Further analysis using GST-CK2 fusion proteins demonstrated that the CK2-p110 interaction occurred through the CK2alpha/alpha' subunits. To identify p110, it was purified using a GST-CK2 affinity column, and internal amino acid sequencing was then performed. p110 was found to be nucleolin, a nucleolar protein that may be important for rRNA synthesis; a possible role of CK2 in the control of this process is suggested. Using the same CK2 overlay technique, another interacting protein, insulin receptor substrate 1 (IRS-1), was also identified. By applying a modified overlay method using individual 35S-labeled CK2 subunits, obtained by in vitro translation in rabbit reticulate lysates, it was determined that CK2 associates with IRS-1 through its alpha/alpha' subunits; i.e. in keeping with the fact that IRS-1 is a known substrate for CK2. However, further work is needed to examine the association of CK2 with IRS-1 in vivo in order to fully understand the significance of the interaction. PMID- 10094413 TI - Multiple forms of protein kinase CK2 present in leukemic cells: in vitro study of its origin by proteolysis. AB - Human recombinant CK2 subunits were incubated for different times with the two main cytosolic proteases m-calpain and 20 S proteasome. Both, m-calpain in a calcium dependent manner and the 20 S proteasome, were able to degrade CK2 subunits in vitro. In both cases, CK2alpha' was more resistant to these proteases than CK2alpha. When these proteases were assayed on the reconstituted (alpha2beta2 holoenzyme), a 37 kDa alpha-band, analogous to that observed in AML extracts, was generated which was resistant to further degradation. No degradation was observed when the 26 S proteasome was assayed on free subunits. Studies with CK2alpha deletion mutants showed that m-calpain and the 20 S proteasome acted on the C-terminus end of CK2alpha. These results pointed to cytosolic proteases as agents involved in the control of the amount of free CK2 subunits within the cell, which becomes evident when CK2 is overexpressed as in AML cells. PMID- 10094414 TI - Sertoli and Leydig cells of the human testis express neurofilament triplet proteins. AB - Using RT-PCR, western blot and enzyme and fluorescence immunocytochemical techniques, the three isoforms of neurofilament proteins (NFPs), namely NF-L (NFP 68 kDa), NF-M (NFP-160 kDa) and NF-H (NFP-200 kDa) were found in Sertoli and Leydig cells of human testes. RT-PCR showed specific for the three NFP fragments in testicular tissue, in isolated seminiferous tubules and in isolated Leydig cells. In protein preparations from the same testicular components, western blot analysis detected bands with molecular weights characteristic for NF-H, NF-M and NF-L. Application of immunofluorescence and immunoenzyme methods on cryostat and paraffin sections resulted in differences in the staining pattern in Sertoli cells and Leydig cells. In these cells, the NFPs showed predominantly a perinuclear location from which bundles emerge that were directed towards the basal, apical and lateral extensions of the Sertoli cells as well as the periphery of Leydig cells. NF-H coexists with vimentin-type filaments as seen by dual staining and staining of consecutive serial sections of material embedded in paraffin. In Sertoli cells, vimentin and NF-H showed distinct dynamic changes depending on the stage of spermatogenesis and some structural variations of seminiferous tubules. Although in some tubules both vimentin and NF-H immunoreactivity was present at high levels, in the Sertoli cells from most individuals an inverse relationship in the staining intensity of vimentin and NF H was observed. The strongest NF-H immunoreactivity was detected in Sertoli cells associated with stage 3 spermatids, whereas vimentin immunoreactivity was most abundant in association with stage 5 spermatids. The leydig cells did not show functional changes of the NFP immunoreactivity. The results obtained provide new evidence for the heterogeneous phenotype of human Sertoli cells and raise the question of their exact nature and origin. PMID- 10094415 TI - Cellular adaptation of the trapezius muscle in strength-trained athletes. AB - The aim of this study was to elucidate the cellular events that occur in the trapezius muscle following several years of strength training. In muscle biopsies from ten elite power lifters (PL) and six control subjects (C), several parameters were studied: cross-sectional area of muscle fibres, myosin heavy chain composition (MHC) and capillary supply [capillaries around fibres (CAF) and CAF/fibre area]. A method was also developed for counting the number of myonuclei and satellite cell nuclei. The proportion of fibres expressing MHC IIA, the cross sectional area of each fibre type and the number of myonuclei, satellite cells and fibres expressing markers for early myogenesis were significantly higher in PL than in C (P<0.05). A significant correlation between the myonuclear number and the cross-sectional area was observed. Since myonuclei in mature muscle fibres are not able to divide, we suggest that the incorporation of satellite cell nuclei into muscle fibres resulted in the maintenance of a constant nuclear to cytoplasmic ratio. The presence of small diameter fibres expressing markers for early myogenesis indicates the formation of new muscle fibres. PMID- 10094416 TI - Neurons with choline acetyltransferase immunoreactivity and mRNA are present in the human cerebral cortex. AB - We examined the cerebral cortex of five autopsied individuals without neurological and psychiatric diseases by immunohistochemistry using an anti-human recombinant choline acetyltransferase (ChAT) polyclonal antibody and in situ hybridization with 35S-labeled human ChAT riboprobes. The immunohistochemistry detected positive neurons which were medium-sized or large pyramidal neurons located predominantly in layers III and V. The density of such neurons was higher in the motor and secondary sensory areas than in other cortical areas; the immunoreactive neurons in layer V were more densely distributed in the motor area and those in layer III were distributed in the secondary sensory areas. Positively stained, non-pyramidal neurons were observed in the superficial layer of the cingulate gyrus and parahippocampus. No immunoreactive neurons were found in the primary sensory areas. The in situ hybridization detected some neurons with signals for ChAT mRNA in the cerebral cortex, most of which were distributed in layer V of the motor area and in layer III of the secondary visual area. These results indicate that the human cerebral cortex contains cholinergic neurons and displays regional and laminal variations in their distribution. PMID- 10094417 TI - A new radiographic procedure for obtaining correction factors of 3H-beta-self absorption for quantitative tritium autoradiography. AB - A 3H-radiographic method based on the absorption of 3H-beta-particles by an overlying tissue section was established for obtaining correction factors of 3H beta-absorption (c.f.s) on the cellular level for all kinds of sections in a simple and more precise way as possible with interferometry. Unlabelled paraffin or Araldite sections were mounted on a thin uniformly 3H-labelled section of resin, and autoradiographs were prepared. Grain densities of neuronal cell types and cell-free areas within and outside the paraffin or Araldite sections were evaluated in autoradiographs, where the exposure time or the thickness of the overlying histological section was varied. From these values c.f.s were calculated applying the Beer-Lambert law. It was shown that corresponding c.f.s determined with this new radiographic method correspond well with each other. However, they will only agree with those c.f.s obtained by interferometry, if relative c.f.s are compared. Since the c.f.s are quite sensitive to the section thickness, a new parameter phi was introduced, which helps to assess whether the microtome used works exactly. Generally, the method presented can be used on the cytological level as well as for whole areas in every other autoradiographic study. PMID- 10094418 TI - Immunohistochemical properties of nerve fibres supplying accessory male genital glands in the pig. A colocalisation study. AB - Immunohistochemical studies have been performed to investigate the occurrence and coexistence of two catecholamine-synthesising enzymes, tyrosine hydroxylase and dopamine-beta-hydroxylase, and several neuropeptides, including neuropeptide Y, vasoactive intestinal polypeptide, Leu5-enkephalin, somatostatin, calcitonin gene related peptide and substance P, in nerve fibres supplying porcine accessory genital glands, the seminal vesicles, prostate (body and the disseminated part) and bulbourethral glands. Three major populations of nerve fibres supplying non vascular elements of the glands have been distinguished (from the largest to the smallest one): (1) noradrenergic fibres, the majority of which contain Leu5 enkephalin, neuropeptide Y or, to a lesser extent, somatostatin, (2) non noradrenergic, putative cholinergic fibres containing vasoactive intestinal polypeptide, neuropeptide Y and/or somatostatin and, (3) nonnoradrenergic, presumably sensory fibres, containing calcitonin gene-related peptide and substance P. Whilst the coexistence patterns within nerves supplying particular glands are similar, the density of innervation varies between the organs. The innervation of the seminal vesicles and prostatic body is more developed than that of the disseminated part of the prostate and bulbourethral glands. The majority of noradrenergic fibres related to blood vessels contain neuropeptide Y only, while the non-noradrenergic nerves contain mainly vasoactive intestinal polypeptide. The possible function and origin of particular nerve fibre populations are discussed. PMID- 10094419 TI - Induction of Fos immunoreactivity by acute glucose deprivation in the rat caudal brainstem: relation to NADPH diaphorase localization. AB - Neuronal nitric oxide (NO) synthase, a NADPH diaphorase (NADPH-d) enzyme, catalyzes formation of the free radical neurotransmitter, NO, and is distributed within several caudal brainstem structures. The following studies investigated whether these neuron populations express immunoreactivity for the inducible nuclear transcription factor, Fos, in response to acute glucose deprivation. Eight days after bilateral ovariectomy and subcutaneous implantation of silastic capsules containing 30 microg estradiol benzoate/ml, adult female rats were injected i.p. with the glucose antimetabolite, 2-deoxy-D-glucose (2DG; 400 mg/kg), or the vehicle, saline, and killed by transcardial perfusion 2 h later. At 150-microm intervals through the midbrain, pons, and medulla 25-microm sections were taken and processed for dual cytoplasmic NADPH-d enzyme activity and nuclear Fos immunoreactivity (Fos-ir). Although NADPH-d-positive neurons were demonstrated in several neural structures, only those in the dorsal raphe nuclei, central subnucleus of the nucleus of the solitary tract, dorsal vagal motor nucleus, lateral paragigantocellular nucleus, nucleus ambiguus, reticular parvocellular nucleus, and medullary A5 noradrenergic cells were colabeled for nuclear Fos-ir following injection of 2DG. While NADPH-d neurons in the midbrain central gray and the latero- and posterodorsal tegmental, lateral parabrachial, motor trigeminal, and gigantocellular nuclei were not immunolabeled for Fos in the 2DG-treated animals, there was a close neuroanatomical proximity between neurons capable of generating NO and others expressing Fos-ir in these sites. These data reveal that only discrete populations of NADPH-d-containing neurons in the caudal brainstem are transcriptionally activated via the Fos stimulus transcription cascade in response to glucose substrate imbalance, and suggest that NO and/or other neurotransmitters released by these neurons may function as neurochemical mediators of glucoprivic regulatory effects within this part of the brain. PMID- 10094420 TI - Pituitary estrogen receptor alpha and dopamine subtype 2 receptor gene expression in transgenic mice with overproduction of heterologous growth hormones. AB - Pituitary somatotrophs are suppressed in mice transgenic for human (h) or bovine (b) growth hormone (GH) genes fused with metallothionein (MT) or phosphoenolpyruvate carboxykinase (PEPCK) promoters. Previous morphologic studies revealed that lactotrophs are inhibited in hGH transgenic lines probably due to prolactin-like effects of hGH whereas in female bGH transgenics, the lactotrophs are stimulated. In the present study, estrogen receptor (ERalpha) mRNA was studied by autoradiographic in situ hybridization (ISH), ERalpha protein by immunocytochemistry, and dopamine subtype 2 receptor (D2R) mRNA by ISH. In MT/ and PEPCK/hGH transgenic mice, silver grains signaling ERalpha mRNA were significantly decreased compared to controls; the reduction was stronger in males (8.6 and 37%) than in females (4.6 and 11%). The decrease in the number of ERalpha-immunoreactive nuclei followed the same pattern (13.3 and 6% in males vs 3.2 and 5.2% in females). In MT/hGH mice the D2R mRNA signal was significantly increased in males (6 and 15.4%) and females (16%). In MT/bGH transgenics, ERalpha mRNA and ERalpha-immunoreactive nuclei were significantly increased (25 and 6%) only in males; D2R mRNA was more decreased in females (23%) than in males (15%). In conclusion, the opposite changes in ERalpha and D2R gene expressions are correlated with lactotroph inhibition in hGH transgenic mice and their stimulation in bGH transgenic mice. The changes in ERalpha expression were stronger in males, whereas those of D2R were more pronounced in females. PMID- 10094421 TI - Bone mineral density of epileptic patients on long-term antiepileptic drug therapy: a quantitative digital radiography study. AB - In order to assess the bone atrophy lesions of epileptic patients, the bone mineral densities (BMDs) of their lumbar spines and femoral necks were measured using quantitative digital radiography (QDR). The study groups were 44 patients on long-term medication for epilepsy and 62 healthy control subjects. We selected patients who had been taking phenytoin, barbiturates, and/or acetazolamide for at least 5 years. BMDs at both sites were significantly lower in the patient group than in the control group. No sex differences were found in BMDs. There were no significant correlations with the onset or the duration of illness and BMD. We compared BMD according to the type of epileptic drug being taken and theorized that phenytoin, barbiturates, and acetazolamide reduced BMD. BMDs of the 15 patients were measured again 7 years later, and were found to be significantly lower at both sites than in the previous examination. These results confirm the presence of bone atrophy lesions in epileptic patients on long-term antiepileptic drugs. Patients on antiepileptic therapy for long periods should have their BMDs checked, because they are prone to developing bone atrophy. PMID- 10094422 TI - Dissociation of mossy fiber sprouting and electrically-induced seizure sensitivity: rapid kindling versus adaptation. AB - It has been shown that massed stimulation (MS) of the amygdala or hippocampus does not result in seizure progression but in the 'phenomenon of adaptation', whereas alternate day rapid kindling (ADRK) produces reliable kindling (Lothman, E.W., Williamson, J.M., 1994. Brain Res. 649, 71-84). The goal of the present experiment was to determine if the two different effects are due to differences in mossy fiber sprouting and/or different seizure and postictal spike propagation patterns. Nine rats underwent MS (66-70 stimulations separated by 5-min interstimulus interval), six were exposed to ADRK (12 stimulations/day, every 30 min, with 4 stimulus days, each separated by 1 stimulus-free day), five rats served as control. All rats had electrodes implanted bilaterally in dorsal and ventral hippocampi (VH) and 14 of them had additional electrodes in the piriform cortex. Animals were stimulated in the left VH at afterdischarge threshold. There was no potentiation in seizure response 4-7 weeks after MS. In contrast, ADRK produced not only kindling but also ongoing epileptogenesis resulting 4-7 weeks later in spontaneous seizures and development of a prolonged convulsive state in response to the initially subconvulsive stimulus. Epileptiform activity during MS was mostly restricted to VH, whereas during ADRK it spread widely among studied structures including piriform cortex. Afterdischarges during MS were elicited frequently but seizures did not progress beyond stage 2-3. During ADRK, afterdischarges were evoked less frequently but seizures reached stage 4-7 by the end of the 3rd and 4th stimulus days. The fully kindled state was not reached at this time, but epileptogenic changes continued to progress. Seven weeks after the initial stimulation, both groups demonstrated mossy fiber sprouting of similar intensity in VH. We suggest, (1) frequent but predominantly local hippocampal afterdischarges induce mossy fiber sprouting, but this is not sufficient to produce significant enhancement in seizure susceptibility, and (2) the involvement of extra-hippocampal structures, possibly piriform cortex, and formation of an aberrant hippocampal-para-hippocampal circuit is required to result in a condition of progressive epileptogenesis. PMID- 10094423 TI - Prediction of presence of hippocampal sclerosis from intracarotid amobarbital procedure memory asymmetry scores and epilepsy on set age. AB - Identification of the pathological status of the hippocampus prior to surgery is important since the absence of hippocampal sclerosis (HS) carries risks to memory function following anterior temporal lobectomy (ATL). We studied 62 patients undergoing ATL (31 L, 31 R) for intractable epilepsy of temporal lobe origin in whom no pathology was identified apart from HS. An intracarotid amobarbital procedure (IAP) was performed as part of the preoperative evaluation. All patients were left hemisphere dominant for language. IAP memory testing was according to the protocol of Loring. We examined IAP memory asymmetry scores at four levels of difference (<2, > or =2, > or =4, > or =6) as a function of the presence (HS+) or absence (HS-) of HS. A logistic regression analysis was performed with HS+ as the dependent variable, and age at onset of epilepsy, age at time of surgery, gender, side of surgery and significant IAP memory asymmetry as independent variables. At each level of memory asymmetry, onset age and memory asymmetry were the only predictors of HS+. Younger age at onset was associated with HS+. Curves were constructed showing probability of HS+ for age at onset for each level of asymmetry. These can be used to predict the likelihood of presence of HS based on age at onset of epilepsy and the IAP memory asymmetry score. It is concluded that IAP memory asymmetry scores reflect the functional and pathological status of the hippocampus, and greater asymmetry increases the probability of finding HS in the resected hippocampus. PMID- 10094424 TI - Lateralizing value of the Wada memory test in non-Western patients with temporal lobe epilepsy. AB - The Wada memory test measures a psychological construct (i.e. memory), which is widely acknowledged to be under the influence of a vast array of moderating variables including culture. Thus, the lateralizing value of the Wada memory test for epileptogenic foci may potentially differ for Western versus non-Western patients with temporal lobe epilepsy (TLE). In the present study, the lateralizing value of the Wada memory test was investigated in 17 Korean patients with medically intractable TLE who were post-operatively seizure-free. The Wada memory stimuli were composed of eight drawings of common objects, animals, and fruits. A clinical criterion of at least 2 points difference between left and right injections correctly classified 14 patients (82%) into left and right TLE groups, with only one patient (6%) falsely classified. This diagnostic accuracy is at least as high as that reported for Western TLE patients. These results indicate that whatever culture-specific factors Korean TLE patients may bring to the Wada memory test, they do not significantly reduce the lateralizing value of the test. PMID- 10094425 TI - The cognitive and behavioural effects of clobazam and standard monotherapy are comparable. Canadian Study Group for Childhood Epilepsy. AB - PURPOSE: To compare the cognitive and behavioural effects of clobazam versus standard monotherapy in the treatment of childhood epilepsy. METHODS: A randomized, double-blind, prospective design was carried out at three Canadian pediatric epilepsy centres. This study was part of a larger multi-centre study on the efficacy of clobazam. Children with newly diagnosed epilepsy were assigned randomly to receive clobazam or carbamazepine. Children who had failed previous treatment with carbamazepine were assigned randomly to clobazam or phenytoin. Children who had failed on any other antiepileptic drug were assigned randomly to receive clobazam or carbamazepine. In a subset of patients neuropsychological assessments were carried out at 6 weeks and 12 months after initiation of medication. Intelligence, memory, attention, psychomotor speed, and impulsivity were assessed. RESULTS: There were no differences between the clobazam and standard monotherapy groups on any of the neuropsychological measures obtained at 6 weeks or 12 months. There was no evidence for a deterioration in performance for those children who remained on clobazam for the entire 12-month study period. CONCLUSION: The cognitive and behavioural effects of clobazam appear to be similar to those of standard monotherapy. PMID- 10094427 TI - Anticonvulsant and neurotoxic effects of intracerebroventricular injection of phenytoin, phenobarbital and carbamazepine in an amygdala-kindling model of epilepsy in the rat. AB - OBJECTIVE: To determine the feasibility of the intracerebroventricular injection of phenytoin (PHT), phenobarbital (PB) and carbamazepine (CBZ) to control seizures in the amygdala kindling model in the rat, and also to determine the associated neurotoxic effects. METHODS: Different doses of PHT (500 and 1250 microl), PB (200, 500 and 1000 microl) and CBZ (200 and 500 microl) were injected intracerebroventricularly into amygdala kindled male Wistar rats. Seizures were induced with a fixed suprathreshold stimulus of 500 microA at times between 15 and 60 min after the injection. Seizure intensity (Racine's scale), latency, seizure duration and afterdischarge duration were measured. Neurotoxicity was tested using ataxia and sedation scales and also using a rotorod. RESULTS: PB was found to be the most powerful anticonvulsant, and both PB and CBZ caused significant reductions in seizure intensity to less than stage 3 with the doses tested. PHT only reduced seizures for the first 15-30 min after application. PB was also the most toxic drug, followed by CBZ and by PHT. Neurotoxicity was acceptable except in the cases of the highest doses during the earliest periods tested. There was no mortality due to the injection of any of the drugs at the doses employed. CONCLUSIONS: The intracerebroventricular route is a feasible way to administer anticonvulsant drugs for seizure control in the kindling model. PMID- 10094426 TI - Congenital malformations due to antiepileptic drugs. AB - To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age. PMID- 10094428 TI - The reduction in paired-pulse inhibition in the rat hippocampus by gabapentin is independent of GABA(B) receptor receptor activation. AB - Previously we have shown that gabapentin causes a reduction of paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which looks very much like the effect of baclofen on paired-pulse inhibition. In addition, it has been proposed that gabapentin increases release of GABA from non-vesicular stores and may, therefore, interact with GABA(B) mechanisms. Here we tested the ability of a GABA(B) agonist, baclofen, and a GABA(B) antagonist, CGP35348, to block the effect of gabapentin on paired-pulse inhibition in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. Both baclofen (6 mg/kg) and gabapentin (100 mg/kg) caused a long-lasting reduction of paired-pulse inhibition in the dentate gyrus when given alone or in combination. CGP35348 (45 mg/kg) blocked the effect of baclofen on paired-pulse inhibition, but did not alter the effect of gabapentin. Gabapentin also caused a reduction of inhibition in the CA1 region, indicating that its effect is not specific for the dentate gyrus. These results suggest that gabapentin produces its effect on paired-pulse inhibition independent from the effect of baclofen and not through non-vesicular release of GABA interacting with the GABA(B) receptor system. PMID- 10094429 TI - Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electrocorticography. AB - Focal cortical dysplasia (FCD) is often associated with severe partial epilepsy. In this study, we performed magnetoencephalography (MEG) and electrocorticogrsphy (ECoG) on four patients with FCD-associated epilepsy to confirm the 'intrinsic' epileptogenicity of FCD. In all patients, we determined the three-dimensional locations of the magnetic sources of the interictal paroxysmal activities by a single dipole model, and then the estimated dipole localization was superimposed on the magnetic resonance image. The dipole clusters were located in the T2 prolonged lesions, namely in the FCD lesions themselves. All patients underwent surgery for their medically intractable epilepsy, and the acute and/or chronic ECoG were thereafter recorded. Either frequent or continuous paroxysmal activities were recorded from the ECoG electrodes which were placed over the surface of the FCD lesion, while few paroxysmal activities were observed on the normal appearing adjacent cortex. Intraoperative depth recordings were performed in a patient with the needle electrode inserted into the FCD lesion and they revealed these paroxysmal foci to be located not on the cortical surface but at a depth of 15 mm from the cortical surface where both abnormal giant neurons and bizarre large eosinophilic cells (so-called balloon cells) were also prominently observed on the postoperative histological sections. Following a lesionectomy combined with the removal of the underlying white matter, three patients demonstrated a favorable seizure outcome. Our findings thus suggest the FCD lesions to be highly and intrinsically epileptogenic lesions. PMID- 10094430 TI - Developing an effective program to complete ictal SPECT in the epilepsy monitoring unit. AB - With the availability of more stable radiopharmaceuticals, the ictal single photon emission computed tomography (SPECT) perfusion study has emerged as a useful noninvasive functional neuroimaging tool in the presurgical evaluation of patients with medically intractable partial epilepsy. The purpose of this study was to determine whether the development of a program using trained electroencephalography (EEG) technologists to perform ictal injections in the epilepsy monitoring unit enabled a more efficient delivery of radiopharmaceuticals and therefore a higher specificity and sensitivity of outcome. All patients admitted to the epilepsy monitoring unit for prolonged video/EEG monitoring as part of the presurgical evaluation were eligible for completion of an ictal SPECT study using a three-way needle-free apparatus. Over a 19-month period, 85 (77%)) of 110 eligible patients were successfully injected during typical partial seizures. Various factors were analyzed including latency of ictal injection (27.3+/-20.8 [S.D.] s), radiopharmaceutical wastage (40% dose utilization), radiation safety parameters (1.6% contamination rate), and preliminary data of localizing value. Our results show that ictal SPECT can be a safe, noninvasive procedure completed on a routine basis in the epilepsy monitoring unit when appropriately trained support staff are utilized as part of a structured multidisciplinary program. PMID- 10094431 TI - Characterization of phenytoin-resistant kindled rats, a new model of drug resistant partial epilepsy: influence of experimental and environmental factors. AB - It has been recently shown that the variable anticonvulsant effect of phenytoin in the kindling model is not a characteristic of all kindled rats. In a population of amygdala-kindled Wistar rats, subgroups can be selected which consistently respond to phenytoin with an increase in afterdischarge threshold (responders) or which never show such an increase (non-responders). This study examined retrospectively the influence of technical and environmental factors on the results of several prospectively performed phenytoin selections during the last few years. Male and female Wistar rats were implanted with bipolar electrodes aimed at the basolateral amygdala and subsequently kindled. The fully kindled rats were tested for their ability to consistently respond to phenytoin (75 mg/kg i.p.) with an increase of afterdischarge threshold in three consecutive trials. Analysis of 158 Wistar rats of both genders revealed no significant influence of either plasma concentration of phenytoin, kindling parameters, precise electrode location, or differences in focal histology on the result of phenytoin selection. Furthermore, the ability to respond to phenytoin was not associated with the season or the ambient atmospheric pressure during the selection procedure. The data suggest that the difference between phenytoin responders and non-responders is not due to experimental factors, but may rather be genetically determined. PMID- 10094432 TI - Characterization of phenytoin-resistant kindled rats, a new model of drug resistant partial epilepsy: influence of genetic factors. AB - It has been recently shown that a subpopulation of amygdala-kindled Wistar rats can be selected which do not respond to phenytoin with an increase in afterdischarge threshold (ADT). Such non-responders could be a perfect model for studying the mechanisms of pharmacoresistance of complex partial seizures. Further studies on these rats suggested that the lack of anticonvulsant response was not due to the influence of experimental factors, but is an inherent property of each rat. In this study the influence of genetic factors on the pharmacoresistance to phenytoin by breeding Wistar rats which have been selected for their ability to consistently respond or not respond to phenytoin is examined. Male and female Wistar rats were implanted with bipolar electrodes in the basolateral amygdala and kindled. The fully kindled rats were repeatedly tested for their ability to respond to phenytoin (75 mg/kg i.p.) with an ADT increase. Responders and non-responders were mated and the offspring underwent the same kindling and repeated phenytoin testing procedure. Altogether, four generations of kindled rats were studied. The incidence of responses to phenytoin, i.e. ADT increased by more than 20% of control, was significantly higher in the F2 generation of the responder line compared to the non-responder line, but the number of responders and non-responders in the offspring generations F1-F3 did not significantly increase. The data suggest that the ability to respond or not to respond to phenytoin is genetically determined, although it does not follow a simple scheme of inheritance. The low reproductive success of the kindled and phenytoin-treated rats made it impossible to achieve a strain of phenytoin non-responders. PMID- 10094433 TI - Length variation of a polyglutamine array in the gene encoding a small conductance, calcium-activated potassium channel (hKCa3) and susceptibility to idiopathic generalized epilepsy. AB - The present association study tested whether length variations of two adjacent polymorphic CAG repeats in the coding sequence of a small-conductance, calcium activated potassium channel (hKCa3) confer susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). We found no significant difference in the allelic length distribution of the CAG repeats between 290 healthy German controls and the entire sample of 126 German IGE patients (Wilcoxon rank-sum test, P = 0.44) or two subgroups, comprising either 78 patients with juvenile myoclonic epilepsy (Wilcoxon rank-sum test, P = 0.74) or 59 patients with idiopathic absence epilepsies (Wilcoxon rank-sum test, P = 0.44). Moreover, the allelic distribution in parents-child trios of 46 IGE offspring did not differ significantly between the transmitted and non-transmitted parental alleles (Wilcoxon rank-sum test, P = 0.48). Therefore, our association study provides no evidence that length variations of polyglutamine arrays in the N-terminus of the hKCa3 channel exert a frequent and relevant effect in the epileptogenesis of common subtypes of IGE. PMID- 10094434 TI - Safety of tiagabine: summary of 53 trials. AB - We reviewed the clinical safety of tiagabine HCl (TGB), a selective CNS GABA uptake inhibitor, in nearly 3100 patients from 53 separate clinical trials. TGB was found to have no clinically important effect upon hepatic metabolic processes, serum concentrations of concomitant antiepileptic drugs (AEDs), laboratory values, or important interactions with any common non-AEDs. Adverse effects were usually mild and involved the nervous system. TGB is safe and well tolerated as add-on therapy for the treatment of partial seizures. PMID- 10094435 TI - Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. AB - Traditional randomized clinical trials for the monotherapy assessment of antiepileptic drugs (AED) involve allocation of newly diagnosed patients to long term treatment with different AEDs in order to determine remission rates and side effect profile. Apart from being time-consuming, however, these trials are unlikely to show significant differences in seizure control between the various drugs, which may lead some regulatory agencies to argue that remission rates could be related to the natural history of the disease rather than to efficacy of the administered drugs. To circumvent this problem, a number of innovative designs for the monotherapy assessment of new AEDs have been developed in recent years. They all share the common feature of being aimed at demonstrating a difference in response rate over a short treatment period between a high dosage of a new AED and some form of suboptimal treatment (placebo or low-dose active control). Patients allocated to suboptimal treatment show unacceptable seizure control more rapidly than patients on high-dose active treatment and therefore they exit the trial at a faster rate: evidence of antiepileptic activity is therefore based on demonstration of differences in rate of deterioration rather than improvement. These trials are conducted with titration schedules, dosages and durations of treatment which are totally unrelated to optimal use of the same AEDs in routine clinical practice. No comparative data with an established reference agent are provided, and allocation of patients to suboptimal treatment raises serious ethical concerns. For these reasons, justification for the continued implementation of these trials is questionable. Randomized long-term comparative trials should be considered the gold-standard for the monotherapy assessment of new AEDs. A review of the literature, however, reveals that long term trials with new AEDs completed to date had significant shortcomings in their design, including excessively rigid or inappropriate dosing schedules, enrollment of patients with heterogeneous seizure disorders, low statistical power and insufficient duration of follow-up. Because these studies are usually aimed at addressing regulatory requirements, the information obtained cannot be meaningfully applied to routine clinical practice. Large longer-term randomized comparative trials using more pragmatic approaches are highly needed to determine the real value of first-line therapy with new AEDs in patients with well defined seizure disorders. PMID- 10094436 TI - Current approaches to diagnosis and treatment of fungal infections in children infected with human immuno deficiency virus. AB - The prolonged survival of profoundly immunocompromised patients has revealed mucosal and invasive fungal infections to be major causes of morbidity and mortality in advanced HIV disease in children of all age groups. Antifungal resistance has become a clinically relevant problem. Paediatricians caring for HIV-infected children need to be aware of these increasingly frequent and often life-threatening infectious complications. This article reviews what is currently known about epidemiology, clinical presentation, diagnosis and treatment of mucosal and invasive fungal infections in children and adolescents with HIV disease. Candida spp. have become a leading bloodstream isolate in hospitalised patients; mucosal candidiasis is the most prevalent opportunistic infection in HIV-infected patients, and in both invasive and superficial infections, non Candida albicans spp. are on the increase. Invasive pulmonary aspergillosis has surfaced as an HIV-associated complication and previously uncommon fungi are more frequently encountered. HIV-infected individuals are particularly susceptible to Peumocystis carinii, Cryptococcus neoformans and infections by endemic fungi, such as Histoplasma capsulatum, Coccidioides immitis, Penicillium marneffei, and others. Newer immunological and molecular-based methods provide early and rapid diagnosis and monitoring. Potent and broad-spectrum third generation triazoles and novel fungicidal lipopeptides of the echinocandin class of antifungal antibiotics have entered clinical trials. Immunmodulation by recombinant cytokines and antifungal vaccines are very actively pursued inroads to adjunctive and preventive immunotherapy. CONCLUSION: Mucosal and invasive fungal infections will remain important complications in HIV-infected children of all age groups. Interventional studies and well documented case series are needed to improve the molecular diagnosis, treatment and prevention of invasive fungal infections in the paediatric HIV-infected population. PMID- 10094437 TI - Stimulatory guanine nucleotide binding protein subunit 1 mutation in two siblings with pseudohypoparathyroidism type 1a and mother with pseudopseudohypoparathyroidism. AB - Pseudohypoparathyroidism (PHP) type la is characterized by multihormone resistance and a constellation of somatic features referred to as Albright hereditary osteodystrophy. Several mutations in the gene coding for the Gs alpha subunit (GNAS1) have been described. Clinical symptoms are heterogeneous and initially laboratory parameters may be normal. We identified a 4 base pair deletion within GNAS1 in two affected siblings with PHP type la and their mother with presumed pseudo PHP. The female proband was diagnosed after an episode of apnoea and seizures. The younger brother was asymptomatic during infancy and had normal plasma parameters. PHP was diagnosed at the age of 4.4 years. Regular check-ups of siblings in families with index cases are therefore important. Molecular genetic analyses or biochemical screening for stimulatory guanine nucleotide binding protein defects should be performed. CONCLUSION: Different symptoms may be seen in patients with the same mutation causing pseudohypoparathyroidism or pseudopseudohypoparathyroidism. Therefore, clinical and biochemical investigations should be performed in all family members with an index patient. PMID- 10094438 TI - Treatment of hyperinsulinaemic hypoglycaemia with nifedipine. AB - We report on two children with mild persistent hyperinsulinaemic hypoglycaemia. In both, oral nifedipine treatment (0.7 and 2.0 mg/kg per day respectively) had a significant clinical effect. In one case, nifedipine monotherapy prevented hypoglycaemia; in the second case, the dosage and the side-effects of other substances could be reduced, thus circumventing surgical therapy. CONCLUSION: Nifedipine treatment has a favourable effect on the clinical course of patients with mild hyperinsulinism. It represents a valuable new substance for the treatment of this disorder. PMID- 10094439 TI - Tachycardia as a potential risk indicator for coronary arterial lesions in Kawasaki disease. AB - Tachycardia is frequently observed in the acute phase of Kawasaki Disease (KD) patients. However, little is known about the association between the tachycardia in the acute phase of KD and the development of coronary arterial lesions (CAL). We examined the association between the mean 24 h heart rate in the acute phase of KD observed using 24 h ambulatory ECG monitoring (24 h-ECG) and the occurrence of CAL in patients. In a study conducted between 1994 and 1997, 26 patients with KD underwent 24 h-ECG within the febrile period and before the 9th day of illness. We compared the mean 24 h heart rate based on 24 h-ECG between patients with and those without CAL. Of 26 patients, 7 had CAL. The groups with and without CAL had similar baseline characteristics. The mean 24 h heart rate in the group with CAL was significantly higher than that in the group without CAL (144 +/- 14 vs. 124 +/- 22, P = 0.033). On multiple regression analysis, the mean 24 h heart rate was significantly correlated with the development of CAL (P = 0.019). CONCLUSION: Marked tachycardia detected by 24 h-ambulatory ECG monitoring in the acute phase of Kawasaki disease might provide important information on the development of coronary arterial lesions. PMID- 10094440 TI - The complement component C4 in sudden infant death. AB - The aim of the present study was to compare partial deletions of the complement C4 gene in victims of totally unexplained sudden infant death (SID) (n = 89) and borderline SID (n = 15) with and without slight infections prior to death, in cases of infectious death (n = 19), and in living infants with and without infections (n = 84). The SID and borderline SID groups were pooled. In this total SID group slight infections prior to death was associated with deletion of either the C4A or the C4B gene (P = 0.033), and the SID victims with such infections had a higher deletion frequency than the controls (P = 0.039). There were no differences between the living infants with and without upper airway infections. CONCLUSION: The present study confirms that partial deletions of the C4 gene in combination with slight upper airway infections may be a risk factor in sudden infant death. PMID- 10094441 TI - Defective sexual development in an infant with 46, XY, der(9)t(8;9)(q23.1;p23)mat. AB - We report on a male infant with ambiguous genitalia (scrotal hypospadias, sinus urogenitalis) trisomic for 8q23-ter and monosomic for 9p23-ter, who shared craniofacial and other abnormalities with either phenotype. Gonadal histology was nearly normal for age. Normal endocrinological findings and exclusion of mutations in SRY, androgen receptor and alpha-reductase genes point to supplementary gene(s) located in 9p2305-ter, haplo-insufficiency (by deletion) of which is expected to cause defective male morphogenesis. CONCLUSION: This observation lends further support to the hypothesis that genetic factors are located at 9p23-ter which are involved in normal sex determination. PMID- 10094442 TI - Homozygous alpha-thalassaemia and hypospadias--common aetiology or incidental association? Long-term survival of Hb Bart's hydrops syndrome leads to new aspects for counselling of alpha-thalassaemic traits. AB - Fetuses with homozygous alpha-thalassaemia develop Hb Bart's hydrops fetalis syndrome, which usually leads either to abortion or fetal/neonatal death. We report diagnosis, intrauterine transfusion therapy, neonatal intensive care management and long-term follow-up of a Vietnamese infant who survived Hb Bart's hydrops fetalis syndrome. During the first 2 years the child had normal development. In addition, the patient exhibited penoscrotal hypospadias. Despite a thorough endocrinological work-up the aetiology of genital ambiguity could not be elucidated. A review of the literature showed an association of homozygous alpha-thalassaemia and hypospadias in all surviving male children, suggesting a common aetiology for both entities. CONCLUSION: On the basis of our findings, we speculate that an unknown gene on chromosome 16 responsible for genital formation is altered in homozygous alpha-thalassaemia. PMID- 10094443 TI - 5-Oxoprolinuria in patients with and without defects in the gamma-glutamyl cycle. AB - In patients with defects in the synthesis, breakdown and metabolism of glutathione (GSH), like glutathione synthetase deficiency (GSD) and 5 oxoprolinase deficiency, urinary excretion of 5-oxoproline, an intermediate of the gamma-glutamyl cycle, is increased. We identified 20 patients with significantly elevated urinary excretion of 5-oxoproline (> or =150 mmol/mol creatinine) during 5 years of selective screening for organic acidurias. In 6 of them, 5-oxoprolinuria was a constant finding including three patients with GSD and one with 5-oxoprolinase deficiency. One patient with constant 5-oxoprolinuria had GM2 gangliosidosis and one was clinically unaffected. In 14 patients, 5 oxoprolinuria was a transient abnormality and most often associated with an inborn error of metabolism outside the gamma-glutamyl cycle. In 9 of them 5 oxoprolinuria was associated with a neonatal urea cycle defect, with tyrosinaemia type I or occurred during metabolic decompensation in propionic acidaemia or methylmalonic acidaemia. Additionally, transient 5-oxoprolinuria was associated with homocystinuria, Stevens-Johnson syndrome, paracetamol intoxication, vigabatrin medication or extreme prematurity. CONCLUSION: 5-Oxoprolinuria is a more common condition than hitherto thought and is primarily associated with defects in the gamma-glutamyl cycle. However, several other inborn errors of metabolism and pathophysiological conditions must be taken into account when discovering 5-oxoprolinuria. PMID- 10094444 TI - Very long-chain fatty acids in Rett syndrome. AB - Rett syndrome (RS), found exclusively in girls, is characterised by a global deceleration of psychomotor development, loss of acquired speech, loss of manual skills and subsequent deceleration of head growth. The cause of this syndrome is so far unknown. To date there are no biological markers for RS; clinical diagnostic criteria were proposed by the Rett Syndrome Diagnostic Criteria Work Group 1988. The first objective of this study was to assay the levels of very long-chain fatty acids (VLCFA), i.e. C22:0, C24:0, C26:0, by gas chromatography in sera of 30 girls with RS. The VLCFA levels in the studied group were lower than the reference range for healthy children and control group. VLCFA levels were again measured after 2 months of L-carnitine administration in the same groups. VLCFA levels had increased. It is possible that the low VLCFA levels have some relation to the lowered carnitine levels. It may be that low carnitine levels impede transportation to mitochondria, thus the oxidation of long-chain fatty acids is inhibited, and compensated to a certain extent by intensified beta oxidation of VLCFA in the peroxisomal system. Raising carnitine levels could improve substrate delivery for mitochondrial beta-oxidation of long-chain fatty acids, thus reducing the use of VLCFA as substrates for beta-oxidation. We consider VLCFA to be secondary to the pathogenesis of RS, but the possible abnormalities in their levels may provide an insight into the development of this disease. CONCLUSION: Very long-chain fatty acid and carnitine levels are decreased in Rett syndrome L-Carnitine administration increased very long-chain fatty acid levels in serum. PMID- 10094445 TI - Lack of effectiveness of dexamethasone in neonatal bacterial meningitis. AB - A clinical trial was conducted to determine whether dexamethasone as adjunctive therapy alters the outcome of bacterial meningitis in neonates. Fifty-two full term neonates with bacterial meningitis were enrolled in a prospective study. Infants were alternately assigned to receive either dexamethasone or not. Twenty seven received dexamethasone in addition to standard antibiotic treatment and 25 received antibiotics alone. Dexamethasone therapy was started 10-15 min before the first dose of antibiotics in a dose of 0.15 mg/kg per 6 h for 4 days. Baseline characteristics, clinical and laboratory features in the two groups were virtually similar. Both groups showed a similar clinical response and similar frequency of mortality and sequelae. Six (22%) babies in the treatment group died compared to 7 (28%) in the control group (P = 0.87). At follow up examinations up to the age of 2 years, 6 (30%) of dexamethasone recipients and 7 (39%) of the control group had mild or moderate/severe neurological sequelae. Audiological sequelae were seen in two neonates in the dexamethasone group compared to one in the control group. CONCLUSION: Adjunctive dexamethasone therapy does not improve the outcome of neonatal bacterial meningitis. PMID- 10094446 TI - Early prediction of chronic lung disease by tracheal aspirate cytology in ventilated newborns. AB - We assessed the specificity of squamous metaplasia in tracheal aspirates of 69 ventilated newborns (gestational age 25-41 weeks) between days 3 and 7 of life for prediction of chronic lung disease (CLD). CLD was diagnosed when the patient was still requiring ventilation or supplementary oxygen at the postconceptional age of 36 weeks (or postnatal age of 28 days for babies born after 32 weeks gestation) and showed X-ray changes compatible with CLD. In the total population the presence of squamous metaplasia had a sensitivity of 59% and a specificity of 74% for the early diagnosis of CLD. The combination of squamous metaplasia and very low birth weight (VLBW) had a much higher specificity (94%), but a lower sensitivity (45%). Our results show that the presence of squamous metaplasia in VLBW babies during the 1st week of life predicts development of CLD with a specificity of 94% and may be helpful for entering patients into early treatment protocols or trials when a high risk population needs to be identified. As sensitivity of this approach is only 45%, further studies are needed to evaluate the predictive value of the combination of cytology with other markers in tracheal aspirate specimens. CONCLUSION: The presence of squamous metaplasia in tracheal aspirates of VLBW babies between days 3 and 7 of life is significantly associated with the development of chronic lung disease. Simple microscopic evaluation of fresh tracheal aspirates enables us to identify patients at high risk of CLD at a very early stage. PMID- 10094447 TI - A detailed analysis of changes in serum C-reactive protein levels in neonates treated for bacterial infection. AB - A prospective study was undertaken to characterize the rate of increase, time of peak values and rates of decrease in serum concentrations of C-reactive protein (CRP) in a group of infants treated for neonatal bacterial infection. A total of 176 consecutively admitted neonates with birth weight > 1500 g and without mechanical ventilation or central lines in situ, who received antibiotic therapy for suspected bacterial infection, were enrolled. The changes in serum CRP concentration in 60 of 63 infants who had CRP values above 20 mg/l 24-48 h after the beginning of treatment were analysed in detail. Initial increase rates in serum CRP levels of up to 4.5 mg/l per h were documented peak were reached at a mean of 19.5 h after antibiotic therapy had been initiated, but in some patients an increase in serum CRP levels occurred up to 40-48 h after the beginning of treatment. The mean serum half-life of CRP in infected neonates was 21 h (range 11.2-38 h). CONCLUSION: In neonates with bacterial infection (defined by a combination of clinical signs and increased C-reactive protein and immature-total quotient values) no differences in the overall pattern nor in any of the particular phases of the C-reactive protein response curves could be observed between neonates with positive (n = 13) or negative blood cultures (n = 47). PMID- 10094448 TI - Maternal plasma homocysteine, placenta status and docosahexaenoic acid concentration in erythrocyte phospholipids of the newborn. AB - The enhanced transport of long-chain polyunsaturated fatty acids, in particular docosahexaenoic acid (22:6 omega-3) (DHA), to the fetus is a placental function important for adequate membrane phospholipid formation and herewith decisive for the quality of fetal CNS myelination. A compromised placental function is correlated with signs of vascular pathology. As elevated plasma total homocysteine (tHcy) concentrations are considered an independent risk for premature occlusive vascular disease, the influence of maternal plasma tHcy concentrations on placental function was indirectly studied, determining the DHA content in erythrocyte membrane phospholipids of the newborn. A total of 60 unselected pregnant women (age range: 21 to 39 years) were investigated at delivery. Gestational age ranged from 26 to 41 weeks. Prior to delivery a placental ultrasound scan was performed. Complete sets of data could be obtained from 43 mothers and their offspring. tHcy concentrations were determined in the plasma of cord and maternal blood. The fatty acid pattern of erythrocyte membrane phospholipids was determined in the mothers and their newborns. Z-scores of the birth weights ranged from -3.4 to 2.1 and of the placental weights from -3.8 to 4.7. The mean maternal plasma tHcy concentration was 6.29 +/- 3.34 micromol/l ranging from below our limit of detection up to 15 micromol/l. These maternal concentrations were correlated with those of their infants (r = 0.71; P < 0.0001). The tHcy concentrations were significantly higher in mothers with pregnancies complicated by gestosis or placental calcifications. The Z-scores of birth weights as well as placental weights showed a significant negative correlation with maternal plasma tHcy concentrations. The mean DHA percentage of total fatty acids in erythrocyte phospholipids was 3.2 +/- 2.2% in the mothers and 3.4 +/- 2.3% in their newborns. Most importantly the maternal plasma tHcy levels and the erythrocyte phospholipid DHA concentrations of their offspring were significantly correlated (r = -0.51; P < 0.0003). CONCLUSION: In this study, total homocysteine concentrations were elevated in the plasma of pregnant women with signs of placental vasculopathy. Maternal plasma total homocysteine concentrations were positively correlated with erythrocyte phospholipid docosahexaenoic acid of their offspring and may be an indicator for the integrity of placental vascular function. The nutritional status as well as predisposing genetic factors of pregnant mothers need to be investigated more thoroughly. PMID- 10094449 TI - EEG evaluation in children and adolescents with chronic headaches. AB - In order to establish the usefulness of EEGs for the diagnosis of headache in children and adolescents, we retrospectively reviewed the records of 425 patients referred to our Paediatric Neurology Service because of recurrent headache. EEG was recorded ictally in 40 patients and interictally in 412 subjects. CONCLUSION: Our results confirm that the EEG is a very helpful tool, particularly in migraine with aura during the ictal phase, because it shows transient abnormalities that may support the diagnosis of this form of headache. On the contrary the EEG performed during the interictal phase is most often normal or it shows aspecific abnormalities with no relationship with to features. PMID- 10094450 TI - Mild closed head injury in children compared to traumatic fractured bone; neurobehavioural sequelae in daily life 2 years after the accident. AB - Two years after an accident resulting in either a mild head injury or a fractured bone, two groups of 22 children each, aged 4-14 years, were examined for the existence of any neurobehavioural symptoms by means of a standardized questionnaire filled out by their caretakers. Selection of the children was based on reports of the Accident and Emergency Department in 1 year. Significantly more symptoms were reported after mild head injury. The main symptoms reported were headache, dizziness, fatigue and memory problems. The total number of symptoms in the children with mild head injury exceeded four times this in the group of children with a fractured bone. CONCLUSION: Even 2 years after a mild head injury there are still residual symptoms in daily life. PMID- 10094452 TI - Sarcoidosis in infancy: a case with pulmonary involvement as a cardinal manifestation. AB - A 5-month-old girl presented with persistent dry cough, intermittent pyrexia and lymphocytosis, arthralgia, nodular skin lesions and an erythema nodosum-like rash. Chest CT scan revealed bilateral pulmonary infiltration. On the grounds of clinical and imaging findings, Gallium scanning and open lung biopsy were performed, providing evidence compatible with sarcoidosis. CONCLUSION: Despite what has previously been reported, sarcoidosis in infancy can present with pulmonary symptomatology. PMID- 10094451 TI - Croup and recurrent croup: their association with asthma and allergy. An epidemiological study on 5-8-year-old children. AB - The cumulative incidence (i.e. lifetime prevalence) of croup and recurrent croup (RC) was investigated by questionnaire in a large group (n = 5756) of 5-8-year old children (mean age: 6.8 +/- 0.6 years) and the risk for asthma and/or wheezing in children with croup and RC assessed. In a random sample of the children, skin prick testing with common inhalant allergens (n = 614) and spirometry (n = 305) were performed and the results were compared between children with or without croup or RC. Of the children, 15.5% had suffered from croup, while 5.0% had had RC. The cumulative incidence was higher in boys than in girls (P < 0.05). In the children with croup or RC an increased risk for wheezing, asthma, usage of anti-asthma medication, rhinitis and hay fever was found (P < 0.01). There was no difference in the prevalence of positive skin prick tests between children with and without croup or RC. Mean percentage predicted forced expiratory volume in 1 s, forced vital capacity and peak expiratory flow was not different between children with and without croup or RC. However, children who had suffered from croup (with or without wheezing) had a lower mean percentage predicted forced expiratory flow at both 50% and 75% of forced vital capacity than those without croup (P = 0.002). A family history of hay fever, chronic bronchitis and eczema was associated with the presence of croup or RC (P < 0.01), while this was hardly the case for a family history of asthma. CONCLUSION: Croup and recurrent croup are associated with bronchial asthma. The association seems essentially based on the presence of hyperreactive airways and less on the presence of atopy, although the latter can be considered an aggravating factor. PMID- 10094453 TI - A macrosomic newborn with a cystic adrenal mass. PMID- 10094454 TI - Cystic fibrosis: a cause of reduced birth weight? PMID- 10094455 TI - Growth hormone treatment of infantile dilated cardiomyopathy. PMID- 10094456 TI - Vitamin D intoxication. PMID- 10094457 TI - Dangers of countercurrent use in swimming-pools. PMID- 10094458 TI - So-called pancreatic acinar metaplasia of the gastric mucosa in two infants: a post-mortem study. PMID- 10094459 TI - Congenital insensitivity to pain with anhidrosis: report of a 68-day-old case. PMID- 10094460 TI - The metabolic parameters of obese children and the role of hyperinsulinism on weight loss. PMID- 10094461 TI - ADAMTS: a novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats. PMID- 10094462 TI - Protection against peroxynitrite. AB - Peroxynitrite formed in vivo from superoxide and nitric oxide can mediate oxidation, nitration, or nitrosation reactions, leading to impaired function, toxicity, and alterations in signaling pathways. Protection against peroxynitrite is important for defense of normal tissue, especially during inflammation. Biological protection against peroxynitrite is organized in three categories: prevention, interception, and repair. Prevention is the control of the formation of peroxynitrite precursors, nitric oxide and superoxide. Interception is by direct reaction with peroxynitrite, leading to non-toxic products. In this regard, organoselenium compounds, metalloporphyrin derivatives, and peroxidases (e.g. glutathione peroxidase and myeloperoxidase) exhibit high second-order rate constants with peroxynitrite. Ebselen, like glutathione peroxidase, protects in a catalytic fashion utilizing glutathione as reductant in the peroxynitrite reductase reaction. Protection by metalloporphyrins can be maintained through glutathione or ascorbate. Repair processes remove damaged products and restitute intact biomolecules. PMID- 10094463 TI - Cloning of a novel four repeat protein related to voltage-gated sodium and calcium channels. AB - Cloning has led to the discovery of more ion channels than predicted by functional studies, yet there remain channels that have not been cloned. We report the cloning of a novel protein that contains the four domain structure found in voltage-gated Ca2+ and Na+ channels. Phylogenetic relationships suggested that the protein might have diverged from an ancestral four repeat channel before the divergence of Ca2+ and Na+ channels. Northern blot analysis showed that mRNA transcripts encoding the protein are expressed predominantly in the brain, moderately in the heart, and weakly in the pancreas. Despite extensive expression attempts, currents from the putative channel were not detected. Based on its sequence, we propose that the novel protein might be a voltage-activated cation channel with unique gating properties. PMID- 10094464 TI - Evidence for an ancient chromosomal duplication in Arabidopsis thaliana by sequencing and analyzing a 400-kb contig at the APETALA2 locus on chromosome 4. AB - As part of the European Scientists Sequencing Arabidopsis program, a contiguous region (396607 bp) located on chromosome 4 around the APETALA2 gene was sequenced. Analysis of the sequence and comparison to public databases predicts 103 genes in this area, which represents a gene density of one gene per 3.85 kb. Almost half of the genes show no significant homology to known database entries. In addition, the first 45 kb of the contig, which covers 11 genes, is similar to a region on chromosome 2, as far as coding sequences are concerned. This observation indicates that ancient duplications of large pieces of DNA have occurred in Arabidopsis. PMID- 10094465 TI - Multiple regulatory elements control the expression of the yeast ACR1 gene. AB - The ACR1 gene, encoding a succinate-fumarate transporter, is required by the yeast Saccharomyces cerevisiae for ethanol utilization. Accordingly, gene expression is induced by ethanol and repressed by glucose. Here, we investigated three carbon source response elements present in its promoter region. Specific deletions as well as functional analysis of the elements in a heterologous promoter confirmed their role in transcriptional regulation. Protein binding to carbon source response elements of the ICL1 promoter was competed by all three elements to various extents by the respective ACR1 sequences. In addition, two putative stress response promoter elements present in the ACR1 promoter were investigated in deletion analyses and shown to contribute to gene expression. PMID- 10094466 TI - Gastrin stimulates the formation of a p60Src/p125FAK complex upstream of the phosphatidylinositol 3-kinase signaling pathway. AB - The molecular events whereby gastrin occupancy of G/CCK(B) receptors leads to phosphatidylinositol (PI) 3-kinase activation have been examined. We report here that this peptide promotes the association between two non-receptor tyrosine kinases, p60Src and p125FAK, and elicits a parallel increase in tyrosine phosphorylation and activity of both kinases. Gastrin-induced PI 3-kinase activity was coprecipitated with p60Src and p125FAK and was inhibited by herbimycin A, the selective Src inhibitor PP-2 or cytochalasin D, which disrupts the actin cytoskeleton and prevents p125FAK activity. These results indicate, for the first time, that a p60Src/p125FAK complex acts upstream of the gastrin stimulated PI 3-kinase pathway. PMID- 10094467 TI - Undercarboxylation of recombinant prothrombin revealed by analysis of gamma carboxyglutamic acid using capillary electrophoresis and laser-induced fluorescence. AB - The gamma-carboxyglutamic acid (Gla) content of several variants of human prothrombin has been measured by using capillary electrophoresis and laser induced fluorescence (CE-LIF). Both plasma-derived prothrombin and recombinant prothrombin contain ten residues of Gla per molecule of protein. In contrast, a variant of human prothrombin (containing the second kringle domain of bovine prothrombin) was separated into two populations that differed in their Gla content. Direct measurement of the Gla content showed an association with the presence or absence of the calcium-dependent conformational change that is required for prothombinase function. Thus, the CE-LIF assay is useful in determining the carboxylation status of recombinant proteins. PMID- 10094468 TI - SDR and MDR: completed genome sequences show these protein families to be large, of old origin, and of complex nature. AB - Short-chain dehydrogenases/reductases (SDR) and medium-chain dehydrogenases/reductases (MDR) are protein families originally distinguished from characterisations of alcohol dehydrogenase of these two types. Screening of completed genome sequences now reveals that both these families are large, wide spread and complex. In Escherichia coli alone, there are no fewer than 17 MDR forms, identified as open reading frames, considerably extending previously known MDR relationships in prokaryotes and including ethanol-active alcohol dehydrogenase. In entire databanks, 1056 SDR and 537 MDR forms are currently known, extending the multiplicity further. Complexity is also large, with several enzyme activity types, subgroups and evolutionary patterns. Repeated duplications can be traced for the alcohol dehydrogenases, with independent enzymogenesis of ethanol activity, showing a general importance of this enzyme activity. PMID- 10094469 TI - Transcriptional activation of the human S100A2 promoter by wild-type p53. AB - S100A2, a calcium binding protein of the EF-hand family, was recently identified to be inducible by etoposide, a p53 activator. A potential p53 binding site was identified in the promoter of the S100A2 gene, which binds to purified p53 as well as p53 in nuclear extract activated by etoposide. Transactivation assays using the promoter driven luciferase reporters revealed that the S100A2 promoter was transcriptionally activated by wild-type p53, but not by p53 mutants, in a dose-dependent as well as a p53 binding site-dependent manner. The p53-induced transactivation of the S100A2 promoter was enhanced by etoposide and blocked by a dominant negative p53 mutant. Furthermore, endogenous S100A2 mRNA expression is induced by etoposide in p53 positive, but not in p53 negative cells. Thus, p53 appears to positively regulate S100A2 expression. PMID- 10094470 TI - Identification of the genes responsive to etoposide-induced apoptosis: application of DNA chip technology. AB - DNA chip technology was used in an attempt to identify target genes responsible for apoptosis induced by etoposide, a p53 activating topoisomerase II inhibitor used clinically as an antitumor agent. 62 Individual mRNAs whose mass changed significantly were identified after screening oligonucleotide arrays capable of detecting 6591 unique human mRNA species. 12 (Nine induced and three repressed) of the etoposide-responsive genes were further studied by Northern analysis and an agreement rate of 92%, was reached. Among the 12 genes studied, two (WAF1/p21 and PCNA) are known p53 regulatory genes, two (glutathione peroxidase and S100A2 calcium-binding protein) appear to be the novel p53 target genes and the others appear to be p53-independent. Based upon these findings, the signalling pathways that possibly mediate etoposide-induced apoptosis are proposed. PMID- 10094471 TI - Increased oxidative stress in the RAW 264.7 macrophage cell line is partially mediated via the S-nitrosothiol-induced inhibition of glutathione reductase. AB - We investigated whether endogenously or exogenously produced nitric oxide (NO) can inhibit cellular glutathione reductase (GR) via the formation of S nitrosothiols to decrease cellular glutathione (GSH) and increase oxidative stress in RAW 264.7 cells. The specificity of this inhibition was demonstrated by addition of a NO-synthase inhibitor, and met- or oxyhemoglobin. Using isolated GR we found that only certain NO donors inhibit this enzyme via S-nitrosothiol. Furthermore, we found that cellular GSH decrease is paralleled by an increase of superoxide anion production. Our results show that the GR enzyme is a potential target of S-nitrosothiols to decrease cellular GSH levels and to induce oxidative stress in macrophages. PMID- 10094472 TI - A new fluorescence-based, hydrophobic photolabeling technique for analyzing membrane-associated proteins. AB - We introduce a new, fluorescent and photoactivatable fatty acid derivative (SANU) for hydrophobic labelling of membrane-bound proteins. The technique allows fast and highly sensitive screening of hydrophobically inserting proteins analyzed by SDS-PAGE with a detection limit below 0.1 pmol. A reliable calculation of labelling efficiencies is achieved by simultaneous densitometry of fluorescence and protein staining. We have applied the new technique on the membrane inserting protein talin, G-actin, and, as a negative control, on RNase, which only binds electrostatically to negatively charged lipid interfaces. In several ways superior to radiolabelling, we can recommend this technique for all laboratories under any circumstances. PMID- 10094473 TI - Growth phase-dependent subcellular localization of nitric oxide synthase in maize cells. AB - A protein band of approximately 166 kDa was detected in the soluble fraction of root tips and young leaves of maize seedlings, based on Western blot analysis using antibodies raised against mouse macrophage nitric oxide synthase (NOS) and rabbit brain NOS. NOS activity was present in these soluble fractions, as determined by L-[U-14C]citrulline synthesis from L[U-14]arginine. Immunofluorescence showed that the maize NOS protein is present in the cytosol of cells in the division zone and is translocated into the nucleus in cells in the elongation zone of maize root tips. These results indicate the existence of a NOS enzyme in maize tissues, with the localization of this protein depending on the phase of cell growth. PMID- 10094474 TI - Oxidation of low density lipoprotein and plasma by 15-lipoxygenase and free radicals. AB - It is generally accepted that the oxidation of pentadiene structures of polyunsaturated lipids by lipoxygenase (LOX) is regio- and enantio-specific, while the free radical-mediated lipid peroxidation gives stereo-random racemic products. It was confirmed that the oxidation of human low density lipoprotein (LDL) by 15-LOX from rabbit reticulocytes gave phosphatidylcholine (PC) and cholesteryl ester (CE) hydroperoxides regio-, stereo- and enantio-specifically. 15-LOX also oxidized human plasma to give specific PC and CE hydroperoxides in spite of the presence of high concentrations of antioxidants. More CE hydroperoxides were formed than PC hydroperoxides from LDL, but the reverse order was observed for plasma oxidation. The S/R ratio of the hydroperoxides decreased during long time incubation but remained significantly larger than one, while free radical-mediated oxidation of LDL and plasma gave racemic products. PMID- 10094475 TI - Gender related differences in ATP-dependent transport of dinitrophenyl glutathione conjugate across murine canalicular liver plasma membrane. AB - The present study reports gender related differences in ATP-dependent transport of dinitrophenyl-glutathione (GSH) conjugate (DNP-SG), a model GSH xenobiotic conjugate, across murine canalicular liver plasma membrane (cLPM). ATP-dependent transport of DNP-SG across female A/J mouse cLPM was mediated by two components, a high-affinity and a low-affinity component, with corresponding Km of 18 microM (Vmax 0.02 nmol/min.mg) and 500 microM (Vmax 0.23 nmol/min.mg), respectively. On the other hand, only one component for the ATP-dependent transport of DNP-SG was observed in male mouse cLPM (K(m) 130 microM; Vmax 0.18 nmol/min.mg). Moreover, the rate of ATP-dependent transport of DNP-SG was markedly higher in the cLPM fraction of male mouse compared with that of the female. Presence of two transport components in female mouse cLPM, but only one system in the cLPM fraction of male mouse, was confirmed by measuring DNP-SG mediated stimulation of ATP hydrolysis (DNP-SG ATPase activity). To the best of our knowledge, the present study is the first report on gender related differences in ATP-dependent murine canalicular transport of GSH conjugates. PMID- 10094476 TI - alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation. AB - Alpha-Tocopheryl succinate (alpha-TOS), but not a-tocopherol, triggered apoptosis in Jurkat T cells. Apoptosis was induced by alpha-TOS in a time- and concentration-dependent mode, and signs of apoptosis were visible at concentrations of alpha-TOS as low as 30 microM, and within 3-5 h after addition of the ester. Employing a specific fluorogenic substrate, caspase-3 was found to be activated rapidly in response to alpha-TOS at 50 microM. We also found that Jurkat T cells challenged with alpha-TOS, when exposed to the lysosomotropic weak base acridine orange, showed decreased lysosomal uptake of the dye. This is suggestive of the involvement of lysosomal destabilisation in apoptosis of the cells. Apoptosis of Jurkat T cells induced with alpha-TOS also involved a drop in the mitochondrial membrane potential, although this phenomenon occurred after the initiation of lysosomal rupture. All apoptotic features observed with alpha-TOS were very similar to those found when cross-linking of the Fas receptor triggered apoptosis. These findings are consistent with the recent idea that vitamin E can contribute to elimination of malignant cells by the induction of apoptosis, and can be of (patho)physiological significance. PMID- 10094477 TI - Differential subcellular localization of endogenous and transfected soluble epoxide hydrolase in mammalian cells: evidence for isozyme variants. AB - Endogenous, constitutive soluble epoxide hydrolase in mice 3T3 cells was localized via immunofluorescence microscopy exclusively in peroxisomes, whereas transiently expressed mouse soluble epoxide hydrolase (from clofibrate-treated liver) accumulated only in the cytosol of 3T3 and HeLa cells. When the C-terminal lie of mouse soluble epoxide hydrolase was mutated to generate a prototypic putative type 1 PTS (-SKI to -SKL), the enzyme targeted to peroxisomes. The possibility that soluble epoxide hydrolase-SKI was sorted slowly to peroxiosmes from the cytosol was examined by stably expressing rat soluble epoxide hydrolase SKI appended to the green fluorescent protein. Green fluorescent protein soluble epoxide hydrolase-SKI was strictly cytosolic, indicating that -SKI was not a temporally inefficient putative type 1 PTS. Import of soluble epoxide hydrolase SKI into peroxisomes in plant cells revealed that the context of -SKI on soluble epoxide hydrolase was targeting permissible. These results show that the C terminal -SKI is a non-functional putative type 1 PTS on soluble epoxide hydrolase and suggest the existence of distinct cytosolic and peroxisomal targeting variants of soluble epoxide hydrolase in mouse and rat. PMID- 10094478 TI - Pax6 and Cdx2/3 form a functional complex on the rat glucagon gene promoter G1 element. AB - Alpha-cell specific transcription of the glucagon gene is mainly conferred by the glucagon promoter G1-element, while additional elements G2, G3, and G4 have broad islet cell specificity. Transcription of the glucagon gene has been shown to be stimulated by Pax6 through binding to the glucagon gene promoter G3-element. In this report, we show that Pax6 additionally binds the glucagon gene promoter G1 element and forms a transcriptionally active complex with another homeodomain protein, Cdx2/3. Two distinct mutations in the G1-element, that both reduce promoter activity by 85-90%, is shown to eliminate binding of either Pax6 or Cdx2/3. Additionally, Pax6 enhanced Cdx2/3 mediated activation of a glucagon reporter in heterologous cells. We discuss how Pax6 may contribute to cell-type specific transcription in the pancreatic islets by complex formation with different transcription factors. PMID- 10094479 TI - Revisiting the S2 specificity of papain by structural analogs of Phe. AB - Papain characteristically has a strong preference for encoded L-aromatic amino acids (Phe > Tyr) at P2 position. We re-examined papain S2 specificity using structural analogs of Phe, in fluorogenic substrates of the series: dansyl-Xaa Arg-Ala-Pro-Trp (Xaa = P2 residue). Kinetic analyses showed that the S2 pocket accommodates a broad spectrum of Phe derivatives. Papain is poorly stereoselective towards Dns-(D/L)-Phe-Arg-Ala-Pro-Trp and binding is not critically affected by replacement of the benzyl ring by the non-aromatic lateral chain of cyclohexylalanine. The Km was significantly improved by mono- and di chlorination of Phe, or by its substitution by an electronegative group-like NO2, but the specificity constant was unchanged. Shortening or lengthening the side chain by adding or removing a methylene group impairs the P2/S2 interactions significantly, as do constrained structural analogs of Phe. Incorporation of benzyl-substituted phenylalanyl amino acid could help to design peptide-derived inhibitors with greater affinity and bioavailability. PMID- 10094480 TI - Pax6 and Pdx1 form a functional complex on the rat somatostatin gene upstream enhancer. AB - The somatostatin upstream enhancer (SMS-UE) is a highly complex enhancer element. The distal A-element contains overlapping Pdx1 and Pbx binding sites. However, a point mutation in the A-element that abolishes both Pdxl and Pbx binding does not impair promoter activity. In contrast, a point mutation that selectively eliminates Pdx1 binding to a proximal B-element reduces the promoter activity. The B-element completely overlaps with a Pax6 binding site, the C-element. A point mutation in the C-element demonstrates that Pax6 binding is essential for promoter activity. Interestingly, a block mutation in the A-element reduces both Pax6 binding and promoter activity. In heterologous cells, Pdx1 potentiated Pax6 mediated activation of a somatostatin reporter. We conclude that the beta/delta cell-specific activity of the SMS-UE is achieved through simultaneous binding of Pdx1 and Pax6 to the B- and C-elements, respectively. Furthermore, the A-element appears to stabilise Pax6 binding. PMID- 10094481 TI - Hydrolysis of alphas1- and beta-casein-derived peptides with a broad specificity aminopeptidase and proline specific aminopeptidases from Lactococcus lactis subsp. cremoris AM2. AB - Aminopeptidase hydrolysis of alpha(s)1 - and beta-casein-derived synthetic peptides containing non-consecutive and consecutive proline residues was characterised. Aminopeptidase P (Pep P) (EC 3.4.11.9) or post-proline dipeptidyl aminopeptidase (PPDA) (EC 3.4.14.5) along with lysine-paranitroanilide hydrolase (KpNA-H) (EC 3.4.11.1) activities are required in the degradation of peptides containing non-consecutive proline residues. However, both Pep P and PPDA along with KpNA-H are required for hydrolysis of peptides containing consecutive proline residues. The results demonstrate the mechanism by which combinations of purified general and proline specific aminopeptidases from Lactococcus lactis subsp. cremoris AM2 hydrolyse peptides containing proline residues. PMID- 10094482 TI - Regulation of capsular polysialic acid biosynthesis by temperature in Pasteurella haemolytica A2. AB - The capsular polysaccharide of Pasteurella haemolytica A2 consists of a linear polymer of N-acetylneuraminic acid (Neu5Ac) with alpha(2-8) linkages. The production of this polymer is strictly regulated by the growth temperature and above 40 degrees C no production is detected. Analysis of the enzymatic activities directly involved in its biosynthesis reveals that Neu5Ac lyase, CMP Neu5Ac synthetase and polysialyltransferase are involved in this regulation. Very low activities were found in P. haemolytica grown at 43 degrees C (at least 25 times lower than those observed when the growth temperature was 37 degrees C). The synthesis of these enzymes increased rapidly when bacteria grown at 43 degrees C were transferred to 37 degrees C and decreased dramatically when cells grown at 37 degrees C were transferred to 43 degrees C. These findings indicate that the cellular growth temperature regulates the synthesis of these enzymes and hence the concentration of the intermediates necessary for capsular polysaccharide genesis in P. haemolytica A2. PMID- 10094483 TI - The ras oncogene inhibits growth factor inducibility of early response genes, and promotes selectively expression of NGFI-A in a PC12 cell line. AB - Expression of oncogenic Ras in UR61 cells (a PC12 subclone) results in neuronal differentiation. We have observed that the oncoprotein selectively increased the levels of NGFI-A transcripts, but was unable to induce NGFI-B or c-fos transcripts. In contrast, nerve growth factor (NGF) elicited a strong induction of the three immediate early genes (IEGs). Thus, activation of Ras alone is sufficient for the induction of NGFI-A by NGF, whereas an additional pathway(s), besides Ras, is required for the stimulation of NGFI-B and c-fos gene expression. These results show that the acquisition of a neuronal phenotype does not correlate with induction of IEG expression. Additionally, Ras markedly reduces the response of the three genes to NGF and to other growth factors. This attenuation could reflect a negative regulatory mechanism acting on signalling pathways normally stimulated by growth factor receptors. PMID- 10094484 TI - Chemical modification of lysine side chains of cyclodextrin glycosyltransferase from Thermoanaerobacter causes a shift from cyclodextrin glycosyltransferase to alpha-amylase specificity. AB - Cyclodextrin glycosyltransferases and alpha-amylases are two groups of enzymes with related secondary structures. However, cyclodextrin glycosyltransferases display transferase activities not present in alpha-amylases, probably derived from the existence of two more domains and different amino acid sequences. The hydrolytic activity of cyclodextrin glycosyltransferases is generally quite low, except for two cyclodextrin glycosyltransferases from termophiles. In this work, we have carried out the chemical modification (with acetic anhydride) of the amino groups of cyclodextrin glycosyltransferase from Thermoanaerobacter to assess their contributions to protein function. The acetylated cyclodextrin glycosyltransferase showed a significant reduction of its cyclization, coupling and disproportionation activities. Surprisingly, the hydrolytic (saccharifying) activity was slightly enhanced. These results suggest the participation of one or more lysine side chains in the interactions contributing to the transferase activity, either in any of the S11 subsites or in the acceptor binding site. PMID- 10094485 TI - Cloning and expression of interleukin-18 binding protein. AB - Interleukin-18 binding protein is a novel glycoprotein that we successfully cloned and expressed. First, murine interleukin-18 binding protein was purified from the sera of mice with endotoxin shock using ligand affinity chromatography. The murine interleukin-18 binding protein cDNA was cloned after RT-PCR using mixed primer pair sequences based on partial murine interleukin-18 binding protein amino acid sequence analysis. Subsequently, human interleukin-18 binding protein cDNA was cloned from cDNA libraries of normal human liver using murine interleukin-18 binding protein cDNA as a probe. Next, we transiently expressed recombinant human and murine interleukin-18 binding proteins in COS-1 cells and purified them from culture supernatants. Both recombinant interleukin-18 binding proteins did not exhibit species specificity and prevented interleukin-18 binding to its receptor. In addition, they inhibited interleukine-18 dependent IFN-gamma production from KG-1 cells effectively. These results suggest that the interleukin-18 binding protein may possess interleukine-18 antagonist activity. PMID- 10094486 TI - Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2). AB - The rabbit polyclonal antibody against rat organic anion transporting polypeptide 2 (oatp2) was raised and immunoaffinity-purified. Western blot analysis for oatp2 detected two bands ( 74 and 76 kDa) in rat brain and a single band (76 kDa) in the liver. By immunohistochemical analysis, the oatp2 immunoreactivity was specifically high at the basolateral membrane of rat hepatocytes. Functionally, the oatp2-expressing oocytes were found to transport dehydroepiandrosterone sulfate, delta1 opioid receptor agonist [D-Pen2,D-Pen5]enkephalin, Leuenkephalin, and biotin significantly, as well as the substrates previously reported. These data reveal the exact distribution of the rat oatp2 at the protein level in the liver, and that oatp2 appears to be involved in the multispecificity of the uptaking substrates in the liver and brain. PMID- 10094487 TI - Functional analysis of the evolutionarily conserved proline 53 residue in Proteus mirabilis glutathione transferase B1-1. AB - The role of the evolutionarily conserved residue Pro-53 in Proteus mirabilis glutathione transferase B1-1 has been examined by replacing it with a serine residue using site-directed mutagenesis. The effect of the replacement on the activity, thermal stability and antibiotic binding capacity of the enzyme was examined. The results presented support the view that Pro-53 participates in the maintenance of the proper conformation of the enzyme fold rather than playing a direct role in the catalytic reaction. Furthermore, this residue appears to be an important determinant of the antibiotic binding to the enzyme. Experiments with wild type and mutated enzymes provide evidence that glutathione transferases may play an important role in antibiotic resistance exhibited by bacteria. PMID- 10094488 TI - Identification of novel interaction partners for the conserved membrane proximal region of alpha-integrin cytoplasmic domains. AB - The alpha3Abeta1 integrin is a laminin receptor with a broad specificity for different laminin isoforms. Furthermore, it regulates the function of other integrins, like alpha2beta1, alpha5beta1 and alpha6Abeta1. In a yeast two hybrid screen of a human placenta cDNA library, we identified cDNAs coding for four different proteins that strongly interact with the conserved region of the cytoplasmic domain of the alpha3A integrin subunit. In addition to the cDNA for nucleotide exchange factor Mss4 and the putative tumour suppressor protein BIN1, two novel cDNAs were identified. Association analysis with different integrin subunits revealed them as cDNAs that encode binding proteins which react with a broad spectrum of alpha subunits. The conserved membrane proximal region of the alpha3A chain was identified as the binding site for all four proteins. They, therefore, may be involved in the regulation of general functions of integrins. PMID- 10094489 TI - Redistribution of protein kinase C isoforms in rat pancreatic acini during lactation and weaning. AB - Freshly enzymatically isolated pancreatic acini from lactating and weaning Wistar rats were used to investigate the role of protein kinase C (PKC) isoforms during these physiologically relevant pancreatic secretory and growth processes. The combination of immunoblot and immunohistochemical analysis shows that the PKC isoforms alpha, delta, and epsilon are present in pancreatic acini from control, lactating and weaning rats. A vesicular distribution of PKC-alpha, -delta, and epsilon was detected by immunohistochemical analysis in the pancreatic acini from all the experimental groups. PKC-delta showed the strongest PKC immunoreactivity (PKC-IR). In this vesicular distribution, PKC-IR was located at the apical region of the acinar cells. No differences were observed between control, lactating and weaning rats. However, the immunoblot analysis of pancreatic PKC isoforms during lactation and weaning showed a significant translocation of PKC-delta from the cytosol to the membrane fraction when compared with control animals. Translocation of PKC isoforms (alpha, delta and epsilon) in response to 12-O tetradecanoyl phorbol 13-acetate (TPA) 1 microM (15 min, 37 degrees C) was comparable in pancreatic acini from control, lactating and weaning rats. In the control group, a significant translocation of all the isoforms (alpha, delta and epsilon) from the cytosol to the membrane was observed. The PKC isoform most translocated by TPA was PKC-delta. In contrast, no statistically significant increase in PKC-delta translocation was detected in pancreatic acini isolated from lactating or weaning rats. These results suggest that the PKC isoforms are already translocated to the surface of the acinar cells from lactating or weaning rats. In addition, they suggest that isoform specific spatial PKC distribution and translocation occur in association with the growth response previously described in the rat exocrine pancreas during lactation and weaning. PMID- 10094490 TI - Denatured states of human carbonic anhydrase II: an NMR study of hydrogen/deuterium exchange at tryptophan-indole-H(N) sites. AB - Hydrogen/deuterium (H/D) exchange measurements in low and moderate concentrations of GuHCI were conducted on the side chain H(N) atoms of the seven tryptophans of pseudo wild-type human carbonic anhydrase II. Tryptophans 5, 16 and 245, situated in or close to the N-terminal domain were found to have little protection against exchange. The H/D exchange results for Trp-123, Trp-192 and Trp-209 showed that a previously identified molten globule and the native state gave a similar protection against exchange. Global unfolding of the protein is necessary for the efficient exchange at Trp-97, which is located in the central part of the beta sheet. PMID- 10094491 TI - Modelling of a voltage-dependent Ca2+ channel beta subunit as a basis for understanding its functional properties. AB - Structure prediction methods have been used to establish a domain structure for the voltage-dependent calcium channel beta subunit, beta1b. One domain was identified from homology searches as an SH3 domain, whilst another was shown, using threading algorithms, to be similar to yeast guanylate kinase. This domain structure suggested relatedness to the membrane-associated guanylate kinase protein family, and that the N-terminal domain of the beta subunit might be similar to a PDZ domain. Three-dimensional model structures have been constructed for these three domains. The extents of the domains are consistent with functional properties and mutational assays of the subunit, and provide a basis for understanding its modulatory function. PMID- 10094492 TI - Cross-linking of the B cell receptor induces activation of phospholipase D through Syk, Btk and phospholipase C-gamma2. AB - Phospholipase D (PLD) has been proposed to play a key role in the signal transduction of cellular responses to various extracellular signals. Herein we provide biochemical and genetic evidence that cross-linking of the B cell receptor (BCR) induces rapid activation of PLD through a Syk-, Btk- and phospholipase C (PLC)-gamma2-dependent pathway in DT40 cells. Activation of PLD upon BCR engagement is completely blocked in Syk- or Btk-deficient cells, but unaffected in Lyn-deficient cells. Furthermore, in PLC-gamma2-deficient cells, BCR engagement failed to activate PLD. These results demonstrate that Syk, Btk and PLC-gamma2 are essential for BCR-induced PLD activation. PMID- 10094493 TI - Crystal structure of the beta-glycosidase from the hyperthermophile Thermosphaera aggregans: insights into its activity and thermostability. AB - The glycosyl hydrolases are an important group of enzymes that are responsible for cleaving a range of biologically significant carbohydrate compounds. Structural information on these enzymes has provided useful information on their molecular basis for the functional variations, while the characterization of the structural features that account for the high thermostability of proteins is of great scientific and biotechnological interest. To these ends we have determined the crystal structure of the beta-glycosidase from a hyperthermophilic archeon Thermosphaera aggregans. The structure is a (beta/alpha)8 barrel (TIM-barrel), as seen in other glycosyl hydrolase family 1 members, and forms a tetramer. Inspection of the active site and the surrounding area reveals two catalytic glutamate residues consistent with the retaining mechanism and the surrounding polar and aromatic residues consistent with a monosaccharide binding site. Comparison of this structure with its mesophilic counterparts implicates a variety of structural features that could contribute to the thermostability. These include an increased number of surface ion pairs, an increased number of internal water molecules and a decreased surface area upon forming an oligomeric quaternary structure. PMID- 10094494 TI - Key role of barstar Cys-40 residue in the mechanism of heat denaturation of bacterial ribonuclease complexes with barstar. AB - The mechanism by which barnase and binase are stabilized in their complexes with barstar and the role of the Cys-40 residue of barstar in that stabilization have been investigated by scanning microcalorimetry. Melting of ribonuclease complexes with barstar and its Cys-82-Ala mutant is described by two 2-state transitions. The lower-temperature one corresponds to barstar denaturation and the higher temperature transition to ribonuclease melting. The barstar mutation Cys-40-Ala, which is within the principal barnase-binding region of barstar, simplifies the melting to a single 2-state transition. The presence of residue Cys-40 in barstar results in additional stabilization of ribonuclease in the complex. PMID- 10094495 TI - Anoxic function for the Escherichia coli flavohaemoglobin (Hmp): reversible binding of nitric oxide and reduction to nitrous oxide. AB - The flavohaemoglobin Hmp of Escherichia coli is inducible by nitric oxide (NO) and provides protection both aerobically and anaerobically from inhibition of growth by NO and agents that cause nitrosative stress. Here we report rapid kinetic studies of NO binding to Fe(III) Hmp with a second order rate constant of 7.5 x 10(5) M(-1) s(-1) to generate a nitrosyl adduct that was stable anoxically but decayed in the presence of air to reform the Fe(III) protein. NO displaced CO bound to dithionite-reduced Hmp but, remarkably, CO recombined after only 2 s at room temperature indicative of NO reduction and dissociation from the haem. Addition of NO to anoxic NADH-reduced Hmp also generated a nitrosyl species which persisted while NADH was oxidised. These results are consistent with direct demonstration by membrane-inlet mass spectrometry of NO consumption and nitrous oxide production during anoxic incubation of NADH-reduced Hmp. The results demonstrate a new mechanism by which Hmp may eliminate NO under anoxic growth conditions. PMID- 10094496 TI - Actin dynamics in lamellipodia of migrating border cells in the Drosophila ovary revealed by a GFP-actin fusion protein. AB - Directional migration of border cells in the Drosophila egg chambers is a developmentally regulated event that requires dynamic cellular functions. In this study, the electron microscopic observation of migrating border cells revealed loose actin bundles in forepart lamellipodia and numerous microvilli extending from nurse cells and providing multiple adhesive contacts with border cells. To analyze the dynamics of actin in migrating border cells in vivo, we constructed a green fluorescent protein-actin fusion protein and induced its expression in Drosophila using the GAL4/UAS system. The green fluorescent protein-actin was incorporated into the actin bundles and it enabled visualization of the rapid cytoskeletal changes in border cell lamellipodia. During the growth of the lamellipodia, the actin bundles that increased in number and size radiated from the bundle-organizing center. Quantification of the fluorescence intensity showed that an accumulation of bundle-associated and spotted green fluorescent protein actin signals took place during their centripetal movement. Our results favored a treadmilling model for actin behavior in border cell lamellipodia. PMID- 10094497 TI - Expression and a role of functionally coupled P2Y receptors in human dendritic cells. AB - We investigated the physiology and function of P2Y receptors expressed in human dendritic cells (DCs) differentiated in vitro from CD14+ cells (DC-14). These were obtained after a 10 day stimulation period in GM-CSF, IL-4 and monocyte conditioned medium. DC-14 were found to express high amounts of MHC class II, B7, CD40 as well as CD83. The functional analysis, using single cell Ca2+ imaging, demonstrated the expression of at least three subtypes of P2Y receptors. We further found using patch-clamp measurements that ATP evoked a pertussis toxin insensitive non-selective cation current with a peak current amplitude of -276+/ 43 pA (holding potential -80 mV, n = 23). This current was not Ca(2+)-activated, since it was still observed under conditions of high intracellular Ca2+ buffering and could be blocked by Gd3+ (0.5 mM). In addition, intracellular application of GTP-gamma-S (0.3 mM) also activated the current. Interestingly, DC-14 redirected the orientation of their dendrites as well as cell shape towards a pipette containing ATP as observed with time lapse microscopy. These data suggest that in human DCs, ATP acts via P2Y receptors and induces chemokine effects. PMID- 10094498 TI - ATP-synthase of Rhodobacter capsulatus: coupling of proton flow through F0 to reactions in F1 under the ATP synthesis and slip conditions. AB - A stepwise increasing membrane potential was generated in chromatophores of the phototrophic bacterium Rhodobacter capsulatus by illumination with short flashes of light. Proton transfer through ATP-synthase (measured by electrochromic carotenoid bandshift and by pH-indicators) and ATP release (measured by luminescence of luciferin-luciferase) were monitored. The ratio between the amount of protons translocated by F0F1 and the ATP yield decreased with the flash number from an apparent value of 13 after the first flash to about 5 when averaged over three flashes. In the absence of ADP, protons slipped through F0F1. The proton transfer through F0F1 after the first flash contained two kinetic components, of about 6 ms and 20 ms both under the ATP synthesis conditions and under slip. The slower component of proton transfer was substantially suppressed in the absence of ADP. We attribute our observations to the mechanism of energy storage in the ATP-synthase needed to couple the transfer of four protons with the synthesis of one molecule of ATP. Most probably, the transfer of initial protons of each tetrad creates a strain in the enzyme that slows the translocation of the following protons. PMID- 10094499 TI - Differential effects of retinoic acid isomers on the expression of nuclear receptor co-regulators in neuroblastoma. AB - Retinoic acid modulates growth and induces differentiation and apoptosis of neuroblastoma cells in vitro, with the all-trans and 9-cis isomers having different biological properties. Transcriptional activation in response to retinoic acid isomers is mediated by retinoic acid receptors and retinoid X receptors. The differential expression of co-activators and co-repressors which preferentially interact with retinoic acid receptors or retinoid X receptors may be a mechanism leading to different cellular responses to 9-cis and all-trans retinoic acid. To test this hypothesis, we have studied the expression of the nuclear receptor co-regulators TIF1alpha, TIF1beta, SUG1 and SMRT in the N-type and S-type neuroblastoma cell lines SH SY 5Y and SH S EP. Transcripts for all four co-regulators were expressed in these neuroblastoma cells. The expression of TIF1alpha, TIF1beta and SUG1 did not change in response to retinoic acid; however, SMRT was induced in both neuroblastoma cell lines, but particularly by all-trans retinoic acid in SH S EP cells. An additional co-activator, Trip3, was isolated by differential mRNA display and shown to be preferentially induced by 9 cis retinoic acid in SH SY 5Y and SH S EP cells. These data suggest that retinoic acid isomer-specific induction of nuclear receptor co-regulators may determine, in part, the differential biological effects of retinoic acid isomers. PMID- 10094500 TI - Kinetics of the interaction of endotoxin with polymyxin B and its analogs: a surface plasmon resonance analysis. AB - Lipopolysaccharide, the invariant structural component of Gram-negative bacteria, when present in minute amounts in the circulation in humans elicits 'endotoxic shock' syndrome, which is fatal in 60% of the cases. Polymyxin B (PMB), a cyclic cationic peptide, neutralizes the endotoxin, but also induces many harmful side effects. Many peptide-based drugs mimicking the activity of PMB have been synthesized in an attempt to reduce toxicity while still retaining the anti endotoxic activity. The study attempts to use the recent technique of surface plasmon resonance (SPR), in determining the kinetics of association and dissociation involved in the interaction of endotoxin with a few selected peptides that have structural features resembling PMB. The results, in conjunction with the thermodynamic data derived using isothermal titration calorimetry (ITC), stress the vital role played by amphiphilicity of the peptides and hydrophobic forces in this biologically important interaction. PMID- 10094501 TI - Purification, characterization and crystallization of ERA, an essential GTPase from Escherichia coli. AB - ERA is an essential GTPase widely conserved in bacteria. Homologues of ERA are also present in higher eukaryotic cells. ERA is involved in bacterial cell cycle control at a point preceding cell division. In order to aid the functional investigation of ERA and to facilitate structure-function studies, we have undertaken the X-ray crystallographic analysis of this protein. Here, we report the purification and crystallization procedures and results. The purified ERA exhibits nucleotide-binding activity and GTP-hydrolytic activity. ERA is one of the very few multi-domain GTPases crystallized to date. PMID- 10094502 TI - Visualization of caveolin-1, a caveolar marker protein, in living cells using green fluorescent protein (GFP) chimeras. The subcellular distribution of caveolin-1 is modulated by cell-cell contact. AB - Caveolin-1, a suspected tumor suppressor, is a principal protein component of caveolae in vivo. Recently, we have shown that NIH 3T3 cells harboring anti-sense caveolin-1 exhibit a loss of contact inhibition and anchorage-independent growth. These observations may be related to the ability of caveolin-1 expression to positively regulate contact inhibition. In order to understand the postulated role of caveolin-1 in contact inhibition, it will be necessary to follow the distribution of caveolins in living cells in response to a variety of stimuli, such as cell density. Here, we visualize the distribution of caveolin-1 in living normal NIH 3T3 cells by creating GFP-fusion proteins. In many respects, the behavior of these GFP-caveolin-1 fusion proteins is indistinguishable from endogenous caveolin-1. These GFP-caveolin-1 fusion proteins co-fractionated with endogenous caveolin-1 using an established protocol that separates caveolae derived membranes from the bulk of cellular membranes and cytosolic proteins, and co-localized with endogenous caveolin-2 in vivo as seen by immunofluorescence microscopy. We show here that as NIH 3T3 cells become confluent, the distribution of GFP-caveolin-1 and endogenous caveolin-1 shifts to areas of cell-cell contact, coincident with contact inhibition. However, unlike endogenous caveolin-1, the levels of GFP-caveolin-1 expression are unaffected by changes in cell density, serum starvation, or growth factor stimulation. These results are consistent with the idea that the levels of endogenous caveolin-1 are modulated by either transcriptional or translational control, and that this modulation is separable from density-dependent regulation of the distribution of caveolin-1. These studies provide a new living-model system for elucidating the dynamic mechanisms underlying the density-dependent regulation of the distribution of caveolin-1 and how this relates to contact inhibition. PMID- 10094503 TI - Crocalbin: a new calcium-binding protein that is also a binding protein for crotoxin, a neurotoxic phospholipase A2. AB - Utilizing Marathon-ready cDNA library and a gene-specific primer corresponding to a partial amino acid sequence determined previously, the complete nucleotide sequence for the cDNA of crocalbin, which binds crotoxin (a phospholipase A2) and Ca2+, was obtained by polymerase chain reaction. The open reading frame of the cDNA encodes a novel polypeptide of 315 amino acid residues, including a signal sequence of 19 residues. This protein contains six potential Ca(2+)-binding domains, one N-glycosylation site, and a large amount of acidic amino acid residues. The ability to bind Ca2+ has been ascertained by calcium overlay experiment. Evidenced by sequence similarity in addition, it is concluded that crocalbin is a new member of the reticulocalbin family of calcium-binding proteins. PMID- 10094505 TI - Definition of the correct sequence in the donor splice site of intron 2 in the human glucose 6-phosphate translocase gene. PMID- 10094504 TI - Protochlorophyllide b does not occur in barley etioplasts. AB - Barley (Hordeum vulgare L.) etioplasts were isolated, and the pigments were extracted with acetone. The extract was analyzed by HPLC. Only protochlorophyllide a and no protochlorophyllide b was detected (limit of detection < 1% of protochlorophyllide a). Protochlorophyllide b was synthesized starting from chlorophyll b and incubated with etioplast membranes and NADPH. In the light, photoconversion to chlorophyllide b was observed, apparently catalyzed by NADPH :protochlorophyllide oxidoreductase. In darkness, reduction of the analogue zinc protopheophorbide b to zinc 7-hydroxy-protopheophorbide a was observed, apparently catalyzed by chlorophyll b reductase. We conclude that protochlorophyllide b does not occur in detectable amounts in etioplasts, and even traces of it as the free pigment are metabolically unstable. Thus the direct experimental evidence contradicts the idea by Reinbothe et al. (Nature 397 (1999) 80-84) of a protochlorophyllide b-containing light-harvesting complex in barley etioplasts. PMID- 10094506 TI - The case against physician assisted suicide. AB - Physician assisted suicide (PAS) engenders debate about the meaning of professional identity, what is proper in the doctor/patient relationship, and the physician's appropriate role in society. Polarization on PAS largely arises from different views on what defines compassion in relieving pain and suffering, and the proper balance between individual autonomy and social imperatives. This paper discusses the ethical, social and economic arguments against PAS, including a historical perspective on other socially-sanctioned inappropriate uses of medical technology and expertise. This paper maintains that a truly dignified death does not come at the hand of a physician-healer, despite compelling arguments that it is a compassionate act. PMID- 10094507 TI - Self-help groups for families of persons with mental illness: perceived benefits of helpfulness. AB - Self-help groups have become important resources for families of persons with mental illness. The present study was an attempt to understand the factors perceived by group members as helpful using Yalom's factors in clarifying the dynamics of groups. Members (N = 202) of the Alliance for the Mentally Ill of Pennsylvania (AMI of PA), an association of self-help groups for families of the mentally ill, were recruited and responded to a self-administered questionnaire. Hierarchical block multiple regression indicated that those AMI members who felt information provision and gaining support and self-understanding from the group process was helpful and were longer term participants in their group were more likely to perceive benefit from belonging to the group. The findings may provide the basis for evaluating and improving self-help group effectiveness and contribute to understanding process factors within a self-help group which members find beneficial. Implications for how these groups can attract and maintain members are discussed. PMID- 10094508 TI - Use, persistence, and intensity: patterns of care for children's mental health across one year. AB - This paper explores the use, persistence, and intensity of services for children's mental health problems across a variety of service sectors during a one year period. Data come from the Great Smoky Mountains Study. Analyses focus on children's psychiatric symptomatology and impairment, service use, and factors that may influence the relationship between psychiatric problems and service use across a one year period. Findings show that approximately 20% of children used some mental health services from some sector during the year. Child's symptomatology and characteristics of parents were associated with use and persistence of services. Parent's perceptions of impact on the family were associated with service use, persistence, and intensity. PMID- 10094509 TI - A comparison of attitudes towards mental illness and knowledge of mental health services between Australian and Asian students. AB - The aim of this study was to investigate whether Asian immigrants in Australia differed from Anglo-Australians in terms of attitudes towards mental illness, and knowledge of mental health services. A questionnaire was administered to 140 university students, including 63 Anglo-Australian students, 47 Asian students, and 30 students from European backgrounds. The results showed that there was a significant ethnic difference in terms of attitudes towards mental illness, and knowledge of mental health services. Furthermore, Asians who spoke a language other than English at home knew less about services for acute mental illness. PMID- 10094510 TI - Mental disorder among homeless and poor people: a comparison of assessment methods. AB - This study assessed mental disorders among 144 homeless and poor adults using four different methods: (a) history of psychiatric hospitalization, (b) structured clinical interview, (c) self-report symptom checklist, and (d) interviewer ratings. These four methods yielded divergent estimates of mental illness, ranging from 3-70%. Correlations assessing the degree of overlap among the measures were generally modest in magnitude. The results suggest that the variation in rates of mental illness across existing studies is due to methodological differences and that, with the exception of the structured interview, the various methods fail to adequately distinguish mental disorder from substance abuse. PMID- 10094511 TI - Psychosocial functioning of youth receiving mental health services in the schools versus community mental health centers. AB - Evaluated psychosocial differences between youth receiving mental health services in Community Mental Health Centers (CMHCs; n = 79) as compared to youth receiving services from a program operating in 10 Baltimore schools (n = 186). Racial and gender differences were shown, with more African American youth and females in the School than CMHC sample. Multivariate analyses that controlled for these racial and gender differences failed to reveal significant effects, indicating comparable functioning on measures of life stress, violence exposure, family support, self-concept, and emotional/behavioral problems for youth from the two samples. However, particularly for those with internalizing disturbances, youth in the School sample were less likely to have received prior mental health services than youth from the CMHCs. Findings support the conclusion that school based mental health programs are reaching youth who need mental health services, who otherwise may not receive them. PMID- 10094512 TI - Perceived ideological differences, job satisfaction and organizational commitment among psychiatrists in a community mental health center. AB - Physician turnover has long been a problem in community mental health centers. While explanations for the problem have been offered, there have been no systematic studies of factors associated with the high turnover. In this study, the Minnesota Satisfaction Questionnaire and the Organizational Commitment Questionnaire were given to psychiatrists employed by a community mental health center. Subjects were also asked to identify their treatment ideology, and to rate their perception of the ideology of other clinicians and administrators with whom they work. Psychiatrists perceived significant differences in many ideological areas. Analysis demonstrated a correlation between these differences and the commitment of the psychiatrists to the organization. PMID- 10094513 TI - New Perspectives in Mitochondrial Research. Proceedings of a workshop in honor of Professor Giovanni Felice Azzone. Padova, Italy, 18-21 September 1997. PMID- 10094514 TI - Recent references. PMID- 10094515 TI - Atopic allergy and other hypersensitivities. Autoimmunity. Web alert. PMID- 10094516 TI - [The characterization and analysis of the activities carried out by the Servizio di Igiene degli Alimenti e della Nutrizione (SIAN)]. PMID- 10094517 TI - Functional interactions between synthetic alkyl phospholipids and the ABC transporters P-glycoprotein, Ste-6, MRP, and Pgh 1. PMID- 10094519 TI - XIV National Meeting on Cytometry. Riccione, Italy. 15-17 October 1997. PMID- 10094518 TI - [Legal malpractice-related aspects of consultation]. PMID- 10094520 TI - [PTPC (Patched). Tumor suppressor gene]. PMID- 10094521 TI - [PML (promyelocytic leukemia). Oncogene]. PMID- 10094522 TI - [French clinical trials of gene therapy with "suicide gene"]. PMID- 10094523 TI - [Ecteinascidin 743]. PMID- 10094524 TI - [Anticancer proteins and drugs: structure, function, and design]. PMID- 10094526 TI - 22nd Australian and New Zealand Scientific Meeting on Intensive Care. Abstracts. PMID- 10094525 TI - 40th annual meeting of the American Society of Hematology. PMID- 10094527 TI - $50m record damages awarded against tobacco company. PMID- 10094528 TI - English judge rules that smokers' claims are "too late". PMID- 10094529 TI - All UK doctors to be required to prove competence. PMID- 10094530 TI - Scientists call for moratorium on genetically modified foods. PMID- 10094531 TI - Israel prepared for "Jerusalem syndrome". PMID- 10094532 TI - Three women win in cancer screening case. PMID- 10094533 TI - Beijing conference reviews Kashin-Beck disease. PMID- 10094534 TI - Legal suit over Norplant collapses. PMID- 10094535 TI - Bristol chief executive appeals against GMC. PMID- 10094536 TI - Bristol parents protest over removal of hearts. PMID- 10094537 TI - New diagnostic criteria for diabetes mellitus. Subjects with impaired glucose tolerance but normal fasting values will not be identified. PMID- 10094538 TI - New diagnostic criteria for diabetes mellitus. A way of identifying all those at risk of long term complications of diabetes is still needed. PMID- 10094539 TI - New diagnostic criteria for diabetes mellitus. Prevalence is reduced using these criteria rather than 1895 WHO criteria. PMID- 10094540 TI - New diagnostic criteria for diabetes mellitus. The reanalysis by the DECODE Study Group needs to be reanalysed. PMID- 10094541 TI - Prescription of proton pump inhibitors. Indications may be more specific than suggested by GP records. PMID- 10094542 TI - Cervical screening for women with learning disability. Concerted effort is needed to ensure these women use preventive services. PMID- 10094543 TI - Cervical screening for women with learning disability. Sefton has multidisciplinary group to promote sexual health care for these women. PMID- 10094544 TI - Cholesterol: how low is low enough? Doctors have been slow in getting evidence on lowering cholesterol into practice. PMID- 10094545 TI - [The role of basophils in the pathogenesis of allergic diseases]. PMID- 10094546 TI - Proceedings of the Conference on Preclinical Pharmacological Studies with and for Radiopharmaceuticals. Orsay, France, October 24-25, 1996. PMID- 10094547 TI - Screening for mutations of the APC gene in 66 Italian familial adenomatous polyposis patients: evidence for phenotypic differences in cases with and without identified mutation. AB - Germline mutations in the APC gene are responsible for familial adenomatous polyposis (FAP), a dominantly inherited syndrome characterized by the development of hundreds to thousands of polyps in the colon and in the rectum of affected individuals and by variable extracolonic manifestations (gastric and duodenal polyps, osteomas, retinal lesions, and desmoid tumors). Through the combined use of single-strand conformation polymorphism (SSCP) analysis and the protein truncation test (PTT), we have screened 66 Italian FAP patients and found 29 different APC mutations in a total of 34 cases. Of the identified mutations, 15 were nonsense, 12 were 1- to 5-bp deletions or insertions and two were complex rearrangements, all leading to the formation of premature stop codons. Only 10 mutations had been already previously described at the germline level, confirming the high heterogeneity of the APC mutational spectrum. The mean age of diagnosis in mutation positive cases and their affected relatives was significantly lower than in cases without identified mutation (30.6 vs 39.1 years, respectively; p = 0.003). In addition, among patients without a family history of polyposis, all mutation-positive cases displayed at least one of the extracolonic manifestations usually associated with FAP, whereas in one-half of the cases without identified mutation, none of these phenotypes was observed. Although a fraction of apparently mutation-negative cases were likely to be due to limitations of the mutation screening strategy, our results suggest, in agreement with previous reports, that allelic and/or genetic heterogeneity might be responsible for the phenotypic variability observed in FAP patients. PMID- 10094548 TI - Detection of mutations in COL4A5 in patients with Alport syndrome. AB - Alport syndrome (AS) can be caused by mutations in COL4A5, one of the six type IV collagen genes. For the purposes of confirming diagnoses, carrier screening and correlating genotype to phenotype, we have screened all 51 exons of this gene by SSCP analysis in 153 families with suspected AS. Mutations were identified in 77 families (of which 20 have previously been reported) and are reported with all available clinical information. All types of mutation were found (missense, nonsense, splicing, small and large deletions and insertions), with the commonest type being those affecting glycine residues in the collagen triple helix. Our 50% detection rate is similar to that of other groups and may imply the presence of mutations outside of the COL4A5 coding region or the existence of a second X linked AS gene. PMID- 10094549 TI - Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity. AB - Usher syndrome is a heterogeneous autosomal recessive trait and the most common cause of hereditary deaf-blindness. Usher syndrome type I (USH1) is characterised by profound congenital sensorineural hearing loss, vestibular dysfunction, and prepubertal onset of retinitis pigmentosa. Of the at least six different loci for USH1, USH1B maps on chromosome 11q13, and the MYO7A gene has been shown to be defective in USH1B. MYO7A encodes myosin VIIA, an unconventional myosin, and it consists of 48 coding exons. In this study, MYO7A was analysed in 34 unrelated Usher type I patients by single-strand conformation polymorphism analysis and direct sequencing. We identified a total of 12 novel and unique mutations, all single base changes. In addition, we found a previously reported nonsense mutation (C31X) on nine alleles of a total of six patients from Denmark. PMID- 10094550 TI - Identification of a 5' splice site mutation in the RPGR gene in a family with X linked retinitis pigmentosa (RP3). AB - We have identified a novel RPGR gene mutation in a large Dutch family with X linked retinitis pigmentosa (RP3). In affected members, a G-->T transversion was found at position +1 of the 5' splice site of intron 5 of the RPGR (retinitis pigmentosa GTPase regulator) gene. Analysis of this mutation at the RNA level showed cryptic splicing upstream of the mutation in exon 5 leading to a frameshift and downstream termination codon. Identification of the causative mutation in this family has facilitated the detection of females at risk of having an affected son. PMID- 10094551 TI - The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor. AB - Denys-Drash and Frasier syndromes are rare human disorders that associate nephropathy with gonadal and genital abnormalities. In DDS there is a predisposition to Wilms' tumor. Heterozygous point mutations in the Wilms' tumor, type1 gene (WT1), particularly those altering the zinc finger (ZF) encoding exons, have been reported in most DDS patients, while mutations in intron 9 of the same gene cause FS. This paper describes two cases of DDS, one FS and one patient with Wilm's tumor and intersex genitalia, in which mutations were searched by sequencing the exons 8 and 9 of WT1 gene. Patient 1 carried a missense point mutation in exon 8 (ZF2), converting a CGA-Arg codon to a TGA-stop codon. Patient 2 presented a single nucleotide deletion within exon 9 (ZF3) introducing a premature chain termination at codon 398. Patients 3 and 4 had a C- >T transition at position +4 of the second alternative splice donor site of exon 9 (this mutation was detected in peripheral blood and in tumor derived DNA of patient 3). However, patient 3 had previously developed a Wilms' tumor. This is the first case of Wilms' tumor development in a phenotypically and genetically confirmed case of FS. PMID- 10094552 TI - A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations. AB - We have retrospectively analyzed 837 random anonymized dried blood spot (DBS) samples from neonatal screening programs in Scandinavia for mutations in HFE, the candidate gene for hemochromatosis. We have found C282Y allele frequencies of 2.3% (+2.0%) (-1.3%) in Greenland, 4.5%+/-1.9% in Iceland, 5.1%+/-2.3% in the Faeroe Islands, and 8.2%+/-2.7% in Denmark. The high prevalence of HFE mutations in Denmark suggests that population screening for the C282Y mutation could be highly advantageous in terms of preventive health care. Long-term follow-up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes will give an indication of the penetrance of the mutations. PMID- 10094553 TI - Identification of twenty-one new mutations in the factor IX gene by SSCP analysis. AB - In this study we have analyzed the factor IX gene from 84 hemophilia B patients of Spanish origin. It included single-strand conformation polymorphism (SSCP) analysis of all functional regions of the gene and further sequencing of all fragments showing abnormal migration. In 76 patients (90.4%), it was possible to identify molecular alterations leading to the appearance of the disease. Twenty one new mutations were identified, including 13 missense mutations, two nonsense mutations, three splice-site mutations, one frameshift deletion, one frameshift insertion, and one non-frameshift deletion. The approach appears to be very suitable for molecular diagnosis of hemophilia B. PMID- 10094555 TI - A new three allele polymorphism at distal 21q22.3, a region relatively devoid of polymorphic markers. Mutations in brief no. 212. Online. AB - We amplified 305bp of the 3'UT region of COL18A1 from 62 healthy chromosomes from Caucasian individuals. SSCP analysis of these PCR products allowed us to identify 3 alleles which were confirmed through sequencing analysis and ASO. The heterozigosity found for this polymorphic region is 74.2%, and mendelian inheritance was demonstrated in 5 two/three generation families. This polymorphism, located in a region relatively devoid of microsatellites, will be very useful for linkage analysis, particularly for narrowing down candidate regions for genes mapped in this area. PMID- 10094554 TI - A simple multiplex FRAXA, FRAXE, and FRAXF PCR assay convenient for wide screening programs. AB - FRAXA, FRAXE, and FRAXF are folate-sensitive fragile sites originally discovered in patients with X-linked mental retardation. The FMR1 gene, whose first exon includes the FRAXA site on Xq27.3, accounts for 15-20% of all X-linked forms of mental retardation. Loss of expression of FMR2, a gene adjacent to the FRAXE site on Xq28, is correlated with FRAXE expansion in some mild mentally retarded patients. FRAXF is a fragile site whose expression has not been associated with any pathological phenotype. The fragility in all three sites is caused by expansions of CGG repeats adjacent to hypermethylated CpG islands. The prevalence of FRAXA, FRAXE, and FRAXF remains uncertain because of the lack of a simple and cost-effective test allowing wide screening programs. For the same reason, the real phenotype-genotype correlations in FRAXE and FRAXF are uncertain as well. We have developed a rapid multiplex polymerase chain reaction (PCR) assay in which hypermethylated CpG islands adjacent to FRAXA, FRAXE, and FRAXF are displayed. The test is very simple and cost-effective, requires only 30 microl of peripheral blood, and can be used for performing diagnoses, postnatal and prenatal, and for screening large groups of control and mentally retarded males and newborn boys. PMID- 10094556 TI - Newly recognized exons induced by a splicing abnormality from an intronic mutation of the dystrophin gene resulting in Duchenne muscular dystrophy. Mutations in brief no. 213. Online. AB - A boy with the clinical phenotype of Duchenne muscular dystrophy had no detectable deletion or duplication in the dystrophin gene by the routine multiplex PCR method. In mRNA extracted from his muscle biopsy, newly recognized extra-exons of 172 bp and 202 bp were present between exon 25 and 26 suggesting a splicing abnormality. Genomic DNA of the intron 25 including the above insertions were amplified and sequenced. There was one nucleotide substitution of A-to-G at 2 Kb downstream from the 5' end of intron 25 which formed consensus dinucleotide 'GT' motif for 5' splice site resulting in aberrant splicing. This is the first patient who had a mutation at the central part of an intron of the dystrophin gene instead of at the exon-intron border. PMID- 10094557 TI - Detection of protein truncating mutations in exons 1-14 of the APC gene using an in vivo fusion protein assay. Mutations in brief no. 214. Online. AB - About 80% of the mutations identified to date in the Adenomatous Polyposis Coli (APC) gene have been found in the 5' half of the coding sequence, the vast majority of which (>95%) are nonsense or frameshift mutations that result in the loss of the carboxyl terminus of APC protein. Using a stop codon assay in yeast recently developed by others (Ishioka et al., 1997), we have screened the 5' half of the APC gene for mutations in 7 unrelated families affected with Familial Adenomatous Polyposis. The assay relies on the expression of a yeast reporter gene fused in frame to one of 3 contiguous segments of the APC open reading frame. Here we report on the detection by this assay of 5 germline mutations, 4 of which lie upstream of exon 15, where lesions appear to be sometimes difficult to detect by standard methods. PMID- 10094558 TI - Identification of eleven novel tumor-associated E-cadherin mutations. Mutations in brief no. 215. Online. AB - The cell adhesion molecule E-cadherin (CDH1; MIM# 192090) has been implicated in numerous cellular functions, ranging from controlling morphogenesis to suppressing tumor invasion. We describe 11 previously unreported somatic E cadherin mutations in two subgroups of gastric and breast cancer showing markedly reduced homophilic cell-to-cell interactions. Using reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing of the entire coding region 5 mutations were detected in diffuse-type gastric cancer specimens. The sequence alterations include 3 missense mutations affecting exons 3, 10, and 12. Furthermore, two in-frame deletions were identified removing 63 and 9 base pairs from exon 4 and 5, respectively. In invasive Lobular breast cancer 6 E-cadherin mutations were detected after RT-PCR amplification and direct sequencing or using single strand conformation polymorphism (SSCP) analysis followed by sequencing. In addition to two nonsense mutations affecting exon 2, four out-of-frame deletions removing 115 base pairs (entire exon 2), 224 base pairs (entire exon 3), 8 base pairs from exon 12 or 1 base pair from exon 13 were seen. Our report confirms the general principle that in diffuse-type gastric cancer E-cadherin mutations result in structurally altered proteins with possible reduced adhesive functions whereas in invasive lobular breast carcinomas complete loss-of-function mutations are characteristic. PMID- 10094559 TI - Identification of the mutation in the alkaptonuria mouse model. Mutations in brief no. 216. Online. AB - Alkaptonuria (aku), an inborn error of metabolism caused by the loss of homogentisate 1,2-dioxygenase (HGD), has been described in a mouse model created by ethylnitrosourea mutagenesis but the mutation in these mice has not previously been identified. We used RT-PCR to amplify the Hgd cDNA from Hgd(aku)/Hgd(aku) mice. Two products shorter than the wild-type product were amplified. Restriction mapping and DNA sequencing were then used to identify the Hgd(aku) mouse mutation, found to be a single base change in a splice donor consensus sequence, causing exon skipping and frame-shifted products. This base change allowed us to create a non-radioactive genotyping assay for this allele. PMID- 10094560 TI - Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online. AB - Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 families affected by severe hypophosphatasia. Fourteen distinct mutations were found, 3 of which were previously reported in the North American or Japanese populations. Seven of the 11 new mutations were missense mutations (M45L, R119H, G145V, C184Y and H154Y, D289V, E459K), the four others were 2 single nucleotide deletions (544delG and 1172delC), a mutation affecting donor splice site (862 + 5A) and a nonsense mutation (R411X). PMID- 10094561 TI - A novel 8-bp insertion in codon 281 of p53 in a patient with acute lymphoblastic leukaemia and 2 separate leukaemic clones. Mutations in brief no. 219. Online. AB - We report a novel p53 insertion in a case of aggressive acute lymphoblastic leukaemia in a 16 year old male, in which 2 separate leukaemic clones were previously identified by T-cell receptor sigma and immunoglobulin heavy chain gene rearrangement studies. Initial p53 mutation screening of blast cells from 29 patients with acute leukaemia by PCR-denaturing gradient gel electrophoresis showed that 2 had a silent codon 213 polymorphism and only the index case had a somatic mutation identified to be an 8 bp insertion in codon 281 (5'CCGGGGGG-3'). This insertion was associated with the second, more aggressive clone which underwent clonal evolution and became resistant to cytotoxic chemotherapy. With an allele-specific primer in PCR, we were able to demonstrate the presence of this clone as a minority at disease presentation, and in 2 of 3 collections of peripheral blood progenitor cells. PMID- 10094562 TI - Identification of CYP21 mutations, one novel, by single strand conformational polymorphism (SSCP) analysis. Mutations in brief no. 218. Online. AB - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common autosomal recessive disorder (MIM# 201910) due to mutations in the 21-hydroxylase (CYP21) gene (GDB Accession # M12792). Using our protocol for single strand conformational polymorphism (SSCP) analysis, we have identified two mutations not known to exist in the 21-hydroxylase pseudogene (CYP21P). One mutation involving codon 169, TGC to AC appears to be novel. The 46,XX patient carried the codon 169 mutation on her paternal allele and a large gene deletion/conversion event on her maternal allele. This patient had been referred in the immediate neonatal period for the evaluation of genital ambiguity and had developed hyponatremia and hyperkalemia. The second patient presented with premature pubic hair. She carried R356Q on her maternal allele and V281L on her paternal allele. PMID- 10094563 TI - Glycogen storage disease type Ia: four novel mutations (175delGG, R170X, G266V and V338F) identified. Mutations in brief no. 220. Online. AB - Deficient activity of glucose-6-phosphatase (G6Pase) causes glycogen storage disease type Ia (GSD Ia). We analysed the G6Pase gene of 16 GSD Ia patients using single strand conformation polymorphism (SSCP) analysis prior to automated sequencing of exon(s) revealing an aberrant SSCP pattern. In all GSD Ia patients we were able to identify mutations on both alleles of the G6Pase gene, indicating that this method is a reliable procedure to identify mutations. Four novel mutations (175delGG, R170X, G266V and V338F) were identified. PMID- 10094564 TI - Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Mutations in brief no. 221. Online. AB - Here we describe the identification of an italian patient homozygote for the D579G mutation affected by a mild form of Cystic Fibrosis with pancreatic sufficiency, minor lung involvement and marked viscosity of the cervical mucous. The D579G mutation causes an A1868G transition, a substitution of an aspartic acid to a glycine residue, generating an important amino acid change (charged to hydrophobic) in the nucleotide-binding domain (NBD). The mutation was first described by Brancolini et al. (1995) on two pancreatic sufficient CF patients, compound heterozygotes for delta508F. Patients were from Southern Italy (Puglia) as the D579G homozygote one, who is a 30 years old woman from Taranto (Puglia), daughter of second cousins born in Bari (Puglia). The identification of a homozygote D579G patient might confirm that this mutation does correlate with pancreatic sufficiency and a mild pulmonary phenotype. PMID- 10094565 TI - Identification of three novel mutations in the dystrophin gene detected by the heteroduplex/SSCA screening procedure. Mutations in brief no. 222. Online. AB - Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X linked neuromuscular disorders associated with alterations in the dystrophin gene. Analysis of 45 DMD/BMD patients has identified 18 patients with no deletion in the dystrophin gene. Heteroduplex analysis (HD), single strand conformation analysis (SSCA), and subsequent sequencing, identified five mutations and nine polymorphisms. Three out of the 5 mutations (780C>G, 2501-1g-->t, 9812 9813ins9800-9812) are first reported here. Furthermore we compare the relative efficiencies of the two alternatives methods (HD and SSCA) for screening sequence alterations. PMID- 10094566 TI - Human genetic diseases of proteolysis. AB - Although in the past protein stability commonly has been considered an inherent property of a given protein, the truth is far more complex. Elaborate enzymatic systems exist in multiple intracellular compartments to hydrolyze proteins. These systems are capable of providing a sensitive mechanism to regulate protein expression, a mechanism that is complementary to the transcriptional and translational control mechanisms that influence protein synthesis. The power of regulated proteolysis has been well-demonstrated in the abrupt degradation of cyclins that underlies eukaryotic cell cycle progression. Coincidental with the recent rapid gains in understanding proteolysis at a biochemical level, several human diseases have been found to result from disordered proteolysis. This article reviews several examples of human disease resulting from mutations of genes encoding serine proteases, cysteine proteases, and their inhibitors. Examples are also presented of human diseases resulting from disorders in the highly intricate ubiquitin-proteasome pathway of protein degradation. It is certain that many more human diseases will be associated in the future with disorders of proteolysis. PMID- 10094567 TI - Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. AB - Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad). PMID- 10094568 TI - Stress. Advice from mice. PMID- 10094570 TI - Marketing. Welcome matters. PMID- 10094569 TI - What to tell families about drug errors. PMID- 10094571 TI - Retinoids and adipose tissues: metabolism, cell differentiation and gene expression. AB - Vitamin A derivatives (retinoids) play a key role in mammalian development and cell differentiation. Isomers of retinoic acid, the main active metabolite of vitamin A, activate retinoid receptors that act as ligand-dependent transcription factors and affect gene expression. White and brown adipose tissues are major sites of storage of vitamin A derivatives and they play an active role in whole body metabolism of retinoids. Moreover, adipose tissues are targets for the action of retinoic acid. In most cases retinoic acid impairs adipocyte differentiation although its final effects on adipose tissue development depend on retinoic acid concentration, isomers availability and expression of retinoid receptor subtypes in the white or brown adipocyte. Retinoic acid (RA) has a specific effect on brown adipose tissue, because it activates transcription of the gene for uncoupling protein-1, responsible for brown fat thermogenesis. PMID- 10094572 TI - The impact of pregnancy on eating behaviour and aspects of weight concern. AB - BACKGROUND: Excessive weight gain in pregnancy and retention of this weight gain is a well known problem. How women with a history of dietary restraint adjust to being pregnant, is of interest, as pregnancy epitomises many of the factors known to trigger overeating. OBJECTIVE: To examine the impact of pregnancy on eating behaviour and weight concern and the role of dietary restraint in mediating any changes. METHODS: Primigravid (n = 50) and non-pregnant nulliparous (n = 50) women completed a questionnaire to describe their profile characteristics, current health behaviours, eating behaviour and weight concern. The pregnant women completed additional retrospective items relating to these factors for the period prior to their pregnancy. RESULTS: The pregnant women reported eating more, showed lower levels of dietary restraint, were less dissatisfied with their body shape and showed higher eating self efficacy than non-pregnant women. Compared to the months prior to their pregnancy, the pregnant women rated themselves as less restrained in their eating behaviour and nearly half stated that they were eating more. In terms of the impact of pre pregnancy levels of dietary restraint, the results showed a significant interaction between restrained eating and pregnancy for both hunger and eating self efficacy. The results showed that the restrained eaters, when pregnant, rated themselves as significantly less hungry and reported less difficulty controlling their food intake than the non pregnant restrained eaters but showed comparable hunger and eating control to the other groups. The results showed no effect of restrained eating on weight change. CONCLUSION: The results suggest that pregnancy both legitimises increased food intake and removes any previous intentions to eat less. PMID- 10094573 TI - Factors associated with obesity in South Asian, Afro-Caribbean and European women. AB - OBJECTIVE: To investigate correlates of body mass index (BMI) and other anthropometric measurements in South Asian, Afro-Caribbean and European women in the UK. SUBJECTS: 291 South Asian, 303 Afro-Caribbean, and 559 European women aged 40-69y in West London, UK. DESIGN: Cross-sectional survey. MAIN OUTCOME MEASURES: BMI, waist-to-height ratio (WHt), and skinfold thicknesses. RESULTS: Compared with European women, South Asian and Afro-Caribbean women were more like to be obese (odds ratios (OR) 1.83 and 3.01, respectively), but less likely to rate themselves as overweight (BMI-adjusted OR 0.19 and 0.34, respectively). The proportion of women who walked at least 2.5 km/d, excluding activity at work, was lower in South Asians (22%) than in Europeans (44%) or Afro-Caribbeans (40%). Among employed women, the proportion who were active at work was higher in South Asians (63%) and Afro-Caribbeans (70%) than in Europeans (49%). In Europeans, obesity was inversely associated with social class, education, smoking, alcohol intake, and distance walked, and positively associated with time spent watching television. Adjustment for alcohol intake, smoking, education and transport, physical activity explained over 80% of the difference in BMI between South Asians and Europeans, but not the difference between Afro-Caribbeans and Europeans. CONCLUSION: The factor that may be most amenable to intervention in South Asian women is low physical activity outside the workplace. The high prevalence of obesity in Afro-Caribbean women, however, is not accounted for by any behavioural factors measured in this study, and the reasons for high rates of obesity in this group remain to be established. PMID- 10094574 TI - Postprandial thermogenesis and alimentary sensory stimulation in human subjects. AB - OBJECTIVE: To study the role of alimentary sensory stimulation on the thermic effect of food. SUBJECTS: Nine male healthy volunteers (age: 20-34y, body mass index (BMI): 17.4-25.3kg/m2). DESIGN AND MEASUREMENTS: Four experimental situations were investigated on different days. Subjects: 1) ate a four course meal containing 2582kJ (meal), 2) saw, smelt and tasted the same courses (alimentary sensory stimulation), 3) saw, smelt and tasted non-alimentary substances (non-alimentary sensory stimulation), 4) received directly into the stomach the previous meal (tube feeding). Energy expenditure (EE) was measured over a 20 min rest period, then for 110 min. RESULTS: The changes over midday rest EE were: meal = +12.0%; alimentary sensory stimulation = +3.2%; non alimentary sensory stimulation= -2.6%; tube feeding = +5.7%. The increase in EE was higher after the meal than after either alimentary sensory stimulation (P < 0.01) or tube feeding (P < 0.01); the increases after the last two were, in turn, greater than after non-alimentary sensory stimulation (P < 0.05). Only after alimentary sensory stimulation, was the increment in EE significantly correlated with BMI (r= -0.700; P < 0.05). CONCLUSIONS: The early phase of postprandial thermogenesis therefore depends on both sensory and metabolic events. Furthermore, the sensory component was more pronounced in the lean subjects. PMID- 10094575 TI - Lipoprotein subfractions in women athletes: effects of age, visceral obesity and aerobic fitness. AB - OBJECTIVE: To examine whether lipoprotein subfractions are associated with age related changes in visceral obesity and maximal aerobic fitness in women athletes. SUBJECTS AND MEASUREMENTS: Body composition was measured using dual energy X-ray absorptiometry (DEXA) and a single slice computed tomography (CT) scan of the abdomen of 39 women athletes (age: 18-69y, body mass index (BMI): 19 24 kg/m2). Lipoprotein lipids were measured in plasma drawn after a 12 h fast using nuclear magnetic resonance (NMR) spectroscopy, which quantifies lipoprotein subfractions by the spectroscopic differences exhibited by lipoprotein particles of various sizes. RESULTS: Total cholesterol (r=0.42; P<0.01) and low-density lipoprotein cholesterol (LDL-C) (r=0.32; P=0.05) correlated positively with age, even after adjustment for age-related decreases in maximal aerobic fitness (VO2 max) and increases in the intra-abdominal fat area. There were no relationships between any of the lipoprotein subfractions or sizes with age. Very-low-density lipoprotein (VLDL) size and VLDL2-TG correlated with total fat mass (r = 0.40 and r= -0.43, respectively; P < 0.05) and with intra-abdominal fat area (r = -0.47 and r = 0.43, respectively; P < 0.01), but not independently of total fat mass. Total cholesterol and LDL-C were negatively related to maximal aerobic fitness (VO2max) (r = -0.37 and r = -0.33, respectively; P < 0.05), while low-density lipoprotein (LDL) size was positively related to VO2max (r = 0.35, P < 0.05). CONCLUSIONS: These results suggest that age-associated changes in lipoprotein concentrations are probably, in part, due to primary aging, rather than age related changes in abdominal obesity and aerobic fitness. PMID- 10094576 TI - Characterization of cytochrome P450 and glutathione S-transferase activity and expression in male and female ob/ob mice. AB - OBJECTIVE: To characterize the effect(s) of gender, age (glycemic status) and obese state, on hepatic biotransformation activities, expression of cytochrome P450 (CYP450) mRNAs and glutathione transferase activity in the ob/ob mouse. DESIGN: Male and female, ob/ob or ob/+ mice were killed at 3-4 months or 7-8 months of age. Hepatic microsomes, cytosol and RNA were prepared from each animal. ANIMALS: Male and female ob/ob and ob/+ mice, 3-4 or 7-8 months of age. MEASUREMENTS: CYP450 form-specific activities of CYP1A1/1A2, CYP3A and CYP2B were estimated by determining the 0-dealkylation of alkoxyresorufin substrates (ethoxy EROD, benzoxy-BROD and pentoxy-resorufin, PROD, respectively). CYP2E1-dependent, 4-nitrophenol hydroxylase (PNP-OH) and CYP3A-dependent erythromycin N-demethylase (ERY-DM) were also measured in hepatic microsomes. CYP1A2, CYP2E1 and CYP3A protein in microsomal fractions was determined by ELISA. Glutathione transferase activity (GST) was determined in hepatic cytosol and CYP1A2 and CYP2E1 mRNA was estimated by Northern blot analysis. RESULTS: Female mice, regardless of glycemic status, showed an obesity enhanced level of CYP2E1-dependent PNP-OH activity and CYP2E1 protein as shown by ELISA. These increases were observed to be independent of the diabetic state, since 7-8 month-old mice had blood glucose levels identical to lean mice. The mRNA level of CYP2E1 in female mice also exhibited age-and obesity-influenced decreases in expression. No significant differences in CYP2E1 activity or expression were observed in male mice. CYP3A-dependent ERY-DM activity was significantly higher in young males, regardless of phenotype. CYP3A and CYP2B activities did not differ among any animals; however, CYP1A activity, while depressed in obese animals of both genders, was significantly different in old animals. Glutathione S-transferase activity was lower in obese male mice, whereas no difference was observed between lean and obese females CONCLUSION: This study supports earlier observations in man and rats that the obese state produces alterations in the expression of important oxidation and conjugation pathways. In addition, this report more thoroughly examines the role of gender and glycemic status on biotransformation activities in the ob/ob mouse as demonstrated by increased CYP2E1 protein and CYP2E1-dependent activity in obese females, decreased CYP1A2 protein and CYP1A2-dependent activity in obese animals, and obesity had no effect of glutathione transferase in female mice, in contrast with the previously reported obesity-dependent decrease of this activity in male mice. PMID- 10094577 TI - The relationship between obesity and idiopathic intracranial hypertension. AB - OBJECTIVES: To evaluate the association between obesity and idiopathic intracranial hypertension (IIH) and establish whether there is a relationship with visual outcome. To calculate the prevalence and degree of obesity in a group of patients with IIH. METHODS: 34 patients (31 female and 3 male) were recruited between 1993 - 1997 with a diagnosis of IIH. Assessment included visual acuity, visual field assessment (Humphrey automated and Goldmann manual perimetry), fundus assessment and measurement of body mass index (BMI). Obesity was defined as a BMI of 30 kg/m2. RESULTS: 70.5% of patients were obese. The relative risk for obesity and IIH was significant at 8 (95%CI: 2,29). This increased to 17 (95%CI: 5,62) for obese females aged 16 to 24 years and 10 (95%CI: 3,35.5) for obese females aged 25 to 34 years. Morbid obesity (BMI > 40) was significantly associated with poor visual outcome. Serial obesity measures showed generally little change in weight over time and there was no correlation between weight change and visual improvement. CONCLUSIONS: This study has documented a relationship between obesity and IIH. A high degree of obesity was associated with a poor visual function and identified as a risk factor for poor outcome. Obesity may be an aetiological factor in this condition although it is unlikely to be the sole cause but more probably a precipitating factor. Weight loss is recommended although failure to lose weight is common. Any weight reduction programme must therefore be actively encouraged and monitored. PMID- 10094578 TI - Relation of plasma leptin to lipoproteins in overweight children undergoing weight reduction. AB - BACKGROUND: In obese children, plasma leptin is elevated and correlates with the body mass index (BMI). In obese adults, plasma leptin decreases during weight reduction. Since the leptin system changes dynamically in puberty, we asked whether weight reduction in obese adolescents has similar consequences for plasma leptin as in overweight adults. In plasma, a portion of leptin is bound to several as yet uncharacterised proteins. We therefore studied the possible association of leptin with plasma lipoproteins. SUBJECTS AND METHODS: We measured plasma leptin, lipoprotein cholesterol and apolipoproteins (apo) A-I and B in 34 obese children (age 12.5+/-1.9 y, relative BMI 165.0+/-28.1%) before and after three weeks of weight reduction in a dietary camp. Lipoprotein binding of endogenous and exogenously radiolabelled leptin was studied by preparative ultracentrifugation. RESULTS: Plasma leptin was higher in obese children than in normal weight controls and fell from 16.5+/-9.8 ng/ml to 10.0+/-8.6 ng/ml after weight reduction (P < 0.001). In multivariate regression, relative BMI and apoA-I were significant predictors of baseline leptin and accounted for 38% (P = 0.003) and 15% (P = 0.006) of the variance of baseline leptin concentrations in obese children. Only the difference in plasma high-density lipoprotein (HDL) cholesterol independently predicted the change of plasma leptin that was associated with weight reduction, explaining 29% of the variance of leptin changes (P = 0.0032). A substantial portion of both endogenous and exogenously labelled leptin was recovered with HDL isolated by ultracentrifugation. CONCLUSIONS: We conclude that plasma leptin decreases in overweight children undergoing short term weight reduction. In obese children, plasma apoA-I and HDL cholesterol are independent predictors of leptin concentrations during weight loss, respectively. In addition, HDLs transport a variable portion of leptin in the circulation. PMID- 10094579 TI - Obesity is associated with increased myocardial oxidative stress. AB - OBJECTIVE: To determine: 1) whether obesity predisposes the myocardium to oxidative stress as evidenced by higher tissue levels of myocardial lipid peroxidation, and 2) what cellular mechanisms are responsible for this predisposition. DESIGN: Comparative, descriptive study of the myocardial tissue of lean and obese Fatty Zucker animals. ANIMALS: 12 month old lean (-/fa; n = 6; mean body weight = 590 g) and obese (fa/fa; na = 7; mean body weight= 882 g) male Fatty Zucker rats. MEASUREMENTS: Basal lipid peroxidation (assessed using thiobarbituric reactive acid substances (TBARS) and cumene hydroperoxide equivalents), oxidative and antioxidant enzyme activities (citrate synthase (CS), superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), thiol content, heat shock protein expression (HSP72/73) and TBARS concentrations following an iron-mediated challenge in vitro. RESULTS: Compared to lean, lipid peroxidation was greater (P < 0.05) in the left ventricle (LV) from obese rats as indicated by higher levels of lipid hydroperoxides (mean = 11.48 vs 13.7 cumene hydroperoxide equivalents (CHPE)/mg lipid) and TBARS (mean = 11.1 vs 13.9 nMol/mg lipid.). The activity of the manganese isoform of superoxide dismutase in the LV was higher (P < 0.05) in obese animals, compared to controls (mean = 135 vs 117 U/mg protein). In contrast, LV catalase and glutathione peroxidase activities did not differ (P > 0.05) between groups. Also, LV levels of HSP 72 (inducible) and 73 (constitutive) did not differ (P > 0.05)( between lean and obese animals. Following an iron-stimulated oxidative challenge in vitro, TBARS concentration was significantly greater (P < 0.05) in LV of obese rats compared to the lean (mean = 12.7 vs 16.7 nMol/mg lipid). CONCLUSIONS: These results support the notion that obesity predisposes the myocardium to oxidative stress. However, the postulate that obesity is associated with elevated myocardial antioxidant enzyme activities and HSPs was only partially supported by these findings. PMID- 10094580 TI - Perception of weight status and dieting behaviour in Dutch men and women. AB - OBJECTIVE: To study the perception of weight status, the accuracy of self assessment of weight status and weight control practices relative to the degree of adiposity in Dutch men and women. DESIGN: A cross-sectional study. SUBJECTS: 2155 men and 2446 women, aged 20-65y, of mostly caucasian origin, non-diabetic, not pregnant or with cancer. MEASUREMENTS: Body weight, height, waist and hip, total cholesterol, high density lipoprotein (HDL) cholesterol, blood pressure, self-administered questionnaire (including questions concerning demographic variables), weight loss practices, dietary intake, participation in sport as part of Dutch Monitoring Project on Risk Factors for Chronic Diseases (MORGEN). RESULTS: In the study population, 53% of men and 39% of women were overweight or obese. An association was shown between degree of adiposity and participation in sport for both men and women, and dietary fat intake in men. Of the subjects studied 56% of men and 52% of women described their weight as appropriate. A degree of inaccuracy in the estimation of relative body weight was observed. While dieting was prevalent, particularly among women, there was a lack of weight control action on the part of many overweight or obese individuals. This effect was most marked in men. Body Mass Index (BMI) was the strongest determinant of weight perception and dieting behaviours with some effect of educational level in men. Physical activity was not widely used as a method of weight control. CONCLUSION: These results point to a need for regular assessment of an individual's relative weight and health risk, gender specific obesity treatments and prevention strategies, and an emphasis in treatment and prevention of obesity on physical activity. PMID- 10094581 TI - Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. AB - OBJECTIVE: To investigate the effects of leptin and the combination of insulin and leptin on glucose metabolism in incubated rat soleus muscle. ANIMALS: Male lean albino rats (50-70 g) of the Wistar strain were used in all experiments. MEASUREMENTS: 2-Deoxy-D-[3H]-glucose (2-DG) uptake, glycogen synthesis, lactate synthesis, glucose and pyruvate decarboxylation. RESULTS: Leptin (1, 10 and 100 nM), increased 2-Deoxyglucose uptake from 4.07+/-0.23 micromol/h(-1)/g(-1) (basal) to 5.88+/-0.29 micromol/h(-1)/g(-1) (100 nM) (P < 0.05); however, leptin did not potentiate the effect of either physiological (100 microU/ml) or supra physiological (10000 microU/ml) insulin concentrations on glucose uptake. Glycogen synthesis rose almost 2-fold in the presence of supra-physiological leptin concentrations (100 nM). The combination of insulin and leptin did not present any additional effect on glycogen synthesis beyond that caused by insulin. Compared to the control group, the decarboxylation of [U-14C] D-glucose increased 75%, 246% and 304% (P < 0.05) in the presence of 1, 10 and 100nM leptin, respectively. When leptin (100 nM) was combined with insulin in the incubation medium, the 14CO2 production rose almost 4-fold (397%) (P < 0.05) and more than 5-fold (527%) (P < 0.05) for the 100 microU/ml and 10000 microU/ml insulin concentrations, respectively. In the presence of leptin (100 nM), the decarboxylation of [1-14C]- and [2-14C]-pyruvate in incubated muscles rose 89% and 49%, respectively, indicating that both pyruvate dehydrogenase and Krebs cycle are activated by leptin. CONCLUSION: These data demonstrate that, in soleus muscle, leptin per se exerts a direct and acute insulin-like effect, stimulating glucose uptake, glycogen synthesis, lactate formation and glucose oxidation. PMID- 10094582 TI - Leptin resistance in a polygenic, hyperleptinemic animal model of obesity and NIDDM: Psammomys obesus. AB - OBJECTIVE: To investigate the effects of leptin administration to Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes mellitus. DESIGN: Longitudinal intervention study utilising three separate leptin treatment protocols lasting 7-14 d. MEASUREMENTS: Body weight and food intake were measured daily, body fat and muscle content were estimated by carcass analysis on completion of the study. Blood glucose, plasma insulin, leptin, triglycerides and cholesterol were measured at baseline and twice each week during the study. RESULTS: Relatively high doses of leptin were required to significantly reduce food intake and body fat content in lean Psammomys obesus, but had no discernible effect on their obese littermates. CONCLUSION: As a species, Psammomys obesus appear to be relatively insensitive to the effects of leptin administration, compared with other rodents. Obese Psammomys obesus are leptin resistant relative to their lean littermates. PMID- 10094583 TI - Predictive value of waist-to-hip ratio on cardiovascular risk events. AB - BACKGROUND: A central distribution of adipose tissue is frequently associated with cardiovascular disease (CVD) and its risk factors. METHODS: Clinical usefulness of waist-to-hip ratio (WHR) for predicting the risk of cardiovascular events, estimated with models based on data from the Framingham and Prospective Cardiovascular Munster (PROCAM) studies was evaluated. SUBJECTS: These were 552 men and 160 women, asymptomatic and at risk for CVD, aged 30-74 y, recruited from an ongoing risk factor screening program conducted at worksites. RESULTS: Abdominal fatness was a strong predictor of cardiovascular complications in subjects whose WHR was in the top quintile (> 0.98 for men and > 0.91 for women). The estimated percentage rate of coronary heart disease (CHD, P <0.01) and death (P < 0.01), myocardial infarction (P < 0.01), stroke (P < 0.01), total CVD (P < 0.001) and death (P < 0.01) increased with increasing quintile of WHR in men and women. In the highest WHR, the number of subjects exceeding a 15% risk of developing a coronary event over the next 10 y was more than two-fold greater (odds ratio (OR) 2.60 (confidence intervals (CI) 1.09-6.54) than in the lowest WHR quintiles. Similar six-year myocardial infarction (MI) risks at each quintile of WHR were observed in men in both Framingham and PROCAM models. In the overall population, CHD estimates increased with increasing quintiles of WHR with the Framingham model and an adapted model for estimating probabilities of disease in the French population of the Prevention Cardiovasculaire en Medecine du Travail (PCV-METRA) group. CONCLUSION: Abdominal deposition of fat assessed by WHR may be of strong clinical value for predicting high risk of cardiovascular events. PMID- 10094584 TI - Anti-obesity action of oolong tea. AB - OBJECTIVE: Oolong tea is traditionally reported to have anti-obesity and hypolipidaemic effects. The present study was performed to clarify whether oolong tea prevented obesity induced in mice by the oral administration of a high-fat diet for 10 weeks. DESIGN: High-fat diet-induced obese mice were treated with oolong tea for 10 weeks. The effects of various active fractions isolated from oolong tea on noradrenaline-induced lipolysis were examined with isolated fat cells and a cell-free system consisting of lipid droplets and hormone-sensitive lipase (HSL). RESULTS: The mean food consumption was not significantly different between high-fat diet-treated mice and high-fat plus oolong tea diet-treated mice. Oolong tea prevented the obesity and fatty liver induced by a high-fat diet. A water extract of oolong tea enhanced noradrenaline-induced lipolysis, and the active substance was identified as caffeine. Caffeine enhanced noradrenaline induced lipolysis in fat cells without a concomitant increase in HSL activity and also accelerated the hormone-induced lipolysis in a cell-free system consisting of lipid droplets and HSL, but not in the cell-free system with sonicated lipid droplets and HSL. Oolong tea extract inhibited pancreatic lipase activity. CONCLUSION: It was demonstrated that the anti-obesity effects of oolong tea in high-fat diet-treated mice might be due partly to the enhancing effect of caffeine isolated from oolong tea on noradrenaline-induced lipolysis in adipose tissue, and to the inhibitory action of some other substance in oolong tea on pancreatic lipase activity. Caffeine was found to enhance lipolysis through acting on lipid droplets but not on HSL. The results suggest that oolong tea may be an effective crude drug for the treatment of obesity and fatty liver caused by a high-fat diet. PMID- 10094585 TI - Studying clinical, humanistic, and economic outcomes: projects from ASHP's Competitive Edge program. PMID- 10094586 TI - Thyroid autonomy. Proceedings of the annual meeting of the German Society of Endocrinology. Ballenstedt, November 27-28, 1998. PMID- 10094587 TI - [Proceedings and abstracts of the XXIV National Congress of the Spanish Association for the Study of the Liver. Madrid, Spain, 18-20 February 1999]. PMID- 10094588 TI - [The 80th anniversary of the journal Likars'ka sprava--Vrachebnoe delo]. PMID- 10094589 TI - Immune responses to inflammation and trauma: a physical training module. Toronto, Ontario, Canada. July 10-11, 1997. PMID- 10094590 TI - Commentary on the case of the meat inspector asked for advice on a roundworm infection. PMID- 10094591 TI - More ethical challenges: commentary on Fischman and Johanson's ethical and practical issues involved in behavioral pharmacology research that administers drug of abuse to human volunteers. PMID- 10094592 TI - [The Physician and Criminal Law. Proceedings of the 21st Symposium for Jurists and Physicians. Berlin, Germany, 13-14 February 1998]. PMID- 10094593 TI - Proceedings of the Food Animal Biotechnology (FAB) Center Symposium on Transgenic Animals and Food Production. St. Paul, Minnesota, USA. June 26, 1998. PMID- 10094594 TI - Guess what? Tungiasis. PMID- 10094596 TI - Guess what? Lichen amyloidosus. PMID- 10094595 TI - Guess what? Wells' syndrome. PMID- 10094597 TI - Efficient synthesis of N-4 alkyl derivatives of 2',3'-dideoxycytidine (ddC). AB - The C-4 triisopropylphenylsulfonyl (TPS) group of the 2,3-dideoxyuridine derivative 2 is readily displaced in situ by nitrogen nucleophiles forming N-4 substituted ddC in acceptable yields. PMID- 10094598 TI - Project 1: longitudinal risk cohort study on the onset, course, prevalence and prevention of illegal drug abuse. PMID- 10094599 TI - Projects 2 and 3: vulnerability and protective factors in early developmental stages of substance use disorders. PMID- 10094600 TI - Project 4: substance use, abuse and dependence among the adult population in a rural and urban region of northern Germany. PMID- 10094601 TI - Project 5: triggering and maintenance factors of remitting from alcohol dependence without formal help. PMID- 10094602 TI - Proceedings of the XIth International Workshop on Development and Function of the Reproductive Organs--Genetic and Endocrine Basis of Gonadal Failure. Amsterdam, the Netherlands, April 16-17, 1998. PMID- 10094603 TI - Minimally invasive surgery: how goes the revolution? PMID- 10094604 TI - Molecular staging of colorectal cancer: a step forward. PMID- 10094605 TI - Early trypsinogen activation in acute pancreatitis. PMID- 10094606 TI - Stress management. PMID- 10094607 TI - Induction and enhancement of stress proteins in a trichloroethylene-degrading methanotrophic bacterium, Methylocystis sp. M. AB - The responses of the trichloroethylene-degrading bacterium Methylocystis sp. M to six different water-pollutants, carbon starvation, and temperature-shock (heat and cold) were examined using 2-dimensional gel electrophoresis. Twenty-eight polypeptides were induced, and these stress-induced proteins were classified into three groups. Some of the chemically induced proteins were the same as those induced by carbon starvation and temperature-shock. Two of the polypeptides were induced by trichloroethylene. Trichloroethylene-stress protein synthesis required 1-2 h at a concentration of trichloroethylene that had no effect on growth. Furthermore, 25 stress-enhanced polypeptides were observed, and one of these was enhanced by trichloroethylene. Based on these results, we discuss applications of chemical-stress induction of proteins to establish effective bioremediation and bioassay by methanotrophs. PMID- 10094608 TI - Bioimpedance measurement of extracellular water. PMID- 10094609 TI - Ca2+ dependence of mechanical injury to lung capillaries. PMID- 10094610 TI - GA strategy for variable selection in QSAR studies: application of GA-based region selection to a 3D-QSAR study of acetylcholinesterase inhibitors. AB - Comparative molecular field analysis (CoMFA) with partial least squares (PLS) is one of the most frequently used tools in three-dimensional quantitative structure activity relationships (3D-QSAR) studies. Although many successful CoMFA applications have proved the value of this approach, there are some problems in its proper application. Especially, the inability of PLS to handle the low signal to-noise ratio (sample-to-variable ratio) has attracted much attention from QSAR researchers as an exciting research target, and several variable selection methods have been proposed. More recently, we have developed a novel variable selection method for CoMFA modeling (GARGS: genetic algorithm-based region selection), and its utility has been demonstrated in the previous paper (Kimura, T., et al. J. Chem. Inf. Comput. Sci. 1998, 38, 276-282). The purpose of this study is to evaluate whether GARGS can pinpoint known molecular interactions in 3D space. We have used a published set of acetylcholinesterase (AChE) inhibitors as a test example. By applying GARGS to a data set of AChE inhibitors, several improved models with high internal prediction and low number of field variables were obtained. External validation was performed to select a final model among them. The coefficient contour maps of the final GARGS model were compared with the properties of the active site in AChE and the consistency between them was evaluated. PMID- 10094611 TI - Binary quantitative structure-activity relationship (QSAR) analysis of estrogen receptor ligands. AB - The use of high throughput screening (HTS) to identify lead compounds has greatly challenged conventional quantitative structure-activity relationship (QSAR) techniques that typically correlate structural variations in similar compounds with continuous changes in biological activity. A new QSAR-like methodology that can correlate less quantitative assay data (i.e., "active" versus "inactive"), as initially generated by HTS, has been introduced. In the present study, we have, for the first time, applied this approach to a drug discovery problem; that is, the study of the estrogen receptor ligands. The binding affinities of 463 estrogen analogues were transformed into a binary data format, and a predictive binary QSAR model was derived using 410 estrogen analogues as a training set. The model was applied to predict the activity of 53 estrogen analogues not included in the training set. An overall accuracy of 94% was obtained. PMID- 10094612 TI - Design of libraries to explore receptor sites. AB - Despite rapid progress in both combinatorial chemistry and high-throughput screening, the number of molecules that could potentially be made and tested for biological activity still far exceeds the capacity for synthesis or screening. Consequently, it is potentially valuable to select and synthesize sublibraries that contain rationally selected subsets. When the structure of the protein receptor site is known, this may be used to impose restrictions of the selection on molecules. This paper describes a method for rapid analysis of large virtual libraries to select a subset that can exhibit at least one conformer which wil interact strongly with the receptor and fit within the receptor site. PMID- 10094613 TI - Universal rotavirus immunizations: should rotavirus vaccine be recommended for universal use? An opposing view. PMID- 10094614 TI - Complexes of salicylaldehyde acylhydrazones: cytotoxicity, QSAR and crystal structure of the sterically hindered t-butyl dimer. AB - A series of acylhydrazones of salicylaldehyde and their transition metal complexes, predominantly copper(II), have been prepared and characterized. The crystal structure of the Cu(II) complex of the sterically hindered t-butyl derivative contains a phenolato bridged dimer with the ligand coordinated as a tridentate moiety. QSAR analyses of the cytotoxicity of the chelators and their Cu(II) complexes reveals that solubility is the dominant factor for activity. Compounds display a maximum with respect to lipophilicity, allowing optimization of the bioactivity for both the ligands and their complexes. Copper complexes are significantly more cytotoxic than the metal-free ligands and complexes of other metals: Cu > Ni > Zn = Mn > Fe = Cr > Cr > Co. PMID- 10094615 TI - AIDS vaccine trial. PMID- 10094616 TI - Proceedings of the 8th International Symposium on Subtypes of Muscarinic Receptors. Danvers, Massachusetts, USA. August 25-29, 1998. PMID- 10094617 TI - New tools in an old trade: CS1 pilus morphogenesis. AB - CS1 pili serve as the prototype for a large class of serologically distinct pili associated with enterotoxigenic Escherichia coli that cause diarrhoea in humans. The four genes essential for CS1 pilus morphogenesis, cooB, A, C and D, are arranged in an operon and encode structural and assembly proteins unlike those of other pilus systems commonly associated with Gram-negative bacteria. CS1 pili are composed primarily of the major pilin subunit, CooA, which determines the serological type of the pilus. The major pilin subunit is assembled into pili by the proteins CooB, CooC and CooD. CooD is both a minor component found at the pilus tip and an essential assembly protein, whereas CooC is an outer membrane protein thought to be involved in pilin transport. CooB is a novel periplasmic chaperone-like protein that forms intermolecular complexes with and stabilizes the major and minor pilins. Unlike other pilin chaperones, CooB also stabilizes the outer membrane component of the assembly system, CooC. The proteins of CS1 pili have no significant homology to those of the well-characterized Pap (pyelonephritis-associated) pili and related systems, although most of the features of pilus morphogenesis are similar. Therefore, these appear to be among the rare cases of convergent evolution. Thus, for CS1 pili, enterotoxigenic E. coli use new protein 'tools' in the old 'trade' of forming functional pili. PMID- 10094618 TI - Fatal attraction of mammalian cells to Legionella pneumophila. AB - Legionella pneumophila is a protozoan parasite that causes Legionnaires' disease. Its ability to do so is dependent on its capacity to replicate intracellularly within a phagosome that is not trafficked through the endosomal-lysosomal pathway and is surrounded by the rough endoplasmic reticulum. Within this unique niche, the bacterium undergoes alterations in gene expression. In addition, many virulence-related phenotypes that are induced in vitro by starvation are expressed intracellularly as the bacteria exit the logarithmic growth phase. (p)ppGpp appears to signal expression of the virulence-related genes in L. pneumophila upon starvation. This growth phase-dependent phenotypical transition is concomitant with lysis of the host cell, in which both necrosis and apoptosis seem to play roles. Many genetic loci that are required for intracellular replication within mammalian and protozoan cells have been identified, and the majority of them are novel. Two secretion systems have been identified, one of which may be distantly related to type IV secretion systems. The other is a type II secretion system similar to the PilBCD piliation system of Pseudomonas aeruginosa. PMID- 10094619 TI - Differential roles of homologous recombination pathways in Neisseria gonorrhoeae pilin antigenic variation, DNA transformation and DNA repair. AB - Neisseria gonorrhoeae (Gc) pili undergo antigenic variation when the amino acid sequence of the pilin protein is changed, aiding in immune avoidance and altering pilus expression. Pilin antigenic variation occurs by RecA-dependent unidirectional transfer of DNA sequences from a silent pilin locus to the expressed pilin gene through high-frequency recombination events that occur at limited regions of homology. We show that the Gc recQ and recO genes are essential for pilin antigenic and phase variation and DNA repair but are not involved in natural DNA transformation. This suggests that a RecF-like pathway of recombination exists in Gc. In addition, mutations in the Gc recB, recC or recD genes revealed that a Gc RecBCD pathway also exists and is involved in DNA transformation and DNA repair but not in pilin antigenic variation. PMID- 10094620 TI - Decorin-binding adhesins from Borrelia burgdorferi. AB - Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia burgdorferi. Ticks deposit B. burgdorferi into the dermis of the host, where they eventually become associated with collagen fibres. We demonstrated previously that B. burgdorferi is unable to bind collagen, but can bind the collagen associated proteoglycan decorin and expresses decorin-binding proteins (Dbps). We have now cloned and sequenced two genes encoding the proteins, DbpA and DbpB, which have a similar structure, as revealed by circular dichroism (CD) spectroscopy of recombinant proteins. Competition experiments revealed a difference in binding specificity between DbpA and DbpB. Western blot analysis of proteinase K-treated intact B. burgdorferi and transmission electron microscopy studies using antibodies raised against recombinant Dbps demonstrated that these proteins are surface exposed. DbpA effectively inhibits the attachment of B. burgdorferi to a decorin substrate, whereas DbpB had a marginal effect, suggesting a difference in substrate specificity between the two Dbps. Polystyrene beads coated with DbpA adhered to a decorin-containing extracellular matrix produced by cultured skin fibroblasts, whereas beads coated with OspC did not. Taken together, these data suggest that Dbps are adhesins of the MSCRAMM (microbial surface component-recognizing adhesive matrix molecule) family, which mediate B. burgdorferi attachment to the extracellular matrix of the host. PMID- 10094621 TI - Role of fimbriae-mediated adherence for neutrophil migration across Escherichia coli-infected epithelial cell layers. AB - This study examined the role of P and type 1 fimbriae for neutrophil migration across Escherichia coli-infected uroepithelial cell layers in vitro and for neutrophil recruitment to the urinary tract in vivo. Recombinant E. coli K-12 strains differing in P or type 1 fimbrial expression were used to infect confluent epithelial layers on the underside of transwell inserts. Neutrophils were added to the upper well, and their passage across the epithelial cell layers was quantified. Infection with the P- and type 1-fimbriated recombinant E. coli strains stimulated neutrophil migration to the same extent as a fully virulent clinical E. coli isolate, but the isogenic non-fimbriated vector control strains had no stimulatory effect. The enhancement of neutrophil migration was adhesion dependent; it was inhibited by soluble receptor analogues blocking the binding of P fimbriae to the globoseries of glycosphingolipids or of type 1 fimbriae to mannosylated glycoprotein receptors. P- and type 1-fimbriated E. coli triggered higher interleukin (IL) 8 secretion and expression of functional IL-8 receptors than non-fimbriated controls, and the increase in neutrophil migration across infected cell layers was inhibited by anti-IL-8 antibodies. In a mouse infection model, P- or type 1-fimbriated E. coli stimulated higher chemokine (MIP-2) and neutrophil responses than the non-fimbriated vector controls. The results demonstrated that transformation with the pap or fim DNA sequences is sufficient to convert an E. coli K-12 strain to a host response inducer, and that fimbriation enhances neutrophil recruitment in vitro and in vivo. Epithelial chemokine production provides a molecular link between the fimbriated bacteria that adhere to epithelial cells and tissue inflammation. PMID- 10094622 TI - The S box regulon: a new global transcription termination control system for methionine and cysteine biosynthesis genes in gram-positive bacteria. AB - The molecular mechanisms for regulation of the genes involved in the biosynthesis of methionine and cysteine are poorly characterized in Bacillus subtilis. Analyses of the recently completed B. subtilis genome revealed 11 copies of a highly conserved motif. In all cases, this motif was located in the leader region of putative transcriptional units, upstream of coding sequences that included genes involved in methionine or cysteine biosynthesis. Additional copies were identified in Clostridium acetobutylicum and Staphylococcus aureus, indicating conservation in other Gram-positive genera. The motif includes an element resembling an intrinsic transcriptional terminator, suggesting that regulation might be controlled at the level of premature termination of transcription. The 5' portion of all of the leaders could fold into a conserved complex structure. Analysis of the yitJ gene, which is homologous to Escherichia coli metH and metF, revealed that expression was induced by starvation for methionine and that induction was independent of the promoter and dependent on the leader region terminator. Mutation of conserved primary sequence and structural elements supported a model in which the 5' portion of the leader forms an anti antiterminator structure, which sequesters sequences required for the formation of an antiterminator, which, in turn, sequesters sequences required for the formation of the terminator; the anti-antiterminator is postulated to be stabilized by the binding of some unknown factor when methionine is available. This set of genes is proposed to form a new regulon controlled by a global termination control system, which we designate the S box system, as most of the genes are involved in sulphur metabolism and biosynthesis of methionine and cysteine. PMID- 10094623 TI - Intracellular expression of the ADP-ribosyltransferase domain of Pseudomonas exoenzyme S is cytotoxic to eukaryotic cells. AB - Exoenzyme S of Pseudomonas aeruginosa is an ADP-ribosyltransferase, which is secreted via a type III-dependent secretion mechanism and has been demonstrated to exert cytotoxic effects on eukaryotic cells. Alignment studies predict that the amino-terminus of exoenzyme S has limited primary amino acid homology with the YopE cytotoxin of Yersinia, while biochemical studies have localized the FAS dependent ADP-ribosyltransferase activity to the carboxyl-terminus. Thus, exoenzyme S could interfere with host cell physiology via several independent mechanisms. The goal of this study was to define the role of the ADP ribosyltransferase domain in the modulation of eukaryotic cell physiology. The carboxyl-terminal 222 amino acids of exoenzyme S, which represent the FAS dependent ADP-ribosyltransferase domain (termed deltaN222), and a point mutant, deltaN222-E381A, which possesses a 2000-fold reduction in the capacity to ADP ribosylate, were transiently expressed in eukaryotic cells under the control of the immediate early CMV promoter. Lysates from cells transfected with deltaN222 expressed ADP-ribosyltransferase activity. Co-transfection of deltaN222, but not deltaN222-E381A, resulted in a decrease in the steady-state levels of two reporter proteins, green fluorescent protein and luciferase, in both CHO and Vero cells. In addition, transfection with deltaN222 resulted in a greater percentage of cells staining with trypan blue than when cells were transfected with either deltaN222-E381A or control plasmid. Together, these data indicate that expression of the ADP-ribosyltransferase domain of exoenzyme S is cytotoxic to eukaryotic cells. PMID- 10094624 TI - Protein-mediated DNA transfer into liposomes. AB - The transfer of a foreign genome into a bacterium by means of phage infection is a very efficient but poorly understood process. To analyse the mechanism of phage DNA transfer at a molecular level, we have reconstituted FhuA, the receptor for phage T5 in the outer membrane of Escherichia coli, into unilamellar vesicles made of natural phospholipids. Cryoelectron microscopy studies showed that the binding of the phage to FhuA triggered the transfer of its double-stranded DNA (121000 bp) into the proteoliposomes. DNA was entrapped within vesicles with a diameter ranging from 70 to 150 nm. The DNA appeared to be densely packed, but its presence did not alter the morphology of the liposomes, suggesting no DNA lipid interactions. These liposomes represent an attractive model system for studying the mechanisms of DNA transport and condensation. They may also serve as alternative vehicles for the transfer of foreign genes into eukaryotic cells. PMID- 10094625 TI - Adaptation of Haemophilus influenzae to acquired and innate humoral immunity based on phase variation of lipopolysaccharide. AB - Phase variation in colony morphology has been associated with the pathogenesis of infection caused by Haemophilus influenzae. This study shows that differences in colony opacity in non-typeable H. influenzae (NTHi) strain H233 involve phase changes in the lipopolysaccharide (LPS) and depend on the expression of licl and lic2, which contain translational switches based on intragenic tandem repeats of 5'-CAAT-3'. Genetic analysis showed that opaque organisms have an out-of-frame number of repeats in both licl, required for the expression of phosphorylcholine (ChoP), and lic2, a putative galactosyl transferase that adds the terminal galactose on Galalpha1-4Gal. Defined variants in these loci were used to examine the contribution of individual LPS structures to resistance to serum bactericidal activity mediated by antibody and C-reactive protein (CRP). The addition of ChoP by licl was the only factor in serum killing involving CRP and complement. The terminal galactose moiety, in contrast, conferred resistance to killing by naturally acquired antibody and complement present in human serum. As Galalpha1 4Gal is also found on human glycolipids, it appears that decoration of the cell surface with this host-like antigen blocks antibody-mediated serum bactericidal activity. Genetic analysis of NTHi within the human respiratory tract demonstrated that Galalpha1-4Gal may not be expressed during carriage but may be advantageous for the organism in inflammatory states such as pneumonia. PMID- 10094626 TI - A complex composed of SycN and YscB functions as a specific chaperone for YopN in Yersinia pestis. AB - Human pathogenic Yersinia resist host defences, in part through the expression and delivery of a set of plasmid-encoded virulence proteins termed Yops. A number of these Yops are exported from the bacteria directly into the cytoplasm of their eukaryotic host's cells upon contact with these cells. The secreted YopN protein (also known as LcrE) is required to block Yop secretion in the presence of calcium in vitro or before contact with a eukaryotic cell in vivo. In this study, we characterize the role of the tyeA, sycN and yscB gene products in the regulation of Yop secretion in Yersinia pestis. Mutants specifically defective in the expression of TyeA, SycN or YscB were no longer able to block Yop secretion in the presence of calcium. In addition, the secretion of YopN was specifically reduced in both the sycN and the yscB deletion mutants. Protein cross-linking and immunoprecipitation studies in conjunction with yeast two-hybrid analyses showed that SycN and YscB interact with one another to form a SycN/YscB complex. Yeast three-hybrid analyses demonstrated that the SycN/YscB complex, but not SycN or YscB alone, specifically associates with YopN. SycN and YscB share amino acid sequence similarity and structural similarities with the specific Yop chaperones SycE and SycH. Together, these results indicate that a complex composed of SycN and YscB functions as a specific chaperone for YopN in Y. pestis. PMID- 10094627 TI - Transcriptional activation of the glycolytic las operon and catabolite repression of the gal operon in Lactococcus lactis are mediated by the catabolite control protein CcpA. AB - The Lactococcus lactis ccpA gene, encoding the global regulatory protein CcpA, was identified and characterized. Northern blot and primer extension analyses showed that the L. lactis ccpA gene is constitutively transcribed from a promoter that does not contain a cre sequence. Inactivation of the ccpA gene resulted in a twofold reduction in the growth rate compared with the wild type on glucose, sucrose and fructose, while growth on galactose was almost completely abolished. The observed growth defects could be complemented by the expression of either the L. lactis or the Bacillus subtilis ccpA gene. The disruption of the ccpA gene reduced the catabolite repression of the gal operon, which contains a cre site at the transcription start site and encodes enzymes involved in galactose catabolism. In contrast, CcpA activates the transcription of the cre-containing promoter of the las operon, encoding the glycolytic enzymes phosphofructokinase, pyruvate kinase and L-lactate dehydrogenase, because its transcription level was fourfold reduced in the ccpA mutant strain compared with the wild-type strain. The lower activities of pyruvate kinase and L-lactate dehydrogenase in the ccpA mutant strain resulted in the production of metabolites characteristic of a mixed acid fermentation, whereas the fermentation pattern of the wild-type strain was essentially homolactic. PMID- 10094628 TI - Cloning of the mating type loci from Pyrenopeziza brassicae reveals the presence of a novel mating type gene within a discomycete MAT 1-2 locus encoding a putative metallothionein-like protein. AB - The mating type loci were cloned from Pyrenopeziza brassicae by chromosome walking from a mating type-linked polymerase chain reaction (PCR) fragment and shown to be idiomorphic by sequence analysis. The MAT 1-1 locus is approximately 3.2 kb and contains a single gene encoding a putative high-mobility group (HMG) domain protein. The MAT 1-2 locus is approximately 3.9 kb with three open reading frames (ORFs) encoding a putative HMG domain, an alpha-1 domain and metallothionein-like proteins. The putative alpha-1 domain ORF on MAT 1-2 is transcribed in the opposite orientation to the other two transcripts and extends into non-idiomorphic sequence. This is the first report of sequence analysis of the mating type loci from a discomycete fungus, which has revealed an interesting mating type infrastructure within the MAT 1-2 locus. Although metallothionein like proteins have been implicated in a number of processes in animals and plants, they have not to date been implicated in the mating process of filamentous fungi. Possible roles for metallothionein-like proteins in the mating process are discussed. PMID- 10094629 TI - The FruA signal transduction protein provides a checkpoint for the temporal co ordination of intercellular signals in Myxococcus xanthus development. AB - During fruiting body morphogenesis in Myxococcus xanthus, the intercellular C signal induces aggregation, sporulation and developmental gene expression. To understand how a single signal system may induce temporally separated processes, we have focused on the class II gene, which codes for an essential component in the C-signal transduction pathway. We report that class II is identical to fruA and codes for a DNA binding response regulator. Transcription of fruA is developmentally regulated and depends on the early acting intercellular A- and E signals. However, fruA transcription is independent of C-signal. Rather, genetic evidence suggests that C-signal controls FruA activity post-translationally. Genetic evidence strongly indicates that FruA is activated by phosphorylation. We propose that C-signalling results in the phosphorylation of FruA, thus activating FruA to interact with downstream targets. In the motility branch of the C signalling pathway, FruA interacts with the Frz motility system; in the sporulation branch, we show that FruA is required for transcription of the sporulation locus devRS. On the basis of the two levels of control of FruA activity, we propose that FruA serves as a control point for the temporal co ordination of intercellular signals during M. xanthus development. PMID- 10094630 TI - Requirement of the VanY and VanX D,D-peptidases for glycopeptide resistance in enterococci. AB - Transposon Tn 1546 confers resistance to glycopeptide antibiotics in enterococci and encodes two D,D-peptidases (VanX and VanY) in addition to the enzymes for the synthesis of D-alanyl-D-lactate (D-Ala-D-Lac). VanY was produced in the baculovirus expression system and purified as a proteolytic fragment that lacked the putative N-terminal membrane anchor of the protein. The enzyme was a Zn2+ dependent D,D-carboxypeptidase that cleaved the C-terminal residue of peptidoglycan precursors ending in R-D-Ala-D-Ala or R-D-Ala-D-Lac but not the dipeptide D-Ala-D-Ala. The specificity constants kcat/Km were 17- to 67-fold higher for substrates ending in the R-D-Ala-D-Ala target of glycopeptides. In Enterococcus faecalis, VanY was present in membrane and cytoplasmic fractions, produced UDP-MurNAc-tetrapeptide from cytoplasmic peptidoglycan precursors and was required for high-level glycopeptide resistance in a medium supplemented with D-Ala. The enzyme could not replace the VanX D,D-dipeptidase for the expression of glycopeptide resistance but a G237D substitution in the host D-Ala:D-Ala ligase restored resistance in a vanX null mutant. Deletion of the membrane anchor of VanY led to an active D,D-carboxypeptidase exclusively located in the cytoplasmic fraction that did not contribute to glycopeptide resistance in a D Ala-containing medium. Thus, VanX and VanY had non-overlapping functions involving the hydrolysis of D-Ala-D-Ala and the removal of D-Ala from membrane bound lipid intermediates respectively. PMID- 10094631 TI - Increased nuclear traffic chaos in hyphae of Aspergillus nidulans: molecular characterization of apsB and in vivo observation of nuclear behaviour. AB - Filamentous fungi are model microorganisms for studying nuclear migration in eukaryotic cells. Two genes, apsA and apsB (=anucleate primary sterigmata), were identified in Aspergillus nidulans that affect nuclear distribution in hyphae and specifically block conidiophore development at the metula stage when mutant. Here we describe the cloning, sequencing and molecular analysis of apsB. The gene encodes a 121 kDa coiled-coil, hydrophilic protein that was localized in the cytoplasm. No protein-protein interaction was detected between ApsB and ApsA, a membrane-associated, previously identified protein. An apsB null mutant was characterized by video epifluorescence microscopy using strains that express green fluorescent protein (GFP) in nuclei. With this novel approach, we have discovered a new mutant phenotype and have found that nuclei display an increased chaotic movement in older hyphal compartments that results in clustering and an uneven distribution of these organelles. These results suggest a regulatory role of ApsB in nuclear migration. PMID- 10094632 TI - Translational control of mRNA processing in the F1845 fimbrial operon of Escherichia coli. AB - Endoribonucleolytic processing followed by differential decay of the cleavage products is an increasingly recognized mechanism for achieving co-ordinate regulation of functionally related proteins encoded by bacterial polycistronic transcripts. Unlike most examples when RNases E or III initiate decay, the daa transcript encoding F1845 fimbriae, a member of the Dr family of adhesins in Escherichia coli, is processed by an as yet unidentified endoribonuclease using a unique recognition mechanism. An open reading frame (ORF) predicted to encode a 57-amino-acid polypeptide was identified flanking the daa processing site. To determine whether this ORF is involved in processing, site-directed mutagenesis was used to generate mutants with altered translational efficiencies. A mutation in the putative ribosome binding site preceding the ORF significantly inhibited processing while the introduction of a premature stop codon abolished processing. Site-directed mutagenesis was used to introduce a limited number of mutations into the ORF, designated daaP, to alter the reading frame such that a different polypeptide of a similar size was encoded. Despite the presumed presence of trafficking ribosomes, this mutant failed to be processed, suggesting that the sequence of the DaaP peptide is important. However, the failure of a wild-type copy of the daaP gene to complement these mutations in trans suggested that the presence of wild-type daaP gene product was not sufficient to promote processing. Although active translation has been found to inhibit processing by RNases E and III, our data suggest that translation of the daaP gene is required in cis to promote processing by the endonuclease, perhaps due to an interaction of the nascent peptide with the ribosome or the daaP mRNA. PMID- 10094633 TI - Ssa1p chaperone interacts with the guanine nucleotide exchange factor of ras Cdc25p and controls the cAMP pathway in Saccharomyces cerevisiae. AB - We have found that the guanine nucleotide exchange factor for ras, Cdc25p, interacts with Ssa1p in Saccharomyces cerevisiae. This interaction was observed with GST-fused Cdc25p polypeptides and confirmed by coimmunoprecipitation with the endogenous Cdc25p. Hsp82 appeared also to be co-immunoprecipitated with Cdc25p, albeit to a lower level than Hsp70. In a strain deleted for SSA1 and SSA2, we observed a reduced cellular content of Cdc25p. Consistent with a reduced activity of the cAMP-dependent PKA pathway, the rate of accumulation of both trehalose and glycogen was stimulated in the ssa-deleted strain. Expression of SSA1 reversed these effects, whereas co-expression of SSA1 and PDE2 restored high accumulation. The expression of genes repressed by cAMP, GAC1 and TPS1, fused to beta-galactosidase, was also stimulated by deletion of SSA genes. The effect of ssa deletion on glycogen accumulation was lost in a strain deleted for CDC25 rescued by the RAS2ile152 allele. Altogether, these results lead to the conclusion that Ssa1p positively controls the cAMP pathway through Cdc25p. We propose that this connection plays a critical role in the adaptation of cells to stress conditions. PMID- 10094634 TI - In vitro and in vivo expression studies of yopE from Yersinia enterocolitica using the gfp reporter gene. AB - The Yersinia outer protein YopE belongs to the translocated effector proteins of pathogenic yersiniae. We constructed various truncated yopE genes fused to gfp (encoding the green fluorescent protein) to study yopE gene expression and YopE GFP translocation of Y. enterocolitica in cell culture and mouse infection models. The hybrid gene fusions were co-expressed in Y. enterocolitica (i) on a low-copy plasmid in the presence of the virulence plasmid pYV08 (in trans configuration) and (ii) after co-integration by homologous recombination of a yopE-gfp-carrying suicide plasmid into pYV08 (co-integrate configuration). After 30min of infection of HEp-2 cell monolayers, extracellularly located yersiniae began to emit green fluorescence after excitation. In contrast, internalized bacteria were weakly fluorescent. Translocation of YopE-GFP into HEp-2 cells by attached yersiniae was visualized by optical sectioning of fluorescent HEp-2 cells using confocal laser scanning microscopy and was confirmed by immunoprecipitation of cytosolic YopE-GFP from selectively solubilized HEp-2 cells. The co-translocation of other Yops was not significantly impaired by YopE GFP as shown by YopH/YopE-mediated suppression of the oxidative burst of infected neutrophils. The time course of yopE-gfp expression (in trans as well as in the co-integrate configuration) in the HEp-2 cell infection model as well as after in vitro induction was studied using a highly sensitive CCD camera and a flow cytometer. Similar results were obtained with a YopE-LUC (firefly luciferase) protein fusion as reporter. After intraperitoneal, intravenous and orogastrical infection of Balb/c mice with the recombinant yersiniae strains, green fluorescing bacteria could be visualized microscopically in the peritoneum, the spleen, the liver and in the Peyer's patches. However, only weakly fluorescent yersiniae were observed in the intestinal lumen. These results were quantified by flow cytometric measurements. The application of gfp as a reporter gene turned out to be promising for the study of protein translocation by protein type III secretion systems and differential virulence gene expression in vivo. PMID- 10094635 TI - The structure of an ECF-sigma-dependent, light-inducible promoter from the bacterium Myxococcus xanthus. AB - Expression of the Myxococcus xanthus gene crtl is controlled by a light-inducible promoter. The activity of this promoter depends on CarQ, a sigma factor of the extracytoplasmic function (ECF) subfamily. Here, we show thatthe minimum DNA stretch reproducing normal expression of crtl extends from a few bases upstream of the -35 position to a site well downstream of the transcriptional start. The downstream DNA contains an enhancer-like element that remains active when displaced upstream of the promoter. Experimental evidence is provided for the activity of the crtl promoter being critically dependent on a pentanucleotide sequence centred at the -31 position. The similarity of this sequence with the consensus for ECF-sigma-dependent promoters from other bacteria is discussed. The activity of the crtl promoter also depends on certain basepairs at the -10 region. Hence, the operation of ECF-sigma-factors seems to require binding to two different DNA sites, although the -10 sequences of different ECF-sigma-dependent promoters are unrelated to one another, and the ECF-sigma-factors themselves lack the conserved domain known to mediate binding of other sigma-factors to the -10 DNA site. PMID- 10094636 TI - D-Erythroascorbic acid is an important antioxidant molecule in Saccharomyces cerevisiae. AB - D-Arabinono-1,4-lactone oxidase catalysing the final step of D-erythroascorbic acid biosynthesis was purified from the mitochondrial fraction of Saccharomyces cerevisiae. Based on the amino acid sequence analysis of the enzyme, an unknown open reading frame (ORF), YML086C, was identified as the ALO1 gene encoding the enzyme. The ORF of ALO1 encoded a polypeptide consisting of 526 amino acids with a calculated molecular mass of 59493Da. The deduced amino acid sequence of the enzyme shared 32% and 21% identity with that of L-gulono-1,4-lactone oxidase from rat and L-galactono-1,4-lactone dehydrogenase from cauliflower, respectively, and contained a putative transmembrane segment and a covalent FAD binding site. Blot hybridization analyses showed that a single copy of the gene was present in the yeast genome and that mRNA of the ALO1 gene was 1.8kb in size. In the alo1 mutants, D-erythroascorbic acid and the activity of D-arabinono-1,4-lactone oxidase could not be detected. The intracellular concentration of D erythroascorbic acid and the enzyme activity increased up to 6.9-fold and 7.3 fold, respectively, in the transformant cells carrying ALO1 in multicopy plasmid. The alo1 mutants showed increased sensitivity towards oxidative stress, but overexpression of ALO1 made the cells more resistant to oxidative stress. PMID- 10094637 TI - Lorazepam for the prevention of recurrent seizures related to alcohol. AB - BACKGROUND AND METHODS: Alcohol abuse is one of the most common causes of seizures in adults. In a randomized, double-blind study, we compared lorazepam with placebo for the prevention of recurrent seizures related to alcohol. Over a 21-month period, we studied consecutive patients with chronic alcohol abuse who were at least 21 years of age and who presented to the emergency departments of two hospitals in Boston after a witnessed, generalized seizure. The patients were randomly assigned to receive either 2 mg of lorazepam in 2 ml of normal saline or 4 ml of normal saline intravenously and then observed for six hours. The primary end point was the occurrence of a second seizure during the observation period. RESULTS: Of the 229 patients who were initially evaluated, 186 met the entry criteria. In the lorazepam group, 3 of 100 patients (3 percent) had a second seizure, as compared with 21 of 86 patients (24 percent) in the placebo group (odds ratio for seizure with the use of placebo, 10.4; 95 percent confidence interval, 3.6 to 30.2; P<0.001). Forty-two percent of the placebo group were admitted to the hospital, as compared with 29 percent of the lorazepam group (odds ratio for admission, 2.1; 95 percent confidence interval, 1.1 to 4.0; P=0.02). Seven patients in the placebo group and one in the lorazepam group were transported to an emergency department in Boston with a second seizure within 48 hours after hospital discharge. CONCLUSIONS: Treatment with intravenous lorazepam is associated with a significant reduction in the risk of recurrent seizures related to alcohol. PMID- 10094638 TI - Medical education and managed care. PMID- 10094639 TI - Geographic favoritism in liver transplantation. PMID- 10094640 TI - Geographic favoritism in liver transplantation. PMID- 10094641 TI - Geographic favoritism in liver transplantation. PMID- 10094642 TI - Geographic favoritism in liver transplantation. PMID- 10094643 TI - Geographic favoritism in liver transplantation. PMID- 10094644 TI - Geographic favoritism in liver transplantation. PMID- 10094645 TI - Seasonal changes in blood pressure in patients undergoing hemodialysis. PMID- 10094646 TI - Seasonal changes in blood pressure in patients undergoing hemodialysis. PMID- 10094647 TI - Isolated noncompaction of the myocardium. PMID- 10094648 TI - Bradykinin and inhibition of angiotensin-converting enzyme in hypertension. PMID- 10094649 TI - Bradykinin and inhibition of angiotensin-converting enzyme in hypertension. PMID- 10094650 TI - Bradykinin and inhibition of angiotensin-converting enzyme in hypertension. PMID- 10094651 TI - Acute HIV infection among patients tested for mononucleosis. PMID- 10094652 TI - Fat distribution in AIDS. PMID- 10094653 TI - Duodenal obstruction from a gastric feeding tube. PMID- 10094654 TI - [Immediate recovery from acute renal insufficiency after abdominal decompression]. PMID- 10094655 TI - [Pain in one leg in cancer patients (correction)]. PMID- 10094656 TI - [A young patient with chronic recurrent leg ulcers; hyperhomocysteinemia and heterozygote for factor V Leiden]. PMID- 10094657 TI - [Clustered and disseminated cutaneous piloleiomyomas]. PMID- 10094658 TI - [Lymphangioma circumscriptum of the tongue]. PMID- 10094659 TI - [Verrucous carcinoma]. PMID- 10094660 TI - [The syndrome of Comel-Netherton (trichorrhexis invaginata, ichthyosis linearis circumflexa and atopic eczema)]. PMID- 10094661 TI - [Chillblains in a pair of riders]. PMID- 10094662 TI - [Recurrent postherpetic erythema multiforme presenting as a polymorphous light eruption and 'juvenile spring eruption]. PMID- 10094664 TI - [Conference abstracts of the section for nocturnal disturbances of respiratory and circulatory regulation. 34th session of the Society for Research on Pulmonary and Respiratory Function. Bochum, 2-5 December 1998]. PMID- 10094663 TI - Special review issue: Exercise testing. PMID- 10094665 TI - [Apnea-hypopnea. Single or two entities?]. PMID- 10094666 TI - [Krakow Stroke Symposium. Krakow, Poland, 23-24 October 1998. Abstracts]. PMID- 10094667 TI - Special issue in honour of Professor Micheal Healy. PMID- 10094668 TI - In honour of Professor Michael Healy. Foreward. PMID- 10094669 TI - [Current aspects of the problem of traumatism and acute poisonings in the Armed Forces]. PMID- 10094670 TI - Control of Hepatitis B in Europe: Where are we in 1997? Proceedings of VHPB International Congress. Madrid, Spain, 17-19 November 1997. PMID- 10094671 TI - In vitro susceptibilities of lactobacilli and organisms associated with bacterial vaginosis to Melaleuca alternifolia (tea tree) oil. PMID- 10094672 TI - Two-component signal transduction in Bacillus subtilis: how one organism sees its world. PMID- 10094673 TI - Chromosome methylation and measurement of faithful, once and only once per cell cycle chromosome replication in Caulobacter crescentus. AB - Caulobacter crescentus exhibits cell-type-specific control of chromosome replication and DNA methylation. Asymmetric cell division yields a replicating stalked cell and a nonreplicating swarmer cell. The motile swarmer cell must differentiate into a sessile stalked cell in order to replicate and execute asymmetric cell division. This program of cell division implies that chromosome replication initiates in the stalked cell only once per cell cycle. DNA methylation is restricted to the predivisional cell stage, and since DNA synthesis produces an unmethylated nascent strand, late DNA methylation also implies that DNA near the replication origin remains hemimethylated longer than DNA located further away. In this report, both assumptions are tested with an engineered Tn5-based transposon, Tn5Omega-MP. This allows a sensitive Southern blot assay that measures fully methylated, hemimethylated, and unmethylated DNA duplexes. Tn5Omega-MP was placed at 11 sites around the chromosome and it was clearly demonstrated that Tn5Omega-MP DNA near the replication origin remained hemimethylated longer than DNA located further away. One Tn5Omega-MP placed near the replication origin revealed small but detectable amounts of unmethylated duplex DNA in replicating stalked cells. Extra DNA synthesis produces a second unmethylated nascent strand. Therefore, measurement of unmethylated DNA is a critical test of the "once and only once per cell cycle" rule of chromosome replication in C. crescentus. Fewer than 1 in 1,000 stalked cells prematurely initiate a second round of chromosome replication. The implications for very precise negative control of chromosome replication are discussed with respect to the bacterial cell cycle. PMID- 10094674 TI - The presence of ADP-ribosylated Fe protein of nitrogenase in Rhodobacter capsulatus is correlated with cellular nitrogen status. AB - The photosynthetic bacterium Rhodobacter capsulatus has been shown to regulate its nitrogenase by covalent modification via the reversible ADP-ribosylation of Fe protein in response to darkness or the addition of external NH4+. Here we demonstrate the presence of ADP-ribosylated Fe protein under a variety of steady state growth conditions. We examined the modification of Fe protein and nitrogenase activity under three different growth conditions that establish different levels of cellular nitrogen: batch growth with limiting NH4+, where the nitrogen status is externally controlled; batch growth on relatively poor nitrogen sources, where the nitrogen status is internally controlled by assimilatory processes; and continuous culture. When cultures were grown to stationary phase with different limiting concentrations of NH4+, the ADP ribosylation state of Fe protein was found to correlate with cellular nitrogen status. Additionally, actively growing cultures (grown with N2 or glutamate), which had an intermediate cellular nitrogen status, contained a portion of their Fe protein in the modified state. The correlation between cellular nitrogen status and ADP-ribosylation state was corroborated with continuous cultures grown under various degrees of nitrogen limitation. These results show that in R. capsulatus the modification system that ADP-ribosylates nitrogenase in the short term in response to abrupt changes in the environment is also capable of modifying nitrogenase in accordance with long-term cellular conditions. PMID- 10094675 TI - acs1 of Haemophilus influenzae type a capsulation locus region II encodes a bifunctional ribulose 5-phosphate reductase- CDP-ribitol pyrophosphorylase. AB - The serotype-specific, 5.9-kb region II of the Haemophilus influenzae type a capsulation locus was sequenced and found to contain four open reading frames termed acs1 to acs4. Acs1 was 96% identical to H. influenzae type b Orf1, previously shown to have CDP-ribitol pyrophosphorylase activity (J. Van Eldere, L. Brophy, B. Loynds, P. Celis, I. Hancock, S. Carman, J. S. Kroll, and E. R. Moxon, Mol. Microbiol. 15:107-118, 1995). Low but significant homology to other pyrophosphorylases was only detected in the N-terminal part of Acs1, whereas the C-terminal part was homologous to several short-chain dehydrogenases/reductases, suggesting that Acs1 might be a bifunctional enzyme. To test this hypothesis, acs1 was cloned in an expression vector and overexpressed in Escherichia coli. Cells expressing this protein displayed both ribitol 5-phosphate dehydrogenase and CDP-ribitol pyrophosphorylase activities, whereas these activities were not detectable in control cells. Acs1 was purified to near homogeneity and found to copurify with ribitol 5-phosphate dehydrogenase and CDP-ribitol pyrophosphorylase activities. These had superimposable elution profiles from DEAE-Sepharose and Blue-Sepharose columns. The dehydrogenase activity was specific for ribulose 5 phosphate and NADPH in one direction and for ribitol 5-phosphate and NADP+ in the other direction and was markedly stimulated by CTP. The pyrophosphorylase showed activity with CTP and ribitol 5-phosphate or arabitol 5-phosphate. We conclude that acs1 encodes a bifunctional enzyme that converts ribulose 5-phosphate into ribitol 5-phosphate and further into CDP-ribitol, which is the activated precursor form for incorporation of ribitol 5-phosphate into the H. influenzae type a capsular polysaccharide. PMID- 10094676 TI - A novel membrane protein influencing cell shape and multicellular swarming of Proteus mirabilis. AB - Swarming in Proteus mirabilis is characterized by the coordinated surface migration of multicellular rafts of highly elongated, hyperflagellated swarm cells. We describe a transposon mutant, MNS185, that was unable to swarm even though vegetative cells retained normal motility and the ability to differentiate into swarm cells. However, these elongated cells were irregularly curved and had variable diameters, suggesting that the migration defect results from the inability of these deformed swarm cells to align into multicellular rafts. The transposon was inserted at codon 196 of a 228-codon gene that lacks recognizable homologs. Multiple copies of the wild-type gene, called ccmA, for curved cell morphology, restored swarming to the mutant. The 25-kDa CcmA protein is predicted to span the inner membrane twice, with its C-terminal major domain being present in the cytoplasm. Membrane localization was confirmed both by immunoblotting and by electron microscopy of immunogold-labelled sections. Two forms of CcmA were identified for wild-type P. mirabilis; they were full-length integral membrane CcmA1 and N-terminally truncated peripheral membrane CcmA2, both present at approximately 20-fold higher concentrations in swarm cells. Differentiated MNS185 mutant cells contained wild-type levels of the C-terminally truncated versions of both proteins. Elongated cells of a ccmA null mutant were less misshapen than those of MNS185 and were able to swarm, albeit more slowly than wild-type cells. The truncated CcmA proteins may therefore interfere with normal morphogenesis, while the wild-type proteins, which are not essential for swarming, may enhance migration by maintaining the linearity of highly elongated cells. Consistent with this view, overexpression of the ccmA gene caused cells of both Escherichia coli and P. mirabilis to become enlarged and ellipsoidal. PMID- 10094677 TI - Mutational analysis of the phoD promoter in Bacillus subtilis: implications for PhoP binding and promoter activation of Pho regulon promoters. AB - The PhoP-PhoR two-component regulatory system controls the phosphate deficiency response in B. subtilis. A number of Pho regulon genes which require PhoP approximately P for activation or repression have been identified. The studies reported here were initiated to understand the PhoP-DNA interaction necessary for Pho promoter regulation. The regulatory region of phoD was characterized in detail using oligo-directed mutagenesis, DNase I footprinting, and in vivo transcription assays. These data reveal basic principles of PhoP binding relevant to PhoP's interaction with other Pho regulon promoters. Our results show that: (i) a dimer of PhoP approximately P is able to bind two consensus repeats in a stable fashion; (ii) PhoP binding is highly cooperative within the core promoter region, which is located from -66 to -17 on the coding strand and contains four TT(A/T/C)ACA-like repeats; (iii) specific bases comprising the TT(A/T/C)ACA consensus are essential for transcriptional activation, but the specific base pairs of the intervening sequences separating the consensus repeats are not important for either PhoP binding or promoter activation; (iv) the spacing between two consensus repeats within a putative dimer binding site in the core region is important for both PhoP binding and promoter activation; (v) the exact spacing between two dimer binding sites within the core region is important for promoter activation but less so for PhoP binding affinity, as long as the repeats are on the same face of the helix; and (vi) the 5' secondary binding region is important for coordinated PhoP binding to the core binding region, making it nearly essential for promoter activation. PMID- 10094678 TI - Regulation of expression of the Lactococcus lactis histidine operon. AB - In Lactococcus lactis, the his operon contains all the genes necessary for histidine biosynthesis. It is transcribed from a unique promoter, localized 300 bp upstream of the first gene. The region corresponding to the untranslated 5' end of the transcript, named the his leader region, displays the typical features of the T box transcriptional attenuation mechanism which is involved in the regulation of many amino acid biosynthetic operons and tRNA synthetase genes in gram-positive bacteria. Here we describe the regulation of transcription of the his operon by the level of histidine in the growth medium. In the absence of histidine, two transcripts are present. One covers the entire operon, while the other stops at a terminator situated about 250 bp downstream of the transcription start point. DNA sequences implicated in regulation of the his operon were identified by transcriptional fusion with luciferase genes and site-directed mutagenesis. In addition to the previously defined sequences necessary for effective T-box-mediated regulation, new essential regions were identified. Eighteen percent of the positions of the his leader region were found to differ in seven distantly related strains of L. lactis. Analysis of the variable positions supports the folding model of the central part of the his leader region. Lastly, in addition to the T-box-mediated regulation, the operon is regulated at the level of initiation of transcription, which is repressed in the presence of histidine. An operator site, necessary for full repression, overlaps the terminator involved in the T box attenuation mechanism. The functionality of the operator is altered on plasmids with low and high copy numbers, suggesting that supercoiling may play a role in the expression of the his operon. The extents of regulation at the levels of initiation and attenuation of transcription are 6- to 8-fold and 14-fold, respectively. Together, the two levels of control allow a 120-fold range of regulation of the L. lactis operon by histidine. PMID- 10094679 TI - Twelve pil genes are required for biogenesis of the R64 thin pilus. AB - The IncI1 plasmid R64 produces two kinds of sex pili: a thin pilus and a thick pilus. The thin pilus, which belongs to the type IV family, is required only for liquid matings. Fourteen genes, pilI to -V, were found in the DNA region responsible for the biogenesis of the R64 thin pilus (S.-R. Kim and T. Komano, J. Bacteriol. 179:3594-3603, 1997). In this study, we introduced frameshift mutations into each of the 14 pil genes to test their requirement for R64 thin pilus biogenesis. From the analyses of extracellular secretion of thin pili and transfer frequency in liquid matings, we found that 12 genes, pilK to -V, are required for the formation of the thin pilus. Complementation experiments excluded the possible polar effects of each mutation on the expression of downstream genes. Two genes, traBC, were previously shown to be required for the expression of the pil genes. In addition, the rci gene is responsible for modulating the structure and function of the R64 thin pilus via the DNA rearrangement of the shufflon. Altogether, 15 genes, traBC, pilK through pilV, and rci, are essential for R64 thin pilus formation and function. PMID- 10094680 TI - Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. AB - Pyrazinamide (PZA) is an important antituberculosis drug. Unlike most antibacterial agents, PZA, despite its remarkable in vivo activity, has no activity against Mycobacterium tuberculosis in vitro except at an acidic pH. M. tuberculosis is uniquely susceptible to PZA, but other mycobacteria as well as nonmycobacteria are intrinsically resistant. The role of acidic pH in PZA action and the basis for the unique PZA susceptibility of M. tuberculosis are unknown. We found that in M. tuberculosis, acidic pH enhanced the intracellular accumulation of pyrazinoic acid (POA), the active derivative of PZA, after conversion of PZA by pyrazinamidase. In contrast, at neutral or alkaline pH, POA was mainly found outside M. tuberculosis cells. PZA-resistant M. tuberculosis complex organisms did not convert PZA into POA. Unlike M. tuberculosis, intrinsically PZA-resistant M. smegmatis converted PZA into POA, but it did not accumulate POA even at an acidic pH, due to a very active POA efflux mechanism. We propose that a deficient POA efflux mechanism underlies the unique susceptibility of M. tuberculosis to PZA and that the natural PZA resistance of M. smegmatis is due to a highly active efflux pump. These findings may have implications with regard to the design of new antimycobacterial drugs. PMID- 10094681 TI - Degradation of 1,2-dibromoethane by Mycobacterium sp. strain GP1. AB - The newly isolated bacterial strain GP1 can utilize 1, 2-dibromoethane as the sole carbon and energy source. On the basis of 16S rRNA gene sequence analysis, the organism was identified as a member of the subgroup which contains the fast growing mycobacteria. The first step in 1,2-dibromoethane metabolism is catalyzed by a hydrolytic haloalkane dehalogenase. The resulting 2-bromoethanol is rapidly converted to ethylene oxide by a haloalcohol dehalogenase, in this way preventing the accumulation of 2-bromoethanol and 2-bromoacetaldehyde as toxic intermediates. Ethylene oxide can serve as a growth substrate for strain GP1, but the pathway(s) by which it is further metabolized is still unclear. Strain GP1 can also utilize 1-chloropropane, 1-bromopropane, 2-bromoethanol, and 2 chloroethanol as growth substrates. 2-Chloroethanol and 2-bromoethanol are metabolized via ethylene oxide, which for both haloalcohols is a novel way to remove the halide without going through the corresponding acetaldehyde intermediate. The haloalkane dehalogenase gene was cloned and sequenced. The dehalogenase (DhaAf) encoded by this gene is identical to the haloalkane dehalogenase (DhaA) of Rhodococcus rhodochrous NCIMB 13064, except for three amino acid substitutions and a 14-amino-acid extension at the C terminus. Alignments of the complete dehalogenase gene region of strain GP1 with DNA sequences in different databases showed that a large part of a dhaA gene region, which is also present in R. rhodochrous NCIMB 13064, was fused to a fragment of a haloalcohol dehalogenase gene that was identical to the last 42 nucleotides of the hheB gene found in Corynebacterium sp. strain N-1074. PMID- 10094682 TI - Role of bkdR, a transcriptional activator of the sigL-dependent isoleucine and valine degradation pathway in Bacillus subtilis. AB - A new gene, bkdR (formerly called yqiR), encoding a regulator with a central (catalytic) domain was found in Bacillus subtilis. This gene controls the utilization of isoleucine and valine as sole nitrogen sources. Seven genes, previously called yqiS, yqiT, yqiU, yqiV, bfmBAA, bfmBAB, and bfmBB and now referred to as ptb, bcd, buk, lpd, bkdA1, bkdA2, and bkdB, are located downstream from the bkdR gene in B. subtilis. The products of these genes are similar to phosphate butyryl coenzyme A transferase, leucine dehydrogenase, butyrate kinase, and four components of the branched-chain keto acid dehydrogenase complex: E3 (dihydrolipoamide dehydrogenase), E1alpha (dehydrogenase), E1beta (decarboxylase), and E2 (dihydrolipoamide acyltransferase). Isoleucine and valine utilization was abolished in bcd and bkdR null mutants of B. subtilis. The seven genes appear to be organized as an operon, bkd, transcribed from a -12, -24 promoter. The expression of the bkd operon was induced by the presence of isoleucine or valine in the growth medium and depended upon the presence of the sigma factor SigL, a member of the sigma 54 family. Transcription of this operon was abolished in strains containing a null mutation in the regulatory gene bkdR. Deletion analysis showed that upstream activating sequences are involved in the expression of the bkd operon and are probably the target of bkdR. Transcription of the bkd operon is also negatively controlled by CodY, a global regulator of gene expression in response to nutritional conditions. PMID- 10094683 TI - HmbR, a hemoglobin-binding outer membrane protein of Neisseria meningitidis, undergoes phase variation. AB - Neisseria meningitidis uses hemoglobin (Hb) as an iron source via two TonB dependent outer membrane receptors, HmbR and HpuB. Analysis of 25 epidemiologically unrelated clinical isolates from serogroups A, B, C, and Y revealed that 64% strains possessed both Hb receptor genes. Examination of the hmbR expression pattern in strains in which the hpuB gene was genetically inactivated revealed two distinct Hb utilization phenotypes. Five strains retained the ability to grow as a confluent lawn, while seven grew only as single colonies around Hb discs. The single-colony phenotype observed for some hpuB mutants is suggestive of phase variation of hmbR. The length of the poly(G) tract starting at position +1164 of hmbR absolutely correlated with the two Hb utilization phenotypes. All five strains that grew as confluent lawns around Hb discs possessed either 9 or 12 consecutive G residues. All seven strains that grew as single colonies around Hb discs had poly(G) tracts of a length other than 9 or 12. These single-colony variants that arose around the Hb discs had poly(G) tracts with either 9 or 12 consecutive G residues restoring the hmbR reading frame. Inactivation of hmbR in these strains resulted in a loss of Hb utilization, demonstrating that the change in the hmbR gene was responsible for the phenotypic switch. The switching rates from hmbR phase off to phase on were approximately 5 x 10(-4) in four serogroup C strains, 2 x 10(-2) in the serogroup A isolate, and 7 x 10(-6) in the serogroup B isolate. PMID- 10094684 TI - Disruption and analysis of the clpB, clpC, and clpE genes in Lactococcus lactis: ClpE, a new Clp family in gram-positive bacteria. AB - In the genome of the gram-positive bacterium Lactococcus lactis MG1363, we have identified three genes (clpC, clpE, and clpB) which encode Clp proteins containing two conserved ATP binding domains. The proteins encoded by two of the genes belong to the previously described ClpB and ClpC families. The clpE gene, however, encodes a member of a new Clp protein family that is characterized by a short N-terminal domain including a putative zinc binding domain (-CX2CX22CX2C-). Expression of the 83-kDa ClpE protein as well as of the two proteins encoded by clpB was strongly induced by heat shock and, while clpC mRNA synthesis was moderately induced by heat, we were unable to identify the ClpC protein. When we analyzed mutants with disruptions in clpB, clpC, or clpE, we found that although the genes are part of the L. lactis heat shock stimulon, the mutants responded like wild-type cells to heat and salt treatments. However, when exposed to puromycin, a tRNA analogue that results in the synthesis of truncated, randomly folded proteins, clpE mutant cells formed smaller colonies than wild-type cells and clpB and clpC mutant cells. Thus, our data suggest that ClpE, along with ClpP, which recently was shown to participate in the degradation of randomly folded proteins in L. lactis, could be necessary for degrading proteins generated by certain types of stress. PMID- 10094685 TI - The acid-inducible asr gene in Escherichia coli: transcriptional control by the phoBR operon. AB - Escherichia coli responds to external acidification (pH 4.0 to 5.0) by synthesizing a newly identified, approximately 450-nucleotide RNA component. At maximal levels of induction it is one of the most abundant small RNAs in the cell and is relatively stable bacterial RNA. The acid-inducible RNA was purified, and the gene encoding it, designated asr (for acid shock RNA), mapped at 35.98 min on the E. coli chromosome. Analysis of the asr DNA sequence revealed an open reading frame coding for a 111-amino-acid polypeptide with a deduced molecular mass of approximately 11.6 kDa. According to computer-assisted analysis, the predicted polypeptide contains a typical signal sequence of 30 amino acids and might represent either a periplasmic or an outer membrane protein. The asr gene cloned downstream from a T7 promoter was translated in vivo after transcription using a T7 RNA polymerase transcription system. Expression of a plasmid-encoded asr::lacZ fusion under a native asr promoter was reduced approximately 15-fold in a complex medium, such as Luria-Bertani medium, versus the minimal medium. Transcription of the chromosomal asr was abolished in the presence of a phoB-phoR (a two-component regulatory system, controlling the pho regulon inducible by phosphate starvation) deletion mutant. Acid-mediated induction of the asr gene in the Delta(phoB-phoR) mutant strain was restored by introduction of the plasmid with cloned phoB-phoR genes. Primer extension analysis of the asr transcript revealed a region similar to the Pho box (the consensus sequence found in promoters transcriptionally activated by the PhoB protein) upstream from the determined transcription start. The asr promoter DNA region was demonstrated to bind PhoB protein in vitro. We discuss our results in terms of how bacteria might employ the phoB-phoR regulatory system to sense an external acidity and regulate transcription of the asr gene. PMID- 10094686 TI - Purification of a glutathione S-transferase and a glutathione conjugate-specific dehydrogenase involved in isoprene metabolism in Rhodococcus sp. strain AD45. AB - A glutathione S-transferase (GST) with activity toward 1, 2-epoxy-2-methyl-3 butene (isoprene monoxide) and cis-1, 2-dichloroepoxyethane was purified from the isoprene-utilizing bacterium Rhodococcus sp. strain AD45. The homodimeric enzyme (two subunits of 27 kDa each) catalyzed the glutathione (GSH)-dependent ring opening of various epoxides. At 5 mM GSH, the enzyme followed Michaelis-Menten kinetics for isoprene monoxide and cis-1, 2-dichloroepoxyethane, with Vmax values of 66 and 2.4 micromol min-1 mg of protein-1 and Km values of 0.3 and 0.1 mM for isoprene monoxide and cis-1,2-dichloroepoxyethane, respectively. Activities increased linearly with the GSH concentration up to 25 mM. 1H nuclear magnetic resonance spectroscopy showed that the product of GSH conjugation to isoprene monoxide was 1-hydroxy-2-glutathionyl-2-methyl-3-butene (HGMB). Thus, nucleophilic attack of GSH occurred on the tertiary carbon atom of the epoxide ring. HGMB was further converted by an NAD+-dependent dehydrogenase, and this enzyme was also purified from isoprene-grown cells. The homodimeric enzyme (two subunits of 25 kDa each) showed a high activity for HGMB, whereas simple primary and secondary alcohols were not oxidized. The enzyme catalyzed the sequential oxidation of the alcohol function to the corresponding aldehyde and carboxylic acid and followed Michaelis-Menten kinetics with respect to NAD+ and HGMB. The results suggest that the initial steps in isoprene metabolism are a monooxygenase catalyzed conversion to isoprene monoxide, a GST-catalyzed conjugation to HGMB, and a dehydrogenase-catalyzed two-step oxidation to 2-glutathionyl-2-methyl-3 butenoic acid. PMID- 10094687 TI - BadR, a new MarR family member, regulates anaerobic benzoate degradation by Rhodopseudomonas palustris in concert with AadR, an Fnr family member. AB - A cluster of genes for the anaerobic degradation of benzoate has been described for the phototrophic bacterium Rhodopseudomonas palustris. Here we provide an initial analysis of the regulation of anaerobic benzoate degradation by examining the contributions of two regulators: a new regulator, BadR, encoded by the benzoate degradation gene cluster, and a previously described regulator, AadR, whose gene lies outside the cluster. Strains with single mutations in either badR or aadR grew slowly on benzoate but were relatively unimpaired in growth on succinate and several intermediates of benzoate degradation. A badR aadR double mutant was completely defective in anaerobic growth on benzoate. Effects of the regulators on transcriptional activation were monitored with an R. palustris strain carrying a chromosomal fusion of 'lacZ to the badE gene of the badDEFG operon. This operon encodes benzoyl-coenzyme A (benzoyl-CoA) reductase, an unusual oxygen-sensitive enzyme that catalyzes the benzene ring reduction reaction that is the rate-limiting step in anaerobic benzoate degradation. Expression of badE::'lacZ was induced 100-fold when cells grown aerobically on succinate were shifted to anaerobic growth on succinate plus benzoate. The aadR gene was required for a 20-fold increase in expression that occurred in response to anaerobiosis, and badR was responsible for a further 5-fold increase in expression that occurred in response to benzoate. Further studies with the badE::'lacZ fusion strain grown with various kinds of aromatic acids indicated that BadR probably responds to benzoyl-CoA acting as an effector molecule. Sequence information indicates that BadR is a member of the MarR family of transcriptional regulators. These studies expand the range of functions regulated by MarR family members to include anaerobic aromatic acid degradation and provide an example of a MarR-type protein that acts as a positive regulator rather than as a negative regulator, as do most MarR family members. AadR resembles the Escherichia coli Fnr regulator in sequence and contains cysteine residues that are spaced appropriately to serve in the capacity of a redox-sensing protein. PMID- 10094688 TI - Binding site recognition by Rns, a virulence regulator in the AraC family. AB - The expression of CS1 pili by enterotoxigenic strains of Escherichia coli is regulated at the transcriptional level and requires the virulence regulator Rns, a member of the AraC family of regulatory proteins. Rns binds at two separate sites upstream of Pcoo (the promoter of CS1 pilin genes), which were identified in vitro with an MBP::Rns fusion protein in gel mobility and DNase I footprinting assays. At each site, Rns recognizes asymmetric nucleotide sequences in two regions of the major groove and binds along one face of the DNA helix. Both binding sites are required for activation of Pcoo in vivo, because mutagenesis of either site significantly reduced the level of expression from this promoter. Thus, Rns regulates the expression of CS1 pilin genes directly, not via a regulatory cascade. Analysis of Rns-nucleotide interactions at each site suggests that binding sites for Rns and related virulence regulators are not easily identified because they do not bind palindromic or repeated sequences. A strategy to identify asymmetric binding sites is presented and applied to locate potential binding sites upstream of other genes that Rns can activate, including those encoding the CS2 and CFA/I pili of enterotoxigenic E. coli and the global regulator virB of Shigella flexneri. PMID- 10094689 TI - Isolation of RNase H genes that are essential for growth of Bacillus subtilis 168. AB - Two genes encoding functional RNase H (EC 3.1.26.4) were isolated from a gram positive bacterium, Bacillus subtilis 168. Two DNA clones exhibiting RNase H activities both in vivo and in vitro were obtained from a B. subtilis DNA library. One (28.2 kDa) revealed high similarity to Escherichia coli RNase HII, encoded by the rnhB gene. The other (33.9 kDa) was designated rnhC and encodes B. subtilis RNase HIII. The B. subtilis genome has an rnhA homologue, the product of which has not yet shown RNase H activity. Analyses of all three B. subtilis genes revealed that rnhB and rnhC cannot be simultaneously inactivated. This observation indicated that in B. subtilis both the rnhB and rnhC products are involved in certain essential cellular processes that are different from those suggested by E. coli rnh mutation studies. Sequence conservation between the rnhB and rnhC genes implies that both originated from a single ancestral RNase H gene. The roles of bacterial RNase H may be indicated by the single rnhC homologue in the small genome of Mycoplasma species. PMID- 10094690 TI - Stabilization of the relaxosome and stimulation of conjugal transfer are genetically distinct functions of the R1162 protein MobB. AB - MobB is a small protein encoded by the broad-host-range plasmid R1162 and required for efficient mobilization of its DNA during conjugation. The protein was shown previously to stabilize the relaxosome, the complex of plasmid DNA and mobilization proteins at the origin of transfer (oriT). We have generated in frame mobB deletions that specifically inactivate the stabilizing effect of MobB while still allowing a high rate of transfer. Thus, MobB has two genetically distinct functions in transfer. The effect of another deletion, extending into mobA, indicates that both functions require a specific region of MobA protein that is distinct from the nicking-ligating domain. The mobB mutations that specifically affected stability also resulted in poor growth of cells, due to increased transcription from the promoters adjacent to oriT. The effects of the mutations could be suppressed not only by full-length MobB provided in trans, as expected, but also by additional copies of oriT, cloned in pBR322. In addition, in the presence of MobA both the full-length and truncated forms of MobB stimulated recombination between oriT-containing plasmids. We propose a model in which MobB regulates expression of plasmid genes by altering the stability of the relaxosome, in a manner that involves the coupling of plasmid molecules. PMID- 10094691 TI - The major phase-variable outer membrane protein of Escherichia coli structurally resembles the immunoglobulin A1 protease class of exported protein and is regulated by a novel mechanism involving Dam and oxyR. AB - Here we report the characterization of an Escherichia coli gene (agn43) which encodes the principal phase-variable outer membrane protein termed antigen 43 (Ag43). The agn43 gene encodes a precursor protein of 107 kDa containing a 52 amino-acid signal sequence. Posttranslational processing generates an alpha43 subunit (predicted Mr of 49,789) and a C-terminal domain (beta43) with features typical of a bacterial integral outer membrane protein (predicted Mr of 51, 642). Secondary structure analysis predicts that beta43 exists as an 18-stranded beta barrel and that Ag43 shows structural organization closely resembling that of immunoglobulin A1 protease type of exoprotein produced by pathogenic Neisseria and Haemophilus spp. The correct processing of the polyprotein to alpha43 and beta43 in OmpT, OmpP, and DegP protease-deficient E. coli strains points to an autocatalytic cleavage mechanism, a hypothesis supported by the occurrence of an aspartyl protease active site within alpha43. Ag43, a species-specific antigen, possesses two RGD motifs of the type implicated in binding to human integrins. The mechanism of reversible phase variation was studied by immunochemical analysis of a panel of well-defined regulatory mutants and by analysis of DNA sequences upstream of agn43. Evidence strongly suggests that phase variation is regulated by both deoxyadenosine methylase (Dam) and by OxyR. Thus, oxyR mutants are locked on for Ag43 expression, whereas dam mutants are locked off for Ag43 expression. We propose a novel mechanism for the regulation of phase switching in which OxyR competes with Dam for unmethylated GATC sites in the regulatory region of the agn43 gene. PMID- 10094692 TI - Iron reductase for magnetite synthesis in the magnetotactic bacterium Magnetospirillum magnetotacticum. AB - Ferric iron reductase was purified from magnetotactic bacterium Magnetospirillum (formerly Aquaspirillum) magnetotacticum (ATCC 31632) to an electrophoretically homogeneous state. The enzyme was loosely bound on the cytoplasmic face of the cytoplasmic membrane and was found more frequently in magnetic cells than in nonmagnetic cells. The molecular mass of the purified enzyme was calculated upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis to be about 36 kDa, almost the same as that calibrated by gel filtration analysis. The enzyme required NADH and flavin mononucleotide (FMN) as optimal electron donor and cofactor, respectively, and the activity was strongly inhibited by Zn2+ acting as a partial mixed-type inhibitor. The Km values for NADH and FMN were 4.3 and 0. 035 microM, respectively, and the Ki values for Zn2+ were 19.2 and 23.9 microM for NADH and FMN, respectively. When the bacterium was grown in the presence of ZnSO4, the magnetosome number in the cells and the ferric iron reductase activity declined in parallel with an increase in the ZnSO4 concentration of the medium, suggesting that the ferric iron reductase purified in the present study may participate in magnetite synthesis. PMID- 10094693 TI - Analysis of the role of trans-translation in the requirement of tmRNA for lambdaimmP22 growth in Escherichia coli. AB - The small, stable RNA molecule encoded by ssrA, known as tmRNA or 10Sa RNA, is required for the growth of certain hybrid lambdaimmP22 phages in Escherichia coli. tmRNA has been shown to tag partially synthesized proteins for degradation in vivo by attaching a short peptide sequence, encoded by tmRNA, to the carboxyl termini of these proteins. This tag sequence contains, at its C terminus, an amino acid sequence that is recognized by cellular proteases and leads to degradation of tagged proteins. A model describing this function of tmRNA, the trans-translation model (K. C. Keiler, P. R. Waller, and R. T. Sauer, Science 271:990-993, 1996), proposes that tmRNA acts first as a tRNA and then as a mRNA, resulting in release of the original mRNA template from the ribosome and translocation of the nascent peptide to tmRNA. Previous work from this laboratory suggested that tmRNA may also interact specifically with DNA-binding proteins, modulating their activity. However, more recent results indicate that interactions between tmRNA and DNA-binding proteins are likely nonspecific. In light of this new information, we examine the effects on lambdaimmP22 growth of mutations eliminating activities postulated to be important for two different steps in the trans-translation model, alanine charging of tmRNA and degradation of tagged proteins. This mutational analysis suggests that, while charging of tmRNA with alanine is essential for lambdaimmP22 growth in E. coli, degradation of proteins tagged by tmRNA is required only to achieve optimal levels of phage growth. Based on these results, we propose that trans-translation may have two roles, the primary role being the release of stalled ribosomes from their mRNA template and the secondary role being the tagging of truncated proteins for degradation. PMID- 10094694 TI - A periplasmic D-alanyl-D-alanine dipeptidase in the gram-negative bacterium Salmonella enterica. AB - The VanX protein is a D-alanyl-D-alanine (D-Ala-D-Ala) dipeptidase essential for resistance to the glycopeptide antibiotic vancomycin. While this enzymatic activity has been typically associated with vancomycin- and teicoplainin resistant enterococci, we now report the identification of a D-Ala-D-Ala dipeptidase in the gram-negative species Salmonella enterica. The Salmonella enzyme is only 36% identical to VanX but exhibits a similar substrate specificity: it hydrolyzes D-Ala-D-Ala, DL-Ala-DL-Phe, and D-Ala-Gly but not the tripeptides D-Ala-D-Ala-D-Ala and DL-Ala-DL-Lys-Gly or the dipeptides L-Ala-L Ala, N-acetyl-D-Ala-D-Ala, and L-Leu-Pro. The Salmonella dipeptidase gene, designated pcgL, appears to have been acquired by horizontal gene transfer because pcgL-hybridizing sequences were not detected in related bacterial species and the G+C content of the pcgL-containing region (41%) is much lower than the overall G+C content of the Salmonella chromosome (52%). In contrast to wild-type Salmonella, a pcgL mutant was unable to use D-Ala-D-Ala as a sole carbon source. The pcgL gene conferred D-Ala-D-Ala dipeptidase activity upon Escherichia coli K 12 but did not allow growth on D-Ala-D-Ala. The PcgL protein localizes to the periplasmic space of Salmonella, suggesting that this dipeptidase participates in peptidoglycan metabolism. PMID- 10094695 TI - Characterization of the pyoluteorin biosynthetic gene cluster of Pseudomonas fluorescens Pf-5. AB - Ten genes (plt) required for the biosynthesis of pyoluteorin, an antifungal compound composed of a bichlorinated pyrrole linked to a resorcinol moiety, were identified within a 24-kb genomic region of Pseudomonas fluorescens Pf-5. The deduced amino acid sequences of eight plt genes were similar to the amino acid sequences of genes with known biosynthetic functions, including type I polyketide synthases (pltB, pltC), an acyl coenzyme A (acyl-CoA) dehydrogenase (pltE), an acyl-CoA synthetase (pltF), a thioesterase (pltG), and three halogenases (pltA, pltD, and pltM). Insertions of the transposon Tn5 or Tn3-nice or a kanamycin resistance gene in each of these genes abolished pyoluteorin production by Pf-5. The presumed functions of the eight plt products are consistent with biochemical transformations involved in pyoluteorin biosynthesis from proline and acetate precursors. Isotope labeling studies demonstrated that proline is the primary precursor to the dichloropyrrole moiety of pyoluteorin. The deduced amino acid sequence of the product of another plt gene, pltR, is similar to those of members of the LysR family of transcriptional activators. pltR and pltM are transcribed divergently from the pltLABCDEFG gene cluster, and a sequence with the characteristics of a LysR binding site was identified within the 486-bp intergenic region separating pltRM from pltLABCDEFG. Transcription of the pyoluteorin biosynthesis genes pltB, pltE, and pltF, assessed with transcriptional fusions to an ice nucleation reporter gene, was significantly greater in Pf-5 than in a pltR mutant of Pf-5. Therefore, PltR is proposed to be a transcriptional activator of linked pyoluteorin biosynthesis genes. PMID- 10094696 TI - RsaL, a novel repressor of virulence gene expression in Pseudomonas aeruginosa. AB - As components of a Pseudomonas aeruginosa quorum-sensing system, LasR and PAI-1 globally regulate expression of multiple virulence determinants, as well as the second P. aeruginosa quorum-sensing system. To date, no information exists on negative regulation of the quorum-sensing cascade in P. aeruginosa. Here we describe a novel gene, rsaL, which is located downstream from lasR and transcribed antisense relative to lasR. In P. aeruginosa, overexpression of rsaL results in reduced lasB expression and decreased elastase activity. With the use of a six-His protein fusion system, we demonstrate that rsaL encodes an 11-kDa protein. Direct quantitation of PAI-1 levels in cultures and studies utilizing Escherichia coli lambda lysogens carrying lacZ transcriptional fusions reveal that RsaL specifically represses transcription of the PAI-1 autoinducer synthase gene, lasI. RsaL's repressive effect on lasI and the associated decrease in elastase activity have important implications for the expression of all LasR-PAI 1-dependent virulence genes and the overall pathogenicity of P. aeruginosa. PMID- 10094697 TI - Transcriptional activation of ydeA, which encodes a member of the major facilitator superfamily, interferes with arabinose accumulation and induction of the Escherichia coli arabinose PBAD promoter. AB - Induction of genes expressed from the arabinose PBAD promoter is very rapid and maximal at low arabinose concentrations. We describe here two mutations that interfere with the expression of genes cloned under arabinose control. Both mutations map to the ydeA promoter and stimulate ydeA transcription; overexpression of YdeA from a multicopy plasmid confers the same phenotype. One mutation is a large deletion that creates a more efficient -35 region (ATCACA changed to TTCACA), whereas the other affects the initiation site (TTTT changed to TGTT). The ydeA gene is expressed at extremely low levels in exponentially growing wild-type cells and is not induced by arabinose. Disruption of ydeA has no detectable effect on cell growth. Thus, ydeA appears to be nonessential under usual laboratory growth conditions. The ydeA gene encodes a membrane protein with 12 putative transmembrane segments. YdeA belongs to the largest family of bacterial secondary active transporters, the major facilitator superfamily, which includes antibiotic resistance exporters, Lac permease, and the nonessential AraJ protein. Intracellular accumulation of arabinose is strongly decreased in mutant strains overexpressing YdeA, suggesting that YdeA facilitates arabinose export. Consistent with this interpretation, very high arabinose concentrations can compensate for the negative effect of ydeA transcriptional activation. Our studies (i) indicate that YdeA, when transcriptionally activated, contributes to the control of the arabinose regulon and (ii) demonstrate a new way to modulate the kinetics of induction of cloned genes. PMID- 10094698 TI - The bspA locus of Lactobacillus fermentum BR11 encodes an L-cystine uptake system. AB - BspA is a basic surface-exposed protein from Lactobacillus fermentum BR11. Sequence comparisons have shown that it is a member of family III of the solute binding proteins. It is 89% identical to the collagen binding protein, Cnb, from Lactobacillus reuteri. Compared with the database of Escherichia coli proteins, BspA is most similar to the L-cystine binding protein FliY. To investigate the function of BspA, mutants depleted for BspA were generated by homologous recombination with a temperature-sensitive plasmid. These mutants were significantly impaired in their abilities to take up L-cystine. Uptake rates of L glutamine, L-histidine, and L-lysine, which are substrates for other binding proteins with similarity to BspA, were unaffected. Evidence was obtained that BspA is necessary for maximal resistance to oxidative stress. Specifically, inactivation of BspA causes defective growth in the presence of oxygen and sensitivity to paraquat. Measurements of sulfhydryl levels showed that incubation of L. fermentum BR11 with L-cystine resulted in increased levels of sulfhydryl groups both inside and outside the cell; however, this was not the case with a BspA mutant. The role of BspA as an extracellular matrix protein adhesin was also addressed. L. fermentum BR11 does not bind to immobilized type I collagen or laminin above background levels but does bind immobilized fibronectin. Inactivation of BspA did not significantly affect fibronectin binding; therefore, we have not found evidence to support the notion that BspA is an extracellular matrix protein binding adhesin. As BspA is most probably not a lipoprotein, this report provides evidence that gram-positive bacterial solute binding proteins do not necessarily have to be anchored to the cytoplasmic membrane to function in solute uptake. PMID- 10094699 TI - Genetic localization and molecular characterization of two key genes (mitAB) required for biosynthesis of the antitumor antibiotic mitomycin C. AB - Mitomycin C (MC) is an antitumor antibiotic derived biosynthetically from 3-amino 5-hydroxybenzoic acid (AHBA), D-glucosamine, and carbamoyl phosphate. A gene (mitA) involved in synthesis of AHBA has been identified and found to be linked to the MC resistance locus, mrd, in Streptomyces lavendulae. Nucleotide sequence analysis showed that mitA encodes a 388-amino-acid protein that has 71% identity (80% similarity) with the rifamycin AHBA synthase from Amycolatopsis mediterranei, as well as with two additional AHBA synthases from related ansamycin antibiotic-producing microorganisms. Gene disruption and site-directed mutagenesis of the S. lavendulae chromosomal copy of mitA completely blocked the production of MC. The function of mitA was confirmed by complementation of an S. lavendulae strain containing a K191A mutation in MitA with AHBA. A second gene (mitB) encoding a 272-amino-acid protein (related to a group of glycosyltransferases) was identified immediately downstream of mitA that upon disruption resulted in abrogation of MC synthesis. This work has localized a cluster of key genes that mediate assembly of the unique mitosane class of natural products. PMID- 10094700 TI - Acid- and base-induced proteins during aerobic and anaerobic growth of Escherichia coli revealed by two-dimensional gel electrophoresis. AB - Proteins induced by acid or base, during long-term aerobic or anaerobic growth in complex medium, were identified in Escherichia coli. Two-dimensional gel electrophoresis revealed pH-dependent induction of 18 proteins, nine of which were identified by N-terminal sequencing. At pH 9, tryptophan deaminase (TnaA) was induced to a high level, becoming one of the most abundant proteins observed. TnaA may reverse alkalinization by metabolizing amino acids to produce acidic products. Also induced at high pH, but only in anaerobiosis, was glutamate decarboxylase (GadA). The gad system (GadA/GadBC) neutralizes acidity and enhances survival in extreme acid; its induction during anaerobic growth may help protect alkaline-grown cells from the acidification resulting from anaerobic fermentation. To investigate possible responses to internal acidification, cultures were grown in propionate, a membrane-permeant weak acid which acidifies the cytoplasm. YfiD, a homologue of pyruvate formate lyase, was induced to high levels at pH 4.4 and induced twofold more by propionate at pH 6; both of these conditions cause internal acidification. At neutral or alkaline pH, YfiD was virtually absent. YfiD is therefore a strong candidate for response to internal acidification. Acid or propionate also increased the expression of alkyl hydroperoxide reductase (AhpC) but only during aerobic growth. At neutral or high pH, AhpC showed no significant difference between aerobic and anaerobic growth. The increase of AhpC in acid may help protect the cell from the greater concentrations of oxidizing intermediates at low pH. Isocitrate lyase (AceA) was induced by oxygen across the pH range but showed substantially greater induction in acid or in base than at pH 7. Additional responses observed included the induction of MalE at high pH and induction of several enzymes of sugar metabolism at low pH: the phosphotransferase system components ManX and PtsH and the galactitol fermentation enzyme GatY. Overall, our results indicate complex relationships between pH and oxygen and a novel permeant acid-inducible gene, YfiD. PMID- 10094701 TI - Genes coding for phosphotransacetylase and acetate kinase in Sinorhizobium meliloti are in an operon that is inducible by phosphate stress and controlled by phoB. AB - Recent work in this laboratory has shown that the gene coding for acetate kinase (ackA) in Sinorhizobium meliloti is up-regulated in response to phosphate limitation. Characterization of the region surrounding ackA revealed that it is adjacent to pta, which codes for phosphotransacetylase, and that these two genes are part of an operon composed of at least two additional genes in the following order: an open reading frame (orfA), pta, ackA, and the partial sequence of a gene with an inferred peptide that has a high degree of homology to enoyl-ACP reductase (fabI). Experiments combining enzyme assays, a chromosomal lacZ::ackA transcriptional fusion, complementation analysis with cosmid subclones, and the creation of mutations in pta and ackA all indicated that the orfA-pta-ackA-fabI genes are cotranscribed in response to phosphate starvation. Primer extension was used to map the position of the phosphate starvation-inducible transcriptional start sites upstream of orfA. The start sites were found to be preceded by a sequence having similarity to PHO boxes from other phosphate-regulated genes in S. meliloti and to the consensus PHO box in Escherichia coli. Introduction of a phoB mutation in the wild-type strain eliminated elevated levels of acetate kinase and phosphotransacetylase activities in response to phosphate limitation and also eliminated the phosphate stress-induced up-regulation of the ackA::lacZ fusion. Mutations in either ackA alone or both pta and ackA did not affect the nodulation or nitrogen fixation phenotype of S. meliloti. PMID- 10094702 TI - Mutations that confer resistance to 2-deoxyglucose reduce the specific activity of hexokinase from Myxococcus xanthus. AB - The glucose analog 2-deoxyglucose (2dGlc) inhibits the growth and multicellular development of Myxococcus xanthus. Mutants of M. xanthus resistant to 2dGlc, designated hex mutants, arise at a low spontaneous frequency. Expression of the Escherichia coli glk (glucokinase) gene in M. xanthus hex mutants restores 2dGlc sensitivity, suggesting that these mutants arise upon the loss of a soluble hexokinase function that phosphorylates 2dGlc to form the toxic intermediate, 2 deoxyglucose-6-phosphate. Enzyme assays of M. xanthus extracts reveal a soluble hexokinase (ATP:D-hexose-6-phosphotransferase; EC 2.7.1.1) activity but no phosphotransferase system activities. The hex mutants have lower levels of hexokinase activities than the wild type, and the levels of hexokinase activity exhibited by the hex mutants are inversely correlated with the ability of 2dGlc to inhibit their growth and sporulation. Both 2dGlc and N-acetylglucosamine act as inhibitors of glucose turnover by the M. xanthus hexokinase in vitro, consistent with the finding that glucose and N-acetylglucosamine can antagonize the toxic effects of 2dGlc in vivo. PMID- 10094703 TI - A conserved domain in Escherichia coli Lon protease is involved in substrate discriminator activity. AB - Lon protease of Escherichia coli regulates a diverse set of physiological responses including cell division, capsule production, plasmid stability, and phage replication. Little is known about the mechanism of substrate recognition by Lon. To examine the interaction of Lon with two of its substrates, RcsA and SulA, we generated point mutations in lon which affected its substrate specificity. The most informative lon mutant overproduced capsular polysaccharide (RcsA stabilized) yet was resistant to DNA-damaging agents (SulA degraded). Immunoblots revealed that RcsA protein persisted in this mutant whereas SulA protein was rapidly degraded. The mutant contains a single-base change within lon leading to a single amino acid change of glutamate 240 to lysine. E240 is conserved among all Lon isolates and resides in a charged domain that has a high probability of adopting a coiled-coil conformation. This conformation, implicated in mediating protein-protein interactions, appears to confer substrate discriminator activity on Lon. We propose a model suggesting that this coiled coil domain represents the discriminator site of Lon. PMID- 10094704 TI - Molecular analysis of a novel methanesulfonic acid monooxygenase from the methylotroph Methylosulfonomonas methylovora. AB - Methylosulfonomonas methylovora M2 is an unusual gram-negative methylotrophic bacterium that can grow on methanesulfonic acid (MSA) as the sole source of carbon and energy. Oxidation of MSA by this bacterium is carried out by a multicomponent MSA monooxygenase (MSAMO). Cloning and sequencing of a 7.5-kbp SphI fragment of chromosomal DNA revealed four tightly linked genes encoding this novel monooxygenase. Analysis of the deduced MSAMO polypeptide sequences indicated that the enzyme contains a two-component hydroxylase of the mononuclear iron-center type. The large subunit of the hydroxylase, MsmA (48 kDa), contains a typical Rieske-type [2Fe-2S] center with an unusual iron-binding motif and, together with the small subunit of the hydroxylase, MsmB (20 kDa), showed a high degree of identity with a number of dioxygenase enzymes. However, the other components of the MSAMO, MsmC, the ferredoxin component, and MsmD, the reductase, more closely resemble those found in other classes of oxygenases. MsmC has a high degree of identity to ferredoxins from toluene and methane monooxygenases, which are enzymes characterized by possessing hydroxylases containing mu-oxo bridge binuclear iron centers. MsmD is a reductase of 38 kDa with a typical chloroplast like [2Fe-2S] center and conserved flavin adenine dinucleotide- and NAD-binding motifs and is similar to a number of mono- and dioxygenase reductase components. Preliminary analysis of the genes encoding MSAMO from a marine MSA-degrading bacterium, Marinosulfonomonas methylotropha, revealed the presence of msm genes highly related to those found in Methylosulfonomonas, suggesting that MSAMO is a novel type of oxygenase that may be conserved in all MSA-utilizing bacteria. PMID- 10094705 TI - Oxygen depletion-induced dormancy in Mycobacterium bovis BCG. AB - Gradual depletion of oxygen causes the shift-down of aerobic growing Mycobacterium bovis BCG to an anaerobic synchronized state of nonreplicating persistence. The persistent culture shows induction of glycine dehydrogenase and alpha-crystallin-like protein and is sensitive to metronidazole. PMID- 10094706 TI - Induction of prophages of enterohemorrhagic Escherichia coli O157:H7 with norfloxacin. AB - Norfloxacin (NFLX) caused induction of prophages VT1 and VT2 of enterohemorrhagic Escherichia coli O157 at subinhibitory concentrations. In time course experiments, we observed the following sequential events: upon induction, the phage genomes underwent multiplication; the amount of stx genes increased; and subsequently, large quantities of toxins VT1 and VT2 were produced. Further studies showed that the molecular mechanism of prophage induction is closely related to the RecA system since the prophage VT2 was not induced with NFLX in a recA mutant strain. PMID- 10094707 TI - Mutational analysis of the vacA promoter provides insight into gene transcription in Helicobacter pylori. AB - Analysis of 12 Helicobacter pylori promoters indicates the existence of a consensus -10 hexamer (TAtaaT) but little conservation of -35 sequences. In this study, mutations in either the H. pylori vacA -10 region or the -35 region resulted in decreased vacA transcription and suggested that an extended -10 motif is utilized. Thus, despite the lack of a -35 consensus sequence for H. pylori promoters, the -35 region plays a functional role in vacA transcription. PMID- 10094708 TI - Structure-function study of MalF protein by random mutagenesis. AB - MalF is one of the two integral inner membrane proteins of the maltose maltodextrin transport system. To identify functional regions in this protein, we characterized a collection of malF mutants obtained by random mutagenesis. We analyzed their growth on maltose and maltodextrins, the steady-state levels and subcellular localization of the mutant proteins, and the subcellular localization of MalK. Only 2 of the 21 MalF mutant proteins allowed growth on maltose and maltodextrins. Most mutations resulting in immunodetectable proteins mapped to hydrophilic domains, indicating that insertions affecting transmembrane segments gave rise to unstable or lethal proteins. All MalF mutant proteins, even those C terminally truncated or with large N-terminal deletions, were inserted into the cytoplasmic membrane. Having identified mutations leading to reduced steady-state level, to partial mislocation, and/or to misfolding, we were able to assign to some regions of MalF a role in the assembly of the MalFGK2 complex and/or in the transport mechanism. PMID- 10094709 TI - The choline-converting pathway in Staphylococcus xylosus C2A: genetic and physiological characterization. AB - A Staphylococcus xylosus C2A gene cluster, which encodes enzymes in the pathway for choline uptake and dehydrogenation (cud), to form the osmoprotectant glycine betaine, was identified. The cud locus comprises four genes, three of which encode proteins with significant similarities to those known to be involved in choline transport and conversion in other organisms. The physiological role of the gene products was confirmed by analysis of cud deletion mutants. The fourth gene possibly codes for a regulator protein. Part of the gene cluster was shown to be transcriptionally regulated by choline and elevated NaCl concentrations as inducers. PMID- 10094710 TI - Genetic organization of the Escherichia coli K10 capsule gene cluster: identification and characterization of two conserved regions in group III capsule gene clusters encoding polysaccharide transport functions. AB - Analysis of the Escherichia coli K10 capsule gene cluster identified two regions, regions 1 and 3, conserved between different group III capsule gene clusters. Region 1 encodes homologues of KpsD, KpsM, KpsT, and KpsE proteins, and region 3 encodes homologues of the KpsC and KpsS proteins. An rfaH mutation abolished K10 capsule production, suggesting that expression of the K10 capsule was regulated by RfaH in a manner analogous to group II capsule gene clusters. An IS3 element and a phiR73-like prophage, both of which may have played a role in the acquisition of group III capsule gene clusters, were detected flanking the K10 capsule genes. PMID- 10094711 TI - Target joining of duplicated insertion sequence IS21 is assisted by IstB protein in vitro. AB - Tandemly repeated insertion sequence IS21, located on a suicide plasmid, promoted replicon fusion with bacteriophage lambda in vitro in the presence of ATP. This reaction was catalyzed in a cell extract containing the 45-kDa IstA protein (cointegrase) and the 30-kDa IstB helper protein of IS21 after both proteins had been overproduced in Escherichia coli. Without IstB, replicon fusion was inefficient and did not produce the 4-bp target duplications typical of IS21. PMID- 10094712 TI - Isolation of an active catalytic core of Streptococcus downei MFe28 GTF-I glucosyltransferase. AB - Truncated variants of GTF-I from Streptococcus downei MFe28 were purified by means of a histidine tag. Sequential deletions showed that the C-terminal domain was not directly involved in the catalytic process but was required for primer activation. A fully active catalytic core of only 100 kDa was isolated. PMID- 10094713 TI - Structure of a new glycolipid from the Mycobacterium avium-Mycobacterium intracellulare complex. AB - From the lipid fraction of a freeze-dried cell mass of a strain of the Mycobacterium avium-Mycobacterium intracellulare complex, a new glycolipid was isolated and was characterized as 5-mycoloyl-alpha-arabinofuranosyl (1-->1') glycerol, mainly on the basis of nuclear magnetic resonance spectroscopy studies. PMID- 10094714 TI - Cellular locations of Pseudomonas syringae pv. syringae HrcC and HrcJ proteins, required for harpin secretion via the type III pathway. AB - The complete hrp-hrc-hrmA cluster of Pseudomonas syringae pv. syringae 61 encodes 28 polypeptides. A saprophytic bacterium carrying this cluster is capable of secreting HrpZ-a harpin encoded by hrpZ-in an hrp-dependent manner, which suggests that this cluster contains sufficient components to assemble functional type III secretion machinery. Sequence data show that HrcJ and HrcC are putative outer membrane proteins, and nonpolar mutagenesis demonstrates they are all required for HrpZ secretion. In this study, we investigated the cellular localization of the HrcC and HrcJ proteins by Triton solubilization, sucrose gradient isopycnic centrifugation, and immunogold labeling of the bacterial cell surface. Our results indicate that HrcC is indeed an outer membrane protein and that HrcJ is located between both membranes. Their membrane localization suggests that they might be involved in the formation of a supramolecular structure for protein secretion. PMID- 10094715 TI - Characterization of mdcR, a regulatory gene of the malonate catabolic system in Klebsiella pneumoniae. AB - The Klebsiella pneumoniae mdcR gene, which encodes a LysR-type regulator, was overexpressed in Escherichia coli. Purified MdcR was found to bind specifically to the control region of either the malonate decarboxylase (mdc) genes or mdcR. We have also demonstrated that MdcR is an activator of the expression of the mdc genes, whereas it represses the transcription of the putative control region of mdcR, PmdcR, indicating a negative autoregulatory control. PMID- 10094717 TI - 14C-chlorpyrifos residues in tomatoes and tomato products. PMID- 10094716 TI - Conserved organization in the cps gene clusters for expression of Escherichia coli group 1 K antigens: relationship to the colanic acid biosynthesis locus and the cps genes from Klebsiella pneumoniae. AB - Group 1 capsules of Escherichia coli are similar to the capsules produced by strains of Klebsiella spp. in terms of structure, genetics, and patterns of expression. The striking similarities between the capsules of these organisms prompted a more detailed investigation of the cps loci encoding group 1 capsule synthesis. Six strains of K. pneumoniae and 12 strains of E. coli were examined. PCR analysis showed that the clusters in these strains are conserved in their chromosomal locations. A highly conserved block of four genes, orfX-wza-wzb-wzc, was identified in all of the strains. The wza and wzc genes are required for translocation and surface assembly of E. coli K30 antigen. The conservation of these genes points to a common pathway for capsule translocation. A characteristic JUMPstart sequence was identified upstream of each cluster which may function in conjunction with RfaH to inhibit transcriptional termination at a stem-loop structure found immediately downstream of the "translocation-surface assembly" region of the cluster. Interestingly, the sequence upstream of the cps clusters in five E. coli strains and one Klebsiella strain indicated the presence of IS elements. We propose that the IS elements were responsible for the transfer of the cps locus between organisms and that they may continue to mediate recombination between strains. PMID- 10094718 TI - Organochlorine compounds in pelicans (Pelecanus crispus and Pelecanus onocrotalus) nesting at Lake Mikri Prespa, north western Greece. PMID- 10094719 TI - Disappearance of 2,4-dinitrotoluene and 2-Amino,4,6-dinitrotoluene by Phanerochaete chrysosporium under non-ligninolytic conditions. PMID- 10094720 TI - Organochlorine pesticide residues in human blood serum of inhabitants of Veracruz, Mexico. PMID- 10094721 TI - Ambient lead levels in urban areas. PMID- 10094722 TI - Essential elements in environmental samples from selected regions in Slovakia. PMID- 10094724 TI - Landscape care pesticide residues in residential drinking water wells. PMID- 10094723 TI - Formation of formaldehyde from methyl tert-butyl ether (MTBE) upon UV irradiation. PMID- 10094725 TI - Sorption of acid dyes by chemically modified peanut hulls. PMID- 10094726 TI - Contribution of nonpolar organic compounds to the toxicity of a chemical works effluent. PMID- 10094727 TI - Assessment of industrial effluent toxicity using flow-through fish egg/alevins/fry (EAF) Toxicity Test. PMID- 10094728 TI - Acute toxicity of permethrin/piperonyl butoxide on hybrid striped bass. PMID- 10094729 TI - Relationship between kinetics of benzo[a]pyrene bioaccumulation and DNA binding in the mussel Mytilus galloprovincialis. PMID- 10094730 TI - Structure-toxicity relationships for selected lactones to Tetrahymena pyriformis. PMID- 10094731 TI - Sensitivity of the sand crab Emerita analoga to a weathered oil. PMID- 10094732 TI - Combined chromium and phenol pollution in a marine prawn fishery. PMID- 10094733 TI - Algae growth potential measurement in distillery wastes. PMID- 10094734 TI - Copper exposure reduced the resistance of the catfish Saccobranchus fossilis to Aeromonas hydrophila infection. PMID- 10094735 TI - Safety evaluation of the fungicide iprodione on cauliflower (Brassica oleracea var. oleracea L.). PMID- 10094736 TI - Metal binding properties of ferritin in Vigna mungo (L.) Hepper (black gram): possible role in heavy metal detoxification. PMID- 10094737 TI - Wound healing in earthworms Lumbricus terrestris: a cellular-based biomarker for assessing sublethal chemical toxicity. PMID- 10094738 TI - Laparoscopic herniorrhaphy: where are we now? PMID- 10094739 TI - Open or laparoscopic preperitoneal mesh repair for recurrent inguinal hernia? A randomized controlled trial. AB - BACKGROUND: Giant prosthetic reinforcement of the visceral sac (GPRVS), an open preperitoneal mesh repair, is a very effective groin hernia repair. Laparoscopic transabdominal preperitoneal repair (TAPP), based on the same principle, is expected to combine low recurrence rates with minimal postoperation morbidity. METHODS: Seventy-nine patients with 93 recurrent and 15 concomitant primary inguinal hernias were randomized between GPRVS (37 patients) and TAPP (42 patients). Operating time, complications, pain, analgesia use, disability period, and recurrences were recorded. RESULTS: Mean operating time was 56 min with GPRVS versus 79 min with TAPP (p < 0. 001). Most complications were minor, except for a pulmonary embolus and an ileus, both after GPRVS. Patients experienced less pain after a laparoscopic repair. Average disability period was 23 days with GPRVS versus 13 days with TAPP (p = 0.03) for work, and 29 versus 21 days, respectively (p = 0.07) for physical activities. Recurrence rates at a mean follow-up of 34 months were 1 in 52 (1.9%) for GPRVS versus 7 in 56 (12.5%) for TAPP (p = 0.04). Hospital costs in U.S. dollars were comparable, with GPRVS at $1,150 and TAPP at $1,179. CONCLUSIONS: Laparoscopic repair of recurrent inguinal hernia has a lower morbidity than GPRVS. However, laparoscopic repair is a difficult operation, and the potential technical failure rate is higher. With regard to recurrence rates, the open preperitoneal prosthetic mesh repair remains the best repair. PMID- 10094740 TI - Laparoscopic hernioplasty: significant complications. AB - BACKGROUND: The aim of this study was to determine the incidence and causes of serious complications after laparoscopic hernioplasty. Complications observed after laparoscopic hernia repair performed by a single surgeon specializing in the technique were analyzed. METHOD: A retrospective review of patients who underwent a laparoscopic hernioplasty, either transabdominal preperitoneal (TAPP) or totally extraperitoneal (TEP), was performed by the author between July 1991 and August 1997. RESULTS: In 1,087 patients, 1,423 hernias had been repaired by the TAPP or TEP approach. These were followed 1 month to 6 years. In patients followed at least 6 months with a median follow-up of 42 months, six repairs recurred (0.4%), and all underwent a remedial operation. Significant complications occurred in 29 patients (2.7%). Three of four intraoperative complications were in the surgeon's first 100 cases and consisted of bleeding from a trocar and injury to the bowel. Significant postoperation complications included pain in 12 patients: re-exploration required in 4, trocar hernia in 6, small bowel obstruction in 1, and hydrocele requiring surgery in 6. The incidence of complications in the first 3 years was 5.6% compared with 0.5% in the last 3 years, and 90% of complications developed in the first 50% of patients. CONCLUSIONS: This study demonstrated that the incidence of significant complications after laparoscopic hernioplasty could be substantially reduced by experience to less than 1%. The risk of complications after a totally extraperitoneal approach may be less than that of a transabdominal approach, but a randomized study is needed to confirm this supposition. PMID- 10094741 TI - A randomized comparison of driver reaction time after open and endoscopic tension free inguinal hernia repair. AB - BACKGROUND: The aim of this study was to assess whether prosthetic tension-free inguinal hernia repair would cause less impairment of reaction times, thus allowing an earlier return to driving than previously recommended after conventional hernia repair. METHODS: Driver reaction times were measured in 64 patients randomized to open tension-free repair or totally extraperitoneal endoscopic inguinal hernia repair. Measurements were made preoperatively and on postoperation days 1, 3, and 6. RESULTS: In the endoscopic group, there was a gradual improvement in hand and foot reaction times over the days tested. In the open group, there was a slowing in both hand and foot reaction times on postoperation days 1 and 3. The difference in foot reaction times between the open and endoscopic groups was significant on these days (p = 0.01 and 0.003, respectively). By day 6, the foot reaction times in the open group were slightly faster than before surgery. CONCLUSIONS: After prosthetic tension-free inguinal hernia repair, patients can return to driving 1 week after the operation. PMID- 10094742 TI - Endoscopic vs conventional hernia repair from an immunologic point of view. AB - BACKGROUND: In this study we tried to estimate the local surgical trauma in patients undergoing endoscopic or conventional hernia repair via the changes in peripheral blood T cell subpopulations (i. e., T-helper 1 (TH1) and TH2 cells), recently shown to be recruited differentially to inflammatory sites. METHODS: Cells were identified flow-cytometrically by intracellular cytokine staining on a single cell level in 30 patients undergoing conventional (Shouldice) or total extraperitoneal patch (TEPP) hernia repair. RESULTS: The TH1 cells decreased postoperatively in Shouldice patients on an average of 20.8-31.4%, whereas in TEPP patients only a minor decline (mean, 7.8-9.2%) was observed. The TH2 cells did not change significantly in TEPP patients, and a small increase (mean, 7.7%) was detected in Shouldice patients. CONCLUSIONS: Our results suggest that the postoperative reduction in TH1 cells reflects local surgical trauma and can be helpful in evaluating different surgical procedures. When conventional and endoscopic hernia repair were compared, the latter proved less traumatizing. PMID- 10094743 TI - How secure are the arteries occluded by a newly developed ultrasonically activated device? AB - BACKGROUND: We developed a new ultrasonically activated device (USAD) for endoscopic surgery. The current investigation was conducted to evaluate the security of the arteries occluded and divided by this USAD. METHODS: The intraperitoneal arteries of anesthetized living pigs were individually occluded by the USAD at power levels of 70% or 100%. The burst pressures of the harvested arteries were measured in vitro. For comparison, arteries occluded by laparoscopic clips or silk ligatures were evaluated in the same manner. RESULTS: The pressures to burst the occluded artery ranged from 353 to 2,148 mmHg with an average of 1,204 mmHg in the USAD group at 70% power level; from 324 to 2,207 mmHg with an average of 1,193 mmHg in the USAD group at 100% power level; from 794 to 1,868 mmHg with an average of 1,421 mmHg in the clip group; and from 618 to 3,207 mmHg with an average of 1,586 mmHg in the silk ligature group. CONCLUSION: The data suggest the improbability that small- to medium-size arteries appropriately occluded and divided by the USAD can burst when exposed to intravascular pressures commonly found in living animals. PMID- 10094744 TI - Laparoscopic partial adrenalectomy. AB - BACKGROUND: Most laparoscopic adrenalectomies involve total removal of the whole adrenal gland, and reports of laparoscopic partial adrenalectomies have been very few. The criteria for performing a laparoscopic partial adrenalectomy have not been described. METHODS: (a) Patients with functioning adrenal tumors smaller than 3 cm in diameter were selected. (b) The solitary adrenal tumors were evaluated by preoperative thin-slice computed tomography (CT) scan. (c) Solitary lesions were reconfirmed with intraoperative ultrasonography. (d) Partial adrenalectomy was performed with at least a 5-mm margin using a vascular stapler. RESULTS: Laparoscopic partial adrenalectomy was performed in five patients using the vascular stapler. Hemostasis was perfect in all five patients. The tumor was located in the inferior part of the right adrenal gland in three cases and in the upper pole of the left adrenal gland in two cases. The postoperation pathologic diagnosis was adrenocortical adenoma in all five patients, and excessive hormonal levels or symptoms all disappeared. CONCLUSIONS: Laparoscopic partial adrenalectomy can be performed safely using a vascular stapler. PMID- 10094745 TI - Complications in thoracoscopic spinal surgery: a study of 90 consecutive patients. AB - BACKGROUND: The literature contains few reports on negative outcomes after thoracoscopic spinal surgery. METHODS: From November 1995 to February 1998, 90 patients underwent minimally invasive spinal surgery by thoracoscopic assistance as treatment for their anterior spinal lesions. The diagnoses included 41 spinal metastases, 13 cases of scoliosis, 12 burst fractures, 10 cases of tuberculous spondylitis, 8 cases of pyogenic spondylitis, 2 thoracic disc herniations, 2 cases of ankylosing spondylitis with discitis, 1 osteoporotic compression fracture, and 1 case of thoracolumbar kyphosis. The procedures included biopsy only (3 patients); thoracic discectomy (3 patients); multilevel anterior releases, discectomy, and fusion (14 patients); corpectomy for decompression (6 patients); corpectomy and interbody fusion (32) patients; and internal instrumentation (28 patients). RESULTS: A total of 30 complications were noted in 22 patients (24.4%). Two fatal complications occurred, resulting from massive blood transfusion in one case and postoperative pneumonia in another. Other nonfatal complications included four cases of transient intercostal neuralgia, three superficial wound infections, three cases of pharyngeal pain, two cases of lung atelectasis, two cases of residual pneumothorax, two cases of subcutaneous emphysema, one inadvertent pericardial penetration due to adhesion, one chylothorax that resolved after conservative management, one vertebral screw malposition, and one graft dislodgement that needed late revision surgery. Three patients required ventilatory support for longer than 72 hours. Five patients with spinal metastases had an estimated intraoperative blood loss of more than 2,000 ml. No injury to the internal organs or spinal cord was observed. There were four conversions to open procedures due to two cases of severe pleural adhesions and two poorly tolerated one-lung ventilation. At the latest follow-up, nine patients had died as a result of cancer dissemination. CONCLUSIONS: (a) Well selected patients and attention to details are essential to optimizing surgical results. (b) A refined technique for less invasive tumor surgery has been developed. (c) Surgeons had better experience with the standard anterior spinal approach and showed no hesitation in converting to an open procedure when necessary. A procedure failure does not mean a treatment failure. PMID- 10094746 TI - Minimally invasive surgery for gastric cancer. AB - BACKGROUND: The use of laparoscopic surgery in the treatment of gastric cancer has not yet met with widespread acceptance; thus, it should be regarded as still in the developmental phase. Nevertheless, the laparoscopic approach appears to have some valuable advantages for the management of gastric cancer patients, and it can be expected to have a dramatic impact on public health expenditures. Herein we present the results of our experience with laparoscopic and laparoscopy assisted gastrectomies for cancer, and we discuss the role of these procedures in current surgical practice. METHODS: Between June 1993 and November 1997, we performed a total of 13 laparoscopic procedures on 13 patients affected with gastric carcinoma. There were eight male and five female patients with a mean age of 65.4 years (range, 42-78). All patients were staged preoperatively with US and CT scan and required to sign a formal consent. RESULTS: Altogether we performed nine D1 laparoscopic total gastrectomies, seven of which were done with a laparoscopy-assisted approach; three D2 laparoscopy-assisted total gastrectomies, associated in one case with a distal pancreasectomy; and one laparoscopy-assisted distal gastrectomy performed on a morbid obese patient. The preliminary laparoscopic staging allowed for a better definition of tumor extension and identification of undetected hepatic metastases in two patients. The mean duration of the intervention was 240 min. Blood losses were as high as 300 cc on average. We recorded one major intraoperative complication, consisting of an inadvertent injury to the proper hepatic artery, which was successfully repaired by the same laparoscopic route. The postoperative course was uneventful in all patients but one, who died of acute hepatic failure on day 6. At a mean follow-up of 27.5 months, 11 patients are still alive. Two of them have hepatic metastases and nine are disease-free. CONCLUSIONS: Although they remain challenging procedures, laparoscopic gastrectomies appear to be oncologically adequate. We believe that a pure laparoscopic approach should be reserved for low-stage lesions (N0, up to T2), while a combined approach is preferable for locally advanced cancer (N1 or higher, T3 or higher). Much work still needs to be done to establish the optimal strategy in both open and laparoscopic surgery, but laparoscopy can be a valuable tool in the decision-making process for patients affected with gastric malignancies. PMID- 10094747 TI - Endosonography during endoscopic mucosal resection to enhance its safety: a new technique. AB - BACKGROUND: We have performed endoscopic mucosal resection of the esophagus (172 cases), stomach (102 cases), and colon (28 cases) using a transparent plastic cap. Because the lesion-bearing mucosa is suctioned up inside the cap under endoscopic suction, the mucosa should be dissected sufficiently from the proper muscle layer to prevent perforation. METHODS: To avert the risk of perforation, we introduced endosonographic assessment of submucosal dissection (47 cases). In all cases, just keeping the ultrasonic probe on the surface of the mucosa allowed us to evaluate whether the mucosal lesion was lifted up sufficiently from the proper muscle layer after local saline injection. RESULTS: It was possible to confirm that the muscle layer was kept outside the strangulating snare by the same procedure (32 of 37 cases, 86.5%). CONCLUSIONS: We experienced five muscular resections in cases without the ultrasonic probe and no muscular resection with the ultrasonic probe. Thus we recommend endosonographic assessment during endoscopic mucosal resection to enhance its safety. PMID- 10094748 TI - Transgastrostomal endoscopic surgery for early gastric carcinoma and submucosal tumor. AB - BACKGROUND: Laparoscopic intraluminal surgery of the stomach is now widely used for a lesion on the posterior wall. However, this procedure has some technical limitation related to the intricate introduction of the surgical instruments into the gastric lumen. In this article, we report our newly developed technique of transgastrostomal endoscopic surgery that overcomes this limitation and is also suitable for full-thickness gastric wall resection of a lesion in the wall. METHODS: After making a 4-cm-long temporary gastrostomy, a Buess-type endoscope is inserted into the gastric lumen through the gastrostomy. The operation is performed inside the gastric lumen under video camera guidance using electrocautery, scissors, and forceps. After resection, the wound in the mucosa or the wound after full-thickness resection is endoluminally sutured. Mucosal resection was performed in six cases of early gastric carcinoma, two cases of atypical epithelium, and one case of ectopic pancreas. Full-thickness wall resection was performed in four cases of a leiomyoma. RESULTS: In all 13 cases, the lesion could be precisely located by the video camera. All lesions were then resected endoluminally. The mean duration of the operation was 148 min. The postoperative course in all cases was uneventful. CONCLUSIONS: Transgastrostomal endoscopic surgery is minimally invasive and an efficient tissue-preserving technique for the removal of early gastric carcinoma or submucosal tumor. PMID- 10094749 TI - Increased tumor growth and spread after laparoscopy vs laparotomy: influence of tumor manipulation in a rat model. AB - BACKGROUND: The use of laparoscopy for assessment and treatment of malignant tumors remains controversial. The aim of this study was to evaluate the impact of tumor manipulation during laparoscopy compared with that of conventional laparotomy on growth and spread of an intraperitoneal tumor in the rat in a randomized, controlled trial. METHODS: Thirty 2-month-old male Lewis rats received a single-site intrapancreatic inoculation of a ductal adenocarcinoma. Fourteen days after cancer implanting, two groups of six animals each underwent a laparotomy (30 min 6 mmHg CO2 pneumoperitoneum). The tumor was manipulated in the one group, and exclusively visualized in the other. In two other groups, a midline laparotomy with (n = 6) or without (n = 6) tumor manipulation was performed. Animals in the control group (n = 6) underwent no procedure. Tumor volume, tumor mass, local regional invasion incidence, lymph node involvement, and liver and lung metastases were evaluated on 28-day tumors. RESULTS: No difference in tumor growth and spread was observed between laparoscopy and laparotomy when tumor manipulation was not carried out. Tumor manipulation increased tumor growth significantly in the laparotomy group, but not in the laparoscopy one. Tumor metastases were correlated to tumor growth and increased significantly after manipulation in both groups. There was no port-site or conventional wound seeding in either the surgical procedure. CONCLUSIONS: This study showed that manipulation is the main factor acting on tumor dissemination in both laparoscopy and laparotomy. Laparoscopic surgery had a beneficial effect on local tumor growth compared with laparotomy in the case of tumor manipulation. This beneficial effect of laparoscopic surgery may be related to a better preservation of immune function in the early postoperative period. PMID- 10094750 TI - Influence of the optical axis-to-target view angle on endoscopic task performance. AB - BACKGROUND: The location of the optical port and the choice of endoscope determine the angle subtended between the optical axis of the endoscope and the plane of the operation target: the optical axis-to-target view (OATV) angle. The aim of the study was to investigate the influence OATV angle on endoscopic task performance. METHODS: The Dundee Endoscopic Psychomotor Tester was used for objective assessment of endoscopic task performance. Ten surgeons carried out a standard task with the optical axis of the endoscope subtending 90 degrees, 75 degrees, 60 degrees and 45 degrees to the target surface. Each subject underwent three test sessions. Each session consisted of one run with each of the OATV angles in a random order. The outcome measures were the errors rate, the execution time, and the force applied on the target. RESULTS: The 90 degrees OATV angle had the best accuracy, the shortest execution time, and the lowest force applied on the back plate. The errors rate increased from 17% with the 90 degrees OATV angle to 79% with the 45 degrees angle. There was a significant increase in execution time and force with the decrease in the OATV angle (p < 0.0001). CONCLUSIONS: The best task performance is obtained when the optical axis of the endoscope is perpendicular to the target plane. PMID- 10094751 TI - Hemodynamic consequences of high- and low-pressure capnoperitoneum during laparoscopic cholecystectomy. AB - BACKGROUND: Peritoneal insufflation to 15 mmHg diminishes venous return and reduces cardiac output. Such changes may be dangerous in patients with a poor cardiac reserve. The aim of this study was to investigate the hemodynamic effects of high (15 mmHg) and low (7 mmHg) intraabdominal pressure during laparoscopic cholestectomy (LC) METHODS: Twenty patients were randomized to either high- or low-pressure capnoperitoneum. Anesthesia was standardized, and the end-tidal CO2 was maintained at 4.5 kPa. Arterial blood pressure was measured invasively. Heart rate, stroke volume, and cardiac output were measured by transesophageal doppler. RESULTS: There were 10 patients in each group. In the high-pressure group, heart rate (HR) and mean arterial blood pressure (MABP) increased during insufflation. Stroke volume (SV) and cardiac output were depressed by a maximum of 26% and 28% (SV 0.1 > p > 0.05, cardiac output p > 0. 1). In the low-pressure group, insufflation produced a rise in MABP and a peak rise in both stroke volume and cardiac output of 10% and 28%, respectively (p < 0.05). CONCLUSIONS: Low-pressure pneumoperitoneum is feasible for LC and minimizes the adverse hemodynamic effects of peritoneal insufflation. PMID- 10094753 TI - Transthoracoscopic needle biopsy for indeterminate lung nodules. AB - BACKGROUND: The usefulness of transthoracoscopic needle biopsy for preoperatively indeterminate intrapulmonary nodules was evaluated. METHODS: Thoracoscopy was performed on 38 patients with pulmonary solitary nodules suspected to be primary lung carcinomas. When the nodule was localized by simple observation or tactile sensor, a biopsy specimen of the tumor was obtained by a biopsy needle introduced through a trocar. RESULTS: The nodules were 7 to 55 mm in diameter. All were located in the peripheral region of the lung. Biopsy specimens were obtained even from 17 nodules with no associated pleural changes. By cytology, all the malignant tumors were precisely diagnosed, 29 as primary lung cancers and 3 as metastatic lung neoplasms. Five of the remaining six benign nodules were not precisely diagnosed. However, they were cytologically classified as class I. CONCLUSIONS: Transthoracoscopic needle biopsy is feasible for diagnosing small intrapulmonary nodules, particularly those of malignant neoplasms. As compared with thoracoscopic excisional biopsy, transthoracoscopic needle biopsy saves time and may reduce the possibility of tumor dissemination during the procedure. PMID- 10094752 TI - A randomized controlled trial to determine the effects of humidified carbon dioxide insufflation during thoracoscopy. AB - BACKGROUND: The humidification of gas insufflated during laparoscopy can reduce the degree of postoperative hypothermia and may result in less peritoneal reaction and less postoperative pain. The present study was designed to determine whether the beneficial effects of humidified gas insufflation also applied to thoracoscopy. METHODS: Six pigs were each studied on three separate occasions with insufflation into the right thoracic cavity of either humidified gas, standard dry gas, or with no insufflation (control procedure). Core body temperature was recorded every 15 min, and biopsies of the parietal pleura were taken at the end of each study for electron microscopy. RESULTS: Humidification of insufflated gas significantly minimized the fall in core temperature during the procedure. Electron microscopy showed that dry gas insufflation resulted in greater structural injury to the pleura than humidified gas insufflation. CONCLUSIONS: The potential benefits of humidifying insufflation gas during thoracoscopy warrant its evaluation in the clinical setting. PMID- 10094754 TI - Effects of laparotomy vs pneumoperitoneum on the hepatic catabolic stress response in ambulatory and stationary settings in pigs. AB - BACKGROUND: We recently demonstrated that laparoscopic cholecystectomy is followed by a much smaller hepatic catabolic stress response than conventional cholecystectomy. It is not known what is responsible for this difference. METHODS: Thirty pigs were randomly allocated to the following five treatment groups: (1) laparotomy, (2) pneumoperitoneum, (3) pneumoperitoneum with insertion of four trocars, (4) laparotomy, (5) pneumoperitoneum. Groups 1-3 were operated on in an ambulatory setting, whereas groups 4 and 5 were operated on in a stationary setting. Urea synthesis, as quantified by functional hepatic nitrogen clearance, and the response of stress hormones and cytokines were assessed. RESULTS: Laparotomy increased the functional hepatic nitrogen clearance by 195% (p < 0.001); pneumoperitoneum and trocars increased it by 145% (p < 0.001); and pneumoperitoneum alone increased it by 113% (p < 0. 001). The difference between laparotomy and both pneumoperitoneum groups was significant. If the stress factor of ambulatory surgery was eliminated, the increase in functional hepatic nitrogen clearance was reduced to 87% (p < 0.01) after laparotomy and 38% (NS) for animals subject to pneumoperitoneum. There were significant differences in concentrations of stress hormones, tumor necrosis factor alpha, and interleukin 8 among groups intra- and postoperatively. CONCLUSIONS: The magnitude of the postoperative hepatic stress response after laparotomy compared to pneumoperitoneum with and without insertion of trocars seems to be caused by the greater trauma to the abdominal wall. Furthermore, an ambulatory setting seems to be an important postoperative stress factor in itself. PMID- 10094755 TI - Safety of preoperation endoscopic tattoo with india ink for identification of colonic lesions. AB - BACKGROUND: Colonic tattooing with india ink is a widely practiced technique regarded as safe, accurate, and reliable. In this series, the largest reported, the safety of this technique is studied. METHODS: A retrospective study of 8,125 consecutive patients who undersent colonoscopy over a 64-month period was conducted. India ink colonic mucosal tattooing was used for either preoperative marking or future endoscopic identification of a lesion. RESULTS: During the study, 195 patients underwent endoscopic injection of india ink. Of these, 50 patients were marked before surgery, and 145 underwent marking with the intent of facilitating future endoscopic localization. Patients were followed by either telephone interviews or physical examination. None of the patients developed fever, persistent abdominal pain, or abdominal tenderness on examination. All surgeons were interviewed. They uniformly reported the tattoo as intensely visible and of great utility in locating the lesions. CONCLUSIONS: Preoperative mucosal tattooing with india ink is recommended as a safe and necessary procedure. PMID- 10094756 TI - Percutaneous endoscopic gastrostomy in burn patients. AB - BACKGROUND: Prolonged enteral feedings are required occasionally in seriously burned individuals. We have employed percutaneous endoscopic gastrostomy (PEG) in selected patients who require particularly prolonged access, thus prompting this review. METHODS: The PEG procedure was performed under general anesthesia in combination with another surgical procedure using a variety of commercially available needle and guidewire kits in 14 patients. RESULTS: These 14 patients had an average age of 55.2 +/- 6.6 years and a burn involving 38 +/- 8% of the body surface. Eleven of these patients had suffered an inhalation injury. The tubes were placed an average of 57 +/- 10.5 days after injury through unburned and unharvested skin in four patients (28%), healed donor sites in five patients (35%), healed burn in one patient (1%), and grafted burn in four patients (28%). One patient, whose catheter was placed through a grafted fascial excision, developed moderate local wound erosion. Tubes were known to have been left in place as long as 155 days. However, most were removed in rehabilitation hospitals, and we were unable to determine how long most were left in place. We are unaware of any problems with the tubes occurring after discharge from the acute care setting. CONCLUSIONS: In selected patients, PEG can provide more comfortable access for prolonged enteral feedings than nasogastric tubes and can be placed with minimal morbidity. PMID- 10094757 TI - Current management of endoscopic feeding tube dysfunction. AB - Surgically placed gastrostomy and jejunostomy feeding tubes allow administration of enteral nutrition for patients who are unable to swallow safely. Several endoscopic techniques have been used for tube placement. Endoscopically placed feeding tubes provide access to the gastrointestinal tract, but only when patent. Use of the approaches presented permits optimal feeding tube care and prolongs tube patency. Table 1 summarizes the recommendations for preventing and restoring patency to feeding tubes. PMID- 10094758 TI - Laparoscopic enucleation of a solitary pancreatic insulinoma. AB - Insulinomas are usually small, benign tumors of the pancreas, often found in obese patients, which require an incision that is out of all proportion to the size of the lesion. A laparoscopic technique for enucleation of a pancreatic insulinoma is described. PMID- 10094759 TI - Pericardio peritoneal window: laparoscopic approach. AB - Transdiaphragmatic approach to the pericarium through the use of the laparoscope is a safe and rapid way to obtain biopsy of the pericardium and create a window. No drainage tubes are needed: pericardial fluid is absorbed by the peritoneum; there is no need for double lumen tubes for one lung ventilation; and the laparoscopy incisions are small and almost painless. PMID- 10094761 TI - EndoScope: world literature reviews PMID- 10094760 TI - Ultrasonic dissection for endoscopic surgery. The E.A.E.S. Technology Group. AB - With the development of endoscopic surgery, new hazards of high-frequency (HF) electrosurgery have been recognized. The potential risks of monopolar electrosurgery, the limitations of bipolar technique, and the need to reduce instrument interchange have favored the use of ultrasonic technology, which becomes more and more popular. This work aims at presenting the main features of the currently available ultrasonically activated scalpels, as well as their advantages, limitations, and indications. PMID- 10094762 TI - Endoscopic intrauterine surgery in primates: overcoming technical obstacles. AB - Current protocols for fetal surgery require cesarean section and partial fetal extraction, both of which impart significant risks to the mother and fetus. Endoscopic fetal surgery is less invasive and will likely reduce some of these risks, but the technical difficulties and feasibility in a primate model have yet to be explored fully. Four pregnant baboons (95 days gestation) were anesthetized, their uteruses exposed via an abdominal incision, and blunt-tipped flanged endoscopic ports inserted. Amniotic fluid was removed, and warmed saline was infused to dilate the uterus. To evaluate instrumentation and wound closure, the tip of the snout was externalized and bilateral cleft lip-like defects made. The lips were then endoscopically repaired by suture (Endostitch, U.S. Surgical) or unique nonpenetrating clips (VCS, U.S. Surgical). The saline was then removed, amniotic fluid returned, and the ports carefully removed. After 4 weeks, the fetuses were delivered and evaluated. Eight cleft lip-like defects were successfully repaired in all four cases. Operative time averaged 83 min. No infections, amniotic leaks, or adhesions developed. Survival was 50% with two fetuses delivering within 48 hours postoperatively: one from preterm labor, the other with fetal demise from retroperitoneal hemorrhage after operative blunt abdominal trauma. We demonstrate the feasibility of endoscopic fetal surgery in primates. The use of blunt-tipped flanged ports provides a fluid tight seal and allows appropriate closure of the fetal membranes, but requires laparotomy and uterine exposure. Distension of the uterus with warmed saline affords a larger operating field, enhancing visualization and instrumentation of the fetus. Grasping the fetus through the exposed uterus gives excellent control for repair. However, such control is also needed in a percutaneous approach. Further instrumentation development is needed to accomplish similar control for the percutaneous approach. PMID- 10094763 TI - To cut is not always to cure. PMID- 10094764 TI - A simple technique for delivery of bulky gallbladders during laparoscopic cholecystectomy. PMID- 10094765 TI - Diagnosis and treatment of diverticular disease: results of a consensus development conference. The Scientific Committee of the European Association for Endoscopic Surgery. AB - BACKGROUND: With the aim of resolving the current controversy over the diagnosis and treatment of diverticular disease, this consensus development conference set out to summarize the actual state of the art. METHODS: A multidisciplinary panel of international experts (n = 16) was selected to take part in the consensus process. Prior to the conference, all experts were asked to answer a series of questions on diverticular disease. The consensus statement compiled out of these evaluations was modified during a joint meeting of the panel members, then presented for discussion in a public session, and finally revised by the expert panel. The finalized statement was mailed to all panel members for approval (Delphi method). RESULTS: Asymptomatic diverticulosis, diverticular disease (with actual or recurrent symptoms), and complicated diverticular disease were defined separately. No agreement was reached on whether barium enema or colonoscopy is the better choice as an initial diagnostic tool in uncomplicated cases. In complicated cases, computed tomography is recommended for diagnosis. After two attacks of diverticular disease, elective resection should be considered. For patients in whom a concomitant carcinoma cannot be excluded and those with chronic complications (fistula, stenosis, or bleeding) surgery is also indicated. Laparoscopic sigmoid colectomy is recommended only for uncomplicated and, after percutaneous drainage of abscesses, Hinchey stage I and II cases. CONCLUSIONS: Laparoscopic surgery has already begun to influence the management of diverticular disease, but the randomized controlled trials needed to support therapy decisions are largely missing. PMID- 10094766 TI - News and notices PMID- 10094768 TI - Extraction method for analysis of detergent-solubilized bacteriorhodopsin and hydrophobic peptides by electrospray ionization mass spectrometry. AB - The analysis of integral membrane proteins or transmembrane peptides by electrospray ionization mass spectrometry (ESI-MS) is difficult since detergents, used to solubilize these hydrophobic proteins and peptides, severely suppress analyte ion formation. This problem has been addressed previously by precipitating the protein, removing the detergent, and resolubilizing the protein in a nonpolar solvent. Here, we demonstrate a method that avoids protein precipitation and resolubilization. Detergent-solubilized bacteriorhodopsin is extracted into a nonpolar solvent phase by adding a chloroform/methanol/water solvent mixture to the aqueous detergent solution. ESI mass spectra of the nonpolar, chloroform-rich phase were dominated by peaks due to bacterioopsin. Bacterioopsin precursors with partially cleaved leader sequences were seen in all mass spectra. Additional peaks were likely due to intact bacteriorhodopsin, i.e., bacterioopsin with the retinal prosthetic group attached, and to bacterioopsin associated with lipid molecules. A separation process that occurred in the fused silica capillary leading to the electrospray tip was essential for obtaining ESI mass spectra of bacterioopsin. The extraction-into-chloroform procedure also worked well with hydrophobic, transmembrane-type peptides that were insoluble in other electrospray solvents, including 100% formic acid, and the method has application to transmembrane peptides formed from digests of integral membrane proteins. PMID- 10094769 TI - Influence of the amino acid residue downstream of (Asp)4Lys on enterokinase cleavage of a fusion protein. AB - We have studied the cleavage efficiency of the protease enterokinase (EK) using the novel vector pESP4. pESP4 is a yeast expression vector equipped with ligation independent cloning sites, a GST purification tag, and a FLAG epitope tag. EK is used to cleave the FLAG and GST tags leaving the protein of interest without any extraneously added amino acids. We have found that EK is relatively permissive of the amino acid residue downstream of the recognition sequence (the P'1 position). This makes EK an ideal choice to use as a protease to cleave any protein of interest cloned within the pESP4 yeast expression vector. PMID- 10094770 TI - Rapid assay for nitric oxide synthase using thin-layer chromatography. AB - A simple, sensitive, and rapid method to determine the nitric oxide synthase (NOS) activity in crude cell extracts has been developed. The method takes advantage of differential migration of arginine and citrulline on silica gel thin layer chromatography (TLC) with the specified buffer system. We have shown that products obtained by treating [14C]arginine with crude mouse hippocampal homogenate can be separated by methanol precipitation followed by TLC. The separated products of the enzyme reaction can be quantitated by radiometric scanning of the TLC plate or by counting in a scintillation counter. Inhibition of conversion of l-arginine to l-citrulline by NG-monomethyl-l-arginine acetate, a specific inhibitor of NOS, confirmed the NOS assay described in this investigation. This method is versatile and allows rapid simultaneous assay of several samples in a short period of time. Therefore, this assay is very useful for both qualitative and quantitative estimation of NOS activity. PMID- 10094771 TI - Quantitation of fluorescent nucleotide incorporation by capillary gel electrophoresis and laser-induced fluorescence detection. AB - A method has been developed by which enzymatically incorporated fluorophore labeled nucleotide sites in nucleic acid can be quantitated by degradation of nanogram quantities of DNA followed by capillary gel electrophoretic analysis with fluorescence detection. In this way the differing relative labeling densities achieved using either C5-substituted dUTP's or N4-substituted dCTP's were determined. The method has proven to be very useful in obtaining quantitative analytical data from the small quantities of complex molecules produced in nick translations. Various polymerization conditions using DNA polymerase I were examined to determine optimal labeling density. Simultaneous copolymerization of green fluorescing dCTP and dUTP nucleotides were undertaken in an attempt to maximize labeling density. PMID- 10094772 TI - RNA-binding properties of in vitro expressed histidine-tagged RB69 RegA translational repressor protein. AB - To facilitate RNA-binding studies of the phage RB69 RegA translational repressor protein, regA was configured to add six histidines to the carboxyl end of the protein. In vitro transcription-translation from the T7 promoter on plasmid pSA1 yielded a RegA69-His6 protein that binds nickel-Sepharose and elutes with 0.5 M imidazole. The system was further modified to avoid cloning and the toxic effects of RegA on Escherichia coli by the polymerase chain reaction (PCR), producing linear templates with the configuration T7 promoter-TIR-regA-His6. A translation initiation region was used that conforms to consensus E. coli and eukaryotic initiation sites and eliminates the target for RegA autogenous repression. RegA69 His6 synthesized in E. coli S30 or wheat germ extracts displayed RNA-binding properties similar to wild-type RB69 RegA. Specificity of RNA binding was demonstrated by in vitro repression of T4 gp44 and gp45 but not beta-lactamase, by differential binding to poly(U)- and poly(C)-agarose, and by site-specific binding to a 23-base gene 44 target RNA but not to mutant 44 RNA. Therefore, addition of the His6 tag to the C-terminus of RB69 RegA does not dramatically alter RNA binding, indicating that this region is not directly involved in site recognition. With access to several T4-like phage genomes and regA mutant sequences, in vitro synthesis of His-tagged proteins directly from linear PCR products provides a convenient and efficient system to study RegA and other interesting RNA-binding proteins. PMID- 10094773 TI - A microplate-based colorimetric assay of the total peroxyl radical trapping capability of human plasma. AB - We developed a colorimetric assay estimating the radical-scavenging activity of human plasma. The test is based on a measure, in 96-well microplates at 450 nm, of the bleaching of carotenoid crocin by peroxyl radicals generated during thermal decomposition of 2, 2'-azobis-(2-amidinopopane) dihydrochloride (ABAP). The inhibition of this bleaching is a function of the antioxidant power of substances added to incubation mixture. We determined the optimal conditions for a sensitive, rapid, and reproducible assay of 50% inhibitory capacity (IC50) of a range of antioxidant substances and of plasma. Only a total of 200 microl of plasma is required in a complete dose-inhibition curve. The IC50 of normal human plasma resulted of 2.70 microl of plasma/250 microl assay volume. The total antioxidant capability (TAC) of plasma was defined as the reciprocal of IC50 and its value in a group of 19 healthy adults resulted in 0. 369 +/- 0.06. Intraassay and interassay coefficients of variation of plasma TAC were 6.13 and 4.80%, respectively. Measurement of samples with different uric acid concentration showed that antioxidant activity of uric acid accounts for approximately two thirds of TAC. PMID- 10094774 TI - Isolation and lipid composition of apical and basolateral membranes of colonic segments of guinea Pig. AB - In adapting several methods of membrane isolation we established a successful way to purify apical and basolateral membranes of guinea pig colon in a parallel procedure. The conventional purification control by marker enzymes was applied. In addition, luminal membrane proteins were stained with Texas Red. Apical and basolateral enterocyte membranes were enriched 10- to 12-fold by differential precipitation and via a continuous sorbitol gradient. The membrane fractions were examined with regard to their phospholipid (PL) and fatty acid patterns and to their cholesterol content. Fluorescence polarization studies were carried out using 1,6-diphenyl-1,3, 5-hexatrien. Remarkable differences in the fatty acid pattern of the proximal and the distal colon were seen. Due to a higher content of oleic acid the saturation index of the apical membranes of the proximal colon is lower compared to that of the apical membranes of the distal colon (0.34 +/- 0.03 vs 0.42 +/- 0.05). The cholesterol content of the apical membranes of the proximal colon is markedly higher than that of the apical membranes of the distal colon (3.42 +/- 0.14 vs 1.88 +/- 0.29 mol/mol PL). There are no differences in the fluidity of these apical membranes. We assume a balancing mechanism between the cholesterol content and the amount of saturated PL-fatty acids. PMID- 10094775 TI - Partial vapor-phase hydrolysis of peptide bonds: A method for mass spectrometric determination of O-glycosylated sites in glycopeptides. AB - In this study we present a method for determination of O-glycosylation sites in glycopeptides, based on partial vapor-phase acid hydrolysis in combination with mass spectrometric analysis. Pentafluoropropionic acid and hydrochloric acid were used for the hydrolysis of glycosylated peptides. The reaction conditions were optimized for efficient polypeptide backbone cleavages with minimal cleavage of glycosidic bonds. The glycosylated residues were identified by mass spectrometric analysis of the hydrolytic cleavage products. Although glycosidic bonds are partially cleaved under acid hydrolysis, the resulting mass spectra allowed unambiguous determination of the glycosylation sites. Examples are shown with mannosyl- and mucin-type glycopeptides. Performing the hydrolysis in vapor eliminates the risk for contamination of the sample with impurities from the reagents, thus allowing analysis of the reaction products without further purification both by matrix-assisted laser desorption/ionization and electrospray ionization mass spectrometry. PMID- 10094776 TI - Determination of copy number of c-Myc protein per cell by quantitative Western blotting. AB - The protooncogene c-Myc plays a key role in growth control, differentiation, and apoptosis. An abnormally high expression of c-myc has been found to be associated with many neoplasms. c-Myc gene expression is usually measured at the mRNA level. Few studies have been published on quantitative Myc protein determination. A major drawback of ELISA (enzyme-linked immunosorbent assay) methods is the uncertainty of the specificity of the antibody reaction. In contrast, antibody specificity can be easily controlled by Western/immunoblotting. Here we describe a method to quantify c-Myc protein in primary human IMR90 lung fibroblasts based on Western blotting. Using a high-resolution polyacrylamide gel, we were able to differentiate the cellular c-Myc protein (64 kDa) from a c-Myc internal standard (65 kDa). We determined both the total c-Myc protein content per cell and its distribution in the cytoplasmic and nuclear fractions. About 4000 c-Myc protein molecules were detected in the cytoplasmic fraction and 29,000 copies in the nuclear fraction for proliferating human lung fibroblasts IMR90. The ratio of nuclear (active) to cytoplasmic (inactive) c-Myc protein changed from 17:1 for proliferating cells to 2.5:1 for confluent cells. PMID- 10094777 TI - High-performance liquid chromatographic assay of the diadenosine polyphosphates in human platelets. AB - Diadenosine pentaphosphate (Ap5A) and diadenosine hexaphosphate (Ap6A) were recently identified in human platelets and were shown to be important modulators of cardiovascular function. Here we describe an HPLC assay for quantitating Ap3A, Ap4A, Ap5A, and Ap6A contents in human platelets simultaneously. Di(1,N6 ethenoadenosine) hexaphosphate was used as internal standard. The extraction procedure consists of (a) deproteinization, (b) selective concentration of the diadenosine polyphosphates with a boronate affinity chromatography, and (c) desalting prior to the HPLC analysis. The assay was validated by PSD-MALDI-mass spectrometry and by addition of authentic diadenosine polyphosphate to platelet samples. The assay was carried out by an ion-pair reversed-phase perfusion chromatography. In platelets from human blood the following amounts of diadenosine polyphosphates were determined: Ap3A, 192.5 +/- 151.0 nM; Ap4A, 223.8 +/- 172.3 nM; Ap5A, 100.2 +/- 81.1 nM; Ap6A, 32.0 +/- 19.6 nM (mean +/- SD, n = 105). The described assay can be used with less than 20 ml blood and allows quantitation of the diadenosine polyphosphates in the picomole range. PMID- 10094778 TI - Use of a phosphotyrosine-antibody pair as a general detection method in homogeneous time-resolved fluorescence: application to human immunodeficiency viral protease. AB - A homogeneous time-resolved fluorescence (HTRF) assay has been developed for human immunodeficiency viral (HIV) protease. The assay utilizes a peptide substrate, differentially labeled on either side of the scissile bond, to bring two detection components, streptavidin-cross-linked XL665 (SA/XL665) and a europium cryptate (Eu(K))-labeled antiphosphotyrosine antibody, into proximity allowing fluorescence resonance energy transfer (FRET) to occur. Cleavage of the doubly labeled substrate by HIV protease precludes complex formation, thereby decreasing FRET, and allowing enzyme activity to be measured. Potential substrates were evaluated by HTRF with the best results being obtained using (LCB)K4AVSQNbeta-NapPIVpYA(NH2) and Eu(K)-pY20 where the peptide titrated with an EC50 of 7.7 +/- 0.3 nM under optimized detection conditions. Using these HTRF detection conditions, HIV protease cleaved the substrate in 50 mM NaOAc, 150 mM KF, 0.05% Tween 20, pH 5.5, with apparent first-order kinetics with a Km of 37.8 +/- 8.7 microM and a kcat of 0.95 +/- 0.07 s-1. Examination of the first-order rate constant versus enzyme concentration suggested a Kd of 9.4 +/- 2.7 nM for the HIV protease monomer-dimer equilibrium. The HTRF assay was also utilized to measure the inhibition of the enzyme by two known inhibitors. PMID- 10094779 TI - Homogeneous proximity tyrosine kinase assays: scintillation proximity assay versus homogeneous time-resolved fluorescence. AB - Two homogeneous proximity assays for tyrosine kinases, scintillation proximity assay (SPA) and homogeneous time-resolved fluorescence (HTRF), have been developed and compared. In both formats, the kinase assay was performed using biotinylated peptide substrate, ATP ([33P]ATP in the case of SPA), and tyrosine kinase in a 96-well assay format. After the kinase reaction was stopped, streptavidin-coated SPA beads or europium cryptate-labeled anti-phosphotyrosine antibody and streptavidin-labeled allophycocyanin were added as detection reagents for SPA or HTRF assays, respectively. Since the assay signal was detected only when the energy donor (radioactivity for SPA, Eu for HTRF) and the energy acceptor molecules (SPA beads for SPA, allophycocyanin for HTRF) were in close proximity, both assays required no wash or liquid transfer steps. This homogeneous ("mix-and-measure") nature allows these assays to be much simpler, more robust, and easier to automate than traditional protein kinase assays, such as a filter binding assay or ELISA. Both assays have been miniaturized to a 384 well format to reduce the assay volume, thereby saving the valuable screening samples as well as assay reagents, and automated using automated pipetting stations to increase the assay throughput. Several advantages and disadvantages for each assay are described. PMID- 10094780 TI - Observation of Escherichia coli ribosomal proteins and their posttranslational modifications by mass spectrometry. AB - Ribosomes from the K-12 strain of Escherichia coli were analyzed with good sensitivity and high mass accuracy using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Fifty-five of the 56 subunit proteins were observable. Mass spectral peak locations were consistent with previously reported post-translational modifications involving N-terminal methionine loss, methylation, thiomethylation, and acetylation for all but one case. The speed and accuracy of mass spectrometry make it a good candidate for phylogenetic studies of ribosomes and the observation of posttranslational modifications in other organisms. PMID- 10094781 TI - Analysis of sialyllactoses in blood and urine by high-performance liquid chromatography. AB - A sensitive and highly selective high-performance liquid chromatography (HPLC) based method has been developed for the analysis of oligosaccharides in biological fluids. In this method, a sample of biological fluid, such as blood serum or urine, is filtered through a 10,000 molecular weight cutoff filter cartridge to remove large molecules such as proteins and lipids. The carbohydrates in the filtrate are then derivatized with 1-phenyl-3-methyl-5 pyrazolone (PMP) as described previously [Anal. Biochem. 180, 351-357, (1989)]. The derivatized carbohydrates are separated by reverse-phase HPLC and monitored by UV absorbance at 245 nm. Quantitative analysis of the carbohydrates can be achieved based on their integration values relative to a standard calibration curve. Since neutral and acidic carbohydrates can be separated by using Dowex 1 X8 anion exchange resin, this method can be used specifically to analyze neutral, acidic, and total carbohydrates in the biological fluids. Because PMP specifically reacts with reducing aldoses, interference from noncarbohydrate components present in the biological fluids is essentially eliminated. This method has proven to be highly sensitive, requiring as little as 5 pmol of analyte for reliable analysis. It has also been used successfully for pharmacokinetic analysis of carbohydrate drugs in human blood and urine samples. PMID- 10094782 TI - Determination of D-amino acids labeled with fluorescent chiral reagents, R(-)- and S(+)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N, N-dimethylaminosulfonyl)-2,1,3 benzoxadiazoles, in biological and food samples by liquid chromatography. AB - D-Amino acids in food and biological samples labeled with R(-)- and S(+)-4-(3 isothiocyanatopyrrolidin-1-yl)-7-(N, N-dimethylaminosulfonyl)-2,1,3 benzoxadiazoles (DBD-PyNCS) were separated by reversed-phase chromatography and detected fluorometrically at 550 nm (excitation at 460 nm). DL-Amino acids were efficiently labeled at 55 degrees C for 20 min in basic medium. The resulting thiocarbamoyl-amino acids were resolved by an isocratic elution using water:30% methanol in acetonitrile (72:28) containing 0.1% trifluoracetic acid as mobile phase for hydrophilic amino acids and gradient elutions using sodium acetate buffer (pH 5. 2)/acetonitrile as gradient solvent mixture for hydrophobic amino acids, respectively. The detection limits (S/N = 3) of DL-amino acids tested were in the range of 0.16-0.75 pmol. The proposed method was applied to determine the D-amino acid(s) in milk, cream, fermented dairy products (yogurt and yakult), tomato products (juice, puree, and catchup), fermented beverages (beer and red wine), and human urine. The existence of D-amino acid(s) was demonstrated in all the samples tested. Furthermore, the identification of the D-amino acid(s) was performed using both isomers of DBD-PyNCS and by on-line HPLC-electrospray ionization-MS. PMID- 10094784 TI - Determination of the entrapped volume of liposomes: dilution method. AB - A novel method was developed for the determination of the entrapped volume of liposomes. The obtained values of the entrapped volume by our "dilution method" agreed very well with those of the conventional "quenching method." The dilution method also offered the great advantages of simple procedure and high reproducibility. The principle and validity of our method are discussed. PMID- 10094783 TI - Viral protease assay based on GAL4 inactivation is applicable to high-throughput screening in mammalian cells. AB - We present an assay for viral proteases that relies on the proteolytic cleavage of substrate leading to the dissociation of the yeast transcription factor GAL4. A consensus substrate for the cytomegalovirus protease is fused between the DNA binding and transactivating domains of GAL4. Proteolysis inactivates the transcription factor which drives a luciferase reporter system. The assay is performed in mammalian cells, has a robust signal-to-noise ratio, and assesses proteolysis in a physiologic context. A unique feature of the assay is its ability to detect inhibitors of viral replication that act on viral targets other than the protease. PMID- 10094785 TI - Quantification of glutamine in proteins and peptides using enzymatic hydrolysis and reverse-phase high-performance liquid chromatography. AB - An enzymatic method for hydrolyzing bovine milk proteins was developed. Purified milk proteins (alpha-lactalbumin, beta-lactoglobulin, and beta-casein) were hydrolyzed in 0.1 M Hepes buffer (pH 7.5) containing pronase E, aminopeptidase M, and prolidase at 37 degrees C for 20 h. Free glutamine and other amino acids were derivatized with phenylisothiocyanate and separated using a C18 Pico-Tag column. Amino acids were eluted from the column with an aqueous sodium acetate acetonitrile gradient with detection at 254 nm. Glutamine recoveries from hydrolyzed alpha-lactalbumin, beta-lactoglobulin, and beta-casein were 78 +/- 4, 98 +/- 3, and 101 +/- 3% of the theoretical values, respectively. The recoveries of most amino acids were comparable with those obtained using acid hydrolysis, except for the recoveries of proline and acidic amino acids. These peptide bonds appeared to be resistant to enzymatic hydrolysis and also to inhibit the hydrolysis of adjacent amino acids. Free glutamine was found to be very stable (97% recovery) under the enzymatic hydrolysis conditions. PMID- 10094786 TI - New fluorogenic substrates for N-arginine dibasic convertase. AB - N-Arginine dibasic (NRD) convertase is a recently described peptidase capable of selectively cleaving peptides between paired basic residues. The characterization of this unique peptidase has been hindered by the fact that no facile assay procedure has been available. Here we report the development of a rapid and sensitive assay for NRD convertase, based on the utilization of two new internally quenched fluorogenic peptides: Abz-GGFLRRVGQ-EDDnp and Abz-GGFLRRIQ EDDnp. These peptides contain the fluorescent 2-aminobenzoyl moiety that is quenched in the intact peptide by a 2, 4-dinitrophenyl moiety. Cleavage by NRD convertase at the Arg-Arg sequence results in an increase of fluorescence. NRD convertase cleaves these peptides efficiently and with high specificity as observed by both HPLC and fluorescence spectroscopy. The rate of hydrolysis of the fluorogenic substrates is proportional to enzyme concentration, and obeys Michaelis-Menten kinetics. The kinetic parameters for the fluorescent peptides (Km values of approximately 1.0 microM, and Vmax values of approximately 1 microM/(min. mg) are similar to those obtained with peptide hormones as substrates. PMID- 10094787 TI - Quantitative investigation of the modular primer effect for DNA and peptide nucleic acid hexamers. AB - The effect on oligonucleotide-template duplex stability upon cohybridization of adjacently annealing oligonucleotides, the modular primer effect, was studied with biosensor technology. DNA and peptide nucleic acid (PNA) hexamer modules and sensor chip-immobilized template DNA strands were designed for analysis of nick, overlap, and gap modular hybridization situations. The fast hybridization kinetics for such hexamer modules allowed for the determination of apparent duplex affinities from equilibrium responses. The results showed that the hybridizational stability of modular hexamer pairs is strongly dependent on the positioning, concentration, and inherent affinity of the adjacently annealing hexamer module. Up to 80-fold increases in apparent affinities could be observed for adjacent modular oligonucleotide pairs compared to affinities determined for single hexamer oligonucleotide hybridizations. Interestingly, also for coinjections of different module combinations where DNA hexamer modules were replaced by their PNA counterparts, a modular primer effect was observed. The introduction of a single base gap between two hexamer modules significantly reduced the stabilization effect, whereas a gap of two bases resulted in a complete loss of the effect. The results suggest that the described biosensor based methodology should be useful for the selection of appropriate modules and working concentrations for use in different modular hybridization applications. PMID- 10094788 TI - Lifetime-based pH sensors: indicators for acidic environments. AB - We characterized the pH-dependent intensity decays of three fluorophores, Oregon green 514 carboxylic acid, Cl-NERF, and DM-NERF, using frequency-domain fluorometry, with the objective of identifying lifetime-based sensors for low pH values. These three probes were originally designed as dual excitation wavelength ratiometric probes, with high photostability and high quantum yields in aqueous solutions. We found that their fluorescence intensity decays were strongly dependent on pH. Moreover, global intensity decays analysis reveals that these probes have double exponential intensity decays at intermediate pH values and that the decay time amplitudes are greatly dependent on pH. The longer lifetime components originated from the unprotonated forms and the shorter components from the protonated forms. Both forms can emit fluorescence at intermediate pH values. The apparent pKa values were also determined from the titration curves of phase angles and modulations versus pH for the purpose of pH sensing. The apparent pKa values range from pH 3 to 5, a range where lifetime-based sensors are not presently reported. Since these probes show low pKa values and display substantial phase and modulation changes with pH, they are suitable as lifetime based pH sensors to monitor the pH changes in acidic environments. One potential application of these probes is to trace the pH in different cellular compartments. PMID- 10094789 TI - The coupling of NAD(P)+-producing reactions to a semiautomated bioluminescent reaction. AB - Many cellular metabolites can be measured with high sensitivity using bioluminescent techniques. These metabolites are coupled to an appropriate enzyme to produce NAD(P)H, which can then be coupled to the bioluminescent reactions. The sensitivity of bioluminescence cannot be readily applied to methods in which cellular metabolites consume NAD(P)H because of the difficulty in measuring, with sufficient sensitivity, decreases in the concentration of NAD(P)H against a high background NAD(P)H concentration. We have overcome these technical difficulties by developing a bioluminescent reagent to measure the production of NAD(P)+. Assays for creatine/creatine phosphate, pyruvate, and succinate, as well as the kinetic measurement of lactate, are described for a range of biological material. The assays are highly sensitive, quantitative, and reproducible and show no sample-specific inhibition. The range of assays and the diverse biological material tested suggests that NAD(P)+ bioluminescence has a wide potential for application. PMID- 10094790 TI - Femtomole quantitation of 7-ethyl-10-hydroxycamptothecine (SN-38) in plasma samples by reversed-phase high-performance liquid chromatography. AB - 7-Ethyl-10-hydroxycamptothecine (SN-38) is the active metabolite of the topoisomerase I inhibitor and antineoplastic agent, irinotecan (CPT-11). Here, we present a new and sensitive reversed-phase high-performance liquid chromatographic method for the determination of SN-38 in human plasma samples. Sample pretreatment involves a protein precipitation of 1-mL samples with 2 mL of acetonitrile, followed by a one-step solvent extraction with 5 mL of chloroform, with camptothecine used as internal standard. Chromatographic separation was achieved on an analytical column packed with Hypersil ODS material (100 x 4.6 mm i.d., 5 microm P.S.), and isocratic elution with a mixture of acetonitrile:0.1 M ammonium acetate containing 10 mM tetrabutylammonium sulfate (23:77, v/v), pH 5.3 (hydrochloric acid). The column effluent was monitored at excitation and emission wavelengths of 380 and 556 nm, respectively. The limit of quantitation of the method presented was at the low femtomole level ( approximately 8.4 fmol; equivalent to 5 pg/mL), with the standard curves being linear over nearly three orders of magnitude. Intraassay precision was <9%, while interassay variations were between 2 and 5%. The extraction efficiency was concentration independent and averaged 88.0 +/- 14.3% (mean +/- standard deviation; n = 59). The described method will be used in future studies to assess the extent of enterohepatic recirculation of SN-38 in cancer patients following intravenous CPT-11 treatment. PMID- 10094791 TI - Labeling of proteins with [35S]methionine and/or [35S]cysteine in the absence of cells. AB - Incubation of [35S]methionine and [35S]cysteine with bovine albumin, globulin, catalase, hemoglobin, or human globulin resulted in incorporation of the 35S label into each of these proteins. Trichloroacetic acid (TCA) precipitation revealed that the percentage of label incorporated ranged from 1 to 15%. The 35S labeling was resistant to dissociation by reducing SDS-PAGE, prolonged dialysis against 4 M urea, heating, TCA precipitation, and dilution by gel filtration. The labeling effect was more efficient with [35S]cysteine than [35S]methionine. Incubation of 35S label with proteins differing in methionine and cysteine content revealed no requirement for sulfur-containing amino acids in the target protein. Protein carboxymethylation reduced but did not prevent 35S label incorporation. Amino acid analysis of labeled proteins revealed that the radioactive label was not consistently associated with an individual amino acid. Differences in the ability of various proteins to spontaneously label with these amino acids suggest caution in the interpretation of metabolic labeling experiments and the necessity for inclusion of additional controls. Alternatively, our experience indicates a potentially useful method for labeling proteins in the absence of cells. PMID- 10094792 TI - Analysis of the three enzymatic activities of HIV-1 integrase in vitro using minigels for detection of the reaction products. PMID- 10094793 TI - Modified differential display technique to generate long cDNA fragments within the coding region. PMID- 10094794 TI - High-pressure liquid chromatographic method for the assay of methionine aminopeptidase activity: application to the study of enzymatic inactivation. PMID- 10094795 TI - mRNA quantification by real time TaqMan polymerase chain reaction: validation and comparison with RNase protection. PMID- 10094796 TI - Systematic differential display: A strategy for a complete assessment of differential gene expression. PMID- 10094797 TI - Successful germ-line transmission of chimeras generated by coculture aggregation with J1 ES cells and eight-cell embryos. PMID- 10094798 TI - Alteration of open reading frames by use of new gene cassettes. PMID- 10094799 TI - Differential quantitation of alternatively spliced messenger RNAs using isoform specific real-time RT-PCR. PMID- 10094800 TI - Liquid N2 bath for the powdering of tissue with a mortar and pestle. PMID- 10094801 TI - Test for stereospecifity of an automated Dd-lactate assay based on selective removal of Ll-lactate. PMID- 10094802 TI - High-resolution preparative-scale purification of RNA using the Prep Cell. PMID- 10094803 TI - An improved method for the purification of large DNA fragments from agarose gels using Wizard Plus SV columns. PMID- 10094804 TI - Transfection of myelomonocytic cell lines: cellular response to a lipid-based reagent and electroporation. PMID- 10094805 TI - Detection of DNA replication intermediates after two-dimensional agarose gel electrophoresis using a fluorescein-labeled probe. PMID- 10094806 TI - Variation in blood concentrations of cadmium and lead in the elderly. AB - This study aims at characterizing blood concentrations of cadmium (B-Cd) and lead (B-Pb) in a group of 176 men and 248 women, 49-92 years of age (mean 68 years), selected from the Swedish Twin Registry. Metal concentrations were determined using graphite furnace atomic absorption spectrophotometry. B-Cd ranged from 0.05 to 6.8 microg Cd/L (median 0.36 microg Cd/L) and B-Pb from 5.6 to 150 microg Pb/L (median 27 microg Pb/L). As expected, smokers had higher B-Cd than nonsmokers (median 1.3 versus 0.32 microg Cd/L), while B-Pb was not significantly related to smoking habits. Among nonsmokers, women had higher B-Cd than men (median 0.35 versus 0.25 microg Cd/L). In men, but not women, B-Cd increased with age and consequently the gender-related difference in B-Cd was most obvious in the youngest age group. On the other hand, women had lower B-Pb than men (median 24 versus 30 microg Pb/L). In both men and women, B-Pb decreased between 50 and 70 years of age, perhaps reflecting decreased energy intake. In women, the highest B Pb in the 50-55 years age group is probably related to an increased release of Pb from the skeleton during postmenopausal bone demineralization. After about 70 years, B-Pb tended to increase, which probably is a cohort effect due to much higher Pb exposure 10-30 years ago when leaded gasoline was used. PMID- 10094807 TI - Homeobox genes and cancer. AB - Homeobox-containing genes are a family of regulatory genes encoding transcription factors that primarily play a crucial role during development. Several indications suggest their involvement in the control of cell growth and, when dysregulated, in oncogenesis. We will describe the implications, in tumor origin and evolution, of members of the homeobox gene families HOX, EMX, PAX, and MSX as well as of other divergent homeobox genes. We will also propose a model for the function of the HOX gene network in controlling cell identity to account for the involvement of some HOX genes in both normal development and oncogenesis. PMID- 10094808 TI - Tumor radiosensitivity and apoptosis. AB - With approximately 50% of all cancer patients receiving radiation therapy at some point in their treatment, increasing the sensitivity of tumor cells to the lethal effects of irradiation has the potential to significantly improve the rate of recovery from many malignancies. The major biological determinant of radiotherapy failure is tumor radioresistance. It is well known that tumors from the same histological group and stage of development are extremely heterogeneous in their sensitivity to radiotherapy. There are many factors which could affect tumor radiosensitivity. One cellular mechanism common to various therapeutic regiments, including radiation, is killing tumor cells via apoptosis. However, this killing is not always efficient. In this review the link between tumor sensitivity to radiation treatment and the capacity of tumor cells to be killed by apoptotic mechanisms will be discussed. PMID- 10094809 TI - Genomic imprinting and cancer. AB - Although we inherit two copies of all genes, except those that reside on the sex chromosomes, there is a subset of these genes in which only the paternal or maternal copy is functional. This phenomenon of monoallelic, parent-of-origin expression of genes is termed genomic imprinting. Imprinted genes are normally involved in embryonic growth and behavioral development, but occasionally they also function inappropriately as oncogenes and tumor suppressor genes. The evidence that imprinted genes play a role in carcinogenesis will be discussed in this review. Additional information about imprinted genes can be found on the Genomic Imprinting Website at: (http://www.geneimprint.com). PMID- 10094810 TI - Gene silencing in the development of cancer. PMID- 10094811 TI - Escaping cell death: survival proteins in cancer. AB - Defects in apoptosis signaling pathways are common in cancer cells. Such defects may play an important role in tumor initiation because apoptosis normally eliminates cells with damaged DNA or dysregulated cell cycle, i.e., cells with increased malignant potential. Moreover, impaired apoptosis may enhance tumor progression and promote metastasis by enabling tumor cells to survive the transit in the bloodstream and to grow in ectopic tissue sites lacking the otherwise required survival factors. Finally, raised apoptosis threshold may have deleterious consequences by rendering cancer cells resistant to various forms of therapy. The intensive apoptosis research during the past decade has resulted in the identification of several proteins which may promote tumorigenesis by inhibiting apoptosis. Of special relevance in human cancer are those commonly expressed in primary tumors and functioning at the common part of the signaling pathway leading to apoptosis. Proteins fulfilling these criteria include antiapoptotic members of the Bcl-2 protein family, heat shock proteins, Hsp70 and Hsp27, as well as survivin, the novel cancer-associated member of the inhibitor of apoptosis protein family. Understanding the molecular mechanisms of action of these proteins may offer novel modes of rationally and selectively manipulating the sensitivity of cancer cells to therapy. PMID- 10094812 TI - The CCN family of angiogenic regulators: the integrin connection. PMID- 10094813 TI - Differentiation-related mechanisms which suppress DNA replication. AB - Differentiation of mammalian cells implies cessation of DNA replication and cell proliferation; the potential controls of this coupling are examined here. It is clear that the known or proposed mechanisms of down-regulation of replicative cellular activities vary in different lineages of cell differentiation, and occur in all phases of the cell cycle. In G1 these regulators include p21/Cip1 or p27/Kip1, pRb, and p53; the novel, recently reported mechanisms of their action are summarized. In S phase the availability of nucleotide precursors, the origin recognition complex (ORC), and other replication proteins may be important in differentiation, and in G2 phase the cdc2/cyclin B complex and replication licensing factors determine normal G2 traverse versus an arrest or polyploidisation. Other replication-related mechanisms include transcription factors, e.g., Sp1, telomerase, and nuclear matrix changes. Thus, differentiation alters the activity not only of the various checkpoint proteins, but also of the components of the replicative machinery itself. PMID- 10094814 TI - Use of a repetitive mouse B2 element to identify transplanted mouse cells in mouse-chick chimeras. AB - Monitoring the migrations of cells during embryonic development requires a system in which cells can be identified in situ during locomotion. One promising system involves the generation of chimeras by transplanting mouse cells into chick embryos in ovo to exploit the wealth of mouse genetic variants. The success of this technique relies on the ability to detect individual mouse cells in a chick environment with high specificity. The murine B2 family of short interspersed elements is present in the mouse genome at copy numbers in excess of 10(5), whereas this sequence is absent in the chick genome based on hybridization techniques. This differential of five orders of magnitude produces signals in mouse cells that are easily identified, even in an environment that is predominantly chick. Thus, the B2 repeat probe is highly effective for the purpose of identifying mouse cells in mouse-chick chimeras. PMID- 10094815 TI - Thrombospondin-1 is a mediator of the neurotypic differentiation induced by EGF in thymic epithelial cells. AB - Thymic epithelial cell component originates from cranial neural crest as well as from endoderm and ectoderm of the third pharyngeal pouch and branchial cleft. Epidermal growth factor (EGF) has been previously shown to play a crucial role in directing thymic epithelial cells toward a neural-oriented cell fate. To identify genes that are involved in the EGF-induced neurotypic differentiation of the thymic stroma-derived TC-1S cell line, we studied EGF-treated and untreated cells by RNA fingerprinting PCR-based differential screening. We obtained 23 distinct sequences including 18 known genes and 5 sequences previously unreported, which are currently under characterization. Here, we describe the involvement of one of the isolated genes, the thrombospondin-1, as a mediator of the neurotypic differentiation induced by EGF in TC-1S cells. We show that thrombospondin-1 mRNA and protein levels are increased by EGF. Moreover, exogenous thrombospondin-1 is able to enhance the outgrowth of neurite-like processes as well as the expression of neurofilaments and neural cell adhesion molecule in TC-1S cells. These observations suggest that the up-regulation of thrombospondin-1 synthesis induced by EGF contributes to the differentiation choice of thymic epithelial cells toward a neural fate, reminiscent of their neural crest origin. PMID- 10094816 TI - Induction of p21(CIP1/Waf1) and activation of p34(cdc2) involved in retinoic acid induced apoptosis in human hepatoma Hep3B cells. AB - The biological activity of retinoic acid (RA) was examined in human hepatoma Hep3B cells. Under serum-deprived conditions, RA induced S/M-phase elevation and mitotic index increase within 24 h, followed by apoptosis. This RA-induced apoptosis was accompanied by p53-independent up-regulation of endogenous p21(CIPI/Waf1) and Bax proteins, as well as activation of p34(cdc2) kinase, and increase of Rb2 protein level and phosphorylation pattern. In addition, RA had no effect on the levels of Bcl-XL; Bcl-XS; cyclins A, B, D1, D3, or E; or Rb1 expression but markedly down-modulated Cdk2 kinase activity and reduced Cdk4 expression. RA also slightly delayed p27(Kip1) expression. Olomoucine, a potent p34(cdc2) and Cdk2 inhibitor, effectively blocked RA-mediated p34(cdc2) kinase activation and prevented RA-induced apoptosis. Furthermore, antisense oligonucleotide complementary to p21(CIP2/Waf1) and p34(cdc2) mRNA significantly rescued RA-induced apoptosis. Our data indicate that p21(CIP2/Waf1) overexpression may not be the only regulatory factor necessary for RA-induced apoptosis in human hepatoma Hep3B cells. RA treatment leads to Rb2 hyperphosphorylation, and p34(cdc2) kinase activation is coincident with an aberrant mitotic progression, followed by appearance of abnormal nucleus. This aberrant cell cycle progression appeared requisite for RA-induced cell death. These findings suggest that inappropriate regulation of the cell cycle regulators p21(CIP2/Waf1) and p34(cdc2) is coupled with induction of Bax and involved in cell death with apoptosis when Hep3B cells are exposed to RA. PMID- 10094817 TI - Molecular characterization of the tight junction protein ZO-1 in MDCK cells. AB - Most of the information on the structure and function of the tight junction (TJ) has been obtained in MDCK cells. Accordingly, we have sequenced ZO-1 in this cell type, because this protein is involved in the response of the TJ to changes in Ca2+, phosphorylation, and the cytoskeleton. ZO-1 of MDCK cells comprises 6805 bp with a predicted open reading frame of 1769 amino acids. This sequence is 92 and 87% homologous to human and mouse ZO-1, respectively. Two nuclear sorting signals located at the PDZ1 and GK domains and 17 SH3 putative binding sites at the proline-rich domain were detected. We found two new splicing regions at the proline-rich region: beta had not been reported in human and mouse counterparts, and gamma, which was previously sequenced in human and mouse ZO-1, is now identified as a splicing region. The expression of different beta and gamma isoforms varies according to the tissue tested. With the information provided by the sequence, Southern blot, and PCR experiments we can predict a single genomic copy of MDCK-ZO-1 that is at least 13.16 kb long. MDCK-ZO-1 mRNA is 7.4 kb long. Its expression is regulated by calcium, while the expression of MDCK-ZO-1 protein is not. PMID- 10094818 TI - Analysis of site-specific phosphorylation of the retinoblastoma protein during cell cycle progression. AB - Differential phosphorylation of the retinoblastoma protein plays a pivotal role in cell cycle regulation. The retinoblastoma protein is specifically phosphorylated during the cell cycle by cyclin-dependent kinase complexes which intersect with many cellular signaling networks. Since the loss of the retinoblastoma signaling pathways occurs in a wide variety of human tumors, understanding the significance of site-specific phosphorylation can clarify the role of selected cyclin-dependent kinase complexes during cell cycle progression. Here we describe the phosphospecificity and cellular characterization of a panel of polyclonal antibodies that recognize unique phosphorylation sites within the retinoblastoma protein. These reagents were used to validate authentic cellular retinoblastoma phosphorylation sites at amino acids 780, 795, and 807/811 correlating with the G1-S transition. PMID- 10094819 TI - Expression of laminins 1 and 10 in carcinoma cells and comparison of their roles in cell adhesion. AB - The expression pattern of laminin (Ln) alpha1 chain has been a controversial topic due to discrepancies between mRNA and protein studies. Recently it was reported that the monoclonal antibody 4C7, previously thought to recognize Ln alpha1 chain, actually detects Ln alpha5 chain. This finding makes it necessary to reestimate the role of Ln alpha1 chain and to compare the expression and functions of Ln alpha1 and alpha5 chains. We studied the expression of Ln alpha1 and alpha5 chains and production of Ln-1 and Ln-10 in cultured human carcinoma cells. Ln alpha1 chain mRNA was detected in JAR choriocarcinoma cells and in all four renal cell carcinoma cell lines studied. In contrast, pancreatic, colon, and lung alveolar carcinoma cell lines did not express or produce Ln alpha1 chain, suggesting that Ln-1 (alpha1 beta1 gamma1) is produced only by certain carcinoma cells. Ln alpha5 chain mRNA was expressed in all carcinoma cells, but was not incorporated into extracellular matrix in vitro, as shown with JAR cells. Immunoprecipitation of metabolically labeled cells showed that cells expressing Ln alpha1 mRNA also produced 400-kDa Ln alpha1 chain, whereas all cells produced 380-kDa Ln alpha5 chain. Adhesion to Ln-1 was inhibited by a functionally blocking antibody against alpha6-integrin subunit, whereas adhesion to Ln-10 was inhibited by an antibody against alpha6-integrin in JAR cells and by an antibody against alpha3-integrin in PANC-1 cells. The results suggest that Ln-10 is a ubiquitously expressed Ln isoform in carcinoma cells, and the mechanism of adhesion to Ln-10 is cell-type specific. PMID- 10094820 TI - Developmental changes in RNA polymerase I and TATA box-binding protein during early Xenopus embryogenesis. AB - Xenopus early embryos are transcriptionally quiescent until the midblastula transition (MBT). We have examined the question of whether the absence of rRNA synthesis is related to a deficiency in the RNA polymerase I (pol I) transcription machinery. Previously we have demonstrated that the maternally provided pol I transcription factor UBF already binds to the inactive rRNA genes of pre-MBT embryos (P. Bell et al., 1997, J. Cell Sci. 110, 2053-2063). Here we have analyzed the fate of pol I and the TATA box-binding protein (TBP) through immunofluorescence and immunoblotting experiments. Pol I stockpiled in the egg is taken up by in vitro assembled pronuclei and concentrated into numerous distinct nuclear domains. Comparable storage sites of template-free pol I are also seen in nuclei of blastula to neurula stage embryos. In contrast, the amount of TBP is relatively low in oocytes and eggs but increases dramatically during the cleavage stages. Most of the newly synthesized TBP colocalizes with the stored form of pol I in the extranucleolar domains of blastula/gastrula embryos. The amount of TBP per embryo reaches peak values at the blastula/gastrula stage and then rapidly declines to normal somatic levels. The positive correlation of maximal TBP levels with the timing of the MBT suggests that overproduction of TBP is required for the formation of productive transcription complexes. PMID- 10094821 TI - Localization of tissue factor in actin-filament-rich membrane areas of epithelial cells. AB - Tissue factor (TF), the cellular receptor and cofactor for clotting factor VII/VIIa (FVII/VIIa), is known mainly as the initiator of the coagulation protease cascade. Recently, it was shown that inactivation of the murine TF gene (TF-/-) results in embryonic lethality which is most likely due to some failure of vascular integrity. On the other hand, gene disruption in mice of coagulation proteins like FVII, prothrombin, and fibrinogen results in phenotypes of embryonic development that contrast with that of TF-/-, suggesting a role for TF beyond fibrin formation in embryogenesis. In addition, there is a growing body of evidence that cellular TF may be involved in nonhemostatic functions. To determine the microtopography of membrane TF with regard to the cytoskeleton organization, we examined the expression patterns of TF and cytoskeletal proteins in various cell lines by means of double immunofluorescence and electron microscopy (EM). In spreading cells, a granular membrane TF expression of the cell cortex and a pronounced granular TF staining of microspikes, lamellipodes, and ruffled membrane areas were observed. Especially, actin and alpha-actinin were in close proximity to TF in these regions. Colocalization of TF and nonmuscle filamin (ABP-280) at the leading edge of spreading cells indicated an association of TF with the actin filament system, too. Using scanning EM we found gold-labeled TF at long processes and actin-filament-containing microspikes of neighboring cells in both branching and contact sites. By the means of immunogold EM we observed that TF is localized at the cell surface in a spotty pattern, at the base and at the top of budding processes. The observed staining pattern points to a connection of TF with elements of the cytoskeleton in these highly dynamic membrane regions, a fact which is underlined by the recently described molecular interaction of TF's cytoplasmic domain with ABP-280. In cells undergoing cytokinesis, we detected also strong TF expression in dynamic membrane areas and protrusions of the midbodies, indicating an accumulation of TF in actin rich membrane areas with high contractile activity. In addition, we were able to demonstrate that immobilized ligands for TF, both catalytically active and inactive FVIIa or anti-TF mAbs, accelerated adhesion and spreading of TF expressing cancer cells. Thus, our findings support the contention that ligation of cellular TF may be involved in morphogenic processes such as adhesion and spreading by an association to cytoskeletal structures. On the other hand, incubation of these cells with proteolytically active FVIIa but not with covalently inactivated FVIIa (DEGR-FVIIa) or anti-TF mAbs in solution resulted in increased motility of these cells, indicating that not only ligation of TF but also the proteolytic activity of TF-FVIIa complex is involved in cell migration. PMID- 10094822 TI - Activation of transfected M1 or M3 muscarinic acetylcholine receptors induces cell-cell adhesion of Chinese hamster ovary cells expressing endogenous cadherins. AB - Expression of endogenous cadherins by Chinese hamster ovary (CHO) cells has not been previously reported. However, we observed that CHO cells adhere to one another upon activation of transfected muscarinic acetylcholine receptors (mAChR), suggesting that the cells express endogenous cadherins. A 160-base pair RT-PCR product with 100% homology to the cytoplasmic domain of human E-cadherin was amplified from CHO cells. A second RT-PCR product amplified from these cells has 92% homology to the cytoplasmic domain of human cadherin-9 and 86% homology to the cytoplasmic domain of human cadherin-6. Western blotting indicates that CHO cells express a 165-kDa protein recognized by E-cadherin antibodies and a 120 kDa protein recognized by an antibody to the cadherin C-terminus sequence. The ability of transfected mAChR subtypes to regulate cadherin-mediated adhesion of CHO cells was tested by measuring the permeation of horseradish peroxidase across confluent CHO cell monolayers, by microscopic examination of the cells, and by aggregation assays. Cell-cell adhesion is induced within 15 min of activating transfected M1 or M3 mAChR which functionally couple to protein kinase C (PKC). In contrast, CHO cell adhesion is not affected by activating transfected M2 mAChR which functionally couple to other effectors. Activation of PKC with phorbol esters also induces cell-cell adhesion of all CHO sublines tested. Immunofluorescence assays reveal that endogenous cadherins redistribute on the plasma membrane of CHO cells following mAChR or PKC activation. Inactivation of cadherins by removal of extracellular Ca2+ abrogates adhesion induced by mAChR or PKC activation. Our demonstration that activation of only odd-numbered mAChR subtypes induces cadherin-mediated adhesion suggests that the unique responses of cells to M1 or M3 mAChR stimulation may involve cadherin activation. PMID- 10094823 TI - Application of the dual-micropipet technique to the measurement of tumor cell locomotion. AB - The objective of this work was to characterize tumor cell locomotion in response to chemotactic stimulation using a dual-micropipet assay. The assay involves two micropipets. An individual A2058 human melanoma cell was retained, without pressure gradient, in a pipet of approximately 14 micrometers i.d. A solution of type IV collagen, chosen as the chemotactic source, was placed in another pipet (approximately 10 micrometers o.d.) with zero pressure at the pipet tip. The smaller pipet was then inserted into the larger one containing the melanoma cell. The initial chemoattractant concentration (C0) and the distance between the tip of the small pipet and the cell surface (delta) provided a gradient (C0/delta) for tumor cell locomotion toward stimulation. This novel assay provides a direct measure of cell movement: cyclic pseudopod protrusion (Lp) and subsequent cell locomotion (Lc). The influences of different adhesion substrates on cell locomotion were also studied. The peak length in Lp precedes the highest locomotion velocity (dLc/dt) by an apparent lag time. C0/delta influences pseudopod protrusion frequency (fp) and dLc/dt, but not significantly on Lp. Substrate adhesions affect dLc/dt, but apparently not Lp or fp. In conclusion, pseudopod protrusion and substrate adhesion are two necessary but mutually independent factors in tumor cell locomotion. dLc/dt correlates with changes in C0/delta, which is in significant correlation with fp but not Lp. PMID- 10094824 TI - Tubular morphogenesis and mesenchymal interactions affect renin expression and secretion in SIMS mouse submandibular cells. AB - We have previously immortalized a mouse submandibular gland (SMG) ductal epithelial cell line, SIMS, from pubertal male mice transgenic for the SV40 large T antigen under the control of the adenovirus 5 E1A promoter. Here we demonstrate the role of the extracellular environment in directing not only the morphogenetic behavior of the cells, but also their functional differentiation in terms of renin expression and secretion. First, we measured renin activity of polarized SIMS cells. Low levels of renin are secreted from both the apical and the basolateral domains; the mechanism appears to be direct as no renin was found to be transcytosed across the cell. Second, we studied homotypic and heterotypic mesenchymal cell interactions with SIMS cells. We found that epithelial mesenchymal coculture in collagen I gels results in branching tubular morphogenesis of SIMS cells and that significant amounts of renin are secreted, probably into the lumen, as the precursor form, prorenin. Third, we investigated the effects of the basement membrane on SIMS cell morphology and function and found that this structure alone is sufficient to allow expression and secretion of both prorenin and active renin. Finally, we established that SIMS cells can express androgen-regulated genes in a transient transfection assay. In addition, in Matrigel cultures androgen receptor expression appears to be induced, suggesting that the SIMS cell line will be useful for further studies on the molecular basis of the observed high-level expression of SMG-specific genes in male mice. PMID- 10094825 TI - Expression of the E6 and E7 genes of human papillomavirus (HPV16) extends the life span of human myoblasts. AB - Primary human myoblasts (satellite cells), like other human cells, have a limited life span in vitro. Here we show that expression of the E6E7 early region from human papillomavirus type 16 can greatly extend the life span of both fetal and satellite cell-derived myoblasts and release them from dependence on the growth factors normally necessary for their proliferation. Expression of either the E6 or the E7 gene alone was not sufficient to confer this phenotype, although expression of E7 did delay cellular senescence. The steady-state level of E6E7 transcripts in clonal cultures correlated with proliferative capacity and inversely with the capacity to differentiate into multinuclear myotubes. The expression of E7 alone markedly inhibited cell fusion in both adult and fetal cultures. These effects on myoblast differentiation could be related in part to the level of retinoblastoma protein (pRb), the major cellular target of E7. Terminal differentiation of skeletal myoblasts is associated with permanent withdrawal from the cell cycle; however, continued expression of E6E7 in differentiated myotubes permits reentry of myotube nuclei into S phase in response to growth factor stimulation. These results support a key role for pRb in the acquisition and maintenance of the differentiated state in human skeletal muscle and, in cooperation with p53, in the control of proliferative capacity and response to external growth factors. PMID- 10094826 TI - Attenuation of NF-kappaB signaling response to UVB light during cellular senescence. AB - The ability of cells to adapt to environmental stresses undergoes a progressive reduction during aging. NF-kappaB-mediated signaling is a major defensive system against various environmental challenges. The aim of this study was to find out whether replicative senescence affects the response of the NF-kappaB signaling pathway to UVB light in human WI-38 and IMR-90 fibroblasts. The exposure of early passage fibroblasts to UVB light inhibited the proliferation and induced a flat phenotype similar to that observed in replicatively senescent fibroblasts not exposed to UVB light. The UVB radiation dose used (153 mJ/cm2) did not induce apoptosis in either early or late passage WI-38 fibroblasts. UVB exposure induced a prominent activation of the NF-kappaB signaling pathway both in early and in late passage WI-38 and IMR-90 fibroblasts. Interestingly, the response to UVB light was significantly attenuated in late passage fibroblasts. This attenuation was most prominent in DNA binding activities of nuclear NF-kappaB complexes. Similar senescence-related attenuation was also observed in the DNA binding activities of nuclear AP-1 and Sp-1 factors after UVB treatment. Immunoblotting and -cytochemistry showed an increase in nuclear localization of p50 and p65 components of NF-kappaB complexes. Supershift experiments showed that the specific NF-kappaB complexes contain p50 and p65 protein components but not p52 and c-Rel proteins. Cytoplasmic IkappaBalpha showed a marked decrease at protein level but an increase in phosphorylation after UVB treatment. Transient transfection assays with TK5-CAT and TK10-CAT plasmids carrying NF-kappaB responsive sites of the TNFalpha promoter were used to analyze the functional activity of the NF-kappaB complexes. Results showed that UVB exposure induced an increase in NF-kappaB-driven CAT expression both in early and in late passage fibroblasts though the response was significantly stronger in early passage fibroblasts. Our results show that the induction of NF-kappaB-mediated signaling by UVB light is highly attenuated in senescent fibroblasts. This attenuation may reduce the stress resistance during cellular senescence. PMID- 10094828 TI - The mechanisms of pyknosis: hypercondensation and death. AB - Intense nuclear condensation with intense refractivity (pyknosis) is the ubiquitous terminus of all apoptosis and some necrosis of vertebrate cells, but its structural basis is unknown. Intense condensations were induced in a model system, the avian erythrocyte, and three different molecular processes distinguished from each other. Two of the hypercondensations, nucleolytic pyknosis, as in mammalian apoptosis, and anucleolytic pyknosis, as in necrosis, appear to be energetically spontaneous and appear to have a conformational basis with the third hypercondensation being a trans-nuclear membrane osmotic pressure compression effect. Nucleolytic pyknosis as per apoptosis was not intrinsic in this system and required exogenous nuclease. The pure anucleolytic pyknosis supported by this system was not induced by the apoptopic induction agents, staurosporine or antitopoisomerases (I and II), indicating a simple but unusual signaling pathway for anucleolytic pyknosis. Molecular weight determinations of the H5, H3, H4, H2a, and H2b, with final errors of +/-1 Da or less, seem to eliminate histone modifications as the basis of anucleolytic pyknosis. The molecular basis of pyknosis is proposed to be from internucleosomal rotational angle freedom that permits internucleosomal sharing of basic histone tails of adjacent nucleosomes and nucleofilaments. Much of the favorable conformational energy of pyknosis may be from the entropy increase of tail delocalization. PMID- 10094827 TI - Signaling via fibroblast growth factor receptor-1 is dependent on extracellular matrix in capillary endothelial cell differentiation. AB - Differentiation of endothelial cells, i.e., formation of a vessel lumen, is a prerequisite for angiogenesis. The underlying molecular mechanisms are ill defined. We have studied a brain capillary endothelial cell line (IBEC) established from H-2Kb-tsA58 transgenic mice. These cells form hollow tubes in three-dimensional type I collagen gels in response to fibroblast growth factor-2 (FGF-2). Culture of IBEC on collagen gels in the presence of FGF-2 protected cells from apoptosis and allowed tube formation (i.e., differentiation) but not growth of the cells. FGF-induced differentiation, but not cell survival, was inhibited by treatment of the cells with an anti-beta1-integrin IgG. Changes in integrin expression in the collagen-gel cultures could not be detected. Rather, cell-matrix interactions critical for endothelial cell differentiation were created during the culture, as indicated by the gradual increase in tyrosine phosphorylation of focal adhesion kinase in the collagen-gel cultures. Inclusion of laminin in the collagen gels led to FGF-2-independent formation of tube structures, but cells were not protected from apoptosis. These data indicate that FGF receptor-1 signal transduction in this cell model results in cell survival. Through mechanisms dependent on cell-matrix interactions, possibly involving the alpha3beta1-integrin and laminin produced by the collagen-cultured IBE cells, FGF stimulation also leads to differentiation of the cells. PMID- 10094829 TI - A p85 subunit-independent p110alpha PI 3-kinase colocalizes with p70 S6 kinase on actin stress fibers and regulates thrombin-stimulated stress fiber formation in swiss 3T3 cells. AB - The signaling pathways linking receptor activation to actin stress fiber rearrangements during growth factor-induced cell shape change are still to be determined. Recently our laboratory demonstrated the involvement of p70 S6 kinase (p70(s6k)) activation in thrombin-induced stress fiber formation in Swiss 3T3 cells. The present work shows that thrombin-induced p70(s6k) activation is inhibited by the PI 3-kinase inhibitors wortmannin and LY-294002. These inhibitors also significantly reduced thrombin-induced stress fiber formation, demonstrating a role for PI 3-kinase activity in this process, most likely upstream of p70(s6k). Furthermore, the p110alpha form of PI 3-kinase was localized to actin stress fibers, as was previously shown for p70(s6k), as well as to a golgi-like distribution. In contrast, PI 3-kinase p110gamma colocalized with microtubules. The PI 3-kinase p85 subunit, known to be capable of association with p110alpha, was present in a predominantly golgi-like distribution with no presence on actin filaments, suggesting the existence of distinctly localized PI 3-kinase pools. Immunodepletion of p85 from cell lysates resulted in only partial depletion of p110alpha and p110alpha-associated PI 3 kinase activity, confirming the presence of a p85-free p110alpha pool located on the actin stress fibers. Our data, therefore, point to the importance of subcellular localization of PI 3-kinase in signal transduction and to a novel action of p85 subunit-independent PI 3-kinase p110alpha in the stimulation by thrombin of p70(s6k) activation and actin stress fiber formation. PMID- 10094830 TI - Telomere length in fibroblasts and blood cells from healthy centenarians. AB - Several lines of evidence indicate that telomere shortening during in vitro aging of human somatic cells plays a causal role in cellular senescence. A critical telomere length seems to be associated with the replicative block characterizing senescent cells. In this paper we analyzed the mean length of the terminal restriction fragments (TRF) in fibroblast strains from 4 healthy centenarians, that is, in cells aged in vivo, and from 11 individuals of different ages. No correlation between mean TRF length and donor age was found. As expected, telomere shortening was detected during in vitro propagation of centenarian fibroblasts, suggesting that in fibroblasts aged in vivo telomeres can be far from reaching a critical length. Accordingly, chromosome analysis did not show the presence of telomeric associations in early passage centenarian fibroblasts. In blood cells from various individuals, the expected inverse correlation between mean TRF length and donor age was found. In particular, a substantial difference (about 2 kb) between telomere length in the two cell types was observed in the same centenarian. Expression analysis of three senescence-induced genes, i.e., fibronectin, apolipoprotein J, and p21, revealed for only the fibronectin expression levels a clear positive correlation with donor age. Our results suggest that (1) telomere shortening could play a different role in the aging of different cell types and (2) the characteristics of fibroblasts aged in vitro might not be representative of what occurs in vivo. PMID- 10094831 TI - Transcriptional mechanisms responsible for the overexpression of the keratin 18 gene in cells of a human colon carcinoma cell line. AB - The keratin 18 (K18) gene is overexpressed in cells of tumorigenic clones isolated from the SW613-S human colon carcinoma cell line, compared to cells of nontumorigenic clones. The isolated minimal promoter (TATA box and initiation site) of the K18 gene has by itself a differential activity in tumorigenic and nontumorigenic cells. An Sp1 binding site located upstream of the TATA box contributes to the high level of expression of the gene in tumorigenic cells. We report here that the Sp1 gene is not differentially expressed between the two cell types and that this is also the case for genes coding for factors of the preinitiation complex known to directly interact with the Sp1 protein. Further, DNase I footprinting experiments and mutagenesis analysis indicated that the mechanism responsible for the differential activity of the minimal K18 promoter apparently does not involve the binding of a factor to a specific sequence. During the course of these experiments, it was found that the initiation site of the K18 promoter is actually located 11 bp upstream of the +1 position previously reported and that the TATA box is the only essential element of the minimal promoter. Treatment of the cells with histone deacetylase inhibitors was more efficient at stimulating the activity of the K18 promoter in nontumorigenic cells than in tumorigenic cells. We propose that overexpression of the K18 gene in tumorigenic cells could result from of a high level of acetylation of histones and/or of factors controlling the activity of the transcription complex. PMID- 10094833 TI - UV radiation is a transcriptional inducer of p21(Cip1/Waf1) cyclin-kinase inhibitor in a p53-independent manner. AB - p53 target genes p21(Cip1/Waf1) cyclin-kinase inhibitor (p21 CKI), GADD45, bax, and cyclin G and genes affecting the redox state of the cells are implicated in p53 damage control responses. In order to attribute their functions and dependency of p53 in UV-damaged cells we undertook an analysis of UVC responses of fibroblasts derived from p53 knock-out mice. UVC radiation efficiently and rapidly inhibited DNA replication in both p53 -/- and +/+ cells. The arrest was persistent in p53 -/- fibroblasts and cells underwent apoptosis, whereas p53 +/+ cells recovered and reentered the cycle. Protein and mRNA analyses of p21 expression showed that it was induced up to sixfold with similar kinetics both in the presence and in the absence of p53. However, high doses of UV abrogated the p21 response in p53 -/- cells, whereas it was maintained in cells with normal p53. UVC radiation transcriptionally activated p21 expression as demonstrated by luciferase reporter assays using deletion constructs of the p21 promoter. The promoter assays further confirmed the independency of p53-binding sites in the activation and linked UV-responsive transcriptional regulation of p21 to two Sp1 consensus binding sites within -61 bp of the transcription initiation site. A weaker regulation was mediated by elements between -1300 to -500 bp relative to the transcription initiation site. The results suggest that in fibroblasts UVC radiation is a rapid and efficient inducer of p21 expression also in a p53 independent manner. PMID- 10094832 TI - Activation of protein kinase C by phorbol esters modulates alpha2beta1 integrin on MCF-7 breast cancer cells. AB - Cellular adhesions to other cells and to the extracellular matrix play crucial roles in the malignant progression of cancer. In this study, we investigated the role of protein kinase C (PKC) in the regulation of cell-substratum adhesion by the breast adenocarcinoma cell line MCF-7. A PKC activator, 12-O tetradecanoylphorbol-l, 3-acetate (TPA), stimulated cell adhesion to laminin and collagen I in a dose-dependent manner over a 1- to 4-h interval. This enhanced adhesion was mediated by alpha2beta1 integrin, since both anti-alpha2 and anti beta1 blocking antibodies each completely abrogated the TPA-induced adhesion. FACS analysis determined that TPA treatment does not change the cell surface expression of alpha2beta1 integrin over a 4-h time interval. However, alpha2beta1 levels were increased after 24 h of TPA treatment. Thus, the enhanced avidity of alpha2beta1-dependent cellular adhesion preceded the induction of alpha2beta1 cell surface expression. Northern blot analysis revealed that mRNA levels of both alpha2 and beta1 subunits were increased after exposure to TPA for 4 h, indicating that the induction of alpha2beta1 mRNA preceded that of its cell surface expression. This further suggested that the TPA-induced avidity of alpha2beta1 was independent of increased expression of alpha2beta1. Pretreatment of cells with the PKC inhibitor calphostin C partially antagonized the TPA induced increase in expression of alpha2beta1 integrin expression and of alpha2beta1-mediated cellular adhesion. To identify a possible mechanism by which TPA could be acting to promote the rapid induction of alpha2beta1 adhesion, we treated the cells with the Rho-GTPase inhibitor Clostridium botulinumexotoxin C3. C3 inhibited TPA-induced adhesion to laminin and collagen I in a dose-dependant manner, suggesting a likely role for Rho in TPA-induced adhesion. Together, these results suggest that PKC can modulate the alpha2beta1-dependent adhesion of MCF-7 cells by two distinct mechanisms: altering the gene expression of integrins alpha2 and beta1 and altering the avidity of the alpha2beta1 integrin by a Rho dependant mechanism. PMID- 10094834 TI - Alterations of cell volume regulation in the development of hepatocyte necrosis. AB - Intracellular Na+ accumulation has been shown to contribute to hepatocyte death caused by anoxia or oxidative stress. In this study we have investigated the mechanism by which Na+ overload can contribute to the development of cytotoxicity. ATP depletion in isolated hepatocytes exposed to menadione-induced oxidative stress or to KCN was followed by Na+ accumulation, loss of intracellular K+, and cell swelling. Hepatocyte swelling occurred in two phases: a small amplitude swelling (about 15% of the initial size) with preservation of plasma membrane integrity and a terminal large amplitude swelling associated with cell death. Inhibition of Na+ accumulation by the use of a Na+-free medium prevented K+ loss, cell swelling, and cytotoxicity. Conversely, blocking K+ efflux by the addition of BaCl2 did not influence Na+ increase and small amplitude swelling, but greatly stimulated large amplitude swelling and cytotoxicity. Menadione or KCN killing of hepatocytes was also enhanced by inducing cell swelling in an hypotonic medium. However, increasing the osmolarity of the incubation medium did not protect against large amplitude swelling and cytotoxicity, since stimulated Na+ accumulation and K+ efflux. Altogether these results indicate that the impairment of volume regulation in response to the osmotic load caused by Na+ accumulation is critical for the development of cell necrosis induced by mitochondrial inhibition or oxidative stress. PMID- 10094835 TI - Cell surface receptors transmit sufficient force to bend collagen fibrils. AB - To better understand the dynamic interaction of cells with their surrounding extracellular matrix, chondrocytes and rat embryo fibroblasts were overlaid with individual collagen fibrils and observed with high-resolution video-enhanced differential interference contrast microscopy. Although the cells had a polygonal shape characteristic of nonmotile cells, they used processes usually associated with cell locomotion to acquire the collagen fibrils. Instead of being transported in a retrograde direction, fibrils on the dorsal cell surface were bent, and regions of the bent fibrils were shifted in diverse directions. A blocking antibody to the beta1 integrin subunit significantly inhibited collagen fibril acquisition and bending. Enhanced actin assembly was only occasionally associated with fibrils undergoing rearrangement. Considering that the relatively stiff collagen fibrils require the application of force to be bent, this study shows that cells with a polygonal morphology (as opposed to a polarized, motile shape) are capable of exerting force through the beta1 integrins on the dorsal surface of the cell. Analysis of the bending patterns indicates that fibril buckling was induced by retrograde force combined with regions held stationary and/or the fibrils were bent by forces acting in opposing directions. PMID- 10094836 TI - Infection of rat brain cell aggregates with neurovirulent and nonneurovirulent strains of herpes simplex virus type 1. AB - Rat brain cell aggregates represent a three-dimensional tissue culture system of brain tissue in the form of small, multicellular spheroids. In the present work, we have infected these "minibrains" with neurovirulent, nonneurovirulent, and nonreplicating strains of HSV-1. The neurovirulent strains 17(+) and KOS(M) spread rapidly through the aggregates, while the nonreplicating ICP4 deletion mutant KD6 infected cells only at the periphery of the aggregates. Spread and replication of the nonneurovirulent strains RE6 and tk-7, and to some extent also of R13/1, were restricted. The interaction between different strains of HSV-1 and the rat brain cell aggregates is thus comparable to that seen in the brain, suggesting that the aggregates represent a useful tool for studying HSV-1 infection of brain tissue in vitro. PMID- 10094837 TI - Alternatively spliced CD44 isoforms containing exon v10 promote cellular adhesion through the recognition of chondroitin sulfate-modified CD44. AB - Correlations have been noted between the expression of certain alternatively spliced CD44 isoforms and the metastatic propensity of various histologically distinct tumor cell types. The precise mechanism by which particular CD44 isoforms contribute to the metastatic process is, however, unclear. In the present study we demonstrate that CD44R2, a CD44 isoform highly expressed on activated and transformed hemopoietic cells, can recognize and bind a common determinant present on CD44H and CD44R1. Importantly, CD44H lacked this activity. Pretreatment of TIL1 cells expressing CD44H or CD44R1 with chondroitinase ABC inhibited adhesion to CD44R2, suggesting that the unique inserted region present within the CD44R2 molecule, encoded by exon v10, mediates cell adhesion by potentiating the recognition of chondroitin sulfate moieties presented in association with other CD44 molecules. These data help explain the differential involvement of v10-containing CD44 isoforms in tumor metastasis. PMID- 10094838 TI - An integral membrane green fluorescent protein marker, Us9-GFP, is quantitatively retained in cells during propidium iodide-based cell cycle analysis by flow cytometry. AB - Previously, we described GFP-spectrin, a membrane-localized derivative of the green fluorescent protein that can be employed as a marker during the simultaneous identification of transfected cells and cell cycle analysis by flow cytometry (Kalejta et al., Cytometry 29: 286-291, 1997). A membrane-anchored GFP fusion protein is necessary because the ethanol permeabilization step required to achieve efficient propidium iodide staining allows cytoplasmic GFP to leach out of the cell. However, viable cells expressing GFP-spectrin are not as bright as cells expressing cytoplasmic GFP and their fluorescence intensity is further diminished after ethanol treatment. Here, we demonstrate that the fluorescence intensity of cells expressing an integral membrane GFP fusion protein (Us9-GFP) is similar to that of cells expressing cytoplasmic GFP and is quantitatively maintained in cells after ethanol treatment. By allowing an accurate assessment of the expression level of GFP, Us9-GFP allows a more precise analysis of the effects of a cotransfected plasmid on the cell cycle and thus represents an improvement upon the original membrane-associated GFP fusion proteins employed in this assay. PMID- 10094839 TI - Receptor-type protein-tyrosine phosphatase mu is expressed in specific vascular endothelial beds in vivo. AB - We investigated the localization of receptor-type protein-tyrosine phosphatase mu (RPTPmu) in tissues by immunofluorescence. RPTPmu immunoreactivity was found almost exclusively within vascular endothelial cells. RPTPmu was more abundant in the arterial tree than in the venous circulation. This pattern of expression was opposite to that of the von Willebrand factor and demonstrated a lack of difference in expression of VE-cadherin. RPTPmu was undetectable in the endocardium. In agreement with previous work on nonendothelial cell lines, RPTPmu was exclusively at the lateral aspects of endothelial cells in vivo and at cell cell contacts as well as ex vivo in two- or three-dimensional endothelial cell cultures, and expression levels were upregulated by cell density. RPTPmu was detected in few other cells: bronchial and biliary epithelia and cardiocytes (intercalated discs). Our results identify RPTPmu as a new marker of endothelial cell heterogeneity and suggest a possible role in endothelial-specific functions, involving cell-cell contact. PMID- 10094841 TI - Dietary curcumin with cisplatin administration modulates tumour marker indices in experimental fibrosarcoma. AB - Curcumin, the active constituent of Curcuma longa, which itself possesses antitumour activity against experimental tumours, enhances the antitumour effect of the widely used anticancer drug cisplatin, when used in combination against fibrosarcoma. Tumour marker enzymes such as aminotransferases, lactate dehydrogenase, gamma-glutamyl transpeptidase, alkaline phosphatase, 5' nucleotidase were analysed in liver and kidney homogenates of experimental rats. All these enzyme activities were markedly increased in tumour bearing animals. On cisplatin administration, the enzyme levels were decreased but not to near normal values. Curcumin, when treated along with cisplatin brought back the enzyme levels to near the control values. Thus curcumin and cisplatin combination may be worth trying against tumours like fibrosarcoma. PMID- 10094840 TI - Drugs preventing Na+ and Ca2+ overload. AB - Cardiac intracellular Na+and Ca2+homeostasis is regulated by the concerted action of ion channels, pumps and exchangers. The Na+, K+-ATPase produces the electrochemical concentration gradient for Na+, which is the driving force for Ca2+removal from the cytosol via the Na+/Ca2+exchange. Reduction of this gradient by increased intracellular Na+concentration leads to cellular Ca2+overload resulting in arrhythmias and contractile dysfunction. Na+and Ca2+overload associated arrhythmias can be produced experimentally by inhibition of Na+efflux (digitalis-induced intoxication) and by abnormal Na+influx via modulated Na+channels (veratridine, DPI 201-106; hypoxia) or via the Na+, H+exchanger. Theoretically, blockers of Na+and Ca2+channels, inhibitors of abnormal oscillatory release of Ca2+from internal stores or modulators of the Na+, Ca2+and Na+, H+exchanger activities could protect against cellular Na+and Ca2+overload. Three exemplary drugs that prevent Na+and Ca2+overload, i.e. the benzothiazolamine R56865, the methylenephenoxydioxy-derivative CP-060S, and the benzoyl-guanidine Hoe 642, a Na+, H+exchange blocker, are briefly reviewed with respect to their efficacy on digitalis-, veratridine- and ischaemia/reperfusion induced arrhythmias. PMID- 10094842 TI - Examination of antibacterial activity of the photoactivated arginine haematoporphyrin derivative. AB - The antibacterial photodynamic effect of arginine haematoporphyrin derivative (HpD-Arg2) was investigated using two methods. The effect proved to be highly antibacterial when it was employed against P. aeruginosa and S. aureus cells floating in the nutrient broth. The reduction of approximately four logarithms of CFU ml-1 after light exposition, as compared to a dark control, was observed. In the second step of the study the photodynamic effect was employed against the same strains of bacteria after their colonization on isolated mouse muscles. In this case the antibacterial effect was observed as well. However, the reduction of CFU ml-1 achieved was much lower and reached one logarithm only. The optimal concentration of photoactivated HpD-Arg2 for S. aureus and P. aeruginosa was 25 microg ml-1 and 800 microg ml-1 for the floating bacteria, and 200 microg ml-1 and 1000 microg ml-1 for sessile bacteria, respectively. We have concluded from our study that the antibacterial effect investigated may offer, in the future, an alternative method for treatment of the tissues superficially infected with pathogens resistant to antibiotics. However, further studies in this field are necessary. PMID- 10094843 TI - The economic consequences of smoking in Ontario. AB - Smoking causes health and social problems such as sickness, death, fire, injury, pain and suffering. This paper provides an estimate of the economic burden imposed by the adverse health and social consequences of smoking in Ontario in 1992. The cost-of-illness method, in particular, the human-capital approach is used to estimate the prevalence-based economic costs of smoking. The direct and indirect components of smoking-related costs are estimated and the total cost in Ontario is US$2.91 billion. Associated with these economic costs are health related harms: 69,318 hospital separations; 1,007,647 days stay in hospitals; 11,648 deaths resulting in more than 171,443 person-years lost. PMID- 10094844 TI - Bioequivalence of levothyroxine tablets administered to a target population in steady state. AB - Two parallel trials were carried out with levothyroxine sodium salt in 50 and 100 microg strengths, respectively, giving 100 microg day-1(50x2 microg day-1 or 100x1 microg day-1) in both trials in a repeated dose regimen. Twenty patients suffering from primary hypothyroidism under treatment with 100 microg day-1 of thyroxine sodium salt were enrolled in each trial. They were clinically and chemically euthyroid. Each trial lasted 114 days, with 57 days being devoted to the first treatment (test or reference) and 57 days to the other (reference or test), according to a two-period, two-sequence, two-formulation design in a steady state without wash-out. The test formulation was prepared with a technological improvement and is being produced to replace that at present on the market. Serum concentrations of free and total levothyroxine, and free and total levotriiodothyronine were assayed repeatedly during the treatment and in timed samples after the last dose of each formulation, using radioimmunoassays. Cmax and AUCss,tau were considered to be target parameters for bioequivalence which was assessed through 90% confidence intervals in the 0.80-1.25 range, as required by EU and US FDA operating guidelines. The results have shown that of these hormones, the free and total parent compound thyroxine is that which most clearly showed a peak after dosing, whereas its metabolite, free and total triiodothyronine, fluctuated around pre-dose concentrations. Bioequivalence was fully assessed with Cmax and AUCss,tau, with all four hormones tested and at both strengths administered. The two test formulations in 50 and 100 microg are thus bioequivalent with the two reference preparations. Tolerability was very good in all cases. PMID- 10094845 TI - Pharmacodynamic modelling of levodopa, 3-O-methyldopa and their effects: an application of the Dixon equation. AB - The modified Dixon equation was applied to describe the relationship between levodopa, 3-O-methyldopa (3OMD) concentrations and tapping test in 16 patients with Parkinson's disease treated with controlled release levodopa/carbidopa association. The sigmoid equation was also used to describe the relationship between levodopa and tapping test, and the results were compared to those obtained using the Dixon equation. Graphically, the fittings using the Dixon equation can be constructed in a three-dimensional space, whereas the fittings using the sigmoid equation can be constructed in a two-dimensional plane. The results show that the fittings in the three-dimensional space are slightly better than those in the two-dimensional plane. The advantage of the Dixon equation over the sigmoid equation is that the Dixon equation can take 3OMD into consideration for pharmacodynamic modelling. PMID- 10094846 TI - Trimetazidine ameliorates the hepatic injury associated with ischaemia reperfusion in rats. AB - Ischaemia-reperfusion induces structural and functional damage to hepatocytes. The purpose of this study was to evaluate the protective effect of trimetazidine, an anti- ischaemic drug, in a rat liver model of ischaemia-reperfusion. Male Wistar rats were divided into groups pretreated with different doses of trimetazidine (1, 5, 10 or 20 mg kg-1 day-1) or saline for 7 days. Liver ischaemia was induced for 120 min and blood reflow was subsequently restored for 30, 60, 90 or 120 min. The activities of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) as well as the bile flow and the liver ATP content were determined. Ischaemia-reperfusion induced major alterations of hepatic functions involving increases of ASAT and ALAT activities, a drop of ATP content and a sharp decrease in bile flow. Trimetazidine pretreatment reduced the liver injury. Indeed, it lowered the increase in ALAT and ASAT activities observed immediately after reperfusion and maintained higher concentrations of hepatic ATP. Simultaneously, bile flow was increased. These effects were dose dependent and 5 mg kg-1 day-1 seemed to be the lowest effective dose. In this experimental model trimetazidine pretreatment reduced the liver damage induced by ischaemia-reperfusion. Our data suggest that trimetazidine may be a useful drug in liver surgery to prevent ischaemia-reperfusion injury. PMID- 10094847 TI - Mechanism of vasodilation by cochlear nerve stimulation. Role of calcitonin gene related peptide. AB - Rabbit aortic rings pre-contracted with 1 microm phenylephrine were exposed to organ fluid of isolated guinea pig cochleas which had been subjected to electrical field stimulation (FS, 50 Hz, 50 V, 0.2 ms over 2 min). This resulted in an endothelium-dependent relaxation of the vessel rings sensitive to glibenclamide, an ATP-sensitive K+channel blocker. Tetrodotoxin (1 microm) added to the cochlear fluid blocked the vasorelaxant effect of cochlear FS and it attenuated vasorelaxation when added to aortic rings. The relaxation response paralleled an increase in the level of calcitonin gene-related peptide (CGRP) in both cochlear and vascular organ fluids from undetectable pre-stimulation values to 0.12+/-0.029 and 0.44+/-0.051 n m, respectively. We conclude that CGRP possibly contributes to cochlear nerve stimulation-induced endothelium-dependent vasorelaxation. PMID- 10094848 TI - Detection of nitric oxide in exhaled air of different animal species using a clinical chemiluminescence analyser. AB - The aim of the present study was to evaluate the nitric oxide (NO) concentrations present in end-expired gas (FENO) of different animal species under basal and stimulated conditions using a clinical chemiluminescence analyser, which has been developed for measurement of single exhalations in humans. Anaesthetised, tracheotomised and artificially ventilated guinea pigs, rats and rabbits were prepared for recording systemic blood pressure and FENO. Stable levels of FENO were detected in expired air over a 1-h observation period in the three animal species tested. Rabbits exhibited the highest concentrations and output (FENO 12.9+/-1.0 ppb, VNO 9.0+/-0.7 nl min-1), followed by guinea pigs (FENO 6.2+/-0.70 ppb, VNO 1.7+/-0.19 nl min-1) and rats (FENO 0.9+/-0.01 ppb, VNO 0.25+/-0.00 nl min-1). L-arginine (1 g kg-1 i.v.) evoked significant increments in VNO in guinea pigs and rabbits but was ineffective in rats. However, L-arginine showed a direct effect on blood pressure in all the animal species tested, causing a rapid fall in the mean arterial blood pressure (MABP; 38, 48 and 50% decrease in rabbits, guinea pigs and rats, respectively; P<0.05). An inhibitor of endogenous NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 20 mg kg-1 i.v.), decreased both basal and L-arginine-induced VNO in guinea pigs and rabbits, but was ineffective in rats. L-NAME increased MABP in all the animal species tested (58% in guinea pigs, 43% in rats and 18% in rabbits; P<0.05). The results indicate that it is possible to detect NO in the exhaled air of different animal species using a clinical chemiluminescence analyser and that different species exhibit striking differences in the levels of basal and stimulated NO output. PMID- 10094849 TI - Cardioprotective effect of enantiomers of cicletanine (BN50417, BN50418) in ischaemic/reperfused isolated working rat hearts: interaction with glibenclamide. AB - In the present study, interaction of the ATP-sensitive K+-channel blocker glibenclamide with enantiomers of the antihypertensive drug, cicletanine, was studied on ischaemic myocardial function, lactate-dehydrogenase (LDH) release, and early reperfusion-induced ventricular fibrillation (VF). Isolated working rat hearts subjected to 10-min coronary artery occlusion followed by 2-min reperfusion were perfused with 1.5x10(-5)-6.0x10(-5)M D-cicletanine[+] (BN50417) and L-cicletanine[-] (BN50418), respectively. Their interaction with 10(-7) M glibenclamide was also studied. The most effective concentration of BN50418 (3x10(-5) M) increased ischaemic aortic flow (AF) from its non-treated control value of 20.3+/-1.16 to 30.3+/-2.6 ml min-1(P<0.01), decreased left ventricular end-diastolic pressure (LVEDP) from 1.81+/-0.05 to 0.97+/-0.08 kPa (P<0.001), attenuated ischaemia-induced increase in LDH leakage from 164+/-41 to 14.8+/-20 mU min-1g-1 wet wt. (P<0.01) at the 10th-min of coronary occlusion, and reduced VF upon reperfusion. Glibenclamide did not considerably affect cardiac performance, however, it inhibited the anti-ischaemic but not the antiarrhythmic effect of BN50418. BN50417 (3x10(-5) M) tended to improve ischaemic AF to 24.2+/ 1.1 ml min-1, and significantly attenuated ischaemia-induced increase in LVEDP to 1.3+/-0.08 kPa (P<0.01), relative increase in LDH release to 29.4+/-44 mU min-1g 1(P<0.05), and alleviated reperfusion-induced VF. Glibenclamide abolished the anti-ischaemic and antiarrhythmic effect of BN50417. The cardioprotective effect of both enantiomers of cicletanine involves a glibenclamide-sensitive mechanism, however, the antiarrhythmic effect of BN50418 is not glibenclamide sensitive. BN50418 is the more potent enantiomer of cicletanine in terms of its cardioprotective effect. PMID- 10094850 TI - Effect of captopril on doxorubicin-induced nephrotoxicity in normal rats. AB - Biochemical evaluations of the effects of the sulfhydryl-containing angiotensin converting enzyme inhibitor (captopril) on the nephrotoxicity induced by doxorubicin in normal rats were carried out. A single dose of doxorubicin (15 mg kg-1) which caused nephrotoxicity was manifested biochemically by the elevation of serum urea after 24 and 48 h of administration. Also a severe decrease in total proteins and albumin after 4, 24 and 48 h was observed. Moreover, a decrease of non-protein sulfhydryl (-SH) concentrations in the kidney tissues after 24 h and an increase in the lipid peroxidation was observed after 4 h administration of doxorubicin. Captopril (60 mg kg-1 i.p.) injection did not induce any change in the biochemical parameters measured, however, captopril administered 1 h before doxorubicin ameliorated the biochemical toxicity induced by doxorubicin. This was evidenced by a significant reduction in serum urea and the lipid peroxidation after 4 and 24 h and a significant reduction in creatinine after 48 h. Also, the captopril amelioration was evidenced by an increase in total proteins and albumin after 4 and 24 h of doxorubicin administration. Captopril did not change non-protein sulfhydryl (-SH) concentrations or protein content in the kidney tissues. These results suggest that captopril may be beneficial as a protective agent against nephrotoxicity induced by doxorubicin. PMID- 10094851 TI - Effects of some natural extracts on the acetylcholine release at the mouse neuromuscular junction. AB - Natural extracts have been proved to be useful in different human pathological conditions. The scientific consideration of the therapeutic potential of plant extracts is still inappropriate due to the lack of both pharmacological and epidemiological basic studies. Here, we started from an electrophysiological point of view, a study on the effects of two extracts on the acetylcholine (ACh) release at the neuromuscular junction. The extracts purified from Sugar cane (policosanol) and Psidium guajava (quercetin) have been submitted to this study. The wide epidemiology of these agents suggests therapeutic potentials not yet well outlined at the basic level. Our data demonstrate some interactions in the modulation of the ACh release at the mouse neuro-muscular junction, which are well correlated with the suggested molecular mechanisms. Policosanol enhances to a small extent either the spontaneous or the evoked ACh release. Furthermore, an increase of the rate of the conformational change induced at the nicotinic receptor-channel complex by ACh is also observed. Quercetin induced a reduction of the ACh evoked release. The possibility that this effect could be ascribed to some interaction with presynaptic calcium channel is noteworthy. The results are discussed in terms of a possible interference with acetylcholinesterase by policosanol and of a presynaptic molecular action of quercetin modulating the cytosolic calcium concentration. PMID- 10094852 TI - Antioxidant status in experimental peritonitis: effects of alpha tocopherol and taurolin. AB - The role of oxidative stress and antioxidant defences in inflammation-induced organ injury is not clearly understood. We determined the effects of Escherichia coli (E. coli) peritonitis in rats on peritoneum lipid peroxidation and antioxidant defences. Tissue malondialdehyde (MDA) levels were measured to determine the free radical-induced lipid peroxidation in peritonitis. Tissue glutathione (GSH) levels, and activities of GSH-peroxidase, GSH-reductase and superoxide dismutase were examined to show antioxidant status. We also examined the effects of alpha-tocopherol (20 mg kg-1 body weight) as antioxidant and taurolin (200 mg kg-1 body weight) as chemotherapeutic agents on the oxidant stress and antioxidant defence. The treatment agents and E. coli were administrated intraperitoneally. Animals were killed at 2 h after the onset symptoms and then the peritoneum were obtained. Untreated rats with peritonitis had significantly higher MDA levels and significantly lower antioxidant activity than that of the control animals. Treatment of alpha-tocopherol and taurolin decreased the antioxidant activity and improved the antioxidant status. Pretreatment with alpha-tocopherol for 3 days prior to the induction of peritonitis (IP) and administration of taurolin at the time of the IP were more effective than treatment with alpha-tocopherol at the time of the IP and pretreatment of taurolin, respectively. These results are consistent with the idea that an oxidant/antioxidant imbalance is involved in animal peritonitis. Uses of alpha-tocopherol and taurolin in peritonitis were effective in decreasing the oxidative stress of tissue during peritonitis. PMID- 10094853 TI - Gonadotropin-releasing hormone in mulberry cells of Saccoglossus and Ptychodera (Hemichordata: Enteropneusta). AB - Mulberry cells are epidermal gland cells bearing a long basal process resembling a neurite and are tentatively regarded as neurosecretory cells. They occur scattered through the ectoderm of the proboscis, collar, and anterior trunk regions of the acorn worms Saccoglossus, usually in association with concentrations of nervous tissue. They contain secretion granules that appear from electron micrographs to be released to the exterior. The granules are immunoreactive with antisera raised against mammalian and salmon gonadotropin releasing hormone (GnRH). Similar results were obtained with another enteropneust, Ptychodera bahamensis, using antisera raised against tunicate-1 and mammalian GnRH. Mulberry cells were not found in either Cephalodiscus or Rhabdopleura (Hemichordata: Pterobranchia). Extracts of tissues from 4200 Saccoglossus contain an area of immunoreactive GnRH that is detected by an antiserum raised against lamprey GnRH when characterized by high-performance liquid chromatography and radioimmunoassay. This is the first report of the occurrence of GnRH in hemichordates, probably the most primitive group clearly belonging to the chordate lineage. The physiological function of GnRH in enteropneusts is unknown, but an exocrine function appears more likely than an endocrine or neurotransmitter role. PMID- 10094854 TI - Sex steroid and corticosterone levels of Adelie penguins (Pygoscelis adeliae) during courtship and incubation. AB - Plasma levels of sex steroids (progesterone, 17alpha-hydroxyprogesterone, total androgens, and estradiol) were measured at six stages from courtship to late incubation in Adelie penguins. The pattern of change detected in the levels of plasma total androgens (males) and estradiol (females) was consistent with that found in many birds, with elevated levels during courtship (total androgens, 4 ng/ml; estradiol, 0.5 ng/ml) declining to low, stable levels during incubation. Progesterone levels declined moderately from 1.3 to 0.75-1.0 ng/ml in females following egg laying, but levels of 0.8-1.2 ng/ml persisted in males throughout the study period. 17alpha-Hydroxyprogesterone levels were consistently low (approximately 0.2 ng/ml) in females but progressively declined in males from 0.75 during courtship to <0.3 ng/ml at egg laying and during foraging. Plasma corticosterone levels were measured over the same period and were elevated in both males and females at courtship (16-18 ng/ml) and while fasting on the nest (11-15 ng/ml), but had declined in birds returning from foraging at sea, suggesting that elevated levels are related to the metabolic demands of fasting. PMID- 10094855 TI - Calcium ionophores lead to apoptotic-like changes in Tilapia pituitary cells. AB - Influx or mobilization of Ca2+ plays an important part in the signal transduction mechanisms regulating release of gonadotropin (GtH) and growth hormone (GH) in teleost fish. In mammals it may also mediate a stimulatory effect on the transcription of the genes encoding these hormones (i.e., LHbeta, FSHbeta, and GH). In the present study, exposure of tilapia pituitary cells in primary culture to two ionophores, A23187 and ionomycin, increased GtH and GH secretion over 5-24 h but led to a significant drop in mRNA levels of GtH IIbeta and GH. The mRNA levels of beta actin were also reduced by this treatment, suggesting a general, nonspecific effect in these cells. The morphology of the ionophore-exposed cells also differed markedly; they lacked cytoplasmic extensions, appeared smaller, and were less aggregated than control cells. Staining the nuclei of these cells with 4,6-diamidino-2-phenyl-dihydrochloride revealed that they had undergone condensation and fragmentation, typical of programmed cell death. Extraction of DNA from the ionophore-exposed cells and its separation on ethidium bromide stained gels revealed that, unlike in control cells, the DNA had been broken into fragments in multiples of approximately 180-200 bp, providing further evidence of apoptotic-like effects of the ionophores on the cells. It is speculated that Ca2+, which mediates stimulation of GtH and GH release by the hypothalamic regulatory hormones, may, under certain conditions, have apoptotic-like effects, which specifically regulate the sizes of gonadotroph and somatotroph cell populations. In addition, the fact that pituitary cells exposed to ionophores may become apoptotic should be borne in mind when experiments on signal transduction are carried out with these substances. PMID- 10094856 TI - Effects of aging and sex steroids on the localization of T cell subsets in the ovary of chicken, Gallus domesticus. AB - The goal of this study was to determine the effects of aging and sex steroids on the frequency of T cells in hen ovary. Cryostat sections of ovarian tissues of immature and laying hens and those of immature hens treated with or without diethylstilbestrol (DES) or progesterone were immunostained for T cells using mouse anti-chicken CD3 (antigen of mature T cells), CD4 (antigen of helper T cells), and CD8 (antigen of cytotoxic T cells) monoclonal antibodies. Positive cells were observed under a light microscope and counted using a computer assisted image analyzer. The frequency of CD3(+), CD4(+), and CD8(+) cells in the ovarian stroma and theca of primary follicles was significantly greater in young laying hens than in immature and old laying hens (P < 0.01). The CD4:CD8 ratio was significantly higher in the ovarian stroma of old laying hens than that of immature hens (P < 0.01), which was due to a greater decrease of CD8(+) cells than of CD4(+) cells. The frequency of CD3(+), CD4(+), and CD8(+) cells was significantly greater in the stroma and theca of primary follicles of DES-treated birds than in those of progesterone-treated and control birds (P < 0.01). Progesterone had no significant effect on the population of each subset of T cells. These results suggest that T cell frequency increases in association with sexual maturation and decreases thereafter during aging with an increase of CD4:CD8 ratio. Also, it is likely that estrogen is one of the factors which stimulates the influx of T cells in the hen ovary. PMID- 10094857 TI - Pharmacological characterization of arginine vasotocin vascular smooth muscle receptors in the trout (Oncorhynchus mykiss) in vitro. AB - Arginine vasotocin (AVT) is present in the neurohypophysis of all nonmammalian vertebrates and it appears to be the antecedent of the neurohypophysial nonapeptide hormones. Relatively little is known about AVT receptors in lower vertebrates, especially fish, and the present study was designed to examine AVT receptor interactions in trout vascular and nonvascular smooth muscle in vitro. AVT produced dose-dependent contraction of isolated rings from celiacomesenteric, coronary, and efferent branchial arteries, ventral aorta, anterior cardinal vein, and strips of ductus Cuvier. The greatest efficacy (magnitude of contraction per unit tissue weight) and sensitivity (effective concentration for half-maximal response, EC50) to AVT was found in the efferent bronchial artery (EBA) and its receptors were characterized further. Other neurohypophysial peptides, including arginine vasopressin (AVP), lysine vasopressin (LVP), isotocin (IST), and oxytocin (OXY), contracted EBA with an efficacy order of (most to least) AVT = AVP = OXY > LVP > IST and a sensitivity order of AVT > OXY >/= AVP > IST > LVP. Neither Desmopressin, an AVP V2-receptor agonist, nor the AVP ring fragment, AVP4 9, contracted EBA nor did they inhibit AVT contraction. Pretreatment of EBA rings with the selective AVP V1-receptor antagonists (deamino-Pen1, O-Me-Tyr2, Arg8 vasopressin and deamino-Pen1, Val4, Arg8-vasopressin), the selective V2-receptor antagonist (adamantaneacetyl1, O-Et-D-Tyr0, Val4, aminobutyryl6, Arg8,9 vasopressin), or the combined V1-oxytocin receptor antagonist (d(CH2)5[Tyr(Me)2, Orn8-AVT]) competitively inhibited AVT contractions without affecting AVT efficacy. Receptor affinity constants (pA2) determined by Schild analysis were in the range of 6.8-7.3, with slightly higher constants for the AVP V1-/oxytocin receptor antagonists than for the selective V2-receptor antagonist. Endothelium removal had no effect on EBA sensitivity to AVT. EBA rings were an order of magnitude more sensitive to AVT than nonvascular gastrointestinal and urinary bladder smooth muscle rings or strips. However, AVT (10(-7) M) was as efficacious as acetylcholine (10(-5) M) in gastrointestinal, gallbladder, and urinary bladder smooth muscle. It is concluded that trout EBA possess an AVT smooth muscle receptor that shares a similar pharmacological profile with the mammalian vascular AVP V1a-receptor and the OXY-receptor, but it is distinct from the previously reported gill epithelial cell receptor. PMID- 10094858 TI - Immunocytochemical characterization of the pancreatic islet cells of the Nile Tilapia (Oreochromis niloticus). AB - The cellular composition and topography of the pancreatic islet of Oreochromis niloticus, now known to be a donor source for islet xenotransplantation studies, were characterized. Whole tilapia islets were harvested using an enzymatic method and then further digested into single-cell preparations. Cell cytospin preparations of islet cells and paraffin sections of whole islets were stained using antisera against tilapia insulin, human glucagon, salmon somatostatin-25 (SST-25), human somatostatin-14 (SST-14), and salmon peptide tyrosine-tyrosine (PYY) using the immunoperoxidase method. Cell counts, performed on cytospin preparations using a Quantimet 570 computerized image analysis system, revealed that O. niloticus islets contained 78% endocrine cells and 22% immunonegative cells (i. e., mainly nucleated erythrocytes and rare tissue eosinophils). The proportions of immunopositive endocrine cell types were: 42.3% insulin immunopositive cells, 11.5% glucagon immunopositive cells, 23.1% SST-25 immunopositive cells, 21.8% SST-14 immunopositive cells, and 1.3% PYY immunopositive cells. Islet cell topography was evaluated using histologic sections of whole endocrine pancreata including large, medium, and small islets. Round to polygonal insulin immunopositive cells with round central nuclei were distributed in clusters throughout both the principal and the smaller islets. Elongate SST-14 immunopositive cells were closely associated with the clusters of insulin immunopositive cells; both were surrounded by SST-25 immunopositive cells, which were similar in shape to the insulin immunopositive cells. There were elongate glucagon immunopositive cells throughout the islets, whereas the PYY immunopositive cells were restricted to the periphery and to channels of fibrovascular connective tissue penetrating the islets. PMID- 10094859 TI - Cloning, expression, and tissue localisation of prolactin in adult sea bream (Sparus aurata). AB - A major action of prolactin (PRL) in teleost fish is the maintenance of hydromineral balance in euryhaline species in fresh water. The function of PRL in marine teleosts is less certain and unlike euryhaline teleosts, such as tilapia and salmon, there is relatively little information about protein or gene structure. Associated with studies to determine potential functions of PRL, pituitary prolactin cDNA has been cloned and sequenced from sea bream (Sparus aurata), a marine teleost. The sequence obtained spanned 1349 bp and contained an open reading frame encoding a protein of 212 amino acids composed of a putative signal peptide of 24 residues and a mature protein of 188 amino acids. N-terminal sequencing of the native protein confirmed unambiguously the cleavage site, Ala24, Val25, predicted from alignments of the sea bream PRL cDNA with that of other teleosts. The presence of only one form of PRL in sea bream was supported by identification using Northern blots of only a single transcript of 1.35 kb. Reverse transcription and polymerase chain reaction techniques coupled with Southern blot analysis resulted in the detection of PRL in the pituitary but also in the intestine, liver, ovary, and testes. PMID- 10094860 TI - Seasonal patterns of sex steroids determined from feces in different social categories of Greylag geese (Anser anser). AB - Seasonal patterns of fecal 17beta-OH-androgen, estrogen, and progesterone equivalents of male and female greylag geese (Anser anser) were analyzed in a flock of free-living geese. These were compared among social categories determined by pairbond status and breeding success. The annual cycle was divided into 13 phases. Phasewise intra-sexual comparisons were made between social categories. The seasonal variation obtained from feces was in general agreement with the literature on plasma patterns in geese and other temperate-zone birds. However, there were distinct differences in seasonal hormone patterns among the social categories. In unpaired males, androgen was elevated for a longer period of time during sexually active phases compared with paired males. In male geese, high levels of androgen did not interfere with parenting but were related to pairbond status, whereas in females, androgen and progesterone were positively related to parental behavior. In the Fall, androgen, progesterone, and estrogen peaked only in unpaired males. In unsuccessful females, estrogen started to increase earlier in the Winter and was higher in amplitude and duration than that in females guarding offspring. In general, fecal steroids showed a clear-cut difference only between sexually active and parental phases of the year in the successfully breeding pairs, whereas unpaired males retained a hormonal state closer to sexually active phases throughout the year. PMID- 10094861 TI - Cloning of a fragment of the osteonectin gene from goldfish, Carassius auratus: its expression and potential regulation by estrogen. AB - During reproduction, female teleost fish display increased plasma estrogen and greatly increased total plasma calcium concentrations; the main source of this calcium seems to be the scale. Osteonectin, a collagen-binding glycoprotein, is a major noncollagenous constituent of mammalian bone and is a product mainly of the osteoblasts. RT-PCT has been applied to clone and sequence part of the osteonectin gene from the goldfish, Carassius auratus. The use of a goldfish scale cell line (GFS) and a specific probe to goldfish osteonectin mRNA has allowed the study of the potential effects of estrogen and other calcitropic hormones on the cells derived from the scales. Osteonectin mRNA was detected in teleost bone, scale, and GFS cells by Northern blot analysis, hybridising to a transcript of approximately 1.6 kb. Expression of osteonectin mRNA was markedly down-regulated by 17beta-estradiol (10(-8) to 10(-11) M) in a dose-dependent fashion but was unaffected by calcitriol, TGFbeta, IL-1beta, calcitonin, and PTHrP. Down-regulation of osteonectin by estrogen is further evidence that estrogen participates in calcium homeostasis during vitellogenesis, acting directly on the cells responsible for matrix and mineral fluxes in scales. PMID- 10094862 TI - Polygenic expression of somatostatin in rainbow trout, Oncorhynchus mykiss: evidence of a preprosomatostatin encoding somatostatin-14. AB - Previously we reported the existence of two distinct cDNAs in rainbow trout that encode for separate preprosomatostatins (PPSS), each containing [Tyr7, Gly10] somatostatin-14. In the present study, we used rainbow trout to further characterize the polygenic origin of somatostatins (SSs), a peptide hormone important in the regulation of growth, development, and metabolism of vertebrates. A two-phase rapid amplification of cDNA ends (RACE)-PCR was used for the isolation of selected cDNAs. We amplified and sequenced a ca. 350-bp 3' RACE PCR fragment. Based upon this sequence we designed a second gene-specific primer for 5' RACE-PCR which yielded a 452-bp fragment. Sequence analysis revealed a 745 bp cDNA containing the complete 5'-untranslated region, a single initiation site 118 bases from the most 5' end, and a single putative polyadenylation site 17 bases from the most 3' end that was terminated with a polyadenylated tail. The deduced protein is a 114-amino acid PPSS molecule that contains a number of putative processing sites, potentially yielding a 26-amino acid peptide that could be processed further to a 14-amino acid peptide identical in structure to mammalian SS-14. Northern analysis revealed that PPSS-I was expressed in the pancreas, stomach, intestine, and brain of rainbow trout. These results suggest a polygenic origin of SS, possibly resulting from gene duplication events prior to the divergence of teleosts. PMID- 10094863 TI - An analysis of physiological mechanisms underlying the antigonadotropic action of intracranial prolactin in ring doves. AB - Intracerebroventricular (ICV) injections of prolactin (PRL) exert potent antigonadal and antigonadotropic effects in ring doves (Streptopelia risoria) at doses that are insufficient to stimulate prolactin-dependent crop growth. To explore the physiological basis of these effects, we tested the ability of ICV injected PRL to influence pituitary responsiveness to chicken gonadotropin releasing hormone-I (cGnRH-I) and to alter GnRH content and concentration in the preoptic area (POA) and median eminence (ME). cGnRH-I-induced changes in plasma LH were monitored by radioimmunoassay (RIA) in photostimulated male doves after they received five daily ICV injections of ovine PRL (1 microg/2 microl) or saline vehicle. Although PRL treatment reduced basal plasma LH levels and testes weight, it did not reduce the amount or alter the pattern of LH released in response to a bolus injection of cGnRH-I. This suggests that ICV PRL does not suppress LH by reducing pituitary responsiveness to GnRH. In two subsequent studies, GnRH content (ng/region) and concentration (pg/microg protein) in the POA and ME were measured in male doves by RIA and by competitive enzyme immunoassay after 5 days of ICV PRL or vehicle treatment. Although ICV PRL reduced plasma LH levels in both studies, no significant PRL-induced alterations in GnRH content or concentration were apparent. In a final study, PRL-treated female doves had lower plasma LH levels than vehicle-treated control females at 12 and 24 h after a single ICV injection. GnRH content of the POA was also lower in PRL-treated females than in controls at 24 h. However, the two treatment groups did not differ in POA or ME GnRH content at earlier postinjection sampling intervals. Analysis of GnRH concentration data revealed no treatment group differences in either region at any sampling interval (1, 6, 12, or 24 h post-PRL injection). Collectively, these results are consistent with the idea that ICV injected PRL acts at the level of the CNS to inhibit the reproductive system. However, the nature of the alterations involved remains to be clarified. Plausible hypotheses are (1) that ICV PRL suppresses the gonadal axis by influencing the activity of GnRH neurons at brain sites other than the POA or ME or (2) that PRL alters the synthesis, storage, degradation, and/or release of GnRH in the POA or ME, but the dynamic changes involved are not reflected in integrated, steady-state measures such as peptide content or concentration in tissue. PMID- 10094864 TI - Steroid levels and reproductive cycle of the Galapagos tortoise, Geochelone nigra, living under seminatural conditions on Santa Cruz Island (Galapagos). AB - The Galapagos Islands are home to 11 subspecies of large terrestrial tortoises (Geochelone nigra). All Galapagos tortoises are considered endangered and approximately 12,000 animals still exist. Until now, the reproductive cycle of the Galapagos tortoise has been studied only in captive animals, and no data from free-ranging tortoises have been available. During a one-year period, blood samples were collected from male and female G. nigra living under seminatural conditions on Santa Cruz Island, Galapagos. Plasma steroid hormones were measured by radioimmunoassays (RIAs). In males, plasma testosterone and corticosterone increased a few months before the onset of the mating season. Peak levels were observed while most copulations occurred and environmental temperatures were highest. Both testosterone and corticosterone showed low levels during the cold and dry nesting season and high levels during the hot and rainy mating season. In females, testosterone and corticosterone also rose during the hot and rainy mating season. Both hormones peaked during the second half of the mating season and decreased during the cooler dry season. Female estradiol levels increased at the onset of the mating season, reaching the highest level at the peak of the mating season, which coincided with the highest annual temperatures measured. Estradiol slowly decreased within the next months and rapidly dropped at the onset of the nesting season when temperatures decreased. Progesterone levels were high close to the time of ovulation and showed clearly elevated levels at the beginning of the nesting season after some females had laid their first clutch. Progesterone decreased during the nesting season, when ambient temperatures began to decrease, and reached minimal levels in the postbreeding period shortly before the onset of the next mating season. There were significant annual variations in plasma testosterone in both males and females. Plasma corticosterone was generally higher in males than in females and varied throughout the year in both sexes. PMID- 10094865 TI - Duality of gonadotropin in a primitive teleost, Japanese eel (Anguilla japonica). AB - The duality of gonadotropin (GTH) is well-established in relatively modern teleosts. In primitive teleosts such as eel and catfish, however, only a single GTH (GTH-II) has been isolated and characterized. Therefore, the objective of this study was to clarify the duality of GTH, particularly the presence of GTH-I in primitive teleosts. We attempted to obtain a cDNA encoding the beta subunit of GTH-I from Japanese eel, Anguilla japonica, as a representative primitive teleost species. Rapid amplification of cDNA ends (RACE) polymerase chain reaction (PCR) was used to amplify GTH-Ibeta cDNA prepared from immature male Japanese eel pituitaries, and the obtained PCR products were subcloned and sequenced. A degenerate PCR primer was designed based on a highly conserved region between teleost GTH-Ibeta and mammalian FSHbeta. DNA sequence analysis of the cloned PCR products confirmed the presence of the predicted complete coding region as well as the 5' and 3' untranslated regions. The deduced amino acid sequence from these clones showed high homology to goldfish GTH-Ibeta (60%), whereas the identity between Japanese eel GTH-Ibeta and GTH-IIbeta was lower (42%). Phylogenetic analysis confirmed that Japanese eel GTH-Ibeta belonged to the teleost GTH-Ibeta group. These results provide a definitive proof of the presence of two types of GTHs (GTH-I and GTH-II) in Japanese eel, as has been shown in other teleosts. The duality of GTHs is applicable for teleosts in general. Northern blot analysis showed the transcripts of Japanese eel GTH-Ibeta and GTH-IIbeta to be 1200 and 750 bases, respectively. GTH-Ibeta gene was expressed in immature fish, while GTH IIbeta gene was expressed in spermiating males and ovulated females, suggesting that two GTHs are differentially expressed at different sexual stages and may play separate roles in the reproductive process in Japanese eel. PMID- 10094866 TI - Feedback control of gonadotropins in Atlantic salmon, Salmo salar, male parr.I. Castration effects in rematuring and nonrematuring fish. AB - Sexual maturation of Atlantic salmon (Salmo salar) male parr is a seasonally recurrent "all or none" response; either a fish matures fully or it does not mature. To study whether gonadal feedback on gonadotropic hormones, GTH I and GTH II, is involved in the control of maturation, previously mature Atlantic salmon male parr were either sham-operated or castrated in spring. They were then sampled during the onset of gonadal growth (late June-early July) or shortly before the breeding season (late September). In autumn, sham-operated males separated into two groups: nonrematuring males with low pituitary and plasma levels of both GTH I and GTH II, and those rematuring with high levels of gonadotropins. Castrated males had low GTH I and GTH II plasma and pituitary levels, similar to those of the nonrematuring fish, suggesting positive feedback mechanisms, separating the sham-operated fish into low and high GTH level groups. In the summer, plasma GTH II was nondetectable in all fish. Pituitary GTH II content was lower in nonrematuring, than in rematuring males and was even lower in castrated fish. In contrast, castration increased pituitary and plasma levels of GTH I in the summer, suggesting a negative feedback at this reproductive stage. There were no significant differences in immunoassayable levels of GTH I in plasma in rematuring and nonrematuring sham-operated males at this time. The control of rematuration is complex and may involve factors other than circulating GTH I levels, possibly with differences in gonadal sensitivity to GTH I. PMID- 10094867 TI - Feedback control of gonadotropins in Atlantic salmon, Salmo salar, male parr.II. Aromatase inhibitor and androgen effects. AB - Both positive and negative feedback on the (hypothalmus)- pituitary-gonad axis occur in salmonids. The aim of the present study was to investigate the role of different androgens, and in particular the involvement of aromatization of androgens to estrogens in feedback mechanisms. Previously mature Atlantic salmon, Salmo salar, male parr were studied in two experiments. In the first experiment, intact fish were implanted with Silastic capsules filled with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) in spring and sampled in the autumn when the rematuring males were starting to display running milt. In the second experiment, castrated males were implanted with capsules containing ATD, the androgens testosterone (T) and 11-ketoandrostenedione (11KA), or ATD and T combined in spring. These fish were sampled in the summer when rematuring fish were starting to show signs of gonadal growth. Pituitary and plasma gonadotropins (GTH I and GTH II) were studied using radioimmunoassay. In autumn, ATD treatment reduced pituitary and plasma GTH II levels. In summer, GTH II was consistently nondetectable in plasma. Castration diminished pituitary GTH II content. Treatment with T increased pituitary GTH II content, an effect that was attenuated when T treatment was combined with ATD. All these results are consistent with the presence of an aromatase-dependent positive feedback of T on GTH II. 11KA also had a stimulatory effect on GTH II, although weaker than that of T. Testicular size and spermiation was reduced by ATD in autumn; the latter of these results is likely to be due to the inhibitory effect of ATD on GTH II. Positive effects of ATD on plasma GTH I were found in autumn, indicative of an aromatase-dependent negative feedback in this phase. On the other hand, castration increased plasma and pituitary GTH I levels in summer, indicating that the gonads in this phase exert a predominantely negative control of GTH I. In summer, negative effects of T on GTH I pituitary levels were not suppressed, but were rather enhanced, by the combined treatment with ATD. Furthermore, plasma GTH I levels were lower after treatment with T in combination with ATD than with T or ATD separately. These negative effects of T were not diminished by ATD, so that they are nonaromatase-dependent. Furthermore, since they were actually more pronounced in the presence of ATD it is suggested that there is also a positive aromatase-dependent feedback component in this phase. In addition, 11KA had a negative effect on plasma and pituitary GTH I in castrated previously mature males. Thus, GTH I secretion is controlled by both aromatase-dependent and nonaromatase-dependent feedback effects, of which at least the former may be positive or negative depending on season. In summary, the feedback control of GTH I appears to be more complex than that of GTH II. PMID- 10094869 TI - IN MEMORIAM: genevieve gorbman PMID- 10094868 TI - Immunohistochemical localization of corticotropin-releasing factor in the brain and corticotropin-releasing factor and thyrotropin-stimulating hormone in the pituitary of chinook salmon (Oncorhynchus tshawytscha). AB - This report describes the distribution of corticotropin-releasing factor (CRF) like immunoreactivity in the brain and the contiguous localization of CRF- and thyrotropin-stimulating hormone (TSH)-like immunoreactivity in the pituitary of hatchery-reared, juvenile chinook salmon (Oncorhynchus tshawytscha). Results show that CRF-immunoreactive cell bodies exist in the parvocellular and magnocellular nuclei of the preoptic area and in a ventral hypothalamic region corresponding to the nucleus lateralis tuberis. CRF-immunoreactive fibers are observed along the rostral edge of the hypothalamus, in the pituitary stalk, and in the pituitary gland. Within the pituitary, CRF-immunoreactive fibers, with terminal-like boutons, were distinguishable in the neurohypophysis, pars distalis (PD), and pars intermedia (PI). In the PD, the CRF-immunoreactive fibers terminate in regions that contain TSH-positive pituitary cells. From this study, we conclude that CRF-immunoreactive fibers travel through, and terminate in, the neurohypophysis. CRF-immunoreactive fibers were also observed to terminate within the basement membrane and within the PD and PI of the adenohypophysis. Furthermore, the contiguous localization of CRF-immunoreactive fibers and TSH immunoreactive pituitary cells suggests that CRF may mediate release of TSH. PMID- 10094870 TI - Aubrey gorbman, 1998 presidential award PMID- 10094871 TI - The role of laparoscopic staging in the management of patients with early endometrial cancer. PMID- 10094872 TI - Laparoscopic-assisted vaginal hysterectomy for endometrial cancer: clinical outcomes and hospital charges. AB - OBJECTIVE: Our objective was to compare the clinical outcomes and associated hospital charges between two methods of hysterectomy for patients with early stage endometrial cancer. METHODS: Retrospective chart review of 320 patients with early-stage endometrial cancer treated by laparoscopic-assisted vaginal hysterectomy (LAVH) or total abdominal hysterectomy (TAH) was performed for the period of July 1, 1991, to September 30, 1996, at Memorial Sloan-Kettering Cancer Center. RESULTS: Sixty-nine patients (22%) were treated by LAVH, and 251 (78%) were treated by TAH. The majority of the patients (80%) had Stage I disease. The mean age was similar for both groups: 60 years for the LAVH vs 61 years for TAH. The mean weight was significantly lower for the LAVH group, 71 kg (range 43-117 kg), than for the TAH group, 82 kg (range 38-200 kg), (P < 0.05). Overall complication rates were lower among patients treated by LAVH. Operating room time was longer for the LAVH group (214 min) than for the TAH group (144 min) (P < 0.05). The median length of stay was significantly shorter for patients treated by LAVH (2.0 days) compared to TAH (6.0 days) (P < 0.05). Room charges were significantly higher for the TAH patients ($6960) compared to the LAVH patients ($3130) (P < 0.05). Overall mean total charges were significantly less for the LAVH group ($11,826) than for the TAH group ($15,189) (P < 0.05). With a median follow-up of 30 months for the TAH group and 18 months for the LAVH group, there was no significant difference in disease recurrence (P = 0.91). CONCLUSION: Patients treated by LAVH for early-stage endometrial cancer had significantly shorter hospitalization and fewer complications, resulting in less overall hospital charges when compared to patients treated by TAH. Long-term outcome was similar. Laparoscopic-assisted vaginal hysterectomy is an attractive alternative for selected patients with early-stage endometrial cancer. PMID- 10094873 TI - A comparison between loop electrosurgical excision procedure and cold knife conization for treatment of cervical dysplasia: residual disease in a subsequent hysterectomy specimen. AB - OBJECTIVE: The purpose of this study was to determine whether the loop electrosurgical excision procedure (LEEP) is as effective as cold knife conization (CKC) in the removal of cervical dysplasia. METHODS: One-hundred sixteen patients with cervical intraepithelial neoplasia were included: 73 cases treated with LEEP and 43 cases treated with CKC. All of these patients underwent subsequent hysterectomy within 6 months of treatment. A thorough histological evaluation of the cone specimens and post-cone hysterectomy specimens was performed. RESULTS: No residual disease in the post-cone hysterectomy specimens was identified in 63% of the LEEP group and 72.1% of the CKC group. There was no significant difference in the proportion of negative residual disease (P > 0.05). The mean diameters of the base as well as the depth of the cone specimens were smaller in the LEEP group than in the CKC group (P < 0.05). The operating time in the LEEP group was significantly shorter than that of the CKC group (P < 0.05). Although thermal artifacts of margin were found in 8.2% of LEEP specimens, there was no difficulty in histological interpretation. Furthermore, the postoperative complications were similar in both groups. CONCLUSION: The findings of this study demonstrate that the LEEP is a convenient, safe, and effective treatment for the management of cervical dysplasia. Cone specimens obtained during LEEP are adequate for thorough histological evaluation of cervical dysplasia. PMID- 10094874 TI - Chemical analysis of adnexal cyst fluid. AB - OBJECTIVE: The purpose of the study was to determine if adnexal cyst fluid glucose, protein, and lactate dehydrogenase (LDH) levels can discriminate between cancerous and noncancerous adnexal masses. METHODS: Intracystic fluid was aspirated from adnexal masses immediately after operative excision. Patient age and menopausal status, mass size, and cyst fluid specific gravity were recorded. Cyst fluid and intraoperative serum glucose, protein, and LDH levels were measured. Masses were grouped by histopathologic diagnosis. Cyst fluid chemical levels and cyst fluid/serum ratios were compared among and between the groups. RESULTS: Fifty-eight adnexal masses were analyzed: 15 nonneoplastic (group 1), 23 benign neoplastic (group 2), and 20 malignant (group 3). There were no significant differences among the groups with regard to patient age, menopausal status, or cyst fluid specific gravity. Cyst size (cm2) was significantly different among the three groups (P < 0.01), with the largest mean size found in the cancer group. No significant differences in cyst chemistries or cyst fluid/serum ratios were found between groups 1 and 2. Comparing groups 1 and 3, all values were significantly different (P < 0.05), with the greatest level of significance attained by comparison of cyst fluid LDH levels (P < 0.001). Groups 2 and 3 statistically differed in cyst fluid levels and cyst fluid/serum ratios of both protein and LDH, with the highest levels of significance achieved by comparisons of cyst fluid levels and ratios of LDH (P = 0.001 and P < 0.001, respectively). The cyst fluid LDH level was found to be the best single chemistry for distinguishing noncancerous (groups 1 and 2) from cancerous (group 3) adnexal masses. A cyst fluid LDH level of >/=451 U/L imparted a 90% sensitivity and 71% specificity for detecting malignancy. CONCLUSIONS: Evaluation of adnexal cyst fluid LDH may help to distinguish benign from malignant adnexal masses. More cases are needed to adequately assess the predictive value and clinical utility of this approach. PMID- 10094875 TI - Discrepancy between ultrasonography and hysteroscopy and histology of endometrium in postmenopausal breast cancer patients using tamoxifen. AB - BACKGROUND: The increased risk of endometrial carcinoma following the use of tamoxifen has stimulated studies on endometrial diagnostic screening methods. In tamoxifen users the endometrial thickening observed with transvaginal ultrasonography (TVU) frequently cannot be confirmed by hysteroscopy or histology. OBJECTIVE: The aim was to investigate the relationship between TVU and hysteroscopic and histologic endometrial findings in postmenopausal patients using tamoxifen. METHODS: Fifty-three asymptomatic postmenopausal tamoxifen-using breast cancer patients underwent a gynecological examination combined with TVU. Patients with an endometrial thickness of >5 mm were offered hysteroscopy and endometrial biopsy. FINDINGS: Thirty-one patients (58%) had an endometrial thickness of >5 mm with enhanced, inhomogeneous echogenicity. Hysteroscopy was performed in 22 patients and 3 underwent hysterectomy. Seven of 22 patients had endometrial polyps, histologically characterized by cystically dilated glands lined with atrophic epithelium and periglandular stromal condensation. Histology of the three hysterectomy specimens showed a similar picture of atrophic luminal epithelium, covering dilated glands lined with atrophic epithelium and surrounded by dense stroma, which resembled the histology of the endometrial polyps. In all three specimens the histologically measured endometrial thickness corresponded with that on TVU. INTERPRETATION: Tamoxifen can induce specific endometrial changes consisting of cystically dilated glands with periglandular stromal condensation while the overlying epithelium remains atrophic. The changes occur either in the endometrium itself or as a protrusion of the endometrium, i.e., as endometrial polyps. These findings explain the discrepancy between ultrasound, hysteroscopy, and histology. Due to the high number of false-positive findings, TVU is not an effective screening instrument in these patients. PMID- 10094876 TI - Growth suppression of human ovarian cancer cell lines by the introduction of a p16 gene via a recombinant adenovirus. AB - OBJECTIVE: The cell cycle regulatory protein p16 (CDKN2/cyclin dependent kinase 4 inhibitor/multiple tumor suppressor-1) causes cell cycle arrest at the G1 checkpoint by inhibiting activity of cyclin D-CDK4 complexes. The purpose of this study is to assess the effect of introduction of the p16 gene into two ovarian cancer cell lines via a recombinant adenoviral vector (Ad5CMV-p16). METHODS: Cells lines used were SKOV3, which has a p16 deletion, and OVCA420, which has normal p16. Transduction efficiency was established by infecting cells with an adenovirus containing the Escherichia coli beta-galactosidase gene (Ad5CMV-beta gal) at multiplicity of infection from 0 to 1000 and staining for X-gal. Cells were infected with Ad5CMV-p16 and cell growth was assessed by counting cells every other day for up to 7 days. Western blotting was done to assess for p16 expression after infection. Fluorescence-activated cell sorting after staining with propidium iodide was done to assess the effect of p16 on the cell cycle. RESULTS: The SKOV3 cell line was transduced with the adenovirus at a slightly lower MOI than the OVCA420 cell line. Growth of the Ad5CMV-p16-infected cells was suppressed 75-80% by cell count in both cell lines and caused morphologic changes of the cells consistent with apoptosis. The p16 protein expression was seen to increase within 24 h after introduction of the p16 gene. G1 arrest of cells occurred beginning 24 h after introduction of the p16 gene. CONCLUSIONS: These results suggest that Ad5CMV-p16 may be further studied as a potential therapeutic agent for ovarian cancer as introduction of the p16 gene into ovarian cancer cell lines causes a G1 arrest and attenuation of growth, regardless of the endogenous p16 status of the cells. PMID- 10094877 TI - Radiation treatment of advanced or recurrent granulosa cell tumor of the ovary. AB - BACKGROUND: Because granulosa cell tumors of the ovary are rare, the optimal treatment for women with gross residual disease after primary surgery or recurrence is not known. Our objective was to review the results of radiotherapy for advanced or recurrent granulosa cell tumor of the ovary. METHODS: This retrospective review identified 34 patients with ovarian granulosa cell tumors treated with radiation at the University of Texas M. D. Anderson Cancer Center between 1949 and 1988. Fourteen received treatment for clinically measurable disease; 20 received adjuvant radiotherapy after surgery for minimal residual (<1 cm) or microscopic residual disease. The 14 patients with measurable disease formed the basis for this review. RESULTS: Ten of 14 patients were treated with moving-strip whole-abdomen radiation (27-28 Gy), 9 with 60Co, and 1 with 6-MeV photons and a pelvic boost of 28 Gy with 22-25 MeV photons. The other 4 patients were treated with pelvic radiotherapy (45-61 Gy) with 22-25 MeV photons. Six of 14 patients (43%) had a clinical complete response to radiotherapy, with a median follow-up of 13 years (range, 5-21 years). Three of 6 who responded to radiation had relapse 4-5 years later; 2 of these 3 died of disease and 1 was alive with disease at last follow-up. Three responders remain alive without evidence of disease 10-21 years after treatment. The 8 nonresponders had a median survival of 12.3 months (range, 1-60 months). CONCLUSIONS: Radiotherapy can induce a clinical response with occasional long-term remission in patients with persistent or recurrent granulosa cell tumor of the ovary. PMID- 10094878 TI - Prognostic factors of adenocarcinoma of the uterine cervix. AB - OBJECTIVE: The prognostic importance of adenocarcinoma of the uterine cervix was investigated. Methods. One hundred ninety-three patients (144 had stage I disease, 41 stage II, and 8 stage III-IV) with invasive adenocarcinoma of the uterine cervix treated initially at the Aichi Cancer Center between 1964 and 1995 were studied. RESULTS: Of all the invasive cervical cancers, 8.8% were adenocarcinomas that had been increasing during the past decade. The overall 5 year survival for stage I was 88.8%, stage II 44.9%, and stage III-IV 0% In univariate analysis, the clinicopathological factors associated with overall survival and disease-free survival were age of patient, stage of disease, presence of nodal metastasis, number of lymph nodes involved, lymph-vascular space invasion, tumor size, and intraperitoneal metastasis. Multivariate analysis performed in all cases identified the clinical stage of disease, the presence of nodal metastasis, number of lymph nodes involved, lymph-vascular space invasion, and tumor size as the independent risk factors for recurrence and survival. In the analysis of stage I disease, lymph node metastasis and tumor size were the significant prognostic factors, while lymph-vascular space invasion and tumor size were the factors in advanced disease. Tumor grade and histological type were not associated with recurrence and survival. CONCLUSION: These results suggested the association of lymph node metastasis with the prognosis of early stage adenocarcinoma of the uterine cervix and lymph-vascular space invasion with the advanced stage. Tumor size was an independent risk factor throughout all stages. PMID- 10094879 TI - Macrophages and microvessel density in tumors of the ovary. AB - Macrophages are members of the mononuclear phagocyte system and synthesize and release many angiogenesis stimulators and inhibitors. Previous studies have demonstrated heterogeneous macrophage populations in ovarian tumors. The aim of this study was to compare macrophage number between different types of ovarian tumors and between regions of high (HVD) and average (AVD) microvessel density (MVD). Macrophages were visualized using CD68 antibody. Previously determined regions of HVD and AVD were located on CD68 immunostained sections and image analysis software was used to count the number of positively stained cells per square millimeter. CD68-positive macrophage number did not differ between benign, mucinous, and serous ovarian tumors or between regions of HVD and AVD (ANOVA; P > 0.05). In both HVD and AVD regions of benign tumors, macrophage number positively correlated with MVD (Spearman rank correlation coefficient; P < 0.03). In contrast, a small but significant negative correlation between macrophage number and MVD was observed in HVD regions of serous tumors (Spearman rank correlation coefficient; P > 0.05). Macrophage infiltration does not appear to differ between ovarian tumor types; however, macrophages may have a positive influence on the vascularization of benign ovarian tumors. PMID- 10094880 TI - Diagnostic utility of Mullerian inhibiting substance determination in patients with primary and recurrent granulosa cell tumors. AB - OBJECTIVES: In this study we evaluated changes in serum Mullerian inhibiting substance (MIS) concentration in a large number of patients with granulosa cell tumors (GCT) to determine whether MIS is elevated at the time of presentation and whether MIS is an index of successful surgical resection and management of recurrences. METHODS: We retrospectively reviewed MIS levels from 17 subjects prior to tumor resection and studied serial MIS samples from 56 subjects following initial tumor resection. Clinical follow-up information was available for 36 of those with postoperative MIS values. Serum MIS was measured by an ELISA. MIS values were compared to a combination of normative values previously established in our laboratory and from more recently obtained samples from older pre- and postmenopausal women, using this assay. RESULTS: Serum MIS was elevated pre-operatively in 6 of 8 (75%) subjects with juvenile GCTs and in 7 of 9 (78%) of those with adult GCTs relative to age-matched controls (76% for both types combined). Post-operative clinical correlation was available for 36 patients. There was no clinical recurrence in 21 subjects with normal or undetectable postoperative values, and incompletely resectable tumor or recurrence was identified in 6 of 15 patients with elevated postoperative values. CONCLUSIONS: The results of this study demonstrate that postoperative serum MIS concentrations may be used to evaluate the completeness of tumor removal following initial surgery and that serial MIS determinations may allow the detection of recurrences. PMID- 10094881 TI - Combination of multiple serum markers using an artificial neural network to improve specificity in discriminating malignant from benign pelvic masses. AB - A panel of four selected tumor markers, CA 125 II, CA 72-4, CA 15-3, and lipid associated sialic acid, was analyzed collectively using an artificial neural network (ANN) approach to differentiate malignant from benign pelvic masses. A dataset of 429 patients, 192 of whom had malignant histology, was retrospectively used in the study. A prototype ANN classifier was developed using a subset of the data which included 73 patients with malignant conditions and 101 patients with benign conditions. The ANN classifier demonstrated a much improved specificity over that of the assay CA 125 II alone (87.5% vs 68.4%) while maintaining a statistically comparable sensitivity (79.0% vs 82.4%) in discriminating malignant from benign pelvic masses in an independent validation test using data from the remaining 255 patients which had been set aside and kept blind to the developers of the ANN system. A similar improvement in specificity was observed among patients under 50 years of age (82.3% vs 62.0%). The ANN system was further tested using additional serum specimens collected from 196 apparently healthy women. The ANN system had a specificity of 100.0% compared to that of 94.8% with the assay CA 125 II alone. PMID- 10094882 TI - The expression of type I growth factor receptors in the squamous neoplastic changes of uterine cervix. AB - AIM: The type I family of growth factor receptors includes ErbB1, ErbB2, ErbB3, and ErbB4 which are frequently overexpressed in various human cancer cells. In this study, we systematically investigated the frequency and distribution of these four receptors in relation to neoplastic changes and tumor behaviors in the uterine cervix. MATERIALS: A total 84 of cases including 12 cases of normal cervical tissues, 6 cases of low grade squamous intraepithelial lesion, 10 cases of high grade squamous intraepithelial lesion, and 56 cases of squamous cells carcinoma were examined. RESULTS: Our results show significant difference with increasing grades of dysplasia in terms of these four receptor expressions. No association was found between these four receptors and cell keratinization/differentiation of squamous cell carcinoma of the cervix. Of the four receptors studied, only the expression of erbB2/neu gene was significantly associated with lymph nodal metastasis. Moreover, we find that the coexpression of ErbB1 and ErbB4 was significant in cervical carcinoma. CONCLUSIONS: The coexpression of ErbB1 and ErbB4 in cervical carcinoma suggests that they may be involved in receptor heterodimerization leading to the activation of signaling pathway in the cervical carcinoma. PMID- 10094883 TI - Lateral microscopic extension of squamous cell carcinoma of the vulva. AB - PURPOSE: The aim of this study was to measure the radial occult microscopic spread of tumor in patients with invasive squamous cell carcinoma of the vulva. MATERIALS AND METHODS: In the operating room the gross tumor border was marked. The pathologist took a radial section in each quadrant and measured the distance of occult lateral spread of the tumor. RESULTS: From 7/01/93 to 6/30/96, 24 tumors from 21 patients were studied. The mean maximum tumor diameter was 3. 2 cm (0.5-7.0) and the mean depth of invasion was 9.1 mm (1.1-28.0). The gross and microscopic extent correlated in 20 tumors. Maximum lateral microscopic extent of the other 4 tumors was 3.5, 5 (to the margin), 10, and 16 mm. These 4 tumors were ulcerative and infiltrative and arose from or involved mucosa. CONCLUSION: The gross and microscopic periphery of most invasive squamous vulvar cancers are approximately the same. Ulcerative tumors with an infiltrative pattern of invasion which involve mucosal epithelium may be more likely to extend beyond what is grossly apparent. Measurement of the tumor-free margin should be included in future studies. PMID- 10094884 TI - Ultrastructural interactions in the microvasculature of human endometrial adenocarcinoma. AB - OBJECTIVES: Our purpose was to study the ultrastructural morphology of the microvasculature of human endometrial adenocarcinoma and to determine the effect of this malignancy on cell-to-cell communication between the components of the microvasculature and with the other tissue compartments of human endometrium. Methods. Multiple cases of human endometrial adenocarcinoma were studied and graded by light microscopy. Six cases of Grade I and six cases of Grade II were selected. Two blocks per case were studied ultrastructurally. RESULTS: In contrast to our expectation that the ultrastructure of tumor vessels would suggest a great deal of proliferation and new vessel formation, we found that tumor vessels displayed a high degree of cellular differentiation, in the form of numerous and varied cell-to-cell contacts, and large amounts of protein production. CONCLUSIONS: The morphology of the microvasculature of endometrial adenocarcinoma suggests an active rather than passive role in tumor vessels. PMID- 10094885 TI - 99m-Tc-tetrofosmin scintigraphy and breast cancer. AB - BACKGROUND: 99m-Tc-tetrofosmin holds significant interest among medical oncologists because of its high positive predictive value (>90%) in pilot trials, exceeding sensitivity and specificity rates of mammography. Objective. Our objective was to assess the diagnostic accuracy of 99m-Tc-tetrofosmin whole-body scintigraphy in outpatients. PATIENTS AND METHODS: Thirty-one patients with an abnormal mammograph (n = 22) or follow-up patients (n = 9), 7 of whom were known to have metastatic disease, were included. Tracer (550 MBq) was injected into the cubital vein. Whole-body planar and single photon emission computed tomography images of regions of interest were obtained. Histology, computed tomography (CT), or magnetic resonance imaging (MRI) were performed to confirm scintigraphic results. Correlation between scintigraphy and CT or MRI was assessed by two independent radiologists. Accuracy, sensitivity, and specificity rates for the diagnosis of local and distant breast cancer lesions were given. RESULTS: Of the 22 first-visit patients, 15 had breast cancer, and 7 had no evidence of any malignant disease. Of all patients examined (n = 31), 21 had distant metastases. Breast tumors were correctly diagnosed in 14/15 patients (93%), with only 1 false negative result. Extrahepatic metastatic lesions (n = 16) were correctly diagnosed in 14 (88%) patients, whereas the method was not suitable for the diagnosis of liver metastases. CONCLUSION: Tetrofosmin scintigraphy has shown very high detection rates of breast tumors and of metastatic lesions and is therefore a valuable option in breast cancer diagnosis. PMID- 10094886 TI - A study of diagnostic failure of loop conization in microinvasive carcinoma of the cervix. AB - OBJECTIVE: The aim of this study was to evaluate the specimen adequacy and the histological interpretation of loop conization for microinvasive cervical carcinoma. METHODS: We retrospectively reviewed the histopathological findings of the original cone specimens together with the final hysterectomy specimens in patients with microinvasive carcinoma of the cervix. From 1990 to 1995, 63 consecutive patients with microinvasive carcinoma of the cervix were included in the study, of which 35 patients underwent loop conization and 28 underwent cold knife conization. All patients had a hysterectomy. RESULTS: The mean width, depth, and cone volume of the conization specimens were 2.44 cm, 2.15 cm, and 3.96 cm3, respectively, in the loop group versus 2.3 cm, 2.35 cm, and 4.38 cm3 in the cold-knife group. No significant differences were seen between the two groups. The application of loop conization was completed in a single slice in 27 patients (77.1%) and multiple slices by the loop in 8 (22.9%), in spite of the attempt to perform conization in a one-pass application when possible. In assessing these cone specimens microscopically, the rate of transection of tissue was significantly higher in the loop cone than in the cold-knife cone (17.1% versus 0%, P = 0.02). Because of transection of tissue and misorientation, pathologic determination of the depth and width of stromal invasion was undetermined in two loop cone specimens compared with none in the cold-knife cones. CONCLUSION: Our study suggests that cold-knife conization is a preferred method in assessing microinvasive carcinoma of the cervix if multiple applications of loop conization are inevitable. PMID- 10094887 TI - Phase II trial of intraperitoneal cisplatin and mitoxantrone in patients with persistent ovarian cancer. AB - OBJECTIVE: The aim of this study was to determine the feasibility and efficacy of intraperitoneal cisplatin and mitoxantrone in patients with very small-volume residual disease at second-look surgery after completion of primary platinum based intravenous chemotherapy. PATIENTS AND METHODS: Between February 1992 and February 1994, 42 patients were treated with up to five cycles of intraperitoneal cisplatin (100 mg/m2)/mitoxantrone (10 mg/m2). Patients were evaluated for surgically defined response rate and followed for progression-free (PFS) and overall survival (OS) using an intention-to-treat analysis, and grouped according to disease volume at initiation of treatment. RESULTS: The mean age of all patients was 48.5 years. Thirty patients (71%) were Stage III at diagnosis; 18 patients (43%) had microscopic disease at the initiation of IP therapy, and 24 patients (57%) had macroscopic disease. Twenty-eight patients completed three or more cycles of protocol therapy, and 14 patients were changed to standard intravenous therapy after receiving fewer than three cycles of treatment secondary to catheter-related problems (12 patients), cisplatin ototoxicity (1 patient), or withdrawal from study (1 patient). Using an intention-to-treat analysis, the median PFS was 22.5 months, and the median OS of all patients (N = 42) was 47 months (6-72 months) with a median follow-up of 62.7 months. When grouped according to size of disease at initiation of treatment, the OS has not been reached at 62.7 months of follow-up in patients (N = 18) with microscopic disease. CONCLUSIONS: (1) The combination of IP mitoxantrone and cisplatin has an unacceptable catheter failure rate due to mitoxantrone toxicity; (2) PFS and OS is longer in patients with microscopic rather than macroscopic residual disease; and (3) intraperitoneal platinum-based chemotherapy in patients with very small volume residual disease may result in improved survival. PMID- 10094888 TI - The accuracy of frozen-section diagnosis in metastatic breast and colorectal carcinoma to the adnexa. AB - OBJECTIVE: The objective of our study was to describe the accuracy of intraoperative frozen-section diagnosis of carcinoma metastatic to the adnexa in women with a history of breast or colorectal carcinoma. METHODS: We conducted a retrospective chart review of all patients with a history of breast or colorectal carcinoma who developed histologically proven pelvic or abdominal metastases between 1988 and 1995. In those patients whose final histologic review revealed carcinoma metastatic to the adnexa, the accuracy of the intraoperative frozen section diagnosis of the adnexal tumor was compared to the final diagnosis. RESULTS: Forty-three patients were identified and in 36 patients the frozen section was obtained from the adnexa. Twenty-one patients (58.3%) had metastatic breast carcinoma and 15 (41.7%) had metastatic colorectal carcinoma to the adnexa. Carcinoma in the adnexa was correctly diagnosed by frozen section in 35 of 36 patients (97.2%). Metastatic carcinoma was identified at frozen section in 17 of 21 patients (81%) with metastatic breast cancer and 13 of 15 patients (86.7%) with metastatic colorectal cancer. In 3 of 21 patients (14.3%) with metastatic breast cancer and in 2 of 15 patients (13.3%) with metastatic colorectal cancer, the frozen-section diagnosis was carcinoma of uncertain origin. One patient had a false-negative frozen section because the small focus of metastatic breast cancer was not sampled at the time of frozen section. CONCLUSION: Intraoperative frozen-section evaluation correctly diagnosed carcinoma in the adnexa in 97% of patients, and in over 80% of cases, the carcinoma was diagnosed as being metastatic in origin. PMID- 10094889 TI - Interest of pelvic and paraaortic lymphadenectomy in patients with stage IB and II cervical carcinoma. AB - OBJECTIVES: The objectives of this study were to evaluate the interest and the potential therapeutic value of systematic pelvic and paraaortic lymphadenectomy in patients with stage Ib and II cervical carcinoma. METHODS: This was a prospective study including 421 patients with cervical cancer treated, from 1985 to 1994, by combined radiation therapy and surgery with systematic pelvic and paraaortic lymphadenectomy. RESULTS: The overall rate of pelvic lymph-node involvement was 26% (106 patients), and the rate of paraaortic metastases was 8% (32 patients). Pelvic nodal involvement was unilateral in 14% (59 patients) and bilateral in 11% (47 patients). Macroscopic positive nodes were found in 12% (52 patients). In a univariate analysis, a young age (<30 years), a tumor size >/=4 cm, stage II disease, and nodal involvement were associated with significantly decreased survival. The nodal status and the characteristics of positive nodes (number and location) were the most significant prognostic factors. In the multivariate analysis, age, the tumor size, and the site of nodal involvement (pelvic or paraaortic) were prognostic factors. Three-year survival was 94% for patients with negative nodes compared to 64% for patients with positive pelvic nodes and 35% for patients with positive paraaortic nodes (P < 0.0001). CONCLUSION: These results confirm the diagnostic and prognostic value of systematic complete lymphadenectomy when planning adjuvant treatment and the therapeutic value of complete removal of bulky positive nodes. PMID- 10094890 TI - The American brachytherapy society survey of brachytherapy practice for carcinoma of the cervix in the United States. AB - PURPOSE: The purpose of this study was to survey the brachytherapy practice for cervical cancer in the United States. METHODS: The Clinical Research Committee of the American Brachytherapy Society (ABS) performed a retrospective survey of individual physicians of the ABS and American Society of Therapeutic Radiologists and Oncologists regarding the details of the brachytherapy techniques they personally used in the treatment of cervical cancer patients for the year 1995. The replies (some of which may have been an estimate only) were tabulated. The scope of this survey did not allow us to verify the data by chart audits. RESULTS: A total of about 3500 questionnaires were mailed out; 521 responses were received. Of these responders, 206 (40%) did not perform any brachytherapy for carcinoma of the cervix in 1995. Of the other 315 responders reporting a total of 4892 patients treated in 1995, 88% used low dose rate (LDR) while 24% used high dose rate (HDR). There was a wide variation in the doses used. For LDR treatments, the median total external beam radiation therapy (EBRT) dose was 45 and 50 Gy and the LDR dose was 42 and 45 Gy for early and advanced cancers, respectively. For HDR treatments, the median EBRT dose was 48 and 50 Gy and the median HDR dose was 29 and 30 Gy for early and advanced cancers, respectively. The median dose per fraction was 6 Gy for a median of five fractions. Interstitial brachytherapy was used as a component of the treatment in 6% of the patients by 21% of responders. Very few responders treated with pulsed or medium dose rates. CONCLUSION: This retrospective survey showed the current brachytherapy practice pattern in the treatment of cervical cancer in the United States and can serve as a basis for future prospective national brachytherapy data registry. There was wide variation in the practice pattern, emphasizing the urgent need for consensus on these issues. PMID- 10094891 TI - Frequency of invasive cancer in surgically excised vulvar lesions with intraepithelial neoplasia (VIN 3). AB - OBJECTIVE: The aim of this study was to determine the frequency of invasive cancer found from specimens removed by surgical excision on patients with diagnosis of VIN 3. METHODS: Seventy-eight patients with biopsy-proven vulvar intraepithelial neoplasia 3 (VIN 3) were treated by surgical excision. RESULTS: Sixteen patients (20.5%) were found to have invasion in the excised surgical specimen. Superficial invasion was seen in 7 patients (9%), 9 were noted to have >1 mm invasion (11.5%), and 1 patient had in situ Paget's disease (1.3%). CONCLUSION: Surgical excision should be considered a preferable method in management of patients with VIN 3. PMID- 10094892 TI - A new technique for performing Syed template interstitial implants for anterior vaginal tumors using an open retropubic approach. AB - The Syed template (Alpha-Omega Services, Bellflower, CA) has been established as an advance in interstitial gynecologic brachytherapy. Unfortunately, enthusiasm for the technique is often tempered by certain tumor geometries which require blind insertion of the interstitial needles, potentially risking inaccurate placement of the radioactive sources and viscus perforation. These concerns arise particularly in the management of anterior vaginal tumors where difficulties in negotiating the pubic arch can prevent optimal needle placement. In answer to this problem, a technique utilizing an open retropubic approach for Syed template interstitial implants in anterior vaginal tumors under direct visualization is described. To date, six procedures have been performed. The disease entities include advanced cervical squamous cell carcinoma, clear cell carcinoma of the vagina, recurrent vaginal carcinoma, recurrent endometrial carcinoma, and urethral adenocarcinoma. Complete response was noted in five of six patients but persistent local control of disease was achieved in only one of five complete responses over a relatively short follow-up interval. Complications included paravaginal abscess (n = 1), postoperative deep venous thrombosis (n = 1), abdominal incision cellulitis (n = 1), and radiation enteritis (n = 1). An open retropubic approach allows direct visualization of the bladder and urethra during interstitial implantation of anterior vaginal malignancies and facilitates negotiation of the pubic arch. In our experience, this technique results in improved needle positioning and is thus intuitively likely to aid in avoiding injury to surrounding normal tissues. Additional accrual of a larger cohort will be necessary to arrive at any meaningful objective conclusions regarding the technique's benefit over current modalities. PMID- 10094894 TI - Management of ovarian cancer in patients older than 80 years of Age. AB - OBJECTIVE: The objective of this study was to examine the treatment, associated morbidity, and survival in very elderly patients with epithelial ovarian cancer. METHODS: A retrospective analysis of patients 80 years of age and older treated for epithelial ovarian cancer by the Gynecologic Oncology faculty at the University of California Irvine was performed. RESULTS: Eighteen patients were older than 80 years of age at the time of diagnosis of ovarian cancer. Median age was 83 years (range 80-86 years). There were 2 stage I, 10 stage IIIC, 4 stage VI, and 2 unstaged patients. One patient had a tumor of low malignant potential, 4 patients had grade II tumors, and 10 patients had tumors that were grade III. Eighty-three percent of patients had one or more preexisting medical illnesses. Cardiac disease, stroke, and hypertension were most common. Sixteen of 18 patients (88%) underwent primary debulking surgery. American Society of Anesthesiologists physical status classification was as follows: 7/16 (44%) class II, 6/16 (38%) class III, and 2/16 (13%) class IV. The procedures performed included 16 bilateral salpingo-oophorectomies, 11 total abdominal hysterectomies, 16 omentectomies, 3 lymph node dissections, and 7 bowel resections. Four (25%) patients were optimally cytoreduced to <1 cm of residual disease. Seventy-five percent of surgical patients received blood transfusions of 2 or more units PRBC. Mean EBL was 600 cc (range 200-4200 cc). Thirty-eight percent of patients experienced major postoperative morbidity. There were 7 patients with postoperative congestive heart failure, 3 with sepsis, 1 with aspiration pneumonia, and 2 postoperative deaths. Seventy-five percent of patients spent time in the intensive care unit. Median number of days was 3 (range 1-22 days). Mean postoperative stay was 8 days (range 6-57 days). Sixty-five percent of patients were discharged to home. The other patients were discharged to intermediate care facilities or nursing homes. Eighty-three percent of patients received chemotherapy. Of the 10 patients (63%) receiving adjuvant chemotherapy, the mean interval from surgery to initiation of therapy was 3 weeks (range 1-4 weeks). Overall median survival was 6 months (range 1-45 months). Median survival in patients with optimal debulking was 32.5 months (range 7-45 months) compared to 3.5 months (range 1-41 months) in patients suboptimally debulked. CONCLUSIONS: In patients older than 80 years of age who undergo debulking surgery for ovarian cancer, serious medical comorbidity and advanced ASA status are common. Despite aggressive surgical effort and frequent blood transfusions, optimal debulking to less than 1 cm is achieved in only 25% of patients. Impressive morbidity and mortality occurs in this group of patients, but most patients are discharged to home and are able to receive postoperative chemotherapy. PMID- 10094893 TI - Down-regulation of bcl-2 is a potential marker of the efficacy of progestin therapy in the treatment of endometrial hyperplasia. AB - OBJECTIVE: The objective of this study was to evaluate the expression of bcl-2, a regulatory protein in programmed cell death, in endometrial hyperplasia before and after progestational therapy. METHODS: Pre- and posttreatment paraffin embedded endometrial tissue samples from 20 women with an initial diagnosis of endometrial hyperplasia were obtained from archived files. Cases were evaluated and classified as either complete resolution of hyperplasia or persistent hyperplasia in response to progestin treatment. Sections were examined for bcl-2, estrogen receptor, and progesterone receptor expression using immunohistochemistry and compared within the treatment response groups. RESULTS: Among the 20 women studied, 13 had complete regression of their hyperplasia with progestin treatment and 7 had evidence of persistent disease after therapy. Bcl-2 expression was significantly decreased after treatment from a mean reactivity score of 2.08 to 0.31 (P = 0.0005) in the group of patients whose hyperplasia completely regressed with progestin administration. Among the women who had persistent hyperplasia after therapy, no significant change was observed between pre- and posttreatment bcl-2 expression, with a mean reactivity of 1.86 to 1. 29, respectively (P = 0.075). Progestational therapy significantly decreased the status of estrogen receptors from a mean score of 2.08 to 0.46 (P = 0.0005) in completely resolved cases of hyperplasia and from 2.00 to 0.43 (P = 0.0025) in persistent hyperplasias. Treatment also significantly decreased the status of progesterone receptors from a mean reactivity score of 1.92 to 0.31 (P = 0.0005) in cases of regressed hyperplasia and from a mean reactivity of 1.86 to 0.29 (P = 0.005) in persistent cases of hyperplasia. CONCLUSIONS: Bcl-2 expression decreases following successful progestin treatment of endometrial hyperplasias, whereas it remains expressed in hyperplasias which persist despite progestational therapy. This suggests that bcl-2 expression may represent a component of the therapeutic effects exerted in the endometium during progestational therapy in the treatment of hyperplasia. The activity of the oncoprotein may be a potential measure of the progress of treatment. PMID- 10094895 TI - Complete clinical responses to neoadjuvant chemotherapy for uterine serous carcinoma. AB - Three cases of serous carcinoma of the uterus with radiographically documented widespread metastases are presented. Following confirmation of histopathology, all were treated with a standard regimen of carboplatin and paclitaxel for eight courses with complete resolution of distant metastases on CT scan prior to postchemotherapy surgical exploration. Two patients had gross disease at laparotomy, and one had only microscopic tumor found in the uterine specimen. This experience offers rationale for treatment of patients with widely metastatic uterine serous carcinoma or other relative contraindications to surgery with primary carboplatin and paclitaxel. In addition, we believe this experience supports the hypothesis that this regimen may result in prolonged disease-free survival when employed as postsurgical adjuvant therapy. PMID- 10094896 TI - Malignant mixed Mullerian tumor with rhabdoid features: a report of two cases and a review of the literature. AB - Rhabdoid tumors were originally described as a type of pediatric renal neoplasm that contains cells resembling rhabdomyoblasts but lacking muscle differentiation. Extrarenal rhabdoid tumors have since been reported in multiple anatomic sites in the pediatric and adult population. These tumors are characterized by an aggressive clinical course, resistance to treatment, and a rapidly fatal outcome. Eight cases of uterine neoplasms with rhabdoid differentiation have been previously reported. In the three cases where clinical follow-up was available, the patients died of disease within 3 to 17 months after the diagnosis was established. We report two cases of uterine malignant mixed Mullerian tumor (carcinosarcoma) with rhabdoid differentiation. The findings and clinical outcome confirm the aggressive nature of uterine tumors with rhabdoid differentiation. One of the patients died of disease 3 months after initial operative treatment while the other patient's tumor recurred in 1 month and she died within 10 weeks. The poor prognosis of these neoplasms makes their histopathologic recognition important. PMID- 10094897 TI - Plasmacytoma of the ovary: a case report and literature review. AB - BACKGROUND: Ovarian plasmacytomas are a unique and unusual presentation of extramedullary plasmacytomas (EMP). A report of the seventh such case is presented with review of the previous six cases. METHODS: Surgical and medical staging were performed on the present case. The literature is reviewed. RESULTS: EMP involving the ovary is usually large at the time of presentation, more likely involving the left side, and without evidence of disseminated disease. As in other plasma cell dyscrasia, IgG paraprotein is more frequently involved. CONCLUSION: Adjuvant treatment for ovarian plasmacytomas is not clearly established; however, if complete surgical resection is achieved and no evidence of multiple myeloma is found, observation should be strongly considered. PMID- 10094898 TI - Primary breast carcinoma of the vulva: a case report and literature review. AB - BACKGROUND: In 1872, Hartung was the first to describe the case of a fully formed mammary gland arising in the left labium majora of a 30-year-old woman. Since Hartung's initial report, 38 additional cases of ectopic vulvar breast tissue have been described. This case report describes the rare occurrence of primary mammary adenocarcinoma arising within the vulva. CASE: A 64-year-old G4P4 white female presented with a 4-year history of a 2 x 1 cm firm, indurated, raised lesion of the left lateral mons. A wide local excision with ipsilateral inguinofemoral lymphadenectomy was performed. Given histological findings characteristic of both invasive ductal carcinoma and invasive lobular carcinoma, in conjunction with the presence of estrogen and progesterone receptors within the tumor, a diagnosis of infiltrating adenocarcinoma arising within ectopic breast tissue was made. CONCLUSIONS: Thirty-nine reported cases of ectopic breast tissue arising within the vulva have been reported in the world literature. Though the diagnosis of primary breast carcinoma arising within the vulva is based primarily upon histologic pattern, estrogen and progesterone receptor positivity provide supporting evidence. Given the rarity of this condition, guidelines for therapy are unavailable; we therefore suggest looking to the current management of breast cancer in order to establish a sensible approach. PMID- 10094899 TI - Epithelioid sarcoma of the vulva. AB - We report a case of a 23-year-old woman diagnosed as having an epithelioid sarcoma of the vulva. She was treated by a clitoris-sparing hemivulvectomy and lymph node sampling of the ipsilateral groin. Vulvar reconstruction was performed with a rectus abdominis myocutaneous flap. Four years after the operation there is no evidence of disease and the patient has a normal sex life. The English literature on this subject is reviewed with special attention to the biological behavior and therapeutic approach. PMID- 10094900 TI - Transvaginal evisceration of small bowel after radical hysterectomy and pelvic lymphadenectomy. AB - Vaginal evisceration is a rare event. This case report describes a 45-year-old woman who presented 8 days following radical hysterectomy and lymph node dissection for stage 1B squamous cell carcinoma of the cervix with small bowel evisceration through the vagina. She was treated by laparotomy and resection anastamosis of a discolored part of the distal ileum. PMID- 10094901 TI - Surgery for cervical cancer: a time for reassessment. PMID- 10094902 TI - Do "high-risk" human papillomavirus (HPV) types lead to cancer by evading the immune system? PMID- 10094903 TI - Toward the development of a universal grading system for ovarian epithelial carcinoma. PMID- 10094904 TI - Does hysteroscopy improve upon the sensitivity of dilation and curettage in the diagnosis of endometrial hyperplasia or carcinoma? PMID- 10094905 TI - Can laparoscopic para-aortic lymphadenectomy help to select patients with pelvic relapse of cervical cancer eligible for pelvic exenteration? PMID- 10094920 TI - Research technologies: fulfilling the promise. PMID- 10094921 TI - IL-10-induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. AB - Specific immunotherapy (SIT) is widely used for treatment of allergic diseases and could potentially be applied in other immunological disorders. Induction of specific unresponsiveness (anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in SIT with whole allergen or antigenic T cell peptides (PIT). The anergy is directed against the T cell epitopes of the respective antigen and characterized by suppressed proliferative and cytokine responses. It is initiated by autocrine action of IL 10, which is increasingly produced by the antigen-specific T cells. Later in therapy, B cells and monocytes also produce IL-10. The anergic T cells can be reactivated by different cytokines. Whereas IL-15 and IL-2 generate Th1 cytokine profile and an IgG4 antibody response, IL-4 reactivates a Th2 cytokine pattern and IgE antibodies. Increased IL-10 suppresses IgE and enhances IgG4 synthesis, resulting in a decreased antigen-specific IgE:IgG4 ratio, as observed normally in patients after SIT or PIT. The same state of anergy against the major bee venom allergen, phospholipase A2, can be observed in subjects naturally anergized after multiple bee stings. Together, these data demonstrate the pivotal role of autocrine IL-10 in induction of specific T cell anergy and the important participation of the cytokine microenvironment in SIT. Furthermore, knowledge of the mechanisms explaining reasons for success or failure of SIT may enable possible predictive measures of the treatment. PMID- 10094922 TI - Up-regulation of microsphere transport across the follicle-associated epithelium of Peyer's patch by exposure to Streptococcus pneumoniae R36a. AB - Transport of antigens through the follicle-associated epithelium (FAE) of Peyer's patch (PP) is the critical first step in the induction of mucosal immune responses. We have previously described that short-term exposure to Streptococcus pneumoniae R36a induced dramatic morphological alterations of the FAE in rabbit PP. These results prompted us to investigate whether the pneumococci-induced modifications were accompanied by enhanced ability of the FAE to transport antigens. We addressed this problem by evaluating the ability of the FAE to bind, internalize, and transport fluorescent polystyrene microparticles, highly specific to rabbit M cells, after exposure to S. pneumoniae. Quantitative study revealed a marked increase in the number of microspheres in PP tissues exposed to S. pneumoniae compared to tissues exposed to either phosphate-buffered saline or Escherichia coli DH5alpha as controls. No sign of bacterially induced damage to the epithelial barrier was observed. Further confocal microscopy analysis of the FAE surface showed that a significant increase in the number of cells that showed both morphological and functional features of M cells took place within pneumococci-treated PP tissues. These data provide the first direct evidence that the FAE-specific antigen sampling function may be manipulated to improve antigen and drug delivery to the intestinal immune system. PMID- 10094923 TI - Micronuclei formation and aneuploidy induced by Vpr, an accessory gene of human immunodeficiency virus type 1. AB - Vpr, an accessory gene of HIV-1, induces cell cycle abnormality with accumulation at G2/M phase and increased ploidy. Since abnormality of mitotic checkpoint control provides a molecular basis of genomic instability, we studied the effects of Vpr on genetic integrity using a stable clone, named MIT-23, in which Vpr expression is controlled by the tetracycline-responsive promoter. Treatment of MIT-23 cells with doxycycline (DOX) induced Vpr expression with a giant multinuclear cell formation. Increased micronuclei (MIN) formation was also detected in these cells. Abolishment of Vpr expression by DOX removal induced numerous asynchronous cytokinesis in the multinuclear cells with leaving MIN in cytoplasm, suggesting that the transient Vpr expression could cause genetic unbalance. Consistent with this expectation, MIT-23 cells, originally pseudodiploid cells, became aneuploid after repeated expression of Vpr. Experiments using deletion mutants of Vpr revealed that the domain inducing MIN formation as well as multinucleation was located in the carboxy-terminal region of Vpr protein. These results suggest that Vpr induces genomic instability, implicating the possible role in the development of AIDS-related malignancies. PMID- 10094924 TI - Random mutagenesis and screening of complex glycoproteins: expression of human gonadotropins in Dictyostelium discoideum. AB - The soil amoeba Dictyostelium discoideum is a host cell that provides simple genetics in combination with complex protein synthesis. We show that the complex human heterodimeric gonadotropins can be produced and secreted by this organism. Furthermore, both follicle stimulation hormone and choriogonadotropin produced by D. dictyostelium bind to their human receptors and elicit a biological response comparable to the wild-type hormones. We also show that structure-function analysis using random mutagenesis and screening of recombinant glycoprotein hormones is feasible. Thus, expression of gonadotropins in D. dictyostelium opens the way to the engineering of potential new therapeutic analogues. PMID- 10094925 TI - Somatostatin controls Kaposi's sarcoma tumor growth through inhibition of angiogenesis. AB - Somatostatin and its analogs are active in the inhibition of SST receptor positive endocrine neoplasms, but their activity and mechanism in nonendocrine tumors is not clear. Somatostatin potently inhibited growth of a Kaposi's sarcoma xenograft in nude mice, yet in vitro the tumor cells did not express any known somatostatin receptors and were not growth inhibited by somatostatin. Histological examination revealed limited vascularization in the somatostatin treated tumors as compared with the controls. Somatostatin was a potent inhibitor of angiogenesis in an in vivo assay. In vitro, somatostatin inhibited endothelial cell growth and invasion. Migration of monocytes, important mediators of the angiogenic cascade, was also inhibited by somatostatin. Both cells types expressed somatostatin receptor mRNAs. These data demonstrate that somatostatin is a potent antitumor angiogenesis compound directly affecting both endothelial and monocytic cells. The debated function of somatostatin in tumor treatment and the design of therapeutic protocols should be reexamined considering these data. PMID- 10094926 TI - Neural cell surface differentiation antigen gp130(RB13-6) induces fibroblasts and glioma cells to express astroglial proteins and invasive properties. AB - Transient expression of the differentiation and tumor cell surface antigen gp130(RB13-6) characterizes a subset of rat glial progenitor cells susceptible to ethylnitrosourea-induced neurooncogenesis. gp130(RB13-6) is as a member of an emerging protein family of ecto-phosphodiesterases/nucleotide pyrophosphatases that includes PC-1 and the tumor cell motility factor autotaxin. We have investigated the potential role of gp130(RB13-6) in glial differentiation by transfection of three cell lines of different origin that do not express endogenous gp130(RB13-6) (NIH-3T3 mouse fibroblasts; C6 and BT7Ca rat glioma cells) with the cDNA encoding gp130(RB13-6). The effect of gp130(RB13-6) expression was analyzed in terms of overall cell morphology, the expression of glial cell-specific marker proteins, and invasiveness. Transfectant sublines, consisting of 100% gp130(RB13-6)-positive cells, exhibited an altered, bipolar morphology. Fascicular aggregates of fibroblastoid cells subsequently developed into mesh-like patterns. Contrary to the parental NIH-3T3 and BT7Ca cells, the transfectant cells invaded into collagen type I. As shown by immunofluorescence staining of the transfectant sublines as well as of primary cultures composed of gp130(RB13-6)-positive and -negative cells, expression of gp130(RB13-6) induced coexpression of proteins typical for glial cells and their precursors, i.e., glial fibrillary acidic protein, the low affinity nerve growth factor receptor, and the neural proteins Thy-1, Ran-2, and S-100. In accordance with its expression in the immature rat nervous system, gp130(RB13-6) may thus have a significant role in the glial differentiation program and its subversion in neurooncogenesis. PMID- 10094927 TI - Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice. AB - Antioxidants can inhibit atherosclerosis in animals, though it is not clear whether this is due to the inhibition of aortic lipoprotein lipid (per)oxidation. Coantioxidants inhibit radical-induced, tocopherol-mediated peroxidation of lipids in lipoproteins through elimination of tocopheroxyl radical. Here we tested the effect of the bisphenolic probucol metabolite and coantioxidant H 212/43 on atherogenesis in apolipoprotein E and low density lipoprotein (LDL) receptor gene double knockout (apoE-/-;LDLr-/-) mice, and how this related to aortic lipid (per)oxidation measured by specific HPLC analyses. Dietary supplementation with H 212/43 resulted in circulating drug levels of approximately 200 microM, increased plasma total cholesterol slightly and decreased plasma and aortic alpha-tocopherol significantly relative to age matched control mice. Treatment with H 212/43 increased the antioxidant capacity of plasma, as indicated by prolonged inhibition of peroxyl radical-induced, ex vivo lipid peroxidation. Aortic tissue from control apoE-/-;LDLr-/- mice contained lipid hydro(pero)xides and substantial atherosclerotic lesions, both of which were decreased strongly by supplementation of the animals with H 212/43. The results show that a coantioxidant effectively inhibits in vivo lipid peroxidation and atherosclerosis in apoE-/-;LDLr-/- mice, consistent with though not proving a causal relationship between aortic lipoprotein lipid oxidation and atherosclerosis in this model of the disease. PMID- 10094928 TI - Transmembrane calcium influx induced by ac electric fields. AB - Exogenous electric fields induce cellular responses including redistribution of integral membrane proteins, reorganization of microfilament structures, and changes in intracellular calcium ion concentration ([Ca2+]i). Although increases in [Ca2+]i caused by application of direct current electric fields have been documented, quantitative measurements of the effects of alternating current (ac) electric fields on [Ca2+]i are lacking and the Ca2+ pathways that mediate such effects remain to be identified. Using epifluorescence microscopy, we have examined in a model cell type the [Ca2+]i response to ac electric fields. Application of a 1 or 10 Hz electric field to human hepatoma (Hep3B) cells induces a fourfold increase in [Ca2+]i (from 50 nM to 200 nM) within 30 min of continuous field exposure. Depletion of Ca2+ in the extracellular medium prevents the electric field-induced increase in [Ca2+]i, suggesting that Ca2+ influx across the plasma membrane is responsible for the [Ca2+]i increase. Incubation of cells with the phospholipase C inhibitor U73122 does not inhibit ac electric field-induced increases in [Ca2+]i, suggesting that receptor-regulated release of intracellular Ca2+ is not important for this effect. Treatment of cells with either the stretch-activated cation channel inhibitor GdCl3 or the nonspecific calcium channel blocker CoCl2 partially inhibits the [Ca2+]i increase induced by ac electric fields, and concomitant treatment with both GdCl3 and CoCl2 completely inhibits the field-induced [Ca2+]i increase. Since neither Gd3+ nor Co2+ is efficiently transported across the plasma membrane, these data suggest that the increase in [Ca2+]i induced by ac electric fields depends entirely on Ca2+ influx from the extracellular medium. PMID- 10094929 TI - Gbetagamma dimers stimulate vascular L-type Ca2+ channels via phosphoinositide 3 kinase. AB - We have previously reported that, in venous myocytes, Gbetagamma scavengers inhibit angiotensin AT1A receptor-induced stimulation of L-type Ca2+ channels (1). Here, we demonstrate that intracellular infusion of purified Gbetagamma complexes stimulates the L-type Ca2+ channel current in a concentration-dependent manner. Additional intracellular dialysis of GDP-bound inactive Galphao or of a peptide corresponding to the Gbetagamma binding region of the beta-adrenergic receptor kinase completely inhibited the Gbetagamma-induced stimulation of Ca2+ channel currents. The gating properties of the channel were not affected by intracellular application of Gbetagamma, suggesting that Gbetagamma increased the whole-cell calcium conductance. In addition, both the angiotensin AT1A receptor- and the Gbetagamma-induced stimulation of L-type Ca2+ channels were blocked by pretreatment of the cells with wortmannin, at nanomolar concentrations. Correspondingly, intracellular infusion of an enzymatically active purified recombinant Gbetagamma-sensitive phosphoinositide 3-kinase, PI3Kgamma, mimicked Gbetagamma-induced stimulation of Ca2+ channels. Both Gbetagamma- and PI3Kgamma induced stimulations of Ca2+ channel currents were reduced by protein kinase C inhibitors suggesting that the Gbetagamma/PI3Kgamma-activated transduction pathway involves a protein kinase C. These results indicate for the first time that Gbetagamma dimers stimulate the vascular L-type Ca2+ channels through a Gbetagamma-sensitive PI3K. PMID- 10094930 TI - Identification and characterization of diadenosine 5',5"'-P1,P2 -diphosphate and diadenosine 5',5"'-P1,P3-triphosphate in human myocardial tissue. AB - We examined whether human cardiac tissue contains diadenosine polyphosphates and investigated their physiological role. Extracts from human cardiac tissue from transplant recipients were fractionated by size exclusion-, affinity-, anion exchange- and reversed-phase chromatography. MALDI-MS analysis of two absorbing fractions revealed molecular masses of 676.2 Da and 756.0 Da. The UV spectra of both fractions were identical to that of adenosine. Postsource decay MALDI mass spectrometry indicated that the molecules with a mass of 676.2 Da and 757.0 Da contained AMP and ATP, respectively. As shown by enzymatic cleavage, both molecules consist of two adenosines interconnected by either two or three phosphates in 5'-positions of the riboses. Two substances can be identified as 5',5"'-P1,P2-diphosphate (Ap2A) and 5',5"'-P1, P3-triphosphate (Ap3A). Ap2A and Ap3A, together with ATP and ADP, are stored in myocardial-specific granules in biologically active concentrations. In the isolated perfused rat heart, Ap2A and Ap3A caused dose-dependent coronary vasodilations. In myocardial preparations, Ap2A and Ap3A attenuated the effect of isoproterenol, exerting a negative inotropic effect. The calcium current of guinea pig ventricular myocytes, stimulated by isoproterenol, was also attenuated by Ap2A and Ap3A. The presence of Ap2A and Ap3A in cardiac-specific granules and the actions of these substances on the myocardium and coronary vessels indicate a role for these substances as endogenous modulators of myocardial functions and coronary perfusion. PMID- 10094931 TI - Genetic analysis of hemopoietic cell cycling in mice suggests its involvement in organismal life span. AB - Normal somatic cells undergo replicative senescence in vitro but the significance of this process in organismic aging remains controversial. We have shown previously that hemopoietic stem cells of common inbred strains of mice vary widely in cycling activity and that this parameter is inversely correlated with strain-dependent mean life span. To assess whether cell cycling and life span are causally related, we searched for quantitative trait loci (QTLs) that contributed to variation of these traits in BXH and BXD recombinant inbred mice. Two QTLs, mapping to exactly the same intervals on chromosomes 7 and 11, were identified that were associated with variation of both cell cycling and life span. The locus on chromosome 11 mapped to the cytokine cluster, a segment that shows synteny with human chromosome 5q, in which deletions are strongly associated with myelodysplastic syndrome. These data indicate that steady-state cell turn-over, here measured in hemopoietic progenitor cells, may have a significant effect on the mean life span of mammals. PMID- 10094933 TI - Gene transfer to mammalian cells using genetically targeted filamentous bacteriophage. AB - We have genetically modified filamentous bacteriophage to deliver genes to mammalian cells. In previous studies we showed that noncovalently attached fibroblast growth factor (FGF2) can target bacteriophage to COS-1 cells, resulting in receptor-mediated transduction with a reporter gene. Thus, bacteriophage, which normally lack tropism for mammalian cells, can be adapted for mammalian cell gene transfer. To determine the potential of using phage mediated gene transfer as a novel display phage screening strategy, we transfected COS-1 cells with phage that were engineered to display FGF2 on their surface coat as a fusion to the minor coat protein, pIII. Immunoblot and ELISA analysis confirmed the presence of FGF2 on the phage coat. Significant transduction was obtained in COS-1 cells with the targeted FGF2-phage compared with the nontargeted parent phage. Specificity was demonstrated by successful inhibition of transduction in the presence of excess free FGF2. Having demonstrated mammalian cell transduction by phage displaying a known gene targeting ligand, it is now feasible to apply phage-mediated transduction as a screen for discovering novel ligands. PMID- 10094932 TI - Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis. AB - Beta2-Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. beta2-Adrenergic and chemokine receptors belong to the G-protein-coupled receptor family whose responsiveness is turned off by the G-protein-coupled receptor kinase family (GRK 1 to 6). GRKs phosphorylate receptors in an agonist-dependent manner resulting in receptor/G-protein uncoupling via subsequent binding of arrestin proteins. We assessed the activity of GRKs in lymphocytes of rheumatoid arthritis (RA) patients by rhodopsin phosphorylation. We found a significant decrease in GRK activity in RA subjects that is mirrored by a decrease in GRK-2 protein expression. Moreover, GRK-6 protein expression is reduced in RA patients whereas GRK-5 protein levels were unchanged. In search of an underlying mechanism, we demonstrated that proinflammatory cytokines induce a decrease in GRK-2 protein levels in leukocytes from healthy donors. Since proinflammatory cytokines are abundantly expressed in RA, it may provide an explanation for the decrease in GRK 2 expression and activity in patients. No changes in beta2-adrenergic receptor number and Kd were detected. However, RA patients showed a significantly increased cAMP production and inhibition of TNF-alpha production by beta2 adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to beta2-adrenergic activation. PMID- 10094934 TI - A molluscan peptide alpha-amidating enzyme precursor that generates five distinct enzymes. AB - Mechanisms underlying the specificity and efficiency of enzymes, which modify peptide messengers, especially with the variable requirements of synthesis in the neuronal secretory pathway, are poorly understood. Here, we examine the process of peptide alpha-amidation in individually identifiable Lymnaea neurons that synthesize multiple proproteins, yielding complex mixtures of structurally diverse peptide substrates. The alpha-amidation of these peptide substrates is efficiently controlled by a multifunctional Lymnaea peptidyl glycine alpha amidating monooxygenase (LPAM), which contains four different copies of the rate limiting Lymnaea peptidyl glycine alpha-hydroxylating monooxygenase (LPHM) and a single Lymnaea peptidyl alpha-hydroxyglycine alpha-amidating lyase. Endogenously, this zymogen is converted to yield a mixture of monofunctional isoenzymes. In vitro, each LPHM displays a unique combination of substrate affinity and reaction velocity, depending on the penultimate residue of the substrate. This suggests that the different isoenzymes are generated in order to efficiently amidate the many peptide substrates that are present in molluscan neurons. The cellular expression of the LPAM gene is restricted to neurons that synthesize amidated peptides, which underscores the critical importance of regulation of peptide alpha-amidation. PMID- 10094935 TI - Resistance to levamisole resolved at the single-channel level. AB - Levamisole is commonly used to treat nematode parasite infections but therapy is limited by resistance. The purpose of this study was to determine the mechanism of resistance to this selective nicotinic drug. Levamisole receptor channel currents in muscle patches from levamisole-sensitive and levamisole-resistant isolates of the parasitic nematode Oesophagostomum dentatum were compared. The number of channels present in patches of sensitive and resistant isolates was similar at 10 microM levamisole, but at 30 microM and 100 microM the resistant isolate contained fewer active patches, suggesting desensitization. Mean Po and open times were reduced in resistant isolates. The distribution of conductances of channels in the sensitive isolate revealed a heterogeneous receptor population and the presence of G25, G35, G40, and G45 subtypes. A G35 subtype was missing in the resistant isolate. Resistance to levamisole was produced by changes in the averaged properties of the levamisole receptor population, with some receptors from sensitive and resistant isolates having indistinguishable characteristics. PMID- 10094937 TI - Biochemistry and molecular biology '99 may 16-20, 1999 san francisco, california PMID- 10094936 TI - A substituted dextran enhances muscle fiber survival and regeneration in ischemic and denervated rat EDL muscle. AB - Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of peripheral surviving muscle fibers. Muscle regeneration is a complex phenomenon in which many agents interact, such as growth factors and heparan sulfate components of the extracellular matrix. We have shown that synthetic polymers, called RGTA (as regenerating agents), which imitate the heparan sulfates, are able to stimulate tissue repair when applied at the site of injury. In crushed muscles, RGTA were found to accelerate both regeneration and reinnervation. In vitro, RGTA act as protectors and potentiators of various heparin binding growth factors (HBGF). It was postulated that in vivo their tissue repair properties were due in part to an increase of bioavailability of endogenously released HBGF. In the present work, we show that ischemic and denervated EDL muscle treated by a unique injection of RGTA differs from the control after 1 wk in several aspects: 1) the epimysial postinflammatory reaction is inhibited and the area of fibrotic tissue among fibers is reduced; 2) the peripheral zone, as measured by the number of intact muscle fibers, was increased by more than twofold; and 3) In the central zone, RGTA enhances the regeneration of the muscle fibers as well as muscle revascularization. These results suggest that RGTA both protects muscle fibers from degeneration and preserves the differentiated state of the surviving fibers. For the first time it is demonstrated that a functionalized polymeric compound can prevent some of the damage resulting from muscle ischemia. RGTA may therefore open a new therapeutic approach for muscle fibrosis and other postischemic muscle pathologies. PMID- 10094938 TI - The pruritus of cholestasis. PMID- 10094939 TI - Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. AB - The semiquantitative histopathological analysis of the liver biopsies obtained before and after 4 years of ursodeoxycholic acid (UDCA) therapy in a cohort of primary biliary cirrhosis (PBC) patients is reported. The relationships between elementary histological lesions before treatment and their progression under therapy were assessed. At baseline, two independent groups of lesions, each of which participate in the development of fibrosis, were individualized, i.e., florid bile duct lesions and ductopenia on one hand and lymphocytic piecemeal necrosis, ductular proliferation, and lobular necroinflammatory changes on the other hand. Four years of UDCA therapy were associated with a significant decrease in the prevalence of florid interlobular bile duct (ILBD) lesions, of epithelioid granuloma (P <.001) without any aggravation in the severity of bile duct paucity. Lobular inflammation and necrosis markedly improved (P <.001) whereas the degree of severity of the lymphocytic piecemeal necrosis and ductular proliferation at entry and at 4 years were similar. Worsening of fibrosis was observed in 14 patients (12 of them had a one grade progression) whereas stabilization was noted in 30 of the remaining patients. Severity of both the lymphocytic piecemeal necrosis and lobular inflammation and necrosis at entry was significantly associated with the progression of fibrosis. The results suggest that UDCA therapy influences the process leading to bile duct destruction. Patients with severe lymphocytic piecemeal necrosis and lobular inflammation may need additional therapeutic intervention because they have increased risk of fibrosis progression. PMID- 10094940 TI - Autoepitope mapping and reactivity of autoantibodies to the dihydrolipoamide dehydrogenase-binding protein (E3BP) and the glycine cleavage proteins in primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of antimitochondrial antibodies (AMA) directed primarily against the E2 subunits of the pyruvate dehydrogenase complex, the branched chain 2-oxo-acid dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, as well as the dihydrolipoamide dehydrogenase-binding protein (E3BP) of pyruvate dehydrogenase complex. The autoantibody response to each E2 subunit is directed to the lipoic acid binding domain. However, hitherto, the epitope recognized by autoantibodies to E3BP has not been mapped. In this study, we have taken advantage of the recently available full-length human E3BP complementary DNA (cDNA) to map this epitope. In addition, another lipoic binding protein, the H-protein of the glycine cleavage complex, was also studied as a potential autoantigen recognized by AMA. Firstly, the sequence corresponding to the lipoic domain of E3BP (E3BP LD) was amplified by polymerase chain reaction and recombinant protein and then purified. Immunoreactivity of 45 PBC sera (and 52 control sera) against the purified recombinant E3BP-LD was analyzed by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Secondly, reactivity of PBC sera was similarly analyzed by immunoblotting against H-protein. It is interesting that preabsorption of patient sera with the lipoic acid binding domain of E3BP completely removed all reactivity with the entire protein by immunoblotting analysis, suggesting that autoantibodies to E3BP are directed solely to its lipoic acid binding domain. Fifty-three percent of PBC sera reacted with E3BP-LD, with the majority of the response being of the immunoglobulin G (IgG) isotype (95%). Surprisingly, there was little IgM response to the E3BP-LD suggesting that the immune response was secondary because of determinant spreading. In contrast, H-protein does not appear to possess (or expose) autoepitopes recognized by PBC sera. This observation is consistent with structural data on this moiety. PMID- 10094941 TI - Generation of monoclonal antibodies to murine bile duct epithelial cells: identification of annexin V as a new marker of small intrahepatic bile ducts. AB - Biliary epithelial cells (BECs) are distributed along the length of both the extrahepatic and intrahepatic biliary tree, but have distinctly different phenotypes and functions according to their anatomical location. It has been reasoned that the distinct appearance of pathogenic lesions in different biliary diseases may be associated with the expression of distinct proteins. These data prompted us to immunize rats with cultured murine BECs with the objective of determining if there are unique antigens on BECs. Of the 45 monoclonal antibodies (mAbs) produced, 12 mAbs (MBEC 1-12) were selected for detailed study based on their classification into three major groups. These groups included four antibodies (MBEC 1-4) that reacted in a staining pattern typical of mucin. A second group of mAbs, MBECs 5 to 8, reacted strongly along the biliary tract and by immunoblot analysis, reacted with several bands ranging from 44 kd to 64 kd. These antibodies were considered as markers of pan BECs and their staining pattern proved similar to that of a control polyclonal pan-cytokeratin. The final group of mAbs, MBECs 9 to 12, recognized a 36-kd antigen using lysates of murine BECs. These antibodies also predominantly stained small peripheral bile ducts. The reactive antigen was purified by immunoprecipitation and microsequenced; the peptides sequenced showed 100% homology with murine annexin V. The identification of annexin V with predominantly intrahepatic bile ducts, is of significant interest because of the multiple roles of annexin V, including that of membrane cytoskeletal interactions during transport and apoptosis. PMID- 10094942 TI - Secretory low-molecular-weight phospholipases A2 and their specific receptor in bile ducts of patients with intrahepatic calculi: factors of chronic proliferative cholangitis. AB - Intrahepatic calculi is characterized by an intractable course and frequent recurrences, requiring multiple operative interventions. Chronic proliferative cholangitis, an active and long-standing inflammation of the stone-containing bile ducts with the hyperplasia of epithelia and the proliferation of the duct associated mucus glands, may underlie the complex nature of the disease. In terms of the pathophysiology, interest has been focused on the role of secretory low molecular-weight phospholipases A2 (sPLA2s) as inflammatory mediators or factors modulating cell functions via their specific sPLA2-receptor, and also on the production and secretion of altered mucin molecules from the inflamed bile ducts. In search of factors involving chronic proliferative cholangitis, the sPLA2 isoforms in the bile such as the pancreatic-type sPLA2 (group IB sPLA2) and the arthritic-type sPLA2 (group IIA sPLA2), were assayed to correlate protein masses of the sPLA2s with alterations in biliary composition. Furthermore, the steady state messenger RNA (mRNA) levels of the sPLA2s, the membrane-bound sPLA2 receptor, cystic fibrosis transmembrane conductance regulator (CFTR), and mucin core polypeptide (MUC) genes in the bile ducts were assayed by reverse- transcriptase polymerase chain reaction (RT-PCR). Immunoreactive sPLA2-IB and sPLA2-IIA levels were significantly higher in the bile from the stone-containing hepatic ducts (2315 +/- 677 for sPLA2-IB; 281 +/- 42 for sPLA2-IIA ng/dL, mean +/ SEM; n = 20) than in the ductal bile from gallbladder stone patients (609 +/- 92, P <.01; 22 +/- 2, P <.01; n = 24). The increased sPLA2 levels were associated with a concomitant increase in lysophosphatidylcholine, prostaglandin E2 (PGE2), and total mucin concentrations. The affected bile ducts showed an increased mRNA level of sPLA2-IB and sPLA2-IIA compared with the ducts from control subjects, in whom the mRNAs of the sPLA2-receptor and other sPLA2 isoforms, such as groups V and X sPLA2s, were coincidently expressed. Reflecting the increased amounts of total biliary mucins, the affected ducts showed an increase in mRNA levels of CFTR as well as MUC2, MUC3, MUC5AC, MUC5B, and MUC6 compared with the ducts from control subjects. In intrahepatic calculi, an enhanced expression of the sPLA2s and their possible cross-talk via sPLA2-receptor may be of pathophysiological significance for the chronic proliferative cholangitis, in association with the enhanced CFTR expression and the alterations in mucin gene expression in the bile ducts, probably through potentiating arachidonate metabolism with associated biliary alterations favoring growth of preexisting stones and even further progressions. PMID- 10094943 TI - Lipopolysaccharide induces cholangiocyte proliferation via an interleukin-6 mediated activation of p44/p42 mitogen-activated protein kinase. AB - The biliary epithelium is exposed to mediators of inflammation such as bacterial endotoxin or lipopolysaccharide (LPS) in a variety of inflammatory conditions. These conditions are also characterized by cholangiocyte proliferation and a predisposition to malignancy. Furthermore, LPS can enhance the expression of interleukin-6 (IL-6), a known biliary mitogen. However, the effects of LPS on cholangiocyte proliferation or IL-6 secretion are unknown. Thus, our aims were to determine if LPS stimulates cholangiocyte proliferation by IL-6-dependent signaling pathways. H69 cells derived from normal human intrahepatic cholangiocytes proliferated in response to LPS. Cholangiocytes responded to LPS (and other inflammatory cytokines such as tumor necrosis factor alpha [TNF-alpha] and IL-1beta) by increased secretion of IL-6, which had a mitogenic effect on H69 cells. Preincubation with anti-IL-6 neutralizing antibodies inhibited LPS-induced proliferation. Furthermore, cholangiocytes possessed the IL-6 receptor complex subunits and intact signaling mechanisms leading to activation of signal transducers and activators of transcription (STAT) factors. Although both p38 and p44/p42 mitogen-activated protein kinases (MAPKs) were constitutively present and active in cholangiocytes, IL-6 increased p44/p42, but not p38 MAPK activity. PD098059 inhibited activation of p44/p42 MAPK in cholangiocytes and completely blocked DNA synthesis in response to IL-6 or LPS. These studies identify a critical role for the p44/p42 MAPK in cholangiocyte proliferation and demonstrate that the proliferative response of cholangiocytes to inflammatory mediators such as LPS involves IL-6-mediated activation of the p44/p42 MAPK pathway. PMID- 10094944 TI - Increased angiogenesis in portal hypertensive rats: role of nitric oxide. AB - Systemic and especially splanchnic arterial vasodilation accompany chronic portal hypertension. Different soluble mediators causing this vasodilation have been proposed, the strongest evidence being for nitric oxide (NO). No data exist if structural vascular changes may partly account for this vasodilatory state. Here, we developed a new in vivo quantitative angiogenesis assay in the abdominal cavity and determined if: 1) portal hypertensive rats show increased angiogenesis; and 2) angiogenesis is altered by inhibiting NO formation. Portal hypertension was induced by partial portal vein ligation (PVL). Sham-operated rats served as controls (CON). During the index operation (day 0), a teflon ring filled with collagen I (Vitrogen 100) was sutured in the mesenteric cavity. After 16 days, rings were explanted, embedded in paraffin, and ingrown vessels counted using a morphometry system. The role of NO was tested by adding an antagonist of NO formation (Nomega-nitro-L-arginine [NNA], 3.3 mg/kg/d) into the drinking water. The mean number of ingrown vessels per implant was significantly higher in PVL rats compared with CON rats, i.e., 1,453 +/- 187 versus 888 +/- 116, respectively (P <.05; N = 5 per group). NNA significantly (P <.01) inhibited angiogenesis in PVL (202 +/- 124; N = 5) and in CON (174 +/- 25; N = 6) rats, respectively. In contrast, the beta-adrenergic blocker, propranolol, did not prevent angiogenesis either in PVL or CON rats in a separate set of experiments (data not shown). The conclusions drawn from this study are that: 1) rats with portal hypertension show increased angiogenesis; and 2) inhibition of NO formation significantly prevents angiogenesis in both PVL and CON rats. Therefore, splanchnic vasodilation in chronic portal hypertension may also be a result of structural changes. PMID- 10094945 TI - Recurrence of primary sclerosing cholangitis following liver transplantation. AB - Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been suggested; however, it has not been fully defined because of numerous complicating factors and the lack of diagnostic criteria. In the present study, we investigated the recurrence of PSC by developing strict criteria and applying them to a large cohort of PSC patients who underwent liver transplantation. Between March 1985 and June 1996, 150 PSC patients underwent liver transplantation at the Mayo Clinic; mean follow up was 55 months. The incidence of nonanastomotic biliary strictures and hepatic histologic findings suggestive of PSC were compared between patients transplanted for PSC and a non PSC transplant control group. Our definition of recurrent PSC was based on characteristic cholangiographic and histologic findings that occur in nontransplant PSC patients. By using strict criteria, 30 patients with other known causes of posttransplant nonanastomotic biliary strictures were excluded leaving 120 patients for analysis of recurrence of PSC. We found evidence of PSC recurrence after liver transplantation in 24 patients (20%). Of these, 22 out of 24 patients showed characteristic features of PSC on cholangiography and 11 out of 24 had compatible hepatic histologic abnormalities with a mean time to diagnosis of 360 and 1,350 days, respectively. Both cholangiographic and hepatic histologic findings suggestive of PSC recurrence were seen in nine patients. The higher incidence and later onset of nonanastomotic biliary strictures in patients with PSC compared with a non-PSC control group is supportive of the fact that PSC does recur following liver transplantation. We were unable to identify specific clinical risk factors for recurrent PSC, and the overall patient and graft survival in patients with recurrent PSC was similar to those without evidence of recurrence. Our observations provide convincing evidence that PSC frequently recurs in the hepatic allograft using strict inclusion and exclusion criteria. PMID- 10094946 TI - Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharide. AB - Vascular endothelial growth factor (VEGF) is an angiogenic peptide with vascular permeability and relaxing properties. This study assessed whether peritoneal macrophages of cirrhotic patients can be up-regulated to produce VEGF under proper stimulatory conditions. Macrophages were isolated from ascites. VEGF protein secretion and mRNA expression were measured in basal conditions and after stimulation with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF alpha), and interleukin-1 (IL-1). These substances induced a time- and dose dependent increase in both VEGF production and transcript expression. Assays with actinomycin D showed that VEGF mRNA induction is secondary to both higher VEGF gene transcription and mRNA stability. Ascites and plasma concentration of VEGF was also measured in cirrhotic patients with (n = 15) and without (n = 10) spontaneous bacterial peritonitis (SBP). Plasma values did not differ between both groups of patients. However, ascites VEGF levels were higher in SBP patients than in noninfected cirrhotic patients (710 +/- 183 vs. 94 +/- 15 pg/mL; P <.025). These results indicate that cytokines and LPS markedly increase VEGF protein secretion and mRNA expression in macrophages of cirrhotic patients, and suggest that this substance could be an important mediator of the pronounced arterial vasodilation frequently occurring in SBP patients. PMID- 10094947 TI - Infections caused by Escherichia coli resistant to norfloxacin in hospitalized cirrhotic patients. AB - Selective intestinal decontamination with norfloxacin is useful to prevent bacterial infections in several groups of cirrhotic patients at high risk of infection. However, the emergence of infections caused by Escherichia coli resistant to quinolones has recently been observed in cirrhotic patients undergoing prophylactic norfloxacin. Our aim is to determine the characteristics of the infections caused by E. coli resistant to norfloxacin in hospitalized cirrhotic patients. One hundred and six infections caused by E. coli in 99 hospitalized cirrhotic patients were analyzed and distributed into two groups: group I (n = 67), infections caused by E. coli sensitive to norfloxacin, and group II (n = 39), infections caused by E. coli resistant to norfloxacin. The clinical and analytical characteristics at diagnosis of the infection were similar in both groups. Previous prophylaxis with norfloxacin was more frequent in group II (15/67, 22.4% vs. 32/39, 82%, P <.0001), as a result of a higher number of patients submitted to continuous long-term prophylaxis in this group, whereas previous short-term prophylaxis was similar in both groups. Infections were more frequently nosocomial-acquired in group II than in group I (17/67, 25.3% vs. 20/39, 51.2%, P =.01). The type of infections was similar in both groups: urinary tract infections 38 in group I and 24 in group II, spontaneous bacterial peritonitis 8 and 2, spontaneous bacteremia 4 and 4, and bacterascites 1 and 0, respectively (pNS). Mortality during hospitalization was similar in the two groups (4/67, 5.9% vs. 5/39, 12.8%, pNS). None of the E. coli resistant to norfloxacin were also resistant to cefotaxime and only one of them was resistant to amoxicillin-clavulanic acid. Prophylaxis with norfloxacin, usually continuous long-term prophylaxis, favors the development of infections caused by norfloxacin resistant E. coli. Long-term antibiotic prophylaxis should therefore be restricted to highly selected groups of cirrhotic patients at high-risk of infection. Infections caused by E. coli resistant to norfloxacin show a severity similar to those caused by sensitive E. coli. No significant associated resistance between norfloxacin and the antibiotics most frequently used in the treatment of bacterial infections in cirrhotic patients has been observed. PMID- 10094948 TI - Low-dose midazolam sedation: an option for patients undergoing serial hepatic venous pressure measurements. AB - The hepatic venous pressure gradient (HVPG) is becoming increasingly used clinically. It is useful in the differential diagnosis of portal hypertension and provides a prognostic index in cirrhotic patients. Performance of serial measurements has been shown to be useful in guiding pharmacological therapy of portal hypertension and variceal hemorrhage. The technique is safe to perform; however, many patients are anxious and reluctant to undergo serial measurements. The effects of sedatives on portal pressure measurements have not yet been defined. The objective of this study was to evaluate the effects of midazolam on the HVPG. Twenty patients with compensated cirrhosis were included in this prospective, double-blind study. The HVPG was determined by subtracting the free hepatic venous pressure (FHVP) from the wedged hepatic venous pressure (WHVP). Patients were randomized to receive either placebo, 0.02 mg/kg midazolam, or 0.03 mg/kg midazolam, administered intravenously over 3 minutes. Immediately after drug administration and every 3 minutes thereafter, for a total of 30 or 40 minutes, measurements were repeated. Three hours later, patients were asked to state whether the sedative affected their state of comfort/relaxation. The effects of both doses of midazolam on HVPG did not differ significantly from those of placebo. Furthermore, neither dose of midazolam induced significant changes in HVPG as compared with baseline values. However, higher-dose midazolam (0.03 mg/kg) was associated with significant reductions in FHVP from baseline and a tendency for a reduction in WHVP. Both doses significantly increased patient comfort and relaxation during the test. Midazolam, used at a dose of 0.02 mg/kg, is effective in increasing patient comfort and relaxation during hepatic venous pressure measurements, without significantly affecting pressures (HVPG, WHVP, or FHVP). It is therefore an acceptable option for patients undergoing serial hepatic venous pressure measurements. PMID- 10094949 TI - Cost analysis for the prevention of variceal rebleeding: a comparison between transjugular intrahepatic portosystemic shunt and endoscopic sclerotherapy in a selected group of Italian cirrhotic patients. AB - The aim of the present study was to compare the cumulative cost of the first 18 month period in a selected group of Italian cirrhotic patients treated with transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic sclerotherapy (ES) to prevent variceal rebleeding. Thirty-eight patients enrolled in a controlled trial were considered (18 TIPS and 20 sclerotherapy). The number of days spent in the hospital for the initial treatment and during the follow-up period were defined as the costs of hospitalization. ES sessions, TIPS procedures, angioplasty or addition of a second stent to maintain the shunt patency, were defined as the costs of therapeutic procedures. The two groups were comparable for age, sex, and Child-Pugh score. During the observation period 4 patients died in the TIPS group, and 2 died and 1 was transplanted in the sclerotherapy group. The rebleeding rate was significantly higher in the sclerotherapy group. Despite this, the number of days spent in the hospital was similar in the two groups. This was because of a higher number of hospital admissions for the treatment of hepatic encephalopathy and shunt insufficiency in the TIPS group. The therapeutic procedures were more expensive for TIPS. Consequently, the cumulative cost was higher for patients treated with TIPS than for those treated with sclerotherapy. The extra cost was because of the initial higher cost of the procedure and the difference was still maintained at the end of the 18-month follow-up. When the cumulative costs were expressed per month free of rebleeding, the disadvantage of TIPS disappeared. In conclusion, a program of prevention of variceal rebleeding with TIPS, despite the longer interval free of rebleeding, is not a cost-saving strategy in comparison with sclerotherapy. PMID- 10094950 TI - Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals. AB - Some patients with autoimmune liver disease present with a clinical and/or histological picture showing characteristic findings of both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Various names, mostly overlap syndrome, have been used to describe these cases, which have thus far not been more closely characterized. The aim of this study was the comparison of 20 patients with overlapping features to representative patients considered suffering from typical AIH or typical PBC (20 patients in each group). We found these patients to indeed show a very mixed picture of both conditions biochemically, serologically, and histologically. However, closer analysis suggested that all of these patients were primarily suffering from PBC as all of them had at least either bile duct destruction on histology or anti-M2 positive antimitochondrial antibodies (AMA). We suggest that these PBC patients because of their genetic susceptibility, evidenced by the AIH-characteristic histocompatibility leukocyte antigen (HLA) type B8, DR3, or DR4, developed a more hepatitic picture. Response to immunosuppressive therapy was excellent. We propose that the name "overlap syndrome" be abandoned for "PBC, hepatitic form." These observations not only have pathophysiological implications, but also suggest that therapy of PBC should be guided by the degree of biochemical and histological hepatic involvement. PMID- 10094951 TI - Infection and hemostasis in decompensated cirrhosis: a prospective study using thrombelastography. AB - Bacterial infections are common complications in decompensated cirrhosis, but their relationship with hemostasis has not been studied. We prospectively assessed whether infection affects hemostasis in cirrhosis using routine hemostasis tests and thrombelastography (TEG), a global test of hemostatic function. Eighty-four cirrhotic patients (Child-Pugh B: 26; C: 58) without overt bleeding or blood-product transfusion were prospectively evaluated with routine hemostasis tests and TEG on admission and/or the first day with signs of infection and 5 days later. There were 30 patients with infection; 15 had infection on admission, and 15 developed infection in hospital. In the patients who developed infection in hospital, there was a significant deterioration in all routine hemostasis tests except platelet count (PLT) and in all TEG parameters, on the first day of infection compared with 7 +/- 3 days previously. The same parameters significantly improved from the first day of infection to day 5 and after (P <.02) only in the 22 patients whose infection resolved, while the r, k, and alpha TEG parameters significantly worsened in the 8 patients with persistent infection. In those who developed infection in hospital and were cured (n = 11), the 5-day parameters did not differ from their preinfection values. In conclusion, bacterial infections frequently impair hemostasis in decompensated cirrhotic patients. Successful treatment of infection usually restores hemostasis parameters to preinfection levels in 5 days. Thus, infection may have a role in the bleeding diathesis of cirrhosis. PMID- 10094952 TI - Down-regulation of insulin-like growth factor binding proteins and growth modulation in hepatoma cells by retinoic acid. AB - We observed that all-trans-retinoic acid (RA) down-regulated insulin-like growth factor binding proteins (IGFBPs) in cultured human hepatoma cells (Hep 3B, PLC/PRF/5, and Hep G2); therefore, we characterized the role of this down regulation in cell growth. Treatment with 10 micromol/L RA revealed a rapid decrease in IGFBP-3 within 2 days, and continued treatment with RA for 6 days resulted in a time-dependent stimulation of Hep 3B cell growth. However, RA treatment decreased IGFBP-1 in PLC/PRF/5 cells and in Hep G2 cells, and the growth-stimulatory activity of RA was transient and less prominent, and was finally obliterated in both cell lines. The addition of 5 ng/mL or 50 ng/mL insulin-like growth factors (IGFs) did not change the growth effects elicited by RA. The addition of IGFBP-3 (1,000 ng/mL) inhibited the growth of Hep 3B cells and counteracted the growth-stimulatory activity of RA, but not completely, suggesting that RA has direct growth-stimulatory activity and that this is enhanced by autocrine down-regulation of IGFBP-3. IGFBP-3 also inhibited the growth of PLC/PRF/5 cells and of Hep G2 cells. Treatment with phosphorylated IGFBP-1 (1,000 ng/mL) alone or with RA did not affect the growth of PLC/PRF/5 cells or Hep G2 cells. However, addition of dephosphorylated IGFBP-1, derived from in vivo dephosphorylation of the phosphorylated form, stimulated the growth of both cell lines, independent of interaction with IGF-I. From these observations, we propose that RA down-regulates IGFBPs, which in turn causes autocrine modulation of cell growth independent of IGF in hepatoma cells in vitro or in vivo. In addition, RA regulates IGFBPs at the posttranscriptional (Hep 3B cells and Hep G2 cells) or transcriptional level (PLC/PRF/5 cells) in a cell specific manner. PMID- 10094953 TI - Preoperative portal vein embolization: an audit of 84 patients. AB - Preoperative portal vein embolization (PVE) was performed in 84 patients before extensive liver resection for various diseases. By the criteria of liver volumetric determination, some patients were candidates for PVE, whereas others were not, even though the same surgical procedure, such as extended right lobectomy (ERL), was scheduled. PVE using gelatin sponge powder induced hypertrophy in the nonembolized lobe (0%-171%; median, 30%) and proportional atrophy in the embolized lobe in 2 weeks without eliciting any major inflammatory or necrotic reaction, as evidenced histologically and by the minimal elevations in the serum aspartate transaminase (AST) and alanine transaminase (ALT) values. Alterations in the total bilirubin level and prothrombin time were also insignificant and transient, indicating that hepatocyte functions were not impaired by PVE. Not all patients who undergo PVE proceed with the scheduled hepatic resection procedure, so it is a great advantage that gelatin sponge causes minimal damage compared with other embolizing materials such as cyanoacrylate and absolute ethanol, which have been reported to induce an inflammatory reaction or histological alteration. Our multiple regression analysis showed that three factors, diabetes mellitus, a high total bilirubin level at the time of PVE, and being male, each reduced the extent of hypertrophy in the nonembolized lobe (r2 =.30). By contrast, cholestasis appeared to accelerate the process of atrophy in the embolized lobe (r2 =.16). In conclusion, PVE by gelatin sponge powder is a safe and effective preoperative maneuver that induces hypertrophy of the section of the liver that will remain after partial hepatectomy. PMID- 10094954 TI - Zonal regulation of gene expression during liver regeneration of urokinase transgenic mice. AB - Liver gene transcription plays a fundamental role in the hepatic reparative response to injury. However, little is known about the functional relationship of gene expression between diseased and regenerative compartments following a liver injury. To address the hypothesis that the control of gene expression and the cellular proliferative response are specific to diseased and regenerative liver compartments independently, we assessed the expression of liver growth modulators, hepatocyte proliferation, and apoptosis in transgenic livers overexpressing the urokinase-type plasminogen activator (uPA). uPA livers have regenerative nodules that are visually distinct from the surrounding diseased compartments. Northern analyses using RNA from microdissected regenerative and diseased compartments showed that, among the known liver growth factors studied, there was a selective increase in the expression of hepatocyte growth factor (HGF) in diseased compartments above the levels seen in regenerative compartments and in livers of nontransgenic littermates. Despite the high level of HGF mRNA in diseased compartments, hepatocyte proliferation was low. In contrast, in regenerative compartments, where HGF mRNA was low, hepatocyte proliferation was abundant. For growth inhibitors, mRNA expression for transforming growth factor beta1 (TGF-beta1), p53, and activin A was increased in diseased compartments, where hepatocytes displayed apoptosis. These findings define a zone-specific regulation of gene expression in injured livers and point to an important role of the diseased microenvironment in the fate of hepatocytes during the regenerative process. PMID- 10094955 TI - Growth inhibition by a triple ribozyme targeted to repetitive B2 transcripts. AB - The B2 family represents a group of short repetitive sequences that are found throughout the rodent genome and are analogous to the human Alu sequences. Certain B2 subfamilies are transcribed by RNA polymerase III (pol III), and this transcription is in part controlled by the retinoblastoma protein. In addition to their putative role in retrotranspositional events, these actively transcribed B2 RNAs show a predicted highly stable secondary structure. Although B2 transcripts are normally confined to the nucleus, they demonstrate altered compartmentation after carcinogen treatment, in cancers, and in immortalized and/or transformed cell lines, the significance of which is unclear. Because modulation of B2 transcripts did not seem feasible with an antisense approach, we designed a triple ribozyme (TRz) construct to down-regulate B2 transcripts. The B2-targeted TRz undergoes efficient self-cleavage, resulting in liberation of the internal hammerhead Rz, which we targeted to a single-stranded region of the consensus B2 sequence. The liberated internal targeted Rz was 20 times more active than the corresponding double-G mutant construct that could not undergo self-cleavage, and 5 times more active than the same Rz flanked by nonspecific vector sequences. The B2-targeted TRz was used to develop stable transfectant clones from an SV40 immortalized hepatocyte cell line. These transfectant clones all showed variably reduced growth rates, accompanied by significant reductions in both cytoplasmic and nuclear B2 RNA levels: linear regression analyses showed that their growth rates were directly related to residual cytoplasmic B2 levels. Reverse transcription polymerase chain reaction (RT-PCR) analyses documented efficient self-liberation of the internal targeted Rz in vivo, and showed that the relative cytoplasmic expression levels generally paralleled the magnitude of the decrease in B2 transcripts. The RT-PCR analyses further demonstrated that up to 20% of the Rz was located in the nucleus, which presumably reflects competition between autocatalytic processing and nucleocytoplasmic transport of the initial TRz transcript. PMID- 10094956 TI - Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. AB - The activity of interferon (IFN) is not elucidated from the viewpoint of cancer prevention in chronic hepatitis C patients en masse. The hepatocellular carcinogenesis rate was analyzed statistically in 1,643 patients with chronic hepatitis C: 1,191 patients with IFN therapy and 452 without IFN therapy. Hepatocellular carcinogenesis rates in the treated and untreated groups were 2.1% and 4.8% at the end of the 5th year, and 7.6% and 12.4% at the 10th year, respectively (P =.0036). Multivariate analysis showed that IFN slightly decreased the risk of carcinogenesis by 33%, compared with that of untreated patients (P =. 14), adjusting for the confounding effects of age, fibrotic stage, gender, and gamma-glutamyl transpeptidase (GGTP) value. Among 1,191 patients with IFN, 461 patients attained persistent loss of hepatitis C virus (HCV) RNA, and the other 145 patients retained normal alanine transaminase (ALT) values without loss of HCV RNA. The hazard of carcinogenesis in these 606 patients with persistent normal ALT with or without HCV-RNA clearance was significantly lower than that of untreated patients (hazard ratio: 0.32; P =.012) and that of the abnormal aminotransferase group. Among patients with chronic hepatitis C, IFN significantly decreased the hepatocellular carcinogenesis rate in those patients with normal or persistent low ALT values. PMID- 10094957 TI - Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver. AB - Fatty liver is common in nonalcoholic, obese individuals and in lean people who consume alcohol chronically. Although fatty liver is typically benign, a subset of individuals with steatosis develop steatohepatitis and eventually cirrhosis. The disparate outcomes of fatty liver suggest that it reflects a generally beneficial, adaptive response to obesity or alcohol-related stress, but may also increase hepatocyte vulnerability to other challenges. Thus, both protective factors (e.g., Bcl-2 and Bcl-xL) and factors that promote hepatocyte death by apoptosis (e.g., Bax) or necrosis (e.g., UCP2) may be increased in fatty livers. To evaluate this possibility, hepatocyte apoptosis, necrosis, and the expression of factors that regulate cellular viability were assessed in two models of fatty liver (i.e., genetically obese [ob/ob] mice and ethanol [EtOH]-fed lean mice). Findings in mice with fatty livers were compared with lean, control mice that did not have hepatic steatosis. Immunohistochemistry showed striking induction of hepatocyte proteins that promote (e.g., Bax) and inhibit (e.g., Bcl-2 and Bcl-xL) apoptosis in both groups with fatty liver. Both models of fatty liver also increased hepatic transcripts for UCP2, a mitochondrial uncoupling protein, and the protein itself was induced in ob/ob hepatocytes. Despite the up-regulation of factors that threaten cell viability, hepatocyte death was not increased in either ob/ob or EtOH-fed mice, confirming that the liver's protective responses were sufficient under the conditions studied. However, if UCP2 induction reduces the efficiency of adenosine triphosphate (ATP) synthesis, this initially harmless response might enhance the vulnerability of hepatocytes to necrosis. PMID- 10094958 TI - Ischemia-reperfusion injury in rat fatty liver: role of nutritional status. AB - Fatty livers are more sensitive to the deleterious effects of ischemia reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P <.01). Accordingly, fasting and fatty degeneration had a synergistic effect in exacerbating liver injury. Mitochondrial damage was a predominant feature of ultrastructural hepatocyte injury in fasted fatty livers. Glucose supplementation partially prevented the fasting-induced depletion of glycogen and improved the 7 day rat survival to 45%. These data indicate that rat fatty livers exposed to normothermic ischemia-reperfusion injury are much more sensitive to fasting than histologically normal livers. Because glucose supplementation improves both the hepatic glycogen stores and the rat survival, a nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers. PMID- 10094959 TI - Gap junctional communication and regulation of the glycogenic response to insulin by cell density and glucocorticoids in cultured fetal rat hepatocytes. AB - Cell culture studies have revealed that metabolic functions of the adult hepatocyte are related to cell density. Development of the glycogenic response to insulin under glucocorticoid control was investigated in 15- and 18-day-old fetal rat hepatocytes plated at different cell densities. After culturing for 48 hours with glucocorticoids, the stimulatory effect of insulin on [14C]glucose incorporation into glycogen after 3 hours progressed from weak response (less than 1.4-fold) in sparse cultures to a maximal response in dense ones (3.0- to 4.5-fold), depending on the fetal stage. The response was always no more than 2.0 fold in the absence of glucocorticoids, even with dense cultures. Such a dual regulation pattern was not found for the glycogenolytic effect of glucagon similarly expressed regardless of culture conditions. When cells were clustered in limited circular regions of the dish, the insulin response was higher than for sparse cultures for a similar number of cells per culture. Using the scrape loading technique with Lucifer Yellow CH, a positive dye transfer was obtained in clustered cultures providing that they were grown in the presence of glucocorticoids; insulin as well as glucagon stimulated twofold intercellular communication. Connexin32 (Cx32) and connexin26 (Cx26) protein levels were assayed by Western immunoblotting and developed according to age and exposure to glucocorticoids. Thus, glucocorticoids through development of gap junctions enabled establishment of intercellular communication that could be stimulated by insulin and glucagon in cultured fetal hepatocytes. Gap junction functioning and the biologic effect of insulin correlated closely. PMID- 10094960 TI - Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. AB - Several members of the multidrug resistance protein (MRP) family are expressed in the liver. Adenosine triphosphate (ATP)-dependent transport of glutathione and glucuronoside conjugates across the hepatocyte canalicular membrane is mediated by the apical MRP isoform, MRP2 (APMRP), also known as canalicular multispecific organic anion transporter (cMOAT). We have cloned an additional MRP isoform, MRP3, from human liver and localized it to the basolateral membrane domain of hepatocytes. Basolateral MRP (BLMRP) is composed of 1,527 amino acids and encoded by 4,581 base pairs of complementary DNA. Northern blotting of various human tissues indicated an expression of MRP3 in the liver, colon, pancreas, and, at a lower level, in the kidney. The amino acid identity of MRP3 with MRP1 and MRP2 is 58% and 48%, respectively. These three isoforms, encoded by genes on different chromosomes, have a similar predicted topology of transmembrane segments and ATP binding domains. Antibodies raised against two peptide sequences of MRP3 that are not shared by other MRP family members detected recombinant MRP3 expressed in polarized MDCK cells. Both antibodies served to localize MRP3 to the basolateral membrane of hepatocytes. Double-label immunofluorescence microscopy confirmed that MRP3 was not detectable in the canalicular membrane domain. A particularly strong expression of the MRP3 protein was observed in the basolateral hepatocyte membrane of two patients with Dubin-Johnson syndrome who are deficient in MRP2. These results indicate that the basolateral MRP isoform, MRP3, may be upregulated when the canalicular secretion of anionic conjugates by MRP2 is impaired. PMID- 10094961 TI - High-level expression of rat class I alcohol dehydrogenase is sufficient for ethanol-induced fat accumulation in transduced HeLa cells. AB - The mechanisms by which ethanol causes fatty liver are complex. Reducing equivalents generated during ethanol oxidation inhibit tricarboxylic acid cycle activity and fatty acid oxidation. In addition, ethanol inhibits lipoprotein export and increases fatty acid uptake and lipid peroxidation. To test the role that alcohol metabolism by alcohol dehydrogenase (ADH) has on cellular lipid metabolism, a cell line expressing rat ADH was generated by transducing HeLa cells with an ADH-expressing retrovirus. The cells expressed high levels of ADH protein and had ADH activity similar to that of liver. Exposure of the cells to 20 mmol/L ethanol for 24 hours led to substantial accumulation of free fatty acids and triacylglycerol in the transduced, but not wild-type, HeLa cells. The rate of synthesis of saponifiable lipid was increased significantly by ethanol under these conditions. Ethanol exposure also promoted triacylglycerol accumulation when the cells were incubated with linoleic acid. This was associated with a decrease in the rate at which the cells oxidized 1-[14-C] linoleic acid. Fat accumulation was not prevented by including alpha-tocopherol in the medium, arguing against a role for lipid peroxidation. However, the presence of methylene blue completely prevented the fat accumulation. This was associated with a return of the elevated lactate/pyruvate ratio toward normal. These data suggest that generation of reducing equivalents by ADH was sufficient to cause fat accumulation in this cell model. PMID- 10094962 TI - Determination of the chelatable iron pool of isolated rat hepatocytes by digital fluorescence microscopy using the fluorescent probe, phen green SK. AB - The intracellular pool of chelatable iron is considered to be a decisive pathogenetic factor for various kinds of cell injury. We therefore set about establishing a method of detecting chelatable iron in isolated hepatocytes based on digital fluorescence microscopy. The fluorescence of hepatocytes loaded with the fluorescent metal indicators, phen green SK (PG SK), phen green FL (PG FL), calcein, or fluorescein desferrioxamine (FL-DFO), was quenched when iron was added to the cells in a membrane-permeable form. It increased when cellular chelatable iron available to the probe was experimentally decreased by an excess of various membrane-permeable transition metal chelators. The quenching by means of the ferrous ammonium sulfate + citrate complex and also the "dequenching" using 2,2'-dipyridyl (2,2'-DPD) were largest for PG. We therefore optimized the conditions for its use in hepatocytes and tested the influence of possible confounding factors. An ex situ calibration method was set up to determine the chelatable iron pool of cultured hepatocytes from the increase of PG SK fluorescence after the addition of excess 2,2'-DPD. Using this method, we found 9.8 +/- 2.9 micromol/L (mean +/- SEM; n = 18) chelatable iron in rat hepatocytes, which constituted 1.0% +/- 0.3% of the total iron content of the cells as determined by atomic absorption spectroscopy. The concentration of chelatable iron in hepatocytes was higher than the one in K562 cells (4.0 +/- 1.3 micromol/L; mean +/- SEM; n = 8), which were used for comparison. This method allowed us to record time courses of iron uptake and of iron chelation by different chelators (e.g., deferoxamine, 1,10-phenanthroline) in single, intact cells. PMID- 10094963 TI - A mechanistic model for the development and maintenance of portocentral gradients in gene expression in the liver. AB - In the liver, genes are expressed along a portocentral gradient. Based on their adaptive behavior, a gradient versus compartment type, and a dynamic versus stable type of gradient have been recognized. To understand at least in principle the development and maintenance of these gradients in gene expression in relation to the limited number of signal gradients, we propose a simple and testable model. The model uses portocentral gradients of signal molecules as input, while the output depends on two gene-specific variables, viz., the affinity of the gene for its regulatory factors and the degree of cooperativity that determines the response in the signal-transduction pathways. As a preliminary validity test for its performance, the model was tested on control and hormonally induced expression patterns of phosphoenolpyruvate carboxykinase (PCK), carbamoylphosphate synthetase I (CPS), and glutamine synthetase (GS). Affinity was found to determine the overall steepness of the gradient, whereas cooperativity causes these gradients to steepen locally, as is necessary for a compartment-like expression pattern. Interaction between two or more different signal gradients is necessary to ensure a stable expression pattern under different conditions. The diversity in sequence and arrangement of related DNA response elements of genes appears to account for the gene-specific shape of the portocentral gradients in expression. The feasibility of testing the function of hepatocyte-specific DNA-response units in vivo is demonstrated by integrating such units into a ubiquitously active promoter/enhancer and analyzing the pattern of expression of these constructs in transgenic mice. PMID- 10094964 TI - In vitro evidence for the presence of hematopoietic stem cells in the adult human liver. AB - Previous studies have identified novel lymphoid phenotypes in the adult human liver and provided evidence to suggest that lymphoid differentiation can occur locally in this organ. The aim of this study was to examine the adult human liver for the presence of hematopoietic stem cells that may provide the necessary precursor population for local hematopoietic and lymphoid differentiation. Hepatic mononuclear cells (HMNC) were extracted from normal adult liver biopsy specimens using a combination of mechanical disruption and enzymatic digestion. The stem cell marker CD34 was found on 0.81% to 2.35% of isolated HMNCs by flow cytometry. CD34(+) HMNCs were positively selected using magnetically labeled beads, and the enriched population was further examined for surface markers characteristically expressed by immature hematopoietic cells and early progenitors. CD45 was expressed by 49% (+/-23%) of CD34(+) HMNCs, indicating their hematopoietic origin. CD38, one of the first markers to be expressed by developing progenitor cells was found on 50% (+/-22%) of CD34(+) HMNCs indicating the presence of both pluripotent stem cells and committed precursors. The majority (90%) of CD34(+) HMNCs coexpressed the activation marker human leukocyte antigen DR, consistent with actively cycling cells. Functional maturation of these hepatic progenitors was shown by the detection of multilineage hematopoietic colony formation after tissue culture. Erythroid (BFU-E), granulocyte-monocyte (CFU-GM), and mixed colonies (CFU-GEMM) were detected after culture of unseparated HMNCs and the enriched CD34(+) HMNC population; 14.3 +/- 13.2 (mean +/- SD) BFU-E, 3.1 +/- 3.1 CFU-GM, and 0.4 +/- 0.9 CFU-GEMM per 1 x 10(5) unseparated HMNCs and 16.0 +/- 9.5 BFU-E and 1.7 +/- 0.9 CFU-GM were identified per 2.4 x 10(3) CD34(+) HMNCs plated. The detection of surface markers characteristic of immature hematopoietic cells and colony formation in tissue culture provides evidence for the presence of hematopoietic stem cells and early progenitor cells in the adult human liver. This would suggest that the adult human liver continues to contribute to hematopoiesis and may be an important site for the differentiation of lymphohematopoietic cells involved in disease states, such as autoimmune hepatitis and graft rejection after liver transplantation. PMID- 10094965 TI - The role of protein phosphatases in the expression of inducible nitric oxide synthase in the rat hepatocyte. AB - Previously, we demonstrated that nuclear factor-kappaB (NF-kappaB) mediates cytokine-induced hepatic inducible nitric oxide synthase (iNOS) expression. NF kappaB activation is regulated by kinases and phosphatases whose function is only beginning to be understood. Therefore, experiments were performed to determine the role of protein phosphatases (PPase) in cytokine-induced iNOS expression. Hepatocytes were stimulated with cytokines in the presence or absence of tyrosine phosphatase inhibitors (pervanadate [PV], phenylarsine oxide [PAO]) and a serine threonine phosphatase inhibitor (okadaic acid [OA]). Cytokines induced hepatocyte iNOS mRNA, protein, and NO2- production that was substantially decreased by the addition of the tyrosine phosphatase inhibitors (PAO and PV). The serine threonine phosphatase inhibitor (OA) decreased NO release and protein levels in a concentration-dependent fashion; however, iNOS mRNA levels were not significantly reduced. Nuclear run-on experiments demonstrated that protein tyrosine phosphatases (PTPases) are required for iNOS transcription, while the serine threonine phosphatase inhibitor (OA) had no effect on iNOS transcription. Electromobility shift assays (EMSAs) revealed that the tyrosine-phosphatase inhibitors blocked cytokine-induced NF-kappaB activation, while OA did not have a significant effect on NF-kappaB DNA binding activity. Therefore, tyrosine phosphatases are involved in the regulation of cytokine-induced activation of NF kappaB, while serine-threonine phosphatases posttranscriptionally regulate iNOS translation. These results identify the regulatory role of specific protein phosphatases (PPases) in hepatic iNOS expression. PMID- 10094966 TI - Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. AB - To search for recurrent and specific genomic alterations in human hepatocellular carcinoma (HCC), we examined 18 cell lines by comparative genomic hybridization (CGH), a molecular cytogenetic approach that allows positional identification of gains and losses of DNA sequences of the entire tumor genome. We report here a distinct pattern of multiple recurrent DNA copy-number gains and losses that include alterations frequently seen in other neoplasias as well as changes potentially specific for HCC. The most frequent gains were localized on 1p34.3 35, 1p33-34.1, 1q21-23, 1q31-32, 6p11-12, 7p21, 7q11.2, 8q24.1-24.2, 11q11-13, 12q11-13, 12q23, 17q11. 2-21, 17q23-24, and 20p11.1-q13.2. Recurrent losses were mapped on 3p12-14, 3q25, 4p12-14, 4q13-34, 5q21, 6q25-26, 8p11.2-23, 9p12-24, 11q23-24, 13q12-33, 14q12-13, 15q25-26, 18q11.2-22.2, and 21q21-22. Seventeen genomic imbalances are novel in HCC, thus extending significantly the map of genetic changes and providing a starting point for the isolation of new genes relevant in pathogenesis of liver neoplasia, as well as providing molecular probes for both diagnosis and monitoring treatment of the disease. PMID- 10094967 TI - Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. AB - Steatosis is a frequent histological finding in chronic hepatitis C infection; however, the pathophysiology of steatosis and its role in disease progression have not been established. We studied 148 consecutive patients with untreated chronic hepatitis C to assess the effect of body mass index, diabetes mellitus, alcohol consumption, hepatic iron content, and viral load on steatosis and hepatic fibrosis. Ninety-one patients (61%) had steatosis: grade 1 (<30% hepatocytes involved) in 61 (41%), grade 2 (30%-70% hepatocytes involved) in 17 (11%), and grade 3 (>70% hepatocytes involved) in 13 (9%). After adjusting for potential confounding variables, a highly significant relationship was found primarily between steatosis and body mass index (P <.0001). The mean (+/-SD) body mass index of patients with no steatosis was 23.9 +/- 4.3 kg/m2, whereas for grade 1 steatosis it was 26.5 +/- 5.1 kg/m2, and for grade 2 and 3 steatosis combined the body mass index was 28.4 +/- 4. 9 kg/m2. Hepatic fibrosis was significantly associated with age (P =. 002). After adjusting for potential confounding variables, including age, hepatic fibrosis was also significantly associated with steatosis (P <.03). There was no significant association between hepatic iron content, alcohol intake, gender, and viral load and steatosis or fibrosis. These findings suggest that increasing body mass index has a role in the pathogenesis of steatosis in chronic hepatitis C and that steatosis may contribute to fibrosis. The association between body mass index and steatosis and fibrosis has important prognostic and therapeutic implications in the management of patients with chronic hepatitis C virus. PMID- 10094968 TI - Recurrent and new hepatitis C virus infection after liver transplantation. AB - Chronic infection with the hepatitis C virus (HCV) is the most common reason for liver transplantation. We examined the results of laboratory tests for HCV on a cohort of patients who received a liver transplant between 1990 and 1994 at three large centers. Seven hundred twenty-two recipients and 604 donors were tested for antibody to HCV (anti-HCV) using a second-generation enzyme-linked immunoassay (EIA-2), followed by recombinant immunoblot (RIBA-2) and HCV RNA confirmation by reverse-transcription polymerase chain reaction (RT-PCR) (with genotyping and viral quantification). Diagnosis of posttransplantation infection required detection of serum HCV RNA that could be genotyped by sequencing or was repeatedly positive despite being unsequenceable. Twenty-five percent of transplantation candidates were seropositive for anti-HCV. Approximately 86% of anti-HCV-positive, 93% of RIBA-positive, and 97% of HCV RNA-positive candidates developed infection after transplantation. Pretransplantation HCV RNA was superior to RIBA-2 for predicting posttransplantation infection. Whereas HCV genotype was identified in nearly all candidates and changed little after transplantation, serum viral levels rose markedly after transplantation. Fifteen donors were either anti-HCV- or HCV RNA-positive. Recipients of grafts from donors with HCV RNA all developed infection, whereas infection was not detected in recipients of grafts from donors with anti-HCV but without detectable HCV RNA. The rate of new infection fell significantly (P =.02) after the introduction of EIA-2 screening of blood. Donor and candidate markers for HCV predict posttransplantation infection. PMID- 10094969 TI - Expression of hepatitis C virus NS5B protein: characterization of its RNA polymerase activity and RNA binding. AB - The nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is considered to possess RNA-dependent RNA polymerase (RdRp) activity and to play an essential role for the viral replication. In this study, we expressed the NS5B protein of 65 kd by a recombinant baculovirus. With the highly purified NS5B protein, we established an in vitro system for RdRp activity by using poly(A) as a template and a 15-mer oligo(U) (oligo(U)15) as a primer. Optimal conditions of temperature and pH for primer-dependent polymerase activity of the NS5B were 32 degrees C and pH 8.0. The addition of 10 mmol of Mg2+ increased the activity. The importance of three motifs conserved in RdRp among other positive-strand RNA viruses was confirmed by introduction of an Ala residue to every amino acid of the motifs by site-directed mutagenesis. All mutants lost RdRp activity, but retained the RNA binding activity, except one mutant at Thr287/Asn291. Deletion mutant analysis indicated that the N-terminal region of NS5B protein was critical for the RNA binding. Inhibition of RdRp activity by (-)beta-L-2', 3'-dideoxy-3'-thiacytidine 5'-triphosphate (3TC; lamivudine triphosphate) and phosphonoacetic acid (PAA) was observed after screening of nucleoside analogs and known polymerase inhibitors. These data provide us not only important clues for understanding the mechanism of HCV replication, but also a new target of antiviral therapy. PMID- 10094970 TI - Two control elements in the hepatitis B virus S-promoter are important for full promoter activity mediated by CCAAT-binding factor. AB - Natural occurring mutations in the preS-region are frequently found during chronic hepatitis B virus (HBV) infection. Here we used the mutated preS-region from a patient to study the transcriptional regulation of the S-promoter. The mutations were a CCAAT-box (MUT1) point mutation, a 6-base pair (bp) deletion (MUT2) 3' of the CCAAT-box, and a 153 bp deletion (MUT3) in the preS2 genome. Transfection experiments revealed for MUT1 and 2 30% to 40% and MUT3 75% of the wildtype (wt) S-promoter activity. In electro-mobility shift assays experiments, binding of a nuclear protein was impaired with MUT1. Ultraviolet cross-linking, South-Western, and gel shift experiments revealed a 30- to 40-kd protein interacting with the wt CCAAT-motif. Computer-assisted analysis and supershift experiments showed that CCAAT-binding factor (CBF) is the CCAAT-box binding protein. Cotransfection experiments with expression vectors for dominant-negative CBF or wt CBF showed that the wt S-promoter but not MUT1 could be regulated through CBF. Additionally, the CBF constructs did not modulate the basal activity of MUT2 but changes the activity of MUT3 like wt HBV. Artificial mutations were introduced in the MUT2 reporter constructs. Transfection experiments revealed that wt promoter activity could not be reconstituted. Therefore these experiments indicated the sterical position of CBF being essential for full S-promoter activity. Our study shows that the CCAAT-box and a second region is essential to mediate full S-promoter activity dependent on CBF. As these mutations also lead to retention of S-protein in the endoplasmic reticulum our results indicate that mutational changes in the preS-region might be linked to the progression of HBV related liver disease. PMID- 10094971 TI - Mannose binding lectin gene mutations are associated with progression of liver disease in chronic hepatitis B infection. AB - Mannose-binding lectin (MBL) plays an important role in immune defense. We examined the MBL gene mutations and MBL levels in Chinese hepatitis B and hepatitis C patients with and without symptomatic cirrhosis. We recruited 190 hepatitis B and C patients, and 117 normal Chinese as controls. Serum MBL levels were measured by enzyme-linked immunosorbent assay. MBL gene mutation at codons 52, 54, and 57 was detected by polymerase chain reaction (PCR) assay. In asymptomatic hepatitis B and C patients, there was no increase in codons 52, 54, and 57 mutation, but the MBL levels were significantly lower than those in the controls. Codon 54 mutation rate was increased to 44.4% (P =.007) in symptomatic hepatitis B cirrhosis and 64.3% (P =.0026) in patients with spontaneous bacterial peritonitis (SBP). There was no increase in codon 54 mutation rate in hepatitis B related hepatocellular carcinoma (HCC). In chronic hepatitis B infection, the odds ratio for an individual with codon 54 mutation to develop cirrhosis was 1.84 (95% CI: 1.21-2. 81) and to develop SBP was 4.58 (95% CI: 1.73-12.16). Chronic hepatitis B and hepatitis C infection lowered the MBL levels, probably by suppressing MBL production. Codon 54 mutation of MBL was associated with progression of disease in chronic hepatitis B infection. PMID- 10094972 TI - Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B. AB - The involvement of precore stop codon 1896-A and base exchanges in the AT-rich region at positions 1762 and 1764 of the hepatitis B core promotor has been controversely discussed in adults with fulminant hepatitis B. Because no data are currently available on children, we analyzed the basic core promotor (BCP) and precore region in children with chronic and fulminant hepatitis B. The BCP and precore region were sequenced directly and after cloning from mothers and infants. Thirteen children suffered from chronic liver disease, 6 of whom were treated with interferon alfa (IFN-alpha). All 13 patients seroconverted from hepatitis B e antigen (HBeAg) to hepatitis B e antigen antibodies (anti-HBe), and sera were analyzed before and after seroconversion. Nine vertically infected infants developed a fulminant course of hepatitis B. The occurrence of BCP (1762 T/1764-A, 7.7%) and precore (1896-A, 7.7%; 1899-A, 15%) mutations in chronic hepatitis B was rare. A genotype shift from D to A was observed in 3 patients after development of anti-HBe. A high number of base exchanges was detected in those infants with fulminant hepatitis B. Eight of nine showed a G-A exchange at positions 1896/97 (89%), 1899 (56%), and/or mutations at nucleotide (nt) positions 1762 (56%) and 1764 (78%). All virus strains belonged to genotype D, whereas in the only surviving infant, a D-to-A shift was detected. Hepatitis B virus (HBV) DNA clones were examined from 3 babies and 5 mothers. Our results showed a heterogeneous virus population in 4 of 5 mothers. In contrast, a homogeneous virus population emerged in the infants. According to our data, the analysis in children with fulminant and chronic hepatitis B revealed a striking presence of BCP and precore mutants in infants with fulminant hepatitis (FH) when compared with clinically inapparent anti-HBe-positive children (P <.002), which could be one factor in the pathogenesis of fulminant hepatitis B in children. PMID- 10094973 TI - No association between hepatitis C and B-cell lymphoma. AB - Chronic viral infection has been implicated in the pathogenesis of B-cell lymphoma, and hepatitis C virus (HCV) infects lymphocytes. Chronic infection with HCV may result in B-cell proliferation. Individuals infected with hepatitis C are often co-infected with the RNA virus GB virus type C. Studies from Europe where hepatitis C infection is more common than in North America have shown a high prevalence of hepatitis C infection in patients with B-cell lymphoma. The aim of this study was to establish the prevalence of HCV and GBV-C infection in patients with B-cell lymphoma in an area of low HCV prevalence. One hundred patients with B-cell lymphoma (10 high grade, 46 intermediate grade, and 44 low grade) and 100 controls with nonhematological malignancies were studied. Serum was analyzed for HCV antibodies by third generation enzyme-linked immunosorbant assay, and HCV RNA and GBV-C RNA was analyzed by reverse transcriptase PCR. None of the controls or lymphoma patients had antibodies to HCV. HCV RNA was undetected in 60 out of 100 lymphoma patients tested. GBV-C RNA was detected in the serum of 5 out of 100 (5%) of lymphoma patients and in 3 out of 100 (3%) controls. Hepatitis C and GBV C are, therefore, unlikely to play a major role in the pathogenesis of B-cell lymphoma in North America. PMID- 10094974 TI - Characterization of the effects of hepatitis C virus nonstructural 5A protein expression in human cell lines and on interferon-sensitive virus replication. AB - The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has been implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy in clinical studies. Biochemical studies have demonstrated that NS5A interacts in vitro with and inhibits the IFN-induced, RNA-dependent protein kinase, PKR, and that NS5A interacts with at least one other cellular kinase. The present study describes the establishment and characterization of various stable NS5A expressing human cell lines, and the development of a cell culture-based assay for determining the inherent IFN resistance of clinical NS5A isolates. Human epithelioid (Hela) and osteosarcoma (U2-OS) cell lines were generated that express NS5A under tight regulation by the tetracycline-dependent promoter. Maximal expression of NS5A occurred at 48 hours following the removal of tetracycline from the culture medium. The half-life of NS5A in these cell lines was between 4 to 6 hours. NS5A protein expression was localized cytoplasmically, with a staining pattern consistent with the location of the Golgi apparatus and endoplasmic reticulum. In the majority of cell lines, no obvious phenotypic changes were observed. However, three genotype 1b NS5A-expressing osteosarcoma cell lines exhibited cytopathic effect and severely reduced proliferation as a result of high-level NS5A expression. Full-length NS5A protein isolated from a genotype 1b IFN-nonresponsive patient (NS5A-1b) was capable of rescuing encephalomyocardititis virus replication during IFN challenge up to 40-fold, whereas a full-length NS5A-1a and an interferon sensitivity determining region (ISDR) deletion mutant (NS5A-1a-triangle upISDR) isolated from a genotype 1a IFN nonresponsive patient showed no rescue activity. The NS5A-1b and NS5A-1a proteins also rescued vesicular stomatitis virus replication during IFN treatment by two- to threefold. These data cummulatively suggest that NS5A expression alone can render cells partially resistant to the effects of IFN against IFN-sensitive viruses, and that in some systems, these effects may be independent of the putative ISDR. A scenario is discussed in which the NS5A protein may employ multiple strategies contributing to IFN resistance during HCV infection. PMID- 10094975 TI - Human leukocyte antigen class II and III alleles and severity of hepatitis C virus-related chronic liver disease. AB - Hepatitis C outcome is likely related both to viral factors and host's immune responses. We correlated the severity of liver disease with human leukocyte antigen (HLA) genes (C4A, C4B, TNFA, TNFB, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, TAP1, and TAP2) in three groups of subjects: 99 patients with chronic hepatitis, 41 asymptomatic carriers, and 179 uninfected controls. Patients with grade/stage 3 to 4 hepatitis significantly differentiated for their low frequency of alleles TNFB*1, DRB1*1104, and DRB3*03, which had a protective role, and high frequency of allele DRB1*1001, which was associated with disease severity. HLA-DRB*11 subtypes were differentially distributed: DRB1*1104 was most frequent in carriers, whereas DRB1*1101 was more frequent in patients. The TAP1C,2A haplotype was also underrepresented in patients with respect to controls. Finally, a decrease of heterozygous subjects was observed in patients with respect to carriers at the DQB1 locus. Multivariate analysis by correspondence analysis and multiple logistic regression indicated that age, sex, and hepatitis C virus (HCV) type were the strongest risk factors; however, some immunogenetic variables (TNFB*1, DRB1*1104, and DRB3*03) showed an independent contribution, especially in comparing patients with extreme manifestations of disease. The involvement of different genes in various HLA subregions suggests that anti-HCV responses are modulated by a complex gene interplay rather than by single alleles. PMID- 10094976 TI - A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C. AB - Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The present open-label, multicenter, dose-escalation phase I/II study was designed to assess tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) in the treatment of chronic hepatitis C. Sixty patients (42 men, 18 women, aged 24-60) were treated with 0.03 microgram/kg (n = 16), 0.1 microgram/kg (n = 14), 0.25 microgram/kg (n = 15), or 0.5 microgram/kg rHuIL-12 (n = 15) for 10 consecutive weeks. rHuIL-12 was generally well tolerated, with 2 patients (3.3%) being withdrawn from treatment for adverse events. Treatment was associated with temporary decreases in neutrophils and lymphocyte counts and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microgram/kg compared with 0.25 microgram/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon gamma (IFN-gamma) were also observed at the highest dose of 0.5 microgram/kg. At the end of treatment hepatitis C virus (HCV) RNA was detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3 of 16 patients of the 0.03-microgram/kg dose group, in 3 of 14 of the 0.10-microgram/kg dose group, in 6 of 15 of the 0.25-microgram/kg dose group, and in 8 of 15 patients of the 0.5-microgram/kg dose group. Although in several cases serum alanine transaminase (ALT) levels decreased either during or after treatment, ALT normalization was observed in only 4 patients at the end of treatment and in 5 patients at the end of follow-up. Significant anti-rHuIL-12 antibody titers were not detectable in any patient. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis C does not appear advantageous in comparison with other currently available treatments. PMID- 10094977 TI - Quantitative antibody responses to structural (Core) and nonstructural (NS3, NS4, and NS5) hepatitis C virus proteins among seroconverting injecting drug users: impact of epitope variation and relationship to detection of HCV RNA in blood. AB - To gain insight into the natural history of hepatitis C virus (HCV), 13 human immunodeficiency virus (HIV)-seronegative injecting drug users were studied who seroconverted for HCV as determined by third-generation enzyme-linked immunosorbent assay, showed an ensuing antibody response to HCV, and were not treated with any antiviral drugs during follow-up. Subjects included 13 untreated HIV-negative individuals, of whom 5 (38.5%) apparently cleared HCV and were polymerase chain reaction (PCR)-negative in at least 3 consecutive samples, 3 (23.1%) showed transient viremia and were PCR-negative in 1 sample during the study period, and the other 5 (38.5%) showed persistent viremia. Viremia was determined longitudinally by reverse-transcription PCR (RT-PCR) and quantified by branched DNA (bDNA). HCV genotypes were determined on serial samples during follow-up. Quantitative antibody levels to core, NS3, NS4, and NS5 were determined using the Chiron RIBA HCV-titering Strip Immunoblot Assay, which is based on HCV genotype 1. The antibody responses to core, NS3, NS4, and NS5 were erratic. In individuals infected with HCV genotype 1, significantly higher median antibody responses to core (P =.02) and to NS4 (P =.04) were found as compared with those infected with other genotypes, showing a significant impact of HCV genotype specificity of the assay. In groups infected with HCV genotype 1, significantly higher median NS3 antibody titers (2.61 relative intensity [RI] vs. 0.38 RI; P =.003) were found in the individuals with persistent viremia than in those with apparent resolution of HCV RNA in blood. In groups infected with genotypes other than genotype 1, significantly higher median NS3 antibody titers (0.89 RI vs. 0.03 RI; P =.0004) and NS5 antibody titers (1.86 RI vs. 0.01 RI; P =.006) were found in the individuals with persistent viremia than in those with apparent resolution of HCV RNA in blood. Individuals with viral persistence had higher HCV-RNA loads with higher antibody responses as compared with individuals with apparent viral clearance from blood. Apparent viral clearance from blood was observed in an unexpectedly high percentage (38.5%), associated with a significant decrease of antibodies to NS3, independent of HCV genotype, as compared with individuals with persistent viremia (P <.005). Apparent viral clearance from blood with gradual loss of antibodies to various HCV proteins, independent of HCV genotype, was observed in 4 of the 5 individuals within approximately 1 year after HCV seroconversion, whereas 1 of these individuals apparently cleared the virus from blood, with complete seroreversion. PMID- 10094978 TI - Comparison of immune reactivity and pharmacokinetics of two hepatitis B immune globulins in patients after liver transplantation. AB - Hepatitis B virus (HBV) immune globulin (HBIg) administration will prevent HBV graft reinfection in HBV patients after orthotopic liver transplantation (OLT). However, the expenditure for such prophylaxis is extremely high ranging between $2,000 to $10,000 per month in various countries for an undefined period and presumably for life. As a consequence, there is a need for introduction of additional and less expensive modes of treatment. In a preliminary clinical trial a new HBIg preparation has been shown to induce longer lasting levels of circulating antibodies to hepatitis B surface antigen (anti-HBs) in patients after OLT compared with previous experience with conventional HBIg preparations. In the present study the pharmacokinetics of this new HBIg, OMRI-Hep-B, were studied and compared with a conventional, licensed preparation, Hepatect. Fifteen post-OLT patients (2-8 years post-OLT, 18-62 years of age, 6 men, 9 women) were treated intravenously with 49 doses of OMRI-Hep-B or Hepatect given at least once, alternately, at 10,000 to 14,000 units per injection ( approximately 130 IU/kg body weight). The new HBIg was well tolerated and no adverse effects were observed. Administration of OMRI-Hep-B was shown to induce high and long-lasting levels of circulating anti-HBs antibodies and greater areas under the curve (AUC) compared with the conventional preparation. Thus, anti-HBs half-life was 22 +/- 1.3 days for OMRI-Hep-B recipients and 13 +/- 1.3 days for Hepatect recipients (P <.001). Time to reach trough anti-HBs levels of 150 mIU/mL was significantly longer after administration of OMRI-Hep-B than after Hepatect (79 +/- 4.5 and 52 +/- 3.8 days, respectively; P <.001). In summary, the pharmacokinetic profile of the new HBIg, and in particular its prolonged elimination half-life, may reduce the cost of administration by approximately 30% and improve the quality of life of patients by extending the interval between repeated immune globulin injections. PMID- 10094979 TI - Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. AB - The aim of this study was to assess the influence of human immunodeficiency virus (HIV) infection on chronic hepatitis B. In a series of 132 (65 anti-HIV positive) homosexual non-drug addicted men with chronic hepatitis B, the liver function was assessed with biochemical tests; the degree of hepatitis B virus (HBV) replication was assessed with serum HBV DNA level and with immunoperoxidase staining of hepatitis B core (HBc) antigen on liver specimens; and the severity of liver lesions was assessed with an histology activity index. Anti-HIV-positive and anti-HIV-negative patients were not different for serum aspartate transaminase activity, bilirubin, prothrombin, and histology activity index. Anti HIV-positive patients had lower serum alanine transaminase activity levels (P =.0001), lower serum albumin levels (P =.0009), and higher serum HBV DNA levels (P =.01). There was a higher prevalence of cirrhosis in anti-HIV-positive patients (P =.04). In homosexual men with chronic hepatitis B, HIV infection is associated with a higher level of HBV replication and a higher risk for cirrhosis without increased liver necrotico-inflammatory process. PMID- 10094980 TI - The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. AB - It is well known that hepatitis C virus (HCV) infection may progress to cirrhosis and is linked to the development of hepatocellular carcinoma (HCC). Previous studies have shown that compensated HCV-cirrhosis is related to a certain morbidity and mortality in European patients, but little is known in regard to the clinical outcomes of a similar group of patients in the United States. This study investigated this category of patients in terms of the incidence of decompensation, development of HCC, mortality, and the predictive risk factors for morbidity and mortality. The potential effects of interferon (IFN) therapy on outcomes of the disease also were assessed. A total of 112 patients with compensated HCV-cirrhosis and a documented history of either intravenous drug abuse (IVDA) or transfusion were consecutively enrolled. The mean follow-up interval was 4.5 (2-7.7) years. The cumulative probabilities for decompensation and development of HCC were 22.2% and 10.1% in 5 years, with an estimated yearly incidence of 4.4% and 2.0%, respectively. The cumulative survival probability was 82.8% from entry and 51.1% from decompensation in 5 years, with estimated yearly events of mortality and liver transplantation of 3.4% and 9. 8%, respectively. It was found that age at entry and initial exposure, initial levels of albumin, platelet count, and prothrombin time (PT) were predictive risk factors for developing decompensation, whereas age at entry and initial exposure, history of transfusion, lower initial levels of albumin, platelet count, and viral load were predictive risk factors for events of mortality and liver transplantation. The incidence of decompensation was significantly lower in patients treated with IFN, but age may have played a contributory role. In contrast, neither HCC development nor mortality was significantly altered by IFN therapy. In conclusion, our study indicated that patients with compensated HCV-cirrhosis in the United States progressed slowly and experienced eventual morbidity and mortality. Once decompensation develops, the disease will be more progressive and result in even higher mortality. Further studies will be required to determine the efficacy of IFN on clinical outcomes in this group of patients. PMID- 10094981 TI - Enhanced duck hepatitis B virus gene expression following aflatoxin B1 exposure. AB - Epidemiological studies have suggested synergistic interactions between chronic hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure in the etiology of hepatocellular carcinoma (HCC), although the molecular mechanisms of their interactions are still not understood. The aim of this study was to use the Pekin duck model to investigate the impact of AFB1 exposure on duck hepatitis B virus (DHBV) replication during the early stages of virus-carcinogen interactions. Six-week-old chronic DHBV-carrier or uninfected ducks were exposed to AFB1 for 5 weeks or treated with dimethylsulfoxide (DMSO) as a control. Animals were observed for 6 to 13 weeks after AFB1 treatment to study the influence of AFB1 exposure on DHBV replication and liver pathologies. Histological analysis showed more marked changes in the livers of AFB1-treated ducks, and these were enhanced by DHBV infection. A significant increase in serum and liver DHBV DNA level was observed in AFB1-treated ducks as compared with DMSO treated controls. In addition, viral RNAs, in particular the pregenomic RNA that is the template of viral replication, and intrahepatic DHBV DNA replicative intermediates, were significantly increased by AFB1 treatment. Moreover, an overexpression and accumulation of DHBV large envelope (L) protein was observed in the hepatocytes of AFB1-exposed animals. The in vitro study has further confirmed an increase in intracellular viral DNA and in virus release in AFB1 treated primary duck hepatocytes. Taken together, our results indicate that AFB1 exposure leads to an increase in virus gene expression associated with intrahepatic accumulation of DHBV L protein and enhanced liver pathology. PMID- 10094982 TI - Population screening for hemochromatosis. PMID- 10094983 TI - Body composition and hepatic steatosis as precursors for fibrotic liver disease. PMID- 10094984 TI - What once was lost, now is found: restoration of hepatitis B-specific immunity after treatment of chronic hepatitis B. PMID- 10094985 TI - Hepatitis C virus dynamics in vivo and the antiviral efficacy of interferon alfa therapy. PMID- 10094986 TI - Aortic bifurcation reconstruction: use of the Memotherm self-expanding nitinol stent for stenoses and occlusions. AB - PURPOSE: To assess the technical success, initial clinical outcome, and intermediate follow-up of the Memotherm nitinol self-expanding stent in aortic bifurcation reconstruction. METHODS: Thirty-three patients (13 male, 20 female), mean age 64 years, were treated, who had symptoms classified by the Surgical Vascular Society/International Society of Cardiovascular Surgery (SVS/ICVS) classification as grade 2 in 11 (33%), grade 3 in 19 (58%) and grade 4 in 3 (9%) patients. Lesions were classified according to severity and type. Indications for placement of a Memotherm nitinol self-expanding stent were failed angioplasty in 14 (42%), chronic occlusions in 12 (37%), and complex stenoses in seven (21%) patients. RESULTS: Sixty-seven stents were technically successfully placed in 66 aorto-iliac segments in 33 patients, with one major complication. Initial clinical outcome was improvement in 25 (81%), no change in four (13%), and a worsening in two (6%) patients by Rutherford criteria. Mean early ankle/brachial pressure index (ABI) gain was 0. 27 for occlusions and 0.05 for stenoses. Clinical follow-up was obtained in all patients, with retrospective angiographic follow-up in 28 (85%) at a mean of 16 months (range 12-26 months). The decrease in ABI and the decrease in angiographic luminal diameter at follow-up was determined as the "late loss." The mean ABI late losses were -0.06, 0.00, and 0.09, and the mean angiographic late losses were 6.7%, 10% and 14% for occlusions, stenoses, and normal segments respectively. Primary clinical patency was 96%, primary angiographic patency was 89%, and secondary angiographic patency was 93%. CONCLUSION: The high technical success of stent placement, the low complication rates for aortic bifurcation reconstruction using the Memotherm self expanding stent, and high clinical and angiographic patency maintained at intermediate follow-up support their use in aortic bifurcation reconstruction. PMID- 10094987 TI - Percutaneous endoluminal stent and stent-graft placement for the treatment of femoropopliteal aneurysms: early experience. AB - PURPOSE: To determine the efficacy of percutaneous endoluminal stents and stent grafts for the treatment of isolated femoropopliteal aneurysms. METHODS: Seven men (age 51-69 years) with femoropopliteal occlusions (n = 6) related to aneurysms and a patent femoropopliteal aneurysm (n = 1) were treated percutaneously. In two patients uncovered Wallstents and in five patients polyester-covered nitinol stents were implanted. Assessment was performed with Doppler ultrasound and duplex ultrasonography 24 hr, 1, 3, 6, 12, and 24 months after the intervention. Additionally, intraarterial angiography was performed at 6 months. RESULTS: Stent placement succeeded in all cases. No immediate adjunctive surgical treatment was necessary. Ankle-brachial index (ABI) improved from 0.29 +/- 0. 29 (SD) before to 0.78 +/- 0.23 (SD) 24 hr after the intervention. One patient was lost to follow-up. Stent-graft occlusion occurred in four patients: after 2 days (n = 1), 1 month (n = 2), and 3 months (n = 1). One of the patients, whose stent occluded at 1 month, underwent successful recanalization with local fibrinolysis therapy. Three of the seven, all with three-vessel run-off, demonstrated patency of the stent, which was assessed by duplex ultrasonography at 29, 31, and 34 months. Breaking of the stent struts or significant stent migration was not observed. CONCLUSIONS: These results in a small number of patients warrant further investigation to evaluate the role of percutaneous stents in femoropopliteal aneurysms. Until further data of clinical studies are available, this method cannot be recommended, and it cannot replace surgical treatment. PMID- 10094988 TI - Elastic deformation properties of implanted endobronchial wire stents in benign and malignant bronchial disease: A radiographic in vivo evaluation. AB - PURPOSE: To evaluate the long-term mechanical behavior in vivo of expandable endobronchial wire stents, we imaged three different prostheses in the treatment of tracheobronchial disease. METHODS: Six patients with bronchial stenoses (three benign, three malignant) underwent insertion of metallic stents. Two self expandable Wallstents, two balloon-expandable tantalum Strecker stents and two self-expandable nitinol Accuflex stents were used. Measurements of deformation properties were performed during voluntary cough by means of fluoroscopy, at 1 month and 7-10 months after implantation. The procedures were videotaped, their images digitized and the narrowing of stent diameters calculated at intervals of 20 msec. RESULTS: After stent implantation all patients improved with respect to ventilatory function. Radial stent narrowing during cough reached 53% (Wallstent), 59% (tantalum Strecker stent), and 52% (nitinol Accuflex stent) of the relaxed post-implantation diameter. Stent compression was more marked in benign compared with malignant stenoses. In the long term permanent deformation occurred with the tantalum Strecker stents; the other stents were unchanged. CONCLUSION: Endobronchial wire stents can be helpful in the treatment of major airway collapse and obstructing bronchial lesions. However, evidence of material fatigue as a possible effect of exposure to recurrent mechanical stress on the flexible mesh tube may limit their long-term use. This seems to be predominantly important in benign bronchial collapse. PMID- 10094989 TI - Treatment of inoperable tracheobronchial obstructive lesions with the Palmaz stent. AB - PURPOSE: The treatment of inoperable tracheobronchial stenoses with Palmaz stents is analyzed in terms of the clinical effect, typical complications, and long-term follow-up. METHODS: Twenty-seven Palmaz stents were placed in 22 patients with the help of a rigid bronchoscope. RESULTS: Stents were implanted in the distal trachea, the main bronchi, and the lower lobe bronchi. Twenty-one of 22 patients reported an immediate subjective improvement in their respiratory situation. The mean survival time was 12 months; in two patients the stents were well tolerated for up to 40 months. A redilation of three stents was successful up to 33 months. In three cases a dislocation of the stent was observed; after bronchoscopic retraction a new stent was successfully implanted in each case. CONCLUSIONoff Treatment of inoperable tracheobronchial stenoses with the Palmaz stent is a safe procedure that provides an immediate improvement of the patient's pulmonary situation. The Palmaz stent shows a minimal complication rate in the long-term follow-up. PMID- 10094990 TI - Transcatheter intracavitary fibrinolysis of loculated pleural effusions: experience in 102 patients. AB - PURPOSE: To assess the efficacy of intrapleural urokinase instillation through small-caliber catheters for the treatment of loculate and/or septate effusions. METHODS: We inserted small-caliber catheters (8.2 Fr) in 102 patients with septate and/or loculate pleural effusions using ultrasonographic guidance. Urokinase (100,000 IU/2 hr, 3 times a day) was instilled through the catheter until the effusion resolved and D-dimer levels were <500 ng/ml. Patients were enrolled regardless of the etiology of the pleural effusion provided there were no contraindications for the use of urokinase. D-dimer levels were determined before and after treatment. Follow-up was performed by chest radiograph and sonography at 1 day, 7 days, and every 30 days thereafter for 6 months. RESULTS: Successful catheter placement was achieved in all cases. The mean time catheters stayed in place was 5.7 days and the mean dose of drug instilled was 690,000 IU. Pleural effusion drainage was complete at the first assessment in all patients. Failure of the treatment, with recurrent effusion at 30 days, occurred in six patients (5.8%). Complete resolution without sequelae was observed in 19 patients (19.6%). In 75 cases (73.5%) resolution was partial, with pleural thickening (>2 mm). Two patients died from unrelated causes within 30 days after catheter placement. Complications were seen in 13 patients (12.74%): hydropneumothorax, nine cases (8.82%); infection of the puncture point, three cases (2.94%); and adverse reaction, one case (0.98%). No further treatment was required. CONCLUSION: The use of intrapleural fibrinolytic agents delivered through small caliber catheters for the treatment of loculate and/or septate pleural effusion is a simple, effective, minimally invasive and inexpensive procedure that can prevent sequelae and shorten drainage time. PMID- 10094991 TI - Efficacy of gastric blood supply redistribution by transarterial embolization: preoperative procedure to prevent postoperative anastomotic leaks following esophagoplasty for esophageal carcinoma. AB - PURPOSE: The aim of this study was to evaluate the effect of preoperative redistribution of gastric blood supply on the prevention of anastomotic leakage following surgical reconstruction of the esophagus. METHODS: In 37 patients with esophageal carcinoma, transarterial embolization (TAE) of the left gastric, right gastric, and splenic arteries was preoperatively performed with coils so that gastric blood supply was dependent only on the right gastroepiploic artery. RESULTS: In 34 of 37 patients, preoperative redistribution was successfully performed. The gastric tissue blood flow (TBF) of a gastric tube was higher than in 12 nonredistributed patients. Reduction in the gastric TBF during preparation of a gastric tube was 27.5% in successful patients, in contrast to 68.9% in 12 nonredistributed patients (p < 0.005). CONCLUSION: Preoperative redistribution by TAE reduced the drop in gastric TBF during preparation of a gastric tube and helped prevent postoperative anastomotic leakage in esophageal reconstruction. PMID- 10094992 TI - Radiologic damage control: evaluation of a combined CT and angiography suite with a pivoting table. AB - PURPOSE: To evaluate retrospectively the integrated diagnostic and therapeutic management of severely polytraumatized patients using a combined computed tomography (CT) and angiography suite with a single pivoting table. METHODS: Eleven patients, aged 16-74 years (median 30 years), were managed with spiral CT and angiography without patient transfer. Four patients were unstable, seven had received blood transfusions (2-18 units) and six were intubated. In 10 patients in whom active bleeding was demonstrated (splenic 5, hepatic 2, renal 2, left inferior epigastric artery 1), hemostatic embolization was obtained. RESULTS: Total procedure time did not exceed 80 min. Immediate hemostasis was achieved in all patients. Recurrent bleeding from the liver required additional embolization in one patient. Median length of stay in the intensive care unit was 4 days and median hospital stay was 27 days. All patients survived without significant sequelae. CONCLUSION: The use of a combined CT-angiography suite enables rapid diagnostic investigation and hemostatic embolization in actively bleeding trauma patients. PMID- 10094993 TI - New oily agents for targeting chemoembolization for hepatocellular carcinoma. AB - PURPOSE: The evaluation of new oily agents for targeting chemoembolization for hepatocellular carcinoma. METHODS: Five types of oily preparation were injected into the hepatic artery of 54 rabbits inoculated with VX2 carcinoma cells in order to evaluate (1) the safety of these preparations, (2) their histologic distribution and the amount of agents remaining at tumor sites, and (3) computed tomographic (CT) images obtained. Of these preparations, three were made by mixing non-iodinated poppy seed oil and a thickener and then adjusted to have a viscosity lower than, equal to, or higher than that of lipiodol. A fourth preparation was a mixture of lipiodol and a thickener with a higher viscosity than lipiodol alone, and the fifth preparation was lipiodol alone. RESULTS: (1) No injury to the hepatic parenchyma was observed hematologically or histologically. (2) With increase in the viscosity, a significantly larger amount of agent remained at the tumor site. No agent was present at normal sites 14 days after intraarterial injection, regardless of which preparation was given. (3) On CT scans following intraarterial injection, tumor cells were visibly deeply stained in the non-iodinated preparation groups, while the lipiodol groups were not evaluable because of excessively high attenuation. CONCLUSION: The non iodinated oily preparations and highly viscous oily preparations developed in the present study were more useful than lipiodol for treatment of hepatic tumors. PMID- 10094994 TI - Chronic aortic dissection: stenting of aortic true lumen obliteration with late dynamic variations of both lumens. AB - Percutaneous endovascular techniques were used to treat an arteriovenous fistula (AVF) associated with pancreatic transplantation. A pancreatic transplant superior mesenteric artery-to-superior mesenteric-vein AVF was successfully embolized while flow to the pancreas transplant was preserved. The embolization was aided by the use of Guglielmi detachable coils and a detachable balloon. No complications were encountered. At 23 months follow-up, the patient is doing well with no recurrence. PMID- 10094995 TI - Temporary Strecker stent for management of acute dissection in popliteal and crural arteries. AB - Stent placement is a widely used bail-out treatment for dissection of peripheral arteries. Below the level of the superficial femoral artery permanent stenting is complicated by a high incidence of subacute thrombosis and restenosis. We present two cases of arterial occlusion due to acute iatrogenic dissection of the popliteal and distal fibular arteries. Successful treatment was achieved with a new bail-out procedure. Strecker stents were implanted to seal off the dissection flap. Stents were retrieved easily after 24 hr using a myocardial biopsy forceps. After stent retrieval the temporarily stented segments were patent and showed a larger lumen compared with segments treated by balloon dilatation alone. Temporary stenting is a simple and safe procedure and offers the advantage of tacking up dissection membranes and preventing recoil. Persistent presence of a metallic implant as a source of continued injury and stimulus for intimal proliferation is avoided. PMID- 10094996 TI - Treatment of rectal hemorrhage by coil embolization. AB - Four patients, aged 54-84 years, presenting with life-threatening rectal bleeding from the superior hemorrhoidal artery, underwent percutaneous fibered platinum coil embolization via coaxial catheters. Pre-procedure sigmoidoscopy had failed to identify the source of hemorrhage, because the rectum was filled with fresh blood. Embolization was technically and clinically successful in all four patients. Subsequent sigmoidoscopy confirmed the diagnoses in three patients as a solitary rectal ulcer, iatrogenic traumatic ulceration following manual evacuation, and a rectal Dieulafoy's lesion. The other case was angiographically seen to be due to a rectal angiodysplasia. Embolization is an effective procedure in life-threatening superior hemorrhoidal arterial bleeding when endoscopic treatment fails, and should be preferred to rectosigmoid resection. PMID- 10094997 TI - Percutaneous embolization of a high-flow pancreatic transplant arteriovenous fistula. AB - Percutaneous endovascular techniques were used to treat an arteriovenous fistula (AVF) associated with pancreatic transplantation. A pancreatic transplant superior mesenteric artery-to-superior mesenteric-vein AVF was successfully embolized while flow to the pancreas transplant was preserved. The embolization was aided by the use of Guglielmi detachable coils and a detachable balloon. No complications were encountered. At 23 months follow-up, the patient is doing well with no recurrence. PMID- 10094998 TI - Balloon occlusion versus wedged hepatic venography using carbon dioxide for portal vein opacification during TIPS. AB - Balloon occlusion hepatic venography using carbon dioxide (CO2) is proposed as a safer yet simpler alternative to wedged catheter techniques that have caused hepatic lacerations during the transjugular intrahepatic portosystemic shunt (TIPS) procedure. The image quality of CO2 wedged catheter and balloon occlusion venograms was comparable in our small series, with no venographic-related complications occurring in the balloon occlusion group. PMID- 10094999 TI - Placement of a PTFE-covered Wallstent through a 12 Fr sheath for the exclusion of a common iliac artery aneurysm. AB - We describe a technique for transfemoral endovascular exclusion of an iliac artery aneurysm with a reconstrained polytetrafluoroethylene (PTFE)-covered Wallstent inserted through a 12 Fr sheath after right femoral artery cutdown. The procedure was successfully performed, with evidence of complete aneurysm exclusion at 4-month follow-up. This technique reduces the caliber of the introducer needed to deploy the covered Wallstent. It should be noted that because of a leak, an additional covered Palmaz stent was also deployed. PMID- 10095000 TI - Expandable metallic stent treatment for malignant colorectal strictures. AB - Four patients were treated by placement of an expandable metallic stent (two Gianturco Z-stents, two Ultraflex stents) for malignant colorectal strictures. All four patients were able to defecate after stent placement. Stent migration was recognized in one patient. Two patients suffered from tenesmus after stent placement. PMID- 10095001 TI - Spiral CT of the thoracic aorta with 3-D volume rendering: A pictorial review of current applications. PMID- 10095002 TI - Cystic artery origin of the segment V hepatic artery. PMID- 10095003 TI - Re: Transbrachial selective pulmonary angiography with a 4 Fr catheter via the antecubital approach. PMID- 10095004 TI - Proceedings of the annual meeting of CIRSE Venice, Italy, September 27-October 1, 1998. Cardiovascular and Interventional Radiological Society of Europe. PMID- 10095006 TI - Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. AB - The herbicide paraquat, bearing structural similarity to the known dopaminergic neurotoxicant MPTP, has been suggested as a potential etiologic factor in Parkinson's disease. Consideration of paraquat as a candidate neurotoxicant requires demonstration that systemic delivery produces substantia nigra dopaminergic neuron loss and the attendant neurobehavioral syndrome reflecting depletion of dopamine terminals within the striatum. To address these issues paraquat was administered systemically into adult C57 bl/6 mice, ambulatory behavior monitored, substantia nigra dopamine neuron number and striatal dopamine terminal density quantified. The data indicate that paraquat like MPTP elicits a dose-dependent decrease in substantia nigra dopaminergic neurons assessed by a Fluoro-gold prelabeling method, a decline in striatal dopamine nerve terminal density assessed by measurement of tyrosine hydroxylase immunoreactivity; and neurobehavioral syndrome characterized by reduced ambulatory activity. Taken together, these data suggest that systemically absorbed paraquat crosses the blood-brain barrier to cause destruction of dopamine neurons in the substantia nigra, consequent reduction of dopaminergic innervation of the striatum and a neurobehavioral syndrome similar to the well characterized and bona fide dopaminergic toxin MPTP. PMID- 10095007 TI - Serotonin-immunoreactive neurones in the visual system of the praying mantis: an immunohistochemical, confocal laser scanning and electron microscopic study. AB - The distribution, number, and morphology of serotonin-immunoreactive (5-HTi) neurones in the optic lobe of the praying mantis Tenodera sinensis were studied using conventional microscopy and confocal laser scanning microscopy. Five or six 5-HTi neurones connect the lobula complex with the medulla, and at least 50 5-HTi neurones appear to be confined to the medulla. In addition, a few large 5-HTi processes from the protocerebrum supply the lobula complex, and two large 5-HTi processes from the protocerebrum ramify in the medulla and lamina, where they show wide field arborisations. In order to provide a basis for understanding the action of serotonin in the lamina, the ultrastructure of its 5-HTi terminals was examined by conventional and immunohistochemical electron microscopy. The 5-HTi profiles were filled with dense core vesicles and made synapses. Output synapses from 5-HTi profiles outnumbered inputs by about 3 to 1. The terminals of the 5 HTi neurones were in close contact with cells of various types, including large monopolar cells, but close apposition to photoreceptor terminals was rare, and no synapses were found between 5-HTi terminals and photoreceptor terminals. PMID- 10095008 TI - HIV infection of fetal human astrocytes: the potential role of a receptor mediated endocytic pathway. AB - HIV infects microglia and astrocytes both in vivo and in vitro. Although there is a significant amount of information about microglial infection, data regarding astrocytes are more limited. For example, little is known about the initial membrane events occurring between HIV and astrocytes. Also, the mechanism by which HIV enters these cells remains to be determined. To address these questions, we exposed human astrocyte cultures to either HIV or to the HIV glycoprotein gp120. The cultures were analyzed for viral infection and gp120 binding to cultured cells by light and electron microscopy (EM) with and without immunocytochemistry, respectively; ligand-receptor biochemistry; and, Western, Northern and Southern blot analyses. The results of these studies showed that HIV binds to astrocytes via gp120 and a cell surface molecule weighing approximately 65 kDa that is neither CD4 nor galactocerebroside. Furthermore, binding of gp120 to astrocytes was concentration dependent and displayed a curve consistent with ligand-receptor binding. Additionally, radiolabeled gp120 binding was displaced by unlabeled gp120 but not by deglycosylated gp120, suggesting that the binding was specific. By EM, HIV virions were seen in clathrin-coated pits and in cytoplasmic vacuoles. This suggests linkage, in astrocytes, between a plasma membrane-associated protein that can act as a receptor for HIV and an endosomal pathway. PMID- 10095009 TI - High vulnerability of GABA-immunoreactive neurons to kainate in rat retinal cultures: correlation with the kainate-stimulated cobalt uptake. AB - Like other areas of the central nervous system, the retina is highly vulnerable to ischemia. In particular, neurons in the inner nuclear layer, including gamma amino butyric acid (GABA)-ergic amacrine neurons, are highly vulnerable. Since excitotoxicity is likely a major mechanism of ischemic retinal injury, using rat retinal cell culture, we examined whether GABAergic retinal neurons are differentially vulnerable to particular excitotoxins. The neuronal population as a whole, identified by anti-microtubule associated protein-2 (MAP-2) immunocytochemistry, was equally vulnerable to kainate, but more resistant to N methyl-d-aspartate (NMDA) than cultured cortical neurons. Compared to Thy-1 immunoreactive neurons, GABA immunoreactive neurons were more vulnerable to kainate, but more resistant to NMDA neurotoxicity. Double staining of cultures with anti-GABA immunocytochemistry and the kainate-stimulated cobalt uptake method, revealed a close correlation between the two. However, unlike in other neuronal cells, there was no clear correlation between GluR2 immunoreactivity and the cobalt staining. The heightened vulnerability of GABAergic neurons to kainate, as compared to the general neuronal population, may be due to the calcium-permeable AMPA/kainate receptors they have, as identified functionally by the kainate-stimulated cobalt uptake staining. Since these neurons are preferentially injured in ischemia, AMPA/kainate receptor-mediated neurotoxicity may contribute significantly to ischemic retinal injury. PMID- 10095010 TI - Tonic regulation of the activity of noradrenergic neurons in the locus coeruleus of the conscious rat studied by dual-probe microdialysis. AB - In the present study, receptor specific compounds were infused via a microdialysis probe in the vicinity of the right locus coeruleus (LC). During the infusion of these compounds, the extracellular content of noradrenaline was recorded in the ipsilateral medial prefrontal cortex (mPFC) with a second microdialysis probe. Agonists and antagonists of various subtypes receptors that have been described to be localized on LC cells, were infused near the LC. The receptors investigated were: alpha2-adrenergic, muscarinic, nicotinic, GABAergic (GABAA and GABAB), glutamatergic (NMDA and non-NMDA). The compounds infused were: clonidine (100 microM), idazoxan (50 microM), bicuculline (50 microM), muscimol (50 microM), baclofen (50 microM), CGP52432 (100 microM), NMDA (300 microM), CPP (300 microM), kainate (100 microM), DNQX (500 microM), oxotremorine (100 microM), atropine (10 microM), nicotine (100 microM) and mecamylamine (100 microM). Evidence was provided that GABAA, NMDA, non-NMDA glutamate, and muscarinic cholinergic receptors in the LC played roles in controlling the activity of noradrenaline neurons. The LC noradrenergic neurons were not tonically excitated by glutamatergic or cholinergic afferent neurons, and were not tonically inhibited by alpha2 autoreceptors. Tonic inhibition was evident for GABAergic neurons, acting via GABAA receptors. PMID- 10095011 TI - Extracellular levels of amino acid neurotransmitters during anoxia and forced energy deficiency in crucian carp brain. AB - The crucian carp is one of the few vertebrates that has the ability to survive long periods of anoxia. A devastating event in the anoxic mammalian brain is a massive release of excitatory neurotransmitters, particularly glutamate. Using microdialysis to measure extracellular levels of several amino acid neurotransmitters and related compounds in the telencephalon of crucian carp in vivo, we show here that this species avoids a release of glutamate during anoxia, which is probably related to its ability to maintain energy charge. Instead, 6 h of anoxia produced a doubling of the extracellular level of GABA, the major inhibitory neurotransmitter in brain. The release of GABA may be a mechanism for lowering neuronal activity and energy use, thereby facilitating the maintenance of energy charge. Perfusing the microdialysis probe with a high-K+ Ringer showed that the telencephalon had the ability to release both glutamate and GABA. Moreover, if energy deficiency was produced during anoxia, by inhibiting glycolysis with iodoacetate (IAA), the resulting release of GABA was more rapid and profound than that of glutamate, possibly reflecting a second line of anoxia defence aimed at minimising the effect of a temporary energy failure. PMID- 10095012 TI - Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially affect voluntary ethanol consumption. AB - Dopaminergic projections to the medial prefrontal cortex (mPFC) were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) to examine how dopamine (DA) asymmetry in the mPFC influences voluntary ethanol consumption. Differences in nucleus accumbens (NAS) DA neurotransmission have been related to individual differences in locomotor activity and in the rewarding efficacy of ethanol. Therefore, differences in locomotor activity were used to further characterize the effects of unilateral mPFC 6-OHDA lesions on ethanol consumption. Male Long Evans rats were assessed for high versus low levels of spontaneous locomotor activity. DA terminals in the left or right mPFC were unilaterally lesioned with 6-OHDA, resulting in an average DA depletion of 54% and 50%, respectively. After a minimum seven-day recovery period, preference for a 10% ethanol solution vs. water was determined in a 24-h 2-bottle home-cage free-choice paradigm. Left mPFC 6-OHDA lesions increased and right lesions decreased ethanol consumption. These differential effects of left and right lesions were primarily attributable to rats exhibiting low locomotor activity prior to surgery. The present data suggest that right greater than left cortical DA asymmetry in combination with low endogenous NAS DA (predicted by low locomotor activity levels) may increase the vulnerability to abuse ethanol. PMID- 10095013 TI - Distribution of semaphorin IV in adult human brain. AB - The semaphorins comprise a family of secreted and membrane bound proteins that influence development of the nervous system as well as non-neural organs. H.SemaIV was originally isolated from a homozygously deleted region involving a subset of small cell lung cancers, a neuroendocrine derived neoplasm. To investigate H.SemaIV expression, specific polyclonal antibodies directed against a unique polypeptide (amino acids 758-773) were developed and their specificity confirmed. In cell lines, H.SemaIV staining was observed in cytoplasmic granules. In the normal adult human brain, we noted three general characteristics of H.SemaIV expression. H.SemaIV was strongly present in specific nuclei or in neuronal regions arranged in defined subnuclear structures. It was also present in neurons but not glial cells or ependymocytes. Lastly, H.SemaIV was not present in cell bodies, but rather in fibers and nerve terminals. Interestingly, an altered pattern of staining was detected in brains of three patients with Alzheimer's disease. PMID- 10095014 TI - Rotation, locomotor activity and individual differences in voluntary ethanol consumption. AB - Spontaneous turning behavior and locomotor activity were evaluated for their ability to predict differences in the voluntary consumption of ethanol in male Long-Evans rats. Animals were assessed for their preferred direction of turning behavior and for high vs. low levels of spontaneous locomotor activity, as determined during nocturnal testing in a rotometer. Subsequently, preference for a 10% ethanol solution vs. water was determined in a 24-h two-bottle home-cage free-choice paradigm. Rats exhibiting a right-turning preference consumed more ethanol than rats showing a left-turning preference. While locomotor activity alone did not predict differences in drinking, turning and locomotor activity together predicted differences in ethanol consumption. Low-activity right-turning rats consumed more ethanol than all the other groups of rats. Previous studies from this laboratory have shown that individual differences in turning behavior are accompanied by different asymmetries in dopamine (DA) function in the medial prefrontal cortex (mPFC). Individual differences in locomotor activity are associated with differences in nucleus accumbens (NAS) DA function. The present data suggest that variations in mPFC DA asymmetry and NAS DA function may underlie differences in the voluntary consumption of ethanol. PMID- 10095015 TI - Protection against amyloid beta peptide toxicity by zinc. AB - Zinc (Zn) is an essential element in normal development and biology, although it is toxic at high concentrations. Recent studies show that Zn at high concentrations accelerates aggregation of amyloid beta peptide (Abeta), the major component of senile plaques in Alzheimer's disease (AD). This study reports the effect of varying Zn concentrations on Abeta toxicity and the mechanism by which low concentrations function in a protective role. At Abeta/Zn molar ratios of 1:0.1 and 1:0.01, Zn produces significant protection against Abeta toxicity in cultured primary hippocampal neurons. At higher concentrations (1:1 molar ratio), Zn offers no protection or enhances Abeta toxicity. The protective effect of Zn against Abeta toxicity is due in part to the enhancement of Na+/K+ ATPase activity which prevents the disruption of calcium homeostasis and cell death associated with Abeta toxicity. Analysis of Na+/K+ ATPase activity in cultured rat cortical cells indicated that Zn exposure alone afforded a 20% increase in enzyme activity, although the differences were statistically insignificant. However, in cortical cultures exposed to a toxic dose of Abeta (50 microM), Zn at concentrations of 5 and 0.5 microM led to significant increases in Na+/K+ ATPase activity compared with levels in cells treated with Abeta alone. Zn at a 1:1 molar ratio (50 microM) led to a significant decrease in enzyme activity. Together, these data suggest that Zn functions as a double-edged sword, affording protection against Abeta at low concentrations and enhancing toxicity at high concentrations. PMID- 10095016 TI - Intra-uterine growth restriction differentially regulates perinatal brain and skeletal muscle glucose transporters. AB - Employing Western blot analysis, we investigated the effect of maternal uterine artery ligation causing uteroplacental insufficiency with asymmetrical intrauterine growth restriction (IUGR) upon fetal (22d) and postnatal (1d, 7d, 14d and 21d) brain (Glut 1 and Glut 3) and skeletal muscle (Glut 1 and Glut 4) glucose transporter protein concentrations. IUGR was associated with a approximately 42% decline in fetal plasma glucose (p<0.05) and a approximately 25% decrease in fetal body weights (p<0.05) with no change in brain weights when compared to the sham operated controls (SHAM). In addition, IUGR caused a approximately 45% increase in fetal brain Glut 1 (55 kDa) with no change in Glut 3 (50 kDa) protein concentrations. This fetal brain Glut 1 change persisted, though marginal, through postnatal suckling stages of development (1d-21d), with no concomitant change in brain Glut 3 levels at day 1. In contrast, in the absence of a change in fetal skeletal muscle Glut 1 levels (48 kDa), a 70% increase was observed in the 1d IUGR with no concomitant change in either fetal or postnatal Glut 4 levels (45 kDa). The change in skeletal muscle Glut 1 levels normalized by d7 of age. We conclude that IUGR with hypoglycemia led to a compensatory increase in brain and skeletal muscle Glut 1 concentrations with a change in the brain preceding that of the skeletal muscle. Since Glut 1 is the isoform of proliferating cells, fetal brain weight changes were not as pronounced as the decline in somatic weight. The increase in Glut 1 may be protective against glucose deprivation in proliferating fetal brain cells and postnatal skeletal myocytes which exhibit 'catch-up growth', thereby preserving the specialized function mediated by Glut 3 and Glut 4 towards maintaining the intracellular glucose milieu. PMID- 10095017 TI - Discriminant power of combined cerebrospinal fluid tau protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease. AB - Alzheimer's disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of tau protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that tau protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF tau protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability. PMID- 10095018 TI - Effect of development and hypoxic-ischemia upon rabbit brain glucose transporter expression. AB - We have cloned and sequenced a full length rabbit GLUT 1 and partial rabbit GLUT 3 cDNAs. The derived rabbit GLUT 3 peptide revealed 84% homology to the mouse, 82% to the rat, human, dog, and sheep, and 69% to the chicken GLUT 3 peptides. Using Northern blot analysis, we investigated the tissue and brain cellular distribution of GLUT 1 and GLUT 3 expression. In addition, we examined the effect of development and hypoxic-ischemia upon brain GLUT 1 and GLUT 3 mRNA levels. While GLUT 1 mRNA was observed in most tissues, GLUT 3 was expressed predominantly in the brain, placenta, stomach, and lung with minor amounts in the heart, kidney and skeletal muscle. In the brain, both GLUT 1 and GLUT 3 were noted in neuron- and glial-enriched cultures. Both GLUT 1 and GLUT 3 mRNA levels demonstrated a similar developmental progression (p<0.05) secondary to post transcriptional mechanisms. Further, while hypoxic-ischemia did not significantly affect brain GLUT 1 mRNA and protein, it altered GLUT 3 mRNA levels in a region specific manner, with a three-fold increase in the cerebral cortex, a two-fold increase in the hippocampus, and a 50% increase in the caudate nucleus (p<0.05). We conclude, that the rabbit GLUT 3 peptide sequence exhibits 82-84% homology to that of other species in the coding region with a 62-89% sequence identity in the 3'-untranslated region. The tissue-specific expression of rabbit GLUT 3 mimics that of the human closely. Postnatal development and hypoxic-ischemia with reperfusion injury cause an increase in brain GLUT 3 expression, as a response to synaptogenesis and substrate deprivation, respectively. PMID- 10095019 TI - A quantitative analysis of G-actin binding proteins and the G-actin pool in developing chick brain. AB - The large G-actin pool in individual actively motile cells has been shown to be maintained primarily by the actin sequestering protein thymosin beta four (Tbeta4). It is not clear whether Tbeta4 or an isoform also plays a primary role in neural tissue containing highly motile axonal growth cones. To address this question we have made a definitive analysis of the relative contributions of all the known G-actin sequestering proteins: Tbeta4, Tbeta10, profilin, and phosphorylated (inactive) and unphosphorylated (potentially active) forms of both ADF and cofilin, in relation to the G-actin pool in developing chick brain at embryonic days 13 and 17. From our measurements we estimate the intracellular concentration of G-actin as 30-37 microM and of Tbeta4 as 50-60 microM in an 'average' brain cell in embryonic chick brain. No other beta thymosin isoforms were detected in these brain extracts. The ratio of soluble, unphosphorylated ADF to Tbeta4 is only 1:7 at 13 embryonic days, but increases to 1:4 at 17 days. Profilin and cofilin concentrations are an order of magnitude lower than Tbeta4. Combining the contributions of Tbeta4, unphosphorylated ADF and unphosphorylated cofilin, we estimate a mean G-actin critical concentration of approximately 0.45 microM and approximately 0.2 microM, respectively, in day 13 and day 17 embryonic brain extracts, suggesting a significant developmental decrease. We conclude that (a) Tbeta4 is the major actin sequestering protein in embryonic chick brain and the only beta thymosin isoform present; (b) ADF may play a significant developmental role, as its concentration changes significantly with age; (c) the known G-actin binding proteins can adequately account for the G-actin pool in embryonic chick brain. PMID- 10095020 TI - Induction of microtubule-associated protein 1B expression in Schwann cells during nerve regeneration. AB - Microtubule-associated protein 1B (MAP1B) is expressed at high levels during development of the nervous system and is localized primarily in neurons while specific phosphorylated isoforms of MAP1B are localized exclusively in growing axons. The levels of MAP1B are down regulated in most regions of the adult CNS, but remain high in neurons and axons of the PNS. This study demonstrates that the expression of MAP1B is induced in adult Schwann cells following sciatic nerve lesion and regeneration. High levels of both mRNA and the MAP1B protein were detected in Schwann cells associated with the axotomized distal stump. Expression of MAP1B was also observed in cultured primary Schwann cells from neonatal rats. The properties of the MAP1B protein in cultured Schwann cells were further characterized by Western blot analysis using specific antibodies that recognize the N-terminal, middle and C-terminal domains of MAP1B. All of these antibodies detected a protein of 320-340 kDa demonstrating that MAP1B expressed by Schwann cells is very similar, or identical, to MAP1B expressed by neurons. The phosphorylation of MAP1B in Schwann cells was also studied using monoclonal antibodies (mAb) that recognize specific phosphorylation epitopes. The results indicated that the expression of MAP1B in Schwann cells exhibited a differential phosphorylation state that was recognized by mAb 1B6 but not by other mAbs, including 1B-P, 150 and RT97, that recognize phosphorylated MAP1B in growing axons. We therefore conclude that MAP1B is expressed in Schwann cells during both development and axonal regeneration, suggesting that the developmental pattern of MAP1B in these cells is recapitulated in adult Schwann cells during the early stages of regeneration and remyelination of injured peripheral axons. The presence of MAP1B in Schwann cells may support morphological changes of these cells, particularly the formation of processes prior to their differentiation into myelin forming Schwann cells. PMID- 10095021 TI - Rectifying effect of exercise on hypertension in spontaneously hypertensive rats via a calcium-dependent dopamine synthesizing system in the brain. AB - The effect of exercise on blood pressure in spontaneously hypertensive rats (SHR) was investigated assuming a mechanism involving calcium-dependent dopamine synthesis in the brain. Male SHR (13 weeks of age) were forced to run for 1 h at a speed of 10 m/min using a programmed motor-driven wheel cage. Systolic blood pressure was reduced after running, and this effect of exercise was decreased by prior intracerebroventricular administration of EDTA (1 nmol/rat), alpha methyltyrosine (inhibitor of tyrosine hydroxylase, 1 mg/rat), sulpiride (D2 receptor antagonist, 50 microg/rat) or eticlopride (D2 receptor antagonist, 100 microg/rat), but was not changed by administration of SCH 23390 (D1 receptor antagonist, 30 microg/rat). Also, the calcium levels in the serum and brain were increased by exercise. Combining these results with our previous reports, it is suggested that exercise leads to an increase in the serum calcium level and subsequently an increase in the brain calcium level. This, in turn, leads to increased brain dopamine synthesis through a calmodulin-dependent system, with the increased dopamine levels inhibiting sympathetic nerve activity via the dopamine D2 receptor in the brain and causing a reduction in blood pressure. PMID- 10095022 TI - Inositol-1,4,5-trisphosphate accumulation induced by urinary pheromones in female rat vomeronasal epithelium. AB - The mechanisms involved in pheromone-induced responses in the vomeronasal neurons, especially in mammals, are still unclear. In the present study, we examined the effects of rat urine samples containing various types of pheromones regulating gonadal functions on the accumulation of cAMP and inositol 1,4,5 trisphosphate (IP3) in a vomeronasal membrane preparation from the female Wistar rat. Stimulation of the preparation with forskolin induced cAMP accumulation, but stimulation with urine samples excreted from the male Wistar rat, the female Wistar rat, and the male Donryu rat did not change cAMP levels. These results were consistent with the electrophysiological results showing that dialysis of a high concentration of cAMP into the vomeronasal neuron does not induce currents. Stimulation with the three urine samples induced the accumulation of IP3 in the membrane preparation. These results are consistent with previous electrophysiological results [K. Inamura, M. Kashiwayanagi, K. Kurihara, Inositol 1,4,5-trisphosphate induces responses in receptor neurons in rat vomeronasal sensory slices, Chem. Senses 22 (1997) 93-103; K. Inamura, M. Kashiwayanagi, K. Kurihara, Blockage of urinary responses by inhibitors for IP3-mediated pathway in rat vomeronasal sensory neurons, Neurosci. Lett. 233 (1997) 129-132]. After the treatment with Pertussis toxin (PTX), the male Wistar urine did not induce IP3 accumulation significantly. Application of the male Wistar urine decreased ADP ribosylation of Gi with PTX, while that of the male Donryu urine decreased ADP ribosylation of Go. Thus, the present results support a mechanism by which the responses of the rat vomeronasal neurons to urinary pheromones are mediated by IP3, Gi and/or Go. PMID- 10095023 TI - The nonpeptide alpha-eudexp6l from Juniperus virginiana Linn. (Cupressaceae) inhibits omega-agatoxin IVA-sensitive Ca2+ currents and synaptosomal 45Ca2+ uptake. AB - Recently, the omega-agatoxin IVA (omega-Aga-IVA)-sensitive Ca2+ channel has been demonstrated to play an important role in the physiological neurotransmitter release in mammalian nerve terminals. In this study, we demonstrate that alpha eudesmol from Juniperus virginiana Linn. (Cupressaceae) inhibits omega-Aga-IVA sensitive Ca2+ channels in rat brain synaptosomes and cerebellar Purkinje cells. Thirty millimolar KCl-induced 45Ca2+ uptake into the synaptosomes was inhibited by omega-Aga-IVA but insensitive to omega-conotoxin GVIA (omega-CTX-GVIA, N-type Ca2+ channel blocker) and nicardipine (L-type Ca2+ channel blocker). We found that alpha-eudesmol concentration-dependently inhibited the above synaptosomal 45Ca2+ uptake with an IC50 value of 2.6 microM. Co-treatment with alpha-eudesmol and omega-Aga-IVA did not cause any additive inhibitory effect against the synaptosomal 45Ca2+ uptake. Using the whole-cell patch clamp electrophysiological technique, we further demonstrated that alpha-eudesmol concentration-dependently inhibited omega-Aga-IVA-sensitive Ca2+ channel currents recorded from Purkinje cells with an IC50 value of 3.6 microM. The current-voltage relationship of the omega-Aga-IVA-sensitive Ca2+ channel currents was not changed by alpha-eudesmol. On the other hand, alpha-eudesmol also displayed an inhibitory effect on N-type Ca2+ channel currents recorded from differentiated NG108-15 cells with an IC50 value of 6.6 microM. However, alpha-eudesmol had little inhibitory effect on L type Ca2+ channel currents. Thus, the present data indicated that alpha-eudesmol is a potent nonpeptidergic compound which blocks the presynaptic omega-Aga-IVA sensitive Ca2+ channel with relative selectivity. PMID- 10095024 TI - Increased nitrotyrosine immunoreactivity in substantia nigra neurons in MPTP treated baboons is blocked by inhibition of neuronal nitric oxide synthase. AB - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase. We previously demonstrated that administration of 7-NI is effective in blocking MPTP toxicity in both mice and baboons. This was suggested to be due to inhibition of the generation of peroxynitrite which can nitrate tyrosines. In the present study we found increased 3-nitrotyrosine immunoreactivity in the substantia nigra of MPTP treated baboons, which was blocked by coadministration of 7-NI. These findings provide further evidence that peroxynitrite may play a role in MPTP induced parkinsonism in baboons. PMID- 10095025 TI - Involvement of P2 purinoceptors and the nitric oxide pathway in [3H]purine outflow evoked by short-term hypoxia and hypoglycemia in rat hippocampal slices. AB - The objective of this study was to study how the outflow of [3H]purines is altered during a brief period of ischemic-like conditions in superfused hippocampal slices and to show whether it is regulated by P2 purinoceptors and the nitric oxide (NO) pathway. The outflow of [3H]purines increased in response to 5 min of combined hypoxia/hypoglycemia. High performance liquid chromatography analysis verified the efflux of [3H]adenosine-triphosphate, [3H]adenosine diphosphate, [3H]adenosine-monophosphate, [3H]adenosine, [3H]inosine, and [3H]hypoxanthine in response to ischemic-like conditions. The P2 receptor antagonists suramin and pyridoxal-phosphate-6-azophenyl-2'-4'-disulphonic-acid tetrasodium (PPADS) reduced significantly the [3H]purine efflux evoked by ischemic-like conditions, showing that P2 purinoceptors are involved in the initiation of purine outflow. The NO synthase inhibitor N-nitro-l-arginine-methyl ester (l-NAME) attenuated significantly the [3H]purine outflow, evoked by ischemic-like conditions, while 7-nitroindazole (7-NI) caused only a mild decrease in the outflow. The NO donor sodium nitroprusside increased significantly the basal efflux of [3H]purines. In summary, a brief period of combined hypoxia/hypoglycemia induced the efflux of ATP in addition to the outflow of other purines. Since P2 receptor antagonists decreased the [3H]purine outflow evoked by ischemic-like conditions we propose that ATP, acting on P2 purinoceptors, is responsible for further efflux of purines after ischemic-like period. It seems likely that NO is also involved in the regulation of purine outflow, since inhibition of NO production attenuated the [3H]purine outflow, evoked by ischemic-like conditions, while exogenous NO facilitated the basal outflow. PMID- 10095026 TI - Effects of enadoline on the development of pentylenetetrazol kindling, learning performance, and hippocampal morphology. AB - Opioids are involved in the development of epileptic seizures. Recently, interest has been focused on the role of the kappa-opioid receptor agonists as novel approaches to the treatment of epilepsy. In the present study we investigated the effects of the kappa-opioid receptor agonist enadoline (Ena) on pentylenetetrazol (PTZ) induced seizures, PTZ kindling, shuttle-box performance and hippocampal neuromorphology. Ena injected i.c.v. in doses of 1 and 10 nmol did not affect acute PTZ seizures. In the course of PTZ kindling development, co-treatment (1 nmol) with the kappa-opioid receptor agonist suppressed seizure strength. Eight days after kindling completion the animals received a challenge dose of PTZ. In reaction to challenge, kindled animals which were pretreated with Ena reached significantly lower seizure scores. Kindling resulted in diminished shuttle-box performance. Learning performance in kindled animals pretreated with Ena was not normalised. Kindling resulted in increased glutamate binding. Interestingly, in comparison with the saline/saline group, neither in the Ena/saline nor in the Ena/PTZ treated groups changes in glutamate binding were found. That means that Ena prevented the increase in glutamate binding in the kindled group. In kindled animals significant cell loss in CA1 of the dorsal hippocampus was found and this was efficaciously counteracted by Ena. However, Ena alone did induce similar cell loss compared to kindled animals. It is hypothesised that the effects of enadoline are mainly due to interferences with glutamatergic systems. PMID- 10095027 TI - Distribution of 5-hydroxytryptamine-immunoreactive boutons on immunohistochemically-identified Renshaw cells in cat and rat lumbar spinal cord. AB - A combination of anti-gephyrin- and anti-calbindin D28k-immunoreactivity was used to identify 129 and 171 Renshaw cells and their dendrites in cat and rat lumbar spinal cord, respectively. Using anti-5-hydroxytryptamine-immunoreactivity to label serotoninergic fibers and boutons, 1048 serotoninergic boutons were observed in close contact with the immunolabeled Renshaw cells, with an average of 4.4 and 2.8 close contacts on cat and rat Renshaw cells, respectively. Two thirds of the observed appositions were formed on the somatic membrane. PMID- 10095028 TI - Immunohistochemical localization of amyloid beta-protein with amino-terminal aspartate in the cerebral cortex of patients with Alzheimer's disease. AB - We investigated immunohistochemically the localization of amyloid beta-protein (Abeta) with amino-terminal aspartate (N1[D]) in brains of patients with Alzheimer's disease, diffuse Lewy body disease and Down's syndrome. A monoclonal antibody, 4G8, which recognizes the middle portion of Abeta, was used as a reference antibody to label the total Abeta deposits. Double staining with anti Abeta(N1[D]) and 4G8 revealed that Abeta deposits in the subiculum and the neocortical deep layers often lacked N1[D] immunoreactivity, indicating N terminal truncation of Abeta in these deposits. Abeta deposits in the neocortical superficial layers and the presubicular parvopyramidal layer always contained Abeta with N1[D]. Such regional as well as laminar differences in the distribution of Abeta beginning at N1[D] suggest that some local factors influence N-terminal processing of Abeta deposited in the brain. PMID- 10095029 TI - Ethanol induced differences in medial prefrontal cortex dopamine asymmetry and in nucleus accumbens dopamine metabolism in left- and right-turning rats. AB - Ethanol (0.5 g/kg i.p.) 15 min prior to sacrifice increased homovanillic acid (HVA) levels in the left medial prefrontal cortex (mPFC) of left-turning rats and in the right mPFC of right-turning rats. In the nucleus accumbens (NAS), ethanol decreased dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and HVA levels in rats that exhibited low levels of locomotor activity but not in rats that exhibited high levels of locomotor activity. This laboratory has previously shown that rats exhibiting differences in turning and locomotor activity behavior display different preferences for ethanol. The present results suggest that ethanol-induced differences in mPFC and NAS DA activity may be related to individual differences in the susceptibility to abuse ethanol. PMID- 10095030 TI - Ibogaine blocked methamphetamine-induced hyperthermia and induction of heat shock protein in mice. AB - Body temperature changes and heat shock protein (HSP-72) induction in the caudate nucleus were studied in female C57BL/6N mice pretreated with ibogaine (50 mg/kg) and sacrificed 48 h. after a single dose of methamphetamine (20 mg/kg). Methamphetamine injection resulted in hyperthermia and induced HSP-72 expression, whereas treatment with ibogaine alone produced hypothermia. The ibogaine followed by methamphetamine injection showed no hyperthermia and decreased HSP-72 expression. These data indicate that pretreatment with ibogaine can completely block methamphetamine-induced hyperthermia and HSP-72 expression in the striatum. PMID- 10095031 TI - Chronic clomipramine administration reverses NMDA-evoked decreases in dopamine release in the raphe nuclei. AB - The effect of acute or chronic treatment with the antidepressant clomipramine (CIM) on basal and N-methyl-d-aspartate (NMDA) evoked release of dopamine (DA) in rat raphe has been studied using microdialysis. Acute injection of CIM (10 or 20 mg/kg) caused a decrease in raphe DA release, as did infusion of NMDA (25-100 microM) into this region. When NMDA infusion was preceded by a single acute injection of CIM no differences between NMDA and NMDA plus CIM treated groups was observed. Chronic (15 day) treatment with CIM caused a dose-dependent increase in basal extracellular DA. In addition the effect of infusing NMDA into the raphe on DA release was markedly reduced or abolished. This suggests that adaptive changes occur in NMDA receptor function during treatment with CIM. PMID- 10095032 TI - Corticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes in rats. AB - We investigated whether corticotropin-releasing factor (CRF) receptor type 1 (CRFR1) is involved in emotional stress-induced inhibition of food intake and behavioral changes in rats. The inhibition of food intake and increase in locomotor activity induced by emotional stress using a communication box were reversed by both intracerebroventricular injection of alpha-helical CRF (9-41), a non-selective CRF receptor antagonist, and intraperitoneal injection of a selective non-peptidic CRFR1 antagonist. These results suggest that CRFR1 mediates at least in part the emotional stress-induced inhibition of feeding behavior and increase in locomotor activity. PMID- 10095033 TI - Possible involvement of p38 MAP kinase in HSP70 expression induced by hypoxia in rat primary astrocytes. AB - The aim of this study was to elucidate the possible mechanism of HSP induction in response to hypoxia in rat primary astrocytes. Treatment with SB203580, a selective p38 MAP kinase (p38 MAPK) inhibitor, attenuated the increase in HSP70 in a concentration-dependent manner. p38 MAPK was activated in response to hypoxic treatment. These results suggest that p38 MAPK positively regulates hypoxia-induced HSP70 expression in astrocytes. PMID- 10095034 TI - An intrinsic neuronal-like network in the rat pineal gland. AB - Recent studies have shown that in rat pineal glands kept in vitro action potential-producing cell clusters are demonstrable. To test whether the clusters interact, multiple-unit recordings were carried out simultaneously from different clusters, with or without electrical stimulation. Clusters with rhythmic burst activity exhibit highly synchronized firing and electrical stimulation of one cluster elicits an immediate response in another one, apparently involving synapses but not gap junctions. It is hypothesized that the interacting clusters form a network. As the firing is affected by norepinephrine, acetylcholine and Ca2+, the network may monitor the interstitial concentrations of these substances and spread this information in the gland, to modulate melatonin secretion. PMID- 10095035 TI - Modulation of serotonin 5-HT3 receptor expression in injured adult rat spinal cord motoneurons. AB - The effects of sciatic nerve lesions on the expression of serotonin 5-HT3 receptor (5-HT3R) alpha subunit in motoneurons of the spinal cord was investigated by semi-quantitative immunohistochemistry. Following sciatic nerve crush, a significant reduction in density of staining in motoneurons was observed in longitudinal sections of the ventral horn at 3 and 15 days on the lesioned side when compared to the contralateral side (p<0.01). At 30 days after crush, after completion of sciatic nerve regeneration and reinnervation of peripheral targets, intensity of staining had returned to normal. Conversely, after sciatic nerve cut, a lesion that does not allow for target reinnervation, highly significant reductions were observed at 3, 15, 30 and 45 days. These results suggest a role for functional contacts with muscular targets in the maintenance of 5-HT3R expression in spinal motoneurons. PMID- 10095036 TI - Regenerative sprouting of retinal ganglion cells of adult hamsters induced by the epineurium of a peripheral nerve. AB - Although it is known that transplantation of a peripheral nerve (PN) to the damaged central nervous system (CNS) promotes axonal regeneration, the interactions of cellular components of the PN with CNS neurons are still not well defined. Schwann cells in the PN are thought to be the major element involved in supporting CNS regeneration, but very little information exists with regard to whether other PN components also play an active role. Using our previously established model of transplanting a PN segment into the vitreous to stimulate regenerative sprouting of retinal ganglion cells (RGCs), we found that the epineurium isolated from a PN which had been pre-injured by transection was able to induce RGC sprouting when implanted intravitreally. Since the epineurium is composed mainly of connective tissue components and is devoid of Schwann cells, our results suggest that other cellular elements of the PN besides Schwann cells may have the potential to support CNS regeneration. PMID- 10095037 TI - Fos expression in the cat brainstem after unilateral vestibular neurectomy. AB - Immediate early genes are generally expressed in response to sensory stimulation or deprivation and can be used for mapping brain functional activity and studying the molecular events underlying CNS plasticity. We immunohistochemically investigated Fos protein induction in the cat brainstem after unilateral vestibular neurectomy (UVN), with special reference to the vestibular nuclei (VN) and related structures. Fos-like immunoreactivity was analyzed at 2, 8, and 24 h, and 1 and 3 weeks after UVN. Data from these subgroups of cats were quantified in light microscopy and compared to those recorded in control and sham-operated animals submitted to anesthesia and anesthesia plus surgery, respectively. Results showed a very low level of Fos expression in the control and sham conditions. By contrast, Fos was consistently induced in the UVN cats. Asymmetrical labeling was found in the medial, inferior, and superior VN (ipsilateral predominance) and in the prepositus hypoglossi (PH) nuclei and the beta subnuclei of the inferior olive (betaIO) (contralateral predominance). Symmetrical staining was observed in the autonomic, tegmentum pontine, pontine gray, locus coeruleus and other reticular-related nuclei. As a rule, Fos expression peaked early (2 h) and declined progressively. However, some brainstem structures including the ipsilateral inferior VN and the bilateral pontine gray nuclei displayed a second peak of Fos expression (24 h-1 week). By comparing these data to the behavioral recovery process, we conclude that the early Fos expression likely reflects the activation of neural pathways in response to UVN whereas the delayed Fos expression might underlie long-term plastic changes involved in the recovery process. PMID- 10095038 TI - Gold-thioglucose-induced hypothalamic lesions inhibit metabolic modulation of light-induced circadian phase shifts in mice. AB - The circadian clock located in the suprachiasmatic nuclei is entrained by the 24 h variation in light intensity. The clock's responses to light can, however, be reduced when glucose availability is decreased. We tested the hypothesis that the ventromedial hypothalamus, a key area in the integration of metabolic and hormonal signals, mediates the metabolic modulation of circadian responses to light by injecting C57BL/6J mice with gold-thioglucose (0.6 g/kg) which damages glucose-receptive neurons, primarily located in the ventromedial hypothalamus. Light pulses applied during the mid-subjective night induce phase delays in the circadian rhythm of locomotor activity in mice kept in constant darkness. As previously observed, light-induced phase delays were significantly attenuated in fed mice pre-treated with 500 mg/kg i.p. 2-deoxy-D-glucose and in hypoglycemic mice fasted for 30 h, pre-treated with 5 IU/kg s.c. insulin or saline, compared to control mice fed ad libitum. In contrast, similar metabolic challenges in mice with gold-thioglucose-induced hypothalamic lesions did not significantly affect light-induced phase delays compared to mice treated with gold-thioglucose and fed ad libitum. These results indicate that destruction of gold-thioglucose-sensitive neurons in the ventromedial hypothalamus prevent metabolic regulation of circadian responses to light during shortage of glucose availability. Therefore, the ventromedial hypothalamus may be a central site coordinating the metabolic modulation of light-induced phase shifts of the circadian clock. PMID- 10095039 TI - Fluoxetine-induced plasticity in the rodent visual system. AB - We studied the effect of fluoxetine, a selective serotonin reuptake inhibitor, in the development and lesion-induced plasticity of retinotectal axons in pigmented rats. Neonatal rats received a daily injection of either fluoxetine or vehicle from postnatal day 1 (PND 1) to PND 10 or from PND 14 to PND 28 (fluoxetine, 7.5 and 10.0 mg/kg, respectively). In the latter group, some animals received a single lesion at the temporal periphery of the left retina at PND 21. Unoperated animals were use as the control. At the end of the treatment, the animals received an intraocular injection of horseradish peroxidase (HRP) in the right (intact) eye to trace the uncrossed retinotectal pathway. Chronic fluoxetine treatment, induced, in unoperated rats, an expansion of the retinal terminal fields along the rostro-caudal axis of the tectum both in the PND 10 and PND 28 groups. Following a retinal lesion in the left eye at PND 21, the vehicle-treated group showed a small reorganization of the intact uncrossed projection. In this group only a few terminals were labeled invading the denervated tectal surface one-week after the lesion. Fluoxetine-treated animals on the other hand, showed a great amplification of plasticity with a conspicuous sprouting of the uncrossed retinal axons into denervated areas. The data suggest that fluoxetine induces extensive axonal rearrangements in neonatal and juvenile central nervous system and amplifies neuroplasticity following retinal lesions late in development. PMID- 10095041 TI - Dorsal raphe nucleus serotonergic neurons innervate the rostral ventrolateral medulla in rat. AB - Stimulation of the dorsal raphe nucleus (DRN) alters arterial pressure, heart rate and cerebral blood flow, yet projections from the DRN to medullary autonomic nuclei have not been described. We examined whether serotonergic (5-HT) projections from the DRN terminate in the rostral ventrolateral medulla (RVL) and if so, whether the projection mediates cardiovascular responses to DRN stimulation. Studies were performed in adult male Sprague-Dawley rats. Horseradish peroxidase or choleratoxin B was injected unilaterally or bilaterally into the RVL. Levels of 5-HT, its precursors L-tryptophan and 5-hydroxytryptophan and the metabolite 5-hydroxyindole acetic acid were measured in the ventral medulla by HPLC three weeks following placement of electrolytic lesions in DRN. Serotonin transporter (3H-cyanoimipramine binding) was quantified by autoradiography in DRN-lesioned animals. Horseradish peroxidase or choleratoxin B injections into the medulla at the level of the RVL resulted in retrogradely labeled neurons bilaterally, with ipsilateral predominance, in the DRN. Labeled cells were preponderant in rostral ventrolateral portions of the DRN, but were also observed in the dorsal, lateral and interfascicular DRN subnuclei; fewer neurons were observed in caudal portions of the DRN. Three weeks following placement of electrolytic lesions in the DRN, the concentrations of 5-HT and 5 hydroxyindole acetic acid, but not L-tryptophan or 5-hydroxytryptophan, were reduced in the medulla by 45 and 48%, respectively, compared to sham-operated or unoperated controls. DRN lesions reduced binding to the 5-HT transporter in the RVL by approximately 30% compared to unlesioned controls. Unilateral lesions of the RVL reduced the evoked blood pressure response by 53+/-15%; bilateral RVL lesions reduced the response by 86+/-9%. The increase in cortical blood flow elicited by DRN stimulation was unchanged after unilateral or bilateral RVL lesions. These studies demonstrate that there is a descending serotonergic projection from the DRN to the RVL. This projection may mediate autonomic changes elicited by DRN stimulation. PMID- 10095040 TI - Cerebral cortical blood flow maps are reorganized in MAOB-deficient mice. AB - Cerebral cortical blood flow (CBF) was measured autoradiographically in conscious mice without the monoamine oxidase B (MAOB) gene (KO, n=11) and the corresponding wild-type animals (WILD, n=11). Subgroups of animals of each genotype received a continuous intravenous infusion over 30 min of phenylethylamine (PEA), an endogenous substrate of MAOB, (8 nmol g-1 min-1 in normal saline at a volume rate of 0.11 microl g-1 min-1) or saline at the same volume rate. Maps of relative CBF distribution showed predominance of midline motor and sensory area CBF in KO mice over WILD mice that received saline. PEA enhanced CBF in lateral frontal and piriform cortex in both KO and WILD mice. These changes may reflect a differential activation due to chronic and acute PEA elevations on motor and olfactory function, as well as on the anxiogenic effects of this amine. In addition to its effects on regional CBF distribution, PEA decreased CBF globally in KO mice (range -31% to -41% decrease from control levels) with a lesser effect in WILD mice. It is concluded that MAOB may normally regulate CBF distribution and its response to blood PEA. PMID- 10095042 TI - Concentration-dependent effects of muscimol to enhance pulsatile GnRH release from GT1-7 neurons in vitro. AB - Immortalized GT1-7 neurons were used to characterize the effect of muscimol, a GABAA receptor agonist, to enhance pulsatile gonadotropin-releasing hormone (GnRH) release. GT1-7 neurons were grown on Cytodex-3 beads and placed in special superfusion microchambers. The cells were superfused at a rate of 6.2 ml x h-1 with Media 199 (pH 7.35) using a commercially available perfusion system. After a pre-muscimol period of 120 min, the cells were exposed for 5 min to 0.35, 1, 5 or 10 microM muscimol or 5 microM muscimol+20 microM of the GABAA receptor antagonist, bicuculline. Following removal of the muscimol (and bicuculline, in the case of the latter experiment), the superfusion was continued for another 115 min. Sample fractions were collected at 5 min intervals throughout the perfusion. Basal GnRH release from the GT1-7 neurons was pulsatile with an average interpulse interval of 45.4+/-0.5 min and an average pulse amplitude of 191.5+/ 22.6 pg x min x ml-1. Our results also demonstrated that the GABAA receptor agonist, muscimol, enhances pulsatile GnRH release from GT1-7 neurons in culture. The response to muscimol was saturable and concentration-dependent with an EC50 of 0.47 microM. The effects of 5 microM muscimol to increase GnRH pulsatility were blocked by co-exposure to the GABAA receptor antagonist, bicuculline. The average GnRH interpulse intervals were 41.7+/-1.8 min, 32.5+/-2.9 min, 30.6+/-0.7 min and 25.5+/-0.4 min in the period following exposure to 0.35, 1, 5 and 10 microM of muscimol, respectively (post-muscimol period). GnRH pulse amplitude (mean-area for each pulse) was increased during exposure to muscimol but not during the pre- or post-muscimol periods. The GABAA receptor antagonist, bicuculline, itself had no effect on pulsatile GnRH release. These results are consistent with previously published reports suggesting that activation of the GABAA receptor stimulates hypothalamic GnRH release in embryonic and neonatal animals. PMID- 10095043 TI - Expression of muscarinic m2 receptor mRNA in dorsal root ganglia of neonatal rat. AB - The expression of mRNA coding for m2 subtype of muscarinic cholinergic receptors was assessed in dorsal root ganglia (DRG) of 15-day post-natal rats. Northern blot analysis on total RNA using a mixture of two different oligonucleotide probes, indicated the presence of a single prominent band of approximately 6.5 kb in rat DRG; a band of the same size was observed both in brainstem and cortex taken as positive controls. Analysis by RT-PCR of the mRNA coding for a region of the third cytoplasmic loop of m2 receptor showed a single signal both in rat DRG and hippocampus. In situ hybridization was then used to identify the neuronal subpopulations expressing the mRNA for M2. The transcripts were preferentially localized in medium-small neurons of the ganglion as well as in satellite cells surrounding the neuron cell body. Large neurons were usually negative. Finally, competition binding experiments, performed in the presence of [3H]-quinuclidinyl benzilate (QNB) and methoctramine (a selective competitor for M2 receptors), demonstrated the presence of M2 receptor protein (Ki=100 nM), as previously observed in chick DRG. The preferential localization of M2 in medium-small neurons of the ganglion suggests the involvement of this receptor subtype in the transduction of nociceptive stimuli. PMID- 10095044 TI - Generation of reactive oxygen species, release of L-glutamate and activation of caspases are required for oxygen-induced apoptosis of embryonic hippocampal neurons in culture. AB - Oxygen-induced cell death in embryonic neurons is a useful in vitro model of neuronal apoptosis to study the molecular mechanisms underlying the cell death induced by oxidative stress. In the present study, we examined the involvement of reactive oxygen species and glutamate in the high (50%) oxygen-induced death of cultured hippocampal neurons. During the course of cell death, increases in O2- and hydrogen peroxide (H2O2) levels were observed. On the other hand, superoxide dismutase (SOD), catalase and deferoxamine (DFX), which have inhibitory effects on the generation of O2-, H2O2 and hydroxyl radicals, respectively, protected the neurons. These results suggested that both O2- and H2O2 play important roles in this apoptosis. Antagonists of NMDA and AMPA/kinate (AMPA/KA) receptors and an inhibitor of glutamate release partially prevented the apoptosis, suggesting that exposure to high oxygen enhances glutamate release, which results in activation of NMDA receptor and AMPA/KA receptor. In addition, specific nitric oxide (NO) scavenger and NO synthetase inhibitors blocked the apoptosis, indicating that NO and/or peroxynitrite are involved in this mechanism of cell death. Caspase inhibitors also blocked the neuronal apoptosis. These results suggested that multiple effectors including generation of reactive oxygen species, release of L glutamate and activation of caspases are activated during the death induced by high oxygen. PMID- 10095045 TI - Unilateral dopamine depletion paradoxically enhances amphetamine-induced Fos expression in basal ganglia output structures. AB - The ability of amphetamine to induce expression of the immediate early gene protein, Fos, was examined by immunocytochemistry in animals with unilateral 6 hydroxydopamine lesions of the nigrostriatal bundle. Amphetamine induced Fos expression in the globus pallidus (GP) on the intact side of the brain, but this response was greatly attenuated on the dopamine-depleted side. In contrast, amphetamine induced little Fos expression in the entopeduncular nucleus (EPN) and the substantia nigra pars reticulata (SNpr) on the intact side of the brain, but resulted in pronounced expression in these structures on the lesioned side. These findings demonstrate that unilateral dopamine depletion results in a pathophysiological state in which some responses to amphetamine are attenuated while others are paradoxically potentiated. One explanation of these effects is that amphetamine may indirectly activate excitatory inputs to the SNpr and the EPN on both sides of the brain. On the intact side, these effects would be opposed by the simultaneous activation of inhibitory pathways arising in the striatum and the GP, with the result that little Fos expression would be seen. On the dopamine-depleted side, however, engagement of these inhibitory pathways would be attenuated and the unopposed effects of the excitatory inputs mobilized by amphetamine would result in exaggerated Fos synthesis. PMID- 10095046 TI - Effect of ethanol on calcium regulation in rat fetal hypothalamic cells in culture. AB - The effects of acute exposure to ethanol on calcium regulation in primary cultures of rat fetal hypothalamic cells was studied with the use of the calcium indicator fura-2 and digital imaging techniques. We found that ethanol caused cytoplasmic calcium to increase in a dose-dependent and reversible manner, and these increases could be observed at pharmacologically relevant doses (34 mM). At 170 mM ethanol 65% of 1059 cells examined responded to ethanol with an increase in cytoplasmic calcium. Removing bath calcium eliminated the ethanol-induced calcium response in most cells (76% of 427 cells). In most cells exposure to thapsigargin (20 nM) had no significant effect on the ethanol-induced calcium increase (87% of 67 cells examined). The ethanol-induced calcium increase was reduced by 79+/-5% (n=110 cells) by the P/Q-type calcium channel blocker omega agatoxin-TK (20 nM), by 51+/-10% (n=115 cells) by the N-type calcium channel blocker omega-conotoxin-GVIA (100 nM), and by 26+/-3% (n=90 cells) by the T-type calcium channel blocker flunarizine (1 microM). The L-type calcium channel blocker nifedipine (1 microM) had complex actions, sometimes inhibiting and sometimes increasing the calcium response. These results demonstrate that ethanol can directly modulate cytoplasmic calcium levels in hypothalamic cells mostly by a pathway that involves extracellular calcium and voltage-dependent calcium channels, and that this response may participate in the biological effects of acute ethanol exposure. PMID- 10095047 TI - Expression of the hexose transporters GLUT1 and GLUT2 during the early development of the human brain. AB - We used immunohistochemistry with anti-glucose transporter antibodies to document the presence of facilitative hexose transporters in the fetal human brain. GLUT1 is expressed in all regions of the fetal brain from ages 10 to 21 weeks. GLUT1 was present in the endothelial cells of the brain capillaries, the epithelial cells of the choroid plexus and neurons. High expression of GLUT2 was observed in the granular layer of the cerebellum in brains 21 weeks old, but GLUT2 immunoreactivity was absent at earlier stages. GLUT3 and GLUT4 immunoreactivities were absent at all stages studied. GLUT5 immunoreactivity was evident only in the cerebellar region of 21-week old fetal brains. We conclude that GLUT1 plays a fundamental role in early human brain development. The data also suggest that the cerebellum of the developing brain has the capacity to transport fructose, a substrate that has not been previously identified as a source of metabolic energy in the adult human brain. PMID- 10095048 TI - Effects of opioid receptor antagonists on the effects of i.v. morphine on carrageenin evoked c-Fos expression in the superficial dorsal horn of the rat spinal cord. AB - This study performed in freely moving rats evaluated the ability of specific opioid receptor antagonists to reverse the inhibitory effects of morphine on carrageenin-induced c-Fos expression in the spinal cord. Our study focused on the superficial dorsal horn (laminae I-II), which is the main termination site of nociceptive primary afferent fibers and is rich in opioid receptors. In order to replicate clinical routes of administration, all agents were administered intravenously (i.v.). As previously demonstrated, pre-administered i.v. morphine (3 mg/kg) produced a marked decrease (58+/-5%) in the number of Fos-LI neurones measured at 2 h after intraplantar (i.pl.) carrageenin (6 mg/150 microl) and yet was without influence on peripheral oedema. This decrease in c-Fos expression was completely blocked by combined administration of morphine with the mu-opioid receptor antagonist, [D-Phe-Cys-Tyr-D-Orn-Thr-Pen-Thr-NH2] (CTOP-1+1 mg/kg). Naltrindole (NTI-1+1 mg/kg), a delta-opioid receptor antagonist partially blocked the effects of systemic morphine, so that the inhibitory effects of morphine after NTI injection are now 40+/-4%. However, this effect of NTI was weak since the depressive effects of morphine were still highly significant (p<0.001). In contrast, nor-binaltorphimine (nor-BNI-1+1 mg/kg), a kappa-opioid receptor antagonist, had no significant effect on the effects of morphine. These results indicate the major contribution of mu-opioid receptors to the antinociceptive effects of systemic morphine at the level of the superficial dorsal horn. The observed effect of NTI is not necessarily related to a direct action of morphine on delta-opioid receptors and some possible actions of this antagonist are discussed. PMID- 10095049 TI - Effects of ethanol on basal and adenosine-induced increases in beta-endorphin release and intracellular cAMP levels in hypothalamic cells. AB - Recently we have shown that the cAMP system is involved in ethanol-regulated beta endorphin (beta-EP) release from rat hypothalamic neurons in primary cultures. The cascade of events that leads to activation of cAMP following ethanol treatment in hypothalamic beta-EP neurons is not apparent. In this study the role of adenosine, a cAMP regulator, in ethanol-regulated beta-EP release was determined by measuring the cellular incorporation of [3H]adenosine, intracellular cAMP levels and media immunoreactive (IR) beta-EP levels in cultures of rat hypothalamic cells following ethanol treatments in the presence and absence of an adenosine agonist and antagonist. Acute exposure to a 50 mM dose of ethanol for a period of 1 h increased media levels of IR-beta-EP and cellular contents of cAMP, but the ethanol treatment decreased [3H]adenosine uptake. Constant exposure to a 50 mM dose of ethanol for a period of 48 h, failed to alter media levels of IR-beta-EP, cell content of cAMP and [3H]adenosine uptake. The media level of IR-beta-EP was elevated following treatment with adenosine receptor agonist phenyl-isopropyl adenosine (PIA) and was reduced following treatment with adenosine receptor antagonist isobutylmethylxanthine (IBMX) or with adenosine uptake inhibitor adenosine deaminase. The level of cellular cAMP was also increased by PIA but was decreased by IBMX and adenosine deaminase. The stimulatory actions of the adenosine agonist PIA on IR-beta-EP release and on cAMP production were potentiated by simultaneous incubation with ethanol for 1 h. However, chronic ethanol exposure reduced PIA-induced IR-beta-EP release and cAMP production. Additionally, both IBMX and adenosine deaminase reduced ethanol-induced IR-beta-EP release and cAMP levels. These results suggest that ethanol inhibits adenosine uptake in IR-beta-EP neurons in the hypothalamus, thereby increasing extracellular levels of adenosine and leading to activation of membrane adenosine receptors, cAMP production and IR-beta-EP secretion from these neurons. Chronic ethanol desensitizes the adenosine-regulated cAMP production and IR-beta-EP release from hypothalamic neurons. PMID- 10095050 TI - Cortical spreading depression reduces paraventricular activation induced by hippocampal neostigmine injection. AB - The firing rate of the neurons of the hypothalamic paraventricular nucleus, the temperatures of the interscapular brown adipose tissue and of the colon (TIBAT and Tc) were monitored in 24 urethane-anesthetized male Sprague-Dawley rats divided into four groups. These variables were measured before and after hippocampal injection of neostigmine (5x10(-7) mol) in the 1st and 2nd groups or of saline in the 3rd and 4th groups. The hippocampal injection was preceded by cortical spreading depression in the 1st and 3rd groups, while the cortical depression was not induced in the 2nd and 4th groups. The results show an increase of firing rate, TIBAT and Tc after neostigmine injection in the rats without cortical depression. Cortical spreading depression significantly reduces these enhancements. These findings demonstrate that: (1) the paraventricular nucleus plays a significant role in the hyperthermia induced by neostigmine injection into the hippocampus; and (2) the cerebral cortex is involved in the control of the paraventricular activity. PMID- 10095051 TI - Dextromethorphan modulates the AP-1 DNA-binding activity induced by kainic acid. AB - We have recently reported that dextromethorphan attenuates the neurotoxicity induced by kainic acid in a dose-related fashion. Pretreatments with dextromethorphan (50 mg/kg, p.o. x2) significantly reduced the activator protein 1 DNA-binding activity and the Fos-related antigen-immunoreactive protein induced by kainic acid (10 mg/kg, i.p.) in the CA1, but not the CA3 or the dentate gyrus sector of the rat hippocampus. Paradoxically, dextromethorphan itself caused an elevated activator protein-1 DNA-binding activity and Fos-related antigen immunoreactive protein in the CA1 region which lasted for at least 4 days. The results suggest that the CA1 area is the critical site for mediating the putative neuroprotective effect induced by dextromethorphan. PMID- 10095052 TI - Exposure and isolation of the superior sagittal sinus elicits Fos in the trigeminal nucleus caudalis and dorsal horn of the cervical spinal cord: how long should you wait? AB - The immunohistochemical detection of the proto-oncogene Fos is widely used as a marker of cell activation in the central nervous system for mapping neurobiological pathways. This study examined the time course of Fos disappearance following surgery by studying neurons in the trigeminocervical complex after three different rest periods, 4, 8 and 24 h. The region of interest was the trigeminocervical complex (TCC) which extends from the caudal medulla to the caudal level of the C2 spinal cord. Animals in the 24 h group had a median of only 66 positive cells, more than six times less cells than in those animals left for only 4 h. This study shows the considerable benefit of waiting 24 h over the more convenient time frame posed by the 4 and 8 h intervals. PMID- 10095053 TI - Effects of chronic benzodiazepine exposure on stress-induced neuroactive steroid levels. AB - Since the neuroactive steroid 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha THP) has pharmacologic actions similar to benzodiazepine agonists such as diazepam, the influences of chronic diazepam exposure on stress-induced brain levels of 3alpha, 5alpha-THP were examined. Groups of male, female, orchidectomized (ORCH), and ovariectomized (OVX) rats were compared, along with OVX groups given hormone replacement. Chronic diazepam exposure diminished stress induced brain levels of 3alpha,5alpha-THP and serum corticosterone, although gender, gonadectomy and hormone replacement had disparate influences on these two endocrine responses to stress. PMID- 10095054 TI - Effects of functional disruption of lateral pericentral cerebral cortex on primate swallowing. AB - Bilateral cold block of the intracortical microstimulation (ICMS)-defined swallow cortex markedly affected the ability of monkeys to carry out swallowing. Significant changes also occurred in swallow-related electromyographic (EMG) activity patterns. These findings provide further evidence that the lateral pericentral cortex plays a critical role in the initiation and regulation of swallowing in the primate. PMID- 10095055 TI - Characterization and expression of the mouse Hsc70 gene. AB - A genomic clone encoding the mouse Hsc70 gene has been isolated and characterized by DNA sequence analysis. The gene is approximately 3. 9 kb in length and contains eight introns, the fifth, sixth and eighth of which encode the three U14 snoRNAs. The gene has been located on Chr 9 in the order Fli1-Itm1-Olfr7 Hsc70(Rnu14)-Cbl by genetic analysis. Expression of Hsc70 is universal in all tissues of the mouse, but is slightly elevated in liver, skeletal muscle and kidney tissue, while being depressed in testes. In cultured mouse NIH 3T3 cells or human HeLa cells, Hsc70 mRNA levels are low under normal conditions, but can be induced 8-fold higher in both lines by treatment with the amino acid analog azetidine. A similar induction is seen in cells treated with the proteosome inhibitor MG132 suggesting that elevated Hsc70 expression may be coupled to protein degradation. Surprisingly, expression of the human Hsc70 gene is also regulated by cell-cycle position being 8-10-fold higher in late G1/S-phase cells as opposed to the levels in early G1-phase cells. PMID- 10095056 TI - Cloning and functional expression of the cytoplasmic form of rat aminopeptidase P. AB - A rat cytoplasmic aminopeptidase P was purified from liver cytosol with a procedure including an affinity elution step with 3 microM inositol 1,3,4 trisphosphate. Proteolytic fragments were generated, sequenced and the enzyme was cloned from a rat liver cDNA library. The structure shows high (87.8% and 95.5%, respectively) sequence identity at the nucleotide and amino acid levels with the previously described human putative cytoplasmic aminopeptidase P. The cloned rat enzyme was functionally expressed in Escherichia coli and also in COS-1 cells. Western blot analysis, using an antibody generated against the recombinant protein, and Northern blot hybridization showed ubiquitous expression of the protein in different tissues with the highest expression level in the testis. PMID- 10095057 TI - Recent and rapid amplification of the sperm basic nuclear protein genes in winter flounder. AB - The high molecular weight basic nuclear proteins (HMrBNPs), which are tightly bound to sperm chromatin in winter flounder, are made up of imperfect reiterations of simple peptide sequences that contain phosphorylatable DNA binding motifs. Genomic Southern blots hybridized with probes to the coding and non-coding regions of HMrBNP mRNA showed that HMrBNP sequences form a complex multi-gene family. Previously, one gene (2B) was used to establish an evolutionary link between histone H1 and the HMrBNPs. Further examination of this complex, multi-gene family has now revealed that the majority of the HMrBNP genes are linked as 4.5 kb direct tandem repeats that each contain a 2.8 kb coding region and a 1.7 kb intergenic region (IR). These findings, combined with the cloning of the IR, established that the tandemly repeated genes lack introns and code for the abundant 3 kb HMrBNP mRNAs that produce the prominent 110 kDa HMrBNP. Southern blotting of DNAs from other righteye flounder species showed that HMrBNP multi-gene families were present in closely related species, though with substantial differences in restriction patterns and band intensities, but were not detected in more distantly related flounders. These observations are consistent with recent and rapid elaboration of the HMrBNP gene family. PMID- 10095058 TI - Cloning and characterization of the rat and human phosducin-like protein genes: structure, expression and chromosomal localization. AB - We isolated and characterized the rat gene encoding phosducin-like protein (PhLP), a putative heterotrimeric G protein modulator. The transcription start site was mapped by primer extension. The putative promoter region lacked a TATA sequence but contained a potential initiator element. Two splice variants were identified by RT-PCR of rat brain RNA, potentially generating either the full length or an amino-truncated protein. Only the full-length protein was immunodetected in all mouse tissues surveyed. Comparison of the conceptual translation product of the rat PhLP gene with those from human and Drosophila clones shows a striking conservation in the amino-terminal region of PhLP from these species. This contrasts with the relatively low degree of homology between PhLP and phosducin in this region, suggesting a functional role for this portion of the PhLP protein. Finally, we mapped the human PhLP gene by PCR analysis of somatic cell hybrids and the Stanford G3 radiation hybrid panel. The human PhLP gene (PDCL) is located on chromosome 9, linked to the polymorphic markers D9S1876 and D9S1674 (66-71 cM). PMID- 10095059 TI - The effect of template RNA structure on elongation by HIV-1 reverse transcriptase. AB - Reverse transcription of the RNA genome of retroviruses has to proceed through some highly structured regions of the template. The RNA genome of the human immunodeficiency virus type 1 (HIV-1) contains two hairpin structures within the repeat (R) region at the 5' end of the viral RNA (Fig. 1Fig. 1Template RNA structure of the HIV-1 R region and the position of reverse transcription pause sites. The HIV-1 R region (nucleotides +1/97) encodes two stable RNA structures, the TAR and polyA hairpins [5]. The latter hairpin contains the AAUAAA hexamer motif (marked by a box) that is involved in polyadenylation. The lower panel shows the predicted structures of the wild-type and two mutant forms of the polyA hairpin that were used in this study. Nucleotide substitutions are boxed, deletions are indicated by black triangle. The thermodynamic stability (free energy or DeltaG, in kcal/mol) was calculated according to the Zucker algorithm [71]. The TAR hairpin has a DeltaG of -24.8 kcal/mol. Minus-strand DNA synthesis on these templates was initiated by a DNA primer annealed to the downstream PBS. The position of reverse transcription pause sites observed in this study are summarized. All numbers refer to nucleotide positions on the wild-type HIV-1 transcript. Filled arrows represent stops observed on the wild-type template, and open arrows mark the pause sites that are specific for the structured A-mutant template. The sizes of the arrows correspond to the relative frequency of pausing. Little pausing was observed on the B-mutant template with the destabilized polyA hairpin.). These structures, the TAR and polyA hairpins, fulfil important functions in the viral life cycle. We analyzed the in vitro elongation properties of the HIV-1 reverse transcriptase (RT) enzyme on the wild type RNA template and mutants thereof with either a stabilized or a destabilized polyA hairpin. Stable RNA structure was found to interfere with efficient elongation of the RT enzyme, as judged by the appearance of pause cDNA products. A direct relation was measured between the stability of template RNA structure and the extent of RT pausing. However, the position of structure-induced pause sites is rather diverse, with significant stops at a position approximately 6 nt ahead of the basepaired stem of the TAR and polyA hairpins. This suggests that the RT enzyme is stalled when its most forward domain contacts the RNA duplex. Addition of the viral nucleocapsid protein (NC) to the in vitro assay was found to overcome such structure-induced RT stops. These results indicate that the RT polymerase has problems penetrating regions of the template with stable RNA structure. This effect was more pronounced at high Mg2+ concentrations, which is known to stabilize RNA secondary structure. Such a structure-induced defect was not apparent in reverse transcription assays performed in virus-infected cells, which is either caused by the NC protein or other components of the virion particle. Thus, retroviruses can use relatively stable RNA structures to control different steps in the viral life cycle without interfering with the process of reverse transcription. PMID- 10095060 TI - Enhancement of UV-induced cytotoxicity by the adeno-associated virus replication proteins. AB - Adeno-associated virus (AAV) normally requires co-infection of a helper virus to complete its life cycle. However, under conditions of cellular stress, such as treatment with carcinogens or ultraviolet (UV) light, a permissive intracellular environment is established and AAV completes its replicative cycle producing low levels of progeny virus. AAV DNA replication is dependent upon viral replication proteins, Rep78 and Rep68. The detailed mechanism by which these proteins interact with host cell factors is unknown. We have used a cell line (Neo6) that inducibly expresses the AAV Rep proteins to study their effects on cells that have undergone UV-induced DNA damage. Induction of Rep protein expression immediately after a sub-lethal dose of UV irradiation resulted in rapid cell killing. Those cells that die had chromatin condensation while cellular membranes remained intact, suggesting that concurrent Rep expression and UV damage induces an apoptosis-like response. However, we did not observe any DNA degradation. Thus we believe that the combination of Rep expression and UV irradiation induces cell death that shares some of the characteristics of apoptosis. UV irradiation and Rep expression induced an increase in the level of the CDK inhibitor, p21Cip, and the appearance of modified forms of both p21Cip and Bcl-2. Alteration of normal expression of these cytostatic/apoptotic proteins provides insight into the intracellular targets of the AAV replication proteins. PMID- 10095061 TI - memA/DRS, a putative mediator of multiprotein complexes, is overexpressed in the metastasizing human melanoma cell lines BLM and MV3. AB - memA was isolated by subtractive hybridization in which the mRNA repertoire was compared in a panel of human melanoma cell lines with different metastasizing potential. Expression of memA mRNA is elevated in the highly metastasizing human melanoma cell lines and derived xenografts, as compared with the non metastasizing ones. In a collection of human tumor cell lines and melanoma metastasis lesions, memA mRNA expression could be detected in the A-431 (epidermoid carcinoma), HT-1080 (fibrosarcoma), JEG-3 and JAR (choriocarcinomas) cell lines and in three out of 11 melanoma metastasis lesions. The distribution of memA mRNA in a collection of healthy human organs is also tissue restricted. Sequence analysis revealed that the MEMA protein is identical with a 160 kDa nuclear 'domain rich in serines' (DRS) protein occurring free in the nucleoplasm and in U2-ribonucleoprotein structures. MEMA is also homologous to pinin, a 140 kDa protein associated with the desmosome-intermediate filament complex, and to a 32 kDa porcine neutrophilic protein that was copurified with components of the NADPH-oxidase enzyme complex. The encoded amino acid sequence predicts that the MEMA protein has three coiled-coil domains, one glycine loop domain, is very hydrophilic and contains regions rich in glutamine/proline, glutamic acid and serine residues. PMID- 10095062 TI - Molecular cloning and characterization of the human topoisomerase IIalpha and IIbeta genes: evidence for isoform evolution through gene duplication. AB - Human DNA topoisomerase II is essential for chromosome segregation and is the target for several clinically important anticancer agents. It is expressed as genetically distinct alpha and beta isoforms encoded by the TOP2alpha and TOP2beta genes that map to chromosomes 17q21-22 and 3p24, respectively. The genes display different patterns of cell cycle- and tissue-specific expression, with the alpha isoform markedly upregulated in proliferating cells. In addition to the fundamental role of TOP2alpha and TOP2beta genes in cell growth and development, altered expression and rearrangement of both genes are implicated in anticancer drug resistance. Here, we report the complete structure of the human topoisomerase IIalpha gene, which consists of 35 exons spanning 27.5 kb. Sequence data for the exon-intron boundaries were determined and examined in the context of topoisomerase IIalpha protein structure comprising three functional domains associated with energy transduction, DNA breakage-reunion activity and nuclear localization. The organization of the 3' half of human TOP2beta, including sequence specifying the C-terminal nuclear localization domain, was also elucidated. Of the 15 introns identified in this 20 kb region of TOP2beta, the first nine and the last intron align in identical positions and display the same phases as introns in TOP2alpha. Though their extreme 3' ends differ, the striking conservation suggests the two genes diverged recently in evolutionary terms consistent with a gene duplication event. Access to TOP2alpha and TOP2beta gene structures should aid studies of mutations and gene rearrangements associated with anticancer drug resistance. PMID- 10095063 TI - Structure and promoter region of the surface membrane protein HS9 gene expressed on the thymic epithelial cells. AB - The HS9 gene encoding a surface membrane protein is expressed in thymic epithelial cells. We have isolated the mouse HS9 gene and determined the sequence of all exons. The mouse HS9 gene is composed of 14 exons spanning approx. 31 kb. Primer extension analysis identified two transcription initiation sites 33 bp and 179 bp upstream from the ATG start codon. DNA sequence analysis of the 5' flanking region of the first exon revealed a number of consensus binding sites for known transcription factors such as GC box, Sp1, NFkappaB, gamma-IRE. Neither typical TATA nor CCAAT boxes were found in this region. These results and the analysis of the luciferase activity showed that transcription of the HS9 gene is regulated at a TATA-less promoter. PMID- 10095064 TI - Characterization of the promoter for the gene encoding the aflatoxin biosynthetic pathway regulatory protein AFLR. AB - Most genes in the aflatoxin biosynthetic pathway in Aspergillus parasiticus are regulated by the binuclear zinc cluster DNA-binding protein AFLR. The aflR promoter was analyzed in beta-glucuronidase reporter assays to elucidate some of the elements involved in the gene's transcription control. Truncation at 118 bp upstream of the translational start site increased promoter activity 5-fold, while truncation at -100 reduced activity about 20-fold. These findings indicate the presence of an important positive regulatory element between -100 and -118 and a negative regulatory region further upstream. Electrophoretic mobility shift assays on nuclear extracts from A. parasiticus induced for aflatoxin expression suggest that AFLR and another, possibly more abundant, protein bind to the -100/ 118 region. Another protein binds to a sequence at position -159 to -164 that matches the consensus binding site for the transcription factor involved in pH dependent gene regulation, PACC. PMID- 10095065 TI - Molecular cloning and biochemical characterization of a truncated, secreted member of the human family of Ca2+-activated Cl- channels. AB - A novel family of chloride channel proteins has recently been discovered including two bovine (Lu-ECAM-1, bCLCA1), one murine (mCLCA1), and two human (hCLCA1 and hCLCA2) members. Here, we describe the cloning, expression, and molecular characterization of a truncated human homolog, tentatively named hCLCA3. It was cloned from a human spleen cDNA library and is expressed in numerous tissues including lung, trachea, spleen, thymus, and mammary gland as determined by reverse transcriptase-polymerase chain reaction. Unlike all previously known CLCA family members which consistently encode an approximately 125-kDa transmembrane protein that is cleaved to form a heterodimer of two proteins of approximately 90 and 35 kDa, the 3.6-kb hCLCA3 mRNA encodes a 37-kDa glycoprotein that corresponds to the N-terminal extracellular domain of its homologs. Moreover, when expressed in human embryonic kidney 293 or Chinese hamster ovary cells, this 37-kDa glycoprotein is secreted into the culture supernatant. These observations suggest that hCLCA3 is a structurally divergent member of the CLCA family of proteins and that it does not act as a channel protein but has distinct, yet unidentified functions. PMID- 10095066 TI - The Bacillus stearothermophilus replicative helicase: cloning, overexpression and activity. AB - As part of biochemical and structural studies of the primosome of a gram positive bacterial species, we describe the cloning of the Bacillus stearothermophilus replicative helicase, DnaB. The protein is 45% and 82% identical to the Escherichia coli and B. subtilis replicative helicases, respectively. Recombinant DnaB was purified and shown to be an active helicase. PMID- 10095067 TI - Cloning, expression, and purification of Bacillus stearothermophilus DNA primase and crystallization of the zinc-binding domain. AB - The dnaG gene encoding DNA primase has been isolated from chromosomal DNA of Bacillus stearothermophilus and its entire nucleotide sequence determined. The deduced amino acid sequence comprised 597 amino acid residues and the molecular mass was calculated to be 67068 Da. B. stearothermophilus primase was overexpressed in Escherichia coli and purified to homogeneity. The N-terminal 12 kDa zinc-binding domain has been crystallized. The crystals are of the monoclinic space group P21 with cell dimensions a=36 A, b=59 A, c=46 A, beta=91.8 degrees and diffract to 1.7 A resolution. PMID- 10095068 TI - Cloning of the gene gob-4, which is expressed in intestinal goblet cells in mice. AB - We isolated the novel cDNA gob-4, which was shown to be expressed in intestinal goblet cells. The deduced amino acid sequence is similar to the gene coding for the Xenopus laevis cement gland-specific XAG-2. These sequence and expression data suggest this gene may be involved in the secretory function. PMID- 10095069 TI - Characterization of a hexokinase encoding cDNA of the parasitic nematode Hhaemonchus contortus. AB - The nematode Haemonchus contortus is an important parasite of cattle and sheep. We describe here the cloning of a cDNA encoding a 53 kDa hexokinase (EC 2.7.1.1). The deduced protein shows 73% identity to a 50 kDa hexokinase deduced from a Caenorhabditis elegans cosmid. Alignment with mammalian hexokinases reveals two short amino acid insertions in the H. contortus hexokinase. Software tools for structural protein analysis (ExPASy server, Geneva) localize these insertions on the surface of the molecule, suggesting these surface changes as potential target sites for chemotherapeutic drugs. PMID- 10095070 TI - Expression of novel homeobox genes in early embryogenesis in rice. AB - We isolated four novel cDNA clones of rice (Oryza sativa L.), which encode predicted proteins with a KN1-like homeodomain. In situ hybridization and RT-PCR analysis with solid cDNA libraries as templates showed that these genes are expressed in distinct patterns during the early stages of rice embryogenesis. PMID- 10095071 TI - Sequence and molecular analysis of the Rhizobium etli glsA gene, encoding a thermolabile glutaminase. AB - We sequenced a 2.1 kb fragment of DNA carrying the structural glsA gene, which codes for the Rhizobium etli thermolabile glutaminase (A). The glsA gene complements the R. etli LM16 mutant that lacks glutaminase A activity, and is expressed in the heterologous host Sinorhizobium meliloti. The deduced amino acid sequence consists of 309 residues, with a calculated molecular mass of 33 kDa. The amino acid sequence shares 53% and 43% identity with two hypothetical glutaminases of E. coli; 42% identity with liver-type; 38% identity with kidney type glutaminase; 41% and 40% identity hypothetical glutaminases of Bacillus subtilis; and 41% and 37% identity with two putative glutaminases of Caenorhabditis elegans. The glsA gene represents the first glutaminase gene cloned and sequenced in prokaryotes. PMID- 10095072 TI - A novel type of non-coding RNA expressed in the rat brain. AB - We have characterized a novel type of non-coding RNA which consists of tandem repeats of similar sequences, approximately 0.9 kb in size. This RNA, termed Bsr (brain specific repetitive) RNA, is encoded at a single locus (6 q31-->q32) in the rat genome, where 100 to 150 copies of the 0.9 kb sequences are repeated in tandem. Bsr RNA is preferentially expressed in the rat central nervous system (CNS), especially in phylogenetically old structures, such as the pareo- and archicortex, amygdala, thalamus and hypothalamus. In the developing brains, Bsr RNA is expressed in the subsets of differentiating cells but not in proliferating cells. Despite the finding that Bsr RNA appears to be conserved only among the Rattus species, the specific expression pattern of Bsr RNA suggests that it might have some role in the rat CNS. PMID- 10095073 TI - Nicotinic receptor binding sites in rat primary neuronal cells in culture: characterization and their regulation by chronic nicotine. AB - We have characterized high affinity neuronal nicotinic acetylcholine receptors labeled by [3H]cytisine in primary neuronal cell cultures from fetal rat brains. After 15 days in culture, the highest density of [3H]cytisine binding sites (Bmax approximately 57 fmol/mg protein) was found in cells from the brainstem, which includes the following subcortical brain areas: the septum, thalamus, hypothalamus, midbrain, pons and medulla. A lower density of sites was found in cells from the cerebral cortex, hippocampus, and caudate nucleus. [3H]Cytisine binds to receptors in primary cells from the brainstem and cerebral cortex with a Kd of approximately 0. 5 nM, and the binding is inhibited by the agonists nicotine, acetylcholine, and epibatidine with IC50 values of 1 to 20 nM, and by carbachol and the antagonist dihydro-beta-erythroidine with IC50 values of 0.5 to 1.5 microM. Chronic treatment of neuronal cultures with nicotine for 7 days differentially affected the number of nicotinic receptors in cells from different brain areas; it significantly increased the number of nicotinic binding sites in cells from the cerebral cortex, hippocampus, and caudate, but not in cells from the brainstem. The nicotine-induced increase of receptors in cerebral cortical cultures was not blocked by either mecamylamine or dihydro-beta-erythroidine. These results indicate that primary cultures of rat neuronal cells provide a good model system in which to study and compare the properties and regulation of native neuronal nicotinic acetylcholine receptors. PMID- 10095074 TI - Gene expression of histamine H1 receptor in guinea pig primary sensory neurons: a relationship between H1 receptor mRNA-expressing neurons and peptidergic neurons. AB - Pharmacological studies have suggested that a subgroup of primary sensory neurons is responsive to histamine via the histamine H1 receptor. We addressed this issue using in situ hybridization histochemistry with a cRNA probe for the guinea pig H1 receptor gene. About 15% of the trigeminal and lumber dorsal root ganglion (DRG) neurons, but none of nodose ganglion neurons, were intensely labeled with this probe. The H1 receptor mRNA-positive neurons were exclusively small in size, and were demonstrated to give rise to unmyelinated fibers by ultrastructural analysis of isolectin B4-labeling. However, the H1 receptor mRNA-expressing DRG neurons were not immunoreactive to substance P (SP) and calcitonin gene-related peptide (CGRP). A marked increase in the number of mRNA-positive DRG neurons were observed 1-5 days after a crush injury of the sciatic nerve (3-4-fold of the control value). These neurons turned mRNA-positive after the nerve crush were also mainly small-sized. The mRNA signals were detected in many peptidergic (SP/CGRP) neurons, in contrast to the normal state. On the other hand, in the neurons which showed intense labeling in the normal condition, the mRNA signals were down-regulated. These results suggest that primary sensory neurons include two kinds of H1 receptor-expressing sensory neurons, one expressing H1 receptor mRNAs in the normal state and the other up-regulating the mRNAs following the peripheral nerve damage. PMID- 10095075 TI - Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress induced damage. AB - It has been postulated that decreases in plasma levels of dehydroepiandrosterone (DHEA) may contribute to the development of some age-related disorders. Along with neuroprotective and memory enhancing effects, DHEA has been shown to display antioxidant properties. Moreover, oxidative stress is known to cause lipid peroxidation and degenerative changes in the hippocampus, an area involved in memory processes and especially afflicted in Alzheimer's disease (AD). Accordingly, we investigated the antioxidant effects of DHEA in models of oxidative stress using rat primary hippocampal cells and human hippocampal tissue from AD patients and age-matched controls. A pre-treatment of rat primary mixed hippocampal cell cultures with DHEA (10-100 microM) protected against the toxicity induced by H2O2 and sodium nitroprusside. Moreover, DHEA (10-100 microM) was also able to prevent H2O2/FeSO4-stimulated lipid oxidation in both control and AD hippocampal tissues. Taken together, these data suggest that DHEA may be useful in treating age-related central nervous system diseases based on its protective effects in the hippocampus. PMID- 10095076 TI - NMDAR-2A subunit protein expression is reduced in the hippocampus of rats exposed to Pb2+ during development. AB - Chronic exposure to lead (Pb2+) produces deficits of learning and memory in children and spatial learning deficits in developing rats. The N-methyl-D aspartate receptor (NMDAR) has been identified as a principal target for Pb2+ induced neurotoxicity. Age-dependent changes in NMDAR subunit gene expression were observed in hippocampi of rats chronically exposed to Pb2+ during development [T.R. Guilarte, J.L. McGlothan, Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure, Brain Res. 790 (1998) 98-107]. These changes were present at blood Pb2+ levels ranging from 20-60 microg/dl. Littermates were used in the present study to determine whether the changes in gene expression were reflected in protein levels. NR1, NR2A, and NR2B subunit protein levels were measured in rat hippocampus and cortex at post natal days (PND) 7, 14, 21, and 28 by Western blot and densitometric analysis. A treatment effect was apparent for NR2A subunit protein expression in the hippocampus (F1,28=10.224, p<0.01). NR2A subunit protein was reduced by 40%, 19%, and 27% from control levels in PND14, 21, and 28 Pb2+-exposed rats, respectively. Mean comparisons indicated that rats at PND14 exhibited the most significant reduction of NR2A (p<0.001). These data concur with our previous finding of reduced NR2A mRNA found in hippocampal pyramidal and granule cells of Pb2+ exposed rats. Pb2+ exposure during development had no effect on NR1 or NR2B subunit protein expression in the hippocampus at any age. No effect was observed on any subunit in the cortex at any age. The developmental profile of the NMDAR 2A subunit protein in the hippocampus is specifically changed by chronic exposure to Pb2+. These data suggest that composition of subunits comprising NMDAR may be altered in Pb2+-exposed rats. PMID- 10095077 TI - Molecular pathways mediating activation by kainate of mitogen-activated protein kinase in oligodendrocyte progenitors. AB - Oligodendroglial cells express ionotropic glutamate receptors of alpha-amino-3 hydroxy-5-methyl-isoxazole-4-propionic acid hydrobromide (AMPA) and kainate (KA) subtypes. Recently, we reported that AMPA receptor agonists increased 45Ca2+ uptake and phospholipase C (PLC) activity. To further elucidate the intracellular signaling mechanisms, we examined the effects of AMPA and KA on mitogen-activated protein kinase (MAPK). KA caused a time- and concentration-dependent increase in MAPK activity (predominantly the p42mapk or ERK2) and the effect was blocked by 6 cyano-7-nitro-quinoxaline-2,3-dione (CNQX), a competitive AMPA/KA receptor antagonist. Furthermore, the noncompetitive antagonists of AMPA receptor GYKI 52466 and LY 303070 prevented the actions of the agonists, indicating that the effect of KA on MAPK activation is mediated through AMPA receptors in oligodendrocyte progenitors. Chelation of extracellular Ca2+ by EDTA or inhibition of PLC with U73122 abolished MAPK activation by KA. In addition, KA stimulated MAPK activation was reduced by the protein kinase C (PKC) inhibitors, H7 and bisindolylmaleimide, as well as downregulation of PKC by prolonged exposure to phorbol esters. The involvement of PKC in the signal transduction pathways was further supported by the ability of KA to induce translocation of PKC measured by [3H]PDBu binding. Interestingly, a wortmannin-sensitive phosphatidylinositol 3-kinase and a pertussis toxin (PTX)-sensitive G protein form part of the molecular pathways mediating MAPK activation by AMPA receptor. A specific inhibitor of MAPK kinase, PD 098059, blocked MAPK activation and reduced KA-induced c-fos gene expression. All together, these results indicate that MAPK is implicated in the transmission of AMPA signaling to the nucleus and requires extracellular Ca2+, and PLC/PKC activation. PMID- 10095078 TI - Differential effects of GDNF and BDNF on cultured ventral mesencephalic neurons. AB - Previous studies have shown that brain derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) can enhance the survival of dopaminergic neurons in the ventral mesencephalon (VM). Here we compared several non-survival functions of the two factors in VM neurons in culture. We found that both BDNF and GDNF elicited an increase in the depolarization-induced release of dopamine, but had no effect on GABA release, in the VM cultures. BDNF, but not GDNF, significantly enhanced the expression of the calcium binding protein calbindin and synaptic protein SNAP25. In contrast, treatment of the cultures with GDNF, but not BDNF, elicited a marked fasciculation of the processes of the VM neurons. Thus, although both act on VM neurons, BDNF and GDNF have distinct functions. PMID- 10095079 TI - Developmental changes in nicotinic receptor mRNAs and responses to nicotine in the suprachiasmatic nucleus and other brain regions. AB - Our previous studies demonstrated that nicotine induces c-fos expression in the suprachiasmatic nucleus (SCN) of the rat during a narrow developmental window occurring in the perinatal period. We have extended these observations by showing that c-fos cannot be induced in the adult SCN by nicotine even during the subjective night, when phase shifts do occur. In contrast to the SCN, significant induction of c-fos and NGFI-A was observed in the medial habenula and paraventricular nucleus at all circadian times. In the fetal rat SCN we show that NGFI-A and junB are also induced by nicotine, but not c-jun. To investigate whether changes in nicotinic acetylcholine receptor (nAChR) expression in the SCN may underlie this change in sensitivity during the perinatal period, we examined nAChR mRNAs across this developmental period. By Northern analyses, alpha2, alpha3 and alpha4 subunit mRNAs are relatively abundant in the fetal SCN but decline substantially in the adult. alpha7 mRNA increases substantially while beta2 mRNA is relatively abundant throughout development. We also examine expression in the whole mouse brain beginning at embryonic day 11. Many mRNA sizes for nAChR subunits in both the rat and mouse are characterized here for the first time by Northern analyses and some show very large changes in expression across development. In particular, a small 1.4 kb alpha2-related mRNA is highly expressed during early development, perhaps indicating an important novel function for this subunit. PMID- 10095080 TI - Cloning and expression of Shaker alpha- and beta-subunits during inner ear development. AB - Sensory cells of the chicken cochlea exhibit different ion channels relative to their position along the epithelium. One of these channels conducts an A-type potassium current which is found primarily in 'short' hair cells. Here, we report the first full length cloning and developmental expression of Shaker genes from this endorgan. Clones were obtained by screening a chicken (Gallus gallus) cochlea cDNA library, using probes made from RHK1 (i.e., Kvalpha1.4) cDNA, a Shaker homologue isolated from rat heart, and hKvbeta1.2 cDNA, a beta homologue isolated from human heart. Sequence analysis revealed a chick homologue of Kvalpha1.4, with a deduced amino acid similarity of 76-79% to mammalian Kvalpha1.4, and a chick homologue of Kvbeta1.1, with a similarity of 95% to mammalian Kvbeta1.1. In addition, we isolated a variant of cKvalpha1. 4 (cKvalpha1.4(m)) that differs in its untranslated regions and shows complete similarity in its coding region, except for the deletion of a single nucleotide. During development of the inner ear, reverse transcription-polymerase chain reaction (RT-PCR) studies show that the beta-subunit is expressed as early as embryonic day 3, whereas alpha- and beta-subunits are coexpressed on embryonic days 7 to 10, 14, and in adult. PMID- 10095081 TI - Regional distribution of nicotinic receptor subunit mRNAs in human brain: comparison between Alzheimer and normal brain. AB - The regional expression of mRNA for the nicotinic acetylcholine receptor (nAChR) subunits alpha3, alpha4 and alpha7 was examined in postmortem brain tissues from controls and patients with Alzheimer's disease (AD) by using quantitative RT-PCR. In parallel, the numbers of nAChRs were measured by receptor binding. Relative quantification of the nAChR gene transcripts in control brains showed that expression of alpha3 was highest in the parietal cortex, frontal cortex and hippocampus, and lower in the temporal cortex and cerebellum. The highest level of alpha4 mRNA was found in the temporal cortex and cerebellum, while alpha7 mRNA was equally distributed in all brain regions except for hippocampus where it was less abundant. In comparison with AD brains, no differences in the expression of alpha3 and alpha4 in the temporal cortex, hippocampus and cerebellum were found. The level of alpha7 mRNA was significantly higher in the hippocampus of AD brains compared to controls. The binding sites for [3H] epibatidine and [3H] nicotine in the temporal cortex and [125I] alpha-bungarotoxin in hippocampus were significantly decreased in AD patients compared to controls. Saturation analysis of [3H] epibatidine binding revealed two classes of binding sites, with a significant reduction of the higher affinity epibatidine binding sites in the temporal cortex of AD brain. The results show that there is a regional distribution of the expression of the different nAChRs subunits in human brain. The findings that the alpha3 and alpha4 mRNA levels were not changed in AD brains suggest that the loss of higher affinity epibatidine binding sites observed in AD patients cannot be attributed to alternations at the transcriptional level of the alpha3 and alpha4 genes and that causes have to be searched for at the translational and/or posttranslational level. The increased mRNA level of alpha7 previously found in lymphocytes, and now also in the hippocampus of AD patients, indicate that subunit specific changes in gene expression of nAChRs is associated with AD. PMID- 10095082 TI - Phase-dependent induction by light of rat Clock gene expression in the suprachiasmatic nucleus. AB - To clarify the role of Clock in the photic signal transduction of rat circadian clock, we cloned and sequenced rat Clock and examined the effect of a single light pulse on the Clock mRNA expression in the suprachiasmatic nucleus (SCN) by in situ hybridization. Rats were exposed to a 30 min light pulse ( approximately 300 lx) at one of six circadian phases in constant darkness (DD), and sacrificed 60 min after the light on. In the rats without light exposure, the mRNA level in the SCN was high at ZT (Zeitgeber time) 6 and low at ZT 18 and 22. Light exposure increased Clock mRNA level in the SCN in phase dependent manner. The mRNA level was significantly increased during the subjective night (ZT10-22). The light had no effect on the mRNA level during the subjective day (ZT2 and 6). The Clock mRNA was also detected in the piriform cortex (PC), and increased by light at ZT14. These results suggest that Clock transcription in the SCN is involved in the photic signal transduction of circadian clock in rats. PMID- 10095083 TI - Dopamine D-1 regulation of caudate neurotensin mRNA in the presence or absence of the nigrostriatal dopamine pathway. AB - Changes in extrapyramidal dopamine (DA) function significantly alter the activity of striatal neurotensin (NT) systems. Specifically, stimulation of DA D-1 or D-2 receptors increases or decreases striatal NT tissue levels, respectively. In contrast, removal of D-2 receptor basal activity with either an antagonist or lesion of the nigrostriatal DA projection increases striatal NT content. To understand better the significance of these changes in the levels of NT peptide, we determined the effects of treatment with the selective D-1 agonist, SKF 82958, alone or in combination with a lesion of the nigrostriatal DA pathway, on the levels of NT mRNA in various regions of the caudate nucleus. Removal of at least 90% of this DA pathway significantly increased NT mRNA in most, but not all, regions throughout the caudate nucleus. In contrast, four, but not one, administrations of SKF 82958 (2 mg kg-1 dose-1) increased NT mRNA levels in principally middle, but not rostral, caudate regions. Lesioning the nigrostriatal DA pathway enhanced the effects of SKF 82958 so that a lower, single dose (1 mg/kg) of this D-1 agonist also increased NT mRNA levels predominantly in the middle caudate sections. These findings demonstrate that DA D-1 receptors profoundly regulate the striatal expression of NT mRNA in a regionally selective fashion, which appears to be unique from that principally influenced by DA D-2 regulation. PMID- 10095084 TI - Identification of cis-acting elements in the proximal promoter region for brain specific exon 1 of the mouse aromatase gene. AB - Among multiple exons 1 of the mouse aromatase gene, brain-specific exon 1 is only utilized in the hypothalamus and amygdala regions. In this study, identification of the promoter region necessary for basal transcription of the aromatase gene in the brain was undertaken. Deletions of various lengths were introduced into the overall promoter region, which was fused to the chloramphenicol acetyltransferase gene. The resulting reporters were transfected into cultured neurons from the diencephala of fetal mouse brains on embryonic day 13 and then their CAT mRNA levels were determined. The reporter plasmid containing the promoter region 202 bp upstream from the transcriptional initiation site gave the greatest expression. Then binding of trans-acting factors in a nuclear extract of the diencephala to the -202 bp promoter region was investigated by DNase I footprint analysis, multiple protected areas, referred to as Arom-Aalpha, Abeta, Agamma, B and C, being found. Gel shift assays, performed with oligonucleotides corresponding to the protected areas, showed that nuclear DNA binding factors form specific complexes exhibiting different mobilities. Substitution in the Arom Aalpha or -B sequence in the promoter region in the CAT reporters decreased the CAT mRNA expression levels to about one-fifth the wild type one. These results suggest that multiple nuclear factors bound to the core promoter region participate in the expression of the aromatase gene in mouse brain neurons. PMID- 10095085 TI - Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice. AB - Stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), a member of the MAP kinase (MAPK) superfamily, plays a key role in a variety of cellular processes. It is well established that SAPK/JNK activation is controlled by SEK1/MKK4, an up-stream MAP kinase kinase. To gain insight into the role of SEK1 during embryonic development and in adult life, we examined the temporal and spatial patterns of sek1 expression in mice by using in situ hybridization and immunohistochemical study. Dynamic changes of sek1 expression were observed during embryogenesis. Strong sek1 expression was detected in most of the central nervous system and in liver and thymus during early stages of development. While the sek1 expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of the sek1 expression in the central nervous system was persisted throughout postnatal development and remained at a stable level in adult brain. These observations provide an anatomical basis for the vital role(s) of SEK1 in development, for example, in hepatogenesis and/or neurogenesis. Although SEK1 was widely expressed in adult brain, more strong expression of the sek1 was observed at layers 2 and 6 in cerebral cortex, in Purkinje cells of cerebellum, and also in hypothalamic nuclei. The strongest expression of the sek1 was found in the CA3 region of hippocampus, the region being highly vulnerable to exitotoxicity-induced apoptosis in kainate-treated animal models. Interestingly, SEK1 was localized not only in cytoplasm but in dendrites and/or in nucleus of neurons depending on the regions of adult mouse brain. Taken together, these results suggest multiple roles of the SEK1 during embryogenesis and in adult brain. PMID- 10095086 TI - Expression of a serine protease (motopsin PRSS12) mRNA in the mouse brain: in situ hybridization histochemical study. AB - Serine proteases are considered to play several important roles in the brain. In an attempt to find novel brain-specific serine proteases (BSSPs), motopsin (PRSS 12) was cloned from a mouse brain cDNA library by polymerase chain reaction (PCR). Northern blot analysis demonstrated that the postnatal 10-day mouse brain contained the most amount of motopsin mRNA. At this developmental stage, in situ hybridization histochemistry showed that motopsin mRNA was specifically expressed in the following regions: cerebral cortical layers II/III, V and VIb, endopiriform cortex and the limbic system, particularly in the CA1 region of the hippocampal formation. In addition, in the brainstem, the oculomotor nucleus, trochlear nucleus, mecencephalic and motor nuclei of trigeminal nerve (N), abducens nucleus, facial nucleus, nucleus of the raphe pontis, dorsoral motor nucleus of vagal N, hypoglossal nucleus and ambiguus nucleus showed motopsin mRNA expression. Expression was also found in the anterior horn of the spinal cord. The above findings strongly suggest that neurons in almost all motor nuclei, particularly in the brainstem and spinal cord, express motopsin mRNA, and that motopsin seems to have a close relation to the functional role of efferent neurons. PMID- 10095088 TI - Presynaptic localization of the PACAP-typeI-receptor in hippocampal and cerebellar mossy fibres. AB - The distribution of PACAP-typeI-receptor (PACAP-I-R) mRNA and protein was studied in mouse using probes and a newly developed antiserum recognizing all known splice variants. RNase protection assays revealed highest expression levels of PACAP-I-R mRNA in brain, in particular the hypothalamus and hippocampus. At the cellular level, in situ hybridization analysis demonstrated widespread distribution of PACAP-I-R mRNA in neurons throughout the brain, while glial cells did not express the gene. Highest expression levels of PACAP-I-R mRNA were observed in three regions: the limbic system, the hypothalamus, and the brainstem. In accordance with data obtained from in situ hybridization analysis, immunohistochemistry showed widespread distribution of PACAP-I-R like immunoreactivity in the neuropil. Rather strong immunoreactivity was found in cerebellar and hippocampal mossy fibres where double immunolabelling revealed the presynaptic localization of the receptor protein. At the ultrastructural level, PACAP-I-R like immunoreactivity was observed around synaptic vesicles and close to the presynaptic grid in hippocampal mossy fibre terminals. This finding is in contradiction to the described postsynaptic localization of the PACAP-I-R in dendritic processes of hippocampal granule cells in rat. Due to their presynaptic induction, mossy fibre LTPs are distinctly different from LTPs in all other hippocampal regions. Therefore, the presynaptic localization of the PACAP-I-R in mossy fibre terminals may implicate this gene in influencing the synaptic strength of the mossy fibre pathway and hence memory consolidation. PMID- 10095087 TI - Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. AB - In Alzheimer's disease (AD), a progressive decline of cognitive functions is accompanied by neuropathology that includes the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature. We have proposed that a fragment of the Alzheimer amyloid precursor protein (APP) comprising the carboxyl-terminal 100 amino acids of this molecule (APP-C100) plays a crucial role in the neurodegeneration and subsequent cognitive decline in AD. To test this hypothesis, we performed behavioral analyses on transgenic mice expressing APP-C100 in the brain. The results revealed that homozygous APP-C100 transgenic mice were significantly impaired in cued, spatial and reversal performance of a Morris water maze task, that the degree of the impairment in the spatial learning was age-dependent, and that the homozygous mice displayed significantly more degeneration of neurons in Ammon's horn of the hippocampal formation than did heterozygous or control mice. Among the heterozygotes, females were relatively more impaired in their spatial learning than were males. These findings show that expression of APP-C100 in the brain can cause age-dependent cognitive impairments that are accompanied by hippocampal degeneration. PMID- 10095089 TI - Cyclic nucleotide-gated cation channel expression in embryonic chick brain. AB - Cyclic nucleotide-gated cation channels mediate sensory transduction in vertebrate photoreceptors and olfactory epithelium. These channels are also present in some non-sensory cells, but little is known of their physiological roles outside sensory systems. Using in situ hybridization we found that cyclic nucleotide channel mRNA is expressed specifically in the embryonic chicken forebrain, thalamus, optic tectum, basal midbrain and hindbrain, as well as in the branchial arches, limb buds and skin. Cyclic nucleotide gated channels may thus contribute to development or to cellular differentiation in the brain and in other tissues. PMID- 10095090 TI - Preproenkephalin mRNA and enkephalin levels in the adult Syrian hamster: the influence from glucocorticoids. AB - Proenkephalin (Penk) gene structure in hamsters and humans are similar but they differ from rats. In this study hamster Penk gene expression was examined after hypophysectomy+/-glucocorticoid receptor blockade with RU 486 (mifepristone). In contrast to rats, basal Penk gene expression in hamster adrenals did not change after treatments that reduced both the influence from glucocorticoids and phenylethanolamine-N-methyltransferase mRNA levels. Meanwhile, striatal preproenkephalin mRNA levels increased under these conditions. PMID- 10095091 TI - Acute intermittent morphine increases preprodynorphin and kappa opioid receptor mRNA levels in the rat brain. AB - We determined the effects of morphine on mRNA levels for the opioid ligands preprodynorphin (PPD) and preproenkephalin (PPE) and the kappa opioid receptor (KOR). Rats received six injections of morphine (6.25 mg/kg/injection) every 2 h, and were sacrificed 30 min later. mRNA levels were measured in brain tissue after removal of the cortex, cerebellum and brainstem. There were increases in PPD and KOR mRNA levels (P<0.05 and P<0.005, respectively), with no alteration of PPE. These alterations in the kappa/dynorphin system may counter morphine-induced effects on the brain. PMID- 10095092 TI - Phospholipase pathway in Alzheimer's disease brains: decrease in Galphai in dorsolateral prefrontal cortex. AB - There is substantial evidence that G-protein-associated signaling pathways in the brain are altered in Alzheimer's disease (AD). Using quantitative immunoblotting we find a significant decrease in Galphai levels in every AD case examined compared to controls (mean Galphai level in AD was 43.5+/-7.4% of control). Galphao levels were slightly decreased, but Galphaq and betagamma were normal. Phospholipase C-beta1, but not gamma1, levels were also decreased. Total phospholipase C activity and ceramide levels were not changed. Thus, in AD, there is impairment in the Galphai-associated signaling pathway in neurons. PMID- 10095093 TI - Regulation of hypothalamic somatostatin and growth hormone releasing hormone mRNA levels by inhibin. AB - Although it is well established that inhibin plays a major role in the regulation of the hypothalamic-pituitary-gonadal axis, its influence in the regulation of other neuroendocrine functions is still poorly understood. Recent results indicate that inhibin suppresses plasma GH levels, but its site of action is yet unknown. Therefore, in the present work we investigated the effects of inhibin on somatostatin and growth hormone releasing hormone (GHRH) mRNA levels in the hypothalamus by 'in situ' hybridization. We found that inhibin administration (4, 12 and 24 h, i.c.v.) led to an increase in somatostatin mRNA levels in the periventricular nucleus, and to a decrease in GHRH mRNA content in the arcuate nucleus of the hypothalamus. These findings indicate that inhibin regulates the hypothalamic levels of somatostatin and GHRH mRNA. PMID- 10095094 TI - Localization of mRNA for Dri 42, subtype 2b of phosphatidic acid phosphatase, in the rat brain during development. AB - The expression of a gene termed Dri 42, a differentiation-related gene originally identified from intestine and a gene encoding phosphatidic acid phosphatase 2b isoform, was localized in developing and matured rat brains by in situ hybridization histochemical analysis. The gene expression was dominant in the ventricular germinal zone without significant expression in the intermediate, mantle and marginal zones throughout embryonic brain and spinal cord. The dominant expression in the ventricular germinal zone was maintained at P0 and P7, but it markedly decreased at later postnatal stages, while persistently high expression was detected in Bergmann glial cells of the cerebellar Purkinje cell layer throughout the postnatal development. PMID- 10095096 TI - Regional and cellular localization of calcitonin gene-related peptide-receptor component protein mRNA in the guinea-pig central nervous system. AB - Recent cloning studies have isolated proteins which confer responsiveness to calcitonin gene-related peptide (CGRP). In this study, we have determined the central nervous system (CNS) distribution of the mRNA of one such protein, termed CGRP-receptor component protein (RCP), by in situ hybridization. CGRP-RCP mRNA was widely expressed in the guinea-pig CNS, being particularly abundant in cerebellum and hippocampus. These data should assist in the determination of the potential physiological function(s) of this protein in the CNS. PMID- 10095095 TI - Sex steroid modulation of neurokinin B gene expression in the arcuate nucleus of adult male rats. AB - Human menopause is associated with hypertrophy and increased gene expression of neurokinin (NKB) neurons in the infundibular (arcuate) nucleus of the hypothalamus. We have hypothesized that these changes are secondary to gonadal failure. In the present study, we determined that orchidectomy resulted in an increase in the mean profile area and the number of neurons expressing NKB mRNA in the rat arcuate nucleus. No changes were seen when orchidectomy was combined with testosterone or estradiol replacement. These findings support our hypothesis and demonstrate that gonadal steroids modulate NKB neurons in the arcuate nucleus of adult male rats. PMID- 10095097 TI - Inducible transcription factor expression in a cell culture model of apoptosis. AB - We have developed a model of nerve cell death based on the toxicity of okadaic acid, a compound that triggers apoptosis in PC12 cells via a protein synthesis dependent mechanism. The cell death process is accompanied by induction of JunB, c-Jun, JunD and Fos proteins. Phosphorylation-specific antibodies were used to demonstrate that c-Jun is phosphorylated at serine 63 and serine 73. Electrophoretic gel mobility shift and pAP1-Luc luciferase assays showed that expression of ITFs is associated with increases in AP-1 binding and in AP-1 transcriptional activity. In addition, dose response and time course studies provided strong correlative evidence that Fos and Jun proteins are involved in the apoptotic death cascades. Thus, this model provides a useful system to investigate the role of inducible transcription factor proteins in apoptosis. PMID- 10095098 TI - Genomic sequence and structural organization of mouse slow skeletal muscle troponin T gene. AB - Three muscle type-specific troponin T (TnT) genes are present in vertebrate to encode a number of protein isoforms via alternative mRNA splicing. While the genomic structures of cardiac and fast skeletal muscle TnT genes have been documented, this study cloned and characterized the slow skeletal muscle TnT (sTnT) gene. Complete nucleotide sequence and genomic organization revealed that the mouse sTnT gene spans 11.1kb and contains 14 exons, which is smaller and simpler than the fast skeletal muscle and cardiac TnT genes. Potentially representing a prototype of the TnT gene family, the 5'-region of the sTnT gene contains fewer unsplit large exons, among which two alternatively spliced exons are responsible for the NH2-terminal variation of three sTnT isoforms. The sTnT gene structure shows that the alternatively spliced central segment found in human sTnT cDNAs may be a result from splicing using an alternative acceptor site at the intron 11-exon 12 boundary. Together with the well-conserved protein structure, the highly specific expression of sTnT in slow skeletal muscles indicates a differentiated function of this member of the TnT gene family. The determination of genomic structure and alternative splicing pathways of sTnT gene lays a foundation to further understand the TnT structure-function evolution as well as contractile characteristics of different types of muscle fiber. PMID- 10095099 TI - Activation of the mouse inositol 1,4,5-trisphosphate receptor type 1 promoter by AP-2. AB - Inositol 1,4,5-trisphosphate receptor (IP3R) functions as a Ca2+ channel that increases the intracellular Ca2+ upon binding to inositol trisphosphates. IP3R is expressed ubiquitously and consists of a multigene family. Since the type 1 IP3R (IP3R1) is highly expressed in the cerebellar Purkinje cells and moderately in hippocampus in the mammalian central nervous system (CNS), it is regarded as a neural member of this gene family. In this work, we investigated transcriptional regulation of the mouse ip3r1 gene. A DNaseI footprinting assay demonstrated that a sequence from -95 to -75, designated as box-II, was a binding site for a cerebellum-enriched factor. A consensus sequence for AP-2 was located in box-II. An electrophoretic mobility shift assay with anti-AP-2 antibody revealed that AP 2 is capable of binding to box-II. Deletion analysis of box-II showed that flanking sequences beside the box-II motif were required for the stable binding. We demonstrated by transient luciferase assay that exogenously expressed AP-2 activated box-II-dependent transcription. Moreover, we showed that endogenous AP 2 induced by retinoic acid also activated transcription via box-II in P19 cells. In-situ hybridization of the mouse brain revealed that AP-2 was predominantly expressed in the cerebellar Purkinje cells and hippocampal CA1 region, where IP3R1 is also highly expressed. From these observations, AP-2 binding to box-II is thought to be responsible for IP3R1 gene regulation in the CNS. PMID- 10095100 TI - Efficient control of tetracycline-responsive gene expression from an autoregulated bi-directional expression vector. AB - The tetracycline-responsive expression system is based on the ability of the chimeric tTA and rtTA transactivators to stimulate specifically transcription from a companion synthetic CMV* or TK* promoter element, and can provide tightly regulated gene expression that can be induced up to five orders of magnitude in cultured cells and transgenic mice. A major problem with the system is that high level expression of the tTA or rtTA transactivators causes cellular toxicity. Under conditions of prolonged expression this results in selective pressure against the stable incorporation of vectors expressing the tTA or rtTA transactivators, and makes the generation of stable cell lines and transgenic mice problematic. In this report we describe the development of a set of autoregulated bi-directional expression vectors in which the weaker TK* promoter is used to direct expression of the rtTA or tTA transactivator and the stronger CMV* element is used to direct cDNA expression. In this format the transactivator and response elements are encoded on the same vector, which simplifies the system and ensures that gene expression is effectively skewed in favor of the cDNA while maintaining a continuously low level of transactivator expression. We find that such an autoregulated system works equally well for both the tTA and rtTA transactivators, provided that they contain a nuclear localization signal. Similar to other versions of the tetracycline-responsive expression system, gene expression is tightly regulated and can be efficiently switched between the off and on expression states by doxycycline. In contrast with other tetracycline responsive systems, however, expression of the rtTA and tTA transactivators from the autoregulated TK* promoter is low enough such that there is no cellular toxicity associated with either expression state. By incorporating a selectable marker into these vectors, all of the components required for using the system are now contained on a single plasmid construct, and we find that this format provides a more reliable and greatly simplified method for the generation of stable cell lines. PMID- 10095101 TI - Ballistic transformation of Caenorhabditis elegans. AB - A novel method to transform the nematode Caenorhabditis elegans is described. DNA coprecipitated with gold particles is shot at worms by means of a helium beam. Transformed worms are either identified by a dominant visible marker or selected by a conditional lethal system. PMID- 10095102 TI - Mass-murdering: deletion of twenty-three ORFs from Saccharomyces cerevisiae chromosome XI reveals five genes essential for growth and three genes conferring detectable mutant phenotype. AB - In the frame of the European Network for Functional Analysis (EUROFAN), two regions from chromosome XI covering 54kb have been subjected to 'mass-murder'. Ten deletions covering 23 novel open reading frames (ORFs) were constructed in haploid and diploid strains. Six deletions were lethal in haploid strains. One deletion caused slow germination of spores and slow cellular growth, and another one was associated with both cellular growth thermosensitivity and poor growth on glycerol. These two defects were assigned to two different genes. All mutant phenotypes were complemented by a single gene, enabling us to identify five genes essential for vegetative growth, three genes with detectable phenotype and 15 dispensable genes under standard physiological conditions. PMID- 10095103 TI - GEM, a cluster of repetitive sequences in the Drosophila subobscura genome. AB - GEM is a new family of repetitive sequences detected in the D. subobscura genome. Two of the four described GEM elements encompass a heterogeneous central module, with no detectable ORF, flanked by two long inverted repeats. These elements are composed of a set of repetitive modules, which are inverted repeat (IR), direct repeat (DR), palindromic sequence (PS), long sequence (LS) and short sequence (SS). These five modules can be found either clustered or dispersed as single modules in the D. subobscura genome, in euchromatic and heterochromatic regions. In addition to the 3' region of Adh retrosequences, single IR and LS blocks were found associated with the promoter region of different genes, in particular, LS like blocks have also been found associated with functional genes in D. melanogaster and D. virilis. Conversely, the DR block is highly similar to satellite DNAs from some other species of the obscura group. In addition, GEM elements share some structural features with IS elements described in different Drosophila species. It is likely that both GEM and IS sequences would be vestiges of an ancestral transposable element. PMID- 10095104 TI - An erythromycin resistance cassette and mini-transposon for constructing transcriptional fusions to cat. AB - A new cassette (Er-Cm cassette) and mini-transposon (mTn) (TnMaxErCm) based on the previously described mTn, TnMax2 [Haas et al., Gene 130, 23-31.], have been constructed. The cassette and mTn make use of an erythromycin resistance (ErR) marker encoded by ermC'. Both the Er-Cm cassette and TnMaxErCm also carry a promoterless cat gene to allow the construction of transcriptional fusions and the measurement of transcriptional activity by assaying for chloramphenicol acetyltransferase. We show the function of these genetic elements by analyzing the regulation of expression of the mglA gene of Francisella novicida and by using TnMaxErCm to probe for promoter activity within an F. novicida recombinant clone. The reporter cassette and mTn described here further expand the family of TnMax transposons and facilitate the study of gene expression in organisms where direct Tn mutagenesis methods are unavailable. PMID- 10095105 TI - Organization of the gene for gelatin-binding protein (GBP28). AB - GBP28 is a novel human plasma gelatin-binding protein that is encoded by apM1 mRNA, expressed specifically in adipose tissue. Three overlapping clones (two lambda clones and one BAC clone) containing the human plasma gelatin-binding protein (GBP28) gene were isolated and characterized. The GBP28 gene spans 16kb and is composed of three exons from 18bp to 4277bp in size with consensus splice sites. The sizes of the two introns were 0.8 and 12kb, respectively. The gene's regulatory sequences contain putative promoter elements, but no typical TATA box. The third exon of this gene contains a long 3'-untranslated sequence containing three Alu repeats. The exon-intron organization of this gene was very similar to that of obese gene, encoding leptin. We also report the chromosome mapping of this gene by fluorescence in situ hybridization (FISH) using a genomic DNA fragment as a probe. The GBP28 gene was located on human chromosome 3q27. The nucleotide sequence data reported in this paper will appear in the DDBJ/EMBL/GenBank nucleotide sequence databases with the accession numbers ABO12163, ABO12164 or ABO12165. PMID- 10095106 TI - TRAG-3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line. AB - The mechanisms responsible for the development of the taxol resistance phenotype are unclear, and are likely explained by multiple mechanisms. To understand the molecular changes associated with drug resistance more fully, a taxol-resistant subline, derived from the human ovarian cancer cell line SKOV-3, was established through selection by culture in incrementally increasing taxol concentrations. Comparison of SKOV-3 to SKOV-3TR by differential display identifies a new gene, TRAG-3 (Taxol Resistance Associated Gene- 3). In comparison to the parental line, SKOV-3, TRAG-3 mRNA is overexpressed in the taxol-resistant cell line SKOV-3TR. The nucleotide sequence of the TRAG-3 cDNA contains an open reading frame of 333bp that predicts for a protein product of 110 amino acids. A GenBank search identifies a cosmid clone containing a genomic sequence corresponding to that of TRAG-3. DNA and protein analysis reveals that TRAG-3 has no homology to any known cDNAs or proteins. Northern analysis demonstrates that TRAG-3 is overexpressed in the taxol-resistant breast cancer cell line MDA 435TR as well as the doxorubicin resistant multiple myeloma cell lines 8226/DOX40 and 8226/MDR10V. A survey of normal tissue shows minimal or absent TRAG-3 mRNA expression. Screening of a wide variety of cancer cell lines demonstrates TRAG-3 expression in many cell lines derived from different tissue types. In summary, TRAG-3 is a novel gene whose expression is associated with the chemotherapy-resistant and neoplastic phenotype. PMID- 10095107 TI - Cloning, expression and chromosomal localization of a human testis 6 phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene. AB - 6-Phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK-2/FBPase-2) is a bifunctional enzyme responsible for the synthesis and breakdown of Fru-2,6-P2, a key metabolite in the regulation of glycolysis. Several genes encode distinct PFK 2/FBPase-2 isozymes that differ in their tissue distribution and enzyme regulation. In this paper, we present the isolation of a cDNA from a human testis cDNA library that encodes a PFK-2/FBPase-2 isozyme. Sequencing data show an open reading frame of 1407 nucleotides that codifies for a protein of 469 amino acids. This has a calculated molecular weight of 54kDa and 97% similarity with rat testis PFK-2/FBPase-2, with complete conservation of the amino acid residues involved in the catalytic mechanism. Fluorescence in-situ hybridization (FISH) localized testis PFK-2/FBPase-2 gene (PFKFB4) in human chromosome 3 at bands p21 p22. A Northern blot analysis of different rat tissues showed the presence of a 2.4-kb mRNA expressed specifically in testis. In mammalian COS-1 cells, the human testis cDNA drives expression of an isozyme with a molecular weight of 55kDa. This isozyme shows clear PFK-2 activity. Taken together, these results provide evidence for a new PFK-2/FBPase-2 gene coding for a human testis isozyme. PMID- 10095108 TI - The gene for an abundant parasite coat protein predicts tandemly repetitive metal binding domains. AB - Immobilization antigens are highly abundant surface membrane proteins that coat the surface of hymenostomatid ciliates. While their function is unknown, recent studies with the common fish parasite, Ichthyophthirius multifiliis, suggest their involvement in a novel mechanism of humoral immunity involving an effect of antibody on parasite behavior. To gain further insight into the nature of these proteins, we have cloned a gene encoding the 48kDa i-antigen of I. multifiliis. Analysis of the gene (designated IAG48[G1]) reveals a single, uninterrupted reading frame that predicts a protein of 442 amino acids. Based on its deduced amino acid sequence, the protein contains hydrophobic amino acid domains at its N and C-terminus that are characteristic of signal peptide and GPI-anchor addition sites, respectively. The most striking feature of the predicted protein, however, is a series of tandem repeats that spans most of its length. The repeats themselves are characterized by periodic cysteine residues that fall into register when the homologous segments are aligned. Interestingly, the spacing of cysteines (C-X2,3-C) within a framework of larger (C-X2-C-X20-C-X3-C-X20-C-X2-C) motifs is entirely consistent with the structure of known zinc-binding proteins. Finally, comparison of the coding sequence of the 48kDa i-antigen gene with a partial cDNA previously thought to encode this protein reveals nearly complete identity except at their 3' ends, suggesting that alternative forms of the antigen exist. PMID- 10095109 TI - Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray. AB - The development of cancer is the result of a series of molecular changes occurring in the cell. These events lead to changes in the expression level of numerous genes that result in different phenotypic characteristics of tumors. In this report we describe the assembly and utilization of a 5766 member cDNA microarray to study the differences in gene expression between normal and neoplastic human ovarian tissues. Several genes that may have biological relevance in the process of ovarian carcinogenesis have been identified through this approach. Analyzing the results of microarray hybridizations may provides new leads for tumor diagnosis and intervention. PMID- 10095110 TI - Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster. AB - The related mouse proteins Miz1 and PIAS3, which have predicted zinc finger domains, interact with the transcription factors Msx2 and STAT3, modulating the ability of Msx2 and STAT3 to regulate transcription. Here, we describe a Drosophila gene, zimp, that encodes a protein with similarity to Miz1 and PIAS3. The zimp gene appears to be post-transcriptionally regulated, as three alternatively spliced forms are detected in a cDNA library screen and on an RNA blot. In addition, all three zimp transcripts are detected in embryonic mRNA, but only two of the transcripts are detected in adult mRNA. The three transcripts have the ability to encode two proteins, of 554 and 522 amino acids. The two Zimp amino acid sequences share an amino-terminal 515-amino-acid region and differ in their carboxy-termini. These proteins and related proteins in other organisms, including mammals, C. elegans, yeast, and plants, share a highly conserved region predicted to form a zinc finger. Deletion of the zimp gene or P-element insertion in zimp is lethal; thus, zimp is an essential gene in Drosophila. These data underscore the potential importance of Zimp-related proteins cross-species, and conservation of the putative zinc finger domain suggests that it is functionally important. PMID- 10095111 TI - Thermo-labile stability of sigmaH (Spo0H) in temperature-sensitive spo0H mutants of Bacillus subtilis can be suppressed by mutations in RNA polymerase beta subunit. AB - We isolated novel temperature-sensitive mutants of spo0H, spo0H1 and spo0H5, having E61K and G30E amino-acid substitutions within the sigmaH protein, respectively, and located in the highly conserved region, "2", among prokaryotic sigma factors that participates in binding to core enzyme of RNA polymerase. These mutants showed a sporulation-deficient phenotype at 43 degrees C. Moreover, we successfully isolated suppressor mutants that were spontaneously generated from the spo0H mutants. Our genetic analysis of these suppressor mutations revealed that the suppressor mutations are within the rpoB gene coding for the beta subunit of RNA polymerase. The mutations caused single amino-acid substitutions, E857A and P1055S, in rpoB18 and rpoB532 mutants that were generated from spo0H1 and spo0H5, respectively. Whereas the sigmaH-dependent expression of a spo0A-bgaB fusion was greatly reduced in both spo0H mutants, their expression was partially restored in the suppressor mutants at 43 degrees C. Western blot analysis showed that the level of sigmaH protein in the wild type increased between T0 and T2 and decreased after T3, while the level of sigmaH protein in spo0H mutants was greatly reduced throughout growth, indicating that the mutant sigmaH proteins were rapidly degraded by some unknown proteolytic enzyme(s). The analysis of the half-life of sigmaH protein showed that the short life of sigmaH in spo0H mutants is prolonged in the suppressor mutants. These findings suggest that, at least to some extent, the process of E-sigmaH formation may be involved in stabilization of sigmaH at the onset of sporulation. PMID- 10095112 TI - Isolation of a gene family that encodes the porin-like proteins from the human parasitic nematode Trichuris trichiura. AB - The major E/S protein of Trichuris trichiura, the human whipworm, is a highly immunogenic 47-kDa protein that has a pore forming activity that is thought to be essential for the attachment of the worm to host mucosal epithelium. By gene analysis, we have demonstrated that this protein belongs to a multigene family, and we have obtained genomic and cDNA information for two of these genes. The encoded proteins are composed of tandem arrays of alternating 50- and 51-amino acid domains within which the positioning of the cysteine residues is highly conserved. This structure resembles that of four disulphide core domain proteins, such as secretory leucocyte proteinase-1 (SLP-1), but the Trichuris protein family differs in being composed of multiple domains of this type (nine in TT50, 17 in TT95). An analysis of the relationship between the domains, and a comparison of the fine arrangement of the genes, suggests that TT95 has arisen relatively recently following duplication of the TT50 gene, which itself arose by duplication of a SLP-1-like ancestor. PMID- 10095113 TI - Rapid changes in the exon/intron structure of a mammalian thrombin inhibitor gene. AB - The genomic organization of the heparin cofactor II (HCII) gene from rat and mouse was investigated and compared with their human counterpart. The genes share a common core structure consisting of five exons interrupted by four introns, but the mouse and rat gene reveal individual additional features. A unique differentially spliced exon is present in the 5'-untranslated region of the rat gene, which most probably has arisen de novo by point mutations in intronic sequences of the ancestor gene. In the mouse HCII gene, a novel intron/exon boundary has been created due to the presence of an additional DNA segment, which simultaneously provides a 3'-splice site and a polypyrimidine stretch leading to an alternatively used exon of increased size. Our data suggest that, in contrast to most other mammalian genes, the exon/intron pattern of the gene coding for HCII is in dynamic evolution. PMID- 10095114 TI - A new series of pET-derived vectors for high efficiency expression of Pseudomonas exotoxin-based fusion proteins. AB - Recombinant immunotoxins (rITs) are highly specific anti-tumor agents composed of monoclonal antibody fragments or other specific carriers coupled to plant or bacterial toxins. A major problem in the purification of rITs is the low periplasmic yield in currently available expression systems. Thus, the aim of this study was the development of a new bacterial expression system for high level production of rITs. We constructed a series of pET-based vectors for pelB directed periplasmic secretion or cytoplasmic production under the control of the T7lac promoter. Expression in Escherichia coli BL21(DE3)pLysS allowed a tightly regulated isopropyl beta-d-thiogalactopyranoside (IPTG) induction of protein synthesis. An enterokinase-cleavable poly-histidine cluster was introduced into this setup for purification by affinity chromatography. A major modification resulted from the insertion of a specifically designed multiple cloning site. It contains only rare restriction enzyme recognition sites used for cloning of immunoglobulin variable region genes, as well as unique SfiI and NotI restriction sites for directed insertion of single-chain variable fragments (scFv) available from established bacteriophage systems. For this purpose, we deleted two naturally occurring internal SfiI consensus sites in a deletion mutant of Pseudomonas aeruginosa exotoxin A (ETA'). Each single structural element of the new vector (promoter, leader sequence, purification tag, scFv sequence, selectable marker, and toxin gene) was flanked by unique restriction sites allowing simple directional substitution. The fidelity of IPTG induction and high level expression were demonstrated using an anti-CD30 scFv (Ki-4) fused to ETA'. These data confirm a bacterial vector system especially designed for efficient periplasmic expression of ETA'-based fusion toxins. PMID- 10095115 TI - Four rice genes encoding cysteine synthase: isolation and differential responses to sulfur, nitrogen and light. AB - Four cDNA clones, rcs1, rcs2, rcs3 and rcs4, encoding cysteine synthase [O acetylserine(thiol)lyase] were isolated from rice. The predicted amino acid sequences contain the conserved PXXSVKDR region characteristic of cysteine synthase, which includes the lysine residue that binds the cofactor, pyridoxal 5' phosphate. Molecular phylogenic analysis suggests that, whereas rcs1 and rcs3 belong to the cytosolic isoform family, rcs2 and rcs4 form a new family of cysteine synthase. Transcript accumulation of each gene was examined for organ specificity, and also for response to sulfur, nitrogen and light. The rcs1 transcript accumulated in all organs examined, and was induced in shoots and roots upon sulfur starvation under non-limiting nitrogen conditions. The rcs2 transcript accumulated in shoots grown in the light, but disappeared almost completely by dark treatment. The rcs3 transcript was found more abundantly in roots than in shoots, and was reduced in the dark, as well as under sulfur and nitrogen deprivation. The rcs4 transcript was scarce in all organs examined. These observations indicate that cysteine synthase genes encode functionally distinct cysteine synthase isoforms, and that they are coordinately regulated by the availability of sulfur, nitrogen, and light. PMID- 10095116 TI - The structural organization of the ascidian, Halocynthia roretzi, calmodulin genes. The vicissitude of introns during the evolution of calmodulin genes. AB - Two distinct calmodulin (CaM) genes are isolated from the ascidian, Halocynthia roretzi, (Hr-CaM A and Hr-CaM B) and those structures are determined. There are three nucleotide substitutions, producing two amino acid differences between Hr CaM A and Hr-CaM B, and those are corresponding to two of the known eight variable residues among metazoan CaMs. Both Hr-CaM A and Hr-CaM B are constructed from six exons and five introns, and the positions of introns are identical. The positions of introns of Hr-CaMs are also identical with those of vertebrate CaMs, except third introns. The third introns of Hr-CaMs are inserted at 28bp upstream when compared with vertebrate CaMs. Thus, sliding of the third intron might have occurred in only the ascidian lineage prior to the gene duplication that also occurred only in that lineage. In addition, with the comparison of the intron positions, we attempt to investigate the vicissitude of introns during the evolution of metazoan CaMs. PMID- 10095117 TI - Characterisation of novel plant genes encoding MEKK/STE11 and RAF-related protein kinases. AB - Various elements of the MAP kinase module have been isolated in plants. We describe here the characterisation of 14 new plant cDNAs and genes encoding putative MAP kinase kinase kinases (MAP3Ks) related to the MEKK/STE11 and RAF protein kinases. Plant MAP3Ks are characterised by a variety of primary structures conserved within closely related proteins. Southern blot analysis suggests that plant MAP3Ks are heterogenous in their genomic structure, existing either as single copy genes or as small gene families. An RT-PCR analysis showed that in Arabidopsis thaliana, all organs studied contain detectable levels of transcripts of each of the MAP3K genes identified; however, signals obtained with mature pollen were weak or non-existent except for AtMAP3Kgamma. None of the reported genes share a cell-cycle or a cold stress regulated expression. PMID- 10095118 TI - Translation elongation factor 2 is encoded by a single essential gene in Candida albicans. AB - Translation elongation factor 2 (eEF2) is a large protein of more than 800 amino acids which establishes complex interactions with the ribosome in order to catalyze the conformational changes needed for translation elongation. Unlike other yeasts, the pathogenic fungus Candida albicans was found to have a single gene encoding this factor per haploid genome, located on chromosome 2. Expression of this locus is essential for vegetative growth, as evidenced by placing it under the control of a repressible promoter. This C. albicans gene, named EFT2, was cloned and sequenced (EMBL accession number Y09664). Genomic and cDNA sequence analysis identified common transcription initiation and termination signals and an 842 amino acid open reading frame (ORF), which is interrupted by a single intron. Despite some genetic differences, CaEFT2 was capable of complementing a Saccharomyces cerevisiae Deltaeft1 Deltaeft2 null mutant, which lacks endogenous eEF2, indicating that CaEFT2 can be expressed from its own promoter and its intron can be correctly spliced in S. cerevisiae. PMID- 10095119 TI - YAC fragmentation with repetitive and single-copy sequences: detailed physical mapping of the presenilin 1 gene on chromosome 14. AB - We constructed new LYS2 fragmentation vectors that allow direct acentric and centric fragmentation of yeast artificial chromosomes (YACs) and selection of fragmented YACs in yeast strain AB1380. The fragmentation vectors were used efficiently with repetitive (e.g., Alu), low-copy (e.g., CA-repeats) and single copy (e.g., exons) sequences. High recombination efficiencies were obtained in fragmenting two different CEPH YACs with the Alu consensus sequence as target sequences for homologous recombination. Analysis of the acentric Alu fragmentation panel of 788H12, containing the presenilin 1 (PSEN1) gene for familial Alzheimer's disease (AD), indicated that high-resolution YAC fragmentation panels covering the entire parent YAC are obtained. Also, marker content analysis of the fragmentation panel indicated that fragmented YACs were propagated stably without rearrangements. The same fragmentation vectors were used efficiently for fragmentation of 788H12 with unique sequences, i.e., exons 3 and 12 of PSEN1 and D14S77, a polymorphic CA repeat, as target sequences. Together, our YAC fragmentation data of 788H12 provided a size estimate for the coding region of PSEN1 of 60kb and a more precise localization of D14S77 at 25kb upstream of PSEN1. PMID- 10095120 TI - Characterization of the 5'-flanking region of the human RNA-specific adenosine deaminase ADAR1 gene and identification of an interferon-inducible ADAR1 promoter. AB - The double-stranded RNA-specific adenosine deaminase (ADAR1) is inducible by interferon (IFN) and is implicated in the editing of viral RNAs during lytic and persistent infection. We have now isolated and characterized human genomic clones that contain the promoter region required for transcription of the ADAR1 gene. Rapid amplification of cDNA 5'-ends (5'-RACE) identified additional upstream exon 1 sequence that was localized on P1-phage and lambda-phage genomic clones by Southern gel-blot analysis and sequence analysis. A Northern gel-blot analysis using a probe corresponding to the 5'-RACE exon 1 sequence and adjacent exon 2 sequence detected a major RNA transcript of approximately 6.7kb that was IFN inducible in human amnion U cells. Transient transfection assays, using chloramphenicol acetyltransferase (CAT) as the reporter in constructs possessing various 5'-flanking fragments of the ADAR1 gene, led to the identification of a functional TATA-less promoter that directed IFN-inducible transcription of CAT. Sequence determination and deletion analysis of the promoter region revealed a consensus copy of the IFN-Stimulated Response Element (ISRE) involved in IFN inducibility that was flanked by a Kinase Conserved Sequence (KCS)-like element previously found to be unique to the human and mouse PKR gene promoters. A 63-bp minimal promoter fragment possessing the KCS-like and ISRE elements was sufficient to drive IFN-inducible transcription. PMID- 10095121 TI - Interaction of the p23/p198 protein with ErbB-3. AB - The processes by which the kinase inactive receptor ErbB-3 transmits the signals of its ligand, heregulin (HRG), are incompletely understood. We used a yeast two hybrid system to identify ErbB-3 interacting proteins that may participate in HRG signal transduction. We found that the protein p23, the human homolog of the mouse transplantation antigen P198, interacted with the cytoplasmic domain of ErbB-3 in the yeast two-hybrid system. P23 bound the 26-amino-acid juxtamembrane domain of ErbB-3 in vitro. The N-terminal end of p23 contained the ErbB-3 interacting region. P23 also bound to ErbB-3 in a human breast cell line. Two p23 mRNA transcripts were detected in normal human epithelial tissues including those of the heart, placenta, lung, brain, kidney, pancreas, skeletal muscle, and liver. These same transcripts were also detected in ErbB-3 overexpressing human tumor cell lines derived from breast and lung carcinomas, and a sarcoma. Transfection of p23 resulted in suppression of colony formation of the ErbB-3 overexpressing human breast cancer cell line, AU565, a decreased rate of cell growth, and induction of differentiation. The interaction of ErbB3 and p23 may play a role in regulation of proliferation of ErbB-3 expressing cells. PMID- 10095122 TI - Cloning and chromosomal localization of the gene encoding human cyclin D-binding Myb-like protein (hDMP1). AB - The murine transcription factor murine cyclin D-binding Myb-like protein (mDmp1) arrests the cell cycle in G1 phase, through an activity that can be overridden by direct interaction with the D-type cyclins. Here, we describe the identification, sequence, chromosomal localization, and expression of the human cognate, hDMP1. The hDMP1 cDNA contains a 2280bp open reading frame that shares a high degree of identity with the mDmp1 coding region. The 4.4kb hDMP1 messenger RNA is ubiquitously expressed in normal human tissues, with highest levels in testis and substructures within the brain. By use of fluorescence in situ hybridization with a human genomic P1 probe, we assigned hDMP1 to chromosome 7, band q21. This chromosomal region is frequently deleted as part of the 7q-minus and monosomy 7 abnormalities of human acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We analyzed hDMP1 copy number by fluorescence in situ hybridization in leukemic blasts from nine patients with abnormalities of the long arm of chromosome 7, and in each case one allele of the hDMP1 gene was deleted. Functional analysis of the mDmp1 protein has shown that it negatively regulates cell proliferation, which suggests that this gene is a candidate suppressor of malignant transformation. Further study will be needed to determine whether gene specific mutations implicate hDMP1 as a tumor suppressor in acute leukemias with deletions of the long arm of chromosome 7 or in other types of human malignancy. PMID- 10095123 TI - A plasmid-encoded two-component regulatory system involved in copper-inducible transcription in Lactococcus lactis. AB - Two regulatory genes (lcoR and lcoS) were identified from a plasmid-borne lactococcal copper resistance determinant and characterized by transcriptional fusion to the promoterless chloramphenicol acetyltransferase gene (cat). RT-PCR analysis indicates that lcoR and lcoS are organized within an operon, controlling the transcription of cat in a copper-inducible manner. The amino acid sequences deduced from lcoR and lcoS show homology to the response and sensor proteins of known two-component regulatory systems. Deletion within either lcoS or both genes inactivated the copper-dependent activity, suggesting the presence of no trans acting lcoR and lcoS homologs in the lactococcal host chromosome. The transcription start site involved in copper induction was mapped by primer extension. PMID- 10095125 TI - Lack of adverse effect of smoking habit on DNA strand breakage and base damage, as revealed by the alkaline comet assay. AB - In our preceding papers [M. Wojewodzka, M. Kruszewski, T. Iwanenko, A.R. Collins, I. Szumiel, Application of the comet assay for monitoring DNA damage in workers exposed to chronic low dose irradiation: I. Strand breakage, Mutat. Res., 416 (1998) 21-35; M. Kruszewski, M. Wojewodzka, T. Iwanenko, A.R. Collins, I. Szumiel, Application of the comet assay for monitoring DNA damage in workers exposed to chronic low dose irradiation: II. Base damage, Mutat. Res. , 416 (1998) 37-57.], we evaluated the DNA breakage and base damage with the use of comet assay in a group of 49 workers chronically exposed to low doses of ionizing radiation. There was a statistically significant difference in the damage levels between the hazard and control group. In this paper we describe a confounding lack of effect of the smoking habit on the DNA damage in the tested groups. The genotoxic effect of the smoking habit, as well as its modifying effect on genome damage inflicted by other agents, have been firmly established. However, no statistically significant effect of smoking was found in our study, neither in the control nor in the hazard group. This lack of effect was seen in all DNA damage determinations, both direct (DNA strand breakage and alkali-labile lesions) and enzyme-combined (base damage) and did not depend on the comet parameters, which were taken as damage indicators. PMID- 10095124 TI - The alkaline single cell gel electrophoresis assay with mouse multiple organs: results with 30 aromatic amines evaluated by the IARC and U.S. NTP. AB - The genotoxicity of 30 aromatic amines selected from IARC (International Agency for Research on Cancer) groups 1, 2A, 2B and 3 and from the U.S. NTP (National Toxicology Program) carcinogenicity database were evaluated using the alkaline single cell gel electrophoresis (SCG) (Comet) assay in mouse organs. We treated groups of four mice once orally at the maximum tolerated dose (MTD) and sampled stomach, colon, liver, kidney, bladder, lung, brain, and bone marrow 3, 8 and 24 h after treatment. For the 20 aromatic amines that are rodent carcinogens, the assay was positive in at least one organ, suggesting a high predictive ability for the assay. For most of the SCG-positive aromatic amines, the organs exhibiting increased levels of DNA damage were not necessarily the target organs for carcinogenicity. It was rare, in contrast, for the target organs not to show DNA damage. Organ-specific genotoxicity, therefore, is necessary but not sufficient for the prediction of organ-specific carcinogenicity. For the 10 non carcinogenic aromatic amines (eight were Ames test-positive and two were Ames test-negative), the assay was negative in all organs studied. In the safety evaluation of chemicals, it is important to demonstrate that Ames test-positive agents are not genotoxic in vivo. Chemical carcinogens can be classified as genotoxic (Ames test-positive) and putative non-genotoxic (Ames test-negative) carcinogens. The alkaline SCG assay, which detects DNA lesions, is not suitable for identifying non-genotoxic carcinogens. The present SCG study revealed a high positive response ratio for rodent genotoxic carcinogens and a high negative response ratio for rodent genotoxic non-carcinogens. These results suggest that the alkaline SCG assay can be usefully used to evaluate the in vivo genotoxicity of chemicals in multiple organs, providing for a good assessment of potential carcinogenicity. PMID- 10095126 TI - Influence of metabolic genotype GSTM1 on levels of urinary mutagens in patients treated topically with coal tar. AB - Fifteen hospitalized, non-smoking, dermatological patients were treated with ointment containing 2% coal tar (CT) in order to assess the influence of metabolic genotype GSTM1 on urinary mutagen levels. Urinary 1-pyrenol, the main metabolite of pyrene, was used to check the high exposure to PAH of this population. The mean levels of urinary 1-pyrenol found in the 24-h urine of our patients were 467. 8+/-211.0 nmoles-24 h (range 94.6-890.1 nmoles-24 h). Mutagenicity was assessed on urine samples collected over a period of 24 h, after three consecutive days of topical application, using the bacterial mutagenesis test on Salmonella typhimurium strains TA98 and YG1024 in the presence of microsomal enzymes. The latter strain turned out to be more sensitive than the former in revealing urinary mutagens in these patients (42 693+/-30 867 vs. 6877+/-6040 net revertants-24 h). The mutagenicity on YG1024 strain and 1-pyrenol levels of urine samples were correlated (Spearman's rank correlation coefficient=0. 6678, P<0.01, z=2.795). The influence of genotype GSTM1 on urinary mutagen levels was assessed on strain YG1024. The values of urinary mutagenicity of subjects with genotype GSTM1-null (n=6) were on average higher than those of GSTM1-positive subjects (n=9) (55 498+/-45 957 vs. 34 156+/-11 933 net rev.-24 h), a non-significant statistical difference. The mean total excretion of mutagens corrected for PAH exposure (net rev./nmoles of urinary 1-pyrenol) in GSTM1-null patients was double that of GSTM1-positive ones (136. 8+/-34.7 vs. 70.8+/-23.3 net rev./nmoles of urinary 1-pyrenol; one-tailed Mann-Whitney U-test, U=11.5, P<0.05). These results indicate a greater body burden of promutagens, resulting from skin application of CT, in GSTM1-null subjects. PMID- 10095127 TI - Micronucleus frequency in Gomel (Belarus) children affected and not affected by thyroid cancer. AB - Cytogenetic monitoring was carried out on a group of children from Gomel (Belarus), one of the areas most severely affected by radioactive contamination following the accident at the Chernobyl nuclear power plant, in 1986. We performed the micronucleus test (MN) in binucleated lymphocytes of 42 children (mean age: 11+/-2.34 years), 16 of whom were affected by thyroid gland tumor. Thirty healthy children living in Pisa (mean age: 14.96+/-2.17 years) were enrolled in the study as controls. Thyroid tumor affected children living in Gomel showed a statistically significant increase in the frequency of micronucleated cells as compared with the healthy children from Pisa. Moreover, a significant correlation was found between MN frequency and both the presence of tumor and higher 137Cs contamination. In addition, higher 137Cs contamination was more frequently observed in tumor affected children. These results suggest that the increased MN frequency is attributable more to 137Cs contamination rather than to the presence of the tumor itself. PMID- 10095128 TI - Genotoxicity and embryotoxicity of urban air particulate matter collected during winter and summer period in two different districts of the Czech Republic. AB - This study is the in vitro part of a long-term program to investigate the impact of air pollution on the health of a population in a polluted region of Northern Bohemia. In order to assess the possible health risks associated with a complex mixture of hundreds of organic compounds adsorbed to air particles, we used a biomarker-directed fractionation procedure to evaluate biological activities of different chemical compound classes. The extractable organic compounds from the air particles collected in both the polluted and the control districts during the summers and winters of 1993-1994 were investigated. The principal aim of this study was to compare the DNA binding activities of those compound classes using an in vitro acellular assay coupled with 32P-postlabeling and an embryotoxicity assay using Chick Embryotoxicity Screening Test (CHEST). In both assays, the highest activity was due to the neutral fractions from which the aromatic subfractions containing mainly polycyclic aromatic hydrocarbons (PAHs) and their methyl-derivates were the most active for both localities and seasons. A good correlation between the levels of DNA adduct formation using S9 metabolic activation and the ED50 for all different complex mixtures of organic compounds was observed (r=0.773, p<0.001). DNA adduct maps and high performance liquid chromatography (HPLC) profiles were similar for samples from both districts and seasons. The major DNA adducts resulting from the crude extracts were identical to those derived from aromatic fractions. The DNA adducts tentatively identified constituted about 50% of the total adducts formed by the crude extracts following S9-metabolic activation. Our results confirmed the similarities of the major ubiquitous emission sources of organic compounds in both districts. This is the first report in which the biological activities of complex mixtures in short-term assays with remarkably different endpoints such as DNA adduct formation and embryotoxicity have been compared. PMID- 10095129 TI - Mutation spectra of chemical mutagens determined by Lac+ reversion assay with Escherichia coli WP3101P-WP3106P tester strains. AB - We previously reported the development of mutation-specific Escherichia coli B tester strains WP3101 to WP3106 from strain WP2uvrA. In this study we constructed their pKM101-containing derivatives WP3101P to WP3106P, and further isolated their rfa derivatives WP4101-WP4106 and WP4101P-WP4106P. The six kinds of F' plasmids (lacI-, lacZ-, proAB+), each of which carries a different lacZ allele, contained in the above strains were originally derived from E. coli K-12 strains CC101-CC106. All the tester strains show Lac- and Trp- phenotype. Assays for transitions and transversions are based upon Lac+ reversion of a specific mutation located within the lacZ gene on an F' plasmid. The trpE65(ochre) allele in the same strains enables them to be used for Trp+ reversion assays as well. In the present paper, we evaluated the sensitivity, specificity, and usefulness of the newly developed tester strains. Strains WP3101P-WP3106P were highly sensitive to determine mutational profile of heterocyclic amines with S9 mix-mediated metabolic activation and most of the oxidative mutagens and free radical generators tested. Every type of base-pair substitutions induced by 2-amino-3,4 dimethylimidazo[4,5-f]quinoline (MeIQ) or 5-diazouracil were detected in strains WP3101P-WP3106P, while A:T-->C:G and G:C-->A:T mutations induced by MeIQ, and A:T ->C:G, G:C-->A:T, and G:C-->C:G by 5-diazouracil were not detected in pKM101-free tester strains. In pKM101-carrying strains, cumene hydroperoxide induced all types of base substitutions, while formaldehyde preferentially induced G:C-->T:A transversions. Phenazine methosulfate induced predominantly G:C-->A:T transitions and G:C-->T:A transversions, while H2O2 induced predominantly G:C-->T:A and A:T- >T:A transversions. Introduction of the rfa mutation considerably enhanced sensitivity to bulky mutagens such as polycyclic aromatic compounds. All six possible base substitutions induced by 9, 10-dimethyl-1,2-benzanthracene (DMBA) were detected in tester strains WP4101P-WP4106P. In conclusion, our tester strains WP3101P-WP3106P and WP4101P-WP4106P permitted rapid and simple detection of specific mutations induced by variety of mutagens. PMID- 10095130 TI - Effects of exposure protocols on induction of kinetochore-plus and -minus micronuclei by arsenite in diploid human fibroblasts. AB - Arsenic, widely distributed in the environment, is a potent human carcinogen. Arsenite genotoxicity has been observed in a variety of cells and animal systems. However, the underlying mechanism is not completely clear. In this study, human fibroblasts (HFW) were treated with 1.25-10 microM arsenite for 24 h (low dose and long exposure) and 5-80 microM for 4 h (high dose and short exposure), and the arsenite accumulation, cytotoxicity, and micronucleus (MN) induction were examined. By these two different protocols, HFW cells showed equivalent levels of arsenite accumulation, but exhibited different kinetics of cell killing and different types of MN generation. Arsenite induced mainly kinetochore-positive MN (K+-MN) in HFW cells by low dose exposure whereas mainly kinetochore-negative MN (K--MN) was induced by high dose exposure. Catalase reduced both K+- and K--MN induced by these two exposure protocols. Except for the case of K+-MN induction by the high dose exposure protocol, N-acetyl-cysteine (NAC) in both low and high dose protocols was also shown to effectively reduce arsenite-induced MN. The present results imply that oxidative stress is involved in arsenite-induced MN in diploid human fibroblasts. However, different protocols for arsenite exposure may result in different cellular damage. PMID- 10095131 TI - beta-carotene as enhancer of cell transforming activity of powerful carcinogens and cigarette-smoke condensate on BALB/c 3T3 cells in vitro. AB - We report the ability of beta-carotene (betaC) to affect the cell transforming activity of 3-methylcholanthrene (3-MCA), benzo(a)pyrene (B(a)P) and cigarette smoke condensate (TAR) in an in vitro medium-term (approximately 8 weeks) experimental model utilizing BALB/c 3T3 cells. Different experimental schedules were performed either in the presence or absence of betaC: (i) cultures treated for 72 h with each chemical (acute treatment), (ii) cultures grown in presence of each chemical for the whole period of the experiment (chronic treatment). These procedures suggested a possible cocarcinogenic potential of the carotenoid following interactions with other chemicals mimicking continuous human exposition to several xenobiotics. Although the pigment did not show any cell transforming potential when tested alone either in acute or chronic treatment, it did augment that of other tested agents. Induction of cell transformation by B(a)P was markedly enhanced by the presence of this carotenoid in either acute or chronic treatment. Only in presence of betaC, was TAR able to significantly act as a cell transforming agent in prolonged, chronic treatment of cultures. Enhanced cell transformation activity could be due to the boosting effect of betaC on P450 apparatus. Indeed, elsewhere we have found that the latter increased the ratio of formation of diol epoxide carcinogenic metabolites of B(a)P as well as other carcinogens present in TAR. By contrast, no differences of cell transforming activity of 3-MCA, an ultimate carcinogen, were seen either in the presence or absence of betaC under the various experimental conditions. These data, which are in keeping with the cocarcinogenic potential of betaC, may help to explain the unexpected lung cancer increases obtained in chemoprevention trials in heavy smokers supplemented with the isoprenoid. Our findings also highlight the potential risk to humans derived from interactions among xenobiotics present in the environment. PMID- 10095132 TI - Inhibition of xenobiotic-induced genotoxicity in cultured precision-cut human and rat liver slices. AB - In this study precision-cut liver slices have been used to evaluate the effects of the flavone tangeretin, the flavonoid glycoside naringin and the flavanone naringenin (the aglycone derived from naringin) on xenobiotic-induced genotoxicity. Liver slices were cultured for 24 h in medium containing [3H]thymidine and the test compounds and then processed for autoradiographic determination of unscheduled DNA synthesis (UDS). The cooked food mutagen 2-amino 1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) markedly induced UDS in cultured human liver slices and both 2-acetylaminofluorene (2-AAF) and aflatoxin B1 (AFB1) induced UDS in cultured rat liver slices. Tangeretin (20 and 50 microM) was found to be a potent inhibitor of 5 and 50 microM PhIP-induced UDS in human liver slices, whereas 20 and 50 microM naringenin was ineffective and naringin only inhibited genotoxicity at a concentration of 1000 microM. In rat liver slices 50 microM tangeretin inhibited 10 and 50 microM 2-AAF-induced UDS, whereas 50 microM naringenin and 100 and 1000 microM naringin were ineffective. None of the three flavonoids examined inhibited 5 microM AFB1-induced UDS in rat liver slices. The inhibition of PhIP- and 2-AAF-induced UDS by tangeretin is probably attributable to the inhibition of the human and rat cytochrome P-450 isoforms which are responsible for the bioactivation of these two genotoxins. Although flavonoids can modulate xenobiotic-induced genotoxicity in human and rat liver slices, any protective effect is dependent on the particular combination of genotoxin and flavonoid examined. These results demonstrate that cultured precision-cut liver slices may be utilised as an in vitro model system to examine the modulation of xenobiotic-induced genotoxicity by flavonoids and other dietary components. PMID- 10095133 TI - An estimator of the mutant frequency in assays using transgenic animals. AB - The Poisson distribution is a fundamental probability model for count data, and is a natural model for the observed plaque counts in mutation assays using animals with lambda or PhiX174 transgenes. The Poisson likelihood for observed counts is a function of the mutant fraction, and it is straightforward to derive the associated maximum likelihood estimate of the mutant fraction and its variance. The estimate is easy to calculate, and if not the same, very similar to ad hoc estimates in current use. The model indicates the proper way to combine data from a number of plates, possibly prepared with different sample dilutions. The estimator of the mutant fraction is biased as a consequence of dividing by a random variable, the plaque count used to calculate the total recovered plaque forming units. Fortunately, the bias becomes negligible as this count becomes large. On the other hand, increasing this count can increase the variance by decreasing the amount of sample assayed for mutant phages. Concurrent heed to the bias and the variance provides some guidance as to the optimum allocation of a sample into portions assayed for mutant phages and total recovered phages. The distribution of the estimate of the mutant fraction is related to the binomial distribution. This relationship implies a binomial distribution for the mutant count conditional on an overall count (either the sum of mutant and counted total plaques or the sum of counted mutant and non-mutant plaques). A special but important case occurs when each plate can be evaluated for mutant plaques and non mutant plaques. Then, the observed proportion of mutants estimates the mutant fraction. More generally, the relationship to a binomial distribution provides a procedure for calculating a confidence interval. PMID- 10095134 TI - Synergistic induction of hydroxyl radical-induced DNA single-strand breaks by chromium(VI) compound and cigarette smoke solution. AB - Chromium(VI) compounds and cigarette smoke are known human carcinogens. We found that K2Cr2O7 and cigarette smoke solution synergistically induced DNA single strand breaks (0.23+/-0.04 breaks per DNA molecule) in pUC118 plasmid DNA. K2Cr2O7 alone or cigarette smoke solution alone induced much less strand breaks (0.03+/-0.01 or 0.07+/-0.02 breaks per DNA molecule, respectively). The synergistic effect was prevented by catalase and by hydroxyl radical scavengers such as deferoxamine, dimethylsulfoxide, d-mannitol, and Tris, but not by superoxide dismutase. Ascorbic acid enhanced the synergism. Glutathione inhibited strand breakage only at high concentrations. Electron spin resonance (ESR) studies using a hydroxyl radical trap demonstrated that hydroxyl radicals were generated when DNA was incubated with K2Cr2O7 and cigarette smoke solution. Hydroxyl radical adduct decreased dose-dependently when strand breakage was prevented by catalase, deferoxamine, dimethylsulfoxide, d-mannitol or Tris, but not significantly by superoxide dismutase. We also used ESR spectroscopy to study the effects of different concentration of ascorbic acid and glutathione. The results showed that hydroxyl radical, which is proposed as a main carcinogenic mechanism for both chromium(VI) compounds and cigarette smoke solution was mainly responsible for the DNA breaks they induced. PMID- 10095135 TI - Reflections in mutation research: an introductory essay. PMID- 10095136 TI - The first oncogene in Drosophila melanogaster. AB - Discovered by Bridges in the 1930s, lethal (2) giant larvae was the first of more than 27 recessive oncogenes identified in Drosophila, which provides an excellent model to study neoplastic mechanisms due to the fact that homologs of human oncogenes and tumor suppressors have been isolated and most of the complexes and associated pathways are conserved. This review explores the potential of neoplastic studies in Drosophila to help understand the genomic mechanisms of neoplastic development in vertebrates and invertebrates. Starting from neoplasms and genetic mutations, the article introduces the reader to one of the possibilities that the studies on neoplastic mechanisms of oncogenes in Drosophila can provide a great understanding of the developmental progression in both vertebrates and invertebrates. PMID- 10095137 TI - Genotoxicity testing of biotechnology-derived products. Report of a GUM task force. Gesellschaft fur Umweltmutationsforschung. AB - Various aspects of genotoxicity testing of biotechnology-derived products are discussed based on information gathered from a questionnaire which was sent to about 30 predominantly European companies. Feedback was received from 13 companies on 78 compounds, mostly recombinant proteins but also on a number of nonrecombinant proteins, which had been assessed for genotoxicity in a total of 177 tests. Four of the 78 compounds appeared to elicit reproducible genotoxic effects. For one of these compounds, the activity could be related to a nonpeptidic linker molecule. No scientifically convincing rationale for the other three compounds could be established, although, at least for two compounds, their activity may be connected with the enzymatic/hormonal activity. In addition to the survey, published reports on genotoxicity testing of biotechnology products were reviewed. The data are discussed relative to whether genotoxicity testing is a valuable exercise when assessing potentially toxic liabilities of biotechnology derived compounds. It is concluded that genotoxicity testing is generally inappropriate and unnecessary, a position which is in accordance with the available guidelines addressing this area. For the 'average' protein, electrophilic reactions are difficult to envision. Indirect reactions via DNA metabolism and growth regulation seem possible for only very specific proteins such as nucleases, growth factors, cytokines. No information on testing of different types of biotechnology-derived products (e.g., ribozymes, antisense oligonucleotides, DNA vaccines) has been received in the questionnaires. Discussion of their potential to cause genotoxic changes was based on literature reports. Even for those products for which concerns of genotoxic/tumourigenic potential cannot be completely ruled out, e.g., because of their interaction with DNA metabolism or proliferation control, the performance of standard genotoxicity assays generally appears to be of little value. All information, including also information on the occurrence of genotoxic impurities, has been utilized to formulate a decision tree approach for the genotoxicity testing of biotechnology derived products. PMID- 10095138 TI - Somatic hypermutation and the three R's: repair, replication and recombination. AB - Somatic hypermutation introduces single base changes into the rearranged variable (V) regions of antigen activated B cells at a rate of approximately 1 mutation per kilobase per generation. This is nearly a million-fold higher than the typical mutation rate in a mammalian somatic cell. Rampant mutation at this level could have a devastating effect, but somatic hypermutation is accurately targeted and tightly regulated. Here, we provide an overview of immunoglobulin gene somatic hypermutation; discuss mechanisms of mutation in model organisms that may be relevant to the hypermutation mechanism; and review recent advances toward understanding the possible role(s) of DNA repair, replication, and recombination in this fascinating process. PMID- 10095139 TI - Are adaptive mutations due to a decline in mismatch repair? The evidence is lacking. AB - The levels of proteins required for methyl-directed mismatch repair appear to decline in stationary-phase and nutritionally-deprived cells of Escherichia coli. It has been hypothesized that error-correction by the system also declines, and this decline is responsible for adaptive or stationary-phase mutations. However, evidence in support of this hypothesis is lacking. The mismatch repair system is no less effective in correcting errors during prolonged selection than it is during growth. Furthermore, mismatch repair proteins supplied in excess reduce both growth-dependent and adaptive mutation. PMID- 10095140 TI - Human cancer, carcinogenic exposures and mutation spectra. PMID- 10095141 TI - Pain-relieving effect of sucrose in newborns during heel prick. AB - We assessed the effect of sucrose as a pain reliever in a population of newborns when cuddled and comforted during heel prick for diagnosis of phenylketonuria. In addition, the influences of gender, gestational age, postnatal age, ponderal index and behavioural state of the infant before the heel prick were studied, as judged by the neonatal infant pain scale (NIPS) score, on crying time (CT) and subsequent NIPS score. 100 healthy full-term infants were enrolled in this double blind, randomized controlled trial. Before the heel prick, the newborns, when cuddled by the parent(s), were either given 2 ml 50% sucrose solution or 2 ml sterile water. The sessions were videotaped and analyzed for determination of CT and NIPS scores. The frequency distribution of CT showed a bimodal pattern in both the sucrose and the placebo groups. Sucrose significantly reduced CT and NIPS scores after the heel prick. No influence of gender, gestational age, postnatal age or ponderal index on CT was found. NIPS scores before the heel prick correlated significantly and positively with CT and subsequent NIPS scores in both the sucrose and the placebo groups. Intra-orally administered sucrose given before heel prick can be recommended as a useful pain reliever. Furthermore, the findings indicate that factors calming the newborn and creating low NIPS scores before the procedure can reduce the pain reaction equivalently and additively to sucrose administration. PMID- 10095142 TI - Longitudinal multicentric study of plasma and red blood cell fatty acids and lipids in preterm newborns fed human milk. AB - The present multicentric study (three centers) deals with the values of plasma and red blood cell fatty acids obtained in a group of 18 preterm newborns after 2 days (D2), 15 days (D15) and 5 weeks (37th week postconception: 37th wk) of human milk feeding. Analytical methods were randomized between the three centers and quality control was evaluated by repeated analysis of reference samples. 20:4 n-6 varied from 10.71 +/- 1.58% to 9.51 +/- 1.65 and 10.10 +/- 1.42% in plasma phospholipids and from 16.59 +/- 3.30% to 14.68 +/- 3.14 and 18.24 +/- 4.09% in red blood cell phosphatidylethanolamine (RBC-PE) at D2, D15 and 37th wk, respectively, contrasting with the important rise of the precursor (18:2 n-6) in all the fractions studied. In RBC-PE, 22:6 n-3 significantly declined from 3.52 +/- 1. 03% at D2 to 2.56 +/- 0.83% at D15 (p < 0.02) and recovered its initial level at 37th wk (4.08 +/- 1.94%). The recovery of long chain polyunsaturated fatty acid homeostasis at that time was also confirmed by the decline of 16:1 n-7 in cholesterol esters (10.69 +/- 3.92 to 4.32 +/- 2.38%). PMID- 10095143 TI - Leukocyte counts in relation to the method of delivery during the first five days of life. AB - The goal of the present study was to evaluate total and differential leukocyte counts during the first 5 days of life in relation to the method of delivery. We included 203 healthy term infants; of these, 114 were born by vaginal delivery, and 89 by elective cesarean section. Total and differential leukocyte counts were evaluated at the following intervals: 0-6, 7-12, 13-24, 25-48, 49-72, 73-96, and 97-120 h after birth. The cord serum cortisol level was measured as an indicator of the degree of delivery-related stress. Mean leukocyte and neutrophil counts were higher in infants born by vaginal delivery in cord blood and up to 12 h of life. No significant differences were observed in the immature: total neutrophil ratios between the two groups of infants. The cord serum cortisol level was higher in vaginally delivered infants. A significant correlation was found between cortisol and leukocyte, neutrophil, or lymphocyte counts. The method of delivery produces significantly different total leukocyte and neutrophil counts during the first 12 h after birth; after this time, there appears to be no more variation of leukocyte counts during the first 5 days of life. PMID- 10095144 TI - Changes in rat papilla microsomal membrane fluidity during development. AB - During maturation, rat renal papillary microsomes suffer a rearrangement in their fatty acid phospholipid composition. The most significant changes in total phospholipids are the increase in their content of the 20:4 and a decrease in the levels of 14:0, 16:0, 18:1, 22:6 and 20:3 fatty acids. The changes in total phospholipid fatty acid content are a reflection of the variations in the individual phospholipid composition. During this period, microsomal cholesterol, phospholipid, and protein concentrations present no variations. Steady state fluorescence anisotropy obtained by using TMA-DPH (see text) as a fluorescence probe denoted higher values for 70- versus 10-day-old microsomes. Using DPH as a probe, steady state fluorescence anisotropy was determined in whole microsomes, as well as in total lipid and phospholipid vesicles, from both 10- and 70-day-old papillary cells. No differences were detected in phospholipid and total lipid vesicles between days 10 and 70. On the other hand, 10-day-old microsomes appeared to be less fluid than adult microsomes. The results indicate that these structural changes in kidney membranes during development might affect protein lipid interaction and, therefore, the activity of many membrane enzymes. PMID- 10095145 TI - Fetal hepatic oxygen consumption under normal conditions in the fetal lamb. AB - Previous measurements of fetal hepatic blood flow have relied on microsphere methodology. Estimates of fetal hepatic oxygen consumption (VO2), based on these measurements and the oxygen content difference across the fetal hepatic circulation, have been quite variable. To estimate hepatic VO2 in the fetal lamb by a different methodology, we applied the Fick principle using the steady-state uptake of indocyanine green (ICG) by the fetal liver to measure left hepatic blood flow in 10 pregnant ewes. Sampling catheters were inserted into the fetal external iliac artery, left hepatic vein, and umbilical vein. ICG was infused to steady state (for approximately 60 min) through a fetal brachial vein. Four sets of ICG concentration differences across the circulation of the left hepatic lobe were determined for each animal, and left hepatic lobe blood flow calculated. The oxygen concentration difference was measured simultaneously and VO2 of the left hepatic lobe calculated. In addition, we measured fetal VO2 and calculated the ratio of hepatic to fetal VO2. Left hepatic lobe blood flow was 382.30 ml/min/100 g tissue (COV = 0.32), a result statistically no different than in 4 animals with an independent measurement of hepatic blood flow using an ethanol equilibration method. Hepatic VO2 was 1.74 micromol/min/g tissue (COV = 0.13), and hepatic to fetal VO2 ratio was 18.23% (COV = 0.19). Our results indicate that normal fetal hepatic oxygen uptake per gram of tissue is less variable than previously suggested, and that ICG can be applied in the fetus for the purpose of hepatic blood flow measurement. PMID- 10095146 TI - Sodium nitroprusside prevents oxygen-free-radical-induced pulmonary vasoconstriction in newborn piglets. AB - The aim of the present study was to test whether hypoxanthine-xanthine oxidase (XO) induced a pulmonary vasoconstriction in newborn piglets, and whether this vasoconstriction could be attenuated or abolished by pretreatment of nitric oxide (NO) donor sodium nitroprusside (SNP). Twenty-five anesthetized newborn piglets (1-3 days old) were randomly assigned to the following four groups: the control group received saline intravenously only; the XO group received 0.1 mmol/kg of hypoxanthine subsequent with XO (1.5 U/kg); the SNP group received the same dosages of hypoxanthine/ XO together with SNP intravenously, allopurinol (ALP) group received ALP intravenously prior to hypoxanthine and XO injection. After giving XO, the pulmonary arterial pressure (PAP) and vascular resistance (PVR) increased, while the cardiac index decreased significantly in the XO group. By contrast, these variables were not significantly modified by XO injection in the SNP and ALP groups. The data suggest that oxygen free radicals induce a pulmonary vasoconstriction in newborn piglets, and this vasoconstriction can be prevented by infusion of the NO donor SNP. PMID- 10095147 TI - Hormonal control of rat fetal pancreas development. AB - Rat fetal pancreas development and maturation were investigated in vitro and in vivo, and the informations available on their controls do not agree. Our main objective was to reinvestigate fetal pancreas growth in vivo through treatments of the dams during their entire pregnancy. Pregnant rats were thus implanted subcutaneously with Alzet minipumps and received cerulein (0.25 microg kg-1 h-1), gastrin-releasing peptide (GRP; 0.18 microg kg-1 h-1), GRP antagonist (12 microg kg-1 h-1), pentagastrin (2.38 microg kg-1 h-1), L-365,260, a cholecystokinin B (CCKB) receptor antagonist (120 microg kg-1 h-1), and hydrocortisone (417 or 833 microg kg-1 h-1). After sacrifice at the end of pregnancy, the pancreata of the dams and those of their fetuses were excised for weight, protein, RNA, DNA, and digestive enzyme determinations. In the fetus, pancreas growth defined as hyperplasia was observed only in response to hydrocortisone, while aplasia occurred in response to cerulein. Gastrin and the GRP antagonist were the most effective hypertrophic agents, and the effect of the CCKB receptor antagonist was atrophic. In conclusion, hydrocortisone caused proliferation of the fetal rat pancreas, whereas gastrin induced its differentiation and maturation probably through CCKB receptor occupation. PMID- 10095148 TI - Treadmill training enhances glucose tolerance more in pregnant than in virgin rats. AB - To determine whether aerobic training throughout gestation modifies glucose tolerance, female Wistar rats were mated or kept nonpregnant and run or not on a 10 degrees slope treadmill for 5 days/week at 20 m/min, starting with a 20-min run, and with a progressive daily increase of 5 min, reaching a 75-min run on the 20th day of protocol or gestation. The exercise protocol did not modify food intake, maternal and fetal weights, litter size or blood lactic acid levels. The rise in blood glucose after an oral glucose load (2 g/kg body weight) did not differ between trained and untrained nonpregnant rats but was lower in trained than in untrained pregnant rats. In the untrained rats the rise in plasma insulin levels after the glucose load was much greater in pregnant than in nonpregnant rats; in trained rats this difference between groups was attenuated by the greater effect of exercise decreasing the plasma insulin response to the glucose load in pregnant than in nonpregnant rats. Thus, an aerobic exercise protocol that does not modify the outcome of pregnancy does significantly reduce the altered oral glucose tolerance in pregnant rats and only has a minor effect in nonpregnant rats. PMID- 10095149 TI - Pseudomembranous colitis: causes and cures. AB - Clostridium difficile is the most common nosocomial pathogen of the gastrointestinal tract and has increased in frequency over time. Typical symptoms of C. difficile infection include diarrhea, which is usually nonbloody, or colitis associated with severe abdominal pain, fever and/or gross or occult blood in the stools. Pseudomembranous colitis (PMC), the severest form of this disease, occurs as a result of a severe inflammatory response to the C. difficile toxins. This review focuses on PMC, as this severe form is associated with the greatest medical concern. Diagnosis rests on detection of C. difficile in the stool, either by culture, tissue culture assay for cytotoxin B or detection of antigens in the stool by rapid enzyme immunoassays. Oral therapy with metronidazole 250 mg 4 times a day for 10 days is the recommended first-line therapy. Vancomycin is also effective, but its use must be limited to decrease the development of vancomycin-resistant organisms such as enterococci. Vancomycin (125-500 mg 4 times a day for 10 days) should be limited to those who cannot tolerate or have not responded to metronidazole, or when metronidazole use is contraindicated, as in the first trimester of pregnancy. A therapeutic response within a few days is usual. Recurrence of symptoms after antibiotics occurs in 20% of cases and is associated with persistence of C. difficile in the stools. Further recurrences then become more likely. Therapy with antibiotics in a pulsed or tapered regimen is often effective as are efforts to normalize the fecal flora. The yeast Saccharomyces boulardii has been proven in controlled trials to reduce recurrences when given as an adjunct to antibiotic therapy. Careful hand washing and environmental decontamination are necessary to prevent epidemics. PMID- 10095150 TI - Role of circulating gastrin in colorectal adenomas and carcinomas. AB - BACKGROUND/AIMS: A trophic role of gastrin has been convincingly demonstrated in the oxyntic mucosa of the stomach, but is still a matter of debate in the lower gastrointestinal tract. METHODS: In order to examine the role of circulating gastrin in colorectal adenoma and carcinoma fasting serum gastrin concentrations were determined in 351 patients undergoing complete colonoscopy. RESULTS: In comparison to controls (n = 145) more patients with either polyps (n = 125) or colorectal carcinoma (n = 81) have slightly increased serum gastrin concentrations, leading to an increased mean, but no change in median serum gastrin levels. In 3 patients preoperatively increased serum gastrin concentrations were normalized after surgical removal of the polyp and/or tumor, suggesting a local release of gastrin from the polyp/tumor. Gastrin concentrations do not correlate with the histopathological classification or malignant potential of adenomatous polyps. CONCLUSION: In view of these findings a significant role of circulating endogenous gastrin in human colorectal carcinogenesis seems to be unlikely. PMID- 10095151 TI - Primary hepatic neuroendocrine tumor: successful hepatectomy in two cases and review of the literature. AB - BACKGROUND/AIMS: Primary hepatic neuroendocrine tumor represents an extremely rare clinical entity with only very few cases having been reported to date. METHODS: The case histories of 2 patients with presumably primary hepatic neuroendocrine tumor were analyzed and a complete follow-up obtained. The literature was reviewed to provide comprehensive data collection. RESULTS: Both patients underwent partial hepatic resection. Histomorphologic diagnosis revealed a neuroendocrine tumor in both cases. Extensive preoperative as well as intra- and postoperative search for the primary tumor did not identify another site of neuroendocrine tumor tissue. Six and ten years after hepatic segmentectomy, the 2 patients are alive and show no clinical signs of malignancy. Their most recent thorough follow-up included computed tomography and somatostatin receptor scintigraphy. Neither a nonhepatic primary neuroendocrine tumor site nor recurrent disease was found in the 2 patients. The literature review resulted in a complete survey of all previously reported cases of primary hepatic neuroendocrine tumors. CONCLUSION: We conclude that the liver was the primary site of the neuroendocrine tumor in both patients. Radical surgery was successfully performed as the only treatment option with curative intention. PMID- 10095152 TI - Establishment and characterization of a human rectal neuroendocrine carcinoma xenograft into nude mice. AB - BACKGROUND: Carcinoid tumor has been recognized as having a much wider spectrum than was previously thought. Now the term 'neuroendocrine carcinoma' (NEC) has been suggested to describe malignant epithelial tumors of neuroendocrine differentiation. Its biological behavior has not been well characterized because of the lack of in vivo models. MATERIALS AND METHODS: A metastatic inguinal lymph node from rectal NEC was used for heterotransplantation into nude mice. Histochemical and immunohistochemical stainings were performed in addition to ultrastructural investigations. Hormonal peptides were measured in both xenograft tumor tissue and serum. RESULTS: We succeeded in heterotransplantation of human rectal NEC into nude mice. To date tumorigenicity has been retained for approximately 38 months. The xenograft tumor was a histopathologically identical tumor. The immunohistochemical expression of the various hormonal peptides in the xenograft was essentially the same as that of the primary rectal tumor. Tissue and serum hormonal peptides in the xenografted tumor were measured. Serum glucagon and serotonin were significantly higher than in control mice. CONCLUSIONS: The expression of various hormonal peptides in NEC may vary depending on the surrounding environment. The establishment of NEC in xenografts provides a model for further study of the biological behavior of NEC, as well as the in vivo effects of chemotherapeutic agents on tumor growth and the release of hormonal peptides. PMID- 10095153 TI - Continuous intravenous octreotide treatment for acute experimental pancreatitis. AB - BACKGROUND: The efficacy of octreotide, the synthetic analogue of the hormone somatostatin, for the treatment of acute pancreatitis is controversial. Octreotide has been commonly administered in subcutaneous bolus injections; however, continuous intravenous infusion may be advantageous for acute conditions. METHODS: Acute experimental pancreatitis was induced in rats by intraparenchymal injections of 1 ml 10% sodium taurocholate, and octreotide (1 microg/kg/h, dissolved in physiological solution, intravenously was started 4 h later and continuously infused for 48 h. Physiological solution infusions, in identical volumes, were used in the controls. The following parameters were examined: mortality; macroscopic and histological damage; hematocrit; plasma pH; acid-base balance; serum glucose; calcium, and amylase. RESULTS: Octreotide treatment had a striking effect on mortality: 8.3 versus 91.6% in the treatment and control groups, respectively (p < 0.001). Octreotide also ameliorated pancreatic edema and intestinal dilatation, and had significant beneficial effects on histopathological damage and the biochemical alterations which are associated with acute pancreatitis. CONCLUSIONS: Continuous intravenous octreotide infusion is a potentially efficacious therapeutic method for acute pancreatitis. PMID- 10095154 TI - Effects of different octreotide dosages on splanchnic hemodynamics and glucagon in healthy volunteers. AB - AIMS: This study evaluated the dependence of portal and mesenteric blood flow and plasma glucagon levels on octreotide dosage and its mode of application. METHODS: Two groups of 10 individuals each received octreotide either subcutaneously (placebo, 100 and 200 microgram) or intravenously (100- microgram bolus i.v., 25 and 100 microgram/h) in a double-blind, random order. Using Doppler ultrasound, we examined portal and mesenteric blood flow and measured plasma glucagon levels at regular intervals within a 4-hour period under fasting conditions. RESULTS: Contrary to placebo, octreotide caused a decrease in portal blood flow (PVF) and in superior mesenteric artery blood flow (SMAF) together with an increase in the mesenteric pulsatility index (PI). The same total dose of 100 microgram octreotide caused a similar PVF response, averaged over 4 h, given either subcutaneously (-28.0 +/- 4.8%), intravenously (-29.4 +/- 4.3%) or as a continuous infusion (-29.3 +/- 4.6%). As concerns intravenous infusions, 100 microgram/h was more effective than 25 microgram/h (-37.8 +/- 6.2 vs. -29.3 +/- 4.6%). The PVF reduction remained constant during intravenous infusion, whereas glucagon levels decreased progressively over the entire observation time. CONCLUSIONS: The decrease in PVF is dependent on the octreotide dose. However, this is not constantly paralleled by a decrease in plasma glucagon concentration. PMID- 10095155 TI - Hyperglycemia reduces pancreaticobiliary secretion in response to modified sham feeding in humans. AB - BACKGROUND/AIMS: We have investigated the effect of acute hyperglycemia on pancreaticobiliary secretion and pancreatic polypeptide (PP) release. METHODS: Duodenal outputs of bilirubin, trypsin, lipase, amylase and bicarbonate were measured using a recovery marker under basal conditions and in response to modified sham feeding (MSF) in 6 healthy subjects on two separate occasions: during normoglycemia and during acute hyperglycemia (15 mmol/l). RESULTS: During hyperglycemia the basal pancreaticobiliary output was significantly (p < 0.05) reduced. During normoglycemia MSF significantly (p < 0.05) increased the output of bilirubin and pancreatic enzymes; during hyperglycemia only the output of pancreatic enzymes increased significantly (p < 0.05) over basal. During MSF the outputs of bilirubin (16 +/- 4 vs. 4 +/- 2 micromol/30 min), trypsin (26 +/- 7 vs. 7 +/- 4 U/30 min), lipase (36 +/- 11 vs. 15 +/- 6 kU/30 min), amylase (3.4 +/ 0.7 vs. 1.4 +/- 0.7 kU/30 min) and bicarbonate (0.8 +/- 0.1 vs. 0.5 +/- 0.1 mmol/30 min) were significantly (p < 0.05) reduced during hyperglycemia compared to normoglycemia. During hyperglycemia basal and MSF-stimulated PP levels were significantly (p < 0.05) reduced compared to normoglycemia. MSF did not significantly influence plasma cholecystokinin levels in both experiments. CONCLUSIONS: This study indicates (1) that the blood glucose levels affect basal and cephalic stimulated pancreaticobiliary secretion and (2) that the PP secretion during hyperglycemia is reduced, suggesting impaired vagal cholinergic activity during hyperglycemia. PMID- 10095156 TI - Effects of tropisetron, a 5-HT3 receptor antagonist, on proximal gastric motor and sensory function in nonulcer dyspepsia. AB - BACKGROUND: Visceral hypersensitivity is claimed to be involved in the pathogenesis of nonulcer dyspepsia (NUD). In a double-blind crossover study, we evaluated the effects of tropisetron, a 5-HT3 receptor antagonist, on gastric accommodation, reflex relaxation, and sensitivity in NUD patients. METHODS: Eight patients and 10 healthy controls received placebo or 5 mg tropisetron on separate days. On each day, gastric accommodation and relaxation were investigated using a gastric barostat. The perception during gastric distension and relaxation was scored by a verbal perception score. RESULTS: Under both medications, gastric accommodation and postprandial gastric reflex relaxation were not impaired in the NUD patients. The visceral perception was increased in the NUD patients and not substantially influenced by tropisetron. CONCLUSIONS: Tropisetron does not influence gastric accommodation, reflex relaxation, or gastric sensitivity in NUD patients and healthy controls. PMID- 10095157 TI - Regulation of the actin cytoskeleton by p125 focal adhesion kinase in rat pancreatic acinar cells. AB - BACKGROUND/AIMS: Activation of p125 focal adhesion kinase by cholecystokinin (CCK)-8 has recently been demonstrated in pancreatic acinar cells. The purpose of this study is to examine downstream events of this kinase. METHODS: Activation of p125 focal adhesion kinase in freshly isolated rat pancreatic acinar cells was determined by Western blot analysis. Actin cytoskeletal changes were visualized on TRITC-phalloidin-stained cryosections. Amylase release was measured by colorimetric assay. RESULTS: CCK-8 caused dose-dependent activation of p125 focal adhesion kinase. Time-course analysis showed rapid activation with maximum between 5 and 10 min and stimulation still detectable after 60 min. Preincubation with 2 microM cytochalasin D specifically inhibited p125 focal adhesion kinase, but not p42 mitogen-activated protein kinase or increases in intracellular calcium concentrations. The actin cytoskeleton showed rapid reorganization after stimulation, with an initial increase in fluorescence followed by a decline after 30 min. Preincubation with cytochalasin D prevented cytoskeletal changes. Amylase release at concentrations up to 0.1 nM CCK-8 was not influenced by cytochalasin D. In contrast, supramaximal inhibition of amylase release was less pronounced after cytochalasin D incubation. CONCLUSION: p125 focal adhesion kinase in acinar cells appears to be part of a signalling pathway leading to changes in cellular morphology via the actin cytoskeleton. Maximal activation of this signalling pathway might participate in supramaximal inhibition of enzyme secretion. PMID- 10095158 TI - Embryology of the pancreatic duct system. AB - BACKGROUND/AIMS: It has been suggested that the distal portion of the dorsal pancreatic duct and the ventral pancreatic duct usually merge into the main pancreatic duct, and the proximal portion of the dorsal pancreatic duct becomes the accessory pancreatic duct. In this study, we investigated the embryology of the accessory pancreatic duct roentgenographically and immunohistochemically. METHODS/RESULTS: The accessory pancreatic duct shows two different patterns in pancreatograms: the long and the short type. The accessory pancreatic duct of the long type forms a straight line and joins the main pancreatic duct at the neck portion of the pancreas. The accessory pancreatic duct of the short type joins the main pancreatic duct near its first inferior branch. Long inferior branches from the accessory pancreatic duct were found in 74.6% with the long type, significantly more often than in the short type (29. 3%). Patency of the long type was (74.5%) significantly greater than in the short type (36.2%). Immunohistochemically, we found the main pancreatic duct between the junction with the accessory pancreatic duct and the neck portion of the autopsy pancreas in the short type was located within the ventral pancreas, characterized by pancreatic polypeptide-rich islets. CONCLUSION: The long type represents a continuation of the main duct of the dorsal primordium. The short type is very likely formed by the proximal main duct of the dorsal primordium and its long inferior branch, with the main duct of the dorsal primordium at the point of connection with the main duct of the ventral primordium being obliterated and replaced by this additional communication. PMID- 10095159 TI - Ethanol feeding aggravates morphological and biochemical parameters in experimental chronic pancreatitis. AB - BACKGROUND AND AIMS: Instillation of trinitrobenzene sulfonic acid (TNBS) into the rat pancreatic ducts induces morphological changes resembling human chronic pancreatitis. In humans, alcoholism is commonly associated with chronic pancreatitis, but ethanol feeding fails to induce pancreatitis in experimental animals. We hypothesized that ethanol would manifest its pathogenetic effects on a duct-injured pancreas. METHODS: Chronic pancreatitis was induced in rats by instillation of TNBS into pancreatic ducts. Thereafter, rats were fed a normal chow diet with or without ethanol supplementation. Control rats received vehicle and a normal diet. A separate group of vehicle-treated rats were also fed with ethanol. At 2 and 4 weeks pancreata were excised and processed for morphological examination or for biochemical assays. From crude homogenates, protein and hydroxyproline were quantified. After sonication, homogenates were also assayed for amylase and DNA. An oral glucose tolerance test was performed on the fourth week. RESULTS: TNBS induced chronic fibrogenic pancreatitis that was associated with a reduction in pancreatic weight, DNA, protein and amylase as compared to control rats. Ethanol feeding to TNBS-treated animals slowed weight gain, increased fasting glucose and impaired glucose tolerance test. Larger areas of gland atrophy were observed with a striking disruption of the normal architecture of the islets. Ethanol accelerated pancreatic involution and collagen deposition as measured by total amylase, protein, DNA and hydroxyproline content. CONCLUSIONS: In TNBS chronic pancreatitis, active fibrogenesis is associated with progressive atrophy of glandular elements. Morphological and biochemical parameters are aggravated by sustained ethanol intake. PMID- 10095160 TI - Psychosocial background and intervention in the irritable bowel syndrome. PMID- 10095161 TI - Study of a primary gastrinoma in the common hepatic duct - a case report. AB - Primary endocrine neoplasms of the biliary tract are exceedingly rare. We report on a 60-year-old man with diarrhea, vomiting and gastroesophageal reflux disease, with a primary gastrinoma of the common hepatic duct. The tumor was positive for a variety of immunohistochemical markers. Postoperatively the patient's symptoms disappeared and in the follow-up the patient was symptom free. To our knowledge, this is the first case in the literature of a primary gastrinoma in the common hepatic duct. The fact that the common hepatic duct is not located within the gastrinoma triangle made the diagnosis difficult and the distinct localization made the surgical treatment demanding. PMID- 10095162 TI - Interpretative difficulties with growth hormone provocative retesting in childhood-onset growth hormone deficiency. AB - A review of literature demonstrates that there are many ill-understood factors that determine the results of GH provocative (re)testing, so that these results should be interpreted with extreme caution when used for diagnosis or confirmation of diagnosis of GHD. GH provocation tests are probably of no value at all for what has been called 'partial GHD'. The phenomenon of 'normalization' of test results after long-term treatment with GH needs no 'transient GHD' hypothesis as it can be largely explained by the very low reproducibility of the tests and by a regression to the mean effect. Moreover, it is possible that 'normal values' increase with age. Other determinants of normal peak values may also change from childhood to adulthood and contribute to 'normalization'. PMID- 10095163 TI - Leptin values in placental cord blood of human newborns with normal intrauterine growth after 30-42 weeks of gestation. AB - OBJECTIVE: To evaluate leptin values in placental cord blood of newborns with normal intrauterine growth after 30-42 weeks of gestation. DESIGN: Leptin, a protein encoded by the ob gene, plays an important role in the regulation of feeding behaviour and energy balance in rodents, primates and humans. The presence of leptin in human amniotic fluid and cord blood has recently been reported in human gestations at term and the possible role of leptin in human fetal growth suggested. However, little is known of leptin synthesis during human foetal development. Thus, the aim of our work was to measure leptin (RIA, Linco Research, Inc.) in placental cord blood of human newborns at different fetal ages. PATIENTS: One hundred and twenty-six healthy newborns with normal intrauterine growth were studied. Twenty-nine were preterm (15 males and 14 females; gestational age: 30-36 weeks) and 99 were at term (49 males and 48 females; gestational age: 37-42 weeks). RESULTS: Leptin values increase progressively throughout gestation from 1.30 +/- 0.53 ng/ml at 30 weeks of gestation to 7.98 +/- 4.96 ng/ml (mean +/- SD) at term, and correlate positively with birth weight (r = 0.56, p < 0. 005, n = 126), length (r = 0.37, p < 0.005, n = 126), BMI (r = 0.57, p < 0.005, n = 126), head circumference (r = 0.37, p < 0.005, n = 126), gestational age (r = 0.48, p < 0.005, n = 126) and placental weight (r = 0.38, p < 0.003, n = 59). Leptin values are statistically significantly lower (p < 0.005) preterm (median: 2.05 ng/ml; range: 0.7-8.3 ng/ml) than at term (median: 7.0 ng/ml; range: 1.1-28.1 ng/ml). Leptin values are also significantly (p < 0.005) higher in females (median: 7.2 ng/ml; range: 0.9 23.6 ng/ml, n = 62) than in males (median: 4.8 ng/ml; range: 0.7-28.1 ng/ml, n = 64), although there are no differences in weight (2,864 +/- 536 g in females vs. 2,937 +/- 744 g in males). Multiple regression analysis shows weight to be a positive sex-independent predictor of serum leptin values (p < 0.0005). Sex also proves to be a predictor of leptin, independently of weight and is higher in females than in males (p < 0.003). CONCLUSION: Leptin is present in placental human cord blood after 30-42 weeks of gestation. Newborn weight and sex are independent predictors of leptin values. PMID- 10095164 TI - Effects of recombinant human growth hormone on height and skeletal maturation in growth hormone-deficient children with and without severe pretreatment bone age delay. AB - The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. METHODS: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score 90%) when they were mixed with lipids before, but ODN's alone were incorporated into sarcoma cells only in a low percentage (< 10%) and concentration. STS cell cultures showed also a relative high ODN uptake compared with cell lines. We propose the liposomal transfection strategy as an efficient method which can be applied to adherent-growing tumor cells. The method allows simultaneously to study transfection rates, apoptosis and cell cycle alterations in vitro. Furthermore, in future, extension on ex vivo and in vivo transgene expression (xenotransplanted sarcomas) will be evaluated. PMID- 10095439 TI - [Telomere lengths and telomerase activity in liposarcomas]. AB - We measured telomerase activity in 36 malignant and seven benign lipomatous neoplasias from 34 patients to assess the role of telomerase in the development of liposarcoma. The sensitive PCR-based telomerase assay (telomeric repeat amplification protocol-TRAP) was applied. We correlated telomerase activity with the shortening or elongation of telomeric repeat fragment length (TRF), measured by using hybridization with a telomere specific oligonucleotide probe. Telomerase activity was demonstrated in 69% of malignant tumors. This information may be helpful in distinguishing benign tumors from malignant neoplasias. Telomerase expression, however, seems to be characteristic of poorly differentiated liposarcomas. Telomerase activity was not correlated with age at the time of diagnosis or with sex. We observed that telomerase expressing tumors had higher proliferation indices than neoplasias lacking telomerase. Telomerase activity was observed in all eight recurrences, suggesting a close association of telomerase with the biologic behavior of liposarcomas. Therefore, we assume that telomerase plays a key role in the establishment and progression of lipomatous tumors. PMID- 10095440 TI - Prognostic relevance of histologic grading, the cell cycle-associated antigen Ki S1 and cell cycle regulators in malignant fibrous histiocytomas: a multivariate analysis. AB - The main aim of this study was to compare the prognostic impact of different histologic grading systems, the expression of the cell cycle-associated antigen DNA-topoisomerase-II-alpha (Ki-S1) and the expression of cell cycle regulators in malignant fibrous histiocytomas (MFH) using multivariate analyses. Paraffin embedded tissue of 161 cases of MFH were studied immunohistochemically for the expression of the proliferation marker Ki-S1, cell cycle regulators (p53, MDM2, waf-1, pRb, p16) and the oncoprotein EGFR. The percentage of immunolabelled tumor cells (index) was assessed. The histologic grade was determined by the two-level grading systems of Costa, Tsujimoto and Pezzi, by the three-level grading systems of Coindre and Van Unnik and by the grading system presented here. Univariate analyses using the LOG rank test showed that all of the applied grading systems produce highly significant differences in survival between the grades of malignancy. Multivariate analyses with COX regression demonstrated that only the grading system presented here, based on the parameters necroses, mitoses and cellularity, had independent prognostic relevance. Moreover, the inclusion of the proposed grading system, the Ki-S1-index and a prognostic index primarily based on the expression of cell cycle regulators into the COX regression was suited for predicting survival in MFH. The grading system presented shows considerable advantages over the grading systems compared in this study for use in the routine pathology of MFH. The prognostic power of the proposed grading system can be enhanced by the combined study of cell cycle regulators and Ki-S1. PMID- 10095441 TI - [Cellular "neurothekeoma": an epithelioid variant of dermatofibroma?]. AB - AIMS: The present series describes 15 cellular neurothekeomas whose clinicopathologic features indicate a close relationship to dermatofibroma. METHODS: Retrospective clinicopathologic study. RESULTS: Lesions preferentially occurred in adolescents to young adults on the upper half of the body, often clinically diagnosed as some kind of fibrohistiocytic tissue response. Besides characteristic whorled nests to fascicles of palely eosinophilic epithelioid cells all lesions showed variable clues pointing to dermatofibroma: acanthosis, ill-defined storiform periphery, peripherally accentuated prominent sclerosis and lymphocytic demarcation/infiltration. All cases were positive with NK1C3 (CD 57), Ki-M1p and proliferating cell nuclear antigen, 7 for neuron specific enolase, 5 for factor XIIIa, 6 for smooth muscle actin and 3 with E9, an anti metallothionein marker. These findings are similar to other types of dermatofibromas, the variability of the profile being best explained by time cycle and function dependent changes. Ultrastructurally, two cases showed microfilaments, attachment plaques, prominent pinocytosis and focal remnants of basal lamina. A careful study of data and microphotographs from the literature reveals that in many cases similar conclusions can be reached. Obvious discrepancies are most likely due to the confusion with myxoid neurothekeoma, a well circumscribed, more spindly and myxoid, S 100 positive lesion of Schwannian origin. CONCLUSION: According to our results cellular neurothekeoma seems to be a whorled-nested to plexiform epithelioid variant of dermatofibroma. PMID- 10095442 TI - Comparative analysis of prognostic indicators for sarcomas of the soft parts and the viscerae. AB - Purpose of this study was to determine which parameters may be best applied to determine the prognosis of soft tissue and visceral sarcomas, the two groups being regarded as biologically different. In a cohort of 184 soft tissue tumors (STT) and 53 gastrointestinal stromal tumors (GIST), the following factors were examined for their diagnostic and prognostic relevance: patient age, sex, tumor location, histological type, tumor size, tumor grade, DNA ploidy status, mitotic count, and immunohistochemical proliferation index. Tumors were graded according to the FNCLCC system, and antibody Ki-S11 (Ki-67) served as a proliferation marker. Median clinical follow-up time was 48 months. In STT, morphological criteria allowed a ready discrimination between benign and malignant lesions, which was only warranted by histopathological grading in GIST. 178 of all 236 tumors were thus classified as malignant. Whilst most parameters yielded significant results in the univariate analysis, age, sex, and histological type were irrelevant. A proliferation index > 20% predicted a poor outcome in soft tissue sarcomas, in contrast to a threshold of 10% for GIST. In both groups, the Cox multivariate analysis selected the proliferation index as the sole independent predictor of overall survival, whereas it was superseded by the tumor grade with respect to metastatic spread. In conclusion, soft tissue and visceral sarcomas appear to behave basically in a similar manner. Both tumor grade and immunohistochemical proliferation index are of major prognostic value. Concerning the growth fraction, however, different cut-off points should be selected for sarcomas of the soft tissues and those of the digestive tract. PMID- 10095443 TI - [Prognostic factors for gastrointestinal stromal tumors]. AB - AIMS: Stromal tumors of the gastrointestinal tract (GIST) constitute a group of phenotypically heterogenous mesenchymal neoplasms with uncertain biological behaviour. METHODS: We examined 31 cases of paraffin-embedded GIST histologically and immunohistochemically in regard to their proliferation. Mitosis were counted, atypical mitosis were noted. Proliferation was measured immunohistochemically by Ki-S5 expression and cytophotometrically by ploidy. Prognostic factors were evaluated and compared to the clinical behaviour. RESULTS: Mitosis counts with a mean of 6.43/10 HPF (range: 0-51). Eight atypical mitosis were noted of which five had mitosis counts of 10 or less. Proliferation index determined by Ki-S5 was 9.47% (range: 0-30%). Nineteen tumors were aneuploid. Prognostic unfavorable factors included younger age at diagnosis, male sex, muscular differentiation, higher cellularity and site (stomach VS intestine). KAPLAN-MEIER analysis revealed a statistical significance for Ki-S5 index (p = 0.00268) and ploidy (p = 0.0014). Mitosis counts > 10/10 HPF as well as atypical mitosis were associated with an aggressive biological behaviour. CONCLUSIONS: There are different prognostic factors to determine the prognosis of GISTs., e.g. Ki-S5 index, ploidy, mitosis counts and atypical mitosis. Ki-S5 index seems to be the most reliable. PMID- 10095444 TI - [Prognostic factors of gastrointestinal stromal tumors of the stomach]. AB - The stomach is the most common gastrointestinal site of mesenchymal tumors which traditionally have been designated as smooth muscle tumors. However, with increasing analytic tools most investigators were unable to demonstrate true myogenic differentiation. Furthermore, the biological behavior of gastrointestinal stromal tumors (GIST) is difficult to predict. The aim of this study was to evaluate MIB-1 and p53 as additional prognostic markers, as well as myogenic differentiation immunohistochemically in GIST. 43 gastric stromal tumors were reviewed, 19 were classified as benign, and 10 as malignant. 14 tumors were considered indeterminate for biological behavior. In addition to MIB-1 and p53, immunohistochemistry was also performed for sm-actin, desmin and S 100-protein (ABC). 41 patients had a clinical follow-up of more than 2.5 years, 5 patients had metastases. Mean proliferation rates defined as percentage of MIB-1 positive tumor cells in 3 HPF were as follows: typical leiomyoma: 0.2%; benign GIST, spindle cell type: 1.8%; benign GIST, epithelioid cell type: 2.4%; borderline GIST, spindle cell type: 2.1%; borderline GIST, epithelioid cell type: 2.5%; malignant GIST, spindle cell type: 4.9%; and malignant GIST, epithelioid cell type: 7.3%. All 5 metastasizing tumors had a proliferation index > 4% (p < 0.0001). 4/5 metastasizing tumors had p53 positive cells (p < 0.05). 36/43 tumors were sm-actin positive, 7 of which were positive for desmin as well. Classification of gastric mesenchymal tumors as GIST is appropriate because only a small percentage show true smooth muscle differentiation. A MIB-1 proliferation index above 4% might indicate a more aggressive course, as well as p53 positivity. PMID- 10095445 TI - [Ultrastructural differential diagnosis of gastrointestinal stromal tumors]. AB - Gastrointestinal stromal tumors (GIST) may present with myogen or neurogen differentiation, mixed differentiation or with morphological features which cannot be further specified. 14 GIST of the stomach (9), the duodenum (2) and small bowel (3) were examined by immunohistochemistry and electron microscopy. Diagnosis was consistent for such tumors located distally from the stomach, however, evaluation of GIST of the stomach was different (apart from one case). Light microscopy and immunohistochemistry did not allow to discriminate between the different subtypes of GIST, however, electron microscopy revealed cellular differentiation. Hence, ultrastructural analysis is an useful tool for diagnosis of GIST, particularly those of the stomach. PMID- 10095446 TI - Cytogenetic and morphologic characteristics of gastrointestinal stromal tumors. Recurrent rearrangement of chromosome 1 and losses of chromosomes 14 and 22 as common anomalies. AB - We present cytogenetic findings in five gastrointestinal stromal tumors (GISTs). Three of these five cases had abnormal karyotypes with clonal chromosomal aberrations. The most common karyotypic pattern was a combined loss of chromosomes 14 and 22 in a total of three cases. Among these cases, additional recurrent chromosomal abnormalities were loss of 1p and/or 9, detected in two cases each. Another karyotypic feature consisted of polyploidisation, leading to hypotetraploid chromosome numbers in one case. These cytogenetic results provide evidence for a characteristic karyotypic pattern consisting of -14 and -22 in a subset of GISTs. PMID- 10095447 TI - [Giant cell tumor of bone. Morphological, immunohistochemical, morphometric and DNA flow cytometric findings]. AB - Giant cell tumour (GCT) of bone is a locally aggressive tumour with a high rate of recurrence if not completely excised. The present study was undertaken to clarify whether flow cytometric, immunohistochemical and morphometric studies can be a useful tool to assess the prognosis of patients with GCT. DNA flow cytometry, cell cycle studies and immunohistochemical investigations with antibodies against CD 68, CD 34, p53 and Ki67 were performed on paraffin embedded tissue of 10 cases of GCT. As a further possible prognostic parameter angiogenesis within the tumour was investigated using an automatic image analysis system. Histologically 4 cases were grade 1 tumours and 6 cases grade 2. Among the Grade 1 cases, all were diploid. Of the Grade 2 cases, 4 were diploid and 2 were aneuploid. Both of the patients with an aneuploid tumour developed a loval recurrence. All GCT revealed large numbers of CD 68 positive giant cells, but mononuclear tumour cells exhibiting CD 68 immunoreactivity were also present. Corresponding to the immunohistochemical findings with MIB-1 the flow cytometric DNA histogram revealed high proliferation rates (mean value 14.9%). None of the tumours exhibited p53 immunoreactive cells. All cases showed high content of vessels with on the average relative vessel area of 7.7%. No correlation between clinical outcome and vascular parameters (number of vessels, vessel area, perimeter) was found. Our findings suggest that DNA flow cytometry is useful in predicting tumour behaviour in some cases. GCT exhibits extensive angiogenesis, but none of the vascular parameters investigated was found to be of prognostic value. PMID- 10095448 TI - [TP53 gene aberrations in chondromatous neoplasms: correlation with immunohistochemical p53 accumulation and MDM2 expression]. AB - Histological differentiation between chondroma and chondrosarcoma is a common problem in surgical pathology. In a former study (3) we were able to show, that immuno-histochemical p53-accumulation in chondromatous neoplasias might be an additional hint for malignancy. Now we tried to find out, whether p53 accumulation is caused by TP53-aberrations or functional inactivation of p53 wildtype protein by MDM2. For this purpose, paraffin-embedded material of 80 chondromatous neoplasms (18 chondromas, 18 chondromatous neoplasms of uncertain dignity (i.e. cytologically suspicious but without definite invasive growth), and 44 chondrosarcomas (24 GI, 13 GII, 7 GIII)) were screened for TP53 gene aberrations by means of DGGE (denaturing gradient gel electrophoresis; exons 5 8). The results were correlated with immunohistochemical p53-accumulation (DO-7, DAKO) and MDM2-expression (AB-1, Oncogene). A total of 43% of all chondromatous neoplasms showed TP53-aberrations in DGGE-analysis, i.e. 27% of chondromas, 50% of chondromatous neoplasms of uncertain dignity, 46% of GI-, 46% of GII- and 71% of GIII-chondrosarcomas. Exon 6 (58% of all cases with aberrations) and exon 8 (47%) were affected most frequently. No significant correlation between TP53 aberration and either p53-accumulation or MDM2-expression was present. A statistically significant correlation could be found between p53-accumulation and MDM2-expression (p < 0.0001). Regarding histological tumor-classification, p53 accumulation and MDM2-expression discriminated between chondromas/chondromatous neoplasms of uncertain dignity and well differentiated chondrosarcomas in a statistically significant manner. In the subgroup of p53-positive and MDM2 negative cases significantly more TP53-aberrations were detected by DGGE-analysis than in the other groups. Interestingly, the subgroup of p53- and MDM2-negative cases showed the second highest rate of TP53-DGGE-aberrations. Nearly 50% of these aberrations, however, were localized in exon 8, a mutation that is known to cause no p53-protein-accumulation. In conclusion, TP53-aberrations occur frequently in chondromatous neoplasms and show no significant association to either immunohistochemical p53-accumulation or MDM2-expression. Functional inactivation of p53 wildtype protein by MDM2-expression seems to be the major cause of p53-accumulation in chondromatous neoplasms and emphasizes the role of these parameters as additional hint for malignancy. PMID- 10095449 TI - [Fibrohistiocytic skin lesions]. AB - AIMS: A new unifying concept of fibrohistiocytic skin lesions. METHODS: Retrospective clinicopathologic study of more than 2,000 dermatofibromas (DF) recruited over the last two decades. RESULTS: As the least common denominator all DF show a reactive fibrohistiocytic tissue response with variable epidermal hyperplasia, peripheral sclerosis and peripherally accentuated lymphohistiocytic tissue response. The histological, immunohistochemical and ultrastructural profile varies according to the time cycle as well as the fibro myofibrohistiocytic differentiation of the lesions. From a conceptual point of view such lesions are best grouped into three categories: 1. DF with cellular/stromal pecularities. All classic variants, from the first description by Unna in 1894 to lesions described in 1978, namely DF, (benign) fibrous histiocytoma, histiocytoma cutis, sclerosing hemangioma, nodular subepidermal fibrosis or fibrous xanthoma, fall into this category; moreover, many of the clinicopathologic variants described over the last two decades such as granular cell, clear cell, myofibroblastic, sclerosing, monster cells, atypical ("pseudosarcomatous"), haemosiderotic ("elusive"), cholesterotic, and myxoid variants. 2. DF with architectural pecularities such as deep penetrating, atrophic, aneurysmal ("angiomatoid"), haemangiopericytoma-like, palisading and ossifying variants. And 3. DF with both cellular/stromal and architectural pecularities including those with a homogenous mixture of components as seen in epithelioid, cellular benign variants, smooth muscle proliferation in DF, multinucleate cell angiohistiocytoma, cellular neurothekeoma, and dermal plexiform fibrohistiocytic tumour; as well as those with heterogeneous mixture of components in composite or mixed dermatofibromas. CONCLUSION: DF is common, the clinicopathological variability manyfold, and their misinterpretation as malignancy such as dermatofibrosarcoma protuberans or Kaposi sarcoma not rare. Such cases have important clinical implications such as unnecessary investigations, controls and livelong anxiety of patients. PMID- 10095450 TI - [Perivascular myoma: a new concept for "myofibroblastic" tumors with perivascular myoid differentiation]. AB - The morphological spectrum of cutaneous adult myofibroma (AM) is presented which has been considered to be the adult counterpart of infantile myofibromatosis. 63 cases of AM were evaluated and various subtypes could be discerned: classical biphasic type with hyalinized basophilic spindle cell nodules and adjacent small primitive pericytic cells forming richly vascularized hemangiopericytomatous sheets; glomangiopericytoma with a predominant hemangiopericytomatous pattern and small glomoid-pericytic cells; myopericytoma with angiocentric proliferation of small pericytic cells; rare variants, e.g. solid myopericytoma, and sclerotic myofibroma. There is considerable morphological overlap, and the morphological spectrum certainly is much wider. It is suggested that these presumably myofibroblastic cutaneous tumors are derived from a pluripotent periendothelial cell capable of differentiating along smooth muscle, pericytic, and glomus cell lines. Following a recent proposal by Granter et al. (7) these tumors are re classified as variants of perivascular myoma, a perivascular tumor with myoid differentiation. The role of the myofibroblast in these tumors is reevaluated. In order to determine whether perivascular myoma is composed of a clonal cell population as opposed to being a polyclonal reactive process, analysis of patterns of X-chromosome inactivation was performed. Clonality of the tissue was determined by analysing the methylation status of two different X-chromosome linked polymorphic markers: the phosphoglycerate kinase gene (PGK) and the human androgen receptor gene (HUMARA). Both methods are based on the amplification of differing gene loci in heterozygous women after digestion of the DNA with methylation sensitive restriction enzymes. Out of 20 investigated female tumors 10 tumors were non-informative, 7 tumors showed a uniform pattern of X-chromosome inactivation (clonal), 3 tumors remained heterozygous (polyclonal). It remains to be determined whether perivascular myoma is a true tumor or a reactive/hyperplastic process. PMID- 10095451 TI - [Cutaneous neural neoplasms--an update]. AB - Until recently, benign cutaneous neural tumours which do not fulfill criteria for either neurofibroma or schwannoma often were lumped into the broad category of benign peripheral nerve sheath tumours (PNST). However, during the last years a number of new entities of neural tumours has been described, and advances in immunohistochemistry and electronmicroscopy have helped us better to understand the cytological differentiation in these neoplasms. The knowledge of these distinctive neoplasms is necessary in order to avoid diagnostic pitfalls and misdiagnosis of more aggressive neoplasms. These distinctive lesions include: Neurothekeoma, which can be divided into classical myxoid and cellular types showing characteristic histological and immunohistochemical features. Typical neurothekeoma (nerve sheath myxoma) is a lobular or nodular dermal neoplasm composed of plump spindled or stellated S-100 positive tumour cells set in a myxoid stroma. In contrast cellular neurothekeoma is characterized as an ill defined dermal neoplasm composed of concentric nests and fascicles of spindle shaped and epitheloid tumour cells, which are S-100 negative but stain positively for NKIC3. The evidence of intermediate forms of neurothekeoma showing features of ordinary, hypocellular neurothekeoma and cellular neurothekeoma, as well as ultrastructural studies emphasize, that both variants represent a spectrum of neurothekeoma. Solitary circumscribed neuroma ("palisaded encapsulated neuroma") manifests mainly as a skin-colored or pink papule or nodule, and is most often located on the face. Histologically, solitary circumscribed neuroma is a well circumscribed round or ovoid dermal neoplasm composed of interwoven fascicles of schwann cells, which stain positively for S-100 protein, and numerous neurofilament positive axons surrounded partly by fibroblasts and EMA-positive perineurial cells. Perineurioma is a rare well-circumscribed neoplasm which occurs mainly in subcutaneous tissue and only rarely in the dermis and in deep soft tissue. Perineurioma is composed of elongated bipolar spindle-shaped tumour cells which are arranged in a storiform, linear or lamellated growth pattern. The tumour cells stain positively for vimentin and EMA, and for CD34 in a number of cases, but lack positivity for S-100 protein, neurofilament and desmoplakin. In addition unusual forms of schwannoma including cellular schwannoma, solitary plexiform schwannoma, and melanocytic schwannoma are briefly discussed. PMID- 10095452 TI - [Genetic alterations in the fibroblastic stroma of invasive colon and breast carcinomas]. AB - While the neoplastic cells have always been in the center of interest in cancer research in recent years, more and more attention has been paid also to the tumor stroma which is today known to play an important role for tumor progression. In early days of histology the interpretation of stroma as either neoplastic or reactive was still a matter of discussion. Today's generally held view is clearly in favor of a secondary induction by tumor cell derived factors. Recent findings of epithelium-mesenchymal transitions of cultured tumor cells now put again a doubt on this exclusive interpretation. In the present work we show for the first time that genetic alterations (allelic losses, microsatellite instabilities and p53 mutations) are not restricted to tumor cells but also occur within the fibroblastic stroma of non-hereditary invasive human colon and breast cancers. In view of the clonality of epithelial and stromal components in the same cases (loss of same alleles and identical MSI patterns) epithelium-mesenchymal transitions are among possible explanations for these findings which could shed a new light on the true nature of tumor stroma. PMID- 10095453 TI - [Intracellular distribution of beta-catenin in soft tissue tumors]. AB - AIMS: beta-Catenin originally known as an intracellular mediator of epithelial cell-to-cell adhesion is also involved in signal transduction processes. Since its important function in colorectal carcinogenesis has recently been recognized, the aim of our study was to investigate whether a similar intracellular distribution of beta-catenin can be detected in sarcomas and sarcoma-like lesions. METHODS: 45 soft tissue tumors were examined by immunohistochemistry. RESULTS: Different types of beta-catenin-distribution were observed: A more continuous localization at the cell membrane was evident especially in epithelioid-like sarcomas. In contrast only focal staining of cell membranes could be found in different tumors as well. Further on increased cytoplasmatic beta-catenin levels were detected in various types of tumors. CONCLUSIONS: The localization of beta-catenin at the cell membrane serves as a hint for a function of beta-catenin in cell adhesion of mesenchymal tumors apart from epithelial tissues. A nuclear and intracellular accumulation of beta-catenin has been observed in progression of colorectal tumors. The findings of increased levels of beta-catenin in soft tissue tumors may indicate a similar important function in the pathogenesis of these neoplasias. PMID- 10095454 TI - [Iron deposits, cell populations and proliferative activity in pigmented villonodular synovitis of the knee joint]. AB - Pigmented villonodular synovitis (PVNS) of the knee is a tumor-like process of uncertain nature. A chronic inflammation as well as a neoplastic process have been proposed in the literature. The aim of our study was to characterise the prevalent inflammatory cells, the proliferating cell populations, and the iron deposit distribution in PVNS in order to get insights into pathogenetically relevant processes of this condition. Thirteen cases of PVNS of the knee as well as 8 normal controls were analysed histochemically for iron deposits and immunohistochemically for the distribution of vascular structures and inflammatory cell populations. Collagen type I expressing fibroblastic cells were identified by in situ hybridization. The proliferative cell compartment was characterized using MIB-1 staining. Our analysis showed no correlation between intra- or extracellular iron deposits and proliferation, giant cell formation, vascularity, number of CD 68-positive cells, and foam cell formation. Instead, iron deposits were associated with collagen matrix formation. All PVNS specimens showed a significant increase of chronic inflammatory infiltrates compared to all normal synovial membrane specimens investigated. The identification of the proliferative cell compartments showed that besides fibroblastic cells many of the mononuclear, partly CD 68 positive cells were Ki-67 positive. Foam cells, iron-loaded cells, and giant cells were, however, negative for the Ki-67 antigen. PVNS appears to originate from the interplay of proliferating, partly CD 68 positive mononuclear cells and fibroblasts, both activated by an excessive iron load. Giant cells probably develop by fusion of CD 68-positive histiocytic cells. Foam cells are most likely secondary to fatty tissue destruction. PMID- 10095455 TI - ["Benign metastasizing leiomyoma"? A case report without evidence for unbalanced cytogenetic aberrations]. AB - There are rare cases of histologically benign appearing uterine leiomyomas with subsequent development of multifocal extrauterine smooth muscle tumors, most often located in the lung. It remains unclear whether this evolves from a morphological innocent appearing low grade sarcoma or from proliferation of multifocal but autochtonous cellular foci. Frequently, and in part recurrent karyotypic abnormalities were described for leiomyomas and leiomyosarcomas. Thus, we looked for imbalanced genetic aberrations in a case of a "benign metastasizing leiomyoma" by means of comparative genomic hybridisation (CGH). A 46-year-old female developed multiple bilateral lung nodules 4 years after hysterectomy. Fine needle biopsy of one nodule and subsequent resection of three lung nodules were performed. These and the hysterectomy specimen were investigated by histology, immunohistochemistry and CGH. Revision of the hysterectomy specimen revealed multiple leiomyomas without any evidence for malignancy. Lung nodules were composed of benign appearing smooth muscle cells with epithelial lined cleft-like spaces. Leiomyomata of the uterus and the lung showed a reactivity against actin, desmin, estrogen- and progesteron receptor antigens. DNA analysis by CGH revealed a normal karyotype without evidence for an imbalanced loss or gain of DNA. Recurrent cytogenetic alterations are common in uterine leiomyomas, most often del (7)(q11.2-22q31-32) and t(12;14)(q14-15; q23-24). Leiomyosarcomas display diverse karyotypic abnormalities, most often involving chromosomes 1, 7, 13 and 14. Thus, the missing karyotypic imbalance in the presented case favors a pathogenesis which is different from usual leiomyomas as well as leiomyosarcomas. PMID- 10095456 TI - [Alveolar rhabdomyosarcoma presenting as acute leukemia]. AB - Rhabdomyosarcoma is the most common soft tissue sarcoma in adolescence and childhood, which manifests by the locally destructive growth of the primary tumor or its metastases. We report on a 29-year-old man with an alveolar rhabdomyosarcoma presenting with an unusual leukemia-like picture. On admission, the patient suffered from diffuse bone pain and renal insufficiency. Peripheral blood analysis showed anaemia, thrombocythaemia and blast-like cells. A bone marrow aspirate revealed extensive infiltration by atypical blast-like cells which were interpreted as acute lymphoblastic leukemia. Although confirmation of this diagnosis by immunophenotyping did not succeed chemotherapy was started immediately and led to partial remission. Histologic analysis of a bone marrow biopsy from the iliac crest, however, revealed an extensive solid tumor with alveolar spaces, lined by primitive round cells with positive PAS-reaction in the cytoplasm. Immunostaining demonstrated a positive reaction of the tumor cells for desmin and in a few tumor cells for smooth-muscle-actin. Chromosomal analysis showed a t(2;13) translocation typical for alveolar rhabdomyosarcoma. Although multiple lytic lesions of the skeletal system became evident during the further clinical course, the site of origin of the primary tumor could not be defined retrospectively. In conclusion, rhabdomyosarcoma should be included in the differential diagnosis of systemic diseases with extensive bone marrow infiltration by tumor cells that could otherwise be misinterpreted as a haematologic malignancy. PMID- 10095457 TI - [Frequency, distribution and prognostic relevance of p53 mutations in soft tissue sarcomas]. AB - Soft tissue sarcomas although rarely occurring (about 1% of malignant tumors), are because of their histo-morphological diversity and often similar appearance to tumor-like lesions difficult to characterize and estimate in their tumor biological behaviour. Analysis of molecular characteristics as alterations in tumor-suppressor and oncogenes may allow insight in STS genesis. We have chosen the in carcinomas well, but in STS not comprehensively investigated tumor suppressor gene p53 for mutational analysis. In 16 out of 146 STS patients we could identify p53-mutations. In a multivariate Cox-regression analysis prognosis was correlated with the p53-mutation type. However, only patients with non frameshift mutations possessed a poorer prognosis (RR = 2.42; p = 0.014) in comparison to patients without mutations, but frameshift-mutations didn't seem to affect prognosis negatively. Compiling our results and those of the literature an overall frequency of 16.3% of p53-mutations in STS, with various frequencies in different entities is detectable. STS specific hotspots are not recognizable. Rather mutational hotspots in codons 175, 245, 248 and 273 well known from studies in carcinomas are also apparent in STS. Summarizing, we want to state that the occurrence of p53-mutations (non-frameshift mutations) is of prognostic importance in STS. Combination of histo-pathological, clinical and molecular characteristics may allow to distinguish in future different groups of patients for an individual treatment. PMID- 10095458 TI - [Significance of differential nuclear expression of Ki-67 in adult soft tissue sarcomas]. AB - As many other nuclear markers, e.g. steroid receptors, Ki-67 epitopes are differentially expressed in tumour cell nuclei. It is unclear whether this phenomenon represents tumour cell heterogeneity, different stages of the cell cycle or a biological phenomenon with prognostic impact. We analysed 104 primary adult soft tissue sarcomas (ASTS), formalin-fixed, paraffin-embedded, by APAAP and LSAB immunohistochemistry, epitope retrieval technique and 2 anti-Ki-67 antibodies (MIB-1 and Ki-S-5). Expression was evaluated by 4 indexes/1000 tumour cells: a) A-index: sum of all (weak, moderate and strong stained) Ki-67-nuclei, b) the weighed R-index: sum of all strong stained Ki-67+ nuclei x3, moderate stained nuclei x2 and weak stained nuclei x1, c) ID1-index: sum of all strong stained Ki-67+ nuclei, and d) ID2-index: sum of all strong and moderate stained Ki-67+ nuclei. Prognostic impact was analysed by Kaplan-Meier and logrank statistics with respect to overall survival. Quantitative Ki-67 expression did not vary significantly if determined by MIB-1 or Ki-S-5. The A-index turned out to be the strongest prognostic parameter within the whole group of ASTS as well as within each single sarcoma type investigated. Significant (p < 0.05) correlations between A-index and overall survival existed in LMS, LPS, MFH, SS, while a trend to significance (p = 0.06) was observed in MPNST. Quantitative evaluation of all three differential expression levels is necessary to obtain the most comprehensive prognostic informations of proliferation markers in ASTS. PMID- 10095459 TI - [Diagnostic and predictive validity of DNA image cytometry in soft tissue tumors]. AB - Malignant neoplasms are associated with chromosomal aberrations. This phenomenon called aneuploidy can be substantiated by interactive DNA cytometry and is accepted as a major prognostic parameter in tumor biology and oncology. In a retrospective study 114 non-infantile soft tissue tumors were analysed by DNA cytometry. The results were compared with classical morphological parameters. As a marker for malignancy in soft tissue lesions, DNA aneuploidy substantiated by cytometry has a sensitivity of 94% and a specifity of 82%: 50 of 53 malignant soft tissue tumors were DNA aneuploid; from 61 non-sarcomatous soft tissue tumors 11 were found to be aneuploid. These lesions were classified as intermediate dignity. No aneuploid tumor could be found among 30 histologically benign soft tissue tumors. The positive predictive value of DNA cytometry was 82%: of 61 aneuploid soft tissue tumors 11 were non-sarcomatous tumors with intermediate dignity. The negative predictive value of DNA cytometry was 97%: from 53 non aneuploid soft tissue tumors only three were found to be sarcomas. Malignant soft tissue tumors demonstrate a significantly higher DNA-index (DI) and DNA grade of malignancy (DNA MG) than benign lesions. Our results show that DNA ploidy may serve as an additional parameter in problematic histological dignity assessments of soft tissue tumors. The histopathological grading levels of sarcomas show significantly different DI and DNA MG, so that DNA cytometry enables substantiated grading of soft tissue. PMID- 10095461 TI - [List of members]. PMID- 10095460 TI - [p53 overexpression as independent prognostic marker in soft tissue sarcomas is antibody dependent]. AB - Most changes in p53 result in a protein with prolonged half life. This permits immunohistochemical detection. P53-overexpression seems to have prognostical relevance in soft tissue sarcomas (STS). The goal of this study was to compare the prognostic relevance of five different p53 antibodies in immunohistochemistry of primary STS using a Cox regression model with adjustment to staging, localization, tumor type, and surgical therapy. We investigated 198 primary STS of six different tumor types for p53-overexpression using the antibodies DO-1, DO 7, Pab1801, Pab240, and CM-1. The rate of positivity (cut of point 10% positive tumor cells) was between 36.2% and 62.6% dependent on the applied antibody. Prognostic significance could be determined only for the N-terminal binding monoclonal antibodies (DO-1, p = 0.0014; DO-7, p = 0.005; Pab1801, p = 0.02) with the highest level for combination of DO-7 and Pab1801 positivity (RR = 2.57, p = 0.0098). Pab240 (epitope amino acids 213-217) and CM-1 (polyclonal) showed no prognostic relevance in the multivariate analysis. We therefore suggest that for immunohistochemical evaluation of p53-overexpression in STS a pannel of two N terminal antibodies should be used at least. PMID- 10095462 TI - A patient classification system for the chronic psychiatric patient. AB - Classification of chronic psychiatric patients to determine staffing needs is an emerging issue confronting many psychiatric nurses. This paper follows the development of a patient classification system for chronic psychiatric patients in the United States. Few tools are available and those cited in the literature tend to report minimal validity and reliability and lack applicability to the setting or for the purpose desired. The tool demonstrated use and acceptance by nurses and was found to meet the comprehensive needs of patients it was designed to serve. PMID- 10095463 TI - Suicide on the Internet: a focus for nursing intervention? AB - The Internet is a means for people who do not know each other to share information to their mutual benefit or harm. Whereas electronic communication without censorship has its benefits, the net has not escaped the attention of people contemplating suicide. If mental health nurses are to assist vulnerable people who surf the net in search of encouragement to complete suicide, they need to know about Internet resources on suicide and to understand how suicide fatalities influence the behaviours of vulnerable people who express suicidal ideation in cyberspace. The importance of suicide modelling, ambivalence, group death wishes, suicide notes and related research is considered. Mental health nurses are invited to consider the implications for suicide prevention. PMID- 10095464 TI - Operationalization of the concept of 'nursing care dependency' for use in long term care facilities. AB - Nursing care dependency and similar terms are frequently used in nursing literature. However, their meanings are still to be adequately defined. This paper seeks to operationalize the concept of dependency for use in long-term nursing care practice. An analysis of the concept of dependency, specifically with regard to nursing care, will present a frame of reference from which a theoretical definition can be stated. Variable dimensions, observable indicators and means for measuring the indicators are presented. The paper concludes with implications for further research. PMID- 10095465 TI - The Round House Gaol: Western Australia's first lunatic asylum. AB - This paper is an account of the social history of the Round House Gaol in Fremantle, Western Australia and of those lunatics that were gathered together into its closed geographical space. The first permanent structure, perched on the most elevated and prominent site in Fremantle, was a gaol; the design for which was based on Jeremy Bentham's Panopticon or Inspection House, created for the purpose of surveillance and control of inmates. Visible in 1997, the Round House still stands as a dominant, physical marker of the landscape, ranking as a premier historical tourist attraction in Western Australia. But its actual use as a place for the containment of lunatics is only cursorily alluded to. This paper addresses the previously ignored period of 1830-1850. PMID- 10095466 TI - Boarding house life for people with mental illness: an exploratory study. AB - The present study explored residents' perceptions of life in boarding houses within the Central Sydney Area Health Service. A purposeful sample of 14 people with a mental illness participated in semistructured interviews. The transcribed interviews were analysed for lifestyle issues to increase understanding of the factors that impact on quality of life from the consumers' perspective. It was encouraging to find that basic needs were being met, but it would appear that there is considerable room for improvement in quality of life for this vulnerable group of people. The findings of the present study should prove valuable for policy makers and health professionals who provide services to people with mental illness resident in boarding houses. PMID- 10095467 TI - Inpatient nursing care of patients with borderline personality disorder: a review of the literature. AB - The present paper reviews the literature on inpatient nursing care of patients with borderline personality disorder (BPD). An overview of the background, major features, recent conceptualizations and predicted outcomes for sufferers of BPD is provided. Literature related to treatment and inpatient nursing care is also discussed. It is argued that nurses are in a position of having to provide care that is less than optimal and that may recreate the victimization and traumatization of the patient's childhood. In addition, without adequate education, support and supervision, nurses may experience significant occupational stress arising from their work with this group of patients. PMID- 10095468 TI - The Mental Health Nursing Clinical Confidence Scale: a tool for measuring undergraduate learning on mental health clinical placements. AB - A significant proportion of the undergraduate preparation of student nurses in the tertiary sector involves the opportunity for experience in a variety of clinical placements. The majority of nursing students in Australian universities spend time in mental health settings. This compulsory clinical experience provides the opportunity for the application of nursing theory and the development of clinical confidence. Whereas there have been attempts to quantify the attainment of confidence to perform skills in general nursing settings, there has been little attention to this issue in mental health settings. The Mental Health Nursing Clinical Confidence Scale was developed as part of a larger study aimed at investigating the impact of mental health clinical placements on undergraduate nurses' attitudes and clinical confidence. Students were surveyed using the scale before and after a mental health nursing placement. The scale revealed robust psychometric properties. Significant changes in the self-reported confidence levels of students were found at the completion of the clinical placement. A number of key factors impacted on student confidence levels both before the clinical and after the placement. The 20 item scale will be a useful instrument in future evaluations of the effectiveness of student learning in mental health settings. PMID- 10095469 TI - Marketing the education approver unit to the general public: AHNA members, we need your help! PMID- 10095470 TI - Energetic interchange: honoring the flow. PMID- 10095471 TI - Holistic researching. PMID- 10095472 TI - Health policy for holistic nurses. PMID- 10095473 TI - World-wide commemorative moment for Florence Nightingale and nursing. PMID- 10095475 TI - Submitting applications to the EAC: what are the responsibilities? PMID- 10095476 TI - The Internet and resources across the lifespan: focus on the elderly. PMID- 10095477 TI - Finding a research topic: Part II. PMID- 10095478 TI - Complementary therapies: integrated or parallel systems? PMID- 10095479 TI - Supporting networkers and growing AHNA networks. PMID- 10095480 TI - Standards of holistic nursing practice: a living document. PMID- 10095481 TI - The challenge of the documentation form. PMID- 10095482 TI - Weaving our joy into nursing. PMID- 10095483 TI - Being well in an environmentally challenged world: canary or phoenix? PMID- 10095484 TI - Opportunities for holistic practice in managed care. PMID- 10095485 TI - Massachusetts Nurse Practice Act now covers holistic nursing and complementary therapies. PMID- 10095486 TI - Alienation and anomie: youth suicide, the media and Hansonism. PMID- 10095487 TI - Theoretical approaches to the study of nurses' clinical reasoning: getting things clear. AB - This paper attempts to clarify both the nature of clinical reasoning and the major theoretical underpinnings of studies that explore nurses' clinical reasoning. It includes a discussion of propositional and procedural knowledge ('knowing that' and 'knowing how') and their relationship in clinical reasoning. Prescriptive and descriptive and rational and phenomenological models are distinguished, and decision theory, information processing theory and (Dreyfusian) skills acquisition theory are discussed and compared. PMID- 10095488 TI - Manuscript reviewing: what reviewers have to say. AB - This paper reports a study that examined the experience of manuscript reviewing. Fifteen reviewers participated, responding to questions about their experience of the process, its perceived strengths and weaknesses, and areas considered worthy of further investigation. Qualitative methodology and analysis were employed. Overall, the study showed that manuscript reviewing brings both extrinsic and intrinsic rewards, but that a price must be paid for these in terms of time spent and frustrations associated with the task. There was some skepticism among reviewers about the value of the peer review process, along with a desire for improvement. Recommendations for further research centre largely around the politics of scholarship and creating a more transparent process. PMID- 10095489 TI - Examination of the preclinical visit in a bachelor of nursing program. AB - When nursing entered the tertiary sector in 1985 the preclinical visit was introduced and became accepted practice. The initial purpose of the preclinical visit was to inform and prepare Clinical Facilitators and Nursing Unit Managers for undergraduate nursing students' clinical experience. The preclinical visit was perceived as a significant factor which potentially impacts on the quality of student learning within the clinical environment. Initial planning of the preclinical visit shapes and determines the outcomes of the clinical experience for all participants. Students personal and professional development often depend upon how well they are received in the ward area. Despite the emphasis placed on the significance of the preclinical visit, its effectiveness has not been evaluated. Ten years after the introduction of nursing to tertiary education, the preclinical visit was evaluated by a group of academics and clinicians who perceived that the preclinical visit was not achieving the desired outcomes. A survey using a convenience sample of Nursing Unit Managers and Clinical Facilitators was conducted at a major metropolitan teaching hospital in New South Wales. This paper reviews the findings of the study evaluating the preclinical visit. From the results of the study it is evident that a structured, clear format is required for the preclinical visit to be effective. PMID- 10095490 TI - Competency standards: clarifying the issues. AB - 'Competency standards' is by now a familiar term to most nurses, and the rate at which many nursing organisations are developing their own set of standards would seem to suggest that competencies are an unproblematic, natural and indeed essential pursuit for us all. However, a review of the literature reveals that the competency movement does not meet with universal agreement or approval and it is timely for nursing groups to exercise cautious deliberation before embracing competencies blindly. PMID- 10095491 TI - Bag ladies: from the wards to the streets. AB - This paper discusses the movement of inmates from mental hospitals to the community with particular focus on homeless women. It raises the question of the fate of bag ladies once the National Mental Health Policy and Plan have run their course in the middle of 1998 when 'community care' has been inadequately resourced. It explores alternative explanations for odd behaviour other than labelling such behaviour psychotic. PMID- 10095492 TI - Working with youth: reflections on a community practicum. AB - This paper was part of my third-year Bachelor of Nursing Degree assessment for the community health module. I hope that the insights from my practicum in the drug and alcohol service will engender a deeper sensitivity and militate against judgmental or directive nursing care in my future nursing practice. Reflection from my community practicum and theoretical constructs are used in this paper to focus on the notions of deviance, labelling, role-taking, and their contribution to the formation of an individual's identity. PMID- 10095493 TI - Violent ethnic wars and world-wide people movement: implications for mental health nursing practice. AB - In recent years, the world has been subjected to violent ethnic wars for autonomy and secession. Violent conflicts over national and international territorial boundaries are marked by a murderous mistrust, hatred and a perpetual life-and death struggle in the present. For the mental health nurse, the world-wide persistent global circumstance of international catastrophe and increasing nationalism mediated through war is inextricably linked to practice as well as the significant health and lifestyle concerns of displaced people. Central to the discussion in this paper will be the mechanisms used by the mental health nurse to maintain empathy and clinical excellence during highly sensitive practice issues; in particular, the management of feelings of frustration, anger, guilt, loneliness and sleeplessness, and repeated mental images of suffering and human butchering, because these issues intersect with national and cultural identity. In rising to the challenges these issues present, mental health nursing must co exist with critical world events and the globalisation of national identity in cultural diversity. PMID- 10095494 TI - The importance of clinical experience in aboriginal communities. AB - The importance of preparing nurses adequately to meet the health needs of Aboriginal people cannot be understated. Much of the reason for negative attitudes among nurses is a lack of knowledge and understanding of cultural differences. Clinical practice in an Aboriginal community can assist in the development of cross-cultural skills among student nurses. In recent times it has been accepted that nursing curricula in Australia must reflect an understanding and awareness of cultural perspectives, diversity and sensitivity. Exposing students to Aboriginal health workers has been found to result in a positive change in attitude among students (Hayes et al. 1994). Providing clinical experiences in Aboriginal communities can increase students' awareness of Aboriginal health status, the socio-cultural and historical influences involved, and the nurse's role in relation to Aboriginal health. Nurses are a major provider of health care within Aboriginal communities throughout Australia. Culturally diverse clinical placements challenge students to become aware of their own health beliefs, attitudes, and values, which can facilitate bridging cross-cultural gaps with clients and also facilitate the delivery of quality nursing care. PMID- 10095495 TI - Eight 'Cs' of caring: a holistic framework for nursing terminally ill patients. AB - This introductory paper describes how nurses can incorporate eight caring elements into nursing care for terminally ill patients. These caring elements can be described as: Compassion, Competence, Confidence, Conscience, Commitment, Courage, Culture and Communication. The Eight Cs of caring are comprised of Simone Roach's five Cs plus three further Cs. According to Roach (1993), who developed the Five Cs (Compassion, Competence, Confidence, Conscience and Commitment), knowledge, skills and experience make caring unique. Here, I extend Roach's work by proposing three further Cs (Courage, Culture and Communication). The paper takes as its framework the concept of holistic care, which encompasses physical, psychological, emotional, spiritual and cultural aspects. Examples are provided as to how the Eight Cs may be applied. Literature from various nursing scholars is included to support the discussion throughout. PMID- 10095496 TI - On problem solving in clinical nursing practice. PMID- 10095497 TI - Reflection: a challenging innovation for nurses. AB - The concepts of reflection and reflective practice have been widely embraced by the nursing profession despite some apparent ambivalence highlighted in the literature. On the one hand, reflection is reported to be a valuable and powerful educational process; it is claimed to develop practice-based theories, encourage practitioners to evaluate their practice, promote learner self-awareness, narrow the theory-practice gap, challenge habitual practice and identify tacit knowledge. On the other hand, commentators point out that there is insufficient empirical evidence to support these claims and that its unstructured implementation can have deleterious effects on practitioners' psychological well being and the outcomes of nursing education. It will be argued in this paper that the realisation of the benefits claimed to accrue from reflective practice together with the avoidance of its potential deleterious personal and educational outcomes hinges on three factors. These are: firstly, that the frameworks or protocols introduced to promote reflective practice are consistent with the purposes it seeks to achieve; secondly, that the essentially political nature of reflective practice is recognised and addressed; and thirdly, that the resourcing requirements for introducing and maintaining reflective practice in clinical units are also recognised and addressed. PMID- 10095498 TI - Complementary therapies: research, education and practice in nursing. AB - There has been an increase in interest in complementary therapies amongst the general public and health care practitioners in recent years. Nurses integrating complementary therapies into their practice are not always adequately prepared due to the diversity of the therapies and the duration of the courses. Guidelines are broad and general, and there is no set standard nor minimum educational requirements related to the therapies in which nurses can integrate in their practice. This paper aims to raise awareness of nurses practising complementary therapies the need for research into practice and efficacy, education and policy development. PMID- 10095499 TI - Trends in the global healthcare environment: the developed countries. AB - The purpose of this paper is to examine trends in the global healthcare environment, especially the developed countries. The developed countries are examined in detail as they have influenced the changes that have occurred in the delivery of healthcare in Australia. The countries discussed include the United States, Canada, Europe and Australia. The most concerning trend is the increase in healthcare spending. There has been a marked rise in the cost of hospital and other institutionalised care and health insurance. The ageing population and the increased use of sophisticated and expensive equipment have also increased costs. Other issues identified are, the declining number of hospitals beds, the shift from care in the hospitals or institutions to care in the home or community, the increase in continuum of care programs, the establishment of health care networks, focus on service quality, the lack of security about gaining health insurance and the focus on treatment rather than prevention. PMID- 10095500 TI - International nurse education: implications for providers. AB - This exploratory study conducted in 1996 described the profiles, roles and preparation of twelve South Australian registered nurses in relation to their provision of education programs for nurses from South East Asia. The research showed respondents were well qualified and highly experienced educators whose roles were complex. Their preparation for providing education programs for nurse from South East Asia had been haphazard and inadequate. Consequently respondents considered they were not fully prepared for the providing this specialised education. Career planning and a more strategic approach to the development of specific expertise are essential to support an international approach to nurse education. Nurse education that values intercultural awareness, and is multicultural and global would benefit both local and international students. Development of germane knowledge, skill, attitudes and behaviours is recommended to ensure excellence in the provision of international nurse education. An action research model is proposed as an alternative to traditional professional development to prepare providers of international education. PMID- 10095501 TI - Caring in context: caring practices in a sample of Hong Kong nurses. AB - In an effort to place the international literature and research in nursing in a Chinese cultural context a study was commenced to examine the caring practices of nurses in Hong Kong. In view of a recent study (Wilkes & Wallis, 1993) which utilised Roach's 5Cs of caring (Roach, 1987, 1992), a pilot study was commenced on a sample of 77 Hong Kong Registered Nurses studying a Diploma of Nursing. An open ended questionnaire was designed which asked nurses to respond to questions about caring in general and the 5Cs: compassion, competence, confidence, conscience and commitment. The questions asked what each of the concepts meant to them as a nurse. Data was analysed into themes based on key words for each of the six areas revealing that the sample of Hong Kong nurses viewed caring in a similar light to those in overseas studies. The sample highlighted compassion and competence as their major features and it is suggested that methodological problems may have inhibited a deeper analysis of their caring attributes and behaviours. When asked to expand on the 5 Cs in terms of their own practice they were able to supply themes which were closely related to Roach's definitions but which may have been more 'textbook' in their origin and certainly lacked a richness of response. The paucity of responses in terms of clarity and richness of data, followed by discussions with the participants led to conclusions about the methodological issues of cross-cultural research and recommendations for future research are made. Highlighted are the problems with attempting to use concepts such as the 5 Cs across cultures and the problems encountered with translation of concepts related to caring from Chinese into English, and vice versa. The study has provided some insights into the concepts of caring in Hong Kong Chinese nurses. In the light of advances in China and unification of previously separate countries these findings provide and offer insights into nursing in China and are encouraging for future research. PMID- 10095502 TI - Integrating life themes of work in the care of older people. AB - This paper examines the role that work themes may play in helping the elderly person to improve integrity, self worth and esteem. The life themes of two older individuals who worked beyond retirement age are identified. One individual worked in paid employment and the other worked in a voluntary capacity. These people to review their life and the themes identified have enabled them to cope through their most difficult times. The themes are situated within psychological and narrative theory. The themes have added richness, variety and meaning to the participants' lives. Gender contrasts have been noted along with functional, personal and interpersonal meanings that their work has held for them. PMID- 10095503 TI - Where to from here: patients of a day hospital rehabilitation programme perceived needs following stroke. AB - The loss of ability to perform routine activities can result in difficulties for the stroke patient to resume their normal lifestyle. A desire to assist stroke patients after discharge prompted this pilot study into the needs of these patients during and after a program of rehabilitation at a day hospital. A longitudinal approach was used for this pilot study. The aim of the study was to identify patients' needs pertaining to the resumption of their lifestyle, and social and emotional well-being, that emerged during the rehabilitation programme at the day hospital, on its completion and within six months of discharge from the day hospital. The study consisted of three semi-structured interviews with ten stroke patients over a period of nine to twelve months. The semi-structured interview employed open-ended questions to collect information from the participants. The interview process sought to elicit the needs of the participants during their time at the day hospital and then after discharge. It was evident from the interviews that the needs of the participants were primarily the opportunity to practice activities which could improve physical capabilities as the physical limitations placed on the participants by the stroke affected their motivation, morale and general sense of self. The day hospital was instrumental in providing participants with opportunities to learn to 'use' what was functioning, and therefore help the participants improve their physical capabilities. This assisted them to regain their independence. During the interviews participants also spoke about social and emotional needs. While they received some support from interactions with the staff and other patients at the day hospital, participants stated that mostly social and emotional support came from their families. After discharge from the day hospital participants were unable to identify specific needs which they believed the day hospital could provide. PMID- 10095504 TI - ALARA study of teaching effectiveness on reducing radiation exposure. AB - The purpose of this study was to measure the effectiveness of radiation safety instruction and the impact on radiation film badge levels. A convenience sample of 144 endoscopy nurses and technicians was pretested for radiation safety knowledge, given a course in radiation safety, and then posttested immediately after the course and then 6 months later. Radiation badges were analyzed for radiation exposure at preinstruction, 1 month postinstruction, and 6 months postinstruction. Results showed that the instruction was effective. There was only a slight decrease in radiation badge readings; the decrease, however, was not statistically significant. PMID- 10095505 TI - Keeping current: computer basics for gastroenterology nurses. AB - The computer age is here! However, many nurses are not using available computer technology. As the uses of computers increase in work, home, and community settings, nurses need to "keep up with the times." This article provides the gastroenterology nurse with a historical perspective on computer technology, some basic information on computers and computer resources, and encourages the nurse to become computer literature. Gastroenterology nurses need to use computer technology to enhance patient care. PMID- 10095506 TI - Transjugular intrahepatic portosystemic shunt (TIPS). AB - A transjugular intrahepatic portosystemic shunt (TIPS) is a recently developed radiologic technique that is useful in the treatment of complications of portal hypertension, variceal bleeding, and ascites. A TIPS is an accepted interventional procedure indicated for the select group of patients who either have variceal bleeding that does not respond to sclerotherapy, variceal banding, pharmacologic means, or who have intractable ascites. In this article, the procedure, along with the pre- and post-procedural nursing care, is described. PMID- 10095507 TI - Improving quality and performance practices using fiberoptic endoscopes in perioperative areas: a case study. AB - In response to the impact of healthcare reform, a re-engineering of problem areas within the University of Maryland's Medical System needed to be initiated. A critical issue to be addressed, within the perioperative areas of the hospital, was the delay in service because of the unavailability of functional fiberoptic endoscopes. This resulted in spiraling operating costs and compromised quality of care of patients. Analysis of the situation using fiberscope inventory data revealed unreliable quality-controlled reprocessing systems and lack of knowledge by the staff in handling and caring for the fiberscopes. A number of actions were taken to improve staff patterns of performance. Graphs, spreadsheets, and diagrams were used to pinpoint the problem areas for each perioperative area and were presented to the staff. These data were up-dated monthly to inform staff and inspire further improvements in performance. This re-engineering of the fiberoptic scope delivery system resulted in economic, operational, customers, and quality of care benefits. Fiberoptic endoscopes are increasingly used is surgical fields outside of the traditional endoscopy unit. Endoscopic nurses need to share expertise to improve the quality of performance in all areas of the hospital where fiberoptic scopes are used. PMID- 10095508 TI - Choosing the correct dual-channel pH catheter for the pediatric patient. PMID- 10095509 TI - Replacing displaced PEG tubes with a Foley catheter. PMID- 10095510 TI - Remicade (infliximab). PMID- 10095511 TI - Technology assessment status evaluation: overtube use in gastrointestinal endoscopy March 1996. PMID- 10095512 TI - SGNA position statement: safe operation of radiographic equipment during GI endoscopic procedures. Society of Gastroenterology Nurses and Associates. PMID- 10095513 TI - The good, the bad and the relative, Part one: Conceptions of goodness in qualitative research. AB - This (part one) paper traces efforts to define 'goodness' in qualitative research within various fields, including nursing. At first closely aligned with the traditional tenets of quantitative research (reliability and validity), over time these are found to be increasingly problematic to uphold within a qualitative context. As alternative criteria more appropriate to qualitative approaches are developed, in many instances these also are wanting in that they continue to reflect a search for order and certainty that permeates the quantitative domain. In reviewing various sets of criteria of goodness, the concepts of reliability and validity in relation to qualitative research are conceived as being championed, translated, exiled, redeemed and surpassed. Part two of the paper addresses the topic of goodness of qualitative research within the philosophical 'problem of the criterion'. Discussion extends to how researchers might usefully juxtapose the rationality of a modern world with a mounting postmodern sensibility. PMID- 10095514 TI - Promoting the nursing profession: the perceptions of non-English-speaking background high school students in Sydney, Australia. AB - By using an ethnographic approach, this paper explores the perceptions of nursing among the non-English-speaking background high school students in Sydney, and describes how the nursing profession could be promoted to them. A volunteer sample of four groups of high school students with parents from Lebanon, Vietnam, Korea and mainland China were recruited. In-depth focus group interviews were conducted. Through constant comparison of categories, 10 concepts emerged from the three major themes to describe the students' career preferences and their influencing factors; their image of nursing and their suggestions on how nursing could be promoted to them. These findings highlighted the significance of social, cultural and political factors that influenced the students' perceptions of nursing and their career choice. Implications and suggestions for marketing and recruitment strategies are discussed. PMID- 10095515 TI - The transforming power of research on practice: involving practitioners in analysis. AB - Nurses were invited to participate in the interpretation of transcribed interviews during the data analysis phase of a phenomenological study. They worked with the investigators in learning and using hermeneutic methods to identify and interpret meanings embedded in exemplars. Their expert clinical knowledge of the field of practice added rigor to the analytical process and depth to the understanding achieved. As the analysis progressed, the nurses began to spontaneously describe transformation occurring in their practice. Involving nurses in data analysis has transformative power on practice. PMID- 10095516 TI - Caring as the ontological and epistemological foundations of nursing: a view of caring from the perspectives of Australian nurses. AB - In a study using unstructured interviews to explore nurses' understanding and interpretations of caring in nursing, one of the major themes emerging from the data is that through caring for patients, nurses discover the meaning and nature of nursing and what it means for them to be nurses. In the process of caring for patients, nurses further develop and understand the knowledge and skill of caring which constitutes the knowledge base of nursing. The data also show that nurses, in their practice, continue to define, develop and shape the meaning and knowledge of caring in nursing. From the evidence of this study, this paper argues that caring can be considered as the ontological and epistemological foundations of nursing. PMID- 10095517 TI - The old get equal care: myth or reality. AB - A national ethics survey was conducted of all registered nurses participating in post-basic specialisation nursing courses in Israel over a one-year period (1994 95) to identify ethical situations which confront Israeli nurses caring for patients of different age groups and in different clinical settings. This study compares the responses of those nurses caring for elderly patients (60 years or older) with those caring for adult patients in other age groups. Nurses caring for the elderly reported encountering ethical dilemmas in 16 out of 37 situations presented to them, more than in the other adult patient age groups. The most frequent dilemmas were concerning mistaken or questionable treatment, patient family conflict, patient referral to an institution or discharge to the home where the family is incapable of caring for him, offensive behaviour by caregivers and physical restraint of the patient for staff convenience. It is recommended that nursing ethics intervention programmes be established to promote ethical decision making and patients' rights. PMID- 10095518 TI - Unlicensed assistive personnel in the critical care unit: what is their role? AB - Driven by an economic imperative, the use of unlicensed assistive personnel (UAP) has proliferated in the health care system, however, their use in the critical care (CC) environment remains relatively new. An analysis of the first phase of a mixed method study, in which interviews with 17 CC nurses were conducted in order to provide data upon which to devise a larger survey, provides insight into the potential uses and misuses of these UAP. An examination of the transcripts, field notes, and diagrams and a comparison of the emerging categories to the literature assisted in identifying several themes important to CC nursing practice. Three themes identified in the analysis--ongoing vigilant assessment, quick response and seeing the whole picture--provide evidence that if UAP are asked to complete tasks allocated to them in other areas, CC nurses will be robbed of vital, albeit subtle, aspects of their nursing practice. As reflective practitioners, CC nurses must be wary of giving away tacit features of their role which enable them to synthesise contextual variables with espoused theory and experience, in order to ensure optimal patient care and outcomes. PMID- 10095519 TI - Priority areas for clinical research in palliative care nursing. AB - This report highlights a number of current research issues and concerns in palliative care nursing. The aim of the study was to identify high clinical nursing research priorities in palliative care, drawing on the expertise of nine (n = 9) clinical nurse consultants currently working in this specialty. The Delphi method was used to collect and process data in the study. Thirteen high research priorities emerged which have relevance for nursing practice, patient and family care in the hospice and community care setting. In the context of this study, the concept of high priority relates to research participant consensus on the most pressing nursing research problems which require investigation to improve clinical practice. Study findings provide direction for clinical research and continuing education in palliative care which may benefit expert nurses and their patients. PMID- 10095520 TI - The role of the community mental health nurse in the administration of depot neuroleptic medication: 'not just the needle nurse!'. AB - An ethnographic study explored the nature of community mental health nurses' involvement with clients during appointments for the administration of depot neuroleptic medication. Little has been written about this aspect of community mental health nursing practice. Findings illustrate how community mental health nurses attempt to engage clients in meaningful interactions when they attend appointments for their injections. Promoting an atmosphere of normalcy and minimising the distress of having neuroleptic medication by injection were key elements in approaches employed by nurses in this study. Results support current discussions in nursing literature concerned with the need for community mental health nurses to have well-developed interpersonal skills to enable them to capitalise therapeutically from the depot injection encounter. PMID- 10095521 TI - Performance indicators and standards of care for coronary angioplasty procedures: a quality initiative. AB - The growth of coronary angioplasty procedures in Australia has provided opportunities for role development in nursing practice. In response to changes in health care demands, the angioplasty nurse specialist role was developed. This paper discusses a quality activity with two goals. First, to facilitate a change in culture within the angioplasty service from the existing fragmented system to a cohesive system based on a quality approach. Second, to develop a process improvement strategy involving a data collection tool that would facilitate the monitoring of performance indicators and patient outcomes. PMID- 10095522 TI - Direct entry midwifery. PMID- 10095523 TI - Midwifery and the next millenium: issues for the future. PMID- 10095524 TI - National education forum--purpose, practice, passion. PMID- 10095525 TI - Mothering and midwifery: sometimes a challenge. AB - This paper attempts to present two levels of argument. Firstly it argues that the use of story, in its entirety, is a valid, relevant and useful tool for informing personal and professional knowing. The second level of debate is elicited by the story itself and the discourse surrounding the challenges of implementing continuity of midwifery care models within the mainstream maternity care system. The author hopes that the telling of the story provides a window through which others can share her experience. It is argued that 'identification' with the challenges involved in implementing innovative models of care is an important and vital step in the process, if these models are to begin, survive and achieve their aim of providing women-centred health care. PMID- 10095526 TI - Perceptions of senior nursing staff about current action, barriers and solutions to working on active and passive smoking in the Liverpool Health Sector. AB - Nurses, particularly those working in antenatal, maternity and paediatrics, can greatly assist their patients to reduce the harms associated with tobacco use. Senior nursing staff from the Division of Women's and Child's Health, and Primary Health in the Liverpool Health Service were surveyed to identify action currently taken with patients, on active and passive smoking. The survey showed that there was an emphasis on assessment and education. Barriers that hindered staff action included the lack of resources, particularly for people of non-English speaking background (NESB), and training. This research also suggests the need for policy development as a way to achieve consistency and maintenance of action. PMID- 10095527 TI - NHMRC report calls for formal recognition of expanded midwives' role. PMID- 10095528 TI - Managing low vision patients. AB - 1. The ophthalmologist and staff are ultimately responsible for identifying low vision patients. 2. Most low vision patients who have a professional low vision evaluation are able to use vision enhancing devices. 3. In addition to optical magnifyers, new computer and television technology enhances use of residual vision. PMID- 10095529 TI - Amblyopia: the condition, the challenge and the cure. AB - 1. Amblyopia needs to be detected early for the patient to have the greatest chance of total vision correction. 2. Compliance with treatment for amblyopia, while not medically complex, may be difficult both socially and emotionally. 3. Support and education, provided by programs such as Prevent Blindness America's Eye Patch Club, facilitate compliance and, therefore, the cure. PMID- 10095530 TI - Compliance with Medicare's chart documentation requirements in evaluation and management (E/M) coding. AB - 1. Use of forced entry charts facilitates proper chart documentation and helps assure compliance with Medicare's chart documentation requirements. 2. Nurses and technicians are responsible for up to two-thirds of the required chart documentation in the patient's record. 3. Performance and documentation are not synonymous. There must be a meticulous written record of what was performed as well as negative and positive findings for both the history and the examination portions of the exam. Recording possible, probable, and rule/out diagnoses enhances the level of complexity of medical decision-making. PMID- 10095531 TI - Managing the keratoconus patient. PMID- 10095532 TI - [Creative fighters succeed. How do body and soul manage a bone marrow transplantation?]. PMID- 10095533 TI - [Concerned? Possibilities of treatment in cancer. Ask your doctor...]. PMID- 10095534 TI - [Geriatric rehabilitation after surgery of the hip joint and knee joint]. PMID- 10095535 TI - [Palliative medicine]. PMID- 10095536 TI - [Incontinence: quality-supported care]. PMID- 10095537 TI - [Management of perioperative coagulation disorders]. PMID- 10095538 TI - [Professional specialty: home care: new and important]. PMID- 10095539 TI - [Taboo topic incontinence]. PMID- 10095540 TI - [Alzheimer and "Alzheimer"]. PMID- 10095541 TI - [The Alzheimer house in Marktbreit]. PMID- 10095542 TI - [New possibilities with biographical work]. PMID- 10095544 TI - [Human Rights Watch: ill-treatment of workers in Saudi Arabia: caution with applications in Saudi Arabia]. PMID- 10095545 TI - [Therapeutic potentials of the Bioptron light: treatment of disorders in wound healing]. PMID- 10095546 TI - [Management of infections in chronic wounds: hydroactive dressing instead of antiseptics?]. PMID- 10095547 TI - [Tumor therapy and quality of life. First results 1999]. PMID- 10095548 TI - [Fashion, art, and science. Respect for life]. PMID- 10095549 TI - [Surgical interventions in geriatric patients]. PMID- 10095550 TI - [Conservative treatment of a venous leg ulcer. Care and dressing techniques]. PMID- 10095551 TI - [Recommendations for local wound care in venous leg ulcers]. PMID- 10095552 TI - [Modern wound care: the era of cotton dressings is ending]. PMID- 10095553 TI - [Experiences with humanitarian interventions in crisis areas]. PMID- 10095554 TI - [Telemonitoring. Ambulatory rather than in hospital. Monitoring of infants at risk in the pediatric hospital]. PMID- 10095555 TI - [The therapeutic activity of the BIOPTRON-lamp in the treatment of disorders of wound healing. Diabetic gangrene]. PMID- 10095556 TI - [Fighting pain gently. Electrostatic energy has an effect on nerve cells]. PMID- 10095559 TI - Investing in ourselves. PMID- 10095560 TI - Substance abuse intervention: Comox's little program that could. PMID- 10095561 TI - Self-employed nurses' survey. PMID- 10095562 TI - Registered Nurses Association of British Columbia. Position statement the self employed nurse. PMID- 10095563 TI - Certification: demonstrating competence in your specialty. PMID- 10095565 TI - RNABC web site member forums go beyond the limits of time and space. PMID- 10095566 TI - Continuing competence: a community experience for hospital nurses. PMID- 10095564 TI - Taking charge of your practice. PMID- 10095567 TI - Telephone advice. PMID- 10095568 TI - What? No nurses? PMID- 10095569 TI - NDUs: alive and kicking. PMID- 10095570 TI - Children: picking up the pieces. PMID- 10095571 TI - Gender differences. PMID- 10095572 TI - Nursing leadership in the US. PMID- 10095573 TI - Investing in women's health. PMID- 10095574 TI - Women's health: mental health needs. PMID- 10095575 TI - The choice is yours. PMID- 10095576 TI - Nursing: the big picture. Interview by Tom Keighley. PMID- 10095577 TI - The Bevan legacy. A sacred NHS. PMID- 10095578 TI - How necessary it was to give nurse education this vote of confidence. PMID- 10095579 TI - Pay: this is just the beginning. PMID- 10095580 TI - Will the wage rise pay off? PMID- 10095581 TI - Fighting back. PMID- 10095582 TI - Propaganda. PMID- 10095583 TI - What's bugging you? PMID- 10095584 TI - A race against time. Interview by Steven Black. PMID- 10095585 TI - Young at heart. PMID- 10095586 TI - Describing prescribing. PMID- 10095587 TI - The discovery of aspirin. PMID- 10095588 TI - Implementing reflective practice. AB - Although nurses understand the need to reflect on their practice, reflection does not occur simply as a result of knowing about it. The author of this literature review seeks to clarify 'reflection' and suggests ways to implement reflective practice. PMID- 10095589 TI - Violence at work. AB - In this article, the authors discuss violence in healthcare settings and the health and safety issues that are involved. PMID- 10095590 TI - Avoiding latex allergy. PMID- 10095591 TI - Forensic and prison nursing. PMID- 10095592 TI - Washing a patient's hair in bed. PMID- 10095593 TI - Sharing good practice. PMID- 10095594 TI - After the final whistle. PMID- 10095595 TI - Watching the waiting. PMID- 10095596 TI - Modern murder mystery. PMID- 10095597 TI - When you're smiling.... Interview by Rebecca Coombes. PMID- 10095598 TI - The last decent pay rise for nurses. PMID- 10095599 TI - Our flexible friends need backing. PMID- 10095600 TI - Good practice network. Joined-up thinking. PMID- 10095601 TI - Good practice network. The missing link. PMID- 10095602 TI - Safety catch. PMID- 10095603 TI - NT/3M National Nursing Awards. Home help. PMID- 10095604 TI - Pensions. PMID- 10095605 TI - Face to face. Interview by Eileen Fursland. PMID- 10095606 TI - The websites every nurse needs. PMID- 10095607 TI - Nurses and the law of consent. PMID- 10095608 TI - Hormone replacement therapy: can nurses help? PMID- 10095609 TI - Dying at home: supporting patient choices. PMID- 10095610 TI - Outreach care: a sensitive approach. AB - This article examines the assertive community treatment model for caring for people with severe mental illness, drawing attention to some of its limitations as well as the authoritarian style that often accompanies its implementation. An alternative model, active client engagement, is described. This aims to engage clients in a collaborative relationship using a team approach that is highly responsive to the changing needs of clients. It concludes that the government's objective of keeping clients engaged with mental health services can better be achieved by the adaptation of such a trusting and therapeutic approach. PMID- 10095611 TI - National implementation of nurse prescribing. PMID- 10095612 TI - Backs at work. PMID- 10095613 TI - Still having ENs on C grade. PMID- 10095614 TI - Labouring on the cheap. PMID- 10095615 TI - Not a penny more. PMID- 10095616 TI - Tabloid prescriptions claim the credit. PMID- 10095617 TI - Consider the emotional cost of nursing. PMID- 10095618 TI - Top-earning nurses: who's in the money.... PMID- 10095619 TI - Discriminating against people with HIV. PMID- 10095620 TI - The future of nursing in the UK. PMID- 10095621 TI - Time to tackle domestic violence. PMID- 10095623 TI - A rare club. PMID- 10095622 TI - System overload. PMID- 10095624 TI - A sense of purpose. PMID- 10095625 TI - Action stations. PMID- 10095626 TI - In our parents' shadow. Riley-Day syndrome. PMID- 10095627 TI - So you want to ... own a care home? PMID- 10095628 TI - Let's put an end to pain. PMID- 10095629 TI - NT/3M National Nursing Awards. Unlocking the community spirit. PMID- 10095630 TI - Viruses. Too close for comfort. PMID- 10095632 TI - Willpower. PMID- 10095631 TI - Feeding a patient in bed. PMID- 10095633 TI - A latex allergy. PMID- 10095634 TI - Nursing language: uses and abuses. AB - Nurses communicate with a variety of people on many different levels. Yet the full importance of nurse language is not fully appreciated. This article examines the use of nursing language and suggests that nurses can increase their professional potential through using language more consciously. PMID- 10095635 TI - When is a patient capable of consent? PMID- 10095636 TI - PICCs: how Doppler ultrasound can extend their use. AB - Peripherally inserted central catheters were relatively unknown in the UK five years ago. Now, however, they are used in more than 100 centres around the country. PICCs have played a key role in improving vascular access for a wide range of patients and the growth in their use has been nurse led. This article explains how nurses can help to extend the use of PICCs to a group of patients who have traditionally been excluded, those with apparently inaccessible antecubital fossa. PMID- 10095637 TI - Meet Crash Max, Basic Buddy and Little Anne. PMID- 10095638 TI - Continence. Women at work. PMID- 10095639 TI - Continence. Taking charge. PMID- 10095640 TI - Continence. Lessons in self-support. PMID- 10095641 TI - Intermittent self-catheterisation: an option for all ages. PMID- 10095642 TI - Continence. Assess all areas. PMID- 10095643 TI - Continence. Case study: time well spent. PMID- 10095644 TI - Staying on track. PMID- 10095645 TI - Tarsal tunnel syndrome. AB - Tarsal tunnel syndrome (TTS) is an often misdiagnosed and evasive compression neuropathy of the posterior tibial nerve and its branches (Muhammed et al., 1995). A variety of causes may lead to the development of this painful foot condition. An awareness of the anatomy and physiology of TTS will allow for its increased recognition and treatment. Nurses in clinical settings such as ambulatory centers, physician offices, and acute care settings (especially orthopaedics and rheumatology units) will be able to apply this information in their practices. PMID- 10095646 TI - The use of low molecular weight heparins in the prevention of venous thromboembolic disease. AB - Deep vein thrombosis (DVT) and pulmonary embolism (PE) are leading causes of morbidity and mortality in the United States. Estimates range between 300,000 and 600,000 hospitalizations a year, with approximately 50,000 deaths related to PE. The incidence of the complication of DVT following total joint replacement is reported to occur in 50% to 75% of all unprotected patients. The increasing number of adults who undergo a total joint replacement dictates that orthopaedic nurses become a vital part of the development team that (1) identifies contributing factors to each patient's risk profile, (2) decreases this risk, and (3) refines the patient's transition through the acute hospitalization into the home or rehabilitation environment. The results of recent studies with a new class of heparins, the low molecular weight heparins, suggest their superiority and demonstrate improvement in decreasing the risk of developing DVT and subsequent PE in the total hip and knee patient population. PMID- 10095647 TI - Postoperative mental status in elderly hip surgery patients. AB - PURPOSE: To determine if elderly patients undergoing hip surgery became delirious postoperatively and, if so, whether age and/or time of day were related to delirium. DESIGN: Repeated measures. SAMPLE: A convenience sample of 70 hip surgery patients 60 years of age and older at a large Midwestern teaching hospital were studied. Patients were excluded who were unconscious, unable to hear, see, and/or verbally communicate in English. Patients were also excluded who had a known history of dementia, Alzheimer's dementia, addiction to alcohol and/or sedative hypnotics, functional psychosis, or any other psychiatric diagnosis. Of the 70 patients, 37 were female and 33 were male. Mean age of the patients was 72.9 years (S.D. = 8.13). Patients were placed into one of three groups: Group 1--age 60 to 69 years (n = 25); Group 2--age 70 to 79 years (n = 25); or Group 3--80 years and older (n = 20). The most common procedure for all groups was total hip replacement (n = 48). METHOD: Data were collected primarily by both objective and subjective assessment of the patients. Both the Folstein's Mini Mental Status Exam (MMSE) and the NEECHAM Confusion Tool were used to collect data. Chart reviews provided additional data. Patients were assessed preoperatively to obtain baseline assessment and screen out patients with preexisting confusion. Assessments were then done once in the morning and once in the evening for 5 days following surgery. MAIN RESEARCH CLASSIFICATIONS: Delirium, sundowning, sundown syndrome. FINDINGS: The MMSE and NEECHAM were found to be highly correlated: Morning NEECHAM vs morning MMSE (Correlation Coefficient = .6515; p = .000), evening NEECHAM vs evening MMSE (Correlation Coefficient = .8301; p = .000). A test of repeated measures was used to examine the data. The Within factor was time, the Between factor was age, and the interaction effect was age by time of day. Dependent variables were total NEECHAM scores and total MMSE scores, in addition to total scores of these tests' subsections. An alpha level of .05 was used for all statistical tests. Age had a significant main effect on the NEECHAM (F = 7.44; p = .001) and MMSE (F = 6.04; p = .004). Time did not have a significant effect on either the MMSE (F = .00; p = .953) or the NEECHAM (F = .43; p = .513). There was no statistically significant interaction between age and time of day (NEECHAM, F = .97, p = .384 and MMSE (F = .19, p = .826). No subjects were assessed as demented per the MMSE. Only 12 episodes of acute confusion were noted using the NEECHAM. CONCLUSION: Patients in this population rarely, if ever, became confused. The older the individual, the more likely he/she was to have confusion. Time of day was neither significant in development of delirium nor on mental status assessment scores in this population. IMPLICATIONS FOR NURSING RESEARCH: Current research literature notes that 10% to 50% of elderly postoperative patients experience delirium. Patients who have had femoral neck fractures can experience delirium three times more than patients having nonorthopaedic surgery. This study found that delirium in hip surgery patients is rare. A study of the more subtle components of delirium such as attention and memory might reveal less obvious changes in mental status following surgery. Type of orthopaedic surgery also might impact incidence of delirium. A comparative study between elderly total knee and total hip replacement patients would be interesting. Studying patients who have emergency hip surgery related to fracture in comparison to patients having elective hip surgery for degenerative conditions might identify other etiologies for delirium following hip surgery. Fatigue rather than time of day might be studied to observe whether it has a significant impact on mental status or delirium scores. PMID- 10095648 TI - Conducting a workshop. AB - Conducting a successful workshop is a rewarding accomplishment. To be successful, organization and planning are key factors. Important steps are started early and performed systematically. This article outlines the steps for a successful workshop. PMID- 10095649 TI - A clinical pathway for the secondary diagnosis of alcohol misuse: implications for the orthopaedic patient. AB - This article presents the process of developing a method of routine identification, assessment, intervention, and follow-up for the trauma patient with a concomitant diagnosis of alcohol misuse. A clinical pathway approach to addressing the needs of the alcohol misuser is outlined, and an alternative method that adapts this approach to other settings is also presented. Ever mindful of decreasing lengths of stay and reimbursement predicated on diagnosis related groups, this pathway is tailored to overlay onto an existing clinical path of care so as not to increase length of stay nor duplicate services. PMID- 10095650 TI - Assessment of learning needs of registered nurses for osteoporosis education. AB - PURPOSE: To answer the questions: How important is osteoporosis education? What are the topics that must be included in osteoporosis education? DESIGN: Nonexperimental descriptive. SAMPLE: 225 questionnaires were distributed to Registered Nurses in acute, ambulatory, and long-term care; 139 (62%) responded. METHODS: Nurse experts in osteoporosis developed and refined a needs assessment questionnaire that was distributed by mail. The 5-page questionnaire included demographic items. Other items inquired about the respondent's perceived need for osteoporosis education for patients and nurses, and the respondent's knowledge of and need for education in 27 specific topics. FINDINGS: Respondents expressed strong interest in and need for an educational program on osteoporosis. They rated their (mean) knowledge of 22 of 27 specific topics as between "limited" and "adequate." Subjects delineated important core content to be included in the educational program. These subjects included risk factors, prevention, assessment, calcium intake, nutrition, menopause, pharmacotherapeutics, and fall prevention. CONCLUSIONS: Subjects found their own knowledge of certain topics in osteoporosis as less than adequate. Subjects documented the need for osteoporosis education for patients and nurses. IMPLICATIONS FOR NURSING EDUCATION: There is a need for continuing education offerings to inform nurses and patients about osteoporosis prevention, detection, and management. PMID- 10095651 TI - Advanced practice nursing role: clinical nurse specialist. AB - The public continues to demand quality health care that focuses on the achievement of quality patient outcomes. The clinical nurse specialist is an advanced practice role that originated in the early 1900s as a result of similar public demand, and continues to evolve to meet quality health care needs. Advanced practice nurses have many opportunities to create expanded nursing roles. Orthopaedic nurses also continue to refine their practice roles, and the clinical nurse specialist is one such example. PMID- 10095652 TI - Advanced practice nursing role: nurse practitioner. AB - Nurse Practitioners are advanced practice nurses (APNs) who provide primary and acute care to individuals in many settings. The NP diagnoses and treats medical and surgical conditions that require acute, short-term management and chronic, long-term treatment. States vary in regulating processes regarding collaborative agreements, prescriptive authority, medical staff privileges, and insurance/third party reimbursement. PMID- 10095653 TI - Cost containment and quality: coexisting in total joint care. AB - National competitive and regulatory pressures are dramatically changing health care. Total joint care programs must redesign to meet these challenges. Multidisciplinary teams must review and refine care across the total joint care continuum, which covers preop through rehab. The six key areas of care on the continuum are preop teaching/testing, implants, care paths, special equipment, discharge and rehab, and documentation/coding. Each of these areas presents opportunities to develop strategies for enhanced efficiencies across the total joint care continuum. The goal is to maintain or improve quality of care while being cost effective. PMID- 10095654 TI - Culture, ethics, and respect: the bottom line is understanding. AB - As the world becomes smaller, there is increasing recognition that the world is more culturally diverse. People within a particular group share customs, habits, and values; however, these individuals may share few, if any, beliefs and practices with people from other cultural groups. This increasing cultural diversity raises questions about ways to deliver appropriate and respectful health care to patients from other cultures. This article discusses culture, culture and health care, and respect for culture. There is a description of means that nurses can use to provide culturally relevant care. Ethical practice requires a recognition of one's biases, a sensitivity to cultural differences, the avoidance of generalizations about cultures, and the provision of culturally relevant care. PMID- 10095655 TI - Focus on cancer survivors. PMID- 10095656 TI - Cleft care. PMID- 10095657 TI - Get into FOCUS. PMID- 10095658 TI - Dermatology assessment tool. PMID- 10095659 TI - Hospice at home: our first year. PMID- 10095660 TI - CF and me. Interview by Anna Sidey. AB - Home care and aggressive management for cystic fibrosis can help to ensure that this disorder fits in to a family's lifestyle and does not dictate it. This pattern of care requires high levels of autonomy, commitment and confidence in the nursing team, alongside a mutually trusting and supportive relationship between the child, the family and the care team. In this case this relationship was between Kelly and the care team. Kelly was initially reluctant to assume responsibility for her lifestyle and increasingly complex treatment and care but once empowered to do so, became a great enthusiast. This enthusiasm led her, in her early teens, to write the following account, which she asked me to publish for her. I knew Kelly for over 10 years, during which her nature demonstrated a complex mixture of compliance and contrariness in both her everyday life and her approach to her CF. Her death followed a rapid deterioration. This account reflects the quality of life she and her family achieved during one of the more fulfilling episodes in her short life. PMID- 10095661 TI - The child first and always? AB - When there is good reason to suspect that parents are deliberately inducing their child's illness, nurses may be best placed to gather sufficient evidence. Sue Bradley examines the ethical implications of covert video surveillance. PMID- 10095662 TI - The role of the retrieval team in severe asthma. AB - Retrieval teams, consisting of staff trained in the transfer of critically ill, patients, step into the breach when local hospitals lack the facilities or expertise needed. Tracy Taylor uses a case study to illustrate their effectiveness. PMID- 10095663 TI - Chronic illness and health development. PMID- 10095665 TI - Delivering the paper. PMID- 10095664 TI - Game plan. PMID- 10095666 TI - Nurse consultants--who will benefit? PMID- 10095667 TI - Essential skills for paediatric nurses. AB - Concerns about the varied nature of practical learning, experiences available to students prompted this study of the skills required to nurse children. Experienced paediatric nurses were surveyed to identify which skills they considered to be essential and which desirable in child branch diplomates. Out of 74 practical skills. 47 were believed to be essential on qualification. This list of skills could provide an expected baseline for students to achieve during their educational programme. PMID- 10095668 TI - Parents' experiences of ambulatory care. AB - In view of the recent rapid developments in paediatric daycare provision and ambulatory care a qualitative study was undertaken to ascertain parents' experiences of this service. A high proportion of the research literature addresses issues in surgical day care only. This study was undertaken to redress the balance. Eleven parents who accessed local ambulatory care services were selected then interviewed at home following discharge. The interviews were analysed using a framework based on grounded theory in order to generate explanations from a parent's perspective. It transpired that parents' experiences of their children's illness extended the bounds of the hospitalised period and professional support was important throughout. Parents who felt cared for in the social sense and received adequate information, appeared to report the more positive experiences and coped better. PMID- 10095669 TI - Compliance with iron chelation therapy in beta thalassaemia. PMID- 10095670 TI - Discharge planning for overseas patients. PMID- 10095671 TI - The growth of hospices in the UK. PMID- 10095672 TI - An infection out of season: respiratory syncytial virus. PMID- 10095673 TI - Managing the child with gastroenteritis. PMID- 10095674 TI - Perceptions about children's pain experience. AB - Children are still enduring unnecessary pain, partly due to misconceptions about pain in children. Nurses need to be aware of these misconceptions and to reflect on their own practice. There are a number of factors that influence how nurses perceive pain in children. Nurses need to be aware of these to ensure good clinical practice. Parents are a valuable asset in the management of children's pain and nurses need to work in partnership with them to manage pain. PMID- 10095675 TI - Developing the role of the CNS in osteoporosis. AB - Nurses can have a major impact on the prevention and treatment of osteoporosis. The role of the osteoporosis nurse specialist is being developed. As nurse specialist posts are created it is essential that UKCC criteria are met. Comparability of grades and areas of expertise are required. PMID- 10095676 TI - Developing common case notes in mental health. PMID- 10095677 TI - Expanding the role of the urology nurse specialist. PMID- 10095678 TI - Running a community nurse-led vascular service. PMID- 10095679 TI - The benefits of using qualitative research. AB - Qualitative research is a way of describing an event in its context and is useful for investigating complex, new or relatively unexplored areas. A central tenet of the qualitative approach is that researchers cannot be truly neutral or detached from data generation and analysis. Qualitative research values the experience of the research participant and can offer valuable insight into the settings and situations in which nurses work. PMID- 10095680 TI - Colostomy. AB - Undergoing surgery for a colostomy and coming to terms with the resulting change in body image can be a traumatic time for patients. This update examines the pre- and postoperative care that nurses should provide. PMID- 10095681 TI - Spasticity. AB - Spasticity affects people with a variety of conditions, including stroke, spinal cord injury and multiple sclerosis. Assessment, physical therapies and pharmacological and invasive treatments are discussed in this Update. PMID- 10095682 TI - Blood glucose measuring systems. AB - Glucose monitoring and lancing systems have proved useful in a range of patient testing applications in hospitals, general practice and for use by patients at home. Products are becoming easier to use and less technique dependent. It is important to be aware of their specific characteristics and to adhere to manufacturers' and local hospital laboratory guidelines. PMID- 10095683 TI - Breast cancer. Part 3: Psychosocial care. AB - Psychosocial care, information-giving and issues surrounding patient choice are important aspects in the nursing care of women with breast cancer. Patients with breast cancer consistently identify communication as an area of central importance. The nurse, specialist or otherwise, has an important role in addressing patients' needs following diagnosis and treatment for breast cancer. PMID- 10095684 TI - Meeting the needs of patients' relatives. AB - Research into stress experienced by the relatives of patients in intensive care may be equally applicable to general wards. Patients are part of a family group and holistic care should include all family members. All nurses should review their practice in relation to relatives' needs. PMID- 10095685 TI - Clarifying higher level roles in nursing practice. AB - There is widespread confusion about the titles nurse practitioner and clinical nurse specialist. A number of broad similarities in and differences between the roles has been identified. A robust, nationally recognised method of regulating these titles is needed. PMID- 10095686 TI - Cleansing regimens for continence care. AB - Soap and water can be harmful when used to cleanse patients with fragile skin. Two alternatives to soap and water were tested with elderly, incontinent patients. Further trials are needed with a larger sample and with different patient populations. PMID- 10095687 TI - The purpose and use of questionnaires in research. AB - The questionnaire can be a cost-effective research tool for use in data collection. A number of sequential steps should be followed in planning and designing questionnaires. Questionnaires should be sent to a pilot sample to check reliability and validity before going to the research sample. PMID- 10095688 TI - Paraplegia. AB - Nurses caring for people who have sustained an injury resulting in paraplegia must have an understanding of both the psychological and physical effects. This Update examines the nurse's role in preparing the patient for the future. PMID- 10095689 TI - Meeting the nutritional needs of the older adult. AB - As a group, older people are more susceptible than others to nutritional problems. Improving nutritional status is a multidisciplinary function, although there is much nurses can do to help patients receive an adequate diet. The education of health professionals is a key factor in ensuring patients receive good nutritional care. PMID- 10095690 TI - Reducing the risk of hepatitis to staff. AB - Hepatitis continues to pose a serious risk to the health of staff and patients. A number of procedures can be put in place to protect the health and safety of nurses exposed to the risk. Nurses should be aware of systems and policies in their own work area. PMID- 10095692 TI - Medical gloves and glove materials. AB - Latex gloves are widely used in health care, but latex allergy is increasingly becoming a problem. Nurses should be aware of the alternatives to latex gloves and when these can be used. Nurses should know their organisation's policy on glove use and latex allergy. PMID- 10095691 TI - Self-administration of drugs for cystic fibrosis. AB - Self-administration of medication encourages individuals to participate in their own health care and provides structure for regular assessment and teaching about their drugs. Patient-friendly drug leaflets can provide consistent information to patients cared for by a number of staff. Self-administration studies found in the nursing literature must be interpreted cautiously because of the lack of true experimental trials. PMID- 10095693 TI - Nursing in the independent sector. PMID- 10095694 TI - [Organizational culture and professional development in nursing]. PMID- 10095695 TI - [Improvement of the quality of life in patients with colostomies by using continence methods]. AB - We analise by means of a descriptive study the improvement in the quality of life of two groups of colostomists after the use of two continence methods respectively: only the plug or the combination of the irrigation and the plug. According to the obtained results, the author confirms for both groups a mayor increase in the activities of life, a low frequency of incidences during the adaptation to the continence method, as well as a significant decrease of noises and smells and a high level of general satisfaction. Therefore we can conclude that these two continence possibilities brings for colostomists a mayor increase in their quality of life. PMID- 10095696 TI - [Finding the original meaning of nursing care]. AB - At the end of the 20th century, a return to the true origin of health care appears, even though this has occurred only in a few services such as those which care for the elderly; when nurses confront dilemmas related to the fundamental questions of life and death; or before the impotence of some treatments, for example AIDS. In a parallel vein, work carried out over these past few years allows us to find the roots of health care and to recuperate its original meaning. Care and treatment are universal and all appear and are elaborated around the two great moments in life: birth and death. PMID- 10095698 TI - [Violence against the elderly. Silence is complicity]. PMID- 10095697 TI - [The University Nursing School of the Puerta del Mar University Hospital]. PMID- 10095699 TI - [Motivation and leadership in nursing]. PMID- 10095700 TI - [Mexico: everybody has a right to health]. PMID- 10095701 TI - [Cardiopulmonary resuscitation. General facts and introduction]. AB - Cardiopulmonary Resuscitation consists of the integration of treatment for cardiorespiratory arrest as a set of standardized steps, whose objective is to first substitute, and later restore, spontaneous respiration and circulation. This calls for a sequential development; this implies that there are not a series of actions which for prematureness influences their order, but these should be applied sequentially at the right time. There are different criteria among the recommendations by the ERC (European Resuscitation Council) and the AHA (American Heart Association). At the present time, the International Liaison Committee of Resuscitation (ILCOR) has developed a series of recommendations which tries to eliminate these differences, as well as simplify the number of steps necessary to achieve a greater diffusion of these techniques which will lead to a higher number of persons saved. There are also agreements on the incorporation of some terms so we will more frequently read the term Basic Vital Support instead of Basic Cardiopulmonary Resuscitation or Advanced Vital Support instead of Advanced Cardiopulmonary Resuscitation. This article is the first of a series of four articles on cardiopulmonary Resuscitation. The remaining articles will appear in later editions of our magazine. PMID- 10095702 TI - [Coverage of tetanus vaccination. Study of the over 59 year old population]. PMID- 10095704 TI - [Etiquette]. PMID- 10095703 TI - [Tibial arteries of the anterior and dorsal foot]. PMID- 10095705 TI - [Treatment of smoking addiction. A guide for professional nurses]. PMID- 10095706 TI - [Do we care for the families of chronically ill patients?]. PMID- 10095707 TI - The real truth about teams: an interview with Jo Manion. PMID- 10095708 TI - Introduction to budgeting. PMID- 10095709 TI - A few lessons learned about teams and teamwork. PMID- 10095710 TI - Teams and teamwork: the critical elements. PMID- 10095711 TI - Moving the organization to operate within team-based approaches. AB - Today's health care systems face enormous challenges. Market changes, workforce shortages, and the new consumerism force us to work in new ways. Inova Health System, a network of health care services providing care in suburban Northern Virginia, has embarked on team-based organizational strategies to meet these demands. We believe our success with team-based work can be attributed to several key factors. These factors are reviewed, and examples of work done in our System are highlighted. The lessons learned may provide insight into how various organizations strive toward team-based work. PMID- 10095712 TI - Creating the executive team to lead team-based organizations. AB - In team-based organizations, senior executives are often the last group to be truly a team. Many factors contribute to the individualism that is characteristic of the leadership of an organization. Factors that produce the success of an executive may be contradictory to the skills needed to be an effective team member. Team-based organizations continue to demonstrate their success in managing the changing and challenging work environments. Health care executive leadership groups must realize the impact they can have on the organization if they become a team. This article reviews how executives can become a team. PMID- 10095713 TI - Team behaviors: working effectively in teams. AB - The work of building and sustaining teams is often underestimated by middle managers. A manager must have the ability to develop and evolve staff toward a new level of competence, required because of radically upgraded expectations. Managers must be clear about what it means to empower teams, to avoid the trappings of giving "lip service" to authority boundaries, which may exist only on paper. Achieving this clarity means understanding the characteristics of effective teams: a high degree of interdependence, strong sense of organizational empowerment, self-determination, competence, commitment, and genuine concern about the quality of work being performed. An important tool for the manager interested in team development is the creation of a performance model, grounded in the foundational relationship competencies necessary for team success. Performance modeling assists not only in identifying of competency gaps that can be addressed by training but also in determining the workplace barriers to team success. PMID- 10095714 TI - Pathway leadership: a mature framework for teams. AB - Shared Governance has been a successful organizational design for Central Baptist Hospital. We are addressing critical issues that impact our success, with involvement and facilitation of the employees who make up the organization. It will continue to change as our environment and system evolve. The movement from a traditional organizational structure and culture to one of embracing shared decision making gives leaders today an additional stressor. It is difficult to critically analyze your organization when you are faced daily with the external pressures of health care competition and the internal daily pressures of operations. It takes extra effort and introspection to recognize that you and your management team must undertake new and different behaviors to lead your organization into the next millennium. One thing is clear: If you do not create an environment that is flexible and able to accommodate change, your competitor will! PMID- 10095715 TI - Changing reward systems for team-based systems. AB - With the rapidly changing pace in health care, hospitals are struggling to keep costs under control and to remain competitive. Leadership is increasingly convinced that old methods of compensation are no longer valid and thus are turning to innovative approaches to pay and reward systems. This article describes some of the new pay methods, with an emphasis on team rewards, showing that compensation can keep pace with the evolving needs of health care. PMID- 10095716 TI - Person-centered code of practice/code of ethics: configuring an ethical commitment to the care provider and care receiver. AB - Transformation in Care Delivery (TCD), a program at Piedmont Medical Center in Atlanta, Georgia, emphasizes building connections and achieving new and different relationships between all persons in the health care system: those who receive services as well as those who give services. A process called opportunity management mandates involvement of all affected people and provides the mechanism for TCD decisions and actions. The desired environment for TCD is a practiced philosophy of person-centeredness, lived through a new Code of Practice/Code of Ethics. The philosophy and Code are built on respect for the diverse beliefs, values, and practices of all people receiving and providing service. This article highlights the way these processes result in improved value for all stakeholders through a new personal and organizational ethical commitment to excellence. PMID- 10095717 TI - Integrating students into interdisciplinary teams: extending the caring circle. AB - Interdisciplinary teams are considered essential for meeting the health care delivery challenges of the 21st century. Integrating students into these teams is critical to attracting and sustaining a future workforce with the knowledge and skills to maximize health care outcomes. This article describes a caring circle approach to interdisciplinary teams that promotes student learning and benefits the team. The caring circle is based on building relationships through shared knowledge, shared practices, and shared values. Specific strategies to build the caring circle using these building blocks are discussed. PMID- 10095718 TI - [Nursing management. At arm's length, at the end of one's strength]. PMID- 10095719 TI - [Understanding nurses' professional burnout syndrome. Interview by Bernadette Fabregas]. PMID- 10095720 TI - [Medical strategy. Evaluation of burnout and its results]. PMID- 10095721 TI - [Nurses are "burning"]. PMID- 10095722 TI - [Psychology. Are we all potential burnouts?]. PMID- 10095723 TI - [Pediatric intensive care, a high risk service]. PMID- 10095724 TI - [Violence and nursing care]. PMID- 10095725 TI - [Studying other methods of organization]. PMID- 10095726 TI - [The quality of nursing practice]. PMID- 10095727 TI - [Utilization of care and attitudes to risk]. PMID- 10095729 TI - [Accreditation goes along with the dynamics of change] [In Process Citation] PMID- 10095728 TI - [Are public toilets dangerous to health?]. PMID- 10095730 TI - ["We have only our loneliness"] [In Process Citation] PMID- 10095731 TI - [Quality/accreditation. Social management and accreditation]. PMID- 10095732 TI - [Influenza vaccination of hospital personnel]. PMID- 10095733 TI - [The Lyons experience 1997-1998. Anti-influenza vaccination]. PMID- 10095734 TI - [Status of drugs]. PMID- 10095735 TI - [Patients' rights. 3. Information and consent]. PMID- 10095736 TI - [What to do about severe temporo-spatial disorientation]. PMID- 10095737 TI - [Personal hygiene. Incapacity of washing oneself, and carrying out one's personal hygiene]. PMID- 10095738 TI - [Nursing management. Support for nursing diagnosis]. PMID- 10095739 TI - [Formalizing the nurses' specific knowledge. Interview by Bernadette Fabregas]. PMID- 10095740 TI - [A nursing care plan for the improvement of physical mobility]. PMID- 10095741 TI - [A nursing care plan for dealing with anxiety]. PMID- 10095742 TI - [Developing the relational aspects of care]. PMID- 10095743 TI - [Quality of nursing service for the lasting capacity of our profession]. PMID- 10095744 TI - [Quality, accreditation. Needs for health and requirements of care]. PMID- 10095745 TI - [Transfusion safety, experiences from the Le Havre Hospital Center]. PMID- 10095746 TI - [Promoting the importance of the profession throughout Europe] [In Process Citation] PMID- 10095747 TI - [A nurse initiates a health center]. PMID- 10095748 TI - [Health care and social problems. Four projects looking for the government green light] [In Process Citation] PMID- 10095749 TI - [Accreditation, advice and directions for use]. PMID- 10095750 TI - [The referent nurse in the primary care of the patient]. PMID- 10095751 TI - [Drug interactions]. PMID- 10095752 TI - [How to treat an unconscious patient]. PMID- 10095753 TI - [Personal care: elimination]. PMID- 10095754 TI - [You don't understand?]. PMID- 10095755 TI - [Therapeutic workshops]. PMID- 10095756 TI - [From dream to reality]. PMID- 10095757 TI - [The story of Yann. Strolling about on the pathways across the sector]. PMID- 10095759 TI - [Cabaret evening, April 3, 1998]. PMID- 10095760 TI - [English studies in the therapeutic club l'Avenir]. PMID- 10095758 TI - ["Dealing with" the violence in a very young child. At the occasion of the complex admission of Ryan]. PMID- 10095761 TI - [The bees of the Blue Cross]. PMID- 10095762 TI - [Packing for autistic and psychotic children]. PMID- 10095763 TI - The role of water structure in conformational changes of nucleic acids in ambient and high-pressure conditions. AB - This review describes and summarizes data on the structure and properties of water under normal conditions, at high salt concentration and under high pressure. We correlate the observed conformational changes in nucleic acids with changes in water structure and activity, and suggest a mechanism of conformational transitions of nucleic acids which accounts for changes in the water structure. From the biophysical, biochemical and crystallographic data we conclude that the Z-DNA form can be induced only at low water activity produced by high salt concentrations or high pressure, and accompanied by the stabilizing conjugative effect of the cytidine O4' electrons of the CG base pairs. PMID- 10095764 TI - Functional characterization of Escherichia coli inorganic pyrophosphatase in zwitterionic buffers. AB - Catalysis by Escherichia coli inorganic pyrophosphatase (E-PPase) was found to be strongly modulated by Tris and similar aminoalcoholic buffers used in previous studies of this enzyme. By measuring ligand-binding and catalytic properties of E PPase in zwitterionic buffers, we found that the previous data markedly underestimate Mg(2+)-binding affinity for two of the three sites present in E PPase (3.5- to 16-fold) and the rate constant for substrate (dimagnesium pyrophosphate) binding to monomagnesium enzyme (20- to 40-fold). By contrast, Mg(2+)-binding and substrate conversion in the enzyme-substrate complex are unaffected by buffer. These data indicate that E-PPase requires in total only three Mg2+ ions per active site for best performance, rather than four, as previously believed. As measured by equilibrium dialysis, Mg2+ binds to 2.5 sites per monomer, supporting the notion that one of the tightly binding sites is located at the trimer-trimer interface. Mg2+ binding to the subunit interface site results in increased hexamer stability with only minor consequences for catalytic activity measured in the zwitterionic buffers, whereas Mg2+ binding to this site accelerates substrate binding up to 16-fold in the presence of Tris. Structural considerations favor the notion that the aminoalcohols bind to the E PPase active site. PMID- 10095765 TI - Purification and characterization of a detergent-requiring membrane-bound metalloendopeptidase from porcine brain. AB - A detergent-requiring metalloendopeptidase cleaving a progastrin-C-terminal peptide (progastrin-(88-101)) mainly at the Arg95-Gly96 bond was solubilized from porcine cerebral vesicular membranes and purified to homogeneity as examined by PAGE. The purified enzyme had a molecular mass of approximately 76 kDa as estimated by both SDS/PAGE and Sephacryl S-300 gel filtration. It hydrolyzed progastrin-(88-101) peptide, BAM-12P, and bradykinin fairly specifically, and more efficiently than various other neuropeptides and related oligopeptides examined as substrates. It was inactive in the absence of detergents, and required certain detergents such as Triton X-100 or Lubrol PX for activity. Its optimum pH was about 6.5 and was strongly inhibited by metal-chelating agents such as EDTA, EGTA, and o-phenanthroline. It was extremely sensitive to EDTA and was completely inhibited even by 0.3 microM EDTA; the activity was fully restored by addition of a 10-fold higher concentration of Zn2+, CO2+, or Mn2+ ions over EDTA. On the other hand, dynorphin A-(1-13) peptide, a strong inhibitor of neurolysin, failed to inhibit the enzyme. The various characteristics indicated that the present enzyme is a unique membrane-bound metalloendopeptidase. PMID- 10095766 TI - Interactions of the Streptomyces lividans initiator protein DnaA with its target. AB - The Streptomyces lividans DnaA protein (73 kDa) consists, like other bacterial DnaA proteins, of four domains; it binds to 19 DnaA boxes in the complex oriC region. The S. lividans DnaA protein differs from others in that it contains an additional stretch of 120 predominantly acidic amino acids within domain II. Interactions between the DnaA protein and the two DnaA boxes derived from the promoter region of the S. lividans dnaA gene were analysed in vitro using three independent methods: Dnase-I-footprinting experiments, mobility-shift assay and surface plasmon resonance (SPR). The Dnase-I-footprinting analysis showed that the wild-type DnaA protein binds to both DnaA boxes. Thus, as in Escherichia coli and Bacillus subtilis, the S. lividans dnaA gene may be autoregulated. SPR analysis showed that the affinity of the DnaA protein for a DNA fragment containing both DnaA boxes from the dnaA promoter region (KD = 1.25 nM) is 10 times higher than its affinity for the single 'strong' DnaA box (KD = 12.0 nM). The mobility-shift assay suggests the presence of at least two classes of complex containing different numbers of bound DnaA molecules. The above data reveal that the DnaA protein binds to the two DnaA boxes in a cooperative manner. To deduce structural features of the Streptomyces domain II of DnaA protein, the amino acid DnaA sequences of three Streptomyces species were compared. However, according to the secondary structure prediction, Streptomyces domain II does not contain any common relevant secondary structural element(s). It can be assumed that domain II of DnaA protein can play a role as a flexible protein spacer between the N terminal domain I and the highly conserved C-terminal part of DnaA protein containing ATP-binding domain III and DNA-binding domain IV. PMID- 10095767 TI - A novel human DNA-binding protein with sequence similarity to a subfamily of redox proteins which is able to repress RNA-polymerase-III-driven transcription of the Alu-family retroposons in vitro. AB - In this study we identified a novel protein which may contribute to the transcriptional inactivity of Alu retroposons in vivo. A human cDNA clone encoding this protein (ACR1) was isolated from a human expression library using South-western screening with an Alu subfragment, implicated in the regulation of Alu in vitro transcription and interacting with a HeLa nuclear protein down regulated in adenovirus-infected cells. Bacterially expressed ACR1 is demonstrated to inhibit RNA polymerase III (Pol III)-dependent Alu transcription in vitro but showed no repression of transcription of a tRNA gene or of a reporter gene under control of a Pol II promoter. ACR1 mRNA is also found to be down-regulated in adenovirus-infected HeLa cells, consistent with a possible repressor function of the protein in vivo. ACR1 is mainly (but not exclusively) located in cytoplasm and appears to be a member of a weakly characterized redox protein family having a central, highly conserved sequence motif, PGAFTPXCXXXXLP. One member of the family identified earlier as peroxisomal membrane protein (PMP)20 is known to interact in a sequence-specific manner with a yeast homolog of mammalian cyclosporin-A-binding protein cyclophilin, and mammalian cyclophilin A (an abundant ubiquitously expressed protein) is known to interact with human transcriptional repressor YY1, which is a major sequence-specific Alu-binding protein in human cells. It appears, therefore, that transcriptional silencing of Alu in vivo is a result of complex interactions of many proteins which bind to its Pol III promoter. PMID- 10095768 TI - Solution structure of the B form of oxidized rat microsomal cytochrome b5 and backbone dynamics via 15N rotating-frame NMR-relaxation measurements. Biological implications. AB - Cytochrome b5 in solution has two isomers (A and B) differing by a 180 degrees rotation of the protoporphyrin IX plane around the axis defined by the alpha and gamma meso protons. Homonuclear and heteronuclear NMR spectroscopy has been employed in order to solve the solution structure of the minor (B) form of the oxidized state of the protein and to probe its backbone dynamics in the microsecond--ms timescale in both oxidation states. A family of 40 conformers has been obtained using 1302 meaningful NOEs and 220 pseudocontact shifts and is characterized by high quality and good resolution (rmsd to the mean structure of 0.055 +/- 0.009 nm and 0.103 +/- 0.011 nm for backbone and heavy atoms, respectively). Extensive comparisons of the structural and dynamics changes associated with the A-to-B form interconversion for both oxidation states were subsequently performed. Propionate 6 experiences a redox-state-dependent reorientation as does propionate 7 in the A form. Significant insights are obtained into the role of the protein frame for efficient biological function and backbone mobility is proposed to be one of the factors that could control the reduction potential of the heme. PMID- 10095769 TI - Restoration of lectin activity to an inactive abrin B chain by substitution and mutation of the 2 gamma subdomain. AB - Abrin is a heterodimeric plant protein that occurs in several isoforms (abrin-a, abrin-b, abrin-c and abrin-d), whose B chains are believed to either have (abrin a and abrin-d) or lack (abrin-b and abrin-c) the ability to bind galactose. The 5' signal sequence and toxin B chain (ATB)-coding region were excised from a preproabrin cDNA [K. A. Wood, J. M. Lord, E. J. Wawrzynczak, and M. Piatak (1991) Eur. J. Biochem. 198, 723-732], tentatively identified as abrin-c, which was predicted to lack lectin activity, and fused in-frame to generate pre-ATB cDNA. Transcripts, synthesized in vitro from pre-ATB cloned into the transcription vector pSP64T, were expressed after microinjection into Xenopus oocytes. The recombinant ATB was shown, using a qualitative sugar-binding assay, to be devoid of lectin activity. Lectin activity could not be restored to this nonbinding ATB by replacing the 2 gamma subdomain with the corresponding galactose-binding 2 gamma subdomain from ricin B chain, but it was restored by replacement with the active galactose-binding 2 gamma subdomain from a different abrin isoform (abrin a). The putative galactose-binding pocket of the nonbinding ATB 2 gamma subdomain contained a His residue at the position occupied by a residue with an aromatic side chain (Tyr or Trp) in functional 2 gamma subdomains. Mutationally converting this His to either Tyr or Trp restored lectin activity to the nonbinding ATB, emphasizing the contribution of an aromatic side chain in a functional 2 gamma subdomain galactose-binding site for members of this lectin family. PMID- 10095770 TI - Iron regulatory protein as an endogenous sensor of iron in rat intestinal mucosa. Possible implications for the regulation of iron absorption. AB - Duodenal enterocytes adjust intestinal iron absorption to the body's state of iron repletion. Here we tested how iron supply from the blood modulates the RNA binding activity of iron regulatory proteins (IRP-1 and IRP-2) in immature duodenal rat enterocytes, and whether the modulation is compatible with the hypothesis that IRPs, in turn, may regulate the expression of iron transport proteins in maturating enterocytes during migration to the villus tips. Tissue uptake of parenterally applied 59Fe along the duodenal crypt-villus axis was compared to local IRP-1 and IRP-2 activity and to duodenal 59Fe transport capacity 12 h, 48 h, and 72 h after intravenous iron administration to iron deficient rats. IRP-1 and IRP-2 activity was significantly increased in iron deficiency. 59Fe administrated from the blood side was almost exclusively taken up by crypt enterocytes. Accordingly, the activity of IRP-1 decreased at this site 12 h after parenteral iron administration, but remained high at the villus tips. After 48 h the bulk of 59Fe containing enterocytes had migrated to the villus tips. Correspondingly, IRP-1 activity was decreased at duodenal villus tips after 48 h. IRP-2 activity also tended to decrease, though the change was statistically not significant. IRP-2 activity remained significantly higher at duodenal villus tips than in crypts, even after 72 h. Intestinal iron absorption capacity decreased with the same delay as IRP-1 activity after intravenous iron administration. In the ileum 59Fe uptake from the blood and IRP activity showed no significant difference between crypt and villus region. Luminal administration of iron decreased duodenal IRP-1 and IRP-2 activity at tips and crypts within 2 h. Thus, recently absorbed iron becomes available to cytosolic IRP during its passage through the enterocyte. Our results are compatible with a role of IRPs in gearing the expression of intestinal iron transporters in the duodenal brushborder to the body's state of iron repletion. PMID- 10095771 TI - Structural elucidation of a novel exopolysaccharide produced by a mucoid clinical isolate of Burkholderia cepacia. Characterization of a trisubstituted glucuronic acid residue in a heptasaccharide repeating unit. AB - The structure of the exopolysaccharide (EPS) produced by a clinical isolate of Burkholderia cepacia isolated from a patient with fibrocystic lung disease has been investigated. By means of methylation analyses, carboxyl reduction, partial depolymerization by fuming HCl and chemical degradations such as Smith degradation, lithiumethylenediamine degradation and beta-elimination, supported by GC/MS and NMR spectroscopic analyses, the repeat unit of the EPS has been identified and was shown to correspond to the acidic branched heptasaccharide with the following structure: [formula: see text]. This partially acetylated acidic polymer, distinguished by the presence of the less usual D-isomer of rhamnose and of a trisubstituted glucuronic acid residue, could represent the main EPS produced by this bacterial species. PMID- 10095772 TI - Identification of cyclin A/Cdk2 phosphorylation sites in B-Myb. AB - B-myb is a highly conserved member of the myb proto-oncogene family that encodes a ubiquitously expressed 110-kDa sequence-specific DNA-binding protein. Transactivation of Myb-inducible promoters by B-Myb is repressed by a regulatory domain located at the C-terminus of the protein. Cyclin A/Cdk2-mediated phosphorylation apparently releases the negative constraint and triggers B-Myb transactivation potential. Two-dimensional tryptic phosphopeptide analysis indicated that the majority of the sites phosphorylated in vivo are targeted in vitro by cyclin A/Cdk2. Six sites in B-Myb fulfil the requirements for recognition by Cdk2. Using point mutation of the phosphorylation sites to nonphosphorylatable amino acids, we show that five of these sites are targets for Cdk2 in vivo. Mutation of one of these residues (T524) to alanine diminished the ability of B-Myb to promote transcription of a reporter gene, suggesting that phosphorylation of B-Myb at this site is important for the regulation of its activity by cyclin A/Cdk2. PMID- 10095773 TI - Mapping of structural determinants for the oligomerization of p58, a lectin-like protein of the intermediate compartment and cis-Golgi. AB - Shortly after synthesis, p58, the rat homologue of the mannose-binding lectin ERGIC-53/MR60, which localizes to pre-Golgi and cis-Golgi compartments, forms dimers and hexamers, after which an equilibrium of both forms is reached. Mature p58, a type I membrane protein, contains four cysteine residues in the lumenal domain which are capable of forming disulphide bonds. The membrane-proximal half of the lumenal domain consists of four predicted alpha-helical domains, one heavily charged and three amphipathic in nature, all candidates for electrostatic or coiled-coil interactions. Using single-stranded mutagenesis, the cysteines were individually changed to alanines and the contribution of each of the alpha helical domains was probed by internal deletions. The N-terminal cysteine to alanine mutants, C198A and C238A and the double mutant, C198/238A, oligomerized like the wild-type protein. The two membrane-proximal cysteines were found to be necessary for the oligomerization of p58. Mutants lacking one of the membrane proximal cysteines, either C473A or C482A, were unable to form hexamers, while dimers were formed normally. The C473/482A double mutant formed only monomers. Deletion of any of the individual alpha-helical domains had no effect on oligomerization. The dimeric and hexameric forms bound equally well to D-mannose. The dimeric and monomeric mutants displayed a cellular distribution similar to the wild-type protein, indicating that the oligomerization status played a minimal role in maintaining the subcellular distribution of p58. PMID- 10095774 TI - Decreases in cAMP phosphodiesterase activity in hepatocytes cultured with herbimycin A due to cellular microtubule polymerization related to inhibition of tyrosine phosphorylation of alpha-tubulin. AB - The increase in cellular cAMP concentration during 10-min incubation of rat hepatocytes with glucagon or forskolin was enhanced markedly when the hepatocytes had been cultured for several hours with herbimycin A. This effect of herbimycin was accompanied by inhibition of tyrosine-phosphorylation of cellular proteins including alpha-tubulin, antagonized by coaddition of Na3VO4 plus H2O2, which also antagonized the herbimycin-induced tyrosine phosphorylation, and overcome by the addition to the 10-min incubation medium of a certain inhibitor of cAMP phosphodiesterase (PDE), which caused a huge accumulation of cAMP. The effective PDE inhibitors were 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone (rolipram) and 4-(3-butyloxy-4-methoxyphenyl)-2-imidazolidinone (Ro-20-1724, a PDE4 inhibitor), in addition to 3-isobutyl-1-methylxanthine (a nonselective inhibitor). Rapid breakdown of the once-accumulated cAMP in cultured hepatocytes during the subsequent incubation without PDE inhibitors was progressively prevented when the concentration of herbimycin was increased from 0.3 to 10 microM during prior culture. This effect of herbimycin to inhibit PDE activity in intact cells was abolished by coaddition of a microtubule-disrupting agent, either colchicine or vinblastine, into the culture, but remained unchanged if the vinblastine-containing medium was further supplemented with taxol, a microtubule stabilizing agent, which by itself mimicked the effect of herbimycin. None of these agents, which thus affected PDE activity in intact cells, inhibited the PDE activity assayable in the cell lysates. The taxol-like and vinblastine suppressible action of herbimycin to stimulate microtubular assembly was antagonized by Na3VO4/H2O2, as confirmed by confocal microscopic images of the cells stained with fluorescein-bound anti-(alpha-tubulin). Thus, 4-h culture of hepatocytes with herbimycin inhibits phosphorylation of the C-terminal tyrosine residue of alpha-tubulin, thereby stimulating formation of a microtubular network which is responsible for the inhibition of PDE4 in the intact cells by an unknown mechanism. PMID- 10095775 TI - Distribution of microsomal glutathione transferase 1 in mammalian tissues. A predominant alternate first exon in human tissues. AB - An extensive Northern blot analysis of microsomal glutathione transferase 1 in human and rat tissues was performed. When normalized against the glyceraldehyde-3 phosphate dehydrogenase or actin expression it was evident that the predominant expression occurs in liver and pancreas. An ontogenetic, as well as a functional, basis for the high levels in these two organs is possible. The relative expression levels in man ranged from: liver and pancreas (100%), to kidney, prostate, colon (30-40%), heart, brain, lung, testis, ovary, small intestine (10 20%), placenta, skeletal muscle, spleen, thymus and peripheral blood leucocytes (1-10%). Liver-enriched expression was detected in human fetal tissues with lung and kidney displaying lower levels (10-20%). No transcripts could be detected in fetal brain or heart. When comparing the expression levels between rat and man it is apparent that human extrahepatic mRNA levels are much higher relative to liver. Rat microsomal glutathione transferase mRNA expression ranges from 0.2 to 10% that of liver, with adrenal, uterus, ovary and stomach displaying the highest levels of the organs tested. Based on these observations, and the fact that the enzyme is encoded by a highly conserved single-copy gene, it is suggested that microsomal glutathione transferase 1 performs essential functions vital to most mammalian cell types. We suggest that protection against oxidative stress constitutes one such function. Human expressed sequence tag (EST) characterization yielded four alternate mRNA transcripts with different 5'-ends (four alternate noncoding exons 1). The predominant exon (based on the observed EST frequency) revealed a tissue distribution similar to that obtained using the reading frame as probe. Thus, it appears that one exon preferentially gives rise to mature mRNA in the human tissues examined. This exon is different from the one reported in the original cDNA characterized. PMID- 10095776 TI - Drosophila melanogaster transferrin. Cloning, deduced protein sequence, expression during the life cycle, gene localization and up-regulation on bacterial infection. AB - Drosophila melanogaster transferrin cDNA was cloned from an ovarian cDNA library by using a PCR fragment amplified by two primers designed from other dipteran transferrin sequences. The clone (2035 bp) encodes a protein of 641 amino acids containing a signal peptide of 29 amino acids. Like other insect transferrins, Drosophila transferrin appears to have a functional iron-binding site only in the N-terminal lobe. The C-terminal lobe lacks iron-binding residues found in other transferrins, and has large deletions which make it much smaller than functional C-terminal lobes in other transferrins. In-situ hybridization using a digoxigenin labeled transferrin cDNA probe revealed that the gene is located at position 17B1 2 on the X chromosome. Northern blot analysis showed that transferrin mRNA was present in the larval, pupal and adult stages, but was not detectable in the embryo. Iron supplementation of the diet resulted in lower levels of transferrin mRNA. When adult flies were inoculated with bacteria (Escherichia coli), transferrin mRNA synthesis was markedly increased relative to controls. PMID- 10095777 TI - Isolation of the CXC chemokines ENA-78, GRO alpha and GRO gamma from tumor cells and leukocytes reveals NH2-terminal heterogeneity. Functional comparison of different natural isoforms. AB - Chemokines are a family of chemotactic peptides affecting leukocyte migration during the inflammatory response. Post-translational modification of chemokines has been shown to affect their biological potency. Here, the isolation and identification of natural isoforms of the neutrophil chemoattractants GRO alpha and GRO gamma and the epithelial-cell-derived neutrophil attractant-78 (ENA-78), is reported. Cultured tumor cells produced predominantly intact chemokine forms, whereas peripheral blood monocytes secreted mainly NH2-terminally truncated forms. The order of neutrophil chemotactic potency of these CXC chemokines was GRO alpha > GRO gamma > ENA-78 both for intact and truncated forms. However, truncated GRO alpha (4,5,6-73), GRO gamma (5-73) and ENA-78(8,9-78) were 30-fold, fivefold and threefold more active than the corresponding intact chemokine. As a consequence, truncated GRO alpha (4,5,6-73) was 300-fold more potent than intact ENA-78 indicating that both the type of chemokine and its mode of processing determine the chemotactic potency. Similar observations were made when intact and truncated GRO alpha, GRO gamma and ENA-78 were compared for their capacity to induce an increase in the intracellular calcium concentration in neutrophilic granulocytes, and to desensitize the calcium response towards the CXC chemokine granulocyte chemotactic protein-2 (GCP-2). It must be concluded that physiological proteolytic cleavage of CXC chemokines in general enhances the inflammatory response, whereas for CC chemokines NH2-terminal processing mostly results in reduced chemotactic potency. PMID- 10095778 TI - Expression of delta, kappa and mu human opioid receptors in Escherichia coli and reconstitution of the high-affinity state for agonist with heterotrimeric G proteins. AB - Human opioid receptors of the delta, mu and kappa subtypes were successfully expressed in Escherichia coli as fusions to the C-terminus of the periplasmic maltose-binding protein, MBP. Expression levels of correctly folded receptor molecules were comparable for the three subtypes and reached an average of 30 receptors.cell-1 or 0.5 pmol.mg-1 membrane protein. Binding of [3H]diprenorphine to intact cells or membrane preparations was saturatable, with a dissociation constant, KD, of 2.5 nM, 0.66 nM and 0.75 nM for human delta, mu and kappa opioid receptors (hDOR, hMOR and hKOR, respectively). Recombinant receptors of the three subtypes retained selectivity and nanomolar affinity for their specific antagonists. Agonist affinities were decreased by one to three orders of magnitude as compared to values measured for receptors expressed in mammalian cells. The effect of sodium on agonist binding to E. coli-expressed receptors was investigated. Receptor high-affinity state for agonists was reconstituted in the presence of heterotrimeric G proteins. We also report affinity values of endomorphins 1 and 2 for mu opioid receptors expressed both in E. coli and in COS cells. Our results confirm that opioid receptors can be expressed in a functional form in bacteria and point out the advantages of E. coli as an expression system for pharmacological studies. PMID- 10095779 TI - The effect of intact talin and talin tail fragment on actin filament dynamics and structure depends on pH and ionic strength. AB - We employed quasi-elastic light scattering and electron microscopy to investigate the influence of intact talin and talin tail fragment on actin filament dynamics and network structure. Using these methods, we confirm previous reports that intact talin induces cross-linking as well as filament shortening on actin networks. We now show that the effect of intact talin as well as talin tail fragment on actin networks is controlled by pH and ionic strength. At pH 7.5, actin filament dynamics in the presence of intact talin and talin tail fragment are characterized by a rapid decay of the dynamic structure factor and by a square root power law for the stretched exponential decay which is in contrast with the theory for pure actin solutions. At pH 6 and low ionic strength, intact talin cross-links actin filaments more tightly than talin tail fragment. Talin head fragment showed no effect on actin networks, indicating that the actin binding sites reside probably exclusively within the tail domain. PMID- 10095780 TI - Heterologous expression of alkene monooxygenase from Rhodococcus rhodochrous B 276. AB - Alkene monooxygenase (AMO) from Rhodococcus rhodochrous (formerly Nocardia corallina) B-276 is a three-component enzyme system encoded by the four-gene operon amoABCD. AMO catalyses the stereoselective epoxygenation of aliphatic alkenes, yielding primarily R enantiomers. The presumed site of alkene oxygenation is a dinuclear iron centre similar to that in the soluble methane monooxygenases of methanotrophic bacteria, to which AMO exhibits a significant degree of amino acid sequence identity. The AMO complex was not expressed in Escherichia coli, at least partly because that host did not produce all of the AMO polypeptides. Expression of AMO was achieved in Streptomyces lividans by cloning the AMO genes into the thiostrepton-inducible expression plasmid pIJ6021. No background of AMO activity was detected in S. lividans cells without amoABCD and expression of AMO activity, at a level comparable to that from wild-type R. rhodochrous B-276, coincided with appearance of the AMO subunits. Recombinant AMO activity in cell-free extracts of S. lividans was stimulated by the addition of NADH and produced R-epoxypropane with comparable enantiomeric excess to AMO purified from the original organism. Although the whole AMO complex could not be expressed in E. coli, the functional coupling protein (AmoB) and reductase (AmoD) were expressed individually in E. coli as fusions with glutathione S-transferase. The expression systems described here now allow structure/function studies on AMO to be carried out by site-directed mutagenesis. PMID- 10095781 TI - Isolation of pigment-binding early light-inducible proteins from pea. AB - The early light-inducible proteins (ELIPs) in chloroplasts possess a high sequence homology with the chlorophyll a/b-binding proteins but differ from those proteins by their substoichiometric and transient appearance. In the present study ELIPs of pea were isolated by a two-step purification strategy: perfusion chromatography in combination with preparative isoelectric focussing. Two heterogeneous populations of ELIPs were obtained after chromatographic separation of solubilized thylakoid membranes using a weak anion exchange column. One of these populations contained ELIPs in a free form providing the first isolation of these proteins. To prove whether the isolated and pure forms of ELIP bind pigments, spectroscopic and chromatographic analysis were performed. Absorption spectra and TLC revealed the presence of chlorophyll a and lutein. Measurements of steady-state fluorescence emission spectra at 77 K exhibited a major peak at 674 nm typical for chlorophyll a bound to the protein matrix. The action spectrum of the fluorescence emission measured at 674 nm showed several peaks originating mainly from chlorophyll a. It is proposed that ELIPs are transient chlorophyll binding proteins not involved in light-harvesting but functioning as scavengers for chlorophyll molecules during turnover of pigment-binding proteins. PMID- 10095782 TI - Ligand recognition and domain structure of Vps10p, a vacuolar protein sorting receptor in Saccharomyces cerevisiae. AB - Vp10p is a receptor that sorts several different vacuolar proteins by cycling between a late Golgi compartment and the endosome. The cytoplasmic tail of Vps10p is necessary for the recycling, whereas the lumenal domain is predicted to interact with the soluble ligands. We have studied ligand binding to Vps10p by introducing deletions in the lumenal region. This region contains two domains with homology to each other. Domain 2 binds carboxypeptidase Y (CPY), proteinase A (PrA) and hybrids of these proteases with invertase. Moreover, we show that aminopeptidase Y (APY) is a ligand of Vps10p. The native proteases compete for binding to domain 2. Binding of CPY(156)-invertase or PrA(137)-invertase, on the other hand, do not interfere with binding of CPY to Vps10p. Furthermore, the Q24RPL27 sequence known to be important for vacuolar sorting of CPY, is of little importance in the Vps10p-dependent sorting of CPY-invertase. Apparently, domain 2 contains two different binding sites; one for APY, CPY and PrA, and one for CPY invertase and PrA-invertase. The latter interaction seems not to be sequence specific, and we suggest that an unfolded structure in these ligands is recognized by Vps10p. PMID- 10095783 TI - Structural heterogeneity of the binding sites of HSA for phenyl-groups and medium chain fatty acids. Demonstration of equilibrium between different binding conformations. AB - A new facet of the very heterogeneous albumin molecule is described. Chromatography at pH 6-9 of human serum albumin (HSA) on a phenyl-sepharose column separates it into two nonconvertible conformations that are, in turn, in equilibrium with its binding and nonbinding forms. The hydrophobic interaction of HSA with phenyl-sepharose depends on ionic strength, pH, and time of contact with the immobilized ligand. Binding as a function of pH shows a minimum at pH 6.5, and the binding profile at pH 7-9 fits the titration of a weak monoprotic acid with a pKa of 7.3. There was no observable difference in the CD spectra or the masses of the two forms. The equilibrium between the albumin forms was examined under defined conditions and cannot be explained by a simple two-state model. Thus rechromatography of the nonbinding fraction derived from a sample in which 50% of the protein was originally retained resulted only in 10-20% bound protein. Correspondingly only 70-80% of the binding form was retained. A model explaining the observations can be derived if two species, I and II, exist in the solution, both being in an equilibrium with a binding and a nonbinding form, but in which I is not in equilibrium with II. The rate of conversion between the binding and nonbinding conformations was determined to be faster than 15 s at room temperature. PMID- 10095784 TI - Characterization of endonuclease activity from excretory/secretory products of a parasitic nematode, Trichinella spiralis. AB - Double-stranded endonuclease activity was demonstrated for the first time in the excretory/secretory (ES) products of a parasitic nematode, Trichinella spiralis, which can reorganize host muscle cells. The endonuclease introduced double stranded breaks to the native DNA. The ES double-stranded endonuclease(s) was sequence nonspecific, with a pH optimum below 6, and required divalent cations as a cofactor. Its activity was inhibited by the Zn2+ ion. It was detected mainly in the ES products of the infective-stage larvae of T. spiralis collected at 37 degrees C and was present in much smaller amounts in samples collected at 43 degrees C and in the products of T. pseudospiralis, a nonencapsulated species. The activity of endonuclease was blocked by antibodies against ES products. Zymographic analysis showed that the endonuclease activity was associated with at least three molecular forms, designated approximately 25, 30 and 58 kDa, respectively. PMID- 10095785 TI - Intracellular degradation of the HIV-1 envelope glycoprotein. Evidence for, and some characteristics of, an endoplasmic reticulum degradation pathway. AB - Analysis of the fate of HIV-1 envelope protein gp160 (Env) has shown that newly synthesized proteins may be degraded within the biosynthetic pathway and that this degradation may take place in compartments other than the lysosomes. The fate of newly synthesized Env was studied in living BHK-21 cells with the recombinant vaccinia virus expression system. We found that gp160 not only undergoes physiological endoproteolytic cleavage, producing gp120, but is also degraded, producing proteolytic fragments of 120 kDa to 26 kDa in size, as determined by SDS/PAGE in non reducing conditions. Analysis of the 120-kDa proteolytic fragment, and comparison with gp120, showed that it is composed of peptides linked by disulfides bonds and lacks the V3-loop epitope and the C terminal domain of gp120 (amino acids 506-516). A permeabilized cell system, with impaired transport of labeled Env from the endoplasmic reticulum (ER) to Golgi compartments, was developed to determine the site of degradation and to define some biochemical characteristics of the intracellular degradation process. In the semipermeable BHK-21 cells, there was: (a) no gp120 production (b), a progressive decrease in the amount of newly synthesized gp160 and a concomitant increase in the amount of a 120-kDa proteolytic fragment. This fragment had the same biochemical characteristics as the 120-kDa proteolytic fragment found in living nonpermeabilized cells, and (c) susceptibility of the V3 loop. This degradation process occurred in the ER, as shown by both biochemical and indirect immunofluorescence analysis. Furthermore, there was evidence that changes in redox state are involved in the ER-dependent envelope degradation pathway because adding reducing agents to permeabilized cells caused dose-dependent degradation of the 120-kDa proteolytic fragment and of the remaining gp160 glycoprotein. Thus our results provide direct evidence that regulated degradation of the HIV-1 envelope glycoprotein may take place in the ER of infected cells. PMID- 10095786 TI - Solution structure of the alpha-subunit of human chorionic gonadotropin. AB - The three-dimensional solution structure of the alpha-subunit in the alpha, beta heterodimeric human chorionic gonadotropin (hCG), deglycosylated with endo-beta-N acetylglucosaminidase-B (dg-alpha hCG), was determined using 2D homonuclear and 2D heteronuclear 1H, 13C NMR spectroscopy at natural abundance in conjunction with the program package XPLOR. The distance geometry/simulated annealing protocol was modified to allow for the efficient modelling of the cystine knot motif present in alpha hCG. The protein structure was modelled with 620 interproton distance restraints and the GlcNAc residue linked to Asn78 was modelled with 30 protein-carbohydrate and 3 intraresidual NOEs. The solution structure of dg-alpha hCG is represented by an ensemble of 27 structures. In comparison to the crystal structure of the dimer, the solution structure of free dg-alpha hCG exhibits: (a) an increased structural disorder (residues 33-57); (b) a different backbone conformation near Val76 and Glu77; and (c) a larger flexibility. These differences are caused by the absence of the interactions with the beta-subunit. Consequently, in free dg-alpha hCG, compared to the intact dimer, the two hairpin loops 20-23 and 70-74 are arranged differently with respect to each other. The beta-GlcNAc(78) is tightly associated with the hydrophobic protein-core in between the beta-hairpins. This conclusion is based on the NOEs from the axial H1, H3, H5 atoms and the N-acetyl protons of beta GlcNAc(78) to the protein-core. The hydrophobic protein-core between the beta hairpins is thereby shielded from the solvent. PMID- 10095787 TI - Further improvement of the thermal stability of a partially stabilized Bacillus subtilis 3-isopropylmalate dehydrogenase variant by random and site-directed mutagenesis. AB - A thermostabilized mutant of Bacillus subtilis 3-isopropylmalate dehydrogenase (IPMDH) obtained in a previous study contained a set of triple amino acid substitutions. To further improve the stability of the mutant, we used a random mutagenesis technique and identified two additional thermostabilizing substitutions, Thr22-->Lys and Met256-->Val, that separately endowed the protein with further stability. We introduced the two mutations into a single enzyme molecule, thus constructing a mutant with overall quintuple mutations. Other studies have suggested that an improved hydrophobic subunit interaction and a rigid type II beta-turn play important roles in enhancing the protein stability. Based on those observations, we successively introduced amino acid substitutions into the mutant with the quintuple mutations by site-directed mutagenesis: Glu253 at the subunit interface was replaced by Leu to increase the hydrophobic interaction between the subunits; Glu112, Ser113 and Ser115 that were involved in the formation of the turn were replaced by Pro, Gly and Glu, respectively, to make the turn more rigid. The thermal stability of the mutants was determined based on remaining activity after heat treatment and first-order rate constant of thermal unfolding, which showed gradual increases in thermal stability as more mutations were included. PMID- 10095788 TI - Transcriptional regulation of fatty acid synthase gene by insulin/glucose, polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats. AB - Transcriptional regulation of the fatty acid synthase (FAS) gene by insulin/glucose, polyunsaturated fatty acids and leptin was investigated in hepatocytes and adipocytes of Wistar fatty rats and their lean littermates. The sequence spanning nucleotides -57 to -35 of FAS gene, which is responsive to insulin/glucose stimulation [Fukuda, H., Iritani, N. & Noguchi, T. (1997) FEBS Lett. 406, 243-248], was linked to a reporter gene containing a heterologous promoter and transfected into rat hepatocytes or adipocytes. The activity of the reporter, chloramphenicol acetyltransferase, in the presence of glucose alone was similar in the primary cultured cells from the lean and obese rats. In the presence of insulin/glucose, however, chloramphenicol acetyltransferase activity was markedly increased in hepatocytes of lean rats, but was not significantly increased in those of obese rats. The stimulation by insulin/glucose was reduced in arachidonic acid-treated cells of lean rats. Similarly, the stimulation by insulin/glucose was reduced in leptin-treated cells and in cells from lean rats containing an expression vector encoding leptin. However, neither polyunsaturated fatty acids nor leptin-treated cells from obese rats responded to insulin stimulation. The same effects were observed at endogenous FAS mRNA and enzyme levels. Similar results were seen in adipocytes, although the stimulation and suppression were much smaller than in hepatocytes. The insulin-binding capacities of the receptors of liver and adipose tissue were reduced in the presence of leptin or polyunsaturated fatty acids. Leptin and polyunsaturated fatty acids appeared to suppress the insulin stimulation of FAS transcription by reducing the insulin-binding capacities of receptors. Leptin converged on the insulin/glucose response element of FAS gene and suppressed the transcription. PMID- 10095789 TI - Detection of membrane-bound cytokinin-binding proteins in Arabidopsis thaliana cells. AB - In order to isolate cytokinin-binding proteins (CBPs), we have developed new affinity probes constituted of a cytokinin such as zeatin riboside ([9R]Z) conjugated to a carrier protein. These probes were used for detecting CBPs in an ELISA procedure. The efficiency of the cytokinin conjugate in detecting CBPs was controlled with protein model: proteins having an affinity for cytokinin such as the monoclonal anti-[9R]Z antibodies did bind the cytokinin conjugate whereas proteins unable to bind cytokinin such as bovine serum albumin did not. Using these new affinity probes, we showed that CBPs are present in the membrane fraction of in vitro cultured Arabidopsis thaliana cells. The nature of the protein at the detected binding sites was demonstrated by submitting the microsomal proteins to a proteolytic treatment, which was found to eradicate the binding. Free biologically active cytokinins or monoclonal anti-[9R]Z antibodies inhibited the binding, thus showing the specificity of the interaction. The detected CBPs were partially solubilized from the membranes with potassium chloride, indicating their peripheral membrane location. The separation by anion exchange chromatography of solubilized microsomal proteins revealed the existence of two different CBPs. They were present at higher levels in cells during the exponential growth phase. PMID- 10095790 TI - Optimal sequences for non-phosphate-directed phosphorylation by protein kinase CK1 (casein kinase-1)--a re-evaluation. AB - A variety of synthetic peptides derived from either the inhibitor-2 (I-2) phosphoacceptor sites or the optimal sequences selected in an oriented peptide library have been compared for their susceptibility to phosphorylation by protein kinase CK1 (also termed casein kinase-1). The I-2-derived peptides are by far preferred over the library peptides by both rat liver CK1 (and by the alpha/beta, gamma and delta/epsilon isoforms immunoprecipitated from it) and recombinant Xenopus laevis CK1 alpha. The superiority of the I-2-derived peptides over the library ones is reflected by Vmax values one to two orders of magnitude higher while the Km values are comparable. Individual substitutions of any of the aspartic acids with alanine in the I-2-derived peptide RRKHAAIGDDDDAYSITA is detrimental, producing both a fall in Vmax and an increase in Km which are more pronounced at position n -3, but also quite significant at positions n -4, n -5 and, to a lesser extent, n -6. The unfavourable effect of these substitutions is more evident with rat liver CK1 than with recombinant Xenopus laevis CK1 alpha. The chimeric peptide IGDDDDAY-S-IIIFFA, resulting from the combination of the N terminal acidic sequence of the I-2 (Ser86) site and the C-terminal hydrophobic cluster selected in the library peptides (MAEFDTG-S-IIIFFAKKK and MAYYDAA-S IIIFFAKKK) is phosphorylated as efficiently as the I-2-derived peptide in terms of both Km and Vmax. These combined data strongly support the conclusion that, at variance with the optimal sequences selected in the library, optimal non phosphate-directed phosphorylation of peptide substrates by CK1 critically relies on the presence of a cluster of acidic residues (preferably aspartic acid) upstream from position n -2, while the highly hydrophobic region downstream from serine selected in the library appears to be dispensable. The reason for these discrepancies remains unclear. The possibility that the library data are biased by the invariant elements forming its scaffold (MA-x-x-x-x-x-SI-x-x-x-x-AKKK) would be consistent with the observation that the library-selected peptides, despite their low Km values, fail to compete against the phosphorylation of protein and peptide substrates by CK1, suggesting that they bind to elements partially distinct from those responsible for substrate recognition. PMID- 10095791 TI - D1-D2 protein degradation in the chloroplast. Complex light saturation kinetics. AB - The D1 and D2 proteins of the photosystem II (PSII) reaction center are stable in the dark, while rapid degradation occurs in the light. Thus far, a quantitative correlation between degradation and photon fluences has not been determined. In Spirodela oligorrhiza, D1-D2 degradation increases with photon flux. We find that kinetics for D2 degradation mirror those for D1, except that the actual half-life times of the D2 protein are about three times larger than those of the D1. The degradation ratio, D2/D1, is fluence independent, supporting the proposal [Jansen, M.A.K., Greenberg, B.M., Edelman, M., Mattoo, A.K. & Gaba, V. (1996), Photochem. Photobiol. 63, 814-817] that degradation of the two proteins is coupled. It is commonly conceived that D1 degradation is predominantly associated with photon fluences that are supersaturating for photosynthesis. We now show that a fluence as low as 5 mumol.m-2.s-1 elicited a reaction constituting > 25% of the total degradation response, while > 90% of the degradation potential was attained at intensities below saturation for photosynthesis (approximately 750 mumol.m-2.s-1). Thus, in intact plants, D1 degradation is overwhelmingly associated with fluences limiting for photosynthesis. D1 degradation increases with photon flux in a complex, multiphasic manner. Four phases were uncovered over the fluence range from 0-1600 mumol.m-2.s-1. The multiphasic saturation kinetics underscore that the D1 and D2 degradation response is complex, and emanates from more than one parameter. The physiological processes associated with each phase remain to be determined. PMID- 10095792 TI - Use of doxycycline-controlled gene expression to reversibly alter milk-protein composition in transgenic mice. AB - A reverse tetracycline transactivator-encoding cDNA under the control of the mammary specific beta-lactoglobulin promoter was linked to a bovine alpha lactalbumin transcription unit driven by a reverse tetracycline-controlled transactivator/doxycycline-inducible human cytomegalovirus promoter. The construct was microinjected into eggs from alpha-lactalbumin-deficient mice. These mice produce a highly viscous lactose-free milk and have a shortened lactation period. Mice from three out of the nine transgenic lines investigated expressed reverse tetracycline-controlled transactivator mRNA in their lactating mammary glands at levels detectable by Northern analysis. Following doxycycline addition to the drinking water, lactation was fully restored in animals from the three lines. Doxycycline removal resulted in a reversal of phenotype. The observed mammary-specific and high expression of the doxycycline inducible reporter gene (up to 5.2 mg of recombinant alpha-lactalbumin.mL-1 of milk, i.e. up to 13-fold induction) opens up exciting prospects to use the tetracycline system to study the development and functioning of the mammary gland, and to control the production level of active pharmaceutical proteins in the milk of transgenic animals. PMID- 10095793 TI - The strict molybdate-dependence of glucose-degradation by the thermoacidophile Sulfolobus acidocaldarius reveals the first crenarchaeotic molybdenum containing enzyme--an aldehyde oxidoreductase. AB - In order to investigate the effects of trace elements on different metabolic pathways, the thermoacidophilic Crenarchaeon Sulfolobus acidocaldarius (DSM 639) has been cultivated on various carbon substrates in the presence and absence of molybdate. When grown on glucose (but neither on glutamate nor casein hydrolysate) as sole carbon source, the lack of molybdate results in serious growth inhibition. By analysing cytosolic fractions of glucose adapted cells for molybdenum containing compounds, an aldehyde oxidoreductase was detected that is present in the cytosol to at least 0.4% of the soluble protein. With Cl2Ind (2,6 dichlorophenolindophenol) as artificial electron acceptor, the enzyme exhibits oxidizing activity towards glyceraldehyde, glyceraldehyde-3-phosphate, isobutyraldehyde, formaldehyde, acetaldehyde and propionaldehyde. At its pH optimum (6.7), close to the intracellular pH of Sulfolobus, the glyceraldehyde oxidizing activity is predominant. The protein has an apparent molecular mass of 177 kDa and consists of three subunits of 80.5 kDa (alpha), 32 kDa (beta) and 19.5 kDa (gamma). It contains close to one Mo, four Fe, four acid-labile sulphides and four phosphates per protein molecule. Methanol extraction revealed the existence of 1 FAD per molecule and 1 molybdopterin per molecule, which was identified as molybdopterin guanine dinucleotide on the basis of perchloric acid cleavage and thin layer chromatography. EPR-spectra of the aerobically prepared enzyme exhibit the so-called 'desulpho-inhibited'-signal, known from chemically modified forms of molybdenum containing proteins. Anaerobically prepared samples show both, the signals arising from the active molybdenum-cofactor as well as from the two [2Fe-2S]-clusters. According to metal-, cofactor-, and subunit composition, the enzyme resembles the members of the xanthine oxidase family. Nevertheless, the melting point and long-term thermostability of the protein are outstanding and perfectly in tune with the growth temperature of S. acidocaldarius (80 degrees C). The findings suggest the enzyme to function as a glyceraldehyde oxidoreductase in the course of the nonphosphorylated Entner Doudoroff pathway and thereby may attribute a new physiological role to this class of enzyme. PMID- 10095794 TI - Purification and characterization of the assembly factor P17 of the lipid containing bacteriophage PRD1. AB - Assembly factors, proteins assisting the formation of viral structures, have been found in many viral systems. The gene encoding the assembly factor P17 of bacteriophage PRD1 has been cloned and expressed in Escherichia coli. P17 acts late in phage assembly, after capsid protein folding and multimerization, and sorting of membrane proteins has occurred. P17 has been purified to near homogeneity. It is a tetrameric protein displaying a rather high heat stability. The protein is largely in an alpha-helical conformation and possesses a putative leucine zipper which is not essential for protein function, as judged by in vitro mutagenesis and complementation analysis. Although heating does not cause structural changes in the conformation of the protein, the dissociation of the tetramer into smaller units is evident as diminished self-quenching of the fluorescently labeled P17. Similarly, dissociation of the tetramer is also obtained by dialysis of the protein against 6-M guanidine hydrochloride (GdnHCl) or 1% SDS. The reassembly of these smaller units upon cooling is evident from resonance energy transfer. PMID- 10095795 TI - Folding stability of the kinetoplastid membrane protein-11 (KMP-11) from Leishmania infantum. AB - Kinetoplastid membrane protein-11 (KMP-11) is a major component of the cell surface of kinetoplastids, and acts as a potent B- and T-cell immunogen during Leishmania infection. Here we report that the Leishmania infantum KMP-11 secondary structure adopts mainly an alpha-helical conformation at pH 7.5 and that its urea- and thermally-induced unfolding constitute a fully reversible two step process. This allows estimation of a half-denaturation temperature of approximately 65 degrees C, a delta GDH2O at 20 degrees C of approximately 14.63 kJ.mol-1, and an increment of the reaction heat of approximately 183.92 kJ.mol-1 and an entropy of approximately 543.4 J.mol-1.deg-1, respectively, for the native denatured equilibrium of the KMP-11 in solution. We also report that the KPM-11 protein is induced to adopt a molten globule state at a pH range between pH 4 and pH 6. As a whole, the stability and the specific features of the denaturing effect induced by changes in pH are similar in KMP-11 to various other lipoproteins. PMID- 10095796 TI - Comparison of effects of quinapril and metoprolol on glycaemic control, serum lipids, blood pressure, albuminuria and quality of life in non-insulin-dependent diabetes mellitus patients with hypertension. Swedish Quinapril Group. AB - OBJECTIVE: To compare the long-term effects of the angiotensin-converting enzyme (ACE)-inhibitor quinapril and the cardioselective beta-adrenergic blocking agent metoprolol on glycaemic control, with glycosylated haemoglobin (HbA1c) as the principal variable, in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertension. DESIGN: A randomized, double-blind, double-dummy, multicentre study during 6 months preceded by a 4 week wash-out and a 3 week run-in placebo period. Quinapril (20 mg) and metoprolol (100 mg, conventional tablets) were given once daily. No change was made in the treatment of diabetes (diet and hypoglycaemic agents). SUBJECTS: Seventy-two patients fulfilling the criteria were randomized and entered the double-blind period. Twelve patients did not complete the study. Sixty patients, 26 on quinapril and 34 on metoprolol, were available for the final analysis. MAIN OUTCOME MEASURES: The effect was assessed by changes in HbA1c, the fasting serum glucose and the post-load serum glucose, C peptide and insulin levels during the oral glucose tolerance test. RESULTS: In the quinapril group, the fasting serum glucose, oral glucose tolerance and the C peptide and insulin responses, determined as the incremental area under the curves (AUC), showed no change, but the mean HbA1c level increased from 6.2 +/- 1.1% to 6.5 +/- 1.3% (P < 0.05). In the metoprolol group, the rise in the mean level of HbA1c, from 6.3 +/- 1.0% to 6.8 +/- 1.3% (P < 0.01), tended to be more marked than after quinapril, although there was no significant difference between the increments. The mean fasting serum glucose showed an increase from 9.1 +/- 1.9 mM to 10.1 +/- 2.8 mM (P < 0.01) which correlated significantly with the duration of diabetes (P < 0.01) and the increase in fasting serum triglycerides (P < 0.001). Moreover, in the metoprolol group we found significant decreases in the oral glucose tolerance as well as C-peptide and insulin responses to the glucose load. CONCLUSIONS: Treatment with quinapril for 6 months appears to have advantages over metoprolol in NIDDM patients with hypertension. Although treatment with quinapril or metoprolol over 6 months was concomitant with a rise in the HbA1c, increased fasting blood glucose, decreased oral glucose tolerance and decreased C-peptide and insulin responses to a glucose challenge were observed only in patients treated with metoprolol. PMID- 10095797 TI - Differential effects of antihypertensive drugs on neurohormonal activation: insights from a population-based sample. AB - OBJECTIVES: The clinical course of hypertension or heart failure may be modified by the extent of concurrent neurohormonal activation. Factors that regulate neurohormones in patients with these conditions are complex. In the present study, we examined the relative contribution of antihypertensive therapy to the variability of neurohormonal levels in a well defined population based sample. DESIGN AND SETTING: Cross-sectional study of a mixed urban and rural population. SUBJECTS: Middle-aged individuals (n = 646) were analysed in order to elucidate determinants of neurohormone levels by uni- and multivariate comparisons. The assessment included anthropometric, echocardiographic and, if appropriate, genotype information. RESULTS: The intake of antihypertensive drugs was related to significant alterations of neurohormone levels that, in part, exceeded the contribution of all other variables studied. Multivariate analyses revealed that renin levels were independently related to the intake of beta blockers (n = 80; 8.4 mU L-1; P = 0.001), angiotensin-converting enzyme (ACE)-inhibitors (n = 39; +15.9 mU L-1; P = 0.0001), diuretics (n = 62; +14.3 mU L-1; P = 0.0001), and calcium channel blockers (n = 45; +5.9 mU L-1; P = 0.05). Aldosterone levels were related to ACE-inhibition (-156.5 pmol L-1; P = 0.04) and diuretic treatment (+422.4 pmol L-1; P = 0.0001) in an opposite fashion whereas beta blockers and calcium channel blockers had no significant independent effects. The levels of the atrial natriuretic peptide were significantly related to the use of beta blockers (+3.9 pmol L-1; P = 0.002) and calcium channel blockers (+3.1 pmol L-1; P = 0.05). Finally, serum angiotensinogen levels and ACE activity were not found to be significantly affected by antihypertensive medication but were rather related to gender or genotype. CONCLUSIONS: The data emphasize that antihypertensive treatment with different classes of drugs may modulate serum levels of neurohormones substantially resulting in distinct patterns of activation. These drug-related effects may require consideration when neurohormonal activation is of functional relevance or when neurohormones serve as prognostic predictors in patients with cardiovascular disorders. PMID- 10095798 TI - Long-term effects of intermittent oral alphacalcidol, calcium carbonate and low calcium dialysis (1.25 mmol L-1) on secondary hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis. AB - OBJECTIVES: (i) To examine the effect of alphacalcidol [1 alpha(OH)D3] given as an oral dose twice weekly in combination with CaCO3 and low-calcium dialysis (1.25 mmol L-1) on the secondary hyperparathyroidism in continuous ambulatory peritoneal dialysis (CAPD). (ii) To examine the changes in peritoneal mass transfer for calcium, phosphorus, magnesium, lactate, creatinine, urea, glucose, pH and albumin after shift to low-calcium dialysis solution. DESIGN: An open study in patients on CAPD. SETTING: Renal division, Rigshospitalet, Copenhagen. SUBJECTS: Thirty-nine patients were included and completed 12 weeks of treatment. Thirty of the patients completed 52 weeks of treatment. A peritoneal equilibrium test (PET) was performed in seven patients. INTERVENTIONS: Following two sets of blood samples obtained as basal values the calcium concentration was reduced in the dialysis fluid from 1.75 mmol L-1 to 1.25 mmol L-1. Increasing doses of oral 1 alpha(OH)D3 were then administered under careful control of p-ionized calcium (p-Ca2+) and p-inorganic phosphate (p-P1). Blood samples were obtained every 2-4 weeks for 52 weeks. PET was performed using standard dialysis fluid and 1 week later using low-calcium dialysis fluid after a preceding overnight dwell. Two litres of glucose 22.7 mg mL-1 were used. MAIN OUTCOME MEASURES: Intact parathyroid hormone (PTH), p-Ca2+, p-P1, doses of CaCO3, doses of 1 alpha(OH)D3, peritoneal mass transfer for calcium, inorganic phosphate, magnesium, lactate, creatinine, urea, glucose and albumin. RESULTS: Thirty nine patients with initial PTH values 144 +/- 26 pg mL-1 were followed for 12 weeks and 30 patients for 52 weeks. A negative calcium balance was induced after shifting to low-calcium dialysis fluid. After 2 weeks of treatment a significant increase of PTH by approximately 60% and a small but significant decrease of p-Ca2+ was observed. After 12 weeks of treatment with increasing doses of 1 alpha(OH)D3 and CaCO3, PTH was again reduced to levels not significantly different from the initial values. After 52 weeks of treatment no deterioration of the secondary hyperparathyroidism was seen. CONCLUSIONS: A calcium concentration of 1.25 mmol L-1 in the CAPD dialysate made it possible to reduce the amount of aluminium-containing phosphate binder, to increase the doses of CaCO3 and to use pulse oral 1 alpha(OH)D3 without causing severe hyper-calcaemia in the patients. After a short elevation of PTH, the PTH levels remained at normal or near normal levels and the long-term results clearly demonstrated that an aggravation of the secondary hyperparathyroidism could be inhibited. PMID- 10095799 TI - Patients hospitalized because of small vessel vasculitides with renal involvement in the period 1975-95: organ involvement, anti-neutrophil cytoplasmic antibodies patterns, seasonal attack rates and fluctuation of annual frequencies. AB - OBJECTIVES: To study organ involvement, anti-neutrophil cytoplasmic antibodies (ANCA) patterns, trends in yearly frequencies and seasonal variations of symptom onset in patients hospitalized because of small vessel vasculitides during a 21 year period (1975-95). DESIGN: A retrospective investigation was conducted of 138 patients hospitalized with a diagnosis of small vessel vasculitides, as defined by the Chapel Hill Consensus Conference, within the County of Orebro, a mixed urban and rural area of central Sweden. SETTING: Orebro Medical Center Hospital, Orebro, Sweden and two district hospitals within the County of Orebro, Sweden. RESULTS: During the studied period there were 19 patients with a diagnosis of Wegener's granulomatosis (WG), 70 patients with microscopic polyangiitis (MPA), 36 patients with renal limited vasculitis (RLV), two with Churge-Strauss vasculitis (C-S), seven with Henoch-Schonleins purpura (HSP) and four with essential cryoglobulinemic vasculitis (ECV). Renal involvement was present in 123 patients (89.1%). A positive c- and/or pANCA was found in nearly 90% of the 111 patients where sera were available. Calculations of frequency data, restricted to the primary catchment area for patients with ANCA associated vasculitis and renal involvement (WG, MPA, RLV) during a 21-year period (1975-95) gave a mean annual frequency of 1.6 per 100,000 adults (95% CI: 1.2-3.1); for this group of patients with the inclusion of those with C-S, HSP and ECV during the last 10 year period (1986-95) gave a mean annual frequency of 2.5 per 100,000 adults (95% CI: 1.7 3.4), for male adults 3 per 100,000 (95% CI: 1.6-4.4), and female adults 1.9 (95% CI: 0.9-2.8). A frequency peak of 6.3 per 100,000 was seen for men aged 55-64. A periodic fluctuation of the frequencies with peaks every 3-4 years was noted for patients with ANCA related vasculitis (WG, MPA, RLV) during the 21-year period 1975-95. Onset of symptoms was predominantly noticed during the winter months (December-February) for patients with a positive cANCA. CONCLUSION: The observed frequencies in our study of patients with small vessel vasculitides were higher than those previously documented. We also showed a periodic fluctuation of the annual frequencies and a seasonal variation of symptom onset. PMID- 10095801 TI - The frequency and severity of retinopathy are related to HbA1c values after, but not at, the diagnosis of NIDDM. AB - OBJECTIVES: To examine the relationship between previous glycaemic exposure and prevalence of retinopathy 8 years after diagnosis of diabetes in 58 islet cell antibodies (ICA)-negative noninsulin-dependent diabetes mellitus (NIDDM) patients and in a group of 14 ICA-positive 'NIDDM' and insulin-dependent diabetes mellitus (IDDM) patients. DESIGN AND METHODS: The Wisconsin retinopathy scale was used to assess the retinopathy which was graded into mild, moderate and severe nonproliferative diabetic retinopathy (NPDR), or proliferative retinopathy (PDR). The frequency and severity of retinopathy was related to HbA1c levels at diagnosis, and 3 and 5 years later. RESULTS: Thirty of the 58 ICA-negative NIDDM patients (52%) but only 2 of the 14 ICA-positive 'NIDDM' or IDDM patients (14%) had mild-moderate-severe NPDR 8 years after diagnosis (P = 0.02). None had PDR. Retinopathy 8 years after diagnosis in NIDDM (= 58 ICA-negative patients) was correlated with the degree of glycaemic control (HbA1c levels) at 3 and 5 years after diagnosis, but not to HbA1c levels at diagnosis. The relative risk for a higher average HbA1c (per percentage) at 3 and 5 years was 1.56 for any retinopathy vs. no retinopathy (95% confidence interval 1.1-2.2; P = 0.01) and 1.68 for moderate to severe NPDR in comparison with no DR and mild NPDR (95% confidence interval 1.0-2.8; P = 0.04). CONCLUSIONS: Retinopathy after 8 years of diabetes in NIDDM patients was associated with impaired glycaemic control during previous years but not with glycaemic control at baseline. Good glycaemic control may prevent retinopathy in patients with NIDDM. PMID- 10095800 TI - Effects of atorvastatin on serum lipids of patients with familial hypercholesterolaemia. AB - OBJECTIVES: The effects of atorvastatin, a new synthetic HMG-CoA reductase inhibitor, were investigated in patients with familial hypercholesterolaemia (FH), with high LDLc levels whilst on standard treatment. DESIGN: Open treatment with 40 mg atorvastatin daily for 6 weeks, followed by another 6 weeks with 80 mg atorvastatin. SETTING: Outpatient lipid clinic of a tertiary referral centre. SUBJECTS: FH was diagnosed when the untreated LDLc concentration was higher than 6 mmol L-1, tendon xanthomas were present at the participant or a first degree relative, and the family history for hypercholesterolaemia was positive. The FH patients were selected for an LDLc above 5.0 mmol L-1 whilst on standard therapy for at least 3 months. Standard therapy consisted of a diet and 40 mg simvastatin, either alone (n = 17), or in combination with 8-12 g colestyramin (n = 12), or 1800 mg nicotinic acid (n = 12). MAIN OUTCOME MEASURE: Effects on LDLc concentration. RESULTS: LDLc concentration significantly decreased during treatment with 80 mg atorvastatin as compared to LDLc levels on 40 mg simvastatin alone or in combination with 8-12 g colestyramin, by 24 +/- 14% (P < 0.01) and 19 +/- 22% (P < 0.01), respectively. LDLc concentration was comparable during treatment with 80 mg atorvastatin or 40 mg simvastatin in combination with 1800 mg nicotinic acid. Atorvastatin was tolerated well, no side-effects were observed. CONCLUSIONS: Atorvastatin is a valuable addition to the treatment possibilities of patients with serious hypercholesterolaemia, like FH. PMID- 10095802 TI - Use of dobutamine echocardiography for cardiac risk stratification of patients with chronic renal failure. AB - OBJECTIVES: This study sought to define the value of dobutamine echocardiography (DbE) for cardiac risk stratification in patients with chronic renal failure (CRF). DESIGN: Outcome study correlating results of DbE with late cardiac events in patients with CRF. SETTING: Academic medical centre. SUBJECTS: All patients with CRF (serum creatinine > 2.5 mg dL-1) undergoing DbE were studied; we analysed 193 consecutive patients (aged 63 +/- 13 years, 73 men). INTERVENTIONS: A standard dobutamine-atropine stress was administered until attainment of peak dose, or the development of severe ischaemia or side-effects. The electrocardiogram (ECG) and echocardiogram were obtained before, during and after stress. Ischaemia was identified by new or worsening wall-motion abnormalities with stress. OUTCOME MEASURES: Patients were followed up after 38 +/- 14 months for cardiac death, myocardial infarction or coronary disease progression requiring revascularization. RESULTS: DbE demonstrated ischaemia in 36 patients (19%), scar in 36 (19%) and a normal study in 121 patients. The heart-rate response to dobutamine was submaximal (< 85% age-predicted heart rate) in the absence of wall-motion abnormalities in 69 patients (36%), 54 of whom completed the protocol. Follow-up data were complete in 191 patients (99%); cardiac events occurred in 33 patients (17%), including 17 with cardiac death, 7 with infarction, and 9 requiring late revascularization. Spontaneous events occurred in 7 patients with ischaemia, 3 with scar (8%), 11 with a nondiagnostic study (16%) and 3 patients with a normal study (6%). Over the entire follow-up, the event-free survival in patients with ischaemia (66%) was markedly lower than those without ischaemia (84%, P = 0.006). However, the event rate in patients with nonischaemic responses increased from 8% to 16% between 24 and 40 months, and whilst ischaemia was an independent predictor of outcome at 24 months, it was not at 40 months. CONCLUSIONS: In patients with CRF, the identification of ischaemia at DbE is associated with a significant risk of adverse cardiac events. Patients with nonischaemic scans have a low frequency of events over short-term follow-up, but this increases at later follow-up. These later events may reflect progressive coronary disease, attributable to the atherogenic milieu of these patients, and imply that repeated testing may be required to maintain cardiac risk stratification in patients with CRF. PMID- 10095803 TI - Afternoon serum-melatonin in sleep disordered breathing. AB - OBJECTIVES: To study afternoon serum-melatonin values in patients with sleep disordered breathing. Melatonin has a strong circadian rhythm with high values during the night-time and low values in the afternoon. Sleep disordered breathing may change the circadian rhythm of melatonin which may have diagnostic implications. SETTING: The Sleep Laboratory, The Department of Internal Medicine, Avesta Hospital, Sweden, and the Department of Anaesthesiology, Glostrup University Hospital, Copenhagen, Denmark. SUBJECTS: We examined 60 consecutive patients admitted for sleep disordered breathing and 10 healthy non snoring controls. The patients underwent a sleep apnoea screening test having a specificity of 100% for the obstructive sleep apnoea syndrome (OSAS) using a combination of static charge sensitive bed and oximetry. Obstructive sleep apnoea syndrome was found in 49 patients, eight patients had borderline sleep disordered breathing (BSDB) and three patients were excluded due to interfering disease. MAIN OUTCOME MEASURES: Patients and controls had an afternoon determination of serum-melatonin. The Epworth Sleepiness Scale was used to score day-time sleepiness. RESULTS: In comparison with normal controls patients suffering from OSAS had significantly higher serum-melatonin levels in the afternoon. However, as a diagnostic test for OSAS in patients with sleep disordered breathing serum melatonin showed a low sensitivity but a high specificity. The results indicate that breathing disorders during sleep in general affect pineal function. CONCLUSIONS: Sleep disordered breathing seems to disturb pineal function. Determination of afternoon serum-melatonin alone or together with a scoring of daytime sleepiness does not identify OSAS-patients in a heterogeneous population of patients complaining of heavy snoring and excessive daytime sleepiness. PMID- 10095804 TI - Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment. AB - OBJECTIVES: Metformin treatment increases circulating homocysteine levels. We studied whether administration of folate reduces serum total homocysteine levels in patients on long-term metformin treatment. DESIGN: A prospective, randomized, double-blind, placebo-controlled study lasting for 12 weeks and taking place in a university hospital setting. SUBJECTS: Thirty patients treated with a metformin dose of at least 1000 mg day-1 for a minimum of 1 year were included. At baseline serum total homocysteine levels were within the reference range. One patient who withdrew and one who died were excluded from the statistical evaluation. Twenty six of the remaining patients suffered from NIDDM, the other two from hyperlipidaemia. INTERVENTION: Patients were randomized into two groups at week 0. The folate group received 0.25 mg day-1 of folate in addition to 60 mg day-1 of Fe2+, while the placebo group received only 60 mg day-1 of Fe2+. MAIN OUTCOME MEASURES: Fasting homocysteine, cysteine, cysteinylglycine, vitamin B12 and folate were measured at week 0, 4 and 12. Changes from week 0 to week 4 and from week 0 to week 12 were calculated. RESULTS: Folate administration reduced serum levels of total homocysteine in the folate group as compared with the placebo group by 13.9% (P < 0.01) and 21.7% (P < 0.001) at week 4 and 12, respectively. In the folate group versus the placebo group serum levels of vitamin B12 increased by 9.9% (P = 0.010) and 9.6% (P = 0.043) while folate levels increased by 96.9 and 89.9% at week 4 and 12, respectively. CONCLUSION: The present study indicates that the homocysteine-increasing effect of metformin can be counteracted by folate administration. PMID- 10095805 TI - Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient. AB - A 73-year-old woman with multiple myeloma experienced four episodes of loss of consciousness, convulsions and profuse sweating whilst she was in the hospital. A thorough investigation in the department of medicine disclosed that with each attack, she had a serum glucose < 1.6 mM L-1, insulin level > 1400 pMol L-1 (N- < 150) and a normal level of serum C-peptide. Since she had no anti-insulin antibodies (which may rarely exist in multiple myeloma), a diagnosis of exogenous injection of insulin was made. A search for a possible perpetrator discovered that the patient had a daughter who was a surgical nurse and who was genuinely concerned whenever she was told that her mother was about to be discharged from the hospital. If she was the perpetrator in the present case, then it is possible that the motive for such an action was to postpone the mother's discharge from hospital. This case is an example of a 'factitious disease by proxy' in an elderly patient. The aim of the present report is to alert the medical personnel to the possibility that Munchausen's syndrome by proxy may also occur in the elderly. PMID- 10095806 TI - Idiopathic oedema with increased cytokine production: a pathogenetic link? AB - We describe four patients with idiopathic oedema and elevated cytokines. All patients shared increased serum concentrations of soluble interleukin-2 receptors (sIL-2R). In three patients tumour necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma) and interleukin-2 (IL-2) were transiently elevated. There was no evidence for an underlying disease. Based on experimental and clinical data it is hypothesized that oedema formation in our patients is the consequence of cytokine induced alteration of endothelial cells. PMID- 10095807 TI - Arthritis after BCG vaccine in a healthy woman. PMID- 10095808 TI - Danaparoid: an anti-thrombotic agent without major impact on triglyceride hydrolysis capacity in humans. PMID- 10095809 TI - Determination of the risk for familial disease in RET mutation-negative patients with medullary thyroid cancer. PMID- 10095810 TI - The effect of clinical trials on treatment in myocardial infarction. PMID- 10095811 TI - Breast cellulitis complicating breast conservation therapy. AB - Breast conservation therapy has gained acceptance as treatment for limited disease due to breast cancer. Unfortunately, a minority of patients who undergo this therapy will develop cellulitis of the breast, often recurrently, months to years later. A definitive pathogen has not been identified in the large majority of cases reported to date. Whilst some patients develop systemic toxicity with local skin changes of cellulitis, others manifest no fever, chills or leukocytosis. Local breast findings gradually clear with antibiotic treatment: when breast changes persist, non-inflammatory causes, including tumour recurrence, of the breast should be considered. More study is needed to define risk factors for the development of breast cellulitis complicating breast conservation therapy. PMID- 10095812 TI - Trends in the treatment of patients with myocardial infarction and coronary revascularization procedures in Finland during 1986-92: the FINMONICA Myocardial Infarction Register Study. AB - OBJECTIVES: To investigate changes in the medical treatment of patients with myocardial infarction and the trends in revascularization procedures in Finland. DESIGN: A population-based myocardial infarction (MI) register study. SETTING: Populations, aged 25-64 years, of the three geographical areas of Finland, provinces of North Karelia and Kuopio in eastern Finland and the Turku-Loimaa area in south-western Finland. MAIN OUTCOME MEASURES: Medical treatment administered prior to the coronary event, during the hospitalization and at discharge from hospital to all patients hospitalized due to suspected myocardial infarction and all CAD deaths occurring during three separate 4-month periods in 1986, 1989 and 1992. Data on coronary bypass surgery and percutaneous coronary angioplasty in the study areas for 1986-92. RESULTS: The most marked change in the medical treatment of hospitalized myocardial infarction patients was the significant increase in the use of thrombolytic treatment (5% of patients in 1986 and 24% in 1992, P < 0.001 for trend). The use of antiplatelet agents increased from 1986 to 1992 prior to the coronary event, during the hospitalization and at discharge. The use of beta-blockers and intravenous nitrates increased and the use of calcium-channel blockers declined significantly in hospitalized patients during the study period. Hospitalized male myocardial infarction patients were treated more often with beta-blockers, nitrates, antiplatelet agents and thrombolytic agents than female patients, suggesting less intensive medical treatment in women. CONCLUSION: The results of the large clinical trials regarding the medical treatment of myocardial infarction patients were adopted in the clinical practice rapidly and the treatment of myocardial infarction patients and the number of revascularization procedures changed markedly from 1986 to 1992 in Finland. These changes may in part explain the favourable changes in mortality from CAD in Finland. PMID- 10095813 TI - Antiplasmin correlates to arterial reactivity in a healthy population of 35-year old men and women. AB - OBJECTIVE: To study whether haemostasis function variables correlate with endothelial function and other vasomotion characteristics of the brachial artery in a randomly selected healthy population of 35-year-old men and women. DESIGN: Endothelial function was measured as flow mediated dilatation (FMD) of the brachial artery during reactive hyperaemia and the nonendothelial dependent dilatation after sublingual nitroglycerin (NTG) was administered. Haemostasis and fibrinolysis function were estimated by analysis of von Willebrand factor, plasminogen activator inhibitor-1, antiplasmin and fibrinogen. SETTING: A general medicine research centre and a university hospital. SUBJECTS: Randomly chosen men (n = 53) and women (n = 56). RESULTS: Univariate correlation analysis showed significant correlations between haemostasis factors, conventional risk factors for cardiovascular disease and indices of vasomotion of the brachial artery. In multivariate analysis, with haemostasis variables and conventional risk factors included, antiplasmin was the strongest explanatory variable for FMD. When antiplasmin was removed from the analysis, the r-value dropped from 0.46 to 0.35. Antiplasmin also correlated with NTG-induced dilatation (positively) and brachial diameter at rest (negatively), albeit less consistently. CONCLUSIONS: Antiplasmin correlates significantly and independently to FMD, reflecting endothelial function, and also to brachial artery diameter at rest and nitroglycerin-induced dilatation. In multivariate analysis these correlations of antiplasmin to arterial characteristics were stronger than for 'conventional' risk factors, such as smoking, blood pressure and serum cholesterol. PMID- 10095814 TI - Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. AB - INTRODUCTION: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable and include epistaxis, gastrointestinal bleeding, pulmonary arteriovenous malformations and cerebral arteriovenous malformations. Early death due to these complications has been described. DESIGN: We report a study on the prevalence and mortality of HHT in a Danish population based on two cross-sectional surveys in combination with a long-term follow-up study. SETTINGS AND SUBJECTS: Prevalent cases of HHT as of 1 January 1974 in the County of Fyn, Denmark, were identified. In 1995-97 a follow-up study of mortality was performed of the initial patient sample, and a new point prevalence rate of HHT as of 1 January 1995 was calculated. All live patients and their families were invited to attend a detailed clinical examination. RESULTS: The prevalence of HHT in the County of Fyn was 13.8 per 100,000 on 1 January 1974 and 15.6 per 100,000 on 1 January 1995. In the HHT group as a whole, we found a slightly increased mortality; however, amongst the HHT patients younger than 60 years at inclusion the mortality of HHT patients was twice the expected. The excess mortality could be fully explained by severe HHT symptoms. CONCLUSION: This study suggests that HHT is more prevalent than previously believed. In young patients the disease is associated with an excess mortality which is fully attributable to HHT. Future research should aim at the identification of HHT patients at particular risk of developing severe complications. PMID- 10095815 TI - The snack is critical for the blood glucose profile during treatment with regular insulin preprandially. AB - OBJECTIVES: To evaluate how a snack influences the blood glucose profile during treatment with preprandial regular human insulin. DESIGN: In a randomized study a mid-morning snack either was or was not served. Insulin was given 30 min before the usual breakfast of the patients. Plasma free insulin and blood glucose were repeatedly determined for 5 h. SETTING: Outpatient clinic at a university hospital. SUBJECTS: Twenty patients with type 1 diabetes treated with multiple injections of regular insulin (Actrapid) and eight non-diabetic subjects. INTERVENTIONS: A mid-morning snack either was or was not served 2 h after the usual morning insulin injection. MAIN OUTCOME MEASURES: A difference in the blood glucose profile after a mid-morning snack. RESULTS: With a snack there was no difference in blood glucose fasting and at 12.30 h, whilst without a snack there was a decrease of almost 4 mmol L-1, several patients experienced low blood glucose and three had hypoglycaemia. An extended peak of free insulin was reached 30 min after the insulin injection with a slow decrease to the fasting level after 5 h. After the insulin injection a significant decrease in blood glucose occurred within 30-45 min. CONCLUSIONS: A snack 2 h after the insulin injection results in a smoother blood glucose profile and reduces the risk of hypoglycaemia in patients with type 1 diabetes treated with preprandial regular human insulin. Furthermore, the recommended interval of 30 min between insulin injection and a meal may be too long. PMID- 10095816 TI - Atorvastatin compared with simvastatin in patients with severe LDL hypercholesterolaemia treated by regular LDL apheresis. AB - OBJECTIVES: Atorvastatin is a new potent HMG-CoA reductase inhibitor. We evaluated whether patients with coronary heart disease and severe hypercholesterolaemia showing insufficient LDL (low-density lipoprotein) cholesterol reduction despite combined therapy with simvastatin and regular LDL apheresis will benefit from atorvastatin therapy. SETTING: Tertiary care centre, university hospital. METHODS: In 21 patients treated by LDL apheresis, concomitant simvastatin therapy (40 mg day-1) was replaced by atorvastatin (40 mg day-1) and increased to 60 and 80 mg day-1 (each for 3 months) if no side-effects were reported and NCEP treatment goals were not reached. RESULTS: In 20 of 21 patients (95%), atorvastatin resulted in significant reduction of LDL cholesterol compared with simvastatin (by 10%, additional 8% and additional 1%, with 40, 60 and 80 mg day-1, respectively). In four patients, NCEP treatment goals were reached (in three by atorvastatin alone, and in one by atorvastatin and apheresis). Patients with little reduction in LDL cholesterol to 40 mg day-1 atorvastatin benefited most by increasing the dose to 60 mg day-1 (additional 13% reduction), whilst those responding to atorvastatin 40 mg day-1 benefited less (additional 1.9% reduction). During atorvastatin therapy, significantly less plasma had to be treated during apheresis resulting in shorter apheresis time. Eight patients (38%) reported side-effects, resulting in discontinuation of atorvastatin in three (14%) and dose reduction in five patients (24%), whilst no elevation of biochemical markers was observed. CONCLUSION: Concomitant atorvastatin therapy is superior to simvastatin therapy in patients with severe hypercholesterolaemia treated with regular LDL apheresis, but is associated with a high rate of subjective side-effects. PMID- 10095817 TI - Decreased heart rate variability in patients with type 1 diabetes mellitus is related to arterial wall stiffness. AB - OBJECTIVE: Low heart rate variability (HRV) is, in several patient groups, related to poor prognosis. The underlying mechanisms are still unclear. The aim was to study if there is a relationship between HRV, which is a measure of baroreceptor function, and atherosclerosis. DESIGN: The relationship between heart rate variability and carotid arterial wall stiffness was studied in subjects with type 1 diabetes mellitus in which autonomic dysfunction and early atherosclerosis are common. HRV was assessed from power spectral analysis of 24-h Holter recordings and arterial wall stiffness was assessed from an ultrasound study of the right common carotid artery. SETTING: A university hospital. SUBJECTS: Fifty-nine patients (41 +/- 8 years) from the Stockholm Diabetes Intervention Study (SDIS) were investigated. These patients were randomized to intensified conventional treatment or standard treatment approximately 12 years before this study. RESULTS: Patients with stiffer arteries had lower HRV in all spectral bands (r = -0.32 to -0.40, P = 0.06-0.001). This relation remained on correcting for age. All spectral parameters of HRV correlated with the mean HbA1c from 10 years of study (r = -0.37 to -0.40, P = 0.004-0.001). CONCLUSIONS: In patients with type 1 diabetes mellitus, heart rate variability and arterial wall stiffness are related to each other. The results suggests that the autonomic nervous system could be a link between diabetes and vascular disease. PMID- 10095818 TI - High prevalence of undiagnosed coeliac disease in adults: a Swedish population based study. AB - OBJECTIVE: To determine the prevalence of coeliac disease in a population-based sample of Swedish adults. DESIGN: Population-based cross-sectional study. SETTING: Northern Sweden. SUBJECTS: A total of 1894 adults (76%) out of 2500 invited, randomly selected from the population register after stratification for age and sex. MAIN OUTCOME MEASURES: Prevalence of biopsy verified coeliac disease, symptoms of undiagnosed cases, and results of antiendomysium and antigliadin serum antibody tests. RESULTS: Coeliac disease was confirmed by intestinal biopsy showing enteropathy in 10 individuals (seven women and three men), corresponding to a prevalence of 5.3 per 1000 (95% CI = 2.5-9.7). The majority of cases (eight out of 10) had not been diagnosed prior to the screening, although many had symptoms compatible with coeliac disease. All individuals with antiendomysium antibody positivity who were subjected to a small intestinal biopsy had enteropathy. Furthermore, all of them also had elevated levels of antigliadin antibodies type IgA and/or IgG. CONCLUSIONS: Coeliac disease is common, albeit mostly undiagnosed, in Swedish adults. It is likely that the situation is no better in other countries. This highlights the importance of keeping coeliac disease in mind, and of promptly investigating individuals with unexplained, even mild, symptoms compatible with the disease. Serological markers, e.g. antigliadin and antiendomysium antibodies, are useful tools within this active case-finding strategy, although the final diagnosis should be based on an intestinal biopsy demonstrating enteropathy. PMID- 10095819 TI - Hypocalcaemia in HIV infection and AIDS. AB - OBJECTIVES: To study the prevalence and possible mechanisms of hypocalcaemia in HIV infection and AIDS. SUBJECTS: 828 patients with HIV infection or AIDS and 549 controls. INTERVENTIONS: Measurements of total serum calcium and albumin levels. Parameters of calcium homeostatis were determined in a subgroup of 21 hypocalcaemic AIDS patients. RESULTS: Mean serum calcium was 2.34 +/- 0.13 mmol L 1 in the HIV group vs. 2.46 +/- 0.10 mmol L-1 in controls (P < 0.0001). After adjusting for serum albumin, hypocalcaemia was present in 6.5% of the HIV group vs. 1.1% of controls. Mean serum calcium was declining according to CDC groups, and differed significantly from controls in each group. Regression coefficients of cacium vs. albumin were 0.147 amongst HIV-infected patients and 0.106 for controls. In the subgroup of hypocalcaemic patients with AIDS, 10/21 had vitamin D deficiency, six of these with low ionized calcium levels. Low serum PTH was found in 2/21 patients. Magnesium deficiency in 1/21. Of the remaining eight patients, only one had secondary hyperparathyroidism, while the other seven lacked an adequate PTH response, despite low ionized calcium levels in four subjects. CONCLUSIONS: Mean serum calcium concentrations were lower through all CDC stages, irrespective of albumin, resulting in a higher prevalence of hypocalcaemia in HIV-positive patients compared with controls. In a considerable number, this seems to be caused by vitamin D deficiency and potentially a lack of adequate PTH secretion, but further studies are needed to confirm this. PMID- 10095820 TI - Fibrinogen and mortality in chronic critical limb ischaemia. AB - OBJECTIVE: Plasma fibrinogen predicts cardiovascular events in patients with stable peripheral arterial occlusive disease, but its predictive value in patients with chronic critical limb ischaemia, a condition associated with a high risk of death, is unknown. DESIGN: A prospective cohort study. SETTING: Determination of fibrinogen and other potential predictors during clinic-based work-up of patients admitted for diagnostic and therapeutic evaluation. SUBJECTS: A total of 108 patients (72 +/- 10 years, 78 males) with atherosclerotic occlusive disease and critical limb ischaemia (pain at rest and/or trophic lesions) followed up for a median period of 1.6 years). (range: 8 days-5.5 years; 218 patient-years). MAIN OUTCOME MEASURES: Total mortality. RESULTS: Forty-five deaths (71% cardiovascular) occurred during the follow-up. Baseline fibrinogen was higher in those who died in the early follow-up period (first 6 months), as were white cell count and serum creatinine, while haematocrit was lower. Plasma fibrinogen values correlated positively with white cell count, and negatively with haematocrit; other cardiovascular prognostic factors did not differ. Only plasma fibrinogen predicted survival independently in multivariate age-corrected Cox regression analysis. Relative risk of death doubled for each standard deviation above the mean and increased with each tertile increase in fibrinogen. CONCLUSIONS: Fibrinogen predicted death in these elderly arteriopaths with critical limb ischaemia, particularly those who died in the first months following critical ischaemia. Inflammatory stimuli secondary to severely defective tissue oxygenation and possibly sepsis and necrosis, might have stimulated fibrinogen, an acute-phase reactant, thereby compromising organ perfusion through increased blood viscosity and/or promoting thrombosis. PMID- 10095821 TI - The response to inhaled and oral steroids in patients with stable chronic obstructive pulmonary disease. AB - BACKGROUND: A significant minority of patients with COPD have favourable response to corticosteroid treatment. In addition, the benefit of corticosteroid treatment may be outweighed by the side-effects. Long-term administration of inhaled steroids is a safe means of treatment. However, only a few studies have addressed the role of inhaled steroids in patients with COPD, with conflicting results. METHODS: Forty-four patients with stable COPD were defined as 'responders to bronchodilators' (increase in FEV1 > or = 20% following administration of beta 2 agonist) (group A), and 124 as 'non-responders to bronchodilators' (group B). All patients were randomized to receive a 6-week course of either a daily dose of 800 micrograms of inhaled budesonide or placebo, separated by 4 weeks when no medication was taken; were randomized again to receive a 6-week course of either 1600 micrograms day-1 of inhaled budesonide, or 800 micrograms day-1 of inhaled budesonide plus placebo; and were randomized once again to receive a 6-week course of either 40 mg day-1 of prednisone or placebo. All stages were performed in a double-blind cross-over design. RESULTS: Following administration of 800 micrograms day-1 of inhaled budesonide, there was an increase in the mean FEV1 from 1.40 +/- 0.20 to 1.92 +/- 0.22 L (P < 0.001) and a significant decrease in inhaled beta 2 agonist consumption in group A. These changes remained almost stable during the increased dose of inhaled budesonide or during prednisone treatment. The mean FEV1 did not change during the placebo period, or in group B in either treatments. CONCLUSIONS: Treatment with inhaled steroids improved spirometry data and inhaled beta 2-agonist consumption in about one-quarter of patients with stable COPD, and this rate increased to about three-quarters in patients who responded to beta 2-agonist inhalation. There was no additional benefit in using a higher dose of inhaled budesonide or prednisone. PMID- 10095822 TI - Intestinal endocrine cells in myotonic dystrophy: an immunocytochemical and computed image analytical study. AB - OBJECTIVES: To study intestinal endocrine cell types in patients suffering from myotonic dystrophy (MD) and diarrhoea. DESIGN: Comparative study between MD patients and matched controls. SETTING: Departments of Medicine, Central Hospital, Boden, and University Hospital, Umea, Sweden. SUBJECTS: Ten patients with MD (four males and six females) and suffering from diarrhoea. Ten healthy volunteers served as controls for the duodenal study and 13 patients under investigation for rectal bleeding and with endoscopically normal mucosa were controls for the rectal study. MEASUREMENTS: The duodenal and rectal endocrine cell types were identified by immunohistochemical investigation and quantified by computed image analysis. RESULTS: The total endocrine cell area in the duodenum as demonstrated by chromogranin A-immunoreactivity was significantly increased in MD as compared with the controls (126 +/- 58 vs. 48 +/- 22 x 10(3) microns 2 mm-2 in crypts and 230 +/- 183 vs. 28 +/- 22 in villi, respectively, P < 0.01). The increase included all types of endocrine cells studied, namely those positive for serotonin, cholecystokinin (CCK)/gastrin, secretin, gastric inhibitory peptide (GIP) and somatostatin. In the rectum, the total endocrine cell area as determined by chromogranin A-immunoreactivity was also significantly increased, but there was no statistical difference between the controls and patients with respect to the area of serotonin-, peptide YY (PYY)-, pancreatic polypeptide (PP) or somatostatin-immunoreactive cells. CONCLUSIONS: The increase in endocrine cell area indicates a disturbed endocrine regulation of the gastrointestinal tract that may contribute to the development of gastrointestinal symptoms encountered in MD patients. PMID- 10095823 TI - Low vitamin E status is a potential risk factor for insulin-dependent diabetes mellitus. AB - OBJECTIVES: To study the association of vitamin E status with occurrence of insulin-dependent diabetes mellitus (IDDM). DESIGN: A case-control study nested within a 21-year follow-up study. SUBJECTS: Nineteen incident IDDM patients with an average age of 28 years and three individually matched controls per patient. MAIN OUTCOME MEASURE: Serum concentrations of alpha-tocopherol. RESULTS: Serum alpha-tocopherol concentration at the baseline examination was inversely associated with IDDM occurring 4-14 years later. The cholesterol-adjusted relative risk of IDDM between the highest and lowest thirds of the vitamin concentration was 0.12 (95% confidence interval = 0.02-0.85). CONCLUSIONS: The finding corroborates the hypothesis of a protective effect of vitamin E against development of IDDM. Because of the relatively old age of the patients in the present population, further epidemiological studies on the topic are warranted. PMID- 10095824 TI - Sickle cell-like crisis and bone marrow necrosis associated with parvovirus B19 infection and heterozygosity for haemoglobins S and E. AB - In the literature, heterozygosity for haemoglobins S and E is known as a clinically benign condition. Nevertheless, we present a case of double heterozygosity manifesting as an infarctive sickle cell-like crisis with acute chest syndrome and reversible bone marrow necrosis. Importantly, these complications were associated with serologically documented parvovirus B19 infection. Reviewing the literature, this case emphasizes a specific role of parvovirus B19 as a precipitating cause. Furthermore, it demonstrates how important the consideration of haemoglobin disorders can be even outside of the historically known areas. PMID- 10095825 TI - Hepatitis C virus transmission following invasive medical procedures. PMID- 10095827 TI - Urinary nucleosides. AB - The methods of analysis, origins, and clinical significance of urinary nucleosides are reviewed through 1997. Structures, chromatographic and mass spectral data and references to the clinical literature are presented for each of the 57 nucleosides currently identified in normal and pathogenic human urine samples. Data from the HPLC separation and GC/MS analysis of 37 individual HPLC fractions are presented and discussed. Methods, including sample preparation techniques, used for the analysis of urinary nucleosides including GC, HPLC, GC/MS, HPLC/MS and immunoassays are compared and the advantages and limitations of each method described. The conclusion is drawn that the urinary nucleosides do serve as biomarkers of cancer and other diseases, but analytical methods need further improvement if clinical decisions are to be made based on the levels of nucleosides in human urine. PMID- 10095828 TI - [Hepatitis E virus: detection of antibodies in blood donors in Lebanon]. AB - One hundred Lebanese volunteers blood donors were tested for the qualitative detection of antibodies against hepatitis E virus (HEV) by an immunoenzymatic method. The results showed 4% of positivity. This figure allows us to confirm the presence of infection due to HEV in Lebanon. More studies on a larger panel are necessary to confirm this result. This study leads us to suspect an HEV infection in front of an acute non A, non B, non C hepatitis even if the patients have not lived in an endemic area. PMID- 10095826 TI - Traffic of the tick embryo basic protein during embryogenesis of the camel tick Hyalomma dromedarii (Acari: Ixodidae). AB - The tick embryo basic protein (TEBP) is present in the nucleus as a counterpart of histones at early embryonic stages of the tick Hyalomma dromedarii. The sharp drop in the TEBP nuclear level and elimination of the N-terminal dipeptide (leucine-serine) between days 12 and 15 after oviposition suggested the transport of TEBP to the cytoplasm for protein turnover. The traffic of TEBP during tick embryogenesis was examined. The level of TEBP was detected in the cytoplasm from the different embryonic stages by the established enzyme-linked immunosorbent assay (ELISA) and confirmed by immunoblotting. At day 12, a 2-fold increase in the cytoplasmic TEBP level coincided with its decrease in the nucleus. This result indicates that TEBP starts to leave the nucleus for the cytoplasm at day 12. The changes in the cytoplasmic leucine aminopeptidase (LAP)-specific activity were followed during tick embryogenesis. The LAP activity started to increase at day 12 and reached its maximum level at day 21. The enzyme displayed an optimum pH between 7.5 and 8.8 and a K(m) value of 0.5 microM for leucine-p-nitroanilide. The involvement of the exopeptidase activity in the TEBP turnover after its translocation to the cytoplasm is discussed. PMID- 10095830 TI - [Endoscopic ethmoidectomy. How to prevent complications?]. AB - The use of the microscope and more recently of the endoscope, improve the conditions of endonasal surgery. These techniques must not give the impression of complete security. The complications of the ethmoidectomy exist. A good knowledge of the anatomy of the sinus cavities and a gradual apprenticeship are the best means to prevent these complications. We present the different types of complications and their preventions. PMID- 10095829 TI - [Stereotaxic approach in deep cerebral lesions]. AB - The authors report a retrospective study (April 92-April 95) of 60 CT guided stereotactic biopsies. The procedure offered accurate histological diagnosis in 56 cases. There were 38 glial tumors, the majority being of high grade (III-IV). Five abscesses were evacuated and medically treated. Complications occurred in 5% of cases. These results are compatible with those reported in the literature. The simplicity and accuracy of stereotactic procedure are confirmed, making it an imperative step in the management of intraxial space occupying lesion when surgical resection is negotiable. The other applications of the stereotactic procedure are exposed. PMID- 10095831 TI - [Lung cancer in Lebanon. Experience at the l'Hotel-Dieu de France in Beirut]. AB - All lung cancer cases admitted in our hospital from the 1st of January 1979 to the 31st of December 1995 were reviewed to allow for the study of the "behaviour" of the disease in Lebanon. A total of 386 cases included 87.5% males and 12.5% females. Mean age was 60 years. 87.3% were smokers. Squamous cell carcinoma was the most frequent histologic type (37.3%) and predominant in men. Adenocarcinoma was more frequent in women (50% v/s 29.9%). Patients often consulted their physician after delays of several months. Diagnosis is commonly confirmed by bronchoscopy. Transthoracic needle aspiration has become, since 1990, a very useful procedure for diagnosis of peripheral lesions with a sensitivity of 90.6%. Metastases are recorded in 30.9% of cases. Histological type distribution and advanced cancer stages found in our study are similar to that encountered in extensive international studies over the last few decades. PMID- 10095832 TI - [Role of ultrasonography in the diagnosis of acute appendicitis in children. Apropos of 35 cases]. PMID- 10095833 TI - [Extrahepatic manifestations of hepatitis C virus]. PMID- 10095834 TI - Reducing pneumonia mortality under the age of 5 years. The WHO guidelines for early diagnosis of pneumonia based on simple clinical signs and application in Lebanon. PMID- 10095835 TI - [Paraquat poisoning in children]. PMID- 10095836 TI - [Renovascular arterial hypertension in the framework of von Recklinghausen's neurofibromatosis. Apropos of a case]. AB - Arterial hypertension in patients with neurofibromatosis is most often due to an associated pheochromocytoma. In rare cases the etiology of arterial hypertension is renovascular. Surgical treatment is mandatory when the stenosis is located in the proximal segment of the vessel. Angioplasty is hazardous in this setting due to the fibrotic nature of the culprit lesion. The authors report a case of ostial narrowing of the right renal artery in a 16-year-old girl with severe arterial hypertension and neurofibromatosis. The operation consisted of resection of the culprit lesion and reimplantation of the renal artery on the aorta. Postoperatively her blood pressure returned to normal. PMID- 10095837 TI - Ultrasound guided percutaneous fine-needle biopsy in a case of eosinophilic gastroenteritis. AB - Eosinophilic gastroenteritis is a rare disease; clinical features depend on which intestinal layer is involved. In our report a 70-year-old woman presented with intestinal subocclusion and ascites. Endoscopic biopsies of gastric mucosa were negative. Ultrasound guided percutaneous fine-needle biopsy showed muscle infiltration by eosinophils of muscle layer of the stomach and jejunum. Muscular and serosal disease are usually diagnosed only by laparotomy or laparoscopy. PMID- 10095838 TI - Late recurrence with malignant degeneration of testicular teratoma. Case report. AB - Radical orchiectomy was performed on a 25-year-old man for benign mature teratoma. A synchronous without change 3 cm retroperitoneal mass was followed for five years. The mass enlarged and became symptomatic twelve years after orchiectomy. Excision of the mass revealed a non-seminomatous germ cell tumor. Possible explanation is malignant degeneration of the teratomatous elements. Testicular teratomas should be treated as potentially malignant non-seminomatous tumor. PMID- 10095840 TI - Shafik Hatem (1910-1988). From Hammana to Beijing. PMID- 10095839 TI - [The harlequin baby. Apropos of a case]. AB - Harlequin foetus is a rare clinical entity and consists in the most severe form of congenital ichthyosis. Here below, we report on a new case of Harlequin baby born from consanguineous first cousin parents. The underlying molecular basis of harlequin ichthyosis is still not definitely determined. Surviving of few cases is due essentially to the use of a synthetic Vitamin A acid. The benefit of that treatment is still questionable. PMID- 10095841 TI - [Intracranial arterial aneurysm: from diagnosis to treatment. A retrospective study of 46 surgically treated cases]. AB - The authors report a series of 46 patients operated for an intracranial aneurysm from January 92 to January 96 in Hotel-Dieu de France. There were 28 males and 18 females ranging from 22 to 69 years. Forty-four patients presented a typical clinical pattern of subarachnoid haemorrhage. In 20 cases (45%), correct diagnosis was not made at the time of bleeding but at another outpatient visit or at a bleeding recurrence. Cerebral angiography was performed in all our patients. The most frequent aneurysmal location was at the anterior communicating artery (n = 20). Surgical total exclusion of the aneurysm was possible in 45 patients. Forty-one patients had a favourable outcome but three presented important neurological sequelae. We encountered 2 postoperative deaths due to irreversible arterial vasospasm. These results suggest that the preoperative neurological state and the occurrence of an arterial vasospasm are the main prognostic factors of the intracranial aneurysm. Early diagnosis and treatment allow to avoid rebleeding, mostly responsible of the poor neurological status, and to better manage the arterial vasospasm in order to improve the outcome. PMID- 10095842 TI - Rates of perinatal mortality and low birth weight among 3367 consecutive births in south of Beirut. AB - 3367 consecutive births were reviewed prospectively. Population belongs mainly to a community with relatively underprivileged living conditions. Perinatal mortality was found at a rate of 22.4/1000 B. Early neonatal mortality formed 6.66/1000 B and stillbirth formed 15.83/1000 B. Low birth weight rate was 5.43% of live birth. Analysis of our findings suggests the need to improve follow-up during gestation to avoid complications resulting in macerated stillbirths, and to review the routine of follow-up and care in the immediate period before delivery, during delivery, in the immediate post partum period including resuscitation procedures, and care in the ICN. The aim is to prevent and appropriately treat intrauterine asphyxia, fetal distress, obstetric complications, and in the post partum period to appropriately resuscitate the newborn and improve ICN procedures. These measures are expected to reduce fresh stillbirth and early neonatal mortality and consequently infant mortality. Lowering rate of low birth weight is of less urgent nature in this population as it is relatively not high, but because a larger portion of early neonatal mortality is among low birth weight infants, with weights below 2000 gms, improving ICN care provided to these neonates is expected to sharply reduce neonatal mortality. In Lebanon we have a growing number of ICN units with wide variability of the quality of medical supervision and facilities. Insufficient number of neonatologists and nurses who are specialized in neonatal intensive care is leaving the chance for sick neonates to be attended by general pediatricians and insufficiently trained nurses. Our medical schools are called to encourage pediatricians to specialize in neonatal intensive care and to create more opportunities for this specialty to meet the national requirement. It is suggested, too, to subject ICN units in Lebanon to standardized requirements concerning attendance and facilities before obtaining official recognition. Centralization of care given to severely sick neonates and to women with high risk pregnancy in optimal conditions is most needed. PMID- 10095843 TI - Endoscopic patterns of primary gastric MALT lymphoma. AB - Primary low grade B-cell lymphoma of the mucosa associated lymphoid tissue (MALT), is an uncommon malignancy with a prolonged period of localized disease, and a possible transition to a high grade MALT lymphoma. The endoscopic diagnosis is often difficult, because of the various macroscopy patterns. The endoscopic aspects seen in 14 patients diagnosed and treated for primary gastric MALT lymphomas, were reviewed. Four main patterns were recognized: 1/Large ulcerations (n = 6, 42.9%), 2/Polypoid lesion (n = 2, 14.3%), 3/Gastritis with small ulcerations (n = 4, 28.5%), and 4/Atypical mucosal relief (AMR): erythema, nodularity, edematous or infiltrated folds (n = 2, 14.3%). In 10 cases (71%) AMR was associated with another endoscopic pattern. Histologically the tumors were of low grade (n = 11) and high grade (n = 3). On initial endoscopy a diagnosis of malignancy was done in 6 out of the 7 patients (85.7%) with large ulcers and the large polypoid mass; in contrast, an adequate endoscopic diagnosis was made in only 3 out of the 7 patients (42.8%) with ulcerative gastritis, AMR, and the small polypoid lesion. The endoscopic aspect of the latter group, representing 50% of all patients and 63.6% of the group with low grade MALT lymphomas, was indistinguishable from a benign lesion. Therefore it is important to be aware of this entity and perform biopsies in every patients with abnormal endoscopic findings. PMID- 10095844 TI - Renal biopsy in children in a developing country in 61 consecutive cases. AB - Percutaneous renal biopsy in children is a safe procedure. It is used for definitive diagnosis, prognosis and evaluation of the response to therapy. Repeated percutaneous biopsies are currently performed especially in allograft kidneys and in native kidneys as well. No major complications were noted in our series. The use of the new automated technique with small disposable needles in a well sedated child and experienced operator minimizes the complication rate. The important clinical benefit of the percutaneous renal biopsy overcomes the minimal risk of the procedure. Mesangiocapillary glomerulonephritis and focal segmental glomerulosclerosis are the predominant histological findings in our series. More data from other centers are necessary to evaluate the real incidence of the different entities of renal diseases in our country. PMID- 10095845 TI - [Video-laryngostroboscopy in phonation]. PMID- 10095846 TI - Spectrum of diverticular disease of the colon in Lebanon AUBMC experience. AB - There is an increasing number of cases of colonic diverticular disease among hospital admissions to AUBMC being more prevalent in patients > 50 years old (76.5%). Colonic diverticular disease were more prevalent in urban population admitted to AUBMC (95.6%). Diverticulitis is the most common complication of colonic diverticular disease among admitted cases with colonic diverticular disease (51%). All patients with diverticulitis who presented without abdominal pain had fever. This finding made diverticulitis part of the differential diagnosis in cases of FUO in patients over 50 years old. PMID- 10095847 TI - [Health financing in Lebanon. I. Organization of health care services, coverage system and contribution of the Ministry of Public Health]. AB - This paper intends to analyze the health care system in Lebanon from the organizational and financial points of view. It allows for an understanding of the health services' market by tackling it from different angles: supply versus demand, private versus public sectors, curative versus preventive services, hospital versus ambulatory care. This study necessitated a review of all previous surveys made in this field, during the after-war period. It also needed the daily collection and follow-up of pertinent data with all private and public agencies and concerned ministries, over a one-year period. In addition, a critical analysis has been made to the survey Conditions de vie des menages, en 1997, that was carried out by the Central Administration of Statistics, that came to complete the missing data concerning household expenditures on insurance and health services. Especially that this survey covered the same period (1997), subject of this study. The paper reveals that, although the private sector is the main provider of both hospital and ambulatory care, private hospitals are flourishing on public money, whereas outpatients care is mainly financed by the households. Evidence shows that the Lebanese health care system succeeded in resolving the problem of accessibility to primary, secondary and tertiary health care, responding thus to the value of equity. But, at the price of an ever escalating cost, threatening the sustainability of the system. This is what is attained in this paper, as it shows clearly that expenditures on health have reached an alarming level of the GDP share. Our purpose being providing solid arguments in favor of reforming the health system. PMID- 10095849 TI - Adenocarcinoma of the prostate with endometrioid features. Review of the literature with a report on six new cases. AB - Six cases of adenocarcinoma of the prostate with endometrioid features are reported; the literature is reviewed; the pathology and the clinical aspects are discussed along with some theoretical considerations. PMID- 10095848 TI - [Guidelines in accidental injury of a caretaker in contact with a blood product in the framework of HIV infection]. PMID- 10095850 TI - Early onset neonatal spontaneous pneumopericardium. AB - Neonatal pneumopericardium is a rare clinical condition which usually occurs in association with other air leaks, especially when there is severe lung pathology, post vigorous resuscitation, or in presence of assisted ventilation. We report the first case of isolated, spontaneous pneumopericardium occurring in the absence of a history of neonatal resuscitation, mechanical ventilation, or of significant lung pathology. In this neonate the pneumopericardium had a relatively benign course resolving on oxygen therapy. We also review the literature and highlight the differences between the early onset, often spontaneously resolving cases, and the late onset usually severe cases. PMID- 10095851 TI - Gleanings in urology from Arabic medical literature. PMID- 10095852 TI - Age-related changes in temporal resolution: envelope and intensity effects. AB - Gap-detection thresholds were determined for 10 younger and 10 older adults at two sensation levels (40 and 60 dB SL) for tone pips with Gaussian amplitude envelopes whose standard deviations were 0.5, 1, 1.5, and 2 ms. Gap-detection thresholds were larger for the older participants under all conditions. For all participants, gap-detection thresholds increased with the standard deviation of the Gaussian amplitude envelope, were relatively independent of sensation level, and were independent of the degree of hearing loss. Because spectral splatter decreases with increasing standard deviation of the Gaussian amplitude envelope, the age-related differences in gap-detection cannot be attributed to differences between how young and old listeners are affected by off-frequency cues. Furthermore, the consistent age difference in gap-detection at all amplitude envelope standard deviations was shown to be incompatible with the hypothesis that temporal integration time is longer for older listeners. PMID- 10095853 TI - Visual search for features and conjunctions in development. AB - Visual search performance was examined in three groups of children 7 to 12 years of age and in young adults. Colour and orientation feature searches and a conjunction search were conducted. Reaction time (RT) showed expected improvements in processing speed with age. Comparisons of RT's on target-present and target-absent trials were consistent with parallel search on the two feature conditions and with serial search in the conjunction condition. The RT results indicated searches for feature and conjunctions were treated similarly for children and adults. However, the youngest children missed more targets at the largest array sizes, most strikingly in conjunction search. Based on an analysis of speed/accuracy trade-offs, we suggest that low target-distractor discriminability leads to an undersampling of array elements, and is responsible for the high number of misses in the youngest children. PMID- 10095854 TI - Intercellular adhesion molecule-1 expression in the inner ear of rats following secondary immune reaction in the endolymphatic sac. AB - An immunological aetiology for inner ear diseases has long been proposed. The endolymphatic sac (ES) is the only immunoprivileged site in the inner ear with a resident population of immunocompetent cells. By keyhole limpet hemocyanin (KLH) challenge into the ES of systemically pre-immunized guinea pigs, we previously demonstrated an infiltration of inflammatory cells into the perilymphatic space of the cochlea. In order to understand the mechanisms involved in the recruitment of immunocompetent cells into the inner ear, and their relation to the development of endolymphatic hydrops (EH), we investigated the expression and time-kinetics of intercellular adhesion molecule 1 (ICAM-1) in the inner ear of systemically pre-immunized rats after antigen (KLH) challenge into the ES, its relation to cell infiltration in the cochlea and subsequent development of EH. By immunohistochemistry, strong ICAM-1 expression was detected in the spiral ligament, suprastrial region, spiral prominence, spiral modiolar veins, spiral collecting venules, surface membrane of the perilymphatic compartment, perilymphatic space and ES of immunized rats, but not of control rats. ICAM-1 expression was detected at 5-6 h, peaked at 10-15 h, and gradually reduced by 2 weeks. Cell infiltration into the cochlea started at 6-12 h and peaked at day one. By 6 h, 50% of challenged rats developed EH. This figure rose to 70% at 12 h, and then gradually reduced. However, immunoreactivity for KLH (antigen) was only detected in the ES. These results emphasize that the sac is the central immunological organ of the inner ear, and suggest that ICAM-1 may play a pivotal role in the aetiology of immune-mediated inner ear diseases through the recruitment of immunocompetent cells into the inner ear and subsequent development of EH. PMID- 10095855 TI - Histaminergic influence on vestibular stimulation-induced locus coeruleus inhibition in rats. AB - In previous reports we have shown that caloric stimulation (CS) of the vestibular apparatus inhibits locus coeruleus (LC)-noradrenergic neuronal activity in urethane-anaesthetized rats. The present study examined the effect of neural histamine depletion by alpha-fluoromethylhistidine (alpha-FMH) on CS-induced LC inhibition. In alpha-FMH treated rats, LC neuronal inhibition caused by CS was still observed. This finding indicates that the central histaminergic neuron system does not participate in the CS-induced LC-noradrenergic inhibition. It is suggested that the noradrenergic neuron system is involved in the development of vestibulo-autonomic response, independent of the histaminergic neuron system. PMID- 10095856 TI - Molecular mechanisms of vestibular compensation in the central vestibular system- review. AB - Vestibular compensation consists of two stages: the inhibition of the contralesional medial vestibular nucleus (contra-MVe) activities at the acute stage after unilateral labyrinthectomy (UL) and the recovery and maintenance of the ipsilesional MVe (ipsi-MVe) spontaneous activities at the chronic stage after UL. In this paper, we reviewed molecular mechanisms of vestibular compensation in the central vestibular system using several morphological and pharmacological approaches in rats. Based on our examinations, we propose the following hypotheses: i) at the acute stage after UL, the activated neurons in the ipsi-MVe project their axons into the flocculus to inhibit the contra-MVe neurons via the NMDA receptor, nitric oxide (NO) and/or GABA-mediated signalling, resulting in the restoration of balance between intervestibular nuclear activities. ii) At the chronic stage after UL, the flocculus depresses the inhibitory effects on the ipsi-MVe neurons via protein phosphatase 2A (PP2A) beta, protein kinase C (PKC) and glutamate receptor (GluR) delta-2, to help the recovery and maintenance of ipsi-MVe activities. PMID- 10095857 TI - Thimerosal-induced Ca2+ mobilization in isolated guinea pig cochlear outer hair cells. AB - Intracellular calcium mobilization of isolated guinea pig cochlear outer hair cells (OHCs) was investigated using thimerosal, a -SH group oxidizing agent, and fura-2 fluorescence ratio imaging microscopy. In the presence of thimerosal, intracellular Ca2+ concentrations ([Ca2+]i) of OHCs were elevated in a dose dependent manner. Even in Ca(2+)-free medium, Ca2+ response was still induced. The effects of thimerosal on [Ca2+]i were completely blocked and reversed by dithiothreiotol (DTT). Neither 1-100 microM ryanodine nor 5-20 mM caffeine altered the effects of thimerosal. Pretreatment with pertussis toxin (PTX) for 30 min did not affect the thimerosal-induced increase in [Ca2+]i. The increase in [Ca2+]i when Ca2+ was added during thimerosal application in Ca(2+)-free medium was almost completely blocked by 500 microM LaCl3, while nifedipine did not inhibit further increase in [Ca2+]i caused by thimerosal. Thus, oxidation of the SH group of the OHC membrane can induce a Ca2+ release from intracellular Ca2+ stores, which are ryanodine- and caffeine-insensitive, and Ca2+ influx through non-specific Ca2+ channels, but not the nifedipine-sensitive Ca2+ channels. The possible oxidation of -SH group gated Ca2+ channels in OHCs is worthy of further study. PMID- 10095858 TI - Optical recording of membrane potential on isolated spiral ganglion cells of newborn mice using a voltage-sensitive dye. AB - Optical imaging methods make monitoring of the membrane potential feasible. With this technique, one can observe different optical signals depending on optical properties, in response to membrane potential, using voltage-sensitive dyes. We used the multiple-site optical imaging system to investigate membrane potentials of the isolated, cultured spiral ganglion cells (SCGs) from newborn mice. We used a voltage-sensitive absorption dye. With high potassium (150 mM K+) exposure, the absorbency of SGCs stained with voltage-sensitive dye increased temporarily under a 700-nm interference filter at approximately 0.3%. This detection of the depolarization of SGCs using an optical recording technique with a voltage sensitive dye is important because it shows that the simultaneous measurement of activity in a variety of regions is possible, as is the exploring of the intercellular signalling pathway. PMID- 10095859 TI - Effects of trimetaphan-induced deliberate hypotension on human cochlear blood flow. AB - In order to observe the reaction of cochlear blood flow (CBF) to trimetaphan (TMP)-induced hypotension, CBF was measured with laser-Doppler flowmetry in 7 human subjects during general anaesthesia for middle ear surgery. All subjects showed a decrease in mean arterial pressure (MAP) during intravenous infusion of TMP, followed by a gradual return to the baseline level after termination of the infusion. The CBF generally followed the MAP changes with the same pattern. Three of the seven subjects demonstrated a CBF change larger than the maximum MAP change, indicating the lack of a local autoregulatory mechanism in CBF. On the other hand, CBF changes were smaller in magnitude than the maximum change in MAP for the rest of the subjects, suggesting an autoregulatory mechanism in CBF. However, since the audiograms from these subjects indicated profound damage along the cochlear basal turn probably due to middle ear inflammation, concomitant vascular damage in this region offers another possible explanation for the inappropriate CBF changes. The present observations may also suggest that deliberately TMP-induced hypotension has a potentially harmful effect on CBF during otological surgery that attempts to preserve or improve hearing. PMID- 10095860 TI - Changes of perilymphatic glutamate and cochlear blood flow following ischemia. AB - Dynamic changes of perilymphatic glutamate and cochlear blood flow were measured simultaneously in the guinea pig following cochlear ischemia. Glutamate was measured by the microdialysis technique with a probe inserted into the scala tympani at the basal turn. Cochlear blood flow was monitored with a laser-Doppler probe on the lateral wall of the second cochlear turn. Both parameters were measured before and after electrocauterization of the anterior inferior cerebellar artery and other vessels supplying the internal auditory canal. In four animals, glutamate increased with a decline of cochlear blood flow and then decreased with recovery of blood flow. No normalization of glutamate was observed in seven animals with a persistent decrease of blood flow. The results of this study indicate that the glutamate regulating system in the cochlea is dependent on cochlear blood flow. PMID- 10095861 TI - Quantitative immunogold cytochemistry reveals sources of glutamate release in inner ear ischemia. AB - Glutamate is thought to be a major neurotransmitter between hair cells and afferent dendrites in the inner ear. However, excessive glutamate is known to be excitotoxic, and may be involved in ischemic neuronal damage in the central nervous system. The glutamate concentration in the perilymph has been reported to increase during ischemia, but the source of glutamate is still unclear. In the present study, we have used post-embedding immunogold cytochemistry to analyse changes in the cellular distribution of glutamate in the guinea pig organ of Corti during ischemia. The areal gold particle densities in the inner hair cells of the ischemic side were lower than those of the control side, indicating that glutamate may be released from the hair cells during ischemia. Adjacent supporting cells (border cells) also showed a decrease in particle density, suggesting that they constitute an additional source of glutamate. PMID- 10095862 TI - Immunohistochemical detection of vasoactive intestinal polypeptide (VIP) and the VIP receptor in the rat inner ear. AB - Vasoactive intestinal polypeptide (VIP) is a 28 amino acid peptide that was originally isolated from porcine duodenum. The presence of VIP has been demonstrated in the central nervous system and peripheral tissues. However, there have been few reports on VIP as a neurotransmitter, especially in the inner ear. To investigate the function of VIP in the rat inner ear, we examined the expression of VIP and the VIP receptor by immunohistochemistry. Using the anti VIP and VIP receptor antibodies, scattered fibres in the cochlear nerve trunk demonstrating VIP-like immunoreactivity were found, and the spiral ganglion cells demonstrated ring-shaped VIP-like immunoreactivity. Immunoreactivity for the VIP receptor was predominantly found in the spiral ganglion cells. Our results suggest that VIP may play an important role as a possible neurotransmitter not only in the local control of cochlear blood flow, but also in the auditory system. PMID- 10095863 TI - Effect of erythromycin on otitis media with effusion in experimental rat model. AB - To understand the mechanism of erythromycin (EM) on otitis media with effusion, we examined its effects on leukocyte accumulation and expression of adhesion molecules L-selectin and Mac-1, using a rat experimental model Administration of EM inhibited leukocyte (neutrophil) accumulation in the middle ear cavity after LPS stimulation. Moreover, EM downregulated L-selectin expression and inhibited interleukin (IL)-8-induced upregulation of Mac-1 on peripheral blood neutrophils. These finding suggests that EM may improve otitis media with effusion by inhibiting neutrophil accumulation in the middle ear cavity through modulating the expression of adhesion molecules L-selectin and Mac-1 on peripheral blood neutrophils. PMID- 10095864 TI - Detection of thromboxane A2 receptor mRNA in the nasal mucosa of patients with allergic rhinitis. AB - Previous reports suggest that thromboxane (TX) A2 plays an important role in bronchial asthma, especially in the development of airway hypersensitivity. Similarly to asthmatic subjects, the nasal mucosa in patients with allergic rhinitis is hypersensitive to non-specific stimuli. Allergic rhinitis is mediated by chemical mediators released from inflammatory cells. However, the involvement of TXA2 in allergic rhinitis has been studied very little. Recently, TXA2 receptors from humans and mice have been characterized at the molecular level. We performed RT-PCR to examine whether TXA2 receptor mRNA expression is elevated higher in allergic rhinitis than in chronic sinusitis. We found that TXA2 receptor mRNA was expressed both in the nasal inferior turbinates with allergic rhinitis and in the maxillary sinus mucosa with chronic inflammation at a similar level. This result suggests that TXA2 receptor mRNA expression is not enhanced in allergic rhinitis. PMID- 10095865 TI - Localization of nitric oxide synthase in human nasal mucosa with nasal allergy. AB - Nitric oxide (NO) plays an important role in the regulation of upper respiratory function. In the nasal cavity, the concentration of NO in the air in patients with untreated allergic rhinitis is higher than that in normal individuals. NO is produced by the action of NO synthase (NOS) using L-arginine as a substrate. To investigate the expression of NOS in human nasal mucosa, histochemical staining for NADPH diaphorase and immunohistochemical staining for NOS isoforms were carried out in nasal inferior turbinate mucosa from patients with nasal allergy. Those without nasal allergy served as controls. NADPH diaphorase histochemical study revealed that NOS was expressed in the nasal epithelium, submucosal glands, nerve fibres and the endothelium in specimens of both allergic and control groups. Immunoreactivity to endothelial NOS (eNOS) was localized to epithelial and endothelial cells in both allergic and control groups. In some specimens in both groups, nerve fibres around submucosal glands stained positively for eNOS. Immunoreactivity to eNOS, however, was slightly stronger in the epithelia of the allergic group than in those of the controls. Immunoreactivity to inducible NOS (iNOS) was localized to epithelial cells, endothelial cells, nasal glands and inflammatory cells. The staining of epithelial cells and inflammatory cells was more marked in the allergic group than the controls. These findings may suggest that the greater amounts of NO in the nasal air of patients with allergic rhinitis are mainly induced by iNOS activity. PMID- 10095866 TI - Effect of roxithromycin on IL-8 synthesis and proliferation of nasal polyp fibroblasts. AB - Although several studies have demonstrated that low-dose, long-term 14-member macrolides (erythromycin (EM), roxithromycin (RXM), clarithromycin (CAM)) are effective in the treatment of chronic airway diseases like chronic sinusitis and diffuse panbronchiolitis (DPB), the mechanism of action of these drugs is not yet clear. Both these airway diseases are associated with an increase in the proliferation of fibroblasts. Moreover, fibroblasts are also an important source of proinflammatory cytokines such as interleukin-8 (IL-8), that play an important role in the pathogenesis of nasal polyps. Therefore, using primary fibroblast lines derived from nasal polyps, we investigated the effect of RXM on the synthesis of IL-8 and proliferation of nasal polyp fibroblasts (NPF). These fibroblasts were either treated with lipopolysaccharide (LPS) and RXM for 24 h, or pre-incubated with RXM for 24 h and then treated with LPS and RXM for 24 h. The level of IL-8 mRNA in NPF was analysed by reverse transcriptase-polymerase chain (RT-PCR) and the level of IL-8 in culture supernatants was measured by ELISA. Next, the proliferative capacity of NPF after treatment with RXM was analysed by cell counting and 3H-thymidine uptake. RXM had no effect on LPS induced IL-8 synthesis by NPF. On the other hand, RXM suppressed the proliferation of NPF in a dose-dependent manner. These findings suggest that, although RXM cannot directly inhibit the synthesis of IL-8, it probably reduces IL-8 production by inhibiting the proliferation of NPF. PMID- 10095867 TI - Contribution of nitric oxide and sensory transmitters to non-adrenergic, non cholinergic innervation of nasal blood vessels. AB - The possible contribution of a non-adrenergic, non-cholinergic (NANC) vasodilator mechanism in human nasal mucosa was studied using an in vitro muscle tension measuring technique. Strips of the nasal mucosa were suspended in a Magnus tube filled with Krebs solution and aerated with 95% O2. Isometric changes in tension were detected on administration of various drugs under electric stimulation and recorded with a transducer. The relaxing reaction under electrical train pulse stimulation with pretreatment of blockers of the autonomic nerves was suppressed by nitric oxide synthase inhibitor (L-NAME) and antagonists to the receptors of sensory nerve transmitters (Spantide, hCGRP8-37). This result suggests that nitric oxide, substance P and CGRP may be mediators in the NANC inhibitory nerve system. PMID- 10095869 TI - Immunohistochemical examination of NOS and SOD in nasal mucosa. AB - An immunohistochemical examination was performed to detect the localization of neural-type nitric oxide synthase (nNOS), endothelial-type NOS (eNOS) and inducible-type NOS (iNOS) in the human and mouse nasal mucosa. nNOS immunoreactive nerve fibers were found in the subepithelial layer and around the seromucous glands of mice. In these fibers, immunodouble staining revealed co localization of nNOS and superoxide dismutase (SOD). In the human nasal mucosa of normal subjects, strong eNOS immunoreactivity and weak iNOS immunoreactivity were found in the columnar epithelium. PMID- 10095868 TI - TrkA expression in mouse olfactory tract following axotomy of olfactory nerves. AB - The olfactory bulb is one of the brain regions that synthesizes the nerve growth factor (NGF). Functional roles of the bulbar NGF remain to be determined. The aim of the present study was, using an antibody specific to the high-affinity NGF receptor (trkA), to examine immunohistochemically the distribution of the NGF receptor in the mouse olfactory tract, under normal conditions and during regenerative processes. In normal mouse olfactory epithelia, trkA immunoreactive cell bodies were only seen in basal cells. Cell bodies of olfactory receptor cells did not express trkA immunoreactivity, but their neuronal processes (olfactory nerve fibres and bundles in the olfactory mucosa and the olfactory bulb) displayed trkA immunoreactivity. After axotomy of olfactory nerves, regenerating olfactory cells (basal cells and olfactory receptor cells) expressed trkA immunoreactivity in intramucosal and intrabulbar neuronal processes of olfactory receptor cells. These results suggest involvement of the bulbar NGF in the process of synaptogenesis and/or regeneration of the olfactory nervous system. PMID- 10095870 TI - Distribution and origin of the intraepithelial nerve fibres in the feline pharyngeal mucosa. AB - Sensory inputs from the pharynx play an important role in initiation of the swallowing reflex and in feedback control of motor activities. Using an immunohistochemical technique and denervation procedures, we examined the distribution and origin of the intraepithelial nerve fibres in the feline pharyngeal mucosa to clarify the role of the afferent nerve in swallowing. The posterior pillar was very densely innervated, and the posterior and lateral walls of the mesopharynx had a moderate nerve density. In contrast, the base of the tongue, the vallecula, the pharyngeal surface of the epiglottis, and the pyriform sinus had only a few nerve fibres. The epithelium of the rostral and caudal portions of the pharyngeal mucosa were innervated by the glossopharyngeal nerve and superior laryngeal nerve, respectively, with a borderline at the middle level of the epiglottis. A portion of the intraepithelial nerve fibres in the lateral and posterior walls of the mesopharynx originated from the pharyngeal branch of the vagus nerve. It is hypothesized that the intraepithelial nerve fibres that exist in densely innervated areas are related to the initiation of the swallowing reflex induced by stimulation of the pharyngeal mucosa. PMID- 10095871 TI - Distribution of NADPH-diaphorase activity in the feline laryngeal mucosa. AB - We studied nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity in the feline laryngeal mucosa using a histochemical technique in an effort to clarify the role of nitric oxide (NO) in the larynx. Many NADPH diaphorase-positive nerve fibres were distributed around the blood vessels and the laryngeal glands. The majority of neuronal cells in the intralaryngeal ganglia were NADPH-diaphorase-positive. It is likely that NADPH-diaphorase positive nerve fibres around the blood vessels and glands in the laryngeal mucosa originate from the intralaryngeal ganglia, and that NO regulates circulation and secretion in the larynx. PMID- 10095872 TI - Ultrastructure of the myelinated nerve fibers in the feline laryngeal mucosa. AB - We studied the myelinated sensory nerve fibers in the feline laryngeal mucosa. Myelinated afferent nerve fibers (A-delta type) present in the lamina propria showed deterioration of the myelin sheath and Schwann cells under the basement membrane. Axons penetrated the basement membrane and entered the intercellular space of the epithelium. Nerve endings with many mitochondria and small clear vesicles existed in the intercellular space. No synapse-like structure was found between the endings and the surrounding epithelial cells. It is likely that these endings act as mechanosensitive receptors that respond to water or chemical stimuli and that participate in eliciting swallowing, coughing, and bronchoconstriction. PMID- 10095873 TI - Morphological observation of laryngeal motoneurons by means of cholera toxin B subunit tracing technique. AB - Gross anatomical and histological studies and immunohistochemical demonstration of cholera toxin B subunit used as a retrograde tracer were performed to investigate distinct muscle fibre bundles (MFBs) in the feline intrinsic laryngeal muscles (ILMs) and to characterize the respective supplying motoneurons in the nucleus ambiguus (AM). Distinct bundles were observed in all ILMs except the lateral cricoarytenoid muscle. Motoneurons supplying MFBs related to phonation located more medially than others. Motoneuron size did not differ between distinct MFBs in the same muscle. Neurodendrites for the cricothyroid muscle (CT) and adductor motoneurons extended dorsomedially, ventrolaterally and ventromedially, while those for the posterior cricoarytenoid muscle (PCA) motoneurons stretched dorsomedially and ventrolaterally. We conclude that distinct MFBs in ILMs play different roles in laryngeal functions, and that corresponding motoneurons have their own specific visceroneural nature allowing regulation of complex laryngeal functions. To receive information from the central nervous system, laryngeal motoneuron dendrites extended to regions locating respiratory, phonatory and swallowing neurons. PMID- 10095874 TI - Plexiform schwannoma of the neck extending deeply to the mediastinum. AB - We describe a 42-year-old man who had tumors occupying the right deep neck through the upper part of the mediastinum. The right vocal cord was fixed and bulgings of the pharyngeal and tracheal wall were observed. At surgery, the masses were subtotally removed as much as possible. Histological examination revealed that they were schwannomas. The postoperative course was uneventful, except for the presence of hoarseness. PMID- 10095875 TI - Nitric oxide synthase and NADPH-diaphorase in neurons of the rat, dog and guinea pig nodose ganglia. AB - Localization of nitric oxide synthase (NOS) in the nodose ganglia of the dog, rat and guinea pig was investigated. A double-staining technique of NOS immunohistochemistry and NADPH-diaphorase (NADPHd) histochemistry was used; then the ratio of NADPHd-positive and NOS-positive cells to the total cells was calculated. The distribution of positive cells within the canine nodose ganglion was also investigated. NADPHd-positive neurons were detected in all the ganglia. Three intensities of reactivity to NADPHd histochemistry (strong, weak or negative) were detected in the neurons of all three species. There were more cells that stained strongly for NADPHd in the rat, but fewer in the dog and guinea pig, indicating that a species difference may exist. NADPHd-positive neurons were less abundant in the rostral third of the canine nodose ganglion than in the middle or caudal thirds. NADPHd reactivity was completely co localized to the cells that demonstrated neuronal NOS immunoreactivity in the canine nodose ganglion. Thus, NADPHd histochemical reactivity may be a reliable marker of NOS in the nodose ganglion. PMID- 10095876 TI - Langerhans cell histiocytosis. AB - Langerhans cell histiocytosis (LCH) is a rare clonal disorder that consists of single or multiple mass lesions composed of cells with an abnormal Langerhans cell phenotype. Its etiology remains unknown, despite extensive searches for evidence of consistent cytogenetic abnormalities, gene rearrangements, or viral genomes. Similarly, the pathogenesis of the disease is enigmatic, although the altered expression of cytokines and cellular adhesion molecules, important for migration and homing of the activated normal Langerhans cell, may play an important role. The biologic behavior of LCH ranges from spontaneous remission to lethal dissemination, and such behavior cannot be predicted on the basis of histologic features. The presence and degree of organ dysfunction, together with the patient's age at diagnosis, remain the most reliable indicators of prognosis. Treatment of severe, refractory disease continues to be controversial and, in many cases, ineffectual. The revised classification scheme for LCH and related disorders recognizes the uncertain biological potential of LCH and its relation to other processes of dendritic and macrophage origin. PMID- 10095877 TI - Atypical prostatic stromal lesions. AB - This commentary addresses the newly proposed classification of the rare atypical prostatic stromal lesions of the prostate. The entity called "prostatic stromal proliferation of uncertain malignant potential" apparently has a benign behavior. The entity "prostatic stromal sarcoma" might have a malignant potential, but its line of differentiation is still unclear. PMID- 10095878 TI - Microinvasive carcinoma of the breast: a diagnosis in search of a definition. AB - This commentary addresses the problems and lack of consensus with regard to the definition of microinvasive breast cancer; the problems in identification of stromal invasion in ductal carcinoma in situ; and the clinical significance of microinvasion. PMID- 10095879 TI - Mantle cell lymphoma. AB - Mantle cell lymphomas comprise 2 to 8% of non-Hodgkin's lymphoma in the United States. They occur in older adults with a distinct male predominance, who present with generalized lymphadenopathy, and often have disseminated disease at the time of diagnosis. Pathologically, mantle cell lymphomas are characterized by a proliferation of small lymphocytes, with irregular nuclei, clumped chromatin, and sparse cytoplasm that can grow in nodular or diffuse patterns in lymph nodes, that localize to the splenic white pulp and that produce interstitial, paratrabecular, and intertrabecular lymphoid aggregates in the bone marrow. Phenotypically, mantle cell lymphomas are B cell neoplasms that express pan B cell lineage antigens, CD5 and CD43, and that are negative for CD10 and CD23. On a genetic level, many cases of mantle cell lymphomas have the t(11;14)(q13;q32) that causes overexpression of cyclin-D1, a protein that can be demonstrated by immunohistochemistry in many examples of mantle cell lymphoma and that can be exploited diagnostically to distinguish mantle cell lymphomas from other low grade B cell lymphoproliferative disorders. The differential diagnosis of mantle cell lymphoma includes small B cell lymphoma, lymphoplasmacytic lymphoma, nodal, extranodal, and splenic marginal zone lymphomas, and follicular small cleaved cell lymphoma. In most instances, these disorders can be separated from one another by morphology, distinctive immunophenotypic profiles, and genetic features. PMID- 10095881 TI - [What indications for assessing acne in the man?]. PMID- 10095882 TI - [Treatment of bullous pemphigoid: general corticosteroid therapy or local corticosteroid therapy?]. PMID- 10095883 TI - [Prospective study of treatment of bullous pemphigoid by a class I topical corticosteroid]. AB - INTRODUCTION: The high mortality at 1 year of patients with bullous pemphigoid is considered to be due mainly to systemic corticosteroids. We report 20 cases of bullous pemphigoid treated solely with class I topical corticosteroid. PATIENTS AND METHODS: Twenty patients with bullous pemphigoid grade 1 and grade 2 were treated with clobetasol propionate 0.05 p. 100 cream at the initial dose of 12 mg/m2/day, progressively tapered over months. Severe forms of bullous pemphigoid covering more than 60 p. 100 of total body area were excluded. RESULTS: 35 p. 100 of the patients obtained a remission and 35 p. 100 healed (62.5 p. 100 of the mild forms, 16.7 p. 100 of the moderate forms). The average follow up was 11 months after the end of treatment. Side-effects were mild (cutaneous infections, dermal atrophy). Transitory biological anomalies were observed, mainly related to systemic absorption of clobetasol propionate. Some systemic adverse reactions were noted not necessarily attributed to treatment. DISCUSSION: Topical steroid treatment was efficient in patients with mild bullous pemphigoid. Our results were comparable to those reported in the literature except for some cutaneous side effects. PMID- 10095885 TI - [Classification and management of mastocytosis in the child]. AB - OBJECTIVE: Mastocytosis is a frequently observed condition in children. We analyzed the initial manifestations and clinical course. PATIENTS AND METHODS: We restrospectively studied 49 cases of mastocytosis in children (29 boys and 20 girls) managed in our unit between 1985 and 1995. All of the children had typical manifestations. Photographic documents were available in all cases. RESULTS: There was pigmentary urticaria in 32 cases and a mastocytoma in 17. Axanthelasmoid aspect and bullae were observed in some cases in both of these clinical forms. Complementary explorations demonstrated one case of duodenal mast cell infiltration. Excepting the case with skin and duodenal manifestation, all of our patients improved and clinical cure was obtained during growth. DISCUSSION: The association of dermal atopia and mastocytosis does not influence the clinical course of these two conditions. The development of bullae does not appear to be a factor of poor prognosis. The xanthelasmoid aspect of the lesions and the similar course in childhood mastocytosis and juvenile xanthogranulma would suggest that a common process with a histological spectrum including mastocytoma and xanthoma is involved. In our experience, counselling against the use of anti-cough medicines containing codeine is an essential part of management. Antihistamine agents may be prescribed for pruritus. PMID- 10095884 TI - [Acne in the male resistant to isotretinoin and responsibility of androgens: 9 cases, therapeutic implications]. AB - INTRODUCTION: Treatment failures with isotretinoin in female patients are frequently related to endocrinological dysfunctions. Such a concept has never been discussed in male patients. CASE REPORTS: An extensive endocrinological work up has been performed in nine male patients who presented with an acne refractory to conventional treatment and to isotretinoin. Adrenal dysfunction was found in four patients and isolated 5-alpha reductase hyperactivity in 2 cases. Three work ups were normal. A suppressive treatment in three patients with adrenal dysfunction provided immediate efficacy. COMMENTS: These results would provide insight into the mechanism of refractory acne in men. PMID- 10095886 TI - [Cutaneous-lymph node Kikuchi-Fujimoto disease]. AB - INTRODUCTION: The subacute necrotizing histiocytic lymphadenitis was reported for the first time in 1972 in Japan by Kikuchi and by Fujimoto and his colleagues. This idiopathic disease can affect the skin. We report a case of Kikuchi-Fujimoto disease with skin and lymph node involvement. OBSERVATION: The Yemani man developed cervical lymphadenitis and arciform papulo-nodular lesions of the face. The histologic examination revealed a necrotizing lymphadenitis with blast cells but devoid of neutrophils. The cutaneous involvement corresponded to an angiocentric infiltration by mononuclear cells among which plasmacytoid cells and caryorrhexis were recognized. A spontaneous resolution of the disease occurred spontaneously within three months. COMMENTARY: The clinical and histologic aspects of the present case resemble in part the presentation of lupus erythematosus. However, some distinctive features suggest Kikuchi-Fujimoto disease cannot be termed a classical type of lupus erythematosus. PMID- 10095888 TI - [Atrial myxoma: cutaneous manifestations]. AB - INTRODUCTION: Atrial myxomas may have variable misleading symptoms, explaining frequent delays in diagnosis. Multiple embolisms with irreversible consequences may occur. The dermatologist has a prominent role to play, as the clinical picture includes cutaneous signs. CASE REPORT: A 60 year old woman, with previous history of joint pain and Raynaud's phenomenon suffered a sudden neurological transitory ischemic event. The cutaneous manifestations associated left forearm erythematous macules, distal ischemia of the left fourth and fifth fingers and livedo of both lower limbs. Cardiac echography confirmed the clinical diagnosis of atrial myxoma. Surgical excision was followed by rapid and complete cure. DISCUSSION: Atrial myxoma is a rare benign tumor usually revealed by prominent cardiac and embolic manifestations. Systemic and cutaneous signs may however be the sole symptoms, warranting the dermatologist's attention. PMID- 10095887 TI - [Eosinophilic pustulosis in an infant accompanied by immune deficit]. AB - BACKGROUND: Eosinophilic is a skin eruption which occurs in the first years of life, progressing by pruriginous flare-ups with amicrobial papulopustulae on a hairless scalp. Eosinophil infiltration of the skin is variable (follicular or perifollicular dermal infiltration). In adults, eosinophilic pustulosis is often associated with immune deficiency, but this association has not been reported in children. We report two cases. CASE REPORTS: Two boys had a pruriginous papulopustular eruption involving the scalp and the trunk which had progressed with periods of exacerbation since birth. Search for bacteriological or mycological involvement was negative. Histology showed folliculitis with major polynuclear eosinophil infiltration. Both children had a past history of repeated skin and extracutaneous infections strongly suggesting an immune deficit. Buckly syndrome was suspected in the second case. DISCUSSION: Juvenile eosinophilic pustulosis belongs to the spectrum of childhood eosinophilic dermatoses. The presence of eosinophil infiltration in the skin demonstrates localized or systemic immune dysfunction. A hematology and immunology work-up is needed in case of associated skin or deep infections. PMID- 10095889 TI - [Extensive Mongolian spot related to Hurler disease]. AB - BACKGROUND: We report a case of a large blue mongolian spot which led to early diagnosis of Hurler's syndrome. This association is uncommon and should be recognized by dermatologists for early diagnosis and management. CASE REPORT: A male infant from Guinea, born to first-cousin parents, was seen at the age of 4.5 months for multiple, particularly extensive blue mongolian spots. Growth was +2 SD for age and the infant's psychomotor development was normal. A slight thickening of the skin was noticed without real dysmorphism. The blue spots extended over the entire posterior aspect and part of the anterior aspect of the trunk and involved all four limbs and the eyelids. The elbow and knee joints were moderately stiff and liver enlargement was palpated. The skin biopsy showed fusiform cells with melanin pigment tattooing the cytoplasm. No vacuolized epidermal cells were observed. Blood cell counts and liver and kidney tests were normal. Tests were positive for vacuolized lymphocytes and Gasser lymphocytes. Urine was positive for mucopolysaccharides and the enzymology study showed an alpha-L-iduronidase deficiency in serum and leukocytes, confirming the diagnosis of Hurler's disease. As no HLA compatible donor was available, no bone marrow graft was attempted. The child is a candidate for organoid gene therapy. DISCUSSION: Mongolian spots predominate in Asian, American Indian and black population (90% of the cases) compared with Caucasians (10%). The pathogenesis and pathogenic associations are unknown. The incidence of large widespread mongolian spots is also unknown and no precise criteria are available to define this entity. A few cases of extended mongolian spots associated with type 1 gangliosidosis and about 20 cases associated with Hurler's disease have been reported in the literature. The association with Hurler's disease is probably not fortuitous and several hypotheses have been put forward. Bone marrow transplantation can improve prognosis if performed early before onset of irreversible visceral disorders, emphasizing the importance of early diagnosis in children. PMID- 10095890 TI - [Toxic dermatitis caused by tramadol]. AB - BACKGROUND: Tramadol chlorhydrate (Topalgic) is a powerful analgesic recently introduced in France where its use has spread rapidly. We report a case where this drug induced a maculopapulous toxic skin reaction with secondary erythrodermia. CASE REPORT: A 47-year-old man was treated for lower back pain with tramadol chlorhydrate (50 mg b.i.d.). Otherwise, he was in good general health and was taking no other medications. Shortly after beginning the treatment, he developed a highly pruriginous maculopapulous eruption involving the entire skin surface, hyperthermia and general degradation. There was no skin exfoliation, mucosal involvement nor nodal enlargement. Tramadol was withdrawn and the patient was given corticosteroid therapy. Secondary erythrodermia developed after termination of the corticosteroids. The lesions regressed after tramadol withdrawal. DISCUSSION: Tramadol-induced skin reactions are uncommon and usually benign. In our case, the delay from onset of tramadol and the development of the maculopapulous eruption was very short (four days). The patient was taking no other medication. We hypothesize that the patient had been sensitized by cross reaction with another compound and recall the fundamental aspects of tramadol and opiate drugs. PMID- 10095891 TI - [Sporadic superficial pemphigus in the child: 2 cases]. AB - INTRODUCTION: Excepting the endemic foliaceus form, childhood pemphigus is uncommon. We report two cases of pemphigus foliaceus in children with typical clinical manifestations. CASE REPORTS: Case n(o) 1. A 5-year-old girl was seen for a vesiculobullous crusted dermatosis involving the trunk and the face which had developed over the last 5 months, predominantly in periorificial and fold localizations. Histology showed intragranulous acatholysis. Direct skin immunofluorescence was positive for anti-intercellular substance IgG and C3. Indirect immunofluorescence was positive for anti-intercellular substance antibodies at 1/500. The diagnosis of superficial pemphigus was retained and the child was given dapsone associated with systemic prednisone (1.5 then 2.5 mg/kg/d). Dapsone was stopped on day 15 due to poor hematological tolerance. Outcome was favorable allowing withdrawal of prednisone at 18 months. Case n(o) 2. A 6-year-old had developed since the age of 18 months a generalized and polycyclic pruriginous erythemato-squamous dermatosis with oozing discharge which started and predominated on the face (periorificial zones). Trace element (copper, selenium, zinc) and vitamin (A, E and B1) assays were within the normal range. Glucagon was normal. Histological examinations of several biopsies were non-contributive. Diagnosis of pemphigus foliaceus was finally obtained after repeated direct immunofluorescence tests which revealed anti-intercellular substance IgG. Indirect immunofluorescence was negative. The child was given prednisone (2 mg/kg/d). DISCUSSION: In children, pemphigus foliaceus has an exceptional frequency and diagnosis is often made quite late (mean 8 months). The diagnosis should always be entertained in children who develop chronic extensive erythemato-squamous and crusted dermatosis, even if formation is absent. Direct skin immunofluorescence confirms the diagnosis and should be repeated if negative in cases with highly suggestive clinical presentations. It would be reasonable to attempt "minor" treatments as the first line approach. Systemic corticosteroids are however the treatment of choice despite the risk of classical side effects. Childhood pemphigus foliaceus is not an attenuated clinical form of adult pemphigus. Mortality is not negligible and is close to that in adults. PMID- 10095892 TI - [Secondary longitudinal melanonychia secondary to onychophagia]. AB - BACKGROUND: Melanonychia of the toenails sometimes results from repeated trauma. This etiology is rarely put forward in lesions affecting the fingernails. CASE REPORT: A 44-year-old woman developed melanonychia affecting 9 fingernails. Genetic predisposition and drug, hormonal or infectious causes were ruled out and we postulated that the lesions were induced by nail biting. DISCUSSION: Nail biting is known to lead to several types of lesions, including melanonychia. The lesions may sometimes disappear several months after stopping this habit. PMID- 10095893 TI - [Lyell syndrome and Stevens-Johnson syndrome caused by lamotrigine]. AB - BACKGROUND: Lamotrigine is a new anticonvulsant belonging to the triazine family. Several cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been described in patients taking this drug. We report 2 cases in children attending the same hospital. CASE REPORTS: Two children, aged 9 and 13 years, developed SJS and TEN respectively, 3 and 28 days after lamotrigine was added to their usual anticonvulsant regimen. In both cases, outcome was favorable despite major decline in psychomotor capacity in one. In the first case, chronological attributability was plausible for lamotrigine and doubtful for sodium valproate, clonazepam and hydrocortisone. In the second case, chronological attributability was probable for amoxicillin, plausible for lamotrigine and doubtful for sodium valproate, but the numerous previous absorptions of amoxicillin made lamotrigine more suspect. DISCUSSION: The risk of Steven-Johnson syndrome and toxic epidermal necrolysis is high with lamotrigine with an estimated frequency of 1/1000. This risk is probably higher than with other anticonvulsants. Associating lamotrigine with sodium valproate increases the frequency of adverse skin reactions. PMID- 10095894 TI - [Bejel: an unusual cause of stomatitis in the child]. AB - INTRODUCTION: Bejel (endemic syphilis) is usually encountered in children living in intertropical areas, although imported cases have been exceptionally reported in Europe. OBSERVATION: We report on a young girl aged 5 diagnosed in France, who had painless stomatitis and enlarged cervical nodes. Diagnosis of bejel was confirmed by serology, and spirochetes were shown inside mucous patches by biopsy specimen silver staining. Favorable clinical and serological outcome occurred following benzathin-penicillin therapy. Contamination is likely to have occurred in Mali where she had been living for several years, but secondary stage manifestations only appeared in France, where she was living for several months. DISCUSSION: Although rare in France, bejel should not be overlooked in children originating from countries where endemic syphilis has a high prevalence. PMID- 10095896 TI - [Familial chronic mucocutaneous candidiasis associated with autoimmune polyendocrinopathy. Treatment with fluconazole: 3 cases]. AB - BACKGROUND: Familial candidiasis endocrinopathy is a hereditary disease variably associated with i) a dysfunction of the parthyroid, adrenal, thyroid, pituitary or ovarian glands as well as the pancreas (diabetes), liver (hepatitis) and gastric wall cells (Biermer's disease); ii) chronic mucocutaneous candidiasis; iii) autoimmune manifestations: chronic keratitis, pelade, vitiligo, hemolytic anemia. CASE REPORTS: We cared for three pediatric patients with chronic mucocutaneous candidiasis associated with an autoimmune polyendocrinopathy. There was a familial context in all cases with an autosomal dominant inheritance in the first case and an autosomal recessive inheritance in the two others who were siblings. In all three cases, the chronic mucocutaneous candidiasis began before the age of 5 years and had preceded the development of the endocrinopathy. Fluconazole was effective in all three cases. DISCUSSION: Chronic mucocutaneous candidiasis may appear as the inaugural symptom of an autoimmune polyendocrinopathy and should lead to a familial study with an andocrinology work up to determine any clinical manifestations and biological evidence of autoimmunity. Fluconazole does not have marketing approval for children, but provides good control of the fungal infection, particularly in the ungueal localization, and is well tolerated. PMID- 10095895 TI - [Eczema-like cutaneous graft versus host disease treated by UV-B therapy in a 2 year-old child]. AB - INTRODUCTION: Chronic graft versus host disease (GVHD) has rarely been reported in children. Optimal treatment should minimize infectious complications and preserve the child's growth. We report a case of cutaneous GVHD in a two year-old boy, who presented an eczema-like eruption and responded well to broad band UV-B therapy. CASE REPORT: A two year-old boy with acute myeloblastic leukemia had a heterologous bone marrow transplantation with a graft issued from an unrelated female donor. Three month later, he developed eczema-like lesions of the trunk, arms and legs associated with diffuse alopecia, despite oral corticosteroids and cyclosporine treatment. Histologic findings were consistent with GVHD. Topical corticosteroids and broad band UV-B therapy were initiated, while oral corticosteroids and cyclosporine doses were tappered off. GVHD lesions cleared, allowing withdrawal of oral corticosteroids and cyclosporine 3 and 12 months respectively after initiation of UV-B therapy. No relapse occurred 24 months after systemic treatment discontinuation and 12 months after broad band UV-B therapy was stopped. CONCLUSION: This observation suggests that broad band UV-B therapy is an effective treatment for eczema-like, cutaneous GVHD. PMID- 10095897 TI - [Protein S 100 is not a chemical reactant]. PMID- 10095899 TI - [Diagnostic case. Trichilemmal cyst]. PMID- 10095898 TI - [Risk of flammable gas from aerosol sprays]. PMID- 10095900 TI - [Diagnostic case. Anaplastic cutaneous lymphoma]. PMID- 10095901 TI - [A new technique for study of cutaneous biology, microdialysis]. PMID- 10095902 TI - [Hydrocolloid dressings]. PMID- 10095903 TI - [Aquagenic pruritus]. PMID- 10095904 TI - [Terbinafine]. PMID- 10095905 TI - [Management of ulcerated graft in patients with joint prosthesis]. PMID- 10095906 TI - [Pheochromocytoma. Report of 10 cases]. AB - We report 10 cases of adrenal pheochromocytoma seen over a period 15-years. A female predominance was noted (8 women/2 men). Patients were aged between 16-46 years with a mean of 34 years. Clinical manifestations consisted of hypertension observed in all cases, with vasomotor symptoms (90%). Time to consultation was prolonged (mean: 23 months). CT scan performed in 7 cases showed pheochromocytoma in all cases, located on the right side in 6 cases, while one pheochromocytoma was located in Zukerkandal organ. All patients were operated via anterior approach and adrenalectomy was performed. A favourable course was observed in 90% of cases with normalisation blood pressure. One death was noted. Histological examination showed no malignancy in all cases. PMID- 10095907 TI - [Adrenal gland pheochromocytoma. Report of 26 cases]. AB - The authors analyse of a series of 26 patients (17 females and 9 males) with a mean age of 32 years (range: 18 to 55 years) operated for adrenal phaeochromocytoma. All patients were hypertensive. The laboratory assessment (assay of blood catecholamines and urinary catecholamine metabolites) performed in more than 2/3 of cases confirmed the diagnosis in more than 80% of cases. The topographic diagnosis was facilitated by computed tomography. Fifteen patients received preoperative treatment with alpha-blockers or calcium channel blockers. Various incisions were used, but a lumbar incision was the most frequent. Blood pressure was controlled postoperatively in 24 patients. Two patients died 1 and 2 postoperatively. New diagnostic modalities (CT, MRI) have facilitated the diagnosis and the site of localization of phaeochromocytomas, thereby improving the choice of incision. Patient-specific preoperative preparation and appropriate anaesthesia facilitate successful adrenal gland surgery. PMID- 10095908 TI - [Double hemorrhagic complication of endo-urologic drainage in single kidney]. AB - Hemorrhage is the most worrisome complication of percutaneous renal procedures, and usually occurs early in the postoperative period. The incidence of severe arterial injury is 1 to 2%. We report a patient who had 2 bleeding episodes on a solitary kidney. The first, which occurred early after the procedure, was due to an arteriocaliceal fistula treated by coil embolization. The second bleeding episode occurred two weeks later, and was caused by erosion of a lumbar artery; it was embolized by microparticles. To our knowledge, this is the first report of the imaging findings. In summary, when bleeding occurs after endourologic procedures, renal as well as extrarenal parietal causes should be investigated. PMID- 10095909 TI - [Hydatid cyst of the kidney. Report of 45 cases]. AB - The kidney is a rare site of hydatid disease. It remains clinically silent for a long time and only presents at the stage of complications. The diagnosis is essentially radiological. Renal hydatid cyst (RHC) raises therapeutic problems due to its complications, which sometimes make kidney-preserving cyst resection surgery difficult. The authors report a series of 45 cases of RHC treated in their department during a 20-year period. This series consisted of 27 men and 18 women with a mean age of 47 years (26-80 years). The clinical features were dominated by pain (80%), flank mass (42%), hydaturia (22%), haematuria (13%), urinary tract infection (6%), hypertension (3%). IVU, performed in all patients, showed calcifications in 35% of cases, renal tumour syndrome in 71% of cases and silent kidney in 22% of cases. Surgery was usually performed via a lumbar incision (75%) or a BARAYA incision (15%). Treatment consisted of 18 cyst roof resections (40%), 6 pericystectomies (13%), partial nephrectomy in 2 cases (4%) and total nephrectomy in 18 cases (40%). The postoperative course was marked by urinary fistula in two patients and one death at the 2nd postoperative month related to associated renal sarcoma. The objective of this study is to analyse the epidemiological, pathological and therapeutic features of this disease, which still constitutes a public health problem in Morocco. PMID- 10095910 TI - [Diagnostic and therapeutic problems of an atypical cyst of the kidney]. AB - Atypical renal cyst raises diagnostic and therapeutic problems. The authors report a case of atypical renal cyst which raised numerous diagnostic and therapeutic problems. The authors discuss theses problems in the light of this case. A farmer consulted for right lumbar pain without hematuria and hydaturia. Hydatic serology was negative. Ultrasonography and CT scan showed atypical cyst in favour of hydatic cyst. Surgical investigations showed a necrotico-hemorragic cyst, and cystectomy was performed. Histological examination revealed a chronic inflammatory process without malignancy. One year after the operation, clinical and radiological examination were normal. PMID- 10095911 TI - [Peritonitis caused by spontaneous rupture of pyonephrosis in pregnancy. Report of a case]. AB - Peritonitis after spontaneous rupture of pyonephrosis into the peritoneal cavity is a rare complication, usually diagnosed intraoperatively. We report a case of a woman presenting with left lumbar pain and fever during pregnancy. On admission, ultrasonography showed a pregnancy with fetal activity for 16 weeks, and pyonephrosis in the left kidney, but on a normal right kidney. After antibiotic therapy and upper urinary, tract stenting renal drainage revealed purulent urine, fever persisted with acute abdomen. Clinical and radiological assessment showed features of acute peritonitis with pyonephrosis. Treatment consisted of laparotomy with nephrectomy and abdominal lavage and drainage. The postoperative complication was septic shock requiring resuscitation and artificial ventilation and prolonged convalescence. PMID- 10095912 TI - [Bilateral Wilm's tumor in the fetus]. AB - The author reports a case of Wilms' tumor in a stillborn fetus and emphasizes the extreme rarity of this diagnosis in fetus and at birth despite monitoring pregnancy frequent sonography. There is no report of in utero ultrasound diagnosis of Wilms' tumor. Wilms' tumor develops from nephrogenic blastema rests which usually disappear after 34 weeks of gestation. Pediatric autopsies show that blastematous foci may persist after birth without necessarily forming nephroblastomas. Their frequency is one hundred times higher than that of nephroblastomas although they are often associated. Wilms' tumors are hereditary and more frequent in patients with congenital malformations related to genetic disorders. Because of therapeutic progress the diagnosis should be made very early particularly in high risk patients using sonography during pregnancy despite problems of interpretation and soon after birth. PMID- 10095913 TI - [Multifocal tubulopapillary tumors of the kidney. Morphologic features and prognosis. Three cases]. AB - Tubulopapillary tumors of the kidney represent a particular group of renal tumors characterized by their less aggressive behavior. These tumors are distinguished from non papillary tumors by their morphologic, cytochemical and genotypic features. They correspond to a continuous spectrum of tumors ranging from papillary renal cell adenoma to papillary renal cell carcinoma. These TTPR show multifocal, bilateral development and chronic lesions of the kidney parenchyma in nearly all cases. The authors report three cases of multifocal TTPR, including one bilateral case. Based on analysis of these cases and a review of the literature, they discuss the histogenetic features and prognosis of TTPR. PMID- 10095914 TI - [Epilepsy disclosing cancer of the kidney]. AB - Cerebral metastases of renal cell carcinoma are not rare, but metastasis which reveal the primary tumor are uncommon. The authors report a case of a 53-year-old woman who presented with renal cell carcinoma revealed by epileptic fit. PMID- 10095915 TI - [Thyroid cancer metastasizing to the kidney. Report of a case]. AB - The authors report a case of renal metastasis from a thyroid adenocarcinoma in a 56-year-old man, occurring 3 years after isthmolobectomy for papillary thyroid carcinoma. He predominant clinical symptoms were low back pain, haematuria and deterioration of the general state. Ultrasonography showed a hypoechoic left renal mass, 56 mm in diameter, with a thickened wall. Renal CT showed a homogeneous low-density formation with a thickened wall in the left kidney. Iodine 131 whole body scan showed increased uptake in the left kidney. The patient wes treated surgically via a subcostal incision. The surgical procedure consisted of radical nephrectomy. Macroscopic examination of the lesion showed a cystic mass. Histological examination of the mass revealed a renal metastasis from moderately differentiated thyroid adenocarcinoma. PMID- 10095916 TI - [What is the future of antibacterial therapy?]. PMID- 10095917 TI - [Effect of calcium gluconate on the toxicity and antitumor of doxorubicin in mice]. AB - The effect of calcium gluconate on the toxicity and specific activity of the anthracycline antibiotic doxorubicin was studied on mice with transplanted hemoblastosis La or plasmocytoma MOPS-406. In both cases after the animal exposure to nontoxic therapeutic doses of doxorubicin no influence of calcium gluconate on the antibiotic antitumor activity was observed. When doxorubicin was used in toxic (and even lethal) doses the antitoxic effect of calcium gluconate and an increase of the antibiotic therapeutic activity were stated. The combination of calcium gluconate and doxorubicin made it possible to significantly increase the maximum therapeutic effect of doxorubicin (higher levels of the animal survival and some cures) and to widen the ranges of the drug therapeutic doses at the account of decreasing the toxicity of the antibiotic and increasing its dose. The results suggested that the antitoxic modifier calcium gluconate could be used for increasing anticancer efficacy of doxorubicin which is given now at the total dose limit of 550 mg/m2 even in cases with preserved tumor sensitivity to the drug. PMID- 10095918 TI - [Mycelial waste of tetracycline production as a component of the nutrient medium]. AB - A new composition of the nutrient medium for cultivation of the tetracycline producing organism was developed with the fermentative hydrolysate of the tetracycline production mycelial waste as a source of nitrogen: 0.02 to 0.04 g/l by amino nitrogen. The use of the medium made it possible to increase the tetracycline yield by 5 to 25 per cent, to exclude cornsteep liquor from the medium composition, to provide a more efficient recovery of the waste and to significantly decrease the environment pollution. PMID- 10095919 TI - [Etiology and treatment of pneumonia in children]. AB - The most widespread pathogens of pneumonia in children i.e. Streptococcus pneumoniae and Haemophilus influenzae and their antibiotic susceptibility are described. The ways of selecting starting antibacterial drugs for the treatment of community-acquired and hospital pneumonia are recommended proceeding from the original findings and some literature data. Oral drugs for the treatment of uncomplicated pneumonia are shown to be preferential. In the treatment of nosocomial or hospital pneumonia the starting regimen should allow for the previous antibacterial therapy. PMID- 10095920 TI - [Use of pefloxacin in the treatment of patients with purulent wounds of soft tissues]. AB - Pefloxacin was used in the treatment of 25 patients with wound infection in a dose of 400 mg orally twice a day for 10-12 days. As the monotherapy it was applied to 15 patients. 7 patients with clinical signs of non-clostridial anaerobic infection were treated with pefloxacin in combination with intravenous metronidazole. Pefloxacin was highly efficient in 96 per cent of the cases with extensive posttraumatic purulent wounds with and without bone affection, acute purulent wounds of the soft tissue, purulent wounds of the soft tissues in diabetic patients, trophic or decubitus ulcer. 266 clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Proteus mirabilis, Enterobacter spp. and Acinetobacter spp, were tested and 75 to 100 per cent of them was shown to be susceptible to pefloxacin and ciprofloxacin. At the same time the isolates of Pseudomonas aeruginosa and Klebsiella spp. were more susceptible to ciprofloxacin. The pathogen eradication and eradication with superinfection in the cases treated with pefloxacin amounted to 92 per cent. The drug tolerance was good. No clinically significant adverse events were recorded. PMID- 10095922 TI - [Pharmacotherapy of eye infection]. PMID- 10095921 TI - [Effectiveness of acipole in prevention of enteric dysbacteriosis due to antibacterial therapy]. AB - Acipole (Lactobacillus acidophilus + Kefir greins) was used to manage antibiotic dysbacteriosis as an adverse reaction of antibacterial therapy. 120 patients treated with antibacterial drugs for acute pneumonia and exacerbations of chronic bronchitis were observed. 54 of them were treated under the routine regimen with antibiotics and 66 were additionally treated with the eubiotic acipole: 1 tablet (5 doses) 3 times a day 30 minutes before meal. Routine bacteriological examination of the feces was applied to all the patients. High frequency of bacteriologically revealed dysbacteriosis was stated. The therapy under the antibiotic + acipole regimen lowered the frequency of dysbacteriosis events and their severity. The fact that the use of acipole simultaneously with the routine antibacterial therapy prevented the development of dysbacteriosis clinical signs is of practical importance. PMID- 10095923 TI - [Regulation of immune processes by peptides of natural origin]. PMID- 10095924 TI - [Progress in the chemotherapy of HIV-infection and AIDS (according to the materials of the Symposium "Highly Active Antiretrovirus Therapy")]. PMID- 10095925 TI - [Contribution of S.A. Waksman to development of science on antibiotics (Semicentennial Jubilee of the Russian Translation of the Book by S.A. Waksman "Microbial Antagonism and Antibiotic Substances")]. PMID- 10095926 TI - In vivo and in vitro studies on the antitumor activities of MCP (Malva crispa L. Powder). AB - Four short-term in vivo and in vitro tests were used to further confirm the antitumor activities of MCP, a vegetable powder, prepared from Malva crispa L. (i) In the H22 hepatoma-transplanting test, MCP had antitumor action, but MCP residue did not show such action; 5-FU appeared to have more potent antitumor activities and more harmful effects than MCP. (ii) In the micronucleus (MN) test, MCP significantly decreased MN frequency. (iii) In the cancer cell culture systems, the MCP fat-soluble extract revealed inhibitory effects on the growth and proliferation of the human hepatoma and the gastric cancer cells in a dose response manner. (iv) In the colony formation test, MCP also altered the morphology of human gastric cancer cells. It was suggested that MCP could be consumed not only by healthy subjects for cancer prevention but also by patients with cancer as supplementary treatment in combination with anticarcinogenic drug such as 5-FU, cyclophosphamide (CP). PMID- 10095927 TI - Chemopreventive effects of black tea polyphenols in mouse skin model of carcinogenesis. AB - In the present investigations, the antitumorigenic effect of black tea polyphenols (BTP) in two-stage mouse skin model of carcinogenesis was studied. The animals were initiated with a single "subcarcinogenic" topical dose (52 micrograms/200 microliters acetone) of 7, 12-dimethylbenzanthracene (DMBA). To evaluate the anti-tumour initiating activity, BTP was topically applied twice a week for three weeks prior to DMBA application, followed by topical treatment with 12-o-tetradecanoyl phorbol-13-acetate (TPA) (5 micrograms/200 microliters acetone, 2x/wk.) as promoter. For evaluation of antitumor promoting activity, BTP was applied prior to each treatment of TPA. BTP application showed marked inhibitory effect as antitumour initiator as well as antitumour promoter in mouse skin model of two-stage carcinogenesis. Since initiation involves genetic pathway and tumour promotion involves epigenetic pathway, it seems that BTP exerts its antitumorigenic effect by altering both genetic and epigenetic pathways. PMID- 10095928 TI - The carriage of Escherichia coli resistant to antibiotics in healthy populations in Shanghai. AB - Healthy populations represent the largest reservoir of bacteria resistant to antibiotics. We investigated the resistance of Escherichia coli to 12 antibiotics in fecal samples from untreated healthy populations in Shanghai, China by using Kirby-Bauer (K-B) method. The results showed that: (i) All subjects carried resistant strains of Escherichia coli. (ii) The carriage rates of Escherichia coli resistant to various antibiotics were different, less than 10% to amikacin and 30% to 100% to others. (iii) In the elder children group aged 10-11 years, the percentages of strains resistant to gentamicin, streptomycin, chloramphenicol, tetracycline, trimethoprim, and sulfamethoxazole were significantly lower than those in the younger group aged 5-6 years. In the adult group, the percentages of strains resistant to ampicillin, piperacillin, amikacin, streptomycin, chloramphenicol, tetracycline, trimethoprim, and sulfamethoxazole were significantly lower than those in the elder children group. (iv) The number of strains resistant to five or more antibiotics accounted for 31.8% in the younger children group, 23.7% in the elder children group, and 12.1% in the adult group. These findings suggest that all healthy people in Shanghai carry resistant strains of Escherichia coli in the intestine. The younger the populations, the higher the level of resistance of fecal Escherichia coli to antibiotics. Improvement of health behaviors and environmental sanitation and rational use of antibiotics could remarkedly decrease the resistant level of bacteria. PMID- 10095930 TI - Competing risk model and its application in assessing the progression of pneumoconiosis. AB - In this paper a more general competing risk model is developed for dealing with censored data with multiple outcomes, as the result of the competition with other risk factors. More reasonable results are obtained by applying the model in the probability and the average duration of pneumoconiosis progress from stage I to stage II in Shanxi Province. PMID- 10095929 TI - The antagonistic effects of L-dopa and eserine on Al-induced neurobehavioral deficits in rats. AB - The main goals of the study were to elucidate the mechanism of Al-induced behavioral toxicity and to explore the possible link between the changes in the metabolism of monoaminergic or cholinergic transmitters and neurobehavioral effects. Three groups (12 rats in each group) were fed with aluminum chloride in drinking water (1600 mg/l) ad libitum through a 90-day exposure period. The controls were fed with distilled water. From the 60th to 90th day of treatment, two of the three Al-treated groups were administered with L-dopa (220 mg/kg.bw) and eserine (0.4 mg/kg.bw) by gavage, respectively. A two-item neurobehavioral test battery consisting of step down test and Morris water maze task was used for rats after three months treatment. In the step-down test, markedly shortened the step-down latency (SDL) and the number of step-down (NSD) were observed in the Al treated group (P < 0.05, vs. control). On the contrary, only slight changes were found in the rats treated with aluminum combined with L-dopa or eserine (P > 0.05, vs control). In eserine and L-dopa antagonized groups, the mean escape latencies of Morris water maze approached a level close to that of the controls (P > 0.05). The results showed that the Al-induced memory and learning impairment could be reduced by L-dopa or eserine. It is suggested that the depletion of dopaminergic and cholinergic transmitters in the central nervous system might play an important role in Al-induced neurotoxicity. PMID- 10095931 TI - Production and characterization of monoclonal antibodies against fumitremorgin B. AB - This paper reports the preparation and identification of two monoclonal antibodies against FTB, and the establishment of an indirect competitive ELISA methods for FTB determination in buckwheat, rice, and corn. Two of the hybridoma cell lines (1C9 and 2D10), which could produce specific antibodies against fumitremorgin B(FTB), were selected and developed. The affinity Kaff constants of the monoclonal antibodies with the coating antigen, FTBS-IgG, were found to be 6 x 10(8) M-1 and 9.8 x 10 M-1, respectively. The isotypes of the monoclonal antibodies are of two isotypes, IgG1 and IgM, respectively. The antibody titers were found around 1 x 10(6) and 1.5 x 10(6). The standard curves showed that as little as 5 pg of FTB in 50 mL could be detected, and the linear range of standard curve was from 10 pg to 1000 pg of standard FTB. There were no cross reaction for McAbs in the assay system with some mycotoxins tested. The mean recovery rate from buckwheat spiked with 10-60 ng/g of FTB was 78-88.7%. PMID- 10095932 TI - Role of dNTPs in mutagenesis. AB - The induced mutation frequency by alkylating mutagen glycidyl methacrylate (GMA) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated with or without perturbation of deoxyribonucleoside triphosphate (dNTP) pools; the influence of short treatment at different concentrations of GMA or MNNG on dNTP pools was also explored. The results indicated that the induced mutation frequency increased greatly at high dosages of mutagen (GMA approximately 64 micrograms/ml, MNNG approximately 8 micrograms/ml) and the perturbation on dNTP pools was carried out before the treatment of mutagen; the short treatment with mutagen could induce distinct fluctuations of dNTP pools, but different mutagen might have different effects on dNTP pools. According to the results of the present study and other reports in literature, we conclude that dNTP pools may be the targets of alkylating mutagens and the fluctuations of dNTP pools are closely associated with mutagenesis. PMID- 10095933 TI - Role of deoxyribonucleoside triphosphates (dNTPs) in cell transformation. AB - Deoxyribonucleoside triphosphate (dNTP) pools were measured in normal BALB/c3T3 cells, transformation-treated cells and transformed cells with reverse-phase HPLC. The fluctuation of dNTP pools was similar after transformation treatment with alkylating mutagen glycidyl methacrylate (GMA) or Nmethyl-N'-nitro-N nitrosoguanidine (MNNG). However, the gap between deoxyguanosine triphosphate + deoxyadenosine triphosphate (dGTP + dATP) pools and deoxythymidine triphosphate + deoxycytidine triphosphate (dTTP + dCTP) pools was greatly intensified. The measurements also indicated that the dNTP pools in transformed cells were quite different from those in normal cells. The results suggested that dNTP pools may play an important role in cell transformation. PMID- 10095934 TI - Protective efficacy of calcium channel blockers in sulphur mustard poisoning. AB - The present study was designed to ascertain the in vivo protective efficacy of Ca(2+)-channel blockers against dermally applied sulphur mustard (SM). Male albino mice were exposed to 1.5 LD50 of SM (232 mg/kg) percutaneously and the control group received an equal volume of vehicle (polyethylene glycol 300). Prior to SM application, the animals were administered nifedipine and dextrose saline containing antibiotic by intraperitoneal route. The protection assessed by the mean survival time (MST) was determined by Dunnett's method. The MST was significantly increased in nifedipine treated group. The characteristic biochemical indices of SM intoxication, i.e. lipid peroxidation and reduced glutathione (GSH) were determined in liver from animals sacrificed at 24, 48 and 72 h after exposure. SM application (1 LD50) caused a reduction in GSH level which was restored in nifedipine treated group. SM-induced lipid peroxidation was also prevented by nifedipine administration. The protective effect of nifedipine may be related to its capacity of attenuating SM-induced lipid peroxidation and glutathione depletion. PMID- 10095935 TI - [Paraventriculovagal path of carbohydrate homeostasis regulation--a perspective biological model in studies on neuroimmunoendocrine interactions]. PMID- 10095936 TI - [Involvement of tactile receptors of the tongue in speech sound formation in children during the first year of life]. PMID- 10095937 TI - [Skin glycosaminoglycans during emotional stress]. PMID- 10095938 TI - [Effects of SOD and NO donor on disturbances of the cardiac rhythm caused by reperfusion in rats]. PMID- 10095939 TI - [Effects leu-enkephalin and dalargin on the cardiac activity in rats during stimulation of postganglionic sympathetic fibers with low frequency impulses]. PMID- 10095940 TI - [Dynamics of respiration enzyme activity in neurons of isolated and symmetrical neocortex regions]. PMID- 10095941 TI - [Reasoning in favor of changes in classification of the hypoxic conditions]. PMID- 10095943 TI - [The role of cytoplasmic factors in stabilization of Ca2+-transporting function of the myocardial sarcoplasmic reticulum during stress adaptation in rats]. PMID- 10095942 TI - [Adaptive potential of granulocytic stem cells in the bone marrow from preleukemic AKR mice]. PMID- 10095944 TI - [L-Arginine effects during central spinal pain syndrome]. PMID- 10095945 TI - [The role of delta-opioid receptors in development of cardiac ischemic arrhythmia]. PMID- 10095946 TI - [Opiatergic mechanisms of cardioprotective and anti-arrhythmic effects of adaptation]. PMID- 10095947 TI - [Histochemical characteristics of lymphoid organs in rats subjected to stress]. PMID- 10095948 TI - [Analysis of anti-arrhythmic effect of allapinin during neurogenic atrial fibrillation]. PMID- 10095950 TI - [Cytochemical brain characteristics of rejecting alcohol Wistar rats with various learning ability]. PMID- 10095949 TI - [Study of the role of intracellular Ca2+ pool in the relaxation effect of sodium nitroprusside in smooth muscle cells of the rat aorta]. PMID- 10095951 TI - [Tap water magnesium deficiency modulate arterial blood pressure, Ca and Mg tissue distribution, and compartmentation of membrane-bound calcium in thrombocytes of normotensive WKY rats]. PMID- 10095952 TI - [Hematopoietic microenvironment transfer units and inducible progenitors of hematopoietic stroma in the bone marrow of thymectomized mice]. PMID- 10095953 TI - [Fetal plasma contains blood coagulation factor XIIIa inhibitor which is not found in normal human plasma]. PMID- 10095954 TI - [Inhibition of the antioxidant protection, microsomal oxidation, and xenobiotic glucuroconjugation in rats with cholestasis and their regulation]. PMID- 10095955 TI - [Effect of colostrum factor on the structure and functional activity of rat liver nuclei late after gamma-irradiation]. PMID- 10095956 TI - [Effect of the new 9-aminoacridine derivative on the working and long-term memory in rats]. PMID- 10095957 TI - [Melatonin as geroprotector: experiments with Drosophila melanogaster]. PMID- 10095958 TI - [Study on the cleavage rate of diadenosine polyphosphates by various tissues from the guinea pig]. PMID- 10095959 TI - [Anxiolytic effect of dalargin on rat behavior in the Vogel conflict test and the raised cross-like labyrinth]. PMID- 10095960 TI - [Comparative assessment of acute toxicity of anti-arrhythmia agents containing amino acids]. PMID- 10095961 TI - [Effects of media conditioned with bone marrow cells on proliferation of stromal clonogenic cells in vitro]. PMID- 10095962 TI - [Prophylaxis of the experimental pseudotuberculosis infection by immunization with porin from Yersinia pseudotuberculosis]. PMID- 10095963 TI - [Effects of 5-HT1a serotonin receptor agonists on sex motivation in male mice]. PMID- 10095964 TI - [Interaction of natural autoantibodies to human ovarian tumor associated antigen with ovarian cancer cells from CaO-1 mice]. PMID- 10095965 TI - [Insulin-binding activity of lymphocytes bearing Fcgamma-receptors in pregnant women with diabetes mellitus]. PMID- 10095966 TI - [Grounds for use of lactobacterin from Lactobacillus fermentum 90-TS-4 in gynecological practice]. PMID- 10095967 TI - [Heat shock pre-conditioning prevents disruption of actin cytoskeleton of endothelial cells due to ATP depletion: the role for heat shock protein HSP27]. PMID- 10095968 TI - Research, introduction, and use: advancing from Norplant. AB - As the first real contraceptive innovation in over 20 years, and as a long-acting method requiring clinical intervention for insertion and removal, Norplant raised an especially wide range of issues. It also encountered a number of difficulties. In April 1997, an Institute of Medicine (IOM) workshop on implant contraceptives reviewed newly available data on Norplant's efficacy, safety, and use; considered lessons learned from the method's development, introduction, and market experience; and explored approaches based on those lessons that could improve the environment for contraceptive research and development and make market entry for new contraceptive technologies less troubled. In addition to presenting the IOM workshop findings, the present article calls attention to the rich scientific prospects available for development of the next generation of contraceptives, and notes signs of an evolving new paradigm, essential if those prospects are to be realized to any significant extent. PMID- 10095969 TI - Oral contraceptives and colorectal tumors. A review of epidemiologic studies. AB - Over the last two decades, the mortality rates of colorectal cancer in many developed countries have declined in women but not in men. One of the explanations of this difference between the genders may be the favorable influence of the spread of exogenous female hormone use (i.e., oral contraceptives [OC] and hormone replacement therapy) Reduced risk in ever-users of OC was found in three of four cohort studies available on this topic, and was significant in the one based on colorectal cancer mortality. The fourth one showed no difference. Of 11 case-control studies (or groups of studies), none showed significantly elevated risk. Five reported lowered colorectal cancer risk among ever-users, with a significant inverse association in the largest investigation available. Recent OC use, more than long duration use, seemed to be related to some risk reduction. One cohort study and three case-control investigations suggested that OC use was not related to the risk of colorectal adenomatous polyps. Thus, at present, it seems that OC use does not increase and may even have a favorable effect on either incidence or mortality of colorectal cancer. PMID- 10095970 TI - Weight change with oral contraceptive use and during the menstrual cycle. Results of daily measurements. AB - Although weight gain is among the most common complaints of women using oral contraceptives (OC) and a frequent reason for discontinuation, studies demonstrate little basis for this perception. We explored this issue by analyzing the daily weights of 128 women during four cycles of triphasic OC use. The mean weight at the end of the fourth cycle of use was the same as baseline weight (average weight change, 0.0 pounds). The largest proportion of women, 52%, remained within 2 pounds (0.9 kg) of their starting weight, and 72% of women had either no weight change or a loss. Over each menstrual cycle, regular but minor weight shifts were observed, with the mean weight rising by one-half pound (0.2 kg) during the first weeks of each cycle and falling by the same amount during the last few days. These results emphasize the lack of association of OC use with weight gain but OC may be blamed at least in part, based on cyclic fluctuations. Counseling should emphasize weight gain as a misperception and stress the fact that a highly effective and safe form of contraception should not be ruled out or discontinued because of concern about weight. PMID- 10095971 TI - Bone density among long-term users of medroxyprogesterone acetate as a contraceptive. AB - The bone density (BD) of 72 women using depot-medroxyprogesterone acetate (DMPA) for at least 1 year was compared with that of 64 women who were not users of hormonal contraceptives. The BD of lumbar spine, femoral neck, Ward's triangle, and trochanter was measured by dual energy X-ray absorptiometry (DEXA-LUNAR DPX). Estradiol (E2) concentrations were measured by radioimmunoassay (RIA). The mean age of DMPA users and nonusers was 31.8 and 31.1 years, respectively. Mean E, was 55.7 pg/mL for users and 149.9 pg/mL for controls (p < 0.001). The BD was significantly lower for DMPA users than for controls in all sites (p < 0.01). In addition, young adult T-scores in the lumbar spine were significantly lower among DMPA users than in controls (p < 0.01). Differences were maintained in a subsample of 47 women per group paired by age and body mass index (BMI). Multiple regression analysis showed that older age, lower BMI, and longer amenorrhea were associated with lower BD in the femoral neck, whereas lower BMI and use of DMPA were associated with lower BD in the lumbar spine. PMID- 10095972 TI - Can intrauterine device removals for bleeding or pain be predicted at a one-month follow-up visit? A multivariate analysis. AB - From 4%-14% of intrauterine device (IUD) users have their IUD removed due to bleeding or pelvic pain in the first year of use. Past studies have analyzed whether baseline patient information can help predict such removals, but no previous analysis has examined whether information provided at the recommended 1 month follow-up visit could improve such predictions. Using data from an international multicenter randomized controlled trial, 89 women with removals for bleeding and pain after the 1-month visit were compared with 2536 continuing users. Logistic regression indicated several significant predictors of removal. Women reporting intermenstrual bleeding since last menses were nearly three times more likely to have removals for bleeding or pain (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.4-5.9). Similarly, those complaining of excessive menstrual flow were 3.5 times more likely to have removals within 12 months (95% CI 1.4-9.2). Women reporting these menstrual problems during scheduled revisits may benefit from counseling and treatment with nonsteroidal anti-inflammatory drugs (NSAID). PMID- 10095973 TI - Analysis of contraceptive failure data in intrauterine device studies. Modern competing risks approach. AB - The life table method used heretofore in case of intrauterine device (IUD) failure data requires grouping of data into intervals. If the termination times are recorded exactly along with the reason of termination, grouping of data results in some loss of information. Modern competing risks techniques are suggested here for the exact IUD failure data. The uses of cumulative incidence functions, which are essentially the quantity given by Potter's net rate, and cause-specific hazard rates are stressed. Also, this paper focuses on the flaws of life table estimates of net and gross rates, which have been widely used during the past three decades in the analysis of contraceptive failures. The methods suggested in this paper can be used in any other situation where the failure times and reasons of failure are recorded. PMID- 10095974 TI - Measuring true contraceptive efficacy. A randomized approach--condom vs. spermicide vs. no method. AB - No investigator has attempted to measure prospectively the true efficacy of a contraceptive method, compared with a control group using no method, because contraceptive trials focus on women trying to avoid pregnancy and ethical concerns do not permit the withholding of contraception. We tested the feasibility of an approach that recruited women who desired pregnancy but were willing to postpone conception by 1 month. In this protocol, we restricted frequency and timing of intercourse to one coital act on the most fertile day of the menstrual cycle, as measured by a luteinizing hormone (LH) detection kit. Participants were randomized to use either a male latex condom, spermicidal film, or no method. In this feasibility study we recruited 58 women at three sites, with one site recruiting 25 women in 5 months. Among 54 women who completed the study, we found a 12% pregnancy rate for the group using no method (2/17; 95% confidence interval [CI], 1-36%) and an 11% pregnancy rate for the group using spermicidal film (2/18; 95% CI, 1-35%). No pregnancies occurred among the 19 women using condoms (0/19; 95% CI, 0-18%). The wide confidence intervals illustrate the small sample size of this pilot study and no conclusions can be drawn about the relative efficacy of the methods. Having demonstrated the feasibility of this study design, we now urge the initiation of a large-scale study to evaluate the efficacy of barrier methods using our randomized approach, with a control arm using no method of contraception. PMID- 10095975 TI - Emergency contraception use and the evaluation of barrier contraceptives. New challenges for study design, implementation, and analysis. AB - The availability of emergency contraception (EC) introduces new complexities to barrier contraceptive evaluation. Researchers must determine whether the primary objective of interest is to measure the effectiveness of the barrier plus EC back up or the effectiveness of the barrier alone. Barrier contraceptive effectiveness study protocols must specify what study volunteers will be told about EC, under what conditions EC will be dispensed, what information about EC use will be collected, and how EC use will be addressed during data analysis. PMID- 10095976 TI - Removal of a Norplant implant located near a major nerve using interventional radiology-digital subtraction fluoroscopy. AB - Norplant implants can be removed easily, if inserted properly. When they are inserted deeply and can not be palpated, or if they are located close to the neurovascular structures of the upper arm, radiological guidance may be needed to locate and remove the implants without causing injury to the surrounding vital structures. Digital subtraction fluoroscopic guidance is helpful in removing deeply located contraceptive implants and those that are close to the neurovascular structures, where blind removal may result in injury to those structures. We describe a case in which an implant that was located close to a major nerve near the axilla was removed under digital subtraction fluoroscopic guidance. PMID- 10095977 TI - Insertion and removal of Implanon. AB - Implanon is a single-rod contraceptive implant containing the progestin etonogestrel. Implants require insertion and removal by medical professionals. Detailed and unbiased counseling before insertion is essential, and should include contraceptive efficacy, insertion and removal procedures, and possible adverse events. Insertion and removal times have been measured in six open studies and in seven comparative studies in which Norplant (the six-capsule levonorgestrel implant) was used as the reference product. In comparative studies, the mean time needed for insertion of Implanon was 1.1 min and removal took 2.6 min. Insertion as well as removal of Implanon was four times faster than with Norplant. Complications with insertion and removal are rare in the hands of medical professionals familiar with the techniques. PMID- 10095978 TI - Pharmacokinetics of Implanon. An integrated analysis. AB - The aims of this paper were to present data on the pharmacokinetics, clearance, bioavailability, and in vivo absorption of etonogestrel (ENG); to present the results of a longitudinal analysis of the plasma concentration-time curves of ENG; and to present the results of a cross-sectional analysis on the association of body weight with serum ENG concentrations. Implanon had an absorption rate of almost 60 micrograms/day after 3 months, which slowly decreased to 30 micrograms/day at the end of 2 years. The bioavailability over this period of time was constant and close to 100%. The clearance remained around 7.5 L/h. With a bioavailability and clearance that remained constant, it was concluded that accumulation of ENG does not occur. After Implanon insertion, serum concentrations increased within 8 h to concentrations associated with ovulation inhibition. Maximum mean serum concentrations (Cmax) amounted to 813 pg/mL and the time (tmax) to reach Cmax was 4 days. After reaching Cmax, ENG serum concentrations declined to about 196 pg/mL at the end of the first year, followed by a slow decline to 156 pg/mL at the end of the third year. After removal of Implanon, serum ENG concentrations declined to levels less than the detection limit of the assay (20 pg/mL) within 1 week. Lower body weight was associated with higher serum ENG concentrations. PMID- 10095979 TI - The pharmacodynamics and efficacy of Implanon. An overview of the data. AB - Implanon is a long-acting reversible contraceptive method, consisting of a single rod that is applied subdermally. Ovulation inhibition was determined by serum progesterone (P) levels and ultrasound scanning (USS) of the ovaries. Ovarian function was further assessed by serum estradiol (E2) levels. The effects of Implanon on serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) and on cervical mucus were also investigated, by means of Insler scores and sperm penetration tests. The effect of the endometrium was assessed by endometrial biopsies and USS. The Pearl index was calculated over 13 studies performed according to Good Clinical Practice (GCP), including 1716 women using Implanon. Return of ovulation after implant removal was determined by P levels and USS of the ovaries. The contraceptive efficacy of Implanon was high, with zero pregnancies during 53,530 cycles (4103 woman-years), resulting in a Pearl index of 0.0 (95% confidence interval, 0.00-0.09). This was achieved by inhibition of ovulation, which was reflected by suppressed P levels, as the primary mode of action. Ovulation was inhibited, but otherwise ovarian activity was still present (follicle growth, E2 synthesis). The FSH serum concentrations were only slightly lower than preinsertion levels and LH surges were prevented. The viscosity of the cervical mucus was increased. The endometrium was thin but not atrophic; it showed primarily inactive or weak proliferation. Return of ovulation after removal of Implanon was rapid. PMID- 10095980 TI - An integrated analysis of vaginal bleeding patterns in clinical trials of Implanon. AB - The vaginal bleeding patterns observed during the use of the single-rod progestin only implant, Implanon, compared with those seen during the use of the six capsule implant, Norplant, have been analyzed. The acceptability of these bleeding patterns was also assessed. An integrated analysis of 13 different trials was done, studying reference periods (RP) of 90 days. These trials included totals of 1716 Implanon users and 689 Norplant users. There were statistically significant lower mean values over RP 2-8 the range over RP 2-8 is presented) for Implanon, for the number of bleeding-spotting days (15.9-19.3 vs 19.4-21.6; p = 0.0169), the number of bleeding days (7.5-10.0 vs. 11.7-13.1; p < 0.001), and the number of bleeding-spotting episodes (2.2-2.7 vs. 3.1-3.3; p < 0.0001). The bleeding patterns of Implanon users appeared to be more variable than those observed with Norplant: Implanon users had more amenorrhea, and slightly more infrequent bleeding, frequent bleeding, and prolonged bleeding than Norplant users. The difference was only statistically significant for amenorrhea (17.9%-24.8% with Implanon compared with 2.0%-7.0% for Norplant over RP 2-8). There were no statistically significant differences in the acceptability of the two products as indicated by the discontinuation rates, which were 30.2% and 0.9% in Europe and Southeast Asia, respectively, for Implanon, and 22.5% and 1.4%, respectively, in the two regions, for Norplant. The individual bleeding pattern was not predictable. However, in general, it can be stated that women initially without bleeding or with infrequent bleeding have only a small chance of becoming frequent bleeders, and vice versa. Dysmenorrhea clearly improved during use of both Implanon and Norplant. Neither Implanon nor Norplant caused anemia. PMID- 10095981 TI - An integrated analysis of nonmenstrual adverse events with Implanon. AB - This integrated analysis evaluates nonmenstrual adverse events, blood pressure, and body weight changes during the use of the single-rod etonogestrel-containing contraceptive implant, Implanon; these aspects are compared for Implanon and Norplant, the six-capsule implant containing levonorgestrel. Overall, 47% of Implanon users had drug-related adverse events, whereas in the comparative studies the figure for those using Implanon (61%) was slightly lower than that for Norplant users (69%). In all Implanon studies, 12 of 1716 women (0.7%) were affected by serious adverse events that were considered drug related. In comparative studies three of the 689 Implanon users (0.4%) and one of 689 Norplant users (0.1%) had such experiences. The most frequently reported drug related adverse events were acne, breast pain, headache and weight gain. The adverse events that most often caused discontinuation of Implanon were weight gain and acne. The development or aggravation of acne was a frequent adverse event (in 18.5% of Implanon and 22.3% of Norplant users in the comparative studies) but individual studies indicated that there were also many subjects whose acne improved during implant use. There were gradual increases in body weight over time but these may be only partly attributable to implant use and partly attributable to normal increases over time. PMID- 10095982 TI - Nutrition. PMID- 10095983 TI - New aspects in the management of obesity: operation and the impact of lipase inhibitors. AB - Obesity is an increasing health problem in most developed countries and its prevalence is also increasing in developing countries. There has been no great success with dietary means and life style modification for permanent weight loss. Various surgical treatment methods for obesity are now available. They are aimed at limiting oral energy intake with or without causing dumping or inducing selective maldigestion and malabsorption. Based on current literature, up to 75% of excess weight is lost by surgical treatment with concomitant disappearance of hyperlipidaemias, type 2 diabetes, hypertension or sleep apnoea. The main indication for operative treatment is morbid obesity (body mass index greater than 40 kg/m2) or severe obesity (body mass index > 35 kg/m2) with comorbidities of obesity. Orlistat is a new inhibitor of pancreatic lipase enzyme. At doses of 120 mg three times per day with meals it results in a 30% reduction in dietary fat absorption, which equals approximately 200 kcal daily energy deficit. In the long term, orlistat has been shown to be more effective than placebo in reducing body weight and serum total and low-density lipoprotein cholesterol levels. Orlistat has a lowering effect on serum cholesterol independent of weight loss. Along with weight loss, orlistat also favourably affects blood pressure and glucose and insulin levels in obese individuals and in obese type 2 diabetic patients. PMID- 10095984 TI - Regulation of cholesterol metabolism by dietary plant sterols. AB - Renewal has occurred in the use of plant sterols for the treatment of hypercholesterolemias. A novel development was to convert plant sterols to corresponding stanols and esterify them to fat soluble form. In contrast to the crystalline plant sterols or stanols, plant stanol esters can be easily consumed during normal food intake in soluble form in different fat-containing food constituents when they have a potent cholesterol-lowering effect, shown in normo- and hypercholesterolemic men and women without or with coronary heart disease, children and diabetes. Cholesterol lowering is approximately 10% for total and 15% for LDL cholesterol, with the respective values for stanol ester margarine (2 3 g/day stanols) being 15% and 20%. Stanol esters reduce cholesterol absorption efficiency by up to 65%, increase cholesterol elimination in feces as cholesterol itself, usually not as bile acids, and stimulate cholesterol synthesis. Serum beta-carotene level is lowered, but no fat malabsorption or lowering of serum fat soluble vitamins have been observed. In contrast to plant sterols, stanols and their esters are minimally absorbed and they reduce serum plant sterol concentrations, also preventing statin-induced increase of plant sterols. Stanol ester margarine has been included in dietary treatment of hypercholesterolemia followed by the addition of drug treatment in resistant cases. PMID- 10095985 TI - Genes, variation of cholesterol and fat intake and serum lipids. AB - Several studies have examined gene-diet interactions in the response of plasma lipid concentrations to changes in dietary fat and/or cholesterol. Among the gene loci examined, APOE has been the most studied, and the current evidence suggests that this locus might be responsible for some of the interindividual variability in dietary response. Other loci, including APOA4, APOA1 and APOB have also been found to account for some of the variability in the fasting and fed states. PMID- 10095986 TI - Flavonoids in food and natural antioxidants in wine. AB - Plant foodstuffs are an important source of a wide variety of flavonoids with protective properties on low-density lipoprotein oxidation as shown in vitro and in some human and animal experiments. Increasing information is available concerning the absorption and pharmacokinetics of these molecules, but their long term protective effect on coronary heart disease still needs further investigation. PMID- 10095987 TI - Beta-carotene supplementation: a good thing, a bad thing, or nothing? AB - Available data from several completed large-scale randomized trials indicate that beta-carotene supplementation for durations up to 12 years has no overall benefit in well-nourished populations on the incidence of cardiovascular disease or the middle-to-late stages of carcinogenesis. Several important questions, however, remain unanswered. The post-trial follow-up of completed trials, together with the results of several ongoing trials of beta-carotene supplementation, will contribute reliable information to the totality of evidence from basic research, animal studies, observational epidemiologic studies, and completed trials, thus allowing more rational clinical decisions for individual patients and policy decisions for the health of the general public. PMID- 10095988 TI - Dietary and genetic interactions in the regulation of plasma lipoprotein(a). AB - Lipoprotein(a) is a plasma particle which is considered to be a risk factor for the development of coronary heart disease. Plasma levels of lipoprotein(a) are affected by different types of dietary fat and steroid hormones. Two regions upstream of the apolipoprotein(a) promoter have been isolated which could be the site of regulation of apolipoprotein(a) gene transcription. PMID- 10095989 TI - Possible mechanisms underlying the cholesterol-raising effect of the coffee diterpene cafestol. AB - Cafestol, a coffee diterpene present in unfiltered coffee brews, potently raises serum lipids in humans. The mechanism through which this dietary compound influences liporotein metabolism is largely unknown. Unravelling the mechanism of action might lead to new insights into the regulation of serum cholesterol levels in humans. This review summaries ways in which cafestol may act on serum lipids. PMID- 10095990 TI - Potential tissue selectivity of dietary phytoestrogens and estrogens. AB - The recent discovery of a second estrogen receptor subtype, estrogen receptor beta, may significantly advance our understanding of tissue specific effects of estrogenic compounds, both natural and synthetic. Although specific effects mediated by estrogen receptor beta in vivo remain to be elucidated, hypothetically the existence of two estrogen receptor subtypes (differing in both tissue distribution and biological activity) may help to explain the curious pharmacological behaviour of many estrogenic and antiestrogenic compounds, including the naturally occurring dietary phytoestrogens. PMID- 10095991 TI - Bibliography. Current world literature. Nutrition. PMID- 10095992 TI - Nutrition and therapeutics. PMID- 10095993 TI - Peroxisome proliferator-activated receptors in atherosclerosis. PMID- 10095994 TI - Lipid metabolism. PMID- 10095995 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 10095996 TI - Therapy and clinical trials. PMID- 10095997 TI - Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. AB - Competition for respiration between substrates in animal tissues has been known for at least 80 years. The most important interaction, quantitatively is between glucose and fatty acids. The starting point in 1963 for the so called Glucose Fatty Acid Cycle was the realisation that the metabolic relationship between glucose and fatty acids is reciprocal and not dependent. Glucose provision promotes glucose oxidation and glucose and lipid storage, and inhibits fatty acid oxidation. Provision of free fatty acids promotes fatty acid oxidation and storage, inhibits glucose oxidation and may promote glucose storage if glycogen reserves are incomplete. This review is concerned predominantly with evidence in man in vivo. In the authors opinion the evidence for inhibitory effects of fatty acids on whole body glucose utilization ad oxidation (predominantly muscles) is decisive and enzyme mechanisms mediating these effects are well established. There is also much evidence that fatty acid oxidation inhibits glucose oxidation and stimulates glucose formation in liver and again enzyme mechanism are known. A permissive role for fatty acids in the insulin secretory response of islet beta cells has now been firmly established and can be visualised as a mechanism to protect continuing provision of respiratory substrate. Longer term exposure of islet beta-cells to fatty acids impairs the insulin secretory response to glucose and mechanisms are known. There is compelling evidence that fatty acid oxidation may impair glucose oxidation in uncontrolled Type 1 and Type 2 diabetes, but no convincing evidence that fatty acids have a role in diminished glucose storage (glycogen deposition) in Type 2 diabetes. The inhibition of glucose storage which may follow prolonged elevation of plasma FFA in man and experimental animals is associated with glycogen repletion whereas the inhibition of glucose storage in Type 2 diabetes is associated with glycogen depletion. The precise role of fatty acids in disturbed carbohydrate metabolism in Type 2 diabetes is an area where future progress is confidently predicted. PMID- 10095998 TI - MHC restriction to T-cell autoaggression: an emerging understanding of IDDM pathogenesis. AB - The Nobel prize-winning discovery of MHC restriction by Zinkernagel and Doherty has led to some of the most exciting advances in immunology over the past two decades. The ongoing progress in our conceptual understanding of the processes governing the immunology to infection, tolerance to self and consequently the immune dysregulation in autoimmunity have all assimilated the laws of restriction as a central tenet. The focus of much of this research has been the T-cell and its interactions. Refinement of the paradigm of MHC restriction at the molecular level has allowed a view of the pathogenesis of insulin-dependent diabetes mellitus (IDDM), a prototypic autoimmune disease, unprecedented in its detail. This article discusses the impact of MHC restriction on the central themes of immunology, and focuses on its utility as a framework in understanding the role of the T-cell in the pathogenesis of IDDM. PMID- 10095999 TI - Islet transplantation: present and future perspectives. AB - Islet cell transplantation can potentially normalize blood glucose levels and stop the progression of clinical complications, and if the transplant is done early in the course of the disease complications may be prevented. Remarkable progress has been made in recent years and islet cell transplantation has resulted in normalization of metabolic control in several patients with Type 1 diabetes in the absence of hypoglycemia. Only a few patients, however, have achieved insulin independence. Issues relating to islet cell engraftment within the liver, prevention of rejection and recurrent autoimmunity, and identification of alternative immunosuppressive drugs that do not adversely affect islet cell function remain to be solved. Thus far, the need for chronic, generalized immunosuppression to prevent rejection of the islets has limited the indication to those patients who have already received another transplant or to those who simultaneously receive islets and another organ (generally a kidney). Identification of immunointervention protocols that allow for engraftment in the absence of deleterious effects on the islets and prevent rejection and recurrent autoimmunity would make this procedure suitable for all patients, including children who have not yet developed long-term complications of the disease. PMID- 10096000 TI - Actual perspectives in biohybrid artificial pancreas for the therapy of type 1, insulin-dependent diabetes mellitus. PMID- 10096001 TI - Insulin expression in the thymus, tolerance, and type 1 diabetes. PMID- 10096002 TI - Lazarus rises: islet regeneration in the 21st century. PMID- 10096003 TI - Neogenesis of islet cells. PMID- 10096004 TI - Cryptic epitope and autoimmunity. PMID- 10096006 TI - [Periodicity of tactile and noxious perception of rat skin mechanoreceptors]. PMID- 10096005 TI - The preliminary report from the nation-wide prevention study for type 1 diabetes initially diagnosed as type 2 in Japan. PMID- 10096007 TI - [The functional characteristics of mouse uterus response to noradrenaline during pregnancy in experiments in situ]. PMID- 10096008 TI - [Ultrastructure of mouse cardiomyocytes after changes in cell membrane physico chemical state]. PMID- 10096009 TI - [Reindeer choice of movement direction in the escape reaction]. PMID- 10096010 TI - [Effect of beta-carotene on nuclear lipids in the rat liver in normal conditions and after low-dose gamma-irradiation]. PMID- 10096011 TI - [The role of surface water in manifestations of biological activity of opiates]. PMID- 10096012 TI - [Vital dyes with properties of modulators of redox processes as potential immunotropic agents with novel mechanism of action]. PMID- 10096013 TI - [Kinetics of amplification of two variants of Drosophila melanogaster retrotransposon MDG4]. PMID- 10096014 TI - [Molecular analysis of complete copy of Drosophila Burdock mobile element]. PMID- 10096015 TI - [Effect of various doses of high molecular weight polyethylene oxide and polyacrylamide on hemodynamics of anesthesized rats]. PMID- 10096016 TI - [Seasonal changes in the brain integrative activity in hibernating animals]. PMID- 10096017 TI - [Dynamics of development of agonistic interactions during pairing in three gerbil species]. PMID- 10096018 TI - S phase and differential DNA replication during Drosophila oogenesis. AB - A modified cell cycle, the endo cycle, produces the polyploid or polytene cells that are present in some tissues of most organisms. In the endo cycle, the S phase alternates with a gap phase, but mitosis does not occur. Genes needed to inhibit mitosis during the endo cycle and to promote the onset of S phase have been identified in Drosophila. Genomic intervals are differentially replicated during the endo cycle S phase such that some regions are under-replicated, while others can be amplified. Cyclin E and E2F are needed for this differential DNA replication during Drosophila oogenesis. PMID- 10096019 TI - Hierarchical and co-operative binding of OmpR to a fusion construct containing the ompC and ompF upstream regulatory sequences of Escherichia coli. AB - BACKGROUND: OmpR is a transcription factor that regulates the expression of the porin genes ompF and ompC in Escherichia coli. The phosphorylation state of OmpR, directed by the osmosensor EnvZ, determines its ability to bind to the upstream regulatory regions of these genes, a total of 14 phospho-OmpR binding sites. While it has been possible to study the stoichiometry and hierarchy of the OmpR DNA interaction in the upstream regions of ompF and ompC, their disunited location on the bacterial chromosome has made it difficult to compare the individual binding affinities of respective sites. RESULTS: Using 1,10 phenanthroline-Cu+ footprinting on a fused construct containing both the ompF and ompC upstream regulatory sequences, and gel shift experiments on oligomers corresponding to individual sites, we have established a comparative hierarchy for OmpR binding, as F1, C1 > F2, F3 > C2 > C3. In addition, the binding patterns reveal an apparent co-operative relationship between OmpR molecules bound at several upstream motifs. Densitometric analyses of the footprinted regions provide support for these observations. Mutational analysis of this construct reveals that the alteration of a conserved cytidine in the F1 motif (-86) causes a loss of OmpR affinity and disrupts hierarchical OmpR-binding in the entire ompF region. CONCLUSIONS: The present results provide a unique view of the OmpR interaction with the two respective promoters, ompF and ompC, and an insight into the question of how the expression of ompF and ompC are reciprocally regulated by medium osmolarity. PMID- 10096021 TI - Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. AB - BACKGROUND: Activating transcription factor-4 (ATF4)--also termed CREB2, C/ATF, and TAXREB67--is a basic-leucine zipper (bZip) transcription factor that belongs to the ATF/CREB family. In addition to its own family members, ATF4 can also form heterodimers with other related but distinct bZIP proteins such as the C/EBP, AP 1 and Maf families, which may give rise to a variety of combinatorial diversity in gene regulation. In order to assess the in vivo essential role of ATF4, we have generated mice lacking ATF4 by gene targeting. RESULTS: ATF4-deficient mice exhibited severe microphthalmia. Although ATF4-deficient eyes revealed a normal gross lens structure up to embryonic day 14.5, later on the ATF4-deficient lens, degenerated due to apoptosis without the formation of lens secondary fibre cells. Retinal development was normal in the mutant mice. The lens-specific expression of ATF4 in the mutant mice led not only to the recovery of lens secondary fibres but also to the induction of hyperplasia of these fibres. CONCLUSION: These results demonstrated that ATF4 is essential for the later stages of lens fibre cell differentiation. PMID- 10096020 TI - Tip60 acetylates six lysines of a specific class in core histones in vitro. AB - BACKGROUND: Tip60, an HIV-1-Tat interactive protein, is a nuclear histone acetyltransferase (HAT) with unique histone substrate specificity. Since the acetylation of core histones at particular lysines mediates distinct effects on chromatin assembly and gene regulation, the identification of lysine site specificity of the HAT activity of Tip60 is an initial step in the analysis of its molecular function. RESULTS: Tip60 significantly acetylates amino-terminal tail peptides of histones H2A, H3 and H4, but not H2B, consistent with substrate preference on intact histones. Preferred acetylation sites for Tip60 are the Lys 5 of histone H2A, the Lys-14 of histone H3, and the Lys-5, -8, -12, -16 of histone H4, determined by a method which combined matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) measurements and Lys-C endopeptidase digestion, or a method detecting the incorporation of radiolabelled acetate into synthetic peptides. CONCLUSION: The lysine site specificity of Tip60 in histone amino-terminal tail peptides in vitro has been characterized by an assay measuring the molecular mass of endopeptidase digested peptides, or a previously described assay. These results agree well with our proposed classification of lysines in core histones. The classification may be useful for an analysis of the relationships between HATs and the substrates of other uncharacterized HATs. PMID- 10096023 TI - [Reconstruction of possible paths of the origin and morphological evolution of bacteriophages]. AB - The problem of the origin and evolution of viruses and, in particular, the origin and evolution of bacteriophages is of considerable interest. However, so far, this problem has not been solved with quantitative methods of molecular systematics. In the present study, an attempt to reconstruct the possible paths of appearance and evolution of bacteriophages based on their structural features and morphogenesis, as well as general characteristics of their life cycles and genome organization, was carried out. A scheme describing phylogeny of the main bacteriophage groups and evolution of their life cycles is suggested. Existence of two independently evaluating types of morphogenesis ("budding outward" and "budding inward") is postulated. PMID- 10096022 TI - Disruption of the midkine gene (Mdk) resulted in altered expression of a calcium binding protein in the hippocampus of infant mice and their abnormal behaviour. AB - BACKGROUND: Midkine (MK) is a growth factor implicated in the development and repair of various tissues, especially neural tissues. However, its in vivo function has not been clarified. RESULTS: Knockout mice lacking the MK gene (Mdk) showed no gross abnormalities. We closely analysed postnatal brain development in Mdk(-/-) mice using calcium binding proteins as markers to distinguish neuronal subpopulations. Intense and prolonged calretinin expression was found in the dentate gyrus granule cell layer of the hippocampus of infant Mdk(-/-) mice. In infant Mdk(+/+) mice, calretinin expression in the granule cell layer was weaker, and had disappeared by 4 weeks after birth, when calretinin expression still persisted in Mdk(-/-) mice. Furthermore, 4 weeks after birth, Mdk(-/-) mice showed a deficit in their working memory, as revealed by a Y-maze test, and had an increased anxiety, as demonstrated by the elevated plus-maze test. CONCLUSION: Midkine plays an important role in the regulation of postnatal development of the hippocampus. PMID- 10096024 TI - [Study of alpha-satellite DNA in cosmid libraries, specific for chromosomes 13, 21, and 22, using fluorescence in situ hybridization]. AB - Fluorescent in situ hybridization (FISH) was employed in mapping the alpha satellite DNA that was revealed in the cosmid libraries specific for human chromosomes 13, 21, and 22. In total, 131 clones were revealed. They contained various elements of centromeric alphoid DNA sequences of acrocentric chromosomes, including those located close to SINEs, LINEs, and classical satellite sequences. The heterochromatin of acrocentric chromosomes was shown to contain two different groups of alphoid sequences: (1) those immediately adjacent to the centromeric regions (alpha 13-1, alpha 21-1, and alpha 22-1 loci) and (2) those located in the short arm of acrocentric chromosomes (alpha 13-2, alpha 21-2, and alpha 22-2 loci). Alphoid DNA sequences from the alpha 13-2, alpha 21-2, and alpha 22-2 loci are apparently not involved in the formation of centromeres and are absent from mitotically stable marker chromosomes with a deleted short arm. Robertsonian translocations t(13q; 21q) and t(14q; 22q), and chromosome 21p-. The heterochromatic regions of chromosomes 13, 21, and 22 were also shown to contain relatively chromosome-specific repetitive sequences of various alphoid DNA families, whose numerous copies occur in other chromosomes. Pools of centromeric alphoid cosmids can be of use in further studies of the structural and functional properties of heterochromatic DNA and the identification of centromeric sequences. Moreover, these clones can be employed in high-resolution mapping and in sequencing the heterochromatic regions of the human genome. The detailed FISH analysis of numerous alphoid cosmid clones allowed the identification of several new, highly specific DNA probes of molecular cytogenetic studies--in particular, the interphase and metaphase analyses of chromosomes 2, 9, 11, 14, 15, 16, 18, 20, 21-13, 22-14, and X. PMID- 10096025 TI - [Effect of pH on cea gene expression in cells irradiated with UV-light and unirradiated Escherichia coli cells]. AB - The effect of pH on the expression of the cea gene encoding colicin EI in Escherichia coli was investigated by measuring the beta-galactosidase activity in the UV-irradiated growing cells carrying the cea-lacZ fusion. Maximum activity was observed at pH 7, and inhibition of expression was observed at pH 6 and pH 8. Treatment of the irradiated cells with 50-mM acetate increased inhibition at pH 6.0-7.5. No correlation between cea expression and the rate of cell growth was observed at different pH levels. Preliminary treatment with acetate at pH 7 reduced the expression of the recA gene, which participates in the regulation of the cea gene to 33% in irradiated cells and to 25% in nonirradiated cells. PMID- 10096026 TI - [Comparative contribution of different genetic factors in induction of MGE transpositions under isogenization]. AB - Localization patterns of mobile genetic element 412 in polytene chromosomes of larvae from the control (riC) line, the balancer line, the F1 and F2 generations of the isogenization scheme, and 10 final isogenic lines were obtained and compared. The contributions of the recombination transfer of mobile genetic element copies from the balancer line, the outbreeding of control and balancer lines, and the inbreeding of isogenized lines to the rate of transposition were determined and estimated. These constituted < 0.187, < 0.30, and > 0.207 events per initial mobile genetic element copy per isogenized haploid genome per isogenization, respectively. During consecutive steps of isogenization (F1-F2 isogenic lines), the total transposition rate decreased: 2.09, 1.78, and 0.69. This was explained in terms of the existence of large selective and random losses in the variability of mobile genetic elements within the sites of their patterns during isogenization. The existence of a recombination transfer does not change the main conclusions and estimates regarding isogenization-induced transpositions. PMID- 10096027 TI - [GC-rich chromomycin-positive (CMA/DA)-blocks in chicken (Gallus gallus domesticus) karyotypes: ideogram and intraspecies variability of the pattern]. AB - Fluorescence pattern on chromosomes stained with chromomycin A3 (CMA) and contrasted with distamycin A (DA) was studied in representatives of seven markedly divergent chicken (Gallus gallus domesticus) breeds. The maps of CMA positive bands on chicken macrochromosomes were constructed, and the frequency of detection of each band was estimated. PMID- 10096028 TI - [Formation of genetic polymorphism in connection with phylogenesis and microevolution of the domestic dog Canis familiaris L]. AB - The analysis of genetic relationships between numerous breeds and populations of domestic dogs of Asian and European origin was performed by studying their polymorphism for 14 loci of biochemical markers. Phylogenetic positions of different breed groups, related to one another and to ancestral forms from the center of domestication, were elucidated. Directions of gene flow in the formation of breed as well as dynamics and vectors of the forming genetic structure in microevolution of this extremely polytypic species, were established. PMID- 10096029 TI - [Increased risk of occurrence of pulmonary adenocarcinoma in man is associated with the presence of rare alleles of the Hras1 minisatellite]. AB - Data on allelotyping of minisatellite sequence within the Hras1 protooncogene locus in 60 patients with lung adenocarcinoma (LAC) are presented. Allele distribution was analyzed with respect to the effect of tobacco smoke carcinogens (smoking factor). Results were compared with the analogous data obtained for patients with squamous-cell-carcinoma and for individuals without cancer. In contrast to the patients with squamous cell-carcinoma, the frequency of the Hras1 locus rare alleles in patients with lung-adenocarcinoma was higher than in individuals without cancer. More striking difference between the latter groups was demonstrated for nonsmoking patients (17.6% versus 2.7% of healthy individuals, P = 0.0005). In smoking LAC patients, higher frequencies of the common a4 allele (2.5 kb in size under the MspI/HpaII digestion) were found. Our findings point to the combined effect of endogenous and exogenous factors on the development of lung adenocarcinomas in humans. In this work, we discuss the possible mechanism of association between the rare minisatellite alleles and the predisposition to lung cancer. PMID- 10096030 TI - [Genogenography of the aboriginal population of Marii El (from data on immunobiochemical polymorphism)]. AB - The geographic distribution of the frequencies of genes related to the immunological and biochemical polymorphism was studied in the Maris, who are the indigenous population of the Marii El Republic. Data on the frequencies of 33 alleles of 10 loci (ABO, TF, GC, PI, HP, AHS, F13B, ACP1, PGM1, and GLO1) in five raions (districts) of Marii El were obtained. Computer interpolation maps were constructed for all alleles. The maps allows to predict the distribution of the alleles throughout Marii El. A map of the reliability of the cartographic prediction was drawn. For the first time, the reliability of predicted gene frequencies were taken into account in constructing and interpreting the maps of gene frequencies. For the entire set of the studied genes, parameters of heterozygosity (HS) and gene diversity (GST) were estimated. Cartographic correlation analysis was performed to reveal the relationship between gene frequencies and geographic coordinates. It was found that 42% of the studied genes predominantly correlated with latitude and 9% with longitude. It was assumed that the genetic structure of Mari populations had been mainly determined by latitude-related factors. A map of Nei's genetic distances between the overall Mari gene pool and the local populations revealed a central core, which was close to the "average Mari" gene pool, and a periphery, which was genetically distant from it. Suggestions on the microevolution of the Mari gene pool were advanced. Maps of the genes with the most characteristic genetic relief (ABO*B, ACP*A, TF*D, GC*1F, PI*M2, HP*1F, and F13B*3) are shown. These maps exhibit a high correlation with the maps of principal components. PMID- 10096032 TI - [Selective structure of the gene pool. IV. Estimation from the selection intensity index Rs]. AB - A new approach for investigating the selective structure of the gene pool reflecting the type and intensity of selection is proposed. Selection pressure is estimated on the basis of interpopulation gene diversity with the use of the selection intensity index: RS(i) = NeS(i) = 1/4(1/FST(i)-1/Fe). Distributions of RS(i) in gene pools of indigenous populations from all continents and five subregions of the northeastern Eurasia were examined. It was shown that, of all theoretical distributions, only beta-distributions provide a good approximation of RS(i) estimates. Based on the confidence intervals of RS obtained from beta distributions, genes can be grouped into the three following classes according to their selective structure: LOWER DIFF, NEUTRAL, and SUPER DIFF. These classes, respectively, include genes subjected mainly to stabilizing selection (RS(i) > 0; LOWER DIFF), genes subjected mainly to differentiating selection (RS(i) < 0; SUPER DIFF), and arbitrarily selectively neutral genes (RS(i) approximately 0; NEUTRAL). Simulation of gene pool sampling (10(6) samples from 50 markers for each gene pool) allowed us to characterize the selective structure by determining markers that fall into the same selective class irrespective of the variant for the sampling process. The selective structure of gene pools from six continents (Europe, Asia, Africa, Australia, America, and southeastern Eurasia) and five subregions of northeastern Eurasia was characterized. It was shown that approximately one-third of genes is subjected to selection irrespective of the hierarchical level of the region. In gene pools of Europe, northeastern Eurasia, and European and Ural subregions, the proportion of genes under stabilizing selection was higher, the proportion of selectively neutral genes, lower. Debatable issues of tests for selective neutrality based on heterogeneity of interpopulation gene diversity are considered. These issues include the effect on FST of the hierarchical population structure, sample size, number of subpopulations, and other factors that shift estimates of gene selective values. PMID- 10096031 TI - [Polymorphism of CYP1A1 and CYP2D6 genes in tundra nentses and European populations of western Siberia]. AB - Data on the first examination of the CYP1A1 and CYP2D6 genes' polymorphism in the populations of Tundra Nentsis (Yamalo-Nenetskii Autonomous District) and migrant population of Western Siberia (Novosibirsk oblast and Altaiskii krai) are presented. The frequency of the 2D6*4 mutant allele in Tundra Nentsis, characterized by a two-component Caucasoid and Mongoloid origin, was shown to be intermediate in Caucasoid and Mongoloid populations. The frequencies of the 2D6*4 and 1A1Val* mutant alleles across migrant inhabitants of Western Siberia (Caucasoid populations) were similar to that reported for the Caucasoid populations overall. Distribution of the CYP1A1 genotypes (Ile/Ile, Ile/Val*, and Val*/Val*) in Tundra Nentsis was similar to that found in Mongoloid groups. However, the frequency of the 1A1Val* allele in Tundra Nentsis was 1.5 times higher than that in the Southern Mongoloid populations (Chinese, Koreans, and Japanese). PMID- 10096033 TI - [Use of a PCR method for controlling pure-breeding of honeybees Apis mellifera mellifera L. in the southern Urals]. AB - A key problem of honeybee (Apis mellifera mellifera) breeding in the Southern Urals is its cross-breeding with the Caucasian honeybee Apis mellifera caucasica. Mitochondrial DNA (mtDNA) in these subspecies differ in the length of a fragment localized between genes CO-I and CO-II, which can be used as a marker. A pair of 20-mer primers for PCR was chosen by means of computer design in order to determine the fragment size in both of the subspecies. The amplified fragment was shown to have a length of 350 bp in A. m. caucasica and 600 bp in A. m. mellifera. The difference in length results from the different ratio between two main elements P and Q, which comprise a major part of this sequence in these subspecies: a copy of P element and two copies of Q element in A. m. mellifera, and a copy of Q element only in A. m. caucasica. This sharply defined distinction allows us to use PCR for differentiating the subspecies, estimating the heterogeneity in the colonies, and rejecting queens in the selection process because of the maternal inheritance of the studied character. The nucleotide sequence of the amplified mtDNA fragment of A. m. mellifera was determined. PMID- 10096034 TI - [Polymorphism of angiotensin-converting enzyme and endothelial nitric oxide synthase genes in people with arterial hypertension, left ventricular hypertrophy, and hypertrophic cardiomyopathy]. AB - Data on polymorphism of the angiotensin-converting enzyme (ACE) and endothelial cell nitric oxide synthase (NOS3) genes in patients having arterial hypertension (AH) with or without left ventricular hypertrophy (LVH) and those with hypertrophic cardiomyopathy (HCM) are presented. An association between polymorphism for the ACE and NOS3 loci and the LVH index among AH patients with LVH and HCM was shown. In AH patients, an association between the NOS3 locus polymorphism and some parameters of blood pressure was revealed. Possible relationships between the ACE and NOS3 polymorphisms and the clinical manifestation of the LVH and AH are discussed. PMID- 10096035 TI - Systematic review of endoscopic ultrasound in gastro-oesophageal cancer. PMID- 10096036 TI - In memory of Victor Mutt. Discoveries of biologically important peptides. PMID- 10096037 TI - Cannabinoid receptor and WIN-55,212-2-stimulated [35S]GTP gamma S binding and cannabinoid receptor mRNA levels in the basal ganglia and the cerebellum of adult male rats chronically exposed to delta 9-tetrahydrocannabinol. AB - The inhibition of motor behavior in rodents caused by the exposure to plant or synthetic cannabinoids has been reported to develop tolerance after repeated exposure. This tolerance seems to have a pharmacodynamic basis, since downregulation of cannabinoid receptors in motor areas, basal ganglia and cerebellum, has been demonstrated in cannabinoid-tolerant rats. The present study was designed to further explore this previous evidence by analyzing simultaneously in several motor areas of delta 9-tetrahydrocannabinol- (delta 9 THC)-tolerant rats: 1. Cannabinoid receptor binding, by using [3H]WIN-55,212-2 autoradiography; 2. Cannabinoid receptor activation of signal transduction mechanisms, by using WIN-55,212-2-stimulated [35S]-guanylyl-5'-O-(gamma-thio) triphosphate ([35S]-GTP gamma S) autoradiography; 3. Cannabinoid receptor mRNA expression, quantitated by in situ hybridization. Results were as follows. As expected, the exposure to delta 9-THC for 5 d resulted in a decrease of cannabinoid receptor binding in the molecular layer of the cerebellum, medial, and lateral caudate-putamen and, in particular, entopeduncular nucleus. We also found decreased cannabinoid receptor binding in the superficial and deep layers of the cerebral cortex, two regions used as a reference to test the specificity of changes observed in motor areas. There were only two brain regions, the globus pallidus and the substantia nigra, where the specific binding for cannabinoid receptors was unaltered after 5 d of a daily delta 9-THC administration. However, in the substantia nigra, the magnitude of WIN-55,212-2-stimulated [35S]-GTP gamma S binding was lesser in delta 9-THC-tolerant rats than controls, thus suggesting a possible specific change at the level of receptor coupling to GTP-binding proteins. This was not seen neither in the globus pallidus nor in the lateral caudate-putamen, where agonist stimulation produced similar [35S]-GTP gamma S binding levels in delta 9-THC-tolerant rats and controls. Finally, animals chronically exposed to delta 9-THC also exhibited a decrease in the levels of cannabinoid receptor mRNA in the medial and lateral caudate-putamen, but there were no changes in the cerebellum (granular layer) and cerebral cortex. In summary, the chronic exposure to delta 9-THC resulted in a decrease in cannabinoid receptor binding and mRNA levels in the caudate-putamen, where cell bodies of cannabinoid receptor-containing neurons in the basal ganglia are located. However, this decrease particularly affected the receptor binding levels in those neurons projecting to the entopeduncular nucleus, but not in those projecting to the globus pallidus and substantia nigra, although, in this last region, a specific decrease in the efficiency of receptor activation of signal transduction mechanisms was seen in delta 9-THC-tolerant rats. The chronic exposure to delta 9-THC also resulted in decreased cannabinoid receptor binding in the cerebellum, although without affecting mRNA expression. PMID- 10096038 TI - Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain. AB - The expression of dopamine D2 receptor mRNA was studied in rat brain following micro-injection of a competitive N-methyl D-aspartate (NMDA) receptor antagonist at the prefrontal cortex. Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with a competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). The levels of mRNA for NMDA-R1 and dopamine D2 receptors were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and D2 receptor density was quantified by [3H]spiperone binding in the cortex and striatum of these animals. In the prefrontal cortex, the levels of NMDA-R1 receptor mRNA showed significant decrease in CPP-treated animals compared to control animals. However, NMDA-R1 mRNA levels in striatum remained unchanged in any of the experimental groups. The D2 receptor mRNA levels and [3H]spiroperidol binding in prefrontal cortical membranes showed no significant difference between the CPP-treated and control groups of animals. In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP. The increase in D2 mRNA level was correlated with an increase in the D2 receptor binding sites in the striatal membranes. These results suggest a possible interaction between prefrontal cortical NMDA receptors and striatal dopamine receptors. PMID- 10096039 TI - Molecular mapping of epitopes involved in ligand activation of the human receptor for the neuropeptide, VIP, based on hybrids with the human secretin receptor. AB - Receptors for the neurotransmitter and neuroendocrine peptides, vasoactive intesinal peptide (VIP) and secretin, both belong to the Type B subfamily of G protein-coupled receptors. This group is evolutionally as well as structurally distinct from the much larger Type A, or rhodopsin-type, subfamily. We have mapped the ligand-activating epitopes of the human VIP1 receptor by the use of hybrid receptor constructs with the human secretin receptor. Twelve chimeras were synthesized the successively replacing portions of the former receptor with corresponding portions of the latter receptor, or by interchanging the first extracellular loops. Each of the different chimeric receptor DNAs were then expressed in murine reporter cells, and their ability to activate cAMP production was investigated on stimulation with the respective natural peptide ligands. We stimulated the reporter cells with secretion or VIP following transient expression of the receptor chimeras. The experiments indicated that there are two molecular domains of importance for the recognition and activation of these peptides, namely, the inner portion of the extracellular tail and the first extracellular loop of the two receptors. PMID- 10096040 TI - Molecular cloning and analysis of Ca2+/calmodulin-dependent protein kinase II from the chicken brain. AB - The goals of this study were to identify specific mRNA for isoforms of calmodulin dependent protein kinase II in chicken forebrain, prepare a cDNA expression library, and perform a sequence analysis of the kinase cDNA. Specific mRNAs for alpha- and beta-subunits of the kinase were identified in Northern blots. The mRNA for the alpha-subunit is larger in the chicken that in the rat, and for the beta-subunit is smaller in the chicken than the rat. Nucleotide sequencing of selected clones demonstrated the presence of an alpha-subunit with a 33 nucleotide insert known as the alpha-B-isoform. Clones of the beta-subunit showed it to contain a deletion of six nucleotides relative to previously described sequences. Variability in the mRNAs of calmodulin kinase II, as shown here, reflect the presence of species-dependent variability in gene structure as well as the presence of different functional isoforms. PMID- 10096041 TI - Pulse-chase experiments revealed beta-secretase cleavage from immature full length amyloid precursor protein harboring the Swedish mutation. Implications for distinct pathways. AB - The molecular mechanisms of the nonamyloidogenic and the amyloidogenic pathways of the amyloid precursor protein (APP) are unknown, but proteolysis of APP is essential for the generation of beta-amyloid. To study the time-course of C terminal fragment generation by alpha- and beta-secretase, we expressed the APP751 isoform with the Swedish mutation in the human neuroblastoma cell line SY5Y as previously described (Urmoneit et al., 1995). We show in pulse-chase experiments that the C-terminal fragments, CT, generated by alpha-secretase and A4CT, generated by beta-secretase, could be generated from immature full-length APP before O-glycosylation is completed. Thus beta A4 may be generated from immature APP that has not passed through the trans-Golgi-network (TGN), which presents experimental evidence for the intracellular localization of beta secretase activity in an earlier Golgi complex. PMID- 10096042 TI - The expression of key oxidative stress-handling genes in different brain regions in Alzheimer's disease. AB - Alzheimer's disease (AD) has been hypothesized to be associated with oxidative stress. In this study, the expression of key oxidative stress-handling genes was studied in hippocampus, inferior parietal lobule, and cerebellum of 10 AD subjects and 10 control subjects using reverse transcriptase-polymerase chain reaction (RT-PCR). The content of Mn-, Cu,Zn-superoxide dismutases (Mn- and Cu,Zn SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) mRNAs, and the "marker genes" (beta-actin and cyclophilin) mRNAs was determined. This study suggests that gene responses to oxidative stress can be significantly modulated by the general decrease of transcription in the AD brain. To determine if the particular oxidative stress handling gene transcription was induced or suppressed in AD, the "oxidative stress-handling gene/beta-actin" ratios were quantified and compared with control values in all brain regions studied. The Mn-SOD mRNA/beta-actin mRNA ratio was unchanged in all regions of the AD brain studied, but an increase of the Cu,Zn-SOD mRNA/beta-actin mRNA ratio was observed in the AD inferior parietal lobule. The levels of peroxidation handling (CAT, GSHPx, and GSSG-R) mRNAs normalized to beta-actin mRNA level were elevated in hippocampus and inferior parietal lobule, but not in cerebellum of AD patients, which may reflect the protective gene response to the increased peroxidation in the brain regions showing severe AD pathology. The results of this study suggest that region-specific differences of the magnitude of ROS mediated injury rather than primary deficits of oxidative stress handling gene transcription are likely to contribute to the variable intensity of neurodegeneration in different areas of AD brain. PMID- 10096044 TI - Mechanical properties of bone in a paraplegic rat model. AB - Pathologic fractures may occur with minimal trauma after spinal cord injury (SCI) because of osteoporosis. Rats were evaluated to determine whether they could be used as an SCI animal model. Male Sprague-Dawley rats underwent spinal cord transection at the ninth thoracic vertebrae. Control rats underwent a sham procedure. Mechanical testing of the humeral shaft, femoral shaft, tibial shaft, femoral neck, distal femur, and proximal tibia was performed separately at 0, 8, and 24 weeks after surgery. At 24 weeks, significant differences between SCI and control rats were found in maximum torque needed to produce failure in the femoral shaft (63 percent of control, p < 0.05) and tibial shaft (63 percent, p < 0.01), and in compressive load to produce failure in cross-sectional specimens of the distal femur (51 percent, p < 0.05) and proximal tibia (50 percent, p < 0.01). No differences were found in the maximum torque needed to produce failure of the humeral shaft (106 percent, p = 0.77) between SCI and control rats. Reductions in relative bone strength in SCI rats at 24 weeks were similar in magnitude to bone mineral density changes reported in humans with chronic paraplegia. Thus, Sprague-Dawley rats appear to be good animal models in which to evaluate changes in bone strength following SCI. PMID- 10096043 TI - The role of NeuroD as a differentiation factor in the mammalian retina. AB - NeuroD, a vertebrate homolog of Drosophila atonal gene, plays an important role in the differentiation of neuronal precursors (Lee et al., 1995). We have investigated whether NeuroD subserves a similar function in mammalian retinal neurogenesis. Expression of NeuroD is detected in successive stages of retinal neurogenesis and is associated with a differentiating population of retinal cells. The association of NeuroD predominantly with postmitotic precursors in early as well as late neurogenesis suggests that NeuroD expression plays an important role in the terminal differentiation of retinal neurons. The notion is supported by observations that overexpression of NeuroD during late neurogenesis promotes premature differentiation of late-born neurons, rod photoreceptors, and bipolar cells, and that NeuroD can interact specifically with the E-box element in the proximal promoter of the phenotype-specific gene, opsin. PMID- 10096045 TI - Review of oxidative stress in brain and spinal cord injury: suggestions for pharmacological and nutritional management strategies. AB - Much of the damage that occurs in the central nervous system (CNS) following trauma is due to secondary effects of glutamate excitotoxicity, Ca2+ overload, and oxidative stress, three mechanisms that in a spiraling interactive cascade end in neuronal death. Oxidative stress activates mechanisms that result in a neutrophil-mediated inflammation that also causes secondary damage. Mechanisms of oxidative stress are reviewed, with particular attention paid to lipid peroxidation and the central role of reduced glutathione in scavenging peroxides. We suggest that decreasing oxidative stress will greatly reduce the amount of secondary damage due to trauma. Oxidative stress can be minimized by 1) maintaining reduced-glutathione levels through the administration of cysteine precursors such as N-acetylcysteine and 2) limiting neutrophil invasion by administering platelet-activating factor antagonists such as BN 52021. Aggressive nutritional support following CNS trauma can also contribute to maximizing antioxidant defenses. Furthermore, we suggest that flavonoids such as quercetin have the potential to be therapeutically effective because of their free radical quenching, iron chelating, and anti-inflammatory properties. PMID- 10096046 TI - Bowel management in children and adolescents with spinal cord injury. AB - There is little in the literature regarding bowel management in children and adolescents with spinal cord injuries (SCI). This study was undertaken to examine specific patterns of bowel care, individual levels of satisfaction with bowel management, the incidence of incontinence in this population, and effects on lifestyle because of time commitment and dependence in bowel management. Surveys were sent to all persons (n = 45) under age 19 with a diagnosis of SCI who had received care at our medical center since 1985. Thirty-one subjects (69 percent) returned the surveys. The average age at injury was 8.1 years, with an average follow-up period of 3.9 years. Fifty-five percent were individuals with tetraplegia and 77 percent had a complete injury (ASIA Class A). A bowel management program, including medications or manual manipulation, was required for 81 percent of the subjects; only two were independent in their bowel management. Over half of the subjects performed evening bowel care and over half performed their care daily. Digital stimulation tended to be used more commonly by younger children. Medications, either oral, rectal, or both, were used by 88 percent. Sixty percent of the subjects reported they were completely or very satisfied with their bowel management. About half the subjects had limited freedom because of their bowel programs, which caused some dissatisfaction. Sixty eight percent reported occasional or frequent interference with school activities because of their bowel programs. No correlation was found between bowel accidents and satisfaction with bowel management, despite the fact that almost 84 percent of the children reported at least rare accidents. Lifestyle limitations, bowel accidents, dependence in bowel management, and subject and family dissatisfaction continue to be significant problems for children and adolescents with SCI. PMID- 10096047 TI - Does refrigeration of urine alter culture results in hospitalized patients with neurogenic bladders? AB - A prospective, blinded study of 40 hospitalized spinal cord injured (SCI) patients was conducted to evaluate the effects of refrigeration on urinalysis and culture results. Urine samples were divided, with one aliquot examined within 4 hours and the other after 24 hours of refrigeration. Comparisons using Wilcoxon Signed Rank analysis showed no significant difference between fresh and refrigerated samples in white blood cell (WBC) count (z = -0.353, p = 0.724), number of bacteria (z = -0.772, p = 0.440), leukocytes (z = -0.277, p = 0.782), or colony counts of E. fecalis, E. coli, Citrobacter, Pseudomonas, Streptococcus, Yeast, or Acinetobacter (z = -1.00, p = 0.317; z = 0.00, p = 1.0; z = 0.00, p = 1.0; z = 0.00, p = 1.0; z = -1.00, p = 0.317; z = 0.00, p = 1.0; z = 0.00, p = 1.0, respectively). A statistically significant difference between fresh and refrigerated samples was found with "mixed" organisms (z = -2.565, p = 0.010) and a difference approaching significance was found with Staph aureus (z = -1.841, p = 0.066), both with colony counts of less than 50 k. No changes in cultures or colony counts occurred following refrigeration that would have resulted in altered treatment regimens. This study indicates that refrigeration of urine samples for up to 24 hours in the hospital setting rarely causes changes in identified organism type and causes no clinically significant changes in urinalysis or urine culture results in SCI patients. PMID- 10096048 TI - Myelopathy secondary to spinal epidural abscess: case reports and a review. AB - Spinal epidural abscess (SEA) is a rare disease with an unknown incidence rate. This paper will illustrate that early diagnosis and rehabilitation may result in improved outcomes for patients with neck or back pain presenting with neurological deficits. Three cases of SEA in individuals without the commonly acknowledged risk factors of intravenous drug abuse (IVDA), invasive procedures, or immunosuppression were seen at our institution during a 10-month period between October 1995 and July 1996. The patients presented with neck or thoracic back pain and progressive neurological deficits without a febrile illness. Predisposing factors were thought to be urinary tract infection with underlying untreated diabetes mellitus in the first case, a history of recurrent skin infection in the second, and alcoholism without a definite source of infection in the third. Leukocytosis, elevated sedimentation rate, and confirmatory findings reported on magnetic resonance imaging (MRI) led to the diagnosis of SEA in all three cases. Immediate surgical drainage and decompression followed by proper antibiotic treatment and early aggressive rehabilitation led to good functional outcomes. All the individuals became independent in activities of daily living, wheelchair mobility, and bowel and bladder management. Two eventually became ambulatory. PMID- 10096049 TI - Empathy in psychotherapy and psychoanalysis. PMID- 10096050 TI - Neural aspects of psychodynamic science. PMID- 10096051 TI - Revisiting the "teach/treat" boundary in psychoanalytic supervision: when the supervisee is or is not in concurrent treatment. PMID- 10096052 TI - Rethinking the role of regressive experience in psychoanalytic supervision. PMID- 10096053 TI - Discussion of Frawley-O'Dea and Sarnat: emotional and interactional factors in the supervisory relationship. PMID- 10096054 TI - Faith, paranoia, and trust in the psychoanalytic relationship. PMID- 10096055 TI - Identity and experience: recasting the ontology of mind. PMID- 10096056 TI - Stress and coping in children traumatized by war. PMID- 10096057 TI - On the clinical relevance of selected postmodern ideas with a focus on Lyotard's concept of "differend". AB - Clinical differends are collisions of language-games in which people become baffled as to the other's meaning. This confusion creates anxiety and speechlessness, which disables their linguistic creativity to communicate effectively. In order to dispell this confusion, one needs to acquire the ability to negotiate a mutual set of rules for local conversation and to navigate these local local definitions without offending. Psychoanalysis can promote this flexibility by relying on the common-sense tactic of asking people what they mean by the words they use, by exploring their meaning in some depth, and by negotiating a nonoffensive local and provisional language with the patient that allows the patient to create a vocabulary for saying what needs to be said. PMID- 10096058 TI - Reuniting the psychoanalytic movement. PMID- 10096059 TI - A Meis family protein caudalizes neural cell fates in Xenopus. AB - A homologue of the Drosophila homothorax (hth) gene, Xenopus Meis3 (XMeis3), was cloned from Xenopus laevis. XMeis3 is expressed in a single stripe of cells in the early neural plate stage. By late neurula, the gene is expressed predominantly in rhombomeres two, three and four, and in the anterior spinal cord. Ectopic expression of RNA encoding XMeis3 protein causes anterior neural truncations with a concomitant expansion of hindbrain and spinal cord. Ectopic XMeis3 expression inhibits anterior neural induction in neuralized animal cap ectoderm explants without perturbing induction of pan-neural markers. In naive animal cap ectoderm, ectopic XMeis3 expression activates transcription of the posteriorly expressed neural markers, but not pan-neural markers. These results suggest that caudalizing proteins, such as XMeis3, can alter A-P patterning in the nervous system in the absence of neural induction. Regionally expressed proteins like XMeis3 could be required to overcome anterior signals and to specify posterior cell fates along the A-P axis. PMID- 10096060 TI - Xenopus brain factor-2 controls mesoderm, forebrain and neural crest development. AB - The forkhead type Brain Factor 2 from mouse and chicken help pattern the forebrain, optic vesicle and kidney. We have isolated a Xenopus homolog (Xbf2) and found that during gastrulation it is expressed in the dorsolateral mesoderm, where it helps specify this territory by downregulating BMP-4 and its downstream genes. Indeed, Xbf2 overexpression caused partial axis duplication. Interference with BMP-4 signaling also occurs in isolated animal caps, since Xbf2 induces neural tissue. Within the neurula forebrain, Xbf2 and the related Xbf1 gene are expressed in the contiguous diencephalic and telencephalic territories, respectively, and each gene represses the other. Finally, Xbf2 seems to participate in the control of neural crest migration. Our data suggest that XBF2 interferes with BMP-4 signaling, both in mesoderm and ectoderm. PMID- 10096061 TI - Temporal and spatial control of the Sycp1 gene transcription in the mouse meiosis: regulatory elements active in the male are not sufficient for expression in the female gonad. AB - Transcription controls active at the initial stages of meiosis are clearly key elements in the regulation of germinal differentiation. Transcription of the Sycp1 gene (synaptonemal complex protein 1) starts as early as the leptotene and zygotene stages. Constructs with Sycp1 5' upstream sequences directed the expression of reporter genes to pachytene spermatocytes in transgenic mice. A short fragment encompassing the transcription start (n.t. -54 to +102) was sufficient for stage-specific expression in the adult male and for temporal regulation during development. Upstream enhancer element(s) quantitatively regulating expression were localized in the region between -54 and -260. The gene is normally expressed both in the male and female gonads, but none of the promoter sequences active in the testis allowed the expression of reporter genes during meiosis in the ovary. PMID- 10096062 TI - HpEts, an ets-related transcription factor implicated in primary mesenchyme cell differentiation in the sea urchin embryo. AB - The mechanism of micromere specification is one of the central issues in sea urchin development. In this study we have identified a sea urchin homologue of ets 1 + 2. HpEts, which is maternally expressed ubiquitously during the cleavage stage and which expression becomes restricted to the skeletogenic primary mesenchyme cells (PMC) after the hatching blastula stage. The overexpression of HpEts by mRNA injection into fertilized eggs alters the cell fate of non-PMC to migratory PMC. HpEts induces the expression of a PMC-specific spicule matrix protein, SM50, but suppresses of aboral ectoderm-specific arylsulfatase and endoderm-specific HpEndo16. The overexpression of dominant negative delta HpEts which lacks the N terminal domain, in contrast, specifically represses SM50 expression and development of the spicule. In the upstream region of the SM50 gene there exists an ets binding site that functions as a positive cis-regulatory element. The results suggest that HpEts plays a key role in the differentiation of PMCs in sea urchin embryogenesis. PMID- 10096063 TI - The Xenopus Ets transcription factor XER81 is a target of the FGF signaling pathway. AB - We report the cloning of a cDNA encoding a Xenopus laevis Ets-type transcription factor. This new Xenopus gene belongs to the PEA3 subfamily of Ets proteins and shows the highest degree of sequence similarity to the mouse and human ER81 genes. The Xenopus ER81 gene (XER81) is transcribed in the embryo after mid blastula transition (MBT) and three transcripts of 3, 4 and 6 kb are detected throughout embryogenesis. XER81 mRNA is localized in the animal pole of the late blastula stage and higher levels of XER81 transcripts are detected in the marginal zone at the onset of gastrulation. In later embryogenesis XER81 transcripts are found in neural crest cells, eyes, otic vesicles and pronephros. The transcription of XER81 can be stimulated by bFGF and eFGF in animal and vegetal cap explants. Expression of the dominant negative FGF receptor mutant in animal caps and embryos blocks XER81 transcription, arguing that the expression of this Ets gene requires active FGF signaling. The spatial overlap of eFGF and XER81 expression domains supports the idea that XER81 transcription could be a marker for regions with active FGF signaling in the embryo. PMID- 10096064 TI - Characterization of the Ets-type protein ER81 in Xenopus embryos. AB - A function for FGF-type peptide growth factors has been implied for early mesodermal patterning events in Xenopus laevis. FGF signalling operates via the MAP kinase cascade that can directly activate the transcription of organizer expressed genes, such as Xbra and Xegr-1. We have recently provided evidence for a critical role of Ets-type transcription factors in FGF mediated Xegr-1 transcription activation. Here, we report on the identification of the Xenopus Ets-type protein ER81 that is expressed in a pattern overlapping with the ones of Xegr-1 and Xbra during gastrulation. Microinjection in XER81 encoding mRNA into ventral blastomeres of Xenopus embryos results in the induction of ectopic, tail like protrusions, whereas dorsal overexpression results in disturbed eye development. In the animal cap assay, ectopic expression of XER81 is found to interfere with activin mediated induction of Xegr-1 and gsc, but not with the Xbra response to activin. PMID- 10096065 TI - The RNA-binding protein gene, hermes, is expressed at high levels in the developing heart. AB - In a screen for novel sequences expressed during embryonic heart development we have isolated a gene which encodes a putative RNA-binding protein. This protein is a member of one of the largest families of RNA-binding proteins, the RRM (RNA Recognition Motif) family. The gene has been named hermes (for HEart, RRM Expressed Sequence). The hermes protein is 197-amino acids long and contains a single RRM domain. In situ hybridization analysis indicates that hermes is expressed at highest levels in the myocardium of the heart and to a lesser extent in the ganglion layer of the retina, the pronephros and epiphysis. Expression of hermes in each of these tissues begins at approximately the time of differentiation and is maintained throughout development. Analysis of the RNA expression of the hermes orthologues from chicken and mouse reveals that, like Xenopus, the most prominent tissue of expression is the developing heart. The sequence and expression pattern of hermes suggests a role in post-transcriptional regulation of heart development. PMID- 10096066 TI - Structure and evolution of a pair-rule interaction element: runt regulatory sequences in D. melanogaster and D. virilis. AB - Pair-rule genes serve two important functions during Drosophila development: they first initiate periodic patterns, and subsequently interact with each other to refine these patterns to the precision required for definition of segmental compartments. Previously, we described a pair-rule input region of the runt gene. Here we further characterize this region through the use of reporter gene constructs and by comparison with corresponding sequences from Drosophila virilis. We find that many but not all regulatory properties of this '7-stripe region' are functionally conserved. Moreover, the similarity between these homologous sequences is surprisingly low. When compared to similar data for gap gene input element, our data suggest that pair-rule target sequences are less constrained during evolution, and that functional elements mediating pair-rule interactions can be dispersed over many kilobases. PMID- 10096067 TI - Negative regulation of axis formation and Wnt signaling in Xenopus embryos by the F-box/WD40 protein beta TrCP. AB - Screening a maternal Xenopus expression library for activities that synergize with low levels of injected beta-catenin, we have isolated a clone encoding the C terminal end of x-beta TrCP-2, a highly conserved protein belonging to the F box/WD40 family of ubiquitin-ligase specificity factors. We show that x-beta TrCP 2 expression reduces dorsal axis formation in Xenopus embryos. A dominant negative mutant lacking the F-box triggers the opposite effect, inducing secondary axes and activating the expression of Wnt responsive genes in ectodermal explants. In light of the existence of beta TrCP transcripts associated with the vegetal cortex, we propose that beta TrCP plays a fundamental role in the establishment of the dorsal determinants during cortical rotation in Xenopus. PMID- 10096068 TI - Expression of the homebox gene Hex during early stages of chick embryo development. AB - Whole mount in situ hybridization studies were performed to investigate the expression pattern of the homeobox gene Hex (also known as Prh) during early stages of chick embryogenesis. At the time of laying, cHex transcripts are detected in Koller's sickle and the forming hypoblast. During gastrulation (HH stage 4), cHex is expressed in anteriorly-displaced hypoblast cells. At stage 6, cHex transcripts are observed within endoderm in an anterior are that overlaps the cardiogenic region. Later cHex expression is observed within pharyngeal endoderm immediately adjacent to the forming myocardium, in the endocardium and in the liver and thyroid gland primordia. cHex transcripts are also detected within blood islands beginning at stage 4, and in extraembryonic and intraembryonic vascular endothelial cells as vessels form. PMID- 10096069 TI - Differential nuclear localization of ER1 protein during embryonic development in Xenopus laevis. AB - The er1 gene is a novel fibroblast growth factor (FGF)-regulated immediate-early gene, first isolated from Xenopus blastulae, that encodes a nuclear protein with potent transcription transactivational activity (Paterno et al., 1997). We report here the expression pattern of the ER1 protein during Xenopus embryonic development. ER1 protein is present in the early embryo but does not begin to appear in the nucleus until the mid-blastula stage. The first cells to show nuclear localization of ER1 are the presumptive mesodermal cells of the stage 8 blastula. ER1 gradually becomes localized to the nucleus of the remaining cells, first in the presumptive ectoderm and finally, in the presumptive endoderm such that by late blastula, all nuclei in the animal hemisphere are stained. By early gastrula, nuclear staining is ubiquitous. During subsequent development, ER1 protein gradually disappears from the nuclei of various tissues. In tailbud stages, ER1 begins to disappear from the nucleus of ectodermally-derived tissues, such as epidermis and brain, while remaining localized in the nucleus of endodermal cells and of mesodermal tissues, such as somites and notochord. In tadpoles, ER1 is no longer detectable in the nucleus of any cells, except for a few endodermal cells. Cytoplasmic staining, on the other hand, is observed in some mesodermal tissues, including somites and muscle cells. Neural tissue is largely unstained except for weak cytoplasmic staining in the eye. PMID- 10096070 TI - Expression of Drosophila trithorax-group homologues in chick embryos. AB - Mll, Brg1 and Brm are vertebrate homologues of Drosophila trithorax group (trxG) genes. We isolated chicken Mll cDNA clones, and examined patterns of Mll, Brg1 and Brm expression in chick embryos. All three genes were expressed from embryonic stage 2 onwards. Mll transcripts were just detectable in all tissues by in situ hybridization, with highest level in dorsal neural tube and notochord. Brg1 transcripts were readily detectable in all tissues, with highest levels in dorsal neural tube, dorsal trunk epithelium and limb bud epithelium and mesenchyme. Brm transcripts were more restricted, being found in dermomyotome, notochord, dorsal limb bud epithelium, eye and the roof and floor plates of the neural tube. PMID- 10096071 TI - Insertion of Escherichia coli alpha-haemolysin in lipid bilayers as a non transmembrane integral protein: prediction and experiment. AB - alpha-Haemolysin is an extracellular protein toxin (approximately 107 kDa) secreted by Escherichia coli that acts at the level of the plasma membranes of target eukaryotic cells. The nature of the toxin interaction with the membrane is not known at present, although it has been established that receptor-mediated binding is not essential. In this work, we have studied the perturbation produced by purified alpha-haemolysin on pure phosphatidylcholine bilayers in the form of large unilamellar vesicles, under conditions in which the toxin has been shown to induce vesicle leakage. The bilayer systems containing bound protein have been examined by differential scanning calorimetry, fluorescence spectroscopy, differential solubilization by Triton X-114, and freeze-fracture electron microscopy. All the data concur in indicating that alpha-haemolysin, under conditions leading to cell lysis, becomes inserted in the target membrane in the way of intrinsic or integral proteins. In addition, the experimental results support the idea that inserted alpha-haemolysin occupies only one of the membrane phospholipid monolayers, i.e. it is not a transmembrane protein. The experimental data are complemented by structure prediction studies according to which as many as ten amphipathic alpha-helices, appropriate for protein-lipid interaction, but no hydrophobic transmembrane helices are predicted in alpha-haemolysin. These observations and predictions have important consequences for the mechanism of cell lysis by alpha-haemolysin; in particular, a non-transmembrane arrangement of the toxin in the target membrane is not compatible with the concept of alpha haemolysin as a pore-forming toxin. PMID- 10096072 TI - A downstream CA repeat sequence increases translation from leadered and unleadered mRNA in Escherichia coli. AB - When placed downstream of the start codon, multimers of the dinucleotide CA stimulated translation from lacZ, gusA and neo mRNAs in the presence or absence of an untranslated leader sequence. Enhanced expression in the absence of a leader and Shine-Dalgarno sequence indicated that stimulation by CA multimers was independent of translation signals contained within the untranslated leader. Multimers of CA stimulated a significantly higher level of lacZ expression than multimers of individual C or A nucleotides. Translation levels increased as the number of CA repeats increased; fewer multimers were required for enhanced expression from leadered mRNA than from mRNA that was deleted for its leader sequence. Addition of down-stream CA multimers increased the ribosome binding strength of mRNA in vitro and the amount of full-length mRNA in vivo, suggesting that the enhanced expression resulted from translation of a more abundant functional message containing a stronger ribosome binding site. The presence of downstream CA-rich sequences, occurring naturally in several Escherichia coli genes, might contribute to translation of other mRNAs. Addition of CA multimers might represent a general mechanism for increasing expression from genes of interest. PMID- 10096073 TI - Differential expression of an hsp70 gene during transition from the mycelial to the infective yeast form of the human pathogenic fungus Paracoccidioides brasiliensis. AB - We have isolated and characterized cDNA and genomic clones that encode a 70 kDa heat shock protein (Hsp70) from the dimorphic human pathogenic fungus Paracoccidioides brasiliensis. The gene encodes a 649-amino-acid protein showing high identity with other members of the hsp70 gene family. The hsp70 gene is induced during both heat shock of yeast cells at 42 degrees C and the mycelial to yeast transition. A differential expression of this gene can be observed between mycelial and yeast forms, with a much higher level of expression in the yeast. We found two introns of 178 and 72 nucleotides in the P. brasiliensis hsp70 gene. Splicing of these introns is regulated during the heat shock process and possibly during infection. In order to analyse the differential accumulation of unspliced mRNA following cellular differentiation and/or heat shock, reverse transcriptase polymerase chain reaction (RT-PCR) experiments were carried out. The temperature induced mycelial to yeast transition results in the transient accumulation of unspliced hsp70 mRNA transcripts. Yeast cells, after adaptation at 36 degrees C, seem to be more proficient at splicing, at least with respect to hsp70 mRNA because, during a severe heat shock (42 degrees C), the unspliced form of this mRNA does not accumulate. The mycelial to yeast differentiation will have the adaptational effect of increasing the resistance of the organism to environmental stress, which may be necessary for parasite survival in the mammalian host. PMID- 10096074 TI - Characterization of nra, a global negative regulator gene in group A streptococci. AB - During sequencing of an 11.5 kb genomic region of a serotype M49 group A streptococcal (GAS) strain, a series of genes were identified including nra(negative regulator of GAS). Transcriptional analysis of the region revealed that nra was primarily monocistronically transcribed. Polycistronic expression was found for the three open reading frames (ORFs) downstream and for the four ORFs upstream of nra. The deduced Nra protein sequence exhibited 62% homology to the GAS RofA positive regulator. In contrast to RofA, Nra was found to be a negative regulator of its own expression and that of the two adjacent operons by analysis of insertional inactivation mutants. By polymerase chain reaction and hybridization assays of 10 different GAS serotypes, the genomic presence of nra, rofA or both was demonstrated. Nra-regulated genes include the fibronectin binding protein F2 gene (prtF2) and a novel collagen-binding protein (cpa). The Cpa polypeptide was purified as a recombinant maltose-binding protein fusion and shown to bind type I collagen but not fibronectin. In accordance with nra acting as a negative regulator of prtF2 and cpa, levels of attachment of the nra mutant strain to immobilized collagen and fibronectin was increased above wild-type levels. In addition, nra was also found to regulate negatively (four- to 16-fold) the global positive regulator gene, mga. Using a strain carrying a chromosomally integrated duplication of the nra 3' end and an nra-luciferase reporter gene transcriptional fusion, nra expression was observed to reach its maximum during late logarithmic growth phase, while no significant influence of atmospheric conditions could be distinguished clearly. PMID- 10096075 TI - The hxB gene, necessary for the post-translational activation of purine hydroxylases in Aspergillus nidulans, is independently controlled by the purine utilization and the nicotinate utilization transcriptional activating systems. AB - Molybdenum-containing enzymes of the hydroxylase class (such as xanthine dehydrogenase, aldehyde oxidase and nicotinate dehydrogenase) require a terminal sulphur atom attached to the molybdenum to hydroxylate their specific substrates. The transulphurylation reaction is carried out in Drosophila melanogaster by the product of the ma-I gene. In Aspergillus nidulans, the activity of the isofunctional and homologous HxB protein is needed in at least two different metabolic contexts, when the organism grows on purines and when it grows on nicotinate as nitrogen sources. We show here that the expression of the hxB gene is not constitutive. It is induced independently and additively by the inducers of the purine and of the nicotinate utilization pathways. Each of these induction pathways is affected independently by mutations in their cognate genes, uric acid induction by mutations in the UaY protein and nicotinate and 6-nicotinate induction by those in the hxnR/aplA complex. It is, in both metabolic contexts, exquisitely sensitive to nitrogen metabolite repression and highly dependent on the AreA GATA factor. PMID- 10096076 TI - Lipid modification of prelipoproteins is dispensable for growth but essential for efficient protein secretion in Bacillus subtilis: characterization of the Lgt gene. AB - We have identified and characterized the Igt gene of Bacillus subtilis. The prelipoprotein diacylglycerol transferase enzyme (Lgt) catalyses the first reaction in lipomodification of bacterial lipoproteins. Inactivation of Igt in B. subtilis by a nonsense mutation (prs-11 mutation) or by disruption was shown here to abolish lipomodification of prelipoproteins completely, as well as the cleavage of signal peptide. However, unlike in Gram-negative bacteria, the Igt mutants of B. subtilis were fully viable. In agreement with this observation, studies of two lipoproteins, PrsA and BlaP, indicated that non-lipomodified precursors of these proteins were functional and translocated across the cytoplasmic membrane. However, there was release of both precursors from cells, resulting in a reduced level of the cell-bound form. We have shown that the reduced level of the PrsA lipoprotein, a foldase involved in protein secretion, caused impaired protein secretion, a prominent phenotype of Igt mutants. There was no indication that non-lipomodified PrsA displayed reduced activity. PMID- 10096077 TI - Fps1p controls the accumulation and release of the compatible solute glycerol in yeast osmoregulation. AB - The accumulation of compatible solutes, such as glycerol, in the yeast Saccharomyces cerevisiae, is a ubiquitous mechanism in cellular osmoregulation. Here, we demonstrate that yeast cells control glycerol accumulation in part via a regulated, Fps1p-mediated export of glycerol. Fps1p is a member of the MIP family of channel proteins most closely related to the bacterial glycerol facilitators. The protein is localized in the plasma membrane. The physiological role of Fps1p appears to be glycerol export rather than uptake. Fps1 delta mutants are sensitive to hypo-osmotic shock, demonstrating that osmolyte export is required for recovery from a sudden drop in external osmolarity. In wild-type cells, the glycerol transport rate is decreased by hyperosmotic shock and increased by hypo osmotic shock on a subminute time scale. This regulation seems to be independent of the known yeast osmosensing HOG and PKC signalling pathways. Mutants lacking the unique hydrophilic N-terminal domain of Fps1p, or certain parts thereof, fail to reduce the glycerol transport rate after a hyperosmotic shock. Yeast cells carrying these constructs constitutively release glycerol and show a dominant hyperosmosensitivity, but compensate for glycerol loss after prolonged incubation by glycerol overproduction. Fps1p may be an example of a more widespread class of regulators of osmoadaptation, which control the cellular content and release of compatible solutes. PMID- 10096078 TI - The XylS-dependent Pm promoter is transcribed in vivo by RNA polymerase with sigma 32 or sigma 38 depending on the growth phase. AB - The Pm promoter of the TOL plasmid of Pseudomonas putida is expressed at high level along the growth curve. This transcription is dependent on the positive regulator XylS activated by 3-methylbenzoate. The sigma factor sigma 38 is required for expression in early stationary phase and thereafter. To test whether sigma 70 was involved in Pm transcription in exponential phase, we have followed mRNA synthesis in a rpoD thermosensitive strain. No difference in Pm transcription was found between the wild type and the thermosensitive strain at the restrictive temperature of 42 degrees C, indicating that transcription was independent of the sigma factor sigma 70. However, basal levels of mRNA expression from Pm in this strain in exponential phase were more than twofold higher at 42 degrees C, suggesting involvement of sigma 32 in Pm transcription. In a rpoH background, no expression of Pm took place in the exponential phase, whereas it increased during stationary phase, and in a rpoH rpoS double mutant no activity from the Pm promoter was detected along the growth curve. We have shown that the increase in the amount of sigma 32 factor necessary for transcription in exponential phase is provided through induction of the heat shock response by the presence of the effector 3-methylbenzoate, which is also required for activation of the positive regulator XylS. We conclude that activation of Pm transcription is achieved through a switch between two stress-responsive factors, sigma 32 in exponential phase and sigma 38 in stationary phase. In both cases, transcription is dependent on the activator XylS and presents the same transcription start point. PMID- 10096079 TI - A single amino acid, outside the AlcR zinc binuclear cluster, is involved in DNA binding and in transcriptional regulation of the alc genes in Aspergillus nidulans. AB - In Aspergillus nidulans, the transcriptional activator AlcR mediates specific induction of a number of alc genes. The AlcR DNA-binding domain is a zinc binuclear cluster that differs from the other members of the Zn2Cys6 family in several respects. Of these, the most remarkable is its ability to bind in vitro as a monomer to single sites, whereas only repeated sites (direct or inverted) are necessary and functional in vivo. Deletion of the first five amino acids (following the N-terminal methionine) upstream of the AlcR zinc cluster or mutation of a single residue, Arg-6, impairs the AlcR in vitro binding mainly to symmetrical sites. In vivo, the same mutations result in the inability of A. nidulans to grow on ethanol. The alc- phenotype results from a drastic decrease in activation of its own transcription and, in addition, that of the two structural genes, alcA and aldA, required for ethanol oxidation. This defect seems to be correlated to the inability of the Arg-6 AlcR mutant protein to bind to AlcR palindrome targets, which are essential in the three alc promoters. AlcR shows a unique pattern of binding and of transactivation among the Zn2Cys6 family. PMID- 10096080 TI - Chemotactic-like response of Escherichia coli cells lacking the known chemotaxis machinery but containing overexpressed CheY. AB - We describe a chemotactic-like response of Escherichia coli strains lacking most of the known chemotaxis machinery but containing high levels of the response regulator CheY. The bacteria accumulated in aspartate-containing capillaries, they formed rings on tryptone-containing semisolid agar, and the probability of counterclockwise flagellar rotation transiently increased in response to stimulation with aspartate (10(-10)-10(-5) M; the response was inverted at > 10( 4) M). The temporal response was partial and delayed, as was the response of a control wild-type strain having a high CheY level. alpha-Methyl-DL-aspartate, a non-metabolizable analogue of aspartate as well as other known attractants of E. Coli, glucose and, to a lesser extent, galactose, maltose and serine caused a similar response. So did low concentrations of acetate and benzoate (which, at higher concentrations, act as repellents for wild-type E. coli). Other tested repellents such as indole, Ni2+ and CO2+ increased the clockwise bias. These observations raise the possibility that, at least when the conventional signal transduction components are missing, a non-conventional chemotactic signal transduction pathway might be functional in E. coli. Potential molecular mechanisms are discussed. PMID- 10096081 TI - Yersinia enterocolitica type III secretion: an mRNA signal that couples translation and secretion of YopQ. AB - Pathogenic Yersinia species export Yop proteins via a type III machinery to escape their phagocytic killing during animal infections. Here, we reveal the type III export mechanism of YopQ. In the presence of calcium, when type III secretion was blocked, yopQ mRNA was not translated. The signal of YopQ sufficient for the secretion of translationally fused reporter proteins was contained within the first 10 codons of its open reading frame. Some frameshift mutations that completely altered the peptide sequence specified by this signal did not impair secretion of the reporter protein. Exchanging the upstream untranslated mRNA leader of yopQ for that of E. coli lacZ also did not affect secretion. However, removal of the first 15 codons abolished YopQ export. Pulse labelled YopE, but not YopQ, could be secreted after the polypeptide had been synthesized within the cytoplasm of Yersinia (post-translational secretion). Thus, YopQ appears to be exported by a mechanism that couples yopQ mRNA translation with the type III secretion of the encoded polypeptide. PMID- 10096084 TI - The molecular basis for the specificity of fimE in the phase variation of type 1 fimbriae of Escherichia coli K-12. AB - The expression of type 1 fimbriae in Escherichia coli is phase variable, with cells switching between fimbriate (ON) and afimbriate (OFF) phases. The phase variation is dependent on the orientation of a 314 bp DNA element (the switch) that undergoes DNA inversion. DNA inversion requires either fimB or fimE, site specific recombinases that differ in both specificity and activity. Whereas fimB promotes recombination with little orientational bias, fimE promotes recombination in the ON-to-OFF direction exclusively. In wild-type cells, fimE activity predominates and, hence, most bacteria are afimbriate. Here, it is shown that fimE specificity is caused by two different, but complementary, mechanisms. First, FimE shows a strong preference for the switch in the ON orientation as a substrate for recombination. Differences in the nucleotide sequence of the recombinase binding sites is a key factor in determining FimE specificity, although one or more additional cis-active sites that flank the fim switch also appear to be involved. Secondly, the orientation of the switch controls fimE in cis, most probably to control recombinase expression. PMID- 10096083 TI - The dimerization and topological specificity functions of MinE reside in a structurally autonomous C-terminal domain. AB - Correct placement of the division septum in Escherichia coli requires the co ordinated action of three proteins, MinC, MinD and MinE. MinC and MinD interact to form a non-specific division inhibitor that blocks septation at all potential division sites. MinE is able to antagonize MinCD in a topologically sensitive manner, as it restricts MinCD activity to the unwanted division sites at the cell poles. Here, we show that the topological specificity function of MinE residues in a structurally autonomous, trypsin-resistant domain comprising residues 31-88. Nuclear magnetic resonance (NMR) and circular dichroic spectroscopy indicate that this domain includes both alpha and beta secondary structure, while analytical ultracentrifugation reveals that it also contains a region responsible for MinE homodimerization. While trypsin digestion indicates that the anti-MinCD domain of MinE (residues 1-22) does not form a tightly folded structural domain, NMR analysis of a peptide corresponding to MinE1-22 indicates that this region forms a nascent helix in which the peptide rapidly interconverts between disordered (random coil) and alpha-helical conformations. This suggests that the N-terminal region of MinE may be poised to adopt an alpha-helical conformation when it interacts with the target of its anti-MinCD activity, presumably MinD. PMID- 10096082 TI - A vital stain for studying membrane dynamics in bacteria: a novel mechanism controlling septation during Bacillus subtilis sporulation. AB - At the onset of sporulation in Bacillus subtilis, two potential division sites are assembled at each pole, one of which will be used to synthesize the asymmetrically positioned sporulation septum. Using the vital stain FM 4-64 to label the plasma membrane of living cells, we examined the fate of these potential division sites in wild-type cells and found that, immediately after the formation of the sporulation septum, a partial septum was frequently synthesized within the mother cell at the second potential division site. Using time-lapse deconvolution microscopy, we were able to watch these partial septa first appear and then disappear during sporulation. Septal dissolution was dependent on sigma E activity and was partially inhibited in mutants lacking the sigma E-controlled proteins SpoIID, SpoIIM and SpoIIP, which may play a role in mediating the degradation of septal peptidoglycan. Our results support a model in which sigma E inhibits division at the second potential division site by two distinct mechanisms: inhibition of septal biogenesis and the degradation of partial septa formed before sigma E activation. PMID- 10096085 TI - IS903 transposase mutants that suppress defective inverted repeats. AB - The inverted repeats (IRs) of the insertion element IS903 are composed of two functional regions. An inner region, consisting of basepairs 6-18, is the transposase binding site. The outer region (positions 1-3) is not contacted during initial transposase binding, but is essential for efficient transposition. We have examined the interaction of the IR with the transposase by isolating transposase suppressors of IR mutations. These suppressors define two patches within the N-terminus of the protein. One class of suppressors, which rescued the majority of outer IR mutants tested, contained mutations in close proximity to an aspartate residue (D121) believed to form part of the catalytic DDE motif, suggesting that their suppressive effect is in the positioning of the catalytic site at the terminus of the transposon. The hypertransposition phenotype of mutant VA119 is also consistent with this hypothesis. The second class was more allele specific and preferentially suppressed a mutation at position 3 of the IR. Finally, we showed that mutations at the termini of the IR elevate the frequency of cointegrate formation by IS903. Other outer IR mutations did not have this effect. These data are consistent with the terminal bases of the transposon playing multiple and distinct roles in transposition. PMID- 10096086 TI - Quorum sensing in Vibrio fischeri: elements of the luxl promoter. AB - Although cell density-dependent regulation of the luminescence genes in Vibrio fischeri is a model for quorum sensing in Gram-negative bacteria, relatively little is known about the promoter of the luminescence operon. The luminescence operon is activated by the LuxR protein, which requires a diffusible acylhomoserine lactone signal. The lux box, a 20 bp inverted repeat, is located in the luxl promoter region and is required for LuxR-dependent induction of the luminescence genes. Using primer extension, we mapped the LuxR-dependent transcriptional start site of the lux operon to 19 bp upstream of the luxl start codon. This indicates that the lux box is centred at -42.5 bp from the start of transcription. To gain evidence about the location of the -10 sequence, we placed a consensus -35 hexamer at different locations relative to the luxl transcriptional start site and measured constitutive levels of luminescence in recombinant Escherichia coli. The strongest constitutive promoter contained a TATAGT hexamer 17 bp from the -35 consensus sequence and 6 bp from the transcriptional start site. We propose that this is the -10 hexamer. Also in recombinant E. coli, both half-sites of the lux box were required for LuxR dependent gene activation and for activation by an autoinducer-independent, monomeric LuxR deletion protein. LuxR-dependent activation of luminescence was eliminated when the lux box was centred at -47.5, -52.5 and -62.5 with respect to the luxl transcriptional start site. Our evidence, taken together with other information, points to a model in which a LuxR dimer overlaps the -35 region of the luxl promoter and functions as an ambidextrous activator with each LuxR subunit interacting with a different region of RNA polymerase. PMID- 10096087 TI - HAP4, the glucose-repressed regulated subunit of the HAP transcriptional complex involved in the fermentation-respiration shift, has a functional homologue in the respiratory yeast Kluyveromyces lactis. AB - In Saccharomyces cerevisiae, the heteromeric HAP transcription factor is necessary for optimal growth on respiratory carbon sources. One of its components, the Hap4p protein, is necessary for transcriptional activation. The same protein is also the regulatory part of the complex in response to carbon sources, as HAP4 is strongly induced during the shift from fermentative to respiratory metabolism in S. cerevisiae. We report here the characterization of a new gene from the respiratory yeast Kluyveromyces lactis, obtained by heterologous complementation of a delta hap4 S. cerevisiae mutant strain. The deduced sequence of the protein (643 amino acids) exhibits two small domains (11 and 16 amino acids respectively) highly homologous to corresponding domains of ScHap4p, while the overall similarity is rather weak. Additional experiments were performed to confirm the functional homology of this new gene with ScHAP4, which we named KIHAP4. The importance of the small highly conserved N-terminal sequence was confirmed by in vitro mutagenesis. All the mutations that interfere with the Hap4p-Hap2/3/5 interaction were localized in it. The discovery of the same regulatory protein in two metabolically distinct yeast species raises the question of its functional significance during evolution. PMID- 10096088 TI - The alarmone (p)ppGpp mediates physiological-responsive control at the sigma 54 dependent Po promoter. AB - Transcription from the Pseudomonas-derived sigma 54-dependent Po promoter of the dmp operon is mediated by the aromatic-responsive regulator DmpR. However, physiological control is superimposed on this regulatory system causing silencing of the DmpR-mediated transcriptional response in rich media until the transition between exponential and stationary phase is reached. Here, the positive role of the nutritional alarmone (p)ppGpp in DmpR regulation of the Po promoter has been identified and investigated in vivo. Overproduction of (p)ppGpp in a Pseudomonas reporter system was found to allow an immediate transcriptional response under normally non-permissive conditions. Conversely (p)ppGpp-deficient Escherichia coli strains were found to be severely defective in DmpR-mediated transcription, demonstrating the requirement for this metabolic signal. A subset of mutations in the beta, beta' and sigma 70 subunits of RNA polymerase, which confer prototrophy on ppGpp0 E. coli, was also found to restore specific DmpR-mediated transcription from Po, suggesting that the metabolic signal is mediated directly through the sigma 54-RNA polymerase. These data provide a direct mechanistic link between the physiological status of the cell and expression from sigma 54 promoters. PMID- 10096089 TI - Phosphorylation of tyrosine 474 of the enteropathogenic Escherichia coli (EPEC) Tir receptor molecule is essential for actin nucleating activity and is preceded by additional host modifications. AB - The enteropathogenic Escherichia coli (EPEC) Tir protein becomes tyrosine phosphorylated in host cells and displays an increase in apparent molecular mass. The interaction of Tir with the EPEC outer membrane protein, intimin, triggers actin nucleation beneath the adherent bacteria. The enterohaemorrhagic E. coli O157:H7 (EHEC) Tir molecule is not tyrosine phosphorylated. In this paper, Tir tyrosine phosphorylation is shown to be essential for actin nucleation activity, but not for the increase in apparent molecular mass observed in target cells. Tyrosine phosphorylation had no role in Tir molecular mass shift, indicating additional host modifications. Analysis of Tir intermediates indicates that tyrosine-independent modification functions to direct Tir's correct insertion from the cytoplasm into the host membrane. Deletion analysis identified Tir domains participating in translocation, association with the host membrane, modification and antibody recognition. Intimin was found to bind a 55-amino-acid region (TIBA) within Tir that topological and sequence analysis suggests is located in an extracellular loop. Homologous TIBA sequences exist in integrins, which also bind intimin. Collectively, this study provides definitive evidence for the importance of tyrosine phosphorylation for EPEC Tir function and reveals differences in the pathogenicity of EPEC and EHEC. The data also suggest a mechanism for Tir insertion into the host membrane, as well as providing clues to the mode of intimin-integrin interaction. PMID- 10096090 TI - DNA restriction dependent on two recognition sites: activities of the SfiI restriction-modification system in Escherichia coli. AB - In contrast to many type II restriction enzymes, dimeric proteins that cleave DNA at individual recognition sites 4-6 bp long, the SfiI endonuclease is a tetrameric protein that binds to two copies of an elongated sequence before cutting the DNA at both sites. The mode of action of the SfiI endonuclease thus seems more appropriate for DNA rearrangements than for restriction. To elucidate its biological function, strains of Escherichia coli expressing the SfiI restriction-modification system were transformed with plasmids carrying SfiI sites. The SfiI system often failed to restrict the survival of a plasmid with one SfiI site, but plasmids with two or more sites were restricted efficiently. Plasmids containing methylated SfI sites were not restricted. No rearrangements of the plasmids carrying SfiI sites were detected among the transformants. Hence, provided the target DNA contains at least two recognition sites, SfiI displays all of the hallmarks of a restriction-modification system as opposed to a recombination system in E. coli cells. The properties of the system in vivo match those of the enzyme in vitro. For both restriction in vivo and DNA cleavage in vitro, SfiI operates best with two recognition sites on the same DNA. PMID- 10096091 TI - The yeast inositol monophosphatase is a lithium- and sodium-sensitive enzyme encoded by a non-essential gene pair. AB - Inositol monophosphatases (IMPases) are lithium-sensitive enzymes that participate in the inositol cycle of calcium signalling and in inositol biosynthesis. Two open reading frames (YHR046c and YDR287w) with homology to animal and plant IMPases are present in the yeast genome. The two recombinant purified proteins were shown to catalyse inositol-1-phosphate hydrolysis sensitive to lithium and sodium. A double gene disruption had no apparent growth defect and was not auxotroph for inositol. Therefore, lithium effects in yeast cannot be explained by inhibition of IMPases and inositol depletion, as suggested for animal systems. Overexpression of yeast IMPases increased lithium and sodium tolerance and reduced the intracellular accumulation of lithium. This phenotype was blocked by a null mutation in the cation-extrusion ATPase encoded by the ENA1/PMR2A gene, but it was not affected by inositol supplementation. As overexpression of IMPases increased intracellular free Ca2+, it is suggested that yeast IMPases are limiting for the optimal operation of the inositol cycle of calcium signalling, which modulates the Ena1 cation-extrusion ATPase. PMID- 10096092 TI - Molecular genetic basis for the variable expression of Lewis Y antigen in Helicobacter pylori: analysis of the alpha (1,2) fucosyltransferase gene. AB - Helicobacter pylori lipopolysaccharides (LPS) express human oncofetal antigens Lewis X and Lewis Y. The synthesis of Lewis Y involves the actions of alpha (1,3) and alpha (1,2) fucosyltransferases (FucTs). Here, we report the molecular cloning and characterization of genes encoding H. pylori alpha (1,2) FucT (Hp fucT2) from various H. pylori strains. We constructed Hp fucT2 knock-out mutants and demonstrated the loss of Lewis Y production in these mutants by enzyme-linked immunosorbent assay (ELISA) and immunoelectron microscopy. The Hp fucT2 gene contains a hypermutable sequence [poly (C) and TAA repeats], which provides a possibility of frequent shifting into and out of coding frame by a polymerase slippage mechanism. Thus, the Hp fucT2 gene displays two major genotypes, consisting of either a single full-length open reading frame (ORF; as in the strain UA802) or truncated ORFs (as in the strain 26695). In vitro expression of Hp fucT2 genes demonstrated that both types of the gene have the potential to produce the full-length protein. The production of the full-length protein by the 26695 fucT2 gene could be attributed to translational-1 frameshifting, as a perfect translation frameshift cassette resembling that of the Escherichia coli dnaX gene is present. Examination of the strain UA1174 revealed that its fucT2 gene has a frameshifted ORF at the DNA level, which cannot be compensated by translation frameshifting, accounting for its Lewis Y off phenotype. In another strain, UA1218, the fucT2 gene is apparently turned off because of the loss of its promoter. Based on these data, we proposed a model for the variable expression of Lewis Y by H. pylori, in which regulation at the level of replication slippage (mutation), transcription and translation of the fucT2 gene may all be involved. PMID- 10096093 TI - LytB, a novel pneumococcal murein hydrolase essential for cell separation. PMID- 10096094 TI - Operator sequences for the regulatory proteins of restriction modification systems. PMID- 10096095 TI - Comments on 'Classification and genetic characterization of pattern-forming Bacilli Mol Microbiol (1998) 27: 687-703. PMID- 10096096 TI - Effect of timing of intravenous administration of myelin basic protein on the induction of tolerance in experimental allergic encephalomyelitis. AB - Immunological tolerance and suppression of clinical and histological experimental allergic encaphalomyelitis (EAE) can be induced by the intravenous (i.v.) administration of myelin basic protein (MBP). In this report we have characterized the effect of the time of i.v. administration of MBP on the course of EAE in Lewis rats. Rats were treated with the i.v. administration of one or two 500 micrograms doses of MBP either before or after active immunization. Results indicated that i.v. administration of MBP in rats before active immunization with MBP/CFA (naive rats) was most effective when given 14 days before active immunization, but treatment of rats actively immunized with MBP (immunized rats) was most effective at the onset of disease. Treatment at other times was less effective. The i.v. administration of the peptide MBP 68-88 (p68 88) containing the dominant encephalitogenic epitope could also suppress MBP induced EAE in a dose dependent manner. Intravenous administration of two injections of p68-88 to naive rats on days 10 and 3 before, or on days 0 and 7 after, active immunization with MBP suppressed the development of EAE in a dose dependent manner. Treatment of rats with i.v. MBP after, but not before, the transfer of MBP-reactive EAE effector cells suppressed the development of EAE in the recipient rats. Transfer of lymphoid cells from tolerized naive rats failed to protect recipient rats against development of active or passive EAE. These results indicate the importance of timing and dose of the antigen on the induction of tolerance and suggests different mechanisms of tolerance induction by intravenous MBP in immunized and naive rats. They also emphasize the importance of timing in designing efficient treatment strategies when i.v. tolerance is contemplated in EAE and possibly multiple sclerosis. PMID- 10096097 TI - The Fatigue Descriptive Scale (FDS): a useful tool to evaluate fatigue in multiple sclerosis. AB - Although fatigue is common among multiple sclerosis (MS) patients, evaluation of this symptom is difficult due to the subjectivity and variability of the complaint. We proposed the Fatigue Descriptive Scale (FDS) as a tool to evaluate the severity and quality of fatigue in a group of patients suffering from MS. As a way to demonstrate the usefulness of this scale we applied the FDS in a group of 155 patients (105 women and 50 men) with clinically-definite multiple sclerosis, as outlined according to Poser's criteria. Age was 36.2 +/- 11.1 years (range 12-62) and time of evolution was 8.3 +/- 9.4 years (range 1-44). The Fatigue Severity Scale (FSS) was also used. Descriptive statistics techniques and techniques for nonparametric distribution (Spearman Rank, Kruskal-Wallis ANOVA) were used. One hundred and eighteen patients reported fatigue (73 spontaneously, 45 when questioned). All descriptions of fatigue were ranked according to FDS categories. Eighty-five patients defined the symptom as fatigue with exercise, 26 as asthenia and seven as the worsening of other symptoms. Fatigue by itself produced limited or disrupted activity in 78 patients; work-related functions were limited in 48 patients; social relations were limited in 29 patients; and self-care difficult for one patient. Fifty-six patients suffered fatigue daily. FDS score was 4.9 +/- 3.9 (range 0-13). FSS was 3.1 +/- 1.7 (range 0.2-6.6). FDS and FSS of Krupp were highly correlated (R = 0.87, p < 0.001). Therefore, in comparison with other scales, the FDS shows remarkable usefulness in classifying, periodicity, and severity of fatigue in MS patients. The high correlation with the FSS implies that it is a valid method to measure the severity of fatigue, as was demonstrated in our paper proposing the FDS. The importance of this new scale is its ability to inform the clinicians in a very quick, easy, and at the same time complete way, how severe the fatigue really is and how it affects the patient. PMID- 10096098 TI - Acute/relapsing experimental autoimmune encephalomyelitis: induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation. AB - Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. We have previously shown that treatment of EAE-mice with high doses of cyclophosphamide (CY) (350 mg kg), followed by syngeneic bone marrow transplantation (SBMT), completely abrogates the clinical paralytic signs and even prevents the appearance of new relapses in the chronic-relapsing model of the disease. In the present study we examined whether this treatment protocol induces long term tolerance and whether this tolerance is antigen-specific. EAE was induced by immunization with spinal cord homogenate (MSCH) in complete Freund's adjuvant (CFA). The treatment with CY and SBMT was performed on day 6 post immunization. Treated and untreated mice were rechallenged with MSCH, or a non-relevant antigen (OVA) in CFA at various stages after the first paralytic attack. In contrast to previous data showing that animals recovering from acute EAE are usually refractory to re-induction of the disease, repeated injections of MSCH at different sites from the initial immunization, followed by i.v. injection of inactivated Bordetella bacteria, 2, 4 and 6 months after the initial EAE induction, caused a severe and usually lethal relapse in all the untreated, control animals. Mice treated with CY and SBMT were resistant to all rechallenges with the same encephalitogenic inoculum. Following the second rechallenge, peripheral lymph node cells were examined in vitro for their proliferative responses to myelin antigens or to OVA. Lymphocytes obtained from CY+SBMT treated mice did not proliferate in vitro in response to myelin basic protein (MBP), but proliferated against OVA, when immunized with this antigen, after SBMT. Adoptive transfer of lymphocytes from tolerant mice to naive recipients did not transfer resistance to EAE-induction. Our results indicate that high doses of CY, followed by SBMT, induce long term antigen-specific tolerance presumably by a mechanism of clonal deletion or anergy. PMID- 10096099 TI - Assessing relapses in treatment trials of relapsing and remitting multiple sclerosis: can we do better? AB - Published Phase III immunomodulatory treatment trials in relapsing and remitting multiple sclerosis have demonstrated a modest decline in attack rates, but only a minor effect on disability. As genuine disability progression is difficult to ascertain in relatively short studies with the conventional rating scales available, the acquisition and analysis of relapse data are critical. However, there are as yet unresolved questions related to the latter. We will first discuss the problems associated with relapse definitions by trial investigators, the paucity of the data collected (especially on the magnitude and duration of exacerbations) and statistical issues in their analysis. We will then suggest practical points for obtaining more accurate information on relapses and evaluating them meaningfully. While there is still general consensus among neurologists that primary endpoints for therapeutic trials should be clinical, improvements for future protocols are essential. PMID- 10096100 TI - [The trends of new drug development in the 21st century]. AB - The trends of new drug development in the 21st century were described. First, the history of drug development including that of the drug delivery system (DDS) was shown. Then, the recent drugs and therapeutic technology were discussed in detail. These topics are biomedicine, gene related technology, vaccine, hybrid artificial organ, chemical and phage library, fetal growth hormone, cell therapy, humanized anti-body and Viagra. In addition, some natural products were introduced, emphasizing the relationship between food and human health. Finally, I stated my opinion about the new drug development in the 21st century in Japan. PMID- 10096101 TI - [Pharmacological evaluation of the development candidate]. AB - In recent years, drugs developed in Japan are used internationally in other countries. The pharmaceutical pre-clinical phase in critical in the drug developing cycle. Pharmacologists contribute to finding the leading compounds and evaluate the right compound for clinical trial. The selection of the right compound for development will save both time and money. In the pharmacological evaluation of a development candidate, in vivo animal studies that can assure the clinician that the drug is both effective and safe are usually required. Studies on the mechanism of action of the drug and how the drug works in the diseased state becomes important since a known target molecule usually serves as the basis for the development of a new drug. PMID- 10096102 TI - [Toxicity evaluation of pharmaceuticals and mechanisms of their effects]. AB - Preclinical studies are defined as experiments other than clinical trials that are conducted in test systems under laboratory conditions for determining the safety of test materials for anticipated human use. It is known that preclinical studies are an indispensable requisite for but constitute time/resource-consuming processes in research and development of new pharmaceuticals. Therefore, they must be designed and conducted in a manner to satisfy the criteria that the obtained data are mutually acceptable among various countries to avoid unnecessary duplication of testing. The purpose of the International Conference on Harmonisation (ICH) has been directed towards the resolution of this issue. Major scientific issues in preclinical studies comprise the interpretation of test data with respect to prediction of potential adverse effects of a test material in humans. Mechanistic consideration of the toxic effects occurring in animals given a test material can usually provide a scientific basis for evaluating the potential hazard of the material in humans. For example, when a test material was found to exhibit a carcinogenic effect in a long-term animal test, one will attempt to determine, on the basis of data from genotoxicity studies, repeated dose toxicity tests, toxicokinetic studies or pharmacology studies on the substance, whether the carcinogenic effect is due to its genotoxicity (genotoxic carcinogen) or a sequela of some secondary mechanisms (non-genotoxic carcinogen). In the cases where a test material was shown to exert toxic effects with either functional manifestation or non-neoplastic morphological manifestation, elucidation of the mechanism will also be useful for extrapolation of animal data to the human situation. It is known that pharmaceuticals induce their toxic effects through various mechanisms such as covalent binding of active intermediates with macrolecules of target cells, oxidative stress-mediated effects, hormone-mediated effects or cytokinemediated effects. As shown in hepatocarcinogenesis or elevation of plasma transaminase activities in rodents attributable to activation of PPAR-alpha, nuclear receptors or ligand-dependent transcription factors are, now, regarded as important targets for toxicity evaluation of pharmaceuticals. PMID- 10096103 TI - [The role of general pharmacological studies and pharmacokinetics in the evaluation of drugs (1): The role of general/safety pharmacology studies in the development of pharmaceuticals: international harmonization of guidelines]. AB - The working group for reevaluation of the Guideline for General Pharmacology Studies has completed a draft guideline for Safety Pharmacology studies and plan to recommend replacing the existing guideline with the revised one. This proposed guideline is now subject to domestic and international consultation. The basic principle of the revision is to harmonize the guideline with the international concepts. The working group decided to change the title of "General pharmacology" to "Safety pharmacology", because the objective of this guideline is to assess the safety of a test substance in humans by examining the pharmacodynamic properties of the substance. The proposed guideline includes studies on vital functions as essential studies that should be performed prior to human exposure. Studies are also required to be conducted when predictable or unexpected observed effects are concerned. The working group recommends a case-by-case approach to select the necessary test items in consideration of the variable information available. PMID- 10096104 TI - [The role of general pharmacological studies and pharmacokinetics in the evaluation of drugs (2): Pharmacokinetics]. AB - Pharmacokinetics studies are performed to clarify the absorption, distribution, metabolism, and excretion of drug candidates. The data are not only useful for the planning of animal toxicity studies and pharmacological studies but also required for establishing the efficacy and safety in humans by indicating the pharmacokinetically appropriate drug formulation and drug usage. Identification of the major metabolic enzymes related to the major metabolism of a drug is also essential for predicting pharmacokinetic drug interactions. Use of human tissues in drug metabolism studies becomes more and more important for rational and efficient drug development. It is necessary to establish an organization in Japan for supplying human tissues originating from the Japanese population. PMID- 10096105 TI - [An evaluation of non-clinical animal data from the point of view of a clinical pharmacologist]. AB - The development of a new chemical entity for human use is a stepwise process based on an assessment of both animal and human data on efficacy and safety of the drug. Clinical pharmacologists always refer to animal data through an Investigator's Brochure (IB) when planning and performing a clinical trial(s). The IB should provide the investigator(s) with useful information to select doses, dosing intervals, and safety monitoring procedures and also to support the clinical management of subjects during the trial(s). Non-clinical animal studies contained in the IB, however, lack a relationship to the pharmacological and toxicological findings of the investigated product(s). Most of the non-clinical animal studies address the methodology and the results obtained, but are lacking in a discussion of the relevance of the findings. The IB should include not only a summary of the findings in each field of animal study but also relationships of the findings through some indicator(s) such as blood and tissue concentrations of the parent drug and/or metabolites. I do hope Pharmaceutical Companies will provide much useful information about their product(s) through the improvement of their system of research and development. PMID- 10096106 TI - [Effects of calcitriol and alfacalcidol on an osteoporosis model in rats with hepatic failure]. AB - To predict the potential utility of calcitriol in human osteoporosis with hepatic dysfunction, we examined the effects of calcitriol and alfacalcidol in ovariectomized (OVX) aged-rats with CCl4-induced hepatic failure. In OVX+CCl4 rats, GOT, GTP, alkaline phosphatase and total bilirubin increased and hepatic enzyme activity (cytochrome b5 and P450) decreased. Repeated oral doses of calcitriol (0.1 and 0.2 microgram/kg) for 51 days inhibited a decrease in serum calcium concentration. This effect was more potent than that of alfacalcidol at the same dose. Both drugs tended to inhibit a decrease in femoral calcium contents. Calcitriol (0.2 microgram/kg) prevented a decrease in femoral bone density (dry and ash weight per volume), unlike alfacalcidol. Soft X-ray imaging analysis revealed that both drugs tended to inhibit the decrease in femoral bone density. There were no differences in the femoral bone strength between OVX+CCl4 and sham-operated rats. The serum calcitriol concentrations increased after the last doses of calcitriol, while they did not increase after the last dose of alfacalcidol. All these effects of calcitriol were related to the serum calcitriol levels. These results suggest that calcitriol, unlike alfacalcidol, may have a clinical therapeutic effect in osteoporosis with hepatic dysfunction. PMID- 10096107 TI - GATHER guide to counseling. PMID- 10096108 TI - Dietary fatty acids and lymphocyte functions. PMID- 10096109 TI - n-3 polyunsaturated fatty acids and immune function. AB - n-3 PUFA have been shown to reduce the risk of cardiovascular and inflammatory diseases. However, they have also been shown to suppress T-cell-mediated immune function, an undesirable effect, especially in immuno-suppressed individuals. Studies have thus far suggested that this immuno-suppression may be in part attributable to increased lipid peroxidation and decreased antioxidant (especially vitamin E) levels, which can be prevented by appropriate vitamin E supplementation. Further well-designed human studies are needed to determine the appropriate levels of n-3 PUFA and vitamin E supplementation to optimize the beneficial anti-inflammatory effect of n-3 PUFA and minimize their suppressive effect on T-cell function. PMID- 10096110 TI - Monounsaturated fats and immune function. PMID- 10096111 TI - In vitro and in vivo effects of n-3 polyunsaturated fatty acids on human monocyte function. PMID- 10096112 TI - The effects of dietary n-3 polyunsaturated fatty acids on neutrophils. AB - The studies of dietary fish oil supplementation in healthy volunteers demonstrate a significant increase in neutrophil EPA content, a concomitant reduction in neutrophil AA content, and suppression of neutrophil LTB4 synthesis by supplementation with dietary fish oil containing approximately 3-4 g EPA daily for a minimum of 4 weeks. Suppression of neutrophil chemotactic responsiveness to LTB4 and FMLP was observed after dietary n-3 PUFA supplementation at these levels. Dietary EPA is more active than DHA in eliciting these effects in human neutrophils. Dietary n-3 PUFA supplementation inhibits neutrophil chemotaxis to these ligands through the inhibition of the signal transduction pathway between the receptor and phospholipase C, as demonstrated by the inhibition of chemotaxin stimulated IP3 formation, in the absence of an effect on the number or affinity of the respective chemotaxin receptors. In patients with RA, dietary supplementation with n-3 PUFA resulted in decreased AA content of cellular lipids, with an augmented EPA content and decreased LTB4 generation by neutrophils. Dietary supplementation with n-3 PUFA also resulted in augmentation of depressed neutrophil chemotaxis to LTB4 and FMLP. Preliminary findings suggest that the decreased responsiveness to chemotaxins of neutrophils from RA patients is due to down-regulation of chemotaxin receptor number, resulting in decreased signaling via chemotaxin receptors. Dietary fish oil PUFA partially reversed the down-regulation of the chemotaxin receptor of neutrophils of RA patients, but had a lesser effect on chemotaxin receptor signaling and function, probably due to a post-receptor inhibition induced by fish oil PUFA, as was previously observed in healthy controls. Several small clinical trials have each suggested that dietary supplementation with n-3 PUFA resulted in modest improvements in disease activity. Meta-analysis of these studies confirms statistically significant improvements in tender joint count and morning stiffness after 3 months of dietary fish oil supplementation in patients with RA. Dietary supplementation with gamma-linolenic acid-rich oils also inhibits neutrophil LTB4 formation, has other anti-inflammatory and immunosuppressive effects, and shows promise of therapeutic efficacy in RA. PMID- 10096113 TI - Dietary lipids and the inflammatory response. PMID- 10096114 TI - The effects of dietary lipids on gene expression and apoptosis. AB - The beneficial effects of dietary FO with respect to autoimmune disease, CVD and some types of cancer are well established. Studies conducted over the last 10-15 years have established the potent effects of FO on gene expression in the previously mentioned diseases. The effects of dietary FO appear to be selective in nature, with the expression of individual genes simultaneously being increased, decreased or completely unaffected. In order to elucidate the molecular mechanism(s) involved, recent studies have focused on analysing the effects of the long-chain polyunsaturated n-3 fatty acids EPA and DHA which are highly enriched in FO and thought to be the primary mediators of its biological activity. Indeed, it has been found that EPA and DHA appear to both directly and indirectly modulate gene expression in vivo, depending on the gene examined. The direct effects of EPA and DHA are most probably mediated by their ability to bind to positive and/or negative regulatory transcription factors, while the indirect effects appear to be mediated through alterations in the generation of intracellular lipid second messengers (e.g. diacylglycerol and ceramide). Future studies need to be focused on further elucidation of the inter- and intracellular signalling events mediated by dietary n-3 fatty acids. Understanding the molecular mechanism(s) modified by dietary FO will ultimately lead to improved dietary strategies to aid in the prevention of autoimmune disease, CVD and/or certain types of cancer. PMID- 10096115 TI - Phospholipase A2 (EC 3.1.1.4) and D (EC 3.1.4.4) signalling in lymphocytes. PMID- 10096116 TI - Dietary n-6 and n-3 fatty acids in immunity and autoimmune disease. AB - Clearly there is much evidence to show that under well-controlled laboratory and dietary conditions fatty acid intake can have profound effects on animal models of autoimmune disease. Studies in human autoimmune disease have been less dramatic; however, human trials have been subject to uncontrolled dietary and genetic backgrounds, infection and other environmental influences, and basic trial designs have been inadequate. The impact of dietary fatty acids on animal autoimmune disease models appears to depend on the animal model and the type and amount of fatty acids fed. Diets low in fat, essential fatty acid-deficient, or high in n-3 fatty acids from fish oils increase the survival and reduce disease severity in spontaneous autoantibody-mediated disease, whilst linoleic acid-rich diets appear to increase disease severity. In experimentally-induced T-cell mediated autoimmune disease, essential fatty acid-deficient diets or diets supplemented with n-3 fatty acids appear to augment disease, whereas n-6 fatty acids prevent or reduce the severity. In contrast, in both T-cell and antibody mediated auto-immune disease the desaturated and elongated metabolites of linoleic acid are protective. Suppression of autoantibody and T lymphocyte proliferation, apoptosis of autoreactive lymphocytes, and reduced pro inflammatory cytokine production by high-dose fish oils are all likely mechanisms by which n-3 fatty acids ameliorate autoimmune disease. However, these could be undesirable long-term effects of high-dose fish oil which may compromise host immunity. The protective mechanism(s) of n-6 fatty acids in T-cell- mediated autoimmune disease are less clear, but may include dihomo-gamma-linolenic acid- and arachidonic acid-sensitive immunoregulatory circuits such as Th1 responses, TGF beta 1-mediated effects and Th3-like responses. It is often claimed that n-6 fatty acids promote autoimmune and inflammatory disease based on results obtained with linoleic acid only. It should be appreciated that linoleic acid does not reflect the functions of dihomo-gamma-linolenic and arachidonic acid, and that the endogenous rate of conversion of linoleic to arachidonic acid is slow (Hassam et al. 1975, 1977; Phylactos et al. 1994; Harbige et al. 1995). In addition to effects of dietary fatty acids on immunoregulation, inflammation as a consequence of immune activation in autoimmune disease may also be an important mechanism of action whereby dietary fatty acids modulate disease activity. In conclusion, regulation of gene expression, signal transduction pathways, production of eicosanoids and cytokines, and the action of antioxidant enzymes are all mechanisms by which dietary n-6 and n-3 fatty acids may exert effects on the immune system and autoimmune disease. Probably the most significant of these mechanisms in relation to our current understanding of immunoregulation and inflammation would appear to be via fatty acid effects on cytokines. The amount, type and balance of dietary fatty acids and associated antioxidant nutrients appear to impact on the immune system to produce immune-deviation or immunosuppressive effects, and to reduce immune-mediated inflammation which will in turn affect the susceptibility to, or severity of, autoimmune disease. PMID- 10096117 TI - n-6 and n-3 essential fatty acids in rheumatoid arthritis and other rheumatic conditions. PMID- 10096118 TI - The anti-cachectic effect of fatty acids. PMID- 10096119 TI - Use of fish oil to prevent graft rejection. PMID- 10096120 TI - Protein-energy malnutrition in older subjects. PMID- 10096121 TI - Malnutrition or healthy senescence. PMID- 10096122 TI - Nutrition assessment methods for the older Irish adult in the clinical and community settings. PMID- 10096123 TI - Taste and flavour perception. PMID- 10096124 TI - Taste, palatability and the control of appetite. PMID- 10096125 TI - Development of food acceptance patterns in the first years of life. AB - As young omnivores, children make the transition from the exclusive milk diet of infancy to consuming a variety of foods. They must learn to accept a set of the foods available in their environmental niche, and they 'come equipped' with a set of predispositions that facilitate the development of food acceptance patterns, constrained by predisposition and limited by what is offered to them. While children are predisposed to like sweet or salty foods and to avoid sour or bitter foods, their preferences for the majority of foods are shaped by repeated experience. The predispositions that shape food acceptance patterns also include neophobia and the predisposition to learn to prefer and accept new foods when they are offered repeatedly. In addition, the predisposition for associative conditioning affects children's developing food acceptance patterns, resulting in preferences for foods offered in positive contexts, while foods presented in negative contexts will become more disliked via the learning of associations with the social and environmental contexts. Children also learn to prefer energy-dense foods when consumption of those foods is followed by positive post-ingestive consequences, such as those produced when high-energy-density foods are eaten when hungry. Although children are predisposed to be responsive to the energy content of foods in controlling their intake, they are also responsive to parents' control attempts. We have seen that these parental control attempts can refocus the child away from responsiveness to internal cues of hunger and satiety and towards external factors such as the presence of palatable foods. This analysis suggests that taking a closer look at what children are learning about food and eating may provide clues regarding the formation of children's food acceptance patterns, and that this approach also suggests potential causative factors implicated in the aetiology of obesity and the emergence of weight concerns. Current data, although limited, suggest that child-feeding practices play a causal role in the development of individual difference in the controls of food intake, and perhaps in the aetiology of problems of energy balance, especially childhood obesity. These relationships should be pursued in future research. PMID- 10096126 TI - Taste and appetite regulation in the elderly. PMID- 10096127 TI - Clinical undernutrition states and their influence on taste. PMID- 10096128 TI - Taste and flavour: their importance in food choice and acceptance. PMID- 10096129 TI - Mutants of Kluyveromyces lactis with altered protein glycosylation are affected in cell wall morphogenesis. AB - We isolated spontaneous mutants resistant to sodium orthovanadate in the biotechnologically significant yeast Kluyveromyces lactis. Resistance behaved as a recessive character in all mutants analyzed. Four genes were defined by complementation analysis, from vga1 to vga4. These mutants showed defects in N linked as well as O-linked glycosylation processes. In addition, the mutants exhibited sensitivity to the aminoglycoside hygromycin B and to calcofluor white, with the exception of vga4; this mutant grew in the presence of the antibiotic as well as the parental wild type and was resistant to calcofluor. The mutations were accompanied by alterations in the cell wall structure, as revealed by the delocalization of chitin, changes in cell shape and size and by the clumpy aspect of the cultures. The mutants isolated provide basic tools for molecular and cellular analysis of glycosylation processes in K. lactis. PMID- 10096130 TI - Secondary metabolites of Aspergillus exert immunobiological effects on human monocytes. AB - This project focused on the effects of aflatoxin B1 (AFB1), a food-contaminating mycotoxin produced by fungi, genus Aspergillus, on the release and genetic expression of some important cytokines, i.e., (interleukin-1 alpha (IL-1 alpha), IL-6, tumor necrosis factor-alpha (TNF alpha)) by human monocytes. Monocytes, preincubated for different time periods with concentrations of AFB1 ranging from 0.01 to 1.0 pg/mL, were then activated with bacterial lipopolysaccharide. Cytokine levels were measured by immunoassay and mRNA by cDNA amplification. Pretreatment of monocytes with AFB1 resulted in a decrease in IL-1, IL-6 and TNF alpha release already at a concentration of 0.05 pg/mL. The gene expression of the cytokines considered was drastically affected by treatment with AFB1. In fact, AFB1 completely blocked the transcription of IL-1 alpha, IL-6 and TNF alpha mRNAs, while it did not affect beta-actin mRNA at the concentrations used. It therefore appears that AFB1 exerts its effect on cytokine release through selective inhibition of specific mRNA, without affecting general protein synthesis. PMID- 10096131 TI - The role of the codon first letter in the relationship between genomic GC content and protein amino acid composition. AB - Analysis of the statistical distribution of amino acid compositions within 22 protein families shows that a GC bias generally affects proteins with a variety of functions from the extreme thermophile Thermus. This results in evident enrichment in amino acids of the group L, V, A, P, R and G and underrepresentation of amino acids of the group I, M, F, S, T, C and W. The strong amino acid composition biases noted in Thermus proteins are not related to thermoadaptation; they were also found in mesophilic homologues encoded by GC rich genes. The results of a comparative analysis on large samples of translated sequences from 30 organisms, representing the three major kingdoms of life and including extremophiles, indicate a universal correlation between the usage of particular amino acids and the genomic GC content. It is concluded that the codon first letter plays a dominant role in translating the genomic GC signature into protein amino acid composition and sequences. PMID- 10096132 TI - Predictive modelling of fluorescent AFLP: a new approach to the molecular epidemiology of E. coli. AB - Amplified fragment length polymorphism (AFLP) permits simultaneous sampling of multiple loci distributed throughout a genome, using restriction site/adaptor specific primers under stringent conditions. Fluorescent detection instrumentation further refines this methodology, permitting internal size standards and accurate, reproducible sizing of amplified fragments. We have evaluated the potential of fluorescent AFLP (FAFLP) as a potentially definitive genotyping method for bacteria, by comparing MseI/EcoRI fragments derived experimentally from the Escherichia coli K12 MG1655 genome with those predicted by analysis of its published sequence. In silico, MseI/EcoRI digestion of this sequence produced 1200 fragments from 36 and 2151 base pairs (bp) in size. Fragment subsets which would be amplified by seven different selective (1-2 bases added to the 3' end of the core primer sequence) primer combinations were modelled. Depending on the primer pair, three to 54 fragments (range 70-400 bp) were predicted, while all seven primer pair combinations together generated 121 predicted fragments. When genomic DNA of strain MG1655 was subjected to experimental FAFLP with these seven primers, 111 correctly sized fragments were observed (+/- 1 bp) out of the 121 predicted (92% accuracy). Twenty-five unpredicted fragments were obtained; an average of four per primer pair. The size and number of fragments in FAFLP, and their gel distribution, were dictated by the choice of restriction endonucleases and the degree of primer selectivity. Our data show that FAFLP is accurate, discriminatory, reproducible and capable of standardisation. Under agreed conditions, this method shows considerable promise as a generally applicable standardised bacterial genotyping method. The fragments predicted in silico to result from amplification of MseI/EcoRI-digested DNA with the seven primer pairs described are here used to define a prototypic FAFLP analysis of E. coli. PMID- 10096133 TI - Isolation and characterisation of a new antagonistic Burkholderia strain from the rhizosphere of healthy tomato plants. AB - A new Burkholderia strain (PVFi5A) which exhibits antagonism towards many bacterial and fungal plant pathogens has been partially characterised. This strain was isolated from the rhizosphere of tomato plants and was referred to the Burkholderia cepacia complex on the basis of cultural, morphological and biochemical characteristics, including determination of the 16S ribosomal DNA sequence and fatty acid profile. Strain PVFi5A is a Gram-negative, aerobic bacterium, oxidase- and catalase-positive, motile with a polar tuft of flagella, able to grow on a variety of media without producing diffusible pigments; it is avirulent to onion, able to grow at 41 degrees C and resistant to several antibiotic substances. Its fatty acid profile contains the hydroxy acids 18:1 20H, 14:0 3OH and 16:0 3OH, but not the hydroxy acids 16:0 2OH. The antagonistic activity of strain PVFi5A is due to its production of various, as yet unidentified, antimicrobial compounds, one or more of which may differ from those reported previously for certain 'B. cepacia' strains. The ability of PVFi5A to suppress the growth of important bacterial and fungal phytopathogens makes this strain a potential biocontrol agent. PMID- 10096134 TI - Genetic relatedness between oral and intestinal isolates of Porphyromonas endodontalis by analysis of random amplified polymorphic DNA. AB - Genomic fingerprints from the DNA of 27 strains of Porphyromonas endodontalis from diverse clinical and geographic origins were generated as random amplified polymorphic DNA (RAPD) using the technique of PCR amplification with a single primer of arbitrary sequence. Cluster analysis of the combined RAPD data obtained with three selected 9- or 10-mer-long primers identified 25 distinct RAPD types which clustered as three main groups identifying three genogroups. Genogroups I and II included exclusively P. endodontalis isolates of oral origin, while 7/9 human intestinal strains of genogroup III which linked at a similarity level of 52% constituted the most homogeneous group in our study. Genotypic diversity within P. endodontalis, as shown by RAPD analysis, suggests that the taxon is composed of two oral genogroups and one intestinal genogroup. This hypothesis remains to be confirmed. PMID- 10096135 TI - Oil-degrading Acinetobacter strain RAG-1 and strains described as 'Acinetobacter venetianus sp. nov.' belong to the same genomic species. AB - Acinetobacter strain RAG-1 (ATCC 31012) is an industrially important strain which has been extensively characterized with respect to its growth an hydrocarbons and its production of a high molecular mass bioemulsifier, emulsan. Although RAG-1 has been investigated in detail for specific biochemical characteristics, its taxonomic status is uncertain and it is usually referred to as A. lwoffii or A. calcoaceticus sensu lato. However, results obtained by restriction analysis of the amplified rDNA and subsequently substantiated by DNA-DNA hybridization, partial 16S rDNA nucleotide sequence comparison and biochemical characterization indicate that RAG-1 belongs to the genomic species recently described as 'A. venetianus'. Furthermore, these data confirm that 'A. venetianus' constitutes a new and distinct genomic species within the genus Acinetobacter. PMID- 10096136 TI - [Child psychiatry aspects of enuresis nocturna]. AB - Nocturnal enuresis is associated with emotional suffering. Psychoanalytic claims of a psychogenic aetiology are not tenable. The rate of behavioural disorders is significantly higher among wetting children, especially among day wetters and secondary nocturnal enuretics. Still, most wetting children are not psychiatrically disturbed. A symptom-oriented therapy with an alarm can raise the self-concept and feelings of self-worth. Play-therapies are indicated only when emotional disorders co-exist. A case of a sandplay therapy is presented, which demonstrates that in addition to empirical methodology, a hermeneutic approach is needed to understand the child's subjective experience and meaning. PMID- 10096137 TI - [Drug therapy of enuresis: sense/nonsense]. AB - Nocturnal enuresis is a very common disorder in childhood. Classification and evaluation through patient history, physical examination, ultrasound of the kidneys and bladder including residual volume, dipstix and urine output protocol are necessary for successful treatment. Genetic, family-associated factors and a lowered nocturnal ADH-secretion are the main causes considered today. Next to behavioral therapy and conditioning, pharmacotherapy form the mainstay of therapy. Desmopressin is indicated when the nocturnal urinary volume exceeds the actual bladder capacity. Together with the right indication and optimal dosage, the therapy should be given for at least 4 to 6 weeks before step-by-step reduction, resulting in a success rate of up to 80%. PMID- 10096138 TI - [Urodynamic studies in the child with urinary incontinence]. AB - Voiding disorders in children are frequent. To establish an exact anamnesis, it has to be distinguished between enuresis and incontinence and this may consequently already have a therapeutical effect. Enuresis is defined as a normal void occurring at an inappropriate time or place. Incontinence is an involuntary loss of urine and a pathological voiding habit, often in combination with urinary infections. The causes of an enuresis are always functional, the causes for incontinence may be organic or functional. Organic causes are neurogenic bladder dysfunctions or structural anomalies of the lower urinary tract. The functional causes are divided in urge incontinence, dysfunctional voiding, lazy bladder syndrome and stress incontinence. The most important screening examination in each child with voiding disorders is the uroflowmetry, in combination with an electromyography (EMG) of pelvic floor and abdominal muscles. For registration of the muscle activity, surface electrodes are used that only show muscle groups, but do not hurt on application. Cystometry, an invasive method, is used as a second step. The therapy of functional incontinence consists in bladder training, physiotherapy of the pelvic floor and biofeedback. Medicaments are given in second priority. The therapy of functional voiding disorders is only successful in cooperation with the child and its parents. PMID- 10096139 TI - [Neurogenic disorders of bladder emptying in childhood]. AB - The treatment of neurogenic bladder dysfunction must be aimed at the protection of the upper urinary tract through complete bladder emptying and normalization of intravesical bladder pressures in rest and during voiding. Nowadays also urinary continence should be restored in childhood. Based on the urodynamic classification modified by Madersbacher the current treatment strategies are presented. Individual pharmacotherapy, especially pharmacological transformation of detrusor hyperreflexia into hyporeflexia and clean intermittent catheterization are the main conservative therapeutic tools. In special cases bladder augmentation, cutaneous vesicostomy and artificial sphincter devices are the method of choice, while bladder substitution should be performed as a last resort. PMID- 10096140 TI - [Differential enuresis nocturna diagnosis]. AB - The symptom of enuresis can be a feature of many conditions, including renal, neurological and organic disease states. It is important to differentiate primary nocturnal enuresis from secondary enuresis and from daytime incontinence with a nocturnal component. It is recommended that the routine investigation of enuretic children should comprise four components: structured interview, physical examination, urine analysis and ultrasound investigation. Additional intensified diagnostic and invasive procedures should be reserved for patients with suspected neurological disorders or urological dysfunction. PMID- 10096141 TI - [Urethral valves and urinary incontinence: bladder function in temporary high diversion]. AB - We report on urodynamic follow-up studies in patients (mean age 8.4 years) with posterior urethral valves (PUV), in which the operative management was finished between 1992 and 1997. The initial therapy included valve resection and transurethral or suprapubic vesical diversion. QUESTION: Does a temporary high diversion have a negative effect on bladder function? Study A was performed at a mean age of 14 months after a high diversion (Sober-non end ureterocutaneostomy) was required for the protection of the dilated upper urinary tract in 7 patients and 13 ureterorenal units. In mean 5.2 years later Study B was performed after undiversion and, in most cases, ureteral reimplantation. In study A the boys with ureterostomy demonstrated higher pathological compliance, capacity and detrusor function. In study B all patients showed improvement of compliance, capacity and detrusor hyperactivity. Surprisingly we found higher values for compliance and capacity in the children with temporary high diversion. CONCLUSION: Improvement of urodynamic results after valve ablation is possible even after bilateral temporary high diversion (Sober stoma). No 'low compliance-low capacity-bladder' developed. PMID- 10096143 TI - Diagnosis and treatment of adrenal disorders. PMID- 10096142 TI - [Enuresis and pediatric urinary incontinence--epidemiology, diagnosis and therapy today]. AB - To describe epidemiology, diagnosis and therapy of enuresis and urinary incontinence in children we have to work with exact definitions. Enuresis is defined as a normal nearly complete emptying of the bladder at a wrong locality at a wrong time at least twice a month after the 5th year of life. Enuresis is regarded as delayed development of bladder function. From enuresis we have to differentiate urinary incontinence in children, which is any kind of loss of urine without normal emptying the bladder. Wetting in those cases is a symptom of a disease (structural, neurogenic, psychogenic or functional). A detailed anamnesis is the most important diagnostic tool in enuresis whereas in the case of urinary incontinence a lot of diagnostics from non-invasive to invasive have to be performed. Enuresis can be treated with alarm or you can apply Desmopressin (DDAVP). Therapy of urinary incontinence in children depends on the disease causing the symptom of wetting. PMID- 10096144 TI - Current concepts in imaging of adrenal masses. AB - Adrenal masses are a common entity. With the advent of improved cross-sectional imaging techniques the detection and characterization of adrenal masses has improved dramatically. We review the imaging features of benign and malignant adrenal masses and other entities that may cause mass-like enlargement of the adrenal glands. PMID- 10096145 TI - Management of incidentally discovered adrenal masses. AB - The incidental discovery of adrenal masses in radiologic imaging studies is becoming increasingly common. Herein we present our experience with 59 cases of incidentally discovered and surgically removed adrenal masses. Of 59 adrenal incidentalomas, 15 cases were hypersecretory tumors, including 11 pheochromocytomas; only 3 were adrenocortical carcinomas. The prevalence of incidentally discovered adrenal masses and their differential diagnosis and management are discussed in a review of the literature. PMID- 10096146 TI - Diagnosis and treatment of primary aldosteronism. AB - Disorders of the adrenal cortex and medulla are often associated with hypertension, which can be cured surgically in many cases or may require specific and timely medical treatments. Therefore, knowledge of adrenal physiology, biochemistry, and molecular biology is essential such that an appropriate diagnostic evaluation can be conducted efficiently. The most common hypertensive disorder of the adrenal cortex is primary aldosteronism. Aldosterone-producing adenoma is the most common form of primary aldosteronism and is most likely to be cured by unilateral adrenalectomy when aldosterone production is highly autonomous from renin-angiotensin, lateralizes to one adrenal gland, and is associated with overproduction of 18-hydroxycortiocosterone and C18 methyloxygenated metabolites of cortisol. Variants of adrenal hyperplasia that share these characteristics can also be cured by unilateral adrenalectomy. PMID- 10096147 TI - Contemporary evaluation and management of Cushing's syndrome. AB - Cushing's syndrome, characterized by unregulated cortisol secretion, may be caused by a variety of adrenal, pituitary, or other tumors. The best biochemical test for establishing the diagnosis is determination of 24-h urinary free cortisol. The specific causes for Cushing's syndrome may be further differentiated by plasma adrenocorticotrophic hormone (ACTH). Primary adrenal cortical diseases are associated with low levels of ACTH and are considered ACTH independent. Pituitary disease and the ectopic ACTH syndrome are associated with normal or elevated ACTH levels and are considered ACTH-dependent. Adrenal forms of Cushing's syndrome may result from either adenoma or carcinoma. The diagnostic approach to Cushing's syndrome and the clinical, biochemical, and radiographic features that distinguish adrenal adenoma and carcinoma are the subjects of this paper. 65-75% of CS [14, 15]. Most cases of Cushing's disease are the result of pituitary adenomas; however, corticotrope hyperplasia is responsible for a small minority of cases. Ectopic production of ACTH from a variety of tumors (bronchial carciniod, thymoma, oat-cell carcinoma, pheochromocytoma, islet-cell tumor, and prostate cancer) accounts for 10-15% of CS. Primary adrenocortical diseases account for the remaining 20-30% of CS, including benign adenoma (10-15%), adrenocortical carcinoma (5-10%), and adenomatous hyperplasia (5%). The purpose of this review is to present a contemporary approach to the evaluation and management of patients with Cushing's syndrome, emphasizing the primary adrenal etiologies pertinent to urologists. PMID- 10096148 TI - Adrenocortical carcinoma. AB - Adrenocortical carcinoma is rare, tends to occur in the first decade as well as the fourth and fifth decades of life, and is slightly more common in women. The tumors are classified as functional or nonfunctional, depending on tumor production of corticosteroid, androgen, estrogen, or mineralocorticoid. Most patients present with large masses and with stage IV disease. Abdominal computerized tomography and magnetic resonance imaging are used in the evaluation of intra-abdominal disease. The most effective treatment for adrenocortical carcinoma is complete resection. Surgical resection remains the only potentially curative treatment for this disease. Early stage and curative resection are the two clinical factors that are of prognostic significance for long-term survival. Mitotane is the chemotherapeutic agent most often used to treat adrenocortical carcinoma. Its efficacy in prolonging survival is limited but may be enhanced by monitoring of serum levels and their maintenance at elevated values. Even for patients who undergo complete resection, recurrent and metastatic disease are extremely common. The only effective treatment for recurrent disease is reoperation. PMID- 10096149 TI - Pheochromocytoma: evaluation, diagnosis, and treatment. AB - Pheochromocytoma is a catecholamine-producing tumor of the sympathetic nervous system. Signs and symptoms are generally related to catecholamine excess; these include hypertension, sweating, palpitatione, headaches, and anxiety attacks. Abdominal imaging and 24-h urine collection for catecholamines are usually be sufficient for diagnosis. Catecholamine blockade with phenoxybenzamine and metyrosine generally ameliorates symptoms and is necessary to prevent hypertensive crisis during surgery. Standard treatment is laparoscopic adrenalectomy, although partial adrenalectomy is gaining enthusiastic support in familial forms of pheochromocytoma. Pheochromocytomas have been estimated to be present in approximately 0.3% of patients undergoing evaluation for secondary causes of hypertension [41]. Pheochromocytomas are usually curable if diagnosed and treated properly, but they can be fatal if they are not diagnosed or are managed inappropriately. Autopsy series suggest that many pheochromocytomas are not clinically suspected and that the undiagnosed tumor can be associated with morbid consequences [42]. PMID- 10096150 TI - Surgical options for open adrenalectomy. AB - We are fortunate that our ability to diagnose the specific adrenal entities that mandate a surgical approach is extremely accurate. The combination of analytical methodology to measure the appropriate adrenocortical and medullary hormone production and the radiology techniques for localization are superb. The management of these adrenal disorders with precise surgical precision following localization is highly successful, resulting in a reversal of both metabolic abnormalities and the hypertension that often accompanies these diseases. Indeed, this has become a true success story with the evolution of these different techniques over the past 50 years. PMID- 10096151 TI - Lateral transperitoneal laparoscopic adrenalectomy. AB - Several laparoscopic approaches to the adrenal gland have been described. The lateral transperitoneal approach has several distinct advantages when contrasted with other techniques for laparoscopic adrenalectomy (LA). We present our technique and results obtained in 50 consecutive transperitoneal LAs. We review 50 consecutive laparoscopic adrenalectomies (28 female, 19 male) performed from 1993 to 1998 S.J. Shichman or R.E. Sosa was either the primary surgeon or the first assistant for all cases. The lateral transperitoneal approach described below was used in all cases. Indications for adrenalectomy included Cushing's syndrome (13), aldosteronoma (15), pheochromocytoma (7), nonfunctioning adenoma (11), hyperplasia (2), and 1 case each of Carney's syndrome and metastasis to the adrenal gland. We performed 5 bilateral, 22 left, and 18 right laparoscopic adrenalectomies. The average time needed for bilateral adrenalectomy was 503 min (range 298-690 min); for left adrenalectomy, 227 min (range 121-337 min); and for right LA, 210 min (range 135-355 min). We demonstrated a yearly trend in lower operative times. The largest adrenal gland removed measured 13.8 x 6.7 x 3.5 cm. Intraoperative blood loss was low. Only one patient received a blood transfusion. Conversion to open adrenalectomy was not required. Postoperative analgesic requirements were low. The average length of stay was 3.8 days for bilateral LA and 3 days for unilateral LA. Complications occurred in 5 patients (2 wound infections, 2 hematomas, and 1 pleural effusion). There was no mortality. Lateral transperitoneal adrenalectomy is a safe and efficient technique for the removal of functional and nonfunctional adrenal masses. This technique is associated with low morbidity, a minimal postoperative analgesic requirement, and a short hospital stay and, in our opinion, is more versatile than the retroperitoneal approach. PMID- 10096152 TI - Retroperitoneoscopic adrenalectomy by a lumbodorsal approach: clinical experience with solo surgery. AB - Laparoscopic adrenalectomy by transperitoneal approaches necessitates the retraction of intraperitoneal organs and, hence, the creation of extra ports for retractors and assistants. The feasibility of retroperitoneoscopic adrenalectomy by a lumbodorsal approach was assessed in 26 patients with adrenal tumors. In six patients the procedure was carried out as solo surgery using the ABSOP robot camera holder, and the performance was compared with that reported for the most recent series of six cases operated upon with one human assistant. The procedures were successful in 25 patients. One patient had to be converted due to tension pneumothorax caused by diaphragmatic injury. The mean blood loss was 43.5 +/- 67.5 ml, and the procedure time averaged 144 +/- 33 min. We required an average of only 3.1 trocars to accomplish solo surgery in 5 of 6 patients (83%). The number of lens smearings decreased to one-fourth of that observed by a human assistant. PMID- 10096153 TI - Acute and chronic interstitial cryotherapy of the adrenal as a treatment modality. AB - Adrenalectomy is indicated for patients with large adrenal lesions or functional tumors. Cryoablation is currently used as a surgical alternative for the treatment of prostate, lung, brain, pharynx, and liver tumors. The purpose of this study was to determine if cryosurgery could be delivered to small areas in the adrenal gland in a controllable and reproducible manner such that tissue could heal in a nonpathologic way. A total of 14 female mongrel dogs underwent acute (n = 8) or chronic (4 weeks, n = 6) cryoablation using the Cryounit. In the acute study using an open transabdominal approach a 2-mm cryoprobe was placed interstitially into the adrenal tissue, whereas 0.032-inch thermocouples were cannulated into the ipsilateral adrenal artery and vein. Adrenal parenchymal temperature changes were measured using 0.032-inch thermocouples placed at 0.4- and 0.8-cm intervals from the cryoprobe. In the chronic study, cryoablation was achieved by transperitoneal laparoscopic access using a standard laparoscopic technique. Interstitial cryoprobe temperatures decreased from 33.1 +/- 1.9 degrees C to -148 +/- 1.2 degrees C following 15 min of freezing in the acute study. Cryoablation of adrenal tissue achieved temperatures of -41.8 +/- 5.7 degrees C and -21.8 +/- 1 degrees C at distances of 0.4 and 0.8 cm from the cryoprobe, respectively. There was no significant change in adrenazl artery or vein temperatures during cryoablation. Histologically there is a clear demarcation between viable and nonviable tissue characterized by areas of multifocal hemorrhage and pyknosis. After 4 weeks of healing a well-defined line of necrotic and viable tissue is visible. Cryoablation of the adrenal can be delivered in an effective, controllable, and reproducible manner. This controllable energy form may provide a new treatment modality for tissue destruction where adrenal gland preservation is necessary and can be performed by the laparoscopic approach. Understanding the effect of adrenal cryoablation may allow us to treat selected patients with small tumors where organ preservation is necessary. PMID- 10096154 TI - [Comments on the new child custody law]. PMID- 10096155 TI - [Anorexia nervosa--the triad of metric index, BMI age-specific percentile curve and goal weight]. AB - Cross sectional and longitudinal data from the Berlin Anorexia Study on the inpatient treatment of n = 133 adolescent females with the principal axis I diagnosis of an eating disorder (n = 104 anorexia nervosa, n = 19 bulimia nervosa, n = 10 eating disorders not otherwise specified; according to ICD-10 and DSM-IV criteria) indicate a significant shift in the frequency distribution of somatometrically assessed types of body shape among patients as categorized by the Metric Index, towards the leptomorphic phenotype (p < 0.050, chi 2/Fisher's). Three explanatory models are discussed. Diagnostic and therapeutic implications, particularly of the determination of target weight in anorexia nervosa based on the individual's type of body shape, are emphasized, and an operational algorithm is proposed which uses the Metric Index and sex-specific BMI age percentiles adjusted for type of body shape. PMID- 10096156 TI - [Family processes in attention and hyperactivity disorder]. AB - The parenting behavior of mothers and interaction within the family were assessed by means of a multi-method procedure consisting of a questionnaire, sculpture test, behavior observation and the data of N = 36 subjects. Analyzed were the data of father, mother and child in six families, each with a boy aged 9 to 12 years who had been diagnosed as hyperactive on the basis of behavior checklists. A second group of six families served as paralleled controls. Mothers of hyperactive children more often report use of punishment as a means of influencing the behavior of their children. Independent observers confirm this, seeing that mothers of hyperactive children more frequently use negative and oppositional behavior and adverse consequences than do mothers of "normal" children. The interaction of father, mother and child in discussing a family conflict was characterized in the clinical group by more use of negative and less use of positive social behavior. Families with a hyperactive child more often attempted to interrupt each other and gave other members of the family less of an opportunity to exert an influence. Different instruments to assess the emotional cohesion and hierarchy within a family revealed significant differences between the two groups. PMID- 10096158 TI - [Incidence of post-traumatic stress disorder in adolescents: results of the Bremen Adolescent Study]. AB - The frequency and comorbidity of posttraumatic stress disorders (PTSD) were assessed together with the resultant psychosocial impairment in 1035 adolescents between the ages of 12 and 17 years. Posttraumatic stress disorder and other psychiatric disorders were coded on the basis of the DSM-IV criteria using the computerized personal interview of the Munich version of the Composite International Diagnostic Interview (CIDI). A total of 17 (1.6%) adolescents met the DSM-IV criteria for PTSD at some point in their life. Slightly more girls than boys met the criteria for the disorder, whose frequency increased with age. The lifetime prevalence of traumatic events is much higher still: 233 (22.5%) adolescents reported one or more traumatic events in their life. The types of traumatic events experienced by the greatest number of adolescents were: physical attack, injury, and serious accident. Boys experienced significantly more traumatic events than did girls. The occurrence of a traumatic event was mostly associated with hypervigilance and recurrent and intrusive psychological distress upon exposure to cues which symbolized the event itself or resembled an aspect thereof. PTSD occurred in highly frequent comorbidity with depressive disorders, somatoform disorders, and substance abuse. Over 90% of those with posttraumatic stress disorder were severely impaired in their daily life and activities. Despite the high-grade psychosocial impairment, only a small number sought professional help. PMID- 10096157 TI - [Test construction, analysis and trial of the Heidelberg Sound Discrimination Test for measuring auditory-kinesthetic perceptual discrimination acuity]. AB - The provisional trial was carried out in a sample of 133 second- and 139 fourth graders from the Heidelberg area. The HD-LT was subjected to an item selection, test criteria were ascertained and temporary percentile norms for the second and fourth grades were established. High item difficulty resulted for both grades, i.e. the test was relatively easy. Test criteria were generally satisfactory. Significant correlations were found in both grades between the HD-LT and the children's spelling ability. The HD-LT accounted for 30% of the spelling variance among second-graders as compared to 10% of that among fourth-graders. This reflects the specific significance of phonetic discrimination ability in the first years of elementary school. Children with spelling difficulties were compared to those with good spelling abilities in respect to their ability to discriminate sound. Spelling-impaired children in both grades exhibited a significantly lower overall HD-LT score. No significant sex differences were found with regard to the auditory and kinesthetic phonetic discrimination ability. Since the HD-LT turns out to be well-suited to indicate a phonetic discrimination disability during the initial phases of acquisition of written language, its further development and extension of its application to the pre school level are recommended. PMID- 10096159 TI - [Urodynamics in diagnosis and therapy of "enuresis"--relevance for child and adolescent psychiatry]. AB - Enuresis and functional urinary incontinence are clinically and pathophysiologically heterogeneous disorders. They differ with regard to their urodynamics, i.e. with regard to the function or dysfunction of the urinary tract. In addition to general measures such as history, physical examination, urinalysis, questionnaires and flow charts, noninvasive sonography and uroflowmetry with pelvic-floor EMG play an important role in diagnosis and therapy. Rates of pathological findings are especially high among day-wetting children and nocturnal enuretics with micturition problems. This group requires a detailed diagnosis, especially children with detrusor-sphincter discoordination, which can be treated effectively by means of uroflow-biofeedback. The relevance of these methods in child and adolescent psychiatry are discussed in detail and practical recommendations are made. PMID- 10096160 TI - [Behavioral pattern and behavioral characteristics of children in two pediatric clinics]. AB - OBJECTIVES: To describe systematically patterns of behavior of children and parents in pediatric hospitals. METHODS: A questionnaire to systematically rate behavior of children and parents was administered by nurses to two independent samples in two different pediatric hospitals. At the von Haunersches Kinderspital, Klinikum Innenstadt of the Ludwig-Maximilian-University of Munich, 659 children were rated, at the Pediatric Hospital of the University of Freiburg, 484 children. Latent class analysis grouped children/parents according to similar patterns of behavior. RESULTS: In Munich a five-class model is most appropriate to classify children/parent behavior, in Freiburg a six-class model best first the data. Four classes in Munich and in Freiburg display nearly identical profiles. Three of them describe inconspicuous behavior of children in different age groups, whereas the fourth group describes disturbed children. These four groups classify 87% of the children in Munich and 73% of those in Freiburg. In Munich 25% of the children are rated as disturbed, as opposed to 39% in Freiburg. CONCLUSIONS: The questionnaire is suitable for everyday clinical practice. Results of both samples mostly correspond. Remaining differences are caused by type of hospital (pediatrics vs. pediatric surgery) and by the differing depth of nurses' rater training. PMID- 10096161 TI - Editorial emerging, re-emerging and drug-resistant infections: a global threat. PMID- 10096162 TI - Growth medium affects the cellular fatty acid composition of Pasteurellaceae. AB - We studied the cellular fatty acid composition of 10 Actinobacillus (A.) and Pasteurella (P.) reference strains grown on 2 types of agar by the MIDI Microbial Identification System (MIS). A. capsulatus, A. equuli, A. lignieresii, A. ureae, A. dagmatis, P. gallinarum, P. haemolytica, P. multocida, P. pneumotropica biotypes Heyl and Jawetz were grown on GC agar supplemented with ascitic fluid and X and V factor (Levinthal's agar = LA agar) or GC agar supplemented with vitox and hemoglobin (VH agar) on 3 to 7 and 7 to 16 occasions respectively and fatty acid methylester (FAME) profiles were submitted to principal component analysis (PCA). All Pasteurellaceae strains showed FAME profiles typical for the family. Maximum coefficients of variation of the percentage of the 3 major FAMEs 14:0, 16:0, and 16:1 cis were 0.03, 0.03 and 0.03 for Pasteurellaceae strains grown on VH agar and 0.09, 0.17 and 0.09 respectively for strains grown on LA agar. PCA of FAME profiles obtained with growth from LA agar generally did not allow species separation of the Pasteurellaceae but most species were clearly discriminated by PCA when they were grown on VH agar. Our findings indicate that the growth medium had a significant effect on the reproducibility of fatty acid profiling in Pasteurellaceae and that PCA of fatty acid data obtained under standardized growth conditions may discriminate Pasteurellaceae species. PMID- 10096163 TI - Identification of a serogroup bataviae Leptospira strain isolated from an ox in Zimbabwe. AB - A strain belonging to the genus Leptospira serogroup Bataviae, isolated from an ox at slaughter in Zimbabwe, was identified by using cross-agglutinin absorption, the monoclonal antibody, restriction fragment length polymorphism, and polymerase chain reaction analyses. Results of both serological tests used showed that the isolate (strain SBF 37) was antigenically similar to reference strain Paidjan and therefore belongs to serovar paidjan. Strain SBF 37 was, however, genetically different from strain Paidjan since their chromosomal DNA had different restriction fragment length polymorphism patterns. The Zimbabwe paidjan strain was identified as belonging to the species Leptospira kirschneri while strain Paidjan reacted as a member of one of the non-kirschneri species in the polymerase chain reaction. The Zimbabwe isolate therefore belongs to Leptospira kirschneri serovar paidjan. PMID- 10096164 TI - Detection of Listeria monocytogenes in milk by the polymerase chain reaction. AB - A on the polymerase chain reaction (PCR) method based was developed for detection of Listeria monocytogenes in milk samples after enrichment culture. It consists of culturing samples in Listeria enrichment broth, followed by DNA extraction and detection of the organism using PCR. Dilutions of L. monocytogenes in milk were subjected to PCR amplification after enrichment culture. When determining the sensitivity of the method, it was found to be possible to detect 37 CFU (colony forming unit gl/ml) of the bacterium in milk. The method was assessed as a sensitive, specific, times-saving and practical way of detecting L. monocytogenes in milk samples. PMID- 10096165 TI - Increased typability of multiresistant Staphylococcus aureus by reverse phage typing. AB - Sixty percent of Staphylococcus aureus isolates from patients in Israeli hospitals proved to be non typable by the conventional phage typing method. Heat pretreatment improved typability only to 54% while reverse typing increased typability to 75%. In general isolates typable by conventional phages belonged to group V, II, III, I, or to mixed groups. While isolates typable only by reverse typing belonged to group III, II, the extended group III + IIIa, or to mixed groups, but seldom to group I. Although most isolates were resistant to penicillin G, only one half were resistant to other antibiotics as well. While one third of these isolates could by typed by conventional phage typing, typability was significantly improved to over 80%, by the use of reverse typing as the additional typing method. Two main groups of oxacillin resistant isolates were identified. The partial resistant group consisting of isolates resistant to penicillin G and oxacillin with no or few other resistances. These isolates were mostly typable by conventional phage typing (group V) and dominated in the first study period (1989-1990) but were only seldom isolated in the second one (1991 1992). The multiresistant group consisted of isolates resistant to penicillin G and oxacillin accompanied by resistances to 3-5 other antibiotics (chloramphenicol, clindamycin, erythromycin, gentamicin and tetracycline). These isolates were mostly typable by reverse typing (the extended group III + IIIa) and showed no change in isolation frequencies during the entire study period. Reverse typing is proposed by us as a typing tool for these multiresistant S. aureus isolates. PMID- 10096166 TI - Experimental studies of chlamydiosis in Japanese quails. AB - Two-week-old Japanese quails were infected intratracheally with six strains of Chlamydia psittaci isolated from calf pneumonia, swine pneumonia, goat abortion, sheep abortion, kid enteritis, and calf conjunctivitis, respectively. The Japanese quails from infected and control groups were closely observed for clinical symptoms. In order to examine the gross and microscopic lesions, quails in each group were sacrificed at 2, 5, 7, 10, 14, 21 and 30 days post infection. Alterations induced by pneumonic strains were more severe than those found in abortion isolates whereas the isolate of conjunctivitis failed to induce any lesion in the quail. Chlamydia psittaci was successfully recovered from lungs, spleen and intestinal contents of sacrificed quails. Calf pneumonia and goat abortion strains could be propagated in quails for a longer period (30 days), than in swine pneumonia, sheep abortion, kid enteritis (15 days each) and calf conjunctivitis isolates (7 days). The control quails were normal and no isolation could be made from them. PMID- 10096168 TI - Inflammatory and immunopharmacological activities of meta-periodate oxidized zymosan. AB - Zymosan (ZYM), a strong complement-activating yeast cell preparation composed mainly of mannan and beta-glucan moieties, is a potent inflammatory substance with immunopharmacological activity. We previously analyzed the metabolism of ZYM in mice and found that it was deposited in liver and spleen for at least several months and then gradually oxidatively degraded. In this paper, we prepared oxidized ZYM by sodium metaperiodate oxidation (NaIO4) and borohydride reduction (I/B-ZYM) and/or limited hydrolysis of oxidized moieties (I/B/H-ZYM). Activities of the resulting products were assessed by (i) vascular permeability in mice, (ii) H2O2 synthesis by macrophages, (iii) TNF-alpha synthesis by macrophages, and (iv) reactivity to anti-ZYM sera. As a general trend, NaIO4, oxidation products exhibited reduced, but still significant, activity. Interestingly, the H2O2 production induced by I/B/H-ZYM was significantly reduced after extensive sonication. Antagonist(s) for H2O2 synthesis were concomitantly solubilized by sonication of I/B/H-ZYM. On the contrary, TNF-alpha production induced by I/B/H ZYM was comparable with that of ZYM. These facts strongly suggest that highly branched 1,3-beta- and 1,6-beta-glucosidic linkages resistant to NaIO4 oxidation are important for biological activity of ZYM. Further, the minimal structure in ZYM necessary for biological activity may depend on the activity tested. PMID- 10096167 TI - In Vitro activity of 6 antimicrobials against propionibacteria isolates from untreated acne papulopustulosa. AB - In the present study, MIC values of 6 antibiotics were determined for 70 Propionibacterium acnes and 13 P.granulosum strains from 71 untreated acne patients using the agar dilution method. The interpretation of in vitro results is difficult because there are only poor data about the concentrations of antibiotics achievable in the sebaceous gland infundibulum. Based on breakpoint concentrations according to DIN 58,944, no resistance was found against chlortetracycline, doxycycline, minocycline, and chloramphenicol. In contrast, 11% of the P.acnes and 31% of the P.granulosum strains were not susceptible in vitro to erythromycin at a breakpoint concentration of 4 micrograms/ml. The present study shows that these strains are not suppressed even at higher erythromycin concentrations up to 256 micrograms/ml. Data from the literature reporting ineffective treatment of patients carrying erythromycin-resistant P.acnes strains may be explained by our study. Concerning clindamycin, resistance was found in only 6.8% of P.acnes and in 0% of the P.granulosum strains. Since sensitivity was seen in 100% of the strains already at a concentration of 16 micrograms/ml, a therapeutic effect may be possible. PMID- 10096169 TI - Incidence of spirochetes (Borrelia sp.) in the tick Ixodes ricinus in the urban environment (capital of Prague) between 1994-1997. AB - A total of 12287 ticks were collected from 10 localities of the capital of Prague between 1994 and 1997 (2978 ticks in 1994, 5612 ticks in 1995-1996, 3686 ticks in 1997). The presence of Borrelia was investigated by the indirect immunofluorescence assay using hyperimmune rabbit sera. The tick infestation ranged between 3.8% and 9.7% (1994), 7.9% and 11.3% (1995), 3.6% and 6.2% (1996) and 4.8% and 9.2% (1997). The results obtained are indicative of a relatively high opportunity for exposure to the causative agent in Prague--the dynamics of the spirochete positivity rates in ticks in different years corresponds with the dynamics recorded in the incidence of Lyme borreliosis in the same region. PMID- 10096170 TI - Growth-stimulating influence of human chorionic gonadotropin (hCG) on Plasmodium falciparum in vitro. AB - In this study, it is reported that human Chorionic Gonadotropin (hCG), being one of the most important hormones of pregnancy, has a growth-stimulating effect on the asexual stages of Plasmodium falciparum in vitro. On the one hand, it is shown that the effect of the hormone is dose-related: The highest growth-rates of Plasmodium falciparum in vitro are achieved, when doses of 8.32 i.u./ml (= 50 i.u. hCG/6 ml) and 16.67 I.U./ml (= 100 i.u. hCG/6 ml) are added to the culture medium. These doses correspond to the physiological peak amounts of hCG between the 9th and 16th week of pregnancy, when parasitaemia also reaches its highest rate. On the other hand, it is shown, that any growth-stimulating effect disappears after inactivation of the hormone by heating at 120 degrees C for 20 minutes. These data support the hypothesis, that hCG does not only possess immunosuppressive properties acting on the response of T-lymphocytes, but also increases the growth of Plasmodium falciparum in vitro. The combination of both effects may explain why malaria still remains one of the most serious complications of pregnancy. PMID- 10096171 TI - Yaws and syphilis in the Garkida area of Nigeria. AB - Sixty-four (4.2%) cases of yaws and forty-one (2.7%) cases of syphilis were encountered during an epidemiological survey for filariasis in the mid-Hawal river valley. This finding is despite the official position that yaws has been eradicated in Nigeria. The focus of the disease was localised in four of the six villages that were surveyed in the Garkida area of the valley. The disease was more common among farmers than among occupational groups. Aspart from yaws, syphilis (2.7%) which is another treponematoid infection was also encountered during the filariasis survey. The present findings imply that there still exists a benign transmission of the disease in the area and unless an immediate and effective control programme is initiated, yaws may still become a very important disease in Nigeria. The epidemiological aspects and public health implication of treponematosis especially of yaws, in this area are discussed. PMID- 10096172 TI - [Vascular effects of gestagens--biochemistry versus epidemiology]. AB - The available epidemiologic data indicate that the sequential addition of progestogens enhances the protective effect of estrogens on the cardiovascular risk. A considerable decrease in LDL-cholesterol is also observed during use of progestogens with androgenic properties. The estrogen-dependent reduction of LDL oxidation is not impaired by progestogens. While estrogens inhibit the endothelial synthesis of adhesion molecules, the activation of monocytes and platelets and the proliferation and migration of smooth muscle cells, the effect of progestogens is rarely investigated. A vasoconstrictory effect of progestogens which may attenuate the estrogen-induced dilation of arteries, was not observed in all clinical investigations. It is presumably based on a reduction of estrogen stimulated release of nitric oxide by progestogens. In most animal experiments, a progestogen-induced enhancement of contractility of arteries was measured, too. A relaxing effect of progesterone was found in in vitro-experiments, while the results on endothelium-independent effects of synthetic progestogens were contradictory. The sex steroids influence the structure of the vessel wall, whereby the elasticity of arteries is enhanced by estrogens and reduced by progestogens. Oral contraceptives may increase the distensibility of veins which correlates with the hormonal potency of the progestogen. During hormone replacement therapy, venous distensibility is also increased which is mainly due to the action of the estrogen. In vitro experiments with veins revealed a dilatory effect of progestogens. With regard to possible unfavourable effects of progestogens on the vessel wall it is recommended to use the additional progestogen at the minimal effective dose necessary for prevention of endometrial hyperplasia. PMID- 10096173 TI - [Johanna the probable--a pregnant pope?]. PMID- 10096174 TI - [Endoscopic axillary lymph node excision--results of a pilot study]. AB - OBJECTIVE: Assessment of axillary nodal status with reduced shoulder-arm morbidity remains a major challenge for primary surgery of breast cancer patients. In a pilot study endoscopic axillary lymph node dissection was evaluated. MATERIAL AND METHODS: In 30 breast cancer patients axillary lymphadenectomy was performed after liposuction using an endoscopic approach. During a learning phase of 15 cases an open revision was routinely carried out. Later complete endoscopic lymph node dissection was performed. The exposition of anatomical landmarks, the number of resected lymph nodes, postoperative lymphorrhea, histopathological signs of traumatisation were assessed as well as intra and postoperative complications. RESULTS: In any case we found excellent exposure of anatomical landmarks. Following a learning curve of 15 cases the average number of resected lymph nodes was equal to the average number of lymph nodes resected with conventional techniques (18.2 vs. 18.4, median 17 vs 18). Minimal intraoperative complications were observed. Postoperative lymphorrhea and seroma rate were not remarkably reduced in comparison with open procedures. CONCLUSIONS: Our study demonstrates, that endoscopic lymph node dissection may be performed with a low complication rate and with identical accuracy as achieved by open techniques. PMID- 10096175 TI - [Hyperthyroidism and acute renal failure in partial bladder mole]. AB - We report on a 31-year-old II gravida I para treated because of a hydatidiform mole, hyperthyroidism and acute renal failure in the 16th week of pregnancy. The pathomechanism of trophoblast-induced hyperthyroidism will be discussed. To our knowledge this is the first report on acute renal failure in association with trophoblast-induced hyperthyroidism. PMID- 10096176 TI - [An unusual trauma in labor: diaphragmatic rupture]. AB - We present a case of a delayed diagnosed traumatic diaphracmatic rupture and herniation in a 49-year-old woman. The rupture was secondary to trauma sustained 26 years ago during delivery, when the obstetrician pressed his hands against the upper abdominal wall of the patient. She perceived a sudden violent pain in her left belly. In the following years the pain never disappeared. But only after the period of more than two decades, diagnosis was made when abdominal organs prolapsed into the thoracic space. After the operation, the patient was free of pain. We believe this to be the first reported case of traumatic diaphragmatic rupture due to delivery. PMID- 10096177 TI - [Prenatal diagnosis of sirenomelia]. AB - OBJECTIVE: What kind of diagnostical methods are usual to detect fetal sirenomelia? MATERIAL AND METHODS: The prenatal diagnosis of fetal sirenomelia combined with bilateral renal agenesis, oligohydramnios and single umbilical artery in a 24-year-old woman, gravida 2, para 1, at a gestational age of 18 + 3 weeks is described in this case report. RESULTS: This fetal malformation was an accidental sonographic found, and caused after confirming diagnosis by amnoinfusion and amniocentesis, the termination of pregnancy. Genetic examination revealed tetrasomia 13. CONCLUSIONS: The sonographic finding of oligohydramnios should cause an exactly sonographical examination with amnioinfusion. In case of sirenomelia genetical examination is necessary. PMID- 10096178 TI - [Hyponatremia and lung edema in endometrium ablation with rollerball ablation]. AB - OBJECTIVE: Absorption of hypotonic irrigating solution with consecutive severe hyponatremia is a potential risk of the endometrial rollerball ablation procedure. MATERIAL AND METHODS: We report the case of a 45-year-old female, who underwent an endometrial rollerball ablation procedure. RESULTS: After irrigating the uterine cavity for 45 min with 10 1 of 2.7% Sorbitol and 0.54% Mannitol she developed clinical signs of pulmonary edema with severe hyponatremia. CONCLUSIONS: A TUR-like syndrome as a potential risk of the rollerball ablation procedure is discussed briefly. Strategies to minimize the risk and to early detect the TUR-like syndrome are suggested. PMID- 10096179 TI - Estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) in the prevention of cardiovascular diseases. PMID- 10096180 TI - [Hormone substitution after carcinoma]. AB - OBJECTIVE: The colorectal carcinoma is one of the most frequent malignomas in western countries. Therefore the gynecologist often will be confronted with the question whether a hormone replacement with sexual steroids is allowed after a curative operation. MATERIAL AND METHODS: Basing on the data of several international publications we have substituted in an own study from 1989 to 1997 42 women with colon and 10 with rectal cancer after successful operation with a combined preparation. RESULTS: In the meantime it could be proved that in the cells of colorectal carcinomas estrogen and progesterone receptors are absent or only existing in a low concentration. Thus analogous to the receptor positive breast cancer the hormone replacement therapy also after curative treatment of a colorectal cancer should be justified. Therefore the benefit of the individual hormone replacement therapy shouldn't be withheld from these women without worsening the prognosis. CONCLUSIONS: After palliative therapy and in the case of a relapse a combined hormone replacement can be an act for diminishing the disease and should be recommended after a corresponding clearing-up and weighing the risk. PMID- 10096181 TI - [SUSILAP-G: a surgical simulator for training minimal invasive interventions in gynecology]. AB - After a brief introduction about virtual reality and model-building this paper describes the special technical and theoretical requirements of dynamic surgical simulation in contrast to traditional static systems. This is done by means of the simulator SUSILAP-G. With SUSILAP-G an example of an application in telemedicine is given. PMID- 10096182 TI - [Emergency measures to control the spread of diseases caused by the human immunodeficiency virus]. AB - Since the middle of 1996 the growth of HIV-infected persons and AIDS morbidity are registered in Russia. In 1997 4,300 new cases of HIV infection were registered, which exceeded 1.6 times the total number of cases for the period of 1987-1996. The highest morbidity rate was observed in the cities of the European part of Russia: Kaliningrad (west), Krasnodar and Rostov-on-Don (south), Nizhny Novgorod and Moscow (center). AIDS patients and HIV-infected persons were registered in 73 out of 89 regions of the country. 90% of HIV-infected persons were drug users in 1997. In 1992-1997 the number of drug addicts increased 3.5 fold and young women in 1987-1997, 6.5 fold. 71 HIV-infected children were registered were born from HIV-infected mothers at present time. The article deals with the main provisions of the federal laws aimed at the prevention of the spread of HIV infection in Russia and characterizes scientific research on AIDS. Evidence is presented that the early detection of HIV-infected persons, as well as rendering timely medical and social assistance to such persons, makes it possible to increase their mean survival time and check the spread of human immunodeficiency virus. PMID- 10096183 TI - [The principles of pre-epidemic diagnosis in the epidemiological surveillance system for HIV infection]. AB - The problem of the general introduction of the principles of the pre-epidemic diagnostics of HIV infection was discussed. These principles should be based on the observation of "model" infections (viral hepatitides B, C, D), multipurpose serological monitoring and sociological methods aimed at obtaining the necessary information. The suggestion that the age and sexual structure of HIV-infected patients would be determined by the route of HIV transmission, prevailing on a given territory, including into infection process adolescents and young women and men was made. PMID- 10096184 TI - [The spread of AIDS among homosexuals in the Commonwealth of Independent States and Baltic countries]. AB - The data on the spread of AIDS among homosexuals (HS) are presented. Studies carried out in the CIS and Baltic countries in 1995-1997 revealed that this group formed a highly favorable environment for the spread of HIV infection and sexually transmitted diseases (STD). The discrepancy between the real number of HIV carriers and the number of detected cases is explained by the specific character of their existence in the society. The potential possibility of the rapid spread of HIV infection among HS required the preparation of a number of minor pilot projects on the prophylaxis of HIV among this group in the capitals of the CIS countries. PMID- 10096185 TI - [The development of HIV infection in the Far-Eastern region of the Russian Federation]. AB - By May 18, 1998, 108 HIV-infected persons were registered in the Far-Eastern region. In recent years young people using narcotic drugs were involved in the epidemic process. The sources of the infection were mainly migrants arriving to the Far East from the Ukraine. HIV-infected persons also were registered in settlements lying north of the Arctic Circle. PMID- 10096186 TI - [HIV infection in children perinatally infected]. AB - During the period from 1987 to the middle of 1996 only 20 children were born of HIV-infected women, while during the following 1.5 years the number of such children were 59, the maximum number of seropositive children being registered in Kaliningrad and the Kaliningrad region, in the Krasnodar Territory, Stavropol and Nizhny Novgorod (altogether 46 children). Out of 79 children born of HIV-infected mothers during the whole period of the epidemic, 8 children died. Out of the children born before 1995 who remained alive, 9 children were struck off the register after 3 years of observation due to the absence of HIV infection. By the end of 1997 63 children were registered, the majority of them born in 1996-1997. PMID- 10096187 TI - [An analysis of an outbreak of HIV infection in the city of Svetlogorsk, the Republic of Byelarus, among persons using injected narcotics]. AB - The examination of all persons suspected in the use narcotics (including suppliers and vendors of drugs) in Svetlogorsk (Belarus) for the presence of antibodies to HIV revealed 811 cases of HIV infection, i.e. 1% of the whole population was found to be infected by HIV. More than 90% of all HIV-infected persons were drug addicts introducing narcotic intravenously; young people aged 18 to 29 years constituted 81% (of these, 76% were males and 24% were females). The rapid spread of HIV was caused by the use of a ready-made HIV-infected drug which had been supplied for sale and could have been infected in the process of manufacture or packing. PMID- 10096188 TI - [The epidemiological characteristics of HIV infection in Turkmenistan]. AB - In the presence of the low spread of HIV infection a sharp increase in sexually transmitted diseases is noted. Nevertheless, taking into account a rise in STD, the reality of the potential risk of the spread of HIV is emphasized. Thus, in 1996 morbidity is syphilis was found to grow 7.2 times in comparison with 1992, amounting to 37.5 cases per 100,000 of the population; morbidity in gonorrhea amounted to 32.4 cases per 100,000 of the population with the proportion coming to medical institutions not exceeding 30%. A high proportion of hepatitis B virus carriers was also established (from 15% to 30% of healthy persons), while morbidity in virus hepatitides rose twofold for the period of 1994-1995. During recent years the service for the prophylaxis of AIDS was noted to considerably decrease measures on mass screening. At the same time the article attracts attention to the necessity of increasing the work on the dissemination of information and education on HIV/AIDS drug among addicts, prostitutes and homosexuals. The Draft National Program of the Prophylaxis of HIV infection and STD for 1998-2002 has been worked out. Great importance of methodological and financial assistance rendered since 1994 by international organizations, including WHO, UNFPA, etc., have been emphasized. PMID- 10096189 TI - [The prevalence of the intravenous use of psychoactive preparations in Nizhegorod Province and the possible ways to prevent HIV infection among the users]. AB - The number of users of intravenous drugs (UID), altogether from 35,000 to 25,000 persons, was determined by the method of coefficients. The analysis of 130 anonymous questionnaires, including 75 street questionnaires (61%) and 51 questionnaires (39%) distributed among UID in narcological and infectious hospitals showed that out of 130 respondents 60% underwent hospital treatment. The study revealed that most of the questioned users used crudely made opiates, 48 (37%) out of 130 persons made injections with used syringes and needles (in younger age groups the proportion of such UID amounted to 63%). 70% of the respondents used individual injection instruments (in a group of persons older than 25 years they amounted to 90%). The conclusion was made on the necessity of introducing a school program on the healthy mode of life and information programs on the prevention of the spread of infection among UID with due regard to different age groups, as well as training outreach workers for disseminating information on the prophylaxis of HIV infection among UID. PMID- 10096190 TI - [The characteristics of HIV infection during a sharp activation of the epidemic process in Rostov Province]. AB - A considerable growth in cases of HIV infection in Rostov Province was registered in 1996-1997. Number of men was 525, number of women--196 cases, were registered. The highest index of HIV infection was noted in group of tested by epidemiological evidence (4494,4 per 100,000 tested persons), which was 57.2 times higher than the average level for this region. The growth in the number of infected persons was due to the import of HIV from the territory of Ukraine and the subsequent spread of the virus among drug addicts introducing drugs by intravenous injection. PMID- 10096191 TI - [The epidemic situation in relation to HIV infection in the Volga River region]. AB - 1,036 HIV-infected persons were detected in the area by March 1, 1998; of these, 552 persons were detected in Nizhny Novgorod Province and 364 persons in Saratov Province. For all that at different periods 150 HIV-infected detainees were kept in the pretrial detention prisons of Nizhny Novgorod Province and 60 HIV-infected detainees, in the pretrial detention prisons of Saratov Province. Some measures permitting the prevention of further increase in the occurrence of HIV infection in the region are proposed. PMID- 10096192 TI - [The epidemic situation in relation to HIV infection in Ukraine (1987-1997)]. AB - The analysis of the dynamics of the epidemic process for 10 years made it possible to find out the presence of two separate epidemic waves of HIV infection. The first wave (1987-1994) was manifested as the slow type of the development of the epidemic, characterized mainly by sexual transmission. During this period 398 persons with HIV infection were detected, 24 persons were found to have AIDS; of these, 13 persons died. The second epidemic wave began in 1995 and was due to the spread of HIV among users of drugs introduced by injection. By the end of 1995 the number of HIV carriers was 34 times greater than that of 1994, reaching 1490 persons. In 1996-1997 this figure increased 8 times (annually). The number of AIDS patients rose to 420 persons. The most unfavorable regions with respect to HIV infection and AIDS morbidity were determined. The western regions of the Ukraine were noted to be in a more favorable situation in this respect with infection indices being lower more than 30 times. Up to 80% of all infected persons were found to be addicts introducing drugs intravenously. Growing morbidity in sexually transmitted disease, particularly in syphilis, contributed to the deterioration of the epidemiological situation. The conclusion was made on the necessity of introducing new prophylactic programs and expanding current ones. The signs of stabilization in Odessa and Nikolayev were observed; in these cities pilot programs aimed at the strategy of the "decrease of harm" have been introduced (in collaboration with UNAIDS) since 1996. PMID- 10096193 TI - [The clinico-epidemiological characteristics of HIV infection and AIDS in Ukraine]. AB - The summarized results of the observations of 449 hospitalized patients, aged mainly 18-37 years (40 patients with active AIDS, 43 patients with AIDS, other patients were HIV carriers and infected at the stage of lymphadenopathy). In most of the HIV-infected patients the infection process progressed in 3-5 years, which was manifested by associated candidiasis in 74.7% of cases. In AIDS patients opportunistic infections of viral etiology (herpes simplex, cytomegalovirus infection, etc.) prevailed. 14 patients were found to have tuberculosis. Clinico epidemiological analysis made it possible to come to the conclusion that the specific features of HIV carriership and AIDS were greatly linked with different groups of risk to which the patients belonged. Thus, a shorter period of carriership, the prevalence of opportunistic viral infections were mostly characteristic of drug addicts. PMID- 10096194 TI - [HIV infection in the penitentiaries of Ukraine]. AB - In connection with a sharp increase of the number of HIV-infected persons in the Ukraine the natural growth of the number of such persons in penitentiary institutions was registered, starting from 1995 (455 persons in 1995, 2,937 persons in 1996, 2,779 persons in 1997 and 173 persons during 5 months of 1998). 83% of HIV infection persons were drug addicts introducing drugs intravenously. In 1997 the strategy of decreasing the risk of infection in penitentiary institutions was worked out in collaboration with UNAIDS experts: repressive and isolation measures were replaced with measures aimed at the "decrease of harm". Special attention is given to circumstances aggravating the epidemic situation in HIV infection, and particularly at the sharp growth of morbidity in tuberculosis and syphilis (10.6 and 10.3 times respectively in 1997 in comparison with 1993). In addition, in 1997 the number of person having drug addiction was noted to increase 2.3 times in comparison with 1993. The necessity of taking constant information and educational measures aimed at decreasing the risk of the spread of HIV infection is emphasized. PMID- 10096195 TI - [The determinants of the spread of HIV among injection drug addicts in Ukraine]. AB - The main tendencies in the development of drug addiction in the Ukraine, the dynamics of the spread of HIV among drug addicts introducing drugs intravenously, epidemiological data on HIV, AIDS and drug addiction, as well as prognoses on the development of HIV infection are presented. Since 1995 the number of HIV-infected persons grew 34-fold, the number of cases of HIV infection resulting from the intravenous use drugs rose to 70% simultaneously with the rise (about 34-fold) of the number of persons infected with HIV through sexual contacts (about 13 fold). In 1996-1997 such tendency increased. On the whole, the proportion of drug addicts introducing drugs by intravenous injection was 83% in the Ukraine. By April 1, 1998, official registration covered 18,800 HIV-infected persons, including 270 foreign nationals, as well as 499 AIDS patients, including 487 Ukrainian citizens, among them 28 children. Out of 18,800 HIV-infected persons, 78.3% were drug addicts, most of them young people aged 15-30 years; about 18% were young people under 20 years of age, 80% being males. According to the model the rapid spread of HIV from the group of drug addicts to the heterosexual population, the total number of HIV-infected persons reaching 1,500,000 is expected in the country by 2014. PMID- 10096196 TI - [The detection of viral hepatitis markers in HIV-infected patients]. AB - The determination of markers of virus hepatitides B, C and D in 63 registered HIV infected persons was made. The use of Russian and foreign EIA systems permitted the detection of markers of virus hepatitides 30.1% of HIV-infected persons, including 26.3% of children. Markers of hepatitis B virus were found to occur in children and adults with the same frequency. Out of 65 persons registered in the Center, 3 persons (4.6%) were drug addicts; of these, 2 were found to have antibodies to antigens of hepatitis viruses. Such persons constituted 3.8% of the total number of HIV-infected persons. Among 8 newly detected and registered HIV infected adults, 2 were found to have antibodies to hepatitis B virus (of these, 1 used drugs intravenously). PMID- 10096197 TI - [HIV infection in Russia in 1998]. AB - The statistic information about the distribution of HIV-infected persons in 1998 in different regions of Russian Federation was presented 3169 new cases of HIV infected persons of Russia registered by 11.5 months in 1998. This are only 82.2% cases in comparison of cases (3856) which registered in 1997. The total number HIV-infected persons registered by 1st of January 1987-16th of November 1998 was 10,193, among them 431 children. 112 children were infected during period of mother's pregnancy and parturitions. PMID- 10096198 TI - [The molecular epidemiological characteristics of the HIV-1 variants circulating among injection drug addicts on the territory of the CIS Nations]. AB - Different strains of HIV-1, circulating among drug addicts introducing drugs intravenously and detected on the territories of Russia, Ukraine and Belarus, have been characterized by the methods of the comparative analysis of genetic sequences of different variants of HIV (gene typing) and the study of the immunological properties of autoimmune sera (serotyping). PMID- 10096199 TI - [The structural and functional organization of the promoter region of the human CD4-receptor gene]. AB - Receptor CD4, expressed on the surface of immunocompetent cells, plays the key role in the pathogenesis of HIV infection, facilitating the penetration of the virus into the susceptible tissues of the host body. In this work the nucleotide sequence of the site on the gene of receptor CD4, responsible for the regulation of its transcription, has been determined. PMID- 10096200 TI - [HIV-1 subtypes in Russia in 1987-1988]. AB - The subtyping of 350 isolates of HIV-1, isolated on the territories of 38 subjects of the Russian Federation, was carried out. The analysis was made by the method of the comparative heteroduplex mobility assay, as well as by the determination of the sequence of genes env [correction of ens] (gp 120) and gag (p17-p24). The study revealed that more than 50% of all cases of HIV-1 infection were caused by closely related variants of subtype A virus. The number of cases of HIV-1 infection caused by recombinant virus A/B was not less than 25%. The total number of cases caused by viruses of subtypes C, D, E, F and H was not more than 5%. PMID- 10096201 TI - [Recombinant human immunodeficiency viruses]. AB - Three types of recombinant human immunodeficiency virus have been found to circulate in Russia. The first type of the virus belongs to genotype gagAenvB, the second type belongs to genotype gagDenvG and the third type, to genotype gagAenvE. The virus of genotype gagAenvB circUlates in the population of drug addicts simultaneously with its "parent" viruses of genotypes gagAenvA and gagBenvB. The recombinant variant gagDenvG has African origin. The recombinant variant gagAenvE has probably been imported to Russia from South-East Asia. PMID- 10096202 TI - [A recombinant HIV-1 strain causing an epidemic among injection drug addicts in Kaliningrad]. AB - The analysis of the genetic structure of HIV causing the epidemic in Kaliningrad Province. A new recombinant virus of subtype A/B was detected with the use of the polymerase chain reaction, the cloning of amplified fragments, sequencing and the phylogenetic analysis of the obtained data. The results thus obtained indicate that the epidemic in Kaliningrad was caused by a recombinant strain, and not due to co-infection caused by two HIV strains of different subtypes. The study of HIV 1 DNA revealed the divergence between the samples was extremely low, which was characteristic of epidemics connected with the transmission of the virus in the process of the intravenous use of narcotic drugs. PMID- 10096203 TI - [The possible role of immunogenetic factors in the pathogenesis of HIV infection]. AB - In this review the data on the presence of associations between immunogenetic markers and the development of HIV infection are presented. Special attention is given to spatial relationships of genetic determinants, responsible for the synthesis of the components of the complement system on one hand and the genes controlling resistance to the causative agents of opportunistic infections and malignant growth on the other hand. Suggestion is made on close relationship between the specific features of the course of HIV infection and the genetic control, responsible for the synthesis of complement components, in particular the genes making up the HLA system. PMID- 10096204 TI - [The HTHIV27 highly productive continuous cell line and its use for solving the fundamental and applied problems of HIV infection]. AB - For the first time the detailed description of continuous cell line HTHIV27, remaining stable for more than 10 years, has been made. The stability of all biological characteristics and high productivity of the strain has made it possible to use it as a HIV producing strain for the construction of a diagnostic test system for the detection of antibodies to HIV. The lysate obtained on the basis of HIV producing cells HTHIV27 has been shown to possess a number of advantages in comparison with the analogous system based on lytically infected cells. On the basis of strain HTHIV27 an in vitro cell system for the analysis of the specific activity of chemotherapeutic preparations intended for the inhibition of HIV has been developed. The use of this newly obtained continuous cell line HTHIV27 has been shown to permit the evaluation of the antiviral activity of compounds, characterized by different molecular mechanisms for the suppression of viral activity. PMID- 10096205 TI - [The use of a method for the quantitative determination of HIV-1 RNA for assessing the severity and prognosis of the development of the disease]. AB - The informatory role of a new marker of HIV infection, characterizing the content of HIV-1 RNA in the biological fluids of the patient's body, is evaluated. The quantitative determination of HIV-1 RNA, carried out in a single assay, was made in the blood of 25 HIV-infected patients. These studies confirmed that the determination of the level of RNA in the plasma (viral load) was a reliable criterion indicating the severity and progress of the disease. The viral load of more than 100,000 copies/ml was a sign prognosticating the future pronounced progress of the disease in spite of moderate clinical manifestations and relatively high values of CD4 cells in the patient's blood at the moment of testing. PMID- 10096206 TI - [The theory and practice of using in-house control in screening and verification studies for the diagnosis of HIV infection]. AB - Three batches of two diagnostic test kits for the in-house control (IHC) HIV infection were made up of the 8 pools of sera, containing antibodies to all antigens of HIV-1 (4) and HIV-negative sera (4) obtained from healthy donors. All sera used for this purpose did not contain antibodies to viruses of hepatitis A, B, C. In the process of the preparation of the batches of diagnostic test kits for IHC 500 individual donor sera and more than 100 of individual sera of HIV infected persons were studied. The sera under study were also tested for the presence (absence) of specific antibodies to HIV-1,2 and viruses of hepatitis A, B, C. The evaluation of IHC in 300,000 tests under the conditions of a screening laboratory and 550 verification tests was done. The study revealed that the use of IHC makes it possible to improve the conditions of work with commercial diagnostic test kits, to introduce the semiquantitative determination of the level of specific antibodies on verification tests and, on the whole, to standardize the tests. PMID- 10096207 TI - [A retrospective study of the expediency of performing the immunoblot in conducting expert diagnosis at a center for the prevention and control of AIDS]. AB - In view of the fact that Russian immunoblot assay systems yield indefinite results, thus making it necessary to carry out prolonged dispensary observations of patients and their multiple examinations, the scheme of the expert diagnostics of HIV infection on the basis of EIA results is proposed. 51 sera which had yielded indefinite results in the immunoblot assay (antibodies to gagl, envl, poll) were handed over for verification to the Regional Center in 1996-1997. Patients from whom the sera had been taken were placed under dispensary observation in the Center for 6-12 months. After the retrospective analysis of these serum samples with the use of the EIA systems 40 samples proved to be negative and 11 samples gave the positive reaction. PMID- 10096208 TI - [The organization of the work to determine antibodies to the human immunodeficiency virus in the Republic of Byelarus]. AB - The study revealed that the method of mass screening for the detection of antibodies to HIV antigen, carried out in the Republic till 1993, proved to be economically and diagnostically unjustified. Starting from 1993, the work on the step-by-step reduction of groups to be tested for the presence of antibodies to HIV began. At the same time from 1997 the proportion of tested donors of blood, organs and tissues, as well as persons belonging to high risk groups, increased in comparison with 1993 (from 23.3% to 40% and from 5.3% to 21% respectively). Voluntary and anonymous testing for the presence of HIV infection was organized and legally introduced. In comparison with 1991, in 1997 the number of persons who voluntarily underwent testing increased 3.7 times. The period of transition from mass screening to selective one was noted to have no effect on the detection of HIV-infected persons. Since 1995 the method of "patrol" epidemiological surveillance was also used. 2,118 persons underwent testing, the results of screening were negative. During the period of 3 years the testing of 12,547 young people called up for military service revealed 28 seropositive persons in the region where an outbreak of HIV infection had been registered among addicts using drugs intravenously. PMID- 10096209 TI - [The testing policy for HIV infection in Ukraine]. AB - The policy of the Ministry of Health of the Ukraine since 1987 concerning the control of the spread of HIV infection was analyzed. The main measure for the prophylaxis and epidemiological control of the infection was mass testing for HIV, carried out in accordance with the law adopted in 1991. In 1997 changes and amendments were supplemented to this Law, which legally abolished obligatory testing for HIV. The data on the effective and less effective testing policy are presented. In particular, these data revealed that the irrational testing policy resulted on the fact that only 5% of the whole population of drug addicts were covered by surveillance. Future prospects were shown to include the introduction of the system of "patrol" epidemiological surveillance, the strengthening of the analytical component of epidemiological surveillance, the approval of the new strategic plan of the prophylaxis for AIDS for 1998-2000, as well as the renewal of the normative and methodological basis. PMID- 10096210 TI - [The characteristics of the course of tuberculosis in HIV-infected patients and prophylactic measures]. AB - Morbidity in HIV infection and tuberculosis in persons having these two infections in association was analyzed. According to the data for the end of the first quarter of 1997 the presence of association of HIV infection with tuberculosis was found in 91 patients. In 70.3% of cases HIV infection was contacted before the appearance of tuberculosis and in 18.7% of cases, after it; in 11% of cases the order of appearance of these two diseases could not be established. The study revealed that the markedness of the clinical picture of tuberculosis was determined by the progress of HIV infection. PMID- 10096211 TI - [The characteristics of the course of Leishmania and Pneumocystis opportunistic infections in immunosuppressed laboratory animals]. AB - Specific features of the course of Leishmania and Pneumocystis infections were studied on experimental models. Laboratory animals were subjected to medicinal suppression with Tricort-40. Leishmania infection in naturally susceptible animals was considerably aggravated (in comparison with the controls) in the presence of even short-term immunosuppression. Pneumocystis infection developed in experimental animals under the effect of double suppression. The process of the reactivation of Pneumocystis infection was influenced by Leishmania infection, rapidly developing in the presence of prolonged immunodeficiency. The results thus obtained make it possible to regard Leishmania infection in animals with reactivated Pneumocystis infection as co-infection having the properties of a biological, immunosuppressant. Such situation may be extrapolated on HIV/visceral leishmaniasis co-infection. PMID- 10096212 TI - [Burkitt's lymphosarcoma in a child with HIV infection]. AB - A case of Burkitt's lymphosarcoma in an HIV-infected girl aged 4 years is described. The child was infected with HIV and hepatitis B virus in the hospital focus of infection at the age of 1 year 4 months. An attempt to treat lymphosarcoma with large doses of prednisolone and cytostatics (vincristine and cyclophosphamide) produced no effect. PMID- 10096213 TI - [Secondary diseases in HIV-infected patients]. AB - During the period of 1980-1996 the dispensary observation of 50 HIV-infected patients was carried out. The clinical forms of the infection were distributed among these patients as follows: asymptomatic forms in 18 patients, persisting generalized lymphadenopathy in 8 patients, pre-AIDS in 14 patients, AIDS in 10 patients. Secondary infections were registered at the pre-AIDS stage. Dermatoses, oropharyngeal candidiasis occurred most frequently: in 52% of the HIV-infected patients. Herpes virus infection was registered in 46% of the patients. At the stage of AIDS during the generalized herpes virus and cytomegalovirus infections were registered in 5 and 7 patients respectively. Generalized forms of combined infections (herpes virus + fungi) prevailed, which caused the death of 7 patients at the terminal stage of AIDS. PMID- 10096214 TI - [The clinical course of HIV infection in children who were parenterally infected]. AB - The data on the study of the clinical course of HIV infection in 127 children, 124 from these infected in nosocomial foci. The overwhelming majority of the children were infected at the period of their stay in hospitals of Elista, Volgograd, Rostov-on-Don, Shakhty (Rostov Province) and Stavropol'. At the end of 9-9.5 years elapsed since the appearance of the first documented cases of parenteral infection 33 children (26%) died. The study revealed that at the age under 1 year the course of HIV infection could rapidly progress into the stage of AIDS in the presence of aggravated premorbid background linked with the unfavorable course of pregnancy in the mother and a severe disease in the child prior to contacting HIV infection. PMID- 10096215 TI - [Autoantibodies to the thrombocytes and erythrocytes in HIV-infected patients]. AB - In 48 patients with HIV infection were tested for the presence of autologous and allogenic antibodies to red blood cells with the use of Coombs' direct and indirect tests. 18 HIV-infected patients had IgG antibodies to thrombocytes, circulating in the blood (detected by the method of EIA) and bound to thrombocytes (detected by the method of RIA). In 5 out of 48 patients Coombs' direct test yielded positive results with red blood cells. 6 out of 18 examined patients had an elevated content of thrombocyte-bound antibodies. The presence of cross reactions between gp120 of human immunodeficiency virus and gp3a thrombocytes led to the formation of antithrombocyte antibodies and, consequently, to a decrease in the number of thrombocytes. PMID- 10096216 TI - [The structure of the secondary diseases in HIV-infected patients in Russia]. AB - In 95 patients with HIV infection (76 males and 19 females), observed in 1993 1997, the structure of secondary diseases was studied. During this period 58 patients (61.1%) died. In the structure of secondary diseases represented by 14 nosoforms prevailed cytomegalovirus and candidal infections, tuberculosis, Kaposi's sarcoma, rarely--pneumocystis pneumonia, cryptococcal meningitis and toxoplasmosis. PMID- 10096217 TI - [The successes and problems in the treatment of HIV infection: a biochemist's view]. AB - The problems of the effectiveness of the treatment of HIV-infected patients with 11 medicinal preparations and their combinations are discussed. 5 preparations (AZT, zalcitabine, videx, stavudine and lamivudine) are the nucleoside inhibitors of the synthesis of provirus DNA, catalyzed by inverse transcriptases; 2 preparations (nevirapine and rescriptor) are the inhibitors of this enzyme, having nonnucleoside nature, and 4 preparations (saquinarin, ritonavir, indinavir and nelfinavir) are the inhibitors of the processing of virus RNA, catalyzed by HIV protease. The modern concepts of the mechanism of action of the above mentioned preparations are presented and the problem of the search of new effective medicinal preparations is discussed. PMID- 10096218 TI - [New approaches to the chemotherapy of HIV infection]. AB - The preclinical analysis of the effectiveness of AZT and new compounds (sulphatized derivate of chitosan (Sch) and adamantileted Sch, contents 10 and 18% of adamantine) prepared on the basis of chitosan (Ch), carried out with the use of the experimental clinical test system (the in vitro model of peripheral blood mononuclears of a concrete patient) developed in laboratory, is presented. Both combinations in concentration 0.01 mkg/ml are decreased HIV antigens till 6.4 and 8.6% accordingly, while whilst initial Sch hare caused less effect in 4-5 fold. PMID- 10096219 TI - [The prevention of HIV infection and STDs among injection drug addicts in Ukraine]. AB - In 1996-1998 joint pilot Projects of the National Committee and the UNAIDS Program were carried out in 10 Ukrainian cities. The behavior determinants contributing to the spread of HIV infection, common for all regions under study, were determined. They were linked with the injections of narcotic drugs, sexual behavior and the level of knowledge on the infection. The effectiveness of the projects was due to the 80% coverage of those drug addicts who could not be reached by common narcotic drug services; to the use of individual syringes (increased from 43% to 95%); to a decrease in the sale of ready-made drugs in used syringes to 14%; to an increase in the index of the return of used syringes; to an increase in the proportion of persons constantly using condoms (58%); etc. Still the situation was found to give no grounds for optimism, and the conclusion was made that the strategy of "decreasing the harm" must become the policy and strategy of the public health system. PMID- 10096220 TI - [The forms and analysis of the results of work in preventing HIV infection among youth]. AB - Specialists of the AIDS Centre distributed questionnaires, specially developed by them, among a group of students of the Pedagogical University. The questionnaire contained 35 questions; of these, 21 questions were intended to find out what information on HIV infection and AIDS the students had and 14 questions dealt with their sexual history and their attitude to the problem. The answers to the questionnaires distributed among 100 students (68% were females and 32% were males) showed that 58% of the respondents had previous sexual experience. 68.5% of the respondents had sexual intercourse after taking alcohol, 7.4% always used condoms, 38.8% seldom and 53.7% never used condoms. The behavior of 68.8% of the respondents was not influenced by information on HIV infection they received, 16% reduced the number of casual sexual partners, 8.6% started using condoms, 6.5% reduced the number of sexual partners. PMID- 10096221 TI - [A questionnaire survey of intravenous drug addicts (Moscow, May 1997-January 1998)]. AB - Questionnaires were distributed among users of intravenous drugs (UID) on the basis of Narcological Hospital No. 17 in Moscow and in the streets of the city (altogether, respondents filled in 298 questionnaires in the hospital and 126 questionnaires in the streets). The average age of the respondents was 21-22 years. The sufficiently wide spread of the joint use of injection instruments was noted (35-41%), the ensuing risk could be consciously evaluated by 38% of the respondents in the hospital and 20% in the streets. According to the observation diaries, HIV was not a priority for many UID. Their priorities included the problems of the treatment of hepatitis, abscesses, overdosage/poisoning, etc. Among the hospital respondents and selected street respondents the spread of hepatitis B and C was noted by 30% and 34% respectively. Under hospital conditions testing for HIV gave negative results in 58% and positive results in 5% of the respondents, while 37% of the respondents stated than they had never been tested. Among street respondents, 62% stated that they had negative results of testing and 39% stated that they had never been tested. The conclusion has been made that the realization of prophylactic programs may augment the level of knowledge concerning risks linked with the intravenous use of drugs, thus giving motivation to UID either to stop their use or to avoid contamination of the blood with HIV while using them. PMID- 10096222 TI - [The results of conducting a rapid assessment of the situation in relation to intravenous narcotic abuse in the city of Rostov-on-Don]. AB - The main aspects of the spread and intravenous use of drugs in the city, contributing to the transmission of HIV infection among users of intravenous drugs (UID) have been studied. Anonymous questionnaires were distributed among 61 UID; of these, 50 were males (82%) and 11 were females (18%), mainly at the age of 19-35 years. In addition, sociological study was carried out among 582 persons; 61% of them were under 18 years of age, 18% were aged 19-25 years, 13% were aged 26-35 years. The drug users regarded their individual risk of getting HIV infection as insignificant in 23% of cases, slight in 21% of cases, high in 15% of cases, and 15% believed they were at no risk. As shown by the results of the sociological study, 91% of the respondents believed that the problem of drug addiction was topical in the city. The analysis of data obtained from physicians treating drug addicts and from the Head Office of Public Health made it possible to calculate that the number of UID in the city was about 9,000-10,000 persons. Taking into account the results of the rapid evaluation of the situation, the development of the draft program of "diminishing the harm" of the intravenous use of drugs is now in progress. PMID- 10096223 TI - [The acceptance of a strategy for decreasing the risk of contracting an HIV infection among drug abusers]. AB - The narcotization level of the country is sufficiently high. According to some expert evaluations, the number of drug users varies between 2-4 million persons. Of these, about 100,000 are registered in narcotics service of the Ministry of Health of the Russian Federation and about 250,000 are registered in the system of the Ministry of Internal Affairs of the Russian Federation. The main annual increase in drug users is given by unemployed young people and students (more than 15% of them are minors). An important task standing at present before the specialists of the service responsible for the prophylaxis of HIV infection is the steady spread of information among executive and legislative authorities, as well as the preparation of public opinion, on the necessity for the state to choose and accept the optimum variant of the strategy for the prophylaxis of HIV infection among drug users. PMID- 10096224 TI - [The behavioral risk factors for contracting HIV infection in the intravenous administration of narcotics in abusers of psychoactive substances in the city of Rostov-on-Don]. AB - 150 persons (drug users) who had applied to the department of psycho-social consultations and voluntary tests for the presence of HIV infection and STD of the Regional AIDS Control Center, as well as partners of HIV-infected addicts in the intravenous use of drugs, were examined. Out of 150 examined persons 63 were found to be positive for HIV infection. Among dangerous behavioral patterns, characteristic of drug addicts introducing drugs intravenously, the practice of repeated aspiration of the drug into syringes from the dose of the drug solution, common for the whole group of addicts, was noted as the most widespread habit. PMID- 10096225 TI - [The prevention of HIV infection in abusers of psychoactive substances as a social behavioral problem]. AB - This research has made it possible to outline and illuminate a range of problems which should be solved in planning concrete measures for the prophylaxis of HIV infection among the users of psychoactive substances. Such measures should also include those aimed at preventing children and adolescents from getting accustomed to the use of drugs at an early age, as well as the search of ways for providing adequate and effective information on the consequences of using narcotic drugs, the prevention of passage from single cases of the tentative use of drugs to systematic narcotization, etc. PMID- 10096226 TI - [The legal status of Russian HIV-infected persons]. AB - According to the data, presented by the author and based on the study of opinions expressed by HIV-infected persons, 80% of them are subjected to discrimination. The article deals with the problem of the legal protection of HIV-infected persons in the Russian Federation. Additions and changes in the current legislation regarding foreign citizens and persons in places of confinement are proposed. PMID- 10096227 TI - [The prostitution situation in a number of cities of Russia, Ukraine and Byelarus]. AB - The analytical study indicating that 25% of prostitutes use drugs by intravenous injection is presented. As determined in this study, prostitutes face the double danger of being infected with HIV (they undergo treatment for drug addiction and sexually transmitted diseases). The conclusion has been made that no educational work on HIV/AIDS is carried out among this group of women, though they run a high risk of infection. According to this study, the requirements which ensure the health of prostitutes may be realized by itinerary educational programs, the publication of information materials, specially intended for distribution among such women. The necessity to supplement information on AIDS with information on STD is noted, alerting the public on the fact that these infections are closely connected. The necessity of educating transport and industrial workers, as well as people working in the system of the Ministry of Defense, with a view to prevent the spread of HIV infection is also considered to be an important factor (on the example of Belarus). PMID- 10096228 TI - [HIV infection: the psychological indices at different stages of the disease]. AB - The pronounced forms of depression and the levels of neuro-psychical adaptation and subjective control (attitude to the disease) were studied in 27 patients with HIV infection. 14 patients were at stage A, 8 patients were at stage B and 5 patients were at stage C of the CDC classification (1994). Starting from the early stages of the disease, neuro-psychical adaptation disturbances were noted: at stage A 10 patients belonged to group 5 of health, at stage B 8 patients and at stage C 2 patients. Most of the patients (15) had a low level of subjective control, 12 patients exhibited a medium level, which should be taken into consideration in prescribing and carrying out curative and diagnostic procedures. PMID- 10096229 TI - [A decrease in harm: a new concept for Russian public health]. AB - The main principles of the concept of the "decrease of harm", realized in many countries of the world, are presented and the expediency of using this concept in Russia is substantiated. The beginning of the realization of the Project "Decrease of Harm: the Russian Federation", aimed at training specialists capable of carrying out prophylactic work among users of intravenous drugs (UID), is demonstrated. The principles of the selection of the groups of trainees are shown: the groups are made up of physicians working at AIDS centres, specialists in narcology and representatives of non-governmental organizations. The course of training provides the basic information on the strategy of the prophylaxis of HIV infection among UID, including evaluation and study, outreach, change of syringes and needles, replacement therapy, the program of the treatment of drug addiction. At the present moment 46 specialists from 18 regions of Russia are taking the course of training. PMID- 10096230 TI - [The road will be mastered by the walker]. AB - Anonymous questioning by the distribution of questionnaires among 1,600 young people (68.9% of them were city dwellers, 31.1% were villagers) was carried out. The questioning covered 1,079 adolescents aged 12-16 years (67.3%), 501 young people aged 16-19 years (31.3%) and 20 respondents aged 19-23 years (1.4%). The analysis of answers to questionnaires indicated that all respondents had the same level of knowledge on the subject, but the information they possessed was not duly analyzed and had no influence on their own behavior. It should be pointed out that 1% of persons aged 12-19 years took drugs by intravenous injection. These data, as well as other materials, gave grounds for the development of a new educational program on the prophylaxis of HIV/AIDS/STD and its introduction in 1997. The program is intended for a school course of 6 years (forms 6-11) and must provide adolescents with reliable and comprehensible information, conductive to the formation of a healthy mode of life. PMID- 10096231 TI - [The educating and informing of the population on HIV/AIDS problems in the Republic of Byelarus]. AB - Data on the spread of knowledge and information among the population of the Republic of Belarus, mainly young people aged 14-20 years as the most susceptible group, are presented. Sociological questioning carried out among students of institutions of higher education indicated that 91% of them did not admit the possibility of getting HIV infection; the majority of students of technical and high schools denied the role of casual sexual relations in the spread of HIV infection. The questioning revealed that the main source of information was television for 83.5% of the questioned students, newspapers and magazines for 82.9% and radio for 35%. The sociological study made it possible to lay special emphasis on educational institutions in the work on the information and education of the population. Programs, recommendations and other information materials on the problem of the prophylaxis of HIV/AIDS were developed. Information is provided in educational institutions during classes and non-class work. Institutions of culture also play their due role in providing better information to young people. The Centre issued 26 video reels, 2 films and 3 audio reels. PMID- 10096232 TI - [Children, adolescents and HIV infection]. AB - The analysis of the occurrence of HIV infection in adults, children and adolescents under 18 years of age on the basis of statistical data by February 1, 1997, is presented. The total number HIV-infected persons registered by this date was 6,232; among them 902 (14.5%) were children and adolescents. 267 children were infected in the hospital focus of HIV infection; of these, 80 children (30%) died of AIDS during the period of 1989-1997. In 1992 only 16 adolescents, HIV infected were registered, while in 1995 the number of HIV-infected adolescents was 34, in 1996 their number rose to 144 and in 1997, to 435. The main cause of adolescent infections (80%) was the intravenous injection of narcotic drugs. PMID- 10096234 TI - [The role of public organizations in the prevention of HIV infection in Russia]. AB - The problem of the role of public organizations in the prevention of the spread of HIV infection in Russia is discussed. The correctly chosen strategy of cooperation between governmental structures and non-governmental public associations corresponds to the modern principles of state policy of enhancing the interest of the population in the problems of public health. Relationships built on the principles of mutual respect and partnership in the common work on the prevention of the spread of HIV infection in Russia must increase its effectiveness. PMID- 10096233 TI - [The role of educational programs on the prevention of HIV infection and the development of a healthy life style for adolescents]. AB - On the basis of answers to questionnaires more active use of local TV channels for educational work in the dissemination of knowledge on the prophylaxis of HIV infection is recommended. It is advisable to enlist the cooperation of school psychologists in the work on the social adaptation of adolescents with a view to make them resistant to negative influences affecting their life and health. PMID- 10096235 TI - [A comparative study of the level of knowledge of schoolchildren about HIV infection and AIDS]. AB - The comparative study of the level knowledge on HIV infection and AIDS among school children was carried out. The prophylactic work among school children yielded positive results, which was statistically confirmed by the analysis of answers to questionnaires, distributed before and after lectures. PMID- 10096236 TI - [The clean syringe and HIV infection. A clean syringe can be obtained by any drug addict in a bus stationed in places of active drug trading]. AB - The results of the work on the Program "Bus" supported by the Charitable Fund "Vozvrashchenie" and the French organization Doctors of the World [correction of Word] are presented. The Program "Bus", in contrast to a number of other programs aimed at the "decrease of harm", extended the project by providing the possibility of organizing, within this program, contacts between specialists and drug addicts, as well as the possibility of carrying out diagnostic procedures. As revealed in the process of the work, a half of those who applied to the "Bus" for help sought advice, psychological support, etc. 70% of the drug addicts asking for clean syringes had never applied for help. Among 900 persons who underwent testing, 90% were found to have markers of hepatitis C virus and 76%, markers of hepatitis B virus. Among those drug addicts who applied to the "Bus" for help 11% were found to have syphilis and 1 person proved to be HIV-infected. The results of the work on this project are indicative of the expediency of using such programs in other regions. PMID- 10096237 TI - [Work with youth--the basis of educational programs aimed at the prevention of HIV infection]. AB - During the recent 10 years, 1987-1997, syphilis morbidity was found to increase 60-fold in Omsk Province. In 1997 adolescents constituted 6.0% in the structure of persons who contacted the disease. In this year more than 500 adolescent using drugs were registered in the region. The introduction of drugs by injection was practiced by 9.6% of the adolescents. The program aimed mainly at changing the behavior of young people with orientation on the choice of a healthy mode of life and theirs information about risk factors associated with sex transmitted diseases particularly HIV infection is discussed. PMID- 10096238 TI - p150 expression and its prognostic value in squamous-cell carcinoma of the esophagus. AB - To investigate p150, a recently cloned protein, and its prognostic value in esophageal squamous-cell carcinoma, 100 samples were analyzed immunohistochemically and 30 fresh samples by the immunoblot method. All 100 patients, from Northern China, over-expressed p150 as compared with controls in the immunohistochemical study, and the same was found for the tumors of the 30 patients analyzed by Western-blot analysis. A close correlation could be observed between p150 over-expression and the state of differentiation, since well differentiated cancers showed high p150 expression, and vice-versa (p < 0.0001). In addition, patients with high p150 expression had significantly fewer tumor metastases (local or distant, p < 0.005). Furthermore, and prognostically more relevant, survival analysis showed that patients with high p150 expression had significantly better overall survival (p < 0.0026). This somehow unexpected result may, however, be typical for squamous carcinoma, since in human cervical carcinoma, another squamous carcinoma, the p150 values were reported to rise early in all tumors, to stay high in patients with longer survival as well. In addition, patients with regional lymph-node metastasis and high p150 expression survived longer than those with regional lymph-node metastasis and lower p150 expression (p < 0.0066). Multivariate analysis showed that p150 is an independent factor for predicting patient survival. The results suggest that p150 may be a new biomarker for squamous-cell carcinoma of the esophagus, with specific prognostic value. PMID- 10096239 TI - VEGF, VEGFR-1, VEGFR-2, microvessel density and endothelial cell proliferation in tumours of the ovary. AB - VEGF is an angiogenic factor with potent endothelial cell (EC) proliferative actions. Our aim was to investigate whether expression of VEGF and its receptors and EC proliferation differ between ovarian tumour types and regions of the vasculature. VEGF, VEGFR-1, VEGFR-2 and EC proliferation were examined immuno histochemically, and in situ hybridisation (ISH) studies of VEGF mRNA expression were performed and assessed in regions of high (HVD) and average (AVD) vessel density. VEGF immunostaining was significantly stronger in HVD regions of malignant compared with borderline serous tumours. VEGF immunostaining did not differ between tumour types; however, the percentage of VEGFR-1- and VEGFR-2 positive vessels was significantly lower in mucinous tumours. No differences were observed between HVD and AVD regions. VEGF ISH signal was observed in 2/7 borderline mucinous tumours, 8/14 malignant serous tumours and 5/13 benign tumours. The EC proliferation index was significantly lower in the HVD regions of serous relative to benign tumours. A negative correlation between VEGFR-1 immunostaining and microvessel density was observed in benign and serous tumours. However, EC proliferation index and VEGFR-1 positivity were positively correlated in benign tumours. Our results suggest that VEGF may play a role in the control of angiogenesis in serous and benign tumours but it does not appear to contribute to the previously reported higher microvessel density in mucinous tumours or to influence heterogeneity of microvessel density in ovarian tumours. PMID- 10096240 TI - Hypermethylation of the MYF-3 gene in colorectal cancers: associations with pathological features and with microsatellite instability. AB - Myf-3 is the human homologue of the murine Myo-D1 gene involved in muscle-cell differentiation. Using Southern blot analysis, we examined methylation of Myf-3 in histologically normal colonic mucosae, adenomas and carcinomas from a large series of patients with primary colorectal cancer. Hypermethylation of this gene in comparison with normal mucosa was observed in 88% of adenomas and in 99% of carcinomas. The pattern of Myf-3 methylation was similar in different areas of the same tumour, suggesting that methylation imbalances occur before the bulk of clonal-cell expansion. Significantly increased levels of Myf-3 methylation were observed in tumours which were more invasive, located in the proximal colon or from older patients. Patients whose tumours had extensive methylation showed a trend for shortened survival, though this was probably related to their being more invasive. Extensive methylation was significantly more frequent in tumours with microsatellite instability. Further work is required to determine whether the hypermethylation of Myf-3 observed in colorectal cancers is a specific alteration with functional significance or whether it reflects non-specific methylation imbalances occurring early during tumorigenesis. PMID- 10096241 TI - DNA sequence copy number increase at 8q: a potential new prognostic marker in high-grade osteosarcoma. AB - Histologic response to chemotherapy is currently the best prognostic parameter in high-grade osteosarcoma but it can be evaluated only after several weeks of chemotherapy. Thus a prognostic parameter known at the time of diagnosis would be of great clinical benefit. In the present study, we present the results of 31 primary high-grade osteosarcomas analyzed by comparative genomic hybridization (CGH). CGH allows for genome-wide screening of a tumor by detecting alterations in DNA sequence copy number. The most frequent aberrations were copy number increases at 1q21 in 58% of the tumors and at 8q (8q21.3-q22 in 52% and 8cen-q13 in 45%), followed by copy number increases at 14q24-qter (35%) and Xp11.2-p21 (35%). The most common losses were detected at 6q16 (32%) and 6q21-q22 (32%). Patients with a copy number increase at 8q21.3-q22 and/or at 8cen-q13 had a statistically significant poor distant disease-free survival (p = 0.003) and showed a trend toward short overall survival (p = 0.04). Patients with a copy number increase at 1q21 showed a trend toward short overall survival (p = 0.04). Thus, specific genetic aberrations detected at the time of the diagnosis could be used in prognostic evaluation of high-grade osteosarcoma. PMID- 10096242 TI - GATA-3 is expressed in association with estrogen receptor in breast cancer. AB - To better understand the molecular basis for the hormone-responsive phenotype in breast cancer, we have used a human cDNA array to compare patterns of gene expression between breast carcinoma cell lines discordant for estrogen receptor (ER) expression. These experiments indicated abundant expression of the transcription factor GATA-3 in the ER-positive cell lines MCF7 and T-47D, with minimal or no expression in the ER-negative cells lines MDA-MB-231 and HBL-100. Northern blot analysis of a panel of human breast carcinoma cell lines demonstrated a correlation between ER and GATA-3 expression. Studies of MCF7 cells grown in the absence or presence beta-estradiol indicated that GATA-3 expression was not responsive to estradiol. Protein immunoprecipitation and gel shift analysis confirmed the presence of functional GATA-3 protein in MCF7 but not in HBL-100 nuclear extracts. A panel of 47 primary breast cancers was characterized for expression of ER and GATA-3 using immunoperoxidase assay. In primary tumors, a statistically significant correlation between ER and GATA-3 expression was established (p < 0.0001, chi2). Our results indicate that GATA-3, in association with ER, is likely to regulate genes critical to the hormone responsive breast cancer phenotype. PMID- 10096243 TI - c-erbB-2 (HER-2/neu) protein and drug resistance in breast cancer patients treated with induction chemotherapy. AB - Expression of c-erbB-2 protein has been associated with poor prognosis and poor response to chemotherapy in breast cancer patients. In the present prospective study, we have analyzed whether c-erbB-2, p53 and P170 proteins may be determinants of tumor resistance in locally advanced breast cancer patients treated with induction chemotherapy. Biopsies (n = 60) were examined by immuno histochemistry; in 62% of cases core or incisional biopsies were taken before drug administration, allowing comparison in paired biopsies of the cytological and molecular changes induced by treatment Sixty percent of the patients received relatively high doses of FAC or FEC (5-fluorouracil, doxorubicin or epirubicin and cyclophosphamide), and 40% received relatively high doses of doxorubicin or epirubicin alone. No significant changes were observed in the molecular markers studied following chemotherapy; in the few biopsies where changes appeared, the changes did not exhibit any significant or similar trend. For 30 of the patients who received FAC/FEC treatment, follow-up reached a median of 34 months. In these cases, neither the clinical (reduction in tumor size) nor the histological (evaluated after neoadjuvant chemotherapy) responses showed statistically significant differences between the patients who developed distant metastases and the disease-free patients. c-erbB-2 was over-expressed in 50% of patients who developed distant metastases vs. 7% of the disease-free patients. Disease free survival (DFS) curves between c-erbB-2-positive and c-erbB-2-negative patients were statistically significant. No correlation between p53 or P170 expression with DFS was found. Our results suggest that c-erbB-2 protein expression is associated with development of distant metastases in breast cancer patients treated with relatively high doses of anthracyclines in induction chemotherapy. PMID- 10096244 TI - Glutathione S-transferase T1 and M1 genotypes in normal mucosa, transitional mucosa and colorectal adenocarcinoma. AB - Gene codings for glutathione S-transferase T1 (GSTT1) and M1 (GSTM1) are polymorphic in humans with null genotypes present in approximately 20 and 50%, respectively. A significant excess of homozygous null GSTT1 and GSTM1 genotypes has been demonstrated among individuals with certain types of cancers. This finding suggests that GSTT1 and GSTM1 may play a role in tumour susceptibility. However, reports concerning colorectal cancer susceptibility are controversial. In the present study, we used a multiplex polymerase chain reaction (PCR) approach to identify and analyze simultaneously the genotypes of both the genes in 99 patients with colorectal cancer and 109 healthy controls. Compared with the control group, a significant excess of homozygous null genotypes for GSTT1 was found in normal mucosa among the cancer patients, but not for GSTM1. Both genes were more frequently deleted in tumours than in corresponding normal mucosa. Furthermore, GSTT1 null genotype in tumour tissue, was significantly related to old age and to poor differentiation of tumours. GSTM1 null genotype in tumour was more frequent in the rectal tumours compared with tumours of left colon and right colon. Our results suggest that individuals with GSTT1 null genotype may be genetically predisposed for an increased risk of developing colorectal cancer. Allele loss in tumour tissue, which reflects genetic instability, may be considered as a marker for evaluating clinico-pathological characteristics of the cancer patients. PMID- 10096245 TI - Cyclin-D1 expression in node-positive (N+) and node-negative (N-) infiltrating human mammary carcinomas. AB - Cyclin-D1 (CD1) expression was analyzed in human mammary carcinomas by immunohistochemical (IHC) and flow-cytometry (FCM) methods: 52.5% and 50% of cases were strong expressors of CD1 by IHC and FCM analysis respectively. The percentage of CD1-positive cells was especially high in node-negative (N-) estrogen-receptor-positive (ER+) tumors, probably as a consequence of CD1 induction by estrogens in steroid-responsive tissues. However, CD1 expression was not related to ER positivity in node-positive tumors (N+). An interesting relationship between CD1 expression and H3-thymidine labelling index (H3Td-LI) was also found: CD1 and H3Td-LI were unrelated in N- tumors, while high CD1 expression was observed in N+ tumors with high DNA synthesis, as assessed by H3Td LI. The combined measurement of DNA and CD1 showed that 27 specimens were aneuploid, 19 of them (19/27; 70%) strongly expressing CD1. Further studies are needed to clarify the role of CD1 in DNA abnormality of breast tumors. However, we cannot exclude that the CD1 may be differently de-regulated in the last phase of tumor progression, and that CD1 over-expression may contribute to the aneuploidy of mammary carcinomas. PMID- 10096246 TI - Comparative immunocytochemical assessment of isolated carcinoma cells in lymph nodes and bone marrow of patients with clinically localized prostate cancer. AB - After radical prostatectomy for clinically localized prostate cancer, biochemical progression is seen in up to 40% of the patients due to persistent local and/or systemic remnants. Isolated disseminated carcinoma cells, undetectable by current staging methods, are of special interest as potential precursors of subsequent overt metastases. In the present study, immunohistochemistry (IHC) was performed to evaluate simultaneously the frequency of occult carcinoma cells in both lymph nodes (LNs) and bone marrow (BM) obtained from the iliac crests of 45 prostate cancer patients with untreated stage T(1-3) pN0 M0 prostatic carcinoma. IHC using monoclonal antibodies (MAbs) against epithelial cytokeratins was performed on 521 paraffin-embedded LNs histopathologically classified as tumorfree (pN0), as well as on BM cytospin preparations. To confirm the prostatic origin of positive cells in LNs, additional IHCs for prostate-specific antigen (PSA) and epithelial glycoproteins were performed. In total, isolated tumor cells in LNs and/or BM were detected in 17 of the 45 patients. Parameters such as tumor stage, grade and volume of the primary tumor as well as blood serum PSA levels could not detect patients harboring disseminated single tumor cells in LNs or BM. Following a median observation time of 24.9 months, no significant correlation between IHC positivity and PSA progression as a measure of early relapse was observed. Although the overall incidence of occult tumor cell spread corresponds to similar incidence of relapses after radical prostatectomy as reported by others, the fate of these cells needs to be evaluated in longer follow-up studies. PMID- 10096247 TI - Mutational analysis of the PTEN gene in gliomas: molecular and pathological correlations. AB - The PTEN gene, recently identified on chromosome 10q23, has been proposed to be a candidate tumor suppressor gene inactivated in multiple cancers including glial tumors. We investigated 47 glioblastomas (GBM), 14 anaplastic astrocytomas (AA), 6 non-pilocytic low-grade astrocytomas (LGA), 21 low-grade and anaplastic oligodendrogliomas (O) and oligoastrocytomas (OA), and 3 ependymomas (E) for mutation of the PTEN gene using denaturing gradient gel electrophoresis (DGGE) followed by DNA sequencing. These tumors have been previously screened for loss of heterozygosity (LOH) on chromosome 10q, p53 mutations and EGFR amplification. Overall, PTEN mutations, detected in 14 of 91 tumors, were present in 13 of 47 GBM and 1 of 14 AA. In contrast, mutations were absent in other glioma subtypes (0/30). In all informative cases, PTEN mutations occurred in tumors showing LOH on chromosome 10q, confirming the inactivation of this gene by a 2-hit mechanism. No correlation was observed between the presence of PTEN mutation and p53 mutation and EGFR amplification. Our results indicate that biallelic PTEN inactivation plays an important role in the pathogenesis of high-grade astrocytomas as a late event. Moreover, they suggest that PTEN alterations are equally involved in the 2 glioblastoma pathways defined by the presence of EGFR amplification and p53 mutation. Finally, correlation analysis with clinical data did not show that PTEN mutation was linked to survival of the patients. PMID- 10096248 TI - TGF-beta1 levels in pre-treatment plasma identify breast cancer patients at risk of developing post-radiotherapy fibrosis. AB - A serious complication of radiotherapy in the treatment of cancer patients is the late onset of fibrosis in normal tissues. Transforming growth factor beta (TGF beta) is emerging as a key mediator of the fibrotic process through its effects on stimulation of fibroblast proliferation, migration and extracellular matrix (ECM) synthesis. The fact that radiation-induced vascular injury tends to precede the development of fibrosis has led to the suggestion that vascular damage is crucial in its pathogenesis. CD105, the specific type III vascular receptor for TGF-beta1 and -beta3, modulates cell proliferation and ECM production in response to TGF-beta in vitro. In this study, we have quantified the levels of TGF-beta1 and soluble CD105-TGF-beta1 complex in 91 pre-radiotherapy plasma samples from early-stage (T1 or T2) breast cancer patients utilising an enhanced chemiluminescence ELISA system. During the follow-up period, 24 patients had developed moderate and one severe fibrosis of the breast. The mean TGF-beta1 level in these 25 patients was 203.2 +/- 37.3 pg/ml, which was significantly elevated above the level for those with no fibrosis. Furthermore, a significantly lower CD105-TGF-beta1 complex level was observed in the former compared to the latter. Spearman's correlation analysis showed that TGF-beta1 was positively correlated and the CD1O5-TGF-beta1 complex inversely correlated with the occurrence of breast fibrosis. Using a cut-off value of 96 pg/ml, the sensitivity and specificity of TGF-beta1 levels in predicting breast fibrosis were 76% and 74%, respectively. Our results indicate that TGF-beta1 and the receptor-ligand complex appear to be of clinical value in identifying patients at risk of developing post-radiotherapy fibrosis. PMID- 10096249 TI - Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. AB - Melanoma cells in culture express a variety of growth factors and cytokines and some of their autocrine and paracrine roles have been investigated. However, less information is available on the potential dynamic changes in expression of these molecules on cells during melanoma development and progression in situ. Using immunohistochemistry, we tested 40 nevi and primary and metastatic melanoma lesions for the expression of 10 growth factors and cytokines and the respective receptors representing 10 cell surface molecules. Nevi and thin (< 1 mm) primary melanomas showed little expression of ligands except weak reactivity of tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8) and reactivity of TGF-betaR and c-kit. Marked up-regulation of growth factors, cytokines and receptor expression was observed in thick (> 1 mm) primary melanomas, which were stained with polyclonal or monoclonal antibodies (MAbs) for IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha, TGF-beta, granulocyte-macrophage colony-stimulating factor (GMCSF) and stem cell factor (SCF), but not IL-2. Metastases showed similar expression patterns except that SCF was absent. Co-expression of ligand and receptor was observed for TGF-beta, GM-CSF and IL-6, suggesting an autocrine role for these ligands. TNF-alpha appears to be a marker of benign lesions; IL-6 and IL-8 expression is associated with biologically early malignancy; TGF-beta, GM-CSF and IL-1alpha are highly expressed in biologically late lesions; and TNF-beta is an apparent marker of metastatic dissemination. Our results indicate that melanoma cells utilize cascades of growth factors and cytokines for their progression. PMID- 10096250 TI - Over-expression and amplification of the c-myc gene in human urothelial carcinoma. AB - To understand the mechanisms underlying increased expression of Myc protein in human urinary bladder cancer, expression of c-myc mRNA and the copy number of the c-myc gene were determined. Expression of mRNA was measured by quantitative RT PCR in 40 urothelial carcinomas and in 18 histologically normal mucosae. Mean expression in tumors was significantly increased (3.23+/-2.63 AU vs. 1.90+/-0.95 AU, p < 0.023) and exceeded the highest level in normal mucosa in 15 (37.5%) tumors. The c-myc gene copy number was higher than in leukocytes and normal bladder mucosa in 14 of 40 tumors, but only 3 among these showed a more than 4 fold increase indicative of gene amplification. Most, but not all, tumors with elevated expression displayed an increased gene copy number (p < 0.0001). In line with other studies of the protein level, no significant association either of c myc mRNA over-expression or of increased gene copy number with tumor stage or grade was observed. The data indicate that elevated mRNA expression as a consequence of increases in c-myc gene copy number often underlies Myc protein over-expression in bladder cancer. This increase may be a consequence of, most frequently, chromosome 8q gain and, occasionally, gene amplification, while in some tumors deregulation of mRNA expression occurs without evident changes in the c-myc gene copy number. PMID- 10096251 TI - Cytoplasmic beta-catenin in esophageal cancers. AB - beta-Catenin has 2 distinct roles in E-cadherin-mediated cell adhesion and carcinogenesis through APC gene mutation. One occurs at cell-adhesion sites, where cadherins become linked to the actin-based cytoskeleton. The others occur in the cytoplasm and nuclei and are thought to regulate cell transformation. We studied these different beta-catenins and evaluated their significance in carcinogenesis. Fresh surgical specimens were obtained from 22 patients with squamous-cell carcinoma of the esophagus. beta-Catenin in the free soluble fraction and the insoluble fraction was immunoblotted separately. At the same time, its localization was observed by immuno-histochemical techniques. In the normal esophageal epithelium, 91% of beta-catenin was detected in the insoluble fraction and beta-catenin staining occurred at the cell membrane, in co-existence with E-cadherin. In cancerous tissues, the amount of soluble beta-catenin was significantly (about 4-fold) higher than in normal tissues. Also, in cancerous tissues with higher amounts of soluble beta-catenin, immuno-histochemical techniques revealed the presence of beta-catenin in the cytoplasm and nuclei, as well as in the cell membrane. However, in samples with lower amounts of beta catenin, expression was found only at the cell boundaries. The amount of soluble beta-catenin was not associated with the clinico-pathological grading of the tumors. Our results show that the accumulation of free soluble beta-catenin in the cytoplasm and nuclei frequently occurs during carcinogenesis of the squamous epithelium of the esophagus. PMID- 10096252 TI - Staging of nasopharyngeal carcinoma: from Ho's to the new UICC system. AB - The independent significance of different tumor factors in 4,514 patients with undifferentiated or non-keratinizing carcinoma of the nasopharynx irradiated at the Queen Elizabeth Hospital during 1976-1985 were analyzed retrospectively. Multivariate analyses showed that the most significant primary factors included cranial nerve palsy, erosion of base of skull and oropharynx. For tumors within the nasopharynx, there was no difference in survival between those with involvement of 1 site vs. more than 1 sites. Patients with cranial nerve palsy had significantly worse prognosis than those with bony erosion alone. Although the nodal characteristics (size, level of extension, fixation, laterality and multiplicity) were inter-related, their independent impact all reached statistical significance. However, the criteria used currently could be simplified: laterality should be revised to unilateral vs. bilateral, level to upper-mid vs. lower neck, and size to < or =6 cm vs. >6 cm. Grouping of N2 together with N3 into Stage IV was inappropriate as the former had significantly better prognosis. Our findings, together with review of the publications, provided clinical data for developing the current UICC staging system for nasopharyngeal carcinoma. Such major revision resulted not only in better distinction of hazards, but also more even distribution of cases between different stages. PMID- 10096253 TI - Epidermal growth factor receptor expression in primary laryngeal cancer: an independent prognostic factor of neck node relapse. AB - Specimens of laryngeal squamous cell carcinoma (LSCC) were examined for epidermal growth factor receptor (EGFR) content using a radioreceptor method; 140 untreated consecutive patients with primary LSCC undergoing initial surgical resection were followed up for a median of 49 months (range 2-84 months) after surgery. Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels were directly associated with the risk of lymph node metastasis. A significant relationship between EGFR status and cervical node metastasis was observed. The cutoff value of 20 fmol/mg protein was the best prognostic discriminator. The 5-year metastasis-free survival (MFS) was 66% for patients with EGFR- tumors compared with 15% for patients with EGFR+ tumors. By multivariate analysis, the EGFR status appeared to be a significant independent prognostic factor for MFS. Our results suggest that the assessment of EGFR status at the time of diagnosis may identify a subset of LSCC patients highly susceptible to neck node metastases thus defining therapy accordingly. PMID- 10096254 TI - Prognostic significance of Bcl-2 in Wilms' tumor and oncogenic potential of Bcl X(L) in rare tumor cases. AB - Anaplastic Wilms' tumors are commonly believed to be rare forms of progression, driven by p53 mutations, of the more common classical Wilms' tumor or nephroblastoma Contrary to classical Wilms' tumors, anaplastic tumors traditionally tend to metastasize, to be drug-resistant and to have a poor prognosis. The Bcl-2 gene product protects cells from programmed cell death, and its over-expression has been proposed to be tumorigenic and to mediate resistance to therapy. Because Bcl-2 has been reported to be transcriptionally repressed by p53, using immuno-histochemistry and mRNA analyses, we have examined Bcl-2 expression in a panel of 10 classical and 3 anaplastic nephroblastomas in which the p53 status had been previously analyzed. We found that classical Wilms' tumors expressed significant amounts of Bcl-2 mRNA and protein, whereas anaplastic tumors did not, regardless of p53 mutations. However, because mortality occurred both among patients with classical and among those with anaplastic tumors, which had divergent Bcl-2 expression, analysis of variance failed to demonstrate prognostic Bcl-2 significance. Therefore, we examined the expression of the Bcl-X and Bax genes, which are known to synergize and antagonize Bcl-2, respectively. With the exception of anaplastic tumor W17, the monotony of Bcl-X and Bax mRNA levels did not suggest that the expression of these apoptosis-regulating genes could have a role in the prognosis of nephroblastoma. In addition to the standard 2.7-kb Bcl-X(L) mRNA, W17 expressed a 3.5-kb mRNA species which had the same coding capacity for Bcl-X(L) as the 2.7-kb mRNA. Western analysis demonstrated that W17 had the highest level of Bcl-X(L) protein, suggesting that Bcl-X(L) over-expression could play a part in the development of anaplasia in rare Wilms' tumor cases without affecting prognosis. PMID- 10096255 TI - 6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. AB - BACKGROUND: 6',7'-Dihydroxybergamottin is a furanocoumarin that inhibits CYP3A4 and is found in grapefruit juice and Seville orange juice. Grapefruit juice increases the oral bioavailability of many CYP3A4 substrates, including cyclosporine (INN, ciclosporin), but intestinal P-glycoprotein may be a more important determinant of cyclosporine availability. OBJECTIVES: To evaluate the contribution of 6',7'-dihydroxybergamottin to the effects of grapefruit juice on cyclosporine disposition and to assess the role of CYP3A4 versus P-glycoprotein in this interaction. METHODS: The disposition of oral cyclosporine was compared in healthy subjects after ingestion of water, grapefruit juice, and Seville orange juice. Enterocyte concentrations of CYP3A4 were measured in 2 individuals before and after treatment with Seville orange juice. The effect of 6',7' dihydroxybergamottin on P-glycoprotein was assessed in vitro. RESULTS: Area under the whole blood concentration-time curve and peak concentration of cyclosporine were increased by 55% and 35%, respectively, with grapefruit juice (P < .05). Seville orange juice had no influence on cyclosporine disposition but reduced enterocyte concentrations of CYP3A4 by an average of 40%. 6',7' Dihydroxybergamottin did not inhibit P-glycoprotein at concentrations up to 50 micromol/L. CONCLUSIONS: 6',7'-Dihydroxybergamottin is not responsible for the effects of grapefruit juice on cyclosporine. Because the interaction did not occur with Seville orange juice despite reduced enterocyte concentrations of CYP3A4, inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible. Reduced enterocyte CYP3A4 by 6',7'-dihydroxybergamottin could be important for other drugs whose bioavailability is less dependent on P glycoprotein. PMID- 10096256 TI - Tobramycin penetration into epithelial lining fluid of patients with pneumonia. AB - OBJECTIVE: To study the penetration of tobramycin in lung tissue evaluated as the concentration in epithelial lining fluid and to characterize the time course of the drug in the treatment of patients with pneumonia. METHODS: The subjects were 16 patients with pneumonia and taking tobramycin who had clinical indications for bronchoscopy. Bronchoscopy with bronchoalveolar lavage of the pneumonic area was performed once on each patient 1/2%, 2, 4, or 8 hours after the previous tobramycin dose. Urea was used as an endogenous marker for quantification of epithelial lining fluid obtained at bronchoalveolar lavage. Tobramycin concentrations in serum were measured for all patients at the aforementioned 4 time points. Tobramycin concentration was determined by means of fluorescent polarization immunoassay modified for bronchoalveolar samples. RESULTS: Levels of tobramycin in the fluid of the epithelial lining were 2.33+/-0.5 at 1/2 hour, 1.67+/-0.6 at 2 hours, 1.62+/-1.19 at 4 hours, and 0.77+/-0.38 microg/mL at 8 hours. The ratio of epithelial lining fluid to serum concentration of tobramycin was 0.30+/-0.03 at 1/2 hour, 0.42+/-0.16 at 2 hours, 0.64+/-0.37 at 4 hours, and 1.53+/-0.76 at 8 hours. The ratio at peak serum time was similar to that reported for tobramycin and netilmicin. CONCLUSIONS: High peak serum concentrations of tobramycin are necessary to obtain microbiologically active concentrations at the alveolar level. The fluid of the epithelial lining constitutes a deep compartment for aminoglycosides. The disappearance of tobramycin was slower than at the serum level. PMID- 10096257 TI - Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. AB - OBJECTIVE: The mutual drug-drug interaction potential of the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin and cyclosporine (INN, ciclosporin) in kidney transplant recipients receiving individual immunosuppressive treatment was evaluated with respect to pharmacokinetic behavior of either drug and tolerability of concomitant use. METHODS: Plasma and urine concentrations of cerivastatin and its major metabolites were determined after administration of 0.2 mg single-dose cerivastatin to 12 kidney transplant recipients (9 men and 3 women) who were receiving stable individual cyclosporine treatment (mainly 200 mg twice a day). These results were compared with the single-dose pharmacokinetic results obtained from a healthy control group (n = 12, age-comparable men). Cerivastatin steady state pharmacokinetics were evaluated in the same patients during continued immunosuppressive treatment 4 to 6 weeks later, after a 7-day treatment of 0.2 mg cerivastatin once a day. Cyclosporine steady-state concentration-time profiles were determined in blood with monoclonal (EMIT [enzyme multiplied immunoassay technique] assay, parent drug specific) and polyclonal antibodies (FPIA [fluorescence polarization immunoassay] assay, cyclosporine plus metabolites) during cerivastatin cotreatment and compared with predosing data. RESULTS: Coadministration of 0.2 mg cerivastatin once a day to the kidney transplant recipients treated with individual doses of cyclosporine and other immunosuppressive agents resulted in a 3- to 5-fold increase in cerivastatin and metabolites plasma concentrations. Cerivastatin and metabolites elimination half lives were unaffected, and no accumulation occurred during multiple-dosing conditions. Cerivastatin had no influence on steady-state blood concentrations of cyclosporine or cyclosporine metabolites in these patients. The concomitant use of both drugs was well tolerated. CONCLUSIONS: Cerivastatin and metabolites plasma concentrations were significantly increased in kidney transplant recipients treated with cyclosporine and other immunosuppressive agents. Displacement from the main site for cerivastatin distribution-the liver-by cyclosporine-inhibited liver transport processes may explain the decrease in both metabolic clearance and volume of distribution for cerivastatin and metabolites. PMID- 10096258 TI - Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2. AB - BACKGROUND AND OBJECTIVES: Pefloxacin is reported to cause clinically relevant inhibition of theophylline metabolism in vivo, but in vitro pefloxacin was only a weak inhibitor of the cytochrome P450 CYP1A2, mediating main theophylline biotransformation. We therefore further characterized the interaction between pefloxacin and CYP1A2. METHODS: A randomized 3-period change-over study was conducted in 12 healthy young volunteers on the steady-state interactions between pefloxacin or enoxacin (400 mg twice a day) with caffeine (183 mg once daily), a validated marker of CYP1A2. Caffeine pharmacokinetics were estimated after its fifth dose. Studies in human liver microsomes were carried out to measure the effect of pefloxacin and norfloxacin on caffeine 3-demethylation, an in vitro CYP1A2 probe, and to identify the enzyme(s) that mediate pefloxacin N-4' demethylation with selective inhibitors. RESULTS: For the in vivo study, ANOVA based point estimates (90% confidence intervals [CI]) for the ratios of caffeine pharmacokinetics with and without pefloxacin coadministration were 1.11 for maximal steadystate plasma concentrations (Cmax,ss; 90% CI, 0.99 to 1.26), 0.53 for total clearance (CLt,ss; 90% CI, 0.49 to 0.58), and 1.04 for the beta-phase distribution volume (Vdbeta; 90% CI, 0.96 to 1.13). The values for enoxacin were 1.99 for Cmax,ss (90% CI, 1.77 to 2.23), 0.17 for CLt,ss (90% CI, 0.16 to 0.19), and 1.01 for Vdbeta (90% CI, 0.90 to 1.13). Thus pefloxacin caused a 2-fold decrease in caffeine clearance, and enoxacin caused a 6-fold decrease in caffeine clearance. In vitro, norfloxacin and pefloxacin competitively inhibited CYP1A2, with inhibition constant (Ki) values of 0.1 and 1 mmol/L, respectively, and CYP1A2 was the only enzyme with a relevant contribution (approximately 50%) to pefloxacin N-4'-demethylation. CONCLUSIONS: Enoxacin and to a lesser extent pefloxacin may cause clinically relevant interactions with further CYP1A2 substrates. The data suggest that the pefloxacin interaction is partly mediated by its major metabolite norfloxacin. PMID- 10096259 TI - Phenotypic-genotypic analysis of CYP2C19 in the Jewish Israeli population. AB - OBJECTIVES: Evaluation of CYP2C19 activity and the frequency of CYP2C19 alleles in the Jewish Israeli population. METHODS: One hundred forty Jewish Israeli subjects received 100 mg racemic mephenytoin and collected urine for 8 hours. Urinary concentrations of mephenytoin enantiomers and 4'-hydroxymephenytoin were determined by gas-liquid chromatography and HPLC, respectively. CYP2C19 activity was derived from urinary S/R-ratio and 8-hour urinary excretion of 4' hydroxymephenytoin. Mutations were identified by polymerase chain reaction and enzyme digestion with SmaI (CYP2C19*2) and BamHI (CYP2C19*3). RESULTS: Deficient mephenytoin hydroxylation was found in 4 subjects (2.9%; 95% confidence interval [CI], 0.1% to 5.7%) who were homozygous for CYP2C19*2. CYP2C19*2 was the major deactivating allele accounting for 15% (95% CI, 11% to 19%) of CYP2C19 alleles, whereas CYP2C19*3 was identified in 2 subjects (1%; 95% CI, 0% to 2%). Among 136 extensive metabolizers, 99 were homozygous for CYP2C19*1 and 37 were compound heterozygous CYP2C19*1/CYP2C19*2 (35 subjects) or CYP2C19*1/CYP2C19*3 (2 subjects). Gene dose effect was noted so that the S/R-ratio was significantly greater and urinary excretion of 4'-hydroxymephenytoin was significantly lower in compound heterozygous than in homozygous extensive metabolizers (0.310+/-0.209 versus 0.225+/-0.176, P < .04 and 48.6%+/-19.2% versus 56.3%+/-16.0%, P < .03, respectively). Female extensive metabolizers had a significantly lower excretion of 4'-hydroxymephenytoin than male extensive metabolizers (49.5%+/-17.6% versus 58.4%+/-16.7%, respectively, P < .005). CONCLUSION: The frequency of poor metabolizers of CYP2C19 and CYP2C19*2 allele in the Jewish Israeli population resembles findings in non-Asian populations. Complete concordance was noted between phenotypic and genotypic findings. CYP2C19 genotyping may enable subclassification of extensive metabolizers into subjects with high and low activity. PMID- 10096261 TI - Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. AB - BACKGROUND: The CYP2D6*10 (*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of about 50%. In this study we studied the effects of the *10 allele on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol. METHODS: The subjects were 67 Japanese inpatients with schizophrenia who had only the wild-type or *10 alleles. Thirty four patients were homozygous for the wild-type allele, and 26 were heterozygous and 7 were homozygous for the *10 allele. All patients had been receiving 12 mg/day haloperidol for at least 2 weeks. Plasma concentrations of haloperidol and reduced haloperidol were measured by HPLC. RESULTS: The mean +/- SD values of haloperidol Css in the patients with 0, 1, and 2 *10 alleles were 22.8+/-11.0, 30.1+/-10.6, and 31.2+/-21.2 nmol/L, respectively, and those values for reduced haloperidol were 6.1+/-2.9, 9.5+/-3.7, and 9.9+/-6.2 nmol/L, respectively. The mean haloperidol Css was significantly (P < .05) higher in the patients with 1 *10 allele than in those with no *10 alleles. The mean Css of reduced haloperidol was significantly (P < .05) higher in the patients with 1 and 2 *10 alleles than in those with no *10 alleles. CONCLUSION: This study suggests that the *10 allele plays an important role in controlling the Css of both haloperidol and reduced haloperidol, especially in Asian subjects. PMID- 10096260 TI - Unexpected effect of verapamil on oral bioavailability of the beta-blocker talinolol in humans. AB - PURPOSE: To quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P-glycoprotein on oral pharmacokinetics of the beta1-adrenergic receptor antagonist talinolol, a substrate of P glycoprotein. SUBJECTS AND METHODS: In a randomized, crossover placebo-controlled study, oral pharmacokinetics of talinolol (50 mg) after concomitant administration of single doses of R-verapamil (120 mg) or placebo were investigated in 9 healthy volunteers. Concentrations of talinolol, verapamil, and its main metabolite norverapamil were measured in serum with HPLC. Concentrations of talinolol were also measured in urine by HPLC. Standard pharmacokinetic parameters were calculated with noncompartmental procedures. RESULTS: The area under the concentration-time curve for talinolol from 0 to 24 hours was significantly decreased after R-verapamil versus placebo (721+/-231 ng x h x mL( 1) versus 945+/-188 ng x h x mL(-1); P < .01). Maximum serum concentration of talinolol was reached significantly earlier after R-verapamil compared with placebo (P < .05). Coadministration of R-verapamil did not affect the renal clearance or half-life of talinolol. Serum pharmacokinetics are paralleled by the results derived from urine concentrations of talinolol. CONCLUSION: This is the first study to show a decreased oral bioavailability of a P-glycoprotein substrate (talinolol) in humans as a result of coadministration of verapamil. This effect is assumed to be caused by changes of the intestinal net absorption of talinolol because its renal clearance remains unaffected by administration of R-verapamil. This unexpected effect of R-verapamil is most likely dose dependent as a result of an interplay between intestinal P-glycoprotein and gut metabolism. PMID- 10096262 TI - Angiotensin-converting enzyme inhibition improves venous endothelial dysfunction in chronic smokers. AB - OBJECTIVE: In arteries and veins smoking is associated with impaired nitric oxide mediated relaxation to endothelium-dependent agonists such as bradykinin. We investigated whether acute local angiotensin-converting enzyme (ACE) inhibition, achieved by enalaprilat, could influence bradykinin-induced vasodilation in veins of smokers. METHODS: We studied 7 smokers and 7 nonsmokers with the hand vein technique. After preconstriction with phenylephrine was performed, endothelium dependent and independent relaxations were assessed by infusing bradykinin (1 to 278 ng/min) and sodium nitroprusside (0.0001 to 3166 ng/min), respectively. Dose response curves were constructed before and during enalaprilat coinfusion (1 microg/min for 40 minutes). RESULTS: Smokers had impaired venodilation to bradykinin compared with nonsmokers (P < .01). Apparent maximal relaxation induced by bradykinin was 78%+/-9% in the control group and 48%+/-9% in smokers (mean +/- SD). ACE inhibition shifted the bradykinin dose-response curve to the left in both groups (P < .001) and was associated with a minimal increase in apparent maximal venodilation in nonsmokers (78%+/-9% to 83%+/-18%). In contrast, in smokers ACE inhibition augmented the magnitude of apparent maximal venodilation to values comparable to those observed in the control group (48%+/ 9% to 102%+/-21%). In both groups the response to sodium nitroprusside was not affected by enalaprilat. CONCLUSIONS: This study shows that acute local ACE inhibition restores bradykinin-induced relaxation in smokers to values found in nonsmokers. This observation suggests that increased vascular metabolism of bradykinin exists in veins of smokers and that the vascular renin-angiotensin system may play a key role in smoking-induced endothelial dysfunction. PMID- 10096263 TI - Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers. AB - OBJECTIVE: The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers. METHODS: Single doses of interleukin-10 (8 microg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide stimulated cytokine (tumor necrosis factor-alpha, interleukin-1beta) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone. RESULTS: No pharmacokinetic alterations in interleukin-10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 or SC50 values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC50 or SC50 values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response. CONCLUSION: Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent. PMID- 10096264 TI - Angiotensin-converting enzyme inhibition facilitates alveolar-capillary gas transfer and improves ventilation-perfusion coupling in patients with left ventricular dysfunction. AB - OBJECTIVE: The backward effects of left ventricular dysfunction include alterations in alveolar-capillary gas transfer and ventilation-perfusion coupling. Because the angiotensin-converting enzyme (ACE) is highly concentrated in the vascular endothelium of the lungs, we examined whether ACE inhibitors may influence the pulmonary function in patients with congestive heart failure. METHODS: In 20 patients with idiopathic cardiomyopathy, pulmonary function and exercise capacity were evaluated at baseline and 6 and 12 months after treatment with enalapril (10 mg twice a day) was started. The study also included 19 age- and sex-matched control subjects with mild primary hypertension and normal left ventricular function who were given enalapril as a standard treatment of high blood pressure. RESULTS: In congestive heart failure, forced expiratory volume in 1 second, vital capacity, and total lung capacity did not vary significantly with enalapril; alveolar-capillary diffusion of carbon monoxide (DL(CO)) increased toward normal; exercise tolerance time, peak exercise oxygen uptake (peak VO2), minute ventilation and tidal volume (peak VT) also increased; and the ratio of volume of dead space (VD) to VT (peak VD/VT) at peak exercise reduced. Changes in peak VO2 showed a direct correlation with those in DL(CO) and an inverse correlation with those in peak VD/VT. Results at 6 and 12 months were comparable. Enalapril did not affect these variables in the control population. CONCLUSIONS: In patients with idiopathic cardiomyopathy heart failure, but not in control subjects, gas transfer and ventilation-perfusion improved with ACE inhibition. These pulmonary changes may contribute to the associated increase in exercise tolerance. PMID- 10096265 TI - Does short-term treatment with modafinil affect blood pressure in patients with obstructive sleep apnea? AB - OBJECTIVE: To investigate the effects of modafinil, a central nonamphetamine awakening substance, on blood pressure and heart rate in hypersomnolent patients with obstructive sleep apnea. DESIGN: This double-blind, randomized, placebo controlled crossover trial was performed over 2 days and 3 nights in a single center study of hospitalized patients from a referred care center. Twenty-six otherwise healthy men (age range, 30 to 60 years) with mild to moderate obstructive sleep apnea were recruited by the outpatient department of the Marburg University Sleep Laboratory. Patients were given 200 mg oral modafinil in the morning and 100 mg at midday. Placebo was given in the same manner in a crossover design. Mean arterial (radial) blood pressure was monitored continuously during nocturnal sleep and during a series of standardized daytime physical and psychologic performance tests. RESULTS: The difference in the main end point between the treatment with modafinil and placebo was 1.17+/-0.83 (mean +/- SE) mm Hg (95% confidence interval: -0.56 to 2.91 mm Hg). The maximal differences in blood pressure values occurred under loaded conditions (systolic blood pressure, ergometry: 5.62+/-1.13 mm Hg; mental stress test: 6.19+/-1.33 mm Hg). CONCLUSION: Short-term administration of modafinil did not elicit a significant response with regard to the main end point. However, cardiovascular effects during mental and physical load were observed. Longterm studies that include subjects with hypertension are necessary to investigate the clinical relevance of the cardiovascular effects of modafinil. PMID- 10096266 TI - Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX 1) and inducible (COX-2) isoforms of cyclooxygenase. The induction of COX-2 after inflammatory stimuli has led to the hypothesis that COX-2 inhibition primarily accounts for the therapeutic properties of NSAIDs. METHODS: Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX-isoform specific assays (serum thromboxane B2 [TXB2] and lipopolysaccharide [LPS]-stimulated whole blood prostaglandin E2 and assays of COX-1 and COX-2 activity, respectively). A double blind, parallel-group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain. RESULTS: Rofecoxib showed a >800-fold COX-2 selectivity with use of CHO cells that express human COX-1 and COX-2. In subjects, dose- and concentration-dependent inhibition of LPS stimulated prostaglandin E2 was observed with both rofecoxib (IC50 [the concentration estimated to produce 50% inhibition], 0.77 micromol/L) and indomethacin (IC50, 0.33 micromol/L). Whereas indomethacin inhibited TXB2, (IC50, 0.14 micromol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen (P > .20). All active treatments showed greater improvement than placebo (P < .001) CONCLUSIONS: Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2. PMID- 10096268 TI - Killer potatoes: where's the data? PMID- 10096267 TI - Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E-3174. PMID- 10096269 TI - More gods and monsters. PMID- 10096270 TI - Feeding the world, harmoniously. PMID- 10096271 TI - Keeping the biotechnology of antisense in context. PMID- 10096272 TI - Spin science. PMID- 10096273 TI - Shorter is better. PMID- 10096274 TI - Stem cell transformations proliferate. PMID- 10096275 TI - UK government supports biotech. PMID- 10096276 TI - USDA appeases organic lobby. PMID- 10096277 TI - Synergen lineage may finally pay off. PMID- 10096278 TI - Overview of FY 2000 US federal budget request. PMID- 10096280 TI - Pharma strategies extend drug lives. PMID- 10096279 TI - Cancer pathways' target not validated by clinical results. PMID- 10096281 TI - Return of the Neuer Markt. PMID- 10096282 TI - A new routine in molecular gymnastics. PMID- 10096283 TI - Piecing together more efficient gene expression. PMID- 10096284 TI - Extending genetic vaccines with chemokines. PMID- 10096285 TI - Smartbombs and cloaking devices. PMID- 10096286 TI - DREB takes the stress out of growing up. PMID- 10096287 TI - Pumping iron. PMID- 10096288 TI - Proteomics: translating genomics into products? PMID- 10096289 TI - Drug approval in Europe. The EMEA gets good grades, but has room for improvement. PMID- 10096290 TI - Synthetic muscle promoters: activities exceeding naturally occurring regulatory sequences. AB - Relatively low levels of expression from naturally occurring promoters have limited the use of muscle as a gene therapy target. Myogenic restricted gene promoters display complex organization usually involving combinations of several myogenic regulatory elements. By random assembly of E-box, MEF-2, TEF-1, and SRE sites into synthetic promoter recombinant libraries, and screening of hundreds of individual clones for transcriptional activity in vitro and in vivo, several artificial promoters were isolated whose transcriptional potencies greatly exceed those of natural myogenic and viral gene promoters. PMID- 10096291 TI - Spliceosome-mediated RNA trans-splicing as a tool for gene therapy. AB - We have developed RNA molecules capable of effecting spliceosome-mediated RNA trans-splicing reactions with a target messenger RNA precursor (pre-mRNA). Targeted trans-splicing was demonstrated in a HeLa nuclear extract, cultured human cells, and H1299 human lung cancer tumors in athymic mice. Trans-splicing between a cancer-associated pre-mRNA encoding the beta-subunit of human chorionic gonadotropin gene 6 and pre-trans-splicing molecule (PTM) RNA was accurate both in vitro and in vivo. Comparison of targeted versus nontargeted trans-splicing revealed a moderate level of specificity, which was improved by the addition of an internal inverted repeat encompassing the PTM splice site. Competition between cis- and trans-splicing demonstrated that cis-splicing can be inhibited by trans splicing. RNA repair in a splicing model of a nonfunctional lacZ transcript was effected in cells by a PTM, which restored significant beta-galactosidase activity. These observations suggest that spliceosome-mediated RNA trans-splicing may represent a general approach for reprogramming the sequence of targeted transcripts, providing a novel approach to gene therapy. PMID- 10096292 TI - Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. AB - We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv-chemokine fusion proteins elicited chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two independent models, vaccination with DNA constructs encoding the corresponding fusions generated superior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen presenting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruitment of APC to tumor by the chemokine. Finally, in addition to superior potency, these fusions were distinguished from lymphoma Ig fusions with granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells. PMID- 10096293 TI - Directed evolution of thymidine kinase for AZT phosphorylation using DNA family shuffling. AB - The thymidine kinase (TK) genes from herpes simplex virus (HSV) types 1 and 2 were recombined in vitro with a technique called DNA family shuffling. A high throughput robotic screen identified chimeras with an enhanced ability to phosphorylate zidovudine (AZT). Improved clones were combined, reshuffled, and screened on increasingly lower concentrations of AZT. After four rounds of shuffling and screening, two clones were isolated that sensitize Escherichia coli to 32-fold less AZT compared with HSV-1 TK and 16,000-fold less than HSV-2 TK. Both clones are hybrids derived from several crossover events between the two parental genes and carry several additional amino acid substitutions not found in either parent, including active site mutations. Kinetic measurements show that the chimeric enzymes had acquired reduced K(M) for AZT as well as decreased specificity for thymidine. In agreement with the kinetic data, molecular modeling suggests that the active sites of both evolved enzymes better accommodate the azido group of AZT at the expense of thymidine. Despite the overall similarity of the two chimeric enzymes, each contains key contributions from different parents in positions influencing substrate affinity. Such mutants could be useful for anti-HIV gene therapy, and similar directed-evolution approaches could improve other enzyme-prodrug combinations. PMID- 10096294 TI - Engineering receptor-mediated cytotoxicity into human ribonucleases by steric blockade of inhibitor interaction. AB - Several nonmammalian members of the RNase A superfamily exhibit anticancer activity that appears to correlate with resistance to the cytosolic ribonuclease inhibitor (RI). We mutated two human ribonucleases-pancreatic RNase (hRNAse) and eosinophil-derived neurotoxin (EDN)-to incorporate cysteine residues at putative sites of close contact to RI, but distant from the catalytic sites. Coupling of Cys89 of RNase and Cys87 of EDN to proteins at these sites via a thioether bond produced enzymatically active conjugates that were resistant to RI. To elicit cellular targeting as well as to block RI binding, transferrin was conjugated to a mutant human RNase, rhRNase(Gly89)-->Cys) and a mutant EDN (Thr87-->Cys). The transferrin-rhRNase(Gly89-->Cys) thioether conjugate was 5000-fold more toxic to U251 cells than recombinant wild-type hRNase. In addition, transferrin-targeted EDN exhibited tumor cell toxicities similar to those of hRNase. Thus, we endowed two human RI-sensitive RNases with greater cytotoxicity by increasing their resistance to RI. This strategy has the potential to generate a novel set of recombinant human proteins useful for targeted therapy of cancer. PMID- 10096295 TI - A synthetic mimic of a discontinuous binding site on interleukin-10. AB - We synthetically reconstructed a discontinuous binding site on interleukin-10 (IL 10) that recognizes the neutralizing anti-IL-10 antibody CB/RS/1. To design the 32-mer IL-10 mimic, a discontinuous interaction site on IL-10 was mapped, and binding studies with epitope-derived peptides led to specific replacement of several amino acids. Both parts of the interaction site were combined by addition of a linker molecule. Systematic analoging of the combined molecule then led to introduction of several additional substitutions in both regions and the linker. All possible disulfide bridge-containing variants of the 32-mer were tested by binding studies. Parallel syntheses were performed on continuous cellulose membranes by spot synthesis. As a result, a conformationally stabilized IL-10 derived molecule was obtained that both binds to and neutralizes the biological activity of CB/RS/1 in the low nanomolar range. This synthetic approach is a powerful alternative to phage display methods for the design of protein mimics. PMID- 10096296 TI - A recombinant, fully human monoclonal antibody with antitumor activity constructed from phage-displayed antibody fragments. AB - A single-chain Fv antibody fragment specific for the tumor-associated Ep-CAM molecule was isolated from a semisynthetic phage display library and converted into an intact, fully human IgG1 monoclonal antibody (huMab). The purified huMab had an affinity of 5 nM and effectively mediated tumor cell killing in in vitro and in vivo assays. These experiments show that nonimmunized phage antibody display libraries can be used to obtain high-affinity, functional, and clinically applicable huMabs directed against a tumor-associated antigen. PMID- 10096297 TI - Iron fortification of rice seed by the soybean ferritin gene. AB - To improve the iron content of rice, we have transferred the entire coding sequence of the soybean ferritin gene into Oryza sativa (L. cv. Kita-ake) by Agrobacterium-mediated transformation. The rice seed-storage protein glutelin promoter, GluB-1, was used to drive expression of the soybean gene specifically in developing, self-pollinated seeds (T1 seeds) of transgenic plants, as confirmed by reverse transcription PCR analysis. Stable accumulation of the ferritin subunit in the rice seed was demonstrated by western blot analysis, and its specific accumulation in the endosperm by immunologic tissue printing. The iron content of T1 seeds was as much as threefold greater than that of their untransformed counterparts. PMID- 10096298 TI - Improving plant drought, salt, and freezing tolerance by gene transfer of a single stress-inducible transcription factor. AB - Plant productivity is greatly affected by environmental stresses such as drought, salt loading, and freezing. We reported previously that a cis-acting promoter element, the dehydration response element (DRE), plays an important role in regulating gene expression in response to these stresses. The transcription factor DREB1A specifically interacts with the DRE and induces expression of stress tolerance genes. We show here that overexpression of the cDNA encoding DREB1A in transgenic plants activated the expression of many of these stress tolerance genes under normal growing conditions and resulted in improved tolerance to drought, salt loading, and freezing. However, use of the strong constitutive 35S cauliflower mosaic virus (CaMV) promoter to drive expression of DREB1A also resulted in severe growth retardation under normal growing conditions. In contrast, expression of DREB1A from the stress inducible rd29A promoter gave rise to minimal effects on plant growth while providing an even greater tolerance to stress conditions than did expression of the gene from the CaMV promoter. PMID- 10096299 TI - Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes. AB - Flap endonucleases (FENs) isolated from archaea are shown to recognize and cleave a structure formed when two overlapping oligonucleotides hybridize to a target DNA strand. The downstream oligonucleotide probe is cleaved, and the precise site of cleavage is dependent on the amount of overlap with the upstream oligonucleotide. We have demonstrated that use of thermostable archaeal FENs allows the reaction to be performed at temperatures that promote probe turnover without the need for temperature cycling. The resulting amplification of the cleavage signal enables the detection of specific DNA targets at sub-attomole levels within complex mixtures. Moreover, we provide evidence that this cleavage is sufficiently specific to enable discrimination of single-base differences and can differentiate homozygotes from heterozygotes in single-copy genes in genomic DNA. PMID- 10096300 TI - Have you bargained away patent rights? Inventors and entrepreneurs need to consider a recent Supreme Court ruling in their patent strategies. PMID- 10096301 TI - Displacement chromatography for biopolymer separation. PMID- 10096302 TI - Web PCR. PMID- 10096303 TI - Mental disorder drug discovery. PMID- 10096304 TI - Familial density of alcoholism and onset of adolescent drinking. AB - OBJECTIVE: Utilizing a longitudinal prospective design, the purpose of this study was to: (1) assess the age of onset to begin drinking in relation to family history of alcoholism using survival analysis, and (2) examine the importance of selected risk factors in predicting outcome, using a Cox proportional hazards model analysis. METHOD: Fifty-two children and adolescents at low risk for developing alcoholism and 73 children and adolescents from high-risk families were studied. Subjects, spanning the ages of 7 to 18, were evaluated annually (268 total evaluations), providing 2.1 waves of longitudinal data concerning age of onset along with a number of predictors (positive familial loading of alcoholism, extraversion, and manifest anxiety scores). RESULTS: High-risk children showed a significantly earlier age of onset to begin drinking. The Cox proportional hazards analysis revealed that the onset could be predicted by a positive familial loading of alcoholism and extraversion. Further analyses revealed that extraversion was a mediator of the familial density effect. CONCLUSIONS: Age of onset to begin drinking has been shown in general population studies to predict the likelihood of developing alcohol/abuse/dependence problems. Further follow-up will determine if these high-risk children develop alcohol abuse/dependence at higher rates than control children. Further follow-up would also establish links between early childhood predictors, such as having an extraverted temperament and development of alcohol problems. PMID- 10096305 TI - Academic achievement in adolescent children of alcoholics. AB - OBJECTIVE: The current study tested whether adolescent children of alcoholics (COAs) showed poorer academic performance than did demographically matched controls, and whether such parent alcoholism effects varied as a function of heterogeneity within the COA sample. In addition, controlling for parent educational attainment, we examined whether relations between parental alcohol dependence and academic performance could be accounted for by COAs' lower levels of task orientation, heightened levels of environmental stress, lowered levels of family organization and less parental involvement in their school activities. METHOD: A sample of 221 adolescent COAs and 196 demographically matched controls (53% boys, mean [+/-SD] age = 12.7+/-1.46 years), and their parents, were included in the current study. Adolescents were selected from a larger 3-year longitudinal study in which participants were interviewed three times at annual intervals. Those who were interviewed at Time 3 and who had academic achievement data were included in the current analyses. Demographic information and diagnoses of parental alcoholism were collected at Time 1, and data on potential mediators were collected at Time 3. Academic achievement data were collected at Time 3 from school records. RESULTS: Multiple regression analyses indicated that COAs received lower school grades than did their non-COA peers (mean = 2.19+/-1.08 vs 2.54+/-1.01, respectively). COAs with two alcoholic parents (mean = 1.80+/-1.17) and COAs with at least one parent diagnosed alcohol dependent (mean = 2.01+/ 1.01) showed particularly low grades. Parental alcohol dependence was also associated with lower math achievement scores (mean = 48.52+/-24.68 vs 62.47+/ 26.71). Evidence indicated that adolescents' task orientation mediated the relation between parental alcohol dependence and adolescent grades (indirect effect, t = -2.93, 289 df, p < .01), and between parental alcohol dependence and adolescent math achievement (indirect effect, t = -1.99, 194 df, p < .01). Adolescents' life stress did not mediate the relations of interest after controlling for task orientation. CONCLUSIONS: The current study confirmed that COAs, particularly those whose parents are alcohol dependent as opposed to having a diagnosis of alcohol abuse, achieve relatively lower academic outcomes in comparison to non-COA peers. Adolescent task orientation partially mediated the relations between parent alcohol dependence and academic achievement, indicating that academic difficulties in COAs may be partly due to impaired motivation and organization. PMID- 10096306 TI - Long-term effects of a community-wide alcohol server training intervention. AB - OBJECTIVE: The Rhode Island Community Alcohol Abuse and Injury Prevention Project (CAAIPP), implemented from 1984 through 1989, employed the "community gatekeeper" approach to reduce alcohol-related injuries and deaths. Targeting alcohol servers rather than drinkers, community-wide interventions were designed and implemented to encourage responsible serving behaviors through the adoption of techniques of responsible service. The primary goal of the CAAIPP server intervention evaluation was to assess both short-term and long-term changes in behavior of alcohol beverage servers who were recipients of CAAIPP training. METHOD: A 5-hour training curriculum on "Responsible Alcohol Service" was offered to all alcohol servers in a randomly selected study community. A prospective study design was used to evaluate long-term changes in the self-reported behavior of 321 trainees using three time-points over 5 years. A cross-sectional survey was conducted 4 years posttraining to compare rates of self-reported server behaviors in the intervention community (n = 106) with two comparison communities (nA = 56, nB = 49). RESULTS: Fifteen months after training, trainees reported significantly higher levels of desired serving behavior than nontrained servers. Though positive effects of server training diminished with time, responsible serving behavior 4 years posttraining remained higher than pretraining levels. The impact appeared greatest for servers with fewer years serving experience, wait-persons, younger servers and servers who worked in establishments without written policies regarding serving practices. CONCLUSIONS: The results with regard to modifying server behavior are positive and indicate that server interventions shown to be efficacious should be implemented. Training programs that target specific serving skills in repeat sessions may be most promising for improving server behavior, particularly among both young and new servers working in establishments without written policies regarding serving practices. PMID- 10096307 TI - A cognitive analysis of server intervention policies: perceptions of bar owners and servers. AB - OBJECTIVE: The present study examined the underlying psychological variables relevant to alcohol server intervention policies. The focus of the research was the theoretical examination of college bar owners' and servers' attitudes and beliefs about server intervention policies. METHOD: Owners (n = 185) and servers (n = 185) of college bars were asked about their attitudes and perceived cognitive outcomes regarding server intervention policies. RESULTS: Although the findings revealed no statistical differences between owners and servers on their attitudes toward the different server intervention policies, statistical differences were found between the different policies (p < .05). Favorable policies focused on providing services to customers, whereas unfavorable policies focused on limiting the sales of alcohol. Finally, structural equation modeling revealed perceived cognitive outcomes related to the attitudes toward different server intervention policies. CONCLUSIONS: According to the present study's theoretical orientation, the attitudes are likely to have a direct influence on the adoption of policies or, on the part of the server, compliance with the policies. These attitudes toward the policies were found to be a function of the perceived hassle of implementing the policies and how effective the policy was in preventing driving under the influence. PMID- 10096308 TI - Beverage sales and drinking and driving: the role of on-premise drinking places. AB - OBJECTIVE: The relationships between on-premise drinking places, beverage specific alcohol sales and drinking and driving were examined in a time series cross-sectional study of place-of-last-drink data from Perth, Western Australia. METHOD: At arrest, 2,411 drinking drivers reported their last location of consumption. Tabulated by 57 premises over 4 years, the rates at which individual premises were referenced as the place-of-last-drink were taken to reflect the relative distributions of numbers of drinking drivers coming from different premise types (hotels, taverns and nightclubs). The data were then statistically related to measures of premise types and characteristics and beverage specific alcohol sales. RESULTS: Significant cross-sectional relationships were obtained between measures of premise types, alcohol sales and drinking and driving. Greatest numbers of drinking drivers came from taverns and from places selling greater amounts of beer and spirits. Significant longitudinal effects were obtained for sales of beer, proportions of high alcohol beer sold and sales of spirits. CONCLUSIONS: As a whole, the results suggest that, at least for Western Australia, outlets selling greater amounts of beer and spirits, and greater amounts of high alcohol beer, will produce larger numbers of drinking drivers. PMID- 10096309 TI - Intoxicated sexual risk taking: an expectancy or cognitive impairment explanation? AB - OBJECTIVE: Two experimental studies tested expectancy and impairment explanations for the association between alcohol consumption and unsafe sexual behaviors. METHOD: Young adults, who were administered alcohol (blood alcohol concentration mean = .08 mg%), placebo or water, rated the likelihood that potential consequences would result from risky sexual practices (Study 1, N = 161) and listed potential consequences that could result from having sex without a condom (Study 2, N = 135). RESULTS: Intoxicated participants reported lower perceptions of risk (mean [+/-SD] = 4.5+/-2.1) than those who received placebo (mean = 5.8+/ 1.3) or water (mean = 5.5+/-1.7). Intoxicated participants also listed fewer negative consequences (mean = 1.3+/-1.2) than those who received placebo (mean = 1.5+/-1.2) or water (mean = 2.1+/-1.5). In addition, participants who expected alcohol to disinhibit their sexual behavior reported stronger postdrinking perceptions of benefit (mean = 2.6+/-1.8) and indicated that they were more likely to engage in risky sexual practices (mean = 2.4+/-1.7) than those who did not expect sexual disinhibition (mean = 2.0+/-1.7, benefit; mean = 1.8+/-1.1, involvement). CONCLUSIONS: Results support the hypotheses that (1) alcohol related impairment reduces the drinker's perception of personal risk, and (2) positive outcome expectancies motivate drinkers to engage in risky sexual practices. PMID- 10096310 TI - The moderating effects of gender and ethnicity on the relationship between effect expectancies and alcohol problems. AB - OBJECTIVE: Research has demonstrated that alcohol outcome expectancies moderate the relationship between psychological states such as stress and negative affect and alcohol use. This study examined whether the relationship between expectancies and alcohol problems would be moderated by gender and ethnicity. METHOD: Using a household survey format, personal interviews were conducted with Puerto Rican and Irish American men and women. The final sample consisted of 412 (231 male) Puerto Ricans and 476 (252 male) Irish Americans. Alcohol expectancies were measured with the Effects of Drinking Alcohol Scale. All subjects resided in the New York metropolitan area. The original study was designed to compare the drinking behaviors and alcohol-related beliefs of groups with varied drinking practices and distinct drinking beliefs. RESULTS: Both gender and ethnicity moderated the links between aggressive and self-control expectancies and drinking problems. For example, anticipated loss of control from drinking was more negatively related to Puerto Rican and female alcohol problems than it was to Irish and male problems. CONCLUSIONS: The present findings suggest that whether an outcome expectancy is associated with more alcohol problems depends upon the particular meaning of the outcome. This meaning, in turn, depends upon an individual's particular sociocultural perspective which is associated with such personal characteristics as gender and ethnicity. PMID- 10096311 TI - Substance use disorders and the risk of HIV infection in gay men. AB - OBJECTIVE: Previous studies have suggested that high rates of recent alcohol or drug use are associated with increased risk for HIV infection in gay men. To examine whether this relationship is mediated by substance use per se or by more enduring patterns of problematic substance use, lifetime DSM-III-R alcohol and other drug dependence disorders were ascertained and used to predict self reported serostatus. METHOD: Gay men (N = 187) who had been tested for HIV and knew their serostatus (31 are HIV+) completed demographic, drug use and sexual practices questionnaires. Formal DSM-III-R psychiatric diagnoses were made on the basis of an individual interview, using the Structured Clinical Interview for DSM III-R. RESULTS: Subjects had lifetime rates of alcohol dependence and drug dependence disorders that were two to three times higher than the general population, and 58% of the subjects who met criteria for alcohol dependence also met criteria for other substance dependence. Logistic regression analysis indicated that serostatus was best predicted by presence of both alcohol and drug dependence, and by race. When analyses were repeated in seronegative men, using unprotected anal sex as the outcome and recent substance use as predictors, no relationship between alcohol and behavior was found. CONCLUSIONS: Data do not support the view that alcohol use alone increases the risk of HIV infection in gay men. Finding that risk for HIV is highest in men with histories of both alcohol and drug problems suggests that the link between HIV infection and substance use may be mediated by "third variables" that may include personality characteristics and situational factors. PMID- 10096312 TI - Who drinks most of the alcohol in the US? The policy implications. AB - OBJECTIVE: The concentration of alcohol consumption in the U.S. among the heaviest drinkers is analyzed with data from two recent probability samples of the adult population. METHOD: Pooled data from four national telephone surveys (N = 7,049; 4,784 drinkers) with uniform methodology are used for the primary analysis, and data from an in-person national household survey (N = 2,058; 1,308 drinkers) are used for confirmatory analysis. Each survey systematically measured self-reported alcohol consumption during the prior year using a "graduated frequencies" approach designed to capture drinking at a series of amount-per-day levels. RESULTS: The two studies produced very similar estimates: the top 2.5% of drinkers by volume account for 27% and 25% of the nation's total self-reported alcohol consumption in the telephone and in-person surveys, respectively; the top 5% account for 42% and 39%; and the top 20% of drinkers account for 89% and 87% in each survey, respectively. Men were overrepresented at the highest volumes, contributing about 76% of the country's total reported consumption. Similarly, young adults aged 18 to 29 are disproportionately represented in the heaviest drinking levels; constituting 27% of the population, they account for about 45% of overall adult drinking. CONCLUSIONS: The bulk of the alcohol reported drunk in the U.S. is consumed by a relatively small population of very heavy drinkers. Prevention policies implied by this concentration include strengthening of social norms discouraging heavy consumption, restricting marketing practices that target heavy drinkers, and implementing measures to reduce consumption by the heaviest drinkers. PMID- 10096313 TI - The modeling of alcohol consumption: a meta-analytic review. AB - OBJECTIVE: Modeling, or the imitation of another's behavior, has been proposed to influence alcohol consumption. The literature dealing with effects of modeling on alcohol consumption was reviewed using meta-analytic procedures in order to determine the strength of the modeling effect and the variables that moderate the effect. METHOD: Thirteen studies were examined in which participant's alcohol consumption in the presence of a high consumption model was compared to a low consumption model condition or a no-model condition. Analyses were conducted for the four dependent measures utilized in the literature: amount consumed, blood alcohol concentration, number of sips taken and volume per sip. Mean effect sizes (d) were calculated for each dependent measure and moderator variables were examined. RESULTS: Modeling had a significant effect on all four dependent measures, with the strongest effects being on amount consumed and blood alcohol concentration. In addition, analyses identified numerous variables that moderate the effect of modeling on alcohol consumption, including the drinking history of the participant, the drinking task used and the nature of the interaction between model and participant. CONCLUSIONS: Results indicated that modeling has a strong effect on alcohol consumption; however, several variables do mediate this effect. PMID- 10096314 TI - Assessing alcohol consumption: beverage-specific versus grouped-beverage questions. AB - OBJECTIVE: The quantity-frequency method is commonly used to measure alcohol intake in large surveys. Because of time and space constraints, questionnaires are often shortened by combining questions on all types of alcohol into a single question. We investigated the effect of this practice using data from the Behavioral Risk Factor Surveillance System. METHOD: We examined data collected from 213,842 respondents to surveys conducted by 32 states and the District of Columbia participating in the years 1987, 1988, 1989 and 1990. The 1987 and 1988 surveys asked questions about respondents' frequency and level of intake of specific alcohol-containing beverages. The 1989 and 1990 surveys asked about the frequency and quantity of intake of alcohol-containing beverages by combining all beverages into a single group. RESULTS: Among drinkers, the mean number of drinks per month was higher for those who were asked beverage-specific questions than for those who were asked grouped-beverage questions (men: 37.0 vs 29.6; women: 17.0 vs 13.9). CONCLUSION: Caution must be used in comparing level of alcohol intake from surveys in which beverages are not grouped identically. PMID- 10096315 TI - The influences of age and gender on blood ethanol concentrations in healthy humans. AB - OBJECTIVE: Previous cross-section studies suggested that blood ethanol concentrations (BAC) increase with age. To establish this, and to account for putative gender differences, we studied four cohorts of nonalcoholic subjects. METHOD: Fifty-seven subjects were studied: 14 men and 14 women in the young (21 40 years) and 14 men and 15 women in the old (> or = 60 years) groups. All subjects received ethanol (0.3 g/kg) on three occasions: orally (PO) after an overnight fast; PO after a standard meal; and by intravenous (IV) infusion after a standard meal. RESULTS: In all four cohorts, PO ethanol in the fasted state produced the greatest average areas under the curve (AUC) for ethanol, followed by IV ethanol and PO ethanol, both in the fed state. Pooled by age, blood ethanol AUCs were significantly greater in old subjects given PO ethanol when fasted (p = .001) and IV ethanol when fed (p < .004) but not after PO ethanol in the fed state. Pooled by gender, blood ethanol AUCs did not separate men and women in any of the experiments. Corrected for relative volumes of distribution (Vdist) among the four cohorts, only elderly women evidenced AUC values that could not be explained by Vdist alone and only in the fasted state. Both elderly men and women in the fasted state showed higher average peak ethanol levels than gender-matched younger cohorts; this effect was most pronounced in elderly women (47% vs 12%). CONCLUSIONS: The data confirm the influence of age, but fail to confirm that of gender, on blood ethanol response after a moderate dose of ethanol. They also show that feeding state can negate differences due to Vdist alone. In the fasted state, Vdist alone explains AUC and peak increases in elderly men but not in elderly women. Neither gastric metabolism nor motility account for age/BAC differences since these were independent of route. These data suggest caution for elderly drinkers or for those prescribing alcoholic beverages to elderly persons as well as for studies of ethanol ingestion that do not account for age and for feeding state. PMID- 10096316 TI - Relating alcohol use and mood: results from the Tromso study. AB - OBJECTIVE: The interrelationships between alcohol consumption and depressed mood were studied in a population to determine if the relationships differed by sex and consumption. METHOD: Alcohol consumption and mood were surveyed at a 7-year interval by self-report (N = 8,260; 4,407 women). Frequency of intoxication was used to divide the sample into moderate and immoderate drinkers. Structural equations modeling was then applied to describe the interrelationships of drinking and mood both cross-sectionally and over time. RESULTS: Overall, self reported drinking was stable over a 7-year period, although drinking patterns were less stable for immoderate drinkers. Drinking predicted higher levels of depressed mood among the immoderate drinkers of both sexes at follow-up. Drinking also weakly predicted depressed mood among moderately consuming men. However, among moderately consuming women dysphoric mood predicted less drinking. Depressed mood was related to higher levels of concurrent drinking among the immoderately drinking men. Among immoderately drinking women, however, concurrent depressed mood predicted more drinking. CONCLUSIONS: Generally, drinking predicted subsequent depressed mood although this pattern was reversed among moderately drinking women. Furthermore, a synchronous effects model indicated that some immoderately drinking women used alcohol as a response to emotional distress. It appears that gender and the level of consumption need to be taken into account in studies relating mood and drinking. PMID- 10096317 TI - Social resources and alcohol-related losses as predictors of help seeking among male problem drinkers. AB - OBJECTIVE: This study examined whether factors other than severity of alcohol related problems add to the explanation of seeking help for drinking problems. METHOD: Help seeking was investigated by comparing male problem drinkers who applied for treatment with male chronic problem drinkers in the general population. Subjects were selected from an outpatient treatment center (n = 129) and from a panel of the general population (n = 86) in the Netherlands. A shortened version of Cahalan's problem-drinking index, including symptoms, social consequences, health problems and frequency of intoxication, was used to indicate the severity of problem drinking. It was hypothesized that in particular drinking problems that indicate losses (social consequences and health problems) were associated with help seeking. Furthermore, resources such as paid work, a spouse, high socioeconomic status, younger age and a "wet" social network were expected to facilitate the continuation of drinking behavior and drinking problems and the avoidance of help seeking. RESULTS: Social and health consequences were associated more strongly with seeking help than were symptoms of problem drinking and intoxication. The effects of type of alcohol-related problem, employment and age were as hypothesized. However, the hypotheses about marital status, socioeconomic status and social network characteristics could not be confirmed. CONCLUSIONS: The results suggest that in particular employed men and men of a younger age deserve attention with regards to detecting problem drinking and targeting prevention. PMID- 10096318 TI - Alcohol and retrograde memory effects: role of individual differences. AB - OBJECTIVE: When alcohol is consumed following learning, the effect on delayed, sober memory can vary from person to person. We examined a range of individual differences to look for predictors of this variability. METHOD: Male social drinkers (N = 65; average age 23.3 years) were exposed to emotionally charged verbal stimulus materials while sober. Participants consumed 1.0 ml/kg alcohol immediately afterward and remained in an environment designed to minimize retrograde interference. Stimulus recall and recognition were tested 24 hours later, when participants had breath-alcohol concentrations of zero. Relationship between memory scores and individual differences (in age, education, alcohol consumption, vocabulary, verbal learning, emotionality, mood state 24 hours after learning, response to alcohol, personality and alcohol expectancies) were determined. RESULTS: Only age and vocabulary were significantly associated with memory score following drinking, probably because they constrained initial understanding of the statements and mediated the effects of alcohol on memory consolidation. CONCLUSIONS: The effects of a given dose of alcohol on emotionally charged verbal memory are similar for men of equal age and verbal skill, but independent of other individual differences. It is most likely that alcohol affects incidental memory by nonspecific enhancement or interference processes. PMID- 10096319 TI - Alcohol consumption and Iowa's control policy shift. PMID- 10096320 TI - Routine screening for acetaminophen (APAP) toxicity of patients requesting alcohol detoxification. PMID- 10096321 TI - Air trapping in primary Sjogren syndrome: correlation of expiratory CT with pulmonary function tests. AB - PURPOSE: The purpose of our study was to correlate the extent of air trapping on expiratory CT scans with results of pulmonary function tests (PFTs) in a large group of patients with primary Sjogren syndrome and to determine whether these techniques may be complementary in assessing small airways obstruction. METHOD: Thirty-four nonsmoking patients with proven primary Sjogren syndrome and 10 healthy nonsmokers underwent paired inspiratory-expiratory thin section CT and PFTs. Expiratory scans were scored for the presence and extent of areas of air trapping. Extent of air trapping was assessed visually and given a score. The functional significance of the extent of air trapping was evaluated in both groups and then correlated with the results of PFTs. RESULTS: Bronchiolar abnormalities were seen in 11 (32%) of 34 patients with primary Sjogren syndrome. On the expiratory CT scans, a mosaic pattern of lung attenuation was identified in 17 patients. Air trapping was found in 44 of 204 lobar observations on the expiratory scans. The median point scale score at end-expiration was 3.6 (20%, Grade 1), ranging from 1 (5.5%, Grade 1) to 9 (50%, Grade 2). The mean total score of air trapping was more prevalent in lower (46/68) lobes (22.4%) than in upper (22/136) lobes (5.3%) (p < 0.001). PFTs were normal in the primary Sjogren syndrome patients as well as the healthy subjects. Air trapping was found more frequently in patients with primary Sjogren syndrome than in the healthy group. Only during exhalation was there evidence of minimal lobular-sized areas or air trapping (Grade 1) in three of the healthy subjects. We did not find any correlation between air trapping and PFTs including the forced expiratory flow rate between 25 and 75% of the forced vital capacity (FEF25-75). CONCLUSION: Expiratory high resolution CT revealed the extent of bronchiolar disease in patients with primary Sjogren syndrome. We also found that the extent of air trapping did not correlate with PFTs, which suggests the existence of a subclinical bronchiolar inflammatory process that may precede detectable abnormalities in lung function tests. PMID- 10096322 TI - Respiratory change in size of honeycombing: inspiratory and expiratory spiral volumetric CT analysis of 97 cases. AB - PURPOSE: The purpose of this study was twofold: to evaluate the change in size of honeycomb cysts with respiration using inspiratory-expiratory spiral volumetric CT (I-E SVCT) and to establish the pathologic basis of this change. METHOD: Ninety-seven patients, who had honeycombing associated with end-stage pulmonary fibrosis on end-inspiratory 1 to 2 mm collimation high-resolution CT (HRCT), underwent I-E SVCT (3 mm collimation, pitch 1, breath-hold time 20 s, reconstruction interval 1 mm, FOV 16-20 cm, high frequency algorithm). I-E SVCT scans were assessed on images obtained in the transverse plane and volumetric sagittal, coronal, and oblique reformations. The histologic findings were assessed in four inflated and fixed lungs that showed honeycombing at postmortem HRCT. RESULTS: In 63 patients (65%), a small percentage of the cysts did not change in size at end-expiration, while in the remaining patients, all the cysts decreased in size. Assessment of volumetric multiplanar reformations showed that cysts that decreased in size during exhalation communicated with airways and represented bronchiolectasis rather than true cysts, while the other cysts did not communicate with the airways. Similar findings were found in pathologic specimens. CONCLUSION: The majority of, but not all, honeycomb cysts seen on HRCT represent dilated bronchioles that communicate with the proximal airways and change in size with respiration. PMID- 10096323 TI - Thoracopancreatic fistula: clinical and imaging findings. AB - PURPOSE: The goal of this work was to describe the clinical and imaging features of thoracopancreatic fistula, a rare complication of pancreatitis. METHOD: Nine cases of thoracopancreatic fistula proved by thoracentesis, endoscopic retrograde cholangiopancreatography (ERCP), or surgery were retrospectively and independently reviewed by two abdominal radiologists. All available imaging examinations [chest radiographs = 9, CT = 9, MR and MR cholangiopancreatography (MRCP) = 2, and ERCP = 6] were analyzed, and findings were recorded on a standardized datasheet. Available medical records (n = 7) were reviewed to determine the clinical presentation of the patients and thoracentesis results. RESULTS: Seven of the nine patients presented with pulmonary symptoms such as dyspnea or cough. Of the seven patients with pleural fluid analysis, all demonstrated elevated amylase levels (mean 13,007 U/L). Imaging examinations revealed pancreaticopleural fistulas in six patients, a mediastinal pseudocyst in one patient, and both a pancreaticopleural fistula and a mediastinal pseudocyst in two patients. Chest radiography showed pleural fluid collections in eight patients. CT demonstrated a fluid-containing fistula in all nine patients. MR and MRCP depicted a fistula extending from the abdomen to the pleural space in the two patients with MR correlation. ERCP showed pancreatic ductal changes characteristic of chronic pancreatitis in the six patients with ERCP correlation but failed to demonstrate the fistula in two of the six patients. CONCLUSION: The CT, MR, MRCP, or ERCP finding of a fluid-filled tract extending from the pancreas to the thorax is characteristic of a thoracopancreatic fistula, particularly when identified in a patient who presents with pulmonary symptoms and a history of chronic pancreatitis. PMID- 10096324 TI - Diagnostic performance of helical CT angiography in trauma to large arteries of the extremities. AB - PURPOSE: The purpose of this work was to assess the performance of helical CT angiography (CTA) in the diagnosis of injuries to large arteries of the extremities. METHOD: We performed helical CTA on 45 consecutive patients referred for conventional angiography for evaluation of suspected arterial injuries after sustaining trauma to the extremities (13 upper, 32 lower). Two radiologists interpreted the helical CTA studies independently. Diagnostic performance parameters evaluated included sensitivity, specificity, receiver operating characteristic (ROC) curves, and interobserver agreement (kappa statistics). Conventional angiography was used as the standard of reference for determination of final diagnoses. RESULTS: Forty-three of 45 patients (96%) had diagnostic helical CTA examinations. Final diagnoses in these 43 patients were arterial occlusion (n = 7), partial obstruction (n = 3), pseudoaneurysm (n = 5), arteriovenous fistula (n = 1), pseudoaneurysm and arteriovenous fistula (n = 3), and normal findings (n = 24). Sensitivity and specificity were 90% [95% confidence interval (CI), 80-99] and 100% (95% CI, 99-100), respectively, for Reader 1 and 100% (95% CI, 99-100) and 100% (95% CI, 99-100), respectively, for Reader 2. ROC curve analysis revealed high diagnostic performance, with areas under the curve of >0.9 for both readers. Interobserver agreement was 0.9. CONCLUSION: The diagnostic performance of helical CTA for detection of major injuries of large arteries of the extremities is high. PMID- 10096325 TI - Interrupted aortic arch: diagnosis with gadolinium-enhanced 3D MRA. AB - PURPOSE: Our goal was to describe the use of gadolinium-enhanced 3D MR angiography (MRA) in the diagnosis of interrupted aortic arch (IAA). METHOD: A review of our MR data base from a 1 year period yielded three patients (1 day, 8 days, and 16 years old) with IAA. All were referred for evaluation of aortic arch abnormalities, only one of whom had suspected IAA. Patients were imaged at 1.5 T with a 3D spoiled gradient echo pulse sequence (TR/TE 3.8-8/1.3-2.7 ms) following the administration of intravenous gadolinium chelates. Surgical correlation was available in all cases. RESULTS: In the patient with clinically suspected IAA, a previously unsuspected aberrant right subclavian artery was identified that was not seen on preoperative echocardiography. In another patient with a history of previous mediastinal surgery, IAA was diagnosed without concomitant cardiac anomalies, suggesting surgical ligation. In the remaining patient, IAA was detected as well as a patent truncus arteriosus. CONCLUSION: Gadolinium-enhanced 3D MRA may provide for a rapid diagnosis of IAA that may not be possible with other noninvasive modalities. The rapid acquisition time enables unstable pediatric patients to spend minimal time in the MR suite. PMID- 10096326 TI - Coronary MRA: use in assessing anomalies of coronary artery origin. AB - PURPOSE: The purpose of this work was to describe the use of coronary MR angiography (MRA) in the clinical evaluation of a series of patients with anomalous origin of the coronary arteries suspected on coronary angiography. METHOD: Eight patients underwent coronary MRA to further define variant coronary anatomy that was found on coronary angiography. A 2D segmented k-space gradient echo sequence was used with breath-holding. MRA images were assessed for traversal of an anomalous artery between the aorta and pulmonary artery trunks, which carries the greatest clinical significance. RESULTS: Of six patients with anomalous origin of the right coronary artery on angiography, two were shown by MRA to have an interarterial course of the anomalous vessel. Neither of two left coronary arteries with ectopic origin coursed between the great arteries, although one passed through the septum. CONCLUSION: Coronary MRA is a useful adjunctive technique to angiography in the evaluation of the relationship of anomalous coronary arteries to the great arteries. PMID- 10096327 TI - MR angiography of internal carotid arteries: breath-hold Gd-enhanced 3D fast imaging with steady-state precession versus unenhanced 2D and 3D time-of-flight techniques. AB - PURPOSE: The purpose of this work was to compare Gd-enhanced breath-hold fast imaging with steady-state precession (Gd-FISP) with unenhanced time-of-flight (TOF) sequences in evaluating internal carotid arteries (ICAs). METHOD: Thirty patients underwent three unenhanced TOF sequences [2D traveling saturation (Travelsat); 3D tilted optimized nonsaturated excitation (TONE); TOF 3D Multislab] and two breath-hold 3D Gd-FISP sequences with automated intravenous contrast agent injection (axial and coronal). ICAs were classified as normal (no stenosis); with mild (<30%), moderate (30-70%), or severe stenosis; or occluded (100%). Digital subtraction angiography (DSA) with aortic arch injection was used as a reference technique. RESULTS: DSA revealed 20 normal ICAs; 11 mild, 9 moderate, and 14 severe stenoses; and 2 occlusions. DSA and all MR angiography (MRA) sequences diagnosed the occlusion of four common carotid arteries. The TOF 2D overestimated 10 stenoses, TOF 3D TONE 9, and TOF 3D Multislab 5; Gd-FISP 3D overestimated only 2 of them, reaching the highest sensitivity and specificity for severe stenoses. Significant differences were found between the overestimation of Gd-FISP and each of the three unenhanced sequences (0.0020 < p < 0.0313, Wilcoxon and McNemar tests). Severe artifacts were observed with TOF techniques only. CONCLUSION: Gd-FISP is an interesting, largely artifact-free improvement for MRA of ICAs. PMID- 10096328 TI - Prospective evaluation of time-of-flight MR angiography in the follow-up of intracranial saccular aneurysms treated with Guglielmi detachable coils. AB - PURPOSE: The purpose of our study was to prospectively evaluate 3D time-of-flight (TOF) MR angiography (MRA) in the follow-up of 27 intracranial aneurysms treated with Guglielmi detachable coils (GDCs). METHOD: From February 1997 to June 1998, 26 patients with 27 aneurysms were included in this prospective study. Aneurysms were located in the anterior circulation in 23 cases and in the posterior circulation in 4 cases. All patients underwent 3D TOF MRA and digital subtraction angiography (DSA) in the same week within 4 months after aneurysmal treatment with GDCs. No clinical events occurred during the follow-up. We analyzed residual flow within the coil mass and within the aneurysmal neck and the patency of the parent and adjacent arteries on MRA and DSA. MRA analysis was based upon MIPPED and source images. DSA was our gold standard. RESULTS: In all cases, the quality of MRA was good enough to be informative. In aneurysmal analysis, the sensitivity, specificity, positive predictive value, and negative predictive value of MRA were, respectively, 80, 100, 100, and 96% to diagnose residual flow within the coil mass (one false-negative case) and 83, 100, 100, and 95.5% to diagnose residual flow within the aneurysmal neck (one false-negative case). In arterial analysis, sensitivity and positive predictive value of MRA were 89 and 100% to diagnose patency of the parent artery (three false-negative cases) and 83 and 100% to diagnose patency of adjacent arteries (seven false-negative cases). CONCLUSION: In the follow-up of intracranial aneurysms treated with GDCs, 3D TOF MRA could be used as a screening test to select patients that should undergo DSA and thus could improve patient follow-up in terms of risk-benefit. PMID- 10096329 TI - Contrast-enhanced CISS MRI of vestibular schwannomas: phantom and clinical studies. AB - PURPOSE: The purpose of this work was to assess the changes of signal intensity on constructive interference in steady state (CISS) 3D Fourier transformation (3DFT) MRI after administration of Gd-DTPA and to evaluate the efficacy of contrast-enhanced CISS-3DFT MRI to depict the seventh and eighth cranial nerves affected by vestibular schwannomas. METHOD: All scans were carried out on a 1.5 T MR unit. First, an experimental study was conducted to evaluate the changes in signal intensity of the CISS-3DFT sequence in relation to the concentration of contrast medium. Second, nine consecutive patients with 11 vestibular schwannomas underwent CISS-3DFT imaging before and after contrast agent administration. Signal intensities of the tumors and nerves were measured and compared between the pre- and postcontrast images. Visualization of the facial and cochlear nerves was rated on pre- and postcontrast CISS imaging independently. RESULTS: On the phantom study, the CISS-3DFT sequence showed a constant increase in signal intensity as the concentration of Gd-DTPA increased. The contrast between the nerves and tumors significantly increased after contrast agent administration (from 0.1 to 9.0 as mean contrast-to-noise ratio). The ability to depict the nerves was also significantly higher for postcontrast CISS-3DFT imaging than for precontrast. CONCLUSION: Although the CISS-3DFT sequence offers similar contrast as other heavily T2-weighted sequences, the signal intensity of contrast-enhanced tumors increased on CISS-3DFT imaging. Contrast-enhanced CISS imaging was valuable for evaluating the seventh and eighth cranial nerves affected by vestibular schwannomas. PMID- 10096331 TI - MRI of acute spinal epidural hematomas. AB - PURPOSE: The purpose of this work was to determine the MR findings that characterize acute spinal epidural hematomas (ASEHs). METHOD: The MR findings of 17 patients with ASEH (9 cervical, 7 thoracic, and 2 lumbar) were reviewed. Fifteen of the hematomas were secondary to trauma and two were spontaneous. Correlation with CT (8 cases) and surgical findings (11 cases) was also performed. RESULTS: Imaging findings in ASEH were the following: (a) a variable signal intensity (on T1-weighted images, 10 showed isointensity to cord and 7 were slightly hyperintense; T2-weighted images showed hyperintensity with areas of hypointensity); (b) capping of epidural fat; (c) direct continuity with the adjacent osseous structures; (d) compression of epidural fat, subarachnoid sac, and spinal cord; (e) usually posterolateral location in the spinal canal. CONCLUSION: Epidural hematomas in the spinal canal are lesions capable of producing sudden spinal cord and/or cauda equina compression. MR provides characteristic findings that allow a prompt diagnosis of acute epidural hematomas. PMID- 10096330 TI - Perfusion-sensitive MRI of cerebral lymphomas: a preliminary report. AB - PURPOSE: To date, there have been no systematic reports examining cerebral lymphomas with perfusion-sensitive MRI. We sought to determine the characteristics of perfusion-sensitive MRI of these tumors. METHOD: Five primary and three secondary cerebral lymphomas were analyzed. None of the patients had a history of AIDS. Various areas of relative cerebral blood volume (rCBV) within tumor were analyzed, and maximum CBV ratios (CBV[tumor/contralateral]) were identified for evaluation. RESULTS: In three primary and three secondary cerebral lymphomas, maximum CBV ratios were <2.5 (mean 1.50). In others, maximum CBV ratios were markedly higher than those of the white matter (5.38 and 5.42). Mean maximum rCBV ratios of primary and secondary cerebral lymphomas were 2.93 and 1.43, respectively. There was no significant difference between the two groups. CONCLUSION: Cerebral lymphomas had a tendency to have low rCBV values. This information may be helpful in diagnosing these tumors. PMID- 10096332 TI - MRI of tuberculous cervical lymphadenopathy. AB - PURPOSE: The purpose of the study was to document the range of appearances of tuberculous cervical lymphadenopathy (TCL) on MRI. METHOD: The MR images of nine patients who were subsequently found to have TCL were retrospectively reviewed. All patients were scanned on a 1.5 T unit using a neck coil (nine patients) and a surface coil (five patients). Each abnormal region was assessed separately for maximum size, pattern of disease, necrosis, calcification, soft tissue edema, muscle involvement, and vascular compression. RESULTS: There were 17 abnormal regions. The posterior triangle was most frequently involved (six patients) followed by the supraclavicular fossa (five patients). There were three patterns of disease, comprising discrete nodes, matted nodes, and confluent masses. Necrosis occurred in 10 of the 17 abnormal regions; necrotic areas were located peripherally in 7 of these 10. The percentage of necrotic to solid areas ranged from <25 to >75% and was not related to the pattern of disease. Edema was present in four patients and was seen with matted nodes and confluent masses. Muscle involvement and vascular compression occurred in three regions. Calcification was not identified. CONCLUSION: MRI revealed three patterns of disease in TCL: discrete nodes, matted nodes, and confluent masses. Necrotic foci, when present, were more frequently peripheral rather than central, and this together with the soft tissue edema may be of value in differentiating TCL from metastatic nodes. PMID- 10096333 TI - Correction for partial volume effects in regional blood flow measurements adjacent to hematomas in humans with intracerebral hemorrhage: implementation and validation. AB - PURPOSE: Reduced blood flow measured with PET and SPECT has been reported in brain surrounding intracerebral hemorrhage (ICH). These studies have not corrected for partial volume effects from adjacent hematomas or ventricles. We have implemented a method to correct for these effects at brain boundaries (but not at internal gray/white matter boundaries), tested it with a brain phantom, and applied it to patients. METHOD: Using PET and X-ray CT images of a Hoffman brain phantom containing artificial hematomas, we segmented CT images to binary images representing brain tissue and convolved these to the 3D resolution of the PET. PET images were then scaled by this net tissue contribution. Corrected images were compared with other images of the same phantom without hematomas. The same correction was then applied to human images. RESULTS: Uncorrected phantom images had artifactual reductions surrounding hematomas that were eliminated by the correction. Corrected images of patients with acute ICH had areas of reduced flow in white and deep gray matter, whereas overlying cortical flow was preserved. CONCLUSION: We have validated a method to correct for artifactual reductions in blood flow measurements at brain boundaries. Using this method, we observe areas with reduced flow near acute hematomas. PMID- 10096334 TI - Correlation of regional cerebral blood flow measured by stable xenon CT and perfusion MRI. AB - PURPOSE: The purpose of this work was to investigate the validity of perfusion MRI in comparison with stable xenon CT for evaluating regional cerebral blood flow (rCBF). METHOD: The rCBF was measured by xenon CT and perfusion MRI within a 24 h interval in 10 patients (mean +/- SD age 63 +/- 10 years). For perfusion MRI, absolute values of rCBF were calculated based on the indicator dilution theory after injection of 0.1 mmol/kg of Gd-DTPA. Eight to 10 regions of interest (37 mm2) were located in the white and gray matter on the rCBF images for each of the 10 patients. RESULTS: The mean +/- SD values of rCBF in gray matter were 48.5 +/- 14.1 ml/100 g/min measured by xenon CT and 52.2 +/- 16.4 ml/100 g/min measured by perfusion MRI. In the white matter, the rCBF was 22.6 +/- 9.1 ml/100 g/min by xenon CT and 27.4 +/- 6.8 ml/100 g/min by perfusion MRI. There was a good correlation of rCBF values between perfusion MRI and xenon CT (Pearson correlation coefficient 0.83; p < 0.0001). CONCLUSION: Comparable to xenon CT, perfusion MRI provides relatively high resolution, quantitative local rCBF information coupled to MR anatomy. PMID- 10096335 TI - Blind source separation of multiple signal sources of fMRI data sets using independent component analysis. AB - PURPOSE: The objective of this study was to separate multiple signal components present in functional MRI (fMRI) data sets. Blind source separation techniques were applied to the analysis of fMRI data to determine multiple physiologically relevant independent signal sources. METHOD: Computer simulations were performed to test the reliability and robustness of the independent component analysis (ICA). Four subjects (3 males and 1 female between 14 and 29 years old) were scanned under various stimulus conditions: (1) rest while breathing room air, (2) bilateral finger tapping while breathing room air, and (3) hypercapnia during bilateral finger tapping. RESULTS: Simulations performed on synthetic data sets demonstrated that not only could the algorithm reliably detect the shapes of each of the source signals, but it also preserved their relative amplitudes. The algorithm also performed robustly in the presence of noise. With use of fMRI time series data sets from bilateral finger tapping during hypercapnia, distinct physiologically relevant independent sources were reliably estimated. One independent component corresponded to the hypercapnic cerebrovascular response, and another independent component corresponded to cortical activation from bilateral finger tapping. In three of the four subjects, the underlying fluctuations in signal related to baseline respiratory rate were identified in the third independent component. Principal component analysis (PCA) could not separate these two independent physiological components. CONCLUSION: With use of ICA, signals originating from independent sources could be separated from a linear mixture of observed data. Limitations of PCA were also demonstrated. PMID- 10096336 TI - Quantitative proton-decoupled 31P MRS of the schizophrenic brain in vivo. AB - Quantitative proton MR spectroscopy (MRS) and proton-decoupled phosphorus MRS were applied in the parietal cortex of 13 schizophrenic subjects (11 drug-treated and 2 neuroleptic-naive) and 15 normal control subjects. Significantly increased concentrations of glycerophosphorylcholine (1.18 +/- 0.16 vs. 0.93 +/- 0.14 mmol/kg brain; p < 0.001), glycerophosphoethanolomine (0.70 +/- 0.19 vs. 0.59 +/- 0.07 mmol/kg; p < 0.04), and phosphocreatine (3.73 +/- 0.39 vs. 3.41 +/- 0.13 mmol/kg; p < 0.007), but no differences in N-acetylaspartate, total creatine, or myo-inositol, were determined in treated schizophrenic subjects. Identical abnormalities were found in two neuroleptic-naive patients. These results provide new evidence of disordered cerebral membrane and high energy phosphate metabolism in schizophrenia. PMID- 10096337 TI - 3D-CT stereoscopic imaging in maxillofacial surgery. AB - We obtained stereoscopic 3D-CT images in maxillofacial bone fracture patients. These images are made at two different angles. One is equivalent to the view obtained by a subciliary incision during surgery. Another is equivalent to the view obtained by oral incision during surgery. A stereoscopic image is created with a pair of images that differ from each other by a 6 degree shift of the z axis. PMID- 10096338 TI - Changes in cerebral blood flow in bulimia nervosa. AB - Bulimia nervosa is an eating disorder of which characterized psychopathological symptoms are a recurrent episode of binge eating. The changes in cerebral blood flow (CBF) in a patient with bulimia nervosa between his or her different eating phases are presented. CBF was measured quantitatively by means of single photon emission computed tomography using I-123 N-isopropyl-p-iodoamphetamine. CBF of the global brain during a binge-eating phase was higher than that during an anorexic state phase. In the anorexic state, the CBF in the temporal, parietal, and occipital lobes on the right side was lower than that on the left side. In the binge-eating state, a lack of laterality between the right and left cerebral hemispheres was found. This finding suggests that cerebral activity differs between the two phases, and that asymmetry is dependent of the eating state. PMID- 10096339 TI - Pancreatic transplantation using portal venous and enteric drainage: the postoperative appearance of a new surgical procedure. AB - PURPOSE: To review the normal radiologic appearance of pancreatic transplants that use portal venous and enteric drainage, and to review the appearance of a variety of postoperative complications. METHOD: We retrospectively reviewed the computed tomographic (CT) scans, magnetic resonance (MR) images, and ultrasounds of patients who had undergone pancreatic transplantation using portal venous and enteric drainage. RESULTS: At CT, the normal pancreatic transplant appears as a heterogeneous mass composed of pancreatic parenchyma, vessels, and omental wrap. On MR imaging, a normal transplant demonstrates intermediate signal intensity on T1- and T2-weighted sequences. Sonographic evaluation of a normal transplant reveals a hypoechoic gland that contains readily detectable low-resistance arterial and venous Doppler waveforms. Acute postoperative complications include acute rejection, which has a nonspecific radiologic appearance, and transplant pancreatitis, which is often manifested on CT by stranding of the peritransplant fat. Chronic postoperative complications include small bowel obstructions, graft pancreatitis secondary to obstruction of the Roux loop, and chronic rejection. CONCLUSION: Knowledge of the radiologic appearance of the normal pancreatic transplant is required before transplant-related complications can be detected. PMID- 10096340 TI - Colorectal mucinous carcinoma: findings on MRI. AB - PURPOSE: The purpose of this work was to define the characteristic MR features of colorectal mucinous carcinomas and to correlate the mucin pool with the signal intensity of this tumor. METHOD: MRI of 12 cases of pathologically proven colorectal carcinoma containing mucin was evaluated. We analyzed the signal intensity of tumor on T1- and T2-weighted MR images and correlated the area of intratumoral high signal intensity on T2-weighted images with the mucinous pool on the pathologic specimens. Two radiologists independently estimated the area of high signal intensity in the tumor on T2-weighted images and one pathologist estimated the amount of mucinous pool in the pathologic specimen. RESULTS: In 9 (75%) of 12 cases, focal or diffuse high signal intensity areas were detected on T2-weighted fast spin echo images. In seven cases in which mucin pools were seen macroscopically, partial (n = 3) or diffuse high signal intensity areas were noted on the T2-weighted images. Among the five cases in which microscopic mucinous pools were detected on the pathologic slides, three cases showed no high signal foci on MR images, and in the remaining two cases, high signal intensity areas were noted as small foci. CONCLUSION: Intratumoral high signal intensity on T2-weighted fast spin echo MR images occurs in mucinous carcinomas and correlates with the mucin pools on pathologic specimens. PMID- 10096341 TI - CT demonstration of fibrous stroma in chronic pancreatitis: pathologic correlation. AB - Fibrous stroma found in two patients with chronic pancreatitis was investigated. The helical CT-pathologic correlation confirmed that fibrous stroma found in the subcapsular zone of the pancreatic parenchyma corresponded to the area that was identified as a hypodense zone in the early phase by spiral CT and became isodense with the internal parenchyma in the delayed phase. These CT findings have an important implication for the diagnosis of chronic pancreatitis. PMID- 10096342 TI - HASTE MR cholangiopancreatography in the evaluation of intraductal papillary mucinous tumors of the pancreas. AB - PURPOSE: The aim of this study was to determine the usefulness of MR cholangiopancreatography (MRCP) of intraductal papillary-mucinous tumors. METHOD: Thirteen patients with intraductal papillary-mucinous tumors were examined by breath-hold MRCP using a half-Fourier acquisition single-shot turbo spin echo (HASTE) sequence with a body phased-array coil. RESULTS: Endoscopic retrograde cholangiopancreatography (ERCP) and MRCP completely imaged the entire main pancreatic duct in 12 and in all 13 patients, respectively. ERCP demonstrated the whole opacification of the cystic lesion in only one patient. MRCP depicted the whole of the cystic lesion in all 11 patients who had cystic lesions. ERCP and MRCP source images depicted a communicating duct between the main pancreatic duct and the cystic lesion in 8 and in all 11 patients, respectively. ERCP depicted papillary projections in the main pancreatic ducts in two patients. MRCP source images depicted papillary projections in the main pancreatic ducts or cystic lesions in five patients. CONCLUSION: MRCP may be more useful to reveal the main pancreatic duct, cystic lesion, communicating duct between the main pancreatic duct and cystic lesion, and papillary projections than ERCP in patients with intraductal papillary-mucinous tumors of the pancreas. PMID- 10096343 TI - Pseudolesion in segments II and III of the liver on CT during arterial portography caused by aberrant right gastric venous drainage. AB - We report three cases of pseudolesions caused by aberrant right gastric venous drainage (AGVD) in segment II/III of the liver as demonstrated on CT during arterial portography (CTAP). On CTAP, the lesions were seen as wedge-shaped perfusion defects, and on hepatic arteriography, AGVD directed to the area with the perfusion defect was visible in all three cases. When a perfusion defect is detected at the edge of segments II/III at CTAP, a pseudolesion caused by AGVD should be suspected. PMID- 10096344 TI - Hepatic angiomyolipoma: report of changing size and internal composition on follow-up examination in two cases. AB - We present two cases of hepatic angiomyolipoma in which the size and internal composition of the tumor changed during the course of follow-up study. The tissue elements composing the tumor are thought to grow or regress independently during the disease's clinical course. Radiologists should be aware that hepatic angiomyolipoma can change in size and internal composition during its natural course. PMID- 10096345 TI - Effects of niacin therapy that simulate neoplasia: hepatic steatosis with concurrent hepatic dysfunction. AB - Niacin, a widely used antihyperlipidemic agent, can produce hepatic steatosis and clinical hepatic abnormalities that together simulate the presentation of hepatobiliary neoplasia. We describe a patient initially suspected of having hepatobiliary neoplasia for whom imaging studies played a pivotal role in reaching the correct diagnosis of niacin-induced hepatotoxicity. Radiologists should become knowledgeable of these niacin-related effects, add niacin effects to the differential diagnosis of hepatic steatosis, and understand the value of correlative imaging in distinguishing these effects from hepatobiliary neoplasia. PMID- 10096346 TI - Ultrafast fetal MR images of intracranial teratoma. PMID- 10096347 TI - Focally spared area of fatty liver that receives blood passing through the sinusoids of a hypervascular hepatocellular carcinoma. PMID- 10096348 TI - Sacroiliac joints: anatomical variants on CT. AB - The purpose of this work was to examine the type and prevalence of anatomical variants of the sacroiliac joints (SJs) in patients without SJ disease on CT examinations. The study comprised 534 consecutive patients undergoing pelvic CT with various indications not related to diseases that could involve the SJ. Images printed on bone window settings were evaluated with reference to any deviation from the usual appearance of the SJ. Physical data and history of low back pain were recorded in each patient. Six types of anatomical variants were observed: accessory joints in 102 patients (19.1%), "iliosacral complex" in 31 (5.8%), bipartite iliac bony plate in 22 (4.1%), crescent-like iliac bony plate in 20 (3.7%), semicircular defects at the sacral or iliac side in 16 (3%), and ossification centers in 3 patients (0.6%). Accessory joints were more common in obese than in normal-weight individuals (p < 0.05) and in older than younger (<60 years) patients (p < 0.001) and presented degenerative alterations especially in patients with episodes of low back pain. Three of these variants (iliosacral complex, bipartite iliac bony plate, and crescent-like iliac bony plate) had higher incidence in women than in men (p < 0.05) and were not associated with degenerative changes. Knowledge of the normal variations in the SJ appearance broadens the understanding of SJ anatomy, facilitating image interpretation. PMID- 10096349 TI - Intrafibular varix: MR diagnosis. AB - We describe a case of a surgically proven intraosseous venous anomaly of the fibula in a patient who presented with ankle pain and swelling with deep venous thrombosis. MRI, including gadolinium-enhanced MR angiography, provides a less invasive means than conventional venography for diagnosing these lesions and assessing venous patency while also allowing for evaluation of extravascular structures. PMID- 10096350 TI - Magnetic resonance imaging of hydatid cyst in skeletal muscle. AB - The typical MRI features of hydatid cyst in soft tissue/muscle are presented and discussed. PMID- 10096351 TI - Aunt Minnie's corner. Autosomal dominant polycystic kidney disease. PMID- 10096352 TI - Diagnostic terminology in fine-needle aspiration biopsy of the breast: redefining the term "atypia". PMID- 10096353 TI - Cytologic features of villoglandular adenocarcinoma of the uterine cervix: comparison with typical endocervical adenocarcinoma with a villoglandular component and papillary serous carcinoma. AB - BACKGROUND: To the authors' knowledge, the cytologic features of villoglandular adenocarcinoma (VGC) have been described in very few publications. The malignant cells are difficult to separate from reactive glandular cells and the majority of VGCs are missed on screening cytology. METHODS: The cytologic findings of a retrospective study of four cases of pure VGC are described and are contrasted with those of papillary serous adenocarcinoma and typical mucinous endocervical adenocarcinoma with a focal component of VGC. RESULTS: Although atypical glandular cells of endocervical origin were reported when the smears from the VGC cases were examined in the screening program, none of the cases was recognized as malignant prior to histologic diagnosis. The smears showed many groups of endocervical glandular cells. Important architectural features included large cohesive groups and sheets of cells showing nuclear crowding and loss of the normal honeycomb pattern. True papillary structures comprising stromal cores covered by well polarized columnar cells with a smooth surface were characteristic. It is important to note that a "feathered edge" appearance of the cell groups was absent. The neoplastic cells were mildly atypical, showing a slight increase in the nuclear-cytoplasmic ratio but minimal hyperchromatism. The cytology smears of four cases of typical adenocarcinoma of endocervical type that had a focal VGC pattern showed cell groups with irregular borders and "feathered" edges comprised of distinctly atypical columnar cells with elongated and irregular hyperchromatic nuclei. Free-lying atypical cells and ball-like clusters of atypical cells also were present in the latter cases but not in pure VGCs. The primary high grade papillary serous adenocarcinomas of the cervix exhibited extreme cytologic atypia that was interpreted readily as malignant. CONCLUSIONS: The diagnosis of VGC on cytology smears often is missed. Papillary fragments, nuclear crowding, and subtle atypia may suggest the diagnosis. PMID- 10096354 TI - The cytomorphology of papillary serous carcinoma of the endometrium in cervical smears. AB - BACKGROUND: An investigation into the determination of cytomorphologic criteria that may distinguish papillary serous carcinoma of the endometrium (PSC) from typical endometrioid carcinoma (TEC) in cervical smears was undertaken. Preoperative identification of this poor prognostic variant of endometrial carcinoma may influence the surgical management of these cases and the choice of adjuvant therapy. METHODS: The cervical smears of 12 cases of histologically confirmed PSC; 12 cases of TEC, including 2 villoglandular/papillary variants, and 6 cases of mixed PSC and papillary endometrioid carcinoma were reviewed. In all cases an initial diagnosis of malignancy had been made on the cervical smears. Twenty-seven criteria were evaluated and the relation between the cytologic characteristics and the type of adenocarcinoma, the degree of association, and the intergroup homogeneity were tested. RESULTS: Features strongly associated with PSC were hypercellular smears with a background tumor diathesis, papillae, bare nuclei, and cells with large pleomorphic nuclei and bulky dense cytoplasm. In contrast, TEC showed a relatively monomorphic population of cells with moderately enlarged oval nuclei and delicate cytoplasm. In the mixed tumors, the features were similar to those of PSC, suggesting preferential exfoliation of the PSC component of the tumor. CONCLUSIONS: Assessment of the cytomorphology of PSC and TEC of the endometrium in Papanicolaou stained cervical smears is possible using statistically significant diagnostic criteria. PMID- 10096355 TI - Ultrasound-guided fine-needle aspiration (FNA) of nonpalpable breast lesions: a review of 1885 FNA cases using the National Cancer Institute-supported recommendations on the uniform approach to breast FNA. AB - BACKGROUND: A probabilistic approach to the classification of fine-needle aspirates (FNAs) of the breast recently was recommended and received endorsement from the National Cancer Institute (NCI). In this system, FNAs are classified as benign, indeterminate/atypical, suspicious/probably malignant, and malignant, but to the authors' knowledge the use of these diagnostic categories has not been evaluated on a large scale. Furthermore, this classification scheme has not been applied to FNAs of nonpalpable lesions of the breast obtained under imaging guidance. Thus, the current study focused on whether the diagnostic categories could be applied usefully to ultrasound-guided FNAs (US-FNAs) of nonpalpable breast lesions. METHODS: Between 1988-1996, 1885 US-FNAs were performed on 1639 patients. The original FNA diagnoses were reclassified into the NCI-supported recommendations for diagnostic categories of breast FNAs. The cytologic findings were correlated with the tissue specimens, which were available in 851 cases, or with clinical follow-up of a minimum of 2 years in 127 of the 274 patients with benign solid lesions. RESULTS: The 1885 cases were categorized as follows: 1057 (56.1%) as benign, 86 (4.6%) as atypical, 79 (4.2%) as probably malignant, 502 (26.6%) as malignant, and 161 (8.5%) as unsatisfactory (defined as < 6 epithelial cell groups on all slides). The benign US-FNAs included 480 (45.4%) cysts and 577 (54.6%) solid lesions. Combined clinical and surgical follow-up showed that the frequency of malignancy was 3.7% in US-FNAs classified as benign, 52.9% in those designated as atypical, 75.8% in those designated as suspicious, and 98.9% in those classified as malignant. Based on combined histologic and clinical follow up, a sensitivity of 97.1% and specificity of 99.1% were found for US-FNAs when definitive benign and malignant diagnoses were considered. A false-negative rate of 3.7% was attributed to sampling error. A false-positive rate of 0.68% was secondary to interpretative error of proliferative lesions. CONCLUSIONS: Application of the NCI-supported diagnostic categories to US-FNA of nonpalpable breast lesions is useful in stratifying aspirates based on the likelihood of underlying malignancy. The subcategories of US-FNAs diagnosed as atypical have similar probabilities of malignancy; this justifies their being grouped as a single category wherein tissue biopsy would be required to exclude carcinoma. Benign and inadequate FNA diagnoses must be correlated with the clinical and imaging findings and in noncorrelative cases the patient should undergo biopsy. US-FNA is a sensitive and specific means with which to diagnose nonpalpable breast lesions. PMID- 10096356 TI - Angiomyolipoma of the liver in fine-needle aspiration biopsies: its distinction from hepatocellular carcinoma. AB - BACKGROUND: Angiomyolipoma (AML) of the liver is an uncommon benign lesion that may be difficult to distinguish clinically, radiographically, and morphologically from hepatocellular carcinoma (HCC). METHODS: Fine-needle aspiration biopsies (FNAB) of three AMLs of the liver were compared with FNABs from eight cases of HCC. Immunoperoxidase stains for HMB-45, muscle specific actin, and CAM 5.2 were performed on two cell blocks and one resection of AML. RESULTS: All three AMLs yielded cellular aspirates. They were composed of clusters of cells with arborizing transgressing endothelium but no peripherally wrapping endothelium. Smooth muscle cells of AML showed fibrillar cytoplasm and indistinct cytoplasmic borders; HCC showed granular cytoplasm and distinct cytoplasmic borders. Extramedullary hematopoiesis was present only in AML. Mitotic figures were seen only in HCC. Intranuclear inclusions, nucleoli, and large, atypical cells were present in both AML and HCC. Fat was seen in only one case of AML and was scant. Immunoperoxidase stains for HMB-45 and smooth muscle actin were positive in AML and negative in adjacent normal liver. CAM 5.2 stain was negative in AML. CONCLUSIONS: The cytologic features seen on FNABs of AML are distinct from those of HCC. Immunoperoxidase stains can aid in the definitive diagnosis on FNAB. It is important to recognize AML on FNAB to allow conservative clinical management. PMID- 10096357 TI - Fine-needle aspiration findings in patients with polymorphous low grade adenocarcinoma of the salivary glands. AB - BACKGROUND: Polymorphous low grade adenocarcinoma of the salivary glands (PLAC) is a low grade neoplasm that predominantly occurs in the minor salivary glands. In this site it is amenable to biopsy and histologic diagnosis. However, experience with fine-needle aspiration (FNA) biopsy findings in these tumors is limited. The authors describe the FNA cytology of this entity. METHODS: Fine needle aspirates from two primary parotid and three metastatic PLACs were reviewed and correlated with their histology. RESULTS: All aspirates showed similar cytologic features, with hypercellular smears showing branching papillae, sheets and clusters composed of bland uniform cells with round-to-oval nuclei, dispersed chromatin, and absent or inconspicuous nucleoli. The cells generally had a scant-to-moderate amount of eosinophilic cytoplasm. Mitoses and nuclear pleomorphism were absent. These cells formed tubular structures containing hyaline globules in all cases and often a dispersed myxohyaline stroma. Bare nuclei also frequently appeared in the background. Two cases, which had prior histologic diagnoses, were diagnosed on FNA as metastatic PLAC. One metastatic case was diagnosed as benign metastasizing pleomorphic adenoma. One primary case was diagnosed as adenoid cystic carcinoma and one case as PLAC on FNA. CONCLUSIONS: The cytologic differential diagnosis of PLAC includes adenoid cystic carcinoma, pleomorphic adenoma, and monomorphic adenoma. PLAC should be considered in the differential diagnosis of head and neck masses, where the cytology suggests one of these tumors, even when the clinical context (involvement of a major salivary gland, lymph node metastasis) is not typical of PLAC. PMID- 10096359 TI - Cytopathology in the 21st century: a medical consultation or a laboratory test? PMID- 10096358 TI - Melanoma-associated antigen recognized by T cells (MART-1): the advent of a preferred immunocytochemical antibody for the diagnosis of metastatic malignant melanoma with fine-needle aspiration. AB - BACKGROUND: HMB-45, an antibody directed against a premelanosome glycoprotein, has thus far been considered the most specific antibody for the immunocytochemical substantiation of the diagnosis of malignant melanoma (MM). A recently described antigen, MART-1, is a transmembrane protein that is present in normal melanocytes and widely expressed in MM. Antibodies to MART-1 have recently become commercially available. Both HMB-45 and MART-1 form the basis of ongoing immunotherapy protocols at the National Institutes of Health/National Cancer Institute. METHODS: The authors evaluated 207 lesions from 160 patients with metastatic MM procured via fine-needle aspiration (FNA) for expression of MART-1 (clone M2-7C10) and HMB-45 prior to commencement of immunotherapy. FNAs were performed on subcutaneous soft tissue masses (190 lesions), lung (8 lesions), liver (5 lesions), pancreas (3 lesions), and brain (1 lesion). To test the specificity of the monoclonal antibody directed against MART-1, the authors evaluated its reactivity in normal tissues as well as in various nonpigmented neoplasms that are often included in the differential diagnosis of MM. RESULTS: Of all lesions tested, 13 (6%) were negative for both MART-1 and HMB-45. Of all patients tested, 20% had 1 or more lesions that were non-immunoreactive with HMB 45, whereas only 10% had 1 or more lesions that were nonimmunoreactive for MART 1. Eight percent of the lesions tested were negative for MART-1 only, whereas 16% of lesions tested were negative for HMB-45 only. In 35% of the lesions, MART-1 stained more cells than HMB-45. In 13%, MART-1 stained fewer cells than HMB-45, and in 52% both antibodies stained an equivalent number of cells. All samples of normal tissue were negative for staining with MART-1, as were the nonpigmented lesions tested. Melanocytes in normal skin samples stained positively for MART-1. CONCLUSIONS: The MART-1 antibody is a superior immunohistochemical marker for the diagnosis of MM. It has the potential to become the preferred antibody over HMB 45 for the diagnosis of metastatic MM in FNA material, as MART-1 stains a higher percentage of lesions in a higher percentage of patients than does HMB-45. PMID- 10096360 TI - Effects of smoking on plasma and erythrocyte antioxidant defense systems. AB - In this study, activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) enzymes were measured in the erythrocytes, and levels of thiobarbituric acid-reactive substances (TBARS) and antioxidant potential (AOP) values were measured in both erythrocyte and plasma samples from smokerS and nonsmokers. No significant differences were observed in erythrocyte parameters, serum triglycerides, and total cholesterol. AOP was significantly lower and TBARS level higher in the plasma samples from smokers compared with those of nonsmokers. Results suggest that smoking causes no impairment in the enzymatic antioxidant defense system and does not lead to oxidant stress in the erythrocytes, possibly because these cells have potent antioxidant defense capacity. PMID- 10096361 TI - DNA-protein cross-link levels in bone marrow cells of mice treated with benzene or trans,trans-muconaldehyde. AB - Increased levels of DNA-protein cross-links (DNAPC) have been observed in vitro and in vivo following treatment with a number of chemotherapeutic alkylating agents and topoisomerase II inhibitors, that is, agents that have also been associated with the development of bone marrow depression and acute myelogenous leukemia. The current studies were undertaken to examine the effect of benzene, a bone marrow toxin and human leukemogen, on DNAPC levels in mouse bone marrow cells. Using a K+/sodium dodecyl sulfate (SDS) precipitation assay for DNAPC determination, the results indicate increased DNA-protein cross-link levels in mouse bone marrow cells at 2 and 4 but not 8 h after a single ip injection of 440 mg/kg benzene. Following the administration of multiple hematotoxic benzene doses (440 or 880 mg/kg, 2x/d for 2 d), increases in DNA-protein cross-link levels were either slight or not present. These results suggest that DNAPC induced by benzene are neither cumulative nor persistent lesions. The toxicity of benzene is mediated by a number of number of ring-hydroxylated and ring-opened compounds; therefore the present studies also examined DNAPC levels in mice administered trans,trans-muconaldehyde (MUC), a ring-opened hematotoxic and genotoxic metabolite of benzene. No marked increases in DNAPC levels were observed in CD- mouse bone marrow cells 1-12 h following a single ip injection of 3 mg/kg muconaldehyde. It is possible that multiple doses of MUC are required to induce elevated DNAPC levels in bone marrow cells of mice, since multiple doses are required for MUC-induced hematotoxicity. Other reactive metabolites and/or an interaction of reactive intermediates may also be involved in DNAPC induced by benzene. PMID- 10096362 TI - Genetic alterations of cancer-related genes in glass fiber-induced transformed cells. AB - Our previous studies have shown that glass fibers induced morphological transformation in BALB/c-3T3 cells and that transformed cells possessed preneoplastic properties and transforming genes. In the current study, possible molecular mechanisms of glass fiber-induced cell transformation related to the activation and/or inactivation of cancer-related genes resulting from gene amplification and/or point mutations were investigated. Gene amplification was determined by Southern blot analysis of K-ras, H-ras, c-myc, and c-fos proto oncogenes. Mutational spectra of the p53 tumor suppressor gene and the K-ras proto-oncogene were characterized by single-stranded conformation polymorphism and DNA sequencing. Southern blot analysis showed that gene amplification was found in 56% (K-ras and c-myc), 67% (c-fos), and 100% (H-ras) of glass fiber transformed cell lines. DNA sequencing analysis revealed that both transition and transversion mutations occurred and were concentrated in exon 2 of K-ras and exon 4 of p53. In addition, multiple mutations in different codons were found in K-ras and p53 These results suggest that (1) glass fiber-induced cell transformation could be attributed to the activation of the H-ras, K-ras, c-myc, and c-fos proto oncogenes and/or the inactivation of the p53 tumor suppressor gene by gene amplification and/or point mutations and (2) multiple mutations might be due to genomic instability resulting from chromosomal alterations induced by glass fibers. PMID- 10096363 TI - DNA repair in primary human keratinocyte cultures after low level exposure to bis(2-chloroethyl)sulfide. AB - The literature has reported the appearance and disappearance of single-strand breaks (SSBs) in the DNA of rat keratinocytes after exposure to low levels of bis(2-chloroethyl) sulfide (BCES). Since SSBs are a consequence of depurination or depyrimidination followed by excision of the apurinic or apyrimidinic site and deoxyguanosine (GdR) is the major alkylation site in DNA exposed to BCES, it was hypothesized that repair occurred by a GdR-specific base replacement and not by large section repair. To test this hypothesis, cultures of human keratinocytes (HK) were preincubated with 5-bromo-2'-deoxyuridine (BUdR), a heavy analog of thymidine (TdR) incorporated into replicating DNA, immediately before exposure to BCES. Cultures were incubated postexposure with BUdR, radiolabeled GdR, and/or deoxyadenosine (AdR), to measure base-specific repair, and/or radiolabeled TdR, to measure DNA replication and large section repair. A CsCl density gradient was used to remove any BUdR-containing postexposure DNA replication. Each gradient was assayed for radioactivity (cpm) and DNA content (absorbance at 260 nm). The peak A260 fractions were pooled and rebanded in another CsCl gradient. If DNA repair had occurred, the specific activity (cpm/A260) of the peak A260 fraction in the gradient would be greater than control. After exposure of the cultures to BCES, there was a concentration-dependent increase in the specific activity for [3H]GdR but not [4C]TdR over the concentration range used (20-50 microM BCES). A concentration-dependent increase in specific activity was also detected after [14C]AdR exposure. The literature has also reported that the removal of damaged DNA bases after alkylation is via glycosylases. In this series of experiments, we have demonstrated that cultures of HK exposed to the alkylating agent BCES repair their damaged DNA by the replacement of the damaged base only. In the case of BCES exposure, it is the GdR base and to a lesser extent the AdR base. PMID- 10096364 TI - Colonization and clearance of environmental microbial agents upon intranasal exposure of strain C3H/HeJ mice. AB - Environmental dissemination of biotechnology agents is becoming a common practice. Most applications use historically innocuous species; however, potential health effects of individual products are not scrutinized unless they contain genetically engineered microorganisms. In order to investigate possible health concerns, four surrogate microbial agents were studied in vivo. Male C3H/HeJ (endotoxin-resistant) mice were administered intranasally (i.n.) with approximately 10(7) Pseudomonas aureofaciens, Burkholderia cepacia, P. fluorescens, or P. putida. To determine clearance of the dosed bacterial strains, lungs, small intestine, large intestine, cecum, mesenteric lymph nodes (MLN), spleen, and liver were homogenized individually, plated, and dilutions inoculated onto selective media. Pseudomonas fluorescens and P. putida were eliminated from the lungs by 2 d posttreatment, and P. aureofaciens was not detected in the lungs by 5 d posttreatment. Burkholderia cepacia was reisolated from the lungs and cecum for the experimental duration (14 d). Translocation to extraintestinal sites (MLN, spleen, and liver) also occurred. Burkholderia cepacia was recovered from the MLN for 10 d after treatment of mice. Pulmonary exposure to several bacterial strains resulted in unexpected mortality. Pseudomonas aureofaciens was lethal at the lowest dose (8.26 x 10(6) CFU/ mouse), while P. fluorescens and B. cepacia were fatal at higher doses (6.15 x 10(8) CFU/mouse and 1.34 x 10(8) CFU/mouse, respectively). By using the model described in this study, human safety issues can be more easily addressed and evaluated. PMID- 10096365 TI - Triphenyltin acetate-mediated in vitro inactivation of rat liver cytochrome P 450. AB - The in vitro effects of the organotin (OT) compound triphenyltin acetate (TPTA) on cytochrome P-450 content and functions were investigated in liver microsomes from untreated, phenobarbital (PB)- or beta-naphthoflavone- (betaNAF) pretreated rats. At a concentration of 0.5 mM, TPTA caused a marked loss in the spectrally detectable content of cytochrome P-450 up to 27% of its original value, along with an increase in the inactive form cytochrome P-420. Both effects were most pronounced in betaNAF-treated microsomes, which showed a shift in the hemoprotein absorption maximum from 448 nm to 451 nm, but in all cases TPTA failed to affect either cytochrome b5 or total heme content, or to increase the production of malondialdehyde. These results suggest that lipid peroxidation of microsomal membranes or damage to the heme moiety should be excluded as contributing factors in the hemoprotein loss. TPTA also produced a concentration-related functional inactivation of cytochrome P-450 that was most pronounced in betaNAF-exposed microsomal preparations, as denoted by a striking reduction in the ethoxyresorufin O-deethylase (EROD) activity (IC50 = 0.088 mM). In contrast, the activities of cytochrome P-450-independent microsomal enzymes such as NADPH cytochrome c reductase and indophenyl acetate esterase (IPA-EST) were not markedly affected even by 0.5 mM TPTA (-30%). As assessed by Lineweaver-Burk plots, the mechanism of inhibition appeared to be noncompetitive for IPA-EST and of mixed type (competitive-noncompetitive) for EROD. Among sulfhydryl-containing compounds, dithiothreitol was considerably more effective than albumin and reduced glutathione in preventing cytochrome P-450 inactivation and even was able to partially reverse the hemoprotein damage when added after TPTA; glycerol, which is known to protect the hydrophobic environment of cytochrome P-450, was as effective as albumin. This study indicates that TPTA behaves as an almost specific and powerful in vitro inhibitor of cytochrome P-450-dependent monooxygenases, apparently through the interaction with critical sulfhydryl groups of the hemoprotein. PMID- 10096366 TI - Saw palmetto extract: newest (and oldest) treatment alternative for men with symptomatic benign prostatic hyperplasia. PMID- 10096367 TI - Phytotherapy for treatment of benign prostatic hyperplasia: case not proven. PMID- 10096368 TI - Ablation of renal tumors in a rabbit model with interstitial saline-augmented radiofrequency energy: preliminary report of a new technology. AB - OBJECTIVES: To evaluate the efficacy of interstitial saline radiofrequency energy for reproducibly ablating nonmalignant (control) and malignant (the VX-2 tumor) renal tissue in a rabbit model, and to determine the ability of conventional gray scale and power sonography to image the tumor and ablative process in real time before, during, and after treatment. METHODS: The VX-2 tumor was implanted beneath the renal capsule in 18 rabbit kidneys. Twelve days after implantation, 50 W of 500-kHz radiofrequency energy was delivered into the surgically externalized renal tumor and contralateral control kidney for 30 or 45-second treatment intervals using an interstitial saline-augmented radiofrequency probe (the virtual electrode). Localization of the tumor and response to treatment were imaged with gray-scale and power Doppler ultrasonography. The effect of radiofrequency and extent of the destructive process on benign and malignant renal tissue were evaluated histologically. RESULTS: Mean tumor size was 1.3 x 0.7 cm. Both 30 and 45-second treatment intervals provided marked tissue/tumor ablation. Gross anatomic and histologic analysis showed time-dependent ablated lesions averaging 1.4+/-0.3 x 1.0+/-0.3 cm (30-second treatment) and 1.8+/-0.4 x 1.5+/-0.3 cm (45-second treatment), with clear demarcation of the surrounding parenchyma. Conventional gray-scale sonography allowed visualization of the ablative process, and power Doppler ultrasound demonstrated changes in the vascular pattern of the tumor both before and after ablation. No immediate treatment-related complications were observed. CONCLUSIONS: These preliminary studies in a rabbit model demonstrate the feasibility of using the interstitial saline-augmented electrode to ablate small renal tumors and the ability to simultaneously visualize the ablative process using real-time ultrasonography. This technology may have the potential to treat small renal tumors in a minimally invasive manner in the clinical setting. PMID- 10096369 TI - Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. AB - OBJECTIVES: Prostate-specific antigen (PSA) is produced exclusively in the prostate gland and is currently the most useful clinical marker for the detection of prostate cancer. In this report, we examine whether serum PSA is also a predictor of important benign prostatic hyperplasia (BPH)-related outcomes, acute urinary retention (AUR), and the need for BPH-related surgery. METHODS: Three thousand forty men were treated with either placebo or finasteride in a double blind, randomized study of 4-year duration. Serum PSA was measured at baseline, and baseline prostate volume was measured in a 10% subset of 312 men. Probabilities and cumulative incidences of AUR and BPH-related surgery, as well as reduction in risk of events with finasteride, were calculated for the entire patient population, stratified by treatment assignment, baseline serum PSA, and prostate volume. RESULTS: The risk of either needing BPH-related surgery or developing AUR ranged from 8.9% to 22.0% during the 4 years in placebo-treated patients stratified by increasing prostate volume and from 7.8% to 19.9% when stratified by increasing serum PSA. In comparison with symptom scores, flow rates, and residual urine volume, receiver operating characteristic curve analyses showed that serum PSA and prostate volume were the most powerful predictors of spontaneous AUR in placebo-treated patients (area under the curve 0.70 and 0.81, respectively). Finasteride treatment reduced the relative risk of needing surgery or developing AUR by 50% to 74% and by 43% to 60% when stratified by increasing prostate volume and serum PSA, respectively. CONCLUSIONS: Serum PSA and prostate volume are powerful predictors of the risk of AUR and the need for BPH-related surgery in men with BPH. Knowledge of baseline serum PSA and/or prostate volume are useful tools to aid physicians and decision makers in predicting the risk of BPH-related outcomes and choosing therapy for BPH. PMID- 10096370 TI - Safety and efficacy of sildenafil in postmenopausal women with sexual dysfunction. AB - OBJECTIVES: Sildenafil has been demonstrated to be safe and effective in the treatment of men with erectile dysfunction. The role of sildenafil in treating women with sexual dysfunction has heretofore not been reported. The purpose of this preliminary study was to ascertain the response of postmenopausal women with self-described sexual dysfunction treated with sildenafil for 3 months. METHODS: Thirty-three consecutive postmenopausal women with sexual dysfunction based on history were entered in this open-label, nonrandomized study. All patients received 50 mg of sildenafil. Efficacy was assessed at weeks 4, 8, and 12 using a newly developed 9-item, self-administered Index of Female Sexual Function (IFSF) and a global efficacy question ([GEQ] Did treatment improve your sexual function?). The IFSF quantifies the domains of desire, quality of sexual intercourse, overall satisfaction with sexual function, orgasm, lubrication, and clitoral sensation. RESULTS: Of the group, 30 women (91 %) completed the study and were available for follow-up at 3 months. Mean baseline IFSF score before therapy was 24.8+/-9.8. Mean usage of sildenafil was 3.1+/-1.4 times per week for the duration of the study. The IFSF score improved to 29.5+/-7.6, 30.3+/-8.5, and 31.4+/-10.4 at 4, 8, and 12 weeks, respectively (P = 0.25). Mean scores for questions 2 (lubrication), 8 (orgasm), and 9 (clitoral sensation) improved by 23.2%, 7.4%, and 31.3%, respectively, at 12 weeks. Seven women (21%) noted improvement on the GEQ. Overall, only 6 (18.1%) of 33 patients had a significant (more than 60% improvement in IFSF score) therapeutic response. Clitoral discomfort and "hypersensitivity" occurred in 7 women (21%), 3 of whom withdrew from the study. Other side effects, which did not result in withdrawal from the study, included headache (n = 5), dizziness (n = 4) and dyspepsia (n = 3). CONCLUSIONS: The data suggest that sildenafil is well tolerated in postmenopausal women with sexual dysfunction. Overall sexual function did not improve significantly, although there were changes in vaginal lubrication and clitoral sensitivity. The role of sildenafil in treating sexual dysfunction in various cohorts of women remains to be determined. PMID- 10096371 TI - Polymerase chain reaction amplification of bacterial 16s rRNA genes in prostate biopsies from men without chronic prostatitis. AB - OBJECTIVES: A previously reported study using nested polymerase chain reaction (PCR) analysis indicated the presence of DNA from a variety of prokaryotic microorganisms in 77% of transperineal prostate biopsies from patients with chronic nonbacterial prostatitis. Because that study did not include a control group, we investigated whether microbial DNA could also be found in transperineal prostate biopsies obtained from men who did not have a history of prostatitis. METHODS: Transperineal biopsies of both lobes of the prostate were obtained under ultrasound guidance from 9 patients with localized adenocarcinoma of the prostate. DNA was extracted from the prostatic tissue and two-round amplification performed using nested primers from a highly conserved region of the bacterial 16s rRNA gene. Amplified DNA was purified and sequenced, and sequences obtained were compared to bacterial rRNA genes recorded in GenBank. Results. Eleven of 18 biopsy specimens from 8 of 9 patients were positive for bacterial DNA by PCR. Sequence data indicated a predominant organism in 8 of 11 specimens, with greater than 95% homology to DNA from several different genera of bacteria, including Escherichia and Bacteroides. All 9 control samples from the instruments before biopsy were negative. CONCLUSIONS: The presence of bacterial 16s rRNA genes in prostatic tissue is not specific for chronic prostatitis and occurred in most of our patients with localized prostate cancer. Whether the presence of such bacteria is related to the development of prostatic diseases such as prostatitis or prostatic cancer will require carefully controlled trials, including appropriate control groups examined identically. PMID- 10096372 TI - Tamm-Horsfall protein excretion and its relation to citrate in urine of stone forming patients. AB - OBJECTIVES: To evaluate the relation of Tamm-Horsfall protein (THP) and citrate, both potent actors in the urinary stone forming process. METHODS: Quantitative determination of THP in calcium oxalate (CaOx) stone-forming patients and healthy subjects was carried out according to the enzyme-linked immunosorbent assay method. RESULTS: THP excretion in 24-hour urine samples of CaOx stone-forming patients was significantly reduced compared with healthy subjects. A significant correlation exists between the concentration of THP and citrate in the stone forming group, as well as in the group of healthy subjects, and for the 24-hour excretion, this correlation persists in the group of CaOx stone-forming patients. CONCLUSIONS: Decreased THP and citrate excretions were found in CaOx stone forming patients. They indicate a tubular dysfunction of the distal section. PMID- 10096373 TI - Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: a pilot study. AB - OBJECTIVES: Cytoreductive nephrectomy is commonly performed in patients with metastatic renal cell carcinoma before systemic interleukin-2 (IL-2) therapy. Open nephrectomy is associated with prolonged recovery during which metastatic disease can progress. The feasibility of laparoscopic cytoreductive surgery in these patients with large renal tumors was examined. The role of tumor morcellation in reducing the recovery period and allowing earlier treatment with IL-2 was investigated. METHODS: Patients with metastatic renal cancer underwent either open nephrectomy (group 1, n = 19) or laparoscopic cytoreductive nephrectomy (n = 11; 6 with tumor morcellation [group 2], 5 with removal of the tumor through a small incision [group 3]). The three groups were compared to evaluate relative recovery, suitability for treatment with IL-2, and laparoscopic port site seeding. RESULTS: A group of 19 patients underwent open nephrectomy (group 1). Eleven patients with a median tumor volume of 377 cm3 (median tumor diameter 9 cm) underwent laparoscopic cytoreductive nephrectomy. Six of these patients underwent tumor morcellation (group 2) and 5 underwent laparoscopic assisted nephrectomy (group 3). There was no difference in patient age, sex, sites of metastatic disease, ECOG status, size of renal tumor, or surgical complication rates among groups. Patients whose tumor was morcellated had reduced postoperative parenteral narcotic requirements and were discharged sooner than patients undergoing open cytoreductive nephrectomy. Time to treatment with IL-2 was shortest in the morcellation group (median time to treatment 37 days). No port site seeding was observed. CONCLUSIONS: Laparoscopic cytoreductive nephrectomy in patients with bulky renal disease is a safe procedure in selected patients. This pilot study demonstrated a significant association of laparoscopic tumor morcellation with less postoperative pain, faster time to discharge, and shorter time to treatment with IL-2. A randomized study is warranted to determine the role of laparoscopic cytoreductive nephrectomy with tumor morcellation. PMID- 10096374 TI - Effects of finasteride in patients with inflammatory chronic pelvic pain syndrome: a double-blind, placebo-controlled, pilot study. AB - OBJECTIVES: To investigate whether treatment of inflammatory chronic pelvic pain syndrome (ICPPS) with finasteride has any influence on symptoms associated with ICPPS. METHODS: Forty-one patients with ICPPS were randomized (1:3) to treatment with either placebo (25%, n = 10) or finasteride 5 mg daily (75%, n = 31 ) for 1 2 months. Efficacy was evaluated by analysis of symptomatic improvement through responses to symptom questionnaires, pain evaluation on an analytical visual scale, analgesic use as reported in patient diaries, urine flow and residual volume, and prostate volume. RESULTS: Prostatitis Symptom Severity Index and prostatism scores dropped significantly in patients in the finasteride group (P < 0.001 and P < 0.05, respectively). There were no statistically significant differences in pain between the groups. There were significant differences in the changes of prostate volume and in serum prostate-specific antigen concentrations between the finasteride and placebo groups (P < 0.03 and P < 0.02, respectively). The groups did not differ with regard to side effects. CONCLUSIONS: Our results indicate that finasteride has an effect in ICPPS. The mechanisms by which finasteride works in these patients are unclear and could not be solved in this pilot study, which had relatively few patients. A further trial with larger numbers is required to confirm these results. PMID- 10096375 TI - Evaluation of flap valve as an alternative continence mechanism in the Florida pouch. AB - OBJECTIVES: To evaluate urodynamic findings in a successful flap valve (FV) continence mechanism in association with a continent colonic urinary reservoir (Florida pouch) and to compare the urodynamic findings of the FV mechanism with the doubly plicated (PI) standard anti-incontinence segment in the same reservoir. METHODS: Thirteen patients who successfully received the Florida pouch between 1988 and 1996 agreed to undergo urodynamic evaluation as part of a pilot study. Eight patients had a PI continence mechanism and a mean time from surgery of 51 months; 5 had a FV continence mechanism and a mean time from surgery of 14 months. Enterocystometry was performed with a trans-stomal Bard triple channel 7F catheter. Volume and pressure at first desire to empty (VFDE, PFDE), as well as maximal enterocystometric capacity and pressure (VMEC, PMEC), were recorded. Maximal outlet pressure (MOP) was recorded using the catheter withdrawal technique. RESULTS: PI and FV groups demonstrated the following mean values respectively: VFDE, 692.7 and 403 mL; PFDE, 19.5 and 19.2 cm H2O; VMEC, 876.5 and 515 mL; PMEC, 25.9 and 24.6 cm H2O; MOP, 57.5 and 51.2 cm H2O (reservoir empty) and 50.5 and 52.6 cm H2O (reservoir full); and functional length of outlet, 24.3 and 24.6 cm. MOP measurement demonstrated greater variability in the PI than in the FV group. CONCLUSIONS: Urodynamic comparison of these mechanisms reveals that MOP measurement was closer to the mean among FV than PI patients. In addition, the mean VFDE (692.7 mL for PI versus 403 mL for FV, P < 0.05) and the mean VMEC (876.5 mL for PI versus 515 mL for FV, P < 0.05) were significantly less in the FV group. Lower VMEC and less variability in MOP indicate that continence may be more dependent on MOP in the FV mechanism. A longer follow-up time and a larger number of patients will be of assistance in clarifying these findings. PMID- 10096376 TI - Paclitaxel and carboplatin in patients with metastatic transitional cell cancer of the urinary tract. AB - OBJECTIVES: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) is currently considered the most effective chemotherapy for metastatic transitional cell cancer (TCC) of the urinary tract, but because of its considerable toxicity, alternative regimens appear very interesting. We evaluated the efficacy and toxicity of a combination of paclitaxel and carboplatin as first-line therapy for metastatic TCC. METHODS: Thirty-two patients (8 women, 24 men; mean age 67.03 years, range 50 to 79) with metastatic TCC of the bladder or upper urinary tract were included in the study. Paclitaxel (175 mg/m2) was given as a 3-hour intravenous infusion, carboplatin was dosed to an area under the plasma concentration curve of 5 mg/m/min calculated according to the Calvert formula [(creatinine clearance + 25) x 5] as a 30-minute intravenous infusion immediately after paclitaxel. Response evaluation was performed after every 2 cycles and additional therapy depended on response. The maximum number of cycles was 6. RESULTS: With a mean follow-up of 13.1 months (range 2 to 28), 23 of 32 patients responded to treatment (response rate 71.9%), with 31.3% complete remission (CR) (10 of 32) and 40.6% partial remission (PR) (13 of 32). Four patients (12.5%) had stable disease, and 5 patients (15.6%) showed progression. These results compare well with the outcome after MVAC. Toxicity was mainly characterized by neurotoxicity grade 3 and 4 in 9.4%, grade 3 and 4 leukopenia in 37.5%, and grade 3 thrombocytopenia in 3.1% of the patients. No nephrotoxicity was observed, but all patients developed alopecia. Time to progression after CR was a mean of 7.0 months (range 4 to 13) and after PR a mean of 5.9 months (range 2 to 9). CONCLUSIONS: Paclitaxel/carboplatin is an effective therapy for metastatic TCC, with low toxicity. PMID- 10096377 TI - Sociodemographic and health status characteristics with prostate cancer screening in a national cohort of middle-aged male veterans. AB - OBJECTIVES: To characterize variables associated with obtaining prostate cancer screening in a nonclinical, nationally distributed, middle-aged male population. METHODS: Telephone interviews were administered to 2652 individual members of the Vietnam Era Twin Registry in 1992 and 1995. Dependent variables were self-report measures of having had a digital rectal examination (DRE) and/or a prostate specific antigen (PSA) test in the past 5 years. Independent variables were current measures of age, household income, education, race, insurance, source of care, and lifetime measures of physical condition, psychiatric illness, and alcohol and nicotine dependence. RESULTS: Thirty-five percent of the sample reported having had a PSA and DRE within the past 5 years. Prevalence of obtaining either a PSA or DRE varied with age, income, education, and race. Subjects with a regular source of care, a regular physician, and health insurance reported higher rates of having had a DRE or PSA and DRE. Persons with a physical or psychiatric illness reported more screening. A multiple regression model revealed that having a regular source of care, having a regular physician, physical illness, psychiatric illness, minority status, higher income, and age predicted having had some form of screening. CONCLUSIONS: A substantial portion of middle-aged men have had both a PSA and DRE performed at least once in the preceding 5 years. It may be possible to further improve prostate cancer screening participation by directing educational programs at men who are not in contact with the healthcare system. If the PSA and DRE screening guidelines that are finally adopted discourage screening among low-risk men younger than age 50, educational programs that emphasize age screening criteria may be warranted. PMID- 10096378 TI - Prolonged neoadjuvant combined androgen blockade leads to a further reduction of prostatic tumor volume: three versus six months of endocrine therapy. AB - OBJECTIVES: In most clinical trials that have investigated the potential beneficial effects of neoadjuvant combined androgen blockade (CAB) in clinically localized prostate cancer, CAB has been given for 3 months, but no data are available on the influence of a longer duration of neoadjuvant CAB on the pathologic features of prostate cancer. METHODS: Prostatectomy specimens of 40 patients, randomized to 3 (n = 18) or 6 (n = 22) months of neoadjuvant CAB, were blindly evaluated with regard to tumor volume, pathologic stage, and surgical margins. The morphologically most vital tumor areas were investigated for nucleolar size and MIB-1 defined proliferative activity. RESULTS: The patients treated for 6 months had a median tumor volume 60% lower than the 3-month treatment group (P = 0.005). In the 6-month treatment group, no residual tumor could be found in 2 cases, but the proportion of prostatectomy specimens with seminal vesical invasion and positive surgical margins was not statistically different from that after 3 months. Compared with untreated controls, tumor proliferative activity assessed by MIB-1 immunoreactivity was significantly lower at 3 and 6 months of neoadjuvant CAB (P = 0.01). However, in 2 of 1 7 examined tumors that had been treated for 6 months, high MIB-1 scores suggested a development toward therapy-resistant cancer. CONCLUSIONS: Prolonged neoadjuvant CAB for 6 months leads to a further decrease in prostatic tumor volume compared with the findings after 3 months. In a few instances, residual tumor areas with substantial MIB-1 defined proliferative activity persist at 6 months, thus indicating that in at least some cases, despite the overall decrease in tumor size, cancer cells can continue the cell cycle under CAB. PMID- 10096379 TI - Intermittent androgen suppression in the management of prostate cancer. AB - OBJECTIVES: Intermittent androgen suppression (IAS) has been suggested as a means of attenuating the androgen deprivation syndrome in men with incurable prostate cancer. Laboratory data suggest that intermittent therapy may prolong the duration of androgen dependence. METHODS: Since October 1993, 54 patients have entered a Phase II protocol consisting of 8 months of total androgen blockade (TAB) using leuprolide (Lupron) depot and nilutamide (Anandron) followed by an off-treatment interval of variable length. Eleven patients had biopsy-proven local failure after radiotherapy, 4 had biochemical failure, 24 had distant metastases (fewer than six axial sites on bone scan), 11 had combined local and distant failure, and 4 were treated as primary management for nodal disease. Mean prostate-specific antigen (PSA) at entry was 37 ng/mL (range 3.8 to 196). After 8 months of TAB, hormonal therapy was discontinued for those patients whose PSA was less than 4.0 ng/mL and stable or decreasing and was resumed (cycle 2) when PSA increased to greater than 10 ng/mL. RESULTS: As of April 1 998, mean follow-up was 33 months (range 14 to 53). Patients have completed at least one, and up to five treatment cycles. The mean time to nadir PSA in cycle 1 was 20 weeks, and the mean time off was 35 weeks (31 weeks for those with metastatic disease versus 39 for local or biochemical failure). In cycle 2, the mean time to PSA nadir was 17 weeks, and the mean time off was 30 weeks (28 weeks for metastatic disease and 38 weeks for local or biochemical failure). In cycle 3, the time to PSA nadir was 19 weeks. Full testosterone data are available for 40 patients in cycle 1. Normal levels were achieved during the off-treatment interval in 73% by a mean of 18 weeks (median 9). Testosterone normalization in cycle 2 was achieved in 71% at a mean time of 17 weeks (median 14). CONCLUSIONS: TAB can be used intermittently, and appears to be more appropriate for patients with local or biochemical failure. Testosterone recovery is not universal in the off-treatment intervals. IAS needs to be investigated in a randomized trial to determine the effect on overall survival and quality of life. PMID- 10096380 TI - Suramin treatment in hormone- and chemotherapy-refractory prostate cancer. AB - OBJECTIVES: Suramin, a polysulfonated naphtylurea with anti-growth factor activity, was used in the treatment of metastatic, hormone- and chemotherapy refractory prostate cancer. Recent studies have proved the effect of suramin on prostate cancer. METHODS: Between March 1990 and January 1994, 27 patients with metastatic prostate cancer were enrolled in this study. Treatment regimen consisted of a loading phase, allowing patients to reach suramin serum levels between 180 and 250 microg/mL using a suramin dose of 1.4 g/m2 at 3-day intervals. Constant suramin serum levels were maintained by a 0.5 to 1-g/m2 dose every 7 to 10 days. Because previous studies showed suramin to have serious toxicity, compromised organ status was excluded by repeated examinations. RESULTS: Six patients did not complete the suramin loading phase because of side effects and were removed from the study. With an average cumulative suramin dose of 14.2 g, 33% of the assessable patients (7 of 21) experienced a more than 50% reduction of prostate-specific antigen (PSA) and/or alkaline phosphatase (AP) serum levels. Mean survival in these suramin-responsive patients was 495 days. Two of these patients experienced a remarkable reduction of metastases in bone scan examinations. Another 48% of the patients (10 of 21) had essentially unchanged AP and PSA serum levels during suramin treatment, indicating stable disease. Mean survival of these patients was 341 days. In 4 patients undergoing suramin treatment, continuous clinical progression of the disease was observed (mean survival 79 days). Toxicity was less or comparable to prior reported studies; the most common side effects were polyneuropathy, allergic skin rash, and vortex keratopathy. CONCLUSIONS: Suramin has limited, but significant, efficacy even in chemotherapy- and hormone-refractory prostate cancer, without serious toxicity. PMID- 10096381 TI - Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. AB - OBJECTIVES: Angiogenesis is believed to play an important role in tumor progression and metastasis. Previous studies have suggested that the microvessel density (MVD) of prostate tumors may be of prognostic value. This study investigated the reliability of assessing MVD in radical prostatectomy specimens and its value as an independent prognostic indicator in men with clinically localized prostate cancer. METHODS: One hundred radical prostatectomy specimens from 1993 to 1995 were randomly selected for this study. Thirteen cases were excluded because the patients had undergone neoadjuvant hormonal therapy or tissue blocks were unavailable. The median follow-up time was 36 months. Tumor blocks were immunostained using the endothelial-specific antibody CD31. MVD was counted in areas with the greatest microvessel immunostaining, which were designated "hot spots." MVD was analyzed for associations with clinical and pathologic factors. In a subset of 60 cases, the same observer repeated the counts three times. RESULTS: Intraobserver reliability for MVD counting was excellent (reliability coefficient 0.82), demonstrating that this method could be reproduced by a single observer. MVD was not associated with Gleason sum, tumor stage, surgical margin status, or seminal vesicle invasion. Of the 87 patients, 20 (23%) had a prostate-specific antigen (PSA) failure during a 36-month median follow-up time. As expected, Gleason sum and tumor stage were strong predictors of PSA failure, with risk ratios of 2.1 and 2.3, respectively. In contrast, MVD was not associated with PSA failure. CONCLUSIONS: MVD, as determined by CD31, can be reliably measured by a single observer, but it is not a useful prognostic indicator for men with clinically localized prostate cancer. PMID- 10096382 TI - Ultrasound-guided needle aspiration in prostatic abscess. AB - OBJECTIVES: To review the clinical presentation of prostatic abscess and to assess the usefulness of ultrasound-guided needle aspiration as a treatment option for this condition. METHODS: Between October 1984 and November 1997, prostatic abscess was diagnosed in 31 patients. The average age was 60 years (range 29 to 79). Prostate ultrasound was performed using either a hypogastric or transrectal approach. Initial therapy included ultrasound-guided needle aspiration in 24 (77.4%), transurethral resection of prostate (TURP) in 5 (16.1%), or conservative management with antibiotic therapy. During follow-up, ultrasound examinations and urine cultures were performed on an outpatient basis. RESULTS: Past medical history most often included previous urinary infection (15 patients, 48%) and bladder outlet obstruction (13 patients, 42%). Sixty-one percent of patients presented with irritative voiding symptoms at the time of diagnosis. Ultrasound-guided needle aspiration resolved 83.3% of cases; 2 patients needed a second procedure. Three patients required TURP for drainage and 2 to remove an obstruction after abscess resolution. CONCLUSIONS: A high degree of suspicion is needed to diagnose prostatic abscess clinically. Transrectal ultrasound is necessary for the differential diagnosis. Transrectal ultrasound guided needle aspiration is a technically simple and effective therapeutic procedure with no morbidity and, in case of failure, may be repeated or a drainage TURP may be undertaken. PMID- 10096383 TI - Race is not independently associated with a positive prostate biopsy in men suspected of having prostate cancer. AB - OBJECTIVES: To examine whether race is associated with the prostate biopsy result after controlling for other clinical factors in men undergoing ultrasound-guided prostate biopsy to evaluate an elevated serum prostate-specific antigen (PSA) or an abnormal digital rectal examination (DRE), or both. METHODS: We reviewed the records of all men undergoing transrectal ultrasound-guided prostate biopsy at our facilities from January 1990 through March 1998. This included 1056 white men and 874 black men. Patient age, serum PSA, indication for prostate biopsy, and race were examined for association with the biopsy result. RESULTS: Of the 1 930 black and white men who underwent prostate biopsy, 639 (33%) had cancer, including 355 (41%) of 874 black men and 284 (27%) of 1056 white men. Serum PSA, abnormal DRE, and age were independent predictors of a prostate biopsy being positive for cancer. Race was not an independent predictor of cancer being identified in the prostate biopsy. CONCLUSIONS: After controlling for PSA, DRE, and age, black men were not at an increased risk of a positive prostate biopsy relative to white men. Our data do not support the need to consider race when estimating the probability that a man has prostate cancer. PMID- 10096384 TI - Clinically unsuspected and undetected (clinical stage t0) prostate cancer diagnosed on random needle biopsy. AB - OBJECTIVES: To describe the findings in 4 patients who underwent radical prostatectomy for clinically undetected and unsuspected prostate cancer detected on random needle biopsy. METHODS: We reviewed the Mayo Clinic Radical Prostatectomy Prostate Cancer Database of 5793 prostatectomies from 1987 to 1997, and identified 4 patients who had prostate cancer detected on random needle biopsy of the prostate with serum prostate-specific antigen (PSA) less than 4 ng/mL and normal digital rectal examination. Each had requested biopsy despite the absence of clinical suspicion of cancer; 3 had normal transrectal ultrasound, and the fourth had a benign hypoechoic lesion contralateral to the cancer. RESULTS: Mean patient age at diagnosis was 65.5 years (range 61 to 67). Mean PSA was 2.4 ng/mL (range 2 to 2.9). Mean tumor volume was 3 cc (range 0.04 to 11.2). Mean Gleason grade at prostatectomy was 5.75 (range 5 to 7). Prostate cancer was Stage T2a in 1 patient (25%), T2c in 2 (50%), and T3a (25%) in 1. Three tumors were DNA diploid, and one was aneuploid. All patients were alive without evidence of cancer at a mean follow-up of 43 months (range 25 to 53) with undetectable serum PSA concentration. CONCLUSIONS: Our findings indicate that clinically unsuspected and undetected (clinical Stage T0) prostate cancer may be clinically significant. Patient insistence on biopsy reflects increasing concern among the public about prostate cancer. Current clinical thresholds for biopsy detection will fail for some patients with clinically significant prostate cancer. PMID- 10096385 TI - Urinary incontinence after non-nerve-sparing radical prostatectomy with neoadjuvant androgen deprivation. AB - OBJECTIVES: The impact of non-nerve-sparing retropubic radical prostatectomy (RRP) for prostate cancer combined with neoadjuvant androgen deprivation on urinary control is not well documented. We examined the incidence and severity of urinary incontinence after such therapy and determined the etiologic factors causing this complication. METHODS: We examined the postoperative continence status of 104 consecutive patients admitted to the National Cancer Center Hospital who underwent RRP with wide resection of the pelvic nerves after neoadjuvant androgen deprivation. Incontinence was scored according to the number of pads used daily by the patient for urinary leakage. The severity of incontinence was analyzed according to patient age, weight of resected specimen, status of cancer stage, duration of neoadjuvant androgen blockade therapy, preoperative length of membranous urethra, and duration of urethral catheterization after surgery. We also measured the configuration and diameter of the reconstructed bladder neck by retrograde cystourethrography. RESULTS: In 104 patients examined, the percentage of patients who became dry postoperatively was 22% at 1 month, 47% at 3 months, 69% at 6 months, and 78% at 1 year. Of 81 patients who became dry postoperatively at any interval, 22 (27%) became continent within 1 month of RRP, 49 (61 %) were continent within 3 months, 71 (88%) became continent by 6 months, and another 10 (12%) became continent between 6 and 12 months postoperatively. Of 48 patients who were followed up for more than 1 year and for whom continence status at 1 month after surgery was available, all patients who used 1 to 2 pads per day (13 of 13) at 1 month after surgery regained continence by 1 year after surgery. However, only 62% of patients (16 of 26) who required more than 3 pads per day at 1 month after surgery became dry by 1 year after surgery. Only age (older than 70 years) and large prostate size (weight of surgical specimen more than 40 g) temporarily influenced the recovery of urinary continence after surgery. Dilation of the bladder neck evaluated by retrograde cystourethrography was prominent in severely incontinent patients in the immediate postoperative period. CONCLUSIONS: Our experience in patients who undergo non-nerve-sparing RRP after neoadjuvant androgen deprivation closely matches published surveys of patient-reported complications. Postoperative incontinence is not a major contraindication for non nerve-sparing RRP after neoadjuvant endocrine therapy. Dilation of the bladder neck affected the recovery from incontinence, highlighting the importance of adequate reconstruction of the bladder neck. PMID- 10096386 TI - Effect of scrambling on the short-term reliability of the American Urological Association Symptom Index. AB - OBJECTIVES: To determine the degree of attention patients pay to the wording of symptom scoring instruments and to determine the short-term reliability of the American Urological Association Symptom Index (AUA SI). METHODS: The AUA SI was administered to 111 volunteers with a mean age+/-SD of 50.8+/-16.4 years (range 23 to 83) in the standard formatting. Without debriefing, the same volunteers were given the AUA SI a second time within 2 weeks. By sequential assignment, 65 of the subjects were given the AUA SI in the same standard format, and for the remaining 46, the sequence of the questions was scrambled and the order of the answers reversed for the second administration. In addition, the Benign Prostatic Hyperplasia Impact Index (BPH II) and the quality of life (QOL) question were answered and urinary flow rates were performed on both occasions to compare the short-term variability between the "subjective" symptom score and the "objective" flow rate recordings. RESULTS: In this group of volunteers with a mean age of 50.8 years, the mean AUA SI was 11.7 points. The mean values in the unscrambled group were 12.4 and 12.9 (NS) and in the scrambled group 10.5 and 10.2 (NS) for the two administrations. Cumulative frequency distribution of differences were nearly identical. Similarly, there were no differences in the mean values for the two administrations in either group for the BPH II, the QOL question, or the peak flow rate. The reproducibility was excellent for each of the individual seven questions in both groups. There was no effect of age (younger or older than 50 years) on the reproducibility, although in general the variability of the scores was higher in older men, presumably due to a higher score in the first assessment. CONCLUSIONS: Subjects pay relatively close attention to the questions of symptom score questionnaires. The reproducibility for each individual question, as well as for the entire score, was very high in the original unscrambled and in the scrambled version. In addition, the short-term variability of the AUA SI is comparable to that of the flow rate recording. These observations should give confidence to those using such scores in clinical practice and clinical research. PMID- 10096387 TI - Long-term effects of finasteride on prostate tissue composition. AB - OBJECTIVES: To determine the long-term effects of finasteride treatment on prostate tissue composition; to relate these effects to clinical outcomes; and to test the hypothesis that finasteride exerts a selective or preferential action on the transition zone. METHODS: Nineteen men with symptomatic benign prostatic hyperplasia (BPH) who completed a 6-month double-blind trial of finasteride were enrolled in a 24-month open-label extension study of drug responders. Magnetic resonance imaging and prostate biopsy for morphometric analysis were performed together 70 times: at baseline (n = 19), after treatment periods of intermediate duration (6 to 18 months, n = 32), and after long-term drug treatment (24 to 30 months, n = 19). At baseline, prostate volume averaged 51 cc, of which 57% was transition zone. RESULTS: Decreases in symptom score, dihydrotestosterone and prostate-specific antigen levels, and prostate volume occurred at 6 months (P <0.01), stabilized, and were maintained without further long-term decreases. Prostate epithelium contracted progressively from baseline (19.2% tissue composition; 6.0-cc volume; 3.2 stroma/epithelial ratio) to intermediate (12.5%, 3.3 cc, and 5.6, respectively) to long-term treatment (6.4%, 2.0 cc, and 17.4, respectively, P <0.01 for all). Percent epithelial contraction was similar in the peripheral and transition zones (P = NS). The transition zone remained a relatively constant proportion (53% to 58%) of whole-prostate volume from baseline to long-term observation. CONCLUSIONS: Long-term finasteride treatment (24 to 30 months) results in a marked involution of the prostate epithelium, which continues to progress for many months after clinical effects stabilize. The effect on the epithelium is similar in the peripheral and transition zones for both morphometric and volumetric changes. Progressive contraction of the prostate epithelium appears to constitute the underlying mechanism for sustained action of finasteride. PMID- 10096388 TI - Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. AB - OBJECTIVES: To assess the utility of prostate-specific antigen (PSA) as a predictor of prostate volume by characterizing the relationship between prostate volume and serum PSA in men with symptomatic benign prostatic hyperplasia (BPH) and no evidence of prostate cancer, stratified by decade of life. METHODS: Placebo-controlled multicenter trials in patients with BPH and a safety study in normal young men provided baseline measurements of serum PSA and prostate volume. The analyses included patients with a baseline prostate volume measured by either transrectal ultrasound (TRUS) or magnetic resonance imaging and baseline serum PSA. A common central laboratory was used for all but one of the individual studies; both laboratories used the Hybritech method. Patients 80 years of age or older were excluded. Patients with a baseline serum PSA greater than 10 ng/mL were excluded to reduce the likelihood of including occult prostate cancer cases. The patients in the BPH trials were screened at baseline by digital rectal examination (DRE) and serum PSA. Those with suspicious findings underwent TRUS guided biopsy; only patients with negative biopsies are included in these analyses. RESULTS: The analyses included 4627 patients, 4448 from the BPH trials and 179 from the safety study. The men in the BPH trials were older (mean age+SE, 63.7+0.10 years) than the men in the safety study (mean age + SE, 30.8+/-0.43), had larger prostates (mean volume+/-SE, 43.7+/-0.38 mL versus 26.3+/-0.49 mL in the safety study), and had higher serum PSA values (mean+/-SE, 2.6+/-0.03 ng/mL versus 0.7+/-0.39 ng/mL in the safety study). The relationship between prostate volume and serum PSA was evaluated using only the BPH trial data. Prostate volume and serum PSA have an age-dependent log-linear relationship (ie, their logarithms are linearly related, and the parameters of the relationship depend on age). Older men tend to have a steeper rate of increase in prostate volume with increasing serum PSA (P < 0.00 for differences between slopes), and there was a slight tendency for PSA density to increase with age. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to predict threshold prostate sizes in men with BPH. The ROC curve analyses revealed that PSA had good predictive value for assessing prostate volume, with areas under the curve ranging from 0.76 to 0.78 for various prostate volume cutoff points (30, 40, and 50 mL). Conclusions. Prostate volume is strongly related to serum PSA in men with BPH and no evidence of prostate cancer, and the relationship depends on age. Since treatment outcome or risk of long-term complications depend on baseline prostate volume, serum PSA can estimate the degree of prostate enlargement sufficiently accurately to be useful for therapeutic decision making. To achieve a specificity of 70% while maintaining a sensitivity between 65% and 70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 mL are PSA > 1.6 ng/mL, >2.0 ng/mL, and >2.3 ng/mL for men with BPH in their 50s, 60s, and 70s, respectively. PMID- 10096389 TI - Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study. AB - OBJECTIVES: In 1994, the Massachusetts Male Aging Study presented an inverse correlation of the serum levels of dehydroepiandrosterone (DHEA) and the incidence of erectile dysfunction (ED). We evaluated the efficacy of DHEA replacement in the treatment of ED in a prospective, double-blind, randomized, placebo-controlled study. METHODS: The inclusion criteria included ED, normal physical and neurologic examinations, serum levels of testosterone, dihydrotestosterone, prolactin, and prostate-specific antigen (PSA) within the normal range, and a serum DHEA sulfate level below 1.5 micromol/L. Also all patients had a full erection after a pharmacologic erection test with 10O microg prostaglandin E1; pharmacocavernosography showed no visualization in corporeal venous structures. Forty patients from our impotence clinic were recruited and randomly divided into two groups of 20 patients each. Group 1 was treated with an oral dose of 50 mg DHEA and group 2 with a placebo one time a day for 6 months. The International Index of Erectile Function (IIEF), a 15-item questionnaire, was used to rate the success of this therapy. RESULTS: Therapy response was defined as the ability to achieve or maintain an erection sufficient for satisfactory sexual performance according to the National Institutes of Health Consensus Development Panel on Impotence. DHEA treatment was associated with higher mean scores for all five domains of the IIEF. There was no impact of DHEA treatment on the mean serum levels of PSA, prolactin, testosterone, the mean prostate volume, and the mean postvoid residual urine volume. CONCLUSIONS: Our results suggest that oral DHEA treatment may be of benefit in the treatment of ED. Although our patient data base is too small to do relevant statistical analysis, we believe that our data show a biologically obvious trend that justifies further extended studies. PMID- 10096390 TI - Seminal plasma biochemical markers and their association with semen analysis findings. AB - OBJECTIVES: To examine the clinical value of six seminal plasma components in the evaluation of sperm quality and in the differential diagnosis of men with infertility. METHODS: We analyzed 202 seminal plasmas for prostate-specific antigen, glucose, pepsinogen C, insulin-like growth factor binding protein-3, prostaglandin D synthase (PGDS), and BRCA1-like immunoreactive protein (BRCA1 LIP) using quantitative immunofluorometric procedures. The semen donors were categorized in four clinical groups: normal, oligospermic, azoospermic, and vasectomy patients. We then evaluated whether any of these biochemical markers were associated with other parameters of sperm quality, including patient age, total cell concentration, percentage of motility, and percentage of normal morphology. RESULTS: We found that only PGDS concentration was significantly associated with other parameters of sperm quality. PGDS concentration correlated positively with total cell concentration (r = 0.55), percentage of motility (r = 0.31), and percentage of normal morphology (r = 0.31). Median PGDS concentration in seminal plasma decreased progressively from normal to oligospermic to azoospermic to vasectomy patients (P <0.001). There was no overlap between seminal plasma PGDS concentration of normal subjects versus vasectomy patients. The only other parameter that was moderately decreased in vasectomy patients was BRCA1-LIP. The source of PGDS in seminal plasma was determined with various techniques, including immunohistochemistry. This protein is produced and secreted by the Sertoli cells. CONCLUSIONS: Our findings suggest that PGDS concentration in seminal plasma correlates with other known indicators of semen quality and is a new marker of post-testicular obstruction. This biochemical parameter could be used to aid in the differential diagnosis of obstructive and nonobstructive azoospermia in men with infertility. PMID- 10096391 TI - Yield and efficacy of biopty gun testis needle biopsy. AB - OBJECTIVES: To assess whether a preliminary skin incision enhances diagnostic yield of percutaneous testis biopsy and to further evaluate the clinical efficacy of this procedure. METHODS: A total of 45 men (67 testes) underwent testicular biopsy with two passes of a Biopty gun spring-loaded needle. Twenty-seven biopsies were performed without a preliminary skin incision (group 1), and 40 were performed after a small scrotal incision (group 2). In 56 testes, needle biopsy histopathologic diagnosis was compared with that of open biopsy or orchiectomy specimens from the same patient. Needle and surgical specimens were fixed in Bouin's solution and sent separately for independent, blinded, histologic interpretation. RESULTS: Complications of the procedure were negligible. In all 67 needle biopsies, specimen quality was adequate for histopathologic interpretation. The mean number of seminiferous tubules obtained from needle biopsy was 28% higher among patients having a preliminary skin incision (25.9) compared with those without (18.7, P = 0.023). Correlation between needle and open histopathologic diagnosis was excellent (55 of 56, 98%). CONCLUSIONS: A preliminary skin incision made before needle biopsy increases the diagnostic yield of percutaneous testis biopsy. Percutaneous testis biopsy using the Biopty gun needle provides equal diagnostic information when compared with open testis biopsy or orchiectomy specimens. The concomitant reduction in morbidity and cost make this an attractive diagnostic procedure. PMID- 10096392 TI - Chordee: varied opinions and treatments as documented in a survey of the American Academy of Pediatrics, Section of Urology. AB - OBJECTIVES: Consensus has not been established as to the best treatment of congenital chordee. Outcomes analysis of treatment options are limited by the prevailing use of ambiguous terminology. We sought to clarify the frequently used term "significant chordee" and to measure the utilization of current treatment strategies. METHODS: A survey covering current practice patterns concerning congenital chordee with hypospadias was sent to 236 members of the American Academy of Pediatrics, Section of Urology. RESULTS: Correction of chordee was the primary concern in hypospadias surgery of 31 % of those responding, but it was not the primary goal of 54% of respondents. Findings indicate that "significant chordee" is clinically defined as curvature greater than 20 degrees, in that 75% of respondents said they would proceed with further intervention. Placement of plicating sutures was the most common therapy chosen for 20 degrees chordee, with 50% of respondents electing this approach. Consensus was reached at 30 degrees chordee, with greater than 99% intervening at this degree of curvature. At 30 degrees curvature, 48% used an incisional Nesbit procedure. As the degree of curvature increased, division or mobilization of the urethral plate became the most common intervention. With 50 degrees chordee, urethral plate manipulation was used 34% of the time. Sixty percent of the respondents believed the urethral plate did not often contribute to chordee. CONCLUSIONS: "Significant chordee" was believed to be a curvature greater than 20 degrees to 30 degrees. With 20 degrees, 30 degrees , and 40 degrees chordee, correction was most often approached dorsally. With 50 degrees chordee, 54% approached the problem ventrally. We hope to encourage the use of more objective measurements and terminology. Objective measurements and long-term follow-up will improve our understanding of the natural history of chordee and improve outcomes analysis. PMID- 10096393 TI - Use of a digital camera in the urologic setting. AB - Urologists are faced with increasing demands for clear documentation of their work. We report the use of a digital camera in our practice to capture images throughout the urologic setting. The digital camera was a quick and convenient means of obtaining good quality reproductions of radiographic and pathologic findings. Use of the camera greatly enhanced the efficiency of our practice by allowing incorporation of images into patient records and an image library. PMID- 10096394 TI - Use of the flexible cystoscope as a vaginoscope to aid in the diagnosis of artificial sling erosion. AB - Two patients with bladder neck suspension by artificial slings presented with complaints of vaginal pain and drainage as well as irritative voiding. Pelvic examination and flexible cystoscopy were negative. Flexible vaginoscopy detected sling erosion in both. Vaginoscopy is a valuable adjunct procedure in detecting this problem. PMID- 10096395 TI - Images in clinical urology. Testicular encasement by retroperitoneal fibrosis: a rare testicular mass. PMID- 10096396 TI - Images in clinical urology. Arteriovenous fistula of the kidney: imaging with three-dimensional computed tomography angiography. PMID- 10096397 TI - Mullerian duct cyst extending into the abdomen. AB - Mullerian duct cysts occupying the pelvic/abdominal region are rare. We describe a mullerian duct cyst extending into the lower abdomen in a 47-year-old man complaining of urinary retention. We removed the cyst through a suprapubic retrovesical approach. No malignancy was found in the surgical specimen. PMID- 10096398 TI - Role of human papillomavirus typing in diagnosis and clinical decision making for a giant verrucous genital lesion. AB - A 60-year-old man presented with a 12.0 x 10.0-cm exophytic, verrucous genital plaque. Multiple biopsy specimens were evaluated by standard histologic analysis and polymerase chain reaction assays for human papillomavirus (HPV) deoxyribonucleic acid. All biopsy specimens showed histopathologic changes consistent with giant condyloma of Buschke-Lowenstein (GCBL), were uniformly positive for HPV 6/11, and showed a weaker signal for HPV 16. Published reports suggest that the presence of HPV may be useful in differentiating GCBL from verrucous carcinoma (VC), but absence of "high-risk" HPV types in GCBL cannot exclude focally invasive squamous cell carcinoma. Screening for HPV may be a helpful adjunct in differentiating GCBL from VC, but histopathologic criteria for malignancy should take precedence over HPV typing when determining management. PMID- 10096399 TI - Expandable metallic stent placement for nutcracker phenomenon. AB - A 40-year-old woman presented with asymptomatic gross hematuria caused by the nutcracker phenomenon. Despite treatment with hemostatic agents and injection of silver nitrate into the renal pelvis, the hematuria had continued, and severe anemia (hematocrit 17%) had developed. We performed expandable metallic stent (EMS) placement across the left renal vein. Although mild hematuria continued, the anemia resolved after this interventional radiotherapy. EMS placement is a minimally invasive therapy for the nutcracker phenomenon. PMID- 10096400 TI - Extraperitoneal ureterocystoplasty with transureteroureterostomy. AB - Ureterocystoplasty enables the bladder to be reliably enlarged and the resultant neobladder to be lined by urothelium. Many techniques have been described for the operative management of the lower ureter, and a number of alternatives have been suggested for reconstruction of the upper renal tract and bladder. This report describes a new approach that allows renal preservation, transureteroureterostomy, and ureterocystoplasty through an extraperitoneal approach. PMID- 10096401 TI - Downregulation by estrogen of nitric oxide synthase activity in the female rabbit lower urinary tract. AB - OBJECTIVES: Because female urinary tract tissues are considered to be targets for estrogen, and because nitric oxide (NO) is known to participate in the nerve induced relaxation in the lower urinary tract, the effect of estrogen on nitric oxide synthase (NOS) in the upper and lower urinary tracts was examined. METHODS: Ovariectomized rabbits were treated with polyestradiol phosphate, and NOS in both cytosolic and particulate fractions from kidney, urinary pelvis, ureter, urinary bladder, trigonum, and urethra was characterized. NOS activity was measured by the formation of [14C]-L-citrulline from [14C]-L-arginine. RESULTS: NOS was considerably higher in cytosolic than in particulate fractions from all urinary tracts, and activity in both fractions was highly calcium dependent. NOS activity was much lower (fourfold to eightfold) in the kidney and pelvis than in the ureter. Estrogen treatment caused no change in NOS in either fraction from upper urinary tract tissues. In the lower urinary tract, NOS was slightly higher in the bladder and trigonum than in the urethra, and activities were comparable to NOS in the ureter. In contrast to the upper urinary tract, estrogen treatment led to a significant reduction of cytosolic NOS in the bladder, trigonum, and urethra. Estrogen, however, caused no significant change in the particulate NOS. CONCLUSIONS: Downregulation by estrogen in cytosolic NOS in the tissue of the lower urinary tract is consistent with the presence of estrogen receptors and suggests a physiologic significance. PMID- 10096402 TI - Effects of estrogen and progesterone on urinary bladder in female rabbit: evaluation by quantitative morphometric analysis. AB - OBJECTIVES: To investigate possible effects of estrogen and/or progesterone on the histologic characteristics of female rabbit urinary bladders, we carried out quantitative morphometric analysis of the rabbit bladders. METHODS: Mature female rabbits were treated by ovariectomy with and without successive estrogen and/or progesterone administration. Area densities of the connective tissue (CT) and smooth muscle (SM) cells, the area of single SM cells, and the thickness of the bladder wall were determined by computer-assisted quantitative morphometric analysis. RESULTS: Six weeks after each treatment, ovariectomy alone resulted in a decrease in CT density of the bladder. Successive estrogen treatment increased the bladder wet weight and SM cell density within the bladder wall. Progesterone treatment reduced CT degradation in ovariectomized rabbits. Sex steroids did not significantly influence the area of each SM cell. There was no significant difference in histologic characteristics between the rabbits treated by estrogen alone and those treated by combination (estrogen and progesterone) therapy. CONCLUSIONS: Ovariectomy and successive hormonal replacement therapy resulted in morphologic changes within the rabbit urinary bladder. Cotreatment with progesterone did not significantly change the morphologic findings produced by estrogen treatment alone. PMID- 10096403 TI - Gastropyeloplasty: a swine model. AB - OBJECTIVES: Struvite calculus formation requires an alkaline urinary pH. An acidic urinary pH will dissolve struvite calculi and prevent recurrent struvite stone formation. Long-term urinary acidification has been unsuccessful. We sought to determine whether a gastric patch (with viable parietal cells) anastomosed to the renal pelvis could create an acidic urinary milieu. METHODS: A vascularized stomach patch (from the greater curvature) was anastomosed to the left renal pelvis in 15 female pigs. The right kidney was used as a control. The first 6 pigs were used to refine the surgical technique. The remaining 9 pigs were subjected to a formal gastropyeloplasty and followed up for 4 weeks. Urine was collected before and after stimulation with pentagastrin. Urine pH was measured from both kidneys in response to gastrin stimulation and oral intake. The kidneys, ureters, and bladders were examined for gross changes and histologic review. RESULTS: The 9 test animals had more acidic urine in the control kidney than in the gastropyeloplasty kidney. Pentagastrin had no significant impact on urinary pH. Hydroureteronephrosis and a concentrating defect were noted in the treated kidney. Histologic review revealed smooth muscle hyperplasia of the left ureter and viable parietal cells in the stomach patch. CONCLUSIONS: An animal model was developed to transfer a gastric patch to the renal pelvis. Hydronephrosis and ureteral dilation were associated with this gastric patch. We were unable to acidify the urine despite viable parietal cells in the transposed stomach segment. Further refinements of this concept may be successful in acidifying urine in the hope of preventing recurrent struvite nephrolithiasis. PMID- 10096404 TI - Cooling-induced bladder contraction: studies on isolated detrusor muscle preparations in the rat. AB - OBJECTIVES: Detrusor muscle contraction and uninhibited micturition after intravesical instillation of ice water is interpreted as a sign of upper motor neuron lesions. The basic mechanism of cooling-induced contraction (CIC) at the level of smooth muscle, however, has not been satisfactorily explained. We therefore designed model experiments with cooling of rat detrusor muscle. METHODS: We recorded isometric tension from strips of rat urinary detrusor muscle in organ baths during stepwise cooling. CIC was tested before and after addition of various standard agents interfering with known neurogenic (autonomic blockers, tetrodotoxin, capsaicin) and myogenic mechanisms of contraction (calcium channel blockers). RESULTS: Stepwise cooling (37 degrees to 5 degrees C) of detrusor muscle induced reproducible graded contractions, inversely proportional to temperature. CIC was not dependent on a neural mechanism (not blocked by tetrodotoxin or capsaicin) or the release of neurotransmitters but was linked to translocation of calcium. It was reduced by calcium channel blockers and Ca(2+) free solution. Blockage of the Ca(2+)-adenosine triphosphatase pump, which inhibits the extrusion of calcium, also plays a significant role in the process and enhances CIC. CONCLUSIONS: Cooling of detrusor muscle preparations induces a graded myogenic contraction inversely proportional to the temperature. The mechanism is not dependent on local nervous control but is related to calcium translocation. PMID- 10096405 TI - Etiology of idiopathic anterior urethritis. PMID- 10096406 TI - High failure rate of seed implantation alone. PMID- 10096407 TI - Surgery or brachytherapy revisited. PMID- 10096408 TI - Renal cryosurgery. PMID- 10096409 TI - Diethylstilbesterol: first-line hormonal therapy for prostate cancer? PMID- 10096410 TI - Prostate volume in university versus Department of Veterans Affairs patients. PMID- 10096411 TI - Bicalutamide versus flutamide in combination therapy. PMID- 10096412 TI - Phonology, semantics, and the role of the left inferior prefrontal cortex. PMID- 10096413 TI - Regional cerebral blood flow during word and nonword reading. AB - The purpose of this study was to examine changes in regional cerebral blood flow (rCBF) using positron emission tomography (PET) during overt word and nonword reading tasks to determine structures involved in semantic processing. Ten young, healthy, right-handed subjects were scanned 12 times, twice in each of six specific conditions. Blood flow was measured by 15O-water using standard PET imaging technology. The rCBFs during different cognitive conditions were compared by using analysis of covariance (SPM94), which resulted in three-dimensional maps of those brain regions more active in one condition relative to another. When the subjects read aloud words with difficult or unusual grapheme-phoneme translations (i.e., third-order approximation to English or irregularly spelled real words), increases in activation were seen in the inferior frontal cortex. When subjects were reading aloud regular and irregular words (which had important semantic components relative to nonwords), activation of the fusiform gyrus was seen. These data are broadly consistent with brain regions generally associated with reading based on other neuropsychological paradigms, and they emphasize the multicomponent aspects of this complex cognitive process. PMID- 10096414 TI - Characterization of cerebral blood oxygenation and flow changes during prolonged brain activation. AB - The behavior of cerebral blood flow and oxygenation during prolonged brain activation was studied using magnetic resonance imaging (MRI) sensitized to flow and oxygenation changes, as well as positron emission tomography sensitized to flow. Neuronal habituation effects and hemodynamic changes were evaluated across tasks and cortical regions. Nine types of activation stimuli or tasks, including motor activation, vibrotactile stimulation, and several types of visual stimulation, were used. Both flow and oxygenation were evaluated in separate time course series as well as simultaneously using two different MRI methods. In most cases, the activation-induced increase in flow and oxygenation remained elevated for the entire stimulation duration. These results suggest that both flow rate and oxygenation consumption rate remain constant during the entire time that primary cortical neurons are activated by a task or a stimulus. PMID- 10096415 TI - Functional anatomy of verbal and visuospatial span tasks in Alzheimer's disease. AB - The aim of the study was to emphasize cerebral regions which subserve the performance of short-term memory tasks in patients with Alzheimer's disease. We correlated scores obtained on span tasks with cerebral metabolism measured at rest with positron emission tomography. Scores obtained on the digit span task correlated with glucose metabolism in a brain area centered on the premotor cortex and extending to the adjacent motor and parietal gyri. There exists some evidence suggesting that this area may subserve the sequential organization of material stored in short-term memory. In a secondary analysis, we also observed significant interregional correlations between left-sided brain areas which are part of the neural network subserving verbal working memory processes in healthy controls. These data suggest that individual performance on verbal span tasks in AD patients may essentially depend on the preservation of their ordination processing capacity. The absence of correlation with prefrontal regions suggests that AD patients might not spontaneously engage central executive resources to reach their maximal span score. For simultaneous visuospatial span task, the performance of patients correlated with posterior brain regions, and not with prefrontal cortices. PMID- 10096416 TI - Follow-up of radial arterial catheterization for positron emission tomography studies. AB - Radial arterial catheterization is needed for repeated arterial blood samples to construct tracer input curves of positron emission tomography (PET) scans (Herscovitch [1993]: Rheum Dis Clin North Am 19:765-794). Complications resulting from such short-term catheterizations are rare. Sixteen investigators followed 106 subjects who had arterial lines placed in the context of a PET study. Abnormalities were reported in 8 of 106 (7.5%) cases. Of these eight cases, three (37.5%) were inpatients diagnosed with anorexia nervosa, a condition that may represent a risk factor. All abnormalities were benign, did not affect motor function, and did not require medical intervention. PMID- 10096417 TI - Striatal recruitment during an implicit sequence learning task as measured by functional magnetic resonance imaging. AB - Prior research has repeatedly implicated the striatum in implicit sequence learning; however, imaging findings have been inconclusive with respect to the sub-territories and laterality involved. Using functional magnetic resonance imaging (fMRI), we studied brain activation profiles associated with performance of the serial reaction time task (SRT) in 10 normal right-handed males. Behavioral results indicate that significant implicit learning occurred, uncontaminated by significant explicit knowledge. Concatenated fMRI data from the entire cohort revealed significant right-lateralized activation in both the caudate and putamen. Analysis of fMRI data from individual subjects showed inter individual variability as to the precise territories involved, including right as well as left caudate and putamen. Interestingly, all seven subjects who manifested robust learning effects exhibited significant activation within the putamen. Moreover, among those seven subjects, the magnitude of signal intensity change within the putamen correlated significantly with the magnitude of reaction time advantage achieved. These findings demonstrate right-sided striatal activation across subjects during implicit sequence learning, but also highlight interindividual variability with respect to the laterality and striatal subterritories involved. In particular, results from individual subjects suggest that, during the SRT, the reaction time advantage garnered via implicit sequence learning might be predominantly associated with activity within the putamen. PMID- 10096418 TI - Testing for anatomically specified regional effects. AB - We present a simple method that allows statistical inferences to be made about the significance of regional effects in statistical parametric maps (SPMs) when the approximate location of the effect is specified in advance. The test can be thought of as analogous to assessing activations with uncorrected P values based on the height of SPMs but, in this instance, using the spatial extent or volume of the nearest activated region. The advantage of the current test is that it eschews a correction for multiple comparisons even though the exact location of the expected activation may not be known. PMID- 10096419 TI - Effects of protocatechuic acid, S-methylmethanethiosulfonate or 5-hydroxy-4-(2 phenyl-(E)ethenyl)-2(5H)-furanone(KYN-54) on 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanone-induced pulmonary carcinogenesis in mice. AB - Modifying effects of dietary exposure of protocatechuic acid (PCA), a natural monophenolic compound, S-methylmethanethiosulfonate (MMTS), an organosulfur compound newly isolated from cauliflower, and 5-hydroxy-4-(2-phenyl-(E)ethenyl) 2(5H)-furanone (KYN-54), a novel retinoidal butenolide compound, on 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (10 micromol, [corrected] single i.p. injection)-induced pulmonary carcinogenesis were examined in female A/J mice. Each of the test chemicals was given in diets during initiation or post initiation phases (PCA, 1000 ppm; MMTS, 100 ppm; KYN-54, 200 ppm). All of these which had been proved to be chemopreventive mainly in digestive-organs carcinogenesis did not exert any preventive effect in this model when the incidence or multiplicity of pulmonary tumors (adenomas) of mice given NNK and the test chemical at the termination of the experiment (4 months) was compared to that of mice exposed to the carcinogen alone. In contrast, the multiplicity of lung tumors of mice receiving KYN-54 during the post-initiation phase was significantly larger than of the animals with NNK alone (P < 0.05), showing that KYN-54 has a promoting effect on pulmonary carcinogenesis in mice. These data indicate an organotropic activity of these compounds and suggest that candidate compounds for cancer chemoprevention need to be carefully examined for effectiveness in multiple organs by different models. PMID- 10096420 TI - Strong expression of glutathione S-transferase placental form in early preneoplastic lesions and decrease with progression in hamster buccal pouch carcinogenesis. AB - The objective of this work was to investigate the expression of glutathione S transferase placental form (GST-P) in 9,10-dimethyl-1,2-benzanthracene (DMBA) induced hamster buccal pouch carcinogenesis. Lesions were classified histopathologically into four categories, simple hyperplasia, papillary and nodular (PN) hyperplasia, papilloma and squamous cell carcinoma (SCC). Respective mean percentage GST-P positive areas were 81.6 +/- 7.3%, 76.1 +/- 7.3%, 25.8 +/- 4.9% and 1.9 +/- 1.2%, with significant (P < 0.001) differences confirmed between each of the lesions. These results indicate that GST-P is a useful positive marker for neoplastic lesions and that a decreased expression occurs with progression so that it may be predictive of future development of malignancy. PMID- 10096421 TI - Enhancement of urinary bladder carcinogenesis in nullizygous p53-deficient mice by N-butyl-N-(4-hydroxybutyl)nitrosamine. AB - We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during carcinogenesis remains unclear. In the present study, heterozygous and nullizygous p53-deficient mice and their littermates were treated with the urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary bladder carcinogenesis but not development of other tumors in the nullizygous p53-deficient mice. Thus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational inactivation of the wild type allele was not apparent in either the single transitional cell carcinoma observed in a wild-type mouse and a hemangiosarcoma in a heterozygote. Overall, it can be concluded that the number of normal p53 alleles is a significant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urinary bladder carcinogenesis may thus be to diminish the threshold for occurrence of additional genetic alterations. PMID- 10096422 TI - Wy-14,643, a peroxisome proliferator, inhibits compensative cell proliferation and hepatocyte growth factor mRNA expression in the rat liver. AB - Previously, we found that a peroxisome proliferator significantly reduced hepatic and plasma hepatocyte growth factor (HGF) levels in male F-344 rats, and that the growth of preneoplastic or neoplastic cells induced by this peroxisome proliferator was markedly inhibited by HGF. Here, we examined the effects of [4 chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643), a peroxisome proliferator, on cell proliferation and HGF mRNA levels in the liver of rats after stimulation of compensative cell proliferation. After 2 weeks of treatment with Wy-14,643, hepatic DNA synthesis caused by partial hepatectomy was decreased by 50% compared with untreated controls. DNA synthesis was maintained at the same reduced level for up to 10 weeks. During this period, hepatic HGF mRNA level was also much lower in Wy-14,643-treated rats than untreated controls. Therefore Wy 14,643, a peroxisome proliferator, would inhibit the growth of normal hepatocytes, and then produce an advantageous circumstance for the selective growth of neoplastic or preneoplastic cells. PMID- 10096424 TI - Occurrence of monosialosyl pentahexaosylceramide GalNAc-GM1 as specific tumor associated ganglioside of human head and neck squamous cell carcinomas. AB - In a recent study of the ganglioside profiles of human head and neck squamous cell carcinomas versus normal tissue, one unidentified GX ganglioside was found exclusively in tumor extracts, migrating between GM1 and GD3 by thin-layer chromatography. To determine the chemical structure of this ganglioside which accounted for 3-8% of the total gangliosides, the lipid samples were pooled and separated by high-pressure liquid chromatography to obtain individual ganglioside species purified to homogeneity. The tumor-associated GX ganglioside was analyzed by gas-liquid chromatography, mass spectrometry and immunostaining on thin-layer plates with mouse monoclonal antibodies after enzymatic cleavage. The data allowed the identification of GX ganglioside as GalNAc-GM1 that has been reported as a very minor brain ganglioside in humans. Thus, GalNAc-GM1 is a specific tumor associated ganglioside in human head and neck squamous cell carcinomas that could be potentially valuable for clinicians. PMID- 10096423 TI - Inhibition of TPA-induced tumor promotion in CD-1 mouse epidermis by a polyphenolic fraction from grape seeds. AB - The anti-tumor promoting activity of a polyphenolic fraction from grape seeds (GSP) was examined in CD-1 mouse skin epidermis. Specifically, the ability of this fraction to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion and two markers of promotion in mouse skin, ornithine decarboxylase (ODC) and myeloperoxidase (MPO) activities, was evaluated. Pretreatment of mouse skin with 5, 10, 20 and 30 mg of GSP resulted in a dose-dependent reduction in TPA-induced epidermal ODC activity of 27, 37, 48 and 70%, respectively, compared to controls. In addition, pretreatment of mouse skin with 1, 5, 10 and 20 mg of GSP resulted in a significant 43, 39, 54 and 73% inhibition of MPO activity, respectively, compared to controls. In 7,12-dimethylbenz[a]anthracene (DMBA) initiated CD-1 mice, biweekly treatment of mouse skin with 5, 10, and 20 mg of GSP 20 min prior to TPA application resulted in a 30, 40, and 60% inhibition of final skin tumor incidence, respectively, compared to controls. In addition, the final number of tumors per mouse in the 5, 10 and 20 mg GSP-treated animals was decreased 63, 51, and 94%, respectively, compared to controls. These studies indicate that GSP possesses anti-tumor promoting activity when applied to CD-1 mouse skin prior to treatment with TPA. The mechanism of this tumor inhibition is due, in part, to a GSP-associated inhibition of TPA-induced epidermal ODC and MPO activities. Thus, GSP warrants further evaluation as a skin cancer chemopreventative agent. PMID- 10096425 TI - Recognition of different antigens of mistletoe extracts by anti-mistletoe lectin antibodies. AB - Anti-mistletoe lectin-1 (ML-1) antibodies are produced during treatment of cancer patients with mistletoe extracts. However, little is known about their ability to recognise distinct epitopes present in mistletoe extracts. To estimate this, ML 1, ML-2 and ML-3 were analysed by Western blot analysis using high titred anti-ML antibody positive sera from cancer patients treated with different mistletoe extracts. In these experiments we could clearly demonstrate that anti-ML antibodies bind to ML-1 A- and B-chains and, in addition, that they recognised a spectrum of other antigens. This kind of immunological response varied from one individual to another and was not influenced by the different mistletoe extracts. Elution studies showed that anti-ML-1 A-chain or B-chain specific antibodies cross-reacted with A- or B-chains of the other lectins indicating homologies between these molecules (probably in the glycosylated side chain). However, the unglycosylated ML-3 A-chain was only detectable by antibodies specific for the ML 3 A-chain. From our data it has to be concluded that different epitopes of the mistletoe extracts are involved in the induction of the humoral immune response during mistletoe therapy and also that cross-reactivity between the different ML exist. PMID- 10096426 TI - Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines. AB - The naturally occurring compound, gossypol, has been previously used as a male oral contraceptive, for the treatment of benign gynaecological conditions and cancer patients. Long-term daily dosing with gossypol is associated with minimal side effects and no myelosuppression. Since gossypol exhibits atropisomerism due to the restricted rotation about the 2,2' carbon bond, we have isolated the l- and d-isomers by Schiff's base formation using a chiral amine and regenerated the enantiomers by acid hydrolysis. The enantiomers and the proposed oxidative metabolite, gossypolone, were characterized by HPLC, 1H-NMR and optical rotation. The cytotoxicity was assessed in cell cultures derived from melanoma, lung, breast, cervix, and leukaemia using the MTT viability assay. The cytotoxicity of gossypolone was similar to racemic gossypol in five out of the six cell lines studied. The l-enantiomer of gossypol induced a dose-dependent cell kill in all cell lines with a mean IC50 of 20 microM and was significantly more potent than racemic gossypol, the d-enantiomer of gossypol and gossypolone. In addition, when the leukaemia line was exposed to l-gossypol (0.5-10 microM) over a 4-day period, a schedule-dependent decrease in cell viability was observed. l-Gossypol was also compared with respective drugs used to treat patients with melanoma, lung cancer and leukaemia. The data indicate that l-gossypol was significantly more active than cisplatin, melphalan and dacarbazine in the two melanoma lines, cisplatin and daunorubicin in the lung line and hydroxyurea and busulphan in the leukaemia line. Preliminary studies using one melanoma line showed that the l-isomer induced cell shrinkage, membrane blebbing and DNA fragmentation, characteristics suggestive of apoptotic cell death. PMID- 10096427 TI - Potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress. AB - Many chemical compounds which induce oxidative stress in the tissue produce carcinogenesis either alone or act as a tumor promoter in carcinogen-initiated animals after prolonged exposure. Here, we report that potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress. KBrO3 administration dose dependently induced renal ornithine decarboxylase (ODC) activity several fold compared to its activity in saline-treated rats. Similarly renal DNA synthesis which has been measured as [3H]thymidine incorporation in DNA also increases. KBrO3 administration also depleted the level of renal glutathione and glutathione reductase activity in a time dependent manner. The maximum depletion in the levels of renal glutathione and glutathione reductase activity was observed 3 h after KBrO3 treatment which was 60 and 40%, respectively, of saline-treated controls. Parallel to these changes, a sharp increase in the blood urea nitrogen and serum creatinine levels was observed which is indicative of the concurrent renal damage. These results suggest that oxidant generating KBrO3 acts as a potent proliferator of kidney and acts by producing oxidative damage. PMID- 10096428 TI - p53 mutations predict non-small cell lung carcinoma response to radiotherapy. AB - In vitro and animal studies, the effect of loss of p53 function on radiosensitivity is controversial. p21Waf1/Cip1 is a potent inhibitor of cyclin dependent kinases and p21 gene polymorphisms are associated with some human cancers. We sought to determine whether p53 mutations or p21 polymorphisms affect response to radiotherapy in patients with recurrent non-small cell lung carcinoma (NSCLC). Thirty-four patients with NSCLC who underwent radiotherapy for recurrent tumors after potentially curative resection were studied. Gene alterations or polymorphisms were analyzed in DNA from the primary tumor tissue, and the response to radiotherapy was based on the metastatic lesion. Mutations in exons 5 8 of the p53 gene were detected by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. p21 gene polymorphisms were identified by restriction digestion (BsmAI or PstI) of PCR products. Mutations in p53 were found in 13 of 34 patients (38.2%). The response rates (complete plus partial) were 15.4% for patients with tumors having p53 mutations and 61.9% for patients with wild-type p53 (P = 0.013). There was no significant difference between p21 polymorphisms and response to radiation. p53 gene mutations predict response to radiotherapy in NSCLC. Our results provide clinical support for the in vitro model that loss of p53 function decreases radiosensitivity. PMID- 10096429 TI - Effects of long term feeding of raw soya bean flour on virus-induced pancreatic carcinogenesis in guinea fowl. AB - The effects of a diet enriched with 25% raw soya bean flour (RSF) on the pancreas and on the avian retrovirus Pts 56-induced pancreatic carcinogenesis in guinea fowl were studied. It has been shown that prolonged RSF feeding of new-hatched virus-infected and uninfected guinea fowl-poults induced enlargement of the pancreas, which was less pronounced when administration of the RSF supplemented diet started at the age of 75 days. Time-dependent multifocal inter- and intralobular hyperplasia of pleomorphic ducts lined by mucin-producing epithelium in the exocrine pancreas of virus-infected guinea fowls fed a RSF supplemented diet was regularly observed. Enlargement of virus-induced ductular neoplasms has been shown only after simultaneous RSF and virus administration. PMID- 10096430 TI - Molecular non-genetic biomarkers of effect related to methyl thiophanate cocarcinogenesis: organ- and sex-specific cytochrome P450 induction in the rat. AB - We used selective biochemical markers of effect to evaluate some non-genotoxic cocarcinogenic properties of methyl thiophanate (MTH) associated with cytochrome P450 (CYP) changes. Several CYP-dependent reactions were monitored in the liver, kidney and lung microsomes of male and female Sprague-Dawley rats treated (i.p.) with a single (285 or 570 mg/kg body weight) or repeated (daily 285 or 570 mg/kg body weight for three consecutive days) doses of this pesticide. No significant changes in absolute or relative liver, kidney and lung weights were observed after MTH injection. Highly specific substrates were used as probes of different isoforms, such as CYP1A1, 1A2, 2B1, 2E1 and 3A. A complex pattern of CYP induction, including organ- and sex-related differences, was observed, particularly in the liver (CYP3A, 2B1), kidney (CYP1A1, 2E1) and lung (CYP3A, 1A1). In the liver, an increase up to 29-fold in the 2B1-like activity, probed by the O-dealkylation of pentoxyresorufin, was observed at lower dose in both sexes, and the induction of CYP 1A2-mediated methoxyresorufin O-demethylase activity (up to 3.6-fold) was recorded at the higher dose in males. In the kidney, the O deethylation of ethoxyresorufin (CYP1A1-linked) was increased up to 28.2-fold and the CYP2E1-dependent p-nitrophenol hydroxylases were enhanced up to 6.3-fold in females receiving higher multiple MTH administration. In the lung, the CYP3A associated activity was the most induced oxidases, as exemplified by the marked increase in the O-demethylation of aminopyrine (up to 3.6-fold) in males. A weak, although significant, reduction of CYP2B1-linked oxidases was also observed in repeated treatment in the kidney (males) and lung (females). These results suggest that the induction of CYP-catalyzed drug metabolism by prolonged exposure to MTH may result in accelerated metabolism of coadministered drugs with important implications for their disposition Together with an alteration of endogenous metabolism, the adverse effects associated with CYP changes such as toxicity/cotoxicity, cocarcinogenicity and promotion may also have clinical consequences. PMID- 10096431 TI - c-fos gene expression in rat liver is induced by phenobarbital. AB - In the present study we investigated c-fos expression in rat livers, that was initiated with the three arylamines, 2-acetylaminofluorene, 2 acetylaminophenanthrene and trans-4-acetylaminostilbene. The tumor promoter phenobarbital was applied chronically for 26, 52 and 100 weeks. Gene expression, determined by the mRNA level, and FOS protein were increased after 52 weeks of treatment in arylamine initiated as well as in phenobarbital only treated animals. Expression of c-fos seems to be a phenobarbital induced effect that is independent of additional initiator treatments. This finding was supported by immunohistochemical studies demonstrating increased FOS levels to be localized around the central vein. The results indicate that phenobarbital, a widely used tumor promoter, induces c-fos expression. In addition, we demonstrated enhanced FOS in GST-P-positive foci and in tumors. PMID- 10096432 TI - Frequent loss of heterozygosity on chromosomes 4, 12 and 19 in radiation-induced lymphomas in mice. AB - We found frequent loss of heterozygosity (LOH) on chromosomes 4, 12 and 19 in radiation-induced lymphomas from (BALB/cHeA x STS/A) F1 hybrid mice by allelotype analysis at polymorphic microsatellite loci. The incidences of LOH were 27% (20 of 74 lymphomas), 57% (42 of 74 lymphomas) and 50% (37 of 74 lymphomas) on chromosomes 4 (at D4Mit31), 12 (at D12Mit17) and 19 (at D19Mit11), respectively. These frequent LOH regions are homologous to human chromosomes 9p and 1p, chromosome 12q32.1 and chromosome 10q, respectively. Strain-specific preferential allele loss was observed only on chromosome 4. However, no bias in the frequency of loss between alleles of maternal and paternal origin was observed, indicating that genomic imprinting may not be predominantly involved in these lymphomas. The results suggest that these three regions might harbor tumor suppressor genes responsible for this lymphomagenesis. PMID- 10096433 TI - Metabolism of carbamazepine by CYP3A6: a model for in vitro drug interactions studies. AB - Carbamazepine (CBZ) is widely used in the treatment of epilepsy. The drug is principally metabolized by CYPs to 10, 11-epoxy carbamazepine (CBZ-E) but this metabolite more toxic than the parent drug, does possess anticonvulsant properties. In humans, CYP3A4, CYP2C8 and CYP1A2 have been shown to be implicated in CBZ biotransformation. Our purpose was to establish an experimental model to determine the interaction of CBZ with other antiepileptic drugs. We first identified the CYP isoforms that metabolized CBZ in rabbit. We used liver microsomes from rabbit treated with various compounds known to induce principally some CYPs subfamilies. Having tested all the compounds we demonstrated that only the animals treated with CYP3A inducers were able to metabolize CBZ strongly. The CBZ biotransformation was inhibited by anti CYP3A antibodies. All the CYP3A subfamily substrates specifically decrease CBZ-E formation. In our experiment we did not observe any inhibition with CYP2C substrate. These data provide evidence that in rabbit the CYP3A subfamily is primarily involved in CBZ metabolism. Using this model we investigated the interaction of CBZ with phenobarbital, phenytoin, ethosuccimide, primidone, progabide, vigabatrin and lamotrigine. PMID- 10096434 TI - Cyclosporin A, but not FK506, increases arachidonic acid release and inhibits proliferation of pituitary corticotrope tumor cells. AB - The selective immunosuppressants cyclosporin A (CsA) and tacrolimus (FK506) are used in the prevention of allogenic transplant rejection and in the therapy of chronic autoimmune inflammatory pathologies. Chronic treatment with CsA leads to secondary functional and trophic alterations of multiple organs and cell systems among which endocrine ones, through insofar uncharacterized mechanisms. With the recent use of FK506 there have been reports of an improved therapeutic efficacy and a reduction of side-effects, as compared to CsA. An intriguing hypothesis is that toxic damage could be due to a systemic CsA activation of arachidonic acid (AA) metabolism, through pathways as yet only partially characterized. The side effects of both drugs have been poorly studied on cells from tissues other than blood or kidney. We have thus proceeded to study their action on AA release in corticotropic AtT-20/D16-16 cells. The results obtained are as follows: 1) during incubation times > or =12 h, basal AA release is increased by CsA, but not FK506; the acute effect (10 min) of melittin, a PLA2 activator, is significantly potentiated starting from a 30 min pretreatment with CsA but not FK506; manoalide, a PLA2 inhibitor, antagonizes the melittin potentiation of AA release by CsA whereas the inhibition of the melittin stimulus by glucocorticoids is antagonized both by CsA and FK506. 2) during longer (>2 d) incubation times, cell growth is inhibited by CsA but not FK506. These results indicate a role for CsA, not apparent for FK506, in the activation of PLA2 and in the inhibition of cell growth. They also suggest that CsA does not have a direct (i.e. not mediated by the immune system) therapeutic effect in inflammatory processes. PMID- 10096435 TI - The role of transforming growth factor-beta on retarded osteoblastic differentiation in vitro. AB - Various matrix growth factors play important roles in the development and growth of cartilage and bone. Among them transforming growth factor-beta superfamily and especially bone morphogenetic proteins are known to be important factors, since they induce bone and cartilage formation in ectopic sites in vivo. We have previously shown that the human osteosarcoma cell line Saos-2 expresses molecules that in vivo induce new bone formation with asymmetric bone maturation. In this study we examined the role of Saos-2-conditioned medium in prolonged cultures of mesenchymal C3H/10T1/2 cells. The C3H/10T1/2 cells were cultured with Saos-2 conditioned medium for 28 days. We show that Saos-2-treated C3H/10T1/2 cells performed retarded osteoblastic differentiation when compared to recombinant BMP 2 and -4 induced differentiation. We further show that this retardation is due to excessive amounts of transforming growth factor-beta in Saos-2-conditioned medium. Our results also suggest that this model can well be used to study additional cofactors involved in retarded osteogenesis. PMID- 10096436 TI - Serotonin, bradykinin and endothelin signalling in a sheep choroid plexus cell line. AB - The secretion of cerebrospinal fluid by the epithelial cells of choroid plexus is regulated by membrane receptors coupled to adenylyl cyclases or to phospholipase C. These intracellular signalling pathways as their interactions were investigated in a sheep choroid plexus cell line. Endothelin-1, bradykinin and serotonin induced a transient dose-dependent increase in intracellular calcium. EC 50 were 10(-8) M for endothelin-1, 10(-8) M for bradykinin and 10(-6) M for serotonin. Maximal increase in intracellular calcium was comparable for bradykinin and serotonin, but was 3 to 5 fold larger for endothelin-1. Successive stimulations with endothelin-1, serotonin or bradykinin elicited calcium increases similar to single stimulations reflecting absence of heterologous desensitization between these receptors. Forskolin-induced cAMP accumulation was potentiated by bradykinin, but not by serotonin and endothelin-1. This potentiation resulted from an increase in cAMP production rather than to an inhibition of cAMP hydrolysis. These data suggest that serotonin, endothelin-1 and bradykinin each use specific signalling pathways in the sheep choroid plexus cells. PMID- 10096437 TI - Neuroprotective effects of a dihydropyridine derivative, 1,4-dihydro-2,6-dimethyl 4-(3-nitrophenyl)-3,5-pyridinedicarbox ylic acid methyl 6-(5-phenyl-3 pyrazolyloxy)hexyl ester (CV-159), on rat ischemic brain injury. AB - CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM) dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6 aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988). PMID- 10096438 TI - Effects of concanavalin A on protein-C activity. AB - Concanavalin A interacts specifically with the oligosaccharides from protein-C and modifies its anticoagulant activity. The lectin activates the protein-C activity in a dose dependent manner as demonstrated by in vitro and in vivo assays. Concanavalin A at low concentration (0.1 to 2 microg/mL) induces an increase on the catalytic activity of protein-C; at higher concentrations (5 to 20 microg/mL), the catalytic activity returns to the baseline. The effect of concanavalin A was prevented by incubating the protein-C with alpha-methyl mannoside or by treating the purified protein-C with alpha-mannosidase; furthermore, cleavage of mannosidic residues diminishes its catalytic activity. Our results indicate that the oligomannosidic portion of protein-C participates in the regulation of the catalytic activity of this protein. PMID- 10096439 TI - Use of acute phenolic denervation to show the neuronal dependence of Ca2+-induced relaxation of isolated arteries. AB - We recently showed that perivascular sensory nerves of mesenteric resistance arteries (MRA) express a receptor for extracellular Ca2+ (CaR) and proposed that activation of the CaR by Ca2+ causes nerve-dependent vascular relaxation. We now describe a novel procedure for acutely denervating isolated arteries and have used this method to test the hypothesis that Ca2+-induced relaxation of MRA is nerve dependent. MRA were studied using a wire myograph equipped with electrodes for electrical field stimulation (EFS) which caused sympathetic nerve-mediated contraction, and when applied in the presence of guanethidine, induced nerve mediated relaxation. Ca2+-induced relaxation was produced by the cumulative addition of Ca2+ to MRA precontracted with norepinephrine. Exposure of MRA to 6.5% phenol in ethanol for 20 sec significantly attenuated EFS-induced contraction and relaxation, and Ca2+-induced relaxation. The magnitude of the relaxation response to EFS correlated significantly with the decrease in Ca2+ induced relaxation. In contrast, endothelium-dependent relaxation induced by acetylcholine was slightly, but nonsignificantly decreased by phenol treatment and did not correlate with Ca2+-induced relaxation. These data indicate that brief exposure of isolated MRA to phenol significantly impairs perivascular nerve function and support the hypothesis that Ca2+-induced relaxation is neurally mediated. PMID- 10096440 TI - Morphine tolerance in arthritic rats and serotonergic system. AB - To understand whether chronic inflammation alters the development of morphine tolerance, the tail-flick test was used to evaluate the analgesic effect of morphine (75 mg tablet, s.c.) in the arthritic rats at the day 9-12 after the inoculation with Freund's adjuvant. Spinal cord monoamines and amino acid neurotransmitters were concomitantly measured. Chronic inflammation attenuated the antinociceptive effect of morphine as tolerance developed faster in the arthritic rats compared to the vehicle-treated controls. In addition, ratio of 5 hydroxyindole-3-acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) increased in the lumbar spinal cord of arthritic rats without any change in the concentrations of norepinephrine, glutamate, aspartate or GABA. Interestingly, increased serotonin turnover in the spinal cord was observed in both control and arthritic rats 24 hours after morphine treatment. Overall, the results suggest a significant role of serotonin up-regulation in the spinal cord during chronic pain and the development of morphine tolerance. PMID- 10096441 TI - Long-term treatment with fluoxetine associates with peripheral effects on rat vas deferens contractility. AB - The aim of this work was to study whether long-term treatment with fluoxetine could induce peripheral effects by modifying vas deferens contractile activity. For this purpose the contractile response to NE, and 5-HT of vas deferens isolated from male Wistar rats that received fluoxetine 10 mg/kg/day i.p., during 21 days, was studied using the isolated organ bath technique. Results show that vas deferens of treated rats presented spontaneous activity, an effect that was abolished by prazosin and isoproterenol and that was not affected by nitroprusside or indomethacin. In addition, fluoxetine did not modify the response to calcium suggesting that spontaneous activity was not a consequence of an abnormal calcium movement. Fluoxetine induced a significant increase in the response of vas deferens to 5-HT and to low NE concentrations while NE maximal effect was unaffected. Fluoxetine treatment did not modify the binding parameters of [3H]-prazosin to vas deferens. It is concluded that long-term treatment with fluoxetine modifies vas deferens contractile activity. This effect could be the result of an alteration of adrenergic neurotransmission and could account for some of the untoward effects observed during clinical course with fluoxetine. PMID- 10096442 TI - Spinal administration of selective opioid antagonists in amphibians: evidence for an opioid unireceptor. AB - In mammals, opioids act by interactions with three distinct types of receptors: mu, delta, or kappa opioid receptors. Using a novel assay of antinociception in the Northern grass frog, Rana pipiens, previous work demonstrated that selective mu, delta, or kappa opioids produced a potent antinociception when administered by the spinal route. The relative potency of this effect was highly correlated to that found in mammals. Present studies employing selective opioid antagonists, beta-FNA, NTI, or nor-BNI demonstrated that, in general, these antagonists were not selective in the amphibian model. These data have implications for the functional evolution of opioid receptors in vertebrates and suggest that the tested mu, delta, and kappa opioids mediate antinociception via a single type of opioid receptor in amphibians, termed the unireceptor. PMID- 10096444 TI - Indentation creep behavior of a direct-filling silver alternative to amalgam. PMID- 10096443 TI - The analgesic tropane analogue (+/-)-SM 21 has a high affinity for sigma2 receptors. AB - The analgesic properties of the tropane analogue (+/-)-SM 21 have been attributed to the antagonism of presynaptic m2 receptors resulting in a potentiation of acetylcholine release. However, drugs targeting a number of other neurotransmitter receptors have been shown to enhance acetylcholine release. In the current study, in vitro studies were conducted in order to determine the affinity of (+/-)-SM 21 for serotonin 5-HT3, 5-HT4, and sigma receptors. Our results indicate that (+/-)-SM 21, and its structural congeners, have a relatively high affinity for sigma2 receptors relative to their reported affinity for muscarinic receptors. The higher affinity for sigma2 versus sigma1 receptors indicates that (+/-)-SM 21 may be a suitable lead compound for developing sigma2 selective ligands. PMID- 10096445 TI - Residual monomer/additive release and variability in cytotoxicity of light-curing glass-ionomer cements and compomers. PMID- 10096446 TI - Oral biology, a dialogue: Solon Arthur Ellison at the State University of New York at Buffalo. PMID- 10096447 TI - Attrition, eruption, and the periodontium. AB - Features of natural masticatory function, of physiological attrition, both occlusal and approximal, and of continuing tooth eruption in adult life need to be borne in mind in considering how the chronic inflammatory periodontal diseases and dental caries have become so widespread. Evidence is reviewed showing that teeth continue to erupt in adulthood, that natural masticatory function prevented plaque accumulation at the approximal risk site of onset of both CIPDs and caries, that epithelial attachment to cementum may be physiological, and that periodontal attachment studies must be age-related. PMID- 10096448 TI - Extracts of Actinobacillus actinomycetemcomitans induce apoptotic cell death in human osteoblastic MG63 cells. AB - Whether an extracellular component of periodontal-disease-causing bacteria induces apoptotic cell death in bone-related cells is unknown. To study the effects on osteoblasts of extracts obtained from sonicated Actinobacillus actinomycetemcomitans and Prevotella intermedia, we cultured human osteoblastic cell lines MG63 and Saos-2 cells and mouse osteoblastic cell line MC3T3-E1 cells in the presence of such extracts. The addition of the extracts from Actinobacillus actinomycetemcomitans induced cell death in MG63 cells in a dose- and time-dependent fashion over the concentration range of 0.1 to 10 microg/mL. By contrast, the extracts from Prevotella intermedia did not induce cell death in these cells, even in the presence of 10 microg/mL protein. By using the Hoechst 33342 staining technique, we observed marked nuclear condensation and fragmentation of chromatin in MG63 cells treated with the extracts of Actinobacillus actinomycetemcomitans. DNA ladder formation, a hallmark of apoptosis, also was detected in MG63 cells treated with extracts from Actinobacillus actinomycetemcomitans. In MG63 cells, DNA ladder formation was dose-dependent, with a maximal effect at a concentration of 10 microg/mL, and time-dependent, from 12 to 48 hrs. However, the extracts from Prevotella intermedia did not induce DNA fragmentation in MG63, Saos-2, or MC3T3-E1 cells. The extracts from Actinobacillus actinomycetemcomitans did not induce cell death and DNA fragmentation in Saos-2 and MC3T3-E1 cells. Sonicated extracts of Actinobacillus actinomycetemcomitans that had been treated with heat and trypsin did not induce DNA ladder formation in MG63 cells, suggesting that the apoptosis inducing factors are proteinaceous. Cycloheximide prevented the Actinobacillus actinomycetemcomitans-induced DNA ladder formation in MG63 cells in a dose dependent fashion, suggesting that new gene transcription and protein synthesis are regulated for Actinobacillus actinomycetemcomitans-induced apoptosis in MG63 cells. Our results indicate that apoptosis in alveolar bone cells induced by Actinobacillus actinomycetemcomitans plays an important role in periodontal diseases. PMID- 10096449 TI - Characterization of recombinant pig enamelysin activity and cleavage of recombinant pig and mouse amelogenins. AB - Enamelysin (MMP-20) is a tooth-specific matrix metalloproteinase that is initially expressed by ameloblasts and odontoblasts immediately prior to the onset of dentin mineralization, and continues to be expressed throughout the secretory stage of amelogenesis. During the secretory stage, enamel proteins are secreted and rapidly cleaved into a large number of relatively stable cleavage products. Multiple proteinases are present in the developing enamel matrix, and the precise role of enamelysin in the processing of enamel proteins is unknown. We have expressed, activated, and purified the catalytic domain of recombinant pig enamelysin, and expressed a recombinant form of the major secreted pig amelogenin rP172. These proteins were incubated together, and the digestion products were analyzed by SDS-PAGE and mass spectrometric analyses. We assigned amelogenin cleavage products by selecting among the possible polypeptides having a mass within 2 Daltons of the measured values. The polypeptides identified included the intact protein (amino acids 2-173), as well as 2-148, 2-136, 2-107, 2-105, 2-63, 2-45, 46-148, 46-147, 46-107, 46-105, 64-148, 64-147, and 64-136. These fragments of rP172 include virtually all of the major amelogenin cleavage products observed in vivo. We propose that enamelysin is the predominant proteinase that processes enamel proteins during the secretory phase of amelogenesis. PMID- 10096450 TI - Langerhans cells from oral epithelium are more effective in stimulating allogeneic t-cells in vitro than Langerhans cells from skin epithelium. AB - Dendritic cells, such as Langerhans cells (LC), in different ectodermal compartments may have different functional capabilities. The present study was undertaken to compare oral Langerhans cells (LC) with those of the epidermis in terms of their ability to co-stimulate T-cells in vitro. A Mixed Epithelial Cell Lymphocyte Reaction (MELR) and a mitogen-driven (concanavalin A) T-cell proliferation assay were used. In both assays, LC in a crude cell suspension of freshly isolated oral epithelial cells were found to be five times more effective in mediating T-cell proliferation than freshly isolated epidermal LC. Twenty-four hour cell culture at 37 degrees C enhanced the T-cell response in the MELR compared with cells cultured at 4 degrees C. This applied to both skin and oral epithelial cells. Oral and skin epithelial cell suspensions depleted of LC lost the capacity to stimulate allogeneic T-cells. Incubation of the epithelial cell suspensions with recombinant Granulocyte/Macrophage-Colony Stimulating Factor (rGM-CSF) did not enhance the co-stimulating capacity of the LC. Titration of different numbers of oral and skin LC to T-cells showed that skin LC were never able to reach more than 44% of the maximal stimulatory capacity of oral LC. Data show that oral LC are more efficient than skin LC in providing co-stimulatory signals to T-cells, suggesting a difference in functional capacity between the two cell populations. PMID- 10096451 TI - Cumulative correlations of lysozyme, lactoferrin, peroxidase, S-IgA, amylase, and total protein concentrations with adherence of oral viridans streptococci to microplates coated with human saliva. AB - Redundancy refers to the observation that many salivary proteins exhibit similar properties in vitro. It is possible that bacterial adherence to salivary pellicle occurs as a cumulative effect of multiple proteins. This study determined the joint and individual contributions of salivary amylase, S-IgA, lysozyme, salivary peroxidase, lactoferrin, and total protein concentrations to adherence by oral viridans streptococci in microplates coated with whole saliva from 123 persons. Strains used were: Streptococcus gordonii Blackburn, 10558, Streptococcus mitis 10712, 903, Streptococcus oralis 10557, 9811, and Streptococcus sanguis 10556, 13379. Rabbit antibody against 13379 was used for the detection of adherence. This antibody cross-reacted with all strains. Absorbance was standardized against saliva pooled from five donors. All saliva samples had been previously assayed for amylase, lactoferrin, lysozyme, secretory IgA, peroxidase, and total protein. Adherence scores for all strains except 13379 were significantly and positively correlated. Salivas binding high or low levels of one strain tended to bind others correspondingly. Multiple regression indicated significant contributions to 10558 adherence from total protein and lactoferrin (positive), and peroxidase and lysozyme (negative). Similar results were obtained for Blackburn and 903. Significant individual correlations were seen for 9811 and total protein (positive), 10557 and peroxidase (negative), and 13379 and lactoferrin (negative). Salivas with high adherence scores contained significantly more protein and lactoferrin, and significantly less peroxidase, than salivas with low adherence scores. These findings support the hypothesis that multiple proteins contribute to the adherence of streptococcal strains in vivo. PMID- 10096453 TI - Origin of sensory and autonomic innervation of the rat temporomandibular joint: a retrograde axonal tracing study with the fluorescent dye fast blue. AB - Previous studies that have used retrograde axonal tracers (horseradish peroxidase alone or conjugated with wheat germ agglutinin) have shown that the temporomandibular joint (TMJ) is supplied with nerve fibers originating mainly from the trigeminal ganglion, in addition to other sensory and sympathetic ganglia. The existence of nerve fibers in the TMJ originating from the trigeminal mesencephalic nucleus is unclear, and the possible innervation by parasympathetic nerve fibers has not been determined. In the present work, the retrograde axonal tracer, fast blue, was used to elucidate these questions and re-evaluated the literature data. The tracer was deposited in the supradiscal articular space of the rat TMJ, and an extensive morphometric analysis was performed of the labeled perikaryal profiles located in sensory and autonomic ganglia. This methodology permitted us to observe labeled small perikaryal profiles in the trigeminal ganglion, clustered mainly in the posterior-lateral region of the dorsal, medial, and ventral thirds of horizontal sections, with some located in the anterior lateral region of the ventral third. Sensory perikarya were also labeled in the dorsal root ganglia from C2 to C5. No labeled perikaryal profiles were found in the trigeminal mesencephalic nucleus. On the other hand, autonomic labeled perikaryal profiles were distributed in the sympathetic superior cervical and stellate ganglia, and parasympathetic otic ganglion. Our results confirmed those of previous studies and also demonstrated that: (i) there is a distribution pattern of labeled perikaryal profiles in the trigeminal ganglion; (ii) some perikaryal profiles located in the otic ganglion were labeled; and (iii) the trigeminal mesencephalic nucleus did not show any retrogradely labeled perikaryal profiles. PMID- 10096452 TI - Possible involvement of histamine in muscular fatigue in temporomandibular disorders: animal and human studies. AB - As an approach to clarifying the molecular basis of pain and fatigue in muscles involved in temporomandibular disorders, we examined the activity of histidine decarboxylase (HDC), the enzyme which forms histamine, in the masseter muscles of mice. In the resting muscle, HDC activity was very low. Direct electrical stimulation of the muscle markedly elevated HDC activity. HDC activity rose within 3 hrs of the electrical stimulation, peaked at 6 to 8 hrs, and then gradually declined. Intraperitoneal injection of a small amount of interleukin-1 (IL-1) (from 1 to 10 microg/kg) produced a similar elevation of HDC activity in the masseter muscle. We also examined the effect of an antihistamine, chlorphenylamine (CP), on temporomandibular disorders in humans and compared it with that of an anti-inflammatory analgesic, flurbiprofen (FB). Two groups received one or the other of the drugs daily for 7 days, and they were asked about their signs and symptoms before and after the treatment. A positive evaluation of their treatment was made by 74% of the CP group, but by only 48% of the FB group. Although the effects of CP on the limitation of mouth-opening and on joint noise were negligible, about 50% of the CP group answered positively concerning the drug's effect on spontaneous pain or pain induced by chewing or mouth-opening. The positive evaluation for CP (50%) in relieving associated symptoms (headache or shoulder stiffness) was significantly greater than for FB (13%). FB showed effectiveness similar to but sometimes weaker than that of CP on several symptoms. On the basis of these and previous results and the known actions of histamine, we propose that the histamine newly formed following the induction of HDC activity, which is itself mediated by IL-1, may be involved in inducing pain and, possibly, stiffness in muscles in temporomandibular disorders. PMID- 10096454 TI - Smallest detectable difference in outcome variables related to painful restriction of the temporomandibular joint. AB - The smallest detectable difference is the smallest statistically significant change in measurement results. In the field of temporomandibular disorders, the smallest detectable difference is not a commonly used concept. Most outcome studies are based on comparisons of group means, although this does not provide information about individual changes or about the clinical relevance thereof. The smallest detectable difference for maximal mouth opening was calculated from previously published reliability coefficients and the standard deviations of different samples of healthy subjects and patients with complaints of the temporomandibular joint. The smallest detectable difference of pain intensity measured with different visual analogue scales was calculated from the reliability coefficients and standard deviations of a heterogeneous group of pain patients. The smallest detectable difference of function impairment was calculated for a group of patients with complaints of the temporomandibular joint. For maximal mouth opening in healthy subjects, the smallest detectable difference was 5 mm. Repeated measurements improved it to 3 mm. The smallest detectable difference on a visual analogue scale was 28 mm for actual pain intensity and 22 mm for minimal pain as well as for maximal pain intensity. For total function impairment of patients with complaints of the temporomandibular joint, the smallest detectable difference was 8 units on a 0 to 68 scale. PMID- 10096455 TI - Age of onset of dental anxiety. AB - Little attention has been given to the issue of the age of onset of dental anxiety, even though it may have a bearing on the origins of this type of fear. This study aimed to identify the age of onset of dental anxiety and to identify differences by age of onset with respect to potential etiological factors, such as negative dental experiences, family history of dental anxiety, and general psychological states. Data were collected by means of two mail surveys of a random sample of the adult population. Of 1420 subjects returning questionnaires, 16.4% were dentally anxious. Half, 50.9%, reported onset in childhood, 22.0% in adolescence, and 27.1% in adulthood. Logistic regression analyses indicated that negative dental experiences were predictive of dental fear regardless of age of onset. A family history of dental anxiety was predictive of child onset only. Adolescent-onset subjects were characterized by trait anxiety and adult-onset subjects by multiple severe fears and symptoms indicative of psychiatric problems. The three groups were similar in terms of their physiological, cognitive, and behavioral responses to dental treatment. However, adolescent- and adult-onset subjects were more hostile toward and less trusting of dentists. These results indicate that child-onset subjects were more likely to fall into the exogenous etiological category suggested by Weiner and Sheehan (1990), while adult-onset subjects were more likely to fall into the endogenous category. PMID- 10096456 TI - The optimum time to initiate habitual xylitol gum-chewing for obtaining long-term caries prevention. AB - Habitual xylitol gum-chewing may have a long-term preventive effect by reducing the caries risk for several years after the habitual chewing has ended. The goal of this report was (1) to determine if sorbitol and sorbitol/xylitol mixtures provide a long-term benefit, and (2) to determine which teeth benefit most from two-year habitual gum-chewing - those erupting before, during, or after habitual gum-chewing. Children, on average 6 years old, chewed gums sweetened with xylitol, sorbitol, or xylitol/sorbitol mixtures. There was a "no-gum" control group. Five years after the two-year program of habitual gum-chewing ended, 288 children were re-examined. Compared with the no-gum group, sorbitol gums had no significant long-term effect (relative risk [RR], 0.65; 95% confidence interval [c.i.], 0.39 to 1.07; p < 0.18). Xylitol gum and, to a lesser extent, xylitol/sorbitol gum had a long-term preventive effect. During the 5 years after habitual gum-chewing ended, xylitol gums reduced the caries risk 59% (RR, 0.41; 95% c.i., 0.23 to 0.75; p < 0.0034). Xylitol-sorbitol gums reduced the caries risk 44% (RR, 0.56; 95% c.i., 0.36 to 0.89; p < 0.02). The long-term caries risk reduction associated with xylitol strongly depended on when teeth erupted (p < 0.02). Teeth that erupted after 1 year of gum-chewing or after the two-year habitual gum use ended had long-term caries risk reductions of 93% (p < 0.0054) and 88% (p < 0.0004), respectively. Teeth that erupted before the gum-chewing started had no significant long-term prevention (p < 0.30). We concluded that for long-term caries-preventive effects to be maximized, habitual xylitol gum-chewing should be started at least one year before permanent teeth erupt. PMID- 10096457 TI - Contact damage resistance and strength degradation of glass-infiltrated alumina and spinel ceramics. AB - All-ceramic crowns are coming into widespread use because of their superior esthetics and chemical inertness. This study examines the hypothesis that glass infiltrated alumina and spinel core ceramics are resistant to damage accumulation and strength degradation under representative oral contact conditions. Accordingly, Hertzian indentation testing with hard spheres is used to evaluate damage accumulation in alumina and spinel ceramics with different pre-form grain morphologies and porosities. Indentation stress-strain curves measured on fully infiltrated materials reveal a marked insensitivity to the starting pre-form state. The glass phase is shown to play a vital role in providing mechanical rigidity and strength to the ceramic structures. All the infiltrated ceramics show subsurface cone fracture and quasi-plastic deformation above critical loads P(C) (cracking) and P(Y) (yield), depending on sphere radius, with P(Y) < P(C). Strength degradation from accumulation of damage in Hertzian contacts above these critical loads is conspicuously small, suggesting that the infiltrated materials should be highly damage-tolerant to the "blunt" contacts encountered during mastication. Failure in the strength tests originates from either cone cracks ("brittle mode") or yield zones ("quasi-plastic mode"), with the brittle mode more dominant in the spinels and the quasi-plastic mode more dominant in the aluminas. Multi-cycle contacts at lower loads, but still above loads typical of oral function, are found to be innocuous up to 10(5) cycles in air and water, although contacts at 10(6) cycles in water do cause significant strength degradation. By contrast, contacts with Vickers indenters produce substantial strength losses at low loads, suggesting that the mechanical integrity of these materials may be compromised by inadvertent "sharp" contacts. PMID- 10096458 TI - The clinician's view of endometriosis. AB - Clinicians have a number of unmet needs regarding the diagnosis and management of endometriosis. The fulfilment of these would result in better advice for patients. PMID- 10096459 TI - Today's treatments: medical, surgical and in partnership. AB - OBJECTIVE: To provide an overview of the medical, surgical and combined therapy options for endometriosis. RESULTS: Available medical options include danazol, progestogens, gestrinone, oral contraceptive agents, analgesics and gonadotropin releasing hormone (GnRH) agonists. Used in the short-term, most of these agents relieve pain in a large proportion of patients and produce disease regression, however, they do not prevent recurrence, and are associated with side-effects. However, few data confirm any benefit of short-term medical therapy on fertility. One of the most promising medical approaches appears to be GnRH agonists with add back hormone replacement therapy. Surgery may relieve pain, eradicate visible disease and improve fertility. A combined approach may facilitate surgery and relieve pain, although any fertility benefit is as yet unproven. CONCLUSION: Both short-term medical treatment and surgery relieve endometriosis-associated pain and decrease endometriotic implants. However, all approaches have side effects which must be balanced against the benefits when defining suitable treatment for a particular patient. PMID- 10096460 TI - Today's treatments: how do you choose? AB - OBJECTIVE: To provide a view on how the clinician can select appropriate treatment when managing individual patients with endometriosis. METHODS: Review of randomized controlled trials and personal experience. RESULTS: The main determinants of therapy choice are personal experience and patient acceptability. Placebo-controlled trial results support the use of naproxen, dydrogesterone, danazol and leuprolide for pain relief. Laser laparoscopy is more effective than expectant management for pain relief. In direct comparisons, oral contraceptives, Zoladex, danazol, gestrinone, nafarelin and leuprolide have similar efficacies in relieving pain, but have different side-effect profiles. In controlled trials, only laser laparoscopy was shown to improve fertility in minimal/mild disease. The physiological response of bone metabolism to GnRH agonist therapy should be seen in context and the place of add-back regimens understood. The general medical history of the patient must be considered when choosing therapy. CONCLUSIONS: The clinician must provide the patient with appropriate information on the treatment options to allow her to make an informed choice. PMID- 10096461 TI - Questioning the approaches. PMID- 10096462 TI - Extending the treatment boundaries: Zoladex and add-back. AB - OBJECTIVE: To review the evidence that add-back hormone replacement therapy (HRT) can ameliorate the metabolic consequences of gonadotropin-releasing hormone (GnRH) agonist treatment in women with symptomatic endometriosis. METHODS: A review of relevant literature. RESULTS: Early studies suggested that add-back HRT maintained bone mineral density (BMD) without reducing the symptomatic benefit of GnRH treatment. Both high-dose progestogen and low dose progestogen plus cyclical etidronate are effective in maintaining BMD. Standard and low dose HRT add-back may be more effective in relieving the hypo-estrogenic side-effects of GnRH agonist therapy. Randomized controlled studies have shown that both low-dose and standard-dose add-back HRT reduce the side-effects of GnRH agonist therapy, and that this benefit extends to 12 months of treatment. CONCLUSIONS: GnRH agonist treatment with add-back HRT seems to offer the hope of improved treatment for women with endometriosis, but the optimum treatment duration and time to start HRT have yet to be defined. PMID- 10096463 TI - Endometriosis and infertility: an integrated approach. AB - OBJECTIVE: To define an integrated approach to endometriosis-associated infertility. METHODS: Review of published literature with grading of evidence by quality. RESULTS: Laparoscopy remains the investigation of choice in cases of endometriosis-associated infertility and allows the possibility of surgical ablation at diagnosis. This improves fertility in minimal/mild disease, whereas danazol therapy has no benefit. Both in vitro fertilization (IVF) and superovulation with intrauterine insemination improve fertility in mild/minimal disease. Neither surgery nor medical treatment have been shown to improve fertility in moderate/severe disease. IVF with prolonged pituitary down regulation produced by long-acting gonadotropin-releasing hormone agonists after surgical debulking offers the best hope in such cases. CONCLUSIONS: Endometriosis related infertility should be treated as rapidly as possible with thorough investigation and the minimum delay between diagnosis and therapy. PMID- 10096464 TI - Towards the millennium: long-term therapy in gynecology. PMID- 10096465 TI - Proteolysis of neuronal cell adhesion molecule by the tissue plasminogen activator-plasmin system after kainate injection in the mouse hippocampus. AB - Tissue plasminogen activator (tPA) is a serine protease that converts inactive plasminogen to the active protease plasmin and mediates extracellular metabolism. tPA is transcriptionally induced in the mouse hippocampus by pharmacological or electrical stimulation of neuronal activity and mediates excitotoxin-induced neuronal degeneration. Therefore, we hypothesized that tPA would be induced in the hippocampus after kainic acid (KA) injection into the lateral cerebral ventricle (LCV) and that the activated tPA-plasmin system would degrade the neuronal cell adhesion molecule (NCAM), which is a component of the extracellular matrix. In order to investigate this possibility, we first examined whether NCAM is a substrate for the tPA plasmin system by incubating mouse brain homogenates with tPA and plasminogen at 37 degrees C. Next, we examined the degradation of NCAM and the changes of tPA activity in the mouse hippocampus with immunohistochemical procedures and histological zymography after KA injection into both LCVs. As a result, we observed neuronal atrophy and a decrease of NCAM immunoreactivity along with an increase of tPA activity in the CA3 area of the hippocampus. These results suggest that activation of the tPA plasmin system after KA injection into the LCVs results in the degradation of NCAM in the CA3 area. PMID- 10096466 TI - Early establishment of lesion-insensitive mature barrelettes corresponding to upper lip vibrissae in developing mice. AB - Vibrissae are tactile sense organs on the face of non-human mammals, and build up topographical representations in the brainstem trigeminal sensory nucleus called barrelettes. In the present study, we examined postnatal development of barrelettes corresponding to upper lip vibrissae by cytochrome oxidase (CO) histochemistry. At nuclear regions corresponding to upper lip vibrissae, a few segregated barrelettes first appeared at postnatal day 2 (P2), and segregation became clear for most upper lip barrelettes at P4. Compared with major barrelettes corresponding to mystacial vibrissae on the snout, the development of segregated pattern formation for upper lip barrelettes was retarded by 1-2 days. When vibrissa-related patterns were examined 5 days after infraorbital nerve transection, upper lip barrelettes became obscure in all mice lesioned at P1 and P2. Lesion-insensitive upper lip barrelettes first emerged in a few mice lesioned at P3 (33%), and the percentage attained 100% at P6. This temporal transition from lesion-sensitive to lesion-insensitive barrelettes was 3 days ahead of mystacial barrelettes. Therefore, upper lip barrelettes achieve rapid development within a narrow time frame during the first postnatal week. The early and rapid establishment of lesion-insensitive, mature barrelettes can be interpreted as suggesting the importance of oral sensory function in neonatal life. PMID- 10096467 TI - Methyllycaconitine-sensitive neuronal nicotinic receptor-operated slow Ca2+ signal by local application or perfusion of ACh at the mouse neuromuscular junction. AB - Local application of acetylcholine (ACh; 0.3 mM, 20 microl) elicited bi-phasic elevation of intracellular Ca2+ concentrations (contractile fast and non contractile slow Ca2- signal measured as aequorin luminescence) in diaphragm muscle preparation. A neuronal nicotinic antagonist methyllycaconitine (MLA; 0.01 1 microM), which did not affect the fast Ca2+ transients and twitch tension, concentration-dependently depressed only the slow Ca2+ component. Ca2+ channel blockers, Cd2+ (200 microM), nitrendipine (1 microM), verapamil (1 microM) and diltiazem (1 microM), or a Na+ channel blocker tetrodotoxin (TTX; 0.1 microM) failed to prevent the generation of slow Ca2+ response. Perfusion of ACh (1 microM) to isolated single skeletal (flexor digitorum brevis) muscle cells pretreated with TTX (0.1 microM) also elicited a slow Ca2+ signal measured as confocal imaging with a fluorescent dye, fluo-3, at the endplate region. MLA (1 microM) antagonized against the ACh perfusion-elicited slow Ca2+ signal. Perfusion of choline (1 mM), a neuronal nicotinic agonist, also elicited the MLA sensitive slow Ca2+ signal. These results strongly suggest that the ACh-induced slow Ca2+ signal reflects Ca2+ entry through a postsynaptic MLA-sensitive neuronal nicotinic ACh receptor subtype at the neuromuscular junction. PMID- 10096468 TI - The tachykinin NK1 receptor antagonist GR205171 abolishes the retching activity of neurons comprising the central pattern generator for vomiting in dogs. AB - Tachykinin NK1 receptor antagonists are known to act centrally and to have broad spectrum antiemetic effects, but their precise site of action has not yet been defined. To identify this site, the effects of the NK1 receptor antagonist GR205171 on the activities of neurons comprising the central pattern generator (CPG) for vomiting were observed in decerebrate paralyzed dogs. A non-respiratory neuron in each of nine dogs was considered to be a CPG neuron based on its response to abdominal vagal stimulation, its location in the CPG area in the reticular formation dorsomedial to the retrofacial nucleus, its firing patterns in prodromal and retching phases and its response to apomorphine. In response to vagal stimulation at 3-10 Hz, the firing of these neurons transiently increased at the onset of stimulation (fast component), gradually increased again (slow component), and finally developed into rhythmic bursts synchronous with retching bursts of the phrenic and abdominal muscle nerves. GR205171 (25-50 microg/kg, i.v.) abolished the slow component and retching bursts in the neurons, and the retching activities of both nerves, but did not change the fast component. The responses of these neurons to repetitive pulse-train vagal stimulation exhibited a vigorous 'wind-up' and finally developed into retching bursts. Both the 'wind up' phenomenon and retching bursts disappeared after the application of GR205171. These results suggest that the site of the antiemetic action of NK1 receptor antagonists is located in the CPG or in the pathway connecting the solitary nucleus to the CPG. PMID- 10096470 TI - Regulation of the gamma-aminobutyric acid transporter activity by protein phosphatases in synaptic plasma membranes. AB - The influence of the phosphorylation dephosphorylation states on the gamma aminobutyric acid (GABA) transporter activity of synaptic plasma membranes (SPM) was studied by using either specific phosphatase inhibitors or activators. Calyculin A and okadaic acid (phosphatase 1 and phosphatase 2A inhibitors) inhibited the GABA uptake by isolated SPM vesicles, whereas cyclosporin A (phosphatase 2B inhibitor) had a stimulatory effect (approximately 10%) which was higher (approximately 38%) when all these drugs were present in the reaction medium. On the other hand, intravesicular Ca2+, up to about 10 microM, inhibited the GABA uptake (approximately 50%) in a manner which appeared to be facilitated in the presence of PP1 and PP2A inhibitors and this inhibition was relieved by the calmodulin antagonist W-7. We also observed that isolated SPM vesicles contain both Ca(2+)-independent phosphatase activity that is significantly inhibited by PP1 and PP2A inhibitors, and Ca(2+)-dependent phosphatase activity that is abolished in the presence of the PP2B inhibitor, cyclosporin A. These results indicate that regulation of the SPM GABA transporter is determined by the internally localized Ca-calmodulin-dependent phosphatase activity (calcineurin), and that other phosphorylated sites, sensitive to PP1 and PP2A inhibitors, potentiate either the positive or negative effects exerted by those internal sites when they are in their phosphorylated or dephosphorylated states, respectively. PMID- 10096469 TI - Dopaminergic modulation of transcallosal activity of cat motor cortical neurons. AB - The effects of dopamine (DA) and its antagonists on the transcallosal activity of pyramidal tract neurons (PTNs) and non-PTNs in the anesthetized cat motor cortex were studied with iontophoretic applications; dopamine, SCH 23390 (D1 antagonist), sulpiride (D2 antagonist) and haloperidol. Neuronal activity was recorded with a multi-barreled glass microelectrode. Transcallosal neuronal activity was evoked by stimulation of the contralateral motor cortex. The number of spikes thus activated was counted for the control and test conditions after application of each drug: (1) dopamine application decreased the number of spikes evoked by transcallosal stimulation; (2) application of SCH 23390, sulpiride and haloperidol restored these decreased spike numbers to the control level; (3) latency of neuronal response to transcallosal stimulation was not affected by the application of either DA, SCH 23390, sulpiride or haloperidol; and (4) there was no significant difference between PTNs and non-PTNs in the manner of response to DA and its antagonist applications. Our conclusion is that dopamine modulated the transcallosal neuronal response in the cat motor cortex in a suppressive manner. This fact suggested that interhemispheric neuronal communications could be subjected to suppressive modification by the dopaminergic system. PMID- 10096471 TI - Novel non-apoptotic morphological changes in neurons of the mouse hippocampus following transient hypoxic-ischemia. AB - Apoptosis has been recently implicated in the dying process of neurons under several pathological conditions including ischemia. However, although apoptosis was originally defined on the basis of its unique ultrastructural features (Kerr et al., 1972. Br. J. Cancer 26, 239-257; Wyllie et al., 1980. Int. Rev. Cytol. 68, 251-306), unambiguous ultrastructural evidence of apoptosis has been rarely demonstrated in the adult brain. In this study, we examined ultrastructural changes in mouse hippocampal neurons after transient hypoxic-ischemia. A small population of dentate granule cells showed typical apoptotic ultrastructures that could be used as internal morphological standards of apoptosis, whereas most other hippocampal neurons consistently showed a distinct form of cellular disintegration. Nuclei of the latter cells shrank and became TUNEL-positive but were distinguishable from apoptotic nuclei by both the presence of characteristic reticular-formed chromatin condensation and the absence of nuclear fragmentation. Perikarya of degenerating neurons also shrank as in apoptosis, but apoptotic bodies were not observed. Although organelles other than mitochondria disappeared almost completely from the perikarya, neither plasma nor mitochondrial membranes were disrupted, indicating that these changes were also different from typical necrosis. The presence of a novel form of cell death suggests the necessity of morphological re-examination of neuronal death, particularly in mature neurons in vivo. PMID- 10096472 TI - Involvement of the adenosine neuromodulatory system in the benzodiazepine-induced depression of excitatory synaptic transmissions in rat hippocampal neurons in vitro. AB - We investigated whether adenosine neuromodulation is involved in a benzodiazepine (midazolam)-induced depression of excitatory synaptic transmissions in the CA1 and dentate gyrus (DG) regions in rat hippocampal slices. Field excitatory postsynaptic potentials (fEPSPs), evoked by electrical stimulation of the CA1 Schaffer collateral or the DG-perforant path, were recorded with extracellular microelectrodes from CA1-stratum radiatum or DG-stratum moleculare in oxygenated ACSF. The initial slope of the fEPSPs was analyzed for assessing the drug effects. Midazolam (1 microM) transiently depressed CA1- and DG-fEPSPs. The fEPSPs were depressed to approximately 75% of the control values, and then gradually recovered. The depression was not affected by bicuculline, a GABAA receptor antagonist, although it was completely antagonized by aminophylline, an adenosine receptor antagonist. Dipyridamole (5 microM), an adenosine uptake inhibitor, depressed the fEPSPs in a similar manner to midazolam. An adenosine deaminase inhibitor, EHNA, also transiently depressed the fEPSPs, but in a different manner. Exogenous adenosine persistently depressed the fEPSPs. The effects of the drugs were not significantly different in the CA1 and DG regions. The results suggest that midazolam (1 microM) depresses excitatory synaptic transmissions through the adenosine neuromodulatory system by inhibiting adenosine uptake in the CA1 and DG regions of the hippocampus. PMID- 10096473 TI - Latency of cross-axis vestibulo-ocular reflex induced by pursuit training in monkeys. AB - To examine the latency of smooth pursuit induced, short-term modifications of the vestibulo-ocular reflex (VOR), Japanese monkeys were rewarded for tracking a vertically moving target spot synchronized with horizontal whole body rotation. Eye movements induced by equivalent rotation in complete darkness were examined before and after training. Before training, the horizontal trapezoidal rotation (peak acceleration approximately 78%/s2) resulted in a collinear VOR with a mean latency of 15.3 ms, and no orthogonal component in any of the three monkeys tested. After training, the collinear VOR remained unchanged but an orthogonal, cross-axis VOR developed. It had a mean latency of 42.4 ms with gain (eye/chair) of 0.19, followed by a decaying phase that had a mean time constant of 80 ms. These results suggest that the cross-axis VOR induced by pursuit-vestibular interaction is different from previously reported cross-axis VOR induced by optokinetic-vestibular interaction. PMID- 10096474 TI - Calcium phosphate-mediated transfection of primary cultured brain neurons using GFP expression as a marker: application for single neuron electrophysiology. AB - We investigated the efficiency of transfecting primary cultured rat postnatal brain neurons (substantia nigra pars compacta neurons and locus coeruleus neurons) with cDNA encoding GFP (jellyfish green fluorescent protein) using a calcium phosphate method. The proportion of transfected neurons (transfection efficiency) was approximately 5%, when cultures from the substantia nigra pars compacta were transfected 3 days after plating. The transfection efficiency decreased when cultures were transfected 10 days after plating (1.7%). Neurons were cotransfected at a very high probability ( > 78%) with the muscarinic m2 receptor cDNAs together with GFP plasmids. Transfected neurons were very healthy as indicated by the zero-current potential and the microscopical appearance. Because the transfection efficiency is low, this method cannot be used for experiments involving the whole cell population. The transfection efficiency of 1.7% corresponded to approximately 20 transfected cells per dish in our culture conditions and these cells are sufficient in number for electrophysiological studies. Therefore, this is an excellent method for studying the influence of exogenous genes on single neurons using electrophysiological techniques. PMID- 10096475 TI - The Hancock II xenograft: a step forward in bioprosthetic valve longevity? PMID- 10096476 TI - Morphologic findings in explanted Hancock II porcine bioprostheses. AB - BACKGROUND AND AIM OF THE STUDY: Heart valve substitutes have been in use for over 30 years. Bioprosthetic heart valves have many advantages, but unfortunately suffer tissue degeneration and calcification. Many approaches, such as antimineralization treatment to prevent or delay these changes, have been tried. We present the morphologic findings from a series of Hancock II (antimineralization-treated) porcine bioprostheses. METHODS: Forty-five Hancock II porcine valve bioprostheses (16 mitral, 29 aortic) surgically explanted between March 1991 and December 1995 at the Toronto Hospital were analyzed for morphologic findings and causes of failure. The prostheses were implanted in 36 adults (mean age 55+/-14.7 years, range: 27 to 75 years) and had been in place between one month and 11 years (mean 5.1+/-3.3 years). RESULTS: Structural valve deterioration (SVD) characterized by tissue degeneration, calcification, cusp tears and increased stiffness, was the single most significant finding and cause of failure, affecting 56% of valves. Some degree of calcification was seen in 55% of prostheses, with severe calcification (grade 3 or 4) in 18%. Aortic bioprostheses showed more severe and earlier calcification than mitral ones (p = 0.03). Compared with the standard Hancock valve, the low incidence of significant calcification suggests a beneficial protective effect of antimineralization treatment. Severe pannus (grade 3 or 4) was seen in 60% of these prostheses. The pattern of pannus growth differs between mitral and aortic sites; mitral prostheses showed pannus on the flow and non-flow surfaces, often associated with cusp tears, mitral regurgitation and mitral leaflet preservation. A similar degree of pannus on aortic prostheses was invariably present on the flow surface and extended onto the valve cusps, leading to changes in the orifice which may cause clinical aortic stenosis. Infective endocarditis was seen in 15 prostheses (five mitral, 10 aortic) from 11 patients, and comprised the second most important cause of prosthesis failure. The risk of recurrent endocarditis was particularly high in patients who had infective endocarditis before valve replacement, even at five and six years post implantation. CONCLUSIONS: SVD is the major finding in explanted Hancock II bioprostheses and is associated with cusp tears and calcification. The incidence of tissue calcification appears lower at the mitral site. These findings suggest that the antimineralization treatment had some beneficial effect. Pannus associated with prosthesis dysfunction at the mitral sites is a prominent finding and on the non-flow surface may be related to the native mitral valve-conserving procedure. PMID- 10096477 TI - Eighteen-year follow up after Hancock II bioprosthesis insertion. AB - BACKGROUND AND AIM OF THE STUDY: The long-term (18 years) results after aortic (AVR), mitral (MVR) and double (aortic/mitral, DVR) valve replacement with Hancock II bioprosthesis were investigated. METHODS: Between 1978 and 1996, 279 Hancock II bioprostheses were implanted in 269 patients (166 males, 113 females; mean age 61.8+/-13.3 years). There were 135 AVR (48.4%), 122 MVR (43.8%) and 22 DVR (7.8%). Preoperatively, 208 patients (77.3%) were in NYHA functional class III/IV, 53 (19.7%) had previous cardiac surgery, and 19 (7.1%) underwent concomitant coronary artery bypass. Follow up (mean seven years) was 96% complete, with a total of 1,857 patient-years. RESULTS: There were 20 early (7.3%), and 78 (29.0%) late deaths. At the last follow up, 68.3% of patients were in NYHA functional class I/II. The actuarial survival rate of patients at 10 and 18 years after discharge was 67.7+/-5.0% and 44.7+/-8.8% after AVR and 64.5+/ 5.6% and 32.7+/-11.5% after MVR, respectively; survival after DVR was 74.0+/ 11.2% at 12 years. At 10 and 18 years, actuarial freedom from thromboembolism was 83.5+/-4.5% and 73.1+/-10.5% after AVR and 82.1+/-4.3% and 73.2+/-7.3% after MVR; it was 78.4+/-15.0% after DVR at 12 years. At these times, actuarial freedom from hemorrhage was 88.7+/-3.8% and 83.5+/-6.2% after AVR and 79.0+/-4.9% and 32.6+/ 23.3% after MVR; freedom after DVR was 36.2+/-26.6%. Probability of freedom from endocarditis at 10 and >15 years was 93.4+/-3.5% and 85.9+/-7.8% after AVR and 97.0+/-2.1% and 97.0+/-2.1% for MVR, respectively; freedom at 10 years after DVR was 75.0+/-21.6%. Freedom from structural deterioration at 10 and 18 years was 77.9+/-5.3% and 18.7+/-14.6% after AVR and 78.3+/-6.0% and 32.1+/-10.2% after MVR; freedom at 10 and 12 years after DVR was 64.0+/-17.5% and 32.0+/-24.2%. A low incidence of structural valve deterioration was found in AVR patients aged >65 years (p = 0.0478). Hemorrhage and paravalvular leak were more frequent in MVR (p = 0.0296 and 0.0309, respectively). No difference was seen in thromboembolism after anticoagulation for one or three months after AVR. Actuarial freedom from explantation at 10 and 18 years was 73.1+/-5.9% and 15.9+/ 13.5% after AVR and 77.1+/-6.1% and 37.3+/-9.7% after MVR; freedom at 10 and 12 years after DVR was 72.0+/-17.8% and 24.0+/-20.4%. CONCLUSION: Over an 18-year follow up, the Hancock II bioprosthesis has shown satisfactory results, with a low incidence of valve-related complications, especially in elderly patients in the aortic position. PMID- 10096478 TI - Fatigue-induced changes in bioprosthetic heart valve three-dimensional geometry and the relation to tissue damage. AB - BACKGROUND AND AIM OF THE STUDY: In a previous study, we used magnetic resonance (MR) imaging to reconstruct, three-dimensionally, porcine bioprosthetic heart valve (PBHV) cusp geometry. Initial results using three valves indicated that accelerated testing induced changes in cuspal shape, including focal regions of high curvature. Since for thin-walled shell structures, such as the PBHV cusp, curvature changes can affect the stress distribution independently from changes to mechanical properties, shape changes might have adverse effects on PBHV durability. METHODS: The MR technique was applied to an expanded valve database to explore more fully shape change with fatigue. The spatial curvature distribution was compared across valves subjected to a range of accelerated test times. RESULTS: Results confirmed our initial findings that PBHV cusps undergo a continuous, non-recoverable deformation with accelerated testing. This deformation resulted in an increase in the portion of cuspal surface exhibiting high curvature values. In one cusp we mapped structural information obtained by small-angle light scattering back to the three-dimensional cuspal surface using an interpolation technique. Results from the mapped cusp demonstrated a strong spatial correlation between elevated curvatures and structural damage. CONCLUSIONS: The observed changes in cuspal shape accelerate PBHV damage due to an increase in flexural strains induced by an increase in curvature reversal during operation, rather than an increase in tension during closure. PMID- 10096479 TI - Distortion of the stentless porcine valve induces accelerated leaflet fibrosis and calcification in juvenile sheep. AB - BACKGROUND AND AIM OF THE STUDY: Stent mounting of a porcine aortic valve induces loss of mobility and reduces the effective orifice area. Any stentless design conserves the flexibility of the valvular apparatus, but unfortunately, these valves require a more elaborate implantation technique which is considered a major drawback by many surgeons. In an attempt to see if the insertion of the Toronto SPV stentless valve could be made easier, we altered the configuration by lowering the profile at the depth of both coronary sinuses. Theoretically, this could enable insertion of the valve by a single suture layer under the two coronary ostia, in addition to some fixation points at the commissures. METHODS: Two modified 20 mm Toronto SPV valves were tested in vitro for hydrodynamics in a computer-controlled pulse duplicator system and compared with two standard 20 mm valves. Animal implant studies using three standard versus three modified valves (21, 23 and 25 mm) were conducted in juvenile sheep for durability and biocompatibility over a period of three months. RESULTS: The standard Toronto SPV valve provided excellent hemodynamics. The altered configuration performed less optimally during hydrodynamic testing with increased transvalvular gradients. In animal implant studies, cusps adjacent to all reduced-height sinuses showed markedly accelerated fibrosis and substantial calcification, in contrast to only mild fibrosis on the inflow aspects of the standard leaflets. CONCLUSIONS: The more pronounced the deformation of the stentless valve, the faster the calcification of the leaflets adjacent to the distorted sinuses. As both valves types were prepared using an identical preservation technique, the role of loss of mobility in leading to early failure is clearly demonstrated. These findings also underline the extreme importance of correct implantation technique for all stentless valves in order to prevent degeneration. PMID- 10096480 TI - Chordal sparing mitral valve replacement. PMID- 10096481 TI - Mitral valve replacement with complete mitral leaflet retention: operative techniques. AB - BACKGROUND AND AIMS OF THE STUDY: This report describes surgical indication and operative technique of complete preservation of the mitral valvular and subvalvular apparatus during mitral valve replacement. METHODS: Twenty patients, 12 with rheumatic lesions and eight with congenital lesions, were operated between 1991 and 1996. The left atrium was opened using a trans-septal approach through the right atrium in 17 patients, and at the intra-atrial groove in three. The valve was sized without excising any mitral valvular or subvalvular tissue. Teflon pledget-reinforced horizontal mattress valve sutures were passed from the left atrium, through the mitral annulus, around the free edge of mitral leaflet, and up through the prosthetic sewing ring. The prosthetic valve was seated and the sutures tied, reefing the native leaflets and compressing them between the sewing ring and native annulus. Thus, chordal tension on the ventricle was evenly maintained. RESULTS: There was no operative or late death. Postoperative results were excellent. Echocardiography showed that none of the patients had any observable anterior leaflet and redundant subvalvular tissue in the left ventricular outflow tract (LVOT); thus, neither LVOT obstruction nor interference with prosthetic valve function occurred. CONCLUSIONS: Based on these findings, it is suggested that when mitral valve replacement is required in patients with mitral insufficiency (MI) or MI with mild stenosis, the mitral valvular and subvalvular tissue should be completely preserved. PMID- 10096482 TI - Reversal of increased diastolic stiffness in mitral stenosis after successful balloon valvuloplasty. AB - BACKGROUND AND AIM OF THE STUDY: Abnormal passive elastic properties have been reported in patients with severe mitral stenosis and have been attributed to either: (i) chamber atrophy due to unloading; (ii) myocardial fibrosis; (iii) right and left ventricular (LV) interaction; or (iv) internal restrictions due to the rigid mitral valve apparatus. The study aim was to evaluate the effect of percutaneous mitral balloon valvuloplasty (PMV) on passive elastic properties in 19 patients with severe mitral stenosis. Ten patients with normal coronary arteries and LV function served as controls. METHODS: LV high-fidelity pressure measurements and simultaneous biplane LV angiograms were obtained before and after PMV (n = 11). The constant of chamber stiffness (b; ml(-1)) was calculated from the diastolic pressure-volume relationship and the constant of myocardial stiffness (beta) from the diastolic stress-strain relationship. The time constant of relaxation (T; ms) was calculated from the LV pressure decay during isovolumic relaxation. Regional ejection fraction (radial axis system) was determined in six regions of the right anterior oblique (RAO) and left anterior oblique (LAO) angiographic projections. RESULTS: Mitral valve area was increased from 1.0 to 2.2 cm2 after PMV, whereas diastolic pressure gradient was reduced from 14 to 4 mmHg. Global LV ejection fraction (EF) was slightly reduced (57% versus 63%; p<0.05) before valvuloplasty and normalized thereafter. Regional EF increased significantly (p<0.05) in the posterolateral region of the LAO projection after intervention. Myocardial stiffness was increased before, and decreased significantly after balloon valvuloplasty (from 16 to 11; p<0.05). The rate of relaxation and chamber stiffness remained unchanged. CONCLUSIONS: Myocardial stiffness is increased in patients with mitral stenosis, but normalized after successful PMV. The improvement in passive elastic properties after valvuloplasty can be explained by the mobilization of the subvalvular apparatus with an improvement in regional LV function. PMID- 10096483 TI - Tricuspid regurgitation late after mitral valve replacement: clinical and echocardiographic evaluation. AB - BACKGROUND AND AIM OF THE STUDY: Significant tricuspid regurgitation (TR) can contribute to increased morbidity and mortality in patients after mitral valve replacement (MVR), both in the immediate and late postoperative period. The aim of this study was to evaluate the prevalence and the clinical importance of TR late after MVR, as assessed both clinically and echocardiographically. METHODS: The study group comprised 65 patients (39 women, 26 men; mean age 61+/-12 years) with rheumatic heart disease who had undergone MVR without tricuspid valve surgery between one and 30 years (mean 11.3+/-8 years) before their last clinical examination. All patients underwent a complete color-Doppler echocardiographic examination. The predominant presurgical mitral lesion was stenosis in 44 patients and regurgitation in 21. The severity of the tricuspid valve disease was assessed echocardiographically using color-Doppler flow images and flow direction in the inferior vena cava or hepatic veins, and by clinical evaluation. RESULTS: Echocardiography revealed significant late TR in 44 patients (67%), which was moderate in 16 and severe in 28, and evident on physical examination in 24 cases (37%). Age (relative risk (RR) = 1.1; C.I. 1-1.1) and female sex (RR = 1.8; C.I. = 1.0-3.2) were identified as statistically significant predictors for late clinical TR development, but only age was found as a statistically significant predictor for echocardiographic TR development. An elevated RR for organic TR and predominant mitral regurgitation was found. In contrast, pre- and postoperative pulmonary artery pressure, predominant mitral lesion, prosthetic valve gradient and regurgitation were similar in patients with and without late TR. CONCLUSIONS: Significant TR diagnosed by echocardiography late after MVR is common, and clinically evident in more than one-third of patients. Therefore, a lower threshold for tricuspid valve repair should be considered when mitral valve surgery is carried out. PMID- 10096484 TI - Left atrial thrombus detection with multiplane transesophageal echocardiography: an echocardiographic study with surgical verification. AB - BACKGROUND AND AIM OF THE STUDY: The detection of left atrial thrombus (LAT) is especially important in patients being evaluated for percutaneous mitral valvuloplasty and elective cardioversion for atrial fibrillation. Transesophageal echocardiography (TEE) is widely used for this indication. This study was undertaken to validate the use of multiplane TEE to detect LAT in the setting of rheumatic mitral valve disease. METHODS: The study population comprised 262 patients (103 men, 159 women, mean age 42.2+/-13.1 years) who underwent open heart surgery for rheumatic mitral valvular disease between January 1994 and October 1997. Of these patients, 178 had mitral stenosis and 84 mitral regurgitation. All patients were examined with multiplane TEE less than three days before valvular surgery. RESULTS: The presence or absence of LAT was confirmed at surgery by direct inspection of the left atrium. Left atrial thrombi were detected by TEE in 34 patients (14 men, 20 women; mean age 51+/-8 years). The presence of all 34 thrombi found by multiplane TEE was confirmed during surgery. Only one thrombus was confirmed surgically among 228 patients shown thrombus-negative by multiplane TEE. The sensitivity, specificity, positive and negative predictive value and diagnostic accuracy for multiplane TEE were 97, 100, 100, 99.6 and 99.6%, respectively. CONCLUSION: Multiplane TEE is exquisitely sensitive for the detection of LAT. PMID- 10096485 TI - Isolated congenital anterior mitral leaflet cleft: a rare cause of mitral insufficiency. AB - BACKGROUND AND AIM OF THE STUDY: Isolated cleft of the anterior mitral leaflet is a rare cause of mitral insufficiency. Although an established entity, due to its rarity the exact anatomic diagnosis is difficult to establish unless sought specifically. METHODS: Four patients (age range: 16 to 26 years) with isolated cleft of the anterior mitral leaflet were treated at the authors' institute. Clinical symptoms were typical of mitral insufficiency; the exact anatomic diagnosis was not established preoperatively in any patient. The cleft was directly sutured in all four patients and additional annuloplasty was performed in three. RESULTS: Postoperative echocardiography confirmed satisfactory results. After a mean follow up of 46.7 months (range: 3 to 84 months), one patient had mild mitral insufficiency and the remaining patients had no mitral regurgitation. CONCLUSION: In severe mitral insufficiency with no obvious mitral valve pathology and an intact atrial septum, a cleft of the anterior mitral leaflet should be sought. Repair of the cleft can restore normal mitral valve function. PMID- 10096486 TI - Mitral valve homograft for mitral valve replacement in acute bacterial endocarditis. AB - Homograft use for aortic valve replacement (AVR) in aortic valve acute bacterial endocarditis (ABE) has gained in popularity, due mainly to the relative resistance of homografts to infection. Recent success with mitral valve homograft use led us to apply homograft mitral valve replacement (MVR) in a patient with severe ABE that was not amenable to valve repair. Following surgery, the patient improved rapidly with normalization of infection parameters and chest radiography, and was discharged home on postoperative day 11. Follow up echocardiography showed good function of the homograft mitral valve with no regurgitation. After four months, the patient had normal valve function, with no evidence of infection. In conclusion, MVR with a mitral valve homograft in the setting of ABE was satisfactory, though patient follow up was relatively short (four months). PMID- 10096487 TI - Mechanical valve replacement in congenital heart disease in children. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to analyze predictive factors of long-term results after mechanical heart valve replacement in children. METHODS: Forty-four patients (19 males, 25 females; mean age 8.9+/-3.9 years, median 7.0 years, range: 1.3 to 15 years) underwent heart valve replacement with mechanical prostheses. Of these patients, 25 had left atrioventricular valve replacement (LavVR) (18 mitral, six tricuspid in corrected transposition of the great arteries (TGA), one common in a univentricular heart), 13 had aortic valve replacement (AVR) and six had tricuspid valve replacement (TVR). The etiology of the valvular disease was congenital in all patients, and complicated by infective endocarditis in seven (16%). Fifteen patients had undergone previous procedures and 16 required simultaneous repair of associated lesions. The mean size of the implanted prosthesis was 26 mm (range: 19-29 mm) for LavVR, 29.7 mm (range: 23-33 mm) for TVR, and 21.9 mm (range: 19-25 mm) for AVR. Postoperatively, all patients received oral anticoagulation. The mean follow up was 6.8+/-3.5 years (total 290 patient-years). RESULTS: There was no early mortality, but three patients (7%) died later; all late deaths occurred in patients with LavVR. There were two sudden deaths, both in patients with complex congenital heart disease and heart failure (before the ACE inhibitor era), and one valve-related death from thrombotic occlusion of a mitral prosthesis. Five patients were reoperated on; three for patient-prosthesis mismatch, one for periprosthetic leak, and one for aortic dissection due to Marfan's syndrome. Thrombotic obstruction occurred in three patients; two in the tricuspid position were treated successfully with thrombolysis, but one in the left atrioventricular position proved fatal. After seven years, the survival rate was 93.4%. CONCLUSIONS: Mechanical heart valve replacement in children aged over one year with congenital heart disease can be performed with satisfactory early and late results. Mechanical valves of >23 mm diameter in the atrioventricular position in the systemic ventricle, and >21 mm in the aortic orifice, can offer excellent long-lasting hemodynamic performance. However, mechanical valves in the tricuspid position are prone to develop thrombotic occlusion. PMID- 10096488 TI - Early results with the Carbo-seal composite valve conduit for aortic root replacement. AB - BACKGROUND AND AIMS OF THE STUDY: Composite graft replacement of the aortic root is still a complex operation, transgraft hemorrhage being one of the most severe complications. The aim of the study was to evaluate early results with the Carbo seal composite conduit for aortic root replacement. METHODS: A retrospective review of 21 patients operated on for ascending aortic aneurysm and/or dissection with the open technique between August 1993 and February 1998 is presented; 12 patients had Marfan syndrome and nine were non-Marfan. RESULTS: There were two operative deaths (9.5%) due to low cardiac output. Two patients were re-explored for bleeding which was not due to transgraft hemorrhage. Postoperative complications were one hemothorax, one pneumothorax and two pericardial effusions. During the follow up, one patient died of rupture of a descending aortic aneurysm, and one patient in atrial fibrillation had a transient ischemic attack. At the closing of the follow up, the remaining patients were well and free of complications. CONCLUSIONS: Carbo-seal may be considered a reliable device for use in aortic root replacement, though a longer follow up and a larger patient population are necessary to confirm these positive early results. PMID- 10096489 TI - A new flow model for Doppler ultrasound study of prosthetic heart valves. AB - BACKGROUND AND AIM OF THE STUDY: Steady and pulsatile flow models used to assess the hydrodynamic aspects of prosthetic heart valves are generally made of Plexiglas and Lucite tubing. They often allow continuous-wave and pulsed-wave Doppler ultrasound velocity measurements to be made parallel to the flow, but cannot be used as such for ultrasound scanning of valve inflow and outflow velocities because of ultrasonic reverberation and refraction by the tubing. The aim of the study was to develop a new flow model which allowed ultrasonic scanning of the prosthetic valve flow for three-dimensional (3D) reconstruction of color Doppler flow distributions. METHODS: The flow model, designed with left ventricular and aortic chambers composed of agar gel which mimics the ultrasound characteristics of biological tissues, was developed and tested for comparative in vitro hydrodynamic and Doppler ultrasonic studies of aortic prosthetic valves. An electromagnetic flowmeter and a pressure monitor provided the flow and pressure signals for the hydrodynamic tests. The Doppler ultrasonic evaluation was performed with an Ultramark 9 HDI ultrasound system and a 3D ultrasound imaging system. The model was designed to enable assessment of prosthetic valve performance by pulsed-wave and continuous-wave Doppler velocity measurements, as well as by 3D color Doppler velocity measurements obtained by ultrasonic scanning of the left ventricle or aortic chamber with an ultrasound probe mounted on a motorized translation assembly. RESULTS: The study results showed that this new flow model can provide 3D color Doppler velocity distributions as well as accurate comparisons of hydrodynamic parameters of mechanical and bioprosthetic heart valves derived from Doppler and catheter measurements, both under steady and pulsatile flow conditions. CONCLUSION: This new flow model can be used to evaluate the usefulness of hydrodynamic parameters for the assessment of prosthetic heart valves using both conventional Doppler echocardiography, as currently used in patients, and 3D color Doppler ultrasonic imaging. PMID- 10096490 TI - High-resolution assessment of velocity fields and shear stresses distal to prosthetic heart valves using high-field magnetic resonance imaging. AB - BACKGROUND AND AIM OF THE STUDY: Complications after replacement of diseased heart valves with mechanical prostheses have been shown to be related to the hemodynamics distal to the valve. For this reason, the velocity patterns have been disclosed in vitro with a variety of different techniques. This study introduces a magnetic resonance imaging (MRI) -based technique, which entails easy acquisition of fluid velocity field data with a high accuracy and spatial resolution. METHODS: A high-field magnetic resonance scanner equipped with short echo time phase-contrast velocity measurement software was applied in a detailed mapping of the axial velocity profile across the entire vessel area at two positions downstream of a bileaflet valve prosthesis inserted in a pulsatile flow system in vitro. The laminar shear forces were calculated from the fluid velocity field data. RESULTS: The velocity profiles very close to the valve reflected the bileaflet design as also shown in previous studies, but the extent and velocities of the jet emanating from the slit between the leaflets were clearly better visualized. However, one diameter downstream of the valve the central jet was completely dispersed and the hemodynamic complexity was significantly reduced. Recirculation and retrograde flow regions that might be relevant for understanding typical long-term complications after implantation were observed close to the valve. CONCLUSIONS: In one scan experiment the presented method provides information on flow characteristics that previously required application of different types of experiment. Thus, the method seems promising as a new technique for detailed and extensive mapping of the velocities and laminar shear stresses downstream of prosthetic heart valves in vitro. PMID- 10096491 TI - Clinical usefulness of the proximal isovelocity surface area method using echocardiography in patients with eccentric aortic regurgitation. AB - BACKGROUND AND AIM OF THE STUDY: The Doppler color flow mapping techniques of the distal jet are influenced by the eccentricity of aortic regurgitation (AR). The aim of this study was to clarify screening variables for assessing AR severity in patients with an eccentric jet. METHODS: Fifty-four patients with eccentric AR were studied. Values of the radius and effective regurgitant orifice area (EROA) determined by the proximal isovelocity surface area (PISA) method using transthoracic echocardiography (TTE) were compared with measurements by multiplane transesophageal echocardiography (m-TEE), aortic angiography and regurgitant fraction. RESULTS: In patients with eccentric AR, values of PISA radius and EROA by TTE correlated well with values made by m-TEE (r = 0.87, p<0.001 and r = 0.86, p<0.001, respectively), angiographic grade (rs = 0.87, p<0.001 and rs = 0.88, p<0.001, respectively) and regurgitant fraction (r = 0.88, p<0.001 and r = 0.84, p<0.001, respectively). Values of PISA radius > or =0.70 cm and EROA > or =0.25 cm2 were always associated with a regurgitant fraction > or =0.40, while PISA radius <0.70 cm and EROA <0.25 cm2 were always associated with a regurgitant fraction <0.40. CONCLUSIONS: Measurements determined by the PISA method, using either TTE or m-TEE, are reliable for assessing the severity of eccentric AR. PISA radius is easy to obtain and therefore widely applicable in clinical practice as a screening tool for evaluating eccentric AR severity. PMID- 10096492 TI - Double valve repair and maze procedure for degenerative valvular disease and chronic atrial fibrillation. AB - A 61-year-old male with degenerative aortic valve regurgitation, mitral valve regurgitation and chronic atrial fibrillation underwent a combined reparative procedure consisting of aortic valve repair, mitral valve repair and maze procedure. Surgery was successful and postoperatively the patient is in NYHA class I, without anticoagulation. To the best of our knowledge, this is the first clinical report of this combined reparative surgery. As advances are made in valve repair surgery, it is expected that similar combined procedures will be performed more frequently in future. The benefits of avoiding valve replacement and anticoagulation after such combination treatment is discussed. PMID- 10096493 TI - Moraxella catarrhalis endocarditis: report of a case and literature review. AB - A 53-year-old man developed severe acute systemic illness three weeks after an upper respiratory tract infection. Serial blood cultures grew Moraxella catarrhalis. During antibiotic treatment, fever and infectious parameters disappeared, but severe aortic regurgitation developed. Aortic valve replacement was performed, during which extensive destruction of the aortic valve was noted. Endocarditis due to M. catarrhalis is very rare with, to our knowledge, only six cases having been reported to date. M. catarrhalis is a normal commensal of the upper respiratory tract, but in unpredictable circumstances can become an important pathogen. Bacteremia due to this organism therefore requires prompt treatment, as serious organ complications, including endocarditis, can occur. PMID- 10096494 TI - Synthesis and biological evaluation of Tc-99m cyclopentadienyltricarbonyltechnetium-labeled octreotide. AB - Octreotide was labeled at its N-terminus with Tc-99m cyclopentadienyltricarbonyltechnetium, and the biodistribution of the labeled conjugate was studied in adult female Sprague-Dawley rats. The synthesis began with the preparation of Tc-99m-(methoxycarbonylcyclopentadienyl) tricarbonyltechnetium from Tc-99m-pertechnetate using a novel double ligand transfer reaction; it was completed in a total of five steps, with an 8% overall radiochemical yield (15% decay-corrected). The 99mTc cyclopentadienyltricarbonyltechnetium-labeled octreotide conjugate (99mTc-CpTT octreotide) showed receptor-mediated uptake in the pancreas and adrenals, which was blocked (80% and 93%, respectively) by excess unlabeled octreotide. These studies illustrate a new method for labeling a peptide with Tc-99m through an organometallic linkage that is stable, nonpolar, and low molecular weight; it complements labeling approaches that utilize inorganic metal complexes. PMID- 10096495 TI - Iodo-QNB cortical binding and brain perfusion: effects of a cholinergic basal forebrain lesion in the rat. AB - This study deals with the question of whether in vivo application of [125I]iodo quinuclidinyl-benzilate (QNB) is able to demonstrate changes in cortical muscarinic receptor density induced by a cholinergic immunolesion of the rat basal forebrain cholinergic system, and whether the potential effects on IQNB distribution in vivo are also associated with effects on regional cerebral perfusion. Immunolesioned and control animals were injected with (R,S) [125]iodo QNB and with [99mTc]-d,l-hexamethylpropyleneamine oxime (HMPAO). The cerebral distribution of both tracers was imaged using double tracer autoradiography. Impaired cholinergic transmission was paralleled by a 10-15% increase of [125I]iodo-QNB binding in the regions of cortex and hippocampus. The local cerebral blood flow remained unchanged after cholinergic lesion. PMID- 10096496 TI - A novel 111In-labeled antisense DNA probe with multi-chelating sites (MCS-probe) showing high specific radioactivity and labeling efficiency. AB - A multi-aminolinked oligodeoxynucleotide (ODN) was synthesized by substitution of dT with aminolinked dU in the sequence, following conjugation with isothiocyanobenzyl-EDTA (IBE) for 111In labeling. As a model target gene, the c erbB-2 protooncogene was used. The probability of the number of aminolinked dU in the 20mer ODN was 5, but there were actually 3 and 4 in the selected antisense and sense ODNs, respectively. The IBE/ODN conjugation levels of probes with multi chelating sites (MCS-probe) were 1.6 (antisense) and 2.4 (sense), more than 50 times higher than those of our previous studies using 5'-end aminolinked ODNs (IBE/ODN = 0.03). Labeling studies using the MCS-probe and 111In indicated that specific radioactivity as high as 48 MBq/nmol could be obtained with a labeling efficiency of over 90%. The 111In-antisense-MCS-probe could bound to sense ODN under physiological conditions, but the 111In-sense-MCA-probe could not. Thus, side-chain modification of ODN for metal labeling is considered to be useful for antisense techniques. PMID- 10096497 TI - Receptor-mediated targeting of 67Ga-deferoxamine-folate to folate-receptor positive human KB tumor xenografts. AB - The radiochemical synthesis and stability of 67Ga-deferoxamine-folate ([67Ga]Ga DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations > or =2.5 microg/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [67Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor positive KB tumors were found to concentrate the 67Ga radiolabel in a dose dependent fashion, consistent with saturable involvement of the folate receptor in mediating tumor accumulation of the radiopharmaceutical. PMID- 10096498 TI - Charge-modified single chain antibody constructs of monoclonal antibody CC49: generation, characterization, pharmacokinetics, and biodistribution analysis. AB - A novel strategy was developed in which an antibody scFv fragment of the monoclonal antibody (MAb) CC49 was modified by engineering DNA coding sequences to lower its isoelectric point. Negatively charged amino acids were added to the carboxy terminus of the CC49 VH region by adding nucleotide sequences in a polymerase chain reaction (PCR) amplification of the coding sequence of CC49 scFv. Two new DNA constructs coding for CC49 scFv with lower isoelectric points of 5.8 and 5.2 were engineered. These novel strategy-generated, charge-modified antibody constructs were compared for their immunological, pharmacokinetic, and biodistribution properties in athymic mice bearing LS-174T human colon carcinoma xenografts. PMID- 10096499 TI - Measurement of P-glycoprotein expression in human neuroblastoma xenografts using in vitro quantitative autoradiography. AB - P-glycoprotein (P-gp) has a role in multidrug resistance (MDR) encountered in human cancers. In this study, we used the colchicine-resistant cell line BE(2) C/CHCb(0.2), a strain of neuroblastoma cell line BE(2)-C, as a model to measure variations of P-gp expression in cells grown in vitro and in vivo. Cells were cultured in the medium supplemented with colchicine. At the beginning of the study the drug was withdrawn and, after 22 days, added back to the culture medium. Cells were harvested at various time points and xenografted in nude mice. P-gp content in cells was measured by self-competitive binding assay and in tumors, by quantitative autoradiography (QAR). Both assays were carried out using 125I-labeled monoclonal antibody MRK16, reactive with P-gp. Concentration of P-gp in cells varied from a maximum of 1,361 pmol/g in the presence of colchicine to a minimum of 374 pmol/g in the absence of colchicine in the culture medium. P-gp concentration in the tumors ranged from 929 to 188 pmol/g, which correlated with P-gp content in the cells at the time of their injection in the mice. QAR is an accurate and reliable method to quantify P-gp expression in tumors. Changes in colchicine concentration in the ambient medium of BE(2)-C/CHCb(0.2) cells growing in vitro resulted in a change in phenotype of P-gp expression, which was stable under conditions of in vivo growth over approximately 9 cell divisions in nude mice xenografts. Therefore, P-gp content in xenografts depends only on the level of resistance of the cells at the time of their injection in the mice. PMID- 10096500 TI - Evaluation of 99mTc-mercaptoacetyltriglycine-biocytin as a new hepatobiliary imaging agent in mice coinjected with bilirubin. AB - We evaluated 99mTc-labeled mercaptoacetyltriglycine (99mTc-MAG3)-biocytin as a hepatobiliary imaging agent in the absence and presence of bilirubin in mice. We then compared its pharmacokinetic parameters; peak liver/heart activity ratio (rmax) and half clearance time (HCT) with those of 99mTc-labeled diisopropyl iminodiacetic acid (99mTc-disofenin). Balb/c mice were injected intravenously with hepatobiliary agent (99mTc-MAG3-biocytin or 99mTc-disofenin) alone or in combination with bilirubin at two doses (7 and 14 mg/kg) dissolved in 5% human serum albumin. Images were acquired every 15 s for 30 min with a gamma-camera equipped with a pinhole collimator. Dynamic images showed rapid hepatic uptake of 99mTc-MAG3-biocytin, with rapid clearance from the blood and rapid excretion via the biliary system. Its hepatic uptake was not affected by bilirubin coinjection, whereas 99mTc-disofenin coinjected with bilirubin showed a higher blood background than 99mTc-disofenin alone. These qualitative findings were reflected in pharmacokinetic parameters, rmax and HCT. The rmax was obtained from plots of time versus liver/heart activity ratios obtained in equal-area regions of interest over the heart and liver. The HCT was calculated from the hepatic clearance curve from plots of time versus liver activity. 99mTc-MAG3-biocytin without bilirubin coinjection showed an rmax of 8.9+/-1.3 and an HCT of 399+/-36 s. These values did not change even when 14 mg/kg of bilirubin were coinjected. By contrast, the parameters for 99mTc-disofenin with bilirubin were significantly (p < 0.01) affected by 14 mg/kg of bilirubin coinjection: rmax was decreased from 7.9+/-2.5 to 1.4+/-0.2 and HCT was increased from 292+/-32 s to 782+/-133 s. 99mTc-MAG3-biocytin hepatobiliary scintigraphy in mice is not affected by bilirubin coinjection, and this hepatobiliary agent appears to offer promise for estimating hepatic function in patients with high bilirubin levels. PMID- 10096501 TI - In vitro studies on the cellular uptake of melanoma imaging aminoalkyl iodobenzamide derivatives (ABA). AB - The cellular uptake of 11 radioiodinated aminoalkyl-iodobenzamides (ABA) was studied using cultivated murine melanoma cells (B16/C3). All derivatives showed a high uptake (up to about 80%) of radioactivity in melanotic melanoma cells; hence, accumulation of all compounds radioiodinated in the ortho position was reduced by approximately 30%. Using the compound para-[131I]iododiethyl aminoethylbenzamide (p-131I-ABA-2-2) a close correlation of the cellular melanin content with the tracer uptake (R2 = 0.95) was verified. The presence of extracellular melanin, however, had no effect on the cellular tracer uptake. Because the accumulation was independent of the specific activity of p-131I-ABA-2 2, a significant contribution to the uptake process by binding to receptor sites could be excluded. PMID- 10096502 TI - Preparation, biodistribution, and dosimetry of 188Re-labeled MoAb ior cea1 and its F(ab')2 fragments by avidin-biotin strategy. AB - The biotinylated monoclonal antibody (MoAb) ior cea1 and its F(ab')2 fragments were labeled with Re-188 by combination of avidin-biotin strategy. 188Re-MoAb, 188Re-MoAb-biotin, 188Re-F(ab')2, and 188Re-F(ab')2-biotin preparations were produced for these studies with specific activities of 1.30+/-0.18 GBq/mg and from instant freeze-dried kit formulations using ethane-1-hydroxy-1,1 diphosphonic acid (EHDP) as a weak competing ligand. There were no significant differences (p > 0.05) between the biodistribution in mice of biotinylated and unbiotinylated 188Re-labeled immunoconjugates. When avidin was injected as a chase after injection of 188Re-MoAb-biotin or 188Re-F(ab')2-biotin, the blood radioactivity level decreased approximately 75% (cumulated activity) and the effective dose decreased almost 25% with respect to that of the radioimmunoconjugates in which the chase effect was not used. Our results suggest that 188Re-labeled biotinylated MoAb ior ceal and its F(ab')2 fragments prepared by this method are stable complexes in vivo. PMID- 10096504 TI - Technetium-99m complexes of polydentate amine-pyrrole and amine-thiophene ligands. AB - Novel polydentate amine-pyrrole and amine-thiophene ligands were synthesized and characterized by 1H and 13C NMR spectroscopy. Radiochemical studies with 99mTc were carried out at 0.1-100 microM of technetium. Complexation yields were estimated from thin layer chromatography (TLC), paper electrophoresis, and solvent extraction studies. The 99mTc complexes formed were found to be neutral and lipophilic. Complexes with the corresponding imine-ligands were formed in lower yields. Biodistribution studies of the 99mTc complexes of these ligands showed no significant uptake in brain or heart, and the clearance was mainly through the hepatobiliary system. PMID- 10096503 TI - Design and synthesis of a redox-active Tc-99m radiopharmaceutical with ferrocenedithiocarboxylate [FcCS = Fe(C5H4CS2)(C5H5)-]. AB - The synthesis, at tracer level, of two Tc-99m complexes having the same chemical composition and structure, but differing by one electron in the total electron counting, is reported. These compounds have been prepared by reacting [99mTcO4]- with the piperidinium salt of the ligand ferrocenedithiocarboxylate {[Fe(II)(C5H4CS2)(C5H5)]- = FcCS}, in the presence of N-methyl S methyldithiocarbazate as donor of N3-groups, and triphenylphosphine or SnCl2 as reducing agents. The formation of the neutral complex [99mTc(N)(FcCS)2] (compound A) and of the monocationic, mixed-valence complex [99mTc(N)(FcCS) (FcCS)]+ (compound B) {FcCS = [Fe(III)(C5H4CS2)(C5H5)]} was obtained in high yield. Both complexes comprise a terminal Tc triple bond N multiple bond and two FcCS ligands coordinated to the metal center through the two sulfur atoms of the -CS2 group, but they differ in the oxidation state of one of the two iron atoms of the coordinated FcCS ligands. In complex A, the two Fe atoms are both in the +2 oxidation state, while in B, one Fe atom is in the +2 and the other is in the +3 oxidation state. Thus, B is a mixed-valence Fe(II)-Fe(III) complex. B is easily converted into A by one-electron exchange with various reductants such as triphenylphosphine and excess SnCl2. Biodistribution studies in rats showed that complexes A and B are mostly retained in lungs and liver without any significant uptake in organs such as heart and brain. PMID- 10096505 TI - Synthesis, characterization, and biodistribution of oxo complexes of technetium 99m with biguanide and N1-substituted ligands. AB - We report the synthesis, characterization, and biodistribution of 99mTc-complexes with the bidentate-N,N chelate biguanide (Big) and the N1-substituted ligands dimethyl (DMBig), phenyl (PBig), and phenethyl (PEBig). Dynamic gamma-camera studies with 99mTc-Big and 99mTc-DMSA in rabbits indicated distinct renal and urinary excretion profiles. 99mTc-Big was cleared more quickly than 99mTc-DMSA, and for the same acquisition times, the contrast in whole-body images favored 99mTc-Big. Also, the estimated radiation absorbed doses by kidneys and blood for 99mTc-DMSA were significantly higher than for 99mTc-Big. These preliminary studies show that 99mTc-Big has favourable practical and dosimetric features for renal imaging as an alternative to 99mTc-DMSA. PMID- 10096506 TI - Prediction of 99mTc-biguanide complex structures and their interactions with biological molecules by molecular mechanics calculations. AB - The structures of some Tc-biguanide complexes are predicted by molecular mechanics calculations. In addition, simulations of molecular interactions between the predicted equilibrium structures with water molecules or peptide chains are correlated with experimental data of partition coefficients and percentage of human protein binding, evaluated for the analogous 99mTc-biguanide complexes. These results suggest the value of computer-assisted design of new Tc radiopharmaceuticals, and in particularly, stress the great interest of using molecular modelling to predict molecular properties that can be successfully correlated with results obtained by in vitro studies. PMID- 10096507 TI - Effects of dopamine on the in vivo binding of dopamine D2 receptor radioligands in rat striatum. AB - The effects of moderate changes in extracellular dopamine concentrations on the in vivo binding of specific dopaminergic D2 radioligands with different affinities and kinetics were investigated in rats. Either [125I]NCQ298 (Kd = 19 pM), or [25I]iodolisuride (Kd = 0.27 nM) or [3H]raclopride (Kd = 1.5 nM) were administered intravenously (IV) to animals 1 h after the intraperitoneal (IP) injection of either alpha-methyl-p-tyrosine (AMPT) (250 mg/kg) or nomifensine (15 mg/kg), or saline. The kinetics of radioactivity concentration in the striatum, cerebellum, and plasma were measured for up to 4 h after [125I]NCQ298 or [125I]iodolisuride injection and up to 1.5 h after [3H]raclopride injection. For each tracer, the striatum-to-cerebellum radioactivity concentration ratios (S/C) and the binding potential (BP), calculated as the association to dissociation binding rate constant ratios (k3/k4), were assessed and related to the changes in extracellular dopamine concentration induced by drug treatments. Results show that S/C and BP of [3H]raclopride were significantly diminished by pretreatment with nomifensine, a drug that increases extracellular dopamine concentration. Nomifensine pretreatment induced no changes in the in vivo binding indexes of the high affinity [125I]NCQ298 and a slight but not significant decrease of the binding indexes of 125I]iodolisuride. Treatment with AMPT, which induced a 40% reduction in dopamine concentration, did not change [125I]NCQ298 binding indexes but slightly increased those of [3H]raclopride and [125I]iodolisuride. In conclusion, the change of dopamine concentration induces modification of radiotracer kinetics. Thus, the combined use of tracers with high and low affinities could allow us to obtain information both on receptor density and neurotransmitter release in vivo. However, as indicated by the [3H]raclopride study with AMPT, small changes in the concentration of intrasynaptic dopamine cannot be easily detected. PMID- 10096508 TI - Synthesis and evaluation of 6-[11C]methoxy-3-[2-[1-(phenylmethyl)-4 piperidinyl]ethyl]-1,2- benzisoxazole as an in vivo radioligand for acetylcholinesterase. AB - 6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole is a high affinity (K(i) = 8.2 nM) reversible inhibitor of acetylcholinesterase (AChE). The carbon-11 labeled form was prepared in high (>97%) radiochemical purity and with specific activities of 37+/-20 GBq/micromol at end of synthesis, by the alkylation of the desmethyl precursor with [11C]methyl trifluoromethanesulfonate in N,N-dimethyl-formamide at room temperature. In vivo studies in mice demonstrated good blood brain permeability but essentially uniform regional brain distribution. Thus, despite in vitro and in vivo activity as an AChE inhibitor, 6 [11C]methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzis oxa zole does not appear to be a good candidate for in vivo imaging studies of AChE in the mammalian brain. PMID- 10096509 TI - Preliminary evaluation of 2-[4-[3-tert-butylamino)-2-hydroxypropoxy]phenyl]-3 methyl-6-me thoxy-4(3H)-quinazolinone ([+/-]HX-CH 44) as a selective beta1 adrenoceptor ligand for PET. AB - (+/-)-3-[11C]Methyl-2-[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-6 -methoxy 4(3H) quinazolinone ([+/-]-[11C]HX-CH 44) was labeled with carbon-11 using [11C]iodomethane with the corresponding N-demethylated precursor. Then, 30-90 mCi (1.10-3.33 GBq) of pure [11C]HX-CH 44 were obtained 30 min after end of bombardment with specific radioactivities of 500-1,400 mCi/micromol (18.5-51.8 GBq/micromol). Myocardial uptake in dogs was 0.340+/-0.043 pmol/mL tissue per nanomole injected, 10-15 min postinjection. Heart-to-lung ratio was 3 from the 5th to the 30th minute. Only 35% of the myocardial radioactivity could be displaced. Tissue uptake could not be blocked with appropriate compounds. Therefore, (+/-)-[11C]HX-CH 44 does not appear to be a suitable ligand for the study of myocardial beta1-adrenoceptors in positron emission tomography. PMID- 10096510 TI - N-(6-18F-fluorohexyl)-N-methylpropargylamine: a fluorine-18-labeled monoamine oxidase B inhibitor for potential use in PET studies. AB - We have synthesized N-(6-18F-fluorohexyl)-N-methylpropargylamine (18F-FHMP) as a positron emission tomography (PET) radiotracer for monoamine oxidase B (MAO-B). The radiosynthesis was carried out by a fluorine-for-bromine substitution in 30 40% radiochemical yield in specific activities of 1-2 Ci/micromol. Selectivity for MAO-B was demonstrated by the high affinity of (R)-deprenyl (IC50 = 6.8 nM) and lower affinity of clorgyline (IC50 = 1.2 microM) for the inhibition of 18F FHMP binding in vitro in rat brain homogenates. In vitro autoradiographic studies in rat brain slices showed localization of 18F-FHMP in regions such as the ependyma of the lateral ventricle, dorsal raphe, area postrema, and other regions such as the cerebellum. The specific binding observed in the autoradiograms was displaced by preincubation with (R)-deprenyl. In in vivo experiments, the uptake of 18F-FHMP in the rat brains was high (0.10-0.20% injected dose/g). The binding of 18F-FHMP in the rat brain correlated with the general distribution of MAO-B and was displaced completely by preadministration of 10 microM (R)-deprenyl. These results suggest that 18F-FHMP is a potential PET radiotracer for MAO-B for use in in vitro and in vivo experiments. PMID- 10096511 TI - Comparative studies of Cu-64-ATSM and C-11-acetate in an acute myocardial infarction model: ex vivo imaging of hypoxia in rats. AB - Copper labeled diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a promising agent for the imaging of hypoxic tissues. In the present study 64Cu(t1/2 = 12.8 h) labeled Cu-ATSM was used in combination with 11C (t1/2 = 20.3 min) labeled acetate as a regional perfusion marker to visualize hypoxic rat heart tissue in an acute left anterior descending (LAD) coronary artery occluded rat model using an ex vivo tissue slice imaging technique. 64Cu-ATSM was injected intravenously c.a. 10 min after occlusion and rats were sacrificed by cervical dislocation 10 min after injection. Carbon-11-acetate was injected 1 min before sacrifice to obtain a measure of blood flow. The heart was dissected, frozen, and cut into 1 mm thick slices with a gauged slicer, and 11C images were obtained with an electronic autoradiography instrument. After decay of 11C, 64Cu images were obtained in the same manner. In ischemic regions, where there was low 11C accumulation, 64Cu showed high accumulation when compared with normal regions. In rats with a large occlusion, the center of the ischemia did not show any accumulation of either 11C or 64Cu, indicating no blood supply. Cu-ATSM appears to be useful for the detection of hypoxia with contrast being observed at short times (10 min) postinjection. PMID- 10096512 TI - Comparative breast tumor imaging and comparative in vitro metabolism of 16alpha [18F]fluoroestradiol-17beta and 16beta-[18F]fluoromoxestrol in isolated hepatocytes. AB - 16beta-[18F]Fluoromoxestrol ([18]betaFMOX) is an analog of 16alpha [18F]fluoroestradiol-17beta ([18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [18F]betaFMOX was predicted to be as effective an imaging agent as [18F]FES. However, in a preliminary PET imaging study with [18F]FMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [18F]betaFMOX was observed. In search for an explanation for the unsuccessful [18F]betaFMOX clinical trial, we have examined the rate of metabolism of [18F]FMOX and [18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone binding globulin (SHBG), which binds [18F]FES better than [18F]betaFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [18F]FES 31 times faster than [18F]betaFMOX, whereas mature rat cells metabolized [18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [18F]betaFMOX. In the presence of SHBG, the metabolic consumption rate for [18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [18F]betaFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [18F]betaFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging. PMID- 10096513 TI - Synthesis, biological evaluation, and baboon PET imaging of the potential adrenal imaging agent cholesteryl-p-[18F]fluorobenzoate. AB - Cholesteryl-p-[18F]fluorobenzoate ([18F]CFB) was investigated as a potential adrenal positron emission tomography (PET) imaging agent for the diagnostic imaging of adrenal disorders. We describe the synthesis, biodistribution, adrenal autoradiography, and baboon PET imaging of [18F]CFB. The synthesis of [18F]CFB was facilitated by the use of a specially designed microwave cavity that was instrumental in effecting 70-83% incorporation of fluorine-18 in 60 s via [18F]fluoro-for-nitro exchange. Tissue distribution studies in mature female Sprague-Dawley rats showed good accumulation of [18F]CFB in the steroid-secreting tissues, adrenals and ovaries, at 1 h postinjection. The effectiveness of [18F]CFB to accumulate in diseased adrenals was shown through biodistribution studies in hypolipidemic rats, which showed a greater than threefold increase in adrenal uptake at 1 h and increased adrenal/liver and adrenal/kidney ratios. Analysis of the metabolites at 1 h in the blood, adrenals, spleen, and ovaries of hypolipidemic and control rats showed the intact tracer representing greater than 86%, 93%, 92%, and 82% of the accumulated activity, respectively. [18F]CFB was confirmed to selectively accumulate in the adrenal cortex versus the adrenal medulla by autoradiography. Normal baboon PET imaging with [18F]CFB effectively showed adrenal localization as early as 15 min after injection of the tracer, with enhanced adrenal contrast seen at 60-70 min. These results suggest that [18F]CFB may be useful as an adrenal PET imaging agent for assessing adrenal disorders. PMID- 10096514 TI - Comparative studies of epibatidine derivatives [18F]NFEP and [18F]N-methyl-NFEP: kinetics, nicotine effect, and toxicity. AB - We have previously shown that [18F]norchlorofluoroepibatidine ([18F]NFEP) would be an ideal radiotracer for positron emission tomography (PET) imaging of nicotinic acetylcholine receptors (nAChR); however, its high toxicity is a limiting factor for human studies. We, therefore, synthesized its N-methyl derivative ([18F]N-Me-NFEP) and carried out comparative studies. The distribution volumes for different brain regions were higher for [18F]N-Me-NFEP than those for [18F]NFEP (average: 52.5+/-0.9 vs. 36.4+/-0.7 for thalamus), though the distribution volume (DV) ratios were similar (3.93+/-0.27 vs. 3.65+/-0.19 for thalamus to cerebellum). Treatment with nicotine reduced the binding of both radiotracers. Toxicology studies in awake rats showed that N-methyl-NFEP has a lower mortality (0 vs. 30%) and smaller effect on plasma catecholamines than NFEP at a dose of 1.5 microg/kg. However, marked alterations in cardiorespiratory parameters were observed after injection of N-methyl-NFEP (0.5 microg/kg, IV) to an awake dog. Our results suggest that although the binding characteristics of [18F]NFEP and [18F]N-Me-NFEP appear to be ideally suited for PET imaging studies of the human brain, their relatively small safety margin will limit their use in humans. PMID- 10096515 TI - Treatment of lung tumor colonies with 90Y targeted to blood vessels: comparison with the alpha-particle emitter 213Bi. AB - An in vivo lung tumor model system for radioimmunotherapy of lung metastases was used to test the relative effectiveness of the vascular- targeted beta-particle emitter 90Y, and alpha-particle emitter, 213Bi. Yttrium-90 was shown to be stably bound by CHXa" DTPA-MAb 201B conjugates and delivered efficiently to lung tumor blood vessels. Dosimetry calculations indicated that the lung received 16.2 Gy/MBq from treatment with 90Y MAb 201B, which was a sevenfold greater absorbed dose than any other organ examined. Therapy was optimal for 90Y with 3 MBq injected. Bismuth-213 MAb 201B also delivered a similar absorbed dose (15Gy/MBq) to the lung. Yttrium-90 was found to be slightly more effective against larger tumors than 213Bi, consistent with the larger range of 2 MeV beta particles from 90Y than the 8 MeV alpha particles from 213Bi. Treatment of EMT-6 tumors growing in immunodeficient SCID mice with 90Y or 213Bi MAb 201 resulted in significant destruction of tumor colonies; however, 90Y MAb 201B was toxic for the SCID mice, inflicting acute lung damage. In another tumor model, IC-12 rat tracheal carcinoma growing in SCID mouse lungs, 90Y therapy was more effective than 213Bi at destroying lung tumors. However, 90Y MAb 201B toxicity for the lung limited any therapeutic effect. We conclude that, although vascular-targeted 90Y MAb can be an effective therapeutic agent, particularly for larger tumors, in this model system, acute damage to the lung may limit its application. PMID- 10096516 TI - Improved survival in patients with insulin-dependent diabetes mellitus and end stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. AB - BACKGROUND: The purpose of pancreatic transplantation in insulin-dependent diabetic patients is to restore normoglycemia and thereby prevent the secondary complications of diabetes. However, uncertainty remains as to whether the mortality rate in diabetic patients can be affected by this procedure. METHOD: We followed 14 patients with insulin-dependent diabetes mellitus (IDDM) and end stage diabetic nephropathy for 10 years after successful combined kidney and pancreas transplantation. Fifteen diabetic patients subjected to kidney transplantation alone have served as controls. The glycemic control has been studied annually for 10 years and diabetic polyneuropathy has been assessed in both groups after 2, 4, and 8 years. RESULTS: In recipients of pancreas-kidney grafts, metabolic control was maintained throughout the observation period, with values of glycated hemoglobin in the normal range. In contrast, glucose metabolism was impaired in the control group, with glycated hemoglobin values around 10%. Nerve conduction and parasympathetic autonomic dysfunction improved in both groups after 2 years; there was no difference between the groups. After 4 years, we found a significant difference between the study group and the control group, and after 8 years it had widened. At the 4-year evaluation, there was no difference in mortality between the groups. At 8 years, however, a significant difference was noted, which was further substantiated at 10 years with a 20% mortality rate in the pancreas-kidney group versus an 80% mortality in the kidney alone group. CONCLUSIONS: We found a substantial reduction in mortality in IDDM patients 10 years after successful combined pancreas and kidney transplantation. We speculate that the decrease in mortality was due to the beneficial effect of long-term normoglycemia on diabetic late complications and suggest therefore that combined pancreas and kidney transplantation, rather than kidney transplantation alone, should be offered to IDDM patients with end-stage diabetic nephropathy. PMID- 10096517 TI - Hydrocortisone activation of human herpesvirus 8 viral DNA replication and gene expression in vitro. AB - BACKGROUND: Patients undergoing chronic steroid therapy for organ transplantation are at increased risk for development of human herpes virus 8(HHV-8)-associated Kaposi's sarcoma (KS). It has also been reported that following steroid withdrawal, KS lesions often undergo partial or complete regression. METHODS: We have examined the effect of corticosteroid treatment on HHV-8 replication, gene expression, and lytic protein expression in BCBL-1 cells in vitro. BCBL-1 cells were collected after culture for 24-72 hr with hydrocortisone (HC) 1-5 microM, phorbol ester 20 ng/ml (positive control), and culture medium only (negative control). HHV-8 genomic conformation was examined by Gardella gel analysis. mRNA expression of viral cyclin (v-Cyc), viral Bcl-2 (v-Bcl-2), viral macrophage inflammatory protein-I (v-MIP-I), viral interferon regulatory factor-1(v-IRF-1), and viral tegument protein (TP) was examined by RT-PCR Southern blot. Viral protein expression within the cells was examined by indirect immunofluorescence using 5 different HHV-8 positive antisera from 4 renal transplant recipients and 1 patient with classic KS. RESULTS: Gardella gel analysis revealed that HC induced an accumulation of the linear replicative genomic form of the virus in a time-dependent fashion. Southern blot analysis of the RT-PCR products revealed that HC induced increased expression of v-IRF-1, v-Bcl-2, and TP mRNA, with little discernible effect on v-Cyc, and v-MIP-I. Immunofluorescence revealed that HC induced increased numbers of cells expressing lytic antigens. CONCLUSIONS: These data indicate that hydrocortisone acts directly on BCBL-1 cells to activate the lytic cycle of HHV-8 and provide further support for the hypothesis that HHV 8 is activated in corticosteroid-treated immunocompromised patients. PMID- 10096518 TI - Injection of mitomycin-C-treated spleen cells induces donor-specific unresponsiveness to cardiac allografts in rats. AB - BACKGROUND: In this study, preoperative mitomycin-C- (MMC) treated donor-specific transfusion (DST) was examined for its ability to induce unresponsiveness to cardiac allografts in rats. METHODS: DA (RT1a) rats were used as donors, BUF (RT1b) or WS (RT1k) rats as recipients, and Lew (RT1l) rats as third party donors. BUF or WS rats were given i.v. injection of DA spleen cells (SPCs) suspension (5x10(7)/l ml) with or without MMC treatment 10 days before cardiac transplantation. Delayed-type hypersensitivity and complement-dependent cytotoxicity assays were carried out in these animals separately to examine in vivo immunosuppressive effect. Suppressor assay was also examined to determine in vitro immunosuppressive effects in allogeneic mixed leukocyte culture. RESULTS: In the full allogeneic DA-to-BUF rat strain combination, preoperative i.v. administration of MMC-treated donor SPCs led to a significant prolongation of graft survival over the control (110+/-66 versus 7.2+/-0.8 days: P<0.01), although administration of nontreated donor SPCs did not (9.3+/-1.0 days). This beneficial effect of MMC treatment was also seen in the DA-to-WS rat combination (31+/-16 days versus donor-specific transfusion alone; 11+/-1.5 days or untreated control; 12+/-1.5 days; P<0.05). However, injection of third party DA SPCs in the Lew-to-BUF combination induced no significant prolongation of cardiac allograft survival compared with the untreated control (11+/-0.6 versus 11+/-2.0 days; NS), indicating that this prolongation effect was induced in an antigen-specific manner. The immunosuppressive effect was also secured for both delayed-type hypersensitivity response and anti-donor cytotoxic antibody production. Moreover, addition of MMC-treated SPCs to mixed lymphocyte culture led to antigen-specific suppression. CONCLUSIONS: Preoperative i.v. injection of MMC-treated donor SPCs is promising for inducing unresponsiveness in rat cardiac allograft model. PMID- 10096519 TI - Serum cytotoxicity to pig cells and anti-alphaGal antibody level and specificity in humans and baboons. AB - BACKGROUND: Removal and/or "neutralization" of anti-Gal alpha1-3Gal (alphaGal) antibodies can prevent or delay the hyperacute rejection of pig organs transplanted into primates. AIM: To determine variations in (1) cytotoxicity to pig kidney (PK15) cells, (2) anti-alphaGal antibody level, and (3) specificity in adult human (n=46) and baboon (n=38) sera. METHODS: Cytotoxicity to PK15 cells was determined by adding rabbit complement to heat-inactivated serum, using a two color fluorescent dye to distinguish live and dead cells. Anti-alphaGal antibody level was determined by ELISA using alphaGal trisaccharide type 2-BSA glycoconjugate as antigen target. Specificity determined by ELISA using four different alphaGal-BSA glycoconjugates: (disaccharide, trisaccharides type 2 and 6, and pentasaccharide). RESULTS: Cytotoxicity of human AB sera varied from 30 100% PK15 relative cell damage (%RCD), although that of baboon sera of all blood groups varied from 35-100% RCD. In human AB sera, anti-alphaGal antibody level (at a dilution of 1:80) varied from undetectable to 0.75 (OD at 405 nm), although in baboon sera of all blood groups, anti-alphaGal antibody level varied from undetectable to >2.0. There was no correlation between anti-alphaGal antibody level and serum cytotoxicity in either species. Specificity varied among individuals in both human and baboon sera. CONCLUSIONS: These studies have demonstrated (1) considerable variation in cytotoxicity and anti-alphaGal antibody level in human and baboon sera, but a lack of correlation between these two parameters; (2) considerable variation in the specificity of anti-alphaGal antibodies; (3) blood group B human and baboon sera have lower levels of anti alphaGal antibodies; (4) no relation between blood group and specificity of anti alphaGal antibodies. Although there are minor differences in the parameters measured, baboons would appear to be suitable surrogates for humans in the pig-to primate xenograft model. PMID- 10096520 TI - Reversal of hyperglycemia in mice after subcutaneous transplantation of macroencapsulated islets. AB - BACKGROUND: Macroencapsulated islets can reverse hyperglycemia in diabetic animals when transplanted i.p. or into the fat pad. The s.c. space is an attractive site for such transplantation because macrocapsules can be implanted with local anesthesia and be easily removed or reloaded with fresh islets. METHODS: Immunoprotective 20 microl ported devices were transplanted under the skin of Streptozocin-diabetic nude mice. Devices were loaded with 1200 rat islets in culture medium or in alginate. Empty devices were implanted for 2 weeks and then loaded with islets. Normal mice and mice with islets transplanted under the renal capsule or under the skin were used as controls. Seven weeks after transplantation, an intraperitoneal glucose tolerance test (IPGTT) was performed, followed by implant removal. RESULTS: Three weeks after transplantation, normal blood glucose levels were observed in all animals. Compared with those of normal controls, IPGTTs showed accelerated blood glucose clearance in mice transplanted with islets either within devices or beneath the kidney capsule. Fasted transplanted mice were hypoglycemic before glucose injection and 2 hr later. After removal of the implants, all recipient mice returned to hyperglycemia. Histological evaluation revealed viable islet cells and a network of close vascular structures outside the devices. CONCLUSIONS: Macroencapsulated islets transplanted into the s.c. space were able to survive and regulate blood glucose levels in mice. The observed differences in glucose metabolism between normal and transplanted mice may be attributed to the site of transplantation and to the use of rat islets, which have a different set point for glucose induced insulin release. PMID- 10096521 TI - Temporal sequence of transcription of perforin, Fas ligand, and tumor necrosis factor-alpha genes in rejecting skin allografts. AB - BACKGROUND: Perforin, Fas ligand (FasL), and tumor necrosis factor-alpha (TNF alpha) have been implicated in cytolytic T lymphocyte (CTL) effector function. However, the relative roles of these effector molecules in allograft rejection are unclear, and there has been no rigorous quantitation of transcription of the respective genes throughout the period from transplantation to rejection. METHODS: We orthotopically transplanted mouse tail skin allografts and estimated the numbers of transcripts of these genes expressed by graft-infiltrating T cells with rigorous quantitative, competitive reverse transcribed PCR (QC-RT-PCR) that enabled the comparison of transcription of different genes. RESULTS: Perforin and FasL mRNA levels correlated closely with the rejection of allografts by normal hosts over the 4 days preceding rejection. Antibody-mediated depletion of host CD4+ T cells retarded perforin transcription and significantly suppressed FasL transcription, suggesting FasL was not required for allograft rejection. TNF alpha transcription was the highest of these genes in this time period, but these levels were dwarfed by TNF-alpha transcription at 24 hr posttransplant when transcription in both autografts and allografts was 30-fold higher than in allografts on the day before rejection. Elimination of the function of these single or paired genes through genetic mutation or antibody treatment had no significant effect on the speed of rejection. CONCLUSIONS: The levels of perforin and FasL transcription appeared to be related to the process of allograft rejection in normal hosts. However, TNF-alpha transcription was highest during the posttransplant period suggesting that the principal role of TNF-alpha is in wound-healing rather than the effector phase of rejection. PMID- 10096522 TI - Acute bleeding after allogeneic bone marrow transplantation: association with graft versus host disease and effect on survival. AB - BACKGROUND: Hemorrhagic complications are frequently implicated clinically for the high morbidity and mortality of acute graft versus host disease (GVHD), however, only few reports characterize the incidence and timing of bleeding in relation to GVHD, and essentially no study has quantified the effect of bleeding on survival of allogeneic patients with GVHD. This study examines the association of bleeding with acute GVHD and the effect of both complications on survival. METHODS: A total of 463 allogeneic patients transplanted at the Johns Hopkins Hospital, were included in the study. Bleeding evaluation was based on daily scores of intensity and blood transfusions. All bleeding sites were recorded. GVHD staging was defined by the extent of rash, serum bilirubin, diarrhea, and confirmatory histology. RESULTS: The incidence of GVHD was 27.4%, bleeding occurred in 40.2%. The incidence of bleeding was higher in patients with GVHD as compared with non-GVHD, and correlated with GVHD severity. The higher bleeding incidence in GVHD was due to gastrointestinal hemorrhage, hemorrhagic cystitis, and pulmonary hemorrhage. While the majority of bleeding (51/75) in non-GVHD patients initiated within 30 days after bone marrow transplantation (BMT), only 32.3% (21/65) of the bleeding in the GVHD group initiated within 30 days, and the risk for bleeding continued until day 100. Bleeding was a late event compared to GVHD, however, most bleeding episodes were associated with active GVHD. Both GVHD and bleeding were individually associated with reduced survival, with profound additive adverse effect: median survival in 221 nonbleeding non-GVHD was >83.2 months, GVHD nonbleeding (39 patients) had median of 10.6 months, bleeding non GVHD (99 patients) had median of 4.3 months, and median survival of the GVHD bleeding group (85 patients) was 3.2 months. CONCLUSIONS: Our results support an association of bleeding with acute GVHD, suggesting that GVHD is a risk factor for bleeding after BMT. The occurrence of bleeding clearly identified poor outcome subgroup within GVHD, suggesting further evaluation for clinical application of bleeding in the assessment of GVHD severity. PMID- 10096523 TI - Pathologic classification of chronic allograft nephropathy: pathogenic and prognostic implications. AB - BACKGROUND: After transplantation renal allografts frequently develop interstitial fibrosis and tubular atrophy, and these pathologic changes are the hallmarks of chronic allograft nephropathy (CN). However, the diagnosis of CN has no specific pathogenic implications. In this study we sought to determined whether a subclassification of CN according to vascular pathology correlates with posttransplant events, particularly acute rejection, and graft survival. METHODS: A total of 419 patients with moderate to severe CN were subdivided into: (1) transplant arteriopathy (TA, n=233, 56%); (2) arteriolar hyalinosis (AH, n=89, 21%); and (3) no characteristic vascular pathology (IFb, n=97, 23%). RESULTS: Patients with AH differed significantly from patients with TA or IFb in the following parameters: (1) AH was diagnosed later after transplantation (P=0.001); (2) fewer patients with AH had acute rejection (AR) before the diagnosis of CN (P<0.0001). For example, 44% of AH and 75% of TA had AR before CN; (3) patients with AH also had fewer AR episodes than the other two groups (P<0.0001); finally, (4) graft survival was better in patients with AH than in patients with TA (P=0.01 by chi2, P=0.001 by Cox). In contrast, there were no significant differences between patients with TA and IFb. By multivariate analysis the survival of grafts with CN correlated with: (1) serum creatinine at diagnosis (P<0.0001), (2) recipient's weight (P=0.004); (3) presence of FGS or level of proteinuria (P=0.03); and (4) the occurrence of AR after the diagnosis of CN (P<0.0001). Regarding the latter, AR were more common (P=0.007) and more numerous (P=0.005) in patients with TA or IFb than in AH. CONCLUSIONS: CN can be classified according to vascular pathology in the majority of cases, and this classification correlates with graft survival. Although some forms of CN are closely associated with the occurrence of AR others are not. This study also uncovered several variables that correlate with the survival of grafts with CN. PMID- 10096524 TI - Impact of transfusions and acute rejection on posttransplantation donor antigen specific responses in two study populations. Cooperative Clinical Trial in Transplantation Research Group. AB - BACKGROUND: We participated in a protocol supported by the National Institutes of Allergy and Infectious Disease, Cooperative Clinical Trial in Transplantation (CCTT), which was designed to investigate the effect of peritransplant donor specific transfusion in non-HLA-identical living donor kidney recipients. METHODS: We determined the donor antigen-specific responses at 1 year after transplantation for the 79 CCTT donor-recipient combinations in this study. A lower rate of donor antigen-specific hyporeactivity was seen in the CCTT recipients (6 of 79=8%) versus our recipients at the University of Minnesota who underwent transplantation in the same period (9 of 55=16%, P=0.16) and versus our combined historical data (33 of 131=25%, P=0.002). Therefore, we studied the differences in the two recipient populations to determine why hyporeactivity was lower in the CCTT group than at our center. RESULTS: Significant differences were seen in the acute rejection rates and the frequency of pretransplantation random transfusion. Overall and early (<3 month) acute rejection rates were higher in CCTT versus Minnesota recipients (overall: 51% vs. 20%, P=0.001) (early: 43% vs. 16%, P=0.001). The frequency of pretransplantation random transfusion was 40% for CCTT recipients (34%) versus 80% for Minnesota recipients (75%) (P=0.0004). CONCLUSIONS: These results provide provocative, although not conclusive, evidence for the importance of pretransplantation transfusion and acute rejection episodes in the development of donor antigen-specific hyporeactivity. Pre-, peri-, and posttransplantation clinical events undoubtedly have an impact on posttransplantation immune parameters. PMID- 10096525 TI - Thrombocytopenia after liver transplantation. AB - BACKGROUND: Thrombocytopenia after orthotopic liver transplantation (OLT) is a well recognized and prevalent early postoperative complication. The etiology, as well as the effect of this phenomenon on transplant outcome, however, are vague. The aims of this study are to identify factors contributing to thrombocytopenia and to ascertain whether there is any correlation with early rejection and ultimate survival. METHODS: This study examines 541 OLTs (541 grafts in 494 patients) that were transplanted at the University of Miami during the 3-year period from June 1994 to September 1997. The patients with severe postoperative thrombocytopenia (nadir platelet count [PLT] < 20,000/mm3), as well as the whole group of patients, were analyzed. The preoperative PLT, intra-operative platelet transfusion requirements, cross-match, recipient and donor cytomegalovirus (CMV) status, infusion of donor bone marrow cells (DBMC), occurrence of early rejection episodes (in the first posttransplant month), and re-transplantation were factors examined for any association with thrombocytopenia. Total bilirubin (TB) and direct bilirubin (dB), hematocrit, white blood cell count (WBC), aspartate aminotransferase and alanine aminotransferase, determined on the day that platelets reached a nadir (nadir day), were also analyzed. RESULTS: In 90.9% of the cases, there was a 56.5%+/-23.5% fall in platelets in the immediate posttransplant period (first 2 weeks), but the mean PLT exceeded preoperative levels during the 3rd and 4th postoperative weeks. The nadir of the drop in the PLT most commonly occurred on posttransplant day 4. For preoperative PLT, platelet transfusions during the operation, re-transplantation, early rejection, cross-match, and recipient CMV status, there was significant statistical correlation with any degree of postoperative thrombocytopenia. Four of these factors, preoperative PLT, intra-operative platelet transfusions, re transplantation, and early rejection, were found to be independently associated with thrombocytopenia in general. None of them was found to be independently correlated with severe thrombocytopenia. A statistically significant correlation between bilirubin and WBC on the nadir day and the degree of thrombocytopenia was observed. No correlation was found between infusion of DBMC or donor CMV serology and thrombocytopenia. Both the nadir PLT and the percentage of the platelet fall were independent predictive factors (p<0.01 and 0.005, respectively) of patient and graft survival. CONCLUSIONS: Thrombocytopenia in the immediate posttransplant period is correlated with low preoperative PLT, massive platelet transfusions, and re-transplantation. These factors reflect a poor preoperative condition. There is also a correlation with allograft dysfunction, rejection, and poorer patient and graft survival. A rise in the mean PLT after the 2nd postoperative week reflects proper graft function. PMID- 10096526 TI - Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients. AB - BACKGROUND: Mycophenolate mofetil (MMF) has been shown to have promise in short term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression. METHODS: Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4-year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity. RESULTS: Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)]. CONCLUSIONS: MMF seems to be an effective alternative immunosuppressive in patients failing CsA based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives. PMID- 10096527 TI - Long-term outcome of living related liver transplantation for patients with intrapulmonary shunting and strategy for complications. AB - BACKGROUND: In 320 living related liver transplantation performed between June 1990 and September 1997, there were 21 living related liver transplantation for patients with intrapulmonary shunting, manifested by digital clubbing, cyanosis, and dyspnea. We report the long-term outcome for more 6 months and our strategy to overcome complications in these recipients. PATIENTS: A total of 21 patients (age range 2-33 years, 19 children and 2 adults, 6 males and 15 females) were classified into three grades according to shunt ratio calculated by TcMAA pulmonary scintigraphy; 5 in mild group (shunt ratio: less than 20%), 6 in moderated group (20%-40%), and 10 in severe group (more than 40%). The original underlying liver disease was biliary atresia in all patients. RESULTS: Spearmen's correlation coefficient rank test revealed that shunt ratio correlated significantly with PaO2 in room air (P=0.0001), PaO2 in 100% oxygen (P=0.0004), hematocrit (P=0.0276), and period of dyspnea before transplantation (P=0.023). COMPLICATIONS: Wound infection occurred in 80, 66, and 80%, and bile leakage in 20, 0, 40% in mild, moderate, and severe group, respectively. Patients who had portal vein thrombosis, and intracranial complication were classified as severe group and the incidence was 20 and 20%, respectively. The patient actuarial one year survival was 80, 66.7, and 48%, in mild, moderate, and severe group, respectively, although there was no significant difference. All patients who survived improved hepatopulmonary syndrome and the length of period required for the resolution was significantly correlated to the preoperative shunt ratio (P=0.023). COMMENTS: Patients with severe shunting are susceptible to wound infection and bile leak. The trend of higher incidence of portal thrombosis and intracranial complications in the severe group was closely related high hematocrit. Secure surgical technique to reduce bile leak and delayed primary wound closure to reduce wound infection were found to be effective. Anticoagulant therapy by infusing heparin through the portal vein followed by coumadin could prevent fatal portal vein thrombosis without counter risk of fatal cerebral hemorrhage. PMID- 10096528 TI - Long-term follow-up of living kidney donors: quality of life after donation. AB - The University of Minnesota has been a strong advocate of living donor kidney transplants. The benefits for living donor recipients have been well documented. The relative low risk of physical complications during donation has also been well documented. Less well understood is the psychosocial risk to donors. Most published reports have indicated an improved sense of well-being and a boost in self-esteem for living kidney donors. However, there have been some reports of depression and disrupted family relationships after donation, even suicide after a recipient's death. To determine the quality of life of our donors, we sent a questionnaire to 979 who had donated a kidney between August 1, 1984, and December 31, 1996. Of the 60% who responded, the vast majority had an excellent quality of life. As a group, they scored higher than the national norm on the SF 36, a standardized quality of life health questionnaire. However, 4% were dissatisfied and regretted the decision to donate. Further, 4% found the experience extremely stressful and 8% very stressful. We used multivariate analysis to identify risk factors for this poor psychosocial outcome and found that relatives other than first degree (odds ratio=3.5, P=0.06) and donors whose recipient died within 1 year of transplant (odds ratio=3.3, P=0.014) were more likely to say they would not donate again if it were possible. Further, donors who had perioperative complications (odds ratio=3.5, P=0.007) and female donors (odds ratio=1.8, P=0.1) were more likely to find the overall experience more stressful. Overall, the results of this study are overwhelmingly positive and have encouraged us to continue living donor kidney transplants. PMID- 10096529 TI - A comparison of recipient renal outcomes with laparoscopic versus open live donor nephrectomy. AB - BACKGROUND: Laparoscopic donor nephrectomy (laparoNx) has the potential to increase living kidney donation rates by reducing the pain and suffering of the donor. However, renal function outcomes of a large series of recipients of laparoNx have not been studied. METHODS: We retrospectively reviewed the records of 132 recipients of laparoNx done at our center between 3/96 and 11/97 and compared them to 99 recipients of kidneys procured by the open technique (openNx) done between 10/93 and 3/96. RESULTS: Significantly more patients in the laparoNx group (25.2%) were taking tacrolimus within the first month than those in the openNx group (2.1%). Mean serum creatinine was higher in laparoNx compared with openNx at 1 week (2.8+/-0.3 and 1.8+/-0.2 mg/dl, respectively; P=0.005) and at 1 month (2.0+/-0.1 and 1.6+/-0.1 mg/dl, P=0.05) after transplant. However, by 3 and 6 months, the mean serum creatinine was similar in the two groups (1.7+/-0.1 versus 1.5+/-0.05 mg/dl, and 1.7+/-0.1 versus 1.7+/-0.1, respectively). By 1 year posttransplant, the mean serum creatinine for laparoNx was actually less than that for openNx (1.4+/-0.1 and 1.7+/-0.1 mg/dl, P=0.03). Although patients in the laparoNx compared to the openNx group were more likely to have delayed graft function (7.6 versus 2.0%) and ureteral complications (4.5 versus 1.0%), the rate of other complications, as well as hospital length of stay, patient and graft survival rates were similar in the two groups. CONCLUSION: Although laparoNx allografts have slower initial function compared with openNx, there was no significant difference in longer term renal function. PMID- 10096530 TI - A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. AB - BACKGROUND: T-cell activation through T-cell receptor engagement requires co stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lastingl year and performed in 10 transplant centers in Europe. METHODS: A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists. RESULTS: There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%). CONCLUSION: Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF. PMID- 10096531 TI - The clinical usefulness of the renal allograft biopsy in the cyclosporine era: a prospective study. AB - BACKGROUND: The renal allograft biopsy is generally accepted as the gold standard for clarifying the cause of renal dysfunction. However, the clinical usefulness of this procedure has rarely been studied prospectively, nor have most studies included follow-up of patients to delineate the influence of the biopsy on clinical outcome. In this study, we evaluated prospectively the clinical usefulness of the allograft biopsy in renal transplant recipients receiving cyclosporine (CyA). METHODS: During a 21-month period, 82 biopsies were performed. In 54 instances (47 patients), we outlined a presumed diagnosis and tentative treatment plan before the procedure. After the biopsy, a definitive diagnosis was made and an appropriate patient management approach was instituted. We analyzed the incidence of change in patient management that resulted from histological findings. All patients were followed to monitor their response to treatment and allograft survival. In cases of biopsy-proven acute cellular rejection (ACR) or cyclosporine (CyA) toxicity, clinical and laboratory data from the day of the biopsy were reviewed to determine their diagnostic value. RESULTS: One biopsy specimen was inadequate for definitive interpretation. The biopsy findings resulted in a change in patient management in 22 (41.5%) of the remaining 53 cases (change group). The incidence of altered patient management was 38.7% in biopsy specimens taken in the first month, 55.6% between 1 and 12 months, and 38.5% after 1 year posttransplantation. A change in management was required in 2 of 2 patients with chronic allograft dysfunction, in 44.4% of the 45 patients with acute allograft dysfunction, and in none of the patients with delayed graft function (n=6). Within the first week of treatment 19 of 22 (86.4%) in the change group and 25 of 31 (80.6%) in the no change group had a positive response to therapy. The 1-year allograft survival rate was also similar between the two groups. None of the clinical and laboratory data was useful in distinguishing ACR from CyA toxicity. CONCLUSIONS: Renal allograft biopsy findings alter patient management recommendations in approximately 40% of patients in whom a presumptive diagnosis had been made on the basis of clinical and laboratory findings. Patients who had a change in patient management because of biopsy findings demonstrated a response to therapy and allograft survival similar to those of patients who had no alteration in management plan after the biopsy. PMID- 10096532 TI - CD2 and CD3 receptor-mediated tolerance: constraints on T cell activation. AB - BACKGROUND: Antigen specific allograft tolerance is induced in mice by anti-CD2 plus anti-CD3epsilon monoclonal antibody (mAb) treatment. Because anti-CD2 mAb inhibits several aspects of anti-CD3epsilon driven T cell activation, we investigated what components of T cell activation are required or may be dispensed with for tolerance induction. Anti-CD3epsilon-mediated T cell activation depends on FcgammaR interactions. METHODS: To assess the role of FcgammaR-mediated T cell activation in tolerance induction, FcgammaR binding IgG or non-binding IgG3 anti-CD3epsilon mAbs were examined. RESULTS: These mAbs, administered in conjunction with anti-CD2, were equally effective in inducing tolerance. Moreover, in vivo administration of a blocking mAb directed against the FcgammaR, or the use of allograft recipients deficient in FcgammaR, had no effect on tolerance induction. Blocking IL-2 using mAb directed against IL-2 or IL-2R also did not prevent the induction of tolerance. These results suggest that complete T cell activation was not required for tolerance induction. However, substitution of a partially activating mAb, directed against the T cell receptor (TCR) beta subunit for anti-CD3epsilon, failed to synergize with anti-CD2 mAb to induce tolerance. The anti-TCRbeta mAb and anti-CD3epsilon mAb were found to differentially down modulate expression of TCR/CD3 complex subunits. In particular, anti-CD3epsilon caused transient down modulation of the TCRbeta receptor subunit and the TCRzeta signaling module, and this pattern was enhanced and prolonged by anti-CD2. Anti-TCRbeta caused persistent TCRzeta modulation but no TCRbeta modulation, and anti-CD2 did not influence this pattern. CONCLUSIONS: These results suggest that, although full T cell activation is not required for the induction of tolerance by anti-CD2 plus anti-CD3epsilon mAb, a signal transduction pathway that is associated with TCRbeta and TCRzeta expression, and, specifically, is perturbed by mAb binding of the CD3epsilon epitope, is critical. PMID- 10096533 TI - Neonatal pig islets induce a lower T-cell response than adult pig islets in IDDM patients. AB - BACKGROUND: Pancreatic pig islets may provide a substitute in the future for difficult to obtain human islets for transplantation in insulin-dependent diabetes millitus (IDDM) patients. However, the immune response to xenografts may significantly hamper this approach. Because neonatal tissue is believed to be less immunogenic, we examined whether the T-cell response to neonatal pig islets differs from the response to adult islets. METHODS: The T-cell proliferative response to different concentrations of sonicated neonatal and adult pig islets, as well as to insulin and mitogens, was tested in 21 recent onset IDDM patients and 21 healthy controls. We determined the presence of various circulating islet autoantibodies and their association with the T-cell response in IDDM patients. RESULTS: In the IDDM patients, sonicated adult pig islets (at 1 microg protein/ml) induced a significantly higher frequency (12 of 21 vs. 1 of 21, p<0.001) and magnitude (2.58+/-0.44 vs. 1.38+/-0.13, p<0.02) of positive T-cell responses than neonatal islets at the same concentration. Similar results were obtained with a 10-fold higher concentration of islet sonicate. There was no significant association between the individual T-cell responses and the presence of circulating autoantibodies in IDDM patients. CONCLUSION: These results indicate that neonatal pig islets induce a lower T-cell reactivity than adult islets, suggesting that the neonatal tissue may be immunologically more suitable for future islet xenotransplantation. PMID- 10096534 TI - Influenza vaccination in liver transplant recipients. AB - BACKGROUND: The immunogenicity of the trivalent inactivated influenza split virus vaccine (Infusplit SSW 97/98) containing A/Bayern/07/95 (H1N1)-like (A/Johannesburg/82/96 [NIB-39]), A/Wuhan/359/95 (H3N2)-like (A/Nanchang/933/95 [Resvir-0]), and B/Beijing/184/93-like (B/Harbin/7/94) hemagglutinin antigens was tested in liver transplant recipients (TXL-R). SUBJECTS AND METHODS: Serum antibody titers were determined 21+/-2 days after a single vaccination in 62 adult TXL-R and 59 adult volunteers. RESULTS: Protective postimmunization antibody titers for the three antigens were similar in TXL-R (protection rates 92%, 92%, and 95%) and the comparison group (97%, 100%, and 100%). Adverse reactions were mild and less frequent in TXL-R. A significant decrease of CD8+CD38+ lymphocytes after vaccination was found in TXL-R. No association between antibody response and age, gender, time interval since transplantation, anti-hepatitis B surface antigen immunoprophylaxis, or immunosuppressive medication was detected. CONCLUSION: Our results show that the vaccine is safe and effective and should be recommended to TXL-R. PMID- 10096535 TI - Novel mutation in the CMV UL97 gene associated with resistance to ganciclovir therapy. AB - Cytomegalovirus (CMV) strains resistant to ganciclovir have been associated with specific mutations in the UL97 and UL54 genes. The UL97 gene of a CMV strain isolated from a renal transplant recipient before and after 438 days of ganciclovir treatment was amplified by polymerase chain reaction and sequenced. A novel mutation resulting in deletion of codons 595 to 603 was identified in the viral DNA from specimens obtained after, but not before, prolonged ganciclovir therapy. Clinical and virological resolution of CMV disease occurred after switching to foscarnet therapy. Although many ganciclovir resistance mutations have been mapped to the UL97 codon range 591-607, this one is unusual in that it involves deletion of half these codons. Because UL97 seems to be necessary for effective CMV replication, this deletion suggests that much of codons 591-607 can be removed without destroying the biological function of UL97, and that this codon range can be altered in various ways to affect ganciclovir susceptibility. Rapid, flexible genotypic assays directed at this part of UL97 may facilitate the early recognition of ganciclovir resistance. PMID- 10096536 TI - Absence of teratogenicity of oral ganciclovir used during early pregnancy in a liver transplant recipient. AB - BACKGROUND: Ganciclovir (GCV) is effective for prevention of cytomegalovirus (CMV) disease. In animals it may cause some teratogenicity. There is little information on the effect of GCV on a human fetus. METHODS: The chart of a liver transplant recipient who received oral GCV during the first trimester was reviewed as was the published literature. RESULTS: There was no evidence of teratogenicity in the baby or in a case reported elsewhere. CONCLUSIONS: GCV has been used in a few female transplant recipients without untoward effects. The still uncertain risk of short term and long term teratogenicity, however, must be weighed against the risk of CMV disease in the recipient and the development of congenital CMV in the baby. PMID- 10096537 TI - The immunosuppressive agent mycophenolate mofetil markedly potentiates the activity of lobucavir [1R(1alpha,2beta,3alpha)]-9-[2,3 bis(hydroxymethyl)cyclobutyl]guanine against different herpes viruses. AB - BACKGROUND: Mycophenolate mofetil (MMF) has been approved as an immunosuppressive agent in kidney transplant recipients and may thus be used concomitantly with antiherpetic agents, the latter for the treatment of intercurrent herpesvirus infections. The parent compound of MMF, mycophenolic acid (MPA), is a potent inhibitor of inosine monophosphate dehydrogenase and causes depletion of the intracellular (deoxy)guanosine triphosphate [(d)GTP] pools. Lobucavir [1R(1alpha,2beta,3alpha)]-9-[2,3-bis(hydroxymethyl)cyc lobutyl]guanine (LBV) is a novel antiviral agent with activity against ganciclovir-resistant cytomegalovirus (CMV) strains, that is in phase II clinical trials for the treatment of CMV infections. LBV triphosphate inhibits the viral DNA polymerase competitively with dGTP. We present the results of our studies on the antiviral effects of the combinations LBV + MMF and LBV + MPA. METHODS: The antiviral effects of LBV either alone or in combination with MMF or MPA on the replication of CMV, herpes simplex virus type- (HSV) 1 (HSV-1), HSV-2, and thymidine kinase-deficient HSV-1 were studied by means of plaque or CPE reduction assays. RESULTS: When combined with LBV, MPA (at concentrations ranging from 0.25 to 10 microg/ml, which are readily attainable in human plasma) markedly potentiated the antiviral efficacy of LBV against HSV-1 and HSV-2, that is a 10- to 100-fold decrease in EC50. Moreover, the EC50 of LBV against TK- HSV-1 decreased up to 1400-fold upon combination with MPA. MPA by itself had little or no effect on the replication of these viruses. Moreover, MPA and MMF resulted in a marked increase in the anti CMV activity of LBV minimal FIC (FICmin: 0.24 and 0.26, respectively). Exogenously added guanosine reversed the potentiating effect of MPA on the antiviral activity of LBV, which indicates that this potentiating effect results from a depletion of the endogenous dGTP pools, thus favoring the inhibitory action of the LBV-triphosphate on the viral DNA polymerase. Ribavirin, another inhibitor of inosine monophosphate-dehydrogenase, also caused a marked enhancement of the antiviral activity of LBV against HSV-1 (12-fold), HSV-2 (20 fold), and TK- HSV-1 (25-fold). CONCLUSION: MMF markedly potentiates the activity of LBV against HSV-1, HSV-2, TK- HSV-1, and CMV. This drug interaction may have important implications when using LBV in the treatment of intercurrent herpesvirus infections in transplant recipients under MMF therapy. PMID- 10096538 TI - Treatment of Epstein-Barr virus-induced posttransplantation lymphoproliferative disorder with foscarnet alone in an adult after simultaneous heart and renal transplantation. AB - BACKGROUND: The kind and intensity of immunosuppression as well as Epstein-Barr virus, a transforming herpes virus that selectively infects B lymphocytes and causes infectious mononucleosis, have been implicated in the development of posttransplantation lymph-proliferative disorders (PT-LPD), a life-threatening complication of solid organ transplantation. The morphologic spectrum of PT-LPD ranges from polymorphous hyperplasia to monomorphous B-non-Hodgkin lymphomas. Among different modalities of treatment, reduction of immunosuppression with or without co-administration of antiviral agents may result in PT-LPD regression especially in mononucleosis-like disease. METHODS: Nonmononucleosis-like PT-LPD in a simultaneous heart and renal recipient was treated with Foscarnet, a potent inhibitor of different herpes viruses with a low profile of toxicity, although intensive immunosuppression therapy was maintained. RESULTS AND CONCLUSIONS: A 4 week course of Foscarnet resulted in relapse-free complete remission (follow-up 10+ months). Thus, antiviral treatment with Foscarnet, may induce prolonged remission in nonmononucleosis-like PT-LPD without reduction of immunosuppression. PMID- 10096539 TI - Intracranial pressure during liver transplantation for fulminant hepatic failure. AB - During orthotopic liver transplantation (OLT) for fulminant hepatic failure (FHF), some patients develop cerebral injury secondary to intracranial hypertension. We monitored intracranial pressure (ICP) and cerebral perfusion pressure (CPP) before and during OLT in 12 FHF patients undergoing transplantation. All four patients who had normal ICP preoperatively maintained normal ICP/CPP throughout OLT. During OLT, four of the eight patients with pretransplant intracranial hypertension had six episodes of ICP increase. These episodes of intracranial hypertension occurred during failing liver dissection (n=3) and graft reperfusion (n=3). At the end of the anhepatic phase, the ICP was lower than the preoperative ICP in all patients, and was below 15 mmHg in all but one patient. These data suggest that in FHF patients who develop intracranial hypertension before OLT, dissection of the native liver and graft reperfusion are associated with a risk of brain injury resulting from intracranial hypertension and cerebral hypoperfusion. PMID- 10096540 TI - Posttransplant diabetes in pediatric recipients on tacrolimus. PMID- 10096541 TI - Determination of high mobility group I(Y) expression level in colorectal neoplasias: a potential diagnostic marker. AB - High mobility group I(Y) [HMGI(Y)] proteins are architectural factors abundantly expressed during embryogenesis, and their overexpression is known to be closely associated with neoplastic transformation of cells. This study was performed to investigate whether determination of HMGI(Y) expression level could assist in (a) differential diagnosis between colorectal carcinoma, adenoma, and normal tissue and (b) determination of the prognosis of patients with colorectal cancer. To this end, HMGI(Y) expression was determined at both the protein and mRNA levels in 30 colorectal carcinomas, 26 adenomas, and 23 normal mucosa samples, and further correlations between the protein expression levels and various clinicopathological parameters, such as depth of tumor invasion, lymphatic and/or venous involvement, regional lymph node metastasis, and Dukes' stage, were determined in 30 carcinoma cases. The expression of HMGI(Y) proteins was significantly increased in carcinoma and adenoma with severe atypia compared with that in adenoma with less atypia and normal colorectal mucosa. This increase in HMGI(Y) protein expression was found to be because of an increase in its mRNA expression by RNA in situ hybridization analysis. Clinicopathological analysis revealed that the level of HMGI(Y) protein expression was significantly correlated with parameters known to be indicative of a poor prognosis in colorectal cancer patients. These findings indicate that the determination of the HMGI(Y) protein expression level could be a potential marker for the diagnosis of colorectal neoplasias and can be of great value in predicting the prognosis of patients with colorectal cancer. PMID- 10096542 TI - Expression of estrogen receptor beta1, beta2, and beta5 messenger RNAs in human breast tissue. AB - A triple-primer PCR assay was developed, based on the coamplification of estrogen receptor (ER)-beta1, -beta2, and -beta5 cDNAs, to investigate the relative expressions of the corresponding mRNAs in breast cancer lines and in 53 independent breast tumors. The expression of ER-beta2 and ER-beta5 mRNAs was higher than that of ER-beta1 mRNA in both cancer cell lines and breast tumors. In breast tumors, increases in the ER-beta2:ER-beta1 and ER-beta5:ER-beta1 mRNA expression ratios were observed, which positively correlated with the level of tumor inflammation and tumor grade, respectively. A trend toward an increase of these ratios was also found in tumors, as compared to the normal adjacent breast tissue available for 13 cases. Our data suggest that changes in the relative expression of ER-beta1, -beta2, and -beta5 mRNAs occur during breast tumorigenesis and tumor progression. PMID- 10096543 TI - Photochemical internalization: a novel technology for delivery of macromolecules into cytosol. AB - The therapeutic usefulness of macromolecules, such as in gene therapy, is often limited by an inefficient transfer of the macromolecule to the cytosol and a lack of tissue-specific targeting. The possibility of photochemically releasing macromolecules from endosomes and lysosomes into the cytosol was examined. Endocytosed macromolecules and photosensitizer were exposed to light and intracellular localization and the expression of macomolecules in the cytosol was analyzed. This novel technology, named photochemical internalization (PCI), was found to efficiently deliver type I ribosome-inactivating proteins, horseradish peroxidase, a p21ras-derived peptide, and a plasmid encoding green fluorescent protein into cytosol in a light-dependent manner. The results presented here show that PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that PCI may have a variety of useful applications for site specific drug delivery, e.g., in gene therapy, vaccination, and cancer treatment. PMID- 10096544 TI - Induction of specific CD8+ T-lymphocyte responses using a human papillomavirus-16 E6/E7 fusion protein and autologous dendritic cells. AB - When intracellular viral proteins are degraded, only a limited number of peptide epitopes are capable of eliciting specific CD8+ cellular immune responses for a given human leukocyte antigen (HLA) haplotype. We sought to induce CD8+ T lymphocyte (CTL) responses to human papillomavirus-16 (HPV-16) E6 and E7 proteins using a recombinant E6/E7 fusion protein and autologous human dendritic cells (DCs). CTLs were generated by in vitro stimulation using a recombinant HPV-16 E6/E7 fusion protein and autologous DCs from a healthy HLA-A*0201 donor. CTL specificity was assessed by cytokine release assays when the cells were reacted with autologous DC targets coincubated with the E6/E7 fusion protein. These CTLs were also reacted with the immunodominant E7 peptides (E711-20 and E7(86-93)) and DCs as a target. As a negative control, DCs were incubated with or without an irrelevant control protein (Helicobacter pylori) as target for the E6/E7-induced CTLs. The E6/E7-induced CTLs were capable of specific recognition of target DCs coincubated with E6/E7 but not the control protein. When E6/E7-specific CTLs were reacted with DCs and either E7(11-20) or E7(86-93), specific peptide recognition was also detected. These data demonstrate that specific CTLs can be elicited using autologous human DCs and a HPV-16 E6/E7 fusion protein. Therefore, extracellular viral proteins seem to be engulfed and processed by DCs; then the immunodominant HLA-A2-restricted peptides become available for CD8+ T-lymphocyte recognition. These data suggest that vaccine strategies using recombinant viral proteins may overcome the limitation of peptide epitopes for specific HLA haplotypes and may, therefore, permit more generalized clinical application. PMID- 10096545 TI - Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. AB - Using real-time quantitative PCR, cell-free EBV DNA was detectable in the plasma of 96% (55 of 57) of nasopharyngeal carcinoma (NPC) patients (median concentration, 21058 copies/ml) and 7% (3 of 43) of controls (median concentration, 0 copies/ml). Advanced-stage NPC patients had higher plasma EBV DNA levels than those with early-stage disease. At 1 month after completion of radiotherapy, plasma EBV DNA was undetectable in 7 of 15 subjects (47%) but remained high in the remaining 8 subjects (53%). Clinical examination revealed that all of the former seven subjects had complete tumor regression, whereas six of the eight latter subjects exhibited evidence of disease persistence or had developed distant metastases. These results suggest that quantitative analysis of plasma EBV DNA may be a useful clinical and research tool in the screening and monitoring of NPC patients. PMID- 10096546 TI - Functional interaction between retinoblastoma protein and stress-activated protein kinase in multiple myeloma cells. AB - Previous studies have demonstrated that gamma-irradiation (IR)-induced apoptosis in multiple myeloma (MM) is associated with activation of stress-activated protein kinase (SAPK). In the present study, we examined the molecules downstream of SAPK/C-Jun N-terminal kinase (JNK), focusing on the role of retinoblastoma protein (Rb) during IR-induced MM cell apoptosis. The results demonstrate that IR activates SAPK/JNK, which associates with Rb both in vivo and in vitro. Far Western blot analysis confirms that SAPK/JNK binds directly to Rb. IR-activated SAPK/JNK phosphorylates Rb, and deletion of the phosphorylation site in the COOH terminus domain of Rb abrogates phosphorylation of Rb by SAPK/JNK. Taken together, our results suggest that Rb is a target protein of SAPK/JNK and that the association of SAPK/JNK and Rb mediates IR-induced apoptosis in MM cells. PMID- 10096547 TI - Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. AB - HER2/neu, a Mr 185,000 tyrosine kinase receptor that is overexpressed in breast cancer, undergoes proteolytic cleavage of its extracellular domain (ECD). In contrast with other membrane-bound proteins, including growth factor receptors, that are cleaved by a common machinery system, we show that HER2 cleavage is a slow process and is not activated by protein kinase C. Pervanadate, a general inhibitor of protein-tyrosine phosphatases, induces a rapid and potent shedding of HER2 ECD. The shedding of HER2 ECD is inhibited by the broad-spectrum metalloprotease inhibitors EDTA, TAPI-2, and batimastat. The tissue inhibitor of metalloproteases-1; an inhibitor of matrix metalloproteases that does not inhibit cleavage by the general protein kinase C-dependent shedding machinery, also inhibited HER2 ECD shedding, whereas tissue inhibitor of metalloproteases-2 did not. These data suggest that HER2 cleavage is a process regulated by an as-yet unidentified distinct protease. PMID- 10096548 TI - Correlation of beta-actin messenger RNA localization with metastatic potential in rat adenocarcinoma cell lines. AB - The actin cytoskeleton is involved in the motility of tumor cells. It has been shown in several cell types that beta-actin mRNA is localized in the protrusions of cells in which actin is actively polymerized, and the ability to localize mRNA is correlated with the efficiency of motility. In this context, we studied the distribution of beta-actin mRNA in two different tumor cell lines and correlated it with their metastatic potential. The two cell lines used were the highly metastatic MTLn3 cells and nonmetastatic MTC cells. Nonmetastatic MTC cells have two different pools of beta-actin mRNA (perinuclear and at the leading edge), whereas highly metastatic MTLn3 cells have only a perinuclear distribution of beta-actin mRNA. These differences in mRNA localization are correlated with profound differences in the polarity and plasticity of cell motility of these cells in culture and the histopathology of primary breast tumors derived from these cells. In particular, MTLn3 cells are unpolarized by all cell shape and motility criteria in culture and in their histopathological organization in primary tumors. By comparison, MTC cells are polarized in all identical measurements. These results suggest that the increased plasticity of cell locomotion and the invasiveness of MTLn3 cells result from the failure of metastatic cells to localize beta-actin mRNA properly, causing them to be less polarized and therefore more flexible in their direction of motility. Thus, differences in the polarized organization of cells in the primary tumor that are correlated with beta-actin mRNA localization may have prognostic value in predicting metastatic potential. PMID- 10096549 TI - Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. AB - Germ-line mutations of the human TSC2 tumor suppressor gene cause tuberous sclerosis (TSC), a disease characterized by the development of hamartomas in various organs. In the Eker rat, however, a germ-line Tsc2 mutation gives rise to renal cell carcinomas with a complete penetrance. The molecular mechanism for this phenotypic difference between man and rat is currently unknown, and the physiological function of the TSC2/Tsc2 product (tuberin) is not fully understood. To investigate these unsolved problems, we have generated a Tsc2 mutant mouse. Tsc2 heterozygous mutant (Tsc2+/-) mice developed renal carcinomas with a complete penetrance, as seen in the Eker rat, but not the angiomyolipomas characteristic of human TSC, confirming the existence of a species-specific mechanism of tumorigenesis caused by tuberin deficiency. Unexpectedly, approximately 80% of Tsc2+/- mice also developed hepatic hemangiomas that are not observed in either TSC or the Eker rat. Tsc2 homozygous (Tsc2-/-) mutants died around embryonic day 10.5, indicating an essential function for tuberin in mouse embryonic development. Some Tsc2-/- embryos exhibited an unclosed neural tube and/or thickened myocardium. The latter is associated with increased cell density that may be a reflection of loss of a growth-suppressive function of tuberin. The mouse strain described here should provide a valuable experimental model to analyze the function of tuberin and its association with tumorigenesis. PMID- 10096550 TI - Differential behaviors toward ultraviolet A and B radiation of fibroblasts and keratinocytes from normal and DNA-repair-deficient patients. AB - Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) are rare genodermatoses transmitted as recessive and autosomal traits that result in reduced capacity to repair UV-induced DNA lesions. Although XP, but not TTD, patients are prone to basal and squamous cell carcinomas, to date no comparative studies of the XP and TTD phenotypes have included epidermal keratinocytes. We compared the DNA repair capacity (by unscheduled DNA synthesis) and cell survival (by clonal analysis) of epidermal keratinocytes and dermal fibroblasts grown from normal individuals and patients with xeroderma pigmentosum and trichothiodystrophy following UVA and UVB irradiation. The same dose of UVB (1000 J/m2) induced twice as many DNA lesions in normal fibroblasts as in normal keratinocytes. UV survival rates were always higher in keratinocytes than in fibroblasts. Normal and TTD keratinocytes survived better following UVA and UVB irradiation than XP-C and XP-D keratinocytes. XP-C keratinocytes exhibited exacerbated sensitivity toward UVA radiation. Unscheduled DNA synthesis at UV doses leading to 50% cell survival indicated that the ratio of DNA repair capacity to cell survival is higher in keratinocytes than in fibroblasts. In addition, UVA and UVB irradiation induced a transition from proliferative to abortive keratinocyte colonies. This transition varied between donors and was in part correlated with their cancer susceptibility. Altogether these data provide the first evidence of the differential behaviors of normal, XP, and TTD keratinocytes toward UV radiation. PMID- 10096551 TI - Walker 256/S carcinosarcoma causes osteoporosis-like changes through ectopical secretion of luteinizing hormone-releasing hormone. AB - We have shown that Walker 256/S mammary carcinoma caused osteoporosis-like changes in young female rats, accompanied by low serum estradiol and hypercalciuria without changes in the serum levels of calcium, phosphorus, and parathyroid hormone-related peptide. In this study, we investigated the cause of bone loss after Walker 256/S inoculation into female 6-week-old Wistar Imamichi rats, focusing on the sex hormone balance in the host animal. Walker 256/S bearing rats showed characteristic osteoporosis, with a significant increase in spleen weight and a significant decrease in uterine weight by 14 days after s.c. tumor inoculation. In the in vitro bone marrow culture, mineralized nodule formation ability decreased according to the time after tumor inoculation, and tartrate-resistant acid phosphatase-positive multinucleated cell formation increased at 7 days after tumor inoculation, but it began to decrease at 14 days after tumor inoculation. This indicates that after inoculation with Walker 256/S tumor, the progenitors of osteoblasts and ostroclasts lost their balance in the bone turnover, resulting in bone resorption. On the other hand, Walker 256/S carcinoma expressed luteinizing hormone-releasing hormone (LH-RH) mRNA, and in Walker 256/S-bearing rats, the serum LH-RH level increased significantly from 3 days after tumor inoculation, whereas in the healthy control rats, this level was very low. Consequently, the serum levels of follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone were significantly lower in the tumor-bearing rats than in the healthy control rats. Because the LH-RH gene is located in the long prolactin release-inhibiting factor (PIF) gene and mRNA amplified by reverse transcription-PCR in this study contained whole LH-RH and a part of PIF, the Walker 256/S tumor is thought to express PIF. Indeed, the serum prolactin level decreased in tumor-bearing rats. The serum level of growth hormone, one of the other pituitary hormones, was not changed. Moreover, the level of an osteolytic cytokine, tumor necrosis factor alpha, increased in the serum of Walker 256/S-bearing rats, although this may be a result of the immune response of the host animal to tumor growth as well as an enlarged spleen. In conclusion, the Walker 256/S tumor lowers estrogen secretion through ectopical oversecretion of LH-RH, and then osteolytic cytokines, such as tumor necrosis factor alpha, increase in tumor-bearing rats, escape the control of estrogen, and activate osteoclasts, resulting in bone loss in a short period. PMID- 10096552 TI - Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. AB - Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer. PMID- 10096553 TI - Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor. AB - The antiangiogenic activity and antitumor efficacy of a newly developed matrix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl phenylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, but not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMPs tested. Daily oral administration of 200 mg/kg BPHA, but not ( )BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth, and liver metastasis. The growth inhibition activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio-endothelioma model, respectively. BPHA also showed 42% inhibition of the liver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential. PMID- 10096554 TI - Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. AB - A fully human IgG2kappa monoclonal antibody (MAb), E7.6.3, specific to the human epidermal growth factor (EGF) receptor (EGFr) was generated from human antibody producing XenoMouse strains engineered to be deficient in mouse antibody production and to contain the majority of the human antibody gene repertoire on megabase-sized fragments from the human heavy and kappa light chain loci. The E7.6.3 MAb exhibits high affinity (KD = 5 x 10(-11) M) to the receptor, blocks completely the binding of both EGF and transforming growth factor alpha (TGF-a) to various EGFr-expressing human carcinoma cell lines, and abolishes EGF dependent cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. The antibody (0.2 mg i.p. twice a week for 3 weeks) prevents completely the formation of human epidermoid carcinoma A431 xenografts in athymic mice. More importantly, the administration of E7.6.3 without concomitant chemotherapy results in complete eradication of established tumors as large as 1.2 cm3. Tumor eradication of A431 xenografts was achieved in nearly all of the mice treated with total E7.6.3 doses as low as 3 mg, administered over the course of 3 weeks, and a total dose of 0.6 mg led to tumor elimination in 65% of the mice. No tumor recurrence was observed for more than 8 months after the last antibody injection, which further indicated complete tumor cell elimination by the antibody. The potency of E7.6.3 in eradicating well-established tumors without concomitant chemotherapy indicates its potential as a monotherapeutic agent for the treatment of multiple EGFr expressing human solid tumors, including those for which no effective chemotherapy is available. Being a fully human antibody, E7.6.3 is expected to exhibit minimal immunogenicity and a longer half-life as compared with mouse or mouse-derivatized MAbs, thus allowing repeated antibody administration, including in immunocompetent patients. These results suggest E7.6.3 as a good candidate for assessing the full therapeutic potential of anti-EGFr antibody in the therapy of multiple patient populations with EGFr-expressing solid tumors. PMID- 10096555 TI - Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. AB - The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer. PMID- 10096556 TI - Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models. AB - Experimental evidence has directly implicated matrix metalloproteinases (MMPs) in the remodeling of the stromal tissue surrounding tumors. Thus, MMP inhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a tumor. Much of the work on the role of MMP inhibitors has concentrated on their inhibitory effects on tumor cell invasion. We have examined the effects of a new MMP inhibitor, KB-R7785 (acting on MMP-1, MMP-3, and MMP-9), on tumor angiogenesis and metastasis of murine colon adenocarcinoma (C-26) in two tumor models in BALB/c mice (transparent chamber model and lung colonization model). KB-R7785 has not shown inhibitory effects on in vitro growth of either C 26 or KOP2.16 murine endothelial cells. In vivo, KB-R7785 administrated twice daily for 15 days (100 mg/kg, i.p.), starting the day of tumor inoculation (5 x 10(5) C26 cells) in transparent chamber, has resulted in 88.2% suppression of tumor growth, compared with that in vehicle-administered mice (controls). Tumors grown in controls have doubled their area in 3.3 days, whereas those treated by KB-R7785 progressed almost four times slower (tumor area doubling time, 12 days). KB-R7785 rendered centrally avascular tumors with only a rim of peripheral neovasculature, which had significant lower functional vascular density and vascular area than the corresponding parameters in control tumors 10 days after inoculation [79.9+/-6.7 cm/cm2 versus 164.1+/-10.1 cm/cm2 (P < 0.01) and 19.8+/ 1.5% versus 42.6+/-2.7% (P < 0.01), respectively]. In the lung colonization model (tail vein inoculation of 5 x 10(5) C-26 cells), administration of KB-R7785 (100 mg/kg, i.p.) twice daily for 20 days has reduced the number of surface metastasis by 85.8% and abolished the tumor burden, as compared with controls. The few metastatic colonies found in the lungs of KB-R7785 treated mice appeared to be dormant (i.e., staining with von Willebrand factor antibody revealed few, if any, positive cells within the metastatic foci from MMP inhibitor-treated lungs, whereas terminal deoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold increase in the rate of tumor cell apoptosis compared with controls. The fact that KB-R7785 interferes with early steps of angiogenesis and cancer spread suggests that MMP inhibitors may control both primary and secondary tumor growths by limiting the expansion of endothelial cells, as well as cancer cells, composing the tumors. PMID- 10096557 TI - Dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1/MDA6 increases the susceptibility of human leukemia cells (U937) to 1-beta-D arabinofuranosylcytosine-mediated mitochondrial dysfunction and apoptosis. AB - The effects of dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 on the apoptotic response of U937 monocytic leukemia cells to 1-beta D-arabinofuranosylcytosine (ara-C) were examined. After a 6-h exposure to 1 microM ara-C, cells stably transfected with a p21WAF1/CIP1 antisense construct were significantly more sensitive to the induction of classic apoptotic morphology, DNA fragmentation, caspase-3 activation, poly(ADP-ribose) polymerase degradation, and underphosphorylation of the retinoblastoma protein (pRb) than their empty-vector counterparts. Enhanced susceptibility of antisense-expressing cells to ara-C was accompanied by a corresponding reduction in clonogenic and suspension culture growth. The increased sensitivity of these cells to ara-C mediated lethality could not be attributed to cytokinetic perturbations, nor did ara-CTP formation or (ara-C)DNA incorporation differ significantly between the cell lines. Moreover, synchronization of p21 antisense-expressing cells in S phase by aphidicolin block resulted in a further increase in ara-C-mediated apoptosis, suggesting enhanced drug sensitivity of the S-phase cell fraction. After exposure to ara-C, p21 antisense-expressing cells displayed a greater decline in mitochondrial membrane potential (deltapsi(m)) and generation of reactive oxygen species than their empty-vector counterparts, as well as early potentiation (e.g., within 2-4 h) of cytochrome c release into the cytosolic S 100 fraction. Lastly, ara-C-mediated increases in mitogen-activated protein kinase activity over basal levels were attenuated in p21 antisense-expressing cells. Collectively, these findings indicate that dysregulation of the cyclin dependent kinase inhibitor p21WAF1/CIP1 increases the susceptibility of U937 human leukemia cells to ara-C-related lethality, and this phenomenon occurs as a relatively early event that is independent of cell cycle or pharmacodynamic factors and is associated with mitochondrial perturbations implicated in activation of the apoptotic protease cascade. PMID- 10096558 TI - A novel, orally administered nucleoside analogue, OGT 719, inhibits the liver invasive growth of a human colorectal tumor, C170HM2. AB - OGT 719 is a novel p.o. bioavailable nucleoside analogue in which galactose is incorporated onto the fluoropyrimidine moiety of the cytotoxic agent 5 fluorouracil (5-FU). OGT 719 has been designed to reduce the systemic toxicity normally associated with 5-FU while retaining activity against disease localized in the liver, in which it may be preferentially localized through the asialoglycoprotein receptor (ASGP-R). We report studies confirming the activity of OGT 719 in inhibiting growth of metastatic human colorectal tumors in the liver of nude mice. The human colorectal cancer cell line C170HM2 readily forms liver metastases in vivo. Oral administration of 1500 mg/kg/day OGT 719 inhibited liver tumor burden by 95% compared with vehicle control, without any observable signs of toxicity. When the tumor burden was increased and the same OGT 719 treatment was compared with a standard clinical dose regimen of 25 mg/kg/day 5 FU/leucovorin given i.v., both treatments were equally efficacious, although 5 FU/leucovorin treatment started 7 days earlier. In contrast to 5-FU, OGT 719 is p.o. bioavailable and has a plasma half-life between 1.5 and 3 h. Several colorectal cancer cell lines express the asialoglycoprotein receptor, although no significant levels can be detected in C170HM2 cells, consistent with the observation that OGT 719 is approximately 3 log orders of magnitude less potent in vitro than 5-FU. Flux through thymidylate synthase, as measured by 3H release from [3H]dUrd, was inhibited by OGT 719 at 4 h. The notable difference in the potency of OGT 719 efficacy on C170HM2 cells in vitro and in vivo supports our model of liver-specific activation of OGT 719. As our data suggest, OGT 719 may significantly inhibit growth of metastatic colorectal tumors in the liver in vivo. This hypothesis is presently being explored in clinical trials for primary hepatocellular carcinoma and colorectal liver metastases. PMID- 10096559 TI - Tumorigenicity of mouse thymoma is suppressed by soluble type II transforming growth factor beta receptor therapy. AB - Many types of tumor cells overexpress transforming growth factor beta (TGF-beta), which is believed to promote tumor progression. We hypothesized that overexpression of the extracellular region of the type II TGF-beta receptor (soluble TbetaRII) would compete for or block TGF-beta binding to TbetaRs on immune cells, preventing TGF-beta-mediated immunosuppression and consequently resulting in the eradication of tumor cells. We tested this in the mouse thymoma cell line EL4, which has been reported to suppress cellular immunity by secreting a large amount of TGF-beta. Transduction of EL4 with recombinant retrovirus encoding soluble TbetaRII resulted in the secretion of heterogeneously glycosylated, 25 to 35 kDa truncated TbetaRII. Inoculation of 1 x 10(4) to 5 x 10(4) soluble TbetaRII-modified EL4 cells (EL4/Ts, EL4 cells transduced with recombinant retrovirus encoding soluble TbetaRII and neomycin resistance gene) s.c. to mice showed reduced tumorigenicity, as indicated by lower overall tumor incidence (7%, 1 of 14; P < 0.001) compared with unmodified EL4 (100%, 9 of 9) or vector-modified EL4 cells (EL4/neo, EL4 cells transduced with recombinant retrovirus encoding neomycin resistance gene; 100%, 4 of 4). Administration of mitomycin C-treated EL4/Ts cells (1 x 10(6)) after EL4 inoculation (1 x 10(4)) reduced tumor incidence from 100% (5 of 5 in mice inoculated with mitomycin C treated EL4/neo) to 40% (4 of 10, P < 0.05), indicating that supply of soluble TbetaRII could actually block TGF-beta-mediated tumorigenesis. In vitro tumor cytotoxicity assays revealed 3-5-fold higher cytotoxic activity with lymphocytes from EL4/Ts-bearing mice compared with those from EL4- or EL4/neo-bearing mice, indicating that the observed tumor rejection was mediated by restoration of the tumor-specific cellular immunity. These data suggest that expression of soluble TbetaRII is an effective strategy for treating highly progressive tumors secreting TGF-beta. PMID- 10096560 TI - Polyamine analogue induction of the p53-p21WAF1/CIP1-Rb pathway and G1 arrest in human melanoma cells. AB - Although polyamines are well recognized for their critical involvement in cell growth, the cell cycle specificity of this requirement has not yet been characterized with respect to the newly delineated regulatory pathways. We recently reported that polyamine analogues having close structural and functional similarities to the natural polyamines produce a distinct G1 and G2-M cell cycle arrest in MALME-3M human melanoma cells. To determine a molecular basis for this observation, we examined the effects of N1,N11-diethylnorspermine on cell cycle regulatory proteins associated with G1 arrest. The analogue is known to deplete polyamine pools by suppressing biosynthetic enzymes and potently inducing the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. Treatment of MALME-3M cells with 10 microM N1,N11-diethylnorspermine caused an increase in hypophosphorylated Rb, which correlated temporally with the onset of G1 arrest at 16-24 h. Rb hypophosphorylation was preceded by an increase in wild-type p53 (approximately 100-fold at maximum) and a concomitant increase in the cyclin dependent kinase inhibitor, p21WAF1/CIP1 (p21; approximately 5-fold at maximum). Another cyclin-dependent kinase inhibitor, p27KIP1, and cyclin D increased slightly, whereas proliferating cell nuclear antigen and p130 remained unchanged. Induction of p21 protein was accompanied by an increase in p21 mRNA, whereas induction of p53 protein was not, suggesting transcriptional activation of the former and posttranscriptional regulation of the latter. SK-MEL-28 human melanoma cells, which contain a mutated p53, failed to induce p53 or p21 and did not arrest in G1. Rather, these cells rapidly underwent programmed cell death within 48 h. Overall, these findings provide the first indication of the cell cycle regulatory pathways by which polyamine antagonists such as analogues might inhibit growth in cells containing wild-type p53 and further suggest a mechanistic basis for differential cellular responses to these agents. PMID- 10096561 TI - Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis. AB - Here, we report the functional expression of CD40 on human malignant melanomas (MMs). Comparison of tumor specimen from MM precursor lesions, primary tumors, and metastases revealed that CD40 surface expression is down-regulated during tumor progression. CD40 expression was confirmed in 7 human MM cell lines established from immunogenic primary tumors or metastases, whereas 11 cell lines established from advanced stages were CD40 negative. CD40 expression could be enhanced in CD40-positive MM by stimulation with IFN-gamma and tumor necrosis factor-alpha but not by interleukin (IL)-1beta or CD40 triggering. CD40 ligation on MM by CD40L-transfected murine L-cells or by a soluble CD40L fusion protein up regulated their expression of intercellular adhesion molecule-1 and MHC class I and class II molecules and their secretion of IL-6, IL-8, tumor necrosis factor a, and granulocyte macrophage colony-stimulating factor and also induced a rapid activation of the transcription factor nuclear factor kappaB. Furthermore, CD40 ligation of a HLA-A2+, MelanA/MART1+ MM cell line enhanced its susceptibility to specific lysis by a HLA-A2-restricted, MelanA/MART-1-specific CTL clone. Finally, CD40 ligation induced growth inhibition and apoptosis in MM. These results indicate that CD40-CD40L interactions may play an important role in augmenting antitumor immunity and inducing apoptosis in some CD40-positive immunogenic human MMs. PMID- 10096562 TI - Lysis of tumor cells by natural killer cells in mice is impeded by platelets. AB - Natural killer (NK) cells provide effective antitumoral activity in the blood stream of mice, leading to reduced metastasis. There are, however, tumor cells that metastasize despite the presence of an intact NK system. The capability of tumor cells to induce platelet aggregation, on the other hand, correlates with their enhanced metastatic potential. A counteractive role of platelets for the NK function in metastasis has never been conceived. Here we demonstrate for the first time that platelets directly protect tumor cells from NK lysis in vitro as well as in vivo. Using three different tumor cell lines in a mouse model of experimental metastasis, tumor seeding in the target organs was reduced when the host was platelet depleted, but only if the tumor cells were NK sensitive. Aggregation of platelets around tumor cells also inhibited in vitro NK tumorilytic activity. This protection of tumor cells by platelets was mouse strain independent and was equally observed with platelets from beta2 microglobulin-deficient mice, excluding a NK inhibitory function of MHC class I on platelets. Thus, even if tumor cells are NK susceptible and cytotoxic NK cells threaten their survival in the blood, platelets are capable of protecting them from cytolysis, thereby promoting metastasis. Surface shielding by platelet aggregates seems to be the main mechanism of this protection. PMID- 10096563 TI - Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. AB - An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC. PMID- 10096564 TI - The FHIT gene is expressed in pancreatic ductular cells and is altered in pancreatic cancers. AB - We examined 2 normal pancreata, 21 primary pancreatic ductal cancers, and 19 pancreatic cancer cell lines for Fhit expression and FHIT gene status. The normal pancreas expressed Fhit protein in the cytoplasm of ductular cells, whereas interlobular and larger ducts, acini, and insulae of Langerhans were negative. Fhit protein was detected by immunoblot assay in 11 pancreatic cancer cell lines; of the 8 cell lines lacking Fhit protein, 7 lacked FHIT mRNA and 1 showed an abnormally sized transcript. DNA from five of these eight cell lines showed homozygous loss of FHIT exon 5. In 8 of the 21 primary cancers, Fhit expression was detected by immunohistochemistry. Reverse transcription-PCR analysis of 6 of the 13 cases lacking Fhit showed normal-sized FHIT product in 3 cases and a mixture of normal and abnormal products in the other 3. Sequencing showed that abnormal bands were missing variable numbers of exons. Loss of microsatellite DNA markers internal to the FHIT gene was observed in 10 of 13 primary cancers lacking Fhit protein (homozygous in two cases) and in only 1 of the 8 cancers expressing Fhit protein. In nine primary cancers, four expressing and five lacking Fhit protein, it was possible to obtain pure cancer DNA by microdissection. Three of the five microdissected cases lacking Fhit protein exhibited homozygous deletion of FHIT exon 5. In conclusion, the lack of Fhit protein in pancreatic cancers correlated with absence or alteration of FHIT mRNA and was often associated with FHIT gene anomalies. PMID- 10096565 TI - Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. AB - Metallothioneins (MTs) are a family of stress-induced proteins with diverse physiological functions, including protection against metal toxicity and oxidants. They may also contribute to the regulation of cellular proliferation, apoptosis, and malignant progression. We reported previously that the human (h)MT IIA isoform is induced in carcinoma cells (A431, SiHa, and HT29) exposed to low oxygen, conditions commonly found in solid tumors. The present study demonstrates that the genes for hMT-IIA and mouse (m)MT-I are transcriptionally activated by hypoxia through metal response elements (MREs) in their proximal promoter regions. These elements bind metal transcription factor-1 (MTF-1). Deletion and mutational analyses of the hMT-IIA promoter indicated that the hMRE-a element is essential for basal promoter activity and for induction by hypoxia, but that other elements contribute to the full transcriptional response. Functional studies of the mMT-I promoter demonstrated that at least two other MREs (mMRE-d and mMRE-c) are responsive to hypoxia. Multiple copies of either hMRE-a or mMRE-d conferred hypoxia responsiveness to a minimal MT promoter. Mouse MT-I gene transcripts in fibroblasts with targeted deletions of both MTF-1 alleles (MTF-1( /-); dko7 cells) were not induced by zinc and showed low responsiveness to hypoxia. A transiently transfected MT promoter was unresponsive to hypoxia or zinc in dko7 cells, but inductions were restored by cotransfecting a mouse MTF-1 expression vector. Electrophoretic mobility shift assays detected a specific protein-DNA complex containing MTF-1 in nuclear extracts from hypoxic cells. Together, these results demonstrate that hypoxia activates MT gene expression through MREs and that this activation involves MTF-1. PMID- 10096566 TI - Loss of heterozygosity at 3p14.2 in clear cell renal cell carcinoma is an early event and is highly localized to the FHIT gene locus. AB - The VHL tumor suppressor gene (TSG) at 3p25-26 is strongly implicated in the pathogenesis of clear cell renal cell carcinoma (cRCC). In addition, 3p14.2 and 3p21 are suspected of harboring additional TSGs in cRCC, with FHIT being a candidate TSG at 3p14.2. We examined 87 microdissected, histologically well defined cRCCs classified according to tumor-node-metastasis (TNM) stage (stage 1, 23 cases; stage 2, 14 cases; stage 3, 24 cases; stage 4, 26 cases) and Fuhrman grade (grade 1, 24 cases; grade 2, 19 cases; grade 3, 19 cases; grade 4, 8 cases; sarcomatoid cRCC, 17 cases) for loss of heterozygosity (LOH) at 3p14.2 and 3p25 26 using a series of precisely mapped microsatellite probes. We found that LOH at 3p14.2 exceeded LOH at 3p25-26 in frequency (69% versus 48.3%; P < 0.03) and was highly localized to markers within the FHIT gene locus (D3S1300 and D3S4260), with the majority of chromosomal breakpoints also mapping to this region. In addition, 3p14.2 LOH (P < 0.03), but not 3p25-26 LOH (P = nonsignificant), was associated with lower tumor grades (grades 1-3). These findings suggest that 3p14.2 genomic deletions may be among the earliest events in cRCC pathogenesis, preceding genomic deletions at the VHL locus. FHIT, or an as yet undiscovered TSG mapping to the D3S4103-D3S4260 interval, could be the molecular target of the 3p14.2 deletions. PMID- 10096567 TI - The plasminogen-plasminogen activator (PA) system in neuroblastoma: role of PA inhibitor-1 in metastasis. AB - Proteases of the plasminogen-plasminogen activator (PA) system play an important role in cancer metastasis. We have examined the expression of these proteases and their cell surface receptors and inhibitors in neuroblastoma, a tumor that originates in cells of the neural crest and is the second most common solid tumor in children. This analysis was performed in seven established human cell lines and 20 primary tumor specimens. Urokinase PA and, in particular, tissue-type PA were expressed in cell lines and in tumor tissues; however, their levels of expression did not correlate with clinical stage. There was little evidence suggesting that neuroblastoma cells concentrate PA activity at their cell surface because urokinase-type PA receptor mRNA was detected in two cell lines and in 5 of 20 tumor samples by reverse transcription-PCR only. PA inhibitor (PAI)-2 was absent in all cell lines and tumor tissue samples examined. However, PAI-1, which was not expressed by the cell lines, was expressed by stromal cells and, specifically, endothelial cells in tumor tissue. By extending the analysis of PAI 1 expression in 64 primary tumor specimens, we found that high PAI-1 expression paradoxically correlated with metastatic stage and tumor recurrence. In vitro experiments indicated that the expression of PAI-1 by human microvascular endothelial cells was stimulated in the presence of SK-N-BE(2) human neuroblastoma cells and neuroblastoma culture medium. Recombinant PAI-1 also promoted SK-N-BE(2) cell detachment from vitronectin and migration from vitronectin toward fibronectin. From these data, we conclude that the up regulation of PAI-1 expression in endothelial cells may promote rather than inhibit metastasis in neuroblastoma. PMID- 10096568 TI - De-N-acetyl-gangliosides in humans: unusual subcellular distribution of a novel tumor antigen. AB - The disialoganglioside GD3 is a major antigen in human melanomas that can undergo 9-O-acetylation of the outer sialic acid (giving 9-OAc-GD3). Monoclonal antibody SGR37 detects a different modification of the GD3, de-N-acetylation of the 5-N acetyl group (giving de-N-Ac-GD3). We found that conventional immunohistochemistry of the SGR37 antigen is limited by a reduction in reactivity upon fixation with aldehydes (which presumably react with the free amino group) or with organic reagents (which can extract glycolipids). We optimized conditions for detection of this antigen in unfixed frozen tissue sections and studied its distribution in human tissues and tumors. It is expressed at low levels in a few blood vessels, infiltrating mononuclear cells in the skin and colon, and at moderate levels in skin melanocytes. In contrast, the antigen accumulates at high levels in many melanomas and in some lymphomas but not in carcinomas. In positive melanomas, expression is sometimes more intense and widespread than that of GD3. Both 9-O-acetylation and de-N-acetylation of GD3 seem to occur after its initial biosynthesis. Isotype-matched antibodies against GD3, 9-O-acetyl-GD3 and de-N acetyl-GD3 were used to compare their subcellular localization and trafficking. 9 O-acetyl-GD3 colocalizes with GD3 predominantly on the cell surface and partly in lysosomal compartments. In contrast, de-N-acetyl-GD3 has a diffuse intracellular location. Adsorptive endocytosis of antibodies indicates that whereas GD3 remains predominantly on the cell surface, de-N-acetyl-GD3 is efficiently internalized into a compartment that is distinct from lysosomes. Rounding up of melanoma cells occurring during growth in culture is associated with relocation of the internal pool of de-N-acetyl-GD3 to the cell surface. Thus, a minor modification of the polar head group of a tumor-associated glycosphingolipid can markedly affect the subcellular localization and trafficking of the whole molecule. The high levels of the SGR37 antigen in melanomas and lymphomas, its selective endocytosis from the cell surface, and its relocation to the cell surface of rounded up cells suggest potential uses in diagnostic or therapeutic approaches to these diseases. PMID- 10096569 TI - Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. AB - The management of human breast cancer frequently includes radiation therapy as an important intervention, and improvement in the clinical efficacy of radiation is desirable. Overexpression of the HER-2 growth factor receptor occurs in 25-30% of human breast cancers and correlates with poor clinical outcome, including earlier local relapse following conservative surgery accompanied by radiation therapy. In breast cancer cells with overexpression of HER-2 receptor, recombinant humanized monoclonal antibodies (rhuMAbs) to HER-2 receptors (rhuMAb HER-2) decrease cell proliferation in vitro and reduce tumor formation in nude mice. Therapy with rhuMAb HER-2 enhances tumor sensitivity to radiation at doses of 1-5 Gy, exceeding remission rates obtained with radiation alone. This benefit is specific to cells with HER-2 overexpression and does not occur in cells without overexpression. Treatment of cells with radiation (2-4 Gy) alone provokes a marked increase in unscheduled DNA synthesis, a measure of DNA repair, but HER-2 overexpressing cells treated with a combination of rhuMAb HER-2 and radiation demonstrate a decrease of unscheduled DNA synthesis to 25-44% of controls. Using an alternate test of DNA repair, i.e., radiation-damaged or undamaged reporter DNA, we introduced a cytomegalovirus-driven beta3-galactosidase into HER-2 overexpressing breast cancer cells that had been treated with rhuMAb HER-2 or control. At 24 h posttransfection, the extent of repair assayed by measuring reporter DNA expression was high after exposure to radiation alone but significantly lower in cells treated with combined radiation and rhuMAb HER-2 therapy. To further characterize effects of rhuMAb HER-2 and the combination of antibody and radiation on cell growth, analyses of cell cycle phase distribution were performed. Antibody reduces the fraction of HER-2-overexpressing breast cancer cells in S phase at 24 and 48 h. Radiation treatment is also known to promote cell cycle arrest, predominantly at G1, with low S-phase fraction at 24 and 48 h. In the presence of rhuMAb HER-2, radiation elicits a similar reduction in S phase at 24 h, but a significant reversal of this arrest appears to begin 48 h postradiation exposure. The level of S-phase fraction at 48 h is significantly greater than that found at 24 h with the combined antibody-radiation therapy, suggesting that early escape from cell cycle arrest in the presence of antireceptor antibody may not allow sufficient time for completion of DNA repair in HER-2-overexpressing cells. Because it is well known that failure of adequate p21WAF1 induction after DNA damage is associated with failure of cell cycle arrest, we also assessed the activity of this critical mediator of the cellular response to DNA damage. The results show induction of p21WAF1 transcripts and protein product at 6, 12, and 24 h after radiation treatment; however, increased levels of p21WAF1 transcript and protein are not sustained in HER-2 overexpressing cells exposed to radiation in the presence of rhuMAb HER-2. Although transcript and protein levels increase at 6-12 h, they are both diminished by 24 h. Levels of p21WAF1 transcript and protein at 24 h are significantly lower than in cells treated by radiation without antibody. A reduction in the basal level of p21WAF1 transcript also occurred after 12-24 h exposure to antibody alone. The effect of HER-2 antibody may be related to tyrosine phosphorylation of p21WAF1 protein. Tyrosine phosphorylation of p21WAF1 is increased after treatment with radiation alone, but phosphorylation is blocked by combined treatment with antireceptor antibody and radiation. This dysregulation of p21WAF1 in HER-2-overexpressing breast cells after treatment with rhuMAb HER-2 and radiation appears to be independent of p53 expression levels but does correlate with reduced levels of mdm2 protein. (ABSTRACT TRUNCATED) PMID- 10096570 TI - Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. AB - The cytokine-inducible endothelial cell adhesion receptor E-selectin has been implicated in cancer metastasis. Previously, we reported that experimental liver metastasis of Lewis lung carcinoma subline H-59 cells could be abrogated in animals treated with an anti-E-selectin antibody. To gain further insight into the functional relevance of E-selectin expression to liver colonization, we investigated here the time course of cytokine and hepatic E-selectin expression after the intrasplenic/portal inoculation of H-59 cells by using a combination of reverse transcription-PCR, Northern blot analysis, immunohistochemistry, and in situ hybridization. In parallel, we analyzed cytokine induction in response to the injection of Lewis lung carcinoma subline M-27 and murine melanoma B16-F1 cells, which do not spontaneously metastasize to the liver. In livers derived from normal or saline-injected mice, only minimal basal levels of TNF-alpha and IL-1 mRNA were detectable by RT-PCR. Rapid cytokine mRNA induction was noted within 30-60 min of H-59 injection, reaching maximal levels at 4-6 h. This was followed by the appearance of E-selectin mRNA, which was detectable at 2 h after injection and reached maximal levels at 6-8 h, declining to basal levels by 24 h. In situ hybridization analysis and immunohistochemistry localized E-selectin mRNA and protein, respectively, to the sinusoidal endothelium. M-27 cells failed to induce cytokine or E-selectin expression, whereas B-16 cells elicited a delayed and more short-lived response. The results demonstrate that upon entry into the hepatic circulation, tumor cells can rapidly trigger a molecular cascade leading to the induction of E-selectin expression on the sinusoidal endothelium and suggest that E-selectin induction may contribute to the liver-colonizing potential of tumor cells. PMID- 10096571 TI - Fas (APO-1/CD95) signaling pathway is intact in radioresistant human glioma cells. AB - Radiation-induced apoptosis can be mediated through pathways initiated by either DNA damage or ceramide-induced Fas signaling. Glioblastoma multiforme is a primary brain tumor that is highly resistant to irradiation, and U-87 MG, SF126, and T98G are glioblastoma-derived cell lines that mimic this characteristic. We found that these radioresistant glioma cells are susceptible to Fas-mediated cell death induced by treatment with either anti-Fas antibody or exogenous ceramide. Fas-mediated cell death in these cell lines is p53-independent. These data demonstrate that apoptosis can be induced by ceramide and mediated through the Fas pathway in glioma cells, although high-dose ionizing radiation fails to trigger this pathway. PMID- 10096572 TI - Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1 mediated apoptosis. AB - Previous studies (Y. Guo and N. Kyprianou, Cell Growth Diff., 9: 185-193, 1998) have demonstrated that overexpression of transforming growth factor (TGF) beta type II receptor (TbetaRII) gene in human prostate cancer cells LNCaP, which are refractory to TGF-beta1 and lack TbetaRII receptor expression, can restore TGF beta1 sensitivity and suppress in vitro tumorigenic growth by inhibiting cell proliferation. In the present study, we investigated the effect of TbetaRII receptor overexpression in LNCaP cells on apoptosis induction and tumorigenicity. The ability of LNCaP cells that overexpress TbetaRII to undergo apoptosis in response to TGF-beta1 was examined by DNA fragmentation and terminal transferase mediated dUTP-biotin end labeling analysis. To explore the potential apoptotic nature of TGF-beta1-mediated antitumor effect against human prostate cancer cells, the expression of apoptotic proteins bcl-2 and bax was examined by Western blot analyses. The significance of caspase 1 in TGF-beta1-mediated apoptosis was also determined by examining the expression and activation of caspase 1 by reverse transcription-PCR and Western blot analyses, respectively. Comparative analysis of tumorigenicity of the parental LNCaP and TbetaRII-overexpressing clones in severely combined immunodeficient mice revealed a significant suppression of tumor growth in TbetaRII transfectant clones compared with parental LNCaP cells and neomycin-control clones (P < 0.05). A significantly higher incidence of endogenous apoptosis was observed in TbetaRII clone-61 derived tumor compared with the parental LNCaP tumors. This induction of apoptosis in the LNCaP tumors with restored TGF-beta1 signaling was associated with decreased bcl-2 expression, increased bax, and caspase-1 immunoreactivty. Moreover, an increased expression of the cyclin-dependent kinase inhibitor p27Kip1 was detected in TbetaRII-overexpressing tumors compared with the parental tumors. LNCaP TbetaRII transfectant cells exhibited a marked induction of apoptosis, paralleled with a decreased bcl-2 expression in response to TGF-beta1 treatment in vitro. This TGF-beta1-mediated apoptosis induction in TbetaRII transfectant cells was significantly protected by the caspase-1 inhibitor (zVAD fmk) in a dose-dependent manner. Furthermore, a significant temporal induction of caspase-1 mRNA and protein expression was detected in TbetaRII cells in response to TGF-beta1 treatment. Our findings suggest that restoration of TGF-beta1 signaling suppresses tumorigenicity of human prostate cancer cells by inducing apoptosis, potentially via a caspase-1-mediated pathway. PMID- 10096573 TI - Elevated constitutive IkappaB kinase activity and IkappaB-alpha phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GRO-alpha transcription. AB - The basal transcription of the CXC chemokine, melanocyte growth stimulatory activity (MGSA)/growth-regulated protein (GRO)-alpha, is up-regulated in Hs294T melanoma cells compared with the normal retinal pigment epithelial (RPE) cells. Previous studies characterized a cytokine-inducible, functional nuclear factor (NF)-kappaB consensus element in the immediate 5' regulatory region of the MGSA/GRO-alpha gene at -78 bp. Although the cytokine-inducible mechanisms for transcription of this gene are fairly well delineated, the mechanisms involved in its basal up-regulation of transcription in Hs294T melanoma cells are poorly understood. Recently, we demonstrated an increased rate of IkappaB-alpha degradation in Hs294T cells, which leads to an increased nuclear localization of NF-kappaB (R. L. Shattuck-Brandt and A. Richmond. Cancer Res., 57: 3032-3039, 1997). Here we demonstrate that Hs294T melanoma cells have elevated basal IkappaB kinase (IKK) activity relative to RPE cells, causing an increased constitutive IkappaB-alpha phosphorylation and degradation. We also show here that the resultant elevated nuclear NF-kappaB (p50/p65) in these cells is responsible for the increased basal transcription of MGSA/GRO-alpha. Pretreatment of Hs294T or RPE cells with proteasome inhibitors MG115 or MG132 captures the slower migrating, constitutively phosphorylated form of IkappaB-alpha in Hs294T melanoma cells, but not in RPE cells. In addition, a phospho-specific antibody that specifically recognizes the inhibitory form of IkappaB that is phosphorylated at Ser-32 reacted with IkappaB-alpha in Hs294T cell, but not in unstimulated RPE cells. Although the basal level of protein expression of IKK-alpha or IKK-beta are the same in both Hs294T and RPE cells, immunoprecipitation with IKK-alpha antibody combined with activity assay reveal a constitutively active IKK complex in Hs294T melanoma cells. Cotransfection of a 350-bp MGSA/GRO-alpha promoter luciferase reporter construct with either the dominant negative IKK-alpha or the repressors of NF-kappaB, the IkappaB-alpha wild type or mutants lacking the inducible phosphorylation sites, demonstrates that the increased basal MGSA/GRO alpha transcription in the Hs294T cells is due to the enhanced nuclear activation of NF-kappaB. PMID- 10096574 TI - Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. AB - In contrast to the negative autoregulation of glucocorticoid receptor (GR) expression seen in most cells and tissues, GR expression is positively autoregulated in human leukemic T cells and in other cells sensitive to glucocorticoid-induced cell death. To determine whether positive autoregulation is a necessary component of glucocorticoid-induced cell death, a wild-type GR gene under the control of a tetracycline-regulated promoter was stably transfected into glucocorticoid-resistant cells lacking endogenous functional receptor. Transfectants grown in the presence of tetracycline contained about 15,000 receptors/cell, a value approximately equal to basal level GR expression in glucocorticoid-sensitive 6TG1.1 cells before steroid treatment. Under these conditions, dexamethasone had a minimal effect on cell growth, elicited little internucleosomal DNA fragmentation, and induced no cell cycle perturbation. In the absence of tetracycline, GR mRNA and protein expression increased 2-3-fold, and cells expressed 48,000 receptors, a level nearly equivalent to that present in 6TG1.1 cells after 18 h of autoinduction. Under these conditions, dexamethasone markedly inhibited cell growth, caused G1 arrest, and induced significant internucleosomal DNA fragmentation. These studies therefore suggest that basal level GR expression is inadequate to mediate glucocorticoid-induced apoptosis in glucocorticoid-sensitive T cells and that positive autoregulation is a necessary component of this process. PMID- 10096575 TI - Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): safety and efficacy studies. AB - 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) significantly inhibits viral reverse transcription and has been reported to sustain low virus load in SIV infected rhesus monkeys. Based on these findings, studies were conducted to assess the safety, efficacy, and placental transfer of PMPA when administered once daily subcutaneously to gravid rhesus monkeys during the second and third trimesters and their offspring (30 mg/kg/day). Fetuses (SIV-infected, N = 6; noninfected, N = 6) were monitored sonographically, and maternal/fetal blood samples were collected at select time points for hematologic, clinical chemical, virologic, immunologic, and pharmacologic assessments. Newborns were delivered by cesarean section at term and nursery reared for postnatal studies. Infants were administered PMPA once daily beginning on day 2 of life until 9 months postnatal age. Results of these studies have shown significant placental transport of PMPA, with peak fetal levels at 1 to 3 hours post-maternal administration; a significant and sustained reduction in viral load in SIV-infected fetuses and infants; and marked improvements in outcome (e.g., survival, growth, health) in SIV-infected offspring. However, decreased infant body weights and alterations of select serum biochemical parameters (e.g., decreased phosphorus levels, elevated alkaline phosphatase) have been shown to occur in approximately 67% of PMPA treated infants, with severe growth restriction and bone-related toxicity in approximately 25% of animals studied. These data suggest that although PMPA holds great promise for HIV-infected patients, there is the potential for bone-related toxicity at chronic, high dosages, particularly in infants. PMID- 10096576 TI - Human cyclophilin has a significantly higher affinity for HIV-1 recombinant p55 than p24. AB - The ability of cyclophilin to bind a panel of recombinant HIV-gag proteins was assessed using sensitive, quantitative, sandwich enzyme-linked immunosorbant assays (ELISAs). Significantly higher binding to cyclophilin was observed when recombinants contained at least 12 carboxy-terminal amino acids of p17 in addition to p24 sequences. These results indicate that the carboxy-terminus of p17 is important for optimal binding of cyclophilin to p24 and support the theory that cyclophilin acts on the uncleaved HIV-1 gag (p17-p24) precursor. PMID- 10096577 TI - AIDS-associated Kaposi's sarcoma is more aggressive in women: a study of 54 patients. AB - OBJECTIVE: To describe the epidemiologic and clinical features of AIDS-associated Kaposi's sarcoma (KS) in women compared with men. METHODS: In a retrospective study, within the Italian Cooperative Group on AIDS and Tumors (GICAT), we compared selected characteristics of 54 women and 108 men with AIDS-associated KS, matched by date of KS diagnosis and referral hospital. The chi2 test was used to test differences among proportions; the Kaplan-Meier method to estimate the survival time, and the Cox proportional hazard model was used to assess the role of gender, age, and CD4 cell count on death's risk. RESULTS: KS occurred at an earlier age (p = .001), was associated with a more severe immunodeficiency (p = .03), more advanced stages of HIV disease (p = .05), and had more aggressive presentation and course in women than in men. At KS diagnosis, women had a significantly increased proportion of visceral disease (p = .009), in particular pulmonary involvement (p = .002) and atypical sites of involvement (p = .008). The number of deaths due to KS was significantly higher (p = .01) in female patients. Both the higher proportion of visceral disease and of KS-related deaths observed in women did not change after adjusting for CD4 cell count and age. Women showed a decreased overall survival compared with men (8.9 and 14.4 months, respectively; p = .07), and the CD4 cell count at diagnosis significantly influenced survival. CONCLUSIONS: This study suggests that KS is more aggressive and life threatening in female than in male patients. This peculiar clinical behavior may reflect an inherently more aggressive biology of KS in women, possibly mediated by the level of immunodeficiency. PMID- 10096578 TI - Trypanosoma cruzi meningoencephalitis in HIV-infected patients. AB - Five cases of Trypanosoma cruzi meningoencephalitis in HIV-infected patients are reported. All patients presented with mass lesions on head computed tomographic scan, trypanosomes in the cerebrospinal fluid and failure to respond to antitoxoplasmosis therapy. Benznidazole therapy was associated with clinical improvement in 1 patient. Another 4 patients had T cruzi identified in a peripheral smear. T cruzi needs to be considered in the differential diagnosis of HIV-infected patients with central nervous system mass lesions if they have a history of appropriate exposure. PMID- 10096579 TI - Effect of renal disease and hemodialysis on foscarnet pharmacokinetics and dosing recommendations. AB - BACKGROUND: Foscarnet is an antiviral agent commonly used for managing patients with cytomegalovirus infection. Despite its clinical usefulness, foscarnet is associated with substantial adverse effects including nephrotoxicity. Moreover, foscarnet is primarily eliminated unchanged through the kidneys, thus requiring aggressive dose adjustment during kidney failure. To develop specific dosage guidelines, information on the disposition of this compound in patients with varying degrees of renal function and those requiring dialysis is essential. DESIGN: Twenty-six subjects were enrolled in this study and divided into five groups depending on their degree of renal dysfunction. Group 1 included subjects with normal renal function; group 5 included subjects requiring maintenance hemodialysis. Nondialysis study subjects received a single 60-mg/kg intravenous dose of foscarnet whereas hemodialysis subjects received two intravenous doses, separated by 1 week, to compare the effects of conventional and high-flux dialysis methods. RESULTS: Mean plasma clearance in control subjects averaged 2.1+/-0.7 ml/minute/kg and declined proportionally with changing renal function as indicated by the regression equation: Clp (ml/minute/kg) = 1.48 [CrCl (ml/minute/kg)]-0.08 (r2 = 0.82). Mean half-life averaged 1.9+/-0.1 hours in normal subjects and increased to a mean of 25+/-19 hours in study subjects with severe impairment not on dialysis. Foscarnet dialysis clearance (based on dialysate recovery) averaged 183 ml/minute with conventional dialysis methods and 253 ml/minute during high-flux procedures, which resulted in removal of 37% and 38% of a dose for the two methods, respectively. CONCLUSIONS: These data indicate that substantial dosage adjustments must be made in renal failure patients. Therefore, a patient-specific dosage nomogram has been developed. PMID- 10096580 TI - Active anti-interferon-alpha immunization: a European-Israeli, randomized, double blind, placebo-controlled clinical trial in 242 HIV-1--infected patients (the EURIS study). AB - This randomized, double-blind, placebo-controlled, phase II/III study was designed to evaluate safety, immunogenicity, and efficacy of an active anti interferon-alpha (anti-IFN-alpha) vaccine in asymptomatic HIV-1-infected patients. The active immunization was aimed at inducing anti-IFN-alpha antibodies to counteract IFN-alpha overproduction. In all, 242 patients, recruited between December 1995 and July 1996 in eight centers in Europe and Israel, with CD4+ counts from 100 to 634 cells/mm3 who were receiving or not receiving antiretroviral therapy (including protease inhibitors) were randomized to receive either anti-IFN-alpha vaccine or placebo. The anti-IFN-alpha immunization regimen consisted of three priming injections delivered intramuscularly at 1-month intervals in a water-in-oil emulsion of inactivated recombinant IFN-alpha-2b (i IFN-alpha) followed by intramuscular booster injections of i-IFN-alpha adsorbed onto calcium phosphate every 3 months. Immunogenicity to vaccine was defined as an increase of anti-IFN-alpha antibody level of more than twofold the preimmunization value. Clinical progression, changes in antiretroviral treatment, and decrease of CD4+ counts to <200 cells/mm3 were considered endpoints for efficacy evaluation. Contrary to our previous experience, in which six to seven oil priming injections induced a >90% response rate, the three oil-adjuvanted injections in this trial were suboptimal because only 40 of 122 vaccinees (33%) had raised anti-IFN-alpha antibody following immunization. In vaccinees, both antibody responders (AbRV) and nonresponders (AbNRV), the tolerance to the vaccine was good and was without evidence of significant safety concerns. During the course of the trial, 62% of vaccine responders, 64% of nonresponders, and 63% of placebo patients elected to add protease inhibitor-containing regimens as new treatment guidelines were established, resulting in a marked decrease in clinical and laboratory progression such that the expected endpoints of the study could not be achieved and further follow-up was halted. Despite the unexpectedly low immunogenicity and fewer than expected endpoints, anti-IFN-alpha vaccine recipients, in comparison with placebo recipients, showed a lower rate of disease progression, nonelective treatment changes, and/or CD4+ count decrease to <200 cells/mm3, but the difference was not statistically significant. Nevertheless, the subgroup of patients immunized to IFN-alpha who experienced a rise in anti IFN-alpha antibodies had a significantly lower rate of occurrence of HIV-1 related events and of any combination of the endpoints compared with those of either placebo patients or vaccinees who failed to develop anti-IFN-alpha antibodies, the latter two groups behaving similarly. Further studies of this approach are warranted because these data suggest a beneficial effect of this adjuvant approach. PMID- 10096581 TI - Tat toxoid as a component of a preventive vaccine in seronegative subjects. AB - Because administration of Tat protein, the HIV-1 toxin that induces immunosuppression and apoptosis, may be deleterious to the host immune system, a chemically inactivated but nonetheless immunogenic Tat preparation, Tat toxoid, was used to immunize seronegative individuals against Tat. In an open, controlled, phase I clinical trial, Tat toxoid turned out to be safe, well tolerated, and able to trigger a specific immune reaction. In particular, a threefold to more than 10-fold increase of circulating antibodies directed against the native Tat was observed after immunization in all of 5 immunized study subjects, together with a positive reaction to delayed-type hypersensitivity (DTH) skin test with Tat toxoid in vivo and increased lymphoproliferative response to native Tat in vitro. Persistent (> or =1 year) high levels of circulating anti-Tat antibodies could prevent the Tat-induced immune suppression and, following HIV-1 exposure, allow the anti-HIV-1 cellular immune response, with its early release of protective beta-chemokines, to occur leading to an increase of host resistance, that is, protection. PMID- 10096582 TI - Estimating AIDS-free survival in a severely immunosuppressed asymptomatic HIV infected population in the era of antiretroviral triple combination therapy. Swiss HIV Cohort Study. AB - BACKGROUND: Antiretroviral triple combination therapies have been evaluated in randomized controlled trials and cohort studies. Little is known about their impact on asymptomatic, severely immunosuppressed, HIV-infected individuals in a real world population. OBJECTIVES: To describe disease progression in a broad asymptomatic population of HIV-infected individuals with a CD4 count <100 cells/mm3 before and after the introduction of combination triple therapy. DESIGN: Six-month homogenous Markov chain consisting of four recurrent AIDS-free states and one absorbing AIDS state: (1) CD4 count > or =100 cells/mm3, (2) CD4 count 75 to 99 cells/mm3, (3) CD4 count 50 to 74 cells/mm3, (4) CD4 count 0 to 49 cells/mm3, and AIDS. SETTING: Swiss HIV Cohort Study database. PATIENTS: A total of 1027 patients contributed to 2634 pairs of 6-month observations from 1993 to 1995, and 681 patients contributed to 2077 pairs of 6-month observations from 1996 to 1997. MEASUREMENT: AIDS-free survival probabilities and the expected AIDS free survival time. RESULTS: The expected number of AIDS-free months in a 3-year period was 17 (95% confidence interval [CI], 16-19) for patients starting in state 4 prior to 1996 versus 26 months (95% CI, 24-28) for patients starting in state 4 after 1996. For these two time periods, the corresponding expected numbers of AIDS-free months were 21 (95% CI, 20-22) versus 30 (95% CI, 28-32) for state 3 and 23 (95% CI, 21-24) versus 33 (95% CI, 32-34) for state 2. CONCLUSION: Expected 3-year AIDS-free survival in severely immunosuppressed individuals with CD4 counts <100 cells/mm3 improved significantly between 1993 to 1995 and 1996 to 1997. PMID- 10096583 TI - Bacterial vaginosis associated with HIV infection in pregnant women from North Carolina. AB - BACKGROUND: We investigated whether bacterial vaginosis is associated with HIV infection in pregnant women in North Carolina, U.S.A. METHODS: At 24 to 29 weeks' gestation, we recruited 724 women receiving prenatal care to provide interview information and vaginal swabs for Gram's stain scoring of vaginal flora. FINDINGS: As vaginal flora score increased, prevalence of HIV increased (trend p = .03). HIV prevalence was 0.8% (4 of 489 patients), 1.2% (1 of 84 patients), and 3.3% (5 of 151 patients) among women with normal, intermediate, and abnormal vaginal flora, respectively. All HIV-infected women were free from AIDS and were taking antiretroviral medication. Compared with women with normal vaginal flora, the relative risk for prevalence of HIV infection with intermediate flora was 1.5 (95% confidence interval [CI], 0.2, 12.9) and with abnormal flora was 4.0 (95% CI, 1.1, 14.9). The association between abnormal vaginal flora and HIV infection could not be explained by age, ethnicity, number of sexual partners in the past 6 months, sexually transmitted diseases (STDs), or douching during pregnancy. INTERPRETATION: In a population with a relatively low HIV prevalence, vaginal flora abnormalities were associated with prevalent HIV infection. We cannot determine whether vaginal flora abnormalities increase women's susceptibility to HIV infection or become more common after infection. The increased prevalence of bacterial vaginosis among HIV-infected pregnant women increases risk for preterm delivery. Incidence studies are required to discern whether control of bacterial vaginosis might reduce HIV infectivity. PMID- 10096584 TI - Kaposi's sarcoma-associated herpesvirus: a sexually transmissible infection? AB - We examined sexual behavior as a risk factor for Kaposi's sarcoma-associated herpesvirus (KSHV) infection and examined the relation between KSHV seropositivity and development of KS in cross-sectional and cohort studies of 130 homosexual men diagnosed with AIDS in Sydney, Australia during the period from 1991 to 1993. KSHV serology was measured using antibody tests to latency associated nuclear antigen (LANA) and lytically expressed open reading frame (ORF) 65.2. In the cross-sectional analysis, 52% (68) of study subjects were KSHV seropositive by either assay. KSHV-seropositive men were significantly more likely to be seropositive to both herpes simplex type 2 (odds ratio [OR] 3.0; 95% confidence interval [CI], 1.2-7.5 for LANA and OR 2.8; 95% CI, 1.3-6.0 for ORF 65) and hepatitis A virus (OR 2.2; 95% CI, 1.1-4.5 for ORF 65). KSHV-seropositive men reported nonsignificantly more casual sexual partners and were nonsignificantly more likely to report insertive oroanal contact with casual partners. These data suggest that KSHV might be sexually transmitted among homosexual men. Men were observed until October 1996 for development of KS. Those seropositive to either KSHV assay at baseline were more likely than the seronegative to develop KS during follow-up (rate ratio [RR] 4.4; 95% CI, 1.9 10.2). Of those seropositive for KSHV, 53% developed KS. PMID- 10096585 TI - Implication of HTLV-I infection, strongyloidiasis, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphomas in an endemic area (Martinique, French West Indies). AB - A clinicopathologic study was conducted to assess the implication of HTLV-I infection, Strongyloides stercoralis (Ss) infection, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphoma (NHL) in Martinique, French West Indies. Two groups of patients, with 22 and 41 participants with B-cell and T-cell lymphoma, respectively, were analyzed. HTLV-I antibodies were detected in 24 (59%) patients with T-cell lymphoma of whom 19 (46%) fulfilled diagnostic criteria of adult T-cell leukemia/lymphoma (ATLL). By comparison with other T-cell lymphomas, patients with ATLL were significantly younger (52 versus 63 years; p = .03), had a significantly higher incidence of hypercalcemia (60% versus 0%; p = .0001), a trend for higher incidence of digestive tract localization (21% versus 4%; p = .1) and significantly shorter median survival (6 versus 17 months; p = .03). Similar results were observed when all 24 HTLV-I-infected patients with T-cell lymphoma were compared with the 17 seronegative patients. Strongyloidiasis was diagnosed in 11 of 34 patients tested for Ss infection. All 4 Ss-infected (Ss-positive) ATLL patients treated with combination chemotherapy achieved complete remission (CR) versus only 2 of 7 Ss negative ATLL patients (p = .04). In addition, survival of Ss-positive patients with ATLL was better than that of the uninfected patients: 27 versus 5 months, p = .04, respectively). P53 expression was assessed by immunohistochemistry on lymph node biopsies from 37 patients including 18 B-cell lymphomas, 14 ATLL, and 5 other T-cell lymphomas. P53 overexpression (P53-positive) was observed in 6 samples that corresponded in all 6 patients with ATLL. All P53-positive ATLL patients had stage IV disease with elevated lactate dehydrogenase (LDH) levels. By comparison with other ATLL patients studied for p53 expression, P53-positive ATLL were characterized by a lower response rate to combination chemotherapy (CR: 0 of 6 versus 4 of 6; p = .04) and a shorter survival (2 versus 9 months, p = .04). Our results suggest that ATLL represents almost 50% of T-cell lymphomas in Martinique; Ss infection during ATLL seems to be linked with a high response rate to chemotherapy and prolonged survival; and P53 overexpression is observed in almost 50% of aggressive ATLL from Martinique and, even in advanced clinical subtypes, is associated with resistance to chemotherapy and short-term survival. PMID- 10096586 TI - Transmission of HTLV-I to rats via peripheral blood mononuclear cells and serum from a patient with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) with amyotrophic lateral sclerosis (ALS)-like features. AB - We tested the possibility that lymphocytes and serum obtained directly from a patient with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) induce infection in rats. Inbred Fischer F344 immunosuppressed rats were inoculated intravenously with 10x10(6) peripheral blood mononuclear cells (PBMC; 3 rats) and serum (3 rats) obtained from a HAM/TSP patient, who was seropositive and polymerase chain reaction (PCR)-positive for the HTLV-I proviral genome. Antibodies to HTLV-I appeared in the rat sera 2 months later; rat peripheral blood lymphocytes, spleen, salivary gland, and spinal cord were found to contain the proviral genome. Control rats inoculated with normal donor PBMC and serum tested negative for the HTLV-I antibodies and for the HTLV-I proviral genome by PCR. The positive control F344 rats inoculated with 5x10(6) cells of a SLB-1 HTLV I cell line were found to be infected after 2 months. This study demonstrates for the first time that HTLV-I can be transmitted not only by human cellular components but also by human cell-free sera in a rat model. PMID- 10096587 TI - Neonatal characteristics and outcome in a cohort of infants born to HIV-1 infected African women from Durban, South Africa. PMID- 10096588 TI - Appreciation: James V. Neel. PMID- 10096589 TI - The Colonel Harlan D. Sanders Award Address for 1998: JC virus and its possible role in oncogenesis. PMID- 10096591 TI - Synteny-defined candidate genes for congenital and idiopathic scoliosis. AB - Idiopathic scoliosis (IS) is a common but poorly understood syndrome. Congenital scoliosis (CS) is less common but comparably unexplored. Previous studies suggest that each has a significant genetic component. However, the occurrence of scoliosis in the presence of other hereditary connective tissue syndromes raises the possibility that IS and CS are in fact a heterogeneous group of disorders with varied pathogenetic mechanisms. Mouse mutations have proven informative in identifying genes that are important in the development of the musculoskeletal system and provided important mechanistic insights regarding their roles in human disease. We sought to identify candidate genes for human IS and CS by reviewing mouse mutations with phenotypes affecting the axial skeleton. We performed a systematic review using the Mouse Genome Database (MGD), the Genome Database (GDB), and the Online Mendelian Inheritance in Man (OMIM) world-wide-web sites with additional searches performed based on the results of this initial search. We identified approximately 400 mouse mutations, reviewed approximately 250 of these for vertebral phenotypes, assessed 45 of these for synteny conservation between mouse and man, and identified 28 mouse mutations for which 29 credible candidates for human scoliosis could be identified based on mouse phenotypic and mapping data. For each of these, we have synthesized information about the mouse mutant phenotype, mapping data, information regarding molecular pathogenesis when a specific causative gene has been identified, and information regarding plausible candidates based on map position when the causative gene has not been identified. Among these were three loci for which the mutant gene had been identified and the human homologue was known. Some of the mouse mutants have phenotypes similar to human syndromes. PMID- 10096590 TI - Commercialization of BRCA1/2 testing: practitioner awareness and use of a new genetic test. AB - It was our purpose to determine the characteristics of practitioners in the United States who were among the first to inquire about and use the BRCA1 and BRCA2 (BRCA1/2) genetic tests outside of a research protocol. Questionnaires were mailed to all practitioners who requested information on or ordered a BRCA1/2 test from the University of Pennsylvania (UPenn) Genetic Diagnostics Laboratory (GDL) between October 1, 1995 and January 1, 1997 (the first 15 months the test was available for clinical use). The response rate was 67% of practitioners; 54% (121/225) were genetic counselors, 39% (87/225) were physicians or lab directors. Most physicians were oncologists, pathologists, or obstetrician/gynecologists, but 20% practiced surgery or internal or general medicine. Fifty-six percent (125/225) had ordered a BRCA1/2 test for a patient; most of the rest had offered or were willing to offer testing. Of those who had offered testing, 70% had a patient decline BRCA1/2 testing when offered. Practitioners perceived that patients' fear of loss of confidentiality was a major reason for declining. Nearly 60% of practitioners reported that their patients had access to a genetic counselor, but 28% of physicians who ordered a BRCA1/2 test reported having no such access, despite the GDL's counseling requirement. The proportion of physicians reporting no access to genetic counselors for their patients increased from 22.4% in the first half of the study to 50% in the last half. Many practitioners have an interest in BRCA1/2 testing, despite policy statements that discourage its use outside of research protocols. Practitioner responses suggest that patient interest in testing seems to be tempered by knowledge of potential risks. An apparent increase in patient concern about confidentiality and inability to pay for testing could indicate growing barriers to testing. Although most practitioners reported having access to counseling facilities, perceived lack of such access among an increasing proportion of practitioners indicates that lab requirements for counseling are difficult to enforce and suggests that an increasing proportion of patients may not be getting access to counseling. PMID- 10096592 TI - Dyskeratosis congenita: an autosomal recessive variant. AB - We describe a woman with dyskeratosis congenita (DKC), microcephaly, and a purple discoloration of the tongue. The latter findings are not commonly described in males with DKC, have been reported in another female patient with this condition, and may represent the phenotype of an autosomal recessive entity of DKC. Results of X chromosome inactivation studies did not support X-linked DKC in our family. The additional findings of an affected brother and parental consanguinity support the hypothesis of autosomal recessive inheritance. PMID- 10096593 TI - Family with low-grade neuroendocrine carcinoma of salivary glands, severe sensorineural hearing loss, and enamel hypoplasia. AB - Four sibs in a family on the Isle of Man, two brothers and two sisters ranging in age from 33 to 45 years, presented with low-grade malignant tumors of the submandibular gland in three cases and of the nasal cavities and maxillary sinuses in one. The neoplasms were all of the same histological type, apparently hitherto undescribed, showing well-differentiated neoplastic ducts, surrounded by neoplastic myoepithelial cells, together with sheets of epithelial cells expressing neuroendocrine markers by immunohistochemistry. Cervical neck node metastases have developed in all four cases. In the sib with a primary sinonasal neoplasm, widespread bloodstream metastases also became manifest and a single such metastasis in his brother. All four sibs have severe enamel hypoplasia and the same lesion is present in 5 of their 11 children. In the two male patients, severe sensorineural hearing loss has developed in adult life, unilateral in the left ear in one brother, bilateral in the other. In the brother with bilateral sensorineural hearing loss, magnetic resonance imaging revealed a vestibular schwannoma on the left side, which is currently under treatment. The inherited hearing loss is thought to be unilateral in this case also. PMID- 10096594 TI - Epidermal nevi and localized cranial defects. AB - We report on a girl with a congenital pigmented hairy nevus of the scalp, epidermal nevi of the right temple, and localized cranial defects. We have not found other reported cases of giant pigmented hairy nevus of the scalp occurring with absence of underlying cranial bone. We speculate that the localized cranial defects are undergrowth anomalies representative of a paracrinopathy from the overlying nevus or simultaneous bone/skin dysplasia, the former having been resorbed. In the absence of a familial history of epidermal nevi and/or seizures, our patient represents a sporadic case, perhaps a somatic mutation. PMID- 10096595 TI - Complex camptopolydactyly: an unusual hand malformation. AB - Different types of polydactylies and other hand malformations are commonly seen. Here, we describe a very unusual type of hand malformation characterised by campto-polydactyly with totally disorganised configuration of digits. The role of possible genes involved in development of hands and digits is discussed. PMID- 10096596 TI - Autosomal dominant secundum atrial septal defect with various cardiac and noncardiac defects: a new midline disorder. AB - We report on a Lebanese family in which 12 persons had an atrial septal defect and various cardiac and noncardiac anomalies. Cardiac anomalies are left axis deviation of QRS, right bundle branch block, atrial fibrillation, Wolff-Parkinson White syndrome, nodal atrioventricular rhythm, aortic stenosis, pulmonic valve stenosis, mitral stenosis (Lutembacher syndrome), and low implantation of the tricuspid valve (Ebstein disease). Noncardiac abnormalities consisted specially of the presence of hypertelorism, cleft lip, and pectus excavatum. This combination appears to constitute a hitherto undescribed autosomal dominant midline disorder of the heart and upper half of the body with almost full penetrance and variable expressivity. The mutation does not map to any known locus involved in atrial septal defect or conduction block. PMID- 10096597 TI - GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. AB - Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene encoding GATA-4, a zinc finger transcription factor implicated in cardiac gene expression and development, localizes to chromosome region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four individuals with del(8)(p23.1) and congenital heart disease were found to be haploinsufficient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth patient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 locus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart disease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2 5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1. PMID- 10096598 TI - Genetic heterogeneity associated with branchio-oto-renal syndrome. PMID- 10096599 TI - Keutel syndrome and miscarriages. PMID- 10096600 TI - Reply to letter to the editor by Schrander-Stumpel--"what's in a name?". PMID- 10096601 TI - Abnormal sterol metabolism in patients with Conradi-Hunermann-Happle syndrome and sporadic lethal chondrodysplasia punctata. AB - The term, "chondrodysplasia punctata" (CDP) denotes a pattern of abnormal punctate calcification of dystrophic epiphyseal cartilage and certain other cartilaginous structures, such as the larynx. CDP occurs in a variety of genetic disorders associated with skeletal dwarfism and can also be caused by prenatal exposure to warfarin. Although the most studied clinical syndrome with CDP, rhizomelic chondrodysplasia punctata (RCDP), is known to be caused by several different abnormalities of plasmalogen biosynthesis, there are many other genetic disorders with CDP for which the biochemical cause is unknown. Because patients with Smith-Lemli-Opitz syndrome, a primary disorder of sterol biosynthesis, often have rhizomesomelic limb shortness and, less commonly, CDP, we assessed sterol levels and metabolism in patients with different clinical forms of CDP. By quantitative sterol analysis of a variety of tissues, we identified 5 patients with similar radiological findings and abnormally increased levels of 8 dehydrocholesterol and cholest-8(9)-en-3beta-ol, suggesting a deficiency of 3beta hydroxysteroid-delta8,delta7-isomerase, a principal enzyme of cholesterol biosynthesis. Cultured cells available from one patient showed increased levels of the same two sterols, decreased synthesis of cholesterol, and a pattern of inhibition by triparanol and AY-9944 consistent with a deficiency of 3beta hydroxysteroid-delta8,delta7-isomerase. Clinical diagnoses among the 5 patients included X-linked dominant Conradi-Hunermann-Happle syndrome and nonspecific lethal CDP. We conclude that abnormal cholesterol biosynthesis is a characteristic of some clinical syndromes with rhizomesomelic dwarfing and CDP. PMID- 10096602 TI - Expression of sonic hedgehog, patched, and Gli1 in developing taste papillae of the mouse. AB - Lingual taste buds form within taste papillae, which are specialized structures that develop in a characteristic spatial and temporal pattern. To investigate the signaling events responsible for patterning and morphogenesis of taste papillae, the authors examined the time course and distribution of expression of several related developmental signaling genes as well as the time course of innervation of taste papillae in mouse embryos from embryonic day 12 (E12) to E18. Lingual expression of the signaling molecule Sonic hedgehog (Shh), its receptor Patched (Ptc), and the Shh-activated transcription factor Gli1 were assayed by using in situ hybridization. Shh is expressed broadly in the lingual epithelium at E12 but becomes progressively restricted to developing circumvallate and fungiform papillary epithelia. Shh is expressed specifically within the central cells of the papillary epithelium starting at E13.5 and persisting through E18. Ptc and Gli1 expression follow a pattern similar to that of Shh. Compared with Shh, Ptc is expressed in larger regions surrounding the central papillary cells and also in the mesenchyme underlying Shh-expressing epithelium. Innervation of taste papillae was examined by using the panneuronal antibody to ubiquitin carboxyl terminal hydrolase (protein gene product 9.5). Nerves reach the basal lamina of developing taste papillae at E14 to densely innervate the papillary epithelium by E16. Thus, the pattern of Shh expression within developing taste papillae is established prior to innervation, ruling out neuronal induction of papillae. The results suggest that the Shh signaling pathway may be involved in: 1) establishing papillary boundaries in taste papilla morphogenesis, 2) papillary epithelial-mesenchymal interactions, and/or 3) specifying the location or development of taste buds within taste papillae. PMID- 10096603 TI - Enhanced survival and morphological features of basal forebrain cholinergic neurons in vitro: role of neurotrophins and other potential cortically derived cholinergic trophic factors. AB - The present study examined survival- and growth-enhancing effects of cortical cells on basal forebrain cholinergic neurons (BFCNs) in culture and the degree to which endogenous nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) contribute to those trophic effects. When fetal (17 days of gestation) basal forebrain (BF) cells were grown for 5 days in coculture with cortical neurons, staining for acetylcholinesterase (AChE) showed a threefold increase in the number of BFCNs relative to BF cultures without cortex. Most of these labeled cells also displayed enhanced somatic, dendritic, and axonal growth. Coculturing cortical neurons with BF cells taken from postnatal animals produced similar results but with a somewhat greater degree of morphologic enhancement. Function-neutralizing antibodies to NGF, BDNF, and NT-3 were employed to determine whether they would block the trophic effects of cortical neurons on postnatal BFCNs. Although no significant changes in numbers or morphological features of AChE(+) neurons were observed with treatment with individual antibodies, cocultures treated with a combination of all three antibodies displayed fewer morphologically enhanced AChE(+) cells and more nonenhanced cells; the total number of AChE(+) neurons was not significantly changed. Treatment of pure BF cultures with exogenous NGF, BDNF, and NT-3 increased the number of AChE(+) neurons but did not reproduce the morphologic enhancement of cortical cells on BFCNs. These results suggest that neurotrophins by themselves can increase survival of postnatal BFCNs in culture and may work in concert with other unknown cortically derived factors to enhance BFCN morphologic differentiation. The unidentified cortical factors may also have strong survival enhancing effects on BFCNs that are independent of the known neurotrophins. PMID- 10096604 TI - Anatomical demonstration of the suprachiasmatic nucleus-pineal pathway. AB - A polysynaptic pathway is proposed to transmit light information from the retina through the suprachiasmatic nucleus of the hypothalamus (SCN) to the pineal. In the present study, the powerful transneuronal tracer, pseudorabies virus (PRV), was used to provide a detailed description of this pathway. PRV injected into the pineal subsequently labeled the superior cervical ganglion, the intermediolateral column of the upper thoracic cord, the autonomic division of the paraventricular nucleus of the hypothalamus (PVN), and the SCN. Neurons in the autonomic division of the PVN were the only PRV-labeled neurons in the hypothalamus shown to receive input from the SCN as demonstrated by the presence of vasoactive intestinal polypeptide axonal contacts. This observation concurred with the presence of ventrally placed neurons in the SCN that could only be observed a day after the appearance of PVN-labeled neurons. Nevertheless the majority of the neurons were found in the dorsomedial position of the SCN, associated with the vasopressin containing population of SCN neurons. Confocal laser scanning microscopy showed double-labeled neurons containing PRV and vasopressin or PRV and vasoactive intestinal polypeptide. Specificity of tracing was also established by prior removal of the superior cervical ganglion, resulting in a complete absence of the tracer but in the pineal. Thus, the present study provides the anatomical basis for circadian control of melatonin secretion. PMID- 10096605 TI - Class III beta-tubulin expression in sensory and nonsensory regions of the developing avian inner ear. AB - A previous study showed that class III beta-tubulin, a widely used neuron specific marker, is expressed in mature and regenerating hair cells but not the support cells of the avian inner ear. We investigated the expression of this marker in the developing avian inner ear. We found that class III beta-tubulin is not neuron-specific in the avian embryo, but appears to accumulate in neuronal cell types, including hair cells, about the time of their differentiation. In the developing inner ear, some degree of class III beta-tubulin immunoreactivity is found in all regions of the otic epithelium from its formation as the otic placode (stage 10 [embryonic day, E1.5]) until about stage 21 (E3.5), when the prospective tegmentum vasculosum begins to lose its staining. By stage 35 (E8-9), most of the nonsensory epithelia have lost their class III beta-tubulin staining, leaving distinct regions of staining between the morphological compartments of the inner ear. Concurrent with the loss of staining from nonsensory regions, the hair cells of the sensory epithelia accumulate class III beta-tubulin, whereas the supporting cells decrease their staining. We also observed a similar pattern of development in another hair cell organ, the paratympanic organ. Double labeling with the 275 kD hair cell antigen (HCA) indicated that the majority of hair cells identifiable with class III beta-tubulin are HCA-positive. Additionally, presumptive hair cells were identified which were not within defined sensory epithelia. Our findings show that class III beta-tubulin can be used as an early marker for hair cell differentiation in all hair cell sensory epithelia in the chicken. PMID- 10096606 TI - Striatal dopaminergic afferents concentrate in GDNF-positive patches during development and in developing intrastriatal striatal grafts. AB - Glial cell line-derived neurotrophic factor (GDNF) has potent trophic action on fetal dopaminergic neurons. We have used a double immunocytochemical approach with antibodies that recognize GDNF and tyroxine hydroxylase (TH) or the phosphoprotein DARPP-32, to study the developmental pattern of their interactions in the rat striatum and in intrastriatal striatal transplants. Postnatally, at one day and also at 1 week, GDNF showed a patchy distribution in the striatum, together with a high level of expression in the lateral striatal border, similar to that observed for the striatal marker DARPP-32 and also for TH. In the adult striatum, there was diffuse, weak immunopositivity for GDNF, together with widespread expression of DARPP-32-positive neurons and TH-immunoreactive (TH-ir) fibers. In 1-week-old intrastriatal striatal transplants, there were some GDNF immunopositive patches within the grafts and although there was not an abundance of TH-positive fibers, the ones that were seen were located in GDNF-positive areas. This was clearly evident in 2-week-old transplants, where TH-ir fibers appeared selectively concentrated in GDNF-positive patches. This pattern was repeated in 3-week-old grafts. In co-transplants of mesencephalic and striatal fetal tissue (in a proportion of 1:4), TH-ir somata were located mainly at the borders of areas that were more strongly immunostained for GDNF, and TH-ir fibers were also abundant in these areas and were found in smaller numbers in regions that were weakly positive for GDNF. These results demonstrate that GDNF-ir is coincident with that for TH and DARPP-32, and suggest that GDNF release by fetal striatal neurons both in normal development and in developing striatal grafts may have not only a trophic but also a tropic influence on TH-ir fibers and may be one of the factors that regulate dopaminergic innervation of the striatum. PMID- 10096607 TI - Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain. AB - Inositol 1,4,5-trisphosphate receptors (IP3R) are mediators of second messenger induced intracellular calcium release. Three isoforms are known to be expressed in brain, but their regional distributions and cellular localizations are little known. In order to better understand the roles of IP3 receptor isoforms in brain function, a first step is to define their distributions. We have used affinity purified antibodies directed against peptides unique to each isoform to determine their sites of expression in rat brain. Type 1 IP3R (IP3R1) is dramatically enriched in Purkinje neurons in cerebellum and neurons in other regions, consistent with previous studies. By contrast, IP3R2 is only detected in glia, whereas IP3R3 is predominantly neuronal, with little detected in glia. IP3R3 is enriched in neuropil, especially in neuronal terminals (which often contain large dense core vesicles) in limbic and basal forebrain regions including olfactory tubercle, central nucleus of the amygdala, and bed nucleus of the stria terminalis. In addition, IP3R1 and IP3R3 have clearly distinct time courses of expression in developing brains. These data suggest separate roles for inositol 1,4,5-trisphosphate receptor isoforms in development, and for glial and neuronal function. The IP3R3 may be involved in regulation of neurotransmitter or neuropeptide release in terminals within specific nuclei of the basal forebrain and limbic system. PMID- 10096608 TI - Single axon analysis of pulvinocortical connections to several visual areas in the macaque. AB - The pulvinar nucleus is a major source of input to visual cortical areas, but many important facts are still unknown concerning the organization of pulvinocortical (PC) connections and their possible interactions with other connectional systems. In order to address some of these questions, we labeled PC connections by extracellular injections of biotinylated dextran amine into the lateral pulvinar of two monkeys, and analyzed 25 individual axons in several extrastriate areas by serial section reconstruction. This approach yielded four results: (1) in all extrastriate areas examined (V2, V3, V4, and middle temporal area [MT]/V5), PC axons consistently have 2-6 multiple, spatially distributed arbors; (2) in each area, there is a small number of larger caliber axons, possibly originating from a subpopulation of calbindin-positive giant projection neurons in the pulvinar; (3) as previously reported by others, most terminations in extrastriate areas are concentrated in layer 3, but they can occur in other layers (layers 4,5,6, and, occasionally, layer 1) as collaterals of a single axon; in addition, (4) the size of individual arbors and of the terminal field as a whole varies with cortical area. In areas V2 and V3, there is typically a single principal arbor (0.25-0.50 mm in diameter) and several smaller arbors. In area V4, the principal arbor is larger (2.0- to 2.5-mm-wide), but in area MT/V5, the arbors tend to be smaller (0.15 mm in diameter). Size differences might result from specializations of the target areas, or may be more related to the particular injection site and how this projects to individual cortical areas. Feedforward cortical axons, except in area V2, have multiple arbors, but these do not show any obvious size progression. Thus, in areas V2, V3, and especially V4, PC fields are larger than those of cortical axons, but in MT/V5 they are smaller. Terminal specializations of PC connections tend to be larger than those of corticocortical, but the projection foci are less dense. Further work is necessary to determine the differential interactions within and between systems, and how these might result in the complex patterns of suppression and enhancement, postulated as gating mechanisms in cortical attentional effects, or in different states of arousal. PMID- 10096609 TI - Changes in axon arrangement in the retinofugal [correction of retinofungal] pathway of mouse embryos: confocal microscopy study using single- and double-dye label. AB - The changes in quadrant-specific fiber order in the retinofugal pathway of the C57-pigmented mouse aged embryonic day 15 were investigated by using single- (1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate; DiI) and double- (N-4-4-didecylaminostyryl-N-methylpyridinium iodide; 4Di-10ASP in addition to DiI) labeling techniques. At this earliest stage of development, before any fibers arrive at their targets, retinal axons display a distinct quadrant-specific order at the optic stalk close to the eye. This order gradually disappears along the stalk and is virtually lost at the chiasm, as shown in single-label preparations. The double-label preparations, in which the population peaks of fibers from two retinal quadrants are shown simultaneously in an image, show a fiber arrangement at the chiasm that is different from the pattern seen in the single-label preparations. A distinct and consistent preferential distribution of fibers from different retinal quadrants is shown in the chiasm. Before the midline, the central part of the cross section of the chiasm is dominated by dorsal fibers, whereas the rostral and caudal parts of the chiasm are dominated by ventral nasal and ventral temporal fibers, respectively. Moreover, the double-label preparations demonstrate a major reshuffling of fiber position after the fibers cross the midline. Fibers from ventral retina are shifted gradually to a rostral position at the threshold of the optic tract, whereas fibers from dorsal retina are shifted caudally. These changes in fiber position indicate a postmidline location in the chiasm, where fibers are re sorted in accordance with their origins in the dorsal ventral axis of the retina, and suggest a change in axon response to guidance signals when the fibers cross the midline of the chiasm. These changes in fiber order may also be related to the re-sorting of fibers according to their ages at the postmidline chiasm. PMID- 10096610 TI - Localization of NADPHd-exhibiting neurons in the spinal cord of the rabbit. AB - Segmental and laminar distributions of nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd)-exhibiting neurons were examined in the rabbit spinal cord by using horizontal, sagittal, and transverse sections. A large number of NADPHd-positive neurons in the spinal cord of rabbit appeared to fall into six categories (N1-N6), but others could not be classified. Major cell groups of NADPHd-exhibiting neurons were identified in the superficial dorsal horn and around the central canal at all spinal levels and in the intermediolateral cell column at thoracic and upper lumbar levels. NADPHd exhibiting neurons of the pericentral region were divided into a thin subependymal cell column containing longitudinally arranged, small bipolar neurons with processes penetrating deeply into the intermediolateral cell column and/or running rostrocaudally in the subependymal layer. The second pericentral cell column located more laterally in lamina X contains large, intensely stained NADPHd-exhibiting neurons with long dendrites radiating in the transverse plane. In the pericentral region (lamina X), close association of NADPHd-exhibiting somata and fibers and mostly longitudinally oriented blood vessels were detected. Neurons of the sacral parasympathetic nucleus, seen in segments S1-S3, exhibited prominent NADPHd cellular staining accompanied by heavily stained fibers extending from Lissauer's tract through lamina I along the lateral edge of the dorsal horn to lamina V. A massive dorsal gray commissure, highly positive in NADPHd staining, was found in segments S1-S3. Scattered positive cells were also found in the deeper dorsal horn, ventral horn, and white matter. Fiberlike NADPHd staining was found in the superficial dorsal horn and pericentral region in all the segments studied. Dense, punctate, nonsomatic NADPHd staining was detected in the superficial dorsal horn, in the pericentral region all along the rostrocaudal axis, and in the nucleus phrenicus (segments C4-C5), nucleus dorsalis (segments Th2-L2), Onuf's nucleus (segments S1-S3), and the dorsal part of the dorsal gray commissure (S1-S3). PMID- 10096611 TI - The "aesthetic subunit" principle in late TRAM flap breast reconstruction. AB - The "aesthetic subunit" principle is well established in facial reconstruction. This principle dictates that the margins of regional reconstructions correspond to existing visual boundaries. This will minimize the visual perception of "abnormal." The subunit principle also applies to secondary TRAM flap breast reconstructions in which the available chest wall skin is of poor quality. In these situations, it might be aesthetically advantageous to replace poor quality chest wall skin with a TRAM flap skin paddle that ends at the inframammary fold. PMID- 10096612 TI - Immediate breast reconstruction with the TRAM flap after neoadjuvant therapy. AB - Neoadjuvant therapy is a relatively new weapon in the chemotherapeutic arsenal against breast carcinoma. However, there has been concern that preoperative chemotherapy might lead to an increased incidence of complications and delays in postoperative treatment. A retrospective study was performed at M.D. Anderson Cancer Center of all patients with locally advanced breast cancer who had undergone neoadjuvant therapy followed by mastectomy and immediate reconstruction with the transverse rectus abdominis musculocutaneous (TRAM) flap. Patients were evaluated for the incidence of complications and any delays in resumption of postoperative chemotherapy. Thirty-one patients underwent immediate reconstruction with the TRAM flap. Twenty-two patients were reconstructed with free TRAM flaps whereas 9 patients were reconstructed with pedicled TRAM flaps. Seventeen patients (55%) had complications postoperatively, but only 2 patients (6%) had a delay in the resumption of chemotherapy. Seven patients were smokers, five (71%) of whom had complications, which was not a significant difference from the rate in nonsmokers (50%). Although delays in postoperative chemotherapy occurred in smokers (29%, vs. 0% in nonsmokers), the number of patients was too small to attain statistical significance. Based on this study it is felt that immediate reconstruction with the TRAM flap can be performed safely in patients on a neoadjuvant protocol. Although not contraindicated, immediate reconstruction with the TRAM flap in smokers in this setting may be associated with higher morbidity. PMID- 10096613 TI - The role of endoscopy and implant texture in transaxillary submuscular breast augmentation. AB - In 1996 the authors reported their experience with 92 consecutive patients undergoing traditional (nonendoscopic) transaxillary submuscular breast augmentation. They reported a capsular contraction rate of 1.1% using textured saline implants, as well as an implant malposition rate of 8.6%. At that time they hypothesized that "the endoscope will lessen the rate of implant malposition." To clarify the role of implant texture and to justify the use of endoscopic techniques in transaxillary submuscular breast augmentation, the authors have studied an additional 58 consecutive patients with two significant changes. First, the endoscope was used to dissect the implant pocket in each patient. Second, smooth-wall implants were substituted for the previously used textured implants. Their rate of implant malposition dropped significantly, from 8.6% to 2.0% (p = 0.10), and their capsular contraction rate remained low, at 2.0% (p = 0.63). They conclude that direct endoscopic control improves implant positioning in the transaxillary submuscular operation, and implant texture does not improve capsular contraction rates when the prosthesis is placed in the submuscular position. PMID- 10096614 TI - The effect of ruby laser light on ex vivo hair follicles: clinical implications. AB - Several clinical studies on the efficacy of ruby laser-assisted hair removal have reported that regrowth of hair after treatment is common. One of the reasons for the regrowth of hair is the incomplete destruction of germinative hair cells due to the insufficient penetration of the ruby laser in the skin. It was the aim of this study to estimate the extent of damage to the hair follicles after one ruby laser treatment and to determine whether the ruby laser destroyed the bulbs and the bulge regions of hair follicles. The extent of laser damage in hair shafts was determined by serial examination of six specimens of ex vivo scalp skin lasered with the Chromos 694 Depilation Ruby Laser at 14 J per square centimeter and 20 J per square centimeter. Another nine specimens of ex vivo scalp skin were similarly lasered, and monoclonal antibody LP2K was used to identify the bulge regions of the hair follicles using the immunoperoxidase technique. Damage to the bulge region was assessed from consecutive specimens, which were stained with hematoxylin-eosin stain. The mean depth of laser damage sustained by hair follicles was 1.34 mm (14 J per square centimeter) and 1.49 mm (20 J per square centimeter) underneath the skin surface. Most of the laser damage involved the bulge regions but fell short of the hair bulbs. The laser damage did not seem to extend far enough down the hair shafts to result in permanent hair destruction. The clinical implications of this finding are discussed. PMID- 10096615 TI - Ruby laser-assisted hair removal: a preliminary report of the correlation between efficacy of treatment and melanin content of hair and the growth phases of hair at a specific site. AB - An unpredictable response, even in patients with dark hair, often undermines successful ruby laser hair removal. A prospective clinical study was carried out to evaluate the roles of melanin content and growth phases of hair in treatment efficacy. Thirty-six volunteers with white skin and dark hair were recruited for the study, and were all treated using the Chromos 694 Depilation Ruby Laser. The overall efficacy of treatment was assessed at the end of 3 months. The efficacy of laser treatment is not due solely to the proportion of hair in the growing or static phase of the hair cycle. There is a lack of correlation between the melanin content and the overall efficacy of laser hair removal in those treated once, but patients with darker hair responded better after repeated treatments. The proportion of hair in the growth phase and the melanin content of hair do not contribute solely to the efficacy of ruby laser hair removal. PMID- 10096616 TI - The use of tissue expanders in staged abdominal wall reconstruction. AB - Reconstruction of large abdominal wall defects not amenable to primary closure remains a challenging problem. Various reconstructive techniques have been described in the surgical literature each with its advantages and disadvantages. In this report the authors describe their experience in treating 11 patients with large abdominal wall defects utilizing prosthetic mesh in conjunction with tissue expanders. Between 1986 and 1997 there were 6 pediatric and 5 adult patients treated with this method. The etiology included three congenital omphaloceles, five cases of necrotizing fasciitis, and three gunshot wounds. All patients initially required insertion of prosthetic mesh to bridge their large abdominal wall defects. This was followed by staged abdominal wall reconstruction with tissue expanders and prosthetic mesh. None of the patients had mesh infection or extrusion, and none developed enteric fistula or recurrent hernia. The tissue expansion process was well tolerated by all patients. One patient had partial exposure of the tissue expander due to thinning of the expanded skin. Our results suggest that the use of tissue expanders provides reliable, well-vascularized soft-tissue coverage and minimizes potential mesh-related complications in abdominal wall reconstruction. PMID- 10096617 TI - Evaluation of the circulation of reconstructive flaps using laser-induced fluorescence of indocyanine green. AB - A new method for evaluating the circulation in surgical flaps using laser-induced fluorescence of indocyanine green (ICG) images is reported. In clinical trials the authors found that ICG imaging demonstrated good circulation accurately in 16 of 21 flaps with no clinical manifestations of compromised circulation. In 3 patients in whom partial discoloration and cyanosis of the flaps were visible, the dye study indicated poor circulation in the identical areas. In 2 other patients in whom flaps appeared clinically satisfactory, the flaps were shown by ICG imaging to have greatly compromised circulation. In a patient in whom the flap was left in place, slough of almost the entire flap resulted. Another flap with questionable circulation was returned to its original location, where it healed. Thus, while it is a still a new approach and under continual evaluation, the use of ICG fluorescence shows promise as a valuable adjunct to current methods of flap evaluation. PMID- 10096618 TI - Aeromonas species isolated from medicinal leeches. AB - Aeromonas hydrophila infections are a recognized complication of the use of medicinal leeches. The authors performed an experiment designed to find a safe and practical way to sterilize the leech gut of pathogenic organisms. Leeches were incubated for a 12-hour period in solutions of antibiotic effective against A. hydrophila. The incubations in the antibiotic solutions failed to eradicate pathogenic bacteria from the gut of the leeches. The authors examined cultures of bacteria isolated from the guts of the commonly used Hirudo medicinalis (European leech) and found a wide variety of pathogenic organisms. A. hydrophila is widely believed to be the most common enteric pathogen, but the authors found A. sobria more frequently in their experiment. They also cultured the guts of the leech H. michaelseni recently used clinically in South Africa. A. caviae was the most common pathogen encountered in these leeches. A. caviae and A. sobria cause a spectra of disease similar to A. hydrophila. The authors endorse the current recommendation that all patients who have leech therapy for congested flaps or replants receive broad-spectrum prophylactic antibiotics. This appears to be the safest and simplest way to prevent leech-related infections. PMID- 10096619 TI - Evaluation of soft-tissue morphology of the face in 1,050 young adults. AB - Anthropometry of the face has always been an interesting subject for artists and plastic surgeons. Since ancient times, many rules have been proposed for the ideal face. The authors measured directly vertical and horizontal proportions of the face and inclinations of the soft-tissue facial profile in 1050 young Turkish adults. Differences between the facial measurements of subjects from seven different geographic regions were analyzed. Some of the measurements were compared further with the measurements of other populations in the literature, and the validity of the neoclassical canons were tested. The special head height measure was shorter than the special face height in the majority of our study group (women/men: equal height, 13%/15%; longer special head height, 28%/30%; shorter special head height, 59%/55%). Faces with three equally high-profile sections were not seen in women or in men. When the forehead height was compared with the nose height, equality was present in a small percentage of the population (women/men: equal height, 17%/18%; longer forehead, 41%/ 42%; shorter forehead, 42%/40%). The nose height was equal to the lower face height in a minority of the population (women/men: equal height, 10%/11%; longer nose, 9%/11%; shorter nose (81%/78%). The forehead height was shorter than the lower face height in the majority of the population (women/ men: equal height, 8%/9%; longer forehead, 12%/13%; shorter forehead, 79%/78%). The intercanthal distance was shorter than the nose width in the majority of the population (women/men: equal width, 20%/19%; wider intercanthal distance, 35%/37%; narrower intercanthal width, 65%/68%). The population was distributed evenly in regard to the variations of the orbital proportion canon (women/men: equal intercanthal width and eye fissure length, 31%/36%; wider intercanthal distance, 34%/27%; narrower intercanthal width, 35%/37%). The mouth width was greater than 1.5 times the nose width in the majority of the population (women/men: equal width, 6%/5%; wider mouth, 53%/54%; narrower mouth, 41%/41%). The nose width was narrower than one quarter of the face width in the majority of the population (women/men: equal width, 4%/3%; wider nose, 30%/39%; narrower nose, 66%/58%). The nose inclination was equal to the ear inclination in a very small fraction of subjects (women/ men: equal inclination, 3%/3%; greater nose inclination, 88%/87%; less nose inclination, 9%/9%). To sketch an outline of the average facial profile in the population studied, a convex facial profile is revealed, with the forehead and the chin retrodisplaced minimally with respect to the midface. The neoclassical canons were found to be invalid for the majority of the population in this study, and different proportional analytic results were obtained. PMID- 10096620 TI - Delayed metastases in skin cancer of the head and neck: the case of the "known primary". AB - Regional metastases from head and neck cutaneous tumors are uncommon, and most present within 2 years from initial diagnosis. Occasionally such metastases may manifest at a later date, increasing the possibility of being derived from a second noncutaneous primary cancer of the head and neck region. The authors studied the course of disease in patients treated for cutaneous neoplasms manifesting with delayed regional metastases. They evaluated patients treated for cutaneous neoplasms with regional metastases presenting more than 3 years from initial treatment. There were 10 cases of squamous cell carcinoma, one case of basal cell carcinoma, and one case of basosquamous carcinoma. Mean duration from initial diagnosis to presenting neck metastases was 4 years 2 months. Mean overall follow-up is 2 years 5 months, and 3 years for patients alive without disease. Four patients died of unrelated causes and 3 patients died of their disease. Five patients are alive and free of disease. A diligent search for a second primary must always be carried out when neck metastases appear. Yet, delayed regional metastases appearing more than 3 years after resection of skin neoplasms is not uncommon and are usually associated with the primary skin cancer. Prolonged follow-up is essential, even in T1 patients. Patients with regional recurrence should be treated aggressively. PMID- 10096621 TI - Formation of 4-hydroxy-2-nonenal-modified proteins and 3-nitro-L-tyrosine in rat island skin flaps during and after ischemia. AB - 4-Hydroxy-2-nonenal (HNE)-modified proteins and 3-nitro-L-tyrosine were evaluated as a specific marker of reactive oxygen species (ROS)- and nitric oxide (NO) mediated peroxynitrite-induced tissue injuries in ischemic and reperfused skin flap by Western blot analysis. Specimens were taken from island skin flaps of rats during the following three conditions: ischemia only, 5 hours of ischemia and reperfusion, and 10 hours of ischemia and reperfusion. HNE-modified proteins and 3-nitro-L-tyrosine increased with ischemic time (3, 6, and 10 hours postischemia). In the reperfused skin flap after both 5 and 10 hours of ischemia, HNE-modified proteins and 3-nitro-L-tyrosine were increased 3 hours postreperfusion, and they reached a maximum 6 hours after reperfusion. HNE modified proteins and 3-nitro-L-tyrosine 1 hour postreperfusion were higher with 10 hours ischemia-reperfusion than with 5 hours ischemia-reperfusion. These results indicate (1) that ROS- and NO-induced peroxynitrite-mediated cytotoxicity in ischemic flaps is dependent on the ischemic period and (2) that ROS- and NO induced peroxynitrite-mediated cytotoxicity occurs during an early stage of reperfusion if the ischemic period is long. PMID- 10096622 TI - Thrombogenic stimulus causes long-term decrease of muscle flap perfusion. AB - This study was designed to evaluate the effect of a continuous thrombogenic insult at the feeding artery on skeletal muscle flap perfusion over 24 hours. Twelve male Sprague-Dawley rats were divided into two experimental groups. In the control group (N = 6) and in the treatment group (N = 6) the right cremaster muscle was isolated on its neurovascular pedicle and the tubular muscle flap was preserved in the medial part of the hind limb over a 24-hour period for subsequent microcirculatory observation. In the treatment group, an inverting suture was applied over half of the circumference of the ipsilateral common iliac artery to create a continuous thrombogenic stimulus. Intravital microcirculatory measurements obtained were red blood cell velocities, vessel diameters, capillary perfusion, endothelial edema index, and leukocytic-endothelial interactions. There were no statistically significant differences seen in red blood cell velocities, vessel diameters, and leukocytic-endothelial interactions between the groups. However, the inverting suture caused a significant drop in capillary perfusion from 6.23 to 1.50 capillaries per visual field (median; p = 0.002). An arterial thrombogenic insult may result in a significant decrease in capillary perfusion in muscle flaps over 24 hours although the blood flow through the thrombogenic main feeding vessel is maintained. PMID- 10096623 TI - Endothelial cell growth factor enhances musculocutaneous flap survival through the process of neovascularization. AB - The effect of an angiogenic growth factor-endothelial cell growth factor (ECGF) was tested in the rat transverse rectus abdominis musculocutaneous (TRAM) flap model based on a single inferior vascular pedicle. The animals were divided into three groups (N = 8 per group) after flap elevation. In group A (control), each animal received both local and local intra-arterial injections of 1 ml saline. In group B (local), each received a 2-mg ECGF local injection and 1-ml saline local intra-arterial injection. In group C (local intra-arterial), each received a 1-ml saline local injection and a 2-mg ECGF local intra-arterial injection. All animals were evaluated on postoperative day 7. There was a significant increase in the percentage of the skin paddle survival area of the TRAM flap in both ECGF treated groups when compared with the control group (group B vs. group A, p < 0.001; group C vs. group A, p < 0.001). This correlated with a significant increase in vascularity in both ECGF-treated groups compared with the control group (group B vs. group A, p = 0.007; group C vs. group A, p = 0.021). The results between groups B and C were not significant. ECGF, when administered via either local or local intra-arterial route, enhances musculocutaneous flap survival through the process of neovascularization. PMID- 10096624 TI - Angiotensin II improves random-flap viability in a rat model. AB - Angiotensin II (AII) is a naturally occurring peptide that has been shown to be angiogenic, cause the proliferation of several primary cell types (including endothelial cells), accelerate the repair of dermal injuries, and increase production of growth factors and extracellular matrix. The effect of a single administration of AII on the viability and vascularity of a random flap was assessed in a rat model. In the control model, the viability of the distal portion of the flap was reduced consistently by postoperative day 8. Initially, AII was administered in an aqueous vehicle (phosphate-buffered saline [PBS]) and a viscous vehicle (10% carboxymethyl cellulose [CMC]). Administration of 1 mg per milliliter AII in PBS did not affect the viability of random flaps (1.2 x 7 cm) in this animal model. However, a single administration of a higher dose of AII in PBS (10 mg per milliliter) or 1 mg per milliliter AII in the CMC vehicle resulted in 67% of the grafts being fully viable at postsurgical day 12, in contrast to vehicle-treated control flaps, none of which were fully viable at day 12. Furthermore, the portion of the flap that was viable was increased significantly (p < or = 0.05). Subsequently, a study was conducted to assess the dose-response curve for AII in a CMC vehicle in this rat model. As the dose of AII was reduced, the percentage of animals with fully viable flaps and the percentage of the flap that was viable decreased correspondingly. Administration of 0.03 mg per milliliter AII and greater increased significantly (p < or = 0.05) the viability of the flaps. In conclusion, AII appears to be highly efficacious in increasing the percentage of distal flap surface area survival when administered as a single topical dose to the wound bed. PMID- 10096625 TI - Topical and systemic calcium channel blockers in the prevention and treatment of microvascular spasm in a rat epigastric island skin flap model. AB - Vasospasm is a frustrating problem commonly encountered in microvascular surgery. Extreme arterial vasoconstriction usually occurs intraoperatively, shortly after release of the vascular clamps, but can be a problem for 48 to 72 hours postoperatively. Failure to alleviate vasospasm can have disastrous consequences in replanted and revascularized tissues, ultimately resulting in microsurgical failure. The authors investigated the efficacy of topical and systemic administration of two commonly prescribed calcium channel blockers-nifedipine and verapamil-in both the prevention and treatment of vasospasm in a rat epigastric island skin flap model. Superficial epigastric island skin flaps were elevated in 60 Sprague-Dawley rats. Femoral vessels were isolated from the inguinal ligament to a point 1 cm distal to the origin of the epigastric vessels, and the feeding vessels were ligated. The flap was returned to its natural anatomic bed and was sutured into place, leaving the femoral vessels exposed. The femoral artery and vein were transected, and anastomoses were performed under the operating microscope. A block of ice was then applied directly to the anastomotic site for 1 minute to induce additional vasospasm. Groups I through III received topical application of solutions of 0.5 ml of either 0.9% normal saline (control), verapamil (2.5 mg per milliliter), or nifedipine (5 mg per milliliter) directly to the anastomotic site immediately prior to release of the vascular clamps. Groups IV through VI received intraperitoneal injections of 1.0-ml solutions of either 0.9% normal saline (control), verapamil (2.5 mg per milliliter), or nifedipine (5 mg per milliliter) at 30 minutes prior to performing the anastomoses. Thermocouple temperature probes reflecting blood flow were placed at the center of the skin flap in a subcutaneous position, at the proximal femoral artery, and at the takeoff of the epigastric artery. Accurate, direct temperature measurements of the isolated skin flap and femoral vessels were recorded at 10, 20, and 30 minutes after release of the vascular clamps. Topical and systemic administration of verapamil and nifedipine moderated significantly the temperature declines observed at 10 minutes at the level of the femoral artery proximally and distally compared with controls. Following this decline, groups I through III (topical) demonstrated significant recovery of temperature toward baseline, with verapamil and nifedipine showing significantly better recovery of temperature than controls. Groups IV through VI (systemic) demonstrated a stabilization of temperature without any significant additional recovery of temperature toward baseline. Verapamil was more effective than nifedipine in its actions when administered topically or systemically. The authors' results suggest a potential role for topical and systemic administration of verapamil and nifedipine in preventing, or at least minimizing, the deleterious effects of vasospasm on flap survival, as demonstrated by its temporizing effect on temperature change across the anastomosis in their model. PMID- 10096626 TI - An unusual case of orbital hydatid cyst: a surgical emergency. AB - A rare case of a 19-year-old man with an orbital hydatid cyst is presented. The lesion caused rapid deterioration of vision and was not responsive to the systemic use of mebendazole. It was treated successfully with emergency surgery. Early detection, surgical excision, and the systemic use of albendazole are suggested for the treatment of orbital hydatid cysts. PMID- 10096627 TI - Flexor tenosynovitis in the hand caused by Mycobacterium terrae. AB - The authors describe an uncommon case of flexor tenosynovitis caused by Mycobacterium terrae, an atypical mycobacterium generally considered nonpathogenic in humans. A prolonged delay in diagnosis and various ineffective therapies led to synovial biopsy and culture. After confirming the diagnosis of M. terrae, appropriate antimycobacterial chemotherapy resolved the synovitis. For chronic tenosynovitis without a clear etiology, limited synovectomy and culture are essential in establishing a diagnosis and in initiating treatment for this atypical mycobacterial infection. PMID- 10096628 TI - An unusual case of hypoglossia-hypodactyly syndrome. AB - Hypoglossia-hypodactyly syndrome is seen very rarely and its appearance is sporadic. Different degrees of tongue hypoplasia and transverse deficiencies in the upper extremities are seen. In the patient presented there was a sulcuslike deformity at the midline of the lower lip, and the continuity of the orbicularis oris muscle was disturbed at this location, in addition to the classic findings of hypoglossia-hypodactyly syndrome. A description of this variant and its treatment are described. PMID- 10096629 TI - Delayed primary closure using Silastic vessel loops and skin staples: description of the technique and case reports. AB - The use of Silastic vessel loops and skin staples for closure of surgical wounds, with or without tissue loss, is a relatively simple technique that can be done at the patient's bedside or in an office setting, using local anesthesia. The vessel loops are tightened or additional staples are placed, as required, until the skin edges are approximated. In a variety of wounds, use of Silastic vessel loops eliminates the need for skin grafting or secondary wound closure and minimizes the morbidity associated with these procedures. PMID- 10096630 TI - Ultimate X-file. PMID- 10096631 TI - Re: Pursestring and skin excision in gynecomastia. PMID- 10096632 TI - Use of flap skin as graft donor site in the reconstruction of flap donor site defects. PMID- 10096633 TI - A new approach in anterior maxillary segmental osteotomy. PMID- 10096634 TI - Sexual predators and the abuse of psychiatry. PMID- 10096635 TI - Issues affecting the lives of older persons with developmental disabilities. AB - Efforts to bring the aging developmentally disabled and mentally handicapped population into the mainstream of professional training and services are encouraging. The impact of managed care on the provision and quality of services for aging developmentally disabled persons who cannot advocate for themselves must be closely researched and monitored so that public funds are used to promote comprehensive and continuous care for this vulnerable population. PMID- 10096636 TI - The depersonalization of health care. PMID- 10096637 TI - Improving pharmacotherapy in a psychiatric hospital. PMID- 10096638 TI - Web sites worth watching. PMID- 10096639 TI - Are sex offenders treatable? A research overview. AB - OBJECTIVE: Recent legislation in several states providing for civil commitment and preventive detention of sexually violent persons has stirred legal, clinical, and public policy controversies. The mandate for psychiatric evaluation and treatment has an impact on public mental health systems, requiring clinicians and public administrators to direct attention to treatment options. It is a common view that no treatments work for disorders involving sexual aggression. The authors examine this assumption by reviewing research on the effectiveness of treatment for adult male sex offenders. METHODS: MEDLINE was searched for key reviews and papers published during the years 1970 through 1998 that presented outcome data for sex offenders in treatment programs, individual case reports, and other clinically and theoretically important information. RESULTS: Although rigorous research designs are difficult to achieve, studies comparing treated and untreated sex offenders have been done. Measurement of outcome is flawed, with recidivism rates underestimating actual recurrence of the pathological behavior. Outcome research suggests a reduction in recidivism of 30 percent over seven years, with comparable effectiveness for hormonal and cognitive-behavioral treatments. Institutionally based treatment is associated with poorer outcome than outpatient treatment, and the nature of the offender's criminal record is an important prognostic factor. CONCLUSIONS: Although treatment does not eliminate sexual crime, research supports the view that treatment can decrease sex offense and protect potential victims. However, given the limitations in scientific knowledge and accuracy of outcome data, as well as the potential high human costs of prognostic uncertainty, any commitment to a social project substituting treatment for imprisonment of sexual aggressors must be accompanied by vigorous research. PMID- 10096640 TI - Issues in the psychiatric treatment of African Americans. AB - African Americans constitute about 12 percent of the United States population. Sixty percent of African Americans live in urban areas, and 25 percent have incomes below the poverty level. Issues in the psychiatric assessment and evaluation of African-American patients include diagnostic bias that has resulted in overdiagnosis of schizophrenia. Use of screening instruments can help standardize assessment, but appropriate screening instruments that have been evaluated and found reliable in this population must be used. Issues in treatment and outcome for African Americans include challenges in establishing rapport in interethnic situations, racial identity as a focus in psychotherapy, and awareness of biological characteristics that affect response to medications. Many African Americans live in high-crime areas where high rates of drug abuse and violence create chronic stresses. Patients with dual diagnoses of chronic mental illness and substance use or abuse need targeted interventions. Strategies for prevention and treatment of the effects of having experienced or witnessed violence have been proposed. Additional research is needed to clarify the true prevalence of specific mental disorders among African Americans and to determine the most effective combinations of treatment strategies for various disorders. PMID- 10096641 TI - Helping parental caregivers and mental health consumers cope with parental aging and loss. AB - As persons with severe and persistent mental illness age, large numbers continue to live with their elderly parents or receive substantial social and economic support from them. Prospective studies suggest that when caregivers die, individuals with mental illness experience housing disruptions and potentially traumatic transitions. This paper describes the scope of the problem and addresses pragmatic and psychological issues involved in preparing both caregivers and patients for parental aging and eventual loss. It outlines the practitioner's role in helping patients and families overcome specific psychological barriers to planning for continuing care management, appropriate residential alternatives for patients, and their timely placement. The discussion emphasizes helping patients control their own futures by proactively ensuring resources for maintaining or improving their quality of life. The Planned Lifetime Assistance Network (PLAN), now available in some states through the National Alliance for the Mentally Ill, is described. PLAN, and similar organizations, provide lifetime assistance to disabled individuals whose parents or other family members are deceased or no longer able to provide care. PMID- 10096642 TI - Personality and clinical predictors of recurrence of depression. AB - OBJECTIVE: To help clinicians more accurately predict outcomes of treatment for depression, variables associated with recurrence of depression in the year after treatment were examined in a group of patients who completed treatment for an index episode of depression. METHODS: Forty-two depressed patients who participated in a double-blind pharmacological treatment study were followed for one year after treatment was discontinued. Length of treatment for the index episode was determined by clinicians and ranged from eight to 76 consecutive weeks. Eighteen patients who had a recurrent episode (43 percent) and 24 patients who did not (57 percent) were compared on sociodemographic and clinical variables, including scores on the Eysenck Personality Questionnaire (EPQ). RESULTS: A combination of three variables predicted recurrence of depression in 90 percent of cases. They were an elevated EPQ score on the neuroticism subscale, a short duration of treatment of the index episode, and a slow onset of response to treatment of the index episode. CONCLUSIONS: The findings suggest that personality traits, treatment duration, and variations in response to treatment might have an impact on long-term treatment outcome. Clinicians should consider these factors when making treatment decisions for depressed patients. PMID- 10096643 TI - Assaults by patients on psychiatric residents: a survey and training recommendations. AB - OBJECTIVE: A survey was conducted to determine the frequency and severity of assaults on psychiatric residents and the level of training they receive in the management of violent patients. METHODS: In early 1997 a survey was randomly distributed to 2,553 psychiatric residents, who represented half of all psychiatric residents in the United States. The survey asked about experiences of assaults and training received in management of violent patients. RESULTS: Completed surveys were received from 517 residents, for a 20 percent response rate. Seventy-three percent reported being threatened, and 36 percent had been physically assaulted. A third received no training in managing violent patients, and a third described their training as inadequate. CONCLUSIONS: Two-thirds of psychiatric residents are either undertrained or feel undertrained in dealing with violent patients. The authors propose a training curriculum based on recommendations of an American Psychiatric Association task force report on clinician safety. PMID- 10096644 TI - A survey of assaultive behavior in Veterans Health Administration facilities. AB - OBJECTIVE: To more clearly define the scope and impact of violence in health care facilities, national data on assaults in VA medical centers and freestanding clinics were examined. METHODS: A survey was distributed to all VA medical centers and freestanding clinics asking for cumulative data for one fiscal year (October 1990 through September 1991). Data were obtained on number, types, and locations of physical assaults and other assaultive behavior; the types of staff assaulted and number of workdays lost due to injuries; diagnoses of perpetrators; recommendations made after the incidents were reviewed; training in prevention and management of assaultive behavior; and the impact of training on rates of assaultive behavior. RESULTS: During the survey year, 24,219 incidents of assaultive behavior were reported by 166 VA facilities; 8,552 incidents involved battery or physical assault. Weapon possession by perpetrators was common (8.5 percent of incidents), and weapons were used in 130 assaults (1.5 percent of assaults). Assaults occurred most frequently in psychiatric units (43.1 percent), followed by long-term-care units (18.5 percent) and admitting or triage areas (13.4 percent). Assault-related injuries were most common among nursing personnel. Perpetrators of assaults were most typically diagnosed as having psychoses, substance use disorders, or dementia. On inpatient psychiatry units, an inverse correlation was found between expenditures on staffing and the frequency of assaultive incidents. Staff training on management of assaultive behavior varied widely. CONCLUSIONS: Assaultive behavior is a significant problem for health care workers. Staff in all clinical areas need to be prepared to deal with assaultive patients. More research is needed on staff training and interventions for preventing and limiting assaults. PMID- 10096645 TI - Repeated assaults by patients in VA hospital and clinic settings. AB - OBJECTIVE: The study aim was to determine the prevalence of repeated assaults on staff and other patients and characteristics of patients who commit repeated assaults in the Veterans Health Administration of the Department of Veterans Affairs. METHODS: Patients in VA medical centers and freestanding outpatient clinics who committed two or more assaults in fiscal years 1995 and 1996 were identified through a survey of facility quality or risk managers. For each repeatedly assaultive patient, structured information, including incident reports, was obtained for all assault occasions. RESULTS: A total of 153 VA facilities responded, for a response rate of 99 percent. The survey identified 8,968 incidents of repeated assault by 2,233 patients, for a mean of 4.02 assaults per patient in the two-year study period. In 92 percent of the incidents, the assaultive patient had a primary or secondary psychiatric diagnosis. The mean age of the repeat assaulters was 62 years. Ninety-eight percent of the repeat assaulters were male, and 76.6 percent were Caucasian. At least 16 percent of the assaulters, 22 percent of the patients assaulted, and 20 percent of the staff assaulted required medical attention for injuries, which, along with the number of lost work days, indicates that repeated assaults are costly. CONCLUSIONS: Repeatedly assaultive patients represent major challenges to their own safety as well as to that of other patients and staff. Identifying patients at risk for repeated assaults and developing intervention strategies is critically important for ensuring the provision of health care to the vulnerable population of assaultive patients. PMID- 10096646 TI - An ethnographic study of the meaning of continuity of care in mental health services. AB - OBJECTIVE: As a step toward developing a standardized measure of continuity of care for mental health services research, the study sought to identify the interpersonal processes of giving and receiving day-to-day services through which individual providers create experiences of continuity for consumers. METHODS: Ethnographic methods of field observation and open-ended interviewing were used to investigate the meaning of continuity of care. Observations were carried out at two community mental health centers and a psychiatric emergency evaluation unit in Boston. Sixteen recipients and 16 providers of services at these sites were interviewed. RESULTS: Six mechanisms of continuity were identified, labeled, defined, and described through analysis of field notes and interview transcripts: pinch hitting, trouble shooting, smoothing transitions, creating flexibility, speeding the system up, and contextualizing. The mechanisms elaborate dimensions and principles of continuity cited by other observers and also suggest new formulations. CONCLUSIONS: The mechanisms identified in this study facilitate operationalization of the concept of continuity of care by specifying its meaning through empirically derived indicators. Ethnography promises to be a valuable methodological tool in constructing valid and reliable measures for use in mental health services research. PMID- 10096647 TI - Comparison of outcomes of acute care in short-term residential treatment and psychiatric hospital settings. AB - OBJECTIVE: The study compared the demographic and diagnostic characteristics of clients and the outcomes of treatment in five short-term acute residential treatment programs and two acute hospital-based psychiatric programs. METHODS: A total of 368 clients in the short-term acute residential treatment programs and 186 clients in the psychiatric hospital programs participated in an observational study. The study used a repeated-measures design and assessed participants on multiple standardized measures of symptoms and functioning at admission, discharge, and four-month follow-up. Comparisons between the two groups were conducted separately by diagnostic category. Measures included the Brief Symptom Inventory, the Behavior and Symptom Identification Scale-32, the Medical Outcomes Short-Form-36, and the Client Satisfaction Questionnaire-8. RESULTS: The two types of programs admit persons with similar levels of acute distress who have comparable levels of improvement at discharge and an equivalent degree of short term stability of treatment gains. Costs of treatment episodes were considerably lower for the short-term residential programs, and client satisfaction with the two types of programs was comparable. CONCLUSIONS: Short-term acute residential treatment is a less costly yet similarly effective alternative to psychiatric hospitalization for many voluntary adult patients. PMID- 10096648 TI - Anxiety disorders among African-American and white primary medical care patients. AB - The prevalence of current anxiety disorders and associated clinical patterns was examined in a sample of 125 African American and 120 white primary medical care patients between ages 18 and 64. Patients who indicated they had at least one mood or anxiety symptom in response to a screening questionnaire were interviewed to determine the presence of a DSM-IV anxiety, mood, or possible alcohol abuse disorder. Demographic data and data on mental- and physical-health-related functioning and health service utilization were also collected. The authors found no racial differences in the proportions of patients who met DSM-IV criteria for the disorders, nor in their symptom patterns, level of functional disability, or rates of health and mental health service utilization. PMID- 10096649 TI - Characteristics of nonresponders to a patient satisfaction survey at discharge from psychiatric hospitals. AB - The study compared the demographic and clinical characteristics of patients treated in the 31 psychiatric hospitals in Japan who did and did not return a satisfaction survey at discharge. Of the 471 patients discharged in a one-month period, 364 agreed to participate. A total of 235 turned in completed forms, 91 turned in incomplete forms, and 38 did not return the form. The latter two groups were defined as nonresponders. Nonresponders were significantly older than responders, but no significant differences were found between the two groups in diagnosis and other demographic characteristics. Responders and incomplete responders had significantly higher scores on the Global Assessment of Functioning scale than those who did not return the survey. PMID- 10096650 TI - Quality-of-life changes among patients with obsessive-compulsive disorder in a partial hospitalization program. AB - Thirty treatment-resistant patients with a primary DSA-IV diagnosis of obsessive compulsive disorder were assessed at admission to and discharge from a partial hospitalization program to determine whether improvement in symptoms of the disorder was associated with improvements in patients' quality of life. Symptom severity was measured using the Yale-Brown Obsessive Compulsive Scale (YBOCS). Quality of life was measured using Lehman's Quality of Life (QOL) scale, which includes several objective and subjective indexes. YBOCS scores significantly improved with treatment, as did scores on the majority of the QOL subjective indexes and on the objective social, health, and activity indexes. No significant association between changes in YBOCS scores and QOL scores was found. PMID- 10096651 TI - Physician service networks and the future for psychiatrists. AB - Physicians are responding to payers' demand for one-stop shopping and providers' desire for increased autonomy by creating physician service networks. These provider-owned and -operated delivery systems offer psychiatrists a model for creating their own behavioral health care organizations. The author describes features of these integrated delivery systems that can enable physicians to regain some of the control they have lost to managed care organizations. He encourages psychiatrists to view physician service networks as a valuable survival strategy in an era of change and uncertainty. Physicians who become involved in provider-owned networks must work to ensure that these organizations do not become indistinguishable from the managed care systems they replace. PMID- 10096652 TI - Tailoring the chart. PMID- 10096653 TI - Tailoring the chart. PMID- 10096654 TI - Safer security pages. PMID- 10096655 TI - Clarifying the scope of occupational therapy. PMID- 10096656 TI - Clarifying the scope of occupational therapy. PMID- 10096657 TI - Clarifying the scope of occupational therapy. PMID- 10096658 TI - Zolpidem for insomnia related to PTSD. PMID- 10096659 TI - Consensus panel report designed to remove barriers to substance abuse treatment for persons with disabilities. PMID- 10096660 TI - President Clinton's budget for fiscal year 2000 calls for 24 percent increase in community mental health funds. PMID- 10096661 TI - CSAT consensus panel supports expanded use of naltrexone for treatment of alcohol dependence. Center for Substance Abuse Treatment. PMID- 10096662 TI - Cyclical changes in epithelial cells of the vaginal cul-de-sac of brushtail possums (Trichosurus vulpecula). AB - The aim of this study was to describe and quantify the changes that occur in cul de-sac tissue, in particular to epithelial cells and their constituents, at specific stages of the estrous cycle in the brushtail possum. Stereological techniques were used to quantify changes in cul-de-sac epithelial cells collected at four stages of the estrous cycle; the time of removal of pouch young (RPY; n = 5), of initial follicle development (n = 5), of preovulatory follicle formation (n = 5), of midluteal stage (n = 4), and again at RPY (n = 5) after completion of the experiment to examine for any effects due to season or time. Tissue was weighed and processed for light microscopy, transmission electron microscopy, and stereological analysis. Cul-de-sac epithelial cell volume increased approximately 17-fold at the time of preovulatory follicle formation compared with that at the time of RPY, before declining (approximately four-fold greater than at RPY) during the midluteal phase. Epithelial cell volume enlargement was correlated strongly with the size of the preovulatory follicle present, and maximum size was coincidental with the formation of extracellular spaces and projection of cell processes between lateral cell membranes. Maximum cell volume was associated with an approximate 25-fold and six-fold increase in cytoplasmic and nuclear volume, respectively. Enlargement of the epithelial cells coincided with an increase in cytoplasmic organelle numbers, microvilli prominence, and accumulation of secretory vesicles. In the possum, the cul-de-sac epithelial cell undergoes phenomenal remodelling during the estrous cycle to accommodate an approximate 17 fold increase in volume. This increase in cell volume is coincident with morphological changes characteristic of secretory activity and appears to be under estrogen regulation. PMID- 10096663 TI - Characterization of ootolith soluble-matrix producing cells in the saccular epithelium of rainbow trout (Oncorhynchus mykiss) inner ear. AB - Although the organic matrix may play an important role in the growth of teleost otoliths, cellular contributions to the production of the organic matrix have been studied in only a small number of teleost species with limited methods, and are still poorly understood. In order to characterize saccular epithelial cells which produce otolith matrix, antiserum was raised against an EDTA-soluble fraction of otolith matrix (otolith soluble-matrix, OSM) of the rainbow trout. The components in the OSM and in the endolymph were characterized by immunoblotting. The saccular epithelium was immunohistochemically stained with the antiserum and the ultrastructure of OSM immunoreactive cells was studied. By immunoblotting, multiple components (> 94.0 kDa [smeared] and 43.0 kDa) in the OSM reacted with the antiserum, whereas only one band (> 94.0 kDa) was detected in the endolymph. Under immunohistochemical staining, reactions to the antiserum were observed in columnar cells lined at the most peripheral region of the sensory epithelium, transitional epithelial cells, and squamous epithelial cells. Electron microscopic observations revealed that all three types of cells were equipped with extended rough endoplasmic reticulum and prominent Golgi apparatus, suggesting the active production of organic material(s). Dilations of translucent vesicles, apocrine-like extrusions of cytoplasm, and vesicles containing many minute globules were frequently associated with the apical surface of these cells. Some ruptured vesicles were observed, releasing their contents into the endolymphatic space. The present study identified columnar cells lining the most peripheral region of the sensory epithelium, transitional epithelial cells, and squamous epithelial cells as the OSM-producing cells. We suggest that the OSM components are secreted and dissolved into the endolymph and subsequently deposited onto the otolith. PMID- 10096664 TI - Distribution of keratins, vimentin, and actin in the testis of two South American camelids: vicuna (Vicugna vicugna) and llama (Lama glama). An immunohistochemical study. AB - The purpose of the present study was to investigate the pattern of distribution of cytokeratins, vimentin and muscular actin in the testis of vicuna (Vicugna vicugna) and llama (Lama glama) two species of camelids native of the Andean high plateau of South America. Testicular biopsies of four vicunas and five llamas were used. Animals were healthy breeders. The tissues were processed by standard immunohistochemistry with antipancytokeratinAE1/AE3, antikeratin 18 (K 18), CAM 5.2 (antikeratin 5, 18, and 19), antivimentin, and smooth-muscle-specific antiactin antibodies to track the cytoskeletal pattern of testicular cells. Using AE1/AE3 antibody the immunostaining was found in the epithelial lining of tubuli recti and rete testis. The reaction was relatively stronger in the apical cytoplasm of epithelial cells. The testicular cells of the two species showed no reaction to K 18 and CAM 5.2 antibodies. Antivimentin antibody stained the basal cytoplasm of the Sertoli cells, the Leydig cells, and the epithelial lining of tubuli recti and rete testis. In the last two structures the immunostain was relatively more intense in the basal cytoplasm of epithelial cells. Antiactin antibody stained the peritubular cells and the muscle cells of the lamina propria oftubuli recti and rete testis. The presence in these species of only some keratins found in man, its coexpression with vimentin in epithelial lining of tubuli recti and rete testis and the peritubule organization, so different from other ungulates may reflect a differential adaptation of the cytoskeleton to particular reproductive strategies. PMID- 10096665 TI - Zyxin and vinculin distribution at the cell-extracellular matrix attachment complex (CMAX) in corneal epithelial tissue are actin dependent. AB - Avian embryonic corneal epithelia are two cell layers thick. If isolated without (-) basal lamina, the basal cells have unorganized actin and project cytoplasmic protrusions termed blebs. The actin-based cytoskeleton at the cell-extracellular matrix junction (termed the actin cortical mat) is disrupted. These epithelia respond to soluble extracellular matrix molecules by reorganizing the actin cortical mat. Sheets of epithelia were isolated + or -basal lamina. Epithelia isolated -basal lamina were cultured +/- laminin-1 and/or +/- cytochalasin D (CD). The intracellular localization of zyxin, vinculin, paxillin, focal adhesion kinase, and tensin was determined using indirect immunohistochemistry. Protein levels were determined by Western blot analysis. Zyxin and vinculin were concentrated in two areas of the tissue. The interface between the upper cell layer (periderm) and the basal cells. The second area of concentration was at the inferior 1-4 microns of the basal cells in an area with multiple actin bundles termed the actin cortical mat. The actin bundles align toward zyxin and vinculin that were located near basal lateral membranes. Zyxin was displaced from the basal compartment of blebbing basal cells. In contrast tensin, vinculin and focal adhesion kinase were found diffusely throughout the blebs. Zyxin and vinculin redistributed to the basal-lateral membranes as actin bundles reorganized in laminin-stimulated epithelia. In contrast to the altered protein distribution, extractable protein levels were similar in blebbing and laminin-stimulated epithelia. Zyxin, vinculin, and other associated proteins were disrupted in the CD-treated tissues and do not colocalize with each other or CD-induced actin aggregates. The intracellular localization of zyxin and vinculin were concentrated in distinct areas along the inferior basolateral membranes of basal cells termed the cell-extracellular matrix attachment complex (CMAX). The distribution of CMAX proteins was dependent upon actin bundle organization. PMID- 10096667 TI - Site of functional bronchopulmonary anastomoses in sheep. AB - The location of bronchopulmonary anastomoses has long been a topic of discussion, and pre-, post-, and capillary sites have all been demonstrated in postmortem examinations. However, there have been few studies that have provided insight into the patency and function of these anastomoses in the intact lung. To identify these functional sites where the bronchial circulation anastomoses with the pulmonary circulation, we studied sheep lungs in situ serial sectioned with high-resolution computed tomography (CT). Differences in radiodensities of blood, air, and nonionic contrast medium were used to differentiate and localize airways and vessels and to identify the effluent from the bronchial circulation. After an initial series of scans to identify the pulmonary arteries and veins adjacent to airways 2-12 mm in diameter, contrast material was infused into the bronchial artery. In three sheep, the major accumulation of contrast medium was found in pulmonary veins. In one of the sheep, a comparable number of pulmonary arteries and veins contained contrast medium. Serial histologic sections were able to identify small bronchial venules lying within subepithelial bronchial folds that drain directly into pulmonary veins. These results using serial CT and histologic images suggest that drainage from the intraparenchymal bronchial vasculature is predominantly into postcapillary pulmonary vessels. PMID- 10096666 TI - ECM-stimulated actin bundle formation in embryonic corneal epithelia is tyrosine phosphorylation dependent. AB - Previous studies demonstrated that corneal epithelial cells isolated without basal lamina respond to extracellular matrix (ECM) in an actin dependent manner; the basal cell surface flattens and the actin cortical mat reorganizes. We hypothesize that the actin reorganization is initiated by intracellular signaling mechanisms that includes tyrosine phoshporylation and activation of the Rho, MAP kinase, and PI3 kinase signal transduction pathways. Our goals were to develop a morphological assay to test this hypothesis by answering the following questions: 1) Do the actin bundle formations in the cortical mat have the same configuration in response to different ECM molecules? 2) What is the minimum time ECM molecules need to be in contact with the tissue for the actin to reorganize? 3) Will blocking tyrosine phosphorylation inhibit reorganization of the actin? 4) Are known signal transduction proteins phosphorylated in response to soluble matrix molecules? The actin cortical mat demonstrated distinct bundle configurations in the presence of different ECM molecules. Soluble fibronectin accumulated at the basal cell surfaces 75-fold over 30 min in a clustered pattern. The cells need contact with ECM for a minimum of 10 min to reform the actin bundles at 2 hr. In contrast, two substances that bind to heptahelical receptors to stimulate the Rho pathway, bombesin and lysophosphatidic acid, reorganized the actin bundles in 15 30 min. Focal adhesion kinase, p190 Rho-GAP, tensin, and paxillin were tyrosine phosphorylated in response to soluble fibronectin, type I collagen, or laminin 1. Erk-1, erk-2, and PI3 kinase were activated after 1 hr stimulation by type I collagen. Herbimycin A blocked actin reorganization induced by ECM molecules. In conclusion, we have developed two morphological assays to examine the response of corneal epithelial cells to ECM molecules. In addition, actin bundle reorganization involved tyrosine phosphorylation, MAP kinase, and PI3 kinase activation. PMID- 10096668 TI - Effect of exogenous gonadotropins on gonadotrophs of the rat pituitary gland. AB - In the human in vitro fertilization (IVF) program a variety of superovulation regimens have been employed to promote follicular stimulation and the recruitment of supernumerary oocytes. This therapy, however, disturbs serum concentrations of estradiol and progesterone and may disrupt the normal feedback systems of the hypothalamo-pituitary axis. This study examines the effects of hyperstimulation on the pituitary gonadotrophs and circulating gonadotrophins. FSH and human chorionic gonadotropin (hCG) were administered to normal cycling female Sprague Dawley rats (n = 12) in phase with their estrous cycle. Control rats (n = 12) were injected with saline. In both the experimental and control groups, six rats were mated on the evening of proestrus and killed 12 hr later, while six animals were killed prior to mating. Blood was collected at the time of sacrifice for radioimmunoassay. The pituitary glands were removed, processed for light microscopy and serially sectioned. Immunocytochemistry for LH and FSH was carried out to determine the area occupied by these cell types. Data were statistically analyzed. Findings were correlated with circulating levels of LH, FSH, estradiol and progesterone. RIA revealed that the concentration of LH, FSH, estradiol and progesterone were significantly different with respect to hyperstimulation and mating. In addition the area occupied by LH and FSH cells was significantly different with respect to both hyperstimulation and mating. Hyperstimulation affects gonadotroph content, as well as gonadotropin and sex steroid hormone concentrations and together with other factors, may disrupt the ideal environment required for implantation. PMID- 10096669 TI - Microvascular architecture of the human urinary bladder wall: a corrosion casting study. AB - The vascular system of the urinary bladder wall effectively performs its function in spite of considerable spatial changes due to the filling/voiding cycle. However, only a few studies have dealt with the microvascular architecture of the bladder wall and only two, using old-fashioned techniques, were devoted to the human bladder. This study presents the microvasculature of the human bladder wall visualized by scanning electron microscopy of vascular corrosion casts. Postoperative bladder specimens obtained from patients with advanced bladder tumors were filled with small amount (80 ml) of saline and perfused via at least four largest arteries with anticoagulant-containing saline followed by paraformaldehyde/glutaraldehyde fixative and Mercox resin. After polymerization of the resin, the vascular casts were macerated with potassium hydroxide, cleaned with formic acid and water and freeze dried. Only regions of the bladder wall distant to the tumor were examined in light and scanning electron microscopes. The almost empty state of the bladder was manifested by extensive folding of the mucosa and tortuosity of almost all vessels other than capillaries. The branches of main arteries and veins formed an adventitial/serosal plexus which directly supplied/drained the capillary network of the muscularis and sent long perpendicular vessels to the mucosal plexus. These vessels had straight or coiled course depending on whether they terminated at the top or at the base of the mucosal folds. The rich mucosal plexus followed the folds parallel to their surface and gave off short, straight, mostly perpendicular twigs communicating with the subepithelial capillary network. Apart from very few vascular interconnections between the mucosal plexus and the muscularis, the submucosa was generally avascular. The subepithelial capillary network showed extreme density and uneven contours of the capillaries, only in less folded areas of trigone and urethral orifice the network was looser and capillaries thinner. The capillary system of the muscularis was poorly developed. Due to its architecture, tortuosity, and coiling/uncoiling capabilities, the microvasculature of the human urinary bladder wall seems to efficiently accommodate changes associated with cyclic contraction and stretching. Disturbances in blood flow induced by overdistension of the bladder reported in several studies may be due to pressure of the urine affecting the patency of the vessels rather than to the spatial insufficiency of the vascular system. PMID- 10096670 TI - Ultrastructural triple localization of laminin-1, nidogen-1, and collagen type IV helps elucidate basement membrane structure in vivo. AB - The basement membrane models which have been proposed to date are generally based on biochemical data, mainly binding studies and artificially synthesized polymers in vitro. Basically these have led to models proposing two three-dimensional laminin-1 and collagen type IV networks interconnected by nidogen-1. Whether they reflect the in vivo basement membrane structure is still not clear. We localized laminin-1, nidogen-1, and collagen type IV ultrastructurally in adult and fetal mouse kidney basement membranes with the help of immunogold-histochemistry performing double and triple localization to try to elucidate the molecular organization of basement membranes in vivo. We found laminin-1, nidogen-1, and collagen type IV distributed over the entire basement membranes in adult and fetal kidneys. This contradicts earlier studies ascribing laminin-1 to the lamina lucida and collagen type IV to the lamina densa. In addition, various basement membrane segments exhibited an organized labeling pattern for the BM components. Double-labeling revealed co-localization of laminin-1 and nidogen-1. We conclude that the combination of laminin-1 with collagen type IV as double-network basement membrane partially interconnected by nidogen-1 is found already in the early fetal kidney in vivo. However, our data cannot exclude the possibility of other variants of basement membrane assemblages. This is also indicated by a changing structure even in individual segments of one basement membrane type which renders a more flexible basement membrane architecture plausible. PMID- 10096671 TI - Nuclear bodies are usual constituents in tissues of hibernating dormice. AB - In previous studies we demonstrated in several tissues of the hazel dormouse Muscardinus avellanarius that during hibernation cell nuclei contain particular structural constituents absent in euthermia. In the present study we examine the same tissues in euthermic and hibernating individuals of the edible dormouse Glis glis in order to investigate possible modifications of nuclear structural constituents occurring during hibernation in this species. Edible dormice were captured in the wild and maintained in an external animal house. Samples of liver, pancreas, brown adipose tissue and adrenal cortex were taken from three hibernating and three euthermic animals and processed for resin embedding. Ultrastructural and immunocytochemical studies were carried out on cell nuclei of these tissues. The most evident feature of cell nuclei of hibernating dormice was the presence of several nuclear bodies, namely fibro-granular material, amorphous bodies, coiled bodies, perichromatin granule-like granules and nucleoplasmic fibrils, the distribution of which was peculiar to each tissue. No one of these constituents was detectable during euthermia. Immunocytochemical analyses revealed that they contain some splicing factors. Apart from some differences, maybe due to the different characteristics of lethargy, the nuclear bodies found in edible dormice were morphologically and immunocytochemically similar to those previously described in the same tissues of hazel dormice. They therefore seem to be strictly correlated to the hibernating state. If they represent storage and/or assembly sites of splicing factors to be rapidly used upon arousal, they could represent a usual structural feature in cells of hibernating species. PMID- 10096672 TI - Bulbus arteriosus of the antarctic teleosts. I. The white-blooded Chionodraco hamatus. AB - The bulbus arteriosus of teleost fish is a thick-walled chamber that extends between the single ventricle and the ventral aorta. The functional importance of the bulbus resides in the fact that it maintains a steady blood flow into the gill system through heart contraction. Despite of this, a thorough study of the structure of the bulbus in teleost fish is still lacking. We have undertaken a morphologic study of the bulbus arteriosus in the stenothermal teleosts of the Antarctic sea. The structural organization of the bulbus arteriosus of the icefish Chionodraco hamatus has been studied here by conventional light, scanning, and transmission electron microscopy. The inner surface of the bulbus shows a festooned appearance due to the presence of longitudinal, unbranched ridges that extend between the ventricle and the arterial trunk. The wall of the bulbus is divided into endocardial, subendocardial, middle, and external layers. Endocardial cells show a large number of moderately-dense bodies. The endocardium invaginates into the subendocardium forming solid epithelial cords that contain numerous secretory vacuoles. Cells in the subendocardium group into small domains, have some of the morphological characteristics of smooth muscle cells, and appear enmeshed in a three-dimensional network of matrix filaments. Cells in the middle layer are typical smooth muscle cells. They appear arranged into layers and are surrounded by a filamentous meshwork that excludes collagen fibers. Orientation of this meshwork occurs in the vicinity of the smooth muscle cells. Elastin fibers are never observed. The external layer is formed by wavy collagen bundles and fibroblast-like cells. This layer lacks blood vessels and nerve fibers. The endocardium and the endocardium-derived cords are secretory epithelia that may be involved in the formation ofmucins or glycosaminoglycans. These mucins may have a protecting effect on the endocardium. The subendocardium and the middle layer appear to be formed by the same cell type, smooth muscle, with a gradient of differentiation from the secretory (subendocardium) to the contractile (middle layer) phenotype. Despite the absence of elastin fibers, the filamentous matrix could maintain the elastic properties of the bulbus wall. Smooth muscle cells appear to be actively involved in bulbus wall dynamics. The restriction of collagen to the external layer suggests that it may control wall dilatation and bulbus compliance. When comparison was possible, structural differences between C. hamatus and temperate teleosts seemed to be not species related, but of phenotypic adaptative significance. This is remarkable since Antarctic fishes have lived isolated in freezing waters for the last two million years. PMID- 10096673 TI - Dynamics of parenchymal cell division, differentiation, and apoptosis in the young adult female mouse submandibular gland. AB - The submandibular salivary gland of the young adult female mouse has two secretory cell types, acinar and granular duct, which are separated by intercalated ducts. Based on the occurrence of autologous cell division in these cells, they have been traditionally classified as expanding populations. However, differentiation from stem or progenitor cells in the intercalated ducts, usually associated with renewing populations, has also been detected. The question of renewing or expanding populations is resolved by quantitating and integrating the rates of autologous cell division, differentiation, and apoptosis for each cell type. The integrated data shows that both acinar and granular duct cell populations exhibit a substantial positive growth index, whereas the growth index for the intercalated duct cells is moderately negative. On balance, it suggests that the submandibular gland of the young adult female mouse is still growing. Comparison of young female mice with older females suggests that, although overall parenchymal growth slows with age, there is no longer a net loss of intercalated duct cells. Comparison with young adult male submandibular glands indicates that gender differences exist in the rates and mechanisms used for maintaining the different cell populations. The acinar and granular duct cell populations in young adult female mouse submandibular glands are expanding at the expense of the intercalated duct cell population, which appears to be contracting. PMID- 10096674 TI - Plectin is concentrated at intercellular junctions and at the nuclear surface in morphologically differentiated rat Sertoli cells. AB - Intermediate filaments in Sertoli cells have a well-defined pattern of distribution. They form a basally situated perinuclear network from which filaments extend peripherally to adhesion plaques at the plasma membrane and to sites of codistribution with other major elements of the cytoskeleton, particularly with microtubules. Although the general pattern of intermediate filament distribution is known, the molecular components involved with linking the filaments to organelles and attachment plaques in these cells have not been identified. One candidate for such a linking element is plectin. In this study we test for the presence of, and determine the distribution of, plectin in Sertoli cells of the rat testis. Fixed frozen sections and fixed epithelial fragments of rat testis were probed for plectin and vimentin using antibodies. Tissue was evaluated using standard fluorescence microscopy and confocal microscopy. Plectin in Sertoli cells was concentrated in a narrow zone surrounding the nucleus, and at focal sites, presumably desmosome-like plaques, at interfaces with adjacent cells. Plectin was also concentrated at sites where intermediate filament bundles project into specialized actin-filament containing plaques at sites of attachment to elongate spermatids. Plectin in Sertoli cells is concentrated at the nuclear surface and in junction plaques associated with the plasma membrane. The pattern of distribution is consistent with plectin being involved with linking intermediate filaments centrally (basally) to the nucleus and peripherally to intercellular attachment sites. PMID- 10096675 TI - Insertion of the abductor hallucis muscle in feet with and without hallux valgus. AB - Textbooks of human anatomy present different opinions on the insertion of the abductor hallucis muscle which is concerned in etiology as well as in therapy of hallux valgus. In plastic and reconstructive surgery the muscle is taken as a graft for flap-surgery. In this study 109 feet (58 right, 51 left) were examined, 18 of these with clinical hallux valgus. The tendon of the muscle may attach to the tendon of the medial head of the short flexor hallucis muscle where a subtendineous bursa can be found. At the head of the first metatarsal bone the joint capsule is reinforced by fibres arising from the medial sesamoid bone which may be called "medial sesamoidal ligament." The tendon passes the first metatarsophalangeal joint plantarily to its transverse axis. Three types of insertion could be distinguished: type A, insertion at the proximal phalanx (N = 42); type B, insertion at the medial sesamoid ligament and at the medial sesamoid bone (N = 65); type C, insertion at the medial sesamoid bone (N = 2). In all types superficial fibres of the tendon extended to the medial and plantar sides of the base of the proximal phalanx, running in a plantar to dorsal direction. Statistical analysis exposed neither significant differences between both sides nor significant difference between normal feet and feet with hallux valgus. Therefore, a specific pattern of insertion of the abductor hallucis muscle in hallux valgus cannot be stated. PMID- 10096676 TI - Spreading, proliferation, and differentiation of the epidermis after wounding a cichlid fish, Hemichromis bimaculatus. AB - A large superficial wound has been experimentally provoked in the cichlid fish Hemichromis bimaculatus to study the interactions between the epidermal cells and the substrate on which they spread, on the one hand, and the restoration of the subepidermal tissues and the epithelial-mesenchymal interactions preceding scale regeneration, on the other hand. The re-epithelialization process, e.g., migration, spreading, differentiation, and proliferation of the epidermal cells, has been followed step by step, using light, scanning and transmission electron microscopy, and tritiated thymidine incorporation, until complete reorganization of the healing epidermis. Wound healing is fast (500 microm/hr) and proceeds centripetally from the wound margins. The epidermal cells spread on a wound surface which is composed of two different matrices: the remains of basement membrane materials covering the scale-pockets, and collagen fibrils of cut dermal strips. Even though both matrices favour cell spreading and attachment, migrating cells show a different behaviour. The re-epithelialization of the wound follows an orderly sequence similar to amphibian and mammalian wound healing, i.e., a "leap frog" mechanism of cell locomotion involving three epidermal layers. The basal layer cells, which spread on the substrate, and the superficial layer cells which protect the epidermis, differentiate first. Whatever the type of substrate over which the epithelium spreads (basement membrane material or collagen fibrils), the epidermal basal layer cells differentiate as soon as they become attached. The incorporation of tritiated thymidine has revealed that there is no proliferation in the healing epidermis until after complete closure of the wound, but that the rapid re-epithelialization of the large surface requires the recruitment of epidermal cells at the wound margins. The present study offers new data on the dynamics of re-epithelialisation and on the resistance of cichlid skin to such wounds. It is also clearly shown that the epidermal basal layer cells differentiate rapidly, a step which is interpreted as the first stage of epithelial-mesenchymal interactions that will lead to scale regeneration. PMID- 10096677 TI - Genetic evidence for larger African population size during recent human evolution. AB - Genetic evidence suggests that the long-term average effective size of sub Saharan Africa is larger than other geographic regions. A method is described that allows estimation of relative long-term regional population sizes. This method is applied to 60 microsatellite DNA loci from a sample of 72 sub-Saharan Africans, 63 East Asians, and 120 Europeans. Average heterozygosity is significantly higher in the sub-Saharan African sample. Expected heterozygosity was computed for each region and locus using a population genetic model based on the null hypothesis of equal long-term population sizes. Average residual heterozygosity is significantly higher in the sub-Saharan African sample, indicating that African population size was larger than other regions during recent human evolution. The best fit of the model is with relative population weights of 0.73 for sub-Saharan Africa, 0.09 for East Asia, and 0.18 for Europe. These results are similar to those obtained using craniometric variation for these three geographic regions. These results, combined with inferences from other genetic studies, support a major role of Africa in the origin of modern humans. It is less clear, however, whether complete African replacement is the most appropriate model. An alternative is an African origin with non-African gene flow. While Africa is an important region in recent human evolution, it is not clear whether the gene pool of our species is completely out of Africa or predominately out of Africa. PMID- 10096678 TI - Determination of age at death: assessment of an algorithm of age prediction using numerical three-dimensional CT data from pubic bones. AB - The determination of age at death is an important part of physical and forensic anthropology. Because of resistance to decomposition and the simplicity/accuracy ratio, the direct observation of the os pubis by Suchey-Brooks phase analysis is the preferred reference system for determination of age at death. We propose an age-prediction system using a pubic symphysis numerical database obtained from CT x-ray through quantification of age-linked parameters. Our system increases the accuracy of age estimation and at the same time preserves the integrity of the archeological material. PMID- 10096679 TI - Growth changes in measurements of upper facial positioning. AB - Growth changes in the position of the midline upper face are examined for samples of Pan troglodytes, Gorilla gorilla, and modern humans. Horizontal and vertical distances between nasion and the anterior end of the cribriform plate are plotted against stage of dental development. Kendall's nonparametric correlations between facial positioning and stage of dental development are tested for significance. In African apes, the upper face becomes more projecting and positioned higher relative to the anterior cranial base. The extent of this horizontal and vertical separation reflects primarily facial size. In modern humans, the upper face becomes more projecting but is relatively stable in its vertical position. Comparison of Pan and modern human crania in the youngest dental age category indicates that the upper face of modern humans is positioned lower early in postnatal life. The position of the upper face (glabella) relative to the anterior and posterior cranial base is presented for several fossil hominid crania. The fossil crania are similar to Pan and modern humans in facial projection relative to the anterior cranial base. However, glabella is positioned low in the fossil crania. Total facial projection (relative to hormion) for Sts 5 is similar to the mean for Gorilla. Fossil Homo and robust australopithecine crania display very projecting upper faces. We suggest that the upper face of Homo is projecting due to the length of the anterior cranial fossa, while robust australopithecines possess a thick frontal bone. PMID- 10096680 TI - Size and shape of the human first permanent molar: a Fourier analysis of the occlusal and equatorial outlines. AB - Form can be viewed as a combination of size and shape. Shape refers to the boundary outline independently from its orientation, relation to reference planes, and dimension (or size). Shape and its changes could be quantified by mathematical methods such as the Fourier series. In this investigation, Fourier analysis has been used to quantify the morphologic characteristics (size and shape) of the outline of the occlusal surface and maximum circumference (equator) in 259 normal, healthy human first permanent maxillary and mandibular molars and to assess the effect of sex. Large within-group variability was found in the Fourier coefficients. Both equatorial and occlusal molar areas were on average larger in male than in female homologous teeth, but the difference was statistically significant only for the equatorial areas. The mean ratios between equatorial and occlusal dental areas were independent from arch (maxillary and mandibular), side, or sex. Both equatorial and occlusal outlines of left and right homologous molars within sex and arch were similar, without size and shape differences. Similarly, no sex differences in shape were found in the comparison of homologous teeth. The method used in the present study could supply information about dental shape in both its entirety and local variations. In particular, the method is extremely sensitive to local variations in dental shape, and it could be usefully employed to compare single teeth to a standard. PMID- 10096682 TI - A prehistoric example of polydactyly from the Iron Age site of Simbusenga, Zambia. AB - Human burials, dated AD 1100-1500, were examined from the Iron Age site of Simbusenga, located some 35 miles northwest of Victoria Falls in Zambia. Pedal polydactyly was discovered in the fragmentary remains of a young adult of indeterminate sex aged 14-25. The preaxial form of polydactyly is indicated with bilateral involvement of the first metatarsals. There is incomplete hypoplastic duplication of both first metatarsals with broad heads for the metatarsal phalangeal joints. No digital malformations were found in the other seven individuals with feet and/or hands from the site. Several studies point to autosomal dominance for cases of isolated polydactyly, but inheritance and patterning of preaxial polydactyly are still incompletely understood. The condition is also found in conjunction with genetic malformation syndromes such as Acrocephalypolysyndactyly, Lambotte, Oro-facio-digital, and VATER. High frequencies of polydactyly are reported for African and African-American populations, but further analysis reveals that the bulk of previously reported cases of polydactyly are representative of the postaxial form as opposed to the preaxial expression seen here. PMID- 10096681 TI - Life history of Eulemur fulvus rufus from 1988-1998 in southeastern Madagascar. AB - In this study, we compare the life-history patterns of male and female Eulemur fulvus rufus based on longitudinal data collected on individuals from two study groups from 1988-1998 in southeastern Madagascar. Mean group size was 9.5 individuals, and groups either contained more adult males than females or equal numbers of both sexes. Females reproduced for the first time between 2 and 4 years of age and reproduced each year, although the mean interbirth interval between surviving offspring was 2.1 years. An average of two adult females reproduced annually in each social group, and age and body weight may positively influence reproductive success. Females also appear to be philopatric but not female-bonded. Young natal males immigrated between 3 and 4.5 years of age and may join a new group within 612 months based on the age of emigrants. Once in a social group, they remained until old age, although a male's spatial position in the social group varied with age. Young nonnatal males were members of the social core and had the first opportunity to mate with all estrous females. Older males were peripheral to the social group and mated with females later in their cycle. We hypothesize that group size, the number of females in the group, and individual variation in reproductive success is influenced by several ecological conditions at this site: extreme variability in food availability during reproductive periods, the lack of large food patches, low plant species diversity, and small numbers of important aseasonal food sources such as Ficus species. PMID- 10096683 TI - Probable evidence of scurvy in subadults from archeological sites in Peru. AB - Subadult scurvy is not well documented in archeological human remains despite the existence of many biomedical references indicating that bone changes do occur in some cases and, because of this, should be observable in human burials. There are several potential reasons for this gap in our knowledge of scurvy. Not all children who suffered from scurvy died of the disease or from other causes when they had scurvy. Scurvy may not leave characteristic bone changes in every case of the disease. Some of the pathological conditions associated with scurvy have been known for many years, but these features may be rare or difficult to differentiate from other pathological conditions. Recently a lesion of the skull has been described that is probably pathognomonic for scurvy, specifically porous and sometimes hypertrophic lesions of the greater wing of the sphenoid. This lesion is bilateral and highly associated with evidence of inflammation at other anatomical sites in the skull. A survey of subadult skulls (N = 363) in the human skeletal collection from Peru at the National Museum of Natural History, Smithsonian Institution, reveals a prevalence of 10% of skulls that exhibit plausible evidence of scurvy. Some cases of scurvy also have cribra orbitalia that has been attributed to anemia. In most of the Peruvian scurvy cases, anemia is an unlikely possibility because there is no evidence of marrow hyperplasia. This highlights the need for caution in using lesions of the orbit as an indicator of anemia when there is no other evidence of this disease elsewhere in the skeleton. Anatomical evidence of scurvy offers the potential of providing new and important evidence of diet in archeological human populations. PMID- 10096684 TI - Dates, caries, and early tooth loss during the Iron Age of Oman. AB - Diets high in fermentable carbohydrates are known to be highly cariogenic, particularly when contained in very sticky food such as dates. This medium allows food to remain in contact with the teeth, thereby resisting the normal flushing action of the saliva. When comprising a large portion of the diet, food such as this can lead to high caries incidence and accelerated tooth loss. This appears to be the situation found in a skeletal series from the late Iron Age in the Sultanate of Oman (100 BC-AD 893). Dental remains from 37 individuals were used in this study. Antemortem tooth loss (AMTL), caries, and dental attrition data were compiled from the 32 adult and juvenile specimens. In this sample, the caries rate is 35.5% of individuals (39.4% corrected), and 18.4% of teeth (32.4% corrected), while AMTL occurs in 100% (ten of ten) of preserved mandibles. Caries onset in permanent molars begins soon after eruption, with tooth loss and remodeling of the alveolus frequently complete by the time of third molar occlusion. PMID- 10096685 TI - The elusive diploic veins: anthropological and anatomical perspective. AB - Diploic veins (Canales diploicae), which were identified in dogs by Dupuytren more than 200 years ago (Hecker [1845] Die anatomische Verhaltnisse und Krankheiten der Venae diploicae und Vasa emissaria. Erfahrungen und Abhandlungen im Gebiete der Chirurgie und Augenheilkunde. Erlangen), have remained inadequately understood and scantily referenced in the anatomical and anthropological literature. The tunnels formed by diploic veins are among the few known skeletal markers of soft tissue alteration. Protected by two bony laminae, diploic vein tunnels often resist postdepositional destruction and may provide a new way to assess living and extinct hominid populations. This basic research was carried out to enable future utilization of the diploic venous channels in anthropologic research. In the present study, diploic venous channels were observed radiographically in 108 human adults aged 19 years and above, 18 infants and children aged 1-18 years (Hamann-Todd Osteological Collection), eight fetuses aged 7-9 months (the Johns Hopkins Collection), and seven nonhuman primates (Hamann-Todd Osteological Collection). In addition, seven documented cases of parents and children were radiographed for genetic evaluation (Osteological Collection of The Hungarian Natural History Museum). Five distinct diploic distribution patterns were identified and described in this study. This was at variance with the impressions reported in dissection-based studies. Independence of diploic vein pattern from demographic (gender and age) and size factors and their tendency to be symmetrical make them amenable and reliable traits for skeletal population study. Diploic vein patterns appeared to be more complicated in humans than in nonhuman primates, raising the possibility of future phylogenetic applications. PMID- 10096686 TI - Effect of taphonomic processes on dental microwear. AB - Taphonomic processes have the potential to affect microscopic wear on teeth and to modify the wear patterns so as to confound dietary reconstructions based on dental microwear which was formed during the lifetime of an animal. This study describes a series of experiments which were conducted to simulate various taphonomic agents and to record their effect on dental microwear. Three types of experiment were carried out in order to explain anomalous microscopic wear that had been found on the dentition of several hominoid specimens from the 15 M.a. site of Pasalar in Turkey. The effect of two different acids-citric and hydrochloric acid-on dental microwear was investigated. Modification to microscopic wear caused by alkali (carbonatite ash) was examined in the second set of experiments. Lastly, the effect of abrasion by three different size classes of sediment from the site of Pasalar-quartz pebbles (grain size varied from 2,000-11,000 microm), coarse sand (grain size ranged from 500-1,000 microm), and medium-sized sand (grain diameters were between 250 and 500 microm)-was investigated. Results confirm previous findings that the taphonomic modification of dental microwear is readily identifiable and causes the obliteration rather than secondary alteration of microwear features. The experiments show that both citric and hydrochloric acid affect dental microwear but to varying degrees, whereas alkali did not cause any modification of microscopic features. The different size classes of sediment also had different effects on the dental microwear. The largest size sediment (quartz pebbles) polished the enamel and removed finer microwear features. The coarse sand, however, did not have any effect on the microwear. The greatest amount of abrasion was caused by the smallest sediment particles -the medium-sized sand. Several hominoid dental specimens from Pasalar display similar microscopic wear to the two types of acid erosion and the abrasion caused by the medium-sized sands. PMID- 10096687 TI - Optimal allele-sharing statistics for genetic mapping using affected relatives. AB - The choice of allele-sharing statistics can have a great impact on the power of robust affected relative methods. Similarly, when allele-sharing statistics from several pedigrees are combined, the weight applied to each pedigree's statistic can affect power. Here we describe the direct connection between the affected relative methods and traditional parametric linkage analysis, and we use this connection to give explicit formulae for the optimal sharing statistics and weights, applicable to all pedigree types. One surprising consequence is that under any single gene model, the value of the optimal allele-sharing statistic does not depend on whether observed sharing is between more closely or more distantly related affected relatives. This result also holds for any multigene model with loci unlinked, additivity between loci, and all loci having small effect. For specific classes of two-allele models, we give the most powerful statistics and optimal weights for arbitrary pedigrees. When the effect size is small, these also extend to multigene models with additivity between loci. We propose a useful new statistic, S(rob dom), which performs well for dominant and additive models with varying phenocopy rates and varying predisposing allele frequency. We find that the statistic S(_#alleles), performs well for recessive models with varying phenocopy rates and varying redisposing allele frequency. We also find that for models with large deviation from null sharing, the correspondence between allele-sharing statistics and the models for which they are optimal may also depend on which method is used to test for linkage. PMID- 10096688 TI - Likelihoods and TDT for the case-parents design. AB - Association studies using diseased cases and their parents avoid biases due to population stratification, and the transmission/disequilibrium test (TDT) is a popular method of analysis. Sample size and power calculations for the TDT method have been reported, but often for the special situation of multiplicative effects of alleles on the genotype relative risks. Furthermore, some of the proposed calculations ignore the dependence of transmitted alleles from a pair of heterozygous parents when the effects are not multiplicative, which can lead to erroneous sample size calculations. We demonstrate how to calculate sample size and power for the TDT method for general genotype relative risks. As an alternative to the TDT method, we present likelihood methods for a variety of genotype relative risk models. Exact likelihood methods are presented to allow for accurate small-sample analyses. We demonstrate by numerical comparisons: (1) that the TDT method is inefficient for recessive patterns of relative risks, (2) for alleles that are not rare, falsely assuming a multiplicative model can lead to gross underestimation of the required sample size for the TDT statistic, and (3) for common alleles, if the true genotype relative risks have an approximately dominant pattern, then the TDT method can be grossly inefficient compared to likelihood methods. An alternative likelihood ratio statistic, based on two degrees of freedom, tends to be robust for a wide range of genotype relative risk models. Finally, we discuss how to use standard software for conditional logistic regression to accurately assess effects of alleles as well as genotype environment interaction. PMID- 10096689 TI - Case-parents design for gene-environment interaction. AB - The scientific and public health implications of gene-environment interaction warrant that the most powerful study designs and methods of analysis be used. Because traditional case-control designs, which use nonrelated subjects, have demonstrated the need for large samples to detect interactions, alternative study designs may be worthwhile, such as sampling diseased cases and their parents. If the transmission of particular alleles from parents to their diseased child appears to be distorted from Mendelian expectation, then this suggests an etiologic association of the alleles with disease; if the frequency of transmission differs between exposed and nonexposed cases, then gene-environment interaction is suggested. We present likelihood-based methods to assess interaction, as well as an extension of the transmission/disequilibrium test (TDT). For these statistical tests, we also derive methods to compute sample size and power. Comparisons of sample size requirements between the case-parents design and the case-control design indicate that the case-parents design can be more powerful to detect gene-environment interactions, particularly when the disease susceptible allele is rare. Also, one of the derived likelihood methods, based on additive effects of alleles, tended to be the most robust in terms of power for a broad range of genetic mechanisms, and so may be useful for broad applications to assess gene-environment interactions. PMID- 10096690 TI - Constructing meiotic maps with known error probability. AB - We propose methods to construct meiotic gene maps while controlling the probability of a decision-error. First, a single step gene ordering procedure is presented whose decision-error probability is bounded above by a prespecified threshold. The bound for the error probability is valid under quite general circumstances. The ordering procedure is optimal in the sense of having maximal predictive probability of correct ordering among all procedures subject to the same bound on the error probability. Second, to reduce the number of hypotheses to be tested, a stepwise ordering procedure is presented. A Monte Carlo simulation study demonstrated the integrity of the proposed error bound for the stepwise procedure under a wide variety of situations, including data coming from different laboratories and marker typing errors. The stepwise procedure was applied to version 2 of the public database maintained by the Cooperative Human Linkage Center and maps of the 23 chromosomes were generated such that the probability that the order of the markers in a given chromosome is incorrect is less than 1%. PMID- 10096691 TI - Likelihood-based approach to estimating twin concordance for dichotomous traits. AB - Genetic epidemiologists are well aware that the casewise and pairwise twin concordances are two different measures. In determining appropriate estimators for each of these measures, the method of ascertainment must be considered. Here, we derive expressions for the concordance estimators and their asymptotic variances appropriate to different twin ascertainment schemes using a likelihood framework, and apply these formulas to existing data. We emphasize the distinction between concordance measures (i.e., the parameters of interest) and the concordance estimators based on the number of pairs observed. Under random or complete ascertainment the casewise estimator is asymptotically unbiased for the casewise concordance, and the pairwise estimator is asymptotically unbiased for the pairwise concordance. Under incomplete ascertainment, the casewise estimator is biased for the casewise concordance, the pairwise estimator is biased for the pairwise concordance, but the probandwise estimator is asymptotically unbiased for the casewise concordance. One can extend the likelihood equations presented here to allow the concordance parameter of interest to depend on zygosity and, if measured, other factors such as cohabitation status and similarity for genetic markers, while concurrently allowing the disease prevalence to depend on measured covariates. PMID- 10096692 TI - Segregation analysis of the specific response to allergens: a recessive major gene controls the specific IgE response to Timothy grass pollen. AB - Segregation analysis of the specific response to allergens (SRA) was performed in a sample of 234 randomly selected Australian families using the regressive models. Various SRA phenotypes were considered using broad and narrow definitions of these phenotypes, according to the type of test used, skin test or RAST test, and the specificity of the response to allergen. Strong evidence for familial dependencies among blood relatives was shown for most SRA phenotypes, especially when using a broad definition. There was no evidence for a Mendelian factor accounting for the familial transmission of these broadest phenotypes, which may involve multiple factors preventing the clear detection of a major effect with Mendelian transmission. However, segregation of a Mendelian recessive major gene was detected for one SRA sub-phenotype, the IgE response to a single allergen, Timothy grass pollen, measured by the RAST test. Identification of a specific SRA phenotype controlled by a major gene may have important implications for further linkage studies. PMID- 10096693 TI - Familial aggregation of body mass index and subcutaneous fat measures in the longitudinal Quebec family study. AB - Family resemblance for several measures of body fat and fat distribution was explored in the longitudinal Quebec Family Study (QFS), including an overall measure of adiposity (body mass index, BMI), total subcutaneous fat (the sum of 6 skinfolds, SF6), and subcutaneous fat distribution (the trunk to extremity ratio, TER). Repeated measures were taken twice approximately 12 years apart. A longitudinal familial correlation model was used to assess familial resemblance at each of times 1, 2, and cross-time, and a univariate model was used for the change score. The change score was assumed to index the degree to which different familial factors impacted on the longitudinal resemblance, while the cross-time comparisons indexed similar familial factors across time. For BMI, the maximal heritability was 44 and 36% at times 1 and 2, respectively, 37% for the change score, and 33-43% for the cross-time comparison. While the etiology of the BMI familial effect at times 1, 2, and cross-time was assumed to be primarily polygenic, that for the change score was a function of cohort effects (environmental). For SF6, the maximal heritability (primarily genetic) was low at time 1 and for the change score (16%), but was nonsignificant at time 2 and cross time. For TER, the maximal heritabilities were significant for each of times 1 (42%), 2 (40%), change score (59%), and cross-time comparisons (35-36%). In summary, simple univariate familial correlation analysis of the change scores and bivariate analysis of the longitudinal measures are useful in delineating the underlying factors leading to both change and stability across time. PMID- 10096694 TI - Celecoxib approved as NSAID with some concessions on class warning. PMID- 10096695 TI - Cilostazol approved for use in intermittent claudication. PMID- 10096696 TI - FDA drug-review, surveillance processes under scrutiny. PMID- 10096697 TI - Priority drugs well represented among 1998 approvals. FDA says all performance goals were met. PMID- 10096698 TI - Smoking-cessation programs need to target college students. PMID- 10096699 TI - Using a pharmacist's progress-note form to manage HIV pharmacotherapy. PMID- 10096700 TI - Ways to help patients quit smoking. PMID- 10096701 TI - Serious surveillance. PMID- 10096702 TI - Metrifonate: a new agent for the treatment of Alzheimer's disease. AB - The pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of metrifonate, a long-acting cholinesterase inhibitor, are discussed. Attempts to correct the central cholinergic deficits associated with Alzheimer's disease have included administration of cholinergic precursors, cholinergic agonists, and cholinesterase inhibitors. To date, two reversible cholinesterase inhibitors tacrine and donepezil-have been marketed. Metrifonate, an organophosphate, is converted nonenzymatically to 2,2-dichlorovinyl dimethyl phosphate (DDVP), the active enzyme inhibitor. DDVP produces irreversible inhibition of brain cholinesterase that lasts for several days; enzyme recovery is dependent on synthesis of new enzyme. Several preclinical studies have demonstrated cognition enhancing effects of metrifonate in animals. Trials in humans have shown improvement on the Alzheimer's Disease Assessment Scale, in Mini-Mental State Examination scores, and in the Clinician's Interview-Based Impression of Change with caregiver input. Clinical improvement noted with metrifonate appears similar to that seen with other cholinesterase inhibitors. Adverse effects noted in clinical trials have been associated primarily with the gastrointestinal tract and have been mild. Metrifonate appears to be a promising agent for the treatment of the symptoms of Alzheimer's disease. PMID- 10096703 TI - Inappropriate prescribing for elderly outpatients. AB - The frequency of potentially inappropriate prescribing for elderly outpatients and factors predicting inappropriate prescribing for these patients were studied. A panel of experts in geriatric medicine and geriatric pharmacology developed a list of 20 drugs generally considered to be inappropriate for elderly patients. Data on outpatient visits by patients aged 65 years or older were extracted from the 1994 National Hospital Ambulatory Medical Care Survey and analyzed with respect to the 20 potentially inappropriate medications. Potentially inappropriate medications were prescribed at 4.45% of elderly outpatient visits involving medications. An estimated 319,302 (95% confidence interval, 256,269 to 382,334) visits involved potentially inappropriate medications. The most frequently prescribed potentially inappropriate medications were diazepam, propoxyphene, dipyridamole, amitriptyline, and chlordiazepoxide; these drugs accounted for 85% of the outpatient visits involving potentially inappropriate medications. Patients were more likely to be prescribed potentially inappropriate medications if they had been referred; had a number of medications prescribed; had a prescription for an antianxiety agent, a sedative, an antidepressant, an analgesic, a platelet inhibitor, or an antispasmodic agent; or had a medication prescribed by a provider from a nonmetropolitan area. Ambulatory care providers prescribed at least one potentially inappropriate medication at 4.45% of visits by elderly patients at which a medication was prescribed; patient characteristics, provider characteristics, and drug-use profiles can be used to predict inappropriate prescribing. PMID- 10096704 TI - Standard gentamicin dosage regimen in neonates. AB - A standard gentamicin dosage regimen intended to result in fewer trough concentrations of >2 microg/mL was studied. At a neonatal intensive care unit, gentamicin dosage guidelines of 2.5 mg/kg (as the sulfate) administered i.v. over 30 minutes every 12, 18, or 24 hours to neonates with a gestational age (GA) of > or =30 weeks were resulting in some relatively high trough serum concentrations (>2 microg/mL). Pharmacokinetic values derived for this baseline group were used to predict the gentamicin concentrations that would result from a standard regimen of gentamicin 3.5 mg/kg i.v. over 30 minutes every 24 hours. No patient in the baseline group was predicted to have a trough of >2 microg/mL with the new regimen, which was then approved for routine use. The new regimen was used for every neonate with a GA of > or =30 weeks who was admitted and treated with gentamicin (the protocol group). One set of concentrations was collected for each infant. Compared with the baseline group, the protocol group had significantly lower trough and significantly higher peak gentamicin concentrations. The total frequency of high troughs in the baseline group (23 [33%] of 69 patients) differed significantly from that in the protocol group (3 [4%] of 74 patients). No patient had or developed renal impairment. A gentamicin dosage protocol of 3.5 mg/kg every 24 hours for neonates with a GA of > or =30 weeks resulted in higher gentamicin peaks, lower troughs, and a lower frequency of troughs of >2 microg/mL, compared with previous dosage practice. PMID- 10096705 TI - Efficient operation of a high-volume anticoagulation clinic. AB - A pharmacist-operated anticoagulation clinic at a Department of Veterans Affairs (VA) medical center is described. An anticoagulation clinic established by the pharmacy service at the Denver VA Medical Center cares for 600 patients by using 1.35 fulltime-equivalent pharmacists. The pharmacists are privileged by medical staff to write prescriptions for warfarin, adjust warfarin dosages, and conduct appropriate laboratory monitoring. A protocol has been developed to standardize care. Patients referred to the clinic are scheduled for a same-day warfarin class and laboratory so that International Normalized Ratios (INRs) are available for the patient's appointment with the pharmacist; the patient's understanding of the material presented in the class is assessed during this appointment. The pharmacist determines the therapeutic range and duration of treatment and schedules a follow-up appointment. A locally developed computer program imports patient data from the hospitalwide computer system and simplifies scheduling and tracking of patient-related information. At any point in time, approximately 67% of clinic patients are in the therapeutic range, 13% are above range, and 20% are below range. From January to December 1994, 1.1% of clinic patients were admitted to the medical center for bleeding compared with 2.0% of patients receiving usual care, and 0.9% of clinic patients had thromboembolic complications compared with 3.1% of usual care patients. A computer program, clinical privileging of pharmacists, and a clinic protocol have helped a pharmacist-operated anticoagulation clinic to provide efficient care to veterans. PMID- 10096706 TI - Risk factors for patient hospitalization. PMID- 10096707 TI - Patient outcomes after formulary conversion from immediate-release to extended release glipizide tablets. PMID- 10096708 TI - Stability of cefepime hydrochloride injection in polypropylene syringes at -20 degrees C, 4 degrees C, and 22-24 degrees C. PMID- 10096709 TI - ASHP therapeutic position statement on smoking cessation. American Society of Health-System Pharmacists. AB - Smoking continues to be the single most important preventable cause of morbidity and mortality in the United States. Pharmacists, in collaboration with other health care providers, have the opportunity to make a significant contribution to addressing this major public health problem. ASHP supports AHCPR's guidelines for smoking cessation. ASHP encourages all health care providers to actively promote smoking cessation and become participants in the provision of smoking-cessation programs or tobacco treatment interventions. Because a majority of smokers start smoking when they are less than 18 years old, emphasis must also be given to the prevention of smoking by children and adolescents. PMID- 10096710 TI - Formularies and therapeutic interchange: the health care setting makes a difference. PMID- 10096711 TI - Multidisciplinary approach to improving pediatric home infusion. PMID- 10096712 TI - Removal of pyrogens by filtration? PMID- 10096713 TI - Useful prescription drug information. PMID- 10096714 TI - Current literature. PMID- 10096715 TI - Incidents and accidents in health care: it's time! PMID- 10096716 TI - The Australian Medication Safety Working Group: developing a strategy for reducing adverse drug events in the Australian health system. PMID- 10096717 TI - Adverse events in health care: setting priorities based on economic evaluation. AB - Adverse events arising from health-care management, rather than a disease process, may place as great a burden on society as all other forms of injury put together. By analysing data from the Quality in Australian Health Care Study (a retrospective review of 14 179 medical records representative of admissions to Australian acute care hospitals in 1992), and applying costing techniques based on Diagnosis Related Group (DRG) cost weights, it is possible to compare the economic impacts of different kinds of adverse events. This can assist in determining priorities for interventions. However, due to limitations inherent in DRG cost weights, there is a need to employ further techniques to refine the costing base of adverse events so that it more closely reflects their resource use. Decisions to invest resources in strategies that reduce the risk of adverse events can then be properly informed by economic data. PMID- 10096718 TI - Frequency, consequences and prevention of adverse drug events. AB - Iatrogenic injuries are important because they are frequent and many may be preventable; those caused by therapeutic drugs are among the most frequent. While medication errors are common, most have little potential for harm. However, some errors, such as giving a patient a drug to which they have a known allergy, are more likely to cause injury. Error theory provides insights into the changes required to reduce medication error injury rates. Data from the Adverse Drug Event (ADE) Prevention study suggest that most serious errors occur at the ordering and dispensing stages, while another, smaller, proportion occur at the administration stage. These data suggest that physician computer-order entry, where physicians write orders on-line with decision support, including patient specific information and alerts about potential problems, has the potential to significantly reduce the number of serious medication errors. PMID- 10096719 TI - The nature and extent of drug-related hospitalisations in Australia. AB - In order to determine the nature and extent of drug-related hospitalisation in Australia, the Australian National Hospital Morbidity Collection, the Quality in Australian Health Care Study and Australian studies assessing drug-related hospital admissions were reviewed. The incidence figures, drugs and conditions most commonly implicated, and estimates of avoidability of medication-related problems were compared. The three data sources were found to provide consistent results, with all sources implicating cytotoxics, antirheumatics, anticoagulants, corticosteroids, antihypertensives and cardiovascular agents in medication related hospitalisations. Estimates of the extent of the problem were also consistent, suggesting that at least 80 000 medication-related hospitalisations occur in Australia each year; between 32% and 69% of these hospitalisations were considered avoidable. It was concluded that medication-related hospitalisations are a major public health problem in Australia. The avoidability estimates suggest that much can and should be done to reduce this problem. PMID- 10096720 TI - A classification for adverse drug events. AB - There is considerable evidence that a large number of patients suffer adverse events arising from their health-care management. A significant proportion of these iatrogenic injuries occur as a result of medication errors. Before prevention strategies can be developed, it is necessary to understand the types of errors that are occurring. In order to set priorities, it is necessary to identify the frequency and impact of the various types of medication errors. To fully investigate medication incidents, it is necessary to classify the information in a way that allows the frequencies, causes and contributing factors to be analysed. The development of a sub-branch of the 'Generic Occurrence Classification', specific to medication incidents, allows this analysis to occur. PMID- 10096721 TI - An analysis of Australian adverse drug events. AB - Previous research has shown that there is a high error rate associated with medication use, resulting in significant patient morbidity and mortality, as well as increasing health care costs. Analysis of available Australian data on adverse drug events shows that incident monitoring and retrospective medical record review provide different, but complementary 'windows' into the errors that occur. While retrospective medical record review provides information on the frequency of specific adverse drug events, incident monitoring gives an insight into the contributing factors. From this information, priorities can be set and preventative strategies can be developed. PMID- 10096722 TI - The Australian National Medicinal Drug Policy. AB - A responsibility of Government is to ensure that safe and efficacious medicines are available for people, from local industry, to treat illness and to maintain health. However, the cost of these medications to the public must be such that access is not denied because of financial barriers. Accessibility alone does not ensure that health outcomes are maximized. It is also necessary to have in place structures and processes which involve all stakeholders in ensuring the quality use of medicines. All of these components need to be incorporated in a national, co-ordinated policy which acts as a reference point for appropriate drug use, policy development and evaluation. PMID- 10096723 TI - Towards system-wide strategies for reducing adverse drug events. AB - Despite the best efforts of committed health-care workers, there are many adverse drug events (ADE). A large proportion of ADE arise from system factors, either directly (e.g. poor equipment design) or indirectly (e.g. inappropriate rostering of staff). This paper represents the proceedings of a workshop focus group that deliberated on priority health-system issues identified as requiring action in order to minimise the risks of ADE. Major issues canvassed were the gathering of appropriate and useful data about ADE, the dissemination of information to professionals and consumers, and effective communication across groups of professionals, and between professionals and consumers. A number of recommendations were put forward as important first steps in addressing these issues. PMID- 10096724 TI - Towards safer drug prescribing, dispensing and administration in hospitals. AB - A multidisciplinary workshop was held in order to identify strategies likely to produce a reduction in adverse drug events, by targeting hospital systems involved in drug prescribing, dispensing and administration. Strategies identified at the workshop included: (i) improving the education and practice development of medical and nursing staff, concerning drug therapy and safe prescribing principles; (ii) introducing and using information technology and electronic prescribing processes; (iii) implementing the Australian Pharmaceutical Advisory Council (APAC) national guidelines to achieve the continuum of quality use of medicines between hospitals and the community; (iv) enhancing the importance of medication history taking as a routine part of the admission process; (v) instituting individual patient supply as the standard method of drug distribution in hospitals; and (vi) stimulating the hospital-based clinical pharmacy workforce. PMID- 10096725 TI - Towards safer drug use in general practice. AB - A voluntary, anonymous incident-monitoring study was set up to identify and characterize events or circumstances which could have or did harm a patient in general practice. The study included 673 practitioners who made 2582 reports, of which half (n = 1294) involved medication problems. Amongst these reports, 1556 adverse drug events (ADE) were identified. More common in general practice than in hospitals were problems with therapeutic use (26% vs. 8%), and prescribing of contraindicated medications (15% vs. 5%). In the latter group, 64 reports (4%) involved the prescription of a medication to which the patient was known to be allergic, 66 (4%) involved medication for which there was a recognized potential for a drug interaction, and 68 (4%) involved contraindicated medications due to pathophysiological factors. It was estimated that computer-based prescribing with decision support could eliminate at least a third of these problems in general practice. Further studies are needed to develop this and other preventive strategies. PMID- 10096726 TI - Towards the safer use of non-steroidal anti-inflammatory drugs. AB - Musculoskeletal conditions afflict most of us at some time in our lives, and we all have relatives and friends who suffer the pain and disability sometimes associated with conditions such as back or neck pain, fibrositis and osteoarthritis. The goal of those of us who try to help individuals with these conditions is to achieve effective, but also safe, management of their musculoskeletal disorders, the commonest symptom of which is pain. This goal can be achieved by better diagnosis and problem formulation (allowing better selection of treatment options); informed selection of non-drug and drug therapeutic options, based on relative cost-benefit considerations; and the judicious, appropriate and safe use of drugs, particularly non-steroidal anti inflammatory drugs (NSAID). Setting realistic goals and maintaining regular surveillance of patients are also important considerations. Finally, the active involvement of the patient in their own management is associated with better and safer outcomes. PMID- 10096727 TI - Towards the safer use of warfarin I: an overview. AB - There has been an exponential increase of warfarin usage in the community since several large and well-designed clinical trials have consistently found that warfarin can safely prevent embolic stroke in people with atrial fibrillation. Safe and effective warfarin treatment requires a case-by-case evaluation of each patient's clinical condition and risk factors for bleeding. It also demands a therapeutic partnership where patients can accept an educated responsibility for managing their own condition. This requires mutually understood plans for ongoing management, including dose adjustment and responses to under- or overdose and to bleeding complications. PMID- 10096728 TI - Towards the safer use of warfarin II: results of a workshop. AB - The use of oral anticoagulation therapy (ACT) is expanding. Due to the combination of the narrow therapeutic range and relatively unpredictable pharmacokinetics and pharmacodynamics, there are relatively high risks involved in using this treatment. The purpose of this paper is to present the results of a focus group's canvassing of ways to improve the management of the use of oral anticoagulants. Recommendations proposed include: (i) better patient selection; (ii) more patient involvement and research into the appropriateness of the current use of ACT in Australia; (iii) increased production, dissemination and implementation of ACT guidelines; (iv) assessment of home and practice ACT monitoring; and (v) research into the effectiveness of academic detailing and the use of management plans by dedicated ACT educators. PMID- 10096729 TI - Towards safer blood transfusion practice. AB - The objective of this study was to determine the current state of transfusion practice at a large metropolitan hospital in South Australia, with a view to making recommendations to improve safety. Transfusion practice was monitored using a questionnaire and a concurrent audit design. Patients identified as having received a packed red blood cell transfusion in the previous 24 h, were selected by a random number generator. Questions included those about blood pack identification, documentation of the transfusion process, and patient observation. The results of this audit indicated that areas of documentation, primarily patient consent, blood pack administration times and patient monitoring required re-evaluation. Recommendations to improve practice were made based on these results. This is an ongoing service provided by the hospital, which has proven invaluable in identifying deficiencies in transfusion practice in order to improve patient care. PMID- 10096730 TI - Towards the safer use of dosettes. AB - Patient compliance has long been recognized to be a problem associated with drug treatment. Dosettes constitute a compliance aid; their aim is to maintain patient independence, while facilitating patient compliance. However, those patients most in need of such devices are the least likely to be able to manage them. It was therefore decided to examine incidents in which problems involving dosettes had been identified; 52 such incidents were found. Half the incidents involved filling errors, and most of these involved nurses; some incidents were potentially dangerous systematic errors. A second type of incident involved a problem with use, mainly caused by hurried or confused patients; these sporadic errors were less dangerous than filling errors. The remainder of the incidents involved patients taking medication in addition to the medication in the dosette. Recommendations include objectively assessing that a dosette is appropriate for the individual patient, and education about the need for compliance, meticulous care and checking when filling, and regular checks to confirm correct use. PMID- 10096731 TI - Application of an in situ PCR hybridization method to detection of human T lymphotropic virus type I-infected cells in the lung. AB - We applied an in situ polymerase chain reaction (PCR) hybridization method in order to detect human T-lymphotropic virus type I-infected cells in routinely processed paraffin sections of the lung from 13 autopsied patients with adult T cell leukemia (ATL). Previously reported protocol resulted in somewhat non specific staining in our sections. Therefore, we used a hot start PCR method using specialized commercially-available polymerase in order to increase the specificity. Of 6 patients with ATL cell invasion into the lungs, 4 exhibited strong positive staining of almost all invading ATL cells. In contrast, 7 patients without ATL cell invasion into the lungs did not demonstrate any significant reactivity. Since the method described here is a relatively simple hot start method and does not yield false-positives, it may allow us to determine whether human T-lymphotropic virus type I (HTLV-I) associated disorders are related to lymphocytes integrating the HTLV-I genome. PMID- 10096732 TI - Effect of intracarotid infusion of etoposide: modification of the permeability of the blood-brain barrier and the blood-tumor barrier in rat brain tumor model. AB - The effect of intracarotid infusion of etoposide on the permeability of the blood brain barrier (BBB) and brain-tumor barrier (BTB) was investigated using a model of rats injected with C6 glioma cells. Fifty four glioma-bearing rats were divided into 3 groups and treated with 0, 3, or 15 mg/kg of etoposide infused into the internal carotid artery. BBB or BTB permeability was evaluated qualitatively by the leakage of Evans blue (6 animals in each group) or quantitatively by the diffusion of carboplatin [cis-diammine (1,1-cyclobutane dicarboxylato) platinum(II); CBDCA] (12 animals in each group) into the normal brain or the tumor tissue. BBB and BTB disruption augmented significantly in proportion to the dose of etoposide. The degree of disruption of BTB was greater than that of BBB, but the rate of disruption of BBB in proportion to increasing the dose of etoposide was higher than that in the BTB. Histopathologically, no obvious changes were observed in the animals of either the control group or the 3 mg/kg group but degenerative changes in the neurons of the hippocampus of the infused hemisphere were seen in the 15 mg/kg group. This change is thought to be caused by apoptosis because of the positive reaction with TdT-mediated dUTP biotin nick-end labeling (TUNEL) method. Our results suggest that intracarotid infusion of etoposide can increase drug delivery of concurrent antitumor agents into tumor tissue, but cerebral parenchymal cell damage is expected with a higher dosage of etoposide. Therefore, the dosage of etoposide for intracarotid infusion should be lower than 15 mg/kg in order to reduce neurotoxicity of both etoposide and concurrent anticancer drugs. PMID- 10096733 TI - Experimental beta-alaninuria induced by (aminooxy)acetate. AB - Experimental beta-alaninuria was induced in rats by injection of (aminooxy)acetate (AOA), a potent inhibitor of aminotransferases, in order to elucidate the pathogenesis of hyper-beta-alaninemia. A 27-fold increase of beta alanine (BALA) excretion was induced by subcutaneous injection of 1 5 mg of AOA per kg of body weight. A 13-fold and a 9-fold increase of beta-aminoisobutyric acid (BAIBA) and gamma-aminobutyric acid (GABA), respectively, were also induced simultaneously by the AOA injection. Identification of BALA and BAIBA isolated from the rat urine was performed by chromatographic and mass spectrometric analyses. The effects of AOA injection on the tissue levels of these amino acids were also studied. Contents of BALA in the liver and kidney and GABA in the brain increased significantly in response to AOA injection. The present study indicates that BALA transaminase is involved in hyper-beta-alaninemia. PMID- 10096734 TI - Formation of gamma-glutamylpropargylglycylglycine from propargylglycine in human blood and erythrocytes. AB - Gamma-Glutamylpropargylglycylglycine (gamma-Glu-PPG-Gly) was isolated as a metabolite of propargylglycine (2-amino-4-pentynoic acid, a natural and synthetic inhibitor of cystathionine gamma-lyase) from human blood incubated with D,L propargylglycine in the presence of L-glutamate and glycine, and identified by fast-atom-bombardment mass spectrometry, indicating that human blood can metabolize propargylglycine to gamma-Glu-PPG-Gly. When whole blood was incubated with 2 mM D,L-propargylglycine in the presence of 10 mM L-glutamate and 10 mM glycine at 37 degrees C for 16h, 0.094+/-0.013 micromol of gamma-Glu-PPG-Gly was formed per ml of whole blood. When erythrocytes were incubated under the same conditions for 16h, 0.323+/-0.060 micromol of gamma-Glu-PPG-Gly was formed per ml of erythrocytes, suggesting a large contribution of erythrocytes to gamma-Glu-PPG Gly formation in whole blood. The apparent Km value of gamma-Glu-PPG-Gly formation in human erythrocytes for D,L-propargylglycine was 0.32 mM. The observed rate of gamma-Glu-PPG-Gly formation and the Km value for D,L propargylglycine suggest that metabolism of propargylglycine to gamma-Glu-PPG-Gly can play a definite biological role in human subjects who are loaded with propargylglycine. PMID- 10096735 TI - The impact of propylthiouracil therapy on lipid peroxidation and antioxidant status parameters in hyperthyroid patients. AB - This study was performed on 17 hyperthyroid patients and 15 healthy controls. The patients were under propylthiouracil (PTU) therapy at a dosage of 3 x 100 mg/day for one month. Blood samples, taken at the beginning and on the 30th day of therapy, were analyzed for hormonal parameters (T3, T4, TSH), lipid peroxidation endproduct [thiobarbituric acid reactive substances (TBARS)] and antioxidant status parameters: glutathione (GSH), glutathione peroxidase (GSH-Px) and CuZn superoxide dismutase (CuZn SOD). Hyperthyroid patients were observed to have significantly higher TBARS, GSH and CuZn SOD levels than controls (P < 0.05, P < 0.001, P < 0.001, respectively). PTU therapy caused a relief in oxidative stress as reflected by significantly decreased TBARS levels (P < 0.001) and a selective modification in the antioxidant status parameters: significant decreases in GSH and CuZn SOD levels (P < 0.001) and a significant increase in GSH Px (P < 0.01) activity. Our findings suggest a selective modification of the antioxidative profile in hyperthyroidism. PTU should also be considered as an in vivo antioxidant, in addition to its antithyroid action. PMID- 10096736 TI - Seroepidemiologic studies of hepatitis C virus infection in a population of Okayama Prefecture screened for liver disease. AB - To better understand the spread of hepatitis C virus (HCV) infection, we studied the association of HCV infection with similarly transmissible hepatitis B virus (HBV) infection and with hepatitis A virus (HAV) infection, which is supposed to be related to a nosocomial transmission of HCV. This was done by studying the presence or absence of antibodies to these viruses, as well as hepatitis B surface antigen, in a population of 1,398 inhabitants with abnormal liver function tests or history of liver disease and/or blood transfusion. This group was drawn from a group of 7,905 examinees screened for liver disease in 26 districts of Okayama prefecture, Japan. The prevalence of antibody-positive cases increased with age for those viruses. Small but significantly increased odds ratios were obtained among anti-HCV antibodies (HCVAb), anti-hepatitis B core antibodies (HBcAb) and anti-hepatitis A antibodies (HAVAb). After adjusting odds ratios by logistic regression analysis, a significant association was present only between HCVAb and HBcAb. The distribution of age-adjusted prevalences (AAP) of HCVAb in 26 districts was significantly wider than those of HBcAb or HAVAb. The district-based AAP of HCVAb, but not of HBcAb and HAVAb, correlated significantly with the district-based prevalence of infectious hepatitis having a tendency of chronicity reported in 1953-1955. Adjusted odds ratios calculated by logistic regression analysis of the virus markers showed that HCVAb was significantly associated with a past history of blood transfusion. Thus, the spread of HCV infection is speculated to have been triggered by blood transfusion, particularly from paid donors initially, followed by transmission by nosocomial or close person-to-person contact. PMID- 10096737 TI - Adequacy and long-term prognosis of endoscopic carpal tunnel release. AB - Forty-one hands of 37 patients with idiopathic carpal tunnel syndrome treated by endoscopic carpal tunnel release (ECTR) were followed up for more than one year after surgery. Surgical results were evaluated using Kelly's criteria, the Semmes Weinstein test, the static and moving 2-point discrimination tests, tip-pinch strength, and motor and sensory nerve conduction studies. Clinical results, according to Kelly's criteria three months after surgery, were excellent or good in 36 hands, and fair or poor in five hands. No recovery was evident at six months and 12 months after surgery in fair and poor hands. Based on these findings, we conclude that a neurolysis of the median nerve and release of constriction of the thenar muscle branch should be performed using the conventional open technique for patients with poor results three months after ECTR if the patients are dissatisfied with ECTR results. PMID- 10096738 TI - Suitable image parameters and analytical method for quantitatively measuring cerebral blood flow volume with phase-contrast magnetic resonance imaging. AB - The aim of this study was to determine suitable image parameters and an analytical method for phase-contrast magnetic resonance imaging (PC-MRI) as a means of measuring cerebral blood flow volume. This was done by constructing an experimental model and applying the results to a clinical application. The experimental model was constructed from the aorta of a bull and circulating isotonic saline. The image parameters of PC-MRI (repetition time, flip angle, matrix, velocity rate encoding, and the use of square pixels) were studied with percent flow volume (the ratio of actual flow volume to measured flow volume). The most suitable image parameters for accurate blood flow measurement were as follows: repetition time, 50 msec; flip angle, 20 degrees; and a 512 x 256 matrix without square pixels. Furthermore, velocity rate encoding should be set ranging from the maximum flow velocity in the vessel to five times this value. The correction in measuring blood flow was done with the intensity of the region of interest established in the background. With these parameters for PC-MRI, percent flow volume was greater than 90%. Using the image parameters for PC-MRI and the analytical method described above, we evaluated cerebral blood flow volume in 12 patients with occlusive disease of the major cervical arteries. The results were compared with conventional xenon computed tomography. The values found with both methods showed good correlation. Thus, we concluded that PC-MRI was a noninvasive method for evaluating cerebral blood flow in patients with occlusive disease of the major cervical arteries. PMID- 10096739 TI - Hydrocortisone sodium succinate suppressed production of interleukin-10 by human peripheral blood mononuclear cells: clinical significance. AB - Corticoids are well known for their immunosuppressive properties. Interleukin-10 (IL-10) is an intrinsic antiinflammatory peptide in immune diseases, originally identified as cytokine synthesis inhibitory factor. We examined the effect of hydrocortisone sodium succinate (HSS) on the production of IL-10 by human peripheral blood mononuclear cells (PBMCs). PBMCs from healthy volunteers and cancer-burden patients were preincubated separately with or without HSS for 1 h, then stimulated with 5 microg/ml lipopolysaccharide (LPS). Production of IL-10 by human PBMCs was detected with LPS stimulation and its production was higher in cancer-burden patients than in normal volunteers, although this was not statistically significant. HSS suppressed production of IL-10 by LPS-stimulated PBMCs in a dose-dependent manner both in normal volunteers and in cancer-burden patients. These results indicate that, in addition to their antiinflammatory properties, corticoids act to restore the immunosuppressive states even in cancer burden states. PMID- 10096740 TI - Carcinoma of the oesophagus. Anastomotic leaks after manual sutures--incidence and treatment. AB - Progress in the development of suture materials results in a lower rate of fistulas. Modern techniques for the diagnosis of leakage (contrast study, CT scan) allow for an early diagnosis and adequate therapy: if possible conservative therapy with drainage of the abscess, adapted antibiotic therapy and parenteral and enteral nutrition are the best methods. In the case of necrosis of the transplant, reoperation permits enables extra time for reconstruction. All the technical possibilities of reconstruction must be known. It is necessary to apply prophylactic precautions to avoid leakage of the anastomosis on the oesophagus. PMID- 10096741 TI - Experimental studies of injection agents for peptic ulcer bleeding endoscopic control. AB - AIM: To evaluate haemostatic effectiveness and tissue effects of injected therapy agents used for peptic ulcer bleeding endoscopic control. METHODS: Bleeding gastric mucosa lesions were produced during operation in 11 heparinised dogs. Bleeding lesions were treated with injections of 1 ml of epinephrine (1:10000), ornipressin (0.2 IU/m]), 98% ethanol, 1% polidocanol, thrombin (1000 U/ml), or fibrin sealant. In another 18 dogs, gastric submucosal injections of tested agents were performed during operations. Dogs were killed 48 h after injections and tissue effects were studied. RESULTS: The agents tested had similar effectiveness in achieving initial control of experimental bleeding (chi2 = 1.43). Vasoconstrictors caused no tissue injury or thrombosis in vessels after 48 h. Ethanol produced mucosa and submucosa necrosis and thrombosis in vessels. Polidocanol caused mucosa necrosis, submucosa oedema and thrombosis in vessels. Thrombin tissue effects were mucosa oedema, submucosa thrombosis in vessels. Fibrin sealant caused agent insertion between mucosa and submucosa, but no tissue injury or thrombosis in vessels. CONCLUSIONS: Experiments did not show significant differences between investigated agents in achieving initial bleeding control. The investigated agents, according to the stomach tissue injury they caused in our experiment, would produce series: epinephrine = ornipressin < fibrin sealant < thrombin < polidocanol < ethanol, and according to their effect on vascular thrombosis: epinephrine = ornipressin = fibrin sealant < polidocanol < ethanol < thrombin. PMID- 10096742 TI - Prognosis of patients with resection of stage IV gastric cancer. AB - We retrospectively analyzed 116 patients who underwent resection of stage IV gastric cancer to investigate the prognostic factors responsible for long-term survival. Statistically significant clinicopathological differences between patients surviving 3 years or more (n = 9) and those surviving less than 3 years (n = 107) were observed in regard to macroscopic type, curability of surgery, lymph node metastasis and blood vessel invasion. These four variables also had a statistically significant influence on survival by univariate analysis. Multivariate analysis revealed that no residual tumor (R0) surgery was a significantly beneficial factor for long-term survival. However, no patients with the diffusely infiltrative type of tumor survived for more than 2 years even if they underwent R0 surgery. Patients without the diffusely infiltrative type who underwent R0 surgery had better survival rates: a 27.3% and 13.6%, 3 and 5 year survival rate, respectively. In conclusion, R0 surgery contributes to long-term survival even in stage IV gastric cancer, and some patients with the not diffusely infiltrative type, in particular, may receive a survival benefit by R0 surgery. PMID- 10096743 TI - Lymph node metastasis in early gastric cancer: how can surgeons perform limited surgery? AB - BACKGROUND: In Japan, the standard treatment policy for all potentially curable patients with gastric cancer is radical resection, including extensive lymph node dissection. The extent of lymph node dissection remains a controversial issue in the management of early gastric cancer. A recent trend in the surgical treatment of early gastric carcinoma has been to limit surgery such that a complete cure is achieved and the patient's quality of life is improved. However, approximately 10% of early gastric cancers are reported to be node positive and little is known about the protocol of surgical treatment most appropriate for the treatment of early gastric cancer. In this study, we examined the clinicopathological features that could distinguish node-positive cancer from node-negative cancer. PATIENTS AND METHODS: The clinicopathological features of 26 patients with node-positive early gastric cancer were reviewed from the database of gastric cancer at the Department of Surgery, Sendai National Hospital. They were compared with those of 239 patients with node-negative cancer. RESULTS: Tumor size, macroscopic appearance, depth of cancer invasion, histological growth pattern and lymphatic invasion were associated with lymph node metastasis. Node-positive patients with early gastric cancer had a poorer survival rate than node-negative patients (P<0.05). CONCLUSION: Limited surgery, such as local resection without lymphadenectomy, can be performed for elevated or flat type cancer, or tumor <2 cm in diameter. Lymphadenectomy is recommended to achieve higher possible cure rates for other early gastric cancers. PMID- 10096744 TI - Gastric leiomyoblastoma: report of three cases. AB - Leiomyoblastoma is a rare smooth muscle tumor characterized by epithelioid cells with clear cytoplasms and an unknown biological behaviour. Since pre-operative diagnosis is difficult, the optimum strategy during the operation could be determined only by having a thorough knowledge about it beforehand. Leiomyoblastoma can be exogastric, intramural or endogastric. In the mostly benign exogastric leiomyoblastomas, total excision with resection of full thickness of gastric wall around the tumor is appropriate. Partial or total gastrectomy should be performed for intramural or endogastric tumors. We report one exogastric and two intramural gastric leiomyoblastoma cases treated in our hospital. PMID- 10096745 TI - The accuracy of diagnostic laparoscopy in trauma patients: a prospective, controlled study. AB - BACKGROUND: Numerous studies advocate the use of diagnostic laparoscopy (DL) for abdominal trauma, but none have documented its ability to diagnose specific injuries. This study tests the hypothesis that DL can accurately identify all significant intra-abdominal injuries in trauma patients. METHODS: Of trauma patients requiring laparotomy for presumed injuries, 47 underwent DL followed by laparotomy. Injuries noted at laparoscopy were compared with those found at laparotomy. RESULTS: Of these, 14 patients had no significant injuries necessitating operative intervention noted at laparoscopy and celiotomy. The remaining 33 patients harbored 93 significant injuries at laparotomy, of which only 57.0% were found by DL. DL possessed poor sensitivity (<50%) for injuries to hollow viscera. Despite DL's poor performance in finding specific injuries, it possessed excellent sensitivity (96.2%), and specificity (100%) for determining the need for therapeutic celiotomy. CONCLUSIONS: DL offers no clear advantage over diagnostic peritoneal lavage and computed tomography in blunt trauma. Its utility lies in assessment of the need for laparotomy in patients with penetrating wounds. Currently, DL cannot consistently identify all abdominal injuries, disqualifying it as a therapeutic tool in abdominal trauma. PMID- 10096746 TI - Percutaneous cholecystostomy in acute cholecystitis in high-risk patients: an analysis of 69 patients. AB - BACKGROUND: Optimal treatment of acute cholecystitis in high-risk patients with acute cholecystitis continues to be a difficult therapeutic problem. With the development of more advanced radiological imaging techniques, percutaneous cholecystostomy (PCS) has been presented as an effective treatment alternative in critically ill patients. This paper reports our experiences of percutaneous cholecystostomy in the treatment of acute cholecystitis in a well defined high risk patient group. METHODS: The data concerning 69 high-risk patients with acute cholecystitis treated by percutaneous cholecystostomy in Oulu University Hospital and Kokkola Central Hospital were analyzed. RESULTS: Ultrasound showed gallbladder stones in 71% (49/69) of the patients and 29% of them presented with acalculous cholecystitis. After PCS, pain diminished in 94% (61/65), fever in 90% (35/39), CRP values in 87% (53/61) and leucocyte count in 84% (46/55) of the patients. Before PCS, the CRP value was 132+/-106 mg/l and after PCS 79+/-73 mg/l (P = 0.001) and corresponding leucocyte counts were 14.7+/-5.0 and 9.3+/-3.2 (P = 0.001), respectively. The antegrade cholecystocholangiography was performed in 29 patients after PCS, and common bile duct stones were detected in 8 patients; these stones were treated by endoscopic papillotomy. Complications after PCS occurred in 17 patients (26%), but only two patients required emergency laparotomy. Mortality was 19% (13/69). Acute cholecystitis alone was the cause of death in only three patients. Mostly, fatal outcome was caused by the serious underlying diseases. CONCLUSION: According to our results, PCS should be the method of choice in high-risk patients with acute cholecystitis. PMID- 10096747 TI - Laparoscopic splenectomy for hematological disorders. Our experience in adult and pediatric patients. AB - Laparoscopic splenectomy has gained increasing acceptance in the surgical management of a variety of splenic disorders, in particular hematological diseases. In this series, we report our experience with 20 patients (male:female ratio of 4:16 with median age of 16 years, range 5-49 years) who underwent this procedure because of ITP in 9 cases, spherocytosis in 7 and Cooley disease, sickle cell anemia, dyserythropoietic and hemolytic anemia in one case each. The patient was placed in a supine position using a fourtrocars technique. We did not perform pre-operative splenic artery embolization in any case. Spleen lower pole and its posterolateral attachments were dissected first, using electrocautery and endoclips. Vascular hilar isolation was achieved with an EndoGIA stapler and the spleen was removed by morcelation within a retrieval bag (16 cases) or via a 4-5 cm left subcostal incision (4 cases). One patient required conversion to open technique (conversion rate 5 %), because of uncontrolled bleeding from splenic hilum. Mean operative time was 165 min (range 100-240 min), mean splenic size was 13.5 cm (range 11-20 cm), with weight ranging between 140 and 1060 g and estimated blood loss was 151 ml (75-280 ml). No patient required a blood transfusion. Median postoperative hospital stay was 4 days (range 3-8 days). Postoperative complications occurred in 2 patients (10%), with no mortality rate in this series. Regarding the low complication rate and the advantages of a small abdominal trauma in the postoperative period, such as less postoperative pain, faster hospital discharge and better cosmetic results, the laparoscopic approach for elective splenectomy in hematological disorders has a substantial benefit for the patient. PMID- 10096748 TI - Surgical resection of traumatic spleen cysts by laparoscopy. AB - Surgical resection of traumatic cysts by means of laparoscopy in two female patients is reported. The patients had sustained severe trauma in the left upper quadrant, were symptomatic and developed large splenic cysts found by computerized tomography, with an average diameter of 8.5 cm. Both patients were submitted to puncture and capsule removal by means of videolaparoscopy and diathermy; splenic parenchyma was preserved and the cyst's bed drained. No intra or postoperative complications occurred. After an average 21 months postoperative follow-up, both patients are symptom-free and no late recurrences were found on tomographic studies. The advantages of this technique over others that have been reported are the preservation of splenic parenchyma, its easy performance and efficient relief of symptoms, as well as being minimally invasive, associated with minimal postoperative pain, shorter length of hospital stay, and no early recurrences. PMID- 10096749 TI - Hydatid cysts of the liver: TN(R)C classification. AB - BACKGROUND: Liver hydatid disease remains a serious public health problem. Its incidence is increasing but still there is no standardised protocol for assessment of the severity of the disease or for classifying the lesion in each individual case. OBJECTIVE: To construct a new and maximally descriptive classification system that could help in better assessing the extent of the disease, both in primary and recurrent cysts. DESIGN: Description of a newly created classification system. SETTING: University hospital. METHOD: Review of the literature and own observations. RESULTS: Classification system describing T (topography of the cyst), N (natural history of the cyst), R (recurrent cyst) and C (complication of the cyst). CONCLUSION: Consideration is given to almost all aspects of classifying liver hydatid cysts. A new concept for classification is presented which can become the basis for further multi-institutional comparison of data. PMID- 10096750 TI - The results of surgical treatment and percutaneous drainage of hepatic hydatid disease. AB - BACKGROUND: Hydatid disease of the liver remains an important and challenging problem in rural areas. Although, surgery is considered the treatment of choice for hydatid disease of the liver, percutaneous drainage is an alternative treatment method for selected cases. The purpose of this study was to evaluate the results of percutaneous drainage and surgery. METHODS: A total of 66 patients underwent surgery; 36 cases had percutaneous drainage and were evaluated preoperatively for treatment choice according to localization, multiplicity, echographic type and size of the cysts in the liver. The patients were also evaluated postoperatively for systemic complications, e.g. fistula formation, infection of residual cyst, recurrence and hospitalization period for each group. RESULTS: Two groups, those with multiple cysts and cysts bigger than 5 cm, were treated by surgery. At the end of two treatment modalities, systemic complications, biliary fistulizations, recurrence and infection of cyst's cavity were seen more frequently in the surgery group and caused a longer hospital stay. CONCLUSIONS: Percutaneous drainage plus medical treatment can be successfully done for type I, type II and some selected type III hydatid cysts of the liver giving less complications, lower recurrence and shorter hospitalization periods. But, surgery is the primary treatment for big, multiple, complicated and recurrent hydatid cysts of the liver. PMID- 10096751 TI - Effective vascular endostapler techniques in hepatic resection. AB - The purpose of this report is to describe the technique of liver resection using an endovascular stapling device. A total of 31 patients underwent major hepatic resections with stapling techniques. The authors have used various approaches to portal structures and hepatic veins with the application of a vascular endostapler device. The specific techniques of different hepatectomies are described and illustrated. There were no deaths. A minor complication (biliary fistula) occurred in one patient, related to binary leak from parenchymal transection. No complications directly attributable to stapler ligations of portal pedicle or hepatic veins were observed. Stapling techniques can be helpful in major hepatic resection procedures. The vascular endostapler can significantly reduce both portal vein and hepatic vein closure time and may expedite the transection of the liver, eliminating the risk of slipped ligature following simple ligation. PMID- 10096752 TI - A new technique of hepatic vein reconstruction in living related liver transplantation. AB - OBJECTIVE: To attempt to reconstruct the hepatic vein safely and easily in living related liver transplantation (LRLT). DESIGN: Retrospective case series. SUBJECTS: Four patients over 15 years of age underwent LRLT. INTERVENTION: A surgical technique of hepatic vein anastomosis, using the common anastomotic orifice of the middle and left hepatic veins of a left lobe graft and the right hepatic vein of the recipient. After reperfusion, the graft is immobilized in a position decided upon using color Doppler ultrasonography to ensure no out-flow block. RESULTS: The graft is lowered below the right diaphragm and rotated 90 degrees. This condition provides good visibility, enabling an accurate anastomosis. Four patients developed no complications included with out-flow block and hemorrhage. CONCLUSIONS: This technique is safe and easy for reconstruction of the hepatic vein in LRLT. PMID- 10096753 TI - Successful procurement of 50 pancreatic grafts using a simple and fast technique. AB - The procurement of a pancreatic graft must be as meticulous as possible and with minimum handling and blood loss so that the transplant procedure can be carried out with no complications. We describe the technique we are using in our institution which, contrary to others, requires that most of the dissection for donor pancreatectomy be done after crossclamping and intravascular flushing of the abdominal organs. We have performed 50 consecutive procurements of pancreatic grafts using this technique. All grafts were successfully transplanted with no evidence of post-transplant primary non-function or graft pancreatitis. We believe that this technique is faster and minimises handling of the pancreas and blood loss resulting in excellent post-transplant metabolic function of the pancreatic graft. PMID- 10096754 TI - Pre-emptive renal transplantation. AB - We report our experience with pre-emptive renal transplantation and review the literature. While eliminating the cost, complications and inconvenience of dialysis, transplantation prior to dialysis therapy can be performed safely and effectively as it does not pose any additional immunological hazards to allograft outcome. It is safe regardless of the immunosuppressive agents employed and is successful without early rejection even in the nonuremic state. PMID- 10096755 TI - Redo operations of Hirschsprung's disease. AB - The purpose of this study was to specify the indications, applicability and final outcome of the redo definitive operations of Hirschsprung's disease. Between 1976 1993, 213 patients had undergone definitive operations of Hirschsprung's disease. In this series, 5 who required a redo pull-through operation were investigated. The redo pull-through operations were performed in 5 patients because of severe anastomotic stricture or total closure of the anastomotic site, recto-urethral fistula, anastomotic stricture, and enterocolitis due to anastomotic disruption. The initial definitive procedures were in 4 patients the Swenson operation and in one patient the Boley operation. As redo pull-through operations, the following were performed with success: in 3 patients, the Duhamel operation; and in 2 patients, the Swenson operation. The final outcome of the redo pull-through alterations were satisfactory and it can be suggested that one should not hesitate to perform a redo pull-through operation in selected Hirschsprung patients. PMID- 10096756 TI - Intra-operative assessment of lymph node metastasis for colorectal carcinoma. AB - We have evaluated the reliability of intra-operative diagnosis for lymph node metastases and assessed the clinical features affecting accuracy of the intra operative diagnosis based on a review of operative and pathological records in 218 patients treated by curative surgery for colorectal carcinoma. The sensitivity and specificity for diagnosis of lymph node metastases was 74.2% and 54.5%, respectively. The clinically positive but pathologically negative [cN(+),pN(-)] lymph nodes group differed significantly from the cN(-),pN(-) group with respect to tumor size, gross appearance and depth of tumor invasion. In the cN(+),pN(+) group, the tumor was larger and depth of tumor invasion was more extensive than in the cN(-),pN(+) group. The postoperative survival curves showed a statistically significant difference between cN(-),pN(-) and cN(+),pN(-) groups (P<0.05). Our data suggest less than satisfactory results for the intra-operative diagnosis of lymph node metastases. Macroscopically, tumor size and gross appearance were important clinical characteristics affecting accuracy in the macroscopic diagnosis of lymph node metastases. Therefore, prophylactic lymph node dissection is recommended, regardless of intra-operative assessment of lymph node metastases. PMID- 10096757 TI - The time interval between primary colorectal carcinoma resection to occurrence of liver metastases is the most important factor for hepatic resection. Analysis of total course following primary resection of colorectal cancer. AB - The lack of any other effective treatment for colorectal liver metastases makes hepatic resection a primary treatment consideration. Between January 1980 and December 1996, 36 patients with metachronous liver metastases who underwent hepatic resection were reviewed. The age, sex, site of primary lesion, stage, size and number of hepatic metastases, and time interval between primary colorectal carcinoma resection to occurrence of liver metastases (disease-free interval, DFI) were documented. DFI was 569 days on average. Complete removal of primary colorectal cancer and metastatic liver tumour with histologically negative resection margins was accomplished in all cases. The 5 year survival rate following the first operation for primary colorectal cancer was 43.1%. The length of DFI influenced, independently, patients' prognoses based upon not only univariate but also multivariate survival analysis (P<0.01). We conclude that the DFI is the independent prognostic factor for metachronous liver metastases after curative resection of primary tumour. PMID- 10096758 TI - An unusual location of cloacogenic carcinoma. AB - A 61 year-old female presented with abdominal pain, rectal bleeding, mucus discharge, tenesmus and constipation. Rectal examination and proctoscopy demonstrated rectal stenosis at 5 cm from the anal verge. Transrectal ultrasonography detected a capsulated lesion as a mesenchymal rectal tumor. Computed tomography and endorectal magnetic resonance detected a mesenchymal lesion in the lower-middle rectal thirds. Serum TPA, GICA, SCC and CYFRA were pathological. At surgery the tumour was fixed to the levator ani muscle with rectal folding. Frozen sections of the levator ani muscle biopsies revealed cloacogenic tumour. Abdominoperineal resection was performed. The rectal lesion was cloacogenic carcinoma at 9 cm from the dentate line (pT4 pN0; Ki67 35%; CD31 181 vessels/mm2). Adjuvant radio-chemotherapy was performed. The patient is alive and disease free at 19 months. Extra-anal cloacogenic tumours are an unusual finding. Perhaps cloacal cells were originally present in the rectal wall, but secondary rectal involvement by cloacal remnant from the levator ani muscle cannot be excluded. PMID- 10096759 TI - Transrectal ultrasonography directed intraprostatic injection of gentamycin xylocaine in the management of the benign painful prostate syndrome. A report of a 5 year clinical study of 75 patients. AB - There is almost a complete failure of the urological profession to study chronic prostate gland pain, which is its most common and difficult condition to manage. Variations in nomenclature for the disease include pelvic floor myalgia syndrome, chronic anxiety syndrome, prostatodynia, interstitial cystitis and abacterial prostatitis, so comparison of treatment populations is difficult. Over 50% of negative prostate biopsies being performed for PSA elevation show prostatitis lesions. Transperineal aminoglycoside injection for 'hard-core' prostatitis reported a 77% cure rate. A 5 year study of 75 patients with recalcitrant benign painful prostate syndrome treated with transrectal ultrasound guided intraprostatic injection of gentamycin and xylocaine produced a 90% cure rate. Of the patients, 74% required only a single injection of 160 mg of gentamycin in 4 cc with 2 cc of 1% xylocaine to achieve a cure. Minimal injection pain was encountered. Some patients required 5 injections over the 5 year period. Multiple injection patients were considered therapeutic failures. Fourteen tumor-negative prostate needle biopsies showed prostatitis lesions. One elevated PSA patient had 3 biopsies. Current medical therapy of prolonged one month antibiotics, anti inflammatory agents and alpha adrenergic blocking agents had failed in all injection treated patients. Of the patients, 60% had prostatic calculi. Cystic seminal vesicle abnormalities were frequent. Complications were only minor, with hematospermia, gross hematuria and mild pain. The 90% cure rate was defined by the absence of symptoms. PMID- 10096760 TI - Surgical outcome of carotid artery disease: analysis of 367 carotid endarterectomies. AB - Carotid endarterectomy is a method of prophylaxis. A total of 367 carotid endarterectomies in 335 patients were performed during the period of 1989-1997: 222 (66.3%) were symptomatic and 113 (33.7%) asymptomatic patients. In all, 262 (78.2%) had unilateral, 41 (12.2%) contralateral occlusion and 32 (9.6%) bilateral artery disease. All were operated on under general anesthesia without using shunt or patch. Of the patients with bilateral occlusive disease, 17 underwent simultaneous and 15 staged endarterectomy. The mortality rate of the first 30 postoperative days was 1.19% and the mortality/stroke rate 2.38%. Transient neurogenic dysfunction occurred in 3.68%, myocardial ischemia in 0.89%, and postoperative hypertension in 16.7%. Endarterectomy of symptomatic and asymptomatic patients with unilateral localisation, contralateral occlusion or bilateral occlusive disease remains a highly acceptable prophylactic method. The future will show whether other endovascular procedures affect the broad application of carotid endarterectomy. PMID- 10096761 TI - Iatrogenic steal syndromes. AB - Vascular steal syndromes result from many causes. Most often, however, they are due to arteriosclerotic occlusive disease and involve the innominate and the subclavian vessels. We have seen a number of patients with the steal syndrome and, in review, a number of unusual iatrogenic-induced steal syndromes. These included subclavian steal from the vertebral and circle of Willis, colonic and small bowel steal with subsequent ischemia, hand and arm steal syndrome in AV access for dialysis. Multiple symptomatology including dizziness, headache, bloody diarrhea, paraplegia, pain and coma were all present. The diagnosis requires realization of the possibility and angiography where necessary. Intensive therapy and possible further surgical intervention can lead to survival and good function. However, a significant percentage of patients may end up with paraplegia or death. Thus, recognition and intervention (where appropriate) are important to minimize the severity of the problem. PMID- 10096762 TI - Is surgical closure of patent ductus arteriosus a safe procedure in premature infants? AB - Despite indomethacin therapy, many premature infants require surgical closure of their patent ductus arteriosus (PDA). Between January 1985 and December 1997, 176 premature infants underwent surgical closure of PDA by vascular clip after failure of medical treatment. The median gestational age and birth weight were 26 weeks (range 23-36 weeks) and 847.5 g (range 400-2300 g), respectively. The median age at diagnosis and at surgery was 4 days (range, 1-37) and 21 days (range, 4-60) respectively. The median weight at surgery was 982.5 g (range 475 2740 g). Of these infants, 168 (95%) were intubated prior to surgery and the median time to extubation was 21 days (range 1-273 days). There were no operative deaths but 11 infants (6.4%) died from complications of prematurity (sepsis, bronchopulmonary dysplasia and pulmonary hemorrhage). The frequency of chest tube insertion at surgery decreased from 41.7% to 10% between the 1985-88 and 1996-97 periods (P<0.01). Three infants (1.7%) developed vocal cord paralysis directly related to the position of the vascular clip. Echocardiography confirmed PDA closure in 43 infants (24.4%) while the remaining 133 had no clinical signs of PDA. Surgical closure of PDA by vascular clip carries a very low morbidity in premature infants. PMID- 10096763 TI - Preferential inhibition of dizocilpine-induced hyperlocomotion by olanzapine. AB - This study examined the putative inhibitory effect of the atypical antipsychotic, olanzapine, on dizocilpine (MK-801)-induced stereotypy and hyperlocomotion. Dizocilpine (0.1, 0.25 and 0.5 mg/kg) produced a dose-dependent increase in both stereotypy and hyperlocomotion. Pretreatment with olanzapine (0.25 and 0.5 mg/kg) inhibited the dizocilpine (0.5 mg/kg)-induced hyperlocomotion but not the stereotypy. At the higher doses (1, 2 and 4 mg/kg), olanzapine blocked both the stereotypy and hyperlocomotion induced by dizocilpine. Similarly, olanzapine, 0.25 and 0.5 mg/kg, did not inhibit apomorphine (3 mg/kg)-induced stereotypy, whereas the higher dose (1 mg/kg) blocked it. We also studied the effect of olanzapine on spontaneous locomotor activity and catalepsy. Olanzapine (0.25 and 0.5 mg/kg) did not induce a decrease in spontaneous locomotor activity but did so at the higher doses (1, 2 and 4 mg/kg). The lower doses (0.25, 0.5 and 1 mg/kg) did not induce catalepsy but higher doses (2 and 4 mg/kg) induced a significant catalepsy which lasted for more than 4 h. The results thus showed that, at lower doses, olanzapine selectively inhibited behaviours mediated by the mesolimbic/mesocortical system while at higher doses it inhibited behaviours mediated by both mesolimbic/mesocortical and nigrostriatal systems. Therefore, the minimal extrapyramidal side-effects produced by olanzapine at effective doses might be due to its preferential action at the mesolimbic/mesocortical area. PMID- 10096764 TI - Different roles of mu-, delta- and kappa-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress. AB - The present study was designed to investigate the role of the endogenous opioid system in the development of ethanol-induced place preference in rats exposed to conditioned fear stress (exposure to an environment paired previously with electric foot shock), using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress induced significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated this ethanol-induced place preference. Moreover, the selective mu-opioid receptor antagonist beta funaltrexamine (3 and 10 mg/kg, i.p.) and the selective delta-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.) significantly attenuated ethanol induced place preference. In contrast, the selective kappa-opioid receptor antagonist nor-binaltorphimine (3 mg/kg, i.p.) significantly enhanced ethanol induced place preference. Furthermore, 75 mg/kg ethanol (which tended to produce place preference) combined with the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3 hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha- octahydroquinolino [2,3,3,-g] isoquinoline (TAN-67; 20 mg/kg, s.c.), at doses which alone did not produce place preference, produced significant place preference. However, co-administration of the selective kappa-opioid receptor agonist trans-3,4-dichloro-N-(2-(1 pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 0.3 and 1 mg/kg, s.c.) with ethanol (300 mg/kg, i.p.) dose dependently attenuated ethanol induced place preference. Moreover, conditioned fear stress shifted the response curve for the aversive effect of U50,488H to the left. These results suggest that mu- and delta-opioid receptors may play critical roles in the rewarding mechanism of ethanol, and that kappa-opioid receptors may modulate the development of the rewarding effect of ethanol under psychological stress. PMID- 10096766 TI - Cardiovascular changes during morphine administration and spontaneous withdrawal in the rat. AB - Morphine maintenance doses of 10 mg kg(-1) day(-1), 20 mg kg(-1) day(-1) and 30 mg kg(-1) day(-1) were administered to three groups of rats via miniosmotic pumps for 7 days to induce physical dependence. They were then allowed to undergo spontaneous withdrawal. Radiotelemetric blood pressure measurements showed that morphine increased systolic and diastolic blood pressure on the first day of morphine treatment and produced a dose dependent decrease in heart rate, systolic and diastolic blood pressure thereafter. After the peak depressive effect, development of tolerance to morphine was observed in systolic and diastolic blood pressure, but not in the heart rate. During spontaneous withdrawal, both systolic and diastolic blood pressure increased beyond pre-morphine levels for all doses and there was a rebound increase in heart rate at the 30 mg kg(-1) day(-1) dose. These results suggest that the improved sensitivity of telemetric measures combined with the use of minipumps for morphine treatment provide an animal model of spontaneous opioid withdrawal. PMID- 10096765 TI - Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid). AB - We have studied the effects in three rodent models of generalised convulsive or absence epilepsy of two antagonists of group I metabotropic glutamate receptors that are selective for the mGlu1 receptor. LY 367385 ((+)-2-methyl-4 carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid) have been administered intracerebroventricularly (i.c.v.) to DBA/2 mice and lethargic mice (lh/lh), and focally into the inferior colliculus of genetically epilepsy prone rats (GEPR). In DBA/2 mice both compounds produce a rapid, transient suppression of sound-induced clonic seizures (LY 367385: ED50 = 12 nmol, i.c.v., 5 min; AIDA: ED50 = 79 nmol, i.c.v., 15 min). In lethargic mice both compounds significantly reduce the incidence of spontaneous spike and wave discharges on the electroencephalogram, from <30 to >150 min after the administration of AIDA, 500 nmol, i.c.v., and from 30 to >150 min after the administration of LY 367385, 250 nmol, i.c.v. LY 367385, 50 nmol, suppresses spontaneous spike and wave discharges from 30 to 60 min. In genetically epilepsy prone rats both compounds reduce sound-induced clonic seizures. LY 367385, 160 nmol bilaterally, fully suppresses clonic seizures after 2-4 h. AIDA is fully effective 30 min after 100 nmol bilaterally. It is concluded that antagonists of mGlu1 receptors are potential anticonvulsant agents and that activation of mGlu1 receptors probably contributes to a variety of epileptic syndromes. PMID- 10096768 TI - The role of nitric oxide in aloe-induced diarrhoea in the rat. AB - The role of nitric oxide (NO) on aloe-induced diarrhoea was studied in the rat. Nine hours after oral administration, aloe produced diarrhoea at doses of 5 g kg( 1)(20% rats with diarrhoea) and 20 g kg(-1) (100% of rats with diarrhoea). Lower doses of aloe (0.1 and 1 g kg(-1) did not produce a diarrhoeal response. Pre treatment (i.p.) of rats with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME 2.5-25 mg kg(-1) reduced the diarrhoea induced by aloe (20 g kg(-1) 9 h after its oral administration. L-NAME (25 mg kg(-1)) also reduced the increase in faecal water excretion produced by aloe (20 g kg(-1). L-arginine (1500 mg kg(-1), i.p.), administered to rats pre-treated with L-NAME (25 mg kg( 1), drastically reduced the effect of L-NAME on diarrhoea and increase in faecal water excretion induced by aloe (20 g kg(-1). Given alone, L-arginine did not modify aloe-induced diarrhoea. Basal Ca2+ -dependent NO synthase activity in the rat colon was dose-dependently inhibited by aloe (0.1-20 g kg(-1)) and by aloin (0.1-1 g kg(-1)), the active ingredient of aloe. These results suggest that endogenous NO modulates the diarrhoeal effect of aloe. PMID- 10096767 TI - Vasoactive substances produced by cultured rat brain endothelial cells. AB - The vasoactive substances synthesized by primary cultures of rat brain endothelial cells were investigated and compared to those from two, immortalized cell lines, RBE4 and GP8. The vasoactivity of endothelium-derived substances was measured on isolated canine coronary artery. Vascular tone was significantly decreased by both primary and GP8, but not by RBE4 cells. Indomethacin pretreatment of primary and GP8 cells turned vasorelaxation into contraction while N(omega)-nitro-L-arginine pretreatment decreased the vasorelaxation induced by primary, but not by GP8 cells. Eicosanoid production was determined after incubation with [14C]arachidonic acid. The predominant vasoactive eicosanoid was prostaglandin E2 in both primary and GP8 cells. RBE4 cells synthetized mainly prostaglandin E2 and thromboxane B2 and significantly less prostaglandin E2 than did either primary or GP8 cells. The capacity of cerebral endothelium to regulate vascular tone by production of dilator and constrictor substances can be preserved under certain circumstances in immortalized cell lines. PMID- 10096769 TI - Comparison of gamma-aminobutyric acid effects in different parts of the cat ileum. AB - The effects of gamma-aminobutyric acid (GABA) and those of a GABA(A) (muscimol) and a GABA(B) (baclofen) receptor agonists were determined on the spontaneous activity of longitudinally or circularly oriented preparations (segments) isolated from terminal, proximal and distal parts of the cat ileum. GABA applied at 1 microM to 2 mM caused dose-dependent biphasic changes (relaxation and contraction) in spontaneous activity of the longitudinal and circular layers in the terminal and distal parts of the cat ileum and monophasic changes (contraction) in the proximal part. The potency of GABA to elicit relaxant and/or contractile effects in different parts of the ileum showed a proximal-to-terminal increasing pattern. In the longitudinal layer of the distal and terminal ileum, muscimol (100 microM) mimicked the relaxation phase of the GABA effect, while baclofen (100 microM) simulated the contractile phase. Bicuculline, atropine and tetrodotoxin abolished GABA- and muscimol-induced relaxation and suppressed, but failed to prevent GABA- and baclofen-induced contractions. In addition, 2 hydroxysaclofen antagonized the baclofen-induced contractile effect, reduced the GABA-induced contractile phase but failed to prevent GABA- and muscimol-induced relaxation. In the circular layer of the same regions, muscimol mimicked the biphasic GABA effects, while baclofen was without effect. Bicuculline, atropine and tetrodotoxin completely prevented the GABA- and muscimol effects, while 2 hydroxysaclofen failed to antagonize them. In the longitudinal and circular layers of the proximal ileum, muscimol (100 microM) exerted a 'GABA-like' transient contractile effect, while baclofen (100 microM) did not elicit any response. Bicuculline, atropine and tetrodotoxin antagonized the GABA- and muscimol-induced contractile responses of longitudinal and circular layers, while 2-hydroxysaclofen was ineffective. The results suggested that the inhibitory and/or excitatory action of GABA on cholinergic transmission in different regions of cat ileum varies along an increasing gradient towards the terminal ileum and is mediated by GABA(A) and GABA(B) receptors in the terminal and distal ileum and by GABA(A) receptors in the proximal ileum. PMID- 10096770 TI - New hyperprolactinemia and anovulation model in common marmoset (Callithrix jacchus) and effect of cabergoline. AB - We aimed to develop an anovulation model, using sulpiride-induced hyperprolactinemia in common marmosets. The serum prolactin level gradually increased during the twice-daily administration of sulpiride and reached a plateau after 4 days. Sulpiride produced as big a response at 10 mg kg(-1) as at 50 mg kg(-1). In this study, the length of the ovarian cycle was approximately 30 days in normal common marmosets. Serum progesterone and estradiol levels showed no consistent change during the first 2 months of treatment with sulpiride. When treatment with sulpiride had been continued for more than 2 months, serum progesterone and estradiol levels fell to within the range seen in the follicular phase of the normal cycle and absence of ovulation was recognized by laparoscopy. A single oral administration of cabergoline (at doses between 0.01 and 0.1 mg kg( 1)) dose dependently reduced the elevated serum prolactin level. Bromocriptine (at an oral dose of 10 mg kg(-1)) also reduced the serum prolactin level at 4 and 8 h after its administration. With bromocriptine, the prolactin level had recovered at 24 h, but with cabergoline at doses of 0.05 mg kg(-1) or more, it had still not recovered at 48 h. In anovulatory common marmosets, oral administration of cabergoline at a daily dose of 0.05 mg kg(-1) restored ovarian function and resulted in ovulation in 100% of the group (following a reduction in the serum prolactin level). Bromocriptine at a daily oral dose of 10 mg kg(-1) resulted in ovulation in 67% of the group, but this dose was about 200 times higher than the dose of cabergoline. We could produce an anovulatory model induced by sulpiride repeatedly administered over a long time period. It is suggested that, in this anovulatory model in common marmosets, cabergoline has a potent and long-lasting action as a dopamine D2 receptor agonist, and thus could be a useful drug for the treatment of galactorrhea and hyperprolactinemic amenorrhea and/or anovulation. PMID- 10096771 TI - Systemic and local dexamethasone treatments prevent allergic eosinophilia in rats via distinct mechanisms. AB - We have studied the effect of local and systemic treatment with dexamethasone for prevention of the pleural eosinophilia triggered by allergen in actively sensitised Wistar rats. Parallel changes in blood and marrow eosinophil numbers were assessed for comparison. The intrapleural (i.pl.) injection of ovalbumin into ovalbumin-sensitised animals led to a long-lasting pleural fluid eosinophilia which peaked from 24 to 72 h post-challenge. At these time points, there was a significant 2- to 3-fold increase in the blood eosinophil numbers, whereas the bone marrow number of mature eosinophils remained unaltered. Systemic treatment with dexamethasone (0.05-0.5 mg/kg, i.p.) abolished the pleural and blood eosinophilia observed 24 and 48 h post-challenge, also causing a significant reduction in marrow eosinophil numbers. Despite being unable to alter blood and bone marrow eosinophil numbers, the local i.pl. administration of dexamethasone (2.5-10 microg/cavity) inhibited dose dependently the allergen induced pleural eosinophil influx at 24 h but not at 48 h post-challenge. This treatment also shortened the time course of eosinophil accumulation in the pleural space from the 48 h time point on. We conclude that the effect of systemic but not of local treatment with dexamethasone on allergen-induced eosinophil recruitment is well correlated with the inhibition of eosinophil production in bone marrow. In contrast, low amounts of dexamethasone injected into the pleural space seem to affect locally eosinophil recruitment and survival. PMID- 10096772 TI - Kupffer cell-mediated differential down-regulation of cytochrome P450 metabolism in rat hepatocytes. AB - Nonparenchymal cells, particularly Kupffer cells, might play an important role in the modulation of xenobiotic metabolism in liver and its pharmacological and toxicological consequences. This intercellular communication via the exchange of soluble factors was investigated in primary rat Kupffer cells and hepatocytes. Freshly isolated rat Kupffer cells were seeded onto cell culture inserts and cocultured with 5 day old serum-free rat hepatocyte monolayer cultures at a ratio of 1:1 for 2 days. Hepatocyte cultures, Kupffer cell cultures or cocultures were treated with 0.1 ng/ml-10 microg/ml lipopolysaccharide (LPS). Within this concentration range, no significant toxicity was observed in either cell type. In LPS-exposed cocultures, tumor necrosis factor alpha (TNFalpha) levels rose up to 5 ng/ml within 5 h; nitric oxide (NO) levels increased up to 70 microM within 48 h of treatment, both in a dose-dependent fashion. The release of negative (albumin) and positive (alpha1-acid-glycoprotein) acute phase proteins from the hepatocytes was strongly down- and up-regulated, respectively. The simultaneous treatment of the cocultures with phenobarbital and LPS (10 ng/ml) or 3 methylcholanthrene and LPS (10 ng/ml) resulted in a strong down-regulation (85%) of the phenobarbital-induced cytochrome P450 (CYP) isoform CYP2B1 in the hepatocytes whereas the 3-methylcholanthrene-induced isoform CYP1A1 was only weakly affected (15%). This specific down-regulation of CYP2B1 was mediated exclusively by TNFalpha, released from the Kupffer cells. It was not linked with NO release from or inducible NO synthase activity in the hepatocytes. The TNFalpha release was not affected by the two xenobiotics. Acetaminophen tested in these cocultures showed no direct interaction with the Kupffer cells. The use of liver cell cocultures is therefore a useful approach to investigate the influence of intercellular communication on xenobiotic metabolism in liver. PMID- 10096773 TI - Vasopressin increases vascular endothelial growth factor secretion from human vascular smooth muscle cells. AB - Vascular endothelial growth factor (VEGF) is a potent and specific mitogen of vascular endothelial cells which promotes neovascularization in vitro. To determine whether vasopressin induces VEGF secretion in human vascular smooth muscle cells, we performed enzyme-linked immunosorbent assays. Vasopressin potently induced a time-dependent and concentration-dependent (maximal, 10(-7) M) increase in VEGF secretion by human vascular smooth muscle cells that was maximal after 24 h. Furthermore, vasopressin also concentration-dependently caused mitogenic effect, as reflected by total protein content of cells per culture well. These vasopressin-induced VEGF secretion increase and mitogenic effect of these cells were potently inhibited by vasopressin V1A receptor antagonists, confirming this is a vasopressin V1A receptor-mediated event. These results indicate that vasopressin increases VEGF secretion in human vascular smooth muscle cells, the magnitude of VEGF secretion being temporally related to the mitogenic effect of vascular smooth muscle cells and the potency of the growth promoting stimulus. Vasopressin-induced VEGF secretion by proliferating vascular smooth muscle cells could act as a paracrine hormone to powerfully influence the permeability and growth of the overlying vascular endothelium, vasopressin play a more fundamental role in the regulation of vascular function than has previously been recognized. PMID- 10096774 TI - Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na+, K+ -ATPase of porcine cortex. AB - Our earlier studies have identified oligomycin sensitivity-conferring protein (OSCP), a subunit of proton F0F1-ATPase/ATP synthase in the mitochondrial inner membranes, as a new estradiol binding protein. This finding suggests that mitochondrial ATPase/ATP synthase could be a potential target for estradiol or compounds with similar structures. Here, we report that estradiol and several other compounds inhibited F0F1-ATPase activity of detergent-solubilized rat brain mitochondrial preparations in a following decreasing order: diethylstilbestrol (half-inhibition concentration, IC50 of 10-25 microM) > alpha-zearalenol, 4 hydroxyestradiol (1C50 of 55 microM) >2-hydroxyestradiol (IC50 of 110 microM), 17beta-estradiol, 17alpha-estradiol > beta-zearalanol > estriol, testosterone, 16alpha-hydroxyestrone > corticosterone, progesterone, dehydroepiandrosterone, dehydroepiandrosterone 3-sulfate, cholesterol (less than 10% inhibition at 140 microM). On the other hand, Na+, K+ -ATPase of porcine cortex showed different sensitivity to the compounds tested above. At 70 microM, the rank of inhibitory potency in decreasing order was as follows: 2-hydroxyestradiol (IC50 of 70 microM) > diethylstilbestrol> 4-hydroxyestradiol > progesterone > alpha zearalenol, while other compounds had little effect (less than 5%). The data indicate that the ubiquitous mitochondrial F0F1-ATPase is a specific target site for estradiol and related estrogenic compounds; however, under this in vitro condition, the effect seems to require pharmacological concentrations. PMID- 10096775 TI - Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes. AB - Insulin-sensitizing thiazolidinediones such as troglitazone and pioglitazone have been shown to lower blood pressure in vivo and cause vasorelaxation in vitro. Rosiglitazone (BRL 49653) is a novel thiazolidinedione which has been reported not to cause vasoleraxation. We therefore compared the effects of troglitazone and rosiglitazone on Ca2+ and K+ currents in rat aorta and pulmonary artery smooth muscle cells. Currents were recorded with the conventional whole cell patch clamp technique. Both drugs reduced the voltage-gated (L-type) Ca2+ current in rat aorta cells, with half-maximal current inhibition by troglitazone and rosiglitazone at 2 and 10 microM, respectively. Troglitazone, 2 microM and rosiglitazone, 20 microM caused a similar hyperpolarizing shift of 12 mV in the potential-dependence of Ca2+ current availability. Troglitazone (20 microM) produced a marked block of the tetraethylammonium- and paxilline-sensitive Ca2+ activated K+ current, while rosiglitazone (20 microM and 60 microM) slightly enhanced this current. Rat pulmonary artery smooth muscle cells have a prominent delayed rectifier K+ current. Troglitazone produced a potent block of this current (half-maximal inhibition at <1 microM), while rosiglitazone caused a smaller inhibition at 10 and 60 microM. These results show that troglitazone has relatively potent blocking effects on a wide variety of ion currents in vascular smooth muscle cells. Rosiglitazone exerts less potent, but similar effects on the Ca2+ current and delayed rectifier K+ current, but it enhances the Ca2+ activated K+ current. reserved. PMID- 10096776 TI - Berberine inhibits ion transport in human colonic epithelia. AB - The effects of berberine on ion transport in both human colonic mucosal epithelia and an intestinal epithelial cell line (T84) were examined. Berberine (concentration range 0-500 microM) reduced both basal and stimulated ion transport responses in human colonic mucosae in a manner which was non-specific for Ca2+ -or cAMP-mediated signals. Similarly, in cultured intestinal epithelial monolayers, berberine inhibited Ca2+ -and cAMP-mediated responses indicating an inhibitory activity directly at the level of the epithelium rather than an indirect effect through other mucosal element(s). Berberine did not alter the rate of generation of cAMP by adenylyl cyclase or the activity of protein kinase A, the effector enzyme of the cAMP pathway. Berberine inhibited carbachol stimulated 86Rb+ efflux from T84 monolayers. Berberine also inhibited K+ conductance in apically-permeabilised re-sected mucosae. These results indicate i) that berberine exerts an anti-secretory action directly upon epithelial cells and ii) the mechanism of action may be at the level of blockade of K+ channels. PMID- 10096777 TI - UCL 1684: a potent blocker of Ca2+ -activated K+ channels in rat adrenal chromaffin cells in culture. AB - The novel K+ channel blocker 6,10-diaza-3(1,3)8,(1,4)-dibenzena-1,5(1,4) diquinolinacy clodecaphane (UCL 1684) has been tested for its ability to inhibit Ca2+ -activated K+ currents in cultured rat chromaffin cells. Low nanomolar concentrations of UCL 1684 produced a rapid and reversible inhibition of the slow, apamin-sensitive, tail current activated by a depolarizing voltage command. This compound also inhibited the muscarine activated outward current with an IC50 of 6 nM. These results confirm UCL 1684 to be the most potent non-peptidic blocker of the apamin-sensitive Ca2+ -activated K+ channel so far described. PMID- 10096778 TI - Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. PMID- 10096779 TI - Insulinotropic action of monosaccharide esters: therapeutic perspectives. PMID- 10096780 TI - Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. AB - Previously published Type I (insulin-dependent) diabetes mellitus incidence in 0 to 14-year-old children from 10 countries or areas was compared with the national annual cow milk protein consumption. Countries which were selected for study had appropriate milk protein polymorphism studies, herd breed composition information and low dairy imports from other countries. Total protein consumption did not correlate with diabetes incidence (r = +0.402), but consumption of the beta casein A1 variant did (r = +0.726). Even more pronounced was the relation between beta-casein (A1+B) consumption and diabetes (r = +0.982). These latter two cow caseins yield a bioactive peptide beta-casomorphin-7 after in vitro digestion with intestinal enzymes whereas the common A2 variant or the corresponding human or goat caseins do not. beta-casomorphin-7 has opioid properties including immunosuppression, which could account for the specificity of the relation between the consumption of some but not all beta-casein variants and diabetes incidence. PMID- 10096781 TI - Impact of glycaemic control, hypertension and insulin treatment on general and cause-specific mortality: an Italian population-based cohort of type II (non insulin-dependent) diabetes mellitus. AB - The aims of this study were to assess the impact of diabetes and associated variables (fasting plasma glucose, blood pressure, antidiabetic treatment, body mass index) on general and cause-specific mortality in an Italian population based cohort with Type II (non-insulin-dependent) diabetes mellitus, comprising mainly elderly patients. The patients (n = 1967) who had Type II diabetes were identified in 1988 with an 80% estimated completeness of ascertainment. In 1995, a mortality follow-up (98% completeness) of the cohort was done amounting to a total of 11153 person-years. Observed and expected number of deaths were 577 and 428.7, respectively, giving a standardized mortality ratio (SMR) of 1.35 (95% CI 1.24-1.46). The most common underlying causes of death were malignant neoplasm, ischaemic heart disease and cerebrovascular diseases, which accounted for 18%, 17.8% and 17.5% of deaths, respectively. Cardiovascular disease as a whole (international classification of disease ICD-9 390-459) accounted for 260 of 577 deaths (SMR 1.21, 95% CI 1.07-1.36). In internal analysis, the most important predictors of general mortality were insulin-treatment (relative risk [RR] 1.72, 95% CI 1.19-2.49) and a fasting plasma glucose greater than 8.89 mmol/l ([RR] 1.29, 95 % CI 1.04-1.60), whereas the most important predictors of cardiovascular diseases were insulin-treatment and hypertension. In conclusion, this population based study showed: 1) slight mortality excess of 35% in Type II diabetes being associated with 2) a 30% increased mortality in subjects with baseline fasting glucose greater than 8.89 mmol/l and 3) a 40% increased risk of death from cardiovascular diseases in hypertensive patients. PMID- 10096782 TI - Uncoupling protein-3 gene expression: reduced skeletal muscle mRNA in obese humans during pronounced weight loss. AB - AIMS: Uncoupling protein-3 is a member of a protein family that serves to dissipate energy in the form of heat thereby modulating energy expenditure. Alternative processing of uncoupling protein-3 transcripts results in two mRNA species that encode a large and small protein, perhaps differing in functional activity. Since obesity is associated with disrupted energy homeostasis, we measured muscle mRNA expression in morbidly obese and lean subjects. METHODS: The two uncoupling protein-3 mRNA species were quantified in muscle tissue using an RNase protection assay. Gene locus effects on mRNA expression were studied by quantitative allele-specific primer extension. RESULTS: In both obese and lean subjects, the mRNA species encoding the small protein isoform was twice as abundant as the mRNA species encoding the large protein isoform. Neither the total uncoupling protein-3 mRNA expression nor the molar abundance ratios of the two mRNA species differed between obese and lean male or female subjects. Women who had lost 37+/-22 kg of weight in response to dietary restriction and continued a hypocaloric diet displayed lower mRNA than obese (p<0.005) or lean women (p<0.05). Primer extension assays in lean and obese subjects showed similar allelic mRNA abundance in all but one subject studied. CONCLUSION: Muscle expression of the two uncoupling protein-3 mRNA species is similar in obese and lean people. In obese patients, prolonged hypocaloric diet downregulates uncoupling protein-3 mRNA expression in muscle and can thereby enhance its energy efficiency. Sequence substitutions at the gene locus may only be minor determinants of mRNA expression in muscle tissue. PMID- 10096783 TI - Increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. AB - We have recently demonstrated that insulin activates farnesyltransferase (FTase) and thereby increases the amounts of cellular farnesylated p21Ras in 3T3-L1 fibroblasts, adipocytes and vascular smooth muscle cells. We postulated that hyperinsulinaemia might considerably increase the the cellular pool of farnesylated p21Ras available for activation by other growth factors. To examine the role of in vivo hyperinsulinaemia in regulating farnesylated p21Ras, we measured the amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. Liver, aorta, and skeletal muscle of ob/ob mice, and mice made obese and hyperinsulinaemic by injection of gold-thioglucose contained greater amounts of farnesylated p21Ras than tissues of their lean normoinsulinaemic counterparts. Similarly, farnesylated p21Ras was increased (67 vs. 35 % in control animals, p<0.01) in the livers of hyperinsulinaemic Zucker rats (fa/fa). Reduction of hyperinsulinaemia by exercise training (2 h/day for 7-8 weeks) resulted in decreases in the amounts of farnesylated p21Ras in these animals. Increased farnesylated p21Ras in hyperinsulinaemic animals reflected increasing increments in the activity of FTase in ob/ob mice (2-fold increase) and fa/fa Zucker rats (3.5-fold increase), while the total amounts of Ras proteins remained unchanged. In contrast to insulin-resistant hyperinsulinaemic animals, denervated insulin resistant rat soleus muscle (in the presence of normoinsulinaemia) showed normal amounts of farnesylated p21Ras. In summary, these data confirm increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. PMID- 10096784 TI - Modulation of insulin receptor signalling by pancreastatin in HTC hepatoma cells. AB - Pancreastatin, a neuropeptide derived from chromogranin A, has a glycogenolytic and counterregulatory effect to insulin in the rat liver. This effect is mediated by calcium and protein kinase C activity. Our aim was to study the possible cross talk between pancreastatin and the insulin signalling system, by using the well studied insulin sensitive rat hepatoma HTC cells. First, we checked the counterregulatory effect of pancreastatin on insulin action. Pancreastatin dose dependently inhibited insulin stimulated glycogen synthesis. This effect was not due to competition for insulin receptors. Moreover, when protein kinase C activation was blocked with staurosporine, this effect of pancreastatin was not observed. Next, we found a dose-dependent inhibition of insulin receptor autophosphorylation by pancreastatin. In addition, phosphorylation of the major substrates of insulin receptor in HTC, i. e. insulin-receptor substrate (IRS) 1/IRS-2 and p62 was also blunted and so was its association with p85 regulatory subunit of phosphatidylinositol-3-kinase. Moreover, the insulin activation of S6 kinase was also blocked by pancreastatin. Again, all these inhibitory effects of pancreastatin were prevented by staurosporine. Furthermore, pancreastatin produced Ser/Thr phosphorylation of insulin receptor by a staurosporine-sensitive mechanism. Finally, we checked the pancreastatin activation of protein kinase C in HTC cells and found that a "classical" isoform of this protein is translocated to the plasma membrane. These findings suggest that pancreastatin could exert its anti-insulin effect in the hepatocyte by interrupting the stimulation of early insulin receptor signalling as a result of phosphorylation. This interaction might have a role in the mechanisms of insulin resistance. PMID- 10096785 TI - Protein metabolism in glucagonoma. AB - Although protein wasting and reduced amino acid concentrations are common findings in glucagonoma patients, the mechanisms underlying these alterations are unclear. Therefore, we studied basal postabsorptive leucine, phenylalanine and tyrosine turnover following L-[D3]-Leucine, L-[D5]-Phenylalanine and L-[D2] Tyrosine i.v. infusions in one male and one female patient with glucagonoma, compared with healthy control volunteers. Plasma amino acid concentrations were reduced (-40 to 80%, delta >2 SD vs. control subjects) in both patients. Plasma leucine, phenylalanine and tyrosine rates of appearance in patients with glucagonoma were similar to values in the control subjects, except leucine rate of appearence in the female patient with glucagonoma (+ approximately 30%, delta >2 SD). In contrast, the intracellular leucine rate of appearence, reflecting protein degradation, was considerably increased in both patients (+60-80%, delta >2 SD). Phenylalanine hydroxylation was moderately higher only in the male patient with glucagonoma (+ approximately 30%, delta >2 SD). Leucine, phenylalanine and tyrosine clearances (+100-300%), as well as phenylalanine hydroxylative clearance (+75-100%) were also increased in the patients. In conclusion, whole-body protein breakdown is enhanced in patients with glucagonoma compared with healthy control subjects. Phenylalanine hydroxylative clearance is also higher. Reduced plasma amino acid concentrations are probably due, at least in part, to their increased clearance. These alterations could contribute to the determination of the catabolic state of the glucagonoma syndrome. PMID- 10096786 TI - Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD4+ and CD8+ lymphocytes from type I diabetic or healthy subjects. AB - The intensity and mechanisms of cell-mediated rejection of pig islet cells were studied in 49 Type I diabetic and 34 healthy subjects. Human peripheral mononuclear cells proliferated strongly in response to pig islet cells (p<0.001), though with notable interindividual variations (stimulation index 2 to 215). The variance of stimulation index was higher in diabetic than healthy subjects (p<0.0001). The response to islet cells was stronger (p<0.01) than that to pig splenocytes. Proliferation in response to islet cells was strongly decreased (p<0.01) when CD4+ T cells were blocked with monoclonal antibodies, whereas the blocking of CD8+ cells or NK cells gave less pronounced effects. The response to islet cells was decreased (p<0.01), but not abolished, after antigen-presenting cells were removed. Purified CD4+ cells alone did not proliferate in response to islet cells but recovered their proliferative ability when mixed with antigen presenting cells, whereas CD8+ cells alone proliferated in the presence of interleukin-2 in response to islet cells. Proliferation was blocked (p<0.01) by anti-DR monoclonal antibodies. During proliferation in response to islet cells, interleukin-10 increased 43-fold (p<0.01) but interferon-gamma increased only slightly. No statistical differences were detected between diabetic and control subjects with respect to lymphocyte subsets and the recognition mechanisms or to interferon-gamma/interleukin-10 production in response to islet cells. These results provide the first detailed information on human cell-mediated xenoreaction to pig islet cells. This situation involves a dominant CD4 class II restricted Th2 response, with an indirect recognition pathway, as well as a CD8 T cell response resulting from direct recognition. This strong reaction constitutes a serious obstacle which may vary in degree among subjects. PMID- 10096787 TI - Finger and penile tactile sensitivity in sexually functional and dysfunctional diabetic men. AB - Tactile sensitivity of the penis is related to sexual functioning, however its role in diabetic erectile problems is unclear. We evaluated penile sensitivity in 10 diabetic men with erectile dysfunction, 17 sexually functional diabetic men and 14 control subjects. Finger and penile thresholds and ratings of intensity and pleasantness for finger and penis were assessed using vibrotactile stimulation. Glycosylated haemoglobin and total and bioavailable testosterone measurements were determined and subjects completed self-reports on sexual function. Diabetic men with erectile problems had higher values of glycosylated haemoglobin than sexually functional diabetic men (p = 0.02) and both groups had lower bioavailable testosterone than control subjects (p< or =0.05). Sexually dysfunctional diabetic men had a higher finger threshold than the other two groups (p<0.01). Penile threshold for the sexually dysfunctional group was also marginally higher compared with the functional diabetic group (p<0.052) but did not differ from control subjects (p = 0.09). Diabetic men with erectile dysfunction exhibited different response patterns than sexually functional men on dimensions of intensity and pleasantness to penile stimulation. Although these data do not directly implicate subjective response to penile stimulation in diabetic erectile problems, they suggest such anomalous response could be one contributing factor. PMID- 10096788 TI - Effects of diabetes and treatment with the antioxidant alpha-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats. AB - Diabetes mellitus is associated with impotence in animal models and patients. Raised reactive oxygen species contribute to diabetic neurovascular deficits, which are amenable to antioxidant treatment. Our aim was to examine the effects of streptozotocin-induced diabetes in rats and long-term treatment with the antioxidant, alpha-lipoic acid, on responses of an in vitro corpus cavernosum preparation. Diabetes duration was 8 weeks and preventive and reversal (4 weeks untreated diabetes, 4 weeks of treatment) studies were done. Four and 8 weeks of diabetes caused an about 41% reduction in endothelium-dependent nitric oxide mediated relaxation to acetylcholine in phenylephrine-precontracted cavernosum. This deficit was prevented (93.9+/-7.1%) by treatment with alpha-lipoic acid; reversal studies showed 64.9+/-19.5% correction. Neither diabetes nor treatment with alpha-lipoic acid altered endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside. Stimulation of corpus cavernosum autonomic innervation caused noradrenergic-mediated contractions that were unaffected by diabetes or alpha-lipoic acid. Non-adrenergic, non-cholinergic nerve responses, largely dependent on nitric oxide, were seen after phenylephrine precontraction in the presence of atropine and guanethidine. Non-adrenergic, non-cholinergic stimulation caused frequency dependent relaxation to a maximum of about 40%. Diabetes reduced this to about 25%, however with preventive alpha-lipoic acid treatment, non-adrenergic, noncholinergic relaxation was in the nondiabetic range. In the reversal alpha-lipoic acid treated diabetic group, its deficit was corrected by 52.1+/-14.6%. Thus, diabetes reduces endothelium and non-adrenergic, noncholinergic nerve nitric oxide-mediated relaxation of corpus cavernosum smooth muscle, which is likely to be the organic base for impotence. Prevention and partial correction by alpha-lipoic acid emphasises the importance of reactive oxygen species and suggests a potential therapeutic approach. PMID- 10096789 TI - Plasma concentration of C-reactive protein is increased in type I diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation. AB - Moderately increased plasma concentrations of C-reactive protein are associated with an increased risk of cardiovascular disease. C-reactive protein, its relation to a low degree of inflammatory activation and its association with activation of the endothelium have not been systematically investigated in Type I (insulin-dependent) diabetes mellitus. C-reactive protein concentrations were measured in 40 non-smoking patients with Type I diabetes without symptoms of macrovascular disease and in healthy control subjects, and in a second group of Type I diabetic patients (n = 60) with normo- (n = 20), micro- (n = 20) or macroalbuminuria (n = 20). Differences in glycosylation of alpha1-acid glycoprotein were assayed by crossed affinity immunoelectrophoresis. Activation of the endothelium was measured with plasma concentrations of endothelial cell markers. The median plasma concentration of C-reactive protein was higher in Type I diabetic patients compared with healthy control subjects [1.20 (0.06-21.64) vs. 0.51 (0.04-9.44) mg/l; p<0.02]. The Type I diabetic subjects had a significantly increased relative amount of fucosylated alpha1-acid glycoprotein (79+/-12% vs. 69+/-14% in the healthy control subjects; p<0.005), indicating a chronic hepatic inflammatory response. In the Type I diabetic group, log(C-reactive protein) correlated significantly with von Willebrand factor (r = 0.439, p<0.005) and vascular cell adhesion molecule-1 (r = 0.384, p<0.02), but not with sE-selectin (r = 0.008, p = 0.96). In the second group of Type I diabetic patients, increased urinary albumin excretion was associated with a significant increase of von Willebrand factor (p<0.0005) and C-reactive protein (p = 0.003), which were strongly correlated (r = 0.53, p<0.0005). Plasma concentrations of C-reactive protein were higher in Type I diabetic patients without (clinical) macroangiopathy than in control subjects, probably due to a chronic hepatic inflammatory response. The correlation of C-reactive protein with markers of endothelial dysfunction suggests a relation between activation of the endothelium and chronic inflammation. PMID- 10096790 TI - Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients. AB - We investigated the regulation of the mRNA expression of the insulin receptor, insulin receptor substrate-1 (IRS-1) and p85alpha-phosphatidylinositol-3-kinase (PI-3K), three major actors of insulin action, in skeletal muscle from 10 healthy lean volunteers, 13 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 7 non-diabetic obese subjects. The in vivo regulation by insulin was studied using a 3-h euglycaemic, hyperinsulinaemic clamp. There were no differences in the basal concentrations of the three mRNAs in skeletal muscle between groups. Insulin infusion produced a twofold reduction in insulin receptor substrate-1 mRNA expression in the three groups (p<0.02). In contrast, insulin increased p85alpha-phosphatidylinositol-3-kinase mRNA expression in muscle from non-diabetic subjects (+98+/-22% in lean and +127+/-16% in obese, p<0.02) but this effect was totally impaired in Type II diabetic patients (+5+/-12%, NS). A similar defect in insulin action on p85alpha-phosphatidylinositol-3-kinase mRNA expression was observed in abdominal subcutaneous adipose tissue (+138+/-25%, p<0.01 in lean and +46+/-14%, p<0.02 in obese and +29+/-11%, NS in Type II diabetic patients). The lack of action of insulin on p85alpha phosphatidylinositol-3-kinase mRNA in diabetic subjects was probably not due to a deleterious effect of hyperglycaemia since improvement of the glycaemic control for 10 days did not restore the response in muscle or in adipose tissue. This study provides evidence for a defect in the regulation by insulin of PI-3K gene expression in Type II diabetic patients, thus reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes. PMID- 10096792 TI - Is glucagon-like peptide 1 an incretin hormone? AB - Glucagon-like peptide-1 (GLP-1) was predicted, based on the proglucagon gene sequence. It is synthesised by specific post-translational processing in L cells (lower intestine) and secreted mainly as "truncated" GLP-1 [7-36 amide] in response to nutrient ingestion. Glucagon-like peptide-1 stimulates insulin secretion during hyperglycaemia, suppresses glucagon secretion, stimulates (pro)insulin biosynthesis and decelerates gastric emptying and acid secretion. On intracerebroventricular injection, GLP-1 reduces food intake in rodents. A GLP-1 receptor antagonist or GLP-1 antisera have been shown to reduce meal-stimulated insulin secretion in animals, suggesting that GLP-1 has a physiological "incretin" function (augmentation of postprandial insulin secretion due to intestinal hormones) for GLP-1. In healthy human subjects, exogenous GLP-1 slows gastric emptying. Consequently, postprandial insulin secretion is reduced, not augmented. Thus, a participation of this peptide in the incretin effect of non diabetic humans has not been definitely proven. Nevertheless, it has potent insulinotropic activity, especially during hyperglycaemia. This suggests new therapeutic options for patients with Type II (non-insulin-dependent) diabetes mellitus. On the other hand, most L cells are located in the lower small intestine. Potent inhibitory actions of GLP-1 on upper gastrointestinal motor and digestive functions (e. g. gastric emptying and acid secretion) in response to nutrients placed into the ileal lumen, argue for a role of this peptide as an "ileal brake". Malassimilation and diarrhea leading to the erroneous presence of nutrients in the lower gut may, via GLP-1, delay gastric emptying and reduce upper gut motility and thereby prevent further caloric losses. PMID- 10096791 TI - Euglycaemic hyperinsulinaemia does not affect gastric emptying in type I and type II diabetes mellitus. AB - Hyperglycaemia slows gastric emptying in both normal subjects and patients with diabetes mellitus. The mechanisms mediating this effect, particularly the potential role of insulin, are uncertain. Hyperinsulinaemia has been reported to slow gastric emptying in normal subjects during euglycaemia. The purpose of this study was to evaluate the effect of euglycaemic hyperinsulinaemia on gastric emptying in Type I (insulin-dependent) and Type II (noninsulin-dependent) diabetes mellitus. In six patients with uncomplicated Type I and eight patients with uncomplicated Type II diabetes mellitus, measurements of gastric emptying were done on 2 separate days. No patients had gastrointestinal symptoms or cardiovascular autonomic neuropathy. The insulin infusion rate was 40 mU x m(-2) x min(-1) on one day and 80 mU x m(-2) x min(-1) on the other. Gastric emptying and intragastric meal distribution were measured using a scintigraphic technique for 3 h after ingestion of a mixed solid/liquid meal and results compared with a range established in normal volunteers. In both Type I and Type II patients the serum insulin concentration had no effect on gastric emptying or intragastric meal distribution of solids or liquids. When gastric emptying during insulin infusion rates of 40 mU x m(-2) x min(-1) and 80 mU x m(-2) x min(-1) were compared the solid T50 was 137.8+/-24.6 min vs. 128.7+/-24.3 min and liquid T50 was 36.7+/-19.4 min vs. 40.4+/-15.7 min in the Type I patients; the solid T50 was 94.9+/-19.1 vs. 86.1+/-10.7 min and liquid T50 was 21.8+/-6.9 min vs. 21.8+/-5.9 min in the Type II patients. We conclude that hyperinsulinaemia during euglycaemia has no notable effect on gastric emptying in patients with uncomplicated Type I and Type II diabetes; any effect of insulin on gastric emptying in patients with diabetes is likely to be minimal. PMID- 10096793 TI - Missense mutation Gly574Ser in the transcription factor HNF-1alpha is a marker of atypical diabetes mellitus in African-American children. PMID- 10096794 TI - Towards a World Health Organization (WHO) approved standard sample for islet cell antibodies, GAD65 and IA-2 autoantibodies. PMID- 10096795 TI - Is plasma homocysteine related to albumin excretion rate in patients with diabetes mellitus? PMID- 10096796 TI - Scant evidence of periodic starvation among hunter-gatherers. PMID- 10096797 TI - Insulin resistance, the key to survival: a rose by any other name. PMID- 10096798 TI - Caution is required with interferon alpha as a potential treatment for type I diabetes. PMID- 10096799 TI - Report on an EASD-Bayer Travel Fellowship for young scientists. European Association for the Study of Diabetes. PMID- 10096800 TI - Taxonomy and identification of dust mites. AB - Taxonomy provides the basis for the identity of species, allowing the construction of keys and the reliable, reproducible identification of dust mites for ecologic purposes and other studies. Details are given of nomenclatorial conventions in taxonomy as applied to dust mites, and taxonomically problematic entities are highlighted, such as Blomia kulagini and the sibling species Dermatophagoides farinae and D. microceras. Current keys to dust mites and advances in interactive computer keys are reviewed. An hypothesis of the phylogeny of the family Pyroglyphidae is presented, based on habitat specificity, geographic distribution, and association with birds. The value of predictive classifications based on phylogenies is stressed. Finally, a pictorial key is presented to the mites found in house dust in Scandinavia. PMID- 10096801 TI - Life cycle and reproduction of house-dust mites: environmental factors influencing mite populations. AB - An understanding of the life cycle of house-dust mites, as well as environmental factors influencing mite populations, can be exploited in mite control. The most important limiting factor for house-dust-mite populations is air humidity. House dust mites osmoregulate through the cuticle and therefore require a high ambient air humidity to prevent excessive water loss. In addition, the supracoxal glands actively take up ambient water vapour, and the protonynph stage of the life cycle is resistant to desiccation. Larger house-dust-mite populations are found when the absolute indoor air humidity is above 7 g/kg (45% relative humidity at 20 degrees C). Consequently, ventilation by air-conditioning systems is being developed as a means of control. A number of other aspects of the domestic environment are also being manipulated in an integrated approach to render the habitat less suitable for mites. The potential exists for developing models for house-dust mite populations, environmental characteristics, and the effects of various approaches to control. PMID- 10096802 TI - Quantification of house-dust-mite populations. AB - Since the proposal that allergen from the mite Dermatophagoides pteronyssinus is identical to the house-dust allergen supposed to cause asthma and allergy, interest in the abundance, species diversity, and frequency of mites in the home has expanded. Surveys and ecologic studies have confirmed the ubiquity of mites in house dust, especially mites of the family Pyroglyphidae, but most do not give an accurate estimate of population size or mite exposure. These are still important issues today in attempts to quantify the exposure to house-dust mite that constitutes a risk, to assess mite-eradication trials, and to determine fluctuations in mite population. The problems encountered with common methods of house-dust sampling. mite extraction, and measuring house-dust allergen are discussed. PMID- 10096803 TI - Distribution and abundance of dust mites within homes. AB - The distribution and abundance of dust mites can be modelled on three scales: the microhabitat scale (different habitats within homes), the macrohabitat scale (between homes), and the regional scale. This paper focuses on the first. Those parts of a home in which dust mite populations thrive will tend to be homogeneous in respect of key habitat suitability determinants. The more widespread such determinants, the greater the risk of high mite populations and allergen load. Habitat suitability determinants include an adequate textile substratum, optimal temperature and humidity, and food resources of appropriate quality, as well as other, currently unknown, requirements. Each determinant will have a characteristic distribution within any home, and they can be conceptualized as a series of overlays, or three-dimensional Venn diagrams, with the areas of overlap representing the most suitable sites for mite survival. That a population of dust mites is focused by constraining biotic and abiotic determinants means that spatial and temporal distribution and abundance are predictable, because the characteristics of the principal foci define optimal conditions for population growth. This concept, known as "focality", provides a framework for prediction of sites of high density of mite population and allergen exposure, as well as a basis for manipulating the microenvironment for control purposes. PMID- 10096804 TI - Occurrence of mites in Norway and the rest of Scandinavia. AB - This paper gives a faunistic review of mites that have been recorded in the indoor environment, particularly homes, barns, and stored products, in Norway and the other Scandinavian countries. Some preliminary results are given from unpublished investigations in Norway. Seven species of pyroglyphid mites have been recorded: Dermatophagoides pteronyssinus, D. microceras, D. farinae, D. evansi, Euroglyphus maynei, Gymnoglyphus longior, and Hirstia chelidonis. D. pteronyssinus was the predominant species, followed by D. microceras in Scandinavia and D. farinae in Denmark. D. evansi was detected in poultry houses in Norway. Lepidoglyphus destructor was the predominant species in barn dust, but large populations of Acarus, Tyrophagus, Tydeus, and Tarsonemidae also occurred. In humid homes, Glycyphagus domesticus was found in high numbers. The result of quantification of mites depends on the method for examination of dust. When one proposes limits for the concentration of mites in relation to risk of allergic sensitization and provocation of symptoms, reference should be made to a well described method for sampling and analyzing dust. The number of mites should be given per area, not only per weight unit of dust. The number of mites per area indicates the number of mites in the home. The number of mites per weight unit of dust describes the concentration of mites in the vacuum cleaner. PMID- 10096805 TI - Epidemiology of house-dust mites. AB - Available epidemiologic data on the occurrence of house-dust mites in dwellings demonstrates a clear association between increased indoor air humidity and the increased occurrence of house-dust mites in house dust. Furthermore, in temperate climates, there is a threshold level of indoor air humidity of 7 g/kg (45% relative humidity at usual indoor air temperatures). Indoor air humidities below this level for extended periods will eradicate house-dust mites from dwellings. A reduction in inhabitant exposure to house-dust mites is implemented by reduction of indoor air humidity by controlled mechanical ventilation. Individual ventilation levels are estimated from the actual size of house, number of inhabitants, and average outdoor air humidity in winter. In contrast, more humid areas of the world with average outdoor humidities above 6-7 g/kg in winter will support uniformly large populations of house-dust mites, and reductions in indoor air humidity will have a comparatively minor effect on the occurrence of house dust mites. Present-day building of energy-efficient houses with increased sealing of the building envelope, paralleled by a similar renovation of older houses, has increased indoor air humidity and is probably the cause of the almost fourfold increase in the occurrence of house-dust mites in Danish dwellings. PMID- 10096806 TI - Reflections on the control of mites and mite allergens. AB - In cool climates, the humidity circumstances in a home during the summer months are more important for allergen accumulation than those in the winter months. For the same reasons, a reduction of humidity will have a much greater impact during the summer months. Not only the relative humidity, but also the removal of the dust mites' food by cleaning can be an important factor in determining the ultimate level of mite allergens. These theoretic deductions remain to be experimentally tested. An understanding of the dynamics of mite populations and allergen concentrations in homes and public buildings is still hampered by gaps in our knowledge. These gaps mainly concern the food availability and food requirements of dust mites and the kinetics of mite allergens. PMID- 10096807 TI - Allergens from mites: implications of cross-reactivity between invertebrate antigens. AB - Group 1 and 2 allergens are probably the most important mite allergens. Some mite allergens, such as tropomyosin, are widely cross-reactive. The prevalence of sensitization to invertebrates cannot be based solely on skin test or serologic data with the allergen extracts currently available. Purified (recombinant) allergens, selected for low cross-reactivity, are urgently needed. PMID- 10096808 TI - Clinical and immunologic aspects of storage mite allergy. AB - Exposure to storage (nonpyroglyphid) mites has been increasingly recognized as a cause of asthma and rhinitis. Several species have been identified in Europe; e.g., Lepidoglyphus destructor, Acarus farris/siro, Tyrophagus spp., Glycyphagus domesticus, and Blomia tjibodas. Blomia tropicalis, on the other hand, predominates in subtropical and tropical areas. Studies from several countries have shown that IgE-mediated allergy in rural populations is of considerable importance and that storage mites are major allergens. Since these mites are found in homes, especially in regions with damp housing conditions, urban populations are at risk of becoming sensitized. Therefore, sensitization is not restricted only to those with occupational exposure. Several major allergens from storage mites have been identified and characterized. There seems to be a limited allergenic cross-reactivity between storage- and house dust mites. Molecular cloning has demonstrated that the Group 2 allergens from storage mites (Lep d 2 and Tyr p 2) show more than 40% sequence identity with the Group 2 allergens from Dermatophagoides spp. The availability of a large number of recombinant dust mite allergens will make it possible to investigate their homology and the number of allergens required for the diagnosis and treatment of storage mite allergy. PMID- 10096809 TI - Identification and quantification of mite allergens. AB - Allergens from the house dust mite are ubiquitous in house dust. Exposure to these allergens can cause acute symptoms in patients who are sensitized to house dust mite and have asthma or other allergic diseases, such as rhinitis or atopic dermatitis. It is not clear how much mite-allergen exposure is a risk factor for the development of sensitization or for triggering acute symptoms. Therefore, it is important to be able to quantify accurately the amount of mite allergen present in the indoor environment in order to carry out studies to identify risk factors for exposure, to investigate exposure-response effects, and to monitor the progress of allergen-reducing regimens. PMID- 10096810 TI - Mite-allergen levels in Norwegian homes. AB - The scarce data published on mite sensitization and mite-allergen levels in Norway indicate that the mites may not be of the same importance in allergic disease in Norway as in countries such as the UK and the rest of Europe. The problem also involves the low allergen levels and small amounts of dust collected for allergen determination, and when the level is to be expressed as mg/g, the lower detection limit will often vary from sample to sample, giving within the same investigation results such as <0.2 microg/g, <0.5 microg/g, and even <2.0 microg/g. The use of allergen levels expressed instead per area (microg/m2) at least results in a uniform lower detection limit, making statistical analysis easier. PMID- 10096811 TI - Mite allergens: significance of enzymatic activity. AB - Ten years ago, the cloning and sequencing of a cDNA encoding the group I allergen of house-dust mites unequivocally determined that protein allergens may have biochemical functions in addition to their ability to bind IgE. Since this discovery, several groups have speculated that the biochemical activities of allergens, or substances associated with allergens, may be involved in their immunogenicity or allergenicity. This paper will focus on just one biochemical function, proteolytic activity, and will be illustrated by examples of our own work that we believe support the hypothesis that this category of molecules are endowed with the properties of proallergic adjuvants. PMID- 10096812 TI - Mite sensitization in the Scandinavian countries and factors influencing exposure levels. AB - Mites are the common sources of indoor allergen and play a major role in sensitization and elicitation of allergic disease. In the Scandinavian countries, mite infestations in the home were not common in the past decades. Recent studies show that sensitization to mites among children, particularly in Sweden, is increasing. Similar trends have also been reported in Norway. Poor indoor climate, e.g., high humidity and poor ventilation as a consequence of energy saving measures, are cited as a possible explanation of this increase. Modern furnishings, e.g., carpets and various kinds of upholstery, may also serve as reservoirs of indoor allergens. At least 2 microg of mite allergen per g of dust is considered to be a risk level for sensitization and symptoms of asthma. As compared to experience from other parts of the world, mite-allergen levels are generally low in the northern Scandinavian regions. Recent studies from Sweden and other European countries show that mite sensitization may occur below 2 microg/g dust. Various environmental adjuvant factors may affect the threshold levels of allergen. In this review, the importance of the indoor environment for the accumulation of mite allergens, sensitization to mites in the Scandinavian countries, and various environmental factors that could influence exposure levels will be discussed. PMID- 10096814 TI - House-dust mites and asthma. A review on house-dust mites as a domestic risk factor for mite asthma. AB - Increased exposure to house-dust mites entails a greatly increased frequency of sensitization and increased frequency of mite asthma in the population. The available case-control studies demonstrate large variations worldwide in sensitization and disease risk dependent on the actual level of population exposure. In areas with comparatively low population exposure to house-dust mites, there is a strong association between exposure and effect, while other areas with a more or less uniformly high population exposure do not demonstrate significant differences between patients and controls because the unexposed groups are too small. As to the existence of a hygienic maximum threshold exposure level, current data all point to a single value of 100 mites/g of dust, corresponding to 2 microg allergen/g of dust. This applies to the risk of sensitization and risk of disease, and when programs of prevention imply exposure below this value, convincing clinical improvement is always observed. Today, the magnitude of the health problem related to population exposure to house-dust mites in many areas is comparable to the effects of active tobacco smoking and traffic accidents. PMID- 10096813 TI - Risk levels for mite allergens. Are they meaningful? AB - Allergens found in house dust are among the most common environmental antigens to which man is naturally exposed. Standardized methods for measuring allergen exposure are essential for assessing the relationship between exposure, sensitization, and the severity of asthma. Monoclonal antibody-based assays are the most widely used method for assessing allergen exposure. In the effort to define the best "index of exposure" to mite allergens, several factors need to be investigated, including: 1) whether allergen should be measured in reservoir dust or airborne 2) whether the results of reservoir measurement should be expressed as recovered allergen per unit weight or per unit area. As yet, airborne sampling is insufficiently sensitive to produce reliable and repeatable results. Therefore, measurement of house-dust-mite allergen concentration in reservoir dust should be regarded as the best-validated index of exposure. The results should be expressed and reported both per unit weight (concentration) and per unit area. The strongest predictor of chronic symptoms and acute exacerbation of asthma is sensitization to indoor allergens. A simple dose-response relationship between IgE-mediated hypersensitivity and allergen exposure has been established. For example, exposure to more than 2 microg Group 1 mite allergen/g dust should be regarded as a risk factor for the development of IgE antibody and asthma in susceptible children. The quantitative relationship between exposure and symptoms in patients already sensitized is complex due to a number of possible confounding factors (e.g., other allergens, viruses, asthma medication). A simple threshold level for provocation of asthmatic symptoms has not been clearly defined. PMID- 10096815 TI - Risk levels for mite allergen: are they meaningful, where should samples be collected, and how should they be analyzed? AB - Indoor allergen exposure plays a major role in the development of sensitization and triggering of asthma in children. All over the world, mites are common sources of indoor allergens. Risk levels for mite-allergen exposure have been recommended. A mite-allergen level of >/=2 microg/g dust is considered a risk level for sensitization and symptoms of asthma. Data from several ongoing prospective studies of children show that mite sensitization may occur below the suggested threshold level. However, from these studies, it seems that high mite allergen exposure increases the risk of early sensitization, whereas low exposure levels probably take a longer time to induce sensitization. Assessment of allergen exposure and consideration of allergen-elimination strategies should not be limited only to the home environment. High levels of mite allergens are also found in day-care centers, schools, and various other public places, such as bars. Thus, in addition to homes, these environments should also be considered when allergen-avoidance measures are taken. Allergen content in dust can be expressed in several units, e.g., ng/g, ng/m2, and ng/sampling, and as the total amount of allergen. At present, there is no consensus on the best way to measure and express mite-allergen levels. In this paper, aspects of threshold levels for mite sensitization, various exposure environments, and sampling, determination, and expression units of mite exposure will be discussed in brief. PMID- 10096816 TI - Mite allergens. Collection, determination, expression of results, and risk levels for sensitization and symptom induction. AB - The presence of mite allergens in dust can be determined by counting mites at different stages of development in dust and by determination of the major allergen content (Der p 1 ) in dust and air, which is crucially important to allergic patients. For comparison of results, similar methods for collection of dust and air must be used. Due to their size, mite bodies and fecal particles are airborne only directly after disturbance. Special filters should be used for dust collection, and upholstered surfaces should be vacuumed for 2 min/m2 (minimum 4 m2) and hard surfaces for 1 min/m2 (minimum 8 m2). Heavy contaminations should be removed. Preferably, the method given in the ISAAC study should be followed. Samples should be deep-frozen for at least some days to kill the mites. ELISA techniques, preferably using polyclonal antibodies and antigen with all isoforms present, should be used for determination of allergens. The allergen load has been given in ng/g of dust, but allergen/m2 or per sample area should be preferred. Allergen in the air should be given in pg/m3. A tentative limit of 2000 ng/g was proposed for sensitization and asthma. This limit is still valid on a population basis, but recent data indicate that highly susceptible young children become sensitized at concentrations 10-100 times lower and that ng levels of cat allergen/m3, as found in schools, induce chronic asthma. PMID- 10096817 TI - House-dust mite hypersensitivity, eczema, and other nonpulmonary manifestations of allergy. AB - The pathogenetic role of house-dust mites (HDM) in atopic dermatitis (AD) remains controversial, mainly because there is no common agreement on a provocation test that mimics ordinary exposure to HDM. This is related to the lack of knowledge of the mechanism of how HDM allergens enter the body. Theoretically, there are two possible routes: directly through the epidermis, or by inhalation. In "atopy patch testing", a concentrated HDM suspension is tested on the skin under occlusion. This method is frequently used as a model of the epidermal route. The clinical relevance of this method as a provocation test for AD is discussed. As opposed to atopy patch testing, we describe another method, namely, "allergen inhalation testing", as a model of the respiratory route. Twenty patients with AD underwent bronchial provocations with HDM extract in a double-blind, randomized, placebo-controlled study. In nine out of 20 AD patients, bronchial challenge with HDM evoked skin symptoms. All patients with HDM-induced dermatitis had a history of asthma, and as a group they had a higher mean total log-transformed IgE level than the "negative skin responders". Thus, the respiratory route may be relevant in the provocation of AD in a subset of AD patients and may represent an appropriate model of provocation in these patients. Furthermore, the role of HDM in urticaria and allergic rhinitis is discussed. PMID- 10096818 TI - Mite elimination--clinical effect on eczema. AB - Allergic reactivity to house-dust mites (HDM) can be detected in patients with atopic eczema by prick and patch test challenge. To determine the clinical relevance of this reactivity, we performed a placebo-controlled, double-blind trial of anti-HDM measures. Active treatment comprised Gortex bags for all the bedding elements, a high-powered vacuum cleaner, and a spray containing benzyl alcohol and tannic acid to kill mites and denature allergens. Placebo treatment was light cotton bags, a cheap vacuum cleaner, and water spray. Forty-eight patients (28 active group) completed the trial, which lasted 6 months. Dust was sampled from the mattress surface and bedroom and living-room carpets before and at monthly intervals after institution of the measures. Dust was weighed and Der p 1 determined by ELISA (ALK). Patients were assessed for area and severity of eczema by a blinded observer. There was a highly significant reduction in bed surface dust - most beds yielded insufficient dust to extract and assay. Carpet Der p 1 levels were reduced to similar minimal levels by both active and placebo treatments (about 250 ng/m2). There were highly significant benefits on the eczema scores, the active treatment being greatly superior to placebo (P< or =0.0006; analysis of covariance). In conclusion, Gortex bed bags were highly effective at containing dust within the bed. This was associated with clinical improvement in most patients with atopic eczema - the biggest improvements were seen in the most severely affected subjects. PMID- 10096819 TI - Peak expiration flow variations may reflect house-dust-mite exposure and patient reactivity. AB - Peak expiration flow records from patients allergic to house-dust mites (Dermatophagoides spp.) may show a characteristic variation from week to week due to the general life cycle of these mites in dwellings. This was demonstrated from the combined records of 10 patients recorded in their own homes, covering a period of 30 consecutive weeks and comprising 973 peak flows. The levels of house dust mites were predicted from published data for floor-dust samples from Danish dwellings. Peak flow increased or decreased in accordance with weekly changes in the concentration of mites, rather than as an immediate reaction to the current concentration of live, active mites. A dose-response relation was demonstrated. This suggests that the patients' peak flow variations might be linked to molting in mites. As such, peak flow measurements have a potential as a tool for the specific diagnosis of, monitoring of, and research in asthma caused by domestic mites. PMID- 10096820 TI - Allergy to mites: relation to lung function and airway hyperresponsiveness. AB - Exposure to house-dust-mite allergens is an important cause of allergic reactions in sensitized patients. In community-based studies, sensitization to house-dust mites, as ascertained by a positive skin test or by an increased allergen specific IgE level in serum, is associated with both diminished lung function and enhanced airway hyperresponsiveness. Sensitization to house-dust mites is an independent risk factor for the development of asthma, especially in areas which favor the growth of house-dust mites. In studies with asthmatic patients, however, the relationship between sensitization to mites and lung function or airway hyperresponsiveness is less clear. The selection of asthmatic individuals (with sensitization to other inhalant allergens) and the use of medication such as inhaled steroids may interfere with the demonstration of a possible association between mite allergy and lung function or airway hyperresponsiveness in asthmatic patients. PMID- 10096821 TI - House dust mite exposure as a risk factor for asthma: benefits of avoidance. AB - There is a dose-response relation between the level of exposure to house dust mite allergen and the risk of acquiring sensitization to this allergen as well as the risk of developing asthma. This relation is apparent at levels of exposure below 10 microg/g. In communities where nearly all houses have house dust mite allergen levels above this threshold, all susceptible individuals will be affected, and the relation to house dust mite exposure will not be apparent. Although these observational data would suggest that reducing exposure to house dust mite allergen should lessen the risk of developing sensitization and asthma, definitive evidence from randomized controlled trials is not yet available. Of the many clinical trials of house dust mite avoidance as therapy for asthma, only a few have produced sustained, substantial reductions in allergen levels in the bed. These effective interventions all included allergen-impermeable encasement of mattresses along with other strategies. In most trials where allergens levels were successfully reduced, there were clinical benefits for patients with asthma. PMID- 10096822 TI - Importance of indoor allergens in the induction of allergy and elicitation of allergic disease. AB - During the last few decades, many countries have experienced an increase in the prevalence and severity of asthma. Over the same period, the population in the developed world has retreated indoors, and homes have become better insulated and more energy efficient, resulting in a warm and humid environment with low ventilation rates, ideally suited to house-dust-mite population growth throughout the year. Increasing exposure and increasing sensitivity to indoor allergens represent a progressively higher risk factor for the development of asthma. The development of sensitivity to indoor allergens and the symptoms and severity of asthma in later childhood are directly related to the exposure to allergens in infancy. It was relatively straightforward to demonstrate a quantitative linear dose-response relationship between exposure to house-dust-mite allergens and subsequent sensitization. However, showing the same for exposure and asthma severity has been more difficult, as the relationship between exposure and asthma symptoms in already sensitized individuals is much more complex than in the case of exposure and sensitization. Nevertheless, sensitized individuals are likely to have more severe asthma if exposed to high allergen levels than if their level of exposure is low. Sensitization to house-dust mites is a major independent risk factor for asthma in all areas where climate is conducive to mite population growth. The relevance of allergens other that mite is not consistent between different areas, and depends on the climate, habits, and socio-economic features of the local community. It would appear that presence of mite allergens in homes "overshadows" other allergens (e.g., cat, dog, or cockroach) as a risk factor for sensitization and subsequent development of allergic disease. It is possible that this is the consequence of the difference in inherent potency between allergen sources, and the question of why mite allergens are so potent in inducing sensitization and atopic disease remains to be answered. PMID- 10096824 TI - RTS, a computer program for the experimental set-up and interpretation of ruggedness tests. AB - A computer program is described for the experimental set-up and interpretation of ruggedness tests. The implemented strategy was based on a number of case studies and contains both recommended designs and minimal designs. The minimal designs reduce the number of experiments, but they cannot be statistically interpreted based on the interaction or dummy factor effects. The use of randomization tests as an alternative statistical interpretation method for the significance of the effects was examined. Some of the minimal designs are expandable to designs with characteristics similar to those of the recommended designs. The program is designed to facilitate the selection of the designs and the interpretation of the results and to prevent or detect problems such as drifting of responses. PMID- 10096825 TI - Coupling SFE to uterotonic bioassay: an on-line approach to analysing medicinal plants. AB - Supercritical fluid extraction has been directly coupled on-line to a uterotonic bioassay, using guinea pig uterine smooth muscle in vitro. This technique was developed for the detection of uterotonic compounds present in medicinal plants used during pregnancy to induce or augment labour. The direct passage of CO2 into the muscle chamber led to adiabatic cooling of the physiological fluid and inhibition of muscle contraction. This was alleviated by the construction of a CO2 reduction interface together with the passage of carbogen which aided in the rapid displacement of excess CO2. The on-line system was evaluated with four plants (Clivia miniata (Lindl.) Regel, Ekebergia capensis Sparrm., Grewia occidentalis L. and Asclepias fruticosa L.) that are currently used during pregnancy by some black South African women. Extractions were performed with water modified supercritical CO2. Fractions of supercritical fluid extracts, obtained by sequentially increasing the pressure from 200 to 300 and 400 atm at constant temperature were transferred directly to the muscle chamber to identify the active fractions. The 400 atm extracts of C. miniata, A. fruticosa and E. capensis displayed maximum uterotonic activity while only the 300 atm extract of G. occidentalis induced uterine muscle contraction. This technique proved to be a safe and sensitive method for analyzing medicinal plants that contain uterotonic substances hence assisting in rapidly validating the uterotonic properties and detecting any toxic effects of these extracts. PMID- 10096826 TI - Separation, identification and quantitative determination of free amino acids from plant extracts. AB - This research presents the results obtained from the separation, identification and quantitative determination of free amino acids from Gingko biloba and Hedera helix leaf extracts, using three modern techniques: thin layer chromatography (TLC), high performance liquid chromatography (HPLC), and gas chromatography-mass spectrometry. The presence of the determined amino acids explains the utilisation of G. biloba and H. helix leaf extracts in cosmetic and pharmaceutical products. PMID- 10096827 TI - Usefulness of the hydrogen--deuterium exchange method in the study of drug metabolism using liquid chromatography-tandem mass spectrometry. AB - The usefulness of the hydrogen-deuterium (H-D) exchange method in the study of drug metabolism was investigated. Metabolite samples of denopamine and promethazine prepared in vitro were introduced to a triple stage quadrupole tandem mass spectrometer via a high performance liquid chromatography (HPLC) system using a deuterated mobile phase. Mass spectra by various ionization modes and collisionally induced dissociation (CID) mass spectra were obtained. A metabolite of denopamine was observed to have a shift of 7 mass units by the H-D exchange method, and this shift proved to be a glucuronidated metabolite. Discrimination between N- or S-oxide formation and hydroxylation observed in the metabolism of promethazine was also easily accomplished by this method. In this manner, the structures of the metabolites were elucidated unequivocally by determining the number of labile hydrogen atoms by the use of the H-D exchange method, since various reactions in drug metabolism are accompanied by an increase or a decrease in the number of labile hydrogen atoms. Additional information on the structures was obtained by analysis of the CID spectra of the molecular ion species. Thus, the combination of the H-D exchange method and tandem mass spectrometry was found to be very useful for the study of drug metabolism. PMID- 10096828 TI - Determination of degradation products from the calcium-channel blocker isradipine. AB - Mass Spectrometry has been used to determine the identity of a number of degradation products from the bulk drug form of Isradipine (DynaCirc). Liquid chromatography coupled with mass spectrometry (LC/MS) was used to analyze the degraded samples and tentative identifications were made based upon the known reactivity of the molecule, molecular weight measurements and mass spectral fragmentation patterns. Isradipine was found to be stable to heating, acidic and basic conditions, but susceptible to degradation from exposure to UV light and oxidative processes. PMID- 10096829 TI - Effect of the sample matrix on the determination of indinavir in human urine by HPLC with turbo ion spray tandem mass spectrometric detection. AB - The HPLC/tandem mass spectrometric (LC/MS/MS) behavior of indinavir, an HIV protease inhibitor, in human urine is presented as an example of a case where endogenous matrix components were found to interfere with the ionization of the target analyte. The MS/MS system used for these experiments was equipped with a turbo ion spray LC interface. Results from two sample preparation procedures (direct dilution of urine vs urine extraction) and two chromatographic systems (low vs. high capacity factor (k')) for the analytes were compared. Additionally, the precision of the analysis that was achieved while using a stable isotope labeled internal standard is contrasted with the results obtained using an analog of indinavir as internal standard. The results obtained indicated that during development and validation of LC/MS/MS based assays the potential effect of co eluting 'unseen' endogenous species should be evaluated to ensure that sample preparation and chromatography is adequate to overcome the matrix effect problems. PMID- 10096830 TI - Fluorimetric and spectrophotometric determination of ritodrine hydrochloride in bulk and pharmaceutical formulations. AB - Two simple sensitive and accurate methods have been developed for the determination of ritodrine hydrochloride in bulk and pharmaceutical preparations. The first method involves the direct measurement of the native fluorescence of the drug in the concentration range 4-9 microg ml(-1), the second method is based on the oxidation of ritodrine HCl with cerium(IV) followed either by spectrophotometric or fluorimetric measurement in the concentration ranges 0.5 1.0 and 0.05-0.1 microg ml(-1), respectively. The interference of various formulation excipients was examined. The reliability of the proposed methods was checked at three different concentrations; the standard deviation varied from 2.7 x 10(-3)-0.109. The described methods have been applied to the determination of ritodrine HCl in tablets and ampoules. The assay results showed insignificant difference with those of the official USP 23 HPLC method. PMID- 10096831 TI - A modified HPLC method for the determination of vancomycin in plasma and tissues and comparison to FPIA (TDX). AB - A modified high performance liquid chromatography (HPLC) method for the quantification of vancomycin levels in plasma and tissues is described. The method uses solid phase extraction (SPE) of vancomycin from the samples and reversed phase HPLC with UV detection. The method was fully validated in terms of recovery, linearity, selectivity and various stability conditions. Vancomycin was determined in plasma samples obtained from 15 patients undergoing cardiopulmonary bypass, before and repeatedly during 12 h after drug administration. The vancomycin levels in plasma were measured by HPLC and by fluorescence polarization immunoassay (FPIA) (TDX). The following correlation was found: TDX = 0.84 HPLC + 1.04. The mean vancomycin levels in skin, fat, atrium, pericardium and sternum, before and after bypass, are reported. PMID- 10096832 TI - Stability study of fotemustine in PVC infusion bags and sets under various conditions using a stability-indicating high-performance liquid chromatographic assay. AB - The stability and compatibility of fotemustine, a nitrosourea anticancer agent, in 5% dextrose solution with polyvinyl chloride (PVC) containers and administration sets were studied under different conditions of temperature and light. The drug was diluted to 0.8 and 2 mg ml(-1) in 100 or 250 ml 5% dextrose injection solutions for 1-h simulated infusions using PVC bags and administration sets with protection from light. After preparation in the PVC bags containing 5% dextrose, fotemustine was also prepared at the same concentrations and stored at 4 degrees C for 48 h and at room temperature (22 degrees C) or at sunray exposure ( > 30 degrees C) over 8 h with or without protection from light. The solution samples were removed immediately at various time points of simulated infusions and storage, and stored at -20 degrees C until analysis. The physical compatibility with PVC and chemical stability in solution of fotemustine were assessed by visual examination and by measuring the concentration of the drug in duplicate using a stability-indicating high-performance chromatographic assay. When admixed with a 5% dextrose solution, fotemustine 2 and 0.8 mg ml(-1) was compatible and stable over 1-h of simulated infusion using PVC bags through PVC administration sets with protection from light. On the other hand, in the same diluent, fotemustine was compatible and stable with PVC bags for at least 8 h at 22 degrees C with protection from light and for at least 48 h at 4 degrees C with protection from light. There were no pH variation, no visual change, no color change, no visible precipitation and no loss of the drug. Conversely, when the solutions were exposed to light (ambient or solar), the drug concentration decreased rapidly, leading to the production of a degradation product as shown by mass spectral analysis and a discoloration of the solutions. Finally, in all cases, no DEHP (di-2-ethylhexyl phthalate) was detected in the injection solution. PMID- 10096833 TI - Fenofibrate raw materials: HPLC methods for assay and purity and an NMR method for purity. AB - HPLC methods for drug content and HPLC and NMR methods for related compounds in fenofibrate raw materials were developed. The HPLC methods resolved 11 known and six unknown impurities from the drug. The HPLC system was comprised of a Waters Symmetry ODS column (100 x 4.6 mm, 3.5 microm), a mobile phase consisting of acetonitrile water trifluoroacetic acid 700/300/l (v/v/v) at a flow rate of 1 ml min(-1). and a UV detector set at 280 nm. Minimum quantifiable amounts were about 0.1% for three of the compounds and less than 0.05% for the other eight. Individual impurities in 14 raw materials ranged from trace levels to 0.25%, and total impurities from 0.04 to 0.53% (w/w). Six unknown impurities were detected by HPLC, all at levels below 0.10%, assuming the same relative response as fenofibrate. An NMR method for related compounds was also developed and it was suitable for 12 known and several unknown impurities. It requires an NMR of 400 MHz, or greater, field strength. Individual impurities in the raw materials analyzed ranged from trace levels to 0.24%, and total impurities from trace levels to 0.59%. Several lots contained small amounts of unknown impurities at trace levels. Three lots, all from the same manufacturer, contained an unknown impurity, not detectable by HPLC, which was not present in the other raw materials. It was estimated to be present at a level greater than 0.2%. The results for related compounds by the two techniques were consistent. The main differences stem from the low sensitivity of the HPLC method for some of the related compounds at 280 nm, or from the higher limits of quantitation by the NMR method for several other impurities using the conditions specified. A fifteenth raw material was not homogeneous in its content of impurity VI, a synthetic intermediate and possible degradation product. The HPLC/MS results provided information on the peak purity (number of components) for minor HPLC peaks, as well as structural data such as the molecular ions and diagnostic fragment ions. The HPLC/MS results showed that there were five unknown drug related impurities, for which there were no standards available. Results for the assay of 15 raw materials by HPLC were within the range 98.5-101.5%. PMID- 10096834 TI - High performance liquid chromatographic analysis of a novel aminoalkylpyridine anticonvulsant 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane. AB - A simple, rapid and specific high performance liquid chromatographic (HPLC) method for the quantitation of 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane (AAP Cl) and identification of its putative metabolite, 2-(4-chlorophenyl)amino-2-(4 pyridyl)ethanol (beta-AA) in rat blood and urine has been developed. AAP-Cl, beta AA and an appropriate internal standard were extracted from rat biofluids by a solid phase extraction technique using C18 cartridges prior to the HPLC analysis. The extractibility was 92% for AAP-Cl and 98% for beta-AA. The HPLC analysis employed a symmetrical or standard reversed-phase HPLC column (Apex ODS, 5 microm, 25 cm x 0.46 cm) for blood or urine analysis, a mobile phase of water methanol acetonitrile (40:30:30) containing 20 microl 100 ml(-1) diethylamine at a flow rate of 1 ml min(-1), and UV detection at 254 nm. The limit of detection was 100 ng ml(-1) for both analytes in both blood and urine. The calibration curves for AAP-Cl in rat biofluids were shown to be linear in both low and high concentration ranges (blood: 0-1 and 1-10 microg ml(-1); urine: 0-10 and 10-100 microg ml(-1)) with intra- and inter-day coefficients of variation of no more than 18% for blood and 14% for urine. The method developed was successfully applied to a preliminary analysis of intact AAP-Cl in both blood and urine obtained from rats dosed with AAP-Cl. PMID- 10096835 TI - Visible diode laser induced fluorescence detection for capillary electrophoretic analysis of amantadine in human plasma following precolumn derivatization with Cy5.29.OSu. AB - Visible diode laser induced fluorescence (VDLIF) detection (620-700 nm) has become important in bioanalysis due to the increased sensitivity and selectivity that can be achieved in biological matrices. A selective and sensitive capillary electrophoretic method employing VDLIF detection has been developed for the analysis of amantadine in plasma. Amantadine was extracted from plasma into toluene under alkaline conditions and the residue was derivatized with the far red label Cy5.29.OSu. The reaction mixture was dried under nitrogen, reconstituted and then injected onto a laboratory constructed capillary electrophoresis system equipped with a laboratory constructed visible diode laser detector temperature tuned to oscillate at 647.8 nm. The selectivity of the technique was evaluated by demonstrating a lack of interfering peaks in extracts of blank plasma. A calibration curve ranging from 1.8 to 461.1 ng ml(-1) was shown to be linear. The precision and accuracy of the assay (n = 6) were determined to be within 17% R.S.D. and 15% difference from the nominal concentration respectively. The limits of detection for unextracted amantadine and for amantadine from the extracted concentrate from plasma were determined to be 9.5 fmol and 115 amol respectively. PMID- 10096836 TI - Capillary electrophoresis separation of an asparagine containing hexapeptide and its deamidation products. AB - A capillary electrophoresis (CE) method was developed for the separation of a model hexapeptide (L-Val-L-Tyr-L-Pro-L-Asn-Gly-L-Ala) and its degradation products. Separations using CE had much shorter analysis times than the RP-HPLC assay used previously. CE was also evaluated for possible use in analyzing peptide samples containing polymers. With a thorough rinsing procedure between runs, the presence of a model polymer did not affect the separation of the peptides. The CE assay can be applied to the study of peptide stability in polymers. PMID- 10096837 TI - Assay and purity evaluation of sunepitron hydrochloride by reversed-phase liquid chromatography using a reference standard composite. AB - A reference standard composite was prepared that contained the active pharmaceutical ingredient sunepitron and three potential impurities. This standard was characterized and used for concomitant quantitation of sunepitron and its potential impurities in samples of drug substance and drug product. This approach minimizes the number and quantity of reference standards which often are expensive to synthesize, characterize, and maintain. In addition, running assays becomes simpler because the number of reference standard solutions required for each assay is reduced. Reference standard composites can also be used for qualitative applications such as demonstrating system suitability or for retention times markers for process related impurities or degradants. PMID- 10096838 TI - The quantitative determination of cilostazol and its four metabolites in human liver microsomal incubation mixtures by high-performance liquid chromatography. AB - A high-performance liquid chromatography-ultraviolet (HPLC-UV) method for the quantitation of cilostazol and four of its principal metabolites (i.e. OPC-13015, OPC-13213, OPC-13217 and OPC-13326) in human liver microsomal solutions was developed and validated. Cilostazol, its metabolites, and the internal standard (OPC-3930), were analyzed by protein precipitation followed by reverse-phase HPLC separation on a TSK-Gel ODS-80TM (150 x 4.6 mm, 5 microm) column and a Cosmil C 18 column (150 x 4.6 mm, 5 microm) in tandem and UV detection at 254 nm. An 80 min gradient elution of mobile phase acetonitrile in acetate buffer (pH = 6.50) was used to obtain quality chromatography and peak resolution. All the analytes were separated from each other, with the resolution being 2.43-17.59. The components of liver microsomal incubation mixture and five metabolic inhibitor probes (quinidine sulfate, diethyl dithiocarbamate (DEDTC), omeprazole, ketoconazole and furafylline) did not interfere with this analytical method. The LOQ was 1000 ng ml(-1) for cilostazol and 100 ng ml(-1) for each of the metabolites. This method has been validated for linear ranges of 100-4000 ng ml( 1) for OPC-13213, OPC-13217 and OPC-13326; 100-2000 ng ml(-1) for OPC-13015; and 1000-20000 ng ml(-1) for cilostazol. The percent relative recovery of this method was established to be 81.2-101.0% for analytes, with the precision (% coefficient of variation (CV)) being 2.8-7.7%. The autosampler stability of the analytes was evaluated and it was found that all analytes were stable at room temperature for a period of at least 17 h. This assay has been shown to be precise, accurate and reproducible. PMID- 10096839 TI - Analysis of clonazepam in a tablet dosage form using smallbore HPLC. AB - A stability indicating, reversed phase high-performance liquid chromatographic method utilizing a smallbore HPLC column has been developed for the determination of clonazepam in a commercial tablet dosage form. The use of a small bore column results in a substantial solvent savings, as well as a greater mass sensitivity, especially in the identification of degradation peaks in a chromatogram. The method involves ultraviolet detection at 254 nm and utilized a 150 x 3.0 mm i.d. column packed with 3 microm octyldecylsilane particles with a mobile phase of water methanol acetonitrile (40:30:30, v/v/v) at a flow rate of 400 microl min( 1) at ambient temperature, with and without the use of 1,2-dichlorobenzene as the internal standard. The current USP method for the analysis of clonazepam using a 300 x 3.9 mm i.d. conventional octyldecylsilane column was utilized as a comparison to the smallbore method. The retention times for clonazepam and the internal standard on the 3.0 mm i.d. column were 4.0 and 12.5 min, respectively. The intra- and interday RSDs on the 3.0 mm i.d. column were < 0.55% (n =4) using the internal standard, and < 0.19% (n = 4) without the internal standard at the lower limit of the standard curve, 50 microg ml(-1) and had a limit of detection of 24 ng ml(-1). The assay using the 3.0 mm i.d. column was shown to be suitable for measuring clonazepam in a tablet dosage form. PMID- 10096840 TI - The characterisation of the major metabolite of salmeterol in the dog. AB - Salmeterol xinafoate is the first of a new class of long acting, selective beta2 adrenoceptor agonists introduced for the treatment of asthma. The major metabolite of salmeterol in the dog has been identified as the 3-catechol sulphate of the benzoic acid derivative. This metabolite was isolated from dog bile and was shown to have very similar physiochemical properties to a major endogenous component of bile, the bile acids, creating a complex analytical challenge. Initial experiments, involving hydrolysis with the enzyme sulphatase, suggested that the metabolite was a sulphate conjugate. However, complete identification of the metabolite was complicated in part due to the loss, by metabolism, of deuterium atoms added to the compound, specifically as a marker for mass spectrometry. Subsequently, a synthesis of salmeterol was completed with deuterium labels in different positions. This material was used as a substrate for dog liver slices, a simpler matrix than dog bile, which provided the basis for the metabolite's identification. The metabolite was characterised by the use of spectroscopic techniques, in particular LC/MS, LC/MS/MS and NMR. PMID- 10096841 TI - Determination of prednisolone in serum: method development using solid-phase extraction and micellar electrokinetic chromatography. PMID- 10096842 TI - Cold injury in mice: a model to study mechanisms of brain edema and neuronal apoptosis. AB - Small rodents, mice in particular, have been widely used for genetic manipulation because of the extensive knowledge in development, embryology and other molecular aspects of this species. However, the use of mice for neurobiology research in the area of brain edema and neuronal injury has not been common. Here we summarize the studies of cold injury-induced brain edema and neuronal apoptosis using mice. Blood-brain barrier (BBB) permeability, demonstrated by extravasation of a serum albumin tracer, Evans Blue, was increased immediately after the injury and returned to the control level by 24 hr. Water content was maximized at 24 hr, whereas a secondary lesion gradually progressed up to 72 hr after cold injury. The mechanism of the development of the cold injury-induced edema and the secondary lesion, involving of oxygen radicals in particular, was determined using superoxide dismutase (SOD)-1 transgenic (Tg) mice with overexpressed copper, zinc-SOD. All of the parameters, BBB permeability, water content and secondary lesion, were attenuated in the Tg mice as compared to littermate non-Tg mice. This clearly demonstrates that oxygen radicals, superoxide anion in particular, mediate cold injury. We also studied whether apoptosis contributes to brain injury following cold injury. Staining with terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling showed the apoptotic cells widespread throughout the entire lesion while still remaining in the margin. DNA laddering was exhibited by gel electrophoresis. These studies indicate that oxidative mediates the development of cold injury-induced edema and the secondary injury, and induces apoptotic cell death. We believe that cold injury in mice provides a simple animal model to study the pathogenesis of brain edema and apoptosis in genetically altered animals. PMID- 10096843 TI - Alzheimer's disease and oxidative stress: implications for novel therapeutic approaches. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a deadly outcome. AD is the leading cause of senile dementia and although the pathogenesis of this disorder is not known, various hypotheses have been developed based on experimental data accumulated since the initial description of this disease by Alois Alzheimer about 90 years ago. Most approaches to explain the pathogenesis of AD focus on its two histopathological hallmarks, the amyloid beta protein- (A(beta)-) loaded senile plaques and the neurofibrillary tangles, which consist of the filament protein tau. Various lines of genetic evidence support a central role of A(beta) in the pathogenesis of AD and an increasing number of studies show that oxidation reactions occur in AD and that A(beta) may be one molecular link between oxidative stress and AD-associated neuronal cell death. A(beta) itself can be neurotoxic and can induce oxidative stress in cultivated neurons. A(beta) is, therefore, one player in the concert of oxidative reactions that challenge neurons besides inflammatory reactions which are also associated with the AD pathology. Consequently, antioxidant approaches for the prevention and therapy of AD are of central interest. Experimental as well as clinical data show that lipophilic antioxidants, such as vitamin E and estrogens, are neuroprotective and may help patients suffering from AD. While an additional intensive elucidation of the cellular and molecular events of neuronal cell death in AD will, ultimately, lead to novel drug targets, various antioxidants are already available for a further exploitation of their preventive and therapeutic potential. reserved PMID- 10096844 TI - Recurrent inhibition in humans. AB - Methods have been developed to investigate recurrent inhibition (RI) in humans. A conditioning reflex discharge is used to evoke in motoneurones (MNs) supplying homonymous and synergistic muscles, an inhibition the characteristics of which are consistent with RI: it appears and increases with the conditioning motor discharge, has a short latency and a long duration, and is enhanced by an agonist of acetylcholine. As in the cat, homonymous RI exists in all explored motor nuclei of the limbs except those of the digits and the pattern of distribution of heteronymous RI closely matches that of monosynaptic Ia excitation. However, striking inter-species differences exist concerning the distribution of heteronymous RI since it is much more widely extended in the human lower limb than in the cat hindlimb, whereas it is more restricted in the upper limb than in the cat forelimb. Changes in transmission in the recurrent pathway have been investigated during various voluntary or postural contractions involving different (homonymous, synergistic, antagonistic) muscles and it has been found that the activation of Renshaw cells (RCs) by the voluntary motor discharge via recurrent collaterals was powerfully controlled by descending tracts: for example, during homonymous contraction, RI evoked by a given conditioning reflex discharge is much smaller during strong than during weak contraction, which suggests that the descending control of RCs might contribute to the regulation of muscle force. The finding that RC inhibition is more marked during phasic than during tonic contraction of similar force of the homonymous muscle is discussed in relation with the projections of RCs to Ia interneurones mediating reciprocal inhibition. Only in patients with progressive paraparesis is there evidence for decreased RI at rest which may contribute to the exaggeration of the passively induced stretch reflex underlying spasticity. However, despite the seemingly normal RI at rest in most patients, the control of RCs during voluntary movements is disturbed in these patients, which probably contributes to their motor disability. PMID- 10096845 TI - Synaptic excitation in the dorsal nucleus of the lateral lemniscus. AB - The dorsal nucleus of the lateral lemniscus (DNLL) is a distinct auditory neuronal group located ventral to the inferior colliculus (IC). It receives excitatory and inhibitory afferent inputs from various structures of the auditory lower brainstem and sends GABAergic inhibitory efferents mainly to the contralateral DNLL and the bilateral IC. The synaptic excitation in DNLL neurons consists of two components, an early fast depolarization and a later long lasting one. Glutamate is the probable excitatory neurotransmitter for DNLL neurons. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate the early part of the excitation while N-Methyl-D-aspartate (NMDA) receptors mediate the long lasting component. The long lasting NMDA receptor mediated component in the DNLL may contribute to a prolonged inhibition in the IC. The DNLL is thought to be a structure for processing binaural information. Most DNLL neurons in rat and bat are sensitive to interaural intensity differences (IIDs). They are excited by stimulation of the contralateral ear and inhibited by stimulation of the ipsilateral ear, showing an excitatory/inhibitory (EI) binaural response pattern. The EI pattern can be attributed to synaptic inputs that originate from various structures in the lower auditory brainstem and impinge on the DNLL neurons. In cat some DNLL neurons are sensitive to IIDs and some are sensitive to interaural time differences. In addition, DNLL neurons exhibit different temporal response patterns to contralateral tonal stimulation and respond to amplitude modulated tones, implying that DNLL may contribute to processing temporally complex acoustic information. DNLL neurons shape binaural responses in the contralateral inferior colliculus and auditory cortex through their inhibitory brainstem projections and contribute to the accuracy with which animals localize sounds in space. PMID- 10096846 TI - Immunomodulatory principles of Dichrocephala bicolor. AB - From the ethanolic extract of Dichrocephala bicolor eight compounds-4,5 dicaffeoyl quinic acid (1); 3,4-dicaffeoyl quinic acid (2); 3,5-dicaffeoyl quinic acid (3); ethyl 4,5-dicaffeoyl quinate (4); methyl 3,5-dicaffeoyl quinate (5); 5 caffeoyl quinic acid (6); caffeic acid (7); and quercetin-3-O-rutinoside (8)-were isolated and identified. All of them were selected for immunopharmacological activity testing. Human mononuclear cells (HMNC) were used as target cells. Cell proliferation was determined by 3H-thymidine uptake. Compounds 2 and 6 potently enhanced HMNC proliferation and interferon-gamma production. Enhancement mechanisms may involve the increase of cytokines production. PMID- 10096847 TI - Antineoplastic agents. 400. Synthesis of the Indian Ocean marine sponge cyclic heptapeptide phakellistatin 2. AB - Solution-phase synthesis of the marine sponge constituent phakellistatin 2 (1), cyclo(Tyr-Pro-Phe-Pro-Ile-Ile-Pro), was completed using a combination of stepwise coupling and (4 + 3) segment condensation. Use of diethyl phosphorocyanidate for the peptide bond formations gave the linear heptapeptide in 54% yield. Cyclization was achieved in high yields utilizing TBTU (2), BOP-C1 (3), PyBroP (4), and HOAt (5), resulting in 50-65% yields of phakellistatin 2 (1) depending on the method employed. The synthetic cyclic peptide was chemically but not biologically identical with the natural product. PMID- 10096848 TI - Sesquiterpene esters of aristolochic acid from the root and stem of Aristolochia heterophylla. AB - Three novel sesquiterpene esters of aristolochic acid, aristoloterpenate-II (2), III (3), and-IV (4), together with known aristoloterpenate-I (1), were isolated and characterized from the root and stem of Aristolochia heterophylla. Their structures were elucidated by spectroscopic methods. The absolute configuration of these compounds at C-4' was determined as R by circular dichroic studies. These compounds showed cytotoxicity against hepatoma G2, 2, 2, 15 cells. PMID- 10096849 TI - New lamellarin alkaloids from the australian ascidian, didemnum chartaceum AB - Five novel lamellarin-class alkaloids have been isolated from a Great Barrier Reef ascidian, Didemnum chartaceum. The structures of the 20-sulfated derivatives of lamellarins B, C, and L (1-3); the 8-sulfated derivative of lamellarin G (4), plus a nonsulfated compound, lamellarin Z (5), were identified by interpretation of spectroscopic data. Lamellarin G 8-sulfate (4) is the first example of this class of compounds sulfated at the C-8 position, while lamellarin Z (5) is the first example of a dimethoxylated lamellarin. The known lamellarins A, B, C, E, G, and L (6-11), plus the triacetate derivatives of lamellarins D (12) and N (13), were also isolated. An aberration in the integration of signals in the 1H NMR spectra of the 20-sulfated derivatives of lamellarins B, C, and L (1-3) led to NMR relaxation studies. T1 values were calculated for all protons in the sulfated lamellarins (1-4) and their corresponding nonsulfated derivatives (7, 8, 10, 11). Interestingly, the protons ortho to the sulfate group in compounds (1-4) had T1 values up to five times larger than the corresponding protons in their nonsulfated derivatives (7, 8, 10, 11). PMID- 10096850 TI - Three novel C-glycosidic ellagitannins, rhoipteleanins H, I, and J, from rhoiptelea chiliantha AB - Three novel C-glycosidic ellagitannins named rhoipteleanins H (1), I (2), and J (3) were isolated from the fruits and bark of Rhoiptelea chiliantha Diels et Hand.-Mazz. (Rhoipteleaceae), and the structures were elucidated on the basis of detailed spectroscopic analysis and chemical evidence. Rhoipteleanin H possesses a unique cyclopentenone carboxyl moiety, which is probably formed by oxidation and subsequent rearrangement of an aromatic ring of a usual C-glycosidic ellagitannin. Rhoipteleanin I is the first ellagitannin having a hydroxynaphthalene glucoside moiety. Rhoipteleanin J is a dimeric ellagitannin generated by dehydrative coupling between two molecules of a monomeric C glycosidic ellagitannin and subsequent oxidation of an aromatic ring. From a chemotaxonomic viewpoint, presence of these characteristic ellagitannins in this plant provides a further support for the establishment of the order Rhoipteleales comprising Rhoipteleaceae as the only family. PMID- 10096851 TI - Isolation and identification of dihydroartemisinic acid from artemisia annua and its possible role in the biosynthesis of artemisinin AB - Dihydroartemisinic acid (2) was isolated as a natural product from Artemisia annua in a 66% yield, and its structure was confirmed by 1H and 13C NMR spectroscopy. Compound 2 could be chemically converted to artemisinin (4) under conditions that may also be present in the living plant. The results suggest that the conversion of 2 into 4 in the living plant might be a nonenzymatic conversion. PMID- 10096853 TI - Biotransformation of the fungistatic sesquiterpenoid patchoulol by botrytis cinerea AB - Biotransformation of the fungistatic sesquiterpenoid patchoulol (1) by the fungus Botrytis cinerea affords the 5-, 7- and (8R)-hydroxy (2, 3, and 5) derivatives as the major metabolites, together with a number of minor metabolites (4, 6-9) arising from hydroxylation at C-2, C-3, C-5, C-9, C-13, and C-14. PMID- 10096852 TI - New phenolic and quinone-methide triterpenes from Maytenus amazonica. AB - The new nortriterpene methylene quinones amazoquinone (1) and (7S, 8S)-7-hydroxy 7,8-dihydro-tingenone (2), and the new norphenolic triterpenes 7,8-dihydro-6-oxo tingenol (3), 23-nor-6-oxo-tingenol (4), and 23-oxo-iso-tingenone (5) were isolated from Maytenus amazonica. Their structures were elucidated by spectroscopic methods. Compounds 1, 2, 3, and 5 showed low antitumor activity against four cancer cell lines. PMID- 10096854 TI - Polymethoxylated flavones derived from citrus suppress tumor necrosis factor alpha expression by human monocytes. AB - Flavonoids isolated from citrus were evaluated for their ability to affect the inflammation response through suppression of cytokine expression by human monocytes. Several polymethoxylated flavones inhibited lipopolysaccharide-induced monocyte expression of tumor necrosis factor (TNFalpha). Subsequent studies centered on the compound 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) which produced the highest inhibition (IC50 = 5 microM). HMF was also a potent inhibitor of macrophage inflammatory protein-1alpha (MIP-1alpha) and interleukin-10 (IL-10) production, but not of IL-1beta, IL-6, or IL-8 production. Suppression of TNFalpha production was at the level of mRNA induction as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). HMF was also a potent inhibitor of human phosphodiesterase activity and was shown to induce a substantial elevation of cAMP levels in monocytes. The similarity of these results to the inhibition profile of the known phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, suggests that the polymethoxylated flavones inhibit cytokine production in part by suppression of phosphodiesterase activity. The ability of HMF to also inhibit IL-10 production suggests the additional existence of a phosphodiesterase-independent mechanism for this compound. PMID- 10096855 TI - Triterpenoid saponins of Acanthopanax nipponicus leaves. AB - Five new triterpenoid saponins, nipponosides A-E (1, 3-6), were isolated from Acanthopanax nipponicus leaves, along with a known saponin, kalopanaxsaponin G (2). Nipponosides A-E were characterized as the 28-O-alpha-L-rhamnopyranosyl(1- >4)-beta-D-glucopyranosyl(1-->6)-beta -D-glucopyranosyl ester of 3 oxohederagenin, oleanolic acid 3-O-beta-D-glucopyranoside, gypsogenin 3-O-beta-D glucopyranoside, 3beta,23,29-trihydroxyolean-12-en-28-oic acid, and 3beta,20alpha, 23-trihydroxy-30-nor-olean-12-en-28-oic acid, respectively. The structures of these new compounds were based on chemical and spectral methods. PMID- 10096856 TI - Saponarioside C, the first alpha-D-galactose containing triterpenoid saponin, and five related compounds from Saponaria officinalis. AB - Six novel triterpenoid saponins, named saponariosides C-H, were isolated from the whole plants of Saponaria officinalis. Their structures were established as saponarioside C (1), 3-O-beta-D-xylopyranosyl-gypsogenic acid-28-O-alpha-D galactopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-- >6)-[beta-D-glucopyranosyl-(1 ->3)]-beta-D-glucopyranoside; saponarioside D (2), 3-O-beta-D-xylopyranosyl gypsogenic acid-28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->6) [beta-D-glucopyranosyl-(1-->3)]-beta-D-glucopyranoside; saponarioside E (3), 3-O beta-D-glucopyranosyl-gypsogenic acid-28-O-beta-D-glucopyranosyl-(1-->2)-beta-D glucopyranosyl-(1-->6) -[beta-D-glucopyranosyl-(1-->3)]-beta-D-glucopyranoside; saponarioside F (4), 3-O-beta-D-xylopyranosyl-16alpha-hydroxygypsogenic acid-28-O beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->6) -[beta-D glucopyranosyl-(1-->3)]-beta-D-glucopyranoside; saponarioside G (5), 3-O-beta-D xylopyranosyl-16alpha-hydroxygypsogenic acid-28-O-beta-D-glucopyranosyl-(1-->6) [beta-D-glucopyranosyl-(1-->3 )]-beta-D-glucopyranoside; and saponarioside H (6), 3-O-beta-D-xylopyranosyl-gypsogenic acid-28-O-beta-D-glucopyranoside, by a combination of extensive NMR (DEPT, COSY, HOHAHA, HETCOR, HMBC, and NOESY) studies and chemical degradation. PMID- 10096857 TI - Antioxidative phenolic glycosides from sage (Salvia officinalis). AB - An investigation of Salvia officinalis L. has led to the isolation of three new phenolic glycosides, 6-O-caffeoyl-beta-D-fructofuranosyl-(2-->1)-alpha-D glucopyranosid e (1), 1-O-caffeoyl-beta-D-apiofuranosyl-(1-->6)-beta-D glucopyrano side (2), and 1-O-p-hydroxybenzoyl-beta-D-apiofuranosyl-(1-->6)-beta D-glucop yranos ide (3). Elucidation of the structures of 1-3 was based on the interpretation of FABMS and 1D and 2D NMR spectra. Compounds 1 and 2 were found to be moderately active as antioxidants in the DPPH test and metmyoglobin test. PMID- 10096858 TI - Excavatolides F-M, new briarane diterpenes from the gorgonian Briareum excavatum. AB - Eight new briarane-type diterpenes, excavatolides F-M (1-8), have been isolated from the gorgonian Briareum excavatum. The structures and relative stereochemistry of these compounds were established by spectral analysis and chemical methods. The cytotoxicity of these compounds toward various cancer cell lines has also been determined. PMID- 10096859 TI - Tumonoic acids, novel metabolites from a cyanobacterial assemblage of Lyngbya majuscula and Schizothrix calcicola. AB - Five new metabolites have been isolated from a lyngbyastatin 1- and dolastatin 12 producing assemblage of Lyngbya majuscula and Schizothrix calcicola collected at Tumon Bay, Guam. Structure elucidation employed 2D NMR techniques and chemical derivatization. These compounds have been assigned the trivial names tumonoic acids A (2), B (1), and C (5); methyl tumonoate A (3), and methyl tumonoate B (4). Compounds 1 and 4 were also found in a lyngbyastatin 1-producing strain of L. majuscula from Guam. PMID- 10096860 TI - Identification and biosynthetic origins of sterols in the marine bryozoan bugula neritina AB - The sterols of Bugula neritina have been isolated and characterized spectroscopically. Cholesterol was found to be the predominant sterol with C28, C29, and C30 sterols recovered as minor components. In vivo biosynthetic experiments revealed that cholesterol is the only sterol produced by de novo biosynthesis, indicating that the other sterols are of dietary origin. Further, biosynthetic experiments using in vitro techniques indicated that 24-alkylated sterols (4, 5, 7, and 8) are produced by alkylation of dietary sterols, while others are exclusively of dietary origin. PMID- 10096861 TI - Remangilones A-C, new cytotoxic triterpenes from Physena madagascariensis. AB - Three new 24,28-dinorolean-3-one derivatives, the remangilones A-C (1-3), were isolated from the dried leaves of Physena madagascariensis using a human mammary carcinoma cell line to guide the isolation. The structures of 1-3 were deduced primarily from NMR studies. Compounds 1 and 3, remangilones A and C, respectively, were found to be cytotoxic against two human breast cancer cell lines and induced apoptosis at concentrations of 2.3 microM. PMID- 10096862 TI - bis-5-Alkylresorcinols from Panopsis rubescens that inhibit DNA polymerase beta. AB - Bioassay-guided fractionation of Panopsis rubescens, using an assay to detect DNA polymerase beta inhibition, led to the isolation of two new bis-5 alkylresorcinols (1 and 2), in addition to one known bis-5-alkylresorcinol (3). The structures of 1-3 were established as 1,3-dihydroxy-5-[14'-(3' ',5' ' dihydroxyphenyl)-cis-4'-tetradecenyl]benzene (1), 1, 3-dihydroxy-5-[14'-(3' ',5' '-dihydroxyphenyl)-cis-7'-tetradecenyl]benzene (2), and 1, 3-dihydroxy-5-[14'-(3' ',5' '-dihydroxyphenyl)tetradecenyl]benzene (3), respectively, by spectroscopic and chemical analyses. Compounds 1-3 exhibited potent inhibition of calf thymus DNA polymerase beta, with IC50 values of 7.5, 6.5, and 5.8 microM, respectively. PMID- 10096863 TI - Activities of plant-derived phenols in a fibroblast cell culture model AB - Fourteen plant phenols of five structural groups (flavones, flavonols, flavan-3 ol, isoflavones, and phenylpropanoids) demonstrated concentration-dependent inhibitory or modulatory effects in a fibroblast cell culture model. The most potent inhibitory activity in this investigation was exhibited by apigenin (4), with flavone (1), chrysin (2), and genistein (9) being of somewhat lesser potency. These findings help to provide a better understanding of the action of these plant phenols in inflammatory/immune responses. PMID- 10096864 TI - A caryophyllene-related sesquiterpene and two 6, 7-seco-caryophyllenes from liquid cultures of hebeloma longicaudum AB - Three new caryophyllene-related sesquiterpenes, hebelophyllenes D (1), E (2), and F (3), were isolated from liquid cultures of the ectomycorrhizal fungus Hebeloma longicaudum. Their structures were determined by modern spectroscopic methods. Hebelophyllene D has a tricyclo[5.4.0.0(2,5)]undecane skeleton, while hebelophyllenes E and F are the first naturally occurring 6,7-seco caryophyllenes. PMID- 10096865 TI - beta-triketones from myrtaceae: isoleptospermone from leptospermum scoparium and papuanone from corymbia dallachiana AB - Naturally occurring beta-triketones, isoleptospermone [3, 5-hydroxy-4-(2-methyl-1 oxopentyl)-2,2,6, 6-tetramethyl-4-cyclohexene-1,3-dione) from Leptospermum scoparium] and papuanone [6, 5-hydroxy-4-(1-oxohexyl)-2,2,6, 6-tetramethyl-4 cyclohexene-1,3-dione from Corymbia dallachiana], have been synthesized. Full spectral data are reported for the first time. The 13C NMR spectra of 3, 6, and the other triketones flavesone (2), leptospermone (4), and grandiflorone (5) found in Myrtaceous plants are fully assigned. PMID- 10096866 TI - Chiral dihydroxylation of acronycine: absolute configuration of natural cis-1,2 dihydroxy-1,2-dihydroacronycine and cytotoxicity of (1R,2R)- and (1S,2S)-1,2 diacetoxy-1,2-dihydroacronycine. AB - Sharpless asymmetric dihydroxylation of acronycine (1) gave (1R, 2R)-1,2 dihydroxy-1,2-dihydroacronycine (2) and (1S,2S)-1, 2-dihydroxy-1,2 dihydroacronycine (3), which allowed determination of the absolute configuration of natural cis-1,2-dihydroxy-1, 2-dihydroacronycine as 1R,2R. The cis isomer had been previously isolated from various Sarcomelicope species. Benzylic reduction of isomers 2 and 3 gave the alcohols 4 (2R) and 5 (2S), respectively. Acetylation of 2 and 3 afforded the corresponding esters 6 and 7. No significant difference of cytotoxicity was observed between these (1R,2R)- and (1S,2S)-enantiomers and the recently described, highly active racemic cis-1,2-diacetoxy-1,2 dihydroacronycine, when tested against L-1210 cells in vitro. PMID- 10096867 TI - A new withanolide glycoside from physalis peruviana AB - A new withanolide glycoside, 17beta-hydroxy-14, 20-epoxy-1-oxo-[22R]-3beta-[O beta-D-glucopyranosyl]-witha-5, 24-dienolide (1), has been isolated from the whole plant of Physalis peruviana. Its identity was determined using a combination of spectroscopic data including 2D NMR techniques and chemical transformations. PMID- 10096868 TI - KR025, a new cytotoxic compound from Myxococcus fulvus. AB - A new bithiazole, KR-025 (1), was isolated from Myxococcus fulvus. Its structure was elucidated by spectroscopic analysis. In addition to 1, the strain produced relatively large quantities of a second, closely related antibiotic, myxothiazol. These compounds demonstrated potent cytotoxicity against human tumor cells. PMID- 10096869 TI - Massarinolins A-C: new bioactive sesquiterpenoids from the aquatic fungus massarina tunicata AB - Massarinolins A-C (1-3), three new bioactive sesquiterpenoids possessing rare ring systems, have been isolated from liquid cultures of the aquatic fungus Massarina tunicata Shearer & Fallah. The structures were determined primarily by analysis of NMR data. Metabolites 1-3 are the first compounds to be reported from any member of the genus Massarina. PMID- 10096870 TI - A novel extracellular diterpenoid with antibacterial activity from the cyanobacterium Nostoc commune. AB - A novel extracellular metabolite with an unprecedented diterpenoid skeleton, 8 [(5-carboxy-2-hydroxy)benzyl]-2-hydroxy-1,1,4a,7, 8-pentamethyl 1,2,3,4,4a,6,7,8,8a,9,10,10a-dodecahydrophenanthrene , has been isolated from the culture medium of the terrestrial cyanobacterium Nostoc commune Vaucher (EAWAG 122b) by means of bioguided isolation. The molecule was designated as noscomin. The structure was determined by spectroscopic methods, mainly NMR and mass spectrometry. Noscomin exhibited antibacterial activity against Bacillus cereus, Staphylococcus epidermidis, and Escherichia coli. PMID- 10096871 TI - Annonaceous acetogenins: recent progress. AB - The Annonaceous acetogenins are promising new antitumor and pesticidal agents that are found only in the plant family Annonaceae. Chemically, they are derivatives of long-chain fatty acids. Biologically, they exhibit their potent bioactivities through depletion of ATP levels via inhibiting complex I of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells. Thus, they thwart ATP-driven resistance mechanisms. This review presents the progress made in the chemistry, biology, and development of these compounds since December 1995. PMID- 10096872 TI - Quantifying membrane asymmetry. PMID- 10096873 TI - DNA-protein cooperative binding through variable-range elastic coupling. AB - Cooperativity plays an important role in the action of proteins bound to DNA. A simple mechanism for cooperativity, in the form of a tension-mediated interaction between proteins bound to DNA at two different locations, is proposed. These proteins are not in direct physical contact. DNA segments intercalating bound proteins are modeled as a worm-like chain, which is free to deform in two dimensions. The tension-controlled protein-protein interaction is the consequence of two effects produced by the protein binding. The first is the introduction of a bend in the host DNA and the second is the modification of the bending modulus of the DNA in the immediate vicinity of the bound protein. The interaction between two bound proteins may be either attractive or repulsive, depending on their relative orientation on the DNA. Applied tension controls both the strength and the range of protein-protein interactions in this model. Properties of the cooperative interaction are discussed, along with experimental implications. PMID- 10096874 TI - Hydrophobic hydration of amphipathic peptides. AB - Biomolecular surfaces and interfaces are commonly found with apolar character. The hydrophobic effect thus plays a crucial role in processes involving association with biomolecular surfaces in the cellular environment. By computer simulation, we compared the hydrogen bonding structures and energetics of the proximal hydration shells of the monomer and dimer from a recent study of an extrinsic membrane peptide, melittin. The two peptides were studied in their amphipathic alpha-helical forms, which possess extended hydrophobic surfaces characterized by different topography. The topography of the peptide-water interface was found to be critical in determining the enthalpic nature of hydrophobic hydration. This topographical dependence has far-reaching implications in the regulation of bioactivities in the presence of amphipathicity. This result also engenders reconsideration of the validity of using free energy parameters that depend solely on the chemical nature of constituent moieties in characterizing hydrophobic hydration of proteins and biomolecules in general. PMID- 10096875 TI - Differential regulation of skeletal muscle L-type Ca2+ current and excitation contraction coupling by the dihydropyridine receptor beta subunit. AB - The dihydropyridine receptor (DHPR) of skeletal muscle functions as a Ca2+ channel and is required for excitation-contraction (EC) coupling. Here we show that the DHPR beta subunit is involved in the regulation of these two functions. Experiments were performed in skeletal mouse myotubes selectively lacking a functional DHPR beta subunit. These beta-null cells have a low-density L-type current, a low density of charge movements, and lack EC coupling. Transfection of beta-null cells with cDNAs encoding for either the homologous beta1a subunit or the cardiac- and brain-specific beta2a subunit fully restored the L-type Ca2+ current (161 +/- 17 pS/pF and 139 +/- 9 pS/pF, respectively, in 10 mM Ca2+). We compared the Boltzmann parameters of the Ca2+ conductance restored by beta1a and beta2a, the kinetics of activation of the Ca2+ current, and the single channel parameters estimated by ensemble variance analysis and found them to be indistinguishable. In contrast, the maximum density of charge movements in cells expressing beta2a was significantly lower than in cells expressing beta1a (2.7 +/ 0.2 nC/microF and 6.7 +/- 0. 4 nC/microF, respectively). Furthermore, the amplitude of Ca2+ transient measured by confocal line-scans of fluo-3 fluorescence in voltage-clamped cells were 3- to 5-fold lower in myotubes expressing beta2a. In summary, DHPR complexes that included beta2a or beta1a restored L-type Ca2+ channels. However, a DHPR complex with beta1a was required for complete restoration of charge movements and skeletal-type EC coupling. These results suggest that the beta1a subunit participates in key regulatory events required for the EC coupling function of the DHPR. PMID- 10096876 TI - An alamethicin channel in a lipid bilayer: molecular dynamics simulations. AB - We present the results of 2-ns molecular dynamics (MD) simulations of a hexameric bundle of Alm helices in a 1-palmitoyl-2-oleoylphosphatidylcholine bilayer. These simulations explore the dynamic properties of a model of a helix bundle channel in a complete phospholipid bilayer in an aqueous environment. We explore the stability and conformational dynamics of the bundle in a phospholipid bilayer. We also investigate the effect on bundle stability of the ionization state of the ring of Glu18 side chains. If all of the Glu18 side chains are ionised, the bundle is unstable; if none of the Glu18 side chains are ionized, the bundle is stable. pKA calculations suggest that either zero or one ionized Glu18 is present at neutral pH, correlating with the stable form of the helix bundle. The structural and dynamic properties of water in this model channel were examined. As in earlier in vacuo simulations (Breed et al., 1996 .Biophys. J. 70:1643 1661), the dipole moments of water molecules within the pore were aligned antiparallel to the helix dipoles. This contributes to the stability of the helix bundle. PMID- 10096877 TI - Backward movements of cross-bridges by application of stretch and by binding of MgADP to skeletal muscle fibers in the rigor state as studied by x-ray diffraction. AB - The effects of the applied stretch and MgADP binding on the structure of the actomyosin cross-bridges in rabbit and/or frog skeletal muscle fibers in the rigor state have been investigated with improved resolution by x-ray diffraction using synchrotron radiation. The results showed a remarkable structural similarity between cross-bridge states induced by stretch and MgADP binding. The intensities of the 14.4- and 7.2-nm meridional reflections increased by approximately 23 and 47%, respectively, when 1 mM MgADP was added to the rigor rabbit muscle fibers in the presence of ATP-depletion backup system and an inhibitor for muscle adenylate kinase or by approximately 33 and 17%, respectively, when rigor frog muscle was stretched by approximately 4.5% of the initial muscle length. In addition, both MgADP binding and stretch induced a small but genuine intensity decrease in the region close to the meridian of the 5.9-nm layer line while retaining the intensity profile of its outer portion. No appreciable influence was observed in the intensities of the higher order meridional reflections of the 14.4-nm repeat and the other actin-based reflections as well as the equatorial reflections, indicating a lack of detachment of cross-bridges in both cases. The changes in the axial spacings of the actin-based and the 14.4-nm-based reflections were observed and associated with the tension change. These results indicate that stretch and ADP binding mediate similar structural changes, being in the correct direction to those expected for that the conformational changes are induced in the outer portion distant from the catalytic domain of attached cross-bridges. Modeling of conformational changes of the attached myosin head suggested a small but significant movement (about 10-20 degrees) in the light chain-binding domain of the head toward the M-line of the sarcomere. Both chemical (ADP binding) and mechanical (stretch) intervensions can reverse the contractile cycle by causing a backward movement of this domain of attached myosin heads in the rigor state. PMID- 10096878 TI - Structure of the 1-36 amino-terminal fragment of human phospholamban by nuclear magnetic resonance and modeling of the phospholamban pentamer. AB - The structure of a 36-amino-acid-long amino-terminal fragment of phospholamban (phospholamban[1-36]) in aqueous solution containing 30% trifluoroethanol was determined by nuclear magnetic resonance. The peptide, which comprises the cytoplasmic domain and six residues of the transmembrane domain of phospholamban, assumes a conformation characterized by two alpha-helices connected by a turn. The residues of the turn are Ile18, Glu19, Met20, and Pro21, which are adjacent to the two phosphorylation sites Ser16 and Thr17. The proline is in a trans conformation. The helix comprising amino acids 22-36 is well determined (the root mean square deviation for the backbone atoms, calculated for a family of 18 nuclear magnetic resonance structures is 0.57 A). Recently, two molecular models of the transmembrane domain of phospholamban were proposed in which a symmetric homopentamer is composed of a left-handed coiled coil of alpha-helices. The two models differ by the relative orientation of the helices. The model proposed by,Simmerman et al. (H.K. Simmerman, Y.M. Kobayashi, J.M. Autry, and L.R. Jones, 1996, J. Biol. Chem. 271:5941-5946), in which the coiled coil is stabilized by a leucine-isoleucine zipper, is similar to the transmembrane pentamer structure of the cartilage oligomeric membrane protein determined recently by x-ray (V. Malashkevich, R. Kammerer, V Efimov, T. Schulthess, and J. Engel, 1996, Science 274:761-765). In the model proposed by Adams et al. (P.D. Adams, I.T. Arkin, D.M. Engelman, and A.T. Brunger, 1995, Nature Struct. Biol. 2:154-162), the helices in the coiled coil have a different relative orientation, i.e., are rotated clockwise by approximately 50 degrees. It was possible to overlap and connect the structure of phospholamban[1-36] derived in the present study to the two transmembrane pentamer models proposed. In this way two models of the whole phospholamban in its pentameric form were generated. When our structure was connected to the leucine-isoleucine zipper model, the inner side of the cytoplasmic domain of the pentamer (where the helices face one another) was lined by polar residues (Gln23, Gln26, and Asn30), whereas the five Arg25 side chains were on the outer side. On the contrary, when our structure was connected to the other transmembrane model, in the inner side of the cytoplasmic domain of the pentamer, the five Arg25 residues formed a highly charged cluster. PMID- 10096879 TI - Molecular dynamics of human methemoglobin: the transmission of conformational information between subunits in an alpha beta dimer. AB - Spectroscopic studies indicate an interaction of the distal histidine with the heme iron as well as the transmission of distal heme perturbations across the alpha1beta1 interface. Molecular dynamics simulations have been used to explain the molecular basis for these processes. Using a human methemoglobin alpha beta dimer, it has been shown that at 235 K after 61 ps, a rearrangement occurs in the alpha-chain corresponding to the formation of a bond with the distal histidine. This transition does not take place in the beta-chain during a 100-ps simulation and is reversed at 300 K. The absence of the distal histidine transition in the isolated chains and with the interface frozen indicate the involvement of the alphabeta interface. A detailed analysis of the simulation has been performed in terms of RMS fluctuations, domain cross-correlation maps, the disruption of helix hydrogen bonds, as well changes in electrostatic interactions and dihedral angles. This analysis shows that the rearrangements in the alpha-chain necessary to bring the histidine closer to the iron involve alterations primarily in the CD loop and at the interface. Communication to the beta-chain distal pocket is propagated by increased interactions of the alpha-chain B helix with the beta chain G-GH-H segment and the flexibility in the EF loop. The G helices shown to be involved in propagation of perturbation across the alpha1beta1 interface extend into the alpha1beta2 interfaces, providing a mechansim whereby distal interactions can modulate the T<==>R transition in hemoglobin. PMID- 10096880 TI - Scanning near-field fluorescence resonance energy transfer microscopy. AB - A new microscopic technique is demonstrated that combines attributes from both near-field scanning optical microscopy (NSOM) and fluorescence resonance energy transfer (FRET). The method relies on attaching the acceptor dye of a FRET pair to the end of a near-field fiber optic probe. Light exiting the NSOM probe, which is nonresonant with the acceptor dye, excites the donor dye introduced into a sample. As the tip approaches the sample containing the donor dye, energy transfer from the excited donor to the tip-bound acceptor produces a red-shifted fluorescence. By monitoring this red-shifted acceptor emission, a dramatic reduction in the sample volume probed by the uncoated NSOM tip is observed. This technique is demonstrated by imaging the fluorescence from a multilayer film created using the Langmuir-Blodgett (LB) technique. The film consists of L-alpha dipalmitoylphosphatidylcholine (DPPC) monolayers containing the donor dye, fluorescein, separated by a spacer group of three arachidic acid layers. A DPPC monolayer containing the acceptor dye, rhodamine, was also transferred onto an NSOM tip using the LB technique. Using this modified probe, fluorescence images of the multilayer film reveal distinct differences between images collected monitoring either the donor or acceptor emission. The latter results from energy transfer from the sample to the NSOM probe. This method is shown to provide enhanced depth sensitivity in fluorescence measurements, which may be particularly informative in studies on thick specimens such as cells. The technique also provides a mechanism for obtaining high spatial resolution without the need for a metal coating around the NSOM probe and should work equally well with nonwaveguide probes such as atomic force microscopy tips. This may lead to dramatically improved spatial resolution in fluorescence imaging. PMID- 10096881 TI - Cooperative Ca2+ removal from presynaptic terminals of the spiny lobster neuromuscular junction. AB - Stimulation-induced changes in presynaptic free calcium concentration ([Ca2+]i) were examined by fluorescent imaging at the spiny lobster excitor motor nerve terminals. The Ca2+ removal process in the terminal was analyzed based on a single compartment model, under the assumption that the Ca2+ removal rate from the terminal cytoplasm is proportional to nth power of [Ca2+]i. During 100 nerve stimuli at 10-100 Hz, [Ca2+]i reached a plateau that increased in a less-than linear way with stimulation frequency, and the power index, n, was about 2. In the decay time course after stimulation, n changed with the number of stimuli from about 1.4 after 10 stimuli to about 2 after 100 stimuli. With the change of n from 1.4 to 2, the rate became larger at high [Ca2+]i (>1.5 microM), but was smaller at low [Ca2+]i (<1 microM). These results suggest that a cooperative Ca2+ removal mechanism of n = 2, such as mitochondria, may play an important role in the terminal. This view is supported by the gradual increase in the [Ca2+]i plateau during long-term stimulation at 20-50 Hz for 60 s and by the existence of a very slow [Ca2+]i recovery process after this stimulation, both of which may be due to accumulation of Ca2+ in the organelle. PMID- 10096882 TI - Mucosal mast cell secretion processes imaged using three-photon microscopy of 5 hydroxytryptamine autofluorescence. AB - The secretion process of the mucosal mast cell line RBL-2H3 was imaged using infrared three photon excitation (3PE) of serotonin (5-hydroxytryptamine, 5-HT) autofluorescence, a measurement previously difficult because of the technical intractability of deep UV optics. Images of prestimulation 5-HT distributions were analyzed in loaded cell populations (those incubated in a 5-HT-rich medium overnight) and in unloaded populations and were found to be strictly quantifiable by comparison with bulk population high-performance liquid chromatography measurements. Antigenically stimulated cells were observed to characteristically ruffle and spread as granular 5-HT disappeared with no detectable granule movement. Individual cells exhibited highly heterogeneous release kinetics, often with quasi-periodic bursts. Neighboring granule disappearances were correlated, indicative of either spatially localized signaling or granule-granule interactions. In one-half of the granule release events, weak residual fluorescence was visible suggestive of leftover 5-HT still bound to the granule matrix. The terminal stages of secretion (>300 s) consisted primarily of unresolved granules and remainder 5-HT leakage from already released granules. PMID- 10096883 TI - Testing the fit of a quantal model of neurotransmission. AB - Many studies of synaptic transmission have assumed a parametric model to estimate the mean quantal content and size or the effect upon them of manipulations such as the induction of long-term potentiation. Classical tests of fit usually assume that model parameters have been selected independently of the data. Therefore, their use is problematic after parameters have been estimated. We hypothesized that Monte Carlo (MC) simulations of a quantal model could provide a table of parameter-independent critical values with which to test the fit after parameter estimation, emulating Lilliefors's tests. However, when we tested this hypothesis within a conventional quantal model, the empirical distributions of two conventional goodness-of-fit statistics were affected by the values of the quantal parameters, falsifying the hypothesis. Notably, the tests' critical values increased when the combined variances of the noise and quantal-size distributions were reduced, increasing the distinctness of quantal peaks. Our results support two conclusions. First, tests that use a predetermined critical value to assess the fit of a quantal model after parameter estimation may operate at a differing unknown level of significance for each experiment. Second, a MC test enables a valid assessment of the fit of a quantal model after parameter estimation. PMID- 10096884 TI - Calcium dynamics in the extracellular space of mammalian neural tissue. AB - In the brain, hundreds of intracellular processes are known to depend on calcium influx; hence any substantial fluctuation in external calcium ([Ca2+]o) is likely to engender important functional effects. Employing the known scales and parameters of mammalian neural tissue, we introduce and justify a computational approach to the hypothesis that large changes in local [Ca2+]o will be part of normal neural activity. Using this model, we show that the geometry of the extracellular space in combination with the rapid movement of calcium through ionic channels can cause large external calcium fluctuations, up to 100% depletion in many cases. The exact magnitude of a calcium fluctuation will depend on 1) the size of the consumption zone, 2) the local diffusion coefficient of calcium, and 3) the geometrical arrangement of the consuming elements. Once we have shown that using biologically relevant parameters leads to calcium changes, we focus on the signaling capacity of such concentration fluctuations. Given the sensitivity of neurotransmitter release to [Ca2+]o, the exact position and timing of neural activity will delimit the terminals that are able to release neurotransmitter. Our results indicate that mammalian neural tissue is engineered to generate significant changes in external calcium concentrations during normal activity. This design suggests that such changes play a role in neural information processing. PMID- 10096885 TI - Cardiac sodium channel Markov model with temperature dependence and recovery from inactivation. AB - A Markov model of the cardiac sodium channel is presented. The model is similar to the CA1 hippocampal neuron sodium channel model developed by Kuo and Bean (1994. Neuron. 12:819-829) with the following modifications: 1) an additional open state is added; 2) open-inactivated transitions are made voltage-dependent; and 3) channel rate constants are exponential functions of enthalpy, entropy, and voltage and have explicit temperature dependence. Model parameters are determined using a simulated annealing algorithm to minimize the error between model responses and various experimental data sets. The model reproduces a wide range of experimental data including ionic currents, gating currents, tail currents, steady-state inactivation, recovery from inactivation, and open time distributions over a temperature range of 10 degrees C to 25 degrees C. The model also predicts measures of single channel activity such as first latency, probability of a null sweep, and probability of reopening. PMID- 10096886 TI - Defining the transmembrane helix of M2 protein from influenza A by molecular dynamics simulations in a lipid bilayer. AB - Integral membrane proteins containing at least one transmembrane (TM) alpha-helix are believed to account for between 20% and 30% of most genomes. There are several algorithms that accurately predict the number and position of TM helices within a membrane protein sequence. However, these methods tend to disagree over the beginning and end residues of TM helices, posing problems for subsequent modeling and simulation studies. Molecular dynamics (MD) simulations in an explicit lipid and water environment are used to help define the TM helix of the M2 protein from influenza A virus. Based on a comparison of the results of five different secondary structure prediction algorithms, three different helix lengths (an 18mer, a 26mer, and a 34mer) were simulated. Each simulation system contained 127 POPC molecules plus approximately 3500-4700 waters, giving a total of approximately 18,000-21,000 atoms. Two simulations, each of 2 ns duration, were run for the 18mer and 26mer, and five separate simulations were run for the 34mer, using different starting models generated by restrained in vacuo MD simulations. The total simulation time amounted to 11 ns. Analysis of the time dependent secondary structure of the TM segments was used to define the regions that adopted a stable alpha-helical conformation throughout the simulation. This analysis indicates a core TM region of approximately 20 residues (from residue 22 to residue 43) that remained in an alpha-helical conformation. Analysis of atomic density profiles suggested that the 18mer helix revealed a local perturbation of the lipid bilayer. Polar side chains on either side of this region form relatively long-lived H-bonds to lipid headgroups and water molecules. PMID- 10096887 TI - Noncontact dipole effects on channel permeation. II. Trp conformations and dipole potentials in gramicidin A. AB - The four Trp dipoles in the gramicidin A (gA) channel modulate channel conductance, and their side chain conformations should therefore be important, but the energies of different conformations are unknown. A conformational search for the right-handed helix based on molecular mechanics in vacuo yielded 46 conformations within 20 kcal/mol of the lowest energy conformation. The two lowest energy conformations correspond to the solid-state and solution-state NMR conformations, suggesting that interactions within the peptide determine the conformation. For representative conformations, the electrostatic potential of the Trp side chains on the channel axis was computed. A novel application of the image-series method of. Biophys. J. 9:1160-1170) was introduced to simulate the polarization of bulk water by the Trp side chains. For the experimentally observed structures, the CHARm toph19 potential energy (PE) of a cation in the channel center is -1.65 kcal/mol without images. With images, the PE is -1.9 kcal/mol, demonstrating that the images further enhance the direct dipole effect. Nonstandard conformations yielded less favorable PEs by 0.4-1.1 kcal/mol. PMID- 10096888 TI - Simulation analysis of the retinal conformational equilibrium in dark-adapted bacteriorhodopsin. AB - In dark-adapted bacteriorhodopsin (bR) the retinal moiety populates two conformers: all-trans and (13,15)cis. Here we examine factors influencing the thermodynamic equilibrium and conformational transition between the two forms, using molecular mechanics and dynamics calculations. Adiabatic potential energy mapping indicates that whereas the twofold intrinsic torsional potentials of the C13==C14 and C15==N16 double bonds favor a sequential torsional pathway, the protein environment favors a concerted, bicycle-pedal mechanism. Which of these two pathways will actually occur in bR depends on the as yet unknown relative weight of the intrinsic and environmental effects. The free energy difference between the conformers was computed for wild-type and modified bR, using molecular dynamics simulation. In the wild-type protein the free energy of the (13,15)cis retinal form is calculated to be 1.1 kcal/mol lower than the all-trans retinal form, a value within approximately kBT of experiment. In contrast, in isolated retinal the free energy of the all-trans state is calculated to be 2.1 kcal/mol lower than (13,15)cis. The free energy differences are similar to the adiabatic potential energy differences in the various systems examined, consistent with an essentially enthalpic origin. The stabilization of the (13,15)cis form in bR relative to the isolated retinal molecule is found to originate from improved protein-protein interactions. Removing internal water molecules near the Schiff base strongly stabilizes the (13,15)cis form, whereas a double mutation that removes negative charges in the retinal pocket (Asp85 to Ala; Asp212 to Ala) has the opposite effect. PMID- 10096889 TI - A possible resolution of the gating paradox. AB - We introduce a Markov model for the gating of membrane channels. The model features a possible solution to the so-called gating current paradox, namely that the bell-shaped curve that describes the voltage dependence of the kinetics is broader than expected from, and shifted relative to, the sigmoidal curve that describes the voltage dependence of the activation. The model also predicts some temperature dependence of this shift, but presence of the latter has not been tested experimentally so far. PMID- 10096890 TI - Lipid transfer between vesicles: effect of high vesicle concentration. AB - The problem of the desorption of a lipid molecule from a lipid vesicle (donor) and its incorporation into another vesicle (acceptor) at high acceptor concentrations, which has been investigated experimentally (Jones, J. D. and Thompson, T. E., 1990. Biochemistry, 29:1593-1600), is analyzed here from a theoretical point of view, formulated in terms of the diffusion equation with appropriate boundary conditions. The goal is to determine whether or not the observed acceleration of the off-rate from a donor is caused by interaction with an acceptor vesicle at short range, or is simply the result of statistical effects due the proximity of the acceptor and its influence on the probability of the test lipid returning to the donor. We establish a correspondence between the theoretical parameters and the experimental, thermodynamic and dynamic variables entering the problem. The solution shows that, because of the extremely high Gibbs activation energy for desorption of a phospholipid, the process would always be first-order, even at very high vesicle concentrations. This means that acceleration of the off-rate must be due to donor-acceptor interactions at short distances, as proposed in the experimental work. PMID- 10096891 TI - Simulation study of a gramicidin/lipid bilayer system in excess water and lipid. I. Structure of the molecular complex. AB - This paper reports on a simulation of a gramicidin channel inserted into a fluid phase DMPC bilayer with 100 lipid molecules. Two lipid molecules per leaflet were removed to insert the gramicidin, so the resulting preparation had 96 lipid molecules and 3209 water molecules. Constant surface tension boundary conditions were employed. Like previous simulations with a lower lipid/gramicidin ratio (Woolf, T. B., and B. Roux. 1996. Proteins: Struct., Funct., Genet. 24:92-114), it is found that tryptophan-water hydrogen bonds are more common than tryptophan phospholipid hydrogen bonds. However, one of the tryptophan NH groups entered into an unusually long-lived hydrogen bonding pattern with two glycerol oxygens of one of the phospholipid molecules. Comparisons were made between the behavior of the lipids adjacent to the channel with those farther away. It was found that hydrocarbon chains of lipids adjacent to the channel had higher-order parameters than those farther away. The thickness of the lipid bilayer immediately adjacent to the channel was greater than it was farther away. In general, the lipids adjacent to the membrane had similar orientations to those seen by Woolf and Roux, while those farther away had similar orientations to those pertaining before the insertion of the gramicidin. A corollary to this observation is that the thickness of the hydrocarbon region adjacent to the gramicidin was much thicker than what other studies have identified as the "hydrophobic length" of the gramicidin channel. PMID- 10096892 TI - Simulation study of a gramicidin/lipid bilayer system in excess water and lipid. II. Rates and mechanisms of water transport. AB - A gramicidin channel in a fluid phase DMPC bilayer with excess lipid and water has been simulated. By use of the formal correspondence between diffusion and random walk, a permeability for water through the channel was calculated, and was found to agree closely with the experimental results of Rosenberg and Finkelstein (Rosenberg, P.A., and A. Finkelstein. 1978. J. Gen. Physiol. 72:327-340; 341-350) for permeation of water through gramicidin in a phospholipid membrane. By using fluctuation analysis, components of resistance to permeation were computed for movement through the channel interior, for the transition step at the channel mouth where the water molecule solvation environment changes, and for the process of diffusion up to the channel mouth. The majority of the resistance to permeation appears to occur in the transition step at the channel mouth. A significant amount is also due to structurally based free energy barriers within the channel. Only small amounts are due to local friction within the channel or to diffusive resistance for approaching the channel mouth. PMID- 10096893 TI - Chloride ion binding to bacteriorhodopsin at low pH: an infrared spectroscopic study. AB - Bacteriorhodopsin (bR) and halorhodopsin (hR) are light-induced ion pumps in the cell membrane of Halobacterium salinarium. Under normal conditions bR is an outward proton transporter, whereas hR is an inward Cl- transporter. There is strong evidence that at very low pH and in the presence of Cl-, bR transports Cl- ions into the cell, similarly to hR. The chloride pumping activity of bR is connected to the so-called acid purple state. To account for the observed effects in bR a tentative complex counterion was suggested for the protonated Schiff base of the retinal chromophore. It would consist of three charged residues: Asp-85, Asp-212, and Arg-82. This quadruplet (including the Schiff base) would also serve as a Cl- binding site at low pH. We used Fourier transform infrared difference spectroscopy to study the structural changes during the transitions between the normal, acid blue, and acid purple states. Asp-85 and Asp-212 were shown to participate in the transitions. During the normal-to-acid blue transition, Asp-85 protonates. When the pH is further lowered in the presence of Cl-, Cl- binds and Asp-212 also protonates. The binding of Cl- and the protonation of Asp-212 occur simultaneously, but take place only when Asp-85 is already protonated. It is suggested that HCl is taken up in undissociated form in exchange for a neutral water molecule. PMID- 10096894 TI - Blockade of HERG channels expressed in Xenopus laevis oocytes by external divalent cations. AB - We have investigated actions of various divalent cations (Ba2+, Sr2+, Mn2+, Co2+, Ni2+, Zn2+) on human ether-a-go-go related gene (HERG) channels expressed in Xenopus laevis oocytes using the voltage clamp technique. All divalent cations inhibited HERG current dose-dependently in a voltage-dependent manner. The concentration for half-maximum inhibition (Ki) decreased at more negative potentials, indicating block is facilitated by hyperpolarization. Ki at 0 mV for Zn2+, Ni2+, Co2+, Ba2+, Mn2+, and Sr2+ was 0.19, 0.36, 0. 50, 0.58, 2.36, and 6.47 mM, respectively. The effects were manifested in four ways: 1) right shift of voltage dependence of activation, 2) decrease of maximum conductance, 3) acceleration of current decay, and 4) slowing of activation. However, each parameter was not affected by each cation to the same extent. The potency for the shift of voltage dependence of activation was in the order Zn2+ > Ni2+ >/= Co2+ > Ba2+ > Mn2+ > Sr2+, whereas the potency for the decrease of maximum conductance was Zn2+ > Ba2+ > Sr2+ > Co2+ > Mn2+. The kinetics of activation and deactivation were also affected, but the two parameters are not affected to the same extent. Slowing of activation by Ba2+ was most distinct, causing a marked initial delay of current onset. From these results we concluded that HERG channels are nonselectively blocked by most divalent cations from the external side, and several different mechanism are involved in their actions. There exist at least two distinct binding sites for their action: one for the voltage-dependent effect and the other for reducing maximum conductance. PMID- 10096895 TI - Regulation of recombinant cardiac cystic fibrosis transmembrane conductance regulator chloride channels by protein kinase C. AB - We investigated the regulation of cardiac cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels by protein kinase C (PKC) in Xenopus oocytes injected with cRNA encoding the cardiac (exon 5-) CFTR Cl- channel isoform. Membrane currents were recorded using a two-electrode voltage clamp technique. Activators of PKC or a cAMP cocktail elicited robust time-independent Cl- currents in cardiac CFTR-injected oocytes, but not in control water-injected oocytes. The effects of costimulation of both pathways were additive; however, maximum protein kinase A (PKA) activation occluded further activation by PKC. In oocytes expressing either the cardiac (exon 5-) or epithelial (exon 5+) CFTR isoform, Cl- currents activated by PKA were sustained, whereas PKC-activated currents were transient, with initial activation followed by slow current decay in the continued presence of phorbol esters, the latter effect likely due to down regulation of endogenous PKC activity. The specific PKA inhibitor, adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS), and various protein phosphatase inhibitors were used to determine whether the stimulatory effects of PKC are dependent upon the PKA phosphorylation state of cardiac CFTR channels. Intraoocyte injection of 1,2-bis(2-aminophenoxy)ethane-N,N, N,N-tetraacetic acid (BAPTA) or pretreatment of oocytes with BAPTA-acetoxymethyl-ester (BAPTA-AM) nearly completely prevented dephosphorylation of CFTR currents activated by cAMP, an effect consistent with inhibition of protein phosphatase 2C (PP2C) by chelation of intracellular Mg2+. PKC-induced stimulation of CFTR channels was prevented by inhibition of basal endogenous PKA activity, and phorbol esters failed to stimulate CFTR channels trapped into either the partially PKA phosphorylated (P1) or the fully PKA phosphorylated (P1P2) channel states. Site directed mutagenesis of serines (S686 and S790) within two consensus PKC phosphorylation sites on the cardiac CFTR regulatory domain attentuated, but did not eliminate, the stimulatory effects of phorbol esters on mutant CFTR channels. The effects of PKC on cardiac CFTR Cl- channels are consistent with a simple model in which PKC phosphorylation of the R domain facilitates PKA-induced transitions from dephosphorylated (D) to partially (P1) phosphorylated and fully (P1P2) phosphorylated channel states. PMID- 10096896 TI - Structural determinants of gating in inward-rectifier K+ channels. AB - The gating characteristics of two ion channels in the inward-rectifier K+ channel superfamily were compared at the single-channel level. The strong inward rectifier IRK1 (Kir 2.1) opened and closed with kinetics that were slow relative to those of the weakly rectifying ROMK2 (Kir 1.1b). At a membrane potential of 60 mV, both IRK and ROMK had single-exponential open-time distributions, with mean open times of 279 +/- 58 ms (n = 4) for IRK1 and 23 +/- 1 ms (n = 7) for ROMK. At -60 mV (and no EDTA) ROMK2 had two closed times: 1.3 +/- 0.1 and 36 +/- 3 ms (n = 7). Under the same conditions, IRK1 exhibited four discrete closed states with mean closed times of 0.8 +/- 0.1 ms, 14 +/- 0.6 ms, 99 +/- 19 ms, and 2744 +/- 640 ms (n = 4). Both the open and the three shortest closed-time constants of IRK1 decreased monotonically with membrane hyperpolarization. IRK1 open probability (Po) decreased sharply with hyperpolarization due to an increase in the frequency of long closed events that were attributable to divalent-cation blockade. Chelation of divalent cations with EDTA eliminated the slowest closed time distribution of IRK1 and blunted the hyperpolarization-dependent fall in open probability. In contrast, ROMK2 had shorter open and closed times and only two closed states, and its Po was less affected by hyperpolarization. Chimeric channels were constructed to address the question of which parts of the molecules were responsible for the differences in kinetics. The property of multiple closed states was conferred by the second membrane-spanning domain (M2) of IRK. The long lived open and closed states, including the higher sensitivity to extracellular divalent cations, correlated with the extracellular loop of IRK, including the "P region." Channel kinetics were essentially unaffected by the N- and C-termini. The data of the present study are consistent with the idea that the locus of gating is near the outer mouth of the pore. PMID- 10096897 TI - Evidence for dimerization of dimers in K+ channel assembly. AB - Voltage-gated K+ channels are tetrameric, but how the four subunits assemble is not known. We analyzed inactivation kinetics and peak current levels elicited for a variety of wild-type and mutant Kv1.3 subunits, expressed singly, in combination, and as tandem constructs, to show that 1) the dominant pathway involves a dimerization of dimers, and 2) dimer-dimer interaction may involve interaction sites that differ from those involved in monomer-monomer association. Moreover, using nondenaturing gel electrophoresis, we detected dimers and tetramers, but not trimers, in the translation reaction of Kv1.3 monomers. PMID- 10096898 TI - Significance of Na/Ca exchange for Ca2+ buffering and electrical activity in mouse pancreatic beta-cells. AB - We have combined the patch-clamp technique with microfluorimetry of the cytoplasmic Ca2+ concentration ([Ca2+]i) to characterize Na/Ca exchange in mouse beta-cells and to determine its importance for [Ca2+]i buffering and shaping of glucose-induced electrical activity. The exchanger contributes to Ca2+ removal at [Ca2+]i above 1 microM, where it accounts for >35% of the total removal rate. At lower [Ca2+]i, thapsigargin-sensitive Ca2+-ATPases constitute a major (70% at 0.8 microM [Ca2+]i) mechanism for Ca2+ removal. The beta-cell Na/Ca exchanger is electrogenic and has a stoichiometry of three Na+ for one Ca2+. The current arising from its operation reverses at approximately -20 mV (current inward at more negative voltages), has a conductance of 53 pS/pF (14 microM [Ca2+]i), and is abolished by removal of external Na+ or by intracellularly applied XIP (exchange inhibitory peptide). Inhibition of the exchanger results in shortening (50%) of the bursts of action potentials of glucose-stimulated beta-cells in intact islets and a slight (5 mV) hyperpolarization. Mathematical simulations suggest that the stimulatory action of glucose on beta-cell electrical activity may be accounted for in part by glucose-induced reduction of the cytoplasmic Na+ concentration with resultant activation of the exchanger. PMID- 10096899 TI - Presynaptic strontium dynamics and synaptic transmission. AB - Strontium can replace calcium in triggering neurotransmitter release, although peak release is reduced and the duration of release is prolonged. Strontium has therefore become useful in probing release, but its mechanism of action is not well understood. Here we study the action of strontium at the granule cell to Purkinje cell synapse in mouse cerebellar slices. Presynaptic residual strontium levels were monitored with fluorescent indicators, which all responded to strontium (fura-2, calcium orange, fura-2FF, magnesium green, and mag-fura-5). When calcium was replaced by equimolar concentrations of strontium in the external bath, strontium and calcium both entered presynaptic terminals. Contaminating calcium was eliminated by including EGTA in the extracellular bath, or by loading parallel fibers with EGTA, enabling the actions of strontium to be studied in isolation. After a single stimulus, strontium reached higher peak free levels than did calcium (approximately 1.7 times greater), and decayed more slowly (half-decay time 189 ms for strontium and 32 ms for calcium). These differences in calcium and strontium dynamics are likely a consequence of greater strontium permeability through calcium channels, lower affinity of the endogenous buffer for strontium, and less efficient extrusion of strontium. Measurements of presynaptic divalent levels help to explain properties of release evoked by strontium. Parallel fiber synaptic currents triggered by strontium are smaller in amplitude and longer in duration than those triggered by calcium. In both calcium and strontium, release consists of two components, one more steeply dependent on divalent levels than the other. Strontium drives both components less effectively than does calcium, suggesting that the affinities of the sensors involved in both phases of release are lower for strontium than for calcium. Thus, the larger and slower strontium transients account for the prominent slow component of release triggered by strontium. PMID- 10096901 TI - Vesicle deformation by an axial load: from elongated shapes to tethered vesicles. AB - A sufficiently large force acting on a single point of the fluid membrane of a flaccid phospholipid vesicle is known to cause the formation of a narrow bilayer tube (tether). We analyze this phenomenon by means of general mathematical methods allowing us to determine the shapes of strongly deformed vesicles including their stability. Starting from a free vesicle with an axisymmetric, prolate equilibrium shape, we consider an axial load that pulls (or pushes) the poles of the vesicle apart. Arranging the resulting shapes of strained vesicles in dependence of the axial deformation and of the area difference of monolayers, phase diagrams of stable shapes are presented comprising prolate shapes with or without equatorial mirror symmetry. For realistic values of membrane parameters, we study the force-extension relation of strained vesicles, and we demonstrate in detail how the initially elongated shape of an axially stretched vesicle transforms into a shape involving a membrane tether. This tethering transition may be continuous or discontinuous. If the free vesicle is mirror symmetric, the mirror symmetry is broken as the tether forms. The stability analysis of tethered shapes reveals that, for the considered vesicles, the stable shape is always asymmetric (polar), i.e., it involves only a single tether on one side of the main vesicle body. Although a bilayer tube formed from a closed vesicle is not an ideal cylinder, we show that, for most practical purposes, it is safe to assume a cylindrical geometry of tethers. This analysis is supplemented by the documentation of a prototype experiment supporting our theoretical predictions. It shows that the currently accepted model for the description of lipid-bilayer elasticity (generalized bilayer couple model) properly accounts for the tethering phenomenon. PMID- 10096900 TI - Hydrodynamic properties of human erythrocyte band 3 solubilized in reduced Triton X-100. AB - The oligomeric state and function of band 3, purified by sulfhydryl affinity chromatography in reduced Triton X-100, was investigated. Size exclusion high performance liquid chromatography showed that a homogeneous population of band 3 dimers could be purified from whole erythrocyte membranes. The elution profile of band 3 purified from membranes that had been stripped of its cytoskeleton before solubilization was a broad single peak describing a heterogeneous population of oligomers with a mean Stokes radius of 100 A. Sedimentation velocity ultracentrifugation analysis confirmed particle heterogeneity and further showed monomer/dimer/tetramer equilibrium self-association. Whether the conversion of dimer to the form described by a Stokes radius of 100 A was initiated by removal of cytoskeletal components, alkali-induced changes in band 3 conformation, or alkali-induced loss of copurifying ligands remains unclear. After incubation at 20 degrees C for 24 h, both preparations of band 3 converted to a common form characterized by a mean Stokes radius of 114 A. This form of the protein, examined by equilibrium sedimentation ultracentrifugation, is able to self associate reversibly, and the self-association can be described by a dimer/tetramer/hexamer model, although the presence of higher oligomers cannot be discounted. The ability of the different forms of the protein to bind stilbene disulfonates revealed that the dimer had the highest inhibitor binding affinity, and the form characterized by a mean Stokes radius of 114 A to have the lowest. PMID- 10096902 TI - Control of lipid membrane stability by cholesterol content. AB - Cholesterol has a concentration-dependent effect on membrane organization. It is able to control the membrane permeability by inducing conformational ordering of the lipid chains. A systematic investigation of lipid bilayer permeability is described in the present work. It takes advantage of the transmembrane potential difference modulation induced in vesicles when an external electric field is applied. The magnitude of this modulation is under the control of the membrane electrical permeability. When brought to a critical value by the external field, the membrane potential difference induces a new membrane organization. The membrane is then permeable and prone to solubilized membrane protein back insertion. This is obtained for an external field strength, which depends on membrane native permeability. This approach was used to study the cholesterol effect on phosphatidylcholine bilayers. Studies have been performed with lipids in gel and in fluid states. When cholesterol is present, it does not affect electropermeabilization and electroinsertion in lipids in the fluid state. When lipids are in the gel state, cholesterol has a dose-dependent effect. When present at 6% (mol/mol), cholesterol prevents electropermeabilization and electroinsertion. When cholesterol is present at more than 12%, electropermeabilization and electroinsertion are obtained under milder field conditions. This is tentatively explained by a cholesterol-induced alteration of the hydrophobic barrier of the bilayer core. Our results indicate that lipid membrane permeability is affected by the cholesterol content. PMID- 10096903 TI - Dynamical properties of phospholipid bilayers from computer simulation. AB - We present the results of a 10-ns molecular dynamics simulation of a dipalmitoylphosphatidylcholine/water system. The main emphasis of the present study is on the investigation of the stability over a long time and the dynamic properties of the water/membrane system. The motion of the lipid molecules is characterized by the center of mass movement and the displacement of individual atom groups. Because of the slow movement of the headgroup atoms, their contributions to the dipole potential vary slowly and with a large amplitude. Nevertheless, the water molecules compensate the strong fluctuations and maintain an almost constant total dipole potential. From the lateral displacement of the center of masses, we calculate the lateral diffusion coefficient to be Dlat = (3 +/- 0.6) x 10(-7) cm2/s, in agreement with neutron scattering results. The rotational motion is also investigated in our simulations. The calculated value for the rotational diffusion coefficient parallel to the molecular long axis, D = (1.6 +/- 0.1) x 10(8) s-1, is in good agreement with the experiment. PMID- 10096904 TI - Membrane fusion promoters and inhibitors have contrasting effects on lipid bilayer structure and undulations. AB - It has been established that the fusion of both biological membranes and phospholipid bilayers can be modulated by altering their lipid composition (Chernomordik et al., 1995 .J. Membr. Biol. 146:3). In particular, when added exogenously between apposing membranes, monomyristoylphosphatidylcholine (MMPC) inhibits membrane fusion, whereas glycerol monoleate (GMO), oleic acid (OA), and arachidonic acid (AA) promote fusion. This present study uses x-ray diffraction to investigate the effects of MMPC, GMO, OA, and AA on the bending and stability of lipid bilayers when bilayers are forced together with applied osmotic pressure. The addition of 10 and 30 mol% MMPC to egg phosphatidylcholine (EPC) bilayers maintains the bilayer structure, even when the interbilayer fluid spacing is reduced to approximately 3 A, and increases the repulsive pressure between bilayers so that the fluid spacing in excess water increases by 5 and 15 A, respectively. Thus MMPC increases the undulation pressure, implying that the addition of MMPC promotes out-of-plane bending and decreases the adhesion energy between bilayers. In contrast, the addition of GMO has minor effects on the undulation pressure; 10 and 50 mol% GMO increase the fluid spacing of EPC in excess water by 0 and 2 A, respectively. However, x-ray diffraction indicates that, at small interbilayer separations, GMO, OA, or AA converts the bilayer to a structure containing hexagonally packed scattering units approximately 50 A in diameter. Thus GMO, OA, or AA destabilizes bilayer structure as apposing bilayers are brought into contact, which could contribute to their role in promoting membrane fusion. PMID- 10096905 TI - Monte Carlo simulation of two-component bilayers: DMPC/DSPC mixtures. AB - In this paper, we describe a relatively simple lattice model of a two-component, two-state phospholipid bilayer. Application of Monte Carlo methods to this model permits simulation of the observed excess heat capacity versus temperature curves of dimyristoylphosphatidylcholine (DMPC)/distearoylphosphatidylcholine (DSPC) mixtures as well as the lateral distributions of the components and properties related to these distributions. The analysis of the bilayer energy distribution functions reveals that the gel-fluid transition is a continuous transition for DMPC, DSPC, and all DMPC/DSPC mixtures. A comparison of the thermodynamic properties of DMPC/DSPC mixtures with the configurational properties shows that the temperatures characteristics of the configurational properties correlate well with the maxima in the excess heat capacity curves rather than with the onset and completion temperatures of the gel-fluid transition. In the gel-fluid coexistence region, we also found excellent agreement between the threshold temperatures at different system compositions detected in fluorescence recovery after photobleaching experiments and the temperatures at which the percolation probability of the gel clusters is 0.36. At every composition, the calculated mole fraction of gel state molecules at the fluorescence recovery after photobleaching threshold is 0.34 and, at the percolation threshold of gel clusters, it is 0.24. The percolation threshold mole fraction of gel or fluid lipid depends on the packing geometry of the molecules and the interchain interactions. However, it is independent of temperature, system composition, and state of the percolating cluster. PMID- 10096906 TI - Evidence for the extended phospholipid conformation in membrane fusion and hemifusion. AB - Molecular-level mechanisms of fusion and hemifusion of large unilamellar dioleoyl phosphatidic acid/phosphocholine (DOPA/DOPC, 1:1 molar ratio) vesicles induced by millimolar Ca2+ and Mg2+, respectively, were investigated using fluorescence spectroscopy. In keeping with reduction of membrane free volume Vf, both divalent cations increased the emission polarization for 1,6-diphenyl-1,3, 5-hexatriene (DPH). An important finding was a decrease in excimer/monomer emission intensity ratio (Ie/Im) for the intramolecular excimer-forming probe 1, 2-bis[(pyren-1 )yl]decanoyl-sn-glycero-3-phosphocholine (bis-PDPC) in the course of fusion and hemifusion. Comparison with another intramolecular excimer-forming probe, namely, 1-[(pyren-1)-yl]decanoyl-2-[(pyren-1)-yl]tetradecanoyl-sn-gl ycero-3-p hosphocholine (PDPTPC), allowed us to exclude changes in acyl chain alignment to be causing the decrement in Ie/Im. As a decrease in Vf should increase Ie/Im for bis-PDPC and because contact site between adhering liposomes was required we conclude the most feasible explanation to be the adoption of the extended conformation (P.K.J., Chem. Phys. Lipids 63:251-258) by bis-PDPC. In this conformation the two acyl chains are splaying so as to become embedded in the opposing leaflets of the two adhered bilayers, with the headgroup remaining between the adjacent surfaces. Our data provide evidence for a novel mechanism of fusion of the lipid bilayers. PMID- 10096907 TI - Orientation of the pore-forming peptide GALA in POPC vesicles determined by a BODIPY-avidin/biotin binding assay. AB - We determined the orientation of a biotinylated version of the pore-forming peptide GALA (WEAALAEALAEALAEHLAEALAEALEALAA) at pH 5.0 in large unilamellar phosphatidylcholine vesicles, using the enhancement of BODIPY-avidin fluorescence subsequent to its irreversible binding to a biotin moiety. GALA and its variants were biotinylated at the N- or C-terminus. BODIPY-avidin was either added externally or was pre-encapsulated in vesicles to assess the fraction of liposome bound biotinylated GALA that exposed its labeled terminus to the external or internal side of the bilayer, respectively. Under conditions where most of the membrane-bound peptides were involved in transmembrane aggregates and formed aqueous pores (at a lipid/bound peptide molar ratio of 2500/1), the head-to-tail (N- to C-terminus) orientation of the membrane-inserted peptides was such that 3/4 of the peptides exposed their N-terminus on the inside of the vesicle and their C-terminus on the outside. Under conditions resulting in reduced pore formation (at higher lipid/peptide molar ratios), we observed an increase in the fraction of GALA termini exposed to the outside of the vesicle. These results are consistent with a model (Parente et al., Biochemistry, 29:8720, 1990) that requires a critical number of peptides (M) in an aggregate to form a transbilayer structure. When the peptides form an aggregate of size i, with i < M = 4 to 6, the orientation of the peptides is mostly parallel to the membrane surface, such that both termini of the biotinylated peptide are exposed to external BODIPY avidin. This BODIPY-avidin/biotin binding assay should be useful to determine the orientation of other membrane-interacting molecules. PMID- 10096908 TI - A microscopic interaction model of maximum solubility of cholesterol in lipid bilayers. AB - We recently reported the equilibrium maximum solubility of cholesterol in a lipid bilayer, chi*chol, to be 0.66 in four different phosphatidylcholines, and 0.51 in a phosphatidylethanolamine (Huang, J.,J.T. Buboltz, and G. W. Feigenson. 1999. Biochim. Biophys. Acta. in press). Here we present a model of cholesterol phospholipid mixing that explains these observed values of chi*chol. Monte Carlo simulations show that pairwise-additivity of nearest-neighbor interactions is inadequate to describe all the chi*chol values. Instead, if cholesterol multibody interactions are assigned highly unfavorable energy, then jumps occur in cholesterol chemical potential that lead to its precipitation from the bilayer. Cholesterol precipitation is most likely to occur near three discrete values of cholesterol mole fraction, 0.50, 0.57, and 0.67, which correspond to cholesterol/phospholipid mole ratios of 1/1, 4/3, and 2/1, respectively. At these solubility limits, where cholesterol chemical potential jumps, the cholesterol phospholipid bilayer mixture forms highly regular lipid distributions in order to minimize cholesterol-cholesterol contacts. This treatment shows that dramatic structural and thermodynamic changes can occur at particular cholesterol mole fractions without any stoichiometric complex formation. The physical origin of the unfavorable cholesterol multibody interaction is explained by an "umbrella model": in a bilayer, nonpolar cholesterol relies on polar phospholipid headgroup coverage to avoid the unfavorable free energy of cholesterol contact with water. Thus, at high cholesterol mole fraction, this unfavorable free energy, not any favorable cholesterol-phospholipid interaction, dominates the mixing behavior. This physical origin also explains the "cholesterol condensing effect" and the increase in acyl chain order parameter in cholesterol-phospholipid mixtures. PMID- 10096909 TI - Time courses of mammalian cell electropermeabilization observed by millisecond imaging of membrane property changes during the pulse. AB - Time courses of electropermeabilization were analyzed during the electric field application using a rapid fluorescent imaging system. Exchanges of calcium ions through electropermeabilized membrane of Chinese hamster ovary cells were found to be asymmetrical. Entry of calcium ions during a millisecond pulse occurred on the anode-facing cell hemisphere. Entry through the region facing the cathode was observed only after the pulse. Leakage of intracellular calcium ions from electropermeabilized cell in low-calcium content medium was observed only from the anode-facing side. The exchanges during the pulse were mostly due to diffusion-driven processes, i.e., governed by the concentration gradient. Interaction of propidium iodide, a dye sensitive to the structural alteration of membrane, with cell membrane was asymmetrical during electropermeabilization. Localized enhancement of the dye fluorescence was observed during and after the pulsation on the cell surface. Specific staining of a limited anode-facing part of the membrane was observed as soon as the pulse was applied. The membrane fluorescence level increased during and immediately after the pulse whereas the geometry of the staining was unchanged. The membrane regions stained by propidium iodide were the same as those where calcium exchanges occurred. The fraction of the membrane on which structural alterations occurred was defined by the field strength. The density of defects was governed by the pulse duration. Electropermeabilization is a localized but asymmetrical process. The membrane defects are created unequally on the two cell sides during the pulse, implying a vectorial effect of the electric field on the membrane. PMID- 10096910 TI - Role of Ca2+ and cross-bridges in skeletal muscle thin filament activation probed with Ca2+ sensitizers. AB - Thin filament regulation of contraction is thought to involve the binding of two activating ligands: Ca2+ and strongly bound cross-bridges. The specific cross bridge states required to promote thin filament activation have not been identified. This study examines the relationship between cross-bridge cycling and thin filament activation by comparing the results of kinetic experiments using the Ca2+ sensitizers caffeine and bepridil. In single skinned rat soleus fibers, 30 mM caffeine produced a leftward shift in the tension-pCa relation from 6.03 +/ 0.03 to 6.51 +/- 0.03 pCa units and lowered the maximum tension to 0.60 +/- 0.01 of the control tension. In addition, the rate of tension redevelopment (ktr) was decreased from 3.51 +/- 0.12 s-1 to 2.70 +/- 0.19 s-1, and Vmax decreased from 1.24 +/- 0.07 to 0.64 +/- 0.02 M.L./s. Bepridil produced a similar shift in the tension-pCa curves but had no effect on the kinetics. Thus bepridil increases the Ca2+ sensitivity through direct effects on TnC, whereas caffeine has significant effects on the cross-bridge interaction. Interestingly, caffeine also produced a significant increase in stiffness under relaxing conditions (pCa 9.0), indicating that caffeine induces some strongly bound cross-bridges, even in the absence of Ca2+. The results are interpreted in terms of a model integrating cross-bridge cycling with a three-state thin-filament activation model. Significantly, strongly bound, non-tension-producing cross-bridges were essential to modeling of complete activation of the thin filament. PMID- 10096911 TI - Structural analysis of DNA-chlorophyll complexes by Fourier transform infrared difference spectroscopy. AB - Porphyrins and metalloporphyrins are strong DNA binders. Some of these compounds have been used for radiation sensitization therapy of cancer and are targeted to interact with cellular DNA. This study was designed to examine the interaction of calf thymus DNA with chlorophyll a (CHL) in aqueous solution at physiological pH with CHL/DNA(phosphate) ratios (r) of 1/160, 1/80, 1/40, 1/20, 1/10, and 1/5. Fourier transform infrared (FTIR) difference spectroscopy was used to characterize the nature of DNA-pigment interactions and to establish correlations between spectral changes and the CHL binding mode, binding constant, sequence selectivity, DNA secondary structure, and structural variations of DNA-CHL complexes in aqueous solution. Spectroscopic results showed that CHL is an external DNA binder with no affinity for DNA intercalation. At low pigment concentration (r = 1/160, 1/80, and 1/40), there are two major binding sites for CHL on DNA duplex: 1) Mg-PO2 and 2) Mg-N7 (guanine) with an overall binding constant of K = 1.13 x 10(4) M-1. The pigment distributions are 60% with the backbone PO2 group and 20% with the G-C base pairs. The chlorophyll interaction is associated with a major reduction of B-DNA structure in favor of A-DNA. At high chlorophyll content (r = 1/10), helix opening occurs, with major spectral alterations of the G-C and A-T bases. At high chlorophyll concentration (1/5), pigment aggregation is observed, which does not favor CHL-DNA complexation. PMID- 10096912 TI - Time-resolved absorption and photothermal measurements with sensory rhodopsin I from Halobacterium salinarum. AB - An expansion accompanying the formation of the first intermediate in the photocycle of transducer-free sensory rhodopsin I (SRI) was determined by means of time-resolved laser-induced optoacoustic spectroscopy. For the native protein (SRI-WT), the absolute value of the expansion is approximately 5.5 mL and for the mutant SRI-D76N, approximately 1.5 mL per mol of phototransformed species (in 0.5 M NaCl), calculated by using the formation quantum yield for the first intermediate (S610) of Phi610 = 0.4 +/- 0.05 for SRI-WT and 0.5 +/- 0.05 for SRI D76N, measured by laser-induced optoacoustic spectroscopy and by laser flash photolysis. The similarity in Phi610 and in the determined value of the energy level of S610, E610 = (142 +/- 12) kJ/mol for SRI-WT and SRI-D76N indicates that Asp76 is not directly involved in the first step of the phototransformation. The increase with pH of the magnitude of the structural volume change for the formation of S610 in SRI-WT and in SRI-D76N upon excitation with 580 nm indicates also that amino acids other than Asp76, and other than those related to the Schiff base, are involved in the process. The difference in structural volume changes as well as differences in the activation parameters for the S610 decay should be attributed to differences in the rigidity of the cavity surrounding the chromophore. Except for the decay of the first intermediate, which is faster than in the SRI-transducer complex, the rate constants of the photocycle for transducer-free SRI in detergent suspension are strongly retarded with respect to wild-type membranes (this comparison should be done with great care because the preparation of both samples is very different). PMID- 10096913 TI - Reversibility and hierarchy of thermal transition of hen egg-white lysozyme studied by small-angle x-ray scattering. AB - To clarify mechanisms of folding and unfolding of proteins, many studies of thermal denaturation of proteins have been carried out at low protein concentrations because in many cases thermal denaturation accompanies a great tendency of aggregation. As small-angle x-ray scattering (SAXS) measurements are liable to use low-concentration solutions of proteins to avoid aggregation, SAXS has been regarded as very difficult to observe detailed features of thermal structural transitions such as intramolecular structural changes. By using synchrotron radiation SAXS, we have found that the presence of repulsive interparticle interaction between proteins can maintain solute particles separately to prevent further aggregation in thermal denaturation processes and that under such conditions the thermal structural transition of hen egg-white lysozyme (HEWL) holds high reversibility even at 5% w/v HEWL below pH approximately 5. Because of the use of the high concentration of the solutions, the scattering data has enough high-statistical accuracy to discuss the thermal structural transition depending on the structural hierarchy. Thus, the tertiary structural change of HEWL starts from mostly the onset temperature determined by the differential scanning calorimetry measurement, which accompanies a large heat absorption, whereas the intramolecular structural change, corresponding to the interdomain correlation and polypeptide chain arrangement, starts much prior to the above main transition. The present finding of the reversible thermal structural transitions at the high protein concentration is expected to enable us to analyze multiplicity of folding and unfolding processes of proteins in thermal structural transitions. PMID- 10096914 TI - Ligand-dependent conformational equilibria of serum albumin revealed by tryptophan fluorescence quenching. AB - Ligand-dependent structural changes in serum albumin are suggested to underlie its role in physiological solute transport and receptor-mediated cellular selection. Evidence of ligand-induced (oleic acid) structural changes in serum albumin are shown in both time-resolved and steady-state fluorescence quenching and anisotropy measurements of tryptophan 214 (Trp214). These studies were augmented with column chromatography separations. It was found that both the steady-state and time-resolved Stern-Volmer collisional quenching studies of Trp214 with acrylamide pointed to the existence of an oleate-dependent structural transformation. The bimolecular quenching rate constant of defatted human serum albumin, 1.96 x 10(9) M-1 s-1, decreased to 0.94 x 10(9) M-1 s-1 after incubation with oleic acid (9:1). Furthermore, Stern-Volmer quenching studies following fractionation of the structural forms by hydrophobic interaction chromatography were in accordance with this interpretation. Time-resolved fluorescence anisotropy measurements of the Trp214 residue yielded information of motion within the protein together with the whole protein molecule. Characteristic changes in these motions were observed after the binding of oleate to albumin. The addition of oleate was accompanied by an increase in the rotational diffusion time of the albumin molecule from approximately 22 to 33.6 ns. Within the body of the protein, however, the rotational diffusion time for Trp214 exhibited a slight decrease from 191 to 182 ps and was accompanied by a decrease in the extent of the angular motion of Trp214, indicating a transition after oleate binding to a more spatially restricted but less viscous environment. PMID- 10096915 TI - Thiol oxidation of actin produces dimers that enhance the elasticity of the F actin network. AB - Slow oxidation of sulfhydryls, forming covalently linked actin dimers and higher oligomers, accounts for increases in the shear elasticity of purified actin observed after aging. Disulfide-bonded actin dimers are incorporated into F-actin during polymerization and generate cross-links between actin filaments. The large gel strength of oxidized actin (>100 Pa for 1 mg/ml) in the absence of cross linking proteins falls to within the theoretically predicted order of magnitude for uncross-linked actin filament networks (1 Pa) with the addition of sufficient concentrations of reducing agents such as 5 mM dithiothreitol or 10 mM beta mercaptoethanol. As little as 1 gelsolin/1000 actin subunits also lowers the high storage modulus of oxidized actin. The effects of gelsolin may be both to increase filament number as it severs F-actin and to cover the barbed end of an actin filament, which otherwise might cross-link to the side of another filament via an actin dimer. These new findings may explain why previous studies of actin rheology report a wide range of values when purified actin is polymerized without added regulatory proteins. PMID- 10096916 TI - Sickle hemoglobin polymer melting in high concentration phosphate buffer. AB - Sickle cell hemoglobin (HbS) prepared in argon-saturated 1.8 M phosphate buffer was rapidly mixed with carbon monoxide (CO)-saturated buffer. The binding of CO to the sickle hemoglobin and the simultaneous melting of the hemoglobin polymers were monitored by transmission spectroscopy (optical absorption and turbidity). Changes in the absorption profile were interpreted as resulting from CO binding to deoxy-HbS while reduced scattering (turbidity) was attributed to melting (depolymerization) of the HbS polymer phase. Analysis of the data provides insight into the mechanism and kinetics of sickle hemoglobin polymer melting. Conversion of normal deoxygenated, adult hemoglobin (HbA) in high concentration phosphate buffer to the HbA-CO adduct was characterized by an average rate of 83 s-1. Under the same conditions, conversion of deoxy-HbS in the polymer phase to the HbS-CO adduct in the solution phase is characterized by an average rate of 5.8 s-1 via an intermediate species that grows in with a 36 s-1 rate. Spectral analysis of the intermediate species suggests that a significant amount of CO may bind to the polymer phase before the polymer melts. PMID- 10096917 TI - Type 2 Cu2+ in pMMO from Methylomicrobium album BG8. AB - EPR spectra were obtained for the type 2 Cu2+ site in particulate methane monooxygenase (pMMO) from Methylomicrobium album BG8 grown on K15NO3 and 63Cu(NO3)2. The concentration of the type 2 Cu2+ signal was approximately 200 microM per 25 mg/ml protein in packed cells and membrane fractions, a concentration that is consistent with its attribution to pMMO, and the EPR parameters were consistent with electron paramagnetic resonance (EPR) parameters previously assigned to pMMO. The superhyperfine structure due to nitrogen is better resolved because I = 1/2 for 15N whereas I = 1 for 14N and A(15N)/A(14N) = 1.4. Under these conditions, superhyperfine structure is resolved in the g region of the X-band spectrum. At low microwave frequency (S-band) the resolution of the nitrogen superhyperfine structure improves. Signals are attributed to type 2 Cu2+ in which cupric ion is bound to four (less likely three) nitrogen donor atoms. PMID- 10096918 TI - Toward objective selection of representative microscope images. AB - Scientists wishing to communicate the essential characteristics of a pattern (such as an immunofluorescence distribution) currently must make a subjective choice of one or two images to publish. We therefore developed methods for objectively choosing a typical image from a set, with emphasis on images from cell biology. The methods involve calculation of numerical features to describe each image, calculation of similarity between images as a distance in feature space, and ranking of images by distance from the center of the feature distribution. Two types of features were explored, image texture measures and Zernike polynomial moments, and various distance measures were utilized. Criteria for evaluating methods for assigning typicality were proposed and applied to sets of images containing more than one pattern. The results indicate the importance of using distance measures that are insensitive to the presence of outliers. For collections of images of the distributions of a lysosomal protein, a Golgi protein, and nuclear DNA, the images chosen as most typical were in good agreement with the conventional understanding of organelle morphologies. The methods described here have been implemented in a web server (http://murphylab.web.cmu.edu/services/TyplC). PMID- 10096919 TI - Quenching of chlorophyll fluorescence by triplets in solubilized light-harvesting complex II (LHCII). AB - The quenching of chlorophyll fluorescence by triplets in solubilized trimeric light harvesting complexes was analyzed by comparative pump-probe experiments that monitor with weak 2-ns probe pulses the fluorescence yield and changes of optical density, DeltaOD, induced by 2-ns pump pulses. By using a special array for the measurement of the probe fluorescence (Schodel R., F. Hillman, T. Schrotter, K.-D. Irrgang, J. Voight, and G. Biophys. J. 71:3370-3380) the emission caused by the pump pulses could be drastically reduced so that even at highest pump pulse intensities, IP, no significant interference with the signal due to the probe pulse was observed. The data obtained reveal: a) at a fixed time delay of 50 ns between pump and probe pulse the fluorescence yield of the latter drastically decreased with increasing IP, b) the recovery of the fluorescence yield in the microseconds time domain exhibits kinetics which are dependent on IP, c) DeltaOD at 507 nm induced by the pump pulse and monitored by the probe pulse with a delay of 50 ns (reflecting carotenoid triplets) increases with IP without reaching a saturation level at highest IP values, d) an analogous feature is observed for the bleaching at 675 nm but it becomes significant only at very high IP values, e) the relaxation of DeltaOD at 507 nm occurs via a monophasic kinetics at all IP values whereas DeltaOD at 675 nm measured under the same conditions is characterized by a biphasic kinetics with tau values of about 1 microseconds and 7-9 microseconds. The latter corresponds with the monoexponential decay kinetics of DeltaOD at 507 nm. Based on a Stern-Volmer plot, the time-dependent fluorescence quenching is compared with the relaxation kinetics of triplets. It is shown that the fluorescence data can be consistently described by a quenching due to triplets. PMID- 10096920 TI - Solution x-ray scattering-based estimation of electron cryomicroscopy imaging parameters for reconstruction of virus particles. AB - Structure factor amplitudes and phases can be computed directly from electron cryomicroscopy images. Inherent aberrations of the electromagnetic lenses and other instrumental factors affect the structure factors, however, resulting in decreased accuracy in the determined three-dimensional reconstruction. In contrast, solution x-ray scattering provides absolute and accurate measurement of spherically averaged structure factor amplitudes of particles in solution but does not provide information on the phases. In the present study, we explore the merits of using solution x-ray scattering data to estimate the imaging parameters necessary to make corrections to the structure factor amplitudes derived from electron cryomicroscopic images of icosahedral virus particles. Using 400-kV spot scan images of the bacteriophage P22 procapsid, we have calculated an amplitude contrast of 8.0 +/- 5.2%. The amplitude decay parameter has been estimated to be 523 +/- 188 A2 with image noise compensation and 44 +/- 66 A2 without it. These results can also be used to estimate the minimum number of virus particles needed for reconstruction at different resolutions. PMID- 10096921 TI - Tracking single secretory granules in live chromaffin cells by evanescent-field fluorescence microscopy. AB - We have observed secretory granules beneath the plasma membrane of chromaffin cells. Using evanescent-field excitation by epiillumination, we have illuminated a thin layer of cytosol where cells adhere to glass coverslips. Up to 600 frames could be recorded at diffraction-limited resolution without appreciable photodynamic damage. We localized single granules with an uncertainty of approximately 30 nm and tracked their motion in three dimensions. Granules in resting cells wander randomly as if imprisoned in a cage that leaves approximately 70 nm space around a granule. The "cage" itself moves only slowly (D = 2 x 10(-12) cm2/s). Rarely do granules arrive at or depart from the plasma membrane of resting cells. Stimulation increases lateral motion only slightly. After the plasma membrane has been depleted of granules by exocytosis, fresh granules can be seen to approach it at an angle. The method will be useful for exploring the molecular steps preceding exocytosis at the level of single granules. PMID- 10096923 TI - Direct sedimentation analysis of interference optical data in analytical ultracentrifugation. AB - Sedimentation data acquired with the interference optical scanning system of the Optima XL-I analytical ultracentrifuge can exhibit time-invariant noise components, as well as small radial-invariant baseline offsets, both superimposed onto the radial fringe shift data resulting from the macromolecular solute distribution. A well-established method for the interpretation of such ultracentrifugation data is based on the analysis of time-differences of the measured fringe profiles, such as employed in the g(s*) method. We demonstrate how the technique of separation of linear and nonlinear parameters can be used in the modeling of interference data by unraveling the time-invariant and radial invariant noise components. This allows the direct application of the recently developed approximate analytical and numerical solutions of the Lamm equation to the analysis of interference optical fringe profiles. The presented method is statistically advantageous since it does not require the differentiation of the data and the model functions. The method is demonstrated on experimental data and compared with the results of a g(s*) analysis. It is also demonstrated that the calculation of time-invariant noise components can be useful in the analysis of absorbance optical data. They can be extracted from data acquired during the approach to equilibrium, and can be used to increase the reliability of the results obtained from a sedimentation equilibrium analysis. PMID- 10096922 TI - High-speed, random-access fluorescence microscopy: II. Fast quantitative measurements with voltage-sensitive dyes. AB - An improved method for making fast quantitative determinations of membrane potential with voltage-sensitive dyes is presented. This method incorporates a high-speed, random-access, laser-scanning scheme (Bullen et al., 1997. Biophys. J. 73:477-491) with simultaneous detection at two emission wavelengths. The basis of this ratiometric approach is the voltage-dependent shift in the emission spectrum of the voltage-sensitive dye di-8-butyl-amino-naphthyl-ethylene pyridinium-propyl-sulfonate (di-8-ANEPPS). Optical measurements are made at two emission wavelengths, using secondary dichroic beamsplitting and dual photodetectors (<570 nm and >570 nm). Calibration of the ratiometric measurements between signals at these wavelengths was achieved using simultaneous optical and patch-clamp measurements from adjacent points. Data demonstrating the linearity, precision, and accuracy of this technique are presented. Records obtained with this method exhibited a voltage resolution of approximately 5 mV, without any need for temporal or spatial averaging. Ratiometric recordings of action potentials from isolated hippocampal neurons are used to illustrate the usefulness of this approach. This method is unique in that it is the first to allow quantitative determination of dynamic membrane potential changes in a manner optimized for both high spatiotemporal resolution (2 micrometers and <0.5 ms) and voltage discrimination. PMID- 10096924 TI - ATP can stimulate exocytosis in rat brown adipocytes without apparent increases in cytosolic Ca2+ or G protein activation. AB - Extracellular ATP activates large increases in cell surface area and membrane turnover in rat brown adipocytes (Pappone, P. A., and Lee, S. C. 1996. J. Gen. Physiol. 108:393-404). We used whole-cell patch clamp membrane capacitance measurements of membrane surface area concurrently with fura-2 ratio imaging of intracellular calcium to test whether these purinergic membrane responses are triggered by cytosolic calcium increases or G protein activation. Increasing cytosolic calcium with adrenergic stimulation, calcium ionophore, or calcium containing pipette solutions did not cause exocytosis. Extracellular ATP increased membrane capacitance in the absence of extracellular calcium with internal calcium strongly buffered to near resting levels. Purinergic stimulation still activated exocytosis and endocytosis in the complete absence of intracellular and extracellular free calcium, but endocytosis predominated. Modulators of G protein function neither triggered nor inhibited the initial ATP elicited capacitance changes, but GTPgammaS or cytosolic nucleotide depletion did reduce the cells' capacity to mount multiple purinergic responses. These results suggest that calcium modulates purinergically-stimulated membrane trafficking in brown adipocytes, but that ATP responses are initiated by some other signal that remains to be identified. PMID- 10096925 TI - Stresses at the cell-to-substrate interface during locomotion of fibroblasts. AB - Recent technological improvements in the elastic substrate method make it possible to produce spatially resolved measurements of the tractions exerted by single motile cells. In this study we have applied these developments to produce maps of the tractions exerted by 3T3 fibroblasts during steady locomotion. The resulting images have a spatial resolution of approximately 5 micrometers and a maximum intensity of approximately 10(2) kdyn/cm2 (10(4) pN/micrometers2). We find that the propulsive thrust for fibroblast locomotion, approximately 0.2 dyn, is imparted to the substratum within 15 micrometers of the leading edge. These observations demonstrate that the lamellipodium of the fibroblast is able to generate intense traction stress. The cell body and posterior seem to be mechanically passive structures pulled forward entirely by this action. PMID- 10096926 TI - A revival of Paul Dudley White: An overview of present medical practice and of our society. PMID- 10096927 TI - Antibiotic treatment trials for secondary prevention of coronary artery disease events. PMID- 10096928 TI - Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. AB - BACKGROUND: Chlamydia pneumoniae commonly causes respiratory infection, is vasotropic, causes atherosclerosis in animal models, and has been found in human atheromas. Whether it plays a causal role in clinical coronary artery disease (CAD) and is amenable to antibiotic therapy is uncertain. METHODS AND RESULTS: CAD patients (n=302) who had a seropositive reaction to C pneumoniae (IgG titers >/=1:16) were randomized to receive placebo or azithromycin, 500 mg/d for 3 days, then 500 mg/wk for 3 months. Circulating markers of inflammation (C-reactive protein [CRP], interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-alpha), C pneumoniae antibody titers, and cardiovascular events were assessed at 3 and 6 months. Treatment groups were balanced, with age averaging 64 (SD=10) years; 89% of the patients were male. Azithromycin reduced a global rank sum score of the 4 inflammatory markers at 6 (but not 3) months (P=0. 011) as well as the mean global rank sum change score: 531 (SD=201) for active drug and 587 (SD=190) for placebo (P=0.027). Specifically, change-score ranks were significantly lower for CRP (P=0.011) and IL-6 (P=0.043). Antibody titers were unchanged, and number of clinical cardiovascular events at 6 months did not differ by therapy (9 for active drug, 7 for placebo). Azithromycin decreased infections requiring antibiotics (1 versus 12 at 3 months, P=0.002) but caused more mild, primarily gastrointestinal, adverse effects (36 versus 17, P=0.003). CONCLUSIONS: In CAD patients positive for C pneumoniae antibodies, global tests of 4 markers of inflammation improved at 6 months with azithromycin. However, unlike another smaller study, no differences in antibody titers and clinical events were observed. Longer-term and larger studies of antichlamydial therapy are indicated. PMID- 10096929 TI - Clinical and angiographic follow-Up after primary stenting in acute myocardial infarction: the Primary Angioplasty in Myocardial Infarction (PAMI) stent pilot trial. AB - BACKGROUND: Restenosis has been reported in as many as 50% of patients within 6 months after PTCA in acute myocardial infarction (AMI), which necessitates repeat target-vessel revascularization (TVR) in approximately 20% of patients during this time period. Routine (primary) stent implantation after PTCA has the potential to further improve late outcomes. METHODS AND RESULTS: Primary stenting was performed as part of a prospective study in 236 consecutive patients without contraindications who presented with AMI of <12 hours' duration at 9 international centers. A mean of 1.4+/-0.7 stents were implanted per patient (97% Palmaz-Schatz) at 17.3+/-2.4 atm. During a clinical follow-up period of 7.4+/-2.6 months, death occurred in 4 patients (1.7%), reinfarction occurred in 5 patients (2.1%), and TVR was required in 26 patients (11.1%). By Cox regression analysis, small reference-vessel diameter and the number of stents implanted were the strongest determinants of TVR. Angiographic restenosis occurred in 27.5% of lesions. By multiple logistic regression analysis, the number of stents implanted and the absence of thrombus on the baseline angiogram were independent determinants of binary restenosis. CONCLUSIONS: A strategy of routine stent implantation during mechanical reperfusion of AMI is safe and is associated with favorable event-free survival and low rates of restenosis compared with primary PTCA alone. PMID- 10096930 TI - Treatment of Helicobacter pylori and Chlamydia pneumoniae infections decreases fibrinogen plasma level in patients with ischemic heart disease. AB - BACKGROUND: Chronic Chlamydia pneumoniae and Helicobacter pylori infections could be a risk factor for ischemic heart disease (IHD), possibly by increasing fibrinogen levels. The aim of our study was to evaluate changes in fibrinogen level in patients with IHD and H pylori and/or C pneumoniae positivity randomly assigned to antibiotic treatment. METHODS AND RESULTS: Eighty-four patients with chronic IHD, H pylori and/or C pneumoniae antibodies, and normal acute-phase reactants were randomly assigned to treatment or no treatment. Treatment consisted of omeprazole, clarithromycin, and tinidazole in H pylori-positive patients and clarithromycin alone in C pneumoniae-positive patients. The effect of treatment and other baseline variables on fibrinogen levels, determined at 6 months, was evaluated by multivariate analysis. Treatment significantly reduced fibrinogen level at 6 months in the overall study population and in the groups of patients divided according to H pylori or C pneumoniae positivity. In the 43 treated patients, mean (+/-SD) basal fibrinogen was 3.65+/-0.58 g/L, and mean final fibrinogen was 3. 09+/-0.52 g/dL (P<0.001), whereas in the 41 untreated patients, mean basal and final fibrinogen levels were 3.45+/-0.70 and 3.61+/-0.71 g/L, respectively. The largest decrease was observed in patients with both infections. Fibrinogen changes were also significantly and negatively correlated with age. CONCLUSIONS: Our data suggest that a short, safe, and effective course of antibiotic therapy might be suggested as a means of interacting with an "emerging" risk factor. PMID- 10096931 TI - Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis. AB - BACKGROUND: Growing evidence suggests that an immunological reaction against heat shock proteins (HSPs) may be involved in atherogenesis. Because HSPs show a high degree of amino acid sequence homology between different species, from prokaryotes to humans, we investigated the possibility of "antigenic mimicry" caused by an immunological cross-reaction between microorganisms and autoantigens. METHODS AND RESULTS: Serum antibodies against the Escherichia coli HSP (GroEL) and the 60-kDa chlamydial HSP (cHSP60) from subjects with atherosclerosis were purified by use of affinity chromatography. Western blot analyses and competitive ELISAs confirmed the cross-reaction of the eluted antibodies with human HSP60 and the bacterial counterparts. The cytotoxicity of anti-GroEL and anti-cHSP60 antibodies was determined on human endothelial cells labeled with 51Cr. A significant difference (40% versus 8%) was observed in the specific 51Cr release of heat-treated (42 degrees C for 30 minutes) and untreated cells, respectively, in the presence of these anti-HSP antibodies and complement. This effect was blocked by addition of 100 microg/mL recombinant GroEL. In addition, seropositivity against specific non-HSP60 Chlamydia pneumoniae antigens is more prominent among high-anti-HSP titer sera than low-titer sera. CONCLUSIONS: Serum antibodies against HSP65/60 cross-react with human HSP60, cHSP60, and GroEL; correlate with the presence of antibodies to C pneumoniae and endotoxin; and mediate endothelial cytotoxicity. These findings suggest that humoral immune reactions to bacterial HSPs, such as cHSP60 and GroEL, may play an important role in the process of vascular endothelial injury, which is believed to be a key event in the pathogenesis of atherosclerosis. PMID- 10096932 TI - Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. AB - BACKGROUND: Ventricular pacing can improve hemodynamics in heart failure patients, but direct effects on left ventricular (LV) function from varying pacing site and atrioventricular (AV) delay remain unknown. We hypothesized that the magnitude and location of basal intraventricular conduction delay critically influences pacing responses and that single-site pacing in the delay-activated region yields similar or better responses to biventricular pacing. METHODS AND RESULTS: Aortic and LV pressures were measured in 18 heart failure patients (mean+/-SD: LV ejection fraction, 19+/-7%; LV end-diastolic pressure, 25+/-8 mm Hg; QRS duration, 157+/-36 ms). Data under normal sinus rhythm were compared with ventricular pacing (VDD) at varying sites and AV delays (randomized order). Right ventricular (RV) apical or midseptal pacing had negligible contractile/systolic effects. However, LV free-wall pacing raised dP/dtmax by 23.7+/-19.0% and pulse pressure by 18.0+/-18.4% (P<0.01). Biventricular pacing yielded less change (+12.8+/-9.3% in dP/dtmax, P<0.05 versus LV). Pressure-volume analysis performed in 11 patients consistently revealed minimal changes with RV pacing but increased stroke work and lower end-systolic volumes with LV pacing. Optimal AV intervals averaged 125+/-49 ms, and within this range, AV delay had less influence on LV function than pacing site. Basal QRS duration positively correlated with %DeltadP/dtmax (P<0.005), but pacing efficacy was not associated with QRS narrowing. Conduction delay pattern generally predicted pacing sites with most effect. CONCLUSIONS: VDD pacing acutely enhances contractile function in heart failure patients with intraventricular conduction delay. Single-site pacing at the site of greatest delay achieves similar or greater benefits to biventricular pacing in such patients. These data clarify pacing-effect mechanisms and should help in candidate identification for future studies. PMID- 10096933 TI - Influence of pulmonary capillary wedge pressure on central apnea in heart failure. AB - BACKGROUND: Recent studies suggest that acute pulmonary congestion induces hyperventilation and that hyperventilation-related hypocapnia leads to ventilatory control instability and central sleep apnea. Whether chronic pulmonary congestion due to congestive heart failure (CHF) is associated with central apnea is unknown. We hypothesized that CHF patients with central apnea would have greater pulmonary capillary wedge pressure (PCWP) than patients without central apnea and that PCWP would correlate with central apnea severity. METHODS AND RESULTS: Seventy-five stable CHF patients underwent right heart catheterization and, on the basis of overnight sleep studies, were divided into central apnea (n=33), obstructive apnea (n=20), or nonapnea groups (apnea hypopnea index [AHI] <5 events per hour). Mean PCWP was significantly greater in the central than in the obstructive and nonapnea groups (mean+/-SEM [range]: 22. 8+/-1.2 [11 to 38] versus 12.3+/-1.2 [4 to 21] versus 11.5+/-1.5 [3 to 28] mm Hg, respectively; P<0.001). Within the central apnea group, PCWP correlated with the frequency and severity of central apnea (AHI: r=0.47, P=0.006) and degree of hypocapnia (PaCO2: r=-0.42, P=0. 017). Intensive medical therapy in 7 patients with initially high PCWP and central apneas reduced both PCWP (29.0+/-2.6 [20 to 38] to 22.0+/-1.8 [17 to 27] mm Hg; P<0.001) and central apnea frequency (AHI) (38.5+/-7.7 [7 to 62] to 18.5+/-5.3 [1 to 31] events per hour; P=0.005). CONCLUSIONS: PCWP is elevated in CHF patients with central apneas compared with those with obstructive apnea or without apnea. Moreover, a highly significant relationship exists between PCWP, hypocapnia, and central apnea frequency and severity. PMID- 10096934 TI - Long-term clinical and echocardiographic follow-up after percutaneous mitral valvuloplasty with the Inoue balloon. AB - BACKGROUND: The objective of this study was to assess the long-term clinical outcome and valvular changes (area and regurgitation) after percutaneous mitral valvuloplasty (PMV). METHODS AND RESULTS: After PMV, 561 patients were followed up for 39 (+/-23) months and clinical/echocardiographic data obtained yearly. Kaplan-Meier and Cox regression analyses were performed to estimate event-free survival, its predictors, and the relative risks of several patient subgroups. There were several nonexclusive events: 19 (3.3%) cardiac deaths, 55 (9.8%) mitral replacements, 6 (1%) repeated PMVs, 56 (10%) cases of restenosis, and 108 (19%) cases of clinical impairment. Survival free of major events (cardiac death, mitral surgery, repeat PMV, or functional impairment) was 69% at 7 years, ranging from 88% to 40% in different subgroups of patients. Wilkins score was the best preprocedural predictor of mitral opening, but the procedural result (mitral area and regurgitation) was the only independent predictor of major event-free survival. Mitral area loss, though mild [0.13 (+/-0.21)cm2], increased with time and was >/=0.3 cm2 in 12%, 22%, and 27% of patients at 3, 5, and 7 years, respectively. Regurgitation did not progress in 81% of patients, and when it occurred it was usually by 1 grade. CONCLUSIONS: Seven years after PMV, more than two thirds of patients were in good clinical condition and free of any major event. The procedural result was the main determinant of long-term outcome, although a high score had also negative implications. Mitral area decreased progressively over time, whereas regurgitation did not tend to progress. PMID- 10096935 TI - Prospective randomized study of ablation and pacing versus medical therapy for paroxysmal atrial fibrillation: effects of pacing mode and mode-switch algorithm. AB - BACKGROUND: Atrioventricular (AV) node ablation and pacing has become accepted therapy for drug-refractory paroxysmal atrial fibrillation (PAF). However, few data demonstrate its superiority over continued medical therapy. The influence of pacing mode and mode-switch algorithm has not been investigated. METHODS AND RESULTS: Symptomatic patients who had tried >/=2 drugs for PAF were randomized to continue medical therapy (n=19) or AV junction ablation and implantation of dual chamber mode-switching (DDDR/MS) pacemakers (slow algorithm [n=19] or fast algorithm [n=18]). Follow-up over 18 weeks was at 6-week intervals and used quality-of-life questionnaires (Psychological General Well Being [PGWB], McMaster Health Index [MHI], cardiac symptom score), exercise testing, echocardiography, and Holter monitoring. Paced patients were randomized to DDDR/MS or VVIR and subsequently crossed over. Ablation and DDDR/MS pacing produced better scores than drug therapy for overall symptoms (-41%, P<0.01), palpitations (-58%, P=0. 0001), and dyspnea (-37%, P<0.05). Changes in score from baseline were better with ablation and DDDR/MS pacing for overall symptoms (-48% versus -4%, P<0.005), palpitation (-62% versus -5%, P<0.001), dyspnea (-44% versus -3%, P<0.005), and PGWB (+12% versus +0.5%, P<0. 05). DDDR/MS was better than VVIR pacing for overall symptoms (-21%, P<0.05), dyspnea (-30%, P<0.005), and MHI (+5%, P<0.03). There were no differences between algorithms. More patients developed persistent AF with ablation and pacing than with drugs at 6 weeks (12 of 37 versus 0 of 19, P<0.01). CONCLUSIONS: Ablation and DDDR/MS pacing produces more symptomatic benefit than medical therapy or ablation and VVIR pacing but may result in early development of persistent AF. PMID- 10096936 TI - Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in humans. AB - BACKGROUND: Pulmonary endothelium has metabolic functions including the conversion of angiotensin I to angiotensin II by angiotensin-converting ectoenzyme (ACE). In this study, we have validated an indicator-dilution technique that provides estimations of dynamically perfused capillary surface area (DPCSA) in humans, and we have characterized pulmonary endothelial ACE in vivo. METHODS AND RESULTS: In 12 adults, single-pass transpulmonary (one or both lungs) hydrolysis of the specific ACE substrate 3H-benzoyl-Phe-Ala-Pro (3H-BPAP) was measured and expressed as % metabolism (%M) and v=-ln(1-M). We also calculated Amax/Km, an index of DPCSA. %M (70.1+/-3.2 vs 67.9+/-3.1) and v (1.29+/-0.14 vs 1. 20+/-0.12) were similar in both lungs and the right lung, respectively, whereas Amax/Km//body surface area decreased from 2460+/-193 to 1318+/-115 mL/min per square meter. CONCLUSIONS: Pulmonary endothelial ACE activity can be assessed in humans at the bedside by means of indicator-dilution techniques. Our data suggest homogeneous pulmonary capillary ACE concentrations and capillary transit times (tc) in both human lungs, and similar tc within the normal range of cardiac index. Amax/Km in the right lung is 54% of total Amax/Km in both lungs, suggesting that Amax/Km is a reliable and quantifiable index of DPCSA in humans. PMID- 10096937 TI - Electrocardiographic signs of chronic cor pulmonale: A negative prognostic finding in chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic cor pulmonale (CCP) is a strong predictor of death in chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the prognostic role of individual ECG signs of CCP and of the interaction between these signs and abnormal arterial blood gases. METHODS AND RESULTS: Two hundred sixty-three patients (217 men) with COPD, mean age 67+/-9 years, were grouped according to whether they had no ECG signs (group 1, n=100) or >/=1 ECG signs (group 2, n=163) of CCP and were followed up for 13 years after an exacerbation of respiratory failure. The median survival was significantly shorter in group 2 than in group 1 (2.58 versus 3. 45 years, respectively; Mantel-Cox test, 9.58; P=0.002). The Cox regression analysis identified S1S2S3 pattern, right atrial overload (RAO), and alveolar-arterial oxygen gradient (PAO2-PaO2) >48 mm Hg during oxygen therapy as the strongest predictors of death, with hazard rate (HR)=1.81 (95% CI, 1.22 to 2.69), HR=1.58 (95% CI, 1.15 to 2.18), and HR=1.96 (95% CI, 1.19 to 3.25), respectively. The median survivals of patients having both S1S2S3 pattern and RAO (n=14) and of patients having either S1S2S3 pattern or RAO (n=77) were 1.33 and 2.70 years, respectively (P=0.022). Group 2 patients had a 3-year survival of 18% or 53%, depending on whether their PAO2-PaO2 during oxygen therapy was or was not >48 mm Hg. CONCLUSIONS: Some ECG signs of CCP and PAO2-PaO2 >48 mm Hg during oxygen therapy qualified as a simple and inexpensive tool for targeting subsets of COPD patients with severe or very severe short-term prognosis. PMID- 10096938 TI - Sympathetic rhythmicity in cardiac transplant recipients. AB - BACKGROUND: Variability of R-R interval and muscle sympathetic nerve activity (MSNA) occurs predominantly at a low frequency (LF, +/-0.1 Hz) and a high frequency (HF, +/-0.25 Hz) in normal humans. Increased sympathetic drive in normal humans is associated with an increased LF component of the R-R interval and MSNA. Patients with severe heart failure have high sympathetic activity but decreased or absent LF power of both R-R and MSNA. We tested the hypothesis that this dysfunction in autonomic modulation in heart failure can be reversed by heart transplantation. METHODS AND RESULTS: We performed spectral analysis of resting MSNA, R-R interval, and respiration in 9 patients with heart transplants, 9 chronic heart failure patients, and 9 normal control subjects, all closely matched for age, sex, and body mass index. MSNA (bursts per minute) was higher in patients with heart transplants (74+/-3) than either patients with heart failure (56+/-6) or normal subjects (40+/-4) (P<0.001). LF variability in the R-R interval was reduced in both heart transplant recipients and heart failure patients compared with the control subjects (P<0.01). The LF variability in MSNA was also nearly absent in the heart failure patients (P<0.01). However, the LF and HF oscillations in MSNA in patients with heart transplants were comparable to those evident in the control subjects. CONCLUSIONS: Cardiac transplantation does not reduce MSNA. However, LF oscillations in sympathetic activity are restored after transplantation such that the MSNA oscillatory profile is similar to that observed in normal subjects. PMID- 10096939 TI - Three-dimensional reconstruction of the color Doppler-imaged vena contracta for quantifying aortic regurgitation: studies in a chronic animal model. AB - BACKGROUND: The purpose of this study was to investigate the use of 3-dimensional (3D) reconstruction of color Doppler flow maps to image and extract the vena contracta cross-sectional area to determine the severity of aortic regurgitation (AR) in an animal model. Evaluation of the vena contracta with 2-dimensional imaging systems may not be sufficiently robust to fully characterize this region, which may be asymmetrically shaped. METHODS AND RESULTS: In 6 sheep with surgically induced chronic AR, 18 hemodynamically different states were studied. Instantaneous regurgitant flow rates were obtained by aortic and pulmonary electromagnetic flowmeters (EMFs) as reference standards, and aortic regurgitant effective orifice areas (EOAs) were determined from EMF regurgitant flow rates divided by continuous-wave (CW) Doppler velocities. Composite video data for color Doppler imaging of the aortic regurgitant flows were transferred into a TomTec computer after computer-controlled 180 degrees rotational acquisition. After the 3D data transverse to the flow jet were sectioned, the smallest proximal jet cross section was identified for direct measurement of the vena contracta area. Peak regurgitant flow rates and regurgitant stroke volumes were calculated as the product of these areas and the CW Doppler peak velocities and velocity-time integrals, respectively. There was an excellent correlation between the 3D-derived vena contracta areas and reference EOAs (r=0.99, SEE=0.01 cm2) and between 3D and reference peak regurgitant flow rates and regurgitant stroke volumes (r=0.99, difference=0.11 L/min; r=0.99, difference=1.5 mL/beat, respectively). CONCLUSIONS: 3D-based determination of the vena contracta cross sectional area can provide accurate quantification of the severity of AR. PMID- 10096940 TI - Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice. AB - BACKGROUND: The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the beta-adrenergic receptor (betaAR) is a key determinant of a cell's response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of betaAR number, increases responsiveness to catecholamine stimulation in vivo. METHODS AND RESULTS: Transgenic mice with cardiac-directed expression of ACVI showed increased transgene AC expression but no change in myocardial betaAR number or G-protein content. When stimulated through the betaAR, cardiac function was increased, and cardiac myocytes showed increased cAMP production. In contrast, basal cAMP and cardiac function were normal, and long-term transgene expression was not associated with abnormal histological findings or deleterious changes in cardiac function. CONCLUSIONS: The amount of AC sets a limit on cardiac beta-adrenergic signaling in vivo, and increased AC, independent of betaAR number and G-protein content, provides a means to regulate cardiac responsiveness to betaAR stimulation. Overexpressing an effector (AC) does not alter transmembrane signaling except when receptors are activated, in contrast to receptor/G-protein overexpression, which yields continuous activation and has detrimental consequences. Our findings establish the importance of AC content in modulating beta-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to betaAR stimulation. PMID- 10096941 TI - Effects of ischemia on discontinuous action potential conduction in hybrid pairs of ventricular cells. AB - BACKGROUND: Acute ischemia often occurs in cardiac tissue that has prior injury, resulting in spatially inhomogeneous distributions of membrane properties and intercellular coupling. Changes in action potential conduction with ischemia, which can be associated with release of catecholamines, may be particularly important in tissue that has discontinuous conduction resulting from prior infarction, hypertrophy, or myopathy. METHODS AND RESULTS: Isolated guinea pig ventricular myocytes were electrically coupled by a coupling-clamp circuit to a comprehensive computer model of a guinea pig ventricular myocyte to assess alterations in the critical value of coupling conductance required for action potential conduction from the real cell to the model cell when the real cell was exposed to a solution that included hypoxia, acidosis, and an elevated extracellular potassium concentration to simulate acute ischemia. The "ischemic" solution increased critical coupling conductance from 6.2+/-0.1 to 7.4+/-0.2 nS and decreased the associated maximum conduction delay from 31+/-1 to 23+/-1 ms (mean+/-SEM, n=11). The ischemic solution plus 1 micromol/L norepinephrine decreased critical coupling conductance from 5.9+/-0.2 to 5.0+/-0.1 nS and increased maximum conduction delay from 31+/-2 to 54+/-4 ms (mean+/-SEM, n=8). CONCLUSIONS: The release of catecholamines with ischemia, in a setting of partially uncoupled cells, may play a major role in producing long conduction delays, which may allow reentrant pathways. PMID- 10096942 TI - Slow intramural heating with diffused laser light: A unique method for deep myocardial coagulation. AB - BACKGROUND: Catheter ablation of postinfarction ventricular tachycardia (VT) may be limited by insufficient myocardial coagulation or excessive endocardial or epicardial damage. We propose that volumetric heating restricted to intramural sites may improve the outcome and safety of this procedure, especially if delivered at rates that enhance heat conduction and forestall adverse tissue changes. METHODS AND RESULTS: A novel optical fiber with a diffusing tip for direct intramural, volumetric laser heating was tested via thoracotomy and percutaneously in normal dogs. Low-power (2.0- to 4.5-W) diode laser light (805 nm) diffused within tissue induced large lesions but no visible surface damage, mural thrombi, or transmural perforation. Mean lesion depth approximated tip length (10 mm). Mean lesion widths in the thoracotomy and percutaneous groups were 5.8+/-0.5 to 9.1+/-0.84 mm and 5.2+/-0.85 to 7.9+/-1.1 mm, respectively, depending on the light dose. Mean volumes in the percutaneous group were 1006+/ 245 to 2471+/-934 mm. ST-segment depression, appearing in unfiltered bipolar electrograms recorded from the guiding catheter, was specific for lesion induction. All dogs survived the protocol, which included a 1-hour observation period. In cross section, lesions were elliptical to spherical and characterized by extensive contraction-band necrosis abruptly bordering viable tissue. No platelets or fibrin adhered to the endocardium. CONCLUSIONS: Slow, volumetric, and direct intramyocardial heating induces large, deep lesions without hazardous tissue damage. Such heating might cure postinfarction VT more successfully and safely than present techniques. Further testing and development of this method seem warranted. PMID- 10096943 TI - Intracoronary flecainide induces ST alternans and reentrant arrhythmia on intact canine heart: A role of 4-aminopyridine-sensitive current. AB - BACKGROUND: The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia. METHODS AND RESULTS: A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (STa) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest STa among 60 leads for evaluation. High-dose flecainide (100 microg. kg-1. min-1) increased STa and evoked a spontaneous VF. The STa in high-dose flecainide loading (8.7+/-3.4 mV; mean+/-SEM) was significantly greater than that in disopyramide or lidocaine (0. 9+/-0.4 and 0.8+/-0.2 mV, P<0.05). Treatment of 4-aminopyridine (4-AP) suppressed the increase in STa and the occurrence of VF evoked by flecainide, while E4031 or verapamil did not inhibit those. CONCLUSIONS: Flecainide caused the ST alternans that was closely correlated to the occurrence of VF. Because the ST alternans was suppressed by 4-AP treatment, a 4-AP-sensitive current such as Ito or Isus may play an important role on this phenomenon. PMID- 10096944 TI - Images in cardiovascular medicine. Right ventricular ischemia by exercise-induced coronary spasm of the right ventricular branch. PMID- 10096945 TI - Limitations to the assessment of reperfusion injury with radiolabeled 2 deoxyglucose. PMID- 10096951 TI - Science or Vanity? PMID- 10096952 TI - Long Range Polymerase Chain Reaction-Based Diagnosis of Friedreich Ataxia in the Clinical Molecular Diagnostics Laboratory. AB - Background: Friedreich ataxia, an autosomal recessive neurodegenerative disease, is one of the recently identified trinucleotide repeat disorders. Approximately 94% of affected individuals are homozygous for an intronic GAA repeat within the frataxin gene. The identification of this trinucleotide expansion as the causative mutation in the majority of affected individuals has resulted in the availability of molecular testing for Friedreich ataxia in the clinical molecular diagnostics laboratory. Methods and Results: A Friedreich ataxia protocol has been implemented using two long-range polymerase chain reaction-based assays primed with the GAA-F/GAA-R and Bam/2500F primer sets [1]. The amplified products are analyzed on precast minigels and visualized by Sybr Green staining. The GAA primer set, which produces a normal product of approximately 500 bp and an expanded product of greater than 800 bp, is used to approximate the size range of expanded repeats. Because the GAA primer set occasionally demonstrates preferential amplification of the normal allele in heterozygotes, the Bam/2500F primer set is used to verify results. Conclusions: This protocol has been used to analyze 42 specimens from patients about whom we had detailed clinical information. Concordant results obtained from the GAA and Bam/2500F primer sets, as well as correlations between clinical information and molecular results, indicate that, for the majority of patient specimens, this protocol allows rapid analysis and sizing of GAA repeats in normal and expanded alleles. PMID- 10096953 TI - Molecular Basis of beta-Thalassemia in Indonesia: Application to Prenatal Diagnosis. AB - Background: To facilitate an effective prevention program, the beta-thalassemia mutations in the different ethnic groups in Indonesia were characterized. Methods and Results: The amplification refractory mutation system and artificially created restriction site were used to detect seven known mutations previously described in the Indonesian population. Other mutant alleles were identified by chemical cleavage mismatch, double-stranded sequencing, and Southern blotting. With these methods 78% of beta-thalassemia mutant alleles have been detected so far. Thirteen different beta-thalassemia mutations were characterized, nine of which had previously been described in the Jakarta population. The most frequent mutation is HbE (29%), followed by IVS1-nt5 (19%), and Cd 35 (8%). The frequencies of the other mutations varied from 4% to less than 1%. Two large gene deletions, Filipino beta-deletion and Hb Lepore, were identified in patients from the eastern part of Indonesia. Conclusions: The ethnicity and clinical hematology of cases in the region should be considered in the screening strategy for carriers and antenatal diagnosis of beta-thalassemia in Indonesia. Direct sequencing proved to be the appropriate method for detecting the unknown mutations, and Southern blotting had to be used for large deletions. PMID- 10096954 TI - Oncogene Expression and Cellular Radiation Resistance: A Modulatory Role for c myc. AB - Background: Being able to predict the response of tumors to radiation therapy would improve the decision-making process involved in choosing treatment options for cancer. Expression of certain oncogenes and/or inactivation of tumor suppressor genes has been shown to alter cellular radiation responses; however, it is still not clear what marker or combination of markers would best indicate a radioresistant tumor, or whether such screening would be clinically useful. Current choices of markers are derived mainly from in vitro studies on cell survival after irradiation. In general, expression of transforming oncogenes increases cellular radioresistance. This was also demonstrated in this study for v-abl, bcr abl, v-Ha-ras, v-mos, and v-fes expressed in rat-1 cells. There are, however, conflicting data. Some of the discrepancies may in part be due to interactions between the oncogene-activated signals and other intrinsic or activated pathways. One downstream pathway that is required for oncogene-induced transformation involves c-myc. There is evidence that in some systems myc expression can potentiate ras-induced radiation resistance. Myc may therefore play an important role in determining tumor radioresistancy in the context of other oncogenes. Methods and Results: In this study, the role of c-myc in modulating intrinsic and oncogene-induced cellular radiation responses was investigated in more detail. Retroviral vectors were used to express c-myc and dominant negative mutant c-myc genes in rat 1 cells, with and without ca transfection of v-abl as measured by clonogenic assay, rat 1. Cells infected with c-myc or v-abl were more resistant to irradiation than neo-transfected cells or control cells; however, cells doubly infected were not resistant, even though they had an increased transformation index. This indicates that transformation related events per se do not necessarily lead to radiation resistance. It also suggests that the effects of c-myc on radioresistance may depend on what other pathways are activated. This conclusion was strengthened by the finding that expression of a dominant negative c-myc (dn-myc) mutant gene blocked v-abl induced radiation resistance, but on its own made rat-1 cells more resistant to radiation. Conclusions: The apparently contradictory effects of c-myc in either enhancing or reducing radioresponsiveness may be explained by the dualistic roles of c-myc in promoting signal transduction pathways resulting in either cell proliferation or death, depending on what other pathways are activated. The studies indicate that it will be difficult to predict tumor response to radiation purely by examining expression of transforming oncogenes and it is likely that a number of markers will need to be examined to derive a reliable indication of tumor radiation response. PMID- 10096955 TI - Telomerase Activation in Malignant Bone Tumors. AB - Background: Telomerase is a ribonucleoprotein that can reconstitute the ends (telomeres) of chromosomes after cell division and thus circumvent the cumulative damage that occurs during mitotic cycles of cells. A unique association has been established between telomerase activity and neoplastic transformation and cellular immortalization. The measurement of telomerase activity has also been considered to be a diagnostic marker for human malignant tumors; however, little is known about the status of telomerase activity in malignant bone tumors. Methods and Results: Thirty-five human bone sarcomas and adjacent noncancerous tissues were subjected for the first time by the modified telomeric repeat amplification protocol (TRAP)-silver staining assay for telomerase activity. The results showed that telomerase activity was present in 82.9% (29/35) of malignant bone tumors. Twenty-two of 26 (84.6%) osteosarcomas, 3 of 5 (60%) chondrosarcomas, 2 of 2 (100%) malignant fibrous histiocytomas, and 2 of 2 (100%) rhabdomyosarcomas contained telomerase activity. In contrast, there was no telomerase activity in 19 adjacent noncancerous tissues. Conclusions: The findings suggest that telomerase might play an important role in the development of malignant bone tumors. The detection of telomerase in malignant bone tumors may have value in increasing the accuracy of diagnosis of malignant bone tumors. PMID- 10096956 TI - Malignant Transformation in Sinonasal Papillomas Is Closely Associated With Aberrant p53 Expression. AB - Background: Sinonasal papillomas are generally benign lesions that arise from the lining of the nasal or paranasal sinuses. Occasionally, however, they may undergo malignant change, an event that is poorly understood. To elucidate the possible molecular basis of this transformation, a series of these lesions were examined for abnormal p53 protein expression and for mutations in the genes of exons 5-8. Methods and Results: Eleven cases of sinonasal papillomas (seven with associated carcinoma) were analyzed immunohistochemically for overexpression of p53 protein, as were three cases of squamous carcinoma. Genetic analysis of exons 5-8 was performed via topographic genotyping of representative tissue and polymerase chain reaction amplification. All seven papillomas with associated carcinoma showed evidence of aberrant function of the p53 gene, as did the three squamous cell carcinomas. Several exhibited point mutations resulting in missense codons. One case possessed a nonsense mutation and was immunonegative. Conclusions: p53 gene mutation appears to be closely associated with malignant transformation in sinonasal papillomas, and genotyping of archival tissues is useful in the evaluation of malignant or potentially malignant lesions. PMID- 10096957 TI - alpha-Thalassemia Subtyping and the Detection of Silent Mutations by High Resolution Fragment Analysis and DNA Sequencing. AB - Background: Sets of polymerase chain reaction (PCR) primers were used that make it possible to study subtypes of the most prevalent mutations that cause alpha thalassemia (-alpha3.7 deletions). These primers (Dev and C3, Dev and C9c) can be used in PCR to amplify regions that are characteristic of the three - alpha3.7 deletion subtypes (alpha3.7i, alpha3.7ii, alpha3.7iii). These subtypes are important because the type of alpha-chain deletion can affect the level of alpha globin production. Methods and Results: The PCR products were screened using automated high-resolution electrophoresis on a DNA sequencer. Subtypes were then identified by automated DNA sequencing. During the screening for subtypes with high-resolution fragment analysis, new fragments were detected that were slightly different from the expected size. DNA sequencing of these fragments demonstrated the presence of three mutations that had not been described or fully characterized before. Conclusions: High-resolution fragment analysis is a convenient way to detect alpha-thalassemia subtypes, and DNA sequencing of silent mutations can lead to a better understanding of the cause of these mutations. PMID- 10096958 TI - Inherited Thrombophilia due to Factor V Leiden Mutation. AB - Inherited thrombophilia due to activated protein C resistance is now recognized as one of the major genetic risk factors in the development of venous thromboembolic disease. Activated protein C resistance is secondary to a point mutation in the factor V gene, factor V Leiden. The high prevalence of this mutation in the general population, mainly in Caucasians of European descent, is a major contributing factor to the high incidence of venous thromboembolic disease in the United States, affecting one in 1000 individuals annually. Heterozygosity and homozygosity for factor V Leiden increase the risk for thrombosis 5- to 10-fold and 50- to 100-fold, respectively, compared with genotypically normal individuals. Factor V Leiden is more common than all other known genetic risk factors for thrombosis, and its presence results in a compounded risk in patients with simultaneous inherited abnormalities such as protein C, protein S, antithrombin III deficiencies, hyperhomocysteinemia, and/or acquired risk factors. Therefore, detection of activated protein C resistance and genotyping for factor V Leiden are important for establishing risk for thrombosis and ultimately for patient management. PMID- 10096959 TI - The one and a half ventricle repair-we can do it, but should we do it? PMID- 10096960 TI - Experience with one and a half ventricle repair. AB - OBJECTIVE: This article presents a 10-year experience with one and a half ventricle repair for right ventricular hypoplasia or dysfunction. METHODS: From November 1986 to December 1996, 30 patients (mean age 6.7 +/- 8.5 years, range 4 months-40 years) with functionally abnormal right ventricles underwent a bidirectional Glenn shunt as part of the repair. Diagnoses included pulmonary atresia with intact ventricular septum (n = 15), Ebstein anomaly (n = 5), levotransposition of the great arteries (n = 3), pulmonary stenosis with right ventricular hypoplasia (n = 2), tetralogy of Fallot (n = 3), dextrotransposition of the great arteries (n = l), and Uhl anomaly (n = l). Concomitantly performed cardiac procedures included atrial septal defect closure (n = 27), fenestration of the atrial septum (n = 2), right ventricular cavity augmentation (n = 8), right ventricular outflow tract enlargement (n = 6), transannular patch (n = 13), modified Blalock-Taussig shunt closure (n = 16), tricuspid replacement (n = 3), tricuspid repair (n = 2), Rastelli procedure (n = 3), tricuspid commissurotomy (n = 2), and double switch (n = l). RESULTS: There were 2 early deaths (6.6%) and 1 late death. Mean early postoperative superior vena caval pressure was 14. 12 +/- 3.55 mm Hg and mean right atrial pressure was 10.3 +/- 5.16 mm Hg. Early oxygen saturation in the operating room with an inspired oxygen fraction of 1 was 97.2 +/- 2.5; oxygen saturation was 92.3 +/- 4.8 on room air at discharge. Mean oxygen saturations were 93.6% +/- 3.6% at 1 year of follow-up (P =.10) and 93.5% +/- 4. 1% at 5 years (P =.12). Overall survival was 90% at 5 years, and 21 patients (77%) were in New York Heart Association class I, 5 (18%) were in class II, and 1 (2.7%) was in class III. CONCLUSION: This procedure provides a valid alternative for correction of right ventricle hypoplasia or dysfunction. Early and intermediate follow-up results compare favorably with those of the Fontan procedure, but long-term follow-up is needed. PMID- 10096961 TI - Surgical treatment of subaortic stenosis: a seventeen-year experience. AB - OBJECTIVE: The aim of the study was to analyze the long-term results of subaortic stenosis relief and the risk factors associated with recurrence and reoperation. METHODS: One hundred sixty patients with subaortic stenosis underwent biventricular repair. Before the operation the mean left ventricle-aorta gradient was 80 +/- 35 mm Hg, 57 patients had aortic regurgitation, and 34 were in New York Heart Association functional class III or IV. Median age at repair was 10 years. For discrete subaortic stenosis (n = 120), 39 patients underwent isolated membranectomy, 67 underwent membranectomy with associated septal myotomy, and 14 underwent septal myectomy. Tunnel subaortic stenosis (n = 34) was treated by myotomy in 10 cases, myectomy in 12, septoplasty in 7, Konno procedure in 3, and apical conduit in 2. Aortic valve replacement was performed in 6 cases, mitral valve replacement in 2 cases, and mitral valvuloplasty in 4 cases. RESULTS: There were 5 early (3.1%) and 4 late (4.4%) deaths. Within 3.6 +/- 3.3 years a recurrent gradient greater than 30 mm Hg was found in 42 patients (27%), 20 of whom had 26 reoperations. According to multivariable Cox regression analysis survival was influenced by hypoplastic aortic anulus (P =.01) and mitral stenosis (P =.048); recurrence and reoperation were influenced by coarctation and immediate postoperative left ventricular outflow tract gradients. At a median follow-up of 13.3 years, mean left ventricle-aorta gradient was 20 +/- 13 mm Hg. Relief of the subaortic stenosis improved the degree of aortic regurgitation in 86% of patients with preoperative aortic regurgitation. Actuarial survival and freedom from reoperation rates at 15 years were 94% +/- 1.3% and 85% +/- 6%, respectively. CONCLUSION: Although surgical treatment provides good results, recurrence and reoperation are significantly influenced by previous coarctation repair and by the quality of initial relief of subaortic stenosis. PMID- 10096962 TI - Surgical management of progressive pulmonary venous obstruction after repair of total anomalous pulmonary venous connection. AB - BACKGROUND: The occurrence of a progressive pulmonary venous obstruction after the repair of the total anomalous pulmonary venous connection is a severe complication. OBJECTIVES: The objectives of this study were to retrospectively review the patients with this condition and to report our experience with a new surgical technique with a sutureless in situ pericardium repair. METHODS: Of 178 patients who underwent correction of total anomalous pulmonary venous connection, 16 patients (9%) experienced the development of a progressive pulmonary venous obstruction in a median interval of 4 months (5 weeks-12 years). Three patients had isolated anastomotic stenosis, 4 patients had isolated pulmonary venous ostial stenosis, and 9 patients had both. Pulmonary venous obstruction was bilateral in 7 patients. The surgical procedures used at reoperation included 8 patch enlargements, 5 ostial endarterectomies, 1 intraoperative stenting, and 7 sutureless in situ pericardium repairs. RESULTS: There were 4 deaths after reoperation (4 of 15 patients; 27%). The only significant mortality risk factor was the bilateral location of the pulmonary venous obstruction (P =.045). In patients with isolated anastomotic stenosis or with only 1 pulmonary venous ostial stenosis (n = 5), there was no death, except the patient presenting with a single ventricle. In patients with 2 or more pulmonary venous ostial stenoses (n = 10), there were 3 deaths; 5 of the 7 survivors were successfully treated with the in situ pericardial technique, with normalized pulmonary artery pressure at a mean follow-up of 26 months. CONCLUSION: Progressive pulmonary venous stenosis after repair of total anomalous pulmonary venous connection remains a severe complication when bilateral. The sutureless in situ pericardial repair offers a satisfactory solution, particularly on the right side. PMID- 10096963 TI - Early results of the extracardiac conduit Fontan operation. AB - BACKGROUND: Among the modifications of the Fontan operation, the extracardiac approach may offer the greatest potential for optimizing early postoperative ventricular and pulmonary vascular function, insofar as it can be performed with short periods of normothermic partial cardiopulmonary bypass and without cardioplegic arrest in most cases. In this study, we reviewed our experience with the extracardiac conduit Fontan operation, with a focus on early postoperative outcomes. METHODS AND RESULTS: Between July 1992 and April 1997, 51 patients (median age 4.9 years) underwent an extracardiac conduit Fontan operation. Median cardiopulmonary bypass time was 92 minutes and has decreased significantly over the course of our experience. Intracardiac procedures were performed in only 5 patients (10%), and the aorta was crossclamped in only 11 (22%). Intraoperative fenestration was performed in 24 patients (47%). There were no early deaths. Fontan failure occurred in 1 patient who was a poor candidate for the Fontan procedure. Transient supraventricular tachyarrhythmias occurred in 5 patients (10%). Median duration of chest tube drainage was 8 days. Factors significantly associated with prolonged resource use (mechanical ventilation, inotropic support, intensive care unit stay, and hospital stay) included longer bypass time and higher Fontan pressure. At a median follow-up of 1.9 years, there was 1 death from bleeding at reoperation. CONCLUSIONS: The extracardiac conduit Fontan procedure can be performed with minimal mortality and morbidity. Improved results may be related to advantages of the extracardiac approach and improved preservation of ventricular and pulmonary vascular function. PMID- 10096964 TI - Fluid dynamic comparison of intra-atrial and extracardiac total cavopulmonary connections. AB - OBJECTIVE: Extracardiac total cavopulmonary connection has recently been introduced as an alternative to intra-atrial procedures. The purpose of this study was to compare the hydrodynamic efficiency of extracardiac and intra-atrial lateral tunnel procedures in total cavopulmonary connections. METHODS: Intra atrial lateral tunnel, extracardiac tunnel, and extracardiac conduit with and without caval vein offset were performed on explanted sheep heart preparations and studied in an in vitro flow loop. A rate of fluid-energy dissipation analysis was performed for each model using simultaneous measurement of pressure and flow at each inlet and outlet of the right side of the heart. Preparations were perfused by using a steady flow blood pump at 4 flow indices (1-6 L/min/m 2) with the inferior vena cava carrying 65% of the total venous return. RESULTS: Fluid power losses were consistently lower for the extracardiac conduit procedure compared with the two tunnel configurations (P <.01). A further reduction in energy dissipation of up to 36% was noted in the extracardiac procedure, with 5 mm offset of the extracardiac conduit toward the distal right pulmonary. The intra-atrial and extracardiac tunnel procedures were least efficient, with losses 73% greater than the optimal extracardiac conduit procedure. CONCLUSIONS: The extracardiac conduit procedure provides superior hemodynamics compared with the intra-atrial lateral tunnel and extracardiac tunnel techniques. This hydrodynamic advantage is markedly enhanced by the use of conduit-superior vena cava offset, particularly at high physiologic flows that are representative of exercise. These data suggest additional rationale for the use of extracardiac conduit procedures for final-stage completion of the Fontan circulation. PMID- 10096965 TI - Ex vivo transfection of transforming growth factor-beta1 gene to pulmonary artery segments in lung grafts. AB - OBJECTIVE: Proximal pulmonary artery segment transfection may provide beneficial downstream effects on the whole-lung graft. In this study, transforming growth factor-beta1 was transfected to proximal pulmonary artery segments, and the efficacy of transforming growth factor-beta1 transfection was examined in ischemia-reperfusion injury and acute rejection models of rat lung transplantation. METHODS: In the ischemia-reperfusion injury model, orthotopic left lung transplantation was performed in F344 rats. In group I, the PPAS was isolated and injected with saline solution. In 2 other groups, lipid67:DOPE:sense (group II) or antisense transforming growth factor-beta1pDNA construct (group III) was injected instead of saline solution. After cold preservation at 4 degrees C for 18 hours, lung grafts were implanted. Graft function was assessed 24 hours later. In the acute rejection model, donor lung grafts were harvested. Proximal pulmonary artery segments were injected with saline solution (group I) or sense (group II) or antisense lipid gene construct (group III) and then implanted. Graft function was assessed on postoperative day 5. RESULTS: In the ischemia-reperfusion injury study, there were no significant differences in oxygenation, wet-to-dry weight ratios, graft myeloperoxidase activity, or transforming growth factor-beta1 levels in platelet-poor serum or proximal pulmonary artery segment homogenates. In the acute rejection study, oxygenation was significantly improved in group II receiving transforming growth factor-beta1 (group II vs I and III, 136.0 +/- 32.5 vs 54.0 +/- 9.6 mm Hg and 53.8 +/- 14.8 mm Hg; P =.016 and.016). There were no significant pathologic differences. Transforming growth factor-beta1 concentrations from proximal pulmonary artery segment homogenates in group II were significantly higher compared with controls. CONCLUSIONS: Ex vivo transfection of transforming growth factor-beta1 to proximal pulmonary artery segments did not affect reperfusion injury of lung isografts. In acute rejection, however, ex vivo transfection of transforming growth factor-beta 1 to proximal pulmonary artery segments improved allograft function. This suggests that transfection to proximal pulmonary artery segments exerts beneficial downstream effects on the whole-lung allograft. PMID- 10096966 TI - Sirolimus (rapamycin) potentiates cyclosporine in prevention of acute lung rejection. AB - BACKGROUND: Cyclosporine-based immunosuppressive regimens (INN: ciclosporin) in human lung transplantation continue to result in a high incidence of acute cellular rejection. We investigated the use of sirolimus, a macrolide with structural similarity to tacrolimus, as monotherapy and in combination with cyclosporine in a rodent lung transplant model. METHODS: Orthotopic left lung transplantation was performed in Lewis recipients from Brown-Norway donor rats with syngeneic Lewis-to-Lewis controls. Open biopsies were performed on postoperative day 7, and the severity of acute lung rejection was graded by a pathologist blinded to the protocol. RESULTS: All recipients survived despite the amount of acute rejection seen on examination of the biopsy tissue. Lewis-to Lewis isografts demonstrated near normal pulmonary architecture. Allogeneic recipients receiving high-dose cyclosporine (25 mg/kg) monotherapy showed mild to moderate acute rejection with some perivascular focal interstitial infiltrates. Recipients receiving low-dose cyclosporine (5 mg/kg) monotherapy or low- or high dose sirolimus (0.5 or 2.0 mg/kg, respectively) monotherapy demonstrated massive cellular infiltration leading to necrosis and infarction and could not be graded. However, the addition of low-dose sirolimus (0.5 mg/kg) to low-dose cyclosporine (5 mg/kg) demonstrated a significant potentiating immunosuppressive effect, and the addition of high-dose sirolimus (2.0 mg/kg) to low-dose cyclosporine (5.0 mg/kg) demonstrated an even greater effect, with rejection scores better than those obtained with high-dose cyclosporine monotherapy and similar to those obtained with isografts. CONCLUSIONS: This study demonstrates that low-dose sirolimus has a cyclosporine-sparing effect and that a higher dose of sirolimus in combination with cyclosporine strongly protects lung allografts from acute cellular rejection. These results suggest that sirolimus may be indicated as an adjunct to current cyclosporine-based immunosuppressive regimens in clinical lung transplantation. PMID- 10096967 TI - Positron emission tomographic imaging with fluorodeoxyglucose isefficacious in evaluating malignant pulmonary disease. AB - OBJECTIVE: Positron emission tomography (PET), when used with the intravenously administered radiopharmaceutical F-18 fluorodeoxyglucose (FDG), has the potential to help in the evaluation of patients with lung cancer because the radiopharmaceutical is concentrated by metabolically active cells. We conducted a retrospective study of PET-FDG in 96 patients evaluated at our institution over the past 2 years for suspected primary pulmonary neoplasms. PET-FDG results were compared with the findings of computed tomographic scans on the same patients. All patients underwent surgical exploration with or without resection of the malignant tumors. Sites of potential malignancy were subjected to biopsy and/or excision, with subsequent pathologic evaluation. RESULTS: A total of 96 patients with suspected or proven primary pulmonary malignant disease were evaluated. Sixty-six patients had histologically confirmed malignant tumors, and 30 had benign masses histologically. PET-FDG had an accuracy of detecting malignancy in pulmonary lesions of 92% (sensitivity 97%; specificity 89%). A total of 111 surgically sampled sites were from lymph nodes. PET-FDG was accurate in predicting the malignancy of nodes in 91% of instances, whereas computed tomography was correct in 64%. The sensitivity, specificity, and predictive accuracy of PET in detecting metastatic lymphadenopathy in mediastinal lymph nodes were 98%, 94%, and 95%, respectively. PET-FDG also changed the M stage in 8 (12%) patients (6 with and 2 without metastases). The 6 malignant (positive) lesions were correctly identified by PET-FDG, and the 2 without tumor were accurately predicted as benign (negative). CONCLUSION: These initial results suggest that PET-FDG is highly accurate in identifying and staging lung cancer. PET-FDG also appears to be more accurate in detecting metastatic mediastinal lymphadenopathy than computed tomographic scan. PMID- 10096968 TI - Diffusing capacity limitations of the extent of lung volume reduction surgery in an animal model of emphysema. AB - OBJECTIVE: The purpose of this study was to investigate in an elastase-induced emphysema rabbit model the effects of increasing resection volumes during lung volume reduction surgery on pulmonary compliance, forced expiratory air flow, and diffusing capacity to assess factors limiting optimal resection. METHODS: Emphysema was induced in 68 New Zealand White rabbits with 15,000 units of aerosolized elastase. Static respiratory system compliance, forced expiratory flow, and single-breath diffusing capacity were measured before the induction of emphysema, after the induction of emphysema, and 1 week after a bilateral upper and middle lobe lung volume reduction operation. RESULTS: Static respiratory system compliance with 60 mL insufflation above functional residual capacity increased with emphysema induction and then decreased progressively with resection of larger volumes of lung tissue (P =.001 by analysis of variance). Expiratory flow improved after lung resection in the rabbits with large resection volumes. In contrast, diffusing capacity tended to deteriorate with larger resection volumes (P =. 18). CONCLUSION: Improvements in respiratory system compliance and forced expiratory flow after lung volume reduction operations may account for the improvements seen clinically. Declines in diffusing capacity with extensive lung reduction may limit the clinical benefits associated with greater tissue resection volumes. Future investigations with animal models may reveal other physiologic parameters that may further guide optimal lung volume reduction procedures. PMID- 10096969 TI - A biologic risk model for stage I lung cancer: immunohistochemical analysis of 408 patients with the use of ten molecular markers. AB - OBJECTIVE: The standard treatment of patients with stage I non-small cell lung cancer is resection of the primary tumor; however, the recurrence rate is 28% to 45%. This study evaluates a panel of molecular markers in a large population of patients with stage I non-small cell lung cancer to determine the prognostic value of each marker and to create a biologic risk model. METHODS: Pathologic specimens were collected from 408 consecutive patients after complete resection for stage I non-small cell lung cancer at a single institution, with follow-up of at least 5 years. A panel of 10 molecular markers was chosen for immunohistochemical analysis of the primary tumor on the basis of differing oncogenic mechanisms. Local tumor expansion requires growth regulating proteins (epidermal growth factor receptor, the protooncogene erb-b2); apoptosis proteins (p53, bcl-2); and cell cycle regulating proteins (retinoblastoma recessive oncogene, KI-67). Local tumor invasion requires angiogenesis (factor viii). The development of distant metastases involves the expression of adhesion proteins (CD-44, sialyl-Tn, blood group A). Cox proportional hazards regression analysis was used to construct an independent risk model for cancer recurrence and death. RESULTS: Multivariable analysis demonstrated significantly elevated risk for the following molecular markers: p53 (hazard ratio, 1.68; P =.004); factor viii (hazard ratio, 1.47 P =. 033); erb-b2 (hazard ratio, 1.43; P =.044); CD-44 (hazard ratio, 1. 40; P =.050); and retinoblastoma recessive oncogene (hazard ratio, 0. 747; P =.084). CONCLUSIONS: Five molecular markers were associated with the risk of recurrence and death, representing independent metastatic pathways: apoptosis (p53), angiogenesis (factor viii), growth regulation (erb-b2), adhesion (CD-44), and cell cycle regulation (retinoblastoma recessive oncogene). This study demonstrates the validity of this molecular biologic risk model in patients with stage I non- small cell lung cancer. PMID- 10096970 TI - The TP53 genotype but not immunohistochemical result is predictive of response to cisplatin-based neoadjuvant therapy in stage III non-small cell lung cancer. AB - BACKGROUND: The cytotoxic effects of cisplatin and anthracyclins have been attributed to apoptosis induction, which has been recognized as a major function of the TP53 gene. The TP53 gene appears to be mutated in about 50% of cases of non-small cell lung cancer. A possible dependence of chemotherapy response on TP53 genotype was evaluated retrospectively in a group of patients with advanced non-small cell lung cancer and induction treatment. METHODS: Patients with complete or partial remission were compared with those with stable or progressive disease with respect to TP53 genotype and overall survival. Mutations in the TP53 gene were detected by complete direct sequencing (exons 2-11). RESULTS: A normal TP53 genotype proved to be significantly associated with major response to chemotherapy (P <.001). Overall, no association was found between p53 protein expression and TP53 genotype. A normal TP53 genotype was found to be highly sensitive in predicting response to treatment, whereas a mutant genotype was revealed to be specific in predicting lack of response. The difference in overall length of survival was significant between patients exhibiting a normal TP53 genotype (corresponding to those whose disease responded to chemotherapy) and patients showing mutant TP53 genotype (corresponding to those who had disease resistant to chemotherapy, P =.027). CONCLUSIONS: In a small cohort of patients with advanced non-small cell lung cancer we found a direct link between normal TP53 genotype and response to cisplatin-based induction treatment and also between mutant genotype and resistance to treatment, whereas p53 immunohistochemical result was predictive of neither. PMID- 10096971 TI - Experimental and clinical evaluation of a new synthetic, absorbable sealant to reduce air leaks in thoracic operations. AB - BACKGROUND: Air leaks after pulmonary resections may contribute to increased patient morbidity, delayed removal of chest drainage tubes, and prolonged hospitalization. OBJECTIVE: The purpose of this study was to investigate the effects of a new synthetic, absorbable sealant on the healing of healthy bronchial and lung tissues (experimental study) and its safety and efficacy to stop air leaks after lung resection (clinical study). METHODS: Fifteen large white pigs underwent a left upper lobectomy. All parenchymal surgical sites were sealed; the bronchial stump was either stapled, sealed, or both (n = 5 each). In the clinical study, 26 consecutive patients were prospectively randomized, intraoperatively, to standard closure of parenchymal surgical sites with (n = 15) or without (n = 11) the sealant. RESULTS: In the experimental study, no postoperative air leaks occurred, with intact bronchial closures and normal tissues at death. In the clinical study, 100% of intraoperative leaks were sealed versus 18% of control patients (P =.001). Although 77% (n = 10) of treated patients remained leak-free from the end of the operation to chest tube removal versus 9% (n = 1) of control patients (P =.001), there was no statistical difference in the duration of postoperative chest tube time, hospital stay, or cost. There were no acute or late undesirable side-effects related to the sealant application. CONCLUSIONS: The surgical adhesive investigated here demonstrated a compelling safety profile and significant clinical efficacy to stop air leaks after lung resections. PMID- 10096972 TI - Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study. AB - INTRODUCTION: Malignant pleural mesothelioma is an ideal model for testing new locoregional multimodality approaches because of its aggressive local behavior. METHODS: This study was planned to investigate the feasibility, safety, and pharmacokinetics of a multimodality therapy including an operation, pleural space perfusion (60 minutes) with cisplatin (100 mg/m2), hyperthermia (41. 5 degrees C), and postoperative radiotherapy (55 Gy to chest wall incisions). The effects of the extent of resection and perfusion temperature on cisplatin pharmacokinetics were evaluated. Ten patients with epithelial or mixed, stage I or II, malignant pleural mesothelioma underwent the following procedures: group A (3 patients), pleurectomy/decortication and normothermic pleural space antineoplastic perfusion; group B (3 patients), pleurectomy/decortication and hyperthermic perfusion; and group C (4 patients), pleuropneumonectomy and hyperthermic perfusion. Operations were selectively applied depending on tumor extent. Platinum levels were serially measured by atomic absorption in systemic blood, perfusate, lung, and endothoracic fascia. RESULTS: The overall procedure was completed in every case, without any death or toxicity. No lung damage was demonstrated after treatment. Major complications included 1 wound infection and 1 diaphragmatic prosthesis displacement. The mean peak platinum plasma levels were reached within 45 to 60 minutes after perfusion was started. Systemic drug concentrations were greater after pleurectomy/decortication than after pleuropneumonectomy (P =.006). The local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than normothermic perfusion. CONCLUSION: This multimodality approach is feasible, pharmacokinetically advantageous, and safe enough to undergo further clinical investigations. PMID- 10096973 TI - Which manufacturing characteristics are predictors of outlet strut fracture in large sixty-degree Bjork-Shiley convexo-concave mitral valves? The Bjork-Shiley Study Group. AB - BACKGROUND: Identification of predictors of outlet strut fracture is important for recipients of large (>/=29 mm) 60-degree Bjork-Shiley convexo-concave mitral valves when it comes to decision making on prophylactic explantation. An association between the manufacturing process of Bjork-Shiley convexo-concave valves and the risk of fracture has been suggested. OBJECTIVE: The aim of this study was to determine which items from the manufacturing records, in addition to known risk factors, were predictive of fracture of large 60-degree Bjork-Shiley convexo-concave mitral valves. METHODS: All Dutch recipients (n = 2264) of Bjork Shiley convexo-concave valves were followed up until fracture, death, reoperation, or end of the study (July 1, 1996). Information was abstracted from the manufacturing records of large 60-degree Bjork-Shiley convexo- concave mitral valves (n = 655) in Dutch recipients and included items that described the manufacturing process and items for which an association with strut fracture had been suggested. Manufacturing records were available for 637 valves (97%), including 25 fractured valves. RESULTS: Multivariate analysis identified age at implantation (hazard ratio 0.95, 95% confidence interval 0.93-0.97), lot size (<175 valves versus >/=175 valves; hazard ratio 6.6, 95% confidence interval 2.2 20.1), number of hook deflection tests performed (0 or 1 versus >/=2; hazard ratio 4.7, 95% confidence interval 1.4-16.2), number of disks that were used (1 versus >/=2; hazard ratio 5.9, 95% confidence interval 1.9-18.5), and lot fracture percentage (hazard ratio 1.6, 95% confidence interval 1.4-1. 8) as independent predictors of fracture. Although the added predictive value of a model with these 5 variables was sizable compared with a model containing age only, it was only slightly better than a model with age, lot size, and lot fracture percentage. CONCLUSION: If the serial number of a large 60-degree Bjork Shiley convexo-concave mitral valve is known, manufacturing information can add significantly to the prediction of fracture. Information on lot size and lot fracture percentage should be made available to clinicians for risk assessment of prophylactic explantation. PMID- 10096974 TI - Risk factors for rupture of chronic type B dissections. AB - OBJECTIVE: This study was an attempt to determine risk factors for rupture and to improve management of patients with type B aortic dissection who survive the acute phase without operation. METHODS: We studied 50 patients by means of serial computer-generated 3-dimensional computed tomographic scans. All patients who did not undergo operative treatment before the completion of at least 2 computed tomographic scans a minimum of 3 months apart after an acute type B dissection were included in the study. The median duration of follow-up was 40 months (range 0.9-112 months). Only 1 patient died of causes unrelated to the aneurysm during follow-up. Nine patients had fatal rupture (18%); 10 patients underwent elective aneurysm resection because of rapid expansion or development of symptoms, and 31 patients remained alive without operation or rupture. Possible risk factors for rupture in patients in the rupture, operative, and event-free groups were compared, as were dimensional data from first follow-up and last computed tomographic scans. RESULTS: Older age, chronic obstructive pulmonary disease, and elevated mean blood pressures were unequivocally associated with rupture (rupture versus event-free survival, P <.05), and pain was marginally significantly associated. Analysis of dimensional factors contributing to rupture was complicated by the fact that patients who underwent elective operation had significantly larger aneurysms and faster expansion rates than did either of the other groups, leaving comparisons of aneurysmal diameter between groups with and without rupture showing only marginal statistical significance. The last median descending aortic diameter before rupture in the rupture group was 5.4 cm (range 3.2-6. 7 cm). CONCLUSIONS: In an environment in which patients with large and rapidly expanding aneurysms are usually referred for surgical treatment, older patients with chronic type B dissections, especially if they have uncontrolled hypertension and a history of chronic obstructive pulmonary disease, are significantly more likely to have rupture than are younger, normotensive patients without lung disease. Neither the presence of a persistently patent false lumen nor a large abdominal aortic diameter appears to increase the risk of rupture. Overall, our nondimensional data strikingly resemble the natural history of patients with nondissecting aneurysms, suggesting that calculations derived from data on chronic descending thoracic and thoracoabdominal aneurysms would provide an overly conservative individual estimate of rupture risk for patients with chronic type B dissection, who tend toward earlier rupture of smaller aneurysms. A more aggressive surgical approach toward treatment of patients with chronic type B dissection seems warranted. PMID- 10096975 TI - Pulmonary thromboendarterectomy for chronic thromboembolic obstruction of the pulmonary artery in piglets. AB - OBJECTIVE: The 2 main causes of death after thromboendarterectomy for chronic pulmonary thromboembolism are incomplete repermeabilization responsible for persistent pulmonary hypertension and acute high-permeability pulmonary edema. We wish to establish an experimental model of chronic pulmonary thromboembolism to replicate the conditions encountered during and after pulmonary thromboendarterectomy. METHODS: Multiple-curled coils and tissue adhesive were embolized in 6 piglets to induce complete obstruction of the left pulmonary artery, documented by angiography. After 5 weeks, the main pulmonary artery was repermeabilized by thromboendarterectomy during circulatory arrest. The left lung was reperfused ex vivo with autologous blood at constant flow, and patency of the pulmonary artery was evaluated on a barium angiogram. The endarterectomy reperfusion procedure was also done in 6 nonembolized piglets that served as the controls. The severity of lung injury induced by 60 minutes of reperfusion was assessed on the basis of measurements of the lung filtration coefficient and of lung myeloperoxidase activity. RESULTS: Marked hypertrophy of the bronchial circulation was seen in the chronic pulmonary thromboembolism group. Thromboendarterectomy removed the organized obstructing thrombus that was incorporated into the arterial wall and restored patency of the pulmonary artery. Acute lung inflammation and high-permeability edema occurred after reperfusion, as indicated by a 1.5-fold increases in both lung filtration coefficient and lung myeloperoxidase values in the chronic pulmonary thromboembolism group; these 2 variables being correlated. CONCLUSIONS: Our model replicated the perioperative conditions of pulmonary thromboendarterectomy, suggesting that it may prove useful for improving the repermeabilization technique and for investigating the mechanisms and prevention of reperfusion injury. PMID- 10096976 TI - Heparin-coated cardiopulmonary bypass equipment. I. Biocompatibility markers and development of complications in a high-risk population. AB - OBJECTIVES: 1. To study possible clinical benefits of heparin-coated cardiopulmonary bypass in patients with a broad range of preoperative risk factors. 2. To evaluate the correlation between the terminal complement complex and clinical outcome. 3. To identify clinical predictors of complement activation and correlates of granulocyte activation during cardiac surgery. METHODS: Blood samples from adults undergoing elective cardiac surgery with Duraflo II heparin coated (n = 81) or uncoated (n = 75) cardiopulmonary bypass sets (Duraflo coating surface; Baxter International, Inc, Deerfield, Ill) were analyzed for activation of complement (C3 activation products, terminal complement complex), granulocytes (myeloperoxidase, lactoferrin), and platelets (beta-thromboglobulin) by enzyme immunoassays. Preoperative risk was assessed by means of the "Higgins' score." Complications (cardiac, renal, pulmonary, gastrointestinal, and central nervous system dysfunction, infections, death) were registered prospectively. Data were analyzed by analysis of variance, logistic regression, and linear regression. RESULTS AND CONCLUSIONS: Sixty-seven percent of the patients had predefined risk factors. Complications developed in 53 patients (34%), equivalently with and without heparin-coated bypass sets (P =. 44-.82), despite a significant reduction in complement and granulocyte activation by heparin coating. No clear-cut relationship between the terminal complement complex and outcome was found, even if it was significant in the models for renal and central nervous system dysfunction and infections (P =.006). The Higgins' score was significantly related to complement activation (P <.05). Approximately 50% of the variation in granulocyte activation was explained by complement (P .8). CONCLUSIONS: C1 activation during bypass was increased by heparin coating, but further classical pathway activation was held in check until administration of protamine. Heparin coating significantly inhibited C3bc and terminal complement complex formation. Terminal complement complex concentrations were related to alternative pathway activation and may be useful for evaluation of differences in bypass circuitry. Increases and intergroup differences in terminal complement complex concentrations were much larger than those in C5a-desArg. PMID- 10096978 TI - Ischemic preconditioning does not acutely improve load-insensitive parameters of contractility in in vivo stunned porcine myocardium. AB - OBJECTIVE: Ischemic preconditioning has been shown to have no beneficial effect on segment shortening in in vivo regionally stunned myocardium. The purpose of this study was to determine whether ischemic preconditioning improves the recovery of postischemic ventricular function when contractility is assessed by load-insensitive measurements including end-systolic pressure length relations, preload recruitable stroke work, and preload recruitable stroke work area in in vivo regionally stunned porcine myocardium. METHODS: Open chest, pentobarbital anesthetized pigs were used. Regional ventricular function was monitored by measurements of segment shortening, stroke work, end systolic pressure length relations, preload recruitable stroke work, and preload recruitable stroke work area. The control group was submitted to 15 minutes of left anterior descending coronary artery occlusion and 3 hours of reperfusion. The preconditioned group underwent 2 cycles of 5-minute left anterior descending coronary artery occlusion and 10-minute reperfusion before 15 minutes of occlusion. RESULTS: There was no infarct in either group. The preconditioning protocol significantly depressed preischemic segment shortening but not regional stroke work. Ischemic preconditioning had no significant beneficial effect on regional stroke work, end systolic pressure length relations, preload recruitable stroke work, or preload recruitable stroke work area. CONCLUSIONS: These results confirm that ischemic preconditioning does not ameliorate in vivo porcine myocardial stunning and indicate that ischemic preconditioning may have a limited cardioprotective role during cardiac operation. PMID- 10096979 TI - Hyperbaric oxygen therapy for massive arterial air embolism during cardiac operations. AB - BACKGROUND: Massive arterial air embolism is a rare but devastating complication of cardiac operations. Several treatment modalities have been proposed, but hyperbaric oxygen is the specific therapy. METHODS: The Israel Naval Medical Institute is the only referral hyperbaric center in this country for acute care patients. We reviewed our experience in the hyperbaric oxygen treatment of massive arterial air embolism during cardiac operations. RESULTS: Seventeen patients were treated between 1985 and 1998. Eight patients (47.1%) experienced a complete neurologic recovery; 6 patients (35.3%) remained unconscious at discharge, and 3 patients (17.6%) died. Mean (+/- SD) delay from the end of the operation to hyperbaric therapy was 9.6 +/- 7.4 hours (range, 1-20 hours). This delay was 4.0 +/- 3.4 hours (1-12 hours) for patients who had a full neurologic recovery, 12.8 +/- 7.1 hours (5-20 hours) for patients with severe neurologic disability, and 18.0 +/- 2.0 hours (16-20 hours) for patients who died (1-way analysis of variance; P =.002). The source of variance among the groups mainly resulted from the short delay for patients who experienced complete recovery compared with the other 2 groups (Tukey test). All 5 patients who were treated within 3 hours from the operation and 50% (2 of 4 patients) of those patients treated 3 to 5 hours from operation experienced a full neurologic recovery. With a delay of 9 to 20 hours, only 1 of 8 patients had a full neurologic recovery. The association between outcome and treatment delay was found to be statistically significant (tau = 0.65 with exact 2-sided P value =.0007). CONCLUSION: Hyperbaric oxygen therapy should be administered as soon as possible after massive arterial air embolism during cardiac operations. PMID- 10096980 TI - Saphenous vein grafts for minimally invasive direct coronary artery bypass. PMID- 10096981 TI - Anomalous origin of the left coronary artery from the pulmonary artery with intramural aortic route: diagnosis and surgical treatment. PMID- 10096982 TI - Endovascular stent-grafting via the aortic arch for chronic aortic dissection combined with coronary artery bypass grafting. PMID- 10096983 TI - Fourier analysis of the intra-aortic balloon pump. PMID- 10096984 TI - The missing flap: considerations about a case of aortic intussusception. PMID- 10096985 TI - Bridge to recovery with the Abiomed BVS-5000 device in a patient with intractable ventricular tachycardia. PMID- 10096986 TI - New operative method for distal aortic arch aneurysm: combined cervical branch bypass and endovascular stent-graft implantation. PMID- 10096987 TI - Paraplegia after coronary bypass operations: relationship to severe hypertension and vascular disease. PMID- 10096990 TI - Introduction of clinical-pathologic conferences section PMID- 10096988 TI - Serum S-100 protein levels after pediatric cardiac surgery: a possible new marker for postperfusion cerebral injury. PMID- 10096991 TI - It takes time to heal a broken heart. PMID- 10096992 TI - Effects of acute L-arginine administration in coronary atherosclerosis. PMID- 10096993 TI - Invited letter concerning surgical repair of recurrent aortic coarctation. PMID- 10096994 TI - What memory is for. AB - Let's start from scratch in thinking about what memory is for, and consequently, how it works. Suppose that memory and conceptualization work in the service of perception and action. In this case, conceptualization is the encoding of patterns of possible physical interaction with a three-dimensional world. These patterns are constrained by the structure of the environment, the structure of our bodies, and memory. Thus, how we perceive and conceive of the environment is determined by the types of bodies we have. Such a memory would not have associations. Instead, how concepts become related (and what it means to be related) is determined by how separate patterns of actions can be combined given the constraints of our bodies. I call this combination "mesh." To avoid hallucination, conceptualization would normally be driven by the environment, and patterns of action from memory would play a supporting, but automatic, role. A significant human skill is learning to suppress the overriding contribution of the environment to conceptualization, thereby allowing memory to guide conceptualization. The effort used in suppressing input from the environment pays off by allowing prediction, recollective memory, and language comprehension. I review theoretical work in cognitive science and empirical work in memory and language comprehension that suggest that it may be possible to investigate connections between topics as disparate as infantile amnesia and mental-model theory. PMID- 10096995 TI - Trading spaces: computation, representation, and the limits of uninformed learning. AB - Some regularities enjoy only an attenuated existence in a body of training data. These are regularities whose statistical visibility depends on some systematic recoding of the data. The space of possible recoding is, however, infinitely large--it is the space of applicable Turing machines. As a result, mappings that pivot on such attenuated regularities cannot, in general, be found by brute-force search. The class of problems that present such mappings we call the class of "type-2 problems." Type-1 problems, by contrast, present tractable problems of search insofar as the relevant regularities can be found by sampling the input data as originally coded. Type-2 problems, we suggest, present neither rare nor pathological cases. They are rife in biologically realistic settings and in domains ranging from simple animat (simulated animal or autonomous robot) behaviors to language acquisition. Not only are such problems rife--they are standardly solved! This presents a puzzle. How, given the statistical intractability of these type-2 cases, does nature turn the trick? One answer, which we do not pursue, is to suppose that evolution gifts us with exactly the right set of recording biases so as to reduce specific type-2 problems to (tractable) type-1 mappings. Such a heavy-duty nativism is no doubt sometimes plausible. But we believe there are other, more general mechanisms also at work. Such mechanisms provide general (not task-specific) strategies for managing problems of type-2 complexity. Several such mechanisms are investigated. At the heart of each is a fundamental poly--namely, the maximal exploitation of states of representation already achieved by prior, simpler (type-1) learning so as to reduce the amount of subsequent computational search. Such exploitation both characterizes and helps make unitary sense of a diverse range of mechanisms. These include simple incremental learning (Elman 1993), modular connectionism (Jacobs et al. 1991), and the developmental hypothesis of "representational redescription" (Karmiloff-Smith 1979; 1992). In addition, the most distinctive features of human cognition--language and culture--may themselves be viewed as adaptations enabling this representation/computation trade-off to be pursued on an even grander scale. PMID- 10096996 TI - Real self-deception. AB - Self-deception is made unnecessarily puzzling by the assumption that it is an intrapersonal analog of ordinary interpersonal deception. In paradigmatic cases, interpersonal deception is intentional and involves some time at which the deceiver disbelieves what the deceived believes. The assumption that self deception is intentional and that the self-deceiver believes that some proposition is true while also believing that it is false produces interesting conceptual puzzles, but it also produces a fundamentally mistaken view of the dynamics of self-deception. This target article challenges the assumption and presents an alternative view of the nature and etiology of self-deception. Drawing upon empirical studies of cognitive biases, it resolves familiar "paradoxes" about the dynamics of self-deception and the condition of being self deceived. Conceptually sufficient conditions for self-deception are offered and putative empirical demonstrations of a kind of self-deception in which a subject believes that a proposition is true while also believing that it is false are criticized. Self-deception is neither irresolvably paradoxical nor mysterious, and it is explicable without the assistance of mental exotica. The key to understanding its dynamics is a proper appreciation of our capacity for acquiring and retaining motivationally biased beliefs. PMID- 10096997 TI - Are there nontrivial constraints on colour categorization? AB - In this target article the following hypotheses are discussed: (1) Colour is autonomous: a perceptuolinguistic and behavioural universal. (2) It is completely described by three independent attributes: hue, brightness, and saturation: (3) Phenomenologically and psychophysically there are four unique hues: red, green, blue, and yellow; (4) The unique hues are underpinned by two opponent psychophysical and/or neuronal channels: red/green, blue/yellow. The relevant literature is reviewed. We conclude: (i) Psychophysics and neurophysiology fail to set nontrivial constraints on colour categorization. (ii) Linguistic evidence provides no grounds for the universality of basic colour categories. (iii) Neither the opponent hues red/green, blue/yellow nor hue, brightness, and saturation are intrinsic to a universal concept of colour. (iv) Colour is not autonomous. PMID- 10096998 TI - The detection and generation of sequences as a key to cerebellar function: experiments and theory. AB - Starting from macroscopic and microscopic facts of cerebellar histology, we propose a new functional interpretation that may elucidate the role of the cerebellum in movement control. The idea is that the cerebellum is a large collection of individual lines (Eccles's "beams": Eccles et al. 1967a) that respond specifically to certain sequences of events in the input and in turn produce sequences of signals in the output. We believe that the sequence in/sequence-out mode of operation is as typical for the cerebellar cortex as the transformation of sets into sets of active neurons is typical for the cerebral cortex, and that both the histological differences between the two and their reciprocal functional interactions become understandable in the light of this dichotomy. The response of Purkinje cells to sequences of stimuli in the mossy fiber system was shown experimentally by Heck on surviving slices of rat and guinea pig cerebellum. Sequential activation of a row of eleven stimulating electrodes in the granular layer, imitating a "movement" of the stimuli along the folium, produces a powerful volley in the parallel fibers that strongly excites Purkinje cells, as evidenced by intracellular recording. The volley, or "tidal wave," has maximal amplitude when the stimulus moves toward the recording site at the speed of conduction in parallel fibers, and much smaller amplitudes for lower or higher "velocities." The succession of stimuli has no effect when they "move" in the opposite direction. Synchronous activation of the stimulus electrodes also had hardly any effect. We believe that the sequences of mossy fiber activation that normally produce this effect in the intact cerebellum are a combination of motor planning relayed to the cerebellum by the cerebral cortex, and information about ongoing movement, reaching the cerebellum from the spinal cord. The output elicited by the specific sequence to which a "beam" is tuned may well be a succession of well timed inhibitory volleys "sculpting" the motor sequences so as to adapt them to the complicated requirements of the physics of a multijointed system. PMID- 10096999 TI - Speed/accuracy trade-offs in target-directed movements. AB - This target article presents a critical survey of the scientific literature dealing with the speed/accuracy trade-offs in rapid-aimed movements. It highlights the numerous mathematical and theoretical interpretations that have been proposed in recent decades. Although the variety of points of view reflects the richness of the field and the high degree of interest that such basic phenomena attract in the understanding of human movements, it calls into question the ability of 'many models to explain the basic observations consistently reported in the field. This target article summarizes the kinematic theory of rapid human movements, proposed recently by R. Plamondon (1993b; 1993c; 1995a; 1995b), and analyzes its predictions in the context of speed/accuracy trade-offs. Data from human movement literature are reanalyzed and reinterpreted in the context of the new theory. It is shown that the various aspects of speed/accuracy trade-offs can be taken into account by considering the asymptotic behavior of a large number of coupled linear systems, from which a delta-lognormal law can be derived to describe the velocity profile of an end-effector driven by a neuromuscular synergy. This law not only describes velocity profiles almost perfectly, it also predicts the kinematic properties of simple rapid movements and provides a consistent framework for the analysis of different types of speed/accuracy trade-offs using a quadratic (or power) law that emerges from the model. PMID- 10097000 TI - Sex differences in pain. AB - Are there sex differences in pain? For experimentally delivered somatic stimuli, females have lower thresholds, greater ability to discriminate, higher pain ratings, and less tolerance of noxious stimuli than males. These differences, however, are small, exist only for certain forms of stimulation and are affected by many situational variables such as presence of disease, experimental setting, and even nutritive status. For endogenous pains, women report more multiple pains in more body regions than men. With no obvious underlying rationale, some painful diseases are more prevalent among females, others among males and, for many diseases, symptoms differ between females and males. Sex differences in attitudes exist that affect not only reporting, coping, and responses to treatment, but also measurement and treatment. So many variables are operative, however, that the most striking feature of sex differences in reported pain experience is the apparent overall lack of them. On the other hand, deduction from known biological sex differences suggests that these are powerful sex differences in the operation of pain mechanisms. First, the vaginal canal provides an additional route in women for internal trauma and invasion by pathological agents that puts them at greater risk for developing hyperalgesia in multiple body regions. Second, sex differences in temporal patterns are likely to give rise to sex differences in how pain is "learned" and stimuli are interpreted, a situation that could lead to a greater variability and wider range of pains without obvious peripheral pathology among females. Third, sex differences in the actions of sex hormones suggest pain-relevant differences in the operation of many neuroactive agents, opiate and nonopiate systems, nerve growth factor, and the sympathetic system. Thus, while inductive analysis of existing data demonstrate more similarities than differences in pain experience between females and males, deductive analysis suggests important operational sex differences in its production. PMID- 10097001 TI - Are there fundamental differences in the peripheral mechanisms of visceral and somatic pain? AB - There are some conspicuous differences between the sensibilities of cutaneous and visceral tissues: (1) Direct trauma, which readily produces pain when applied to the skin, is mostly without effect in healthy visceral tissue. (2) Pain that arises from visceral tissues is initially often poorly localised and diffuse. (3) With time, visceral pains are often referred to more superficial structures. (4) The site of referred pain may also show hyperalgesia. (5) In disease states, the afflicted viscera may also become hyperalgesic. In this target article, I consider to what extent differences in the physiology, anatomy, and chemistry of peripheral processing systems explain these different sensibilities. In almost every aspect, there are subtle differences in the properties of the processing mechanisms for cutaneous and visceral information. These may arise because of distinct developmental cues operating in the two domains. Many of the differences between visceral and cutaneous afferents are quantitative rather than qualitative. The quantitative differences, for example in the density of afferent innervation, can be large. The quantitative differences in the numbers of afferents alone may be a sufficient explanation for some aspects of the differential sensibility, for example, the poor localisation of sensation and the apparent insensitivity to focal yet tissue-damaging stimuli. In addition, the few clear qualitative differences apparent in the innervations of the two tissue types may be of special importance. That the encoding of visceral nociceptive events may occur by an intensity mechanism rather than a specificity mechanism could be the key difference in viscerosensory and somatosensory processing. PMID- 10097002 TI - Plasticity: implications for opioid and other pharmacological interventions in specific pain states. AB - The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors--therefore opioids can both increase and decrease activity in descending pathways. These pathways could exhibit considerable plasticity. There is increasing evidence that delta opioid receptor agonists have the potential to replace morphine as major analgesics with reduced side-effect profiles. The concept of preemptive analgesia, based on preventing the induction of some of the negative plastic influences on opioid controls and the detrimental effects of pain, is sound, but experimental verification in the clinical setting is difficult. For example, a delayed compensatory upregulation of inhibitory systems, particularly in inflammation, may counter persistent painful inputs. Combination therapy with opioids may be beneficial in many pain states where either negative influences are blocked or inhibitory controls are enhanced. Finally, developmental aspects of these systems are discussed in connection with the treatment of pain in young children, where inhibitory systems in the spinal cord are immature. PMID- 10097003 TI - Peripheral and central hyperexcitability: differential signs and symptoms in persistent pain. AB - This target article examines the clinical and experimental evidence for a role of peripheral and central hyperexcitability in persistent pain in four key areas: cutaneous hyperalgesia, referred pain, neuropathic pain, and postoperative pain. Each suggests that persistent pain depends not only on central sensitization, but also on inputs from damaged peripheral tissue. It is instructive to think of central sensitization as comprised of both an initial central sensitization and an ongoing central sensitization driven by inputs from peripheral sources. Each of these factors, initial sensitization, ongoing central sensitization, and inputs from peripheral sources, contributes to the net activity in dorsal horn neurons and thus influences the expression of persistent pain or hyperalgesia. Since each factor, peripheral inputs and central sensitization (initial or ongoing), can contribute to both the initiation and maintenance of persistent pain, therapies should target both peripheral and central sources of pathology. PMID- 10097004 TI - Central inhibitory dysfunctions: mechanisms and clinical implications. AB - Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue. PMID- 10097005 TI - Sympathetic nervous system and pain: a clinical reappraisal. AB - The target article discusses various aspects of the relationship between the sympathetic system and pain. To this end, the patients under study are divided into three groups. In the first group, called "reflex sympathetic dystrophy" (RSD), the syndrome can be characterized by a triad of autonomic, motor, and sensory symptoms, which occur in a distally generalized distribution. The pain is typically felt deeply and diffusely, has an orthostatic component, and is suppressed by the ischemia test. Under those circumstances, the pain is likely to respond to sympatholytic interventions. In a second group, called "sympathetically maintained pain" (SMP) syndrome, the principal symptoms are spontaneous pain, which is felt superficially and has no orthostatic component, and allodynia. These symptoms, typically confined to the zone of a lesioned nerve, may also be relieved by sympathetic blocks. Since the characteristics of the pain differ between RSD and SMP, the underlying kind of sympathetic-sensory coupling may also vary between these cases. A very small third group of patients exhibits symptoms of both RSD and SMP. The dependence or independence of pain on sympathetic function reported in most published studies seems to be questionable because the degree of technical success of the block remains uncertain. Therefore, pain should not be reported as sympathetic function independent until the criteria for a complete sympathetic block have been established and satisfied. PMID- 10097006 TI - The neural basis of cognitive development: a constructivist manifesto. AB - How do minds emerge from developing brains? According to "neural constructivism," the representational features of cortex are built from the dynamic interaction between neural growth mechanisms and environmentally derived neural activity. Contrary to popular selectionist models that emphasize regressive mechanisms, the neurobiological evidence suggests that this growth is a progressive increase in the representational properties of cortex. The interaction between the environment and neural growth results in a flexible type of learning: "constructive learning" minimizes the need for prespecification in accordance with recent neurobiological evidence that the developing cerebral cortex is largely free of domain-specific structure. Instead, the representational properties of cortex are built by the nature of the problem domain confronting it. This uniquely powerful and general learning strategy undermines the central assumption of classical learnability theory, that the learning properties of a system can be deduced from a fixed computational architecture. Neural constructivism suggests that the evolutionary emergence of neocortex in mammals is a progression toward more flexible representational structures, in contrast to the popular view of cortical evolution as an increase in innate, specialized circuits. Human cortical postnatal development is also more extensive and protracted than generally supposed, suggesting that cortex has evolved so as to maximize the capacity of environmental structure to shape its structure and function through constructive learning. PMID- 10097007 TI - Long-term potentiation: what's learning got to do with it? AB - Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy following high-frequency stimulation of afferent fibers. Since the first full description of the phenomenon in 1973, exploration of the mechanisms underlying LTP induction has been one of the most active areas of research in neuroscience. Of principal interest to those who study LTP, particularly in the mammalian hippocampus, is its presumed role in the establishment of stable memories, a role consistent with "Hebbian" descriptions of memory formation. Other characteristics of LTP, including its rapid induction, persistence, and correlation with natural brain rhythms. provide circumstantial support for this connection to memory storage. Nonetheless, there is little empirical evidence that directly links LTP to the storage of memories. In this target article we review a range of cellular and behavioral characteristics of LTP and evaluate whether they are consistent with the purported role of hippocampal LTP in memory formation. We suggest that much of the present focus on LTP reflects a preconception that LTP is a learning mechanism, although the empirical evidence often suggests that LTP is unsuitable for such a role. As an alternative to serving as a memory storage device, we propose that LTP may serve as a neural equivalent to an arousal or attention device in the brain. Accordingly, LTP may increase in a nonspecific way the effective salience of discrete external stimuli and may thereby facilitate the induction of memories at distant synapses. Other hypotheses regarding the functional utility of this intensely studied mechanism are conceivable; the intent of this target article is not to promote a single hypothesis but rather to stimulate discussion about the neural mechanisms underlying memory storage and to appraise whether LTP can be considered a viable candidate for such a mechanism. PMID- 10097008 TI - In search of common foundations for cortical computation. AB - It is worthwhile to search for forms of coding, processing, and learning common to various cortical regions and cognitive functions. Local cortical processors may coordinate their activity by maximizing the transmission of information coherently related to the context in which it occurs, thus forming synchronized population codes. This coordination involves contextual field (CF) connections that link processors within and between cortical regions. The effects of CF connections are distinguished from those mediating receptive field (RF) input; it is shown how CFs can guide both learning and processing without becoming confused with the transmission of RF information. Simulations explore the capabilities of networks built from local processors with both RF and CF connections. Physiological evidence for synchronization, CFs, and plasticity of the RF and CF connections is described. Coordination via CFs is related to perceptual grouping, the effects of context on contrast sensitivity, amblyopia, implicit influences of color in achromotopsia, object and word perception, and the discovery of distal environmental variables and their interactions through self-organization. Cortical computation could thus involve the flexible evaluation of relations between input signals by locally specialized but adaptive processors whose activity is dynamically associated and coordinated within and between regions through specialized contextual connections. PMID- 10097009 TI - Deictic codes for the embodiment of cognition. AB - To describe phenomena that occur at different time scales, computational models of the brain must incorporate different levels of abstraction. At time scales of approximately 1/3 of a second, orienting movements of the body play a crucial role in cognition and form a useful computational level--more abstract than that used to capture natural phenomena but less abstract than what is traditionally used to study high-level cognitive processes such as reasoning. At this "embodiment level," the constraints of the physical system determine the nature of cognitive operations. The key synergy is that at time scales of about 1/3 of a second, the natural sequentiality of body movements can be matched to the natural computational economies of sequential decision systems through a system of implicit reference called deictic in which pointing movements are used to bind objects in the world to cognitive programs. This target article focuses on how deictic binding make it possible to perform natural tasks. Deictic computation provides a mechanism for representing the essential features that link external sensory data with internal cognitive programs and motor actions. One of the central features of cognition, working memory, can be related to moment-by-moment dispositions of body features such as eye movements and hand movements. PMID- 10097010 TI - The development of features in object concepts. AB - According to one productive and influential approach to cognition, categorization, object recognition, and higher level cognitive processes operate on a set of fixed features, which are the output of lower level perceptual processes. In many situations, however, it is the higher level cognitive process being executed that influences the lower level features that are created. Rather than viewing the repertoire of features as being fixed by low-level processes, we present a theory in which people create features to subserve the representation and categorization of objects. Two types of category learning should be distinguished. Fixed space category learning occurs when new categorizations are representable with the available feature set. Flexible space category learning occurs when new categorizations cannot be represented with the features available. Whether fixed or flexible, learning depends on the featural contrasts and similarities between the new category to be represented and the individuals existing concepts. Fixed feature approaches face one of two problems with tasks that call for new features: If the fixed features are fairly high level and directly useful for categorization, then they will not be flexible enough to represent all objects that might be relevant for a new task. If the fixed features are small, subsymbolic fragments (such as pixels), then regularities at the level of the functional features required to accomplish categorizations will not be captured by these primitives. We present evidence of flexible perceptual changes arising from category learning and theoretical arguments for the importance of this flexibility. We describe conditions that promote feature creation and argue against interpreting them in terms of fixed features. Finally, we discuss the implications of functional features for object categorization, conceptual development, chunking, constructive induction, and formal models of dimensionality reduction. PMID- 10097011 TI - A common structure for concepts of individuals, stuffs, and real kinds: more Mama, more milk, and more mouse. AB - Concepts are highly theoretical entities. One cannot study them empirically without committing oneself to substantial preliminary assumptions. Among the competing theories of concepts and categorization developed by psychologists in the last thirty years, the implicit theoretical assumption that what falls under a concept is determined by description ("descriptionism") has never been seriously challenged. I present a nondescriptionist theory of our most basic concepts, "substances," which include (1) stuffs (gold, milk), (2) real kinds (cat, chair), and (3) individuals (Mama, Bill Clinton, the Empire State Building). On the basis of something important that all three have in common, our earliest and most basic concepts of substances are identical in structure. The membership of the category "cat," like that of "Mama," is a natural unit in nature, to which the concept "cat" does something like pointing, and continues to point despite large changes in the properties the thinker represents the unit as having. For example, large changes can occur in the way a child identifies cats and the things it is willing to call "cat" without affecting the extension of its word "cat." The difficulty is to cash in the metaphor of "pointing" in this context. Having substance concepts need not depend on knowing words, but language interacts with substance concepts, completely transforming the conceptual repertoire. I will discuss how public language plays a crucial role in both the acquisition of substance concepts and their completed structure. PMID- 10097012 TI - Theory of mind in nonhuman primates. AB - Since the BBS article in which Premack and Woodruff (1978) asked "Does the chimpanzee have a theory of mind?," it has been repeatedly claimed that there is observational and experimental evidence that apes have mental state concepts, such as "want" and "know." Unlike research on the development of theory of mind in childhood, however, no substantial progress has been made through this work with nonhuman primates. A survey of empirical studies of imitation, self recognition, social relationships, deception, role-taking, and perspective-taking suggests that in every case where nonhuman primate behavior has been interpreted as a sign of theory of mind, it could instead have occurred by chance or as a product of nonmentalistic processes such as associative learning or inferences based on nonmental categories. Arguments to the effect that, in spite of this, the theory of mind hypothesis should be accepted because it is more parsimonious than alternatives or because it is supported by convergent evidence are not compelling. Such arguments are based on unsupportable assumptions about the role of parsimony in science and either ignore the requirement that convergent evidence proceed from independent assumptions, or fail to show that it supports the theory of mind hypothesis over nonmentalist alternatives. Progress in research on theory of mind requires experimental procedures that can distinguish the theory of mind hypothesis from nonmentalist alternatives. A procedure that may have this potential is proposed. It uses conditional discrimination training and transfer tests to determine whether chimpanzees have the concept "see." Commentators are invited to identify flaws in the procedure and to suggest alternatives. PMID- 10097014 TI - Linear correlates in the speech signal: the orderly output constraint. AB - Neuroethological investigations of mammalian and avian auditory systems have documented species-specific specializations for processing complex acoustic signals that could, if viewed in abstract terms, have an intriguing and striking relevance for human speech sound categorization and representation. Each species forms biologically relevant categories based on combinatorial analysis of information-bearing parameters within the complex input signal. This target article uses known neural models from the mustached bat and barn owl to develop, by analogy, a conceptualization of human processing of consonant plus vowel sequences that offers a partial solution to the noninvariance dilemma--the nontransparent relationship between the acoustic waveform and the phonetic segment. Critical input sound parameters used to establish species-specific categories in the mustached bat and barn owl exhibit high correlation and linearity due to physical laws. A cue long known to be relevant to the perception of stop place of articulation is the second formant (F2) transition. This article describes an empirical phenomenon--the locus equations--that describes the relationship between the F2 of a vowel and the F2 measured at the onset of a consonant-vowel (CV) transition. These variables, F2 onset and F2 vowel within a given place category, are consistently and robustly linearly correlated across diverse speakers and languages, and even under perturbation conditions as imposed by bite blocks. A functional role for this category-level extreme correlation and linearity (the "orderly output constraint") is hypothesized based on the notion of an evolutionarily conserved auditory-processing strategy. High correlation and linearity between critical parameters in the speech signal that help to cue place of articulation categories might have evolved to satisfy a preadaptation by mammalian auditory systems for representing tightly correlated, linearly related components of acoustic signals. PMID- 10097013 TI - Precis of statistical significance: rationale, validity, and utility. AB - The null-hypothesis significance-test procedure (NHSTP) is defended in the context of the theory-corroboration experiment, as well as the following contrasts: (a) substantive hypotheses versus statistical hypotheses, (b) theory corroboration versus statistical hypothesis testing, (c) theoretical inference versus statistical decision, (d) experiments versus nonexperimental studies, and (e) theory corroboration versus treatment assessment. The null hypothesis can be true because it is the hypothesis that errors are randomly distributed in data. Moreover, the null hypothesis is never used as a categorical proposition. Statistical significance means only that chance influences can be excluded as an explanation of data; it does not identify the nonchance factor responsible. The experimental conclusion is drawn with the inductive principle underlying the experimental design. A chain of deductive arguments gives rise to the theoretical conclusion via the experimental conclusion. The anomalous relationship between statistical significance and the effect size often used to criticize NHSTP is more apparent than real. The absolute size of the effect is not an index of evidential support for the substantive hypothesis. Nor is the effect size, by itself, informative as to the practical importance of the research result. Being a conditional probability, statistical power cannot be the a priori probability of statistical significance. The validity of statistical power is debatable because statistical significance is determined with a single sampling distribution of the test statistic based on H0, whereas it takes two distributions to represent statistical power or effect size. Sample size should not be determined in the mechanical manner envisaged in power analysis. It is inappropriate to criticize NHSTP for nonstatistical reasons. At the same time, neither effect size, nor confidence interval estimate, nor posterior probability can be used to exclude chance as an explanation of data. Neither can any of them fulfill the nonstatistical functions expected of them by critics. PMID- 10097015 TI - Parity still isn't a generalisation problem. AB - Clark & Thornton take issue with my claim that parity is not a generalisation problem, and that nothing can be inferred about back-propagation in particular, or learning in general, from failures of parity generalisation. They advance arguments to support their contention that generalisation is a relevant issue. In this continuing commentary, I examine generalisation more closely in order to refute these arguments. Different learning algorithms will have different patterns of failure: back-propagation has no special status in this respect. This is not to deny that a particular algorithm might fortuitously happen to produce the "intended" function in an (oxymoronic) parity-generalisation task. PMID- 10097016 TI - A role for ovarian hormones in sexual differentiation of the brain. AB - Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in development, with males and testosterone-treated females having larger callosa than control females as early as Day 30. The effects of ovariectomy do not appear until after Day 55. These findings are more consistent with other evidence of a later sensitive period for ovarian feminization as compared to androgenic masculinization. PMID- 10097017 TI - Testosterone and dominance in men. AB - In men, high levels of endogenous testosterone (T) seem to encourage behavior intended to dominate--to enhance one's status over--other people. Sometimes dominant behavior is aggressive, its apparent intent being to inflict harm on another person, but often dominance is expressed nonaggressively. Sometimes dominant behavior takes the form of antisocial behavior, including rebellion against authority and low breaking. Measurement of T at a single point in time, presumably indicative of a man's basal T level, predicts many of these dominant or antisocial behaviors. T not only affects behavior but also responds to it. The act of competing for dominant status affects male T levels in two ways. First, T rises in the face of a challenge, as if it were an anticipatory response to impending competition. Second, after the competition, T rises in winners and declines in losers. Thus, there is a reciprocity between T and dominance behavior, each affecting the other. We contrast a reciprocal model, in which T level is variable, acting as both a cause and effect of behavior, with a basal model, in which T level is assumed to be a persistent trait that influences behavior. An unusual data set on Air Force veterans, in which data were collected four times over a decade, enables us to compare the basal and reciprocal models as explanations for the relationship between T and divorce. We discuss sociological implications of these models. PMID- 10097018 TI - Innate talents: reality or myth? AB - Talents that selectively facilitate the acquisition of high levels of skill are said to be present in some children but not others. The evidence for this includes biological correlates of specific abilities, certain rare abilities in autistic savants, and the seemingly spontaneous emergence of exceptional abilities in young children, but there is also contrary evidence indicating an absence of early precursors of high skill levels. An analysis of positive and negative evidence and arguments suggests that differences in early experiences, preferences, opportunities, habits, training, and practice are the real determinants of excellence. PMID- 10097019 TI - Representation is representation of similarities. AB - Advanced perceptual systems are faced with the problem of securing a principled (ideally, veridical) relationship between the world and its internal representation. I propose a unified approach to visual representation, addressing the need for superordinate and basic-level categorization and for the identification of specific instances of familiar categories. According to the proposed theory, a shape is represented internally by the responses of a small number of tuned modules, each broadly selective for some reference shape, whose similarity to the stimulus it measures. This amounts to embedding the stimulus in a low-dimensional proximal shape space spanned by the outputs of the active modules. This shape space supports representations of distal shape similarities that are veridical as Shepard's (1968) second-order isomorphisms (i.e., correspondence between distal and proximal similarities among shapes, rather than between distal shapes and their proximal representations). Representation in terms of similarities to reference shapes supports processing (e.g., discrimination) of shapes that are radically different from the reference ones, without the need for the computationally problematic decomposition into parts required by other theories. Furthermore, a general expression for similarity between two stimuli, based on comparisons to reference shapes, can be used to derive models of perceived similarity ranging from continuous, symmetric, and hierarchical ones, as in multidimensional scaling (Shepard 1980), to discrete and nonhierarchical ones, as in the general contrast models (Shepard & Arabie 1979; Tversky 1977). PMID- 10097020 TI - The frame/content theory of evolution of speech production. AB - The species-specific organizational property of speech is a continual mouth open close alternation, the two phases of which are subject to continual articulatory modulation. The cycle constitutes the syllable, and the open and closed phases are segments-vowels and consonants, respectively. The fact that segmental serial ordering errors in normal adults obey syllable structure constraints suggests that syllabic "frames" and segmental "content" elements are separately controlled in the speech production process. The frames may derive from cycles of mandibular oscillation present in humans from babbling onset, which are responsible for the open-close alternation. These communication-related frames perhaps first evolved when the ingestion-related cyclicities of mandibular oscillation (associated with mastication [chewing] sucking and licking) took on communicative significance as lipsmacks, tonguesmacks, and teeth chatters--displays that are prominent in many nonhuman primates. The new role of Broca's area and its surround in human vocal communication may have derived from its evolutionary history as the main cortical center for the control of ingestive processes. The frame and content components of speech may have subsequently evolved separate realizations within two general purpose primate motor control systems: (1) a motivation-related medial "intrinsic" system, including anterior cingulate cortex and the supplementary motor area, for self-generated behavior, formerly responsible for ancestral vocalization control and now also responsible for frames, and (2) a lateral "extrinsic" system, including Broca's area and surround, and Wernicke's area, specialized for response to external input (and therefore the emergent vocal learning capacity) and more responsible for content. PMID- 10097021 TI - Folk biology and the anthropology of science: cognitive universals and cultural particulars. AB - This essay in the "anthropology of science" is about how cognition constrains culture in producing science. The example is folk biology, whose cultural recurrence issues from the very same domain-specific cognitive universals that provide the historical backbone of systematic biology. Humans everywhere think about plants and animals in highly structured ways. People have similar folk biological taxonomies composed of essence-based, species-like groups and the ranking of species into lower- and higher-order groups. Such taxonomies are not as arbitrary in structure and content, nor as variable across cultures, as the assembly of entities into cosmologies, materials, or social groups. These structures are routine products of our "habits of mind," which may in part be naturally selected to grasp relevant and recurrent "habits of the world." An experiment illustrates that the same taxonomic rank is preferred for making biological inferences in two diverse populations: Lowland Maya and Midwest Americans. These findings cannot be explained by domain-general models of similarity because such models cannot account for why both cultures prefer species-like groups, although Americans have relatively little actual knowledge or experience at this level. This supports a modular view of folk biology as a core domain of human knowledge and as a special player, or "core meme," in the selection processes by which cultures evolve. Structural aspects of folk taxonomy provide people in different cultures with the built-in constraints and flexibility that allow them to understand and respond appropriately to different cultural and ecological settings. Another set of reasoning experiments shows that Maya, American folk, and scientists use similarly structured taxonomies in somewhat different ways to extend their understanding of the world in the face of uncertainty. Although folk and scientific taxonomies diverge historically, they continue to interact. The theory of evolution may ultimately dispense with the core concepts of folk biology, including species, taxonomy, and teleology; in practice, however, these may remain indispensable to doing scientific work. Moreover, theory-driven scientific knowledge cannot simply replace folk knowledge in everyday life. Folk-biological knowledge is not driven by implicit or inchoate theories of the sort science aims to make more accurate and perfect. PMID- 10097022 TI - The dynamical hypothesis in cognitive science. AB - According to the dominant computational approach in cognitive science, cognitive agents are digital computers; according to the alternative approach, they are dynamical systems. This target article attempts to articulate and support the dynamical hypothesis. The dynamical hypothesis has two major components: the nature hypothesis (cognitive agents are dynamical systems) and the knowledge hypothesis (cognitive agents can be understood dynamically). A wide range of objections to this hypothesis can be rebutted. The conclusion is that cognitive systems may well be dynamical systems, and only sustained empirical research in cognitive science will determine the extent to which that is true. PMID- 10097023 TI - Learning by imitation: a hierarchical approach. AB - To explain social learning without invoking the cognitively complex concept of imitation, many learning mechanisms have been proposed. Borrowing an idea used routinely in cognitive psychology, we argue that most of these alternatives can be subsumed under a single process, priming, in which input increases the activation of stored internal representations. Imitation itself has generally been seen as a "special faculty." This has diverted much research towards the all or-none question of whether an animal can imitate, with disappointingly inconclusive results. In the great apes, however, voluntary, learned behaviour is organized hierarchically. This means that imitation can occur at various levels, of which we single out two clearly distinct ones: the "action level," a rather detailed and linear specification of sequential acts, and the "program level," a broader description of subroutine structure and the hierarchical layout of a behavioural "program." Program level imitation is a high-level, constructive mechanism, adapted for the efficient learning of complex skills and thus not evident in the simple manipulations used to test for imitation in the laboratory. As examples, we describe the food-preparation techniques of wild mountain gorillas and the imitative behaviour of orangutans undergoing "rehabilitation" to the wild. Representing and manipulating relations between objects seems to be one basic building block in their hierarchical programs. There is evidence that great apes suffer from a stricter capacity limit than humans in the hierarchical depth of planning. We re-interpret some chimpanzee behaviour previously described as "emulation" and suggest that all great apes may be able to imitate at the program level. Action level imitation is seldom observed in great ape skill learning, and may have a largely social role, even in humans. PMID- 10097024 TI - Gender differences in opinions and practices with regard to a "healthy diet". AB - Socio-cultural theories about gender differences with regard to food and health constitute the point of departure for this paper, which is based on data from two representative surveys in the Norwegian population. Both were carried out in the autumn of 1994; the first with 1050, the second with 13 200 respondents above 15 years of age. The surveys included questions on: (1) opinions on food and health related issues; (2) self reported dietary changes during the last 3 years prior to the study; (3) frequency of consumption of selected foods. Gender differences are analysed and related to various socio-economic variables. Such differences, although not as pronounced as expected, were found for most of the aspects studied. The responses from women were less related to socio-economic variables than those of men, both concerning opinions on what constitutes a healthy diet, and frequency of consumption of some foods (vegetables, fruits and dairy products). Gender differences were more pronounced between than within socio economic groups. In line with theories about women's higher health consciousness, women in general reported dietary changes corresponding to the dietary recommendations, and may also have learned more about health than men through their choice of information sources. PMID- 10097025 TI - Dietary patterns in high and low consumers of meat in a Swedish cohort study. AB - The objective was to examine relationships between meat and other food items which have been associated with higher risk of cancer in the colon and prostate in some epidemiological studies. The study was conducted as a population-based cohort study comprising 11648 subjects (4816 male and 6742 female) born between 1926 and 1945 and living in the city of Malmo, Sweden. Data on mean daily intake of foods and nutrients were assessed with a diet history method combining a 7-day menu book and a food frequency questionnaire. Increasing meat intake, expressed in quintiles and adjusted for energy, was associated with decreasing intakes of poultry, fish, fruits, bread, cereals and cheese in both sexes. Low negative correlations between meat intake and ascorbic acid (r= -0.11) and fiber (r= -0.16 to -0.20) were noted. The average intake of fat from meat out of total fat intake was 13.6% in men and 11.9% in women. No major associations were noted between meat and the cholesterol raising fatty acids C:12:0, C:14:0, C:160 nor for C:20:4 or its precursor C:18:2. In conclusion, our findings indicate that meat consumption is negatively associated with food groups rich in antioxidants and fiber and the positive covariance reported between meat and cancer and coronary heart disease might, therefore, not be directly linked to components in meat. PMID- 10097026 TI - Changes in food attitudes as a function of hunger. AB - This experiment investigated whether hunger selectively influences attitudes toward common food items. Participants completed a take-home questionnaire on which they rated their attitudes toward food and non-food items when they were either hungry (45 participants) or not hungry (45 participants); after returning the questionnaire, participants completed a second take-home questionnaire in the opposite hunger condition. Results of both between-subject and within-subject analyses revealed that participants rated foods more positively when hungry compared to not hungry and that there was no difference in the ratings of non foods when hungry vs. not hungry. Moreover, attitudes toward high-fat foods changed more as a function of hunger than attitudes toward low-calorie foods. As attitudes are important for guiding behavior, these results suggest that food attitudes influence daily eating patterns and consumer decisions regarding food purchases. The findings may also have important health implications because hunger exerts a greater influence on attitudes toward high-fat foods. PMID- 10097027 TI - Chocolate craving and hunger state: implications for the acquisition and expression of appetite and food choice. AB - The importance of hunger state for the acquisition and expression of chocolate craving was investigated. Seventeen chocolate cravers and 12 non-cravers were supplied with chocolate and instructed to eat some twice a day for 14 days. Within each group, subjects were allocated to one of two conditions, hungry- or full-trained. Hungry-trained subjects were asked to eat the chocolate exclusively at least 2 h after last eating; full-trained subjects were asked only to eat the chocolate 15-30 min after eating a meal. A diary was kept to encourage and allow assessment of compliance. At the start and end of the 2 weeks, subjects rated their craving for and anticipated intake of chocolate prior to eating it; then, on initial tasting, pleasantness of the taste was rated. All subjects made these ratings on one day when hungry and on another when full, as defined above. For cravers and non-cravers who ate chocolate exclusively when hungry, chocolate craving increased post-training, but, at least for cravers, only when ratings were made while hungry. For full-trained subjects, chocolate craving decreased post-training, but this decrease did not depend on whether subjects were currently hungry or full. A similar pattern of results was found for anticipated intake and pleasantness of taste, except that pleasantness did not increase in hungry-trained subjects. The results are interpreted with reference to learned control of appetite and in particular to recent findings on incentive learning processes. Craving for chocolate or other foods may be an expression of a strong appetite elicited by hunger that has been acquired by repeated experience of eating the craved food when hungry. PMID- 10097028 TI - The effect of naltrexone on taste detection and recognition threshold. AB - Eighteen healthy female volunteers were administered 50 mg naltrexone in a double blind, placebo control study. Relative taste detection and recognition thresholds for sweet, salty, sour and bitter taste and liking for and perception of sucrose solutions were determined at baseline and 1 hour after administration of naltrexone. Naltrexone did not alter relative taste detection and recognition thresholds for any of the four tastes or perception of sweetness. However, a significant, but slight, decrease in liking for sucrose solutions occurred after naltrexone administration. These findings suggest that opioid-dependent intake is independent of changes in taste perception in humans. PMID- 10097029 TI - Exercise increases the preference for salt in humans. AB - Salt preference was evaluated in 21 male students before and after 1 h routine exercise by measuring their preferred concentration of NaCl in tomato soup. Before exercise, baseline measures of preference were similar to those of 21 matched student controls that did not exercise. Immediately after exercise, the amount of NaCl added to flavour the soup increased by approximately 50% in comparison to pre-exercise baselines and to non-exercising controls. Concentration of sugar flavouring tea was unaltered. Twelve hours after exercise, preferred concentrations of both salt in soup and of sugar in tea were elevated. There were no changes, at any of these time intervals, in the preferences of the control students that did not exercise. These delayed and non-specific changes in preferences are attributed to hunger. However, we speculate that the immediate and specific increase in NaCl preference after exercise is due to sodium loss (in perspiration) and/or sympathetic arousal that activates the hormones, aldosterone and angiotensin II in humans, and that in animals increases salt preference. Our findings provide further evidence for the physiological regulation of salt preference in humans. PMID- 10097030 TI - Assessing food neophobia: the role of stimulus familiarity. AB - The present study assesses the effects of food familiarity on food ratings of neophobics and neophilics by having them sample and evaluate familiar and novel foods. Level of neophobia was assessed using the Food Neophobia Scale (FNS). Participants rated their familiarity with each food, their willingness to try the foods and expected liking for the foods, as well as their actual liking for the foods after they were sampled. Willingness to try the foods again in the future, and the amount of food sampled were also assessed. Evaluations of the foods were more positive for familiar vs. unfamiliar foods across all study participants. The responses of neophobics and neophilics were similar for familiar foods, but differed when the foods were unfamiliar, with neophobics making more negative evaluations. Neophobics and neophilics differed least in their liking ratings of the stimuli that were made after the foods were actually sampled, and differed most in their ratings of willingness to try the foods. It is concluded that neophobics have different expectancies about unfamiliar foods, and that these expectancies influence food sampling and rating behaviors. The neophobic's negative attitude toward an unfamiliar food may be ameliorated, but is not eliminated, once sensory information about the food is obtained. PMID- 10097031 TI - Pelmeni in the Eastern and Northern Russian diet: could fortification "make a silk purse out of a sow's ear"? PMID- 10097032 TI - Ingestive behaviour in female rats: influence of the ovarian cycle. PMID- 10097033 TI - Ontogeny of hyperphagia in the Zucker (fa/fa) rat: role of neuropeptide Y. PMID- 10097034 TI - Role of GLP-1 in meal-taking. PMID- 10097035 TI - Abstracts from the 7th food choice conference at the international congress of applied psychology PMID- 10097036 TI - The dual role of calcium: pore blocker and modulator of gating. PMID- 10097037 TI - Oral tolerance with copolymer 1 for the treatment of multiple sclerosis. PMID- 10097038 TI - Microbial polyketide synthases: more and more prolific. PMID- 10097039 TI - Crisis intervention: the role of telomerase. PMID- 10097040 TI - Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease. PMID- 10097042 TI - Geology, Mineralogy, and Human Welfare. Proceedings of a colloquium. Irvine, California, USA. November 8-9, 1998. PMID- 10097043 TI - Characterization of complex mineral assemblages: implications for contaminant transport and environmental remediation. AB - Surface reactive phases of soils and aquifers, comprised of phyllosilicate and metal oxohydroxide minerals along with humic substances, play a critical role in the regulation of contaminant fate and transport. Much of our knowledge concerning contaminant-mineral interactions at the molecular level, however, is derived from extensive experimentation on model mineral systems. Although these investigations have provided a foundation for understanding reactive surface functional groups on individual mineral phases, the information cannot be readily extrapolated to complex mineral assemblages in natural systems. Recent studies have elucidated the role of less abundant mineral and organic substrates as important surface chemical modifiers and have demonstrated complex coupling of reactivity between permanent-charge phyllosilicates and variable-charge Fe oxohydroxide phases. Surface chemical modifiers were observed to control colloid generation and transport processes in surface and subsurface environments as well as the transport of solutes and ionic tracers. The surface charging mechanisms operative in the complex mineral assemblages cannot be predicted based on bulk mineralogy or by considering surface reactivity of less abundant mineral phases based on results from model systems. The fragile nature of mineral assemblages isolated from natural systems requires novel techniques and experimental approaches for investigating their surface chemistry and reactivity free of artifacts. A complete understanding of the surface chemistry of complex mineral assemblages is prerequisite to accurately assessing environmental and human health risks of contaminants or in designing environmentally sound, cost effective chemical and biological remediation strategies. PMID- 10097041 TI - Luminal loop of the ryanodine receptor: a pore-forming segment? PMID- 10097044 TI - Surface geochemistry of the clay minerals. AB - Clay minerals are layer type aluminosilicates that figure in terrestrial biogeochemical cycles, in the buffering capacity of the oceans, and in the containment of toxic waste materials. They are also used as lubricants in petroleum extraction and as industrial catalysts for the synthesis of many organic compounds. These applications derive fundamentally from the colloidal size and permanent structural charge of clay mineral particles, which endow them with significant surface reactivity. Unraveling the surface geochemistry of hydrated clay minerals is an abiding, if difficult, topic in earth sciences research. Recent experimental and computational studies that take advantage of new methodologies and basic insights derived from the study of concentrated ionic solutions have begun to clarify the structure of electrical double layers formed on hydrated clay mineral surfaces, particularly those in the interlayer region of swelling 2:1 layer type clay minerals. One emerging trend is that the coordination of interlayer cations with water molecules and clay mineral surface oxygens is governed largely by cation size and charge, similarly to a concentrated ionic solution, but the location of structural charge within a clay layer and the existence of hydrophobic patches on its surface provide important modulations. The larger the interlayer cation, the greater the influence of clay mineral structure and hydrophobicity on the configurations of adsorbed water molecules. This picture extends readily to hydrophobic molecules adsorbed within an interlayer region, with important implications for clay-hydrocarbon interactions and the design of catalysts for organic synthesis. PMID- 10097045 TI - Contaminant bioavailability in soils, sediments, and aquatic environments. AB - The aqueous concentrations of heavy metals in soils, sediments, and aquatic environments frequently are controlled by the dissolution and precipitation of discrete mineral phases. Contaminant uptake by organisms as well as contaminant transport in natural systems typically occurs through the solution phase. Thus, the thermodynamic solubility of contaminant-containing minerals in these environments can directly influence the chemical reactivity, transport, and ecotoxicity of their constituent ions. In many cases, Pb-contaminated soils and sediments contain the minerals anglesite (PbSO4), cerussite (PbCO3), and various lead oxides (e.g., litharge, PbO) as well as Pb2+ adsorbed to Fe and Mn (hydr)oxides. Whereas adsorbed Pb can be comparatively inert, the lead oxides, sulfates, and carbonates are all highly soluble in acidic to circumneutral environments, and soil Pb in these forms can pose a significant environmental risk. In contrast, the lead phosphates [e.g., pyromorphite, Pb5(PO4)3Cl] are much less soluble and geochemically stable over a wide pH range. Application of soluble or solid-phase phosphates (i.e., apatites) to contaminated soils and sediments induces the dissolution of the "native" Pb minerals, the desorption of Pb adsorbed by hydrous metal oxides, and the subsequent formation of pyromorphites in situ. This process results in decreases in the chemical lability and bioavailability of the Pb without its removal from the contaminated media. This and analogous approaches may be useful strategies for remediating contaminated soils and sediments. PMID- 10097046 TI - Airborne minerals and related aerosol particles: effects on climate and the environment. AB - Aerosol particles are ubiquitous in the troposphere and exert an important influence on global climate and the environment. They affect climate through scattering, transmission, and absorption of radiation as well as by acting as nuclei for cloud formation. A significant fraction of the aerosol particle burden consists of minerals, and most of the remainder- whether natural or anthropogenic consists of materials that can be studied by the same methods as are used for fine-grained minerals. Our emphasis is on the study and character of the individual particles. Sulfate particles are the main cooling agents among aerosols; we found that in the remote oceanic atmosphere a significant fraction is aggregated with soot, a material that can diminish the cooling effect of sulfate. Our results suggest oxidization of SO2 may have occurred on soot surfaces, implying that even in the remote marine troposphere soot provided nuclei for heterogeneous sulfate formation. Sea salt is the dominant aerosol species (by mass) above the oceans. In addition to being important light scatterers and contributors to cloud condensation nuclei, sea-salt particles also provide large surface areas for heterogeneous atmospheric reactions. Minerals comprise the dominant mass fraction of the atmospheric aerosol burden. As all geologists know, they are a highly heterogeneous mixture. However, among atmospheric scientists they are commonly treated as a fairly uniform group, and one whose interaction with radiation is widely assumed to be unpredictable. Given their abundances, large total surface areas, and reactivities, their role in influencing climate will require increased attention as climate models are refined. PMID- 10097047 TI - Oceanic minerals: their origin, nature of their environment, and significance. AB - The chemical and isotopic compositions of oceanic biogenic and authigenic minerals contain invaluable information on the evolution of seawater, hence on the history of interaction between tectonics, climate, ocean circulation, and the evolution of life. Important advances and greater understanding of (a) key minor and trace element cycles with various residence times, (b) isotopic sources and sinks and fractionation behaviors, and (c) potential diagenetic problems, as well as developments in high-precision instrumentation, recently have been achieved. These advances provided new compelling evidence that neither gradualism nor uniformitarianism can explain many of the new important discoveries obtained from the chemistry and isotopic compositions of oceanic minerals. Presently, the best developed geochemical proxies in biogenic carbonates are 18O/16O and Sr/Ca ratios (possibly Mg/Ca) for temperature; 87Sr/86Sr for input sources, Cd/Ca and Ba/Ca ratios for phosphate and alkalinity concentrations, respectively, thus also for ocean circulation; 13C/12C for ocean productivity; B isotopes for seawater pH;, U, Th isotopes, and 14C for dating; and Sr and Mn concentrations for diagenesis. The oceanic authigenic minerals most widely used for chemical paleoceanography are barite, evaporite sulfates, and hydrogenous ferromanganese nodules. Marine barite is an effective alternative monitor of seawater 87Sr/86Sr, especially where carbonates are diagenetically altered or absent. It also provides a high resolution record of seawater sulfate S isotopes, (evaporite sulfates only carry an episodic record), with new insights on factors affecting the S and C cycles and atmospheric oxygen. High-resolution studies of Sr, Nd, and Pb isotopes of well-dated ferromanganese nodules contain invaluable records on climate driven changes in oceanic circulation. PMID- 10097048 TI - Mineral surfaces and bioavailability of heavy metals: a molecular-scale perspective. AB - There is a continual influx of heavy metal contaminants and pollutants into the biosphere from both natural and anthropogenic sources. A complex variety of abiotic and biotic processes affects their speciation and distribution, including adsorption onto and desorption from mineral surfaces, incorporation in precipitates or coprecipitates, release through the dissolution of minerals, and interactions with plants and microbes. Some of these processes can effectively isolate heavy metals from the biosphere, whereas others cause their release or transformation to different species that may be more (or less) bioavailable and/or toxic to organisms. Here we focus on abiotic adsorption and precipitation or coprecipitation processes involving the common heavy metal contaminant lead and the metalloids arsenic and selenium in mine tailings and contaminated soils. We have used extremely intense x-rays from synchrotron sources and a structure sensitive method known as x-ray absorption fine structure (XAFS) spectroscopy to determine the molecular-level speciation of these elements at concentrations of 50 to several thousand ppm in the contaminated environmental samples as well as in synthetic sorption samples. Our XAFS studies of As and Pb in the mine tailings show that up to 50% of these contaminants in the samples studied may be present as adsorbed species on mineral surfaces, which makes them potentially more bioavailable than when present in sparingly soluble solid phases. Our XAFS studies of Se(VI) sorption on Fe2+-containing sulfates show that this element undergoes redox reactions that transform it into less bioavailable and less toxic species. This type of information on molecular-level speciation of heavy metal and metalloid contaminants in various environmental settings is needed to prioritize remediation efforts and to assess their potential hazard to humans and other organisms. PMID- 10097049 TI - Long-range transport of mineral dust in the global atmosphere: impact of African dust on the environment of the southeastern United States. AB - Soil dust is a major constituent of airborne particles in the global atmosphere. Dust plumes frequently cover huge areas of the earth; they are one of the most prominent and commonly visible features in satellite imagery. Dust is believed to play a role in many biogeochemical processes, but the importance of dust in these processes is not well understood because of the dearth of information about the global distribution of dust and its physical, chemical, and mineralogical properties. This paper describes some features of the large-scale distribution of dust and identifies some of the geological characteristics of important source areas. The transport of dust from North Africa is presented as an example of possible long-range dust effects, and the impact of African dust on environmental processes in the western North Atlantic and the southeastern United States is assessed. Dust transported over long distances usually has a mass median diameter <10 microm. Small wind-borne soil particles show signs of extensive weathering; consequently, the physical and chemical properties of the particles will greatly depend on the weathering history in the source region and on the subsequent modifications that occur during transit in the atmosphere (typically a period of a week or more). To fully understand the role of dust in the environment and in human health, mineralogists will have to work closely with scientists in other disciplines to characterize the properties of mineral particles as an ensemble and as individual particles especially with regard to surface characteristics. PMID- 10097050 TI - Biological impact on mineral dissolution: application of the lichen model to understanding mineral weathering in the rhizosphere. AB - Microorganisms modify rates and mechanisms of chemical and physical weathering and clay growth, thus playing fundamental roles in soil and sediment formation. Because processes in soils are inherently complex and difficult to study, we employ a model based on the lichen-mineral system to identify the fundamental interactions. Fixed carbon released by the photosynthetic symbiont stimulates growth of fungi and other microorganisms. These microorganisms directly or indirectly induce mineral disaggregation, hydration, dissolution, and secondary mineral formation. Model polysaccharides were used to investigate direct mediation of mineral surface reactions by extracellular polymers. Polysaccharides can suppress or enhance rates of chemical weathering by up to three orders of magnitude, depending on the pH, mineral surface structure and composition, and organic functional groups. Mg, Mn, Fe, Al, and Si are redistributed into clays that strongly adsorb ions. Microbes contribute to dissolution of insoluble secondary phosphates, possibly via release of organic acids. These reactions significantly impact soil fertility. Below fungi-mineral interfaces, mineral surfaces are exposed to dissolved metabolic byproducts. Through this indirect process, microorganisms can accelerate mineral dissolution, leading to enhanced porosity and permeability and colonization by microbial communities. PMID- 10097051 TI - A risk assessment for exposure to grunerite asbestos (amosite) in an iron ore mine. AB - The potential for health risks to humans exposed to the asbestos minerals continues to be a public health concern. Although the production and use of the commercial amphibole asbestos minerals-grunerite (amosite) and riebeckite (crocidolite)-have been almost completely eliminated from world commerce, special opportunities for potentially significant exposures remain. Commercially viable deposits of grunerite asbestos are very rare, but it can occur as a gangue mineral in a limited part of a mine otherwise thought asbestos-free. This report describes such a situation, in which a very localized seam of grunerite asbestos was identified in an iron ore mine. The geological occurrence of the seam in the ore body is described, as well as the mineralogical character of the grunerite asbestos. The most relevant epidemiological studies of workers exposed to grunerite asbestos are used to gauge the hazards associated with the inhalation of this fibrous mineral. Both analytical transmission electron microscopy and phase-contrast optical microscopy were used to quantify the fibers present in the air during mining in the area with outcroppings of grunerite asbestos. Analytical transmission electron microscopy and continuous-scan x-ray diffraction were used to determine the type of asbestos fiber present. Knowing the level of the miner's exposures, we carried out a risk assessment by using a model developed for the Environmental Protection Agency. PMID- 10097052 TI - Potential effects of gas hydrate on human welfare. AB - For almost 30 years. serious interest has been directed toward natural gas hydrate, a crystalline solid composed of water and methane, as a potential (i) energy resource, (ii) factor in global climate change, and (iii) submarine geohazard. Although each of these issues can affect human welfare, only (iii) is considered to be of immediate importance. Assessments of gas hydrate as an energy resource have often been overly optimistic, based in part on its very high methane content and on its worldwide occurrence in continental margins. Although these attributes are attractive, geologic settings, reservoir properties, and phase-equilibria considerations diminish the energy resource potential of natural gas hydrate. The possible role of gas hydrate in global climate change has been often overstated. Although methane is a "greenhouse" gas in the atmosphere, much methane from dissociated gas hydrate may never reach the atmosphere, but rather may be converted to carbon dioxide and sequestered by the hydrosphere/biosphere before reaching the atmosphere. Thus, methane from gas hydrate may have little opportunity to affect global climate change. However, submarine geohazards (such as sediment instabilities and slope failures on local and regional scales, leading to debris flows, slumps, slides, and possible tsunamis) caused by gas hydrate dissociation are of immediate and increasing importance as humankind moves to exploit seabed resources in ever-deepening waters of coastal oceans. The vulnerability of gas hydrate to temperature and sea level changes enhances the instability of deep-water oceanic sediments, and thus human activities and installations in this setting can be affected. PMID- 10097053 TI - Health impacts of domestic coal use in China. AB - Domestic coal combustion has had profound adverse effects on the health of millions of people worldwide. In China alone several hundred million people commonly burn raw coal in unvented stoves that permeate their homes with high levels of toxic metals and organic compounds. At least 3,000 people in Guizhou Province in southwest China are suffering from severe arsenic poisoning. The primary source of the arsenic appears to be consumption of chili peppers dried over fires fueled with high-arsenic coal. Coal samples in the region were found to contain up to 35,000 ppm arsenic. Chili peppers dried over high-arsenic coal fires adsorb 500 ppm arsenic on average. More than 10 million people in Guizhou Province and surrounding areas suffer from dental and skeletal fluorosis. The excess fluorine is caused by eating corn dried over burning briquettes made from high-fluorine coals and high-fluorine clay binders. Polycyclic aromatic hydrocarbons formed during coal combustion are believed to cause or contribute to the high incidence of esophageal and lung cancers in parts of China. Domestic coal combustion also has caused selenium poisoning and possibly mercury poisoning. Better knowledge of coal quality parameters may help to reduce some of these health problems. For example, information on concentrations and distributions of potentially toxic elements in coal may help delineate areas of a coal deposit to be avoided. Information on the modes of occurrence of these elements and the textural relations of the minerals and macerals in coal may help predict the behavior of the potentially toxic components during coal combustion. PMID- 10097054 TI - Nuclear waste forms for actinides. AB - The disposition of actinides, most recently 239Pu from dismantled nuclear weapons, requires effective containment of waste generated by the nuclear fuel cycle. Because actinides (e.g., 239Pu and 237Np) are long-lived, they have a major impact on risk assessments of geologic repositories. Thus, demonstrable, long-term chemical and mechanical durability are essential properties of waste forms for the immobilization of actinides. Mineralogic and geologic studies provide excellent candidate phases for immobilization and a unique database that cannot be duplicated by a purely materials science approach. The "mineralogic approach" is illustrated by a discussion of zircon as a phase for the immobilization of excess weapons plutonium. PMID- 10097055 TI - Illite and hydrocarbon exploration. AB - Illite is a general term for the dioctahedral mica-like clay mineral common in sedimentary rocks, especially shales. Illite is of interest to the petroleum industry because it can provide a K-Ar isotope date that constrains the timing of basin heating events. It is critical to establish that hydrocarbon formation and migration occurred after the formation of the trap (anticline, etc.) that is to hold the oil. Illite also may precipitate in the pores of sandstone reservoirs, impeding fluid flow. Illite in shales is a mixture of detrital mica and its weathering products with diagenetic illite formed by reaction with pore fluids during burial. K-Ar ages are apparent ages of mixtures of detrital and diagenetic end members, and what we need are the ages of the end members themselves. This paper describes a methodology, based on mineralogy and crystallography, for interpreting the K-Ar ages from illites in sedimentary rocks and for estimating the ages of the end members. PMID- 10097056 TI - Manganese oxide minerals: crystal structures and economic and environmental significance. AB - Manganese oxide minerals have been used for thousands of years-by the ancients for pigments and to clarify glass, and today as ores of Mn metal, catalysts, and battery material. More than 30 Mn oxide minerals occur in a wide variety of geological settings. They are major components of Mn nodules that pave huge areas of the ocean floor and bottoms of many fresh-water lakes. Mn oxide minerals are ubiquitous in soils and sediments and participate in a variety of chemical reactions that affect groundwater and bulk soil composition. Their typical occurrence as fine-grained mixtures makes it difficult to study their atomic structures and crystal chemistries. In recent years, however, investigations using transmission electron microscopy and powder x-ray and neutron diffraction methods have provided important new insights into the structures and properties of these materials. The crystal structures for todorokite and birnessite, two of the more common Mn oxide minerals in terrestrial deposits and ocean nodules, were determined by using powder x-ray diffraction data and the Rietveld refinement method. Because of the large tunnels in todorokite and related structures there is considerable interest in the use of these materials and synthetic analogues as catalysts and cation exchange agents. Birnessite-group minerals have layer structures and readily undergo oxidation reduction and cation-exchange reactions and play a major role in controlling groundwater chemistry. PMID- 10097057 TI - Negative pH, efflorescent mineralogy, and consequences for environmental restoration at the Iron Mountain Superfund site, California. AB - The Richmond Mine of the Iron Mountain copper deposit contains some of the most acid mine waters ever reported. Values of pH have been measured as low as -3.6, combined metal concentrations as high as 200 g/liter, and sulfate concentrations as high as 760 g/liter. Copious quantities of soluble metal sulfate salts such as melanterite, chalcanthite, coquimbite, rhomboclase, voltaite, copiapite, and halotrichite have been identified, and some of these are forming from negative-pH mine waters. Geochemical calculations show that, under a mine-plugging remediation scenario, these salts would dissolve and the resultant 600,000-m3 mine pool would have a pH of 1 or less and contain several grams of dissolved metals per liter, much like the current portal effluent water. In the absence of plugging or other at-source control, current weathering rates indicate that the portal effluent will continue for approximately 3, 000 years. Other remedial actions have greatly reduced metal loads into downstream drainages and the Sacramento River, primarily by capturing the major acidic discharges and routing them to a lime neutralization plant. Incorporation of geochemical modeling and mineralogical expertise into the decision-making process for remediation can save time, save money, and reduce the likelihood of deleterious consequences. PMID- 10097058 TI - La roca magica: uses of natural zeolites in agriculture and industry. AB - For nearly 200 years since their discovery in 1756, geologists considered the zeolite minerals to occur as fairly large crystals in the vugs and cavities of basalts and other traprock formations. Here, they were prized by mineral collectors, but their small abundance and polymineralic nature defied commercial exploitation. As the synthetic zeolite (molecular sieve) business began to take hold in the late 1950s, huge beds of zeolite-rich sediments, formed by the alteration of volcanic ash (glass) in lake and marine waters, were discovered in the western United States and elsewhere in the world. These beds were found to contain as much as 95% of a single zeolite; they were generally flat-lying and easily mined by surface methods. The properties of these low-cost natural materials mimicked those of many of their synthetic counterparts, and considerable effort has made since that time to develop applications for them based on their unique adsorption, cation-exchange, dehydration-rehydration, and catalytic properties. Natural zeolites (i.e., those found in volcanogenic sedimentary rocks) have been and are being used as building stone, as lightweight aggregate and pozzolans in cements and concretes, as filler in paper, in the take up of Cs and Sr from nuclear waste and fallout, as soil amendments in agronomy and horticulture, in the removal of ammonia from municipal, industrial, and agricultural waste and drinking waters, as energy exchangers in solar refrigerators, as dietary supplements in animal diets, as consumer deodorizers, in pet litters, in taking up ammonia from animal manures, and as ammonia filters in kidney-dialysis units. From their use in construction during Roman times, to their role as hydroponic (zeoponic) substrate for growing plants on space missions, to their recent success in the healing of cuts and wounds, natural zeolites are now considered to be full-fledged mineral commodities, the use of which promise to expand even more in the future. PMID- 10097059 TI - Synthetic zeolites and other microporous oxide molecular sieves. AB - Use of synthetic zeolites and other microporous oxides since 1950 has improved insulated windows, automobile air-conditioning, refrigerators, air brakes on trucks, laundry detergents, etc. Their large internal pore volumes, molecular size pores, regularity of crystal structures, and the diverse framework chemical compositions allow "tailoring" of structure and properties. Thus, highly active and selective catalysts as well as adsorbents and ion exchangers with high capacities and selectivities were developed. In the petroleum refining and petrochemical industries, zeolites have made possible cheaper and lead-free gasoline, higher performance and lower-cost synthetic fibers and plastics, and many improvements in process efficiency and quality and in performance. Zeolites also help protect the environment by improving energy efficiency, reducing automobile exhaust and other emissions, cleaning up hazardous wastes (including the Three Mile Island nuclear power plant and other radioactive wastes), and, as specially tailored desiccants, facilitating the substitution of new refrigerants for the ozone-depleting chlorofluorocarbons banned by the Montreal Protocol. PMID- 10097061 TI - Keeping America secure for the 21st century. PMID- 10097060 TI - Biochemical evolution III: polymerization on organophilic silica-rich surfaces, crystal-chemical modeling, formation of first cells, and geological clues. AB - Catalysis at organophilic silica-rich surfaces of zeolites and feldspars might generate replicating biopolymers from simple chemicals supplied by meteorites, volcanic gases, and other geological sources. Crystal-chemical modeling yielded packings for amino acids neatly encapsulated in 10-ring channels of the molecular sieve silicalite-ZSM-5-(mutinaite). Calculation of binding and activation energies for catalytic assembly into polymers is progressing for a chemical composition with one catalytic Al-OH site per 25 neutral Si tetrahedral sites. Internal channel intersections and external terminations provide special stereochemical features suitable for complex organic species. Polymer migration along nano/micrometer channels of ancient weathered feldspars, plus exploitation of phosphorus and various transition metals in entrapped apatite and other microminerals, might have generated complexes of replicating catalytic biomolecules, leading to primitive cellular organisms. The first cell wall might have been an internal mineral surface, from which the cell developed a protective biological cap emerging into a nutrient-rich "soup." Ultimately, the biological cap might have expanded into a complete cell wall, allowing mobility and colonization of energy-rich challenging environments. Electron microscopy of honeycomb channels inside weathered feldspars of the Shap granite (northwest England) has revealed modern bacteria, perhaps indicative of Archean ones. All known early rocks were metamorphosed too highly during geologic time to permit simple survival of large-pore zeolites, honeycombed feldspar, and encapsulated species. Possible microscopic clues to the proposed mineral adsorbents/catalysts are discussed for planning of systematic study of black cherts from weakly metamorphosed Archaean sediments. PMID- 10097063 TI - Helionitronium trication (NO2He3+) and helionitrosonium trication (HeNO3+). AB - The structures and stabilities of helionitronium trication NO2He3+ and helionitrosonium trication HeNO3+ were calculated at the ab initio MP2/6-31G** level. The Cs symmetry structure was found to be a minimum for the NO2He3+ trication, which is isoelectronic and isostructural with the previously studied NO2H2+. Dissociation of the Cs symmetry structure into NO+ and OHe2+ is thermodynamically preferred by 183.1 kcal/mol (1 cal = 4.18 J), although a kinetic barrier of 12.4 kcal/mol has to be overcome. The Cinfinityv symmetry structure was also found to be a minimum for the HeNO3+ trication. PMID- 10097062 TI - Probing cell-surface architecture through synthesis: an NMR-determined structural motif for tumor-associated mucins. AB - Cell-surface mucin glycoproteins are altered with the onset of oncogenesis. Knowledge of mucin structure could be used in vaccine strategies that target tumor-associated mucin motifs. Thus far, however, mucins have resisted detailed molecular analysis. Reported herein is the solution conformation of a highly complex segment of the mucin CD43. The elongated secondary structure of the isolated mucin strand approaches the stability of motifs found in folded proteins. The features required for the mucin motif to emerge are also described. Immunocharacterization of related constructs strongly suggests that the observed epitopes represent distinguishing features of tumor cell-surface architecture. PMID- 10097065 TI - Screw rotations and glide mirrors: crystallography in Fourier space. AB - The traditional crystallographic symmetry elements of screw axes and glide planes are subdivided into those that are removable and those that are essential. A simple real-space criterion, depending only on Bravais class, determines which types can be present in any space group. This terminological refinement is useful in expressing the complementary relation between the real-space and Fourier-space formulations of crystal symmetry, particularly in the case of the two nonsymmorphic space groups that have no systematic extinctions (I212121 and I213). A simple analysis in Fourier space demonstrates the nonsymmorphicity of these two space groups, which finds its physical expression not in a characteristic absence of Bragg peaks, but in a characteristic presence of electronic level degeneracies. PMID- 10097064 TI - Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. AB - A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC50 = 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study. PMID- 10097066 TI - Design of highly specific cytotoxins by using trans-splicing ribozymes. AB - We have designed ribozymes based on a self-splicing group I intron that can trans splice exon sequences into a chosen RNA target to create a functional chimeric mRNA and provide a highly specific trigger for gene expression. We have targeted ribozymes against the coat protein mRNA of a widespread plant pathogen, cucumber mosaic virus. The ribozymes were designed to trans-splice the coding sequence of the diphtheria toxin A chain in frame with the viral initiation codon of the target sequence. Diphtheria toxin A chain catalyzes the ADP ribosylation of elongation factor 2 and can cause the cessation of protein translation. In a Saccharomyces cerevisiae model system, ribozyme expression was shown to specifically inhibit the growth of cells expressing the virus mRNA. A point mutation at the target splice site alleviated this ribozyme-mediated toxicity. Increasing the extent of base pairing between the ribozyme and target dramatically increased specific expression of the cytotoxin and reduced illegitimate toxicity in vivo. Trans-splicing ribozymes may provide a new class of agents for engineering virus resistance and therapeutic cytotoxins. PMID- 10097067 TI - A cytosine analog that confers enhanced potency to antisense oligonucleotides. AB - Antisense technology is based on the ability to design potent, sequence-specific inhibitors. The G-clamp heterocycle modification, a cytosine analog that clamps on to guanine by forming an additional hydrogen bond, was rationally designed to enhance oligonucleotide/RNA hybrid affinity. A single, context-dependent substitution of a G-clamp heterocycle into a 15-mer phosphorothioate oligodeoxynucleotide (S-ON) targeting the cyclin-dependent kinase inhibitor, p27(kip1), enhanced antisense activity as compared with a previously optimized C5 propynyl-modified p27(kip1) S-ON and functionally replaced 11 C5-propynyl modifications. Dose-dependent, sequence-specific antisense inhibition was observed at nanomolar concentrations of the G-clamp S-ONs. A single nucleotide mismatch between the G-clamp S-ON and the p27(kip1) mRNA reduced the potency of the antisense ON by five-fold. A 2-base-mismatch S-ON eliminated antisense activity, confirming the sequence specificity of G-clamp-modified S-ONs. The G clamp-substituted p27(kip1) S-ON activated RNase H-mediated cleavage and demonstrated increased in vitro binding affinity for its RNA target compared with conventional 15-mer S-ONs. Furthermore, incorporation of a single G-clamp modification into a previously optimized 20-mer phosphorothioate antisense S-ON targeting c-raf increased the potency of the S-ON 25-fold. The G-clamp heterocycle is a potent, mismatch-sensitive, automated synthesizer-compatible antisense S-ON modification that will have important applications in the elucidation of gene function, the validation of gene targets, and the development of more potent antisense-based pharmaceuticals. PMID- 10097068 TI - SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor. AB - SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor copressor) mediate transcriptional repression of important regulators that are involved in many signaling pathways. SMRT and N-CoR are related proteins that form complexes with mSin3A/B and histone deacetylases to induce local chromatin condensation and transcriptional repression. However, SMRT is substantially smaller than N-CoR, lacking an N-terminal domain of approximately 1,000 aa that are present in N-CoR. Here, we report the identification of SMRT-extended (SMRTe), which contains an N-terminal sequence that shows striking similarity with N-CoR. As in N-CoR, this SMRTe-N-terminal domain also represses basal transcription. We find that SMRTe expression is regulated during cell cycle progression and SMRTe transcripts are present in many embryonic tissues. These data redefine a structurally and functionally more related nuclear receptor corepressor family and suggest an additional role for SMRTe in the regulation of cycle-specific gene expression in diverse signaling pathways. PMID- 10097069 TI - Deduction of consensus binding sequences on proteins that bind IIAGlc of the phosphoenolpyruvate:sugar phosphotransferase system by cysteine scanning mutagenesis of Escherichia coli lactose permease. AB - Mediated by the protein IIAGlc, the phosphoenolpyruvate:sugar phosphotransferase system plays a role in the regulation of activity of other sugar transport systems in Escherichia coli. By using a direct binding assay, a collection of single-Cys replacement mutants in cytoplasmic loops of lactose permease were evaluated for their capacity to bind IIAGlc. Selected Cys replacements in loops IV/V or VI/VII result in loss of binding activity. Analysis of the mutagenesis results together with multiple sequence alignments of a family of proteins that interacts with IIAGlc provides the basis for developing two regions of consensus sequence in those partner proteins necessary for binding to IIAGlc. The requirement for two interaction regions is interpreted in the regulatory framework of a substrate-dependent conformational change that brings those two regions into an orientation optimal for binding IIAGlc. PMID- 10097070 TI - Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. AB - Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step in the regulation of cell growth and differentiation. This step is the NAD-dependent oxidation of inosine 5' monophosphate (IMP) to xanthosine 5' monophosphate, the rate-limiting step in the synthesis of the guanine nucleotides. Two isoforms of IMPDH have been identified, one of which (type II) is significantly up- regulated in neoplastic and differentiating cells. As such, it has been identified as a major target in antitumor and immunosuppressive drug design. We present here the 2.9-A structure of a ternary complex of the human type II isoform of IMPDH. The complex contains the substrate analogue 6-chloropurine riboside 5'-monophosphate (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine dinucleotide, the selenium derivative of the active metabolite of the antitumor drug tiazofurin. The enzyme forms a homotetramer, with the dinucleotide binding at the monomer-monomer interface. The 6 chloro-substituted purine base is dehalogenated, forming a covalent adduct at C6 with Cys-331. The dinucleotide selenazole base is stacked against the 6-Cl-IMP purine ring in an orientation consistent with the B side stereochemistry of hydride transfer seen with NAD. The adenosine end of the ligand interacts with residues not conserved between the type I and type II isoforms, suggesting strategies for the design of isoform-specific agents. PMID- 10097071 TI - Nitroreductase A is regulated as a member of the soxRS regulon of Escherichia coli. AB - Nitroreductase A catalyzes the divalent reduction of nitro compounds, quinones, and dyes by NADPH. In this paper, nitroreductase A is induced in Escherichia coli by exposure to paraquat in a manner that depends on the expression of soxR. Nitroreductase activity was only slightly induced by paraquat in a strain bearing a mutational defect in the gene encoding nitroreductase A, but it was approximately 3-fold induced in the parental strain. Nitroreductase A thus appears to be a member of the soxRS regulon and probably contributes to the defenses against oxidative stress by minimizing the redox cycling attendant upon the univalent reduction of nitro compounds, quinones, and dyes. PMID- 10097072 TI - Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. AB - A receptor that mediates osteoprotegerin ligand (OPGL)-induced osteoclast differentiation and activation has been identified via genomic analysis of a primary osteoclast precursor cell cDNA library and is identical to the tumor necrosis factor receptor (TNFR) family member RANK. The RANK mRNA was highly expressed by isolated bone marrow-derived osteoclast progenitors and by mature osteoclasts in vivo. Recombinant OPGL binds specifically to RANK expressed by transfected cell lines and purified osteoclast progenitors. Transgenic mice expressing a soluble RANK-Fc fusion protein have severe osteopetrosis because of a reduction in osteoclasts, similar to OPG transgenic mice. Recombinant RANK-Fc binds with high affinity to OPGL in vitro and blocks osteoclast differentiation and activation in vitro and in vivo. Furthermore, polyclonal Ab against the RANK extracellular domain promotes osteoclastogenesis in bone marrow cultures suggesting that RANK activation mediates the effects of OPGL on the osteoclast pathway. These data indicate that OPGL-induced osteoclastogenesis is directly mediated through RANK on osteoclast precursor cells. PMID- 10097073 TI - Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. AB - Biochemical studies of Wnt signaling have been hampered by difficulties in obtaining large quantities of soluble, biologically active Wnt proteins. In this paper, we report the production in Drosophila S2 cells of biologically active Xenopus Wnt8 (XWnt8). Epitope- or alkaline phosphatase-tagged XWnt8 proteins are secreted by concentrated S2 cells in a form that is suitable for quantitative biochemical experiments with yields of 5 and 0.5 mg per liter, respectively. Conditions also are described for the production in 293 cells of an IgG fusion of the cysteine-rich domain (CRD) of mouse Frizzled 8 with a yield of 20 mg/liter. We demonstrate the use of these proteins for studying the interactions between soluble XWnt8 and various Frizzled proteins, membrane anchored or secreted CRDs, and a set of insertion mutants in the CRD of Drosophila Frizzled 2. In a solid phase binding assay, the affinity of the XWnt8-alkaline phosphatase fusion for the purified mouse Frizzled 8-CRD-IgG fusion is approximately 9 nM. PMID- 10097074 TI - Replication fork assembly at recombination intermediates is required for bacterial growth. AB - PriA, a 3' --> 5' DNA helicase, directs assembly of a primosome on some bacteriophage and plasmid DNAs. Primosomes are multienzyme replication machines that contribute both the DNA-unwinding and Okazaki fragment-priming functions at the replication fork. The role of PriA in chromosomal replication is unclear. The phenotypes of priA null mutations suggest that the protein participates in replication restart at recombination intermediates. We show here that PriA promotes replication fork assembly at a D loop, an intermediate formed during initiation of homologous recombination. We also show that DnaC810, encoded by a naturally arising intergenic suppressor allele of the priA2::kan mutation, bypasses the need for PriA during replication fork assembly at D loops in vitro. These findings underscore the essentiality of replication fork restart at recombination intermediates under normal growth conditions in bacteria. PMID- 10097075 TI - The role of threonine 37 in flavin reactivity of the old yellow enzyme. AB - Threonine 37 is conserved among all the members of the old yellow enzyme (OYE) family. The hydroxyl group of this residue forms a hydrogen bond with the C-4 oxygen atom of the FMN reaction center of the enzyme [Fox, K. M. & Karplus, P. A. (1994) Structure 2, 1089-1105]. The position of Thr-37 and its interaction with flavin allow for speculations about its role in enzyme activity. This residue was mutated to alanine and the mutant enzyme was studied and compared with the wild type OYE1 to evaluate its mechanistic function. The mutation has different effects on the two separate half-reactions of the enzyme. The mutant enzyme has enhanced activity in the oxidative half-reaction but the reductive half-reaction is slowed down by more than one order of magnitude. The peaks of the absorption spectra for enzyme bound with phenolic compounds are shifted toward shorter wavelengths than those of wild-type OYE1, consistent with its lower redox potential. It is suggested that Thr-37 in the wild-type OYE1 increases the redox potential of the enzyme by stabilizing the negative charge of the reduced flavin through hydrogen bonding with it. PMID- 10097076 TI - Combinatorial protein engineering by incremental truncation. AB - We have developed a combinatorial approach, using incremental truncation libraries of overlapping N- and C-terminal gene fragments, that examines all possible bisection points within a given region of an enzyme that will allow the conversion of a monomeric enzyme into its functional heterodimer. This general method for enzyme bisection will have broad applications in the engineering of new catalytic functions through domain swapping and chemical synthesis of modified peptide fragments and in the study of enzyme evolution and protein folding. We have tested this methodology on Escherichia coli glycinamide ribonucleotide formyltransferase (PurN) and, by genetic selection, identified PurN heterodimers capable of glycinamide ribonucleotide transformylation. Two were chosen for physical characterization and were found to be comparable to the wild-type PurN monomer in terms of stability to denaturation, activity, and binding of substrate and cofactor. Sequence analysis of 18 randomly chosen, active PurN heterodimers revealed that the breakpoints primarily clustered in loops near the surface of the enzyme, that the breaks could result in the deletion of highly conserved residues and, most surprisingly, that the active site could be bisected. PMID- 10097077 TI - Rational design of a scytalone dehydratase-like enzyme using a structurally homologous protein scaffold. AB - The generation of enzymes to catalyze specific reactions is one of the more challenging problems facing protein engineers. Structural similarities between the enzyme scytalone dehydratase with nuclear transport factor 2 (NTF2) suggested the potential for NTF2 to be re-engineered into a scytalone dehydratase-like enzyme. We introduced four key catalytic residues into NTF2 to create a scytalone dehydratase-like active site. A C-terminal helix found in scytalone dehydratase but absent in NTF2 also was added. Mutant NTF2 proteins were tested for catalytic activity by using a spectroscopic assay. One of the engineered enzymes exhibited catalytic activity with minimal kcat and Km values of 0.125 min-1 and 800 microM, respectively. This level of catalytic activity represents minimally a 150-fold improvement in activity over the background rate for substrate dehydration and a dramatic step forward from the catalytically inert parent NTF2. This work represents one of the few examples of converting a protein scaffold into an enzyme, outside those arising from the induction of catalytic activity into antibodies. PMID- 10097078 TI - Crystal structure of human p32, a doughnut-shaped acidic mitochondrial matrix protein. AB - Human p32 (also known as SF2-associated p32, p32/TAP, and gC1qR) is a conserved eukaryotic protein that localizes predominantly in the mitochondrial matrix. It is thought to be involved in mitochondrial oxidative phosphorylation and in nucleus-mitochondrion interactions. We report the crystal structure of p32 determined at 2.25 A resolution. The structure reveals that p32 adopts a novel fold with seven consecutive antiparallel beta-strands flanked by one N-terminal and two C-terminal alpha-helices. Three monomers form a doughnut-shaped quaternary structure with an unusually asymmetric charge distribution on the surface. The implications of the structure on previously proposed functions of p32 are discussed and new specific functional properties are suggested. PMID- 10097079 TI - Thermal adaptation analyzed by comparison of protein sequences from mesophilic and extremely thermophilic Methanococcus species. AB - The genome sequence of the extremely thermophilic archaeon Methanococcus jannaschii provides a wealth of data on proteins from a thermophile. In this paper, sequences of 115 proteins from M. jannaschii are compared with their homologs from mesophilic Methanococcus species. Although the growth temperatures of the mesophiles are about 50 degrees C below that of M. jannaschii, their genomic G+C contents are nearly identical. The properties most correlated with the proteins of the thermophile include higher residue volume, higher residue hydrophobicity, more charged amino acids (especially Glu, Arg, and Lys), and fewer uncharged polar residues (Ser, Thr, Asn, and Gln). These are recurring themes, with all trends applying to 83-92% of the proteins for which complete sequences were available. Nearly all of the amino acid replacements most significantly correlated with the temperature change are the same relatively conservative changes observed in all proteins, but in the case of the mesophile/thermophile comparison there is a directional bias. We identify 26 specific pairs of amino acids with a statistically significant (P < 0.01) preferred direction of replacement. PMID- 10097080 TI - Engineering precision RNA molecular switches. AB - Ligand-specific molecular switches composed of RNA were created by coupling preexisting catalytic and receptor domains via structural bridges. Binding of ligand to the receptor triggers a conformational change within the bridge, and this structural reorganization dictates the activity of the adjoining ribozyme. The modular nature of these tripartite constructs makes possible the rapid construction of precision RNA molecular switches that trigger only in the presence of their corresponding ligand. By using similar enzyme engineering strategies, new RNA switches can be made to operate as designer molecular sensors or as a new class of genetic control elements. PMID- 10097081 TI - Designing conditions for in vitro formation of amyloid protofilaments and fibrils. AB - We have been able to convert a small alpha/beta protein, acylphosphatase, from its soluble and native form into insoluble amyloid fibrils of the type observed in a range of pathological conditions. This was achieved by allowing slow growth in a solution containing moderate concentrations of trifluoroethanol. When analyzed with electron microscopy, the protein aggregate present in the sample after long incubation times consisted of extended, unbranched filaments of 30-50 A in width that assemble subsequently into higher order structures. This fibrillar material possesses extensive beta-sheet structure as revealed by far-UV CD and IR spectroscopy. Furthermore, the fibrils exhibit Congo red birefringence, increased fluorescence with thioflavine T and cause a red-shift of the Congo red absorption spectrum. All of these characteristics are typical of amyloid fibrils. The results indicate that formation of amyloid occurs when the native fold of a protein is destabilized under conditions in which noncovalent interactions, and in particular hydrogen bonding, within the polypeptide chain remain favorable. We suggest that amyloid formation is not restricted to a small number of protein sequences but is a property common to many, if not all, natural polypeptide chains under appropriate conditions. PMID- 10097082 TI - Mutually compensatory mutations during evolution of the tetramerization domain of tumor suppressor p53 lead to impaired hetero-oligomerization. AB - We have measured the stability and stoichiometry of variants of the human p53 tetramerization domain to assess the effects of mutation on homo- and hetero oligomerization. The residues chosen for mutation were those in the hydrophobic core that we had previously found to be critical for its stability but are not conserved in human p73 or p51 or in p53-related proteins from invertebrates or vertebrates. The mutations introduced were either single natural mutations or combinations of mutations present in p53-like proteins from different species. Most of the mutations were substantially destabilizing when introduced singly. The introduction of multiple mutations led to two opposite effects: some combinations of mutations that have occurred during the evolution of the hydrophobic core of the domain in p53-like proteins had additive destabilizing effects, whereas other naturally occurring combinations of mutations had little or no net effect on the stability, there being mutually compensating effects of up to 9.5 kcal/mol of tetramer. The triple mutant L332V/F341L/L344I, whose hydrophobic core represents that of the chicken p53 domain, was nearly as stable as the human domain but had impaired hetero-oligomerization with it. Thus, engineering of a functional p53 variant with a reduced capacity to hetero oligomerize with wild-type human p53 can be achieved without any impairment in the stability and subunit affinity of the engineered homo-oligomer. PMID- 10097083 TI - Crystal structure of a thermostable type B DNA polymerase from Thermococcus gorgonarius. AB - Most known archaeal DNA polymerases belong to the type B family, which also includes the DNA replication polymerases of eukaryotes, but maintain high fidelity at extreme conditions. We describe here the 2.5 A resolution crystal structure of a DNA polymerase from the Archaea Thermococcus gorgonarius and identify structural features of the fold and the active site that are likely responsible for its thermostable function. Comparison with the mesophilic B type DNA polymerase gp43 of the bacteriophage RB69 highlights thermophilic adaptations, which include the presence of two disulfide bonds and an enhanced electrostatic complementarity at the DNA-protein interface. In contrast to gp43, several loops in the exonuclease and thumb domains are more closely packed; this apparently blocks primer binding to the exonuclease active site. A physiological role of this "closed" conformation is unknown but may represent a polymerase mode, in contrast to an editing mode with an open exonuclease site. This archaeal B DNA polymerase structure provides a starting point for structure-based design of polymerases or ligands with applications in biotechnology and the development of antiviral or anticancer agents. PMID- 10097084 TI - Cytoplasmic RNA modulators of an inside-out signal-transduction cascade. AB - A vaccinia virus-based RNA expression system enabled high-level cytoplasmic expression of RNA aptamers directed against the intracellular domain of the beta2 integrin LFA-1, a transmembrane protein that mediates cell adhesion to intercellular adhesion molecule-1 (ICAM-1). In two different cell types, cytoplasmic expression of integrin-binding aptamers reduced inducible cell adhesion to ICAM-1. The aptamers specifically target, and thereby define, a functional cytoplasmic subdomain important for the regulation of cell adhesion in leukocytes. Our approach of aptamer-controlled blocking of signaling pathways in vivo could potentially be applied wherever targeted modulation of a signal transduction cascade is desired. PMID- 10097085 TI - Expression of Batis maritima methyl chloride transferase in Escherichia coli. AB - Methyl chloride transferase, a novel enzyme found in several fungi, marine algae, and halophytic plants, is a biological catalyst responsible for the production of atmospheric methyl chloride. A previous paper reports the purification of this methylase from Batis maritima and the isolation of a cDNA clone of the gene for this enzyme. In this paper, we describe the isolation of a genomic clone of the methylase gene and the expression of recombinant methyl chloride transferase in Escherichia coli and compare the kinetic behavior of the wild-type and recombinant enzyme. The recombinant enzyme is active and promotes the production of methyl chloride by E. coli under in vivo conditions. The kinetic data indicate that the recombinant and wild-type enzymes have similar halide (Cl-, Br-, and I-) binding capacities. Both the recombinant and wild-type enzymes were found to function well in high NaCl concentrations. This high salt tolerance resembles the activity of halobacterial enzymes rather than halophytic plant enzymes. These findings support the hypothesis that this enzyme functions in the control and regulation of the internal concentration of chloride ions in halophytic plant cells. PMID- 10097086 TI - Telomerase in kinetoplastid parasitic protozoa. AB - We have identified telomerase activity in extracts of three evolutionarily diverse kinetoplastid species: Trypanosoma brucei, Leishmania major, and Leishmania tarentolae. Telomerase activity was initially detected in extracts from insect form cells of all three kinetoplastid species by using a modification of the one-tube telomere repeat amplification protocol [Kim, N., et al. (1994) Science 266, 2011-2015], although better results were subsequently achieved with the two-tube telomere repeat amplification protocol [Autexier, C., Pruzan, R., Funk, W. & Greider, C. (1996) EMBO J. 15, 5928-5935]. The activity in T. brucei extracts was sufficiently robust to enable its detection in a direct assay of telomerase; enzyme processivity was found to be relatively low. The in vitro properties of telomerase suggest a possible templating domain sequence for the telomerase RNA of T. brucei. Telomerase activity is likely to contribute to telomere maintenance in these parasitic organisms and provides a new target for chemotherapeutic intervention. PMID- 10097087 TI - Ectopic expression of the minimal whiE polyketide synthase generates a library of aromatic polyketides of diverse sizes and shapes. AB - The single recombinant expressing the Streptomyces coelicolor minimal whiE (spore pigment) polyketide synthase (PKS) is uniquely capable of generating a large array of well more than 30 polyketides, many of which, so far, are novel to this recombinant. The characterized polyketides represent a diverse set of molecules that differ in size (chain length) and shape (cyclization pattern). This combinatorial biosynthetic library is, by far, the largest and most complex of its kind described to date and indicates that the minimal whiE PKS does not independently control polyketide chain length nor dictate the first cyclization event. Rather, the minimal PKS enzyme complex must rely on the stabilizing effects of additional subunits (i.e., the cyclase whiE-ORFVI) to ensure that the chain reaches the full 24 carbons and cyclizes correctly. This dramatic loss of control implies that the growing polyketide chain does not remain enzyme bound, resulting in the spontaneous cyclization of the methyl terminus. Among the six characterized dodecaketides, four different first-ring cyclization regiochemistries are represented, including C7/C12, C8/C13, C10/C15, and C13/C15. The dodecaketide TW93h possesses a unique 2,4-dioxaadamantane ring system and represents a new structural class of polyketides with no related structures isolated from natural or engineered organisms, thus supporting the claim that engineered biosynthesis is capable of producing novel chemotypes. PMID- 10097088 TI - The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2. AB - Cytokines interact with hematopoietin superfamily receptors and stimulate receptor dimerization. We demonstrate that chemoattractant cytokines (chemokines) also trigger biological responses through receptor dimerization. Functional responses are induced after pairwise crosslinking of chemokine receptors by bivalent agonistic antichemokine receptor mAb, but not by their Fab fragments. Monocyte chemoattractant protein (MCP)-1-triggered receptor dimerization was studied in human embryonic kidney (HEK)-293 cells cotransfected with genes coding for the CCR2b receptor tagged with YSK or Myc sequences. After MCP-1 stimulation, immunoprecipitation with Myc-specific antibodies revealed YSK-tagged receptors in immunoblotting. Receptor dimerization also was validated by chemical crosslinking in both HEK-293 cells and the human monocytic cell line Mono Mac 1. Finally, we constructed a loss-of-function CCR2bY139F mutant that acted as a dominant negative, blocking signaling through the CCR2 wild-type receptor. This study provides functional support for a model in which the MCP-1 receptor is activated by ligand-induced homodimerization, allowing discussion of the similarities between bacterial and leukocyte chemotaxis. PMID- 10097089 TI - Uncoupling of transfer of the presequence and unfolding of the mature domain in precursor translocation across the mitochondrial outer membrane. AB - Translocation of mitochondrial precursor proteins across the mitochondrial outer membrane is facilitated by the translocase of the outer membrane (TOM) complex. By using site-specific photocrosslinking, we have mapped interactions between TOM proteins and a mitochondrial precursor protein arrested at two distinct stages, stage A (accumulated at 0 degrees C) and stage B (accumulated at 30 degrees C), in the translocation across the outer membrane at high resolution not achieved previously. Although the stage A and stage B intermediates were assigned previously to the forms bound to the cis site and the trans site of the TOM complex, respectively, the results of crosslinking indicate that the presequence of the intermediates at both stage A and stage B is already on the trans side of the outer membrane. The mature domain is unfolded and bound to Tom40 at stage B whereas it remains folded at stage A. After dissociation from the TOM complex, translocation of the stage B intermediate, but not of the stage A intermediate, across the inner membrane was promoted by the intermembrane-space domain of Tom22. We propose a new model for protein translocation across the outer membrane, where translocation of the presequence and unfolding of the mature domain are not necessarily coupled. PMID- 10097090 TI - The inositol polyphosphate 4-phosphatase forms a complex with phosphatidylinositol 3-kinase in human platelet cytosol. AB - Inositol polyphosphate 4-phosphatase (4-phosphatase) is an enzyme that catalyses the hydrolysis of the 4-position phosphate from phosphatidylinositol 3,4 bisphosphate [PtdIns(3,4)P2]. In human platelets the formation of this phosphatidylinositol, by the actions of phosphatidylinositol 3-kinase (PI 3 kinase), correlates with irreversible platelet aggregation. We have shown previously that a phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase forms a complex with the p85 subunit of PI 3-kinase. In this study we investigated whether PI 3-kinase also forms a complex with the 4-phosphatase in human platelets. Immunoprecipitates of the p85 subunit of PI 3-kinase from human platelet cytosol contained 4-phosphatase enzyme activity and a 104-kDa polypeptide recognized by specific 4-phosphatase antibodies. Similarly, immunoprecipitates made using 4-phosphatase-specific antibodies contained PI 3 kinase enzyme activity and an 85-kDa polypeptide recognized by antibodies to the p85 adapter subunit of PI 3-kinase. After thrombin activation, the 4-phosphatase translocated to the actin cytoskeleton along with PI 3-kinase in an integrin- and aggregation-dependent manner. The majority of the PI 3-kinase/4-phosphatase complex (75%) remained in the cytosolic fraction. We propose that the complex formed between the two enzymes serves to localize the 4-phosphatase to sites of PtdIns(3,4)P2 production. PMID- 10097091 TI - Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor alpha knockout mouse uterus. AB - Estrogen is known to increase progesterone receptor (PR) levels in the wild-type mouse uterus, and this estrogen induction was thought to be important for progesterone action through the PR. The estrogen receptor alpha knockout (ERKO) mouse uterus was observed to express PR mRNA that cannot be induced by estrogen. Progesterone action was characterized to determine whether it was diminished in ERKO mice. The PR protein is present in the ERKO uterus at 60% of the level measured in a wild-type uterus. The PR-A and PR-B isoforms are both detected on Western blot, and the ratio of isoforms is the same in both genotypes. Although the level of PR is reduced in the ERKO uterus, the receptor level is sufficient to induce genomic responses, since both calcitonin and amphiregulin mRNAs were increased after progesterone treatment. Finally, the ERKO uterus can be induced to undergo a progesterone-dependent decidual response. Surprisingly, the decidual response is estrogen independent in the ERKO, although it remains estrogen dependent in a wild type. These results indicate that estrogen receptor alpha modulation of PR levels is not necessary for expression of the PR or genomic and physiologic responses to progesterone in the ERKO uterus. PMID- 10097092 TI - Factor-specific modulation of CREB-binding protein acetyltransferase activity. AB - CREB-binding proteins (CBP) and p300 are essential transcriptional coactivators for a large number of regulated DNA-binding transcription factors, including CREB, nuclear receptors, and STATs. CBP and p300 function in part by mediating the assembly of multiprotein complexes that contain additional cofactors such as p300/CBP interacting protein (p/CIP), a member of the p160/SRC family of coactivators, and the p300/CBP associated factor p/CAF. In addition to serving as molecular scaffolds, CBP and p300 each possess intrinsic acetyltransferase activities that are required for their function as coactivators. Here we report that the adenovirus E1A protein inhibits the acetyltransferase activity of CBP on binding to the C/H3 domain, whereas binding of CREB, or a CREB/E1A fusion protein to the KIX domain, fails to inhibit CBP acetyltransferase activity. Surprisingly, p/CIP can either inhibit or stimulate CBP acetyltransferase activity depending on the specific substrate evaluated and the functional domains present in the p/CIP protein. While the CBP interaction domain of p/CIP inhibits acetylation of histones H3, H4, or high mobility group by CBP, it enhances acetylation of other substrates, such as Pit-1. These observations suggest that the acetyltransferase activities of CBP/p300 and p/CAF can be differentially modulated by factors binding to distinct regions of CBP/p300. Because these interactions are likely to result in differential effects on the coactivator functions of CBP/p300 for different classes of transcription factors, regulation of CBP/p300 acetyltransferase activity may represent a mechanism for integration of diverse signaling pathways. PMID- 10097093 TI - Molecular characteristics of fibroblast growth factor-fibroblast growth factor receptor-heparin-like glycosaminoglycan complex. AB - Fibroblast growth factor (FGF) family plays key roles in development, wound healing, and angiogenesis. Understanding of the molecular nature of interactions of FGFs with their receptors (FGFRs) has been seriously limited by the absence of structural information on FGFR or FGF-FGFR complex. In this study, based on an exhaustive analysis of the primary sequences of the FGF family, we determined that the residues that constitute the primary receptor-binding site of FGF-2 are conserved throughout the FGF family, whereas those of the secondary receptor binding site of FGF-2 are not. We propose that the FGF-FGFR interaction mediated by the 'conserved' primary site interactions is likely to be similar if not identical for the entire FGF family, whereas the 'variable' secondary sites, on both FGF as well as FGFR mediates specificity of a given FGF to a given FGFR isoform. Furthermore, as the pro-inflammatory cytokine interleukin 1 (IL-1) and FGF-2 share the same structural scaffold, we find that the spatial orientation of the primary receptor-binding site of FGF-2 coincides structurally with the IL 1beta receptor-binding site when the two molecules are superimposed. The structural similarities between the IL-1 and the FGF system provided a framework to elucidate molecular principles of FGF-FGFR interactions. In the FGF-FGFR model proposed here, the two domains of a single FGFR wrap around a single FGF-2 molecule such that one domain of FGFR binds to the primary receptor-binding site of the FGF molecule, while the second domain of the same FGFR binds to the secondary receptor-binding site of the same FGF molecule. Finally, the proposed model is able to accommodate not only heparin-like glycosaminoglycan (HLGAG) interactions with FGF and FGFR but also FGF dimerization or oligomerization mediated by HLGAG. PMID- 10097094 TI - Spin-lattice relaxation of laser-polarized xenon in human blood. AB - The nuclear spin polarization of 129Xe can be enhanced by several orders of magnitude by using optical pumping techniques. The increased sensitivity of xenon NMR has allowed imaging of lungs as well as other in vivo applications. The most critical parameter for efficient delivery of laser-polarized xenon to blood and tissues is the spin-lattice relaxation time (T1) of xenon in blood. In this work, the relaxation of laser-polarized xenon in human blood is measured in vitro as a function of blood oxygenation. Interactions with dissolved oxygen and with deoxyhemoglobin are found to contribute to the spin-lattice relaxation time of 129Xe in blood, the latter interaction having greater effect. Consequently, relaxation times of 129Xe in deoxygenated blood are shorter than in oxygenated blood. In samples with oxygenation equivalent to arterial and venous blood, the 129Xe T1s at 37 degrees C and a magnetic field of 1.5 T were 6.4 s +/- 0.5 s and 4.0 s +/- 0.4 s, respectively. The 129Xe spin-lattice relaxation time in blood decreases at lower temperatures, but the ratio of T1 in oxygenated blood to that in deoxygenated blood is the same at 37 degrees C and 25 degrees C. A competing ligand has been used to show that xenon binding to albumin contributes to the 129Xe spin-lattice relaxation in blood plasma. This technique is promising for the study of xenon interactions with macromolecules. PMID- 10097095 TI - Single-pair fluorescence resonance energy transfer on freely diffusing molecules: observation of Forster distance dependence and subpopulations. AB - Photon bursts from single diffusing donor-acceptor labeled macromolecules were used to measure intramolecular distances and identify subpopulations of freely diffusing macromolecules in a heterogeneous ensemble. By using DNA as a rigid spacer, a series of constructs with varying intramolecular donor-acceptor spacings were used to measure the mean and distribution width of fluorescence resonance energy transfer (FRET) efficiencies as a function of distance. The mean single-pair FRET efficiencies qualitatively follow the distance dependence predicted by Forster theory. Possible contributions to the widths of the FRET efficiency distributions are discussed, and potential applications in the study of biopolymer conformational dynamics are suggested. The ability to measure intramolecular (and intermolecular) distances for single molecules implies the ability to distinguish and monitor subpopulations of molecules in a mixture with different distances or conformational states. This is demonstrated by monitoring substrate and product subpopulations before and after a restriction endonuclease cleavage reaction. Distance measurements at single-molecule resolution also should facilitate the study of complex reactions such as biopolymer folding. To this end, the denaturation of a DNA hairpin was examined by using single-pair FRET. PMID- 10097096 TI - Comparing in vitro, in situ, and in vivo experimental data in a three-dimensional model of mammalian cochlear mechanics. AB - Normal mammalian hearing is refined by amplification of the motion of the cochlear partition. This partition, comprising the organ of Corti sandwiched between the basilar and tectorial membranes, contains the outer hair cells that are thought to drive this amplification process. Force generation by outer hair cells has been studied extensively in vitro and in situ, but, to understand cochlear amplification fully, it is necessary to characterize the role played by each of the components of the cochlear partition in vivo. Observations of cochlear partition motion in vivo are severely restricted by its inaccessibility and sensitivity to surgical trauma, so, for the present study, a computer model has been used to simulate the operation of the cochlea under different experimental conditions. In this model, which uniquely retains much of the three dimensional complexity of the real cochlea, the motions of the basilar and tectorial membranes are fundamentally different during in situ- and in vivo-like conditions. Furthermore, enhanced outer hair cell force generation in vitro leads paradoxically to a decrease in the gain of the cochlear amplifier during sound stimulation to the model in vivo. These results suggest that it is not possible to extrapolate directly from experimental observations made in vitro and in situ to the normal operation of the intact organ in vivo. PMID- 10097097 TI - Alanine is helix-stabilizing in both template-nucleated and standard peptide helices. AB - Alanine-based peptides of defined sequence and length show measurable helix contents, allowing them to be used as a model system both for analyzing the mechanism of helix formation and for investigating the contributions of side chain interactions to protein stability. Extensive characterization of many peptide sequences with varying amino acid contents indicates that the favorable helicity of alanine-based peptides can be attributed to the large helix stabilizing propensity of alanine. Based on their analysis of alanine-rich sequences N-terminally linked to a synthetic helix-inducing template, Kemp and coworkers [Kemp, D. S., Boyd, J. G. & Muendel, C. C. (1991) Nature (London) 352, 451-454; Kemp, D. S., Oslick, S. L. & Allen, T. J. (1996) J. Am. Chem. Soc. 118, 4249-4255] argue that alanine is helix-indifferent, however, and that the favorable helix contents of alanine-based peptides must have some other explanation. Here, we show that the helix contents of template-nucleated sequences are influenced strongly by properties of the template-helix junction. A model in which the helix propensities of residues at the template-peptide junction are treated separately brings the results from alanine-based peptides and template-nucleated helices into agreement. The resulting model provides a physically plausible resolution of the discrepancies between the two systems and allows the helix contents of both template-nucleated and standard peptide helices to be predicted by using a single set of helix propensities. Helix formation in both standard peptides and template-peptide conjugates can be attributed to the large intrinsic helix-forming tendency of alanine. PMID- 10097098 TI - In situ atomic force microscopy study of Alzheimer's beta-amyloid peptide on different substrates: new insights into mechanism of beta-sheet formation. AB - We have applied in situ atomic force microscopy to directly observe the aggregation of Alzheimer's beta-amyloid peptide (Abeta) in contact with two model solid surfaces: hydrophilic mica and hydrophobic graphite. The time course of aggregation was followed by continuous imaging of surfaces remaining in contact with 10-500 microM solutions of Abeta in PBS (pH 7.4). Visualization of fragile nanoscale aggregates of Abeta was made possible by the application of a tapping mode of imaging, which minimizes the lateral forces between the probe tip and the sample. The size and the shape of Abeta aggregates, as well as the kinetics of their formation, exhibited pronounced dependence on the physicochemical nature of the surface. On hydrophilic mica, Abeta formed particulate, pseudomicellar aggregates, which at higher Abeta concentration had the tendency to form linear assemblies, reminiscent of protofibrillar species described recently in the literature. In contrast, on hydrophobic graphite Abeta formed uniform, elongated sheets. The dimensions of those sheets were consistent with the dimensions of beta-sheets with extended peptide chains perpendicular to the long axis of the aggregate. The sheets of Abeta were oriented along three directions at 120 degrees to each other, resembling the crystallographic symmetry of a graphite surface. Such substrate-templated self-assembly may be the distinguishing feature of beta-sheets in comparison with alpha-helices. These studies show that in situ atomic force microscopy enables direct assessment of amyloid aggregation in physiological fluids and suggest that Abeta fibril formation may be driven by interactions at the interface of aqueous solutions and hydrophobic substrates, as occurs in membranes and lipoprotein particles in vivo. PMID- 10097099 TI - Mechanical and chemical unfolding of a single protein: a comparison. AB - Is the mechanical unraveling of protein domains by atomic force microscopy (AFM) just a technological feat or a true measurement of their unfolding? By engineering a protein made of tandem repeats of identical Ig modules, we were able to get explicit AFM data on the unfolding rate of a single protein domain that can be accurately extrapolated to zero force. We compare this with chemical unfolding rates for untethered modules extrapolated to 0 M denaturant. The unfolding rates obtained by the two methods are the same. Furthermore, the transition state for unfolding appears at the same position on the folding pathway when assessed by either method. These results indicate that mechanical unfolding of a single protein by AFM does indeed reflect the same event that is observed in traditional unfolding experiments. The way is now open for the extensive use of AFM to measure folding reactions at the single-molecule level. Single-molecule AFM recordings have the added advantage that they define the reaction coordinate and expose rare unfolding events that cannot be observed in the absence of chemical denaturants. PMID- 10097100 TI - Suppression of breast cancer growth and metastasis by a serpin myoepithelium derived serine proteinase inhibitor expressed in the mammary myoepithelial cells. AB - A serpin was identified in normal mammary gland by differential cDNA sequencing. In situ hybridization has detected this serpin exclusively in the myoepithelial cells on the normal and noninvasive mammary epithelial side of the basement membrane and thus was named myoepithelium-derived serine proteinase inhibitor (MEPI). No MEPI expression was detected in the malignant breast carcinomas. MEPI encodes a 405-aa precursor, including an 18-residue secretion signal with a calculated molecular mass of 46 kDa. The predicted sequence of the new protein shares 33% sequence identity and 58% sequence similarity to plasminogen activator inhibitor (PAI)-1 and PAI-2. To determine whether MEPI can modulate the in vivo growth and progression of human breast cancers, we transfected a full-length MEPI cDNA into human breast cancer cells and studied the orthotopic growth of MEPI transfected vs. control clones in the mammary fat pad of athymic nude mice. Overexpression of MEPI inhibited the invasion of the cells in the in vitro invasion assay. When injected orthotopically into nude mice, the primary tumor volumes, axillary lymph node metastasis, and lung metastasis were significantly inhibited in MEPI-transfected clones as compared with controls. The expression of MEPI in myoepithelial cells may prevent breast cancer malignant progression leading to metastasis. PMID- 10097101 TI - GADD45 induction of a G2/M cell cycle checkpoint. AB - G1/S and G2/M cell cycle checkpoints maintain genomic stability in eukaryotes in response to genotoxic stress. We report here both genetic and functional evidence of a Gadd45-mediated G2/M checkpoint in human and murine cells. Increased expression of Gadd45 via microinjection of an expression vector into primary human fibroblasts arrests the cells at the G2/M boundary with a phenotype of MPM2 immunopositivity, 4n DNA content and, in 15% of the cells, centrosome separation. The Gadd45-mediated G2/M arrest depends on wild-type p53, because no arrest was observed either in p53-null Li-Fraumeni fibroblasts or in normal fibroblasts coexpressed with p53 mutants. Increased expression of cyclin B1 and Cdc25C inhibited the Gadd45-mediated G2/M arrest in human fibroblasts, indicating that the mechanism of Gadd45-mediated G2/M checkpoint is at least in part through modulation of the activity of the G2-specific kinase, cyclin B1/p34(cdc2). Genetic and physiological evidence of a Gadd45-mediated G2/M checkpoint was obtained by using GADD45-deficient human or murine cells. Human cells with endogenous Gadd45 expression reduced by antisense GADD45 expression have an impaired G2/M checkpoint after exposure to either ultraviolet radiation or methyl methanesulfonate but are still able to undergo G2 arrest after ionizing radiation. Lymphocytes from gadd45-knockout mice (gadd45 -/-) also retained a G2/M checkpoint initiated by ionizing radiation and failed to arrest at G2/M after exposure to ultraviolet radiation. Therefore, the mammalian genome is protected by a multiplicity of G2/M checkpoints in response to specific types of DNA damage. PMID- 10097102 TI - The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. AB - betaarrestins mediate the desensitization of the beta2-adrenergic receptor (beta2AR) and many other G protein-coupled receptors (GPCRs). Additionally, betaarrestins initiate the endocytosis of these receptors via clathrin coated pits and interact directly with clathrin. Consequently, it has been proposed that betaarrestins serve as clathrin adaptors for the GPCR family by linking these receptors to clathrin lattices. AP-2, the heterotetrameric clathrin adaptor protein, has been demonstrated to mediate the internalization of many types of plasma membrane proteins other than GPCRs. AP-2 interacts with the clathrin heavy chain and cytoplasmic domains of receptors such as those for epidermal growth factor and transferrin. In the present study we demonstrate the formation of an agonist-induced multimeric complex containing a GPCR, betaarrestin 2, and the beta2-adaptin subunit of AP-2. beta2-Adaptin binds betaarrestin 2 in a yeast two hybrid assay and coimmunoprecipitates with betaarrestins and beta2AR in an agonist-dependent manner in HEK-293 cells. Moreover, beta2-adaptin translocates from the cytosol to the plasma membrane in response to the beta2AR agonist isoproterenol and colocalizes with beta2AR in clathrin-coated pits. Finally, expression of betaarrestin 2 minigene constructs containing the beta2-adaptin interacting region inhibits beta2AR endocytosis. These findings point to a role for AP-2 in GPCR endocytosis, and they suggest that AP-2 functions as a clathrin adaptor for the endocytosis of diverse classes of membrane receptors. PMID- 10097103 TI - Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. AB - Phosphorylation is thought to be an essential first step in the prompt deactivation of photoexcited rhodopsin. In vitro, the phosphorylation can be catalyzed either by rhodopsin kinase (RK) or by protein kinase C (PKC). To investigate the specific role of RK, we inactivated both alleles of the RK gene in mice. This eliminated the light-dependent phosphorylation of rhodopsin and caused the single-photon response to become larger and longer lasting than normal. These results demonstrate that RK is required for normal rhodopsin deactivation. When the photon responses of RK-/- rods did finally turn off, they did so abruptly and stochastically, revealing a first-order backup mechanism for rhodopsin deactivation. The rod outer segments of RK-/- mice raised in 12-hr cyclic illumination were 50% shorter than those of normal (RK+/+) rods or rods from RK-/- mice raised in constant darkness. One day of constant light caused the rods in the RK-/- mouse retina to undergo apoptotic degeneration. Mice lacking RK provide a valuable model for the study of Oguchi disease, a human RK deficiency that causes congenital stationary night blindness. PMID- 10097104 TI - Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening. AB - Human fibroblasts whose lifespan in culture has been extended by expression of a viral oncogene eventually undergo a growth crisis marked by failure to proliferate. It has been proposed that telomere shortening in these cells is the property that limits their proliferation. Here we report that ectopic expression of the wild-type reverse transcriptase protein (hTERT) of human telomerase averts crisis, at the same time reducing the frequency of dicentric and abnormal chromosomes. Surprisingly, as the resulting immortalized cells containing active telomerase continue to proliferate, their telomeres continue to shorten to mean lengths below those in control cells that enter crisis. These results provide evidence for a protective function of human telomerase that allows cell proliferation without requiring net lengthening of telomeres. PMID- 10097105 TI - Import of DNA into mammalian nuclei by proteins originating from a plant pathogenic bacterium. AB - Import of DNA into mammalian nuclei is generally inefficient. Therefore, one of the current challenges in human gene therapy is the development of efficient DNA delivery systems. Here we tested whether bacterial proteins could be used to target DNA to mammalian cells. Agrobacterium tumefaciens, a plant pathogen, efficiently transfers DNA as a nucleoprotein complex to plant cells. Agrobacterium-mediated T-DNA transfer to plant cells is the only known example for interkingdom DNA transfer and is widely used for plant transformation. Agrobacterium virulence proteins VirD2 and VirE2 perform important functions in this process. We reconstituted complexes consisting of the bacterial virulence proteins VirD2, VirE2, and single-stranded DNA (ssDNA) in vitro. These complexes were tested for import into HeLa cell nuclei. Import of ssDNA required both VirD2 and VirE2 proteins. A VirD2 mutant lacking its C-terminal nuclear localization signal was deficient in import of the ssDNA-protein complexes into nuclei. Import of VirD2-ssDNA-VirE2 complexes was fast and efficient, and was shown to depended on importin alpha, Ran, and an energy source. We report here that the bacterium derived and plant-adapted protein-DNA complex, made in vitro, can be efficiently imported into mammalian nuclei following the classical importin-dependent nuclear import pathway. This demonstrates the potential of our approach to enhance gene transfer to animal cells. PMID- 10097106 TI - Raft association of SNAP receptors acting in apical trafficking in Madin-Darby canine kidney cells. AB - We have investigated the relationships between the apical sorting mechanism using lipid rafts and the soluble N-ethyl maleimide-sensitive factor attachment protein receptor (SNARE) machinery, which is involved in membrane docking and fusion. We first confirmed that anti-alpha-SNAP antibodies inhibit the apical pathway in Madin- Darby canine kidney (MDCK) cells; in addition, we report that a recombinant SNAP protein stimulates the apical transport whereas a SNAP mutant inhibits this transport step. Based on t-SNARE overexpression experiments and the effect of botulinum neurotoxin E, syntaxin 3 and SNAP-23 have been implicated in apical membrane trafficking. Here, we show in permeabilized MDCK cells that antisyntaxin 3 and anti-SNAP-23 antibodies lower surface delivery of an apical reporter protein. Moreover, using a similar approach, we show that tetanus toxin insensitive, vesicle-associated membrane protein (TI-VAMP; also called VAMP7), a recently described apical v-SNARE, is involved. Furthermore, we show the presence of syntaxin 3 and TI-VAMP in isolated apical carriers. Polarized apical sorting has been postulated to be mediated by the clustering of apical proteins into dynamic sphingolipid-cholesterol rafts. We provide evidence that syntaxin 3 and TI-VAMP are raft-associated. These data support a raft-based mechanism for the sorting of not only apically destined cargo but also of SNAREs having functions in apical membrane-docking and fusion events. PMID- 10097107 TI - Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex. AB - The Arp2/3 complex, a stable assembly of two actin-related proteins (Arp2 and Arp3) with five other subunits, caps the pointed end of actin filaments and nucleates actin polymerization with low efficiency. WASp and Scar are two similar proteins that bind the p21 subunit of the Arp2/3 complex, but their effect on the nucleation activity of the complex was not known. We report that full-length, recombinant human Scar protein, as well as N-terminally truncated Scar proteins, enhance nucleation by the Arp2/3 complex. By themselves, these proteins either have no effect or inhibit actin polymerization. The actin monomer-binding W domain and the p21-binding A domain from the C terminus of Scar are both required to activate Arp2/3 complex. A proline-rich domain in the middle of Scar enhances the activity of the W and A domains. Preincubating Scar and Arp2/3 complex with actin filaments overcomes the initial lag in polymerization, suggesting that efficient nucleation by the Arp2/3 complex requires assembly on the side of a preexisting filament-a dendritic nucleation mechanism. The Arp2/3 complex with full-length Scar, Scar containing P, W, and A domains, or Scar containing W and A domains overcomes inhibition of nucleation by the actin monomer-binding protein profilin, giving active nucleation over a low background of spontaneous nucleation. These results show that Scar and, likely, related proteins, such as the Cdc42 targets WASp and N-WASp, are endogenous activators of actin polymerization by the Arp2/3 complex. PMID- 10097108 TI - A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. AB - Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. Much of our current understanding of checkpoints comes from genetic studies conducted in yeast. In the fission yeast Schizosaccharomyces pombe (Sp), SpRad3 is an essential component of both the DNA damage and DNA replication checkpoints. The SpChk1 and SpCds1 protein kinases function downstream of SpRad3. SpChk1 is an effector of the DNA damage checkpoint and, in the absence of SpCds1, serves an essential function in the DNA replication checkpoint. SpCds1 functions in the DNA replication checkpoint and in the S phase DNA damage checkpoint. Human homologs of both SpRad3 and SpChk1 but not SpCds1 have been identified. Here we report the identification of a human cDNA encoding a protein (designated HuCds1) that shares sequence, structural, and functional similarity to SpCds1. HuCds1 was modified by phosphorylation and activated in response to ionizing radiation. It was also modified in response to hydroxyurea treatment. Functional ATM protein was required for HuCds1 modification after ionizing radiation but not after hydroxyurea treatment. Like its fission yeast counterpart, human Cds1 phosphorylated Cdc25C to promote the binding of 14-3-3 proteins. These findings suggest that the checkpoint function of HuCds1 is conserved in yeast and mammals. PMID- 10097109 TI - Specific interaction of the yeast cis-Golgi syntaxin Sed5p and the coat protein complex II component Sec24p of endoplasmic reticulum-derived transport vesicles. AB - The generation of transport vesicles at the endoplasmic reticulum (ER) depends on cytosolic proteins, which, in the form of subcomplexes (Sec23p/Sec24p; Sec13p/Sec31p) are recruited to the ER membrane by GTP-bound Sar1p and form the coat protein complex II (COPII). Using affinity chromatography and two-hybrid analyses, we found that the essential COPII component Sec24p, but not Sec23p, binds to the cis-Golgi syntaxin Sed5p. Sec24p/Sed5p interaction in vitro was not dependent on the presence of [Sar1p.GTP]. The binding of Sec24p to Sed5p is specific; none of the other seven yeast syntaxins bound to this COPII component. Whereas the interaction site of Sec23p is within the N-terminal half of the 926 aa-long Sec24p (amino acid residues 56-549), Sed5p binds to the N- and C-terminal halves of the protein. Destruction by mutagenesis of a potential zinc finger within the N-terminal half of Sec24p led to a nonfunctional protein that was still able to bind Sec23p and Sed5p. Sec24p/Sed5p binding might be relevant for cargo selection during transport-vesicle formation and/or for vesicle targeting to the cis-Golgi. PMID- 10097110 TI - Probing the Saccharomyces cerevisiae centromeric DNA (CEN DNA)-binding factor 3 (CBF3) kinetochore complex by using atomic force microscopy. AB - Yeast centromeric DNA (CEN DNA) binding factor 3 (CBF3) is a multisubunit protein complex that binds to the essential CDEIII element in CEN DNA. The four CBF3 proteins are required for accurate chromosome segregation and are considered to be core components of the yeast kinetochore. We have examined the structure of the CBF3-CEN DNA complex by atomic force microscopy. Assembly of CBF3-CEN DNA complexes was performed by combining purified CBF3 proteins with a DNA fragment that includes the CEN region from yeast chromosome III. Atomic force microscopy images showed DNA molecules with attached globular bodies. The contour length of the DNA containing the complex is approximately 9% shorter than the DNA alone, suggesting some winding of DNA within the complex. The measured location of the single binding site indicates that the complex is located asymmetrically to the right of CDEIII extending away from CDEI and CDEII, which is consistent with previous data. The CEN DNA is bent approximately 55 degrees at the site of complex formation. A significant fraction of the complexes are linked in pairs, showing three to four DNA arms, with molecular volumes approximately three times the mean volumes of two-armed complexes. These multi-armed complexes indicate that CBF3 can bind two DNA molecules together in vitro and, thus, may be involved in holding together chromatid pairs during mitosis. PMID- 10097111 TI - Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. AB - The p38 mitogen-activated protein kinase is activated by treatment of cells with cytokines and by exposure to environmental stress. The effects of these stimuli on p38 MAP kinase are mediated by the MAP kinase kinases (MKKs) MKK3, MKK4, and MKK6. We have examined the function of the p38 MAP kinase signaling pathway by investigating the effect of targeted disruption of the Mkk3 gene. Here we report that Mkk3 gene disruption caused a selective defect in the response of fibroblasts to the proinflammatory cytokine tumor necrosis factor, including reduced p38 MAP kinase activation and cytokine expression. These data demonstrate that the MKK3 protein kinase is a critical component of a tumor necrosis factor stimulated signaling pathway that causes increased expression of inflammatory cytokines. PMID- 10097112 TI - Regulation of p53 expression by thymidylate synthase. AB - Previous studies showed that thymidylate synthase (TS), as an RNA binding protein, regulates its own synthesis by impairing the translation of TS mRNA. In this report, we present evidence that p53 expression is affected in a similar manner by TS. For these studies, we used a TS-depleted human colon cancer HCT-C cell that had been transfected with either the human TS cDNA or the Escherichia coli TS gene. The level of p53 protein in transfected cells overexpressing human TS was significantly reduced when compared with its corresponding parent HCT-C cells. This suppression of p53 expression was the direct result of decreased translational efficiency of p53 mRNA. Similar results were obtained upon transfection of HCT-C cells with pcDNA 3.1 (+) containing the E. coli TS gene. These findings provide evidence that TS, from diverse species, specifically regulates p53 expression at the translational level. In addition, TS overexpressing cells with suppressed levels of p53 are significantly impaired in their ability to arrest in G1 phase in response to exposure to a DNA-damaging agent such as gamma-irradiation. These studies provide support for the in vivo biological relevance of the interaction between TS and p53 mRNA and identify a molecular pathway for controlling p53 expression. PMID- 10097113 TI - Deletion of the loop region of Bcl-2 completely blocks paclitaxel-induced apoptosis. AB - At high concentrations, the tubule poison paclitaxel is able to kill cancer cells that express Bcl-2; it inhibits the antiapoptotic activity of Bcl-2 by inducing its phosphorylation. To localize the site on Bcl-2 regulated by phosphorylation, mutant forms of Bcl-2 were constructed. Mutant forms of Bcl-2 with an alteration in serine at amino acid 70 (S70A) or with deletion of a 60-aa loop region between the alpha1 and alpha2 helices (Deltaloop Bcl-2, which also deletes amino acid 70) were unable to be phosphorylated by paclitaxel treatment of MDA-MB-231 cells into which the genes for the mutant proteins were transfected. The Deltaloop mutant completely inhibited paclitaxel-induced apoptosis. In cells expressing the S70A mutant, paclitaxel induced about one-third the level of apoptosis seen with wild type Bcl-2. To evaluate the role of mitogen-activated protein kinases (MAPKs) in Bcl-2 phosphorylation, the activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 was examined. Paclitaxel induced apoptosis was associated with phosphorylation of Bcl-2 and activation of ERK and JNK MAPKs. If JNK activation was blocked by transfections with either a stress-activated protein kinase kinase dominant-negative (K-->R) gene (which prevents the activation of a kinase upstream of JNK) or MAPK phosphatase-1 gene (which dephosphorylates and inactivates JNK), Bcl-2 phosphorylation did not occur, and the cells were not killed by paclitaxel. By contrast, neither an ERK inhibitor (PD098059) nor p38 inhibitors (SB203580 and SB202190) had an effect on Bcl-2 phosphorylation. Thus, our data show that the antiapoptotic effects of Bcl 2 can be overcome by phosphorylation of Ser-70; forms of Bcl-2 lacking the loop region are much more effective at preventing apoptosis than wild-type Bcl-2 because they cannot be phosphorylated. JNK, but not ERK or p38 MAPK, appear to be involved in the phosphorylation of Bcl-2 induced by paclitaxel. PMID- 10097114 TI - Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development. AB - The vertebrate lens is a tissue composed of terminally differentiated fiber cells and anterior lens epithelial cells. The abundant, preferential expression of the soluble proteins called crystallins creates a transparent, refractive index gradient in the lens. Several transcription factors such as Pax6, Sox1, and L-Maf have been shown to regulate lens development. Here we show that mice lacking the transcription factor c-Maf are microphthalmic secondary to defective lens formation, specifically from the failure of posterior lens fiber elongation. The marked impairment of crystallin gene expression observed is likely explained by the ability of c-Maf to transactivate the crystallin gene promoter. Thus, c-Maf is required for the differentiation of the vertebrate lens. PMID- 10097115 TI - The anterior determinant bicoid of Drosophila is a derived Hox class 3 gene. AB - The Drosophila gene bicoid functions as the anterior body pattern organizer of Drosophila. Embryos lacking maternally expressed bicoid fail to develop anterior segments including head and thorax. In wild-type eggs, bicoid mRNA is localized in the anterior pole region and the bicoid protein forms an anterior-to-posterior concentration gradient. bicoid activity is required for transcriptional activation of zygotic segmentation genes and the translational suppression of uniformly distributed maternal caudal mRNA in the anterior region of the embryo. caudal genes as well as other homeobox genes or members of the Drosophila segmentation gene cascade have been found to be conserved in animal evolution. In contrast, bicoid homologs have been identified only in close relatives of the schizophoran fly Drosophila. This poses the question of how the bicoid gene evolved and adopted its unique function in organizing anterior-posterior polarity. We have cloned bicoid from a basal cyclorrhaphan fly, Megaselia abdita (Phoridae, Aschiza), and show that the gene originated from a recent duplication of the direct homolog of the vertebrate gene Hox3, termed zerknullt, which specifies extraembryonic tissues in insects. PMID- 10097116 TI - Morphogenetic movements at gastrulation require the SH2 tyrosine phosphatase Shp2. AB - The SH2 domain-containing tyrosine phosphatase Shp2 plays a pivotal role during the gastrulation of vertebrate embryos. However, because of the complex phenotype observed in mouse mutant embryos, the precise role of Shp2 during development is unclear. To define the specific functions of this phosphatase, Shp2 homozygous mutant embryonic stem cells bearing the Rosa-26 LacZ transgene were isolated and used to perform a chimeric analysis. Here, we show that Shp2 mutant cells amass in the tail bud of embryonic day 10.5 chimeric mouse embryos and that this accumulation begins at the onset of gastrulation. At this early stage, Shp2 mutant cells collect in the primitive streak of the epiblast and thus show deficiencies in their contribution to the mesoderm lineage. In high-contribution chimeras, we show that overaccumulation of Shp2 mutant cells at the posterior end of the embryo results in two abnormal phenotypes: spina bifida and secondary neural tubes. Consistent with a failure to undergo morphogenic movements at gastrulation, Shp2 is required for embryo fibroblast cells to mount a positive chemotactic response to acidic fibroblast growth factor in vitro. Our results demonstrate that Shp2 is required at the initial steps of gastrulation, as nascent mesodermal cells form and migrate away from the primitive streak. The aberrant behavior of Shp2 mutant cells at gastrulation may result from their inability to properly respond to signals initiated by fibroblast growth factors. PMID- 10097117 TI - Distribution of haplotypes from a chromosome 21 region distinguishes multiple prehistoric human migrations. AB - Despite mounting genetic evidence implicating a recent origin of modern humans, the elucidation of early migratory gene-flow episodes remains incomplete. Geographic distribution of haplotypes may show traces of ancestral migrations. However, such evolutionary signatures can be erased easily by recombination and mutational perturbations. A 565-bp chromosome 21 region near the MX1 gene, which contains nine sites frequently polymorphic in human populations, has been found. It is unaffected by recombination and recurrent mutation and thus reflects only migratory history, genetic drift, and possibly selection. Geographic distribution of contemporary haplotypes implies distinctive prehistoric human migrations: one to Oceania, one to Asia and subsequently to America, and a third one predominantly to Europe. The findings with chromosome 21 are confirmed by independent evidence from a Y chromosome phylogeny. Loci of this type will help to decipher the evolutionary history of modern humans. PMID- 10097118 TI - Horizontal gene transfer among genomes: the complexity hypothesis. AB - Increasingly, studies of genes and genomes are indicating that considerable horizontal transfer has occurred between prokaryotes. Extensive horizontal transfer has occurred for operational genes (those involved in housekeeping), whereas informational genes (those involved in transcription, translation, and related processes) are seldomly horizontally transferred. Through phylogenetic analysis of six complete prokaryotic genomes and the identification of 312 sets of orthologous genes present in all six genomes, we tested two theories describing the temporal flow of horizontal transfer. We show that operational genes have been horizontally transferred continuously since the divergence of the prokaryotes, rather than having been exchanged in one, or a few, massive events that occurred early in the evolution of prokaryotes. In agreement with earlier studies, we found that differences in rates of evolution between operational and informational genes are minimal, suggesting that factors other than rate of evolution are responsible for the observed differences in horizontal transfer. We propose that a major factor in the more frequent horizontal transfer of operational genes is that informational genes are typically members of large, complex systems, whereas operational genes are not, thereby making horizontal transfer of informational gene products less probable (the complexity hypothesis). PMID- 10097119 TI - Genomic evolution during a 10,000-generation experiment with bacteria. AB - Molecular methods are used widely to measure genetic diversity within populations and determine relationships among species. However, it is difficult to observe genomic evolution in action because these dynamics are too slow in most organisms. To overcome this limitation, we sampled genomes from populations of Escherichia coli evolving in the laboratory for 10,000 generations. We analyzed the genomes for restriction fragment length polymorphisms (RFLP) using seven insertion sequences (IS) as probes; most polymorphisms detected by this approach reflect rearrangements (including transpositions) rather than point mutations. The evolving genomes became increasingly different from their ancestor over time. Moreover, tremendous diversity accumulated within each population, such that almost every individual had a different genetic fingerprint after 10,000 generations. As has been often suggested, but not previously shown by experiment, the rates of phenotypic and genomic change were discordant, both across replicate populations and over time within a population. Certain pivotal mutations were shared by all descendants in a population, and these are candidates for beneficial mutations, which are rare and difficult to find. More generally, these data show that the genome is highly dynamic even over a time scale that is, from an evolutionary perspective, very brief. PMID- 10097120 TI - An exon that prevents transport of a mature mRNA. AB - In Caenorhabditis elegans, pre-mRNA for the essential splicing factor U2AF65 sometimes is spliced to produce an RNA that includes an extra 216-bp internal exon, exon 3. Inclusion of exon 3 inserts an in-frame stop codon, yet this RNA is not subject to SMG-mediated RNA surveillance. To test whether exon 3 causes RNA to remain nuclear and thereby escape decay, we inserted it into the 3' untranslated region of a gfp reporter gene. Although exon 3 did not affect accumulation or processing of the mRNA, it dramatically suppressed expression of green fluorescent protein (GFP). We showed by in situ hybridization that exon 3 containing gfp RNA is retained in the nucleus. Intriguingly, exon 3 contains 10 matches to the 8-bp 3' splice-site consensus. We hypothesized that U2AF might recognize this octamer and thereby prevent export. This idea is supported by RNA interference experiments in which reduced levels of U2AF resulted in a small burst of gfp expression. PMID- 10097121 TI - Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. AB - Dissecting aortic aneurysm is the hallmark of Marfan syndrome (MFS) and the result of mutations in fibrillin-1, the major constituent of elastin-associated extracellular microfibrils. It is yet to be established whether dysfunction of fibrillin-1 perturbs the ability of the elastic vessel wall to sustain hemodynamic stress by disrupting microfibrillar assembly, by impairing the homeostasis of established elastic fibers, or by a combination of both mechanisms. The pathogenic sequence responsible for the mechanical collapse of the elastic lamellae in the aortic wall is also unknown. Targeted mutation of the mouse fibrillin-1 gene has recently suggested that deficiency of fibrillin-1 reduces tissue homeostasis rather than elastic fiber formation. Here we describe another gene-targeting mutation, mgR, which shows that underexpression of fibrillin-1 similarly leads to MFS-like manifestations. Histopathological analysis of mgR/mgR specimens implicates medial calcification, the inflammatory fibroproliferative response, and inflammation-mediated elastolysis in the natural history of dissecting aneurysm. More generally, the phenotypic severity associated with various combinations of normal and mutant fibrillin-1 alleles suggests a threshold phenomenon for the functional collapse of the vessel wall that is based on the level and the integrity of microfibrils. PMID- 10097122 TI - DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae. AB - In addition to DNA polymerase complexes, DNA replication requires the coordinate action of a series of proteins, including regulators Cdc28/Clb and Dbf4/Cdc7 kinases, Orcs, Mcms, Cdc6, Cdc45, and Dpb11. Of these, Dpb11, an essential BRCT repeat protein, has remained particularly enigmatic. The Schizosaccharomyces pombe homolog of DPB11, cut5, has been implicated in the DNA replication checkpoint as has the POL2 gene with which DPB11 genetically interacts. Here we describe a gene, DRC1, isolated as a dosage suppressor of dpb11-1. DRC1 is an essential cell cycle-regulated gene required for DNA replication. We show that both Dpb11 and Drc1 are required for the S-phase checkpoint, including the proper activation of the Rad53 kinase in response to DNA damage and replication blocks. Dpb11 is the second BRCT-repeat protein shown to control Rad53 function, possibly indicating a general function for this class of proteins. DRC1 and DPB11 show synthetic lethality and reciprocal dosage suppression. The Drc1 and Dpb11 proteins physically associate and function together to coordinate DNA replication and the cell cycle. PMID- 10097123 TI - A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. AB - Imprinted genes tend to occur in clusters. We have identified a cluster in distal mouse chromosome (Chr) 2, known from early genetic studies to contain both maternally and paternally imprinted, but unspecified, genes. Subsequently, one was identified as Gnas, which encodes a G protein alpha subunit, and there is clinical and biochemical evidence that the human homologue GNAS1, mutated in patients with Albright hereditary osteodystrophy, is also imprinted. We have used representational difference analysis, based on parent-of-origin methylation differences, to isolate candidate imprinted genes in distal Chr 2 and found two oppositely imprinted genes, Gnasxl and Nesp. Gnasxl determines a variant G protein alpha subunit associated with the trans-Golgi network and Nesp encodes a secreted protein of neuroendocrine tissues. Gnasxl is maternally methylated in genomic DNA and encodes a paternal-specific transcript, whereas Nesp is paternally methylated with maternal-specific expression. Their reciprocal imprinting may offer insight into the distal Chr 2 imprinting phenotypes. Remarkably, Gnasxl, Nesp, and Gnas are all part of the same transcription unit; transcripts for Gnasxl and Nesp are alternatively spliced onto exon 2 of Gnas. This demonstrates an imprinting mechanism in which two oppositely imprinted genes share the same downstream exons. PMID- 10097124 TI - Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain. AB - Dosage compensation in mammals occurs by X inactivation, a silencing mechanism regulated in cis by the X inactivation center (Xic). In response to developmental cues, the Xic orchestrates events of X inactivation, including chromosome counting and choice, initiation, spread, and establishment of silencing. It remains unclear what elements make up the Xic. We previously showed that the Xic is contained within a 450-kb sequence that includes Xist, an RNA-encoding gene required for X inactivation. To characterize the Xic further, we performed deletional analysis across the 450-kb region by yeast-artificial-chromosome fragmentation and phage P1 cloning. We tested Xic deletions for cis inactivation potential by using a transgene (Tg)-based approach and found that an 80-kb subregion also enacted somatic X inactivation on autosomes. Xist RNA coated the autosome but skipped the Xic Tg, raising the possibility that X chromosome domains escape inactivation by excluding Xist RNA binding. The autosomes became late-replicating and hypoacetylated on histone H4. A deletion of the Xist 5' sequence resulted in the loss of somatic X inactivation without abolishing Xist expression in undifferentiated cells. Thus, Xist expression in undifferentiated cells can be separated genetically from somatic silencing. Analysis of multiple Xic constructs and insertion sites indicated that long-range Xic effects can be generalized to different autosomes, thereby supporting the feasibility of a Tg based approach for studying X inactivation. PMID- 10097125 TI - Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1. AB - The activity of copolymer 1 (Cop 1, Copaxone, glatiramer acetate) in suppressing experimental autoimmune encephalomyelitis (EAE) and in the treatment of multiple sclerosis patients when injected parenterally has been extensively demonstrated. In the present study we addressed the question of whether Cop 1 can induce oral tolerance to EAE similar to myelin basic protein (MBP). We now have demonstrated that oral Cop 1 inhibited EAE induction in both rats and mice. Furthermore, oral Cop 1 was more effective than oral MBP in suppressing EAE in rats. The beneficial effect of oral Cop 1 was found to be associated with specific inhibition of the proliferative and Th1 cytokine secretion responses to MBP of spleen cells from Cop 1-fed mice and rats. In all of these assays, oral Cop 1 was more effective than oral MBP. The tolerance induced by Cop 1 could be adoptively transferred with spleen cells from Cop 1-fed animals. Furthermore, Cop 1-specific T cell lines, which inhibit EAE induction in vivo, could be isolated from the above spleen cells. These T cell lines secrete the anti-inflammatory cytokines IL-10 and transforming growth factor type beta, but not IL-4, in response to both Cop 1 and MBP. In conclusion, oral Cop 1 has a beneficial effect on the development of EAE that is associated with down-regulation of T cell immune responses to MBP and is mediated by Th2/3 type regulatory cells. These results suggest that oral administration of Cop 1 may modulate multiple sclerosis as well. PMID- 10097126 TI - HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. AB - The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02(+) healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02(-) HTLV-I carriers. An association of HLA DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections. PMID- 10097127 TI - Ontogeny of T cell tolerance to peripherally expressed antigens. AB - Transgenic expression of the influenza virus hemagglutinin (HA) in the pancreatic islet beta cells of InsHA mice leads to peripheral tolerance of HA-specific T cells. To examine the onset of tolerance, InsHA mice were immunized with influenza virus A/PR/8 at different ages, and the presence of nontolerant T cells was determined by the induction of autoimmune diabetes. The data revealed a neonatal period wherein T cells were not tolerant and influenza virus infection led to HA-specific beta cell destruction and autoimmune diabetes. The ability to induce autoimmunity gradually waned, such that adult mice were profoundly tolerant to viral HA and were protected from diabetes. Because cross-presentation of islet antigens by professional antigen-presenting cells had been reported to induce peripheral tolerance, the temporal relationship between tolerance induction and activation of HA-specific T cells in the lymph nodes draining the pancreas was examined. In tolerant adult mice, but not in 1-week-old neonates, activation and proliferation of HA-specific CD8(+) T cells occurred in the pancreatic lymph nodes. Thus, lack of tolerance in the perinatal period correlated with lack of activation of antigen-specific CD8(+) T cells. This work provides evidence for the developmental regulation of peripheral tolerance induction. PMID- 10097128 TI - Ubiquitin-dependent degradation of IkappaBalpha is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1. AB - Activation of the transcription factor nuclear factor kappa B (NF-kappaB) is controlled by proteolysis of its inhibitory subunit (IkappaB) via the ubiquitin proteasome pathway. Signal-induced phosphorylation of IkappaBalpha by a large multisubunit complex containing IkappaB kinases is a prerequisite for ubiquitination. Here, we show that FWD1 (a mouse homologue of Slimb/betaTrCP), a member of the F-box/WD40-repeat proteins, is associated specifically with IkappaBalpha only when IkappaBalpha is phosphorylated. The introduction of FWD1 into cells significantly promotes ubiquitination and degradation of IkappaBalpha in concert with IkappaB kinases, resulting in nuclear translocation of NF-kappaB. In addition, FWD1 strikingly evoked the ubiquitination of IkappaBalpha in the in vitro system. In contrast, a dominant-negative form of FWD1 inhibits the ubiquitination, leading to stabilization of IkappaBalpha. These results suggest that the substrate-specific degradation of IkappaBalpha is mediated by a Skp1/Cull 1/F-box protein (SCF) FWD1 ubiquitin-ligase complex and that FWD1 serves as an intracellular receptor for phosphorylated IkappaBalpha. Skp1/Cullin/F-box protein FWD1 might play a critical role in transcriptional regulation of NF-kappaB through control of IkappaB protein stability. PMID- 10097129 TI - Crystal structure of the HLA-Cw3 allotype-specific killer cell inhibitory receptor KIR2DL2. AB - Killer cell inhibitory receptors (KIR) protect class I HLAs expressing target cells from natural killer (NK) cell-mediated lysis. To understand the molecular basis of this receptor-ligand recognition, we have crystallized the extracellular ligand-binding domains of KIR2DL2, a member of the Ig superfamily receptors that recognize HLA-Cw1, 3, 7, and 8 allotypes. The structure was determined in two different crystal forms, an orthorhombic P212121 and a trigonal P3221 space group, to resolutions of 3.0 and 2.9 A, respectively. The overall fold of this structure, like KIR2DL1, exhibits K-type Ig topology with cis-proline residues in both domains that define beta-strand switching, which sets KIR apart from the C2 type hematopoietic growth hormone receptor fold. The hinge angle of KIR2DL2 is approximately 80 degrees, 14 degrees larger than that observed in KIR2DL1 despite the existence of conserved hydrophobic residues near the hinge region. There is also a 5 degrees difference in the observed hinge angles in two crystal forms of 2DL2, suggesting that the interdomain hinge angle is not fixed. The putative ligand-binding site is formed by residues from several variable loops with charge distribution apparently complementary to that of HLA-C. The packing of the receptors in the orthorhombic crystal form offers an intriguing model for receptor aggregation on the cell surface. PMID- 10097130 TI - Characterization of inhibitory and stimulatory forms of the murine natural killer cell receptor 2B4. AB - The receptor 2B4 belongs to the Ig superfamily and is found on the surface of all murine natural killer (NK) cells as well as T cells displaying non-MHC-restricted cytotoxicity. Previous studies have suggested that 2B4 is an activating molecule because cross-linking of this receptor results in increased cytotoxicity and gamma-interferon secretion as well as granule exocytosis. However, it was recently shown that the gene for 2B4 encodes two different products that arise by alternative splicing. These gene products differ solely in their cytoplasmic domains. One form has a cytoplasmic tail of 150 amino acids (2B4L) and the other has a tail of 93 amino acids (2B4S). To determine the function of each receptor, cDNAs for 2B4S and 2B4L were transfected into the rat NK cell line RNK-16. Interestingly, the two forms of 2B4 had opposing functions. 2B4S was able to mediate redirected lysis of P815 tumor targets, suggesting that this form represents an activating receptor. However, 2B4L expression led to an inhibition of redirected lysis of P815 targets when the mAb 3.2.3 (specific for rat NKRP1) was used. In addition, 2B4L constitutively inhibits lysis of YAC-1 tumor targets. 2B4L is a tyrosine phosphoprotein, and removal of domains containing these residues abrogates its inhibitory function. Like other inhibitory receptors, 2B4L associates with the tyrosine phosphatase SHP-2. Thus, 2B4L is an inhibitory receptor belonging to the Ig superfamily. PMID- 10097131 TI - The p42 variant of ETS1 protein rescues defective Fas-induced apoptosis in colon carcinoma cells. AB - ETS1 is a cellular homologue of the product of the viral ets oncogene of the E26 virus, and it functions as a tissue-specific transcription factor. It plays an important role in cell proliferation, differentiation, lymphoid cell development, transformation, angiogenesis, and apoptosis. ETS1 controls the expression of critical genes involved in these processes by binding to ets binding sites present in the transcriptional regulatory regions. The ETS1 gene generates two proteins, p51 and a spliced variant, p42, lacking exon VII. In this paper we show that p42-ETS1 expression bypasses the damaged Fas-induced apoptotic pathway in DLD1 colon carcinoma cells by up-regulating interleukin 1beta-converting enzyme (ICE)/caspase-1 and causes these cancer cells to become susceptible to the effects of the normal apoptosis activation system. ICE/caspase-1 is a redundant system in many cells and tissues, and here we demonstrate that it is important in activating apoptosis in cells where the normal apoptosis pathway is blocked. Blocking ICE/caspase-1 activity by using specific inhibitors of this protease prevents the p42-ETS1-induced apoptosis from occurring, indicating that the induced ICE/caspase-1 enzyme is responsible for killing the cancer cells. p42 ETS1 activates a critical alternative apoptosis pathway in cancer cells that are resistant to normal immune attack, and thus it may be useful as an anticancer therapeutic. PMID- 10097132 TI - Regulation of T cell receptor (TCR) beta gene expression by CD3 complex signaling in immature thymocytes: implications for TCRbeta allelic exclusion. AB - During alphabeta thymocyte development, clonotype-independent CD3 complexes are expressed at the cell surface before the pre-T cell receptor (TCR). Signaling through clonotype-independent CD3 complexes is required for expression of rearranged TCRbeta genes. On expression of a TCRbeta polypeptide chain, the pre TCR is assembled, and TCRbeta locus allelic exclusion is established. We investigated the putative contribution of clonotype-independent CD3 complex signaling to TCRbeta locus allelic exclusion in mice single-deficient or double deficient for CD3zeta/eta and/or p56(lck). These mice display defects in the expression of endogenous TCRbeta genes in immature thymocytes, proportional to the severity of CD3 complex malfunction. Exclusion of endogenous TCRbeta VDJ (variable, diversity, joining) rearrangements by a functional TCRbeta transgene was severely compromised in the single-deficient and double-deficient mutant mice. In contrast to wild-type mice, most of the CD25(+) double-negative (DN) thymocytes of the mutant mice failed to express the TCRbeta transgene, suggesting defective expression of the TCRbeta transgene similar to endogenous TCRbeta genes. In the mutant mice, a proportion of CD25(+) DN thymocytes that failed to express the transgene expressed endogenous TCRbeta polypeptide chains. Many double-positive cells of the mutant mice coexpressed endogenous and transgenic TCRbeta chains or more than one endogenous TCRbeta chain. The data suggest that signaling through clonotype-independent CD3 complexes may contribute to allelic exclusion of the TCRbeta locus by inducing the expression of rearranged TCRbeta genes in CD25(+) DN thymocytes. PMID- 10097133 TI - The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. AB - Interleukin 12 (IL-12)-induced T helper 1 (Th1) development requires Stat4 activation. However, antigen-activated Th1 cells can produce interferon gamma (IFN-gamma) independently of IL-12 and Stat4 activation. Thus, in differentiated Th1 cells, factors regulated by IL-12 and Stat4 may be involved in IFN-gamma production. Using subtractive cloning, we identified ERM, an Ets transcription factor, to be a Th1-specific, IL-12-induced gene. IL-12-induction of ERM occurred in wild-type and Stat1-deficient, but not Stat4-deficient, T cells, suggesting ERM is Stat4-inducible. Retroviral expression of ERM did not restore IFN-gamma production in Stat4-deficient T cells, but augmented IFN-gamma expression in Stat4-heterozygous T cells. Ets factors frequently regulate transcription via cooperative interactions with other transcription factors, and ERM has been reported to cooperate with c-Jun. However, in the absence of other transcription factors, ERM augmented expression of an IFN-gamma reporter by only 2-fold. Thus, determining the requirement for ERM in Th1 development likely will require gene targeting. PMID- 10097134 TI - A logical analysis of T cell activation and anergy. AB - Interaction of the antigen-specific receptor of T lymphocytes with its antigenic ligand can lead either to cell activation or to a state of profound unresponsiveness (anergy). Although subtle changes in the nature of the ligand or of the antigen-presenting cell have been shown to affect the outcome of T cell receptor ligation, the mechanism by which the same receptor can induce alternative cellular responses is not completely understood. A model for explaining both positive (cell proliferation and cytokine production) and negative (anergy induction) signaling of T lymphocytes is described herein. This model relies on the autophosphorylative properties of the tyrosine kinases associated with the T cell receptor. One of its basic assumptions is that the kinase activity of these receptor-associated enzymes remains above background level after ligand removal and is responsible for cellular unresponsiveness. Using a simple Boolean formalism, we show how the timing of the binding and intracellular signal-transduction events can affect the properties of receptor signaling and determine the type of cellular response. The present approach integrates into a common framework a large body of experimental observations and allows specification of conditions leading to cellular activation or to anergy. PMID- 10097135 TI - Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug permeability barrier. AB - The blood-brain barrier and a blood-cerebrospinal-fluid (CSF) barrier function together to isolate the brain from circulating drugs, toxins, and xenobiotics. The blood-CSF drug-permeability barrier is localized to the epithelium of the choroid plexus (CP). However, the molecular mechanisms regulating drug permeability across the CP epithelium are defined poorly. Herein, we describe a drug-permeability barrier in human and rodent CP mediated by epithelial-specific expression of the MDR1 (multidrug resistance) P glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP). Noninvasive single-photon-emission computed tomography with 99mTc-sestamibi, a membrane-permeant radiopharmaceutical whose transport is mediated by both Pgp and MRP, shows a large blood-to-CSF concentration gradient across intact CP epithelium in humans in vivo. In rats, pharmacokinetic analysis with 99mTc-sestamibi determined the concentration gradient to be greater than 100-fold. In membrane fractions of isolated native CP from rat, mouse, and human, the 170-kDa Pgp and 190-kDa MRP are identified readily. Furthermore, the murine proteins are absent in CP isolated from their respective mdr1a/1b(-/-) and mrp(-/-) gene knockout littermates. As determined by immunohistochemical and drug-transport analysis of native CP and polarized epithelial cell cultures derived from neonatal rat CP, Pgp localizes subapically, conferring an apical-to-basal transepithelial permeation barrier to radiolabeled drugs. Conversely, MRP localizes basolaterally, conferring an opposing basal-to apical drug-permeation barrier. Together, these transporters may coordinate secretion and reabsorption of natural product substrates and therapeutic drugs, including chemotherapeutic agents, antipsychotics, and HIV protease inhibitors, into and out of the central nervous system. PMID- 10097136 TI - Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. AB - Mice generated by disrupting the clotting factor IX gene exhibit severe bleeding disorder and closely resemble the phenotype seen in hemophilia B patients. Here we demonstrate that a single intraportal injection of a recombinant adeno associated virus (AAV) vector encoding canine factor IX cDNA under the control of a liver-specific enhancer/promoter leads to a long-term and complete correction of the bleeding disorder. High level expression of up to 15-20 microgram/ml of canine factor IX was detected in the plasma of mice injected with 5.6 x 10(11) particles of an AAV vector for >5 months. The activated partial thromboplastin time of the treated mice was fully corrected to higher than normal levels. Liver specific expression of canine factor IX was confirmed by immunofluorescence staining, and secreted factor IX protein was identified in the mouse plasma by Western blotting. All treated mice survived the tail clip test without difficulty. Thus, a single intraportal injection of a recombinant adeno associated virus vector expressing factor IX successfully cured the bleeding disorder of hemophilia B mice, proving the feasibility of using AAV-based vectors for liver-targeted gene therapy of genetic diseases. PMID- 10097137 TI - Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. AB - Deficiency in genes involved in DNA mismatch repair increases susceptibility to cancer, particularly of the colorectal epithelium. Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide. Experiments using Msh2 deficient cells in vitro suggest that an element of this effect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N'-nitro-N nitrosoguanidine, and cisplatin. This was not influenced by the in vivo depletion of O6-alkylguanine-DNA-alkyltransferase after administration of O6-benzylguanine. By analyzing mice mutant for both Msh2 and p53, we found that the Msh2-dependent apoptotic response was primarily mediated through a p53-dependent pathway. Msh2 also was required to signal delayed p53-independent death. Taken together, these studies characterize an in vivo Msh2-dependent apoptotic response to methylating agents and raise the possibility that Msh2 deficiency may predispose to malignancy not only through failed repair of mismatch DNA lesions but also through the failure to engage apoptosis. PMID- 10097138 TI - RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/- mice. AB - Alterations in pathways mediated by retinoblastoma susceptibility gene (RB) product are among the most common in human cancer. Mice with a single copy of the Rb gene are shown to develop a syndrome of multiple neuroendocrine neoplasia. The earliest Rb-deficient atypical cells were identified in the intermediate and anterior lobes of the pituitary, the thyroid and parathyroid glands, and the adrenal medulla within the first 3 months of postnatal development. These cells form gross tumors with various degrees of malignancy by postnatal day 350. By age of 380 days, 84% of Rb+/- mice exhibited lung metastases from C-cell thyroid carcinomas. Expression of a human RB transgene in the Rb+/- mice suppressed carcinogenesis in all tissues studied. Of particular clinical relevance, the frequency of lung metastases also was reduced to 12% in Rb+/- mice by repeated i.v. administration of lipid-entrapped, polycation-condensed RB complementary DNA. Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells. Restoration of RB function in humans may prove an effective general approach to the treatment of RB deficient disseminated tumors. PMID- 10097139 TI - Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. AB - Amyloid beta peptide (Abeta), the principal proteinaceous component of amyloid plaques in brains of Alzheimer's disease patients, is derived by proteolytic cleavage of the amyloid precursor protein (APP). Proteolytic cleavage of APP by a putative alpha-secretase within the Abeta sequence precludes the formation of the amyloidogenic peptides and leads to the release of soluble APPsalpha into the medium. By overexpression of a disintegrin and metalloprotease (ADAM), classified as ADAM 10, in HEK 293 cells, basal and protein kinase C-stimulated alpha secretase activity was increased severalfold. The proteolytically activated form of ADAM 10 was localized by cell surface biotinylation in the plasma membrane, but the majority of the proenzyme was found in the Golgi. These results support the view that APP is cleaved both at the cell surface and along the secretory pathway. Endogenous alpha-secretase activity was inhibited by a dominant negative form of ADAM 10 with a point mutation in the zinc binding site. Studies with purified ADAM 10 and Abeta fragments confirm the correct alpha-secretase cleavage site and demonstrate a dependence on the substrate's conformation. Our results provide evidence that ADAM 10 has alpha-secretase activity and many properties expected for the proteolytic processing of APP. Increases of its expression and activity might be beneficial for the treatment of Alzheimer's disease. PMID- 10097140 TI - The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. AB - Alterations of human chromosome 8p occur frequently in many tumors. We identified a 1.5-Mb common region of allelic loss on 8p22 by allelotype analysis. cDNA selection allowed isolation of several genes, including FEZ1. The predicted Fez1 protein contained a leucine-zipper region with similarity to the DNA-binding domain of the cAMP-responsive activating-transcription factor 5. RNA blot analysis revealed that FEZ1 gene expression was undetectable in more than 60% of epithelial tumors. Mutations were found in primary esophageal cancers and in a prostate cancer cell line. Transcript analysis from several FEZ1-expressing tumors revealed truncated mRNAs, including a frameshift. Alteration and inactivation of the FEZ1 gene may play a role in various human tumors. PMID- 10097141 TI - Specific association of the gene product of PKD2 with the TRPC1 channel. AB - The function(s) of the genes (PKD1 and PKD2) responsible for the majority of cases of autosomal dominant polycystic kidney disease is unknown. While PKD1 encodes a large integral membrane protein containing several structural motifs found in known proteins involved in cell-cell or cell-matrix interactions, PKD2 has homology to PKD1 and the major subunit of the voltage-activated Ca2+ channels. We now describe sequence homology between PKD2 and various members of the mammalian transient receptor potential channel (TRPC) proteins, thought to be activated by G protein-coupled receptor activation and/or depletion of internal Ca2+ stores. We show that PKD2 can directly associate with TRPC1 but not TRPC3 in transfected cells and in vitro. This association is mediated by two distinct domains in PKD2. One domain involves a minimal region of 73 amino acids in the C terminal cytoplasmic tail of PKD2 shown previously to constitute an interacting domain with PKD1. However, distinct residues within this region mediate specific interactions with TRPC1 or PKD1. The C-terminal domain is sufficient but not necessary for the PKD2-TRPC1 association. A more N-terminal domain located within transmembrane segments S2 and S5, including a putative pore helical region between S5 and S6, is also responsible for the association. Given the ability of the TRPC to form functional homo- and heteromultimeric complexes, these data provide evidence that PKD2 may be functionally related to TRPC proteins and suggest a possible role of PKD2 in modulating Ca2+ entry in response to G protein coupled receptor activation and/or store depletion. PMID- 10097142 TI - Transient excess of MYC activity can elicit genomic instability and tumorigenesis. AB - Overexpression of the MYC protooncogene has been implicated in the genesis of diverse human tumors. Tumorigenesis induced by MYC has been attributed to sustained effects on proliferation and differentiation. Here we report that MYC may also contribute to tumorigenesis by destabilizing the cellular genome. A transient excess of MYC activity increased tumorigenicity of Rat1A cells by at least 50-fold. The increase persisted for >30 days after the return of MYC activity to normal levels. The brief surfeit of MYC activity was accompanied by evidence of genomic instability, including karyotypic abnormalities, gene amplification, and hypersensitivity to DNA-damaging agents. MYC also induced genomic destabilization in normal human fibroblasts, although these cells did not become tumorigenic. Stimulation of Rat1A cells with MYC accelerated their passage through G1/S. Moreover, MYC could force normal human fibroblasts to transit G1 and S after treatment with N-(phosphonoacetyl)-L-aspartate (PALA) at concentrations that normally lead to arrest in S phase by checkpoint mechanisms. Instead, the cells subsequently appeared to arrest in G2. We suggest that the accelerated passage through G1 was mutagenic but that the effect of MYC permitted a checkpoint response only after G2 had been reached. Thus, MYC may contribute to tumorigenesis through a dominant mutator effect. PMID- 10097143 TI - Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis. AB - Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidated. betagamma subunits of heterotrimeric G proteins (Gbetagamma) are known to activate mitogen-activated protein (MAP) kinases after stimulation of certain G protein-coupled receptors; however, their relevance in VSM mitogenesis in vitro or in vivo is not known. Using adenoviral-mediated transfer of a transgene encoding a peptide inhibitor of Gbetagamma signaling (betaARKct), we evaluated the role of Gbetagamma in MAP kinase activation and proliferation in response to several mitogens, including serum, in cultured rat VSM cells. Our results include the striking finding that serum-induced proliferation of VSM cells in vitro is mediated largely via Gbetagamma. Furthermore, we studied the effects of in vivo adenoviral-mediated betaARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the betaARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, Gbetagamma plays a critical role in physiological VSM proliferation, and targeted Gbetagamma inhibition represents a novel approach for the treatment of pathological conditions such as restenosis. PMID- 10097144 TI - Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. AB - Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the peroxisome proliferator-activated receptor-gamma ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts characteristic of differentiation in the adipocyte lineage was induced. There was also a marked reduction in immunohistochemical expression of Ki-67, a marker of cell proliferation. Together, these data indicate that terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor. PMID- 10097145 TI - Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome. AB - The dose-limiting toxicity of interleukin-2 (IL-2) and immunotoxin (IT) therapy in humans is vascular leak syndrome (VLS). VLS has a complex etiology involving damage to vascular endothelial cells (ECs), extravasation of fluids and proteins, interstitial edema, and organ failure. IL-2 and ITs prepared with the catalytic A chain of the plant toxin, ricin (RTA), and other toxins, damage human ECs in vitro and in vivo. Damage to ECs may initiate VLS; if this damage could be avoided without losing the efficacy of ITs or IL-2, larger doses could be administered. In this paper, we provide evidence that a three amino acid sequence motif, (x)D(y), in toxins and IL-2 damages ECs. Thus, when peptides from RTA or IL-2 containing this sequence motif are coupled to mouse IgG, they bind to and damage ECs both in vitro and, in the case of RTA, in vivo. In contrast, the same peptides with a deleted or mutated sequence do not. Furthermore, the peptide from RTA attached to mouse IgG can block the binding of intact RTA to ECs in vitro and vice versa. In addition, RTA, a fragment of Pseudomonas exotoxin A (PE38-lys), and fibronectin also block the binding of the mouse IgG-RTA peptide to ECs, suggesting that an (x)D(y) motif is exposed on all three molecules. Our results suggest that deletions or mutations in this sequence or the use of nondamaging blocking peptides may increase the therapeutic index of both IL-2, as well as ITs prepared with a variety of plant or bacterial toxins. PMID- 10097146 TI - Loss of transformed phenotype in cancer cells by overexpression of the uteroglobin gene. AB - Uteroglobin (UG) is a multifunctional, secreted protein that has receptor mediated functions. The human UG (hUG) gene is mapped to chromosome 11q12.2-13.1, a region frequently rearranged or deleted in many cancers. Although high levels of hUG expression are characteristic of the mucosal epithelia of many organs, hUG expression is either drastically reduced or totally absent in adenocarcinomas and in viral-transformed epithelial cells derived from the same organs. In agreement with these findings, in an ongoing study to evaluate the effects of aging on UG knockout mice, 16/16 animals developed malignant tumors, whereas the wild-type littermates (n = 25) remained apparently healthy even after 11/2 years. In the present investigation, we sought to determine the effects of induced-expression of hUG in human cancer cells by transfecting several cell lines derived from adenocarcinomas of various organs with an hUG-cDNA construct. We demonstrate that induced hUG expression reverses at least two of the most important characteristics of the transformed phenotype (i.e., anchorage-independent growth on soft agar and extracellular matrix invasion) of only those cancer cells that also express the hUG receptor. Similarly, treatment of the nontransfected, receptor-positive adenocarcinoma cells with purified recombinant hUG yielded identical results. Taken together, these data define receptor-mediated, autocrine and paracrine pathways through which hUG reverses the transformed phenotype of cancer cells and consequently, may have tumor suppressor-like effects. PMID- 10097147 TI - MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. AB - The DNA mismatch repair (MMR) is a specialized system, highly conserved throughout evolution, involved in the maintenance of genomic integrity. To identify novel human genes that may function in MMR, we employed the yeast interaction trap. Using the MMR protein MLH1 as bait, we cloned MED1. The MED1 protein forms a complex with MLH1, binds to methyl-CpG-containing DNA, has homology to bacterial DNA repair glycosylases/lyases, and displays endonuclease activity. Transfection of a MED1 mutant lacking the methyl-CpG-binding domain (MBD) is associated with microsatellite instability (MSI). These findings suggest that MED1 is a novel human DNA repair protein that may be involved in MMR and, as such, may be a candidate eukaryotic homologue of the bacterial MMR endonuclease, MutH. In addition, these results suggest that cytosine methylation may play a role in human DNA repair. PMID- 10097148 TI - Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen. AB - Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg = 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension. PMID- 10097149 TI - Hepatocyte gene therapy in a large animal: a neonatal bovine model of citrullinemia. AB - The development of gene-replacement therapy for inborn errors of metabolism has been hindered by the limited number of suitable large-animal models of these diseases and by inadequate methods of assessing the efficacy of treatment. Such methods should provide sensitive detection of expression in vivo and should be unaffected by concurrent pharmacologic and dietary regimens. We present the results of studies in a neonatal bovine model of citrullinemia, an inborn error of urea-cycle metabolism characterized by deficiency of argininosuccinate synthetase and consequent life-threatening hyperammonemia. Measurements of the flux of nitrogen from orally administered 15NH4 to [15N]urea were used to determine urea-cycle activity in vivo. In control animals, these isotopic measurements proved to be unaffected by pharmacologic treatments. Systemic administration of a first-generation E1-deleted adenoviral vector expressing human argininosuccinate synthetase resulted in transduction of hepatocytes and partial correction of the enzyme defect. The isotopic method showed significant restoration of urea synthesis. Moreover, the calves showed clinical improvement and normalization of plasma glutamine levels after treatment. The results show the clinical efficacy of treating a large-animal model of an inborn error of hepatocyte metabolism in conjunction with a method for sensitively measuring correction in vivo. These studies will be applicable to human trials of the treatment of this disorder and other related urea-cycle disorders. PMID- 10097150 TI - Ectopic expression of prion protein (PrP) in T lymphocytes or hepatocytes of PrP knockout mice is insufficient to sustain prion replication. AB - The cellular form of the Prion protein (PrPC) is necessary for prion replication in mice. To determine whether it is also sufficient, we expressed PrP under the control of various cell- or tissue-specific regulatory elements in PrP knockout mice. The interferon regulatory factor-1 promoter/Emu enhancer led to high PrP levels in the spleen and low PrP levels in the brain. Following i.p. scrapie inoculation, high prion titers were found in the spleen but not in the brain at 2 weeks and 6 months, showing that the lymphoreticular system by itself is competent to replicate prions. PrP expression directed by the Lck promoter resulted in high PrP levels on T lymphocytes only but, surprisingly, did not allow prion replication in the thymus, spleen, or brain following i.p. inoculation. A third transgenic line, which expressed PrP in the liver under the control of the albumin promoter/enhancer-albeit at low levels-also failed to replicate prions. These results show that expression of PrP alone is not sufficient to sustain prion replication and suggest that additional components are needed. PMID- 10097151 TI - Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. AB - Expression of the DMP1 transcription factor, a cyclin D-binding Myb-like protein, induces growth arrest in mouse embryo fibroblast strains but is devoid of antiproliferative activity in primary diploid fibroblasts that lack the ARF tumor suppressor gene. DMP1 binds to a single canonical recognition site in the ARF promoter to activate gene expression, and in turn, p19(ARF) synthesis causes p53 dependent cell cycle arrest. Unlike genes such as Myc, adenovirus E1A, and E2F-1, which, when overexpressed, activate the ARF-p53 pathway and trigger apoptosis, DMP1, like ARF itself, does not induce programmed cell death. Therefore, apart from its recently recognized role in protecting cells from potentially oncogenic signals, ARF can be induced in response to antiproliferative stimuli that do not obligatorily lead to apoptosis. PMID- 10097152 TI - Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. AB - Estrogen receptor (ER) modulators produce distinct tissue-specific biological effects, but within the confines of the established models of ER action it is difficult to understand why. Previous studies have suggested that there might be a relationship between ER structure and activity. Different ER modulators may induce conformational changes in the receptor that result in a specific biological activity. To investigate the possibility of modulator-specific conformational changes, we have applied affinity selection of peptides to identify binding surfaces that are exposed on the apo-ERs alpha and beta and on each receptor complexed with estradiol or 4-OH tamoxifen. These peptides are sensitive probes of receptor conformation. We show here that ER ligands, known to produce distinct biological effects, induce distinct conformational changes in the receptors, providing a strong correlation between ER conformation and biological activity. Furthermore, the ability of some of the peptides to discriminate between different ER alpha and ER beta ligand complexes suggests that the biological effects of ER agonists and antagonists acting through these receptors are likely to be different. PMID- 10097153 TI - Identification of the block in targeted retroviral-mediated gene transfer. AB - A chimeric retroviral vector (33E67) containing a CD33-specific single-chain antibody was generated in an attempt to target cells displaying the CD33 surface antigen. The chimeric envelope protein was translated, processed, and incorporated into viral particles as efficiently as wild-type envelope protein. The viral particles carrying the 33E67 envelope protein could bind efficiently to the CD33 receptor on target cells and were internalized, but no gene transfer occurred. A unique experimental approach was used to examine the basis for this postbinding block. Our data indicate that the chimeric envelope protein itself cannot participate in the fusion process, the most reasonable explanation being that this chimeric protein cannot undergo the appropriate conformational change that is thought to be triggered by receptor binding, a suggested prerequisite to subsequent fusion and core entry. These results indicate that the block to gene transfer in this system, and probably in most of the current chimeric retroviral vectors to date, is the inability of the chimeric envelope protein to undergo this obligatory conformational change. PMID- 10097154 TI - A mutant of Mycobacterium smegmatis defective in the biosynthesis of mycolic acids accumulates meromycolates. AB - Mycolic acids are a major constituent of the mycobacterial cell wall, and they form an effective permeability barrier to protect mycobacteria from antimicrobial agents. Although the chemical structures of mycolic acids are well established, little is known on their biosynthesis. We have isolated a mycolate-deficient mutant strain of Mycobacterium smegmatis mc2-155 by chemical mutagenesis followed by screening for increased sensitivity to novobiocin. This mutant also was hypersensitive to other hydrophobic compounds such as crystal violet, rifampicin, and erythromycin. Entry of hydrophobic probes into mutant cells occurred much more rapidly than that into the wild-type cells. HPLC and TLC analysis of fatty acid composition after saponification showed that the mutant failed to synthesize full-length mycolic acids. Instead, it accumulated a series of long-chain fatty acids, which were not detected in the wild-type strain. Analysis by 1H NMR, electrospray and electron impact mass spectroscopy, and permanganate cleavage of double bonds showed that these compounds corresponded to the incomplete meromycolate chain of mycolic acids, except for the presence of a beta-hydroxyl group. This direct identification of meromycolates as precursors of mycolic acids provides a strong support for the previously proposed pathway for mycolic acid biosynthesis involving the separate synthesis of meromycolate chain and the alpha branch of mycolic acids, followed by the joining of these two branches. PMID- 10097155 TI - The meningococcal PilT protein is required for induction of intimate attachment to epithelial cells following pilus-mediated adhesion. AB - The ability of Neisseria meningitidis (MC) to interact with cellular barriers is essential to its pathogenesis. With epithelial cells, this process has been modeled in two steps. The initial stage of localized adherence is mediated by bacterial pili. After this phase, MC disperse and lose piliation, thus leading to a diffuse adherence. At this stage, microvilli have disappeared, and MC interact intimately with cells and are, in places, located on pedestals of actin, thus realizing attaching and effacing (AE) lesions. The bacterial attributes responsible for these latter phenotypes remain unidentified. Considering that bacteria are nonpiliated at this stage, pili cannot be directly responsible for this effect. However, the initial phase of pilus-mediated localized adherence is required for the occurrence of diffuse adherence, loss of microvilli, and intimate attachment, because nonpiliated bacteria are not capable of such a cellular interaction. In this work, we engineered a mutation in the cytoplasmic nucleotide-binding protein PilT and showed that this mutation increased piliation and abolished the dispersal phase of bacterial clumps as well as the loss of piliation. Furthermore, no intimate attachment nor AE lesions were observed. On the other hand, PilT- MC remained adherent as piliated clumps at all times. Taken together these data demonstrate that the induction of diffuse adherence, intimate attachment, and AE lesions after pilus-mediated adhesion requires the cytoplasmic PilT protein. PMID- 10097156 TI - Evolution of microbial diversity during prolonged starvation. AB - Models of evolutionary processes postulate that new alleles appear in populations through random spontaneous mutation. Alleles that confer a competitive advantage in particular environments are selected and populations can be taken over by individuals expressing these advantageous mutations. We have studied the evolutionary process by using Escherichia coli cultures incubated for prolonged periods of time in stationary phase. The populations of surviving cells were shown to be highly dynamic, even after many months of incubation. Evolution proceeded along different paths even when the initial conditions were identical. As cultures aged, the takeovers by fitter mutants were incomplete, resulting in the coexistence of multiple mutant forms and increased microbial diversity. Thus, the study of bacterial populations in stationary phase provides a model system for understanding the evolution of diversity in natural populations. PMID- 10097157 TI - Vibrio cholerae O1 El Tor: identification of a gene cluster required for the rugose colony type, exopolysaccharide production, chlorine resistance, and biofilm formation. AB - The rugose colony variant of Vibrio cholerae O1, biotype El Tor, is shown to produce an exopolysaccharide, EPSETr, that confers chlorine resistance and biofilm-forming capacity. EPSETr production requires a chromosomal locus, vps, that contains sequences homologous to carbohydrate biosynthesis genes of other bacterial species. Mutations within this locus yield chlorine-sensitive, smooth colony variants that are biofilm deficient. The biofilm-forming properties of EPSETr may enable the survival of V. cholerae O1 within environmental aquatic habitats between outbreaks of human disease. PMID- 10097158 TI - Segregating the functions of human hippocampus. AB - It is now accepted that hippocampal lesions impair episodic memory. However, the precise functional role of the hippocampus in episodic memory remains elusive. Recent functional imaging data implicate the hippocampus in processing novelty, a finding supported by human in vivo recordings and event-related potential studies. Here we measure hippocampal responses to novelty, using functional MRI (fMRI), during an item-learning paradigm generated from an artificial grammar system. During learning, two distinct types of novelty were periodically introduced: perceptual novelty, pertaining to the physical characteristics of stimuli (in this case visual characteristics), and exemplar novelty, reflecting semantic characteristics of stimuli (in this case grammatical status within a rule system). We demonstrate a left anterior hippocampal response to both types of novelty and adaptation of these responses with stimulus familiarity. By contrast to these novelty effects, we also show bilateral posterior hippocampal responses with increasing exemplar familiarity. These results suggest a functional dissociation within the hippocampus with respect to the relative familiarity of study items. Neural responses in anterior hippocampus index generic novelty, whereas posterior hippocampal responses index familiarity to stimuli that have behavioral relevance (i.e., only exemplar familiarity). These findings add to recent evidence for functional segregation within the human hippocampus during learning. PMID- 10097159 TI - Functional identification and reconstitution of an odorant receptor in single olfactory neurons. AB - The olfactory system is remarkable in its capacity to discriminate a wide range of odorants through a series of transduction events initiated in olfactory receptor neurons. Each olfactory neuron is expected to express only a single odorant receptor gene that belongs to the G protein coupled receptor family. The ligand-receptor interaction, however, has not been clearly characterized. This study demonstrates the functional identification of olfactory receptor(s) for specific odorant(s) from single olfactory neurons by a combination of Ca2+ imaging and reverse transcription-coupled PCR analysis. First, a candidate odorant receptor was cloned from a single tissue-printed olfactory neuron that displayed odorant-induced Ca2+ increase. Next, recombinant adenovirus-mediated expression of the isolated receptor gene was established in the olfactory epithelium by using green fluorescent protein as a marker. The infected neurons elicited external Ca2+ entry when exposed to the odorant that originally was used to identify the receptor gene. Experiments performed to determine ligand specificity revealed that the odorant receptor recognized specific structural motifs within odorant molecules. The odorant receptor-mediated signal transduction appears to be reconstituted by this two-step approach: the receptor screening for given odorant(s) from single neurons and the functional expression of the receptor via recombinant adenovirus. The present approach should enable us to examine not only ligand specificity of an odorant receptor but also receptor specificity and diversity for a particular odorant of interest. PMID- 10097160 TI - Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents. AB - Experimental lemurs either were infected orally with the agent of bovine spongiform encephalopathy (BSE) or were maintained as uninfected control animals. Immunohistochemical examination for proteinase-resistant protein (prion protein or PrP) was performed on tissues from two infected but still asymptomatic lemurs, killed 5 months after infection, and from three uninfected control lemurs. Control tissues showed no staining, whereas PrP was detected in the infected animals in tonsil, gastrointestinal tract and associated lymphatic tissues, and spleen. In addition, PrP was detected in ventral and dorsal roots of the cervical spinal cord, and within the spinal cord PrP could be traced in nerve tracts as far as the cerebral cortex. Similar patterns of PrP immunoreactivity were seen in two symptomatic and 18 apparently healthy lemurs in three different French primate centers, all of which had been fed diets supplemented with a beef protein product manufactured by a British company that has since ceased to include beef in its veterinary nutritional products. This study of BSE-infected lemurs early in their incubation period extends previous pathogenesis studies of the distribution of infectivity and PrP in natural and experimental scrapie. The similarity of neuropathology and PrP immunostaining patterns in experimentally infected animals to those observed in both symptomatic and asymptomatic animals in primate centers suggests that BSE contamination of zoo animals may have been more widespread than is generally appreciated. PMID- 10097161 TI - Shift in speed selectivity of visual cortical neurons: a neural basis of perceived motion contrast. AB - The perceived speed of motion in one part of the visual field is influenced by the speed of motion in its surrounding fields. Little is known about the cellular mechanisms causing this phenomenon. Recordings from mammalian visual cortex revealed that speed preference of the cortical cells could be changed by displaying a contrast speed in the field surrounding the cell's classical receptive field. The neuron's selectivity shifted to prefer faster speed if the contextual surround motion was set at a relatively lower speed, and vice versa. These specific center-surround interactions may underlie the perceptual enhancement of speed contrast between adjacent fields. PMID- 10097162 TI - Optical imaging of functional domains in the cortex of the awake and behaving monkey. AB - As demonstrated by anatomical and physiological studies, the cerebral cortex consists of groups of cortical modules, each comprising populations of neurons with similar functional properties. This functional modularity exists in both sensory and association neocortices. However, the role of such cortical modules in perceptual and cognitive behavior is unknown. To aid in the examination of this issue we have applied the high spatial resolution optical imaging methodology to the study of awake, behaving animals. In this paper, we report the optical imaging of orientation domains and blob structures, approximately 100-200 micrometer in size, in visual cortex of the awake and behaving monkey. By overcoming the spatial limitations of other existing imaging methods, optical imaging will permit the study of a wide variety of cortical functions at the columnar level, including motor and cognitive functions traditionally studied with positron-emission tomography or functional MRI techniques. PMID- 10097163 TI - Evidence of a role for cyclic ADP-ribose in long-term synaptic depression in hippocampus. AB - Ca2+ released from presynaptic and postsynaptic intracellular stores plays important roles in activity-dependent synaptic plasticity, including long-term depression (LTD) of synaptic strength. At Schaffer collateral-CA1 synapses in the hippocampus, presynaptic ryanodine receptor-gated stores appear to mobilize some of the Ca2+ necessary to induce LTD. Cyclic ADP-ribose (cADPR) has recently been proposed as an endogenous activator of ryanodine receptors in sea urchin eggs and several mammalian cell types. Here, we provide evidence that cADPR-mediated signaling pathways play a key role in inducing LTD. We show that biochemical production of cGMP increases cADPR concentration in hippocampal slices in vitro, and that blockade of cGMP-dependent protein kinase, cADPR receptors, or ryanodine sensitive Ca2+ stores each prevent the induction of LTD at Schaffer collateral CA1 synapses. A lack of effect of postsynaptic infusion of either cADPR antagonist indicates a probable presynaptic site of action. PMID- 10097164 TI - A nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat. AB - Cholinergic neurons respond to the administration of nerve growth factor (NGF) in vivo with a prominent and selective increase of choline acetyl transferase activity. This suggests the possible involvement of endogenous NGF, acting through its receptor TrkA, in the maintenance of central nervous system cholinergic synapses in the adult rat brain. To test this hypothesis, a small peptide, C(92-96), that blocks NGF-TrkA interactions was delivered stereotactically into the rat cortex over a 2-week period, and its effect and potency were compared with those of an anti-NGF monoclonal antibody (mAb NGF30). Two presynaptic antigenic sites were studied by immunoreactivity, and the number of presynaptic sites was counted by using an image analysis system. Synaptophysin was used as a marker for overall cortical synapses, and the vesicular acetylcholine transporter was used as a marker for cortical cholinergic presynaptic sites. No significant variations in the number of synaptophysin immunoreactive sites were observed. However, both mAb NGF30 and the TrkA antagonist C(92-96) provoked a significant decrease in the number and size of vesicular acetylcholine transporter-IR sites, with the losses being more marked in the C(92-96) treated rats. These observations support the notion that endogenously produced NGF acting through TrkA receptors is involved in the maintenance of the cholinergic phenotype in the normal, adult rat brain and supports the idea that NGF normally plays a role in the continual remodeling of neural circuits during adulthood. The development of neurotrophin mimetics with antagonistic and eventually agonist action may contribute to therapeutic strategies for central nervous system degeneration and trauma. PMID- 10097165 TI - Ephrin-dependent growth and pruning of hippocampal axons. AB - Neuronal connections are arranged topographically such that the spatial organization of neurons is preserved by their termini in the targets. During the development of topographic projections, axons initially explore areas much wider than the final targets, and mistargeted axons are pruned later. The molecules regulating these processes are not known. We report here that the ligands of the Eph family tyrosine kinase receptors may regulate both the initial outgrowth and the subsequent pruning of axons. In the presence of ephrins, the outgrowth and branching of the receptor-positive hippocampal axons are enhanced. However, these axons are induced later to degenerate. These observations suggest that the ephrins and their receptors may regulate topographic map formation by stimulating axonal arborization and by pruning mistargeted axons. PMID- 10097166 TI - Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6 hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo. AB - 6-Hydroxydopamine (6-OHDA) is widely used to selectively lesion dopaminergic neurons of the substantia nigra (SN) in the creation of animal models of Parkinson's disease. In vitro, the death of PC-12 cells caused by exposure to 6 OHDA occurs with characteristics consistent with an apoptotic mechanism of cell death. To test the hypothesis that apoptotic pathways are involved in the death of dopaminergic neurons of the SN caused by 6-OHDA, we created a replication defective genomic herpes simplex virus-based vector containing the coding sequence for the antiapoptotic peptide Bcl-2 under the transcriptional control of the simian cytomegalovirus immediate early promoter. Transfection of primary cortical neurons in culture with the Bcl-2-producing vector protected those cells from naturally occurring cell death over 3 weeks. Injection of the Bcl-2 expressing vector into SN of rats 1 week before injection of 6-OHDA into the ipsilateral striatum increased the survival of neurons in the SN, detected either by retrograde labeling of those cells with fluorogold or by tyrosine hydroxylase immunocytochemistry, by 50%. These results, demonstrating that death of nigral neurons induced by 6-OHDA lesioning may be blocked by the expression of Bcl-2, are consistent with the notion that cell death in this model system is at least in part apoptotic in nature and suggest that a Bcl-2-expressing vector may have therapeutic potential in the treatment of Parkinson's disease. PMID- 10097167 TI - Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. AB - Hearing loss is most often the result of hair-cell degeneration due to genetic abnormalities or ototoxic and traumatic insults. In the postembryonic and adult mammalian auditory sensory epithelium, the organ of Corti, no hair-cell regeneration has ever been observed. However, nonmammalian hair-cell epithelia are capable of regenerating sensory hair cells as a consequence of nonsensory supporting-cell proliferation. The supporting cells of the organ of Corti are highly specialized, terminally differentiated cell types that apparently are incapable of proliferation. At the molecular level terminally differentiated cells have been shown to express high levels of cell-cycle inhibitors, in particular, cyclin-dependent kinase inhibitors [Parker, S. B., et al. (1995) Science 267, 1024-1027], which are thought to be responsible for preventing these cells from reentering the cell cycle. Here we report that the cyclin-dependent kinase inhibitor p27(Kip1) is selectively expressed in the supporting-cell population of the organ of Corti. Effects of p27(Kip1)-gene disruption include ongoing cell proliferation in postnatal and adult mouse organ of Corti at time points well after mitosis normally has ceased during embryonic development. This suggests that release from p27(Kip1)-induced cell-cycle arrest is sufficient to allow supporting-cell proliferation to occur. This finding may provide an important pathway for inducing hair-cell regeneration in the mammalian hearing organ. PMID- 10097168 TI - Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. AB - Remyelination of focal areas of the central nervous system (CNS) in animals can be achieved by transplantation of glial cells, yet the source of these cells in humans to similarly treat myelin disorders is limited at present to fetal tissue. Multipotent precursor cells are present in the CNS of adult as well as embryonic and neonatal animals and can differentiate into lineage-restricted progenitors such as oligodendroglial progenitors (OPs). The OPs present in adults have a different phenotype from those seen in earlier life, and their potential role in CNS repair remains unknown. To gain insights into the potential to manipulate the myelinating capacity of these precursor and/or progenitor cells, we generated a homogenous culture of OPs from neural precursor cells isolated from adult rat subependymal tissues. Phenotypic characterization indicated that these OPs resembled neonatal rather than adult OPs and produced robust myelin after transplantation. The ability to generate such cells from the adult brain therefore opens an avenue to explore the potential of these cells for repairing myelin disorders in adulthood. PMID- 10097169 TI - Long-range signaling within growing neurites mediated by neurotrophin-3. AB - In addition to well established trophic functions, neurotrophins acutely affect neurotransmitter secretion from the presynaptic nerve terminal, influence synaptic development, and may serve as selective retrograde messengers that regulate synaptic efficacy. The crucial question related to the mechanisms of neurotrophin-mediated signaling is whether acute effects of neurotrophins are spatially restricted to the activated synapses. Here we have used a local perfusion technique for local delivery of neurotrophin-3 (NT-3) to various regions of developing Xenopus embryo neurons in culture. Within minutes after a focal exposure of a soma or a small ( approximately 30 micrometer in length) axonal segment to NT-3, we observed an increase in the spontaneous neurotransmitter secretion from the presynaptic nerve terminals located approximately 300-400 micrometer away from the site of NT-3 application. Secretory activity along the axonal shaft was not affected. Our findings suggest that the NT-3-mediated signal may rapidly travel through neuronal cytoplasm over unexpectedly long distances and modulate neurotransmitter release specifically at the presynaptic nerve terminals. PMID- 10097170 TI - Coordinate regulation of gonadotropin-releasing hormone neuronal firing patterns by cytosolic calcium and store depletion. AB - Elevation of cytosolic free Ca2+ concentration ([Ca2+]i) in excitable cells often acts as a negative feedback signal on firing of action potentials and the associated voltage-gated Ca2+ influx. Increased [Ca2+]i stimulates Ca2+-sensitive K+ channels (IK-Ca), and this, in turn, hyperpolarizes the cell and inhibits Ca2+ influx. However, in some cells expressing IK-Ca the elevation in [Ca2+]i by depletion of intracellular stores facilitates voltage-gated Ca2+ influx. This phenomenon was studied in hypothalamic GT1 neuronal cells during store depletion caused by activation of gonadotropin-releasing hormone (GnRH) receptors and inhibition of endoplasmic reticulum (Ca2+)ATPase with thapsigargin. GnRH induced a rapid spike increase in [Ca2+]i accompanied by transient hyperpolarization, followed by a sustained [Ca2+]i plateau during which the depolarized cells fired with higher frequency. The transient hyperpolarization was caused by the initial spike in [Ca2+]i and was mediated by apamin-sensitive IK-Ca channels, which also were operative during the subsequent depolarization phase. Agonist-induced depolarization and increased firing were independent of [Ca2+]i and were not mediated by inhibition of K+ current, but by facilitation of a voltage insensitive, Ca2+-conducting inward current. Store depletion by thapsigargin also activated this inward depolarizing current and increased the firing frequency. Thus, the pattern of firing in GT1 neurons is regulated coordinately by apamin sensitive SK current and store depletion-activated Ca2+ current. This dual control of pacemaker activity facilitates voltage-gated Ca2+ influx at elevated [Ca2+]i levels, but also protects cells from Ca2+ overload. This process may also provide a general mechanism for the integration of voltage-gated Ca2+ influx into receptor-controlled Ca2+ mobilization. PMID- 10097171 TI - Quantitative fine-structural analysis of olfactory cortical synapses. AB - To determine the extent to which hippocampal synapses are typical of those found in other cortical regions, we have carried out a quantitative analysis of olfactory cortical excitatory synapses, reconstructed from serial electron micrograph sections of mouse brain, and have compared these new observations with previously obtained data from hippocampus. Both superficial and deep layer I olfactory cortical synapses were studied. Although individual synapses in each of the areas-CA1 hippocampus, olfactory cortical layer Ia, olfactory cortical area Ib-might plausibly have been found in any of the other areas, the average characteristics of the three synapse populations are distinct. Olfactory cortical synapses in both layers are, on average, about 2.5 times larger than their hippocampal counterparts. The layer Ia olfactory cortical synapses have fewer synaptic vesicles than do the layer Ib synapses, but the absolute number of vesicles docked to the active zone in the layer Ia olfactory cortical synapses is about equal to the docked vesicle number in the smaller hippocampal synapses. As would be predicted from studies on hippocampus that relate paired-pulse facilitation to the number of docked vesicles, the synapses in layer 1a exhibit facilitation, whereas the ones in layer 1b do not. Although hippocampal synapses provide as a good model system for central synapses in general, we conclude that significant differences in the average structure of synapses from one cortical region to another exist, and this means that generalizations based on a single synapse type must be made with caution. PMID- 10097172 TI - Modulation of nicotinic acetylcholine receptors by strychnine. AB - Strychnine, a potent and selective antagonist at glycine receptors, was found to inhibit muscle (alpha1beta1gammadelta, alpha1beta1gamma, and alpha1beta1delta) and neuronal (alpha2beta2 and alpha2beta4) nicotinic acetylcholine receptors (AcChoRs) expressed in Xenopus oocytes. Strychnine alone (up to 500 microM) did not elicit membrane currents in oocytes expressing AcChoRs, but, when applied before, concomitantly, or during superfusion of acetylcholine (AcCho), it rapidly and reversibly inhibited the current elicited by AcCho (AcCho-current). Although in the three cases the AcCho-current was reduced to the same level, its recovery was slower when the oocytes were preincubated with strychnine. The amount of AcCho-current inhibition depended on the receptor subtype, and the order of blocking potency by strychnine was alpha1beta1gammadelta > alpha2beta4 > alpha2beta2. With the three forms of drug application, the Hill coefficient was close to one, suggesting a single site for the receptor interaction with strychnine, and this interaction appears to be noncompetitive. The inhibitory effects on muscle AcChoRs were voltage-independent, and the apparent dissociation constant for AcCho was not appreciably changed by strychnine. In contrast, the inhibitory effects on neuronal AcChoRs were voltage-dependent, with an electrical distance of approximately 0.35. We conclude that strychnine regulates reversibly and noncompetitively the embryonic type of muscle AcChoR and some forms of neuronal AcChoRs. In the former case, strychnine presumably inhibits allosterically the receptor by binding at an external domain whereas, in the latter case, it blocks the open receptor-channel complex. PMID- 10097173 TI - Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. AB - We have identified a novel beta amyloid precursor protein (betaAPP) mutation (V715M-betaAPP770) that cosegregates with early-onset Alzheimer's disease (AD) in a pedigree. Unlike other familial AD-linked betaAPP mutations reported to date, overexpression of V715M-betaAPP in human HEK293 cells and murine neurons reduces total Abeta production and increases the recovery of the physiologically secreted product, APPalpha. V715M-betaAPP significantly reduces Abeta40 secretion without affecting Abeta42 production in HEK293 cells. However, a marked increase in N terminally truncated Abeta ending at position 42 (x-42Abeta) is observed, whereas its counterpart x-40Abeta is not affected. These results suggest that, in some cases, familial AD may be associated with a reduction in the overall production of Abeta but may be caused by increased production of truncated forms of Abeta ending at the 42 position. PMID- 10097174 TI - Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation. AB - Although an excitotoxic mechanism of neuronal injury has been proposed to play a role in chronic neurodegenerative disorders such as Alzheimer's disease, and neurotrophic factors have been put forward as potential therapeutic agents, direct evidence is lacking. Taking advantage of the fact that mutations in the presenilin-1 (PS1) gene are causally linked to many cases of early-onset inherited Alzheimer's disease, we generated PS1 mutant knock-in mice and directly tested the excitotoxic and neurotrophic hypotheses of Alzheimer's disease. Primary hippocampal neurons from PS1 mutant knock-in mice exhibited increased production of amyloid beta-peptide 42/43 and increased vulnerability to excitotoxicity, which occurred in a gene dosage-dependent manner. Neurons expressing mutant PS1 exhibited enhanced calcium responses to glutamate and increased oxyradical production and mitochondrial dysfunction. Pretreatment with either basic fibroblast growth factor or activity-dependent neurotrophic factor protected neurons expressing mutant PS1 against excitotoxicity. Both basic fibroblast growth factor and activity-dependent neurotrophic factor stabilized intracellular calcium levels and abrogated the increased oxyradical production and mitochondrial dysfunction otherwise caused by the PS1 mutation. Our data indicate that neurotrophic factors can interrupt excitotoxic neurodegenerative cascades promoted by PS1 mutations. PMID- 10097175 TI - Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage. AB - Thioredoxin (TRX) plays important biological roles both in intra- and extracellular compartments, including in regulation of various intracellular molecules via thiol redox control. We produced TRX overexpressing mice and confirmed that there were no anatomical and physiological differences between wild-type (WT) mice and TRX transgenic (Tg) mice. In the present study we subjected mice to focal brain ischemia to shed light on the role of TRX in brain ischemic injury. At 24 hr after middle cerebral artery occlusion, infarct areas and volume were significantly smaller in Tg mice than in WT mice. Moreover neurological deficit was ameliorated in Tg mice compared with WT mice. Protein carbonyl content, a marker of cellular protein oxidation, in Tg mice showed less increase than did that of WT mice after the ischemic insult. Furthermore, c-fos expression in Tg mice was stronger than in WT mice 1 hr after ischemia. Our results suggest that transgene expression of TRX decreased ischemic neuronal injury and that TRX and the redox state modified by TRX play a crucial role in brain damage during stroke. PMID- 10097176 TI - Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane beta-subunit homolog. AB - Voltage-dependent and calcium-sensitive K+ (MaxiK) channels are key regulators of neuronal excitability, secretion, and vascular tone because of their ability to sense transmembrane voltage and intracellular Ca2+. In most tissues, their stimulation results in a noninactivating hyperpolarizing K+ current that reduces excitability. In addition to noninactivating MaxiK currents, an inactivating MaxiK channel phenotype is found in cells like chromaffin cells and hippocampal neurons. The molecular determinants underlying inactivating MaxiK channels remain unknown. Herein, we report a transmembrane beta subunit (beta2) that yields inactivating MaxiK currents on coexpression with the pore-forming alpha subunit of MaxiK channels. Intracellular application of trypsin as well as deletion of 19 N-terminal amino acids of the beta2 subunit abolished inactivation of the alpha subunit. Conversely, fusion of these N-terminal amino acids to the noninactivating smooth muscle beta1 subunit leads to an inactivating phenotype of MaxiK channels. Furthermore, addition of a synthetic N-terminal peptide of the beta2 subunit causes inactivation of the MaxiK channel alpha subunit by occluding its K+-conducting pore resembling the inactivation caused by the "ball" peptide in voltage-dependent K+ channels. Thus, the inactivating phenotype of MaxiK channels in native tissues can result from the association with different beta subunits. PMID- 10097177 TI - Mapping the active site in vasoactive intestinal peptide to a core of four amino acids: neuroprotective drug design. AB - The understanding of the molecular mechanisms leading to peptide action entails the identification of a core active site. The major 28-aa neuropeptide, vasoactive intestinal peptide (VIP), provides neuroprotection. A lipophilic derivative with a stearyl moiety at the N-terminal and norleucine residue replacing the Met-17 was 100-fold more potent than VIP in promoting neuronal survival, acting at femtomolar-picomolar concentration. To identify the active site in VIP, over 50 related fragments containing an N-terminal stearic acid attachment and an amidated C terminus were designed, synthesized, and tested for neuroprotective properties. Stearyl-Lys-Lys-Tyr-Leu-NH2 (derived from the C terminus of VIP and the related peptide, pituitary adenylate cyclase activating peptide) captured the neurotrophic effects offered by the entire 28-aa parent lipophilic derivative and protected against beta-amyloid toxicity in vitro. Furthermore, the 4-aa lipophilic peptide recognized VIP-binding sites and enhanced choline acetyltransferase activity as well as cognitive functions in Alzheimer's disease-related in vivo models. Biodistribution studies following intranasal administration of radiolabeled peptide demonstrated intact peptide in the brain 30 min after administration. Thus, lipophilic peptide fragments offer bioavailability and stability, providing lead compounds for drug design against neurodegenerative diseases. PMID- 10097179 TI - Calcium block of Na+ channels and its effect on closing rate. AB - Calcium ion transiently blocks Na+ channels, and it shortens the time course for closing of their activation gates. We examined the relation between block and closing kinetics by using the Na+ channels natively expressed in GH3 cells, a clonal line of rat pituitary cells. To simplify analysis, inactivation of the Na+ channels was destroyed by including papain in the internal medium. All divalent cations tested, and trivalent La3+, blocked a progressively larger fraction of the channels as their concentration increased, and they accelerated the closing of the Na+ channel activation gate. For calcium, the most extensively studied cation, there is an approximately linear relation between the fraction of the channels that are calcium-blocked and the closing rate. Extrapolation of the data to very low calcium suggests that closing rate is near zero when there is no block. Analysis shows that, almost with certainty, the channels can close when occupied by calcium. The analysis further suggests that the channels close preferentially or exclusively from the calcium-blocked state. PMID- 10097178 TI - NADH-quinone oxidoreductase: PSST subunit couples electron transfer from iron sulfur cluster N2 to quinone. AB - The proton-translocating NADH-quinone oxidoreductase (EC 1.6.99.3) is the largest and least understood enzyme complex of the respiratory chain. The mammalian mitochondrial enzyme (also called complex I) contains more than 40 subunits, whereas its structurally simpler bacterial counterpart (NDH-1) in Paracoccus denitrificans and Thermus thermophilus HB-8 consists of 14 subunits. A major unsolved question is the location and mechanism of the terminal electron transfer step from iron-sulfur cluster N2 to quinone. Potent inhibitors acting at this key region are candidate photoaffinity probes to dissect NADH-quinone oxidoreductases. Complex I and NDH-1 are very sensitive to inhibition by a variety of structurally diverse toxicants, including rotenone, piericidin A, bullatacin, and pyridaben. We designed (trifluoromethyl)diazirinyl[3H]pyridaben ([3H]TDP) as our photoaffinity ligand because it combines outstanding inhibitor potency, a suitable photoreactive group, and tritium at high specific activity. Photoaffinity labeling of mitochondrial electron transport particles was specific and saturable. Isolation, protein sequencing, and immunoprecipitation identified the high-affinity specifically labeled 23-kDa subunit as PSST of complex I. Immunoprecipitation of labeled membranes of P. denitrificans and T. thermophilus established photoaffinity labeling of the equivalent bacterial NQO6. Competitive binding and enzyme inhibition studies showed that photoaffinity labeling of the specific high-affinity binding site of PSST is exceptionally sensitive to each of the high-potency inhibitors mentioned above. These findings establish that the homologous PSST of mitochondria and NQO6 of bacteria have a conserved inhibitor binding site and that this subunit plays a key role in electron transfer by functionally coupling iron-sulfur cluster N2 to quinone. PMID- 10097180 TI - Distinguishing surface effects of calcium ion from pore-occupancy effects in Na+ channels. AB - The effects of calcium ion on the Na+ activation gate were studied in squid giant axons. Saxitoxin (STX) was used to block ion entry into Na+ channels without hindering access to the membrane surface, making it possible to distinguish surface effects of calcium from pore-occupancy effects. In the presence of STX, gating kinetics were measured from gating current (Ig). The kinetic effects of external calcium concentration changes were small when STX was present. In the absence of STX, lowering the calcium concentration (from 100 to 10 mM) slowed the closing of Na+ channels (measured from INa tails) by more than a factor of 2. Surprisingly, the voltage sensitivity of closing kinetics changed with calcium concentration, and it was modified by STX. Voltage sensitivity apparently depends in part on the ability of calcium to enter and block the channels as voltage is driven negative. In external medium with no added calcium, INa tail current initially increases in amplitude severalfold with the relief of calcium block, then progressively slows and gets smaller, as calcium diffuses out of the layers investing the axon. INa tails seen just before the current disappears suggest that closing in the absence of channel block is very slow or does not occur. INa amplitude and kinetics are completely restored when calcium is returned. The results strongly suggest that calcium occupancy is a requirement for channel closing and that nonoccupied channels fold reversibly into a nonfunctional conformation. PMID- 10097181 TI - A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease. AB - Central core disease is a rare, nonprogressive myopathy that is characterized by hypotonia and proximal muscle weakness. In a large Mexican kindred with an unusually severe and highly penetrant form of the disorder, DNA sequencing identified an I4898T mutation in the C-terminal transmembrane/luminal region of the RyR1 protein that constitutes the skeletal muscle ryanodine receptor. All previously reported RYR1 mutations are located either in the cytoplasmic N terminus or in a central cytoplasmic region of the 5,038-aa protein. The I4898T mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. The response of the mutant RyR1 Ca2+ channel to the agonists halothane and caffeine in a Ca2+ photometry assay was completely abolished. Coexpression of normal and mutant RYR1 cDNAs in a 1:1 ratio, however, produced RyR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca2+ release were reduced by 67%. [3H]Ryanodine binding indicated that the heterozygous channel is activated by Ca2+ concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells showed a significantly increased resting cytoplasmic Ca2+ level and a significantly reduced luminal Ca2+ level. These data are indicative of a leaky channel, possibly caused by a reduction in the Ca2+ concentration required for channel activation. Comparison with two other coexpressed mutant/normal channels suggests that the I4898T mutation produces one of the most abnormal RyR1 channels yet investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected central core disease individuals. PMID- 10097182 TI - A single point mutation in the pore region of the epithelial Na+ channel changes ion selectivity by modifying molecular sieving. AB - The epithelial Na+ channel (ENaC) belongs to a new class of channel proteins called the ENaC/DEG superfamily involved in epithelial Na+ transport, mechanotransduction, and neurotransmission. The role of ENaC in Na+ homeostasis and in the control of blood pressure has been demonstrated recently by the identification of mutations in ENaC beta and gamma subunits causing hypertension. The function of ENaC in Na+ reabsorption depends critically on its ability to discriminate between Na+ and other ions like K+ or Ca2+. ENaC is virtually impermeant to K+ ions, and the molecular basis for its high ionic selectivity is largely unknown. We have identified a conserved Ser residue in the second transmembrane domain of the ENaC alpha subunit (alphaS589), which when mutated allows larger ions such as K+, Rb+, Cs+, and divalent cations to pass through the channel. The relative ion permeability of each of the alphaS589 mutants is related inversely to the ionic radius of the permeant ion, indicating that alphaS589 mutations increase the molecular cutoff of the channel by modifying the pore geometry at the selectivity filter. Proper geometry of the pore is required to tightly accommodate Na+ and Li+ ions and to exclude larger cations. We provide evidence that ENaC discriminates between cations mainly on the basis of their size and the energy of dehydration. PMID- 10097183 TI - Loss of the circadian clock-associated protein 1 in Arabidopsis results in altered clock-regulated gene expression. AB - Little is known about plant circadian oscillators, in spite of how important they are to sessile plants, which require accurate timekeepers that enable the plants to respond to their environment. Previously, we identified a circadian clock associated (CCA1) gene that encodes an Myb-related protein that is associated with phytochrome control and circadian regulation in plants. To understand the role CCA1 plays in phytochrome and circadian regulation, we have isolated an Arabidopsis line with a T DNA insertion that results in the loss of CCA1 RNA, of CCA1 protein, and of an Lhcb-promoter binding activity. This mutation affects the circadian expression of all four clock-controlled genes that we examined. The results show that, despite their similarity, CCA1 and LHY are only partially redundant. The lack of CCA1 also affects the phytochrome regulation of gene expression, suggesting that CCA1 has an additional role in a signal transduction pathway from light, possibly acting at the point of integration between phytochrome and the clock. Our results indicate that CCA1 is an important clock associated protein involved in circadian regulation of gene expression. PMID- 10097184 TI - Characterization of maize (Zea mays L.) Wee1 and its activity in developing endosperm. AB - We report the characterization of a maize Wee1 homologue and its expression in developing endosperm. Using a 0.8-kb cDNA from an expressed sequence tag project, we isolated a 1.6-kb cDNA (ZmWee1), which encodes a protein of 403 aa with a calculated molecular size of 45.6 kDa. The deduced amino acid sequence shows 50% identity to the protein kinase domain of human Wee1. Overexpression of ZmWee1 in Schizosaccharomyces pombe inhibited cell division and caused the cells to enlarge significantly. Recombinant ZmWee1 obtained from Escherichia coli is able to inhibit the activity of p13(suc1)-adsorbed cyclin-dependent kinase from maize. ZmWee1 is encoded by a single gene at a locus on the long arm of chromosome 4. RNA gel blots showed the ZmWee1 transcript is about 2.4 kb in length and that its abundance reaches a maximum 15 days after pollination in endosperm tissue. High levels of expression of ZmWee1 at this stage of endosperm development imply that ZmWee1 plays a role in endoreduplication. Our results show that control of cyclin dependent kinase activity by Wee1 is conserved among eukaryotes, from fungi to animals and plants. PMID- 10097185 TI - Control of fertilization-independent endosperm development by the MEDEA polycomb gene in Arabidopsis. AB - Higher plant reproduction is unique because two cells are fertilized in the haploid female gametophyte. Egg and sperm nuclei fuse to form the embryo. A second sperm nucleus fuses with the central cell nucleus that replicates to generate the endosperm, a tissue that supports embryo development. To understand mechanisms that initiate reproduction, we isolated a mutation in Arabidopsis, f644, that allows for replication of the central cell and subsequent endosperm development without fertilization. When mutant f644 egg and central cells are fertilized by wild-type sperm, embryo development is inhibited, and endosperm is overproduced. By using a map-based strategy, we cloned and sequenced the F644 gene and showed that it encodes a SET-domain polycomb protein. Subsequently, we found that F644 is identical to MEDEA (MEA), a gene whose maternal-derived allele is required for embryogenesis [Grossniklaus, U., Vielle-Calzada, J.-P., Hoeppner, M. A. & Gagliano, W. B. (1998) Science 280, 446-450]. Together, these results reveal functions for plant polycomb proteins in the suppression of central cell proliferation and endosperm development. We discuss models to explain how polycomb proteins function to suppress endosperm and promote embryo development. PMID- 10097186 TI - Conversion of cucumber linoleate 13-lipoxygenase to a 9-lipoxygenating species by site-directed mutagenesis. AB - Multiple lipoxygenase sequence alignments and structural modeling of the enzyme/substrate interaction of the cucumber lipid body lipoxygenase suggested histidine 608 as the primary determinant of positional specificity. Replacement of this amino acid by a less-space-filling valine altered the positional specificity of this linoleate 13-lipoxygenase in favor of 9-lipoxygenation. These alterations may be explained by the fact that H608V mutation may demask the positively charged guanidino group of R758, which, in turn, may force an inverse head-to-tail orientation of the fatty acid substrate. The R758L+H608V double mutant exhibited a strongly reduced reaction rate and a random positional specificity. Trilinolein, which lacks free carboxylic groups, was oxygenated to the corresponding (13S)-hydro(pero)xy derivatives by both the wild-type enzyme and the linoleate 9-lipoxygenating H608V mutant. These data indicate the complete conversion of a linoleate 13-lipoxygenase to a 9-lipoxygenating species by a single point mutation. It is hypothesized that H608V exchange may alter the orientation of the substrate at the active site and/or its steric configuration in such a way that a stereospecific dioxygen insertion at C-9 may exclusively take place. PMID- 10097187 TI - Genetic evidence for the role of GDP-mannose in plant ascorbic acid (vitamin C) biosynthesis. AB - Vitamin C (L-ascorbic acid; AsA) acts as a potent antioxidant and cellular reductant in plants and animals. AsA has long been known to have many critical physiological roles in plants, yet its biosynthesis is only currently being defined. A pathway for AsA biosynthesis that features GDP-mannose and L-galactose has recently been proposed for plants. We have isolated a collection of AsA deficient mutants of Arabidopsis thaliana that are valuable tools for testing of an AsA biosynthetic pathway. The best-characterized of these mutants (vtc1) contains approximately 25% of wild-type AsA and is defective in AsA biosynthesis. By using a combination of biochemical, molecular, and genetic techniques, we have demonstrated that the VTC1 locus encodes a GDP-mannose pyrophosphorylase (mannose 1-P guanyltransferase). This enzyme provides GDP-mannose, which is used for cell wall carbohydrate biosynthesis and protein glycosylation as well as for AsA biosynthesis. In addition to genetically defining the first locus involved in AsA biosynthesis, this work highlights the power of using traditional mutagenesis techniques coupled with the Arabidopsis Genome Initiative to rapidly clone physiologically important genes. PMID- 10097188 TI - Cladistic association analysis of Y chromosome effects on alcohol dependence and related personality traits. AB - Association between Y chromosome haplotype variation and alcohol dependence and related personality traits was investigated in a large sample of psychiatrically diagnosed Finnish males. Haplotypes were constructed for 359 individuals using alleles at eight loci (seven microsatellite loci and a nucleotide substitution in the DYZ3 alphoid satellite locus). A cladogram linking the 102 observed haplotype configurations was constructed by using parsimony with a single-step mutation model. Then, a series of contingency tables nested according to the cladogram hierarchy were used to test for association between Y haplotype and alcohol dependence. Finally, using only alcohol-dependent subjects, we tested for association between Y haplotype and personality variables postulated to define subtypes of alcoholism-antisocial personality disorder, novelty seeking, harm avoidance, and reward dependence. Significant association with alcohol dependence was observed at three Y haplotype clades, with significance levels of P = 0.002, P = 0.020, and P = 0.010. Within alcohol-dependent subjects, no relationship was revealed between Y haplotype and antisocial personality disorder, novelty seeking, harm avoidance, or reward dependence. These results demonstrate, by using a fully objective association design, that differences among Y chromosomes contribute to variation in vulnerability to alcohol dependence. However, they do not demonstrate an association between Y haplotype and the personality variables thought to underlie the subtypes of alcoholism. PMID- 10097189 TI - A modern human pattern of dental development in lower pleistocene hominids from Atapuerca-TD6 (Spain). AB - The study of life history evolution in hominids is crucial for the discernment of when and why humans have acquired our unique maturational pattern. Because the development of dentition is critically integrated into the life cycle in mammals, the determination of the time and pattern of dental development represents an appropriate method to infer changes in life history variables that occurred during hominid evolution. Here we present evidence derived from Lower Pleistocene human fossil remains recovered from the TD6 level (Aurora stratum) of the Gran Dolina site in the Sierra de Atapuerca, northern Spain. These hominids present a pattern of development similar to that of Homo sapiens, although some aspects (e.g., delayed M3 calcification) are not as derived as that of European populations and people of European origin. This evidence, taken together with the present knowledge of cranial capacity of these and other late Early Pleistocene hominids, supports the view that as early as 0.8 Ma at least one Homo species shared with modern humans a prolonged pattern of maturation. PMID- 10097190 TI - Re-light your lamp. PMID- 10097191 TI - ED short staffing: It is time to take a hard look at a growing problem and strategies such as standard nurse-patient ratios. PMID- 10097194 TI - ED noise: one family's experience. PMID- 10097196 TI - A 6-year-old with a pancreatic injury from bicycle handlebars. PMID- 10097197 TI - Elderly patients' perceptions of care in the emergency department. AB - OBJECTIVE: Patients' perceptions and satisfaction are areas of growing concern in health care research, but little has been reported from the perspective of elderly persons. The purpose of this study was to describe elderly patients' perceptions of care in the emergency department. METHODS: A qualitative, descriptive study design was used. Twelve elderly people were interviewed following a treatment episode in 1 of 3 emergency departments in the western United States and data were submitted to content analysis according to qualitative, interpretive methodology. FINDINGS: The following 5 themes emerged from the analysis: "needs for information," "observations of waiting time," "perceptions of professional competency and caring service," "concerns about process and facility design," and "personal tolerance." DISCUSSION: Findings support some aspects of existing literature and offer additional information regarding care of elderly persons in the emergency department. Results also support the need for more research in the area of the actual experience of elderly patients in the emergency department. PMID- 10097198 TI - Needlestick injuries and subsequent disease: first-person accounts from 3 nurses. PMID- 10097199 TI - Fulminate pneumococcal septicemia in the asplenic patient: A case study with urgent implications for recognition and prevention. PMID- 10097200 TI - Developing a domestic violence program in an inner-city academic health center emergency department: the first 3 years. PMID- 10097201 TI - Ethylene glycol and methanol poisoning: diagnosis and treatment. PMID- 10097203 TI - The admission nurse: A way to expedite and improve the admissions process and stop ED diversions. PMID- 10097204 TI - Computerization of prehospital medical records: A planning primer from one EMS system. PMID- 10097205 TI - Tips for helping the families of patients transported by helicopter. PMID- 10097207 TI - WWW: something for everyone. PMID- 10097208 TI - Should peer review be an open process? PMID- 10097209 TI - A 14-year-old victim of sexual assault with an imperforate hymen and urethral meatus tear. PMID- 10097210 TI - The 3 P's of airway. PMID- 10097211 TI - A 4-month-old infant with feeding problems. PMID- 10097212 TI - The abbreviated life of acronyms. PMID- 10097213 TI - Bailout coronary stenting: not always a foolproof safety net. PMID- 10097214 TI - Why is mortality rate after percutaneous transluminal coronary angioplasty higher in women? PMID- 10097215 TI - Percutaneous intervention in the very elderly: weighing the risks and benefits. PMID- 10097216 TI - Variations in the use of cardiac procedures: what is the explanation? PMID- 10097217 TI - Does pregnancy affect the durability of valvular bioprostheses? PMID- 10097218 TI - Lone atrial fibrillation: epidemiology and natural history. PMID- 10097219 TI - Do cardiologists and general internists differ in testing and treating patients with aortic stenosis or mitral regurgitation? A preliminary study with editorial perspective. PMID- 10097220 TI - What to do with acute atrial fibrillation? PMID- 10097221 TI - Coronary stent implantation in acute myocardial infarction. AB - BACKGROUND: The purpose of this study was to provide an overview on stenting in acute myocardial infarction (MI). METHODS AND RESULTS: A search of MEDLINE and the scientific sessions abstracts in peer review journals through May 1998 was carried out to identify any publications on stenting in MI. The settings were retrospective and prospective case series on stenting in MI, nonrandomized and randomized trials comparing primary stenting and primary percutaneous transluminal coronary angioplasty (PTCA) in MI, and stenting in cardiogenic shock complicating MI. Reported outcomes included procedural success, reocclusion, restenosis, and target vessel revascularization rates; incidence of death, MI, recurrent ischemia, major bleeding, and vascular complications; and incidence of cerebrovascular accidents. Procedural success rates were better for stenting than primary PTCA, and postprocedural minimum luminal diameters were larger. This resulted in lower reocclusion and restenosis rates and a lesser need for target vessel revascularization with primary stenting. The incidence of death, MI, and recurrent ischemia was also reduced with primary stenting. Major bleeding and vascular complications were confined to patients receiving anticoagulation as opposed to antiplatelet agents after stenting. Finally, a strategy of bailout stenting for failed PTCA in MI appears to be inferior to a primary stenting strategy. CONCLUSIONS: Stenting in MI is an effective and safe reperfusion strategy with many advantages compared with primary PTCA. PMID- 10097223 TI - Pathology of bailout coronary stenting in human beings. AB - OBJECTIVES: The aim of this study was to perform detailed postmortem analysis of bailout coronary stenting to gain insights into the mechanism of success or failure of the procedure. Bailout stenting is increasingly used for acute or threatened arterial closure after angioplasty. Few pathologic data from bailout stenting have been reported. METHODS AND RESULTS: The coronary arteries from 6 cases of bailout stenting were analyzed at autopsy. All stents were placed for extensive coronary dissection or abrupt vessel closure after balloon angioplasty. Twenty stents (11 Palmaz-Schatz and 9 Gianturco-Roubin stents) were placed in 8 coronary arteries, ranging from 1 to 5 stents per artery. After stenting, angiography showed good coronary flow in 3 of 6 cases. All patients died secondary to acute myocardial infarction. Histologically, in all cases, the stents were well opposed to the coronary artery wall, with a focally widely patent lumen by compression of the dissection plane. However, in 4 of 6 cases, there was residual dissection present in the nonstented portion of the arteries proximal, proximal to, and between stents or distal to the stented segment, resulting in focal luminal compression or obstruction. In 2 cases, bailout stenting effectively covered the dissection and prevented luminal compression. CONCLUSIONS: Bailout stenting for dissection after balloon angioplasty restores lumen patency in the stented segment. Residual dissection in nonstented segments adversely affects outcome and supports the need for continued development of new stents with increased trackability and tapering designs to more effectively treat major coronary dissections. PMID- 10097222 TI - Smoking status and outcome after primary coronary angioplasty for acute myocardial infarction. AB - BACKGROUND: Because of the increased propensity of intracoronary thrombi to form in cigarette smokers, percutaneous transluminal angioplasty (PTCA) for acute myocardial infarction (AMI) may be less effective in smokers. We sought to determine the impact of smoking status on outcome after PTCA for AMI. METHODS: Patients enrolled in the GUSTO IIb Angioplasty Substudy were randomly assigned to receive PTCA or tissue-plasminogen activator (tPA) for AMI. The interaction of smoking status (nonsmokers = 344, former smokers = 294, current smokers = 490) and treatment strategy with the occurrence of death, nonfatal reinfarction, or nonfatal, disabling stroke at 30 days was analyzed. Procedural success (residual stenosis <50% and Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) was also analyzed for patients who underwent PTCA (n = 444). RESULTS: Among patients who underwent PTCA, nonsmokers had worse percent stenosis of the culprit lesion before reperfusion (P =.03) and more often had TIMI flow grade 0 (P <.05). Procedural success was more common in smokers (65.6%) than in former smokers (53.3%) and nonsmokers (52. 4%; P =.02), reflecting a higher rate of postprocedure TIMI 3 flow. PTCA was associated with a better 30-day outcome than tPA for current smokers (odds ratio [95% confidence interval] = 0.41 [0.19 to 0.88]), with a similar trend for former smokers (0.73 [0.34 to 1. 58]) and nonsmokers (0.77 [0.42 to 1.40]). At 6 months, smokers randomly assigned to PTCA also had fewer deaths and reinfarction (0. 58 [0.31 to 1.07]). CONCLUSIONS: Although smoking status affects angiographic variables before and after PTCA for AMI, PTCA is associated with a better 30-day outcome than tPA regardless of smoking status and should be considered when readily available. PMID- 10097224 TI - Carvedilol prevents remodeling in patients with left ventricular dysfunction after acute myocardial infarction. AB - OBJECTIVE: The aim of the study was to assess the effects of carvedilol, a vasodilating nonselective beta-blocker, on the indexes of left ventricular remodeling after acute myocardial infarction in those with left ventricular dysfunction. METHODS AND RESULTS: Forty-nine patients with predischarge left ventricular ejection fraction <45% after acute myocardial infarction were evaluated in a double-blind, randomized, placebo-controlled, parallel group study (selected from the database of the Carvedilol Heart Attack Pilot Study: CHAPS). Patients received medication after thrombolysis and continued to do so for 6 months. Two-dimensional echocardiography was performed before discharge (7 to 10 days after admission) and at 3 months after acute myocardial infarction. Analysis of variance showed that wall thickness opposite the site of infarction decreased from (mean +/- SD) 12.3 +/- 2.1 mm to 11.0 +/- 2.4 mm with carvedilol compared with 11.6 +/- 1.9 mm to 12.2 +/- 1.9 mm with placebo (P =.01). Left ventricular mass changed from 235 +/- 74 g to 217 +/- 64 g with carvedilol compared with 227 +/- 80 g to 252 +/- 85 g with placebo ( P =.02). Carvedilol prevented alteration of sphericity index (ratio of long and short axis of left ventricle) that changed from 1.65 +/- 0.29 to 1.66 +/- 20 with carvedilol compared with 1.58 +/- 0.33 to 1.39 +/- 0.19 with placebo (P =.02); alteration was also prevented of wall thickening abnormality at infarct site, which changed from 9.2 +/- 3.1 cm2 to 9.1 +/- 3.5 cm 2 with carvedilol compared with 10.3 +/- 3.3 cm2 to 13.5 +/- 4.6 cm2 with placebo (P =.002). CONCLUSION: Carvedilol administered early after acute myocardial infarction results in attenuation of left ventricular remodeling in patients with persistent left ventricular dysfunction before discharge. PMID- 10097225 TI - Influence of gene polymorphisms of the renin-angiotensin system on clinical outcome in heart failure among the Chinese. AB - BACKGROUND: An association between the DD allele of the angiotensin-converting enzyme gene and a poorer outcome in patients with heart failure has been found in whites. The DD allele frequency is lower in Chinese, but the M235T variant of the angiotensinogen gene is more common in Chinese than whites; it is not known to what extent polymorphisms of the renin-angiotensin system affect clinical status or prognosis in Chinese patients with heart failure. METHODS: We assessed the relations among polymorphism of the angiotensin-converting enzyme gene, angiotensinogen M235T (AGT) gene, and angiotensin type I receptor A1166C gene with left ventricular systolic function, left and right ventricular diastolic function, serum angiotensin-converting enzyme, plasma aldosterone and atrial natriuretic peptide levels at presentation, and clinical outcome at 1 year (survival, hospital admissions) in a cohort of Chinese patients with typical systolic heart failure (n = 82). RESULTS: We confirmed the low prevalence of the angiotensin-converting DD and the angiotensin type I receptor CC genotypes, and high prevalence of the AGT TT genotype in Chinese subjects compared with whites. There was no relation between the various gene polymorphisms and survival at 1 year assessed by multiple regression or Cox regression survival analysis. The AC variant of the angiotensin type I receptor gene was associated with morbidity over a 1-year period (hospital admissions) and increased baseline aldosterone levels, but none of the other polymorphisms correlated with systolic or diastolic function, aldosterone or atrial natriuretic peptide levels. By multiple regression for effects on mortality rate, only atrial natriuretic peptide and age were significant. CONCLUSIONS: In Chinese patients with heart failure, polymorphisms of the renin-angiotensin system do not appear to be related to survival or severity, probably because of the different prevalence of these genotypes in the Chinese. Thus this study illustrates that large interethnic differences in the frequencies of genotype polymorphisms of the renin-angiotensin system exist and results from one ethnic group cannot be extrapolated to another. PMID- 10097226 TI - Long-term beta-blocker therapy improves autonomic nervous regulation in advanced congestive heart failure: a longitudinal heart rate variability study. AB - BACKGROUND: beta-Blocker therapy is believed to modulate the detrimental effect of overcompensating neurohormonal activation in chronic heart failure. However, clinical doubts remain, particularly the physiologic sympathovagal balance. METHODS: To respond to clinical concern about worsening autonomic nervous perturbation in beta-blocker therapy of advanced congestive heart failure, 15 consecutive patients were longitudinally studied to elucidate the evolution of cardiac function versus 24-hour heart rate variability (HRV) before and after 1, 3, and 6 to 9 months of atenolol-combined therapy. RESULTS: Two patients died prematurely within 1 month. All 13 surviving patients showed improvement in New York Heart Association functional class, with decrease in left ventricular end systolic and end-diastolic dimensions and increase in fraction shortening and ejection fraction by echocardiography after at least 3 months of atenolol use. The retarded therapeutic effect was accompanied by a general rise of total, very low, low-, and high-frequency components (9.0 +/- 0.5, 8.8 +/- 0.5, 6.2 +/- 0.6, and 6.1 +/- 0.5 vs 10.9 +/- 0.3, 10.7 +/- 0.4, 8.6 +/- 0.3, and 7.8 +/- 0.3; all P <.02) of daily HRV. This implied recovery of parasympathetic and baroreceptor function. Return of sympathovagal interaction was further supported by the suppression of Cheyne-Stokes type HRV as detected by Wigner-Ville distribution. CONCLUSIONS: Long-term beta-blocker therapy for advanced congestive heart failure upwardly regulates the autonomic nervous interaction in synchrony with the evolution of cardiac function performance. PMID- 10097227 TI - Neurohumoral activations in congestive heart failure: correlations with cardiac function, heart rate variability, and baroreceptor sensitivity. AB - BACKGROUND: The clinical significance of the determination of heart rate variability and baroreceptor sensitivity relating to cardiac function and neurohumoral factors remains to be established. METHODS AND RESULTS: We investigated the relation between conventional clinical variables and frequency domain analysis of heart rate variability and baroreceptor sensitivity in 146 patients with heart failure. Cardiac function including left ventricular ejection fraction, left ventricular dimensions, and left atrial size was different by the plasma atrial natriuretic peptide level but not by the norepinephrine level. The total power and low-frequency power were correlated with plasma norepinephrine, whereas baroreceptor sensitivity was correlated with plasma atrial natriuretic peptide. None of the frequency domain variables and baroreceptor sensitivity was correlated with cardiac function. There was a positive correlation between the low-frequency power and baroreceptor sensitivity. CONCLUSIONS: Heart rate variability and baroreceptor sensitivity, which reflect autonomic regulation, may be an indicator independent from cardiac function in patients with heart failure. PMID- 10097228 TI - QT dispersion in patients with Duchenne-type progressive muscular dystrophy. AB - BACKGROUND: A high degree of QT dispersion is a risk factor for arrhythmic sudden death in patients with myocardial infarction and cardiomyopathy. Duchenne-type progressive muscular dystrophy (DMD) is also associated with the development of ventricular arrhythmias. The purpose of this study was to determine the relationship between QT interval dispersion and ventricular arrhythmias in patients with DMD. METHODS: Sixty-seven patients with DMD were studied. Standard 12-lead electrocardiograms and 24-hour Holter electrocardiograms were recorded, and the QT interval was determined in every lead of the standard electrocardiogram to determine the QT dispersion. QT dispersion was compared with the frequency of ventricular arrhythmias and the severity of skeletal muscle damage on the basis of the Swinyard and Deaver 8-stage scale. RESULTS: QT dispersion in all 67 patients averaged 54 +/- 18 ms. The QT dispersion was 49 +/- 16 ms in stage 5 patients, 61 +/- 22 ms in stage 6 patients, 52 +/- 17 ms in stage 7 patients, and 56 +/- 17 ms in stage 8 patients. Ventricular arrhythmias of Lown grade III or higher were observed in 3 of 35 patients with QT dispersion <60 ms and in 14 of 32 patients with QT dispersion >/=60 ms. Logistic regression analysis demonstrated that QT dispersion is an independent risk factor for ventricular arrhythmias of grade III or higher in patients with DMD. CONCLUSIONS: The incidence of ventricular arrhythmias of Lown grade III or higher was greater in patients with QT dispersion >/=60 ms than in patients with QT dispersion >60 ms. QT dispersion therefore is a risk factor for serious ventricular arrhythmias in patients with DMD. PMID- 10097229 TI - QT dispersion in athletic left ventricular hypertrophy. AB - OBJECTIVE: To assess whether physiologic left ventricular hypertrophy as a result of physical training is associated with an increased QT length or dispersion. METHODS: Thirty-three subjects were assessed. These consisted of a group of international endurance athletes (including 8 rowers, 2 cyclists, and 1 triathlete), a group of 12 professional soccer players, and a further group of 10 control subjects. Each underwent 2-dimensional echocardiography and 12-lead electrocardiographic examination. RESULTS: Left ventricular mass index was considerably greater in both the endurance athlete (163.3 +/- 14.4 g/m2; P <.01) and soccer player groups (144.2 +/- 5.5 g/m 2; P <.05) compared with the controls (109.2 +/- 6.3 g/m2). In spite of these large differences in cardiac structure there were no significant differences in QT parameters between the groups (QT dispersion 56.9 +/- 5.5, 68.5 +/- 9.5, and 67.2 +/- 12.6 ms; QTc dispersion 61.4 +/- 9.2, 69.4 +/- 13.3, and 54.2 +/- 6.5 ms; maximum QT 402 +/- 10.3, 404 +/- 9.6, and 392 +/- 14.0 ms; and maximum QTc 404 +/- 7.0, 413 +/- 9.3, and 399 +/- 9.9 ms among endurance athletes, soccer players, and controls, respectively). CONCLUSION: Left ventricular hypertrophy occurring as a consequence of athletic training does not appear to be associated with a major increase in QT length or QT dispersion. PMID- 10097230 TI - Survival of DDD pacing mode after atrioventricular junction ablation and pacing for refractory atrial fibrillation. AB - BACKGROUND: Patients with recurrent forms of atrial fibrillation may receive dual chamber pacemakers after atrioventricular junction ablation for refractory symptoms. These patients are at risk for chronic atrial fibrillation, which would negate the benefits of dual-chamber pacing. The purpose of this study was to examine the survival of dual-chamber pacing modes in patients undergoing ablate and pace therapy. METHODS AND RESULTS: One hundred fifty-six patients underwent ablate and pace therapy for medically refractory chronic (70 patients) or recurrent (86 patients) atrial fibrillation. Seventy-eight percent of patients had structural heart disease. The mean age was 66 +/- 11 years, with an average ejection fraction of 48% +/- 18%. The choice of pacing mode and programming were at the discretion of the investigators. At implantation, 91 patients (58%) were programmed to VVI mode, 47 (30%) were programmed to DDD mode, and 18 (12%) were programmed to DDI mode. After 1 year of follow-up, 10 DDD patients were reprogrammed to VVI mode (7 patients) or DDI mode (3 patients), most frequently for chronic atrial fibrillation (7 patients). Two patients with DDI mode were reprogrammed to VVI and DDD modes (1 patient each). Survival of the DDD mode was 76% at 1 year by Kaplan-Meier analysis. Reprogramming from DDD mode was not associated with patient age, left ventricular ejection fraction, discontinuation of antiarrhythmic drugs, or the duration of atrial fibrillation symptoms before ablation. CONCLUSIONS: Seventy-six percent of patients with recurrent atrial fibrillation who are initially programmed to DDD mode remain in DDD mode 1 year after ablation and pacing therapy. The modest rate of progression to chronic atrial fibrillation supports the use of dual-chamber pacing in this setting. PMID- 10097231 TI - Lone atrial fibrillation: prognostic differences between paroxysmal and chronic forms after 10 years of follow-up. AB - BACKGROUND: Lone atrial fibrillation (LAF) is defined by the presence of atrial fibrillation unassociated with other evidence of organic heart disease. There are conflicting data concerning the prognostic importance, rate of embolic complications, and survival in subjects affected by this arrhythmia. METHODS AND RESULTS: One hundred forty-five patients younger than 50 years at the time of the first diagnosis were identified; 96 had paroxysmal and 49 had chronic LAF. They were followed up with clinical and echocardiographic controls, and we recorded every thromboembolic complication and death. During the follow-up (10 +/- 8 years) among patients with paroxysmal LAF, 1 (1%) had an ischemic stroke, 2 a transient ischemic attack, and 1 a myocardial infarction. In the group with chronic LAF, 1 patient had moderate heart failure, 2 myocardial infarction, and 1 transient ischemic attack. In this group, 8 embolic complications in 7 (16.3%) patients were observed. One patient with intestinal embolism died during surgery; 2 (6.1%) patients died suddenly. CONCLUSIONS: The prognosis of young patients with paroxysmal LAF appears to be excellent, whereas patients with chronic LAF are at increased risk of embolic complications and higher mortality rates. Our results suggest that LAF is not always a benign disorder, as suggested by previous studies. Subgroups with substantially increased risk for thromboembolic events caused by LAF should be better identified. PMID- 10097232 TI - Impaired forearm blood flow and vasodilator reserve in healthy postmenopausal women. AB - BACKGROUND: The natural process of cessation of ovarian estrogen production is associated with an increasing incidence of cardiovascular disease. OBJECTIVE: We aimed to determine whether postmenopausal women had menopause-associated vasomotor disturbances develop. METHODS: We studied the vascular forearm function using strain-gauge venous occlusion plethysmography in 12 healthy postmenopausal women (mean age +/- SD, 47 +/- 3 years; time-lapse from menopause >1 year). Twelve premenopausal subjects matched for age and biophysical characteristics were used as a control group. RESULTS: No differences were observed in heart rate or mean blood pressure between the 2 groups of women. Forearm blood flow at supine resting was lower in postmenopausal than in premenopausal women (2.4 +/- 0.8 vs 3.1 +/- 0.5 mL/100 mL/min; P <.05). Local vascular resistance was higher in postmenopausal than in premenopausal women (43.5 +/- 17.5 vs 31.1 +/- 4.3 mm Hg/mL/100 mL/min; P <.05). Moreover, peak forearm flow in response to forearm ischemia was 20.8 +/- 7.9 mL/100 mL/min in postmenopausal women and 26.6 +/- 9.7 mL/100 mL/min in premenopausal women (P <.01). Plasma concentration of noradrenaline in the supine position was significantly higher in postmenopausal than in premenopausal women (286 +/- 22 pg/mL vs 195 +/- 33 pg/mL; P <.01). Finally, a significant positive relation was revealed in postmenopausal women between the amount of vasodilator reserve (D flow) in local peripheral circulation and levels of circulating estradiol-17beta. CONCLUSIONS: Abnormalities observed in forearm blood flow and vasodilator capacity in postmenopausal women may be attributed to a critical loss of the vasodilating property of physiologic estrogen. Our data support the possibility that reduction in dilator capacity of the vasculature may contribute to the increase of cardiovascular disease after menopause. PMID- 10097233 TI - Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease. AB - BACKGROUND: Genes encoding components of the renin-angiotensin system have been associated with elevated blood pressure (BP) and an increased risk of coronary artery disease. To explore the role of the angiotensinogen (AGT) gene in coronary atherosclerosis and thrombosis, we studied the effect of the AGT M235T gene variant on plasma AGT levels and BP in patients with coronary artery disease and in the subgroup of survivors of myocardial infarction as compared with angiographically defined control subjects. METHODS AND RESULTS: This was a case control study of 301 white male subjects examined at Frankfurt University medical center. Plasma AGT levels increased stepwise according to the number of T235 alleles present (no T235 allele, 14.8 +/- 3.9 nmol/L; 1 allele, 15.7 +/- 5.1 nmol/L; 2 alleles, 17.3 +/- 4.7 nmol/L; P =.006). In a multivariate model, circulating AGT emerged as the most important predictor of diastolic pressure (P =.001). In addition, AGT M235T gene polymorphism remained a significant predictor of diastolic BP in a multivariate model adjusted for age, body mass index, fasting glucose, apolipoprotein B, presence of coronary artery disease, and treatment with antihypertensive agents ( P <.05). Finally, homozygosity for T235 was associated with increased univariate risk of coronary artery disease and myocardial infarction (odds ratio estimates 1.5; 95% confidence intervals 1.1 to 2.1, P =.03, and 1.0 to 2.1, P =.05, respectively). CONCLUSIONS: The significant relations observed between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating AGT in the pathogenesis of coronary artery disease. PMID- 10097234 TI - Variations in the use of cardiac procedures in the Veterans Health Administration. AB - BACKGROUND: Considerable variability exists in the use of cardiac procedures for patients with heart disease. One cause for this variability is the availability of local facilities to perform these procedures. This study was initiated to identify health system features that are related to rates of catheterization, percutaneous coronary angioplasty, and coronary artery bypass graft surgery in the Veterans Affairs health care system in which structured referral systems are intended to compensate for variation in local resource availability. METHODS: Medical records of 30,901 patients admitted to a Veterans Affairs medical center with coronary artery disease were analyzed. Odds ratios (OR) and 95% confidence intervals (CI) for undergoing each procedure, based on clinical variables (age, sex, race, coronary artery disease type, and a computed comorbidity score), and local Veterans Affairs facility features (geographic region, primary service area size, and hospital complexity) were estimated by logistic regression. RESULTS: Regression models demonstrated significant associations between the odds of undergoing each procedure and medical center geographic and complexity features, after adjustment for clinical variables. Associations included the presence of a cardiac catheterization laboratory for undergoing catheterization (OR 1.86, CI 1.76 to 1.95) and the presence of a cardiac surgical program for angioplasty (OR 1.46, CI 1.36 to 1.57) and bypass grafting (OR 1.43, CI 1.34 to 1.53). Including health system variables in addition to clinical variables in the regression models improved the discriminating ability of the models by 44.2% to 51.4%. CONCLUSIONS: Geographic location and the complexity of the local Veterans Affairs hospital are important determinants of the use of cardiac procedures in the Veterans Affairs health care system, even though referral networks are intended to correct for local differences in hospital complexity. PMID- 10097235 TI - Effect of pregnancy on the duration of bovine pericardial bioprostheses. AB - BACKGROUND: This study sought to evaluate the effect of pregnancy on the rate of deterioration of bovine pericardial bioprostheses. To avoid the fetal and maternal risks associated with anticoagulant therapy during pregnancy, the use of bioprostheses has been advocated for young women with cardiac valve disease who may later wish to bear children. Several reports have suggested the probability of pregnancy-related accelerated deterioration of these valves. METHODS AND RESULTS: The incidence of prosthetic dysfunction and the freedom from deterioration were investigated in 48 women who had 58 pregnancies and in a control group of 167 patients in the same age range. There were 39 cases of prosthetic dysfunction (deaths plus reoperations resulting from valve failure): 12 in the pregnant group for a linearized rate of 3.5% +/- 0.99% (SE) per patient year and 27 in the control group or 3.4% +/- 0.65% per patient-year (P = not significant). The actuarial freedom from dysfunction was 90.4% (95% confidence interval 77.9 to 96.2) at 5 years and 77.0% (59.7 to 88.3) at 8 years for the pregnancy group and 86.3% (77.3 to 92.0) and 73.4% (56.6 to 84.8), respectively, for the control group ( P = not significant). In the Cox proportional hazard regression analysis, pregnancy did not influence dysfunction. A direct correlation was found between freedom from dysfunction and the patient's age at surgery. CONCLUSIONS: Pregnancy does not accelerate the rate of deterioration of bovine pericardial bioprostheses. It is more likely that biological valves deteriorate more rapidly in these patients because of their young age. PMID- 10097236 TI - Thrombosis of bileaflet tricuspid valve prosthesis: clinical spectrum and the role of nonsurgical treatment. AB - BACKGROUND: Thrombosis of a mechanical tricuspid valve prosthesis is a potentially hazardous event. This study aimed to explore the incidence and the clinical presentation of tricuspid valve thrombosis occurring in bileaflet valves and to evaluate the diagnostic and the therapeutic approach. METHODS AND RESULTS: Tricuspid valve thrombosis was sought in 22 late survivors with the CarboMedics valve in a follow-up period of 36.0 +/- 20.8 months. Limited leaflet motion and/or a visible thrombus were considered diagnostic of valve thrombosis. Eight episodes of tricuspid valve thrombosis were diagnosed among 5 patients (12.1 episodes per 100 patient-years). Anticoagulation was inadequate in 3 patients and fair in 2. Florid right heart failure occurred in 3 episodes. Common physical findings included increased jugular venous pulse (5 patients), diastolic tricuspid murmur (4 patients), and peripheral edema (4 patients). The diagnosis was suspected in all clinically and by transthoracic echocardiography and confirmed by fluoroscopy and/or transesophageal echocardiography. In 4 patients, both leaflets were involved. No thrombi were visualized. Three patients received thrombolytic therapy in 4 episodes (complete success in 3, partial success in 1) without hemorrhagic or embolic complications. One patient responded to aggressive anticoagulant therapy. One patient required an emergent repeat surgery. In 1 patient, valve thrombosis recurred thrice. CONCLUSIONS: In patients with fair or poor anticoagulation, a bileaflet valve in the tricuspid position is associated with a high incidence of valve thrombosis. Hinge entrapment requires only a small amount of thrombotic material. Valve thrombosis may be asymptomatic. Involvement of both leaflets is usually required to produce symptoms. A nonsurgical approach (thrombolysis or intensified anticoagulation) is usually successful. Patients should be instructed about heralding signs of valve thrombosis. PMID- 10097237 TI - Acronyms of clinical trials in cardiology--1998. PMID- 10097238 TI - Significance of coronary flow reserve. PMID- 10097240 TI - Circadian variation and triggering of acute coronary events. AB - The recognition that the onset of cardiovascular events follows a circadian periodicity and is frequently triggered by physical or mental stresses has created new possibilities for disease prevention. Morning peaks in occurrence are now well-documented for acute myocardial infarction, sudden cardiac death, transient myocardial ischemia, and ischemic stroke. The morning increase in events begins after subjects assume an upright posture and start the day's activities, during a time of sympathetic nervous system activation. Additional triggers of onset include heavy physical exertion, sexual activity, and anger, the risks of which have been quantified in the Determinants of Myocardial Infarction Onset Study. A general hypothesis of the triggering of coronary thrombosis has been proposed. The process begins with the development of a vulnerable atherosclerotic plaque, which may become disrupted by internal forces or by external hemodynamic or vasoconstrictive changes. Once disrupted, the plaque becomes a thrombogenic focus. An occlusive thrombus is more likely to form if other factors come into play to increase coagulability and vasoconstriction. From a clinical standpoint these findings provide theoretical support for the use of long-acting agents to provide adequate anti-ischemic protection during the higher risk morning hours in patients already taking anti-ischemic medications. From a research standpoint this new information on triggering provides clues to a mechanism of onset that might lead to more effective preventive therapy. Because most deaths from coronary artery disease occur before any type of acute therapy can be given, further efforts to explore this new field are warranted. PMID- 10097241 TI - Update on aspirin in the treatment and prevention of cardiovascular disease. AB - The effects of low-dose aspirin on cardiovascular disease have been tested in randomized trials in 3 types of populations: (1) patients with a history of cardiovascular disease; (2) patients with evolving acute myocardial infarction (MI), and (3) apparently healthy subjects. In a very wide range of patients with prior occlusive cardiovascular disease, aspirin reduces the risks of nonfatal MI, nonfatal stroke, and vascular death. Initiating aspirin therapy within 24 hours after the onset of symptoms of an acute MI also confers conclusive reductions in the risk of nonfatal reinfarction, nonfatal stroke, and total cardiovascular death. In primary prevention trials, aspirin has been shown to reduce the risk of a first MI in men, but the data on stroke and total cardiovascular death are not sufficient to allow firm conclusions to be drawn; randomized data from studies in women are not yet available. The Women's Health Study, an ongoing large-scale trial in female health care professionals, will provide the data necessary to assess the balance of benefits and risks of aspirin in primary prevention. Until then, the decision to use aspirin in primary prevention should be based on the clinical judgment of the physician and considered as an adjunct in the management of other cardiovascular disease risk factors. PMID- 10097242 TI - Chronopharmacology and chronotherapy of cardiovascular medications: relevance to prevention and treatment of coronary heart disease. AB - Biological functions and processes, including cardiovascular ones, exhibit significant circadian (24-hour) and other period rhythms. Ambulatory blood pressure assessment reveals marked circadian rhythms in blood pressure both in normotensive persons and hypertensive patients, whereas Holter monitoring substantiates day-night patterns in electrocardiographic events of patients with ischemic heart disease. The concept of homeostasis, that is, constancy of the milieu interne, which has dominated the teaching, research, and practice of medicine during the 20th century,is now being challenged by emerging concepts from the field of chronobiology-the science of biological rhythms. Epidemiologic studies document the heightened morning-time risk of angina, myocardial infarction, and stroke. Circadian rhythms in coronary tone and reactivity, plasma volume, blood pressure, heart rate, myocardial oxygen demand, blood coagulation, and neuroendocrine function plus day-night patterns in the nature and strength of environmental triggers all contribute to this morning vulnerability. Homeostatically devised pharmacotherapies, that is, medications formulated to ensure a near-constant drug concentration, may not be optimal to adequately control diseases that vary in risk and severity during the 24 hours. Moreover, circadian rhythms in the physiology of the gastrointestinal tract, vital organs, and body tissues may give rise to administration-time differences in the pharmacokinetics and effects of therapies. Thus the same medication consumed in the same dose under identical conditions in the evening and morning may not exhibit comparable pharmacokinetics and dynamics. New technology makes possible chronotherapy, that is, increase of the efficiency and safety of medications by proportioning their concentrations during the 24 hours in synchrony with biological rhythm determinants of disease. The chronotherapy of peptic ulcer disease achieved by the evening dosing of H 2-receptor antagonists and of asthma by the evening dosing of special drug delivery forms of theophylline and morning methylprednisolone administration has proven to be beneficial. Controlled-onset extended-release verapamil constitutes the first chronotherapy of essential hypertension and ischemic heart disease; once-a-day bedtime dosing results in a high drug concentration in the morning and afternoon and a reduced one overnight. Studies demonstrate effective 24-hour control of blood pressure, including the attenuation of its rapid rise in the morning, without induction of nighttime hypotension. Moreover, this formulation effectively controls angina, especially in the morning when the risk of ischemia is greatest. Determination of the role of verapamil chronotherapy in the primary prevention of cardiovascular morbidity and mortality awaits the results of the CONVINCE trial now in progress. PMID- 10097243 TI - Secondary prevention of myocardial infarction: role of beta-adrenergic blockers and angiotensin-converting enzyme inhibitors. AB - beta-Blockers reduce cardiovascular death and reinfarction in patients with a history of myocardial infarction (MI), and angiotensin-converting enzyme (ACE) inhibitors provide an overall survival benefit in patients with signs or symptoms of left ventricular (LV) dysfunction and a history of acute MI. Despite this, these agents remain underused in clinical practice. Appropriate patient selection in standard clinical practice should be encouraged in order to achieve a mortality rate reduction comparable to that seen in clinical trials. It appears from the findings of recent studies that the greatest benefit from beta-blocker therapy is achieved in patients who are more than 60 years of age and in patients at moderate or high risk for reinfarction and death (eg, patients with LV dysfunction or arrhythmias or both). Patients with class I-IV heart failure treated with ACE inhibitors have fewer recurrent infarctions, a lower incidence of severe congestive heart failure, and a reduced incidence of total cardiovascular death and sudden cardiac death. In addition to the studies completed in patients with MI, there are ongoing studies evaluating whether or not ACE inhibitors can reduce myocardial ischemic events in patients without a prior infarction who have coronary artery disease or hypertension and preserved LV function. There is also growing evidence that concomitant therapy with a beta blocker and an ACE inhibitor may reduce mortality rates beyond that observed with ACE inhibitors alone in survivors of MI who have LV dysfunction. PMID- 10097244 TI - Androgen effects on bone metabolism: recent progress and controversies. AB - Androgens have beneficial effects on skeletal development and maintenance in women and men. The detection and functional characterization of androgen receptors in bone cells has implicated bone tissue as a potential target tissue for androgens. Gonadal and adrenal androgens directly regulate various aspects of osteoblastic lineage cells, including proliferation, differentiation, mineralization, and gene expression. These effects may differ depending on the stage of differentiation, the number of androgen receptors, and other inherent characteristics (species, site, cell biology) of the osteoblastic cell system. In addition, recent studies have suggested that some of the anabolic and anti resorptive effects of androgens on bone may be mediated by regulation of autocrine and paracrine factors in the bone microenvironment, including transforming growth factor-beta, insulin-like growth factors (and their binding proteins), and interleukin-6. This review summarizes the recent progress made in our knowledge of androgen receptor action, local androgen metabolism in bone, and direct and indirect effects of gonadal and adrenal androgens as well as androgen receptor antagonists on bone cells. PMID- 10097245 TI - Lymphocyte traffic and homing in autoimmune thyroid disorders. PMID- 10097246 TI - Targeted disruption of the Ahch (Dax-1) gene: knockout of old concepts. PMID- 10097247 TI - Pluripotent PPARgamma polymorphisms. PMID- 10097249 TI - Paradoxical GH response to TRH during status epilepticus in man. AB - Information on GH in relation to epilepsy is sparse, and to our knowledge there is no information on GH levels during status epilepticus in man. We studied GH in serum in six patients during status epilepticus, and in a control group of six seizure-free patients with epilepsy, before and after injection of TRH. The baseline GH values before TRH administration were within the normal range in all patients. After injection of TRH all patients with status epilepticus showed a paradoxical peak-shaped increase of GH to at least twice their baseline levels within 45 min after the injection (median basal GH value 1.5 mU/l and median peak GH value 6. 5 mU/l, mean increase 330%). No uniform reaction to TRH was observed in the control group (median basal GH value 2.7 U/l and median of the highest value within 45 min 5.2mU/l). A paradoxical peak reaction of GH to TRH was significantly more frequent in the status epilepticus group compared with the control group (P=0.008, Fisher exact probability test). TRH is not considered a GH-releasing hormone in humans during normal conditions, but a paradoxical response of GH to TRH, similar to that observed during status epilepticus, has been reported in various other pathological conditions, such as acromegaly, liver cirrhosis, mental depression and hypothyroidism. Our results of GH release after TRH administration in patients with status epilepticus suggest an altered regulation of GH as a result of the long-standing epileptic activity. PMID- 10097248 TI - Natural killer cell activity in the peripheral blood of patients with Cushing's syndrome. AB - BACKGROUND: Natural killer (NK) cells are CD3(-)CD16(+)CD56(+) bone-marrow derived lymphocytes mediating first-line defence by direct cytotoxicity against various types of target cells without prior immunization. NK cell activity is positively regulated by immune interferon (IFN-gamma); among hormones, glucocorticoids are potent in vitro and in vivo inhibitors, whereas ACTH and beta endorphin in many experimental circumstances enhance NK cytotoxicity. DESIGN: We measured NK cytotoxicity of peripheral blood mononuclear cells (PBMC) obtained at 0800h and 2000h from 26 patients with Cushing's syndrome (12 pituitary-dependent, 12 adrenal-dependent and two dependent on ectopic ACTH secretion). In vitro responsiveness to IFN-gamma or cortisol was also tested. METHODS: NK activity was measured in a 4-h direct cytotoxicity assay using K562 cells as targets. Plasma ACTH, serum and urinary free cortisol were concomitantly measured with commercially available kits. RESULTS: Spontaneous activity and responsiveness to IFN-gamma or cortisol were significantly greater in 15 age- and sex-matched controls than in Cushing's patients at 0800h. In pituitary-dependent Cushing's patients, plasma ACTH correlated positively with mean levels of spontaneous NK activity (r=0.64, P<0.05) and negatively with cortisol-dependent percentage inhibition (r=-0.69, P<0.02). In adrenal-dependent Cushing's patients, a negative correlation was observed between levels of spontaneous NK activity and urinary free cortisol (r=-0.67, P<0.02). CONCLUSIONS: Our data indicate that excess endogenous glucocorticoids affect spontaneous NK cell activity and responsiveness to exogenous IFN-gamma or cortisol. The differential patterns observed between pituitary-dependent and adrenal-dependent groups are compatible with a positive immunomodulatory role of pituitary pro-opiomelanocortin-derived peptides that effectively counterbalance, at least partially, glucocorticoid immunosuppression. PMID- 10097250 TI - Normal spontaneous and stimulated GH levels despite decreased IGF-I concentrations in cystic fibrosis patients. AB - OBJECTIVE: The aim of the present study was to investigate whether patients with cystic fibrosis (CF) are GH resistant with increased GH release and decreased concentrations of IGF-I as a result of malabsorption, increased catabolism and impaired glucose tolerance. DESIGN: Twenty CF patients were included, ten with normal glucose tolerance (five male, five female, median age 25.5 years (range 20 31)) and ten with diabetes mellitus (five male, five female, median age 25.3 years (range 17-45). Twenty healthy individuals served as controls (ten male, ten female, median age 28.4 years (range 18-36)). METHODS: GH status was evaluated by 12h spontaneous GH release during the night time, arginine-stimulated GH release and the basal concentrations of IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3). Twelve hour spontaneous GH profiles were estimated using a constant blood withdrawal technique with sampling every 30min and the Pulsar method was used for the analysis of profiles. RESULTS: No significant differences were found in spontaneous and stimulated GH release in CF patients compared with healthy controls, whereas IGF-I and IGFBP-3 were significantly decreased in CF patients compared with healthy controls. The combination of reduced IGF-I and IGFBP-3 with normal GH release points to a relative GH resistance or a disturbance in the pituitary axis in patients with CF. The spontaneous GH release, the stimulated GH release and the basal concentrations of IGF-I and IGFBP-3 were not significantly different in diabetic CF patients compared with CF patients with normal glucose tolerance and the presence of diabetes mellitus was not consistent with increased GH resistance in CF patients. CONCLUSION: CF patients with normal glucose tolerance and diabetic CF patients had normal GH release and decreased concentrations of IGF-I indicating a relative GH resistance. PMID- 10097251 TI - Radionuclide angiocardiographic evaluation of the cardiovascular effects of recombinant human IGF-I in normal adults. AB - OBJECTIVE: IGF-I possesses specific myocardial receptors and is able to promote cardiac remodelling and even inotropic effects in both humans and other animals. In fact, reduced cardiac mass and performance are present in GH deficiency and these alterations are counteracted by recombinant human (rh) GH replacement, restoring IGF-I levels. Recently, the acute administration of 60 microg/kg rhIGF I has also been reported to be able to improve cardiac performance evaluated by echocardiography or impedance cardiography in normal subjects. The aim of our study was to verify the effects of a subcutaneous low dose of rhIGF-I (20 microg/kg) on cardiac performance in humans. METHODS: In six healthy male adults (mean+/-S. e.m.: 35.7+/-4.3 years of age), the effects of rhIGF-I on left ventricular function evaluated by radionuclide angiocardiography and on circulating IGF-I, GH, insulin, glucose and catecholamines levels were studied. RESULTS: Administration of rhIGF-I increased circulating IGF-I (peak at +150 min vs baseline: 330.2+/- 9.6 vs 199. 7+/-8.7 microg/l, P<0.03) to levels which persisted similarly up to +180min. Neither GH nor catecholamine levels were modified by rhIGF-I administration, while insulin and glucose levels showed a slight but significant decrease. Basal left ventricular ejection fraction (61.8+/ 2.0%) significantly increased at +180 min after rhIGF-I (65.3+/-2.7%, P<0.03). No change was recorded in mean blood pressure while a non-significant trend towards a reduction of heart rate was present by +120 min. CONCLUSIONS: These findings indicate that even subcutaneous administration of a low dose of rhIGF-I has acute inotropic effects as evaluated by radionuclide angiocardiography in healthy adults. PMID- 10097252 TI - Interobserver and intraobserver variations in sonographic measurement of thyroid volume in children. AB - OBJECTIVE: To determine the interobserver and intraobserver variations in sonographic measurement of thyroid volume in children. DESIGN: Thyroid volumes of 30 healthy children were measured by three separate observers. Additionally each observer measured thyroid volumes of ten separate children three times. METHODS: The data were used to assess intraobserver and interobserver variations in measurement of thyroid volume. Interobserver and intraobserver variations in measuring each diameter of the thyroid gland were also determined. The effect of thyroid size on interobserver and intraobserver variations was analyzed. RESULTS: Intraobserver variation in measurement of thyroid volume was 8.4+/-6.7% (mean+/ s. d.). Interobserver variation was 13.3+/-8.2%. The widest interobserver variation was encountered in determining the craniocaudal diameter of the thyroid gland. No correlation was found between thyroid volume and interobserver variation (r=-0.12, P=0.27), whereas a slight but statistically significant correlation was found between thyroid volume and intraobserver variation (r= 0.26, P=0.012). CONCLUSION: Significant interobserver and intraobserver variation occurs in sonographic measurement of thyroid volume in children. PMID- 10097253 TI - Acute fasting diminishes the circadian rhythm of biochemical markers of bone resorption. AB - OBJECTIVE: Biochemical markers of bone turnover exhibit circadian rhythms with the peak during the night/early morning and the nadir in the late afternoon. The nocturnal increase in bone resorption could theoretically be caused by the absence of food consumption which brings about a decrease in net calcium absorption and an increase in parathyroid hormone (PTH), followed by increased bone resorption in response to the body's demand for calcium. The aim of the present study was to assess the influence of a 33-h fast on the circadian variation in biochemical markers of bone turnover. DESIGN: Eleven healthy premenopausal women (age: 24+/-5 years) participated in a randomised, cross-over study consisting of two periods: either 33h of fasting (fasting) followed 1 week later by a 33-h period with regular meals eaten at 0800-0830h, 1130-1230h and 1800-1900h (control) or vice versa. METHODS: Urinary CrossLaps (U-CL/Cr) corrected with creatinine, as a marker of bone resorption; serum osteocalcin (sOC) as a marker of bone formation; serum intact PTH (iPTH); serum phosphate; and serum calcium corrected with albumin. RESULTS: Both the fasting and the control periods showed a significant circadian rhythm in U-CL/Cr (P<0.001), but the decrease was significantly less pronounced in the morning hours during the fasting period. Fasting resulted in a significant decrease in serum iPTH (throughout the study period) as compared with the control period (P<0.05-0.001). No change was observed in sOC by fasting. CONCLUSION: Food consumption has a small influence on the circadian variation in bone resorption, independent of PTH. The fall in iPTH during fasting may be secondary to an increased bone resorption produced by fasting. PMID- 10097254 TI - Antihypertensive effect of insulin via nitric oxide production in the Zucker diabetic fatty rat, an animal model for non-insulin-dependent diabetes mellitus. AB - It has been reported that insulin treatment improves hypertension in patients with diabetes mellitus. The mechanisms of the antihypertensive effect of insulin, however, remain to be fully elucidated. In the present study, we investigated a possible involvement of nitric oxide (NO) in insulin-induced reduction of blood pressure using the Zucker diabetic fatty (ZDF) rat, an animal model of non insulin-dependent diabetes mellitus. The animals were divided into three groups and treated for 4 weeks with daily subcutaneous injections of insulin (25U/kg body weight) with or without oral administration of l-nitro-arginine methyl ester (L-NAME, 50mg/kg/day body weight as drinking water), an inhibitor of NO synthase (NOS). Saline solution was injected subcutaneously in the control groups. During the experimental period, body weight gain was greater in the insulin-treated groups than in the control groups whereas water intake was considerably decreased in the insulin-treated groups. Insulin treatment resulted in a decrease in plasma glucose and blood pressure, and an increase in both NO metabolites (NOx) in the plasma and NOS activity in the aorta tissue. L-NAME treatment blunted not only the antihypertensive effect of insulin but also the changes in NOx and NOS activity. These findings suggest that insulin reduces blood pressure in the ZDF rat by stimulating NOS activation and NO production. PMID- 10097255 TI - Lack of effects of recombinant human GH on spermatogenesis in the adult cynomolgus monkey (Macaca fascicularis). AB - OBJECTIVE: The effects on male reproductive parameters after 1 year of treatment with recombinant human GH to the cynomolgus monkey were investigated. DESIGN: Twenty-four male cynomolgus monkeys were given daily subcutaneous doses of 0 (vehicle) (n=7), 0.4 (n=5), 2.0 (n=5) and 10.0 (n=7) IU/kg bodyweight for 52 weeks. At completion of the treatment period two control and two high-dose animals were left for a 12-week treatment-free period. METHODS: Before and during the treatment period and during the recovery period, sperm analyses, testicular volume measurements and hormone analyses of prolactin (PRL), LH, FSH, testosterone and IGF-I in serum, and analysis of serum antibodies against human GH were performed. Testicular morphology was monitored by biopsies, predose and on day 15 of the study, and with light microscopy on organ samples collected at time of death, at the end of the treatment, and during recovery periods respectively. RESULTS: Of all studied parameters, alterations were observed only in serum levels of IGF-I and PRL. IGF-I showed a dose-dependent increase throughout the treatment, with a normalisation during the treatment-free period. PRL decreased significantly in animals given 10.0IU/kg per day from week 14 of treatment and throughout the study but with a normalisation upon cessation of treatment. Spermatogenesis, as judged from semen analysis, testicular volume measurements and testicular morphology was not affected. CONCLUSION: This controlled preclinical study demonstrates that high doses of human GH do not alter male reproductive parameters in a non-human primate model. PMID- 10097256 TI - Expression of menin gene mRNA in pituitary tumours. AB - OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder characterised by the combined occurrence of parathyroid, endocrine pancreas and anterior pituitary tumours. The gene responsible for MEN 1, the menin gene, a putative tumour-suppressor gene located on human chromosome 11q13, has been cloned. To investigate the role of the menin gene in sporadic anterior pituitary tumorigenesis, its mRNA was assessed in a group of pituitary tumours. METHODS: Menin gene expression, along with glyceraldehyde phosphate dehydrogenase (GAPDH) gene expression, has been studied in a group of normal pituitaries and in 23 pituitary tumours not associated with the MEN 1 syndrome. The pituitary tumours included 4 prolactinomas, 11 growth-hormone-secreting tumours and 8 non-functional tumours. Total RNA was extracted from the normal pituitaries and tumours, and cDNA was synthesised with standard reverse transcriptase methods. Duplex polymerase chain reaction (PCR) was standardised in order to quantify the expression of the menin gene using intron-spanning primers across exons 9 and 10 in relation to the 'house-keeping' gene GAPDH. The PCR products were separated on agarose gel and densitometric analysis of the bands allowed semi-quantification. RESULTS: There was no evidence for a change in menin gene expression in any of the pituitary tumours when compared with normal pituitaries. CONCLUSIONS: These studies complement previous work on mutational analysis, and do not suggest a major role for the menin suppressor gene in sporadic pituitary tumorigenesis. PMID- 10097257 TI - No loss of sst receptors gene expression in advanced stages of colorectal cancer. AB - As demonstrated by several studies, the pan-inhibitory peptide somatostatin (SS) is implicated in a large variety of physiological processes in the gastrointestinal tractus. SS inhibits hormonal and gastric acid secretions, and decreases gastric and intestinal motility, mesenteric blood flow and intestinal absorption. In vitro and in vivo studies showed also that the antiproliferative potency of SS analogs may be a target to improve the prognosis of colorectal cancer. Here we report the expression profile of the five SS receptor subtypes (hsst1-5) mRNAs in a large set of tumoral and normal colon. Using reverse transcription-PCR, we showed that hsst5, hsst1 and hsst2 mRNA subtypes were the most frequently expressed hsst mRNA subtypes in normal and pathological colon. Interestingly, we found that the frequency of hsst5 mRNA expression in the left colon was significantly higher in tumors than in normal samples: 81. 2% (13/16) and 36.4% (4/11) respectively (0.025>P>0.01, chi2 test with Yates' correction). We did not find any influence of Dukes' stage on hsst mRNAs expression. Of interest, no loss of hsst2 and hsst5 mRNA expression in advanced stages was noted. Some differences in the frequency of expression of hsst mRNAs according to the origin of the tissue (left or right colon) were evident. The expression of hsst5 and hsst2 mRNA in advanced colorectal carcinoma associated with the development of new SS analogs boost the relevance of colorectal cancer treatment by somatostatin analogs. PMID- 10097258 TI - Type 1 deiodinase is stimulated by iodothyronines and involved in thyroid hormone metabolism in human somatomammotroph GX cells. AB - BACKGROUND: Local 5'-deiOdination of l-thyroxine (T4) to the active thyroid hormone, 3,3',5-tri-iodothyronine (T3) via two deiodinase isoenzymes (D1 and D2) has an important role for various T3-dependent functions in the anterior pituitary. However, no evidence has been presented yet for thyroid hormone inactivation via the 5-deiodinase (D3) in anterior pituitary models. METHODS: Using the human somatomammotroph cell line, GX, we analysed effects of T3 and its 5'-deiodination product, 3,5-di-iodothyronine (3,5-T2), on deiodinase activities, measuring release of iodide-125 (125I-) from phenolic-ring- or tyrosyl-ring labelled substrates respectively. RESULTS: T3 and 3,5-T2 rapidly stimulated D1 activity in GX cells in the presence of serum in the culture medium, whereas D2 activity was not detectable under these conditions. However, when the cells were kept under serum-free conditions, specific activity of D2 reached levels similar to those of D1. With tyrosyl-ring labelled 3, 5-[125I]-,3'-T3 as substrate, a significant release of 125I- was observed in GX cell homogenates. This is comparable to the D1 activity of liver membranes, which preferentially catalyses 5'-deiodination, but to some extent also 5-deiodination, at the tyrosyl ring. CONCLUSIONS: D1 activity of human GX cells is increased by T3 and 3,5-T2. Inactivation of T3 in the anterior pituitary might occur by deiodination at the tyrosyl ring via D1, thus terminating the stimulatory thyroid hormone signal in human somatomammotroph cells. PMID- 10097259 TI - Iodide, thyroid and stomach carcinogenesis: evolutionary story of a primitive antioxidant? PMID- 10097260 TI - Disadvantages to mandatory reporting of domestic violence. PMID- 10097261 TI - More on homeless patients at risk for harm. PMID- 10097263 TI - [Extraembryonic motor activity during embryogenesis of higher vertebrates]. AB - Rhythmic motor activity of the extra-embryo structures as well as the embryo motor activity play a major part in normal development of higher vertebrates. When comparing birds and mammals, a trend towards complication of the motor activity regulation is observed. Reptiles as a class of the vertebrates have not been studied enough in this respect. Apart from the regular changes of extra embryonic rhythmic motor activity, there are some changes in this activity depending on alterations of environmental factors (temperature, gas composition of air, etc.). The extra-embryonic rhythmic motor activity seems to take part in adaptation of the embryo to changing environmental conditions thus maintaining homeostasis of developing embryo. PMID- 10097264 TI - [Effect of lysophasphatidylcholine on sensitivity of the heart to acetylcholine and binding of quinuclidinyl benzilate to myocardial membranes]. AB - Chemical nature of the blood serum factor exerting cholinolytic effect on the animal heart, was determined. The effect is due to the serum lipid component: lysophosphatidylcholine. The latter in concentration 1-25 microM suppresses the sensitivity of the frog perfused heart ventricle to acetylcholine. Phosphatidylcholine was found to protect the heart from the lysophosphatidylcholine effect. Lysophosphatidylcholine also affected the binding of the acetylcholine high affinity antagonist [3H]-quinuclidinylbenzilate to the rabbit atria cell membranes. The mechanism of this effect is related to an increased ability of muscarinic receptors to form oligomeric complexes in presence of lysophosphatidylcholine, the latter manifesting a positive cooperativity on binding to ligand. PMID- 10097265 TI - [Endoplasmic reticulum and mitochondria as elements of mechanism of intracellular signaling in neurons]. AB - The temporal and spatial characteristics of a transitory increase in free Ca2+ ("calcium signals") concentration were determined in various types of the mice and rat neurones. Intracellular structures: endoplasmatic reticulum and mitochondria, were shown to play a major part in formation of these signals, the structures being able to absorb the Ca2+ ions from cytosol and release them back. The contribution of these processes proves rather varying depending on internal organisation and functional assignment of a neurone. PMID- 10097266 TI - [Intracellular regulation of neuronal nicotinic cholinergic receptors]. AB - Effects of substances affecting intracellular secondary messengers on the membrane currents evoked by ionophoretic application of acetylcholine (ACh currents) and on the excitatory postsynaptic currents (EPSC) evoked by single stimuli applied to preganglionic nerve fibres, were studied in neurones of the rat isolated superior cervical ganglion. Forskolin, the protein kinase A activator, and isobutyl-methyxanthine, the phosphodiesterase inhibitor, decreased the ACh currents. Neither forskolin nor isobutyl-methylxanthine affected the EPSC amplitude or the EPSC decay time constant. Phorbol ester, the protein kinase C activator, decreased the ACh current but did not affect either EPSC amplitude or the EPSC decay time constant. Thapsigargin, the intracellular calcium releaser, decreased the ACh current and the EPSC amplitude but did not affect the EPSC decay time constant. The data obtained suggest that nicotinic acetylcholine receptors (nAChRs) of ganglion neurones are not modulated through the pathways involving protein kinase A or protein kinase C. The nAChRs sensitivity to both exogenous and nerve-released acetylcholine is reduced by intracellular calcium without affecting kinetics of their ionic channels. PMID- 10097267 TI - [Ionic channel blocking as an approach to investigation of AMPA receptor subtypes]. AB - The role of diversity of the AMPA receptor subtypes, their property and function in the principal cells and interneurones of hippocampus, cerebellum and striatum, are discussed. The data obtained suggest that drugs capable of blocking an open channel of the AMPA receptor may be used as a tool for identification of the AMPA receptor subtypes and for elucidating their function under both normal and pathological conditions. PMID- 10097268 TI - [Hormonal regulation of the Ca+ transport in blood and vascular cells]. AB - The main pathways of regulation of cytoplasm Ca2+ level with hormones and growth factors, as well as mechanisms of regulation of G-proteins, phospholipase C, Ca channels, adenylate cyclase, guanylate cyclase, and protein kinase C, are discussed. Regulation of cytoplasm Ca2+ in vascular and blood cells with inositol phosphates, cAMP and cGMP, is stressed. The review summarises data on membrane receptors, G-proteins, protein kinases and their targets involved in regulation of Ca2+ turnover in platelets, endothelial and smooth muscle cells. PMID- 10097269 TI - [Differentiation of dopaminergic neurones in situ, in vitro, and in the transplant]. AB - Four stages were distinguished in differentiation of the hypothalamic dopaminergic (DA) neurones: a) origin of the neurone, b) expression of enzymes and dopamine specific synthesis and of the dopamine transmembrane transportation mechanisms, c) development of permanent and transient efferent connections, d) forming of afferent innervation and synaptogenesis. The differentiating DA neurones revealed sexual dimorphism in the neurone origin dynamics and in expression of the enzyme synthesis. The maternal and placenta factors did not affect the differentiation of the DA neurones. The period from the 6th to 10th foetal week was found to be optimal for transplantation of the neurones to the striatum of parkinsonian patients. Grafted DA neurones seem to get involved in regulation of the target neurones in the striatum. PMID- 10097270 TI - [Transmitter-dependent involvement of the respiratory interneurons in the locomotor rhythm in the pulmonate mollusc Lymnaea]. AB - Pedal cell RPeD1 of the pond snail L. stagnalis becomes involved in a central rhythm identified as an activity of the central pattern generator (CPG) for locomotion. The RPeD1 rhythm developed as driven by a synaptic input in isolated CNS preparations treated with 0.05 mM serotonin (5HT) or 0.1 mM 5 hydroxytryptophan (5HTP). The 5HT-induced co-ordinated rhythmic activity was retained by each of two pedal ganglia after complete isolation thus suggesting that the respective CPG lies entirely within the pedal portion of the CNS and is paired. The findings suggest that the RPeD1 switching from one network to another represents a neurotransmitter-dependent phenomenon. PMID- 10097271 TI - [Cholinergic receptors in early (pre-nervous) sea urchin embryos]. AB - Agonists of nicotinic acetylcholine receptors (nAChR) nicotine and 1-acetyl-4 methylpiperazine do not act on the early sea urchin embryogenesis but evoke calcium shock in both oocytes and early embryos under certain conditions. Many nAChR ligands protect both oocytes and embryos against this shock. There seem to exist putative nAChR on the cell surface of the early sea urchin oocytes and early embryos. Pre-nervous acetylcholine seems to be functionally coupled via these receptors with the second messengers, endogenous activators of the protein kinase C. PMID- 10097272 TI - [Quantitative analysis of ligand-receptor interactions in physiological experiments]. AB - In isolated smooth muscles of the sea cucumber, the rat intestine, vas deferens and portal vein, and in chick embryonic amnion, contractile responses of smooth muscles to transmitters and their agonists were described with two equations: p = (Pm.A(n))/(EC50n + A(n)) [7] or p = [(Pm1.An1)/(EC50(1)n1 + An1)] + [(Pm2.An2)/(EC50(2)n2 + An2)] [8]. The findings reveal a possibility of ligand receptor interaction according to several models: a single receptor pool with n = 1 or n not equal to 1; two receptor pools in the same effector system with n1 = n2 or n1 not equal to n2. PMID- 10097273 TI - [Neurotoxicity of the environmental pollutants: tin (Sn2+) effects on currents induced by acetylcholine in the snail neurons]. AB - In isolated single neurone or in whole ganglia preparation, SnCl2 caused a decrease in the acetylcholine-induced inward current in a dose-dependent way. Threshold concentration was 0.1 mkM and saturated at 5 mkM SnCl2. After 10-min. pre-treatment with SnCl2 the effect was more obvious (by 20%) than after 3-min pre-treatment. Sn(CH3)2 decreased the amplitude of Ach-induced current similarly to the inorganic Sn. The effect of Sn(CH3)2 was irreversible. The findings support earlier data that the agonist-activated channels are important targets for toxic metals. Direct action upon neuronal membrane seems to be an important event in modulation of synaptic transmission. PMID- 10097274 TI - [Electrical feedback in the chemical synapses]. AB - Electrical feedback in chemical synapses and the efficacy of synaptic transmission grow with the increase in the gap resistance, so they should be higher in invaginated synapses than in the flat ones. So the plastic changes in the invagination depth may provide a morphological basis for long-term changes in synaptic efficacy: long-term potentiation (LTP) in brain and retinal synapses. In retinal photoreceptor triad synapses, the electrical feedback can provide an "operational" (instantaneous) control of synaptic transmission. PMID- 10097275 TI - [Functional characteristics of the input-output correlation in the frog vestibular nuclei]. AB - Field and intracellular potentials were recorded in the vestibular nuclear complex of the frog perfused brain following stimulation of the anterior branch of the ipsilateral vestibular nerve and spinal cord. Mono- and polysynaptic EPSPs with orthodromic APs were recorded from vestibular neurones following vestibular nerve stimulation. Antidromic activation of neurones sending their axons to the labyrinth was also recorded. Antidromic APs of vestibulo-spinal neurones evoked with mean latency of 1.43 and 2.19 ms to stimulation of cervical and lumbar cords, respectively, were revealed. PMID- 10097276 TI - [Nitric oxide in the rat cerebral cortex in seizure models: potential ways of pharmacological modulation]. AB - Seizures induced with Thiosemicarbaside, Pentylenetetrasole, N-methyl-D,L aspartate were used as models. The NO content increased 4-5-fold in the brain cortex at the peak of seizures. The increase could be prevented by pre-treatment with N-nitro-L-arginine and the seizures were weakened. Anticonvulsant drugs reduced the seizure manifestations and partially prevented the NO generation enhancement. The latter seems to be involved in pathophysiological mechanisms underlying the seizures. PMID- 10097278 TI - [Dependence of the elastic characteristics and contractile activity of the rat tail artery on the transmural difference of potentials]. AB - Change in the diffuse portion of the double electric layer at the blood-vascular wall border under the effect of thorium nitric oxide and heparin affects the tone and contractile ability of the rat tail artery: thorium diminishes the vessel rigidity and the amplitude of its contractile response, whereas heparin augments the rigidity as well as the amplitude of the response. Thorium nitric oxide also diminishes rigidity of the vessel connective tissue skeleton. The difference of potentials between the vessel lumen and its wall seems to be capable of affecting the contractile apparatus of the smooth muscle cells by means of activation of potential-sensitive ionic channels. PMID- 10097277 TI - [Anxiety-inducing and -inhibiting agents: differential effect of pentagastrins on the white rat behavior]. AB - Parenteral administration of des-BOC-Pentagastrin induced the anxiety and fear manifestations, depressing also explorative behaviour in open field experiments in rats. Intranasal administration evoked similar effects, whereas pentagastrin reduced the anxiety level, increasing explorative behaviour. Pentagastrin and des BOC-Pentagastrin displayed antagonism at the receptor level. PMID- 10097279 TI - [Regulation of expression of adrenergic receptors by steroid hormones]. AB - Steroid hormones regulate density of adrenergic receptors in peripheral tissues and in the brain. The hormones affect transcription of the adrenergic receptors genes, the receptor protein synthesis and modifications. Steroid-induced changes in adrenergic receptors densities may be an important link for the effects of steroid hormones on hormone-dependent functions and behaviour. PMID- 10097280 TI - [Synchronization of secretion of the evoked transmitter quanta as mechanism of the facilitating action of sympathomimetics]. AB - Noradrenaline, isoproterenol, dobutamine were found to modulate kinetics of quanta secretion so as to synchronize the transmitter release. This effect could be prevented with blocking agents of beta-adrenoreceptor (atenolol, propranolol). Activators of beta-adrenoreceptors klonidine and phenylephrine did not change the kinetics of quanta secretion, whereas phentolamine did not affect the synchronizing effect of noradrenaline. The change in the time course of the secretion induced by noradrenaline increased the end-plate current amplitude. There seems to exist a specific presynaptic mechanism involving beta adrenoreceptors for facilitation of effects of sympathomimetics. PMID- 10097281 TI - [Modulating role of ATP in the neuromuscular junction]. AB - Review of modulating role of the ATP in neuro-muscular junction is based on experiments and literature references. Endogenous ATP was found to inhibit the transmitter release due to a direct interaction with the P2 receptors on the motor nerve endings, and to modulate development of postsynaptic potentiation due to interaction with cholinoreceptors of the postsynaptic membrane. PMID- 10097282 TI - [Peptide mediators in adrenal chromaffin cells: regulation of catecholamine selective secretion]. AB - The data obtained suggest a potential mechanism that may account for the selective control of adrenaline and noradrenaline release from adrenal chromaffin cells. Some neuropeptides seem to affect in a different way the release from A- and NA-adrenal cells by means of regulating a set of cytochemical events: specific reception of cholinergic transmitters, expression of the second messenger system including cGMP and changes in Ca channels activity, changes in the catecholamine biosynthesis in adrenal chromaffin cells. Modulating function of substance P, endothelins, PACAP, and ANF, is discussed. PMID- 10097283 TI - [Dopaminergic mechanisms of the neostriatum in the corticoliberin regulation of adaptive behavior]. AB - Administration of corticotropin-releasing Hormone (CRH) to dorsal striatum in the course of active avoidance and open-field behaviour of genetically selected rats exerted different effects on adaptive behaviour of high-acquisition (KHA) and low acquisition (KLA) rats. The findings suggest an important role of striatal dopamine in behavioural effect of the CRH. PMID- 10097284 TI - [NO donors transform neuronal response to glutamate]. AB - Electrophysiological experiments on three identified neurones were performed. Two NO donors, sodium nitroprusside (SNP) and sodium nitrite, as well as NO synthase inhibitor, were used. In each neurone, bath application of glutamate caused hyperpolarization and suppression of firing. Combined application of glutamate and SNP resulted in that the same cells responded to identical glutamate solutions with depolarization and excitation. Application of N-monomethyl-L arginin (NMMA) arrested the glutamate-induced firing and depolarization. The findings suggest involvement of NO in the mechanism of transformation of glutamate-induced inhibition into excitation and a mediation of the latter by the N-methyl-D-aspartate-like receptors in the Helix brain. PMID- 10097285 TI - Neurochemical monitoring of the acutely injured human brain. AB - The main goal of modern neurointensive care (NIC) of patients with acute brain injury (traumatic brain injury, neurovascular disease) is to prevent additional loss of viable brain tissue due to secondary injury processes. It is generally held that secondary injury, mediated by, for example, cerebral hypoxia/ischemia and destructive molecular cascades on the cellular level, contributes significantly to the extent of brain damage after head injury and stroke. The basic concept is that improved knowledge of the secondary injury processes will lead to new therapeutic approaches in NIC. New methods by which secondary injury processes can be detected and monitored in NIC patients are therefore greatly needed. This paper describes intracerebral microdialysis as a novel approach to neurochemical monitoring of the human brain. The main objectives are (i) to monitor cortical energy metabolism in order to detect secondary ischemia and (ii) to monitor secondary injury processes, such as glutamate receptor overactivation and increased free radical production, in NIC patients. PMID- 10097286 TI - Mechanisms that regulate the anticoagulant function of coagulation factor V. AB - Coagulation factor V is composed of domains A1-A2-B-A3-C1-C2 and is activated by thrombin through proteolytic cleavage at Arg 709, Arg 1018 and Arg 1545. Upon thrombin activation, the B-domain is released and the active factor Va is formed by the heavy (A1-A2) and light chains (A3-C1-C2). Factor Va functions as an essential cofactor to factor Xa in the conversion of prothrombin to thrombin during coagulation. Recently it was shown that coagulation factor V, apart from being a precursor form to the procoagulant factor Va, also has anticoagulant properties, as it functions as a cofactor to activated protein C (APC). APC is a member of the anticoagulant pathway and downregulates the coagulation process through proteolytic inactivation of factors VIII/VIIIa and factors V/Va. In a factor VIIIa degradation assay, the APC-mediated inactivation of factor VIIIa is potentiated by the synergistic cofactors protein S and factor V. Protein S alone has little cofactor activity, whereas in the presence of factor V it is dramatically enhanced. This study provides insights into the molecular mechanisms that regulate the anticoagulant activity of factor V. Thrombin cleavage of factor V occurs in a sequential order. The thrombin cleavage site Arg 1545 is kinetically less favored than the other two sites, and cleavage at this site is the last to occur during thrombin activation of factor V As a consequence of this, different activation intermediates exist that express different levels of procoagulant activity. The anticoagulant activities of these intermediates have now been studied. It was found that factor V could be cleaved by thrombin at both Arg 709 and Arg 1018 and still work fully as a cofactor to APC, whereas cleavage at Arg 1545 completely abolished the anticoagulant activity of factor V. This suggests that the APC cofactor function of factor V depends on the B-domain remaining attached to the A3 domain. This study further shows that APC converts coagulation factor V into a member of the anticoagulant pathway by cleaving factor V in the A2 domain at Arg 506. By cleavage of factor V, APC not only produces an anticoagulant cofactor, but at the same time eliminates the pool of procoagulant factor V, since APC cleaved factor V will have no future as a cofactor in the coagulation. The unique way by which APC and thrombin, through proteolytic cleavage, can convert factor V into either an anticoagulant or a procoagulant adds to the intriguing mechanisms that balance the procoagulant and anticoagulant forces. PMID- 10097287 TI - Tissue PSA is the best predicting variable for the outcome of endocrine treatment of prostatic carcinoma. AB - In order to evaluate the prognostic value of tissue-PSA (prostatic-specific protein, measured in aspiration biopsies) 231 hormonally treated patients with verified carcinoma of the prostate (CaP) but without metastasis were studied retrospectively. T-PSA was determined at the time of diagnosis in all patients and in 52 of these also at 6, 12 and 24 months after diagnosis. Of the 231 patients, 79 died of prostatic carcinoma and 152 were still alive or had died of other diseases at the end of the observation period (more than 71 months). In a first set of evaluations the predictive value of a single analysis at the time of diagnosis was studied in 179 patients. It was found that tissue PSA was the most important factor for predicting both time to progression and time to death in CaP. Other competing factors were S-PSA, free S-PSA, age, clinical stage, grade and DNA-ploidy. Further evaluations regarding serial PSA determinations were performed in 52 patients. Tissue PSA increased during treatment in all patients who died of CaP. In all patients who survived or died for other reasons, tissue PSA decreased during treatment and remained low. The change of tissue PSA seen between 0, 6 and 12 months could in all cases predict the clinical outcome. It is concluded that a single analysis of tissue PSA at the time of diagnosis can predict the clinical outcome in most cases and that serial determinations can predict the outcome in almost all cases of a CaP without metastasis at the time of diagnosis. This requires that we use this assay when selecting between patients who will survive on hormonal treatment and those who most probably would benefit from a more aggressive treatment. PMID- 10097288 TI - A new approach for studying gene regulation by distant DNA elements in transgenic mice. AB - Apolipoprotein B (apo-B) plays a crucial role in the assembly of lipoproteins in the liver and the intestine. Here, we review how transgenic mouse expression studies with large genomic clones have been used to define distant cis-acting regulatory DNA sequences that control the expression of the apo-B gene. In early studies, apo-B transgenic mice were generated with approximately 80-kb P1 bacteriophage clones spanning either the human or the mouse apo-B genes. Both the human and mouse clones directed high levels of transgene expression in the liver, but transgene expression was absent in the intestine. The absence of transgene expression in the intestine was surprising because both P1 clones contained more than 11 kb of flanking sequences both 5' and 3' to the gene. Subsequently, we isolated and characterized 145-kb and 207-kb bacterial artificial chromosome (BAC) clones that spanned the human apo-B gene. Each of these BAC's contained extensive 5 and 3' flanking sequences and each directed spatially and physiologically appropriate apo-B gene expression in the intestines of transgenic mice. To define the location of the sequences that control intestinal expression of the apo-B gene, we generated transgenic mice by co-microinjecting the approximately 80-kb P1 bacteriophage clone (which did not confer intestinal expression of apo-B) with either the 5' sequences or the 3' sequences from the 145-kb BAC. Analysis of the apo-B expression pattern in those mice revealed that the DNA sequences controlling intestinal expression were located 5' to the apo-B gene. Next, we used recA-assisted restriction endonuclease (RARE) cleavage to truncate specific segments of the 5' and 3' flanking sequences from the 145-kb BAC. A series of the truncated BAC's containing different lengths of 5' and 3' sequences was used to generate more than 40 additional lines of human apo-B transgenic mice. Analysis of human apo-B gene expression in those mice demonstrated that the sequences controlling the expression of the apo-B gene in the intestine are located more than 50 kb 5' to the apo-B gene. Our studies demonstrate that the RARE cleavage/transgenic expression strategy is a powerful approach for examining gene regulation by distant gene-regulatory elements. PMID- 10097289 TI - [From district therapist to general practitioner]. PMID- 10097290 TI - [Principles of prehospital emergency medical care organization for therapeutic profile patients in Moscow]. PMID- 10097291 TI - [Results and trends in development of present-day critical cardiology in N.V. Sklifosovskii Institute of Emergency Care]. PMID- 10097292 TI - [Current potentialities of prehospital diagnosis of cardiovascular diseases in diagnostic centers]. PMID- 10097293 TI - [Attitude of urban population to health and knowledge about risk factors of cardiovascular diseases according to postal questionnaire]. AB - AIM: To elucidate attitude of urban population of Tyumen city to own health and compare the knowledge of cardiovascular disease risk factors in different population groups using postal questionnaire. MATERIALS AND METHODS: 3200 men and women were included into the lists of population selection, 400 subjects in each group according to the age and sex. 71.5% of those on the lists agreed to take part in the survey. RESULTS: The population knew about the risk factors in the following order: hypercholesterolemia (44.6%), arterial hypertension (74.8%), low physical activity (75.2%), smoking (75.7%), obesity (83.7%), stress (93.7%). The knowledge of the risk factors among persons with higher education was greater than among less educated individuals. CONCLUSION: Most respondents worried about their health, especially males, understand the importance of preventive approach to cardiovascular diseases, are aware of the major risk factors but they have low trust in public health service. PMID- 10097294 TI - [Cardiac rhythm in sleeping healthy adolescents as recorded by holter ECG monitoring]. AB - AIM: To characterise cardiac rhythm dynamics in sleeping adolescents by heart rate trend in Holter monitoring (HM). MATERIALS AND METHODS: Synchroneous HM and classical night EEG-polygraphy from 22.00 to 08.00 were conducted in 9 healthy adolescents (5 boys and 4 girls) aged 10-15 years. The heart rate trends in sleep exhibited periods of stable rhythm (PSR) and periods of enhanced dispertion (PED) which took 38.4 and 61.6% of the sleep duration, respectively. PED occurred 5.3 +/- 0.16 times per night. The comparison of the heart rate trends to night sleep structure reflected at EEG indicated that fast sleep coincided with PED in 100% of cases being in the middle of PED cycle. PED incorporated also fragments I and II of slow wave sleep (SWS). PSR were represented primarily with phases II and IV of SWS. Step-by-step scanning of the right space of the interval histograms showed that maximal slowering of cardiac rhythm occurred in SWS phase II and fast sleep (76.5 and 23.5%, respectively). CONCLUSION: The profile of the heart rate night trend in HM reflects an independent ultradian rhythm. Maximal cardiac rhythm unstability and bradycardia occurred, respectively, in fast sleep and phase II of SWS. PMID- 10097295 TI - [Clinical significance of blood pressure variability in hypertension]. AB - AIM: To specify blood pressure (BP) rhythm and variabily at 24-hour monitoring. MATERIALS AND METHODS: 24-hour BP monitoring, cardiac echocardiography, measurements of central hemodynamics and vegetative regulation of cardiac rhythm and psychic status were performed in 178 hypertensive subjects. RESULTS: Progression of cardiac function impairment is associated with reduced lowering of night blood pressure and sleep variability, stable BP variability in awake patients. A close negative relationship exists between night BP fall and peripheral resistance, BP night variability and anxiety level. CONCLUSION: Decreased lowering of night BP seems to reflect morphological changes in the vascular wall, increased variability of wakeful BP reflects less exercise tolerance, that of night BP variability--of growing somatogenically conditioned sympathicotonia and associated anxiety disorders. PMID- 10097296 TI - [Relations between blood insulin concentration, renin-angiotensin-aldosterone system and clinical picture of hypertension]. AB - AIM: To analyse relationships between blood insulin concentration, renin angiotensin-aldosteron system and clinical picture of hypertension. MATERIALS AND METHODS: Measurements of insulin, renin, aldosteron, angiotensin I, total cholesterol, HDLP cholesterol and triglycerides in the blood were made in 60 males with essential hypertension. The examination also included echo-CG, glucose tolerance test, Ketle's index estimation. RESULTS: Patients suffering from essential hypertension with borderline hyperinsulinemia (insulin within 5.7-12.7 mcU/ml) were characterized by a combination of blood hypertension with a metabolic disorder (obesity or defects in carbohydrate metabolism), activation of renin-angiotensin-aldosteron system and left ventricular diastolic dysfunction. Patients with essential hypertension and marked hyperinsulinemia (insulin exceeded 12.7 mcU/ml) had manifest metabolic syndrome (hypertension, obesity, disturbance of carbohydrate metabolism and hypertriglyceridemia), hyperactivity of renin-angiotensin-aldosterone system, elevated diastolic arterial pressure, remodelling of left ventricular myocardium with development of its concentric hypertrophy and impairment of the diastolic function. CONCLUSION: It is suggested that enhanced activity of renin-angiotensin-aldosterone system may underlie development of insulin-resistance and hyperinsulinemia. The latter plays a significant pathogenetic role in forming clinical picture of essential hypertension in insulin levels > 12.7 mcU/ml. PMID- 10097297 TI - [Treatment of mild and moderate hypertension with enalapril (multicenter study of enap and enap N in Ukraine)]. AB - AIM: Assessment of efficiency and safety of enalapril (enap) and its combination with hydrochlorotiaside (enap-N). MATERIALS AND METHODS: 127 patients with mild and moderate blood hypertension entered an open non-comparative multicenter trial. 60 of them received enap (group 1), 67--enap N (group 2). Group 1 patients were given enap for 2 weeks in a dose 10 mg/day. If this dose was not adequate to normalize blood pressure, it was raised to 20-40 mg/day. Patients of group 2 received enap-N one tablet a day for 3 weeks. If the pressure persisted higher than 140/90 mm Hg, the treatment was continued for 3 weeks more in a dose of 2 tablets a day. RESULTS: Blood pressure lowered under 140/90 mm Hg in 40 patients of group 1 (66.7%). Systolic pressure dropped by 10 mm Hg minimum and diastolic by 5 mm minimum in 18 group 1 patients (30%). Enap-N reduced blood pressure under 140-90 mm Hg in 44 of 67 patients (65.7%). Systolic and diastolic pressure dropped, respectively, in 23(34.3%) patients. CONCLUSION: Enap and enap-N tablets were found highly effective and well tolerated. Side effects were caused by lowering of blood pressure. PMID- 10097298 TI - [Clinical efficacy of non-invasive evaluation of intra- and interatrial conduction in patients with ischemic heart disease]. AB - AIM: To try feasibility of non-invasive registration of intra- and interatrial conduction by means of simultaneous registration of echo-CG (in B and M modes) and ECG. MATERIALS AND METHODS: The time of intra- and interatrial conduction was measured at simultaneous registration of echo- CG (B and M modes) and ECG in standard lead II. The time of atrial conduction was registered in ms from the start of ECG wave "P" to beginning of echo-CG mechanical contractions. The results were compared to those obtained at the direct method (registration of atrial conduction by electrode fixed on the atrial myocardium). RESULTS: The data by the two above methods showed high correlation (for intraatrial conduction r = 0.93, for the interatrial one r = 0.85). The study confirmed the leading role of end-diastolic volume of the left ventricle and/or uneven wave movement along the atria in development of supraventricular arrhythmia in coronary heart disease. CONCLUSION: The proposed non-invasive method can find application for estimation of atrial conduction both in clinical practice and experiment. The time of exitation conduction through the atria measured by the new non-invasive method and the direct method is almost the same. PMID- 10097299 TI - [Trimetazidine effects on exercise tolerance and left ventricular diastolic function in patients with coronary heart disease]. AB - AIM: Trial of trimetasidine effects on exercise tolerance (ET) and left ventricular diastolic function (LVDF) in patients with coronary heart disease (CHD). MATERIALS AND METHODS: The study group included 40 CHD patients. Of them 10, 18 and 12 had myocardial infarction, unstable angina pectoris and stable angina, respectively. 38 CHD patients of the control group had these disorders, respectively, in 5, 15 and 18 cases. 2-3-month therapy with nitrates, beta blockers (BB) and inhibitors of angiotensin-converting enzyme (ACE) was given to both groups with adjuvant trimetasidine (60 mg/d) given to patients of the study group. The effects were judged by the results of cycle exercise tests and echo-CG including the loading one. RESULTS: Adjuvant use of trimetasidine improved exercise tolerance, mean threshold capacity, LVDF. When added to BB treatment, trimetasidine reduced damage to LVDF under dipiridamol test. CONCLUSION: Trimetasidine addition to combined treatment of CHD raises exercise tolerance and improves LVDF. PMID- 10097300 TI - [Clinico-statistical analysis of chronic cardiac failure]. AB - AIM: To analyse epidemiologically chronic heart failure (CHF) according to 1996 records for patients admitted to therapeutic and cardiological departments of Moscow city hospital N 64. MATERIALS AND METHODS: An individual sheet has been developed for computer. The statistical processing has been conducted according to Access 97 program. It has covered 4019 case histories for 1996. 1232 patients were hospitalized for chronic cardiac failure this making 30.6% of all the hospitalizations. RESULTS: CHF was encounted in 60.9% of females and 39.1% of males. It was due to: ischemic heart disease (63.7%, with myocardial infarction in 73%), hypertension (17.5%), valvular disease (13.7%), dilated cardiomyopathy (3.7%), myocarditides and perocarditis (1.4%). Age groups 30-39 years, 40-49, 50 59, 60-69, 70-79, 80-89, 90-99 consisted of 0.6, 4, 11, 35.2, 31.4, 16.9, 0.6% of patients respectively. Females prevailed in the oldest age groups. The time from CHF diagnosis was 2, 3, 4, 5, 6, 7, 8, 9 and > 10 years in 26, 10.9, 4, 5.7, 0.9, 1.4, 1.7, 0.6 and 4% of patients, respectively. 72.9% of patients were admitted to hospital once a year. 19.7%, 5.2%, 0.9%, 0.6%, 0.9% of patients were hospitalized 2, 3, 4, 5 and more than 6 times, respectively. CHF was responsible for 50(27.8%) lethal outcomes of 180. Lethality resulted from cardiovascular insufficiency (50%), thromboembolism (30%), pneumonia (10%). CONCLUSION: CHF is a frequent cause of hospitalizations. Development of CHF, lethality, age groups distribution are closely associated with the patients' gender. PMID- 10097302 TI - [Feasibility of chronic pulmonary heart diagnosis by ECG criteria]. AB - AIM: To determine diagnostic value of the method of ECG in 12 conventional leads for diagnosis of pulmonary heart. MATERIALS AND METHODS: The ECG data for 41 patients with clinical diagnosis "pulmonary heart", a risk group of 59 patients with suspected diagnosis "pulmonary heart" and healthy residents of the Komi Republic (n = 968) and Arkhangelsk region (n = 62) have been analysed. The ECGs were recorded using standard electrocardiographs with manual measurement of the amplitude and temporal parameters. RESULTS: We have analysed 215 diagnostic ECG criteria of "pulmonary heart" used in practice, selected 19 informative indices and developed 19 new ones. On the basis of 17 most significant criteria a short algorithm and a program of diagnosis of "pulmonary heart" for IBM PC have been elaborated. The test of the algorithm efficiency by a blind method confirmed the clinical diagnosis in 81.3% of cases, hypodiagnosis and hyperdiagnosis in 6.2 and 12.5%, respectively. CONCLUSION: A widespread and noninvasive ECG method proved promising in diagnosis of pulmonary heart. PMID- 10097301 TI - [Masks of subacute infectious endocarditis]. AB - AIM: Formulation of approaches to differential diagnosis and treatment policy for subacute infectious endocarditis (SIE) when it is masked by another monoorganic or systemic disease. MATERIALS AND METHODS: The course of SIE was analysed in 132 patients of whom 74(56%) had erroneous admittance diagnoses. Rheumocarditis was not confirmed in 34 patients, 24 patients had nonspecific reactions masking SLE (4 cases), glomerulonephritis (7 cases), myocarditis (4 cases), hemorrhagic vasculitis, nodular periarteritis, polymyositis (9 cases). RESULTS: The "masks" made the SIE diagnosis more difficult, resulted in late or invalid treatment- monotherapy with steroid hormones, in particular. This complicated the diagnostic process and aggravated the disease course. CONCLUSION: To detect SIE it is necessary besides analysis of case record and symptoms to performe echocardiography in dynamics, because of possible late development of valvular defect. High-dose antibiotic therapy is justified for diagnosis of ex juvantibus when the diagnosis remains controversial. PMID- 10097303 TI - [Effective long-term use of colchicine in secondary AA-amyloidosis]. PMID- 10097304 TI - [Assessment of tissue microcirculation in patients with aseptic necrosis of femur heads in systemic lupus erythematosus (SLE)]. AB - AIM: To study microcirculation in the tissues above the hip joints with and without aceptic necrosis of the femur head for diagnosis of necrosis stages. MATERIALS AND METHODS: 22 SLE patients were examined for blood flow above the region of affected and intact (control) hip joints using clearance of Xe-133 from the intratissue deposit. Basal circulation and factors of its regulation were investigated with laser dopplerflowmetry. RESULTS: Effective skin blood flow above the hip joints with necrosis stage I significantly differed from that of the control. Basal skin blood flow above the hip joints in suspected stage I of aceptic necrosis differed significantly from the control and that in stage II osteonecrosis. CONCLUSION: The study of tissue microcirculation above the hip joints in SLE patients with aceptic necrosis of the femur heads allows making diagnosis both at early and late stage of osteonecrosis. PMID- 10097305 TI - [Efficacy of D-penicillamine and methotrexate in the treatment of rheumatoid arthritis in relation to levels of circulating rheumatoid factors of different classes]. AB - AIM: To optimize treatment for rheumatoid arthritis (RA) and to define indications for D-penicillamine and methotrexate therapies on an individual basis by taking into account the levels of rheumatoid factor (RF) isotopes circulating in blood. MATERIALS AND METHODS: A total of 105 patients (mean age 46.39 +/- 1.35 years) with varying RA were observed. Indirect solid-phase enzyme immunoassay was used to analyze RF isotopes; the pattern of the disease and the efficiency of therapy for RA were compared with the patients' immunity. RESULTS: With elevated RF IgG levels, the cardiovascular system, thyroid, mucous membranes were found to be more frequently impaired and vasculitis was diagnosed. CONCLUSION: The use of cuprenil and methotrexate in RA substantially improves patients' immunity. PMID- 10097306 TI - [Changes of arterial bed in essential hypertension and treatment policy]. PMID- 10097307 TI - [Dyslipidemia in diabetes mellitus: statins treatment raises survival of patients]. PMID- 10097308 TI - [Role of tobacco smoking on cardiovascular morbidity and mortality in today's Russia]. PMID- 10097309 TI - [Assignment of diet with various protein content in combination with keto-analogs of essential amino acids for management of chronic renal failure. State-of-the art]. PMID- 10097310 TI - Antimicrobial resistance: the Government responds to Lords' concerns. PMID- 10097311 TI - Enforcement of SRM controls: industry to pay. PMID- 10097312 TI - Epizootic of morbilliviral disease in common dolphins (Delphinus delphis ponticus) from the Black sea. AB - Forty-seven common dolphins (Delphinus delphis ponticus) were stranded on the northern shores of the Black Sea between mid-July and early September 1994, more than in previous or subsequent years. Two of the 47 dolphins were examined in detail to try to determine the cause of the increased stranding rate. Their lesions included broncho-interstitial pneumonia with type II epithelial cell hyperplasia and multinucleate syncytial cells, neuronal necrosis, gliosis, and non-suppurative meningitis of the brain, necrotic stomatitis, gastroenteritis and cholangitis, and lymphoid depletion of the spleen and lymph nodes. The diseased tissues stained positive in an immunoperoxidase test, using a polyclonal antiserum to measles virus as the primary antibody, and electron microscopy showed that they contained regularly-shaped intranuclear particles about 22 nm in diameter. They were positive by the polymerase chain reaction (PCR) for the nucleoprotein gene of morbillivirus. However, there was no evidence of morbillivirus in frozen tissues either by virus isolation or by antigen capture ELISA. The concentration of sigma DDTS in the blubber of both dolphins was about 50 to 100 times higher than the levels in toothed cetaceans from the North Sea, North Atlantic Ocean, and Baltic Sea. The lesions were consistent with those found in other species with morbilliviral disease, and the positive immunoperoxidase test, PCR and electron microscopical examination confirmed a morbillivirus as the primary cause of these lesions. PMID- 10097313 TI - Lesions of so-called flank biting and necrotic ear syndrome in pigs. AB - Skin lesions were established on the flanks of pigs aged 10 to 12 weeks, in the areas of the ribs, the mid-upper leg, the shoulder and the tuber ischii. Skin lesions on the ear tips, known as porcine necrotic ear syndrome, were detected in weaners throughout the raising period. By the histological examination of 50 samples of skin lesions from the flank, two stages of epidermal and dermal changes were established; the milder stage had epidermal changes with marked acanthosis, rete ridges formed deep in the dermis and mild infiltrates of mononuclear cells in the layers around the capillaries in the dermis; the more severe stage had ulcers, under which there were infiltrates of polymorphonuclear cells. The same histological changes were observed in 23 samples of skin lesions taken from the tips of ears with necrotic ear syndrome. On healthy skin from the flank and ear tip, micrococci were the dominant organism, whereas on skin lesions from both the affected areas staphylococci were dominant. Since the histological lesions on the flanks were identical to those in necrotic ear syndrome, which has been associated with Staphylococcus hyicus infection, the pathogenesis of the lesions on the flanks is probably the same. PMID- 10097314 TI - High incidence of otognathia in a sheep population. PMID- 10097315 TI - First reported case of elephant rabies in Sri Lanka. PMID- 10097316 TI - Activity of eprinomectin in goats against experimental infections with Haemonchus contortus, Teladorsagia circumcincta and Trichostrongylus colubriformis. PMID- 10097317 TI - EU ban on four antibiotic feed additives. PMID- 10097318 TI - Foot trimming by lay people. PMID- 10097319 TI - Packaging of vaccines. PMID- 10097320 TI - Advertisement featuring bullfighting. PMID- 10097322 TI - Survey provides a snapshot of the profession in the UK. PMID- 10097321 TI - Ban on beef on the bone remains in place. PMID- 10097323 TI - Behaviour of pigs exposed to mixtures of gases and the time required to stun and kill them: welfare implications. AB - Pigs were exposed individually to either 90 per cent argon in air (anoxia), a mixture of 30 per cent carbon dioxide and 60 per cent argon in air (hypercapnic anoxia) or 80 to 90 per cent carbon dioxide in air (hypercapnic hypoxia) and the times to loss of posture, the onset and duration of convulsions, vocalisation and cessation of gagging (respiratory arrest) were determined. The duration of convulsions and the time to onset of respiratory arrest were longer when the pigs were exposed to argon than when they were exposed to the mixture of carbon dioxide and argon or to the high concentration of carbon dioxide in air. A second experiment was carried out under commercial conditions to determine the duration of unconsciousness and insensibility based on the response to a nose prick, and the incidence of death induced by exposing pigs to either 90 per cent argon in air or a mixture of 30 per cent carbon dioxide and 60 per cent argon in air for different periods. The results showed that when pigs were exposed for three minutes to either argon or the mixture of carbon dioxide and argon they should be bled within 25 seconds from the end of exposure to the gas to prevent them regaining consciousness during bleeding. When the pigs were exposed to either argon or the mixture of carbon dioxide and argon for five minutes and bleeding out began within 45 seconds they did not regain consciousness or suffer convulsions while being bled. The majority of the pigs died when they were exposed to argon for seven minutes, and all of them died when they were exposed to the mixture of carbon dioxide and argon for seven minutes. PMID- 10097324 TI - Evaluation of secondary haemostasis in canine leishmaniasis. AB - Secondary haemostasis was evaluated in 26 dogs with leishmaniasis and 10 normal dogs by measurements of modified one-stage prothrombin time (m-OSPT), activated partial thromboplastin time (APTT), thrombin time, fibrinogen concentration and fibrin degradation products. There were no significant differences between the groups in the m-OSPT, fibrinogen concentration, or levels of fibrin degradation products. The APTT was significantly (P = 0.006) longer in the infected dogs than in the control group, and in infected dogs with alanine aminotransferase (ALT) activities > 50 U/litre. There was a significant linear regression between ALT and APTT. Thrombin time was significantly (P = 0.003) longer in the infected dogs than in the normal dogs. There were no significant differences between the thrombin times of sick dogs with different levels of creatinine or activities of ALT, or between male and female dogs, whether diseased or normal. PMID- 10097325 TI - Antibody response to glycoprotein E after bovine herpesvirus type 1 infection in passively immunised, glycoprotein E-negative calves. AB - This study was conducted to determine whether young calves with maternal antibodies against bovine herpesvirus type 1 (BHV-1) but without antibodies against glycoprotein E (gE) can produce an active antibody response to gE after a BHV-1 infection. Five calves received at birth colostrum from gE-seronegative cows which had been vaccinated two or three times with an inactivated BHV-1, gE deleted marker vaccine. After inoculation with a wild-type virulent strain of BHV 1, all the passively immunised gE-negative calves shed virus in large amounts in their nasal secretions. All the calves seroconverted to gE within two to four weeks after inoculation and then had high levels of gE antibodies for at least four months. The development of an active cell-mediated immune response was also detected by in vitro BHV-1-specific interferon-gamma assays. All the calves were latently infected, because one of them re-excreted the virus spontaneously and the other four did so after being treated with dexamethasone. The results showed that under the conditions of this work the gE-negative marker could also distinguish between passively immunised and latently infected calves. PMID- 10097326 TI - Acid-fast bacterial infection and its control in guppies (Lebistes reticulatus) reared on an ornamental fish farm in Venezuela. AB - There was a spontaneous outbreak of mycobacteriosis in fancy veiltail guppies, Lebistes reticulatus, raised on an ornamental fish farm in Venezuela. The clinical signs included listlessness, emaciation, spinal curvature, sunken eyes and loss of colour. Numerous acid-fast bacteria, identified as Mycobacterium species, were detected in smears from the kidneys, liver, mesentery and spleen of the fish, from fresh faecal material, and from the unborn embryos of infected gravid females. The bacteria were eradicated by the addition of kanamycin sulphate to the water at a concentration of 50 ppm, the dose being repeated on four occasions with 48 hours between each dose. Fifteen days after the treatment, none of the clinical signs described were detected in any of the treated fish. The offspring born to treated females were healthy and normal, and did not harbour acid-fast bacteria. PMID- 10097327 TI - A movement disorder in boxer pups. PMID- 10097328 TI - In-straw dilution of bovine blastocysts after vitrification with the open-pulled straw method. PMID- 10097329 TI - Foley catheter technique for removal of a tracheal foreign body in a cat. PMID- 10097330 TI - Health of dogs purchased from animal rescue centres. PMID- 10097331 TI - Health of dogs purchased from animal rescue centres. PMID- 10097332 TI - Behavioural changes following limb amputation in dogs. PMID- 10097333 TI - Control of equine viral arteritis. PMID- 10097334 TI - 'Omnicompetent' graduates. PMID- 10097335 TI - 'Omnicompetent' graduates. PMID- 10097336 TI - 'Omnicompetent' graduates. PMID- 10097338 TI - Veterinary nurse training. PMID- 10097340 TI - Use of antimicrobials--advice from the Veterinary Products Committee. PMID- 10097337 TI - Borna disease in cats. PMID- 10097341 TI - A review of the road transport of cattle. AB - The transport of farm animals has been the subject of much research in recent years. This paper reviews the recent scientific literature pertinent to the road transport of cattle. The state of knowledge is summarised and recommendations for best practice based upon this are given. Areas which require further work are also identified. PMID- 10097342 TI - Monitored control programme for proliferative enteropathy on British pig farms. AB - The effect of control programmes on proliferative enteropathy and its causative agent (Lawsonia intracellularis) was investigated on four farrow-to-finish pig farms in Britain. Faeces samples from groups of boars and gilts in breeding programmes, and from preweaning and postweaning pigs were monitored prospectively every month for six months by a L intracellularis-specific polymerase chain reaction (PCR). On one farm with 150 sows, an outbreak of acute proliferative enteropathy in boars and gilts was controlled clinically by the use of tiamulin and chlortetracycline. The percentage of detectable PCR-positive pigs decreased from between 50 to 70 per cent to zero in the treated pigs and their progeny less than 14 weeks old, but clinical signs of the disease and PCR-positive pigs were detected in some 14-week-old pigs derived from the treated groups. On another farm with 160 sows, an outbreak of chronic proliferative enteropathy in six-week old pigs (23 to 26 per cent PCR-positive) was controlled by the use of oral tylosin phosphate. Faeces samples from the medicated pigs on this farm remained PCR-negative during the study period, whereas samples from unmedicated control pigs showed that the infection persisted in some pigs for at least six weeks. The two other monitored farms remained PCR-negative and clinically negative for the disease during the study period. These farms treated the pigs regularly with oral chlortetracycline. PMID- 10097343 TI - Relationships between leg disorders and changes in the behaviour of broiler chickens. AB - The relationships between the severity of lameness, the presence of tibial dyschondroplasia, and the frequency of dustbathing behaviour and duration of tonic immobility were studied in 96 broiler chicks kept from day-old in groups of four in wire-floored cages. Dustbathing was observed when the birds were given access for one hour to a tray containing sand or straw. The duration of tonic immobility and the severity of lameness were scored during weeks 3, 4, 5 and 6. After slaughter at 41 or 45 days of age the birds were examined for tibial dyschondroplasia; 34 birds were classified as having tibial dyschondroplasia and 54 had detectable lameness problems. Birds with tibial dyschondroplasia had a higher lameness score (P < 0.001), dustbathed on fewer days (P < 0.0001), and had longer periods of tonic immobility (P < 0.03) at six weeks than birds which did not have the condition. However, almost all the chicks, including those with tibial dyschondroplasia dustbathed on day 27 after they had not been given access to the tray for three days, significantly more than on days when they had not been deprived of the tray (P < 0.0001). Furthermore, lame birds and birds with tibial dyschondroplasia also dustbathed less with age. Studies of the vertical wing-shaking element of dustbathing confirmed that tibial dyschondroplasia reduced dustbathing (P < 0.05) and also showed that during the one-hour tests, sand resulted in more dustbathing than straw (P < 0.01). PMID- 10097344 TI - Bile duct hamartoma in a calf. PMID- 10097346 TI - Charging for enforcement of controls on SRM. PMID- 10097345 TI - Isolation of Mycoplasma bovis from the abomasal contents of an aborted bovine fetus. PMID- 10097347 TI - Young camelids in 'pets corners'. PMID- 10097349 TI - 'Omnicompetent' graduates. PMID- 10097348 TI - 'Omnicompetent' graduates. PMID- 10097350 TI - 'Omnicompetent' graduates. PMID- 10097351 TI - Neutering pet rabbits. PMID- 10097352 TI - Iliac cancellous bone in drug addicts: a histomorphometric study. AB - Histomorphometry was used to determine structural bone changes in drug addicts. Iliac crest bone biopsies were obtained at autopsy from 28 subjects (21 male, 7 female, aged 18 to 45 years) who had a history of drug abuse and had died due to overdose of illicit drugs. For histomorphometry, undecalcified sections were investigated using the Merz grid. The following histomorphometric indices were measured and calculated: BV/TV, BS/BV, Tb.Th, Tb.N, Tb.Sp, OV/TV, OS/BS, Ob.S/BS, O.Th, ES/BS, Oc.S/BS, and N.Oc/T.A. In 28 controls (24 male, 4 female, aged 17 to 47 years) trabecular bone specimens were investigated in the same way. The parameters in drug addicts did not show any correlation to age, body weight, height or sex differences. Trabecular bone volume and trabecular thickness were slightly but not significantly increased (BV/TV: 23.37 +/- 5.77% (mean, SD), controls 22.23 +/- 5.08%, p = 0.434; Tb.Th: 172.67 +/- 36.83 mcm, controls 169.73 +/- 36.13 mcm, p = 0.764). Only the eroded surface was significantly different to the controls (ES/BS: 8.16 +/- 2.04%, controls 6.96 +/- 2.17%, p = 0.038). We conclude that the incidence of metabolic bone disease in drug addicts is low. PMID- 10097353 TI - Analysis of blunt trauma injuries: vertical deceleration versus horizontal deceleration injuries. AB - There are several similarities found in blunt trauma injuries to humans sustained as a result of vertical deceleration (falling) and those sustained as a result of deceleration in a horizontal plane (automobile accidents). However, examination of the patterns of traumatic skeletal injuries can distinguish those injuries associated with falling from heights from those associated with automobile accidents. While there is considerable variation within each type of blunt trauma injury dependent on the angle at which one falls or is struck, there are several characteristic skeletal features associated with each type of trauma. In this study we review both the current literature and human skeletal remains from the University of New Mexico's Documented Collection known to have been subjected to blunt trauma. This collection is used to characterize and differentiate the pattern of skeletal injuries to various parts of the body for each type of trauma. These assessments are applied to investigate the traumatic skeletal lesions observed in a forensic case where the manner of death is unknown. Analyses suggest two possible scenarios that would explain the death of the individual investigated, with death most likely related to a vehicular-pedestrian accident. PMID- 10097354 TI - A study of illicit cocaine seizure classification by pattern recognition techniques applied to metal data. AB - Fifteen metallic species, silver (Ag), aluminum (Al), calcium (Ca), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), potassium (K), magnesium (Mg), manganese (Mn), sodium (Na), nickel (Ni), lead (Pb), strontium (Sr) and zinc (Zn), were determined in 46 cocaine samples confiscated by the Spanish police in Galicia (northwest Spain). Classification of these cocaine samples according to their geographic origin (Colombia and Venezuela) was achieved by the application of pattern recognition techniques to the metallic content data. Cocaine samples, around 0.5 g, were directly dissolved in 2 mL of 35.0% (v/v) HNO3, diluted to 10 mL with ultrapure water. The metals were quantified by means of electrothermal atomic absorption spectrometry (Ag, Al, Cd, Cr, Cu, Mn, Ni, Pb and Sr), flame atomic absorption spectrometry (Ca, Fe, Mg and Zn), and flame atomic emission spectrometry (K and Na). Results show that two geographic origins can be established through the presence of trace and major elements. PMID- 10097355 TI - Practical GC/MS analysis of oxidation dye components in hair fiber as a forensic investigative procedure. AB - The purpose of this study was to improve the reliability of discrimination (or identification) of dyed hair by analyzing chemical substances present in the hair, as an addition to the conventional macroscopical and microscopical examinations and ABO blood group examination. Oxidation hair-dye components such as p-phenylenediamine (PPDA), toluylene-2,5-diamine (T-2,5-DA), o-aminophenol (OAP), m-aminophenol (MAP), p-aminophenol (PAP) and p-amino-o-cresol (PAOC) were selected as the object of study. After alkaline-digestion, hair samples were adjusted to a pH of 12.6 to 12.8, and applied onto an Extrelut column. After 15 min, the components were simultaneously extracted and derivatized with n-hexane including 1% heptafluoro-n-butyryl (HFB) chloride. Their HFB derivatives within a condensed sample were diluted in ethyl acetate, and analyzed by gas chromatography-mass spectrometry (GC-MS) with full mass scanning or selected ion monitoring. For estimating their levels, 2,4,6-trimethylaniline was used as the internal standard. Standard curves obtained by preparing a 5 cm segment of control hair spiked with authentic substances were linear, ranging from 0.1 to 4.0 micrograms for PPDA and T-2,5-DA, and from 0.01 to 0.4 microgram for OAP, MAP, PAP and PAOC. The coefficient of variation of inter-day precisions (each n = 4) was below 16% for PPDA, below 20% for OAP and PAP and below 24% for T-2,5-DA, MAP and PAOC. These components were detectable even at 6 ng for PPDA, T-2,5-DA, MAP and PAP, 8 ng for OAP, and 4 ng for PAOC. Recovery percents using this procedure ranged from 54 to 86%. By using actual dyed hair samples this method was shown to provide high sensitivity for accurate detection. PMID- 10097356 TI - Assassination in the United States: an operational study of recent assassins, attackers, and near-lethal approachers. AB - This study is the first operational exploration of the thinking and behavior of all 83 persons known to have attacked, or approached to attack, a prominent public official or public figure in the United States since 1949. In addition to data about each attack or near-attack and each subject's demographic and background characteristics, information was gathered about each subject's ideas and actions in the days and weeks before their attacks or near-lethal approaches. Questions were examined about each subject's movement from the idea of attack to actual attack, motives, selection of targets, planning, communication of threat and intent, symptoms of mental illness, and significant life experiences. In every case, the attack or near-attack was the end result of an understandable, and often discernible, process of thinking and action. Implications for protectors, investigators, and researchers are discussed. PMID- 10097357 TI - Suicides may be overreported and accidents underreported among fatalities due to dextropropoxyphene. AB - Among prescribed drugs in Sweden dextropropoxyphene (DXP) is the medical compound most frequently responsible for self-inflicted fatal poisonings. To analyze the process leading to the classification of the manner of death in cases of fatalities where DXP caused or contributed to death, a set of explicit and implicit operational criteria was applied retrospectively to fatal DXP poisonings among autopsy cases performed at one department of forensic medicine in Sweden during the six-year period from 1992 to 1997. DXP fatality was found in 113 (2.6%) of the total 4306 autopsy cases. Suicide was recorded in 84 (74%) of these cases, and an undetermined manner of death in 24 (21%). Explicit unambiguous expressions of the intent of the decedent were found in 29 (26%) of the 109 analyzed cases. (In four cases no analysis could be performed). In 46 cases only implicit and no explicit criteria were found. The total number of implicit criteria in individual cases without explicit criteria never exceeded three and in 34 cases no criteria of any type were documented. It is concluded that the classification of the manner of death at DXP fatalities was often based on very limited grounds when the operational criteria were used as a standard for comparison. Information from relatives, friends and others concerning the decedent was rarely accessible. The shortage of information probably led to deficiencies in the death statistics concerning DXP fatalities. Considerable underreporting of accidents and probable overreporting of suicides were found. Failure to report DXP deaths as accidents may delay discovery of the high toxicity of this drug. This might be one of the reasons why the DXP fatality rate is still constantly high in Sweden, while both Denmark and Norway have managed to decrease their DXP death rates by vast restrictions, based on alarming reports of accidental DXP fatalities. In order to guarantee valid death statistics concerning self-inflicted poisoning, the information base leading to classification of the manner of death has to be enlarged. This requires implementation of new routines, including interviews of relatives, acquaintances and significant others to get the information needed to assess the decedent's intention to die. Operational criteria may facilitate the difficult classification process by providing a structured standard, and the set of explicit and implicit criteria applied in this study is recommended. PMID- 10097358 TI - Evaluation of clinician accuracy in describing gunshot wound injuries. AB - A large series of gunshot wounds is analyzed to determine, first, whether the wounds were described with enough detail to estimate the distance and direction of fire; and second, to utilize the autopsy description to determine accuracy. All of the University of Miami-Jackson Medical Center (UM-JMC) records coded as gunshot wounds and treated during calendar year 1995 were included in this study. The analysis is of 566 shootings from bullets in which 1259 wounds were described in the hospital records. Of the 1259 bullet wounds, the size and/or shape was described in only 63 (5%) and only four wounds (0.3%) had any indication of distance of fire. The location of the wound could be determined to within 3 cm in 655 (52%) and only 39 (3%) of the wounds were measured from some landmark. Directionality was neither indicated nor determinable in 897 (71%) of the wounds examined. Fifty-five (9%) cases resulted in death and were compared with medical examiner autopsies. Clinical information was inadequate for comparison in three (6%) of these cases. In 22 cases that were said to have one wound, only 14 (64%) of these were correctly documented. Of 16 cases with 2 wounds, 9 (56%) were correctly identified by the clinicians. When greater than 2 wounds were present (14), the clinicians were wrong 93% of the time. This study demonstrates that clinicians responsible for treating gunshot-wounded persons do not adequately document or interpret these wounds. PMID- 10097359 TI - Detection of anabolic steroids in head hair. AB - We developed a gas chromatography/mass spectrometry method for detection and quantitation of anabolic steroids in head hair. Following alkaline digestion and solid-phase extraction, the MO-TMS derivatives gave a specific fragmentation pattern with EI ionization. For stanozolol, the TMS-HFBA derivative showed several diagnostic ions. For androstanolone, mestanolone (methylandrostanolone), and oxymetholone two chromatographic peaks for cis and trans isomers of derivatives were seen. Recoveries were 35 to 45% for androstanolone, oxymetholone, chlorotestosterone-acetate, dehydromethyltestosterone, dehydrotestosterone, fluoxymesterone, mestanolone, methyltestosterone, and nandrolone; 52% for mesterolone, trenbolone; 65% for bolasterone; 24% for methenolone and 17% for stanozolol. Limits of detection were 0.002 to 0.05 ng/mg and of quantitation were 0.02 to 0.1 ng/mg. Seven white male steroid abusers provided head hair samples (10 to 63 mg) and urine. In the hair samples, methyltestosterone was detected in two (confirmed in urine); nandrolone in two (also confirmed in urine); dehydromethyltestosterone in four (but not found in urine); and clenbuterol in one (but not in urine). Oxymethalone was found in urine in one, but not in the hair. One abuser had high levels of testosterone: 0.15 ng/mg hair, and 1190 ng/mL urine. We conclude that head hair analysis has considerable potential for the detection and monitoring of steroid abuse. PMID- 10097360 TI - Morphine perfused rabbits: a tool for experiments in forensic entomotoxicology. AB - In order to establish an animal model for entomotoxicological studies, the kinetics of morphine elimination from blood after a single intravenous injection of morphine and the concentration of morphine in tissues following a continuous perfusion were studied. The aim of these experiments was to obtain controlled morphine tissue concentrations similar to those encountered in fatal human heroin overdoses. These tissues can be used as a food source for developing fly larvae in entomotoxicological studies. In the single injection experiment, seven rabbits were administered 1 or 2 mg/kg body weight of morphine chlorhydrate via the main ear artery. Blood samples of 200 microL were removed regularly via a catheter. Morphine concentration was determined using RIA techniques. Morphine was found to be first rapidly distributed and then slowly eliminated, following a two exponential equation. Elimination of morphine from blood can be described as a two-compartment model. Constants of the equation were determined using the Kaleidagraph program. Using those constants, the main pharmacokinetics parameters were calculated. Results of these parameters showed the following: clearance from 13.3 to 16.2 L.h.1, half-life of the distribution phase from 0.6 to 0.9 min, and half-life of the elimination phase from 21 to 26 min. These results were used to calculate the rate of perfusion of morphine for rabbits to obtain desired, controlled, and constant concentrations of morphine in tissues. In the second experiment, three rabbits received a perfusion of morphine intravascularly at a rate of 2 mg/kg/h for a period of 3 h. These rabbits were sacrificed and analyses performed on several abdominal and thoracic organs. Results showed that the concentrations of morphine differed according to the organ analyzed, but were reproducible for organs between animals. These concentrations were similar to those normally encountered in cases of human death due to heroin overdoses. PMID- 10097361 TI - Determination of drug levels in larvae of Lucilia sericata (Diptera: Calliphoridae) reared on rabbit carcasses containing morphine. AB - This study concerns the determination of morphine concentrations in fly larvae reared on rabbits administered different concentrations of morphine and a correlation between concentrations of the drug in larvae and tissues. Three rabbits (R1, R2 and R3) were given dosages of 12.5, 25.0 and 50.0 mg/h of morphine over a 3 h period via continuous ear artery perfusion. These dosages and time of perfusion were calculated to create tissue concentrations of morphine similar to those encountered in human death due to overdose. Morphine blood level plateau was attained after 1 h of perfusion. A fourth rabbit was used as a control. To evaluate drug concentrations, tissues were sampled using a coelioscopic technique. Approximately 400 eggs of Lucilia sericata, all of the same age category, were placed in eyes, nostrils and mouth of each rabbit carcass. Larvae and puparia were regularly collected from each rabbit for toxicological analysis. The concentrations of the drug in the tissues sampled were determined to be similar to those normally encountered in human overdoses and were correlated with the dosage of morphine that had been administered. Morphine was detected in all larvae and pupae fed on tissues from carcasses administered morphine, except for puparia from the colony fed on the R1 animal which received 12.5 mg/h dosage of morphine. All samples from the control rabbit were negative for morphine. Concentrations of morphine in larvae reared on rabbit carcasses containing morphine were 30 to 100 times lower than the concentrations found in the tissues. A correlation between the tissue concentrations and larval concentrations was found in only 3rd instar larvae (80 to 140 h following hatching). No correlations were found between administered dosages, tissue concentrations and younger larvae, prepuparial larvae or puparia. PMID- 10097362 TI - Effects of morphine in decomposing bodies on the development of Lucilia sericata (Diptera: Calliphoridae). AB - This study concerns the effects of morphine in tissues on the rate of development of Lucilia sericata (Diptera: Calliphoridae) using those tissues as a food source. Lucilia sericata is a species of fly commonly found on human corpses in Europe during the early stages of decomposition and thus of forensic interest. Three rabbits were administered 12.5, 25.0 and 50.0 mg/h of morphine chlorhydrate via ear perfusion over a period of 3 h. These dosages and duration of perfusion were calculated to give tissue concentrations of morphine similar to those encountered in fatal human overdoses. A fourth rabbit was used as a control. Following administration of the drug, rabbits were sacrificed and 400 eggs of Lucilia sericata, all of the same age, were placed in the eyes, nostrils and mouth of each rabbit. Developing larvae were sampled daily to determine growth rate and weight. Puparia and emerging adult flies were also sampled. Data were analyzed using analysis of variance (ANOVA) and Student's T-test. Results of this study show that an underestimation of the postmortem interval of 24 h is possible if the presence of morphine in tissues is not considered. This study demonstrates again the necessity of considering the possible effects of drugs in tissues on insect growth rates when estimating the postmortem interval using entomological techniques. PMID- 10097363 TI - Methamphetamine-related deaths in San Francisco: demographic, pathologic, and toxicologic profiles. AB - A study was undertaken to develop demographic, toxicologic, and pathological profiles of methamphetamine-related deaths. Anatomic and toxicologic findings in 413 deaths where methamphetamine was detected were compared with findings in a control group of 114 drug-free trauma victims. The number of cases per year did not change significantly over the course of the study. Mean age was 36.8 years, but 11% were over the age of 50. Decedents were overwhelmingly male (85.2%) and Caucasian (75%). Blood concentrations of methamphetamine and amphetamine were indistinguishable in cases where methamphetamine was related to the cause of death (MR) and cases where it was not (non-MR) (2.08 vs. 1.78 mg/L, p = 0.65, and 0.217 vs. 0.19 mg/L, p = 0.82). Coronary artery disease, ranging from minimal to severe multivessel, was identified in 79 of the 413 drug users, but in only six of the 114 drug-free controls (p = 0.0004), and MR decedents had enlarged hearts compared with controls. There were also ten cases of subarachnoid and intracranial hemorrhage in the MR group. Abnormalities of the liver (34%) and lungs (24.7%) were frequent. In 65% of these cases, death was due to accidental methamphetamine toxicity. In the remaining cases, methamphetamine was an incidental finding. We conclude that, in our jurisdiction, neither the rate of detection nor the number of methamphetamine deaths has increased significantly in the past 13 years. Decedents are almost all Caucasian males, and many were approaching middle-age. Methamphetamine use is strongly associated with coronary artery disease and with subarachnoid hemorrhage. PMID- 10097364 TI - Zolpidem distribution in postmortem cases. AB - Zolpidem is the prototype of a class of sedative hypnotic drugs that are derivatives of imidazopyridine and is sold in the United States under the trade name Ambien. Over a four-year period, zolpidem was identified in eight cases investigated by the Office of the Chief Medical Examiner, State of Maryland. Zolpidem was identified by gas chromatography-nitrogen-phosphorus detection (GC NPD) following an alkaline extraction and was confirmed by full-scan electron impact gas chromatography/mass spectrometry. Zolpidem was quantitated by GC-NPD in all specimens received. Five of the cases presented were deaths due to drug intoxication. In three of these cases, zolpidem was an incidental finding because the drug fatalities resulted from other drugs. In the other two cases of drug intoxication, zolpidem was present in elevated concentrations and was a contributing, but not exclusive cause of the drug intoxication. The remaining three cases were deaths that were not caused by drugs. The blood zolpidem concentrations in these cases were therapeutic (0.28, 0.12 and 0.19 mg/L, respectively). In six of the eight cases where both blood and urine were analyzed, the blood concentration was higher than the urine concentration. The distribution of zolpidem into the liver and kidney failed to identify any sequestration of the drug into either specimen. PMID- 10097365 TI - Determination of lysergic acid diethylamide in body fluids by high-performance liquid chromatography and fluorescence detection--a more sensitive method suitable for routine use. AB - A new method for determination of lysergic acid diethylamide (LSD) in body fluids by high-performance liquid chromatography and fluorescence detection was developed based on previously published methods. The new method is suitable for confirmation of samples tested positive by immunoassay, avoiding loss of LSD by absorption to surfaces. The reduced loss of LSD results in improved sensitivity. This is achieved by adding ethylene glycol to the samples, which cover glass surfaces. This principle can similarly be used to improve analysis of other drugs. Body fluids for analysis included urine and whole blood. An internal standard was applied for quantification of LSD. The new method offers satisfying precision data and has a detection limit of less than 0.05 ng/nL. PMID- 10097366 TI - The determination of lysergide (LSD) in urine by high-performance liquid chromatography-isotope dilution mass spectrometry (IDMS). AB - The use of isotope dilution mass spectrometry (IDMS) has been investigated for the forensic confirmation of lysergic acid diethylamide (LSD) in urine by LC-MS. The advantages of using a deuterated analog of LSD as an internal standard over methysergide are discussed. This study includes a comparison of the electrospray mass spectra of LSD, LSD-d3 and methysergide, and discusses the choice of suitable ions for use in selected ion monitoring (SIM) mode. An IDMS method is presented for the LC-MS confirmation of LSD in urine, with a limit of quantification (LOQ) of 0.5 ng/mL, reflecting the forensic requirement at this laboratory. Under some circumstances the LOQ can be improved to 0.1 ng/mL. This method is linear in the range tested (up to 10 ng/mL LSD in urine) and has been validated in terms of accuracy and precision. PMID- 10097367 TI - Use of combined frequencies for RFLP and PCR based loci in determining match probability. AB - Statistical analysis was performed on a subset of the Pennsylvania State Police Caucasian, African American and Hispanic database for the purpose of determining Hardy-Weinberg equilibrium and associations across the RFLP loci D1S7, D2S44, D4S139, D5S110, D10S28 and D17S79 and the PCR-based loci HLA-DQA1, LDLR, GYPA, HBGG, D7S8 and Gc. Overall, the statistical results are consistent with a population in equilibrium both within and between loci. The assumption for independence is valid. PMID- 10097368 TI - Allele frequency distribution of the STR loci HUMTPOX, HUMTH01 and HUMVWA in Asturias (north Spain). AB - In order to use genetic loci in forensic identity testing, some population data are needed. This paper presents a report of allele frequency data for the loci HUMTH01, HUMTPOX and HUMVWA in a population sample from Northern Spain. No deviation from the Hardy-Weinberg equilibrium was detected in any of the three markers investigated and there was no evidence of association between the alleles of these loci. Statistical analysis was also carried out to obtain some parameters of medicolegal interest and comparative studies were carried out with other populations studied to date for these five loci. The Asturian sample does not differ substantially from other Caucasian and Spanish populations. PMID- 10097369 TI - Maine Caucasian population DNA database using twelve short tandem repeat loci. AB - A population study of Caucasians residing in Maine was conducted using the AmpF1STR Profiler PCR Amplification Kit and the AmpF1STR Profiler Plus PCR Amplification Kit (Applied Biosystems Division (ABD) of Perkin Elmer, Foster City, CA). The kits contain the reagents necessary to amplify 12 different STR loci and the gender marker Amelogenin using two multiplex PCR, each containing nine STR loci. Thus, there is an overlap of six STR loci. The 12 STR loci are TH01, TPOX, CSF1PO, D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, and D7S820. These loci represent 12 of the 13 core loci selected by the CODIS STR standardization project. Dye-labeled amplification products were separated and detected using the capillary electrophoresis instrument ABI Prism 310 Genetic Analyzer. Allele frequencies were determined for the 12 STR loci. Statistical analysis of the data included Hardy-Weinburg equilibrium (HWE) analysis, pairwise independence testing, power of discrimination (PD), and probability of exclusion (PE). PMID- 10097371 TI - Computed dental radiography used to reproduce antemortem film position. AB - Visual comparison of conventional antemortem and postmortem dental radiographs is often included in forensic identification. Ten forensic cases employing dry mandibular and maxillary bones and a dry study skull were exposed using the CDR digital dental X-ray system developed by Schick Technologies, Inc. Exposures of 0.08s at 10 mA and 70 kVp were taken with an INTREX intraoral dental X-ray unit. Digital radiography has the ability to produce an image instantaneously, allowing an operator to retake an incorrectly aligned radiograph almost immediately. It gives the forensic scientist a simplified method for reproducing antemortem radiographic position more efficiently and often with greater accuracy than conventional radiography. PMID- 10097370 TI - Simple and rapid color screening tests for flunitrazepam (Rohypnol). AB - Three new color/screening tests for flunitrazepam (Rohypnol) are reported. The two-step tests are simple, sensitive, highly specific, and effective for both cut and uncut flunitrazepam and standard over-the-counter preparations of flunitrazepam (i.e., Rohypnol tablets). PMID- 10097372 TI - The use of cadaver dogs in locating scattered, scavenged human remains: preliminary field test results. AB - Specially trained air scent detection canines (Canis familiaris) are commonly used by law enforcement to detect narcotics, explosives or contraband, and by fire investigators to detect the presence of accelerants. Dogs are also used by police, military, and civilian groups to locate lost or missing persons, as well as victims of natural or mass disasters. A further subspecialty is "cadaver" searching, or the use of canines to locate buried or concealed human remains. Recent forensic investigations in central Alberta demonstrated that the use of cadaver dogs could be expanded to include locating partial, scattered human remains dispersed by repeated animal scavenging. Eight dog-and-handler teams participated in a two-month training program using human and animal remains in various stages of decay as scent sources. Ten blind field tests were then conducted which simulated actual search conditions. Recovery rates ranged between 57% and 100%, indicating that properly trained cadaver dogs can make significant contributions in the location and recovery of scattered human remains. PMID- 10097373 TI - Preparation of carboxyhemoglobin standards and calculation of spectrophotometric quantitation constants. AB - A method was developed for the preparation of carboxyhemoglobin (COHB) standards, which were stable for more than four months with the prepared control remaining within acceptable limits during this time. A mathematical equation was developed to more accurately determine the constants A and B used in the equation COHB% = 100[(C - B)/(A - B)], where B = 0% COHB peak ratio at 540 nm and 579 nm; A = 100% COHB peak ratio at 540 nm and 579 nm; and C = the peak ratio at 540 nm and 579 nm for the blood being analyzed. The following equations were developed to calculate A and B: B = Pavg - (P) [(Pavg - Navg)/(P - N)]; A = B + (Pavg - Navg)/(P - N), Pavg = average peak ratio 540/579 for the positive standard run on the spectrophotometer; P = average decimal concentration measured on the CO-OXIMETER for the positive standard; Navg = average peak ratio 540/579 for the negative standard; N = average decimal concentration measured on the CO-OXIMETER for the negative standard. The new equations provided results consistent with those obtained from a CO-OXIMETER. PMID- 10097374 TI - Erotomania, triangulation, and homicide. AB - A case of homicide by a 29-year-old male with erotomanic delusional disorder and various personality disorders is reported. Following a month of pursuit of a female stranger with whom he had briefly conversed in a local bar, he assaulted an automotive plant where she worked, delusionally believing that she was at imminent risk and needed to be rescued. One plant manager was killed and two police officers were wounded. The case illustrates the phenomenon of triangulation, where rage toward the rejecting object is displaced onto a third party, which is then perceived as impeding access to the victim and may be at risk for violent assault. PMID- 10097375 TI - Death during percutaneous insertion of an intraaortic balloon pump. AB - Intraaortic balloon counterpulsation is currently the most widely used mechanical technique for temporary support of the circulation. We report a rare fatal case of perforation of the right common iliac artery during percutaneous insertion of an IABP. PMID- 10097376 TI - Methods for identification of 28 burn victims following a 1996 bus accident in Spain. AB - A car collided head-on with a bus containing 56 passengers plus the driver. A few seconds after the crash, the bus caught fire and 28 persons (15 male and 13 female) lost their lives. All the deceased were almost completely incinerated. To establish the identity of the victims, the judge in charge of the case designated a multidisciplinary Identification Commission. Postmortem procedures included a general external examination, routine photographs, dental examination, dental (intraoral and extraoral) and general radiographs (chest, ankle, etc.), and complementary biological methods for identification (e.g., DNA analysis). The antemortem information, including dental and medical records available, were transcribed onto the INTERPOL disaster victim identification forms. The detailed ante- and postmortem information were compared manually. In this disaster dental identity could be established in 57% of the victims, whereas dental evidence did not allow by itself the identification of 12 burned victims. Odontological examination and complementary radiographic procedures were found to be accurate, economic and rapid methods of identifying badly burned victims in this bus accident. PMID- 10097377 TI - Human herpesvirus-6 and sudden death in infancy: report of a case and review of the literature. AB - Investigation of sudden death in infancy is a vital function of the medical examiner's office. Surveillance of these cases may lead to recognition of new diseases or new manifestations of previously described diseases. Human herpesvirus-6 (HHV-6) is a relatively newly described virus that has been recognized as a cause of acute febrile illness in early childhood. While most cases are apparently self-limited, seven fatal cases have been reported. We present a case of a seven-month-old Latin American male with recent otitis media and vomiting who was found dead in bed. Autopsy revealed interstitial pneumonitis with an atypical polymorphous lymphocytic infiltrate in the liver, kidney, heart, spleen, lymph nodes, and bone marrow, associated with erythrophagocytosis. Polymerase chain reaction (PCR) analysis of formalin-fixed paraffin-embedded tissue was positive for HHV-6 and negative for Epstein-Barr virus (EBV) and cytomegalovirus (CMV). HHV-6 was also detected in the atypical lymphoid infiltrate by in-situ hybridization. PMID- 10097378 TI - Sudden death in right ventricular dysplasia with minimal gross abnormalities. AB - Arrhythmogenic right ventricular cardiomyopathy is emerging as a relatively common cause of exercise-induced sudden death in the young. The diagnostic criteria at autopsy are, however, not fully established, leading to both over- and underdiagnosis. We report a young man and a young woman dying suddenly of right ventricular dysplasia during exercise, in whom the gross autopsy findings in the right ventricle were minimal or even absent. However, the histologic features in both right and left ventricles were typical of the disease, and consisted of fibrofatty infiltrates with typical myocyte degeneration of the right ventricle and subepicardial regions of the left ventricle. These cases illustrate that microscopic findings are diagnostic and may be present in the absence of gross findings. Marked fat replacement is not essential for the diagnosis of right ventricular dysplasia, and the right ventricle should be extensively sampled histologically in all cases of sudden unexpected death, especially those that are exercise related. PMID- 10097379 TI - An unusual case of railway suicide. AB - A rare case of suicide in which the victim had been lying along the railway track in a supine position and with extended extremities is described. The wheels of a train caused longitudinal hemisection with complete evisceration. Epidemiological data on train suicides are given and the relationship between this method of suicide and mental illnesses and consumption of alcohol are discussed. PMID- 10097380 TI - Another death due to ingestion of Nicotiana glauca. AB - Deaths attributed to ingestion of Nicotiana glauca are extremely rare. We report here a case where a 43-year-old man was found dead after apparently drinking a water extract of Nicotiana glauca. The primary alkaloid in the plant is anabasine. Toxicological analysis by capillary gas chromatography showed the deceased had a blood anabasine concentration of 2.2 mg/L. Clinically, the features of poisoning are nicotine-like and if death occurs it results from respiratory paralysis. The case further supports the view that, in the human, anabasine is considerably more toxic than nicotine. PMID- 10097381 TI - Allele and genotype frequencies for the STR locus D18S51 in a western German population. AB - Genetic marker typing based on DNA amplification by the polymerase chain reaction (PCR) increasingly is being employed in forensic casework and for paternity testing. Allele frequencies were determined using PCR for 102 unrelated Germans (Rhine area) for the locus D18S51. Twelve alleles were observed, with frequencies ranging from 0.005 (allele 11) to 0.191 (allele 14). The observed heterozygosity was 0.867, and the power of discrimination was 0.968. There was no deviation from expectations under Hardy-Weinberg assumptions (P = 0.451). PMID- 10097382 TI - Genetic interactions of the Arabidopsis flowering time gene FCA, with genes regulating floral initiation. AB - The genes controlling the timing of the transition from vegetative to reproductive growth are likely candidates for regulators of genes initiating floral development. We have investigated the interaction of one particular gene controlling flowering time, FCA, with the meristem identity-genes TERMINAL FLOWER 1 (TFL1), APETALA 1 (AP1) and LEAFY (LFY) and the floral repression gene EMBRYONIC FLOWER 1 (EMF1). Double mutant combinations were generated and the phenotypes characterized. The influence of strong and intermediate fca mutant alleles on the phenotype conferred by a 35S-LFY transgene was also analysed. The results support a model where FCA function promotes flowering in multiple pathways, one leading to activation of LFY and AP1, and another acting in parallel with LFY and AP1. Only the latter pathway is predicted to be non functional in the intermediate fca-4 allele. The results are also consistent with AP1 and TFL1 negatively regulating FCA function. Combination of Columbia fca and emf1 mutant alleles confirmed that FCA is required for the early flowering of emf1. EMF1 and FCA are therefore likely to operate in different floral pathways. PMID- 10097383 TI - Regulation of gibberellin biosynthesis genes during flower and early fruit development of tomato. AB - Gibberellins (GAs) are essential for the development of fertile flowers in tomato, and may also be required immediately after fertilization. In the GA biosynthetic pathway, the reactions catalyzed by GA 20-oxidases have been implicated as site of regulation. To study the regulation of GA biosynthesis in flower and early fruit development, we isolated three tomato GA 20-oxidase cDNA clones, Le20ox-1, -2 and -3. The three genes showed different organ-specific patterns of mRNA accumulation. Analysis of the transcript levels of the three GA 20-oxidase genes, as well as those of copalyl diphosphate synthase (LeCPS) and GA 3 beta-hydroxylase (Le3OH-2) during flower bud and early fruit development, revealed temporally distinct patterns of mRNA accumulation. Up until anthesis, transcripts were observed for LeCPS, Le20ox-1, -2 and Le3OH-2, with an accumulation of Le20ox-1 mRNA. In contrast to the high level of Le3OH-2 transcripts in the fully open flower, mRNA levels of Le20ox-1, -2 and LeCPS were reduced at this stage. After anthesis, LeCPS and Le20ox-1 transcripts increased again. In addition, Le20ox-3transcripts increased whereas the transcripts of Le3OH-2 decreased to an undetectable level. In situ hybridization results demonstrated that during early stages of bud development, Le20ox-2 transcripts were localized in the tapetum and placenta. The presented results supply novel data about localization of GA biosynthesis gene transcripts, and indicate that transcript levels of GA biosynthesis genes are all highly regulated during flower bud development. PMID- 10097385 TI - Silencing of an aleurone-specific gene in transgenic rice is caused by a rearranged transgene. AB - In rice, silencing of the aleurone-specific Ltp2-gus transgene, causing easily detectable staining patterns on the grain surface, offers a convenient tool to study quantitative aspects of gene silencing in monocots. In this paper we analyzed phenotypes, occurrence, inheritance and environmental effects on the silencing. We also report on the cloning of transgenes, determination of their structure and analysis of transcripts from the transgene loci. The results show that various patterns of silencing appeared in the R2 generation at which most of the transgenes became homozygous and that they were inherited for five generations. In addition, silencing independently occurred in three generations and reversion to full expression was also found. Cloning of transgenes from a silenced L3.3 line demonstrated that this line carried two transgene loci: one carried an intact Ltp2-gus gene and the other carried a rearranged transgene in which part of the gus gene was in the antisense orientation. Analysis of gus transcripts indicated that partial antisense RNA derived from the rearranged transgene was present in silenced lines and was polyadenylated but that it was absent in non-silenced lines. RNA analyses suggested that the Ltp2-gus silencing in the aleurone layer was post-transcriptional and that it may be caused by interaction of partial antisense gus transcripts with normal sense transcripts. Possible involvement of antisense transcripts in post-transcriptional silencing is discussed. PMID- 10097386 TI - Analysis of alternative transcripts of the flax L6 rust resistance gene. AB - The L6 rust resistance gene from flax generates at least four transcript classes by alternative splicing of the third intron. The most abundant transcript class encodes a resistance protein containing domains that include nucleotide binding site motifs and a leucine-rich repeat region (NBS-LRR). The remaining three transcript classes encode truncated products which lack most of the C-terminal part of the protein containing the leucine-rich region (LRR). The four transcript classes occur in all plant organs examined and no induction of L6 expression was observed following infection of resistant plants with an avirulent rust strain expressing the corresponding A-L6 avirulence gene. Flax plants transgenic for an intronless L6 gene, incapable of encoding truncated resistance proteins by alternative splicing, expressed L6 resistance indistinguishable from that of the wild-type gene. Therefore, a definitive role for alternative transcripts and their predicted truncated products could not be assigned in the flax/flax rust system. PMID- 10097388 TI - Cold-regulated gene expression and freezing tolerance in an Arabidopsis thaliana mutant. AB - Low temperature is an important environmental factor influencing plant growth and development. In this study, we report the characterization of a genetic locus, HOS2, which is defined by three Arabidopsis thaliana mutants. The hos2-1, hos2-2 and hos2-3 mutations result in enhanced expression of RD29A and other stress genes under low temperature treatment. Gene expression in response to osmotic stress or ABA is not affected in the hos2 mutants. Genetic analysis indicates that the hos2 mutations are recessive and in a nuclear gene. Compared with the wild-type plants, the hos2-1 mutant plants are less capable of developing freezing tolerance when treated with low non-freezing temperatures. However, the hos2-1 mutation does not impair the vernalization response. These results indicate that HOS2 is a negative regulator of low temperature signal transduction important for plant cold acclimation. PMID- 10097389 TI - Light regulates alternative splicing of hydroxypyruvate reductase in pumpkin. AB - Hydroxypyruvate reductase (HPR) is a leaf peroxisomal enzyme that functions in the glycolate pathway of photorespiration in plants. We have obtained two highly similar cDNAs for pumpkin HPR (HPR1 and HPR2). It has been revealed that two HPR mRNAs might be produced by alternative splicing from a single type of pre-mRNA. The HPR1 protein, but not the HPR2 protein, was found to have a targeting sequence into leaf peroxisomes at the C-terminus, suggesting that alternative splicing controls the subcellular localization of the two HPR proteins. Immunoblot analysis and subcellular fractionation experiments showed that HPR1 and HPR2 proteins are localized in leaf peroxisomes and the cytosol, respectively. Moreover, indirect fluorescence microscopy and analyses of transgenic tobacco cultured cells and Arabidopsis thaliana expressing fusion proteins with green fluorescent protein (GFP) revealed the different subcellular localizations of the two HPR proteins. Both mRNAs were induced developmentally and by light, but with quantitative differences. Almost equal amounts of the mRNAs were detected in pumpkin cotyledons grown in darkness, but treatment with light greatly enhanced the production of HPR2 mRNA. These findings indicate that light regulates alternative splicing of HPR mRNA, suggesting the presence of a novel mechanism of mRNA maturation, namely light-regulated alternative splicing, in higher plants. PMID- 10097390 TI - Expression of cysteine proteinase during developmental events associated with programmed cell death in brinjal. AB - Here we show that the expression of a cysteine proteinase coincides with several developmental events associated with programmed cell death (PCD) in Solanum melongena (brinjal), i.e. during leaf senescence, fruit senescence, xylogenesis, nucellar cell degeneration and anther senescence. We have isolated a cDNA encoding brinjal cysteine proteinase (SmCP) that shares high (90-92%) amino acid identity to cysteine proteinases of tobacco (CYP-8) and tomato (LCYP-2) that have not been previously reported to be senescence-associated. In contrast, SmCP shows lower (39-41%) amino acid identity to other senescence-related cysteine proteinases and, unlike most of them, it is not preferentially expressed in certain organs or cell types. Northern analysis of leaves, fruits and flowers at different stages of development showed that SmCP expression increased significantly at senescence in leaf and fruit, but was highly expressed throughout flower development. In situ hybridization studies on flower sections using an antisense RNA probe localized the SmCP mRNA to the xylem, the epidermis and the endothecium of the anther and the nucellar cells, suggesting its involvement in PCD during xylogenesis, anther senescence and ovule development, respectively. Its expression during nucellar cell degeneration suggests that protein reserves of the nucellus are released to the developing embryo. Polarity in its pattern of expression in the nucellus of the developing seed (40DAP) further implies a directional flow of these nutrients. PMID- 10097391 TI - Divergence time estimates for the early history of animal phyla and the origin of plants, animals and fungi. AB - In the past, molecular clocks have been used to estimate divergence times among animal phyla, but those time estimates have varied widely (1200-670 million years ago, Ma). In order to obtain time estimates that are more robust, we have analysed a larger number of genes for divergences among three well-represented animal phyla, and among plants, animals and fungi. The time estimate for the chordate-arthropod divergence, using 50 genes, is 993 +/- 46 Ma. Nematodes were found to have diverged from the lineage leading to arthropods and chordates at 1177 +/- 79 Ma. Phylogenetic analyses also show that a basal position of nematodes has strong support (p > 99%) and is not the result of rate biases. The three-way split (relationships unresolved) of plants, animals and fungi was estimated at 1576 +/- 88 Ma. By inference, the basal animal phyla (Porifera, Cnidaria, Ctenophora) diverged between about 1200-1500 Ma. This suggests that at least six animal phyla originated deep in the Precambrian, more than 400 million years earlier than their first appearance in the fossil record. PMID- 10097392 TI - Atypically low rate of cytochrome b evolution in the scleractinian coral genus Acropora. AB - Unexpectedly low levels of mitochondrial DNA (mtDNA) cytochrome b sequence divergence are found between species of the scleractinian coral genus Acropora. Comparison of 964 positions of the cytochrome b gene of two out of the three Caribbean Acropora species with seven of their Pacific congeners shows only 0.3 0.8% sequence difference. Species in these biogeographic regions have been evolving independently for at least three million years (since the rise of the Isthmus of Panama) and this geological date is used to estimate nucleotide divergence rates. The results indicate that the Acropora cytochrome b gene is evolving at least 10-20 times slower than the 'standard' vertebrate mtDNA clock and is one of the most slowly evolving animal mitochondrial genes described to date. The possibility is discussed that, unlike higher animals, cnidarians may have a functional mtDNA mismatch repair system. PMID- 10097393 TI - An apparent excess of sex- and reproduction-related genes on the human X chromosome. AB - We describe here the results of a search of Mendelian inheritance in man, GENDIAG and other sources which suggest that, in comparison with autosomes 1, 2, 3, 4 and 11, the X chromosome may contain a significantly higher number of sex- and reproduction-related (SRR) genes. A similar comparison between X-linked entries and a subset of randomly chosen entries from the remaining autosomes also indicates an excess of genes on the X chromosome with one or more mutations affecting sex determination (e.g. DAX1), sexual differentiation (e.g. androgen receptor) or reproduction (e.g. POF1). A possible reason for disproportionate occurrence of such genes on the X chromosome could be that, during evolution, the 'choice' of a particular pair of homomorphic chromosomes for specialization as sex chromosomes may be related to the number of such genes initially present in it or, since sex determination and sexual dimorphism are often gene dose dependent processes, the number of such genes necessary to be regulated in a dose dependent manner. Further analysis of these data shows that XAR, the region which has been added on to the short arm of the X chromosome subsequent to eutherian marsupial divergence, has nearly as high a proportion of SRR genes as XCR, the conserved region of the X chromosome. These observations are consistent with current hypotheses on the evolution of sexually antagonistic traits on sex chromosomes and suggest that both XCR and XAR may have accumulated SRR traits relatively rapidly because of X linkage. PMID- 10097394 TI - Visual cues to female physical attractiveness. AB - Evolutionary psychology suggests that a woman's sexual attractiveness is based on cues of health and reproductive potential. In recent years, research has focused on the ratio of the width of the waist to the width of the hips (the waist-to-hip ratio (WHR). A low WHR (i.e. a curvaceous body) is believed to correspond to the optimal fat distribution for high fertility, and so this shape should be highly attractive. In this paper we present evidence that weight scaled for height (the body mass index (BMI)) is the primary determinant of sexual attractiveness rather than WHR. BMI is also strongly linked to health and reproductive potential. Furthermore, we show how covariation of apparent BMI and WHR in previous studies led to the overestimation of the importance of WHR in the perception of female attractiveness. Finally, we show how visual cues, such as the perimeter-area ratio (PAR), can provide an accurate and reliable index of an individual's BMI and could be used by an observer to differentiate between potential partners. PMID- 10097395 TI - The mitochondrial DNA molecule of the aardvark, Orycteropus afer, and the position of the Tubulidentata in the eutherian tree. AB - An outstanding problem in mammal phylogeny is the relationship of the aardvark (Orycteropus afer), the only living species of the order Tubulidentata, to the extant eutherian lineages. In order to examine this problem the complete mitochondrial DNA (mtDNA) molecule of the aardvark was sequenced and analysed. The aardvark tRNA-Ser (UCN) differs from that of other mammalian mtDNAs reported and appears to have reversed to the ancestral secondary structure of non mammalian vertebrates and mitochondrial tRNAs in general. Phylogenetic analysis of 12 concatenated protein-coding genes (3325 amino acids) included the aardvark and 15 additional eutherians, two marsupials and a monotreme. The most strongly supported tree identified the aardvark as a sister group of a clade including the armadillo (Xenarthra) and the Cetferungulata (carnivores, perissodactyls, artiodactyls and cetaceans). By applying three molecular calibration points the divergence between the aardvark and armadillo-cetferungulates was estimated at ca. 90 million years before present. PMID- 10097396 TI - Sex-biased dispersal in sperm whales: contrasting mitochondrial and nuclear genetic structure of global populations. AB - The social organization of most mammals is characterized by female philopatry and male dispersal. Such sex-biased dispersal can cause the genetic structure of populations to differ between the maternally inherited mitochondrial DNA (mtDNA) and the bi-parental nuclear genome. Here we report on the global genetic structure of oceanic populations of the sperm whale, one of the most widely distributed mammalian species. Groups of females and juveniles are mainly found at low latitudes, while males reach polar waters, returning to tropical and subtropical waters to breed. In comparisons between oceans, we did not find significant heterogeneity in allele frequencies of microsatellite loci (exact test; p = 0.23). Estimates of GST = 0.001 and RST = 0.005 also indicated negligible if any nuclear DNA differentiation. We have previously reported significant differentiation between oceans in mtDNA sequences. These contrasting patterns suggest that interoceanic movements have been more prevalent among males than among females, consistent with observations of females being the philopatric sex and having a more limited latitudinal distribution than males. Consequently, the typical mammalian dispersal pattern may have operated on a global scale in sperm whales. PMID- 10097397 TI - Virulence evolution in a virus obeys a trade-off. AB - The evolution of virulence was studied in a virus subjected to alternating episodes of vertical and horizontal transmission. Bacteriophage f1 was used as the parasite because it establishes a debilitating but non-fatal infection that can be transmitted vertically (from a host to its progeny) as well as horizontally (infection of new hosts). Horizontal transmission was required of all phage at specific intervals, but was prevented otherwise. Each episode of horizontal transmission was followed by an interval of obligate vertical transmission, followed by an interval of obligate horizontal transmission etc. The duration of vertical transmission was eight times longer per episode in one treatment than in the other, thus varying the relative intensity of selection against virulence while maintaining selection for some level of virus production. Viral lines with the higher enforced rate of infectious transmission evolved higher virulence and higher rates of virus production. These results support the trade-off model for the evolution of virulence. PMID- 10097398 TI - Does vestibular stimulation activate thalamocortical mechanisms that reintegrate impaired cortical regions? AB - Caloric stimulation induced a transient reversal of multimodal hemispatial cognitive deficits in an 81-year-old woman with an acute left cerebral hemisphere stroke. The patient had unawareness of her right hand (asomatognosia), right sided visual unawareness (hemineglect), aphasia and right-sided weakness (hemiplegia) prior to the stimulation. Transient improvements in impaired sensory, motor, linguistic and cognitive function developed within 30 s following application of the caloric stimulus and onset of horizontal nystagmus. The effect persisted for 3 min and ceased completely after 5 min. While several recent reports have described the capacity of caloric stimulation to transiently improve or reverse a wide range of attentional, cognitive and motor impairments, most examples are in right-hemisphere-damaged patients with long-standing brain injury. Typically, patients have been tested several months or years after the onset of the deficit. A possible mechanism for the temporary reintegration of multiple cognitive functions in this patient is discussed. PMID- 10097399 TI - Tamoxifen metabolism in rat liver microsomes: identification of a dimeric metabolite derived from free radical intermediates by liquid chromatography/mass spectrometry. AB - Tamoxifen has been shown to be a potent liver carcinogen in rats, and generates covalent DNA adducts. On-line high performance liquid chromatography/electrospray ionisation mass spectrometry (HPLC/ESI-MS) has been used to further study the metabolites of tamoxifen formed by rat liver microsomes in the presence of NADPH with a view to identifying potential reactive metabolites which may be responsible for the formation of DNA adducts, and liver carcinogenesis. A metabolite has been detected with a protonated molecule at m/z 773. The mass of this compound is consistent with a dimer of hydroxylated tamoxifen (m/z 388). Analysis of 4-hydroxytamoxifen incubated with a rat liver microsomal preparation showed the formation of a similar metabolite with an apparent MH+ ion at m/z 773, believed to be a dimer of 4-hydroxytamoxifen formed by a free radical reaction. The retention time for this metabolite from 4-hydroxytamoxifen is identical to that of the tamoxifen metabolite, suggesting that these two compounds are the same. The levels of the dimer were higher when 4-hydroxytamoxifen was used as substrate and, in addition, two isomers were detected. It is proposed that tamoxifen was first converted to arene oxides which react with DNA or to 4 hydroxytamoxifen, either directly or via 3,4-epoxytamoxifen, which then undergoes activation via a free radical reaction to give reactive intermediates which can then react with DNA and protein, or with themselves, to give the dimers (m/z 773). PMID- 10097400 TI - The effect of solvent and matrix combinations on the analysis of bacteria by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry. AB - The ability to rapidly identify the taxonomic class of the wide variety of microorganisms involved in human and animal disease is becoming increasingly important, especially with the increasing development of resistance to the antibiotics which form the main defence against them. A number of groups have recognised the utility of matrix-assisted laser desorption/ionisation time-of flight mass spectrometry MALDI-TOF in the analysis of these microorganisms. However, no consistent methodology has been developed which is in general use. In particular the use of different solvent extraction systems and mass spectrometric matrices can have significant effects on the quality of the data obtained. We have now studied a number of the commonly used matrices and a range of solvent systems of widely varying polarity in an attempt to devise an optimum analytical strategy for the rapid characterisation of these organisms by MALDI-TOFMS. The E. coli ATCC 9637 organisms were initially washed to remove growth medium contaminants, followed by extraction with one of a range of solvents prior to admixing with a number of different single matrices or binary and ternary combinations of these matrices. The results obtained indicate that a binary combination of 2-(4-hydroxyphenylazo)benzoic acid and 2-mercaptobenzothiazole (1:1) as matrix provides the best data after the proteinaceous material from the organism cell surface was extracted with 17% formic acid, 33% isopropyl alcohol and 50% water, (solvent 2 in this work). PMID- 10097401 TI - Structural elucidation studies of erythromycins by electrospray tandem mass spectrometry. AB - Erythromycin A (EryA) was studied by electrospray ionisation tandem mass spectrometry (ESI-MS/MS) with the aim of developing a methodology for the structural elucidation of novel erythromycins developed by biological synthetic methods. Skimmer dissociation along with sequential mass spectrometry studies (up to MS5) have been employed in this study. In the low-resolution MS/MS analysis of the polyketides, there are several fragment ions that are easily assigned to various neutral losses. These have all been confirmed by accurate-mass measurements. There is also a series of peaks due to ring opening and fragmentation that can only be assigned by high-resolution MSn analysis. Further experiments were performed in deuterated media (D2O/CD3OD 50%) which, along with the high-resolution MSn of erythromycin analogues, has enabled us to identify some of the steps in the ring fragmentation, particularly the loss of the polyketide starter acid. This is an essential step for determining structural alterations in the novel polyketides, but further labelling experiments and studies on more erythromycin analogues are required before the complete fragmentation pathway can be confirmed. PMID- 10097402 TI - Supersonic molecular beam-hyperthermal surface ionisation coupled with time-of flight mass spectrometry applied to trace level detection of polynuclear aromatic hydrocarbons in drinking water for reduced sample preparation and analysis time. AB - Analysis of sub-ppb levels of polynuclear aromatic hydrocarbons (PAHs) in drinking water by high performance liquid chromatography (HPLC) fluorescence detection typically requires large water samples and lengthy extraction procedures. The detection itself, although selective, does not give compound identity confirmation. Benchtop gas chromatography/mass spectrometry (GC/MS) systems operating in the more sensitive selected ion monitoring (SIM) acquisition mode discard spectral information and, when operating in scanning mode, are less sensitive and scan too slowly. The selectivity of hyperthermal surface ionisation (HSI), the high column flow rate capacity of the supersonic molecular beam (SMB) GC/MS interface, and the high acquisition rate of time-of-flight (TOF) mass analysis, are combined here to facilitate a rapid, specific and sensitive technique for the analysis of trace levels of PAHs in water. This work reports the advantages gained by using the GC/HSI-TOF system over the HPLC fluorescence method, and discusses in some detail the nature of the instrumentation used. PMID- 10097403 TI - Deconvolution gas chromatography/mass spectrometry of urinary organic acids- potential for pattern recognition and automated identification of metabolic disorders. AB - The National Institute of Standards and Technology (NIST) Automated Mass Spectral Deconvolution and Identification System (AMDIS) is applied to a selection of data files obtained from the gas chromatography/mass spectrometry (GC/MS) analysis of urinary organic acids. Mass spectra obtained after deconvolution are compared with a special user library containing both the mass spectra and retention indices of ethoxime-trimethylsilyl (EO-TMS) derivatives of a set of organic acids. Efficient identification of components is achieved and the potential of the procedure for automated diagnosis of inborn errors of metabolism and for related research is demonstrated. PMID- 10097404 TI - Biomedical applications of accelerator mass spectrometry-isotope measurements at the level of the atom. AB - Accelerator mass spectrometry (AMS) is a nuclear physics technique developed about twenty years ago, that uses the high energy (several MeV) of a tandem Van de Graaff accelerator to measure very small quantities of rare and long-lived isotopes. Elements that are of interest in biomedicine and environmental sciences can be measured, often to parts per quadrillion sensitivity, i.e. zeptomole to attomole levels (10(-21)-10(-18) mole) from milligram samples. This is several orders of magnitude lower than that achievable by conventional decay counting techniques, such as liquid scintillation counting (LSC). AMS was first applied to geochemical, climatological and archaeological areas, such as for radiocarbon dating (Shroud of Turin), but more recently this technology has been used for bioanalytical applications. In this sphere, most work has been conducted using aluminium, calcium and carbon isotopes. The latter is of special interest in drug metabolism studies, where a Phase 1 adsorption, distribution, metabolism and excretion (ADME) study can be conducted using only 10 nanoCurie (37 Bq or ca. 0.9 microSv) amounts or less of 14C-labelled drugs. In the UK, these amounts of radioactivity are below those necessary to request specific regulatory approval from the Department of Health's Administration of Radioactive Substances Advisory Committee (ARSAC), thus saving on valuable development time and resources. In addition, the disposal of these amounts is much less an environmental issue than that associated with microCurie quantities, which are currently used. Also, AMS should bring an opportunity to conduct "first into man" studies without the need for widespread use of animals. Centre for Biomedical Accelerator Mass Spectrometry (CBAMS) Ltd. is the first fully commercial company in the world to offer analytical services using AMS. With its high throughput and relatively low costs per sample analysis, AMS should be of great benefit to the pharmaceutical and biotechnology industries as well as other life science areas. PMID- 10097405 TI - A new pyoverdin from Pseudomonas aureofaciens. PMID- 10097406 TI - Heat-induced changes in the photochemical centres and the protein secondary structures of photosystem II studied by variable fluorescence and difference FT IR spectroscopy. AB - Variable fluorescence (Fv), i.e., Fv = Fm-Fo where Fo is the minimal fluorescence and Fm the maximum fluorescence, and difference Fourier transform infrared (FT IR) spectroscopy were used to study the effect of heat stress in the 25-55 degrees C range on photosystem II (PSII) structure and function. First, the Fv intensity reflects accurately the changes in the number of open photochemical centers in PSII. Secondly, the use of Fv in combination with FT-IR spectroscopy can disclose structure-function correlations in the heat inactivation of the PSII complex. Analysis of the midpoint temperatures of thermal denaturation, i.e., 50% inactivation, reported so far in investigations of the thylakoid membrane components has revealed that most of the thermal transitions attributed to PSII are in the 39-46 degrees C range. In this work, it is shown specifically that the midpoint temperature of PSII inactivation is at about 40 degrees C. Moreover, it was clearly demonstrated that the heat-induced changes above 40 degrees C are the result of a marked decrease in the number of open photochemical centers in PSII. It was also seen that above this same temperature the loss of photochemical centers has its structural counterpart in overall modifications of the secondary structures of the PSII proteins resulting from the decrease in the alpha-helix content concomitant with the increase in extended chain (beta-strand) conformations. In brief, a novel finding reported here is that the number of open photochemical centers in PSII is dependent on a dynamic equilibrium between the contents of the PSII proteins in alpha-helix and extended chains (beta-strands), but not in beta-sheets and beta-turn structures except for the antiparallel-beta sheet conformations. This therefore associates the thermal inactivation of the photochemical centers in photosystem II with distinct conformational changes in the proteins of the PSII supramolecular complex. In the particular context of the present study, these findings constitute a significant contribution to the investigation of structure-function correlations in the photosynthetic membrane. In a broader context, this information might be essential for the comprehension of the molecular arrangements or local structure order that are involved directly or indirectly in biological catalysis. PMID- 10097407 TI - Anticandidial effect of phenylbutene derivatives and their interaction with ergosterol. AB - This paper reports the effect of phenylbut-3-en-2-one, of its analogues, bearing 3-nitro, 4-nitro, 4-chloro- and 4-dimethylamino substituents at the phenyl moiety, and of the hydrazide, phenylhydrazide and oxime of 4-nitrophenylbut-3-en 2-one on the growth and germ-tube formation of Candida spp., as well as their ability to interact with ergosterol in water/dimethylformamide (DMF) solution and their acute toxicity for mice. 3-Nitro-, 4-nitro- and 4-chlorophenylbut-3-en-2 ones inhibit candidial growth in vitro in concentrations ranging from 0.01 to > 0.4 mM and their activity is comparable to that of ketoconazole (in mg/l) and lower than that of amphotericin B. The rest of the compounds are inactive at > 0.4 mM. Germ-tube formation of C.albicans is inhibited at 0.04 mM 4 nitrophenylbut-3-en-2-one and at 0.005 mM of the 3-nitro isomer. A decrease in the absorption maxima in ergosterol mixtures with 4-dimethylamino, 3 nitrophenylbut-3-en-2-one and the oxime of the 4-nitrophenylbut-3-en-2-one was observed, indicative of interaction in water/DMF solutions, while no changes in the UV spectra of the remaining compounds were detectable. That suggests that the growth inhibiting effect is not in correlation with their ability to interact with ergosterol, despite the resemblance to polyenes. LD50 for mice is 367 mg/kg for 4-nitrophenylbut-3-en-2-one and 398 mg/kg for the 3-nitro isomer. PMID- 10097408 TI - Synthesis and anti-virus activity of some nucleosides analogues. AB - New 3'-, 5'-, 5-bromo-2'-deoxyuridine (3a-g) and 3'-, 5'-thymidine (4a-i) analogues with amino acid and peptide residues were synthesized and evaluated for antiviral activity. The influence of long peptide chains, essential amino acids and the effect of this structural modification on the antiviral activity has been also reported. Three 5-bromo-2'-deoxyuridine derivatives containing glycyl-, glycyl-glycyl- and glycyl-glycyl-glycyl- residues (3a, 3b, 3c) showed a strong activity against the herpes virus PsRV and a moderate one vs. HSV-1. The corresponding thymidine analogues were considerably less effective, and only compounds 4d and 4h showed a borderline effect against PsRV. PMID- 10097409 TI - Guanosine 3':5'-cyclic monophosphate-dependent particulate protein kinase activity from yeast (Saccharomyces cerevisiae). AB - Continuing our studies on cGMP in growing yeast we detected a particulate cGMP dependent protein kinase (Pk-G), which was solubilized by detergents and NaCl. It achieves maximum activity at 25 degrees C and pH = 6.8, high concentrations of substrate proteins or cGMP produce saturation. Casein and histones are appropriate substrates, phosphatase-pretreated histone H-2a provokes outstandingly high activity. Pk-G differs from cAMP-dependent protein kinase (Pk A) with respect to pH optimum, temperature tolerance above 50 degrees C, and stability. Partial purification is achieved by chromatography with DEAE cellulose, Sepharose, and cGMP-substituted Sepharose. The latter step also markedly removes Pk-A. At least three proteins with Pk-G-activity and high cGMP affinity are separated by polyacrylamide-gel-electrophoresis. Their apparent molecular masses, as deduced from comigrating marker proteins, differ considerably from those of other Pk-G's, but also of Pk-A's. PMID- 10097411 TI - Identification and cloning of a gene locus encoding peptide synthetase of Pseudomonas fluorescens by two sets of PCR primers. AB - A chromosomal locus encoding biosynthetic genes for a putative peptide synthetase of Pseudomonas fluorescens was identified and cloned. To achieve this, two sets of degenerated oligonucleotide primers KAGGA:SGTTG and TGD:LGG were used in PCR. These primers were selected based on highly conserved units of known peptide synthetases involved in adenylation and thiolation regions of Bacillus subtilis. The discrete amplified bands from PCR ca. 300 bp for KAGGA:SGTTG and ca. 500 bp for TGD:LGG proved to be integral part of the genomic DNA of P. fluorescens were cloned and sequenced. Sequence alignments of both fragments confirmed the putative peptide synthetase genes in P. fluorescens. The present study describes the identification and cloning of peptide synthetase genes of P. fluorescens, which can be used to identify a genetic locus encoding peptide synthetase in other microbial species. PMID- 10097410 TI - Ouabain-insensitive Na(+)-ATPase activity in Trypanosoma cruzi epimastigotes. AB - In the present paper, the presence of a ouabain-insensitive Na(+)-stimulated, Mg(2+)-dependent ATPase activity in T. cruzi epimastigotes CL14 clone and Y strain was investigated. The increase in Na+ concentration (from 5 to 170 mM), in the presence of 2 mM ouabain, increases the ATPase activity in a saturable manner along a rectangular hyperbola. The Vmax was 18.0 +/- 1.0 and 21.1 +/- 1.1 nmoles Pi x mg-1 x min-1 and the half-activation value (K50) for Na+ was 34.3 +/- 5.8 mM and 37.7 +/- 5.3 in CL14 clone and in Y strain, respectively. The Na(+) stimulated ATPase activity was inhibited by 5-[aminosulfonyl]-4-chloro-2-[(2 furanylmethyl)-amino] benzoic acid (furosemide) in a dose-dependent manner. The half-inhibition value (I50) was 0.22 +/- 0.03 and 0.24 +/- 0.07 mM, and the Hill number (n) was 0.99 +/- 0.2 and 2.16 +/- 0.29 for CL14 clone and Y strain, respectively. These data indicate that both cell types express the ouabain insensitive Na(+)-ATPase activity, which might be considered the biochemical expression of the second Na+ pump. PMID- 10097412 TI - Expression of functionally P-glycoprotein in MA104 kidney cells. AB - Rhesus monkey kidney MA104 cells are a polarized epithelium with some unusual characteristics, including a resistance to ouabain, although their Na(+)-K(+) ATPase has normal affinity with this drug. This work suggests that MA104 cells have high expression of functionally P-glycoprotein in their membranes. This was established using four complementary methods to investigate the expression and function of P-glycoprotein in these cells. MA104 cells were strongly resistant to vincristine, which could be reversed by three known P-glycoprotein modulators: verapamil, cyclosporin A and trifluoperazine. In addition, MA104 cells accumulate little rhodamine 123, and the incubation with verapamil increased this accumulation. The mdr1-mRNA was detected by reverse transcription-polymerase chain reaction and a subcloned 283-bp product was identified. Its nucleotide sequence was compared with the related region of human mdr1, showing a high identity (96%) between the two sequences. The expression of P-glycoprotein in the cell membrane was observed by Western blot and immunofluorescence. The results taken together suggest that MA104 cells intrinsically have a high expression of functionally P-glycoprotein in their membranes. PMID- 10097413 TI - An incremental Hebbian learning model of the primary visual cortex with lateral plasticity and real input patterns. AB - We present a simplified binocular neural network model of the primary visual cortex with separate ON/OFF-pathways and modifiable afferent as well as intracortical synaptic couplings. Random as well as natural image stimuli drive the weight adaptation which follows Hebbian learning rules stabilized with constant norm and constant sum constraints. The simulations consider the development of orientation and ocular dominance maps under different conditions concerning stimulus patterns and lateral couplings. With random input patterns realistic orientation maps with +/- 1/2-vortices mostly develop and plastic lateral couplings self-organize into mexican hat type structures on average. Using natural greyscale images as input patterns, realistic orientation maps develop as well and the lateral coupling profiles of the cortical neurons represent the two point correlations of the input image used. PMID- 10097414 TI - Endemic goitre: a research protocol elaboration for eradication. AB - The iodine deficiency (ID), which affects 1 person out of 6, is relatively neglected by the responsible of Public Health Service, particularly in developing countries. Consequences of ID are far from being negligible: mental retardation, hypofertility, hyperplasia, carcinoma, early ageing and, in very exposed areas, endemic cretinism. Nevertheless, eradication is easy and cheap but it requires rigorous protocols and control of results. The elaboration of these protocols is complex because it must be adapted to environment, population and financial possibilities of concerned countries. Based on our experience in this field, we propose a combined protocol, between the Public Health too liberal approach and that of too expensive research, which can be adapted to several situations. PMID- 10097415 TI - Genetic factors in iodine deficiency disorders: a general review. AB - This review presents a summary of what is known about genetic factors possibly involved in iodine deficiency disorders. After an overview on thyroid iodine metabolism and the role of environmental factors in endemic goitre, we analyse genetic studies on endemic goitre reported in the literature. We hypothesize that endemic goitre is a multifactorial disease in which the major factor would be of environmental nature (iodine deficiency) with a lesser role for genetic factors. Mutations, in a heterozygote state, of one of the genes involved in tiered hormonogenesis could lead to a less effective metabolic pathway in the iodine transport or hormonogenesis. We also briefly review various hereditary disorders which may be involved in endemic goitre. Then, we postulate that the presence of some genetic variants in the population or the heterozygote status of individuals for thyroid hereditary disorders may influence the degree of the thyroid enlargement and/or hypothyroidism. PMID- 10097416 TI - Thyroid and fertility. AB - The aim of this work is to specify the relationship between the thyroid function and the hypothalamo-hypophyso-gonadal axis. Qualitative and quantitative repercussions of a thyroid pathology on human or animal fertility, male or female are very variable. A review of mechanisms of action is presented, illustrating: the complexity of the phenomena in cause; the necessity not to dissociate thyroid and reproductive function either clinically or biologically; the serious consequences of either undetected or untreated neo-natal thyroid pathology. PMID- 10097417 TI - Endemic cretinism in a traditional society in Mali: from the collectivity to the individual. AB - The prevalence of endemic cretinism was measured in a village belonging to the Bwa ethnic group in Mali liable to iodine deficiency and suffering from endemic goitre. In this village according to mental and motor handicaps found in cretinism, we used two psychometric tests: the Raven's Progressive Matrice (PM 47) and a "peg test". Using the fiduciary inference method on the two tests associated with a clinical and qualitative approach, we obtained a prevalence of myxedematous cretinism close to 1.2%. PMID- 10097418 TI - The prevalence of goitre and cretinism in a population of the west Ivory Coast. AB - Iodine deficiency is a major public health problem in developing countries. The main areas where goitre is prevalent have been identified, but the different degrees of severity and the populations affected have not. Most countries are now attempting to obtain reliable and more extensive data. A pilot study was carried out in the Ivory Coast in order to improve epidemiological knowledge of iodine deficiency and collect the information required to set up an elimination programme. The aim of this study was to assess the prevalence of goitre and cretinism and to measure the main biochemical indicators of thyroid function (T3, T4 and TSH). The study involved 1433 people identified from a census. The prevalence of goitre was 50.3%. There was a significant difference between the examined ethnic groups: 52.7% of the Yacouba and 28.6% of the non-Yacouba had goitre. The most affected age group was 15-45 year. The predominance of women demonstrated the susceptibility of women at child-bearing age to develop the condition. The prevalence of cretinism was approximately 1.5%. Through the assessment carried out using a grid of clinical indicators, it was possible to identify 10 cases of laboratory proven myxedematous cretinism due to hypothyroidism. The concentration of iodine in foodstuffs was below the limit of detection (< 7.5 micrograms/kg) and iodine could not be detected in the water (< 1 microgram.l) The biological profile of the population was affected to a very limited extent, with a mean value (+/- standard deviation) for TSH of 1.93 (+/- 1.56) mIU/l (0.1-4.0) and a free T4 value of 10 (+/- 3.46) pmol/l (8.2-20). These initial results confirm the high prevalence of endemic goitre and the low iodine content of the soil, water and food in the investigated region. The study will be complemented by a nutritional investigation to improve the understanding of iodine balance, after which an appropriate action plan will be proposed. PMID- 10097419 TI - Epidemiology and prophylaxis of endemic goitre in the Bwa village of Sirao (Mali). AB - A study was conducted in Mali, in some villages exposed to iodine deficiency disorders (IDD). To treat and, above all, prevent endemic goitre, Lipiodol UF was dispensed in two ways: by intra-muscular injection (475 mg I) or by oral administration (48 mg I to 240 mg I). In two cases, hormone levels regained normal values and thyroid hypertrophies regressed significantly. Nevertheless, the impact of the treatment on the size of the goitres seems to be in favour of injections; which is probably due to the fact that in the village which received Lipiodol UF per os, many goitres were nodular. PMID- 10097420 TI - Brassiodol, a new iodised oil for goitrous patients. AB - A new iodised oil, called Brassiodol, is proposed to prevent or eradicate 127I deficiency disorders. Its original synthesis utilises rapeseed oil as vehicle of iodination, allowing the covalent binding of 127I atoms to all olefin groups of fatty acids (FAs). The final product contains 376 mg 127I/mL, manifests high refractoriness to degradative processes and is well tolerated by goitrous patients. The proposed dosage is 1 mL/year in adults owing to the rapid deiodination and massive 127I leakage of larger amounts in the urinary output. About 300-350 mg 127I may undergo tissue sequestration, insuring appropriate iodine coverage during 9-12 months. Clinical follow-up, hormonal data, and 127I excretory kinetics point to the normalisation of thyroid function within 3 months is stages I and II of the goitrous disease. This iodised oil, characterised by low cost, easy handling and high nutritional efficiency, seems ideally suited to meet public health and economical problems in countries facing severe goitrous areas. PMID- 10097421 TI - Registers and follow-up methods of populations in a public health survey: the example of the village Glanle in Ivory Coast. AB - Demography has a fundamental place in a public health survey, and it is essential to provide the population follow-up. A population exhaustive census is the first compulsory phase. It turns out that this phase is necessary if we want to know with precision the size of the population studied and its main demographic characteristics (sex, age ...). The census allows us to provide a real population follow-up, in order to measure the evolution of the different disorders and to estimate the effects of a prophylaxis on each individual in a precise time. This follow-up requires a computerized population register which contains all the information concerning every individual. This data file is updated with new data collected by next surveys. The realization of the nominal population pyramid, is a complementary tool to the population follow-up. Each individual, characterized by sex and age, is allocated a position in the pyramid by his identification number. The figurative contrasts show several cases noticed according to the studied events. The reconstruction of the genealogy represents another form of the population follow-up, by reconstructing biological kinship relationships between the inhabitants. PMID- 10097422 TI - Effect of dietary fish supplementation on lipoprotein levels in patients with hyperlipoproteinemia. AB - Effect of dietary fish was investigated in 51 study group patients and 50 age- and sex-matched control group patients, all with type II-b hyperlipoproteinemia. In the study and control group, 21 and 22 patients, respectively, had well regulated non-insulin dependent diabetes mellitus. Neither the study group nor control group patients smoked or consumed alcohol beverages. Blood pressure was within normal limits (16/11-20/12 kPa) in both groups. During a six-month study period, the study group took 0.5-1 kg breaded pilchard per week, whereas the control group patients were on their standard hypolipoproteinemic diet. The following parameters were determined in both study and control group patients before the study, every 3 months during the study, and 3 months after the completion of the study, total cholesterol, HDL cholesterol (HDL2 and HDL3), LDL cholesterol, VLDL cholesterol, triglycerides, blood glucose and uric acid. Fish intake was found to statistically significantly decrease the levels of total cholesterol (-10.7%), LDL cholesterol (-11.7%), VLDL cholesterol (-14.8%) and triglycerides (-12.3%) (p < 0.05), whereas a statistically significant increase was observed in the levels of HDL cholesterol (+5.3%) and HDL3 (+7.4%) (p < 0.05). Three months after the completion of the study, when the study group patients had resumed their standard hypolipoproteinemic diet without extra fish intake, the levels of lipoprotein fractions returned to those recorded before the study. There were no statistically significant changes in the levels of blood glucose, uric acid and HDL2. In the control group, no statistically significant changes in lipoprotein fractions were recorded. Our findings suggested that dietary intake of 0.5-1 kg fish containing a small amount of omega-3 fatty acids, along with the standard hypolipoproteinemic diet, may decrease the level of atherogenic lipoprotein fractions, and increase the level of lipoprotein protective fractions, thus reducing or at least delaying the development of atherosclerosis. PMID- 10097423 TI - Multi-indicator survey on children's nutrition in Croatia (MICS) (up to 5 years of age). AB - Multi-Indicator Survey (MICS) on children in Croatia was supported by UNICEF's Zagreb Office. The purpose of this research was to establish the present situation in terms of breastfeeding, nutrition and prevention of the most significant health problems in primary health care i.e. acute respiratory and diarrhoeal diseases in children (ARI/CDD), and the level of knowledge. The survey for MICS in Croatia included altogether 370 segments, and from each 40 households were selected. This resulted in 14,800 households being selected for the final sample. 1563 (or 10.6%) of households selected had children under 5 years of age. In the whole sample there were altogether 1937 children under 5 years of age. Having summarized all relevant data, several general conclusions and assumptions may be drawn. The breast-feeding rate is very low, and therefore unsatisfactory. At the age of 4 months, more than 50% of all mothers have already stopped breast feeding their infants, and only 20% of infants were breast-fed after the age of 6 months. We noticed an unfavourable trend towards a decrease in the rate of breast feeding in war areas. The was has negatively affected breast-feeding. The prevalence of feeding using diluted cow's milk during the first six months is very high (30% in the first, and 60% in the second six months). On the basis of this research, further activities should be planned. PMID- 10097424 TI - Anthropometric and health-related fitness characteristics in middle-aged obese women. AB - The purpose of this investigation was to determine the possible relationships between anthropometrical and health-related fitness parameters in obese middle aged women. Twenty one obese (BMI > 27 kg/m2) and 12 control (BMI < 27 kg/m2) middle-aged females (35-45 yrs) participated in this investigation. Three series of anthropometrical measurements on the right side of the body were taken according to the O-scale physique assessment system. The Heath-Carter anthropometric somatotyping method was used and the ratio of waist to hip circumferences was calculated. The body composition was measured using bioelectrical impedance method (Bodystat-500, UK). The following health-related fitness tests used were: dynamic sit-up, hand grip, sit-and-reach, single leg balance and plate tapping. Physical working capacity (PWC) was measured using single ergometer test. Obese women possessed significantly higher (p < 0.05) values for skinfold, girth and breadth measurements. While the differences in somatotype indices were not statistically significant (p > 0.05) between obese and control groups, the transformation of somatotype characteristics to the effect sizes (ESs) revealed that these differences were large (ectomorphy: ES = 1.73; endomorphy: ES = 1.64; mesomorphy: ES = 1.71). Relative aerobic fitness (VO2max/kg, calculated from PWC) and dynamic sit-up were higher (p < 0.05) in control subjects, while obese women presented significantly higher values for hand grip strength. The thicker skinfold thicknesses increased the absolute value of PWC in obese group (r = 0.39-0.57; p < 0.05). In contrast, the thinner skinfold thicknesses in suprailiac and mid-thigh significantly increased the absolute value of PWC in control women. There were only a few significant correlations between girth and breadth measures, and health-related fitness parameters. In addition, somatotype characteristics seldom influenced the results of health-related fitness tests. Stepwise multiple regression analysis demonstrated that health-related fitness test items were more dependent on the anthropometrical parameters in obese than in control women. PMID- 10097425 TI - Development and growth of immature hips. AB - The authors investigated the development of the bony acetabulum in type IIa+ immature hips using ultrasound follow-up evaluation of the alpha and beta angle. The study comprised 900 hips in one-month old infants. In the initial ultrasound examination the alpha angle measured less than 60 degrees and the beta angle more than 55 degrees. In the second ultrasound examination at the age of two months a discrepancy between the bony and cartilaginous acetabular component was found in 15% of the hips, which means that the type IIa+ hips were transformed into the type IIa-. The infants with type IIa- hips had more than two risk factors for developmental dysplasia of the hip. The statistical relative risk was 17. These hips were treated with the Pavlik harness during two months on average. After treatment all hips had normal values the alpha and beta angles (more than 60 degrees and less than 55 degrees respectively). This study showed that each newborn and infant with a sonographically confirmed hip development disorder has to be included in the follow-up evaluation of acetabular development, which makes it possible to choose the most adequate therapeutic and prophylactic measures. PMID- 10097426 TI - Effects of preeclampsia and eclampsia on cord blood coagulation tests. AB - Blood coagulation tests were determined in fifty-three paired umbilical cord blood and maternal venous blood samples originating from term singleton vaginal cephalic deliveries. The index group comprised seventeen deliveries complicated by preeclampsia or eclampsia, and the control group comprised thirty-six healthy women with uneventful pregnancies and deliveries. Mean values obtained from the coagulation and fibrinolytic assays did not significantly differ between study groups, except for antithrombin III levels in index group of neonates, which were significantly lower. Comparison of coagulation and fibrinolytic characteristics between mothers and their neonates produced expected level of difference due to immaturity of their haemostatic mechanisms. We found alterations in maternal blood coagulation and fibrinolysis and evidence of increased intravascular coagulation with severe preeclampsia and IUGR. PMID- 10097428 TI - Bronchopulmonary sequestration and dextrocardia. AB - Bronchopulmonary sequestration (BPS) is usually a rare congenital anomaly, which is most frequently extralobar or intralobar. The case of a patient with positional congenital anomaly--dextrocardia (situs thoracalis inversus) and intrapulmonary sequestration (IPS) is presented. Clinical and radiological characteristics of EPS and IPS are discussed, and new combinations of congenital anomalies with bronchopulmonary sequestration are described, dextrocardia and intrapulmonary sequestration. The importance of the algorithm of diagnostic examinations is emphasized, from detection of bronchopulmonary sequestration on the chest roentgenogram to establishing a definite diagnosis by means of angiography. PMID- 10097427 TI - Features of uremic neuropathy in long-term dialysis. AB - In order to assess the influence of long term hemodialysis on progression of uraemic neuropathy (UN), 16 different electroneurographic (ENG) parameters on 158 dialysis patients were performed. The ENG parameters were compared in three groups of patients of different dialysis age. Group I: high dialysis age (HDA) comprising of, 31 patients being more than 10 years on dialysis; Group II: intermediate dialysis age (IDA) comprising of 53 patients between 5 and 10 years on HD and group III: low dialysis age (LDA) comprising of 74 patients being less than 5 years on dialysis. The influence of sex and age was also analyzed. All sixteen tested parameters were altered in uremic patients when compared to 140 healthy controls (p < 0.01). HDA pts compared to LDA pts and the older group versus the younger had 11 and 9 out of 16 ENG parameters significantly worsened, respectively (p < 0.01). The most profound and reproducible lesion was in prolongation of evoked potential of tibialis posterior and peroneus nerve (FWt, HWt, FWp). HDA, especially after 10 yrs and the age but not the sex is clearly associated with a further progression of UN. However, for unknown reasons, the progression of UN in dialyzed patients is not followed by a parallel worsening of clinical symptoms (p > 0.05). PMID- 10097429 TI - Hypothermia and acute renal failure in the elderly. AB - During 1993-1998, in winter time 14 elderly patients: 8 female and 6 male aged 65 88, were treated because of hypothermia. Rectal temperature on admission was 20 34.9 degrees C. Sopor was present in 2 and various grades of coma were present in 10 patients. Arterial hypotension was recorded in 5, and shock in 9 patients. Increased serum creatinine level was found in 8 patients. The mean rectal temperature in the whole group was 31.3 degrees C +/- 4.7, ranging from 20.0 to 34.9 degrees C, and the mean serum creatinine level was 172.2 +/- 93.5, in range of 66.0 to 360.0 mumol/L. Negative correlation between those two parameters was found: r = -0.572. In 2 of them parameters of renal failure were analyzed: urine sodium concentration, creatinine urine/plasma ratio, urine osmolality, urine/plasma osmolality ratio, renal failure index and fractional excretion of filtered sodium. In one of the patients all parameters were within the range of functional oliguria, in an other the urine sodium concentration serum showed acute renal failure, but all other findings showed borderline values between functional oliguria and acute renal failure. Twelve out of 14 patients died within 1-216 hours from admission. PMID- 10097430 TI - Dermatoglyphic analysis in borderline personality disorder and schizophrenia- results of a Croatian study. AB - Dermatoglyphic features of 52 male patients with borderline personality disorder (BPD) were compared with those of 200 male controls (control group-CG) and 195 males with schizophrenia (SCH). Quantitative analysis showed statistically significant differences between BPD-CG and between BPD-SCH, mainly regarding the palmar traits, but also the 5th, the 4th and the 1st finger of the right hand as well as the 5th and the 4th finger of the left hand between BPD and SCH patients. The canonical discriminant analysis permitted correct classification with 69.84% probability between the BPD and CG and with 76.11% probability between the BPD and the SCH group. Qualitative finger and palmar traits analysis showed differences between the BPD and SCH groups on the 3rd finger of the left hand, total frequency for all fingers and in the III interdigital space. Significant differences between the BPD and CG were found on the 3rd finger of the left hand. Our results show that the dermatoglyphic features of BPD differ from those of schizophrenia and from those of control subjects. The possible significance of these findings is discussed. PMID- 10097431 TI - Apolipoprotein E genotypes and metabolic risk factors for coronary heart disease in middle-aged women. AB - Apo E genotypes and plasma metabolic risk factors (total cholesterol, triglycerides, HDL and LDL cholesterol, total/HDL cholesterol ratio, lipoprotein Lp (a), apolipoprotein A-I, A-II, apo B, and apo E) were determined in 134 healthy middle-aged (X +/- SD 49.62 +/- 4.83) women. The aim of this study was to investigate metabolic risk markers according to various apo E genotypes, and to evaluate a possible risk for coronary heart disease. The results revealed that the frequencies of apo E3/3 are the most frequent (46%), followed by E4/4 (2%), E3/4 (14%), E2/3 (14%), and E2/4 (2%) in the middle-aged women. Higher mean triglycerides, LDL-C and apo B levels were found with apo E3/4, and lower mean levels of HDL-C i.e. apo A-I than in other analyzed genotypes. Greater mean of total/HDL ratio and lower levels of apo A-II were seen with E2/4. Serum lipoprotein Lp (a) concentration was higher in women with genotypes E3/3. Apo E concentration was the lowest with genotypes E4/4, i.e. the highest with E2/3. Serum total cholesterol tended to be higher in women with genotypes E4/4. Genotype E3/4 is connected with the highest concentrations of (X +/- SD) triglycerides (1.74 +/- 0.78), LDL (4.28 +/- 1.88), apo B (1.03 +/- 0.32) and with the lowest concentrations of HDL cholesterol (1.11 +/- 0.21) in the relation to the other analyzed genotypes. This group of women could possibly represent high risk women for CHD. Genotype E3/3 is associated with the highest concentration of independent genetic risk marker for CHD, lipoprotein Lp (a) (0.19 +/- 0.27). The genotype E4/4 has the highest concentration of total cholesterol (5.93 +/- 1.01), and has to be taken in account for risk evaluation in women. High level of apo E (0.11 +/- 0.05) and low level of apo A-I (1.80 +/- 0.44) were associated with E2/3 genotypes. The significance of E3/4 with the high total/HDL ratio (5.52 +/- 2.21) and low apo A-II (0.53 +/- 0.09) is important indicator, because total/HDL cholesterol ratio represents independent Established Risk Factor (ERF) for CHD. Apolipoprotein E genotypes as genetic markers and investigation of serum metabolic risk markers appear to be important in view for further evaluation of high risk women for CHD in our population. PMID- 10097432 TI - HLA class II gene and haplotype diversity in the population of the island of Hvar, Croatia. AB - The DRB1, DRB3, DRB5, DQA1 and DQB1 allele polymorphisms were analysed in 3 western and 3 eastern villages of the island of Hvar using PCR-SSOP method and 12th International Workshop primers and probes. Three DQB1 alleles (*0304, *0305, *0607) detected in the population of the island of Hvar (HP) have not yet been observed in general Croatian population (GCP). Significant differences were observed between two regions of Hvar for: a) DRB1*0701 allele (p < 0.001), b) DQA1*0201 allele (p < 0.01), and c) DRB1*0101-DQA1*0101-DQB1*0501 haplotypic association (p < 0.05). Two unusual haplotypic associations, which have not yet been described in general Croatian population (GCP), DRB1*0101-DQA1*0102 DQB1*0501 and DRB1*1501-DQA1 *0102-DQB1*0604 were observed in the population from the island of Hvar (HP). Measures of genetic kinship and genetic distances revealed isolation and clusterization which coincides with the known ethnohistorical, as well as biological and biocultural data obtained from a series of previous investigations. The five studied village subpopulations formed two clusters (East-West) to which the far eastern village (with the highest rii of 0.0407) joined later, thus indicating possible impact of historical immigrations from the mainland. PMID- 10097433 TI - Assessment of position of foramen mandibulae in recent adult population. AB - Accurate knowledge about the morphology and topography of foramen mandibulae is of great practical importance in anaesthesia of inferior alveolar nerve. A certain number of skeletotopical relations may be used as valuable orientation points. Because of the controversies about these marking points it has been decided to perform measurements on a large sample of macerated mandibulae that are significant to location and shape of foramen mandibulae (FM) and lingula in relation to the surrounding orientation points. The measurements were taken in antero-posterior and infra-superior directions. In AP direction the distance between PRR and FM was measured; the obtained sample average was 15.03 at variability of Qv 12.18%; ARR-FM distance had the average value of 17.52 at Qv of 50%; the CT-FM distance had the average of 14.81 at Qv of 8.17%. In infra superior direction the following measurements were made: AM-FM with the average of 21.10 at Qv of 13.98%; IM-IF with the average of 25.19 at Qv of 16.18%; PCO-FM with the average of 44.17 at Qv of 10.48%; and PCR-FM with the average of 42.79 at Qv of 10.87%. Extreme heterogeneity was noticed in the measurements of lingula. In the antero-posterior plane the FM is located in the middle of the CT PRR distance, i.e., in measurements in which the external oblique line was used as anterior point, FM was located at the juncture of two anterior thirds and the posterior third of ramus mandibulae. In infra-superior direction the lowest FM point was closer to AM than to IM, indicating a somewhat lower position of FM. The mean value of FM depth was 4.31 and the most commonly found shape of the foramen was that of the elongated type (45%). The lingula was prominent, although unevenly, in 51% of study samples. PMID- 10097434 TI - "C"-shaped canal configuration of mandibular second permanent molar. AB - Roots of the second mandibular molar often fuse so the purpose of this investigation was to examine the appearance of "C"-shaped root canals and to classify different root canal types. A hundred and twelve randomly chosen second lower permanent molars-after extraction due to periodontal disease-were prepared and then analysed. Contrast liquid (methylene blue) was injected into prepared teeth. Each tooth was cut into slices to view the root canal morphology. Results of the analysis revealed fusion, either total or partial in 14 cases (12.5%). As a conclusion various appearances were classified into 5 types according to the fused canal shapes and the frequency of different types varied from 0.89%-6.25%. PMID- 10097435 TI - Estimation of referent cephalometric parameters in dental prosthetics. AB - Estimation of the inclination of the occlusal plane and its spatial orientation during the insertion of plaster casts in the articulators space, and control during the clinical phase of the prosthetic work, is one of the key problems in dental prosthetics. The aim of this investigation was to compare the relations of the basic roentgencephalometric parameters applied and to determine their reliability. Five angular variables were analysed: OP-MdP, OP-PP, OP-CP, OP-FP and OP-SNP, on a sample of 86 radiographs of subjects with almost normal occlusion by applying basic statistical parameters and the correlation's analysis. The results gave mean values of the investigated variables with estimation of their variability and level of mutual correlation, which can be used when determining individual inclination of the occlusal plane. Parameters FP and SNP showed significant stability and reliability which can be successfully applied in prosthodontics. PMID- 10097436 TI - A biomechanical analysis of deformation and strain on lower jaw model. AB - Forces, occurring as result of orthodontic appliances, present a guiding system which controls force activity during the growth and development of lower jaw. By qualitative photoelasticimetric analysis author decided to evaluate the influence of extension apparatus to the lower jaw. The concentration and stress distribution, intensity and force direction on contacts with insert (extensor device) were analysed on araldyte lower jaw models. Three different loadings 41.0, 57.4 and 73.8 N under four different loading conditions with and without the correction appliance were used. The results of investigation indicated that the force created by the orthodontic appliance is correct at the beginning. The change from surface contact to linear and punctual contact increased the static moment and local stress, resulting in new regional conditions. PMID- 10097437 TI - The phenomenon of envy in theory and therapy. AB - The authors present a review of theoretical views on envy through the developmental perspective of the personality. The theoretical considerations are substantiated by examples from individual and group psychotherapy which illustrate possible approaches to such sensitive feelings as envy. PMID- 10097438 TI - Study of eating attitudes and body image perception in the preadolescent age. AB - Eating attitudes and body image have been studied in a group of 109 girls, pupils of the fifth primary school grade (average age 10 years and 8 months). The Children's Eating Attitude Test (ChEAT) has been used in the study of eating attitudes. The mean questionnaire score is 11.38 +/- 8 with a range of 0 to 45. Fourteen girls (12.8%) had a total score higher than 20, making them an eating disorder risk group. A set of seven schematic figures showing silhouettes of girls ranging from very thin to very heavy has been used in the study of body image perception. The girls were supposed to indicate the figure having the highest resemblance to their own figure (self figure), and the figure they would like to have (ideal self figure). The mean value of the current figure was 4.28, and that of the ideal figure 3.95. Satisfaction with their figure was expressed by 46.79% of the girls; 39.45% wanted to be thinner, and 13.45% to be heavier. When these data were compared with BMI, 27.52% (of the total) of the girls wanting to be thinner were found to have a normal BMI, and 11.93% a > 95 centile BMI. Among the girls satisfied with their figure 2 had a low and 2 a high BMI, while 43.12% were within the normal BMI range. Out of the 13.45% of girls wanting to be heavier, 6.42% (of the total) had a low BMI, 6.42% a normal BMI, and 0.92% (one girl) a > 95 centile BMI. The girls were divided into two groups in terms of the ChEAT score: ChEAT+ (anorexia risk) and ChEAT-. The groups differed in terms of body weight and BMI (the ChEAT+ group was heavier); ChEAT+ girls tended to prefer a thinner figure and experienced themselves as being heavier. PMID- 10097439 TI - On some neurobiological and cultural-anthropological aspects of the contralateral neglect syndrome. AB - Contralateral neglect is a frequent clinical syndrome which can be provoked by lesions in several brain areas (primarily inferior parietal and frontal) and includes symptoms of motor and perceptual negligence of both real and imaginative contralateral hemi-space. Attentional and representative theories attempting to explain neglect are presently the most popular. This paper analyzes two cases of neglect patients. Paying attention especially to their reading defects, a possible role of the persons with contralateral neglect is proposed in the development of script. Other neurobiological and cultural-anthropological questions arising from the analysis of these cases are also discussed. PMID- 10097440 TI - Role behaviours among urban women as revealed by time allocation. AB - The present study, conducted among 190 urban middle-class women of Calcutta city, examines the differences between a group of working mothers and a socioeconomically comparable group of non-working mothers with respect to their time use pattern. The underlying hypotheses are: (a) working mothers have less time for certain household responsibilities compared to non-working mothers; and (b) combined job and family responsibilities generate role conflicts among the working mothers, due to lack of support in the family and/or outside it. Results suggest that though the working mothers had contributed significantly less time in parental, domestic, conjugal and individual activities compared to their non working counterparts, they hardly faced role conflicts as corroborated from their lower anxiety scores. PMID- 10097441 TI - Health profile of two social groups living in a squatter settlement in Calcutta. AB - Health and well-being of individuals largely depend on socioeconomic and environmental conditions. The low socioeconomic groups face the highest health burdens. In the present study an attempt has been made to compare and contrast the health related traits prevalent in two social groups (Hindu and Muslim), living in a squatter settlement in Calcutta, India. The study has been conducted on women between 20 to 40 years of age. The results show that the Muslims are more frequently affected with respect to most of the traits than the Hindus, but the difference is significant with respect to only a few traits. Thus, micro cultural traits associated with religion do not seem to have much effect on the health related traits considered in this study. PMID- 10097442 TI - Gender difference in health status and health care facilities in some social groups and subgroups of southern West Bengal, India. AB - In recent years, social scientists are concerned with individual well-being and also in identifying the high-risk groups. In South Asia, gender is an important determinant of variation in resource allocation. Three contrasting social groups of southern West Bengal, India have been studied to find out whether there is any gender discrimination in allocation of health facilities and also to assess the health status of these groups. In general, a tendency towards favouring the males appears to exist in respect of allocation of health facilities. Also, females are more affected with the ailments associated with hard work. PMID- 10097443 TI - The projection questionnaire: design, use and utility. AB - Projection is a widespread mechanism of defence. It is an important issue in a number of anthropological researches. To estimate changes in intensity and flexibility of the projection a measuring instrument is unavoidable. MATERIAL: To standardise the questionnaire answers of 250 examinees were used. They were divided in two independent groups. Group 1 consisted of 125 patients treated at Clinic for Psychological Medicine and Group 2 of 125 students in the third year of the Medical Faculty in Zagreb. METHODS: To process the results a statistical package SPSS was used. A chi 2 test was employed and tables of contingency were made. A factor analysis of "The Projection Questionnaire" was employed and varimax rotation separated five factors which characteristic roots were greater than one. RESULTS: A new instrument for measuring the projection, "The Projection Questionnaire", is developed and standardised. A considerable use of the projection by normal population is confirmed. PMID- 10097444 TI - Inheritance of hypodontia in twins. AB - The aim of this study was to establish prevalence of hypodontia in the twin sample and to assess the degree of its heritability. A study was performed in a sample of 96 twin pairs, 38 pairs being monozygotic (MZ) and 58 pairs dizygotic (DZ), from north-west Croatia. The sample included 25.82% of all twins born in the region during a ten-year period. The twin zygosity was determined according to the WHO recommendations (1996). A revised Holzinger's index (Hc') according to Allen was applied to calculate the degree of heritability. Hypodontia was found in 22 out of the total of 192 twins analyzed (11.5%). Among 96 pairs of twins, hypodontia was observed in 17 pairs (7 MZ and 10 DZ pairs). Among the MZ, 4 pairs were found to be concordant for hypodontia, among the DZ one pair only. The heritability index was 0825. A prevalence of hypodontia in twins observed in this study is significantly higher than in the general population. A high index of heritability (Hc' = 0.825) points to a high genetic determination. PMID- 10097445 TI - Osteometric dimensions of metacarpal bones with respect to the professional exposure to vibration. AB - The comparative analysis of the osteometric dimensions of metacarpal bones in three groups of males (aged from 23 to 63 years) differing with respect to the presence of the professionally connected long-term exposure to the vibration is performed. The sample encompasses forest workers employed in wood industry (exposed to heavy physical work and to the daily use of hand-held vibrating tools) from two regions of Croatia: Podravina (n = 192) and Gorski Kotar (n = 115). The control group is formed using the random sample (selected according to age criterion) of phenotypically healthy male inhabitants of rural communities of Eastern Adriatic islands and peninsula (n = 200). Additionally, the influence of the level of calcium in diet, as a regional nutritional characteristic of particular regions of Croatia, is also considered. The regression of the percent cortical area (PCA) of the second left metacarpal bone and age showed that significant decrease of PCA in older age can be observed only in males from Eastern Adriatic (the control group), while that is not so in either group of males professionally exposed to vibration. Authors conclude that the analysis of the osteometric dimensions performed on males professionally daily exposed to vibration missed to provide evidence to support the hypothesis of long-term exposure to vibration as a risk for accelerated osteoporosis of metacarpal bones. PMID- 10097446 TI - Morphometric dimensions of metacarpal bones in the population structure analysis (island of Krk, Croatia). AB - The population structure analysis by means of the osteometric dimensions of metacarpal bones in the population groups of the northern Adriatic island of Krk, Croatia was performed. The sample consisted of randomly sampled adult islanders (94 males and 79 females) aged from 18 to 85 years from six villages of the island of Krk. "Biological distances" were estimated by the Mahalanobis D2 analysis for bone length (L), total diaphysis width (T) and medullary canal width (M) dimensions of the second left metacarpal bone. Analysis of the osteometric dimensions of metacarpal bones as a measure of biological distance between population groups of the island of Krk indicated bio-cultural and socio-cultural events, rather than geographical distances, to be the primary determinants of anthropogenetic structure of today's population groups of the island. PMID- 10097447 TI - The introduction of photodynamic therapy for tumorous patients in Croatia based on our experimental experiences and clinical approaches of the other groups. PMID- 10097448 TI - Surgical therapy of thyroid cancer. PMID- 10097449 TI - [Effects of octreotide (somatostatin analog SMS 201-995) on superior mesenteric artery blood flow in swine. An experimental study using Doppler color ultrasonography]. AB - The effect of octreotide on splanchnic haemodynamics was investigated in 25 domestic pigs by mean of US-colordoppler. In a blind-operator design the superior mesenteric artery (SMA) blood flow was evaluated before and after i.m. injection of 5, 10, 20, 25 micrograms/kg or of an equivalent volume of saline solution. Seven serial measurements were taken every 10 min in each pig excluding the higher and the lower values. The administration of 5 and 10 micrograms/kg determined a rapid and stable (3 hours) decrease of the SMA blood flow (6 and 8.5% respectively) (p < 0.05). The blood flow decreased by 27-29% (p < 0.001) in response to the administration of 20 and 25 micrograms/kg respectively. The reduction started 30 min after injection and the blood flow remained lower than basal for up to 5 hours. Because of the mean standard error of US blood flow assessment is 10% due to the interobserver and intraobserver variations, we considered statistically significant only the reduction occurred after the administration of 20 or 25 micrograms/kg. Authors findings suggest that high dose of octreotide is effective in reducing the splanchnic haemodynamics in the pig. Such animal can be used in experimental setting planed to assess the effect of splanchnic blood flow reduction. PMID- 10097450 TI - [A case of thymoma: histological and diagnostic aspects and surgical considerations]. AB - The histological and diagnostic features of a thymoma case observed recently have been investigated in the present study. Comparing the case under investigation with the literature, the Authors conclude that the proper surgical approach is that indicated by Jaretsky. By means of a longitudinal sternotomy associated with minimal cervical incision, the whole mediastinal cellular tissue together with that of the thyroid inferior poles is easily removed. Moreover oncological and myastenic recurrences have a very low incidence in cases surgically treated with this procedure. PMID- 10097451 TI - [Renal hemangiopericytoma. Anatomo-pathologic and clinico-therapeutic considerations. A case report]. AB - The Authors report a case of renal hemangiopericytoma, whose interest is related to the extreme rarity (24 cases reported until today), its insidious growth, the late in diagnosis, its uncertain clinical-biological evolution, not always predictable. Considering chemotherapy and radiotherapy ineffectiveness, an adequate treatment for such a neoplasm requires the surgical therapy, which must be followed by a careful follow-up. PMID- 10097452 TI - [Hilar localization of splenic cyst does not always exclude the possibility of resective treatment]. AB - Non parasitic cysts of the spleen require surgical treatment because of their progressive growth and in order to prevent the potential severe complications associated with such cysts. Since it is now well known that total splenectomy, especially in young patients, has potential for short- and long-term complications, much emphasis has been placed on splenic salvage, suggesting partial splenectomy as procedure of choice for splenic cysts. However various Authors suggest that many but not all splenic cysts can be treated with partial splenectomy. In particular cystic mass arising from the anterior aspect of the hilum near to vascular peduncle contraindicate partial resection requiring splenectomy. In a case observed TC scan demonstrated a very large epidermoid cyst penetrating hilar parenchyma just above splenic vessels insertion. Preoperative imaging suggested splenectomy as the only possible procedure to remove the cyst. At operation the exposure of the splenic artery extended proximally along the pancreatic tail showed an arterial branch running with satellite vein in the splenopancreatic ligament for inferior segment of the spleen. As we found this branch it was possible to resect cyst preserving a large inferior parenchymal segment normally perfused and functioning at postoperative scintigraphic controls. In conclusion not all hilar cysts must be considered an absolute indication to splenectomy. An accurate and extensive exposure of splenic artery and vein can demonstrate vascular anatomical variations permitting resection also for large cysts located near the splenic hilum. PMID- 10097453 TI - [Clinical study on the treatment of differentiated carcinoma of the thyroid gland]. AB - A study on 88 patients operated for a differentiated thyroid carcinoma (63 papillary and 25 follicular cancer) is reported. In 66 cases a total thyroidectomy was performed (in 16 associated with an ipsilateral lymphadenectomy), in 11 a subtotal thyroidectomy and in 11 a lobar isthmectomy. In the follow-up there were 3 deaths and 4 recurrences. Notwithstanding the limited number of cases, the Authors registered a worse diagnosis for the follicular carcinomas (2 deaths and 2 recurrences on 25) compared to the papillary (1 death and 2 recurrences on 63). PMID- 10097455 TI - [Rare neoplasms of the breast: our experience concerning nonepithelial malignant breast tumors]. AB - The Authors report their experience about some clinical cases of uncommon breast neoplasms observed at the Division of Surgical Pathology, referring particularly on non epithelial malignant tumors. Signalled more meaningful anatomopathologic elements, they describe diagnostic difficulties and therapeutic of such neoplasias; for their rarity they would deserve a study more deepened finalized to the formulation of diagnostic and therapeutic guidelines as so as in the most common breast carcinoma. PMID- 10097454 TI - [Primary carcinoma of the cystic duct: a case report and review of the literature]. AB - The Authors, after a short introduction concerning the primary carcinoma of the cystic duct and the exact definition according to Farrar's criteria, report a case occurred to their observation, the 35th case of international literature. In particular the importance of some hemato-clinical parameters and instrumental investigation (ERCP, angio-CT) to underlined in order to surgical indication. In the case here reported cholecystectomy uses informed with partial resection of the hepato-choledochus and excision of some periductal and pericholedochus lymph nodes. Finally, the Authors discuss about clinical data and diagnostic and therapeutic trends, on the case of their experience and literature review. PMID- 10097456 TI - Interposition vein cuff in infrainguinal prosthetic bypasses. AB - The Authors describe the interposition vein cuff technique as an adjuvant method to infrainguinal prosthetic bypass grafts. The haemodynamic, mechanical and humoral factors thought to be involved in the beneficial effects of the vein cuff are herein discussed. The results of the main series suggest the use of this method particularly in patients without any available autologous vein conduit requiring a below-knee popliteal or crural reconstruction. PMID- 10097457 TI - [Endoscopic ligation in the prevention of hemorrhage after polypectomy: our experience]. AB - The Authors report their experience with the use of the Olympus Endoloop HX-20L for the prevention of haemorrhages after endoscopic polypectomy. They emphasize the utility of this therapeutic device that will find its right application only in a well selected group of patients. PMID- 10097458 TI - [Unreliability of the lidocaine test as a prognostic indicator of acute liver failure: an experimental study in swine]. AB - It has been reported, in the recent literature, that fifteen minutes lidocaine MEGX (monoethylglycinexylidide) test can also be used in case of acute hepatic failure because in these conditions the test allows a rapid evaluation of the hepatic damage, uneffected by te infusion of liquid or fresh plasma which can alter conventional laboratory parameters. The Authors have demonstrated, in a experimental model, the unreliability of the lidocaine-MEGX test as measure of functional hepatic damage in the early stages of an acute liver failure. The slight decrease of the rate of the MEGX test in these animals submitted to one stage hepatic devascularization suggests that the hepatic failure is not so early detected by this specific liver function test. Accordingly, the 15' MEGX test should not be used as isolated discriminatory measure to detect an early hepatic failure following fulminant hepatitis or an early hepatic insufficiency as a result of extensive liver resection. PMID- 10097460 TI - EEG and MEG: forward solutions for inverse methods. AB - A solution of the forward problem is an important component of any method for computing the spatio-temporal activity of the neural sources of magnetoencephalography (MEG) and electroencephalography (EEG) data. The forward problem involves computing the scalp potentials or external magnetic field at a finite set of sensor locations for a putative source configuration. We present a unified treatment of analytical and numerical solutions of the forward problem in a form suitable for use in inverse methods. This formulation is achieved through factorization of the lead field into the product of the moment of the elemental current dipole source with a "kernel matrix" that depends on the head geometry and source and sensor locations, and a "sensor matrix" that models sensor orientation and gradiometer effects in MEG and differential measurements in EEG. Using this formulation and a recently developed approximation formula for EEG, based on the "Berg parameters," we present novel reformulations of the basic EEG and MEG kernels that dispel the myth that EEG is inherently more complicated to calculate than MEG. We also present novel investigations of different boundary element methods (BEM's) and present evidence that improvements over currently published BEM methods can be realized using alternative error-weighting methods. Explicit expressions for the matrix kernels for MEG and EEG for spherical and realistic head geometries are included. PMID- 10097459 TI - [New issues in surgery of adrenal pheochromocytoma]. AB - The adrenal pheochromocytoma still arouses great interest among the experts. The Authors give here a report of a study carried out on the personal case history of 32 patients and the concerning literature. A correct clinical and diagnostic approach is important to detect, at a preoperative level, the benign forms from the malignant ones (10-15% of cases according to literature) and the polyendocrine syndromes (21% of our series). Video-laparoscopy technique is recommended in pheochromocytomas surgery, mainly in asymptomatic and incidental forms and in all benign symptomatic forms less than 5 cm in size. At least, uni- or bilateral adrenalectomy associated with total thyroidectomy is also suggested in case of a polyendocrine syndrome. PMID- 10097461 TI - Patterns of and mechanisms for shock-induced polarization in the heart: a bidomain analysis. AB - This paper examines the combined action of cardiac fiber curvature and transmural fiber rotation in polarizing the myocardium under the conditions of a strong electrical shock. The study utilizes a three-dimensional finite element model and the continuous bidomain representation of cardiac tissue to model steady-state polarization resulting from a defibrillation-strength uniform applied field. Fiber architecture is incorporated in the model via the shape of the heart, an ellipsoid of variable ellipticity index, and via an analytical function, linear or nonlinear, describing the transmural fiber rotation. Analytical estimates and numerical results are provided for the location and shape of the "bulk" polarization (polarization away from the tissue boundaries) as a function of the fiber field, or more specifically, of the conductivity changes in axial and radial direction with respect to the applied electrical field lines. Polarization in the tissue "bulk" is shown to exist only under the condition of unequal anisotropy ratios in the extra- and intracellular spaces. Variations in heart geometry and, thus, fiber curvature, are found to lead to change in location of the zones of significant membrane polarization. The transmural fiber rotation function modulates the transmembrane potential profile in the radial direction. A higher gradient of the transmural transmembrane potential is observed in the presence of fiber rotation as compared to the no rotation case. The analysis presented here is a step forward in understanding the interaction between tissue structure and applied electric field in establishing the pattern of membrane polarization during the initial phase of the defibrillation shock. PMID- 10097462 TI - Visualization of epileptogenic phenomena using cross-correlation analysis: localization of epileptic foci and propagation of epileptiform discharges. AB - The main objectives of the preoperative evaluation of a patient with medically intractable epileptic seizures are localization of the foci and propagation of the epileptiform discharges. Electrocorticographic (ECoG) data of intractable focal epilepsy were analyzed using an AR model, wavelet analysis, and cross correlation analysis. In order to derive the time-shifts, the cross correlations of the epileptiform discharges were calculated between electrodes for every unit of time. Further analyses were made by means of a set of contour maps of the time shifts and sequential two- and three-dimensional visualizations of the time-shift maps in order to localize the epileptic foci and study their propagation process. Two types of foci and propagation were revealed in the results. In the first type, epileptiform discharges were generated at localized focal sites and spread quickly to other sites. In the second type, the foci of epileptiform discharges, which appeared soon after the former bursts, were localized at more than one site, and the discharges tended to spread more slowly. The findings suggest that epileptic phenomena can be caused by at least two kinds of mechanisms in one patient: in the former, the propagation might be mediated through synaptic projections, while in the latter, the extracellular diffusion of an excitatory factor might play an important role. In addition, our newly developed visualization technique for the localization of epileptic foci and the propagation of epileptiform discharges should prove useful in the study of epileptogenesis etiology. PMID- 10097463 TI - Multineuronal spike classification based on multisite electrode recording, whole waveform analysis, and hierarchical clustering. AB - We proposed here a method of multineuronal spike classification based on multisite electrode recording, whole-waveform analysis, and hierarchical clustering for studying correlated activities of adjacent neurons in nervous systems. Multineuronal spikes were recorded with a multisite electrode placed in the hippocampal pyramidal cell layer of anesthetized rats. If the impedance of each electrode site is relatively low and the distance between electrode sites is sufficiently small, a spike generated by a neuron is simultaneously recorded at multielectrode sites with different amplitudes. The covariance between the spike waveform at each electrode site and a template was calculated as a damping factor due to the volume conduction of the spike from the neuron to the electrode site. Calculated damping factors were vectorized and analyzed by hierarchical clustering using a multidimensional statistical test. Since a cluster of damping vectors was shown to correspond to an antidromically identified neuron, spikes of different neurons are classified by referring to the distributions of damping vectors. Errors in damping vector calculation due to partially overlapping spikes were minimized by successively subtracting preceding spikes from raw data. Clustering errors due to complex spike bursts (i.e., spikes with variable amplitudes) were avoided by detecting such bursts and then using only the first spike of a burst for clustering. These special procedures produced better cluster separation than conventional methods, and enabled multiple neuronal spikes to be classified automatically. Waveforms of classified spikes were well superimposed. We concluded that this method is particularly useful for separating the activities of adjacent neurons that fire partially overlapping spikes and/or complex spike bursts. PMID- 10097464 TI - The use of fuzzy integrals and bispectral analysis of the electroencephalogram to predict movement under anesthesia. AB - The objective of this study was to design and evaluate a methodology for estimating the depth of anesthesia in a canine model that integrates electroencephalogram (EEG)-derived autoregressive (AR) parameters, hemodynamic parameters, and the alveolar anesthetic concentration. Using a parameters, and the alveolar anesthetic concentration. Using a parametric approach, two separate AR models of order ten were derived for the EEG, one from the third-order cumulant sequence and the other from the autocorrelation lags of the EEG. Since the anesthetic dose versus depth of anesthesia curve is highly nonlinear, a neural network (NN) was chosen as the basic estimator and a multiple NN approach was conceived which took hemodynamic parameters, EEG derived parameters, and anesthetic concentration as input feature vectors. Since the estimation of the depth of anesthesia involves cognitive as well as statistical uncertainties, a fuzzy integral was used to integrate the individual estimates of the various networks and to arrive at the final estimate of the depth of anesthesia. Data from 11 experiments were used to train the NN's which were then tested on nine other experiments. The fuzzy integral of the individual NN estimates (when tested on 43 feature vectors from seven of the nine test experiments) classified 40 (93%) of them correctly, offering a substantial improvement over the individual NN estimates. PMID- 10097465 TI - Three machine learning techniques for automatic determination of rules to control locomotion. AB - Automatic prediction of gait events (e.g., heel contact, flat foot, initiation of the swing, etc.) and corresponding profiles of the activations of muscles is important for real-time control of locomotion. This paper presents three supervised machine learning (ML) techniques for prediction of the activation patterns of muscles and sensory data, based on the history of sensory data, for walking assisted by a functional electrical stimulation (FES). Those ML's are: 1) a multilayer perceptron with Levenberg-Marquardt modification of backpropagation learning algorithm; 2) an adaptive-network-based fuzzy inference system (ANFIS); and 3) a combination of an entropy minimization type of inductive learning (IL) technique and a radial basis function (RBF) type of artificial neural network with orthogonal least squares learning algorithm. Here we show the prediction of the activation of the knee flexor muscles and the knee joint angle for seven consecutive strides based on the history of the knee joint angle and the ground reaction forces. The data used for training and testing of ML's was obtained from a simulation of walking assisted with an FES system [39]. The ability of generating rules for an FES controller was selected as the most important criterion when comparing the ML's. Other criteria such as generalization of results, computational complexity, and learning rate were also considered. The minimal number of rules and the most explicit and comprehensible rules were obtained by ANFIS. The best generalization was obtained by the IL and RBF network. PMID- 10097466 TI - SVD-based on-line exercise ECG signal orthogonalization. AB - An orthogonalization method to eliminate unwanted signal components in standard 12-lead exercise electrocardiograms (ECG's) is presented in this work. A singular value-decomposition-based algorithm is proposed to decompose the signal into two time-orthogonal subspaces; one containing the ECG and the other containing artifacts like baseline wander and electromyogram. The method makes use of redundancy in 12-lead ECG. The same method is also tested for reconstruction of a completely lost channel. The online implementation of the method is given. It is observed that the first two decomposed channels with highest energy are sufficient to reconstruct the ST-segment and J-point. The dimension of the signal space, on the other hand, does not exceed three. Data from 23 patients, with duration ranging from 9 to 21 min, are used. PMID- 10097467 TI - Observer of the human cardiac sympathetic nerve activity using noncausal blind source separation. AB - We present a novel method for the blind reconstruction of the cardiac sympathetic nerve activity (CSNA) in the low-frequency (LF) band (0.04-0.15 Hz) using only heart rate and arterial blood pressure. The originality of the method consists in the application of blind source separation techniques to obtain an observer of CSNA. We show how this observer can be deduced from a linear model of the cardiovascular system by introduction of the fundamental assumptions about the independence of the cardiac sympathetic an parasympathetic outflow. In cardiovascular applications, the reliability of the observer has been assessed by verification of the fundamental assumption for the given data. A primer qualitative validation has been performed using the muscle sympathetic nerve activity as an indirect indicator of CSNA. Very satisfying and promising results have been obtained. Moreover, we have performed quantitative validations of the observer in various experimental conditions known to elicit selectively cardiac sympathetic or parasympathetic response. The experimental conditions include a supine-to-60 degrees tilt test, indirect sympathetic stimulation/inhibition by medication, and sympathetic stimulation by isometric handgrip. We show that the observer allows to highlight changing levels of the cardiac sympathetic activity in the LF band in all these experimental conditions. PMID- 10097468 TI - Extrinsic Fabry-Perot interferometer for measuring the stiffness of ciliary bundles on hair cells. AB - We have developed an extrinsic Fabry-Perot interferometer (EFPI) to measure displacements of microscopic, living organelles in the inner ear. The EFPI is an optical phase-shifted instrument that can be used to measure nanometer displacements. The instrument transmits a coherent light signal to the end of a single glass optical fiber where the measurement is made. As the coherent light reaches the end of the fiber, part of this incident signal is reflected off the internal face of the fiber end (reference reflection) and part is transmitted through the end of the fiber. This transmitted light travels a short distance and is reflected off the surface whose displacement is to be measured (the target). This sensing reflection then reenters the fiber where it interferes with the reference reflection. The resulting interference signal then travels up the same optical fiber to a detector, where it is converted into a voltage that can be read from an oscilloscope. When the target moves, the phase relation between reference and sensing reflections changes, and the detector receives a modulated signal proportional to the target movement. Reflections of as little as 1% at both the sensor tip and target surfaces produce good results with this system. We use the EFPI in conjunction with fine glass whiskers to measure the stiffness (force per unit deflection) of stereociliary bundles on hair cells of the inner ear. The forces generated are in the tenths of picoNewton range and the displacements are tens of nanometers. Here we describe the EFPI and its development as a method for measuring displacements of microscopic organelles in a fluid medium. We also report experiments to validate the accuracy of the EFPI output and preliminary measurements of ciliary bundle stiffness in the posterior semicircular canal. PMID- 10097469 TI - Strategies to improve electrode positioning and safety in cochlear implants. AB - An injection-molded internal supporting rib has been produced to control the flexibility of silicone rubber encapsulated electrodes designed to electrically stimulate the auditory nerve in human subjects with severe to profound hearing loss. The rib molding dies, and molds for silicone rubber encapsulation of the electrode, were designed and machined using AutoCad and MasterCam software packages in a PC environment. After molding, the prototype plastic ribs were iteratively modified based on observations of the performance of the rib/silicone composite insert in a clear plastic model of the human scala tympani cavity. The rib-based electrodes were reliably inserted farther into these models, required less insertion force and were positioned closer to the target auditory neural elements than currently available cochlear implant electrodes. With further design improvements the injection-molded rib may also function to accurately support metal stimulating contacts and wire leads during assembly to significantly increase the manufacturing efficiency of these devices. This method to reliably control the mechanical properties of miniature implantable devices with multiple electrical leads may be valuable in other areas of biomedical device design. PMID- 10097470 TI - A hybrid inverse approach applied to the design of lumped-element RF coils. AB - A combination of inverse procedures is employed in the design of radio-frequency (RF) coils with specific examples in, but not restricted to, magnetic resonance imaging. The first inverse procedure is the use of functional methods for the optimization of coil characteristics subject to restrictions on the field behavior. Continuous current distributions are derived from analysis of the fields they are required to produce. To make use of these distributions at a desired frequency, the method of moments is applied as a second inverse procedure to a discretized version of the current distribution. The advantage of this hybrid technique is that it provides a computational algorithm for optimization of feeding, tuning, impedance matching and other aspects of RF coil design. A prototype RF coil has been built using the engineering values predicted by the theory. Experimental results including images acquired from the prototype coil are presented. PMID- 10097471 TI - Mean blood velocity measurement with a narrow ultrasound beam and an asymmetric velocity profile. AB - Previous discussions of the measurement of spatial mean blood velocity using Doppler ultrasound with a narrow beam have required the velocity profile in the cross section to be symmetric about the vessel axis. A type of asymmetry is put forward which incurs no error in mean velocity measurement when the beam is directed through the point of maximum velocity. Assuming correct alignment of the beam, errors due to profile asymmetry are, therefore, related to the degree of departure of the asymmetry from this acceptable form. PMID- 10097472 TI - Surgical treatment for hypoplastic left heart syndrome. AB - Once considered a uniformly fatal condition, the outlook for newborns with hypoplastic left heart syndrome has been dramatically improved with either a protocol of staged reconstruction or cardiac transplantation. Currently, a significant shortage of suitable donor hearts restricts the applicability of transplantation for most newborns. At the University of Michigan, we have adopted a policy of staged reconstruction for all patients with hypoplastic left heart syndrome, reserving transplantation only for those unsuitable for reconstructive techniques. Between January 1990 and September 1998, 303 patients underwent the Norwood operation for classic hypoplastic left heart syndrome with an overall hospital survival of 76%. Among patients considered at standard risk, survival was significantly higher (86%) than that for those patients with important risk factors (42%), p = 0.0001. Adverse survival was most strongly associated with significant associated noncardiac congenital conditions (p = 0.008) and severe preoperative obstruction to pulmonary venous return (p = 0.03). Survival following second stage reconstruction with a hemi-Fontan or bidirectional Glenn procedure was 98%. The Fontan procedure has been completed in 117 of these patients with a hospital survival rate of 91%. Survival after the Fontan procedure improved significantly when the second stage of the reconstruction was completed with a hemi-Fontan procedure compared to a bidirectional Glenn, 98% vs 81%, p < .05. Among the patients considered at standard risk, actuarial survival was 70% at 5 years. The largest decrease in survival occurred in the first month of life and late deaths affected primarily those patients in the high risk group. Neurodevelopmental outcome studies demonstrated normal verbal and performance scores in the majority of patients. Among centers utilizing a protocol of transplantation, donor organ shortages have resulted in a mortality of approximately 25% while awaiting transplantation with 5 year survival rates for those actually receiving organs essentially equal to those for staged reconstruction. Staged reconstruction and transplantation have significantly improved the intermediate-term outlook for patients with hypoplastic left heart syndrome. Factors addressing improvements in early first stage survival following the Norwood would be expected to add significantly to an overall improved late outcome. Outcome following cardiac transplantation is limited by donor availability in addition to the late complications of infection, rejection, graft atherosclerosis, and lymphoproliferative disease. PMID- 10097473 TI - Early and mid-term outcomes of cardiac and thoracic aortic surgery in over-75 year-olds with postoperative quality of life assessment. AB - The early and mid-term outcomes of cardiac and thoracic aortic surgery were reviewed in seventy-two consecutive patients aged 75 years and older, together with assessment of postoperative quality of life. Twenty-six patients had ischemic heart disease, twenty had valvular heart disease, one had congenital heart disease, and twenty-five had thoracic aortic aneurysm. Twenty-five (34.7%) required an emergency operation. There were 6 early deaths (8.3%) and 11 late deaths (17.2%), of which the emergency cases had higher mortality of 5 early deaths (20.0%) and 3 late deaths (15.0%). In particular, most cases with a ruptured thoracic aortic aneurysm died eventually from various complications including neurological dysfunction. The others with a non-ruptured aneurysm also had atherosclerotic aortic or arterial lesions which caused a lethal cerebrovascular accident or ischemic heart disease. The quality of life of 51 of 53 survivors was assessed using the Rosser and Watts index being based on disability and distress scores. The response was satisfactory--the disability score was 2.6 +/- 1.9 and the distress score was 1.4 +/- 0.4. The patients with a thoracic aortic aneurysm had worse quality of life scores than those of the ischemic heart disease or valvular heart disease patient-groups because of various perioperative complications. Our experiences demonstrate that the results including the postoperative quality of life following cardiac and aortic surgery in the elderly is satisfactory except for emergency cases. The results would prompt us to operate, if possible, electively in their stable conditions, even on elderly over-75-year-olds. PMID- 10097474 TI - Mitral valve replacement in patients younger than 6 years of age. AB - We present our experience in mitral valve replacement (including left-sided tricuspid valve in corrected transposition) in patients younger than 6 years of age. The long term results were examined with special focus on re-replacement of the valve. Between 1974 and 1995, we performed mitral valve replacement in 14 patients younger than 6 years of age, with no operative mortality. There were 3 late deaths, caused by endocarditis, valve thrombosis, and congestive heart failure, respectively. The five-year-survival rate after primary replacement was 85%, and the ten-year-survival rate was 75%, using Kaplan-Meier analysis. Ten patients (11 occasions) required repeated mitral valve replacements at 2 months to 17 years after the original replacement. The indication for the second or third mitral valve replacement was paravalvular leakage (2 patients), valve thrombosis (1 patient), degeneration in the porcine prosthesis (3 patients), and patient outgrowth of the original small prosthesis (5 patients). Again there was no operative mortality. One patient who suffered from multiple occasions of valve thrombosis died at two years after the second replacement. All patients who had outgrown the prosthetic valve received larger prosthesis at the second replacement than at the primary replacement. The actuarial percentage of freedom from valve-related events at 3 years, 5 years, and at 10 years, was 50%, 37%, and 8%, respectively. CONCLUSIONS: Mitral valve replacement in patients younger than 6 years of age can be performed relatively safely, but meticulous follow-up and appropriate decision making for re-replacement is mandatory for the long-term survival of these patients. PMID- 10097475 TI - Expression of CD10 on lymphoid cells associated with thymoma. AB - BACKGROUND: The thymoma is a mixture, in varying proportions, of epithelial and lymphoid cells. The aim of this study was to detect immature T-lineage components of lymphoid cells infiltrating thymoma tissue. METHODS: Tissue-infiltrating lymphoid cells (N = 10) and normal thymocytes (TC, N = 3) were retrieved from surgical specimens. The surface antigens of these lymphocytes were examined with flow cytometry. RESULTS: CD3 was detected on 48 +/- 19% of tissue-infiltrating lymphoid cells and 66 +/- 16% of TC, while CD19 was expressed on neither. CD4 and CD8 were co-expressed on 70 +/- 21% of Tissue-infiltrating lymphoid cells and 68 +/- 28% of TC. CD10 was expressed on 22 +/- 10% of tissue-infiltrating lymphoid cells, but was not expressed on TC (5 +/- 3%, p = 0.0003). Two-color analysis showed that the CD10+ fraction was weakly stained with CD3. It was also stained with anti-CD38 and anti-CD4, but not with anti-CD34. CONCLUSIONS: Tissue infiltrating lymphoid cells included CD10-positive T-lineage cells. This fraction corresponds to very immature thymocyte subsets. These observations suggest that the epithelial component of a thymoma either inhibits the normal differentiation of T-lineage cells, or attracts immature T-lineage cells of bone-marrow origin. PMID- 10097476 TI - Prognosis of Marfan and non-Marfan patients with cystic medial necrosis of the aorta. AB - The characteristics and prognosis of patients with cystic medial necrosis of the aorta were reviewed. Subjects were 46 patients who underwent aortic and/or aortic valve surgery between August 1965 and October 1994. All had histologically documented cystic medial necrosis including 22 Marfan patients. The patients with Marfan syndrome were substantially younger (median age, 32 vs 50 years; p < 0.05), and experienced annulo-aortic ectasia more frequently {81% (17/22) vs 46% (11/24); p < 0.05} than those without the syndrome. Sixty-eight percent (15/22) of the Marfan patients and 63% (15/24) of the non-Marfan patients experienced complications with aortic dissection, although not to a significant degree. The hospital mortality rate was 14% (3/22) in the Marfan group and 21% (5/24) in the non-Marfan group, which was also not significant. Of the 38 survivors, developments in the health of 37 were completely followed-up until October 1997. The cardiovascular event-free rate for Marfan patients at 10 years (28%) was lower than that for non-Marfan patients (68%, p = 0.057), whereas the actuarial survival rates at 10 years were nearly equal (72% for the Marfan patients and 74% for the non-Marfan patients). Reoperation was the first cardiovascular event in 77% (10/13) of the Marfan patients and in 14% (1/7) of the non-Marfan patients (p < 0.05). Cardiovascular event was the main cause of late death both for Marfan patients (80%; 4/5) and for non-Marfan patients (86%; 6/7). In conclusion, independent of the presence of Marfan syndrome, careful follow-up is necessary for patients with cystic medial necrosis of the aorta to eliminate serious late complications. PMID- 10097477 TI - The effect of fibrin glue on inhibition of pericardial adhesions. AB - The effect of fibrin glue on inhibition of pericardial adhesions was tested using 26 beagle dogs. Dacron patches were sutured to the heart and tincture of iodine was applied to promote adhesions. Fibrin glue (3 ml) was sprayed over the patches in 15 dogs (test group), and was not separated in the remaining 11 dogs (control group). All animals in the test group had minimal adhesions between the pericardium and the epicardium or patched region, and an accumulation of gelatinous material was found in the subpericardial space. Marked fibrosis and a poor demarcation of the subpericardial space were found in the control group. The adhesion score and the visibility of coronary anatomy in the test group were significantly better than in the control group. The tension strength in the test group was significantly less than in the control group. We concluded, therefore, that fibrin glue may also be useful as an adhesion inhibitor. PMID- 10097478 TI - Aortic dissection in an elderly patient with atrial septal defect. AB - We report a case of acute aortic dissection that occurred in the late course of surgically untreated atrial septal defect. A 60-year-old man with acute aortic dissection and atrial septal defect was operated on successfully, and we discuss the causal relationship between these two unusual conditions. PMID- 10097479 TI - Surgical treatment of traumatic aneurysm of the ascending aorta. AB - Traumatic aneurysm of the ascending aorta is a rare event. This case describes a patient with such an aneurysm, resulting from injuries received in a motorcycle accident. The patient was admitted to the emergency room of a local hospital complaining of chest pain, and was subsequently referred to our institution. On admission, a chest x-ray showed mediastinal widening. Computed tomography and aortography revealed an ascending aortic aneurysm and contusion of the upper lobe of the right lung. Due to concerns about bleeding from the lung contusion, surgery was delayed for one week. During surgery, intimal tears were detected at two sites in the ascending aorta. The wall of the ascending aorta was subsequently resected and a prosthetic graft inserted. The postoperative period was uneventful and a postoperative aortogram showed that the graft had molded well. PMID- 10097480 TI - Fontan with pedicled pericardium. AB - Pedicled pericardium is a useful viable material for cardiac surgery. In an adolescent case, the extracardiac lateral tunnel of a Fontan connection was successfully constructed with pedicled pericardium. This procedure is expected to allow the growth of the tunnel and to need no anti-coagulant therapy, while careful long-term follow-up is necessary. PMID- 10097481 TI - Algorithms for resource allocation of substance abuse prevention funds based on social indicators: a case study on state of Florida--Part 3. AB - The purpose of Part 3 is to develop an algorithm for an equitable distribution of state prevention funds to its substate jurisdictions based on the need for prevention services. In this series, the need for prevention services is measured in terms of the existing social indicators observed at the county level. In order to establish a conceptual link as well as the empirical relevance of the selected social indicators as proxy measurements of the estimated need for prevention at the county level, we have employed both concurrent and construct validity tests using the following three constructs as the criterion variables in a multiple regressing setting: 1) county-based composite drug use index score (COMDRUG) measured via the statewide drug survey; 2) county-based proportions of prevention target populations using the conceptual definition advanced by the Institute of Medicine (IOM); and 3) the composite risk factor score (COMRISK) assembled from a list of twenty-two risk and protective factors observed for each county. These constructs were identified previously in Parts 1 and 2. While employing eight social indicators to estimate the overall prevention needs observed at the county level, the social indicators thus selected were able to explain 69 percent of the variations in COMDRUG, 68 percent of the variation in the proportions of students in need of prevention services using IOM definition, and 60 percent of the variation in COMRISK. Following successful validations of the social indicators as viable media with which to estimate county-based prevention needs, the ensuing multiple regression equation is, then, used to build a resource allocation model by determining the proportion of each county's share of the total statewide COMDRUG-predicted from the social indicators and, then, by weighting the latter proportion by the population size of each county under age eighteen. In this way, we have devised county-based Prevention Needs Index (PNI) scores based solely on social indicators. Finally, the county's share of PNI score is computed as a proportion of to the total statewide PNI score. Following this line of algorithm for resource allocation, we were able to develop yet another resource allocation model solely based on social indicators without the benefits of survey data. Comparing the funding results originating from four resource allocation models (i.e., COMDRUG, IOM Definition, COMRISK, and Social Indicators), it has been learned that there is a remarkable similarity from one funding level to another. Since all four schedules of county-based prevention funding levels have shown very high intercorrelations with a range from .9862 to .9993, it has been determined that these schedules are measuring essentially either the same domain or latent domains that are functionally equivalent to one another. Accordingly, no preference is made among the resource allocation models suggested, although it is suggested that the final decision on the level of funding must be based on the selection of the schedule for resource allocation rather than the suggested amount or level of funding computed for each county. PMID- 10097482 TI - Assessment of drug abuse prevention curricula developed at the local level. AB - Public schools are a critical site for drug abuse prevention and education. Although in recent years prevention curriculum developers have been able to identify successful strategies, it is not clear how well these findings have been transferred to local schools. This article reports on a study of schools that have developed their own drug abuse prevention curriculum. The process that these schools used is compared to a model of curriculum development. In general, the process that local schools use is characterized by high levels of involvement by a variety of personnel, low levels of training, little use of resources outside the school corporation, poor training of teachers who will be implementing the curriculum, and little evaluation. Availability of external funds for development from federal or state sources were powerful motivators for curriculum development. Recommendations for changes in professional development and curriculum materials availability are made. PMID- 10097483 TI - Drug prevention with high risk families and young children. AB - The effects of a school and home-based drug prevention program on risk factors for subsequent alcohol, tobacco, and other drug (ATOD) use among children were studied. Data on parent and child risk factors for ATOD use were collected from fifty-six low-income parents and their children, ages four to six years, using a pretest-posttest design. The parent-child intervention was conducted over a two month period. The intervention had no effect on parent or child risk factors. However, the program was favorably received by parents and children. Almost two thirds of the parents at the experimental school were involved in the program. Almost half of the parents had high depressive symptoms. The high rates of ATOD use and depressive symptoms among these parents are cause for concern. PMID- 10097484 TI - Self-efficacy for refusal mediated by outcome expectancies in the prediction of alcohol-dependence amongst young adults. AB - The present study examined the relative importance of outcome expectancies and self-efficacy [1] in the prediction of alcohol dependence [2] and alcohol consumption in a sample of young adult drinkers drawn from a milieu previously reported as supportive of risky drinking. In predicting alcohol dependence, outcome expectancies were found to mediate self-efficacy and the same pattern was found for both males and females. This suggests that male and female drinkers may become more similar as they progress along the drinking continuum from risky drinking to dependent drinking. However, in women, in comparison to men, a greater array of expectancies and self-efficacy scales were found to predict heavy drinking, as measured by quantity and frequency. These results suggest that heavy drinking women are particularly at risk of developing drinking related complications and that preventative education needs to take into account gender differences. PMID- 10097485 TI - Implementation and process evaluation of a school-based drug abuse prevention program: Project Towards No Drug Abuse. AB - The present study provides an implementation, process, and immediate outcomes evaluation of the classroom component of Project Towards No Drug Abuse (TND). This project involves development and evaluation of a school-based drug abuse prevention curriculum for continuation high school youth, who are at relatively high risk for drug abuse. Three randomized conditions were evaluated: a standard care, classroom only, and classroom plus school-as-community. The latter condition was an enhanced school-based condition which involved outside-of classroom meetings and activities. Implementation was high in both program conditions even though this was a higher risk context. Process evaluation data were favorable and did not vary between the two program conditions. Immediate outcomes data (knowledge) was higher in the two program conditions than in the standard care condition. Regarding the classroom program, addition of extra classroom activities does not appear to alter the quality of delivery of the program. PMID- 10097486 TI - A tobacco and alcohol use profile of San Francisco's Chinese community. AB - Relatively little is known about Asian American tobacco and alcohol use patterns. This is particularly true of Chinese living in the United States--either U.S. born or non-U.S.-born Chinese. This article presents data from a research project studying tobacco and alcohol use patterns in San Francisco's Chinese community. Data were secured both from focus groups and a self-report telephone survey of a random sample of 1,808 Chinese residents in San Francisco. This results indicate that the prevalence of both tobacco and alcohol use is lower for San Francisco's Chinese population than for the general population. Moreover, those persons who report smoking tend to be different from those who report consuming alcohol. The study concludes that specific, culturally relevant tobacco and alcohol prevention programs should be designed to better reach this target population. PMID- 10097488 TI - [Biochemical indicators of metabolic disorders in bone tissue. I. Bone resorption]. PMID- 10097487 TI - [Receptor endocytosis of polyenic acids: sensitivity and resistance to atherosclerosis (review of the literature)]. PMID- 10097490 TI - [Assessing the immune status in acute infections: a new methodological approach]. AB - A pathogenetic approach to assessing the immune status of infectious patients is proposed. It consists in detection of the major variants of immune response in this or that infection by the characteristic time course of proliferative activity of phytohemagglutinin-stimulated T lymphocytes. Four similar types of immune response were distinguished in children with acute respiratory viral infection and oropharyngeal diphtheria by this method. These types differ by the intensity of antibody production, production of antigen-specific factors of immune defense (cytokines, immunoglobulins, and complement components), and the clinical symptoms. Antigen-specific profiles of each type of immune response in relation to the balance between two forms of defence, cell-mediated and humoral are described. PMID- 10097489 TI - [Measurement of calcium content in the blood and other biological fluids by Arsenazo III complexone]. AB - A method of photometric measurement of total calcium in the serum and other biological liquids using Arsenazo III color complexone is offered. Physicochemical characteristics of Arsenazo III (mol extinction, affinity for other ions, spectral characteristics, and its complex with calcium) are described. Calcium was measured in 750 normal subjects, its reference value was 2.15-2.75 mmol/liter, the mean value 2.47 mmole/liter. In semiautomated measurement CV% was about 5%. The reagent is convenient, particularly for automated analyzers; no other reagent are needed, it can be stored for a long time at room temperature, and gives stable results. PMID- 10097491 TI - [Non-laboratory causes of erroneous results of laboratory studies]. PMID- 10097492 TI - [Current diagnosis of acute leukemia (lecture)]. PMID- 10097493 TI - [Technology of laboratory studies in emergency states. 2]. PMID- 10097494 TI - [Recommended methods for measuring alkaline phosphatase, lactate dehydrogenase and amylase (recommendations of the Northern Work Group)]. PMID- 10097495 TI - [Our Scandinavian colleagues (Twenty-Sixth Northern Congress on Clinical Chemistry)]. PMID- 10097496 TI - [Status and measures of improvement of laboratory support in diagnosis and treatment of patients at the Public Health Institutions of the Russian Federation]. PMID- 10097497 TI - [Symposium on New Analytical and Diagnostic Technologies in Clinical Laboratories]. PMID- 10097498 TI - [Immune system and immunodeficiency]. PMID- 10097499 TI - [Chronic nonobstructive bronchitis]. PMID- 10097500 TI - [Philosophy in the system of medical education]. PMID- 10097501 TI - [Diagnostic and prognostic aspects of myxoma syndrome]. AB - The analysis is presented of clinicomorphological and laboratory characteristics of myxoma syndrome which are of prognostic value. Early diagnosis of the syndrome is essential in making decision on the intraoperative and long-term postoperative treatment policy. PMID- 10097502 TI - [Study of mineral bone density in patients with SLE using quantitative computer tomography]. PMID- 10097503 TI - [Implication of clinical and morphological types of chronic glomerulonephritis, tubulointerstitial changes in prognosis of disease progression]. AB - A highly significant relationship has been established between rapid progression of chronic glomerulonephritis and belonging to unfavorable category of clinical types according to classification of M. Ya. Ratner et al. (chi-square = 84.3, p < 0.001), to unfavorable category of morphological types (chi-square = 13.2, p < 0.01) and the presence of tubulointerstitial changes (chi-square = 32, p < 0.0001). PMID- 10097504 TI - [Laser therapy and its application in gastroenterology]. PMID- 10097505 TI - [Clinical course of cryptococcosis in HIV infection]. AB - Cryptococcosis was detected in 17% of examines with AIDS. The disease was caused by fungus Cryptococcus neoformans. Most frequently cryptococcosis affected CNS (meningitis and encephalitis). The symptoms were scare and nonspecific, e.g. positive meningitis indicators occurred only in 9% of the patients. Cryptococcosis tends to hematogenic spread with severe dissemination. The diagnosis was made primarily basing on the results of mycological investigations of the biosubstrates, i.e. discovery of Cryptococcus neoformans. PMID- 10097507 TI - [The sixth report of Joint national commission on prevention, detection, assessment and treatment of hypertension]. PMID- 10097506 TI - [Therapy of cardio-neurotic diseases in general practice: clinical experience with atarax]. AB - An open study of efficiency and safety of atarax (hydroxisine) enrolled 55 outpatients (23 males and 32 females, mean age 45.91 +/- 1.91) with generalized anxious and somatoform disorders running as cardioneurosis as well as nosogenic reactions (maladaptation), manifestations of cardiovascular pathology (acute myocardial infarction, angina of effort functional class II-III, postinfarction cardiosclerosis, essential hypertension in 5, 13, 2 and 5 patients, respectively). The patients received atarax for 28 days (daily dose 50 mg). The course was completed in 54 patients. In 47 of them, the overall score value by Hamilton Anxiety Scale dropped by 10 scores, the reduction being more obvious in patients with somatic anxiety. Hydroxysine is well tolerated and safe both in patients with somatic pathology and those with cardiovascular disorders. PMID- 10097508 TI - [Diagnosis and differential diagnosis of bronchial asthma and chronic obstructive bronchitis as see by a general practitioner]. PMID- 10097509 TI - [Risk assessment of dioxins and the effect as the endocrine disrupters]. AB - In 1990, WHO recommended the TDI (Tolerable Daily Intake) of 10 pg/kg bw/day for dioxin. Since then, industrialized countries have set TDIs or exposure limits based on their own evaluation of the exposure levels and the toxicity of dioxin. In Japan, the MHW announced 10 pg TCDD/kg bw/day as the temporary TDI in 1996. WHO reevaluated the TDI in May 1998 and announced the TDI in the range of 1-4 pg TEQ/kg bw/day including coplanar PCBs, which will definitely have a big impact all over the world. Moreover, dioxins, as endocrine disrupting chemicals, are reviewed on their hazards on health and the mechanism of actions. PMID- 10097510 TI - [The utilization and safety of medicinal plants and crude drugs]. AB - Recently, herbal remedy and health caring food are widely used throughout the generation. These main plant materials have been characterized and classified into 5 categories, by the Ministry of Health and Welfare (MHW), Japanese Government, in 1971, which include 3 medicine divisions and 2 food divisions. These categories, having only limited number of plants, were quite difficult to classify the newly imported plant materials. In order to solve this problem, each category was updated to include new herbal materials in March 1998. Kampo medicines are Japanese traditional medicines, which has been used for the patients mostly by doctors of western medicine and 3 kinds of Kampo prescription had been reevaluated by the drug reevaluation system of Japan. But, along with the expanding consumption of the Kampo medicines in the clinical treatments, several side effects of the Kampo medicines has recently been reported by the collection of adverse reaction data of MHW, these side effects are important signals for believing the safety of natural drugs. The chapter I is definition of medicinal plant and crude drugs, and chapter II is reported of WHO guidelines for the traditional medicines. Chapter III is 4 section; 1. safety of the medicinal plants and crude drugs is included the poisonous plant and the side effect of Kampo medicines, 2. the pesticide for the crude drugs in Japanese Pharmacopoeia, 3. limited test of contamination of microorganisms, 4. Identification of medicinal plant names. Chapter IV is the definition of drugs and food. The chapter V is the drugs type materials used in young generation for hallucinogenic or sexual purpose. Chapter VI is the stance to research work for the new drugs from plant gene resources in the world. PMID- 10097511 TI - [Studies on mechanism of drug incorporation into hair]. AB - Drugs and endogenous compounds circulating in the blood are partially incorporated into the growing hair and are retained there for a long time. Therefore, hair analysis has been used as a useful method for detecting and monitoring drugs from days to years after ingestion. Although numerous drugs and metabolites have been detected in hair, many factors are still not cleared on the mechanisms responsible for the incorporation and retention of drugs in hair. In this study, the incorporation mechanisms of drugs from blood into hair were investigated with respect to the contributions of the physicochemical properties of the drugs. The following conclusions were drawn from the results. 1. Drug concentrations in hair were compared to their pharmacokinetic parameters using an animal model, and it was shown that the incorporation of drugs from plasma into hair distinctly depended upon the physicochemical properties of each drug. 2. As an index of facility of incorporation of a drug into hair, Incorporation Rate (ICR) was defined as the ratio of drug concentration in hair to the area under the concentration versus time curve (AUC) in plasma. The effects of structural factors on ICRs were determined using amphetamine analogs, and it was shown that the basicity and lipophilicity affected the drug incorporation into hair. 3. In in vitro experiments, ICRs positively correlated with melanin affinity and lipophilicity. In particular, melanin affinity principally controls the incorporation of basic drugs into hair. 4. In distinguishing legitimate amphetamine--like OTC drug use from illegal amphetamine/methamphetamine use, hair samples were more useful than urine samples due to the easier long term detection of parent drugs or specific metabolites in hair. PMID- 10097512 TI - [Plant defense-related proteins as latex allergens]. AB - Immediate-type allergic reactions to latex products made from natural rubber are called latex allergy. One of the notable features of latex-allergic people is their cross-reactivity to various vegetable foods and pollen. The structurally similar proteins which most kinds of plants potentially induce must be responsible for these cross-reactions. However, the taxonomical dissimilarity among the causative plants has kept us from concrete explanations of such cross reactive allergens. We have speculated that plant defense-related proteins are a possible cause of the latex allergy. The well-known serologic relationships and sequence similarities of these ubiquitous plant proteins can explain the cross reactivity without difficulty. Rubber trees cultured in plantation farms are repeatedly tapped and treated with phytohormones. These stresses would result in the significant induction of defense-related proteins. Indeed, we were able to detect defense-related enzymes in latex extracts. Moreover, three hydrolytic enzymes (beta-1,3-glucanase, chitinase/lysozyme, and carboxylesterase) that are very likely to take a defensive role were specifically recognized by the IgE antibodies of latex-allergic people and atopic patients. These experimental results strongly support our hypothesis. Because of their conserved structures, defense-related proteins should form a family of plant pan-allergens. PMID- 10097513 TI - [Stereoselective epoxidation with bulky dioxiranes generated from substituted cyclohexanones]. AB - Dioxiranes have recently been shown to be important and versatile oxidants, which are generated from potassium monoperoxysulfate (KHSO5) and ketones. Dimethyldioxirane, a dioxirane generated from acetone as a ketone, is particularly useful as an oxidation reagent with a broad scope of synthetic applications. Several papers have been reported about stereoselective epoxidation using dimethyldioxirane. However, there have been only a few examples using dioxiranes generated from other ketones. Dioxiranes derived from sterically hindered ketones are expected to be "bulky oxidant", and to be useful for stereoselective epoxidation. In a CH2Cl2-buffered water (two-phase system) in the presence of phase-transfer agent under neutral condition (pH 7.8) according to the reported procedure, the epoxidations with hindered alpha-substituted cyclohexanones proceeded in very low yields. After a survey of possible conditions we found that basic (pH 11) CH2Cl2-MeOH-buffer system was effective for the epoxidations of olefins with Oxone (active constituent KHSO5) and substituted cyclohexanones. We carried out epoxidation of cyclohexen derivatives with dioxiranes derived from alpha-substituted cyclohexanones in a CH2Cl2-MeOH buffer solvent system at pH 11. High trans selectivities were obtained. Furthermore, according to this method acyclic silyl ethers were stereoselectively oxidized to afford erythro epoxides. PMID- 10097514 TI - [Interindividual differences in efficacy and toxicity induced by therapeutic drugs and xenobiotics in relation to genetic polymorphisms in xenobiotic metabolizing enzymes]. AB - Humans incessantly ingest wide-variety of chemicals through the administration of therapeutic drugs, diets and beverages. Humans are also exposed to environmental mutagens and carcinogens and substances causing endocrine disruption. Metabolism and disposition have been regarded as one of the most important determinants of efficacy and toxicity induced by ingested chemicals, since remarkable individual difference was observed in the plasma concentration and/or urinary excretion after the administration of wide variety of therapeutic drugs such as isoniazid, sulfamethazine, debrisoquin, sparteine, mephenytoin and so on. This variability is resulted from pharmacogenetically regulated difference in the activities of xenobiotic metabolizing enzymes (so called genetic polymorphisms). Polymorphic appearance of xenobiotic metabolism has also been observed with various toxic substances such as ethanol, acetaldehyde, benzene, organic phosphates and environmental mutagens and carcinogens. Enzymes which show genetic polymorphisms include cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, CYP2C19, CYP2D6 and CYP2E1) and phase II drug metabolizing enzymes (arylamine N-acetyltransferases, glutathione S transferases and UDP-glucuronosyl transferases). A number of mutations on the genes encoding polymorphic xenobiotic metabolizing enzymes have been associated with the remarkable individual difference in the metabolism and disposition in vivo. Individuals with distinct alleles of genes which encode defective enzymes have been shown to be at higher risk to toxic side effects by therapeutic drugs and more susceptible to certain malignant diseases. Research has to be conducted for each human race concerning risk assessment of chemicals, since ethnic differences in frequency of distinct alleles of genes encoding xenobiotic metabolizing enzymes are reported. In case of type 1 Crigler-Najjar syndrome causing unconjugated hyperbilirubinemia, complete loss of bilirubin-detoxifing UDP-glucuronosyl transferase has been attributed to nonsense, missense, and/or frameshift mutations that occurred at various sites on UGT1 gene. Thus, genetic polymorphisms of xenobiotic metabolizing enzymes are one of the most important factors influencing efficacy of therapeutic drugs and toxicity by wide-variety of chemicals. PMID- 10097516 TI - [Development of NIHS Information and Computing Infrastructure (NICI)]. AB - We describe the development of NICI, which we extended during June 1996 to May 1998. The direct lines between our Experimental Stations for Medicinal Plants at Tsukuba and Tsukuba Node for Inter Ministry Network, and newly opened Pharmaceuticals and Medical Devices Evaluation Center at Minato-ku and NIHS at Setagaya-ku in Tokyo, were constructed. Although the main frame in NIHS at Setagaya is not different since May 1996, we provided many databases and useful information on Drugs, Foods and Chemicals, constructing the interface between World Wide Web and databases. Our Home Page was timely updated. PMID- 10097515 TI - [Inhibitory effect of green tea infusion of hepatotoxicity]. AB - We first showed a drinking of green tea infusion can inhibit chemically induced possible hepatic tissue damages in animal experiments, although it has been shown that oral administration of green tea extract can inhibit some organ toxicities. In this review, our data are summarized and a possibility of the effectiveness in humans is discussed. Male rats or mice in the series of experiments were given 2% green tea infusion as a drinking water 1 or 2 weeks before the chemical treatment and until the termination. In the study of rats, green tea effectively inhibited the hepatotoxicity induced by a single intraperitoneal injection or by repeated gavage administration of 2-nitropropane, and a single intraperitoneal injection of galactosamine. However, any possible effects were not observed when green tea was given, on the hepatotoxicity by a single or repeated gavage administration of carbon tetrachloride. In the study of mice, green tea inhibited the hepatotoxicity induced by administration of pentachlorophenol in diet. In conclusion, 2% green tea infusion can prevent the hepatotoxicity by at least some chemicals in experimental animals. It is inferred that the amount of green tea taken by animals in this experiment might be equivalent to the daily intake in Japanese general population, by calculation based on the content of epigallocatechin gallate, a major component of green tea, and the species differences between experimental animals and humans, suggesting the preventive effectiveness in humans. PMID- 10097517 TI - [NO2-/NO3- levels in blood and principal organs in rats treated with lipopolysaccharide]. AB - It is well revealed that activation of macrophages stimulated by endotoxin resulted in induction of nitric oxide synthase which catalyze nitric oxide (NO) formation from L-arginine. Consequently, blood concentrations of NO2-/NO3- (NOx-) are shown to increase. We studied on pharmaco/toxicokinetics of NOx- in serum and principal organs in Wistar male rats after i.p. administrations of LPS and NaNO3. The serum levels of NOx- at 1 h and 6 h after nitrate administration (10 mg/kg, i.p.) were 240 and 120 microM, respectively. Tissue levels of NOx- in lung, liver and kidneys were ca.1/2 of the serum level. Those levels in spleen and brain were ca.1/4 and 1/10 of the serum level, respectively. The correlation of NOx- levels in serum and these 5 organ tissues between 1 h and 6 h after administration of nitrate was r = 0.992 suggesting no specific accumulation of NOx- in these organs. The serum level of NOx- at 18 h after LPS treatment (1 mg/kg, i.p.) was 430 microM. The correlation of NOx- levels in serum and 5 organ tissues between LPS and nitrate administrations was shown to be r = 0.851. NOx- levels of serum, lung, kidneys and brain showed good correlation but liver and spleen showed out of the correlation. The liver tissue level of NOx- after LPS treatment was low compared with the expected value from the serum level. The reason may be explained partially by the liver weight increase and the liver toxicity with increased GPT and gamma-GT levels due to LPS. Contrary to this, NOx- level of spleen tissue after LPS treatment was more than 2-fold compared with the expected value from the serum level suggesting NO formation in the spleen. This was supported by the markedly high concentration (73.2 nmol/g tissue) of NO2- in the spleen tissue. NO2- levels in lung (34.5 nmol/g tissue) and brain (14.3) were also found to be significantly high after stimulation with LPS suggesting NO formation in these organs. Increased formation of NO2- in these organs by LPS stimulation suggests the formation of active nitrogen oxides such as N2O3 which is an effective nitrosating agent in non-acidic conditions in vivo. PMID- 10097518 TI - [A 13-week subchronic oral toxicity study of chlorophyll in F344 rats]. AB - A 13-week subchronic toxicity study of chlorophyll (containing 40% oil) was performed in both sexes of F344 rats by feeding of CRF-1 powder diet containing 0, 0.18%, 0.55%, 1.66% and 5%, and vehicle (oil) alone. No animals died during the administration period and no changes in body weights and food intakes were found in any dosed groups. Some hematological, serum biochemical and histopathological changes were observed for the 5%-treated group, but these did not suggest obvious toxicity. These findings indicate that the treatment with 1.66% chlorophyll in diet for 13 weeks does not cause any changes in rats and the 5% feeding is not obviously toxic. PMID- 10097519 TI - [Determination of tocopherols in oils of mixed tocopherol as food additive using reverse-phase high-performance liquid chromatography]. AB - Simultaneous determination of four tocopherols was developed using reverse-phase high-performance chromatography with a mixture of methanol and water (88:12) as a mobile phase. The alpha-, beta-, gamma- and delta-tocopherols in oils of mixed tocopherol as food additive were determined. It is clarified that the proposed method is useful for the quality control of food additive. PMID- 10097520 TI - [Study on evaluating methods for the quality control of glycoprotein products. (II)--Erythropoietin products. Part 2]. AB - Using recombinant human erythropoietin (rh-EPO) from three different sources, the usefulness of HPAEC-PAD (high-pH anion exchange chromatography with pulsed amperometric detection) for evaluation of carbohydrate moieties of rh-EPO products was evaluated. It is well known that in vivo bioactivity and metabolic fate of EPO are dependent on the number of sialic acids and the degree of branching in the carbohydrate moieties. Here we show that HPAEC analysis reveals differences in the number of sialic acids as well as in the structure of desialylated N-glycans among the rh-EPO products. Therefore, HPAEC is useful for evaluation of the quality of rh-EPO products. PMID- 10097521 TI - [A qualitative analytical method for nonpermitted food colors by HPLC]. AB - The Ministry of Health and Welfare has been proposed an analytical method for food colors by HPLC. Conditions in the method and modified conditions of the proposed method were applied for permitted and nonpermitted food colors, and relative retention times were obtained. The relative retention times would be a clue of the confirmation of these nonpermitted colors by other method. PMID- 10097522 TI - [Health and environmental risk assessment of organotin pollution in Japan]. AB - In the course of developing the Concise International Chemical Assessment Document (CICAD) on triphenyltin compounds for the IPCS, the author assessed health and environmental risks paused by major organotin species, i.e., triphenyltin compounds and tributyltin compounds. Organotin has been used widely as biocide in such applications as antifouling paints of boats and for other purposes, until its use was restricted in 1980's after discovery of severe damages on aquatic ecosystem caused by this agent. Among many other deleterious effects of organotin to aquatic species, imposex is one of the most conspicuous effects which is the development of male reproductive organs by female gastropods at concentrations as low as a few ng/l. Although environmental concentrations of organotin have declined as a result of tight regulations, periodical monitoring in these years shows their levels in the water still range several ng/l in Tokyo bay area which are hazardous to certain aquatic lives. Human intake of organotin in foods has been estimated through market basket surveys in Japan which showed intake of triphenyltin or tributyltin compound in 1997 as 2.29 micrograms/day (as tributyltin chloride) and 2.69 micrograms/day (as triphenyltin chloride), respectively. The intake value for tributyltin chloride corresponds to 5.2% of the provisional acceptable daily intake (ADI) estimated for bis(tributyltin) oxide (TBTO) in Japan, and 28.0% of the guidance value suggested in the CICAD draft for TBTO, respectively. The intake value for triphenyltin chloride corresponds to 10.8% of the ADI estimated by the FAO/WHO Joint Meeting on Pesticide Residues. Potential critical effects on human health observed in animal tests are the effects on immune systems and reproduction. Based on this investigation, needs for future research on mechanism of toxicity and further control of risks are discussed. PMID- 10097523 TI - [Preparation of the database and the homepage on chemical accidents relating to health hazard]. AB - We collected the data on accidents due to chemicals occurred in Japan, and prepared the database. We also set up the World Wide Web homepage containing the explanation on accidents due to chemicals and the retrieval page for the database. We designed the retrieval page so that users can search the data from keywords such as chemicals (e.g. chlorine gas, hydrogen sulfide, pesticides), places (e.g. home, factory, vehicles, tank), causes (e.g. reaction, leakage, exhaust gas) and others (e.g. cleaning, painting, transportation). PMID- 10097524 TI - [Dissemination of drug information by the Internet]. AB - We reported a system for dissemination of the drug information and its related subjects through the Internet (Drug Info Guide) in Bull. Natl. Inst. Health Sci. 1996. Since then, further information were added in the system. These include the web site for ICH Guideline in Japanese and English, and Australasian Cochrane Centre mirror site. Furthermore, the titles and their abstracts which were reviewed by Cochrane groups in Cochrane Library were translated in Japanese, and these information together with the search guide for useful resource regarding the drug information were also presented on WWW. PMID- 10097525 TI - [First drafts of the environmental health criteria (EHC) circulated for comments by IPCS in 1997.4-1998.3]. AB - Summaries of the first draft of Environmental Health Criteria (EHC), which were circulated for comments by IPCS in the period of 1997.4-1998.3, are presented. EHC drafts on 7 compounds were received in this period. PMID- 10097526 TI - [Studies on development and improvement of toxicity guidelines conducted at the Biological Safety Research Center]. AB - From FY 1990, studies aimed at development and improvement of toxicity guidelines have been conducted at the Biological Safety Research Center, in collaboration with the Environmental Health Bureau. To date, researches have focused on acute toxicity, antigenicity, reproductive toxicity, immunotoxicity, etc. In this report, brief summary of studies on cytotoxicity, toxicokinetics, neurotoxicity, genetic toxicity and structure-activity relationship performed during FY 1995-97, is presented. PMID- 10097527 TI - [Estimated production by the official inspection of coal-tar dyes (including dye aluminum lakes) in 1997]. AB - The number of official inspection of coal-tar dyes and their lakes from April in 1997 till March in 1998 were 571 in total. The quantity which passed inspection amounted to 160.3 ton in Japan. The production of color in each month was summarised in Table 1, and by each producing company in Table 2. The food coal tar dye produced in the largest quantity was Food Yellow No.4, occupying 39.8% in this period. PMID- 10097528 TI - [Simultaneous analysis and detection of pesticides in fresh fruits and vegetables by HPLC and GC]. AB - A method was established for simultaneous determination of pesticide residue in fresh fruits and vegetables by HPLC and GC. CH3CN extraction/NaCl partiton method was used in order to recover hydrophilic pesticide such as acephate, methamidophos. Dimethoate and methamidophos from okra and DDVP from strawberry were detected by GC. On the other hand confirmation method by GC and GC/MS was studied for peaks detected by HPLC with UV and/or FL detector. OPP, TBZ, imazalil chlorpyrifos etc. in citrus fruits were detected by the proposed method. PMID- 10097529 TI - [Potassium Sucrose Octa Sulfate Reference Standard (Control 961) of National Institute of Health Sciences]. AB - The raw material of potassium sucrose octa sulfate was examined for the preparation of the "Potassium Sucrose Octa Sulfate Reference Standard (Control 961)". Analytical data obtained were as follows: infrared spectrum, the same as that of the Potassium Sucrose Octa Sulfate Reference Standard (Control 901); high performance liquid chromatography, one impurity was detected; water content, 8.1%; assay of sucrose octa sulfate, 99.6%. Based on the above results, the raw material was authorized to be the Potassium Sucrose Octa Sulfate Reference Standard of the National Institute of Health Sciences. PMID- 10097530 TI - [Thrombin Reference Standard (Control 961) of National Institute of Health Sciences]. AB - The "Thrombin Reference Standard (Control 961)" of National Institute of Health Sciences was prepared. The precision of filling into ampoule was about 1% as C.V. The content of a-thrombin was about 87%. The thrombin potency of the standard material was assayed against the Thrombin Reference Standard (Control 8710) according to the method of JP XIII and the potency was 1033 +/- 59 unit/ampoule. From the results, the potency of the proposed material for Thrombin Reference Standard was defined as 1,030 units per ampoule. PMID- 10097531 TI - [Kallidinogenase Reference Standard (Control 971) of National Institute of Health Sciences]. AB - The "Kallidinogenase Reference Standard (Control 971)" of National Institute of Health Sciences was prepared. The kallidinogenase potency of the standard material was assayed against the 2nd Kallidinogenase Reference Standard (Control 854) by the enzyme assay method using H-D-valyl-L-leucyl-L-arginine-p-nitro anilide as the substrate. The potency of the Kallidinogenase Reference Standard material thus obtained was defined as 119 unit per ampoule. PMID- 10097532 TI - [Retinol Acetate Reference Standard (Control 971) and Retinol Palmitate Reference Standard (Control 971) of National Institute of Health Sciences]. AB - The "Retinol Acetate Reference Standard (Control 971)" and "Retinol Palmitate Reference Standard (Control 971)" of National Institute of Health Sciences using the assay of vitamin A ester were prepared. The proposed materials were evaluated in collaboration with four laboratories. Analytical data obtained were as follows. 1) The purities of retinol acetate and retinol palmitate measured by HPLC were 99.9 +/- 0.06% and 94.5 +/- 0.06%, respectively. 2) ultraviolet spectrum of retinol acetate and retinol palmitate showed the lambda max at 326 327 nm. 3) The difference in relative extinction of retinol acetate and retinol palmitate at 300 nm, 310 nm, 320 nm, 330 nm, 340 nm and 350 nm are within the range provided in JPXIII. 4) The contents of retinol acetate and retinol palmitate were 52,000 IU/g and 52,200 IU/g, respectively. Based on the above results, these proposed materials were authorized to be the Reference Standards of the National Institute of Health Sciences. PMID- 10097533 TI - [Cholecalciferol Reference Standard (Control 971) of National Institute of Health Sciences]. AB - The raw material for cholecalciferol was examined for preparation of the "Cholecalciferol Reference Standard (Control 971)". Analytical data obtained were as follows: melting point, 83.8 degrees C; UV and infrared spectra, the same as those for JP Cholecalciferol Reference Standard (Control 945), respectively; specific absorbance at 265 nm, E1 cm 1% = 485; optical rotation, [alpha]D20 = +107.4 degrees; thin-layer chromatography and high-performance liquid chromatography (HPLC), no impurity was detected; assay, 98.9% by HPLC. Based on the above results, the raw material was authorized as the Cholecalciferol Reference Standard (Control 971) of National Institute of Health Science. PMID- 10097534 TI - [Tocopherol Acetate Reference Standard (Control 971) of National Institute of Health Sciences]. AB - The raw material of tocopherol acetate was examined for the preparation of the "Tocopherol Acetate Reference Standard (Control 971)". Analytical data obtained were as follows: infrared spectrum, the same as that of the Tocopherol Acetate Reference Standard (Control 941); specific absorbance, E1 cm 1% (284 nm) = 43.0; thin-layer chromatography, no impurities were detected until 50.0 micrograms of the loaded raw material; high-performance liquid chromatography (HPLC), one impurity was detected and the amount was estimated to be about 0.68%; assay by HPLC, 100.2%. Based on the above results, the raw material was authorized as the Tocopherol Acetate Reference Standard (Control 971) of National Institute of Health Sciences. PMID- 10097535 TI - [Ergocalciferol Reference Standard (Control 971) of National Institute of Health Sciences]. AB - The raw material for ergocalciferol was examined for preparation of the "Ergocalciferol Reference Standard (Control 971)". Analytical data obtained were as follows: melting point, 116.7 degrees C; UV and infrared spectra, the same as those for JP Cholecalciferol Reference Standard; specific absorbance, E1 cm 1% = 461(265 nm); optical rotation, [alpha]D20 = +102.5 degrees; thin-layer chromatography and high-performance liquid chromatography (HPLC), no impurity was detected; assay, 102.4% by HPLC. Based on the above results, the raw material was authorized as the Ergocalciferol Reference Standard (Control 971) of National Institute of Health Sciences. PMID- 10097536 TI - [Thiamine Hydrochloride Solution Reference Standard (Control 971) of National Institute of Health Sciences]. AB - The raw material of thiamine hydrochloride solution was examined for the preparation of the "Thiamine Hydrochloride Solution Reference Standard (Control 971)". Analytical data obtained were as follows: assay by HPLC, 100.8%; spectrophotometric assay, 99.8%. Based on the above results, the raw material was authorized to be the Thiamine Hydrochloride Solution Reference Standard of the National Institute of Health Sciences. PMID- 10097537 TI - [Prednisolone Reference Standard (Control 971) of National Institute of Health Sciences]. AB - The raw material of prednisolone was examined for the preparation of the "Prednisolone Reference Standard (Control 971)". Analytical data obtained were as follows: melting point, 238.4 degrees C (decomposition); infrared spectrum, the same as that of the Prednisolone Reference Standard (Control 911); UV spectrum, lambda max = 243 nm; specific absorbance, E1 cm 1% (243 nm) = 414.8; loss on drying, 0.06%; thin-layer chromatography, one impurity was detected; high performance liquid chromatography (HPLC), 4 to 5 impurities were detected and the total amount was estimated to be about 0.51%; assay by HPLC, 100.6%. Based on the above results, the raw material was authorized as the Prednisolone Reference Standard (Control 971) of National Institute of Health Sciences. PMID- 10097538 TI - [Validation of dissolution testing: evaluation of vibration levels of dissolution apparatuses]. AB - The collaborative study participated by seven laboratories was carried out to develop a dissolution standard for evaluating vibration levels of dissolution apparatuses using enteric-coated granules of cefalexin (EG). Dissolution apparatuses could be divided into two groups according to their vibration levels and the dissolution test results of EG by the rotating basket method at 50 rpm. The critical value of acceleration was about 0.05 m/s2. The upper limit of normal dissolution rates of EG was calculated from the results of the rotating basket method at 50 rpm obtained from low vibration apparatuses. All high vibration apparatuses used in this study were distinguished by the limit from low vibration apparatuses, although most of them were not distinguished by current USP calibrators. These results suggest that EG would be useful as a calibrator for detection of apparatuses on high vibration levels. PMID- 10097539 TI - [Assessment of stability variation among batches, packaging, and formulations- application of matrixing and bracketing]. AB - Assessment of shelf-life equivalence among batches, packaging or formulations of pharmaceutical products, which was based on the range of shelf-life estimates, was proposed as an alternative method to an analysis of variance (ANOVA). The power of this analysis was not significantly affected by assay error, whereas that of ANOVA decreased markedly as assay error increased. Thus, ANOVA exhibites a tendency to overlook the stability variation from stability data of a larger assay error, but this is not the case for the proposed method. PMID- 10097540 TI - [Aristolochic acids in herbal medicines]. AB - Aristolochic acids are nitrophenanthrenes with a carboxylic acid fanction which have been found only among the Aristolochiaceae. In 1993, rapidly progressive interstitial renal fibrosis has been reported in women have been on a slimming regimen including Chinese herbal medicines in Belgium. In Japan, at the Kansai district, several cases of Chinese herbs nephropathy have been reported quite recently. In both cases, aristolochic acids was detected in the Chinese herbal medicines taken by the patients. We have Asiasarum Root, a species of Aristolochiaceae, in Japanese Pharmacopoeia. Therefore, we quantitatively analysed aristolochic acids in these herbal medicines and related plants. PMID- 10097541 TI - [On the "system repeatability" specified in the operating conditions for HPLC assay in JP monographs]. AB - The system repeatability tests in the operating conditions for the HPLC assay by absolute calibration method are specified in 9 monographs in JP13 (Part 1). The reasonableness of the specified system repeatability, expressed in relative standard deviation(%), is discussed in consideration with the specified content and also the probability of Type 1 error(alpha). For simplification, it was assumed that the variance due to the analytical system(sigma s2) is equal to that due to other error sources(sigma e2). Based on the above considerations, it was concluded that the present specification of system repeatability(sigma s) in JP monographs is not always reasonable and some of them should be reexamined following to the described considerations in the text. PMID- 10097542 TI - [Postoperative respiratory management in patients undergoing radical surgery with three fields lymph node dissection for thoracic esophageal cancer: clinical benefits of assisted ventilation with mini-tracheostomy]. AB - The benefits of early extubation and assisted ventilation with mini-tracheostomy and preventive positive pressure ventilation in the early stage after thoracic esophageal cancer operation are examined and compared. Subjects were 23 patients who underwent radical operation for thoracic esophageal cancer in our hospital over a 5 year period. Ten patients (A group) underwent positive pressure ventilation with postoperative intubation for a certain period. Thirteen patients (B group) were extubated the day after operation, then immediately mini tracheostomized, and then intermittent high-frequency jet ventilation during the daytime and pressure controlled ventilation during the nighttime were conducted. There were no differences in background factors between the two groups. The mean period of tracheal intubation was 8.8 days in the A group and 1.6 days in the B group. The mean period of stay in ICU was 13 days in the A group and 7 days in the B group. Both such periods were significantly shorter in the B group than in the A group. Respiratory control by early extubation and mini-tracheostomy after thoracic esophageal cancer operation is considered to have the following two benefits; 1. The method is performed safely, and makes sputum suction easier and assisted respiration conductible. 2. The method reduces the incidence of pulmonary complications and shortens the period of stay in ICU. PMID- 10097543 TI - [Coronary artery bypass surgery in octogenarian]. AB - Between May 1992 and December 1997, 14 parents aged 80 or older underwent CABG with cardiopulmonary bypass. (Group A: mean age 82.1 +/- 1.73). This group was compared with 127 patients aged 70s. (Group B: mean 73.3 +/- 0.70). Left main trunk stenosis was more frequent in group A (p < 0.05), and number of patient who had old myocardial infarction was also frequent (p < 0.05). Emergency operation and preoperative use of intra aortic balloon pump was frequent in group A (p < 0.05). While there was no significant change in the number of graft per patient and used number of internal thoracic artery between the two groups, postoperative complications such as atrial arrhythmia and respiratory failure was appeared more frequently in group A (p < 0.05). The hospital mortality did not differ between the groups (21.4% for group A and 14.2% for group B). In group A, 11 patients are alive without recurrence of angina. In conclusion, while there is many problems pre and post operative term, CABG in over 80 years patients of age was satisfactory result, so we should not exclude octogenarian because of age alone. PMID- 10097544 TI - [Catheter drainage of late cardiac tamponade guided by computed tomography]. AB - Delayed cardiac tamponade is an unusual but serious complication of cardiac surgery. Echocardiography and computed tomography (CT) are well established methods for the detection of pericardial effusions. Catheter insertion guided by CT has been used to accomplish non operative drainage of symptomatic postoperative pericardial effusion in seven cases. These patients were grouped into four types according to distribution of the fluid. General pericardial effusion around the heart is classified as type 1, effusion adjacent to the right side of the heart as type 2 and left side as type 3, effusion localized only at the apex as type 4. CT imaging is useful not only to localize and assess the size of the effusions, but also to select the way of catheter insertion. As the fluid might be trapped in compartments, for instance right-sided or left sided type, investigation of the pericardial spaces is important in planning a catheter pericardiocentesis. PMID- 10097545 TI - [Minimally invasive coronary artery bypass (MIDCAB) for double vessel using Y arterial graft which consists of left internal thoracic artery and right inferior epigastric artery]. AB - MIDCAB is a rapidly evolving technique to revascularize the left anterior descending coronary artery (LAD) with the left internal thoracic artery (LITA). Our case is a 60-year-old female with unstable angina due to restenosis of the proximal LAD following PTCA and proximal stenosis of the large first diagonal branch (D1). She underwent double vessel MIDCAB (LITA-LAD and LITA-RIEA-D1) using Y composite arterial conduit with LITA and right epigastric artery (RIEA), because of chronic renal failure on maintenance hemodialysis. Postoperative course was uneventful and postoperative angiography revealed a patent Y graft. Y graft using IEA appears to be an interesting operative method in double vessel MIDCAB. PMID- 10097546 TI - [A case of Bentall's operation for an 11-year-old patient with Marfan syndrome]. AB - An 11-year-old girl who was diagnosed to have Marfan syndrome in her infancy, visited us with complaints of easy fatigability and chest discomfort. She was pointed out to have acute development of annuloaortic ectasia with severe aortic regurgitation and mild mitral regurgitation. She underwent replacement of the ascending aorta and aortic valve using composite graft with prosthetic valve (Bentall's operation) and circular annuloplasty of the mitral valve. Bentall's operation for infants and children is remarkably rare because in this generation, acute development of aortic dilatation leading rupture and dissection is quite infrequent while main death is caused by mitral regurgitation. PMID- 10097547 TI - [Current appraisal of endoscopic thoracic sympathectomy: results of the national questionnaire surgery]. AB - A questionnaire survey was performed in order to investigate the current status of endoscopic thoracic sympathectomy in Japan. Four hundred and twenty-nine (429) university, national or public hospitals with a minimum of 400 beds were included. A total of 248 of these hospitals responded. Among them 63 (25%) performed this procedure. The total of the cases was 1116. The number of access port and the technique for defunctioning the sympathetic chain were broadly divided into three methods. These methods were equally carried out among the departments. The clinical results were judged as satisfactory in the great majority of patients and the frequency of complications was low. On the other hand, the overall incidence of compensatory sweating remained relatively high and accumulated as the number of cases increased. But the reported frequency differed strikingly from hospital probably for lack of an objective way of quantifying following sympathectomy. Although overall complications were infrequent, the need for conventional thoracotomy to stop bleeding occurred in some cases. Therefore even this simple endoscopic operation demands the utmost surgical care, skill and experience. A few recurrences of preoperative symptoms were seen in the follow-up suggesting that all patients must be continually monitored after the operation. PMID- 10097548 TI - [Effect of compression with aerosolized fibrin sealant on surgical hemostasis]. AB - In order to decrease complications following incomplete hemostasis after surgery, especially in the case of arterial bleeding, we experimentally investigated an effective way of applying fibrin glue as a sealant. Using white rabbits as a model, in which arterial bleeding from the abdominal aorta was induced, fibrin glue and a related hemostatic agent were tested to evaluate the hemostatic effectiveness. Group I (n = 9): Fibrin glue was applied by spraying it on the fingertip and then placing the fingertip on the bleeding part and pressing. Group II (n = 9): Fibrin glue was applied with oxycellulose on the fingertip and then placing the fingertip on the bleeding part and pressing. The results demonstrated that: 1) Although complete hemostasis could not be obtained with finger-pressing alone in 30 second, it could be obtained in 9/9 cases 100%) in Group I but in only 3/9 cases (33%) in Group II. 2) Pressure-resistant force was higher for Group I at an earlier time after hemostasis (p < 0.05). 3) Pathological study reconfirmed the predominance of Group I. We conclude from this study that ideal hemostasis can be obtained with fibrin glue applied simply by spraying it on the fingertip and then placing the fingertip on the bleeding part and pressing. PMID- 10097549 TI - [Results of muscle flap repair for deep mediastinitis and graft patency after coronary artery bypass grafting]. AB - Between 1978 and 1997, 9 patients developed poststernotomy mediastinitis after coronary artery bypass grafting. Four of these patients (group A) were treated with open drainage and mediastinal irrigation or omental transfer. The other 5 patients (group B) were treated with primary wound closure by the technique of muscle flap mobilization. The purpose of this study was to compare the surgical results and graft patency of both groups. The hospital mortality of group A was 100 per cent. All patients in group B survived for 35 months of the mean postoperative periods without complaints. Postoperative coronary angiography revealed the complete graft patency in group B. We conclude that muscle flap mobilization may be a superior measure for the patient survival and graft patency as the treatment of mediastinitis after coronary artery bypass grafting. PMID- 10097550 TI - [A case of an 86-year-old patient treated with thoracoscopic pericardiectomy of recurrent pericardial effusion]. AB - We performed thoracoscopic pericardiectomy to an 86-year-old patient with recurrent pericardial effusion of unknown origin. Etiology of pericardial effusion was established by this procedure. Postoperative course was uneventful. She was discharged within two weeks and has been well 8 months postoperatively. Thoracoscopic surgery is superior to thoracotomy in terms of less invasion and postoperative pain. Thoracoscopic surgery is replacing standard thoracotomy in the management of many thoracic diseases. PMID- 10097551 TI - [Mapping-guided focal cryoablation and endoaneurysmorrhaphy for a case of ischemic ventricular tachycardia with left ventricular aneurysm]. AB - A 74-year-old woman admitted with exertional dyspnea. Echocardiography revealed the giant left ventricular aneurysm. In the hospital course, she fell into sustained monomorphic ventricular tachycardia. Coronary angiogram showed complete obstruction of the LAD. Left ventricular ejection fraction was 20%. The origin of tachycardia seems to be at infero-apicallateral area of LV by electrophysiology study. Because of the failure of RF energy ablation, we planned mapping-guided cryoablation, CABG and endoaneurysmorrhaphy. To prevent air embolism and myocardial ischemic damage for long aortic cross clamp, intraoperative endocardial mapping was carried out on beating heart due to continuous normothermic coronary blood perfusion (300 ml/min) from the aortic root cannula under aortic clamping. Cold crystalloid cardioplegia changed into the root cannula after EPS, focal cryoablation (-100 degrees C) was performed 3 times on cardiac arrest. Sustained VT was not inducible in the following study. CABG and endoaneurysmorrhaphy was performed on repeated cardiac arrest during single aortic clamp. Postoperative course was uneventful, and she discharged 8 weeks after the operation. PMID- 10097552 TI - [A successful surgical case of giant arch aneurysm with severe pulmonary dysfunction and angina pectoris]. AB - A 70-year-old female was admitted to our unit with chief complaints of dyspnea on effort and angina pectoris. She had suffered from chronic bronchitis. Chest CT scan demonstrated a giant arch aneurysm which strongly attached to the left anterior chest wall. Coronary angiogram showed two vessels disease. She successfully underwent coronary artery bypass grafting and total arch replacement under selective cerebral perfusion. She needed long respiratory care because of her pulmonary dysfunction. But she could wean from the ventilator under intensive respiratory care on 46th postoperative days and was discharged on foot. PMID- 10097553 TI - [The effect of milrinone for the shock patients after cardiac surgery]. AB - The effect of milrinone in the 16 postoperative shock patients of cardiovascular surgery was studied. The preoperative hemodynamic status were 12 of cardiogenic shock, 2 cases of chronic heart failure and 2 cases of unstable angina pectoris. The operative procedure were 8 cases of coronary artery bypass grafting, 4 cases of valvular surgery, 2 cases of closure of ventricular septal perforation, 2 cases of Bentall operation and 1 case of ascending aortic replacement. The postoperative hemodynamic status were 15 cases of cardiogenic shock, 10 cases of hemorrhagic shock and 1 case of septic shock. Continuous intravenous infusion of 0.5 microgram/kg/min without initial bolus loading was administered immediately after the entrance of the intensive care unit. Significant increase in the maximum blood pressure 3 hours after the infusion were observed (84 +/- 17 mmHg vs 94 +/- 12, p = 0.033). The maximum blood pressure was increased gradually until 24 hours after the infusion. Significant increase in the peripheral body temperature 3 hours after the infusion were observed (32.5 +/- 2.0 degrees C vs 35.9 +/- 1.1 degrees C, p = 0.001). The difference between the peripheral temperature and the central body temperature diminished until 24 hours after the infusion. No significant change in the central venous pressure, pulmonary arterial pressure, pulmonary and cardiac index wedge pressure were observed. No significant change in the platelet number was observed until 3 days after the infusion. Twenty patients (75%) were discharged. Four hospital deaths included 1 cardiac and 3 septic cause were seen. These data suggest that the administration of milrinone for the shock patients after cardiac surgery showed safe and that the continuous intravenous infusion of 0.5 microgram/kg/min without bolus loading showed effective for the recovery of the peripheral circulation. PMID- 10097554 TI - [Acquired pulmonary stenosis caused by mediastinal mature teratoma: a case report]. AB - A 13-year-old girl was admitted with a sudden onset of chest oppression. Mediastinal teratoma was suspected on chest X-ray and CT scan. A grade 2/6 systolic murmur was heard at the upper left sternal area and cardiac catheterization showed mild pulmonary stenosis. After resection of the tumor, the murmur disappeared and histopathological diagnosis was mature teratoma. This is a rare case report of pulmonary stenosis caused by mediastinal mature teratoma. PMID- 10097555 TI - [Thoraco-abdominal impalement injury with diaphragmatic injury: a case report]. AB - A 60-year-old man was admitted to our hospital because of impalement injury due to traffic accident. Chest X-ray on admission revealed normal lung field. CT scans of the chest and abdomen revealed slight pneumothorax and intra-abdominal organ protruding from abdominal cavity. An emergency operation was performed. Diaphragmatic injury was not detected during the abdominal procedure. On exploring the back wound, we found a laceration of 8 cm in diameter in the diaphragm and repaired it. Impalement injuries which have aspects of both blunt and penetrating trauma are uncommon. Accordingly, wound exploration and debridement of fistulous tract are necessary. In the case of thoraco-abdominal injuries by impalement, one should bear in mind the existence of diaphragmatic injury even with normal diaphragmatic shadow on chest X-ray. PMID- 10097556 TI - [Two surgical cases of intrathoracic lipoma]. AB - We experienced two cases of intrathoracic lipoma arising from the chest wall. The first case was a 55-year-old male, and another case was a 70-year-old female. In the second case, the computed tomography was highly suggestive of a pleural tumor with almost same density as the subcutaneous adipose tissue. This findings may be diagnostic in assessing intrathoracic chest wall type lipoma. Both cases had thoracotomy to remove the tumors. The tumors were easily resectable, though their capsules were partially unclear. We resected the tumors completely together with pleura, periosteum and intercostal muscle. The diagnosis of intramuscular lipoma was confirmed postoperatively by histopathologic examination in each case. When the capsule of lipoma is not clear, combined resection of the tumor and chest wall should be considered. There have been no recurrence of the tumors in our cases. PMID- 10097557 TI - [A case of bronchogenic in situ carcinoma originating in fourth order bronchi]. AB - A case of bronchogenic in situ carcinoma originating in forth order bronchi was reported. Sputum cytology showed class IV in lung cancer mass screening in a 69 year-old male, although X-ray was negative. Bronchofiber scopy was repeated twice, and fine granular change of spur between Blai and ii was found in the second time. Right upper lobectomy was underwent, and post-surgical histology was in situ squamous cell carcinoma. The literature on early lung cancer was reviewed, and implication for management of bronchofiberscopic early lung cancer in general rule for clinical and pathological record of lung cancer was discussed. PMID- 10097558 TI - [Public and occupational health and industrial ecology]. AB - The authors present results of theoretic and experimental analysis of ecologic safety in Russia. New composite discipline--"human ecology"--takes an important place in solution of medical and ecologic problems associated with correlation between natural and occupational factors influencing humans. Present medical, social and ecologic circumstances define the most vital scientific and applied directions covering medical and ecologic humanization of occupational and natural environment for humanity nowadays. Those directions are prophylaxis of ecologic stress, specification of informational technology for medical and occupational monitoring, creation of data bank on human ecology. PMID- 10097559 TI - [Quantitative ranges and methods of evaluation of occupational reliability of aviation specialists]. AB - The authors present concept of occupational reliability of an operating human. The concept is based on systemic approach to analysis of erroneous acts as results of stochasticity of inner human traits and outer interferences. The authors justify universal, systemic criterion to analyze reliability of occupational activities (potential unreliability of acts). The criterion helped to solve practical problems of quantitative evaluation and forecast of outer influence on occupational reliability of a pilot. The criterion is adequate for analysis of "risk-profit" correlation to optimize material expenses among the components of "human-machine" system being under elaboration, preparation and in use. PMID- 10097560 TI - [Methodologic approaches to solving problems concerning development and improvement of means protecting against detrimental ecological factors]. AB - The article covers scientific and applied aspects of ergonomic (physiologic, hygienic, engineering and psychologic) improvement of protective and salvage means for aviation specialists in up-to-date ecologic circumstances. The authors justify and present a concept of higher ergonomic efficiency of those means when exposed to combined hazards. The concept suggests possibility of considerably increased occupational readiness and occupational health in aviation specialists owing to more complete consideration of operator's personal characteristics. PMID- 10097561 TI - [Methodological approaches to quantitative evaluation of the influence of pilot overload on functional durability and occupational health of pilots (basic concepts)]. AB - The article presents various concepts underlying the quantitative methods that assess influence of piloting overload on pilots. The authors also consider principal differences between acute and chronic overload of + Gz direction, its adaptational and cumulative effects. The most important items are based on phasic nature of physiologic response to single and repeated overload of + Gz direction, on a law describing summation of delta-effects caused by various conditions of pilot's occupational activities, considering the risk of disorders determining potential unreliability of pilots in maneuver flight and probability of cumulative effects. The theoretical items are illustrated by some practical examples. PMID- 10097562 TI - [Principles and methods of evaluation of radiation risk and pilots' health in accidents of nuclear power objects]. AB - The article deals with methodic approaches to health state evaluation of pilots who participated in liquidation of events following accidents at nuclear power objects. The main approaches are indeterminancy principle for late radiation effects, economic approach to evaluation of radiation risk, principle of risks comparison, consideration of summarized effect of environmental factors, etc. Some authors' viewpoints are presented. PMID- 10097563 TI - [Functional homology in response of human cardiorespiratory system to effects of hypoxia and hypercapnia under different environmental conditions]. AB - The authors studied physiologic peculiarities associated with cardiorespiratory response to hypoxia and hypercapnia in various climate and geographic conditions, to combined effects of hypoxia, hypercapnia and physical burden, in artificial atmosphere with various velocity of hypoxia and hypercapnia increase. The studies were based on a hypothesis of universal mechanism that describes regulation of gas-transporting system and is aimed to supply oxygen to the body under ecologic hazards. The authors revealed similarity of circulatory and respiratory responses to hypoxia and hypercapnia in various ecologic circumstances. PMID- 10097564 TI - [Need to correct indicators of "physiological norm" in pilots]. AB - Examination including echocardiography and Doppler-cardiography covered 222 pilots and revealed that 27-64% of pilots had reliable cardiodynamic peculiarities, if compared with healthy individuals not involved into piloting. The authors necessitate introducing a concept of "pilot's heart" into medical expert examination for piloting. This concept should be considered a variant of functional adaptational "stress-norm". PMID- 10097565 TI - [Current approaches to the problem of noise as an ecologic factor in aviation medicine]. PMID- 10097566 TI - [Study of skin resorptive effects of solution 7-50C-3]. PMID- 10097567 TI - [Current aspects of vibration disease pathogenesis]. AB - The authors proved impaired venous drainage and lower vascular tone to be among the first signs of vibration disease. Adaptational and trophic disorders, compromised humoral regulation appear to be characteristic for vibration disease and associated with disturbances of sympathetic autonomous system. The experiments diagnosed phases in sympathetic and adrenals response to vibration. Vibration appeared to depress functional activity of "pituitary-gonads" system. PMID- 10097568 TI - [The role of associated factors in the evaluating the effet of local vibration influence]. AB - Present measurement method of local vibration dose and of corresponding factors characterizes degree of unfavorable effects caused by those components in humans rather indistinctly, because of the following reasons: 1) considering muscular efforts put on a vibrating instrument, "vibration-force" complex incompletely accounts static load on flexor muscles of fingers, if those efforts referred to individual functional abilities; 2) work hardiness used in this method sometimes inadequately reflects value of static muscular efforts in "vibration-force" complex; 3) combined effect of cooling microclimate parameters are evaluated, rather inexactly. PMID- 10097569 TI - [Electromyography in the diagnosis of vibration diseases]. AB - A total of 50 vibration disease patients were assessed by stimulation and needle myography. The authors revealed highly diagnostic parameters: wider range of excitation velocity in motor axons of mixed nerves, preferential decrease in minimal motor velocity, lower number of motor units (MU) functioning, denervation changes of MU action potentials, potentials of spontaneous activity of muscular fibers and fasciculations. Distal muscles of limbs demonstrate the most striking changes in electric activity of MU. PMID- 10097571 TI - [Clinical morphological aspects of chronic gastroduodenitis in patients with vibration disease]. AB - The article covers data of endoscopy, histologic and bacteriologic study of gastric lavage in 55 vibration disease patients (random select). Duodenal peptic ulcer was found in 1 patient, gastric polyp--in 1 patient, erosive gastroduodenitis in 14 (25.45%) patients, chronic gastroduodenitis without destruction of mucosa--in 39 (70.91%) patients. Contamination with Helicobacter pylori appeared in 97% of cases, being significant and subject to therapy only in 35.29% of patients. PMID- 10097570 TI - [Ultrasonographic evaluation of major vessels in patients with vibration disease]. AB - Common carotic arteries, odd visceral branches of abdominal aorta were subgected to ultrasound Doppler examination and color duplex ultrasound in 100 vibration disease patients and 57 liquidators of Chernobyl power accident consequences. Stenosis of various degree and thickened vascular wall were revealed in 23.6 +/- 4.5% of vibration disease patients and in 46.2 +/- 7.98% of liquidators (p < 0.05). These data prove that the liquidators being younger (4 years average age difference) than the vibration disease patients demonstrate more significant atherosclerotic changes of vascular wall. PMID- 10097572 TI - [Segmental autonomic nervous system disorders in patients with vibration disease due to local vibration]. AB - Cardiovascular tests in vibraton disease patients revealed failure of efferent vegetative paths. Degree of segmentary neurologic disorders increases as vibration disease progresses. PMID- 10097573 TI - [The health status assessment in miners and metal workers based on immunological and bacteriological criteria]. AB - Immunologic and bacteriologic criteria to evaluate health state in miners and metallurgists are defined. These criteria are specific agglomeration of leukocytes, lysozyme level in saliva, phagocytic activity of neutrophils and parameter of deep skin microbes. These criteria could be recommended as the most informative and simple in mass screening and express evaluation of health state in industrial workers. PMID- 10097574 TI - [The study of ecology-induced pathologies in regions and settlements (analytical review)]. AB - The authors analyze a problem associated with necessity to single ecologically induced disorders out of general mass of diseases. Diagnosis of ecologically induced disorders necessitates use of ecologic and hygienic monitoring systems designed by the authors, examination combined with observation of environmental changes and health state in population, group and organism. PMID- 10097575 TI - [Clinical standards and the role of occupational medical professionals: a foreigner's view of the Russian experience]. PMID- 10097576 TI - [The morphology and constitution-based criteria for the assessment of individual risk for the development of vibration disease]. AB - The authors studied morphologic and constitutional features in individuals with various durability to vibration. Patients fragile to vibration were pectoral and indefinite somatotypes with connective tissue dysplasia and small congenital abnormalities (spondylodysplasia, venous wall deficiency. "dysplastic" heart signs and others). Patients durable to vibration were muscular and abdominal somatotypes with rare connective tissue dysplasia and small congenital abnormalities (2.5-10.2% of cases). Evaluation of morphologic and constitutional characteristics is recommended in preliminary and periodic medical examinations of workers subjected to vibration, for assessment of individual risk degree and differential medical follow-up. PMID- 10097577 TI - [The evaluation of the assessment indices of mental-sensory abilities among managers of Moscow commercial companies]. PMID- 10097578 TI - [The influence of the yttrium high-temperature superconducting ceramics on rats' viscera]. PMID- 10097579 TI - [Economic significance of diabetes in Germany]. PMID- 10097580 TI - [Restless leg syndrome]. PMID- 10097581 TI - [Antibiotics--development and trends. Unwanted aspects of resistance]. PMID- 10097582 TI - [Carbohydrates and ballast material. Potatoes, grains and grain products]. PMID- 10097583 TI - Births, marriages, divorces, and deaths: provisional data for November 1998. PMID- 10097584 TI - The development and clinical feasibility of percutaneous transluminal coronary angioscopy. PMID- 10097585 TI - Effects of temperature and preservation time on the pharmacological response of isolated vascular endothelial and smooth muscle function. AB - In clinical transplantation and cardiovascular surgery, cold preservation is usually used because it is a simple method. However, the established temperature is by no means exact. The aim of this study was to find the optimum storage temperature for preservation of the vasculature by observing the pharmacological endothelium and smooth muscle response. The thoracic aorta of 36 male Wister rats were studied in organ baths: as fresh control after 24 hours, 48 hours and 72 hours of storage at 0.5 degree C, 4 degrees C and 8 degrees C in Krebs-Henseleit bicarbonate (KHB) solution. Acetylcholine (Ach) was used to elicit endothelium dependent relaxation, and sodium nitroprusside (SNP) to elicit smooth muscle dependent relaxation. The contractility caused by Phenylephrine (Ph) was influenced by time but before 48 hours it was not influenced by preservation temperature. Significant responsive deterioration by Ach and SNP was seen after 24 hours of storage at 0.5 degree C as compared with storage at 4 degrees C. The endothelium-dependent relaxing function and smooth muscle-dependent relaxing function were best preserved at 4 degrees C and 8 degrees C. These results indicate that precise temperature control is necessary for vessel preservation in clinical situations. PMID- 10097586 TI - [Induction of noradrenergic supersensitivity following cordotomy in neonatal rat spinal motoneurons]. AB - Patients with spinal cord lesions frequently show autonomic hyperreflexia. The mechanism of autonomic hyperreflexia has been thought to be an acute general autonomic overactivity in response to cutaneous or visceral stimuli, but it remains uncertain. Several kinds of experiments suggest that amplified spinal sympathetic reflexes in the decentralized cord are attributable to the denervation supersensitivity of denervated neurons, which is a well-known phenomenon in denervated muscle fibers. In the present study, changes in the supersensitivity of motoneurons after cordotomy were studied in the spinal cord of neonatal rats. Responses to bath-applied noradrenaline (NA) were recorded from a ventral root of the isolated spinal cord of 6-day-old rats. In normal spinal cords, NA induced depolarization in motoneurons dose-dependently. alpha 1 antagonist prazosin (3 microM) inhibited the deporalization induced by NA, and alpha 2-antagonist rauwolscine (1 microM) potentiated it. In one group of rats, cordotomy was performed 4 days after birth by complete transection of the spinal cord at vertebrate 8th-10th thoracic level, and NA response was examined two days later (when they were 6 days old). In cordotomized rats, NA-induced depolarization was increased with respect to both amplitude and duration. alpha 1 as well as alpha 2-antagonists inhibited the NA response in the spinalized rats. Especially, both antagonists shortened the duration of NA response as compared to normal level. It is concluded that the denervation supersensitivity to NA appears 2 days after cordotomy in the spinal motoneurons of neonatal rats and that the supersensitivity to NA is attributable to the upregulation of both alpha 1- and alpha 2-adrenoceptors on the motoneurons, indicating that a new type of alpha 2 adrenoceptor function appears. PMID- 10097587 TI - Modified Fontan operation. Considerations for the determination of the appropriate procedure. AB - BACKGROUND: Although the surgical results of the modified Fontan operation continues to improve, there are various advantages and disadvantages in terms of the post operative condition associated with the Fontan modifications. Late morbidity and mortality are mainly due to arrhythmias, thromboembolic complications, systemic venous hypertension and infective endocarditis. We reported our experience of the modified Fontan operation to determine an appropriate procedure for each patient. METHODS AND RESULTS: Seven patients (ranging from the age 1-14 years) underwent a modified Fontan operation including a lateral tunnel (n = 1), extracardiac conduit (n = 2) and autogenous atrial tunnel (n = 4). There was one hospital death due to sepsis in which the patient underwent lateral tunnel procedure. The mean follow up of another six patients was 20 months (ranging from 1-39 months) and all patients were classified as NYHA class I, and remained in normal sinus rhythm without any thromboembolic complications. CONCLUSIONS: When using the autogenous atrial tunnel, there are potential advantages; it is not associated with thromboembolism or endocarditis and has growth potential. However, in high-risk patients with increased pulmonary vascular resistance, impaired ventricular function and pre-operative atrial arrhythmias, it appears reasonable to use an extracardiac conduit. PMID- 10097588 TI - Effect of age on urinary excretion of N-acetyl-beta-D-glucosaminidase. AB - To examine the relationship between the concentrations of urinary NAG and age, we measured ratios of urinary N-acetyl-beta-D-glucosaminidase (NAG) to urinary creatinine (NAG index) in 137 healthy subjects, aged from 19 to 88 years. The study is also designed to evaluate the relationship between urinary NAG and blood pressure. The subjects were divided into 7 subgroups, according to their age (< 30, 30-39, 40-49, 50-59, 60-69, 70-79, 80 or more years). There was a positive correlation between NAG index and age (r = 0.36; P < 0.001). The regression equation relating NAG index (y) to age (x) was y = 0.065x + 0.97. The mean NAG indexes for the 7 subgroups divided by age were significantly different (P < 0.01). There was a positive correlation between NAG index and systolic blood pressure (r = 0.18; P < 0.05), but was not between diastolic blood pressure and NAG index. In multiple regression analysis, age and BUN significantly correlated with NAG index (r = 0.32; P < 0.01, r = 3.3; P = 0.07, respectively), although there was no correlation between systolic blood pressure and NAG index. This cross-sectional study showed a clear elevation in NAG index with age. The rate of elevation was 0.65 per decade. Urinary excretion of NAG may be unrelated to blood pressure. PMID- 10097589 TI - Spontaneous gastrointestinal perforation in patients with lymphoma receiving chemotherapy and steroids. Report of three cases. AB - Spontaneous gastrointestinal perforations in three patients with lymphoma were considered to be treatment-related conditions. All three were diagnosed as having malignant lymphoma by histological examination, and treated with chemotherapy and steroids. Four to 14 days after the start of chemotherapy, they complained of abdominal pain and plain roentgenograms revealed pneumoperitoneum. The interval between the onset of peritonitis and operation was almost 24 h. Emergency operations were carried out; one patient with a jejunal perforation underwent resection of the jejunum, another with a gastric perforation received a simple closure with omental patch, and the third with a gastric perforation underwent gastrectomy. Two patients recovered from the surgery, while the gastrectomy patient died due to sepsis. The favorable outcome of the surgical intervention is attributed to early diagnosis, prompt exploration, and selective operative procedures. We recommended a simple closure with omental patch for gastroduodenal perforation. Resection and primary anastomosis are possible only in the small bowel. PMID- 10097590 TI - Fibroin allergy. IgE mediated hypersensitivity to silk suture materials. AB - Delayed-type hypersensitivity with granulomatous lesions to silk sutures is rather rare. Yet, braided silk sutures often act as a non-immunologic foreign body and cause a granulomatous inflammatory reaction years after surgery. We report here a case of recurrent granulomas with remarkable infiltration of eosinophils that may have resulted from an IgE-mediated hypersensitivity reaction to silk fibroin, a component of the braided silk suture. Under normal circumstances exposure to fibroin is rather rare. Therefore, the present patient may have developed this reaction to the silk sutures used in a previous surgery. PMID- 10097591 TI - [In vitro fertilization and embryo transfer. Present and future]. PMID- 10097592 TI - [Clinical features and management of elderly patients with dementia]. PMID- 10097593 TI - [Treatments for vascular dementia and Alzheimer's disease]. PMID- 10097594 TI - [Metastatic brain tumor]. PMID- 10097595 TI - Bone histomorphometrical analysis in patients on long-term dialysis treatment for more than ten years. AB - In Japan there is a steady increase in patients who have been on dialysis therapy for more than 10 years. Bone lesions could emerge as a serious problem during this dialysis period. From 1986 to 1993, bone lesions were examined by histomorphometry of the bone tissues (40 biopsis, 17 autopsies) in fifty seven patients who have undergone a long-term hemodialysis treatment (37 males, 20 females) at Toranomon hospital. Mean age of the patients was 56 +/- 11 (SD) years (range; 22 to 74) and mean dialysis period, 14.5 +/- 11 (SD) years (range; 10 to 28). The results were compared with biochemical and endocrinological data. The subjects were classified into osteitis fibrosa group (33%), osteomalacia group (12%), mixed group (7%) and mild group (48%). Intact parathyroid hormone (PTH) and alkaline phosphatase (Al-P) value were significantly higher in osteitis fibrosa and mixed groups, all cases showing intact-PTH values greater than 500 pg/ml (normal value; 20-53), but not in osteomalcia and mild groups. The analysis of 32 cases with intact-PTH higher than 500 pg/ml showed osteitis fibrosa in 59.4% mixed in 12.5%, osteomalacia in 3.1% and mild in 25%. Aluminum was positive in 41% for osteitis fibrosa, 25% for mixed, 60% for osteomalacia and 52% for mild group. In summary, cases having undergone hemodialysis more than 10 years showed higher frequency of osteitis fibrosa when intact-PTH exceeded 500 pg/ml. Al-P values in such cases were high in association with the intact-PTH values. There was no significant correlation between aluminum deposition and respective bone tissue types. PMID- 10097596 TI - Long-term prognostic factors for chemotherapy of ovarian cancer. AB - Patients with progressive ovarian cancer who underwent a remission-induction therapy in our department; intermittent chemotherapy (IC) of CDDP was performed every 3 months, and good outcome has been obtained. However, ineffective cases are sporadically seen. As long-term prognostic factors influencing the IC, we studied glutathione S-transferase-pi (GST-pi) and silver-binding nucleolar organizer regions (AgNORs), and examined their changes during CDDP therapy immunohistologically to clarify their significance as long-term prognostic factors in CDDP therapy. In 58 patients who underwent postoperative CDDP therapy in the past 15 years, the prevalence of GST-pi was 79.3%, and the rate in the case of clear cell carcinoma was significantly higher than that in the case of serous cystadenocarcinoma. Among 37 patients with progressive ovarian cancer, patients for whom remission-induction was impossible, the prevalence of GST-pi expression and the number of NORs were significantly large. In the comparison between before and after the remission-induction, elevation in the staining score of GST-pi was found in 83.3%, and an increase in NORs number was seen in 50%. On the other hand, in the patients who showed aggravation in the IC group, 5 patients underwent second look operation, and all of them showed elevation in the staining score of GST-pi and 4 of them showed increase in NORs number. Therefore, examination of GST-pi and the number of NORs wes considered to be useful in suggesting prognosis for progressive ovarian cancer, particularly the case having IC. PMID- 10097598 TI - Pulmonary vasoconstriction during lidocaine administration are modulated by endothelium-derived relaxing factor. AB - We examined the role of endothelium-derived relaxing factor (EDRF) in lidocaine induced pulmonary vasoconstriction in experiments using the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA) and EDRF precursor L-arginine in a canine cross-circulation model. The left lower lobe of one dog lung was perfused with venous blood from another dog at a constant rate of flow. Pretreatment of ibuprofen was performed to exclude the effects of vasoactive prostanoids. L-NNA significantly inhibited acetylcholine- and bradykinin-induced pulmonary vasodilation without affecting the vasodilatory responses to isoproterenol in pulmonary vessels preconstricted with thromboxane analogue U46619 or prostaglandin F2 alpha. Pulmonary vasoconstriction by 40 micrograms.ml-1 lidocaine infusion after pretreatment with L-NNA was significantly greater than that before pretreatment with L-NNA, and was reversed to the level present without L-NNA treatment by additional administration of L-arginine. We conclude that lidocaine-induced pulmonary vasoconstriction is modulated by the EDRF/NO pathway in dog lung. PMID- 10097597 TI - Differential apoptotic susceptibility to anti-Fas IgM and anticancer drugs in a human endometrial adenocarcinoma cell line HHUA on laminin and type I collagen. AB - Apoptotic susceptibility of epithelial cells is known to be regulated by cell adhesions to basement membranes. In this study differences in anticancer drug sensitivities of early and advanced endometrial adenocarcinomas were examined by using highly-differentiated human endometrial adenocarcinoma cell line, HHUA, whose apoptotic susceptibility was hypothesized to be modulated by extracellular matrices. The cells express high levels of laminin receptors and laminin suppressed Fas-mediated apoptosis of the cells. However laminin did not show any effect on apoptotic susceptibility to 4 anticancer drugs. These results suggest that there is little variation in drug-sensitivity associated with disruption of endometrial stromal tissue, and that pathological staging of endometrial carcinoma is not likely to have any relation to drug sensitivity. PMID- 10097599 TI - Alteration in the differentiated phenotypes of cultured chondrocytes from human articular cartilage under various culture conditions. AB - Chondrocytes produce proteoglycans and type II collagen as their main matrix components, which can also be considered to be indices of their differentiated phenotype. Each differentiation step occurs in accordance with the environment of each cell. The analysis of the properties of chondrocytes has mostly been performed in cultured cells. In this report, we examined the effects of the culture media and fetal calf serum on cultured human articular chondrocytes. It was confirmed that the quantity of proteoglycan produced by the chondrocytes changed according to the different kinds of media used, and that the molecular size of the proteoglycans showed a tendency towards de-differentiation with decreasing fetal calf serum concentrations. We conclude that our experimental results which are obtained in cultured human articular chondrocytes should be discussed with consideration to the finding of this report. PMID- 10097600 TI - Granuloma formation and in vitro macrophage activation in mice by mycoloyl glycolipids from Nocardia asteroides and related taxa. AB - Cord factor (trehalose 6,6'-dimycolate: TDM) is a well-known toxic glycolipid in Mycobacterium tuberculosis. We isolated various mycoloyl glycolipids from Nocardia asteroides 23,167 and related species which are closely related taxonomically to Mycobacterium. Since Nocardia is also an opportunistic pathogen co-infected with HIV, we examined in vivo granuloma formation and the in vitro macrophage activation in mice. We found that cord factor (TDM) and glucose monomycolate (GM) from Nocardia asteroides and Rhodococcus species with shorter chain mycolic acids also exhibited distinctive granuloma-forming activity in lungs, spleen and liver in mice and in vitro induction of prostaglandin E2 (PGE2) and interleukin 1 (IL-1) synthesis. We also found that mycoloyl glycolipids possessing trehalose or glucose as a carbohydrate moiety exhibited immunomodulatory activity, and that mycoloyl glycolipids with longer chain mycolic acids exhibited stronger activity in mice than did those with shorter chain mycolic acids. The mycoloyl glycolipids from Nocardia asteroides directly activated macrophages. Stimulation of above concentration with 0.16 microgram/ml of TDM or 0.8 microgram/ml of GM markedly enhanced production of PGE2 by mouse peritoneal macrophages. At higher concentrations above 100 micrograms/ml of TDM or 500 micrograms/ml of GM, IL-1 release was also enhanced. PMID- 10097601 TI - Peripheral blood stem cell transplantation for non-Hodgkin's lymphoma in complete remission. AB - High-dose chemotherapy with PBSCT as consolidation therapy was administered to 15 patients with non-Hodgkin's lymphoma admitted to our department between November 1991 and March 1998. The average number of CD34-positive cells harvested was 3.1 x 10(6)/kg and the median time to a granulocyte count above 500/microliter was 12.8 days. Of the patients, one died from cytomegalovirus pneumomonia after WBC count recovered, 2 relapsed, and 12 patients are still alive and disease-free. The average disease-free survival period was 50.0 months. Stem cell harvesting is relatively simple and hematopoietic recovery is mory rapid with PBSCT than with ABMT. Our findings suggest that PBSCT can be used for consolidation therapy in NHL patients who have achieved complete remission with standard chemotherapy. PMID- 10097602 TI - CJC introduces bill as part of three-pronged strategy. PMID- 10097603 TI - Society challenges Medicare policy on admitting privileges. PMID- 10097605 TI - QMBs could face access to care problems due to budget change. PMID- 10097606 TI - Society persuades DPW to alter indemnification clause. PMID- 10097604 TI - Society granted right to challenge Highmark merger. PMID- 10097607 TI - The right to change tracks. PMID- 10097608 TI - Unlocking the door. PMID- 10097609 TI - Dealing with stress in medical practice. PMID- 10097610 TI - [Transmission of binding]. PMID- 10097611 TI - [Transmission of binding over generations--contribution of the Adult Attachment Interview]. AB - A new domain has been established within attachment research that deals with mental representations of attachment in adults, particularly in parents. This contribution describes the procedure of the Adult Attachment Interview (AAI) developed by George et al. (1996) and the scoring and classification system by Main and Goldwyn (1994). This method allow trained coders a reliable classification of different states of mind with respect to attachment based on a content and discourse analysis of the interview transcripts. By means of observational procedure of the Strange Situation for infants and the AAI for the adults, several studies support the assumption of a transmission of attachment relationships from one generation to the next one. These findings reveal that parents with secure autonomous attachment representations predominantly have infants with secure attachment patterns, parents with insecure-dismissing attachment representations mostly have children with an avoidant attachment and parents with insecure-preoccupied representations often have children with an insecure-ambivalent attachment. Less consistent results have been found for the correspondence between parents unresolved attachment status with respect to traumatic experiences and their infants' disoriented/disorganized attachment patterns. A recent study assessing attachment in six year olds revealed as well the transmission from mothers' attachment representations to those of their children for this older age. Since many studies have confirmed the correspondence of parents' and infants' attachment classifications, research interests are now directed towards the mediating processes of transmission. PMID- 10097612 TI - [Contribution of maternal sensitivity in transgenerational promotion of binding quality]. AB - Attachment research revealed evidence for a relationship between the quality of parental attachment representations as assessed with the Adult Attachment Interview and quality of infant's attachment representations using the Ainsworth Strange Situation. Current research indicates that parental sensitivity is one of the main variables connecting the parent's internal attachment representations with the quality of their infants' attachment. Sensitivity is not only operationalized on the behavioral as well as on the representational level, but is particularly operationalized as perspective-taking behavior and reflection. In order to illustrate this position, individual differences of 3 mothers with different attachment representations in the Adult Attachment Interview and their behavior during the Strange Situation are presented. PMID- 10097613 TI - [Transgenerational promotion of binding: correlation between mental binding models of mothers, binding patterns of their infants and perception and behavior of mothers in transition to parenthood]. AB - The Adult Attachment Interview (AAI; George et al. 1996) was conducted with 28 mothers in order to assess their mental representations of attachment 4 years after giving birth to their first child. The interviews were coded and classified according to the method of Main and Goldwyn (1994). Using longitudinal data from the "Heidelberg Study on Transition to Parenthood", a significant correspondence was found between mothers' attachment representations and their childrens' patterns of attachment in the Ainsworth Strange Situation procedure after the first year of life. Additionally, further connections emerged between the mothers' attachment representation, their pre and post natal conceptions of their first child, their early bonding behavior, and their sensitive behavior with their 5-month-old infant in family interactions at home. These findings support the assumption of a transgenerational transmission of attachment quality and moreover indicate the usefulness of the Adult Attachment Interview in German speaking countries, especially for studies on the transition to parenthood. PMID- 10097614 TI - [Transmission of binding by mothers and their children in the preschool age]. AB - A new method is presented in order to assess attachment representations in preschoolers. Using the symbolic medium of doll play and story completions the internal representations of attachment in children beyond infancy can be assessed. Additionally the thesis of transmission of attachment across generations was tested empirically in a sample of 28 German families from middle class socioeconomic background as part of longitudinal study. Transmission of attachment means that parents transmit their different attachment representations to preschool-aged children. Secure and insecure attachment representation in mothers assessed with the Adult Attachment Interview, are associated systematically with their childrens' attachment representations coded from the doll play. In the present study the Adult Attachment Interview was conducted with mothers during the fifth year post delivery. Their first-born children, 17 boys and 11 girls with a mean age of 6;4 years participated in the story completion session. Using a two-fold distinction (secure and insecure) as well as a converted 4-level scale of attachment security, results revealed a correspondence between maternal and child attachment representations. According to psychometric indicaters the story completion procedure demonstrates satisfying reliability and convergent validity with the Separation Anxiety Test. Finally, reasons for the high match of mothers' and childrens' attachment representations are discussed. Maternal sensitive behavior, maternal reflection of their own childhood triggered by the observation of their own child, and various learning processes may operate as mediating factors in this case. PMID- 10097615 TI - Stability and folding of domain proteins. PMID- 10097616 TI - Ab initio characterization of building units in peptides and proteins. PMID- 10097617 TI - COOP Charts in French: translation and preliminary data on instrument properties. AB - This paper describes the procedure used to translate the COOP Charts into French and provides preliminary information on the instrument's acceptability, reliability and validity. The charts were translated in several steps: seven initial translations were combined into a first pilot version, which was then tested for acceptability, clarity and alternative wordings in two convenience samples taken from the general population (n = 53). The modified version was then reviewed by a lay panel and another translator and submitted by mail to 209 congress participants to test several construct validity hypotheses through known groups comparisons. A panel of public health professionals discussed the content validity of the charts. Finally, test-retest reliability and concurrent validity with SF-36 Health Survey scores were examined among 65 patients with end-stage renal disease. The translation process identified a wide variability in translation options for several items. The acceptability of the charts was excellent. The test-retest correlations ranged from 0.60 to 0.87. Content validity appeared to be appropriate, except for the chart on 'social support', which combines the questions of need and availability of social support. The utility of illustrations was questioned by some respondents: many claimed not to have used the illustrations in selecting their response, while others found them to be not expressive enough. Most preliminary tests of construct validity were consistent with theory. This French translation of the COOP Charts appears to be ready for more extensive testing in the intended target population of ambulatory patients. PMID- 10097618 TI - Development and preliminary validation of the multiattribute Rhinitis Symptom Utility Index. AB - The Rhinitis Symptom Utility Index (RSUI) was developed as a preference-based measure of rhinitis symptoms. The RSUI consist of ten questions on the severity and frequency of stuffy or blocked nose, runny nose, sneezing, itching, watery eyes and itching nose or throat over a 14 day period. A cross-sectional survey of 100 adults with allergic rhinitis was completed, with data collected on rhinitis history and severity, physician-rated rhinitis severity, the Rhinitis Quality of Life Questionnaire (RQLQ) and the Health Utilities Index Mark 2 (HUI2). The mean age of the patients was 37 +/- 11 years and 60% were female and 38% had a diagnosis of asthma. A multiplicative multiattribute utility function was developed from patient-derived preferences for different rhinitis-related symptom states. The mean RSUI score for this sample was 0.72 +/- 0.23, with a range of 0.15-1.0. Two week reproducibility of the RSUI was weak (ICC = 0.40). The index differentiated patients by physician-rated severity (p < 0.05) and was correlated 0.35 (p < 0.001) with the HUI2 and -0.67 (p < 0.001) with the RQLQ total score. The RSUI is brief and easy to administer and the results of this study support its reliability and validity. The modest reproducibility reflects the day to day variability of rhinitis. The RSUI may be a useful patient outcome for clinical trials and for cost-effectiveness studies comparing medical treatments for rhinitis. PMID- 10097619 TI - Predicting patients' utilities from quality of life items: an improved scoring system for the UBQ-H. AB - The Utility-based Quality of Life--Heart Questionnaire (UBQ-H) is a cardiovascular extension of the Health Measurement Questionnaire. It is a multidimensional instrument that can be scored to yield a utility estimate using the Rosser Index and a classification algorithm developed for the Health Measurement Questionnaire. The aim of this study was to employ a statistical modelling approach to devise an improved scoring system. A sample of 201 cardiovascular patients completed the UBQ-H and assessed the utility of their own health state using standard gamble and time trade-off questions in an interview. Two new scoring methods were devised by regressing the UBQ-H data against patients' self-assessed utilities. The new methods gave utility estimates that correlated with angina/dyspnoea grades, life satisfaction scores and General Health Questionnaire (GHQ) scores. In a second sample of 1,112 cardiovascular patients, the UBQ-H utilities were able to distinguish between patients who had/had not experienced an adverse event (e.g. myocardial infarction) and were responsive to changes in health over time. The new scoring methods were not particularly more sensitive to quality of life effects than the original method based on the Rosser Index. However, they produced significantly lower estimates and more accurately reflected patients' self-assessed utilities. PMID- 10097620 TI - Correlates of health-related quality of life in upper aerodigestive tract cancer patients. AB - Reflecting a limited understanding of the definition and determinants of health related quality of life (HRQoL), the majority of research in this field has concentrated upon the effect of disease- and treatment-related variables. That work specifically investigating HRQoL among upper aerodigestive tract (UADT) cancer patients is no exception to this observation. Treating subject-related and non-subject-related variables separately, the aim of this study was to investigate predictors of global HRQoL rating in a sample of UADT cancer patients, concentrating upon the relative importance of sociodemographic and clinical variables. A cross-sectional study design was used with a sample of 188 UADT cancer patients. Global HRQoL was assessed using the EORTC QLQ-C30 instrument, global domain (global QoL). Other study variables were collected by subject interview and chart review. Two multivariate regression models were independently developed, containing, respectively, subject-rated and non-subject rated variables. In the model containing subject-rated predictors of global QoL, emotional, breathing, physical, financial, pain and appetite problems were significant predictors (F = 14.6, p < 0.0001 and r2 = 0.54). Among non-subject rated sociodemographic and clinical variables tested, unemployment, older age, female gender, being dentate and a more advanced disease stage predicted worse global QoL rating, while oral as opposed to pharyngeal or laryngeal cancer predicted a better global QoL rating (F = 5.1, p < 0.0001 and r2 = 0.21). In the latter model, a greater proportion of the variance was explained by sociodemographic variables than by clinical variables. PMID- 10097621 TI - Responsiveness of the Dermatology-specific Quality of Life (DSQL) instrument to treatment for acne vulgaris in a placebo-controlled clinical trial. AB - The Dermatology-specific Quality of Life (DSQL) instrument is a new tool which has been developed to address the effects of skin disease and its treatment on physical and social functioning and self-perceptions. Previous reports have demonstrated its cross-sectional validity. The current study examines the DSQL's responsiveness to 12 weeks of acne treatment in a placebo-controlled randomized clinical trial. The DSQL change scores were moderately correlated (r = 0.18 to 0.37) with treatment efficacy parameters including: dermatologist's rating of improvement of acne and a skin irritation score, and highly correlated with patient's global rating of acne severity. Within treatment groups, the DSQL discriminated clinically meaningful changes associated with small and moderate effect sizes. The DSQL total score showed statistically significant differences on nearly all comparisons with placebo. The DSQL dimension scores were sensitive to the most effective therapy compared to placebo. Responsiveness benchmarks are provided for small and moderatesized treatment effects. As a comprehensive instrument, the DSQL is a practical and psychometrically sound tool for use in clinical trials in dermatology. PMID- 10097623 TI - Quality of life among diabetic patients in Swedish primary health care and in the general population: comparison between 1992 and 1995. AB - To assess change over time in health-related quality of life (HRQoL) in diabetic patients in primary health care and differences to general Swedish population samples, 341 diabetic subjects in 1992 and 413 in 1995, aged 20-84 years, were chosen from three community health centres (CHCs) in the Metropolitan Stockholm area and compared to controls matched by age and sex in randomly selected samples of 2,366 subjects in 1991 and 2,500 in 1995 from the general population. HRQoL was assessed by the Swedish Health-Related Quality of Life Survey (SWED-QUAL), adapted from the Medical Outcomes Study, which measures aspects of physical, mental, social and general health in 13 scales. Information on diabetic and general medical data were extracted from the medical records at the CHCs. HRQoL was lower in diabetic subjects compared with the general population in both 1992 and 1995 in all scales except family functioning and marital functioning. The level of HRQoL did not change significantly between the diabetic samples, but decreased in the population samples, making the difference compared to diabetic patients smaller in five of the scales. The most significant predicting factors for the SWED-QUAL results in diabetic patients in 1995 were the vascular and non vascular co-morbidity. PMID- 10097622 TI - Social networks, stress and health-related quality of life. AB - Although evidence suggests that social networks reduce the risk of mortality and are negatively associated with severe mental disability, little is known about their relationship to everyday functioning and health-related quality of life (HRQoL). In addition, the importance of social networks in the presence of chronic stress remains unclear. We examined the association between social networks and aspects of mental functioning (mental health, vitality and role emotional functioning) and the relationship between social networks and mental functioning in the presence of stressors. Multiple linear and logistic regression models were used to examine data in 47,912 middle-aged and older healthy women. The Medical Outcomes Study Shortform Health Survey measured dimensions of quality of life. We observed strong associations between levels of social networks and multivariate-adjusted quality of life scores, particularly in potentially high stress situations. Compared to the most socially integrated, women who were socially isolated had reductions in mental health and vitality scores of 6.5 and 7.4 points, respectively and a 60% increased risk of limitation in role-emotional functioning. Social networks are positively associated with mental functioning in women. This association is strongest for women reporting high levels of home and work stressors. PMID- 10097625 TI - [Primary preventive medicine and laboratory medicine]. AB - Nutrition plays an important role in the primary preventive medicine. In 1999, we have introduced the Dietary Reference Intakes (DRI) established by the National Academy of Sciences of U.S. into Recommended Dietary Allowances (RDAs) for the Japanese population. Where, reference intervals for the concentration of nutrient in blood are required in setting an Adequate Intakes (AI). For vitamins, also the AI is experimentally determined based on the reference intervals of healthy people, and the assessment of the nutritional status by laboratory investigations is an important part of preventive medicine. In 1997, we founded the Japan Committee for Vitamin Laboratory Standards and standardized whole blood vitamin B1 levels using HPLC method. Reference intervals for vitamin A, vitamin C and vitamin E might be presented in future report. We annually examined 15,000 participants in national nutrition survey. We proposed a use of results of this research for setting AI of vitamins. Genetic investigation should be introduced in future primary preventive medicine, and stress markers such as "biopyrrin" for oxidative stress, uropepsin, and urinary 17KS-S seems to be very important for medical examination. PMID- 10097624 TI - The problem of measuring change in individual health-related quality of life by postal questionnaire: use of the patient-generated index in a disabled population. AB - The Patient-generated Index (PGI) is a health-related quality of life (HRQoL) measure which asks respondents to nominate the areas of their lives which are most affected by their health condition, so that they can then rate the severity of the effects and weight their relative importance. It is unusual amongst such measures in that it is designed for postal administration. This study assessed the ability of the revised PGI to measure change in HRQoL in a population of 161 people who had previously been identified as having limiting long-term illness. A questionnaire, including a revised version of the PGI and the developmental version of the SF-36, was mailed at two time points (T1 and T2), 4.5 months apart. The PGI was subsequently assessed in terms of practicality, validity, reliability and responsiveness. At T1, 62% of those who felt that they still had a health problem affecting their life completed the PGI correctly. These people were significantly younger and had spent longer in education than the remaining 38%. Only 19 respondents completed the PGI correctly on both occasions, rendering reliability and responsiveness testing inconclusive. The value of the PGI is significantly diminished by the fact that many people cannot complete it correctly. Future development of the instrument is appraised in the context of related measurement methods. PMID- 10097627 TI - [Clinical computer applications in the radiology department]. AB - The information society is currently developing. In the field of radiology, the PACS (picture archiving and communication system) and teleradiology are widely employed in medical practice. The Ministry of Health and Welfare (MHW) reported that physicians should consider some problems in Telemedicine in December 1997. The technology of storage media is improving and we encourage the standardization of data formatting and the transmission protocol to utilize medical electronic information. Several standards exist in the medical imaging field, the DICOM (digital imaging and communications in medicine) standard, the IS&C (image save and carry) standard and the Common Standard that the Medical Information System Development Center (MEDIS-DC) defined for the electronic storage. The PACS requires high transmission speed, integrated services digital network and an asynchronous transfer mode switching system. The MHW needed a technical requirement for the electronic image storage without films in March 1994. The requirement was divided into three parts, (1) security, (2) long-term reproducibility, (3) common usage. The MEDIS-DC published the Common Standards for electronic storage in 1996. When we use the PACS via network, we must consider the security. The present network may have low security, and falsification, such as illegal login may occur. In the future, these problems will be solved, and the network-wide PACS will likely become a commonly used system. PMID- 10097628 TI - [The use of computers and networking in the neurosurgical field]. AB - Due to the improvements in computer and network technology, we are able to use medical information easily and safely on the network in medical institutions. In our department, we constructed and used an original Intranet with light fibers. The network links the outpatient room, ward, operation room, staff room and the examination room. Moreover, many computers and medical instruments are connected to the Intranet. Since our original Intranet has no connection with the outside network, we are able to access the patient's medical information safely. Using access management of identity and a password on the server, the client can present the medical information with sound and movie upon request of the patients and their families, medical students, nurses and doctors. Doctors can also search and input the patient's most recent medical information on a network database of every client. By linking the examination machine and operation aided instrument to the Intranet, we were able to forward the patient's medical information to the operation aided instrument easily and quickly. Furthermore, we will be able to perform tele-medicine and tele-operation in the near future: that is, the medical staff can guide the neurosurgical operation outside of the operation room with a microscope and computer view using picture mutual communication devices. By strict access to the management of our Intranet, we are able to use the medical information effectively for patient's treatment, operation, education and study on the network with no connection to the outside network. PMID- 10097629 TI - [Expert systems and automatic diagnostic systems in histopathology--a review]. AB - In this decade, the pathological information system has gradually been settled in many hospitals in Japan. Pathological reports and images are now digitized and managed in the database, and are referred by clinicians at the peripherals. Tele pathology is also developing; and its users are increasing. However, in many occasions, the problem solving in diagnostic pathology is completely dependent on the solo-pathologist. Considering the need for timely and efficient supports to the solo-pathologist, I reviewed the papers on the knowledge-based interactive expert systems. The interpretations of the histopathological images are dependent on the pathologist, and these expert systems have been evaluated as "educational". With the view of the success in the cytological screening, the development of "image-analysis-based" automatic "histopathological image" classifier has been on ongoing challenges. Our 3 years experience of the development of the pathological image classifier using the artificial neural networks technology is briefly presented. This classifier provides us a "fitting rate" for the individual diagnostic pattern of the breast tumors, such as "fibroadenoma pattern". The diagnosis assisting system with computer technology should provide pathologists, especially solo-pathologists, a useful tool for the quality assurance and improvement of pathological diagnosis. PMID- 10097630 TI - [The state of the art of the computer applications in clinical laboratory medicine]. AB - For all kinds of purposes, a huge amount of data are processed at a clinical laboratory, including not only letters and numerical values, but also waves and graphics. So various computer applications have been developed for it, although only a small part of them has survived through severe use in practice. They have to cope with many exceptions that will occur at any time, and also to adapt progressive changes in medicine and in needs to medicine, otherwise they cannot increase the productivity of their users, rather they will decrease it. To avoid such failures, (1) one should make a comprehensive system analysis before planning, (2) one should understand completely what will happen at the user interface of the system, (3) one should make systems so flexible that they can adapt the alteration of needs of their users. This paper present some outstanding examples that are used or are going to be used successfully in each practical application of laboratory medicine, and point out the key factors of each success. PMID- 10097631 TI - [Effect of macro-creatine kinase in serum on dry chemistry methods results for total creatine kinase activity]. AB - Most enzymes in serum that are measured in clinical laboratories can occur in macro-molecular forms in a significantly number of patients. Within dry chemistry (DC) multilayer film, physical barriers may prevent contact macro-molecular enzyme forms with the active reagent ingredients. Here, serum samples with macro creatine kinase (macro-CK) type 1: CK-immunoglobulin complex or type 2: oligomer mitochondrial CK (CKm) were analyzed for total CK activity on three different DC analyzers: VITROS 700XR, FUJIDRYCHEM 5000, SPOTCHEM SP4410 and a classic wet chemistry (WC) analyzer: HITACHI 7350. Macro-CKs were detected and identified by electrophoresis on cellulose acetate. Serum with high amounts of oligomer CKm gave CK values by all of DC methods significantly lower than that by the WC method (p < 0.05). Oligomer CKm gradually converts into monomer forms in serum after storage. With increase in day after storage at 4 degrees C, there was a gradual shift in which percent of total CK activity for oligomer CKm decreased while the ratio of total CK activity, DC method/WC method increased. The principle of analytical method for CK activity determination is commonly to all of the DC methods, the WC method and the electrophoretic analysis. These suggest that oligomer CKm is sieved by DC multilayer film elements. In contrast, each of DC method produced highly corrected CK activities for sample containing CK immunoglobulin complex. This difference in the effects of macro-CKs may depend upon physicochemical characteristics of analytical DC elements. PMID- 10097632 TI - [Influence of abnormal structure beta chain of luteinizing hormone on endocrinological kinetics of luteinizing hormone and gynecologic diseases]. AB - With recent progress in endocrinology and in procreation physiology, the importance of kinetics of pituitary gonadotropin has been increasing, and the measurement method has been improved. In the present study, however, we found inconsistency in measured LH values between IRMA (SPAC-S LH) as the conventional method and CLEIA (IMMULYZE LH) as the newly developed method. The inconsistency between the SPAC-S LH value and the IMMULYZE LH value was observed in 10.0% of the healthy group and in 12.5% of the patient group. The cause of this discrepancy was due to a reaction of the SPAC-S LH of the intact LH monoclonal antibodies to the LH with the abnormal structure beta chain by two point mutation in the LH beta gene. The response of LH-RH test varied depending on the measurement reagent of LH in patients who had the LH with the abnormal structure beta chain, which made it difficult to determine the lesion and histological grading regarding the ovulation mechanism. Therefore, in patients with abnormal beta chain, an accurate treatment protocol was indeterminate. In this study, although a relationship between various gynecological diseases and the point mutation of LH was not clarified, we suggest that LH of the abnormal structure beta chain may cause excessive secretion in the early stage, and lead to some effect on physical activities. PMID- 10097633 TI - [Complement activation in citrate plasma--inhibitory effect of anticoagulants on serum complement activation]. AB - It is generally accepted that complement activation does not proceed in EDTA- and citrate-plasma because of calcium chelation by EDTA and citrate. However, there were several cases with low CH50 level in serum and citrate plasma and normal CH50 level in EDTA plasma, suggesting that complement might be activated in citrate-plasma but not in EDTA-plasma. The present study deals with the inhibitory effect of EDTA and citrate on complement activation. CH50 was assayed in serum or plasma containing various concentrations of EDTA or citrate after incubation with latex particles bearing immunoglobulin. It was revealed that complement activation proceeded in the presence of 2.0 mmol/l of EDTA but was inhibited in the presence of 2.5 mmol/l of EDTA, while blood coagulation was inhibited in plasma containing EDTA higher than 2.0 mmol/l. As to citrate, complement activation proceeded in the presence of 25 mmol/l of citrate but was inhibited in the presence of 50 mmol/l of citrate, while blood coagulation was inhibited in plasma containing citrate higher than 6.2 mmol/l. Thus, it was indicated that, as usual plasma in clinic contains 3.5 mmol/l of EDTA or 10.9 mmol/l of citrate, complement can be activated in citrate-plasma but not in EDTA plasma. Similar conclusion was obtained by another experiment using ordinary vacuum-type blood collection tube for EDTA-2K plasma, EDTA-2Na plasma and citrate plasma. PMID- 10097634 TI - [Estimation of healthy reference intervals for elderly people through the use of outpatient data]. AB - It is important to determine transferable reference intervals as well as uniformity in measured values for inter-regional and inter-institutional availability of clinical test results. For that purpose, the National Committee for Clinical Laboratory Standards (NCCLS) issued forth guidelines in 1995. Some regional institutions in Japan are making efforts to determine normal reference intervals based on these guidelines. We, the Fukuoka Five Hospitals Group, have selected 3,375 healthy reference individuals and have determined the normal reference intervals for the age groups of 20-29, 30-39, 40-49, and 50-59 years old. The rapidly increasing percentage of elderly people gives rise to ever increasing health-care needs for the elderly, which requires normal reference intervals for older age groups. However, we were unable to collect the required number of the reference individuals above 60 years of age. To obtain reference intervals with adequate reliability and usefulness temporally, we made use of the laboratory data of outpatients at Kyushu University Hospital, and were then easily able to collect the required number of elderly individuals. By performing a very simple selection from among the outpatients, our outpatient group became virtually indistinguishable from the group of healthy reference individuals established by us, with regard to many clinical tests, thus enabling us to estimate reference intervals for older age groups. This approach could be adopted in other regions. PMID- 10097635 TI - [Antimicrobial susceptibility testing for Mycobacterium tuberculosis by measuring mycobacterial adenosine triphosphate]. AB - The antimicrobial susceptibility test for Mycobacterium tuberculosis H37Rv and 43 clinical isolates was performed using a bioluminescence assay by measuring the content of adenosine triphosphate (ATP) derived from mycobacteria. The drugs tested were isoniazid (INH), rifampicin (RFP), ethambutol (EB), streptomycin (SM), and kanamycin (KM). The ATP contents of M. tuberculosis incubated in the Middle-brook 7H9 broth medium containing antituberculous agents were measured at days of 0, 1, 3, 5, 7 and 10. A reduction of ATP content, indicating growth inhibition, was observed in susceptible strains within 5 to 10 days of incubation. Optimal concentrations to distinguish between susceptible and resistant strains were determined as being INH 0.20, RFP 0.50, EB 5.0, SM 4.0, KM 6.0 g/ml. The agreements of ATP method (evaluated at 10 days) with Vite Spectrum and MIC determinations were 81.4% and 100%, respectively. Susceptibilities to most drugs, except for EB, could be determined within 7 days. This method is simple, rapid, nonradiometric, and can be used for drug susceptibility. PMID- 10097636 TI - [A case-study in bed-side teaching of clinical laboratory medicine]. AB - In Akita Medical School, a new curriculum on clinical undergraduate education has started since June 1997. The Department of Clinical and Laboratory Medicine had two-weeks practice by small groups of medical students. We introduced a case study in the practice with a general instructional objective and specific behavioral objectives for students to understand more the clinico-pathological process of diseases. A patient for primary hypothyroidism with chronic renal failure was chosen as the case, which had been found based on the abnormality on essential laboratory tests. The reversed-CPC was carried out to make a diagnosis with the patient's history and clinical examinations, and then the clinico pathological process for the patient was re-checked, discussed and explained by students for themselves. They felt harder to see how abnormal data were related to diseases, according to their own evaluation of the practice. The further education for the patho-physiology of diseases and the logic of the test combination will be required. PMID- 10097637 TI - [A case of atypical polypoid adenomyoma with intramural myoma-like growth]. AB - We encountered a case of a large atypical polypoid adenomyoma (APA) which showed characteristic intramural appearance. As many cases of APA of the uterus have been reported in recent years, macro- and microscopic findings of the lesion and its clinical characteristics have been investigated. However the pathogenesis and the natural history of the lesion remained to be solved owing to still limited number of the cases. We report this case to discuss the macroscopic findings and clinicopathologic characteristics of the lesion. PMID- 10097638 TI - [Anti-myeloperoxidase and anti-lactoferrin antibodies in patients with IgA nephropathy and Henoch-Schonlein purpura]. AB - Antineutrophil cytoplasmic antibodies (ANCA) for two antigens, i.e. myeloperoxidase (MPO) and lactoferrin (LF) in sera from 19 IgA nephropathy (IgAN), 3 adult Henoch-Schonlein purpura (HSP) and 8 child HSP patients were examined by enzyme-linked immunoabsorbent assay (ELISA) for immunoglobulin isotypes. All of child HSP patients showed negative ANCA. On the other hand, one IgAN patient and two adult HSP patients showed weak positivity for IgA class anti MPO antibody. There was no patients who showed positivity for IgG and IgM class anti-MPO antibody. In anti-LF antibody, one IgAN and one adult HSP showed positivity in IgG class; 2 IgAN and 2 HSP in IgA class and 2 IgAN and one HSP in IgM class. These results indicate that adult HSP patients have higher prevalence of IgA class anti-MPO antibody and anti-LF antibody than IgAN or child HSP. PMID- 10097639 TI - [Diagnostic assessment in lumbar back pain. I. Anamnesis and clinical examination]. AB - The diagnostic assessment of the low back pain patient is often unsatisfactory because a clear morphological alteration explaining the patient's symptoms can only be found in 10-20% of the cases. The majority of the patients is suffering from non-specific low back pain. However, the high incidence of benign, self limiting low back pain leads to the risk of overlooking specific causes such as tumor or infection. Similarly, relevant paresis and bladder and bowel dysfunction must be diagnosed in time. Furthermore, the aim of the diagnostic work-up is to diagnose and treat specific causes of back and leg pain (e.g. disc herniation and spinal stenosis) to avoid chronicity. In the majority of the cases, history and clinical examination alone allow to differentiate between specific and non specific low back pain and may lead to a further diagnostic work-up by imaging studies. PMID- 10097640 TI - [Diagnostic assessment in lumbar back pain. II. Imaging and image-guided infiltrations]. AB - The diagnostic assessment of low back pain should predominantly be based on history and clinical examination rather than on imaging studies. The problem of diagnostic imaging in low back pain is related to the high rate of asymptomatic morphological alterations in the lumbar spine. The diagnosis should therefore not be guided by findings in imaging. The imaging studies (standard radiographs and MRI) should verify the clinically suspected diagnosis and further lead to imaging guided injection studies (e.g. nerve root block, facet joint block, sacro-iliac joint block, provocative discography) to differentiate between symptomatic and asymptomatic morphological alterations. With longlasting local anaesthetics and steroids it is possible to achieve a diagnostic as well as a therapeutic effect. PMID- 10097641 TI - [Pain in the sole of the foot. Differential diagnosis and therapy]. AB - Plantar foot pain can be caused by a wide variety of diseases. To facilitate diagnosis and treatment differentiation of two entities is useful. The first group contains those painful disturbances that are due to mechanical overload, the second group has no relation to biomechanical problems. Tightness of the gastrocnemius muscles and hamstrings are the main factors leading to mechanical overload. Therefore, thorough evaluation of these muscles and treatment of shortening by stretching exercises is of paramount importance. PMID- 10097642 TI - [Alcoholism: old and new approaches to diagnosis and therapy]. AB - Several different possibilities concerning pharmacotherapy of alcoholism are discussed on the background of new neurobiochemical findings. Contributions to a new understanding of relapse are made and the complexity of the treatment of patients with double diagnosis is explained. PMID- 10097643 TI - [QALY or willingness to pay?]. PMID- 10097644 TI - [Dyspnea, fever in immunodeficiency. Pneumocystis carinii pneumonia]. PMID- 10097645 TI - ["You must live with this pain"]. PMID- 10097646 TI - [Homocysteine: a cardiovascular risk factor?]. AB - Elevated plasma homocysteine levels may lead to an increased risk for atherosclerosis. Besides genetic factors a deficiency of folate, vitamin B6 and/or vitamin B12 may lead to an increase in the plasma concentration of this sulfur containing amino acid. Homocysteine may enhance by several direct and/or indirect mechanisms the pathogenesis of atherosclerosis. In this review selected aspects of homocysteine in relation to clinical practice will be discussed. PMID- 10097647 TI - [Modern therapy of paroxysmal supraventricular tachycardia]. AB - Paroxysmal supraventricular tachycardia (SVT) may have numerous electro physiologic mechanisms. The most common type of SVT is AV-nodal reentry tachycardia (60%) followed by the bypass tract-mediated SVT (preexcitation. 30%) and a smaller group (10%) comprising paroxysmal atrial flutter or fibrillation and atrial ectopic tachycardia. In persons with otherwise normal hearts symptoms are usually mild and include palpitations or an uneasy feeling in the chest. But some describe precordial pain. Weakness, dizziness, nausea, vomiting, and even syncope. Whenever possible a 12-lead-ECG during an episode of SVT should be obtained. If not possible the use of several Holter-ECG or of an event-recorder may be helpful. Conversion of a SVT can be accomplished by vagal maneuvers or intravenous adenosine (6-18 mg bolus injection). Further diagnostic procedures should prove or rule out a significant structural heart disease. Therapeutic options (expectative, pharmacological prophylaxis, invasive electrophysiologic testing and catheter-mediated modification or ablation) are chosen according to the objective threat (e.g. ventricular fibrillation due to 1:1 conducted atrial fibrillation in a preexcitation syndrome) and the subjective complaints. Definitive healing of the AV-nodal reentry tachycardia and the bypass tract mediated SVT can be achieved by use of catheter-mediated modification or ablation in 95 to nearly 100%. PMID- 10097648 TI - [Violence our medical trauma in specialized multidisciplinary consultation]. AB - In this article a particular patient/physician relationship is described and analyzed: The described interaction between patient and physician during a consultative investigation by several specialists differs markedly from the common trustful relation between a patient and his family doctor. In this context the term and phenomenon pain is discussed and the necessity for an understandable, patient-oriented presentation of diagnosis and hypotheses considering the patient's individual bio-psycho-social dimension is stressed. Consequences for student education are mentioned. PMID- 10097649 TI - [Indinavir-associated lipodystrophy]. PMID- 10097650 TI - [Genital ulcer with maculopapular exanthema without urticaria]. PMID- 10097652 TI - [Cambrian explosion and diversification of genes]. PMID- 10097653 TI - [Diversity of visual pigments and phototransduction systems on the basis of both molecular phylogenetic and functional protein analyses]. PMID- 10097654 TI - [Molecular aspects of craniofacial development and evolution: morphogenesis of the jaw apparatus and lamprey embryology]. PMID- 10097655 TI - [Genome rearrangement and gene duplication in chordate evolution]. PMID- 10097656 TI - [Evolution of the genetic program controlling brain development]. PMID- 10097657 TI - [Regulation of cell division by ubiquitin-dependent proteolysis and spindle assembly checkpoint]. PMID- 10097659 TI - [Capillary electrophoresis (2): What the capillarity brought about]. PMID- 10097658 TI - [Roles of the cell surface purinergic receptors for extracellular adenosine and ATP in T-cell development and effector functions]. PMID- 10097660 TI - [Establishment of human ES cell lines: its potential significance and ethical consideration]. PMID- 10097661 TI - The impact of advanced technology on critical care. Dilemmas in the making. AB - Advanced technology has enhanced our ability to diagnose and treat critically ill patients, thereby assisting in prolonging life for many. However, its high cost has been prohibitive, and it may impose more burdens than benefits on some patients. Although technological advances have accelerated social change, many have also fuelled legal and ethical concerns. Consequently, the rationale for the use of advanced technology in the care of critically ill patients should be clear and ethically justified. PMID- 10097662 TI - Where are we now? PMID- 10097663 TI - Asthma in the English-speaking Caribbean. AB - The prevalence of asthma in the Caribbean is high and seems to be increasing. Asthma research in this region has been biased towards the paediatric population and there is little published on adult disease. There is a high prevalence of other allergic diseases in the patients studied, with skin reactivity to at least one allergen in 50-81% of subjects. Reactivity to house dust mite, especially Dermatophagoides pteronyssinus, occurred most commonly and sensitivity to this mite correlated with high levels of mite proteins in mattress and bedroom dust. Asthmatic admissions to hospitals are highest in the last quarter of the year but fall to their lowest levels in April. Admission rates are influenced by climatic variables such as relative humidity and wind speed. In some territories current management of asthma remains reliant on the use of oral bronchodilators with underutilization of inhaled beta-agonists and corticosteroid preparations. PMID- 10097664 TI - Bronchial asthma deaths in Jamaica. AB - Many countries have reported an increase in the death rate from bronchial asthma. Evaluation of the situation in Jamaica was undertaken to see if the trend is similar to that reported from elsewhere by analysing deaths for the period 1980 to 1989. There was an increase in the death rate during the period studied, most marked in females in rural areas. Most of the deaths occurred outside medical facilities. The reasons for these trends are not clear. PMID- 10097665 TI - CCMRC/GINA. Workshop on asthma management and prevention in the Caribbean. July 1 3, 1997, Trinidad. Commonwealth Caribbean Medical Research Council. Global Initiative for Asthma. PMID- 10097666 TI - Evaluation of a home kit blood glucose monitoring device. AB - A blood glucose monitoring device, the Diascan, is commonly used in Trinidad and Tobago. A prospective study was conducted to examine the accuracy of a Diascan unit in measuring blood glucose levels in or capillary venous blood of patients in a hospital ward. The Diascan measurements were compared to those from two laboratories which independently measured the venous blood or the venous plasma glucose levels. Although there was reasonably good correlation between measurements from the two laboratories (r = 0.85) results from the Diascan showed poor correlations with those from the laboratories, with Pearson's correlation coefficients ranging from 0.32 to 0.64. An error grid analysis showed that the Diascan measurements would have resulted in inappropriate decisions relating to treatment regimens in 26% of cases. The results suggest that, when crucial decisions have to be made with respect to patients' blood glucose levels, it may be risky to rely solely on measurements from the Diascan. PMID- 10097667 TI - Alternative medicine and "conventional" medicine--overview. PMID- 10097668 TI - Complementary/alternative and conventional medicine. PMID- 10097669 TI - Alternative and complementary medicine. PMID- 10097670 TI - Dumping syndrome in a young Jamaican child. AB - The dumping syndrome in childhood is an uncommon complication of gastro oesophageal surgery, principally Nissen fundoplication. A Jamaican child developed the syndrome after fundoplication and pyloroplasty to relieve gastro oesophageal reflux complicating the repair of a congenital tracheo-oesophageal fistula. He developed marasmus and failed to gain weight on the standard remedial milk-based high-energy diet. An oral glucose tolerance test confirmed the diagnosis of dumping syndrome. A low sugar low milk diet based on adult type meals with continuous nibbling of fried dumplings relieved his diarrhoea and hypoglycaemia and he gained weight. This is a cheaper and more practical dietary therapy than the regimens described previously. PMID- 10097671 TI - Spontaneous rupture of the spleen. AB - A 10 year old boy presented to the surgical service of the Queen Elizabeth Hospital with spontaneous rupture of the spleen and was later discovered to have chronic myeloid leukaemia. He has been in haematological remission for five years followed splenectomy and alpha-interferon therapy. PMID- 10097672 TI - Performing euthanasia may have an adverse effect on the doctor-patient trust. PMID- 10097673 TI - Surveillance of resistant pathogens and rational use of antibiotics: general remarks. AB - Surveillance of resistant pathogens should lead to improved treatment of patients and to a rational use of antibiotics. The process for decision making between microbiology, general practice and health policy is still to be documented with careful studies. PMID- 10097674 TI - Bacterial resistance to antimicrobial agents: an overview from Korea. AB - Antimicrobial resistance of bacteria has become a worldwide problem. Available data suggest that the resistance problem is comparatively more serious in Korea. In large hospitals, the proportion of methicillin-resistant Staphylococcus aureus (MRSA) has been reported at over 70%, and of penicillin-nonsusceptible Streptococcus pneumoniae at around 70%. Infection or colonization of vancomycin resistant enterococci has started to increase. Extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae has become widespread and even carbapenem-resistant Pseudomonas aeruginosa has been increasing. Community acquired pathogens such as Salmonella, Shigella and Neisseria gonorrhoeae are often resistant to various antimicrobial agents. The prevalence of resistant bacteria can lead to erroneous empirical selection of either noneffective or expensive drugs, prolonging hospitalization and higher mortality. The emergence and spread of resistant bacteria are unavoidable unless antimicrobial agents are not used at all. The high prevalence of resistant bacteria in Korea seems to be related to antibiotic usage: 1) easy availability without prescription at drug stores, 2) injudicious use in hospitals, and 3) uncontrolled use in agriculture, animal husbandry, and fisheries. Nosocomial infection is an important factor in the spread of resistant bacteria. Antimicrobial resistance problems should be regarded as the major public health concern in Korea. It is urgently required to ban the sale of antibiotics without prescription, to use antibiotics more judiciously in hospitals by intensive teaching of the principles of the use of antibiotics, and to establish better control measures of nosocomial infections. Regulation of antimicrobials for other than human use should also be required. These issues are not easy to address and require the collective action of governments, the pharmaceutical industry, health care providers, and consumers. PMID- 10097675 TI - Current susceptibility patterns of anaerobic bacteria. AB - While antibiotic resistance among anaerobes continues to increase, the frequency of antimicrobial susceptibility testing for anaerobes is declining. Because anaerobic infections are often mixed and detailed bacteriology of the organisms involved may take some time, physicians must institute empiric therapy before susceptibility testing results are available. Also, economic realities and prudent use of resources mandate that careful consideration be given to the necessity for routine susceptibility testing of anaerobic bacteria. Determination of appropriate therapy can be based on published antibiograms; however, since patterns may vary within geographic regions and even within hospitals, it is strongly recommended that each hospital center periodically test their isolates to determine local patterns and detect any pockets of resistance. As a general guide, antibiograms from the last several years of susceptibility testing at the Wadsworth Anaerobe Laboratory are reported. PMID- 10097676 TI - Why do antimicrobial agents become ineffectual? AB - Antibiotic resistance has evolved over the past 50 years from a merely microbiological curiosity to a serious medical problem in hospitals all over the world. Resistance has been reported in almost all species of gram-positive and negative bacteria to various classes of antibiotics including recently developed ones. Bacteria acquire resistance by reducing permeability and intracellular accumulation, by alteration of targets of antibiotic action, and by enzymatic modification of antibiotics. Inappropriate use of an antibiotic selects resistant strains much more frequently. Once resistant bacteria has emerged, the resistance can be transferred to other bacteria by various mechanisms, resulting in multiresistant strains. MRSA is one of the typical multiresistant nosocomial pathogens. A study of the PFGE pattern of endonuclease-digested chromosomal DNA showed that MRSA of a few clones were disseminated among newborns in the NICU of a Japanese hospital. In this regard, it is important to choose appropriate antibiotics and then after some time, to change to other classes to reduce the selection of resistant strains. Since the development of epoch-making new antibiotics is not expected in the near future, it has become very important to use existing antibiotics prudently based on mechanisms of antibiotic action and bacterial resistance. Control of nosocomial infection is also very important to reduce further spread of resistant bacteria. PMID- 10097677 TI - The characteristics of extended-spectrum beta-lactamases in Korean isolates of Enterobacteriaceae. AB - Extended-spectrum beta-lactamases (ESBLs) in gram-negative organisms have been implicated as the enzymes responsible for resistance to oxyimino-cephalosporins. The incidence of ESBL-producers in Korean isolates of Escherichia coli and Klebsiella pneumoniae were in the range of 4.8-7.5% and 22.5-22.8%, respectively. The ESBL-producing isolates revealed variable levels of resistance to cefotaxime, ceftazidime and aztreonam. They also showed the elevated MIC values of non-beta lactam antibiotics. SHV-12 and SHV-2a were the enzymes most frequently found in K. pneumoniae strains, but TEM-52 was the most prevalent in E. coli isolates. About 15% of ESBL-producing isolates of Enterobacteriaceae produced CMY-1 enzyme, which conferred resistance to cephamycins such as cefoxitin as well as oxyimino cephalosporins. Thus, the most common types of ESBLs in Korea are TEM-52, SHV-12 SHV-2a, and CMY-1. PMID- 10097678 TI - Plasmid-encoded AmpC beta-lactamases: how far have we gone 10 years after the discovery? AB - The dogma that ampC genes are located exclusively on the chromosome was dominant until about 10 years ago. Since 1989 over 15 different plasmid-encoded AmpC beta lactamases have been reported from several countries. Most of these enzymes evolved in two clusters. The major cluster includes several enzymes with a high similarity to CMY-2, which is the closest related chromosomal AmpC enzyme of Citrobacter freundii. A second cluster centers around CMY-1. It is less homogeneous and not closely related chromosomal AmpC enzymes. Molecular diversification by amino acid substitutions does not usually translate into a change in the resistance phenotype. At this time, CMY-2 appears to be the most prevalent and widely distributed. Further global increase of prevalence and diversity of plasmidic AmpC beta-lactamases have to be anticipated in the next millenium. PMID- 10097679 TI - Acquisition of methicillin resistance and progression of multiantibiotic resistance in methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) produces specific penicillin binding protein, PBP2', which shows remarkably low affinities to most beta-lactam antibiotics except those such as penicillin G and ampicillin. The region surrounding mecA has been called additional DNA or mec and is thought to be of extraspecies origin. From the study of mec, we found that mec is a novel mobile genetic element and designated as staphylococcal cassette chromosome mec (SCCmec). There are three types of SCCmec. In the past decades, MRSA has become resistant to many antibiotics, such as carbapenems, new quinolones, and minocycline etc. It seems to be a characteristic of MRSA to acquire multi resistance by accumulating multiple resistance genes around the mecA gene inside SCCmec. PMID- 10097680 TI - Molecular analysis of fluoroquinolone-resistance in Escherichia coli on the aspect of gyrase and multiple antibiotic resistance (mar) genes. AB - We analyzed the fluoroquinolone resistance mechanism of 28 isolates of ciprofloxacin-resistant E. coli from patients who received ciprofloxacin as a regimen of a selective gut decontamination. Isolates distinctive by infrequent restriction site polymerase chain reaction (IRS-PCR) were subjected to Hinf I restriction fragment length polymorphism analysis, single-stranded conformation polymorphism (SSCP), and nucleotide sequencing of the quinolone resistance determining region (QRDR) in gyrA. Double mutations in QRDR of gyrA (Ser83 Leu and Asp87Asn) were found from most of the strains. Nucleotide sequencing of the marR locus showed that 18 out of 28 (64%) ciprofloxacin-resistant E. coli strains had three types of base change in marR loci: a double-base change at nucleotides 1628 and 1751, or 1629 and 1751: and a single-base change at 1751. However, all the mutated strains showed no tolerance to cyclohexane test, suggesting the mutation in the marR region had no influence on overexpression of the MarA protein. In conclusion, mutation in gyrA was the main mechanism of ciporfloxacin resistance in E. coli from patients with selective gut decontamination. Therefore, mutation in the mar region did not influence the levels of ciprofloxacin resistance in our isolates. PMID- 10097681 TI - A mutation in QRDR in the ParC subunit of topoisomerase IV was responsible for fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae. AB - Forty-one strains of Streptococcus pneumoniae were isolated at Seoul National University Children's Hospital from 1991 to 1997. Isolates were divided into six groups based on MICs of three quinolones, ciprofloxacin, ofloxacin and norfloxacin. Sequencing showed that the isolates which were intermediately resistant to three quinolones or resistant to at least one kind of quinolone had one missense mutation, Lys137-->Asn(AAG-->AAT) substitution in the ParC subunit of topoisomerase IV without additional mutation in QRDR of the GyrA subunit of DNA gyrase. In conclusion, the ParC subunit of DNA topoisomerase IV is the primary target site for fluoroquinolone in S. pneumoniae and Lys137-->Asn substitution renders the quinolone resistance in S. pneumoniae. PMID- 10097682 TI - Emergence and spread of antimicrobial resistance of Streptococcus pneumoniae in Korea. AB - Pneumococcal resistance has become a global issue during the past three decades. One of the major foci of pneumococcal resistance worldwide is the Asian region including Korea, Japan, and Hong Kong. Korea had not been recognized as a focus of pneumococcal resistance until 1995, when serial reports documented the alarmingly high prevalence of penicillin resistance among clinical isolates. Serial reports on penicillin resistance among pneumococcal isolates in Korea ranged from 68% to 77% as of 1995. Multidrug resistance was also noted in 34% of Korean isolates. Penicillin-binding protein profile analysis, pulsed-field gel electrophoresis, ribotyping, and fingerprinting analysis of pbp genes showed that antibiotic-resistant pneumococci isolated in Korea were genetically related. Data documented the extensive spread of a resistant clone within Korea and between different countries. Besides the injudicious use of antimicrobial agents or the high prevalence of serotypes 23 and 19, the spread of a resistant clone may play an important role in the rapid increase of penicillin resistance in Korea. PMID- 10097683 TI - Antimicrobial resistance in enterococci. AB - Enterococci have emerged as a major nosocomial pathogen and as an ever-increasing problem in antimicrobial resistance. They are ubiquitous in the intestinal flora of humans and animals and inherently resistant to a wide array of antimicrobial agents, and, more alarmingly, they seem to have a potential facility for acquiring new resistance determinants, including beta-lactamase production, high level resistance to aminoglycosides, and recently, glycopeptide resistance. Collectively, all of these properties make enterococci one of most difficult nosocomial pathogens to treat and control today. The purpose of this review was to examine the epidemiology, the mechanisms, and laboratory detection of resistance of enterococci to the two major groups of antibiotics: aminoglycosides and glycopeptides. PMID- 10097684 TI - Vancomycin-resistant enterococcal infections in Korea. AB - Enterococci recently became the second-to-third most commonly isolated organism from nosocomial infections. Enterococci are intrinsically more resistant to many antimicrobial agents and often show acquired resistance to many antimicrobial agents including high-level aminoglycosides. With the increased use of vancomycin, vancomycin-resistant enterococci (VRE) has become an important nosocomial pathogen. In Korea, the proportion of VRE among all enterococcal of VRE is no longer low in some settings and recent observations of a sudden increase of VRE isolation in several hospitals in Korea suggests that VRE infection may become a serious problem in the near future. The most important considerations are that vancomycin-resistant genes may spread to other highly virulent genera, such as MRSA, and that there are no approved and convincingly effective antibiotics for the treatment of VRE. Therefore, current efforts have concentrated on limiting the spread of these organisms within the hospital environment. Prudent use of antimicrobial agents and strict adherence to preventive measures such as aggressive communication, education, and infection control practices are essential to control the spread of this organism. However, hospital infection control protocols and the laboratory support they require are costly in terms of space and supplies, as well as in personnel resources. These factors add further pressure to already stretched hospital budgets. Nevertheless, policies or programs defining and managing VRE infection or colonization should be established and now is the time to enforce an overall management strategy against VRE. PMID- 10097685 TI - Korean Nationwide Surveillance of Antimicrobial Resistance of bacteria in 1997. AB - Antimicrobial-resistant bacteria are known to be prevalent in tertiary-care hospitals in Korea. Twenty hospitals participated to this surveillance to determine the nationwide prevalence of resistance bacteria in 1997. Seven per cent and 26% of Escherichia coli and Klebsiella pneumoniae were resistant to 3rd generation cephalosporin. Increased resistance rates, 19% of Acinetobacter baumannii to ampicillin/sulbactam, and 17% of Pseudomonas aeruginoa to imipenem, were noted. The resistance rate to fluoroquinolone rose to 24% in E. coli, 56% in A. baumannii and 42% in P. aeruginosa. Mean resistance rates were similar in all hospital groups: about 17% of P. aeruginosa to imipenem, 50% of Haemophilus influenzae to ampicillin, 70% of Staphylococcus aureus to methicillin, and 70% of pneumococci to penicillin. In conclusion, nosocomial pathogens and problem resistant organisms are prevalent in smaller hospitals too, indicating nosocomial spread is a significant cause of the increasing prevalence of resistant bacteria in Korea. PMID- 10097686 TI - Antimicrobial resistance patterns of Bacteroides fragilis group organisms in Korea. AB - Antimicrobial resistance patterns of 913 clinical isolates of Bacteroides fragilis group organisms were monitored during an 8-year period in Korea. In general the resistance rates of the non-fragilis B. fragilis group species were higher than those of B. fragilis for all the drugs tested. The rate of resistance to clindamycin remarkably increased and those to some beta-lactam drugs such as piperacillin and cefotaxime also increased. No isolates were found to be resistant to imipenem, metronidazole, or chloramphenicol. beta-lactam and beta lactamase inhibitor combinations and cefoxitin were more active than the other beta-lactams. Therefore, these agents may be considered when empirical selection of antimicrobial agents is required to treat severe anaerobic infections. PMID- 10097687 TI - Epidemiological typing of methicillin-resistant Staphylococcus aureus outbreak isolates by pulsed-field gel electrophoresis and antibiogram. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common nosocomial pathogens. In April 1997, there were five MRSA-infected patients among 16 patients in the Neonatal Intensive Care Unit (NICU), Seoul National University Hospital, which is a tertiary-care hospital with 1,500 beds. The infections had spread from twin patients with MRSA who had transferred from Hospital C. MRSA was isolated from the axilla of 15 (94%) of the 16 patients, including the two patients with obvious infections. Three (19%) of 16 doctors and nine (30%) of 30 nurses had MRSA colonization of the anterior nares. Six different PFGE patterns (A through F) were identified in the 53 isolates of MRSA tested. Twelve of 13 isolates from infected sites of five patients showed pattern F. Three MRSA strains obtained from hospital C showed closely or possibly related pattern F. MRSA of type F was isolated from three of 16 patients' axilla, and one of 3 doctors' and three of 30 nurses' nasal swabs. The antibiogram code for 12 of 13 MRSA isolates from five infected patients was 66,754. PFGE patterns of these isolates were either F, F1, F2 or Fa. Only one of three strains isolated from clinical specimens of patients in Hospital C showed the antibiogram code 66754, although they were all PFGE types F1 and Fa. In conclusion, the presumptive sources of the outbreak of MRSA infection in NICU were the twin patients transferred from hospital C. Antibiogram correlated reasonably well to the PFGE type. An effective notification system is needed when a MRSA-infected patient is transferred to another hospital to control the spread of the infection. PMID- 10097688 TI - Antibiotic use at a pediatric age. AB - For infections in infants and children, the successful antibiotic treatment depends primarily on rapid diagnosis of the disease, identification of pathogenic microorganisms, and appropriate application of specialized pharmacokinetic and pharmacodynamic knowledge of antibiotics in children. In infants and children, the absorption, distribution, metabolism, and excretion of drugs may differ considerably in comparison with adults. Because of known toxicity, certain drugs such as chloramphenicol in high doses, the sulfonamides, and tetracycline should not be used in neonates. In this article, we describe these peculiarities of children and discuss the proper use of antibiotics in children. PMID- 10097689 TI - Nocardia osteomyelitis in a pachymeningitis patient: an example of a difficult case to treat with antimicrobial agents. AB - Antimicrobial agents played a miraculous role in the treatment of bacterial infections until resistant bacteria became widespread. Besides antimicrobial resistant bacteria, many factors can influence the cure of infection. Nocardia infection may be a good example which is difficult to cure with antimicrobial agents alone. A 66-year-old man developed soft tissue infection of the right buttock and thigh. He was given prednisolone and azathioprine for pachymeningitis 3 months prior to admission. Despite surgical and antimicrobial treatment (sulfamethoxazole-trimethoprim), the infection spread to the femur and osteomyelitis developed. The case showed that treatment of bacterial infection is not always as successful as was once thought because recent isolates of bacteria are more often resistant to various antimicrobial agents, intracellular parasites are difficult to eliminate even with the active drug in vitro, and infections in some sites such as bone are refractory to treatment especially when the patient is in a compromised state. In conclusion, for the treatment of infections, clinicians need to rely on laboratory tests more than before and have to consider the influence of various host factors. PMID- 10097690 TI - Use of vaccine in the era of antimicrobial resistance: need of effective pneumococcal vaccines. AB - Streptococcus pneumoniae is an important pathogen causing invasive infections particularly in children. Penicillin-nonsusceptible pneumococci are very prevalent in Korea and a difficult problem in antimicrobial treatment. Immunization with effective vaccines including viral and bacterial vaccines has proven to be the most effective and reliable method to prevent the target disease. Universal immunization to infants with Haemophilus influenzae type b conjugate vaccine has dramatically proven to be very effective in reducing invasive Hib diseases and also the carriage rate. The 23-valent pneumococcal polysaccharide vaccine is effective in preventing invasive diseases in young adults and covers most of the penicillin-nonsusceptible types. It has not proven very effective in the prevention of otitis media, and is unable to elicit adequate antibody response in children younger than 2 years of age. Recently a new polysaccharide-protein conjugate vaccine was developed which can elicit antibody response in children younger than 2 years of age. However, the vaccine is only 8-valent at the moment. Studies are required to determine the possible idiotypic modulation and nonproductive immune response when polysaccharide vaccine is administered to infants. Part of the problem of antimicrobial resistant pneumococcal infection may be solved in the future with the use of improved vaccine. Preventing pneumococcal infections with safe and effective vaccines will not only reduce the development of antibiotic resistance, but could also be the most cost-effective method to control pneumococcal disease. PMID- 10097691 TI - Cytologic diagnosis of two rarities. Granulocytic sarcoma and microsporidiosis. PMID- 10097692 TI - Cytologic detection of microsporidia spores in bile. A comparison of stains. AB - OBJECTIVE: To compare stains in preparations of bile in a patient with AIDS and microsporidial cholangitis. STUDY DESIGN: Bile was obtained from a 30-year-old male with AIDS and symptoms of cholangitis. Comparative staining of the specimen was performed using a formalin-fixed preparation stained with Chromotrope 2R stain and with alcohol-fixed preparations stained with Gram and Giemsa stain and Diff-Quik. An alcohol-fixed ThinPrep slide was stained with Papanicolaou stain. RESULTS: Diagnostic microsporidia spores were detected under oil immersion using Papanicolaou, Chromotrope 2R, Giemsa and Gram stain. The Diff-Quik-stained preparation also revealed microsporidia but with suboptimal morphology. CONCLUSION: Detection of microsporidia in bile can be achieved using several different stains routinely available to cytologists, most optimally with alcohol fixed Papanicolaou- or Giemsa-stained preparations or with Chromotrope 2R stain, which is available in parasitology laboratories. These findings should be applicable to fluids from other body sites with this emerging pathogen in AIDS. PMID- 10097693 TI - Usefulness of endometrial aspiration cytology for the preoperative diagnosis of ovarian carcinoma. AB - OBJECTIVE: To evaluate the usefulness of endometrial aspiration cytology for the preoperative diagnosis of ovarian carcinoma. STUDY DESIGN: A total of 210 patients with ovarian carcinoma were investigated by endometrial aspiration cytology. RESULTS: Fifty-five of 210 patients (26.2%) had positive endometrial aspiration cytology. The positive rates of endometrial cytology were 3.9% in stage I, 23.8% in stage II, 36.5% in stage III and 53.3% in stage IV. When classified by histologic type, the positive rates of endometrial cytology in patients with serous adenocarcinoma, mucinous adenocarcinoma, clear cell adenocarcinoma, undifferentiated carcinoma and yolk sac tumor were 38.9%, 11.8%, 21.1%, 16.7% and 16.7%, respectively. One hundred twenty-eight of 210 patients (61.0%) were positive on peritoneal cytology, and 54 of these 128 cases (42.2%) were also positive on endometrial cytology. The positive rates of endometrial cytology were especially high in patients with serous adenocarcinoma (51.2%) and those with clear cell adenocarcinoma (40.0%) among those who were positive on peritoneal cytology. Of 74 patients who were negative on peritoneal cytology, only one (1.4%) with mucinous adenocarcinoma had positive endometrial cytology. Hysterectomy was performed on 130 patients, and the positive rate of endometrial cytology was 100% in 4 patients with endometrial invasion and 15.9% in 126 cases without invasion. CONCLUSION: Endometrial aspiration cytology can detect ovarian carcinoma cells not only in patients with endometrial involvement but also in patients with positive peritoneal cytology. Endometrial aspiration cytology appears to be useful for the preoperative diagnosis of ovarian carcinoma. PMID- 10097694 TI - Microglandular hyperplasia of the uterine cervix. Cytologic diagnosis in cervical smears. AB - OBJECTIVE: To identify cytomorphologic features specific to microglandular hyperplasia (MGH) in cervical cytologic smears. STUDY DESIGN: Twenty-four cervical smears from 24 patients obtained before the histologic diagnosis of MGH made on colposcopically directed biopsies during a period of two years (1995 1997) were evaluated. RESULTS: Of cases with MGH, 13/24 (54%) showed the presence of bidimensional or tridimensional cellular clusters made up of cubic or cylindrical glandular cells with vacuolated cytoplasm; cells with dense cytoplasm, basaloid in appearance, corresponding to immature squamous metaplasia; and subcylindrical reserve cells with small, round nuclei and scant cytoplasm. Clusters showed microlumina or fenestrated spaces, preserved polarity and absence of nuclear peripheral dispersion. In the control group these cellular clusters were found in 6/100 (6%). Statistical analysis (chi 2) showed a strong, highly significant association (P < 0.001) of the cytologic parameters selected and the histologic diagnosis of MGH. CONCLUSION: Until now, no specific cytologic parameters were described for MGH. This study underscored the value of cytomorphologic parameters described for typical cellular clusters showing microlumina or fenestrated spaces with shared party walls and an admixture of glandular cells, and immature squamous metaplastic and subcylindrical reserve cells in the cytologic diagnosis of MGH. PMID- 10097695 TI - Efficacy of fine needle capillary sampling in the diagnosis of stage III and IV cervical carcinoma. AB - OBJECTIVE: To test the sensitivity of fine needle capillary sampling (FNCS) as compared to scrape cytology in cervical carcinoma, stage III and IV, and to study the quality of material obtained by FNCS. STUDY DESIGN: Prospective. In 48 cases of cervical carcinoma, clinically stage III and IV, FNCS was done along with scrape cytology. The results were compared, considering histopathology as the gold standard. The quality of material obtained by both methods was compared using the parameters background, cellularity and cellular preservation. RESULTS: FNCS had a sensitivity of 87.5% as against 62.5% for scrape cytology. Material obtained by FNCS had a cleaner background and better cellularity and morphologic preservation. CONCLUSION: FNCS is superior to scrape cytology for the diagnosis of stage III and IV cervical carcinoma. PMID- 10097696 TI - AgNOR count in exfoliative cytology of normal buccal mucosa. Effect of smoking. AB - OBJECTIVE: To compare the argyrophilic nucleolar organizer region (AgNOR) count of cells collected from normal buccal mucosa of cigarette smokers with that obtained from nonsmokers. STUDY DESIGN: Cytologic smears of normal buccal mucosa from 20 smokers and 20 nonsmokers were stained for AgNORs. The AgNOR count was established on 100 cells. The count values of groups were compared and analyzed using Student's unpaired t test. RESULTS: The AgNORs were round and had a clustered distribution in both groups. The mean AgNOR count was statistically higher in cells of smokers than nonsmokers (P < .01). CONCLUSION: Analysis of AgNORs suggests that cigarette smoking influences proliferative activity in cells of normal buccal mucosa. PMID- 10097697 TI - Cytologic features of secretory meningioma. AB - OBJECTIVE: To describe the cytologic features of secretory meningioma on crush preparations. STUDY DESIGN: In five cases, the diagnosis of secretory meningioma was made and crush preparations were available. In each case, crush preparations were made at the time of intraoperative consultation from an open biopsy specimen or stereotactic biopsy. RESULTS: Hematoxylin and eosin-stained crushes showed the presence of clusters of cohesive cells containing variable numbers of inclusions among less cohesive typical meningothelial cells. In two cases, the inclusions were especially prominent. Inclusions varied in size from 3 to 40 microns, had a well-defined rim and contained finely granular or hyaline material and a central core. CONCLUSION: Secretory meningiomas demonstrate distinct cytologic features on crush preparations. Recognition of these inclusions is important since their prominence in some stereotactic smear preparations may lead to diagnostic problems. PMID- 10097698 TI - Fine needle aspiration cytology of cutaneous and subcutaneous metastatic deposits from epithelial malignancies. An analysis of 146 cases. AB - OBJECTIVE: To analyze cases suggestive of cutaneous/subcutaneous metastatic deposits from a known carcinoma or as the first manifestation of an unknown carcinoma using fine needle aspiration cytology (FNAC). STUDY DESIGN: The study group consisted of 146 patients (86 males and 60 females) ranging in age from 34 to 82 years. In 135 cases there was a previous history of carcinoma, and in these cases FNAC showed the tumor to be similar to the carcinoma that had been treated by surgery and/or radiotherapy. In 11 patients no tumor had been found previously, and the site of the unknown primary was suggested by immunostaining. Aspirations were performed using a 22-gauge needle. The material was collected in 30% ethyl alcohol, and filter preparations and cell blocks were made. RESULTS: The size of metastatic nodules ranged from 1.5 to 2 cm. The sites of metastases were on the chest wall (n = 35), back (n = 8), abdomen (including umbilicus) (n = 46), head and neck (n = 35), upper extremity (n = 12), lower extremity ((n = 6), penile skin (n = 1) and vulva (n = 3). The sites of known primary carcinomas were breast (n = 39), lung (n = 35), gastrointestinal tract (n = 38), endometrium (n = 2), cervix (n = 3), urinary tract (n = 4), prostate (n = 3), hand (n = 1), scalp (n = 1), tongue (n = 1), brain (n = 1), ear (n = 3) and ovary (n = 4). The sites of primary carcinomas unknown at the time of aspiration and found after FNAC were the gastrointestinal tract (n = 3), lung (n = 2), prostate (n = 1), breast (n = 3), liver (n = 1) and kidney (n = 1). No false negatives or positives were observed, and no second primary tumors were found. Cytologic preparations were sufficient for diagnosis and typing in tumors with a known primary tumor. Immunostaining was helpful in establishing a diagnosis of carcinoma and in determining the likely primary site in tumors with unknown primaries. CONCLUSION: Cutaneous and subcutaneous metastatic deposits from previously known carcinomas can be diagnosed rapidly and accurately utilizing FNAC. A combination of FNAC and immunostaining may also help define the site of an unknown primary. PMID- 10097700 TI - Follicular variant of papillary carcinoma of the thyroid. A cytologic study of 15 cases. AB - OBJECTIVE: To study the cytologic findings of follicular variant of papillary thyroid carcinoma (FVPTC) and to compare them with the cytologic findings on other thyroid lesions. STUDY DESIGN: The study group consisted of aspirate smears from 15 cases of histologically proven FVPTC. The control group consisted of 152 cases, including adenomatous colloid goiter (70), usual papillary carcinoma (40), follicular adenoma (30), Hurthle cell neoplasm (7) and medullary carcinoma (5). RESULTS: The smears of FVPTC revealed numerous colloid balls in the background, multilayered microfollicles (rosettes), numerous nuclear grooves and inclusions in the monolayer sheets of follicular cells, very rare giant cells, absence of calcification and papillary clusters. Rosettelike microfollicles and numerous colloid balls were not seen in the control group. CONCLUSION: The combination of numerous colloid balls and rosettelike microfollicles was frequently seen in FVPTC. This combination was not observed in the control group. PMID- 10097699 TI - Combined hepatocellular-cholangiocarcinoma. Diagnostic challenge in hepatic fine needle aspiration biopsy. AB - OBJECTIVE: To study the cytohistologic features of combined hepatocellular cholangiocarcinoma (CHCC-CC) in fine needle aspiration biopsy (FNAB) material. STUDY DESIGN: Six hepatic FNAB cases with cell blocks (five) and hepatic resections (two) were analyzed cytohistologically and immunohistochemically. RESULTS: The six cases were diagnosed as CHCC-CC based on clinicopathologic correlation. Unequivocal hepatocellular carcinoma (HCC) cells corresponding to Edmondson and Steiner's grade 3 lesions were identified in the FNAB in three instances. Adenocarcinoma, represented by cohesive columnar cells with ovoid, basal nuclei displaying nuclear palisading, acini and/or papillary structures with variable intracytoplasmic intraacinar or brush border mucin production, was identified in all cases. Intermediate cells with hybrid/polymorphic cytologic features straddling malignant hepatocytes and glandular cells were identified in five instances. Tissue alpha-fetoprotein was negative. There was brush border and/or diffuse cytoplasmic p-carcinoembryonic antigen immunoreactivity in the glandular elements. CONCLUSION: FNAB diagnosis of CHCC-CC is possible if the clinical, cytohistologic and immunohistochemical findings support the presence of HCC and adenocarcinoma. Intermediate cells pose a great challenge to recognize and define: they tend to lose the classic cytologic features of malignant hepatocytes and acquire glandular characteristics. At the very least, there should be a high index of suspicion. These cases underscore the necessity for clinicopathologic correlation in enhancing the precision of FNAB diagnoses. PMID- 10097701 TI - Logistic regression analysis of low grade spindle cell lesions. A cytologic study. AB - OBJECTIVE: To identify key diagnostic cytologic criteria for various low grade spindle cell lesions. STUDY DESIGN: We reviewed 20 synovial sarcomas, 18 benign neural tumors, 10 reparative lesions, 24 other benign and 27 additional malignant low grade spindle cell lesions. All specimens were coded as to the presence or absence of the following variables: high cellularity, tissue fragments, tissue culture appearance, epithelial fragments, vessel fragments, vascular arcades, fibrillar ground substance, myxoid background, microcystic areas, parallel arrangement of nuclei, naked nuclei, single cells, binucleate cells, multinucleate cells, long filamentous cells, short spindle cells, stellate cells, lipoblasts, nuclear pleomorphism, nuclei with pointed ends, comma/fishhook nuclei, cigar-shaped nuclei, ovoid/round nuclei, small nucleoli, large nucleoli, mitotic figures, intranuclear vacuoles and background histiocytes. A logistic regression analysis was performed to identify the variables predictive of malignant lesions, specifically synovial sarcomas, benign neural tumors and reparative lesions. RESULTS: Statistical analysis selected high cellularity, short spindle cells, small nucleoli and absence of tissue culture appearance as the main criteria for malignant neoplasms. Tissue fragments and high cellularity were selected as the primary criteria and absence of long filamentous cells and of myxoid background as the secondary criteria for synovial sarcomas. It selected fibrillar ground substance and absence of ovoid/round nuclei as the key criteria for benign neural tumors. The presence of a tissue culture appearance was the major criterion for reparative lesions. CONCLUSION: There are many previously described cytologic criteria, but we found that when subjected to statistical analysis, only a few features were significant in the evaluation of low grade spindle cell lesions. PMID- 10097702 TI - Fine needle aspiration diagnosis of mycobacterial lymphadenitis. Sensitivity and predictive value in the United States. AB - OBJECTIVE: Fine needle aspiration (FNA) has proven valuable in diagnosing tuberculous lymphadenitis in countries with endemic mycobacterial infection (MI). Its role in developed countries, where sensitivity and positive predictive value are likely to be lower, has not been adequately explored. STUDY DESIGN: This retrospective, five-year study from a public hospital in the United States examined the predictiveness of 238 nodal FNAs in patients with MI; 59% of patients were also HIV+. RESULTS: Diagnostic results (stainable acid-fast bacilli or positive culture) were present in nearly half the aspirates; sensitivity was 46%, specificity 100%, positive predictive value (PPV) 100% and negative predictive value (NPV) 94%. If granulomatous inflammation (GI) was also considered a positive result, sensitivity increased to 53%; false positive cases of GI reduced PPV to 80%, while specificity (98%) and NPV (95%) changed little. Considered alone, GI had the lowest sensitivity (25%) and PPV (65%). CONCLUSION: FNA was useful in this U.S. population with MI, identifying almost half the affected patients. However, nondiagnostic results, such as granulomatous inflammation, should be interpreted with caution. PMID- 10097703 TI - Correlation of fine needle aspiration biopsy and dynamic contrast-enhanced 3D magnetic resonance imaging of the breast. AB - OBJECTIVE: To correlate and assess the utility of dynamic contrast-enhanced three dimensional gadolinium-enhanced magnetic resonance imaging (Gd-3DMRI) and fine needle aspiration biopsy (FNAB) findings in patients with suspected breast disease. STUDY DESIGN: Beginning in 1993, all patients who underwent percutaneous FNAB of the breast and had concurrent Gd-3DMRI evaluation of the breast were selected for this study. Findings for FNAB and Gd-3DMRI were stratified into two categories, positive and negative. Subsequent clinical management decisions, which included surgical intervention and/or clinical follow-up, were recorded for all patients. RESULTS: There were 69 FNABs in 59 patients with corresponding Gd 3DMRI evaluation. A positive result by both FNAB and Gd-3DMRI was found in 15 of 18 malignant cases. FNAB missed one case, and Gd-3DMRI missed two, and each of these was thought to be technical. Combining the methods yielded 100% sensitivity. False positive results on Gd-3DMRI (17 cases) were all confirmed to be benign by FNAB and subsequent tissue evaluation. All 32 cases with combined negative results by FNAB and Gd-3DMRI demonstrated a benign process, yielding a specificity of 100% (32/32). CONCLUSION: Our combined testing modalities showed a high degree of specificity and good sensitivity. FNAB used with dynamic contrast enhanced Gd-3DMRI can contribute valuable information for physicians treating patients with suspected breast abnormalities. PMID- 10097705 TI - Accuracy of touch imprint cytology of image-directed breast core needle biopsies. AB - OBJECTIVE: To evaluate the accuracy of touch imprint (TI) cytology of image directed core needle biopsy (CNB) specimens of nonpalpable breast lesions. STUDY DESIGN: Fifty-two consecutive CNBs from 44 patients were performed under mammographic or ultrasound guidance. Air- dried TIs of CNBs were stained with Diff-Quik. TI cellularity was considered adequate if six or more ductal cell groups were identified. CNBs and TIs were interpreted in a blinded fashion. RESULTS: TI cellularity was adequate in 37/52 (71%) cases, including 17/20 carcinomas and 20/32 benign lesions. Among 17 carcinomas, TIs were positive in 12, suspicious in 4 and atypical in 1. One case of lactational change was suspicious on TI, and 5/8 fibroadenomas were atypical. No benign lesions were called "carcinoma" on cytology. When lesions categorized as "carcinoma" or "suspicious" were considered positive and those classified as "atypical" or "benign" were scored as negative, TI sensitivity and specificity were 94% and 95%, respectively. When the "atypical" cases were grouped with the positive cases, TI sensitivity was 100%, with 75% specificity. CONCLUSION: With satisfactory cellularity, TIs of CNBs are highly accurate. When immediate evaluation of CNB specimens is important, TIs can potentially decrease the number of biopsy passes required and provide preliminary diagnoses. PMID- 10097704 TI - Ultrasound-guided fine needle aspiration cytology of impalpable breast lesions in a rural setting. Comparison of cytology with imaging and final outcome. AB - OBJECTIVE: To analyze the effectiveness of fine needle aspiration (FNA) cytology in a multidisciplinary setting in rural Australia and to compare the imaging (mammographic and ultrasound) appearances and cytomorphologic findings with the final outcome. STUDY DESIGN: Prospective analysis of ultrasound-guided FNA cytology results from 426 women, aged 40-86 years, with screening-detected mammographic abnormalities. Cases of microcalcification, assessed mainly by stereotactatic core biopsy, were not included in the study. The FNAs were performed at a rural breast screening and assessment program in New South Wales, Australia, over a three-year period between May 1993 and May 1996. RESULTS: Imaging, FNA and combined imaging and FNA results from 426 women were as follows. The imaging diagnoses included 176 (41%) benign, 34 (8%) probably benign, 17 (4%) equivocal, 104 (24%) suspicious and 95 (23%) malignant cases. The FNA findings showed 59 (14%) no epithelial cells seen (nondiagnostic), 175 (41%) benign, 36 (8%) atypical, 41 (10%) suspicious and 115 (27%) malignant. Combined imaging and cytologic results comprised 224 (52.6%) benign, 10 (2.3%) atypical/equivocal, 59 (13.9%) suspicious and 133 (31.2%) malignant cases. All the malignant cases, by combined assessment, had malignant histology, and all the benign cases behaved in a benign fashion. In 80% of the suspicious lesions, the histologic diagnosis was malignant, but only 10% of the atypical/equivocal lesions had malignant histology. The positive predictive value of diagnosis of malignancy by combined imaging and FNA was 100%, and the false negative rate was 0%. CONCLUSION: Despite the recent surge in the popularity of core biopsy, FNA cytology of impalpable, mammographically detected lesions, when practiced in a multidisciplinary setting, is an extremely accurate test with high sensitivity, specificity, predictive values and efficacy. FNA cytology of the breast is a well-tolerated, relatively noninvasive test with a very low risk of complications. The sensitivity and positive predictive values for malignant and suspicious mammographic categories are also very high. PMID- 10097706 TI - Cytologic features of malignant peripheral nerve sheath tumor. AB - OBJECTIVE: To study the cytomorphologic features of malignant peripheral nerve sheath tumor (MPNST), including the epithelioid cell variant, and to establish differential diagnostic features with benign neurogenic tumors and other sarcomas. STUDY DESIGN: Cytologic smears from primary, recurrent and metastatic tumors in 10 patients with MPNST were reviewed. Three patients had neurofibromatosis 1 (NF1), and in two others the tumor arose from a preexisting neurofibroma. Immunocytochemical evaluation of S-100 protein was performed in four cases. A complete pathologic study was available in all cases. To assess the validity of morphologic recognition, a blinded study, including eight cases of spindle MPNST among smears from histologically proven schwannomas, synovial sarcomas, leiomyosarcomas, malignant fibrous histiocytomas and liposarcomas, was performed. RESULTS: Neurogenic differentiation was recognizable in four cases (differentiated), while the other four (anaplastic) were indistinguishable from other pleomorphic sarcomas. The presence of elongated, slender, often wavy nuclei and less commonly a delicate, fibrillary metachromatic stroma were features suggestive of nerve sheath differentiation. Other cytologic, as well as clinical, features permitted their identification as malignant. Two cases of epithelioid MPNST disclosed large, polygonal to plasmocytoid tumor cells without specific cytologic features. S-100 immunoexpression was positive in two of the four cytologic samples tested. CONCLUSION: Although no morphologic findings are specific to MPNST, the above-mentioned cytologic features may suggest, in differentiated cases, its neurogenic differentiation. On the basis of morphologic features alone, the diagnosis of anaplastic and epithelioid MPNST is not possible, and immunocytochemical and ultrastructural studies are necessary. A specific cytodiagnosis is possible in recurrences, metastases and cases of NF1 or a preexisting neurofibroma. PMID- 10097707 TI - Renal fine needle aspiration cytology. AB - OBJECTIVE: To audit and evaluate the pitfalls in renal fine needle aspiration (FNA) cytology. STUDY DESIGN: A retrospective analysis of 180 renal FNAs from 163 patients, encountered at Canberra Hospital, Australian Capital Territory, between June 1989 and July 1997 was undertaken. The FNA procedures had been performed by radiologists under computed tomography (CT) or ultrasound (US) guidance. The study correlated the FNA results with biopsy findings and clinical outcome. RESULTS: The initial cytologic diagnoses included 84 (47%) benign, 6 (3%) atypical, 7 (4%) suspicious, 70 (39%) malignant and 13 (7%) inadequate. Six of the 13 cytologically inadequate group, on further investigation, had malignant histology. The benign cytologic categories contained 79 benign conditions and 5 cases with a malignant outcome. The atypical cytologic group contained 5 benign and 1 malignant case. All nine cytologically suspicious cases had malignant histology. The cytologically malignant group contained 62 malignant, 7 benign and 1 patient lost to follow-up. The sensitivity was 92.5%, specificity was 91.9%, positive predictive value was 89.9%, negative predictive value was 94.0%, and efficacy of the test was 92.2%. CONCLUSION: Renal FNA can provide an accurate diagnosis in most instances; however, aspiration cytology of the kidney has limitations and pitfalls. Low grade renal cell carcinoma has to be differentiated from oncocytoma, angiomyolipoma, renal infarct and reactive conditions. Renal FNA has a high negative predictive value, which is useful in reassuring patients with radiologically and cytologically benign lesions. Negative FNA does not exclude malignancy in the presence of a radiologic suspicion. PMID- 10097708 TI - Fine needle aspiration cytology in the diagnosis of tuberculous mastitis. AB - OBJECTIVE: To study the relationship between granulomas in the breast and tuberculous mastitis. STUDY DESIGN: Retrospective analysis of 22 breast aspirates that showed epithelioid cell granulomas. The aspirates were reviewed and the cytomorphologic findings summarized. RESULTS: Aspiration cytology revealed epithelioid cell granulomas along with giant cells, necrosis and inflammatory cell infiltrate. Overall acid-fast bacillus (AFB) positivity was 22.7%. AFB positivity was greater in the presence of necrosis when epithelioid cells were absent. CONCLUSION: In a country like India, the diagnosis of granulomatous mastitis must be made with caution, even in the absence of AFB. Only after a sufficient trial of antituberculosis treatment has been given and the patient fails to respond should an alternative diagnosis be suggested. PMID- 10097709 TI - Increased incidence of cervical intraepithelial neoplasia in young women in the Mitte district, Berlin, Germany. AB - OBJECTIVE: To investigate whether the incidence of cervical intraepithelial neoplasia (CIN), in particular of high grade CIN, increased in Berlin during the period 1970-1989 and whether the ages of women with CIN had decreased. STUDY DESIGN: In the former German Democratic Republic, which had a highly centralized public health system, all gynecologic operations performed on women living in the Mitte district of Berlin were carried out during the period 1970-1989 (when the Berlin Wall fell) in the gynecologic clinic of the Charite Hospital. RESULTS: The incidence of all CIN increased from year to year over the observation period: 0.04% (1970-1971), 0.10% (1980-1981), 0.39% (1988-1989). There was a particularly high increase in the incidence of high grade intraepithelial neoplasms (CIN 3): 0.016% (1970-1971), 0.056% (1980-1981), 0.25% (1988-1989). With a virtually unchanged age distribution for women in the Mitte district of Berlin, the median age of women with CIN 3 decreased significantly from 1970 to 1989, from 39.5 (1970) to 33 (1989) (P < .001). CONCLUSION: The increase in the incidence of CIN, especially of high grade CIN, as well as the reduction in age for onset of the disease, makes high participation in screening necessary, above all among young women. PMID- 10097710 TI - Cytologic findings in vitreous fluids. Analysis of 74 specimens. AB - OBJECTIVE: To review the cytologic findings of vitreous specimens and propose a simplified approach to them. STUDY DESIGN: Seventy-four vitreous specimens from 60 patients obtained either during a pars plana vitrectomy or by vitreous aspiration were reviewed. Clinical correlation was obtained on all patients. RESULTS: Findings suggestive of a specific disorder were present in 30 specimens (41%); cytologic examination of the remaining 44 showed nonspecific changes. A lymphoproliferative disorder, the intraocular malignancy suspected most often in this series, was identified in eight specimens (11%). Large cell lymphomas were evident in 5 specimens, 2 specimens were suspicious for lymphoma, and 1 specimen was consistent with plasmacytoma. Twelve specimens (16%) contained hemorrhage. In rare instances, specific infectious agents, such as parasites (5%), bacteria (1%) and fungi (3%), could be identified. The diagnosis of viral infections required ancillary studies. Lens fragments were identified in four cases (5%), and a diagnosis of lens-induced endophthalmitis could be rendered in one case (1%). Changes consistent with sarcoidosis were present in 3% of cases. CONCLUSION: Based on this experience with vitreous specimens submitted for clinical reasons, we found that they could be divided into three broad diagnostic categories: inflammation/infection (54 specimens/41 patients), hemorrhage (12 specimens/12 patients) and malignancy (8 specimens/7 patients). PMID- 10097711 TI - Pheochromocytoma. Cytologic findings on intraoperative scrape smears in five cases. AB - BACKGROUND: There have been few studies describing the cytology of adrenal pheochromocytoma (PC). Although fine needle aspiration (FNA) for a preoperative diagnosis of PC is generally considered a contraindication, this tumor can be an unsuspected finding in adrenal FNA performed for other reasons. STUDY DESIGN: Scrape cytology smears prepared in five cases of PC were examined for different cytomorphologic features. The results were correlated with the corresponding permanent histologic sections. RESULTS: Previously described features, like cellular smears showing cells with abundant, poorly defined fragile cytoplasm, bare nuclei, anisonucleosis, "salt and pepper" chromatin, variable nucleoli and few ganglion cell-like cells, were noted. In addition, several previously unreported cytologic features were observed: (1) loosely cohesive PC cells along a ramifying, delicate central core; (2) intracytoplasmic microvesicular (not hyaline/homogeneous) globules; and (3) different arrangements of capillary-stroma and PC cells (Zellballen pattern; empty capillary rings; stroma with adherent, intact PC cells or fragments of disrupted PC cell cytoplasm). CONCLUSION: The cytologic appearance of PC may resemble that of other neuroendocrine tumors; however, it can be diagnostic when combined with proper clinical data and ancillary tests. PMID- 10097712 TI - Rehydration of air-dried smears. An alternative method for cytologic analysis of exfoliative cells. AB - OBJECTIVE: To compare the cytologic characteristics of gastric mucosal cell smears prepared by air drying and rehydration prior to alcohol fixing with cells wet fixed in alcohol. STUDY DESIGN: Gastric mucosal cells were obtained from 55 consecutive patients undergoing gastroscopy. Paired smears were made, one immediately fixed in 95% ethanol for 20 minutes (wet fixed [WF]) and the other air dried for at least 20 minutes prior to rehydration with normal saline for 30 seconds and fixation in 95% ethanol for 20 minutes (air dried/rehydrated/fixed [ARF]). Both slides were stained by the Papanicolaou method. Coded slides were examined blind and graded 1 (superior), 2 (satisfactory) or 3 (poor) with respect to staining of chromatin, nuclear membrane, nucleoli, cytoplasm/cell border and group morphology. Histology confirmed a benign disease process or normal mucosa. RESULTS: Comparing grade 1 versus grades 2 and 3, ARF slides were significantly better than WF slides for all cytologic features (P < .05). Comparing grade 1 and 2 versus grade 3, there was no significant difference between ARF and WF slides (P > .05) (chi 2 analysis). CONCLUSION: The cytologic features of ARF smears of gastric cells were equal or superior to those of WF smears. This method of preparing smears is simpler and avoids some of the problems of ethanol fixation of wet smears. PMID- 10097714 TI - Cytology of ascitic fluid in a patient with granulocytic sarcoma (extramedullary myeloid tumor). A case report. AB - BACKGROUND: Granulocytic sarcoma (GS) is the rare extramedullary manifestation of acute myeloid leukemia that may precede or be concurrent with leukemic infiltration of bone marrow or herald blastic transformation of a chronic myeloproliferative disorder. It has been found in most body sites and shows no age or sex predilection, necessitating its inclusion in the differential diagnosis of undifferentiated neoplasms. CASE: A 36-year-old female presented with a three-year history of abdominal pain, jaundice and fluctuating abdominal girth. Cytology of the ascitic fluid revealed myeloid cells of eosinophilic lineage at all stages of differentiation, with many undifferentiated cells. Immunohistochemical studies on a cell block confirmed the diagnosis of granulocytic sarcoma, which excluded the differential diagnoses of Hodgkin's disease, non-Hodgkin's lymphoma and Langerhans histiocytosis. CONCLUSION: Granulocytic sarcoma may present as a serous effusion and can be diagnosed on a cytologic specimen. PMID- 10097713 TI - Immunocytochemistry applied to aspiration biopsy cytology. Diagnostic contribution in 100 cases of previously stained, routine specimens. AB - OBJECTIVE: To assess the contribution of immunocytochemistry (ICC) to aspiration biopsy cytology (ABC), in a diagnostic context, on routine, previously stained cytologic specimens. STUDY DESIGN: Among 5,221 consecutive cases of ABC, 5.3% were subjected to ICC in the clinical-morphologic context. One hundred of these cases, with a final clinical and histopathologic diagnosis, were studied to determine the contribution of this ancillary technique to the final cytologic diagnosis. All cases had histopathologic study and prospective ICC, performed on usual smears, alcohol fixed and previously stained by the Papanicolaou technique, and were subjected to an avidinbiotin-peroxidase complex method. RESULTS: ICC was contributory in 82% of cases. The contribution of ICC to ABC of lymphoid tissue, thyroid and related organs, soft tissue and miscellaneous cases was, respectively, 84% (39 cases), 88% (26), 72% (18) and 76% (17). ICC was noncontributory in 18 cases, due mainly to misleading interpretation (6%), uncharacteristic profile (5%) and inconclusive immunostain (7%). CONCLUSION: ICC could be successfully applied in routine ABC specimens since the usually investigated antigenic determinants are preserved, allowing previous morphologic study and screening of the smears. The principal contribution of ICC applied to lymph nodes, thyroid and soft tissue aspirates was, respectively, confirmation of metastatic neoplasms, differential of follicular versus C-cell proliferation and assessment of mesenchymal lineages. PMID- 10097715 TI - Ectopic hamartomatous thymoma. Report of a case with fine needle aspiration biopsy findings. AB - BACKGROUND: Ectopic hamartomatous thymoma is a rare, benign tumor occurring exclusively in the supraclavicular and suprasternal regions. To the best of our knowledge, there are no English-language reports on its cytologic findings. CASE: A fine needle aspiration specimen from a mass in the suprasternal region in a 63 year-old male revealed epithelial cell nests, spindle cells, a cluster of mature adipocytes and a small number of lymphocytes. CONCLUSION: Although ectopic hamartomatous thymoma is very rare, fine needle aspiration cytology may contribute to the correct diagnosis in conjunction with the characteristic clinical findings. PMID- 10097716 TI - Fine needle aspiration diagnosis of transitional cell carcinoma metastatic to the brain. A case report. AB - BACKGROUND: Transitional cell carcinoma (TCC) rarely metastasizes to the brain. In this case, aspiration of a cystic brain lesion was performed and a cytologic diagnosis made. To the best of our knowledge, this is the first reported case of TCC metastatic to the brain diagnosed by fine needle aspiration. CASE: A 72-year old male with a past medical history of invasive TCC, colonic adenocarcinoma and prostatic adenocarcinoma presented with a large, right, temporal, cystic mass. Fine needle aspiration was performed intraoperatively, and a cytologic diagnosis of metastatic TCC was rendered and confirmed by subsequent tissue examination. CONCLUSION: Intraoperative fine needle aspiration of cystic tumors can be useful in identifying the primary site. The cytologic features of intracerebral metastatic TCC can differ significantly from those observed in urinary tract specimens of high grade TCC. A predominance of large fragments of malignant cells with numerous mitotic figures and apoptotic bodies was seen in the former. The background showed high grade, single transitional cells similar to those observed in urinary tract samples of TCC. PMID- 10097717 TI - Posttransplantation lymphoproliferative disorder mimicking a nonspecific lymphocytic pleural effusion in a bone marrow transplant recipient. A case report. AB - BACKGROUND: Serous effusions are rare complications of bone marrow transplantation (BMT) and result mainly from infections or tumor relapse. CASE: We report a case of posttransplantation lympho-proliferative disorder (PTLD) revealed by cytodiagnostic examination of serous effusions in a BMT recipient. The effusion was initially considered reactive, but morphologic, immunocytologic and molecular studies subsequently revealed PTLD. CONCLUSION: This case demonstrates the importance of cytologic examination of effusions in BMT or organ recipients. Since most PTLDs are Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders and T cells predominate in reactive effusions, appropriate initial immunostaining, including CD3, CD79a and EBV latent membrane protein, should aid in their early detection. PMID- 10097718 TI - Cytologic findings in noninvasive intraductal papillary-mucinous carcinoma of the pancreas. A report of two cases. AB - BACKGROUND: Intraductal papillary-mucinous carcinoma of the pancreas is a new diagnostic term proposed by the 1996 World Health Organization classification of the exocrine pancreas. So far, there have been only a few reports concerning its cytologic findings, especially in noninvasive cases. CASES: The clinical and cytohistologic findings in two cases of noninvasive intraductal papillary mucinous carcinoma of the pancreas were reviewed. Cytologic specimens were obtained from pure pancreatic juice in the dilated main pancreatic duct during the operation (case 1) and during endoscopic retrograde pancreatography (ERP) (case 2). Both cases showed three-dimensionally or individually scattered tumor cells with an increased nuclear/cytoplasmic ratio and prominent nucleoli. CONCLUSION: Our cases suggest that pancreatic juice cytology during ERP or surgery is useful in diagnosing pancreatic cancers and that it may detect noninvasive intraductal papillary-mucinous carcinoma of the pancreas. PMID- 10097719 TI - HIV-1 (p24)-positive multinucleated giant cells in HIV-associated lymphoepithelial lesion of the parotid gland. A report of two cases. AB - BACKGROUND: Cystic benign lymphoepithelial lesion (CBLL) is a well-recognized parotid disorder the diagnosis of which can be made on the basis of clinical findings, human immunodeficiency virus (HIV) testing, image studies and fine needle aspiration (FNA). Most aspirations are cystic, and the lesion can be recognized if the triad of foamy macrophages, lymphoid and epithelial (squamous) cells is observed. CASES: The authors recently observed FNA cytologic features of two HIV-associated cases that exhibited numerous multinucleated giant cells (MGCs) but failed to show the epithelial component. A subsequent surgical resection was performed in one patient. Similarly to what has been described for nasopharyngeal (adenoid and tonsil) lymphoid tissue of HIV-positive patients, intense immunoexpression of S-100 and p24 (HIV-1) protein was present in MGC. CONCLUSION: The diagnosis of HIV-associated CBLL should always be considered if a parotid cystic lesion presents with numerous MGCs. Immunocytochemical detection of p24 (HIV-1) protein in MGC becomes a very useful diagnostic aid and extends to parotid CBLL many of those pathogenic features of HIV-1 infection already noted in other HIV-1-infected, lymphoid oropharyngeal lesions. PMID- 10097720 TI - Cytologic features of central neurocytomas of the brain. A report of three cases. AB - BACKGROUND: Although cytologic smears are major tools for intraoperative diagnosis of intracranial tumors, cytologic features of central neurocytoma, a tumor that has been recognized for only about 15 years, have not been described. CASES: Typical central neurocytomas were encountered in three patients: 40 years old/M, 44/M and 31/F. Intraoperative cytologic smears were reviewed, and all tumors were subsequently examined by conventional histology, immunohistology and, in one case, electron microscopy. The important cytologic appearances were sheets of round cells with finely stippled nuclear chromatin and perinuclear haloes. Calcospherites, neuropil islands and rosettelike structures were focally encountered. The background neuropil was finely fibrillated, but the tumor cells possessed no appreciable cellular processes. CONCLUSION: Central neurocytomas possess distinct cytologic features that help with the intraoperative distinction from oligodendrogliomas and other intraventricular tumors. A combined radiologic and morphologic approach to the diagnosis of this tumor is advised. PMID- 10097721 TI - Inflammatory pseudotumor of the urinary bladder with aberrant expression of cytokeratin. Report of a case with cytologic, immunocytochemical and cytogenetic findings. AB - BACKGROUND: Cytologic descriptions of inflammatory pseudotumor of the urinary bladder are exceedingly rare. We describe here an additional case of this disease, including its cytologic features and aberrant expression of cytokeratin. CASE: A 35-year-old male presented with gross hematuria but no history of bladder surgery. Urine cytology revealed a few atypical spindle cells suspicious for sarcoma. Histologically, the lesion consisted of spindle cells of various sizes and shapes, proliferating in irregularly running bundles, but no severe nuclear atypia or pathologic mitosis was found. Immunocytochemically, these cells were unexpectedly positive for cytokeratin as well as for vimentin and muscle actin. All metaphase cells examined revealed a normal male karyotype. CONCLUSION: Inflammatory pseudotumor must be distinguished in particular from leiomyosarcoma and spindle cell carcinoma. To avoid an erroneous diagnosis, recognition of this entity is important, together with careful histologic examination and awareness of the possible aberrant expression of cytokeratin. PMID- 10097723 TI - Allergic fungal sinusitis. A report of two cases with diagnosis by intraoperative aspiration cytology. AB - BACKGROUND: Allergic fungal sinusitis (AFS) is a newly recognized form of sinusitis characterized by opacification of the paranasal sinuses by "allergic mucin" (AM) admixed with scattered fungal organisms. AM consists of necrotic, or partially necrotic, eosinophils and Charcot-Leyden crystals suspended in lakes of laminated, mucinous material. AFS is characterized by the absence of bone or soft tissue invasion, purulent exudate or granulomatous inflammation. Clinically, it is important to differentiate AFS from both acute invasive fungal sinusitis and noninvasive mycetoma because the three diseases are treated with different modalities and have different prognoses. Although the radiologic features of AFS are often characteristic, occasionally it may be difficult to exclude neoplasia. CASES: Two cases of AFS, in which intraoperative diagnosis was made on the basis of the presence of both AM and fungal organisms, are reported. CONCLUSION: Cytologic diagnosis of AFS can be made from intraoperative sinus aspirates from the presence of AM and fungal elements. AM and fungi provide presumptive evidence for a noninvasive, allergic fungal disease and can help reassure clinicians intraoperatively and guide clinical management. PMID- 10097722 TI - Giant cell carcinoma of the lung. Report of a case with cytohistologic and clinical correlation. AB - BACKGROUND: Giant cell carcinoma (GCC) of the lung is an unusual tumor characterized by an aggressive outcome. CASE: A peripheral lung tumor was observed in an elderly male. At presentation the clinical symptoms were cough, thoracic pain and hemoptysis. Chest roentgenography showed a left pleural effusion and neutrophilia in the blood. Bronchoscopic examination showed a peripheral tumor mass that could not be biopsied. Bronchoalveolar lavage was negative. The patient underwent a cerebrovascular accident and died. The autopsy showed a peripheral giant cell tumor of the left lung that involved regional and mediastinal lymph nodes. Touch imprints showed tridimensional clusters of pleomorphic and large cells, some of which were multinucleated, containing leukocytes in their cytoplasm. CONCLUSION: This case illustrates the typical cytohistologic features of GCT of the lung, which should be considered in the differential diagnosis of any peripheral lung tumor composed of large cells. Clinical correlation is helpful in reaching the correct diagnosis. PMID- 10097724 TI - Diagnosing invasive cystic hypersecretory duct carcinoma of the breast with fine needle aspiration cytology. A case report. AB - BACKGROUND: Cystic hypersecretory duct carcinoma (CHC) of the breast, first described in 1984, is a rare variant of duct carcinoma. Histologically it is characterized by the formation of dilated ducts and cysts containing an eosinophilic secretory product resembling thyroid colloid. The lining epithelium of the cysts atypically proliferates to form intraductal carcinoma. Only four cases of invasive cystic hypersecretory carcinoma have been reported. CASE: We present a case of invasive CHC with tumor emboli in many lymphatic spaces and axillary nodal metastases. The lesion was also evaluated by fine needle aspiration. Direct smears with Papanicolaou stain were highly cellular and had abundant, intensely staining, orange-to-gray-green thyroid colloid-like material. Epithelial cells, showing a variety of cellular patterns, were indistinguishable from usual ductal carcinoma cells. These cytologic findings may be characteristic enough to suggest cystic hypersecretory carcinoma. CONCLUSION: The cytologic features of CHC are distinctive and correlate with histology. This was the first presentation of colloidlike secretory material in cytologic material with Papanicolaou stain in such a case. Invasive CHC tends to have aggressive behavior. Cystic hypersecretory hyperplasia coexisted in this case. PMID- 10097725 TI - Lymphoepithelial cyst with crystalloid formation. Cytologic features of two cases. AB - BACKGROUND: The presence of amylase crystalloids (AC) in cystic lesions of the parotid gland is a rare occurrence and has been diagnosed to date as sialadenitis. We report the first two cases of parotid lymphoepithelial cyst (LC) containing this type of crystalloid. CASES: Case 1, a 56-year-old male, presented with a 3-cm parotid cyst. Fine needle aspiration (FNA) was performed on the mass. Smears showed numerous crystalloids identical to those described as crystallized amylase. Case 2, a 36-year-old female, had a 2-cm parotid mass. FNA smears exhibited the same features as did case 1. The two patients were treated with superficial parotidectomy, and an LC containing AC was diagnosed in both cases. CONCLUSION: When the above findings are present on FNA of parotid gland, the diagnosis of LC must be considered. PMID- 10097726 TI - Calcium oxalate crystals in benign cyst fluid from the breast. A case report. AB - BACKGROUND: Two types of calcification have been observed in breast lesions. The more common is composed mostly of calcium phosphate and is detected in routine histologic tissue sections of frequently malignant lesions. The rare type is calcium oxalate and is found exclusively in benign cysts. CASE: In a 47-year-old female, strongly birefringent polyhedral crystals of calcium oxalate were detected in benign breast cyst fluid. CONCLUSION: Calcium oxalate is not clearly visible on routine histologic sections, and examination of the cytologic specimens under polarized light reveals them. Awareness of this potential pitfall might lead to conservative management. PMID- 10097727 TI - Exfoliative cytology of a lymphoepithelioma-like carcinoma in a cervical smear. A case report. AB - BACKGROUND: Lymphoepithelioma-like carcinoma of the cervix (LELC) is cytologically identical to its counterparts at other sites, such as the nasopharynx. LELC can be suspected on a cervical cytologic smear. The differential diagnosis includes nonkeratinizing squamous cell carcinoma with prominent stromal inflammation, carcinoma with intense stromal eosinophilia, glassy cell carcinoma, malignant lymphoma (especially lymphoepitheloid-Lennerts lymphoma) and metastatic Schmincke-Regaud tumor. CASE: A 55-year-old female presented with an ulcerated endophytic tumor in the cervix. Exfoliative cytology showed uniform, large tumor cells, often associated with inflammatory cells, with round or oval nuclei and one or more prominent nucleoli. The cytoplasm was finely granular to flocculent, and the nuclei were uniformly vesicular. The chromatin was peripherally marginated. The cell borders were indistinct. There was no evidence of dyskeratotic or keratinized cells, koilocytes or glandlike formations. These findings were highly suspicious for LELC and were confirmed by biopsy. Flow cytometry showed DNA aneuploidy, with a DNA index of 1.08. In situ hybridization was negative for human papillomavirus 16 and 18. CONCLUSION: LELC of the uterine cervix has cytologic features that are sufficiently characteristic for a specific cytologic diagnosis. The diagnosis, nevertheless, has to be proven by histology. PMID- 10097728 TI - Scrape cytology of oral pemphigus. Report of a case with immunocytochemistry and light, scanning electron and transmission electron microscopy. AB - BACKGROUND: Pemphigus vulgaris is a disseminated disease of the skin and mucous membranes characterized by recurrent vesicular and bullous lesions due to the autoantigen belonging to the cadherin type of cell adhesion molecules. The presence of acantholysis associated with immunoglobulins in the intercellular spaces and on the cell membrane are diagnostic features. However, the appearance of smears from the oral cavity by scanning (SEM) and transmission electron microscopic (TEM) study as well as immunocytochemistry of cadherin does not appear to have been previously reported. CASE: A 67-year-old female developed erosion on her gingiva with severe pain. On oral examination, there were ulcerations on the palate, and the Nikolsky sign was positive. The characteristic cytologic findings from oral scrapes were high cellularity, a bloody background and a predominant cell population consisting of polygonal basal and parabasal cells with pronounced nucleoli. Also present were degenerative cell changes: e.g., cytoplasmic vacuoles and a homogeneous nuclear appearance. Immunocytochemical staining for IgG and cadherin gave a positive reaction in the intercellular spaces and on the cell membranes. The surface of cells in pemphigus vulgaris by SEM showed somewhat irregularly distributed microridges, and TEM revealed desmosomal attachments, degenerated tonofilaments with pronounced nucleoli and heterochromatin. As a result of cytodiagnosis, additional appropriate specimens were obtained at the time of the scraping for confirmatory immunocytochemistry for cadherin, SEM and TEM studies. CONCLUSION: The results demonstrate that a precise diagnosis of pemphigus vulgaris can be rendered on cellular material and cadherin immunocytochemistry obtained by scrape from the oral mucosa. PMID- 10097729 TI - Fine needle aspiration diagnosis of extraadrenal myelolipoma presenting as a pleural mass. A case report. AB - BACKGROUND: Myelolipoma is a benign tumor composed of mature adipose tissue and hematopoietic cells. Although they are commonly found in adrenal glands, extraadrenal myelolipomas (EMLs) are rare but well documented. They have been found in various sites, including mediastinum, liver, stomach, lungs, pelvis, spleen, retroperitoneum, presacral region and mesentery. EMLs must be distinguished from extramedullary hematopoieses, which are also composed of hematopoietic elements but may lack adipose tissue and are associated with anemia and marked bone marrow hyperplasia. CASE: We describe a case of a pleura-based, extraadrenal myelolipoma in a 53-year-old female with unremarkable bone marrow findings that were initially encountered on fluoroscopy-guided fine needle aspiration (FNA). One year later the mass was removed via open thoracotomy. It showed typical EML features histologically. CONCLUSION: EML manifests on aspiration cytology as a cellular specimen with numerous trilineage hematopoietic cells and a variable proportion of mature adipose cells. To our knowledge, FNA cytology of EML has not been found in this location before. Aspiration biopsy offers a simple and reliable method for the diagnosis of EML in the presence of appropriate clinical settings. PMID- 10097730 TI - Association of body cavity-based lymphoma and human herpesvirus 8 in an HIV seronegative male. Report of a case with immunocytochemical and molecular studies. AB - BACKGROUND: Recently lymphomas arising primarily in serosal surfaces have been found in patients with advanced acquired immunodeficiency syndrome (AIDS), but they very rarely seem to occur in human immunodeficiency virus (HIV)-negative patients. Studies on a subset of these lymphomas suggested that they represent a distinct entity associated with Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8 (HHV-8). CASE: An 83-year-old, HIV-negative male was admitted to the hospital with a massive pleural effusion. Abdominal and chest computed tomographic scanning was normal. Cytologic analysis of the pleural effusion revealed a large cell, non-Hodgkin's lymphoma. Polymerase chain reaction analyses on genomic DNA from the pleural effusion demonstrated the presence of HHV-8 sequences in the absence of Epstein-Barr virus. CONCLUSION: It is possible and advantageous to diagnose body cavity-based lymphoma with a combination of cytologic, immunocytochemical and molecular studies of the pleural effusion in conjunction with clinical and radiographic information. PMID- 10097731 TI - Fine needle aspiration cytology and core biopsy histology in infiltrating syringomatous adenoma of the breast. A case report. AB - BACKGROUND: Infiltrating syringomatous adenoma is a rare tumor of the breast that can radiologically mimic invasive duct carcinoma. Detailed fine needle aspiration cytology and needle core biopsy findings on this lesion have not been previously described. CASE: The clinical, radiologic and pathologic findings of an infiltrating syringomatous adenoma of the breast in a 71-year-old female who presented with a subareolar lump are described. The cytology of the tumor was characterized by a combination of a background of plump, fibroblastoid cells and cohesive sheets of bland epithelial cells. Histologically the tumor showed infiltrating, duct-like structures with squamous metaplasia and a desmoplastic stroma. CONCLUSION: Fine needle aspiration cytology and needle core biopsy can distinguish infiltrating syringomatous adenoma from malignant disease of the breast. PMID- 10097732 TI - Nested polymerase chain reaction on vaginal smears of tuberculous cervicitis. A case report. AB - BACKGROUND: Tuberculous cervicitis (TC) is a rare disease the diagnosis of which is based on the microscopic and/or cultural recognition of mycobacteria. In recent years, the polymerase chain reaction (PCR), especially with double-round amplification ("nested" PCR [nPCR]), has been increasingly used for rapid detection of mycobacteria in clinical samples. CASE: The present case is the first example of tuberculosis diagnosed with the aid of nPCR amplification of mycobacterial DNA fragments on smeared and Papanicolaou-stained cytologic material. First detected on vaginal smears, the amplicon IS6110 was subsequently identified also on paraffin-embedded tissue sections. CONCLUSION: The technique described here could also be applied to aspiration cytology smears to give rapid and accurate information on mycobacterial infections. PMID- 10097733 TI - Fine needle aspiration cytology of thyroglossal duct cyst: an analysis of 10 cases. PMID- 10097734 TI - High grade adenosquamous carcinoma of the breast diagnosed by fine needle aspiration cytology. PMID- 10097735 TI - Balloon melanoma cells mimicking foamy histiocytes. PMID- 10097736 TI - Epidermoid cyst of the terminal phalanx of the right thumb diagnosed by fine needle aspiration cytology. PMID- 10097737 TI - Importance of Papanicolaou-stained smears and immunocytochemistry in the diagnosis of Rosai-Dorfman disease. PMID- 10097738 TI - [Thrombopoietin: current and future status]. AB - Thrombopoietin (TPO), which is a major physiological regulator of platelet production, was cloned in 1994. It has already been shown that the administration of recombinant TPO increases platelet production and accelerates platelet recovery after cytoablative therapy in preclinical and clinical trials. In addition, recent results indicate that the effects of TPO on hematopoiesis are more widespread than initially anticipated. In this article, physiological activities of TPO and results of clinical trials are briefly reviewed, and possible clinical application and some problems in its clinical use are discussed. PMID- 10097739 TI - [Improving the anti-tumor activity of 5-fluorouracil by methotrexate]. AB - The first clinical application of biochemical modulation (BCM) of 5-fluorouracil (5-FU) was the sequential MTX/5-FU regimen proposed in 1977 by Bertino for the treatment of colorectal cancer. In Japan, sequential MTX/5-FU therapy was mainly used as a new method of treating gastric cancer, and attracted a great deal of attention because it proved effective in many cases of advanced gastric cancer that had been unresponsive to the previous chemotherapy, particularly scirrhous gastric cancer with poor prognosis. Its therapeutic efficacy varied according to histologic type, it was effective in cases of peritoneal dissemination and disseminated intravascular coagulopathy (DIC), it was associated with fewer adverse effects, and it was a multidrug chemotherapy based on a clear rationale. With sequential MTX/5-FU therapy as a starting point, fundamental studies of BCM and its clinical applications have expanded rapidly in Japan. This paper provides an outline of sequential MTX/5-FU therapy from the aspects of its mechanism of action, indications, therapeutic efficacy, relevance to adjuvant therapy, counter measures to adverse effects, and emergence of resistance to the drugs involved. The high therapeutic efficacy of this therapy in certain histologic types is also discussed, and its combined use with other forms of BCM, as in triple BCM (LV/5 FU + CDDP/5-FU + MTX/5-FU), is introduced. PMID- 10097740 TI - [Leucovorin and 5-FU for advanced gastrointestinal cancer]. AB - During the last 40 years, 5-fluorouracil 5-FU) has been the drug of choice for treatment of patients with gastrointestinal cancer. However, its effectiveness is far from satisfactory. It has been determined that leucovorin (LV) potentiates the cytotoxic effect of 5-FU through prolonged inhibition of thymidylate synthase. A series of 10 trials comparing LV.5-FU with 5-FU alone were reported. A significantly higher objective response rate was seen with LV.5-FU, but there was no increase in survival. In randomized trials comparing low-dose and high dose LV as modulates of 5-FU in treating advanced colorectal cancer, high doses of LV presented no advantage over low doses. Adjuvant LV.5-FU was compared to surgery alone in large group trials, demonstrated and a statistically significant decrease in disease and increase in overall survival. These data suggest that LV.5-FU is a very effective combination and most clinicians worldwide now regard it as the standard therapy for colorectal cancer. PMID- 10097741 TI - [Mechanism and possible biochemical modulation of capecitabine (Xeloda), a newly generated oral fluoropyrimidine]. AB - A new 5-FU analog, Capecitabine (Xeloda; N-[1-(5-deoxy-b-D-ribofuranosyl)-5 fluoro-1, 2-dihydro-2-oxo-4-pyrimidyl]-n-penyl carbamate), was generated to decrease the incidence of GI toxicity and to increase the efficacy. Capecitabine is designed as a prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which is clinically used for gastric, breast and colorectal cancer patients undergoing single or combination chemotherapy in Japan. Capecitabine was converted to 5' DFUR by either human carboxyestelase or cytidine deaminase, which were mainly localized in human liver. 5'-DFUR was converted to the active form of 5-FU by thymidine phosphorylase (dThdPase) in human tumors. The expression of dThdPase was higher in malignant tumors than in noninvolved normal tissues. In this regard, a high concentration of either 5'-DFUR or 5-FU in malignant tumors may be obtained by oral administration of Capecitabine. In addition, in vivo study showed synergistic or additive effects of Capecitabine combined with anti-cancer agents (Taxanes, Mitomycin C or Cyclophosphamide), cytokines, growth factors and hormonal agents. Capecitabine may be biochemically modulated by those agents in vivo. In the results of an early phase II study on breast cancer patients in Japan, a high efficacy rate and low toxicity were observed. Also, Capecitabine was already registered as 2nd- or 3rd-line treatments for breast cancer patients by the Food & Drug Administration of the USA. Capecitabine is one of the most promising orally administered 5-FU analogs. PMID- 10097742 TI - [Combination therapy of continuous venous infusion (CVI) of 5-FU and low dose consecutive cisplatin (CDDP), and the new oral anti-cancer drug S-1 for advanced gastro-intestinal cancer]. AB - Highly effective treatment is required for patients with advanced GI cancer. Returning to the starting point for reconsideration of cancer chemotherapy, with the aim of attaining a therapy (self rescuing concept: SRC) with more potential efficacy and less toxicity than current therapy, we report two kinds of chemotherapy in the present paper. They were set up preclinically using the theory of 5-FU biochemical modulation, and demonstrated their usefulness in clinical practice. S-1 is a newly developed oral anti-cancer drug which is a combination of Tegafur (FT), a prodrug of 5-FU and two modulators (CDHP, an inhibitor of 5-FU degradation and Oxo, a selective inhibitor GI toxicity by 5-FU) at a molar ratio of 1:0.4:1. In combination with CDHP, 5-FU gradually released from FT remained longer in plasma, and consequently had high anti-tumor activity, while the combined Oxo significantly suppressed GI toxicity due to 5-FU. The response rate to S-1 of stomach cancer in a phase II study was 46.5% (60/129). Toxicity at more than G3 was less than 10%. In the combination therapy employing 5-FU by CVI (5-FU: 250-350 mg/body for 24 h, 4-6 wks) and low dose consecutive CDDP, CDDP acts mainly as a modulator of 5-FU (to increase 5-FU sensitivity for tumor by inhibition of intracellular Met incorporation). For this purpose, it was found that daily consecutive administration is required, even at low dose of CDDP (3-5 mg/body/day for 5 days). A high response rate (40-60%) was obtained for advanced GI cancer. Toxicity at more than G3 was less than 10%. On the other hand, the possibility has been suggested that so far as 5-FU is concerned, CVI every other day (500-750 mg/body/day for 3 days) is more favorable than long term CVI, with regard to decreasing GI and myelotoxicities based upon the difference in generation time between normal cell (GI mucous membrane and stem cell) and tumor cell cycles. The possibility is suggested that the above-mentioned chemotherapy can become a standard therapy for GI cancer. PMID- 10097744 TI - [Clinical evaluation of S-1, a new anticancer agent, in patients with advanced gastrointestinal cancer. S-1 Cooperative Gastrointestinal Study Group]. AB - In developing a new anticancer agent, it is most important to balance the antitumor activity and toxicity of the agent. S-1 was designed to achieve high activity and low toxicity. In it tegafur, a prodrug of 5-FU, is combined with two classes of modulators. CDHP, an inhibitor of 5-FU degradation in the liver, and Oxo, an inhibitor of 5-FU phosphoribosylation in the digestive tract. In both early and late Phase II studies, S-1 was effective against advanced or recurrent gastrointestinal cancer. Toxicities were generally mild, and there were no toxic deaths. PMID- 10097743 TI - [Biochemical modulation of 5-FU--effect of low dose CDDP]. AB - A pilot study of continuous or intermittent low dose 5-FU and cisplatin chemotherapy (low-dose FP therapy) was conducted at the Department of Surgery of Sapporo Medical University School of Medicine (Group A) and Sapporo Tsukisamu Hospital, and at the Department of Internal Medicine of the Kochi Prefectural Center Hospital (Group B). The cases with esophageal cancer, stomach cancer, pancreatic cancer, hepatocellular carcinoma or colonic cancer co-existing with their inoperable lesion(s) were considered in this chemotherapy. The rates of complete and partial response and of side effects were studied. Also, the effects of low-dose FP on the prognosis of the patients with pancreatic or colonic cancers were investigated. The procedure consisted of continuous 5-FU 320 mg/m2 i.v. with daily CDDP 2.5 mg/m2 i.v. for five days/week rescue was performed for at least four weeks as a rule. The rates of complete response and partial response were 64% (Group A) and 56% (Group B) in esophageal cancer, 62% (Group A and B) in stomach cancer, 48% (Group A) and 57% (Group B) in colonic cancer, and 8% (Group A) and 21% (Group B). The overall response rate was 57.8%. The frequencies of severe side effect(s) (grades 3 and 4) were within three to eight percent, and no death from side effect(s) was experienced. The effects of low dose FP therapy on the prognosis of stage IV colonic cancer and stage IV b pancreatic cancer were studied retrospectively. It is suggested that this chemotherapy might contribute to the survival of patients with these two cancers. Otherwise, the chemotherapy of intermittent administration (day by day) of 5-FU 750 mg/m2 i.v. and CDDP 2.5 mg/m2 i.v. was selected in order to decrease the rate of side effects and their severity. The pilot study encountered no severe side effects, no cases with grade 4 side effect were experienced but the remission rates were mostly similar to that of sequential low-dose FP therapy. However, the side effect of low grade ones as symptoms in gastrointestinal tract were observed in more patients. We concluded that sequential or intermittent 5-FU/CDDP therapy might be fairly effective, and since the adjuvant chemotherapy of choice for advanced or recurrent gastrointestinal cancer, their FP therapy might be one of the adjuvant treatments. PMID- 10097745 TI - [A late phase II clinical study of RP56976 (docetaxel) in patients with advanced or recurrent gastric cancer: a cooperative study group trial (group B)]. AB - A late phase II clinical study of RP56976 (docetaxel) in patients with advanced or recurrent gastric cancer was performed to evaluate the anti-tumor activity and clinical toxicity as a multicenter cooperative trial. Docetaxel was administered intravenously at a dose of 60 mg/m2 every 3-4 weeks. Of 72 patients enrolled, 63 patients were eligible and 59 patients were evaluable for response. The anti tumor effects obtained complete response (CR) in one patient partial response (PR) in 13, minor response (MR) in 3, no change (NC) in 20, and progressing disease (PD) in 22 patients. The overall response rate in 59 patients was 23.7% (14/59). For 14 CR or PR cases, a response appeared 10 to 107 days (median 33.5 days) and 1 to 8 (median 2) times of dosing after the initial administration. The response rate was 9.5% in the primary tumor, 31.3% livers, 50.0% abdominal tumor, and 24.1% lymph nodes, respectively. The major adverse reactions were gastrointestinal symptoms including nausea/vomiting, anorexia, fatigue, alopecia and fever. Leukocytopenia and neutrocytopenia were also observed with a high incidence, but they recovered after 8 days from the nadir. The results show that docetaxel is an effective anti-tumor agent for advanced or recurrent gastric cancer. It is necessary to conduct another clinical trial by concomitant administration with other anti-tumor agents. PMID- 10097746 TI - [Experimental study on intraperitoneal administration of 5-fluorouracil for liver metastasis in comparison with intravenous administration]. AB - We studied the effects of 5-fluorouracil intraperitoneal administration using mouse liver metastasis model. We inoculated 50 microliters Colon26 cell suspension into the spleen and resected it 15 min after cell inoculation under general anesthesia with Ketamine. Control group (n = 7) had no treatment. The intraperitoneal (i.p.) group (n = 8) and intravenous (i.v.) group (n = 7) underwent the treatment on the 2nd and 4th day after the operation. Experimental chemotherapies consisted of 1.5 ml 5-fluorouracil solution (50 mg/kg) for i.p. group and 0.2 ml 5-fluorouracil solution (50 mg/kg) for i.v. group. On the 14th day after the cell implantation, necropsies were performed. Deposits on mouse livers were counted and the mouse livers weighted. Counting of metastatic liver deposits revealed the number of deposits in the control group was 25.6 +/- 12.9, against 2.9 +/- 1.9 and 16.0 +/- 15.6, in the i.p. and i.v. group, respectively. Significant differences in the number of liver deposits were obtained between the control group and i.p. group, and between i.p. group and i.v. group (p < 0.05). The mean liver weight (mg)/mouse body weight (g) were 76.3 +/- 24.7 in the control group, 54.3 +/- 4.7 in the i.p. group and 60.0 +/- 12.7 in the i.v. group. A significant difference was observed only between the control group and the i.p. group (p < 0.05). I.p. administration of 5-fluorouracil was superior to i.v. administration for control of the liver metastasis. Moreover, the side effect by 5-fluorouracil i.p. treatment was milder than by i.v. therapy. We confirmed the effectiveness of 5-fluorouracil intraperitoneal chemotherapy for the potential liver metastasis and liver micrometastasis. Intraperitoneal chemotherapy is also useful for peritoneal seeding. We think intraperitoneal chemotherapy is a recommendable administration route for gastrointestinal malignancies. PMID- 10097747 TI - [Preventive effect of prostaglandin E1 on cisplatin-induced nephrotoxicity]. AB - In order to prevent the nephrotoxicity induced by cisplatin (CDDP), prostaglandin E1 (PGE1) was administered intravenously after anticancer chemotherapy to six patients with lung cancer. All patients underwent two courses of multi-drug chemotherapy with the same regimen including a single administration of 80 mg/m2 CDDP. From the 7th day of the 2nd course of chemotherapy, 120 micrograms PGE1 had been administered for five days. During the two courses of chemotherapy, serum creatinine, blood urea nitrogen, creatinine clearance (Ccr), 24-h excretions of beta 2-microglobulin (beta 2-MG) and N-acetylglucosaminidase (NAG) in urine were measured every week in all patients. The mean value of Ccr was higher in the 2nd course than in the control course (65 ml/min vs. 74 ml/min). The 24-h excretions of beta 2-MG and NAG were also reduced in the 2nd course. Out of six patients, only one was complicated by mild phlebitis at the PGE1 infusion site. From these results it was suggested that PGE1 was effective for prevention of CDDP nephrotoxicity. PMID- 10097748 TI - [Prophylaxis of recurrence in superficial bladder carcinoma by intravesical chemotherapy--comparative study between instillation of combined double anticancer agents and single anticancer agent]. AB - We performed a study to compare the usefulness of double or single anticancer agents in the prophylactic treatment after the transurethral resection (TUR) of superficial bladder cancer. We experienced 127 superficial bladder cancer cases. Of these cases, 42 were treated with intravesical adriamycin (ADR) and peplomycin (PEP), 56 with ADR, PEP, epirubicin (epi-ADR) or pirarubicin (THP) only, and the remaining 29 with TUR only. Nonrecurrence rates were significantly higher in the intravesical treated cases than in the cases with TUR only, and also significantly higher in the cases treated with ADR and PEP than the other treated cases. We concluded that intravesical chemotherapy with combined agents was more effective than with a single agent. PMID- 10097749 TI - [The control survey in CD marker analysis of leukemic cells]. AB - Analysis of cell surface antigens is thought to be more objective compared to classification by the morphology. However, it has been indicated that the evaluated data are different each other between institutes. Therefore, we performed a control survey of CD marker analysis in leukemia cells using flow cytometry in six commercial laboratories. The expression of CD2, 4, 5, 7, 8, 10, 13, 14, 19, 20, 33, 34, 38, and 71, HLA-DR in tumor cells from megakaryoblastic leukemia, lymphoblastic crisis of CML, and ALL patients, were examined. There were large differences in the results of CD marker analysis among the six commercial laboratories. One possible reason for this result is the differences in gating condition and monoclonal antibodies used in each laboratory. However, there were the differences in the results even when the same gating condition and antibodies were used. The reasons for the difference in transport or treatment conditions for samples remain a matter of considerable controversy. In the present condition, it was suggested that the exchange of information about the origin of tumor cells between the physician in charge and examination experts is thought to be the best way to analyze proper cell surface antigen expression. Further, no national survey has been carried out, but the establishment of a standard assay is preferred to obtain proper data for the patients and medical parties concerned. PMID- 10097750 TI - [A case in which palatal squamous cell carcinoma responded to UFT therapy]. AB - We administered UFT to a 70-year-old female with squamous cell carcinoma of the palatal mucosa (T1 N0 M0) who had not consented to radical surgical treatment. The tumor disappeared grossly and histopathologically after 1 month, and no adverse reaction to oral administration of UFT was noted. The patient remains under observation. PMID- 10097752 TI - [Palliation for a recurrent lung cancer patient with superior vena cava syndrome by arterial infusion of CDDP through the implantable port system--a case report]. AB - A case of lung cancer with superior vena cava syndrome treated with internal thoracic arterial infusion of anti-cancer drugs by the implantable port system was reported with our technique. In this case, blood supply was mainly from internal thoracic artery. A trans-catheterial contrast enhanced helical CT was very helpful to identify the routes of blood supply to the lung cancer. PMID- 10097751 TI - [Nedaplatin and etoposide combination chemotherapy in a patient with small cell carcinoma undergoing hemodialysis]. AB - A 61-year-old man with chronic renal failure caused by polycystic kidney disease requiring hemodialysis three times weekly developed small cell carcinoma of the lung. The patient received combination chemotherapy with nedaplatin (50 mg) and etoposide (50 mg). Blood levels were monitored, showing that nedaplatin was more dialyzable than cisplatin. The patient achieved a complete response. These results suggest that nedaplatin-etoposide combination chemotherapy may be safer than cisplatin-containing regimen for patients with chronic renal failure hemodialysis and that a satisfactory response can be expected. PMID- 10097753 TI - [Relationship between cancer chemotherapeutic drug-induced delayed emesis and plasma levels of substance P in two patients with small cell lung cancer]. AB - We investigated the relationship between delayed emesis caused by cisplatin (CDDP) based chemotherapy and plasma levels of serotonin, 5-hydroxy-indoleacetic acid (5-HIAA), and substance P in two patients with small cell lung cancer. In each of the cases, we used the 5-HT3 receptor antagonist ramosetron every morning on day 1-4 of the chemotherapy. In case 1, plasma levels of serotonin were low, whereas substance P levels increased since 24 hours after the injection of CDDP. The increase in substance P levels paralleled the onset of vomiting. In this case, however, substance P levels decreased and yet vomiting occurred. Similarly, in case 2, plasma levels of serotonin were low, whereas substance P levels increased since 24 hours. The increase in plasma levels of substance P and the onset of vomiting were observed at the same time 2-3 days after cisplatin administration. In this case, however, vomiting was not observed during the 5 days when the substance P was highest. Therefore, we suggested that substance P was closely associated with CDDP-induced delayed emesis, though some chemical mediators other than substance P might also be related to the emesis. PMID- 10097754 TI - [A case of advanced gastric cancer successfully treated by neoadjuvant chemotherapy with CPT-11, CDDP and 5-FU]. AB - A patient with advanced gastric cancer was treated with combined administration of CPT-11 CDDP and 5-FU before operation. CPT-11 was given intravenously at a dose of 30 mg/m2/day on day 1 and day 8. At the same time, 5 mg/m2/day CDDP and 350 mg/m2/day 5-FU were infused for 2 weeks. The patient experienced no other adverse reaction than a mild degree of nausea. Histological examination of the resected specimen revealed complete disappearance of cancer cells both in the stomach and the regional lymphnodes. PMID- 10097755 TI - [Successful combination chemotherapy for a case of small cell carcinoma of the rectum with multiple liver metastasis]. AB - A 69-year-old-man with small cell carcinoma of the rectum and multiple liver metastases was admitted in December 1996. Poorly differentiated adenocarcinoma was preoperatively diagnosed in a biopsy specimen from the rectum. Chemolipiodolization using 50 mg DXR and 6 ml lipiodol was performed for the multiple liver metastases. Ten days later, he underwent rectal amputation including lymph node dissection combined with the implantation of reservoir for hepatic arterial infusion chemotherapy. After operation 5-FU (500 mg, days 1-5) and CDDP (10 mg, days 1-5) were injected for 3 weeks through hepatic arterial route. The metastatic lesions in the liver represented a good response to the chemolipiodolization, though the metastatic tumor in the liver S4 region did not disappear on CT scan. The histological diagnosis of the resected rectum revealed small cell carcinoma so we attempted additional chemotherapy according to the regimen for treatment of small cell lung cancer. ETP + CDDP therapy was performed, in which ETP (100 mg, days 1-3) and CDDP (80 mg, day 1) were intraarterially infused. After three courses of this therapy, he achieved a complete response (CR) for the liver metastasis. Two courses of ETP + CDDP therapy were additionally performed in the outpatient department, and treatment is currently continued by oral administration of ETP (75 mg/day). He has been free of the disease for 16 months with few side effects. The combination therapy of chemolipiodolization and hepatic arterial infusion chemotherapy with ETP and CDDP may assure a good prognosis for multiple liver metastases of small cell rectal cancer. PMID- 10097756 TI - [Thermo-chemotherapy using low-dose CPT-11 in a patient with local recurrence of rectal cancer]. AB - We report a case of pelvic recurrence of advanced rectal carcinoma, presenting a favorable response with a low dose (25 mg/m2) of CPT-11 (Irinotecan) combined with topical hyperthermia for relapse after treatment with 4 cycles of high-dose (100 mg/m2) CPT-11 chemotherapy alone. This combination therapy was safely carried out on an outpatient basis. The degrees of recovery of the left lower limb pain and edema, and of serum CEA reduction were comparable to those in high dose chemotherapy alone. No significant adverse effects were encountered in the thermo-chemotherapy attempted. Since hyperthermic treatment enhances the cytotoxic effects of CPT-11 in vitro, topical hyperthermia with low-dose CPT-11 therapy may produce a response comparable to that in high-dose CPT-11 chemotherapy alone. However, an optimal dose and comparative study with other chemotherapeutic agents would be needed. This regimen may be advantageous in the maintenance of quality of life for the palliation of postoperative pelvic recurrence since this treatment can be performed on an outpatient basis. PMID- 10097757 TI - [Preoperative chemotherapy targeting lymphatic apparatus in the peritoneal cavity of gastric cancer patients with serosal invasion using mitomycin C bound to activated carbon particles]. PMID- 10097758 TI - [Interferons alpha-2a and gamma increase the antitumor activity, detected by histoculture drug response assay, of doxifluridine against clinical renal cell cancers]. PMID- 10097759 TI - [Comparative study of 5'-deoxy-5-fluorouridine between older cancer patients versus younger cancer patients]. PMID- 10097760 TI - [Dysfunction of cadherin cell adhesion system in cancer invasion and metastasis]. AB - Dysfunction of the cadherin-mediated cell adhesion system involved in cancer metastasis occurs by several mechanisms: alterations of E-cadherin, alpha- and beta-catenin genes, CpG methylation of the promoter region of E-cadherin, and aberrant tyrosine phosphorylation of beta-catenin. In addition to the cell adhesion function, beta-catenin, which is an intracytoplasmic cadherin binding molecule and thought to be a regulator of cadherin-mediated cell adhesion function, has been proven to associate with both the growth factor receptors, including c-erbB-2, EGF receptor and k-sam and APC tumor suppressor gene product. These data indicate that the cadherin-mediated cell adhesion system plays important roles not only in cancer metastasis but in carcinogenesis. PMID- 10097761 TI - Administrative support of programs for the prevention of poor perinatal outcomes. PMID- 10097762 TI - The hospice is dead. PMID- 10097763 TI - Creating dialogue. The New Jersey experience. PMID- 10097764 TI - Hospital consolidation. Applying stakeholder analysis to merger life-cycle. AB - Nearly three of every five hospitals in the United States have been involved in some form of consolidation during the past 5 years. Within this turbulent hospital merger environment, nurse executives are confronted with organizational, professional, and personal decisions. Stakeholder analysis is offered as one strategy to facilitate effectiveness throughout the hospitals' merger life-cycle. PMID- 10097765 TI - Changing roles in nursing. Perceptions of nurse administrators. AB - Nursing roles and administrative responsibilities have changed over the past 10 years. Although nurses' choices in graduate educational programs have been documented by the American Association of Colleges of Nursing and the National League for Nursing, little empirical data exist related to specific role changes. The purpose of this study was to describe current responsibilities of nurse administrators and their perceptions regarding role changes in their organizations. This study also identified educational recommendations of nurse administrators for nurses pursuing graduate degrees with implications and recommendations for nurse leaders. PMID- 10097766 TI - Healthcare reform. Its effects on nurses. AB - Healthcare reform has been a major economic and political focus throughout the 1990s. In a national survey of registered nurses about work life and health, many narrative comments addressed changes in the healthcare system. This qualitative study an analysis of these comments, identified themes related to nurses' perceptions of changes and the effect of healthcare reform on the practice of nursing. PMID- 10097767 TI - Telephone nursing interventions in ambulatory care. AB - Telephone nursing practice is becoming a major nursing activity in ambulatory care settings, yet little is known about the type and extent of nursing interventions that occur during telephone interactions. A pilot study was conducted in two sites to see whether nursing diagnoses and interventions could be captured and related to nursing care during telephone consultation. This initial pilot demonstrated that nurses have an appropriate role in telephone interactions and that standardized nursing language can be used in telephone nursing to document nursing care despite the many challenges in its use in the field. PMID- 10097768 TI - Revitalizing a departmental committee. AB - Committees are vital and as such should be evaluated regularly for congruence with organizational mission and contribution to outcomes. The authors present an approach to revitalizing a committee, using the nursing education committee as an exemplar. Phases used in achieving this revitalization are: evaluating the congruence of the existing committee with the organizational strategic plan, addressing gaps between existing committee functions and the organizational plan, soliciting support for the new committee direction, and evaluating the new committee direction. PMID- 10097769 TI - Aging, culture, and cognition. AB - There is evidence that East Asians are biased to process information in a holistic, contextual fashion, whereas Western Europeans process information in an analytic, feature-based style. We argue that these cultural differences in information-processing styles are so pervasive that they affect cognitive function at the most basic levels, including the mechanics of cognition. However, as individual age, it is not always the case that culture effects on cognitive processes magnify, despite many additional years of exposure to the culture. Neurobiological decline in cognitive function that occurs with age is a cognitive universal and can limit the strategies used in late adulthood, resulting in more similarity in cognitive function in late adulthood across cultures than is observed in young adulthood. We present a theoretical framework for understanding the impact of aging on cognitive function cross-culturally. The importance of developing culture-invariant measures of processing resources is emphasized and methodological issues associated with the cross-cultural study of aging are addressed. PMID- 10097770 TI - Self-perceptions of health: a prospective analysis of mortality, control, and health. AB - A growing number of studies show that self-perceptions of health are an important predictor of mortality. The present study was designed to extend this research by examining the relation between health perceptions and a range of other outcome measures besides mortality, including control beliefs and morbidity. The results show that older adults who rated their health as "bad/poor" and "fair" were more than twice as likely to die within three to three-and-a-half years following the initial survey than those who perceived their health as "excellent." However, although health perceptions assessed in 1991/92 were related to health perceptions four years later, they did not predict morbidity. Health perceptions also predicted perceived control and use of control-enhancing strategies in dealing with age-related challenges, as assessed in 1995. These findings contribute to our understanding of the benefits of positive health perceptions by showing that they are connected to an adaptive psychological profile including perceptions of control and use of control-enhancing strategies that are linked to health and well-being. PMID- 10097771 TI - A preliminary study of the association between changes in mood and cognition in a mixed geriatric psychiatry sample. AB - The relationship between measures of mood state and cognitive function was investigated in a sample of geriatric psychiatry inpatients. All were admitted to an urban hospital with varying degrees of cognitive impairment. Patients with diminishing negative affects and depressive symptoms during the course of hospitalization improved significantly on three cognitive tests, and half of the group members were no longer impaired according to their performance on a mental status exam. Correlations between cognition and mood-scale change scores were significant on tests emphasizing spatial processing and learning. Although the effects were modest in this heterogenous sample, the data demonstrate a significant influence of changing mood state on neuropsychological test performance. PMID- 10097772 TI - Insight in dementia: when does it occur? Evidence for a nonlinear relationship between insight and cognitive status. AB - Lack of insight or impaired awareness of deficits in patients with dementia is a relatively neglected area of study. The aim of this study was to evaluate insight in a group of demented patients with two assessment scales and to assess their relationship with the cognitive level of disease severity. Sixty-nine consecutive patients affected by Alzheimer's disease (n = 37) and vascular dementia (n = 32) with a wide range of cognitive impairment (MMSE = 17.0 +/- 6.4) were recruited. Insight was evaluated with the Guidelines for the Rating of Awareness Deficits (GRAD)--specifically targeted to memory deficits--and the Clinical Insight Rating scale (CIR), evaluating a broader spectrum of insight (reason for the visit, cognitive deficits, functional deficits, and perception of the progression of the disease). In the whole sample, GRAD and CIR were significantly associated with MMSE (Spearman's coefficient = .51, p < .001; and r = -.55, p < .001) and with Clinical Dementia Rating scale (-.57, p < .001; and r = .57, p < .001) respectively. The shape of the relationship of MMSE with CIR and GRAD scales was assessed with spline smoothers suggesting that the relationship follows a trilinear pattern and is similar for both scales. Insight was uniformly high for MMSE scores > or = 24, showed a linear decrease between MMSE scores of 23 and 13, and was uniformly low for MMSE scores < or = 12. The trilinear model of the association between insight and cognitive status reflects more closely the observable decline of insight and can provide estimates of when the decline of insight begins and ends. PMID- 10097773 TI - Longitudinal changes in quantitative and qualitative indicators of word and story recall in young-old and old-old adults. AB - The present study examined longitudinal changes in quantitative and qualitative measures of episodic memory. The sample, taken from the Victoria Longitudinal Study, consisted of 158 young-old adults (initially 55 to 70 years old) and 84 old-old adults (initially 71 to 86 years old) who were tested three times over six years. Average word and text recall, as well as five indicators of qualitative aspects of word recall (e.g., number of categories recalled) and one indicator of structure of text recall (i.e., levels of information) were used. For word recall, although both age groups exhibited negative longitudinal changes in quantitative performance, overall qualitative performance was generally stable. Two qualitative indicators (number of categories and intrusions) showed modest decline and one (organization at recall) showed improvement. Results for overall text recall showed significant performance increments for the young-old group, whereas the old-old group exhibited slight declines in overall performance. Analyses of qualitative measures showed stable structure of hierarchical recall, with the old-old being impaired at all levels of detail in the stories. Overall results suggest that some underlying structural characteristics of word and text recall may be maintained into late life even when significant overall decline is observed. PMID- 10097774 TI - A method for assessing clinically relevant individual cognitive change in older adult populations. AB - The evaluation of individual cognitive change has relied heavily upon the raw change score, defined simply as the difference between follow-up and baseline scores. However, raw changes scores are susceptible to the confounding effects of both regression-to-the-mean and practice effect. The clinical relevance of raw change scores for the older adult is also obscured by normal, age-related cognitive change. The present study illustrates the use of a standardized regression-based (SRB) methodology to generate an alternative to the raw change score; the SRB change score. SRB change scores provide a standardized alternative to the raw change score, allowing the clinician to evaluate the magnitude of change on one or more variables along a common metric that controls for practice effect, regression-to-the-mean, and normal cognitive decline. Case data illustrate how SRB change scores can identify clinically relevant cognitive change in the individual older adult patient. PMID- 10097775 TI - The effects of context and feedback on age differences in spoken word recognition. AB - We investigated the hypothesis that age differences in speech discrimination would be reduced by enhancing the distinctiveness of the speech processing event in terms of both the context of encoding and the response outcome. Younger and older adults performed an auditory lexical decision task in which the degree of semantic constraint (context) and type of feedback were manipulated. Main effects of age indicated that older adults generally showed lower discriminability (D) and greater bias (B) toward reporting signals to be words. Consistent with the environmental support hypothesis, older adults were differentially facilitated in discriminability by feedback, but only when semantic context was provided. Also, for both younger and older adults, feedback and context each had the effect of reducing bias and facilitating the speed of rejecting nonwords. Contrary to one suggestion in the literature that aging brings an insensitivity to environmental contingency, older adults were at least as capable as the young in taking advantage of feedback to normalize the speech signal so as to increase discriminability and decrease bias. PMID- 10097776 TI - Retirement intentions and spousal support: a multi-actor approach. AB - OBJECTIVES: This study investigates the role of the partner in the retirement decision-making process. It determines the extent to which the support and intentions of partners regarding early retirement influence each other, and which partner dominates. METHODS: Data have been collected directly from 1,052 older employees working in Dutch industry and trade, and from their spouses. Because it is conceptualized that husbands' and wives' retirement intentions/support are related in a reciprocal way, a two-stage least squares regression analysis (2SLS) is used to establish the specified mutual relationships. RESULTS: Intentions and support of both partners concerning retirement are strongly related. The results of the 2SLS suggest that early retirement of one of the spouses is the result of influence processes within the household, and that early retirement can be considered, to a certain extent, a household decision. This holds for married men's early retirement in particular. There seems to be no direct causal relationship between a couple's own decision making with respect to early retirement and the retirement behavior of a couple's social network. DISCUSSION: Future research on the retirement decision-making process should focus on the family unit rather than simply on the individual worker, and be extended to different types of retirement behavior. PMID- 10097777 TI - Behavior sequences of long-term care residents and their social partners. AB - OBJECTIVES: This study examines similarities and differences in social interactions of residents of an assisted living facility and those of a nursing home. Given increasingly popular alternative models of long-term care such as assisted living, the study seeks to identify how these long-term care settings differentially promote dependence and independence among their residents. METHODS: Data were collected during 256 observations of 64 residents and their social partners at meal times in public areas. Sequences of antecedent and response behaviors relating to independence and dependence in the two different long-term care settings were examined. RESULTS: Social partners responded consistently to behavior of long-term care residents, and the behavior of residents was consistently affected by that of their social partners. These sequential interactions were not affected by setting. DISCUSSION: Differences in the nursing home and assisted living facilities' stated philosophies of care were not manifested in the interactions of their staff and residents. PMID- 10097778 TI - Subjective health and mortality in French elderly women and men. AB - OBJECTIVES: To examine the predictive value of subjective health on mortality separately in women and men, independently of other health measures, and to explain the differences between sexes by way of cognition, depression, and disability. METHODS: The PAQUID (Personnes Agees QUID) cohort is a representative sample of 3,660 nondemented elderly community residents, aged 65 and older. The relationship between subjective health and 5-year mortality was studied using the Cox model with delayed entry. RESULTS: In men, subjective health was a predictor of mortality, independent of sociodemographic characteristics, physical health status, depressive symptomatology, cognitive function, and disability, particularly in the middle-range categories of subjective health. In women, the relationship between subjective health and mortality was explained by physical health status and disability. DISCUSSION: Self-rated health seems to be a better predictor of mortality in men than in women. In men, the way in which self ratings of health are produced remains unknown. In order to better understand sex differences, the pathways from healthy life to dependency and death, and their related changes in subjective health, should be explored further. PMID- 10097779 TI - Vascular dementia versus dementia of Alzheimer's type: do they have differential effects on caregivers' burden? AB - OBJECTIVES: We investigated homecare patients with dementia of Alzheimer's type (DAT; n = 36) or vascular dementia (VD; n = 36) and their care-providing relatives regarding clinical and psychosocial variables to determine whether DAT and VD impose different burdens on caregivers. METHOD: All patients were diagnosed according to ICD-10 criteria. The diagnoses were confirmed by internal medical, clinical-neurological, and psychiatric parameters. The severity of the dementias was graded according to the Global Deterioration Scale (GDS). Caregiving relatives responded to the Behavioral Pathology in Alzheimer's Disease Rating Scale (BAD), the Blessed Dementia Scale (BDS), and the Screen for Caregiver Burden (SCB). RESULTS: Analyses revealed that caregivers' burden (SCB), disease symptoms and personality changes of patients (BAD), and the patients' inability to cope with everyday tasks (BDS) were sharply higher for DAT than for VD patients in the group with severe dementia. Concerning patients with mild or moderately severe disease, scores in the DAT group were similar or lower than those in the VD group. CONCLUSION: In early stages, VD patients impose a greater burden on relatives than do patients with DAT. In severe stages this relationship undergoes a reversal, with relatives of DAT patients experiencing the burden more adversely than those of VD patients. The differences in the onset and course characteristics, as well as the specific differences between these two types of dementia with respect to caregiver burden factors, call for their diagnostic separation and the development of specific homecare support systems for family caregivers. PMID- 10097780 TI - Stress and the devaluation of highly salient roles in late life. AB - OBJECTIVE: To see whether older adults cope with stress in highly salient roles by devaluing the importance of the role in which the event emerged. METHODS: Interviews were conducted with a nationally representative sample of elderly people at two points in time: 1992-1993 and 1996-1997. Complete data are available for 589 older adults. Respondents were asked to identify which of eight roles they value most highly at both points in time. Information on the number of stressful events arising in each role was also obtained. RESULTS: The findings indicate that elderly people are less likely to devalue highly salient roles when stressful events are encountered in them. DISCUSSION: The results suggest that instead of turning away from highly cherished roles when stressful life events arise, older adult may become more committed to them. PMID- 10097781 TI - Adding values: an experiment in systematic attention to values and preferences of community long-term care clients. AB - OBJECTIVES: We tested the effects of providing case managers with tools to assess and respond to client values and preferences on their subsequent knowledge of clients' values and their practices in arranging long-term care. METHOD: Using a quasi-experimental design with newly enrolled, cognitively intact clients, we compared case managers, clients, and care plans at the experimental and control agency. RESULTS: Three weeks after enrollment, experimental clients were significantly more likely to report that case managers had asked them about their own preferences and offered them choices about services. Actual client values reported at the 3-month follow-up were similar for the two groups, with experimental case managers only slightly more accurate judges of their clients' responses to values questions. At follow-up, experimental case managers reported more case activity tailoring plans to client preferences, a finding confirmed by record reviews. Client acuity, measured by ADL functioning and prior hospital use, was associated with less perceived discussion of client preferences during the initial care planning process, but more case activity related to client preferences during the first three months. DISCUSSION: The study suggests it is possible to sensitize case managers to the importance of assessing and acting on client values. Getting them to do so consistently, however, may require changes in the practice environment. PMID- 10097782 TI - The role of antiphospholipid antibodies in reproduction: questions answered and raised at the 18th Annual Meeting of the American Society of Reproductive Immunology. PMID- 10097783 TI - Why did your mother reject you? Immunogenetic determinants of the response to environmental selective pressure expressed at the uterine level. AB - PROBLEM: Maternal "rejection" of the implanted conceptus is considered to account for a significant proportion of miscarriages (abortions) in both humans and animals. Our understanding of mechanisms has been limited, and hence, explanations for nonrejection have remained largely speculative. Losses, when they occur, could represent either random accidental failure of protective mechanisms or a more purposeful discrimination. METHOD OF STUDY: An analysis of the most recent data. RESULTS AND CONCLUSIONS: The embryo is most akin to a parasite, and pregnancy is most akin to a host-parasite interaction. If one excludes chromosome abnormalities in the embryo as a cause of death, activation of coagulation mechanisms, leading to vasculitis affecting the maternal blood supply to the implanted embryo, appears to represent a major loss-causing mechanisms--a form of ischemic autoamputation. Proinflammatory T-helper (Th) 1 type cytokines trigger this process via upregulation of a novel prothrombinase, fgl2. Th2/3 cytokines, such as interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-beta 2, may antagonize the processes involved. Cytokine balance is determined by the genetics of the mother, which regulate her response to stress; endotoxin (LPS); and paternal antigens, selectively expressed on the trophoblast of the embryo, via imprinting. Based on studies in abortion-prone mice, where immunity to paternal alloantigens prevents loss, three distinct gene products in the embryo are proposed to determine the cytokine response to maternal lymphomyeloid cells in the uterus. PMID- 10097784 TI - Mechanisms of action of major-histocompatibility-complex-linked genes affecting reproduction. AB - PROBLEM: To provide insight into the mechanisms of action of the major histocompatibility-complex (MHC)-linked genes affecting reproduction. METHOD OF STUDY: The data were obtained using a variety of cellular and molecular techniques in experimental animals and from population genetic studies in humans. RESULTS: In the mouse, the preimplantation embryonic development (Ped) locus, whose functional gene is Q9, regulates fast and slow cleavage of the early embryo. There is also evidence for a growth and reproduction complex (Grc)-like region from serologic, molecular, and cytogenetic studies. In the human, the human leukocyte antigen (HLA)-G gene has been associated with an increased rate of embryonic cleavage in those embryos that express the HLA-G antigen. Sharing of HLA antigens in couples has been associated with recurrent spontaneous abortions, gestational trophoblastic tumors, and unexplained infertility. Detailed mapping studies showed that the genes responsible are not the HLA genes themselves, but genes closely linked to the HLA-DR-DQ-B genes. The HLA region genes can interact epistatically with the C3 allele of transferrin to increase the incidence of fetal loss. In the rat, the Grc region, which is closely linked to the MHC, has been associated with embryonic loss, growth defects, and susceptibility to chemical carcinogens. The Grc can interact epistatically with the tail anomaly lethal (Tal) gene or the hood restriction (Hre) gene to enhance these effects. CONCLUSIONS: There are two basic mechanisms for the effects of MHC-linked genes on reproduction and development: individual gene effects (Ped [Q9], HLA-G) and extended genetic effects (MHC-linked genes in the rat [Grc] and in the human). The nature of these genetic effects, particularly the MHC-linked effects, can also provide some insight into the different theories of human origins: These effects are most consistent with the monogenic theory. PMID- 10097785 TI - Decidual mast cells might be involved in the onset of human first-trimester abortion. AB - PROBLEM: The aim of the present study was to identify the role of mast cells and substance P (SP)-containing nerve fibers in human decidua in normal and pathological pregnancies. METHOD OF STUDY: We collected decidua from women undergoing termination of normal pregnancies and from abortions. The presence of mast cells and SP was detected by immunohistochemistry. RESULTS: We observed a sparse distribution of mast cells in the normal pregnancies (36.7 tryptase+ mast cells/mm2 decidua). In the decidua from abortion, we found a dramatic increase in the number of mast cells (448.7 and 469.2 tryptase+ mast cells/mm2 decidua in primary and secondary abortions, respectively). In addition, we observed an increase of SP-positive nerve fibers in the decidua of abortions. CONCLUSIONS: Our data suggest that decidual mast cells may play an important role in the onset of abortion, due to the production of cytokines, such as tumor necrosis factor alpha. PMID- 10097786 TI - Fas and Fas-ligand are expressed in the uteroplacental unit of first-trimester pregnancy. AB - PROBLEM: Fas and Fas-ligand (FasL) are thought to provide a strategy for reducing graft rejection in immunologically 'privileged' tissues by controlling injurious lymphocyte reactions. As the uteroplacental unit is often defined as an immune privileged site, we investigated the expression of Fas and FasL in this tissue in the first trimester of pregnancy. METHOD OF STUDY: Western blotting, immunohistochemistry, and double immunofluorescence were used for this examination. RESULTS: Western blotting with purified first-trimester trophoblast cells revealed one specific band for FasL. The presence of FasL on different trophoblast populations could be confirmed by immunohistochemistry and double immunofluorescence. In the villous part of the placenta, FasL is mostly located on cytotrophoblast cells with no access to maternal blood flow, whereas in trophoblast-invaded uterine tissue, interstitial trophoblast cells, which are in close contact with maternal leukocytes, revealed a strong signal for FasL, but no staining for Fas on these cells. However, Fas was found on CD45+ maternal leukocytes. CONCLUSION: Based on our experimental findings, we speculate that the abundant presence of FasL on trophoblast cells within the maternal decidua may play an important role in the maintenance of immune privilege in the pregnant uterus by endowing fetal trophoblast cells with a defense mechanism against activated maternal leukocytes, whereas in the villous part of the placenta, the Fas FasL system seems to be involved in the regulation of placental growth. PMID- 10097787 TI - Histologic distribution and biochemical properties of alpha 1-microglobulin in human placenta. AB - PROBLEM: The embryo is protected from immunologic rejection by the mother, possibly accomplished by immunosuppressive molecules located in the placenta. We investigated the distribution and biochemical properties in placenta of the immunosuppressive plasma protein alpha 1-microglobulin. METHOD OF STUDY: Placental alpha 1-microglobulin was investigated by immunohistochemistry and, after extraction, by electrophoresis, immunoblotting and radioimmunoassay. RESULTS: alpha 1-Microglobulin staining was observed in the intervillous fibrin and in syncytiotrophoblasts, especially at sites with syncytial injury. Strongly stained single cells in the intervillous spaces and variably stained intravillous histiocytes were noted. Solubilization of the placenta-matrix fraction and placenta membrane fraction released predominantly the free form of alpha 1 microglobulin, but, additionally, an apparently truncated form from the placenta membrane fraction. The soluble fraction of placenta contained two novel alpha 1 microglobulin complexes. CONCLUSIONS: The biochemical analysis indicates the presence in placenta of alpha 1-microglobulin forms not found in blood. The histochemical analysis supports the possibility that alpha 1-microglobulin may function as a local immunoregulator in the placenta. PMID- 10097788 TI - Jeg-3 human choriocarcinoma-induced immunosuppression: downregulation of interleukin-2, interleukin-2 receptor alpha-chain, and its Jak/Stat signaling pathway. AB - PROBLEM: The mechanisms of the immunosuppressive and immunosuppression-inducing capacities of Jeg-3 human choriocarcinoma cell line supernatants (HCSs) are not yet completely understood. The influence on interleukin (IL)-2, IL-4 and interferon (IFN)-gamma production; IL-2 receptor (IL-2R) alpha-, beta-, and gamma chain; and the signaling pathway molecules Janus kinase (Jak)1, Jak3, signal transducers and activators of transcription (Stat)1, Stat3, and Stat5 should be investigated. METHOD OF STUDY: For assessment of IL production, whole peripheral venous blood from healthy donors was stimulated with phorbol-myristate-acetate and ionomycine. Secretion of ILs was blocked with monensine. Intracellular ILs were analyzed by flow cytometry. For IL-2R and signaling pathway molecule analysis, peripheral blood lymphocytes were stimulated with phytohemagglutinin (PHA). IL-2R chains were measured by flow cytometry, and Jaks/Stats by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. RESULTS: Phorbol-myristate-acetate and ionomycine strongly increase the percent age of IL-2+ cells; an additional 50% HCSs significantly suppresses the percentage to, or below the level of unstimulated cells. IFN-gamma production is strongly decreased by HCSs in some cases, but not in others. PHA stimulates IL-2R alpha-, beta-, and gamma-chain expression and their signaling pathway molecules Jak1, Jak3, Stat1, Stat3, and Stat5. 50% HCS downregulates the alpha-chain and slightly upregulates the beta-chain. Jak1, Jak3, Stat1, Stat3, and Stat5 expression is suppressed approximately to, or below the level of unstimulated cells. CONCLUSIONS: HCS forcefully blocks the production of IL-2; the IL-2R alpha chain; and Jak1, Jak3, Stat1, Stat3, and Stat5 expression. The observed phenomena might be caused by downregulation of an IL-2R regulation gene, and might play a key role in the expansion of choriocarcinoma, and possibly in the survival of the fetal allograft. PMID- 10097789 TI - First-trimester human chorionic villi express both immunoregulatory and inflammatory cytokines: a role for interleukin-10 in regulating the cytokine network of pregnancy. AB - PROBLEM: T-helper 2 (TH2)-type cytokines [i.e., interleukin (IL)-6, IL-10, and IL 13] and transforming growth factor (TGF)-beta are expressed by the murine decidua and/or placenta and are likely to suppress inflammatory cytokine [i.e., IL-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-1 alpha, and IL-1 beta] production at the maternal-fetal interface. In addition, class I IFNs may protect the fetus from immunologic rejection and viral infections. This study examines the expression of inflammatory/immunoregulatory cytokines and IL-10 production by first-trimester chorionic villi. METHOD OF STUDY: Gestational tissues (n = 5) were obtained following elective terminations performed between 7 and 9 weeks of gestation. Chorionic villous tissues were separated from fetal membranes and decidua, and total RNA was extracted. Cytokine expression was assessed by a reverse transcriptase-polymerase chain reaction technique. Chorionic villi (n = 9; 6-12 weeks gestation) were maintained in organ culture, and human chorionic gonadotropin (hCG) and IL-10 levels were determined by immunoradiometric and enzyme-linked immunosorbent assays, respectively. RESULTS: IFN-gamma and IL-2 were generally not expressed by first-trimester chorionic villi. Low to moderate levels of expression were noted for IL-1 alpha, IL-1 beta, and TNF-alpha. High levels of mRNA were noted for IFN-alpha and IFN-beta, but IFN tau was not expressed. In all tissues, TGF-beta 1 and IL-13 were either weakly expressed or not expressed. In contrast, moderate to high levels of IL-6 and IL 10 mRNA were detected in each chorionic villous sample. In chorionic villous explants obtained at 6-11 weeks gestation production of hCG and IL-10 was greatest during the first 24 hr ([hCG] = 6961 +/- 815 mIU/mL, [IL-10] = 92 +/- 11 pg/mL) and then declined through 72 hr. CONCLUSIONS: TH1-type cytokines (IL-2, IFN-gamma) are not expressed by first-trimester chorionic villous tissues: This is possibly due to local production of IL-10. In contrast, macrophage-associated cytokines (IL-1 beta and TNF-alpha) are expressed and their regulation may be critical for fetal survival. Finally, class 1 IFNs expressed by early chorionic tissues may protect the fetus from maternal rejection and viral transmission. PMID- 10097790 TI - Placenta growth factor: potential role in pregnancy. AB - PROBLEM: In spite of the known requirement for adequate vascularity during placentation, little is known regarding the regulation of angiogenic growth factor production by trophoblast. Placenta growth factor (PIGF) is a recently discovered angiogenic growth factor whose expression is relatively limited to trophoblast. METHOD OF STUDY: Current literature of PIGF was reviewed, with emphasis on its expression, regulation, role in angiogenesis, and potential function(s) at the maternal-fetal interface. RESULTS: PIGF is abundantly expressed by trophoblast, which implies that it could act in a paracrine manner to modulate vascular development, stability, and/or function within the decidua and placental villi. In addition, expression of the PIGF receptor, fms-like tyrosine kinase (flt-1) receptor, on trophoblast raises the potential for an autocrine role of PIGF in regulating trophoblast growth and/or function. CONCLUSIONS: The potential for PIGF to influence both vascular endothelial cells and trophoblast suggests that aberrant trophoblast production of PIGF could compromise cellular function during gestation and contribute to the vascular and placental pathologies noted in many obstetric complications. PMID- 10097791 TI - Prevalence of autoantibodies in patients with recurrent miscarriages. AB - PROBLEM: It is well known that the prevalence of several autoantibodies is higher in patients with recurrent miscarriages than in normal women. However, links between individual autoantibodies are unclear. The present study focuses on the possible association between beta 2-glycoprotein I (beta 2-GPI)-dependent anticardiolipin antibody (aCL), lupus anticoagulant (LA), and antinuclear antibody (ANA) in patients with recurrent miscarriages. METHOD OF STUDY: Three hundred and one patients, with a history of two or more unexplained miscarriages, were studied. The titers of beta 2-GPI-dependent aCL and LA were then compared between single-antibody-positive and three-antibody-positive groups. RESULTS: The prevalences of beta 2-GPI-dependent aCL, LA, and ANA were 3.3, 10.0, and 25.2%, respectively. Four of the 301 patients had all three antibodies. The LA titers in patients with positive values for three antibodies was significantly higher than in cases with only LA. CONCLUSION: beta 2-GPI-dependent aCL, LA, and ANA define three distinct, but partly related populations in patients with recurrent miscarriage. We should test at least two kinds of autoantibodies in recurrent aborters, because it has been found that, e.g., beta 2-GPI-dependent aCL and LA are predictors for miscarriages. PMID- 10097792 TI - Immunopathology of the implantation site utilizing monoclonal antibodies to natural killer cells in women with recurrent pregnancy losses. AB - PROBLEM: Placental lesions of 71 women with documented recurrent spontaneous abortions of unknown etiology were evaluated using immunohistochemical staining. METHOD OF STUDY: Placental tissue blocks (less than 12 weeks gestation) from prior pregnancy losses were obtained, recut, and analyzed utilizing monoclonal antibody to identify the trophoblast (cytokeratin 8/18) and natural killer (NK) cells (CD57) at the implantation site. The following features were evaluated: trophoblast invasion pattern; syncytium formation; vasculitis and thromboembolism of decidual vessels; decidual inflammation; decidual necrosis; fibrin deposition at the decidual necrosis site; mononuclear-cell infiltration in villi and intervillous space; perivillous fibrin deposition; trophoblast morphology; and quantitation of CD57+ NK cells within the decidual tissue near the implantation site. Controls consisted of 20 healthy women with no history of recurrent pregnancy losses, who had their pregnancies electively terminated. RESULTS: Of the women studied, 29.6% demonstrated elevated CD57+ NK cells at the implantation site (P = 0.030), 54.1% had inadequate cytotrophoblast invasion depth (P = 0.000), 44.1% demonstrated inadequate syncytium formation (P = 0.004), and 33.9% presented thromboembolism in decidual vessels (P = 0.025). CONCLUSION: Some women with recurrent spontaneous abortions demonstrate abnormal placental lesions at the implantation site. Immunopathologic evaluation of the placental implantation site that terminated in a spontaneous abortion may reveal the immunopathogenesis of previous pregnancy losses. PMID- 10097793 TI - Natural killer (NK) cell subsets and NK cell cytotoxicity in women with histories of recurrent spontaneous abortions. AB - PROBLEM: Natural Killer (NK) cell measurement and NK cytotoxicity are two measurements for assessing the cellular immune response. Both of the techniques have been reported to be prognostic for women with recurrent spontaneous abortion (RSA). We evaluated the two methods to determine the relationship of the two assays. Because both methods portend to evaluate the same process, the previous clinical data suggested that the methods evaluate the same phenomena. We undertook these studies to determine whether simple NK cell counts may be sufficient in the evaluation of NK activity in RSA. METHOD OF STUDY: The NK cell cytotoxicity at effector-to-target ratios of 50:1 and 25:1 was determined using a flow cytometric NK cell cytotoxicity assay. These values were then correlated with the percentages and absolute counts of three peripheral blood NK cell subsets. RESULTS: The data indicate that the flow cytometric assay is reproducible and precise and can be successfully used to evaluate patient samples. Linear regression analysis indicated a lack of correlation between peripheral blood NK cell cytotoxicity and percentages or absolute counts of CD56+CD16+, CD56+CD16- or CD3+CD56+ lymphocyte subsets (range of correlation coefficients, 0.1-0.3). CONCLUSIONS: NK cell cytotoxicity and peripheral blood NK cell values measure different aspects of NK cells and do not correlate. These data indicate that simple enumeration of NK cells may not be sufficient in the evaluation of NK cells in RSA. PMID- 10097794 TI - Increase in the production of interleukin-6, interleukin-10, and interleukin-12 by lipopolysaccharide-stimulated peritoneal macrophages from women with endometriosis. AB - PROBLEM: To verify whether the peritoneal macrophage (PM) is activated in endometriosis. METHOD OF STUDY: We examined the synthesis of nitric oxide (NO), total antioxidant, interleukin (IL)-6, IL-10, and IL-12 by cultured PMs, which were either unstimulated or stimulated with lipopolysaccharide (LPS), from women with endometriosis (early, n = 12; advanced, n = 11) or without endometriosis (n = 13). RESULTS: After stimulation with 2 ng/mL LPS for 24 hr, PMs from women with early-stage endometriosis secreted more NO, IL-6, and IL-10 than the controls. Higher IL-12 levels were noted in women with advanced endometriosis when compared with the controls. After 2 ng/mL-LPS stimulation for 24 hr, we also detected higher total antioxidant levels in the advanced-endometriosis group than those in the early-endometriosis group. CONCLUSION: The increased production of IL-6, IL 10, and IL-12 by stimulated PMs confirmed previous observations that the PM is the principle source of these cytokines in peritoneal fluid. PMID- 10097795 TI - Teratozoospermia and its effect on male fertility potential. AB - Teratozoospermia and its significance for male fertility problems is discussed. Different points of view and available information concerning the phenomenon of teratozoospermia have been presented. Ongoing debate about the influence of sperm morphology on male infertility and IVF results emphasizes the fact that when sperm morphology is evaluated using strict criteria, this parameter is thought to have an excellent predictive value and shows a significant positive correlation with successful fertilization. Selective abilities of zona pellucida to differentiate between morphologically normal and abnormal spermatozoa, the superior role of acrosomal morphology assessment in the prediction of IVF outcome, and the involvement of cell surface molecules in the adhesion of spermatozoa to oocytes are described. The usefulness of the hamster oocyte penetration assay (HOPA), which is important not only because of its predictive value of sperm function, but also because of its role as a tool for visualizing sperm chromosomes, was found to be questionable in cases of teratozoospermia. Cytogenetic findings related to teratozoospermia are controversial as classical methodology of visualizing sperm chromosomes (through HOPA) may cause selection of sperm metaphases which can be obtained only from good-penetrating spermatozoa. There are few reports presenting chromosome complements of abnormal sperm visualized with the help of micromanipulation. There is clear evidence that a variety of genetic defects can affect spermatogenesis. The possible genetic background of teratozoospermia is discussed. PMID- 10097796 TI - Effects of single polychlorinated biphenyls on the morphology of cultured rat tubuli seminiferi. AB - The effects of single polychlorinated biphenyls (PCB) on isolated tubuli seminiferi of the rat were studied. Freshly isolated rat tubuli seminiferi were prepared according to their transillumination pattern, i.e. dark or pale. Tubuli seminiferi with the dark pattern included stages II to VIII and tubuli with the pale pattern represented stages IX to XIV and stage I of the seminiferous cycle. Afterwards, tubuli seminiferi were exposed to single polychlorinated biphenyls for 5 or 24 h in vitro. PCB 126, PCB 77, and PCB 118 were used in final parts per billion (p.p.b.) concentrations as determined by quantitative PCB analysis. Eventually, the specimens were plastic embedded, cut into semithin sections, stained, and morphology was evaluated by light microscopy. Single PCB congeners induced morphological alterations in cultivated rat tubuli seminiferi in a time- and stage-dependent manner. Effects comprised loosened intercellular contacts between germ cells and Sertoli cells as well as cellular fragmentation in the layer of round spermatids. Early spermiogenesis seems particularly susceptible to single PCB congeners in concentration of background magnitude. The target cell has still to be discovered. PMID- 10097797 TI - Changes in rat testicular antioxidant defence profile as a function of age and its impairment by hexachlorocyclohexane during critical stages of maturation. AB - Age-related changes in rat testicular oxidative stress parameters were investigated. A biphasic pattern was evident for lipid peroxidation and for the activity ratio of superoxide dismutase to catalase and glutathione peroxidase with increasing age. In the first phase of life (birth-7 days), a linear fall in lipid peroxidation was accompanied by a gradual increase in the enzyme ratio which was reversed in the second phase (15-600 days). Glutathione and ascorbic acid levels increased from birth to the 45th day and remained unchanged up till 365 days and then reduced at 600 days of age. The maximum level of H2O2 observed at birth gradually decreased till 90 days and remained unchanged up till 365 days of age; thereafter its level was elevated on day 600. The results suggest that an antioxidant defence system plays a crucial role in development and maturation of the rat testis. When the rats were treated with hexachlorocyclohexane during critical stages of testicular development (6th-30th day) and responses were evaluated on the 46th day of age, elevations in the levels of testicular lipid peroxidation and H2O2 along with reduction in levels of superoxide dismutase, catalase and ascorbic acid were observed. However, no change in glutathione and its metabolizing enzymes was recorded. On the other hand, hexachlorocyclohexane elevated total testicular Ca(2+)-Mg(2+)-ATPase activity. The results advocate for impairment of testicular functions in adult age as a consequence of some permanent lesions induced by hexachlorocyclohexane during critical stages of sexual maturation. PMID- 10097798 TI - Relationship between human sperm lipid peroxidation, comprehensive quality parameters and IVF outcome. AB - The membranes of human spermatozoa contain an extremely high concentration of polyunsaturated fatty acids and are therefore susceptible to lipid peroxidation damage. The aim of this study was to retrospectively determine the association between the lipid peroxidation levels of washed spermatozoa, as indicated by thiobarbituric-acid-reactive substance concentration, and: (a) semen quality evaluated by basic routine, biochemical, cytological and quantitative ultramorphological analyses; (b) IVF fertilization rate. Semen samples from 45 male partners of couples who had been referred for IVF treatment due to a female infertility factor were evaluated for quality as well as for thiobarbituric-acid reactive substance concentrations. The latter were found to have a negative correlation with total sperm count, semen volume, zinc/fructose ratio, and the integrity of sperm acrosome and axonema. It was suggested that lipid peroxidation has a deleterious effect on the ultramorphological status of the sperm cells and, thereby, on the male fertilization potential. The content of the seminal fluid, about 30% of which is produced by the prostate, may protect spermatozoa from this destructive process. A negative correlation was also found between thiobarbituric acid-reactive substance concentrations and IVF fertilization rate. When the patients were subdivided into fertilizing (fertilization rate > 0%) and nonfertilizing (fertilization rate = 0%) subgroups (n = 33 and n = 12, respectively), the former exhibited significantly lower thiobarbituric-acid reactive substance concentrations than the latter. A new IVF fertilization index based on the lipid peroxidation level was established. This index had a predictive power of 93% (94% sensitivity and 92% specificity). The clinical value of this index should be further verified. PMID- 10097799 TI - The effect of p-nonylphenol, an environmental toxicant with oestrogenic properties, on fertility potential in adult male rats. AB - Infertility is a sad reality and it is now evident that several aspects of male reproductive health have changed for the worse over the past 30-50 years. para nonylphenol (p-NP), an environmental toxicant with oestrogenic properties, was tested for its effect on male fertility potential. When adult male rats were exposed to 100 mg kg-1 p-NP the histological parameters of the seminiferous tubules were adversely affected. Although spermatogenesis was already established in these males at the time exposure commenced, p-NP still had an effect on the histology of the seminiferous tubules. Increasing the level to 250 mg kg-1 additionally resulted in a smaller weight gain and signs of epididymal toxicity, while 400 mg kg-1 also impaired testicular mass and sperm count. In the last two groups spermatogenesis was also affected in some animals. Because p-NP had an effect on established spermatogenesis in the rat, one could speculate that the same effects might also occur in humans. It would appear that p-NP had toxic effects on both the testis and epididymis and both structures might be important in impairing male fertility. Bio-accumulation may enhance the negative effects at even lower p-NP concentrations over longer exposure periods than reported here. PMID- 10097800 TI - The effect of p-nonylphenol on the fertility potential of male rats after gestational, lactational and direct exposure. AB - There is growing concern that abnormalities in male reproductive health are becoming more frequent. The most fundamental change has been the striking decline in sperm counts and semen quality. The effect of maternal exposure of rats to the oestrogenic environmental substance p-nonylphenol (p-NP) was determined in this study. Exposure to p-NP for the experimental period impaired general growth. The lower testicular mass indicated a direct toxic effect on the testis in animals exposed to p-NP during foetal life, the postnatal period and after weaning until termination at 10 weeks of age. The epididymal mass was also negatively affected by p-NP; this was supported by the decrease in the epididymal ratio. The total cauda epididymal sperm count was significantly lower in the 250 mg kg-1 p-NP dosage group compared to the control and 100 mg kg-1 p-NP groups. The overall lower sperm count with increased p-NP concentrations corresponded with the decreased testicular and epididymal masses. This emphasized the toxicity of p-NP on both testis and epididymis. Seminiferous tubule diameter, lumen diameter and seminiferous epithelium thickness were smaller in the exposed groups, even at the low dose level. These histological measurements further supported the finding of a low testicular mass. In spite of the measurements being smaller, p-NP had no effect on the stages of spermatogenesis except for one animal with disrupted spermatogenesis in some tubules, while others were normal. PMID- 10097801 TI - Neuroanatomical correlates of visually evoked sexual arousal in human males. AB - Brain areas activated in human male sexual behavior have not been characterized precisely. For the first time, positron emission tomography (PET) was used to identify the brain areas activated in healthy males experiencing visually evoked sexual arousal. Eight male subjects underwent six measurements of regional brain activity following the administration of [15O]H2O as they viewed three categories of film clips: sexually explicit clips, emotionally neutral control clips, and humorous control clips inducing positive but nonsexual emotions. Statistical Parametric Mapping was used to identify brain regions demonstrating an increased activity associated with the sexual response to the visual stimulus. Visually evoked sexual arousal was characterized by a threefold pattern of activation: the bilateral activation of the inferior temporal cortex, a visual association area; the activation of the right insula and right inferior frontal cortex, which are two paralimbic areas relating highly processed sensory information with motivational states; and the activation of the left anterior cingulate cortex, another paralimbic area known to control autonomic and neuroendocrine functions. Activation of some of these areas was positively correlated with plasma testosterone levels. Although this study should be considered preliminary, it identified brain regions whose activation was correlated with visually evoked sexual arousal in males. PMID- 10097802 TI - Compulsive voyeurism and exhibitionism: a clinical response to paroxetine. AB - The compulsive behaviors seen in sexual paraphilias may be related to those of obsessive-compulsive disorder (OCD). Based primarily upon case reports as well as studies indicating the effectiveness of serotonin reuptake inhibitors in the treatment of sexual paraphilias, it has been speculated that sexual paraphilias lie within the obsessive-compulsive spectrum. There have been no reports of the use of paroxetine in the treatment of sexual paraphilias. This is a report of two patients, the first a voyeur and the second an exhibitionist, both of whom responded to treatment with paroxetine. The discussion addresses the need for further comparative studies investigating the role of the serotonin system in the pathogenesis of sexual paraphilias and OCD as well as the effect of serotonin reuptake inhibitors in comparison to other pharmacologic modalities used in the treatment of paraphilias. PMID- 10097803 TI - Prenatal exposure to anticonvulsants and psychosexual development. AB - Animal studies have shown that prenatal exposure to the anticonvulsant drugs phenobarbital and phenytoin alters steroid hormone levels which consequently leads to disturbed sexual differentiation. In this study, possible sequelae of prenatal exposure to these anticonvulsants on gender development in humans were investigated. A follow-up study was carried out in phenobarbital- and phenytoin exposed subjects and control subjects matched for age, sex, and the mothers' ages. Subjects were born in the Academic Medical Center between 1957 and 1972. Out of 243 exposed and 222 control subjects who were asked to volunteer, 147 exposed subjects (72 male, 75 female) and equal numbers of their matched control subjects participated in the follow-up study. They were interviewed and were asked to fill out questionnaires on gender role behavior, gender development, and sexual orientation. As a group, exposed and control subjects did not differ with respect to gender role behavior, although higher numbers of prenatally anticonvulsant-exposed subjects reported current or past cross-gender behavior and/or gender dysphoria. Three prenatally anticonvulsant-exposed subjects were transsexuals and had undergone sex reassignment surgery, a remarkably high rate given the rarity of transsexualism. In addition, two exposed males had exclusively homosexual experiences, whereas none of the control males reported exclusive homosexual behavior. The groups did not differ in attainment of pubertal psychosexual milestones. PMID- 10097804 TI - Dyadic coorientation: reexamination of a method for studying interpersonal communication. AB - The coorientation method is used rarely to study communication in sexual dyads or other relationships due to uncertainty regarding the optimal way to calculate key variables (i.e., understanding, agreement, and perceived agreement). We examined this matter empirically, assessing sexual coorientation among 76 cohabiting couples; 152 adults completed measures of their own and their partners' sexual preferences as well as sexual satisfaction. Three sets of sexual preference coorientation variables were calculated using correlational, difference score, and combined approaches. These variables were then correlated with the sexual adjustment measures to determine which coorientation approach had greater explanatory power across several hypothesized relationships. Results clearly favored the correlational method. We identify several potential applications of the coorientation method and provide guidelines for its application to research on dyadic relationships. PMID- 10097805 TI - Sexual activity prior to coital initiation: a comparison between males and females. AB - The sexual activities college students reported engaging in prior to their first coital experience were investigated. A volunteer sample of 311 students (120 male and 191 female) completed a self-report anonymous questionnaire. Both males and females reported considerable precoital sexual experience. Although males reported more frequent activity than females on all items of assessment, the difference between groups, with the exception of masturbation, was not significant. The majority of both males and females reported at least one experience, and a sizable minority reported considerably more experience, with cunnilingus and fellatio, risk behaviors for the transmission of STDs, prior to their first coitus. Attention is drawn to the dearth of information on sexual activity prior to coital initiation. Given the potential risks of some of these activities, recommendations to further explore and address the precoital sexual behavior of adolescents are suggested. PMID- 10097806 TI - The reported sex and surgery satisfactions of 28 postoperative male-to-female transsexual patients. AB - From 1980 to July 1997 sixty-one male-to-female gender transformation surgeries were performed at our university center by one author (A.M.). Data were collected from patients who had surgery up to 1994 (n = 47) to obtain a minimum follow-up of 3 years; 28 patients were contacted. A mail questionnaire was supplemented by personal interviews with 11 patients and telephone interviews with remaining patients to obtain and clarify additional information. Physical and functional results of surgery were judged to be good, with few patients requiring additional corrective surgery. General satisfaction was expressed over the quality of cosmetic (normal appearing genitalia) and functional (ability to perceive orgasm) results. Follow-up showed satisfied who believed they had normal appearing genitalia and the ability to experience orgasm. Most patients were able to return to their jobs and live a more satisfactory social and personal life. One significant outcome was the importance of proper preparation of patients for surgery and especially the need for additional postoperative psychotherapy. None of the patients regretted having had surgery. However, some were, to a degree, disappointed because of difficulties experienced postoperatively in adjusting satisfactorily as women both in their relationships with men and in living their lives generally as women. Findings of this study make a strong case for making a change in the Harry Benjamin Standards of Care to include a period of postoperative psychotherapy. PMID- 10097807 TI - Psychological evaluation of intersex children. PMID- 10097808 TI - Acquired haemophilia. AB - Acquired haemophilia is a rare but life-threatening acquired bleeding diathesis caused by autoimmune depletion of factor VIII. This occurs most frequently in elderly patients who lack disease associations. Acquired haemophilia may also arise in association with SLE rheumatoid arthritis, Sjogren's syndrome, other autoimmune conditions, lymphoproliferative malignancy, pregnancy and as a drug reaction. Acquired haemophilia has an equal sex distribution. The aims of treatment are to eliminate the inhibitor by immunosuppression and to treat the bleeding, which is the most common cause of death in patients with acquired haemophilia. The inhibitor is abolished in up to 70% of patients using prednisolone and cyclophosphamide, although other immunosuppressive regimens may also be used. These include azathioprine, vincristine and other cytotoxic agents, high-dose immunoglobulin and cyclosporin A. Bleeding may be controlled using porcine factor VIII or recombinant factor VIIa, although human factor VIII and prothrombin complex concentrates also have a limited role as haemostatic agents in this condition. PMID- 10097809 TI - Acquired factor V inhibitors. AB - One hundred and five cases of factor V inhibitors were published between 1955 and 1997. According to pathogenesis, factor V inhibitor patients can be divided into five groups: patients exposed to bovine thrombin; patients after surgery without exposure to bovine proteins; miscellaneous associated conditions; 'idiopathic' inhibitors; inhibitors in congenital factor V deficiency. The clinical and biochemical properties are described. The overall prognosis of factor V inhibitors is good, but there are differences among the five groups with the best prognosis in patients exposed to bovine thrombin and the worst prognosis in 'idiopathic' inhibitors. Only a few treatment options are available. Immunoadsorption and plasmapheresis seem to be the most effective methods for therapy of acute bleeding. Many inhibitors disappear spontaneously and it is uncertain whether an immunosuppressive treatment hastens the disappearance of the inhibitor. PMID- 10097810 TI - Acquired von Willebrand disease. AB - Acquired von Willebrand disease (AvWD) is an acquired bleeding disorder which may suddenly become manifest in individuals, usually in the absence of a personal or family history of bleedings and frequently in association with monoclonal gammopathies, lymphoproliferative, myeloproliferative and autoimmune disorders. In a minority of the cases AvWD may develop in association with drugs or solid tumours. Pathogenetic mechanisms involve autoantibodies directed against von Willebrand factor (vWF) resulting in a rapid clearance of vWF from the circulation and/or inactivation of plasma vWF; absorption or adsorption of plasma vWF to malignant cells; drug-induced or cell-mediated proteolysis of plasma vWF; acquired decrease in synthesis of vWF and/or release of vWF from storage sites; or precipitation of plasma vWF. Treatment options include--whenever possible- treatment of the underlying disorder or symptomatic treatment aimed at replacing the loss of vWF by either infusion of vWF-rich concentrates or administration of desmopressin (DDAVP). In selected cases with anti-vWF antibodies, administration of high-dose intravenous gammaglobulin, plasma exchange or extracorporeal immunoadsorption may be successful. PMID- 10097811 TI - Immune-mediated thrombocytopenias: basic and immunological aspects. AB - Acute idiopathic or autoimmune thrombocytopenic purpura (AITP) is a disorder found mainly in children, usually preceded by a viral infection, with a higher incidence in the autumn and winter. The platelet-specific autoantibodies in acute childhood AITP are more often of the IgM class. Chronic AITP occurs mostly in adults. The platelet immunofluorescence test (PIFT) detects platelet-specific autoantibodies with a sensitivity of 65-75%. The autoantibodies in chronic AITP are classified as IgG in 95%, IgM in 26% and IgA in 4% of cases. The antibodies are usually bound to platelets and are detectable as free circulating antibodies in about 40%. AITP in pregnancy may cause neonatal AITP by autoantibodies of the IgG class which pass the placenta barrier. The rare neonatal alloimmune thrombocytopenic purpura (NAITP) are caused by IgG alloantibodies against HPA-1a in 75-90%, HPA1b in 3-5%, HPA 3a in 4-5%, HPA5b in 6-19% and against private platelet antigens in 3%. To confirm the diagnosis of NAITP requires extensive serological testing of the child, and the parents have to be typed for the important platelet-specific antigens by PIFT, monoclonal antibody immobilisation of platelet antigens (MAIPA) and/or enzyme-linked immunosorbent assay (ELISA) techniques. Three mechanisms of drug-induced thrombocytopenias are described. Platelets of both the donor and the patient are destroyed in post-transfusion thrombocytopenic purpura (PTP) but PTP does not occur again if incompatible platelets are re-administered. PMID- 10097812 TI - Inhibitory and activating human antiplatelet antibodies. AB - Platelets are essential for the maintenance of haemostasis and, on the other hand, play a pivotal role in the formation of a thrombus. It is clear that reduced platelet activity will result in a bleeding tendency, whereas stimulation of platelets can lead to thrombosis. Human antiplatelet antibodies may not only result in thrombocytopenia, but they have also been found either to inhibit or activate platelets. Inhibition by antibodies of the function of different receptors on platelets, such as collagen receptors, the glycoprotein (GP) Ib/IX (acquired Bernard-Soulier syndrome) or the GPIIb/IIIa complex (acquired Glanzmann's thrombasthenia), results in a haemorrhagic disorder very similar to the situation where the respective receptors are absent. On the other hand, reports have described a number of antibodies that activate platelets. The mechanism by which they do so varies and can involve interaction with the Fc receptor present on platelets, activation of the complement system or direct activation by binding to a signal-transducing antigen. Although the presence of such antibodies is expected to aggravate the problems due to the frequently occurring immune thrombocytopenia, treatment of these patients essentially relies on classical immunosuppressive therapy. In the case of activating antibodies, antithrombotic measures, such as anticoagulants or antiplatelet agents, can be envisaged. PMID- 10097813 TI - Immune thrombocytopenic purpura in adults: clinical aspects. AB - Immune thrombocytopenic purpura (ITP) is a relatively common immune-mediated disorder characterized by thrombocytopenia due to clearance of opsonized platelets by the reticuloendothelial system. The acute form, more common in children, is a self-limiting, often post-viral disease. In contrast, the adult form is typically a chronic disorder, which initially responds to corticosteroids. Splenectomy offers a 70% chance of cure. Major progress has been achieved in the elucidation of the immune pathology in ITP, and we review contemporary advances in the treatment of chronic ITP. Practical guidelines for the diagnosis and treatment of various aspects of ITP were established in 1996 by the American Society of Hematology. Since these recommendations will most probably substantially influence patient care, they are discussed in detail. Human immunodeficiency virus (HIV)-associated ITP is a common problem in countries with a high prevalence of HIV infection. The pathogenesis of this subtype probably differs from that of classic ITP, and is considered separately. PMID- 10097814 TI - Immune thrombocytopenic purpura in pregnancy. AB - Of all pregnant women 1.2% have platelet counts below 100 x 10(9)/l. Only a small proportion of these have immune thrombocytopenic purpura (ITP). ITP is caused by antibodies directed against one's own platelets and may affect the mother as well as the fetus. No cases with documented intrauterine fetal bleeding have been reported. The most critical time for the fetus is usually a few days after birth. Hitherto the patient's history has been the best predictor of maternal and neonatal complications. Diagnostic cordocentesis entails a considerable risk and is to be discouraged in most situations. Intrauterine transfusions are effective only for a very limited period. There is no evidence that caesarean section protects the thrombocytopenic infant from intracranial haemorrhage. We therefore recommend restricting caesarean section to obstetric indications and to situations with proven fetal thrombocytopenia and enhanced obstetric risk. The safe cut-off level has yet to be ascertained. It is mandatory to control the newborn's platelet count during the first three days of life. PMID- 10097815 TI - Acute autoimmune thrombocytopenia. AB - Childhood acute autoimmune thrombocytopenia is defined as a bleeding disorder in otherwise healthy children caused by transient destruction of platelets. It is benign, presenting mostly with skin purpura and minor bleeds. The diagnosis requires information about previous infections or immunizations, a physical examination looking for signs or symptoms for other causes of thrombocytopenia and a complete blood count with examination of the peripheral blood smear focusing on the number and morphology of platelets. Bone marrow examination is indicated only when in doubt and should be considered if prednisone therapy is planned. A threshold platelet count dividing high- and low-risk groups in immune thrombocytopenia (ITP) is not known because of problems with platelet counting in thrombocytopenia and the lack of clinical data. Immunoglobulins or glucocorticoids increase the platelet count, probably by blockage of the phagocytic monocyte-macrophage system. However, it is unclear whether this increase influences bleeding or mortality or whether the disadvantages of these medications might outweigh their benefits. PMID- 10097816 TI - The fetal and neonatal consequences of maternal alloimmune thrombocytopenia. AB - Alloimmune thrombocytopenia is a relatively common and under-recognized entity. Prospective screening studies have suggested that at least 1 in every 1000 babies will be affected. While the severity of prospectively identified neonates is not as great as those 'routinely' identified as newborns, the incidence of intracranial haemorrhage in the fetus and neonate is the highest for any immune thrombocytopenia. Diagnosis is complex for the laboratory in view of the large number of platelet antigens and the importance of having sufficient numbers of typed controls. The importance of identifying the affected newborn extends to the likely need for antenatal management of the subsequent affected fetus. Studies to determine the optimal approach to this problem are ongoing. Ideally, prenatal screening of all pregnant women could be performed but this is not currently in practice. PMID- 10097817 TI - Thrombopoietin and its receptor: structure, function and role in the regulation of platelet production. PMID- 10097818 TI - Thrombopoietin: its role in platelet disorders and as a new drug in clinical medicine. PMID- 10097819 TI - Heparin-induced thrombocytopenia: diagnostic tests and biological mechanisms. AB - The discovery of the role of PF4 in the development and pathogenicity of heparin dependent antibodies which trigger heparin-induced thrombocytopenia (HIT), a rare but severe adverse effect of heparin therapy, has allowed us to revisit the diagnosis of this complication and the pathological mechanisms involved. In this review, diagnostic tests available for confirmation or prediction of HIT are analysed, and new diagnostic strategies are discussed. Factors involved in the development of the heparin-dependent immune response in some heparin-treated patients are then presented. Lastly, it is hypothesized that the presence of antibodies is a risk factor for HIT. The mechanisms which contribute to the development of complications and the role of additional risk factors, including the patient's clinical state and the type of heparin used, are discussed (Magnani, 1993). PMID- 10097820 TI - Heparin-induced thrombocytopenia: pathophysiology and clinical concerns. AB - Heparin-induced thrombocytopenia (HIT) is a severe immunological adverse effect of heparin treatment. Recently the pathogenesis of HIT has been resolved regarding the mechanisms of platelet activation, the nature of the most important antigens and the involvement of the clotting cascade. HIT seems to be associated with massive generation of thrombin, which contributes to the thromboembolic complications. Based on these findings, treatment of patients with acute HIT should include cessation of all heparins and further treatment with an anticoagulant with antithrombin activity. Currently, the two most important compounds for further anticoagulation of HIT-patients are danaparoid-sodium and recombinant hirudin. PMID- 10097821 TI - Thrombotic thrombocytopenic purpura: diagnosis, pathogenesis and modern therapy. AB - Thrombotic thrombocytopenic purpura (TTP) is an uncommon multisystem disorder, sometimes associated with predisposing conditions such as pregnancy, cancer, exposure to certain drugs, bone marrow transplantation and HIV-1 infection. An abnormal interaction between the vascular endothelium and platelets which occurs in certain organs leads to thrombosis, endothelial proliferation, minimal inflammation and micro-angiopathic haemolysis. Recent studies suggest that endothelial cell perturbation and apoptosis caused by an as yet unknown plasma factor(s) may lead to the release of abnormal von Willebrand factor which facilitates the deposition of platelet microthrombi. Exchange transfusions of plasma or plasma-cryosupernatant remain the cornerstone of the treatment of TTP along with corticosteroids, platelet inhibitor drugs, vincristine and splenectomy. In most cases remissions can be attained, and cures are now common although approximately one-half of the patients will relapse. While relapses are usually milder, they still carry a significant mortality and preventive therapies are not always effective. PMID- 10097822 TI - The haemolytic-uraemic syndrome in childhood. AB - Haemolytic-uraemic syndrome (HUS) is a clinical syndrome characterized by acute haemolytic anaemia with fragmented erythocytes, thrombocytopenia and acute renal failure. It is one of the leading causes of acute renal failure in childhood. HUS in children can be divided into the so-called typical, diarrhoea-associated HUS, and atypical HUS, which is not preceded by acute gastroenteritis. Infection with verocytotoxin-producing Escherichia coli is the main cause of diarrhoea associated HUS. In this chapter the pathogenesis of diarrhoea-associated HUS and the role of verocytotoxin-producing Escherichia coli in this form of HUS is emphasized. PMID- 10097823 TI - Deficiency of von Willebrand factor-cleaving protease in familial and acquired thrombotic thrombocytopenic purpura. AB - Excessive intravascular platelet agglutination in patients with thrombotic thrombocytopenic purpura (TTP) appears to be associated with excessive release from endothelial cells of unusually large von Willebrand factor (vWF) multimers and/or impaired degradation of these multimers by a 'depolymerase' cleaving vWF to smaller, non-agglutinating molecular forms. We studied the activity of a recently described vWF-cleaving protease in four patients, including two brothers, with chronic relapsing TTP. All four patients had lacking or strongly reduced vWF-cleaving protease activity. In another patient with chronic relapsing TTP, the protease deficiency was due to the presence in the patient plasma of an inhibitor that was found to be an IgG. We conclude that constitutional as well as acquired deficiency of vWF-cleaving protease may predispose to clinical manifestation of TTP. PMID- 10097824 TI - The influence of maturation and gender on the anti-arrhythmic effect of ischaemic preconditioning in rats. AB - The aim of this study was to investigate the influence of maturation and gender on the anti-arrhythmic effect of myocardial ischaemic preconditioning in rats. Coronary artery occlusion was carried out in either rats anaesthetised with sodium pentobarbitone or in rat isolated hearts. Cardiac arrhythmias occurring in the 30 min post-occlusion period were assessed. In anaesthetised 3 month (m) old male rats ischaemic preconditioning, with a 3 min temporary coronary artery occlusion, significantly reduced the total number of ventricular ectopic beats (VEBs) from 2074 +/- 206 to 490 +/- 139 and the incidence of ventricular fibrillation (VF) from 40 to 0% during a subsequent 30 min occlusion (P < 0.05). In middle-aged male rats (16 m) the anti-arrhythmic effect of preconditioning was unaltered (VEBs were reduced from 1958 +/- 121 to 245 +/- 66 and VF from 70 to 0%). In 3 m old anaesthetised female rats the effect of ischaemic preconditioning was also evident (VEBs reduced from 961 +/- 170 to 154 +/- 48; P < 0.05). In non preconditioned age-matched female animals the total number of VEBs (961 +/- 170), VF (0%) and mortality (0%) were significantly (P < 0.05) lower than in respective male animals. In female rats, attenuation of ischaemia-induced arrhythmic severity was most pronounced in the oestrus state. In hearts isolated from weight matched male and female rats the incidence of ventricular tachycardia (81 vs 25%) and the total number of VEBs (351 +/- 73 vs 81 +/- 50) were significantly (P < 0.05) different. It is concluded that in rats neither maturation nor gender influence the anti-arrhythmic effect of ischaemic preconditioning. However, female rats exhibit a lower level of arrhythmic activity during sustained coronary artery occlusion than male rats both in vivo and in vitro. PMID- 10097825 TI - Characterisation of the function of adult guinea-pig ventricular myocytes following co-culture with neonatal rat myocytes. AB - Adult guinea-pig myocytes were co-cultured with a layer of spontaneously contracting neonatal rat myocytes based on a method described by Weisensee D. (In Vitro Cell Dev Biol 31: 190-195, 1995). Contractile studies were performed on freshly isolated, 24 and 48 h co-cultured adult guinea-pig myocytes to investigate whether alterations in contractile function had occurred. No difference was found between freshly isolated and 24 h co-cultured adult guinea pig myocytes in terms of sensitivity to calcium, isoprenaline, frequency response and beat duration. After 48 h, the frequency response was depressed (P < 0.02) and the beat was prolonged (P < 0.05) when compared to that of freshly isolated myocytes. In the presence of the SR Ca2+ ATPase inhibitor, thapsigargin, the beat was significantly prolonged (P = 0.003) in 24 h co-cultured myocytes but not in freshly isolated myocytes. These findings show that adult guinea-pig myocytes can be maintained in co-culture with neonatal rat myocytes with little change in contractile function for 24 h but after this time contractile function begins to deteriorate. PMID- 10097826 TI - Effects of a factor Xa inhibitor, DX-9065a, in a novel rabbit model of venous thrombosis. AB - The objective of this study was to evaluate the effects of DX-9065a, a nonpeptide, direct inhibitor of factor Xa (FXa), in a novel experimental model of venous thrombosis. The experiments were conducted on anesthetized rabbits in which a veno-venous shunt with cotton threads was inserted into the vena cava. DX 9065a was administered intravenously to the rabbits as an initial bolus followed by a maintenance infusion using the following dosing schedules: DX-I: 0.25 mg/kg + 3 micrograms/kg/min.; DX-II: 0.75 mg/kg + 9 micrograms/kg/min.; DX-III: 1.5 mg/kg + 18 micrograms/kg/min.; DX-IV: 3.0 mg/kg + 36 micrograms/kg/min.; DX-V: 6.0 mg/kg + 72 micrograms/kg/min. DX-9065a induced a dose-dependent increase in the time to occlusion and a dose-dependent decrease in thrombus weight. Because of the unique character of the model, we were also able to show a dose-dependent increase in blood flow through the shunt. In addition, there were dose-dependent increases in prothrombin time (PT) and activated coagulation time (ACT) with more variable responses in the activated partial thromboplastin time (APTT). DX-9065a had little effect on thrombin time (TT) or bleeding time at all doses tested. In conclusion, dose-dependent antithrombotic efficacy was documented with DX-9065a in this new model of venous thrombosis. Although the in vivo potency of the compound was not striking, the results support the utility of FXa inhibition in venous thrombosis and demonstrate the utility of this experimental model for evaluating the efficacy of novel anticoagulants. PMID- 10097827 TI - Pretreatment with allopurinol in cardiac hypoxic-ischemic reperfusion injury in newborn lambs exerts its beneficial effect through afterload reduction. AB - The aim of this study was to determine whether allopurinol (ALLO) reduces reperfusion injury inflicted upon the heart resulting from excess production of free oxygen radicals after hypoxia and ischemia (HI) in newborn animals. We, therefore, produced severe HI in 13 newborn lambs by low O2-ventilation and blood volume reduction. One hour before HI seven lambs received ALLO (20 mg/kg i.v.), six received a placebo (CONT). Cardiac function and hemodynamic parameters were assessed by sequential measurement of left ventricular (LV) contractility through the end-systolic pressure-volume relation (ESPVR) using the conductance catheter method. Stroke volume (SV), cardiac output (CO), and aortic pressure (Pao) were measured and ejection fraction and total peripheral resistance (TPR) were calculated before HI, upon resuscitation (UR), and at 60 and 120 min post-HI. To estimate the effect of ALLO on redox status and anti-oxidative capacity, we measured concentrations of uric acid, sulfhydryl (SH), malondialdehyde (MDA), ascorbic acid (AA), and dehydroxylated ascorbic acid (DHAA) in plasma obtained from the coronary sinus and calculated the AA/DHAA ratio. Compared to CONT lambs, TPR in ALLO treated lambs decreased significantly, accompanied by a rise in CO and SV. ALLO did not affect myocardial contractility, because the ESPVR showed no significant differences between groups. AA/DHAA and SH showed a significant decrease in ALLO animals vs pre-HI, but not in CONT animals. Uric acid was significantly decreased in ALLO as compared to pre-HI and CONT animals. MDA was significantly increased in CONT animals at 15 min post-HI as compared to pre-HI, whereas in ALLO animals MDA showed a significant increase at 120 min post-HI vs CONT. We conclude that pretreatment with ALLO has a beneficial effect on the pump function by afterload reduction but not by changes in contractility. Furthermore, ALLO inhibited uric acid formation with a consequent decrease in anti-oxidative capacity. PMID- 10097828 TI - Preconditioning-induced cardioprotection and release of the second messenger inositol (1,4,5)-trisphosphate are both abolished by neomycin in rabbit heart. AB - The mechanisms responsible for infarct size reduction with preconditioning remain controversial. Our aim was to determine whether release of the second messenger inositol (1,4,5)-triphosphate (Ins(1,4,5)P3) during the preconditioning stimulus may play a role. To test this concept, Langendorff-perfused rabbit hearts underwent sham perfusion, 5 min of coronary artery occlusion (CO), or 5 min of CO + infusion of neomycin, an agent which inhibits formation of Ins(1,4,5)P3. Direct quantitation (by competitive binding assay) revealed a 2-fold increase in Ins(1,4,5)P3 content with brief ischemia vs shams (0.69 +/- 0.14 vs 0.34 +/- 0.05 pmol/mg tissue; p < .05) that was blocked by neomycin (0.15 +/- 0.04 pmol/mg). Infarct size (by tetrazolium staining) was assessed in additional hearts that underwent 30 min of sustained CO and 2 h of reperfusion. As expected, two 5-min episodes of preconditioning ischemia reduced infarct size versus controls (30 +/- 6% versus 63 +/- 3% of the myocardium at risk; p < .01). In contrast, infarct size was comparable (54-56% of the risk region) in neomycin-treated control and preconditioned hearts. These results demonstrate that myocardial Ins(1,4,5)P3 content is increased in response to brief preconditioning ischemia and are consistent with the concept that Ins(1,4,5)P3 may be a potential mediator of infarct size reduction with preconditioning in isolated rabbit heart. PMID- 10097829 TI - Variation in tau, the time constant for isovolumic relaxation, along the left ventricular base-to-apex axis. AB - Tau (tau), the time constant for isovolumic relaxation, is often used as a measure of cardiac diastolic function. However, several methods of calculating tau have been published which may produce different results and, thereby, different conclusions. The purpose of this study was to determine if the method of tau calculation effects the results when left ventricular pressure (LVP) is measured at different positions along the base-to-apex axis. In 16 dogs, we measured LVP at 6 positions along the base-to-apex axis. We calculated tau using three different methods: 1) a monoexponential model (P(t) = [P0-Pasym]eAt + Pasym, where t = time, P0 = LVP at t = 0, Pasym is asymptotic pressure as t- >infinity, A is -1/tau) with a zero asymptote 2) a monoexponential model with a variable asymptote in which the monoexponential decay equation is differentiated with respect to time and substituted into the original equation so that dP/dt vs. LVP is A (-1/tau), and 3) a monoexponential decay model with variable asymptote in which Pasym and A are varied until the best fit line is reached by minimizing the residual sum of squares. When tau is calculated using method 1, tau measured at the LV base is 98.01% +/- 8.85% of tau at the apex. If calculated using method 2, tau measured at the LV base was 75.46 +/- 39.4% of tau measured at the apex. When method 3 is used for tau calculations, base tau increases to 117.76 +/- 4.91% of the apical tau. We conclude: 1) the method used to calculate tau will effect the results and, thus, conclusions drawn from tau data. 2) When using Method 3, which appears to be the best method for tau calculation, tau increases at the LV base compared to the apex. PMID- 10097830 TI - Transmural myocardial blood flow distribution in hypertrophic cardiomyopathy and effect of treatment. AB - Verapamil alleviates symptoms in patients with hypertrophic cardiomyopathy (HCM), but the underlying mechanism of improvement remains speculative. Baseline and dipyridamole myocardial blood flow (MBF) were measured in 15 HCM patients (14 men, 42 +/- 10 years), before and after 4 weeks of verapamil SR 480 mg daily, using 15O labelled water the positron emission tomography (PET). Subendocardial (endo) and subepicardial (epi) MBF was measured in the septum (thickness 25.4 +/- 5.8 mm). Pre-treatment baseline whole heart MBF was 1.02 +/- 0.28 ml/min/g and 1.01 +/- 0.30 ml/min/g on treatment (p = ns). Dipyridamole MBF was 1.39 +/- 0.31 ml/min/g off treatment and 1.23 +/- 0.34 ml/min/g on treatment (p = ns). Coronary flow reserve (dipyridamole/resting MBF) was 1.45 +/- 0.52 and 1.30 +/- 0.51, respectively (p = ns). At baseline, the septal endo/epi MBF ratio was uniform off and on treatment (1.13 +/- 0.18 vs 1.18 +/- 0.21, p = ns). Before treatment, the endo/epi ratio following dipyridamole decreased to 0.93 +/- 0.24 (p < 0.01 vs baseline) and 5/15 (33%) patients had a ratio < 0.8 which would suggest subendocardial underperfusion. During treatment, the endo/epi ratio following dipyridamole was no more different from baseline (1.06 +/- 0.24, p = ns vs baseline) and 2/14 (14%) patients had an endo/epi < 0.8. PET can be successfully used to determine transmural MBF in vivo in patients with hypertrophied ventricles. Despite symptomatic improvement, high dose verapamil therapy does not increase total MBF in patients with HCM but may improve septal transmural MBF distribution during dipyridamole in some patients. PMID- 10097831 TI - 23Na NMR demonstrates prolonged increase of intracellular sodium following transient regional ischemia in the in situ pig heart. AB - This study tests the hypothesis that Na+i increases during regional ischemia in the in situ pig heart. An extracorporeal shunt was created between the carotid artery and the left anterior descending artery of 14 open chest pigs. 23Na and 31P NMR spectroscopy measured myocardial Na+i and high energy phosphates (HEPs). The protocol consisted of three 40 min periods: pre-ischemia (shunt pressure, 76 +/- 23 mmHg (S.D.)), ischemia (shunt pressure, 25 +/- 7 mmHg), and post-ischemia (shunt pressure, 53 +/- 11 mmHg). The pre-ischemia Na+i concentration was 6.7 +/- 4.2 mM. Phosphocreatine (PCr) was 15.3 +/- 0.5 mM, ATP 9.4 +/- 0.4 mM, inorganic phosphate (Pi) 1.5 +/- 0.2 mM, and pHi 7.16 +/- 0.09. At the end of ischemia Na+i had increased to 10.5 +/- 2.8 mM (p < 0.0002); PCr decreased to 5.9 +/- 2.1 mM (p < 0.0002); ATP was 6.5 +/- 0.5 mM (p < 0.003); Pi had increased to 6.3 +/- 1.0 mM (p < 0.0002), and pHi was 6.41 +/- 0.06 (p < 0.0002). During the first 10 min of the reperfusion, Na+i increased further to 12.4 +/- 2.8 mM (p < 0.025), whereas HEPs all returned to pre-ischemic values. Na+i increases during regional ischemia in the in situ pig heart, suggesting reduced Na+/K+ ATPase activity. While ATP probably does not limit Na+/K+ ATPase activity, increases in Pi and decreases in pHi may reduce Na+/K+ ATPase activity. Additional Na+i increases during reperfusion suggest either augmented Na+ influx or decreased Na+ efflux. PMID- 10097832 TI - Paraphrenia redefined. AB - BACKGROUND: Paraphrenia is a disorder similar to paranoid schizophrenia but with better-preserved affect and rapport and much less personality deterioration. It is now diagnosed relatively infrequently and is not listed in the current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) or International Classification of Diseases (ICD-10). However, it appears that some psychiatrists recognize the illness but label it "atypical psychosis," "schizoaffective disorder," or "delusional disorder" for lack of a better diagnostic category. Virtually no systematic research on paraphrenia has been conducted in the past 60 years. METHOD: The authors distinguish paraphrenia from "late paraphrenia," a diagnosis used mainly in the United Kingdom, and provide a neo-Kraepelinian description of paraphrenia that would be compatible with the formats of DSM-IV and ICD-10. Using a questionnaire adapted from this description, intake cases in 2 Canadian psychiatric centres (Ottawa [Ontario] and Dartmouth [Nova Scotia]) were surveyed. Cases of paraphrenia were distinguished from those of schizophrenia and delusional disorder and were examined at the time of intake and immediately prior to discharge. RESULTS: For logistical reasons, collecting a totally consecutive series was not possible. However, during an 18-month period, investigators in both centres identified 33 cases closely fitting paraphrenia. The outstanding features of these cases are enumerated, and an outline description of paraphrenia is derived. CONCLUSION: It is possible to define and recognize paraphrenia; it is a viable diagnostic entity. Further research would benefit paraphrenia and schizophrenia patients. Cases in this study have been coded to permit follow-up investigations. PMID- 10097833 TI - Risk and Protective Factors Scale: reliability and validity in preadolescents. AB - OBJECTIVE: To describe the reliability and validity of a novel scale, the Risk and Protective Factors Scale (RPFS), in preadolescents. The RPFS is designed to predict the development of disruptive behaviour disorders (DBDs). METHOD: A controlled study of 120 children aged 6-12 years in DBD and normal groups. Measures include the RPFS and the Revised Child Behaviour Profile (RCBP). RESULTS: Cohen kappa for interrater reliability is 0.81, 92% agreement. Pearson correlation for test-retest reliability is 0.76, 94% agreement. Cronbach alpha for internal consistency is 0.89. Pearson correlation between the RPFS and RCBP is 0.82. The total scores and subscores of the RPFS discriminate significantly between DBD and control groups by student t-test. CONCLUSION: The RPFS has good internal consistency and interrater and test-retest reliability. It has concurrent validity to the RCBP and discriminant validity between DBD and normal groups. This scale may help identify children at risk for DBD, which would allow early intervention, but requires a longitudinal study to establish its predictive power. PMID- 10097834 TI - Identification of childhood psychiatric disorder by informant: comparisons of clinic and community samples. AB - OBJECTIVE: To compare the identification of psychiatric disorder as informed by parents versus teachers in children aged 6-11 years and parents versus adolescents in youth aged 12-16 years in clinic versus community samples. METHOD: Study data come from parallel surveys in Hamilton, Ontario, of children aged 6-16 years. The surveys included consecutive referrals (N = 1150) between 1989 and 1991 to the region's 2 agencies providing outpatient child mental health services. Also, a simple random sample (N = 1689) was used, drawn in 1989 from students attending public schools. Conduct disorder, hyperactivity, emotional disorder, and somatization disorder were assessed by informants using the original Ontario Child Health Study scales. RESULTS: The percentage of children identified with a disorder was markedly higher in the clinic sample, irrespective of the type of disorder, the age and sex of the child, and who provided the assessment. Also, there was a statistically significant differential shift between parents and teachers in the percentage of children identified with disorder. The ratio of children aged 6-11 years identified with conduct disorder or hyperactivity by parents versus teachers was higher in the clinic sample than in the community sample. Among youth aged 12-16 years, a similar pattern emerged for parents as informants versus the adolescents themselves, but it was statistically nonsignificant. CONCLUSIONS: The data suggest that the relative contribution of informants to the identification of childhood psychiatric disorder varies by sample type: clinic and community. If risk factors for child disorder are influenced by contextually specific factors wedded to informants, then studies conducted in clinic versus community samples may lead to discrepant information about the determinants of psychopathology. The extent of this problem needs to be assessed by comparing the results of parallel studies conducted in clinic versus community samples. PMID- 10097835 TI - Long-term medical conditions and major depression in the Canadian population. AB - OBJECTIVES: To evaluate associations between long-term medical conditions and major depression in the Canadian population, and to examine the impact of these conditions on health care service use and disability. METHODS: Data from the first wave of the Canadian National Population Health Survey (NPHS) were used. The NPHS used a probability sample of 17,626 Canadians and included questions about long-term medical conditions, health care service use, and disability and a brief predictor of major depression. Contingency tables and graphical techniques were used to evaluate associations between the variables of interest. RESULTS: Various chronic medical conditions were associated with an elevated prevalence of major depression. There was no evidence that subjects with major depression and comorbid medical conditions were more likely to be admitted to hospital or to be high users of physician services. However, major depression comorbid with chronic medical conditions was associated with a greater than expected extent of activity limitations. CONCLUSIONS: Chronic illness may increase the risk of depression or the duration of depressive episodes; either effect could lead to an increased prevalence. Alternatively, major depression may predispose individuals to certain chronic illnesses. Comorbid major depression and chronic medical conditions are associated with a considerable burden of disability in the Canadian population but not excessive use of physician services. PMID- 10097836 TI - Clinical predictors of short-term outcome in electroconvulsive therapy. AB - OBJECTIVES: Electroconvulsive therapy (ECT) remains one of the most effective biological treatments for major depression. However, there is little information on the clinical use of ECT, and most studies were conducted before the introduction of newer antidepressants and before improvements in ECT delivery. This study examined ECT use in a university teaching hospital to determine predictors of short-term ECT outcome. METHODS: This was a retrospective chart review of ECT over the period 1994-1996. Data extracted from the chart included demographic information, clinical features of depression, and documented antidepressant trials. Outcome measures, based on the chart notes, included Clinical Global Impression (CGI) and cognitive side effects of ECT at 1 week post ECT or at discharge if sooner. RESULTS: Of 174 patients who received ECT, 130 had a diagnosis of unipolar major depressive disorder. Of these 130 patients, 92% were refractory to at least 1 antidepressant medication. After a clinical course of ECT, 87% were rated as "much" or "very much" improved on the CGI. Moderate side effects were noted in 16% of patients, while only 7% had marked side effects. Medication resistance was not related to ECT response. No significant clinical predictors (symptoms, chronicity, number of antidepressant trials) of ECT outcome were found on a stepwise multiple-regression analysis. CONCLUSIONS: These results support previous studies showing that ECT results in very good short-term response in major depressive disorder and that the cognitive side effects of ECT are reasonable. Despite the limitations of this study (retrospective, chart review, global measures), the results will inform clinicians who are recommending ECT for their patients. PMID- 10097837 TI - Optimal haloperidol dosage in first-episode psychosis. AB - OBJECTIVE: To determine optimal doses of haloperidol for the treatment of a first episode of psychosis. METHOD: A 4-week prospective controlled clinical trial with "optimal dose" defined as the dose at which either of the following occurs: 1) significant improvement, defined as a 15% or greater decrease in scores on the Positive And Negative Syndrome Scale (PANSS), or 2) the onset of extrapyramidal symptoms. Beginning with 2 mg daily, haloperidol was increased weekly to 5 mg, 10 mg, and finally 20 mg daily until either 1) or 2) occurred. RESULTS: Optimal doses for the 36 subjects were 2 mg daily for 15 subjects, 5 mg daily for 11, 10 mg daily for 7, and 20 mg daily for 3. On average, subjects whose optimal dose was 2 mg daily showed the greatest improvement. Among the 27 subjects evidencing clinical response to treatment, 20 had plasma haloperidol levels below 5 ng/ml. CONCLUSION: Many people suffering a first psychotic episode respond to haloperidol doses well below levels in common use. PMID- 10097839 TI - Confronting the confounders: the meaning, detection, and treatment of confounders in research. AB - When one variable is studied to try to explain another, the relationship between them may be biased by a third variable. The bias, known as "confounding," is common and must be minimized in research. This description is deceptively simple, though. Identifying confounding is complex but can be reduced to a stepped procedure. By way of examples, this article describes confounding and how to recognize it. PMID- 10097838 TI - A comparison of short-term group and individual therapy for sexually abused women. AB - OBJECTIVE: To compare the effectiveness of 10 sessions of group therapy with that of 10 sessions of individual therapy in a sample of 86 adult women seeking treatment for the effects of childhood sexual abuse. METHOD: Participants were randomly assigned to the 2 treatment modalities and tested at assessment, pretherapy following a 10-week wait condition, posttherapy, and 6-month and 12 month follow-up. RESULTS: Participants had fewer symptoms and better psychosocial functioning posttherapy and were further improved at the 6- and 12-month follow up. Neither treatment modality was superior to the other. Approximately one-half of the sample sought further treatment during the follow-up periods. CONCLUSIONS: Improvement in symptoms and functioning was associated with short-term treatment in both modalities, but many patients remained distressed and required further treatment. Future research should investigate whether sexually abused women who meet criteria for specific diagnoses require more focused and/or longer-term therapy. PMID- 10097840 TI - The impact of primary mental health care in a prison system in Brazil. AB - OBJECTIVE: To analyze the impact of a psychiatric service in a prison general hospital that refers prisoners with mental disorders to a separate forensic psychiatric hospital (FPH). METHOD: Analysis of data on prison population and referrals to the FPH. RESULTS: Despite a 10.9% increase in the overall prison system population over 3 years, referrals from the prison general hospital with the new psychiatric service to the FPH were reduced by 36.5%, whereas referrals from other prisons increased by 120.4%. CONCLUSION: Our results demonstrate the efficiency of the new primary health care approach. PMID- 10097841 TI - Valproic acid intoxication in a patient with bipolar disorder and chronic uremia. PMID- 10097842 TI - Validity of hospital-discharge data. PMID- 10097843 TI - Risperidone as an adjunct to valproic acid. PMID- 10097844 TI - Treatment of schizophrenia with antipsychotics in combination. PMID- 10097845 TI - An attempted suicide using transdermal nicotine patches. PMID- 10097846 TI - Clozapine does not increase ECT-seizure duration. PMID- 10097847 TI - Factors influencing ratio of motor and EEG seizure duration in ECT. PMID- 10097848 TI - Graduating teachers' knowledge and attitudes about attention-deficit hyperactivity disorder: a comparison with practicing teachers. PMID- 10097849 TI - [Liver metastases--a locoregional problem?]. PMID- 10097850 TI - [Diagnosis and staging of liver metastases with imaging methods]. AB - Liver metastases are much more common than primary hepatic malignancies and may occur in up to 80% of patients with extrahepatic malignancies. To optimize the patient's management, precise detection or exclusion of liver metastases, as well as assessment of their number and extent, is indispensable. For imaging of liver metastases, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), scintigraphy, and angiography can be utilized. All these methods have been technically improved with benefits for diagnostic utility. Biphasic contrast enhanced spiral CT (SCT) and MRI with modern pulse sequences and tissue-specific contrast agents are superior to other imaging modalities in terms of diagnostic efficacy and reproducibility of results. With SCT and MRI sensitivities and specificities in the diagnosis of focal hepatic disease are in the range of 80 95%. Moreover, their non-invasiveness is a strong advantage. The diagnostic strategy in the assessment of liver metastases has to take into account both the strengths and limitations of the respective method. Additionally, the clinical situation of a particular patient has to be considered, and conclusive diagnostic results have to be achieved in a short time in order to ensure a favourable cost effectiveness relation. PMID- 10097851 TI - [Principles of curative resection of liver metastases]. AB - For patients with liver metastases, surgery currently represents the only possibility for cure, with a mean 5-year survival rate of 25-35%. Due to refinement in operative and anesthetic techniques and improved critical care with decreased morbidity (< 25%) and mortality (< 5%), hepatic resection is a safe and efficient procedure. Surgery has repeatedly achieved long-term disease-free survival in 20-25% of patients. However, only 10-25% of patients with colorectal liver metastases can undergo potentially curative liver resection. Therefore, accurate staging plays a pivotal role in selecting patients who would benefit from surgery. For metastatic colorectal cancer, resection offers the only potential for cure. For symptomatic neuroendocrine tumors, hepatic resection offers long-term palliation in many cases and cure in some. The role of hepatic resection for noncolorectal and nonneuroendocrine metastases, however, is less well defined. Recurrence of hepatic metastases after seemingly curative resection is observed in about 40-60% of the cases. Only 20-35% of these recurrent metastases appear to be resectable, resulting in an overall 3-year survival rate of about 30%. The morbidity and mortality from repeat hepatectomy is similar to that of first hepatic resection. All results together demonstrate that resection and re-resection of liver metastases can provide long-term survival rates and can be beneficial in a carefully selected group of patients without extrahepatic disease. PMID- 10097852 TI - [Therapeutic options in non-resectable liver metastases. Percutaneous radiological interventions]. AB - In patients with irresectable liver metastases the following spectrum of oncological concepts is in use. Percutaneous interventional methods allows for an optimized local control rate in strictly intrahepatic disease. Regional short term time chemotherapy and transarterial chemoembolization (TACE) belong to regional methods. As local ablative methods, intratumoral drug application, endotumoral chemotherapy and alcohol instillation can be used. The most promising thermotherapeutic strategies are radiofrequency and laser-induced thermotherapy (LITT). In a prospective study 278 patients suffering from liver metastases were treated with MR-guided LITT and exact data for the local control rate and survival rate were evaluated. The overall cumulative survival rate (Kaplan-Meier) of patients with liver metastases was 40.8 months (median: 40.97 months, 95% confidence interval 36.3-45.2). PMID- 10097853 TI - [Retrospect and prospects]. PMID- 10097854 TI - [Reliable case figures for performance-correct compensation? On the problem of risk selection in relation to cost measures]. PMID- 10097855 TI - [Comment on the consensus report by medical staff on compensation for ambulatory and inpatient treatment]. PMID- 10097856 TI - [Does the "impact factor" kill the German language?]. PMID- 10097857 TI - [Standards, guidelines, are their value proven?]. PMID- 10097858 TI - [The status of regional long-term chemotherapy in liver metastasis]. AB - In numerous tumors, metastasis can be limited to the liver. In non-resectable patients, regional treatment modalities, especially arterial cytostatic infusion, are favored in contrast to systemic chemotherapy, whereas intraportal or intraperitoneal application is not successful. Improved results with high response rates have been reported after development of intra-arterial (i.a.) long term regimens with FUdR in patients with colorectal liver metastases using implantable pumps and ports. However, a survival benefit could only be demonstrated in comparison with a control group only treated symptomatically. Because of several reports on major local toxicity of i.a. FUdR treatment (i.e. chemical hepatitis and biliary sclerosis) several other effective i.a. 5-FU regimens have been developed. A randomized study has demonstrated superiority of i.a. 5-FU versus i.a. FUdR. In comparison with systemic treatment, superiority has only been demonstrated in patients with an intrahepatic tumor burden of < 25%. Publications about regional treatment of patients with breast, gastric cancer or carcinoid liver metastases are rare. Despite the high response rates reported, the benefit of arterial chemotherapy remains questionable. Overall, local long-term chemotherapy cannot be recommended outside of studies as a primary treatment. However, extensive experience and new drugs support the idea of conducting further regional studies. PMID- 10097859 TI - [Cryosurgery--renaissance or real progress?]. AB - The development and improvement of the cryosurgical technique in combination with intraoperative ultrasonographic imaging enables reliable destruction of liver tumors--although not free of complications--given that tried and tested rules of cryosurgical research are obeyed. In this respect, we can speak of real progress. On the basis of a 3-year testing phase with the CRYO6 cryosurgical apparatus from ERBE, a protocol for the cryosurgical technique for liver tumors is introduced. The spectrum of indications for cryosurgery includes the destruction of irresectable hepatic secondaries or primary tumors with curative intention and the freezing of insufficient or incomplete resection margins. The preliminary results of this treatment modality are encouraging. However, there remains a need for further clinical research to allow final judgement of the cryosurgical method. PMID- 10097860 TI - [Hepatocellular transplantation--from the beginning to clinical application]. AB - Within the past 30 years hepatocyte transplantation has been developed in rodents for the cure of acute and chronic liver failure. Organ shortage and the enormous costs of orthotopic liver transplantation have promoted intensive research in transplantation of isolated hepatocytes. Transplanted syngeneic hepatocytes survive indefinitively in rodents, allowing correction of various inherited liver enzyme defects or enhancing recipient survival in experimentally induced acute liver failure. The clinical application of hepatocyte transplantation has been recently demonstrated in a young patient suffering from Crigler-Najjar syndrome type I, with successful long-term survival of allogeneic hepatocytes. This review reports the historical development and the published data on experimental and clinical hepatocyte transplantation. PMID- 10097861 TI - [Segmental anatomy of the liver--a sonomorphological viewpoint]. AB - The liver is an ideal organ for ultrasonography. In this context, intrahepatic structures allow the identification of segments according to Couinaud by ultrasonography. This article describes, step by step, the ultrasonographic segmental anatomy of the liver. PMID- 10097862 TI - [Liver transplantation preserving the vena cava and a temporary portocaval shunt]. AB - The experience with laterolateral cavocavostomy for hepatovenous reconstruction in liver transplantation is reviewed with and without the use of a temporary portocaval shunt. A total of 65 liver transplantations were analyzed. In 49 transplantations a laterolateral cavocaval anastomosis was performed (group I). In group II (n = 16) the same technique was used after a temporary portal caval shunt was constructed. Mean arterial pressure (mmHg): group I 128 +/- 34; group II 109 +/- 32. Cardiac output (l/min) decrease during the anhepatic phase was 2.3 +/- 1.9 and 1.2 +/- 1.5, respectively (P < 0.05). The peroperative blood loss measured as the number of packed cells transfused was 16.4 +/- 15.8 versus 1.2 +/ 2.3 (P < 0.04) and fresh frozen plasma 19.0 +/- 14.7 versus 3.7 +/- 4.0 (P < 0.02). Course on ICU (days), liver function tests, renal function and the need for reoperation because of bleeding were not statistically significantly different between the groups. One-year patient survival was 82.7 and 85.7%, respectively. In conclusion, we found that despite preservation of the caval flow during hepatectomy, the additional use of a temporary portocaval shunt was advantageous with regard to peroperative hemorrhage and hemodynamic stability and can potentially facilitate implantation of the liver graft. PMID- 10097863 TI - [Distribution pattern and involvement of regional lymph nodes in non-small-cell bronchial carcinoma]. AB - Despite the important role of lymph node infiltration for the classification and prognosis of non-small-cell lung cancer (NSCLC), no standards exist to evaluate the quality of mediastinal lymphadenectomy. Researches at several centers are not convinced that complete ipsilateral lymphadenectomy is necessary. We investigated 270 consecutive patients undergoing a potential curative operation for NSCLC including complete ipsilateral lymph node dissection in order to ascertain whether or not there is a correlation between tumor localization and lymph node infiltration. Patients were classified into the UICC (1987) stages I (n = 115), II (n = 42), and IIIa (n = 113). In patients with N1-positive lymph nodes (n = 61) we found higher 5-year survival for patients with only intrapulmonary lymph node infiltration (39%) than for patients with hilar infiltration (21%). Patients with N2 disease showed skip metastases in up to 81% of cases. We found that no tumor location predicted the lymph node infiltration. Due to the variability of lymph node infiltration and the frequently occurring skip metastases, complete ipsilateral lymphadenectomy should be the standard for curative operations for NSCLC. PMID- 10097864 TI - [Effects of argon gas embolism during pneumoperitoneum]. AB - In a porcine model, ten animals with a mean body weight of 18.9 (15-24) kg were exposed either to intravenous boli of 10, 20, and 30 ml argon (n = 5) or CO2 gas (n = 5). Gas embolism with argon led to increased pulmonary artery pressure (P > 0.001) and induced a decrease in end tidal CO2 (P < 0.001) and reduced cardiac output (P < 0.001) with a consecutive decrease in mean arterial pressure (P < 0.05). One animal died in cardiac shock after a 20 ml argon gas embolism and another after a 30 ml argon bolus. A third animal recovered after resuscitation with noradrenaline after a 30 ml argon bolus. Animals in the CO2 group receiving 10, 20, or 30 ml bolus neither required resuscitation nor died. Hemodynamic parameters were not affected by a 10 to 30 ml bolus of CO2 gas. Thus, gases with a low solubility in blood like argon should not be used during procedures with an increased risk of gas embolism. PMID- 10097865 TI - [Increasing frequency of bariatric surgery interventions since replacement of gastroplasty by laparoscopic gastric banding in the treatment of morbid obesity]. AB - Between 1984 and 1996 we performed a Mason gastroplasty for the treatment of morbid obesity: 14 patients (average age 40 (26-48) years, body mass index (BMI) 48 (37-71) kg/m2, excessive body weight 67 (41-116) kg). Since the end of 1996 we now apply adjustable laparoscopic gastric banding (lab band): 73 patients (average age 39 (22-64) years, BMI 45 (32-69) kg/m2, excessive body weight 66 (41 116) kg). We compared the early and late results of both methods. Early results: no relevant morbidity or mortality for neither method. Late/intermediate results: reoperation rate for both methods 15%. After an average of 3.7 years the excessive body weight loss (EWL) for gastroplasty was 54 (22-96)%. The EWL after lab band for 24 patients after 12 months was 47 (11-127)% and for 8 patients after 18 months 51 (28-139)%. Since the introduction of the lap band the number of bariatric operations has greatly increased. Nevertheless, the perioperative complication rate has remained low, and the long-term outcome is similar for both methods. PMID- 10097866 TI - [Surgical therapy of morbid obesity with laparoscopic "gastric banding". Technique and results of 370 cases]. AB - The application of an adjustable silicone gastric band is a very efficient and long-term method to reduce the weight in morbid obesity. The surgical technique is exacting; standardization of the procedure diminishes the complication rate. 370 patients with morbid obesity underwent the laparoscopic application of a gastric band between May 1996 and September 1997. Two different kinds of gastric bands were used in these surgeries. The data are shown in two series. The total morbidity rate was 16.8%, in series II 4.5%. The mortality rate was 0%. The average loss of weight came to 12 kg (5.3%) after 4 weeks, 18% after 3 months, 37.4% after 6 months and 48.4% after 1 year. PMID- 10097867 TI - [The VCS clip--experimental experiences with a new vascular suture stapling device]. AB - Despite improvements in technique and suture material, vascular anastomosis is still associated with a significant rate of early (stenosis, thrombosis) and late (intimal hyperplasia) complications. Although automatic mechanical staplers were practical und comparatively safe to use, they did not play a major role in vascular surgery, probably due to the complexity and difficult handling. In an experimental study with the VCS clip system, we found a significant improvement in performing a hepatic artery anastomosis [9.2 +/- 1.5 min (VCS) vs 20.6 +/- 2.7 min (suture), P < 0.001], early patency and flow rate [150 +/- 29.1 ml/min (1.0 h)-->79.9 +/- 24.0 ml/min (24 h) (suture) vs 186 +/- 45 ml/min (1.0 h)-->162 +/- 48 ml/min (VCS), P < 0.005]. Besides easy handling, the VCS clip system allows for a fast, standardized vascular anastomosis without intimal penetration. PMID- 10097868 TI - [Laparoscopically-assisted trans-mediastinal esophagectomy]. AB - In esophageal cancer blunt dissection of the esophagus is reasonable in high-risk patients. Manual dissection can compromise the heart and reduce blood pressure. This can be avoided by laparoscopically assisted transmediastinal dissection of the esophagus. We describe the operative procedure and report on a patient with coronary heart disease who suffered from cancer of the cardia spreading into the esophagus as well as into the stomach. Esophagogastrectomy was performed with jejunal replacement. PMID- 10097869 TI - [Bilobar liver hematoma and spontaneous rupture after cesarean section]. AB - A 25-year-old woman delivered a healthy baby in the 34th week of gestation by caesarean section due to placental abruption and fetal bradycardia. On the following day she developed dyspnea, tachycardia, hypotension and rising serum transaminase levels. After exclusion of a pulmonary embolism, the abdominal CT scan and cavography revealed a subcapsular hematoma of the entire dorsal liver surface and compression of the retrohepatic vena cava. During laparotomy a spontaneous rupture of the liver capsule with intraperitoneal hemorrhage was found. The dorsal liver was decapsulated and the subcapsular hematoma completely removed. The postoperative course was uneventful. PMID- 10097870 TI - [Knee ligament injuries. Anatomy, biomechanics, diagnosis, indications]. PMID- 10097871 TI - Foundations of behavior therapy in the contemporary healthcare context. AB - The purpose of this review article is to provide an overview of behavior therapy. Both historical and contemporary perspectives will be addressed. Particular attention will be given to description of behavioral treatment interventions. Description of alternative treatment options, including psychopharmacology, will also be reviewed. The article will conclude with an examination of the importance of behavior therapy in the current managed care environment. PMID- 10097872 TI - A synthesis of psychological interventions for the bereaved. AB - Several interventions have been implemented to address the adverse psychological and physical consequences associated with bereavement. In this review, we summarize four major theories of bereavement, present a qualitative review of bereavement intervention studies, and assess the overall effectiveness of bereavement intervention studies in a quantitative meta-analysis. Summaries of the theories are drawn from published theoretical works. The qualitative and quantitative reviews were based on searches of Medline, PsychINFO, and Dissertation Abstracts International databases using the keywords "bereaved" and "bereavement." Overall, the interventions were largely methodologically flawed, rarely specified what theory of bereavement they were testing, and slowed surprisingly weak effect sizes. Possible interpretations for the small effect sizes are discussed, and future directions are outlined. PMID- 10097873 TI - Adopted children's behavior problems: a review of five explanatory models. AB - Although the majority of adopted children are well-adjusted, adopted children evidence proportionately more behavior problems when compared to nonadopted children in both clinic and nonclinic populations. An extensive literature examining behavioral, diagnostic, and demographic characteristics of adopted children has provided several plausible explanations for the high rate of behavior problems among adopted children. In this review, the existing literature is organized into five explanatory models: (a) genetic or "biosocial" factors, (b) pathogenesis of the adoption process, (c) long-term effects of impaired preadoption childrearing, (d) referral bias in adoptive parents, and (e) impaired adoptive parent-adoptee relations. We conclude that evidence for each model is mixed at best. Especially noteworthy is the mixed results for genetic or biosocial studies and the relative absence of studies focused on identifying factors associated with disruptions in the adoptive parent-adoptee relationship. We propose that a psychosocial model to explain the high rate of behavior problems among adopted children is highly plausible and further suggest that it may be time for a new awareness and appreciation for the normative aspects of adoption. An overview of parenting and family characteristics associated with risk factors for antisocial behavior is provided as a guide for future research. PMID- 10097874 TI - Psychosocial treatments for adolescent depression. AB - Major Depressive Disorders affect between 2% and 5% of adolescents at any one point in time. Depression in adolescence is associated with serious psychosocial deficits and has negative effects on functioning during young adulthood. Starting with the pioneering work of Lenore Butler and her colleagues, many psychosocial interventions have been developed and studied, with generally positive results. On the basis of a meta-analysis of the existing cognitive-behavioral therapy (CBT) studies we estimate an overall effect size of 1.27 and that 63% of patients show clinically significant improvement at the end of treatment. It seems reasonable to conclude that CBT has been demonstrated to be an effective treatment for depressed adolescents. In this article we describe these interventions, most of which are meant to address the problems shown by depressed adolescents. The purpose of our article is to bring this literature to the attention of clinicians in a manner which quickly and clearly summarizes the key features of the interventions to make it easy for clinicians to take advantage of this wealth of information and to avail themselves of the existing resources. We conclude by suggesting future directions and several additional areas of application for adolescent depression treatments. PMID- 10097875 TI - Depression and anxiety among Asian American elders: a review of the literature. AB - Depression and anxiety are often reported to be the most common psychological disorders among older adults in the United States. As the population of older Asian American adults steadily increases, mental health practitioners will need to be apprised of the etiological, diagnostic, and treatment issues in working with this population. This article reviews the existing literature on depression and anxiety among older Asian American adults. Little empirical research has been conducted, and more research on the mental health status and needs of older Asian American adults is needed. In addition, improved recruitment of Asian Americans into the health-care professions as well as improved clinical and research training in an increasingly diverse society are imperative to addressing the lack of attention to the mental health needs of older Asian American adults. PMID- 10097876 TI - Interpersonal and psychological correlates of marital dissatisfaction in late life: a review. AB - Developmental studies suggest that marital quality improves in old age (e.g., Guilford & Bengtson, 1979). However, many of the studies are replete with sampling biases that probably led to an overinflated positive report of marital satisfaction in older adults. Our review evaluated contemporary studies that have investigated interpersonal and psychological factors associated with dissatisfaction in long-term marriages. Recent investigations indicate that older marriages benefit from lower levels of conflict and greater sources of mutual pleasure following child-rearing cessation. Studies of social support in long term marriages suggest that perceptions of spousal support are more strongly related to marital satisfaction and general well-being for older women than for men. A few investigations have found a significant relationship between depression and marital discord in older adult samples, and the causal flow between these two variables appears to be unidirectional in that depression has a detrimental impact on late-life marital quality. Indeed, depression has been found to mediate the link between many age-related stressors (e.g., ill health, retirement) and declines in marital adjustment. However, our preliminary analysis of marital adjustment within a depressed, older adult, outpatient sample of married individuals did not confirm statistically that marital discord is associated with depressive symptomatology. This, in part, was attributed to the very narrow range of older adults sampled (i.e., clinic patients suffering from depression). However, the majority of depressives characterized their marriages as discordant. The implications for these findings are discussed and future directions are offered. PMID- 10097877 TI - Cortical visual-vestibular interaction for spatial orientation and self-motion perception. PMID- 10097878 TI - Visual-vestibular control of posture and gait: physiological mechanisms and disorders. AB - The scientific analysis of clinical disorders of posture and gait is an emerging field. Precise definition of the forces and postural movements involved has been pivotal to understanding many aspects of the visual and vestibular contributions to balance. However, a great deal of argument still surrounds the question of how much gait and posture laboratories actually contribute to improve the clinical management of individual patients. One of the reasons why gait analysis techniques have not penetrated rehabilitation clinics may be that the research questions asked have been aimed at understanding mechanisms rather than at quantifying disability. The condition known as primary orthostatic tremor, which is not too well known to many neuro-otologists and posturographists, is briefly reviewed here. We propose that posturography could be the easiest way to diagnose this treatable condition. PMID- 10097879 TI - Neurology of saccades and smooth pursuit. AB - During the period covered by this review a number of papers have been published on saccade and smooth pursuit research, conducted experimentally in monkeys and clinically in humans. In monkeys, using mainly electrophysiological methods, the roles of the frontal eye field, parietal eye field and supplementary eye field at the cortical level, and those of the paramedian pontine reticular formation, nucleus prepositus hypoglossi, interstitial nucleus of Cajal and superior colliculus at the brainstem level have been studied in great detail. In humans the same cortical areas have also been examined, mainly using functional imaging resulting in new information on the location of these areas and new hypotheses on the role of the superior parietal lobule in visual attention and that of the posterior part of the anterior cingulate cortex in motivation. Saccades, smooth pursuit and clinical applications of eye movement research are dealt with separately. PMID- 10097880 TI - Neuropharmacologic aspects of the ocular motor system and the treatment of abnormal eye movements. AB - Neuropharmacology is aiding our understanding of the control of eye movements in at least three ways. First, neurotransmitters have been identified in the pathways that coordinate gaze. Second, the technique of pharmacologic inactivation has provided a powerful method to determine the contributions of populations of neurons to specific behaviors, such as steady gaze holding. Finally, the results of basic neuropharmacologic studies have been used to identify candidate drugs for therapeutic trials of abnormal eye movements. PMID- 10097881 TI - Vestibular autonomic regulation (including motion sickness and the mechanism of vomiting). AB - Autonomic manifestations of vestibular dysfunction and motion sickness are well established in the clinical literature. Recent studies of 'vestibular autonomic regulation' have focused predominantly on autonomic responses to stimulation of the vestibular sense organs in the inner ear. These studies have shown that autonomic responses to vestibular stimulation are regionally selective and have defined a 'vestibulosympathetic reflex' in animal experiments. Outside the realm of experimental preparations, however, the importance of vestibular inputs in autonomic regulation is unclear because controls for secondary factors, such as affective/emotional responses and cardiovascular responses elicited by muscle contraction and regional blood pooling, have been inadequate. Anatomic and physiologic evidence of an extensive convergence of vestibular and autonomic information in the brainstem suggests though that there may be an integrated representation of gravitoinertial acceleration from vestibular, somatic, and visceral receptors for somatic and visceral motor control. In the case of vestibular dysfunction or motion sickness, the unpleasant visceral manifestations (e.g. epigastric discomfort, nausea or vomiting) may contribute to conditioned situational avoidance and the development of agoraphobia. PMID- 10097882 TI - Vestibular and hearing loss in genetic and metabolic disorders. AB - Hearing loss affects about 4% of people under 45 years of age and comprises a broad spectrum of clinical presentations (congenital or late-onset, conductive or sensorineural, and syndromic or nonsyndromic). Approximately 30% of genetically determined deafness is reported to occur in syndromic form and 70% in nonsyndromic form. This review highlights recent advances in the molecular and genetic basis of hearing loss, which will help in understanding the biology of normal and abnormal hearing. PMID- 10097883 TI - Cochlear implants and electrical brainstem stimulation in sensorineural hearing loss. AB - Cochlear implants and multichannel auditory brainstem implants enable patients with bilateral total or profound hearing loss to receive at least acoustic information. Both types of prosthesis are based on electrical stimulation of the auditory pathway. Different speech coding strategies and the number of electrodes used may influence the postoperative results. The preoperative evaluation of patients is of utmost importance. The cochlear implant is suitable for patients with hearing loss due to inner ear disorders, but who have functioning hearing nerve. Patients with a defect of the hearing nerve can be provided with an auditory brainstem implant. PMID- 10097884 TI - Stroke: the neurological emergency. PMID- 10097885 TI - Genetic susceptibility and ischaemic stroke. AB - In the past year the search for genetic susceptibility factors involved in ischaemic stroke has motivated a number of important studies in humans and animals. These have been focused on genetic susceptibility as a risk factor for ischaemic stroke, or as a determinant of ischaemic stroke outcome. Because there is increasing evidence that genetic factors play a role, it seems that epidemiological studies assessing both environmental and genetic risk factors may help to understand the cause of ischaemic stroke better. This may have therapeutic and preventive implications. PMID- 10097886 TI - Cerebrovascular ultrasound. AB - Rapid progress in noninvasive ultrasound techniques has resulted in a wide variety of clinical applications for assessment of both extracranial and intracranial arterial diseases. Recent highlights in cerebrovascular ultrasound research include imaging methods for characterization of intracranial aneurysms, use of echocontrast agents for improved evaluation of acute stroke patients and transient response harmonic imaging for depiction of brain perfusion. The important role of transcranial Doppler microembolism detection in carotid endarterectomy has been defined, new approaches to noninvasive Doppler measurement of intracranial pressure are progressing, and the clinical indications for transcranial Doppler monitoring of intracranial vasospasm to prevent secondary stroke have expanded. New functional transcranial Doppler applications, which are complementary to positron emission tomography and functional magnetic resonance imaging studies, are evolving for evaluation of functional recovery after stroke; investigation of perfusion asymmetries during complex spatial tasks; assessment of hemispheric dominance in surgical candidates for epilepsy surgery; and elucidation of temporal patterns of regional neuronal activity. With increasing sophistication of cerebrovascular ultrasound methodology, it is essential that standards for data acquisition and interpretation be established. Three recent consensus meetings have provided detailed recommendations on quantification of carotid artery stenosis, on characterization of carotid artery plaques and on microembolism detection by transcranial Doppler. PMID- 10097887 TI - Imaging developing brain infarction. AB - Continued advances in neuroimaging technology have made it practical to image multiple aspects of evolving brain infarction during the potential window period of therapeutic opportunity in stroke. Recent methodologic developments include computed tomography angiography and perfusion, and the description of quantitative parameters for magnetic resonance blood oxygen level-dependent perfusion imaging. In pathophysiologic studies, metabolism and function in the ischemic focus and the peri-infarct tissue have been further characterized. Clinical studies have focused on the applications of computed tomography and magnetic resonance imaging for prethrombolysis patient selection. These methods have an important role in the evaluation and development of new pharmaceutical agents and will be increasingly used in clinical practice as new therapies become available. PMID- 10097888 TI - Clinical trial update: neuroprotection against acute ischaemic stroke. AB - One of the most recent advances and hopes in stroke therapy concerns neuroprotection, which has recently been investigated in several clinical trials. Furthermore, some new neuroprotective drugs, which are based on newly identified cellular and molecular mechanisms that underlie the development of focal ischaemic injury, will be tested in stroke patients in the future. It must be emphasized, however, that the concept and application of neuroprotection must remain within the frame of the global network and organization of acute stroke care, because neuroprotection at best may become only a link among many other management strategies for acute stroke. PMID- 10097889 TI - Bibliography. Current world literature. Neuro-ophthalmology and neuro-otology. PMID- 10097890 TI - Bibliography. Current world literature. Cerebrovascular disease. PMID- 10097891 TI - Improving prognosis of type 1 diabetes. Mortality, accidents, and impact on insurance. AB - OBJECTIVE: Individuals with type 1 diabetes applying for insurance (life, health, accident, etc.) may either see their application being declined by the insurance company or find their premiums being substantially higher than the standard premium. During the last 40-50 years, the prognosis of patients with type 1 diabetes has improved dramatically, partly as a consequence of improved metabolic regulation and partly due to introduction of better treatment for late diabetic complications. The aim of the present study was to determine whether the increased premiums paid by diabetic patients for life insurance and accident insurance reflect the true risk of a diabetic individual. RESEARCH DESIGN AND METHODS: Mortality: 3,000 type 1 diabetic patients were followed for 12-51 years. The impact of age, sex, year of diagnosis, and development of nephropathy on excess mortality was analyzed. Accidents: A cohort of nearly 7,000 members of the Danish Diabetes Association participating in group accident insurance was followed for 3 years. The risk and outcome of accidents in the diabetic group was compared with similar risks in a nondiabetic group. RESULTS: Mortality: Over a 40 year period, the median life expectancy of type 1 diabetic patients increased by more than 15 years. The decrease was predominantly explained by a decreasing incidence of nephropathy, so that a simple model for estimating insurance premiums (including age of diagnosis, sex, and presence or absence of diabetic nephropathy) could be established. Accident insurance: Individuals with type 1 diabetes experienced a risk of accidents that was not in excess of that found in two control groups, and the outcome (degree of disability) after the accidents did not differ between the diabetic and the nondiabetic group. CONCLUSIONS: Type 1 diabetic patients still have a mortality in excess of nondiabetic individuals. Life insurance premiums should, however, always reflect the changing prognosis of type 1 diabetes and thus, continuous monitoring and revisions are needed. For accident insurance, we found no increased risk of accidents; thus, diabetic individuals should be offered accident insurance on normal terms. PMID- 10097892 TI - Primary and secondary prevention strategies of pre-type 1 diabetes. Potentials and pitfalls. AB - Over the past decade, a large part of type 1 diabetes research has focused on the possibility of preventing the disease. The objective of this article is to analyze which potential and pitfalls different preventive strategies may involve from the individual, epidemiological, and ethical perspectives. Two potential prevention strategies are considered: l) to try to arrest or delay an already ongoing immune destruction of the beta-cells, and 2) to try to intervene with exposures that may initiate this process. In addition to the potential effects of immune modulation, this prevention strategy depends on screening for risk markers. There are inherent ethical problems with screening because of the introduction of awareness of risk in healthy individuals and also because false positivity, the rate of which differs tremendously in high- and low-risk groups. Because of these latter circumstances, the most promising low-risk preventive treatments presently used in trials, i.e., nicotinamide and insulin, will probably only be feasible in high-risk groups, such as family members, though this group covers only 10-15% of potential cases. The second strategy aiming at eradicating environmental initiators of the beta-cell destruction will avoid the problem of screening and approach a total population at risk. Potential risk factors, such as food components (cow's milk proteins, gliadin or nitroso products) or different viruses, are indicated by animal and epidemiological studies. So far, however, no single environmental risk factor has been proven to be necessary and certainly not sufficient for the disease causation, and the etiological fractions estimated in population-based studies are low. It is concluded that more basic research is warranted before effective and safe prevention can be introduced for type 1 diabetes. Most probably, different preventive strategies must be applied to different groups and populations and in different phases of the beta-cell destruction. PMID- 10097893 TI - Immunologic "vaccination" for the prevention of autoimmune diabetes (type 1A). AB - Diabetes type 1A is an autoimmune condition characterized by lymphocytic infiltration of islets and selective destruction of insulin-secreting beta-cells. Numerous investigators have prevented diabetes in animal models with a variety of antigens and routes of administration. It is also now possible to identify high risk individuals even before the appearance of autoantibodies. These advances have created the opportunity to design and begin human prevention trials. This review focuses on a variety of immunomodulatory approaches (including administration of adjuvants, autoantigens, T-cells, T-cell receptors, and DNA) that we have collectively termed immunologic "vaccination." In addition, we discuss the potential benefits and dangers of these approaches and issues relating to the design of human trials. PMID- 10097894 TI - Nicotinamide in type 1 diabetes. Mechanism of action revisited. AB - Treatment with high doses of nicotinamide (niacinamide, vitamin B3) prevents or delays insulin-deficient diabetes in several animal models of type 1 diabetes and protects islet cells against cytotoxic actions in vitro. In recent-onset type 1 diabetes, nicotinamide administration improves beta-cell function, without significantly decreased insulin requirements. This review discusses the possible mechanism of action of nicotinamide in vivo. It is proposed that the key target of nicotinamide is the poly(ADP-ribose)polymerase (PARP), and to a lesser extent (mono)ADP-ribosyl transferases (ADPRTs). Suppression of PARP activity by nicotinamide not only decreases consumption of NAD+, the substrate of PARP, but also has major regulatory effects on gene expression, as shown for the major histocompatibility complex class II gene. In addition, PARP activity controls early steps of apoptosis. The possible suppression of ADPRTs by nicotinamide would also affect CD38, a membrane-bound external ADP-ribosyl transferase with potent immunoregulatory properties. Taken together, it is proposed that high doses of nicotinamide primarily affect ADP-ribosylation reactions in beta-cells as well as in immune cells and the endothelium. As a consequence, cell death pathways and gene expression patterns are modified, leading to improved beta-cell survival and an altered immunoregulatory balance. PMID- 10097895 TI - Fiber intake, serum cholesterol levels, and cardiovascular disease in European individuals with type 1 diabetes. EURODIAB IDDM Complications Study Group. AB - OBJECTIVE: A cross-sectional analysis of dietary fiber intake was performed in European type 1 diabetic patients enrolled in the EURODIAB IDDM Complications Study to explore its potential relationship to serum cholesterol levels and the prevalence of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Dietary intake was assessed by a standardized 3-day dietary record. For analysis of fiber intake (total, soluble, and insoluble) and its associations with CVD (past history or electrocardiogram abnormalities), complete data were available from 1,050 male and 1,012 female individuals. Relationships of fiber intakes to serum cholesterol levels (total, HDL, and LDL cholesterol) were examined in 926 men and 881 women with type 1 diabetes. RESULTS: Higher intakes of total fiber (g/day) were independently associated with significantly higher levels of HDL cholesterol in male (P = 0.01) and female individuals (P = 0.03). Fiber intakes of men with type 1 diabetes were also inversely related to ratios of total cholesterol to HDL cholesterol (P = 0.0001) and levels of LDL cholesterol (P = 0.0002). A protective effect of total fiber intake against CVD was observed for female subjects, where a significant trend was maintained after adjustment for potential confounders, including energy and saturated fat (P = 0.03 vs. P = 0.2 in men). Results were similar in separate analyses of soluble and insoluble fiber. CONCLUSIONS: The present study demonstrates that higher fiber intakes are independently related to beneficial alterations of the serum cholesterol pattern in men and to a lower risk for CVD in European insulin-dependent women. Beneficial effects can already be observed for fiber amounts within the range commonly consumed by outpatients with type 1 diabetes. PMID- 10097896 TI - Intensified treatment and education of type 1 diabetes as clinical routine. A nationwide quality-circle experience in Germany. ASD (the Working Group on Structured Diabetes Therapy of the German Diabetes Association). AB - This contribution describes the nationwide implementation of an intensive treatment and education program for type 1 diabetic patients in the clinical routine of the German health care system. Based on the formation of a working group (Arbeitsgemeinschaft Strukturierte Diabetestherapie [ASD]) of presently 57 general internal medicine departments, mainly from secondary and tertiary care levels in city and country hospitals throughout the country, a peer-review quality circle was formed as an official working group of the German Diabetes Association. The participating institutions performed a structured program of intensive treatment and education in all type 1 diabetic patients referred to them on a routine basis. The program includes multiple daily insulin injections or continuous subcutaneous insulin infusion, several times daily blood glucose self-monitoring and self-adaptation of insulin dosages and other aspects of treatment by the patients, and a far-reaching liberalization of the nutrition regimen. The group has attempted to document and to improve the quality of the structure and process of type 1 diabetes care in its participating institutions by a system of peer supervision. Furthermore, all member institutions volunteered to collect outcome data based on systematic 1-1.3 years' follow-up examinations of consecutive type 1 diabetic patients. For the 1997 evaluation of 1,103 type 1 diabetic patients, significant decreases of GHb levels and of incidence rates of severe hypoglycemia (from 0.35 to 0.16 cases per patient-year) and ketoacidosis (from 0.08 to 0.02 cases per patient-year) are presented. The ASD quality circle represents a model to improve principal aspects of type 1 diabetes care on a nationwide basis. PMID- 10097897 TI - Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes. A systematic review and meta-analysis. AB - OBJECTIVE: We conducted a systematic review of randomized controlled trials (RCTs) of intensive insulin therapy (IIT) in type 1 diabetes to determine the effect on macrovascular complications. RESEARCH DESIGN AND METHODS: MEDLINE (1966 1996), Citation Index, reference lists, and personal files were used to identify RCTs of > 2 years' duration comparing IIT to conventional therapy (CT) in type 1 diabetes. Two independent reviewers applied selection criteria and identified 11 studies; 5 were subsequently excluded because no data were available for macrovascular complications. Data were extracted on macrovascular disease and cardiovascular risk factors. Macrovascular disease was defined as angina, myocardial infarction, angioplasty, coronary artery bypass graft, stroke, claudication, or peripheral bypass. The first event of each type was counted. RESULTS: IIT decreased the number of macrovascular events (odds ratio [OR] 0.55, [95% CI 0.35-0.88], P = 0.015) but had no significant effect on the number of patients developing macrovascular disease (OR 0.72, [95% CI 0.44-1.17], P = 0.22) or on macrovascular mortality (OR 0.91, [95% CI 0.31-2.65], P = 0.93). CONCLUSIONS: IIT decreases the extent of early macrovascular disease in young individuals with type 1 diabetes but has no effect on the number of patients affected or on macrovascular mortality. These data suggest that IIT may stabilize macrovascular disease or prevent progression in those at risk. PMID- 10097898 TI - Dead-in-bed syndrome in young diabetic patients. AB - The so-called dead-in-bed syndrome refers to sudden death in young diabetic patients without any history of long-term complications. Autopsy is typically negative. The present report summarizes frequency data on this condition from studies in the U.K. and the Scandinavian countries. It appears that such deaths occur in 6% of all deaths in diabetic patients below age 40 years. The frequency may also be expressed as 2-6 events per 10,000 [corrected] patient-years. The causes are by definition unknown, but a plausible theory is a death in hypoglycemia, since a history of nocturnal hypoglycemia is noted in most cases. While waiting for the clarification of the underlying pathophysiology, one should attempt to identify patients who are at particular risk of hypoglycemia and advocate caution in efforts to normalize blood glucose and HbAlc in these cases. PMID- 10097899 TI - How to ameliorate the problem of hypoglycemia in intensive as well as nonintensive treatment of type 1 diabetes. AB - Maintenance of long-term near-normoglycemia by intensive therapy largely, if not fully, prevents the onset of microangiopathic complications and delays progression of complications in type 1 diabetic patients. However, intensive therapy has been reported to increase the frequency of severe hypoglycemia. In addition, a number of experimental studies have shown that a few episodes of mild, recurrent hypoglycemia blunt the symptom and hormonal responses to hypoglycemia over the next few days. At present, the critical "post-DCCT" (Diabetes Control and Complications Trial) questions are: is it possible to maintain long-term HbA1c < 7.0%, first, without increasing the frequency of severe hypoglycemia, and second, without increasing the frequency of mild, recurrent hypoglycemia? The answer is yes. The key factors are use of a physiological model of insulin replacement and the education of patients to appropriate the decision of insulin dose based on blood glucose monitoring and eating patterns. Hypoglycemia unawareness should be suspected whenever HbA1c is < 6.0 (upper normal limit 5.5%) and the patient does not report autonomic symptoms when their blood glucose level is < 3.0 mmol/l. The unaware patients should be treated with a short-term program of meticulous prevention of hypoglycemia, which reverses the abnormalities of responses of symptoms, hormonal counterregulation, and brain cognitive function. In turn, reversal of these abnormalities decreases the risk for severe hypoglycemia. Importantly, a program of meticulous prevention of hypoglycemia does not result in loss of long-term near-normoglycemia, i.e., it is compatible with the glycemic targets of intensive therapy. PMID- 10097900 TI - Genetics and the prediction of complications in type 1 diabetes. AB - OBJECTIVE: Epidemiological evidence suggests that genetic factors can affect the course of type 1 diabetes complications produced by long-lasting hyperglycemia. In this review, the current strategies applicable to identifying these genetic factors are examined, as are recent findings on the genetics of diabetic nephropathy and whether these are applicable to type 1 diabetes patient care. RESEARCH DESIGN AND METHODS: Whole-genome screening and candidate gene strategies can be applied to the genetics of type 1 diabetes complications. The search for candidate genes can focus on enzymes involved in glucose metabolism or on those affecting non-glycemic-dependent vascular risk. For each candidate, the level of evidence may vary from case-control to intervention studies. Literature on diabetic complications and a possible role for genetics was examined systematically. RESULTS: The most significant results were obtained regarding a role for polymorphisms of the renin-angiotensin system in diabetic nephropathy. Several studies suggest a role for angiotensin I converting enzyme insertion/deletion polymorphism in the development of renal complications. However, the level of evidence is currently not sufficient to recommend treatment strategy based on this or any other polymorphism. CONCLUSIONS: The search for a genetic basis of type 1 diabetes complications is an important avenue to examine their pathophysiologies. However, it is still premature to apply the current findings in this domain to type 1 diabetes patient care. PMID- 10097901 TI - Crucial points at diagnosis. Type 2 diabetes or slow type 1 diabetes. AB - Two major types of diabetes have been recognized since the late 1930s. However, in recent times there have been major changes in classification and understanding of these types, including improved knowledge of maturity-onset diabetes in the young, with the identification of mutations relating to impaired insulin secretion and the recognition of slow-onset type 1 diabetes in adults now designated as latent autoimmune diabetes in adults (LADA). A major problem area in diabetes classification concerns cases of slowly progressive forms of type 1 and type 2 diabetes, particularly in adults aged 25-50 years. This is a more contemporary problem because cases of type 2 diabetes are presenting at an increasingly younger age. In the landmark U.K. Prospective Diabetes Study of type 2 diabetes, islet cell antibodies (ICAs) and antibodies to glutamic acid decarboxylase (anti-GAD) were measured at diagnosis in 3,672 patients. The overall proportion with ICAs was 6%, and anti-GADs was 10%. These subjects clearly had type 1 diabetes or LADA by both phenotypic and genotypic features. The presence of auto antibodies correlated particularly with a younger age and phenotypic features consistent with type 1 diabetes (e.g., early age at diagnosis, lower BMI, and reduced beta-cell function). Overall, of patients requiring insulin by 6 years, 38% were anti-GAD+ at baseline compared with 5.3% of those not on insulin at 6 years. Antibodies to GAD indicate an underlying autoimmune process and have a high positive predictive value for type 1 diabetes and future insulin dependency in adults. PMID- 10097902 TI - Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. AB - Protein alteration resulting from a nonenzymatic reaction between ambient glucose and primary amino groups on proteins to form glycated residues called Amadori products is termed the Maillard reaction. By dehydration and fragmentation reactions, Amadori products are transformed to stable covalent adducts called advanced glycosylation end products (AGEs). In diabetes, accelerated synthesis and tissue deposition of AGEs is proposed as a contributing mechanism in the pathogenesis of clinical complications. Uremia in diabetes is associated with both a high serum level of AGEs and accelerated macro- and microvasculopathy. Diabetic uremic patients accumulate advanced glycosylated end products in "toxic" amounts that are not decreased to normal by hemodialysis or peritoneal dialysis but fall sharply to within the normal range within 8 h of restoration of half normal glomerular filtration by renal transplantation. It follows that the higher mortality of hemodialysis-treated diabetic patients compared with those given a renal transplant may relate, in part, to persistent AGE toxicity. Pharmacologic prevention of AGE formation is an attractive means of preempting diabetic microvascular complications because it bypasses the necessity of having to attain euglycemia, an often unattainable goal. Pimagidine (aminoguanidine) interferes with nonenzymatic glycosylation and reduces measured AGE levels leading to its investigation as a potential treatment. The mechanism by which pimagidine prevents renal, eye, nerve, and other microvascular complications in animal models of diabetes is under investigation. Separate multicenter clinical trials of pimagidine in type 1 and type 2 diabetes, where proteinuria is attributable to diabetic nephropathy, are in progress. The effect of treatment on the amount of proteinuria, progression of renal insufficiency, and the course of retinopathy will be monitored. PMID- 10097903 TI - Characteristics and prognosis of normoalbuminuric type 1 diabetic patients. AB - Intervention in type 1 diabetic patients with increased urinary albumin excretion (UAE) represents a great step forward in modern diabetology. At the moment, the consensus calls for antihypertensive treatment in normotensive type 1 diabetic patients with persistent microalbuminuria. However, recent data indicate that substantial pathophysiological changes have already taken place at the microalbuminuric stage. Thus, prevention of progression from normo- to microalbuminuria would be a major clinical turning point. A considerable number of potential risk factors for progression to microalbuminuria have been proposed, among which are blood pressure elevation and disturbancies in circadian blood pressure variation. We performed 24-h ambulatory blood pressure (AMBP) monitoring in 115 normoalbuminuric (UAE < 20 micrograms/min) patients, along with performing an assessment of circadian blood pressure and heart rate (HR) variation and a short-term power spectral analysis of RR interval oscillations. Patients with UAE above the median had significantly higher systolic and diastolic AMBP compared to the low normoalbuminuric group. The difference in blood pressure between the two groups was most pronounced for the night blood pressure (P < 0.01 and 0.02). A positive correlation between UAE and circadian variation (described as diastolic night/day ratio) was present--that is, the higher the normoalbuminuria, the more blunted the night/day ratio. The patients characterized by a combination of high normal UAE and blunted circadian variation also proved to have significantly higher HbA1c values, higher 24-h mean arterial blood pressure, and lower vagal activity. In conclusion, high-normal UAE, poor metabolic control, and cigarette smoking are at present the only established risk factors for progression from normo- to microalbuminuria. However, new data emphasizes the close relation between blood pressure and albumin excretion. Pathophysiological abnormalities (poorer glycemic control, higher blood pressure, and attenuated vagal activity) tend to cluster in patients characterized by high-normal UAE and blunted circadian variation of blood pressures, and this patient group might constitute a putative high-risk group. PMID- 10097904 TI - Diabetic hypertensive patients. Is this a group in need of particular care and attention? AB - Morbidity and mortality in diabetes are caused mainly by its vascular complications, both in the microcirculation and in the large vessels. Diabetic nephropathy and retinopathy are the clinical hallmarks of microangiopathy, which may lead to end-stage renal failure and blindness. The cardiovascular complications in diabetes consist mainly of an accelerated form of atherosclerosis. Systemic hypertension is an early and frequent phenomenon. Nocturnal hypertension is also more frequent in people with diabetes compared with the nondiabetic population. Capillary hypertension has been demonstrated in type 1 diabetic patients. Poor metabolic control may induce elevation in blood pressure, but data are conflicting. The prevalence of white-coat hypertension in the diabetic population is comparable with that in the nondiabetic population. Prospective observational studies in type 1 and type 2 patients have revealed that abnormally increased urinary albumin excretion and other potentially modifiable risk factors--such as hypertension, smoking, poor metabolic control, and social class--predict increased all-cause mortality and cardiovascular mortality. Arterial hypertension is a risk factor in the initiation and progression of diabetic micro- and macroangiopathy. Diabetes, hypertension, and smoking are the three most important risk factors for fatal and nonfatal stroke. A randomized, double-blind, parallel study has revealed that the 5-year major cardiovascular disease rate was lowered by 34% for antihypertensive treatment compared with placebo. Furthermore, the study found a trend for lower all-cause mortality for low-dose antihypertensive-treated diabetic patients. Effective blood pressure reduction with ACE inhibitors and/or non-ACE inhibitors, frequently in combination with diuretics, reduces albuminuria, delays the progression of nephropathy, postpones end-stage renal failure, and improves survival in diabetic nephropathy. PMID- 10097905 TI - How can we improve prognosis in diabetic patients with end-stage renal disease? AB - Diabetes has become the single most important cause of end-stage renal failure, but survival of diabetic patients with renal replacement therapy continues to be poor. The major causes of death are cardiovascular complications. Most cardiovascular complications, particularly coronary atheroma, accumulate before patients enter renal replacement programs. This observation points to the need for improved patient care in pre-end-stage renal failure. In the diabetic patient, dialysis should be started earlier than in the nondiabetic patient, and prophylactic vascular access should be established when the glomerular filtration rate is approximately 20 ml/min. Proposals to improve prognosis of the diabetic patient with renal failure include interdisciplinary care for the patients with renal disease, strict normotension, administration of ACE inhibitors, administration of lipid-lowering agents, near-normalization of anemia using recombinant human erythropoietin, and improvement of diabetic foot care in the patient on renal replacement therapy. PMID- 10097906 TI - Improving prognosis in type 2 diabetes. Diabetic neuropathy is in trouble. AB - Painful sensory syndromes and the anesthetic foot result in much clinical morbidity and patient unhappiness in diabetes. As yet, a satisfactory and fundamental therapy is not available to us to help patients. Effective blood glucose control and vigilant screening programs for foot problems are all we have to offer. Clinical observation of neuropathic syndromes and measures of nerve function have not led to significant understanding of pathogenesis. The primary source of understanding of pathways to nerve damage come from animal studies, despite the fears that the model in diabetes in no way reflects the human situation. Therapeutic hope at the moment from such animal work must focus on the interference of pathways known to lead to neural blood-flow abnormalities and a variety of metabolic abnormalities, as well as the possibility that addition of nerve growth factor will assist repair and regeneration. The understanding of these multiple pathways in the animal model underlines the likely enormous complexity in the final picture of understanding in diabetic neuropathy. Modern imaging techniques such as magnetic resonance imaging should, in the future, allow more significant investigation of the human subject. PMID- 10097908 TI - Limb salvage experience in a multidisciplinary diabetic foot unit. AB - OBJECTIVE: To assess the results of the strategy used in avoiding major amputations in patients admitted to a vascular surgical department with a new multidisciplinary diabetic foot unit. RESEARCH DESIGN AND METHODS: The study was retrospective. A total of 162 patients (172 limbs) were classified into three groups. Group A1 had limb-threatening ischemia and were undergoing revascularization (85 patients, 91 legs). Group A2 had limb-threatening ischemia, but revascularization was not feasible for them (23 patients). Group B had foot ulcers due to peripheral neuropathy and did not require arterial reconstruction (54 patients, 58 legs). RESULTS: In group A1 there were 115 revascularizations; 42 conduits had outflow to crural arteries and 14 to pedal arteries. Resection of gangrene was required in 43% of the limbs. The chances of preserved limb at 1 and at 24 months were 95 and 85%, respectively, and the chances of patient survival were 89 and 64%. In group A2, the chances of preserved limb at 1 and at 24 months were only 35 and 17%, respectively, and the chances of patient survival were only 64 and 16%. In group B, 51 of 58 limbs suffered invasive infection; debridement of the ulcers required resection of toes or part of the foot in 64% of cases. The chances of preserved limb at 1 and at 24 months was 98 and 86%; the chances of patient survival were 98 and 68%. Ankle and toe systolic pressures were less suitable than repeated clinical examinations in deciding the need for revascularization. CONCLUSIONS: Major amputation can be avoided in about 80% of patients with limb-threatening ischemia and in about 95% with foot ulceration complicated with infection. Multifactorial treatment of the complex foot lesions by a multidisciplinary foot care team is considered mandatory to obtain satisfactory limb salvage. PMID- 10097907 TI - How to improve the cardiac prognosis for diabetes. AB - Cardiovascular disease is a leading cause of death in diabetic patients. It has been reported to count for almost 80% of all deaths. About three-fourths of these deaths result from coronary artery disease. Studies have shown that diabetic patients who have had an acute myocardial infarction (AMI) have a mortality of about twice that of nondiabetic patients. Various medications have been shown to improve the prognosis among diabetic patients suffering from ischemic heart disease. They include beta-blockers, thrombolytic agents, aspirin, ACE inhibitors, and lipid-lowering drugs. Experiences indicate that treatment with beta-blockers, thrombolytic agents, and ACE inhibitors is particularly advantageous in diabetic patients who have suffered AMI. Metabolic control also may be of major importance during the acute cardiac event because it is assumed that fatty acid metabolism is increased with a compromised glycolysis not only in ischemic but also in the nonischemic areas. One way to suppress free fatty acid oxidation is by the infusion of insulin-glucose. In the Swedish Diabetes Mellitus and Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study, patients with diabetes and AMI were randomized to receive insulin-glucose infusion followed by intensive subcutaneous insulin treatment or to be control subjects. The 1-year mortality was reduced 30% by insulin treatment. Diabetic patients who suffer from coronary artery disease have a particularly adverse prognosis. Previous experiences indicate that treatment with beta-blockers, thrombolytic agents, and ACE inhibitors is particularly advantageous in diabetic patients who have suffered AMI. Aspirin and lipid-lowering drugs should be offered to these patients on traditional indications as well. Metabolic control seems to be of major importance for the outcome. PMID- 10097909 TI - How to improve prognosis in type 1 diabetic pregnancy. Old problems, new concepts. AB - OBJECTIVE: To improve the prognosis of pregnancy in type 1 diabetes. RESEARCH DESIGN AND METHODS: This study is an epidemiological analysis of pregnancy outcome in type 1 diabetic mothers attending the combined diabetic antenatal clinic at the Royal Maternity Hospital, Belfast, from 1940 to 1990. Short-term measurement of maternal insulin sensitivity and of intrauterine fetal habituation was taken in selected pregnancies. The article also assesses the European and U.K. recommendations for diabetes in pregnancy, with a goal "to achieve pregnancy outcome in the diabetic woman that approximates that of the non-diabetic woman." RESULTS: Outcomes from 1985 to 1995 in > 800 pregnancies, of which about 60% were delivered at the Regional Centre, suggested that the perinatal mortality was lower for those managed throughout at the center. The highest obstetric risk was in those pregnancies referred to the center at some point later in the pregnancy from a peripheral obstetric clinic. Studies of insulin sensitivity in normal and preeclamptic pregnancy by minimal-model analysis of a frequently sampled intravenous glucose tolerance test and of glycosylated hemoglobin in a large survey of nondiabetic pregnancy indicate that the pregnant state may unmask an increase in insulin resistance, causing both pregnancy-induced hyperglycemia and pregnancy-induced hypertension. Fetal habituation, studied by responses to a variable sound stimulus, was less effective in diabetic pregnancy, which may indicate changes in fetal brain function. CONCLUSIONS: Pregnancy in a type 1 diabetic mother remains a high-risk obstetrical situation, even with presently available intensive diabetic supervision. PMID- 10097910 TI - Long-acting insulin analogs. AB - Once daily injection of existing intermediate/long-acting insulin preparations does not provide a 24-h basal insulinemia in most patients. High variability, pronounced insulin peaks, and (as a result) a high risk of nocturnal hypoglycemia only poorly simulate normal physiology. One principle to prolong insulin action is the shift of the isoelectric point of insulin towards neutral. One example is HOE 901, which shows in healthy volunteers a constant peakless profile over the entire 24-h clamp period. In 4-week trials in comparison to NPH insulin, significant lower fasting plasma glucose levels were achieved with lower rates of nocturnal hypoglycemia. Another principle to prolong insulin action is the use of soluble fatty acid acylated insulins that are bound to albumin after absorption. The combination of long- and short-acting insulins might provide the tools towards the final goal of achieving sustained normoglycemia in diabetic patients. PMID- 10097911 TI - Risks and benefits of kidney and pancreas transplantation for diabetic patients. AB - Type 1 diabetic patients with end-stage renal disease can choose dialysis or transplantation for renal replacement therapy. For patients choosing transplantation, a kidney from a living related donor is associated with longer allograft and patient survival. When a living donor is not available, then a combined cadaveric kidney and pancreas transplant can be considered. The addition of a pancreas transplant incurs greater morbidity and may require higher levels of immunosuppression. However, there may be substantial benefits, including improvement in quality of life and stabilization of neuropathy. Patients with type 1 diabetes younger than 45 years with little or no atherosclerotic vascular disease are ideal candidates for a combined kidney and pancreas transplant. Patients who do not meet these criteria but who have life-threatening hypoglycemia may also wish to consider pancreas transplantation, but have an increased risk of serious complications. The risks and benefits of combined kidney and pancreas transplantation are outlined in this review and should be carefully considered by potential transplant recipients and their physicians. PMID- 10097912 TI - Glucose metabolism in vitro of cultured and transplanted mouse pancreatic islets microencapsulated by means of a high-voltage electrostatic field. AB - The aim of this study was to assess the function of mouse pancreatic islets microencapsulated using a high-voltage electrostatic field. Islets were microencapsulated in alginate/poly-L-lysine/alginate (APA) capsules and maintained in tissue culture. Rates of glucose oxidation and insulin release were then assessed. Glucose metabolism was also measured in microencapsulated islets retrieved after transplantation to normal syngeneic mice. The high-voltage electrostatic system made possible the production of uniformly sized microcapsules, which were smaller than those produced by co-axial air-jet systems. Nonencapsulated islets were used as controls. Empty microcapsules or islet-containing microcapsules were transplanted intraperitoneally and retrieved after 2 weeks for assessment of foreign-body reactions and glucose oxidation rates. After 1 day and 2 weeks in tissue culture, both control islets and microencapsulated islets increased their rates of glucose oxidation and insulin release 7- to 10-fold in response to an increase in glucose concentration from 1.7 to 16.7 mmol/l. Both empty and islet-containing microcapsules, retrieved 2 weeks after transplantation, showed high rates of glucose oxidation at both low and high glucose concentrations, suggesting overgrowth with metabolically active fibroblasts. Morphological studies indicated a marked foreign-body reaction on the surface of all transplanted microcapsules. The islets in cultured microcapsules had a normal histological appearance, whereas the islets within transplanted microcapsules showed a range of morphological appearances, from intact islets to cell debris. In conclusion, this study shows that mouse pancreatic islets survive and remain functionally competent for at least 2 weeks in vitro after microencapsulation in APA capsules generated in an electrostatic field. However, a foreign-body reaction with cellular growth on the capsular surface was present after intraperitoneal syngeneic transplantation. PMID- 10097913 TI - Clinical presentation and early course of type 1 diabetes in patients with and without thyroid autoimmunity. AB - OBJECTIVE: To evaluate the prevalence of thyroid autoimmunity (TAI) in patients with recent-onset type 1 diabetes and to determine the influence of TAI on the clinical presentation and evolution of type 1 diabetes. RESEARCH DESIGN AND METHODS: We studied 111 newly diagnosed type 1 diabetes patients > 13 years old. The diagnosis of TAI was based on medical history and measurement of thyroid peroxidase (microsomal) antibodies (TPOAs). Clinical presentation of diabetes, beta-cell autoimmune markers (GADAs and 1A2As), and evolution of insulin secretory reserves and metabolic control during the first 2 years of follow-up were analyzed. Differences between groups were evaluated by Student's t test or the chi 2 test. The influence of TAI on follow-up data was evaluated by multiple logistic regression analysis. RESULTS: TAI was present in 31 patients (14 TPOA+ patients with normal thyroid function, 12 TPOA+ patients with thyroid dysfunction, and 5 patients with previously diagnosed TAI). TAI was more prevalent in women than in men (43.7 vs. 15.9%, P = 0.001). beta-Cell autoimmunity was more prevalent in patients with TAI than in those without TAI (93.5 vs. 76.3%, P = 0.03). The evolution of insulin requirements, metabolic control, and insulin-secretory reserves was comparable in the two groups. CONCLUSIONS: TAI is present in many type 1 diabetes patients at the time of diagnosis and is associated with a high prevalence of thyroid dysfunction. The clinical presentation of diabetes and the evolution of metabolic control and insulin-secretory reserves are not influenced by the presence of TAI. Patients with type 1 diabetes should be screened for TAI at diagnosis. PMID- 10097914 TI - Incidence, outcomes, and cost of foot ulcers in patients with diabetes. AB - OBJECTIVE: To determine the incidence of foot ulcers in a large cohort of patients with diabetes, the risk of developing serious complications after diagnosis, and the attributable cost of care compared with that in patients without foot ulcers. RESEARCH DESIGN AND METHODS: Retrospective cohort study of patients with diabetes in a large staff-model health maintenance organization from 1993 to 1995. Patients with diabetes were identified by algorithm using administrative, laboratory, and pharmacy records. The data were used to calculate incidence of foot ulcers, risk of osteomyelitis, amputation, and death after diagnosis of foot ulcer, and attributable costs in foot ulcer patients compared with patients without foot ulcers. RESULTS: Among 8,905 patients identified with type 1 or type 2 diabetes, 514 developed a foot ulcer over 3 years of observation (cumulative incidence 5.8%). On or after the time of diagnosis, 77 (15%) patients developed osteomyelitis and 80 (15.6%) required amputation. Survival at 3 years was 72% for the foot ulcer patients versus 87% for a group of age- and sex matched diabetic patients without foot ulcers (P < 0.001). The attributable cost for a 40- to 65-year-old male with a new foot ulcer was $27,987 for the 2 years after diagnosis. CONCLUSIONS: The incidence of foot ulcers in this cohort of patients with diabetes was nearly 2.0% per year. For those who developed ulcers, morbidity, mortality, and excess care costs were substantial compared with those for patients without foot ulcers. The results appear to support the value of foot ulcer prevention programs for patients with diabetes. PMID- 10097915 TI - Noninvasive exploration of cardiac autonomic neuropathy. Four reliable methods for diabetes? AB - OBJECTIVE: The purpose of this work was to assess relevant information that could be provided by various mathematical analyses of spontaneous blood pressure (BP) and heart rate (HR) variabilities in diabetic cardiovascular neuropathy. RESEARCH DESIGN AND METHODS: There were 10 healthy volunteers and 11 diabetic subjects included in the study. Diabetic patients were selected for nonsymptomatic orthostatic hypotension in an assessment of their cardiovascular autonomic impairment. Cardiac autonomic function was scored according to Ewing's methodology adapted to the use of a Finapres device. The spontaneous beat-to-beat BP and HR variabilities were then analyzed on a 1-h recording in supine subjects. The global variabilities were assessed by standard deviation, fractal dimension, and spectral power. The cardiac baroreflex function was estimated by cross spectral sequences and Z analyses. RESULTS: In diabetic patients, Ewing's scores ranged from 1 to 4.5, confirming cardiovascular autonomic dysfunction. In these diabetic patients, global indices of variabilities were consistently lower than in healthy subjects. Furthermore, some of them (standard deviation and fractal dimension of HR, spectral power of systolic blood pressure and HR) were significantly correlated with the Ewing's scores. The Z methods and the spectral analysis found that the cardiac baroreflex was less effective in diabetic subjects. However, the baroreflex sensitivity could not be reliably assessed in all the patients. The sequence method pointed out a decreased number of baroreflex sequences in diabetic subjects that was correlated to the Ewing's score. CONCLUSIONS: Indices of HR spontaneous beat-to-beat variability are consistently related to the degree of cardiac autonomic dysfunction, according to Ewing's methodology. The Z method and spectral analysis confirmed that the cardiac baroreflex was impaired in diabetic patients. These methods might be clinically relevant for use in detecting incipient neuropathy in diabetic patients. PMID- 10097916 TI - Day-to-day variability of fasting plasma glucose in newly diagnosed type 2 diabetic subjects. AB - OBJECTIVE: To determine the day-to-day intraindividual variability of fasting plasma glucose (FPG) in newly diagnosed Caucasian type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: A total of 193 newly diagnosed, previously untreated, Caucasian type 2 diabetic subjects (135 men, 58 women) had FPG measured on two consecutive days (FPG1, FPG2). Ethical approval and subjects' full informed consent were obtained. Subjects fasted for 12 h before each study day and rested for at least 30 min before blood was taken. Plasma glucose was analyzed by a glucose oxidase method with intra- and interassay coefficients of variation (CVs) < 2%. Variability of FPG was assessed by comparison of percentage differences (PDs): PD = 100 (FPG2 - FPG1)/FPG1, with averaged FPG (FPGaver = [FPG1 + FPG2]/2). Biological and analytical variability were determined by use of SD2total = SD2biological + SD2analytical, where SD2analytical approximately equal to 2 x (CVglucose measurement)2. Given normally distributed data with zero mean, 95% of daily percentage differences will be expected to fall within a range of +/ 2 SDtotal. RESULTS: Subjects were age 54 +/- 10 years (mean +/- SD) and had BMI of 29.3 +/- 5.3 kg/m2. FPG values for both days were 12.2 +/- 3.4 mmol/l (FPG1) and 12.1 +/- 3.3 mmol/l (FPG2), with a mean paired difference (95% CI) of 0.1 (0.0 to 0.3) mmol/l. The variance of these differences increased with increasing FPGaver. The PDs did not exhibit this effect and were normally distributed (mean 0.6% [-1.7 to 0.4]; SD 7.4% [6.8 to 8.3]), giving a 95% variability (2 SD) of 14.8%. Biological variability (2 SDbiological) was 13.7%. No significant difference in PD was found between men and women (mean difference 1.3% [-1.0 to 3.6]; SDmale 7.4%, SDfemale 7.3%; P = 0.62). CONCLUSIONS: A total of 95% of the FPG values for this group of newly diagnosed type 2 diabetic subjects varied within approximately +/- 15% on a daily basis, with approximately 14% caused by biological variability. As these results are expressed in percentage terms, subjects in the group with higher FPG values are likely to experience larger changes in FPG values measured from day to day. This variability should be considered when using FPG for the diagnosis and/or monitoring of response to treatment in patients with type 2 diabetes. PMID- 10097917 TI - Impaired fasting glucose or impaired glucose tolerance. What best predicts future diabetes in Mauritius? AB - OBJECTIVE: To determine if impaired fasting glucose (IFG; fasting plasma glucose level 6.1-6.9 mmol/l) can predict future type 2 diabetes as accurately as does impaired glucose tolerance (IGT; 2-h plasma glucose level 7.8-11.0 mmol/l). RESEARCH DESIGN AND METHODS: A longitudinal population-based study was performed with surveys in 1987 and 1992 on the island of Mauritius, assessing diabetes status by the oral glucose tolerance test. A total of 3,717 subjects took part in both surveys. Of these subjects, 3,229 were not diabetic in 1987 and formed the basis of this study. RESULTS: At baseline, there were 607 subjects with IGT and 266 subjects with IFG. There were 297 subjects who developed diabetes by 1992. For predicting progression to type 2 diabetes, the sensitivity, specificity, and positive predictive values were 26, 94, and 29% for IFG and 50, 84, and 24% for IGT, respectively. Only 26% of subjects that progressed to type 2 diabetes were predicted by their IFG values, but a further 35% could be identified by also considering IGT. The sensitivities were 24% for IFG and 37% for IGT in men and 26% for IFG and 66% for IGT in women, respectively. CONCLUSIONS: These data demonstrate the higher sensitivity of IGT over IFG for predicting progression to type 2 diabetes. Screening by the criteria for IFG alone would identify fewer people who subsequently progress to type 2 diabetes than would the oral glucose tolerance test. PMID- 10097918 TI - Racial and ethnic differences in glycemic control of adults with type 2 diabetes. AB - OBJECTIVE: To evaluate glycemic control in a representative sample of U.S. adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Third National Health and Nutrition Examination Survey included national samples of non-Hispanic whites, non-Hispanic blacks, and Mexican Americans aged > or = 20 years. Information on medical history and treatment of diabetes was obtained to determine those who had been diagnosed with type 2 diabetes by a physician before the survey (n = 1,480). Fasting plasma glucose and HbA1c were measured, and the frequencies of sociodemographic and clinical variables related to glycemic control were determined. RESULTS: A higher proportion of non-Hispanic blacks were treated with insulin and a higher proportion of Mexican Americans were treated with oral agents compared with non-Hispanic whites, but the majority of adults in each racial or ethnic group (71-83%) used pharmacologic treatment for diabetes. Use of multiple daily insulin injections was more common in whites. Blood glucose self monitoring was less common in Mexican Americans, but most patients had never self monitored. HbA1c values in the nondiabetic range were found in 26% of non Hispanic whites, 17% of non-Hispanic blacks, and 20% of Mexican Americans. Poor glycemic control (HbA1c > 8%) was more common in non-Hispanic black women (50%) and Mexican-American men (45%) compared with the other groups (35-38%), but HbA1c for both sexes and for all racial and ethnic groups was substantially higher than normal levels. Those with HbA1c > 8% included 52% of insulin-treated patients and 42% of those taking oral agents. There was no relationship of glycemic control to socioeconomic status or access to medical care in any racial or ethnic group. CONCLUSIONS: These data indicate that many patients with type 2 diabetes in the U.S. have poor glycemic control, placing them at high risk of diabetic complications. Non-Hispanic black women, Mexican-American men, and patients treated with insulin and oral agents were disproportionately represented among those in poor glycemic control. Clinical, public health, and research efforts should focus on more effective methods to control blood glucose in patients with diabetes. PMID- 10097919 TI - Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes. AB - OBJECTIVE: To clarify the predictive value of islet cell antibody (ICA) and GAD65 antibody (GADA) present at diagnosis with respect to the need for insulin treatment 6 years after diagnosis in young adults initially considered to have type 2 or unclassifiable diabetes. RESEARCH DESIGN AND METHODS: The patient material was representative of the entire Swedish population, consisting of patients who were 15-34 years old at diagnosis of diabetes in 1987-1988 but were not considered to have type 1 diabetes at onset. At follow-up, 6 years after the diagnosis, it was noted whether the patient was treated with insulin. The presence of ICA was determined by an immunofluorescence assay, and GADAs were measured by a radioligand assay. RESULTS: Six years after diagnosis, 70 of 97 patients were treated with insulin, and 27 of 97 patients were treated with oral drugs or diet alone. At diagnosis, ICAs and GADAs were present in 41 (59%) of 70 patients and 41 (60%) of 68 patients, respectively, of those now treated with insulin, compared with only 1 (4%) of 26 patients and 2 (7%) of 27 patients who were still not treated with insulin. For either ICA or GADA, the corresponding frequencies were 50 (74%) of 68 for patients who were later treated with insulin and 3 (12%) of 26 for those who were still not treated with insulin, respectively. The sensitivity for later insulin treatment was highest (74%) for the presence of ICA or GADA, and the specificity was highest (100%) for ICA and GADA. The positive predictive value was 100% for the combination of ICA and GADA, 98% for ICA alone, and approximately 95% for GADA alone. CONCLUSIONS: Determination of the presence of ICA and GADA at diagnosis of diabetes improves the classification of diabetes and predicts the future need of insulin in young adults. PMID- 10097920 TI - Plasma leptin concentrations in Pima Indians living in drastically different environments. AB - OBJECTIVE: Plasma leptin, an important signal for the regulation of energy stores, is known to be influenced by many hormonal factors, but may also be affected by behavioral and environmental factors. The purpose of this study was to investigate the impact of lifestyle (diet composition, level of physical activity) on plasma leptin concentrations among Pima Indians living in drastically different environments. RESEARCH DESIGN AND METHODS: We studied 224 Mexican Pima Indians (115 women, 109 men) living a traditional lifestyle in a remote, mountainous area of northwest Mexico and 418 U.S. Pima Indians (281 women, 137 men) living a North American lifestyle on the Gila River Indian Reservation in Arizona. We hypothesized that the absolute value of leptin would be lower in Mexican Pima Indians because of their lower percent body fat, but could be further influenced by their lifestyle, independent of body composition. RESULTS: Leptin concentration (enzyme-linked immunosorbent assay [ELISA]) was strongly correlated with percent fat (bioimpedance) in Mexican Pima Indians (r = 0.83, P < 0.0001) and U.S. Pima Indians (r = 0.86, P < 0.0001). Among U.S. Pima Indians, independent of percent fat, subjects with type 2 diabetes had lower leptin than nondiabetic subjects (difference = 6.9 +/- 1.0 ng/ml, P < 0.002). Among nondiabetic subjects, Mexican Pima Indians had lower absolute leptin concentrations than U.S. Pima Indians, but higher after adjustment for percent body fat, waist circumference, age, and sex. In a subset of 70 pairs of subjects matched for sex and percent body fat, leptin concentration was 4.4 +/- 1.0 ng/ml (P < 0.0001) higher in Mexican Pima Indians versus U.S. Pima Indians. CONCLUSIONS: These results suggest that independent of body composition, leptin concentration may be increased by environmental factors, such as a high carbohydrate diet and a high level of physical activity. PMID- 10097921 TI - Effect of selective screening for gestational diabetes. AB - OBJECTIVE: To estimate the percentage of pregnant women who would not be screened and the percentage of women with gestational diabetes mellitus (GDM) who would possibly remain undiagnosed if the American Diabetes Association's (ADA's) new selective screening recommendations are used rather than universal screening for GDM. RESEARCH DESIGN AND METHODS: Since 1987, the University of Michigan Health System has performed universal screening for GDM. In 1997, the ADA recommended that women having all four of the following characteristics need not be screened: age < 25 years, not members of an ethnic/racial group with a high prevalence of diabetes, normal body weight, and no family history of diabetes. We studied a random sample of the 25,118 deliveries at the University of Michigan between 1987 and 1997 to determine the prevalence of these four characteristics in our obstetric population. We also studied the prevalence of these four characteristics in 200 women who were diagnosed with GDM in the Endocrine Testing Unit and delivered at the University of Michigan between 1987 and 1997. RESULTS: Approximately 10-11% of women who delivered possessed all four low-risk characteristics and would not have been screened for GDM according to the new ADA recommendations. Only 4% of women (5 of 141) with GDM who delivered and for whom data on all four characteristics were reported possessed all four low-risk characteristics and would not have been screened. CONCLUSIONS: If the new ADA selective screening recommendations are used, few women with GDM will be missed (4%) but approximately 90% of pregnant women will still need to be screened for GDM. PMID- 10097922 TI - Diabetic nephropathy is associated with an increased familial risk of stroke. AB - OBJECTIVE: To test the hypothesis that genetic susceptibility to diabetic nephropathy is associated with an increased familial risk of vascular disease, we have examined the causes and rates of death of parents of individuals with type 1 diabetes complicated by diabetic nephropathy compared with the causes and rates of death of parents of control subjects with diabetes uncomplicated by nephropathy. RESEARCH DESIGN AND METHODS: Individuals with at least a 14-year duration of type 1 diabetes complicated by diabetic nephropathy were identified and matched for age, sex, and duration of diabetes to control subjects. A total of 118 patients and 118 matched control subjects were identified and approached to obtain information on parental age and cause of death. For parents who had died, the cause of death was ascertained from the death certificate. RESULTS: Kaplan-Meier curves showed that parents of subjects with nephropathy (PN) had reduced survival compared with parents of diabetic subjects without nephropathy (PC) (log rank test P < 0.05). There was an excess of all vascular deaths and, in particular, strokes in the parents of subjects with nephropathy (PN: 20 of 103 deaths, 19% vs. PC: 3 of 66 deaths, 4%; Fisher's exact test P < 0.01). CONCLUSIONS: Parents of diabetic patients with nephropathy have reduced survival. This seems to be largely explained by an increase in vascular deaths and, in particular, a four-fold increase in the number of strokes. This supports the hypothesis that a common hereditary risk factor predisposes to both vascular death and diabetic renal disease. PMID- 10097924 TI - Relationships of fasting and postload glucose levels to sex and alcohol consumption. Are American Diabetes Association criteria biased against detection of diabetes in women? AB - OBJECTIVE: To compare, in men and women, the prevalence of undiagnosed type 2 diabetes assessed using criteria from the American Diabetes Association (ADA) and the World Health Organization (WHO) and to investigate risk factors associated with fasting and 2-h postload plasma glucose. RESEARCH DESIGN AND METHODS: Data from two companion surveys of Europeans, South Asians, and Afro-Caribbeans in west London were used. A total of 4,367 men and women aged 40-64 years who were not known to have diabetes underwent an oral glucose tolerance test after an overnight fast. The prevalence of undiagnosed diabetes was estimated using the ADA (fasting plasma glucose > or = 7.0 mmol/l) and WHO (2-h postload glucose > or = 11.1 mmol/l) criteria for epidemiologic studies. The association of body fat and usual alcohol intake with plasma glucose and diabetes prevalence was assessed. RESULTS: Compared with the WHO criterion, the ADA criterion gave a higher prevalence of diabetes in men (6.4 vs. 4.7%) but a lower prevalence in women (3.3 vs. 4.2%). In Afro-Caribbeans, the sex difference in diabetes prevalence was reversed. Women had significantly lower fasting glucose than men despite higher 2-h glucose levels. Alcohol intake was positively associated with fasting glucose in men and women but not with 2-h glucose levels. CONCLUSIONS: The new ADA criterion, based on fasting glucose alone, does not take account of sex differences in metabolic response to fasting or possible artifactual effects on fasting glucose. With the ADA criterion, alcohol intake was a significant risk factor for diabetes in our study population; this was not the case with the WHO criterion. PMID- 10097923 TI - Prevalence of undiagnosed diabetes and abnormalities of carbohydrate metabolism in a U.S. Army population. AB - OBJECTIVE: The Third National Health and Nutrition Examination Survey (NHANES III) reported that 4.3-6.3% of adult Americans have undiagnosed diabetes. 15.6% have impaired glucose tolerance, and 10.1% have impaired fasting glucose. By design, NHANES III excluded people in the U.S. military. The purpose of this study was to determine the prevalence of undiagnosed diabetes, impaired glucose tolerance, and impaired fasting glucose among U.S. Army soldiers. RESEARCH DESIGN AND METHODS: A 2-h, 75-g oral glucose tolerance test was performed on a prospective, consecutive sample of 625 asymptomatic soldiers presenting to a U.S. Army medical clinic for physical examinations. Age of subjects was 32 +/- 9 years (mean +/- SD), and 81.0% of subjects were male. BMI was 26.2 +/- 3.7 kg/m2. Race/ethnicity categories included Caucasian (54.4%), African-American (24.4%), Hispanic (17.4%), and other (3.7%). A family history of diabetes was reported by 25.4% of the subjects, and the number of exercise sessions per week was 4.0 +/- 1.5. RESULTS: The prevalence of undiagnosed diabetes was 3 of 625 (0.5%) (95% CI, 0.1-1.4): impaired glucose tolerance, 11 of 598 (1.8%) (0.9-3.3); and impaired fasting glucose 6 of 585 (1.0%) (0.4-2.2). CONCLUSIONS: In this low-diabetes risk U.S. Army population, the prevalence of undiagnosed diabetes, impaired glucose tolerance, and impaired fasting glucose were 0.5, 1.8, and 1.0%, respectively. The prevalence rates found in this study are approximately one-tenth of those found in NHANES III. PMID- 10097925 TI - Standardized comparison of glucose intolerance in west African-origin populations of rural and urban Cameroon, Jamaica, and Caribbean migrants to Britain. AB - OBJECTIVE: To compare the prevalence of glucose intolerance in genetically similar African-origin populations within Cameroon and from Jamaica and Britain. RESEARCH DESIGN AND METHODS: Subjects studied were from rural and urban Cameroon or from Jamaica, or were Caribbean migrants, mainly Jamaican, living in Manchester, England. Sampling bases included a local census of adults aged 25-74 years in Cameroon, districts statistically representative in Jamaica, and population registers in Manchester. African-Caribbean ethnicity required three grandparents of this ethnicity. Diabetes was defined by the World Health Organization (WHO) 1985 criteria using a 75-g oral glucose tolerance test (2-h > or = 11.1 mmol/l or hypoglycemic treatment) and by the new American Diabetes Association criteria (fasting glucose > or = 7.0 mmol/l or hypoglycemic treatment). RESULTS: For men, mean BMIs were greatest in urban Cameroon and Manchester (25-27 kg/m2); in women, these were similarly high in urban Cameroon and Jamaica and highest in Manchester (27-28 kg/m2). The age-standardized diabetes prevalence using WHO criteria was 0.8% in rural Cameroon, 2.0% in urban Cameroon, 8.5% in Jamaica, and 14.6% in Manchester, with no difference between sexes (men: 1.1%, 1.0%, 6.5%, 15.3%, women: 0.5%, 2.8%, 10.6%, 14.0%), all tests for trend P < 0.001. Impaired glucose tolerance was more frequent in Jamaica. CONCLUSIONS: The transition in glucose intolerance from Cameroon to Jamaica and Britain suggests that environment determines diabetes prevalence in these populations of similar genetic origin. PMID- 10097926 TI - Prevalence and correlates of the insulin resistance syndrome among Native Americans. The Inter-Tribal Heart Project. AB - OBJECTIVE: The clustering of factors characterizing the insulin resistance syndrome has not been assessed among Native Americans, a population at high risk for diabetes and cardiovascular disease. We examined the distribution and correlates of the insulin resistance syndrome among individuals in three Chippewa and Menominee communities in Wisconsin and Minnesota. RESEARCH DESIGN AND METHODS: Cross-sectional data from 488 men and 822 women ages > or = 25 years in the Inter-Tribal Heart Project (1992-1994) were included. The clustering of each individual trait (hypertension, diabetes, high triglycerides, and low HDL cholesterol) with the other traits and the association of the number of traits with measures of adiposity and insulin levels were examined. RESULTS: Among the men, 40.4, 32.6, 17.4, and 9.6% had none, one, two, or at least three of the four traits, respectively; among the women, the respective percentages were 53.2, 25.6, 15.3, and 6.0%. The percentage of individuals with each particular trait significantly increased (P < 0.01) among those with none, one, or at least two other syndrome traits. Having more syndrome traits was significantly related (P < 0.001) to higher BMI, conicity index, waist circumference, and waist-to-hip and waist-to-thigh ratios. Among individuals with normal glucose levels, having more syndrome traits was significantly related (P < or = 0.05) to higher fasting insulin levels after adjusting for age and measures of adiposity, although associations were attenuated with adjustment for either BMI or waist circumference. CONCLUSIONS: Traits characterizing the insulin resistance syndrome were found to be clustered to a significant degree among Native Americans in this study. Comprehensive public health efforts are needed to reduce adverse levels of these risk factors in this high-risk population. PMID- 10097927 TI - Persistence of depressive symptoms in diabetic adults. AB - OBJECTIVE: To determine the level and pattern of persistent depressive symptoms among adults with diabetes and identify factors associated with increased risk of being persistently depressed. RESEARCH DESIGN AND METHODS: A self-report depression symptom inventory was administered to 245 patients at two initial time points--the beginning and end of a comprehensive outpatient diabetes education program--and at 6-month follow-up. RESULTS: Only 13% of subjects were persistently depressed (i.e., exceeded the criterion for depression symptoms at all three time points). The rate of being depressed at follow-up was 10% for those negative for depression symptoms at either of the initial time points, 36% for those positive at one initial time point, and 73% for those positive at both initial time points (P < 0.0001). Those at increased risk for being persistently depressed were those who did not graduate from high school, had more than two complications of diabetes, and were not treated with insulin. CONCLUSIONS: Persistent depressive symptomatology is present in a substantial number of diabetic adults and can be effectively predicted using simple screening instruments during initial contacts. Risk factors for being persistently depressed only partly overlap those for transient depressive symptoms and represent a possible biological dimension. PMID- 10097928 TI - Role of systolic blood pressure and plasma triglycerides in diabetic peripheral arterial disease. The Edinburgh Artery Study. AB - OBJECTIVE: To determine the risk factors for peripheral arterial disease (PAD) in a diabetic population and to examine whether different levels of these risk factors might explain why diabetic subjects have an increased risk of PAD compared with normal glucose tolerance subjects. RESEARCH DESIGN AND METHODS: There were 1,592 men and women aged 55-74 years selected at random from the age sex registers of 11 general practices in Edinburgh, Scotland. Subjects underwent a comprehensive medical examination, including assessment for PAD (intermittent claudication on World Health Organization questionnaire or major asymptomatic disease on noninvasive testing) and a glucose tolerance test. RESULTS: Of the subjects, 288 (18.7%) were found to have diabetes or impaired glucose tolerance (IGT). The prevalence of PAD was greater in those with diabetes/IGT (20.6%) compared with those with normal glucose tolerance (12.5%) (odds ratio [OR] 1.64, 95% CI 1.17-2.31). Among the diabetes/IGT group, mean levels of smoking, systolic blood pressure, and triglycerides were higher in subjects with PAD than in those without PAD (P < or = 0.05). Mean levels of systolic blood pressure and plasma triglycerides were also higher in diabetic subjects than in nondiabetic subjects with PAD (P < or = 0.05). In multivariate analysis, those with diabetes/IGT no longer had a significantly higher risk of PAD after adjusting separately for systolic blood pressure (OR 1.22, 95% CI 0.85-1.73) and plasma triglycerides (OR 1.26, 95% CI 0.89-1.79). Simultaneous adjustment for both systolic blood pressure and triglycerides reduced the risk of PAD among diabetic subjects to 1.11 (95% CI 0.78-1.58). CONCLUSIONS: Increased mean levels of triglycerides and systolic blood pressure may help to explain the higher prevalence of PAD in diabetic subjects compared with that in normal glucose tolerance subjects. PMID- 10097929 TI - Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients. AB - OBJECTIVE: Insulin Mix25 is a new premixed insulin analog containing 25% insulin lispro and 75% neutral protamine lispro (NPL) suspension (NPL insulin). The aim of the study was to compare serum glucose and insulin responses after breakfast in type 2 diabetic patients who received Mix25, premixed regular/NPH (30%/70%), or NPH insulin before the meal. RESEARCH DESIGN AND METHODS: We studied 22 type 2 diabetic patients of age 62 +/- 1 years, BMI 30 +/- 1 kg/m2, duration of diabetes 15 +/- 2 years, duration of insulin therapy 6 +/- 1 years, insulin dose 65 +/- 6 U/day, and HbA1c 7.9 +/- 0.2%. Ten healthy individuals (age 56 +/- 1 years, BMI 28 +/- 1 kg/m2) served as control subjects. Each patient (except healthy subjects, who were studied once each) was studied three times in a double-blind, randomized fashion. After an overnight fast, the patients received 36 +/- 4 U of test insulin. Ten minutes after insulin injection, the patients ingested a breakfast meal (512 kcal, 60% carbohydrate, 20% fat, and 20% protein), identical in all studies. Blood samples were taken before and at 10- to 30-min intervals for 240 min after the breakfast meal. RESULTS: The peak rise in serum glucose was lower after Mix25 (76 +/- 7 mg/dl) than after 30/70 (94 +/- 5 mg/dl, P < 0.05) or NPH (113 +/- 4 mg/dl, P < 0.005) insulin. The incremental area under the serum glucose curve was 36% smaller after Mix25 than after 30/70 (P < 0.01) and 56% smaller than after NPH (P < 0.005) insulin. The peak rise in serum insulin concentration was higher after Mix25 (103 +/- 18 mU/l) than after 30/70 (87 +/- 13 mU/l, P < 0.05) or NPH (62 +/- 12 mU/l, P < 0.01) insulin. The incremental area under the serum insulin curve was higher after Mix25 than after 30/70 during the first 2-3 h (P < 0.02), but the difference disappeared by the end of the 4-h follow-up period. After Mix25 injection, there was an inverse correlation between the glucose response to a meal and insulin dose (r = -0.56, P < 0.01) or the incremental area under the serum insulin curve (r = -0.39, P < 0.05). No such correlations were observed with the other insulins. CONCLUSIONS: Because of its faster initial absorption rate, the new premixed insulin analog Mix25 reduces blood glucose response to a breakfast meal in type 2 diabetic patients compared with premixed 30/70 (regular/NPH) or NPH insulin. PMID- 10097930 TI - A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. AB - OBJECTIVE: Repaglinide is a newly developed oral blood glucose-lowering agent that exerts its effect by stimulating insulin secretion. This multicenter study was designed to compare the efficacy and safety of this drug with glyburide in a 1-year randomized double-blind study of outpatients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 424 subjects (154 women, 270 men) participated and had the following characteristics: age, 61 +/- 9 years; duration of diabetes. 8 years (range 0.5-35); BMI, 28.3 +/- 3.5 kg/m2; HbA1c, 7.1 +/- 1.4%; and fasting plasma glucose, 10.8 +/- 3.1 mmol/l. The majority of the subjects (91%) were previously treated with sulfonylurea, alone or in combination with metformin. The patients were randomized to a 2:1 ratio of repaglinide (0.5-4 mg t.i.d.) or glyburide (1.75-10.5 mg daily) treatment. The study protocol included a screening visit to assess patient eligibility; a titration period of 6 8 weeks, during which the dosages of repaglinide and glyburide were optimized; and a subsequent 12-month treatment period on fixed, optimal dosages. RESULTS: The trial was completed by 320 subjects, 211 (74%) in the repaglinide and 109 (78%) in the glyburide group. HbA1c initially decreased in both groups and then increased during the second half-year of the maintenance period to a similar extent in the repaglinide and glyburide subjects (0.58 and 0.45% vs. at screening, respectively). In the small group of subjects who previously controlled their condition with diet only (n = 37), a sustained improvement of metabolic control could be observed with both drugs, which was slightly better with glyburide than with repaglinide (theta HbA1c -2.4 vs. -1.0%; P < 0.05). The same trends were seen with fasting plasma glucose. There were no changes in serum lipids. Over the course of the study, 15% of the repaglinide-treated and 13% of glyburide-treated subjects withdrew due to adverse events, mostly hyperglycemia. No differences in adverse events between both drugs were reported. There were no differences in incidences of hypoglycemia. CONCLUSIONS: Repaglinide is a safe and efficacious oral blood glucose-lowering agent, with a potency similar to that of glyburide. Its rapid onset of action and hepatic clearance allows meal-related administration, including in subjects with impaired kidney function. PMID- 10097931 TI - Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime. AB - OBJECTIVE: To establish whether the short-acting insulin analog lispro can be successfully implemented in long-term intensive insulin therapy in type 1 diabetes, and if so, what its effects are on glycemic control and frequency and awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: We randomized 56 type 1 diabetic patients to treatment with either lispro (n = 28) or human regular insulin (Hum-R; n = 28) as mealtime insulin for 1 year (open design, parallel groups). Lispro was injected at mealtime and Hum-R was given 10-40 min before meals (bedtime NPH was continued on both occasions). With lispro, NPH was added at breakfast (approximately 70/30), lunch (approximately 60/40), and supper (approximately 80/20) (mixing percentage of lispro/NPH) to optimize premeal and bedtime blood glucose. RESULTS: Total daily insulin units were no different in the two treatment groups, but with lispro approximately 30% less short-acting insulin at meals and approximately 30% more NPH was needed versus Hum-R (P < 0.05). The bedtime NPH dosage was no different. With lispro + NPH, the mean daily blood glucose was lower than with Hum-R (8.0 +/- 0.1 vs. 8.8 +/- 0.1 mmol/l; P < 0.05), HbA1c was lower (6.34 +/- 0.10 vs. 6.71 +/- 0.11%, mean value over 1 year; P < 0.002), and hypoglycemia (blood glucose < or = 3.8 mmol/l) was less frequent (7.4 +/- 0.5 vs. 11.5 +/- 0.7 episodes/patient-month) and tended to occur more within 90 min after meals than in the postabsorptive state (P < 0.05 vs. Hum-R). After 1 year, plasma adrenaline and symptom responses to experimental, stepped hypoglycemia improved with lispro and were closer to the responses of 12 nondiabetic control subjects versus Hum-R both in terms of thresholds and magnitude (P < 0.05). CONCLUSIONS: We concluded that mealtime injection of lispro + NPH improves the 24-h blood glucose and the percentage HbA1c as compared with Hum-R. The improvement can be maintained long term. Intensive therapy with lispro + NPH results in less frequent hypoglycemia and better awareness and counterregulation of hypoglycemia. PMID- 10097932 TI - Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. AB - OBJECTIVE: To evaluate kidney function 7 years after the end of treatment with cyclosporine A (CsA) (initial dosage of 9.3 tapered off to 7.0 mg.kg-1.day-1) in young patients (mean age 20 years) with newly diagnosed type 1 diabetes participating in a randomized, double-blind, placebo-controlled CsA trial. RESEARCH DESIGN AND METHODS: In this study, 21 patients received CsA for 12.5 +/- 4.0 months (mean +/- SD) and 19 patients received placebo for 14.4 +/- 3.8 months. The two groups were similar with regard to mean arterial blood pressure (BP), urinary albumin excretion rate (UAER), serum creatinine, and estimated glomerular filtration rate (GFR [Cockcroft and Gault]) at initiation of CsA treatment (baseline). HbA1c (mean +/- SEM) during 7 years of follow-up was also the same: 8.7 +/- 0.4 vs. 8.3 +/- 0.4% in the CsA and placebo groups, respectively. RESULTS: During the 7 years after cessation of study medication, two CsA group patients and one control patient were lost to follow-up. One placebo-treated patient developed IgA nephropathy (biopsy proven) and was excluded. Four CsA-treated patients developed persistently elevated UAER > 30 mg/24 h (n = 3 with microalbuminuria), whereas all the 17 placebo-treated patients had normal UAER (< 30 mg/24 h) after 7 years of follow-up. At the end of follow-up, the CsA group had a more pronounced rise in UAER: 2.5-fold (95% CI 1.4 4.5) higher than baseline value vs. 1.1-fold (0.7-1.7) in the placebo-treated group (P < 0.05). Estimated GFR (ml.min-1.1.73 m-2) declined from baseline to end of follow-up (1994) by 6.3 +/- 6.0 in the former CsA group, whereas it rose by 7.4 +/- 5.0 in the placebo group (P = 0.05). In 1994, 24-h blood pressure was nearly the same: 131/77 +/- 4/2 vs. 127/75 +/- 2/2 mmHg (NS) in the CsA and placebo groups, respectively. Five randomly selected CsA-treated patients had a kidney biopsy performed shortly after the CsA treatment was stopped. Interstitial fibrosis/tubular atrophy and/or arteriolopathy were present in two subjects who both subsequently developed persistent microalbuminuria. CONCLUSIONS: The results of our 7-year follow-up study suggested that short-lasting CsA treatment in young, newly diagnosed type 1 diabetic patients accelerated the rate of progression in UAER and tended to induce a loss in kidney function. Longer term follow-up is mandatory to clarify whether CsA-treated patients are at increased risk of developing clinical nephropathy. PMID- 10097933 TI - Hyperhomocysteinemia is a risk factor for coronary arteriosclerosis in Japanese patients with type 2 diabetes. AB - OBJECTIVE: An increased plasma homocysteine level is an important risk factor for vascular disease, including coronary atherosclerosis, in the general population. However, the role of hyperhomocysteinemia in the development of coronary artery disease (CAD) in patients with type 2 diabetes is unknown. Therefore, we have endeavored to determine the relationship between plasma homocysteine levels and the presence of coronary arteriosclerosis in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The study group consisted of 145 Japanese patients (95 men and 50 women) who underwent routine coronary angiography to assess chest pain or suspected CAD. Plasma total homocysteine level, lipid level, and parameters of fibrinolytic activity were measured. All patients were identified as diabetic or nondiabetic by the new American Diabetes Association (ADA) criteria. The diagnoses of all patients studied were confirmed by coronary angiography. The severity of coronary artery stenosis was quantified using CAD scoring on the basis of prior reports, and subjects were graded as nonstenotic, stenotic single-vessel, stenotic two-vessel, or stenotic three-vessel based on the number of stenotic coronary arteries. Patients were classified into two groups: those with stenotic vessels and those without stenotic vessels. RESULTS: The plasma homocysteine level was significantly higher in patients with than in patients without stenotic vessels (13.8 +/- 3.9 vs. 11.7 +/- 3.9 mumol/l, respectively; P = 0.0009). The number of stenotic coronary arteries, which was used to grade each case as nonstenotic, stenotic single-vessel, stenotic two vessel, or stenotic three-vessel, was related only to the total homocysteine level in the diabetic (diabetes mellitus [DM]) group, but it was associated with lipoprotein(a) in the nondiabetic (non-diabetes mellitus [non-DM]) group. Spearman's rank correlation test demonstrated that the plasma homocysteine level was strongly correlated with CAD score, both in the entire study group and in the DM group (P = 0.003 for the entire group and P = 0.011 for the DM group). Hyperhomocysteinemia, which was defined as total homocysteine level > 14.0 mumol/l, was seen in 57 (39.3%) of the patients. The CAD score was highest in diabetic patients with hyperhomocysteinemia (P < 0.05). CONCLUSIONS: There seems to be a clear relationship between hyperhomocysteinemia and an increased risk of coronary arteriosclerosis in Japanese patients with type 2 diabetes. PMID- 10097934 TI - Effects of nisoldipine and lisinopril on left ventricular mass and function in diabetic nephropathy. AB - OBJECTIVE: To compare the effects of the calcium channel blocker, nisoldipine, and the ACE inhibitor, lisinopril, on left ventricular mass (LVM) and systolic function in type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: M-mode echocardiography was performed in 50 hypertensive type 1 diabetic patients with diabetic nephropathy enrolled in a 1-year, randomized, double-blind, parallel study of antihypertensive treatment with nisoldipine CC (20-40 mg/day) or lisinopril (10-20 mg/day). Ambulatory 24-h blood pressure was measured with the Takeda TM 2420 device (A & D, Tokyo, Japan) every 3 months. Three patients dropped out and seven patients were excluded due to technical difficulties. RESULTS: The 24-h diastolic blood pressure was reduced from 83 to 80 mmHg in the nisoldipine group (P = 0.06) and from 85 to 80 mmHg in the lisinopril group (P = 0.02). The decline in systolic blood pressure was not significant with any of the two treatments, and no difference in reduction of blood pressure was seen between groups. LVM corrected for body surface area (LVMI) was comparable between groups at baseline and increased from 96 +/- 5 to 107 +/- 6 g/m2 (mean +/- SEM; P = 0.007) in the nisoldipine group and from 95 +/- 4 to 103 +/- 5 g/m2 (P = 0.03) in the lisinopril group. The mean difference between the change in LVMI in the two groups was 2.9 (95% CI 6.8 to 12.7) g/m2. The prevalence of left ventricular hypertrophy rose from 18 (95% CI 6-30) to 30% (16-44) during the study period. A multiple linear regression analysis revealed that after 1 year of treatment, LVMI increased with higher systolic blood pressure level and declining glomerular filtration rate (R2 = 0.25). Fractional shortening was within normal range at baseline, 42 +/- 1 vs. 41 +/- 1% with nisoldipine and lisinopril, respectively, and did not change during follow-up. CONCLUSIONS: Antihypertensive treatment with nisoldipine or lisinopril to bring diastolic blood pressure level within the normal target range does not hinder a rise in LVMI in type 1 diabetic patients with diabetic nephropathy. PMID- 10097936 TI - Natural history of diabetic gastroparesis. AB - OBJECTIVE: The major aim of this study was to evaluate the prognosis of diabetic gastroparesis. RESEARCH DESIGN AND METHODS: Between 1984 and 1989, 86 outpatients with diabetes (66 type 1, 20 type 2; 40 male, 46 female) underwent assessment of solid and liquid gastric emptying and esophageal transit (by scintigraphy), gastrointestinal symptoms (by questionnaire), autonomic nerve function (by cardiovascular reflex tests), and glycemic control (by HbAlc and blood glucose concentrations during gastric emptying measurement). These patients were followed up in 1998. RESULTS: Of the 86 patients, solid gastric emptying (percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50% emptying time) was delayed in 24 (28%) patients. At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups. Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive. After adjustment for the effects of other factors that showed a relationship with the risk of dying, there was no significant relationship between either gastric emptying or esophageal transit and death. CONCLUSIONS: In this relatively large cohort of outpatients with diabetes, there was no evidence that gastroparesis was associated with a poor prognosis. PMID- 10097935 TI - Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group. AB - OBJECTIVE: The predictive value of microalbuminuria (MA) in children with type 1 diabetes has not been defined. We describe the natural history of MA in a large cohort of children recruited at diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: Between 1985 and 1996, 514 children (279 male) who developed type 1 diabetes before the age of 16 years (91% of those eligible from a region where ascertainment of new cases is 95%) were recruited for a longitudinal study with central annual assessment of HbAlc and albumin excretion (three urine samples). Dropout rates have been < 1% per year, and 287 children have been followed for > 4.5 years. RESULTS: MA (defined as albumin-to-creatinine ratio > or = 3.5 and > or = 4.0 mg/mmol in boys and girls, respectively) developed in 63 (12.8%) and was persistent in 22 (4.8%) of the subjects. The cumulative probability (based on the Kaplan-Meier method) for developing MA was 40% after 11 years. HbAlc was worse in those who developed MA than in others (mean difference +/- SEM: 1.1% +/- 0.2, P < 0.001). In subjects who had been 5-11 years of age when their diabetes was diagnosed, the appearance of MA was delayed until puberty, whereas of those whose age was < 5 years at diagnosis of diabetes, 5 of 11 (45%) developed MA before puberty. The adjusted proportional probability (Cox model) of MA was greater for female subjects (200%), after pubertal onset (310%), and with greater HbAlc (36% increase for every 1% increase in HbAlc). Despite earlier differences based on age at diagnosis of diabetes (< 5, 5-11, and > 11 years), the overall cumulative risks in these groups were similar (38 vs. 29 vs. 39%, respectively) after 10 years' duration of diabetes. CONCLUSIONS: Prepubertal duration of diabetes and prepubertal hyperglycemia contribute to the risk of postpubertal MA. The differences in rates of development of MA relating to HbAlc, sex, and age at diagnosis relative to puberty may have long-term consequences for the risk of subsequent nephropathy and for cardiovascular risk. PMID- 10097937 TI - The war against diabetes. How will we know if we are winning? PMID- 10097938 TI - American Diabetes Association Annual Meeting, 1998. Insulin resistance, exercise, and obesity. PMID- 10097939 TI - Pseudohypoparathyroidism, obesity, and type 2 diabetes. A hypothesis. PMID- 10097940 TI - Hepatocyte nuclear factor-1 alpha G319S. A private mutation in Oji-Cree associated with type 2 diabetes. PMID- 10097941 TI - Insulin autoimmune syndrome after therapy with imipenem. PMID- 10097942 TI - C282Y and H63D mutations of the hemochromatosis candidate gene in type 2 diabetes. PMID- 10097943 TI - Concordance between the 1997 fasting American Diabetes Association criteria and the World Health Organization criteria in healthy Mexican subjects. PMID- 10097944 TI - Metformin as adjuvant to insulin therapy in type 2 diabetic patients. PMID- 10097945 TI - Antioxidant effects of gliclazide and soluble adhesion molecules in type 2 diabetes. PMID- 10097946 TI - Diabetes treatment satisfaction questionnaire. Change version for use alongside status version provides appropriate solution where ceiling effects occur. PMID- 10097947 TI - Keep metformin guidelines intact. PMID- 10097949 TI - Screening low-risk women for gestational diabetes mellitus. Let's not muddy the waters further. PMID- 10097948 TI - Poor level of care among diabetic patients. Is that a unique picture? PMID- 10097950 TI - [The role of bacterial superantigens in pathophysiology of the skin]. AB - In contrast to conventional antigens, bacterial superantigens activate a large percentage of an organism's total T-cell repertoire. This has clinical implications particularly in the case of infections with Gram-positive bacteria. Unravelling the molecular mechanisms of superantigen-mediated T-cell activation has yielded new insights in the pathogenesis of a number of diseases, in the field of dermatology namely atopic dermatitis and psoriasis. Moreover, therapeutic applications of superantigens have begun to emerge. PMID- 10097951 TI - [Microdissection. Use in molecular oncologic dermatology]. AB - Microdissection allows the procurement of selective cell populations or single cells of archival sections or frossen tissue. Most cutaneous tumors can not be cultivated or consist of heterogeneous cell populations. Thus, microdissection is an important pre-requisite for molecular genetic analyses of cutaneous neoplasms. This review describes the microdissection and its application in dermatologic oncology is demonstrated. PMID- 10097952 TI - [Decreased rate of progression and induction of tumor-specific immune response by adjuvant immunotherapy in stage IV melanoma]. AB - Stage IV melanoma is still a disease with poor prognosis. Although modern chemo- or chemoimmunotherapies give high response rates in stage IV patients, remissions are usually followed by fast relapses. In order to avoid early relapses after chemotherapy, patients with stage IV disease and either stable disease or partial or complete remission following therapy were treated with 9 million IU IFN alpha subcutaneously 5 times weekly and 6 million IU IL-2 subcutaneously twice weekly. Compared with untreated controls, the rate of progression in the treatment group was reduced from 95% to 35%. Also, time to progression was significantly prolonged. Median survival times in the control group were 25 weeks, whereas median survival time in the treatment group has not yet been reached. Furthermore, TNF-ELISPOT assays showed a significant increase in MAGE-3 reactive cytotoxic T-cells in the treatment, but not in the control group. Thus, immunotherapy in stage IV disease seems to prolong survival in melanoma patients. PMID- 10097953 TI - [Photodynamic therapy of cutaneous T-cell lymphoma at special sites]. AB - Therapy of the heterogenous group of primary cutaneous B- and T-cell lymphomas is based upon type of lymphoma and its staging. Treatment, especially for rare forms, has not yet been standardised. Two patients with uncommon primary cutaneous T-cell lymphomas received both traditional therapy and topical photodynamic therapy (PDT) in areas that are difficult to reach with classic methods (ear, eyebrow, side of foot). The first patient had a rare type of medium/large cell pleomorphic, CD8-positive, CD30-negative, primary cutaneous T cell lymphoma with primary involvement of the ear. As the tumor progressed during PUVA, interferon alpha and retinoid therapy, topical PDT was employed. A histologically confirmed partial remission was obtained. As the disease further evolved the patient received radiotherapy and has now been in complete remission for 10 months. The other patient preserted with the classical picture of mycosis fungoides in initial tumour stage. This patient received in addition to PUVA therapy and interferon alpha, topical PDT to the eyebrow and side of the foot. A complete remission was achieved and histologically confirmed. In the palliative treatment of cutaneous T-cell lymphoma, PDT is a new experimental method, especially for problem locations. It is tissue sparing, has few side effects, can be repeated as often as necessary and achieves good cosmetic results. PMID- 10097954 TI - [Acquired reactive perforating dermatosis. Successful treatment with allopurinol in 2 cases]. AB - Perforating disorders represent a heterogenous group of dermatoses characterized by transepithelial elimination of dermal structures. Primary perforating disorders should be distinguished from secondary perforating disorders in which perforation with transepithelial elimination is a rare component of a variety of dermatoses. The primary perforating disorders are hyperkeratosis follicularis et parafollicularis in cutem penetrans (Kyrle's disease), elastosis perforans serpiginosa and perforating folliculitis. Acquired reactive perforating dermatosis (also known as acquired reactive perforating collagenosis) together with the hereditary variant of the reactive perforating collagenosis represent further examples of the primary perforating disorders. We report on 84 year old and 96 year old female patients with an acquired perforating dermatosis. Both of the patients additionally showed diabetes and hyperuricemia. Oral administration of allopurinol (100 mg daily) led to a healing of the disseminated skin lesions in 1-2 weeks. After a follow-up period of 6 months, both patients were in complete remission. On one hand, these results prove again the existence and the severity of this disease, and on the other hand suggest an immunomodulating or differentiation-promoting action in addition to the uricostatic effect of allopurinol. PMID- 10097955 TI - [Prenatal diagnosis of recessive hereditary dystrophic epidermolysis bullosa with haplotype analysis of the type VII collagen gene]. AB - DNA-based prenatal testing of the fetal genotype was performed in a family at risk for recurrence of recessive dystrophic epidermolysis bullosa (RDEB). DNA from cultured fibroblasts and leukocytes from the peripheral blood of the previously affected offspring, DNA from parental leukocytes and DNA from fetal tissue obtained by chorionic villus biopsy was analysed by direct PCR amplification of known polymorphic regions within or flanking the type VII collagen gene, the candidate gene in RDEB. One flanking marker (D3S2/Mspl) as well as two intragenic polymorphisms (C7/Mspl, C7/Eco01091) in exons 30 and 84 were informative in this family. Thus, based on the haplotype analysis and the lack of evidence for locus heterogeneity in RDEB, a phenotypically healthy child was predicted. This prediction was confirmed by the birth of a healthy female infant. The study reports successful determination of the fetal genotype by PCR based prenatal diagnosis in a family at risk for recurrence of severe RDEB. PMID- 10097956 TI - [Pseudo-scabies transmitted by red fox]. AB - Pseudoscabies, i.e. infestation of human skin with animal mites may occasionally occur and should be considered in the differential diagnosis of pruritic and papular skin disease. We report here on a 52-year-old woman with pseudoscabies or canine scabies (Sarcoptes scabiei var. canis), transmitted by indirect contact with a red fox in the urban area of Berlin. Red foxes may live in unhabited areas of metropolitan large cities, i.e. in garages, car wrecks and cellars. Full remission of the prolonged and pruritic rush was seen after topical administration of lindane together with systemic corticosteroids. PMID- 10097957 TI - [Severe course of a mutilating pansclerotic circumscribed scleroderma in childhood. Clinical aspects and therapy]. AB - Disabling pansclerotic morphea of childhood is the most severe variant of localized scleroderma. It is characterized by rapid progression of deep cutaneous fibrosis expanding over large areas of body surface. The prognosis in terms of normal life activity is poor and the disease may even take a fatal course. Presented is a case with extremely severe and rapidly progressive lesions resulting in cutaneous ulcerations joint contractures, and multilaing deformities of the extremities. Histopathological analysis revealed extensive intravascular calcinosis of the small vessels, which may be an important factor in the pathogenesis of this poorly understood disease. UVA1-phototherapy was performed and induced a softening of sclerosis and a distinct decrease of skin thickness. Based on these observations UVA1-phototherapy may be promising in the treatment of extensive sclerotic disease of this kind, and possibly other diseases accompanied by excessive sclerosis. PMID- 10097958 TI - ["Acute generalized exanthematic pustulosis induced by nystatin"]. PMID- 10097959 TI - [Contact eczema in housewives]. PMID- 10097960 TI - [The skin biopsy]. PMID- 10097961 TI - [A new congenital photosensitivity syndrome. Smith-Lemili-Opitz syndrome]. PMID- 10097962 TI - Collaborative community research consortium: a model for HIV prevention. AB - In 1991, the Center for AIDS Prevention Studies (CAPS) at the University of California, San Francisco, set out to develop a model of community collaborative research that would bring the skills of science to the service of HIV prevention and the knowledge of service providers into the domain of research. Essential elements of the model were training for community-based organizations (CBOs) in research protocol writing, partnership between CBOs and CAPS researchers, program research funding, support to implement studies and analyze results, and a program manager to oversee the effort and foster the relationships between CBOs and researchers. In this article, the authors describe the CAPS model of consortium based community collaborative research. They also introduce a set of papers, written by researchers and service providers, that describes collaborative research projects conducted by research institutions and CBOs and illustrates how collaboration can change both HIV prevention research and service. PMID- 10097963 TI - Targeting "risky" gender ideologies: constructing a community-driven, theory based HIV prevention intervention for youth. AB - Since the beginning of the HIV epidemic, school-based HIV prevention education targeting youth has taken many forms. Although there has been some success, educators continue to be challenged by situations in which youth are knowledgeable about HIV but continue to engage in risky sexual behavior. In this article, the authors propose that the underlying or implicit theories about teenagers' sexual risk behavior that guide most of these prevention activities are not accurate descriptions or valid explanations of sexual risk in this population. The article is divided into three major sections. First, the authors articulate the theories underlying HIV prevention activities that are typically found in standard school-based prevention curricula, discussing both their limitations and strengths. Second, they discuss their increased awareness of the role of gender ideologies and sexual scripts in the sexual lives of youth. Finally, the authors describe their current HIV prevention activity ("The Game") as it emerges and is shaped by their increasing understanding of the critical role of gender-based ideologies and sexual scripts in young people's sexual risk behavior. PMID- 10097964 TI - Sex in the New World: an empowerment model for HIV prevention in Latina immigrant women. AB - In 1996, nearly 60% of U.S. AIDS cases among Latinas were attributed to unprotected sex with men. Economic disadvantage, language barriers, and strong cultural gender norms regarding sex exacerbate the risk for HIV infection among Latina immigrant women. Through a collaboration among scientists and providers, this study was designed to evaluate the impact of a multifaceted empowerment program for Latina immigrant women on HIV risk behaviors. Women (N = 74) were followed for the first 6 months of their participation and attended up to nine distinct types of activities (e.g., information meetings, friendship circles, and workshops). Although the program was not developed to specifically target HIV risk behaviors, women showed significant increases in sexual communication comfort, were less likely to maintain traditional sexual gender norms, and reported changes in decision-making power. Targeting broader sociocultural issues may increase the necessary skills for Latina women to prevent HIV infection from their sexual partners. Successful collaborations between scientists and providers are critical in developing effective, community-relevant interventions. PMID- 10097965 TI - A collaborative evaluation of a needle exchange program for youth. AB - Limited research has been conducted to examine the effectiveness of existing HIV prevention and harm reduction interventions targeted to injection drug-using youth. Moreover, although there are a growing number of needle exchange programs being developed for youth throughout the United States, the effects of these services have yet to be systematically evaluated. This article describes a collaborative evaluation conducted by the Division of Adolescent Medicine, Childrens Hospital Los Angeles, and Clean Needles Now, a needle exchange serving young injection drug users. The evaluation employed a multimethod research design that included both qualitative and quantitative methods. Findings are presented about how a community-based agency's service delivery philosophy can affect the design and implementation of an evaluation. Lessons learned from this collaborative evaluation are presented, including the potential benefits of incorporating harm reduction principles into research activities. PMID- 10097966 TI - Collaborative research to prevent HIV among male prison inmates and their female partners. AB - Despite the need for targeted HIV prevention interventions for prison inmates, institutional and access barriers have impeded development and evaluation of such programs. Over the past 6 years, the authors have developed a unique collaborative relationship to develop and evaluate HIV prevention interventions for prison inmates. The collaboration includes an academic research institution (the Center for AIDS Prevention Studies at the University of California, San Francisco), a community-based organization (Centerforce), and the staff and inmate peer educators inside a state prison. In this ongoing collaboration, the authors have developed and evaluated a series of HIV prevention interventions for prison inmates and for women who visit prison inmates. Results of these studies support the feasibility and effectiveness of HIV prevention programs for inmates and their partners both in prison and in the community. Access and institutional barriers to HIV intervention research in prisons can be overcome through the development of collaborative research partnerships. PMID- 10097967 TI - The collaboration process in HIV prevention and evaluation in an urban American Indian clinic for women. AB - Collaboration between providers and researchers can be key to doing women's HIV prevention that is holistic, gender sensitive, and responsive to communities. This report centers on providers' and evaluators' experiences in developing and implementing a project promoting "healthy relationships" with low-income women from different ethnicities at an urban American Indian clinic. During planning, decisions on the health problems to be targeted, division of labor, program goals, resource allocation, evaluation design, and outcome measures were jointly made. Other factors were the input of participants and the influence of American Indian values at the clinic. The implementation process was fully collaborative. There are implications for creating conditions for successful collaborations in health education. PMID- 10097968 TI - "Out-of-the-mainstream" youth as partners in collaborative research: exploring the benefits and challenges. AB - Forming collaborations between university-based researchers and community-based organizations (CBOs) serves to improve health promotion research and service. Unfortunately, members of the targeted populations are typically not included in such collaborations. This article describes the development and maintenance of a successful university-CBO collaboration that was formed to explore HIV-related risk rates and prevention strategies for suburban street youth and discusses the benefits and challenges of including out-of-the-mainstream youth as full collaborative partners in the research. Specific benefits included population specific modifications of the research methods and instruments, recruitment of hard-to-reach youth, greater ease in tracking participants, and increased project acceptability and credibility. Among the challenges were issues related to boundaries, confidentiality, commitment, and burnout. Although such collaborations require increased time and commitment, the synergistic knowledge and experience of university researchers, community-based service providers, and out-of-the-mainstream youth can result in the development of unique and informative research and service programs. PMID- 10097969 TI - Organizing community research partnerships in the struggle against AIDS. AB - Despite pharmaceutical advances, AIDS remains a health problem difficult to treat, leaving preventive interventions as the primary means of promoting risk avoidance. Increasing the capacity of university-based researchers to develop culturally, developmentally, and contextually appropriate AIDS prevention strategies requires the collaboration of community service and advocacy partners. To date, neither university researchers nor community providers have a great deal of partnership experience. Thus, a common language and set of experiences are yet to be developed. This article reviews the history of university-community and researcher-community collaboration for AIDS research and intervention, placing the innovative work of the University of California, San Francisco (UCSF) Center for AIDS Prevention Studies and its community and foundation partnerships among those efforts at the forefront of the community-university dialogue. It concludes with suggestions derived from the collaborative work of UCSF researchers and community service partners to strengthen efforts to develop theory, research methods, and results that are immediately useful and productive of long-term prevention research efforts. PMID- 10097970 TI - [Pain in chronic peripheral arterial occlusive disease. Pathogenesis and therapy]. PMID- 10097971 TI - [Symptomatic treatment of painful diabetic neuropathies]. PMID- 10097972 TI - [Chronic facial pain]. PMID- 10097973 TI - [Migraine and other "vascular" headache]. PMID- 10097974 TI - [Chronic pain in herpes zoster]. PMID- 10097975 TI - [Pain therapy in oncology]. PMID- 10097976 TI - [Diagnosis and therapy of neuropathic pain in tumor diseases]. PMID- 10097977 TI - [Special aspects of pain therapy in childhood]. PMID- 10097978 TI - [Diagnostic imaging in intensive care medicine. Techniques, indications, diagnostic signs--I]. PMID- 10097980 TI - [44-year-old patient with dyspnea, chest pain and syncope]. PMID- 10097979 TI - [A 73-year-old patient with hypertensive crisis. Was the use of calcium antagonist nifedipine justified?]. PMID- 10097981 TI - [Anticoagulation in renal failure]. PMID- 10097982 TI - [Therapy indications in positive Borrelia titer]. PMID- 10097983 TI - [Catheter-induced urinary tract infections]. PMID- 10097984 TI - [Value of PSA in diagnosis of prostate carcinoma]. PMID- 10097985 TI - [Aquagenic pruritus and hepatitis C]. PMID- 10097986 TI - [Vitamin K agonists in cerebral microembolism?]. PMID- 10097987 TI - [Patent foramen ovale]. PMID- 10097988 TI - [Thrombocytopenia caused by gold fillings?]. PMID- 10097989 TI - Calcium antagonists. Results of recent studies and their significance for general practice. PMID- 10097990 TI - [Important differences in metabolism of CSE inhibitors]. PMID- 10097993 TI - Exploring the boundaries of pervasive developmental disorder not otherwise specified: analyses of data from the DSM-IV Autistic Disorder Field Trial. AB - This study aimed to explore the boundaries between PDD and related disorders and to develop classificatory algorithms for what is currently called Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS). Data collected by means of a standard coding system for the DSM-IV field trial for autistic disorder were used. Information on diagnostic criteria for autistic disorder as listed in ICD 10 and DSM-IV was compared between subjects functioning at least in the mildly retarded range and clinically classified as autistic disorder (n = 205), PDDNOS (n = 80) and other non-PDD disorders (n = 174). Only a limited number of items from the ICD-10 and DSM-IV systems for autistic disorder significantly discriminated the PDDNOS group from other disorders. A scoring rule based on a short set of 7 ICD-10/DSM-IV criteria with a cutoff of 3 items and 1 social interaction item set as mandatory had the best balance between high sensitivity and high specificity in discriminating PDDNOS from non-PDD disorders. These rules yielded a somewhat better prediction than most effective rules based on the full set of 12 criteria for autistic disorder with a cutoff of 4 items and 1 social item as mandatory. Generally accepted and well-validated criteria to identify individuals with PDDNOS should facilitate both research and clinical services. PMID- 10097991 TI - Intelligence patterns among children with high-functioning autism, phenylketonuria, and childhood head injury. AB - High-functioning children with autistic-spectrum disorder show the typical pattern of lower Comprehension relative to their own scores on Block Design. This profile is shared, almost exactly, by age- and IQ-matched children with poorer control PKU. Quite distinct profiles are shown by children with better control PKU, who show no difference between Block Design and Comprehension, and by children with head injury involving frontal lobe contusion, who show slightly better Comprehension that Block Design. The data bear on several questions: the relation between Comprehension deficits and language functions measured by Vocabulary; the limits of the advantages conveyed by higher IQ to autistic individuals; whether impaired Comprehension in autism indexes persisting symptoms and/or impairments on theory of mind tasks; the possibility that dopamine deficiency is common to autism and poorer control PKU; and the need for future research aimed at understanding the relations among neurodevelopmental disorders. PMID- 10097992 TI - Brain mapping of language and auditory perception in high-functioning autistic adults: a PET study. AB - We examined the brain organization for language and auditory functions in five high-functioning autistic and five normal adults, using [15O]-water positron emission tomography (PET). Cerebral blood flow was studied for rest, listening to tones, and listening to, repeating, and generating sentences. The autism group (compared to the control group) showed (a) reversed hemispheric dominance during verbal auditory stimulation; (b) a trend towards reduced activation of auditory cortex during acoustic stimulation; and (c) reduced cerebellar activation during nonverbal auditory perception and possibly expressive language. These results are compatible with findings of cerebellar anomalies and may suggest a tendency towards atypical dominance for language in autism. PMID- 10097994 TI - Autism and congenital blindness. AB - The nature of autism in congenitally blind children has long been a source of interest and perplexity. A group of nine congenitally blind children with an autism-like syndrome were closely matched on chronological age and verbal mental age with nine sighted autistic children, and were compared on the Childhood Autism Rating Scale (Schopler, Reichler, & Renner, 1986) and the Behavior Checklist for Disordered Preschoolers, together with the Play Items for Disordered Preschoolers (Sherman, Shapiro, & Glassman, 1983). A checklist of clinical features characteristic of autism (derived from DSM-III-R) was also completed through an interview with teachers. There was substantial similarity between the groups, but also suggestive evidence of possible group differences, specifically in the domain of social-emotional responsiveness. Research on the psychological development of congenitally blind children promises to yield insights into the nature of autism itself. PMID- 10097995 TI - The understanding of the emotional meaning of facial expressions in people with autism. AB - Ten autistic individuals (mean age: 12.7 years, SD 3.8, range 5.10-16.0), 10 Down individuals (12.3 years, SD 3.0, range 7.1-16.0), and a control group of 10 children with normal development (mean age: 6.3 years, SD 1.6, range 4.0-9.4), matched for verbal mental age, were tested on a delayed-matching task and on a sorting-by-preference task. The first task required subjects to match faces on the basis of the emotion being expressed or on the basis of identity. Different from the typical simultaneous matching procedure the target picture was shortly presented (750 msec) and was not visible when the sample pictures were shown to the subject, thus reducing the possible use of perceptual, piecemeal, processing strategies based on the typical features of the emotional facial expression. In the second task, subjects were required to rate the valence of an isolated stimulus, such as facial expression of emotion or an emotional situation in which no people were represented. The aim of the second task was to compare the autistic and nonautistic children's tendency to judge pleasantness of a face using facial expression of emotion as a meaningful index. Results showed a significantly worse performance in autistic individuals than in both normal and Down subjects on both facial expression of emotion subtasks, although on the identity and emotional situation subtasks there were no significant differences between groups. PMID- 10097996 TI - The TOM test: a new instrument for assessing theory of mind in normal children and children with pervasive developmental disorders. AB - This article describes a first attempt to investigate the reliability and validity of the TOM test, a new instrument for assessing theory of mind ability in normal children and children with pervasive developmental disorders (PDDs). In Study 1, TOM test scores of normal children (n = 70) correlated positively with their performance on other theory of mind tasks. Furthermore, young children only succeeded on TOM items that tap the basic domains of theory of mind (e.g., emotion recognition), whereas older children also passed items that measure the more mature areas of theory of mind (e.g., understanding of humor, understanding of second-order beliefs). Taken together, the findings of Study 1 suggest that the TOM test is a valid measure. Study 2 showed for a separate sample of normal children (n = 12) that the TOM test possesses sufficient test-retest stability. Study 3 demonstrated for a sample of children with PDDs (n = 10) that the interrater reliability of the TOM test is good. Study 4 found that children with PDDs (n = 20) had significantly lower TOM test scores than children with other psychiatric disorders (e.g., children with Attention-deficit Hyperactivity Disorder; n = 32), a finding that underlines the discriminant validity of the TOM test. Furthermore, Study 4 showed that intelligence as indexed by the Wechsler Intelligence Scale for Children was positively associated with TOM test scores. Finally, in all studies, the TOM test was found to be reliable in terms of internal consistency. Altogether, results indicate that the TOM test is a reliable and valid instrument that can be employed to measure various aspects of theory of mind. PMID- 10097997 TI - Brief report: theory of mind in high-functioning children with autism. PMID- 10097998 TI - Brief report: two-year control of behavioral symptoms with risperidone in two profoundly retarded adults with autism. PMID- 10097999 TI - Receptive communication in late-stage Rett syndrome: a cautionary note. PMID- 10098000 TI - The auditory system, brain maturation, and development in autistic children. PMID- 10098001 TI - Autism or a related developmental disability. PMID- 10098002 TI - Pathophysiology of acute coronary syndromes leading to acute myocardial infarction. AB - Acute coronary syndromes, including unstable angina, myocardial infarction, and sudden death, account for more than 250,000 deaths annually. They are the manifestation of a progressive atherosclerotic process, which culminates in the rupture of atherosclerotic plaques and the formation of mural thrombi. This article reviews recent and current research, which has shed light on key events and evolutionary processes leading to acute coronary syndromes. The article details the development of vulnerable plaques, factors that promote plaque rupture, and triggering events related to plaque rupture. Also discussed are sequelae of acute coronary syndromes, including Q wave and non-Q wave infarction and left ventricular remodeling. PMID- 10098003 TI - Patient delay in seeking treatment for acute myocardial infarction symptoms. AB - Patient delay before seeking treatment for the symptoms of acute myocardial infarction has a significantly negative effect on morbidity and mortality. Most patients delay 2 or more hours before accessing the emergency medical system, which limits the ability to use reperfusion strategies. This article reviews variables that have been implicated in delay and explores possible explanations for why certain characteristics may be associated with longer delays. The outcomes of educational campaigns that have targeted delay behavior will be examined and directions for future research are identified. PMID- 10098004 TI - Acute myocardial infarction and posttraumatic stress disorder: the consequences of cumulative adversity. AB - This article examines the experiences of acute myocardial infarction (AMI) patients who are at high risk for reinfarction or sudden death to determine the impact of posttraumatic stress disorder (PTSD), accumulated burden of adversity, and trauma spectrum disorder on subsequent AMI care-seeking. Individuals experiencing an AMI have been studied with regard to depression and anxiety disorders, but negligible attention has been given to the PTSD potential of the total cardiovascular disease experience. Yet, growing evidence suggests the traumatogenic potential of AMI, with its sudden and unexpected onset, dramatic changes in life circumstance, and the additive effect of comorbid life events, is significant in producing impaired and extended coping during subsequent ischemic events. Consideration of PTSD and a continuum of cumulative adversity provides a more complex and fully drawn understanding of the circumstances surrounding AMI coping and reasons for delayed access to thrombolysis. PMID- 10098005 TI - Thrombolytic therapy versus primary angioplasty in the treatment of acute myocardial infarction. AB - The quest to identify the acute interventional approach that will achieve the lowest mortality rate with the fewest adverse events has led to a continued controversy surrounding the relative merits of thrombolytic therapy compared with primary angioplasty in the setting of acute myocardial infarction. This article summarizes the benefits and limitations of each reperfusion strategy and highlights adjunctive therapies that will enhance either treatment strategy. PMID- 10098006 TI - Influence of psychosocial factors and biopsychosocial interventions on outcomes after myocardial infarction. AB - Management of the myocardial infarction patient may extend beyond the physiologic to include psychosocial factors that may adversely affect cardiac health. Psychosocial factors such as depression, coronary-prone behavior, hostility, social isolation, anxiety, anger, and stress are related to increased cardiac death and illness. Various interventions including cognitive-behavioral therapies, techniques that elicit the relaxation response, meditation, exercise, and increasing social networks, may play a role in improving health outcomes. This article explores the relationship of these psychosocial factors to cardiac health and proposes a biopsychosocial model of care. PMID- 10098007 TI - Family-centered care after acute myocardial infarction. AB - The experience of a cardiac event is a significant source of stress for both patients and their family members. The acute phase after myocardial infarction reflects a crisis for patients and family members as they attempt to reconcile the affect of the event and adapt to the uncertainties associated with hospitalization and the initial recovery process. This article reviews empirical research available to cardiovascular nurses that may guide family-centered care during the acute phase after myocardial infarction. Directions for practice and research focus on cardiovascular nursing interventions that address family needs after an acute myocardial infarction. The experience of an acute myocardial infarction is a source of stress for both patients and their family members and may be viewed as a crisis that significantly disrupts family functioning and dynamics. The trajectory of cardiovascular disease involves multiple adjustments by patients and family members as they attempt to reconcile the affect of the event and adapt to the uncertainties associated with the acute phase of illness. Efforts by patients and family members to manage the stressors associated with the acute phase of cardiovascular illness are often associated with alterations in physiologic and psychologic functioning. PMID- 10098008 TI - Women and cardiac rehabilitation: referral and compliance patterns. AB - Heart disease is the primary killer among American women. Differences in referral for cardiac rehabilitation, as well as compliance rates, have been reported between male and female cardiac patients. This study explored the use of Phase I and Phase II cardiac rehabilitation programs by male and female patients. In particular, the study aimed to investigate the relationship between eligibility and subsequent referral to Phase II cardiac rehabilitation in both men and women, as well as their compliance rates in completing Phase II. In addition, for those patients who never started a Phase II program, their reasons for nonparticipation were explored. Structured patient interviews and chart audits were used to explore cardiac rehabilitation eligibility criteria, referral and completion rates. The sample consisted of 87 patients (46 women and 41 men) who were admitted with a medical diagnosis of angina, myocardial infarction, coronary artery bypass grafting, or valve replacement surgery. Men had higher eligibility rates for Phase I, whereas women had higher eligibility rates for Phase II; more men received a referral for Phase II from their physician than women did. Men had a higher completion rate with Phase II compared with women. For those patients who chose not to start a Phase II program, the most common reasons cited included transportation problems, insurance issues, and having exercise equipment at home. Although women are being referred for cardiac rehabilitation, fewer complete the programs. Continued education is essential to teach women the importance of cardiac rehabilitation to overall recovery and adaptation to an acute cardiac event. In addition, cardiac rehabilitation programs must be structured to meet the unique needs of women and thereby remove obstacles that have prevented higher participation rates by women in the past. PMID- 10098009 TI - Effect of ambient temperature and cardiac stability on two methods of cardiac output measurement. AB - The dependence of cardiac output measurement precision on ambient temperature and cardiac output stability was assessed by concurrent continuous and bolus thermodilution methods in postoperative cardiac surgery patients. The degree of agreement between the two methods was depended on room temperature (0.1 L/min for each degree below 25 degrees C). The agreement was also closer in trials where cardiac output was stable (< 10% variation). The continuous thermodilution method shows sufficient agreement with the bolus method for use in critical care; however, improved precision of cardiac output thermodilution measurements can be achieved by use of correction factors for cardiac instability and for ambient temperature. PMID- 10098010 TI - Effect of hospital type, insurance type, and gender on the treatment of cardiovascular disease in middle-aged adults. AB - The cost and duration of cardiovascular care was studied for 4,804 episodes of hospitalization in patients between 45 and 64 years of age. Men were more likely than women to be treated in urban medical centers for shorter, more expensive hospital care; women were more likely to be treated in rural hospitals for longer, less expensive care. Cost of treatment per day was not dependent on the type of insurance, but Medicaid claims (which represent low income patients) were associated with greater lengths of stay. PMID- 10098011 TI - Case study: analysis of an acute anterior-lateral myocardial infarction in a 16 year-old patient with familial hypercholesterolemia. AB - This article presents a case study of a 16-year-old male patient with a significant family history for hypercholesterolemia and coronary artery disease, who suffered an anterior lateral myocardial infarction. On admission, his electrocardiograms revealed the classic pattern of an anterior lateral acute myocardial infarction plus a left anterior hemiblock. His cholesterol level was 750 mg/dL, and his low-density lipoprotein was 650 mg/dL. He underwent a cardiac catheterization that revealed an occluded left anterior descending artery requiring a percutaneous transluminal angioplasty and three coronary stents. The 12-lead electrocardiograms on admission and before discharge are analyzed. This article discusses the electrocardiogram characteristics of anterior lateral wall myocardial infarction coupled with a left anterior hemiblock. PMID- 10098012 TI - Epithelial lymphocyte and macrophage distribution in the adult and fetal equine lung. AB - Leucocytes in the lung epithelium play an important role in the ability of an animal to respond appropriately to inhaled pathogens. The distribution of lymphoid and myeloid cells associated with the lung epithelium was examined immunohistochemically throughout the respiratory tract of four horses, comprising two adults from an abattoir, one pregnant mare, and her fetus (in the final stage of gestation). Cross and tangential cryosections were labelled with monoclonal antibodies against T-cell, B-cell, macrophage/dendritic myeloid cell, and major histocompatibility Class (MHC) II surface antigens. Cell numbers were determined by microscopy. In the three adult horses, epithelial CD3+ T-cell numbers decreased progressively from the upper to the lower respiratory tract, but in the fetus there were low numbers of T cells (at most, 10% of those seen in the adult airways) and little variation in different parts of the respiratory tract. MHC Class II was expressed on the airway epithelium of the two abattoir horses, but not that of the mare and her fetus. In these two animals occasional large, mostly irregularly-shaped, Class II-positive cells were seen. Very few epithelium associated cells in any animal were labelled by anti-CD21 antibody, which identifies B cells, or anti-myeloid cell antibodies; an anti-rat macrophage antibody (ED2) was shown, for the first time, to identify mature equine alveolar macrophages. Despite the small number of animals, the results suggest that in normal adult horses the greatest numbers of epithelial T cells are found where there is greatest contact with airborne antigens, and that there is constitutive epithelial MHC Class II expression. The low level of MHC Class II expression in the fetus, together with the reduced numbers of T cells, was consistent with the suggestion that the fetal immune system requires exposure to airborne stimuli for full development. The low level of MHC Class II expression in the mare may have reflected the immunosuppression that accompanies pregnancy. PMID- 10098013 TI - Infection with equine herpesvirus 1 (EHV-1) strain HVS25A in pregnant mice. AB - The abortigenic effects of equine herpesvirus 1 (EHV-1) strain HVS25A, given intranasally, were assessed in pregnant BALB/c, C57BL/6J and Quakenbush mice at day 16 of pregnancy. All EHV-1-infected BALB/c mice showed clinical signs typical of EHV-1-induced disease, together with evidence of abortion. However, although there were fetal and neonatal deaths in some C57BL/6J and Quakenbush litters, the respiratory and systemic effects of EHV-1 infection in the dams were inconsistent. BALB/c dams were then inoculated at day 15 of pregnancy with either EHV-1 or rabbit kidney (RK) cell lysate (controls) and animals were killed at days 1-5 post-inoculation (pi), i.e., before the occurrence of abortions. EHV-1 infected mice showed a significant fall in rectal temperature between days 1 and 2 pi and lost weight during the first 4 days pi, demonstrating a significant mean difference in weight gain from the control group at days 2, 3, 4 and 5 pi. Death in utero was seen in five of 90 fetuses of EHV-1-infected mice, but in no fetuses from RK-inoculated mice. On days 1, 2, 3, 4 and 5 pi, the fetuses from EHV-1 infected dams were significantly smaller than those from RK-inoculated dams. Congestion and necrosis of the middle layer of trophoblast and chorionic necrosis were observed in the placentae from EHV-1-infected dams and assessed by a scoring system. Virus was isolated rarely from the fetuses (1/73), placentae (3/72) and uteri (1/16) of EHV-1-infected dams, and only from those killed on day 1 or 2 pi. This indicates that, as in the horse, abortion caused by EHV-1 infection in mice is not necessarily a consequence of fetal infection but may be due to fetal compromise due to vascular effects on the placenta. PMID- 10098014 TI - Immunocytochemical detection of metallothionein (MT1 and MT2) in copper-enhanced sheep brains. AB - The role of metallothionein (MT) in the brain in heavy metal detoxification is relatively unexplored. Brain copper (Cu) elevation although unusual in chronic Cu poisoning in sheep, has been shown to occur after treatment with the chelating agent ammonium tetrathiomolybdate (TTM). The aim of this study was to investigate the expression of MT in TTM Cu-enhanced sheep brains, with immunohistochemical techniques. Brains from TTM-treated, Cu-poisoned sheep were examined for MT immunolabelling with a mouse monoclonal antibody (E9) for MT1 and MT2, and compared with brains from untreated sheep. Brain samples were analysed separately for Cu and zinc (Zn) by atomic absorption spectrophotometry. Markedly increased MT immunoreactivity was found in astrocytes of the cerebellum, thalamus/hypothalamus, cerebrum and medulla oblongata of the high-Cu brains, corresponding to the regional Cu elevations. MT immunolabelling was also found in the pia mater, choroid plexus and ependymal cells. Neurons were rarely labelled. MT induction within astrocytes and at the blood-brain barrier suggests that these are sites of stabilization and possibly transport for Cu and supports the hypothesis that the astrocyte compartment modulates metal homeostasis, conferring protection on vulnerable neurons and effecting damage limitation. PMID- 10098015 TI - Tissue damage in cattle infected with Theileria annulata accompanied by metastasis of cytokine-producing, schizont-infected mononuclear phagocytes. AB - The distribution of schizont-infected cells in six calves undergoing acute, lethal sporozoite-induced infections with Theileria annulata was examined, the calves being killed in the early, middle or late stages of disease. A combination of histological and immunocytochemical techniques showed that schizont-infected cells became disseminated rapidly through the lymphoid tissues from the prescapular lymph node draining the site of inoculation to distant lymph nodes (e.g., precrural, mesenteric and mediastinal) and to the spleen and thymus. The parasitized cells also spread rapidly into non-lymphoid organs, being found in the liver, kidney, lung, abomasum, adrenal glands and pituitary gland by day 7, in the brain by day 12 and in the heart by day 14 after infection. As infection progressed, the schizonts differentiated into merozoites. By the late stages of disease, the cells containing merozoites greatly out-numbered schizont-infected cells. The parasitized mononuclear cells were labelled by antibodies to bovine interferon-alpha1 and tumour necrosis factor-alpha and, during the later stages of the disease, contained erythrocytes parasitized by piroplasms. The results suggested that the parasitized mononuclear cells themselves played a role in the development of clinical disease and in tissue damage. These findings provide new evidence that tropical theileriosis can no longer be viewed as a lymphoproliferative disease resulting from the uncontrolled multiplication and metastasis of lymphoid cells infected with T. annulata schizonts, but is caused by a parasite that lives in, and is disseminated by, cytokine-secreting, proliferating mononuclear phagocytes. PMID- 10098017 TI - Distribution of a Korean strain of porcine reproductive and respiratory syndrome virus in experimentally infected pigs, as demonstrated immunohistochemically and by in-situ hybridization. AB - In an experiment with 40 specific pathogen-free pigs aged 3 days, the distribution of a Korean isolate of porcine reproductive and respiratory syndrome virus (PRRSV) was assessed immunohistochemically and by in-situ hybridization for a period of 28 days after intranasal inoculation. The most consistent and intense labelling for PRRSV was in the lung, the virus persisting in pulmonary macrophages for at least 28 days. The middle lobe of the lung was the optimum site for the detection of PRRSV antigens and nucleic acids, and the interstitial macrophage was the main cell type in which PRRSV was identified. Other tissues and cells in which the virus was detected included macrophages and dendritic cells in the tonsil, lymph nodes, spleen and Peyer's patches, and macrophages in the hepatic sinusoids and adrenal gland. The experiment suggested that the pathogenesis of PRRSV infection may be summarized thus: initial entry of virus through tonsillar and pulmonary macrophages, followed within 3 days by viraemia and subsequent interstitial pneumonia. PMID- 10098016 TI - Pathological, immunohistochemical, and in-situ hybridization studies of natural cases of postweaning multisystemic wasting syndrome (PMWS) in pigs. AB - Fifteen pigs from five farms on which there had been a previous clinical and histopathological diagnosis of postweaning multisystemic wasting syndrome (PMWS) were investigated. At necropsy, enlargement of lymph nodes was the most obvious lesion; other lesions were non-collapsed lungs, ulceration of the gastric pars oesophagica, and cranioventral pulmonary consolidation. Microscopical lesions attributable to PMWS were found in lymphoid organs (including lymph nodes, tonsil, Peyer's patches and spleen), liver, kidney and lungs. Varying degrees of lymphocellular depletion, affecting both lymphoid follicles and parafollicular zones, and progressive multifocal to diffuse infiltration of lymphoid tissue by large histiocytic cells were the characteristic lesions. Syncytial cells were seen frequently, especially in lymphoid organs. A prominent finding was the presence of sharply demarcated, spherical, basophilic, cytoplasmic inclusions in histiocytic cells. The lymphoid lesions were suggestive of immunosuppression. Non lymphoid lesions included interstitial pneumonia, periportal mononuclear inflammatory infiltration of the liver in varying degrees, and interstitial nephritis. Porcine circovirus (PCV) antigen and nucleic acid were regularly found in lymphoid organs, lung, liver and, to a lesser degree, kidney. Target cells for PCV replication included monocyte/macrophage lineage and antigen-presenting cells. To a lesser extent, epithelial cells such as renal tubular, bronchial and bronchiolar cells, endothelial cells, hepatocytes and lymphocytes were also labelled. One pig did not show PCV nucleic acid; sequence differences among different viral isolates are discussed as the probable cause of this lack of labelling by the in-situ hybridization PCV-specific probe. PMID- 10098018 TI - Neoplasia in snakes at the National Zoological Park, Washington, DC (1978-1997). AB - Of 291 juvenile and adult snakes examined post mortem over a 20-year period (1978 1997) at the National Zoological Park (NZP) in Washington, DC, 36 (24 females and 12 males) had neoplasms. Two snakes had tumours of two or three different types, but the other 34 snakes had only one type. All affected animals were adults and their average time on exhibit at the NZP was 108-9 months. Malignant neoplasms (79.5%) outnumbered benign neoplasms (20.5%). Of the malignant tumours, 19 (61.3%) were considered to have arisen in mesenchymal tissues, 11 (35.5%) were of epithelial origin, and one (3.2%) was derived from neuroectodermal tissues. All the benign neoplasms were of epithelial origin. Neoplasms of the lymphoid and haematopoietic tissues were the most common (12 cases), followed by tumours of the liver and biliary tract (seven cases) and the gastrointestinal tract (four cases). PMID- 10098019 TI - Oral metastasis of renal cell carcinoma in a horse. AB - A 14-year-old hunter gelding presented with an ulcerated mass on the left premaxilla. Biopsy of the mass revealed a poorly differentiated carcinoma. Surgical excision was attempted, but local regrowth followed several months later, at which point radiotherapy was carried out. An initial improvement was followed by marked deterioration and the animal was humanely killed. Post-mortem examination revealed a massively enlarged right kidney and associated widespread metastases. A metastatic clear cell renal carcinoma was identified by histological examination. PMID- 10098020 TI - Histological characterization of an ependymoma in the fourth ventricle of a cat. AB - A tumour occupying the fourth ventricle in a 3-year-old cat was removed surgically and characterized as a tanycytic ependymoma on the basis of histological features of low cellularity, inconspicuous perivascular pseudorosettes and fascicular architecture. Immunohistochemical analysis of sections revealed that the neoplastic cells were immunoreactive for glial fibrillary acidic protein (GFAP), vimentin and S-100. The histological and immunohistochemical findings were similar to those of human tanycytic ependymoma, a subclassification of ependymoma not previously described in domestic species. PMID- 10098021 TI - Surgical approaches for revision total hip replacement surgery: the anterior trochanteric slide and the extended conventional osteotomy. PMID- 10098022 TI - The vascularized scaphoid window for access to the femoral canal in revision total hip arthroplasty. PMID- 10098023 TI - Vastus slide and controlled perforations. PMID- 10098024 TI - Extended proximal femoral osteotomy. PMID- 10098025 TI - Retroperitoneal exposure in revision total hip arthroplasty. PMID- 10098026 TI - A new classification system for the management of acetabular osteolysis after total hip arthroplasty. PMID- 10098027 TI - Acetabular bone loss during revision total hip replacement: preoperative investigation and planning. PMID- 10098028 TI - Revision arthroplasty of the acetabulum in association with loss of bone stock. PMID- 10098029 TI - Total acetabular allografts. PMID- 10098030 TI - Transfemoral approach to the deficient proximal femur. PMID- 10098031 TI - Impaction morcellized allografting and cement. PMID- 10098032 TI - Surgical management of inflammatory arthritis of the adult hip and knee. PMID- 10098033 TI - Evaluation and treatment of infection at the site of a total hip or knee arthroplasty. PMID- 10098034 TI - Distal femoral varus osteotomy: indications and surgical technique. PMID- 10098035 TI - Proximal valgus tibial osteotomy for osteoarthritis of the knee. PMID- 10098037 TI - Unicondylar arthroplasty: an option for high-demand patients with gonarthrosis. PMID- 10098036 TI - Arthroscopic management for degenerative arthritis of the knee. PMID- 10098038 TI - Specialized surgical exposure for revision total knee: quadriceps snip and patellar turndown. PMID- 10098039 TI - Medial epicondylar osteotomy: a technique used with primary and revision total knee arthroplasty to improve surgical exposure and correct varus deformity. AB - The epicondylar osteotomy is a valuable tool for use in both primary and revision knee arthroplasty. Without damaging the ligamentous structures, this technique provides the surgeon with a means of accessing the knee, correcting deformity, and restoring knee stability. I have not experienced any clinical problems associated with this procedure. PMID- 10098040 TI - The quadriceps myocutaneous composite flap for the exposure of the distal femur and knee in tumor resection and reconstruction. PMID- 10098041 TI - Planning for revision total knee arthroplasty. PMID- 10098042 TI - Bone loss with revision total knee arthroplasty: defect classification and alternatives for reconstruction. AB - Although the best method for managing large bone defects has not been established, the variables to consider are: (1) implant constraint (posterior stabilized, varus-valgus-constrained, rotating hinge); (2) stem configuration (straight versus tapered, standard, or long-stemmed); (3) stem fixation (cement versus press-fit); and (4) method of bone-defect repair (cement, augments, bone graft). In principle, an implant with the least constraint required for satisfactory knee stability is selected to reduce stress on the implant-fixation interface with compromised bone. The severity of bone loss largely influences stem length. Canal-filling stems and cementless stem fixation are indicated when major structural allografts are used. Bone defects can be successfully and reliably repaired with metal augments, allograft bone, or cement, as long as long stemmed components without excessive constraint are selected. Because structural allografts do not revascularize, the major advantage of the allograft, as compared to cement fill or augments, is the ability to unite to damaged host bone that has a poor cancellous structure. PMID- 10098043 TI - Cementless fixation issues in revision total knee arthroplasty. AB - Although massive solid allografts can be expected to vascularize and form new bone, variable amounts of replacement as well as collapse and necrosis may be prominent features of these large block allografts. Immunocompatibility seems to be an important factor in allograft healing and incorporation. Large block allograft of the acetabulum appears to be more likely to succeed if autograft is used. Rejection appears to be a significant factor in survival of large allografts. Although bone itself is not highly immunogenic, the role of marrow elements in the cancellous bone graft may be crucial. When possible, marrow contents should be washed carefully from the interstices of cancellous bone to remove cellular elements that do not contribute to osteoinduction but do produce an inflammatory immune response that can compromise healing and bone formation. Washing and soaking the components in antibiotic solution has the additional benefit of making available a reservoir of antibiotic that is released slowly during the postoperative period. Morcellized cancellous bone, rather than finely ground bone which tends to be destroyed by phagocytosis, is the best available choice for reconstructing large volumes of deficient bone stock. Fixation is completely dependent on the existing bone, so that massive defects must be protected until sufficient rigidity develops in the grafted material to allow sharing of weightbearing loads. Clinical experience has shown that migration of the tibial component after reconstruction with morcellized allograft is rare during the first 2 to 5 years after surgery (Fig. 8). These results are surprising in light of reported experience with structural allografts of the acetabulum. Jasty and Harris reported loosening of acetabular components after 4 years in 32% of their cases. The biologic behavior of morcellized allograft differs from that of block allograft, however. Vascularization and ossification are rapid and a permanent, competent loadbearing structure is achieved by filling large deficient areas. The biologic response obtained with the correct technique appears to be early and vigorous. It does not seem likely that progressive collapse would occur after remodeling and healing have been established (Fig. 9). Bone graft handling probably is crucial to the success of grafting of the knee. Antibiotic soaking and washing, removal of bone marrow, and adequate support of the implants are all necessary factors for consistent success of this technique. The results of this salvage procedure have been encouraging. The grafting technique appears to provide long-term support for the implants, so that repeat revision is unlikely. PMID- 10098045 TI - The posterior cruciate ligament injured knee: principles of evaluation and treatment. PMID- 10098044 TI - Factors contributing to function of the knee joint after injury or reconstruction of the anterior cruciate ligament. PMID- 10098046 TI - Disorders of the Achilles tendon insertion and Achilles tendinitis. PMID- 10098047 TI - Achilles tendon ruptures. PMID- 10098048 TI - Ankle osteoarthritis: distinctive characteristics. PMID- 10098049 TI - Arthroscopic ankle debridement and fusion: indications, techniques, and results. AB - The use of the arthroscope in arthritis of the ankle has been well described and there is no question that it is a significant part of the armamentarium for the orthopaedic surgeon dealing with these patients. Unfortunately, those patients with advanced arthritis and loss of joint space do not respond well to traditional arthroscopic debridement, removal of loose bodies, debridement and drilling of osteochondral lesions, and removal of anterior osteophytes. These procedures should only be used on those patients with minimal to no degenerative arthritis. Arthroscopic ankle arthrodesis is becoming more of the accepted primary procedure for most cases of arthritis of the ankle, in my opinion. Some varus or valgus tilting of the tibial talar joint can be accepted if clinical alignment is relatively normal. Significant malalignments cannot be corrected with arthroscopic fusion. PMID- 10098050 TI - Joint distraction as treatment for ankle osteoarthritis. PMID- 10098051 TI - Arthrodesis of the ankle: technique, complications, and salvage treatment. PMID- 10098052 TI - Total ankle arthroplasty: state of the art. AB - Total ankle arthroplasty results from the 1970s and 1980s were comparatively poor. The outcomes of these surgeries deteriorated rather dramatically with time. Causes of failure were multifactorial, but the 2 features that seemed central to implant failure were constrained designs and cement fixation. Total ankle operations are considered technically demanding procedures, with relatively high early postoperative complication rates. As yet, the ideal total ankle patient remains to be defined. With the current implant results as a guide, the optimal patient is an older person who is low demand and has multiple joint problems involving either the ipsilateral foot or knee or contralateral ankle. Good alignment and ligamentous stability are essential. Osteonecrosis and profound osteoporosis are associated with poor results due to problems with bony fixation. Patients should be advised that the implant may fail, and that this may require further surgery, including the potential need for an ankle fusion or below-knee amputation. The results of ankle fusions, although usually initially good, seem to deteriorate with time (Table 2). Not uncommonly, patients develop either transverse tarsal or subtalar degenerative joint disease several years after an ankle arthrodesis. Because of the associated pain and functional limitations that can follow ankle fusion, efforts to develop a workable total ankle replacement continue. At present, the long-term results of most new designs are unknown. Today, total ankle arthroplasty probably should be limited to centers where surgeons have the volume of patients to master the demanding techniques needed for these operations and conduct prospective clinical trials to determine what factors lead to successful and unsuccessful outcomes. PMID- 10098053 TI - Surgical treatment for neuropathic arthropathy of the foot and ankle. PMID- 10098055 TI - Evaluation of the diabetic foot. PMID- 10098054 TI - Periarticular osteotomies: the importance of limb alignment. PMID- 10098056 TI - Total contact casting. PMID- 10098057 TI - Diabetic foot infections. PMID- 10098058 TI - Principles of partial foot amputations in the diabetic. AB - Unfortunately, amputation surgery is still a very important part of the treatment for diabetic foot problems. The decision-making process must be done thoughtfully, remembering that blood flow is not the only issue. Many factors enter into the decision to perform a partial foot amputation or to perform a more proximal level amputation. Adherence to good surgical principle, proven techniques, and gentle soft-tissue handling can make the difference between a successful and durable amputation or continued complications and frustrations. PMID- 10098059 TI - Complications after hallux valgus surgery. PMID- 10098060 TI - Arthroscopy of the great toe. AB - The few available reports of arthroscopic treatment of the first MTP joint in the literature indicate favorable outcome. However, arthroscopy of the great toe is an advanced technique and should only be undertaken by experienced surgeons. PMID- 10098061 TI - Osteonecrosis of the humeral head. PMID- 10098062 TI - Complications of shoulder surgery. PMID- 10098063 TI - Epicondylitis in the athlete. AB - Since the first description of epicondylitis of the elbow in 1882, there have been volumes of descriptive, diagnostic, and therapeutic reports detailing every aspect of this entity. It is now known that epicondylitis can be caused both by occupational and sports-related activities, that its diagnosis may be confused with a variety of other pathologic entities affecting the elbow, that the majority of patients will respond favorably to well-guided nonsurgical treatment, and that in those patients whose rersistent symptoms make them unable to return to their activities, surgical treatment results in reliable pain relief and return to preinjury level of activity. PMID- 10098064 TI - Medial collateral ligament instability and ulnar neuritis in the athlete's elbow. AB - Athletes who participate in overhand sports may sustain a host of injuries to the medial elbow. The chronic repetitive stress caused by the high velocity nature of the overhand throwing mechanism predisposes these athletes to overuse injuries. Medial collateral ligament instability and ulnar neuritis are common disorders seen in this patient population. A thorough understanding of the anatomy of the medial elbow as well as the pathophysiology of these disorders and their nonsurgical and surgical treatments are essential to providing these athletes with optimal care and hastening their return to sports. PMID- 10098065 TI - Osteochondritis dissecans of the elbow. AB - Osteochondritis dissecans of the elbow remains one of the leading causes of permanent elbow disability in adolescents and young adults engaged in throwing sports or gymnastics. The insidious onset of lateral elbow pain and restriction of full extension should alert the physician and prompt further investigation. Early recognition and appropriate treatment may allow for the prevention of long term sequelae. Conservative care following early detection provides the best opportunity for a complete recovery. Surgical management at this point consists primarily of excision or removal of the osteochondral fragment with drilling or burring of the base of the lesion. Prognosis is fair with approximately half of all patients experiencing chronic pain or limitation of motion in the elbow. Research efforts are currently focusing on the treatment of established articular surface defects. Newer procedures such as the transplantation of osteochondral, perichondral, and periosteal tissues, chondrocyte transplantation, and the biochemical manipulation of the chondrocyte environment may provide us with exciting new approaches to an old problem. Osteochondritis dissecans of the elbow continues to present a difficult challenge to the treating physician. The current literature provides very little guidance for the clinician but active and innovative investigations into the treatment of articular cartilage defects may soon provide the answers. PMID- 10098066 TI - Arthroscopic treatment of posterior elbow impingement. PMID- 10098067 TI - Biceps tendon injury. PMID- 10098068 TI - Nonsurgical treatment of thoracic and lumbar fractures. AB - The treatment of thoracolumbar trauma remains controversial. As more and more data are collected, there appears to be information that substantiates both surgical and nonsurgical treatment. Orthopaedic surgeons must all be cognizant of the fact that we draw our conclusions from data and not subjective prejudicial opinions. Nonsurgical treatment is still a viable and effective treatment for thoracic and lumbar fractures and should be part of the armamentarium available to all practitioners involved in the treatment of these patients. PMID- 10098069 TI - Measuring outcomes in cervical myelopathy and radiculopathy. PMID- 10098070 TI - Surgical management of cervical myelopathy. PMID- 10098071 TI - Introduction to thoracolumbar fractures. PMID- 10098072 TI - Thoracolumbar trauma imaging overview. PMID- 10098073 TI - Nonsurgical treatment of cervical degenerative disease. AB - A regular exercise program, even something as simple as a daily walk, can help to keep the ongoing degenerative process at bay. Such efforts at prevention can help with the patient's general health and should be encouraged by the spine physician. The vast majority of patients with degenerative cervical disease that is manifesting itself as neck and arm pain will respond to nonsurgical treatment. However, a very small percentage of patients who have cervical radiculopathy will require surgical treatment. Each practitioner must develop his or her own protocol based on personal experience, using a combination of the methods we have just discussed. An accurate diagnosis is necessary to avoid treating the wrong problem (i.e., lung cancer, shoulder impingement, etc). Patients should be knowledgeable about their disease. They should be empowered to participate in their care and encouraged to work with the physician and/or therapist to accomplish the goal of returning to a reasonable lifestyle at work as well as at home. An ongoing exercise program and an ergonomic evaluation at home and work can be helpful in reducing recurrences. PMID- 10098074 TI - Classification of thoracolumbar fractures and posterior instrumentation for treatment of thoracolumbar fractures. AB - In treating thoracolumbar injuries, an accurate diagnosis of the structural injury to the spine is critical. I recommend the Allen classification, but all classifications assist in obtaining an accurate understanding of the spine dynamics resulting from the injury. It is essential to remember that the majority of thoracolumbar injuries result from high-energy trauma. It is incumbent upon the spinal surgeon to ensure that multisystem trauma and life-threatening injuries, with the exception of a deteriorating neurologic injury, are cared for before embarking on spinal surgery. Even treatment of these injuries may have to be delayed if cardiovascular or abdominal hemorrhagic injuries take precedence. A critically important piece of information is the neurologic diagnosis. I recommend the ASIA Motor Index as the gold standard for diagnosing injuries and prognosticating outcome. Accurate neurologic diagnosis must be obtained prior to surgery. Finally, I recommend a firm understanding and a good working relationship with the device system used for fixation. Other instructional course authors agree that whether the anterior or the posterior approach is used, familiarity with the device nuances, by not only the surgeon but also the operating team, is very helpful in achieving a successful uncomplicated implantation. If all of the above recommendations are followed, successful outcome and optimal patient recovery can be anticipated in most cases. PMID- 10098075 TI - Combined anterior and posterior surgery for fractures of the thoracolumbar spine. PMID- 10098076 TI - Evaluation of the spine utilizing the AMA Guides to the Evaluation of Permanent Impairment, 4th edition. PMID- 10098077 TI - Intra-articular fractures of the distal aspect of the radius. AB - Intra-articular distal radius fractures are a heterogeneous group of injuries with different fracture patterns. The existing classification systems are helpful for describing the fractures but not for assessing their stability or for deciding which surgical approach to use. Patients who have a fracture with at least 1.0 mm of displacement of the articular surface may benefit from open surgical treatment. Improved diagnostic imaging with CT is helpful for fracture classification and surgical planning. The options for surgical treatment include limited open reduction and internal fixation, arthroscopically assisted internal fixation, and open reduction and internal fixation. The surgical approach is determined on the basis of the initial displacement of the fracture. Patients who have a displaced fracture of the volar rim may benefit from a volar approach; those who have a dorsally displaced fracture, from a dorsal approach; and those who have an impacted fracture such as a die-punch fracture, from a dorsal approach that provides better visualization of the articular surface. The long term functional outcome is determined in part by the severity of the fracture as defined by the amount of comminution, the initial severity of displacement, and the number of fracture fragments. The accuracy of the reconstruction of the articular surface, with the goal of establishing congruency to within 1.0 mm, is also important in order to minimize the risk of late osteoarthrosis. Of all of the extra-articular parameters, restoration of the length of the radius is the most important for enhancing recovery of motion and grip strength and for preventing problems involving the distal radioulnar joint--the so-called forgotten joint in distal radial fractures. PMID- 10098078 TI - Surgical treatment of acetabular fractures. PMID- 10098079 TI - Fractures of the proximal tibia. PMID- 10098080 TI - Knee dislocations. PMID- 10098081 TI - Back pain in childhood and adolescence. AB - A variety of disorders can account for back pain in the child or adolescent (Outline 1). Some of these can result in significant morbidity if not properly diagnosed and treated. Fortunately, nearly all can be correctly diagnosed by taking a thorough medical history, performing a complete physical examination, and obtaining appropriate imaging and laboratory studies. Although back pain in children and adolescents may result from overuse or minor trauma and will respond to rest and anti-inflammatories, this review should enable the orthopaedist to systematically recognize those back disorders in need of more aggressive medical intervention. PMID- 10098082 TI - Current concepts in myelomeningocele. PMID- 10098083 TI - The treatment of neuromuscular scoliosis. PMID- 10098084 TI - Treatment of hip and knee problems in myelomeningocele. PMID- 10098085 TI - Orthopaedic oncology for the nononcologist orthopaedist: introduction and common errors to avoid. AB - A number of the more frequently encountered diagnostic and management errors and pitfalls have been discussed. However, if a physician will recognize his or her own limits and will always consider the diagnostic possibility of a neoplastic process, then appropriate steps can usually be taken, improving the patient's health care. The following chapters will outline the appropriate steps in the evaluation and work-up of patients with suspected tumors, as well as the currently recommended approach for biopsy, treatment, and follow-up. PMID- 10098086 TI - Biopsy. AB - Obtaining tissue for diagnosis of bone and soft-tissue tumors is one of the goals of all biopsies. The biopsy, however, must be well planned so as to avoid creating inadvertent tumor spread, thereby compromising the ability to perform limb-sparing resectional surgery. PMID- 10098087 TI - Treatment options for orthopaedic oncologic entities. AB - Over the past 2 decades, tremendous advancement in the understanding of tumor natural history and treatment has occurred. If the basic principles are followed, the evaluation and appropriate treatment of musculoskeletal tumors can be reproduced successfully by any conscientious surgeon. Many benign bone and soft tissue tumors can and probably should be treated by the community orthopaedic surgeon, and this chapter is biased toward treatment of those lesions. The encounter of a malignant lesion is probably beyond the scope of practice of most practicing orthopaedic surgeons. The assessment of the patient and treatments rendered in the first meetings may well dictate the ultimate outcome of survival and limb preservation: thus, patients with such lesions should be treated by experienced orthopaedic oncologists. With the small numbers of these lesions and the extreme consequences of mishandling them, it would be imprudent to do otherwise. PMID- 10098088 TI - Appropriate follow-up of orthopaedic oncology patients. AB - In summary, there is no gold standard of the appropriate follow-up of orthopaedic patients. Patients with musculoskeletal neoplasms should be watched closely for local recurrence. Those patients whose tumors have metastatic potential should be followed up closely for metastatic disease. The timing of the suggested follow-up intervals varies, depending on the aggressiveness and growth rate of the tumor. There is no objective, data-based study to define the optimal follow-up intervals for the various entities. In general, the earlier recurrent or progressive disease can be detected, the better the chance of disease eradication. However, there is still some question as to whether the earlier detection of metastatic disease will change the eventual outcome in these patients. PMID- 10098089 TI - Presentation and evaluation of bone tumors. PMID- 10098090 TI - The pathologist's role in the diagnosis of bone tumors: informed versus uninformed. PMID- 10098091 TI - Evaluation of soft-tissue tumors. AB - Soft-tissue masses present a challenge to the practicing physician. Most are of little or no concern and do not need medical attention, but the consequences of missing a sarcoma are significant. It is important to give careful consideration to each soft-tissue mass seen and decide which need further evaluation and which do not. Periodic reexamination is recommended for patients with masses not thought to need biopsy. Patients with more worrisome soft-tissue masses should have at least an MRI scan and then, usually, a biopsy. PMID- 10098092 TI - Biologic restoration of articular surfaces. PMID- 10098093 TI - The role of cartilage repair techniques, including chondrocyte transplantation, in focal chondral knee damage. PMID- 10098094 TI - The biology of bone grafting. AB - Allograft bone continues to play an important role in revision hip and knee arthroplasty with well documented clinical success. A basic understanding of allograft biology and immunology is important in order to optimize outcome. The importance of the interaction of immunologic factors with the biologic processes involved in bone graft incorporation has yet to be fully understood. A better understanding may, in the future, enable an improvement in the quality and uniformity of clinical outcome. PMID- 10098095 TI - Current options and approaches for blood management in orthopaedic surgery. PMID- 10098096 TI - Outcomes assessment in the information age: available instruments, data collection, and utilization of data. PMID- 10098097 TI - Amputation surgery in peripheral vascular disease. PMID- 10098098 TI - Work-related upper extremity complaints. PMID- 10098099 TI - Medical malpractice: defending yourself. PMID- 10098100 TI - Competitive inhibition of p-aminohippurate transport by quinapril in rabbit renal basolateral membrane vesicles. AB - The mechanism of quinapril's interaction with the organic anion transporter was characterized by studying its effect on the transport of p-aminohippurate (PAH) in rabbit renal basolateral membrane vesicles (BLMV). Cis-inhibition studies demonstrated that quinapril was a specific and potent inhibitor of PAH. The Ki of quinapril was about 20 microM, a value similar to that of probenecid and eight times lower than the K(m) value of 165 microM for PAH. Even though quinapril resulted in trans-inhibition of PAH uptake during counterflow studies, kinetic studies revealed that quinapril was a competitive inhibitor of PAH transport. This latter findings suggests that quinapril and PAH share a common binding site on the transporter. Overall, the results indicate that quinapril is a high affinity inhibitor of the organic anion transporter in renal BLMV, and that drug drug interactions may occur with other organic anions at the basolateral membrane of proximal cells. PMID- 10098101 TI - Fourth-generation model for corticosteroid pharmacodynamics: a model for methylprednisolone effects on receptor/gene-mediated glucocorticoid receptor down regulation and tyrosine aminotransferase induction in rat liver. AB - A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg i.v. bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine amino-transferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45-50% of the baseline in 8-10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1-2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects. PMID- 10098102 TI - Rapid attainment of steady state plasma drug concentrations within precise limits. AB - We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the lower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration-time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed. PMID- 10098103 TI - Pharmacokinetic and pharmacodynamic evaluation for tissue-selective inhibition of cholesterol synthesis by pravastatin. AB - The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after i.v. bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions. PMID- 10098104 TI - Predictive performance of a semiparametric method to estimate population pharmacokinetic parameters using NONMEM. AB - Routine clinical pharmacokinetic (PK) data collected from patients receiving inulin were analyzed to estimate population PK parameters; 560 plasma concentration determinations for inulin were obtained from 90 patients. The data were analyzed using NONMEM. The population PK parameters were estimated using a Constrained Longitudinal Splines (CLS) semiparametric approach and a first-order conditional method (FOCE). The mean posterior individual clearance values were 7.73 L/hr using both parametric and semiparametric methods. This estimation was compared with clearances estimated using standard nonlinear weighted least squares approach (reference value, 7.64 L/hr). The bias was not statistically different from zero and the precision of the estimates was 0.415 L/hr using parametric method and 0.984 L/hr using semiparametric method. To evaluate the predictive performances of the population parameters, 17 new subjects were used. First, the individual inulin clearance values were estimated from drug concentration-time curve using a nonlinear weighted least-squares method then they were estimated using the NONMEM POSTHOC method obtained using parametric and CLS methods as well as an alternative method based on a Monte Carlo simulation approach. The population parameters combined with two individual inulin plasma concentrations (0.25 and 2 hr) led to an estimation of individual clearances without bias and with a good precision. This paper not only evaluates the relative performance of the parametric and the CLS methods for sparse data but also introduces a new method for individual estimation. PMID- 10098105 TI - Too much sex. Is there such a thing? PMID- 10098106 TI - Sexually abused boys often suffer in silence. PMID- 10098107 TI - From the other side of the door: patient views of seclusion. AB - 1. Patient participants viewed seclusion as a form of punishment that maintains physical, and at times, psychological control over the secluded person. 2. A seclusion episode should serve a greater function than simply containment or preserving safety. During this period of crisis for the patient, they felt an even greater need for a therapeutic intervention. 3. Environmental, procedural, and attitudinal changes were emphasized by the patients in this study as a means to enhance the therapeutic potential of seclusion. PMID- 10098108 TI - Forensic evaluation for maternal reunification. AB - 1. Forensic evaluation reports provide an expert opinion including basis for the opinion and supporting research, if available. 2. Maternal protection of a child is evaluated by past and present behavior. 3. Risk assessment factors for child abuse include child characteristics, caregiver characteristics, parent-child relationship, severity of child abuse, chronicity of child abuse, predator access, and social and economic factors. PMID- 10098109 TI - Can we create a therapeutic relationship with nursing home residents in the later stages of Alzheimer's disease? AB - 1. Despite their entrance into advanced illness, the majority (83%) of participants in the study displayed evidence of having begun a therapeutic relationship with their assigned advanced practice nurse. 2. With one exception, those participants who did not evidence development of the relationship had severely limited speech, perseverative speech, or did not speak at all. 3. It is time to challenge the assumption that individuals in the middle and later stages of Alzheimer's disease are not good candidates for developing a therapeutic relationship. PMID- 10098110 TI - Potential for violence toward psychiatric nursing students: risk reduction techniques. AB - 1. Nursing students could be vulnerable targets of violence in their psychiatric nursing clinical rotations by virtue of their predominant gender, and meek, insecure attitudes. 2. Nurses are taught to put the patients' needs first and students may blame themselves or minimize situations where they have been threatened or assaulted by a patient. Priority consideration must also be given to our own safety and that of our students, given the risk for occupational injury in the nursing workplace. 3. Affiliating agencies may restrict disabled students from patient care areas. Allowing a disabled student to participate in a clinical rotation on a psychiatric unit could put staff at unnecessary risk of violence if called on to protect the vulnerable student. PMID- 10098111 TI - Child sexual abuse prevention programs in Texas public elementary schools. AB - This survey determined if selected Texas public school districts provided an established child sexual abuse prevention program for elementary schools. The survey examined the type of program being implemented, training available for faculty and staff type of evaluation used, involvement of local agencies, and type of funding sources. Survey data were obtained from a nonrandomized sample of 89 largest public school districts in Texas, all recording an average daily attendance over 5,000. Fifty-eight of the 89 districts addressed child sexual abuse as a formal prevention program or as an awareness program. Training for child sexual abuse prevention program presenters was offered in 89% of districts. Consistent, effective evaluation was minimal. Funding for prevention programs was limited or unknown. Results confirmed the need for consistent, effective child sexual abuse prevention programs in elementary schools. PMID- 10098112 TI - Developing a computer-assisted health knowledge quiz for preschool children. AB - The project evaluated the reliability of a computer-assisted health education knowledge quiz, a multiple-choice picture identification assessment tool for nutrition and health-related knowledge in preschool age children. Pearson's product moment correlation coefficients were computed to assess overall and componential stability between test/retest scores of 51 children (mean age 3.6 years) enrolled in a Head Start preschool center. Cronbach alpha coefficients were calculated to determine the internal consistency of the subscales. Overall reliability for the computer-assisted quiz was high at .82 (p < .01). For individual subscales, test/retest correlations were highest for Nutrition, Safety, and Environment (r = .56 to .81) and lower but still significant for Dental, Smoking, and Fitness (r = .37 to .48). Results suggest a computer assisted knowledge quiz can provide a reliable tool to assess health education knowledge in young children. In addition, the computer-assisted test format is highly acceptable to preschool children and enables researchers to administer a more extensive test to young children with brief attention spans in a manner that engages their full cooperation and effort. In this respect it offers several advantages over traditional paper-and-pencil formats. PMID- 10098113 TI - Screening for asthma in an inner-city elementary school in Minneapolis, Minnesota. AB - To the extent that the asthma morbidity so prevalent in children today is due to underdiagnosis or lack of appropriate treatment, schools are increasingly faced with the issue of defining their role in the care of children with asthma. This paper describes efforts to conduct schoolwide screening for asthma in an inner city elementary school over the past two years. Screening methodology adopted for the project resulted in a simple and noninvasive approach for identifying children with current asthma in a school setting. While not as medically comprehensive as would be required to conclusively diagnose asthma, the simple screening approach proved efficient in identifying a population of elementary school children with a significant level of asthma morbidity. The paper discusses the effectiveness and feasibility of the screening efforts and proposes how such a screening program might be incorporated into the routine health activities undertaken at any elementary school. PMID- 10098114 TI - Professional preparation of elementary teachers in Ohio: status of K-6 health education. AB - Improving the health status of children and youth depends to an extent on the adequate preparation of elementary teachers to teach health education. This survey: 1) examined the status of health education preparation that preservice elementary education majors receive from Ohio colleges and universities (n = 50); 2) determined the type of health education courses that Ohio colleges and universities require for elementary education majors; and 3) assessed the extent to which Ohio colleges and universities incorporate health and pedagogy-related content in their courses for elementary education majors. Results showed that 40 of the 50 institutions offered a health course. Twelve different textbooks were used in the courses. Coverage of course content ranged from much to none for 10 survey items ranging from the National Health Education Standards to the K-6 Health Instruction Responsibilities and Competencies. PMID- 10098115 TI - Health risk behaviors of Texas students attending dropout prevention/recovery schools in 1997. AB - This study determined prevalence of health risk behaviors of 9th through 12th grade students attending dropout prevention/recovery alternative schools in Texas in 1997. Participants were 470 youth whose health risk behaviors were assessed using the Youth Risk Behavior Survey in an anonymous, self-administered format. Behaviors measured included frequency of weapon-carrying and fighting, suicide related behaviors, substance use, and sexual behaviors. A substantial percentage of alternative school students reported participating in behaviors that placed them at acute or chronic health risk. Differences in the prevalence of risk behaviors were noted by gender, racial/ethnic, and age subgroups. In addition, alternative school students frequently engaged in multiple risk behaviors. These findings suggest a need for comprehensive school-based health education/intervention programs to reduce the prevalence of risk behaviors in populations of alternative school students. PMID- 10098116 TI - Determinants of physical activity in active and low-active, sixth grade African American youth. AB - This study compared the determinants of physical activity in active and low active African-American sixth grade students (N = 108, 57 F, 51 M). Objective assessments of physical activity over a seven-day period were obtained using the CSA 7164 accelerometer. Students were classified as active if they exhibited three or more 20-minute bouts of moderate to vigorous physical activity over the seven-day period. Relative to low-actives, active boys reported significantly higher levels of self-efficacy, greater involvement in community physical activity organizations, and were significantly more likely to perceive their mother as active. Relative to low-actives, active girls reported significantly higher levels of physical activity self-efficacy, greater positive beliefs regarding physical activity outcomes, and were significantly less likely to watch television or play video games for > or = 3 hrs/day. These observations provide preliminary guidance as to the design of physical activity interventions targeted at African-American youth. PMID- 10098117 TI - Parental reasons for non-response following a referral in school vision screening. PMID- 10098118 TI - Monoclonal antibodies specific for leukocyte adhesion molecules. Selective protocols of immunization and screening assays for generation of blocking, activating and activation reporter antibodies. PMID- 10098119 TI - Epitope mapping. PMID- 10098120 TI - Sequencing of antibodies. PMID- 10098121 TI - Purification through affinity chromatography and microsequencing. PMID- 10098122 TI - Functional analysis of cell adhesion molecules. PMID- 10098123 TI - Application of polymerase chain reaction for the discovery of new adhesion molecule family members. PMID- 10098124 TI - Construction and purification of adhesion molecule immunoglobulin chimeric proteins. PMID- 10098125 TI - Immunofluorescence of cultured cells. PMID- 10098126 TI - Detection of adhesion molecules by immunohistochemistry on human and murine tissue sections. PMID- 10098127 TI - In situ hybridization with RNA probes. PMID- 10098128 TI - Purification of fibronectin from human plasma. PMID- 10098129 TI - Adhesion to matrix proteins. PMID- 10098130 TI - Leukocyte-endothelial monolayer adhesion assay (static conditions). PMID- 10098131 TI - Cell-cell adhesive interactions in an in vitro flow chamber. PMID- 10098132 TI - Adhesion of tumor cells to endothelium under static conditions. PMID- 10098133 TI - Adhesion of tumor cells under flow. PMID- 10098134 TI - Platelet adhesion to the subendothelium under flow. PMID- 10098135 TI - Leukocyte transmigration through vascular endothelium. An in vitro method. PMID- 10098136 TI - Cell migration into a wounded area in vitro. PMID- 10098137 TI - Determination of the endothelial barrier function in vitro. PMID- 10098138 TI - Induction of intracellular signals through binding of adhesive molecules. Activation of p125FAK tyrosine phosphorylation. PMID- 10098139 TI - Induction of Ca2+ flux by adhesion molecules in lymphocytes. PMID- 10098140 TI - Integrin-mediated stimulation of tyrosine phosphorylation in lymphoid cells. PMID- 10098141 TI - The identification of signaling molecules by the yeast two-hybrid system. PMID- 10098142 TI - [Integration of stroke unit and rehabilitation in a single clinic--a new model?]. PMID- 10098143 TI - [Current diagnosis in muscular dystrophies. New developments, methods of examination and case examples]. AB - Recent progress in the field of molecular genetics revealed a broader spectrum of dystrophin-related disorders than previously assumed. In addition, the pathogenetic basis of other types of muscular dystrophies could be identified: some autosomal-recessive limb girdle dystrophies are caused by mutations of sarcoglycan genes, others are caused by deficiency of the sarcoplasmatic enzyme calpain-3. Emery-Dreifuss muscular dystrophy is due to the deficiency of the nuclear membrane protein emerin. About 50% of congenital muscular dystrophies are related to mutations of a extracellular matrix protein merosin (alpha-laminin). A series of monoclonal antibodies for immunohistochemistry is now available recognizing many cytoskeletal muscle proteins. In combination with molecular genetics a diagnostic flow chart can be developed which allows a definite diagnosis in most cases. In this review disease entities are illustrated by case reports. We discuss the significance of immunohistochemical and molecular methods for diagnosis. PMID- 10098144 TI - [Neuroprotection in stroke. A critical overview]. AB - Cerebral ischemia leads to a cascade of pathophysiological processes which contribute to ischemic cell damage. In addition to the excitotoxicity, which is characterized by a massively elevated extracellular concentration of excitatory amino acids and an intracellular overload with calcium, the increased formation of free radicals, the inflammation and the apoptosis are also involved in ischemic damage. Neuroprotection, a pharmacological interaction with these pathophysiological processes, is one possibility to attenuate the consequences of cerebral ischemia. In experimental studies it could be demonstrated that glutamate antagonists, calcium antagonists or radical scavengers reduce the ischemic damage. Substances which interact with inflammation or apoptosis have also been shown to be protective. Clinical trials, however, showed no beneficial effects. This discrepancy is mainly due to differences in the design of the studies. In experimental studies the substances were often applied before or at the onset of ischemia, the survival time after ischemia was very short and the effects of neuroprotection were mainly evaluated by morphological examinations. Considering these points in future preclinical studies it is hoped that neuroprotective substances will be found which may be effective in clinical trials. PMID- 10098145 TI - [Enzyme defects of the urea cycle in differential acute encephalopathy diagnosis in adulthood. Diagnosis and current therapy concepts]. AB - Six enzyme defects of the urea cycle have been described. Ornithine transcarbamylase deficiency is the most frequent of these diseases. The cumulative frequency is 1:8000. Most patients become symptomatic in childhood, but onset of symptoms may occur later in childhood or even adulthood. The patients present with recurrent episodes of an unspecific acute encephalopathy, seizures and clouding of consciousness to a variable degree. Focal neurological signs such as hemiparesis, aphasia or ataxia may also occur. These episodes may be triggered by infection, protein overload or drugs. Diagnostic are increased blood ammonia levels. Characteristic patterns of plasma amino acids and the determination of orotic acid in the urine mostly discriminate the individual disorders. Further diagnostic steps include the allopurinol challenge test, liver or skin biopsy for measurement of enzyme activity and molecular genetic studies. Treatment requires restriction of protein intake, supplementation of arginine and activation of alternative pathways of nitrogen excretion with benzoate or phenylbutyrate. Untreated, the acute episode may be lethal. Long-term treatment improves the clinical outcome considerably. Urea cycle defects should be included in the differential diagnosis of any encephalopathy or coma of unclear origin, and blood ammonia should be determined early in the evaluation of such patients. PMID- 10098146 TI - [Early summer meningoencephalitis. Extension of the endemic area to mid-Hessia]. AB - Tick-borne encephalitis (TBE) is the most severe arbovirus disease transmitted by ticks. The mortality of the central European form is 0.7-2%. Active immunisation is recommended for endemic regions. We report on 4 patients with TBE acquired in Middle-Hessen between 1994 and 1997 (2 in 1997). After repeated CSF and serum testing the TBE-specific antibodies were found in all 4 cases. In one case there was also evidence for a prior infection with borrelia burgdorferi. The results of the initial CSF-analysis were atypical in 2 cases (high cell count of 136 cells/mm3, total protein up to 1.5 g/l). The endemic region for TBE has expanded in northern direction into Middle-Hessen, a region in which Lyme borreliosis is also endemic. Thus, true double infections are possible. This and the initially frequently atypical CSF-findings make the differential diagnosis difficult. Therefore, repetitive CSF and blood examinations are recommended. PMID- 10098147 TI - [Fibrinolysis of intraventricular hematoma with rt-PA]. AB - Intraventricular administration of recombinant tissue plasminogen activator (rt PA) is an experimental therapy to hasten the lysis of intraventricular hemorrhages. We report nine patients (7 male, 2 female, mean age 64a) with intracerebral hematoma with ventricular extension who were treated with intraventricular infusion of rt-PA (2-32 mg, mean dose 17 mg). In two patients, clinically significant bleeding complications were associated with the fibrinolytic therapy. In one of these patients, fibrinolytic therapy was stopped. Other complications could not be observed. In eight of all nine patients, a rapid and extensive reduction of the amount of intraventricular blood occurred. A persistent shunt became necessary in two patients. We conclude, that intraventricular fibrinolysis probably leads to a faster clearance of intraventricular blood. Despite of fibrinolytic treatment, a permanent shunt becomes necessary in some cases. Intraventricular fibrinolysis is a potentially hazardous therapy with the risks of bleeding complications and infection. PMID- 10098148 TI - [Disease picture of myotonic muscular dystrophy in patients with large CTG triplet expansion]. AB - Myotonic dystrophy is an autosomal dominant multisystem disorder involving muscle, brain, heart, eyes, and endocrine organs. The underlying mutation is an expanding trinucleotide CTG repeat in the 3'prime untranslated region of a serine threonine kinase gene on chromosome 19q. A statistical correlation exists between the CTG copy number and the severity of the disease. Infants with severe congenital myotonic dystrophy have been shown to have on average a greater amplification of the CTG repeat than is seen in the non-congenital myotonic dystrophy population. However, not all patients with many CTG copies develop congenital myotonic dystrophy. We present 13 patients with more than 1500 CTG trinucleotide repeats and show their variable clinical course. PMID- 10098149 TI - [Dysautonomia in Guillain-Barre syndrome]. AB - About 20% of all GBS patients have symptoms of dysautonomia: labile hypertension, orthostatic hypotension, sinustachycardia or sinus arrest. This rate rises to 75% in patients with tetraplegia. Proprioceptive loss predicts dysautonomia independently from the severity of weakness. It is frequently responsible for dysautonomia. The afferent limb of cardiovascular regulation contains more myelinated fibers than the sympathetic and parasympathetic efferences, which determine the common classification of dysautonomia. The frequence of mixed sympathetic and parasympathetic hyperactivity is hard to explain by efferent lesions. Afferent conduction block releases the sympathetic efference of the baroreceptor reflex. The resulting catecholamine excess explains hypertension, tachycardia, ECG-changes and hyperglycemia. Norepinephrine sensitizes left ventricular stretch receptors. They induce cardiovascular depression and neurocardiogenic syncope which has a temporal behaviour similar to the blood pressure variations of GBS. Conduction block of sinoatrial stretch receptors causes inappropriate secretion of ADH and renin. Dysbalance between myelinated and unmyelinated afferents which decrease and increase heart rate may cause parasympathetic hyperactivity, as exemplified by pulmonary stretch receptors that are stimulated by artificial ventilation. Wrong afferent feedback is responsible for many cardiovascular instabilities in GBS. Blockade of misguided efferent reactions is an attractive therapeutical approach. PMID- 10098150 TI - [Stroke treatment with stroke unit and rehabilitation by a team. A model for a staged management]. AB - This is a report of an interdisciplinary approach to diagnosis and treatment of stroke, combining a stroke unit and rehabilitation in one clinic. This series contains unselected patients from a narrow surrounding. Mean age of 559 patients was 68.7 years (median 70 years). 25% of patients had an initial Barthel index of < 30, 20% presented with TIA's and PRIND's. 9% suffered from cerebral hemorrhage. The unbroken chain of care allowed a relative short length of stay in the acute care (9.4 days) without prolonging the rehabilitation phase. The one month mortality was 6.7%, one year mortality 18.3%. Discharge to a nursing home was necessary in 5.4%. Overall more than 90% of our patients have been treated continuously in our clinic. Combining modern diagnostics with early onset rehabilitation seem advantageous. PMID- 10098151 TI - [Spiroergometry in diagnosis of mitochondrial diseases]. AB - Cardiopulmonary exercise testing (CPX) is a non-invasive method of recording quantitative data from gas exchange and ventilation for the evaluation of oxidative metabolism at rest and during exercise. Determination of oxygen uptake (VO2) and carbon dioxide output (VCO2) describes the activity of anaerobic vs aerobic metabolism. An incremental exercise test measuring gas exchange, ventilation and lactate release was performed in healthy volunteers and in patients suffering from mitochondrial disorders. At rest as well as during exercise patients with mitochondrial disorders differ from healthy subjects with regard to gas exchange and ventilation parameters. During exercise, the decreased oxygen utilization of skeletal muscle and early activation of anaerobic metabolism in these patients are mirrored by a reduced anaerobic threshold, reduced maximal oxygen uptake and reduced oxygen pulse. Our study shows that CPX is a sensitive and practical clinical screening method of investigating mitochondrial disorders. PMID- 10098152 TI - [Hexosaminidase deficiency as differential spinocerebellar diseases]. AB - Tay-Sachs disease is caused by Hexosaminidase A deficiency. Symptoms of the enzyme deficiency rarely become clinically manifest in adult age; then the course of the disease differs in a wide range. We report on a patient with cerebellar ataxia and lower motor neuron disease. Neurophysiological investigations, neuro imaging (CT, MRI), and muscle biopsy reveal pathological but nonspecific findings. Determination of hexosaminidase A and B activities leads to the diagnosis. In patients with spinocerebellar ataxia hexosaminidase deficiency has to be considered as a differential diagnosis. PMID- 10098153 TI - [Neuroborreliosis with extensive cerebral vasculitis and multiple cerebral infarcts]. AB - We report on a patient who suffered from borreliosis-induced severe cerebral vasculitis accompanied by multiple cerebral infarctions leading to hemiparesis, hemianopsia and reduced consciousness. Despite antibiotic and immunosuppressive therapy with ceftriaxon and prednisolone the patients condition deteriorated. Cerebral angiography showed multiple stenoses of large arteries of the posterior circulation and ubiquitous irregularities of small vessel wails. General reduced perfusion reflected an increased peripheral resistance. After 4 weeks of additional immunosuppressive treatment with cyclophosphamide the neurological status and angiographic findings improved dramatically. PMID- 10098154 TI - [Serum concentration of anticonvulsants. Practical guidelines for measuring and useful interpretation. Therapy Committee of the German Section of the International Epilepsy League]. AB - The clinical relevance of being informed on the serum concentration of antiepileptic drugs has been judged very differently during the last decades. Therefore the Commission on the treatment of epilepsy (German section of the International League against Epilepsy) had the task to outline the importance of therapeutic monitoring of anticonvulsant serum concentrations. The possibility of determining the serum concentration of anticonvulsants induced the elaboration of "therapeutic drug level ranges". The usefulness of determining serum concentrations of antiepileptic drugs in clinical management of patients with epilepsy depends decisively on the following questions: Can the efficacy of antiepileptic drug treatment be increased by serum concentration monitoring? Can the rate of adverse effects of antiepileptic drugs be reduced by serum concentration monitoring? Clinical experience suggests numerous indications of therapeutic drug monitoring, scientific studies however, supporting these empirical guidelines are not available. Therefore, therapeutic drug monitoring may be restricted for some special situations which have to be justified in every single case. Tailored determinations with specific purposes are e.g.: resistance to therapy, including suspected irregular intake; suspected intoxication, particularly during combined therapy; the possibility of significant changes in the dosage-serum concentration relationship (interactions with other drugs, unusual pharmacokinetics in childhood, in pregnancy etc.). PMID- 10098155 TI - [Bone marrow and stem cell transplantation in multiple sclerosis?]. PMID- 10098157 TI - [Physical trauma and multiple sclerosis. Additional comments from historical neurology]. PMID- 10098156 TI - [PRISMS Study. Interferon-beta 1a (Rebif) in relapsing multiple sclerosis]. PMID- 10098158 TI - Overview of antibody use in immunocytochemistry. PMID- 10098160 TI - Purification of antibodies using ion-exchange chromatography. PMID- 10098159 TI - Purification of antibodies using ammonium sulfate fractionation or gel filtration. PMID- 10098161 TI - Purification of antibodies using affinity chromatography. PMID- 10098162 TI - Purification of antibodies using protein A-sepharose and FPLC. PMID- 10098163 TI - Conjugation of fluorochromes to antibodies. PMID- 10098164 TI - Biotinylation of antibodies. PMID- 10098165 TI - Overview of cell fixatives and cell membrane permeants. PMID- 10098166 TI - Preparation of frozen sections for analysis. PMID- 10098167 TI - Processing of cytological specimens. PMID- 10098168 TI - Processing of tissue-culture cells. PMID- 10098169 TI - Processing of tissue specimens. PMID- 10098170 TI - Antigen retrieval for immunohistochemical reactions in routinely processed paraffin sections. PMID- 10098171 TI - Overview of fluorochromes. PMID- 10098172 TI - Direct immunofluorescent labeling of cells. PMID- 10098173 TI - Fluorescence labeling of surface antigens of attached or suspended tissue-culture cells. PMID- 10098174 TI - Fluorescence labeling of intracellular antigens of attached or suspended tissue culture cells. PMID- 10098175 TI - Fluorescent labeling of surface or intracellular antigens in whole-mounts. PMID- 10098176 TI - TUNEL assay for apoptotic cells. PMID- 10098177 TI - Overview of fluorescence analysis with the confocal microscope. PMID- 10098178 TI - Overview of laser microbeam applications as related to antibody targeting. PMID- 10098179 TI - Overview of fluorescence photomicrography. PMID- 10098180 TI - Overview of antigen detection through enzymatic activity. PMID- 10098181 TI - The peroxidase-antiperoxidase (PAP) method and other all-immunologic detection methods. PMID- 10098182 TI - The avidin-biotin complex (ABC) method and other avidin-biotin binding methods. PMID- 10098183 TI - Avidin-biotin labeling of cellular antigens in cryostat-sectioned tissue. PMID- 10098184 TI - Multiple antigen immunostaining procedures. PMID- 10098185 TI - ELISA on attachment-dependent or suspension grown cells. PMID- 10098186 TI - Use of immunogold with silver enhancement. PMID- 10098187 TI - Overview of flow cytometry and fluorescent probes for cytometry. PMID- 10098188 TI - Tissue disaggregation. PMID- 10098189 TI - Indirect immunofluorescent labeling of viable cells. PMID- 10098190 TI - Indirect immunofluorescent labeling of fixed cells. PMID- 10098191 TI - Fluorescent labeling of DNA. PMID- 10098192 TI - Deparaffinization and processing of pathologic material. PMID- 10098193 TI - Assay for phagocytosis. PMID- 10098194 TI - Assay for filamentous actin. PMID- 10098195 TI - Assay for chemoattractant binding. PMID- 10098196 TI - Assay for oxidative metabolism. PMID- 10098197 TI - Fixation and embedding. PMID- 10098198 TI - Preparation of colloidal gold. PMID- 10098199 TI - Conjugation of colloidal gold to proteins. PMID- 10098200 TI - Colloidal gold/streptavidin methods. PMID- 10098201 TI - Pre-embedding labeling methods. PMID- 10098202 TI - Postembedding labeling methods. PMID- 10098203 TI - Overview of in situ hybridization. PMID- 10098204 TI - In situ hybridization to human chromosomes of an alkaline phosphatase-labeled centromeric probe. PMID- 10098205 TI - Fluorescence in situ hybridization using whole chromosome library probes. PMID- 10098206 TI - In situ RT-PCR and hybridization techniques. PMID- 10098207 TI - Overview of the clinical immunohistochemistry laboratory: regulations and troubleshooting guidelines. PMID- 10098208 TI - Overview of immunocytochemical approaches to the differential diagnosis of tumors. PMID- 10098209 TI - Overview of automated immunostainers. PMID- 10098211 TI - [Preparation of unilamellar fusogenic liposomes using the Sendai virus]. AB - We describe a method to prepare unilamellar fusogenic liposomes (FL) that can deliver their content directly into tissue cells and cancer cells of living animals as well as into cultured animal cells. The method consists of three important steps: 1) preparation of unilamellar liposomes encapsulating the molecules to be delivered: 2) preparation of the Sendai virus using fertilized chicken eggs; and 3) preparation of FLs by fusing UV-inactivated Sendai virus particles and naked liposomes. Purified FLs are stable at 4 degrees C for 3 weeks and can be stored indefinitely below -70 degrees C without loss of activity. The FL-mediated delivery is applicable to cells originating from various tissues, including those of humans, monkeys, cows, dogs, mice, rats, hamsters, and rabbits. However, human primary T cells primary B cells, and B cell lines are not susceptible to delivery. FLs are best suited to an examination of the biological activity of cytokines in the tissue cells of living animals. We also describe the possibility of developing FL-based hybrid vectors, which would mimic the functions of viruses and chromosomes. PMID- 10098210 TI - [Paracrine regulation of renal hemodynamics]. AB - There has been an intense interest in multiple interacting paracrine systems that influence renal hemodynamics. The contractile responses at different sites along the renal vascular network exhibit distinct characteristics, depending on their receptor populations or activation mechanisms. These differences in effector mechanisms have also coupled with variations in paracrine signals from adjoining endothelial and epithelial cells. In this review, we have focused on the roles of nitric oxide (NO) and adenosine in the regulation of renal microvasculature and how they interact with other vasoactive factors. Vasopressin (VP) V2 receptors as well as V1 receptors exist in renal vasculature, especially in afferent arterioles, and V2-receptor stimulation induced vasodilation. V2-receptor mediated vasodilation was attenuated by L-NNA. In addition, Ang II did not affect the diameter of isolated rabbit afferent arterioles, but after the treatment of L NNA, Ang II exerted a dose-dependent vasoconstriction. Thus, NO modulated the renal vascular actions of VP and Ang II. Adenosine causes vasoconstriction via the A1 receptors, which are restricted primarily to the afferent arterioles. This selective action of adenosine suggests that adenosine exerts selective control of the renal vasculature. Adenosine augmented renal vasoconstriction by NE and Ang II via the adenosine A1 receptor, and the A1 receptor antagonist significantly reduced NE- or Ang II-induced renal vasoconstriction. The plurality of these interactions indicates that while it is very important to understand the specific direct cellular actions of each individual factor, it is equally important to understand how the various interactions are orchestrated under in vivo conditions. PMID- 10098212 TI - [A method for the assay of histidine decarboxylase activity]. AB - The histamine-forming enzyme histidine decarboxylase (HDC) is induced in various tissues of mice in response to various physiological or inflammatory stimuli including stress, physical exercise, proinflammatory cytokines and hematopoietic cytokines. The induction of HDC also occurs in mast cell-deficient mice. The newly formed histamine produced through the induction of HDC diffuses away from its site of formation without being stored. Therefore, in addition to the release of histamine from mast cells or basophils, the induction of HDC is an important alternative mechanism for supplying histamine. Studies on the newly formed histamine may clarify new physiological or pathological roles of histamine. Here, we introduce a method that we devised for the simultaneous assay of HDC activity of many samples taken from mice. This method is based on (i) a simple method for the preparation of histamine-free enzyme solutions and (ii) a simple manual method for the separation of histamine formed in reaction mixtures containing HDC. PMID- 10098213 TI - [Effect of KW-8232 on bone turnover in ovariectomized rats]. AB - The effects of 3-[bis(4-hydroxyphenyl)methyl]-2-[4-(2-chlorophenyl)- piperazin-1 ylcarbonyl]-1-(2-dimethylamino ethyl) indole methanesulfonate (KW-8232) on the bone turnover in ovariectomized (OVX) rats were studied by the oral administration for 6 weeks. KW-8232 inhibited the decreased bone mineral densities of the femur and tibia in OVX rats. OVX induced the increase of serum alkaline phosphatase and osteocalcin levels, markers of high bone turnover, and also increased urinary hydroxyproline, pyridinoline and deoxypyridinoline excretion, markers of bone resorption. KW-8232 significantly inhibited the increase of serum alkaline phosphatase level at doses of 10 and 30 mg/kg and the increase of osteocalcin level at a dose of 3 mg/kg. KW-8232 (1 mg/kg) markedly suppressed the OVX-induced increase of urinary hydroxyproline, pyridinoline and deoxypyridinoline excretion. KW-8232 didn't affect serum calcium level, but significantly decreased urinary calcium excretion at doses of 10 and 30 mg/kg. These results suggest that KW-8232 decreased bone loss in this model by suppressing bone resorption. PMID- 10098214 TI - [Protective effects of teprenone and gefarnate against taurocholate/hydrochloric acid-induced acute gastric mucosal lesions in rats]. AB - To evaluate the effects of teprenone on acute gastritis, its inhibitory effects on gastric mucosal damage were compared to that of gefarnate in taurocholate/hydrochloric acid-induced acute gastric mucosal lesions in rats. After oral administration of 160 mM taurocholic acid and 250 mM hydrochloric acid, hemorrhage and erosion were macroscopically observed in the gastric mucosal surface layer. Edema in the submucosal tissue and decreased PAS staining in the mucosa were histomorphologically observed. Concerning macroscopic findings, pretreatment with teprenone at a dose of 50 mg/kg or more significantly reduced pathological changes in the mucosa of the fundic glandular area. However, gefarnate slightly inhibited these changes in at a dose of 50 mg/kg and significantly inhibited them at a dose of 200 mg/kg. With regards to histomorphological findings in the fundic glandular area, teprenone slightly inhibited erosion at a dose of 50 mg/kg, and it significantly and slightly inhibited the decrease in PAS staining in this area at doses of 50 and 200 mg/kg, respectively. Gefarnate at doses of 50 and 200 mg/kg showed significant inhibition of decreased PAS staining in the fundic glandular area. In the pyloric mucosa, decreased PAS staining was slightly inhibited by teprenone at both doses but not by gefarnate at either dose. The differences between teprenone and gefarnate observed in this model appear to be due to their differences in mucus production ability. These results suggest that teprenone was more effective than gefarnate for the treatment of gastritis. PMID- 10098215 TI - A quantitative method for the detection of edges in noisy time-series. AB - A modification of the edge detector of Chung & Kennedy is proposed in which the output provides confidence limits for the presence or absence of sharp edges (steps) in the input waveform. Their switching method with forward and backward averaging windows is retained, but the output approximates an ideal output function equal to the difference in these averages divided by the standard deviation of the noise. Steps are associated with peak output above a pre-set threshold. Formulae for the efficiency and reliability of this ideal detector are derived for input waveforms with Gaussian white noise and sharp edges, and serve as benchmarks for the switching edge detector. Efficiency is kept high if the threshold is a fixed fraction of the step size of interest relative to noise, and reliability is improved by increasing the window width W to reduce false output. For different steps sizes D, the window width for fixed efficiency and reliability scales as 1/D2. Versions with weighted averaging (flat, ramp, triangular) or median averaging but the same window width perform similarly. Binned above-threshold output is used to predict the locations and signs of detected steps, and simulations show that efficiency and reliability are close to ideal. Location times are accurate to order square root of W. Short pulses generate reduced output if the number of data points in the pulse is less than W. They are optimally detected by choosing W as above and collecting data at a rate such that the pulse contains approximately W data points. A Fortran program is supplied. PMID- 10098216 TI - Model scenarios for evolution of the eukaryotic cell cycle. AB - Progress through the division cycle of present day eukaryotic cells is controlled by a complex network consisting of (i) cyclin-dependent kinases (CDKs) and their associated cyclins, (ii) kinases and phosphatases that regulate CDK activity, and (iii) stoichiometric inhibitors that sequester cyclin-CDK dimers. Presumably regulation of cell division in the earliest ancestors of eukaryotes was a considerably simpler affair. Nasmyth (1995) recently proposed a mechanism for control of a putative, primordial, eukaryotic cell cycle, based on antagonistic interactions between a cyclin-CDK and the anaphase promoting complex (APC) that labels the cyclin subunit for proteolysis. We recast this idea in mathematical form and show that the model exhibits hysteretic behaviour between alternative steady states: a Gl-like state (APC on, CDK activity low, DNA unreplicated and replication complexes assembled) and an S/M-like state (APC off, CDK activity high, DNA replicated and replication complexes disassembled). In our model, the transition from G1 to S/M ('Start') is driven by cell growth, and the reverse transition ('Finish') is driven by completion of DNA synthesis and proper alignment of chromosomes on the metaphase plate. This simple and effective mechanism for coupling growth and division and for accurately copying and partitioning a genome consisting of numerous chromosomes, each with multiple origins of replication, could represent the core of the eukaryotic cell cycle. Furthermore, we show how other controls could be added to this core and speculate on the reasons why stoichiometric inhibitors and CDK inhibitory phosphorylation might have been appended to the primitive alternation between cyclin accumulation and degradation. PMID- 10098217 TI - Possible role of neuropeptides in obsessive compulsive disorder. AB - The most consistent finding in clinical research of obsessive compulsive disorder (OCD) is the significant treatment advantage of potent serotonin uptake inhibitors (SUIs) over other classes of antidepressant and antianxiety drugs. Clinical neurobiological studies of OCD, however, have yielded limited and inconsistent evidence for significant fundamental abnormalities in monoamine systems including serotonin, norepinephrine and dopamine. Furthermore, one-third to one-half of OCD patients do not experience a clinically meaningful improvement with SUI treatment. Investigation beyond the monoamine systems may be necessary in order to more fully understand the pathophysiology of obsessive-compulsive symptoms and develop improved treatments. Evidence from preclinical studies suggests that neuropeptides may have important influences on memory acquisition, maintenance and retrieval; grooming, maternal, sexual and aggressive behavior; fixed action patterns; and stereotyped behavior; these phenomena may relate to some features of OCD. In addition, extensive interactions have been identified in the brain between neuropeptidergic and monoaminergic systems, including co localization among specific populations of neurons. The purpose of this review is to present the current knowledge of the role of neuropeptides in the clinical neurobiology of children, adolescents and adults with OCD focusing primarily on results from pharmacological challenge and cerebrospinal fluid studies. Where evidence exists, developmentally regulated differences in neuropeptide function between children and adolescents versus adults with OCD will be emphasized; these data are intended to underscore the potential importance of establishing the age of symptom onset (childhood versus adult) in individual patients with OCD participating in clinical neurobiological investigations. Likewise, where information is available, differences in measures of neuropeptides between patients with non-tic-related OCD versus tic-related OCD will be highlighted; these data will demonstrate the critical value of diagnostic precision, as these two particular subtypes of OCD may have different neurochemical underpinnings. PMID- 10098218 TI - 1998 Curt P. Richter Award. Brain mechanisms in cytokine-induced anorexia. AB - Our research focuses on the mechanisms underlying cytokine action in the central nervous system (CNS) using an integrative and multidisciplinary strategy organized through supracellular (behavioral analysis by computerized monitoring systems), cellular (extracellular and intracellular neurophysiological recording), and molecular (patch-clamp recording, and DNA, RNA and protein analyses) approaches. An integrative strategy that combines computerized meal pattern analyses with cellular and molecular biology approaches allows the study of underlying brain mechanisms in cytokine- and disease-associated anorexia. This paper presents a comprehensive discussion of our laboratory's previously published data on brain mechanisms involved in cytokine-induced anorexia including the relevance of meal pattern analysis (meal size, meal duration, meal frequency, intermeal intervals), modulation of hypothalamic neuronal activity, molecular processes involving ionic conductances, cytokine-cytokine and cytokine peptide interactions, and modulation of cytokine and peptide/neuropeptide system components (ligands, endogenous inhibitors, receptor subtypes, signal transduction molecules, intracellular mediators) and cytokine feedback systems. PMID- 10098219 TI - 1998 Curt P. Richter Award. The effect of hormone replacement therapy on cognitive function in elderly women. AB - Although evidence seems to indicate favorable effects of hormone replacement therapy (HRT) on cognitive functions and mood in elderly healthy and demented women, some questions remain. For instance, the nature of the long term effect of HRT, e.g. in preventing cognitive decline is still unclear. In this respect, the addition of progestagens in combined HRT has been mentioned to oppose some of the beneficial effects of estrogens. The present paper aims to illuminate these questions and presents two studies. In the first study, the long term effects of combined HRT in healthy postmenopausal women was investigated using a parallel groups (HRT-users vs. controls) design. HRT subjects were always tested during the estrogen-progestagen phase. Results indicated that after 6 and 12 months, women in the HRT-treatment group had higher scores on several indicators of the subjective feeling of well being (sleep, physical and psychological complaints) than matched controls, although at baseline both groups were not severely impaired. Effects of HRT on memory functions were seen when HRT treated subjects were compared with their own baseline functioning, but not when compared with controls. Hence, the addition of progestagen did not oppose the effects of estrogens on subjective feelings of well being or on memory. Our second (case control) study involved women of middle-age who were unaware of the purpose of the experiment. No positive effects of HRT use on subjective scales of well being or on memory were found. However, women with HRT were faster on basic sensorimotor speed tasks as compared with controls. It should be kept in mind that double blind testing in an experimental study is difficult due to withdrawal bleeding and the reduction of flushes. Expectancy effects may have confounded the results of the first study. However, our findings indicate that the use of a particular design and type of memory test can explain the controversial results of studies into the effect of HRT on cognitive function. Furthermore, it was concluded that HRT has a global activating, instead of specific direct effect on cognitive functions. PMID- 10098220 TI - Pregnancy, the postpartum, and steroid hormones: effects on cognition and mood. AB - The effects of pregnancy on cognition and mood were examined using a repeated measures design. Nineteen women, average age 33, were tested with a comprehensive neuropsychological battery during their last 2 months of pregnancy and again within 2 months of delivery. Blood samples were obtained from all subjects and assayed for a variety of steroid hormones implicated in cognitive and mood functioning. Most participants also completed several self-report measures of mood. In comparison with performance after delivery, women showed significantly more impairment in aspects of verbal memory during pregnancy and also tended to report more negative mood states. Memory deficits were not explained by mood disturbances. No hormone assayed consistently related to cognitive performance during pregnancy. During pregnancy, higher levels of progesterone (P) were associated with greater mood disturbances and higher levels of dehydroepiandrosterone (DHEA) with better mood. After delivery, testosterone (T) was strongly and consistently associated with greater reported mood disturbances. Our results confirm a peripartal memory deficit, which cannot be explained by the dramatic rise in circulating steroid hormones, or by mood status during pregnancy. Steroidal hormones, namely P, DHEA and T, appear to play a role in mood disturbances during, and after, pregnancy. Studies beginning earlier in pregnancy and continuing for an extended period of time after delivery are needed to confirm and expand these observations. PMID- 10098221 TI - Evidence for attenuation of gonadotropin pulse frequency in hypergonadotropic women with estradiol secretion in the menopausal transition. AB - To investigate neuroendocrine interventions for climacteric symptoms in peri- and post-menopausal periods, the association between endocrine status and symptoms was examined in 519 peri- and post-menopausal women with climacteric symptoms. Furthermore, we evaluated the nature of putative disturbances in pulsatile gonadotropin (FSH and LH) secretion in 14 hypergonadotropic women with estradiol secretion and 16 hypergonadotropic women with hypoestrinism. We observed that 68.6% (356/519) of women with climacteric symptoms and 49.2% (121/246) of women in good health showed hypergonadotropinemia, and that 39.3% (140/356) of hypergonadotropic women with climacteric symptoms and 23.1% (28/121) of healthy women (controls) showed estradiol secretion (p < .002). In particular, the endocrinological profile of hypergonadotropinemia with estradiol secretion was observed in 67.1% (60/92) of pre-menopausal women with climacteric symptoms, approximately 2 x higher than that in healthy women (p < .005). Mental symptoms were observed at a significantly higher incidence in women with the endocrinological profile of hypergonadotropinemia with estradiol secretion compared with that in women with hypergonadotropic hypoestrinism showing a symptomatic profile, namely 25.0 versus 6.9% for mood lability (p < .001), and 21.4 versus 9.3% for anxiety symptoms (p < .001). Moreover, in vivo FSH and LH pulse frequencies were observed in only 14.3 and 18.6% of women with hypergonadotropinemia with estradiol secretion whereas such pulses were observed in all women with hypergonadotropic hypoestrinism. We also observed FSH and LH pulse frequencies in hypergonadotropinemia with estradiol secretion 0.14 +/- 0.35 and 0.29 +/- 0.45/3 h, respectively compared with those in hypergonadotropinemia without estradiol secretion 2.25 +/- 0.91 and 2.81 +/- 0.73/3 h, respectively (p < .001). Such findings are considered to be consistent with diminished hypothalamic GnRH impulse strength. In summary, we infer that decreased pulse frequencies in FSH and LH secretion are due to decreased hypothalamic GnRH impulse strength in women with the endocrinological profile of hypergonadotropinemia with estradiol secretion. As the potential mechanisms of this finding, it should be considered that specific endocrine environments damage the pulse generator mechanism in the diencephalon, and that changes occur in the pituitary responsiveness to GnRH (changes in receptor function). PMID- 10098222 TI - Influence of acute tryptophan depletion on mood and immune measures in healthy males. AB - Depressive illness has been associated with variations of several aspects of immune functioning, as well as alterations of cytokine production in stimulated lymphocytes. In the present investigation we sought to determine whether pharmacologically-induced reductions of mood in healthy, male subjects would be associated with alterations in the levels of circulating IL-1 beta or IL-6 or to in vitro lymphocyte proliferation in response to T cell mitogens, PHA and Con A. Lowering tryptophan levels by means of a tryptophan-deficient amino acid mixture, which reduced plasma tryptophan and serotonin (5-HT) levels, produced a lowering of mood in a subset of male subjects (that had no personal or family history of depression) relative to subjects that received a balanced amino acid mixture. Correlational analyses revealed that the change of mood (particularly depression and anger) in subjects that received the tryptophan-free mixture was related to the extent of the tryptophan or 5-HT reductions. However, while fenfluramine administration resulted in recovery of tryptophan and 5-HT levels, this was not accompanied by recovery of mood. Furthermore, it was observed that the lowering of tryptophan levels and the reduced mood were not accompanied by variations of the cytokine levels or cell proliferation. Evidently, transient and modest alterations of 5-HT or mood induced by a tryptophan-free amino acid mixture were insufficient to promote variations of immune activity or circulating IL-1 beta or IL-6 levels. Even if depression were related to immune disturbances, the mood and 5-HT alterations associated with this type of manipulation may be too brief to promote immune changes comparable with those ordinarily associated with severe or chronic depressive illness. PMID- 10098224 TI - Congenital heart disease: six decades of progress. AB - Congenital heart malformations occur in approximately 1 in 100 live births. Since Robert Gross successfully ligated a persistent ductus arteriosus 60 years ago, there has been enormous progress in the surgical management of even the most complex lesions. More recently, the interventional cardiologist armed with balloons, stents, coils, umbrellas, and laser beams is providing an alternative to surgery for many lesions. Echocardiography combined with Doppler studies is now the most informative diagnostic modality, and its usefulness is being expanded by transesophageal studies. Magnetic resonance imaging is helpful for some lesions not well visualized on echo. Some complex lesions continue to challenge caregivers, especially the hypoplastic left heart syndrome and several variants of pulmonary atresia. Neurological complications in patients with congenital heart disease are not uncommon and are the main theme of this issue. PMID- 10098223 TI - Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. AB - Raloxifene hydrochloride (HCl) is a selective estrogen receptor modulator with estrogen agonist effects on bone and lipid metabolism and estrogen antagonist effects on reproductive tissues. Animal studies suggest that raloxifene may affect brain function as well, although the effects of raloxifene on the human brain remain to be established. This paper presents an early safety assessment of raloxifene effects on cognition and mood in postmenopausal women participating in a randomized, double-blind osteoporosis treatment trial. Psychometric test batteries were administered to postmenopausal women at baseline and 1, 6, and 12 months after initiating treatment with raloxifene (60 and 120 mg/day). The Memory Assessment Clinics (MAC) battery and Walter Reed Performance Assessment Battery (PAB) were used to assess multiple and independent aspects of cognitive function, while mood was assessed with the Geriatric Depression Scale (GDS). After 12 months of treatment, there were no significant differences between the raloxifene groups and placebo on performance in either the MAC battery or the PAB. The only significant difference observed was a slight increase in performance favoring the raloxifene 120 mg/day group in an assessment of verbal memory on the MAC battery after 1 month of treatment. Scores on the GDS and the self-reported incidence of mood-related events were not different between treatment groups at any of the assessment periods. These data do not suggest that raloxifene impairs cognition or affects mood in postmenopausal women treated for 1 year. Studies to further assess the safety and potential efficacy of raloxifene with respect to cognitive function are ongoing. PMID- 10098225 TI - Developmental progress of children with congenital heart defects requiring open heart surgery. AB - Recent advances for infants requiring early open heart surgery have resulted in a dramatic decline in mortality and severe morbidity. The developmental progress of these new survivors is currently being defined. Causes contributing to brain injury are multifactorial, and may involve preoperative, intraoperative, and postoperative events. Before surgery, these children often exhibit hypotonia, poor state regulation, microcephaly, and developmental delays. These findings are particularly prevalent in newborns. In the acute postoperative period, neurodevelopmental deficits continue to manifest clinically. Long-term follow-up studies indicate that subtle neurological deficits and global developmental lags are characteristic of this population. Overall, severe neurological sequelae are uncommon; however, mild to moderate developmental disabilities are prevalent. Functional limitations, academic achievements, and health-related quality of life are areas that deserve further attention. PMID- 10098226 TI - Structural evidence of injury or malformation in the brains of children with congenital heart disease. AB - Neurological and developmental deficits are common in children with congenital heart disease (CHD). These are due to multiple factors that include the etiology of the CHD, the effects of abnormal cardiovascular function, and the possible sequelae of open heart surgery. CHD is frequently part of a multiple malformation syndrome that includes the brain. The causes of these syndromes include known or putative genetic defects. Abnormal cardiovascular function may be associated with poor brain growth, embolic infarction, cerebrovascular thrombosis, and abscess formation. Perioperative neurological complications include diffuse hypoxic ischemic injury (particularly in neonates who undergo more than 45 to 60 minutes of hypothermic circulatory arrest), cerebral macro- and micro-emboli, dural sinus thrombosis, and cerebral hemorrhage. Neuroimaging, especially magnetic resonance imaging, is a useful prognostic instrument, can easily display gross congenital and acquired lesions, and should be performed preoperatively in addition to genetic studies. In some instances poor brain function may not be predicted unless slow head growth or microcephaly is present and thorough preoperative neurodevelopmental evaluation is encouraged. PMID- 10098227 TI - Monitoring the central nervous system in children with congenital heart defects: clinical neurophysiological techniques. AB - The neurological sequelae following surgery for complex cardiac malformations is being increasingly recognized. The electroencephalogram (EEG) and evoked potentials may be used as monitors of neurological integrity. Criteria for a successful intensive care unit monitoring system have been proposed. EEG findings in the preoperative, perioperative, and postoperative periods are reviewed and may aid in the prediction of neurological sequelae. Recent advances in the development of a computerized neurophysiological monitor at the Montreal Children's Hospital are reviewed. Evoked potentials, auditory, somatosensory, and visual can be used to monitor children with complex cardiac lesions and evaluate them for potential neurological sequelae. PMID- 10098229 TI - Experimental models of hypothermic circulatory arrest. AB - This article reviews information obtained from experimental models of hypothermic circulatory arrest, which models have been developed in our and other laboratories over the past several years. The described experiments clearly demonstrate an ability to produce and completely reverse hypothermic circulatory arrest in newborn and developing animals, allowing for a comprehensive evaluation of those physiological variables and therapeutic interventions that would potentially reduce or accentuate ischemic brain damage. Further experiments will allow for a determination of whether or not specific modalities of therapy will reverse secondary systemic complications, thereby allowing for more complete recoverability and ultimately reduced brain damage. PMID- 10098228 TI - Mechanisms of brain injury during infant cardiac surgery. AB - Neurological injury is a major and often debilitating complication of congenital heart disease and open-heart surgery. Paradoxically, the full impact of this complication has been underscored by the marked decrease in mortality and the rescue of infants with desperate and previously lethal heart conditions. Although recent focus has been on mechanisms of brain injury originating during open-heart surgery, this article also emphasizes the importance of mechanisms initiated or perpetuated during the preoperative and postoperative periods. In addition to the usually implicated mechanism of hypoxia-ischemia, recent genetic advances suggest an important role for genetic deletion syndromes. Inflammatory cascades have been implicated in the end-organ injury seen after cardiopulmonary bypass and might play a role in neurological dysfunction. These mechanisms are reviewed, with an emphasis on recent developments in our understanding of brain injury in this population. PMID- 10098230 TI - The pursuit of effective neuroprotection during infant cardiac surgery. AB - Advances in infant cardiac surgery have resulted in a dramatic decline in mortality rates; however, neurological morbidity remains an important concern. The effectiveness of a number of interventional strategies to prevent or minimize brain injury during open heart surgery are currently being investigated. This article provides an overview of two approaches: (1) interventions to enhance intraoperative cerebral oxygenation so as to prevent hypoxic-ischemic insults, and (2) the application of cerebral rescue therapies to attenuate the cascade of brain injury. Infant cardiac surgery provides a controlled environment in which to apply these neuroprotective approaches, so as to optimize the quality of life of these vulnerable children. PMID- 10098231 TI - The role of the pediatric neurologist in the management of children with congenital heart defects: a commentary. AB - Central nervous system integrity is the major extracardiac determinant of the quality of life for children with congenital heart disease. As the specialist in the evaluation of the pediatric nervous system, the child neurologist has particular skills and expertise to offer the interdisciplinary team responsible for the management of this clinical entity. This article highlights the ways in which the child neurologist can make a difference in congenital heart disease. PMID- 10098232 TI - Ratite production as an agricultural enterprise. AB - The ratite industry remains in the market introduction stage of evolution; basic information on markets and production is limited. It is uncertain when, or perhaps whether, either the ostrich or emu industries will progress to the market growth stage. Until significant expansion occurs, ratite operations are likely to be faced with low or even nonexistant profits. It is the authors' observation that the ostrich industry is making slow but significant progress toward introducing products into potential growth markets. The fact that ostrich products were in demand prior to the ostrich being introduced into North America has helped the industry. The future of the emu industry appears to be much less certain. In the authors' opinion, in order for the emu industry to become profitable and grow, significant promotion of emu meat and immediate resolution of the value of the oil must be achieved. Meat sales alone will not carry emu production as a profitable commercial enterprise. Veterinarians can derive significant conclusions from this information. Currently, ratite production is composed of firms generating losses or minimal profits. South African producers are receiving approximately the same amount for a slaughter ostrich as North American producers. It is unlikely that North American ostrich prices will increase significantly. Prices of ostrich breeders of $2,000 to $4,000 per pair and $400 to $450 for slaughter birds are likely to remain the same for some time. Given that world demand has increased at a slower rate than supply, prices may decrease further. Breeder and slaughter birds will continue to require significant veterinary care; however, the producer will be forced to perform more farm treatments, given the negligible margins. Based on the differences in efficiency of existing operations, there are ample opportunities for veterinarians and extension services to assist producers. Vertical coordination in the ratite industry may evolve slowly in the future, especially in the arid regions of the country; however, economies of size in ratite slaughter are likely to remain uncaptured in the short run, limiting the rate at which vertical coordination evolves. If significant opportunities develop for veterinarians in vertically integrated ratite firms, the emphasis, as with other intensive livestock operations, will be preventative rather than therapeutic medicine, and will involve the integration of nutrition, management, genetics, and the control of disease. PMID- 10098233 TI - Restraint and housing of ratites. AB - Large animal practitioners are called upon to assist producers to prevent and control disease and to manage flocks. The concerns that exist in traditional livestock and poultry management are also applicable to ratites. Adequate ventilation, shelter, and space allocation are the foundations of flock health. Practitioners need to know how to handle ratites in order to perform a through physical examination and collect diagnostic samples. PMID- 10098234 TI - Health examinations and clinical diagnostic procedures of ratites. AB - It is important to remember when performing health examinations and clinical diagnostic procedures on ratites that all protocols mentioned in this article should be followed; this includes reviewing history, environmental evaluation, proper handling, complete hands-on physical examination, diagnostic testing, and postmortem examination. The individual ratite examination is becoming rare, but veterinarians and producers must remember that individual birds make up the flock. Flock health is maintained by diagnosing disease and health problems early in the most susceptible animals. The most successful producers will use veterinarians as a major element to their management program to raise the most desirable birds for the future of the industry. PMID- 10098235 TI - Ratite diagnostic imaging. AB - Diagnostic imaging of ratite species is a challenge, even to the specialist. A portable radiography unit is frequently inadequate to penetrate the coelomic cavity of large birds, but should provide diagnostic quality radiographs of the extremities. Ultrasonography allows visualization of the coelomic structures, but will not penetrate gas or air. Use of both technologies often provides diagnostic information helpful to the clinician. PMID- 10098236 TI - Ratite reproduction. AB - The role of the veterinarian in ostrich production in the future will be to develop least-cost management programs. This article focuses on the ostrich as the only current commercially viable ratite species. Managing a successful ranch involves disease prevention, genetic selection, environmental management, and nutrition. PMID- 10098237 TI - Infectious diseases and parasites of ratites. AB - This article discusses infectious and parasitic disease conditions in the three ratite species. Diseases and parasitic conditions are reviewed in relation to etiology, transmission, pathology, diagnosis, treatment, and prevention. To ensure optimum reproduction and growth of birds on large production units, a veterinarian must understand management in relation to biosecurity and disease problems. PMID- 10098238 TI - Current ratite therapy. AB - This article describes the use of drugs and therapeutic techniques in the treatment of ratite diseases. Effective routes of administration are documented. Appropriate selection and dose regimens are provided for bacterial and parasitic conditions. This article includes empirical formularies for antibiotics and anthelmintics. Metabolic drug dosage and nutrient scaling for ratites are outlined. PMID- 10098239 TI - Anesthesia and surgery of ratites. AB - Veterinary practitioners should apply common principles of anesthesia and surgery used in domestic livestock to ratites. Routine procedures can be accomplished in the field or in a veterinary hospital, provided practitioners become familiar with response of ratites to sedation and anesthesia. PMID- 10098240 TI - Jurisprudence for ratite practitioners. AB - Veterinarians are frequently confronted with medico-legal issues relating to certification, malpractice and the responsibilities of owners and managers. This article reviews relevant principles to guide practitioners. PMID- 10098241 TI - United States food and drug laws and ratites as emerging food animals. AB - The ratite practitioner must balance the need to treat patients with the obligation to minimize the risk of drug residues. If a practitioner treats birds intended for market, the possibility of residues should be considered before administering therapeutic agents. Improved management practices can and will preclude the need in many instances for drug therapy. Practitioners should be aware of the conditions that must be met in order to justify extralabel use. When treating ratites intended for food, practitioners should comply with the documentation requirements listed in these regulations and be aware of the list of prohibited drugs. The Food Animal Residue Avoidance Databank (FARAD), at 1-888 US-FARAD (1-888-873-2723) or by electronic mail at farad@ucdavis.edu or farad@ncsu.edu, is a valuable source of information regarding residue avoidance. Emergence of ratites as food species should stimulate research to provide answers to questions concerning pharmacokinetics and tissue depletion in order to improve the quality of veterinary services for flock owners, to obtain approval for drugs for these species, and to provide information by which to establish appropriate withdrawal periods. PMID- 10098242 TI - Doppler echocardiography. I. Pulsed-wave and continuous-wave examinations. AB - Doppler echocardiography is a specialized processing of cardiac ultrasound that is characterized by a continuously updated display of blood velocity during the cardiac cycle. Doppler examinations, which include color-coded Doppler echocardiography, pulsed-wave examination, and continuous-wave studies, are readily applicable to veterinary patients. PMID- 10098243 TI - Doppler echocardiography. II. Color Doppler imaging. AB - Color Doppler imaging (CDI) is a sophisticated form of ultrasound technology that overlays blood flow and velocity information onto a B-mode, two-dimensional, gray scale image. This imaging technique--also called color Doppler echocardiography, color-coded Doppler, Doppler color-flow imaging, and color-flow imaging--is a type of pulsed-wave Doppler echocardiography. Because the anatomical site of received Doppler-shift information can be readily determined, CDI is useful for documenting normal blood flow patterns and screening the heart and great vessels for areas of abnormal flow. PMID- 10098244 TI - Holter monitoring and cardiac event recording. AB - The detection and characterization of transient arrhythmias is possible with continuous ambulatory electrocardiography (Holter monitoring) or cardiac event recording. These techniques have significantly increased our appreciation of transient arrhythmias, often undetected with routine echocardiography and have provided highly sensitive means to assess need and efficacy of antiarrhythmic therapy. Correlation of heart rate and arrhythmia with the patient's activity or clinical signs is also possible. PMID- 10098245 TI - Heart rate variability. AB - Heart rate variability (HRV), usually performed from 24 hour ambulatory ECG recordings, measures the variability of the heart rate. Alterations in autonomic balance and baroreceptor function, increased plasma norepinephrine levels, and reduced HRV have been associated with progressive myocardial failure. Not only has reduced HRV been associated with the degree of myocardial failure, possibility of prognostic significance, but also increased sudden death risk in both ischemic and nonischemic cardiomyopathy in humans. Heart rate variability analysis in the dog is confounded by pronounced sinus arrhythmia, and whether or not this technique has clinical utility in the dog remains to be demonstrated. PMID- 10098246 TI - High-resolution electrocardiography. AB - High-resolution electrocardiography, often referred to as signal averaged electrocardiography (SAECG), has clinical utility in human medicine for detecting ventricular late potentials (LP) as predictors of future arrhythmic events, specifically reentrant type of ventricular tachycardia (VT). Time-domain analysis of the SAECG is conceptually similar to standard ECG analysis, but the primary objective is to detect LP, the marker for reentrant pathways within the myocardium. Frequency-domain analysis is investigational but provides the same information as time-domain analysis and both methods of analysis have limitations. The presence of LP has been associated with the ability to induce VT, unexplained syncope, and sudden arrhythmic death. Some cardiomyopathic dogs with VT have SAECG that appear to contain LP, and sudden death has occurred in these dogs. PMID- 10098247 TI - Insights into the hereditability of canine cardiomyopathy. AB - There is evidence for a genetic etiology of dilated cardiomyopathy in at least two breeds, the Doberman pinscher and the Boxer dog. Significant effort toward determining a genetic etiology in these breeds will depend on careful characterization of the disease, determination of criteria for diagnosing asymptomatic affected individuals, determination of a pattern of inheritance, and, eventually, molecular evaluation of the specific gene. PMID- 10098248 TI - Therapy of feline hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common form of feline heart disease. Affected cats have concentrical or asymmetrical left ventricular hypertrophy without an identifiable cause. Although many diseases can cause concentrical left ventricular hypertrophy, the term hypertrophic cardiomyopathy is used here exclusively to refer to the idiopathic disease. PMID- 10098249 TI - Diagnosis and treatment of systemic hypertension. AB - Systemic hypertension is often observed in dogs and cats with chronic renal failure and other metabolic and endocrinological abnormalities. High systemic arterial blood pressure has been associated with chronic renal failure, ocular injury, neurologic complications, and cardiovascular changes. Recent advances in our knowledge of the prevalence and consequences of systemic hypertension dictate that proper diagnosis and treatment of this problem should become a component of routine therapy for many of our patients. PMID- 10098250 TI - The effectiveness of taurine and levocarnitine in dogs with heart disease. AB - In this article, the current state of knowledge of the potential role of taurine and L-carnitine deficiency and supplementation in the genesis and management of cardiovascular disease in dogs is presented. There is limited direct evidence to support the recommendations found in this article or elsewhere in the literature. The temptation to "do something" for our patients can be overwhelming. Whether it be the administration of drugs or prescribing nutraceuticals or prescription diets, the veterinarian should strongly consider the source of the information, the strength of the evidence presented, the financial costs to the owner, and the potential risks and benefits to the patient. PMID- 10098251 TI - Advances in antiarrhythmic therapy. AB - The therapy of cardiac arrhythmias in small animals can be confusing and challenging. This article reviews the current concepts of cardiac rhythm, including impulse generation, automaticity, and conduction in normal and diseased cardiac tissues. The mechanisms of arrhythmogenesis (abnormal automaticity and triggered events) and automatic modulation of cardiac arrhythmias are also discussed. Finally, a review of the clinical management of specific cardiac arrhythmias provides the practicing veterinarian with the current concepts of cardiac rhythm control. PMID- 10098252 TI - Clinical significance of feline heartworm disease. AB - The clinical signs and diagnostic approach are different in the cat as compared with the dog, which has impaired the veterinarian's ability to detect this parasite in the cat. New techniques and methodologies have enabled the cat owner and veterinarian to recognize this potentially severe disease. Although much is now known about the pathophysiology and biology of this parasite in the cat, the practical application and rapid development of this information to daily practice has led to confusion. PMID- 10098253 TI - Critical care cardiology. AB - Emergency management of the patient with cardiac disease is an important part of veterinary practice. Although the causes of cardiac disease may be diverse, the understanding of basic pathophysiology will enable the clinician to formulate a rational diagnostic and therapeutic plan. The veterinary clinician must be able to triage the emergency patient, assess the clinical condition, and provide appropriate therapy. Close monitoring of the critically ill patient is crucial to patient survival and will help tailor therapy. PMID- 10098254 TI - Multiplex amplification of mitochondrial DNA for human and species identification in forensic evaluation. AB - We describe a method combining in a single-round polymerase chain reaction amplifications of both cytochrome b and hypervariable D-loop mitochondrial DNA allowing species determination and individual human identification. Following the amplification step, amplicons are first screened on an agarose gel. The presence of only one band indicates that the sample is nonhuman, while the presence of two bands indicates a human origin. Subsequent DNA sequencing of the hypervariable D loop region DNA allows for individual human identification as the presence of cytochrome b fragment does not interfere with the analysis. Similarly, further species determination on the basis of the phylogenetically variable cytochrome b gene is possible by sequencing of the cytochrome b DNA fragment. PMID- 10098255 TI - Rectal temperature time of death nomogram: sudden change of ambient temperature. AB - Cooling experiments on dummies known as body-like cooling were performed with sudden decrease and increase of ambient temperature in the order of 15 degrees C. In the case of a sudden decrease of ambient temperature, a second 'temperature plateau' occurs which is shorter than the known plateau at the beginning of body cooling. The cooling curves can be described mathematically by a three-step procedure based on the two-exponential term of the 'nomogram method'. The second plateau at the beginning of the second cooling phase in sudden decreased ambient temperature requires a lower value of the constant A (1.15) compared with the known value (1.25) at the beginning of body cooling. In the case of a sudden increase of ambient temperature in the order of 15 degrees C no procedure could be found to model the cooling curves mathematically. PMID- 10098256 TI - A comparison of fatal with non-fatal knife injuries in Edinburgh. AB - Assault using a knife is a common problem in the United Kingdom. Between February 1992 and December 1996, 120 individuals died or received hospital treatment in Edinburgh after being assaulted with a knife. Twenty individuals (17%) died as a result of their injuries. Comparison of the survivors with non-survivors revealed both groups to have similar age and sex distributions, but those who died had significantly more severe injuries when scored according to the Abbreviated Injury Scale. Eight individuals died of unsurvivable chest injuries at the scene of the attack and of the remainder, only five reached hospital with signs of life. Analysis of hospital treatment using TRISS methodology revealed there to be two unexpected survivors and no unexpected deaths. The risk of death appears to depend mostly upon injuries sustained and also to a lesser extent upon other factors such as alcohol consumption and the presence of a bystander capable and willing to request emergency medical assistance. There does not appear to be much potential to save lives by improving hospital treatment for those assaulted with a knife in Edinburgh. Instead, greater focus needs to be placed upon rapid transfer to hospital and upon restricting the possession and use of knives. PMID- 10098257 TI - Evaluation of cardiac troponin I immunoreaction in autopsy hearts: a possible marker of early myocardial infarction. AB - Postmortem diagnosis of early myocardial infarctions is an ever recurrent problem in pathology. In the present study we determined the troponin I expression in 46 autopsy hearts using an immunohistochemical technique. Troponin I has, as a specific cardiac muscle protein, become a widespread used marker in testing patients with acute chest pain. The hearts were divided into three groups based on the macroscopical findings: definite signs of infarction, possible signs of infarction and no signs of infarction. All 14 cases of definite myocardial infarction showed a well-defined area with loss of troponin I. Twenty-three of 24 cases of possible myocardial infarction also showed a well-defined area with loss of troponin I. None of the eight non-cardiac death controls showed loss of troponin I expression. The results suggest troponin I expression as a sensitive test in diagnosis of early myocardial infarction. PMID- 10098258 TI - A sandwich enzyme immunoassay for human muscle-specific beta-enolase and its application for the determination of skeletal muscle injury. AB - A sensitive sandwich enzyme immunoassay for human beta-enolase was developed and used to examine beta-enolase in blood or bloodstains as a marker for the determination of skeletal muscle injury. Human beta-enolase was purified from human skeletal muscle, and then an antibody against it was prepared. Polystyrene balls coated with rabbit anti-human beta-enolase IgG were incubated with human beta-enolase and then with anti-human beta-enolase Fab'-peroxidase conjugate. Peroxidase activity bound to the polystyrene balls was assayed by fluorometry using 3-(4-hydroxyphenyl)propionic acid as a hydrogen donor. The detection limit for human beta-enolase was 2.6 pg (30 amol) per assay. The degree of cross reaction of the sandwich enzyme immunoassay for other organs except for heart (1/10) was about 1/150 or less. Moreover, the localization of beta-enolase in various human tissues was examined by Northern blot analysis, and this confirmed that beta-enolase was expressed only in skeletal and cardiac muscle. Antigenic activity in bloodstains containing beta-enolase was recovered well after storage for 60 days at room temperature. The ratio of beta-enolase to total protein in bloodstains made from non-traumatic blood, nasal hemorrhage and menstrual blood, was within the normal range. In contrast, the ratio of beta-enolase in bloodstains from traumatic blood was obviously elevated (10-30 fold) in comparison with non-traumatic blood. Furthermore, the ratio of beta-enolase was proved to be higher in stains adhering to weapons that had passed through skeletal muscle, indicating that detection of beta-enolase in bloodstains could be used to distinguish crime weapons. These results suggest that beta-enolase is a useful marker for identification of skeletal muscle injury as well as for detecting the origin of bleeding. PMID- 10098259 TI - Fatal poisoning with alcohol and drugs in the Greater Amman County. AB - A study of fatal poisoning due to alcohol and drugs was carried out, to examine the mortality resulting from alcohol and drugs in the Greater Amman County, Jordan. A retrospective review of all autopsy records and certified deaths issued by the Department of Forensic Medicine at Jordan University Hospital in the greater Amman county was undertaken. During the 18 years (1978-1996) 6109 postmortem cases were performed in our department. A total of 60 cases were identified and analyzed according to age, race, sex, manner of death of the victims along with blood alcohol concentration, the drug detected at autopsies, the scene circumstances, and the geographic location of the accident and death. PMID- 10098260 TI - A chemical and physicochemical study of an Egyptian mummy 'Iset Iri Hetes' from the Ptolemaic period III-I B.C. AB - Chemical and physicochemical examinations of the fragments of an Egyptian mummy dated between the 3rd and 1st century B.C. were performed. The chemical examinations indicated the presence of resin in the skull and in the fragments of bandages wrapped around the mummy. An analysis of the infrared spectra of the fragments indicated a type of resin originating from the Copal group. Physicochemical investigations showed that main chemical elements such as Ca, Mg, Na, K, P and trace chemical elements such as Fe, Zn, Cu, and Pb occurred in bone fragments in proportions typical for people living today. In tooth fragments, values were similar to normal except for K, P, and Zn, which were lower, and Pb, which was absent. In the fingernails, most elements were found in much higher concentrations except for Cu and Pb, which were lower. The results of the study in terms of their implications on mummification are discussed. PMID- 10098261 TI - A serological and histological study of the Egyptian mummy 'Iset Iri Hetes' from the Ptolemaic period III-I B.C. AB - Serological and histological examinations of the muscles of the calf of an Egyptian mummy dated between the third and first centuries B.C. were performed. Human protein was identified, the ABO phenotype was determined as type B, and morphological disruption of the cells was observed. PMID- 10098262 TI - Indirect measures of gene flow and migration: FST not equal to 1/(4Nm + 1). AB - The difficulty of directly measuring gene flow has lead to the common use of indirect measures extrapolated from genetic frequency data. These measures are variants of FST, a standardized measure of the genetic variance among populations, and are used to solve for Nm, the number of migrants successfully entering a population per generation. Unfortunately, the mathematical model underlying this translation makes many biologically unrealistic assumptions; real populations are very likely to violate these assumptions, such that there is often limited quantitative information to be gained about dispersal from using gene frequency data. While studies of genetic structure per se are often worthwhile, and FST is an excellent measure of the extent of this population structure, it is rare that FST can be translated into an accurate estimate of Nm. PMID- 10098263 TI - Confirmed quantitative trait loci for fatness and growth on pig chromosome 4. AB - Quantitative trait loci (QTLs) with large effects on fatness and growth have been identified previously on pig chromosome 4 in an intercross between the European wild pig and Large White domestic pigs. Two F2 sows, heterozygous for the actual chromosome region, were backcrossed to a Large White boar, and two backcross (BC1) boars were in turn backcrossed to Large White/Landrace sows. One of the boars was heterozygous for an intact wild pig-derived QTL region, whereas the other carried a recombinant haplotype. A total of 85 BC2 animals were produced. Phenotypical measurements included daily weight gain, ultrasonic measurements of fat depth at 70 and 90 kg and several carcass traits. QTL segregation was deduced using 15 markers previously assigned to chromosome 4. Highly significant QTL effects were observed on all fatness traits and on the length of the carcass. A small but significant effect on growth was also observed. The results confirm the presence of one or more QTLs on chromosome 4 affecting fatness and growth. There was a good agreement between the estimates of QTL effects in the F2 and BC2 generations. The results from the recombinant sire family allowed us to map the major QTL effect distal to the recombination breakpoint. We propose that this confirmed QTL with a major effect on fatness is designated FAT1. PMID- 10098264 TI - Is the heritability for courtship and mating speed in Drosophila (fruit fly) low? AB - Empirical studies indicate that heritable variation for courtship behaviour in Drosophila is often not detectable, whereas mating speed has a low heritability. These patterns have been used to make inferences about the association between mating behaviours and fitness. However, mating behaviours have been scored as single events, which can lead to underestimates of heritability values relevant to the lifetime fitness of an organism. To test this, repeated measurements on the same individuals were undertaken for time to courtship and mating in Drosophila melanogaster in both parental and offspring generations. Although there was no detectable heritable variation for both traits when parent-offspring comparisons were based on single events, heritabilities were significant and intermediate when the behaviour of each individual was averaged over several events. Estimates for mating behaviours relevant to the fitness of organisms are therefore much higher than indicated by single-event experiments. PMID- 10098265 TI - Cross-order transfer of Wolbachia from Muscidifurax uniraptor (Hymenoptera: Pteromalidae) to Drosophila simulans (Diptera: Drosophilidae). AB - Bacteria of the genus Wolbachia are widespread in arthropods and can induce different effects on the host such as cytoplasmic incompatibility (CI), thelytoky (T) or feminization (F). In some Wolbachia-infected hosts, no effect (N) has been found. Successful transfer of Wolbachia by microinjection from one host to an uninfected one has been established with CI, F, N-Wolbachia but not with T Wolbachia. In this paper a transfer experiment of T-Wolbachia from the parasitoid Muscidifurax uniraptor to Drosophila simulans is described. The infection could be detected in the new host for several generations by polymerase chain reaction (PCR). However, no specific effects on the host were detected, and the bacteria were not stably maintained. PMID- 10098267 TI - Variation in morphological traits of Drosophila melanogaster (fruit fly) under nutritional stress. AB - The effect of nutritional stress on phenotypical and genetic variation was examined for five morphological traits (thorax length, wing length, sternopleural chaeta number, abdominal chaeta number and arista branch number) in 30 isofemale lines of Drosophila melanogaster. Phenotypical variation of all traits except sternopleural chaeta number and fluctuating asymmetry of all bilateral traits were significantly higher in flies reared under poor feeding conditions. Estimates of isofemale line heritability (coefficients of intraclass correlation) did not show a consistent pattern among traits. However, additive genetic variance was generally higher in poor feeding conditions in all traits except sternopleural chaeta number, although these differences were not statistically significant. Similarly, estimates of evolvability were higher under nutritional stress for all traits except sternopleural chaeta number. These results suggest that nutritional stress increases the expression of genetic variation for some morphological traits in Drosophila and, in this respect, is similar to the effects of temperature stress studied previously. PMID- 10098268 TI - Consistent responses of human mothers to prelinguistic infants: the effect of prelinguistic repertoire size. AB - The salience of infants' vocal and visual cues was examined to evaluate the efficacy of prelinguistic vocalizations to guide adult behavior. A videotape, constructed of brief behavioral episodes from 3 infants with different-sized vocal repertoires, was played to 40 mothers of prelinguistic infants. Playback mothers' responses to the episodes were consistent, demonstrating that preverbal behavior elicits comparable reactions across unfamiliar receivers. The audio and video components of the infants' episodes were then recombined. As the vocal repertoire of the stimulus infants increased, changes in the audio component more often led playback mothers to change responses. Thus, playback mothers used vocalizations as cues as the infants' vocal repertoires became larger. PMID- 10098269 TI - Heart rate responses to social interactions in free-moving rhesus macaques (Macaca mulatta): a pilot study. AB - Heart rate telemetry was explored as a means to access animal emotion during social interactions under naturalistic conditions. Heart rates of 2 middle ranking adult females living in a large group of rhesus macaques (Macaca mulatta) were recorded along with their behavior. Heart rate changes during 2 types of interactions were investigated, while controlling for the effects of posture and activity. The risk of aggression associated with the approach of a dominant individual was expected to provoke anxiety in the approachee. This prediction was supported by the heart rate increase after such an approach. No increase was found when the approacher was a kin or a subordinate individual. The tension reduction function of allogrooming was also supported. Heart rate decelerated faster during the receipt of grooming than in matched control periods. PMID- 10098270 TI - Visual list memory in capuchin monkeys (Cebus apella). AB - Memory of 3 capuchin monkeys, Cebus apella, was tested with lists of 4 travel slide pictures and different retention intervals. They touched different areas of a video monitor to indicate whether a test picture was in a list. At short retention intervals (0 s, 1 s, 2 s), memory was good for the last list items (recency effect). At a 10-s retention interval, memory improved for 1st list items (primacy effect). At long retention intervals (20 s and 30 s), primacy effects were strong and recency effects had dissipated. The pattern of retention interval changes was similar to rhesus monkeys, humans, and pigeons. The time course of recency dissipation was similar to rhesus monkeys. The capuchin's superior tool-use ability was discussed in relation to whether it reflects a superior general cognitive ability, such as memory. In terms of visual memory, capuchin monkeys were not shown to be superior to rhesus monkeys. PMID- 10098271 TI - Temporal aspects of female musk shrew (Suncus murinus) sexual behavior. AB - The effects of testing condition on sexual behavior were examined in female musk shrews (Suncus murinus). Females were tested in 2 conditions, a pair test and a paced test. The pair test was similar to traditional sex test conditions in which the female and male are placed into the same chamber together until mating occurs. The paced condition allowed the female to leave the male's chamber and revisit him at will, thus "pacing" the interaction. Females displayed receptivity continuously for 14 days in both conditions. In the paced condition, females were less likely to become receptive within 30 min and mate to ejaculation. However, few additional differences were found between test conditions. Because this is the 1st experiment to use a pacing test paradigm in a species with induced ovulation, the authors speculate that the absence of pacing behavior during mating may be shown by other species that have induced ovulation. PMID- 10098272 TI - Formal dominance: the emperor's new clothes? AB - I previously argued that formal dominance requires the ability to attribute knowledge to other individuals (D. Maestripieri, 1996). Formal dominance is otherwise indistinguishable from the way dominance has previously been conceptualized. For example, the notion that nonhuman primates have social relationships and that 2 individuals express their knowledge about the state of their relationship with signals of dominance and submission is intrinsic to the concept of dominance and not peculiar to formal dominance. Moreover, the claims made by formal dominance supporters that macaque signals such as the bared-teeth display are always displayed unidirectionally to other group members and never directed to predators are incorrect. If the mentalistic terms used to describe formal dominance must not be taken literally, then the interpretation of submissive signals such as the bared-teeth display from a formal dominance perspective remains unclear. PMID- 10098273 TI - Microbial enzymes: new industrial applications from traditional screening methods. AB - Enzymes have applications in many fields, including organic synthesis, clinical analysis, pharmaceuticals, detergents, food production and fermentation. The application of enzymes to organic synthesis is currently attracting more and more attention. The discovery of new microbial enzymes through extensive and persistent screening will open new, simple routes for synthetic processes and, consequently, new ways to solve environmental problems. PMID- 10098274 TI - The metabolic effects of native and transgenic hemoglobins on plants. AB - The strictly aerobic bacterium Vitreoscilla expresses a hemoglobin-like protein, VHb, when subjected to oxygen stress. When expressed in plants, this has several intriguing physiological effects, such as improving the overall growth rate, speeding germination and flowering, and increasing the productivity of certain oxygen-requiring metabolic pathways. Although the mechanisms behind the effects of VHb in heterologous hosts are not yet fully characterized, it has been suggested that VHb facilitates oxygen transport and/or storage. This hypothesis is supported by the kinetic properties of VHb, which allow very rapid dissociation of oxygen from the protein. PMID- 10098275 TI - Single-administration vaccines: controlled-release technology to mimic repeated immunizations. AB - The most effective mechanism for the elimination of disease from society is the use of vaccinations, but these often require repeated administration. However, single-administration vaccine formulations provide the repeated administrations automatically. One approach is the development of injectable controlled-release microsphere formulations containing the vaccine antigen that is released as a pulse 1-6 months after injection. The time of the pulse is dependent upon the rate of polymer degradation, which is dictated by the polymer's composition and molecular weight. This controlled-release technology may provide complete protection against disease after a single administration. PMID- 10098276 TI - Genetic optimization of recombinant glycoprotein production by mammalian cells. AB - Genetically modified mammalian cells are the preferred system for the production of recombinant therapeutic glycoproteins. Other applications include engineering of cell lines for drug screening and cell-based therapies, and the construction of recombinant viruses for gene therapy. This article highlights contemporary core genetic technologies and emerging strategies for genetically engineering mammalian cells for optimal recombinant-protein expression. PMID- 10098277 TI - Is stuttering a speech disorder? PMID- 10098278 TI - On being dyslexic. An inside view. PMID- 10098279 TI - Native American health care services--a dream job. PMID- 10098280 TI - Your service: the many face(t)s of ASHA's National Office. PMID- 10098281 TI - Two decades of the public health approach to skin cancer control in Australia: why, how and where are we now? AB - Incidence and mortality rates due to skin cancer are rising in most Western countries. Early detection of these tumours at a stage when they can be easily cured is the primary approach taken by many people wishing to deal with the problem. A primary prevention approach, that is, reduction in sunlight exposure, is being considered by an increasing number of organizations. The public health approach to primary prevention of skin cancer, including melanoma, requires an understanding of the role of sunlight in the production of these tumours. Despite a clear understanding of exactly how sunlight does this, there is enough epidemiological and laboratory evidence to suggest a broad approach to the problem. This includes reduction of sunlight exposure, particularly in childhood and adolescence. It also suggests the need to recommend avoidance of suntanning and particularly the excessive exposures that lead to sunburn. Widespread primary prevention public health programmes have been running in Australia for almost 20 years. The data measuring the effect of these programmes indicate a very large shift in knowledge attitudes and beliefs about sunlight exposure and suntans, and major shifts in behaviour. Suntans are no longer as popular as they were and people are reducing their sunlight exposure by a variety of methods encapsulated in Slip! Slop! Slap! Cohort analysis of the incidence rates for melanoma and non melanoma skin cancer show that the incidence of these tumours is levelling out in young people and is dropping in some instances. These are the people who were able to be influenced by the public health programmes in recent decades. Finally, following initial dramatic changes in all the behavioural variables related to the programme, a period of consolidation with continuing effort and more specific targeting will be required in the coming decades to maintain the improvement. PMID- 10098282 TI - A review of the epidemiology of tinea unguium in the community. AB - Tinea unguium is a common, chronic fungal infection of the nails. Many epidemiological studies have looked at the frequency with which this condition is seen in hospital outpatients clinics or mycological laboratories along with other dermatomycoses. Only recently have studies begun to emerge looking at the prevalence of this condition in populations. Hospital and mycological laboratory based studies give valuable information about tinea unguium prevalence in a particular clinic, but cannot be compared with other studies due to confounding factors inherent in the different people attending individual clinics. From population-based studies the prevalence of tinea unguium lies between 2 and 8%. Tinea unguium increases steadily with age. It is infrequent but definitely found in children. With the increasing life expectancy in the Western world the prevalence of tinea unguium is likely to increase further without adequate prevention and treatment. PMID- 10098283 TI - Photobiological aspects of sunscreen re-application. AB - A single application of a high sun protection factor (SPF) sunscreen has been shown to prevent sunburn, but the existence of a further protective effect following re-application of sunscreen has received little attention. The aim of this study was to quantify the ultraviolet radiation (UVR) protection against sunburn afforded by a re-application of sunscreen relative to a single application. The study methods were based on the Australian Standard SPF testing regimen, using human volunteers, standardized applications of sunscreen and an artificial solar simulating UVR source. Sunscreen was initially applied, followed by a suberythemal UVR dose; sunscreen was then re-applied, followed immediately by a second period of controlled UV exposure sufficient to induce mild erythema. Compared to the first application, the second sunscreen application afforded 3.1 times more protection against minimal UVR-induced erythema. The combined effect of two sunscreen applications gave on average 2.5 times better protection from UVR than a single sunscreen application. Health authorities worldwide have recommended sunscreen re-application for the prevention of sunburn for some time. This is the first quantitative study to substantiate such recommendations. PMID- 10098284 TI - Differential expression of epidermal growth factor receptor in melanocytic tumours demonstrated by immunohistochemistry and mRNA in situ hybridization. AB - Differential expression of the epidermal growth factor receptor (EGFR) has been reported in melanocytic lesions. To evaluate these differences in EGFR expression in melanocytic tumours, formalin-fixed, paraffin embedded sections from 33 benign melanocytic neoplasms and 77 cutaneous melanomas were analysed for EGFR protein and mRNA expression using immunohistochemistry and mRNA in situ hybridization. The majority of benign and malignant lesions expressed EGFR at both protein and mRNA levels. In 7% (7/100) samples, mRNA but not protein expression was observed. Overall, a higher proportion of cells expressed EGFR protein in malignant lesions compared with benign lesions (P = 0.06), and the intensity of mRNA expression was higher in the malignant tumours (P < 0.001). No significant differences in EGFR protein or mRNA expression with tumour progression within the malignant lesions were seen. These results indicate that EGFR mRNA and protein expression is common to benign and malignant melanocytic lesions, and that an overall increase in expression is associated with malignant transformation. However, differential EGFR expression between in situ melanomas and invasive or metastatic lesions was not observed. PMID- 10098285 TI - Surgical treatment of lentigo maligna and lentigo maligna melanoma. AB - Lentigo maligna (LM) is well known as an irregularly pigmented macular lesion usually presenting on the sun-damaged head and neck of older patients. Lentigo maligna (LM) has the potential to develop into invasive melanoma (LMM). A method of surgical excision for the treatment of LM and LMM using paraffin sections with tissue mapping to ensure clear margins before delayed defect closure is described. The results of applying this method in the treatment of 66 cases over a 40 month period are presented. Thirty-eight per cent of cases required two excisions or more to clear the tumour and 32% of cases showed evidence of invasive melanoma. Only one case has recurred thus far, and none have developed metastatic disease. PMID- 10098286 TI - IgA multiple myeloma presenting as an acquired bullous disorder. AB - A 63-year-old man presented with an intensely pruritic vesiculo-bullous eruption on the limbs and was subsequently found to have an IgA kappa multiple myeloma. The eruption clinically and histologically was suggestive of linear IgA disease (LAD), dermatitis herpetiformis (DH), epidermolysis bullosa acquisita (EBA), or bullous lupus erythematosus (LE), with the skin biopsy revealing subepidermal bullae and dermal papillary micro-abscesses. However, direct immunofluorescence showed a unique pattern of diffuse dermal IgA staining. Although chemotherapy produced a dramatic resolution of the lesions, which paralleled the fall in serum IgA paraprotein level, the myeloma later became progressive and the resulting paraprotein increase was accompanied by recurrence of the eruption. We propose that this patient's rash was the presenting manifestation of his multiple myeloma, and was a consequence of transudation of IgA paraprotein into the dermis. PMID- 10098287 TI - Dermatofibrosarcoma protuberans: an early non-protuberant phase of the tumour. AB - A 40-year-old female patient presented with a flat scar like plaque on the upper chest. The patient's perception of subtle change in the lesion was of paramount importance in the decision to biopsy this lesion of innocuous clinical appearance. Histopathological findings were those of dermatofibrosarcoma protuberans. This case illustrates the early clinical features of the tumour and a recommendation for taking a biopsy of any scar-like plaque where there is no clear history of preceding trauma. PMID- 10098288 TI - Crusted scabies in two immunocompromised children: successful treatment with oral ivermectin. AB - Two immunodeficient children, aged 4 and 12 years, with crusted scabies were successfully treated with a single oral dose of ivermectin (200 micrograms/kg). One child had been diagnosed in infancy with an undefined congenital T cell immunodeficiency and the other with chronic mucocutaneous candidiasis. Both had failed to respond to conventional topical therapy. In view of the excellent therapeutic response and absence of side-effects, ivermectin should be considered in the treatment of recalcitrant crusted scabies in children. PMID- 10098289 TI - Specific skin lesions occurring in a patient with Hodgkin's lymphoma. AB - A 47-year-old man presented with a several month history of non-specific acquired ichthyosis, an unknown period of generalized lymphadenopathy and a short history of erythematous papules and nodules affecting the cutaneous drainage area of his right axillary lymph nodes. Histology confirmed these lesions to be specific lesions of Hodgkin's lymphoma; that is, metastatic retrograde lymphatic spread from his axillary lymph nodes of CD30+, CD15+, Reed-Sternberg cells as well as mononuclear Hodgkin's cells. This is the most common site and mode of spread of Hodgkin's disease to the skin. As is typical of advanced Hodgkin's disease, as evidenced by specific cutaneous involvement, this patient died shortly after definitive diagnosis was made. PMID- 10098291 TI - Band-like sebaceous hyperplasia over the penis. AB - Sebaceous hyperplasia is a benign condition that is seen commonly on the face of elderly persons as single or multiple yellowish papules. It also occurs on the lips oral mucosa, neck and the penis. An unusual presentation of a band-like sebaceous hyperplasia over the penis in a 54-year-old man is described. PMID- 10098290 TI - Multicentric reticulohistiocytosis in a child. AB - A case of multicentric reticulohistiocytosis in an 8-year-old girl, which is a diagnosis rarely seen in children, is presented. Multicentric reticulohistiocytosis is a disorder of unknown aetiology, predominantly affecting the joints, skin and mucosa. Joint symptoms, but not cutaneous lesions, have improved with treatment with methotrexate. PMID- 10098292 TI - Allergic contact dermatitis due to para-tertiary-butylcatechol in a resin operator. AB - Para-tertiary-butylcatechol (PTBC) is a rare but potent contact allergen. This is a report of occupational allergic contact dermatitis to PTBC in a resin operator. PMID- 10098293 TI - The PABA story. AB - The qualities of para-aminobenzoic acid (PABA) are discussed and an account is given of how it came to be the favourite sunscreen of the post World War II era. Slowly, however, dermatologists became aware that it was a fairly common sensitizer and that it tended to cross-sensitize with compounds of similar chemical structure both in contact with the skin and given as systemic drugs. Furthermore, continued exposure to chemicals of this type could lead to autoimmune responses especially systemic lupus erythematosus and dermatomyositis. Discussion of these complications from the use of PABA took place at two meetings of the Dermatological Association of Australia in 1964 and 1965, and played a part in the slow withdrawal of PABA from sunscreens. PMID- 10098294 TI - Can we afford to scrap Medicare? PMID- 10098295 TI - NHMRC Clinical Trials Centre. Advancing research. PMID- 10098296 TI - Examining shoulder muscles. PMID- 10098297 TI - How Greek GPs manage hepatitis C infected patients: experiences gained from a primary health care district in rural Crete. PMID- 10098298 TI - Awareness of natural family planning. PMID- 10098299 TI - ENT malignancies. What the GP needs to know. AB - BACKGROUND: The head and neck are sites that are accessible to examination, therefore early detection of cancers in these sites should be simple. OBJECTIVE: This article discusses the commoner malignant tumours encountered in the various head and neck subsites. It gives an overview of the types of tumours that occur and the presenting features which allow us to distinguish them from benign disorders and facilitate much earlier diagnosis. Recent advances in diagnostic imaging and treatment are discussed. DISCUSSION: Improved outcomes for patients with head and neck cancers will occur with earlier detection and community education about risk factors. PMID- 10098300 TI - Practical guide to otitis externa. AB - BACKGROUND: Otitis externa is a common condition in warm humid climates, hence the term tropical ear. It is more likely to occur in a population were swimming is a popular pastime. OBJECTIVE: This article discusses otitis externa in terms of the clinicopathological categorisation. Its aim is to provide practical advice for the diagnosis, office management and prevention of this condition. DISCUSSION: The key elements to successful treatment of otitis externa are appropriate microbiological diagnosis and meticulous management. PMID- 10098301 TI - The management of postnasal drip. AB - BACKGROUND: Postnasal drip is a symptom that can be very irritating to both patient and doctor. OBJECTIVE: The aim of this article is to give an approach to diagnosis and treatment of postnasal drip. DISCUSSION: In order to have an approach to management of this problem the pathophysiology needs to be understood. The causes of increased mucus awareness need to be known. Investigations are aimed at trying to clearly define the cause of the increased mucus and then specific treatment can be given to remedy the situation. Treatment is generally medical, however, surgical treatment is required in certain situations. PMID- 10098302 TI - Stress in carers of the elderly. A controlled study of patients attending a Sydney family medical practice. AB - AIM: To examine stress in carers of the elderly who attended a solo family medical practice. METHOD: Eighty-seven carers were compared with 102 non caregiving controls. Subjects were asked to complete survey questionnaires either in the surgery or at home. The General Health Questionnaire (CHQ) was used to assess psychological morbidity, the Relative Stress Scale as a measure of subjective burden and information was collected on activities of daily living and instrumental activities of daily living. RESULTS: No significant difference was found in GHQ scores, reflecting the high level of stress in this family practice sample (mean GHQ = 4.7, standard deviation = 6.2). Psychological morbidity in carers was associated with the provision of assistance with instrumental activities of daily living such as shopping, cooking and finances. CONCLUSIONS: We suggest that because carers often encounter specific challenges which may be amenable to intervention, general practitioners should familiarise themselves with these issues, determine the caregiving status of their patients and provide information about community services to carers. PMID- 10098303 TI - General practice based diabetes clinics. An integration model. AB - BACKGROUND: Diabetes is a common chronic health problem in general practice. The quality of care for patients with diabetes has been shown to depend on many factors involving the patient and the general practitioner (GP) as well as the care environment. OBJECTIVE: To measure the benefits of general practice based diabetes clinics that integrate all patient care needs in the one place at the one time. METHODS: General practice based diabetes clinics were conducted in the rooms of 23 practices involving 54 GPs. The clinic team consisted of a diabetes educator, a dietitian and the usual GP. The clinic was conducted in accordance with the NSW Clinical Management of Diabetes Guidelines. RESULTS: Follow up after 12 months showed a significant drop in the number of patients with very poorly controlled diabetes (HbA1c > 3% of normal range). Management of co-morbidities (hypertension, hyperlipidaemia, microalbuminuria) improved and complication screening for active/high risk feet and diabetic retinopathy were performed. CONCLUSIONS: This coordinated and integrated approach to the management of diabetes improved glycaemic control of the poorly controlled patient with diabetes and improved GPs' management of complication risk factors. PMID- 10098304 TI - Understanding and managing common baldness. AB - BACKGROUND: Society places importance on physical attributes especially the appearance of our hair. Common baldness or androgenetic alopecia is a normal physiological process of hair loss in genetically predisposed individuals. Premature or accelerated hair loss can engender considerable negative thoughts and anxiety associated with feelings of diminished attractiveness. OBJECTIVE: To enable general practitioners to recognise the various treatment options available, therefore offering patients reasonable hope and informed choices. DISCUSSION: Common baldness can be prevented by currently available mediums and regrowth may be achieved in a significant percentage of cases. Correct use of these agents requires an understanding of the pathogenesis of androgenetic alopecia, its natural history and the time course of response to treatment. PMID- 10098306 TI - Patient information: colposcopy. PMID- 10098305 TI - Colposcopy. PMID- 10098307 TI - It's tennis elbow: but what is that? PMID- 10098308 TI - Is this back pain real? PMID- 10098309 TI - Could this be a drug side effect? PMID- 10098310 TI - Fever and rash in a young boy. PMID- 10098311 TI - Practice tip. Minimising the pain of injections. PMID- 10098312 TI - Now doctors are my customers! PMID- 10098313 TI - A day in the life of a GP. PMID- 10098314 TI - Outbreak of meningococcal disease in South Wales follows general increase in disease activity. PMID- 10098315 TI - Newborn babies exposed to smear positive tuberculosis. PMID- 10098316 TI - Outbreak of meningococcal disease in South Wales--update. PMID- 10098317 TI - Methicillin resistance in Staphylococcus aureus isolated from blood in England and Wales: 1994 to 1998. PMID- 10098318 TI - Professionalism in medical education. PMID- 10098319 TI - Complementary and alternative medicine (CAM): a review for the primary care physician. AB - It is difficult to find a satisfactory title for this review, because both the word "complementary" and "alternative"-are not very politically correct currently. It is probable that there is no fully politically correct word, except for "non-allopathic," which is unfamiliar to many MDs. Accurately used, the term "allopathic" is as opposed to "homeopathic," so from its origins, "allopathic medicine" should include herbal medicine. However, in practice, herbal and many other non-homeopathic treatments are called "non-allopathic," whereas conventional medicine is called "allopathic." "Complementary" usually would include practices that are used with conventional western medical treatments, and "alternative" would include those practices that are used instead of western medical treatments. For most of this review, the terms "non-allopathic," "alternative," and "complementary" could be used interchangeably. This topic has gained interest, and received some allopathic legitimacy, in part because of an article that David Eisenberg, M.D., published in the New England Journal.' In 1990, he performed a telephone survey of about 1,500 adults in the U.S. and asked them about the use of treatments and practices that were "alternative," which he defined as not generally being taught in the U.S. medical schools and not being readily available in U.S. hospitals. From his sample, he extrapolated that in 1990, about 60 million Americans used alternative medical treatments, at an estimated cost of $13.7 billion. There were more visits to alternative healers than to primary care MDs that year, and over two-thirds of people who did use alternative medical treatments did not tell their doctors about it. Now that third party figures are becoming interested in paying for alternative medical practices (especially naturopathic, chiropractic, and acupuncture services), allopathic physicians will be increasing in the position of being able to refer people to alternative providers, and insurers will pay for services that MDs approve. Therefore, it will become increasingly important for physicians to have a degree of familiarity with alternative treatments (including efficacy and risks). So far, to date, there have been no cases of malpractice for giving advice about the use of alternative medical treatments, but liability will certainly exist to anyone who delivers treatments, such as acupuncture or spinal manipulation, in the event of an adverse effect. This review will briefly introduce some of the most common alternative practices likely to be seen in Hawaii communities: Homeopathy, Herbs, Naturopathy, Chinese Medicine and Acupuncture, and Chiropractic and spinal manipulation, and a brief discussion of Dr. Eisenberg's recent position paper on advising patients about alternative practices. PMID- 10098320 TI - Occupational exposures and knowledge of universal precautions among medical students. AB - PURPOSE: To examine the relationship between occupational exposures and knowledge of universal precautions among medical students. METHOD: Graduating medical students were given a survey regarding occupational exposures suffered during their clinical rotations. The survey also tested students' knowledge of universal precautions by asking them to indicate what combination of gloves, mask, and eyeshields should be worn to satisfy universal precautions for ten common procedures. RESULTS: At a seminar one week before graduation, 45 senior medical students were given the questionnaire. The response rate was 100% 84% of the surveyed students suffered at least one occupational exposure during their clinical training. Of those who had an exposure, 42% reported at least once to an exposure center. The mean percentage of correct answers on the protective equipment questionnaire was 71%. No correlation between number of exposures and score on the protective equipment questionnaire was found (r = 0.0). CONCLUSION: Occupational exposures to blood are common among medical students. Few students report to exposure centers. Knowledge of universal precautions may not correlate with reduced risk of occupational exposures among medical students. PMID- 10098321 TI - Cytokine pleiotropy and redundancy--gp130 cytokines in human implantation. PMID- 10098322 TI - HLA-G: a tolerance molecule from the major histocompatibility complex. PMID- 10098323 TI - Advances in cancer immunotherapy. PMID- 10098324 TI - Alloimmunization for immune-based therapy and vaccine design against HIV/AIDS. AB - Recent studies have demonstrated protective effects of alloimmunization in the SIV model. Here, Gene Shearer, Ligia Pinto and Mario Clerici raise the possibility that alloimmunization against a spectrum of HLA-disparate leukocytes be considered for immune-based therapy and as an AIDS vaccine. PMID- 10098325 TI - Multiple gamma c-dependent cytokines regulate T-cell development. AB - Mutations in the common gamma chain (gamma c) of cytokine receptors account for human X-linked severe combined immunodeficiency disease. gamma c contributes to ligand binding and signaling as a component of five cytokine receptors: interleukin-2-receptor (IL-2R), IL-4R, IL-7R, IL-9R and IL-15R. Here, Thomas Malek and colleagues discuss the contribution of individual gamma c-dependent cytokines in both conventional and intraepithelial T-cell development. PMID- 10098326 TI - Direct and indirect recognition: the role of MHC antigens in graft rejection. AB - In graft rejection, T-cell stimulation by donor APCs and self-APCs (presenting peptides of donor origin) has been called 'direct' and 'indirect' recognition, respectively. Here, Dina Gould and Hugh Auchincloss consider the traditional arguments favoring direct recognition and highlight recent findings suggesting the importance of indirect responses, thereby questioning some of our basic concepts of transplantation immunology. PMID- 10098327 TI - CD13--not just a marker in leukemia typing. AB - Membrane peptidases are a multifunctional group of ectoenzymes that have been implicated in the control of growth and differentiation of many cellular systems. Here, using aminopeptidase N/CD13 as an example, Dagmar Riemann and colleagues discuss the role of cell-cell contact in peptidase regulation and the influence of peptidases on cellular functions. PMID- 10098328 TI - Chemokine receptors and HIV-1: the fusion of two major research fields. AB - Chemokines mediate their effects by binding to cell-surface receptors that belong to the seven-transmembrane-domain superfamily of proteins. Chemokine receptors have been subject to intense scrutiny following the recent discovery that several of them are co-receptors for HIV-1. Here, Richard Horuk reviews the latest developments in chemokine receptor research with a particular focus on their role as HIV-1 co-receptors. PMID- 10098329 TI - Immune modulation by the cholera-like enterotoxins: from adjuvant to therapeutic. AB - Cholera toxin and its close relative, Escherichia coli heat-labile enterotoxin, are potent immunogens and mucosal adjuvants. The recent findings that their B subunits can promote tolerance highlights the complexity of their interactions with the immune system. Here, Neil Williams and colleagues review the mechanisms by which these molecules modulate leukocyte populations and seek to explain the paradox. PMID- 10098330 TI - Immunobiology of zinc and zinc therapy. PMID- 10098331 TI - Immunomodulation by n-3 polyunsaturated fatty acids. PMID- 10098332 TI - Collaborative bioengineering: clinical activities in Ireland. PMID- 10098333 TI - Modelling medical devices: the application of bioengineering in surgery. AB - Medical device technology has an increasingly important role in surgical procedures. In this article, five case studies of bioengineering in surgery are described as follows: computer-aided design of vascular grafts; middle-ear prostheses; hip prosthesis stems for optimal cement pressurisation; prototype development of a device for measurement of abdominal sounds for monitoring digestive tract activity and a hand-access device for laparoscopic surgery. In each case, new bioengineering design methodologies are demonstrated. The general principles underlying the application of bioengineering in surgery are discussed. PMID- 10098334 TI - Simple preparation of the major urinary metabolites of flunitrazepam and nitrazepam. AB - An alarming increase in the misuse/abuse of nitrobenzodiazepine derivatives, especially flunitrazepam, prompted us to establish reliable analytical protocols for their routine detection. Whilst the parent drugs are readily available from a number of commercial sources, it was found difficult to obtain samples of the corresponding amino metabolites which were required as analytical standards. This lead us to develop the straightforward synthetic protocol described here, to convert the readily available parent drugs, namely flunitrazepam and nitrazepam, to their respective 7-amino derivatives. The method requires minimum laboratory facilities. It involves the reduction of the nitro functionality in the parent drug to an amino group using tin (II) chloride under mild conditions, using ultrasonication at room temperature. The method is simple and should give toxicology laboratories better access to these much needed compounds. PMID- 10098335 TI - Thoracoscopic Hellers myotomy for oesophageal achalasia. AB - Surgical myotomy is the mainstay of treatment for oesophageal achalasia. Minimally invasive surgical techniques, if feasible, reduce patient morbidity and mortality. In this study we review our experience of thoracoscopic Heller's myotomy. Thoracoscopic myotomy was undertaken in 9 patients (male = 3; female = 6, mean age = 37). All patients presented with dysphagia of 1 to 8 yr duration. Diagnosis was based on barium swallow and manometry. Two patients had previous dilatations and 1 had a transabdominal myotomy. All patients had a 5 port thoracoscopic technique. Thoracoscopic Heller's myotomy was completed in 8 out of 9 patients. In 1 patient extensive oesophagitis and peri-oesophagitis precluded both a thoracoscopic and an open myotomy, and oesophagectomy was subsequently performed. The mean duration of surgery was 142 min. Completion of myotomy and mucosal integrity was confirmed by intraoperative gastroscopy. All patients had an uneventful post-operative recovery. The mean hospital stay was 4 days. All patients are now asymptomatic, with documented weight gain. No patients have reflux oesophagitis symptoms. Our preliminary experience would suggest that thoracoscopic Heller's myotomy is a safe alternative to open surgery, with satisfactory results and reduced hospital stay. PMID- 10098336 TI - Median sternotomy for parathyroid adenoma. AB - Most mediastinal parathyroid tumours lie within the thymus gland and may be retrieved when cervical thymectomy is carried out in the course of neck exploration for primary hyperparathyroidism (HPT). We report 4 patients, each of whom required sternotomy for removal of a true mediastinal parathyroid adenoma. Subtraction isotope scintigraphy suggested the presence of a mediastinal tumour prior to cervical exploration in 2 individuals and prior to re-exploration in a third. When localisation before initial exploration for HPT suggests a parathyroid tumour within the chest, consideration should be given to proceeding to sternotomy, at first operation if a comprehensive neck exploration, including cervical thymectomy, fails to uncover the adenoma. Uniquely, one of our patients underwent sternotomy for HPT when 23 weeks pregnant. PMID- 10098337 TI - The Limerick Leg-Ulcer Project: early results. AB - Nurse led clinics in joint hospital and community settings are now being advocated as the most effective and economic way of dealing with leg ulcers. However, little information exists on the profile and outcome of patients with venous ulcers treated either in the community or in the hospital setting. Over a 2 yr period we assessed 134 patients with leg ulcers of whom 122 were deemed suitable for compression bandaging therapy. Thirty-four patients (28 per cent) were treated by the newly developed community service and 88 (72 per cent) were treated at the hospital clinic. Our overall healing rate for venous ulcers was 50 per cent @ 40 weeks. This probably reflects the long duration (48 per cent > 2 yr) and large size (0.5-600 cm2) of ulcer prior to treatment. There were no differences in outcome between hospital (50 per cent @ 40 weeks) and community (35 per cent @ 40 weeks) based treatment (p > 0.05). We conclude that most venous ulcers can be effectively treated in the community and resources should be provided to achieve this goal. PMID- 10098338 TI - Farmer's lung in Ireland (1983-1996) remains at a constant level. AB - A prospective study was undertaken by the Departments of Respiratory Medicine and Medical Microbiology at the Cork University Hospital, a. to investigate the epidemiology of Farmer's Lung (F.L.) in the Republic of Ireland (pop. 3.5 million), with special reference to the South Western Region of this country (pop. 536,000) and b. to assess any relationship between the prevalence/incidence of F.L. with climatic factors in South West Ireland, between 1983 and 1996. F.L. incidence remained constant throughout the 13 yrs studied both on a national and a regional basis. A significant relationship was also found between total rainfall each summer and F.L. incidence and prevalence over the following yr (p < 0.005) in South-West Ireland. The persistence of F.L. in Ireland at a constant level suggests that farmers' working environment and farm practices need to be improved. PMID- 10098339 TI - An audit of the effect of intravenous antibiotic treatment on spirometric measures of pulmonary function in cystic fibrosis. AB - BACKGROUND: This retrospective audit was undertaken to compare the efficacy of home intravenous (i.v.) antibiotic therapy, hospital i.v. antibiotic therapy and a combination of these 2 approaches, as determined by spirometric measures of lung function in cystic fibrosis (CF) patients, each with an acute respiratory exacerbation. METHODS: Pulmonary function, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow rate between 25 per cent and 75 per cent of vital capacity (FEF25 75), and peak expiratory flow rate (PEFR) were compared between groups at the beginning and at the end of an IV antibiotic course. RESULTS: Treatment of exacerbations resulted in a significant improvement (p < 0.05) in lung function irrespective of where patients were treated. The percentage improvement in FEV1, FVC, and FEF25-75, were significantly greater in patients treated in hospital compared to those who had home i.v. treatment (p < 0.05). CONCLUSION: Hospital i.v. antibiotic therapy resulted in greater improvements in FEV1, FVC and FEF25 75 than home i.v. antibiotic therapy in CF patients with an acute respiratory infection. PMID- 10098340 TI - The impact of reminder letters on attendance for breast cancer screening. AB - OBJECTIVE: The aims of this investigation was to analyse the response to second and third postal invitations from a group of patients previously invited for mammographic screening and to identify any demographic differences between responders and non-responders. SUBJECTS: The subjects were females aged 50-64 yr resident in 6 adjacent District Electoral Divisions (DEDs) in North Dublin where screening had not been carried out prior to the study. METHOD: Non-responders to an invitation for screening were re-invited by computer-generated letter to attend for screening 6 weeks after issue of the first invitation and a final invitation was issued at 12 weeks. Data sources used for the project register were the Eastern Health Board General Medical Services data base (GMS), Voluntary Health Insurance Board (VHI) data and self-registration. RESULTS: There were 1,310 females in the target age group who were eligible for screening. The response rate to the first invitation was 60.7 per cent. Issue of second invitation increased the response rate by 17.9 per cent. A third invitation increased the response rate by a further 7.6 per cent. Those with private medical insurance were more likely to respond to the first and third invitations. The was no difference in response rate to the second invitation for those with and without private insurance. Women aged 55-64 were more likely to respond to first, second or third invitations than those aged less than 55 yr. CONCLUSIONS: Issue of second mailed invitations to women in the target age for mammography screening is cost-effective and should be incorporated into routine policy. Response to third invitations is not cost-effective. PMID- 10098341 TI - Salivary SIgA and SIgA 1 in coeliac disease, inflammatory bowel disease and controls. AB - Levels of secretory IgA1 (SIgA1) in the saliva have not been measured previously in either coeliac disease (CD) or inflammatory bowel disease (IBD). Saliva was collected from coeliacs, IBD patients and controls. The concentration of total SIgA in saliva was measured by enzyme linked immunosorbent assay (ELISA) with an anti-human SIgA antibody as the bound phase and human SIgA isolated from colostrum as the standard. The concentration of SIgA1 was determined using an ELISA with a lectin with a high affinity for human SIgA1. The IBD patients have a significantly higher concentration of SIgA1 than the controls. The rate of secretion of saliva and %SIgA1 was significantly lower in coeliacs than in the control and IBD groups. The rate of secretion of SIgA1 was significantly higher in the IBD than in the coeliacs. We describe hitherto unreported levels of SIgA1 in CD and IBD. PMID- 10098342 TI - Co-abuse of opiates and benzodiazepines. AB - The objective of the study was to assess what differences exist between individuals who are dependent on opiates and benzodiazepines and compare to those who are dependent on opiates. A questionnaire was compiled and administered to patients who had been consecutively admitted to an inpatient drug treatment unit. The prevalence of benzodiazepine dependency was 54 per cent [n = 34]. Patients dependent on benzodiazepines and opiates were significantly older, had been admitted for methadone stabilisation and were more likely to have been prescribed a methadone maintenance programme prior to admission. They had used heroin longer, benzodiazepines more frequently, at larger doses for a longer duration of time and tended to use more drugs in general. They were found to be more psychologically vulnerable than those not dependent on benzodiazepines as they were significantly more likely to have described a past experience of depression and a past episode of deliberate self harm. PMID- 10098343 TI - Effect of 3 growth control substances on foreign body sarcomagenesis: IFN, IUdR, MGBG. AB - The purpose was to observe the effect on sarcomagenesis of 3 substances reported to inhibit neoplastic growth--interferon alpha-2/alpha-1 hybrid (IFN), 5-iodo-2 deoxyuridine (IUdR) and methylglyoxal bis(guanylhydrazone) (MGBG). Inhibitory effect might help diminish the sarcoma risk of human implants. The substances were applied respectively to groups of 25mm cellulose filters which were implanted subcutaneously 1 per animal in randomly assigned respective groups of 50 female BALB/c mice. The implant sites were palpated weekly. On detection of a tumour the animal was sacrificed. The number of tumours arising and the accumulated weeks of exposure to the implants were recorded per group and compared to those of controls with untreated filters. Tumour incidence in the 2 IFN groups was 33/45 and 35/48 mice--160 per cent that of the controls, 22/48 (chi-square p < 0.05). In the IUdR group tumour incidence was 24/44 mice--194 per cent that of controls (p < 0.05), and in the MGBG group 15/43--122 per cent that of controls (p < 0.75). Although the substances inhibit tumour growth in man, they did not inhibit but increased film sarcomagenesis, not significant for MGBG. Observation of the effects of such substances with dual neoplastic activity may furnish clues to the control processes of neoplasia. PMID- 10098344 TI - Efficacy of a new quarternary ammonium compound against TB. AB - Ten of 12 strains of Mycobacteria (11 M. tuberculosis, 1 M. bovis) including 7 resistant strains were found to be sensitive to tetradecyl-dimethyl-benzyl ammonium fluoride (TDBAF) at a concentration of 15-7.75 micrograms/ml (end point 10 micrograms/ml). A single multi-resistant strain of M. tuberculosis and a culture of M. bovis were also sensitive but at a slightly higher level. PMID- 10098346 TI - Q fever endocarditis revisited. AB - A diagnosis of Q fever endocarditis was made in 7 patients, 6 with predisposing factors and 3 with occupational risk factors. Prompt recognition of Coxiella burnettii endocarditis is required when clinical signs of endocarditis such as fever, anaemia, elevated liver transaminases, congestive cardiac failure are accompanied by negative blood cultures. Serological evidence of elevated antibody titres to Phase I and Phase II antigens of Coxiella burnettii are diagnostic. Prolonged antimicrobial therapy combined with surgery has resulted in the marked reduction of mortality from 50 per cent of 17 per cent when Q fever endocarditis is revisited almost 20 yr later. PMID- 10098345 TI - Long-term outcomes of treatment of hyperthyroidism in Ireland. AB - We investigated the long-term outcome of treatment in 159 patients with hyperthyroidism first seen between 1979 and 1992. Median duration of follow-up was 10 1/2 years. We also inquired into current practice for the follow-up of hyperthyroidism by other endocrinologists in Ireland. Seven cases of unrecognised hyperthyroidism (4 per cent) and one of unrecognised hypothyroidism were identified. Among patients with Graves' disease, of those treated with an antithyroid drug, 28 per cent were in remission, 68 per cent had relapsed and 4 per cent had become hypothyroid. Of those treated by sub-total thyroidectomy, 31 per cent were in remission, 19 per cent had relapsed, 19 per cent were hypothyroid and 31 per cent were sub-clinically hypothyroid. Among patients treated with radioiodine, 19 per cent were euthyroid, 3 per cent were still hyperthyroid and three-quarters had become hypothyroid. In contrast, after radioiodine for toxic nodular goitre, 63 per cent were euthyroid and only 32 per cent had become hypothyroid (Chi Squared v. Graves' disease, P = 0.001). Of 73 patients receiving thyroxine replacement, plasma TSH was normal in only 41 per cent, although 82 per cent of patients had been seen by the family doctor within the previous 12 months. Seven of 17 other endocrinologists undertook long-term follow-up of hyperthyroid patients in their specialist clinics but none was using a computerised system to co-ordinate this. The findings confirm that careful follow-up is required for all hyperthyroid patients. The family doctor is well positioned to undertake this, but education and auditing are required. PMID- 10098347 TI - Effects of dioxins on human health: a review. AB - The toxicity of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) has been known since 1950s. TCDD is a by-product of herbicide 2,4-dichloroacetophenol (2,4-D) and 2,4,5-trichloroacetophenol (2,4,5-T), but it was first found in fryash of municipal incinerator in 1979 in Japan. In 1998, the survey of municipal incinerators revealed that 105 out of 1,641 produced above the allowed emission level of 80 ng TEQ/m3. Total annual release of dioxins is estimated to be about 5,000 g TEQ in 1997 in Japan. Japanese government started a comprehensive survey for dioxin levels in milk and blood of residents around incinerators, and their health effects. Human effects by dioxin exposures in Western countries were mostly acute and at high level in accidentally and/or occupationally. Health effects of low-dose and long lasting exposure has not been well understood. Certain amount of polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF) and polychlorinated biphenyls (PCB) is accumulated in our body. Mother's milk is also contaminated by PCDD/PCDF. Health effects of the polychlorinated chemicals are summarized, and the necessity of regulations and recommendations for making a guideline is discussed in this review. PMID- 10098348 TI - Dietary soybeans intake and bone mineral density among 995 middle-aged women in Yokohama. AB - To investigate relationship of dietary factors, especially source of calcium intake, to bone mineral density (BMD) among Japanese middle-aged women, a total of 995 healthy women age of 40 to 49 (mean +/- SD, 45 +/- 3), who lives in Yokohama-city, were recruited through convenience sampling by the municipal information paper and health announcement at each 18 public health center in 18 wards for the three-day course on prevention of osteoporosis from October 1996 to March 1998. The BMD of the 2nd metacarpal bone was measured using Computed X-ray Densitometry (CXD) method, by a trained radiologist. Dietary intake of calcium was assessed by self-reporting food frequency questionnaire on calcium dietary sources such as milk, dairy products, small fish, vegetables, and soybeans and carefully checked by trained dietician. An independent gradient of non-adjusted and adjusted BMD for age and weekly calcium intake, through soybeans intake frequency (p = 0.03) was noted. This study suggest soybeans, through possible beneficial effects of vitamin-K, soyprotein, and isoflavonoid, may affect BMD of middle aged women. PMID- 10098349 TI - Process and current status of the epidemiologic studies on cedar pollinosis in Japan. AB - This paper reviews the present situation and future aspects of epidemiologic studies on Japanese cedar pollinosis. Increase of allergic rhinitis patients is observed in both the Patient Survey and the Reports on the Surveys of Social Medical Care Insurance Services, however, these surveys are conducted when cedar pollens do not pollute the air. Many have reported on the prevalence of pollinosis in limited areas but only a few nationwide epidemiologic surveys have been conducted. Most of the studies were conducted at special medical facilities such as university hospitals. There is a high possibility that patients who visit the specific facilities do not exactly represent the actual number of patients and epidemiologic pictures of pollinosis in Japan. The rapid advances in laboratory test methods may change the diagnostic criteria and increase the number of reported patients. Therefore, the prevalence of Japanese cedar pollinosis in Japan has not been determined yet. Determination of the prevalence of cedar pollinosis and description of the epidemiologic pictures constitute the essential steps toward the control of this clinical entity. Thus it is necessary to conduct an epidemiologic survey on Japanese representative samples with a standardized survey form with clear and concise diagnostic criteria. PMID- 10098350 TI - Asthma-like disease in the children living in the neighborhood of Mt. Sakurajima. AB - We conducted self-administered questionnaire surveys of school children living in the vicinity of Mt. Sakurajima using ATS-DLD questionnaire. In this paper, we report the results of analysis comparing the proportion of children with asthma like disease in the area exposed to the volcanic ash and gases released by Mt. Sakurajima and control areas. Asthma-like disease was ascertained using ATS-DLD questionnaire and the definition proposed by the study group established by Environmental Protection Agency in Japan. The proportion of children with asthma like disease was not different between the exposed and control groups. The odds ratio of asthma-like disease comparing the exposed and control groups was 1.1 and its 95% confidence interval was 0.7-1.8 (P = 0.583). When the exposed area was divided into Tarumizu city. Sakurajima town and Kagoshima city, none of them showed an elevated proportion of children with asthma-like disease when compared with the control area. In the entire study population including both the exposed and control groups, the proportion of children with asthma-like disease was 6 and 3% in boys and girls, respectively. These values were quite similar to those obtained from a survey of 45,674 school children in western districts in Japan in 1992. In conclusion, the present study indicates that the proportion of children with asthma-like disease is not elevated in the exposed area. Further investigations are necessary to confirm our conclusions. PMID- 10098351 TI - Lipoprotein(a) levels and apolipoprotein(a) isoforms related to life style risk factors. AB - Lipoprotein(a) [Lp(a)] has been considered to be a predictor of premature coronary heart disease and other cardiovascular diseases. Lp(a) levels are largely genetically determined, but the detailed mechanism of Lp(a) elevation is uncertain. We examined the association between Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes as well as that of Lp(a) level and other various conditions. The subjects were 280 healthy Japanese (102 males and 178 females) aged 39 to 70 years who were living in a rural community in 1992. We obtained apo(a) phenotypes determined by SDS-PAGE as well as Lp(a) levels and other cardiovascular risk factors. We combined apo(a) phenotypes form 4 groups according to molecular weights (from high apo(a) molecular weight to low: I, II, III and IV). Lp(a) levels were associated with apo(a) phenotype-groups, that is, they were inversely associated with apo(a) molecular weight. Small apo(a) phenotypes were less frequent than large ones. The median Lp(a) level was higher in smoking (29.2 mg/dL) than in non-smoking subjects (18.5 mg/dL) in phenotype-group III. Adjusted means of total cholesterol and fibrinogen levels in apo(a) phenotype-group IV were the highest of all phenotype-groups. Age, apo(a) phenotype, smoking status, total cholesterol and fibrinogen were positively correlated with Lp(a) levels by multiple regression analysis. Lp(a) levels were found to be mainly associated with apo(a) phenotype, but varied broadly within the same apo(a) phenotype at various conditions, such as smoking status and high total cholesterol. PMID- 10098352 TI - Effect of life styles on the risk of subsite-specific gastric cancer in those with and without family history. AB - To evaluate a combined effect of gastric cancer family history (GCFH) and selected living habits on the subsite-specific of gastric cancer, a hospital based case-referent study was conducted in Tokai area of Japan. The study subjects were 850 newly diagnosed gastric cancer (GC) patients and 28,619 cancer free first-visit outpatients. Odds ratios (ORs) of all subsites of GC in subjects with both GCFH and habitual smoking were significantly higher (OR = 4.22) compared with those with merely GCFH (OR = 1.81) or habitual smoking (OR = 2.83). When positive GCFH subjects frequently consumed raw vegetable, the risk of GC decreased in cardia (OR = 0.68), antrum (OR = 0.43) and all subsites (OR = 0.74). Our findings provided evidence that GCFH and habitual smoking increased the risk of GC with family history, while frequent intake of raw vegetable decreased the risk and it was modified by other environmental factors. PMID- 10098353 TI - Time trends in the mortality rates for tobacco- and alcohol-related cancers within the oral cavity and pharynx in Japan, 1950-94. AB - Mortality data of oral cancer over 40 years in Japan were analyzed to investigate time trends of the disease site-specifically and discuss the relation between these trends and the changing patterns of consumption of tobacco and alcohol beverages. Mortality rates were adjusted to the world standard population. In the males, overall oral cancer (ICD-9: 141-149) mortality rates have increased consistently from the lowest value of 1.25 (per 100,000 per year) in 1956 to 2.40 in 1992. The rates for females were constantly lower than those for males, and formed a modest peak of 0.96 in 1979. Regarding site-specific mortality rates, tongue cancer (141) presented a decreasing trend, while oro/hypopharyngeal (146, 148) and mouth (143-145) cancers showed increasing patterns, particularly in males. When the changing patterns of male truncated rates for ages 35-64 were compared with those of the annual consumption of cigarette and alcohol per capita, the time trend of oro/hypopharyngeal cancer mortality was analogous to cigarette consumption rather than to alcohol consumption, mouth cancer vice versa, and tongue cancer was not related to tobacco or alcohol consumption. The present findings suggest that tobacco and alcohol have different site-specific effects on the development of cancers within the oral cavity and pharynx. PMID- 10098354 TI - A superpotent topical steroid for constricting breast cancer symptoms. PMID- 10098355 TI - Epilepsy: a possible contraindication for transcutaneous electrical nerve stimulation. PMID- 10098356 TI - Observations on the effects of intermittent positive pressure on ischemia in a lower extremity. PMID- 10098357 TI - Neuropathic pain after anti-HIV gene therapy successfully treated with gabapentin. PMID- 10098358 TI - Differences in physician access patterns to hospice care. AB - Few issues in health care have recently generated as much discussion as the two seemingly unrelated topics of out-of-hospital health care financing and compassionate care of patients at the end of life. These two topics meet where health care costs cross paths with the economic viability of hospice and palliative medicine. In this study, we evaluated 101 admissions to a large Medicare-certified hospice in the last quarter of 1995 to assess factors associated with timing of referral to hospice. Mean length of stay in hospice was 55 days; median was 23 days. The majority of patients had cancer diagnoses (74%). Contrary to our hypothesis, there was no statistically significant difference in mean patient lengths of stay between oncologist-referred and nononcologist referred patients. However, when we compared patient lengths of stay lasting less than--versus longer than--30 days, more patients referred by nononcologists were in hospice longer than 30 days (chi 2 = 3.92, P < 0.05). With further evaluation, this difference was attributable to longer stays by patients covered by the Medicine hospice benefit, by those with noncancer diagnoses, and by those who were older. More of these patients were referred by nononcologists. The difference in referral patterns between oncologists and nononcologists disappeared when only cancer patients were considered. Consistent with initial hypotheses, caregivers of patients with shorter lengths of stay were significantly less satisfied with hospice care (t = -4.06, P < 0.001). These results suggest that health care benefits and other patient-specific issues influence timing of hospice referral rather than simply preferences by types of physicians. The impact on Medicare expenditures and hospice viability is discussed. PMID- 10098359 TI - Injected morphine in postoperative pain: a quantitative systematic review. AB - This systematic review of single-dose, placebo-controlled, randomized trials assessed pain relief from subcutaneous, intramuscular or intravenous morphine compared with placebo in postoperative pain. Pain relief or pain intensity difference over 4 to 6 hours was extracted and converted into the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. In 15 trials, comparing intramuscular morphine 10 mg (486 patients) with placebo (460 patients) morphine had an NNT of 2.9 (95% confidence interval 2.6-3.6). This meant that one of every three patients with moderate or severe postoperative pain treated with 10 mg intramuscular morphine had at least 50% pain relief, and would not have achieved this had they been given placebo. Minor adverse effects were more common with morphine (34%) than with placebo (23%) (relative risk 1.49 [1.09-2.04]), but drug related study withdrawal was rare (1.2% overall) and no different from placebo. PMID- 10098360 TI - Iontophoretic vincristine in the treatment of postherpetic neuralgia: a double blind, randomized, controlled trial. AB - The effect of iontophoretic administration of vincristine in the treatment of postherpetic neuralgia (PHN) was investigated in a prospective, double-blind, placebo-controlled trial. Twenty patients with intercostal or lumbar PHN for more than 6 months that was unresponsive to conventional medical therapy were randomized to receive vincristine 0.01% (n = 11) or saline (n = 9), by iontophoresis over 1 hour daily for 20 days. Demographics and median duration of pain were similar in both groups. Pain scores decreased over the treatment period and were significantly lower on day 20 compared to baseline in both groups. Pain relief was described as moderate or greater in 40% of patients with vincristine and 55% of patients with placebo. There was no statistical difference an actual pain scores on day 20 between the two groups. Moderate or greater pain relief was maintained in 30% of patients with vincristine and 33% of patients with placebo at follow-up on day 90. We conclude that iontophoresed vincristine is no better than iontophoresed saline in the treatment of PHN. The maintained improvement in both groups at 3 months follow-up may reflect the natural history of PHN, or might possibly by related to a beneficial effect of iontophoresis. PMID- 10098361 TI - Chronic pain in Holocaust survivors. AB - There is limited research on the connection between the Holocaust and chronic pain, despite evidence suggesting that medical and psychological sequelae are common in survivors. The goals of this study were: (1) to define Holocaust survivors' (n = 33) chronic pain characteristics as manifested 50 years after the war, (2) to compare survivors with controls (n = 33) who did not experience World War II atrocities, and (3) to investigate the connection between past trauma and chronic pain. Data were collected through questionnaires that included a detailed medical and pain history, visual analog scale (VAS), McGill Pain Questionnaire (MPQ), Beck Depression Inventory (BDI), Symptom Check List-90 (SCL-90), and Pain Disability Index (PDI). A comparison of variables between the two groups was conducted using multivariate analysis of variance (MANOVA) and ANOVA, and canonical discriminant analysis. Results showed that Holocaust survivors reported higher pain levels (73 +/- 18 vs. 56 +/- 21; P < 0.005), more pain sites (4.5 6 2.8 vs. 2.7 6 1.4; P < 0.05), and significantly higher depression scores (17.6 +/ 8.4 vs. 9.2 +/- 4.6; P < 0.001); they tended to utilize more medical services (5.9 +/- 3.0 vs. 5.1 +/- 2.8). Nonetheless, survivors did not regard themselves more disabled as compared with controls. They reported a higher activity level as measured by walking distance capacity, and spent significantly fewer hours resting (4.3 +/- 3.6 vs. 7 +/- 4.6; P < 0.05). This paradoxical combination of high pain intensity, moderate to severe depression, and high activity level characterizes Holocaust survivors' chronic pain. It is conceivable that by remaining active Holocaust survivors fight back their pain, distress, and depression. These findings suggest that Holocaust atrocities affect survivors' chronic pain even years later. PMID- 10098362 TI - Attitudes toward euthanasia and physician-assisted suicide among Italian primary care physicians. AB - The public debate about euthanasia and assisted suicide is less pronounced in Italy than in other countries, and data about this topic are lacking. The aim of this study was to investigate primary care physicians' experience in requests for and opinions about euthanasia and/or assisted suicide for terminally ill patients and the relationship between attitudes and professional variables. Three-hundred thirty-six general practitioners completed the Euthanasia Questionnaire to assess attitudes toward euthanasia and/or assisted suicide and the Maslach Burnout Inventory to examine burnout symptoms. The rate of requests for euthanasia or assisted suicide was low (11% and 4.5%, respectively). Only a minority of the physicians endorsed euthanasia and/or assisted suicide. Agreement with the practice of euthanasia/assisted suicide was correlated with non-Catholic religious affiliation, inexperience in treating terminally ill patients, and the burnout dimension of depersonalization. The fact that professional as well as individual factors (e.g., inexperience, non-Catholic affiliation, burnout) were associated with favorable attitudes toward euthanasia and/or assisted suicide underscores the need to examine the problem as a complex phenomenon involving the dyadic patient-doctor relationship. PMID- 10098363 TI - A guide to enternal drug administration in palliative care. AB - Enternal feeding is indicated in patients unable to ingest sufficient nutrients but whose gastrointestinal function is adequate for digestion and absorption. Indications in palliative care include patients with radical esophageal surgery, upper gastrointestinal tract obstruction, anorexia, and dysphagia. As the oral route is the preferred method of palliative drug delivery, the enternal feeding tube can become an important tool for drug administration. A number of questions must be asked before a drug is considered for enteral administration. Firstly, is the drug in a suitable dosage form for administration? If not, can a different dosage form (or drug) be substituted or can the physical form of the original product be altered? Secondly, is the drug compatible with the enteral feed? Finally, are there any complicating factors that may affect drug absorption or clearance? This review attempts to answer these questions, provide easily understood guidelines for the successful enteral administration of medications, and discuss clinical implications for palliative care. PMID- 10098364 TI - Radiotherapy for bone metastases: a critical appraisal of outcome measures. AB - Pain from bone metastases is a common problem in patients with advanced cancer, and radiotherapy plays an important role in its palliation. Single fraction treatments are often prescribed, but there is no clear consensus on this issue and clinical practice shows significant variability. This situation is unsatisfactory for all patients--the patient, the clinician, and the health care administrator. Randomized trials may use poor outcome measures and this contributes to practice variability. The credibility of outcome studies is often reduced due to poor study design, small sample sizes, and the use of endpoints that are both unreliable and unsuitable. The endpoints used have been narrowly defined, the patient's perspective has generally been overlooked, and quality of life has only once been used as an endpoint. A review of the current literature suggests that instruments specific to bone metastases are required. These must be based on patient experience, and rely on self-report. In addition, there is a need to understand the relative priority that patients attribute to treatment outcomes. The use of better instruments and methodologies in future trials will enhance the credibility of results and reduce practice variations. PMID- 10098365 TI - Complicated delirium in a cancer patient successfully treated with olanzapine. AB - Delirium is common among cancer patients, especially those with advanced disease. Typical treatment involves addressing the underlying cause if possible; eliminating nonessential and/or other drugs that can worsen confusion, manipulating the environment; and administering antipsychotic drugs to control symptoms and agitated behavior, and attempt to clear the patient's sensorium. The newer atypical antipsychotics may have potential in the treatment of delirium and also have the added benefit of causing less akithisia and other extrapyramidal side effects. This is illustrated by the case of a 59-year-old woman with leukemia and pain of unclear etiology who developed a delirium and a moderate to severe extrapyramidal syndrome (EPS) in the setting of escalation of her pain medications and concomitant escalation of prochlorperazine. The patient presented with confusion and moderate to severe cogwheeling rigidity, masked facies, bradykinesia, and tremor. Additionally, the patient had a relatively recent history of subdural hematoma and one seizure. Conservative management including eliminating multiple nonessential medications (including the prochlorperazine); changing her opioid analgesic; providing a 24-hour companion: and administering low doses of haloperidol (0.5 mg-2.0 mg) were not effective in treating the patient's delirium. The patient's EPS was dramatically worse following haloperidol doses. After approximately I week without improvement, the patient was started on olanzapine 5 mg daily with initial improvement but with residual confusion in the evenings and overnight. The dose was titrated up to 10 mg nightly with 2.5 mg as needed during the day. After 3 days on this regimen, the patient's mental status exam was normal and she was discharged home. We discuss the potential utility of this atypical antipsychotic in the palliative care setting. PMID- 10098366 TI - Visual disturbances in advanced cancer patients: clinical observations. AB - Visual disturbances in advanced cancer patients are very rarely signaled, evaluated, or adequately treated. The main causes of sight disturbances are primary eye tumors, ocular metastases, and some paraneoplastic syndromes. Sight alteration can also be associated with asthenia, fatigue, anemia, and hypovitaminosis. These symptoms can be monocular or binocular, and their gravity and evolution can vary. Based on a survey of 156 patients, we estimate the prevalence of visual disturbances to be 12% in advanced cancer patients. PMID- 10098367 TI - [1997 status of tuberculosis in Germany]. PMID- 10098368 TI - [CT-assisted transthoracic puncture of pulmonary lesions and mediastinal infiltrations. A retrospective study of 300 patients]. AB - With this retrospective study we evaluated the results and the complications of our 343 CT-guided transthoracic biopsies, which we performed in 300 patients with localised and infiltrative lesions of the lung and the mediastinum during 4 years, using the VacuCut-needle in 96% of our cases. In 256 pts. bronchoscopy without final diagnosis was performed before transthoracic biopsy. In 219 pts. (73.0%) we had positive results. In 209 pts. with malignancies the positive rate was 73.7%. In patients with benign processes the positive rate was less (67.8%). Out of 32 pts, suffering from mediastinal lesions 29 had malignancies. In 79.3% positive results were obtained. The rate of complications was low (9%) in 311 biopsies of pulmonary lesions, most were pneumothoraces (7.7%). Haemorrhages occurred in 4 pts. (1.3%) 5 pts. (1.6%) required drainage because of pneumothorax. On the base of our good results and the low complication rate we recommend CT-guided transthoracic aspiration biopsy with the VacuCut-needle as a useful and accurate diagnostic technique. PMID- 10098369 TI - [Early diagnosis of bronchial carcinoma. Technical endoscopic progress--a step toward new screening concepts?]. AB - Lung cancer is the most common neoplasm of our days. Its mortality has remained invariably high over the last decades and the search for effective preventive and therapeutic strategies is as imperative as ever. Carcinogenesis is a process requiring years until invasive malignancy has developed and hence offers a sufficient period for early detection of (pre-)malignant lesions. Now, tools seem available to achieve this goal: technical refinements advocate a reappraisal of screening methods for lung cancer. Also, apart from conventional diagnostic procedures, which are reviewed in this article, photodynamic and autofluorescence bronchoscopy deserve particular attention. Recent data, showing sensitivity for detection of premalignant lesions increased by factor 1.9 to 2.7 as compared to white light bronchoscopy, suggest markedly improved diagnostic options. With these new instruments, especially when combined with screening programs of high risk groups, earliest possible diagnosis and successful therapeutic intervention seem a promising concept of reduction of lung cancer mortality. PMID- 10098370 TI - [Legal social status of management with portable liquid oxygen devices in Germany]. AB - This survey is based on three successful German sociolegal court proceedings instituted against relevant statutory medical cost bearers in respect of providing pulmonary patients with portable light-weight oxygen equipment. The sociolegally relevant indications for liquid oxygen treatment are described contrasting with conventional oxygen suppliers such as concentrators or steel flasks. Also detailed are the sociolegally appropriate prescription procedures for patients suffering from chronic respiratory insufficiency who can be mobilised by treatment with oxygen. PMID- 10098371 TI - [Intra-oral therapy of borderline sleep-related respiratory disorders with a modified protrusion-fixation of the mandible]. AB - BACKGROUND: Aim of this study was the investigation of the efficacy and acceptance by mechanic-prosthetic mandibular protrusion for patients with mild to moderate OSAS. METHODS AND PATIENTS: During interdisciplinary teamwork between pneumology (sleep medicine) and dentistry we studied the change in the apnoea index (AI) of 21 unselected patients treated with a modified oral appliance according to Lyon using less protrusion of the mandible and individual occlusion of the jaws. All patients were asked to rate their complaint-score using the oral appliance. RESULTS: 21 patients--aged 55.03 +/- 9.71 years; body mass index (BMI) 28.6 +/- 2.4 kg/m2 (mean value +/- SD)--had an improvement of apnoea-index (1/h) high significant (p < 0.0005). (Al before therapy 15.25 +/- 6.6; Al with therapy 6.07 +/- 3.7). Using a validated ambulatory respiratory evaluation device we saw an improvement in the Al of 57% +/- 19% during the estimated sleeptime of 6 h 12 min +/- 30 min. After a wearing-time of about 6 months the low complaint-score of the patients verified the high acceptance and efficacy of the modified oral appliance. CONCLUSION: The modified oral appliance of Lyon can improve disease severity, life- and sleep-quality of patients with mild to moderate OSAS. Engaged teamwork of sleep medicine and dentistry is necessary to take care of a very individual and carefully fixation and occlusion of the mandible, resulting a continuing compliance and efficacy for the patients. PMID- 10098372 TI - [Flexible bronchoscopic implantation of Accuflex and Strecker stents in malignant bronchial stenoses]. AB - Silicone and metal stents are available for the treatment of malignant bronchial stenoses. This project sought to compare the self-expanding nitinol Accuflex stent (Boston Scientific Corp; Watertown, Mass) with the passively expandable tantalum Strecker stent (Boston Scientific Corp; Watertown, Mass), both implanted by flexible bronchoscopy under local anesthesia and sedation. In 51 patients with malignant bronchial stenosis, 14 nitinol and 51 tantalum stents were used and stenoses of 75 to 100% were treated. The intervention was successful in all but one patient, a mean patency of 93% was achieved. In the follow-up period, the probability of survival was significantly lower in patients with total bronchus occlusion than in patients with stenotic alteration (44 vs 109 days; p < 0.05). In 10 patients, lung function analysis after stent implantation revealed a significant increase in PaO2 (65 vs 71 mm Hg; p < 0.01), inspiratory vital capacity (2.5 vs 2.7 L; p < 0.05), and FEV1 (1.8 vs 2.0 L; p < 0.05). Mucus retention was the main (39%) adverse factor in the early phase after stent implantation, whereas tumor penetration became the most frequent problem (67%) in the later phase. Recanalizing interventions were necessary in 18% of the cases in which tumor penetration occurred. Stent distortion occurred in 12 patients with Strecker and in none with Accuflex stents. In comparison to the Strecker stent, the self-expanding Accuflex stent is preferable owing to its excellent flexibility and faster delivery system. Both types of stents could be sufficiently deployed within the lesions and allowed for highly precise positioning. Furthermore, no general anesthesia was required. The fiber bronchoscopy mode of implantation under sedation is very efficient even for tumor patients with severe impairment of their physical and respiratory condition. PMID- 10098373 TI - [ISAAC, the world-wide study of asthma and allergies in childhood]. PMID- 10098374 TI - [Report on the 1st German Lung Day]. PMID- 10098375 TI - Making the case for psychophysiology during the era of molecular biology. AB - The Office of Behavioral and Social Sciences Research (OBSSR) at the National Institutes of Health opened in 1995 to facilitate the advancement of research on social and behavioral influences on health. The establishment of the OBSSR coincided with the ascendancy of molecular biology, with its emphasis on more reductionistic influences on health. This greater emphasis on genetic aspects of health has the potential to produce a widening chasm between biomedical research and social, behavioral, and psychological research. We discuss the chasm between sociobehavioral and biomedical research during what might be considered the era of molecular biology and propose the concept of levels of analysis as a unifying framework for research in the health sciences, using research on hypertension in African Americans as a representative example. We also argue for the primacy of psychophysiological research in bridging the chasm and furthering a multilevel perspective and summarize some of the activities of the OBSSR that are relevant to this perspective. PMID- 10098377 TI - An investigation of the auditory streaming effect using event-related brain potentials. AB - There is uncertainty concerning the extent to which the auditory streaming effect is a function of attentive or preattentive mechanisms. The mismatch negativity (MMN), which indexes preattentive acoustic processing, was used to probe whether the segregation associated with the streaming effect occurs preattentively. In Experiment 1, alternating high and low those were presented at fast and slow paces while subjects ignored the stimuli. At the slow pace, tones were heard as alternating high and low pitches, and no MMN was elicited. At the fast pace a streaming effect was induced and an MMN was observed for the low stream, indicating a preattentive locus for the streaming effect. The high deviant did not elicit an MMN. MMNs were obtained to both the high and low deviants when the interval between the across-stream deviance was lengthened to more than 250 ms in Experiment 2, indicating that the MMN system is susceptible to processing constraints. PMID- 10098376 TI - Sleep state and vagal regulation of heart period patterns in the human newborn: an extension of the polyvagal theory. AB - The influence of sleep state (i.e., active and quiet) on heart period, heart period variability, respiratory sinus arrhythmia (RSA), and the coupling between RSA and heart period was evaluated in 24 healthy full-term newborns. Electrocardiogram (ECG) data were collected, and sleep state was coded 1 hr after feeding until at least 10 min of data were collected in states of active and quiet sleep. ECG data were analyzed for the first five continuous minutes of each sleep state. Relative to active sleep, quiet sleep was associated with significantly higher amplitude RSA, lower heart period variability, and longer heart periods. Because RSA amplitude reflects the functional output of vagal pathways originating in the nucleus ambiguus, it was hypothesized that sleep state would influence how these vagal pathways regulate instantaneous changes in heart period. A new method, evaluating the instantaneous coupling of RSA and heart period, demonstrated that coupling was significantly greater during active sleep. The neurophysiological explanation extends the polyvagal theory to include potential cortical-brain stem connections. PMID- 10098378 TI - Automated face analysis by feature point tracking has high concurrent validity with manual FACS coding. AB - The face is a rich source of information about human behavior. Available methods for coding facial displays, however, are human-observer dependent, labor intensive, and difficult to standardize. To enable rigorous and efficient quantitative measurement of facial displays, we have developed an automated method of facial display analysis. In this report, we compare the results with this automated system with those of manual FACS (Facial Action Coding System, Ekman & Friesen, 1978a) coding. One hundred university students were videotaped while performing a series of facial displays. The image sequences were coded from videotape by certified FACS coders. Fifteen action units and action unit combinations that occurred a minimum of 25 times were selected for automated analysis. Facial features were automatically tracked in digitized image sequences using a hierarchical algorithm for estimating optical flow. The measurements were normalized for variation in position, orientation, and scale. The image sequences were randomly divided into a training set and a cross-validation set, and discriminant function analyses were conducted on the feature point measurements. In the training set, average agreement with manual FACS coding was 92% or higher for action units in the brow, eye, and mouth regions. In the cross-validation set, average agreement was 91%, 88%, and 81% for action units in the brow, eye, and mouth regions, respectively. Automated face analysis by feature point tracking demonstrated high concurrent validity with manual FACS coding. PMID- 10098379 TI - Phasic pupil dilation response to noxious stimulation in normal volunteers: relationship to brain evoked potentials and pain report. AB - Pupillary response to noxious stimulation was investigated in men (n = 11) and women (n = 9). Subjects experienced repeated trials of noxious electrical fingertip stimulation at four intensities, ranging from faint to barely tolerable pain. Measures included pupil dilation response (PDR), pain report (PR), and brain evoked potentials (EPs). The PDR began at 0.33 s and peaked at 1.25 s after the stimulus. Multivariate mixed-effects analyses revealed that (a) the PDR increased significantly in peak amplitude as stimulus intensity increased, (b) EP peaks at 150 and 250 ms differed significantly in both amplitude and latency across stimulus intensity, and (c) PR increased significantly with increasing stimulus intensity. Men demonstrated a significantly greater EP peak amplitude and peak latency at 150 ms than did women. With sex and stimulus intensity effects partialled out, the EP peak latency at 150 ms significantly predicted PR, and EP peak amplitude at 150 ms significantly predicted the PDR peak amplitude. PMID- 10098380 TI - An electrophysiological investigation of semantic priming with pictures of real objects. AB - Event-related potentials were recorded using color pictures of real objects. Participants made relatedness judgments for pictures that were highly, moderately, or unrelated to a picture of a preceding prime object (Experiment 1) or object identification decisions for related/easily identified, unrelated/easily identified, and unrelated/unidentifiable objects preceded by prime objects (Experiment 2). Unrelated pictures elicited larger event-related potential negativities between 225 and 500 ms than did related pictures, although the first portion of this epoch had a more frontal distribution than did the later portion. The later epoch differentiated the unrelated from the moderately related and the moderately related from the highly related pictures (Experiment 1), but the early epoch produced differences only between the unrelated and related pictures (Experiments 1 and 2). This pattern supports the existence of two separate components, an anterior, image-specific N300 and a later, central/parietal amodal N400. PMID- 10098381 TI - Fear appears fast: temporal course of startle reflex potentiation in animal fearful subjects. AB - The temporal course of startle reflex modulation and autonomic response patterns to fear-relevant and fear-irrelevant pictures in subjects with high and low levels of animal fear was investigated. Thirty-eight high-fear and 48 low-fear volunteers viewed photos of snakes and spiders and pictures of neutral and pleasant content. The slides were presented for 6 s or for only 150 ms, depending on the group. Acoustic startle probes were presented at five different times after slide onset. Relative potentiation of the startle responses started 300 ms after onset of snake/spider pictures in fearful subjects. This fear-potentiated startle effect was maintained for the later probe times and was identical in the 150-ms condition. Fear-relevant pictures also prompted a sympathetically dominated autonomic response profile in fearful persons. These data support the idea that fear can be activated very rapidly, requiring only minimal stimulus input. PMID- 10098382 TI - Neurophysiological measures of reading difficulty in very-low-birthweight children. AB - Twenty-four 8-10-year-old children (13 very low birthweight, 11 control) performed a lexical decision and a semantic classification task while event related potentials (ERPs) were recorded. Both groups were within normal range on standardized reading tests, but the very-low-birthweight group had lower scores. There were no differences between groups in reaction times or accuracy for ERP tasks. On analyses of P2a (246 ms anteriorly), P2p (336 ms posteriorly), N2a (356 ms anteriorly), and N2p (396 ms posteriorly) peaks and a late positive component, control children showed greater right than left asymmetry at P2p and greater left than right asymmetry at N2a. Very-low-birthweight children showed less asymmetry. For the late positive component, both groups showed greater left than right asymmetry, which was more marked for the semantic classification task. The results suggest that very-low-birthweight children display differing cortical utilization during reading. PMID- 10098383 TI - Workday communication and ambulatory blood pressure: implications for the reactivity hypothesis. AB - Ambulatory blood pressure monitoring was used to investigate the cardiovascular correlates of naturally occurring interpersonal interactions. Participants were New York City traffic agents, who routinely engage in conflict-prone communication with the public under relatively fixed conditions. Talking with the public, supervisors, or coworkers was associated with levels of systolic and diastolic blood pressure and heart rate that exceeded a resting baseline. Blood pressure was higher when agents were talking to the public than when they were talking to coworkers or engaged in a noncommunicative work task. Systolic blood pressure response during communication was associated with the agent's mood. Blood pressure effects associated with communication appear to persist after the communication has ceased. Implications of these data for the reactivity hypothesis of the pathogenesis of cardiovascular disease are discussed. PMID- 10098384 TI - EEG complexity and performance measures of creative thinking. AB - The electroencephalogram (EEG) was used because of its dimensional complexity to establish a differentiation of divergent versus convergent thought, considered fundamental modes of cortical processing. In 28 men, the EEG was recorded while solving tasks of divergent and convergent thinking and during mental relaxation. The EEG during divergent thought was compared between subjects achieving high versus low performance scores on this type of task. The dimensional complexity of the EEG was greater during divergent thinking than during convergent thinking. While solving tasks of divergent thinking, subjects with high performance scores had a lower EEG dimension than did subjects with low scores, in particular over frontal cortical areas. The changes were not reflected in single frequency bands of conventional EEG analysis. Based on Hebb's view of neuron assemblies as functional processing units, the higher EEG complexity during divergent than convergent thinking could be the result of the concurrent activation of a greater number of independently oscillating processing units. PMID- 10098385 TI - Impedance cardiography-derived hemodynamic responses during baroreceptor testing with amyl nitrite and phenylephrine: a validity and reliability study. AB - Baroreflex (BR) testing with phenylephrine (PE) and amyl nitrite (AN) provided an opportunity to evaluate the ability of impedance cardiography (IC) to track the rapid hemodynamic (HD) changes elicited by these drugs. The AN response was measured after inhalation and the PE response was measured after a bolus injection in 19 subjects on two occasions. High reliability was observed for all of the HD measures. Blood pressure (BP), peripheral resistance (PR), and preejection period (PEP) decreased significantly after administration of AN, whereas heart rate (HR) and cardiac output (Q) increased. BP and total PR increased significantly after administration of PE; HR and Q decreased and PEP did not change significantly. Stroke volume did not change significantly with either drug. The BR slope was reliably elicited with AN and PE. The IC and Finapres BP consistently detected short-term changes in HD responses to AN and PE. The pharmacological interventions demonstrated that IC measures followed the course predicted by the actions of the drugs. Change in PEP and dZ/dt reflected increased contractility. The BR sensitivity was also reproducible. PMID- 10098386 TI - EEG differences in monozygotic twins discordant and concordant for schizophrenia. AB - In an electroencephalographic (EEG) study of 27 pairs of monozygotic (MZ) twins discordant for schizophrenia, 13 pairs of MZ twins concordant for schizophrenia, 40 pairs of healthy MZ twins, and 91 healthy, unrelated subjects with repeated assessments, we investigated (a) the trait quality of brainwave patterns with respect to interindividual differences, intraindividual stability over time, and within-pair MZ concordance; (b) the EEG characteristics that enable discrimination between affected and unaffected individuals; and (c) the EEG characteristics that reflect the severity of illness. In comparison with healthy control subjects, the MZ twins who were discordant and concordant for schizophrenia exhibited a much lower within-pair EEG concordance, so that EEG abnormalities associated with schizophrenia and manifested differently in the co twins concordant for schizophrenia seemed to reflect nongenetic, pathological developments of genetically identical brains. PMID- 10098387 TI - Effects of task complexity in young and old adults: reaction time and P300 latency are not always dissociated. AB - Twelve young and 11 elderly men (mean ages 21.1 and 70.1) performed a choice reaction time (RT) task in which stimulus degradation and stimulus-response (S-R) compatibility were manipulated. The extant literature has suggested that the effects of age on RT are usually augmented (multiplicative) in more difficult task conditions, but also that the effects of age on the latency of the P300 component of the event-related brain potential (ERP) are constant (additive). The results indicated that the effects of age on RT were enhanced in more difficult conditions, whether the difficulty consisted of stimulus degradation or S-R incompatibility. However, the effects of age on P300 latency were enlarged as the stimuli were degraded, but not if the S-R mapping was incompatible. Thus, it appears that task content determines if effects of age on P300 latency are additive or multiplicative. A simple model is proposed that produces the obtained pattern of effects. PMID- 10098388 TI - Concerning the automaticity of syntactic processing. AB - In a within-subjects design, event-related potentials were compared for two types of sentence-final syntactic errors: Incorrect verb inflection and incorrect word category (phrase structure). In a grammatical judgment task, these errors triggered robust N400 and P600 components. To assess the degree of automaticity of the underlying linguistic processes, the N400 and P600 effects were measured in a task for which the participants judged whether a word in a sentence was printed in upper case. In this physical judgment task, the N400 and P600 following verb inflection errors were greatly attenuated or absent, whereas those elicited by word category violation were only slightly diminished in amplitude. The data suggest that word category information is processed more automatically than inflectional information. The P600 appears to reflect a relatively controlled language-related process. PMID- 10098389 TI - Measuring liability for schizophrenia using optimized antisaccade stimulus parameters. AB - The ability to identify unaffected gene carriers within families may be crucial to the success of schizophrenia genetics studies. Data collected from three family samples (N = 365) demonstrated that poor antisaccade performance is an exceptionally promising indicator of liability for schizophrenia. A particular antisaccade task version provides large separations (5-6 sigma) between proband and normal groups. Poor antisaccade performance alone correctly identified 70% of patients in California, Utah, and Micronesia schizophrenia samples. Twenty-five to 50% of these patients' nonpsychotic first-degree relatives also had poor antisaccade performance, yielding risk ratios around 20:1 for simplex and 50:1 for multiplex schizophrenia families. Poor antisaccade performance is associated with dorsolateral prefrontal cortex pathology, suggesting that dysfunction of this circuitry also may predispose individuals to developing this disease. PMID- 10098390 TI - Combining electrophysiological and hemodynamic measures of the auditory oddball. AB - The neural mechanisms of deviancy and target detection were investigated by combining high density event-related potential (ERP) recordings with functional magnetic resonance imaging (fMRI). ERP and fMRI responses were recorded using the same paradigm and the same subjects. Unattended deviants elicited a mismatch negativity (MMN) in the ERP. In the fMRI data, activations of transverse/superior temporal gyri bilateral were found. Attended deviants generated an MMN followed by an N2/P3b complex. For this condition, fMRI activations in both superior temporal gyri and the neostriatum were found. These activations were taken as neuroanatomical constraints for the localization of equivalent current dipoles. Inverse solutions for dipole orientation provide evidence for significant activation close to Heschl's gyri during deviancy processing in the 110-160-ms time interval (MMN), whereas target detection could be modeled by two dipoles in the superior temporal gyrus between 320 and 380 ms. PMID- 10098391 TI - [Dimensions of work stress and job satisfaction in psychiatric-psychotherapeutic practice]. AB - Empirical studies of nursing in psychiatry and psychosomatics rarely consider the dialectics between work load and positive aspects of social support. Resulting from theoretical considerations and practical experiences seven dimensions were defined that might influence overall job satisfactions and stress. To measure this, a questionnaire containing 53 items was developed. This instrument was answered by 134 nurses of a psychiatric hospital. The results show that factor analysis and item analysis only partly confirm the presumptions. The five empirical scales include "stress due to work conditions and patients", "collaboration in teamwork", "collaboration with physicians and therapists", "collaboration with superiors in nursing" and "responsibility, competence and decision-making". Theoretical dimensions and empirical scales are discussed. The high work stress caused by work conditions and difficult patients is compensated by a positive evaluation of the collaboration in the nursing-team with physicians and therapists as well as with superiors. PMID- 10098393 TI - [Psychodynamic personality markers of psychotherapists in relation to therapy outcome]. AB - In the Berlin psychotherapy study data were collected not only from the patients but also from the therapists. Thus, the influence of personality variables of the therapists on the multidimensionally registered therapy success could be studied. To this end a nonlinear k-sets canonical analysis was applied resulting in a sample-specific optimal scaling. The relationship pattern of the two sets of variables found was satisfactory as regards the internal criteria of the programme as well as its clinical meaningfulness. The results can be used in similar studies for specifying therapist-related hypotheses. PMID- 10098392 TI - [Practicability and clinical relevance of routine psychological screening of patients in general internal medicine units]. AB - In medical patients, anxiety and depression are frequent but often undiagnosed problems. The aim of the present study was to test and evaluate a psychological screening in medical in-patients. Using the Hospital Anxiety and Depression Scale (HADS), we screened 454 out of 743 consecutive medical in-patients. Physical symptoms and diagnoses were also recorded. Elevated scores for anxiety and depression were found in 20.8% and 23.9%, respectively. They were relatively independent of physical findings but correlated with subjective symptoms. In a subgroup who completed the questionnaire twice, HADS scores remained constant until discharge. Cardiological patients with abnormal baseline anxiety stayed significantly longer in hospital than those who were not anxious. Over a one-year follow-up, initially depressed patients had a risk of in-hospital death that was 2.5 times higher. This effect remained stable after controlling for baseline diagnoses and indices of severity of the disease. PMID- 10098394 TI - [Forgetting of word associations in relation to indicators of emotionality. A possibility for evaluating Freud's concept of repression?]. AB - In replication of the well-known study by Levinger & Clark, 30 subjects were presented a list with 60 words under several conditions. In the first part of the experiment they had to tell the first word which came to mind as a response to the stimuli read by the experimenter. Reaction times and skin conductance reactions (SCRs) during associations were recorded. Immediately afterwards the list was read again with the instruction to recall the associations given before. In part 2 of the study, one week later, subjects had to recall again their first associations; in addition, they scaled the emotionality of the word stimuli. Intraindividual correlations were computed for indices of emotionality (reaction time, SCR, perceived emotionality) and forgetting in both short-term and long term memory. Associations accompanied by larger electrodermal reaction and showing longer reaction time were more likely to be forgotten both for short and long intervals. This is in line with Freuds concept of repression. However, alternative explanations should also be discussed. PMID- 10098395 TI - [The problem of randomization in psychotherapy studies]. PMID- 10098396 TI - Subunit positioning in photosystem II revisited. PMID- 10098397 TI - The domains of death: evolution of the apoptosis machinery. AB - Recent progress in research into programmed cell death has resulted in the identification of the principal protein domains involved in this process. The evolution of many of these domains can be traced back in evolution to unicellular eukaryotes or even bacteria, where the domains appear to be involved in other regulatory functions. Cell-death systems in animals and plants share several conserved domains, in particular the family of apoptotic ATPases; this allows us to suggest a plausible, even if still incomplete, scenario for the evolution of apoptosis. PMID- 10098398 TI - The N-termini of FAK and JAKs contain divergent band 4.1 domains. PMID- 10098399 TI - Glutamine repeats and neurodegenerative diseases: molecular aspects. AB - Eight severe inherited neurodegenerative diseases are caused by expansion of glutamine repeats in the affected proteins. In every case, proteins with repeats of fewer than 38 glutamine residues are harmless, but those with repeats of more than 41 glutamine residues form toxic neuronal nuclear aggregates in the affected neurons. Similarly, proteins that have repeats of fewer than 37 glutamine residues are soluble in vitro, whereas proteins with repeats of more than 40 glutamine residues precipitate as insoluble fibres, apparently because of a structural transition associated with the increased length. PMID- 10098400 TI - Non-mitochondrial ATP transport. AB - Exchange of organelle ATP with cytosolic ADP through the ADP/ATP carrier is a well-characterized feature of mitochondrial metabolism. Obligate intracellular bacteria, such as Rickettsia prowazekii, and higher-plant plastids possess another type of adenylate transporter, which exchanges bacterial or plastidic ADP for ATP from the eukaryotic (host cell) cytoplasm. The bacterial and plastidic transporters are similar but do not share significant sequence similarities with the mitochondrial carrier. Recent molecular and biochemical studies are providing deeper insight into the functional and evolutionary relationships between the bacterial and the plant transport proteins. PMID- 10098401 TI - Oncogenic alterations of metabolism. AB - Over seven decades ago, classical biochemical studies showed that tumors have altered metabolic profiles and display high rates of glucose uptake and glycolysis. Although these metabolic changes are not the fundamental defects that cause cancer, they might confer a common advantage on many different types of cancers, which allows the cells to survive and invade. Recent molecular studies have revealed that several of the multiple genetic alterations that cause tumor development directly affect glycolysis, the cellular response to hypoxia and the ability of tumor cells to recruit new blood vessels. PMID- 10098402 TI - The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. AB - E-cadherin-mediated cell-cell adhesion is lost during the development of most epithelial cancers. Recent evidence indicates that the loss of E-cadherin function, besides causing loss of cell-cell adhesion, might also convey signals that actively induce tumour-cell invasion and metastasis. PMID- 10098403 TI - Is protein folding hierarchic? II. Folding intermediates and transition states. AB - The folding reactions of some small proteins show clear evidence of a hierarchic process, whereas others, lacking detectable intermediates, do not. Evidence from folding intermediates and transition states suggests that folding begins locally, and that the formation of native secondary structure precedes the formation of tertiary interactions, not the reverse. Some notable examples in the literature have been interpreted to the contrary. For these examples, we have simulated the local structures that form when folding begins by using the LINUS program with nonlocal interactions turned off. Our results support a hierarchic model of protein folding. PMID- 10098404 TI - New lines of host defense: inhibition of Ty1 retrotransposition by Fus3p and NER/TFIIH. AB - The genomes of all organisms examined contain transposons whose uncontrolled movement threatens genome function. Fortunately, host cells have evolved defense mechanisms to minimize the level of transposition. In this review we discuss recent work showing that proteins involved in signal transduction and RNA transcription/DNA repair inhibit Ty1 retrotransposition in the yeast Saccharomyces cerevisiae. On the basis of these examples, we hypothesize that the level of Ty1 retrotransposition may be modulated in response to environmental stress signals that affect cellular differentiation and DNA repair. PMID- 10098405 TI - Mendel stayed home. Genomic imprinting and environmental disease susceptibility, National Institute of Environmental Health Sciences and Duke University Medical Center, Durham, NC, USA, 8-10 October 1998. PMID- 10098406 TI - Why are human G-protein-coupled receptors predominantly intronless? PMID- 10098407 TI - How the worm was won. The C. elegans genome sequencing project. AB - The genome sequence of the free-living nematode Caenorhabditis elegans is nearly complete, with resolution of the final difficult regions expected over the next few months. This will represent the first genome of a multicellular organism to be sequenced to completion. The genome is approximately 97 Mb in total, and encodes more than 19,099 proteins, considerably more than expected before sequencing began. The sequencing project--a collaboration between the Genome Sequencing Center in St Louis and the Sanger Centre in Hinxton--has lasted eight years, with the majority of the sequence generated in the past four years. Analysis of the genome sequence is just beginning and represents an effort that will undoubtedly last more than another decade. However, some interesting findings are already apparent, indicating that the scope of the project, the approach taken, and the usefulness of having the genetic blueprint for this small organism have been well worth the effort. PMID- 10098408 TI - Teeth. Where and how to make them. AB - Organs have to develop at precisely determined sites to ensure functionality of the whole organism. Organogenesis is typically regulated by a series of interactions between morphologically distinct tissues. The developing tooth of the mouse is an excellent model to study these processes and we are beginning to understand the networks regulating reciprocal tissue interactions at the molecular level. Synergistic and antagonistic effects of signaling molecules including FGFs and BMPs are recursively used to induce localized responses in the adjacent tissue layer (mesenchyme or epithelium). However, at different phases of odontogenesis these secreted growth factors have distinct effects and at the same time they are regulated by different upstream factors. The mesenchymal transcription factors Msx1 and Pax9 are initially regulated by epithelial FGFs and BMPs, but subsequently they function upstream of these signaling molecules. This cascade provides a molecular model by which reciprocal tissue interactions are controlled. PMID- 10098409 TI - It's a noisy business! Genetic regulation at the nanomolar scale. AB - Many molecules that control genetic regulatory circuits act at extremely low intracellular concentrations. Resultant fluctuations (noise) in reaction rates cause large random variation in rates of development, morphology and the instantaneous concentration of each molecular species in each cell. To achieve regulatory reliability in spite of this noise, cells use redundancy in genes as well as redundancy and extensive feedback in regulatory pathways. However, some regulatory mechanisms exploit this noise to randomize outcomes where variability is advantageous. PMID- 10098410 TI - Upheaval in the bacterial nucleoid. An active chromosome segregation mechanism. AB - Recent advances have completely overturned the classical view of chromosome segregation in bacteria. Far from being a passive process involving gradual separation of the chromosomes, an active, possibly mitotic-like machinery is now known to exist. Soon after the initiation of DNA replication, the newly replicated copies of the oriC region, behaving rather like eukaryotic centromeres, move rapidly apart towards opposite poles of the cell. They then determine the positions that will be taken up by the newly formed sister nucleoids when DNA replication has been completed. Thus, the gradual expansion of the diffuse nucleoid camouflages an underlying active mechanism. Several genes involved in chromosome segregation in bacteria have now been defined; their possible functions are discussed. PMID- 10098411 TI - RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. AB - Messenger RNAs are monitored for errors that arise during gene expression by a mechanism called RNA surveillance, with the result that most mRNAs that cannot be translated along their full length are rapidly degraded. This ensures that truncated proteins are seldom made, reducing the accumulation of rogue proteins that might be deleterious. The pathway leading to accelerated mRNA decay is referred to as nonsense-mediated mRNA decay (NMD). The proteins that catalyze steps in NMD in yeast serve two roles, one to monitor errors in gene expression and the other to control the abundance of endogenous wild-type mRNAs as part of the normal repertoire of gene expression. The NMD pathway has a direct impact on hundreds of genetic disorders in the human population, where about a quarter of all known mutations are predicted to trigger NMD. PMID- 10098412 TI - Finding a mouse: the International Mouse Strain Resource (IMSR). PMID- 10098413 TI - [Quality improvement in management of polytrauma patients]. PMID- 10098414 TI - [Management of polytrauma patients in an international comparison]. AB - Worlwide there will be an increase in polytraumatized patients. The number of death after trauma will increase from 5.1 Mill. to 8.4 Mill. The reason is the technical progress in the third world. In western countries there was a decrease in trauma death, in Germany below 8,000 due to traffic accidents in 1998. In most countries the paramedic system and ATLS are established (USA, South Africa). Long rescue times and inadequate shock treatment preclinically are the biggest problems in Russia and Greece. Worldwide the institution of trauma centers (Level I, II, III) has brought much better results comparing to nontrauma centers but is economically expensive. The annual number of polytraumatized patients (Level I 600-1,000 severe trauma, > 65 personal experience) is essential for the success rate. Infrastrucure, Algorithmus and the personal experience of the trauma leader are the keys for optimal results. One parameter for Quality measurement is the number of potentially preventable deaths. Retrospective analysis of treatment protocols and pathological results by an expert team is the best practical way. The results of level I trauma teams reach between 1 and 2% preventable deaths. A further instrument of quality improvement are Trauma registers like in US and England (MTOS) and the German Trauma register of the German Society of Trauma. The Trauma register in Germany contents till now 2.069 polytraumatized patients. The lethality is 18.6% (ISS 21 +/- 13), comparing to MTOS (ISS 12.8 +/- 11.3, lethality 9.2%). The differences in injury pattern show in the US three times more penetrating injuries than in the German Traumaregister (21.1% versus 7.2%). PMID- 10098415 TI - [Computer-assisted performance documentation. Effects in orthopedics and trauma surgery on budgets and reimbursement]. AB - Since 1995 German health maintenance laws require hospitals to document and code all referrals, admissions and discharges using the 4-digit ICD. Operative procedures are documented and coded using the ICPM. Beginning in January 1996, reimbursement for health services requires a diagnosis-related billing and payment for special procedures. The decision for billing is based on documented diagnosis and therapy. This extended request for documentation makes an online access to diagnosis and therapy with a computer-assisted coding system advisable. In 1996 in our hospital each diagnosis and operation was manually documented and coded on a form. Since the beginning of 1997, documentation and coding has been exclusively computer-assisted. On the basis of documented diagnosis and therapy the computer provides the route of reimbursement. Retrospectively we evaluated the number of charged diagnosis-related billings and payments for special procedures from January to April of 1996 and 1997. It became evident that with computer-assisted documentation and coding the number of detected and charged diagnosis-related billings and payments for special procedures was significantly increased in comparison with the previous year. PMID- 10098416 TI - [Effects of injury pattern on the predictability of 4 multiple trauma scores. Presentation of a method for identifying artifacts]. AB - When comparing two populations of multiply injured patients differences in patient characteristics must be controlled for. To measure the overall severity of injury, scaling systems are used. If after adjustment for injury severity, the proportion of deaths in the two data sets are still different, the difference is to be considered as due to the quality of care. However, this conclusion is only valid after excluding the possibility that the scale in use fails to adequately reflect certain injuries. The scope of the study is to demonstrate a method for examining this potential interference. As an example, four widely used scales were applied to the data of 418 multiply injured patients. By means of multiple logistic regression analysis, variables were selected which have an influence on prognosis in addition to a scale, thus indicating a subgroup of patients who are underrepresented by the respective scoring system. For the scales examined, these additional variables were: Head and thoracic trauma for the Polytrauma score (Oestern), abdominal and thoracic trauma for the Trauma index (Schreinlechner), thoracic trauma and age for the Trauma score (Champion), head trauma and age for the Injury Severity Score (Baker). We conclude that each score analyzed had its characteristic weak points. Prognostic quality was affected by casemix. Therefore, comparisons between groups of polytraumatized patients may be invalidated. The method outlined here is a useful means for checking a scoring system for these types of interfering variables. Therefore, it is recommended to search routinely for potentially interfering variables before applying a scale. In a given data set of multiply injured patients, appropriate adjustments can then be made for the deficiencies of the scoring system. PMID- 10098417 TI - [Dynamic gait analysis. Means for quality assurance after surgically treated ankle joint fractures]. AB - Forty-nine patients (mean age, 54 years) admitted for displaced ankle fractures were observed retrospectively to determine by clinical examination and measurement of plantar pressure distribution whether successful surgical treatment of ankle fractures had led to gait symmetry. The mean followup was 36 months (range, 19-54 months). The deviation in gait was quantified using peak pressure. Using a clinical score, most of the patients had satisfactory results. The plantar pressure distribution showed significant load asymmetries of patients with satisfactory results and those with non-satisfactory results. Dynamic gait analysis allows quantification of gait asymmetry and clinically non-visible gait disorder. PMID- 10098418 TI - [Replacement of the anterior cruciate ligament. Biomechanical studies for patellar and semitendinosus tendon fixation with a poly(D,L-lactide) interference screw]. AB - Anterior cruciate ligament (ACL) reconstruction using autologous hamstring tendons are being performed more frequently and satisfactory results have been reported. Advantages such as low donor site morbidity and ease of harvest as well as disadvantages like low initial construct stiffness have been described. Recently, it has been demonstrated that graft fixation close to the original ACL insertion sites increases anterior knee stability and graft isometry. Hamstring tendon fixation techniques using interference screws offer this possibility. To reduce the risk of graft laceration, a round threaded titanium interference screw (RCI) was developed. To improve initial fixation strength, fixation techniques for hamstring tendons with separate or attached tibial bone plugs were introduced. However, data on fixation strength do not yet exist. With respect to the proposed advantages of biodegradable implants, like undistorted magnetic resonance imaging, uncompromised revision surgery and a decreased potential of graft laceration during screw insertion, we performed pullout tests of round threaded biodegradable and round threaded titanium interference screw fixation of semitendinosus (ST) grafts with and without distally attached tibial bone plugs. Data were compared with bone-tendon-bone (BTB) graft fixation using biodegradable and conventional titanium interference screws. We used 56 proximal calf tibiae to compare maximum pullout force, screw insertion torque, and stiffness of fixation for biodegradable direct ST tendon and bone plug fixation (group I: without bone plug, group II: with bone plug) versus titanium interference screw fixation (group III: without bone plug, group IV: with bone plug). A round threaded biodegradable poly-(D, L-lactide) (Sysorb) and a round threaded titanium interference screw (RCI) were used. As a control calf bone-tendon-bone (BTB) grafts fixed with either poly-(D, L-lactide) (group V) or conventional titanium (group VI) interference screws were used. ST tendons were harvested either with or without their distally attached tibial bone plugs from human cadavers and were folded to a three-stranded graft. Specimen were loaded in a material testing machine with the applied load parallel to the long axis of the bone tunnel. Maximum pullout force of ST bone plug (group III: 717 N +/- 90, group IV: 602 N +/- 117) fixation was significantly higher than that of direct tendon (group I: 507 N +/- 93, group III: 419 N +/- 77) fixation. Maximum pullout force of biodegradable screw ST fixation was higher than that of titanium screw fixation in both settings. There was no significant difference in pullout force between biodegradable (713 N +/- 210) and titanium (822 N +/- 130) BTB graft fixation or between ST fixation with bone plug and biodegradable screw with BTB fixation. Pullout force of hamstring tendon interference screw fixation can be improved by using a biodegradable implant. In addition, initial pullout force can be greatly improved by harvesting the hamstring tendon graft with its distally attached tibial bone plug. This may be important, especially in improving tibial graft fixation. This study encourages further research in tendon-bone healing with direct interference screw fixation to confirm the potential of this advanced method. PMID- 10098419 TI - [The value of CT in classification and decision making in acetabulum fractures. A systematic analysis]. AB - The classification of acetabular fractures and especially the diagnosis of additional lesions can be misleading, when the personal experience is limited and the decisions are based only on conventional radiographs. The introduction of Spiral-CT with multiplanar reformations and 3-D views has improved the quality of visualization. Due to their higher costs, the need of these additional diagnostic tools is frequently questioned. This paper discusses the relevance of plain radiographs, 2-D-CTs, 3-D-CTs and Femursubtraction-CTs (FsCT) for the classification of acetabular fractures, based on a controlled study. METHODS: Thirty physicians with different levels of experience in acetabular surgery were divided in three groups of 10 each: group I comprised residents without operative experience in acetabular surgery, group II was physicians with 3-10 years of operative experience, and group III was experts in acetabular surgery. A total of 10 complete radiographic cases of high quality providing all levels of preoperative diagnostics (plain radiographs, 2-D-CT, CT with multiplanar reformation, 3-D-CT, Fs-CT) of different acetabular fracture types were prepared. The task for each candidate was to classify the fracture according to Letournel and to identify all additional injuries within the hip joint (e.g. marginal impaction, head fractures, etc.). The different diagnostic "levels" could be ordered stepwise according to personal need and no time limit was given. The case was finished when the candidate presented his final diagnosis. The use of the different radiographs, the preliminary diagnosis, the changes in diagnosis, and the final decisions were recorded. These findings were correlated with the different levels of experience and against a "consensus classification" which was generated by thorough discussion, and the use of intraoperative information and postoperative radiographs not accessible to the candidates. RESULTS: The "correct" fracture classification based on plain radiographs was: group I, 11%; group II, 32%; group III, 61%. Based on 2-D-CT a "correct" diagnosis was reached by 30% in group I, by 55% in group II, and by 76% in group III. With consideration of the "transient forms" in acetabular fractures based on Letournel and the 3-D-CT used mainly by group I, the rate of "correct" classifications rose to 65% in group I, 64% in group II and 83% in group III. The modifiers were diagnosed "correctly" in group I by 37%, in group II by 56%, and in group III by 73%. The use of the 3-D-CT and especially the Fs-CT by group I resulted in an improvement in the rate of correct classifications to 61%, whereas in group II the Fs-Ct was used only exceptionally. The 2-D-CT was the basis for the diagnosis of the additional lesions in acetabular fractures within all groups resulting in 73% complete diagnoses in group III. This study showed the importance of CT for the exact analysis and classification of acetabular fractures. In particular, the secondary reformations in CT and the 3-D-views dramatically improved the rate of "correct" classifications in the group of surgeons with limited personal experience in acetabular surgery. This allows the less experienced an acceptable level of "correct" diagnoses, so that the treatment options can be weighed correctly. Among the "experts" a rate of divergent classifications of approximately 20% was observed, especially in "transient" forms of acetabular fractures. PMID- 10098420 TI - [Fractures of the diaphysis in childhood. 1: Lower extremity]. PMID- 10098421 TI - [Prolonged transitory paralysis after pneumatic tourniquet use on the upper arm]. AB - A case of paralysis in a youth lasting 7.5 months caused by application of a tourniquet is described. The paralysis was induced by the brief application of excessive cuff pressure. The function of the arm nerves returned spontaneously. PMID- 10098422 TI - [Comments on the topic of attesting to health status at arrest during medical emergency care]. AB - A common problem for Emergency Room doctors on call is whether or not an arrested patient is sufficiently healthy to allow his transfer to jail. When there are signs of injury, or doubts about the patient's condition, the police must bring the patient in for medical examination to get a certification of the patient's health condition. He must be examined according to the information about his health and pre-existing conditions. Additional treatment should be undertaken, depending on patient's condition. The diagnoses must be written and summarized accurately and concisely. Additional documentation, such as photographic evidence must also be saved in the medical records. Should there be symptoms of a serious but difficult to diagnose condition, like traumatic head injury, the patient should always be admitted to the hospital. The medical certification or permission for imprisonment can not be enforced when the medical condition of the patient changes. PMID- 10098423 TI - What's your position? We have a need to know. PMID- 10098424 TI - The role of androgen deprivation in the definitive management of clinically localized prostate cancer treated with radiation therapy. AB - PURPOSE: Multiple studies exploring the use of androgen deprivation given in combination with radiotherapy (RT) for localized prostate cancer have reported significant improvements in the rates of local, regional, and biochemical control (BC). The impact of this therapeutic strategy on overall and cancer specific survival (CSS) has not been established, however. We performed a MEDLINE search of all available studies on this topic to determine if any conclusions could be reached on the efficacy of this treatment approach and the patients most suitable for its application. MATERIALS AND METHODS: A MEDLINE search was conducted to obtain all articles in the English language on the use of androgen deprivation in combination with RT for the treatment of localized prostate cancer. The medical subject headings (MeSH) used to search the MEDLINE database included: a) prostatic neoplasms; b) prostatic neoplasms/radiotherapy; c) prostatic neoplasms/androgen deprivation; d) hormone therapy; e) English; and f) 1980 to 1998. RESULTS: A total of 14 retrospective studies were identified that compared some form of androgen deprivation given in combination with RT. Most studies showed significant improvements in various measures of local/regional control and disease-free survival (DFS). Three of four studies that analyzed BC rates showed significant improvements in this endpoint but conflicting results were obtained for overall survival (OS). No study showed an improvement in CSS. Six prospective randomized trials were identified that directly compared RT with or without androgen deprivation. Again, all six studies showed improvements in some measure of local/regional control or DFS but only two studies showed an improvement in OS. One study reported a statistically significant improvement in CSS and another study showed an improvement in the rate of negative biopsies with combined treatment. CONCLUSIONS: When all available literature on androgen withdrawal given in combination with RT for the definitive treatment of localized prostate cancer was reviewed, no definite conclusions could be reached on the impact of this treatment approach on OS and CSS. However, local/regional control, DFS, and BC were almost uniformly improved with the use of androgen withdrawal suggesting that these impressive early results may translate into improved cure rates. Data from recently initiated and completed randomized trials will be needed, however, to define the impact of this approach on cancer specific mortality and the patients most suitable for it's use. PMID- 10098425 TI - The long-term effect on PSA values of incidental prostatic irradiation in patients with pelvic malignancies other than prostate cancer. AB - PURPOSE: To determine the effect of external beam radiation therapy on serum prostate-specific antigen (PSA) production by the benign prostate. METHODS AND MATERIALS: We studied a cohort of 24 men receiving treatment for cancer of the bladder or rectum. The radiation fields in all cases encompassed the prostate gland, and none of the patients were known to have prostate cancer. All patients had 2 or more PSA estimations obtained in the years following their radiation treatment. A second group of 46 patients who had undergone radical external beam radiation therapy for prostate cancer and who were clinically disease free 8-22 years later were also observed, with a median of 5.8 years of PSA observations. RESULTS: Only 3 of the 24 patients in the first group showed a significant rise of > 0.2 ng/ml in their serum PSA levels, with a median of 3.3 years follow-up from the first PSA test. Seven of 24 showed progressive declines, and 14 of 24 showed steady levels. The median PSA for this group was < or = 0.5 ng/ml. Only 6 of the 46 in the second group showed a PSA rise of > 0.2 ng/ml. Thirty-four had stable values, and 6 had further declines. Again, the median PSA for the entire group was < or = 0.5 ng/ml. CONCLUSION: Recovery of prostatic secretory function is an uncommon event after external beam radiation. The concern that this might significantly confound new definitions of biochemical failure after radical radiation for prostate cancer that are based on progressively rising PSA values thus appears to be unfounded. PMID- 10098426 TI - A comparison of daily CT localization to a daily ultrasound-based system in prostate cancer. AB - PURPOSE: Daily CT localization has been demonstrated to be a precise method of correcting radiation field placement by reducing setup and organ motion variations to facilitate dose escalation in prostate carcinoma. The purpose of this study was to evaluate the feasibility and accuracy of daily ultrasound guided localization utilizing daily CT as a standard. The relatively simple computer-assisted ultrasound-based system is designed to be an efficient means of achieving daily accuracy. METHODS AND MATERIALS: After five weeks of conformal external beam radiation therapy, 23 patients underwent a second CT simulation. Prostate-only fields based on this scan were created with no PTV margin. On each of the final conedown treatment days, a repeat CT simulation and isocenter comparison was performed. Ten of the above patients also underwent prostate localization with a newly developed ultrasound-based system (BAT) that is designed to facilitate patient positioning at the treatment machine. The portable system, which electronically imports the CT simulation target contours and isocenter, is situated adjacent to the treatment couch. Transverse and sagittal suprapubic ultrasound images are captured, and the system overlays the corresponding CT contours relative to the machine isocenter. The CT contours are maneuvered in three dimensions by a touch screen menu to match the ultrasound images. The system then displays the 3-D couch shifts required to produce field alignment. RESULTS: The BAT ultrasound system produced good quality images with minimal operator training required. The localization process was completed in less than 5 min. The absolute magnitude difference between CT and ultrasound was small (A/P range 0 to 5.9 mm, mean 3 mm +/- 1.8; Lat. range 0 to 7.9 mm, mean 2.4 mm +/- 1.8; S/I range 0 to 9 mm, mean 4.6 mm +/- 2.8). Analysis confirmed a significant correlation of isocenter shifts (A/P r = 0.66, p < 0.0001; Lat. r = 0.58, p < 0.003; S/I r = 0.78, p < 0.0001) in all dimensions, and linear regression confirmed the equivalence of the two modalities. CONCLUSIONS: Daily CT localization is a precise method to improve daily target localization in prostate carcinoma. However, it requires significant human and technical resources that limit its widespread applicability. Conversely, localization with the BAT ultrasound system is simple and expeditious by virtue of its ability to image the prostate at the treatment machine in the treatment position. Our initial evaluation revealed ultrasound targeting to be functionally equivalent to CT. This ultrasound technology is promising and warrants further investigation in more patients and at other anatomical sites. PMID- 10098427 TI - Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study. AB - PURPOSE: To study the effects on gastrointestinal and urological acute morbidity, a randomized toxicity study, comparing conventional and three-dimensional conformal radiotherapy (3DCRT) for prostate carcinoma was performed. To reveal possible volume effects, related to the observed toxicity, dose-volume histograms (DVHs) were used. METHODS AND MATERIALS: From June 1994 to March 1996, 266 patients with prostate carcinoma, stage T1-4N0M0 were enrolled in the study. All patients were treated to a dose of 66 Gy (ICRU), using the same planning procedure, treatment technique, linear accelerator, and portal imaging procedure. However, patients in the conventional treatment arm were treated with rectangular, open fields, whereas conformal radiotherapy was performed with conformally shaped fields using a multileaf collimator. All treatment plans were made with a 3D planning system. The planning target volume (PTV) was defined to be the gross target volume (GTV) + 15 mm. Acute toxicity was evaluated using the EORTC/RTOG morbidity scoring system. RESULTS: Patient and tumor characteristics were equally distributed between both study groups. The maximum toxicity was 57% grade 1 and 26% grade 2 gastrointestinal toxicity; 47% grade 1, 17% grade 2, and 2% grade > 2 urological toxicity. Comparing both study arms, a reduction in gastrointestinal toxicity was observed (32% and 19% grade 2 toxicity for conformal and conventional radiotherapy, respectively; p = 0.02). Further analysis revealed a marked reduction in medication for anal symptoms: this accounts for a large part of the statistical difference in gastrointestinal toxicity (18% vs. 14% [p = ns] grade 2 rectum/sigmoid toxicity and 16% vs. 8% [p < 0.0001] grade 2 anal toxicity for conventional and conformal radiotherapy, respectively). A strong correlation between exposure of the anus and anal toxicity was found, which explained the difference in anal toxicity between both study arms. No difference in urological toxicity between both treatment arms was found, despite a relatively large difference in bladder DVHs. CONCLUSIONS: The reduction in gastrointestinal morbidity was mainly accounted for by reduced toxicity for anal symptoms using 3DCRT. The study did not show a statistically significant reduction in acute rectum/sigmoid and bladder toxicity. PMID- 10098428 TI - Long-term morbidity and quality of life in patients with localized prostate cancer undergoing definitive radiotherapy or radical prostatectomy. AB - PURPOSE: To assess morbidity, side effects, and quality of life (QoL) in patients treated for localized prostate cancer with curative aim. METHODS AND MATERIALS: This descriptive cross-sectional study comprises 154 patients who had undergone definitive radiotherapy (RAD) and 108 patients with radical prostatectomy (PRECT) at the Norwegian Radium Hospital during 1987-1995. At least 1 year after treatment the patients completed several questionnaires assessing quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 instrument [EORTC QLQ-C30]), lower urinary tract symptoms (LUTS): International Prostate Symptom Score (IPSS), or sexuality (selected questions from the Psychosocial Adjustment to Illness Scale [PAIS]). Urinary incontinence and bowel distress were evaluated by ad hoc constructed questionnaires. A control group (OBS) consisted of 38 patients following the watch-and-wait policy. RESULTS: Twenty percent of the patients from the RAD Group had moderate (14%) or severe (6%) LUTS as compared to 12% in the PRECT group. However, 35% of men from the latter group reported moderate to severe urinary incontinence. "Overall" sexuality was moderately or severely impaired in 71% of the PRECT and 50% of the RAD patients. In the former group high age was correlated with erectile impotency (p < 0.001). In the RAD comorbidity was associated with erectile impotency (p < 0.001). Between 13-38% of the patients recorded moderate or severe bowel distress (blood per rectum: 13%; bowel cramps: 26%; flatulence: 38%), without significant differences comparing patients who had received conventional small 4-field box radiotherapy and patients who had undergone strictly conformal radiotherapy. Despite malignancy and/or treatment-related morbidity, QoL was comparable in both groups with respectively 9% and 6% RAD and PRECT patients, reporting moderately or severely impaired QoL. In the multivariate analysis physical function, emotional function and fatigue were significantly correlated with QoL, whereas sexuality, lower urinary symptoms, and urinary incontinence correlated with QoL only in the univariate analysis. CONCLUSION: In spite of considerable malignancy and/or treatment-related morbidity QoL was good or only slightly impaired in the majority of patients with localized prostate cancer who presented with stable disease > 1 year after definitive radiotherapy or radical prostatectomy with no difference as compared to the age-matched normal population. Clinicians should be aware of the fact that general QoL dimensions (physical function, emotional function, fatigue) are as a rule of greater significance for QoL than sexuality and lower urinary tract symptoms. PMID- 10098429 TI - No serious late cardiac effects after adjuvant radiotherapy following mastectomy in premenopausal women with early breast cancer. AB - PURPOSE: To assess cardiac mortality, coronary artery disease, myocardial dysfunction, and valvular heart disease in women younger than 65 years of age, at least 10 years after adjuvant radiotherapy following mastectomy in early breast cancer. METHODS AND MATERIALS: Ninety women (45-64 years old) with Stage II breast cancer without relapse, included in the South Sweden Breast Cancer Trial (premenopausal arm), with or without adjuvant postoperative radiotherapy +/- cyclophosphamide were examined with myocardial scintigraphy and echocardiography/Doppler, 10-17 years after radiotherapy. Thirty-four patients had been irradiated for left-sided tumors, 33 for right-sided tumors, and 23 patients had not been treated with radiotherapy. The radiotherapy (conventional roentgen, electron beams, and high-energy photon beams combined, in each patient) included the chest wall and the regional lymph nodes, with a specified target dose of 38-48 Gy, administered in daily fractions of 1.9-2.4 Gy, 5 days/week. RESULTS: No cardiac deaths were found among the original 275 patients randomized to adjuvant therapy. In the 90 patients examined, abnormal findings were recorded for ECG (14 patients), exercise test (5 patients), myocardial scintigraphy (6 patients), thickening of valve cusps (14 patients), and mild valvular regurgitation (20 patients). All patients had normal systolic function. Diastolic dysfunction was observed in 6 patients (abnormal relaxation in 4 patients and restrictive filling abnormality in 2 patients). Although no significant differences were found between the 3 study groups, there was a tendency to more abnormal findings after radiotherapy. CONCLUSION: Women younger than 50 years of age at the time of adjuvant radiotherapy following mastectomy in early breast cancer, had no serious cardiac sequelae 13 years (median) later, despite partly old-fashioned radiation techniques. PMID- 10098430 TI - Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada. AB - PURPOSE: To compare the risk of mortality from myocardial infarction (MI) after left-sided postlumpectomy radiotherapy (RT) to the risk after right-sided postlumpectomy RT. METHODS: We conducted a population-based cohort study of cases of invasive female breast cancer in Ontario, diagnosed between January 1, 1982 and December 31, 1987 (n = 25,570). Records of the Ontario Cancer Registry (OCR) were linked to hospital procedure and discharge abstracts and to RT records from Ontario cancer centers. A case was labelled as lumpectomy if this was the maximum breast surgery within 4 months of diagnosis. Postlumpectomy RT occurred up to 1 year postdiagnosis. Laterality was assigned from the laterality descriptor of the RT records. A case was labelled as having had a fatal MI if ICD code 410 (myocardial infarction) was recorded as the cause of death in the OCR. We used logistic regression to compare the likelihood of utilization of: 1. Dose per fraction > 2.00 Gy; 2. cobalt vs. linac; and 3. boost RT. We used life table analysis and the log rank test comparing the time to fatal MI from diagnosis of breast cancer between women who received left-sided postlumpectomy RT and women who received right-sided. We used Cox proportional hazards models to study the relative risk for left-sided cases overall, and stratified by age, RT characteristics, and among conditional survival cohorts. RESULTS: Postlumpectomy RT was received by 1,555 left-sided and 1,451 right-sided cases. With follow-up to December 31, 1995, 2% of women with left-sided RT had a fatal MI compared to 1% of women with right-sided RT. Comparison of the time to failure between women who had left-sided RT and women who had right-sided RT showed the left-sided RT group to be associated with a higher risk of fatal MI (p = 0.02). Adjusting for age at diagnosis, the relative risk for fatal MI with left-sided postlumpectomy RT was 2.10 (1.11, 3.95). CONCLUSION: Among women who received postlumpectomy RT for breast cancer in Ontario between 1982-1987, left-sided postlumpectomy RT was associated with a higher risk of fatal MI compared to right-sided. PMID- 10098431 TI - Figo IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy. AB - PURPOSE: To define patient, tumor, and treatment factors that influence the outcome of patients with FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix. METHODS AND MATERIALS: The records of 1,096 patients treated with radiation therapy between 1960 and 1993 for FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix were reviewed retrospectively. Of these, 983 (90%) were treated with curative intent and 113 were treated only to achieve palliation of symptoms. Of 907 patients who completed the intended curative treatment, 641 (71%) were treated with a combination of external beam irradiation (EBRT) and intracavitary irradiation (ICRT) and 266 (29%) were treated with EBRT only. The median duration of treatment for these 907 patients was 51 days. Between 1966 and 1980, only 52% of patients who completed treatment with curative intent received ICRT, compared with 92% of patients treated during 1981-1993, an increase that reflects an evolution in the philosophy of treatment for advanced tumors. In general, the intensity of ICRT correlated inversely with the dose of EBRT to the,central pelvis. Median follow-up of surviving patients was 134 months. RESULTS: For 983 patients treated with initial curative intent, disease specific survival (DSS) was significantly worse for those who were < 40 years old, had experienced more than a 10% weight loss, or had a hemoglobin level < 10 g/dl before or during radiation therapy. Tumor factors that correlated with a relatively poor DSS were bilateral pelvic wall involvement, clinical tumor diameter > or = 8 cm, hydronephrosis, lower vaginal involvement, and evidence of lymph node metastases on lymphangiogram (p < 0.01 in all cases). For the 907 patients who completed treatment with curative intent, 641 who had ICRT had a DSS of 45% at 5 years, compared with 24% for those treated with EBRT alone (p < 0.0001). Those who received > 52 Gy of EBRT to the central pelvis had DSS rates of 27-34%, compared with 53% for patients treated with lower doses of EBRT to the central pelvis and more intensive ICRT (p < 0.0001). At 5 years, the actuarial risk of major complications was also greater for patients treated with > 52 Gy of EBRT to the central pelvis (57-68%), compared with those who had 48-52 Gy (28%) and those who had < or = 47 Gy of EBRT to the central pelvis (15%) (p < 0.0001). Outcome was also compared for four time periods during which different treatment policies were in place for patients with Stage IIIB disease. The highest DSS (51%) and lowest actuarial complication rate (17%) were achieved during the most recent period (1981-1993) when modest doses of EBRT were combined with relatively intensive ICRT (p < 0.01 for both comparisons). CONCLUSION: Aggressive use of ICRT, carefully balanced with pelvic EBRT, is necessary to achieve the best ratio between tumor control and complications for patients with FIGO Stage IIIB carcinoma of the cervix. In our experience, the highest DSS rates and the lowest complication rates were achieved with a combination of 40-45 Gy of EBRT combined with ICRT. PMID- 10098432 TI - Tumor diameter/volume and pelvic node status assessed by magnetic resonance imaging (MRI) for uterine cervical cancer treated with irradiation. AB - PURPOSE: To evaluate the prognostic value of tumor diameter/volume and pelvic node status assessed by magnetic resonance imaging (MRI) in patients with uterine cervical cancer treated with radiation therapy. METHODS AND MATERIALS: Forty-four patients with intact uterine cervical squamous carcinoma treated with a combination of external irradiation and high-dose-rate intracavitary therapy were analyzed. Actuarial disease-free survival (DFS), pelvic control rate (PC), and distant metastasis-free rate (DMF) were analyzed by tumor diameter, volume, and pelvic node status assessed by pretreatment MRI. RESULTS: Anteroposterior (AP) and lateral (RL) tumor diameter significantly affected DFS. The 2-year DFS was 74% for patients with < 40 mm in AP diameter tumor, and 24% for > or = 40 mm tumor (p = 0.02). Whereas PC was not influenced, DMF was significantly affected by AP tumor diameter. Tumor volume did not significantly affect any endpoints. Patients with enlarged pelvic nodes had significantly poorer outcome compared to those with none on PC, DMF, and DFS. The 2-year DFS was 78% for node-negative, and 10% for node-positive patients (p = 0.0001). CONCLUSION: AP tumor diameter and pelvic lymph node status assessed by MRI were the significant prognostic factors in uterine cervical cancer treated with irradiation. Prognostic value of tumor volume should be reassessed prospectively with an appropriate imaging technique. AP tumor diameter predominantly affected the incidence of distant metastasis, and lymph node status affected both pelvic control and distant metastasis. PMID- 10098433 TI - Preirradiation evaluation and technical assessment of involved-field radiotherapy using computed tomographic (CT) simulation and neoadjuvant chemotherapy for intracranial germinoma. AB - PURPOSE: To investigate the importance of preirradiation mental and endocrinological evaluation, and the effectiveness of involved-field radiotherapy following neoadjuvant chemotherapy. METHODS AND MATERIALS: Following etoposide and cisplatin with or without ifosfamide, 13 patients with nondisseminated disease received involved-field irradiation of 24 Gy in 12 fractions within 3 weeks and 2 patients with disseminated germinoma received 24 Gy craniospinal irradiation (CSI). CT simulation was used to cover the tumor bed. RESULTS: Full scale intelligence quotient (IQ) tests given at the time of the initial radiotherapy showed less than 90 in 7 of 11 patients who had tumors involving the neurohypophyseal region, but the 4 patients who had solitary pineal tumors showed higher scores. Panhypopituitarism was observed in 9 patients with tumors involving the neurohypophyseal region. All patients are alive without disease, with a median follow-up period of 40 months. No in-field relapse was noted after the involved-field radiotherapy. One patient experienced a recurrence outside of the planning target volume. CONCLUSION: Decline of neurocognitive and endocrine functions were often seen in patients with tumors involving the hypophyseal region, but not in patients with solitary pineal germinoma before radiotherapy. Involved-field radiotherapy using 24 Gy is effective with the help of CT simulation and neoadjuvant chemotherapy. PMID- 10098434 TI - Reirradiation and lomustine in patients with relapsed high-grade gliomas. AB - PURPOSE: The aim of this study was to evaluate the toxicity, response, and survival of patients with relapsed high-grade gliomas after radiation therapy (RT) combined with lomustine (CCNU). METHODS AND MATERIALS: Thirty-one patients with relapsed gliomas at least 6 months after completion of RT were reirradiated. Twenty-four patients had a pathological diagnosis of high-grade gliomas, whereas 7 had a radiological diagnosis of relapsed malignant gliomas. The study focused on patients with high-grade relapsed gliomas. A total dose of 34.5 Gy was delivered in 23 fractions over 4.5 weeks. Oral administration of CCNU (130 mg/m2) was begun at the same time as RT, and was repeated every 6 weeks until disease progression, or up to 12 courses. RESULTS: Twelve of 24 patients had surgery before RT plus CCNU treatment. Median interval between RT courses was 14 months (range 6-73). All patients received a complete course of RT, and 22 of 24 patients received at least one course of CCNU. Objective responses were seen in 14 evaluable patients: 3 with partial response, 5 with stable disease, and 6 with progressive disease. Duration of partial response was 20, 9, and 8 months. Median time to progression and overall survival from the onset of retreatment were 8.4 months (range 1-22) and 13.7 months (range 1-63+), respectively. One case of G4 thrombocytopenia was observed. Five patients had G1 or G2 leucopenia and 3 patients had G3 leucopenia. Moderate nausea and vomiting were reported in 4 patients. One patient, after one course of CCNU, refused further chemotherapy. No significant difference in survival from relapse was found between patients who underwent surgery before RT plus CCNU and those who received only RT plus CCNU (p = 0.74). CONCLUSION: Overall, the acute toxicity was moderate, and patient compliance was good. Reirradiation of high-grade glioma was associated with modest subjective and objective response rates. It is remarkable that median overall survival from relapse was 13.7 months. PMID- 10098435 TI - Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. AB - PURPOSE: Prognostic factors in 1292 patients with brain metastases, treated in a single institution were identified in order to determine subgroups of patients suitable for selection in future trials. MATERIALS AND METHODS: From January 1981 through December 1990, 1292 patients with CT-diagnosed brain metastases were referred to the Department of Radiation Oncology, Daniel den Hoed Cancer Center, Rotterdam. The majority of patients were treated with whole brain radiotherapy (84%), the remainder were treated with steroids only or surgery and radiotherapy. Information on potential prognostic factors (age, sex, performance status, number and distribution of brain metastases, site of primary tumor, histology, interval between primary tumor and brain metastases, systemic tumor activity, serum lactate dehydrogenase, response to steroid treatment, and treatment modality) was collected. Univariate and multivariate analyses were performed to determine significant prognostic factors. Results were compared with literature findings using a review of prognostic factors in 18 published reports. RESULTS: Overall median survival was 3.4 months, with 6-month, 1-year, and 2-year survival percentages of 36%, 12%, and 4% respectively. Survival was statistically significantly different between treatment modalities, with median survival of 1.3 months in patients treated with steroids only, 3.6 months in patients treated with radiotherapy, and 8.9 months in patients treated with neurosurgery followed by radiotherapy (p < 0.0001). Multivariate analysis confirmed literature findings of the major prognostic value of treatment modality on survival of patients with brain metastases. Performance status, response to steroid treatment, systemic tumor activity, and serum lactate dehydrogenase were independent prognostic factors with the strongest impact on survival, second only to treatment modality. Site of primary tumor, age, and number of brain metastases were also identified as prognostic factors in our material, although with lesser importance. In patients with lung primaries, sex was found to have significant impact on survival. In patients with breast primaries, interval between primary tumor and development of brain metastases appeared to be a statistically significant prognostic factor. Histology in patients with lung primaries and distribution of brain metastases were not found to be statistically significant in multivariate analysis. CONCLUSIONS: In this large database, the value of established prognostic factors was confirmed and, furthermore, some less well-recognized parameters such as response to steroid treatment, serum lactate dehydrogenase, age, sex in lung primaries, and site of primary tumor were established. From the three strongest prognostic factors--performance status, response to steroids, and evidence of systemic disease--simple identification of favorable and unfavorable subgroups of patients with brain metastases can be constructed. PMID- 10098436 TI - Place of radiotherapy in the treatment of Graves' orbitopathy. AB - PURPOSE: The aim of this study is to evaluate the response of Graves' orbitopathy to irradiation, and to specify the prognostic factors allowing one to better define the indications of orbital radiotherapy. METHODS AND MATERIALS: From 1977 to 1996, 199 patients received bilateral orbital irradiation delivering 20 Gy in 10 fractions and 2 weeks for a progressive Graves' orbitopathy. 195 patients were seen between 1 and 6 months after radiotherapy. The different symptoms were studied and their response to radiation was analyzed. Factors such as age, sex, evolution of thyroid disease, history of symptoms, and previous or combined treatments were analyzed. RESULTS: The results revealed that 50 patients (26%) had a good or excellent response, 98 (50%) had a partial response, 37 (19%) were stable, 10 (5%) had a progression of disease. The signs that best responded to radiotherapy were the infiltration of soft tissues and the corneal involvement. Responses of proptosis or oculomotor disorders were more complete when these signs were not advanced at the time of treatment. Irradiation seemed to have the same efficacy when applied as first-line treatment or after failure of corticosteroids. Neither modality of treatment of hyperthyroidism nor thyroid status at the time of orbital irradiation modified the results. The best results were recorded for early or moderately advanced presentation (p = 0.05). Patients treated within a delay of 7 months after the beginning of the ophthalmopathy had better responses than patients treated later (p = 0.10). CONCLUSION: Radiation therapy was successful in Graves' orbitopathy by stopping the progression of disease in almost all cases, by improving the comfort of patients, by obtaining objective responses, and by avoiding surgical treatments particularly when signs were moderate. PMID- 10098438 TI - An analysis of anatomic landmark mobility and setup deviations in radiotherapy for lung cancer. AB - PURPOSE: To identify thoracic structures that exhibit little internal motion during irradiation and to determine setup variations in patients with lung cancer. METHODS AND MATERIALS: Intrafractional images were generated with an electronic portal-imaging device from the AP fields of 10 patients, during several fractions. To determine the intrafractional mobility of thoracic structures, visible structures were contoured in every image and matched with a reference image by means of a cross-correlation algorithm. Setup variations were determined by comparing portal images with the digitized simulator films using the stable structures as landmarks. RESULTS: Mobility was limited in the lateral direction for the trachea, thoracic wall, paraspinal line, and aortic notch, and in the craniocaudal direction for the clavicle, aortic notch, and thoracic.wall. Analysis of patient setup revealed random deviations of 2.0 mm (1 SD) in the lateral direction and 2.8 mm in the craniocaudal direction, while the systematic deviations were 2.5 and 2.0 mm (1 SD) respectively. CONCLUSIONS: We have identified thoracic structures that exhibit little internal motion in the frontal plane, and recommend that these structures be used for verifying patient setup during radiotherapy. The daily variation in the setup of lung cancer patients at our center appears to be acceptable. PMID- 10098437 TI - The incidence and clinical consequences of treatment-related bowel injury. AB - OBJECTIVE: To assess the frequency and clinical features of treatment-induced bowel injury in rectal carcinoma patients receiving perioperative external beam radiotherapy (EBRT). The frequency of and factors associated with treatment induced intestinal injury have previously not been well quantified for rectal cancer patients. Postoperative adjuvant chemoirradiation is recommended for Stage II and III rectal cancers, making such data of significant interest. METHODS AND MATERIALS: The records of 386 consecutive patients undergoing radiotherapy with or without chemotherapy (CT) for rectal carcinoma between 1981-90 were reviewed. Eight-two patients were excluded for receiving nontherapeutic EBRT or modalities other than EBRT. RESULTS: Symptomatic acute treatment-related enteritis (within 30 days of EBRT +/- CT) was diagnosed in 13 patients, 3 of whom developed chronic bowel injury. Chronic treatment-related enteritis was identified in 18 patients and reoperation was required in 17 (5% of the 304 patients with complete follow up). Chronic proctitis was documented in 38 patients, including 3 patients with small bowel injury. The probability of developing treatment-induced bowel injury at 5 years following treatment was 19%. Variables associated with an increased risk of bowel injury using multivariate analysis were transanal excision (p = 0.002), escalating radiation dose (p = 0.005), and increasing age (p = 0.01). Twenty of the affected patients required operative treatment, and 2 deaths resulted from treatment-induced enteritis. CONCLUSION: Patients with rectal carcinoma treated with EBRT +/- CT have the risk of developing treatment-induced bowel injury. The pelvic radiation dose should be limited to < or = 5040 cGy unless small bowel can be displaced. Reperitonealization of the pelvis, or other surgical methods of excluding the small intestine should be used whenever possible. PMID- 10098439 TI - The situation of radiation oncology training programs and their graduates in 1997. AB - PURPOSE: In light of concerns about the job market, the American College of Radiology (ACR) studied the employment situation of 1997 radiation oncology graduates, and the status and plans of radiation oncology training programs. METHODS AND MATERIALS: In April-May 1997, and in a December follow-up, the ACR surveyed all radiation oncology residency directors about the employment situation of their 1997 residency and fellowship graduates and about their programs. Ninety-four percent of those surveyed responded. We compared findings with surveys from 1995 and 1996. Differences were assessed with p < or = 0.05 as the test of statistical significance. RESULTS: By six months after graduation, 98% of residency graduates and all fellowship graduates were employed. Program directors reported approximately 95% of graduates had positions that reasonably matched their training and personal employment goals. Programs have reduced beginning residency slots by 22% over the past three years, and further reductions are planned. Many observers were disappointed with fill rates in the 1997 National Match, but by the December follow-up, 96% of beginning-year residency slots were filled. CONCLUSION: Unemployment continues to be low, and one "softer" indicator, the job market perceptions of residency program directors, showed improvement. PMID- 10098441 TI - Changes in the noninvasive, in vivo electrical impedance of three xenografts during the necrotic cell-response sequence. AB - PURPOSE: To investigate the noninvasive, in vivo use of electrical impedance spectroscopy (EIS) as a method for observing the real-time, cellular-level responses of a volume of tissue to therapies. Here, we studied the EIS response during the development and progression of hyperthermia-induced coagulative necrosis in three diverse human xenografts. METHODS AND MATERIALS: A necrotic cell response sequence was selectively induced in three types of subcutaneously grown human tumor xenografts by applying hyperthermia at 44.5 degrees C. The electrical impedance of the tumors was measured from 100 Hz to 10 MHZ, noninvasively, in vivo during the treatments. From the full spectrum EIS, ratios between resistivities at selected frequencies (p-ratios) were used as indicators of the changes in the electrical impedance spectra of each tumor's cell population. RESULTS: The rho-ratios consistently demonstrated characteristic, early, rapid increases which coincided with cell and organelle swelling typical of early necrosis. These increases subsequently slowed, but no decrease began before the end of treatment, unlike previous, similarly treated, thermo-sensitive EMT6 mouse tumors. This was consistent with the xenograft histology, which revealed ubiquitous, early-stage coagulative necrosis, with no gross plasma membrane damage at the end of treatment. The extent of both the necrosis and p ratio changes were similar to those seen early in the EMT6 tumor treatment. Within several days after treatment, the xenograft volumes regressed nearly completely, suggesting completion of the cell populations' necrotic response (lysing) during this period. Consistent with this, extended EIS measurements over a 24-h posttreatment period allowed tracking of the necrotic response sequence through this lysing phase for one type of xenograft. CONCLUSION: The change in the electrical impedance of a volume of tumor tissue which occurs during and/or after a hyperthermia treatment can be correlated with the extent of necrosis observed histologically in the cell population. PMID- 10098440 TI - Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study. AB - PURPOSE: To establish a successful treatment of subcutaneous fibrosis developing after high doses of gamma rays, suitable for use in clinical practice. METHODS AND MATERIALS: We used an animal model of acute localized gamma irradiation simulating accidental overexposure in humans. Three groups of 5 Large White pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of necrosis developed within a few weeks which had healed after 26 weeks to leave a block of subcutaneous fibrosis involving skin and skeletal muscle. One experimental group of 5 pigs was dosed orally for 26 weeks starting 26 weeks after irradiation with 1600 mg/120 kg body weight of pentoxifylline (PTX) included in the reconstituted food during its fabrication, and another group of 5 was dosed orally for the same period with a daily dose of 1600 mg/120 kg body weight of PTX combined with 2000 IU/120 kg body weight of alpha-tocopherol. Five irradiated control pigs were given normal food only. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Depth of scar tissue was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 26 weeks after treatment started. The density, length, width, and depth of the block of fibrotic scar tissue, and the areas and volume of its projected cutaneous surface, were compared before treatment, 6 and 13 weeks thereafter, and at 26 weeks. RESULTS: The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. No modifications were observed in the block of fibrotic scar tissue of pigs dosed with PTX alone. However, significant softening and shrinking of this block were noted in the pigs dosed with PTX + alpha-tocopherol 13 weeks after treatment started and at autopsy, when mean regression was approximately 30% for length, approximately 50% for width and depth, and approximately 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar tissue. The 50% decrease in the linear dimensions of the scar tissue, were comparable to the results obtained in our previous clinical studies, and were highly significant compared to the clinical and autopsy results for the controls. Histologic examination of the residual scar tissue revealed tissue which was more homogenous and less cellular and inflammatory than in control and PTX-dosed pigs. The tissular and cellular immunolocalization of tumor necrosis factor alpha (TNFalpha) was similar in the residual fibrotic tissues of all three groups of pigs, whereas the immunostaining of transforming growth factor beta-1(TGFbeta-1) diminished much more in the residual fibrotic scar tissue of the PTX + alpha tocopherol-dosed pigs than in the two other groups. CONCLUSIONS: The present results showed a striking regression of the subcutaneous fibrotic scar tissue that develops as a consequence of high doses of gamma rays. PMID- 10098442 TI - Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia. AB - PURPOSE: Experiments were conducted to elucidate the relationship between the changes in oxygen partial pressure (pO2) and blood flow in heated tumors with an ultimate goal of using mild temperature hyperthermia (MTH) to increase tumor oxygenation. METHODS AND MATERIALS: The blood flow and pO2 in the R3230 adenocarcinoma grown (subcutaneously) in the right hind limbs of Fischer rats were measured immediately or 24 h after heating at 40.5 degrees-43.5 degrees C for 30 or 60 min. The blood flow was measured with the radioactive microsphere method and the tumor pO2 was measured polarographically using an Eppendorf pO2 histograph. RESULTS: The tumor PO2 significantly increased immediately and 24 h after heating for 30 min at 40.5 degrees-43.5 degrees C or for 60 min at 40.5 degrees and 41.5 degrees C. On the other hand, in tumors heated at 42.5 degrees C for 60 min, the tumor pO2 immediately after heating was similar to the control value whereas that 24 h after heating was about threefold greater than the control tumor pO2. Heating at 43.5 degrees C for 60 min resulted in a significant decline in pO2 immediately after and 24 h after heating. The increase in tumor pO2 immediately after heating appeared to be due to an increase in tumor blood flow. However, the changes in tumor pO2 and tumor blood flow 24 h after heating, particularly after high thermal doses (e.g., 60 min heating at 42.5 degrees or 43.5 degrees C), were not correlated. CONCLUSION: Heating at mild temperatures (i.e., 40.5 degrees-42.5 degrees C for 30-60 min), caused thermal dose-dependent increases in pO2 in the R3230 AC tumors of Fischer rats during 0-24 h after heating. Such an increase in tumor oxygenation after MTH appeared to be due to an increase in tumor blood flow. PMID- 10098443 TI - Thrombopoietin promotes hematopoietic recovery and survival after high-dose whole body irradiation. AB - PURPOSE: The therapeutic potential of thrombopoietin (TPO), the major regulator of platelet production, was evaluated for hematopoietic recovery and survival in mice following lethal and supralethal total body irradiation (TBI). METHODS AND MATERIALS: Hematopoietic recovery was studied in C57BL6/J mice after 8 Gy TBI (gamma-rays). Survival experiments were performed with C57BL6/J and BCBA F1 mice. Two protocols of TPO administration were evaluated: treatment for 7 consecutive days (7 x 0.3 microg/mice) beginning 2 h after exposure, or a single dose (0.3 microg/mice) administered 2 h after irradiation. RESULTS: TPO improved the platelet nadir and accelerated the platelet reconstitution of irradiated mice in comparison to placebo-treated mice. Recovery of neutrophils and erythrocytes was stimulated as well. TPO induced an accelerated recovery of hematopoietic progenitors and immature multilineage progenitors in bone marrow and spleen. In addition, TPO administration induced approximately 90% survival of 8 Gy irradiated C57BL6/J mice, a TBI dose which resulted in 100% mortality within 30 days for placebo-treated mice. Single TPO administration was as effective as repeated injections for hematopoietic recovery and prevention of mortality. Dose effect survival experiments were performed in BCBA F1 mice and demonstrated that TPO shifted the LD50/30 from approximately 9.5 Gy to 10.5 Gy TBI given as a single dose, and from 14 Gy to as high as 17 Gy when TBI was given in three equal doses, each separated by 24 h. CONCLUSION: These results demonstrate that the multilineage hematopoietic effects of TPO may be advantageously used to protect against lethal bone marrow failure following high dose TBI. PMID- 10098444 TI - Growth factors: biological and clinical aspects. AB - PURPOSE: The purpose of this meeting summary is to provide an overview of cytokine research and its role in radiation oncology. METHODS AND MATERIALS: The sixth annual Radiation Workshop was held at the International Festival Institute at Round Top, TX. RESULTS: Presentations of seventeen speakers provided the framework for discussions on the biological and clinical aspects of cytokine research. CONCLUSION: Orchestration of coordinated cellular responses over the time course of radiation effects requires the interaction of many growth factors with their receptors as well as cell-cell and cell-matrix interactions. Cytokine networks and integrated systems are important in tumor development, cancer treatment, and normal and tumor response to cancer treatment. PMID- 10098445 TI - CT and PET lung image registration and fusion in radiotherapy treatment planning using the chamfer-matching method. AB - PURPOSE: We present a validation study of CT and PET lung image registration and fusion based on the chamfer-matching method. METHODS AND MATERIALS: The contours of the lung surfaces from CT and PET transmission images were automatically segmented by the thresholding technique. The chamfer-matching technique was then used to register the extracted lung surfaces. Arithmetic means of distance between the two data sets of the pleural surfaces were used as the cost function. Matching was then achieved by iteratively minimizing the cost function through three-dimensional (3D) translation and rotation with an optimization method. RESULTS: Both anatomic thoracic phantom images and clinical patient images were used to evaluate the performance of our registration system. Quantitative analysis from five patients indicates that the registration error in translation was 2-3 mm in the transverse plane, 3-4 mm in the longitudinal direction, and about 1.5 degree in rotation. Typical computing time for chamfer matching is about 1 min. The total time required to register a set of CT and PET lung images, including contour extraction, was generally less than 30 min. CONCLUSION: We have implemented and validated the chamfer-matching method for CT and PET lung image registration and fusion. Our preliminary results show that the chamfer-matching method for CT and PET images in the lung area is feasible. The described registration system has been used to facilitate target definition and treatment planning in radiotherapy. PMID- 10098446 TI - Beam intensity modulation to reduce the field sizes for conformal irradiation of lung tumors: a dosimetric study. AB - PURPOSE: In conformal radiotherapy of lung tumors, penumbra broadening in lung tissue necessitates the use of larger field sizes to achieve the same target coverage as in a homogeneous environment. In an idealized model configuration, some fundamental aspects of field size reduction were investigated, both for the static situation and for a moving tumor, while maintaining the dose homogeneity in the target volume by employing a simple beam-intensity modulation technique. METHODS AND MATERIALS: An inhomogeneous phantom, consisting of polystyrene, cork, and polystyrene layers, with a 6 x 6 x 6 cm3 polystyrene cube inside the cork representing the tumor, was used to simulate a lung cancer treatment. Film dosimetry experiments were performed for an AP-PA irradiation technique with 8-MV or 18-MV beams. Dose distributions were compared for large square fields, small square fields, and intensity-modulated fields in which additional segments increase the dose at the edge of the field. The effect of target motion was studied by measuring the dose distribution for the solid cube, displaced with respect to the beams. RESULTS: For the 18-MV beam, the field sizes required to establish a sufficient target coverage are larger than for the 8-MV beam. For each beam energy, the mean dose in cork can significantly be reduced (at least a factor of 1.6) by decreasing the field size with 2 cm, while keeping the mean target dose constant. Target dose inhomogeneity for these smaller fields is limited if the additional edge segments are applied for 8% of the number of monitor units given with the open fields. The target dose distribution averaged over a motion cycle is hardly affected if the target edge does not approach the field edge to within 3 mm. CONCLUSIONS: For lung cancer treatment, a beam energy of 8 MV is more suitable than 18 MV. The mean lung dose can be significantly reduced by decreasing the field sizes of conformal fields. The smaller fields result in the same biological effect to the tumor if the mean target dose is kept constant. Intensity modulation can be employed to maintain the same target dose homogeneity for these smaller fields. As long as the target (with a 3 mm margin) stays within the field portal, application of a margin for target motion is not necessary. PMID- 10098447 TI - Inclusion of geometrical uncertainties in radiotherapy treatment planning by means of coverage probability. AB - PURPOSE: Following the ICRU-50 recommendations, geometrical uncertainties in tumor position during radiotherapy treatments are generally included in the treatment planning by adding a margin to the clinical target volume (CTV) to yield the planning target volume (PTV). We have developed a method for automatic calculation of this margin. METHODS AND MATERIALS: Geometrical uncertainties of a specific patient group can normally be characterized by the standard deviation of the distribution of systematic deviations in the patient group (Sigma) and by the average standard deviation of the distribution of random deviations (sigma). The CTV of a patient to be planned can be represented in a 3D matrix in the treatment room coordinate system with voxel values one inside and zero outside the CTV. Convolution of this matrix with the appropriate probability distributions for translations and rotations yields a matrix with coverage probabilities (CPs) which is defined as the probability for each point to be covered by the CTV. The PTV can then be chosen as a volume corresponding to a certain iso-probability level. Separate calculations are performed for systematic and random deviations. Iso-probability volumes are selected in such a way that a high percentage of the CTV volume (on average > 99%) receives a high dose (> 95%). The consequences of systematic deviations on the dose distribution in the CTV can be estimated by calculation of dose histograms of the CP matrix for systematic deviations, resulting in a so-called dose probability histogram (DPH). A DPH represents the average dose volume histogram (DVH) for all systematic deviations in the patient group. The consequences of random deviations can be calculated by convolution of the dose distribution with the probability distributions for random deviations. Using the convolved dose matrix in the DPH calculation yields full information about the influence of geometrical uncertainties on the dose in the CTV. RESULTS: The model is demonstrated to be fast and accurate for a prostate, cervix, and lung cancer case. A CTV-to-PTV margin size which ensures at least 95% dose to (on average) 99% of the CTV, appears to be equal to about 2Sigma + 0.7sigma for three all cases. Because rotational deviations are included, the resulting margins can be anisotropic, as shown for the prostate cancer case. CONCLUSION: A method has been developed for calculation of CTV-to-PTV margins based on the assumption that the CTV should be adequately irradiated with a high probability. PMID- 10098448 TI - Geometric accuracy of field alignment in fractionated stereotactic conformal radiotherapy of brain tumors. AB - PURPOSE: To assess the accuracy of field alignment in patients undergoing three dimensional (3D) conformal radiotherapy of brain tumors, and to evaluate the impact on the definition of planning target volume and control procedures. METHODS AND MATERIALS: Geometric accuracy was analyzed in 20 patients undergoing fractionated stereotactic conformal radiotherapy for brain tumors. Rigid head fixation was achieved by using cast material. Transfer of stereotactic coordinates was performed by an external positioning device. The accuracy during treatment planning was quantitatively assessed by using repeated computed tomography (CT) examinations in treatment position (reproducibility of isocenter). Linear discrepancies were measured between treatment plan and CT examination. In addition, for each patient, a series of 20 verifications were taken in orthogonal projections. Linear discrepancies were measured between first and all subsequent verifications (accuracy during treatment delivery). RESULTS: For the total group of patients, the distribution of deviations during treatment setup showed mean values between -0.3-1.2 mm, with standard deviations (SD) of 1.3-2.0 mm. During treatment delivery, the distribution of deviations revealed mean values between 0.7-0.8 mm, with SDs of 0.5-0.6 mm, respectively. For all patients, deviations for the transition to the treatment machine were similar to deviations during subsequent treatment delivery, with 95% of all absolute deviations between less than 2.8 and 4.6 mm. CONCLUSION: Random fluctuations of field displacements during treatment planning and delivery prevail. Therefore, our quantitative data should be considered when prescribing the safety margins of the planning target volume. Repeated CT examination are useful to detect operator errors and large random or systematic deviations before start of treatment. Control procedures during treatment delivery appear to be of limited importance. In addition, our findings should help to determine "cut-off points" for corrective actions in stereotactic conformal radiotherapy of brain tumors. PMID- 10098449 TI - Scanning E-field sensor device for online measurements in annular phased-array systems. AB - PURPOSE: A measurement device for noninvasive and simultaneous control of antennas during regional radiofrequency (rf) hyperthermia and, subsequently, the estimation of the power distribution in the interior of patients are essential preconditions for further technological progress. Aiming at this, the feasibility of an electro-optical electric field sensor was investigated during clinical rf hyperthermia. MATERIAL AND METHODS: The electro-optical electric field (E-field) sensor is based on lithiumniobate crystals and the Mach-Zehnder interferometer structure, and was tested in an earlier phantom study. For this study, a mechanical scanning device was developed allowing the registration of the E-field during clinical application. Data were recorded along a curve in the water bolus of the SIGMA 60 applicator of the annular phased-array system BSD-2000 (BSD Medical Corp., Salt Lake City, UT) close to the base points of the flat biconical dipole antennas. The results were compared with modeling calculations using the finite-difference time-domain (FDTD) method. For the latter, different antenna models were assumed. For systematic registration of the E-field curves in amplitude and phase, we employed an elliptical lamp phantom with fat-equivalent ring (filled with saline solution) and an elliptical polyacrylamide phantom with acrylic glass wall. Further measurements were carried out during the treatment of 5 patients with 20 hyperthermia treatments. RESULTS: Data of both phantom and patient measurements can be satisfactorily described by the FDTD method, if the antenna model is refined by taking into account the conical form of the dipoles and the special dielectric environment of the feeding point. Phase deviations can be entered ex posteriori for correction in the calculation algorithm. A comparison of amplifier power measurement (forward and backward power) and bolus E-field scans near the antenna base points demonstrates that E-field measurements between antennas and patient are a necessity for the appropriate characterization of antenna radiation properties. These measurements are sensitive to variations of the lossy medium in position and shape, and can be correctly predicted with current models. However, the differences between different patients are moderate and unspecific in both calculations and measurements, with fluctuations at maximum of 30 degrees in phases and 40% in amplitudes. CONCLUSIONS: The measurement method presented here turned out to be a practical tool for online registration of E-fields in phases and amplitudes along arbitrary curves in a water bolus or phantom. It can be utilized to evaluate antenna design and modeling calculations and leads, thus, to a better understanding of complicated multiantenna systems. In clinical routine, it can be employed as input for patient-specific hyperthermia planning and, finally, for the realization of online control with subsequent optimization of the power distribution in the patient. PMID- 10098450 TI - Regarding Maor et al. IJROBP 41:647-650; 1998. PMID- 10098451 TI - The study of untreated syphilis in the negro male: regarding Brawley IJROBP 40:5 8; 1998. PMID- 10098452 TI - Defense against reactive oxygen species. AB - As part of the European Commission Concerted Action on Functional Food which was managed by the International Life Sciences Institute (Europe) a series of Theme Papers was produced which examined the 'state of the art' with respect to the subject matter and made recommendations for research. This paper is a summary of the paper concerned with Defence Against Reactive Oxygen species. Having reviewed the scientific literature the authors concluded that certain stringent criteria, which they identified, would need to be satisfied in order to be able to conclude that free radical events are involved in certain human diseases, and that antioxidants are capable of modulating these events and thus reducing the risk of disease. Although there is some evidence that would lead to this conclusion the authors demonstrated that there is at present insufficient evidence available on which to base a firm conclusion that antioxidants are capable of reducing risk of disease, and very little evidence that addresses the important question as to how much of the nutrients concerned are required in the diet to achieve the objective of reducing risk. Research priorities address the need in particular for the development and validation of cellular markers of oxidative damage which are required before there can be new human studies that address the question. There is also a need for more information as to the pharmacokinetics of uptake from diet, distribution and cellular concentration of the antioxidants. PMID- 10098453 TI - Can oxidative DNA damage be used as a biomarker of cancer risk in humans? Problems, resolutions and preliminary results from nutritional supplementation studies. AB - Damage to DNA by oxygen radicals and other reactive oxygen/nitrogen/chlorine species occurs in vivo despite the presence of multiple antioxidant defence and repair systems. Such damage is thought to make a significant contribution to the age-related development of cancer. Modulation of oxidative DNA damage by diet thus constitutes a "biomarker" putatively predictive of the effect of diet on cancer incidence, provided that DNA damage can be accurately quantitated by validated methods. Current issues addressed in this article include the problems of artifactual DNA oxidation during isolation and analysis, the relative merits of different analytical methods, the advantages and disadvantages of relying on measurement of 8-hydroxydeoxyguanosine (8OHdG, 8-oxodG) as an index of oxidative DNA damage, and the limited data that are so far available on how diet can affect "steady-state" levels of oxidative DNA damage in humans. It appears that such damage can be modulated by vegetable intake, although the effects of vegetables may be mediated by components different from the "classical" antioxidants vitamin C, alpha-tocopherol and beta-carotene. PMID- 10098454 TI - Excision repair of 8-hydroxyguanine in mammalian cells: the mouse Ogg1 protein as a model. AB - 8-Hydroxyguanine (8-OH-Gua) is a major mutagenic lesion produced on DNA by the oxidative stress induced by either the endogen metabolism or the exposure to external agents. In bacteria and yeast this modified base can be removed by specific DNA glycosylases. Recently a human gene coding for an 8-OH-Gua DNA glycosylase/AP lyase has been identified by its homology to the yeast OGG1. This gene is located in human chromosome 3p25, a region commonly rearranged in various cancers, specially in lung tumor cells. We report here the cloning, by sequence homology to the yeast OGG1, of a mouse cDNA coding for a 8-OH-Gua DNA glycosylase with 84% and 38% identity to the human and yeast relevant proteins, respectively. The Ogg1 gene is localized to the mouse chromosome 6E. The mouse Qgg1 cDNA, when expressed in Eschierichia coli, is capable of suppressing the spontaneous mutator phenotype of a DNA repair deficient fpg mutgamma strain. The mouse Ogg1 protein acts efficiently on duplexes in which the 8-OH-Gua is paired with a cytosine but is inactive on 8-OH-Gua: Ade pair, consistently with its proposed biological role in the avoidance of mutations. A comparison of the mouse enzyme with other eukaryotic Ogg1 enzymes is also presented. The isolation of this gene will allow the development of an animal model to study the effects of oxidative stress on carcinogenesis and degenerative diseases. PMID- 10098455 TI - Mapping oxidative DNA damage at nucleotide level. AB - DNA damage induced by reactive oxygen species (ROS) is considered an important intermediate in the pathogenesis of human conditions such as cancer and aging. By developing an oxidative-induced DNA damage mapping version of the Ligation mediated polymerase chain reaction (LMPCR) technique, we investigated the il vivo and in vitro frequencies of DNA base modifications caused by ROS in the human p53 and PGK1 gene. Intact human male fibroblasts were exposed to 50mM H2O2, or purified genomic DNA was treated with 5 mM H2O2, 100 microM Ascorbate, and 50 microM, 100 microM, or 100 microM of Cu(II), Fe(II), or Cr(VI) respectively. The damage pattern generated in vivo was nearly identical to the in vitro Cu(II) or Fe(III) damage patterns; damage was non-random with guanine bases heavily damaged. Cr(VI) generated an in vitro damage pattern similar to the other metal ions, although several unique thymine positions were damaged. Also, extra nuclear sites are a major contributor of metal ions (or metal-like ligands). These data show that the local probability of H2O2-mediated DNA damage is determined by the primary DNA sequence, with chromatin structure having a limited effect. The data suggest a model in which DNA-metal ion binding domains can accommodate different metalions. LMPCR's unique aspect is a blunt-end ligation of an asymmetric double stranded linker, permitting exponential PCR amplification. An important factor limiting the sensitivity of LMPCR is the representation of target gene DNA relative to non-targeted genes; therefore, we recently developed a method to eliminate excess non-targeted genomic DNA. Restriction enzyme-digested genomic DNA is size fractionated by Continuous Elution Electrophoresis (CEE), capturing the target sequence of interest. The amount of target DNA in the starting material for LMPCR is enriched, resulting in a stronger amplification signal. CEE provided a 24-fold increase in the signal strength attributable to strand breaks plus modified bases created by ROS in the human p53 and PGK1 genes, detected by LMPCR. We are currently taking advantage of the enhanced sensitivity of target gene-enriched LMPCR to map DNA damage induced in human breast epithelial cells exposed to non-cytotoxic concentrations of H2O2. PMID- 10098456 TI - Methodological considerations and factors affecting 8-hydroxy-2-deoxyguanosine analysis. AB - Oxidative stress is related to a number of diseases due to the formation of reactive oxygen species (ROS). There are also several substances found in the occupational environment or as life style related situations that generates ROS. A stable biomarker for oxidative stress on DNA is 8-hydroxy-2'-deoxyguanosine (8 OH-dG). A potential problem in the work-up and analysis of 8-OH-dG is oxidation of dG with false high levels as a result of analysis. This paper summarizes and discusses some of the critical moments in terms of auto-oxidation. The removal of transition metals, low temperatures, absence of isotopes (or 2'-deoxyguanosine) and incubation times are all important factors. Removal of oxygen is complicated while the problem is reduced if a nitroxide (TEMPO) is added during work-up. Certain reducing agents and enzymes could be critical if added during work-up. The application of the 32p-HPLC method to analyze 8-OH-dG is discussed. The 32P HPLC method is suitable for 8-OH-dG analysis and avoids several factors that oxidizes dG by removal of dG before addition of isotopes. Factors of crucial importance (columns, eluents, gradients and detection of 32p) for the analysis of 8-OH-dG are commented upon and certain recommendations are made to make it possible to apply the 32P-HPLC methodology for this type of analysis. PMID- 10098457 TI - Experimental study of oxidative DNA damage. AB - Animal experiments allow the study of oxidative DNA damage in target organs and the elucidation of dose-response relationships of carcinogenic and other harmful chemicals and conditions as well as the study of interactions of several factors. So far the effects of more than 50 different chemical compounds have been studied in animal experiments mainly in rats and mice, and generally with measurement of 8-oxodG with HPLC-EC. A large number of well-known carcinogens induce 8-oxodG formation in liver and/or kidneys. Moreover several animal studies have shown a close relationship between induction of dative DNA damage and tumour formation. In principle the level of oxidative DNA damage in an organ or cell may be studied by measurement of modified bases in extracted DNA by immunohistochemical visualisation, and from assays of strand breakage before and after treatment with repair enzymes. However, this level is a balance between the rates of damage and repair. Until the repair rates and capacity can be adequately assessed the rate of damage can only be estimated from the urinary excretion of repair products albeit only as an average of the entire body. A number of model compounds have been used to induce oxidative DNA damage in experimental animals. The hepatocarcinogen 2-nitropropane induces up to 10-fold increases in 8-oxodG levels in rat liver DNA. The level of 8-oxodG is also increased in kidneys and bone marrow but not in the testis. By means of 2-nitropropane we have shown correspondence between the increases in 8-oxodG in target organs and the urinary excretion of 8-oxodG and between 8-oxodG formation and the comet assay in bone marrow as well potent preventive effects of extracts of Brussels sprouts. Others have shown similar effects of green tea extracts and its components. Drawbacks of the use of 2-nitropropane as a model for oxidative DNA damage relate particularly to formation of 8-aminoguanine derivatives that may interfere with HPLC-EC assays and have unknown consequences. Other model compounds for induction of oxidative DNA damage, such as ferric nitriloacetate, iron dextran, potassium bromate and paraquat, are less potent and/or more organ specific. Inflammation and activation of an inflammatory response by phorbol esters or E. coli lipopolysaccharide (LPS) induce oxidative DNA damage in many target cells and enhance benzene-induced DNA damage in mouse bone marrow. Experimental studies provide powerful tools to investigate agents inducing and preventing oxidative damage to DNA and its role in carcinogenesis. So far, most animal experiments have concerned 8-oxodG and determination of additional damaged bases should be employed. An ideal animal model for prevention of oxidative DNA damage has yet to he developed. PMID- 10098458 TI - Facts and artifacts in the measurement of oxidative base damage to DNA. AB - This short survey is aimed at critically evaluating the main available methods for measuring oxidative base damage within cellular DNA. Emphasis is placed on separative methods which are currently widely applied. These mostly concern high performance liquid chromatography (HPLC) and gas chromatography (GC) associated with sensitive detection techniques such as electrochemistry (EC) and mass spectrometry (MS). In addition, the comparison is extended to 32p-postlabeling methods, immunoassays and measurement of two main classes of oxidative DNA damage within isolated cells. It may be concluded that the HPLC-electrochemical detection (ECD) method, even if restricted to the measurement of only a few electroactive oxidized bases and nucleosides, is the simplest and safest available method at the moment. In contrast, the more versatile GC-MS method, which requires a HPLC pre-purification step in order to prevent artifactual oxidation of overwhelming normal bases to occur during derivatization, is more tedious and its sensitivity may be questionable. Alternative simpler procedures of background prevention for the GC-MS assay, which, however, remain to be validated, include low-temperature for derivatization and addition of antioxidants to the silylating reagents. Interestingly, similar levels of 8-oxo 7,8-dihydroguanine were found in cellular DNA using HPLC-ECD, HPLC-MS/MS and HPLC/32P-postlabeling methods. However, it should be noted that the level of cellular 8-oxodGuo, thus determined, is on average basis 10-fold higher than that was inferred for more indirect measurement involving the use of DNA repair enzymes with methods on isolated cells. Further efforts should be made to resolve this apparent discrepancy. In addition, the question of the biological validation of the non-invasive measurement of oxidized bases and nucleosides in urine is addressed. PMID- 10098459 TI - Facts about the artifacts in the measurement of oxidative DNA base damage by gas chromatography-mass spectrometry. AB - Recently, several papers reported an artifactual formation of a number of modified bases from intact DNA bases during derivatization of DNA hydrolysates to be analyzed by gas chromatography-mass spectrometry (GC/MS). These reports dealt with 8-hydroxyguanine (8-OH-Gua), 5-hydroxycytosine (5-OH-Cyt), 8-hydroxyadenine (8-OH-Ade), 5-hydroxymethyluracil (5-OHMeUra) and 5-formyluracil that represent only a small percentage of the 20 or so modified DNA bases that can be analyzed by GC/MS. Removal of intact DNA bases by prepurification of calf thymus DNA hydrolysates using HPLC was shown to prevent artifactual formation of these modified bases during derivatization. It needs to be emphasized that the procedures for hydrolysis of DNA and derivatization of DNA hydrolysates used in these papers substantially differed from the established procedures previously described. Furthermore, a large number of relevant papers reporting the levels of these modified bases in DNA of various sources have been ignored. Interestingly, the levels of modified bases reported in the literature were not as high as those reported prior to prepurification. Most values for the level of 5-OH-Cyt were even lower than the level measured after prepurification. Levels of 8-OH-Ade were quite close to, or even the same as, or smaller than the level reported after prepurification. The same holds true for 5-OHMeUra and 8-OH-Gua. All these facts raise the question of the validity of the claims about the measurement of these modified DNA bases by GC/MS. A recent paper reported a complete destruction of 2, 6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-Gua) and 4,6-diamino-5 formamidopyrimidine (FapyAde) by formic acid under the conditions of DNA hydrolysis prior to GC/MS. The complete destruction of FapyGua and FapyAde by formic acid is in disagreement with the data on these compounds in the literature. These two compounds were measured by GC/MS following formic acid hydrolysis for many years in our laboratory and by other researchers with no difficulties. These facts clearly raise the question of the validity of the claims made about the previous measurements of these compounds by GC/MS. PMID- 10098460 TI - Oxidative DNA damage in vivo: relationship to age, plasma antioxidants, drug metabolism, glutathione-S-transferase activity and urinary creatinine excretion. AB - Oxidative DNA modification has been implicated in development of certain cancers and 8-oxodG, the most abundant and mutagenic DNA modification, has for some time been considered a biomarker of this activity. Urinary excretion of 8-oxodG over 24h has been used to estimate the rate of damage to DNA, and animal studies have supported this rationale. Reported determinants include tobacco smoking, heavy exercise, environmental pollution and individual oxygen consumption. Samples from three published studies were used to determine the association of urinary 8-oxodG excretion with age, plasma antioxidants, the glutathione-S-transferase phenotype and the activity of the xenobiotic metabolising enzyme CYP1A2. In the age range 35-65 years, age was not related to urinary 8-oxodG excretion, and there were no relations to either the glutathione-S-transferase phenotype or to the plasma antioxidants: vitamin C, alpha-tocopherol, beta-carotene, lycopene or coenzyme Q10. The activity of CYP1A2 showed a significant correlation in two of the three studies, as well as a significant correlation of 0.26 (p < 0.05) in the pooled data set. Regression analysis of CYP1A2 activity on 8-oxodG indicated that 33% increase in CYP1A2 activity would correspond to a doubling of 8-oxodG excretion. This finding needs to be confirmed in independent experiments. Spot morning urine samples can under certain circumstances be used to estimate 8-oxodG excretion rate provided that creatinine excretion is unchanged (in paired experiments) or comparable (in un-paired experiments), as evaluated from the correlation between 8-oxodG excretion in 24 h urine samples and in morning spot urine samples corrected for creatinine excretion (r = 0.50, p < 0.05). We conclude that 8-oxodG excretion is determined by factors like oxygen consumption and CYP1A2 activity rather than by factors like plasma antioxidant concentrations. PMID- 10098461 TI - Age-associated change in mitochondrial DNA damage. AB - There is an age-associated decline in the mitochondrial function of the Wistar rat heart. Previous reports from this lab have shown a decrease in mitochondrial cytochrome c oxidase (COX) activity associated with a reduction in COX gene and protein expression and a similar decrease in the rate of mitochondrial protein synthesis. Damage to mitochondrial DNA may contribute to this decline. Using the HPLC-Coularray system (ESA, USA), we measured levels of nuclear and mitochondrial 8-oxo-2'-deoxyguanosine (8-oxodG) from 6-month (young) and 23-month-old (senescent) rat liver DNA. We measured the sensitivity of the technique by damaging calf thymus DNA with photoactivated methylene blue for 30s up to 2h. The levels of damage were linear over the entire time course including the shorter times which showed levels comparable to those expected in liver. For the liver data, 8-oxodG was reported as a fraction of 2-deoxyguanosine (2-dG). There was no change in the levels of 8-oxodG levels in the nuclear DNA from 6 to 23-months of age. However, the levels of 8-oxodG increased 2.5-fold in the mitochondrial DNA with age. At 6 months, the level of 8-oxodG in mtDNA was 5-fold higher than nuclear and increased to approximately 12-fold higher by 23 months of age. These findings agree with other reports showing an age-associated increase in levels of mtDNA damage; however, the degree to which it increases is smaller. Such damage to the mitochondrial DNA may contribute to the age-associated decline in mitochondrial function. PMID- 10098462 TI - Reduction of 8-hydroxyguanine in human leukocyte DNA by physical exercise. AB - We investigated the effect of physical exercise on the level of 8-hydroxyguanine (8-OH-Gua), a form of oxidative DNA damage, and its repair activity in human peripheral leukocytes. Whole blood samples were collected by venipuncture from 21 healthy male volunteers (10 trained athletes and 13 untrained men), aged 19-50 years, both before and after physical exercise. Trained athletes showed a lower level of 8-OH-Gua (2.4+/-0.5/10(6) Gua, p = 0.0032) before exercise when compared to that of untrained men (6.2+/-3.5). The mean levels of 8-OH-Gua of untrained subjects decreased significantly (p = 0.0057) from 6.2+/-3.5/10(6) Gua (mean+/ SD/10(6) Gua) to 3.3+/-1.4/10(6) Gua after physical exercise. On the other hand, the mean levels of repair activity of untrained subjects significantly increased after exercise (p = 0.0093) from 0.037+/-0.024 (mean DNA cleavage ratio+/-SD) to 0.056+/-0.036. In the trained athletes 8-OH-Gua level and its repair activity were not changed before and after the exercise. We also observed inter-individual differences in 8-OH-Gua levels and its repair activities. These results suggest that physical exercise causes both rapid and long-range reduction of oxidative DNA damage in human leukocytes, with individually different efficiencies. PMID- 10098463 TI - DNA oxidation products determined with repair endonucleases in mammalian cells: types, basal levels and influence of cell proliferation. AB - Purified repair endonucleases such as Fpg protein, endonuclease III and IV allow a very sensitive quantification of various types of oxidative DNA modifications in mammalian cells. By means of these assays, the numbers of base modifications sensitive to Fpg protein, which include 8-hydroxyguanine (8-oxoG), were determined to be less than 0.3 per 10(6) bp in several types of untreated cultured mammalian cells and human lymphocytes and less than 10 per 10(6) bp in mitochondrial DNA from rat and porcine liver. Oxidative 5,6-dihydropyrimidine derivatives sensitive to endonuclease III and sites of base loss sensitive to endonuclease IV or exonuclease III were much less frequent than Fpg-sensitive modifications. Here, we summarize our indications that all Fpg-sensitive modifications are recognized under the assay conditions and that on the other hand there is no artifactual generation of oxidative damage during the analysis. In addition, we show that the steady-state levels of Fpg-sensitive modifications in human lymphocytes and in two mammalian cell lines were higher in proliferating than in resting (confluent) cells. Only some of the Fpg-sensitive base modifications induced by various oxidants are 8-oxoG residues, as demonstrated for the damage under cell-free conditions. The percentage was dependent on the species ultimately responsible for the DNA damage and was approx. 40% in the case of hydroxyl radicals and peroxynitrite, 75% for type II photosensitizers (reacting via singlet oxygen) and only 20-30% in the case of type I photosensitizers such as riboflavin and acridine orange, which are assumed to react directly with the DNA. PMID- 10098464 TI - High fat diet induced oxidative DNA damage estimated by 8-oxo-7,8-dihydro-2 deoxyguanosine excretion in rats. AB - The role of dietary fats and energy in carcinogenesis has been partly related to oxidative damage to DNA. We have investigated the effect of dietary fat content and saturation on the urinary excretion of 8-oxo-7,8dihydro-2'-deoxyguanosine (8 oxodG) in male and female rats. Groups of Fischer F344 rats (n = 6-10) were fed control chow (3.4% fat) or diets containing 21.8% corn oil or 19.8% coconut oil + 2% corn oil for 12-15 weeks. At the end of the diet intervention period 24h urine was collected for determination of 8-oxodG by HPLC. In the male groups fed control, corn oil and coconut oil diet the excretion of 8-oxodG was 403+/-150, 932+/-198 and 954+/-367pmol/kg 24 h, respectively (p < 0.05). In the female groups fed control and corn oil diet the excretion of 8-oxodG was 752+/-80 and 2206+/-282 pmol/kg 24 h, respectively (p < 0.05). Calculated per whole animal the excretion was 137+/-51, 324+/-70 and 328+/-128 pmol/24 h in the control, corn and coconut oil male groups and 156+/-21 and 464+/-56 pmol/24 h in the control and corn oil female groups, respectively ( p < 0.05). Thus, per animal or per consumed energy there was much less difference in 8-oxodG excretion between the corresponding male and female groups and only significant difference between the high fat groups. There was a close correlation (r = 0.7; p < 0.05) between 8 oxodG excretion and the energy intake. The present study suggests that a high fat diet increases oxidative DNA modification substantially irrespective of the saturation level of the fat. Energy intake appears to be the major determinant of the rate of modification. PMID- 10098465 TI - ESCODD: European Standards Committee on Oxidative DNA Damage. PMID- 10098466 TI - Measuring oxidative damage to DNA; HPLC and the comet assay compared. AB - Depending on the analytical method employed estimates of background levels of base oxidation in human DNA vary over orders of magnitude. It is now realised that oxidation of guanine in vitro can result in serious overestimation of the nucleoside by HPLC (with electrochemical detection). We have modified procedures of isolation, hydrolysis and storage of DNA with the aim of eliminating this artefact. Vacuum- or freeze-drying, and dialysis, tend to encourage oxidation. We compare results obtained with HPLC and with the comet assay, which employs lesion specific enzymes to introduce breaks in DNA at sites of oxidative damage. Although estimates of background levels of DNA oxidation using the comet assay are several-fold lower than the estimates by HPLC, both approaches have been used successfully to detect differences between human subjects or population groups that seem to relate to human disease and nutritional factors. PMID- 10098467 TI - Late onset administration of oral antioxidants prevents age-related loss of motor co-ordination and brain mitochondrial DNA damage. AB - We have studied the effect of aging on brain glutathione redox ratio, on brain mitochondrial DNA damage and on motor co-ordination in mice and the possible protective role of late onset administration of sulphur-containing antioxidants. Glutathione redox ratios change to a more oxidized state in whole brain with aging but the changes are much more pronounced when this ratio is measured in brain mitochondria. The levels of 8-oxo-7,8-dihydro-2 '-deoxyguanosine in mitochondrial DNA are much higher in the brain of old animals than in those of young ones. Late onset oral administration of sulphur-containing antioxidants partially prevents oxidation of mitochondrial glutathione and DNA. There is an inverse relationship between age-associated oxidative damage to mitochondrial DNA and motor co-ordination in old mice. PMID- 10098468 TI - Is the oocyte a non-professional phagocyte? AB - Although fertilization has been described as a series of events during which the spermatozoon penetrates the oocyte, introducing its nuclear contents, there is strong evidence that either gamete can be the active partner at different stages of this process. Indeed, while sperm motility is essential for its penetration of the egg vestments, immotile spermatozoa are capable of entering the ooplasm once they adhere to the oolemma. Entry of the spermatozoon into the oocyte appears to require two distinct but perhaps related events, namely gamete cell membrane fusion, at the level of the equatorial segment of the sperm acrosome with the oolemma, and a quasi-phagocytic event involving the incorporation by the oocyte of the rostral portion of the acrosome-reacted spermatozoon head within an oolemmal-derived vesicle. This review explores the biology of phagocytosis by macrophages and non-professional phagocytes, and in particular the roles played by phagocytosis-promoting receptors (FcgR, complement receptors and integrins), in both signal transduction and their linkage with the cytoskeleton. It asks whether the oocyte might not utilize similar mechanisms during its incorporation of the spermatozoon. PMID- 10098469 TI - Hyperactivated motility of human spermatozoa: a review of physiological function and application in assisted reproduction. AB - Hyperactivated motility is a specific movement pattern which has been recognized in mammalian spermatozoa for over 25 years. During this time, it has been established that hyperactivation is part of the complex process of sperm capacitation, which is necessary before fertilization can occur. The recent introduction of computed sperm motility analysis has allowed detailed studies of sperm movement characteristics to be undertaken, and evidence is accumulating that hyperactivated motility may correlate with fertility. In this review, the physiological consequences of hyperactivated motility, methods of measurement and their application in assisted reproduction are discussed. PMID- 10098470 TI - Is cloning the absolute evil? PMID- 10098471 TI - How identical would cloned children be? An understanding essential to the ethical debate. AB - The ban on human cloning in many countries worldwide is founded on an assumption that cloned children will be identical to each other and to their nuclear donor. This paper explores the scientific basis for this assumption, considering both the principles and practice of cloning in animals and comparing genetic and epigenetic variation in potential human clones with that in monozygotic twins. PMID- 10098472 TI - A spare or an individual? Cloning and the implications of monozygotic twinning. AB - The creation of Dolly, the cloned sheep, raises the scenario of cloning in humans. Neither the case for, nor against, the ethics of cloning in humans is discussed in this paper. Instead, it considers the neglected issue of the likely happiness or otherwise of the resulting children if they are born as monozygotic twins or triplets. The advantages and disadvantages of twinship are discussed in detail, and it is concluded that recognized medical risks, and incompletely understood psychological effects, should be given serious consideration. PMID- 10098473 TI - Dynamics of human follicular growth and in-vitro oocyte maturation. AB - The physiological trigger for meiotic resumption in the human oocyte is the surge of luteinizing hormone, but it can also occur spontaneously if oocytes are released from antral follicles and cultured in vitro. The development of novel techniques for the culture of murine oocytes has raised the possibility of growing human oocytes to maturity in vitro. Such a system could open the door to a number of techniques with revolutionary consequences. It would clearly be of benefit in basic physiological studies of follicular development, as well as being used to test the effect of toxicological substances on oocyte maturation. More significantly, such a system could provide a source of human oocytes for in vitro fertilization (IVF) where immature or germinal vesicle oocytes are cultured to maturity before being fertilized. If this can be achieved, it might facilitate oocyte cryopreservation, where surplus oocytes are stored, thus avoiding the need for repeated superovulation. A combination of immature oocyte cryopreservation for later maturation and IVF will provide the opportunity to establish oocyte banks and help overcome some of the practical and ethical dilemmas that are currently shadowing the field of reproductive medicine. PMID- 10098474 TI - Ultrastructure and viability of isolated bovine preantral follicles. AB - Techniques for the isolation of ovarian follicles and maturation of oocytes in vitro have enormous reproductive potential. Preservation of normal tissue function is vital. This study emphasizes the ultrastructure and viability of mechanically isolated bovine small (diameter 40-100 microm) preantral and large (140-450 microm) preantral/early antral follicles. Viability studies were performed for small preantral follicles. The presence of esterase activity, active mitochondria and dead cells served as parameters of oocyte and granulosa cell viability. After 1 day of culture, all follicles had a viable granulosa, displaying active mitochondria and/or esterase activity in all their cells, although a few (generally <5) dead granulosa cells were present in 17% of the follicles. Of the oocytes, 35 and 80% had esterase activity and active mitochondria respectively, whereas 8% appeared dead. The percentages of oocytes showing esterase activity and active mitochondria decreased during culture, whereas the percentage of follicles with dead oocytes or dead granulosa cells strongly increased. More than 90% of the isolated small follicles showed a poor ultrastructure, especially of their oocyte, which points to a negative selective isolation of poor follicles in the present study and/or an isolation procedure induced damage of follicles. With respect to large preantral follicles, 42% of those distributed in the cortex and 64% of those isolated and cultured for 1 day had a poor ultrastructure. In contrast with the small ones, the percentage of ultrastructurally poor large preantral follicles had decreased to 27% after 5 days of culture, possibly due to better isolation and culture conditions. It is recommended to use ultrastructural and/or viability cell markers for in-vitro grown follicles to evaluate their quality, and particularly that of their oocytes. PMID- 10098475 TI - Chromosome abnormalities in human embryos. AB - The presence of numerical chromosome abnormalities in human embryos was studied using fluorescence in-situ hybridization with four or more chromosome-specific probes. When most cells of an embryo are analysed, this technique allows differentiation to be made between aneuploidy, mosaicism, haploidy and polyploidy. Abnormal types of fertilization, such as unipronucleated, tripronucleated zygotes and zygotes with uneven pronuclei, were studied using this technique. We have found a strong correlation between some types of dysmorphism with chromosomal abnormalities. In addition, the more impaired the development of an embryo, the more chromosomal abnormalities were detected in those embryos. Maternal age and other factors were linked to an increase in chromosome abnormalities (hormonal regimes, temperature changes), but not to intracytoplasmic sperm injection. PMID- 10098476 TI - Preparation of endometrium for egg donation. AB - Nowadays oocyte donation is a well established method of assisted reproduction and offers the unique opportunity to treat patients with various clinical indications, with or without ovarian function, in a novel way. In women with ovarian failure, artificial menstrual cycles are required before proceeding to oocyte donation. Oestrogen may be delivered in the form of oral tablets, transdermal patches in order to bypass the gastrointestinal tract thus avoiding first pass metabolism and by vaginal application. Our regimen is oestradiol valerate given in various concentrations, in order to mimic the regular cyclic fluctuations throughout the cycle. Progesterone may be administered in the form of oral tablets, intravaginal suppositories or rings and i.m. injections. Our results, as of most other groups, strongly support the vaginal route of progesterone administration. In women with retained ovarian function, synchronization of donor-recipient cycle presents a special problem, as there is strong evidence that a temporal window of maximal endometrial receptivity exists. Cryopreservation of donated embryos may be used to overcome the problem, but this approach has the important drawback of embryonic loss occurring after freezing and thawing. The method of choice is the administration of gonadotrophin releasing hormone agonists (GnRHa) to render the patients functionally agonadal in order to circumvent cycle asynchrony between the donor and recipient. PMID- 10098477 TI - Recombinant follicle stimulating hormone: development of the first biotechnology product for the treatment of infertility. Recombinant Human FSH Product Development Group. AB - Genes encoding the common gonadotrophin alpha subunit and follicle stimulating hormone (FSH)-specific beta subunit were isolated from a DNA library derived from human fetal liver cells, and inserted into separate expression vectors containing a selectable/amplifiable gene. These vectors were inserted into the genome of the Chinese hamster ovary cell line, resulting in expression of large amounts of biologically active human (h)FSH. This cell line was cultured on microcarrier beads in a large-scale bioreactor. hFSH in the cell culture supernatant was purified to homogeneity by a multistep process. The mature beta subunit had seven fewer amino acid residues than reported in the literature and three other differences were found in the sequence. Similar oligosaccharide structures were present on recombinant (r)-hFSH and a purified urinary (u)-hFSH preparation. In vitro and in-vivo, the biological activities of u- and r-hFSH were indistinguishable. r-hFSH was formulated in ampoules containing 75 IU FSH activity (approximately 7.5 microg FSH), which accounts for >99% of the protein content of the preparation. Studies in non-human primates and human volunteers showed the pharmacokinetics of u- and r-hFSH to be similar. In healthy volunteers, r-hFSH stimulated follicular development and induced significant increases in serum oestradiol and inhibin. Clinical experience with r-hFSH has shown it is more effective at stimulating ovarian follicle growth than urinary gonadotrophins. It is also effective at initiating spermatogenesis when given together with human chorionic gonadotrophin. PMID- 10098478 TI - Controversies in the modern management of hydrosalpinx. AB - The management of hydrosalpinx is a difficult clinical problem. Surgical treatment includes fimbrioplasty for patients with fimbrial obstruction and salpingostomy to fashion a stoma in the distal Fallopian tube in patients with a damaged fimbrial end. Surgery is only suitable for a small thin-walled hydrosalpinx with healthy mucosa. These operations can be performed via laparoscopy or open microsurgery. The proper selection of patients for surgical treatment and of the type of surgical technique are essential to achieve good results. The results of open microsurgery and laparoscopic surgery are summarized. In general, the prognosis of surgery is poor; however, in well selected cases, good results can be achieved by an experienced surgeon. In-vitro fertilization (IVF) is the main line of treatment for infertility caused by hydrosalpinx. In 1991, our group was the first to report on fluid accumulation in the uterine cavity before embryo transfer as a possible hindrance for implantation. Later, several publications reported an association between patients with hydrosalpinx and a reduced pregnancy rate when treated by IVF. The cause of a low pregnancy rate could be due to mechanical, chemical or toxic effects of the tubal fluid on the endometrium preventing implantation. All these mechanisms are reviewed in detail. The literature is controversial concerning the effect of transvaginal aspiration of hydrosalpinx on the outcome of IVF. Several reports suggest that surgical correction of the hydrosalpinx may improve the outcome of IVF. Further studies are required to verify this assumption and to find out the most suitable surgical procedure and if there is a subgroup of patients who could benefit most from salpingectomy. PMID- 10098479 TI - Seminal tract infections: impact on male fertility and treatment options. AB - Bacterial and viral infections of the genital tract may be important aetiological factors for male infertility. Infectious processes may lead to deterioration of spermatogenesis, impairment of sperm function and/or obstruction of the seminal tract. Detection of bacteria in semen does not necessarily signify infection since bacteriospermia may represent contamination, colonization or infection. Reported prevalence of Ureaplasma urealyticum in human semen varies from 10 to 40%. Enterobacteria can even be found in up to 90% of semen samples depending on the sensitivity of detection methods used. Chlamydia trachomatis is the most frequent sexually transmitted bacterial organism in industrialized countries. It is suggested that its main influence is due to sexual transmission resulting in tubal disease and subsequent infertility in the female partner rather than a direct influence on male reproductive functions. The effect of leukocytospermia on male fertility is controversial. This is probably due to different detection methods, different populations studied and to the fact that leukocyte subtypes in semen may have different functions. In addition to potentially negative effects, leukocytes may even have protective effects on spermatozoa. Only recently have amplification methods been established to detect viruses in semen with high sensitivity and specificity. It is unclear if these infections significantly contribute to male infertility. PMID- 10098480 TI - Insulin in obstetrics: a main parameter in the management of pregnancy. AB - Insulin plays a central role in human pregnancy. Maternal insulin sensitivity decreases with advancing gestation in order to provide glucose and possibly other nutrients for feto-placental growth and energy needs. Moreover, alterations of insulin metabolism are clearly involved in the development of gestational diabetes. In recent years, hyperinsulinaemia has been also proposed as a possible pathogenic factor in the development of gestational hypertension and preeclampsia; furthermore it has also been postulated that there is an involvement of insulin sensitivity in fetal growth restriction. These intriguing data have stimulated our interest in summarizing the physiopathological mechanisms by which the pancreatic hormone could be involved in obstetrics. PMID- 10098481 TI - Parathyroid hormone-related protein in cardiovascular development and blood pressure regulation. PMID- 10098483 TI - Neither functional rod photoreceptors nor rod or cone outer segments are required for the photic inhibition of pineal melatonin. AB - Pineal melatonin production is rapidly suppressed by light. In mammals, the photoreceptors mediating this response are ocular; however, definitive information regarding their nature and precise location is absent. In an attempt to define these photoreceptors, we examined the sensitivity of pineal melatonin production to inhibition by controlled irradiance monochromatic green light (lambda max 509 nm) in C3H mice bearing either of two mutations affecting the retina: retinal degeneration (rd), a disruption of rod phototransduction, and retinal degeneration slow (rds), an ablation of photoreceptor outer segments. Diurnal profiles of pineal melatonin content were similar in both mutant genotypes and in wild-type mice; melatonin peaked between 3-5 h before lights on. All three genotypes exhibited irradiance dependent inhibition of pineal melatonin content; 2.6 x 10(-2) microwatts/cm2 509 nm light induced complete suppression in all three genotypes, whereas lower irradiances were ineffective in all cases. Bilateral enucleation abolished responses even to 6 microwatts/cm2 509 nm light. These results demonstrate that the process of irradiance detection for pineal melatonin inhibition is buffered against considerable loss of photoreceptive capacity and that neither rod photoreceptors nor rod or cone outer segments are required for mediating this response in mice. PMID- 10098482 TI - Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression. AB - Leptin is believed to act through hypothalamic centers to decrease appetite and increase energy utilization, in part through enhanced thermogenesis. In this study, we examined the effects of fasting for 2 days and exogenous s.c. leptin, 200 microg every 8 h for 2 days, on the regulation of uncoupling protein (UCP) subtypes in brown adipose tissue (BAT) and gastrocnemius muscle. Northern blot analysis (UCP-1) and ribonuclease protection (UCP-2 and 3) were used for quantitative messenger RNA (mRNA) analysis, and specific antibodies were used to measure UCP-1 and UCP-3 total protein expression. Leptin, compared with vehicle, did not alter BAT UCP-1 or UCP-3 mRNA or protein expression when administered to normal ad libitum fed rats. Fasting significantly decreased BAT UCP-1 and UCP-3 mRNA expression, to 31% and 30% of ad libitum fed controls, respectively, effects which were prevented by administration of leptin to fasted rats. Fasting also significantly decreased BAT UCP-1 protein expression, to 67% of control; however, that effect was not prevented by leptin treatment. Fasting also decreased BAT UCP 3 protein, to 85% of control, an effect that was not statistically significant. Fasting, with or without leptin administration, did not affect BAT UCP-2 mRNA; however, leptin administration to ad libitum fed rats significantly increased BAT UCP-2 mRNA, to 138% of control. Fasting significantly enhanced gastrocnemius muscle UCP-3 mRNA (411% of control) and protein expression (168% of control), whereas leptin administration to fasted rats did not alter either of these effects. In summary, UCP subtype mRNA and protein are regulated in tissue- and subtype-specific fashion by leptin and food restriction. Under certain conditions, the effects of these perturbations on UCP mRNA and protein are discordant. PMID- 10098484 TI - Corticotropin-releasing factor type 1 and type 2alpha receptors regulate phosphorylation of calcium/cyclic adenosine 3',5'-monophosphate response element binding protein and activation of p42/p44 mitogen-activated protein kinase. AB - CRF exerts a key neuroregulatory control on the function of the hypothalamic pituitary-adrenal axis. These effects are thought to be mediated primarily through activation of Gs-coupled plasma membrane receptors. In the present study, we investigated the effects of activation of CRF receptors by sauvagine on signaling pathways that converge on phosphorylation of the transcription factor calcium/cAMP response element-binding protein (CREB). Studies were undertaken using CHO cell lines transfected with either rat CRF-1 or CRF-2alpha receptors. Signaling pathways were investigated using immunocytochemical, Western blot, and imaging techniques. Treatment with sauvagine increased phosphorylation of p42/p44, but not of p38 or stress-activated protein kinase (SAPK)/JUN N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases correlating with increased p42/p44 MAP kinase activity. Mobilization of intracellular Ca2+ stores was observed in cells treated with high concentrations (100 nM, 1 microM) of sauvagine. A time- and dose-dependent increase in phosphorylation of the transcription factor CREB was observed in cultures treated with sauvagine. Phosphorylation of CREB occurred at lower concentrations of sauvagine than those required to mobilize intracellular calcium stores, and phosphorylation was not blocked by the mitogen-activated protein kinase kinase inhibitor PD98059 at a concentration (1 microM) that fully inhibited phosphorylation of MAP kinase. Cotreatment of cultures with the protein kinase A inhibitor H89 (10 microM) blocked fully the stimulatory actions of sauvagine (0.1 nM, 1 nM) on phosphorylation of CREB, but not those on phosphorylation of MAP kinase. Phosphorylation of MAP kinase was partially blocked by the phosphoinositide 3 kinase inhibitor LY294002 (5 microM) and by the phosphoinositide-phospholipase C inhibitor U73122 (10 microM). These data demonstrate that cAMP-, Ca2+-, and MAP kinase-dependent signaling pathways are activated by stimulation of CRF-1 and CRF 2alpha receptors. However, in these cells, only protein kinase A-dependent pathways contribute significantly to enhanced phosphorylation of CREB. These represent the first reported observations of CRF receptor-mediated phosphorylation of the transcription factor CREB and activation of MAP kinase signal transduction pathways. PMID- 10098485 TI - Postnatal overexpression of insulin-like growth factor II in transgenic mice is associated with adrenocortical hyperplasia and enhanced steroidogenesis. AB - The influence of postnatal insulin-like growth factor II (IGF-II) overexpression on adrenal growth and function was investigated in 3-month-old male phosphoenolpyruvate carboxykinase (PEPCK) promoter human IGF-II transgenic mice, which are characterized by 4-to 6-fold elevated postnatal IGF-II serum levels. Plasma corticosterone levels of PEPCK-IGF-II transgenic mice were 2-fold higher than in age- and sex-matched controls, both in the morning (7.4 +/- 1.5 vs. 17.8 +/- 3.9 ng/ml, P < 0.01) and in the evening (33.3 +/- 6.5 vs. 65.3 +/- 12 ng/ml, P < 0.01). When PEPCK-IGF-II transgenic mice were subjected to an ACTH challenge, corticosterone levels were stimulated 6-fold, to 396 +/- 17 ng/ml after 60 min, compared with 230 +/- 24 ng/ml in the control group. In contrast to corticosterone, plasma ACTH levels were similar in transgenic and control mice, excluding an indirect effect of IGF-II at the hypothalamic or pituitary level. In vitro, the basal and ACTH-induced corticosterone production of adrenal glands from transgenic mice was higher (2-fold and 1.8-fold, respectively) than that of control organs. However, when normalized for adrenal weight, the in vitro corticosterone secretion was similar in both groups. At autopsy, adrenal weights of transgenic mice were significantly greater than those of control adrenal glands (3.3 +/- 0.2 vs. 2.0 +/- 0.2 mg, P < 0.01, n = 10). Furthermore, a local expression of human IGF-II could be demonstrated in transgenic adrenal glands by RT-PCR, whereas in normal adult mice, no adrenal expression of IGF-II was detected. Stereological investigation of adrenal glands from another set of PEPCK IGF-II transgenic mice and controls (6-month-old males) demonstrated that the increase in adrenal weight in transgenic mice is mainly caused by a 50% increase in the number of zona fasciculata cells, whereas cell volume and zonation of transgenic adrenal glands remained unchanged. In conclusion, our data indicate that postnatal overexpression of IGF-II induces an increased adrenal weight and elevated corticosterone serum levels, presumably by a direct mitogenic effect of IGF-II on adrenocortical fasciculata cells. PMID- 10098486 TI - Role of thyroid hormone in regulation of renal phosphate transport in young and aged rats. AB - In the present study, we have examined the cellular mechanisms mediating the regulation of renal proximal tubular sodium-coupled inorganic phosphate (Na/Pi) transport by thyroid hormone (T3) in young and aged rats. Young hypothyroid rats showed a marked decrease in Na/Pi cotransport activity, which was associated with parallel decreases in type II Na/Pi cotransporter (NaPi-2) protein and messenger RNA (mRNA) abundance. In contrast, administration of long-term physiological and supraphysiological doses of T3 resulted in significant increases in Na/Pi cotransport activity, protein, and mRNA levels. Nuclear run-on experiments indicated that thyroid hormone regulates NaPi-2 mRNA levels by a transcriptional mechanism. In aged rats, although there were no changes in T3 serum levels (when compared with young animals), there were significant decreases in serum Pi concentration, renal Na/Pi cotransport activity, and NaPi-2 protein and mRNA abundance. These effects were mediated, at least in part, by a reduction in the transcriptional rate of the NaPi-2 gene, probably caused by, among other factors, a smaller response to the stimulatory action of T3. Compared with young rats, the old rats exhibited less sensitivity of the Na/Pi cotransporter to thyroid hormone, with-decreased effects in both hypothyroid (inhibitory) and hyperthyroid (stimulatory) animals. PMID- 10098487 TI - Increases in circulating insulin-like growth factor I levels by the oral growth hormone secretagogue MK-0677 in the beagle are dependent upon pituitary mediation. AB - It has been well established that the spiroindoline sulfonamide MK-0677 stimulates GH secretion from the pituitary both in vitro and in vivo. MK-0677 has also been shown to increase serum insulin-like growth factor I (IGF-I) and cortisol levels in vivo; these increases are assumed to be driven by the increased serum GH and ACTH levels, respectively. However, such increases could also be due to a direct stimulatory action of MK-0677 at the level of the liver and adrenal cortex. To address this possibility, we investigated whether MK-0677 increased IGF-I and cortisol levels in hypophysectomized dogs. Baseline GH, IGF I, and cortisol responses to MK-0677 (1 mg/kg, orally) were initially determined. Hypophysectomy (hypox; n = 7) or sham surgery (sham; n = 5) was then carried out. Six days postsurgery, the GH and cortisol responses to MK-0677 were reevaluated in each dog. In addition, each dog was treated with porcine GH (PST; 0.1 IU/kg, s.c.) to confirm the responsiveness of the GH-IGF-I axis. The mean peak GH increases in response to MK-0677 in the presham dogs (83.7 +/- 19.2 ng/ml), post sham dogs (108 +/- 26.2 ng/ml), and pre-hypox dogs (121.2 +/- 13.6 ng/ml) were not significantly different. Mean peak GH levels were unchanged after MK-0677 administration in the hypox dogs (2.3 +/- 0.7 ng/ml). Before surgery, serum IGF-I levels increased to 243 +/- 27 and 224 +/- 47 ng/ml in the sham and hypox groups, respectively, after MK-0677 administration. Surgery was associated with a marked (> or =50%) decrease in serum IGF-I levels. MK-0677 administration increased IGF I levels in the sham dogs from 78 +/- 14 to 187 +/- 31 ng/ml, whereas IGF-I levels remained unchanged (17.7 +/- 2.4 ng/ml) in the-hypox dogs. PST treatment increased IGF-I levels in the sham dogs from 162 +/- 30 to 325 +/- 32 ng/ml. In the hypox dogs PST treatment restored IGF-I to physiological levels (from 17.7 +/ 2.4 to 199 +/- 41 ng/ml). Cortisol was increased after MK-0677 administration 3.7-fold in the pre-sham, 3.6-fold in the post-sham, and 3.6-fold in the pre hypox dogs, but no increase was seen in the post-hypox dogs. ACTH GEL administration (2.2 U/kg, i.m.) to hypox dogs returned cortisol to normal physiological levels, demonstrating the functional integrity of the adrenal cortex. This study demonstrates that the GH secretagogue MK-0677 does not directly stimulate an increase in serum IGF-I or cortisol levels, but depends upon the presence of an intact pituitary. PMID- 10098488 TI - Interleukin-11 stimulates proopiomelanocortin gene expression and adrenocorticotropin secretion in corticotroph cells: evidence for a redundant cytokine network in the hypothalamo-pituitary-adrenal axis. AB - We recently characterized leukemia inhibitory factor (LIF) as an important modulator of hypothalamo-pituitary-adrenal (HPA) axis activity. We now describe the role of interleukin (IL)-11, another member of the IL-6 cytokine family, in the neuro-immuno-endocrine modulation of the HPA axis. In murine hypothalamus, pituitary and corticotroph AtT-20 cells, IL-11 messenger RNA (mRNA) was detectable by RT-PCR only, whereas IL-11R mRNA transcripts were demonstrated by Northern blot. Using RT-PCR, IL-11 and IL-11R gene expression were also detected in normal human pituitaries, as well as in corticotropic and nonfunctioning pituitary adenomas. Incubation of AtT-20 cells for 24 h with 10(-9) M IL-11 stimulated ACTH secretion 1.4 +/- 0.1-fold (P < 0.01), whereas LIF at the same concentration caused a 1.5 +/- 0.1-fold increase (P < 0.001). POMC mRNA expression was induced by IL-11 (0.5 x 10(-9) M) and LIF (0.5 x 10(-9) M) 1.5 +/- 0.18-fold (P < 0.05) and 1.7 +/- 0.13-fold (P < 0.01), respectively. POMC promoter activity, assayed by a -706/+64 rat POMC promoter-luciferase construct, was stimulated by 0.5 x 10(-9) M IL-11 (1.9 +/- 0.06-fold; P < 0.001) and 5 mM Bu2cAMP (7.1 +/- 0.52-fold, P < 0.001), and combined treatment of IL-11 plus Bu2cAMP caused a synergistic 11.7+/-0.71-fold increase ofluciferase activity (P < 0.001 vs. Bu2cAMP alone). Gene expression of SOCS-3, an intracellular inhibitor of cytokine action, peaked as early as 60 min after incubation with IL-11 (0.5 x 10(-9) M) and was induced 3.5-fold. In comparison to mock-transfected AtT-20 cells (AtT-20M), stable overexpression of SOCS-3 (AtT-20S) resulted in significant inhibition of ACTH secretion induced by IL-11 alone (1.5 +/- 0.09 vs. 1.1 +/- 0.04-fold induction, P < 0.01) and IL-11 plus Bu2cAMP (2.1 +/- 0.21 vs. 1.5 +/- 0.06-fold, P < 0.05), but not by Bu2cAMP alone (1.5 +/- 0.12 vs. 1.4 +/- 0.06). In summary, human and murine pituitary express IL-11 and IL-11R transcripts. In murine corticotroph AtT-20 cells, IL- 11 induces POMC gene transcription and ACTH secretion. IL-11 induction of SOCS-3 indicates an intracellular negative feedback control of cytokine-induced POMC expression and ACTH secretion. Thus, IL-11 regulates the HPA axis similarly to LIF, providing further evidence for a redundant cytokine network in the neuro-immuno-endocrine regulation of the HPA axis. PMID- 10098489 TI - In vivo and in vitro ob gene expression and leptin secretion in rat adipocytes: evidence for a regional specific regulation by sex steroid hormones. AB - As a sexual dimorphism appears in plasma leptin levels, the aim of the present study was to investigate, in vivo and in vitro, the influence of sex steroid hormones on ob messenger RNA (mRNA) and leptin expressions in rat fat cells from various anatomical localizations. In male rats, castration resulted in a modulation of ob gene mRNA expression which was increased by 2-fold in perirenal and half-reduced in sc adipocytes. Moreover, in isolated fat cells from both perirenal and s.c. fat depots, ob gene mRNA expression was reduced by 20% after a 24-h in vitro exposure to dihydrotestosterone (10(-8) M). This effect of dihydrotestosterone on ob mRNA was prevented by exposure to the antiandrogen cyproterone acetate and also by actinomycin D. In contrast, leptin secretion from both perirenal and sc adipocytes was unchanged after 24 h exposure to dihydrotestosterone. In female rats, ovariectomy induced a 25% decrease in ob gene mRNA expression in perirenal fat cells. In vitro studies revealed that a 24 h exposure to 17-beta estradiol (10(-8) M) induced a 1.4-, 1.2-, and 1.75-fold increase in ob mRNA expression and a 3.8-, 1.65- and 2-fold increase in leptin secretion in sc, perirenal and parametrial adipocytes, respectively. Moreover, these effects were prevented by the antiestrogen ICI182780 and also by actinomycin D. Altogether, these results demonstrate that in rat adipocytes, estrogens, and androgens modulate ob gene expression at the mRNA level through sex steroid receptor-dependent transcriptional mechanisms. PMID- 10098490 TI - Connective tissue growth factor (IGFBP-rP2) expression and regulation in cultured bovine endothelial cells. AB - Media from large vessel endothelial cells (pulmonary artery, aorta) contained intact connective tissue growth factor (CTGF) and a dominant 19-kDa band. N terminal analysis of the 19-kDa band showed sequence corresponding to CTGF amino acid 181-190, suggesting that the 19-kDa band represented a proteolytic fragment of CTGF. Intact CTGF was increased by cAMP but not by transforming growth factor beta (TGFbeta). CTGF messenger RNA (mRNA) was not changed by cAMP nor TGFbeta. In two microvessel endothelial cells, mRNA was found at low levels by PCR and Northern analysis, but no CTGF protein was seen on Western analysis. In the microvessel cells, TGFbeta increased and cAMP did not change CTGF mRNA levels, with neither TGFbeta nor cAMP increasing CTGF protein. The discordance between protein and mRNA levels in large vessel and microvessel endothelial cells was mostly explained by the effects of cAMP and TGFbeta on media proteolytic activity; in large vessel cells, cAMP inhibited degradation of CTGF, whereas in microvessel cells, TGFbeta and cAMP stimulated proteolytic activity against CTGF. We conclude that in large vessel endothelial cells, cAMP increased intact CTGF protein by inhibiting degradation of CTGF, whereas TGFbeta stimulated neither CTGF mRNA nor protein; in microvessel cells, TGFbeta increased CTGF mRNA, while both TGFbeta and cAMP stimulated CTGF degradation. PMID- 10098491 TI - Expression of a leptin receptor in immortalized gonadotropin-releasing hormone secreting neurons. AB - Leptin is secreted by adipocytes and regulates food intake and energy balance through the activation of specific receptors (OB-R). Recent evidence suggests that it is also involved in the control of reproductive processes, by possibly acting on central and peripheral targets. In particular, it has been shown that leptin may indirectly stimulate GnRH release from hypothalamic fragments by acting on interneurons impinging on GnRH-secreting neurons. The possibility that leptin might additionally modulate the activity of GnRH-secreting neurons in a direct way has been addressed in the present study, by using the immortalized GnRH-secreting cell line GT1-7. The presence of OB-R messenger RNA (mRNA) (long form) was detected by RT-PCR analysis of total RNA from GT1-7 cells. An OB-R protein is also expressed in these cells, as shown by immunocytochemistry and by Western blot analysis. The latter has revealed the presence of a single immunoreactive OB-R with an approximate size of 130 kDa. To study the functionality of these receptors, the effect of leptin treatment on GnRH secretion and gene expression in GT1-7 cells were evaluated. Under static conditions, GnRH release was stimulated by exposure to low concentrations of leptin (10(-12) M after 30 min; 10(-10) M after 60 min). The 10(-12) M dose was selected for studying the effect of leptin on GnRH secretion under dynamic conditions. To this purpose, GT1-7 cells were placed in a perifusion system; treatment with leptin (10(-12) M) for 60 min stimulated GnRH release with no changes of pulse frequency. On the contrary, exposure to leptin (10(-12)-10(-10) M) for 1, 3, 6, and 24 h did not affect GnRH gene expression in GT1-7 cells. The present results indicate that GT1-7 cells possess OB-Rs and that leptin may directly affect their function. Taken together with the available reports, these findings suggest that leptin might participate in the regulation of reproductive processes by acting at multiple levels, both centrally and peripherally. PMID- 10098492 TI - A corepressor and chicken ovalbumin upstream promoter transcriptional factor proteins modulate peroxisome proliferator-activated receptor-gamma2/retinoid X receptor alpha-activated transcription from the murine lipoprotein lipase promoter. AB - Complex physiological stimuli differentially regulate the tissue-specific transcription of the lipoprotein lipase (LPL) gene. A conserved DNA recognition element (-171 to -149 bp) within the promoter functions as a transcriptional enhancer when bound by the peroxisome proliferator-activated receptor-gamma2 (PPARgamma2)/retinoid X receptor alpha (RXRalpha) heterodimer, but serves as a transcriptional silencer in the presence of unidentified double and single stranded DNA-binding proteins. To address this apparent paradox, the current study examined the effect of two classes of candidate comodulatory proteins, COUP TF (chicken ovalbumin upstream promoter transcriptional factor) and the corepressor SMRT (silencing mediator of retinoic acid receptor and thyroid receptor). The expression of COUP-TF was detected by Western and Northern blots in a preadipocyte 3T3-L1 cell model during periods corresponding to increased LPL transcription. Cotransfection of COUP-TF expression constructs in the renal epithelial 293T cell line significantly increased transcription from the LPL promoter in synergy with PPARgamma2/RXRalpha heterodimers. The COUP-TFII (ARP-1) protein specifically bound the LPL PPAR recognition element inelectromobility shift assays and interacted directly with the ligand-binding domain of PPARgamma in pull-down experiments. In contrast, cotransfection of SMRT repressed PPARgamma2/ RXRalpha-mediated LPL transcription in the absence or presence of COUP-TFII (ARP-1). The interaction between PPARgamma2 and SMRT localized to the receptor-interactive domain 2 (amino acids 1260-1495) of the SMRT protein based on cotransfection and pull-down assays. These in vitro data indicate that COUP-TF proteins and SMRT modulate PPARgamma-mediated LPL transcription in the 293T cell line. PMID- 10098493 TI - Characterization of recombinant monoclonal antithyrotropin receptor antibodies (TSHRAbs) derived from lymphocytes of patients with Graves' disease: epitope and binding study of two stimulatory TSHRAbs. AB - Anti-TSH receptor autoantibodies (TSHRAbs) are known to be involved in Graves' disease. To elucidate the molecular mechanism of the pathogenesis of Graves' disease, we previously isolated and reconstituted the Ig genes of two B cell clones (101-2 and B6B7) producing a monoclonal thyroid-stimulating antibody (TSAb), a stimulating type of TSHRAb, obtained from patients with Graves' disease. In the present study, we produced a large amount of recombinant monoclonal TSAbs in eukariotic cells using these genes and characterized them. First, we tried to identify their epitopes in the TSHR, by using a panel of mutants of the extracellular domain of the TSH receptor (TSHR). Substantial cell surface expression level of each mutant was confirmed by fluorescence-activated cell sorter analysis using a TSHRAb. Mutations in the N-terminal (but not C terminal) region of the extracellular domain of TSHR abrogated or reduced TSAb activities of both antibodies, whereas they had opposite effects on TSH activity; cAMP generation by 101-2 significantly decreased in the receptors mutated in amino acids 52-56 and 58-61, and that by B6B7 decreased in amino acids 34-37 and 58-61. Secondly, purified antibodies were radiolabeled and tested for binding to cells expressing high levels of TSHR. Although their affinities were lower than that of TSH, their binding was not displaced by TSH. The antibody binding was not mutually competitive. These findings suggest that these antibodies interact with the N-terminal region of the receptor and transduce a signal through binding sites different from TSH. We believe that this is the first report of the characterization of human monoclonal TSHRAbs on their epitopes and bindings, confirming previous reports using patient sera or murine monoclonal antibodies. PMID- 10098494 TI - Characterization of two nuclear androgen receptors in Atlantic croaker: comparison of their biochemical properties and binding specificities. AB - Two distinct androgen receptors (ARs) with different characteristics were identified in the brain and ovary of Atlantic croaker, Micropogonias undulatus. A nuclear AR, AR1, was identified in the brain that had high affinity binding sites for testosterone (T; Kd, 1.1 +/- 0.15 nM; binding capacity, 1.4 +/- 0.14 pmol/g tissue; n = 16). A second nuclear AR, AR2, was found in the ovary that had high affinity binding sites for 5alpha-dihydrotestosterone (DHT; Kd, 0.62 +/- 0.1 nM; binding capacity, 0.38 +/- 0.06 pmol/g tissue; n = 14). AR2 has physiochemical properties similar to those of other vertebrate ARs. AR2 has high affinity binding for a broad spectrum of natural and synthetic androgens, including 17alpha-methyl-5alpha-dihydrotestosterone, which has a relative binding affinity of DHT = 100% > T > mibolerone > 11-ketotestosterone = 16%, a rapid association (t1/2, 44 min) and a slow dissociation (t1/2, 45 h) rate, as well as specific binding to purified DNA. The cytosolic AR2 interacts with heat shock proteins in a manner similar to other steroid receptors, as sodium molybdate stabilizes the receptor, and it has a 7.4-7.8S sedimentation coefficient in a 5-20% sucrose gradient. In contrast, AR1 is highly specific for only a few androgens, with T = 100% relative binding affinity >> DHT >> 11-ketotestosterone > mibolerone > 17alpha-methyl-5alpha-dihydrotestosterone = 0, has rapid association (t1/2, 15 min) and dissociation (t1/2, 2.6 +/- 0.7 h) rates, and has specific binding to purified DNA upon heat activation. The cytosolic binding component sediments at 5.6-5.7S in a 5-20% sucrose gradient and is not affected by sodium molybdate, which suggests that AR1 does not interact with heat shock proteins in the usual manner. This is the first report of the presence of two different nuclear ARs displaying markedly different steroid binding specificities within a single vertebrate species. PMID- 10098495 TI - Roles of Gi and Gq/11 in mediating desensitization of the luteinizing hormone/choriogonadotropin receptor in porcine ovarian follicular membranes. AB - Although desensitization of most guanine nucleotide-binding (G) protein receptors is triggered by phosphorylation of the receptor, desensitization of the LH/CG receptor (-R) in porcine follicular ovarian membranes appears to be independent of LH/CG-R phosphorylation. We therefore evaluated whether desensitization of the LH/CG-R reflected a direct inhibition of adenylyl cyclase (AC) activity by either the alpha-subunit of Gi or betagamma-subunits derived from any of the membrane G proteins activated in response to LH/CG-R activation or whether desensitization reflected a competition between Gs and a G protein that activated phospholipase C for binding sites on the LH/CG-R. The results showed that follicular membrane AC activity was not inhibited upon activation of the LH/CG-R despite evidence that the ACs in follicular membranes, when maximally activated by forskolin, could be inhibited when membrane G proteins were activated by guanyl-5'-yl imidodiphosphate, and that pertussis toxin pretreatment of membranes raised forskolin-stimulated AC activity, consistent with a tonic inhibition of follicular membrane AC activity. Similarly, agonist-stimulated desensitization of LH/CG-R-stimulated AC activity was not inhibited by pertussis toxin. Therefore, desensitization is not the result of inhibition of AC mediated by an inhibitory Gi subunit. Follicular membrane AC was also not inhibited by Gbetagamma subunits freed with activation of Gs Gq/11, or G13, based on the inabilities of exogenous Gbetagamma to promote desensitization and of a protein that sequesters Gbetagamma to inhibit desensitization. Desensitization was also not inhibited by a Gq/11 C terminal peptide or antiserum directed toward the C-terminus of Gq/11, nor was it reversed with the addition of Gbetagamma to membranes exhibiting desensitized LH/CG-R, suggesting that desensitization is independent of coupling of the LH/CG R to Gq/11. These results indicate that agonist-dependent desensitization of LH/CG-R-stimulated AC activity is mediated by a unique mechanism. PMID- 10098496 TI - Functional receptors in the avian kidney for C-type natriuretic peptide. AB - Renal actions of avian-specific C-type natriuretic peptide (chCNP) were investigated in the conscious Pekin duck. Under conditions of steady-state renal water and salt elimination, systemic chCNP administration (6 and 30 pmol/min x kg BW for 20 min) dose dependently induced transient natriuresis and diuresis. Mean arterial pressure and heart rate remained constant throughout the experiment. Employing receptor autoradiography, binding sites specific for [125I]BH-chCNP could be localized at high density in glomeruli of both reptilian- and mammalian type nephrons, and arterioles of the avian kidney. The distal tubular zone revealed [125I]BH-chCNP binding sites at medium, the medullary cone area at low density. Using an enriched kidney membrane fraction, competitive displacement studies with [125I]BH-chCNP as radioligand and various unlabeled peptide analogs (chANP, chCNP, rANP, rBNP, frANP, rANP(4-23)) allowed the discrimination of high affinity (IC50 values 10(-10)-10(-9) M) and low-affinity (IC50 values 10(-8)-10( 7) M) binding sites different from typical mammalian receptor subtypes. Intracellular cyclic GMP formation could be demonstrated immunocytochemically for both types of glomeruli and cells of the distal tubular zone in fixed tissue sections after in vivo application of chCNP (0.8 nmol/min x kg BW; 5 min). The results obtained by combination of physiological in vivo studies and in vitro receptor analysis indicate an important role for chCNP in the modulation of avian kidney function. PMID- 10098497 TI - Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. AB - Both bone mass and serum leptin levels are increased in obesity. Because osteoblasts and adipocytes arise from a common precursor in bone marrow, we assessed the effects of human recombinant leptin on a conditionally immortalized human marrow stromal cell line, hMS2-12, with the potential to differentiate to either the osteoblast or adipocyte phenotypes. By RT-PCR and Western immunoblot analysis, the hMS2-12 cells expressed messenger RNA (mRNA) and protein for the leptin receptor. Leptin did not affect hMS2-12 cell proliferation, but resulted in dose- and time-dependent increases in mRNA and protein levels of alkaline phosphatase, type I collagen, and osteocalcin, and in a 59% increase in mineralized matrix. Leptin increased mRNA levels of lipoprotein lipase at 3 days, but decreased mRNA levels of adipsin and leptin at 9 days and decreased lipid droplet formation by 50%. Leptin did not affect the expression of Cbfa1 or peroxisome proliferator-activated receptor-gamma2, transcription factors involved in commitment to the osteoblast and adipocyte pathways, respectively. Thus, leptin acts on human marrow stromal cells to enhance osteoblast differentiation and to inhibit adipocyte differentiation. Our data support the hypothesis that leptin is a previously unrecognized, physiological regulator of these two differentiation pathways, acting primarily on maturation of stromal cells into both lineages. PMID- 10098498 TI - Signal transduction of arginine vasopressin-induced arachidonic acid release in H9c2 cardiac myoblasts: role of Ca2+ and the protein kinase C-dependent activation of p42 mitogen-activated protein kinase. AB - The mechanism of arginine vasopressin (AVP)-induced arachidonic acid (AA) release was examined in the cardiac myoblast cell line, H9c2. Stimulation of cells with AVP induced dose-dependent AA release, and this effect was completely inhibited by the V1 receptor antagonist, d(CH)5[Tyr(Me)2]AVP. AVP also produced dose dependent stimulation of inositol phosphate formation; this was not affected by pertussis toxin, indicating the presence of the V1 receptor/Gq protein/PLCbeta pathway in H9c2 cells. The concentration-response curves for these two effects of AVP overlapped. AVP induced a rapid increase in [Ca2+]i, followed by a sustained increase. The Ca2+ ionophore, A23187 or ionomycin, mimicked the effect of AVP, whereas the protein kinase C (PKC) activator, TPA, only induced a slight increase in AA release. Both the AVP- or A23187-stimulated AA release and the AVP-induced sustained [Ca2+]i increase were completely blocked in the absence of external Ca2+. The receptor-operated Ca2+ channel blocker, SKF 96365, and the inorganic Ca2+ channel blockers, Ca2+ and Ni2+, also inhibited the AVP-induced AA release. Western blots demonstrated expression of PKCalpha, betaI, epsilon, delta, and zeta in H9c2 cells; PKC inhibitors (staurosporine or Ro 31-8220) or down regulation of PKCalpha, betaI, epsilon, and delta by long-term (24 h) TPA treatment caused a partial blockade of the AVP-induced response, whereas the A23187-induced AA release was unaffected by down-regulation of these isoforms. AVP-induced, but not A23187-induced, AA release was partially blocked by the p42 MAPK cascade inhibitor, PD 98059. AVP and TPA, but not A23187, induced an increase in activity and tyrosine phosphorylation of p42 MAPK, together with a molecular weight shift, consistent with phosphorylation, of cytosolic PLA2. AVP- or TPA-induced activation and tyrosine phosphorylation of p42 MAPK were completely blocked by down-regulation of PKCalpha, betaI, epsilon, and delta, but still occurred, together with the cytosolic PLA2 mobility shift, in the absence of external Ca2+. These results show that AVP-induced AA release in H9c2 cells is secondary to activation of the V1 receptor/Gq protein/PLCP pathway, leading to an influx of extracellular Ca2+ and activation of PKCalpha, betaI, epsilon, and delta. The influx of extracellular Ca2- and DAG act, respectively, through PKC /MAPK-independent or PKC-dependent MAPK pathways to mediate AA release. PMID- 10098499 TI - 1Alpha,25-dihydroxyvitamin D3 up-regulates Bcl-2 expression and protects normal human thyrocytes from programmed cell death. AB - Apoptosis is thought to play an important role in the pathogenesis of autoimmune thyroid disease. 1alpha,25-dihydroxyvitamin D3 (VD3) has been shown to suppress several autoimmune diseases. However, the mechanism by which VD3 has these effects is not known. We evaluated the alterations in apoptosis, induced by VD3. Thyrocytes were treated with VD3, and the expression of the Bcl-2 family molecules was studied at both the messenger RNA and protein levels. It was found that VD3 significantly induced the expression of Bcl-2 messenger RNA and protein in thyrocytes but had no effect on the expression of Bcl-xl and Bax. The increase in Bcl-2 expression, mediated by VD3, correlated with protection of thyrocytes against the induction of apoptosis by either staurosporine or UV irradiation. VD3 induced increases in the expression of Bcl-2 could be mimicked by VD3 analogs with high nuclear receptor affinity, but not by analogs only with nongenomic actions. These data indicate a role for Bcl-2 in the regulation of apoptosis in thyrocytes and raise the possibility that VD3 or its agonists may have therapeutic benefit in thyroid disorders. PMID- 10098500 TI - Insulin-like growth factor I-triggered cell migration and invasion are mediated by matrix metalloproteinase-9. AB - MCF-7 cells migrate through vitronectin-coated filters in response to insulin like growth factor I (IGF-I); migration is inhibited by the matrix metalloproteinase (MMP) inhibitor BB-94, but not by the serine proteinase inhibitor aprotinin. MMP-9 was identified in the conditioned medium of MCF-7 cells; in addition, fluorescence-activated cell sorting analysis revealed its presence on the cell surface, where MMP-9 activity was also found using a specific fluorogenic peptide. Furthermore, the messenger RNA encoding MMP-9 was detected in MCF-7 cells by PCR. The IGF-I concentration leading to maximal MCF-7 invasion produces an increase in cell surface proteolytic activity after short incubation periods. At 18 h, however, preincubation of MCF-7 cells with IGF-I produces at 18 h a dose-dependent decrease in cell-associated MMP-9 activity and an increase in soluble MMP-9. MCF-7 invasion is dependent on the alpha(v)beta5 integrin, a vitronectin receptor. The levels of alpha(v)- and beta5-subunits expressed in MCF-7 cells depend on the IGF-I concentration, which triggers an increase in both of these subunits. Based on these results, we suggest that IGF-I induced MCF-7 cell migration is mediated by the MMP-9 activity on the cell surface and by alpha(v)beta5 integrin. PMID- 10098501 TI - Interactive effects of triiodothyronine and androgens on prostate cell growth and gene expression. AB - T3 plays an important role in the regulation of cell growth and differentiation. In this study, we show the interactive effects of T3 and androgens on the growth response and expression of the prostate-specific genes, PSA (prostate-specific antigen) and hK2 (human glandular kallikrein), in the human prostate cancer cell line, LNCaP. T3 alone showed pronounced growth enhancement in a dose-dependent fashion. However, in the presence of androgens, higher concentrations of T3 were required to produce additional proliferative effects. T3, androgens, or a combination of the two up-regulated PSA protein production in a dose-dependent fashion, but T3 had little stimulatory effect on hK2 protein expression, regardless of the presence or absence of androgens. Using gene transfer assays, T3 alone showed no effect on transcriptional activation of a reporter gene mediated by the PSA or hK2 enhancer/promoters. T3 potentiated the androgen mediated transcription of the PSA gene but not that of the hK2 gene. A previous study suggested that the T3 effect on PSA protein expression was caused by an up regulation of the androgen receptor (AR) protein by T3. Our results contradict these. Although AR expression was increased by T3 alone, Western blot analysis showed that the total cellular AR level was not further increased by T3 in the presence of androgens, in comparison with cells stimulated by androgens alone. Both Western blot analysis and a gel DNA band shift assay revealed that nuclear AR was not increased by T3. This study suggests that transcription factor(s) other than the AR may mediate T3 enhancement of androgenic induction of PSA expression. PMID- 10098502 TI - Developmental expression and regulation of adrenocortical cytochrome P4501B1 in the rat. AB - A 57-kDa protein whose expression in rat adrenocortical microsomes is increased after weaning has been identified as cytochrome P4501B1 (CYP1B1). Levels of CYP1B1 protein were moderately expressed in late gestation fetuses and on postnatal day 1 (pdl), but were nearly undetectable on pd6 and pd1O. CYP1B1 expression initially increased in the late preweaning period (pd17-19) and again immediately postweaning (pd21-24). The temporal coincidence of CYP1B1 expression and weaning was not due to transition from suckling to solid food, as neonates that were prematurely weaned showed no increase in adrenal CYP1B1 compared with normally weaned littermates. The pattern of CYP1B1 expression paralleled changes in microsomal metabolism of 7,12-dimethylbenz[a]anthracene (DMBA), a marker of CYP1B1 activity. Twice daily injections of ACTH to rat pups (pd3-10) failed to significantly increase the expression of CYP1B1 in pd 10 adrenals, although the injections weakly stimulated steroidogenesis. Adrenocortical cells from pd17 neonates and adult cells, when cultured for 3 days, responded similarly to ACTH induction, although neonates showed more than 4-fold less basal activity. It is concluded that rat adrenal CYP1B1 may be developmentally suppressed, and its expression is independent of diet or the presence of a dam. This suppression is retained in cell culture, but is not due to deficient ACTH signaling. These results may explain the reported resistance of neonatal rat adrenals to the toxic effects of polycyclic aromatic hydrocarbons, which are metabolized by CYP1B1 into mutagenic by-products. PMID- 10098503 TI - Growth hormone regulates steroidogenic acute regulatory protein expression and steroidogenesis in Leydig cell progenitors. AB - Gonadal development and differentiation is dependent in part on GH, as GH deficiency has been implicated as a cause of lowered fertility and spermatogenic cessation in humans and some biological models. In this study, we demonstrate that GH receptor messenger RNA (mRNA) is preferentially expressed in progenitor Leydig cells (PLCs) isolated and purified from 21-day-old rats. GH induces significant increases in the levels of steroidogenic acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase (3beta-HSD) expression, and androgen production in PLCs. Additionally, the cytokine interferon-gamma (IFNgamma) markedly inhibits GH-stimulated StAR mRNA and protein levels. When cells are cultured with both GH and IFNgamma, IFNgamma decreases the stimulating effect of GH on androgen production. Treatment of PLCs with cycloheximide does not prevent the GH-induced StAR mRNA, indicating that GH induction of StAR transcripts does not require de novo protein synthesis. In contrast, the induction of 3beta-HSD mRNA by GH is altered by cycloheximide treatment. H7, a serine/threonine kinase inhibitor, completely abrogates the increases in StAR mRNA by GH, whereas the tyrosine kinase inhibitor genistein does not. Moreover, GH further enhances StAR and 3beta-HSD mRNA expression in isolated adult rat Leydig cells despite their increased basal expression subsequent to maturational acquisition of these steroidogenic components. These data provide the first demonstration of the direct effects of GH on testicular steroidogenesis during progenitor Leydig cell differentiation. PMID- 10098504 TI - Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. AB - Plasma levels of glucagon-like peptide-1 (GLP-1) rise rapidly after nutrient ingestion, suggesting the existence of a proximal gut signal regulating GLP-1 release from the L cells of the distal small intestine. Glucose-dependent insulinotropic peptide (GIP) has been shown to be one such proximal signal; however, the dependence of GIP on gastrin-releasing peptide, a neuromodulator, suggested a role for the nervous system in this proximal-distal loop. Investigations into the nature of this proximal signal were therefore conducted in an in situ model of the rat gastrointestinal system. Infusions of corn oil into a 10-cm segment of duodenum that was isolated by loose ligation (to ensure that the luminal contents did not progress to the ileal L cell) increased the secretion of GLP-1 in parallel with that of gut glucagon-like immunoreactivity (gGLI; r = 0.85; P < 0.05). Infusion of fat into a transected segment of duodenum also significantly raised gGLI secretion compared with saline infusion, reaching a peak value of 132 +/- 37 pg/ml above basal (P < 0.05). However, peak secretion was significantly delayed when the gut was transected compared with that after ligation alone (19 +/- 4 vs. 6 +/- 1 min, respectively; P < 0.05). Furthermore, bilateral subdiaphragmatic vagotomy in conjunction with gut transection completely abolished the fat-induced rise in gGLI secretion (P < 0.001). Consistent with a role for the vagus in the regulation of the L cell, stimulation of the distal end of the celiac branch of the subdiaphragmatic vagus nerve significantly stimulated the secretion of gGLI to a level of 71 +/- 14 pg/ml above basal (P < 0.05). As found previously, supraphysiological infusion of GIP significantly increased gGLI secretion in control animals by 123 +/- 32 pg/ml (P < 0.05); this was not prevented by hepatic branch vagotomy (96 +/- 25 pg/ml; P < 0.05). In contrast, although infusion of GIP at physiological levels into sham vagotomized animals also increased gGLI secretion, by 40 +/- 6 pg/ml (P < 0.05), selective hepatic branch vagotomy abolished GIP-induced gGLI secretion (P < 0.05). The results of these experiments therefore demonstrate that the secretion of GLP-1 and gGLI from the ileal L cell in response to fat is regulated by a complex neuroendocrine loop, involving the enteric nervous system, the afferent and efferent vagus nerves, as well as the duodenal hormone GIP. PMID- 10098505 TI - Sp1 dependence of natriuretic peptide receptor A gene transcription in rat aortic smooth muscle cells. AB - The atrial natriuretic peptide receptor (NPR-A) Is expressed in smooth muscle cells of the vasculature, where it is thought to signal the vasodilatory properties of the peptide. Despite its important role as a regulator of cardiovascular homeostasis, relatively little is known of the genomic factors governing expression of this gene. We show here that NPR-A promoter activity is reduced by 50-75% when any of three GC-rich sites are mutated. Simultaneous mutation of all three leads to a >90% reduction in NPR-A promoter activity. Transfection of wild-type, but not mutant, decoy oliogonucleotides encoding any one of the sites reduces NPR-A activity, presumably reflecting competition for a common transcription factor. Gel shift analyses show that each of the wild-type, but not the mutant, sites interferes with the formation of selected DNA-protein complexes on the other sites. These complexes share similar electrophoretic mobility. Immunoperturbation studies show that one of these shared complexes contains Sp1, whereas two others contain Sp3. Overexpression of either Sp1 or Sp3 in a cell type containing very low levels of these transcription factors (i.e. Drosophila Schneider cells) leads to induction of the wild-type, but not the mutant, NPR-A promoter. The data suggest that the Sp1 family of transcription factors plays a central role in NPR-A gene transcription. The association of Sp1 family members with transcriptional regulation of a number of genes involved in hemodynamic control will be discussed. PMID- 10098506 TI - Normal suppression of the reproductive axis following stress in corticotropin releasing hormone-deficient mice. AB - The hypothalamic neuropeptide CRH has been postulated to inhibit LH secretion by a central action within the brain. To characterize the physiological significance of CRH in stressor-induced inhibition of LH secretion, CRH-deficient and wild type mice were subjected to restraint or food withdrawal, and plasma LH levels were determined. The proestrus LH surge of female mice was equally suppressed by restraint in both genotypes, and central administration of a CRH antagonist did not alleviate this suppression in either genotype. Male mice of both genotypes also demonstrated suppression of both LH and testosterone secretion following restraint. Furthermore, food withdrawal caused similar suppression of LH secretion in both female and male mice regardless of CRH status. These data demonstrate that CRH is not necessary to inhibit LH secretion following either restraint or food withdrawal and that other molecules are able to suppress LH secretion during the response to stress in the context of CRH deficiency. PMID- 10098507 TI - Single exposure to heat induces stage-specific germ cell apoptosis in rats: role of intratesticular testosterone on stage specificity. AB - Short term exposure of the testis to heat causes degeneration of germ cells. However, the mechanisms underlying this process are poorly understood. The major objectives of this study were to determine whether the heat-induced loss of germ cells in the adult rat occurs via apoptosis, to document its stage-specific and cell-specific distribution, and to examine whether intratesticular testosterone (T) plays any role in the stage specificity of heat-induced germ cell death. Testes of adult male Sprague-Dawley rats were exposed to 22 C (control) or 43 C for 15 min. Animals were killed on days 1, 2, 9, and 56 after heat exposure. Germ cell apoptosis was characterized by DNA gel electrophoresis and in situ terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling assay. The incidence of germ cell apoptosis [apoptotic index (AI)] was quite low in control rats (AI = 0.04-0.1). Mild hyperthermia within 1 or 2 days resulted in a marked activation (AI = 4.7-5.6) of germ cell apoptosis predominantly at early (I-IV) and late (XII-XIV) stages. Stages V-VI and VII-VIII were relatively protected from heat-induced apoptosis. Spermatocytes, including pachytenes at stages I-IV and IX-XII, diplotene and dividing spermatocytes at stages XIII-XIV, and early (steps 1-4) spermatids, were most susceptible to heat. On day 9, the majority of the tubules were severely damaged and displayed only a few remaining apoptotic germ cells. By day 56, spermatogenesis was completely recovered, and the incidence of germ cell apoptosis was compatible with the control levels. To determine whether intratesticular T plays a role in protecting germ cells at stages VII-VIII against heat-induced cell death, adult rats were exposed to local testicular heating on day 2 or were given a daily sc injection of GnRH antagonist (GnRH-A) for 4 days with and without a single exposure of testes to heat applied on day 2. By day 4, the incidence of increased germ cell apoptosis at stages other than VII-VIII were not different between heat-treated and GnRH-A- plus heat treated groups, whereas the control group and the group treated with GnRH-A alone showed minimal apoptosis. GnRH-A addition to heat resulted in a further increase in apoptosis (by 3.2-fold) at stages VII-VIII over the values measured in the heat-treated group, and it became comparable to that at all other stages. Collectively, these results provide evidence that 1) heat induces germ cell apoptosis in a stage-specific and cell-specific fashion; and 2) intratesticular T plays a pivotal role in protecting germ cells at stages VII-VIII against heat induced cell death. However, the possible involvement of various other factors, including growth factors, thermoprotectants, cytokines, and various death-related proteins, in protecting germ cells against heat-induced apoptosis cannot be ruled out. PMID- 10098508 TI - Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport. AB - We recently described a homozygous frameshift mutation in the human leptin (ob) gene associated with undetectable serum leptin and extreme obesity in two individuals. This represented the first identified genetic cause of morbid obesity in humans. Preliminary data suggested a defect in the secretion of this truncated (delta133) mutant leptin. In the present investigation, we have examined the mechanisms underlying the defective secretion of the delta133 leptin in transient transfection studies in Chinese hamster ovary and monkey kidney epithelium cells. Consistent with our previous observations, only immunoreactive wild-type (wt) leptin was secreted. In pulse chase experiments, intracellular wt leptin levels decreased, concomitant with secretion into the medium. In contrast, though immunoreactive delta133 leptin disappeared from cell lysates with kinetics similar to those of wt leptin (half-life, 45 min), it was not detected in the medium. Inhibition of the proteasome, using the inhibitor clastolactacystin beta lactone, led to a significant increase in the intracellular levels of delta133 leptin, indicating a role for the proteasome in the degradation pathway. Although intracellular immunoprecipitated wt and delta133 leptin levels were comparable, analysis of total cell lysates revealed a 7-fold increase in total intracellular delta133 leptin, compared with wt leptin. Size-exclusion membrane filtration demonstrated that intracellular delta133 leptin accumulated in an aggregated form, presumably as a result of misfolding in the endoplasmic reticulum. Consistent with this, an endoplasmic reticulum-like localization for delta133 leptin was detected by immunofluorescence microscopy. In conclusion, the delta133 mutant leptin is not secreted but accumulates intracellularly, as a consequence of misfolding/aggregation, and is subsequently degraded by the proteasome. These studies further define the genotype/phenotype correlation in this paradigmatic case of human leptin deficiency. PMID- 10098509 TI - Thyrotropin regulates c-Jun N-terminal kinase (JNK) activity through two distinct signal pathways in human thyroid cells. AB - c-Jun N-terminal kinases (JNK) participate in cellular responses to mitogenic stimuli and environmental stresses. We investigated whether and how TSH, which promotes the proliferation and differentiation of thyroid cells, regulates JNK activity in primary cultured human thyroid cells. TSH stimulated JNK activity in cytosolic fractions of thyroid cells measured by in vitro kinase assay. A low concentration of TSH (10(-11) M) stimulated JNK activity but at a higher dose (10(-8)-10(-7) M), TSH suppressed JNK activity without any change of JNK protein level. Activation of JNK by TSH was also observed in CHO cells stably transfected with TSH receptor complementary DNA (cDNA), suggesting a ligand-receptor specific interaction. TSH stimulated JNK activity through a pertussis toxin-sensitive pathway. We next elucidated the signal transduction pathways in TSH-induced JNK activation by examining the involvement of four distinct intracellular signal molecules; protein kinase C (PKC), cAMP, Ca2+, and PI3-kinase. The stimulation of JNK by TSH was blocked by two PKC inhibitors and suppressed by 8-bromo-cAMP or forskolin. These findings demonstrate that TSH regulates JNK activity biphasically in human thyroid cells through an interaction between Gi-PKC and cAMP-PKA pathways. PMID- 10098510 TI - Leptin modulates the glucocorticoid-induced ovarian steroidogenesis. AB - Leptin regulates food intake and other activities through its hypothalamic receptor. Leptin receptors are also found in other organs, including the ovary. Direct effects of leptin in ovarian steroid production were studied in primary rat granulosa cells and in rat and human granulosa cell lines. Leptin (0.6-18 nM) suppressed ovarian steroid synthesis costimulated by FSH and dexamethasone. Production of pregnenolone, progesterone, and 20alpha-hydroxy-4-pregnen-3-one was inhibited by leptin. This inhibition was due at least in part to reduced expression of adrenodoxin, a component of the P450scc system enzyme. Costimulation of progesterone production by forskolin and dexamethasone was also inhibited by leptin, whereas the forskolin-induced cAMP production was not affected. We find that leptin induces c-Jun expression and attenuates the transcriptional activity of the glucocorticoid receptor (GR) in granulosa cells. Elevation of c-Jun expression by other means, e.g. 12-O tetradecanoyl-phorbol-13 acetate or transfecting with a c-Jun expression vector, abolished the transcriptional activity of the GR. A leptin-induced elevation of c-Jun modulates the transcriptional activity of the GR, possibly leading to the observed attenuation of steroidogenesis. It was recently shown that glucocorticoids stimulate leptin expression in vivo, which in turn, inhibits cortisol synthesis. A direct action of leptin on the ovary is an additional element of a regulatory network that maintains the homeostasis of steroid production. PMID- 10098511 TI - Functional assessment of the calcium messenger system in cultured mouse Leydig tumor cells: regulation of human chorionic gonadotropin-induced expression of the steroidogenic acute regulatory protein. AB - The steroidogenic acute regulatory (StAR) protein, a 30-kDa mitochondrial factor, is a key regulator of steroid hormone biosynthesis, facilitating the transfer of cholesterol from the outer to the inner mitochondrial membrane. StAR protein expression is restricted to steroidogenic tissues, and it responds to hormonal stimulation through different second messenger pathways. The present study was designed to explore the mechanisms of extracellular calcium (Ca2+) involved in the hCG-stimulated expression of StAR protein and steroidogenesis in a mouse Leydig tumor cell line (mLTC-1). Extracellular Ca2+ (1.5 mmol/liter) enhanced the hCG (50 microg/liter)-induced increases in StAR messenger RNA (mRNA) and protein levels (1.7 +/- 0.3-fold; 4 h), as monitored by quantitative RT-PCR and immunoblotting. The potentiating effect of Ca2+ on the hCG-stimulated StAR response correlated with the acute progesterone (P) response. In accordance, omission of Ca2+ from the extracellular medium by specific Ca2+ chelators, EDTA or EGTA (4 mmol/liter each), markedly diminished the hCG-stimulated P production. The Ca2+ effect on hCG-induced StAR mRNA expression was dramatically suppressed by 10 micromol/liter verapamil, a Ca2+ channel blocker. The Ca2+-mobilizing agonist, potassium (K+; 4 mmol/liter), greatly increased the hCG responses of StAR expression and P production, which conversely were attenuated by Ca2+ antagonists, further supporting the involvement of intracellular free Ca2+ ([Ca2+]i) in these responses. The interaction of Ca2+ or K+ with hCG accounted for a clear increase in the StAR protein level (1.4-1.8-fold; 4 h) compared with that after hCG stimulation. Inhibition of protein synthesis by cycloheximide (CHX) drastically diminished the hCG-induced StAR protein content, indicating the requirement for on-going protein synthesis for hCG action. The transmembrane uptake of 45Ca2+ was increased by 26% with hCG and was strongly inhibited by verapamil. [Ca2+]i moderately augmented the response to hCG in fura-2/AM-loaded mLTC-1 cells within 30-40 sec, reaching a plateau within 1-3 min. Interestingly, the calcium ionophore (A23187) clearly increased (P < 0.01) StAR mRNA expression, in additive fashion with hCG. Northern hybridization analysis revealed four StAR transcripts at 3.4, 2.7, 1.6, and 1.4 kb, with the 1.6-kb band corresponding to the functional StAR protein; all of them were up-regulated 3- to 5-fold upon hCG stimulation, with a further increase in the presence of Ca2+. The mechanism of the Ca2+ effect on hCG-stimulated StAR expression and P production was evaluated by assessing the involvement of the nuclear orphan receptor, steroidogenic factor 1 (SF-1). Stimulation of hCG significantly elevated (2.1 +/- 0.3-fold) the SF-1 mRNA level, which was further augmented in the presence of Ca2+, whereas EGTA and verapamil completely abolished the increase caused by Ca2+. Cells expressing SF-1 marginally increased StAR expression, but coordinately elevated StAR mRNA levels in response to hCG and hCG plus Ca2+ compared with those in mock-transfected cells. On the other hand, overexpression of the nuclear receptor DAX-1 remarkably diminished (P < 0.0001) the endogenous SF-1 mRNA level as well as hCG-induced StAR mRNA expression. In summary, our results provide evidence that extracellular Ca2+ rapidly increases [Ca2+]i after hCG stimulation, presumably through opening of the transmembrane Ca2+ channel. Neither extracellular Ca2+ nor K+ alone has a noticeable effect on StAR expression and steroidogenesis, whereas they clearly potentiate hCG induction. The Ca2+-mediated increase in hCG involved in StAR expression and P production is well correlated to the levels of SF-1 expression. The stimulatory effect of hCG that rapidly increases [Ca2+]i is responsible at least in part for the regulation of SF-1-mediated StAR expression that consequently regulates steroidogenesis in mouse Leydig tumor cells. PMID- 10098512 TI - Growth hormone (GH)-releasing factor differentially activates cyclic adenosine 3',5'-monophosphate- and inositol phosphate-dependent pathways to stimulate GH release in two porcine somatotrope subpopulations. AB - Somatotropes comprise two morphologically and functionally distinct subpopulations of low (LD) and high (HD) density cells. We recently reported that GRF induces different patterns of increase in the cytosolic free Ca2+ concentration in single porcine LD and HD somatotropes, which for LD cells required not only Ca2+ influx but also intracellular Ca2+ mobilization. This suggested that GRF may activate multiple signaling pathways in pig LD and HD somatotropes to stimulate GH secretion. To address this question, we first assessed the direct GRF effect on second messenger activation in cultures of LD and HD cells by measuring cAMP levels and [3H]myo-inositol incorporation. Secondly, to determine the relative importance of cAMP- and inositol phosphate (IP)-dependent pathways, and of intra- and extracellular Ca2+, GRF-induced GH release from cultured LD and HD somatotropes was measured in the presence of specific blockers. GRF increased cAMP levels in both subpopulations, whereas it only augmented IP turnover in LD cells. Accordingly, adenylate cyclase inhibition by MDL-12,330A abolished GRF-stimulated GH release in both subpopulations, whereas phospholipase C inhibition by U-73122 only reduced this effect partially in LD cells. Likewise, blockade of Ca2+ influx with Cl2Co reduced GRF-stimulated GH secretion in both LD and HD somatotropes, whereas depletion of thapsigargin sensitive intracellular Ca2+ stores only decreased the secretory response to GRF in LD cells. These results demonstrate that GRF specifically and differentially activates multiple signaling pathways in two somatotrope subpopulations to stimulate GH release. Thus, although the prevailing signaling cascade employed by GRF in both subpopulations is adenylate cyclase/cAMP/extracellular Ca2+, the peptide also requires activation of the phospholipase C/IP/intracellular Ca2+ pathway to exert its full effect in porcine LD somatotropes. PMID- 10098513 TI - Activin and inhibin binding to the soluble extracellular domain of activin receptor II. AB - Activins and inhibins belong to the transforming growth factor-beta-like superfamily of growth and differentiation factors that exert pleiotropic effects in many target tissues. Heteromeric association of activin with two structurally related receptor serine/threonine kinases, activin receptor types I and II, initiates downstream signaling events. The extracellular domain of type II mouse activin receptor (ActRII ECD) was expressed in the baculovirus system, purified in three steps by lectin affinity, anion exchange, and reverse phase chromatography, and further characterized by mass spectrometry. The reduction in the apparent size of the purified ActRII ECD on SDS-PAGE after treatment with glycosidases provided evidence for N- and O-linked oligosaccharides. Specific receptor/ligand complexes of [125I] activin A to ActRII ECD or [125I]ActRII ECD to activin A were analyzed by cross-linking and immunoprecipitation. Two major radiolabeled bands were observed on SDS-PAGE with mobilities consistent with the expected size of ActRII ECD/betaA or ActRII ECD/betaAbetaA. When inhibin A was cross-linked to [125I]ActRII ECD, a slower migrating complex corresponding to ActRII ECD/betaAalpha was also observed. The apparent dissociation constant (Kd) for activin A binding to ActRII ECD was 2-7 nM. This Kd value is approximately an order of magnitude greater than that of the full-length membrane-associated type II receptor. Treatment of cultured rat anterior pituitary cells with ActRII ECD attenuated FSH secretion in response to exogenous activin A or endogenous activin B. These data indicate that the soluble ActRII ECD has structural determinants that are sufficient for high affinity ligand binding. PMID- 10098514 TI - Androgen modulation of luteinizing hormone secretion by female rat gonadotropes. AB - In the female, androgens can have negative and positive actions in the regulation of LH, but it is not clear how they may function during the reproductive cycle. Toward resolving these potentially conflicting roles for androgen, we used an in vitro model of preovulatory gonadotropes to examine the effect of proestrous levels of testosterone (1.7 nM) or dihydrotestosterone (DHT; 0.7 nM) on LH secretion in response to pulsatile GnRH (1 nM) or elevated extracellular K+ (54 mM). For female rat pituitary cells cultured in 17beta-estradiol (E2)-containing medium, androgen treatment for 16 h, but not for 4 h, inhibited the LH secretory response to a pulse of either GnRH or K+ by about 60% and suppressed the acute augmentation action of 20 nM progesterone on GnRH- or K+-induced LH secretion. In the absence of E2, DHT also decreased LH secretion induced by a pulse of GnRH. DHT's suppressive effect on progesterone could be partially overcome with increased progesterone (200 nM) or by removal of DHT during progesterone exposure. For pituitary cells transfected with a reporter plasmid containing three progesterone response elements, DHT only partially suppressed progesterone stimulated transcriptional activity. The positive action of androgen (16 h) on LH secretion was elicited by multiple GnRH pulses with a latency of about 2 h after the first pulse; this facilitatory action of androgen did not require an E2 background and, therefore, is distinct from GnRH self priming. In summary, these data demonstrate both facilitatory and inhibitory actions of androgen on LH secretion function in female gonadotropes in vitro in the absence or presence of E2; these actions occur with a time course suggestive of a role for androgen in shaping the preovulatory LH surge. Androgen also markedly suppresses progesterone augmentation of stimulated LH secretion, which could be due in part to interference with the trans-activation function of the progesterone receptor. PMID- 10098515 TI - Characterization of a region of the lutropin receptor extracellular domain near transmembrane helix 1 that is important in ligand-mediated signaling. AB - The lutropin receptor (LHR), a member of the G protein-coupled receptor family, contains a relatively large N-terminal extracellular domain, accounting for about half of the receptor and responsible for high affinity ligand binding, and a standard heptahelical portion with connecting loops and a C-terminal tail. LHR and the other two glycoprotein hormone receptors, i.e. the follitropin and TSH receptors, contain an invariant 10-amino acid residue sequence, FNPCEDIMGY (residues 328-337 in rat LHR), in the extracellular domain separated by only a few amino acid residues from the beginning of transmembrane helix 1. In view of the invariant nature of this region in the three glycoprotein hormone receptors and preliminary data in the literature on the importance of Glu332 and Asp333 in signal transduction, we undertook a systematic investigation of all 10 amino acid residues because this region may function as a switch or trigger for communicating ligand binding to the extracellular domain with a conformational change of the membrane-embedded C-terminal half of the receptor to activate G proteins, particularly Gs. A total of 36 single, double, and multiple replacements, as well as two deletions, of LHR were prepared and characterized in transiently transfected COS-7 cells. Of these mutants LHRs, 26 expressed on the cell surface in sufficient numbers that quantitative assessments could be made of human choriogonadotropin binding and ligand-mediated cAMP production. Replacements of Cys331 abolished ligand binding to intact cells, although binding could be detected after solubilization of the cells. Replacements of the other nine amino acid residues that did not interfere with receptor folding or trafficking had no significant effect on ligand binding affinity; however, replacements of Pro330, Glu332, and Asp333 resulted in diminished signaling, especially for the two acidic residues. An interesting observation was made in which replacement of Tyr337 with Ala or Asp, while having no profound change on receptor function, could overcome to some extent limited expression of replacements at positions 332 and/or 333, thus permitting a more definitive analysis of signaling. Replacement of the decapeptide sequence with Gly10 prevents expression, whereas deletion of all 10 residues and deletion of Glu332 Asp333 prevents functional expression at the cell surface. Thus, this invariant sequence in the glycoprotein hormones is required for proper folding, trafficking, and ligand-mediated signaling, but not ligand binding, in LHR. Amino acid residues, Glu332, Asp333, and to a limited extent, Pro330, are important in ligand-mediated signaling but not ligand binding. PMID- 10098516 TI - Thyroid hormone effects on mouse oocyte maturation and granulosa cell aromatase activity. AB - In the present study we evaluated the role of T3 on the in vitro processes of mouse cumulus cell-oocyte complex expansion, oocyte meiotic maturation, and granulosa cell aromatase activity. Results obtained from cumuli oophori isolated from immature and adult mice ovaries demonstrated that T3 at all concentrations tested (0.1-100 nM) did not affect basal or FSH-induced cumulus expansion or interfere with oocyte meiotic maturation up to metaphase II stage. On the contrary, T3 inhibited in a time- and dose-dependent manner FSH-induced aromatase activity in cultured granulosa cells obtained from either adult or immature female mice. The half-maximal dose (ED50) of T3 inhibition was 0.87 +/- 0.21 nM, which is in agreement with the reported dissociation constant of T3 nuclear receptor (Kd = 0.4-5 nM) in mammalian granulosa cells. Time-course experiments demonstrated higher sensitivity to T3 of adult granulosa cells with respect to immature granulosa cells in culture. Indeed, in immature granulosa cells T3 inhibition became significantly evident only after 6 days of hormonal treatment, whereas in adult granulosa cells the inhibitory effect was present after only 2 days of treatment. (Bu)2cAMP- or 3-isobutyl-1-methyl-xanthine-stimulated aromatase activity was also significantly decreased by T3, thus suggesting that the inhibition was downstream from cAMP formation. Lastly, analysis of aromatase messenger RNA (mRNA) levels by semiquantitative RT-PCR demonstrated the ability of FSH to increase aromatase mRNA level in cultured granulosa cells by 2.4 +/- 0.5-fold. In agreement with the effect on enzyme activity, the stimulatory effect of FSH on aromatase mRNA level was greatly reduced after T3 cotreatment. In conclusion, T3 inhibition of aromatase activity may be of physiological relevance in the complex multihormonal regulation of mammalian follicle development and may contribute to explaining the alteration in female reproductive functions after thyroid hormone hypo- or hypersecretion. PMID- 10098517 TI - Galanin within the normal and hyperplastic anterior pituitary gland: localization, secretion, and functional analysis in normal and human growth hormone-releasing hormone transgenic mice. AB - Studies evaluating estrogen-induced anterior pituitary tumors revealed a strong direct correlation between expression of the peptide galanin and tumor growth. To evaluate further the potential roles of galanin in the hyperplastic pituitary, we used a model of estrogen-independent anterior pituitary tumor formation, the male human GH-releasing hormone (hGHRH) transgenic mouse. Pituitaries of hGHRH transgenic mice are characterized by a hyperplasia of somatotrophs and contain markedly elevated levels of galanin. We examined the population of galanin producing pituitary cells in 4- to 6-month-old male hGHRH transgenic mice and their nontransgenic siblings. The percentage of galanin-containing pituitary cells was significantly increased within the anterior pituitaries of hGHRH transgenic mice. By using the cell immunoblot assay we found that the basal secretion of galanin and GH from individual pituitary cells of hGHRH transgenic mice was significantly greater than that from pituitary cells of nontransgenic mice. By modifying the cell immunoblot assay, we determined that somatotrophs from both hGHRH transgenic and normal mice that were positive for galanin immunoreactivity secreted significantly greater amounts of GH than those somatotrophs devoid of galanin immunoreactivity. Moreover, immunoneutralization of galanin significantly decreased GH secretion from pituitary cells obtained from hGHRH transgenic mice. Thus, we now show that the increased levels of galanin peptide within the hyperplastic pituitaries of hGHRH transgenic mice are due to an increase in the population of cells containing galanin, and that galanin participates in the augmented secretion of GH from hyperplastic proliferating pituitary cells. PMID- 10098518 TI - Lymphoguanylin: cloning and characterization of a unique member of the guanylin peptide family. AB - Guanylin and uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a uroguanylin complementary DNA (cDNA) detected uroguanylin-like messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84% and 40% of its residues with preprouroguanylin and preproguanylin, respectively. A 15-amino acid, uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide product lymphoguanylin because the source of the first cDNA isolated was spleen and its mRNA is expressed in all of the lymphoid tissues tested. A 15-amino acid form of lymphoguanylin containing a single disulfide bond was synthesized that activates the guanylate cyclase receptors of human T84 intestinal and opossum kidney (OK) cells, although with less potency than uroguanylin and guanylin. Northern and/or RT-PCR assays detected lymphoguanylin mRNA transcripts in many tissues and organs of opossums, including those within the lymphoid/immune, cardiovascular/renal, reproductive, and central nervous organ systems. Lymphoguanylin joins guanylin and uroguanylin in a growing family of peptide agonists that activate transmembrane guanylate cyclase receptors, thus influencing target cell function via the intracellular second messenger, cGMP. PMID- 10098519 TI - Regulation of androgen receptor messenger ribonucleic acid expression in the developing rat forebrain. AB - By postnatal day 10 (PND-10), males express more androgen receptor (AR) messenger RNA (mRNA) than females in the principal portion of the bed nucleus of the stria terminalis (BSTpr) and medial preoptic area (MPO), but not in the ventromedial hypothalamus. The development of these region-specific sex differences in AR mRNA expression may be critical for the organization of male-typical neural circuitry and may represent the onset of sex differences in the sensitivity of the rat brain to the actions of androgens. In this study, we used a 35S-labeled riboprobe and in situ hybridization to address whether postnatal testosterone exposure is important for the up-regulation of AR mRNA content in the developing rat forebrain. In the BSTpr and the MPO of PND-10 rats, males gonadectomized on PND-0 or PND-5 had lower levels of AR mRNA compared with intact or sham-operated control males. Daily replacement of testosterone to animals gonadectomized on PND 0 maintained AR mRNA content in the BSTpr and the MPO at levels equal to those in intact males. In contrast, there was no effect of gonadectomy or testosterone replacement on AR mRNA expression in the ventromedial hypothalamus. Thus, the postnatal hormonal environment may permit the development of region-specific sex differences in AR mRNA. Significant alterations in AR mRNA expression in the BSTpr and MPO in PND-10 male rats were induced by gonadectomy as late as PND-8. Males gonadectomized on PND-8 had levels of AR mRNA significantly lower than those in intact males, but significantly higher than those in intact females. Further, when animals were gonadectomized on PND-0 and given testosterone on PND 8 and PND-9, levels of AR mRNA were also intermediate between those found in intact males and intact females. The exact time course for transcriptional regulation of AR mRNA in the developing rat brain is unknown. However, others have shown significant regulation of AR mRNA within hours of hormone treatment, so that 2 days of hormone withdrawal or replacement are probably sufficient to achieve new steady state levels of message. Moreover, sexually dimorphic neuronal loss has been documented to peak in hypothalamic cell groups during the first postnatal week. Thus, it is likely that changes in the number of AR mRNA expressing cells as well as the amount of AR mRNA expression per cell are responsible for the development of male-typical AR mRNA content. PMID- 10098520 TI - Targeted overexpression of parathyroid hormone-related protein (PTHrP) to vascular smooth muscle in transgenic mice lowers blood pressure and alters vascular contractility. AB - PTH-related protein (PTHrP) and its receptor are expressed in vascular smooth muscle cells and are believed to participate in the local regulation of vascular tone. To explore the function of locally produced PTHrP in vascular smooth muscle in vivo, we developed transgenic mice that overexpress PTHrP in smooth muscle using a smooth muscle alpha-actin promoter to direct expression of the transgene. In the PTHrP-overexpressing mice, messenger RNA expression was mainly restricted to smooth muscle-containing tissues. Several founders also expressed the transgene in bone and heart and exhibited striking abnormalities in the development of these tissues. In PTHrP-overexpressing mice, blood pressure was significantly lower than that in wild-type controls (121 +/- 3 vs. 135 +/- 2 mm Hg; P < 0.01). Moreover, the magnitude of the vasorelaxant response to iv infusions of PTHrP-(1-34)NH2 was significantly attenuated in the transgenic animals. A similar desensitization to PTHrP was observed in aortic ring and portal vein preparations. Surprisingly, PTHrP-overexpressing mice were also significantly less responsive to the hypotensive action of infused acetylcholine in vivo and to the relaxant actions of acetylcholine on aortic vessel preparations in vitro. In summary, we have successfully targeted overexpression of PTHrP to the smooth muscle of transgenic mice. When expressed in its normal autocrine/paracrine setting, PTHrP lowers systemic blood pressure and decreases vascular responsiveness to further relaxation by PTHrP and other endothelium dependent vasorelaxants such as acetylcholine. We postulate that the heterologous desensitization to acetylcholine-induced relaxation in PTHrP-overexpressing blood vessels involves desensitization of second messenger/effector signaling pathways common to PTHrP and acetylcholine. PMID- 10098521 TI - Reduced blood pressure and increased sensitivity of the vasculature to parathyroid hormone-related protein (PTHrP) in transgenic mice overexpressing the PTH/PTHrP receptor in vascular smooth muscle. AB - PTH-related protein (PTHrP) is produced in vascular smooth muscle, where it is postulated to exert vasorelaxant properties by activation of the PTH/PTHrP type 1 receptor. As a model for studying the actions of locally produced PTHrP in vascular smooth muscle in vivo, we developed transgenic mice that overexpress the PTH/PTHrP receptor (PTHrP-R) in smooth muscle. Oocyte injection with a SMP8-PTHrP R fusion construct yielded six founder mice. F1 offspring were viable and demonstrated selective overexpression of the SMP8-PTHP-R messenger RNA in smooth muscle-rich tissues. Baseline blood pressure measured in conscious mice by tail sphygmomanometry was significantly lower in the receptor-overexpressing mice than that in controls (117 +/- 4 vs. 133 +/- 3 mm Hg; P < 0.05). In anesthetized animals, iv infusion of PTHrP-(1-34)NH2 caused a significantly greater reduction in blood pressure and total peripheral resistance in transgenic mice than in control animals. Vascular contractility was studied in paired, isometrically mounted aortas from 9-week-old transgenic and wild-type mice. The force of contraction in response to phenlyephrine was not significantly different between transgenic and wild-type mice. However, PTHrP-(1-34) NH2 relaxed aortic vessel preparations from transgenic mice to a greater extent than in controls (77.1 +/- 3% vs. 38.4 +/- 4%; P < 0.001). To determine the impact of overexpression of PTH/PTHrP type 1 receptor and its ligand on the development of the cardiovascular system, double transgenic mice were created by crossing SMP8-PTHrP-R transgenic mice with mice overexpressing PTHrP (SMP8-PTHrP). Double transgenic mice died around day E9 with abnormalities in the developing heart. In conclusion, overexpression of PTH/PTHrP type 1 receptor in vascular smooth muscle of transgenic mice reduces blood pressure, probably through sustained activation of the receptor by endogenous ligand. The cardiovascular defects observed in mice overexpressing both PTHrP and its receptor suggest that PTHrP may play a role in the normal development of the cardiovascular system. PMID- 10098522 TI - Regulatory role of p27kip1 in the mouse and human testis. AB - p27kip1 is a cyclin-dependent kinase inhibitor that regulates the G1/S transition of the cell cycle. Immunohistochemical analysis showed that during mouse testicular development p27kip1 is induced when the fetal germ cells, gonocytes, become quiescent on day 16 postcoitum, suggesting that p27kip1 is an important factor for the G1/G0 arrest in gonocytes. In the adult mouse and human testis, in general, spermatogonia are proliferating actively, except for undifferentiated spermatogonia that also go through a long G1/G0 arrest. However, none of the different types of germ cells immunohistochemically stained for p27kip1. During development, Sertoli cells are proliferating actively and only occasionally were lightly p27kip1 stained Sertoli cells observed. In contrast, in the adult testis the terminally differentiated Sertoli cells heavily stain for p27kip1. Twenty to 30% of both fetal and adult type Leydig cells lightly stained for p27kip1, possibly indicating the proportion of terminally differentiated cells in the Leydig cell population. In p27kip1 knockout mice, aberrations in the spermatogenic process were observed. First, an increase in the numbers ofA spermatogonia was found, and second, abnormal (pre)leptotene spermatocytes were observed, some of which seemingly tried to enter a mitotic division instead of entering the meiotic prophase. These observations indicate that p27kip1 has a role in the regulation of spermatogonial proliferation, or apoptosis, and the onset of the meiotic prophase in preleptotene spermatocytes. However, as p27kip1 is only expressed in Sertoli cells, the role of p27kip1 in both spermatogonia and preleptotene spermatocytes must be indirect. Hence, part of the supportive and/or regulatory role of Sertoli cells in the spermatogenic process depends on the expression of p27kip1 in these cells. Finally, we show that the expression of p27kip1 transiently increases by a factor of 3 after x-irradiation in whole testicular lysates. Hence, p27kip1 seems to be involved in the cellular response after DNA damage. PMID- 10098523 TI - The insulin-sensitive glucose transporter (GLUT4) is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor. AB - Children with uncontrolled type I (insulin-dependent) diabetes mellitus are characterized by a slow growth rate, which improves upon adequate therapy. While skeletal growth is an energy-consuming process involving high glucose utilization, the role of glucose transporters (GLUT) and their regulation in the bone formation process are not yet fully understood. Thus, we studied both in vivo and in vitro early endochondral bone formation in control and streptozotocin induced young diabetic mice. Using in situ hybridization and immunohistochemistry techniques, we demonstrated the novel existence of the insulin-sensitive glucose transporter (GLUT4), as well as GLUT1, in juvenile-derived murine mandibular condyles and in the humeral growth plate-two models for endochondral bone formation. Insulin-like growth factor (IGF) I receptors (IGF-I-R), but not insulin receptors (IR), were shown to have cellular distribution similar to GLUT4, being more abundant in mature chondrocytes. Further, in the skeletal growth centers of streptozotocin-induced diabetic mice, GLUT4, IGF-I, and IGF-I and insulin receptor levels, but not GLUT1 were markedly reduced. The decrease in GLUT4 and in IGF-I and insulin receptors was associated with severe histological changes in the mandibular condyles and humeral growth plate. Insulin therapy restored IR levels to normalcy, whereas IGF-I-R and GLUT4 levels were only partially recovered. Thus, GLUT4 and IGF-I-R have a potential role in early bone growth in mice. Further, during early bone growth GLUT4 may be regulated through the IGF-I receptor rather than via the insulin receptor. We propose that skeletal growth retardation in type I diabetes may be associated with reduced expression of the GLUT4 and IGF-I receptor in the bone growth center. PMID- 10098524 TI - Restricted spatiotemporal expression of lactoferrin during murine embryonic development. AB - Lactoferrin is a member of the transferrin family of iron-binding glycoproteins. Lactoferrin is induced by estrogen in the mouse uterus during early pregnancy. However, the expression and function, if any, of lactoferrin in the preimplantation embryo during this developmental period has not been investigated. In the current study, the spatiotemporal expression of lactoferrin during murine embryogenesis was examined using in situ hybridization and immunohistochemical analyses. Lactoferrin expression was first detected in the 2 4 cell fertilized embryo and continued until the blastocyst stage of development. Interestingly, at the 16-cell stage, coinciding with the first major differentiation step in the embryo, lactoferrin messenger RNA (mRNA) is synthesized by the inner cells, whereas the protein is selectively taken up by the outside cells. This differential pattern of lactoferrin messenger RNA and protein localization continues until the blastocyst stage, with expression almost absent in the hatched blastocyst. Lactoferrin expression does not resume in the embryo until the latter half of gestation, where it is first detected in neutrophils of the fetal liver at embryonic day 11.5 and later in epithelial cells of the respiratory and digestive systems. Our results show that lactoferrin is expressed in a tightly regulated spatiotemporal manner during murine embryogenesis and suggest a novel paracrine role for this protein in the development of the trophoectodermal lineage during preimplantation development. PMID- 10098525 TI - Effects of castration and androgen replacement on erectile function in a rabbit model. AB - We investigated, in a rabbit model, the effects of castration and testosterone replacement on: 1) the hemodynamics of the corpus cavernosum; 2) alpha-1 adrenergic receptor protein expression; 3) neural NO synthase protein expression and activity; 4) phosphodiesterase type 5 activity; and 5) trabecular smooth muscle/connective tissue balance. One week after bilateral orchiectomy, animals were treated for 7 days with vehicle alone, testosterone, or estradiol. Intact control animals received vehicle only. Systemic arterial blood and intracavernosal pressures (ICP) were measured in each animal before and after electrical stimulation of the cavernosal nerve. Alpha1-adrenergic receptor protein expression was determined by ligand binding studies. NO synthase expression and activity were determined by Western blot analyses and conversion of L-arginine to citrulline, respectively. Phosphodiesterase type 5 activity was determined by hydrolysis of guanosine 3',5'-cyclic monophosphate (cGMP) in tissue extracts in the absence or presence of 100 nM sildenafil. Smooth muscle content was assessed by Masson's trichrome staining and computer-assisted histomorphometry. Castration significantly reduced ICP, but it did not alter systemic arterial blood pressure during stimulation of the cavernosal nerve. Testosterone, but not estradiol, treatment prevented the effects of castration and restored ICP to values similar to those obtained in intact animals. Castration reduced expression of alpha1-adrenergic receptor, and this reduction was prevented or reversed by testosterone replacement. Neural NO synthase protein expression and total activity were not altered significantly by castration or after testosterone replacement. However, phosphodiesterase type 5 activity increased in castrated animals treated with testosterone. Castration significantly reduced trabecular smooth muscle content, and this reduction was restored by testosterone (but not estradiol) treatment. The results of this study demonstrate that androgen deprivation alters the functional responses and structure of erectile tissue. PMID- 10098527 TI - Cytoplasmic liberation of protein gene product 9.5 during the seasonal regulation of spermatogenesis in the monkey (Macaca fuscata). AB - Primate spermatogenesis is distinguished by yet unidentified mechanisms to regulate its spermatogenetic activity. In contrast to the well documented hormonal regulators, the cellular events responsible for the regulation of the spermatogenesis has not been addressed. By using PGP 9.5-immunohistochemistry, our previous study demonstrated that the monkey spermatogonia are divided into two distinct sub-populations, i.e. cytoplasmic PGP 9.5-positive and cytoplasmic PGP 9.5-negative spermatogonia. By comparing the cytoplasmic expression of PGP 9.5 between the breeding and nonbreeding seasons of the Japanese monkey (Macaca fuscata) in association with PCNA labeling, the present study demonstrates that the cytoplasmic PGP 9.5-positive Ap spermatogonia significantly increases when the spermatogenetic activity declines in the nonbreeding season. An ultrastructural subcellular localization of PGP 9.5 suggests that the increase of the cytoplasmic PGP 9.5 expression is due to a liberation of PGP 9.5 molecule from the nucleus into the cytoplasm. The results provide a theoretical basis by which PGP 9.5 serves as a novel marker for spermatogonial subtypes, which will have further implications for future studies on spermatogenesis. The analysis using this novel marker suggests that the Ap spermatogonia is a key stage to regulate the amount of the sperm produced in response to the hormonal regulators, and the cytoplasmic liberation of PGP 9.5 may serve as a pivotal phenomenon that enables the fully restorable, transient suppression of spermatogenesis in primate. PMID- 10098526 TI - Evidence for stanniocalcin gene expression in mammalian bone. AB - Stanniocalcin (STC) acts as a regulator of calcium and phosphate homeostasis in an endocrine manner in bony fish. Recently, complementary DNAs encoding human and mouse STC have been characterized, and the messenger RNA (mRNA) expression was identified in various tissues, such as kidney, small intestine, prostate, thyroid, and ovary. Because previous studies concerning the effects of fish STC on mammalian bone have been discussed, there is a good possibility that mammalian STC is a local factor in bone. Here, we demonstrated STC mRNA expression in neonatal mouse calvaria, the primary cultured mouse osteoblast-rich fractions, and human and mouse osteoblastic cell lines. We also mapped the cellular distribution of the STC mRNA in femur and calvaria in developing mice. Several transcripts with a major 4-kb band were detected in all samples. The cellular distribution of the mRNA expression corresponded closely to osteoblasts in both femur and calvaria. Significant labeling of the STC mRNA was also identified in chondrocytes but not in osteoclasts and other bone marrow elements. These results are the first evidence that hormone may be actually expressed in osteoblasts and chondrocytes, and they strongly implicate the involvement of local STC in both endochondral and membrane bone as an autocrine/paracrine factor. PMID- 10098528 TI - Thyroid hormone is essential for pituitary somatotropes and lactotropes. AB - Mice homozygous for a disruption in the alpha-subunit essential for TSH, LH, and FSH activity (alphaGsu-/-) exhibit hypothyroidism and hypogonadism similar to that observed in TSH receptor-deficient hypothyroid mice (hyt) and GnRH-deficient hypogonadal mutants (hpg). Although the five major hormone-producing cells of the anterior pituitary are present in alphaGsu-/- mice, the relative proportions of each cell type are altered dramatically. Thyrotropes exhibit hypertrophy and hyperplasia, and somatotropes and lactotropes are underrepresented. The size and number of gonadotropes in alphaGsu mutants are not remarkable in contrast to the hypertrophy characteristic of gonadectomized animals. The reduction in lactotropes is more severe in alphaGsu mutants (13-fold relative to wild-type) than in hyt or hpg mutants (4.5- and 1.5-fold, respectively). In addition, T4 replacement therapy of alphaGsu mutants restores lactotropes to near-normal levels, illustrating the importance of T4, but not alpha-subunit, for lactotrope proliferation and function. T4 replacement is permissive for gonadotrope hypertrophy in alphaGsu mutants, consistent with the role for T4 in the function of gonadotropes. This study reveals the importance of thyroid hormone in developing the appropriate proportions of anterior pituitary cell types. PMID- 10098529 TI - Selective effects of genistein, a soybean isoflavone, on B-lymphopoiesis and bone loss caused by estrogen deficiency. AB - Genistein, an isoflavone abundantly present in soybeans, has structural similarity to estrogen, suggesting that genistein may act as a phytoestrogen. To examine the possible role of genistein in hemopoiesis and bone metabolism, female mice were either sham-operated or ovariectomized (OVX), and selected OVX mice were administered genistein for 2-4 weeks (0.1-0.7 mg/day) or 17beta-estradiol (E2; 0.01-0.1 microg/day) s.c., using a miniosmotic pump (Alza Corp., Palo Alto, CA). In OVX mice, uterine weight declined but was completely restored by E2 administration. In contrast, genistein did not demonstrate a reversal of the OVX induced uterine atrophy. The number of bone marrow cells markedly increased, 2-4 weeks after OVX, and most of these were B220-weakly positive pre-B cells. The increased B-lymphopoiesis was completely restored, not only by E2 but also by genistein administration. In OVX mice, the trabecular bone volume of the femoral distal metaphysis, measured by microcomputed tomography scanning and dual-energy x-ray absorptiometry, was markedly reduced; and genistein restored this, as did E2. These results indicate that genistein exhibits estrogenic action in bone and bone marrow, to regulate B-lymphopoiesis and prevent bone loss, without exhibiting estrogenic action in the uterus. Phytoestrogens may be useful for preventing bone loss caused by estrogen deficiency in females. PMID- 10098530 TI - Testosterone stimulates insulin-like growth factor-I and insulin-like growth factor-I-receptor gene expression in the mandibular condyle--a model of endochondral ossification. AB - Puberty is associated with an increase in the plasma concentration of sex steroids, GH, and insulin-like growth factor-I (IGF-I). Gonadal steroid hormones are important for the normal pubertal growth spurt and skeletal growth. The mechanism by which gonadal steroids induce skeletal growth is still not fully understood. To better understand the direct effect sex steroids have on bone growth, we studied an isolated organ culture system of the mandibular condyle, derived from 3.5-5.5-week-old male and female mice. We found that testosterone 10(-6) M, but not estradiol, stimulated thymidine incorporation into the DNA of male-derived condyle. Three days of testosterone treatment doubled the condyle size and increased the chondroprogenitor zone, while maintaining the normal gradient of the developing chondrocytes. Immunohistochemistry and in situ hybridization techniques showed that testosterone stimulated IGF-I and IGF-I-R and their messenger RNAs (mRNAs) mainly in the mature chondrocyte layer. Immunoneutralization of IGF-I in the testosterone-treated condyle caused the disappearance of the chondroblast and young chondrocyte layers, though the progenitor cell layer remained almost unaffected. Overtreatment with testosterone (dose or duration) accelerated condylar ossification. In the presence of testosterone 10(-5) M (high dose), calcification "climbs" up to the chondroprogenitor zone, and most of the condylar chondrocytes are replaced by bone tissue. Similar changes occurred after 7 days of testosterone treatment (long duration) with 10(-6) M. In conclusion, testosterone stimulates growth and local production of IGF-I and IGF-I-R in chondrocyte cell layers of an isolated organ culture of mice mandibular condyle. Part of the effect testosterone has on condylar growth is mediated by IGF-I. PMID- 10098531 TI - Calcium sensing in cultured chondrogenic RCJ3.1C5.18 cells. AB - The availability of Ca2+ in the extracellular fluid plays an important role in regulating cartilage and bone formation. We hypothesized that chondrocytes detect changes in the extracellular [Ca2+] ([Ca2+]o) and modify their function. The effects of changing [Ca2+]o on the expression of matrix proteins were quantified by staining of cartilage nodules with alcian green and assessing RNA levels of cartilage-specific genes in chondrogenic RCJ3.1C5.18 (C5.18) cells. Alcian green staining in these cells decreased with increasing [Ca2+]o in a dose-dependent and reversible manner (ID50, approximately 2 mM Ca2+). RNA levels for aggrecan and type II collagen decreased with increasing [Ca2+]o (ID50, approximately 2.0 and 4.1 mM Ca2+, respectively). RNA levels for type X collagen and alkaline phosphatase were also reduced by high [Ca2+]o with ID50 values of approximately 2.9 and 1.6 mM Ca2+, respectively. These responses were rapid, in that increasing [Ca2+]o from 1.0 to more than 6 mM suppressed aggrecan RNA levels by about 50%, and lowering [Ca2+]o from 2.9 to 1.0 mM increased aggrecan RNA levels by about 300% within 4 h. As Ca2+ receptors (CaRs) mediate extracellular Ca2+ sensing in parathyroid and kidney, we assessed the expression of CaRs in these cells. C5.18 cells stained positively for CaR protein with an anti-CaR antiserum and for CaR RNA by in situ hybridization. An approximately 150-kDa protein was detected by immunoblotting with anti-CaR antiserum. CaR antisense oligonucleotides suppressed the expression of CaR protein and enhanced RNA levels of aggrecan in C5.18 cells. These data support the idea that CaRs are expressed in this cell system and may be involved in regulating chondrogenic gene expression. PMID- 10098532 TI - Early effects of castration on the vascular system of the rat ventral prostate gland. AB - Recent studies have found that blood flow to the rat ventral prostate gland is drastically reduced at an early time after castration. These observations caused us to reevaluate the effects of castration on the various cell populations of the ventral prostate, especially those in the prostatic vascular system. Sections of ventral prostate glands obtained at different times after castration were analyzed using the TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick END labeling) staining method to quantify apoptosis in different cell types. The results of this analysis showed a significant increase in TUNEL staining of prostate endothelial and (nonendothelial) stromal cells as early as 12 h postcastration that continued to 24 h after castration. In contrast, TUNEL labeling of prostate epithelial cells was not significantly increased compared with control values until 72 h after castration. The use of dual immunohistochemical staining procedures (anti-CD31 for endothelial cells or antismooth muscle actin for smooth muscle cells combined with TUNEL labeling) allowed us to confirm that the TUNEL-positive vascular cells at these early times after castration were endothelial in nature, whereas smooth muscle cells surrounding the prostate glands or portions of the afferent vascular endothelium were rarely TUNEL labeled. Electron microscopic evaluation of ventral prostate tissues at 48 h after castration provided further morphological evidence for the occurrence of apoptosis in prostate endothelial cells. Finally, the Lendrum Fraser histochemical procedure used to identify fibrin leakage in tissues with vascular damage was applied to sections of the ventral prostate gland. This stain revealed diffuse fibrin accumulation in periglandular areas outside the capillaries and blood vessels in prostates from 24-h castrated rats, but not in prostates of sham-operated rats. Our results confirm an early effect of castration on the vascular system of the rat ventral prostate identified by increased apoptosis of endothelial cells and vascular leakiness. As these changes temporally precede the loss of epithelial cells, we propose that they may be causal rather than incidental to regression of the rat ventral prostate after castration. PMID- 10098533 TI - Prostaglandin E2 cooperates with TRANCE in osteoclast induction from hemopoietic precursors: synergistic activation of differentiation, cell spreading, and fusion. AB - It was recently found that osteoblastic cells express TRANCE (tumor necrosis factor-related activation-induced cytokine), a newly identified member of the tumor necrosis factor superfamily, and that expression was increased by calciotropic hormones. Furthermore, soluble recombinant TRANCE induces osteoclast formation and resorption in stroma-free populations of hemopoietic precursor cells. However, overexpression of the decoy receptor osteoprotegerin in vivo shows that there are substantial differences in the sensitivity of different sites to resorption-inhibition, suggesting that either alternative ligands exist or the sensitivity of osteoclasts to TRANCE can be modified by cofactors. We therefore tested the possibility that cofactors might enhance osteoclast formation by TRANCE. We found that the number of tartrate-resistant acid phosphatase-positive and calcitonin receptor-positive cells was increased by a factor of 10 by the presence of PGE2 in the absence of stromal cells. Moreover, although the tartrate-resistant acid phosphatase-positive cells that formed in TRANCE alone were typically mononuclear and poorly spread, the addition of PGE2 induced the formation of large, well spread multinuclear cells. There was an increase in bone resorption that corresponded with the increase in osteoclast number. PGE2 did not synergize with TRANCE for resorption-stimulation in mature cells. 8-Bromo-cAMP showed a similar syngergistic effect on osteoclastic differentiation. Thus, PGE2 appears to stimulate bone resorption through a direct effect on hemopoietic precursors, primarily through a synergistic effect on the ability of TRANCE to induce osteoclastic differentiation. PMID- 10098534 TI - Pregnenolone, pregnenolone sulfate, and cytochrome P450 side-chain cleavage enzyme in the amphibian brain and their seasonal changes. AB - To clarify whether the amphibian brain synthesizes de novo neurosteroids, we examined pregnenolone, pregnenolone sulfate ester, and cytochrome P450 side-chain cleavage enzyme (cytochrome P450scc), an enzyme converting cholesterol to pregnenolone, using amphibians. Pregnenolone and its sulfate ester in the brain, gonad, and plasma of Xenopus laevis were measured by a specific pregnenolone RIA. The concentrations of these two steroids in the female brain were significantly larger than those in the ovary and plasma. A similar tendency was evident in the male. In both sexes, pregnenolone and its sulfate ester were concentrated more highly in the cerebellum than in the telencephalon, diencephalon, or midbrain. An immunoreactive protein band of electrophoretic mobility in the proximity of bovine adrenal P450scc was detected in the Xenopus brain as well as the testis by Western blot analysis. Immunohistochemical analysis indicated that Purkinje cells in the Xenopus cerebellum were specifically immunostained with the P450scc antibody. P450scc-like immunoreactive cells were further found in several telencephalic and diencephalic regions, such as the pallium mediale and nucleus preopticus, in the Xenopus brain. A similar localization of P450scc-like immunoreactive cells was evident in Rana nigromaculata, a seasonally breeding amphibian. In the present study, seasonal changes in pregnenolone and its sulfate ester were further examined as a possible physiological change using R. nigromaculata. In both sexes, pregnenolone concentrations in the brain were almost constant during the seasonally breeding cycle. In contrast, the pregnenolone sulfate concentration in the brain was significantly lower in the hibernating quiescent phase and higher in the breeding and postbreeding active phases, independent of the plasma steroid level. These results taken together suggest that the amphibian brain possesses steroidogenic enzyme P450scc and produces pregnenolone and its sulfate ester. Pregnenolone sulfate may function well during the breeding and postbreeding active phases of the year in the seasonal breeder. PMID- 10098535 TI - Regional expression of mRNA encoding a second form of gonadotropin-releasing hormone in the macaque brain. AB - In mammals, reproduction is thought to be controlled by a single neuropeptide, gonadotropin-releasing hormone (GnRH-I), which regulates the synthesis and secretion of gonadotropins from the pituitary gland. However, another form of this decapeptide (GnRH-II), of unknown function, also exists in the brain of many vertebrate species, including humans; it is encoded by a different gene and its amino acid sequence is 70% identical to that of GnRH-I. Here we report the cloning of a GnRH-II cDNA from the rhesus macaque (Macaca mulatta), and show for the first time by in situ hybridization that GnRH-II mRNA is expressed in the primate midbrain, hippocampus and discrete nuclei of the hypothalamus, including the supraoptic, paraventricular, suprachiasmatic and arcuate. Because the regional distribution pattern of cells containing GnRH-II mRNA is largely dissimilar to that of cells containing GnRH-I mRNA, it is likely that these two cell populations receive distinct neuroendocrine inputs and thus regulate GnRH synthesis and release differently. PMID- 10098536 TI - Is gonadotrope expression of the gonadotropin releasing hormone receptor gene mediated by autocrine/paracrine stimulation of an activin response element? AB - Expression of the FSHbeta subunit and GnRH receptor (GnRHR) genes in gonadotropes is stimulated by activin. We sought to identify the cis-acting element(s) in the murine GnRHR gene promoter which confer activin responsiveness. We established that 600 bp of 5'flanking sequence from the murine GnRHR gene were sufficient to confer activin responsiveness in the gonadotrope-derived alphaT3-1 cell line. Since alphaT3-1 cells, like gonadotropes, secrete activin, we examined the ability of follistatin, an activin binding protein, to block the activin response. Increasing concentrations of follistatin from 0 to 100 ng/ml resulted in a dose dependent decrease in activity of the -600 promoter. Contained within this region are three elements important for expression in alphaT3-1 cells: a Steroidogenic Factor-1 binding site (SF-1), an Activator Protein-1(AP-1) element, and an element termed the GnRH receptor activating sequence or GRAS. A block mutation of GRAS inhibited the ability of the promoter to respond to follistatin. A more refined analysis using a series of two-bp mutations which scan GRAS and flanking sequence revealed exact convergence of GRAS with activin/follistatin responsiveness. Finally, a construct consisting of 3 copies of GRAS placed upstream of a heterologous minimal promoter (3xGRAS-PRL-LUC) was responsive to both activin stimulation and follistatin inhibition in alphaT3-1 cells. Thus, autocrine/paracrine stimulation of gonadotropes by activin illustrates a unique mechanism for cell-specific gene expression. PMID- 10098537 TI - Pesticides interfere with the nongenomic action of a progestogen on meiotic maturation by binding to its plasma membrane receptor on fish oocytes. AB - Although many environmental contaminants disrupt endocrine function by binding to nuclear steroid receptors, it is not known whether they are capable of binding to steroid membrane receptors and interfering with nongenomic actions of steroids. The binding of several organochlorine pesticides to the plasma membrane receptor for the maturation-inducing steroid, 17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S), in the ovaries of spotted seatrout (Cynoscion nebulosus) was investigated in in vitro competition assays. Kepone and o,p'-DDD were competitive inhibitors of 20beta-S binding and caused concentration-dependent displacement of [3H]-20beta-S from its receptor site over the range of 10(-4) to 10(-6) or 10(-7) M, whereas several other pesticides had lower affinities for the receptor. Interference with the nongenomic actions of 20beta-S on final meiotic maturation of spotted seatrout oocytes (final oocyte maturation, FOM) was examined in an in vitro bioassay. A concentration-dependent inhibition of FOM in response to 20beta S was observed after 5 min and 12 h exposure to the same range of Kepone and o,p' DDD concentrations (10(-4) to 10(-6) or 10(-7) M). The close correspondence between competitive binding of the two pesticides to the 20beta-S membrane receptor and their inhibition of 20beta-S induced FOM suggests a mechanism of endocrine disruption mediated by binding to a steroid membrane receptor and antagonism of a nongenomic steroid action. PMID- 10098538 TI - Expression of steroid receptor coactivator-1 mRNA in the developing mouse embryo: a possible role in olfactory epithelium development. AB - Ligand-dependent nuclear hormone receptors (NRs), such as retinoic acid and thyroid hormone receptors, play critical roles in diverse aspects of development. They enhance or repress transcription by recruiting an array of coactivator and corepressor proteins, which function as signaling intermediates between the NRs and the basal transcriptional machinery. To study the possible involvement of these cofactors on tissue-specific regulation of gene expression by NRs, we examined the expression of the coactivator SRC-1 mRNA during mouse embryogenesis by in situ hybridization (ISH). 35S-labeled riboprobe specific for SRC-1 mRNA was used for analysis. The distribution of this transcript was studied from 8.5 to 18.5 embryonic days (E8.5-E18.5) and in postnatal day 15 (P15). The SRC-1 transcript was largely ubiquitously expressed, even on E8.5. At E14.5 and E18.5, highest levels of SRC-1 transcript was found in the olfactory epithelium. Significant SRC-1 hybridization signal was also detected in the neocortex, anterior pituitary and heart. We conclude that (1) SRC-1 mRNA is widely expressed in the developing embryo, and (2) SRC-1 mRNA is expressed at the highest level in the olfactory epithelium, suggesting that this coactivator may be involved in the development and/or function of the olfactory system. PMID- 10098539 TI - Cerebral polyopia with extrastriate quadrantanopia: report of a case with magnetic resonance documentation of V2/V3 cortical infarction. AB - This is a case report of the occurrence of cerebral diplopia with right-side superior homonymous quadrantanopia in a young woman after chiropractic neck manipulation. Magnetic resonance imaging confirmed an infarct in the left inferior V2/V3 (extrastriate) cortex. The characteristics of the diplopia are illustrated with the patient's drawings, and persisting abnormalities in perception are described in the area of the initial field defect after static (computed) visual field testing yielded normal results. PMID- 10098540 TI - Prevalence of periocular depigmentation after repeated botulinum toxin A injections in African American patients. AB - Botulinum toxin A (Botox), administered by subcutaneous or intramuscular injection, is the most commonly used and most successful medication for many craniocervical dystonias. Although some patients experience side effects related to the neuroparalytic action of the medication, these side effects are temporary. In 1996, permanent periocular cutaneous depigmentation was reported in three white patients after repeated Botox injections, suggesting that loss or alteration of melanin pigment might be a permanent side effect of long-term Botox injections. The authors examined and photographed 26 African American patients who were receiving periocular Botox injections for hemifacial spasm and essential blepharospasm. The authors found no evidence of periocular cutaneous depigmentation in any of these patients. PMID- 10098541 TI - Cerebral metastasis presenting with altitudinal field defect. AB - A 75-year-old man presented with a unilateral inferior altitudinal visual field defect and a history of weight loss and night sweats. The acuity in the affected eye was 20/200, otherwise his ocular examination was normal. Neuroimaging demonstrated a post-fixed chiasm, with a frontal metastasis compressing the intracerebral portion of the optic nerve. A chest x-ray showed classical cannon ball lesions, secondary to malignant melanoma. This is the first case report of an intracerebral tumor producing an inferior altitudinal field defect. PMID- 10098542 TI - The Pulfrich phenomenon: its symptoms and their management. PMID- 10098543 TI - Visual environmental rotation: a novel disorder of visiospatial integration. AB - A 70-year-old man experienced an unusual disorder of visual perception after undergoing a ventriculoperitoneal shunt for normal-pressure hydrocephalus. The disorder was characterized by transient episodes of 90 degrees rotation of the visual environment, rather than the retinotopic visual field. This phenomenon is different from standard visual allesthesia and may have been caused by disordered integration of vestibular and visual inputs to the posterior parietal cortex or perseveration of a pre-existing environmental memory trace. PMID- 10098544 TI - Neuro-ophthalmology of the pregeniculate afferent visual system: December, 1997 May, 1998 (Part I). PMID- 10098545 TI - A multiple sclerosis-like illness in a man harboring the mtDNA 14484 mutation. AB - In most cases of Leber's hereditary optic neuropathy (LHON) the only clinical manifestation is visual loss. A multiple sclerosis-like illness has been infrequently reported in association with LHON. Most patients are women harboring the mtDNA 11778 mutation. We present a young man with clinical and paraclinical evidence of a demyelinating process with profound bilateral visual loss who harbored the mtDNA 14484 mutation associated with LHON. PMID- 10098546 TI - Acquired convergence-evoked pendular nystagmus in multiple sclerosis. AB - Nystagmus seen only with convergence is unusual. We describe four cases of acquired convergence-evoked pendular nystagmus in patients with multiple sclerosis. The nystagmus was horizontal and asymmetric in all patients. Eye movement recordings in one subject showed a conjugate rather than a convergent divergent relationship of the phase of movement between the two eyes. All patients had evidence of optic neuropathy and cerebellar dysfunction. Occlusion of either eye during fixation of near targets led to divergent drift of the covered eye and a decrease in nystagmus. Intravenous scopolamine reduced nystagmus in one patient. Base-in prisms alleviated symptoms of oscillopsia at near and improving reading visual acuity. Convergence-evoked pendular nystagmus may be more common than currently appreciated, particularly among patients with multiple sclerosis. PMID- 10098547 TI - Ocular microtremor in oculomotor palsy. AB - OBJECTIVES: Ocular microtremor (OMT) is a high frequency tremor of the eyes present in all individuals. Recent reports suggest that OMT may be a useful indicator of brainstem function. However, the actual origin of ocular microtremor remains controversial. This study aims to provide evidence that OMT has a neurogenic origin. MATERIALS AND METHODS: The OMT activity of five subjects with unilateral oculomotor nerve palsy and one subject with complete unilateral internal and external ophthalmoplegia were recorded from both eyes of each subject using the piezoelectric strain gauge technique, with the normal eye acting as a control. Five parameters of OMT activity were studied in each subject: the peak count, the power of the high frequency peak, the percentage power between 60 and 100 Hz, the percentage power between 70 and 80 Hz, and the 10 dB cut-off point. RESULTS: In the five subjects with oculomotor nerve palsy, the mean peak count in the normal eye was 88.4 Hz (SD+/-16.9) and in the affected eye was 59 Hz (SD+/-8.6), P < 0.0096. There was also a fall in the peak power, the power between 60 and 100 Hz, and the power between 70 and 80 Hz. In subject six, who had complete opthalmoplegia, there was no evidence of OMT activity in the denervated eye. CONCLUSIONS: These results suggest that innervation of the extraocular muscles is necessary for normal OMT activity, and OMT therefore has a neurogenic origin. PMID- 10098548 TI - Inferior division third nerve paresis from an orbital dural arteriovenous malformation. AB - Isolated inferior division third nerve palsies are rare. The authors report a patient with an isolated, pupil-involving inferior division third cranial nerve palsy from an intraorbital dural arteriovenous malformation. Despite spontaneous thrombosis of the malformation, the third nerve palsy persisted. To the authors' knowledge, this is the first case report of an inferior division third nerve palsy caused by an orbital dural arteriovenous malformation. PMID- 10098549 TI - Visual loss with Langerhans cell histiocytosis: multifocal central nervous system involvement. AB - A 42-year-old woman with a 6-year history of diabetes insipidus and progressive hypersomnolence presented with visual loss. Neuroimaging showed infiltration in the hypothalamus, the optic nerve, and the chiasm, as well as multiple lesions in other areas of the brain parenchyma. Biopsy showed Langerhans cell histiocytosis. This is an unusual presentation of Langerhans cell histiocytosis, involving the visual pathways without manifestations outside of the central nervous system. The differential diagnosis and the magnetic resonance imaging findings will be discussed. PMID- 10098550 TI - A sneak peek: a case of early thyroid eye disease. PMID- 10098551 TI - Endoscopic sinus surgery in the management of mucormycosis. AB - This is a report of the use of endoscopic sinus surgery in the management of three patients diagnosed with rhino-orbital or rhino-orbito-cerebral mucormycosis. A retrospective review was performed of the clinical examinations and imaging studies of three patients who underwent endoscopic sinus surgery as part of their therapy for mucormycosis. In addition to endoscopic surgery, all patients had aggressive control of underlying risk factors (diabetes mellitus, immunosuppression) and prolonged intravenous amphotericin B therapy. All three patients survived and avoided orbital exenteration. In selected patients with rhino-orbito-cerebral mucormycosis, endoscopic techniques can play a valuable role in diagnosis and management. PMID- 10098552 TI - Neuro-ophthalmologic manifestations of Maffucci's syndrome and Ollier's disease. AB - Patients with Ollier's disease (multiple skeletal enchondromas) and Maffucci's syndrome (multiple enchondromas associated with subcutaneous hemangiomas) may develop skull base chondrosarcomas or low-grade astrocytomas as a delayed consequence of these disorders. We report three patients with Ollier's disease and Maffucci's syndrome who had diplopia as the initial manifestation of intracranial tumors. Since patients with Maffucci's syndrome and Ollier's disease are at risk for the delayed development of brain and systemic neoplasms, neuroophthalmologists must be aware of the need for long-term surveillance in patients affected by these conditions. PMID- 10098553 TI - Optic atrophy and chronic acquired polyneuropathy. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic, multifocal disorder usually defined as limited to the peripheral nervous system. Multifocal motor neuropathy, an acquired demyelinating neuropathy with conduction block affecting motor neurons only, may be a pathogenically distinct syndrome or a predominantly motor variant of chronic inflammatory demyelinating polyneuropathy. Central nervous system demyelination including optic neuropathy has been reported uncommonly previously in these entities. We report two cases and review the literature on the possible association of optic neuropathy and chronic acquired polyneuropathy. PMID- 10098554 TI - Consumer Assessment of Health Plans Study (CAHPS). Foreword. PMID- 10098555 TI - The use of cognitive testing to develop and evaluate CAHPS 1.0 core survey items. Consumer Assessment of Health Plans Study. AB - OBJECTIVES: The main goal of the Consumer Assessments of Health Plans Study (CAHPS) is to develop an integrated set of tested, standardized surveys to obtain meaningful information from health plan enrollees about their experiences. The CAHPS project benefits from the complementary strengths of psychometric and cognitive testing. METHODS: The CAHPS team conducted 150 cognitive interviews across three organizations in different geographic locations using multiple interview methods with different consumer populations. This article explains how cognitive testing was used in the CAHPS survey development process and shares the main findings from the cognitive interviews. RESULTS: A modified report format is more appropriate when asking about specific aspects of plan enrollees' experiences, whereas a rating format is useful for asking about overall assessments. Specifying a longer reference period is preferable to asking about the most recent visit when capturing experiences with care, because some respondents get frustrated when they cannot include experiences other than the most recent visit. Explicit screeners and tailored inapplicable response categories are beneficial in mail questionnaires, so people know that they should not answer questions about which they have no relevant experience. CONCLUSION: Cognitive testing was integral in the development and refinement of the CAHPS instrument. The cognitive testing findings contributed to an improved instrument that should capture consumers' health care and plan experiences with less response error than one not subjected to such testing. The cognitive testing process and findings can be useful to other researchers with similar survey development goals. PMID- 10098556 TI - Psychometric properties of the CAHPS 1.0 survey measures. Consumer Assessment of Health Plans Study. AB - OBJECTIVES: Consumer surveys are being used increasingly to assess the quality of care provided by health plans, physician groups, and clinicians. The purpose of the Consumer Assessment of Health Plans Study (CAHPS) is to develop an integrated and standardized set of surveys designed to collect reliable and valid information about health plan performance from consumers. This article reports psychometric results for the CAHPS 1.0 survey items in samples of individuals with Medicaid or private health insurance coverage. METHODS: Reliability estimates for CAHPS 1.0 measures were estimated in a sample of 5,878 persons on Medicaid and 11,393 persons with private health insurance. Correlations of the CAHPS global rating of the health plan with willingness to recommend the plan and intention to re-enroll were estimated in a sample of 313 persons on Medicaid. The association of the rating of the health plan with ratings using a 5-point Excellent-to-Poor response scale also was investigated in the latter sample and in a sample of 539 persons with private health insurance. RESULTS: The CAHPS measures appeared to have good reliability, particularly at the health-plan level. Responses from 300 consumers per health plan tend to yield estimates that are reliable enough for health plan comparisons, especially among the privately insured. The global health plan rating was significantly correlated with consumers' willingness to recommend the plan to family and friends and to their intention to re-enroll in the plan if given a choice. CONCLUSIONS: The CAHPS 1.0 survey instrument appears to have excellent psychometric properties. PMID- 10098557 TI - Making survey results easy to report to consumers: how reporting needs guided survey design in CAHPS. Consumer Assessment of Health Plans Study. AB - OBJECTIVES: CAHPS is designed to report information about health care quality from the consumer perspective. Enrollees are surveyed about their experiences with their health plan and medical care, and results are reported to other consumers choosing among health plans. Based on survey instruments designed to elicit reliable and valid information about health plan experiences from plan enrollees, the aim of the CAHPS team was to design a series of reporting products that present survey results so that consumers find the information understandable, meaningful, and useful in choosing among health plans. METHODS: Design of the survey instruments and reporting products were closely linked. The approach to reporting was based on previous research on consumers' information interests and needs in evaluating and choosing among plans. Cognitive tests were conducted with consumers to get their reactions to mock-ups of various approaches to reporting CAHPS survey results. RESULTS: Findings from previous research and cognitive testing, together with feedback from various experts and the public, were used to modify the survey questions, response options, and reporting formats to make it easier for consumers to understand and use reports. Changes included dropping topics of less interest to consumers, changing question wordings that were hard to understand, minimizing the number of different response categories, and revising questions to make them easier to group together for purposes of reporting. CONCLUSIONS: The CAHPS focus on reporting results to consumers presented an unusual challenge for survey design, requiring close coordination between instrument design and report development to produce a survey and reporting kit that serves consumers' information needs. PMID- 10098558 TI - Comparing telephone and mail responses to the CAHPS survey instrument. Consumer Assessment of Health Plans Study. AB - OBJECTIVES: The Consumer Assessment of Health Plans (CAHPS) survey is designed to collect member experiences with getting medical care. The objective was to evaluate the comparability of answers to CAHPS questions when data are collected by mail and by telephone interview. METHODS: Two studies comparing phone and mail responses used a pretest instrument with parallel samples drawn from Medicaid beneficiaries in California (n = 217 telephone, 97 mail) and adults with chronic conditions who had health insurance through the State of Washington (n = 98 telephone, 109 mail). A third study used a revised instrument with two parallel cross-section samples of adults covered through the State of Washington (n = 446 telephone, 609 mail). Questions covered respondents' experiences with getting medical care through their health plans. RESULTS: In the first two tests, numerous significant differences were found in the rates at which questions that potentially did not apply to all respondents were answered: some ratings were more positive on the telephone. In the test of a revised instrument, nine of 58 comparisons differed significantly by mode. The systematic differences in response to questions that did not apply to all respondents were greatly reduced. Only one of four ratings and one of seven multi-item composite measures of quality of care were significantly different by mode. CONCLUSION: Although further steps to reduce the remaining mode effects are needed, the data indicate that when the revised CAHPS questions are used, mode of data collection will have little effect on the key results. PMID- 10098559 TI - Respondent selection by mail: obtaining probability samples of health plan enrollees. AB - OBJECTIVES: This study was done to assess the feasibility of respondent selection by mail to obtain random samples of both child and adult enrollees of health plans when only subscriber contact information is available. METHODS: The subjects were enrollees of health plans covered under the policies of employees of the State of Washington. Subscribers were eligible for inclusion in the study samples if they had been enrolled for at least 6 months and, depending on the test, had at least one child and/or a spouse enrolled under their policy. Subjects were randomly assigned to six groups: three approaches for sampling children, two approaches for sampling adults, and one test of parents' willingness to return a questionnaire about themselves. Child selection protocols involved asking respondents to complete either a child-only or a dual questionnaire, asking them to follow a decision rule to choose a sample person, and collecting data in two phases, asking respondents to return material twice. RESULTS: Results indicated that asking subscribers to select an adult respondent by mail was not a success. At least given the procedures we used, adults did not demonstrate good compliance with the respondent selection process offered them. In contrast, parents proved willing to follow a more complicated child selection rule and to do it nearly perfectly. CONCLUSIONS: Parents will follow a decision rule to select an eligible child, but requiring this additional respondent selection step may be associated with a slightly decreased response rate. Asking parents to return materials twice is feasible, but it is too cumbersome a procedure to be practical. It is possible to collect data about both an adult and a child using a dual instrument; however, the increase in information is tempered by a decrease in response rates. PMID- 10098560 TI - The impact of having parents report about both their own and their children's experiences with health insurance plans. AB - OBJECTIVES: The aim of this study was to determine whether parents rate their children's care differently when they also rate their own care than when they do not. METHODS: Subjects were employees of Washington State who had been enrolled in a health plan for at least 6 months and who had at least one covered child. Subjects were randomly assigned to four study groups that were surveyed using different protocols. To assess the stability of responses over time, a follow-up telephone interview was conducted with individuals in two of the groups. RESULTS: Parents or guardians who received both the Adult and Child Surveys were less likely to complete a survey than those who received only one survey. Responses to selected survey questions were quite stable between survey administrations. Parents who rated only their child's health care experiences generally gave more positive responses than those who also rated their own care, although few of these differences were statistically significant. This may have been due, in part, to the lower response rates in the latter group. The pairs of survey questions that ask about the adult's and child's experiences with the same aspects of care had moderate to high levels of association. The pair with the weakest association asked how clearly the doctor or nurse explained things to the adult or the child. CONCLUSIONS: Sending both an adult and child survey to an adult could have an effect on the pattern of responses and result in lower response rates, but this might be a cost-effective way to collect reports about both adult and child health care. PMID- 10098561 TI - Special issues addressed in the CAHPS survey of Medicare managed care beneficiaries. Consumer Assessment of Health Plans Study. AB - OBJECTIVES: This article describes the process through which the MMC survey was developed and examines issues in using this survey with Medicare beneficiaries that have implications for all CAHPS surveys. These include the ability of Medicare beneficiaries to use MMC navigational features, whether access measures are meaningful for this population, and whether beneficiaries' familiarity with managed care influences their health plan assessments. BACKGROUND: The Health Care Financing Administration (HCFA) is mandated to provide comparative plan information, based partly on consumer surveys, to Medicare beneficiaries. The Consumer Assessments of Health Plans Study (CAHPS) is an integrated set of tested, standardized surveys of health plan enrollees. To meet its goal, HCFA has invested in the development of a CAHPS survey of beneficiaries enrolled in Medicare Managed Care plans (MMC). METHODS: Cognitive interviews were completed with 31 Medicare beneficiaries. A field test also was conducted with beneficiaries to examine patterns of survey response. A sample of 956 eligible individuals was selected from six health plans. Using a combination of mail and telephone data collection, 663 (69%) questionnaires were completed. This article provides selective results from these tests. RESULTS: The use of screening questions, skip instructions, and tailored "not applicable" response options appeared to facilitate the response task. Some CAHPS access questions were not meaningful to Medicare beneficiaries. The data do not support the need to adjust for length of plan enrollment. CONCLUSION: Analyses suggested changes to improve the MMC survey and to make other CAHPS surveys consistent with these changes. PMID- 10098562 TI - Special issues in assessing care of Medicaid recipients. AB - OBJECTIVES: The authors describe the process used to develop and test survey items targeted to Medicaid consumers for the Consumer Assessment of Health Plans Study (CAHPS). In addition, the authors highlight the special challenges in locating and surveying Medicaid recipients and provide recommendations for increasing response rates. METHODS: The RAND CAHPS team reviewed the literature and existing questionnaires to identify health care issues and concepts important to Medicaid consumers. Three focus groups and 66 one-on-one cognitive interviews were conducted to test the relevance of our concepts and items and to identify additional concepts important to Medicaid consumers. After the cognitive interviews, the CAHPS Medicaid consumer survey was field tested using a sample of 930 adults and children receiving both Medicaid and Aid to Families with Dependent Children in Los Angeles County and Oklahoma. To determine if one particular mode were preferable for surveying a Medicaid population, our field test sample was divided randomly into a telephone-mode sample, a mixed-mode sample, and a second telephone-mode sample with enhanced locating procedures. Before finalizing the CAHPS 1.0 surveys, the full CAHPS item set was subjected to a formal literacy review. RESULTS: The results of the focus groups and cognitive testing informed iterative versions of the list of concepts addressed by the Medicaid-targeted items. Concepts that were not relevant to Medicaid consumers or that consumers were unable to accurately attribute to a health plan were discarded. New concepts addressing important aspects of health care and the health care experience of Medicaid consumers were identified and added. Item wording and format were revised and refined based on the findings from focus groups, cognitive testing, the field test, and the formal literacy review. In the field test, the mixed-mode method achieved the best results with a 56% completion rate. CONCLUSIONS: The testing and formatting efforts described in this article, in combination with a formal literacy review, led to the development of a Medicaid questionnaire that measures the important health care experiences of Medicaid consumers in a format that is "respondent-friendly." Our recommendations for surveying Medicaid recipients can benefit any survey of a Medicaid population. PMID- 10098563 TI - Translating the CAHPS 1.0 Survey Instruments into Spanish. Consumer Assessment of Health Plans Study. AB - OBJECTIVES: Collecting accurate health data on the growing number of ethnic minorities in the United States has increased in policy relevance in recent years. Today, most general population sample surveys conducted in the United States, including the CAHPS 1.0 Surveys, require translation into Spanish and often other languages as well. This article discusses the process used to translate the CAHPS 1.0 survey instruments into Spanish and the techniques used to evaluate these instruments. METHODS: The CAHPS team used a technique of translation-backtranslation to translate the survey instruments into Spanish and conducted cognitive testing and pretesting of preliminary versions of the 1.0 Survey Instruments in both English and Spanish. RESULTS: The translation backtranslation method produced Spanish-language versions of the survey instruments that were adequate for more educated respondents but were inadequate for less educated respondents and respondents who seemed to be less acculturated. CONCLUSION: Adept translation of a survey instrument is an integral part of the instrument-development process, but it alone does not ensure that a culturally appropriate survey instrument will result. Producing a survey instrument that is culturally appropriate for Latinos in the United States may require modifying the English versions of instruments as well as subjecting Spanish-language instruments to more rigorous testing that includes cognitive testing, pretesting, and an evaluation of the reading level by a literacy expert. PMID- 10098564 TI - Epilogue: Early lessons from CAHPS Demonstrations and Evaluations. Consumer Assessment of Health Plans Study. AB - OBJECTIVES: The Consumer Assessment of Health Plans Study (CAHPS) was developed to provide an integrated set of tested, standardized surveys to obtain meaningful information from health plan enrollees and their experiences. Many organizations began to implement CAHPS in 1997. Formal evaluations of the experiences of three demonstration sites with implementing CAHPS (ie, process evaluations) and the impact of CAHPS on consumer's choices (ie, outcome evaluations) were conducted. This article reports on the early findings and feedback from our process evaluations about the sites' experiences with using CAHPS. Results are presented from the first round demonstration sites, including the lessons learned during the demonstrations. Our plans for future demonstrations and evaluations are included. METHODS: A similar evaluation design and instruments were used across demonstration sites. The process evaluation to monitor program intervention included on-site interviews, off-site review of documents, and focus groups with consumers. RESULTS: There are 4 early results from the CAHPS demonstrations: (1) the CAHPS survey covers topics of importance to sponsors, is of reasonable length, and can be administered quickly; (2) the report templates are being used effectively, but sponsors vary widely in their preferences for summarizing and presenting CAHPS ratings; (3) standardized or off-the-shelf products are aspects of CAHPS that sponsors value highly, while emphasizing need for further development; and (4) because surveys like CAHPS require multiple within-plan samples to make plan comparisons, they require a substantial investment and may be affordable only for large sponsors. CONCLUSION: The first round CAHPS demonstrations highlighted the strengths of the integrated surveys and the areas for improving the products and the implementation process. PMID- 10098565 TI - Agency for Health Care Policy and Research. PMID- 10098566 TI - Variation in inpatient resource use in the treatment of HIV: do the privately insured receive more care? AB - OBJECTIVE: To estimate the impact of insurance status on inpatient resource use after adjusting for health upon admission and site of care. DESIGN: Detailed patient information linked to billing records from the AIDS Cost and Service Utilization Survey (ACSUS), a longitudinal analysis of inpatient and outpatient care between March 1991 and August 1992. SETTING: Hospitalizations of human immunodeficiency virus (HIV) patients from 10 US cities with high incidence of AIDS. PATIENTS: One thousand, nine hundred and forty nine adolescents and adults at various stages of HIV. MAIN OUTCOME MEASURES: We estimate inpatient charges, payments and length of stay as a function of patient, and provider and reimbursement characteristics for more than 1,500 hospitalizations to HIV patients. We control for patient characteristics and underlying risk factors including disease stage, CD4 percentage, mode of transmission, discharge status, type of admission, and region. We use hospital-fixed effects to control for unmeasured differences across facilities. RESULTS: Unadjusted means indicate that uninsured patients or patients covered by public insurance have significantly lower charges and payments than privately insured patients with similar medical conditions. We find that those differences are substantially reduced after controlling for the hospital in which care is received. Further, we find little evidence that "underinsured" patients are discharged sooner on average. CONCLUSIONS: Inpatient resource use is affected by both the hospital in which care is received and the type of patient admitted. Failure to control for unmeasured differences across hospitals is likely to overstate the impact of insurance substantially. PMID- 10098567 TI - Facility characteristics associated with hospitalization of nursing home residents: results of a national study. AB - OBJECTIVES: To test the effect of facility characteristics on the probability of hospitalization of nursing home residents, controlling for resident characteristics and the competing risk of death. RESEARCH DESIGN: Study data were derived from the evaluation of the implementation of the Resident Assessment Instrument, the Minimum Data Set (MDS) in 1993. The data consisted of 2080 residents in 253 NHs as well as the annual On-Line Survey Certification of Automated Records (OSCAR). MEASURES: Multinomial logistic regression was used to determine the effects of selected resident and facility characteristics on hospitalization or death within 6 months of baseline, adjusting for the complex sampling design (using SUDAAN). RESULTS: By controlling for resident demographics, advance directives, diagnoses, selected clinical signs, and type of payer, we found that homes with special care units, more physicians (above the median 0.08 FTE physicians on staff or contract), and any physician extenders (nurse practitioners or physician assistants) were less likely to hospitalize their residents. Homes in which over 3.6% of the residents received respiratory treatment were more likely to hospitalize their residents. CONCLUSIONS: Findings suggest that Medicare HMOs should consider the capacity of nursing facilities, especially in terms of medical care capacity and clinical resources, to limit hospital admissions. PMID- 10098568 TI - Application of the ambulatory care groups in the primary care of a European national health care system: does it work? AB - BACKGROUND: Ambulatory Care Groups (ACGs), a US case-mix system that uses the patient as the unit of analysis, is particularly appropriate for health care systems in which physicians serve a defined list of patients. OBJECTIVE: To determine the extent to which the categorization of patients according to ACGs would account for the utilization of primary care services in a national health care system within the European Union. METHODS: Of all subjects continuously assigned to 9 physicians from public primary health care centers in Bizkaia, Basque Country (Spain) over a 12-month period, those visited at least once (n = 9,093) were included. According to the subject's age, sex, and ICD-9-CM diagnoses assigned during a year of patient-provider encounters, patients were classified by means of the ACGs system. RESULTS: Multiple linear regression analyses indicated that age and sex did not explain more than 7.1% of the variance in annual visits made by adults and 25.7% by children to primary care physicians. However, the r2 adjusted to the ACGs model was 50% and 48%, respectively, and even higher, that is 58% and 64% for another component of the system, the Ambulatory Diagnostic Groups (ADGs). CONCLUSIONS: Those results support the inadequacy of using the patient's age and sex alone to estimate physicians' workload in the primary health setting and the need to consider morbidity categories. The ACGs case-mix system is a useful tool for incorporating patients' morbidity in the explanation of the use of primary health care services in a European national health system. PMID- 10098569 TI - Application of random effects models and other methods to the analysis of multidimensional quality of life data in an AIDS clinical trial. AB - BACKGROUND: Current analytic methods applied to multidimensional health-related quality of life (HRQOL) data do not borrow strength across analyses and do not produce summary estimates of effect. OBJECTIVES: To compare a random effects modelling approach for the analysis of multidimensional HRQOL data to the following: (1) separate analyses for each dimension; (2) O'Brien's global test procedure; and (3) multivariate analysis of variance (MANOVA). RESEARCH DESIGN: Randomized clinical trial comparing 3 treatments (Trimethoprim-Sulfamethoxazole [TS], Dapsone-Trimethoprim [DT], and Clindamycin-Primaquine [CP] for Pneumocystis carinii pneumonia [PCP]). SUBJECTS: Patients with PCP enrolled in AIDS Clinical Trials Group Protocol 108. MEASURES: A 33-item battery assessing 7 dimensions of HRQOL: physical functioning, pain, energy, general health perceptions, disability, pulmonary symptoms, and constitutional symptoms. RESULTS: Analyses focused on changes in score from baseline to Day 7 (n = 145). Separate analyses for each dimension suggested a trend favoring CP versus TS, but using a Bonferroni correction no differences were statistically significant. O'Brien's global procedure for a test of no-treatment effect versus superiority of one treatment yielded P = 0.07. MANOVA did not reveal significant differences among treatment groups. A random effects model using fixed treatment and dimension effects and separate random effects for each person showed a significant overall treatment effect (P = 0.02); changes in scores for CP averaged 10 points greater than for TS. CONCLUSIONS: Random-effects models provide a flexible class of models for analyzing multidimensional quality of life data and estimating treatment effects because they borrow strength across dimensions. PMID- 10098570 TI - The rural health care workforce implications of practice guideline implementation. AB - BACKGROUND: Rural health care workforce forecasting has not included adjustments for predictable changes in practice patterns, such as the introduction of practice guidelines. PURPOSE: To estimate the impact of a practice guideline for a single health condition on the needs of a rural health professional workforce. METHODS: The current care of a cohort of rural Medicare recipients with diabetes mellitus was compared with the care recommended by a diabetes practice guideline. The additional tests and visits that were needed to comply with the guideline were translated into additional hours of physician services and total physician full-time equivalents. RESULTS: The implementation of a practice guideline for Medicare recipients with diabetes in rural Minnesota would require over 30,000 additional hours of primary care physician services and over 5,000 additional hours of eye care professionals' time per year. This additional need represents a 1.3% to 2.4% increase in the number of primary care physicians and a 1.0% to 6.6% increase in the number of eye-care clinicians in a state in which the rural medical provider to population ratios already meet some recommended workforce projections. CONCLUSIONS: The implementation of practice guidelines could result in an increased need for rural health care physicians or other providers. That increase, caused by guideline implementation, should be accounted for in future rural health care workforce predictions. PMID- 10098571 TI - Patient decision support intervention: increased consistency with decision analytic models. AB - BACKGROUND: Patient Decision Support (PDS) tools assist patients in using medical evidence to make choices consistent that are with their values and in using evidence about consequences of medical alternatives. OBJECTIVE: To evaluate a PDS intervention for perimenopausal hormone replacement therapy. We assessed the impact of the PDS on (1) consistency between the decision to take estrogen replacement therapy (ERT) or progesterone/estrogen replacement therapy (PERT) and the expected utility of treatment and (2) likelihood to take ERT and PERT pre- and postintervention. DESIGN: Content of the PDS was standardized. Randomized trial of three intensities of intervention: (1) brochure; (2) lecture/discussion; and (3) active decision support. SUBJECTS: Participants were perimenopausal community volunteers between the ages of 40 and 65 (n = 248). MEASURES: (1) Consistent with values (correlation between expected utility (EU) and likelihood of taking hormones); and (2) Likelihood to take hormone replacement therapy. RESULTS: (1) The brochure group was less consistent with the decision analytic model than the lecture/discussion and active decision support groups. (2) Influence on decisions: PDS tools increased the number of women certain about whether or not to take hormones. There were no differences among experimental groups. Of 99 women uncertain about ERT pre-PDS, 65% changed. Twenty-one (32%) decided against ERT and 44 (68%) decided for ERT. (3) More intensive interventions produced modest gains in a normative direction. CONCLUSIONS: PDSs using any of 3 formats reduce uncertainty and assist women to make informed decisions. Increased consistency with decision analytic models appears to be driven by better estimates of likelihood of outcomes. PMID- 10098572 TI - Do hip replacements improve outcomes for hip fracture patients? AB - BACKGROUND: Hip fracture is a common problem among older Americans. Two types of procedures are available for repairing hip fractures: hip replacement and open or closed reduction with or without internal fixation. The assumption has been that hip replacement produces better functional outcomes. Although that is the common wisdom, outcome studies evaluating hip replacement for treatment of hip fracture are few and have not clearly documented its superiority. OBJECTIVES: To compare outcomes of hip fracture patients who receive hip replacement versus another stabilizing procedure (open or closed reduction with or without internal fixation). DESIGN: Prospective cohort study. PARTICIPANTS: We studied 332 patients (age, > 65) who were hospitalized for a femoral neck fracture and discharged alive. MEASUREMENTS: We examined 2 treatment groups, hip replacement versus another procedure, on 6 outcomes [Activities of Daily Living (ADLs), walking, living situation (institutionalized or not), perceived health (excellent/good vs. fair/poor), rehospitalization, and mortality] at 3 postdischarge times (6 weeks, 6 months and 1 year). RESULTS: Mean age was 80, 80% were female, 96% White, 28% married, and 71% had a hip replacement. The treatment groups were similar at baseline (3 months before admission as reported at discharge) on ADLs, walking, living situation, and perceived health (all P > 0.24). After adjusting for demographics, clinical characteristics, fracture characteristics, and prior ADLs, walking ability, living situation, and perceived health, patients with a hip replacement did not do better at 6 weeks, 6 months, or 1 year post-discharge on any of the 6 outcome measures (all 18 P > 0.10). A global test of all 6 outcomes finds hip replacement patients doing less well at one year (P = 0.02). CONCLUSIONS: Despite the commonly held belief that hip replacement is a superior treatment for hip fracture, we found no suggestion of better outcomes for hip replacement on any of 6 key outcomes. PMID- 10098573 TI - Grading the graders: how hospitals in California and New York perceive and interpret their report cards. AB - BACKGROUND: Concerns about quality of care are increasing as hospitals struggle to lower costs. Hospital report cards are controversial, but little is known about their impact. OBJECTIVES: To determine whether recent hospital report cards are viewed more favorably than pioneering federal efforts; whether a report based on clinical data is viewed more favorably than one based on administrative data; and whether attitudes toward report cards are related to hospital characteristics. DESIGN: Mailed survey of chief executives at 374 California hospitals and 31 New York hospitals listed in report cards on myocardial infarction and coronary bypass mortality. SUBJECTS: Two-hundred-and-seventy-four hospitals in California (73.3% response) and 27 in New York (87.1% response). California hospitals were categorized on ownership, size, occupancy, risk adjusted mortality, teaching status, patient volume, and surgical capability. MEASURES: Number of hospital units that received or discussed the report card, ratings of its quality, perceptions of its usefulness, and knowledge of its methods. RESULTS: In both states, report cards were widely disseminated within hospitals. The mean quality rating was higher (P = 0.0074) in New York than in California; New York respondents appeared to be more knowledgeable about key methods. One or more hospital characteristics was associated with each outcome measure. Leaders at high-mortality hospitals were especially critical and did not find the report useful, despite limited understanding of its methods. CONCLUSIONS: Recent hospital report cards were rated better than pioneering federal efforts. A report based on clinical data was rated better, understood better, and disseminated more often to key staff than one that was based on administrative data. Barriers to constructive use of outcomes data persist, especially at high mortality hospitals. PMID- 10098574 TI - Utilization of mental health and substance abuse services among homeless adults in Los Angeles. AB - OBJECTIVES: Even though psychiatric disorders are disproportionately present among the homeless, little is known about the extent to which homeless people receive treatment for those problems or the factors that are associated with receiving treatment. This article examines utilization and predictors of mental health and substance abuse treatment among a community-based probability sample of homeless adults. METHODS: The data analyzed here were collected through face to-face interviews with 1,563 homeless individuals. Bivariate analyses examined differences between homeless men and women in (1) the prevalence of major mental illnesses and substance dependence and (2) utilization of inpatient and outpatient treatment services for those with specific diagnoses. Logistic regression analyses identified predictors of mental health treatment among those with chronic mental illness and substance abuse treatment among those with recent substance dependence. RESULTS: Two-thirds of these homeless adults met criteria for chronic substance dependence, whereas 22% met criteria for chronic mental illness, with substantial overlap between those two disorders: 77% of those with chronic mental illness were also chronic substance abusers. Only one-fifth of each of those two groups reported receiving treatment for those disorders within the last 60 days. Mental health service utilization was predicted largely by factors related to need (eg, diagnosis, acknowledgment of a mental health problem), whereas substance abuse service utilization was predicted by myriad additional factors, reflecting, in part, critical differences in the organization and financing of these systems of care. CONCLUSIONS: More attention must be directed at how to better deliver appropriate mental health and substance abuse services to homeless adults. PMID- 10098575 TI - The relationship of gender and in-hospital death: increased risk of death in men. AB - OBJECTIVES: The prognostic importance of gender in hospitalized patients has been poorly studied. The current study compared in-hospital death rates between men and women after adjusting for severity of illness. DESIGN: Retrospective cohort study. PATIENTS: 89,793 eligible patients with 6 common nonsurgical diagnoses who were discharged from 30 hospitals in Northeast Ohio in 1991 to 1993. METHODS: Admission severity of illness (ie, predicted risk of death) was calculated using multivariable models that were based on data abstracted from patients' clinical records (ROC curve areas, 0.83-0.90). In hospital death rates were then adjusted for predicted risks of death and other covariates using logistic regression analysis. RESULTS: Adjusted odds of death were higher (P < 0.05) in men, compared with women, for 4 diagnoses (stroke [OR, 1.60]; obstructive airway disease [OR, 1.38]; gastrointestinal hemorrhage [OR 1.32]; pneumonia [OR, 1.18]) and similar for two diagnoses (congestive heart failure [OR, 1.12]; and acute myocardial infarction [OR, 0.97]). These differences were somewhat attenuated by excluding patients discharged to skilled nursing facilities or other hospitals from analysis; nonetheless, the odds of death in men remained higher for 3 diagnoses. CONCLUSIONS: The findings indicate that inhospital death rates are generally higher in men than in women, after adjusting for severity of illness. In addition, the risk of in-hospital death in men and women was influenced by diagnosis. These differences may reflect gender-related variation in the utilization of hospital services, the effectiveness of care, over- or underestimation of severity of illness, or biological differences in men and women. PMID- 10098577 TI - Adequacy of dialysis revisited. PMID- 10098576 TI - Pathogenesis and treatment of secondary hyperparathyroidism in chronic renal disease. PMID- 10098578 TI - Novacor left ventricular assist device: present experience. PMID- 10098579 TI - Factors influencing arteriovenous fistula dysfunction in Japanese patients on chronic hemodialysis. AB - Arteriovenous fistula dysfunction is a constant problem in chronic hemodialysis patients. We investigated the factors influencing fistula dysfunction in 184 patients on chronic hemodialysis. Stepwise regression analysis and Cox proportional hazards model were used to assess the relationship between fistula dysfunction and age, sex, duration of hemodialysis, diabetes mellitus, hematocrit, serum creatinine, blood urea nitrogen, Kt/V, prothrombin time, blood pressure, anticoagulant therapy, dose of erythropoietin, calcium channel blocker therapy, and angiotensin-converting enzyme inhibitor therapy. Fistula dysfunction showed a significant relationship with a low systolic blood pressure, a low hematocrit, the presence of diabetes mellitus, and angiotensin-converting enzyme inhibitor therapy. These results suggested that treatment with angiotensin converting enzyme inhibitors may help to prevent fistula dysfunction. PMID- 10098580 TI - Hemodialysis as a treatment of severe ethanol poisoning. AB - A 64-year-old woman presented with coma and shock due to severe ethanol intoxication. Her initial, markedly elevated blood alcohol level of 136.5 mM fell only by 16% after a 4-hour period of conservative treatment consisting of mechanical respiration and the administration of intravenous fluids, vasopressors and inotropics. Subsequent hemodialysis rapidly reduced her blood ethanol concentrations to less threatening levels, with prompt restoration of her consciousness. Hemodialysis may be life-saving and should be considered in patients with severe ethanol intoxication. PMID- 10098581 TI - Static state hemodynamic variables estimation model for the moving-actuator type total artificial heart. Part. I--cardiac output estimation. AB - Cardiac output estimation is a very important study for the artificial heart. In this paper, we developed a cardiac output estimation model for the moving actuator type total artificial heart (MA-TAH) that was developed at Seoul National University Hospital. The proposed model is simple and provides beat-by beat mean cardiac output estimation. Moreover, it uses non-invasively acquired signals. Model parameters were adjusted with in vitro data by least mean square (LMS) algorithm. Results showed that the proposed scheme gives a mean estimation error of about 0.1 (l/min) for the given data. This ensures the suitability of the proposed model. PMID- 10098582 TI - Temporary extracorporeal liver support for severe acute alcoholic hepatitis using the BioLogic-DT. AB - Patients with severe acute alcoholic hepatitis develop multiple organ failure which is associated with production of inflammatory cytokines and a poor prognosis. The aim of the present pilot study was to evaluate the effects of the BioLogic-DT sorption-suspension dialyser in patients with severe acute alcoholic hepatitis. Ten patients with encephalopathy (grade II-IV) were entered into the study, 5 received treatment with the BioLogic-DT for 6 hours daily for 3 days and 5 received conventional treatment as controls. The system was biocompatible with no adverse effects on blood pressure or platelet counts, factor V, fibrinogen or antithrombin III. No bleeding episodes were observed even with the use of small doses of heparin. After 3 days, blood ammonia was lower in the BioLogic-DT treated patients than in the controls, although blood lactate was higher. There were slight increases in plasma TNF and IL-8 during treatment over and above the higher levels present initially, possibly as a result of activation of white cells in the extracorporeal circuit. The further development of the BioLogic-DT dialyser with the addition of a plasma treatment module capable of removing cytokines would be worth evaluating in acute alcoholic hepatitis. PMID- 10098583 TI - Time-related contact angle measurements with human plasma on biomaterial surfaces. AB - Axisymmetric drop shape analysis by profile (ADSA-P) was used to assess in time contact angle changes of human plasma drops placed on four different biomaterials. Results were related with conventional blood compatibility measurements: albumin adsorption, fibrinogen adsorption and platelet adhesion. While contact angle measurements with water are material-related but constant in time, contact angle measurements with plasma changed over time owing to protein adsorption on the solid-liquid interface. The contact medium plasma did not influence the initial contact angle. Contact angles on PDMS decreased most in time (41 degrees) and demonstrated highest levels of conventionally measured albumin and fibrinogen adsorption and platelet adhesion. PTFE, with the lowest contact angle decrease over a 500 minutes period (19 degrees), showed low fibrinogen and albumin adsorption as well as low platelet adhesion. PU and HDPE demonstrated almost similar initial contact angles with plasma and contact angle decreases (26 and 27 degrees), intermediate protein adsorption, and platelet adhesion. We conclude that biocompatibility properties of the tested materials may be more related to the behaviour of their contact angles in time, than to the initial hydrophobic or hydrophilic state. PMID- 10098584 TI - Plasma-exchange in chronic peripheral neurological disorders. AB - We investigated 19 patients affected by chronic peripheral neurological disorders treated with therapeutic plasma exchange (TPE) to verify the efficacy of the therapeutic protocol used in these diseases. Every patient was clinically considered after 5 TPE. Those who showed an improvement started chemotherapy and continued TPE at the rate of 2 procedures/week for 2 weeks, then 1 procedure/week for 1 month and finally 1 procedure every 2 weeks for 2 months. Intravenous immunoglobulins (IVIg) were infused at the end of apheretic treatment in one of the patients affected by neurological disorders due to monoclonal gammopathy undetermined significance. HCV-positive patients with cryoglobulins were treated with alpha-interferon (alpha-IFN) for 6 months before TPE. Eleven patients (58%) had a symptomatic improvement, 2 (1.5%) stopped TPE treatment owing to side effects and 6 (31.5%) did not respond to apheretic therapy. In order to improve the advantages of TPE we suggest using IVIg at the end of apheretic therapy, while in HCV-positive patients, at least one year of alpha-IFN therapy is required before initiating TPE. PMID- 10098585 TI - Reducing perioperative blood loss in patients undergoing total hip arthroplasty. AB - In this prospective, randomised, double-blind study, we investigated the effect of epidural anaesthesia and an antifibrinolytic agent, Aprotinin (500,000 KIU in bolus before surgery and 500,000 KIU h(-1) in drip form during surgery), on intra and postoperative blood loss and transfusion requirements in total hip arthroplasty. Sixty patients were allocated randomly to four groups (A: epidural + general anesthesia + Aprotinin, B: epidural + general anesthesia + placebo (equal volume), C: general anaesthesia + Aprotinin, D: general anaesthesia + placebo). Postoperative analgesia: epidural analgesia in groups A and B, systemic analgesia with opiates in groups C and D. Blood loss during surgery was monitored and salvaged with the Compact-A Dideco, and postoperative blood loss with the BT 797 Recovery Dideco for the first 24 hours. Perioperative blood loss, frequency and quantity of transfusions were significantly higher in group D (p<0.0001). Total blood loss was reduced by 31.3% by epidural anaesthesia, 20.4% by Aprotinin and 51.4% using a combination of the two techniques. PMID- 10098586 TI - The "Aachen" keratoprosthesis: a new approach towards successful keratoprosthesis surgery. AB - BACKGROUND: None of the keratoprostheses available today is absolutely successful in the long term, neither the problems of extrusion, retroprosthetic membrane formation and intraocular pressure rise are yet solved. A new type of keratoprosthesis is required which can show improved ingrowth characteristics and allow intraocular pressure measurements. In order to possibly meet the above mentioned requirements we developed a flexible silicone keratoprosthesis with scleral fixation and chemical surface modification. METHODS: The one-piece keratoprosthesis is made of silicone rubber. Its optical zone has a diameter of 11 mm and is 0.3 mm thick. The surface-modified haptic consists of a scleral rim and eight branches for scleral fixation. A ridge at the back of the keratoprosthesis fitting into the trephination hole shall avoid leakage and retroprosthetic membrane formation. Optical and mechanical qualities are characterised by tensile tests, spectrophotometry and topography. RESULTS: A method for keratoprosthesis-production was established. The optical quality of the device was improved by submicron lathing of the mould. Spectrophotometry showed high visible and ultraviolet light transmission of the silicone. Mechanical tests with silicone samples revealed high tensile strength and elongation at break. The mechanical properties were not impaired by surface modification. CONCLUSIONS: The production of a flexible silicone keratoprosthesis with high optical and mechanical properties was established. Its use both for the treatment of permanently opacified corneas and as temporary keratoprosthesis seems to be possible. PMID- 10098587 TI - The Cobe Trima system as a tool for optimizing component collection. A further step towards total apheresis. PMID- 10098588 TI - Reproducibility of fasting plasma leptin concentration in lean and obese humans. AB - We determined the reproducibility of plasma leptin levels in 20 healthy subjects (10 men, 10 women; 10 lean, 10 obese) at stable body weight. Blood samples were obtained, after an overnight fast, between 0700 and 0800 on days 1, 2, 3, 4, 5, 12, 19, and 26. Body weights were recorded on the same days. Plasma leptin was measured using a specific radioimmunoassay. The mean +/- SE baseline body weights (kg) were 65.8 +/- 3.6 (lean) and 96.4 +/- 7.1 (obese). The body mass indices (BMI) were 22.9 +/- 2.8 kg/m2 (lean) and 32.7 +/- 2.2 kg/m2 (obese). The mean daily fasting plasma glucose level was 98.7 +/- 3.7 mg/dl. Baseline plasma leptin levels (ng/ml) were 5.3 +/- 0.75 in lean men, 14.9 +/- 4.6 in obese men, 11.2 +/- 2.8 in lean women, and 27.1 +/- 8.4 in obese women. Fasting leptin levels on days 2 to 26 were highly correlated with the baseline levels on day 1 (r2 = 0.9, P<0.0001). Body weights remained within 98%-102% of baseline, whereas intra individual leptin levels fluctuated between 80% and 120% of baseline values, throughout the 26 days of study. We conclude that fasting plasma leptin levels are reproducible, with a maximum day-to-day variation of approximately 20%, in healthy, free-living, lean and obese persons who maintain a stable body weight. PMID- 10098589 TI - Stimulatory effect of leukemia inhibitory factor on ACTH secretion of dispersed rat pituitary cells. AB - Cytokines are recognized to play an important role in modulating the immune and neuroendocrine system. We recently reported leukemia inhibitory factor (LIF) increased ACTH secretion and pro-opiomelanocortin mRNA level in the murine corticotroph tumor cell line (AtT-20). In this study, the expression of LIF in normal rat pituitary could be demonstrated by ribonuclease protection assay. LIF (1 nM) caused a slight, but significant increase in ACTH secretion (43.7% increase versus control, P<0.01), while showing statistically no significant change of growth hormone and prolactin level in dispersed rat pituitary cells. CRH (10 nM) also induced ACTH secretion 2.5-fold (P<0.01), and co-treatment of LIF and CRH exhibited 2.8-fold increase of ACTH secretion but no statistical difference from CRH treated group. These findings suggest that LIF also has same enhancing effect of ACTH secretion in primary pituitary cultured cells of rat as in AtT-20 cell and LIF acts as a paracrine or autocrine factor to modulate neuroendocrine function in the pituitary. PMID- 10098590 TI - Ontogeny of 3beta-hydroxysteroid dehydrogenase expression in the rat adrenal gland as studied by immunohistochemistry. AB - The enzyme 3beta-hydroxysteroid dehydrogenase plays a crucial role in the steroidogenic process in the adrenal gland. In the present study we tried to characterize its localization and developmental changes in the rat adrenal cortex during the postnatal period, using immunohistochemical methods. The development of the different zones evidenced specific particularities: the zona glomerulosa almost lacked 3beta-HSD in the first days after birth; then, 3beta-HSD increased, attaining a maximum around day 20 and afterwards it decreased again and remained less intense than the neighbouring zona fasciculata up until adulthood (65 days of age). The zona fasciculata was already intensely stained at birth and the expression of 3beta-HSD increased rapidly reaching a maximum after 2 weeks of life and that level was maintained from then on. The inner part of the zona fasciculata and the zona reticularis both of which develop postnatally were faintly immunostained before day 20. The expression of 3beta-HSD increased after that age to become approximately as intense as in the outer zona fasciculata and so remaining until day 90. The development of the zona glomerulosa was parallel to the secretion of aldosterone. The same did not occur with the zona fasciculata as the intensity of staining during the first 14 postnatal days was accompanied by very low levels of corticosterone. PMID- 10098591 TI - Adrenomedullin and calcitonin gene-related peptide (CGRP) interact with a common receptor of the CGRP1 subtype in the human adrenal zona glomerulosa. AB - Frozen sections of normal adrenal glands, obtained from patients undergoing unilateral nephrectomy for kidney cancer, were labeled in vitro with human [125I]ADM(1-52). Autoradiography showed the presence of abundant ADM binding sites in the zona glomerulosa (ZG) and the outermost portion of the zona fasciculata, which were completely displaced by the addition of an excess of cold ADM(1-52). Calcitonin gene-related peptide (CGRP) and the non-selective ligand of the CGRP-receptor subtypes 1 and 2 CGRP(8-37) eliminated [125I]ADM(1-52) binding in the ZG, while the selective ligand of CGRP receptor subtype 2 [Cys(acm)2,7] CGRP and CGRP(1-8) were ineffective. These findings confirm the presence of ADM binding sites in the human ZG, and provide the first morphological evidence that ADM and CGRP interact with a common receptor of the CGRP1 subtype. PMID- 10098592 TI - Lithium-induced alterations in the testis of the male roseringed parakeet (Psittacula krameri) : evidence for significant structural changes and disruption in the spermatogenetic activity. AB - In this report, we have examined the effects of lithium on testicular morphology in a male subtropical wild avian species, the roseringed parakeet (Psittacula krameri). Adult male birds were collected during the months of February-March, a time when the testicular gametogenic activity in these seasonally breeding birds is at its peak. They were injected, intramuscularly, twice daily (07:00 and 19:00 h) with lithium chloride (Sigma Chemical Company) at a dosage of 0.5 mEq/Kg body weight either for 5 or 10 days. A significant decrease in both the absolute and relative testicular weights was evident in the lithium-treated birds as compared to those of the saline-injected control animals. Light microscopic studies of the testis in the lithium-treated animals showed a wide range of degenerative changes. These included a) a significant reduction in the diameter of seminiferous tubules; b) necrosis and exfoliation of most of the germ cells in the seminiferous tubular lumen with the exception of the spermatogonia; and c) a significant reduction in the number of mature spermatozoa in the tubular lumen. These degenerative changes were dependent on the duration of lithium treatment and were evident when the plasma lithium concentrations were well below the human therapeutic range. Leydig cell morphology was not affected by lithium however. Our results provide the first experimental evidence of lithium's adverse reproductive function in an avian species. These data provide further support to the view that lithium adversely affects the male reproductive system and that these effects extend beyond mammalian species. PMID- 10098593 TI - Acute in vivo effects of ACTH by exo utero microinjection on differentiation, steroidogenesis and proliferation of fetal mouse adrenocytes. AB - Mouse embryos on embryonic day (E)13 or 14 were treated with ACTH1-24 by exo utero microinjection and the adrenal was examined after 16 and 32 h. Light microscopic morphometry showed that the ACTH treatment increased cell size and decreased cell density of the adrenocortical cells. Bromodeoxyuridine-labeling index did not alter significantly after the ACTH treatment. By immunohistochemistry, both number of cells expressing 11beta-hydroxylase and the staining intensity increased in the ACTH-treated glands compared to controls whereas expression of aldosterone synthase was detectable in neither the treated nor control groups. Ultrastructurally, the adrenocytes of the inner cortical zone of the ACTH-treated glands were characterized by strikingly increased content of the smooth endoplasmic reticulum, increased mitochondria with more vesicular cristae, lipid droplets with a much higher electron density along with the distribution altered from that in controls. All of the significant differences between the ACTH-treated and control glands occurred at 16 h but not at the 32 h interval. The present results indicated that the mouse fetal adrenocytes are already sensitive to ACTH during early period (E13 and 14) of their functional differentiation. In vivo acute treatment of ACTH stimulates cell-size, increase of fetal adrenocytes but not proliferation, and may directly or indirectly regulate multiple steps of the steroidogenic process of the fetal mouse adrenal. PMID- 10098594 TI - Mechanism of the augmentative effect of high polyethylene glycol (PEG) concentrations on the thyroid stimulating activity in TSAb-IgG using a porcine thyroid cell assay. AB - We previously demonstrated that high polyethylene glycol (PEG) concentrations (5% PEG) significantly augmented cAMP production in response to TSAb-IgG using the porcine thyroid cell (PTC) assay. The mechanism of the stimulatory effect of 5% PEG on cAMP production was examined by a two-step incubation with PTC. TSAb-IgG was preincubated with or without addition of 5% PEG in the PTC assay for 2.5 hr (1st incubation) and separated PTC was re-incubated with fresh Hank's buffer for 5 hr (2nd incubation). cAMP production in the 1st incubation medium by co incubation of TSAb-IgG and 5% PEG for 2.5 hr was significantly increased (3.3 fold) compared to that without 5% PEG. When the cAMP content in PTC and the incubation medium were compared in the same volume of incubation medium after co incubation of TSAb-IgG and 5% PEG for 2.5 hr, cAMP contents in PTC were about 7 fold higher than that in the incubation medium, and this ratio did not change in the incubation medium of TSAb-IgG without 5% PEG. Similar increases in cAMP contents in PTC (6.6-fold) compared to the incubation medium were also observed with bTSH, although there was no augmentative effect of 5% PEG on cAMP production by bTSH in either the incubation medium or PTC. When PTC, which had been preincubated with normal-IgG and 5% PEG in the 1st incubation, was re-incubated with TSAb-IgG in the 2nd incubation medium, cAMP production by TSAb-IgG was not stimulated by 5% PEG. The augmentative effect of 5% PEG on cAMP production by TSAb-IgG was observed whenever 5% PEG and TSAb-IgG were co-incubated in either the 1st or 2nd incubation. However, no stimulatory effect of 5% PEG on bTSH was observed. These results suggested the stimulatory effect of 5% PEG on TSAb-IgG stimulated cAMP production may be due to the increase of binding or incorporation of TSAb-IgG into the membranes of PTC compared to TSH. PMID- 10098595 TI - Effect of PTU treatment on histone acetylation pattern in the developing rat brain. AB - The effect of hypothyroidism induced m female rats on histone acetylation pattern m the neonatal rat brain was studied. It is likely that thyroid hormone regulates the acetylation of histones and thereby influence their interaction with DNA and modulates transcription. Propylthiouracil (PTU), administered to induce hypothyroidism, resulted in a significant reduction m the thyroid and brain weight of neonatal rats. The circulating thyroxine levels were undetectable in both 14 and 21 day old pups. The hypothyroid condition was further confirmed by low levels of T4 (94.31 ng/g brain tissue vs 1811.29 ng/g in controls and 144.67 ng/g vs 1087.72 ng/g in controls at 14 and 21 days, respectively) and T3 (42.19 ng/g brain tissue vs 879.97 ng/g in controls and 60.62 ng/g vs 766.68 ng/g in controls at 14 and 21 days, respectively) in the neonatal rat brain. Histone acetylation pattern was similar in treated and control groups m the 14 day old rats. PTU treatment, however, resulted in significant (p<0.01) reduction in acetylation in the H3 fraction at 21 days whereas no such changes were recorded in other histone fractions. Lower histone acetylation in the 21 day old pups suggest a reduction m the transcriptional activity due to fewer initiation sites for RNA polymerase. It may be concluded that thyroid hormone may stimulate transcription of specific genes by increasing the acetylation of nucleosomal histones. PMID- 10098596 TI - Differential diagnosis of thyroid crisis and malignant hyperthermia in an anesthetized porcine model. AB - The intra-operative differential diagnosis between thyroid crisis and malignant hyperthermia can be difficult. Also stress alone can trigger MH. The purposes of this study were: 1) to investigate the metabolic and hemodynamic differences between thyroid crisis and MH, 2) determine how thyroid crisis affects the development of MH, and 3) determine if the stress of thyroid crisis can trigger MH in susceptible individuals. We studied MH susceptible and normal swine. Two groups of animals (MH susceptible and normal) were induced into thyroid crisis (critical core hyperthermia, sustained tachycardia and increase in oxygen consumption) by pretreatment with intraperitoneal triiodothyronine (T3) followed by large hourly intravenous injections of T3. Two similar groups were given intravenous T3 but no pretreatment. These animals did not develop thyroid crisis and served as controls. Thyroid crisis did not result in metabolic changes or rigidity characteristic of an acute episode of MH. When the animals were subsequently challenged with MH triggering agents (halothane plus succinylcholine) dramatic manifestations of fulminant MH episodes (acute serious elevation in exhaled carbon dioxide, arterial CO2, rigidity and acidemia) were noted only in the MH susceptible animals. Although thyroid crisis did not trigger MH in the susceptible animals it did decrease the time to trigger MH (14.1 +/- 7.2 minutes versus 47.2 +/- 17.7 minutes, p < 0.01) in susceptible animals. Hormone induced elevations in temperature and possibly other unidentified factors during thyroid crisis may facilitate the triggering of MH following halothane and succinylcholine challenge. PMID- 10098597 TI - Effects of granulocyte-macrophage colony-stimulating factor on incisional wound healing in an experimental diabetic rat model. AB - The exact nature of poor wound healing in diabetes is uncertain. Neutrophils play a critical role in the host defense mechanism, and it is suggested that impaired neutrophil functions cause healing difficulties with or without infections in diabetic patients. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is used clinically when given systematically to increase the circulating neutrophils, but its wound-healing effects have not been systematically studied. This study was undertaken to examine the effects of GM-CSF on incisional wound healing in an experimental diabetic rat model. Forty rats were randomly divided into three groups, group I receiving saline as control, diabetes-induced group II receiving saline and diabetes-induced group III receiving GM-CSF. The anesthetized rats in all groups were wounded 21 days after diabetes induction by streptozotocin. Blood neutrophil counts and neutrophil fractions were also determined three days after wounding. Tensile strengths of wounded skin and the hydroxyproline (hyp) level of the wound were determined and wound healing processes were evaluated by light and electron microscopy, fourteen days after wounding. Neutrophil counts and phagocytosis were significantly increased in group III and neutrophil counts decreased in group II (p < 0.05). Although the hydroxyproline level of wound tissue significantly decreased in group II as compared with group III (p < 0.05), there was no differences of tensile strength between group II and III (p < 0.05). Wound score in group II was less than that in groups I and III (p < 0.05). It is concluded that PMN may have a role in modulating wound healing. GM-CSF may be useful for creating better wound healing healing. GM-CSF may be useful for creating better wound healing in risky patients such as diabetics. PMID- 10098598 TI - Cytochemical demonstration of the glucocorticoid receptor in skeletal cells of the rat. AB - The in vivo localization of the glucocorticoid receptor (GR) was studied in cartilage and bone cells of femurs of young adult rats. Deparaffinized sections were treated with a polyclonal antibody raised against the amino-terminus of human GR; the immunoreaction was detected with the streptavidin-biotin amplification method. Histomorphometric, computer-assisted analysis of GR positive cells was performed by counting the percentage of GR-immunostained cells in the proliferative and maturative/hypertrophic zone of the epiphyseal growth plate cartilage, and of the percentage of positive osteoblasts (OBs), osteoclasts (OCLS) and osteocytes (OCs) in the metaphyseal secondary ossification zone. Numbers of OBs and OCLs per mm of metaphyseal endosteal perimeter, and numbers of OCs per mm2 of trabecular area were also counted. Immunopositive cells were found both in cartilage and bone, with variable degree of nuclear and/or cytoplasmic immunostaining; immunonegative cells were present among the positive ones. Histomorphometry showed that about 54% of chondrocytes in the proliferative zone, and 55% of chondrocytes in the maturative/hypertrophic zone of the growth plate were labeled; in metaphyseal bone, 68% of OBs, 65% of OCs, and 98% of OCLs were GR-positive. The density of positive cells was 12.06 OBs/mm, 3.32 OCLs/mm, and 520.40 OCs/mm2. These results, for the first time obtained in vivo, show that GR is present in cartilage and bone cells, and that the degree of GR-immunostaining is variable in the same type of cell. This may be dependent on the cell cycle and stage of differentiation, and may reflect a variable cellular sensitivity to the stimulation of the glucocorticoid hormone. PMID- 10098599 TI - The effect of hypo- and hyperthyroidism on uterine and cervical collagens and glycosidases in albino rats. AB - The effect of hypo- and hyperthyroidism on uterine and cervical collagen and glycosidases were studied in mature albino rats. Hypothyroidism significantly increased the salt-soluble, acid-soluble, insoluble and total collagen in the uterus and cervix. However, all of these collagens were significantly decreased in the hyperthyroid condition. The activities of alpha- and beta-galactosidases and glucosidases were significantly decreased in the uterus and cervix of hypothyroid rats, whereas, in hyperthyroid rats, all of these enzymes were significantly increased in the uterus and cervix. The data obtained in the present study suggested that the increase in lysosomal enzymes increased the degradation of uterine and cervical collagen. In contrast, the decrease in lysosomal enzymes in hypothyroid condition increased uterine and cervical collagen by decreasing degradation. PMID- 10098600 TI - Regulation of N-acetylgalactosamine 4-sulfatase expression in retrovirus transduced feline mucopolysaccharidosis type VI muscle cells. AB - As a preliminary step toward muscle-mediated gene therapy in the mucopolysaccharidosis (MPS) type VI cat, we have analyzed the transcriptional regulation of feline N-acetylgalactosamine 4-sulfatase (f4S) gene expression from various retroviral constructs in primary cultures of muscle cells. Two retroviral constructs were made containing the f4S cDNA under the transcriptional control of the human polypeptide chain-elongation factor 1alpha (EF1alpha) gene promoter or the cytomegalovirus (CMV) immediate-early promoter. Two further retroviral constructs were made with the murine muscle creatine kinase (mck) enhancer sequence upstream of the internal promoter. Virus made from each construct was used to transduce feline MPS VI myoblasts. The mck enhancer significantly upregulated f4S gene expression from both the EF1alpha promoter and the CMV promoter in transduced myoblasts and in differentiated myofibers. The highest level of 4S activity was observed in myoblasts and myofibers transduced with the retroviral construct Lmckcmv4S, in which the f4S gene is under the transcriptional regulation of the mck enhancer and CMV immediate-early promoter. Lmckcmv4S-transduced myofibers demonstrated correction of glycosaminoglycan storage and contained a 58-fold elevated level of 4S activity compared with normal myofibers. Recombinant f4S secreted from Lmckcmv4S-transduced myofibers was endocytosed by feline MPS VI myofibers, leading to correction of the biochemical storage phenotype. PMID- 10098602 TI - The unr gene: evolutionary considerations and nucleic acid-binding properties of its long isoform product. AB - The unr transcription unit is located just upstream of the N-ras gene in the genome of mammals, in which unr, like N-ras, is ubiquitously expressed. To determine at what point in evolution the unr/N-ras linkage was created, analysis of nucleic acids by Southern and Northern blotting was performed, allowing us to track the presence of the unr gene to the start of vertebrate evolution and the unr/N-ras linkage to the time at which the reptilian and bird lines diverged. We have investigated, with specific anti-unr antibodies, a potential relation between unr protein levels and cellular processes in which N-ras is implicated. A positive correlation in the proliferation of 3T3 cells, but not differentiation of PC12 cells induced by nerve growth factor (NGF), was found. To study the nucleic acid-binding properties of unr, a protein with multiple repeats of a nucleic acid-binding motif, we expressed the long splicing isoform in a eukaryotic cell line and purified it in native form. The results obtained-a high affinity of unr for single-stranded DNA and RNA and lower affinity for double stranded DNA without regard to nucleic acid sequence, and its intracellular localization in both the nuclear and non-nuclear compartments, together with its ubiquious expression in mammalian tissues-provide molecular information about the function of one of the closest gene tandems in mammalian cells (unr-N-ras). PMID- 10098603 TI - Improved immunogenicity of HIV-1 epitopes in HBsAg chimeric DNA vaccine plasmids by structural mutations of HBsAg. AB - To improve the immunogenicity of epitopes from the envelope protein of HIV-1, we have developed gene gun-delivered subunit DNA vaccines by inserting the sequences encoding the V3 region into the hepatitis B virus (HBV) envelope gene, often called the surface antigen (HBsAg). We have examined the possibility of modifying the immune response to V3 by introducing modifications into the carrier HBsAg in gene gun DNA immunization of mice. In some plasmid constructions, the V3 sequence was introduced into the preS2 region of the HBsAg. Although this region is not present in all protein subunits of the HBsAg particles produced, abolishing the internal translational initiation site for the S protein had no effect on the immune response to V3. Expression of V3 at the N-terminal or C-terminal part of the HBsAg protein resulted in equal anti-V3 antibody and cytotoxic T-lymphocyte (CTL) responses. However, elimination of secretion by single amino-acid mutations in the HBsAg decreased the anti-HBsAg antibody response but enhanced the anti-V3 antibody response. In contrast, the CTL response to V3 was independent of the structural mutations but could be improved by a total deletion of the HBsAg sequence part. Thus, the immune response to heterologous epitopes can be altered by modifications in the carrier HBsAg protein. Modifications of the HBsAg carrier might interfere with the dominant immune response to the HBsAg epitopes, allowing better antibody induction to less immunogenic foreign epitopes. However, for induction of CTL responses, the expression of minimal epitopes may be advantageous. PMID- 10098601 TI - Ku autoimmune antigen is involved in placental regulation of rat P450c17 gene transcription. AB - The steroidogenic enzyme P450c17 (17alpha hydroxylase/C17,20 lyase) regulates a key branchpoint in steroidogenesis, as its activity directs the steroid biosynthetic pathways toward glucocorticoid or sex hormone synthesis. Expression of the P450c17 gene is transcriptionally regulated in steroidogenic tissues by cAMP. We showed that DNA between -84 and -55 in the rat P450c17 gene was bound uniquely by steroidogenic factor-1 (SF-1), which regulated both basal and cAMP stimulated transcription in mouse adrenocortical and Leydig cells. SF-1 gene ablation experiments in mice indicate that SF-1 is not mandatory for placental steroidogenesis. We studied P450c17 gene regulation in the placenta using human placental JEG-3 trophoblast cells. Transfection of reporter luciferase gene constructs containing serial deletions of the 5' flanking region of the rat P450c17 gene showed that DNA between -98 and +13 mediated basal and cAMP regulated transcription in placental JEG-3 cells, as it did in adrenal and Leydig cells. DNase footprints further identified a region between -88 and the TATA box that was bound by protein. Transfection of luciferase reporter constructs containing -84 to -55 of the rat P450c17 DNA ligated to the minimal promoter of the thymidine kinase gene showed that this DNA increased both basal and cAMP simulated luciferase activity. Gel mobility shift assays identified two DNA protein complexes with JEG-3 cell nuclear extracts that were different from complexes formed with MA-10 cell extracts and did not involve SF-1. Mutational analysis of the -84/-55 DNA showed that JEG-3 nuclear proteins bound to a site containing, but not identical to, the SF-1 sequence. One complex involved Ku autoimmune antigen, which bound to DNA sequence specifically. Overexpression of Ku antigen in MA-10 cells stimulated rat P450c17 gene transcription, thus demonstrating a biologic effect of Ku. Ku also bound to a similar region of the human P450c17 gene, and the DNA region to which Ku bound was transcriptionally active in JEG-3 cells. Ku was also found in extracts from rat placenta and bound to the -84/-55 rat P450c17 DNA. These data demonstrate a role of Ku in regulating P450c17 gene expression. These data further indicate that although human P450c17 is not normally expressed in the placenta, factors that could activate this gene are indeed present. PMID- 10098604 TI - Maternal transcripts of mitotic checkpoint gene, Xbub3, are accumulated in the animal blastomeres of Xenopus early embryo. AB - Maternally transcribed mRNAs play the important role during early embryogenesis. Especially in patterning, distribution of the maternal transcripts has a causal relation to axis formation in the early embryo. We compared the quantity of mRNAs among four blastomeres of Xenopus 8-cell-stage embryos by the differential display method. A novel gene, Xbub3, was cloned by screening the oocyte cDNA library with an animal blastomere-enriched PCR product. Xbub3 is a homolog of the human mitotic checkpoint gene hBub3. A transcript of Xbub3 was 2940 bp and encoded a predicted protein of 330 amino acids with six WD repeats. Expression of Xbub3 was observed from oocyte to tadpole. Whole-mount in situ hybridization showed that Xbub3 mRNAs were uniformly distributed in the early stages of oogenesis but gradually localized to the animal hemisphere, especially in the perinuclear cytoplasm of full-grown oocytes. In the cleavage-stage embryos, the maternal transcripts of Xbub3 were recruited into each blastomere, associating closely with chromosomes. Zygotic expression of Xbub3 was widely detected in gastrula ectoderm and was gradually restricted to the central nervous systems, eyes, and branchial arches by the tadpole stage. This evidence contributes to understanding of the regulatory mechanism of the cell cycle and cell differentiation in the early embryo. PMID- 10098605 TI - A Drosophila clathrin light-chain gene: sequence, mapping, and absence of neuronal specialization. AB - Because mammalian light chains have been implicated in the regulation of clathrin coat assembly and neuronal specialization of clathrin-mediated vesicle trafficking, a clathrin light-chain gene of Drosophila has been sought as a genetically tractable model for these developmental membrane-trafficking systems. A light-chain gene has been identified and its expression examined in various developmental stages and tissues by reverse transcriptase-polymerase chain reaction (RT-PCR). A cDNA clone, originally identified from a partial sequence in the Berkeley Drosophila Genome Project EST database, has been sequenced completely and shown to encode a polypeptide with extensive sequence similarity to vertebrate and invertebrate clathrin light chains. Secondary structure algorithms predict an extensive coiled-coil over a region extending from amino acid residues 100 to 170, in excellent agreement with previous analyses of mammalian light chains. By in situ hybridization to larval polytene chromosomes, the gene has been mapped to cytologic position 77A on the left arm of chromosome 3. An RT-PCR analysis, coupled with PCR analysis of genomic DNA, showed that there is no neural specialization of the Drosophila clathrin light chain corresponding to that observed in mammalian neuronal light chains. The neuron specific alternative splicing of clathrin light chains thus appears to be restricted to vertebrates, where it may contribute to the more complex information-processing capacity of higher nervous systems. PMID- 10098606 TI - Characterization of expression of the gene for human pterin carbinolamine dehydratase/dimerization cofactor of HNF1. AB - Pterin carbinolamine dehydratase/dimerization cofactor of HNF1 (PCD/DCoH) is a dual-function protein. In the cytoplasm it acts as a dehydratase in the regeneration of tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases. In the nucleus, it functions as a dimerization cofactor of HNF1 and increases the transcriptional activity of HNF1. To deepen our understanding of this protein, we characterized its expression in human tissues and cells. Human PCD/DCoH was present predominantly in liver and kidney, with significant amounts in testis and ovary, trace amounts in lung, and undetectable levels in whole brain, heart, and spleen. It was expressed in all of the cells that were examined. Importantly, it was also present in the nucleus of HeLa cells, which lack HNF1, and in the cytoplasm of fibroblasts that have little or no tetrahydrobiopterin. The expression of human PCD/DCoH in the liver and nonhepatic cells was compared at both the mRNA and protein levels. Although the mRNA level in liver was only fourfold higher than that in keratinocytes and fibroblasts, the hepatic PCD/DCoH protein level was 20-fold higher than that in normal human epidermal keratinocytes and dermal fibroblasts. Cloning of the 5' and 3' untranslated region (UTR) of human keratinocyte PCD/DCoH revealed that it has 53 bp more of GC-rich 5' untranslated sequence than the published liver PCD/DCoH. In vitro transcription and translation analysis showed that the longer 5' UTR resulted in about a 35% decrease in translation efficiency. These data show that human PCD/DCoH is not only present in cells where tetrahydrobiopterin is synthesized or HNF1 is present but is a widely distributed protein. Its differential expression in different tissues and cells is regulated not only at the transcriptional level but also at the translational level. PMID- 10098607 TI - Identification and functional characterization of the murine Rac2 gene promoter. AB - Rac2, a member of the Rho family of GTPases, is highly expressed in myeloid cells and is a regulator of the NADPH-oxidase complex. A murine genomic clone was isolated that contains the 5' end and putative promoter region of the Rac2 gene. Ribonuclease protection experiments detected 13 transcription initiation sites scattered 50 to 130 bp upstream of the translation initiation site. Transient transfection studies revealed that -7 kb to +31 bp (relative to the strongest transcription initiation site) of the Rac2 gene 5'-flanking region exhibited strong promoter activity in both RAW 264.7 macrophage cells that express the endogenous Rac2 gene and NIH-3T3 fibroblast cells that do not express the endogenous gene. Truncated Rac2 promoter fragments containing as little as the 74 to +31 bp sequence produced full transcriptional activity. However, a -57 to +31 promoter fragment directed significantly less transcription, and a -39 to +31 promoter fragment was transcriptionally inactive. In vitro binding assays revealed sequence-specific and widely expressed DNA-binding activities that interacted within the -74 to -58 Rac2 promoter cis element. Oligonucleotide competition and antibody disruption studies indicated that these complexes contained the transcription factors Spl and Sp3. Specific ablation of the Sp1/Sp3 binding site significantly decreased Rac2 promoter activity in both RAW 264.7 and NIH-3T3 cells. Additional cis elements may be required to restrict Rac2 promoter activity to hematopoietic cells expressing the endogenous gene. PMID- 10098608 TI - A numerical study of magnetic resonance images of pulsatile flow in a two dimensional carotid bifurcation: a numerical study of MR images. AB - A numerical method to simulate magnetic resonance angiographic images is proposed. The new method greatly simplifies the calculation of the average phase in a voxel, the bottleneck of previous simulations, and reduces the computation time by more than a factor of 5. Both the Navier-Stokes and the Bloch equations are solved on the same mesh to obtain the distributions of the modulus and phase of the magnetization. The data in the frequency domain are reordered according to the gating strategy to generate the final images. Pulsatile flow through a 2D normal carotid bifurcation is considered as a test case. Images for magnetic resonance angiography with an uncompensated gradient waveform, a velocity compensated gradient waveform and an uncompensated short-TE gradient waveform are compared. Systolic gating images are shown to have degraded image quality. Images acquired with diastolic-gating have little variation in magnetization strength throughout the pulsatile cycle and provide a better representation of the vessel lumen. PMID- 10098609 TI - Analysis of titanium induced CT artifacts in the development of biomechanical finite element models. AB - X-ray computerized tomography (CT) is capable of providing detailed information about the geometry and mineral density of skeletal structures. Such accurate data are of great interest in studying the effects of orthopaedic implants on bone adaptive behaviour in vivo. Metallic implants, however, generate artifacts, typically seen as starburst streaking. These artifacts can degrade the capabilities of CT images to provide accurate information about the geometry and mineral density of bone structures. The aim of this work was to investigate the possibility of developing finite element models (FEM) of the human femur after hip joint arthroplasty using CT images acquired directly after surgery. The capability of modern CT scanners to accurately reconstruct the cross-section geometry of titanium alloy hip joint prosthetic stems was primarily investigated. A new measuring procedure dealing with the geometry of real stems was developed and its accuracy assessed. Secondly, the artifacts generated by a prosthetic stem on the radiological density of the bone were analysed, and their effects on the assessment of FEM material properties were evaluated. Results showed that CT images provide accurate information on metal stem geometry. An average error of 0.45 mm was estimated in the reconstruction of stem cross-section geometry. Concerning bone density estimation around the implant, it was observed that the effect of metal artifacts on tissue density becomes zero at a distance of 2 mm from the implant. PMID- 10098610 TI - A method for assessment and processing of biomedical signals containing trend and periodic components. AB - A method for assessment and second-order polynomial detrending of signals containing periodic components is proposed. The analytically derived properties of this method are validated with synthesized signals, processed by the computational procedure developed. It is shown that, in addition to accurate detrending, the proposed method reveals the periodicity of various biomedical and other types of signals and thus contributes to performance improvement of their spectral analysis. An application to processing of R-R interval series is presented. PMID- 10098611 TI - Nonlinear analysis of the EEG of schizophrenics with optimal embedding dimension. AB - We estimated the correlation dimensions of EEGs in patients with schizophrenia to investigate the dynamical properties underlying the EEG. We employed a new method, proposed by Kennel et al. (Kennel MB, Brown R, Abarbanel HDI. Determining embedding dimension for phase-space reconstruction using a geometrical construction. Phys Rev A 1992;45:3403-11), to calculate the correlation dimension D2. That method determined the proper minimum embedding dimension by looking at the behaviour of nearest neighbours under a change in the embedding dimension d from d to d + 1. We demonstrated that for limited noisy data, our algorithm was strikingly faster and more accurate than previous ones. We estimated the D2 of EEGs from 16 channels in patients with schizophrenia according to DSM-IV whereas previous studies, which estimated chaoticity of EEG in schizophrenia, recorded EEG only in a limited number of channels. Schizophrenic patients had a lower correlation dimension in the left inferior frontal and anterior temporal regions compared with controls. Our finding of decreased left frontal and temporal chaotic activity in schizophrenics is in line with the findings of a hypofrontality and hypotemporality reported in previous clinical studies such as EEG, blood flow, brain MRI and positron emission tomography studies in schizophrenia. This result suggests that chaos analysis may be a useful tool in analysing EEG data to explore the brain mechanism of schizophrenia. PMID- 10098612 TI - Finite element analysis of a Gamma nail within a fractured femur. AB - Failures of Gamma nails which treat unstable femoral fractures have been reported. In this paper, a finite element model to include a Gamma nail within a fractured femur was used to investigate the stresses in the Gamma nail. The effects for different types of fracture were investigated. The results show that its use for subtrochanteric fractures will cause higher stresses at the lag screw and upper distal screw insertion holes in the nail than when used for femur neck fractures. PMID- 10098614 TI - Tuning non-linear adaptive compensators in non-ideal noise environment. AB - Adaptive compensation has been popular in a variety of biomedical signal processing applications. One of the major limitations of this method is the requirement for a primary signal + noise channel and a secondary noise channel, with the noises in the two channels being strongly correlated. In the majority of real-life biomedical applications this requirement can rarely be fulfilled since the secondary channel inevitably contains certain representation of the signal from the primary channel thus jeopardizing the adaptive compensation process. In the present work we describe a method for tuning an adaptive compensator containing a non-linear real-time multiplier in the reference channel in such non ideal noise environment. The method is based on iterative adjustments of an exponential non-linear function which modifies in real-time the signal-to-noise balance in the reference channel in favor of the noise, preserving the correlation of the latter with the noise in the primary (signal + noise) channel but diminishing the signal content in the reference channel. Sets of model signals and noises are used to illustrate this methodology with a particular emphasis on biomedical signal applications. A quantitative description of the iterative tuning procedure is provided and the capabilities and limitations of this novel method for adaptive compensation are outlined. PMID- 10098613 TI - Measurement of the deformation of isolated chondrocytes in agarose subjected to cyclic compression. AB - Mechanically induced cell deformation is one of a number of possible mechanotransduction pathways by which chondrocytes sense and respond to changes in their mechanical environment. The present study describes a system for measuring the deformation of isolated chondrocytes in agarose during both static and cyclic compression. A test rig mounted on the stage of an inverted microscope was used to apply precise levels of compressive strain to individual cell-agarose constructs bathed in culture medium. Images of the cells were recorded using a CCD video camera attached to the microscope. Cell deformation was quantified in terms of a deformation index (X/Y) representing the ratio of cell diameters measured parallel (X) and perpendicular (Y) to the axis of compression. Cyclic compression between 0 and 15% strain, at 0.3 Hz, resulted in cyclic deformation of the cells at the same frequency. However, during the unstrained phase the cells did not fully recover to their initially spherical morphology (X/Y = 1.0). During the strained phase, the level of deformation (X/Y = 0.59) was initially similar to that observed during static 15% strain. However, this level of cell deformation reduced over a 20 min period of cyclic compression (X/Y = 0.72), although during static compression the cell deformation remained constant. This system may be used to examine cellular events under a range of dynamic mechanical stimuli. PMID- 10098615 TI - Correlation between hydroxyapatite osseointegration and Young's Modulus. AB - From the standpoint of hard tissue response to implant materials, calcium phosphate is probably the most compatible of materials known. During the last few years, much attention has been paid to hydroxyapatite and beta-tricalcium phosphate as potential biomaterials for a bone substitute. Good implantation of biomaterials in the skeleton is evidenced by an ability to reach full integration of the non-living implant with living bone. The aim of this study is to correlate hydroxyapatite osseointegration with Young's Modulus. Cylinders (5-6 mm in diameter) of these ceramics were packed into holes made in the femur diaphysis of a mature sheep. At 2, 4, 8, 12, 16, 20, 28, 36 and 48 weeks after the operation, samples of the bone/implant interface were embedded in polymethylmethacrylate. We used the PIXE method (Particles Induced X-rays Emission) to measure the distribution of mineral elements (Ca, P, Sr, Zn, Mn and Fe) at the bone/implant interface. At 4, 8, 12, 16, 20, 28, 36 and 48 weeks after implantation we studied Young's Modulus on a biopsy of the ceramic. Young's Modulus increased with time after implantation and is linked with biomaterials integration into cortical bone. PMID- 10098616 TI - Fundamentals of power spectra of extracellular potentials produced by a skeletal muscle fibre of finite length. Part II: Effect of parameters altering with functional state. AB - The reasons for dependence of the power spectra of extracellular potentials (EPs) produced by a skeletal muscle fibre of finite length, on parameters altering with functional state was analysed. The sensitivity of the EP power spectra to alterations in the parameters depends on the distance of the observation point from the fibre. At large distances the sensitivity can change with longitudinal position as well. The differences in the sensitivity are due to the changes in the inter-relations between the power spectra of the input signal (the first temporal derivative of the intracellular action potential) and of the impulse response (IR) of the fibre of finite length as a linear system of EP generation. It was shown that not only the parameters affecting the IR (propagation velocity of the waves of depolarisation), but also the parameters determining the input signal (intracellular action potential duration and after-potential) can affect the characteristic frequencies of the EP power spectra. PMID- 10098617 TI - Force-displacement behaviour of biological tissue during distraction osteogenesis. AB - Limb lengthening and bone transport treatments are used frequently, and complications during treatment are common. Knowledge of the origin of tensile forces which resist distraction and the force-displacement response of biological tissues during extension would assist in reducing complication rates. Two tibial diaphyseal lengthenings carried out using an Ilizarov fixator were monitored by a displacement transducer to determine extension of the lengthening tissue (the regenerate bone), and by force transducers to determine tensile forces in the tissues that resist extension. The position of the force vector within a cross section of the limb at the regenerate (provided by CT) was used to determine the origin of these forces. The muscle groups and adjacent fascia resisting extension were the gastrocnemius in one subject and the anterior and peroneal compartments in the other. In response to distraction, these tissues had relatively high stiffness (> 200 N/mm), less "immediate" displacement (< 35% of long term non recoverable displacement) and inconsistent force relaxation properties (0-90%). In contrast, when the force vector was located in the vicinity of the regenerate, tissue exhibited lower stiffness (< 50 N/mm) and more immediate displacement (> 65% of long term nonrecoverable displacement), but also exhibited inconsistent force relaxation (0-67%). PMID- 10098618 TI - Isolation, characterization and biological activity of a diuretic myokinin neuropeptide from the housefly, Musca domestica. AB - A competitive ELISA employing a polyclonal antiserum raised against leucokinin-I was used to isolate and purify a myokinin (muscakinin) from 1.05 kg of adult houseflies (Musca domestica). Following solid-phase purification, seven HPLC column steps were used to purify 4.8 nmol of leucokinin-immunoreactive material. Sequence analysis and mass spectrometry were consistent with the structure Asn Thr-Val-Val-Leu-Gly Lys-Lys-Gln-Arg-Phe-His-Ser-Trp-Gly NH2. This peptide was synthesized and co-eluted with the natural peptide on three different HPLC columns. The activities of natural and synthetic muscakinin were identical, with both producing a 4-5 fold increase in fluid secretion by housefly Malpighian tubules at nanomolar concentrations. The presence of a pair of basic residues (Lys-Lys) suggested muscakinin might be processed further, with the peptide pGlu Arg-Phe-His-Ser-Trp-Gly NH2 being produced by conversion of an N-terminal glutamine to pyroglutamic acid. However, this analog was 1000-fold less active than the intact peptide, comparable to the activity of AK-V which shares the same C-terminal pentapeptide sequence. The diuretic activity of muscakinin is more than double that of a previously identified CRF-related diuretic peptide (Musca DP) from the housefly, and the two peptides act synergistically in stimulating fluid secretion. Muscakinin also increased the frequency and amplitude of contractions by housefly hindgut which might further contribute to the excretory process. PMID- 10098620 TI - Hemolymph and tissue-bound peptidase-resistant analogs of the insect allatostatins. AB - While neuropeptides of the allatostatin family inhibit in vitro production of juvenile hormone, which modulates aspects of development and reproduction in the cockroach, Diploptera punctata, they are susceptible to inactivation by peptidases in the hemolymph, gut, and bound to internal tissues. Patterns of peptidase cleavage were investigated in two allatostatin analogs in which sterically bulky components were incorporated into the active core region to block peptidase attack. The results were used to design and synthesize the first pseudopeptide analog of an insect neuropeptide resistant to degradation by both hemolymph and tissue-bound peptidases. This pseudotetrapeptide allatostatin mimetic analog represents a valuable tool to neuroendocrinologists studying mechanisms by which the natural peptides operate and the physiological consequences of challenging an insect with an allatostatin that is not readily degraded via peptidase enzymes. Disruption of critical physiological processes modulated by neuropeptides such as the allatostatins via peptidase-resistant mimetic analogs could form the basis for novel pest insect management strategies in the future. PMID- 10098619 TI - The molecular evolution of the allatostatin precursor in cockroaches. AB - Allatostatins (ASTs) of the Tyr/Phe-Xaa-Phe-Gly Leu/Ile-NH2 family are a group of insect neuropeptides that inhibit juvenile hormone biosynthesis by the corpora allata. We have obtained genomic DNA sequences that specify the preproallatostatin precursor for the cockroaches, Blatta orientalis, Blattella germanica, Blaberus (cranufer and Supella longipalpa. The sequences obtained are similar to those of Diploptera punctata and Periplaneta americana reported previously. The precursors of all these cockroach species are similar in size, and the organization of the ASTs that they contain (there are 13 or 14, depending on the species) have been conserved. With the sequences of these precursors, and using the homologous sequence in the orthopteran Schistocera gregari as an outgroup, a phylogenetic analysis using parsimony was carried out. The dendrograms obtained from these analyses. using the amino acid as well as the nucleotide sequences, are comparable with current models for cockroach phylogeny. Parsimony analysis was also used to study the genealogy of the different ASTs within the same precursor. Results suggest that the AST sequences were generated through a process of internal gene duplication which occurred before these species diverged from each other in evolutionary time. PMID- 10098621 TI - Isolation and identification of three RFamide-immunoreactive peptides from the mosquito Aedes aegypti. AB - Three RFamide-immunoreactive peptides were isolated from headless Aedes aegypti mosquitoes. Their structures were identified by Edman degradation or a combination of amino acid composition analysis and mass spectrometry to be: Aedes head peptide 1 [23], [Pro4]-Aedes head peptide (i.e., pGlu-Arg-Pro-Pro-Ser-Leu Lys-Thr- Arg-Phe-amide), and Leu-Lys-Thr-Arg-Phe-amide which have been named Aedes head peptides 3 and 4, respectively. PMID- 10098622 TI - Led-NPF-1 stimulates ovarian development in locusts. AB - For more than a decade, immunohistochemical results on FMRFamide related peptides (FaRP's) have been reported extensively, suggesting many possible roles for these peptides associated with behavioural and physiological events as well as reproduction. This study provides a clear effect in vivo of members of this family of insect neuropeptides. The effect of two neuropeptide F-related peptides from the Colorado potato beetle, Leptinotarsa decemlineata, Led-NPF-1 and Led-NPF 2 as well as the locusts myotropins, Lom-PK-1, Lom-PK-2 and Lom-SK, was screened in an ovarian development assay in the African migratory locust and the grey fleshfly, Neobellieria bullata. Led-NPF-1 (Ala-Arg-Gly-Pro-Gln-Leu-Arg-Leu-Arg Phe-NH2) was shown to be a potent gonadostimulin in Locusta migratoria, but not in Neobellieria bullata. A minimal dose of 0.05 microg of Led-NPF-1 per animal, every 12 h, during 5 consecutive injections into 6 day old virgin females, could accelerate egg development. Higher doses of prolonged injections were demonstrated to be even more potent in the ovarian development assay. Led-NPF-2 (Ala-Pro-Ser-Leu-Arg-Leu-Arg-Phe-NH2) was far less active. The other tested peptides scored no reproducible effect what so ever on ovarian growth, in locusts, nor in flies. The gonadotropic action of a NPF-like peptide on oocyte growth implies a complex regulation of oogenesis in the locust and adds to our knowledge of insect neuroendocrinology in general. The results also suggest that a peptide of similar sequence also resides in the locust. PMID- 10098623 TI - Neural transmitters and a peptide modulate Drosophila heart rate. AB - Neural messengers affect Drosophila heart rate. Serotonin increases larval, pupal, and adult heart rate. Octopamine and dopamine are inactive in larva, decrease pupal rate, and increase adult heart rate. Acetylcholine and nicotine decrease larval and pupal heart rate, while acetylcholine decreases and nicotine increases adult heart rate. Muscarine decreases pupal heart rate, but is inactive in larva and adult. GABA is inactive in larva and adult, but decreases pupal heart rate. Glutamate is inactive in larva and pupa, but decreases adult heart rate. Proctolin decreases heart rate in all three stages. Caffeine acts only to decrease adult heart rate. PMID- 10098624 TI - A cardioactive peptide from the southern armyworm, Spodoptera eridania. AB - A cardioactive peptide was isolated from extracts of whole heads of the southern armyworm, Spodoptera eridania. This peptide has the sequence ENFAVGCTPGYQRTADGRCKPTF (Mr = 2516.8), determined from both Edman sequencing and tandem mass spectrometry in combination with off-line micropreparative capillary liquid chromatography. This peptide, termed Spoer-CAP23, has excitatory effects on a semi-isolated heart from larval Manduca sexta, causing an inotropic effect at low concentrations of peptide and chronotropic and inotropic effects at high doses. The threshold concentration for stimulatory effects of the synthetic peptide on the semi-isolated heart was about 1 nM, suggesting a physiological role as a neuropeptide. PMID- 10098625 TI - Comparison of rates of penetration through insect cuticle of amphiphylic analogs of insect pyrokinin neuropeptides. AB - Rates of penetration through the cuticle of amphiphylic analogs, synthesized by addition of 6-phenylhexanoic acid or 9-fluoreneacetic acid or 1-pyrenebutyric acid to the amino terminus of the pentapeptide Phe-Thr-Pro-Arg-Leu-amide, were assessed by quantitative analysis using reversed phase liquid chromatography. The analogs effectively penetrated the cuticle of both the adult American cockroach and tobacco budworm moth. However, the amounts of analogs that penetrated the cuticle of the cockroach were significantly lower and the rates of penetration were slower than for moth cuticle. Penetration of the analogs through the cuticle was dependent upon the size of the lipidic attachment to the pentapeptide. The 6 phenylhexanoic acid analog penetrated most rapidly followed by the 9 fluoreneacetic acid analog and the 1-pyrenebutyric acid analog penetrated slowest. All of the analogs exhibited an initial rapid period of penetration lasting 2-3 h followed by the establishment of a steady slow release state which lasted between 9-24 h and was dependent upon both the size and surface area of the aromatic lipidic portion of the analog and species of insect to which the analog was applied. The results confirmed the hypothesis that the insect cuticle could be employed as a slow release device for delivery of analogs of insect neuropeptides. PMID- 10098626 TI - Prenatal melatonin influences developmental changes of tachykinins in response to estradiol benzoate. AB - The developmental changes of hypothalamic, pituitary, striatum and pineal gland tachykinin concentrations, as well as the response to estradiol-benzoate (EB) administration, were studied in offspring of control and melatonin (MEL) treated mother rats. Female rats were studied throughout different phases of the sexual development: infantile, prepubertal and pubertal periods, in the four following groups; control-offspring+vehicle; control-offspring+EB; MEL-offspring+vehicle; MEL-offspring+EB. Hypothalamic NKA in control-offspring+ vehicle was significantly increased only at 27 days of age and in control-offspring+EB at 27 days of age and during the infantile period. Hypothalamic SP levels increased similarly in control-offspring+EB during the infantile period but the EB influence was more pronounced with significantly increased concentrations at 32 days of age. Prenatal melatonin treatment produced major alterations in these patterns of postnatal development. In MEL-offspring+EB tachykinins concentrations in the hypothalamus during infantile and prepubertal periods did not increase, however at 37 days of age, they showed significantly higher values than in control-offspring+EB groups. The developmental pattern of pituitary NKA and SP concentrations in both; control-offspring+vehicle and control-offspring+EB groups, showed similar values from the infantile period to puberty, indicating that NKA and SP concentrations remained at similar levels independently of the sexual stage, only at 27 days of age in control-offspring+EB significantly increased values were found as compared to MEL-offspring+EB. Prenatal melatonin did not produce marked modifications, only significantly lower NKA and SP concentrations in MEL-offspring+EB group were observed at 25 days of age in comparison to control-offspring+EB group. Striatal NKA and SP concentrations showed a similar developmental pattern. In control-offspring, EB treatment produced NKA and SP decreased concentrations at the infantile period than in control-offspring+vehicle and significantly increased concentrations during the prepubertal period, then during the pubertal period NKA and SP concentrations decreased in control-group+EB. However, prenatal melatonin treatment reduced the levels of striatal NKA and SP during the prepubertal period after EB treatment and delayed until pubertal period the increase previously observed in control group during the prepubertal period. In MEL-offspring+vehicle group striatal concentrations of both tachykinins remained at low levels from infantile period until pubertal period. Prenatal melatonin and EB did not produce major alterations in SP pineal concentrations throughout sexual development. Plasma estradiol concentrations were significantly higher in the groups that received EB treatment than in those that received vehicle during prepubertal and juvenile periods in control-offspring+EB group and during the pubertal period in MEL offspring+EB group. These data indicate that prenatal MEL treatment may influence NKA and SP developmental pattern from the infantile period until adulthood in the female rat. PMID- 10098627 TI - Sex differences in neuropeptide distribution in the rat brain. AB - We have investigated possible sex differences in the regional concentrations of neuropeptides in the rat brain. Immunoreactive neurotensin (NT), neurokinin A (NKA), galanin (GAL), calcitonin gene-related peptide (CGRP), substance P (SP) and neuropeptide Y (NPY) were measured by radioimmunoassay in frontal cortex, occipital cortex, hippocampus, striatum, hypothalamus and pituitary in male and female pre- and postpubertal rats. Sex differences were found for NPY (p < 0.001), NT (p < 0.01) and GAL (p < 0.05), in particular in hippocampus, striatum, hypothalamus and pituitary, but not for CGRP, SP and NKA. Results from analysis of neuropeptides in one sex may not be entirely applicable to the other. PMID- 10098628 TI - Proopiomelanocortin (POMC) mRNA and POMC-derived peptides immunolocalization in the skin of Protopterus annectens, an African lungfish. AB - Antisera against adrenocorticotropic hormone (ACTH), alpha-melanocyte stimulating hormone (alpha-MSH) and beta-endorphin were used to localize, by immunohistochemistry, proopiomelanocortin (POMC)-derived peptides in the skin excised from different regions of the African lungfish Protopterus annectens. Immunoreactivity was observed in the epidermis mainly in the germinal layer. Using human POMC cDNA as hybridization probe, POMC-like mRNA was identified in situ in epidermal cells. The demonstration in the same cells of POMC mRNA and POMC-related peptides immunoreactivity indicates a local production of opiate hormones. PMID- 10098629 TI - N-methyl-D-aspartate (NMDA)-mediated corticotropin-releasing factor (CRF) release in cultured rat amygdala neurons. AB - Corticotropin-releasing factor (CRF) plays an important role in the activation of centrally mediated responses to stress. The amygdala, a limbic structure involved in the stress response, has a significant number of CRF cell bodies and CRF receptors. Activation of glutamatergic projections to the amygdala has been implicated in the stress response. Few studies have evaluated neurotransmitter stimulated CRF release in the amygdala. We measured the effects of glutamate (0.1 1000 microM) and N-methyl-D-aspartate (NMDA, 0.1-1000 microM) on CRF release from the amygdala using primary neuronal cultures from embryonic rat brains (E18-19). Experiments were performed after the cultures grew for 17-20 days. CRF was measured using radioimmunoassay. The excitatory amino acid neurotransmitters, glutamate and NMDA, stimulated CRF release in a concentration-dependent manner. The apparent EC50 values for glutamate and NMDA were 17.5 microM and 12 microM, respectively. Consistent with a NMDA receptor-driven event, glutamate-stimulated CRF release was blocked by the NMDA antagonist, 2-amino-5-phosphonovaleric acid (AP-5, 1-100 microM) and antagonized by the addition of 1.2 mM MgCl2 to the incubation medium. These results implicate an inhibition of CRF release in the amygdala as a possible mechanism for the reported anxiolytic effects of NMDA antagonists. PMID- 10098630 TI - Respiratory depression after intravenous administration of delta-selective opioid peptide analogs. AB - We compared the effects of three micro-(DAMGO, DALDA, TNPO) and three delta (DPDPE, DELT, SNC-80) opioid agonists on arterial blood gas after IV administration in awake sheep. None of the mu agonists altered pO2, pCO2 or pH. All three mu agonists decreased pO2 increased pCO2 and decreased pO2, and this effect was not sensitive to naloxone or TIPPpsi, a delta-antagonist, suggesting that it is not mediated by beta-opioid receptors. When administered to pregnant animals, there were significant changes in fetal pCO2 and pH. It may be possible to develop delta-selective opioid agonists which do not produce respiratory depression. PMID- 10098631 TI - Electroconvulsive seizures increase levels of pGlu-Glu-Pro-NH2 (EEP) in rat brain. AB - We have previously reported that electroconvulsive seizures (ECS) increases the level of prepro-TRH-derived peptides in hippocampus, amygdala and pyriform cortex but not the striatum of male rats and that this increase is significantly correlated with reduced immobility (increased swimming) in the Porsolt forced swim test. An abstract by Mabrouk and Bennett published in 1993 described increased locomotor activity in rats following IP injection of TRH (pGlu-His-Pro NH2) and EEP (pGlu-Glu-Pro-NH2). We have examined the effect of three daily transcorneal ECS on the levels of EEP in various brain regions and their correlation with results from the Porsolt forced swim test. The EEP level (ng/g wet weight) was measured by RIA in 6 brain regions: amygdala (AY), hippocampus (HC), pyriform cortex (PYR), anterior cortex (AC), striatum (STR) and motor cortex (MC). ECS significantly increased EEP levels in AY, HC and PYR. The increased swim behavior following ECS, as measured in the Porsolt test, correlated significantly with the EEP levels in HC and MC within individual subjects. Intraperitoneal (IP) injection of EEP (1.0 mg/kg) resulted in a rapid and sustained rise in EEP levels throughout the brain and a clearance half-time from blood of 2.0 h. Intracardiac injection of 0.5 mg EEP resulted in a peak EEP level in CSF at 2 h followed by a t1/2 of 0.35 h. A 3 compartment model for EEP transport from blood into CSF and then brain was developed. This model revealed a 1.75 h delay in the transit time of EEP from blood to CSF followed by rapid clearance from the CSF but long retention time within various brain tissues. We conclude that (1) ECS significantly increases EEP levels in limbic regions, but not in striatum, of the rat brain, (2) EEP, like TRH, is a potential mediator of the antidepressant effect of ECS and (3) EEP, after IP or IV administration, is readily taken up by, and has a long residence time in, brain tissue. PMID- 10098632 TI - Bombesin activates MAP kinase in non-small cell lung cancer cells. AB - The effects of bombesin (BB) on mitogen activated protein (MAP) kinase were investigated using non-small cell lung cancer (NSCLC) cells. By Western blot, both 42 and 44 kDalton forms of MAP kinase were present in NCI-H1299 and NCI-H838 cells. Addition of BB to NCI-H1299 cells resulted in phosphorylation of the MAP kinase substrate myelin basic protein (MBP). Phosphorylation of MBP was maximal 6 min after the addition of 10 nM BB to NCI-H1299 cells. Addition of gastrin releasing peptide (GRP) or GRP14-27 but not GRP1-16 to NCI-H 1299 cells caused MBP phosphorylation. The effects of BB were inhibited by BW2258U89, a BB receptor antagonist, and PD98059, a MAP kinase kinase inhibitor. Also, PD98059 inhibited the clonal growth of NCI-H1299 cells. These data suggest that MAP kinase may be an important regulatory enzyme in NSCLC. PMID- 10098633 TI - Adrenomedullin promotes epithelial restitution of rat and human gastric mucosa in vitro. AB - We have investigated the effect of adrenomedullin (AM) on restitution of mucosal integrity following damage in rat and human gastric mucosa, measuring the potential difference (PD) on a mucosal strip mounted on an Ussing chamber. Mucosal damage was induced by 0.5, 1.0, and 2.0 M NaCl solution, and it caused an immediate and significant decrease in PD. In the rat AM group, PD recovered significantly more than in control group at 120 min after exposure to 0.5 M (p < 0.01) and 1.0 M (p < 0.05) NaCl solution. In the human AM group, PD completely recovered at 120 min after exposure to 0.5 M (p < 0.05) NaCl solution. In rat mucosa damaged by 0.5 M NaCl solution, the effect was inhibited by human (h) CGRP(8-37) and there was no significant difference between the h-CGRP(8-37) group and control group. On immunohistochemical examination of rat gastric mucosa, AM was detected within the chief cell. AM probably promotes epithelial restitution primarily through the CGRP receptor, but it does not ameliorate more severe damage of gastric mucosa in vitro. PMID- 10098634 TI - On the nature and distribution of enterostatin (Val-Asp-Pro-Asp-Arg)-like immunoreactivity in rat plasma. AB - Enterostatins, pentapeptides represented at the amino-terminus of the procolipase molecule, are derived following tryptic cleavage of the procolipase molecule in the lumen of the gut. Val-Pro-Asp-Pro-Arg or VPDPR is one such enterostatin. Despite pharmacologic studies suggesting a role for VPDPR in appetite regulation and insulin secretion, the function of this endogenous peptide has been impossible to discern due to the lack of a suitable assay. Using polyclonal antibodies raised against VPDPR and different chromatographic methods, we examined the nature and distribution of enterostatin-like immunoreactivity in rat plasma. The results reported here show for the first time the presence of VPDPR like immunoreactivity in rat plasma. Further characterization of the plasma VPDPR like immunoreactivity revealed that a) it is not due to APGPR, VPGPR, or VPDPR but to another peptide similar to VPDPR, and b) plasma VPDPR-like immunoreactivity may circulate bound to large carrier proteins. PMID- 10098635 TI - Tachykinin-related peptides in invertebrates: a review. AB - Peptides with sequence similarities to members of the tachykinin family have been identified in a number of invertebrates belonging to the mollusca, echiuridea, insecta and crustacea. These peptides have been designated tachykinin-related peptides (TRPs) and are characterized by the preserved C-terminal pentapeptide FX1GX2Ramide (X1 and X2 are variable residues). All invertebrate TRPs are myostimulatory on insect hindgut muscle, but also have a variety of additional actions: they can induce contractions in cockroach foregut and oviduct and in moth heart muscle, trigger a motor rhythm in the crab stomatogastric ganglion, depolarize or hyperpolarize identified interneurons of locust and the snail Helix and induce release of adipokinetic hormone from the locust corpora cardiaca. Two putative TRP receptors have been cloned from Drosophila; both are G-protein coupled and expressed in the nervous system. The invertebrate TRPs are distributed in interneurons of the CNS of Limulus, crustaceans and insects. In the latter two groups TRPs are also present in the stomatogastric nervous system and in insects endocrine cells of the midgut display TRP-immunoreactivity. In arthropods the distribution of TRPs in neuronal processes of the brain displays similar patterns. Also in coelenterates, flatworms and molluscs TRPs have been demonstrated in neurons. The activity of different TRPs has been explored in several assays and it appears that an amidated C-terminal hexapeptide (or longer) is required for bioactivity. In many invertebrate assays the first generation substance P antagonist spantide I is a potent antagonist of invertebrate TRPs and substance P. Locustatachykinins stimulate adenylate cyclase in locust interneurons and glandular cells of the corpora cardiaca, but in other tissues the putative second messenger systems have not yet been identified. The heterologously expressed Drosophila TRP receptors coupled to the phospholipase C pathway and could induce elevations of inositol triphosphate. The structures, distributions and actions of TRPs in various invertebrates are compared and it is concluded that the TRPs are multifunctional peptides with targets both in the central and peripheral nervous system and other tissues, similar to vertebrate tachykinins. Invertebrate TRPs may also be involved in developmental processes. PMID- 10098636 TI - Recombinant feline leukemia virus (FeLV) variants establish a limited infection with altered cell tropism in specific-pathogen-free cats in the absence of FeLV subgroup A helper virus. AB - Feline leukemia virus subgroup B (FeLV-B) is commonly associated with feline lymphosarcoma and arises through recombination between endogenous retroviral elements inherited in the cat genome and corresponding regions of the envelope (env) gene from FeLV subgroup A (FeLV-A). In vivo infectivity for FeLV-B is thought to be inefficient in the absence of FeLV-A. Proposed FeLV-A helper functions include enhanced replication efficiency, immune evasion, and replication rescue for defective FeLV-B virions. In vitro analysis of the recombinant FeLV-B-like viruses (rFeLVs) employed in this study confirmed these viruses were replication competent prior to their use in an in vivo study without FeLV-A helper virus. Eight specific-pathogen-free kittens were inoculated with the rFeLVs alone. Subsequent hematology and histology results were within normal limits, however, in the absence of detectable viremia, virus expression, or significant seroconversion, rFeLV proviral DNA was detected in bone marrow tissue of 4/4 (100%) cats at 45 weeks postinoculation (pi), indicating these rFeLVs established a limited but persistent infection in the absence of FeLV-A. Altered cell tropism was also noted. Focal infection was seen in T-cell areas of the splenic follicles in 3/4 (75%) rFeLV-infected cats analyzed, while an FeLV-A infected cat showed focal infection in B-cell areas of the splenic follicles. Nucleotide sequence analysis of the surface glycoprotein portion of the rFeLV env gene amplified from bone marrow tissue collected at 45 weeks pi showed no sequence alterations from the original rFeLV inocula. PMID- 10098637 TI - Lesions and transmission of experimental adenovirus hemorrhagic disease in black tailed deer fawns. AB - Adenovirus infection was the cause of an epizootic of hemorrhagic disease that is believed to have killed thousands of mule deer (Odocoileus hemionus) in California during the latter half of 1993. A systemic vasculitis with pulmonary edema and hemorrhagic enteropathy or a localized vasculitis associated with necrotizing stomatitis/pharyngitis/glossitis or osteomyelitis of the jaw were common necropsy findings in animals that died during this epizootic. To study transmission of adenovirus infection in deer and susceptibility of black-tailed deer (Odocoileus hemionus columbianus) fawns to adenovirus infection, six 3-6 month-old black-tailed fawns were divided into two treatment groups. One group was inoculated intravenously and the other group was inoculated through the mucous membranes of the eyes, nose and mouth with purified adenovirus. Each treatment group also included two additional fawns (four total) that were not inoculated but were exposed to inoculated animals (contact animals). One fawn served as a negative control. Between 4 and 16 days postinoculation, 8/10 fawns developed systemic or localized infection with lesions identical to lesions seen in animals with natural disease that died during the epizootic. Transmission was by direct contact, and the route of inoculation did not affect the incubation period or the distribution of the virus (systemic or the localized infection). Immunohistochemical analysis using polyclonal antiserum against bovine adenovirus type 5 demonstrated staining in endothelial cells of vessels in numerous tissues in animals with systemic infection and endothelial staining only in vessels subtending necrotic foci in the upper alimentary tract in animals with the localized form of the disease. All inoculated or exposed animals had staining in the tonsillar epithelium. Transmission electron microscopic examination of lung and ileum from two fawns with pulmonary edema and hemorrhagic enteropathy demonstrated endothelial necrosis and adenovirus virions in endothelial cell nuclei. Adenovirus was reisolated in black-tailed deer pulmonary artery endothelial cells using lung homogenate of the first fawn that developed systemic adenovirus infection. Serum virus neutralization test results suggest that this deer adenovirus is a new serotype. PMID- 10098638 TI - Expression of vascular endothelial growth factor in N-butyl-N-(4 hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis. AB - Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are proteins implicated in tumor-associated microvascular angiogenesis. Expressions of VEGF and bFGF in various stages of chemical-induced rat bladder carcinogenesis were immunohistochemically investigated. Thirty-two male 6-week old Wistar rats were given drinking water containing 0.05% N-butyl-N-(4 hydroxybutyl)nitrosamine (BBN) for 20 weeks. VEGF and bFGF were not detected in the normal bladder epithelium. In simple hyperplasia, intensive expression of VEGF was observed in a few epithelial cells, and the expression of epithelial VEGF became more pronounced in papillary or nodular (PN) hyperplasia and papilloma. In carcinoma, heterogeneous expression of VEGF was observed in focal tumor cells, intensely expressed in the invading tumor cells. Ultrastructurally, carcinoma cells showed VEGF immunoreactivity in the cytoplasmic matrix and some rough endoplasmic reticulum, and VEGF-positive and -negative carcinoma cells were also clearly defined. High levels of VEGF mRNA were observed in the carcinoma. However, bFGF was not detected in the epithelium throughout the carcinogenesis. Increased microvessel counts appeared at simple hyperplasia and became more pronounced in PN hyperplasia, papilloma, and carcinoma (F-test; P < 0.05). In the carcinoma, the microvessel counts of the VEGF-expressing tumor areas were significantly higher than that of the non-VEGF-expressing tumor areas (U-test; P < 0.05). The present study suggests that upregulation of epithelial VEGF may begin at a quite early stage in BBN-induced rat bladder carcinogenesis, but bFGF may not be involved. PMID- 10098639 TI - Overexpression of c-Ras in hyperplasia and adenomas of the feline thyroid gland: an immunohistochemical analysis of 34 cases. AB - Formalin-fixed, paraffin-embedded thyroid glands from 18 cats diagnosed with hyperthyroidism were evaluated immunohistochemically for overexpression of the products of oncogenes c-ras and bcl2 and the tumor suppressor gene p53. Fourteen thyroid glands from euthyroid cats without histologically detectable thyroid lesions were examined similarly as controls. Results from these investigations showed that all cases of nodular follicular hyperplasia/adenomas stained positively for overexpression of c-Ras protein using a mouse monoclonal anti human pan-Ras antibody. The most intensely positively staining regions were in luminal cells surrounding abortive follicles. Subjacent thyroid and parathyroid glands from euthyroid cats did not stain immunohistochemically for pan-Ras. There was no detectable staining for either Bc12 or p53 in any of the cats. These results indicated that overexpression of c-ras was highly associated with areas of nodular follicular hyperplasia/adenomas of feline thyroid glands, and mutations in this oncogene may play a role in the etiopathogenesis of hyperthyroidism in cats. PMID- 10098640 TI - Pathogenesis of Newcastle disease in chickens experimentally infected with viruses of different virulence. AB - Groups of 4-week-old White Rock chickens were inoculated intraconjunctivally with nine isolates of Newcastle disease virus representing all pathotypes. Birds were monitored clinically and euthanatized sequentially, with collection of tissues for histopathologic examination and in situ hybridization using an anti-sense digoxigenin-labeled riboprobe corresponding to the sequence of the gene coding for the matrix protein. Disease was most severe with velogenic viscerotropic pathotypes and was characterized by acute systemic illness with extensive necrosis of lymphoid areas in the spleen and intestine. Viral nucleic acid was detected in multiple tissues but most prominently in macrophages associated with lymphoid tissue. Velogenic neurotropic isolates caused central nervous system disease despite minimal amounts of viral nucleic acid detected in neural tissue. Mesogenic and lentogenic pathotypes caused no overt disease; however, viral nucleic acid was present in myocardium and air sac epithelium following infection with these isolates. Compromise of air sac and myocardium may predispose mesogen- and lentogen-infected chickens to secondary infection and/or decreased meat and egg production. PMID- 10098641 TI - In situ hybridization for the detection and localization of swine Chlamydia trachomatis. AB - Gnotobiotic piglets were inoculated intralaryngeally with swine Chlamydia trachomatis strain R33 or orally with swine C. trachmatis strain R27. Archived formalin-fixed, paraffin-embedded tissues from piglets euthanatized 4-7 days postinoculation were examined by in situ hybridization for C. trachomatis nucleic acid using a nonradioactive digoxigenin-labeled DNA probes that targeted specific ribosomal RNA or omp1 mRNA molecules of the swine C. trachomatis strains. Positive hybridization signals were detected in bronchial epithelial cells, bronchiolar epithelial cells, pneumocytes, alveolar and interstitial macrophages, and jejunal and ileal enterocytes. Chlamydia-infected cells had a strong signal that was confined to the intracytoplasmic inclusions. Positive hybridization signals were not detected in tissue sections from an uninfected control piglet or in C. psittaci-infected sheep placenta. The morphology of host cells was preserved despite the relatively high temperature required in parts of the incubation procedure. The data indicate that in situ hybridization can be used to detect swine C. trachomatis in formalin-fixed, paraffin-embedded tissue specimens. PMID- 10098642 TI - Histology and tissue chemistry of tidemark separation in hamsters. AB - Adult articular cartilage is divided by the tidemark into a deep calcified layer and a more superficial uncalcified layer. Histologic examination of articular cartilage from the knee joint of golden Syrian hamsters 123 days of age or older revealed defects at the tidemark in the tibia. Defects ranged from small separations of the calcified and uncalcified layers along the tidemark to progressively larger defects apparently formed by dissolution. These larger defects appeared as cavities in the noncalcified cartilage, had smooth rather than rough edges, frequently contained coalesced debris, and often resulted in a bulge in the articular surface. Occasionally, these large defects broke through the articular surface. Defects were not observed in tibial cartilage of younger (<90 days old) hamsters or in femoral cartilage from hamsters of any age. Exercise neither protected against nor increased the severity of the defects. Collagen cross-linking by pyridinoline was examined as a function of age and increased from 1,090 to 3,062 micromoles of pyridinoline/mole of hydroxyproline over the period of 1-9 months of age but was not correlated with defect formation. With increasing age, these focal tidemark defects could lead to osteoarthrosis-like cartilage lesions. PMID- 10098643 TI - Lysis of myelocytes in chickens infected with infectious bursal disease virus. AB - In specific-pathogen-free chickens infected with the highly virulent HPS-2 strain or virulent reference GBF-1 strain of infectious bursal disease virus (IBDV), pathologic changes of the bone marrow were investigated. On histologic examination, bone marrow lesions were prominent in the HPS-2 group but only mild in the GBF-1 group. The bone marrow of the HPS-2 group showed severe lysis and depletion of heterophil myelocytes with pyknotic nuclear alteration 2-3 days after inoculation. On examination with an electron microscope, heterophil myelocytes were characterized by shrinkage of the cytoplasm and peripheral condensation of nuclear chromatin. IBDV particles were not detected in altered myelocytes. A terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling method demonstrated a positive reaction in only heterophil myelocytes. In contrast, nucleosomal DNA fragmentation in HPS-2 infected bone marrow cells was indiscernible by agarose gel electrophoresis. These findings indicate that lysis of bone marrow cells is selectively induced in heterophil myelocytes at an early stage after IBDV infection and independent of virus replication. PMID- 10098644 TI - Salinomycin-induced polyneuropathy in cats: morphologic and epidemiologic data. AB - In April 1996, an outbreak of toxic polyneuropathy in cats occurred in the Netherlands. All cats had been fed one of two brands of dry cat food from one manufacturer. Chemical analyses of these foods, stomach contents, and liver and kidney of affected cats revealed contamination with the ionophor salinomycin. Epidemiologic and clinical data were collected from 823 cats, or about 1% of the cats at risk. In 21 affected cats, postmortem examination was performed. The affected cats had acute onset of lameness and paralysis of the hindlimbs followed by the forelimbs. Clinical and pathologic examination indicated a distal polyneuropathy involving both the sensory and motor nerves. PMID- 10098645 TI - Amylopectinosis in fetal and neonatal Quarter Horses. AB - Three Quarter Horses, a stillborn filly (horse No. 1), a female fetus aborted at approximately 6 months of gestation (horse No. 2), and a 1-month-old colt that had been weak at birth (horse No. 3), had myopathy characterized histologically by large spherical or ovoid inclusions in skeletal and cardiac myofibers. Smaller inclusions were also found in brain and spinal cord and in some cells of all other tissues examined. These inclusions were basophilic, red-purple after staining with periodic acid-Schiff (both before and after digestion with diastase), and moderately dark blue after staining with toluidine blue. The inclusions did not react when stained with Congo red. Staining with iodine ranged from pale blue to black. Their ultrastructural appearance varied from amorphous to somewhat filamentous. On the basis of staining characteristics and diastase resistance, we concluded that these inclusions contained amylopectin. A distinctly different kind of inclusion material was also present in skeletal muscle and tongue of horse Nos. 1 and 3. These inclusions were crystalline with a sharply defined ultrastructural periodicity. The crystals were eosinophilic and very dark blue when stained with toluidine blue but did not stain with iodine. Crystals sometimes occurred freely within the myofibers but more often were encased by deposits of amylopectin. This combination of histologic and ultrastructural features characterizes a previously unreported storage disease in fetal and neonatal Quarter Horses, with findings similar to those of glycogen storage disease type IV. We speculate that a severe inherited loss of glycogen brancher enzyme activity may be responsible for these findings. The relation of amylopectinosis to the death of the foals is unknown. PMID- 10098646 TI - Inflammatory pseudotumor in a cat with cutaneous mycobacteriosis. AB - A 5-year-old, castrated male, domestic Shorthair Cat had an ulcerated mass with fistulous tracts on the left hind paw. Homogeneous tan tissue diffusely infiltrated the dermis and subcutis of the paw and extended proximally so that, short of amputation, complete excision was not feasible. Biopsy specimens consisted of granulation tissue with marked proliferation of spindle cells. Neutrophils and histiocytic cells were scattered among the spindle cells. The histiocytic cells had abundant foamy or vacuolated cytoplasm, but features of granulomatous inflammation, such as epithelioid macrophages or granuloma formation, were not observed. The initial impression was inflammatory granulation tissue, but the degree of fibroplasia prompted inclusion of fibrosarcoma in the differential diagnosis. Cutaneous mycobacteriosis was diagnosed when numerous acid-fast bacteria were identified with Kinyoun's stain; Mycobacterium avium was subsequently cultured. The cat was euthanatized because of lack of response to enrofloxacin therapy. At necropsy, lesions were localized to the hind limb. Not only is mycobacteriosis an uncommon cause of cutaneous masses in cats, but this case was unusual because of the lack of granuloma formation and the similarity of the mass to a spindle cell tumor. PMID- 10098647 TI - Lymphangiosarcomas in cats: a retrospective study of 12 cases. AB - Clinical, macroscopic, and histologic features of 12 lymphangiosarcomas in cats are described. Nine tumors were located in the subcutaneous tissue at the caudoventral abdominal wall (eight cats) or in the neck (one cat). The remaining three cats had lymphangiosarcomas around the cranial mesenteric artery (two cats) or precardial in the mediastinum (one cat). Macroscopically, the tumors were noncircumscribed, white, edematous, and intermixed with fat tissue. Histologic features varied from cleft-forming and cavernous growth to papilliform and solid patterns. Follow-up data were available for seven cats with subcutaneous lymphangiosarcomas. All these cats died or were euthanatized within 6 months after surgery because of poor wound healing, local recurrence, or distant metastases. The cats with abdominal or thoracic masses were either euthanatized at surgery or within 6 months after the first surgery because of recurrent chylothorax, chyloperitoneum, or distant metastases. PMID- 10098648 TI - Mucinous vacuolar change of porcine urothelium induced by regional embolism or cryoablation. AB - Porcine urinary tract epithelium responds to systemic infections with an increase in mucin secretion that has been called "mucinous degeneration." Here we describe similar changes in calyceal, pelvic, and ureteric urothelium in pig renal tracts 14 days after local embolism and cryoablation (four kidneys) or cryoablation alone (six kidneys). Large mucin-filled vacuoles surrounded by smaller cytoplasmic vesicles were present in the affected urothelium but were rare in calyceal urothelium of normal kidneys. These mucinous vacuolar changes were proportional to the extent of renal necrosis and could be important in the pathologic responses of xenotransplanted pig kidneys. PMID- 10098649 TI - Dermatitis with invasive ciliated protozoa in dolphins that died during the 1987 1988 Atlantic Bottlenose Dolphin morbilliviral epizootic. AB - Dermatitis with intradermal cilated protozoa was identified in 18 of 95 (19%) Atlantic Bottlenose Dolphins (Tursiops truncatus) that died during the 1987-1988 Atlantic-dolphin morbillivirus epizootic. The lesions were characterized by focally extensive suppurative and histiocytic dermatitis and cellulitis with ulceration and variable numbers of dermal and hypodermal ciliates. Vasculitis, thrombosis, and/or intravascular ciliates were rarely present. In one dolphin, there was an associated lymphadenitis with ciliates, and in another, bronchopneumonia with rare intrabronchiolar ciliates. Ten of the dolphins were female, and eight were male. The animals ranged in length from 148 to 260 cm. Eleven were from Virginia, four were from New Jersey, and three were from Florida. In 13 dolphins, results of immunohistochemical and/or polymerase chain reaction (PCR) tests were positive for morbillivirus infection. Results of immunohistochemical tests were negative in four dolphins that were not also tested with PCR. Results were also negative in one dolphin tested using both methods. Nine dolphins had concomitant bacterial, fungal, and/or other protozoal infections. Fourteen other dolphins with ciliate-associated dermatitis were identified from 414 Atlantic bottlenose dolphin cases (3%) archived at the Armed Forces Institute of Pathology. The incidence of dermatitis with invasive ciliates is much greater in dolphins that died during the 1987-1988 epizootic. PMID- 10098651 TI - A new generation of fluorescent chemosensors demonstrate improved analyte detection sensitivity and photobleaching resistance. AB - Molecular chemosensors have found increased utility in the development of precise and sensitive detection devices. However, chemosensors that report binding via fluorescence through UV excitation are susceptible to destruction via photodegradation of the fluorophore. In the following report, the dansyl fluorophore in a previously reported chemosensor for peptides is replaced with an acridone derivative that is highly resistant to photobleaching. Its spectral properties are closely matched to those of the original dansyl fluorophore, and although quite structurally dissimilar, the new more photostable acridone chemosensor analogue exhibits only minor differences in binding/detection characteristics. PMID- 10098650 TI - Intranasally inoculated Mycoplasma hyorhinis causes eustachitis in pigs. AB - Specific-pathogen-free pigs were experimentally inoculated with Mycoplasma hyorhinis, Pasteurella multocida, or both bacterial isolates to evaluate the role of these bacteria in the pathogenesis of otitis media. Six pigs were inoculated intranasally with 4.4 X 10(8) colony-forming units (CFU) of M. hyorhinis. Twenty one days later, three of these six pigs were inoculated intranasally with 5.0 X 10(8) CFU of P. multocida. Three additional pigs were also inoculated intranasally at the time with P. multocida alone. Two pigs served as uninoculated controls. Seven days later, all pigs were euthanatized. Histologically, subacute inflammation was found in 10 auditory tubes of six pigs and two tympanic cavities of two pigs inoculated with M. hyorhinis. Immunohistochemically, M. hyorhinis antigens were detected on the luminal surface of eight of 10 inflamed auditory tubes, and ultrastructural examination confirmed mycoplasmal organisms in two pigs. M. hyorhinis was isolated from the inflamed tympanic cavities of two pigs. None of the pigs inoculated only with P. multocida had otitis, and P. multocida was not isolated from the tympanic cavity. These findings indicate that M. hyorhinis can cause eustachitis but rarely otitis media in specific-pathogen-free pigs. PMID- 10098652 TI - Stereoselective synthesis of novel cyclopropyl analogues of known cysteine protease inhibitors. AB - Efficient synthesis of two novel analogues of some known protease inhibitors, via the isosteric replacement of oxirane/aziridine moiety of the parent compounds by cyclopropane ring, is described. PMID- 10098653 TI - Preparation and properties of 2',5'-linked oligonucleotide analogues containing 3'-O,4'-C-methyleneribonucleosides. AB - Bicyclic nucleoside analogues, 3'-O,4'-C-methyleneuridine and -5-methyluridine, were successfully incorporated into oligonucleotides via connection with 2',5' phosphodiester linkage, and hybridization behavior and nuclease stability of the modified oligonucleotides were investigated. PMID- 10098654 TI - Liquid phase combinatorial synthesis of benzylpiperazines. AB - A novel method for soluble, inexpensive polymer-supported synthesis of piperazine and piperidine libraries on the basis of nucleophilic benzylic substitution and N acylation is reported. Disubstituted piperazine and piperidine derivatives, that are potential drug candidates, can be isolated in high yields and excellent purity by simple precipitation and washing. This liquid phase method proves to be a useful tool for constructing combinatorial libraries containing diamine moieties. PMID- 10098655 TI - Novel nonsteroidal selective estrogen receptor modulators. Carbon and heteroatom replacement of oxygen in the ethoxypiperidine region of raloxifene. AB - Compounds were synthesized where oxygen in the ethoxypiperidine region of raloxifene is replaced with carbon, sulfur, or nitrogen linkages. Thia- and aza substituted compounds were prepared by novel methodology. The compounds were evaluated in vitro as selective estrogen receptor modulators (SERMs). Calculations suggested the compounds exhibit an ER-alpha binding affinity/conformational energy relationship. PMID- 10098656 TI - Synthesis and biological evaluation of alpha,alpha-difluorobenzylphosphonic acid derivatives as small molecular inhibitors of protein-tyrosine phosphatase 1B. AB - A series of alpha,alpha-difluorobenzylphosphonic acids having a hydrophobic functional group were prepared via the Stille coupling reaction from halogenated alpha,alpha-difluorobenzylphosphonates. Evaluation of inhibitory activity toward protein tyrosine phosphatase (PTP 1B) revealed that the ethynyl, phenylethynyl and (E)-styryl groups on the benzene nuclei increased the inhibitory activity of alpha,alpha-difluorobenzylphosphonic acid. Inhibitory activities significantly increased upon introducing both (E)-styryl and bis-methylsulfonamide functional groups onto the benzene nuclei of alpha,alpha-difluorobenzylphosphonic acid. PMID- 10098658 TI - Allosteric modulators of the AMPA receptor: novel 6-substituted dihydrophthalazines. AB - Novel analogs of the allosteric AMPA receptor modulator SYM 2206 have been prepared. Structure/activity correlations of these novel analogs and other dihydrophthalazines (DHPs) reveal the important contribution of the heteroatom based aryl substituents in this class of noncompetitive inhibitors. One of the analogs (6, SYM 2189) is equipotent with the early series, but with reduced sedation. PMID- 10098657 TI - (3-substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents. AB - A series of 3-[(2,4-dioxothiazolidin-5-yl)methyl]benzamide derivatives was prepared as part of a search for antidiabetic agents. A structure-activity relationship study of these compounds led to the identification of 5-[(2,4 dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluorome thyl) phenyl]methyl]benzamide (KRP-297) as a candidate drug for the treatment of diabetes mellitus. PMID- 10098659 TI - Synthesis of 5,8-dimethoxy-3-hydroxy-4-quinolone, a reported inhibitor of HIV RT, and evidence the original proposed structure was incorrect. AB - An unambiguous total synthesis of the title compound, a semi-synthetic derivative reported to be a non-nucleoside reverse transcriptase inhibitor, was conducted in four steps from 2,5-dimethoxyaniline. The synthetic material differed from that reported in the literature, both in its physical properties and 1H NMR spectrum. Biological evaluation indicated that synthetic 2 was inactive against HIV-1 RT, suggesting that the previous structural assignment of the semi-synthetic derivative was incorrect. PMID- 10098660 TI - Convergent solution-phase synthesis of a nucleopeptide using a protected oligonucleotide. AB - A nucleopeptide was prepared in a convergent manner via segmental coupling of the protected biopolymers in solution. The resulting nucleopeptide (4b, 72%) containing the binding site of lambda repressor and a peptide containing the consensus sequence of the DNA binding helix of the helix turn-helix-proteins was obtained using only five equivalents of the peptide relative to the oligonucleotide. This demonstrates that the recently developed method for the solution phase coupling of protected oligonucleotides is amenable to the convergent synthesis of larger nucleopeptides that are potentially capable of adopting secondary structure. PMID- 10098661 TI - Inhibition of 4-hydroxyphenylpyruvate dioxygenase by sethoxydim, a potent inhibitor of acetyl-coenzyme A carboxylase. AB - Sethoxydim, a commercially available cyclohexanedione class herbicide by targeting the enzymatic activity of acetyl-coenzyme A carboxylase, has been found to moderately inhibit the activity of 4-hydroxyphenylpyruvate dioxygenase, a key enzyme in the biosynthesis of plastoquinones and tocopherols in plants. PMID- 10098662 TI - Phospholipase A2-like catalytic antibody. AB - The phospholipase A2-like catalytic antibody 13C2-1F6 was elicited against the hapten 1 as the transition state analog for the hydrolysis of the C2 ester in the phospholipid. The Michaelis-Menten kinetics for the hydrolysis of the phospholipid 2 by 13C2-1F6 afforded a kcat of 1.0 x 10(-2) min(-1) and aKm of 71 microM. This antibody hydrolyzes the C2 ester in (R)-2, regio- and enantioselectively. PMID- 10098663 TI - Nonpeptide small-molecular inhibitors of dipeptidyl peptidase IV: N phenylphthalimide analogs. AB - A novel series of nonpeptide small-molecular dipeptidyl peptidase IV (DPP-IV) inhibitors with an N-phenylphthalimide skeleton has been developed. Some of the compounds, including 4-amino-(2,6-dimethylphenyl)phthalimides (7), 4- and 5 hydroxy-(2,6-diethylphenyl)phthalimide (11 and 14), 4-hydroxy-(2,6 diisopropylphenyl)phthalimide (12), and thiocarbonyl analogs of (2,6 diisopropylphenyl)phthalimide and their 4,5,6,7-tetrafluorinated derivative (18, 19 and 20), were more potent than the well-known DPP-IV-specific inhibitor, Pro boroPro (PBP). Among them, 18 was revealed to be a DPP-IV-specific inhibitor, while the others also showed inhibitory activity toward another peptidase, aminopeptidase N (APN). PMID- 10098664 TI - Synthesis and evaluation of backbone/amide-modified analogs of leualacin. AB - Leualacin (1), a cyclic depsi-pentapeptide, and its backbone/amide-modified analogs 2-4 were synthesized. Amide analogue 3 exhibited stronger vasodilatory effects. It also strongly inhibited collagen- and arachidonic acid (AA)-induced platelet aggregations with IC50s of 0.6 microM and 2.0 microM, respectively. PMID- 10098665 TI - Syntheses and biological activities of bis(3-indolyl)thiazoles, analogues of marine bis(indole)alkaloid nortopsentins. AB - The thiazole analogues of the marine bis(indole)alkaloid nortopsentins, 2,4-bis(3 indolyl)thiazoles, were synthesized using Hantzsch reaction between indole-3 thioamides and 3-(alpha-bromoacetyl)indoles as the key step, and these analogues showed potent cytotoxic activities against a variety of human cancer cell lines in vitro. PMID- 10098666 TI - High affinity retinoic acid receptor antagonists: analogs of AGN 193109. AB - A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated. PMID- 10098667 TI - Design, synthesis, and evaluation of azapeptides as substrates and inhibitors for human rhinovirus 3C protease. AB - A series of azapeptides was prepared and assessed as inhibitors of the human rhinovirus 3C protease. Boc-VLFaQ-OPh was a slow-turnover substrate that gave transient (ca. 1-2 h) inhibition as it underwent hydrolysis. Boc-VLFaG-OPh gave very slow but essentially irreversible inhibition. PMID- 10098668 TI - Modified PNAs: a simple method for the synthesis of monomeric building blocks. AB - The synthesis of PNA-monomers with variations in the substitution pattern using the Ugi-Reaction is described. The one-pot procedure leads to new totally protected PNA-monomers which can be selectively cleaved to N-protected monomeric building blocks for PNA synthesis. PMID- 10098669 TI - Synthesis and sar of 2- and 3-substituted 7-azaindoles as potential dopamine D4 ligands. AB - 7-azaindole compounds bearing a cyclic amine moiety linked by a one or two carbon chain attached at the 2- or 3-position were synthesised and evaluated as potential dopamine D4 ligands. Highest affinity and selectivity for the D4 receptor resided in the 3-aminomethyl-7-azaindole series. PMID- 10098670 TI - Stereoselective synthesis and receptor activity of conformationally defined retinoid X receptor selective ligands. AB - Retinoid X Receptor (RXR) specific ligands are currently being investigated for the treatment of metabolic diseases such as type II diabetes. We report the synthesis of conformationally locked retinoids, which are potent RXR selective ligands, and the attempted synthesis of 9-cyclopropyl locked analogs of RA and 9 cis RA. PMID- 10098671 TI - Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives. AB - We have synthesised and evaluated a series of anthranilamide based modulators of P-glycoprotein. These studies have identified XR9576(2), a potent inhibitor of P glycoprotein in vitro and in vivo. The general synthesis and the SAR of these compounds are described. PMID- 10098672 TI - Sialidase inhibitors related to zanamivir: synthesis and biological evaluation of 4H-pyran 6-ether and ketone. AB - Synthesis of 5R-Acetamido-4S-amino-4H-pyran-6R-O-( -ethyl)propyl and 6R-(1-oxo-2 ethyl)butyl 2-carboxylic acids (4 and 5) and their evaluation as inhibitors of influenza virus sialidase is described. Both compounds showed good inhibitory activity with marked selectivity for influenza A sialidase. PMID- 10098673 TI - Synthesis of tetrasubstituted bicyclo[3.2.1]octenes as potential inhibitors of influenza virus sialidase. AB - Several racemic bicyclo[3.2.1]octene derivatives have been synthesised and evaluated as inhibitors of influenza virus sialidases. The 5-acetamido bicyclo[3.2.1]octenol 4 showed modest activity against influenza A and B virus sialidases. PMID- 10098674 TI - Synthesis of a tetrasubstituted bicyclo [2.2.2] octane as a potential inhibitor of influenza virus sialidase. AB - A novel synthesis of the bicyclo [2.2.2] octane ring system has been achieved utilising a tandem Henry cyclisation as the key stage. This chemistry has been employed in the synthesis of a potential inhibitor of influenza virus sialidase. PMID- 10098675 TI - Homoisofagomines: chemical-enzymatic synthesis and evaluation as alpha- and beta glucosidase inhibitors. AB - Methyl- and hydroxymethyl derivatives of the highly potent glycosidase inhibitor isofagomine are accessible via aldolase-catalyzed C-C bond formation and competitively inhibit beta-glucosidase at low micromolar concentrations. PMID- 10098676 TI - Benzofuro[3,2-b]pyridines as mixed ET(A)/ET(B) and selective ET(B) endothelin receptor antagonists. AB - The discovery, synthesis and structure-activity relationships of a series of novel benzofuro[3,2-b]pyridines as non-selective endothelin ET(A)/ET(B) as well as selective ET(B) receptor antagonists are described. The most potent non selective inhibitor 7s displayed an IC50 of 21 nM and 41 nM for ET(A) and ET(B) receptors, respectively, whereas 7ee merely showed affinity for the ET(B) receptor (IC50 = 3.6 nM). PMID- 10098677 TI - Solid-phase synthesis of novel inhibitors of farnesyl transferase. AB - A novel diphosphate mimic, the 2,3,6-trifluoro-5-hydroxy-4-nitrophenoxy group (1), has been employed as the template in the solid-phase synthesis of novel farnesyl transferase inhibitors using the Mitsunobu reaction. The most potent inhibitor (farnesyloxy-5-hydroxy-2,3,6-trifluoro-4-nitrobenzene) displayed an IC50 of 6.3 microM versus farnesyl transferase. PMID- 10098678 TI - Nucleomimetic strategy for the inhibition of HIV-1 nucleocapsid protein NCp7 activities. AB - We report the synthesis and biological properties of three modified dinucleotides T*G, G*T and T*T in which the natural phosphodiester linkage has been replaced by a methylene carboxamide unit. They have been designed to act as nucleomimetics of a sequence recognized by the HIV-1 nucleocapsid protein NCp7 and to inhibit this interaction. PMID- 10098679 TI - Regioselective hydrolysis of peracetylated alpha-D-glycopyranose catalyzed by immobilized lipases in aqueous medium. A facile preparation of useful intermediates for oligosaccharide synthesis. AB - Penta-O-acetyl-alpha-D-glucopyranose was selectively deacetylated in aqueous media by lipases from Candida cilindracea (CCL) adsorbed on octyl-agarose support. Enzymatic hydrolyses was regioselective at the 4-position under neutral pH and towards the 6 position under acidic conditions. This enzymatic approach allows the one step synthesis of 1,2,3,6-tetra-O-acetyl-alpha-D-glucopyranoses 1, a useful intermediate in oligosaccharide synthesis. PMID- 10098680 TI - Diagnosis of malignant catarrhal fever by PCR using formalin-fixed, paraffin embedded tissues. AB - A previously described polymerase chain reaction (PCR) assay (amplification of a 238-bp fragment of ovine herpesvirus 2 [OHV-2] genomic DNA) for diagnosis of sheep-associated malignant catarrhal fever (MCF) was adapted for use on formalin fixed, paraffin-embedded tissues. Variables affecting its use were examined. Archived tissues from cattle, white-tailed deer (Odocoileus virginianus), and bison (Bison bison) diagnosed with MCF by clinical signs or histologic lesions were obtained from 2 veterinary diagnostic laboratories. Tissues from healthy animals and from animals diagnosed with other common bovine viral diseases were examined as controls. A total of 86 blocks from 37 suspect MCF cases were examined. Forty-one blocks from healthy animals and animals with unrelated viral diseases were examined as controls. The assay was specific for sheep-associated MCF and did not yield false-positive signals from healthy animals or from cases of infectious bovine rhinotracheitis, bovine virus diarrhea, mucosal disease, or parainfluenza-3 virus infection. A wide variety of tissues were suitable substrates, including spleen, lymph node, intestine, brain, lung, and kidney. Extracted DNA provided a more suitable target than did unextracted tissue lysate. The highest levels of viral DNA were present in lymphoid organs and intestine, but the data indicate that in acute clinical cases, most organs contain sufficient viral DNA to serve as a suitable diagnostic specimen. Fixation of 0.5 cm3 blocks of tissue in 10% neutral buffered formalin was deleterious to the target DNA, and PCR signals progressively diminished after fixation for >45 days. Detection of genomic DNA of OHV-2 by PCR was successful for archived tissues that were 15 years old. PMID- 10098681 TI - Quantitation of sheep-associated malignant catarrhal fever viral DNA by competitive polymerase chain reaction. AB - A single-step, competitive polymerase chain reaction technique was developed to quantitate sheep-associated malignant catarrhal fever (SA-MCF) viral DNA. The assay employed coamplification of a fixed quantity of target DNA with graded amounts of a competitor, generated by truncation of the target sequence lying between the 2 primer binding sites. The assay yielded a linear response (r = 0.98) for DNA measurement within the range of 30-300,000 copies. Amplification efficiency analysis by coamplification of target and competitor in equal copy numbers for various numbers of cycles showed that the relative abundance of the coamplified products remained constant with increasing cycle numbers up to 40. Reproducibility was assessed by repetitively assaying a set of blind-coded samples from a variety of animals and tissues. Results indicated that the assay is reliable and reproducible for quantitation of SA-MCF viral DNA in samples from asymptomatically infected sheep and from animals with clinical SA-MCF. PMID- 10098682 TI - Comparison of PCR, virus isolation, and indirect fluorescent antibody staining in the detection of naturally occurring feline herpesvirus infections. AB - Cats with clinical signs suggestive of ocular infection with feline herpesvirus type 1 (FHV 1) and cats without such signs were assayed by 3 methods to detect FHV. Comparison of polymerase chain reaction (PCR), virus isolation, and indirect fluorescent antibody staining techniques for the detection of FHV demonstrated higher sensitivity of PCR in detecting this common infectious agent of cats. Compared with PCR, sensitivity and specificity for virus isolation was 49% and 100%, respectively, and those of indirect immunofluorescence were 29% and 96%, respectively. FHV was detected in 13.7% of client-owned cats with conjunctivitis and in 31% of shelter cats with no ocular signs. The use of FHV PCR as a diagnostic test for FHV-associated disease is limited because of the occurrence of healthy carriers. PMID- 10098683 TI - Isotype- and subclass-specific responses to infection and reinfection with parainfluenza-3 virus: comparison of the diagnostic potential of ELISAs detecting seroconversion and specific IgM and IgA. AB - Isotype- and subclass-specific indirect enzyme-linked immunosorbent assays were developed to detect parainfluenza-3 virus-specific IgG1, IgG2, IgM, and IgA responses. Sera were treated with protein G-agarose prior to testing for specific IgM and IgA to eliminate the possibility of false-positive results due to IgM rheumatoid factor and to remove interisotypic competition due to specific IgG. IgM and IgA absorbance values were expressed as a percentage of the absorbance values of positive reference sera included on each plate (S/P%), and respective positive/negative threshold values of 15.0% and 28.0% were determined. The mean interval between experimental infection of 3 calves and initial detection of specific IgG1 and IgG2 responses was 8.0 and 9.3 days respectively, rising rapidly to an initial plateau 13.7 and 11.0 days postinfection (dpi). Reinfection of these calves at 30 dpi resulted in further rapid increases, with higher plateau values reached 13.0 (IgG1) and 13.7 (IgG2) days later. The mean interval between infection and the first positive IgM and IgA responses was 6.7 and 12.3 days, respectively. IgM S/P% values peaked at 13.0 dpi, with all 3 calves showing a secondary anamnestic response to reinfection, peaking 4.7 days later. The IgA response to initial infection was weak, with only 2 calves showing an obvious peak response at 15.0 dpi. A strong anamnestic IgA response to reinfection occurred in 2 calves, with a peak response 9.5 days later. Apparent biphasic and triphasic IgM and IgA responses were evident in some calves. Acute and convalescent serum samples from 80 calves involved in 17 outbreaks of respiratory disease were tested for specific IgM and IgA. Positive IgM results were detected in 15 outbreaks, with 71 sera from 44 calves testing positive. Although IgA positive results were detected in the same 15 outbreaks, only 42 sera from 31 calves were positive. In a previous study, seroconversion was detected in 21 of these calves from 10 outbreaks. Thus the diagnostic potential of the assays was in the order IgM > IgA > seroconversion. The correlations between IgM and IgA, IgM and seroconversion, and IgA and seroconversion results for each calf were 73.8%, 58.8% and 62.5%, respectively. PMID- 10098684 TI - Encephalitis induced by bovine herpesvirus 5 and protection by prior vaccination or infection with bovine herpesvirus 1. AB - Calves were intranasally challenged with bovine herpesvirus 5 (BHV5) and followed for the development of viral infection, clinical encephalitis, histologic lesions in the brain, and viral sequences in the trigeminal ganglia. Calves that were previously vaccinated with bovine herepesvirus 1 (BHV1, n = 4) or previously infected with BHV1 (n = 5) or that had not been exposed to either virus (n = 4) were compared. No calf developed signs of encephalitis, although all calves developed an infection as indicated by nasal secretion of BHV5 and seroconversion to the virus. Histologic lesions of encephalitis consisting of multifocal gliosis and perivascular cuffs of lymphocytes were observed in calves not previously exposed to BHV1. BHV5 sequences were amplified from the trigeminal ganglia of calves previously vaccinated and from calves not previously exposed to BHV1; calves sequentially challenged with BHV1 and later BHV5 had exclusively BHV1 sequences in their trigeminal ganglia. Administration of dexamethasone 28 days after BHV5 challenge did not influence clinical disease or histologic lesions in either previously unexposed calves (n = 2) or previously immunized calves (n = 2), although it did cause recrudescence of BHV5, as detected by nasal virus secretion. PMID- 10098685 TI - Development of an oligonucleotide-specific capture plate hybridization assay for detection of Haemophilus parasuis. AB - An oligonucleotide-specific capture plate hybridization assay has been developed to rapidly, specifically, and sensitively detect Haemophilus parasuis from nasal swabs. Several in vitro studies have been performed to determine the sensitivity and specificity of the test, and in vivo studies have validated this technique in pigs. Results suggest that the assay detects <100 colony-forming units/ml in a pure culture and gives a positive result when H. parasuis is present in a ratio of 1:10(3)-10(4) in a mixed culture, and the probe does not hybridize with other related species found in the upper respiratory tract. This assay is more sensitive than culture for detection of the microorganism from nasal swabs and lesions. PMID- 10098686 TI - Prevalence of genotypes for fimbriae and enterotoxins and of O serogroups in Escherichia coli isolated from diarrheic piglets in Korea. AB - Polymerase chain reaction for 4 fimbriae (F4, F5, F6, F41), 2 heat-stable enterotoxins (STa, STb), and 1 heat-labile enterotoxin (LT) were performed on 400 Escherichia coli isolates to determine their genotype prevalence among enterotoxigenic E. coli isolates from preweaned pigs with diarrhea in the Republic of Korea. A total of 200 of the 400 E. coli isolates were also selected for characterization of the O serogroup. Of these 200 isolates, serogroup could be determined in 139 (69.5%) but not in 61 isolates (30.5%). Isolates of serogroup O101 were the most common, followed in descending order by 08, 020, 0162, 0141, and 0149. Ninety-seven (24.3%) of the 400 E. coli isolates carried genes for at least 1 of the entertoxins or fimbrial adhesins. Of these 97 isolates, 27 carried genes for at least 1 of the fimbrial adhesins and entertoxins. Sixty-six percent of the isolates that carried fimbrial adhesin genes carried genes for at least 1 of the enterotoxins, and 71% of the isolates that carried enterotoxin genes carried genes for at least 1 of the fimbrial adhesins. Genes for the F6 fimbriae were detected in 6% of the E. coli isolates, and F4+, F41+, and F5+ genes were detected in 4.3%, 3.3%, and 2% of the isolates, respectively. Genes for STa, STb, and LT were detected in 10%, 8.5%, and 4.3% of the isolates, respectively. The 6 major genotypes observed in this study (in decreasing order) were F6+, STb+, F41+, STa+STb+, F6+STa+, and STa+. PMID- 10098687 TI - Genomic fingerprinting and development of a dendrogram for Brucella spp. isolated from seals, porpoises, and dolphins. AB - Genomic DNA from reference strains and biovars of the genus Brucella was analyzed using pulsed-field gel electrophoresis (PFGE). Fingerprints were compared to estimate genetic relatedness among the strains and to obtain information on evolutionary relationships. Electrophoresis of DNA digested with the restriction endonuclease XbaI produced fragment profiles for the reference type strains that distinguished these strains to the level of species. Included in this study were strains isolated from marine mammals. The PFGE profiles from these strains were compared with those obtained from the reference strains and biovars. Isolates from dolphins had similar profiles that were distinct from profiles of Brucella isolates from seals and porpoises. Distance matrix analyses were used to produce a dendrogram. Biovars of B. abortus were clustered together in the dendrogram; similar clusters were shown for biovars of B. melitensis and for biovars of B. suis. Brucella ovis, B. canis, and B. neotomae differed from each other and from B. abortus, B. melitensis, and B. suis. The relationship between B. abortus strain RB51 and other Brucella biovars was compared because this strain has replaced B. abortus strain 19 for use as a live vaccine in cattle and possibly in bison and elk. These results support the current taxonomy of Brucella species and the designation of an additional genomic group(s) of Brucella. The PFGE analysis in conjunction with distance matrix analysis was a useful tool for calculating genetic relatedness among the Brucella species. PMID- 10098688 TI - Complementary randomly amplified polymorphic DNA (RAPD) analysis patterns and primer sets to differentiate Mycoplasma gallisepticum strains. AB - Randomly amplified polymorphic DNA (RAPD) analysis was used to differentiate 7 strains of Mycoplasma gallisepticum. Six commercially available primers or primer combinations were screened for their ability to differentiate vaccine and type strains. Although major and minor bands were produced with each primer, many of the primers were unsuitable for strain differentiation. The use of primer 6 and combined primers 3 and 4 resulted in complementary RAPD banding patterns for each M. gallisepticum strain. Eleven different isolates representing 7 different strains were segregated into 7 different patterns, corresponding to the 7 strains. PMID- 10098689 TI - Cloning of Mycoplasma synoviae genes encoding specific antigens and their use as species-specific DNA probes. AB - A genomic library of Mycoplasma synoviae (MS) was generated by using bacteriophage lambda gt11 as a cloning and expression vector. Identification of recombinant clones highly specific to MS was achieved by screening the library for expression of MS proteins with polyclonal antiserum that had been preadsorbed with 6 heterologous avian mycoplasma species antigens. Expression of the recombinant clones in Escherichia coli followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis of the total cell lysates and immunoblot yielded a predominant reactive fusion protein of 165 kD. Two clones (MS2/28 and MS2/12) that yielded inserts of different size were selected. The 2 MS DNA inserts were subcloned in a plasmid vector, labeled with digoxigenin, and used as probes for the specific recognition of several MS strains. A high degree of conservation was demonstrated for the MS2/12 and MS2/28 genes in tested MS strains. In addition, neither DNA fragment recognized any other avian mycoplasma species (M. gallisepticum, M. meleagridis, M. gallinarum, M. iners, M. anatis, and M. iowae), thus indicating their high specificity to MS. The sensitivity of the slot blot hybridization method using digoxigenin-labeled MS2/12 and MS2/28 probes for direct detection of MS from broth cultures of field isolates was 10(5) colony-forming units/ml. These results demonstrate the effectiveness of adsorbed antisera for the isolation of species-specific mycoplasma DNA and the potential for its use as probes for the specific and direct detection of MS from broth cultures of field isolates. PMID- 10098690 TI - Value of Western blotting in the clinical follow-up of canine leishmaniasis. AB - Specific serum antibody levels in Leishmania infantum-infected dogs treated with a combination of glucantime and allopurinol were estimated by indirect immunofluorescence and Western blotting. The sensitivity of Western blot was greater than that obtained with immunofluorescence titration. In general, both diagnostic methods concurred with the post-treatment clinical status of the animals. Clinical improvement of successfully treated dogs was related to lower immunofluorescence titers and simpler and/or less reactive immunodetection patterns in Western blotting. The recognition, by infected dogs, of certain low molecular weight antigens, particularly one of approximately 26 kDa, was restricted to pretreatment samples and a single animal in relapse thus apparently constituting an active infection marker. PMID- 10098691 TI - Group G streptococcal infection in a cat colony. PMID- 10098692 TI - Lower motor neuronopathy in a Dutch Belted-Sembra bull. PMID- 10098693 TI - Bilateral testicular leiomyosarcoma in a stallion. PMID- 10098694 TI - Atlanto-occipital malformation, osteoarthropathy, and myelopathy in a Duroc boar. PMID- 10098695 TI - Canine LaCrosse viral meningoencephalomyelitis with possible public health implications. PMID- 10098696 TI - Aeromonas hydrophila isolated from cases of bovine seminal vesiculitis in south Brazil. PMID- 10098697 TI - Metastatic oral squamous cell carcinoma in a Montagu's harrier (Circus pigargus). PMID- 10098698 TI - Cutaneous chytridiomycosis in poison dart frogs (Dendrobates spp.) and White's tree frogs (Litoria caerulea). PMID- 10098699 TI - Psoralen photobiology and photochemotherapy: 50 years of science and medicine. AB - In 1998 it is appropriate to commemorate the 50th anniversary of el Mofty's use of purified 8-methoxypsoralen (8-MOP) in the treatment of vitiligo (el Mofty AM. A preliminary clinical report on the treatment of leukoderma with Ammi majus linn. J R Egypt Med Assn 1948,31:651 65. el Mofty AM, el Sawalhy H, el Mofty M. Clinical study of a new preparation of 8-methoxypsoralen in photochemotherapy. Int J Dermatol 1994;8:588 92). Two young American dermatologists (Aaron Lerner and Thomas Fitzpatrick) were intrigued by the potency of this material. After Lerner determined that artificial long wavelength ultraviolet (320-400 nm, UVA) radiation was the most efficient for activating 8-MOP. the development of artificial sources enabled the efficient delivery of these photons to skin containing 8-MOP. Their initial studies for vitiligo led to further development of this therapy for the treatment of psoriasis (Parrish JA, Fitzpatrick TB, Tannenbaum L, et al. Photochemotherapy of psoriasis with oral methoxsalen and long-wave ultraviolet light. New Engl J Med 1974;291:1207-11. Honigsmann H, Fitzpatrick TB, Pathak MA, et al. Oral photochemotherapy with psoralen and UVA (PUVA): principles and practice. In: Fitzpatrick TB, Eisen AZ, Wolf K, editors. Dermatology in General Medicine. New York: McGraw-Hill, 1987:1728-54). This photochemotherapy came to be called 'PUVA' (psoralen + UVA). The position PUVA holds today as one of the most common procedures performed in dermatology can be traced to their initial curiosity and their subsequent ingenuity. Further developments in more recent years capitalized on their seminal work. The therapy met with unprecedented success from the outset, leaving little perceived need to understand underlying science. However, in recent years there has been a new found interest in the basic aspects of psoralen photobiology and molecular mechanistic events contributing to therapeutic responses as well as to the development of skin cancers in PUVA patients. These will be surveyed in this review commemorating the 50 years of modern psoralen photobiology and photomedicine. PMID- 10098700 TI - PUVA therapy: current concerns in Japan. AB - Photochemotherapy using methoxsalen in combination with long-wave ultraviolet light (PUVA) is an essential modality in the treatment of various skin diseases. Major therapeutic regimens include oral, topical and water-delivery methods. An adequate regimen should be chosen regarding cases of disease, extent of involvement and the age of patients. In Japan, however, treatment techniques and protocols have not yet been standardized. PUVA therapy may be a first choice in the early stages of mycosis fungoides and a second choice or an adjunctive measure in other diseases, such as psoriasis, vitiligo and atopic dermatitis, which have been disabling or resistant to conventional treatments. Japanese guidelines for PUVA therapy of psoriasis are being prepared to be produced. Risks and benefits must be weighed and the patient orientation is necessary to complete the treatment and also to minimize side-effects. Although possible risks for skin cancers in Japanese patients have been reported to be much lower, a careful monitoring of the patient's skin changes is recommended. While action mechanisms are not completely understood, recent investigations suggest that both antiproliferative and immunomodulatory effects are involved. This review article deals with the recent progress in clinical and basic research on PUVA therapy, focusing on our current concerns. PMID- 10098701 TI - Extracorporeal photochemotherapy in human and murine graft-versus-host disease. AB - Extracorporeal photochemotherapy (ECP) is an immunotherapy that has found a role in the therapy of cutaneous T cell lymphoma, a disease of mature activated T cells. Graft-versus-host disease (GVHD) is also mediated by activated T cells, and thus often responds to therapies that target T cells. Murine models for both GVHD and ECP can be combined to study the impact of this immunotherapy on GVHD. In this paper we present a patient with GVHD who demonstrated a beneficial therapeutic response to treatment with ECP. The findings of this case are compared with the observations from a murine model for GVHD-ECP. The potential mechanisms of ECP in the treatment of GVHD are discussed. along with the similarities observed with ECP in the treatment of other conditions. PMID- 10098702 TI - Modulation of cytokine production by 8-methoxypsoralen and UVA. AB - Modulatory effects on cytokine expression of 8-MOP in conjunction with UVA have been investigated in different systems using different cell types, including keratinocytes, lymphocytes, monocytes and endothelial cells. The vast majority of data have exhibited reduced production of cytokines in 8-MOP/UVA-treated cells and skin, reflecting its simplistic cellular damage. However, 8-MOP/UVA at modest doses stimulate T lymphocytes to produce Thl cytokines such as interferon-gamma, suggesting that some activational events may occur in certain types of cells phototreated with 8-MOP. Both the inhibitory and augmentative effects of 8 MOP/UVA on cytokine production appear to participate in the mechanisms underlying the therapeutic efficacy of PUVA and extracorporeal photochemotherapy (photopheresis). In particular, photopheresis may exert beneficial effects on cutaneous T-cell lymphoma as a cytokine modifier. PMID- 10098703 TI - Minoxidil increases 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase activity of cultured human dermal papilla cells from balding scalp. AB - Minoxidil is known to induce hair growth in male pattern baldness, for which development androgen plays a central role. We studied the effect of minoxidil on testosterone metabolism by cultured dermal papilla cells from balding or nonbalding scalp and dermal fibroblasts. In all three groups, 17beta hydroxysteroid dehydrogenase activity was much higher than 5alpha-reductase activity. Minoxidil increased 17beta-hydroxysteroid dehydrogenase activity by nearly 40% (P < 0.001) in dermal papilla cells of balding scalp, whereas the effect was less marked in dermal papilla cells from nonbalding scalp and dermal fibroblasts. 5alpha-Reductase activity was also slightly increased by minoxidil in dermal papilla cells from balding scalp. Again, the effect on 5alpha-reductase activity was insignificant in the other two groups of cells. Whether such modification of testosterone metabolism in dermal papilla cells of balding scalp by minoxidil is related to its therapeutic effect remains unknown. PMID- 10098704 TI - Arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the mutation in epidermolytic hyperkeratosis. AB - Keratin intermediate filaments are expressed in specific type I/type II pairs in the stage of differentiation of keratinocytes. The mutations in the keratin genes expressed in the epidermis are etiologically responsible for several epidermal genetic skin diseases, such as epidermolysis bullosa simplex, epidermolytic hyperkeratosis (EHK), ichthyosis bullosa of Siemens, palmoplantar keratoderma, pachyonchia congenita and white sponge nevus. The mutations of keratins 1/10 which are expressed in spinous and granular layers are confirmed to cause EHK. There are several trials to correlate between the clinical phenotypes and sites of mutations of the keratin genes. One of these is that EHK is divided into two groups: the palms and soles involvement (PS) group and the non-palms and soles (NPS) group. So far the PS group had the mutations in the keratin 1 and the NPS group in keratin 10. Most of the mutations of the NPS group were reported in the beginning of the 1A rod domain and over 2/3 of the mutations in the 1A rod domain were the base pair substitution of arginine. Here we find two different mutations in two unrelated Korean kindreds classified as NPS group-R156C and R156H-in the 1A rod domain of keratin 10. Our results are compatible with the above classification and suggest that the arginine in the beginning of the 1A rod domain is the hot spot for the mutation of the keratin 10 gene. PMID- 10098705 TI - Reduced amount of secretory component of IgA secretion in tears of patients with atopic dermatitis. AB - Coupled with the previous finding that sIgA excretion was reduced onto the surface of the skin, we demonstrated that sIgA secretion in the tears of patients with atopic dermatitis (AD) was significantly lower than that of normal subjects, using a small stick made of nitrocellulose membrane. In the bacterial cultures, we have also detected a higher frequency of Staphylococcus aureus in the tears from patients with AD compared to normal subjects. These findings suggested reduced sIgA secretion on the mucous membrane might play a crucial role in the pathomechanisms of the ocular lesions, such as abnormal bacterial flora and ocular complications as well as the establishment of skin lesions in AD. PMID- 10098706 TI - Detecting expression of keratins 8/18 in human HaCaT keratinocytes. AB - Differences in treatment solution affect the efficiency of keratin extraction in cultured human squamous cell carcinomas, malignant melanomas, and melanocytes. Using an aqueous solution that is excellent for cultured cells, we focused this study on the expression of keratin subunits in the spontaneously immortalized human keratinocyte cell line HaCaT. We extracted several keratin (K) subunits, namely K4, K7, K8, K15, K17, and K18, and ATP synthase alpha-chain, in addition to those previously reported by Boukamp et al. (J Cell Biol 1988;106:761-771) in human HaCaT keratinocytes. In particular, K8 and K18 subunits, which are related to tumorigenesis, may be very important subunits within the specificities of immortalized HaCaT cells. Vimentin, which is frequently co-expressed in cultured epithelial cell lines, was not expressed. PMID- 10098707 TI - Expression of Th1 and Th2 cytokine mRNAs in freshly isolated peripheral blood mononuclear cells of a patient with cutaneous paragonimiasis. AB - Using semiquantitative reverse transcriptase polymerase chain reaction, we examined the levels of various cytokine mRNAs of freshly isolated peripheral blood mononuclear cells (PBMCs) from a cutaneous paragonimiasis patient in the course of successful treatment with praziquantel administration. The pre treatment levels of Th2 cytokines such as interleukin (IL)-4, IL-5, IL-10 and IL 13 mRNAs in PBMCs of the patient were much higher than those of healthy controls. The levels of IL-4, IL-5 and IL-13 mRNAs slightly elevated on day 2 of the treatment and then declined to the control levels on day 25. The IL-10 mRNA level rapidly decreased after the chemotherapy. In contrast, the mRNA levels of interferon (IFN)-gamma, a Th1 cytokine, remained in the control levels during the course. Peripheral eosinophil counts and levels of total IgE and eosinophil cationic protein in the sera correlated well with the levels of these Th2 cytokine mRNAs. These results suggested the major role of Th2 cytokines in clinical manifestation of human helminthic infection. PMID- 10098708 TI - Mechanical properties of frog muscle fibres at rest and during twitch contraction. AB - Data reported in the literature suggest that crossbridges in rapid equilibrium between attached and detached states (weakly binding bridges), demonstrated in relaxed skinned fibres at low ionic strength, could be present also in intact fibres under physiological conditions. In addition, it was suggested that the well known leading of stiffness over force during the tension development in stimulated muscle fibres could be due to an increased number of weakly binding bridges induced by the stimulation. The experiments reviewed in this paper were made to investigate these possibilities. Fast ramp length changes were applied to single frog muscle fibres at rest and during the early phases of activation. The corresponding force changes were analysed, searching for the components expected from the presence of weakly binding bridges. The results showed no mechanical indication for the presence of weakly binding bridges in both skinned and intact fibres, either at rest or during activation. It was also found that a portion of the fibre stiffness increase induced by stimulation leads the formation of crossbridges. PMID- 10098709 TI - Specific contributions of various muscle fibre types to human muscle performance: an in vitro study. AB - Human skeletal muscle fibres can be divided in five groups: 1, 1-2A, 2A, 2A-2B and 2B, by using myosin heavy chain (MHC) isoforms as molecular markers. This study aimed to define the contribution of each fibre type to the contractile performance of human muscles. Single fibre segments were dissected from bioptic samples of vastus lateralis and chemically skinned. Force-velocity properties, including isometric tension (P0), maximal shortening velocity (Vmax), maximum power output (Wmax) and the velocity at which Wmax is reached (Vopt), were determined at maximum calcium activation. Among these parameters Wmax showed the largest range of variation: about nine times between 2B and slow fibres. Vopt also showed large (about four times) and significant variations between fibre types. Force development at submaximum calcium activation was studied and force pCa curves were obtained for each fibre type. Calcium sensitivity was greater in 2B than in 2A and in slow fibres. The slope of the force-pCa curve was greater in fast than in slow fibres. At the end of the experiment the MHC isoform composition of each fibre segment was determined by gel electrophoresis. The functional properties of each fibre type are discussed in the light of the motor unit recruitment mechanism to understand their possible physiological role. PMID- 10098710 TI - Human skeletal muscle architecture studied in vivo by non-invasive imaging techniques: functional significance and applications. AB - The internal architecture plays an essential role in determining the functional features of skeletal muscle. Both length-force and force-velocity relationships depend on the spatial arrangement of muscle fibres in skeletal muscle. The degree of muscle pennation determines both the amount of contractile tissue packed along the tendons and fibre length, and is reflected by the force-generating capacity and shortening velocity of the muscle and by the elastic properties of the muscle tendon complex. Until recently, knowledge on human muscle architecture was based on measurements performed on cadavers, whose muscle fibres were often shrunk by the preserving medium and by age. With the introduction of non-invasive imaging techniques, it has become possible to study muscle architecture in vivo at rest and the changes thereof upon contraction. This paper discusses the applications of these techniques, namely ultrasonography and nuclear magnetic resonance imaging, and their relevance in physiology and biomechanics. PMID- 10098711 TI - Repeatability of surface EMG variables during voluntary isometric contractions of the biceps brachii muscle. AB - The repeatability of initial value and rate of change of mean spectral frequency (MNF), average rectified values (ARV) and muscle fiber conduction velocity (CV) was investigated in the dominant biceps brachii of ten normal subjects during sustained isometric voluntary contractions. Four levels of contraction were studied: 10%, 30%, 50% and 70% of the maximal voluntary contraction level (MVC). Each contraction was repeated three times in each of three different days for a total of nine contractions/level/subject and 90 contractions per level across the ten subjects. Repeatability was investigated using the Intraclass Correlation Coefficient (ICC) and the standard error of the mean (SEM) of the estimates for each subject. Contrary to observations in other muscles, CV estimates appeared to be very repeatable both within and between subjects. CV showed a small but significant increase when contraction force increased from 10% to 50% MVC but no change for further increase of force. As force increased, MNF showed a slight decrease possibly related to a wider spreading of the CV values. The rate of time decrement of MNF and CV increased with the level of contraction. The normalized decrement (% of initial value per second) was in general higher for MNF than for CV and was more repeatable between subjects at 10% MVC than at 70% MVC. A final observation is that a resting time of 5 minutes may not be sufficient after a contraction at 50% or 70% MVC. PMID- 10098712 TI - Force generation performance and motor unit recruitment strategy in muscles of contralateral limbs. AB - The purpose of the present study was to determine whether the motor unit (MU) recruitment strategy of the agonist and antagonist muscles in the dominant arm differs from that in the non-dominant arm. The median frequency (MF) of the power density spectrum (PDS) of the electromyogram (EMG) was used as a tracking parameter to describe the MU recruitment. In 8 subjects the EMG was recorded from the biceps brachii and triceps brachii of each limb during isometric elbow flexion performed in a ramp fashion. Force was increased from 0 to 100% of the maximum voluntary contraction (MVC) in 3 s following a track displayed on an oscilloscope. When comparing the dominant versus non-dominant arm we found no statistical difference in the MU recruitment pattern of the biceps brachii and the triceps. Because the dominant arm was not always the better performing arm, we grouped the data according to the ability of the subjects to track the ramp signal. In this case we found a statistically significant difference between the better and worse performing arm in the full MU recruitment of the biceps. A more precise and accurate control of the increase in force was obtained when the central nervous system selected a slower and prolonged recruitment of MUs in the agonist muscle. PMID- 10098713 TI - Force and surface mechanomyogram relationship in cat gastrocnemius. AB - The aim of this study was to compare the force (F) and the muscle transverse diameter changes during electrical stimulation of the motor nerve. In four cats the exposed motor nerves of the medial gastrocnemius were stimulated as follows: (a) eight separate trials at fixed firing rates (FR) from 5 to 50 Hz (9 s duration, supramaximal amplitude); (b) 5 to 50 Hz linear sweep in 2.5, 5, 7.5 and 10 s (supramaximal amplitude, separate trials); (c) four separate trials at 40 Hz, the motor units (MUs) being orderly recruited in 2.5, 5, 7.5 and 10 s. The muscle surface displacement was detected by a laser distance sensor pointed at the muscle surface. The resulting electrical signal was termed surface mechanomyogram (MMG). In stimulation patterns (a) and (b) the average F and MMG increased with FR. With respect to their values at 50 Hz the amplitude of the unfused signal oscillations at 5 Hz was much larger in MMG than in force. The signal rising phase was always earlier in MMG than in F. In (c) trials, F increased less in the first than in the second half of the recruiting time. MMG had an opposite behaviour. The results indicate that the force and the lateral displacement are not linearly related. The different behaviour of F and MMG, from low to high level of the MUs' pool activation, suggests that the force generation and the muscle dimensional change processes are influenced by different components of the muscle mechanical model. PMID- 10098714 TI - Quantitative evaluation of the stretch reflex before and after hydro kinesy therapy in patients affected by spastic paresis. AB - The aim of this study was the quantitative evaluation of the myotatic reflex in a group of 26 patients affected by stationary spastic paresis (6: hemiparesis; 5: paraparesis; 8: tetraparesis; 7: multiple sclerosis) before and after a treatment of hydro-kinesy therapy. The treatment was carried out in an indoor pool containing warm (32 degrees C) sea water and consisted of active and passive motion exercises, coordination exercises and immersion walking. The measured parameters were: (i) the peak input force (FpH) measured by means of an instrumented hammer with which the patellar tendon was hit; and (ii) the peak value of the corresponding reflex force of the quadriceps femoris (FpQ) measured by means of a load cell connected to the subject's ankle. The peak values of the reflex response (FpQ) were found to increase as a function of the intensity of the imposed stimulus and to reach a plateau between 15 and 30 N of FpH. A Student's t test applied to the paired values of FpQ (as measured at plateau conditions) on both the lower limbs, before and after therapy, showed no significant changes due to the treatment in the four groups of subjects. However, if all subjects were grouped regardless the type of illness: 1) the average reflex response of the affected limb (the one characterized before therapy by the higher FpQ values) was found to decrease following the treatment (75.1+/-26.7 N pre therapy and 69.1+/-29.3 N post therapy, p = 0.07, n = 26); and 2) the effect of the treatment was found to be significantly larger (p = 0.04, n = 26) on the affected limb (delta FpQ = 6.07+/-16.5 N) as respect with the contra lateral one (delta FpQ = -0.16+/-12.1 N). PMID- 10098715 TI - Cost of walking and locomotor impairment. AB - The aim of the present study was to evaluate the importance and the necessity of metabolic measurements to quantify locomotor impairment in a clinical context. Oxygen consumption, heart rate, pulmonary ventilation and walking speed were measured during locomotion in 14 normal subjects, used as a control group, and 82 patients with different pathologies [hemiparetic, paraparetic, tetraparetic, orthopaedic and paraplegic patients, who walked using a reciprocating gait orthosis (RGO)]. The subjects were characterized on the basis of a cumulative impairment score (CIS), based on clinical scales commonly used to evaluate impairment and disability in locomotion. Appropriate indices of energy, cardiac and ventilatory costs expressed per metre walked, globally called physiological costs, were obtained. It resulted that the most comfortable speed (MCS) of normal subjects was significantly higher than that of each group of patients. Normal subjects' physiological costs were found to be significantly lower than those of patients who needed either a device or the help of a person to walk. All measured parameters correlated significantly with each other. The MCS was found to be the most correlated parameter with the CIS (r = 0.8), and therefore it must be considered the best single measurement, if only one is to be used. Measurements more precise than MCS, such as the physiological costs, may be necessary in clinical trials. PMID- 10098716 TI - Improved growth of cultured brain microvascular endothelial cells on glass coated with a biological matrix. AB - An improved method for culturing primary rat brain capillary endothelial cells on glass has been developed, using a corneal extracellular matrix coat. Since the collagen-coated plastic attachment surface conventionally used for primary cultures of brain microvascular endothelium gives a high level of background fluorescence in microfluorimetric studies, an alternative attachment surface was tested involving no plastic element. Five substrata combinations were examined and a new combination of glass and corneal endothelial extracellular matrix coat was found to provide excellent cell adhesion, culture growth and purity. Other established substrata combinations tested for comparison, either involved plastic, or used glass with collagen or carbodiimide and collagen coating but the last two gave poor endothelial cell adhesion and growth. Our method using this new attachment surface combination results in stable and pure endothelial cultures, as verified by immunocytochemistry, which are suitable for fluorimetric investigations. PMID- 10098717 TI - The family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype. AB - The acidic amino acids, glutamate and aspartate, are the predominant excitatory neurotransmitters in the mammalian CNS. Under many pathologic conditions, these excitatory amino acids (EAAs) accumulate in the extracellular fluid in CNS and the resultant excessive activation of EAA receptors contributes to brain injury through a process known as 'excitotoxicity'. Unlike many other neurotransmitters, there is no evidence for extracellular metabolism of EAAs, rather, they are cleared by Na+-dependent transport mechanisms. Therefore, this transport process is important for ensuring crisp synaptic signaling as well as limiting the excitotoxic potential of EAAs. With the cloning of five distinct EAA transporters, a variety of tools were developed to characterize individual transporter subtypes, including specific antibodies, expression systems, and probes to delete/knock-down expression of each subtype. These tools are beginning to provide fundamental information that has the potential to impact our understanding of EAA physiology and pathophysiology. For example, biophysical studies of the cloned transporters have led to the observation that some subtypes function as ligand-gated ion channels as well as transporters. With these reagents, it has also been possible to explore the relative contributions of each transporter to the clearance of extracellular EAAs and to begin to examine the regulation of specific transporter subtypes. In this review, an overview of the properties of the transporter subtypes will be presented. The evidence which suggests that the transporter, GLT1/EAAT2, may be sufficient to explain a large percentage of forebrain transport will be critically reviewed. Finally, the studies of regulation of GLT-1 in vitro and in vivo will be described. PMID- 10098718 TI - Nitric oxide and potassium chloride-facilitated striatal dopamine efflux in vivo: role of calcium-dependent release mechanisms. AB - Previous studies investigating the calcium-dependency of nitric oxide-facilitated striatal dopamine efflux have produced conflicting results. In the current study, we have investigated the role of extracellular calcium in nitric oxide and potassium chloride-evoked striatal dopamine efflux in vivo using microdialysis. Dialysis probes were implanted in the anterior dorsal striatum of chloral hydrate anesthetized rats. Intrastriatal infusion (20 min fraction) of the nitric oxide generators sodium nitroprusside (200 microM, 500 microM, or 1 mM) and 3 morpholinosydnonimine (1 mM) increased extracellular dopamine levels. The facilitatory effects of 3-morpholinosydnonimine and potassium chloride on dopamine efflux were attenuated following pretreatment (100 min) and co-infusion of calcium free artificial cerebral spinal fluid containing magnesium chloride. Local potassium chloride infusion (100 mM) administered alone elevated striatal dopamine efflux to a similar degree as potassium chloride (100 mM) delivered 60 min after 3-morpholinosydnonimine infusion. These results demonstrate that like potassium chloride, nitric oxide facilitates striatal dopamine efflux in vivo via a mechanism largely dependent on extracellular calcium. Also, as intrastriatal potassium chloride infusion evoked similar increases in extracellular dopamine levels in controls and subjects receiving pretreatment with the NO-generator 3 morpholinosydnonimine, it is unlikely that the functional integrity of DA nerve terminals is compromised via a neurotoxic disruption of plasma membrane potential following enhanced striatal NO production. PMID- 10098719 TI - Protective effect of neurotrophic factors, neuropoietic cytokines and dibutyryl cyclic AMP on hydrogen peroxide-induced cytotoxicity on PC12 cells: a possible link with the state of differentiation. AB - We present evidence that the survival of PC12 cells exposed to hydroxyl radicals generated by hydrogen peroxide applied for 30 min at 1 mM was effective when they were differentiated in response to Nerve Growth Factor (NGF) and/or other inducers of neurite outgrowth such as basic-fibroblast growth factor and dibutyryl cyclic AMP. The time- and dose-dependent differentiation triggered by NGF was (1) markedly increased by basic fibroblast growth factor, interleukin-6 or dibutyryl cyclic AMP; (2) diminished by leukemia inhibitory factor or ciliary neurotrophic factor; (3) not potentiated by insulin-like growth factor I or progesterone. The influence of these various factors and agents on PC12 cells was evaluated by the estimation of neurite outgrowth, whereas their possible protective effects were assessed by the measurement of cell survival. Our results would indicate that the factors and agents that induced differentiation were also able to protect the cells against an oxidative stress. PMID- 10098720 TI - Effect of bimoclomol (N-[2-hydroxy-3-(1-piperidinyl) propoxy]-3 pyridine carboximidoyl-chloride) on iminodipropionitrile-induced central effects. AB - Dyskinesia is frequently seen in neurological disorders affecting the basal ganglia. Iminodipropionitrile (IDPN) produces a somewhat similar motor syndrome in rodents, one that is a possible model for dyskinesia. Because in previous studies the compound (N-[2-hydroxy-3-(1-piperidinyl) propoxy]-3 pyridine carboximidoyl-chloride) (Bimoclomol, BRLP-42) was shown to provide protection against IDPN-induced retinopathy; we investigated the effect of BRLP-42 on IDPN induced motor changes and on IDPN-induced cerebral amino acid level changes in rats and mice. IDPN had a biphasic effect on motor activity in C57BL/6 mice: it was a depressant for 24 days and a stimulant after 30 days. Bimoclomol inhibited the motor depressant effect and enhanced the stimulatory effect of IDPN in this mouse strain. In BALB/cBy mice and Sprague Dawley rats IDPN produced persistent vertical head movements and changes in the level of glutamic acid in brain. Bimoclomol reduced the effect of IDPN on head movements and blocked the effect on cerebral glutamate; by itself it had no effect on motor activity in either species. Bimoclomol inhibited ischemia-induced [3H]norepinephrine release from rat hippocampal slices. Our findings indicate that Bimoclomol could have a beneficial effect on some dyskinesias, and on drug-induced vertical head movements. PMID- 10098721 TI - Serotonin transporter on rat platelets: levels of mRNA underlie inherited differences in uptake kinetics. AB - By the breeding selection for the extreme values of platelet serotonin transporter activity, two sublines of Wistar-derived rats, with constitutionally high or low platelet serotonin uptake (PSU), were previously developed. In order to study the genetic background of these inherited differences, comparative Northern blot analysis of the platelet serotonin transporter messenger RNA levels of the animals from the two sublines was performed. If the values of animals from the high-PSU subline are taken as 100%, animals from the low-PSU subline demonstrated lower values of both platelet serotonin uptake and transporter mRNA levels (amounting to 62 and 76% respectively). Correlation between platelet serotonin uptake and the respective levels of messenger RNA for the serotonin transporter (r = 0.829, P < 0.01, N = 8) points to the same direction, indicating that the process of breeding selection for the extreme values of transporter kinetics has influenced transcription mechanisms of the serotonin transporter gene. PMID- 10098722 TI - Acute ethanol exposure attenuates expression of junD in human neuroblastoma cells. AB - This study describes the effects of acute ethanol exposure on the mRNA levels of c-jun,junB and junD in the human neuroblastoma SH-SY5Y cell line. An acute exposure to 100 mM ethanol did not influence the basal and phorbol ester-induced expression of c-jun and junB, whereas the basal mRNA level of junD was attenuated by 30%. This effect was dose- and time-dependent with maximal inhibition being detected 2 h after 100 mM ethanol treatment and the mRNA levels gradually returned towards normal afterwards. Ethanol also inhibited phorbol ester-induced expression of junD. The fact that ethanol did not influence degradation of the junD mRNA suggests that acute ethanol suppresses the transcription of the gene. These results indicate that acute ethanol exerts different effects on expression of Jun transcription factors, suggesting that as compared to c-jun and junB, the junD gene may be more sensitive to acute ethanol treatment in neuronal cells. PMID- 10098723 TI - Effects of 4-hydroxynonenal, a lipid peroxidation product, on dopamine transport and Na+/K+ ATPase in rat striatal synaptosomes. AB - Incubation of rat striatal synaptosomes in ascorbic acid induced the production of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and 4 hydroxynonenal (4-HNE), a lipid peroxidation aldehydic product. Incubations with 4-HNE, used at a range of concentrations comparable to those obtained during peroxidation, induced a simultaneous, dose-dependent decrease of dopamine (DA) uptake and Na+/K+ ATPase activity and a loss of sulfhydryl (SH) groups. Similar results were observed in a previous study when lipid peroxidation was induced after incubation of synaptosomes in ascorbic acid. Taken together, these data suggest that 4-HNE is an important mediator of oxidative stress and may alter DA uptake after binding to SH groups of the DA transporter and to Na+/K+ ATPase. These toxic events may contribute to the onset and progression of Parkinson's disease. PMID- 10098724 TI - Effects of retinoic acid on rat forebrain cells derived from embryonic and perinatal rats. AB - All-trans retinoic acid (RA), a potent inducer of neural development in non committed neuroectodermal precursors and also, a teratogenic agent for early prosencephalic development is reported to promote the survival and differentiation of embryonic forebrain neurons, in vitro. In cultures of embryonic (E13, E15) rat forebrain cells, long-term (2-5 days) treatment with RA increased the number of neurons and the overall neurofilament immunoreactivity. Treatment with RA for periods longer than 1 h resulted in enhanced binding of the non-competitive NMDA-receptor antagonist, TCP, by embryonic and fetal (E17, E18) cells, but not by cells derived from perinatal (E19, P0) forebrains. As TCP binding-sites are localised within the channel-complex, treatment with RA was thought to result in an opening of the NMDA receptor channel. In direct binding assays, however, RA had no detectable effect, while conditioned media taken from RA-treated embryonic or fetal cells increased the TCP-binding, immediately. Analyses on conditioned media taken from control cultures of cells with various in vivo or in vitro ages revealed a stable extracellular glutamate level ([Glu]e) of 1-3 microM. This basal [Glu]e was restored within 24 h after addition of 100 microM exogenous glutamate. In the presence of RA, however, [Glu]e was stabilised at an approximately three-fold higher (4-10 microM) level by cells derived from embryonic and fetal brains. RA-treatment did not influence the [Glu]e in cultures of perinatal cells. The RA-induced rise in the neurofilament-immunoreactivity of embryonic brain cell cultures was prevented by simultaneous treatment with APV, a competitive antagonist of NMDA-receptors. The data suggest that a RA-induced shift in the set-point of extracellular glutamate-balance plays an important role in the promotion of survival and maturation of developing neurons, in culture. PMID- 10098725 TI - Brain catecholaminergic and tryptophan responses to restraint are attenuated by nitric oxide synthase inhibition. AB - Increases in the brain concentrations of tryptophan and in serotonin (5-HT) metabolism are commonly observed in animals under stress. Previous experiments indicated that the increase in brain tryptophan and 5-hydroxyindoleacetic acid (5 HIAA) observed in response to administration of endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) were largely prevented by pretreatment with N-nitro L-arginine methylester (L-NAME), an inhibitor of NO synthase (NOS). Therefore we tested whether the increases in tryptophan and 5-HT metabolism observed following restraint and footsthock were similarly affected. Mice were injected with L-NAME (30 mg/kg) or saline and restrained for 40 min. Restraint caused increases in concentrations of tryptophan and the catabolites of dopamine (DA), norepinephrine (NE) and 5-HT in the medial prefrontal cortex, hypothalamus, and brain stem. The L-NAME pretreatment significantly attenuated, but did not prevent, the changes in tryptophan and catecholamine metabolism, with a very small effect on the increase in plasma corticosterone. When mice pretreated with L-NAME were subjected to 30 min footshock, the NOS inhibitor had no statistically significant effects on the increases in DA, NE and 5-HT metabolism, but tended to attenuate the increases in tryptophan. We interpret these results to indicate that NOS plays a relatively small role in the cerebral neurochemical responses to restraint and footshock, but the role in the restraint-induced changes was greater than that in the footshock-induced ones. The attenuation of the restraint-related effects on the catecholamines most probably reflects a contribution to the CNS responses from peripheral vascular changes which are likely to be limited by the inhibition of NOS. PMID- 10098726 TI - Effect of nitric oxide synthesis inhibition on mouse liver and brain metallothionein expression. AB - The role of nitric oxide (NO) production on metallothionein (MT) regulation in the liver and the brain has been studied in mice by means of the administration of nitric oxide synthase (NOS) inhibitors. Mice injected with either the arginine analog NG-monomethyl-L-arginine (L-NMMA) or the heme binding compound 7-nitro indazole (7-NI) showed consistently increased liver MT-I mRNA and MT-I + II total protein levels, suggesting that NO is involved in the hepatic MT regulation. In agreement with the liver results, in situ hybridization analysis demonstrated a significant upregulation of the brain MT-I isoform in areas such as the cerebrum cortex, neuronal CA1-CA3 layers and dentate gyrus of the hippocampus, and Purkinje cell layer of the cerebellum, in 7-NI treated mice. The same trend was observed for the brain specific isoform, MT-III, but to a much lower extent. The effect of NOS inhibition was also evaluated in a MT-inducing condition, namely during immobilization stress. In both the liver and the brain, stress upregulated the MT-I isoform, and 7-NI significantly reduced or even blunted the MT-I response to stress, suggesting a mediating role of NO on MT-I regulation during stress. Stress also increased the MT-III mRNA levels in some brain areas, an effect blunted by the concomitant administration of 7-NI, which in some areas even decreased MT-III mRNA levels below the saline injected mice. Results in primary culture of neurons and astrocytes demonstrate significant effects of the NOS inhibitors in some experimental conditions. The present results suggest that NO may have some role on MT regulation in both the liver and the brain. PMID- 10098727 TI - Expression of GABA transaminase immunoreactivity in interneurons of the rat neostriatum. AB - Immunoreactivity for gamma-aminobutyric acid transaminase (GABA-T), a degradation enzyme for GABA, was localized by immunocytochemistry in the rat neostriatum and the globus pallidus using a monoclonal antibody. Immunoreactivity for GABA-T was found primarily in interneurons and in the neuropilar elements in the neostriatum. Many of GABA-T-immunoreactive neurons were found to display parvalbumin immunoreactivity. This indicates many of the GABA-T-immunoreactive neurons are striatal GABAergic interneurons. Occasionally, GABA-T-immunoreactive glial cells were found. In the globus pallidus, many pallidal neurons also displayed GABA-T immunoreactivity and many of the immunoreactive neurons were seen to express parvalbumin immunoreactivity. Immunoreactivity for GABA-T was also detected in the neuropil of the globus pallidus. The present results indicate the GABAergic interneurons in the neostriatum and a subpopulation of pallidal neurons play an important role in metabolic degradation of GABA in the basal ganglia. PMID- 10098728 TI - Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines. AB - Transforming growth factor beta (TGF-beta) exerts a growth inhibitory effect on many cell types through binding to two types of receptors, the type I and II receptors. Resistance to TGF-beta due to lack of type II receptor (RII) has been described in some cancer types including small cell lung cancer (SCLC). The purpose of this study was to examine the cause of absent RII expression in SCLC cell lines. Northern blot analysis showed that RII RNA expression was very weak in 16 of 21 cell lines. To investigate if the absence of RII transcript was due to mutations, we screened the poly-A tract for mutations, but no mutations were detected. Additional screening for mutations of the RII gene revealed a GG to TT base substitution in one cell line, which did not express RII. This mutation generates a stop codon resulting in predicted synthesis of a truncated RII of 219 amino acids. The nature of the mutation, which has not previously been observed in RII, has been linked to exposure to benzo[a]-pyrene, a component of cigarette smoke. Since RII has been mapped to chromosome 3p22 and nearby loci are often hypermethylated in SCLC, it was examined whether the lack of RII expression was due to hypermethylation. Southern blot analysis of the RII promoter did not show altered methylation patterns. The restriction endonuclease pattern of the RII gene was altered in two SCLC cell lines when digested with Smal. However, treatment with 5-aza-2'-deoxycytidine did not induce expression of RII mRNA. Our results indicate that in SCLC lack of RII mRNA is not commonly due to mutations and inactivation of RII transcription was not due to hypermethylation of the RII promoter or gene. Thus, these data show that in most cases of the SCLC cell lines, the RII gene and promoter is intact in spite of absent RII expression. However, the nature of the mutation found could suggest that it was caused by cigarette smoking. PMID- 10098729 TI - Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer. AB - To study the involvement of DNA mismatch-repair genes in sporadic breast cancer, matched normal and tumoral DNA samples of 22 patients were analysed for genetic instability and loss of heterozygosity (LOH) with 42 microsatellites at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMSH6 (2p16), hPMS1 (2q32) and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11-q13 were found hemizygously deleted in 46% and 23% of patients respectively. Half of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlapping (SRO) deletions were delimited by markers D3S1298 and D3S1266 at 3p21 and by D5S647 and D5S418 at 5q11-q13. Currently, the genes hMLH1 (3p21) and hMSH3 (5q11-q13) are the only known candidates located within these regions. The consequence of these allelic losses is still unclear because none of the breast cancers examined displayed microsatellite instability, a hallmark of mismatch-repair defect during replication error correction. We suggest that hMLH1 and hMSH3 could be involved in breast tumorigenesis through cellular functions other than replication error correction. PMID- 10098730 TI - Butyrate augments interferon-alpha-induced S phase accumulation and persistent tyrosine phosphorylation of cdc2 in K562 cells. AB - Interferon-alpha (IFN-alpha) is a clinically useful cytokine for treatment of a variety of cancers, including chronic myelocytic leukaemia (CML). Most CML cells are sensitive to IFN-alpha; however, its biological effects on leukaemic cells are incompletely characterized. Here, we provide evidence that IFN-alpha induces a significant increase in the S phase population in human CML leukaemic cell line, K562, and that the S phase accumulation was augmented by sodium butyrate. In contrast, neither sodium butyrate alone, nor sodium butyrate plus IFN-gamma, affected the cell cycle in K562 cells. These data suggest that the effect of sodium butyrate depended upon IFN-alpha-mediated signalling. The ability of leukaemic cells to exhibit the S phase accumulation after stimulation by IFN alpha plus sodium butyrate correlated well with persistent tyrosine phosphorylation of cdc2, whereas treatment with IFN-gamma plus sodium butyrate did not affect its phosphorylation levels. Considering that dephosphorylation of cdc2 leads to entry to the M phase, the persistent tyrosine phosphorylation of cdc2 may be associated with the S phase accumulation induced by IFN-alpha and sodium butyrate. In addition, another human CML leukaemic cell line, MEG-01, also showed the S phase accumulation after stimulation with IFN-alpha plus sodium butyrate. Taken together, our studies reveal a novel effect of sodium butyrate on the S phase accumulation and suggest its clinical application for a combination therapy with IFN-alpha, leading to a great improvement of clinical effects of IFN alpha against CML cells. PMID- 10098731 TI - The chemokine RANTES is secreted by human melanoma cells and is associated with enhanced tumour formation in nude mice. AB - Modulation of tumour cell growth by tumour-infiltrating leucocytes is of high importance for the biological behaviour of malignant neoplasms. In melanoma, tumour-associated macrophages (TAM) and tumour-infiltrating lymphocytes (TIL) are of particular interest as inhibitors or enhancers of cell growth. Recruitment of leucocytes from the peripheral blood into the tumour site is mediated predominantly by chemotaxins, particularly by the group of chemokines. The aim of this study was to identify peptides released by human melanoma cells with monocyte chemotactic properties. To assure the presence of biologically active mediators, biochemical purification and biological characterization of peptides was based on a detection system dependent on bioactive, monocyte chemotactic activity in vitro. Cell culture supernatants of melanoma cells were fractioned by heparin-sepharose followed by preparative reversed-phase HPLC steps to enrich monocyte chemotactic activity in one single band on a sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) gel. These purified fractions were shown to react with RANTES-specific antibodies in an enzyme-linked immunosorbent assay (ELISA) as well as in Western blot analysis. Amino acid sequencing of the N terminal protein fragment confirmed 100% homology to the RANTES protein. Further analysis showed that four out of eight melanoma cell lines constitutively expressed and secreted the beta-chemokine RANTES as detected by ELISA. The amount of RANTES protein secreted (up to 50 ng ml(-1)) was about 5-50 times higher than interleukin 8 (IL-8), determined in the same supernatant samples. Tumour necrosis factor alpha, (TNF-alpha), not, however, IL-2, interferon-gamma (IFN-gamma), or (alpha-melanocyte-stimulating hormone (alpha-MSH) was able to up-regulate RANTES and interleukin 8 secretion. Furthermore, higher levels of RANTES secretion in vitro were associated with increased tumour formation upon s.c. injection of six human melanoma cell lines in nude mice. Our data provide evidence that a subset of melanoma cells express mRNA and secrete RANTES protein which may be partly responsible for the recruitment of monocytes, T-cells and dendritic cells into the tumours. However, transplantation experiments in nude mice suggest that effects of RANTES may also benefit tumour progression. Further studies are needed to dissect the underlying mechanisms. PMID- 10098732 TI - Restoration of p16INK4A protein induces myogenic differentiation in RD rhabdomyosarcoma cells. AB - p16INK4A (p16) tumour suppressor induces growth arrest by inhibiting function of cyclin-dependent kinase (CDK)4 and CDK6. Homozygous p16 gene deletion is frequent in primary rhabdomyosarcoma (RMS) cells as well as derived cell lines. To confirm the significance of p16 gene deletion in tumour biology of RMS, a temperature sensitive p16 mutant (E119G) gene was retrovirally transfected into the human RMS cell line RD, which has homozygous gene deletion of p16 gene. Decrease from 40 degrees C (restrictive) to 34 degrees C (permissive) culture temperature reduced CDK6-associated kinase activity and induced G1 growth arrest. Moreover, RD-p16 cells cultured under permissive condition demonstrated differentiated morphology coupled with expressions of myogenin and myosin light chain. These suggest that deletion of p16 gene may not only facilitate growth but also inhibit the myogenic differentiation of RD RMS cells. PMID- 10098733 TI - Ku70/80 gene expression and DNA-dependent protein kinase (DNA-PK) activity do not correlate with double-strand break (dsb) repair capacity and cellular radiosensitivity in normal human fibroblasts. AB - The expression of the Ku70 and Ku80 genes as well as the activity of the DNA dependent protein kinase (DNA-PK) were studied in 11 normal human fibroblast lines. The proteins studied are known to be part of a double-strand break (dsb) repair complex involved in non-homologous recombination, as was demonstrated for the radiosensitive rodent mutant cell lines of the complementation groups 5-7. The 11 fibroblast lines used in this study represent a typical spectrum of normal human radiosensitivity with the surviving fraction measured for a dose of 3.5 Gy, SF3.5 GY, ranging from 0.03 to 0.28. These differences in cell survival were previously shown to correlate with the number of non-repaired dsbs. We found that the mRNA signal intensities of both Ku70 and Ku80 genes were fairly similar for the 11 cell lines investigated. In addition, the DNA-PK activity determined by the pulldown assay was fairly constant in these fibroblast lines. Despite the correlation between cell survival and dsb repair capacity, there was no correlation between dsb repair capacity and DNA-PK activity in the tested normal human fibroblast lines. Obviously, in this respect, other proteins/pathways appear to be more relevant. PMID- 10098734 TI - Constitutive expression of CD26/dipeptidylpeptidase IV on peripheral blood B lymphocytes of patients with B chronic lymphocytic leukaemia. AB - We have investigated the expression of the ectoenzyme dipeptidylpeptidase IV (DPP IV)/CD26 on lymphocytes obtained from patients with B chronic lymphocytic leukaemia (B-CLL) and compared it with healthy subjects. Using two-colour immunofluorescence analysis with CD26 and CD20 or CD23 monoclonal antibodies, CD26 was found undetectable on peripheral resting B-cells (CD20+ CD23-) from normal donors whereas it was expressed on B-cells activated in vitro with interleukin (IL)-4 and Staphylococcus aureus strain cowan I (CD20+ CD23+). The expression of CD26 on leukaemic B-cells (CD20+ CD23+) was clearly induced in 22 out of 25 patients examined. Consequently, induced levels of CD26 cell surface expression on either normal activated and malignant B-cells coincided with the enhancement of DPP IV activity detected on the surface of these cells. Reverse transcription polymerase chain reaction analyses showed that the transcript levels of the CD26 gene was higher in normal activated B-cells and B-CLL cells than in resting B-cells, suggesting that CD26 was expressed at the level of transcriptional activation. These observations provide evidence of the abnormal expression of DPPIV/CD26 in B-CLL which, therefore, may be considered as a novel marker for B-CLL. Further investigation in relation to CD26 expression and other B malignancies needs to be defined. PMID- 10098735 TI - Mutation analysis of the Fanconi anaemia A gene in breast tumours with loss of heterozygosity at 16q24.3. AB - The recently identified Fanconi anaemia A (FAA) gene is located on chromosomal band 16q24.3 within a region that has been frequently reported to show loss of heterozygosity (LOH) in breast cancer. FAA mutation analysis of 19 breast tumours with specific LOH at 16q24.3 was performed. Single-stranded conformational polymorphism (SSCP) analysis on cDNA and genomic DNA, and Southern blotting failed to identify any tumour-specific mutations. Five polymorphisms were identified, but frequencies of occurrence did not deviate from those in a normal control population. Therefore, the FAA gene is not the gene targeted by LOH at 16q24.3 in breast cancer. Another tumour suppressor gene in this chromosomal region remains to be identified. PMID- 10098737 TI - Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts. AB - The photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm2) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1 4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2-4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC. Tissue concentrations of mTHPC and pegylated mTHPC were measured by high-performance liquid chromatography in non-irradiated animals 4 days after administration. There was no significant difference in tumour uptake between the two sensitizers in mesothelioma, adenocarcinoma and squamous cell carcinoma xenografts. Tissue concentration measurements were of limited use for predicting photosensitization in this model. PMID- 10098736 TI - Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918. AB - The acridone carboxamide derivative GG918 (N-{4-[2-(1,2,3,4-tetrahydro-6,7 dimethoxy-2-isoquinolinyl)-ethyl]-pheny l}-9,10dihydro-5-methoxy-9-oxo-4-acridine carboxamide) is a potent inhibitor of MDR1 P-glycoprotein-mediated multidrug resistance. Direct measurements of ATP-dependent MDR1 P-glycoprotein-mediated transport in plasma membrane vesicles from human and rat hepatocyte canalicular membranes indicated 50% inhibition at GG918 concentrations between 8 nM and 80 nM using N-pentyl-[3H]quinidinium, ['4C]doxorubicin and [3H]daunorubicin as substrates. The inhibition constant K for GG918 was 35 nM in rat hepatocyte canalicular membrane vesicles with [3H]daunorubicin as the substrate. Photoaffinity labelling of canalicular and recombinant rat Mdr1b P-glycoprotein by [3H]azidopine was suppressed by 10 muM and 40 muM GG918. The high selectivity of GG918-induced inhibition was demonstrated in canalicular membrane vesicles and by analysis of the hepatobiliary elimination in rats using [3H]daunorubicin, [3H]taurocholate and [3H]cysteinyl leukotrienes as substrates for three distinct ATP-dependent export pumps. Almost complete inhibition of [3H]daunorubicin transport was observed at GG918 concentrations that did not affect the other hepatocyte canalicular export pumps. The high potency and selectivity of GG918 for the inhibition of human MDR1 and rat Mdr1b P-glycoprotein may serve to interfere with this type of multidrug resistance and provides a tool for studies on the function of these ATP-dependent transport proteins. PMID- 10098738 TI - Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases. AB - The possibility of using interleukin 2 (IL-2)-activated natural killer cells (A NK) to carry methoxymorpholinyl doxorubicin (MMDX; PNU 152243) to liver infiltrating tumours was explored in mice bearing 2-day established M5076 reticulum cell sarcoma hepatic metastases. In vitro, MMDX was 5.5-fold more potent than doxorubicin against M5076 tumour cells. MMDX uptake by A-NK cells correlated linearly with drug concentration in the incubation medium [correlation coefficient (r) = 0.999]; furthermore, as MMDX incorporation was readily reproducible in different experiments, the amount of drug delivered by A-NK cells could be modulated. In vivo experiments showed that intravenous (i.v.) injection of MMDX-loaded A-NK cells exerted a greater therapeutic effect than equivalent or even higher doses of free drug. The increase in lifespan (ILS) following A-NK cell delivery of 53 microg kg(-1) MMDX, a dosage that is ineffective when administered in free form, was similar to that observed in response to 92 microg kg(-1) free drug, a dosage close to the 10% lethal dose (ILS 42% vs. 38% respectively). These results correlated with pharmacokinetic studies showing that MMDX encapsulation in A-NK cells strongly modifies its organ distribution and targets it to tissues in which IL-2 activated lymphocytes are preferentially entrapped after i.v. injection. PMID- 10098739 TI - In vitro radiosensitivity of tumour cells and fibroblasts derived from head and neck carcinomas: mutual relationship and correlation with clinical data. AB - The aim was to characterize the variation in the cellular in vitro radiosensitivities in squamous cell carcinomas of the head and neck, and to test for a possible correlation between different measures of radiosensitivity and the clinical and histopathological data. Cellular in vitro radiosensitivities were assessed in tumour biopsies from 71 patients using the modified Courtenay-Mills soft agar clonogenic assay combined with an immunocytochemical analysis. Radiosensitivity was quantified as the surviving fraction after a radiation dose of 2 Gy irrespective of cell type (overall SF2), or based on identification of cell type (tumour cell SF2, fibroblast SF2). Sixty-three biopsies were from primary tumours, and eight were from recurrences. Overall plating efficiency ranged from 0.005 to 1.60% with a median of 0.052%. The majority of the colonies obtained from the biopsies were fibroblast marker-positive; the proportion of tumour marker-positive colonies ranged from 1 to 88% with a median of 15%. The median overall SF2 was 0.47 (range 0.24-0.96), the median tumour cell SF2 was 0.50 (range 0.11-1.0) and the median fibroblast SF2 was 0.49 (range 0.24-1.0). Comparing data from independent experiments, the overall SF2 was significantly correlated with the SF2 of fibroblasts (2P = 0.006) but not with the tumour cell SF2. The tumour cell and fibroblast radiosensitivities measured in the same individuals were not correlated (r= 0.06, 95% CI [-0.19, 0.30]):This finding seems to preclude a strong correlation between the radiosensitivity of tumour cells and fibroblasts. Concerning the clinical characteristics, neither of the measures of tumour radiosensitivity was correlated with T- and N-category, stage, tumour size, sex and age. However, the tumour cell radiosensitivity decreased with increasing grade of histopathological differentiation (2P = 0.012). The same tendency was found in two independent analyses of the same patient material. This correlation was not significant in case of the overall SF2 or the fibroblast SF2. PMID- 10098740 TI - Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation. AB - The radiosensitizing activity of S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, was assessed in a model of non-metabolic hypoxia achieved in an atmosphere of 95% nitrogen-5% carbon dioxide. A 10 min preincubation of hypoxic EMT-6 cells (10 x 10(6) ml(-1)) with 0.1 and 1 mM SNAP before radiation resulted in an enhancement ratio of 1.6 and 1.7 respectively. The level of spontaneous NO release, measured by a NO specific microsensor, correlated directly with the concentration of SNAP and was enhanced 50 times in the presence of cells. Dilution of the cell suspension from 10 to 0.1 x 10(6) ml(-1) resulted in a 16 fold decline in NO release, but only a twofold decrease in radiosensitization was observed. Preincubation of hypoxic cells with SNAP for 3 min up to 30 min caused an increasing radiosensitizing effect. Extended preincubation of 100 min led to the loss of radiosensitization although the half-life of SNAP is known to be 4-5 h. Taken together, these observations suggest that SNAP generates NO predominantly by a bioreductive mechanism and that its biological half-life is unlikely to exceed 30 min. The lack of correlation between free NO radical and radiosensitizing activity may reflect a role of intracellular NO adducts which could contribute to radiosensitization as well. PMID- 10098741 TI - Dual mechanism of daunorubicin-induced cell death in both sensitive and MDR resistant HL-60 cells. AB - Exposure of some acute myeloid leukaemia (AML) cells to daunorubicin leads to rapid cell death, whereas other AML cells show natural drug resistance. This has been attributed to expression of functional P-glycoprotein resulting in reduced drug accumulation. However, it has also been proposed that P-glycoprotein expressing multidrug-resistant (MDR) cells are inherently defective for apoptosis. To distinguish between these different possibilities, we have compared the cell death process in a human AML cell line (HL-60) with a MDR subline (HL 60/Vinc) at doses that yield either similar intracellular daunorubicin concentrations or comparable cytotoxicity. Adjustment of the dose to obtain the same intracellular drug accumulation in the two cell lines did not result in equal cytotoxicity, suggesting the presence of additional resistance mechanisms in the P-glycoprotein-expressing HL-60/Vinc cells. However, at equitoxic doses, similar cell death pathways were observed. In HL-60 cells, daunorubicin induced rapid apoptosis at 0.5-1 microM and delayed mitotic cell death at 0.1 microM. These concentrations are within the clinical dose range. Similarly, HL-60/Vinc cells underwent apoptosis at 50-100 microM daunorubicin and mitotic cell death at 10 microM. These results show, for the first time, that anthracyclines can induce cell death by a dual mechanism in both sensitive and MDR cells. Our results also show that not only the cytotoxicity, but also the kinetics and mechanism of cell death, are dose dependent. Interestingly, regrowth was observed only in association with delayed cell death and the formation of enlarged, often polyploid, cells with micronucleation, suggesting that morphological criteria may be useful to evaluate treatment efficacy in patients with myeloid leukaemias. PMID- 10098742 TI - Inhibition of transforming growth factor alpha (TGF-alpha)-mediated growth effects in ovarian cancer cell lines by a tyrosine kinase inhibitor ZM 252868. AB - The modulating effects of the epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor ZM 252868 on cell growth and signalling have been evaluated in four ovarian carcinoma cell lines PE01, PE04, SKOV-3 and PE01CDDP. Transforming growth factor alpha (TGF-alpha)-stimulated growth was completely inhibited by concentrations > or =0.3 microM in the PE01 and PE04 cell lines and by > or =0.1 microM in SKOV-3 cells. TGF-alpha inhibition of PE01CDDP growth was reversed by concentrations > or =0.1 microM ZM 252868. TGF-alpha-stimulated tyrosine phosphorylation of both the EGF receptor and c-erbB2 receptor in all four cell lines. The inhibitor ZM 252868, at concentrations > or =0.3 microM, completely inhibited TGF-alpha-stimulated tyrosine phosphorylation of the EGF receptor and reduced phosphorylation of the c-erbB2 protein. EGF-activated EGF receptor tyrosine kinase activity was completely inhibited by 3 microM ZM 252868 in PE01, SKOV-3 and PE01CDDP cells. These data indicate that the EGF receptor targeted TK inhibitor ZM 252868 can inhibit growth of ovarian carcinoma cells in vitro consistent with inhibition of tyrosine phosphorylation at the EGF receptor. PMID- 10098743 TI - Induction of JNK and c-Abl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and -deficient cells. AB - Loss of DNA mismatch repair has been observed in a variety of human cancers. Recent studies have shown that loss of DNA mismatch repair results in resistance to cisplatin but not oxaliplatin, suggesting that the mismatch repair proteins serve as a detector for cisplatin but not oxaliplatin adducts. To identify the signal transduction pathways with which the detector communicates, we investigated the effect of loss of DNA mismatch repair on activation of known damage-responsive pathways, and recently reported that cisplatin differentially activates c-Jun NH2-terminal kinase (JNK) and c-Abl in repair-proficient vs. deficient cells. In the current study, we directly compared differential activation of these pathways by cisplatin vs. oxaliplatin. The results confirm that cisplatin activates JNK kinase 5.7 +/- 1.5 (s.d.)-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that the c-Abl response to cisplatin is completely absent in DNA mismatch repair-deficient cells. In contrast, there was no detectable activation of the JNK or c-Abl kinases in DNA mismatch repair-proficient or -deficient cells exposed to oxaliplatin. The present study demonstrates that, despite the similarity of the adducts produced by cisplatin and oxaliplatin, they appear to be recognized by different detectors. The DNA mismatch repair system plays an important part in the recognition of cisplatin adducts, and activation of both the JNK and c-Abl kinases in response to cisplatin damage is dependent on the detector function of the DNA mismatch repair proteins. In contrast, this detector does not respond to oxaliplatin adducts. PMID- 10098744 TI - Human thyroid cancer cells as a source of iso-genic, iso-phenotypic cell lines with or without functional p53. AB - Differentiated thyroid carcinomas (in contrast to the rarer anaplastic form) are unusual among human cancers in displaying a remarkably low frequency of p53 mutation and appear to retain wild-type (wt) p53 function as assessed by the response of derived cell lines to DNA damage. Using one such cell line, K1, we have tested the effect of experimental abrogation of p53 function by generating matched sub-clones stably expressing either a neo control gene, a dominant negative mutant p53 (143ala) or human papilloma virus protein HPV16 E6. Loss of p53 function in the latter two groups was confirmed by abolition of p53-dependent 'stress' responses including induction of the cyclin/CDK inhibitor p21WAF1 and G1/S arrest following DNA-damage. In contrast, no change was detected in the phenotype of 'unstressed' clones, with respect to any of the following parameters: proliferation rate in monolayer, serum-dependence for proliferation or survival, tumorigenicity, cellular morphology, or tissue-specific differentiation markers. The K1 line therefore represents a 'neutral' background with respect to p53 function, permitting the derivation of functionally p53 + or clones which are not only iso-genic but also iso-phenotypic. Such a panel should be an ideal tool with which to test the p53-dependence of cellular stress responses, particularly the sensitivity to potential therapeutic agents, free from the confounding additional phenotypic differences which usually accompany loss of p53 function. The results also further support the hypothesis that p53 mutation alone is not sufficient to drive progression of thyroid cancer to the aggressive anaplastic form. PMID- 10098745 TI - Mediastinal lymph node metastasis model by orthotopic intrapulmonary implantation of Lewis lung carcinoma cells in mice. AB - This study is designed to establish a pulmonary tumour model to investigate the biology and therapy of lung cancer in mice. Current methods for forming a solitary intrapulmonary nodule and subsequent metastasis to mediastinal lymph nodes are not well defined. Lewis lung carcinoma (LLC) cell suspensions were orthotopically introduced into the lung parenchyma of C57/BL6 mice via a limited skin incision without thoracotomy followed by direct puncture through the intercostal space. The implantation process was performed within approximately 50 s per mouse, and the operative mortality was less than 5%. Single pulmonary nodules developed at the implanted site in 93% of animals and subsequent mediastinal lymph node metastasis was observed in all mice that formed a lung nodule after intrapulmonary implantation. The size of tumour nodule and the weight of mediastinal lymph node increased in a time-dependent manner. The mean survival time of mice implanted successfully with LLC cells was 21+/-2 days (range 19-24 days). Histopathological analysis revealed that no metastatic tumour was detectable in the mediastinal lymph nodes on day 11, but metastatic foci at mediastinal lymph nodes were clearly observed on days 17 and 21 after implantation. Other metastases in distant organs or lymph nodes were not observed at 21 days after the implantation. Comparative studies with intrapleural and intravenous injections of LLC cells suggest that the mediastinal lymph node metastasis by intrapulmonary implantation is due to the release of tumour cells from the primary nodule, and not due to extrapulmonary leakage of cells. An intravenous administration of cis-diamine dichloro platinum on day 1 after tumour implantation tended to suppress the primary tumour nodule and significantly inhibited lymph node metastasis. Thus, a solitary pulmonary tumour nodule model with lymph node metastasis approximates clinical lung cancer and may provide a useful basis for lung cancer research. PMID- 10098746 TI - Expression of CD3-zeta on T-cells in primary cervical carcinoma and in metastasis positive and -negative pelvic lymph nodes. AB - Lymphocytic infiltrate is often present in cervical cancer lesions, possibly reflecting an ongoing, but ineffective, immune response to the tumour. Recently, evidence has accumulated for systemically impaired T-cell functions in cancer patients, associated with decreased expression of signal-transducing zeta (zeta) chain dimer molecules on circulating T-cells and NK-cells. Here, we report on the intralesional down-regulation of zeta chain expression on T-cells in cervical carcinoma. Paraffin-embedded or snap-frozen sections from 24 different cervical cancer specimens were studied. Paraffin-embedded tumour-positive (n = 7) and tumour-negative (n = 15) pelvic lymph nodes were also included in the study. Immunostaining was performed on consecutive sections with antibodies specific for CD3-epsilon or the CD3-associated zeta chain dimer. Antigen retrieval by sodium citrate/microwave treatment was essential for zeta staining of paraffin sections. The amount of zeta positive cells was quantitated and related to the number of CD3-epsilon+ cells in corresponding tumour areas. Of the 24 cervical cancer specimens studied, zeta chain dimer expression was reduced in seven cases and strongly reduced in the other 17 samples. In tonsil control sections, CD3-epsilon and CD3-zeta were always co-expressed in almost equal numbers. Also, both tumour negative and -positive lymph nodes showed zeta chain expression which equalled that of CD3-epsilon expression. These data indicate that a decreased expression of signal-transducing zeta molecules on tumour-infiltrating T-cells is frequent in cervical cancer. The apparently unimpaired zeta chain expression within draining lymph nodes suggests that local tumour-derived factors at the primary site are instrumental in zeta chain down-regulation. PMID- 10098747 TI - Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate. AB - Hyaluronan (HA), an extracellular high-molecular-mass polysaccharide, is supposed to be involved in the growth and progression of malignant tumours. We studied the cellular expression of HA in 215 operated stage I-IV gastric cancer patients using a specific biotinylated probe. Most (93%) of the tumours showed HA staining in their parenchyma, whereas the stroma inside and around the tumour was stained in every case. When HA expression was compared with the clinical and histological features of the tumours, a strong staining intensity in the tumour parenchyma was found to be associated with deep tumour invasion (pT3 or 4) and with mixed type of Lauren. A high proportion of HA-positive cells of all neoplastic cells was significantly associated with deep tumour invasion, nodal metastasis, positive lymphatic invasion, poor differentiation grade, as well as with inferior prognosis in univariate survival analysis. However, in multivariate analysis, only pT, pN, and vascular and lymphatic invasion emerged as independent predictors of survival in gastric cancer. The results indicate that ectopic HA expression is a frequent feature of gastric adenocarcinoma, and is associated with tumour progression and poor survival rate. PMID- 10098748 TI - Elderly Japanese women with cervical carcinoma show higher proportions of both intermediate-risk human papillomavirus types and p53 mutations. AB - The p53 mutation has been found only in 0-6% of cervical carcinomas. In light of recent studies demonstrating that mutation of p53 gene was found in over 20% of the patients with vulvar carcinoma, a disease of elderly women and a known human papillomavirus (HPV)-related malignancy, we analysed mutation of the p53 gene in 46 women with cervical carcinomas at the age of 60 or more (mean; 71 years, range; 60-96 years). The presence of HPV and its type were analysed by polymerase chain reaction (PCR)-based assay using the consensus primers for L1 region. Mutation of the p53 gene was analysed by PCR-based single-strand conformation polymorphism and DNA sequencing technique. Point mutation of the p53 gene was detected in 5 out of 46 (11%) cervical carcinomas: 1 of 17 (6%) samples associated with high-risk HPVs (HPV 16 and HPV 18) and 4 of 27 samples (15%) with intermediate-risk HPVs (P= 0.36) whereas no mutation was found in 2 HPV negative cases. The mutated residues resided in the selective sequence known as a DNA binding domain. The immunohistochemistry revealed the overexpression in cancer tissues positive for p53 mutation. All of the observed mutations of the p53 gene were transition type, suggesting that the mutation may be caused by endogenous mutagenesis. Although falling short of statistical significance reduces the strength of the conclusion, data presented here imply that p53 gene mutation, particularly along with intermediate-risk HPV types, may constitute one pathogenetic factor in cervical carcinoma affecting elderly women. PMID- 10098749 TI - Thymidine phosphorylase/platelet-derived endothelial cell growth factor is upregulated in advanced solid types of gastric cancer. AB - Previous studies demonstrated that the immunohistochemical expression of thymidine phosphorylase (dThdPase) was related with distant metastasis and disease progression. In this study we investigated the production of dThdPase/platelet-derived endothelial cell growth factor in gastric cancer quantitatively. In a total of 75 tumour tissues and 60 normal gastric mucosa specimens, dThdPase protein concentrations were determined by ELISA. The amount of dThdPase was significantly higher in the tumour tissue than in the normal tissue. Intratumoural dThdPase concentrations were significantly higher in Borrmann types I and II macroscopically, in poorly differentiated and solid type histologically, in the medullary type of the tumour stroma, and in the tumour invading serosa. In the medullary type of the amount of tumour stroma, protein levels of dThdPase were positively correlated with the vertical diameter of the tumour (r = 0.580, P = 0.019). By immunohistochemical study, dThdPase expression on tumour cells was observed in all seven specimens with high dThdPase protein levels, but not in all 14 cases with low dThdPase protein levels (P < 0.05). In summary, these data indicated that dThdPase is up-regulated in advanced solid types of gastric cancer, suggesting that dThdPase production in carcinoma cells might be induced by the microenvironment. PMID- 10098750 TI - Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia. AB - Mutations of the p53 tumour suppressor gene are infrequent at presentation of both acute myeloblastic leukaemia (AML) and acute lymphoblastic leukaemia (ALL), being found in between 5-10% of AML and 2-3% of ALL. Here we have studied the frequency of detection of p53 mutations at relapse of both AML and B-precursor ALL. In those patients with detectable mutations at relapse we investigated whether the mutation was detectable at presentation and was thus an early initiating event or whether it had arisen as a late event associated with relapse. Bone marrow samples from 55 adults and children with relapsed AML (n = 41) or ALL (n = 14) were analysed for p53 gene alterations by direct sequencing of exons 5-9. For samples where a p53 mutation was found at relapse, analysis of presentation samples was carried out by direct sequencing of the exon involved, or by allele-specific polymerase chain reaction (PCR) if the mutation could not be detected using direct sequencing. A p53 mutated gene was found at relapse in seven out of 55 cases. The frequency was higher in relapsed ALL (four out of 14 cases; 28.6%) compared to AML (three out of 41 cases; 7.3%). In five out of the seven cases presentation samples were available to study for the presence of the mutation. In two out of two AML patients the p53 mutation was detectable in the presentation sample by direct sequencing. In three ALL patients analysis of presentation material by direct sequencing showed a small mutant peak in one case, the other two being negative despite the sample analysed containing > 90% blast cells. However in both of these patients, the presence of p53 mutation was confirmed in the presentation sample using allele-specific PCR. In one of these patients the emergence of a subclone at relapse was confirmed by clonality analysis using IgH fingerprinting. Our results confirm that in ALL p53 mutations are present in a proportion of patients at relapse. Furthermore cells carrying the mutation are detectable at presentation in a minor clone suggesting that p53 mutations in ALL may be a mechanism contributing to disease relapse. PMID- 10098751 TI - Phase II trial of topically applied miltefosine solution in patients with skin metastasized breast cancer. AB - Skin deposits from breast cancer can present serious therapeutic problems, especially when resistant to conventional therapy. Topical application of a cytotoxic drug may represent an attractive new treatment modality devoid of major systemic toxicity. Miltefosine was selected because of its efficacy in breast cancer models. A mixture of alkylated glycerols of various chain lengths and water was used as the pharmaceutical vehicle to dissolve and to further facilitate tissue penetration of miltefosine. In our Institute a phase II study was performed to determine the efficacy and tolerability of topically applied miltefosine in patients with cutaneous metastases from breast cancer. Thirty three patients in total entered the trial. A 6% miltefosine solution was applied once daily in the first week and twice daily in the following weeks. The planned minimum treatment duration was 8 weeks. We found an overall response rate of 43% for 30 evaluable patients, composed of 23% complete response and 20% partial response. The median response duration was 18 weeks, range 8-68. Toxicity consisted mainly of localized skin reactions, which could be controlled by a paraffin-based skin cream and, where appropriate, by dose modification. No systemic toxicities were observed. We conclude that topical miltefosine is an effective treatment modality in patients with skin metastases from breast cancer. PMID- 10098752 TI - The association between CD2+ peripheral blood lymphocyte subsets and the relapse of bladder cancer in prophylactically BCG-treated patients. AB - We investigated the potential existence of differences in the distribution of T lymphocyte subsets and in the proliferative response of these CD2+ cells to polyclonal mitogens in patients with transitional cell bladder carcinoma (SBTCC) treated with prophylactic intracavitary instillations of bacillus Calmette-Guerin (BCG) according to their clinical response to this treatment. Before BCG treatment, different subset distribution (CD8+ and CD3+ CD56+), activation antigen expression (CD3+ HLA- DR+) and proliferative response to mitogenic signals were found in CD2+ cells from SBTCC patients prophylactically treated with BCG who remained free of disease or those who had recurrence of tumour. Otherwise, the prophylactic intracavitary BCG instillations in SBTCC patients are associated with a transitory variation of T-lymphocyte subset distribution (CD4 and CD8) and activation antigens expression (CD25). PMID- 10098753 TI - Motility-related protein (MRP-1/CD9) and KAI1/CD82 expression inversely correlate with lymph node metastasis in oesophageal squamous cell carcinoma. AB - Although the mechanisms of action of the transmembrane superfamilies, motility related protein-1 (MRP-1/CD9) and KAI1/CD82, are not well known, they are reported to suppress the metastasis of several kinds of cancers. The suppression of cell motility by MRP-1/CD9 may cause suppression of the metastasis. As we could not find any reports concerning the expression of MRP-1/CD9 and KAI1/CD82 in oesophageal cancers we investigated their expression in oesophageal specimens. We conducted immunohistochemical staining for MRP1/CD9 against 108 cases of oesophageal squamous cell carcinoma using anti-MRP-1/CD9 monoclonal antibody M31 15, and for KAI1/CD82 against 104 cases using anti-KAI1/CD82 monoclonal antibody C33. To investigate the gradual expression of MRP-1/CD9 and KAI1/CD82, 24 oesophageal dysplasias were immunohistochemically stained using the same method and then investigated. The expression of both MRP-1/CD9 and KAI1/CD82 were positive on the cell membranes of normal oesophageal epithelial cells, but reduced or negative in the cancer cells. Reduced MRP-1/CD9 expressions significantly correlated to tumour depth (P = 0.0009). We found a significantly greater number of reduced or negative expression of MRP-1/CD9 and KAI1/CD82 in lymph node metastatic cases (P = 0.0003 and P= 0.0129, respectively), but not in distant metastatic cases. The 5-year survival rate of MRP-1/CD9-negative and reduced patients was significantly worse than those of positive patients (n = 108, curative cases, RO). Few cases remained KAI1/CD82-positive (9.6%; 10/104) in oesophageal cancer. Twenty (83.3%) and twenty-two (91.7%) cases out of 24 dysplasias were defined as KAI1/CD82-positive and MRP1/CD9-positive, respectively. The decrease in MRP-1/CD9 and KAI1/CD82 expression may facilitate lymph node metastasis in oesophageal squamous cell carcinomas. Knowing the status of the expression of MRP-1/CD9 appears helpful in predicting the prognosis for each patient. PMID- 10098754 TI - Ifosfamide/etoposide alternating with high-dose methotrexate: evaluation of a chemotherapy regimen for poor-risk osteosarcoma. AB - Fifteen patients with relapsed osteosarcoma were treated with an intensive combination chemotherapy schedule. Ifosfamide 2.5 g m(-2) daily and etoposide 150 mg m(-2) daily coincidentally for 3 days and high-dose methotrexate 8 g m(-2) (with folinic acid rescue) on days 10-14 in a planned 21 -day cycle. Feasibility, toxicity and response to this alternative combination for the treatment of relapsed osteosarcoma was assessed. There were 98 evaluable cycles for toxicity and tolerability. The majority of cycles were well tolerated. Haematological toxicity of grade 3/4 (common toxicity criteria) was seen in all courses. Renal tubular loss of electrolytes, particularly magnesium, occurred in 71% of cycles. Thirteen per cent of cycles were repeated within 21 days and 61% within 28 days. In the thirteen patients evaluable for response, a partial response rate of 31% was seen after two cycles. However, patients with stable disease continued on therapy, and an overall consequent response rate of 62% was observed. Four patients were alive with no evidence of disease at 8-74 months. Three are alive with disease (at 8-19 months). There were six deaths, all disease related. This regimen exhibits an encouraging response rate in a group of children with poor prognosis disease, with a tolerable toxicity profile. PMID- 10098755 TI - A high incidence of vertebral fracture in women with breast cancer. AB - Because treatment for breast cancer may adversely affect skeletal metabolism, we investigated vertebral fracture risk in women with non-metastatic breast cancer. The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population. The incidence of vertebral fracture, however, was nearly five times greater than normal in women from the time of first diagnosis [odds ratio (OR), 4.7; 95% confidence interval (95% CI), 2.3-9.9], and 20-fold higher in women with soft tissue metastases without evidence of skeletal metastases (OR, 22.7; 95% CI, 9.1 57.1). We conclude that vertebral fracture risk is markedly increased in women with breast cancer. PMID- 10098756 TI - Interleukin 10 (IL-10): an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma. AB - Interleukin 10 (IL-10) is an immunosuppressive factor and has been detected in tumour cell cultures of renal cell carcinoma and of malignant melanoma. IL-10 has been described as a cytokine of the Th2 response; it is able to suppress antigen presenting cells (APCs) and may lead to down-regulation of HLA class I and II molecules on dendritic cells and to anergy of T-lymphocytes. We evaluated pretreatment serum levels of soluble IL-10 and various clinical parameters to determine their prognostic value in 80 advanced renal cell carcinoma patients seen at our institution between May 1990 and April 1996. For statistical evaluation we used both univariate and multivariate Cox proportional hazards models. An elevated pretreatment serum level of IL-10 was a statistically independent predictor of unfavourable outcome (P < 0.0028), in addition to the well-known clinical and biochemical risk factors. These data support risk stratification for future therapeutic trials and identify a predictor which needs to be validated in prospective studies and may potentially influence decision making in palliative management of patients with metastatic renal cell carcinoma. These data also suggest a potential role of IL-10 in the development of advanced renal cell carcinoma and in the future design of therapeutic strategies. PMID- 10098757 TI - Overexpression of p53 protein in primary Ewing's sarcoma of bone: relationship to tumour stage, response and prognosis. AB - Biopsy tissues of 52 patients with Ewing's sarcoma of bone treated between 1983 and 1993 were examined immuno-histochemically to determine the significance of p53 protein in diagnosis and prognosis of Ewing's sarcoma. Mean age at diagnosis was 17 years (range 6-36) and minimum follow-up was 30 months. The tumours were located in the extremities and central bones in 35 and 17 patients respectively. Metastases were present in seven patients at diagnosis. Treatment consisted of chemotherapy, surgery and/or radiotherapy in all the patients. Overexpression of p53 protein was demonstrated in seven patients (14%). There was no relationship between expression of p53 and site of tumours. Patients who overexpressed p53 protein appeared to have more advanced diseases at diagnosis and poorer response to chemotherapy than those without p53 overexpression. The 5-year relapse-free survival and overall survival in patients without metastases at the time of diagnosis were 66% and 71%, respectively, in p53 protein-negative patients compared with 20% relapse-free and overall survival in those with p53 protein overexpression (P= 0.01). The poorer prognosis in p53 protein-positive patients was independent of site, local treatment or necrosis of the tumours (P < 0.05). Over-expression of p53 protein is an independent poor prognostic factor in Ewing's sarcoma of bone. PMID- 10098758 TI - Prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) in cytosols and pellet extracts derived from 892 breast cancer patients. AB - To evaluate the clinical relevance of urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) measured by a recently developed enzyme-linked immunosorbent assay (ELISA), we analysed both components in samples derived from 892 patients with primary breast cancer (median follow-up 99 months). The assays were performed in cytosolic extracts as well as in corresponding detergent extracts of pellets obtained after ultracentrifugation, which was carried out when preparing the cytosolic fractions for routine steroid hormone receptor determination. Statistically significant correlations were found between the cytosolic levels and those determined in the pellet extracts (Spearman correlation coefficient r = 0.60, P < 0.0001 for uPA and r = 0.65, P < 0.0001 for PAI-1). Furthermore, strong correlations were found between the levels of both uPA (r = 0.85, P < 0.0001) and PAI-1 (r = 0.90, P< 0.0001) in the cytosols and their levels previously measured with ELISAs based on commercial reagents. In both Cox univariate and multivariate analysis, high cytosolic levels of uPA or PAI-1 were significantly associated with increased rates of relapse and death. The levels of uPA and PAI-1 in the pellet extracts also provided prognostic information, although to a lesser extent compared with the cytosolic extracts. The prediction of prognosis on the basis of uPA and PAI-1 assessed by an alternative ELISA once again emphasizes the established prognostic role and usefulness of these parameters in selection of breast cancer patients at high or low risk of recurrence. PMID- 10098759 TI - Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience. Societe Francaise d'Oncologie Pediatrique. AB - Conventional therapy for intracranial germinomas is craniospinal irradiation. In 1990, the Societe Francaise d'Oncologie Pediatrique initiated a study combining chemotherapy (alternating courses of etoposide-carboplatin and etoposide ifosfamide for a recommended total of four courses) with 40 Gy local irradiation for patients with localized germinomas. Metastatic patients were allocated to receive low-dose craniospinal radiotherapy. Fifty-seven patients were enrolled between 1990 and 1996. Forty-seven had biopsy-proven germinoma. Biopsy was not performed in ten patients (four had diagnostic tumour markers and in six the neurosurgeon felt biopsy was contraindicated). Fifty-one patients had localized disease, and six leptomeningeal dissemination. Seven patients had bifocal tumour. All but one patient received at least four courses of chemotherapy. Toxicity was mainly haematological. Patients with diabetus insipidus (n = 25) commonly developed electrolyte disturbances during chemotherapy. No patient developed tumour progression during chemotherapy. Fifty patients received local radiotherapy with a median dose of 40 Gy to the initial tumour volume. Six metastatic patients, and one patient with localized disease who stopped chemotherapy due to severe toxicity, received craniospinal radiotherapy. The median follow-up for the group was 42 months. Four patients relapsed 9, 10, 38 and 57 months after diagnosis. Three achieved second complete remission following salvage treatment with chemotherapy alone or chemo-radiotherapy. The estimated 3 year survival probability is 98% (CI: 86.6-99.7%) and the estimated 3-year event free survival is 96.4% (CI: 86.2-99.1%). This study shows that excellent survival rates can be achieved by combining chemotherapy and local radiotherapy in patients with non-metastatic intracranial germinomas. PMID- 10098760 TI - Prognostic implications of various models for calculation of S-phase fraction in 259 patients with soft tissue sarcoma. AB - The S-phase fraction (SPF) in flow cytometric DNA histograms in soft tissue sarcoma (STS) can be calculated in various ways. The traditional planimetric method of Baisch has been shown to be prognostic, but is hampered by a failure rate of around 40%. We therefore tested other models to see if this rate could be decreased with retained prognostic value. In 259 STS of the locomotor system the SPF was calculated according to Baisch and with commercial parametric MultiCycle software using different corrections for background. Using the Baisch model, 159 histograms could be evaluated for SPF. The 5-year metastasis-free survival rate (MFSR) was 0.94 for the low-risk group (defined with SPF), and 0.53 for the high risk group. In the low-risk group, four of the seven patients who developed metastasis did so after 5 years Using the MultiCycle software, SPF could be calculated in 253 tumours. Depending on type of background correction used, the 5 year MFSR varied between 0.67 and 0.82 for the low-risk group, and between 0.47 and 0.53 for the high-risk group. The late metastasis pattern in the low-risk group was never seen using the MultiCycle software. We conclude that in paraffin archival material, calculation of SPF according to Baisch is preferable in clinical use due to better separation between low-risk and high-risk groups, and also the possibility to identify patients who metastasize late. PMID- 10098761 TI - European randomized study of prostate cancer screening: first-year results of the Finnish trial. AB - Approximately 20000 men 55-67 years of age from two areas in Finland were identified from the Population Registry and randomized either to the screening arm (1/3) or the control arm (2/3) of a prostate cancer screening trial. In the first round, the participation rate in the screening arm was 69%. Of the 5053 screened participants, 428 (8.5%) had a serum prostate-specific antigen (PSA) concentration of 4.0 ng/ml or higher, and diagnostic examinations were performed on 399 of them. A total of 106 cancers were detected among them corresponding to a positive predictive value of 27%, which is comparable with mammography screening for breast cancer. The prostate cancer detection rate based on a serum PSA concentration of 4.0 ng ml(-1) or higher was 2.1%. Approximately nine out of ten screen-detected prostate cancers were localized (85% clinical stage T1-T2) and well or moderately differentiated (42% World Health Organization (WHO) grade I and 50% grade II), which suggests a higher proportion of curable cancers compared with cases detected by other means. PMID- 10098762 TI - Cladribine with cyclophosphamide and prednisone in the management of low-grade lymphoproliferative malignancies. AB - The feasibility of combining cladribine with cyclophosphamide and prednisone in the management of indolent lymphoid malignancies was determined. Nineteen patients [nine chronic lymphocytic leukaemia (CLL), seven non-Hodgkin's lymphoma (NHL) and three macroglobulinaemia (M))] received cladribine 0.1 mg kg(-1) per day as a subcutaneous bolus injection on days 1-3 (up to 5 injections) with intravenous cyclophosphamide 500 mg m(-2) on day 1 and oral prednisone 40 mg (m 2) on days 1-5 at 4-weekly intervals up to a maximum of six courses. A total of 80 courses were given. Overall response rate was 88%, with four patients achieving a complete clinical and haematological response and 12 achieving a partial response. Neutropenia WHO grade 4 in two patients and WHO grade 3 infection in one patient were the limiting toxicities on treatment. During the follow-up, WHO grade >3 haematological complications occurred in five patients and WHO grade >3 non-haematological complications in five patients. There were no treatment-related deaths. This study demonstrates the feasibility of the cladribine/cyclophosphamide/prednisone (CCP) combination that appears highly active and safe in the management of indolent lymphoid malignancies. PMID- 10098763 TI - Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. AB - The present study investigated the interaction between c-erbB2 overexpression and the response to first-line endocrine therapy in patients with advanced breast cancer. The primary tumours of 241 patients who were treated at first relapse with endocrine therapy were assessed for overexpression of c-erbB2 by immunohistochemistry. c-erbB2 was overexpressed in 76 (32%) of primary breast cancers and did not correlate with any other prognostic factor. The overall response to treatment and time to progression were significantly lower in patients with c-erbB2-positive tumours compared to those that were c-erbB2 negative (38% vs 56%, P = 0.02; and 4.1 months vs 8.7 months, P < 0.001, respectively). In multivariate analysis, c-erbB2 status was the most significant predictive factor for a short time to progression (P = 0.0009). In patients with ER-positive primary tumours treated at relapse with tamoxifen (n = 170), overexpression of c-erbB2 was associated with a significantly shorter time to progression (5.5 months vs 11.2 months, P < 0.001). In conclusion, overexpression of c-erbB2 in the primary tumour is an independent marker of relative resistance to first-line endocrine therapy in patients with advanced breast cancer. In patients with ER-positive primary tumours, the overexpression of c-erbB2 defines a subgroup less likely to respond to endocrine therapy. PMID- 10098764 TI - Follow-up of breast cancer in primary care vs specialist care: results of an economic evaluation. AB - A randomized controlled trial (RCT) comparing primary-care-centred follow-up of breast cancer patients with the current standard practice of specialist-centred follow-up showed no increase in delay in diagnosing recurrence, and no increase in anxiety or deterioration in health-related quality of life. An economic evaluation of the two schemes of follow-up was conducted concurrent with the RCT Because the RCT found no difference in the primary clinical outcomes, a cost minimization analysis was conducted. Process measures of the quality of care such as frequency and length of visits were superior in primary care. Costs to patients and to the health service were lower in primary care. There was no difference in total costs of diagnostic tests, with particular tests being performed more frequently in primary care than in specialist care. Data are provided on the average frequency and length of visits, and frequency of diagnostic testing for breast cancer patients during the follow-up period. PMID- 10098765 TI - Tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA is elevated in advanced stages of thyroid carcinoma. AB - Tumour cell invasion and metastasis is a multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative regulators of MMPs and thus prevent tumour cell invasion and metastasis by preserving extracellular matrix (ECM) integrity. In the present study we examined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour specimens and two thyroid carcinoma cell lines (NPA and SW579). We also investigated the effect of high TIMP-1 expression on the invasive potential of NPA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcripts was found in stages III and IV vs benign goitre (P < 0.0001). However, TIMP-1 expression was not increased in NPA and SW579 cells, both of which are derived from poorly differentiated thyroid tumours. Immunohistochemical study showed strong TIMP-1 staining in the stroma cells of advanced stages of carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a significant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of TIMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyroid tumour invasion/metastasis suppressor. PMID- 10098766 TI - The expression of CCAAT/enhancer binding protein (C/EBP) in the human ovary in vivo: specific increase in C/EBPbeta during epithelial tumour progression. AB - The CCAAT/enhancer binding protein (C/EBP) family of transcription factors is involved in metabolism and differentiation of cells, especially in rodent liver cells and adipocytes. Their roles in vivo and in particular during pathophysiological conditions in humans are largely unknown. We have investigated the presence of C/EBPalpha, -beta, -delta and -zeta in normal ovaries and in epithelial ovarian tumours of different stages. Immunohistochemical experiments demonstrated that C/EBPalpha and C/EBPbeta were preferentially expressed in epithelial/tumour cells irrespective of stage or grade of the tumour. C/EBPbeta was located in the nuclei of the cells, in contrast to C/EBPalpha, which was present only in the cytoplasm of these cells. The nuclear localization of C/EBPbeta indicates an active role of this transcription factor in tumour cells, whereas the cytoplasmic distribution suggests a more passive function of C/EBPalpha. C/EBPdelta and -zeta demonstrated a more diverse distribution with predominant localization to epithelial cells, but stromal distribution was also noted. The intracellular distribution was confined to both the nucleus and the cytoplasm for C/EBPdelta and -zeta. Western blotting demonstrated that C/EBPalpha, -beta, -delta and -zeta were present in a majority of the samples. The amount of C/EBPbeta increased markedly with malignancy, i.e. with degree of dedifferentiation, while the other members of the C/EBP family displayed a more constant expression level. These results demonstrate an association between the expression of members of the C/EBP family and the formation of epithelial ovarian tumours, with C/EBPbeta as a potential marker for these tumours. As C/EBPbeta is known to be expressed during proliferation of cells in vitro, it may participate in the proliferative process of ovarian epithelial tumour cells in vivo and play a central role in tumour progression. PMID- 10098767 TI - Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers. AB - Angiogenesis contributes to the growth and secondary spreading of solid tumours. Platelet-derived endothelial cell growth factor (PD-ECGF) is identified as such an angiogenic factor. In the present study, the prognosis of the patients with high PD-ECGF uterine cervical cancers was worse than those with low PD-ECGF cancers, and PD-ECGF expression correlated with cellular proliferation and with vascular density and venous invasion in uterine cervical cancers. Therefore, PD ECGF might contribute to the growth of uterine cervical cancers via angiogenesis related to vascular spreading. Furthermore, PD-ECGF and its mRNA had a wide range and were highly expressed in uterine cervical cancers, especially squamous cell carcinoma, regardless of clinical stage. Therefore, PD-ECGF in uterine cervical cancers might play a role of basic angiogenesis in all processes of advancing of uterine cervical cancers. This indicates that 5'-deoxy-5-fluorouridine might be highly effective in squamous cell carcinoma of the cervix, which possesses a high activity of thymidine phosphorylase to convert 5'-deoxy-5-fluorouridine to 5 fluorouracil, and that some angiogenic inhibitors of new capillary formation might be effective in the inhibition of tumour growth and spreading associated with angiogenesis. PMID- 10098768 TI - Prognostic value of p53 protein expression for patients with gastric cancer--a multivariate analysis. AB - Mutations in the p53 gene, one of the most common genetic alterations in human cancer, are implicated in tumorigenesis and tumour progression. Although p53 protein expression appears to be correlated to prognosis in patients with malignancy, its prognostic role in gastric cancer has remained controversial. We examined the clinical significance of p53 overexpression in 427 patients with gastric cancer, using multivariate analysis. Tumour sections of gastric cancer tissues from these 427 Japanese patients were stained immunohistochemically with monoclonal antibody PAb1801. The presence of p53 expression was statistically compared with clinicopathological features and post-operative survival, using univariate and multivariate analyses. p53 expression was detected in 38.6% (165 out of 427) of these gastric cancers and immunoreactivity was not observed in normal mucosa adjacent to the tumour. A higher rate of p53 detection was observed among large tumours and in those with a prominent depth of invasion, lymphatic and vascular invasion and lymph node involvement. Prognosis was significantly worse for patients with p53-positive-staining tumours. The 5-year survival rate was 62.5% for patients with p53-negative tumours and 43.3% for those with positive malignancies. p53 expression was a significant prognostic factor for node-positive gastric cancers in subjects undergoing treatment with curative resection, as assessed by Cox regression analysis. Thus, the expression of p53 was closely related to the potential for tumour advance and a poorer post operative prognosis for patients with gastric cancer. PMID- 10098769 TI - FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas. AB - Colorectal carcinoma cells have recently been shown to express Fas ligand (FasL). This ligand could allow the tumour cells to evade activated tumour-infiltrating lymphocytes (TILs) by inducing their apoptosis and would thus promote tumour survival and possibly metastasis formation. To test this hypothesis in vivo we analysed the expression of FasL mRNA and protein in paired tissue samples of normal colonic mucosa (N), primary colorectal carcinomas (T) and their metastases (M) from a total of 21 patients by four different methods. Additionally, the presence and activation status of infiltrating lymphocytes, which might contribute to the total amount of FasL in the tissue, was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) in the same samples. The frequency of FasL detection was 30-40% in T and was 60-100% in M, depending on the sensitivity of the method. Simultaneously, the amount of CD25 mRNA, used as a measure of the number of activated TILs, was in 90% of patients lower in M than in T. The increased frequency of FasL detection in liver metastases was therefore not due to the presence of activated TILs. We conclude that metastasizing subpopulations of colorectal tumour cells express FasL more frequently than the primary carcinomas and may be able to eliminate activated TILs in vivo via Fas/FasL-induced apoptosis or other hitherto unknown mechanisms. PMID- 10098770 TI - Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role? AB - In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy. PMID- 10098771 TI - Is sunlight an aetiological agent in the genesis of retinoblastoma? AB - The incidence of unilateral, but not bilateral, retinoblastoma in human populations at different geographical locations increases significantly with ambient erythemal dose of ultraviolet B radiation from sunlight. This supports the hypothesis that sunlight plays a role in retinoblastoma formation. PMID- 10098772 TI - Cancer mortality in East and Southeast Asian migrants to New South Wales, Australia, 1975-1995. AB - Routinely collected data for New South Wales were used to analyse cancer mortality in migrants born in East or Southeast Asia according to duration of residence in Australia. A case-control approach compared deaths from cancer at particular sites with deaths from all other cancers, adjusting for age, sex and calendar period. Compared with the Australian-born, these Asian migrants had a 30 fold higher risk of dying from nasopharyngeal cancer in the first 2 decades of residence, falling to ninefold after 30 years, and for deaths from liver cancer, a 12-fold risk in the first 2 decades, falling to threefold after 30 years. The initial lower risk from colorectal, breast or prostate cancers later converged towards the Australian-born level, the change being apparent in the third decade after migration. The relative risk of dying from lung cancer among these Asian migrants was above unity for each category of duration of stay for women, but at or below unity for men, with no trend in risk over time. An environmental or lifestyle influence for nasopharyngeal and liver cancers is suggested as well as for cancers of colon/rectum, breast and prostate. PMID- 10098773 TI - Food groups and colorectal cancer risk. AB - Most studies of diet and colorectal cancer have considered nutrients and micronutrients, but the role of foods or food groups remains open to debate. To elucidate the issue, we examined data from a case-control study conducted between 1992 and 1997 in the Swiss canton of Vaud. Cases were 223 patients (142 men, 81 women) with incident, histologically confirmed colon (n= 119) or rectal (n= 104) cancer (median age 63 years), linked with the Cancer Registry of the Swiss Canton of Vaud, and controls were 491 subjects (211 men, 280 women, median age 58 years) admitted to the same university hospital for a wide spectrum of acute non neoplastic conditions unrelated to long-term modifications of diet. Odds ratios (OR) were obtained after allowance for age, sex, education, smoking, alcohol, body mass index, physical activity and total energy intake. Significant associations were observed for refined grain (OR = 1.32 for an increase of one serving per day), and red meat (OR = 1.54), pork and processed meat (OR = 1.27), alcohol (OR = 1.28), and significant protections for whole grain (OR = 0.85), raw (OR = 0.85) and cooked vegetables (OR = 0.69), citrus (OR = 0.86) and other fruits (OR = 0.85), and for coffee (OR = 0.73). Garlic was also protective (OR = 0.32 for the highest tertile of intake). These findings in a central European population support the hypothesis that a diet rich in refined grains and red meat increases the risk of colorectal cancer; they, therefore, support the recommendation to substitute whole grains for refined grain, to limit meat intake, and to increase fruit and vegetable consumption. PMID- 10098774 TI - Cancer mortality and morbidity among plutonium workers at the Sellafield plant of British Nuclear Fuels. AB - The mortality of all 14 319 workers employed at the Sellafield plant of British Nuclear Fuels between 1947 and 1975 was studied up to the end of 1992, and cancer incidence was examined from 1971 to 1986, in relation to their exposures to plutonium and to external radiation. The cancer mortality rate was 5% lower than that of England and Wales and 3% less than that of Cumbria. The significant excesses of deaths from cancer of the pleura and thyroid found in an earlier study persist with further follow-up (14 observed, 4.0 expected for pleura; 6 observed, 2.2 expected for thyroid). All of the deaths from pleural cancer were among radiation workers. For neither site was there a significant association between the risk of the cancer and accumulated radiation dose. There were significant deficits of deaths from cancers of mouth and pharynx, liver and gall bladder, and larynx and leukaemia when compared with the national rates. Among all radiation workers, there was a significant positive association between accumulated external radiation dose and mortality from cancers of ill-defined and secondary sites (10-year lag, P = 0.04), leukaemia (no lag, P = 0.03; 2-year lag, P = 0.05), multiple myeloma (20-year lag, P = 0.02), all lymphatic and haematopoietic cancers (20-year lag, P= 0.03) and all causes of death combined (20-year lag, P= 0.008). Among plutonium workers, there were significant excesses of deaths from cancer of the breast (6 observed, 2.6 expected) and ill-defined and secondary cancers (29 observed, 20.1 expected). No significant positive trends were observed between the risk of deaths from cancers of any specific site, or all cancers combined, and cumulative plutonium and external radiation doses. For no cancer site was there a significant excess of cancer registrations compared with rates for England and Wales. Analysis of trends in cancer incidence showed significant increases in risk with cumulative plutonium plus external radiation doses for all lymphatic and haematopoietic neoplasms for 0-, 10- and 20 year lag periods. Taken as a whole, our findings do not suggest that workers at Sellafield who have been exposed to plutonium are at an overall significantly increased risk of cancer compared with other radiation workers. PMID- 10098775 TI - Prevalence of BRCA1 and BRCA2 Jewish mutations in Spanish breast cancer patients. AB - We screened the 185delAG and 5382insC (BRCA1) and the 6174delT (BRCA2) mutation in 298 Spanish women with breast cancer. Two women (one with Sephardic ancestors) presented the 185delAG mutation and the same haplotype reported in Ashkenazim with this mutation. This suggests a common origin of the 185delAG in both Sephardic and Ashkenazi populations. PMID- 10098776 TI - Risk of breast cancer and other cancers in heterozygotes for ataxia telangiectasia. AB - Mortality from cancer among 178 parents and 236 grandparents of 95 British patients with ataxia-telangiectasia was examined. For neither parents nor grandparents was mortality from all causes or from cancer appreciably elevated over that of the national population. Among mothers, three deaths from breast cancer gave rise to a standardized mortality ratio of 3.37 (95% confidence interval (CI): 0.69-9.84). In contrast, there was no excess of breast cancer in grandmothers, the standardized mortality ratio being 0.89 (95% CI: 0.18-2.59), based on three deaths. This is the largest study of families of ataxia telangiectasia patients conducted in Britain but, nonetheless, the study is small and CIs are wide. However, taken together with data from other countries, an increased risk of breast cancer among female heterozygotes is still apparent, though lower than previously thought. PMID- 10098778 TI - Swimming-associated outbreak of Escherichia coli O157:H7. AB - In 1997 the first outbreak of Escherichia coli O157:H7 infections involving 14 cases occurred in Finland. A case was defined as a resident of Alavus with an episode of diarrhoea between 5 and 17 July 1997, and from whom E. coli O157:H7 was isolated from stool. The investigation included case searching and a population-based case control study. Five primary and eight symptomatic secondary cases of E. coli O157:H7 illness were detected. In the 10 days before the outbreak, all 5 primary patients (aged 3-8 years), but only 6 of 32 population controls from the same age range (Fisher's test, P < 0.001) and 4 of 10 sibling controls (P < 0.05) had visited (but had not necessarily bathed in) a shallow beach popular among young children. Four out of 5 primary cases had remained within 5 m of the beach while swimming and had swallowed lake water compared to 1 of 5 population controls. These analytical epidemiologic findings incriminated fresh lake water as the vehicle of E. coli O157:H7 transmission. PMID- 10098777 TI - Alcohol consumption and breast cancer oestrogen and progesterone receptor status. AB - We examined the role of alcohol on the risk of breast cancer by the joint oestrogen receptor (ER) and progesterone receptor (PR) status of the tumour using data from two case-control studies conducted in Los Angeles County, USA. Eligible premenopausal patients were 733 women aged < or =40 years and first diagnosed from 1 July 1983 to 1 January 1989. Eligible postmenopausal patients were 1169 women aged 55-64 years and first diagnosed from 1 March 1987 to 31 December 89. Patients were identified by the University of Southern California Cancer Surveillance Program. Neighbourhood controls were individually matched to patients by parity (premenopausal patients) and birth date (+/-3 years). ER and PR status were obtained from medical records for 424 premenopausal and 760 postmenopausal patients. The analyses included 714 premenopausal and 1091 postmenopausal control subjects. Alcohol use was generally not associated with premenopausal risk of breast cancer, regardless of hormone-receptor status. Among the postmenopausal women, those who consumed, on average, > or =27 g of alcohol/d experienced an odds ratio (OR) of 1.76 [95% confidence interval (CI) 1.14-2.71] for ER-positive/PR-positive breast cancer relative to women who reported no alcohol consumption. Alcohol use was less clearly associated with risk of other receptor types among postmenopausal women. These data suggest that alcohol may preferentially increase risk of ER-positive/PR-positive breast cancer in postmenopausal women. PMID- 10098779 TI - Presence of Campylobacter and Salmonella in sand from bathing beaches. AB - The purpose of this study was to determine the presence of thermophilic Campylobacter spp. and Salmonella spp. in sand from non-EEC standard and EEC standard designated beaches in different locations in the UK and to assess if potentially pathogenic strains were present. Campylobacter spp. were detected in 82/182 (45%) of sand samples and Salmonella spp. in 10/182 (6%). Campylobacter spp. were isolated from 46/92 (50%) of samples from non-EEC standard beaches and 36/90 (40%) from EEC standard beaches. The prevalence of Campylobacter spp. was greater in wet sand from both types of beaches but, surprisingly, more than 30% of samples from dry sand also contained these organisms. The major pathogenic species C. jejuni and C. coli were more prevalent in sand from non-EEC standard beaches. In contrast, C. lari and urease positive thermophilic campylobacters, which are associated with seagulls and other migratory birds, were more prevalent in sand from EEC standard beaches. Campylobacter isolates were further characterized by biotyping and serotyping, which confirmed that strains known to be of types associated with human infections were frequently found in sand on bathing beaches. PMID- 10098780 TI - The risk of Guillain-Barre syndrome following infection with Campylobacter jejuni. AB - To estimate the incidence of Guillain-Barre syndrome (GBS) following Campylobacter jejuni infection (CI) we studied three populations where outbreaks of CI had occurred involving an estimated 8000 cases. No case of GBS was detected in the 6 months following the outbreaks in the local populations. The point estimate for the risk of GBS following CI estimated in this study was 0 in 8000 (95% confidence interval 0-3). PMID- 10098781 TI - Phage type conversion in Salmonella enterica serotype Enteritidis caused by the introduction of a resistance plasmid of incompatibility group X (IncX). AB - The plasmid pOG670, a 54 kb, conjugative plasmid that specifies resistance to ampicillin and kanamycin and belonging to the incompatibility group X (IncX), was transferred into 10 isolates of Salmonella enterica serotype Enteritidis belonging to 10 different phage types (PT1, 2, 3, 4, 8, 9, 9b, 10, 11 and 13). Acquisition of the plasmid by these strains did not result in the loss of any resident plasmids but resulted in phage type conversion in 8 of the 10 strains (PT1, 2, 4, 8, 9, 9b, 10 and 11). The observed changes in phage type were found to result from the loss of sensitivity to 3 of the 10 typing phages used (phages 3, 5 and 7). Where the conversion resulted in a change to a defined phage type, both the new and original PTs belonged to the same, previously described, evolutionary lines. Enteritidis PTs 1, 4 and 8, commonly associated with poultry world-wide, were converted to PTs 21, 6 and 13a respectively. The results indicate a different route for phage type conversion Enteritidis from others reported in the literature and, although IncX plasmids are not normally present in PT8 or PT13a, may suggest a possible mechanism/link connecting these phage types. PMID- 10098782 TI - Enteropathogenic bacteria in faecal swabs of young children fed on lactic acid fermented cereal gruels. AB - The influence of consumption of a lactic acid-fermented cereal gruel togwa with pH < or = 4 on the presence of faecal enteric bacteria such as campylobacter, enterohaemorrhagic Escherichia coli (EHEC:O157), enterotoxigenic Escherichia coli (ETEC), salmonella and shigella was evaluated. Under 5 years old healthy children listed in an ascending order of age were alternatively assigned and given either a lactic-acid fermented cereal gruel togwa (test diet) or an unfermented cereal gruel uji (control diet) once a day for 13 consecutive days. The presence of the enteropathogens was examined in rectal swabs collected from the children at baseline (before feeding session started), on days 7 and 13, and additionally 14 days (follow-up day) after the feeding session had stopped. The swabs were cultured on to different optimal media for respective enteropathogen and confirmed by standard microbiological and serological methods. Campylobacter spp. dominated among the enteropathogens (62% out of total) followed by Salmonella spp., ETEC and Shigella spp. Children with isolated enteropathogens in the togwa group was significantly reduced (P < 0.001) from 27.6% at baseline to 7.8, 8.2 and 12.7% on days 7, 13 and follow-up day, respectively. The effect was more pronounced in those children taking togwa > 6 times during the study period. In the control group, there was a slight decrease from 16.7% at baseline to 11.4% on day 7 and 8.1% on day 13. On the follow-up day, enteropathogens were found in 22.6% of the children, which was significantly higher than in those children taking togwa > 6 times. We conclude, that regular consumption of togwa with pH < or = 4, once a day, three times a week may help to control intestinal colonization with potential diarrhoea-causing pathogens in young children. PMID- 10098783 TI - Molecular typing of Salmonella serotype Thompson strains isolated from human and animal sources. AB - One-hundred-and-thirteen isolates of Salmonella serotype Thompson from diverse sources in seven countries were characterized by PvuII ribotyping and IS200 fingerprinting. Ten PvuII ribotypes were observed. The predominant PvuII ribotype 1 represented a major clone of world-wide distribution but was not found in Australia; PvuII ribotypes 2 and 3 represented minor clones. HincII ribotyping discriminated subtypes within PvuII ribotype 1: HincII ribotype 1 was distributed widely but HincII ribotype 2 was found mainly in Scottish isolates. None of 101 isolates of PvuII ribotypes 1-3 contained copies of IS200. All 12 isolates of PvuII ribotypes 4-10 were from Australia and 7 of them contained copies of IS200 of 5 different profiles. These results suggest the existence of at least two lineages of Salmonella Thompson with a different geographical distribution. The finding that most isolates from man and poultry in Scotland belonged to the same ribotype (PvuII 1/HincII 2) and were IS200-negative suggests that poultry is an important source of human infection in Scotland. PMID- 10098784 TI - Is group C meningococcal disease increasing in Europe? A report of surveillance of meningococcal infection in Europe 1993-6. European Meningitis Surveillance Group. AB - A surveillance system to assess the impact and changing epidemiology of invasive meningococcal disease in Europe was set up in 1987. Since about 1991, contributors from national reference laboratories, national communicable disease surveillance centres and institutes of public health in 35 European countries provided information on all reported cases of meningococcal disease in their country. We describe some trends observed over the period 1993-6. The main findings were: the overall incidence of meningococcal disease was 1.1 per 100000 population but there was some evidence of a slow increase over time and with northern European countries tending to have a higher incidence (Kendall correlation 0.5772, P < 0.001), an increasing predominance of serogroup C, and a shift in the age distribution towards teenagers and away from younger children (chi2 test for trend 44.56, P < 0.0001), although about half of the cases were under 5 years of age. The overall case fatality rate was 8.3% and the most common serosubtypes were B:15:P1.7,16 and C:2a:P1.2,5. PMID- 10098785 TI - Factors associated with pharyngeal carriage of Neisseria meningitidis among Israel Defense Force personnel at the end of their compulsory service. AB - In this 1 year cross-sectional study of personnel being discharged from compulsory military service, an available database of health-related information was used to examine the association of meningococcal carriage with socio demographic factors. A representative, systematic sample of 1632 personnel was interviewed and had throat cultures taken. The overall meningococcal carriage rate was 16%. Serogroups B and Y accounted for 76% and 13% of the isolates respectively. In univariate analysis, carriage was associated with male gender (P < 0.0001), < 12 years school education (P = 0.002), smoking (P = 0.014), and service at a 'closed' base, reflecting greater interpersonal contact (P < 0.0001). In multivariate analysis, only service on a closed base and male gender retained significance. School education of < 12 years remained significant for females only. Variables not associated with carriage included number of siblings, intensity of smoking, and use of the contraceptive pill. In this setting, meningococcal carriage was associated with the type of base on which soldiers served; and smoking was not an independent risk factor for carriage. PMID- 10098786 TI - Clinical and epidemiological features of group A streptococcal bacteraemia in a region with hyperendemic superficial streptococcal infection. AB - Reports of increasing incidence and severity of invasive group A streptococcal (GAS) infections come mainly from affluent populations where exposure to GAS is relatively infrequent. We conducted a 6-year retrospective review of GAS bacteraemia in the Northern Territory of Australia, comparing the Aboriginal population (24% of the study population), who have high rates of other streptococcal infections and sequelae, to the non-Aboriginal population. Of 72 episodes, 44 (61%) were in Aboriginal patients. All 12 cases in children were Aboriginal. Risk factors were implicated in 82% of episodes (91% in adults) and there was no significant difference in the proportion of Aboriginal compared to non-Aboriginal patients with at least one risk factor. Genetic typing of isolates revealed no dominant strains and no evidence of a clone which has been a common cause of these infections elsewhere. PMID- 10098787 TI - Proteinuria is associated with persistence of antibody to streptococcal M protein in Aboriginal Australians. AB - Aboriginal communities in Northern Australia with high rates of group A streptococcal (GAS) skin infection in childhood also have high rates of renal failure in adult life. In a cross-sectional study of one such high risk community, albuminuria was used as a marker of renal disease. The prevalence of albuminuria increased from 0/52 in subjects aged 10-19 years to 10/29 (32.9%) in those aged 50 or more (P < 0.001). Antibodies to streptococcal M protein, markers of past GAS infection, were present in 48/52 (92%) at ages 10-19 years, 16/32 (50%) at ages 30-39, and 20/29 (69%) in those aged 50 or more. After allowing for the age-dependencies of albuminuria and of M protein antibodies (P < 0.001) albuminuria was significantly associated with M protein antibodies (P < 0.01). Thus, 72% of adults aged 30 or more with M protein antibodies also had albuminuria, compared with only 21% of those who were seronegative. More detailed modelling suggested that although most Aboriginal people in this community developed M protein antibodies following GAS infection in childhood, the development of proteinuria was associated with the persistence of such seropositivity into adult life. The models predicted that proteinuria developed at a mean age of 30 years in seropositive persons, at 45 years in seronegative persons who were overweight, and at 62 years in seronegative persons of normal weight. We demonstrated a clear association between evidence of childhood GAS infection and individual risk of proteinuria in adult life. This study provided a strong rationale for prevention of renal disease through the more effective control of GAS skin infections in childhood and through the prevention of obesity in adult life. PMID- 10098788 TI - Epidemiology of Streptococcus pneumoniae infection in Malaysia. AB - During a 1-year period from October 1995 to September 1996, 273 isolations of Streptococcus pneumoniae were made from various types of clinical specimens. The majority of the isolates (39.2%) were from sputum whilst 27.5% were from blood, CSF and other body fluids. The organism was isolated from patients of all age groups, 31.1% from children aged 10 years and below, 64.7% of which come from children aged 2 years or below. The majority of the isolates belong to serotypes 1, 6B, 19B, 19F and 23F. Serotypes 1 and 19B were the most common serotypes associated with invasive infection. About 71.9% of the invasive infections were due to serotypes included in the available 23 valent polysaccharide vaccine. The rates of resistance to penicillin and erythromycin were 7.0 and 1.1% respectively. Our findings show that the serotypes of S. pneumoniae causing most invasive infections in Malaysia are similar to those in other parts of the world and the available vaccine may have a useful role in this population. PMID- 10098789 TI - Diarrhoea prevention in Bolivia through point-of-use water treatment and safe storage: a promising new strategy. AB - A novel water quality intervention that consists of point-of-use water disinfection, safe storage and community education was field tested in Bolivia. A total of 127 households in two periurban communities were randomized into intervention and control groups, surveyed and the intervention was distributed. Monthly water quality testing and weekly diarrhoea surveillance were conducted. Over a 5-month period, intervention households had 44% fewer diarrhoea episodes than control households (P = 0.002). Infants < 1 year old (P = 0.05) and children 5-14 years old (P = 0.01) in intervention households had significantly less diarrhoea than control children. Campylobacter was less commonly isolated from intervention than control patients (P = 0.02). Stored water in intervention households was less contaminated with Escherichia coli than stored water in control households (P < 0.0001). Intervention households exhibited less E. coli contamination of stored water and less diarrhoea than control households. This promising new strategy may have broad applicability for waterborne disease prevention. PMID- 10098790 TI - Active infection with Helicobacter pylori in healthy couples. AB - The mode of spread of Helicobacter pylori infection is subject to ongoing debate. Recent studies among patients with gastrointestinal disorders suggest a potential role of conjugal transmission. In this study, the clustering of H. pylori infection was assessed among 110 employees of a health insurance company and their partners. Active infection with H. pylori was measured by the 13C-urea breath test. Information on potential confounders was collected by a standardized questionnaire. Overall, 16 employees (14.5%) and 24 partners (21.8%) were infected. While only 7% (6/86) of employees with an uninfected partner were infected, this applied to 42% (10/24) of employees with an infected partner. A very strong relation between partners' infection status persisted after control for age and other potential confounders (adjusted odds ratio, 7.0; 95% confidence interval, 1.8-26.7). Furthermore, the risk of infection increased with the number of years lived with an infected partner. These results support the hypothesis of a major role of spouse-to-spouse transmission of H. pylori infection. PMID- 10098791 TI - Assessing the sensitivity of STD surveillance in the Netherlands: an application of the capture--recapture method. AB - The capture-recapture method was used to estimate the sensitivity of case finding in two national STD surveillance systems: (1) STD registration at municipal health services (STD-MHS); (2) statutory notification by clinicians (NNS). To identify those cases common to both surveillance systems, cases from 1995 were compared using individual identifiers. Estimated sensitivities for syphilis were: STD-MHS 31% (95% CI: 27-35%), NNS 64% (56-71%); and for gonorrhoea: STD-MHS 15% (14-18%), NNS 22% (19-25%). The combined sensitivity of both systems was 76% for syphilis and 34% for gonorrhoea. Differences in the sensitivity of the systems were significant. The NNS was more sensitive than the STD-MHS, and the identification of cases was significantly more sensitive for syphilis than for gonorrhoea. A stratified analysis showed comparable results for the two sexes. Knowledge on the sensitivity of surveillance systems is useful for public health decisions and essential for international comparisons. PMID- 10098792 TI - Automated outbreak detection: a quantitative retrospective analysis. AB - An automated early warning system has been developed and used for detecting clusters of human infection with enteric pathogens. The method used requires no specific disease modelling, and has the potential for extension to other epidemiological applications. A compound smoothing technique is used to determine baseline 'normal' incidence of disease from past data, and a warning threshold for current data is produced by combining a statistically determined increment from the baseline with a fixed minimum threshold. A retrospective study of salmonella infections over 3 years has been conducted. Over this period, the automated system achieved > 90% sensitivity, with a positive predictive value consistently > 50%, demonstrating the effectiveness of the combination of statistical and heuristic methods for cluster detection. We suggest that quantitative measurements are of considerable utility in evaluating the performance of such systems. PMID- 10098793 TI - Epidemiology of Chlamydia pneumoniae infection in a randomly selected population in a developed country. AB - This cross-sectional study of 400 sera from a randomly selected adult population in Northern Ireland, using a microimmunofluorescence assay, demonstrated high overall seropositivity (70%) for IgG Chlamydia pneumoniae antibodies in developed populations. Seropositivity was shown to be unrelated to gender, age or smoking but there was an inverse trend between infection and educational level achieved as a measure of socio-economic status. IgG levels were also higher during the winter months suggesting seasonal variation of Chlamydia pneumoniae infection. The high prevalence of evidence of exposure to Chlamydia pneumoniae as described in this study may have implications for prevention of cardiovascular disease if further evidence conclusively determines that infection with this organism is a risk factor for cardiovascular disease. PMID- 10098794 TI - Seroprevalence of IgG antibodies to the chlamydia-like microorganism 'Simkania Z' by ELISA. AB - The newly described microorganism 'Simkania Z', related to the Chlamydiae, has been shown to be associated with bronchiolitis in infants and community acquired pneumonia in adults. The prevalence of infection in the general population is unknown. A simple ELISA assay for the detection of serum IgG antibodies to 'Simkania Z' was used to determine the prevalence of such antibodies in several population samples in southern Israel (the Negev). The groups tested included 94 medical and nursing students, 100 unselected blood donors, 106 adult members of a Negev kibbutz (communal agricultural settlement), and 45 adult Bedouin, residents of the Negev. IgG antibodies to 'Simkania Z' were found in 55-80% of these presumably healthy individuals, independently of antibodies to Chlamydia trachomatis and Chlamydia pneumoniae. The Bedouin had a seropositivity rate of 80%, while all other groups had rates of between 55 and 64%. These results indicate that 'Simkania Z' infection is probably common in southern Israel. PMID- 10098795 TI - Acute hepatitis B infection in England and Wales: 1985-96. AB - Confirmed acute hepatitis B infections are reported to the Public Health Laboratory Service Communicable Disease Surveillance Centre by laboratories in England and Wales. These reports have been used to monitor trends in the incidence of hepatitis B virus (HBV) infection over time, and between exposure categories and age groups. Between 1985 and 1996 a total of 9252 cases of acute HBV infection were reported; the number of reports fell from 1761 in 1985 to 581 in 1996. Most infections were reported in adults aged 15-44 years [n = 7365 (80%)], and infections were more commonly reported in males [n = 6490 (70%)] than females [n = 2658 (29%)]. The probable means of acquisition was known for just over half of all adult cases [4827/8956 (54%)]. Injecting drug use was the most common exposure [n = 1901 (21%)], followed by sex between men and women [n = 1140 (13%)] and sex between men [n = 1025 (11%)]. The number of infections in injecting drug users fell in the late 1980s, but increased again from 1991 onwards. In children aged under 15 years, infections acquired by mother to baby transmission accounted for 35/170 (21%) of the total. Surveillance indicates that the incidence of acute hepatitis B infection fell in the late 1980s, probably reflecting changed behaviour in injecting drug users. An increase in the number of infections in injecting drug users since 1993 may indicate ongoing transmission that has not been contained by the introduction of needle exchange schemes or by selective vaccination. PMID- 10098796 TI - The prevalence of hepatitis B infection in adults in England and Wales. AB - Cost effectiveness analyses of alternative hepatitis B vaccination programmes in England and Wales require a robust estimate of the lifetime risk of carriage. To this end, we report the prevalence of infection in 3781 anonymized individuals aged 15-44 years whose sera were submitted in 1996 to 16 microbiology laboratories in England and Wales. One hundred and forty-six individuals (3.9%) were confirmed as anti HBc positive, including 14 chronic carriers (0.37%). The prevalence of infection and carriage was higher in samples collected in London and increased with age. No increased risk of infection was seen in sera from genito-urinary (GUM) clinics. Only 15 sera positive for hepatitis B were also positive for hepatitis C. Our results confirm the low prevalence of hepatitis B in England and Wales, are consistent with previous estimates of carriage and suggest that many infections were acquired while resident outside the UK. Future prevalence studies should determine the country of birth and other risk factors for each individual in order to confirm these findings. PMID- 10098797 TI - Seroprevalence of hepatitis B virus, hepatitis C virus and GB virus-C infections in Siberia. AB - We studied the seroprevalence of hepatitis B virus (HBV), hepatitis C virus (HCV) and GB virus-C (GBV-C) infections in 348 Siberian natives who lived in the Kamchatka Peninsula of Russia. Of 348 samples studied, the seroprevalence of HBsAg and anti-HBs were 11.8% (41 of 348 samples) and 35.9% (125 of 348 samples), respectively. The prevalence of HCV infection was 1.4% (5 of 348 samples), and that of GBV-C RNA, using RT-PCR methods, was 7.5% (26 of 348 samples). In Siberia, the prevalences of HBV and GBV-C infections were about tenfold higher than those in Japan. The prevalence of HBsAg in subjects under 50 years of age was significantly higher than that in those over 50 years old (P < 0.05). Because HBV infection is highly endemic in Siberia, we propose that the community-based mass immunization must be conducted as soon as possible in this area. PMID- 10098798 TI - A community outbreak of food-borne small round-structured virus gastroenteritis caused by a contaminated water supply. AB - In August 1994, 30 of 135 (23%) bakery plant employees and over 100 people from South Wales and Bristol in the United Kingdom, were affected by an outbreak of gastroenteritis. Epidemiological studies of employees and three community clusters found illness in employees to be associated with drinking cold water at the bakery (relative risk 3.3, 95%, CI 1.6-7.0), and in community cases with eating custard slices (relative risk 19.8, 95%, CI 2.9-135.1) from a variety of stores supplied by one particular bakery. Small round-structured viruses (SRSV) were identified in stool specimens from 4 employees and 7 community cases. Analysis of the polymerase and capsid regions of the SRSV genome by reverse transcription-polymerase chain reaction (RT-PCR) demonstrated viruses of both genogroups (1 and 2) each with several different nucleotide sequences. The heterogeneity of the viruses identified in the outbreak suggests that dried custard mix may have been inadvertently reconstituted with contaminated water. The incident shows how secondary food contamination can cause wide-scale community gastroenteritis outbreaks, and demonstrates the ability of molecular techniques to support classical epidemiological methods in outbreak investigations. PMID- 10098799 TI - Molecular epidemiology of respiratory syncytial virus in The Gambia. AB - Respiratory syncytial virus (RSV) infection in The Gambia occurs seasonally in association with the rainy season. This study examined the genetic variability of RSV isolates from four consecutive epidemics from 1993-6. Each epidemic was made up of a number of variants which were replaced in subsequent epidemics. Analysis of attachment (G) protein gene sequences showed that isolates were closely related to those observed in the rest of the world. However, many isolates from 1993 and 1994 were unlike other isolates observed in the developed world during this period and were more similar to isolates from 1984 in Europe. In addition, the most commonly observed genotype in the UK in the 1990s was not detected in The Gambia during this period. PMID- 10098800 TI - Changing epidemiology of dengue hemorrhagic fever in Thailand. AB - Dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) are reportable diseases, the third most common causes for hospitalization of children in Thailand. Data collected from the Ministry of Public Health were analysed for trends. Rates of DHF increased in Thailand until 1987 when the largest epidemic ever, 325/100000 population, was recorded. Whereas the disease used to be confined to large cities, the rate is now higher in rural (102.2 per 100000) than urban areas (95.4 per 100000 in 1997). The age of highest incidence has increased, and the age group most severely affected is now those 5-9 years old (679/100000 in 1997). The case fatality rate has decreased with improved treatment and is now only 0.28%. PMID- 10098801 TI - Quantifying the risks of TB infection to cattle posed by badger excreta. AB - Despite strong circumstantial evidence to suggest that the main route of TB transmission from badgers to cattle is via contaminated badger excreta, it is unclear whether the associated risks are high enough to account for the prevalence of the disease in south-west England. To decide whether this was a viable route of transmission, cattle contact with badger excreta was investigated using a deterministic approach to quantify the risks to cattle posed by badger excreta. Levels of investigative and grazing contacts between cattle and badger urine and faeces could each account for the disease prevalence in south-west England. An infection probability of 3.7 x 10(-4) per bite from pasture contaminated with badger urine infected with Mycobacterium bovis could account for the prevalence of TB in cattle in south-west England. Infection probabilities of 6.9 x 10(-7) per investigation and 1.1 x 10(-7) per bite from badger latrines could each account for the prevalence of TB in cattle in the south-west. When considering only the high risk areas of south-west England these bounds fell by a factor of eight. However, badger excreta may still constitute a high level of risk to cattle. The levels of cattle contact with badger excreta are far higher than previously thought, suggesting that it is the probability of infection per given contact with infected badger excreta which has the greater influence on the probability of transmission and not the level of contact. The infection probability per cattle contact with infected badger excreta is in all likelihood extremely low. PMID- 10098803 TI - Interface pressure and the prediction of car seat discomfort. AB - The technique of interface pressure measurement has generated considerable interest in the automotive industry as a method, which could be used to predict driver discomfort during the development of prototype seat designs. Two repeated measures experiments were carried out to evaluate the practical application of the technique. The variables of foam density and posture were used to create discomfort, the whole emphasis of the work being to generate results with real world applicability. A clear, simple and consistent relationship between interface pressure and driving discomfort was not identified. Future studies using this technique should provide information regarding such factors as gender, body mass, anthropometric data, posture and foam hardness due to the confounding nature of these variables. PMID- 10098802 TI - Clonality of Campylobacter sputorum bv. paraureolyticus determined by macrorestriction profiling and biotyping, and evidence for long-term persistent infection in cattle. AB - Eighteen strains of Campylobacter sputorum bv. paraureolyticus (isolated over a 12-month period from seven dairy cows contained in a single herd) were examined by resistotyping, and macrorestriction profiling using pulsed field gel electrophoresis (PFGE). The resistotypes of these strains were identical, although repeat testing indicated resistance to metronidazole was not a reliable trait for typing purposes. Five SmaI-derived genotypes were identified among the 18 strains. In 5 of 7 cows, isolates obtained from the same animal, but from different time periods, were genotypically indistinguishable, indicating persistence of infection. Macrorestriction profiles of 5 strains representing the 5 SmaI genotypes and 8 other strains of C. sputorum from various sources, were prepared using 4 endonucleases (SmaI, SalI, BamHI and KpnI). The only other strain of C. sputorum bv. paraureolyticus examined (a Canadian isolate from human faeces), was found to have a SmaI macrorestriction profile identical with one of the five clones isolated from the cattle. Moreover, SalI and BamHI profiles of all bv. paraureolyticus strains were similar, while digestion with KpnI was not observed. By contrast, the seven strains of C. sputorum bv. sputorum yielded various macrorestriction profiles with all the enzymes used, and features distinguishing the two biovars studied could be identified. This study indicates that C. sputorum can persist in cattle for at least 12 months and exhibits a clonal population genetic structure. PMID- 10098804 TI - The role of working memory, field dependence, visual search, and reaction time in the left turn performance of older female drivers. AB - Older drivers have difficulties at intersections, especially in their performance of left turns. Older females are especially at risk in intersection maneuvers. Information processing abilities have been most promising in explaining the crash involvement of elderly drivers. This study examines the relationship of field dependence, visual search skills, and working memory to the decision to make a left turn at an intersection as well as to gap choice. Participants included thirty-three women ranging in age from 61 to 84 years. The results show that working memory plays a very important role in left-turn performance. Implications for appropriate interventions are discussed. PMID- 10098805 TI - Evaluation of interrater reliability for posture observations in a field study. AB - This paper examines the interrater reliability of a quantitative observational method of assessing non-neutral postures required by work tasks. Two observers independently evaluated 70 jobs in an automotive manufacturing facility, using a procedure that included observations of 18 postures of the upper extremities and back. Interrater reliability was evaluated using percent agreement, kappa, intraclass correlation coefficients and generalized linear mixed modeling. Interrater agreement ranged from 26% for right shoulder elevation to 99 for left wrist flexion, but agreement was at best moderate when using kappa. Percent agreement is an inadequate measure, because it does not account for chance, and can lead to inflated measures of reliability. The use of more appropriate statistical methods may lead to greater insight into sources of variability in reliability and validity studies and may help to develop more effective ergonomic exposure assessment methods. Interrater reliability was acceptable for some of the postural observations in this study. PMID- 10098806 TI - The design of a simulated forcible entry test for fire fighters. AB - This study investigated the physiological responses and performances for 20 fire fighters when completing simulated forcible entry tests. The purpose was to establish the validity of using a tire striking test and to examine the effects of varying the test parameters. The tests consisted of striking a reinforced structure and a weighted truck tire on a plywood covered table with either a 4.54 or a 5.60 kg sledge hammer. The results indicate that the simulated forcible entry tests are short in duration (range = 8.0-17.6 s), but are also physically demanding in terms of cardiovascular response (range = 86.5-97.2 for a percentage of heart rate reserve). The differences in striking a reinforced structure versus hitting a tire were insignificant according to most of the measures taken. The parameters for the simulated forcible entry test that were determined to be most appropriate were to move the tire 30 cm and use the 4.54 kg sledge hammer. PMID- 10098808 TI - The ability of non-ergonomists in the health care setting to make manual handling risk assessments and implement changes. AB - The health care setting presents particular risks from manual handling and it is known that training in manual handling techniques is ineffective in reducing these risks when used as a stand-alone measure. The 'Manual Handling Operations Regulations 1992' requires employers to consider hazardous manual handling, advising the use of an ergonomics approach. However, it is not known how well equipped non-ergonomists in the health care setting are to deal with this approach. Therefore, the ability of non-ergonomists to make manual handling risk assessments, with or without additional training, and to implement changes to the work environment was investigated. Twenty-five pairs of subjects from a broad cross section of departments in a busy teaching hospital were studied; training and a guide book were provided for one of each pair and the guide book only for the other. Subjects then independently prioritised three tasks in their department and undertook a full assessment of a specified task. All work was repeated by an ergonomist and the subjects' assessments were scored in comparison with the ergonomist. Each department was followed up after six months to assess progress with implementing recommendations. Trends in the data indicated that both groups appeared able to identify hazards though not necessarily to prioritise the tasks. The trained group tended to score better in assessments although wide variation existed within both groups and inter-group differences were not significant at the 5% level. Approximately half of staff assessments were considered 'adequate' to 'very good', in comparison with the ergonomist. Implementation of assessment recommendations ranged from nil to almost full compliance. Incomplete implementation seemed to be related to an apparent confusion in some departments over who was responsible for making changes, a lack of finances for changes and overstretched managers having other priorities. PMID- 10098807 TI - Elderly and young driver's reaction to an in-car enforcement and tutoring system. AB - A system that contrasts driver behaviour with normative behaviour was tested in an advanced driving simulator. Drivers were provided with auditory and visual tutoring messages if deviations were detected from normative, i.e. legally allowed behaviour with respect to a selection of offences. Results showed that the system was very effective in increasing law-abiding behaviour, which has a major positive effect on traffic safety. However, driver mental effort, as indicated by self-reports and drivers' physiological states, was slightly increased in conditions where drivers received feedback. Opinion about the tutoring system was positive in terms of usefulness. Self-reports on satisfaction differed between age groups; young drivers rated it low, while elderly drivers held a positive attitude. PMID- 10098809 TI - On using psychophysical techniques to achieve urgency mapping in auditory warnings. AB - It is well established that warning implementation should aim to achieve urgency mapping between the perceived urgency of the warning itself and the situational urgency of the condition that it indicates. This paper describes how Stevens Power Law [Psychological Review, 64, 153 181, 1957], which quantifies the relationship between objective parameters (such as the pitch of a warning) and subjective parameters (such as perceived urgency), can be applied to the design of auditory warnings to facilitate such urgency mapping. Studies that have quantified and predicted the effects of different warning parameters on perceived urgency using an application of Stevens Power Law are reported. PMID- 10098810 TI - Measurement of forces applied to handgrips and pedals for a sample population of Mexican males. AB - Equipment design requirements for newly industrializing nations often differ from those of highly industrialized nations. In order to develop a 'culturally relevant' technology in Mexico, this paper reports the results of a study, conducted in Guanajuato state, designed to measure the maximum static forces exerted on pulling handgrips and pedals by seated male subjects. The project included the design and construction of an adjustable measuring apparatus. Handgrip measurements were taken with left and right arms at five different elbow angles; pedal measurements with left and right legs at three different knee angles. The arm data indicate that the relationship between appendage angle and force is similar for these data and those previously reported for a US sample, although there are some significant differences in magnitude. Implications of these results for machinery design are discussed. PMID- 10098811 TI - Mood and cognition in pregnant workers. PMID- 10098812 TI - Virtual environments applications and applied ergonomics. AB - The usability of virtual environments has attracted considerable efforts from ergonomists. Work has included studies of the side or after effects of participation in a virtual environment (VE) as well as the appropriateness of the Virtual Reality hardware and software interfaces and the understanding of factors which determine participant performance. Equally important for applied ergonomics is to understand how best to specify, build, implement and evaluate virtual environment solutions to everyday industrial, commercial, educational and medical problems. The potential value of ergonomics applied to virtual environments, and vice versa, are discussed. Two particular instances of VE development relevant to applied ergonomics are described - structured development and evaluation of industrial training and participatory redesign of workplaces. This paper is one of a number of contributions to a special issue on ergonomics in the study and use of virtual environments. PMID- 10098813 TI - VRUSE--a computerised diagnostic tool: for usability evaluation of virtual/synthetic environment systems. AB - A special questionnaire (VRUSE) has been designed to measure the usability of a VR system according to the attitude and perception of its users. Important aspects of VR systems were carefully derived to produce key usability factors for the questionnaire. Unlike questionnaires designed for generic interfaces VRUSE is specifically designed to cater for evaluating virtual environments, being a diagnostic tool providing a wealth of information about a user's viewpoint of the interface. VRUSE can be used to great effect with other evaluation techniques to pinpoint problematical areas of a VR interface. Other applications include bench marking of competitor VR systems. PMID- 10098814 TI - Motion sickness and proprioceptive aftereffects following virtual environment exposure. AB - To study the potential aftereffects of virtual environments (VE), tests of visually guided behavior and felt limb position (pointing with eyes open and closed) along with self-reports of motion sickness-like discomfort were administered before and after 30 min exposure of 34 subjects. When post- discomfort was compared to a pre-baseline, the participants reported more sickness afterward (p < 0.03). The change in felt limb position resulted in subjects pointing higher (p < 0.038) and slightly to the left, although the latter difference was not statistically significant (p = 0.08). When findings from a second study using a different VE system were compared, they essentially replicated the results of the first study with higher sickness afterward (p < 0.001) and post- pointing errors were also up (p < 0.001) and to the left (p < 0.001). While alternative explanations (e.g. learning, fatigue, boredom, habituation, etc.) of these outcomes cannot be ruled out, the consistency of the post- effects on felt limb position changes in the two VE implies that these recalibrations may linger once interaction with the VE has concluded, rendering users potentially physiologically maladapted for the real world when they return. This suggests there may be safety concerns following VE exposures until pre exposure functioning has been regained. The results of this study emphasize the need for developing and using objective measures of post-VE exposure aftereffects in order to systematically determine under what conditions these effects may occur. PMID- 10098816 TI - Measurement of postural stability before and after immersion in a virtual environment. AB - Research into the effects of simulators has led to suggestions that postural instability occurring after immersion in a virtual reality virtual environment (VR/VE) may have direct implications for the safety of post-immersion activities such as driving or operating machinery. However, experimental studies have highlighted a lack of standardisation in the postural stability measurement techniques applied and subsequent inconsistencies in the results obtained. An experiment was conducted to evaluate the use of static, dynamic and posturographic postural stability measures in determining the effect of participation in an interactive virtual environment (VE) for 20 min. The results demonstrate differences in the sensitivity of postural stability measurement techniques and variations in inter- and intra-individual responses to measures. The VE immersion was found to produce postural instability only when measured using a posturographic technique under normal stance static posture, and then only mildly and not long-lasting. No associations were found between reported symptoms of simulator sickness and postural stability with postural stability measures. This paper discusses issues relating to postural stability measurement and the implications for evaluation of virtual environment effects. PMID- 10098815 TI - The nauseogenicity of two methods of navigating within a virtual environment. AB - This study compared the nauseogenicity of two different strategies for exploring virtual environments whilst wearing an immersive head-mounted display. In the first, the head was kept still and movement was achieved solely by manipulating a hand-control. In the second, the subject was free (and encouraged) to move his or her head when exploring the virtual world. Fourteen subjects completed both of the 20 min trials, three further subjects withdrew from the study after one trial. Subjects reported increases in adverse symptoms when using each strategy and, for the group as a whole, nausea increased steadily during each immersion period. However, significantly larger changes were reported when the head moved than when it was still, as predicted from sensory conflict theory. PMID- 10098817 TI - Oculomotor changes within virtual environments. AB - This paper discusses the oculomotor changes which might be expected to occur during immersion in a virtual environment whilst wearing a Head mounted display (HMD). To do so, it first examines the stimulus presented to the eyes, and then considers how this stimulus could affect the visual system. Theoretical analysis and empirical results from the use of three different HMDs point towards the same conclusion, that in this context a mismatch between the instrument inter-ocular distance (IOD) and the user's inter-pupillary distance is of little concern, unlike the mismatch between the instrument IOD and the inter-screen distance. PMID- 10098818 TI - Developing visual systems and exposure to virtual reality and stereo displays: some concerns and speculations about the demands on accommodation and vergence. AB - Little is known about the developmental plasticity of the vergence and accommodative systems, an important issue since abnormalities can lead to visual problems, e.g. strabismus. One way of artificially altering the links between accommodation and vergence is to vary the stimulus to vergence while fixing the accommodative stimulus, as is found in virtual reality displays. While it would be of interest to study developmental plasticity in this situation, since many children are exposed to games machines which use this arrangement, no studies to date have tackled this issue. There is, however, some indication that long-term VR viewing in adults can lead to visual problems. It seems important to determine the safety of these systems for the developing human visual system before they come into common use. In this paper, adaptation of the accommodation and vergence systems and the effect of VR viewing in adults is discussed. The sparse literature on adaptation in children is then reviewed, and suggestions made for approaches that would enhance our knowledge of plasticity of accommodation and vergence in children. PMID- 10098819 TI - Physical ergonomics of virtual environment use. AB - This paper describes an investigation of the types of problems that may be experienced by Virtual Reality (VR) users. Initial concerns have been voiced about various issues concerning the design of VR equipment, particularly the physical ergonomics of head-mounted displays (HMDs) and hand-held input devices, and the problems associated with display resolution and lags. This study investigated a number of VR users' perceptions of the types of physical ergonomics issues that they were aware of when participating in a number of different virtual environments (VEs), using different VR systems. Several different methods were employed, including questionnaires, body mapping, user observation and interviews. Issues highlighted as either causing participants discomfort or interfering with their experience of the VE were: discomfort from static posture requirements, general discomfort from wearing the HMD, difficulty becoming accustomed to 3D hand held input devices, dissatisfaction with deficits in the visual display and fear of getting 'tangled' in connecting cables. The implications of these findings for developers, implementers and users of VR are discussed. PMID- 10098820 TI - Nonpharmacological treatment of late-life insomnia. AB - This article reviews the evidence regarding the efficacy of nonpharmacological interventions for the treatment of late-life insomnia. Outcome data from more than a dozen treatment studies conducted with community-dwelling older adults indicate that behavioral approaches produce reliable and durable therapeutic benefits. as evidenced by improved sleep efficiency and continuity and enhanced satisfaction with sleep patterns. Treatment is also helpful for reducing hypnotic usage among older adults who are dependent on sleep medications. Treatment methods such as stimulus control and sleep restriction, which target maladaptive sleep habits, are especially beneficial for older insomniacs, whereas relaxation based interventions. aimed at decreasing arousal, produce more limited effects. Cognitive and educational interventions are instrumental in altering age-related dysfunctional beliefs and attitudes about sleep. Integrated behavioral and pharmacological therapies have received very little empirical attention thus far. Although a limited number of older adults resume "normal" sleep patterns after treatment, outcome is clinically meaningful as most patients report greater satisfaction with their sleep patterns, use less medications, and display less psychological distress and concerns about sleep. PMID- 10098821 TI - Sociodemographic factors in mental disorders associated with infertility in Nigeria. AB - The mental status of 37 female patients with infertility and that of 37 healthy controls was evaluated using General Health Questionnaire, Present State Examination, and clinical assessment. An interview schedule, designed to elicit information on sociodemographic, psychiatric predisposing, and obstetric factors, was also administered. A significantly higher proportion (29.7%) of the patients was found to have diagnosable psychopathology, mainly depressive episode and generalized anxiety disorder. Compared with the control group, the infertile women experienced poorer marital relationships, had a significant family history of infertility, were more negatively predisposed to child adoption. and had a greater history of surgery and induced abortion. Polygamy was found to have a close association with psychopathology in the sample of infertile women. The implications of these findings and ways of improving the mental status of the infertile woman are discussed. PMID- 10098822 TI - Differential effects of harassment on cardiovascular and salivary cortisol stress reactivity and recovery in women and men. AB - To explore the differential effects of harassment on cardiovascular and neuroendocrine stress reactivity and recovery, 28 men and 32 women were randomized to a harassment or no-harassment control condition (four groups in total). The harassment consisted of three scripted statements delivered during performance of a mental arithmetic stress task. The harassing statements were delivered on a fixed schedule during the task by a same-gender experimenter. Cardiovascular, salivary cortisol, and state affect measures were taken at baseline, immediately posttask, and throughout an extended recovery period. In comparison to the control condition, harassment accentuated the stress reactivity responses on all measures, physiological and self-report of subjective affect. In addition, several gender differences in response to the stressor and during the recovery period were observed. Harassed men had the largest reactivity on cortisol and diastolic blood pressure, whereas the harassed women showed a more pronounced response on heart rate and self-reported hostility. The harassed groups were the only ones to show significant cortisol responses. Within the harassed condition, comparison of effect sizes revealed that cortisol reactivity in men was twice that of women. Control groups did not exhibit significant cortisol changes. During the recovery period, harassed men exhibited attenuated return to baseline on cardiovascular indices and cortisol, whereas women, overall, tended to exhibit an overcompensation response on cardiovascular measures. These results contribute to showing a pathway that may link negative affect (i.e., hostile or angry feelings) with the development of cardiovascular disease. PMID- 10098823 TI - Behavioral effects of a comprehensive, multifactorial program for lifestyle change after percutaneous transluminal coronary angioplasty: a prospective, randomized controlled study. AB - A group of 93 coronary patients recently treated with percutaneous transluminal coronary angioplasty (PTCA) were randomly assigned to either an intervention or a control group. Subjects in the intervention group participated in a comprehensive behaviorally oriented program aimed at achieving significant long-term changes in risk factor-related lifestyle behavior. Assessments of lifestyle behaviors, psychological factors, biological risk factors, and rehabilitation as well as secondary prevention endpoints were carried out, at inclusion and after 12 months. Results showed that the intervention patients, as compared with controls, improved significantly on measures assessing smoking, exercise, and diet habits. These self-rated changes were confirmed by weight reductions and improved exercise capacity, as well as by between-group differences in subclinical chest pain during an exercise test. However, few effects were found on the different psychological variables, as well as on morbidity or return to work. PMID- 10098824 TI - Depression, illness perception and coping in rheumatoid arthritis. AB - This study aimed to establish the relationship between depression, illness perception, coping strategies, and adverse childhood events in rheumatoid arthritis patients. Sixty-two out-patients with rheumatoid arthritis (RA) completed the Hospital Anxiety and Depression Scale, Illness Perception Questionnaire, London Coping with Rheumatoid Arthritis Questionnaire, and Childhood Development Questionnaire, and underwent a clinical assessment of their physical state. Depressed patients were more disabled than the nondepressed, had a more negative view of their illness, and used more negative coping strategies. There was no association between depression and childhood adversity. Once disability was controlled for, there continued to be a significant correlation between depression and: (i) viewing the consequences of the illness negatively (Spearman's correlation coefficient [r]=0.37, p=0.003); and (ii) the perceived ability to control the illness (r= -0.26, p=0.04). The relationship between depression and negative coping strategies became insignificant. This study indicates the close relationship between depression and a negative view of the illness. PMID- 10098825 TI - Religiosity is associated with affective and immune status in symptomatic HIV infected gay men. AB - This study examines the relationship between religiosity and the affective and immune status of 106 HIV-seropositive mildly symptomatic gay men (CDC stage B). All men completed an intake interview, a set of psychosocial questionnaires, and provided a venous blood sample. Factor analysis of 12 religiously oriented response items revealed two distinct aspects to religiosity: religious coping and religious behavior. Religious coping (e.g., placing trust in God, seeking comfort in religion) was significantly associated with lower scores on the Beck Depression Inventory, but not with specific immune markers. On the other hand, religious behavior (e.g., service attendance, prayer, spiritual discussion, reading religious literature) was significantly associated with higher T-helper inducer cell (CD4+) counts and higher CD4+ percentages, but not with depression. Regression analyses indicated that religiosity's associations with affective and immune status was not mediated by the subjects' sense of self-efficacy or ability to actively cope with their health situation. The associations between religiosity and affective and immune status also appear to be independent of symptom status. Self-efficacy, however, did appear to contribute uniquely and significantly to lower depression scores. Our results show that an examination considering both subject religiosity as well as sense of self-efficacy may predict depressive symptoms in HIV-infected gay men better than an examination that considers either variable in isolation. PMID- 10098826 TI - Long-term outcome of hypochondriacal personality disorder. AB - Hypochondriacal personality disorder diagnosed according to the Personality Assessment Schedule, a structured clinical interview, was related to outcome after 2 years and 5 years in a randomized, controlled trial of treatment of generalized anxiety, panic, and dysthymic disorders. Seventeen individuals (9%) from a population of 181 patients had hypochondriacal personality disorder and they experienced a significantly worse outcome than other patients, including those with other personality disorders, in terms of symptomatic change and health service utilization. This lack of improvement was associated with persistent somatization in hypochondriacal personality disorder. The results give further support to the belief that hypochondriacal personality disorder is a valid clinical diagnosis that has important clinical correlates, but further work is needed to establish the extent of its overlap with hypochondriasis as a mental state disorder. PMID- 10098827 TI - A structural modeling analysis of anxiety and depression in patients undergoing coronary artery bypass graft surgery: a model generating approach. AB - The present study is a longitudinal study designed to explore structural relationships between anxiety, depression, personality, and background factors (e.g., gender, age, and complicated medical characteristics) in patients undergoing coronary artery bypass graft (CABG) surgery. At two timepoints before and two after CABG, 217 patients completed self-report questionnaires. To explore structural relationships, the structural equation modeling (SEM) method was applied. Using the model-generating approach, a model was developed, providing a good fit. The structural relationships revealed, in particular, the key position of neuroticism, which was related to both pre- and postoperative anxiety and depression. Relationships between anxiety and depression over time, both intra- and interrelationships, were relatively weak. Relationships between anxiety and depression at the same points in time were relatively strong, with preoperative depression leading to preoperative anxiety, and postoperative anxiety leading to postoperative depression. To provide a useful framework for development of intervention strategies, further research is needed to evaluate the plausibility of the final structural model. PMID- 10098828 TI - Interferons enhance HLA-G mRNA and protein in transfected mouse fibroblasts. AB - The HLA class Ib gene, HLA-G, has a 16-bp deletion in its Enhancer A/interferon response element (IRE). We used a model system consisting of mouse fibroblasts transfected with 6.0 kb of HLA-G DNA, the S14/8 cells, to test the postulate that this deletion prevents interferons (IFNs) from enhancing transcription. Northern blot hybridization experiments showed that after 48 h of treatment with IFN alpha, IFN-beta or IFN-gamma, steady-state levels of HLA-G mRNA in the S14/8 cell line were doubled. Proteins were also increased by IFNs as demonstrated in flow cytometry and immunocytochemical experiments that used monoclonal antibodies to all HLA class I antigens (W6/32), HLA-G heavy chains (87G) and light chains (beta2m). Thus, interferons enhance expression of HLA-G and would be expected to improve host defense at the maternal-fetal interface by increasing the ability of maternal immune cells to recognize and destroy infected HLA-G+ cells. PMID- 10098829 TI - Human choriocarcinoma-derived JEG-3 cells transfected with murine MHC class II Aq expression vectors present antigen to Aq-restricted murine T-cell hybridoma. AB - MHC class II molecules are not normally expressed on the cell surface of placental cells. This absence of class II molecules is assumed to be of importance for mammalian reproduction, since such expression is likely to increase the risk of harmful anti-placental immune responses. The present study was aimed to clarify whether post-transcriptional events prohibit proper cell surface expression of MHC class II molecules in cell lines of placental origin. The murine trophoblast cell line SM9-1 as well as the human choriocarcinoma derived cell line JEG-3 were transiently co-transfected with MHC class II Aq a and b genes under the control of viral promoter systems. The transfected cells were stained for surface expression of MHC class II and assayed for antigen presentation in vitro. Only a small proportion of the transfected murine SM9-1 cells showed detectable class II cell surface expression, which made functional studies of this cell line difficult. The transfected JEG-3 cells, however, showed a high proportion of cells with distinct surface expression of murine class II Aq molecules and the antigen presentation assays revealed T cell activation upon addition of processed antigen, but not with unprocessed antigen. These results show that ectopic MHC class II gene transcription can result in cell surface expression of immunohistochemically detectable MHC class II on cells of placental origin. The fact that murine class II molecules could be expressed in a functional manner on human JEG-3 cells also strongly suggests that proper accessory gene activities are not essential for obtaining surface expression. PMID- 10098830 TI - Intrauterine infusion of bacterial lipopolysaccharide (LPS) prior to mating has no adverse effect on fertility, fetal survival and fetal development. AB - Lipopolysaccharide (LPS, endotoxin) is a component of the cell wall of gram negative bacteria and a potent inducer of severe inflammatory reactions. In mice, systemically administered LPS induces fetal resorption and increases fetal mortality. However, effects of intrauterine LPS on fertility, fetal survival and development have not been reported. In the present study, pigs were used to determine the effect of intrauterine infused LPS on fertility, fetal survival and development. Prior to mating, gilts received intrauterine infusion of either a single dose of saline or increasing doses of LPS in saline using an insemination catheter. On day 30 of pregnancy, gilts were hysterectomized and litter size, fetal length, number of corpora lutea (CL), ovarian and placental weights, and allantoic and amniotic fluid volumes were recorded. Blood progesterone levels from days 10-30 of pregnancy were also determined. Results indicated that intrauterine infusion of LPS had no adverse effects on blood progesterone levels, fertility, fetal survival or fetal development. Intrauterine injection of LPS did cause an increase in fetal weight and amniotic fluid volume (P < 0.05). These results suggest that sperm, oocytes and gametes are tolerant of local LPS challenge and, to some extent, this mechanism protects gametes and conceptuses from maternal response to mating introduced bacteria and their potential endotoxins. PMID- 10098831 TI - Characterization of antigens expressed in normal baboon trophoblast and cross reactive with HIV/SIV antibodies. AB - Electron microscopic studies have revealed the presence of endogenous retroviral (ERV) particles in normal primate placental tissues. These particles have ultrastructural similarities to type C retroviral particles and are mainly associated with the trophoblast. In normal human placental tissues, they have antigenic similarity with exogenous retroviruses, such as the human immunodeficiency virus (HIV), and may have a role to play in the regulation of cellular gene expression, syncytiotrophoblast formation or pregnancy-related immunosuppression. In this study, a panel of antibodies (polyclonal and monoclonal antibodies) against viral proteins (anti-HIV and anti-SIV) and endogenous retroviral (ERV) proteins were assessed by immunohistochemistry and immunoblotting, for their cross-reactivity with ERV particles isolated from normal baboon placental tissues. The antibodies (anti-HERV-K RT, anti-ERV3 env, anti-HIV-1 p17, anti-HIV-2 gp120) reacted positively with the syncytiotrophoblast and each antibody recognized one or two proteins of molecular weights (MW) 38, 58 or 64 kDa present in the baboon placental villous tissues and SIV-infected molt-4 Cl8 cells, but not in uninfected cells. The results of this study confirm the specific expression of retroviral cross-reactive antigens in normal baboon placental tissues and suggest placental cellular proteins may have antigenic similarity with those recognized by anti-HIV/SIV antibodies. The role of these retroviral-related proteins expressed at the maternal-fetal interface remain unclear. PMID- 10098832 TI - Transfusion of fetal cord blood cells: an improved method of hematopoietic stem cell transplantation? AB - Hematopoietic stem cells circulate in the fetal blood and may be isolated from the placenta through the umbilical cord after birth. These cells have been safely isolated, and transplanted into recipients to treat malignancies and marrow failure. Cord blood stem cells may be used for genetic disorders. Compared to other sources of stem cells, recipients of cord blood stem cells have fewer and less severe episodes of graft versus host disease. This may be because intrauterine graft (fetus) versus host (mother) disease is harmful to the pregnancy. Controversies persist surrounding the harvest and use of these cells. PMID- 10098833 TI - Polycystic ovary syndrome and ovarian autoimmunity--assessment of ovarian antibodies by EIA. AB - There are conflicting reports of an association of ovarian antibodies, detected by immunofluorescence, with polycystic ovary syndrome (PCOS). The objective of this study was to evaluate the association of ovarian autoimmunity with PCOS. A validated immunoassay for ovarian antibodies was used to assess serum from women with PCOS and with menopause and normal cycling women as controls. The frequency of ovarian antibodies was similar (25%) among the controls and PCOS. Thus, unlike the association of ovarian antibodies detected with this test in patients with unexplained infertility and premature menopause, the prevalence of ovarian antibody in patients with PCOS is not significantly different to controls. PMID- 10098834 TI - Molecular cloning of multiple splicing variants of JIP-1 preferentially expressed in brain. AB - Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is activated by a variety of cellular or environmental stresses. Proper regulation of the SAPK/JNK pathway may be critical for cell survival or death under various conditions. In this study, we report the molecular cloning of novel isoforms of JIP-1, which harbor a putative phosphotyrosine interaction domain and a helix loop-helix domain, as well as an SH3 homologous region in the C terminus. Northern analysis indicates that transcription variant jip-1 is expressed in brain and kidney and transcription variants jip-2 and jip-3 are specifically expressed in brain. In situ hybridization data showed that the hybridized jip messages were heavily concentrated in adult brain, and were particularly enriched in the cerebral cortex and hippocampus, the brain regions vulnerable to pathological states such as hypoxia-ischemia, epilepsy, and Alzheimer's disease. All the deduced protein products of the jip transcription variants appear to have a similar property in that they inhibit the SAPK/JNK stimulation when overexpressed. Inhibition of SAPK activation by overexpression of the novel isoform JIP-2a resulted in suppression of etoposide-induced cell death in a neuroglioma cell line, N18TG. These findings suggest that JIP may play an important role in regulation of the SAPK pathway that is involved in stress induced cellular responses. PMID- 10098835 TI - Salmonid olfactory system-specific protein (N24) exhibits glutathione S transferase class pi-like structure. AB - A salmonid olfactory system-specific protein (N24) that has been identified in lacustrine sockeye salmon (Oncorhynchus nerka) was characterized by biochemical and molecular biological techniques. N24 is a homodimer, and the intact molecular mass is estimated as approximately 43.3 kDa by gel filtration. Furthermore, N24 was located only in the cytosolic fraction of the olfactory tissues as determined by subcellular fractionation. cDNA encoding the lacustrine sockeye salmon N24 was isolated and sequenced. This cDNA contained a coding region encoding 216 amino acid residues and the molecular mass of this protein is calculated to be 242,224.77. The protein and nucleotide sequencing demonstrates the existence of a remarkable homology between N24 and glutathione S-transferase (GST; EC 2.5.1.18) class pi enzymes. Northern analysis showed that N24 mRNA with a length of 950 bases is expressed in lacustrine sockeye salmon olfactory epithelium. Olfactory receptor cells showed strong hybridization signals for N24 mRNA in the olfactory epithelium. N24 demonstrated glutathione binding activity in affinity-purified GST column experiments. The present study describes for the first time cDNA cloning of GST in fish olfactory epithelium. PMID- 10098836 TI - Glial fibrillary acidic protein transcription responses to transforming growth factor-beta1 and interleukin-1beta are mediated by a nuclear factor-1-like site in the near-upstream promoter. AB - Elevated expression of glial fibrillary acidic protein (GFAP) is associated with astrocyte activation during responses to injury in the CNS. Because transforming growth factor-beta1 (TGF-beta1) and interleukin-1beta (IL-1beta) are released during neural responses to injury and because these cytokines also modulate GFAP mRNA levels, it is of interest to define their role in GFAP transcription. The increases of GFAP mRNA in response to TGF-beta1 and decreases in response to IL 1beta were shown to be transcriptionally mediated in rat astrocytes transfected with a luciferase-reporter construct containing 1.9 kb of 5'-upstream rat genomic DNA. Constructs containing sequential deletions of the rat GFAP 5'-upstream promoter identified a short region proximal to the transcription start (-106 to 53 bp) that provides full responses to TGF-beta1 and IL-1beta. This region contains an unusual sequence motif with overlapping nuclear factor-1 (NF-1)- and nuclear factor-kappaB (NF-kappaB)-like binding sites and homology to known TGF beta response elements. Mutagenesis (3-bp exchanges) in -70 to -68 bp blocked the induction of GFAP by TGF-beta1 and the repression by IL-1beta. Gel shift experiments showed that the DNA segment -85 to -63 bp was bound by a factor(s) in nuclear extracts from astrocytes. The concentrations of these DNA binding factors were increased by treatment of astrocytes with TGF-beta1 and decreased by IL 1beta. Binding of these nuclear factors was blocked by mutation of -70 to -68 bp. Despite homology to NF-1 or NF-kappaB binding sites in the GFAP promoter at segment -79 to -67 bp, anti-NF-kappaB or anti-NF-1 antibodies did not further retard the gel shift of the nuclear factors/DNA complex. Moreover, astrocytic nuclear proteins do not compete for the specific binding to NF-1 consensus sequence. Thus, nuclear factors from astrocytes that bind to the -85- to -63-bp promoter segment might be only distantly related to NF-1 or NF-kappaB. These findings are pertinent to the use of GFAP promoter constructs in transgenic animals, because cisacting elements in the GFAP promoter are sensitive to cytokines that may be elaborated in response to expression of transgene products. PMID- 10098837 TI - Cloning and characterization of zRICH, a 2',3'-cyclic-nucleotide 3' phosphodiesterase induced during zebrafish optic nerve regeneration. AB - We previously reported cloning of cDNAs encoding both components of a protein doublet induced during goldfish optic nerve regeneration. The predicted protein sequences showed significant homology with the mammalian 2',3'-cyclic-nucleotide 3'-phosphodiesterases (CNPases). CNPases are well-established markers of mammalian myelin; hence, the cDNAs were designated gRICH68 and gRICH70 (for goldfish Regeneration-Induced CNPase Homologues of 68 and 70 kDa). Homologous cDNAs have now been isolated from zebrafish encoding a highly related protein, which we have termed zRICH. RNase protection assays show that zRICH mRNA is induced significantly (fivefold) in optic nerve regenerating zebrafish retinas 7 days following nerve crush. Western blots show a single band in zebrafish brain and retina extracts, with immunoreactivity increasing three-fold in regenerating retinas 21 days postcrush. Immunohistochemical analysis indicated that this increase in zRICH protein expression is localized to the retinal ganglion cell layer in regenerating retina. We have characterized and evaluated the relevance of a conserved beta-ketoacyl synthase motif in zRICH to CNPase activity by means of site-directed mutagenesis. Two residues within the motif, H334 and T336, are critical for enzymatic activity. A cysteine residue within the motif, which corresponds to a critical residue for beta-ketoacyl synthase, does not appear to participate in the phosphodiesterase activity. PMID- 10098838 TI - Characterization of a novel serotonin receptor from Caenorhabditis elegans: cloning and expression of two splice variants. AB - Serotonin [5-hydroxytryptamine (5-HT)] modulates feeding activity, egg-laying, and mating behavior in the free-living nematode, Caenorhabditis elegans. We have cloned a novel receptor cDNA from C. elegans (5-HT2Ce) that has high sequence homology with 5-HT2 receptors from other species. When transiently expressed in COS-7 cells, 5-HT2Ce exhibited 5-HT binding activity and activated Ca2+-mediated signaling in a manner analogous to other 5-HT2 receptors. However, 5-HT2Ce displayed unusual pharmacological properties, which resembled both 5-HT2 and 5 HT1-like receptors but did not correlate well with any of the known 5-HT2 subtypes. Two splice variants of 5-HT2Ce that differ by 48 N-terminal amino acids were identified. The two isoforms were found to have virtually identical binding and signaling properties but differed in their levels of mRNA expression, with the longer variant being four times more abundant than the shorter species in all developmental stages tested. Taken together, the results describe two variants of a novel C. elegans 5-HT receptor, which has some of the properties of the 5-HT2 family but whose pharmacological profile does not conform to any known class of receptor. PMID- 10098839 TI - Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3' untranslated region of the human serotonin transporter gene. AB - The human serotonin transporter (hSERT) gene is a candidate for involvement in the aetiology of affective disorders. In humans, multiple transcripts of the gene have been detected by northern blot analysis of brain and other tissues. We performed 3' rapid amplification of cDNA ends to identify the common sites of polyadenylation in hSERT mRNA from human JAR cells and whole blood. Two major polyadenylation sites were identified: one 567 bp downstream of the stop codon, consistent with the usage of the polyadenylation signal AATGAA, and a second site 690 bp downstream of the stop codon. The putative polyadenylation signal upstream of this site contained a single nucleotide polymorphism (AG/TTAAC). However, allelic variation at this site did not influence polyadenylation site usage, and there were no significant differences in the abundance of the two alleles of this polymorphism between 329 control subjects, 158 individuals with major depression, and 130 individuals with bipolar affective disorder. This single nucleotide polymorphism in the 3' untranslated region of the hSERT gene should provide a useful genetic marker in the evaluation of hSERT as a candidate gene influencing susceptibility to mood disorders. PMID- 10098840 TI - Fyn tyrosine kinase reduces the ethanol inhibition of recombinant NR1/NR2A but not NR1/NR2B NMDA receptors expressed in HEK 293 cells. AB - NMDA receptors are potentiated by phosphorylation in a subunit- and kinase specific manner. Both native and recombinant NMDA receptors are inhibited by behaviorally relevant concentrations of ethanol. Whether the phosphorylation state of individual subunits modulates the ethanol sensitivity of these receptors is not known. In this study, the effects of Fyn tyrosine kinase on the ethanol sensitivity of specific recombinant NMDA receptors expressed in HEK 293 cells were investigated. Whole-cell mode patch clamp and ratiometric calcium imaging demonstrated that the degree of ethanol inhibition of NR1/NR2B receptors was unaffected by Fyn tyrosine kinase. In contrast, the inhibition of NR1/NR2A receptors by ethanol (100 mM) was significantly reduced under conditions of enhanced Fyn-mediated tyrosine phosphorylation of the NR2A subunit. This effect was not observed at lower concentrations of ethanol (< or = 50 mM). These results suggest that tyrosine phosphorylation of specific NMDA receptors by Fyn tyrosine kinase may regulate the sensitivity of these receptors to the sedative/hypnotic concentrations of ethanol. PMID- 10098841 TI - Oxidative stress, mitochondrial function, and acute glutamate excitotoxicity in cultured cerebellar granule cells. AB - On exposure to glutamate, cultured rat cerebellar granule cells undergo a delayed Ca2+ deregulation (DCD), which precedes and predicts cell death. We have previously shown that mitochondria control the sensitivity of the neurons to DCD. Mitochondrial depolarization by rotenone/oligomycin before glutamate addition is strongly neuroprotective, and the indication is therefore that mitochondrial Ca2+ loading leads to a delayed loss of bioenergetic function culminating in DCD and cell death. In this report it is shown that superoxide (O2.-) generation in intact cells, monitored by oxidation of hydroethidine to ethidium, was enhanced by glutamate only when mitochondria were polarized. Production of superoxide was higher in the subset of cells undergoing DCD. In the presence of rotenone and oligomycin, addition of glutamate did not result in increased superoxide generation. Menadione-generated superoxide enhances the DCD of cells exposed to glutamate; in contrast, glutamate-induced DCD was potently inhibited by the presence of the cell-permeant antioxidant manganese(III) tetrakis(4-benzoic acid) porphyrin. An inverse correlation is observed between the cytoplasmic free Ca2+ maintained in individual cells in the presence of glutamate and the ability of these cells to restore basal Ca2+ when NMDA receptors are inhibited and mitochondrial Ca2+ is released. It is concluded that mitochondrial Ca2+ accumulation and reactive oxygen species each contribute to DCD, probably related to damage to a process controlling Ca2+ efflux from the cell. PMID- 10098842 TI - Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins. AB - BIT (brain immunoglobulin-like molecule with tyrosine-based activation motifs) is a membrane glycoprotein that has two cytoplasmic TAMs (tyrosine-based activation motifs). We previously reported that tyrosine-phosphorylated TAMs of BIT interact with the Src homology 2 domain-containing protein tyrosine phosphatase SHP-2 both in vitro and in transfected cells, and this association results in a potent stimulation of the phosphatase activity of SHP-2. Both BIT and SHP-2 are highly expressed in the mammalian brain, and they may play important roles in the regulation of synaptic function. In this study, we found that nerve growth factor (NGF) treatment of PC12 cells leads to the tyrosine phosphorylation of BIT and a subsequent complex formation between BIT and SHP-2. Furthermore, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) also induced the tyrosine phosphorylation of BIT and the association with SHP-2 in primary cultured rat neurons. Our results suggest that the BIT-SHP-2 signaling pathway is a novel signal transduction mechanism of neurons that acts in response to neurotrophic factors such as NGF, BDNF, and NT-3. PMID- 10098843 TI - Activation of the endothelin receptor inhibits the G protein-coupled inwardly rectifying potassium channel by a phospholipase A2-mediated mechanism. AB - To develop a malleable system to model the well-described, physiological interactions between Gq/11 - coupled receptor and Gi/o-coupled receptor signaling, we coexpressed the endothelin A receptor, the mu-opioid receptor, and the G protein-coupled inwardly rectifying potassium channel (Kir 3) heteromultimers in Xenopus laevis oocytes. Activation of the Gi/o-coupled mu opioid receptor strongly increased Kir 3 channel current, whereas activation of the Gq/11-coupled endothelin A receptor inhibited the Kir 3 response evoked by mu opioid receptor activation. The magnitude of the inhibition of Kir 3 was channel subtype specific; heteromultimers composed of Kir 3.1 and Kir 3.2 or Kir 3.1 and Kir 3.4 were significantly more sensitive to the effects of endothelin-1 than heteromultimers composed of Kir 3.1 and Kir 3.5. The difference in sensitivity of the heteromultimers suggests that the endothelin-induced inhibition of the opioid activated current was caused by an effect at the channel rather than at the opioid receptor. The endothelin-1-mediated inhibition was mimicked by arachidonic acid and blocked by the phospholipase A2 inhibitor arachidonoyl trifluoromethyl ketone. Consistent with a possible phospholipase A2-mediated mechanism, the endothelin-1 effect was blocked by calcium chelation with BAPTA-AM and was not affected by kinase inhibition by either staurosporine or genistein. The data suggest the hypothesis that Gq/11-coupled receptor activation may interfere with Gi/o-coupled receptor signaling by the activation of phospholipase A2 and subsequent inhibition of effector function by a direct effect of an eicosanoid on the channel. PMID- 10098844 TI - Distinct secretases, a cysteine protease and a serine protease, generate the C termini of amyloid beta-proteins Abeta1-40 and Abeta1-42, respectively. AB - The carboxy-terminal ends of the 40- and 42-amino acids amyloid beta-protein (Abeta) may be generated by the action of at least two different proteases termed gamma(40)- and gamma(42)-secretase, respectively. To examine the cleavage specificity of the two proteases, we treated amyloid precursor protein (APP) transfected cell cultures with several dipeptidyl aldehydes including N benzyloxycarbonyl-Leu-leucinal (Z-LL-CHO) and the newly synthesized N benzyloxycarbonyl-Val-leucinal (Z-VL-CHO). All dipeptidyl aldehydes tested inhibited production of both Abeta1-40 and Abeta1-42. Changes in the P1 and P2 residues of these aldehydes, however, indicated that the amino acids occupying these positions are important for the efficient inhibition of gamma-secretases. Peptidyl aldehydes inhibit both cysteine and serine proteases, suggesting that the two gamma-secretases belong to one of these mechanistic classes. To differentiate between the two classes of proteases, we treated our cultures with the specific cysteine protease inhibitor E-64d. This agent inhibited production of secreted Abeta1-40, with a concomitant accumulation of its cellular precursor indicating that gamma(40)-secretase is a cysteine protease. In contrast, this treatment increased production of secreted Abeta1-42. No inhibition of Abeta production was observed with the potent calpain inhibitor I (acetyl-Leu-Leu norleucinal), suggesting that calpain is not involved. Together, these results indicate that gamma(40)-secretase is a cysteine protease distinct from calpain, whereas gamma(42)-secretase may be a serine protease. In addition, the two secretases may compete for the same substrate. Dipeptidyl aldehyde treatment of cultures transfected with APP carrying the Swedish mutation resulted in the accumulation of the beta-secretase C-terminal APP fragment and a decrease of the alpha-secretase C-terminal APP fragment, indicating that this mutation shifts APP cleavage from the alpha-secretase site to the beta-secretase site. PMID- 10098845 TI - Extended ceramide exposure activates the trkA receptor by increasing receptor homodimer formation. AB - Binding of nerve growth factor (NGF) to the trkA tyrosine kinase receptor results in receptor homodimer formation, transphosphorylation, and kinase activation that supports neuronal differentiation and survival. We have shown previously that short-term exposure of PC12 cells to brain-derived neurotrophic factor or to C2 ceramide activates a signaling pathway that results in serine phosphorylation of the trkA intracellular domain and reduces the ability of trkA to respond to NGF. Here we demonstrate that extended C2-ceramide exposure dramatically increases NGF induced trkA activation and further show that C2-ceramide augments trkA tyrosine phosphorylation even in the absence of neurotrophin. This increase in trkA receptor phosphotyrosine is reflected in increased activation of both Erk1 and Erk2 and of the catalytic subunit of phosphatidylinositol 3-kinase. The C2 ceramide-mediated increase in tyrosine phosphorylation is blocked completely by the trk kinase inhibitor K252A, indicating that this increase results from an effect of C2-ceramide on trkA kinase activity. Consistent with this, crosslinking studies show that C2-ceramide promotes the formation of active trkA receptor homodimers. Together, these data suggest that chronic C2-ceramide treatment increases trkA activation by altering properties of the plasma membrane, which favors the formation of trkA homodimers. PMID- 10098846 TI - Differentiated human NT2-N neurons possess a high intracellular content of myo inositol. AB - myo-Inositol plays a key role in signal transduction and osmotic regulation events in the CNS. Despite the known high concentrations of inositol in the human CNS, relatively little is known about its distribution within the different cell types. In this report, inositol homeostasis was studied in NT2-N cells, a unique cell culture model of human CNS neurons. Differentiation of precursor NT2 teratocarcinoma cells into NT2-N neurons by means of retinoic acid treatment resulted in an increase in inositol concentration from 24 to 195 nmol/mg of protein. After measurement of intracellular water spaces, inositol concentrations of 1.6 and 17.4 mM were calculated for NT2 and NT2-N cells, respectively. The high concentrations of inositol in NT2-N neurons could be explained by (1) an increased uptake of inositol (3.7 vs. 1.6 nmol/mg of protein/h, for NT2-N and NT2 cells, respectively) and (2) a decreased efflux of inositol (1.7%/h for NT2-N neurons vs. 9.0%/h for NT2 cells). Activity of inositol synthase, which mediates de novo synthesis of inositol, was not detected in either cell type. The observation that CNS neurons maintain a high intracellular concentration of inositol may be relevant to the regulation of both phosphoinositide signaling and osmotic stress events in the CNS. PMID- 10098847 TI - Group I metabotropic glutamate receptors mediate phospholipase D stimulation in rat cultured astrocytes. AB - We have studied the activation of phospholipase D (PLD) by glutamate in rat cultured astrocytes by measuring the PLD-catalyzed formation of [32P]phosphatidylbutanol in [32P]Pi-prelabeled cells, stimulated in the presence of butanol. Glutamate elicited the activation of PLD in cortical astrocytes but not in cortical neurons, whereas similar glutamate activation of phosphoinositide phospholipase C was found in both astrocytes and neurons. The extent of PLD stimulation by glutamate was similar in astrocytes from brain cortex and hippocampus, but no effect was found in cerebellar astrocytes. In cortical astrocytes, the glutamate response was insensitive to antagonists of ionotropic glutamate receptors and was reproduced by agonists of metabotropic glutamate receptors (mGluRs) with a rank order of agonist potency similar to that reported for group I mGluR-mediated phosphoinositide phospholipase activation [quisqualate > (S)-3,5-dihydroxyphenylglycine > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid]. The response to (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid was inhibited by the mGluR antagonist (S)-alpha-methyl-4-carboxyphenylglycine and, less potently, by 1-aminoindan-1,5-dicarboxylic acid and 4-carboxyphenylglycine, two antagonists of group I mGluRs that display higher potency on mGluR1 than on mGluR5. The mGluR5-selective agonist (RS)-2-chloro-5-hydroxyphenylglycine also activated PLD in astrocytes. These findings indicate the involvement of group I mGluRs, most likely mGluR5, in the glutamate activation of PLD in cultured rat cortical astrocytes. PMID- 10098848 TI - Inhibition of excessive neuronal apoptosis by the calcium antagonist amlodipine and antioxidants in cerebellar granule cells. AB - Neuronal cell death as a result of apoptosis is associated with cerebrovascular stroke and various neurodegenerative disorders. Pharmacological agents that maintain normal intracellular Ca2+ levels and inhibit cellular oxidative stress may be effective in blocking abnormal neuronal apoptosis. In this study, a spontaneous (also referred to as age-induced) model of apoptosis consisting of rat cerebellar granule cells was used to evaluate the antiapoptotic activities of voltage-sensitive Ca2+ channel blockers and various antioxidants. The results of these experiments demonstrated that the charged, dihydropyridine Ca2+ channel blocker amlodipine had very potent neuroprotective activity in this system, compared with antioxidants and neutral Ca2+ channel blockers (nifedipine and nimodipine). Within its effective pharmacological range (10-100 nM), amlodipine attenuated intracellular neuronal Ca2+ increases elicited by KCl depolarization but did not affect Ca2+ changes triggered by N-methyl-D-aspartate receptor activation. Amlodipine also inhibited free radical-induced damage to lipid constituents of the membrane in a dose-dependent manner, independent of Ca2+ channel modulation. In parallel experiments, spontaneous neuronal apoptosis was inhibited in dose- and time-dependent manners by antioxidants (U-78439G, alpha tocopherol, and melatonin), nitric oxide synthase inhibitors (N-nitro-L-arginine and N-nitro-D-arginine), and a nitric oxide chelator (hemoglobin) in the micromolar range. These results suggest that spontaneous neuronal apoptosis is associated with excessive Ca2+ influx, leading to further intracellular Ca2+ increases and the generation of reactive oxygen species. Agents such as amlodipine that block voltage-sensitive Ca2+ channels and inhibit cellular oxidative stress may be effective in the treatment of cerebrovascular stroke and neurodegenerative diseases associated with excessive apoptosis. PMID- 10098849 TI - Novel effects of FCCP [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone] on amyloid precursor protein processing. AB - Amyloidogenic processing of the beta-amyloid precursor protein (APP) has been implicated in the pathology of Alzheimer's disease. Because it has been suggested that catabolic processing of the APP holoprotein occurs in acidic intracellular compartments, we studied the effects of the protonophore carbonyl cyanide p (trifluoromethoxy)phenylhydrazone (FCCP) and the H+-ATPase inhibitor bafilomycin A1 on APP catabolism in human embryonic kidney 293 cells expressing either wild type or "Swedish" mutant APP. Unlike bafilomycin A1, which inhibits beta-amyloid production in cells expressing mutant but not wild-type APP, FCCP inhibited beta amyloid production in both cell types. Moreover, the effects of FCCP were independent of alterations in total cellular APP levels or APP maturation, and the concentrations used did not alter either cellular ATP levels or cell viability. Bafilomycin A1, which had no effect on beta-amyloid production in wild type cells, inhibited endocytosis of fluorescent transferrin, whereas concentrations of FCCP that inhibited beta-amyloid production in these cells had no effect on endosomal function. Thus, in wild-type-expressing cells it appears that the beta-amyloid peptide is not produced in the classically defined endosome. Although bafilomycin A1 decreased beta-amyloid release from cells expressing mutant APP but not wild-type APP, it altered lysosomal function in both cell types, suggesting that in normal cells beta-amyloid is not produced in the lysosome. Although inhibition of beta-amyloid production by bafilomycin A1 in mutant cells may occur via changes in endosomal/lysosomal pH, our data suggest that FCCP inhibits wild-type beta-amyloid production by acting on a bafilomycin A1-insensitive acidic compartment that is distinct from either the endosome or the lysosome. PMID- 10098850 TI - Interleukin-10 inhibits both production of cytokines and expression of cytokine receptors in microglia. AB - Microglia, macrophage-like cells in the CNS, are multifunctional cells; they play an important role in removal of dead cells or their remnants by phagocytosis in the CNS degeneration and are one of important cells in the CNS cytokine network to produce and respond to a variety of cytokines. The functions of microglia are regulated by inhibitory cytokines. We have reported the expression of interleukin (IL)-10, one of the inhibitory cytokines, and its receptor in mouse microglia; therefore, IL-10 may affect microglial functions. In this study, we investigated the effects of IL-10 on purified microglia in culture. IL-10 inhibited lipopolysaccharide-induced IL-1beta and tumor necrosis factor-alpha production, lysosomal enzyme activity, and superoxide anion production in a dose-dependent manner, but did not affect granulocyte/ macrophage colony-stimulating factor dependent proliferation of microglia. IL-10 also decreased the expression of both IL-6 receptor and lipopolysaccharide-induced IL-2 receptor but not IL-4 receptor on microglia as measured by flow cytometric analysis with an indirect immunofluorescence technique. IL-10 also decreased mRNA expression of IL-2 and IL 6 cytokine receptors. These results suggest that IL-10 is a unique and potent inhibitory factor in the CNS cytokine network involved in decreasing the expression of cytokine receptors as well as cytokine production by microglia. PMID- 10098851 TI - Phoneutria nigriventer toxin Tx3-1 blocks A-type K+ currents controlling Ca2+ oscillation frequency in GH3 cells. AB - GH3 cells present spontaneous Ca2+ action potentials and oscillations of intracellular Ca2+, which can be modified by altering the activity of K+ or Ca2+ channels. We took advantage of this spontaneous activity to screen for effects of a purified toxin (Tx3-1) from the venom of Phoneutria nigriventer on ion channels. We report that Tx3-1 increases the frequency of Ca2+ oscillations, as do two blockers of potassium channels, 4-aminopyridine and charybdotoxin. Whole cell patch clamp experiments show that Tx3-1 reversibly inhibits the A-type K+ current (I(A)) but does not block other K+ currents (delayed-rectifying, inward rectifying, and large-conductance Ca2+-sensitive) or Ca2+ channels (T and L type) in these cells. In addition, we describe the sequence of a full cDNA clone of Tx3 1, which shows that Tx3-1 has no homology to other known blockers of K+ channels and gives insights into the processing of this neurotoxin. We conclude that Tx3-1 is a selective inhibitor of I(A), which can be used to probe the role of this channel in the control of cellular function. Based on the effect of Tx3-1, we suggest that I(A) is an important determinant of the frequency of Ca2+ oscillations in unstimulated GH3 cells. PMID- 10098852 TI - Tumor necrosis factor-alpha and phorbol 12-myristate 13-acetate differentially modulate cytotoxic effect of nitric oxide generated by serum deprivation in neuronal PC12 cells. AB - Nitric oxide (NO) is a signaling molecule that mediates several physiological processes in a range of cell and tissue types. Here we investigated the effect of serum deprivation in the absence or presence of phorbol 12-myristate 1 3-acetate (PMA) or tumor necrosis factor-alpha (TNFalpha) on cell viability, NO formation, inducible NO synthase (iNOS) induction, and activation of mitogen-activated protein kinase in neuronal PC12 cells. Within 24 h of serum deprivation, apoptosis occurred in up to 65-70% of the cells, and significant levels of NO were generated. When PMA was added in serum-free medium, NO formation and cell death were decreased. In contrast, addition of TNFalpha in serum-free medium increased the levels of NO formation and apoptosis compared with those in serum deprived cells. We have demonstrated that differential generation of NO levels by PMA or TNFalpha under conditions of serum deprivation is mediated by the same pattern of iNOS induction. NO formation via iNOS induction resulted in the activation of c-Jun N-terminal kinase (JNK) but not extracellular signal regulated kinase. From this study it is suggested that the differential formation of cytotoxic NO by serum deprivation plus PMA or TNFalpha is primarily mediated by the induction of iNOS enzymes in neuronal PC12 cells and that its action is mediated by the activation of JNK. PMID- 10098853 TI - Agonist stimulation of the serotonin1A receptor causes suppression of anoxia induced apoptosis via mitogen-activated protein kinase in neuronal HN2-5 cells. AB - Previous studies have indicated that stimulation of neuronal inhibitory receptors, such as the serotonin1A receptor (5-HT1A-R), could cause attenuation of the activity of both N-type Ca2+ channels and N-methyl-D-aspartic acid receptors, thus resulting in protection of neurons against excitotoxicity. The purpose of this study was to investigate if the 5-HT1A-R is also coupled to an alternative pathway that culminates in suppression of apoptosis even in cells that are deficient in Ca2+ channels. Using a hippocampal neuron-derived cell line (HN2-5) that is Ca2+ channel-deficient, we demonstrate here that an alternative pathway is responsible for 5-HT1A-R-mediated protection of these cells from anoxia-triggered apoptosis, assessed by deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL). The 5-HT1A-R agonist-evoked protection was eliminated in the presence of pertussis toxin and also required phosphorylation mediated activation of mitogen-activated protein kinase (MAPK), as evidenced by the elimination of the agonist-elicited rescue of neuronal cells by the MAPK kinase inhibitor PD98059 but not by the phosphatidylinositol 3-kinase (PI-3K) inhibitor wortmannin. Furthermore, agonist stimulation of the 5-HT1A-R caused a 60% inhibition of anoxia-stimulated caspase 3-like activity in the HN2-5 cells, and this inhibition was abrogated by PD98059 but not by wortmannin. Although agonist stimulation of the 5-HT1A-R caused an activation of PI-3Kgamma in HN2-5 cells, our results showed that this PI-3Kgamma activity was not linked to the 5 HT1A-R-promoted regulation of caspase activity and suppression of apoptosis. Thus, in the neuronal HN2-5 cells, agonist binding to the 5-HT1A-R results in MAPK-mediated inhibition of a caspase 3-like enzyme and a 60-70% suppression of anoxia-induced apoptosis through a Ca2+ channel-independent pathway. PMID- 10098854 TI - Developmental neurotoxicity of phenytoin on granule cells and Purkinje cells in mouse cerebellum. AB - Phenytoin (PHT) is a primary antiepileptic drug. Cerebellar malformations in human neonates have been described following intrauterine exposure to PHT. The neonatal period of development in the cerebellum in mice corresponds to the last trimester in humans. To examine the neurotoxic effects of PHT in the developing cerebellum, we administered PHT orally to newborn mice once a day during postnatal days 2-4. We observed many apoptotic cells in the external granular layer (EGL) on postnatal day 5, labeled cells in the EGL still remaining 72 h after labeling with 5-bromo-2'-deoxyuridine, and EGL thicker than that in the control on postnatal day 14. These results showed that PHT induced cell death of external granule cells and inhibited migration of granule cells in cerebella. In specimens immunostained with antibody against inositol 1,4,5-trisphosphate receptor type 1, Purkinje cells in the treated group had poor and immature arbors, and partially showed an irregular arrangement. The motor performance of the treated mice in a rotating rod test was impaired, although there were no changes in muscular strength or in walking pattern at the period of maturity. These findings indicate that PHT induces neurotoxic damage to granule cells and Purkinje cells in the developing cerebellum and impairs selected aspects of motor coordination ability. PMID- 10098855 TI - Anoxia-induced dopamine release from rat striatal slices: involvement of reverse transport mechanism. AB - Incubation of rat striatal slices in the absence of oxygen (anoxia), glucose (aglycemia), or oxygen plus glucose (ischemia) caused significant increases in dopamine (DA) release. Whereas anoxia decreased extracellular 3,4 dihydroxyphenylacetic acid levels by 50%, aglycemia doubled it, and ischemia returned this aglycemia-induced enhancement to its control level. Although nomifensine, a DA uptake blocker, completely protected the slices against anoxia induced DA depletion, aglycemia- and ischemia-induced increases were not altered. Moreover, hypothermia differentially affected DA release stimulated by anoxia, aglycemia, and ischemia. Involvement of glutamate in DA release induced by each experimental condition was tested by using MK-801 and also by comparing the glutamate-induced DA release with that during anoxia, aglycemia, or ischemia. MK 801 decreased the anoxia-induced DA depletion in a dose-dependent manner. This treatment, however, showed a partial protection in aglycemic conditions but failed to improve ischemia-induced DA depletion. Like anoxia, DA release induced by exogenous glutamate was also sensitive to nomifensine and hypothermia. These results indicate that anoxia enhances DA release by a mechanism involving both the reversed DA transporter and endogenous glutamate. Partial or complete lack of effect of nomifensine, hypothermia, or MK-801 in the absence of glucose or oxygen plus glucose also suggests that experimental conditions, such as the degree of anoxia/ischemia, may alter the mechanism(s) involved in DA depletion. PMID- 10098856 TI - Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats. AB - The differential behavioral and neurochemical effects of exogenous L-DOPA in animals with intact versus dopamine (DA)-denervated striata raise questions regarding the role of DA terminals in the regulation of dopaminergic neurotransmission after administration of exogenous L-DOPA. In vivo microdialysis was used to monitor the effect of exogenous L-DOPA on extracellular DA in intact and DA-denervated striata of awake rats. In intact striatum, a small increase in extracellular DA was observed after administration of L-DOPA (50 mg/kg i.p.) but in DA-denervated striatum a much larger increase in extracellular DA was elicited. Additional experiments assessed the role of high-affinity DA uptake and impulse-dependent neurotransmitter release in the effect of exogenous L-DOPA on extracellular DA in striatum. Pretreatment with GBR-12909 (20 mg/kg i.p.), a selective DA uptake inhibitor, enhanced the ability of L-DOPA to increase extracellular DA in intact striatum. However, in DA-denervated striatum, inhibition of DA uptake did not alter the extracellular DA response to L-DOPA. Impulse-dependent neurotransmitter release was blocked by the infusion of tetrodotoxin (TTX; 1 microM), an inhibitor of fast sodium channels, through the dialysis probe. Application of TTX significantly attenuated the L-DOPA-induced increase in extracellular DA observed in striatum of intact rats pretreated with GBR-12909. In a similar manner, TTX infusion significantly attenuated the increase in extracellular DA typically observed in striatum of 6-OHDA-lesioned rats after the administration of L-DOPA. The present results indicate that DA terminals, via high-affinity uptake, play a crucial role in the clearance of extracellular DA formed from exogenous L-DOPA in intact striatum. This regulatory mechanism is absent in the DA-denervated striatum. In addition, this study has shown that DA synthesized from exogenous L-DOPA primarily is released by an impulse-dependent mechanism in both intact and DA-denervated striatum. The latter result suggests an important role for a nondopaminergic neuronal element in striatum that serves as the primary source of extracellular DA formed from exogenous L-DOPA. PMID- 10098857 TI - Insulin causes a transient tyrosine phosphorylation of NR2A and NR2B NMDA receptor subunits in rat hippocampus. AB - NMDA receptors play a critical role in various aspects of CNS function. Hence, it is important to identify mechanisms that regulate NMDA receptor activity. We have shown previously that insulin rapidly potentiates NMDA receptor activity in both native and recombinant expression systems. Here we report that insulin causes a transient phosphorylation of NR2A and NR2B NMDA receptor subunits on tyrosine residues. Rat hippocampal slices were exposed to 1 microM insulin for 20 and 60 min and then solubilized. NR2A and NR2B subunits were immunoprecipitated and probed for tyrosine phosphorylation. Insulin incubation of hippocampal slices for 20 min elicited an increase in tyrosine phosphorylation to 176 +/- 16% (NR2A) and 203 +/- 15% (NR2B) of control levels. In contrast, 60 min of insulin incubation did not alter NR2 tyrosine phosphorylation levels (NR2A: 85 +/- 13% of control; NR2B: 93 +/- 10% of control). Although the consequence of insulin-stimulated tyrosine phosphorylation is unknown, it is possible that this site(s) is responsible for insulin potentiation of NMDA receptor activity. This possibility is consistent with our earlier finding that insulin potentiates hippocampal NMDA receptor activity after 20 min, but not after 60 min, of insulin exposure. PMID- 10098858 TI - RGS mRNA expression in rat striatum: modulation by dopamine receptors and effects of repeated amphetamine administration. AB - Single injections of cocaine, amphetamine, or methamphetamine increased RGS2 mRNA levels in rat striatum by two- to fourfold. The D1 dopamine receptor-selective antagonist SCH-23390 had no effect by itself but strongly attenuated RGS2 mRNA induction by amphetamine. In contrast, the D2 receptor-selective antagonist raclopride induced RGS2 mRNA when administered alone and greatly enhanced stimulation by amphetamine. To examine the effects of repeated amphetamine on RGS2 expression, rats were treated with escalating doses of amphetamine (1.0-7.5 mg/kg) for 4 days, followed by 8 days of multiple daily injections (7.5 mg/kg/2 h x four injections). Twenty hours after the last injection the animals were challenged with amphetamine (7.5 mg/kg) or vehicle and killed 1 h later. In drug naive animals, acute amphetamine induced the expression of RGS2, 3, and 5 and the immediate early genes c-fos and zif/268. RGS4 mRNA levels were not affected. Prior repeated treatment with amphetamine strongly suppressed induction of immediate early genes and RGS5 to a challenge dose of amphetamine. In sharp contrast, prior exposure to amphetamine did not reduce the induction of RGS2 and RGS3 mRNAs to a challenge dose of amphetamine, indicating that control of these genes is resistant to amphetamine-induced tolerance. These data establish a role for dopamine receptors in the regulation of RGS2 expression and suggest that RGS2 and 3 might mediate some aspects of amphetamine-induced tolerance. PMID- 10098859 TI - Characterization of detergent-insoluble complexes containing the familial Alzheimer's disease-associated presenilins. AB - Many cases of early-onset familial Alzheimer's disease have been linked to mutations within two genes encoding the proteins presenilin-1 and presenilin-2. The presenilins are 48-56-kDa proteins that can be proteolytically cleaved to generate an N-terminal fragment (approximately 25-35 kDa) and a C-terminal fragment (approximately 17-20 kDa). The N- and C-terminal fragments of presenilin 1, but not full-length presenilin-1, were readily detected in both human and mouse cerebral cortex and in neuronal and glioma cell lines. In contrast, presenilin-2 was detected almost exclusively in cerebral cortex as the full length molecule with a molecular mass of 56 kDa. The association of the presenilins with detergent-insoluble, low-density membrane microdomains, following the isolation of these structures from cerebral cortex by solubilization in Triton X-100 and subsequent sucrose density gradient centrifugation, was also examined. A minor fraction (10%) of both the N- and C terminal fragments of presenilin-1 was associated with the detergent-insoluble, low-density membrane microdomains, whereas a considerably larger proportion of full-length presenilin-2 was present in the same membrane microdomains. In addition, a significant proportion of full-length presenilin-2 was present in a high-density, detergent-insoluble cytoskeletal pellet enriched in beta-actin. The presence of the presenilins in detergent-insoluble, low-density membrane microdomains indicates a possible role for these specialized regions of the membrane in the lateral separation of Alzheimer's disease-associated proteins within the lipid bilayer and/or in the distinct functions of these proteins. PMID- 10098860 TI - Molecular cloning of a novel member of the HSP110 family of genes, ischemia responsive protein 94 kDa (irp94), expressed in rat brain after transient forebrain ischemia. AB - To identify genes induced by transient forebrain ischemia, we used the mRNA differential display technique in the four-vessel occlusion model in rats. Some genes were identified as candidates that encode ischemia-responsive protein, and one of them was cloned as ischemia-responsive protein 94 kDa (irp94) from the rat hippocampal cDNA library. Sequence analysis suggested that rat irp94 was a transcriptional variant or a homologue of mouse apg-2 and human heat shock protein (hsp) 70RY and a member of the HSP110 family, because IRP94 was >90% identical to APG-2 and HSP70RY and approximately 60% identical to the other members of the HSP110 family. Although irp94 mRNA was constitutively expressed in the normal hippocampus, it was clearly enhanced 4-24 h after ischemia for 10 (1.9 fold increase) and 15 min (3.4-fold increase). These changes mainly occurred in neuronal cells, as judged by the localization of irp94 mRNA using in situ hybridization histochemistry. On the other hand, hyperthermic stress did not enhance irp94 mRNA expression, suggesting that irp94 expression was enhanced under ischemic stress and not related to the heat shock signaling mechanism. Our study suggested that irp94, a novel member of the HSP110 family, might play an important role in the environment altering neuronal functions, especially after transient forebrain ischemia. PMID- 10098861 TI - Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease. AB - Recent findings indicate that estrogen is neuroprotective, a cellular effect that may contribute to its clinical benefits in delaying the development of Alzheimer's disease. In this report, we identify a novel neuronal action of estrogen that may contribute to its neuroprotective mechanism(s). Specifically, we report that estrogen significantly increases the expression of the antiapoptotic protein Bcl-xL in cultured hippocampal neurons. This effect presumably reflects classic estrogen transcriptional regulation, as we identified a putative estrogen response element in the bcl-x gene. Estrogen-induced enhancement of Bcl-xL is associated with a reduction in measures of beta-amyloid induced apoptosis, including inhibition of both caspase-mediated proteolysis and neurotoxicity. A similar relationship between estrogen, Bcl-xL expression, and resistance to degeneration was also observed in human hippocampus. We report neuronal colocalization of estrogen receptor and Bcl-xL immunoreactivities that is most prominent in hippocampal subfield CA3, a region that shows relatively little immunoreactivity to paired helical filament-1, a marker of Alzheimer's disease neurodegeneration. These data suggest a novel mechanism of estrogen neuroprotection that may be relevant to estrogen's suggested ability to modulate neuronal viability across the life span, from neural sexual differentiation and development through age-related neurodegenerative conditions. PMID- 10098863 TI - A nuclear microscopic study of elemental changes in the rat hippocampus after kainate-induced neuronal injury. AB - The effect of intracerebroventricular kainate injection on the elemental composition of the hippocampus was studied in adult Wistar rats, at 1 day and 1, 2, 3, and 4 weeks postinjection, using a nuclear microscope. An increase in calcium concentration was observed on the injected side from 1 day postinjection. The increase peaked at 3 weeks postinjection, reaching a concentration of 18 times normal. Large numbers of glial cells but no neurons were observed in the lesioned CA fields at this time, suggesting that an increased calcium level was present in glial cells. This was confirmed by high-resolution elemental maps of the lesioned areas, which showed very high intracellular calcium concentrations in almost all glial cells. It is possible that the high intracellular calcium level could activate calcium-dependent enzymes, including calpain II and cytosolic phospholipase A2, shown to be expressed in reactive glial cells after kainate injections. In addition to calcium, an increase in iron content was also observed at the periphery of the glial scar at 4 weeks postinjection. Because free iron could catalyze the formation of free radicals, the late increase in iron content may be related to oxygen radical formation during neurodegeneration. PMID- 10098862 TI - Proteolytic fragments of Alzheimer's disease-associated presenilin 1 are present in synaptic organelles and growth cone membranes of rat brain. AB - Previous studies have demonstrated the molecular linkage of three causative genes for early-onset Alzheimer's disease: the presenilin 1 gene on chromosome 14, the presenilin 2 gene on chromosome 1, and the amyloid precursor protein gene on chromosome 21. In the present study, we have investigated the distributions of the approximately 20-kDa C-terminal and approximately 30-kDa N-terminal fragments of presenilin 1 and the amyloid precursor protein in rat brain and compared them with the distribution of several marker proteins. The fragments of presenilin 1 are present in synaptic plasma membranes, neurite growth cone membranes, and small synaptic vesicles of rat brain. Both proteolytic fragments are coenriched in the corresponding tissue fractions. Based on this observation, it seems likely that N- and C-terminal presenilin 1 fragments form a functional unit while remaining associated. In contrast to a predominant subcellular localization of presenilin 1 to the endoplasmic reticulum and Golgi apparatus in different cell lines, our results indicate that rat brain presenilin 1 fragments exit from these biosynthetic compartments to reach synaptic organelles in neurons. PMID- 10098864 TI - Metabolic consequences of the cytochrome c oxidase deficiency in brain of copper deficient Mo(vbr) mice. AB - Biochemical micromethods were used for the investigation of changes in mitochondrial oxidative phosphorylation associated with cytochrome c oxidase deficiency in brain cortex from Mo(vbr) (mottled viable brindled) mice, an animal model of Menkes' copper deficiency syndrome. Enzymatic analysis of cortex homogenates from Mo(vbr) mice showed an approximately twofold decrease in cytochrome c oxidase and a 1.4-fold decrease in NADH:cytochrome c reductase activities as compared with controls. Assessment of mitochondrial respiratory function was performed using digitonin-treated homogenates of the cortex, which exhibited the main characteristics of isolated brain mitochondria. Despite the substantial changes in respiratory chain enzyme activities, no significant differences were found in maximal pyruvate or succinate oxidation rates of brain cortex homogenates from Mo(vbr) and control mice. Inhibitor titrations were used to determine flux control coefficients of NADH:CoQ oxidoreductase and cytochrome c oxidase on the rate of mitochondrial respiration. Application of amobarbital to titrate the activity of NADH:CoQ oxidoreductase showed very similar flux control coefficients for control and mutant animals. Alternately, titration of respiration with azide revealed for Mo(vbr) mice significantly sharper inhibition curves than for controls, indicating a more than twofold elevated flux control coefficient of cytochrome c oxidase. Owing to the reserve capacity of respiratory chain enzymes, the reported changes in activities do not seem to affect whole brain high-energy phosphates, as observed in a previous study using 31P NMR. PMID- 10098865 TI - Pyrrolidine dithiocarbamate induces bovine cerebral endothelial cell death by increasing the intracellular zinc level. AB - The antioxidant and metal-chelating effects of pyrrolidine dithiocarbamate (PDTC) have been extensively studied. PDTC prevents cell death induced by various insults. However, PDTC itself may cause cell death in selected experimental paradigms. PDTC induced bovine cerebral endothelial cell death. However, in serum depleted medium, PDTC did not affect the cell viability, suggesting that certain factors in serum may mediate the cytotoxic effect of PDTC. The metal chelators bathocuproine disulfonic acid, o-phenanthroline, bathophenanthroline disulfonic acid, and N,N,N',N'-tetrakis(2-pyridyl-methyl)ethylenediamine (TPEN) prevented the cell death induced by PDTC. In a serum-deprived condition, addition of exogenous metals, copper or zinc, restored the cytotoxic effect of PDTC. These data indicate that metals such as copper or zinc in serum may mediate the cytotoxic effect of PDTC. The potency of zinc for PDTC-induced endothelial cell death was greater than that of copper. Zn-EDTA did not block PDTC-induced cell death, whereas Ca-EDTA and Cu-EDTA were able to prevent this PDTC effect. PDTC increased the intracellular fluorescence of the zinc probe dye N-(6-methoxy-8 quinolyl)-p-toluenesulfonamide, which was quenched by TPEN or various EDTA preparations but not by Zn-EDTA. Results suggest that an increase in intracellular zinc concentration is required in PDTC-induced cerebral endothelial cell death. PMID- 10098866 TI - Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. AB - Having shown a decrease in serotonin2A receptors in the dorsolateral prefrontal cortex (DLPFC) from schizophrenic subjects, we have now determined if this change was reflective of widespread changes in neurochemical markers in DLPFC in schizophrenia. In Brodmann's area (BA) 9 from 19 schizophrenic and 19 control subjects, we confirmed a decrease in the density of [3H]ketanserin binding to serotonin2A receptors in tissue from the schizophrenic subjects [39 +/- 3.3 vs. 60 +/- 3.6 fmol/mg estimated tissue equivalents (ETE); p < 0.005]. In addition, the density of [3H]muscimol binding to GABA(A) receptors was increased in the schizophrenic subjects (526 +/- 19 vs. 444 +/- 28 fmol/mg ETE; p < 0.02). [3H]YM 09151-2, N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine, [3H]SCH 23390, [3H]mazindol, and N(G)-nitro-L-[3H]arginine binding to BA 9 did not differ between groups, and there was no specific binding of [3H]raclopride or 7-hydroxy 2-(di-n-[3H]propylamino)tetralin to BA 9 from either cohort of subjects. This suggests the density of dopamine D1-like and NMDA receptors, the dopamine transporter, and nitric oxide synthase activity are not altered in BA 9 from schizophrenic subjects. The selective nature of the changes in serotonin2A and GABA(A) receptors in DLPFC could indicate that these changes are involved in the pathology of schizophrenia. PMID- 10098867 TI - Molecular isoform distribution and glycosylation of acetylcholinesterase are altered in brain and cerebrospinal fluid of patients with Alzheimer's disease. AB - The glycosylation of acetylcholinesterase (AChE) in CSF was analyzed by lectin binding. AChE from Alzheimer's disease (AD) patients was found to bind differently to two lectins, concanavalin A and wheat germ agglutinin, than AChE from controls. As multiple isoforms of AChE are present in both CSF and brain, we examined whether the abnormal glycosylation of AD AChE was due to changes in a specific molecular isoform. Globular amphiphilic dimeric (G2a) and monomeric (G1a) isoforms of AChE were found to be differentially glycosylated in AD CSF. Glycosylation of AChE was also altered in AD frontal cortex but not in cerebellum and was also associated with an increase in the proportion of light (G2 and G1) isoforms. This study demonstrates that the glycosylation of AChE is altered in the AD brain and that changes in AChE glycosylation in AD CSF may reflect changes in the distribution of brain isoforms. The study also suggests that glycosylation of AChE may be a useful diagnostic marker for AD. PMID- 10098868 TI - Mediation by membrane protein kinase C of zinc-induced oxidative neuronal injury in mouse cortical cultures. AB - Transsynaptic movement of endogenous zinc may play a key role in selective neuronal death after brain ischemia and prolonged seizures. As to the mechanism, we have reported recently that zinc-induced neuronal death occurs mainly by oxidative stress in cortical cultures. Here we present evidence supporting the idea that activation of membrane protein kinase C (PKC) in neurons is likely to play a key role in zinc-induced oxidative neuronal injury. Exposure of cortical cultures to 300 microM zinc for 15 min induced increases in the activity, without changing the amount, of membrane PKC to two- to threefold of control values, followed by neuronal death over the next day. Addition of a zinc chelator, Ca EDTA, or PKC inhibitors with zinc completely abolished the zinc-induced increase in the membrane PKC activity. Indicating the participation of PKC in zinc-induced oxidative stress and neuronal death, the selective PKC inhibitor GF109203X attenuated both. Furthermore, as in zinc-induced neuronal death, activation of PKC with phorbol esters induced free radical generation and neuronal death, which were blocked by GF109203X or an antioxidant, Trolox. The present results support the idea that zinc influx activates PKC in the membrane, which contributes to free radical generation and neuronal death. As an increasing body of evidence suggests that zinc neurotoxicity is an important mechanism of pathological neuronal death, timely prevention of PKC activation after acute brain insult may prove useful in ameliorating this type of neuronal death. PMID- 10098869 TI - 4-Hydroxy-2(E)-nonenal inhibits CNS mitochondrial respiration at multiple sites. AB - A destructive cycle of oxidative stress and mitochondrial dysfunction is proposed in neurodegenerative disease. Lipid peroxidation, one outcome of oxidative challenge, can lead to the formation of 4-hydroxy-2(E)-nonenal (HNE), a lipophilic alkenal that forms stable adducts on mitochondrial proteins. In this study, we characterized the effects of HNE on brain mitochondrial respiration. We used whole rat brain mitochondria and concentrations of HNE comparable to those measured in patients with Alzheimer's disease. Our results showed that HNE inhibited respiration at multiple sites. Complex I-linked and complex II-linked state 3 respirations were inhibited by HNE with IC50 values of approximately 200 microM HNE. Respiration was apparently diminished owing to the inhibition of complex III activity. In addition, complex II activity was reduced slightly. The lipophilicity and adduction characteristics of HNE were responsible for the effects of HNE on respiration. The inhibition of respiration was not prevented by N-acetylcysteine or aminoguanidine. Studies using mitochondria isolated from porcine cerebral cortex also demonstrated an inhibition of complex I- and complex II-linked respiration. Thus, in neurodegenerative disease, oxidative stress may impair mitochondrial respiration through the production of HNE. PMID- 10098870 TI - Differential involvement of central and peripheral norepinephrine in the central lipopolysaccharide-induced interleukin-6 responses in mice. AB - Intracerebroventricular injection of lipopolysaccharide (LPS) induces a marked increase in circulating interleukin (IL)-6 levels and in IL-6 mRNA expression in brain and peripheral organs. Recently, it was reported that intraperitoneal administration of alpha-adrenoceptor antagonists inhibits centrally injected LPS induced increases in plasma IL-6 levels, suggesting the involvement of the norepinephrine (NE) system in the central LPS-induced IL-6 response. However, the localization (either central or peripheral) of NE involvement in the central LPS induced IL-6 response has not been characterized. In the present study, mice were pretreated with 6-hydroxydopamine (6-OHDA) administered intracerebroventricularly or intraperitoneally to deplete central or peripheral stores of NE, respectively. Intracerebroventricular LPS (50 ng/mouse) markedly increased plasma IL-6 levels and IL-6 mRNA expression in choroid plexus, hypothalamus, pituitary, adrenals, heart, liver, spleen, and lymph nodes, but with minimal effect in lung, kidney, and testis, as revealed by RT-PCR. Pretreatment with intracerebroventricular 6 OHDA (50 microg/mouse) decreased the LPS-induced plasma IL-6 levels by 39% and the LPS-induced IL-6 mRNA expression in liver, spleen, and lymph nodes, but not in choroid plexus, hypothalamus, pituitary, adrenals, and heart. Pretreatment with intraperitoneal 6-OHDA (100 mg/kg) decreased the LPS-induced plasma IL-6 levels by 36% and the LPS-induced IL-6 mRNA expression in all the peripheral organs displaying increased IL-6 mRNA. Central LPS-induced increase in plasma corticosterone levels was decreased slightly by central but not by peripheral NE depletion. These results suggest that central NE and peripheral NE are differentially involved in the central LPS-induced IL-6 mRNA expression in peripheral organs. PMID- 10098871 TI - Carboxyfullerene prevents iron-induced oxidative stress in rat brain. AB - Carboxyfullerene, a water-soluble carboxylic acid derivative of a fullerene, was investigated as a protective agent against iron-induced oxidative stress in the nigrostriatal dopaminergic system of anesthetized rats. Intranigral infusion of exclusive carboxyfullerene did not increase lipid peroxidation in substantia nigra or deplete dopamine content in striatum. Infusion of ferrous citrate (iron II) induced degeneration of the nigrostriatal dopaminergic system. An increase in lipid peroxidation in substantia nigra as well as decreases in K+-evoked dopamine overflow and dopamine content in striatum were observed 7 days after the infusion. Co-infusion of carboxyfullerene prevented iron-induced oxidative injury. Furthermore, tyrosine hydroxylase-immunoreactive staining showed that carboxyfullerene inhibited the iron-induced loss of the dopaminergic nerve terminals in striatum. The antioxidative action of carboxyfullerene was verified by in vitro studies. Incubation of brain homogenates increased the formation of the Schiff base fluorescent products of malonaldehyde, an indicator of lipid peroxidation. Both autooxidation (without exogenous iron) and iron-induced elevation of lipid peroxidation of brain homogenates were suppressed by carboxyfullerene in a dose-dependent manner. Our results suggest that intranigral infusion of carboxyfullerene appears to be nontoxic to the nigrostriatal dopaminergic system. Furthermore, the potent antioxidative action of carboxyfullerene protects the nigrostriatal dopaminergic system from iron-induced oxidative injury. PMID- 10098872 TI - Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. AB - Brain serotonin synthesis and metabolism (turnover), as indicated by CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), may depend on plasma concentrations of the essential amino acid L-tryptophan (TRP). We investigated the biochemical effects of acute plasma TRP depletion (ATD) in normal volunteers undergoing a 36-h CSF collection via lumbar drain. Six subjects who were in good health were put on a low-TRP diet (160 mg/day) 24 h before lumbar puncture; this diet was continued for the first 22 h of the CSF collection. At hour 22, subjects ingested a TRP-deficient 15-amino acid drink shown previously to deplete plasma TRP. Total plasma TRP, free plasma TRP, and CSF TRP subsequently decreased 86.3, 86.5, and 92.3%, respectively. CSF 5-HIAA decreased by 32.8%. Plasma total and free TRP concentrations were both decreased at approximately 2 h following ingestion of the TRP-free amino acid drink and were lowest approximately 6 h after ATD; CSF TRP and 5-HIAA were decreased at 2.5 h and approximately 4 h after ATD, respectively. CSF TRP was lowest 8.0 h later. CSF 5-HIAA continued to decrease 14 h after the TRP-deficient amino acid drink was given. PMID- 10098873 TI - Association of the dystroglycan complex isolated from bovine brain synaptosomes with proteins involved in signal transduction. AB - Dystroglycan is a transmembrane heterodimeric complex of alpha and beta subunits that links the extracellular matrix to the cell cytoskeleton. It was originally identified in skeletal muscle, where it anchors dystrophin to the sarcolemma. Dystroglycan is also highly expressed in nonmuscle tissues, including brain. To investigate the molecular interactions of dystroglycan in the CNS, we fractionated a digitonin-soluble extract from bovine brain synaptosomes by laminin-affinity chromatography and characterized the protein components. The 120 kDa alpha-dystroglycan was the major 125I-laminin-labeled protein detected by overlay assay. This complex, in addition to beta-dystroglycan, was also found to contain Grb2 and focal adhesion kinase p125FAK (FAK). Anti-FAK antibodies co immunoprecipitated Grb2 with FAK. However, no direct interaction between beta dystroglycan and FAK was detected by co-precipitation assay. Grb2, an adaptor protein involved in signal transduction and cytoskeleton organization, has been shown to bind beta-dystroglycan. We isolated both FAK and Grb2 from synaptosomal extracts by chromatography on immobilized recombinant beta-dystroglycan. In the CNS, FAK phosphorylation has been linked to membrane depolarization and neurotransmitter receptor activation. At the synapses, the adaptor protein Grb2 may mediate FAK-beta-dystroglycan interaction, and it may play a role in transferring information between the dystroglycan complex and other signaling pathways. PMID- 10098874 TI - Alpha-conotoxin ImI inhibits the alpha-bungarotoxin-resistant nicotinic response in bovine adrenal chromaffin cells. AB - The activity of alpha-conotoxin (alpha-CTX) ImI, from the vermivorous marine snail Conus imperialis, has been studied on mammalian nicotinic receptors on bovine chromaffin cells and at the rat neuromuscular junction. Synthetic alpha CTX ImI was a potent inhibitor of the neuronal nicotinic response in bovine adrenal chromaffin cells (IC50 = 2.5 microM, log IC50 = 0.4 +/- 0.07), showing competitive inhibition of nicotine-evoked catecholamine secretion. Alpha-CTX ImI also inhibited nicotine-evoked 45Ca2+ uptake but not 45Ca2+ uptake stimulated by 56 mM K+. In contrast, alpha-CTX ImI had no effect at the neuromuscular junction over the concentration range 1-20 microM. Bovine chromaffin cells are known to contain the alpha3beta4, alpha7, and (possibly) alpha3beta4alpha5 subtypes. However, the secretory response of bovine chromaffin cells is not inhibited by alpha-bungarotoxin, indicating that alpha7 nicotinic receptors are not involved. We propose that alpha-CTX Iml interacts selectively with the functional (alpha3beta4 or alpha3beta4alpha5) nicotinic acetylcholine receptor to inhibit the neuronal-type nicotinic response in bovine chromaffin cells. PMID- 10098875 TI - Autoradiographic reevaluation of the binding properties of 125I [Leu31,Pro34]peptide YY and 125I-peptide YY3-36 to neuropeptide Y receptor subtypes in rat forebrain. AB - 125I-[Leu31,Pro34]peptide YY (PYY) and 125I-PYY3-36, initially described as selective neuropeptide Y Y1 and Y2 receptor ligands, respectively, were recently shown to label also Y4 and Y5 receptors. We used receptor autoradiography to assess whether these ligands can be reliably used to investigate the various neuropeptide Y receptors in rat forebrain. In most of the brain regions examined (in coronal sections at the level of dorsal hippocampus), specific 125I [Leu31,Pro34]PYY binding was completely inhibited by 1 microM BIBP-3226, a selective Y1 receptor ligand, but unaffected by 10 nM rat pancreatic polypeptide, selectively inhibiting Y4 receptors, suggesting that Y4 receptors are present in negligible numbers compared with Y1 receptors in the areas examined. Significant numbers of BIBP-3226-insensitive 125I-[Leu31,Pro34]PYY binding sites were measured in the CA3 subfield of the hippocampus only, possibly representing Y5 receptors. 125I-PYY3-36 binding was unchanged by 1 microM BIBP-3226, whereas a population of 125I-PYY3-36 binding sites was sensitive to 100 nM [Leu31,Pro34]neuropeptide Y, likely representing Y5 receptors. The possibility of distinguishing between Y2 and Y5 receptors using 125I-PYY3-36 as radioligand was validated by their different regional distribution and their distinct changes 24 h after kainate seizures, i.e., binding to Y5 receptors was selectively decreased in the outer cortex, whereas binding to Y2 receptors was enhanced in the hippocampus. Thus, the use of selective unlabeled compounds is required for distinguishing the various receptor subtypes labeled by 125I-[Leu31,Pro34]PYY and 125I-PYY3-36 in rat brain tissue. PMID- 10098876 TI - Expression and signaling of group I metabotropic glutamate receptors in astrocytes and microglia. AB - Stimulation of astrocytes with the excitatory neurotransmitter glutamate leads to the formation of inositol 1,4,5-trisphosphate and the subsequent increase of intracellular calcium content. Astrocytes express both ionotropic receptors and metabotropic glutamate (mGlu) receptors, of which mGlu5 receptors are probably involved in glutamate-induced calcium signaling. The mGlu5 receptor occurs as two splice variants, mGlu5a and mGlu5b, but it was hitherto unknown which splice variant is responsible for the glutamate-induced effects in astrocytes. We report here that both mRNAs encoding mGlu5 receptor splice variants are expressed by cultured astrocytes. The expression of mGlu5a receptor mRNA is much stronger than that of mGlu5b receptor mRNA in these cells. In situ hybridization experiments reveal neuronal expression of mGlu5b receptor mRNA in adult rat forebrain but a strong neuronal expression of mGlu5a mRNA only in olfactory bulb. Signals for mGlu5a receptor mRNA in the rest of the brain were diffuse and weak but consistently above background. Activation of mGlu5 receptors in astrocytes yields increases in inositol phosphate production and transient calcium responses. It is surprising that the rank order of agonist potency [quisqualate > (2S,1 'S,2'S)-2 (carboxycyclopropyl)glycine = trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD) > glutamate] differs from that reported for recombinantly expressed mGlu5a receptors. The expression of mGlu5a receptor mRNA and the occurrence of 1S,3R-ACPD-induced calcium signaling were found also in cultured microglia, indicating for the first time expression of mGlu5a receptors in these macrophage-like cells. PMID- 10098877 TI - The sulfate moieties of glycosaminoglycans are critical for the enhancement of beta-amyloid protein fibril formation. AB - Our previous studies have demonstrated that perlecan and perlecan-derived glycosaminoglycans (GAGs) not only bind beta-amyloid protein (Abeta) 1-40 and 1 42, but are also potent enhancers of Abeta fibril formation and stabilize amyloid fibrils once formed. However, it was not determined which moieties in perlecan heparan sulfate GAG chains may be responsible for the observed effects and whether other GAGs were also capable of a similar enhancement of Abeta fibril formation as observed with perlecan GAGs. In the present study, thioflavin T fluorometry (over a 1-week period) was used to extend our previous studies and to test the hypothesis that the sulfate moiety is critical for the enhancing effects of heparin/heparan sulfate GAGs on Abeta 1-40 fibrillogenesis. This hypothesis was confirmed when removal of all sulfates from heparin (i.e., completely desulfated N-acetylated heparin) led to a complete loss in the enhancement of Abeta fibrillogenesis as demonstrated in both thioflavin T fluorometry and Congo red staining studies. On the other hand, removal of O-sulfate from heparin (i.e., completely desulfated N-sulfated heparin), and to a lesser extent N-sulfate (i.e., N-desulfated N-acetylated heparin), resulted in only a partial loss of the enhancement of Abeta 1-40 fibril formation. These studies indicate that the sulfate moieties of GAGs are critical for enhancement of Abeta amyloid fibril formation. In addition, other sulfated molecules such as chondroitin-4-sulfate, dermatan sulfate, dextran sulfate, and pentosan polysulfate all significantly enhanced (greater than twofold by 3 days) Abeta amyloid fibril formation. These latter findings indicate that deposition and accumulation of other GAGs at sites of Abeta amyloid deposition in Alzheimer's disease brain may also participate in the enhancement of Abeta amyloidosis. PMID- 10098878 TI - Prominent 85-kDa oligomannosidic glycoproteins of rat brain are signal regulatory proteins and include the SHP substrate-1 for tyrosine phosphatases. AB - The glycoprotein component in rat brain reacting most strongly with Galanthus nivalis agglutinin (GNA) on western blots migrates as an 85-kDa band. GNA identifies mannose-rich oligosaccharides because it is highly specific for terminal alpha-mannose residues. After purification of this 85-kDa glycoprotein band by chromatography on GNA-agarose and preparative gel electrophoresis, binding of other lectins demonstrated the presence of fucose and a trace of galactose, but no sialic acid. Treatment with N-Glycanase or endoglycosidase H produced a 65-kDa band, indicating that it consisted of about one-fourth N-linked oligomannosidic carbohydrate moieties. High-performance anion-exchange chromatography and fluorescence-assisted carbohydrate electrophoresis indicated that the major carbohydrate moiety is a heptasaccharide with the structure Manalpha1-6(Manalpha1-3)Manalpha1-6(Manalpha1-3) Manbeta1-4Glc-NAcbeta1-4GlcNAc (Man5GlcNAc2). Determination of amino acid sequences of peptides produced by endoproteinase digestion demonstrated that this 85-kDa mannose-rich glycoprotein component contained the SHP substrate-1 for phosphotyrosine phosphatases and at least one other member of the signal-regulatory protein (SIRP) family. The unusually high content of oligomannosidic carbohydrate moieties on these receptor like members of the immunoglobulin superfamily in neural tissue could be of functional significance for intercellular adhesion or signaling. PMID- 10098879 TI - Delineation of the structural determinants of the N-methyl-D-aspartate receptor glycine binding site. AB - In this study, we have further delineated the domains of the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine co-agonist binding site. Taking an iterative approach, we have constructed truncation mutants of the NR1 subunit, transiently expressed them in HEK-293 cells, and determined the binding of the glycine site antagonist [3H]L-689,560. Amino acids 380-811 were sufficient to form a glycine binding site with affinities for [3H]L-689,560 and glycine that were not significantly different from wild-type NR1. More extensive deletions, from either the amino- or the carboxy-terminal end, resulted in loss of ligand binding. Additional constructs were made starting from amino acids 380-843 of NR1, replacing the transmembrane (TMI-TMIII) domain with intervening linker sequences while retaining the TMIV domain so as to anchor the polypeptide to the membrane. Although robust amounts of polypeptides were synthesised by transfected cells, only low levels of [3H]L-689,560 binding sites could be detected. This suggests that only a small proportion of the synthesised polypeptide folds in the appropriate manner so as to form a ligand binding site. These data indicate that although it is possible to reduce the glycine binding site to minimal so-called S1 and S2 domains, efficient folding of the polypeptide so as to form a ligand binding site may require sequences within the TMI-TMIII domain. PMID- 10098881 TI - Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. AB - The mammalian AMP-activated protein kinase is a heterotrimeric serine/threonine protein kinase with multiple isoforms for each subunit (alpha, beta, and gamma) and is activated under conditions of metabolic stress. It is widely expressed in many tissues, including the brain, although its expression pattern throughout the CNS is unknown. We show that brain mRNA levels for the alpha2 and beta2 subunits were increased between embryonic days 10 and 14, whereas expression of alpha1, beta1, and gamma1 subunits was consistent at all ages examined. Immunostaining revealed a mainly neuronal distribution of all isoforms. The alpha2 catalytic subunit was highly expressed in neurons and activated astrocytes, whereas the alpha1 catalytic subunit showed low expression in neuropil. The gamma1 noncatalytic subunit was highly expressed by neurons, but not by astrocytes. Expression of the beta1 and beta2 noncatalytic subunits varied, but some neurons, such as granule cells of olfactory bulb, did not express detectable levels of either beta isoform. Preferential nuclear localization of the alpha2, beta1, and gamma1 subunits suggests new functions of the AMP-activated protein kinase, and the different expression patterns and cellular localization between the two catalytic subunits alpha1 and alpha2 point to different physiological roles. PMID- 10098880 TI - Activity-dependent phosphorylation of SNAP-25 in hippocampal organotypic cultures. AB - Synaptosomal-associated protein of 25 kDa (SNAP-25) is thought to play a key role in vesicle exocytosis and in the control of transmitter release. However, the precise mechanisms of action as well as the regulation of SNAP-25 remain unclear. Here we show by immunoprecipitation that activation of protein kinase C (PKC) by phorbol esters results in an increase in SNAP-25 phosphorylation. In addition, immunochemical analysis of two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels shows that SNAP-25 focuses as three or four distinct spots in the expected range of molecular weight and isoelectric point. Changing the phosphorylation level of the protein by incubating the slices in the presence of either a PKC agonist (phorbol 12,13-dibutyrate) or antagonist (chelerythrine) modified the distribution of SNAP-25 among these spots. Phorbol 12,13-dibutyrate increased the intensity of the spots with higher molecular weight and lower isoelectric point, whereas chelerythrine produced the opposite effect. This effect was specific for regulators of PKC, as agonists of other kinases did not produce similar changes. Induction of long-term potentiation, a property involved in learning mechanisms, and production of seizures with a GABA(A) receptor antagonist also increased the intensity of the spots with higher molecular weight and lower isoelectric point. This effect was prevented by the PKC inhibitor chelerythrine. We conclude that SNAP-25 can be phosphorylated in situ by PKC in an activity-dependent manner. PMID- 10098882 TI - Transcriptional regulation of mouse type 1 inositol 1,4,5-trisphosphate receptor gene by NeuroD-related factor. AB - The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is a Ca2+ channel protein that is expressed abundantly in the CNS, such as in the cerebellar Purkinje cells and hippocampus. We previously demonstrated that the box-I element, which is located -334 relative to the transcription initiation site of the mouse IP3R1 gene and includes an E-box consensus sequence, is involved in the up-regulation of such IP3R1 gene expression. Furthermore, the previous study also indicated that some CNS-related basic helix-loop-helix (bHLH) factors bind to the box-I and activate IP3R1 gene expression. In this study, we demonstrated that one of the CNS-related bHLH factors, neuronal differentiation factor (NeuroD)-related factor (NDRF), specifically bound to the box-I sequence with a ubiquitously expressed bHLH protein, E47, and activated IP3R1 gene expression. In situ hybridization of adult mouse brain revealed that IP3R1 and NDRF mRNA were co expressed in many subsets of neurons, highly in Purkinje cells and hippocampus and moderately in cerebral cortex, olfactory bulb, and caudate putamen. Furthermore, the spatiotemporal expression patterns of these two genes resembled one another throughout postnatal development of the mouse CNS. From these results, we suggest that NDRF is involved in the tissue-specific regulation of IP3R1 gene expression in the CNS. PMID- 10098883 TI - Subunit assembly and domain analysis of electrically silent K+ channel alpha subunits of the rat Kv9 subfamily. AB - Alpha-subunits of the voltage-gated potassium channel (Kv) subfamily Kv9 show no channel activity after homomultimeric expression in heterologous expression systems. This report shows that heteromultimeric expression of rKv9.1 and rKv9.3 specifically suppresses the currents mediated by alpha-subunits of the Kv2 and Kv3 subfamilies but does not affect currents mediated by alpha-subunits of the Kv1 and Kv4 subfamilies. To understand the molecular basis of the electrical silence of Kv9 homomultimeric channels, crucial functional domains (amino and carboxy terminus, S4 segment, and pore region) were exchanged between Kv9 alpha subunits and rKv1.3. Electrophysiological studies of these chimeras revealed that the pore region is involved in determining the nonconductive behavior of homomultimeric Kv9 channels. This analysis was extended by protein interaction assays, aiming to identify the region of Kv9 subunits responsible for the specific suppression of rKv2.1- and rKv3.4-mediated currents. We could show that the amino-terminal domain of Kv9 alpha-subunits does not support homomultimeric assembly but interacts specifically with the rKv2.1 amino-terminal region. Conversely, the specific intersubfamily assembly of rKv3.4 with rKv9.1 or rKv9.3 is governed by the hydrophobic core and not the amino-terminal domain. PMID- 10098884 TI - Differential subcellular redistribution of protein kinase C isozymes in the rat hippocampus induced by kainic acid. AB - Protein kinase C (PKC) consists of a family of Ca2+/phospholipid-dependent isozymes that has been implicated in the delayed neurotoxic effects of glutamate in vitro. In the present study, we assessed the effect of the glutamate analogue kainic acid (KA) on the subcellular expression of PKC isozymes in the hippocampus (HPC) in the period preceding (0.5, 1.5, 12, and 24 h) and during (120 h) hippocampal necrosis using western blot analysis and PKC isozyme-specific antibodies. Before subcellular fractionation (cytosol + membrane), hippocampi were microdissected into "HPC" (fields CA1-CA3) and "dentate gyrus" (DG; granule cells + hilus) regions. Four general patterns of alterations in PKC isozyme expression/distribution were observed following KA treatment. The first pattern was a relative stability in expression following KA treatment and was most apparent for cytosol PKCalpha (HPC + DG) and membrane (HPC) and cytosol (DG) PKCbetaII. The second pattern, observed with PKCgamma and PKCepsilon, was characterized by an initial increase in expression in both membrane and cytosolic fractions before seizure activity (0.5 h) followed by a gradual decrease until significant reductions are observed by 120 h. The third pattern, exhibited by PKCdelta, involved an apparent translocation, increasing in the membrane and decreasing in the cytosol, followed by down-regulation in both fractions and subsequent recovery. The fourth pattern was observed with PKCzeta only and entailed a significant reduction in expression before and during limbic motor seizures followed by a dramatic fivefold increase in the membrane fraction during the period of hippocampal necrosis (120 h). Although these patterns did not segregate according to conventional PKC isozyme classifications, they do indicate dynamic isozyme-specific regulation by KA. The subcellular redistribution of PKC isozymes may contribute to the histopathological sequelae produced by KA in the hippocampus and may model the pathogenesis associated with diseases involving glutamate-induced neurotoxicity. PMID- 10098885 TI - Intracellular polyamine levels are involved in NMDA-evoked nitric oxide production in chick retina cells. AB - The NMDA-sensitive glutamate receptor complex can be modulated by numerous drugs and endogenous substances such as polyamines. We studied the pathway of arginine/nitric oxide/cyclic GMP in cultured chick retina cells through NMDA receptor activation, seen as a function of both differentiation stages of culture and intracellular polyamine levels. In our experimental conditions, the nitric oxide synthase activity was stimulated by NMDA from three to four times between embryonic day (E) 8 plus 5 days in vitro (C) and E8C7. The NMDA response was blocked by MK-801 (10 microM) by >60% at stage E8C5. During culture differentiation, the NMDA-induced increase in nitric oxide synthase activity at the E8C5 stage was blocked by preliminary incubation (24 h) of the cells with alpha-difluoromethylornithine, the inhibitor of polyamine biosynthesis. This effect was assessed by a reduction of NMDA-evoked cyclic GMP formation in polyamine-depleted retina cells. Thus, intracellular polyamine levels are involved in NMDA-evoked nitric oxide production. Our results indicate that (a) the developmental pattern of polyamine levels can be associated with the modulation of NMDA-evoked events and (b) the NMDA-mediated effects have been reduced in alpha-difluoromethylornithine-treated cell cultures. These observations provide evidence for a physiological interaction between polyamines and NMDA-sensitive glutamate receptors during differentiation stages of cultured chick retina cells. PMID- 10098886 TI - Induction of glucose-6-phosphate dehydrogenase by lipopolysaccharide contributes to preventing nitric oxide-mediated glutathione depletion in cultured rat astrocytes. AB - Treatment of cultured rat astrocytes with lipopolysaccharide (LPS; 1 microg/ml) increased mRNA expression of glucose-6-phosphate dehydrogenase (G6PD), the rate limiting step in the pentose phosphate pathway (PPP), in a time-dependent fashion (0-24 h). This effect was accompanied by an increase in G6PD activity (1.74-fold) and in the rate of glucose oxidation through the PPP (6.32-fold). Inhibition of inducible nitric oxide synthase (iNOS) activity by 2-amino-5,6-dihydro-6-methyl 4H-1,3-thiazine (AMT; 50 microM) did not alter the LPS-mediated enhancement of G6PD mRNA expression or PPP activity. Blockade of nuclear factor-kappaB (NF kappaB) activation by N-benzyloxycarbonyl-Ile-Glu-(O-tert-butyl)-Ala-leucinal (1 microM) prevented the expression of both iNOS mRNA and G6PD mRNA, suggesting that iNOS and G6PD are co-induced by LPS through a common transcriptional pathway involving NF-kappaB activation. Incubation of cells with LPS for 24 h increased intracellular NADPH concentrations (1.63-fold) as compared with untreated cells, but GSH concentrations were not modified by LPS treatment up to 60 h of incubation. However, inhibition of G6PD activity by dehydroepiandrosterone (DHEA; 100 microM), which prevented LPS-mediated enhancements in PPP activity and NADPH concentrations, caused a 50% decrease in the GSH/GSSG ratio after 24-36 h and in GSH concentrations after 60 h of incubation. Furthermore, the changes in glutathione concentrations caused by DHEA were abolished by AMT, suggesting that nitric oxide and/or its reactive derivatives would be involved in this process. From these results, we conclude that LPS-mediated G6PD expression prevents GSH depletion due to nitric oxide and suggest that this phenomenon may be a contributing factor in the defense mechanisms that protect astrocytes against nitric oxide-mediated cell injury. PMID- 10098888 TI - Neuronal apoptosis in mouse trisomy 16: mediation by caspases. AB - Hippocampal neurons from the trisomy 16 (Ts16) mouse, a potential animal model of Down's syndrome (trisomy 21) and neurodegenerative disorders such as Alzheimer's disease (AD), die at an accelerated rate in vitro. Here, we present evidence that the accelerated neuronal death in Ts16 occurs by apoptosis, as has been reported for neurons in AD. First, the nuclei of dying Ts16 neurons are pyknotic and undergo DNA fragmentation, as revealed by terminal transferase-mediated dUTP nick end-labeling. Second, the accelerated death of Ts16 neurons is prevented by inhibitors of the caspase family of proteases, which are thought to act at a late, obligatory step in the apoptosis pathway. In the presence of maximally effective concentrations of caspase inhibitors, Ts16 neuron survival was indistinguishable from that of control neurons. These results suggest that overexpression of one or more genes on mouse chromosome 16 leads to caspase mediated apoptosis in Ts16 neurons. PMID- 10098887 TI - The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme. AB - The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied. Delta9-Tetrahydrocannabinol (THC), the major active component of marijuana, produced a malonyl-CoA-independent stimulation of carnitine palmitoyltransferase I (CPT-I) and ketogenesis from [14C]palmitate. The THC induced stimulation of ketogenesis was mimicked by the synthetic cannabinoid HU 210 and was prevented by pertussis toxin and the CB1 cannabinoid receptor antagonist SR141716. Experiments performed with different cellular modulators indicated that the THC-induced stimulation of ketogenesis was independent of cyclic AMP, Ca2+, protein kinase C, and mitogen-activated protein kinase (MAPK). The possible involvement of ceramide in the activation of ketogenesis by cannabinoids was subsequently studied. THC produced a CB1 receptor-dependent stimulation of sphingomyelin breakdown that was concomitant to an elevation of intracellular ceramide levels. Addition of exogenous sphingomyelinase to the astrocyte culture medium led to a MAPK-independent activation of ketogenesis that was quantitatively similar and not additive to that exerted by THC. Furthermore, ceramide activated CPT-I in astrocyte mitochondria. Results thus indicate that cannabinoids stimulate ketogenesis in astrocytes by a mechanism that may rely on CB1 receptor activation, sphingomyelin hydrolysis, and ceramide-mediated activation of CPT-I. PMID- 10098890 TI - A new framework for vision-enabled and robotically assisted minimally invasive surgery. AB - This paper presents our on-going research at bringing the state-of-the-art in vision and robotics technologies to enhance the emerging minimally invasive surgery, in particular the laparoscopic surgical procedure. A framework that utilizes intelligent visual modeling, recognition, and serving capabilities for assisting the surgeon in maneuvering the scope (camera) in laparoscopy is proposed. The proposed framework integrates top-down model guidance, bottom-up image analysis, and surgeon-in-the-loop monitoring for added patient safety. For the top-down directives, high-level models are used to represent the abdominal anatomy and to encode choreographed scope movement sequences based on the surgeon's knowledge. For the bottom-up analysis, vision algorithms are designed for image analysis, modeling, and matching in a flexible, deformable environment (the abdominal cavity). For reconciling the top-down and bottom-up activities, robot servoing mechanisms are realized for executing choreographed scope movements with active vision guidance. The proposed choreographed scope maneuvering concept facilitates the surgeon's control of his/her visual feedback in a handless manner, reduces the risk to the patient from inappropriate scope movements by an assistant, and allows the operation to be performed faster and with greater ease. In this paper, we describe the new framework and present some preliminary results on laparoscopic image analysis for segmentation and instrument localization, and on instrument tracking. PMID- 10098889 TI - Brain neurotransmitter deficits in mice transgenic for the Huntington's disease mutation. AB - Huntington's disease (HD) is associated with an expansion in the CAG repeat sequence of a gene on chromosome 4, resulting in a neurodegenerative process particularly affecting the striatum and with profound but selective changes in content of various neurotransmitters. Recently, transgenic mice expressing a fragment of the human HD gene containing a large CAG expansion have been generated; these mice exhibit a progressive neurological phenotype that includes motor disturbances, as well as neuronal deficits. To investigate their underlying neurotransmitter pathology, we have determined concentrations of GABA, glutamate, and the monoamine neurotransmitters in several brain regions in these mice and control animals at times before and after the emergence of the behavioural phenotype. In contrast to the findings in HD, striatal GABA was unaffected, although a deficit was observed in the cerebellum, consistent with a dysfunction of Purkinje cells. Losses of the monoamine transmitters were observed, some of which are not seen in HD. Thus, 5-hydroxytryptamine and, to a greater extent, 5 hydroxyindoleacetic acid levels were diminished in all brain regions studied, and noradrenaline was particularly affected in the hippocampus. Dopamine was decreased in the striatum in older animals, parallelling evidence for diminished dopaminergic activity in HD. PMID- 10098891 TI - Fast image accessing based on an analysis of the picture archiving and communications system in Kochi Medical School. AB - A large-scale picture archiving and communication system was developed by Kochi Medical School. Using JPEG to achieve 90% compression, this system was capable of storing several years worth of CT and MR examination records and eliminated the bottleneck in conventional systems caused by slow data access in the filing system. Under the new system, access of image files from client PCs was checked for bottlenecks. The image file retrieval from the image database on the server was found to require the longest time. Two methods were considered to eliminate this bottleneck. One was a multiimages filing into a file. Another was an image transmission with multiparallel transmission sessions, which is proposed in this article. By adopting the latter method, the system can transmit 50 CT images from the image database server to a client PC in about 10 s. PMID- 10098892 TI - Value of spiral CT in hemodynamically stable patients following blunt chest trauma. AB - INTRODUCTION: Features of spiral CT (SCT)-fast scanning, dynamic injection of contrast allowing optimal vessel opacification, and supplemental multiplanar imaging-promises to provide increased accuracy in the diagnosis of acute and non acute thoracic vascular disease. Recent work demonstrating the cost effective triage of hemodynamically stable patients after blunt chest trauma for angiography based on dynamic CT findings has prompted an investigation into the accuracy of SCT in this clinical setting. METHODS: A retrospective review of all patients seen in the emergency department over the period of one year for aortic, thoracic, or blunt chest trauma evaluation was performed (74 patients) and all SCT scans available were reviewed and data reformatted for optimal delineation of pathology using maximum intensity projection and multiplanar reformation. The accuracy and predictive positive and negative values of SCT were calculated with respect to angiography, surgical, and/or clinical follow up evaluation. RESULTS: Twenty three (31%) patients went directly to angiography owing to mediastinal widening on chest film and hemodynamic instability, of which four were positive and required emergent surgery. Seven hemodynamically stable patients (9%) had noncontrast SCT owing to mediastinal widening on chest film, all of which had angiography with none having great vessel trauma. Fourty four hemodynamically stable patients (60%) had contrast enhanced SCT (ceSCT), of which five (11%) were abnormal and underwent angiography, four of these were positive for aortic damage, one for a subclavian artery laceration. Of the remaining 39 patients who had normal ceSCT; five had angiography, all of which were normal. Of the remaining 34 patients that had normal ceSCT none had adverse outcome on clinical follow-up, minimum of 12 months. CONCLUSION: The predictive positive value for aortic trauma of ceSCT in blunt trauma is 80%, with a predictive negative value of 100%, indicating that it is feasible for SCT to be a first line exam in blunt chest trauma in the future. PMID- 10098893 TI - Image-guided MR spectroscopy volume of interest localization for longitudinal studies. AB - Longitudinal magnetic resonance spectroscopy (MRS) studies require accurate repositioning of the volume of interest (VOI) over which measurements are made. In this work we present and evaluate a method for the image-guided repositioning of brain volumes of interest. The point-based registration technique we developed allows the repositioning to be performed on-line (i.e. while the patient is in the scanner). MR image volumes were acquired from six subjects, three scans each over the course of a month. During the first scan, two spectroscopy VOIs are visually selected: one in the frontal white matter, the other in the superior cerebellar vermis. The coordinates of 13 internal brain landmarks are also identified. During both subsequent scans, the same 13 landmarks are identified, and the transformation that registers the first set of landmarks to the subsequent set is computed. This result is used to automatically map the position of the spectroscopy VOIs from the first volume to the current volume. For the six subjects evaluated to date, we show an average repositioning error of the spectroscopy VOIs in the order of 1 mm. This accuracy allows us to conclude that any variations in the MR spectra are unlikely to be due to repositioning error. PMID- 10098894 TI - Knowledge-based method for segmentation and analysis of lung boundaries in chest X-ray images. AB - We present a knowledge-based approach to segmentation and analysis of the lung boundaries in chest X-rays. Image edges are matched to an anatomical model of the lung boundary using parametric features. A modular system architecture was developed which incorporates the model, image processing routines, an inference engine and a blackboard. Edges associated with the lung boundary are automatically identified and abnormal features are reported. In preliminary testing on 14 images for a set of 18 detectable abnormalities, the system showed a sensitivity of 88% and a specificity of 95% when compared with assessment by an experienced radiologist. PMID- 10098895 TI - Computer-assisted image analysis of small cell lymphoma of the thyroid gland. Comparison of nuclear parameters of small lymphocytes in lymphomas and Hashimoto's thyroiditis. AB - The nuclear parameters of the small lymphocytes in nine cases of small cell lymphomas of the thyroid gland and 17 cases of Hashimoto's thyroiditis were assessed by computer-assisted image analysis. The nuclear area, maximal, minimal and averaged Ferret diameters, perimeter, regularity factor and elongation factor were gauged. Statistically, the nuclear area was ascertained to be the optimum descriptor discriminating between small neoplastic and reactive lymphocytes. Application of a novel variable, combining a nuclear area cut-off value of 14 microm2 with a nuclear averaged Ferret diameter cut-off value of 4.5 micron, allows for the distinction - with a high degree of sensitivity and specificity - between small neoplastic lymphocytes in thyroidal lymphomas and the reactive lymphocytes in Hashimoto's thyroiditis. PMID- 10098896 TI - Chloroacetonitrile (CAN) induces glutathione depletion and 8-hydroxylation of guanine bases in rat gastric mucosa. AB - Chloroacetonitrile (CAN) is detected in drinking-water supplies as a by-product of the chlorination process. Gastroesophageal tissues are potential target sites of acute and chronic toxicity by haloacetonitriles (HAN). To examine the mechanism of CAN toxicity, we studied its effect on glutathione (GSH) homeostasis and its impact on oxidative DNA damage in gastric mucosal cells of rats. Following a single oral dose (38 or 76 mg/Kg) of CAN, animals were sacrificed at various times (0-24 h), and mucosa from pyloric stomach were collected. The effects of CAN treatment on gastric GSH contents and the integrity of genomic gastric DNA were assessed. Oxidative damage to gastric DNA was evaluated by measuring the levels of 8-Hydroxydeoxyguanosine (8-OHdG) in hydrolyzed DNA by HPLC-EC. The results indicate that CAN induced a significant, dose- and time dependent, decrease in GSH levels in pyloric stomach mucosa at 2 and 4 hours after treatment (56 and 39% of control, respectively). DNA damage was observed electrophoretically at 6 and 12 hours following CAN administration. CAN (38 mg/Kg) induced significant elevation in levels of 8-OHdG in gastric DNA. Maximum levels of 8-OHdG in gastric DNA were observed at 6 hours after CAN treatment [9.59+/-0.60 (8-OHdG/10(5)dG) 146% of control]. When a high dose of CAN (76 mg/Kg) was used, a peak level of 8-OHdG [11.59+/-1.30 (8-OHdG/10(5)dG) 177% of control] was observed at earlier times (2 h) following treatment. When CAN was incubated with gastric mucosal cells, a concentration-dependent cyanide liberation and significant decrease in cellular ATP levels were detected. These data indicate that a mechanism for CAN-induced toxicity may be partially mediated by depletion of glutathione, release of cyanide, interruption of the energy metabolism, and induction of oxidative stress that leads to oxidative damage to gastric DNA. PMID- 10098897 TI - Decrease of hepatic catalase level by treatment with diallyl sulfide and garlic homogenates in rats and mice. AB - Diallyl sulfide (DAS) is a flavor compound derived from garlic and is active in the inhibition of chemically induced cytotoxicity and carcinogenicity in animal models. This study was conducted to examine the effects of the treatment of DAS and garlic homogenates on the activities of catalase, glutathione peroxidase, and superoxide dismutase. Male Sprague-Dawley rats were treated with DAS i.g. at daily doses of 50 or 200 mg/kg for 8 days, causing the hepatic catalase activity to decrease by 55 and 95%, respectively. Such a decrease in hepatic catalase activity was also observed when the DAS treatment was extended to 29 days. Western blot analysis showed that the DAS treatments resulted in corresponding decreases in the liver catalase protein level. No significant change in the catalase activity in the kidney, lung, and brain was observed with the treatments, but a slight decrease in heart catalase activity was observed. These treatments did not cause significant changes in superoxide dismutase and glutathione peroxidase activities in these tissues. Treatment with DAS at a daily dose of 200 mg/kg for 1-7 days resulted in a gradual decrease in the liver catalase activity to 5% of the control level, but it did not decrease the erythrocyte catalase activity. Treatment of rats with fresh garlic homogenates (2 or 4 g/kg, i.g., daily for 7 days) caused a 35% decrease in liver catalase activity. A/J mice treated with DAS and garlic homogenates also showed a decrease in the liver catalase activity. Diallyl sulfone (DASO2), a DAS metabolite, however, did not effectively decrease catalase activity in mice. The catalase activity was not inhibited by either DAS or DASO2 in vitro. The present results demonstrate that treatment with DAS and garlic homogenates decrease the hepatic catalase level in rats and mice. PMID- 10098898 TI - Galactosamine decreases nitric oxide formation in cultured rat hepatocytes: lack of involvement in cytotoxicity. AB - Galactosamine hepatotoxicity in vivo has long been associated with rapid and extensive depletion of hepatic uridine nucleotides. Depletion of uridine nucleotides is considered to be causal in the toxicity, as evidenced by the protective effect of uridine administration. However, the exact mechanism of galactosamine-induced hepatic necrosis is still unclear. We have previously shown that the addition of galactosamine to rat primary hepatocyte cultures dramatically decreases production of nitric oxide, as measured in the 24 hour culture medium. The present study investigates whether decreased nitric oxide production contributes to the toxicity of galactosamine in primary hepatocyte cultures. Similar concentration-response curves were observed for the decrease in nitric oxide production and galactosamine cytotoxicity, raising the possibility that there is a similar mechanism for these effects. Suppression of NO synthesis was a direct effect of galactosamine, rather than an indirect effect due to loss of cells from the cultures. Both cytotoxicity and the decrease in nitric oxide production were attenuated by coaddition of 3 mM uridine. However, galactosamine cytotoxicity was not enhanced by prior inhibition of hepatocellular NO synthesis nor was it attenuated by maintenance of culture NO levels with molsidomine or diethylamine NONOate. These data do not support a role for decreased hepatocyte nitric oxide production in galactosamine hepatocyte toxicity. PMID- 10098900 TI - Effects of Cd2+ and two cadmium organic complexes on isolated rat liver mitochondria. AB - Effects of Cd2+ and two complexes of bivalent cadmium with 1,3-bis(4 chlorbenzylidenamino)-guanidine and anabasine on ion permeability of the inner membrane and respiration of isolated rat liver mitochondria were studied. Starting from 5 microM, Cd2+ decreased state 3 and DNP-stimulated respiration of mitochondria and increased their state 4 respiration. At 30 microM, Cd2+ decreased state 4 respiration. The complexes, particularly complex of Cd2+ with 1,3-bis(4-chlorbenzylidenamino)-guanidine, inhibited the mitochondrial respiration at lower concentration of Cd2+. Nonenergized mitochondria incubated in media containing 125 mM of NH4NO3 or KNO3 showed more pronounced swelling in experiments with 10 microM of the complexes than with Cd2+. The complexes produced swelling of the mitochondria energized by 5 mM of succinate and incubated in medium containing 25 mM K-acetate and 100 mM sucrose. Uptake of 137 Cs by succinate-energized mitochondria in the presence of 10(-8) M of valinomycin was substantially decreased in experiments with 10 microM of the complexes than with Cd2+. Ruthenium red (7.5 microM) prevented this effect with 10 microM of complex of Cd2+ with 1,3-bis(4-chlorbenzylidenamino)-guanidine and especially complex of Cd2+ with anabasine and Cd2+. These results indicate that the cadmium organic complexes affect respiration and perturb ion permeability significantly stronger than Cd2+. PMID- 10098899 TI - Galactosamine decreases nitric oxide formation in cultured rat hepatocytes: mechanism of suppression. AB - We have shown that nitric oxide production is dramatically decreased in rat primary hepatocyte cultures exposed to galactosamine. Cotreatment of the cells with uridine, which is known to prevent cytotoxicity, was found to also attenuate NO loss. In the present study, two possible mechanisms for the decreased nitric oxide production were examined. First, we examined the possibility that galactosamine could interfere with the uptake of extracellular arginine by the cultured hepatocytes. Cellular uptake of arginine was determined after addition of 14C-arginine at the time of hepatocyte attachment. Uptake of arginine was rapid in control cultures, and both the rate and level of uptake were unchanged by the addition of a cytotoxic concentration of galactosamine (4 mM). In addition, increased concentrations of arginine in the cell culture medium did not ameliorate the galactosamine-induced decrease in production of nitric oxide. Second, we determined whether the synthesis of inducible nitric oxide synthase in the hepatocyte cultures was inhibited by addition of galactosamine. Hepatocyte levels of inducible nitric oxide synthase were determined immunochemically at various times after the addition of galactosamine (4 mM). In control cultures, inducible nitric oxide synthase was detectable at 7 and 24 hours after attachment. In contrast, no nitric oxide synthase protein was detectable at any time in the galactosamine-treated cultures. Furthermore, addition of galactosamine after inducible nitric oxide synthase had already been synthesized (6.5 h after attachment) did not result in suppression of nitric oxide production in the hepatocyte cultures. The present studies suggest that galactosamine suppresses nitric oxide production in hepatocyte cultures by inhibiting synthesis of inducible nitric oxide synthase, rather than by interference in cellular uptake of arginine. PMID- 10098901 TI - Biotransformations of oxaliplatin in rat blood in vitro. AB - The partitioning and biotransformations of oxaliplatin [trans-l-1,2 diaminocyclohexaneoxalatoplatinum(II)] were investigated in the blood of Wistar male rats in vitro. [3-H]-Oxaliplatin was incubated with rat blood at 37 degrees C in 5% CO2 and the concentrations of all Pt complexes containing the [3-H]-dach carrier ligand were followed for up to 12 hours. Decay for both oxaliplatin and Pt-dach in the plasma ultrafiltrate (PUF) was rapid (t 1/2 oxaliplatin = 0.68 h and t 1/2 for Pt-dach in the PUF = 0.85 h). After 9 hours, the concentration of oxaliplatin fell below the detection limit. By 4 hours, the PUF-Pt-dach reached a plateau, which was 12% of total Pt-dach. The binding of Pt-dach to red blood cells (RBCs) and plasma proteins was also very rapid (t 1/2 RBCs = 0.58 h and t 1/2 plasma proteins = 0.78 h) and reached equilibrium by 4 hours. At equilibrium, 35% of total Pt-dach was bound to plasma proteins, 12% was in the plasma ultrafiltrate, and 53% was found associated with RBCs. Of the Pt-dach associated with RBCs, 23% was bound to the RBC membrane, 58% was bound to RBC cytosolic proteins, and 19% was in the RBC cytosol ultrafiltrate. Thus, these studies confirm previous observations of oxaliplatin accumulation by rat RBCs. To better characterize the determinants of this accumulation, oxaliplatin and other Pt-dach complexes were compared with respect to both their uptake by rat RBCs and their partition coefficients in octanol and water. The rank order for the rate of uptake was ormaplatin approximately Pt(dach)Cl2 > oxaliplatin > Pt(dach)(mal); while the rank order for hydrophobicity was ormaplatin > Pt(dach)Cl2 > Pt(dach)(mal) > oxaliplatin. Thus, in general, Pt-dach complexes appeared to be taken up better by RBCs than cisplatin or carboplatin, and the hydrophobicity of most of the Pt-dach complexes appeared to correlate with uptake. However, factors other than the dach carrier ligand and hydrophobicity clearly influence uptake. The biotransformations of oxaliplatin in rat blood were characterized utilizing reverse-phase high-pressure liquid chromatography (HPLC). In the RBC cytosol, both oxaliplatin and Pt(dach)Cl2 were observed at early times, while Pt(dach)(GSH)2, Pt(dach)(Cys)2, Pt(dach)(GSH), and free dach accumulated and reached steady-state levels by 4 hours. Thus, in the RBC cytosol, only chemically unreactive biotransformation products such as free dach and Pt-dach complexes with cysteine and glutathione accumulated in significant amounts. Furthermore, only Pt(dach)(Cys)2 and free dach appeared to efflux from RBCs. Thus, RBCs do not appear to serve as a reservoir for cytotoxic Pt-dach complexes. Finally, the biotransformation products of oxaliplatin in the plasma were identified as Pt(dach)Cl2, Pt(dach)(Cys)2, Pt(dach)(GSH), Pt(dach)(Met), Pt(dach)(GSH)2, and free dach. Among these compounds, Pt(dach)Cl2 formed transiently, while Pt(dach)(Cys)2, Pt(dach)(Met), and free dach accumulated and were the major biotransformation products by 4 hours. Thus, this study has identified the major inert and reactive biotransformation products of oxaliplatin in both plasma and RBCs and thus provides the information required for detailed pharmacokinetic and biotransformation studies of oxaliplatin. [figure in text] PMID- 10098902 TI - ADP-ribose pyrophosphatase-I partially purified from livers of rats overdosed with acetaminophen reveals enzyme inhibition in vivo reverted in vitro by dithiothreitol. AB - Free ADP-ribose reacts nonenzymatically with proteins and can lead to intracellular damage. The low-Km ADP-ribose pyrophosphatase-I (ADPRibase-I) is well suited to control free ADP-ribose and nonenzymatic ADP-ribosylation. In vitro, the acetaminophen metabolite N-acetyl-p-benzoquinoneimine (NAPQI) decreases ADPRibase-I Vmax and increases Km, effects not reverted by dithiothreitol (DTT) and attributed to enzyme arylation. The present study was conducted to test whether acetaminophen overdose affected ADPRibase-I in vivo. Rats pretreated with 3-methylcholanthrene and L-buthionine-[S,R]-sulfoximine to potentiate acetaminophen toxicity received an intraperitoneal dose of either acetaminophen (800 mg/ kg; n = 5) or vehicle (n = 3). ADPRibase-I partially purified from acetaminophen-overdosed rats showed a decreased Vmax (0.32+/-0.09 versus 0.60+/-0.03 mU/mg of liver protein; p<0.01) not reverted by DTT and an increased Km for ADP-ribose (1.39+/-0.31 versus 0.67+/-0.05 microM; p<0.01) that, contrary to the in vitro NAPQI effect, was reverted by DTT. Incubation of partially purified ADPRibase-I from normal rat liver with oxidized glutathione elicited a time- and dose-dependent, DTT-reverted increase of Km, without change of Vmax. The results indicate that the activity of ADPRibase-I can be regulated by thiol exchange and that the increase of Km, elicited by acetaminophen overdosage was related to the oxidative stress caused by the drug. It remains to be seen whether an increase of free ADP-ribose concomitant to ADPRibase-I inhibition could contribute to the hepatotoxicity of acetaminophen. PMID- 10098903 TI - Time- and concentration-dependent production of superoxide anion, nitric oxide, DNA damage and cellular death by ricin in the J774A.1 macrophage cells. AB - The time- and concentration-dependent effects of ricin on some biomarkers of cellular toxicity, including production of superoxide anion (O2-), nitric oxide (NO), and DNA single strand breaks (SSB), as well as cellular death, have been examined in the J774A.1 macrophage cell cultures. Various concentrations of ricin have been added to various cell cultures, and the cells were incubated for 12, 24, 36, and 48 hours. Following 12 hour incubation, ricin did not cause significant increases in any of those biomarkers. However, time- and concentration-dependent increases were observed in the induction of all the biomarkers after incubation for 24-48 hours. Approximately twofold increases in the production of O2- were observed after incubation with 1 and 10 ng/mL of ricin for 24 and 36-48 hours, respectively. The concentrations of ricin that caused approximately twofold increases in the rate of DNA-SSB are 10 and 1-10 ng/mL after 24 and 36-48 hours incubation, respectively. Approximately twofold increases in NO production were only observed after incubation of the cultures with 1-10 ng/mL of ricin for 36-48 hours. Fifty percent reductions in cellular viability were also observed with ricin concentrations of 10-100, 10, and 1-10 ng/mL, after incubation for 24, 36, and 48 hours, respectively. PMID- 10098904 TI - Flavin-containing monooxygenase isoform 2: developmental expression in fetal and neonatal rabbit lung. AB - Mammalian flavin-containing monooxygenase functions in the oxygenation of numerous xenobiotics containing a soft nucleophile, usually a nitrogen or sulfur. A total of five distinct flavin monooxygenase (FMO) isoforms are expressed in mammals. Individual isoforms are expressed in a sex-, age-, and tissue-specific fashion. In this study, we document the early developmental appearance of the major isoform in rabbit lung, FMO2. FMO2 catalytic activity as well as protein and mRNA are not only present in fetal and neonatal lung but, in some instances, approach levels found in the adult. The expression pattern of FMO2 is similar to that of the two major constitutive cytochromes P450 found in rabbit lung, 2B4 and 4B1. The early developmental appearance of these monooxygenases indicate an important role in the protection of the fetus and neonate against toxic insult from foreign chemicals. PMID- 10098905 TI - A novel group of ovarian toxicants: the psoralens. AB - The psoralens are naturally occurring metabolites found in many crop plants; synthetic forms of 5-methoxypsoralen (bergapten) and 8-methoxypsoralen (xanthotoxin) are widely used in skin photochemotherapy. Our previous research documented that dietary bergapten and xanthotoxin reduced birthrates in female rats when males and females were exposed to these chemicals. The present study was designed to determine the cause of this reduced birthrate and whether this resulted from direct impact on the females. The study demonstrates that bergapten and xanthotoxin administered, either alone or in combination to female rats (mated to undosed males), significantly reduced the number of implantation sites, pups, and corpora lutea in dosed females compared with control animals. Additionally, full uterine weight and empty uterine weight were significantly reduced. These compounds also significantly reduced circulating estrogen levels in a dose-dependent manner. Interestingly, the psoralens significantly induced mRNAs of liver enzymes typically induced by polycyclic aromatic hydrocarbons, CYP1A1 and UGT1A6; the higher the dose, the greater the induction. UGT 2B1 mRNA, typically induced by phenobarbital-like compounds, was not significantly affected. Thus, enhanced oxidative metabolism and conjugation of estrogens in psoralen-treated animals may provide a partial explanation for the effects observed. These findings are also consistent with psoralen-induced reduction in ovarian follicular function and ovulation. PMID- 10098906 TI - A biologically based pharmacodynamic model for lipid peroxidation stimulated by trichloroethylene in vitro. AB - It is often necessary for chemical risk assessment to determine a quantitative relationship between the internal dose of a chemical and its biological effect. The tool best suited for this purpose is a biologically based pharmacodynamic (BBPD) model. Such a BBPD model was developed previously (10) to simulate chemically induced lipid peroxidation, and it was experimentally calibrated in precision-cut mouse liver slices in vitro. The BBPD model simulated formation of lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS) over time and was originally calibrated with different concentrations of tert-butyl hydroperoxide and bromotrichloromethane. The objective of the present work is to refine this BBPD model so it can describe the kinetics and the dose response of lipid peroxidation induced by a weakly pro-oxidant chemical, trichloroethylene (TCE). The chemical-dependent model parameters were optimized to reflect the chemistry of TCE. Two basic algorithms, linear and square root, for the description of stoichiometric free radical production from TCE were tested. Predictions with the square root algorithm fit the experimental data employing TBARS as an end point better than those by the linear algorithm. The calibrated BBPD model will be used to support our future mathematical description of TCE pharmacodynamics in vivo. PMID- 10098907 TI - Impact of diseases on detoxication. PMID- 10098908 TI - Drug disposition as determined by the interplay between drug-transporting and drug-metabolizing systems. PMID- 10098909 TI - Drug metabolizing enzymes in lymphocytes. PMID- 10098910 TI - Race in the "decade of the brain". AB - Despite NIMH efforts to facilitate the study of women and minorities in federally funded schizophrenia research, there is a significant lack of information about race differences in brain morphology and neuropsychological function in schizophrenia. A review of three major psychiatric journals between 1994 and 1996 revealed that only 14 (2.8%) of 502 schizophrenia articles reported the results of race analyses. Only 84 (16.7%) even reported the racial composition of the study sample. The study of race differences in schizophrenia, although fraught with methodological complexity and social/political tension, is necessary to prevent inappropriate generalization of research results across racial groups. PMID- 10098911 TI - Is Schizophrenia a lateralized brain disorder? Editor's introduction. AB - Lateralization of brain function was established on the basis of clinical pathological correlations over a century ago. In the past two decades, this line of research has attempted to link the complex behaviors evident in schizophrenia to the failure to develop and maintain a normal pattern of hemispheric activity. This issue of Schizophrenia Bulletin reviews and presents data from multiple perspectives of methods applied to the study of laterality in schizophrenia. Brain disorders affecting systems that modulate complex behavior are commonly related to laterality. Therefore, this dimension of brain function merits further investigation in schizophrenia. PMID- 10098912 TI - Early theory and research on hemispheric specialization. AB - This article provides an account of early theory and research on hemispheric specialization. It begins by tracing theory and research on localization of function that set the stage for the discovery of hemispheric specialization. After that, it describes the studies of Paul Broca, John Hughlings-Jackson, and others on hemisphere specialization and reviews some of the proposed explanations for the phenomenon. It then turns to the study of hemispheric specialization and mental illness, and it ends by identifying some of the linkages between theory and research from the past and the present. PMID- 10098913 TI - Laterality in animals: relevance to schizophrenia. AB - Anomalies in the laterality of numerous neurocognitive dimensions associated with schizophrenia have been documented, but their role in the etiology and early development of the disorder remain unclear. In the study of normative neurobehavioral organization, animal models have shed much light on the mechanisms underlying and the factors affecting adult patterns of both functional and structural asymmetry. Nonhuman species have more recently been used to investigate the environmental, genetic, and neuroendocrine factors associated with developmental language disorders in humans. We propose that the animal models used to study the basis of lateralization in normative development and language disorders such as dyslexia could be modified to investigate lateralized phenomena in schizophrenia. PMID- 10098914 TI - Atypical handedness in schizophrenia: some methodological and theoretical issues. AB - An updated review of the literature strongly supports the view that in schizophrenia there is an atypical leftward shift in the handedness distribution that, while comprising different subtypes, is characterized by a more variable and less completely lateralized pattern of manual preference, referred to as mixed handedness (MH) or ambiguous handedness (AH). Only two studies revealed an increased prevalence of left-handedness suggestive of pathological left handedness (PLH). This article also examines the current status of neurodevelopmental factors and mechanisms in schizophrenia that purport to explain these pathological shifts in handedness (PLH, MH, AH). Different theoretical positions were evaluated, each involving some aspect of left hemisphere insult (unilateral or bilateral). Finally, it was shown that these shifts predict certain key symptoms and neural substrates in schizophrenia including thought disorder, negative symptoms, neuropsychological impairment, family history, and brain anatomy. These subtypes may represent neurodevelopmental markers of insult during intrauterine life that are nongenetic in origin. PMID- 10098915 TI - Neuropsychological laterality indices of schizophrenia: interactions with gender. AB - Neurobehavioral laterality indices were examined across motor, sensory, language versus spatial, and verbal memory versus spatial memory domains for 75 patients with schizophrenia (45 men, 30 women) and 75 demographically matched healthy controls. Patients were impaired across tasks, and laterality results varied by domain. There was no evidence for diagnosis by hemisphere interactions in motor, sensory, or memory tasks. However, patients were more impaired in language than in spatial domains, which suggests relatively greater left hemisphere dysfunction. This finding was mediated by the sex of the participant. While patients as a group showed greater language than spatial impairment, male patients showed expected superiority in spatial relative to language performance, whereas female patients performed the same on both functions. These results underscore the importance of examining sex differences in laterality effects. The findings also demonstrate that, although the left hemisphere model of schizophrenia may be partially supported by data on higher cognitive functions, this support does not extend to more basic motor and sensory domains. PMID- 10098916 TI - Functional neuropsychophysiological asymmetry in schizophrenia: a review and reorientation. AB - In reviewing the neuropsychophysiological evidence of functional asymmetry it is proposed that schizophrenia is characterized by a greater dispersion of leftward and rightward asymmetries. The two extremes are represented by active (left greater than right) and withdrawn (right greater than left) syndromes, as is the case with psychometric schizotypy. Syndrome-asymmetry relations extended beyond fronto-temporal systems to include posterior activity, infracortical motoneuron excitability, and individual differences in interhemispheric connectivity and directional biases. Central to these are lateral imbalances in thalamo-cortical and callosal arousal systems, while centrality to schizophrenia follows evidence of reversals in asymmetry with changes in symptom profile, clinical recovery, and neuroleptic treatment. Affinities are found in intact animals from challenge induced turning tendencies representing coordinated activity of attentional, motor, and reinforcement systems. In both patients and animals, neuroleptics have reciprocal interhemispheric effects, with a bidirectionality that depends on syndrome or endogenous turning preference. Bidirectionality implicates nonspecific thalamic system (NSTS) and not limbic projections. It is proposed that the asymmetries arise from endogenous influences of genes, hormones, and early experience including stressors on NSTS asymmetry, and these underpin approach/withdrawal behavior that is manifested in temperament, personality, and clinical syndrome, and which precedes language development. PMID- 10098917 TI - Structural asymmetries of the human brain and their disturbance in schizophrenia. AB - Asymmetries of the brain have been known about for at least a century, but they have been explored in detail only relatively recently. It has become clear that, although different asymmetries are common throughout the animal kingdom, they are most marked in the human brain. Disturbances in asymmetry are particularly striking in patients with schizophrenia and perhaps all psychotic illnesses, and may provide the neurological substrate for the etiology and clinical manifestations of the illness. PMID- 10098918 TI - Laterality in functional brain imaging studies of schizophrenia. AB - Brain laterality in schizophrenia has been examined through the application of functional neuroimaging methods. These methods have included the 133Xenon technique for measuring cerebral blood flow (CBF); positron emission tomography for assessing rates of glucose metabolism, CBF, and neuroreceptor functioning; single photon emission computerized tomography for studying CBF and neuroreceptors; and functional magnetic resonance imaging for measuring changes attributable to CBF. This article highlights the application of this technology in schizophrenia research, emphasizing more recent studies that have evaluated hemispheric differences. There is evidence for lateralized abnormalities in some studies that have examined this dimension. In general, the results implicate abnormalities in left hemispheric activity. Recent advances in basic and clinical neuroscience provide an opportunity for focused application of functional imaging in neurobiological studies of schizophrenia. PMID- 10098919 TI - Depression during the longitudinal course of schizophrenia. AB - This prospective research investigated the occurrence and persistence of depression during the longitudinal course of schizophrenia. The research goals were to (1) compare depression in schizophrenia with that in schizoaffective and major depressive disorders, (2) assess whether some schizophrenia patients are vulnerable to depression, and (3) assess the relationship of depression to posthospital adjustment in schizophrenia. A total of 70 schizophrenia, 31 schizoaffective depressed, 17 psychotic unipolar major depressed, and 69 nonpsychotic unipolar major depressed patients were assessed during hospitalization and prospectively assessed for depression, psychosis, and posthospital functioning at 4.5- and 7.5-year followups. A large number (30% to 40%) of schizophrenia patients evidenced full depressive syndromes at each followup, including a subgroup of patients who evidenced repeated depression. Even when considering the influence of psychosis on outcome, depression in schizophrenia was associated with poor overall outcome, work impairment, lower activity, dissatisfaction, and suicidal tendencies. During the post-acute phase assessed, neither the rates nor the severity of depressive syndromes differentiated depression in schizophrenia from schizodepressive or major depressive disorders. However, the depressed schizophrenia patients showed poorer posthospital adjustment in terms of less employment, more rehospitalizations, and more psychosis than the patients with primary major depression. The high prevalence of depression in schizophrenia warrants its incorporation into theory about the disorder. A continuum of vulnerability to depression contributes to the heterogeneity of schizophrenia, with some schizophrenia patients being prone to depression even years after the acute phase. Depression in schizophrenia is one factor, in addition to psychosis, associated with poor outcome and requires specific attention to the treatment strategies by psychiatrists. PMID- 10098920 TI - Neurocognitive and social functioning in schizophrenia. AB - This cross-sectional study examined the relationships between neurocognitive and social functioning in a sample of 80 outpatients with DSM-III-R schizophrenia. The neurocognitive battery included measures of verbal ability, verbal memory, visual memory, executive functioning, visual-spatial organization, vigilance, and early information processing. Positive and negative symptoms were assessed with the Positive and Negative Syndrome Scale. A range of social behaviors were assessed using the Social Functioning Scale (SFS), the Quality of Life Scale (QLS), and a video-based test, the Assessment of Interpersonal Problem-Solving Skills (AIPSS). Social functioning as assessed by the SFS was unrelated to neurocognitive functioning. Poor cognitive flexibility was associated with low scores on the QLS and the AIPSS. Verbal ability and verbal memory were also significantly associated with the AIPSS. Visual-spatial ability and vigilance were associated with the sending skills subscale of the AIPSS. In this study, which used a wide range of neurocognitive tests and measures of community functioning and social problem solving, results support earlier research that suggests an association between certain aspects of neurocognitive functioning and social functioning. PMID- 10098921 TI - First person account: coming apart--a tribute to Mark. PMID- 10098922 TI - Introduction to studies on cell adhesion using invertebrate models. PMID- 10098923 TI - Cell adhesion and histocompatibility in sponges. AB - Sponges are the lowest extant metazoan phylum and for about a century they have been used as a model system to study cell adhesion. There are three classes of molecules in the extracellular matrix of vertebrates: collagens, proteoglycans, and adhesive glycoproteins, all of them have been identified in sponges. Species specific cell recognition in sponges is mediated by supramolecular proteoglycan like complexes termed aggregation factors, still to be identified in higher animals. Polyvalent glycosaminoglycan interactions are involved in the species specificity, representing one of the few known examples of a regulatory role for carbohydrates. Aggregation factors mediate cell adhesion via a bifunctional activity that combines a calcium-dependent self-interaction of aggregation factor molecules plus a calcium-independent heterophilic interaction with cell surface receptors. Important cases of cell adhesion are the phenomena involved in histocompatibility reactions. A long-standing prediction has been that the evolutionary ancestors of histocompatibility systems might be found among primitive cell-cell interaction molecules. A surprising characteristic of sponges, considering their low phylogenetic position, is that they possess an exquisitely sophisticated histocompatibility system. Any grafting between two different sponge individuals (allograft) is almost invariably incompatible in the many species investigated, exhibiting a variety of transitive qualitatively and quantitatively different responses, which can only be explained by the existence of a highly polymorphic gene system. Individual variability of protein and glycan components in the aggregation factor of the red beard sponge, Microciona prolifera, matches the elevated sponge alloincompatibility, suggesting an involvement of the cell adhesion system in sponge allogeneic reactions and, therefore, an evolutionary relationship between cell adhesion and histocompatibility systems. PMID- 10098924 TI - Towards an understanding of the molecular basis of immune responses in sponges: the marine demosponge Geodia cydonium as a model. AB - The phylogenetic position of the phylum Porifera (sponges) is near the base of the kingdom Metazoa. During the last few years, not only rRNA sequences but, more importantly, cDNA/genes that code for proteins have been isolated and characterized from sponges, in particular from the marine demosponge Geodia cydonium. The analysis of the deduced amino acid sequences of these proteins allowed a molecular biological approach to the question of the monophyly of the Metazoa. Molecules of the extracellular matrix/basal lamina, with the integrin receptor, fibronectin, and galectin as prominent examples, and of cell-surface receptors (tyrosine kinase receptor), elements of sensory systems (crystallin, metabotropic glutamate receptor) as well as homologs/modules of an immune system (immunoglobulin-like molecules, scavenger receptor cysteine-rich [SRCR]- and short consensus repeats [SCR]-repeats), classify the Porifera as true Metazoa. As living fossils, provided with simple, primordial molecules allowing cell-cell and cell-matrix adhesion as well as processes of signal transduction as known in a more complex manner from higher Metazoa, sponges also show pecularities not known in later phyla. In this paper, the adhesion molecules presumably involved in the sponge immune system are reviewed; these are the basic adhesion molecules (galectin, integrin, fibronectin, and collagen) and especially the highly polymorphic adhesion molecules, the receptor tyrosine kinase as well as the polypeptides comprising scavenger receptor cysteine-rich (SRCR) and short consensus repeats (SCR) modules. In addition, it is reported that in the model sponge system of G. cydonium, allogeneic rejection involves an upregulation of phenylalanine hydroxylase, an enzyme initiating the pathway to melanin synthesis. PMID- 10098925 TI - Cell adhesion and the immune system: a case study using earthworms. AB - In the earthworm's immune system, cell adhesion, which occurs by putative receptors on leukocytes, is essential after recognition of self vs. non-self. Confrontation with foreign antigens is a normal event in the environment, replete with microbial pathogens that pose a threat to survival. To better understand what happens when an effector cell first recognizes a foreign target followed by its adhesion to it, isolated leukocytes, in sufficient quantities to be subjected to various analyses, have been extremely beneficial. In vitro approaches when accompanied by biochemical, immunological, and molecular technologies, have opened up new vistas concerning the immune response of earthworms and other invertebrates. The most recent discovery includes the preliminary identification of cell differentiation (CD) markers that play vital roles in recognitive and adhesive events. Certain leukocyte effectors show characteristics of natural killer (NK) cells that may act differently depending upon their source, whether autogeneic, allogeneic, xenogeneic, or expressed under normal or varying environmental conditions including exposure to xenobiotics. At the level of earthworm evolution, there is apparently a dissociation of phagocytosis from the process of killing by NK-like effectors. There are at least three future challenges. First, it is essential to determine the precise nature of the CD markers with respect to their molecular structure. Second, once their molecular and biochemical characteristics have been defined, the role of these markers in cellular and humoral mechanisms must be clarified in order to define effector cell products and resulting immune responses. Third, there is a need to differentiate between the several lytic factors that have been found in earthworms with respect to molecular structure, and biochemical and functional characterization. PMID- 10098926 TI - Cell-substrate interactions in cnidaria. AB - Studies on morphogenesis and regeneration in cnidarians have a long history, and the importance of cell-ECM (extracellular matrix) interactions for these processes has been well recognized and studied since the middle of the 20th century. Cnidarians have a life cycle with a larva, a polyp, and often a medusa generation. In the medusa, the ECM (mesoglea) is very prominent and essentially shapes the animal. In the larva and the polyp, the ECM is a thin layer. Some of the ECM components known from vertebrates have been identified in cnidarians by immunohistochemistry, electron microscopy, rotary shadowing, biochemistry, and molecular cloning. In vivo and in vitro experiments suggest that the cnidarian ECM plays a role in cell migration and morphogenesis comparable to that known from other developmental systems. In the fresh water polyp Hydra, regeneration of body patterns and migration of nematocytes seems to require the presence of ECM ligands and the corresponding cell receptors. In hydrozoan medusae, DNA replication and the stability of the differentiated state of isolated tissue can be influenced by altering the properties of the ECM substrate. When cultured, most cnidarian cells survive only when attached to ECM substrates, they rarely divide and die within short times. PMID- 10098927 TI - Cell adhesion in the process of asexual reproduction of tunicates. AB - Cell adhesion during budding of tunicates is reviewed from the viewpoints of histology, cytology, biochemistry, and molecular biology. Two kinds of multipotent cells play important roles in bud formation and development: epithelial cells, such as the atrial epithelium of botryllids and polystyelids, and mesenchymal cells, referred to as haemoblasts. Haemoblasts are able to aggregate to form a solid mass of cells, which soon becomes a hollow vesicle. The vesicular epithelium has junctional complexes that contain adherens junctions, and, sometimes, tight junctions; both occur apicolaterally on the plasma membrane. The hollow vesicle develops into the heart, the pyloric gland and duct, the gonad, including germ cells, and even the multipotent epithelium of buds. Cell culture studies suggest that multipotent epithelial cells may be interchangeable with haemoblasts. Several kinds of calcium-dependent, galactose binding tunicate lectins (TC-14s) have been isolated and sequenced, and have been found to facilitate both in vivo and in vitro cell aggregation and migration. Tunicate homologs of cadherin and integrin genes have recently been isolated from Botryllus and Polyandrocarpa, respectively. Their unique molecular characteristics are discussed in the context of roles that they play in cell adhesion in the process of tunicate budding. PMID- 10098928 TI - Dissociated cells of the calcareous sponge clathrina: a model for investigating cell adhesion and cell motility in vitro. AB - The study of cell-cell and cell-substratum adhesion in vitro is useful for understanding cell behavior in a three-dimensional pattern. We have used dissociated cells (choanocytes represent the main fraction) from the calcareous sponge Clathrina, namely C. cerebrum and C. clathrus, to illustrate our present understanding on three main aspects of cell-cell and cell-substratum adhesion in vitro: (1) cytoskeletal protrusions; (2) cell behaviours on organic substrata; and (3) paths of locomotory sponge cell. Cell locomotion occurs by the extensions of scleropodial and lamellipodial protrusions, by way of actin polymerization. The extent to which cells produce these cytoplasmic processes varies according to the substratum (e.g., collagen, fibronectin, laminin, polylysine). It was found that more cell extensions were produced on collagen substrata, and this led to greater cell movement. Advancing choanocytes are not polarized. Their paths are particularly complicated, showing linear segments, which produce a more efficent cellular translocation, and winding tracts with frequent turns or loops. Small amoeboid cells describe more linear paths with a wide range of speed variation than larger cells. The presence of cell-derived substratum reduces the progressive dispersion of cells and allows cells to encounter one another in such a way that the initial random walking later turns into non-random displacement. Even though cAMP-treated cells exhibit different aggregative tactics, cAMP 10(-8) M remarkably enhances cell encounters and supports the existing information that this cyclic nucleotide represents a signal that affects cell morphology and locomotion. The bulk of data on sponge cell-cell and cell-substratum adhesion has been evaluated by mentioning the significant advances and references concerning studies of other cell systems. PMID- 10098929 TI - Dynamic control of reversible cell adhesion and actin cytoskeleton in the mouth of Beroe. AB - Cell-cell adhesion in the various types of intercellular junctions of differentiated tissues is relatively stable and permanent. In migrating cells of embryos, or in wound closure, inflammatory responses and tumors of adult tissues, however, bonds between cells are made and broken and made again, i.e., cell-cell adhesions are transient and reversible. These nonjunctional contacts lack the organized structure of intercellular junctions, but may initiate their tissue specific formation during development. Investigation of dynamic, nonjunctional cell-cell adhesions has been hampered by the asynchronous and heterogeneous distribution of these transient contacts among groups of moving cells. We recently discovered a novel system of reversible cell adhesion in a differentiated tissue that overcomes this difficulty. Here I review our current knowledge of this system, particularly its unique experimental advantages for investigating the mechanisms and control of dynamic cell adhesion. PMID- 10098930 TI - Molecular self-recognition and adhesion via proteoglycan to proteoglycan interactions as a pathway to multicellularity: atomic force microscopy and color coded bead measurements in sponges. AB - During the emergence of multicellular organisms, molecular mechanisms evolved to allow maintenance of anatomical integrity and self-recognition. We propose that carbohydrates from proteoglycans, as the most peripheral cell surface, and matrix molecules might have provided these key adhesion and recognition functions. If so, the Porifera as the simplest metazoans alive today should retain, at least in part, proteoglycan adhesion and recognition mechanisms. Early work on cell adhesion of dissociated marine sponge cells provided important phenomenological evidence for cell sorting. Here is reviewed recent work on molecular mechanisms of cell recognition and adhesion mediated by cell surface proteoglycans purified from three marine sponge species, Microciona prolifera, Halichondria panicea, and Cliona celata. Biochemical characterization of isolated proteoglycans showed that each species expressed a unique type of primordial molecule named glyconectins. These proteoglycans displayed species-specific self-recognition and adhesion in color-coded bead, cell, and blotting assays. The specificity of homophilic proteoglycan to proteoglycan interactions in the Porifera approaches the binding selectivity of the evolutionarily advanced immunoglobulin superfamily system. Such xeno-selectivity may be a new paradigm for the molecular self-recognition, which was a fundamental requirement in the self/non-self discrimination during the emergence of multicellularity and further divergence of species. We have used atomic force microscopy (AFM) technology to directly measure intermolecular binding strength between individual pairs of ligand and receptor molecules in physiological solution. Homophilic glyconectin interactions were investigated by AFM after covalent attachment of the protein core to the sensor tip and to a flat surface, leaving the carbohydrates unmodified. AFM measurements of the binding strength between glyconectins indicated that one pair of molecules could theoretically hold the weight of 1,600 cells in physiological solution. These results provided the first essential and quantitative evidence that proteoglycan proteoglycan binding can perform the adhesion function that we have assigned to it. Our investigations with purified proteoglycans from the marine sponge M. prolifera (glyconectin 1) using bead and cell adhesion assays have provided evidence that a new molecular mechanism of polyvalent and specific glycan-glycan binding between proteoglycans can mediate cell recognition and adhesion. Partial sequencing of the glycans has revealed two new cell adhesion carbohydrate structures: (3)GlcNAc(3OSO3)beta1-3Fuc and Pyr4,6Galbeta1-4GlcNAcbeta1-3Fuc. PMID- 10098931 TI - unc-45 gene of Caenorhabditis elegans encodes a muscle-specific tetratricopeptide repeat-containing protein. AB - The unc-45 gene of the nematode, Caenorhabditis elegans, is essential for muscle organization and embryonic development. Genetic evidence suggests the unc-45 gene product controls muscle thick filament assembly. We report here on the determination of the gene's chromosomal location and the isolation and sequencing of its cDNA. The amino terminus of the predicted unc-45 protein contains three tandem repeats that belong in the tetratricopeptide repeat family. Tetratricopeptide motifs have been shown to be involved in protein interactions, and some of the closest homologues have chaperone-like activity. The carboxy terminus of the protein has homology with the related fungal proteins, CRO1 and She4p, which have been postulated to play a role in assembly of or interactions with a cytoplasmic myosin. We have also determined the sequence of the homologous gene from C. briggsae, which demonstrates a high level of conservation. We show that the unc-45 gene promoter can drive reporter gene expression, which is limited to muscle tissues (pharyngeal, body wall, vulval, and anal muscles), consistent with a role for the unc-45 gene in muscle development or function. PMID- 10098932 TI - Activities of the EM10 protein from Echinococcus multilocularis in cultured mammalian cells demonstrate functional relationships to ERM family members. AB - The ezrin-radixin-moesin (ERM) homolog EM10 is expressed by the larval stage of the parasite E. multilocularis and shows 46.9% overall identity in the primary structure with human ezrin. To determine whether EM10 has similar activities to ERM proteins, we investigated properties of the protein expressed in mammalian cells. In particular, we transiently expressed haemagglutinin-tagged (HA-tagged) versions of the full-length EM10 as well as the amino- and the carboxy-terminal halves of EM10 in HtTA-1 cells. In addition we stably transfected NIH-3T3 cells with untagged full-length EM10. The data demonstrate that EM10 polypeptides behave like their corresponding portions of radixin when transiently expressed in mammalian cells. The full-length and amino-terminal EM10 polypeptides were localized to cortical structures. Cells expressing the carboxy-terminal polypeptide of EM10 showed long actin-filled protrusions. Cells expressing full length EM10 showed a reduction in endogenous moesin-staining at cortical structures. In stably transfected NIH-3T3 cells EM10 was not crisply localized but rather was diffuse throughout the cytoplasm. These cells showed a conspicuous loss of stress-fibers, a phenotype that was not seen in analogous experiments with ERM proteins. The results demonstrate both similarities and differences between the functional properties of EM10 and ERM proteins expressed in vertebrate cells. PMID- 10098933 TI - NuMA is a component of an insoluble matrix at mitotic spindle poles. AB - NuMA associates with microtubule motors during mitosis to perform an essential role in organizing microtubule minus ends at spindle poles. Using immunogold electron microscopy, we show that NuMA is a component of an electron-dense material concentrated at both mitotic spindle poles in PtK1 cells and the core of microtubule asters formed through a centrosome-independent mechanism in cell-free mitotic extracts. This NuMA-containing material is distinct from the peri centriolar material and forms a matrix that appears to anchor microtubule ends at the spindle pole. In stark contrast to conventional microtubule-associated proteins whose solubility is directly dependent on microtubules, we find that once NuMA is incorporated into this matrix either in vivo or in vitro, it becomes insoluble and this insolubility is no longer dependent on microtubules. NuMA is essential for the formation of this insoluble matrix at the core of mitotic asters assembled in vitro because the matrix is absent from mitotic asters assembled in a cell-free mitotic extract that is specifically depleted of NuMA. These physical properties are consistent with NuMA being a component of the putative mitotic spindle matrix in vertebrate cells. Furthermore, given that NuMA is essential for spindle pole organization in vertebrate systems, it is likely that this insoluble matrix plays an essential structural function in anchoring and/or stabilizing microtubule minus ends at spindle poles in mitotic cells. PMID- 10098934 TI - Architectural dynamics and gene replacement of coronin suggest its role in cytokinesis. AB - Coronin is a ubiquitous actin-binding protein representing a member of proteins portraying a WD-repeat sequence, including the beta-subunits of trimeric G proteins. Coronin has been suggested to participate in multiple, actin-based physiological activities such as cell movement and cell division. Although the slow growth of coronin deletion mutants has been attributed to a defect in the fluid-phase uptake of nutrients, the exact role of coronin in cytoskeletal organization has not been elucidated. In this study, we examined a role of coronin in cytokinesis by analyzing the effect of coronin deletion on the actin cytoskeleton and its dynamic distribution using a green fluorescent protein (GFP) coronin fusion protein. We show that GFP-coronin works similarly to natural coronin in vivo and in vitro. In live cells, GFP-coronin was found to accumulate into the cleavage furrow during cytokinesis. The fluorescence pattern suggests its association to the contractile ring throughout cytokinesis. Interestingly, a substantial amount of coronin was also bound to F-actin at the prospective posterior cortex of the daughter cells. We also show that the coronin null cells reveal irregularities in organization of actin and myosin II and divide by a process identical to the traction-mediated cytofission reported in myosin II mutants. Overall, this study suggests that coronin is essential for organizing the normal actin cytoskeleton and plays a significant role in cell division. PMID- 10098935 TI - Perturbation of the actin cytoskeleton induces PAI-1 gene expression in cultured epithelial cells independent of substrate anchorage. AB - Perturbation of cellular architecture with agents that alter cytoskeletal organization provides a means to assess the relationship between cell shape and gene expression. Induced transcription of the plasminogen activator inhibitor type-1 (PAI-1) gene in serum-free cultures of normal rat kidney (NRK-52E) cells following disruption of actin microfilament structures with cytochalasin D (CD) provides a simple model to probe mechanisms underlying shape-related expression control. Transition from the typical flat epithelial cell shape to an "arborized" phenotype was a concomitant of the PAI-1 inductive response. Stimulated expression occurred rapidly (i.e., within 2 h of CD addition), involved increases in both PAI-1 mRNA abundance and de novo protein synthesis, and was dependent upon the concentration of CD used. A series of culture conditions were designed (e.g., use of bacteriological surfaces, poly-HEMA coated surfaces, maintenance in suspension on agarose) to discriminate cell shape from adhesive influences on CD stimulated PAI-1 expression. Cytoskeletal disruption, and not simply changes in cell shape, was a critical aspect of CD-mediated PAI-1 expression in NRK cells cultured under serum-free conditions; induced expression was independent of substrate anchorage. Low concentrations of CD (1-2 microM) failed to cause cell arborization or increase either relative PAI-1 mRNA/protein abundance levels suggesting, however, that cell rounding may be a necessary but not sufficient aspect in CD-mediated PAI-1 induction. Transfection of PAI-1 promoter-CAT reporter constructs into NRK cells followed by stimulation with CD or serum additionally indicated that CD-induced PAI-1 expression did not utilize the same functional complement of serum-responsive promoter sequences, thus, further defining differences in the growth factor- and cytoskeletal-mediated pathways of PAI-1 gene regulation. PMID- 10098936 TI - Regulation of neurofilament axonal transport by phosphorylation in optic axons in situ. AB - Axonal transport of neurofilament (NFs) is considered to be regulated by phosphorylation. While existing evidence for this hypothesis is compelling, supportive studies have been largely restricted to correlative evidence and/or experimental systems involving mutants. We tested this hypothesis in retinal ganglion cells of normal mice in situ by comparing subunit transport with regional phosphorylation state coupled with inhibition of phosphatases. NF subunits were radiolabeled by intravitreal injection of 35S-methionine. NF axonal transport was monitored by following the location of the peak of radiolabeled subunits immunoprecipitated from 9x1.1 mm segments of optic axons. An abrupt decline transport rate was observed between days 1 and 6, which corresponded to translocation of the peak of radiolabeled subunits from axonal segment 2 into segment 3. Notably, this is far downstream from the only caliber increase of optic axons at 150 mu from the retina. Immunoblot analysis demonstrated a unique threefold increase between segments 2 and 3 in levels of a "late-appearing" C terminal NF-H phospho-epitope (RT97). Intravitreal injection of the phosphatase inhibitor okadaic acid increased RT97 immunoreactivity within retinas and proximal axons, and markedly decreased NF transport rate out of retinas and proximal axons. These findings provide in situ experimental evidence for regulation of NF transport by site-specific phosphorylation. PMID- 10098937 TI - Antiepileptic teratogen valproic acid (VPA) modulates organisation and dynamics of the actin cytoskeleton. AB - The antiepileptic drug valproic acid (VPA) and teratogenic VPA analogues have been demonstrated to inhibit cell motility and affect cell morphology. We here show that disruption of microtubules or of microfilaments by exposure to nocodazole or cytochalasin D had different effects on morphology of control cells and cells treated with VPA, indicating that VPA affected the cytoskeletal determinants of cell morphology. Furthermore, VPA treatment induced an increase of F-actin, and of FAK, paxillin, vinculin, and phosphotyrosine in focal adhesion complexes. These changes were accompanied by increased adhesion of VPA-treated cells to the extracellular matrix. Treatment with an RGD-containing peptide reducing integrin binding to components of the extracellular matrix partially reverted the motility inhibition induced by VPA, indicating that altered adhesion contributed to, but was not the sole reason for the VPA mediated inhibition of motility. In addition it is shown that the actomyosin cytoskeleton of VPA-treated cells was capable of contraction upon exposure to ATP, indicating that the reduced motility of VPA-treated cells was not caused by an inhibition of actomyosin contraction. On the other hand, VPA caused a redistribution of the actin severing protein gelsolin, and left the cells unable to respond to treatment with a gelsolin-peptide known to reduce the amount of gelsolin bound to phosphatidylinositol bisphosphate (PIP2), leaving a larger amount of the protein in a potential actin binding state. These findings indicate that VPA affects cell morphology and motility through interference with the dynamics of the actin cytoskeleton. PMID- 10098938 TI - Differential projections to the intralaminar and gustatory thalamus from the parabrachial area: a PHA-L study in the rat. AB - The organization of projections from the parabrachial (PB) area to the ventral posterior parvicellular (VPpc) "gustatory" and intralaminar nuclei of the thalamus was studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L), into subregions of the PB area. The present study is a follow-up of three former studies (Bernard et al. [1993] J. Comp. Neurol. 329:201 229; Alden et al. [1994] J. Comp. Neurol. 341:289-314; Bester et al. [1997a] J. Comp. Neurol. 383:245-281) that examined PB projections onto the amygdala, the bed nucleus of the stria terminalis, and the hypothalamus. Our data showed that (1) the region centered in the internal lateral PB subnucleus projects densely with a bilateral and symmetric pattern to the caudal portion of the paracentral and, to a lesser extent, to the adjacent portion of the central and parafascicular medial thalamic nuclei; (2) the mesencephalic PB region centered in the ventral lateral subnucleus and scattered neurons in the subjacent brachium conjunctivum project primarily, although diffusely, to the central medial thalamic nucleus. The third region includes two subgroups: (3a) the medial subgroup, including the medial, the waist area, and the ventral lateral subnuclei of the pontine PB area, projects bilaterally but with a weak ipsilateral predominance to the VPpc, terminals bearing large varicosities. Additionally, a diffuse projection with small varicosities spreads in the area between the two VPpc nuclei and the central medial nucleus. (3b) The lateral subgroup, centered in the external medial subnucleus, projects with a contralateral predominance in the periphery of the VPpc nuclei, most terminals being located around the dorsomedial tip. It is suggested that the PB projections to the intralaminar nucleus could be involved in cortical limbic arousal processing in relation with nociceptive, (somatic, visceral, and intraoral) and gustatory aversive stimuli. The projection with large varicosities inside the VPpc could process gustatory discrimination. PMID- 10098939 TI - Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent. AB - Endomorphins are endogenous peptides that have high affinity and selectivity for the mu-opiate receptor and potent analgesic activity. The distributions of endomorphin 1 (Tyr-Pro-Trp-Phe-NH2; EM1) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH2; EM2) in the rat central nervous system were determined by immunocytochemistry with two antisera, each demonstrating clear preference for the target antigen. Perikarya expressing EM2-like immunoreactivity were present in the posterior hypothalamus, whereas those expressing EM1-like immunoreactivity were present in both the posterior hypothalamus and the nucleus of the solitary tract (NTS). EM1 like immunoreactivity was more widely and densely distributed throughout the brain than was EM2-like immunoreactivity, whereas EM2-like immunoreactivity was more prevalent in the spinal cord than was EM1-like immunoreactivity. The greatest density of EM1-like-immunoreactive fibers was detected in the parabrachial nucleus and the NTS, with notable staining in the septum, diagonal band, bed nucleus of the stria terminalis, organum vasculosum, nucleus of Meynert, paraventricular thalamic nucleus, posterior hypothalamic nucleus, periaqueductal gray, locus coeruleus, nucleus accumbens, and amygdala. The greatest density of EM2-like-immunoreactive fibers was detected in the superficial laminae of the spinal cord dorsal horn and the nucleus of the spinal trigeminal tract. The overall pattern of immunoreactivities was similar in rat, mouse, and guinea pig, but some differences were observed. In many but not in all locations, immunoreactive fibers were prominently present in regions in which mu receptors are reported to be concentrated. The neuroanatomical results suggest that endomorphins participate in modulating nociceptive and autonomic nervous system processes and responsiveness to stress. PMID- 10098940 TI - Ultrastructural localization of dynorphin in the dentate gyrus in human temporal lobe epilepsy: a study of reorganized mossy fiber synapses. AB - Substantial reorganization of mossy fibers from granule cells of the dentate gyrus occurs in a high percentage of humans with medically intractable temporal lobe epilepsy. To identify these fibers and determine their ultrastructural features in human surgical specimens, we used preembedding immunoperoxidase labeling of dynorphin A, an opioid peptide that is abundant in normal mossy fibers. In electron microscopic preparations, dynorphin A immunoreactivity was highly associated with dense core vesicles and was localized predominantly in axon terminals in the inner molecular layer of the dentate gyrus, although some dynorphin-labeled dense core vesicles were also observed in dendritic shafts and spines. The labeled terminal profiles were numerous, and, whereas they varied greatly in size, many were relatively large (2.3 microm in mean major diameter). The terminals contained high concentrations of clear round vesicles and numerous mitochondrial profiles, formed distinct asymmetric synapses, often had irregular shapes, and, thus, exhibited many features of normal mossy fiber terminals. The dynorphin-labeled terminals formed synaptic contacts primarily with dendritic spines, and some of these spines were embedded in large labeled terminals, suggesting that they were complex spines. The labeled terminals frequently formed multiple synaptic contacts with their postsynaptic elements, and perforated postsynaptic densities, with and without spinules, were present at some synapses. These findings suggest that the reorganized mossy fiber terminals in humans with temporal lobe epilepsy form abundant functional synapses in the inner molecular layer of the dentate gyrus, and many of these contacts have ultrastructural features that could be associated with highly efficacious synapses. PMID- 10098941 TI - Evidence that nerve growth factor influences recent memory through structural changes in septohippocampal cholinergic neurons. AB - We compared, in 4- and 23-month-old Fischer-344 rats, the effects of nerve growth factor (NGF) on basal forebrain cholinergic neurons with behavioral performance in acetylcholine-dependent memory tasks (recent and reference memory). Noncholinergic monoamine markers in target fields of cholinergic neurons were also investigated. We found that NGF has contrasting effects on recent memory in the two age groups in causing improvement in aged rats and deterioration in young rats. In addition, NGF caused significant increase in the size of cholinergic perikarya in all sectors of the basal nucleus complex (BNC). Higher doses of NGF were required to produce hypertrophy in aged animals, a pattern consistent with a lower sensitivity to NGF of aged cholinergic neurons. Analysis of covariance showed that the behavioral effects of NGF were eliminated after covarying out the hypertrophy of cholinergic perikarya. Therefore, NGF causes hypertrophy of cholinergic perikarya regardless of age, and this neurobiological measure correlates with the effects of NGF on recent memory. Reference memory improved moderately only in old rats. This mild effect covaried with an increase in choline acetyltransferase activity in neocortex. Cortical terminal fields of noradrenergic and serotoninergic pathways were not affected by NGF. Taken together, our results indicate that NGF influences recent memory in an age- and transmitter-specific fashion. We postulate that the direct cause of the effects of NGF on memory is not perikaryal hypertrophy per se but rather an increased density of terminals, which always accompanies perikaryal hypertrophy. Although these results continue to support the use of NGF for the treatment of Alzheimer's disease, they raise questions regarding the therapeutic role of NGF for degeneration of BNC neurons occurring in young age. PMID- 10098942 TI - Tangential migration of young neurons arising from the subventricular zone of adult rats is impaired by surgical lesions passing through their natural migratory pathway. AB - In the brain of adult rodents, young neurons arising from the subventricular zone (SVZ) of the lateral ventricle migrate tangentially along the rostral migratory stream (RMS) toward the olfactory bulb. The aim of this study was to determine whether surgical lesions placed through the RMS could affect the rostral migration of these newly formed neurons. Confocal and electron microscopy were used to characterize their anatomical organization within the intact and lesioned forebrains. As soon as 7 days and up to 45 days after placing a surgical lesion through the proximal portions of the RMS, numerous cells immunostained for polysialylated neural cell adhesion molecule (PSA-NCAM) were detected both (1) throughout the lesional cavity extending from the cortex to the anterior commissura, and (2) within the tissue located caudal to the lesion. In both regions, these PSA-NCAM-immunostained cells were labeled for neuronal markers but were negative for glial fibrillary acidic protein (GFAP). After administration of the proliferation marker bromodeoxyuridine (BrdU), nuclear labeling was associated with cells immunostained for PSA-NCAM but GFAP-negative, that accumulated within the lesional cavity and in the tissue caudal to the lesion. For the longest postlesional delays, a number of the PSA-NCAM-immunostained neurons located in various portions of the lesional cavity exhibited intense immunostaining for gamma-aminobutyric acid, whereas only a few of them exhibited faint immunostaining for tyrosine hydroxylase. These data indicate that surgical lesions placed through the RMS of adult rats impede the migration toward the olfactory bulb of the neuroblasts arising from the SVZ, inducing their accumulation and their partial differentiation in forebrain regions caudal to the lesion. PMID- 10098943 TI - Estrogen receptor immunoreactivity in the adult primate brain: neuronal distribution and association with p75, trkA, and choline acetyltransferase. AB - The neuroactive steroid hormone, estrogen, has been implicated in both the prevention and treatment of Alzheimer's disease. Interactions between estrogen and neurotrophic systems may partially explain the beneficial effects of estrogen therapy. Previous studies have identified estrogen binding sites colocalized with neurotrophin-related proteins and mRNA within the rodent brain. Extending these studies to a model more relevant to human systems, we have mapped the distribution of estrogen receptor alpha (ER-alpha)-immunoreactive neurons in adult nonhuman primate brains. In addition, we used double-label immunohistochemistry to examine colocalization of ER-alpha with the low- and high affinity neurotrophin receptors, p75 and trkA, and with the cholinergic marker choline acetyltransferase. Large numbers of ER-alpha-immunoreactive cells were detected in several amygdaloid and hypothalamic nuclei. ER-alpha-labeled cells were also found in the lateral septum, nucleus of the stria terminals, subfornical organ, and periaqueductal gray. Only rare, scattered ER-alpha immunoreactive cells were noted in the cholinergic basal forebrain. In contrast to rodents, no cells exhibited ER-alpha and p75 or ER-alpha and trkA double labeling. However, ER-labeled neurons in the amygdala, a region containing putative nerve growth factor-producing cells and exhibiting a role in memory, were densely and specifically invested with cholinergic terminals projecting from the basal forebrain. Estrogen-labeled neurons were also present in the lateral septal nucleus, a system that receives hippocampal inputs and projects to the neurotrophin-sensitive medial septum. Thus, interactions between neurotrophin sensitive neurons and ER-bearing neurons exist in the primate brain, providing a potential paracrine basis for estrogen-state modulation of vulnerability to Alzheimer's disease. PMID- 10098944 TI - Three-dimensional reconstruction of the antennal lobe in Drosophila melanogaster. AB - We present the first three-dimensional map of the antennal lobe of Drosophila melanogaster, based on confocal microscopic analysis of glomeruli stained with the neuropil-specific monoclonal antibody nc82. The analysis of confocal stacks allowed us to identify glomeruli according to the criteria shape, size, position, and intensity of antibody labeling. Forty glomeruli were labeled by nc82, eight of which have not been described before. Three glomeruli previously shown exclusively by backfills were not discernible in nc82 stainings. We distinguish three classes of glomeruli: (1) "landmark" glomeruli that are constant in all four criteria mentioned above, (2) less well-demarcated glomeruli that deviate in a single criterion, and (3) poorly defined glomeruli that vary in more than one criterion. All class 2 and 3 glomeruli can be identified by comparison with landmark neighbors. To further aid identification, our model assigns glomeruli to five arrays, each of which is defined by a prominent landmark glomerulus. Six glomeruli consist of distinct, but contiguous structural units, termed "compartments." Glomerular variability observed occasionally between males and females is in the same range as between individuals of the same sex, suggesting the lack of a significant sexual dimorphism in the glomerular pattern. We compare the new model with a previous map and address its potential for mapping activity and expression patterns. An important goal of this work was to create three dimensional reference models of the antennal lobe, which are accessible on-line. PMID- 10098945 TI - Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. AB - Dendritic cells (DC) are regarded as the 'sentinels' of the immune system. They play a crucial role in surveillance of peripheral tissues, trapping antigens encountered there, and migrating via the lymphatics to lymphoid organs where they interact with naive T cells thus generating antigen-specific primary immune responses. Until now it has been assumed DC are largely absent from the brain, meninges, and the choroid plexus within the ventricles. Such a situation was thought to partly explain the 'immune privileged' nature of the central nervous system (CNS). The present study of normal rat tissues using single and double immunohistochemistry reveals for the first time that extensive networks of major histocompatability (MHC) class II+/OX62+ DC are widely distributed in sites which may potentially encounter CNS antigens. These sites included the dura mater, leptomeninges, and the choroid plexus. These putative DC were negative when stained with the anti-resident tissue macrophage monoclonal antibody ED2. In addition to the rich networks of DC, dense populations of resident tissue macrophages (ED2+ and ED1+) were also demonstrated in the dura mater, leptomeninges and to a lesser extent in the choroid plexus. The presence of rich networks of DC and macrophages in the vascular and supporting tissues of the brain may play an important role in inflammatory and immune-mediated disorders affecting the CNS, including auto-immune demyelinating diseases such as multiple sclerosis. PMID- 10098946 TI - A stretch-sensitive Cl- channel in human corpus cavernosal myocytes. AB - With the patch clamp method we demonstrate a stretch-sensitive Cl- currents as well as stretch-sensitive Cl- channels in a small group (5%,n 117) of cultured human corpus cavernosal muscle cells. The current and the channel activities had the following characteristics: (1) Their equilibrium potentials changed with extracellular Cl- concentration close to that predicted by Nernst equation provided that the relevant channels had high permeability to Cl- but low permeability to acetate ions; (2) They were blocked by mM concentrations of Zn2+; (3) The i-v relation of single channel current was almost linear for holding potentials varied from -70 to +60 mV; and (4) The channels had unitary conductances of approximately 140-170 pS. PMID- 10098947 TI - Enhanced contractility of rabbit corpus cavernosum smooth muscle by oxidized low density lipoproteins. AB - We have investigated the effect of oxidatively-modified low density lipoproteins (ox-LDL) on the contractility of rabbit trabecular smooth muscle. Low density lipoproteins (LDL) were isolated from fresh human plasma pooled from multiple donors and oxidized by exposure to copper. Corpus cavernosum strips from New Zealand White rabbits were studied in organ chambers for isometric tension measurement. Corporeal strips in which moderate tone was induced by phenylephrine, contracted when exposed to ox-LDL, but not when exposed to either native LDL (nLDL) or LDL protected from oxidation by butylated hydroxytoleune (BHT-LDL). Removal of the endothelium, or treatment of the corporeal strips with N(omega)-nitro-L-arginine (nitric oxide synthase inhibitor), methylene blue of LY83583 (guanylate cyclase inhibitors/superoxide producing agents), did not prevent ox-LDL-induced contraction. ox-LDL, dose-dependently, enhanced the contractile response of corporeal strips to low and moderate concentrations by phenylephrine. nLDL had no significant effect on phenylephrine-induced contraction of corporeal strips. ox-LDL, nLDL or BHT-LDL had no effect on relaxation induced by the endothelium-dependent dilator, acetylcholine, or the nitric oxide donor, nitroprusside. In conclusion, this present study demonstrates significant pro-contractile effects of ox-LDL on corporeal smooth muscle, this effect is independent of the endothelium or the nitric oxide/cGMP pathway. The pro-contractile effect of ox-LDL may interfere with penile smooth muscle relaxation, necessary for the initiation and maintenance of penile erection. PMID- 10098948 TI - Progressive treatment of erectile dysfunction with intracorporeal injections of different combinations of vasoactive agents. AB - To account for severity of disease in patients with erectile dysfunction, we introduced a progressive treatment technique using four protocols of drug injections. The study group consisted of 452 men aged 26-85 gamma with erectile dysfunction. Protocol I. All patients began with a combination of papaverine and Regitine in doses adjusted to the estimated severity of dysfunction and to age, up to a maximum dose of 25 mg papaverine and 1.5 mg of Regitine. Protocol II. Patients who could not achieve sufficient rigidity on protocol I were switched to prostin VR, to a maximum of 25 mcg. Protocol III. Patients who failed protocol II received papaverine, Regitine and prostin VR. Protocol IV. Patients who failed protocol III received atropine sulfate (0.02-0.06 mg) in addition to papaverine, Regitine and prostin. Sufficient rigidity was achieved as follows: Protocol I=305 (67.4%) of the original cohort; Protocol II= 61 of the 147 failures with Protocol I (41.5%); Protocol III = 55 of the 86 failures with Protocol 11 (63.9%); Protocol IV = 20 of the remaining 31 patients (64.5%). Overall, sustained rigidity was achieved in 441 of the 452 patients (97.5%). Eleven patients (2.5%) failed all four protocols and were offered a penile prosthesis. Therefore, using our progressive method, by starting with the most available and inexpensive drugs, patients with erectile dysfunction can be given optimal treatment according to the severity of their disease. The success rate is high while costs are kept to a minimum. PMID- 10098949 TI - Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction. AB - In a three-year follow-up study of 69 patients found that erectile dysfunction (ED) impairs many elderly men's life: up to 25% of the men aged 65 y and 80% of those aged 75 y suffer from erectile dysfunction. The most effective non-surgical treatment of ED is intracavernosal pharmacotherapy, and the most common vasoactive agent currently used is prostaglandin E1 (PGE1). The purpose of this study was to assess the long-term outcome of PGE1 treatment and the patients' overall satisfaction with their sexual life. Sixty-nine patients who had started ICI therapy three years earlier were invited to a control examination. The mean age of the patients was 60.5 y. The patients filled in a questionnaire, which included questions about the use of PGE1 treatment at home. All the patients evaluated their own satisfaction with their erection, ejaculation, orgasm and libido on a visual analytical scale (VAS, 0-100%). A clinical examination was made, and the penile shaft was examined by ultrasonography. Erection with the home dose of PGE1 was estimated by Rigiscan, and the degree of erection was also estimated clinically (grades 0-5) by a doctor. The most common doses of PGE1 used at home were between 10 and 20 m (58%), 46.4% of the patients had discontinued PGE1 therapy, the mean time of using PGE1 was 23.3 months. The mean coital frequency with PGE1 was 2.8 times per month. 34.8% of the patients (24 out of 69) reported that their own spontaneous erections had improved after the beginning of PGE1 therapy. The most common problem was hematomas in 10.1% of the patients (7 out of 69), which, however, were small and did not cause discontinuation of the therapy. There were three instances of priapism (4.3%), and four patients (5.8%) had fibrosis in ultrasonography. The patients' satisfaction with their erection at home was 67.3% with PGE1. The mean coital frequency with PGE1 therapy was quite low, 2.8 times per month, even though the patients' mean age was only 60.5 y, one reason may be the high price of PGE1 injections. The rate of improvement of spontaneous erections while using PGE1 was quite high, accounting for 34.8% of the patients. Most of the patients who discontinued the PGE1 therapy had a psychogenic etiology. There were no systemic side-effects with PGE1. Only 7.2% of the patients had prolonged pain after the injection, leading to drug discontinuation. It can be concluded that treatment with intracavernous injections of PGE1 is well tolerated and involves only minor problems. The patients' satisfaction with their erections at home with PGE1 therapy was good. Precise determination of the home dose of PGE1 and the teaching of the technique of injection are important at the beginning of this treatment modality. PMID- 10098950 TI - Infection control in outpatient unicomponent penile prosthesis surgery. AB - The aim of this work is evaluate the efficacy of infection control measures with unicomponent penile implants in two ambulatory surgery units in Cairo and Jeddah. This was a retrospective study of 117 consecutive cases. A patient selection and infection control protocol was followed to implant 12 hydraulic, 53 mechanical and 52 malleable prostheses under local bupivacaine penile ring anesthesia and intravenous propofol. No infection occurred that required prosthesis removal, none required hospitalization or urinary catheterization, one crural and two septal perforations were managed intraoperatively; one case was reoperated upon for mechanical failure, two for oversizing and one for undersizing the girth. We conclude that implantation of unicomponent penile implants under triple antibiotic coverage in an ambulatory surgery setting, with rigid infection control measures appears to be effective in preventing infection. PMID- 10098951 TI - Maximisation of the erectile response in the investigation of impotence. AB - The aim of this study was to assess whether redosing with a combination of intracavernosal (IC) vasoactive agents could produce a complete erectile response, thereby providing a reliable and reproducible method of dynamic investigation of erectile dysfunction. Forty-one impotent men were redosed with a combination intracavernosal agents until a constant penile rigidity was achieved. They were then shown audiovisual sexual stimulation (VES) by means of a videotape. The erectile responses were monitored continuously by RigiScan (Dacomed). RESULTS: Despite a constant rigidity with intracavernous injection (ICI), 16 men (39%) still had an improved response with VES that was clinically detectable. CONCLUSION: Dynamic investigation of erectile dysfunction with a combination and redosing of IC agents may still lead to an incomplete erectile response. This may potentially lead to patients being incorrectly labelled and confirms the limitations of follow-up studies using dynamic tests of erectile function. PMID- 10098952 TI - Transcutaneous nitroglycerine in the treatment of erectile dysfunction: a placebo controlled clinical trial. AB - Transcutaneous nitroglycerine has previously been reported to be effective in the treatment of erectile dysfunction. We present our results with the drug in a randomised, placebo controlled, double-blind crossover study. The effect of the drug has been evaluated both under laboratory conditions and in a home study. Eighteen men were included in the study. No effect of nitroglycerine could be demonstrated under laboratory conditions by application of the Rigiscan Monitor. In the home study there was no statistical significant effect of transcutaneous nitroglycerine compared to placebo (P= 0.2813). PMID- 10098953 TI - The use of acupuncture in the treatment of erectile dysfunction. AB - The efficacy of acupuncture as a mono-therapy was evaluated in a pilot study of 16 patients suffering from erectile dysfunction (ED). In nine patients no organic co-morbidity was encountered. In a period of four weeks, acupuncture treatment was performed twice a week for a total of eight sessions. Each treatment session consisted of puncture of the same eight acupoints, four of which were connected to a Swiss made constant current Doltron ESA 600 stimulator. Low frequency electrical stimulation (5 Hz and 10 mA) was applied to these four acupoints, whereas no stimulation was applied to the other four points. After 30min, the electrical stimulation was terminated and all needles removed. Blood samples were drawn according to a fixed time schedule, to study the profile of a number of stress hormones, for example, adrenocorticotropic hormone, antidiuretic hormone and cortisol, the gonadotrophines follicle stimulating hormone and leutinizing hormone, and the sex steroid testosterone and its binding globulin, within the treatment period. Based on a diary of both patient and partner, and an interview one month after the end of treatment, the changes of sexual activity were evaluated over a period of 12 weeks, starting from the four weeks prior to the treatment, the four weeks during the treatment period and the four weeks after the treatment. An improvement of the quality of erection was experienced by 15% of patients, while 31% reported an increase in their sexual activity. No changes in the profiles of hormones were detected. The use of acupuncture as a mono therapeutic modality in ED, did not influence the profile of the stress and sex hormones, but did improve the quality of erection and restored the sexual activity with an overall effect of 39%. No definite conclusions can be drawn from this pilot study. A controlled and blinded study including more patients will be needed before any definitive conclusion can be reached. PMID- 10098954 TI - Predictive value of patient history and correlation of nocturnal penile tumescence, colour duplex Doppler ultrasonography and dynamic cavernosometry and cavernosography in the evaluation of erectile dysfunction. AB - AIMS: The results of history and physical examination, nocturnal penile tumescence testing (NPT), colour flow duplex Doppler ultrasonography and dynamic infusion cavernosometry and cavernosography (DICC) were retrospectively correlated in 207 patients with erectile dysfunction. METHODS AND MATERIALS: The predictive value of the patient's own subjective assessment of early morning and nocturnal erections, history of cigarette smoking, the presence of vascular risk factors was correlated to the outcome of investigations. The result of Rigiscan NPT was correlated to the peak systolic velocity (PSV) and the resistance index (RI) determined at colour flow duplex Doppler ultrasonography, and the maintenance flow rate (Qm) determined at DICC. RESULTS: Eighty-five out of two hundred and seven patients (41%) had normal NPT comprising 48 out of 85 patients (56%) who described rigid early morning and nocturnal erections, 15 out of 85 patients (18%) who smoked cigarettes and 9 out of 85 patients (11%) with other positive vascular risk factors. 72 out of 85 patients (85%) had a normal PSV (>30 cm/s), 80 out of 85 patients (94%) had a normal RI (>0.85) and 82 out of 85 patients (96%) had a normal Qm), (<10 ml/min). Vascular investigations in this group identified 71 out of 85 patients (84%) with no penile vascular disease, 11 out of 85 patients (13%) with arteriogenic impotence, 2 out of 85 patients (2%) with mixed vasculogenic impotence and 1 out of 85 patients (1%) with cavernosal venous leakage (CVL). One hundred and twenty-two out of two hundred and seven patients (59%) had an abnormal NPT comprising 18 out of 122 patients (15%) who continued to experience rigid early morning erections, 65 out of 122 patients (53%) who smoked cigarettes, 59 out of 112 patients (48%) with other positive vascular risk factors, 36 out of 112 patients (29%) had an abnormal PSV (<30 cm/s), 49 out of 122 patients (40%) had an abnormal RI (<0.85) and 55 out of 122 patients (45%) had an abnormal Qm (>10 ml/min). Vascular investigations in this group identified five patients with no penile vascular disease, 51 out of 122 patients (41%) with arteriogenic impotence, 31 out of 122 patients (25%) with cavernosal venous leakage (CVL) and 35 out of 122 patients (29%) with mixed vasculogenic impotence. CONCLUSIONS: (1) a history of cigarette smoking and positive vascular risk factors are good predictors of organic impotence whereas the patient's subjective assessment of his own early morning erections is unreliable; (2) normal NPT correlates well with normal PSV, RI and Qm but does not exclude organic impotence; (3) abnormal NPT correlates well with abnormal PSV, RI and Qm. PMID- 10098955 TI - Erectile dysfunction due to a 'hidden' penis after pelvic trauma. AB - We describe a twenty-six year old patient who presented us with a dorsally retracted 'hidden' penis, which was entrapped in scar tissue and prevesical fat, 20y after a pelvic fracture with symphysiolysis. Penile 'lengthening' was performed by V-Y plasty, removal of fatty tissue, dissection of the entrapped corpora cavernosa followed by ventral fixation. PMID- 10098956 TI - One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats. AB - Persistent cognitive deficits are one of the most important sequelae of head injury in humans. In an effort to model some of the structural and neuropharmacological changes that occur in chronic postinjury brains, we examined the longitudinal effects of moderate vertical controlled cortical impact (CCI) on place learning and memory using the Morris water maze (MWM) test, morphology, and vesicular acetylcholine (ACh) transporter (VAChT) and muscarinic receptor subtype 2 (M2) immunohistochemistry. Vertical CCI (left parietal cortex, 4 m/sec, 2.5 mm; n = 10) or craniotomy (sham) was produced in male Sprague-Dawley rats (n = 10). Place learning was tested at 2 weeks, 4 weeks, 3 months, 6 months, and 12 months postinjury with the escape platform in a different maze quadrant for each time point. At each interval, rats received 5 days of water maze acquisition (latency to find hidden platform), a probe trial to measure place memory, and 2 days of visible platform trials to control for nonspecific deficits. At 3 weeks, half the animals were sacrificed for histology. At these injury parameters, CCI produced no significant differences in place learning between injured and sham rats at 2 weeks, 4 weeks, or 6 months after injury. However, at 3 and 12 months, the injured rats took significantly longer to find the hidden platform than the sham rats. Probe trial performance differed only at 12 months postinjury between injured (25.73+/-2.1%, standard error of the mean) and sham rats (44.09+/-7.0%, p < 0.05). The maze deficits at 1 year were not due to a worsening of performance, but may have resulted from a reduced ability of injured rats to benefit from previous water maze experience. Hemispheric loss of 30.4+/-5.5 mm3 was seen at 3 weeks after injury (versus respective sham). However, hemispheric loss almost doubled by 1 year after injury (51.5+/-8.5 mm3, p < 0.05 versus all other groups). Progressive tissue loss was also reflected by a three- to fourfold increase in ipsilateral ventricular volume between 3 weeks and 1 year after injury. At 1 year after injury, immunostaining for VAChT was dramatically increased in all sectors of the hippocampus and cortex after injury. Muscarinic receptor subtype 2 (M2) immunoreactivity was dramatically decreased in the ipsilateral hippocampus. This suggests a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission. Moderate CCI in rats produces subtle MWM performance deficits accompanied by persistent alteration in M2 and VAChT immunohistochemistry and progressive tissue atrophy. The inability of injured rats to benefit from repeated exposures to the MWM may represent a deficit in procedural memory that is independent of changes in hippocampal cholinergic systems. PMID- 10098957 TI - Reducing hemoglobin oxygen affinity does not increase hydroxyl radicals after acute subdural hematoma in the rat. AB - Extensive evidence is available to show the importance of ischemia after severe human head injury. We have previously shown that pharmacologically increasing the release of oxygen in brain tissue where the local oxygen pressure is low reduces infarct size in animal models. To study the possible negative effects of this strategy, we tested the effect of an allosteric modifier of hemoglobin (RSR13) on free radical production in the rat acute subdural hematoma (ASDH) model, both under normoxic as well as under hyperoxic, normobaric conditions. When compared to baseline, induction of ASDH resulted in a significant increase (p < 0.05) in 2,3-DHBA (2,3 dihydroxybenzoic acid, produced from salicylate after attack by hydroxyl radicals) at 30 and 60 min postinduction, both for the control group (39% and 91%) as well as the RSR13-treated group (41% and 62%). The 2,5-DHBA also increased significantly (p < 0.05) in the drug-treated animals at the 30- and 60 min time points when compared to baseline (49% and 77%). At all time points, except the 30-min, the increase in 2,3-DHBA was less marked in the RSR13 animals than in the control group. Similarly, the 2,5-DHBA increase after ASDH was lower at all time points except for the 30-min time point in the RSR13-treated group. These results indicate that enhanced tissue oxygen release by the allosteric modifier of hemoglobin RSR13 does not increase hydroxyl radical production after ASDH. Clinical trials are needed to test this compound in humans after severe head injury. PMID- 10098959 TI - Temporal and spatial profile of apoptotic cell death in transient intracerebral mass lesion of the rat. AB - Apoptosis is involved in the pathogenesis of cerebral ischemia. Previous studies have confirmed that the brain surrounding an intracerebral hematoma develops ischemia. We investigated the number and distribution of cells exhibiting DNA fragmentation with apoptotic morphology in the transient intracerebral mass lesion to determine whether apoptosis contributed to the lesion progress after intracerebral hemorrhage (ICH). Transient intracerebral mass was created by inflation of a microballoon for 10 min (group A) or 2 h (group B) in the caudoputamen in rats, and brains were examined 1, 3, 6, 24, and 48 h after microballoon deflation. The lesion volume was calculated using parallel coronal sections with cresyl violet staining. Terminal deoxynucleotidyl transferase (TdT) mediated deoxyuridine (dUTP)-biotin nick end labeling (TUNEL) was used to detect cells undergoing DNA fragmentation. Immunohistochemistry for Fas antigen was also done to ascertain molecular mechanisms of apoptosis. Histological examination of hematoxylin and eosin-stained sections showed the typical appearance of neuronal necrosis in the caudoputaminal lesion. Lesion volume in the caudoputamen gradually increased as time advanced from 1 to 48 h. Cells stained heavily by TUNEL with apoptotic morphology were detected in the lesion, but not in the inner boundary zone of the lesion. The number of these cells significantly increased from 6 to 24 h in each experimental group (p < 0.05). The cells with positive immunoreactivity for Fas antigen was prominently observed in the lesion at 6 h. The distribution of apoptotic cells and the rapid increase in the number of apoptotic cells after 24 h propose that apoptotic cell death may contribute to lesion core formation but not to gradual development of the lesion. PMID- 10098958 TI - Glutamate and taurine are increased in ventricular cerebrospinal fluid of severely brain-injured patients. AB - Glutamate contributes to secondary brain damage, resulting in cell swelling and brain edema. Under in vitro conditions, increased extracellular levels of the amino acid taurine reflect glutamate-induced osmotic cell swelling. In vivo, increases in cerebrospinal fluid (CSF) taurine could, therefore, unmask glutamate mediated cytotoxic edema formation and possibly differentiate it from vasogenic edema. To test this hypothesis, ventricular CSF glutamate and taurine levels were measured in 28 severely brain-injured patients on days 1, 5, and 14 after trauma. Posttraumatic changes in CSF amino acids were investigated in regard to extent of tissue damage and alterations in brain edema as estimated by computerized tomography. On day 1, CSF glutamate and taurine levels were significantly increased in patients with subdural or epidural hematomas (8+/-0.8/71+/-12 microM), contusions (21+/-4.1/122+/-18 microM), and generalized brain edema (13+/ 3.2/80+/-15 microM) compared to lumbar control CSF (1.3+/-0.1/12+/-1 microM; p < 0.001). CSF amino acids, however, did not reflect edema formation and resolution as estimated by computerized tomography. CSF taurine correlated positively with glutamate, eventually depicting glutamate-induced cell swelling. However, parallel neuronal release of taurine with its inhibitory function cannot be excluded. Thus, the sensitivity of taurine in unmasking cytotoxic edema formation is weakened by the inability in defining its origin and function under the conditions chosen in the present study. Overall, persisting pathologic ventricular CSF glutamate and taurine levels are highly suggestive of ongoing glial and neuronal impairment in humans following severe traumatic brain injury. PMID- 10098960 TI - Apoptotic versus necrotic characteristics of retinal ganglion cell death after partial optic nerve injury. AB - We have investigated time course and characteristics of retinal ganglion cell (RGC) death after partial optic nerve injury. In situ end labeling of DNA fragments with the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine (dUTP)-biotin nick end labeling (TUNEL) method revealed the presence of apoptotic cells on as early as 5 days postcrush with a very high number of TUNEL-positive cells 1 week postinjury. At the ultrastructural level, features of apoptosis were clearly present in the ganglion cell layer at this time point. Moreover, TUNEL-positive cells could be identified as retinal ganglion cells by retrograde labeling with fluorogold. In addition, DNA laddering characteristic for apoptosis was found 1 week postinjury. A considerable number of TUNEL-labeled cells was still found after 2 weeks postinjury. Retinal whole mounts prepared at postlesion days 2-5, however, revealed that many cell bodies with ruptured membranes as evidenced by nucleosomal Sytox staining were present. These cells were also identified as retinal ganglion cells by retrograde labeling with fluorogold. Moreover, at this early stages of RGC degeneration necrotic cellular profiles could be detected by electron microscopic analysis. Thus, evidence is provided that necrosis and apoptosis follow a distinctly different time course after partial optic nerve injury. PMID- 10098961 TI - Expression of ICAM-1 and CD11b after experimental spinal cord injury in rats. AB - We have performed an immunohistochemical study on the expression of the adhesion molecules ICAM-1 and CD11b 1 h to 1 week following a compression injury to the rat spinal cord. The spinal cord of control animals showed ICAM-1 expression in some vessels and in the leptomeninges. Mechanical compression of the spinal cord induced an endothelial upregulation of ICAM-1 that was maximal in rats surviving 1-2 days after injury. This reaction was seen at the center of the lesion as well as in the perifocal zones. Apart from the endothelial upregulation, increased ICAM-1 expression also was found in leptomeningeal and ependymal cells of traumatized animals. In control animals resting microglial cells were moderately CD11b immunoreactive. Trauma induced a rapid microglial upregulation of CD11b in the white matter that was evident even at 1 h after injury. By 1 day to 1 week posttrauma conformational changes consistent with microglial activation, i.e., transformation into phagocytic microglial cells, were seen in the white matter. In the gray matter, CD11b immunohistochemistry revealed massive infiltration of phagocytic microglial cells and macrophages in animals surviving 1 day to 1 week. Intravascular and infiltrating leukocytes were intensely CD11b immunopositive. As reflected by CD11b immunohistochemistry, the maximal infiltration of polymorphonuclear leukocytes occurred at 2 days after the insult. Endothelial upregulation of ICAM-1 facilitates adhesion and extravasation of leukocytes by binding to the counterreceptor CD11b. Knowledge regarding the expression and cellular distribution of such molecules after central nervous system trauma is important since inflammatory mechanisms have been suggested to be involved in secondary neurological damage and thus constitute potential targets of therapy. PMID- 10098962 TI - Operant conditioning of H-reflex increase in spinal cord--injured rats. AB - Operant conditioning of the spinal stretch reflex or its electrical analog, the H reflex, is a new model for exploring the mechanisms of long-term supraspinal control over spinal cord function. Primates and rats can gradually increase (HRup conditioning mode) or decrease (HRdown conditioning mode) the H-reflex when reward is based on H-reflex amplitude. An earlier study indicated that HRdown conditioning of the soleus H-reflex in rats is impaired following contusion injury to thoracic spinal cord. The extent of impairment was correlated with the percent of white matter lost at the injury site. The present study investigated the effects of spinal cord injury on HRup conditioning. Soleus H-reflexes were elicited and recorded with chronically implanted electrodes from 14 rats that had been subjected to calibrated contusion injuries to the spinal cord at T8. At the lesion epicenter, 12-39% of the white matter remained. After control-mode data were collected, each rat was exposed to the HRup conditioning mode for 50 days. Final H-reflex amplitudes after HRup conditioning averaged 112% (+/-22% SD) of control. This value was significantly smaller than that for 13 normal rats exposed to HRup conditioning, in which final amplitude averaged 153% (+/-51%) SD of control. As previously reported for HRdown conditioning after spinal cord injury, success was inversely correlated with the severity of the injury as assessed by white matter preservation and by time to return of bladder function. HRup and HRdown conditioning are similarly sensitive to injury. These results further demonstrate that H-reflex conditioning is a sensitive measure of the long term effects of injury on supraspinal control over spinal cord functions and could prove a valuable measure of therapeutic efficacy. PMID- 10098963 TI - Effect of treatment with 21-aminosteroid U-74389G and glucocorticoid steroid methylprednisolone on somatosensory evoked potentials in rat spinal cord during mild compression. AB - The purpose of this investigation was to compare the effects of treatment with glucocorticoid steroid methylprednisolone (MP) and the 21-aminosteroid U-74389G on the conduction of somatosensory evoked potentials (SEPs) during experimental spinal cord compression. Forty-five adult male Wistar rats were anesthetized and a laminectomy performed at the Th9-Th10 level. Animals with the same SEP patterns prior to and after laminectomy were randomly allocated to one of three groups (15 rats in each). A 14.8-g weight was applied to the dural surface of the spinal cord for 60 min. The SEPs were continually recorded during compression. The rats received a single intravenous bolus dose of three different agents two minutes after the start of compression. Animals in the first group received 0.5 ml of 0.9% NaCl, the second group received 30 mg/kg methylprednisolone and the third group received 3 mg/kg U-74389G. Following drug infusion the time period required for the SEPs to be completely suppressed was assessed. If the SEPs were not fully suppressed, the amplitude of the most stable and significant component of the SEPs was measured. The time taken to complete the SEPs suppression was significantly shorter in the control group (p < 0.001, Wilcoxon) than in the groups with either MP or U-74389G. However, the time taken to achieve full suppression was not significantly different between the MP and U-74389G groups. The proportional reduction of amplitude N1P1 was significantly different between the control and MP groups as well as between the control and U-74389G groups. The proportional reduction of amplitude N1P1 was not significant between the MP and the U-74389G groups. The present data indicate that both the glucocorticoid steroid MP and the 21-aminosteroid U-74389G protect spinal cord function to a similar extent during mild compression. PMID- 10098964 TI - Professor Ebashi's impact on the study of the regulation of striated muscle contraction. AB - The field of striated muscle regulation has changed tremendously over the last forty years. Many of the problems solved by Dr. Ebashi and by those stimulated by him offer new challenges for future generations of scientists. Many questions remain to be solved, and it should give particular pleasure to Dr. Ebashi to see how the seeds sown by him and his colleagues have now grown into a beautiful tree that bears rich fruit at present and will continue to do so for a long time in the future. PMID- 10098966 TI - Calcium ion regulation of muscle contraction: the regulatory role of troponin T. AB - The relaxation and contraction in vertebrate skeletal muscle are regulated by Ca2+ through troponin and tropomyosin, which are located in the thin filament. Troponin is composed of three components, troponins C, I and T. In this review article, the Ca2+ -regulatory mechanism is discussed with particular reference to the regulatory properties of troponin T. PMID- 10098965 TI - Troponin I: inhibitor or facilitator. AB - TN-I occurs as a homologous group of proteins which form part of the regulatory system of vertebrate and invertebrate striated muscle. These proteins are present in vertebrate muscle as isoforms, Mr 21000-24000, that are specific for the muscle type and under individual genetic control. TN-I occupies a central position in the chain of events starting with the binding of calcium to troponin C and ending with activation of the Ca2+ stimulated MgATPase of the actomyosin filament in muscle. The ability of TN-I to inhibit the MgATPase of actomyosin in a manner that is accentuated by tropomyosin is fundamental to its role but the molecular mechanism involved is not yet completely understood. For the actomyosinATPase to be regulated the interaction of TN-I with actin, TN-C and TN T must undergo changes as the calcium concentration in the muscle cell rises, which result in the loss of its inhibitory activity. A variety of techniques have enabled the sites of interaction to be defined in terms of regions of the polypeptide chain that must be intact to preserve the biological properties of TN I. There is also evidence for conformational changes that occur when the complex with TN-C binds calcium. Nevertheless a detailed high resolution structure of the troponin complex and its relation to actin/tropomyosin is not yet available. TN-I induces changes in those proteins with which it interacts, that are essential for their function. In the special case of cardiac TN-I its effect on the calcium binding properties of TN-C is modulated by phosphorylation. It has yet to be determined whether TN-I acts directly as an inhibitor or indirectly by interacting with associated proteins to facilitate their role in the regulatory system. PMID- 10098967 TI - Thermodynamic analyses of calcium binding to troponin C, calmodulin and parvalbumins by using microcalorimetry. AB - Results of microcalorimetric titrations of calcium-binding proteins with calcium or magnesium have been reviewed and evaluated. Results were analyzed mostly in terms of heat capacity changes, which is most closely related to the structural changes of the molecule on metal binding. Two high-affinity sites of rabbit skeletal troponin C are distinguishable in terms of their affinity to calcium and associated enthalpy changes. Heat capacity changes on calcium binding to one of the two high-affinity sites is negative and is in the range ascribed to the ligand binding. In contrast, that to the other of the high-affinity sites is large and positive, indicating that a substantial area of hydrophobic groups become exposed to the solvent. In frog skeletal troponin C, the anomalous positive heat capacity changes occur in one of the low-affinity calcium-specific sites, so that this may be involved in the regulation of contraction. Unlike skeletal troponin C, both of the two high-affinity sites of cardiac troponin C show negative heat capacity changes. In calmodulin, heat capacity changes are positive but small, indicating that calcium binding may induce clustering of the hydrophobic residues on the surface of the molecule. In parvalbumins, heat capacity changes are negative, characteristic of most ligand binding. PMID- 10098968 TI - A strange calmodulin of yeast. AB - Calmodulin of Saccharomyces cerevisiae has different Ca2+ binding properties from other calmodulins. We previously reported that the maximum number of Ca2+ binding was 3 mol/mol and the fourth binding site was defective, which was different from 4 mol/mol for others. Their macroscopic dissociation constants suggested the cooperative three Ca2+ bindings rather than a pair of cooperative two Ca2+ bindings of ordinary calmodulin. Here we present evidence for yeast calmodulin showing the intramolecular close interaction between the N-terminal half domain and the C-terminal half domain, while the two domains of ordinary calmodulin are independent of each other. We will discuss the relationship of the shape and the shape change caused by the Ca2+ binding to the enzyme activation in yeast. The functional feature of calmodulin in yeast will also be considered, which might be different from the one of vertebrate calmodulin. PMID- 10098969 TI - Regulation by molluscan myosins. AB - Molluscan myosins are regulated molecules that control muscle contraction by the selective binding of calcium. The essential and the regulatory light chains are regulatory subunits. Scallop myosin is the favorite material for studying the interactions of the light chains with the myosin heavy chain since the regulatory light chains can be reversibly removed from it and its essential light chains can be exchanged. Mutational and structural studies show that the essential light chain binds calcium provided that the Ca-binding loop is stabilized by specific interactions with the regulatory light chain and the heavy chain. The regulatory light chains are inhibitory subunits. Regulation requires the presence of both myosin heads and an intact headrod junction. Heavy meromyosin is regulated and shows cooperative features of activation while subfragment-1 is non-cooperative. The myosin heavy chains of the functionally different phasic striated and the smooth catch muscle myosins are products of a single gene, the isoforms arise from alternative splicing. The differences between residues of the isoforms are clustered at surface loop-1 of the heavy chain and account for the different ATPase activity of the two muscle types. Catch muscles contain two regulatory light chain isoforms, one phosphorylatable by gizzard myosin light chain kinase. Phosphorylation of the light chain does not alter ATPase activity. We could not find evidence that light chain phosphorylation is responsible for the catch state. PMID- 10098970 TI - The properties and function of invertebrate new muscle protein. AB - We found out a new protein from natural actomyosin prepared from adductor muscle of Hokki clam, bivalve shell. We isolated this protein and determined some properties. It has a large molecular weight (230 kDa) and the star diagram of amino acid composition was very similar to that of paramyosin (110 kDa). When this protein was added to Hokki clam myosin, the Mg2+ -ATPase activity was more activated in the presence of 10(-7) M Ca2+ and further inhibited in the presence of 10(-4) M Ca2+ as compared with those of myosin. From these results, we suggest that Hokki clam adductor muscle contains another myosin-linked regulatory protein, myonin, which is different from the myosin-linked system, the myosin light chain-linked system. We named this protein 'myonin'. PMID- 10098971 TI - Actin binding proteins that change extent and rate of actin monomer-polymer distribution by different mechanisms. AB - Actin binding proteins control actin assembly and disassembly by altering the critical concentration and by changing the kinetics of polymerization. All of these control mechanisms in some way or the other make use of the energy of hydrolysis of actin-bound ATP. Capping of barbed filament ends increases the critical concentration as long as ATP hydrolysis maintains a difference in the actin monomer binding constants of the two ends. A further increase in the critical concentration on adding a second cap, tropomodulin, to the other, pointed filament end also requires ATP hydrolysis as described by the model presented here. Changes in the critical concentration are amplified into much larger changes of the monomer pool by actin sequestering proteins, provided their actin binding equilibrium constants fall within a relatively narrow range around the values for the two critical concentrations of actin. Cofilin greatly speeds up treadmilling, which requires ATP hydroysis, by increasing the rate constant of depolymerization. Profilin increases the rate of elongation at the barbed filament end, coupled to a lowering of the critical concentration, only if ATP hydrolysis makes profilin binding to the barbed end independent of its binding constant for actin monomers. PMID- 10098972 TI - A phosphorus-31 nuclear magnetic resonance study on the complex of chicken gizzard myosin subfragment 1 with adenosine diphosphate. AB - The complex of Mg-ADP with chicken gizzard myosin subfragment 1 (S1), obtained by the treatment with Staphylococcus aureus V8 proteinase, was observed with 31P NMR at various temperatures between 0 and 25 degrees C. The signal of S1.ADP complex was observed at -2 to -3 ppm as a rather broad peak. As compared with the results for rabbit skeletal muscle S1.ADP complex (Tanokura M, Ebashi S: J Biochem 113: 19-21, 1993), the signal was assigned to beta-phosphate of ADP in the S1.ADP complex. The signal of the complex was so broad and weak that the dependences on temperature and magnetic field strength were not clear. The observation suggests the tight interaction of S1 with the phosphate moieties of ADP in the complex and the extremely anisotropic distribution of electrons around phosphorus nuclei. PMID- 10098973 TI - Interactions of protein phosphatase type 1, with a focus on myosin phosphatase. AB - It has been established for many years that MLCK is regulated by the intracellular Ca2+ concentration via the formation of the Ca2+ -calmodulin-MLCK complex. A more recent discovery has been that the myosin phosphatase may also be regulated. This is manifest at suboptimal Ca2+ levels where under certain conditions (e.g. stimulation with several agonists) the MP is inhibited. The net result being that the extent of myosin phosphorylation for a fixed Ca2+ level is increased, i.e. an enhanced Ca2+ -sensitivity. Spurred by this intriguing discovery several laboratories began studies on MP with an emphasis to determine the regulatory, or inhibitory, mechanism. A similar preparation was obtained by 3 laboratories and consisted of a catalytic subunit, PP1delta, plus a large subunit (M130/133 for gizzard, M130 for bladder and M110 for rat aorta) and a smaller subunit of 20-21 kD. The isolated catalytic subunit has a much lower activity towards phosphorylated myosin than the holoenzyme, thus the non-catalytic subunits may serve as targeting proteins and in addition may play a regulatory role. Because of the difference in activities between the catalytic subunit and holoenzyme, one mechanism of regulation may involve dissociation of the trimeric complex, and such was proposed for the effect of arachidonic acid. Another suggested regulatory mechanism was that phosphorylation of the large subunit in its C-terminal half caused inhibition of phosphatase activity. The two mechanisms need not be mutually exclusive and in addition several kinases could influence the activity of the myosin phosphatase. In order to understand the molecular basis of phosphatase regulation it is necessary to determine the topography of the holoenzyme and identify sites of interaction between subunits and substrate. This work is in progress. Using various truncation mutants of M130/133 it has been determined that the binding sites for both PP1c and substrate are located within the N-terminal part of the molecule. The M20 subunit binds to the C terminal end, although the functional significance of this is not established. Many questions remain to be answered concerning the biochemistry of the myosin phosphatase. An exciting and challenging focus will be to determine the mechanism(s) of regulation and to unravel the signaling cascade(s) that are initiated by agonist-receptor complex formation. In addition, the location of the MP is not known and it is important to establish which (if any) of the cytoskeletal elements are involved in binding to MP. Finally, it is assumed that the trimeric phosphatase, as discussed above, is specific for myosin dephosphorylation and does not act on other substrates. Because of the breadth of its distribution in different tissues and the wide range of proteins interacting with the ankyrin repeats it is possible that this phosphatase, or variants thereof, has roles in other cellular processes. PMID- 10098974 TI - Myosin light chain kinase from skeletal muscle regulates an ATP-dependent interaction between actin and myosin by binding to actin. AB - Myosin light chain kinase (MLCK) has been purified from various muscles as an enzyme to phosphorylate myosin light chains. While the regulatory role of smooth muscle MLCK is well understood, the role of skeletal muscle MLCK in the regulation of contraction has not been fully characterized. Such characterization of skeletal muscle MLCK is difficult because skeletal muscle myosin interacts with actin whether or not the myosin is phosphorylated. Taking the hint from our recent finding that smooth muscle MLCK inhibits the actin-myosin interaction by binding to actin (Kohama et al., Biochem Biophys Res Commun 184: 1204-1211, 1992), we investigated the regulatory role of the actin-binding activity of MLCK from chicken breast muscle in the actin-myosin interaction. The amount of MLCK that bound to actin increased with increases in the concentration of MLCK. However, MLCK hardly bound to myosin. The actin-binding activity of MLCK was affected when Ca2+ and calmodulin (Ca2+ -CaM) were present. The effect of MLCK on the actin-myosin interaction was examined by an in vitro motility assay; the movement of actin-filaments on a myosin-coated glass surface was inhibited by increasing the concentration of MLCK. When CaM was present, the inhibition was overcome in a Ca2+ -dependent manner at microM levels. The inhibition of the movement by MLCK and the recovery from the inhibition by Ca2+ -CaM were not altered whether we use phosphorylated or unphosphorylated myosin for the assay, ruling out the involvement of the kinase activity of MLCK. PMID- 10098975 TI - Ca2+ -induced Ca2+ desensitization of myosin light chain phosphorylation and contraction in phasic smooth muscle. AB - The temporal relationship between Ca2+ -induced contraction and phosphorylation of 20 kDa myosin light chain (MLC) during a step increase in Ca2+ was investigated using permeabilized phasic smooth muscle from rabbit portal vein and guinea-pig ileum at 25 degrees C. We describe here a Ca2+ -induced Ca2+ desensitization phenomenon in which a transient rise in MLC phosphorylation is followed by a transient rise in contractile force. During and after the peak contraction, the force to phosphorylation ratio remained constant. Further treatment with cytochalasin D, an actin fragmenting agent, did not affect the transient increase in phosphorylation, but blocked force development. Together, these results indicate that the transient phosphorylation causes the transient contraction and that neither inhomogeneous contractility nor reduced thin filament integrity effects the transient phosphorylation. Lastly, we show that known inhibitors to MLC kinase kinases and to a Ca2+ -dependent protein phosphatase did not eliminate the desensitized contractile force. This study suggests that the Ca2+ -induced Ca2+ desensitization phenomenon in phasic smooth muscle does not result from any of the known intrinsic mechanisms involved with other aspects of smooth muscle contractility. PMID- 10098976 TI - Growing and differentiating characterization of aortic smooth muscle cell line, p53LMAC01 obtained from p53 knock out mice. AB - Recently we have established an aortic smooth muscle cell line, p53LMAC01 obtained from p53 knockout mice. This cell line showed some differentiated properties which were accelerated by 5-azacytidine treatment [1]. In this study, further characterization of p53LMAC01 cell line was investigated according to cell growth and differentiation, and especially focused into the changes of cell feature, actin filaments' formation, and changes of intracellular calcium concentrations to sympathetic nerve transmitter, norepinephrine. While the cell feature was changed from flattened shape to extended form during 4 days, actin filaments were developing, arranging in parallel to longitudinal direction, and gathering under the surface membrane. In 11 days many cells died and detached from substrate, while actin filaments became poor except for the surface membrane in the remained cells. Appearance of calcium response to noradrenalin needed several days after passage as well as a morphological change of the cells for the extended form and development of actin filaments. The calcium response was maintained on 11 days, which coincided with the result that the cells hold actin filaments under the surface membrane. These results suggest that p53LMAC01 cell line maintains several differentiated characters of adult smooth muscle cell and that their expression needs several days after passage. PMID- 10098978 TI - Roles of intracellular Ca2+ receptors in the pancreatic beta-cell in insulin secretion. AB - Ca2+ is the central second messenger in the regulation of insulin release from the pancreatic beta-cell; and intracellular Ca2+ -binding proteins, classified into two groups, the EF hand proteins and the Ca2+/phospholipid binding proteins, are considered to mediate Ca2+ signaling. A number of Ca binding proteins have been suggested to participate in the secretory machinery in the beta-cell. Calmodulin, the ubiquitous EF hand protein, is the predominant intracellular Ca2+ receptor that modulates insulin release via the multiplicity of its binding to target proteins including protein kinases. Other Ca binding proteins such as calcyclin and the Ca2+/phospholipid binding proteins may also be suggested to be involved. Ca2+ influx from the extracellular space appears to be responsible for exocytosis of insulin via Ca2+ -dependent protein/protein interactions. On the other hand, intracellular Ca2+ mobilization resulting in secretory granule movement may be controlled by Ca2+/calmodulin-dependent protein phosphorylation. Thus, Ca2+ exerts versatile effects on the secretory cascade via binding to specific binding proteins in the pancreactic beta-cells. PMID- 10098979 TI - Organization of connectin/titin filaments in sarcomeres of differentiating chicken skeletal muscle cells. AB - Very long, elastic connectin/titin molecules position the myosin filaments at the center of a sarcomere by linking them to the Z line. The behavior of the connectin filaments during sarcomere formation in differentiating chicken skeletal muscle cells was observed under a fluorescent microscope using the antibodies to the N terminal (located in the Z line), C terminal (M line), and C zone (myosin filament) regions ofconnectin and was compared to the incorporation of alpha-actinin and myosin into forming sarcomeres. In early stages of differentiating muscle cells, the N terminal region of connectin was incorporated into a stress fiber-like structure (SFLS) together with alpha-actinin to form dots, whereas the C terminal region was diffusely distributed in the cytoplasm. When both the C and N terminal regions formed striations in young myofibrils, the epitope to the C zone of A-band region, that is the center between the A-I junction and the M-line, initially was diffuse in appearance and later formed definite striations. It appears that it took some time for the N and C terminal regions of connectin to form a regular organization in a sarcomere. Thus the two ends of the connectin filaments were first fixed followed by the specific binding of the middle portion onto the myosin filament during sarcomere formation. PMID- 10098977 TI - Expressional regulation of smooth muscle cell-specific genes in association with phenotypic modulation. AB - Phenotypic modulation of smooth muscle cells (SMCs) plays an integral role in atherosclerosis, hypertension and leiomyogenic tumorigenicity. The morphological, functional, and biochemical characteristics of SMCs in different phenotypes such as differentiated and dedifferentiated states have been well studied. Recent researches have focused on the expressional regulation of SMC-specific marker genes in association with phenotypic modulation of SMCs. The SMC-specific marker genes are regulated at the levels of transcription and splicing. The caldesmon, smooth muscle myosin heavy chain, alpha-smooth muscle actin, calponin, SM22, alpha- and beta-tropomyosins, and alpha1 integrin genes are transcriptionally regulated; transcription of these genes except for the alpha-smooth muscle actin gene is upregulated in differentiated SMCs, but is downregulated in dedifferentiated SMCs. The expression pattern of alpha-smooth muscle actin is opposite in vascular and visceral SMCs. In almost all promoter regions of these genes, the CArG box and serum response factor (SRF) are involved in as the positive cis-element and the trans-acting factor, respectively. Isoform changes of caldesmon, alpha-tropomyosin, vinculin/metavinculin, and smooth muscle myosin heavy chain are regulated by alternative splicing in a SMC phenotype-dependent manner. Among them, isoform interconversions of caldesmon and alpha-tropomyosin are completely coordinated with phenotype of SMCs. The purpose of this paper is to summarize current knowledge of the expressional regulation of SMC-specific marker genes in different phenotypes of SMCs. PMID- 10098980 TI - Detection of a sequence involved in actin-binding and phosphoinositide-binding in the N-terminal side of cofilin. AB - Cofilin is an actin-binding protein of low molecular weight which is widely distributed in eukaryotes and is deeply involved in the dynamics of actin assembly in the cytoplasm. The actin-binding ability of cofilin is inhibited by inositol phosphates (PIP2), and the PIP2- and actin-binding site(s) has been localized in residues W104-M115 of the cofilin primary sequence (Yonezawa et al. 1991 ). In the present study, in order to further clarify the functional domains in cofilin molecule, we constructed expression vectors containing cDNAs of different size with deletion at the 3'-region of the open reading frame. The truncated cofilin molecules produced in E. coli were purified and examined for their actin-binding and PIP2-binding ability. We found that the truncated cofilin molecule without C-terminal residues #100-#166 including the previously-described actin-binding site could be cross-linked with actin by EDC, a zero-length cross linker. In addition, these truncated peptides as well as synthetic peptides corresponding to the N-terminal sequence of cofilin suppressed the inhibitory action of PIP2 on actin-cofilin interaction. These results strongly suggest that additional actin- and PIP2-binding sites exist in the N-terminal region of cofilin. PMID- 10098982 TI - Structural basis of the function of endothelin receptor. AB - Endothelin receptor is a good model for analysis of the function of heptahelical G-protein coupled receptor. In ligand binding to the heptahelical receptor, the receptor has two functions, i.e. 'message' and 'address' functions. Each function has been assigned to different domain of the receptor. A different part of the ligand structure also corresponds to each domain of the receptor. Classically, classification of receptor has been done according to the difference of address domain, i.e. affinity difference of the receptor. However, present results predict that the classification of receptor is also possible according to the message domain. After stimulation of ET receptor by a ligand, the receptor transmits a signal to G-protein. Several kinds of G-proteins can possibly be activated. Different structural domains of the receptor are assigned to the coupling of the different Galpha-protein. Activated G-protein transmits the message to effector. Each Galpha-protein acts on different target molecules, resulting in different responses. However, the activation of each Galpha-protein presumably depends on its intracellular level. Even if the same receptor is activated with the same ligand, resulting final response is different from cell to cell. Therefore, classification of receptor according to the function of the receptor is difficult. PMID- 10098981 TI - Creatine kinase, cell membrane and Duchenne muscular dystrophy. AB - In 1958 Professor Setsuro Ebashi found that serum creatine kinase activity is increased in patients suffering from various muscular dystrophies, especially Duchenne muscular dystrophy (DMD). He and others proposed that creatine kinase passes through the cell membrane as it is released from DMD muscle fibers. Since then, it has been found that dystrophin and dystrophin-associated proteins are connected to several other components, including the basal lamina and subsarcolemmal cytoskeletal networks on the cell membrane, while dystrophin anchors these dystrophin-associated proteins to the actin filaments inside the muscle cell. In DMD muscle, dystrophin has been found to be absent and dystroglycans and sarcoglycans decreased. However, how creatine kinase molecules can pass through the DMD muscle cell membrane still remains unanswered. On the basis of recent findings on the structure of the protein layers which sandwich the lipid bilayer of muscle cell membranes, this essay stresses the importance of these lipid bilayers in protecting creatine kinase release from protoplasma in normal muscle. It further indicates the possibility that the absence of dystrophin in DMD muscle during muscle contraction may result in temporal damage to the lipid bilayer. PMID- 10098983 TI - Stimulation of plasma membrane Ca2+ -pump ATPase of vascular smooth muscle by cGMP-dependent protein kinase: functional reconstitution with purified proteins. AB - A 240-kDa protein isolated from porcine aortic smooth muscle as a substrate for cGMP-dependent protein kinase (cGMP kinase) whose phosphorylation was in a close association with stimulation of partially purified plasma membrane Ca2+ -pump ATPase by the kinase was later shown to represent splicing variants of type 1 inositol 1,4,5-trisphosphate (IP3) receptor. To further clarify the role played by this protein in the stimulation of Ca2+ -pumpATPase, it was attempted in thepresent study to specifically remove the protein by immunoprecipitation with an antibody specific to type 1 IP3 receptor. Contrary to expectation, stimulation of the ATPase by cGMP kinase was still observed after removal of the IP3 receptor. Furthermore, cGMP kinase stimulated a highly purified preparation of Ca2+ -pump ATPase deprived of IP3 receptor when the concentrations of the ATPase were low enough (10-20 nM) to make it retain a monomeric form, while it did not produce stimulation when the concentration of the enzyme was increased to 40 nM at which the enzyme is known to take an oligomeric, fully activated form insensitive to activation by calmodulin. Heat-inactivated cGMP kinase and cGMP kinase without cGMP failed to stimulate the highly purified Ca2+ -pumpATPase. In addition, type Ialpha but not type Ibeta cGMP kinase was found to stimulate the ATPase. The stimulation of Ca2+ -pump ATPase by cGMP kinase occurs without any detectable phosphorylation of the ATPase. In conclusion, cGMP kinase can stimulate the plasma membrane Ca2+ -pump ATPase when it is in a monomeric form without phosphorylating the Ca2+ -pump ATPase and that of the two cGMP kinase isozymes found in the vascular smooth muscle, only type Ialpha cGMP kinase participates in the stimulation. PMID- 10098984 TI - Chemical modification of an arginine residue in the ATP-binding site of Ca2+ transporting ATPase of sarcoplasmic reticulum by phenylglyoxal. AB - Phenylglyoxal (PGO) was used as a reagent for chemical modification of the ATP binding site of Ca2+ -transporting ATPase of rabbit skeletal muscle sarcoplasmic reticulum (SR-ATPase). When 1 mM PGO was reacted with SR-ATPase at 30 degrees C at pH 8.5, PGO was bound to the ATPase molecule in two-to-one stoichiometry with concomitant loss of activity of the ATPase to form the phosphorylated intermediate (E-P). ATP and ADP prevented the binding of PGO and thereby protected the enzyme from inactivation. The SR membranes were labeled with [14C]PGO and then digested with pepsin to identify the attachment site of PGO. A 14C-labeled peptide (402Ile-Arg*-Ser-Gly-Gln406) was purified to homogeneity by C18-reversed phase HPLC (Arg* denotes the binding site of [14C]PGO). These results indicate that Arg403 is located in the ATP binding site of the SR-ATPase. PMID- 10098985 TI - Intrinsic inhibitor of inositol 1,4,5-trisphosphate binding. AB - Rat brain cytosol was applied to a heparin column and eluted with 0.9 M-NaCl. The total binding activity of [3H]inositol 1,4,5-trisphosphate to the eluate was increased about 6-fold compared with the original cytosol. When the eluate was mixed with a flow-through fraction from the heparin column, however, the activity returned to the original level, suggesting that the flow-through fraction contained an inhibitory factor(s) which prevented the binding. The factor(s) was purified by sequential column chromatography using gel permeation, a hydrophobic gel, and finally, a hydroxylapatite gel. Silver staining of sodium dedecyl sulfate gel electrophoresis of the sample thus purified showed a broad band located between the authentic molecular weight markers of 580 and 390 k. A carbohydrate staining method showed that the factor is a glycoprotein. PMID- 10098986 TI - Dynamic regulation of intracellular calcium signals through calcium release channels. AB - After the seminal work of Ebashi and coworkers which established the essential role of the intracellular Ca2+ concentration ([Ca2+]i) in the regulation of skeletal muscle contraction, we have witnessed an explosive elongation of the list of cell functions that are controlled by the [Ca2+]i. In numerous instances, release of intracellular Ca2+ stores plays important roles in Ca2+ signalling which displays significant variation in spatio-temporal pattern. There are two families of Ca2+ release channels, ryanodine receptors and inositol 1,4,5 trisphosphate (IP3) receptors. These Ca2+ release channels are structurally and functionally similar. In particular, the activity of both types of channels is regulated by the [Ca2+]i. The [Ca2+]i dependence of the Ca2+ release channel activity provides both types of channels with properties of a Ca2+ signal amplifier. This function of the ryanodine receptor is important in striated muscle excitation-contraction coupling, whereas that of the IP3 receptor seems to be the basis of the generation of Ca2+ waves. Thus the wide variety of Ca2+ signalling patterns seem to be critically dependent on the [Ca2+]i dependence of the Ca2+ release channels. PMID- 10098987 TI - Comparison of properties of Ca2+ release channels between rabbit and frog skeletal muscles. AB - Biochemical investigation of Ca2+ release channel proteins has been carried out mainly with rabbit skeletal muscles, while frog skeletal muscles have been preferentially used for physiological investigation of Ca2+ release. In this review, we compared the properties of ryanodine receptors (RyR), Ca2+ release channel protein, in skeletal muscles between rabbit and frog. While the Ryr1 isoform is the main RyR of rabbit skeletal muscles, two isoforms, alpha- and beta RyR which are homologous to Ryr1 and Ryr3 isoforms in mammals, respectively, coexist as a homotetramer in a similar amount in frog skeletal muscles. The two isoforms in an isotonic medium show very similar property in [3H]ryanodine binding activity which is parallel to Ca2+ -induced Ca2+ release (CICR) activity, and make independent contributions to the activities of the sarcoplasmic reticulum. CICR and [3H]ryanodine binding activities of rabbit and frog are qualitatively similar in stimulation by Ca2+, adenine nucleotide and caffeine, however, they showed the following quantitative differences. First, rabbit RyR showed higher Ca2+ affinity than the frog. Second, rabbit RyR showed higher activity in the presence of Ca2+ alone with less stimulation by adenine nucleotide than the frog. Third, rabbit RyR displayed less enhancement of [3H]ryanodine binding by caffeine in spite of having a similar magnitude of Ca2+ sensitization than the frog, which may explain the occasional difficulty by researchers to demonstrate caffeine contracture with mammalian skeletal muscles. Finally, but not least, rabbit RyR still showed marked inhibition of [3H]ryanodine binding in the presence of high Ca2+ concentrations in the 1 M NaCl medium, while frog RyR showed disinhibition. Other matters relevant to Ca2+ release were also discussed. PMID- 10098988 TI - Impact of chronic liver disease due to hepatitis viruses as cause of hospital admission and death in HIV-infected drug users. AB - The life expectancy of HIV-positive individuals has been prolonged in recent years, as a consequence of the wide use of antiretroviral drugs and primary prophylaxis for the most common opportunistic infections. In HIV-positive persons infected parenterally, chronic viral liver disease (CVLD), mainly that caused by hepatitis C virus (HCV), is frequently seen. Moreover, chronic hepatitis C seems to present a more accelerated course in HIV-infected patients, leading to cirrhosis and liver failure in a shorter period of time. The aim of the present study was to investigate the impact of CVLD on the morbidity and mortality of HIV positive patients. A retrospective analysis of the causes of hospital admission during a 4.5-year period in a reference centre for AIDS situated in Madrid was performed. Decompensated liver disease (encephalopathy, ascites, jaundice), or complications directly related to it (gastrointestinal bleeding, hepatorenal syndrome, peritonitis) were diagnosed in 143 (8.6%) of 1670 hospital admissions. These episodes of CVLD corresponded to 105 different individuals, a quarter of whom had two or more re-admissions. HCV alone or in combination with other hepatotropic viruses was involved in 93 (88.6%) patients admitted for CVLD. Death directly associated with CVLD occurred in 15 individuals, which represented 4.8% of the total causes of inhospital mortality during the study period, and represented the fifth cause of death in hospital for HIV-infected patients. In conclusion, CVLD represents an important cause of hospital admission and death in HIV-infected drug users. PMID- 10098989 TI - A computer model of the spread of hepatitis C virus among injecting drug users. AB - A number of behavioural and clinical parameters influence the transmission of an infectious agent through direct contact between two individuals. The behavioural parameters encountered in such situations are also likely to exhibit an enormous amount of variability. With the spread of hepatitis C among injecting drug users, the parameters associated with injecting behaviour play an important role in the modelling of the transmission process. Computer simulation modelling is an ideal approach to deal with a large number of parameters as well as high levels of variability without excessive simplification. The simulation model presented in this paper is tested on data from a cohort of injecting drug users and the results obtained are very encouraging from a public health perspective. The model clearly indicates that the rate at which HCV spreads through a population of injecting drug users is extremely sensitive to the interaction rate and to the probability of infection through a single contact with an infective. At the same time it shows that rate of spread is not very sensitive to initial prevalence, which is very encouraging from a public health perspective. PMID- 10098990 TI - Risk factors of hepatitis C virus infection in patients on hemodialysis: a multivariate analysis based on a dialysis register in Central Italy. AB - A seroprevalence survey of antibodies to HCV was carried out among 2788 hemodialysis (HD) patients in a region of central Italy. Anti-HCV seroprevalence was 28.6%. A multivariate analysis of risk factors showed a significant association with time on HD, history of blood transfusion and metropolitan area of residence. Our study clearly showed that HCV infection is common among HD patients and is partially associated with preventable factors. PMID- 10098992 TI - Bibliometric analysis of Spanish scientific publications on tobacco use during the period 1970-1996. AB - Spanish scientific publications on tobacco use during the period 1970-1996 were studied, including all published work carried out in Spanish institutions indexed in IME or in MEDLINE and available on CD-ROM, using the search criteria fuma* and taba* in the first database, and tobacco and smoking in the second. A total of 405 papers were found by IME, published in Spanish journals, and another 194 in MEDLINE, published in foreign journals. In the latter database, a time-related increase in the number of papers was detected. Original articles accounted for 80.6% of the papers analyzed. The degree of collaboration between authors, research centres and institutions was 88.6%, 30.7% and 21.8%, respectively. The most productive Spanish communities were Catalonia and Madrid. The Spanish papers were published in 83 Spanish journals, of which 36 (43.4%) published just one paper, and in 124 foreign journals, of which 85 (68.5%) published a single paper. The average number of authors per paper was 4.02+/-2.46 in Spanish journals and 4.96+/-2.26 in foreign ones. The total number of authors was 1633, of whom 1162 (71.2%) appeared on a single paper. The contribution of Spanish scientific production concerning tobacco use, in international terms, has increased in recent years, but a higher level of cooperation between research centres and institutions is desirable. PMID- 10098991 TI - Spatial autocorrelation of cancer in Western Europe. AB - We applied the techniques of spatial autocorrelation (SA) analysis to 40 cancer mortality distributions in Western Europe. One of the aims of these methods is to describe the scale over which spatial patterns of mortalities occur, which may provide suggestions concerning the agents bringing about the patterns. We analyzed 355 registration areas, applying one- and two-dimensional SA as well as local SA techniques. We find that cancer mortalities are unusually strongly spatially structured, implying similar spatial structuring of the responsible agents. The small number of spatial patterns (4 or 5) in the 40 cancer mortalities suggests there are fewer spatially patterned agents than the number of cancers studied. SA present in variables will bias the results of conventional statistical tests applied to them. After correcting for such bias, some pairwise correlations of cancer mortality distributions remain significant, suggesting inherent, epidemiologically meaningful correlations. Local SA is a useful technique for exploring epidemiological maps. It found homogeneous high overall cancer mortalities in Denmark and homogeneous low mortalities in southern Italy, as well as a very heterogeneous pattern for ovarian cancer in Ireland. PMID- 10098993 TI - Results of a five-year community-based programme for cardiovascular disease prevention: the ATS-Sardegna Campaign. AB - The objective of this study was to evaluate the effects of the ATS-Sardegna Campaign on lifestyle and cardiovascular disease (CVD) risk factors in the Sardinian population. The Campaign was a community-based public health action programme funded by the Sardinian Government with a view to prevent CVD and promote healthy behaviour. It was also part of the Targeted Project FAT.MA. of the Italian National Research Council (CNR), with the main purpose of evaluating the effects of this public health initiative after a five-year intervention. The evaluation was effected with three parallel procedures: individual interviews with 1486 randomly chosen people; assessment of eating patterns through a food frequency questionnaire; measurement of the mean levels of the major CVD risk factors in 1729 randomly chosen subjects (1044 in the calendar year 1992, and 685 in 1995, two and five years, respectively, after the beginning of the Campaign). Overall, we recorded a favourable trend in eating habits in both sexes; a significant decrease in LDL-cholesterol in males, and in systolic and diastolic blood pressure in both sexes; a non-significant decrease in prevalence of smokers among males and increase among females. The ATS-Sardegna Campaign was the first CVD prevention programme in Italy to have attained reduction in the risk profile of an entire region at the lowest ever borne cost. PMID- 10098994 TI - Socioeconomic risk factors in the prevalence of asthma and other atopic diseases in children 6 to 7 years old in Valencia Spain. AB - A cross-sectional survey of a cohort study was carried out between June and December 1994 in Valencia, Spain (population in 1994: 764,293 inhabitants). Two hundred sixty public and private schools randomly selected from the total of schools in Valencia were invited to participate; 3948 children aged 6-7 years cooperated in our study after informed consent was obtained from parents and school director. The survey in Valencia is part of the International Study of Asthma and Allergy in Childhood (ISAAC). Prevalences for asthma, rhinitis and atopic dermatitis were determined and contrasted with socioeconomic status (SES) among children. No statistically significant associations were established between the prevalences of asthma, rhinitis and atopic dermatitis, and SES. However, atopic dermatitis was found to be common among upper class children (21.5 per 100 children). Likewise, significant associations were observed between the severity of atopy (2 or 3 atopic manifestations) and SES (p = 0.000), being greater for lower strata (4.5 per 100 children); for the three SES level significant differences were established (p = 0.008) regarding passive exposure to tobacco smoke in the home. PMID- 10098995 TI - Factors associated with obesity in Kuwaiti children. AB - The prevalence of adult obesity in Kuwait is among the highest in the Arab peninsula, and cardiovascular disease, for which obesity is a risk factor, is the leading cause of death. This study reports familial and environmental factors associated with childhood obesity; in addition to adverse effects of obesity on children's serum lipids, lipoproteins, apolipoproteins, insulin, and blood pressure profiles. The authors carried out a pair-matched case-control study including 460 obese (body mass index >90th percentile of the age/sex specific reference value of the National Center for Health Statistics), school children 6 to 13 years old matched by age and gender to 460 normal weight controls. We ascertained obese children in a cross-sectional survey of a representative sample of 2400 school children selected from 20 schools by multistage stratified random sampling. Biochemical variables and blood pressure were adversely affected in obese children. The conditional logistic regression analysis showed that family history of obesity, and diabetes mellitus, respiratory and bone diseases in child were significant associated factors with obesity after adjusting for social and behavioural factors. Physical activity and parental social class were not significant. We recommend early preventive measures with emphasis on families in which one or both parents are overweight. PMID- 10098996 TI - Health and work among women in Italy: an overview of the epidemiological literature. AB - The objective of this paper is to give an overview of the epidemiological studies completed in Italy during the past 25 years, about the role of occupational exposures on the development of adverse health effects on women. The implications for research developments are also discussed. The epidemiological investigations of selected categories of work-related health effects published in Italy in the years 1970-1995 were identified from the medical literature databases. The total number of studies is 142, including cohort mortality studies (n = 12), case control studies of different neoplasms (n = 14), investigations of adverse reproductive effects (n = 8) and studies of occupational diseases different from the above (n = 94). In most investigations, women workers were not the main study objective and hence the number of females under study was small. The conclusions is that in Italy, given the dearth of studies of female workers and the preponderance of women in many economic sectors, i.e. the textile and shoe industry, health care, personal services and schools, there is a need to identify women workers in the above industries and occupations as priorities for epidemiological research and surveillance. PMID- 10098997 TI - Legal abortion in Asturias (Spain) after the 1985 law: sociodemographic characteristics of women applying for abortion. AB - STUDY OBJECTIVE: To describe the use of induced abortion (IA) in Asturias after its legalisation as well as the socio-demographic characteristics of women applying for abortion. DESIGN AND SETTING: Descriptive study, population-based, using data collected by the regional abortion surveillance system for the period 1988 1994. MAIN RESULTS: The number of IA and the abortion rate (AR) (10 per 1000 women aged 15-49) have been stable in Asturias during the study period. The highest ARs were found for women in the age group 20-34, for divorced/separated, for women with a higher educational level and for women with only one child. The proportion of pregnancies which ended in abortion was one in four; for teenagers and women over 34 years it was one in two. This proportion was also higher for women not married, students and women with two or more children. Ninety-eight percent of all abortions took place in private clinics, the woman's physical/mental health being the medical indication for these abortions. Abortion was most often performed within eight weeks of gestation (65%). Late abortion ocurred more frequently among teenagers and women of low educational level. Eighteen percent of women had repeated abortions. A high proportion (61%) of women applying for abortion had not used the Family Planning (FP) services in the previous two years; adolescents and women of low educational level had the lowest frequencies of FP use. CONCLUSIONS: Compared with that of other European countries, the AR in Asturias was intermediate. The results regarding adolescents show the need for evaluation and promotion of sex education and contraceptive programmes. The lower and later use of abortion by women of low educational level shows inequalities that call for specific action. PMID- 10098998 TI - Differential risk factor profiles for indoor and outdoor falls in older people living at home in Nottingham, UK. AB - The objectives of this work were: to estimate the incidence of falls within an at risk group of community-dwelling elderly people; to assess the risk factors associated with incident falls; to examine the effects of incident falls on survival. A random sample of 1042 community-dwelling older people in Nottingham (UK) were interviewed in 1985 and survivors re-interviewed at 4-year follow-up. The at-risk group was defined as survivors who had not fallen in the year prior to the baseline interview (n = 444). One-year fall recall was assessed using a questionnaire and included physical health, mobility, prescribed drugs and time spent walking. Body-weight and handgrip strength were measured. Eight-year post fall mortality was recorded. In 1989 117 new fallers were identified. These people fell a total of 233 times in the year prior to re-interview (incidence rate: 524.8 per 1000 person-years at risk; 95% confidence intervals (CI): 473.3 576.3). People aged less than 75 were more likely to fall outdoors than people aged 75 and over (chi2 = 5.715, df = 1, p = 0.017). Risk factors associated with falling were: being less healthy (odds ratio (OR): 0.55; p = 0.052); having a walking speed in the range stroll/very slow/nonambulant compared with normal/brisk/fast (OR: 1.99; p<0.01); and number of prescribed drugs (OR: 1.30; p = 0.01). When analysed separately, indoor and outdoor falls presented differential risk profiles, with evidence that indoor falls were associated with frailty, while outdoor falls were associated with compromised health status in more active people. In 8-year post-fall monitoring, multiple (3+) fallers and indoor fallers showed a significant excess mortality. The differences in risk factors for, and prognoses following, indoor and outdoor falls, emphasise the complex interactions between intrinsic and extrinsic factors associated with falling among older people. PMID- 10098999 TI - Epidemiology of epidemic diphtheria in three regions, Russia, 1994-1996. AB - BACKGROUND: A massive diphtheria epidemic which began in the former Soviet Union in 1990 is the first large-scale diphtheria epidemic in developed countries in more than 30 years and has primarily affected adults. In response, health authorities attempted to maximize vaccination for children and conducted an unprecedented campaign to vaccinate adults. METHODS: We analyzed diphtheria surveillance data (case report forms and diphtheria vaccine coverage data) from three Russian regions from January 1994 to December 1996 and estimated vaccine effectiveness by the screening method. RESULTS: We reviewed records from 2243 (97.2%) of 2307 reported cases. The highest cumulative incidence in the period was among children aged 5 to 9 years (106 cases per 100,000 population); adults aged 40-49 years had the highest adult incidence for disease (88 cases per 100,000) and the highest incidence of any age group of clinically severe disease (29 cases per 100,000) and death (5.1 deaths per 100,000). The incidence among women aged 2049 years (82 per 100,000 women) was higher than among men (47 per 100,000, p<0.01). The annual incidence decreased from 25.2 cases per 100,000 population in 1994 to 9.4 cases per 100,000 in 1996. The decrease occurred as adult coverage increased from an estimated 25-30% in December 1992 to 88% in December 1995. Vaccine effectiveness was high among both children and adults. CONCLUSIONS: The Russian diphtheria epidemic primarily affected adults, especially women; this pattern is likely representative of diphtheria epidemics in immunized populations. Raising childhood immunization coverage and mass adult vaccination was effective in controlling the Russian epidemic. An improved understanding of the current epidemiology of diphtheria will be useful to design public health responses to prevent or control modern epidemics. PMID- 10099000 TI - Multiresistant non-fermentative gram-negative bacteria in cystic fibrosis patients: the results of an Italian multicenter study. Italian Group for Cystic Fibrosis microbiology. AB - We carried out an epidemiological study on 2717 patients seen on a regular basis at Italian Cystic Fibrosis Centers with the aim of defining the prevalence of multiresistant Gram-negative strains in Italy. We found 272 multiresistant strains out of 1560 Gram-negative strains isolated in 1012 Italian cystic fibrosis patients. From our results in Italian cystic fibrosis patients we may conclude: (1) the beta-lactam antibiotics are moderately active; ceftazidime is the most efficacious even if 59.9% of multiresistant strains are not sensitive to this drug; (2) the aminoglycosides are poorly efficacious; 93% of multiresistant strains are resistant in vitro to tobramycin; and (3) the quinolones, notwithstanding their relatively recent introduction into clinical practice, have very poor activity against multiresistant strains, 89.7% of which are not sensitive. PMID- 10099001 TI - Serosurvey of wild rodents for Rickettsioses (spotted fever, murine typhus and Q fever) in Java Island, Indonesia. AB - The prevalence of antibodies against spotted fever group rickettsia (SFGR), murine typhus and Q fever were investigated in wild rats captured in Indonesia. Sera of 327 rats were collected from Jakarta and Boyolali on Java Island. The prevalences of antibodies against SFGR and murine typhus were 128 (39.1%) and 48 (14.7%), respectively. Antibodies against Q fever were not detected in these serum samples. Antibodies against SFGR were found in all species of rats (20.8 51.9%). The antibody positive rate against murine typhus in Rattus norvegicus (38.0%) was significantly higher than that in other rat species (0-4.8%, p<0.01). The antibody positive rates against SFGR and murine typhus in rats captured in Jakarta were significantly higher than those in rats captured in Boyolali (p<0.01). In this survey, all species of rats had antibodies against SFGR, indicating that the 4 species of tested rats (R. norvegicus, R. rattus, R. exulans, R. tiomanicus) were infected with SFGR and that SFGR may infest the whole of Java Island. Most of the rats that were antibody-positive against murine typhus were captured in Jakarta. Therefore, R. norvegicus and R. rattus are likely to be important hosts of murine typhus in Jakarta. The antibody-positive rates against SFGR and murine typhus in rats captured in the dry season were significantly higher than those in rats captured in the rainy season. This may coincide with the active periods of ticks and fleas in Indonesia. PMID- 10099003 TI - Detection of alpha-macroglobulin in the heart of mice infected with Trypanosoma cruzi. AB - The aim of this work was to investigate the presence of alpha-macroglobulin (AM) in the heart of mice during acute experimental Chagas' disease and to study its localization as related to the presence of the parasite and/or to their antigens. Frozen heart tissue sections obtained from Swiss albino male mice at different days postinfection with Trypanosoma cruzi were examined for triple immunofluorescence in response to parasite antigen (green), AM (red), and nuclei (blue) from both cells. AM was found in the heart of all the infected animals studied. Parasites were seen arranged in nests inside heart muscle cells. Usually, AM staining corresponded in position to parasite nests and to their antigens spread in large areas of the myocardium. The most intense staining of AM was observed at days 9 and 11 postinfection, when the highest tissue-infection level occurs. These observations relate the presence of AM to that of T. cruzi antigen in the same areas of the inflamed myocardium of the chagasic animals. PMID- 10099002 TI - Outbreaks of Mycoplasma pneumoniae infections in Iceland 1987 to 1997 - a ten and a half years review. PMID- 10099004 TI - Purification and partial characterization of N-acetyl-beta-D-glucosaminidase from Tritrichomonas foetus. AB - Cells of Tritrichomonas foetus were suspended in buffer (0.1 M phosphate, 0.15 M NaCl, pH 7), sonicated for 2 min on ice, and centrifuged at low speed (500 g/40 min) at 4 degrees C. The resulting supernatant was centrifuged at 100,000 g for 30 min at 4 degrees C. The N-acetyl-beta-D-glucosaminidase activity as assayed by fluorimetric assay using 4-methylumbelliferil beta-D-N-acetylglucosamine (4MU GlcNAc) was found predominantly (> 95%) in the supernatant. Isolation of the enzyme was achieved by a combination of gel filtration with ion-exchange chromatography. Non-denaturing gel electrophoresis indicated that N-acetyl-beta-D glucosaminidase activity was present in two bands. When the two fluorescent bands were excised from the non-denaturing gel and rerun on denaturing 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis they exhibited two proteins with molecular masses of 40 and 45 kDa. The pH optimum is approximately 7.5 and the temperature optimum is approximately 37 degrees C. PMID- 10099005 TI - Changes in peripheral blood lymphocyte subpopulations and parasite-specific antibody responses in Trypanosoma evansi infection of sheep. AB - This paper reports on changes in the lymphocyte composition of the peripheral blood in sheep infected with Trypanosoma evansi. In addition, parasite-specific IgG1 and IgM antibody responses were monitored using a double-sandwich enzyme linked immunosorbent assay (ELISA) technique. Eight sheep were infected with 2 x 10(6) T. evansi TREU 2143. The infection was characterised by chronicity and ended in self-cure in two of the sheep. These two sheep were designated group A, whereas the other six sheep, which remained parasitaemic until treated, were designated group B. Analysis of the peripheral blood lymphocytes (PBLs) by indirect immunofluorescence staining and flow cytometry revealed significant alterations in the numbers of T- and B-cell subsets detected in all infected sheep. In group A, whereas the numbers of CD8+ cells decreased, CD4+ cells showed marginal decreases, remaining at or above pre-infection figures and resulting in increase in the CD4:CD8 ratio. In group B, CD8+ cells showed few marginal decreases, being at or above pre-infection figures most of the time, whereas CD4+ cells decreased significantly from day 26 post infection (p.i.) such that the CD4:CD8 ratio decreased. Infection also resulted in significant increases (P < 0.001) as of day 26 p.i. in circulating B-cells in group B as shown by the numbers of sIg+, CD45R+, CD1+ and major histocompatibility complex (MHC) II+ cells. The increases, however, were moderate and biphasic in group A. T. evansi specific IgM and IgG1 antibody isotypes were detected in all infected sheep, but their levels were significantly higher in group A than in group B (IgM P < 0.05; IgGI P < 0.01). In addition, although an initially higher level of IgM response was subsequently replaced by a higher level of IgG1 response in group A, this was never the case in group B until after drug treatment. PMID- 10099006 TI - A chromosome study of the tapeworm Bathybothrium rectangulum (Bloch, 1782) (Cestoda: Pseudophyllidea). AB - The diploid number 2n = 18 was revealed in Bathybothrium rectangulum, a specific parasite of barbels (Barbus spp.). All chromosome pairs were biarmed (pairs 1, 4, 7, 8, and 9 were metacentric; pairs 2, 3, and 6 were meta-submetacentric; and pair 5 was submetacentric) and small (from 1.49 to 2.95 microm). The C-banding method revealed pericentromeric heterochromatin in pairs 1, 3, 5, and 7; distinct C-bands in pairs 2, 4, 8, and 9; and a slight band in short arms of pairs 1 and 6. The karyotype of B. rectangulum is discussed with respect to the irresolute taxonomic position of B. rectangulum within the Pseudophyllidea. PMID- 10099007 TI - Investigation of different ontogenetic stages of Raillietiella sp. (Pentastomida: Cephalobaenida): excretory functions of the midgut. AB - The midgut of Raillietiella sp. was investigated in different ontogenetic stages. The developing embryo, the hatched first-stage larva, the infective fourth-stage larva from the intermediate host, and juveniles and adults from the definitive host were viewed ultrastructurally. From the fourth-stage larva onward, spherocrystals were visible in the midgut cells. They contained only small amounts of calcium and iron, depending on the ontogenetic stage. The cycle of crystal formation and destruction or excretion, respectively, is described herein. Their role in ion regulation and excretion is discussed with regard to similar inclusions in other arthropods. PMID- 10099008 TI - Considerations about the ontogenesis of Reighardia sternae in comparison with Raillietiella sp. (Pentastomida: Cephalobaenida). AB - The ontogenetic development of the cephalobaenids Reighardia sternae and Raillietiella sp. was compared and considerable differences with regard to stage size, development terms, habitat preference, and feeding behavior were found. On the basis of these differences we present a new interpretation of the life cycle of R. sternae, considering this species as an obligatory one-host parasite that has shifted its intermediate host phase into the egg. Therefore, the hatching stage directly infects the respiratory system of the definitive host, which is unique among pentastomids. PMID- 10099009 TI - Clustering of Acanthamoeba isolates from human eye infections by means of mitochondrial DNA digestion patterns. AB - A total of 90 Acanthamoeba isolates from human eye infections from 15 countries were clustered into distinct genotypes according to their mtDNA restriction fragment patterns. Closely related digestion phenotypes (sequence difference 0.1 1.5%) were integrated into a single genotype, whereas phenotypes with greater than 4.76% difference were considered distinct. Approximately 80% of the human isolates studied fell into 7 of 22 genotypes, indicating that virulence may be associated with specific clusters of cladistic groups of Acanthamoeba. This technique is useful for large-scale surveying of this particular pathogen. PMID- 10099010 TI - Trichinella spiralis: the infectivity of synchronous newborn larvae of different ages inoculated intraocularly. AB - Trichinella spiralis infection results in the transformation of muscle cells into a new, non-muscular cell called the nurse cell, and the nurse cell-muscle larva complex is finally created. To investigate whether T. spiralis infectivity is NBL age-dependent, five groups of synchronous newborn larvae (sNBL) were obtained at 1, 9, 24, 48, and 72 h of age and were inoculated into mice by intravenous injection into the retro-orbital venous plexus. When both "young" groups of sNBL (1 and 9 h old) were injected, the highest number of larvae were capable of infecting the muscle cells. The highest infectivity of 80.0 % was observed for 9 h-old sNBL. In older sNBL the infectivity gradually decreased; thus, for 72-h-old sNBL the lowest level - 0.1% - was detected. Therefore, an "age limit" for NBL infectivity in the present study was precisely determined. PMID- 10099011 TI - Cell-surface sialoglycoconjugate structures in wild-type and mutant Crithidia fasciculata. AB - The cell-surface expression of sialoglycoconjugate structures in wild-type Crithidia fasciculata and its TFR(R1) drug-resistant mutant was analyzed with the aid of an influenza C virus strain, lectin, enzymatic treatment, and flow cytofluorimetry analysis probed with fluorescein isothiocyanate-labeled (FITC) lectins. 9-O-Acetyl-N-acetyl neuraminic acid (Neu5,9Ac2) structures mediate influenza C virus cell-binding. The SAalpha2,3Gal and SAalpha2,6Gal sequences are specifically recognized by Maackia amurensis (MAA) and Sambucus nigra (SNA) lectins, respectively. On the basis of these parameters the TFR(R1) mutant strain of C. fasciculata was found to contain exposed sialoglycoconjugates bearing Neu5,9Ac2 surface structures. After the removal of sialic acid residues by neuraminidase activity the marked increases in PNA (peanut agglutinin)-mediated agglutinating activity showed that those acidic units on C. fasciculata cells were glycosidically linked to D-galactose. The bond involves SAalpha2,6Gal and SAalpha2,3Gal linkages as suggested by the use of FITC-SNA and FITC-MAA lectins, respectively. Both SAalpha2,3Gal and SAalpha2,6Gal sequences were preferentially expressed by the TFR(R1) mutant. The SAalpha2,6 linkage markedly predominated. In the TFR(R1) mutant, but not in wild-type cells, two distinct populations of cells were distinguished by reactivity with FITC-SNA, one of which was enriched with surface SAalpha2,6Gal sequences. These diverse findings suggest that sialoglycoconjugate structures present on the flagellate surface may be associated with mutation and the cell growth cycle in C. fasciculata. PMID- 10099012 TI - Activity of key enzymes in glucose catabolism during the growth and metacyclogenesis of Leishmania infantum. AB - This paper follows the development in the activity of the key enzymes of glycolysis and dehydrogenases of the pentose phosphate shunt throughout the in vitro growth and metacyclogenesis of two human strains of Leishmania infantum - one visceral (VL) and the other cutaneous (CL) - together with changes in the glucose, ammonium, and proton concentrations in the culture medium. In the first stage, ammonium was generated and no glucose was consumed. Later on, all the glucose was consumed and, finally, ammonium was generated again. The ammonium concentration increased 16- and 21-fold in cultures of VL and CL strains, respectively. The activities of the glycosomal enzymes hexokinase and phosphofructokinase differed in each strain, always being higher in CL than in VL and increasing throughout the culture period in CL while decreasing in VL. This probably indicates a different capability to adapt to the culture medium conditions. The activities of the pentose phosphate shunt enzymes examined indicate that 6-phosphogluconate dehydrogenase is possibly a rate-limiting enzyme for this pathway. Pyruvate kinase is a cytosolic control enzyme of glycolysis in trypanosomatids, and its activity decreased throughout the growth and differentiation of both strains of L. infantum, as occurs in other trypanosomatids. It was also observed that glucose catabolism was more active in the cutaneous strain than in the visceral one. PMID- 10099013 TI - Identification, isolation, and characterization of a species-specific 30-kDa antigen of Oesophagostomum dentatum. AB - In the search for a serology tool for the diagnosis of nonpatent as well as patent infections with Oesophagostomum dentatum in pigs a water-soluble, unglycosilated antigen of about 30 kDa specific for the third-stage larvae of the parasite was purified by ion-exchange chromatography. In Western blots, the antigen was first detected by antibodies at day 7 postinfection. Cross-reactivity with O. quadrispinulatum, Ascaris suum, or Trichuris suis was not detected. It is suggested that this protein is a suitable tool for the species-specific serodiagnosis of O. dentatum infection in pigs. PMID- 10099014 TI - Investigation of different ontogenetic stages of Raillietiella sp. (Pentastomida: Cephalobaenida): the midgut in nutrition and digestion. AB - The midgut of Raillietiella sp. was investigated ultrastructurally in different ontogenetic stages from the intermediate (cockroach) and the final host (small lizards). In the embryo the midgut anlage is an accumulation of cells filled with glycogen granules. During embryogenesis the cells organize and form a narrow tube. During postembryogenesis the contribution of the midgut to the alimentary tract rises considerably from the first larva to the adult parasites. In all stages the midgut is not divided into zones; however, two cell types (crystal and noncrystal cells) are distinguishable. Digestion takes place extracellularly. The main storage product of the midgut cells and the surrounding muscle cells is glycogen. A slight cyclic course of the digestive process is discernible. PMID- 10099015 TI - Interaction of ivermectin with gamma-aminobutyric acid receptors in Trichinella spiralis muscle larvae. AB - The value of the gamma-aminobutyric acid (GABA) receptor of nematodes as a target for ivermectin's mode of action remains unclear. Using binding assays, we examined extracts from Trichinella spiralis muscle larvae for the presence of [3H]-ivermectin and [3H]-GABA binding sites. Tissue preparations displayed affinity binding sites for [3H]-ivermectin with a dissociation constant (Kd) of 83 nM and a receptor density (Bmax) of 145 fmol/mg protein. We also identified a specific [3H]-GABA binding activity with a Kd of 1.2 microM and a Bmax of 4.78 pmol/mg protein. In competition studies, ivermectin was found to be a competitive inhibitor of specific [3H]-GABA binding activity with an inhibition constant (K(i)) of 3.39 nM, suggesting that GABA receptors could be implicated in the mechanism of action of ivermectin in nematodes. PMID- 10099016 TI - DEAD-box protein HEL64 from Trypanosoma brucei: subcellular localization and gene knockout analysis. AB - RNA helicases are molecules that play a central role in the control of ribonucleic acid metabolism. Only two putative RNA helicase genes of the DEAD-box family have been identified in the protozoan parasite Trypanosoma brucei brucei. One of these genes is HEL64, a single-copy gene of unknown function. In this study we conducted targeted gene-disruption experiments of the HEL64 locus with the aim of identifying a phenotype that would suggest a function for the encoded protein. It is likely that HEL64 is an essential gene in insect-stage trypanosomes, since all attempts to create a HEL64 double-allele knockout cell line failed. Instead, we obtained a mutant derived from an unusual recombination event that nonetheless contained a functional copy of the gene. One allele of HEL64 is sufficient for the survival of the parasite. Single-allele knockout mutants showed no gross change in cell morphology and multiplied with a cell doubling time identical to that of wild-type trypanosomes. Though HEL64 has high sequence homology with the nuclear DEAD-box protein p68, it is localized in the cytosol of trypanosomes and, thus, cannot be a homologue of p68 as previously suggested. Since the protein did not cross-hybridize with an anti-eIF-4A antibody, we excluded the possibility that HEL64 might be a homologue of the translation initiation factor eIF-4A. Although the function of HEL64 remains unknown, the present data indicate that the encoded DEAD-box protein plays an important role during the insect life-cycle stage of the parasite. PMID- 10099017 TI - Evaluation of the effect of peptidyl membrane-interactive molecules on avian coccidia. AB - This study examined the lytic effect of seven different synthetic peptidyl membrane-interactive molecules (Peptidyl-MIMs) on sporozoites of five different species of Eimeria infecting chickens and merozoites of two different species that infect chickens. All Peptidyl-MIMs (pMIMs) demonstrated antiparasitic effects at concentrations of 1-50 microM during incubation periods varying from 1 to 20 min. In addition, electron microscopy showed that ultrastructural degeneration of the pellicle of sporozoite stages of the parasites occurred within 5-10 min of exposure to 5-microM concentrations of three different pMIMs. Pore-like openings were seen in the pellicle of the sporozoites at the ultrastructural level, which indicated that the pMIMs had the same mechanism of action on the parasites as that reported from studies done on bacteria. A reduction in lesion scores was seen in chickens treated orally with 10-, 50-, or 75-microM concentrations of two different proteolytic stabilized (methylated) pMIMs after challenge with three different species of avian coccidia in battery cage trials. Collectively these data indicate that pMIMs may be useful in the control of coccidiosis in poultry. PMID- 10099018 TI - Host-parasite relationships between Echinostoma caproni and RAG-2-deficient mice. AB - The RAG-2-deficient mouse, a strain of genetically altered mice lacking B- and T lymphocytes, was used as a host for Echinostoma caproni. In all, 12 male RAG mice were exposed to 25 cysts each, and 12 served as uninfected controls. Mice were necropsied at 2 and 3 weeks postinfection (p.i.). The mean number+/-SE (9.7+/ 2.4) of worms recovered from infected mice at 2 weeks p.i. was not significantly different from that recovered at 3 weeks p.i. (6.5+/-2.2). The intestinal circumference of infected RAG mice was significantly greater than that of the controls at 2 and 3 weeks p.i. A significant goblet cell hyperplasia occurred at 2 weeks p.i., but the response was not effective in eliminating worms from the RAG mice. The effect of a high cyst burden was examined by exposure of 8 RAG and 8 ICR mice to 100 cysts each. The body length and area and the oral sucker area of worms grown in RAG mice were significantly greater than those of worms grown in ICR mice. Worm recovery at up to 3 months p.i. was examined in RAG mice exposed to 25 cysts and necropsied every 2 weeks p.i. The mean worm recovery recorded at 2 weeks p.i. was significantly greater than that noted at 12 weeks p.i., at which time worm rejection from the RAG mouse host first occurred. The RAG mouse is a useful host for studies on E. caproni in a murine host that lacks B- and T-lymphocytes. PMID- 10099019 TI - Characterization of protein profiles and cross-reactivity of Blastocystis antigens by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analysis. AB - The protein profiles of Blastocystis hominis, B. lapemi, and B. ratti were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and species could be differentiated by this means as well as by Western-blot analysis with polyclonal antibodies. No intraspecies difference could be distinguished between the two B. hominis isolates or the three B. ratti isolates. Western-blot analysis showed extensive cross-reactivity of B. lapemi and B. hominis antigens with anti-B. ratti serum. Some of the cross-reactive antigens were glycoproteins as determined on the basis of their sensitivity to periodate treatment. PMID- 10099020 TI - Field study on the insecticidal efficacy of Advantage against natural infestations of dogs with lice. AB - A clinical field trial was performed to evaluate the efficacy of imidacloprid, the active ingredient of Advantage 10% Spot-On, against natural lice infestations on dogs. Imidacloprid was highly effective against both sucking (Linognathus setosus) and biting (Trichodectes canis) lice over the 6-week period of the trial. The duration of efficacy exceeded the egg-to-imago development period of both lice. Signs of remission of dermatitis and alopecia became visible to the pet owners at 2 weeks after treatment. The constant pruritus caused by the lice was seen for up to 2-4 weeks after treatment even in the absence of lice. PMID- 10099021 TI - Total tooth loss among persons aged > or =65 years--selected states, 1995-1997. AB - Loss of all natural permanent teeth (edentulism) substantially reduces quality of life, self-image, and daily functioning. Although loss of teeth results from oral diseases such as dental caries and periodontitis, it also reflects patient and dentist attitudes, availability and accessibility of dental care, and the prevailing standard of care. One of the national health objectives for 2000 is to reduce to no more than 20% the proportion of persons aged > or =65 years who have lost all their natural teeth (objective 13.4). Edentulism has been declining in the United States since the 1950s, but few state-specific data are available on adult tooth loss. To estimate the prevalence of edentulism among persons aged > or =65 years, CDC analyzed data from the 46 states that participated in the oral health module of the 1995-1997 Behavioral Risk Factor Surveillance System (BRFSS). This report summarizes the findings from this analysis, which indicate a large state-specific variation in edentulism and that many states have not yet achieved the national health objective for preventing total tooth loss. PMID- 10099022 TI - Outbreaks of gastrointestinal illness of unknown etiology associated with eating burritos--United States, October 1997-October 1998. AB - From October 1997 through October 1998, 16 outbreaks of gastrointestinal illness associated with eating burritos occurred in Florida, Georgia, Illinois, Indiana, Kansas, North Dakota, and Pennsylvania. All but one outbreak occurred in schools, and most of the approximately 1700 persons affected were children. This report summarizes investigations of two of these outbreaks and describes the collaborative efforts of CDC, the U.S. Department of Agriculture (USDA), and the Food and Drug Administration (FDA) to identify the etiologic agent(s); these outbreaks may have been caused by an undetected toxin or a new agent not previously associated with illness. PMID- 10099023 TI - Adult Blood Lead Epidemiology and Surveillance--United States, second and third quarters, 1998, and annual 1994-1997. AB - Chronic lead exposure in adults can damage the cardiovascular, central nervous, renal, reproductive, and hematologic systems. CDC's Adult Blood Lead Epidemiology and Surveillance (ABLES) program monitors laboratory-reported elevated blood lead levels (BLLs) among adults in the United States. During 1998, 27 states reported surveillance data to ABLES. This report presents prevalence data for elevated BLLs for the second and third quarters of 1998 and compares them with corresponding quarters of 1997, and presents annual prevalence data for elevated BLLs from 1994 through 1997 for each participating state. The findings indicate that of the approximately 20,000 persons tested for blood lead and reported to ABLES each quarter, approximately 4000 BLLs were elevated. The 1994-1997 prevalence rates of elevated BLLs among adults provide a crude comparison of the levels and trends among the 27 states participating in the program. PMID- 10099024 TI - The effects of bovine respiratory syncytial on normal ovine lymphocyte responses to mitogens or antigens in vitro. AB - In the present study peripheral blod mononuclear cells (MNC) obtained from normal uninfected lambs were used to study the possible effects of bovine respiratory syncytial virus (BRSV) on lymphocyte responses to the mitogens, phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM) in vitro. Live BRSV had a depressive effect on the proliferative responses of normal MNC to PHA, Con A and PWM. Inactivated BRSV and a commercial preparation of prostaglandin E2 were also found to depress the proliferative responses of normal ovine MNC to PHA but recombinant tumour necrosis factor-alpha (TNF-alpha) had no such effect. Serum samples obtained from BRSV-infected lambs contained substances inhibitory to PHA-driven lymphocyte blastogenesis. Memory blastogenic responses to border disease virus (BDV) of lymyphocytes obtained from lambs previously primed with BDV were significantly reduced when lymphocytes were exposed to infectious BRSV. PMID- 10099025 TI - Moderate protective effect of 6-MFA, a microbial metabolite obtained from Aspergillus ochraceus on immunological liver injury in mice. AB - Hepatoprotective effect of 6-MFA, obtained from fungus Aspergillus ochraceus ATCC 28706, was evaluated by employing three different immunological liver injury mice models. The first liver injury model was induced by injecting anti-basic liver protein (BLP) antibody into mice previously immunised with rabbit IgG (RGG). The other models were simulated by injecting antiliver specific protein (LSP) antibody or by injecting bacterial lipopolysaccharide (LPS) into mice pretreated with Corynebacterium parvum (C. parvum). 6-MFA treatment inhibited the increased transaminases (GOT and GPT) activities and showed a tendency to inhibit the histopathological changes of the liver in all the models studied. Furthermore, 6 MFA treatment inhibited deoxycholic acid induced transaminase release from cultured rat hepatocytes in vitro, but failed to affect the formation of hemolytic plaque forming cells in immunised mice spleens and hemolytic activity of guinea pig complement in immunohemolytic reaction. Our findings, therefore, suggested that the moderate hepatoprotective effect of 6-MFA could be related to it's protective effect on hepatocyte plasma membrane rather than the direct inhibitory effects on the antibody formation and/or complement activity. PMID- 10099026 TI - Dot-enzyme linked immunosorbent assay for demonstration of Newcastle disease virus infection. AB - Dot-enzyme linked immunosorbent assay (ELISA) was standardised to detect Newcastle disease virus (NDV) specific antigen in chicken tissues, embryos and allantoic fluid samples. Samples positive by virus isolation were also found positive by haemagglutination (HA) and haemagglutination inhibition (HI) tests and by dot-ELISA but negative samples were found negative by all the serological tests used. Dot-ELISA was able to detect 0.25-0.50 HA units of virus. The emerging utility of dot-ELISA for diagnosis of Newcastle disease virus infection has been discussed. PMID- 10099027 TI - The ELISA for the examination of hare sera for anti-Brucella antibodies. AB - Hare brucellosis is caused primarily by Brucella suis biovar 2. Hares along with wild boars are the natural reservoir of this microorganism. In view of restriction of applicability of traditional serological methods the work aimed to develop the ELISA to examine hare sera for the presence of anti-Brucella antibodies. Lipopolysaccharide (LPS) antigen obtained from the strain S19 of Brucella abortus and the conjugate of antibodies against rabbit immunoglobulin with horseradish peroxidase were used in the test. Hares' sera positive and negative in the CFT were used as controls of the ELISA. The sera collected from 9 hares suspected to be infected with Brucella organisms, positive in CFT (in this number 7 hares revealed clinical symptoms or anathomopathological lesions characteristic of brucellosis), 6 sera from hares showing no symptoms of the disease, negative in CFT and 520 sera from hares monitored for brucellosis were tested. All serum samples from hares suspected for Brucella infection were positive in ELISA and 2 of them were negative in RBPT. Additionally among the samples from hares monitored 12 sera were positive in ELISA and CFT, whereas 9 sera from 12 ones were also positive in the RBPT. The obtained results indicated that the ELISA developed in our laboratory proved to be equivalent in specificity to CFT. In addition, ELISA proved to be more sensitive than RBPT for the diagnosis of Brucella infection in hares. PMID- 10099028 TI - Pathology, diagnosis and epidemiology of the rodent Helicobacter infection. AB - Since the first isolation of Helicobacter pylori from humans in 1983, 18 Helicobacter species have been identified during the last decade in domestic and laboratory animals. Several Helicobacter species have been isolated from the gastrointestinal tracts of various mammalian species and birds. Helicobacter hepaticus, H. muridarum, H. bilis, H. rodentium and Flexispira rappini have been isolated from mice. Among these species, only H. hepaticos has been clearly recognized as a pathogen. Indeed, it displays the pathogenic potential to elicit hepatitis in several strains of mice; moreover in A/JCr mice, it is strongly associated with hepatic cancer. Among the five murine helicobacter species, apart from H. hepaticus, F. rappini has not been found associated with lesions, H. muridarum has been observed in gastric glands of mice with chronic gastritis, and H. bilis has been reported in the liver of mice with chronic hepatitis. When associated with H. rodentium, H. bilis is able to induce diarrhea in SCID mice. In no case has pathogenicity of a single species been clearly proven. In rats, H. trogontum and H. muridarum have been isolated from the intestine, without any information concerning their respective pathogenicity. H. cinaedi and H. cholecystus have been identified from the intestine and the gallbladders of hamsters, respectively. The diagnosis of Helicobacter species by polymerase chain reaction (PCR) is a rapid, specific and sensitive technique. One of the most promising diagnostic techniques of these infections seems to be the PCR detection of Helicobacter sp. from feces based on the 16S rRNA sequences, then a restriction enzyme analysis to identify the actual species. Several drug regimens have also been evaluated to eradicate H. hepaticus from mice. Helicobacter infections, particularly H. hepaticus and H. bilis, seem to be widespread in laboratory mouse colonies and have also been detected from commercial breeders. PMID- 10099029 TI - Comparison of adjuvants with respect to serum IgG antibody response in orally immunized chickens. AB - We have previously shown that oral immunization with non-replicating antigens hardly induced serum IgG antibody response in chickens and addition of sodium fluoride (NaF) to the immunogen markedly improved their immunological states. In the present study, taurine, lithium and Quillaja saponin (Q-SAP) were compared with NaF with respect to their enhancement of serum IgG antibody response in chickens after oral immunization. The antibody titer of chickens which received Q SAP as the mucosal adjuvant tended to be higher than that of chickens which received antigen plus NaF. Simultaneous administration of antigen with lithium or taurine elicited a higher antibody titer in chickens compared to those of chickens orally immunized with antigen alone, but the effect of these two adjuvants was less efficient compared with that of NaF. These results suggested that Q-SAP as well as NaF is useful as an oral adjuvant for chickens. PMID- 10099030 TI - Preliminary studies on the use of solid-phase immunosorbent techniques for the rapid detection of Wesselsbron virus (WSLV) IgM by haemagglutination-inhibition. AB - Serum samples from 446 randomly selected persons belonging to different age groups and locations in Nigeria were tested for the presence of WSLV IgM using the flavivirus haemagglutination-inhibition (HI) test adopted to the solid-phase immunosorbent technique (SPIT). 61 (14%) persons had IgM to WSLV only, while 9 (2%) persons had heterologous IgM to WSLV and two other flaviviruses, namely yellow fever and Uganda S viruses. There was a high prevalence of IgM in people of younger age groups than those in older groups. The majority of the IgM positive sera (67 (96%) of the 70 positive sera reacted to high titres (>21:80). With the conventional HI tests, 314 (70%) of the total sera tested had HI antibodies to one or more flaviviruses (yellow fever, West Nile, Potiskum, Zika and Uganda S) out of which 305/314 (97%) had antibodies to 3 or more flaviviruses used in the tests. Although SPIT may not be as sensitive as the conventional HI test, it was found to be more specific and could be adopted for the detection of early WSLV infections in flavivirus hyperendemic environments. PMID- 10099031 TI - Superior oblique tendon resection or inferior oblique muscle recession in vertical deviations. AB - This study reports the results on patients undergoing superior oblique (SO) tendon resections with or without inferior oblique (IO) muscle recession to correct vertical deviations. The design of this study was nonrandomized, baseline controlled, and postsurgical versus presurgical and was performed in a solo practice affiliated with a university ophthalmology department. One hundred ninety-five patients underwent surgery. Patients were evaluated presurgically and postoperatively in the major fields of muscle action. Resections were based on measurements at 14 inches in the field of major function of the SO. The surgical approach was a radial, rather than circumferential, incision extending from the limbus to the tarsus parallel to the lateral border of the superior rectus, followed by resection of the SO tendon. Surgery resulted in improved fusion in 78% of the cases. Average deviation in the left superior oblique field in SO tendon resection only (n = 14) was reduced from 11.0 to 1.7 prism diopters, and fusion improved 85% after treatment. In 181 cases of SO tendon resection or IO recession, the left superior oblique field was reduced from 15.8 to 3.6 diopters. SO tendon resection was successfully utilized to treat underacting SO muscle and vertical deviations. A radial incision facilitated the surgical procedure, and its use is recommended to those performing the surgery. PMID- 10099032 TI - Lack of pharmacokinetic drug interactions between tiagabine and carbamazepine or phenytoin. AB - Two single-center, open-label studies examined the potential effects of tiagabine on the pharmacokinetics and safety of carbamazepine and phenytoin at steady state. Twelve adult patients with seizures controlled by an individualized fixed dosage of antiepilepsy medication (carbamazepine or phenytoin) participated in each study. On day 1, the pharmacokinetics of the baseline antiepilepsy drug were determined. On days 2 through 18, tiagabine was titrated from 8 to 48 mg/d (or the maximum tolerated dose up to 48 mg/d), and the usual fixed dosage of carbamazepine or phenytoin was continued. The pharmacokinetic assessment was repeated on day 18. There were no statistically significant differences in carbamazepine, carbamazepine epoxide, and phenytoin pharmacokinetic parameters when either drug was administered alone or in combination with tiagabine. In each study, 11 of 12 patients (92%) experienced treatment-emergent adverse events after tiagabine was added. The most frequent adverse events were dizziness, headache, difficulty concentrating, drowsiness, and tremor. Most symptoms were mild or moderate in severity and resolved without further treatment, although tiagabine dosage reductions were required by 4 patients in the carbamazepine study and by 3 patients in the phenytoin study. There were no clinically important effects on physical examination or neurologic test results, laboratory values, or vital signs. The results suggest that addition of tiagabine to a fixed regimen of either carbamazepine or phenytoin is generally well tolerated and that carbamazepine and phenytoin steady-state pharmacokinetics are unaffected by the addition of tiagabine. PMID- 10099033 TI - Effects of delapril in combination with indapamide on blood pressure and left ventricular mass in elderly hypertensive patients. AB - We present a single-blinded, placebo-controlled trial of the effects on blood pressure and left ventricular mass and of the safety of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65-85 years (mean age, 69 +/- 1) with sitting systolic/diastolic blood pressure of 160-200/95-115 mm Hg (at the end of the placebo period). After a 2-week placebo run-in, patients took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. Twenty-four-hour ambulatory blood pressure was monitored and M- and B-mode echocardiography were performed before and after 24 weeks of treatment. Blood pressure decreased from 156 +/- 1.5/101 +/- 1 mm Hg before treatment to 133 +/- 1/73 +/- 1 mm Hg after treatment. The total blood pressure burden also decreased; the percentage of measurements with a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure > or = 90 mm Hg decreased from 48.7% +/- 5%/31.5% +/- 4.3% to 23.5% +/- 4%/20.5% +/- 2.9% (p < 0.0005 and p < 0.05). The area under the curve of the 24-hour blood pressure decreased from 250 +/- 41/103 +/- 21 mm Hg to 97 +/ 21/37 +/- 8.5 mm Hg (p < 0.001 and p < 0.005). The left ventricular mass index (LVMI) in the 15 patients with pretreatment left ventricular hypertrophy was reduced after therapy from 167.5 +/- 8.5 g/m 2 to 152.2 +/- 7.6 g/m 2 (p < 0.05). A positive correlation was observed between percent changes of the area under the curve of the 24-hour diastolic blood pressure and percent changes of LVMI (r = 0.6; p < 0. 05) in the 15 patients with left ventricular hypertrophy. Only 2 patients reported side effects: 1 developed skin rash and 1 developed headache. The safety of the treatment was confirmed by laboratory tests. In elderly hypertensive patients, the combination of delapril and indapamide at low doses reduced blood pressure and had favorable effects on LVMI with few side effects. PMID- 10099034 TI - Clinical and neurohormonal effects of nicardipine hydrochloride in patients with severe chronic heart failure receiving angiotensin-converting enzyme inhibitor therapy. AB - It has been proposed that worsening of heart failure with dihydropyridines, such as nicardipine, is related to the activation of the neuroendocrine system. To test this, we evaluated 20 patients with severe heart failure (mean age, 55 +/- 13 years; New York Heart Association functional class III; left ventricular ejection fraction, 18% +/- 8% on maintenance therapy with captopril, digoxin, and diuretics) who were randomized to nicardipine (60 or 90 mg/d) or placebo during a 4-month double-blind protocol. The following measurements were obtained at baseline, monthly, and at 4 months or last follow-up visit: rest and exercise radionuclide ventriculography, maximal treadmill time, 6-minute walking test distance, serum norepinephrine and aldosterone concentrations, and plasma renin activity. During the follow-up period, worsening of heart failure occurred in 6 patients in the nicardipine group and in 2 patients in the placebo group (p = 0.06). The maximal treadmill time for a 6-minute walking distance and exercise radionuclide ejection fraction at the last follow-up visit did not change in patients who did not deteriorate with heart failure in the placebo or nicardipine groups as compared with baseline values. In this study group of patients with severe heart failure receiving therapy with digoxin, captopril, and diuretics, nicardipine was associated with worsening heart failure without an apparent activation of the neurohormones. However, because of the small number of patients and a significant number of patients who deteriorated during the follow-up period, no definitive conclusions can be made. PMID- 10099035 TI - Hepatic encephalopathy and role of antibenzodiazepines. AB - The majority of pharmacological agents are designed to accomplish a specific effect based on the established mechanisms of a disease. However, there are a few examples in which investigation of a pharmacological action has led to a previously unknown mechanism, i. e. the drug effect was observed initially before its mechanism became known. For example, the opiates had been in use for their analgesic effect for centuries before the question of endogenous substances that might explain the presence of opiate binding sites in the central nervous system (CNS) was raised, leading to the discovery of the opioids. A somewhat analogous development has occurred in another investigative arena, the observation that the administration of the benzodiazepine antagonist, flumazenil, has reversed the encephalopathy of hepatic failure. This has refocused research to discover whether one or more endogenous substances that bind to the benzodiazepine receptor in the CNS are responsible for the inhibition of CNS function of advanced liver failure. The investigative impetus was initiated by observations that patients with liver failure were highly vulnerable to benzodiazepines; therapeutic dosages precipitated coma or near-coma, and this effect was prolonged. The question was raised whether any given patient presenting with a coma-like state associated with advanced liver dysfunction might have received a benzodiazepine in the recent past, under circumstances overlooked or not recorded, that might be a contributing factor to the patient's condition. This led to testing the effects of the antagonist, with transitory success in arousing patients or improving their level of stupor. Further inquiry revealed that this improvement in mental function occurred in the absence of prior exposure to benzodiazepines. There followed a search for endogenous substances capable of binding to the benzodiazepine receptor, with CNS inhibitory effects. These investigations have resulted in the identification of several substances that may play a role in encephalopathy and can be displaced from the CNS receptor by properly designed antagonists-an ongoing investigative effort. PMID- 10099036 TI - Dopamine: pharmacologic and therapeutic aspects. AB - Dopamine is a biogenic amine synthesized in the hypothalamus, in the arcuate nucleus, the caudad, and various areas of the central and peripheral nervous system. It has been widely established that dopamine and its agonists play an important role in cardiovascular, renal, hormonal, and central nervous system regulation through stimulation of alpha and beta adrenergic and dopaminergic receptors. There are several agonists of dopamine-2 (DA 2 ) dopaminergic receptors, such as bromocriptine, pergolide, lisuride, quinpirole, and carmoxirole, which inhibit norepinephrine release and produce a decrease in arterial blood pressure; in some cases, bromocriptine and pergolide also reduce heart rate. From a therapeutic point of view, the above-mentioned agonists are used for treating Parkinson's disease, acting over DA 2 dopaminergic receptors of the nigrostriatal system. Bromocriptine and the other dopaminergic agonists mentioned act over DA 2 receptors of the tuberoinfundibular system, inhibiting prolactin release and decreasing hyperprolactinemia and tumor size. Among DA 1 receptor agonists, we can mention fenoldopam, piribedil, ibopamine, SKF 3893, and apomorphine (nonspecific). Activation of these receptors decreases peripheral resistance, inducing lowering of arterial blood pressure and increases in heart rate, sympathetic tone, and activity of the renin aldosterone system. Among DA 2 receptor antagonists, we can mention metoclopramide, domperidone, sulpiride, and haloperidol. From a therapeutic point of view, metoclopramide and domperidone are used in gastric motility disorders, and haloperidol is used in psychotic alterations. Antagonists of DA 1 receptors are SCH23390 and clozapine. Clozapine is used for treating schizophrenia. PMID- 10099037 TI - Management of opportunistic infections in acquired immunodeficiency syndrome. I. Treatment. AB - A case report of a patient infected with human immunodeficiency virus (HIV) is described. The patient presents with a multitude of medical complaints that are of acute or subacute onset. The medical examination of these complaints is described and includes algorithms for the diagnosis and treatment of the most common HIV-related opportunistic infections, including Pneumocystis carinii pneumonia, toxoplasmosis, Mycobacterium avium complex, cytomegalovirus infection, and cryptococcal meningitis. PMID- 10099038 TI - Clinical therapeutic conference: recurrent venous thrombotic and thromboembolic disease. AB - Recurrent venous thrombotic and thromboembolic disease, once thought to be an uncommon entity, is increasingly being recognized. Etiologies of recurrent deep venous thrombosis usually include elements of Virchow's triad. Venous stasis (e.g., immobilization, congestive heart failure, acute myocardial infarction, obesity), hypercoagulability (e.g., malignancy, inflammatory bowel disease, hyperhomocysteinemia, protein C resistance, antithrombin III, protein C or S deficiency) and endothelial trauma (e.g., surgical trauma, venous trauma, in dwelling venous instrumentation) are risk factors. Diagnosis is dependent on objective testing, including venography duplex Doppler (color) ultrasonography and impedance plethysmography. Treatment is usually started with heparin or low molecular-weight heparin and advanced to warfarin (adjusted to international normalized ratio). Prophylaxis may continue using low-molecular-weight heparin, warfarin, venacaval interruption (Greenfield filter), or concomitant use of the platelet-active agent indobufen and graduated compression stockings. PMID- 10099039 TI - Effect of multiple doses of oral isradipine on atrioventricular conduction in patients with first-degree atrioventricular block. AB - The purpose of this study was to investigate the effect of multiple doses of orally administered isradipine on atrioventricular nodal conduction in patients with first-degree atrioventricular block. Forty-eight patients with a P-R interval > or =0.22 seconds on a surface electrocardiogram (ECG) (first-degree atrioventricular block) with or without a bundle-branch block were randomized to one of four groups for 6 weeks of treatment with either placebo or 5.0 mg/d, 7.5 mg/d, or 10.0 mg/d isradipine. P-R interval prolongation was assessed at baseline and posttreatment using resting 12-lead ECGs and 24-hour Holter monitoring. The effect of isradipine on the following parameters were assessed: systolic and diastolic blood pressures, heart rate, respiration rate, oral temperature, and weight. Neither isradipine nor placebo treatment had a statistically significant treatment effect on the change from baseline in P-R interval, QRS duration, Q-T interval (uncorrected), or sinus heart rate at week 7 as measured by 12-lead ECG. All treatment groups, however, had small, statistically insignificant decreases from baseline in the mean P-R interval. The largest decrease (from 0.26 seconds at baseline to 0.22 seconds at week 7) was recorded for the 7.5 mg/d isradipine group, which also had the greatest posttreatment decreases in QRS duration, sinus heart rate, and systolic and diastolic blood pressures. The treatment groups did not differ significantly with respect to the change from baseline to study end in P-R interval prolongation or degree of atrioventricular block (as measured by 24 hour Holter monitoring), radial pulse rate, respiration rate, weight, or oral temperature. In this study, isradipine did not have a negative dromotropic effect on the atrioventricular node. The trend toward a posttreatment decrease in P-R interval suggests that isradipine may actually improve atrioventricular nodal conduction in patients with first-degree atrioventricular block and thus may be used safely in this population. PMID- 10099040 TI - Pharmacokinetic drug interaction study: administration of ceftibuten concurrently with the antacid mylanta double- strength liquid or with ranitidine. AB - This study investigated the influence of antacid (Mylanta Double-Strength Liquid; J & J-Merck Consumer, Fort Washington, PA) and the H2 antagonist ranitidine on the pharmacokinetics of ceftibuten, a once-daily oral cephalosporin. Eighteen male volunteers received, in a randomized, three-way, crossover design, a single oral 400-mg dose of ceftibuten after an overnight fast (1) alone, (2) with antacid (60 mL), and (3) with ranitidine (after 3 days of dosing, 150 mg/12 hours). Serial blood and urine samples were collected during a 24-hour period after each administration, with a 1-week washout between treatments. Ceftibuten, and its metabolite ceftibuten-trans, were analyzed in plasma and urine by high performance liquid chromatography. Bioavailability parameters, maximum plasma concentration and area under the plasma concentration-time curve to infinity of ceftibuten were unaffected by treatment with antacid. These parameters were somewhat higher when ceftibuten was administered with ranitidine, but they were still within the ranges seen in normal healthy volunteers. The excretion of ceftibuten was independent of treatment. The concentrations of ceftibuten-trans were low in both plasma and urine with all three treatments. It is concluded that the co-administration of antacid and ranitidine are unlikely to affect the bioavailability and antibacterial efficacy of ceftibuten. PMID- 10099041 TI - Lack of a clinically significant pharmacokinetic drug interaction between tiagabine and valproate. AB - This single-center, open-label study examined the safety and potential effect of tiagabine on valproate pharmacokinetics under steady-state conditions. Twelve adult patients with seizures controlled by an individualized fixed dosage of valproate participated in the study. On day 1, the pharmacokinetics of valproic acid were determined. On days 2 through 14, tiagabine was titrated from 8 to 24 mg/d (or the maximum tolerated dose up to 24 mg/d), and the patients continued to take their usual fixed dosage of valproate. Valproic acid pharmacokinetics were assessed again on day 14. The mean maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC0-tau ) for valproic acid were reduced approximately 10% and 12%, respectively (p < or = 0.05), when valproate and tiagabine were administered concomitantly, compared with the mean values when valproate was administered alone. The concomitant administration of these drugs was generally well tolerated. Ten patients reported treatment-emergent adverse events during the study, the most common of which was dizziness(n = 8). Only one patient experienced events that were considered to be severe. There were no clinically important effects on laboratory values, vital signs, or physical exam findings. The small decreases in mean valproic acid Cmax and AUC0-tau observed during the concomitant administration of tiagabine and valproate are probably of limited clinical importance, given the broad therapeutic range of valproate (50-100 microg/mL). PMID- 10099042 TI - Metoclopramide and domperidone block the antihypertensive effect of bromocriptine in hypertensive patients. AB - This study was conducted in normotensive and hypertensive subjects at the Vargas Hospital of Caracas. Normotensive subjects received, in a cross-over fashion, placebo, metoclopramide (MTC), or domperidone (DOMP), 40 mg of each drug, daily for 1 week. The first group of patients under placebo for 1 week received a single 2.5-mg oral dose of bromocriptine (Br). The second group of patients received 30 mg MTC daily (divided into three doses) for 1 week. At the end of the period a single dose of 2.5 mg Br was administered to each patient. The third group of eight hypertensive patients received DOMP for 1 week at 30 mg/d and then a single 2.5-mg Br dose. Cardiovascular and biochemical parameters including arterial pressure, heart rate, plasma renin activity, and plasma aldosterone were evaluated during the 6-hour period before and after the administration of Br. Neither DOMP nor MTC significantly modified blood pressure and heart rate in normotensive patients. Br reduced both systolic and diastolic arterial pressure in hypertensive subjects. The peak of the antihypertensive effect appeared 3 hours after drug administration, but reduction of arterial pressure lasted approximately 6 hours. At the same time, Br reduced plasma aldosterone levels and plasma renin activity. MTC and DOMP reversed the antihypertensive effect of Br and its effect on aldosterone levels and plasma renin activity. We conclude from these findings that Br acts as an antihypertensive agent at peripheral and central levels by stimulating dopamine-2 receptors, which are involved in the aldosterone and renin secretion. PMID- 10099044 TI - The action of 10 mg famotidine versus 200 mg cimetidine: onset and magnitude of antisecretory action within the first 2 hours after administration. AB - The introduction of over-the-counter histamine2 -receptor antagonists (H2 -RAs) makes it important to characterize these agents in terms of their different times to onset of action and magnitude of effect. The time to onset of action and the degree of gastric acid inhibition of the H2 -RAs famotidine and cimetidine at dosage levels approved for over-the-counter use (10 mg famotidine and 200 mg cimetidine) were compared. Twenty-four subjects with a history of heartburn of at least 2 months duration received 10 mg famotidine, 200 mg cimetidine, or placebo in a randomly assigned sequence of three treatment periods. Each period began with an overnight fast, followed by insertion of an intragastric pH probe during a 1-hour baseline monitoring phase, and, 1 hour later, administration of the test medications and monitoring of intragastric pH for an additional 2-hour period. The onset of acid inhibition occurred approximately 35 minutes after administration of either famotidine or cimetidine. Famotidine provided a significantly greater degree of efficacy on all three parameters monitored: percentage of time that gastric pH values were greater than 3.0, mean area-under the-pH-curve-versus-time curve, and median pH (obtained at 5-minute intervals). Clearly, the over-the-counter dosage of famotidine (10 mg) provided gastric pH elevations that were as rapid and of superior degree than those induced by cimetidine 200 mg. PMID- 10099043 TI - Nandrolone decanoate for men with osteoporosis. AB - To compare the efficacy and safety of nandrolone decanoate and calcium (NDC) with those of calcium alone (CAL) in men with idiopathic osteoporosis, a 12-month, randomized, prospective, controlled study, was performed in an outpatient clinic. Twenty-one men with idiopathic osteoporosis (as determined by radiological and dual energy x-ray absorptiometry findings) were randomly allocated to either 50 mg nandrolone decanoate intramuscularly (im) weekly and 1,000 mg oral calcium carbonate daily (NDC group) or to 1,000 mg oral calcium carbonate daily (CAL group). Bone densitometry (total body, left femur, and lumbar spine), serum, and urine biochemical parameters were measured at 3-month intervals. In the NDC group, bone mineral density initially increased, reached a plateau, and then decreased to near baseline levels at 12 months. Increases in lean muscle mass mirrored these changes. Free and total testosterone significantly decreased. Hemoglobin increased in all patients in this group. Patients in the CAL group exhibited no significant change in either total body or bone mineral density or biochemical parameters. Thus, nandrolone decanoate, 50 mg im weekly, transiently increases the bone mass of men with idiopathic osteoporosis in this preliminary study. Careful monitoring is necessary. PMID- 10099045 TI - The benefits of angiotensin II receptor blockers in patients with renal insufficiency or failure. AB - Hypertension occurs frequently in patients with renal disease and contributes to the development of end-stage renal disease. Because the renin angiotensin system (RAS) influences hypertension and renal disease, angiotensin-converting enzyme (ACE) inhibitors have been used successfully to treat and reduce renal consequences of hypertension. This review assesses how angiotensin II (A-II) influences renal disease and explores the effectiveness of losartan, a selective A-II receptor blocker, in patients with renal disease. Clinical trials have demonstrated that losartan is a safe and effective treatment for hypertension in renally impaired patients and produces renal hemodynamic effects akin to those seen with ACE inhibitors. However, losartan demonstrates a greater uricosuric effect than ACE inhibitors and does not produce cough, a significant side effect frequently associated with ACE inhibitors. Further studies will determine whether combination therapy with an ACE inhibitor and A-II receptor blocker will provide additional RAS blockade and synergistic benefits in patients with renal disease. PMID- 10099046 TI - Dipyridamole in the nephritides. AB - A summary is given of the properties of dipyridamole and of the trials at the time this article was written that indicate its potential efficacy in the therapy of glomerulonephritides. PMID- 10099047 TI - Severe cardiac dysrhythmia in patients using bromocriptine postpartum. AB - Used worldwide since 1980 for the prevention of breast engorgement in the puerperium, in 1994 bromocriptine mesylate was withdrawn from the American market as an agent suitable for ablactation. The relevant recommendation of the Food and Drug Administration rested on case reports that described severe vasospastic reactions among users of the drug. Some patients so affected suffered stroke, intracranial bleeding, cerebral edema, convulsions, myocardial infarction, and puerperal psychosis. More recently, it has been suggested that the side effects of the drug may also include circulatory collapse secondary to cardiac dysrhythmia. This report describes two additional cases in this category. The antepartum clinical evaluation of these women suggested that they were predisposed to arrhythmias. PMID- 10099048 TI - Superwarfarin toxicity. PMID- 10099049 TI - Candida krusei sinusitis. PMID- 10099050 TI - Clinical application of the nitroglycerin lingual spray. AB - The effect of sublingually administered nitrate spray was investigated with noninvasive methods. During 3 months, 82 patients were entered into the study: 40 with angina pectoris, 15 with acute myocardial infarction, 18 with hypertensive crisis, and 9 with left ventricular failure or acute pulmonary edema. The hemodynamic effects of two jets of nitroglycerin spray (0.8 mg Nitrolingual spray; Pohl-Boskamp, Hohenlocksted, Germany) was measured on heart rate, blood pressure, and flow velocity at baseline and 1, 5, and 10 minutes after drug administration. Flow velocities were measured through the left ventricular outflow tract and the mitral valve (early diastolic wave and atrial wave) with bedside Doppler echocardiography. The time to improvement and occurrence of adverse events was analyzed. Heart rate was constant after the therapy (75 +/- 8, 75 +/- 10, 75 +/- 10, and 75 +/- 9 beats per min; not significant), and systolic blood pressure decreased significantly 1 minute after administration and remained decreased throughout the examination (135 +/- 27, 124 +/- 21, 125 +/- 19, and 124 +/- 22 mm Hg, respectively; p < 0.001). The diastolic blood pressure was also significantly decreased (82 +/- 17, 79 +/- 14, 78 +/- 12, 78 +/- 14 mm Hg; p < 0.001). A significant increase in flow velocities in the left ventricular outflow tract was detected (90 +/- 8, 101 +/- 10, and 114 +/- 13 cm/s; p < 0.001) concomitantly with a significant increase in the early diastolic flow (46 +/- 4, 65 +/- 6, and 76 +/- 8 cm/s; p < 0.001) and the atrial wave (101 +/- 9, 110 +/- 10, and 118 +/- 9 cm/s; p < 0.001). This increase of flow velocity was less pronounced through the mitral valve than through the left ventricular outflow tract. PMID- 10099051 TI - Myocardial collagen in cardiac hypertrophy resulting from chronic aortic regurgitation. AB - Myocardial fibrosis and abnormal myocardial collagen content are common in many forms of pathological cardiac hypertrophy, including that mediated by pressure overload. Recently, in an experimental animal model of chronic aortic regurgitation (AR), we found a strong relation between myocardial fibrosis and congestive heart failure development. To determine if these fibrotic lesions are composed of collagen, as they are in pressure overload, and to determine if potential preventive therapies should be developed similarly in both diseases, we assessed left ventricular collagen content at three time points after AR induction. Moderate to severe AR was induced in 19 New Zealand White rabbits by inserting a catheter through the carotid artery to perforate the aortic valve leaflets. Animals were killed (1) when they showed echocardiographically discernible systolic dysfunction or (2) if normal cardiac function continued, either early (1 month) or late (>3 years) after operation. Fourteen age-matched, sham-operated controls and seven normal unoperated rabbits also were studied. Collagen concentrations were determined biochemically by hydroxyproline measurement. Fibrosis was measured histologically using Mason's trichrome stain and the fibrous collagen-specific stain, Picro-Sirius Red. Our results show an age-related increase in left ventricular collagen concentration with no specific increase among animals with evidence of fibrosis. We conclude that, unlike pressure overload, volume overload produces fibrotic lesions not composed predominantly of excess collagen and that the therapy needed to prevent fibrosis may be different in these conditions. Further study is needed to define the chemical characteristics of the fibrous lesions and the pathophysiological importance of this finding. PMID- 10099052 TI - Pidotimod in the management of vulvar papillomatosis: double-blind clinical trial versus placebo. AB - To investigate whether the immune system improvement induced by pidotimod increases the rate of spontaneous disappearance of vulvar papillomatous lesions, a multicenter, double-blind, placebo-controlled, randomized clinical trial was performed. Forty-nine patients (23 in the pidotimod group and 26 in the placebo group) with first diagnosis of vulvar papillomatosis as shown by clinical and histological findings underwent 90-day treatment with oral 800-mg pidotimod once a day or identical placebo. The main outcome measure was the difference between vulvar papillomatous infected area before and after treatment judged by the following: complete regression (complete disappearance of all papillomatous lesions); partial regression (a decrease of at least 75% of the infected area); no response (a decrease of less than 75% of the infected area or new viral lesions not present at baseline). Forty patients completed the trial according to the study protocol and were entered in the "per protocol" analysis of efficacy. Complete regression was observed in 12 of 18 patients (66.7%) receiving pidotimod compared with 7 of 22 patients (31.8%) receiving placebo. The total infected surface area at the end of treatment was 10.1 +/- 18.5 mm2 (mean +/- SD) in the pidotimod arm and 198.3 +/- 399.2 mm2 in the placebo arm (p < 0.05 between treatment). Notwithstanding the fact that better results were obtained in the pidotimod group, more data are needed to confirm our encouraging results. PMID- 10099053 TI - Pharmacokinetics and electrocardiographic effect of ebastine in young versus elderly healthy subjects. AB - The objective of this study was to compare the single- and multiple-dose pharmacokinetics and electrocardiographic effect of a 10-mg oral dose of ebastine in elderly (ages, 65-85 years) and young (ages, 18-35 years) healthy volunteers. Thirty-seven subjects completed this randomized, double-blind, multiple-dose, placebo-controlled, parallel group study. The elderly group consisted of 18 subjects, with 13 subjects receiving 10 mg ebastine and 5 receiving matching placebo. The young group consisted of 19 subjects, with 13 subjects receiving 10 mg ebastine and 6 receiving matching placebo. On study days 1 and 3 through 10, each subject received a single 10-mg dose of ebastine or matching placebo in the morning with a standard breakfast. No drug was administered on study day 2 because of pharmacokinetic sampling. Blood samples were collected at selected times postdose on study days 1, 2, and 10. Plasma samples were analyzed for ebastine and its active metabolite, carebastine, using a validated high performance liquid chromatography method. No plasma ebastine concentrations were detected, suggesting essentially complete metabolic conversion of ebastine to its metabolites. Analysis of variance showed no statistically significant differences between young and elderly single- and multiple-dose carebastine pharmacokinetics with respect to area under the plasma concentration-time curve, maximum concentration (Cmax ), terminal elimination rate constant, apparent oral clearance, or apparent volume of distribution. The mean time of maximum concentration value for young subjects was 1 hour longer than that for elderly subjects after single-dose administration but was comparable after multiple-dose administration. Within-group comparisons of both the young and elderly showed that pharmacokinetics between single dose and steady state were not statistically different. However, the mean steady-state carebastine Cmax values were approximately twofold greater than the mean Cmax values obtained after single dose administration. A twofold increase in Cmax values between single-dose and steady-state administration is predicted for drugs such as carebastine, because its input interval is approximately equal to its elimination half-life. Twelve lead electrocardiography was performed before dosing on day 1 and repeated 4 hours postdose on days 1, 5, and 10. Twenty-four hour Holter monitoring was also performed before and at the end of the study. No clinically relevant findings were found by electrocardiography or Holter monitoring between ebastine and placebo in the elderly and young subjects. PMID- 10099054 TI - Use of beta-hydroxybutyric acid levels in the emergency department. AB - The impact of a new test on the market, the beta-hydroxybutyric acid (BOH) assay, on clinical decision-making in the emergency department (ED) has not been well studied. In this retrospective analysis, we studied the potential benefit of this new test in the ED decision-making process in diabetic patients. BOH levels were measured on all patients who had glucose and acetone levels ordered by the emergency physician during a 3-month period in the ED of a university tertiary referral center. Two groups were analyzed: group 1 was acetone-positive and BOH positive (n = 13); group 2 was acetone-negative BOH-positive (n = 31). There was no difference between the two groups in terms of gender (p = 0.55) or age (p = 0. 47). The length of stay (p = 0.97) and number of complications (p = 0.89) were also similar between the two groups. CONCLUSION: This study suggests that in those diabetic patients with a negative acetone test and a positive BOH test, the addition of the positive result on the BOH test may provide additional prognostic information for predicting hospital length of stay and number of in-hospital complications. PMID- 10099055 TI - Retrospective case-control evaluation of the use of parenteral ketorolac tromethamine in patients after surgery. AB - The aim of this study was to assess medication usage and to determine differences in selected outcomes in patients who received either parenteral ketorolac tromethamine or narcotics after surgery. A retrospective case-control study was used in patients on a surgery service who were postoperative. Forty patients who received parenteral ketorolac tromethamine as their primary postoperative pain medication were matched by surgical procedure, age, and sex to 40 patients who did not receive parenteral or oral ketorolac tromethamine. Patient data were collected by chart review, and fiscal information was obtained through hospital computer data bases. Simple t-tests were used to examine between-group differences in outcomes measured by interval scales, and contingency table analyses using the chi-square statistic were used to examine differences in dichotomous and ordinal scale outcomes. Parenteral ketorolac was prescribed in accordance with Food and Drug Administration (FDA)-approved guidelines 55% of the time, but actual patient use was in accordance with FDA guidelines 75% of the time. There were no differences between groups in any measure of analgesia prescription. Significant findings between patients receiving ketorolac tromethamine versus controls included a longer length of hospital stay (14.6 +/- 13.0 v 9.2 +/- 8.3 days), higher pharmacy cost ($69. 57 +/- $87.00 v $5.20 +/- $6.10), and higher use of histamine-2 antagonists (59.0% v 35.0%). Subgroup analysis showed that patients with a principle gastrointestinal diagnosis had the greatest differences in length of stay. Prospective studies are needed to assess patient outcomes when parenteral ketorolac tromethamine is prescribed for postoperative pain. PMID- 10099056 TI - Relative bioavailability of Cardizem CD and Tiazac controlled-release diltiazem dosage forms after single and multiple dosing in healthy volunteers. AB - The purpose of this study was to determine the relative bioavailability of Cardizem CD compared to Tiazac after single and multiple doses. Twenty-three healthy males were enrolled in this open-label, two-way, complete crossover investigation. During each of the two treatment periods, a single 240-mg dose of diltiazem HCl was given in the morning on study day 1, then once daily on days 3 through 9. Serial plasma samples were obtained and pharmacokinetic parameters were calculated from the single-dose and steady-state concentration-time profiles. After single doses, mean diltiazem maximum plasma concentration (Cmax ) was 46% higher with the Tiazac formulation compared with Cardizem CD, and the mean area under the plasma concentration-time profile (AUC) was 19% higher with Tiazac. At steady-state, similar Cmax and AUC for the 24-hour dosing interval were found for Cardizem CD and Tiazac. However, Tiazac produced a 21% lower diltiazem minimum plasma concentration, a 28% lower trough concentration (the concentration in the plasma sample obtained just before the daily dose was given), and a 1.5-times higher fluctuation in maximum to minimum diltiazem plasma concentration compared with Cardizem CD. The pharmacokinetic profiles of the two pharmacologically active diltiazem metabolites, desacetyldiltiazem and N desmethyldiltiazem, followed that of parent drug after single and multiple doses of Cardizem CD and Tiazac. From these results, it is concluded that the pharmacokinetic profiles of Tiazac and Cardizem CD are significantly different. PMID- 10099057 TI - Subcutaneous infiltrates induced by injection of mistletoe extracts (Iscador). AB - Iscador, an aqueous extract of Viscum album L., has been widely used as an anti cancer drug for several decades. Mistletoe lectins have the capacity to activate nonspecific defense mechanisms, and lectin-carbohydrate interactions may be involved in clinically applicable immunomodulation. During treatment with whole plant mistletoe extract, an inflammatory reaction usually occurs at the site of the injection, early in therapy. These injection sites were examined histologically. Seven subjects received three subcutaneous injections of Iscador QuFrF or Iscador Qu Spezial (twice 0.1 mg and once 2.5 mg) during 9 days. In all subjects, examination of skin biopsies showed a normal epidermis. The dermal and subcutaneous regions contained a dense perivascular lymphocyte infiltrate and increased monocytes. We could not document any increase of plasma cells, eosinophils, mast cells, neutrophils, or granulocytes, as would be the case for a granulomatous infiltrate. In the blood, we observed a significant increase in neutrophils and monocytes 24 hours after administration of 2.5 mg of Iscador. PMID- 10099058 TI - Effect of montelukast on single-dose theophylline pharmacokinetics. AB - The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist in development for treatment of asthma, on single-dose theophylline plasma concentrations was studied in three separate clinical trials. Montelukast was evaluated at 10 mg once daily (the clinical dosage), 200 mg once daily, and 600 mg (200 mg three times daily). At the clinical dosage, montelukast did not change single-dose theophylline plasma concentration in a clinically important manner. The geometric mean ratios for theophylline area under the plasma concentration versus time curve (AUC0-->infinity ) (0.92) and maximal plasma concentration (Cmax ) (1.04) were well within the predefined and generally accepted bioequivalence range of 0.80 and 1.25. Montelukast decreased theophylline Cmax by 12% and 10%, AUC0-->infinity by 43% and 44%, and elimination half-time by 44% and 39% at 200 mg/d (oral and intravenous, respectively), and at 600 mg/d, montelukast decreased theophylline Cmax by 25%, AUC0-->infinity by 66%, and elimination half-time by 63%. These results show that montelukast at the clinical dosage did not change theophylline pharmacokinetics in a clinically important manner, but at 20- to 60-fold higher dosages, montelukast significantly reduced the theophylline pharmacokinetics parameters; an apparent dosage dependence is suggested. PMID- 10099059 TI - Treatment of Helicobacter pylori infection. AB - Helicobacter pylori infection has been shown to be the principal cause of peptic ulcer disease and has been associated with MALT lymphoma and gastric cancer. Eradication of H. pylori has been shown to change the natural history of peptic ulcer disease by preventing relapse and to reduce health care expenditures when compared with traditional therapy. Two-drug regimens have been superceded by three-drug regimens because they are more effective in eradication. Therapies with the highest efficacy are cost-effective because failed eradication is associated with high costs. PMID- 10099060 TI - University of Miami Division of Clinical Pharmacology Therapeutic Rounds: ischemic renal disease. AB - Ischemic renal disease (IRD) is defined as a significant reduction in glomerular filtration rate and/or loss of renal parenchyma caused by hemodynamically significant renal artery stenosis. IRD is a common and often overlooked clinical entity that presents in the setting of extrarenal arteriosclerotic vascular disease in older individuals with azotemia. IRD is an important cause of chronic renal failure and end-stage renal disease (ESRD), and many patients with a presumed diagnosis of hypertensive nephrosclerosis may actually have undiagnosed ischemic nephropathy as the cause of their ESRD. The primary reason for establishing the diagnosis of IRD is the hope that correction of a renal artery stenosis will lead to improvement of renal function or a delay in progression to ESRD. There are six typical clinical settings in which the clinician could suspect IRD: acute renal failure caused by the treatment of hypertension, especially with angiotensin-converting enzyme inhibitors; progressive azotemia in a patient with known renovascular hypertension; acute pulmonary edema superimposed on poorly controlled hypertension and renal failure; progressive azotemia in an elderly patient with refractory or severe hypertension; progressive azotemia in an elderly patient with evidence of atherosclerotic disease; and unexplained progressive azotemia in an elderly patient. It is important for the clinician to identify IRD, because IRD represents a potentially reversible cause of chronic renal failure in a hypertensive patient. PMID- 10099061 TI - Ciprofloxacin resistance in methicillin-resistant Staphylococcus aureus: associated factors and resistance to other antibiotics. AB - At the University of Illinois Hospital, antibiotic susceptibility testing was retrospectively performed on 254 stored clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates cultured from 1985 through 1990 to characterize resistance to ciprofloxacin and other antibiotics. In case-control analyses, inpatients with and without ciprofloxacin-resistant strains were compared. Ciprofloxacin-resistance increased from 7% before 1988 to 83% in 1990. A sudden increase in resistance to trimethoprim-sulfamethoxazole also occurred in 1988, and by 1990, 65% of strains were resistant to both antibiotics. In 95 patients with recent MRSA isolation (70 acquired nosocomially, 25 acquired in the community), ciprofloxacin resistance was more common in the nosocomial group (80% v 60%, P < 0.05). In that group, no host or in-hospital factors were associated with ciprofloxacin resistance. Among community cases, a greater proportion with ciprofloxacin-resistant MRSA had diabetes mellitus (60% v 0%, P = 0. 002). Thus, with use, ciprofloxacin resistance emerged rapidly in MRSA and developed particularly among strains resistant to trimethoprim-sulfamethoxazole. Combined resistance to these antibiotics, uncommon in previous reports, severely limits oral therapy as an option for MRSA carriage or infection. PMID- 10099062 TI - Metoclopramide enhances labetalol-induced antihypertensive effect during handgrip in hypertensive patients. AB - The effects of metoclopramide, labetalol, and metoclopramide plus labetalol treatments on baseline cardiovascular parameters and isometric handgrip-induced changes were evaluated in 11 hypertensive subjects. Although all treatments were effective in reducing resting systolic (SBP) and diastolic (DBP) blood pressures, the combination of metoclopramide and labetalol appeared to provide a greater decrease (changes in SBP/DBP: 15/11 mm Hg, P < 0.05; from 149 +/- 4/95 +/- 4 mm Hg to 134 +/- 5/84 +/- 3 mm Hg) than did labetalol alone (changes in SBP/DBP: 10/9 mm Hg, P < 0.05; from 149 +/- 4/95 +/- 4 to 139 +/- 4/86 +/- 3 mm Hg). At 2 minutes, handgrip increased blood pressure on placebo (changes in SBP/DBP: 34/7 mm Hg, P < 0. 001). In the presence of metoclopramide and metoclopramide plus labetalol, however, handgrip induced lesser increases in blood pressure (changes in SBP/DBP: 23/7 mm Hg, P < 0.01, and 18/4 mm Hg, P < 0.01, for metoclopramide and metoclopramide plus labetalol treatments). We conclude that (1) metoclopramide lowers blood pressure in hypertensive patients; (2) metoclopramide attenuates blood pressure response to isometric handgrip; and (3) both compounds, labetalol and metoclopramide, seem to have a pharmacologic interaction concerning blood pressure decrease. A clinical significance is suggested for the metoclopramide effect. PMID- 10099063 TI - Prospective assessment of an intervention to rationalize prescribing of nonsteroidal anti-inflammatory drugs. AB - Guidelines for the prescription of nonsteroidal anti-inflammatory drugs (NSAIDs), drawn in the Health Ministry and published by the Drug Regulatory Agency, were introduced in the emergency department of a university hospital. The main objective was to determine, in this prospective, before-and-after study, whether a teaching program could help doctors improve their NSAID prescribing practices. Correct prescribing included limiting NSAIDs to their most admitted indications, avoiding their prescription to accident-prone patients, and reducing treatment duration and daily dosage. An overall reduction of NSAID prescriptions was also expected. Prescribing errors were divided into violations (prescribing when unwarranted or against a contraindication) and inadequacies (if the compound or treatment schedule was not suited to the condition addressed). We measured the effect of the intervention 45 days after its initiation. Twenty-seven doctors participated in the two study phases (595 and 520 patients) and wrote 50 NSAID prescriptions in each (8.4% and 9. 6% of patients, respectively; P = 0.44). Prescribing errors decreased from 20% to 14% of cases (P = 0.60). There was a trend toward more prescriptions conforming to the Drug Regulatory Agency guidelines (P = 0.08). Treatment duration decreased from 10.4 +/- 5. 4 to 9.0 +/- 4.0 days (P = 0.03). The teaching of guidelines has helped physicians to improve their NSAID prescribing practices; however, it did not succeed in curbing the overall prescription rate. Unrestricted lists that include soft indications may influence younger doctors into prescribing more NSAIDs. PMID- 10099064 TI - Effect of benazepril on endothelial function in previously untreated hypertensive patients. The Working Group of Cardiology of the Academic Committee of Veszprem, Hungary. AB - The aim of this study was to determine whether angiotensin-converting enzyme inhibitor administration improves the endothelial function of patients with previously untreated essential hypertension. Using high-resolution ultrasonography, we measured the arteria brachialis diameter at rest, during reactive hyperemia (endothelium-dependent flow-mediated dilatation [FMD]), and after sublingual nitroglycerin (endothelium-independent dilatator). Twenty-one previously untreated hypertensive patients participated in the study (13 men, 8 women; mean age, 39.1 +/- 15 years). In the 21 patients, the basal FMD was 5.02% +/- 4.1%. Two hours after the first 10-mg benazepril dose, the FMD was 6.67% +/- 3.9%, and after 1 month of daily 10-mg benazepril administration, the FMD was 5.59% +/- 2.9%. These changes were not significant compared with the baseline value. Nine patients had relatively normal FMD (>5%), whereas the other 12 patients had abnormal FMD (<5%) at baseline. In the latter group, the first 10 mg benazepril produced significant improvement in FMD, from 2.4% +/- 2.5% to 5.08% +/- 2.4% (P < 0.05), but 10 mg benazepril daily for 1 month resulted in no further improvement (4.78% +/- 2.7%) compared with the acute effect. No difference was found between groups with regard to age, gender, blood pressure, blood lipids, and basal arteria brachialis diameter. The previously untreated patients with essential hypertension have endothelial dysfunction, but individual differences were found. The angiotensin-converting enzyme inhibitor treatment improves endothelial function only in those patients who had endothelial dysfunction before the treatment. PMID- 10099065 TI - Nebivolol versus nifedipine in the treatment of essential hypertension: a double blind, randomized, comparative trial. AB - The efficacy and acceptability of 5 mg nebivolol once daily, a long-acting, vasodilating cardioselective beta blocker that additionally facilitates the L arginine/nitric oxide system, was assessed in a double-blind, randomized trial in comparison with 20 mg nifedipine retard twice daily in patients with essential hypertension. At 2 weeks of treatment, nebivolol was significantly more effective. Thereafter, both drugs effectively and similarly lowered systolic and diastolic pressures without orthostatic effect. Nebivolol had a trough-to-peak antihypertensive effect ratio of 90%. Nifedipine gave the expected side effects of headache, flushing, and edema. Nebivolol was well tolerated. Nebivolol slightly but significantly lowered heart rate. Neither drug adversely affected plasma levels of lipids. PMID- 10099066 TI - Comparative efficacy and safety of once-daily versus twice-daily loratadine pseudoephedrine combinations versus placebo in seasonal allergic rhinitis. AB - The objective of this study was to compare the efficacy and safety of Claritin-D 24 Hour (once daily) with that of Claritin-D 12 Hour (twice daily) and placebo in the treatment of patients with seasonal allergic rhinitis (SAR). In this double blind, placebo-controlled, multicenter study, 469 patients with moderate-to severe SAR symptoms were treated for 2 weeks with one of the following: Claritin D 24 Hour (a combination tablet formulation of loratadine 10 mg in the coating and pseudoephedrine sulfate 240 mg in an extended-release core), Claritin-D 12 Hour (a combination tablet formulation of loratadine 5 mg in the tablet coating and 120 mg pseudoephedrine sulfate, 60 mg in the coating and 60 mg in the core), or placebo. Claritin-D 24 Hour and Claritin-D 12 Hour were consistently superior to placebo (P < 0.01) in reducing total, nasal, and nonnasal symptom scores. Patients in the Claritin-D 24 Hour and Claritin-D 12 Hour groups also had significantly greater (P 90% decrease in virus load in 3 of them. Protection from mucosal rectal infection with SIV was significantly associated with an increase in the CD8 suppressor factor (which was generated by the iliac lymph node), RANTES, and MIP-1beta (P<.01). PMID- 10099127 TI - Mucosal vaccination strategies for women. AB - Women were immunized orally, rectally, or vaginally with a recombinant cholera toxin B-containing vaccine to determine which of these mucosal immunization routes generate the greatest levels of antibody in the female genital tract and rectum. ELISA was used to measure concentrations of cholera toxin B-specific IgA and IgG antibody in serum and secretions before and after three immunizations. Each immunization route similarly increased specific IgG in serum and specific IgA in saliva. Only the vaginal route increased IgA antibodies in genital tract secretions and could be shown to induce a local IgG response. However, vaginal immunization failed to produce antibody in the rectum. In a similar fashion, rectal immunization elicited highest concentrations of locally derived IgA and IgG antibody in the rectum but was ineffective for generating antibody in the genital tract. The data suggest that local immunization may induce the greatest immune responses in the female genital tract and rectum of humans. PMID- 10099128 TI - Catalytic promiscuity and the evolution of new enzymatic activities. AB - Several contemporary enzymes catalyze alternative reactions distinct from their normal biological reactions. In some cases the alternative reaction is similar to a reaction that is efficiently catalyzed by an evolutionary related enzyme. Alternative activities could have played an important role in the diversification of enzymes by providing a duplicated gene a head start towards being captured by adaptive evolution. PMID- 10099129 TI - Small molecule cytokine mimetics. AB - A number of reports describe small peptides, and even bona fide small organic molecules, that activate homodimeric cytokine receptors and show cytokine-like activity in vitro and in vivo. These cases can be examined in light of the mechanistic and thermodynamic principles that govern cytokine-receptor activation. PMID- 10099130 TI - Bifunctional inhibitors of the trypsin-like activity of eukaryotic proteasomes. AB - BACKGROUND: The 20S proteasome is a multicatalytic protease complex that exhibits trypsin-like, chymotrypsin-like and post-glutamyl-peptide hydrolytic activities associated with the active sites of the beta2, beta5 and beta1 subunits, respectively. Modulation of these activities using inhibitors is essential for a better understanding of the proteasome's mechanism of action. Although there are highly selective inhibitors of the proteasome's chymotryptic activity, inhibitors of similar specificity have not yet been identified for the other activities. RESULTS: The X-ray structure of the yeast proteasome reveals that the sidechain of Cys118 of the beta3 subunit protrudes into the S3 subsite of the beta2 active site. The location of this residue was exploited for the rational design of bidentated inhibitors containing a maleinimide moiety at the P3 position for covalent linkage to the thiol group and a carboxy-terminal aldehyde group for hemiacetal formation with the Thr1 hydroxyl group of the active site. Structure based modelling was used to determine the optimal spacing of the maleinimide group from the P2-P1 dipeptide aldehydes and the specificity of the S1 subsite was exploited to limit the inhibitory activity to the beta2 active site. X-ray crystallographic analysis of a yeast proteasome-inhibitor adduct confirmed the expected irreversible binding of the inhibitor to the P3 subsite. CONCLUSIONS: Maleoyl-beta-alanyl-valyl-arginal is a new type of inhibitor that is highly selective for the trypsin-like activity of eukaryotic proteasomes. Despite the reactivity of the maleinimide group towards thiols, and therefore the limited use of this inhibitor for in vitro studies, it might represent an interesting new biochemical tool. PMID- 10099131 TI - Molecular basis of Celmer's rules: the role of two ketoreductase domains in the control of chirality by the erythromycin modular polyketide synthase. AB - BACKGROUND: Polyketides are compounds that possess medically significant activities. The modular nature of the polyketide synthase (PKS) multienzymes has generated interest in bioengineering new PKSs. Rational design of novel PKSs, however, requires a greater understanding of the stereocontrol mechanisms that operate in natural PKS modules. RESULTS: The N-acetyl cysteamine (NAC) thioester derivative of the natural beta-keto diketide intermediate was incubated with DEBS1-TE, a derivative of the erythromycin PKS that contains only modules 1 and 2. The reduction products of the two ketoreductase (KR) domains of DEBS1-TE were a mixture of the (2S, 3R) and (2R,3S) isomers of the corresponding beta-hydroxy diketide NAC thioesters. Repeating the incubation using a DEBS1-TE mutant that only contains KR1 produced only the (2S,3R) isomer. CONCLUSIONS: In contrast with earlier results, KR1 selects only the (2S) isomer and reduces it stereospecifically to the (2S, 3R)-3-hydroxy-2-methyl acyl product. The KR domain of module 1 controls the stereochemical outcome at both methyl-and hydroxyl bearing chiral centres in the hydroxy diketide intermediate. Earlier work showed that the normal enzyme-bound ketoester generated in module 2 is not epimerised, however. The stereochemistry at C-2 is therefore established by a condensation reaction that exclusively gives the (2R)-ketoester, and the stereo-chemistry at C 3 by reduction of the keto group. Two different mechanisms of stereochemical control, therefore, operate in modules 1 and 2 of the erythromycin PKS. These results should provide a more rational basis for designing hybrid PKSs to generate altered stereochemistry in polyketide products. PMID- 10099132 TI - Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens. AB - BACKGROUND: The development of estrogen pharmaceutical agents with appropriate tissue-selectivity profiles has not yet benefited substantially from the application of combinatorial synthetic approaches to the preparation of structural classes that are known to be ligands for the estrogen receptor (ER). We have developed an estrogen pharmacophore that consists of a simple heterocyclic core scaffold, amenable to construction by combinatorial methods, onto which are appended 3-4 peripheral substituents that embody substructural motifs commonly found in nonsteroidal estrogens. The issue addressed here is whether these heterocyclic core structures can be used to prepare ligands with good affinity for the ER. RESULTS: We prepared representative members of various azole core structures. Although members of the imidazole, thiazole or isoxazole classes generally have weak binding for the ER, several members of the pyrazole class show good binding affinity. The high-affinity pyrazoles bear close conformational relationship to the nonsteroidal ligand raloxifene, and they can be fitted into the ligand-binding pocket of the ER-raloxifene X-ray structure. CONCLUSIONS: Compounds such as these pyrazoles, which are novel ER ligands, are well suited for combinatorial synthesis using solid-phase methods. PMID- 10099133 TI - The identification of myriocin-binding proteins. AB - BACKGROUND: Myriocin is a natural product that potently induces apoptosis of a murine cytotoxic T lymphocyte cell line (CTLL-2) and inhibits a serine palmitoyltransferase (SPT) activity that has been detected in cell extracts and is thought to initiate sphingolipid biosynthesis. Because SPT has never been biochemically purified and a comprehensive appraisal of myriocin-binding proteins has not been conducted, we isolated specific targets using myriocin-based affinity chromatography. RESULTS: Myriocin derivatives were synthesized and evaluated using CTLL-2 proliferation and SPT activity assays. Guided by these results, affinity chromatography matrices were prepared and two specific myriocin binding proteins were isolated from CTLL-2 lysates. Analyses of these polypeptides establish conclusively that they are murine LCB1 and LCB2, mammalian homologs of two yeast proteins that have been genetically linked to sphingolipid biosynthesis. CONCLUSION: The ability of myriocin-containing matrices to bind factors that have SPT activity and the exclusive isolation of LCB1 and LCB2 as myriocin-binding proteins demonstrates that the two proteins are directly responsible for SPT activity and that myriocin acts directly upon these polypeptides. PMID- 10099134 TI - Extremely high and specific activity of DNA enzymes in cells with a Philadelphia chromosome. AB - BACKGROUND: Chronic myelogenous leukemia (CML) results from chromosome 22 translocations (the Philadelphia chromosome) that creates BCR-ABL fusion genes, which encode two abnormal mRNAs (b3a2 and b2a2). Various attempts to design antisense oligonucleotides that specifically cleave abnormal L6 BCR-ABL fusion mRNA have not been successful. Because b2a2 mRNA cannot be effectively cleaved by hammerhead ribozymes near the BCR-ABL junction, it has proved very difficult to engineer specific cleavage of this chimeric mRNA. Nonspecific effects associated with using antisense molecules make the use of such antisense molecules questionable. RESULTS: The usefulness of DNA enzymes in specifically suppressing expression of L6 BCR-ABL mRNA in mammalian cells is demonstrated. Although the efficacy of DNA enzymes with natural linkages decreased 12 hours after transfection, partially modified DNA enzymes, with either phosphorothioate or 2' O-methyl groups at both their 5' and 3' ends, remained active for much longer times in mammalian cells. Moreover, the DNA enzyme with only 2'-O-methyl modifications was also highly specific for abnormal mRNA. CONCLUSIONS: DNA enzymes with 2'-O-methyl modifications are potentially useful as gene inactivating agents in the treatment of diseases such as CML. In contrast to conventional antisense DNAs, some of the DNA enzymes used in this study were highly specific and cleaved only abnormal BCR-ABL mRNA. PMID- 10099135 TI - Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyces lavendulae NRRL 2564. AB - BACKGROUND: The mitomycins are natural products that contain a variety of functional groups, including aminobenzoquinone- and aziridine-ring systems. Mitomycin C (MC) was the first recognized bioreductive alkylating agent, and has been widely used clinically for antitumor therapy. Precursor-feeding studies showed that MC is derived from 3-amino-5-hydroxybenzoic acid (AHBA), D glucosamine, L-methionine and carbamoyl phosphate. A genetically linked AHBA biosynthetic gene and MC resistance genes were identified previously in the MC producer Streptomyces lavendulae NRRL 2564. We set out to identify other genes involved in MC biosynthesis. RESULTS: A cluster of 47 genes spanning 55 kilobases of S. lavendulae DNA governs MC biosynthesis. Fourteen of 22 disruption mutants did not express or overexpressed MC. Seven gene products probably assemble the AHBA intermediate through a variant of the shikimate pathway. The gene encoding the first presumed enzyme in AHBA biosynthesis is not, however, linked within the MC cluster. Candidate genes for mitosane nucleus formation and functionalization were identified. A putative MC translocase was identified that comprises a novel drug-binding and export system, which confers cellular self-protection on S. lavendulae. Two regulatory genes were also identified. CONCLUSIONS: The overall architecture of the MC biosynthetic gene cluster in S. lavendulae has been determined. Targeted manipulation of a putative MC pathway regulator led to a substantial increase in drug production. The cloned genes should help elucidate the molecular basis for creation of the mitosane ring system, as well efforts to engineer the biosynthesis of novel natural products. PMID- 10099136 TI - Gene therapy approaches to HIV-infection: immunological strategies: use of T bodies and universal receptors to redirect cytolytic T-cells. AB - Combined regimens of classical antiviral treatments have not, until now, lead to the eradication of HIV-1. A specific anti-HIV immune response may have to be boosted or transferred to patients after suppression of viral replication, in order to eradicate residual infected cells from their sanctuaries. Cytotoxic T cells engineered to express recombinant chimeric receptors can be redirected against HIV-infected cells and could represent the basis of a new type of immunotherapy. Several HIV epitopes have been targeted successfully in vitro. Two types of binding domains (antibody fragments, CD4) fused with various signal transducing units (zeta chain of the CD3 complex, Fc epsilon RI gamma chain) have been tested for their ability to redirect effector cells to HIV infected lymphocytes. CD4-zeta-expressing myeloid and natural killer cells conferred SCID mice protection against challenge with tumor cells expressing HIV-env. Finally, the safety of the adoptive transfer of syngeneic CD4-zeta -modified T cells in HIV-infected individuals is currently under evaluation. PMID- 10099137 TI - The Alzheimer's plaques, tangles and memory deficits may have a common origin. Part V: why is Ca2+ signal lower in the disease? AB - The state of intracellular Ca2+ in aging and in Alzheimer's disease (AD) is a key but highly controversial issue and direct measurement of the Ca2+ fluctuations in the living human brain has not been possible thus far. We therefore further considered this issue from a theoretical perspective. Ca2+ signaling mediates many life processes including: fertilization, gene expression, cell division, growth and differentiation, muscle contraction, neurotransmission and memory formation. It is common observation that these Ca2+-mediated activities in human life are highest in young adulthood but diminish during aging, indicating that Ca2+ signaling potency (or intracellular Ca2+ levels) must be decreased in aging and AD. A potential explanation for this phenomenon could be that the Ca2+ mediated processes are also energy-dependent processes, because they all utilize the free energy reserve of the body for "useful" work, and it is known that Ca2+ gradient formation and Ca2+ movement across cell membrane are driven by energy dependent systems. This intimate relationship between energy and Ca2+ signaling implies that the potency of Ca2+ signaling would be affected by changes of energy levels, which would necessarily decline in aging. These may underlie the deficit of Ca2+ signaling in the presymptomatic stage of AD. These considerations also support our view that Abeta and tau accumulation in AD is the result of inactivation of calcium-dependent enzymes, rather than overactivation of beta/( secretases and some tau kinases. This is because most enzyme activities should be diminished, rather than overactivated, during aging. Furthermore, since energy/Ca2+ deficit is a natural event in aging, it follows that the accumulation of Abeta and tau would be initiated "spontaneously" as a result of "natural" aging, not necessarily by a "pathological" factor. Based on the analyses, we propose that intracellular Ca2+ deficit is most likely the primary and common cause (among the many contributing, secondary or individualized factors) for the plaque and tangle accumulation underlying sporadic AD. And we predict that this contention, though in contrast to many competing models, will be confirmed by the proposed experimentation in the future. PMID- 10099138 TI - Molecular surface sequence analysis of several E. coli enzymes and implications for existence of casein kinase-2 bacterial predecessor. AB - Casein kinase-2 (CK2) is known as pleiotropic eukaryotic protein kinase that phosphorylates significant number of cellular proteins. Not all functions of the protein were registered up to the present time. However, it is known that this Ser/Thr-specific kinase is involved in the cell cycle progression and is essentially required for the eukaryotic cell viability. Fully automated molecular surface analysis procedure for identification of functionally significant surface residues and sequences on the base of protein spatial structure was elaborated. Using the elaborated procedure, several E. coli enzymes spatial structures and sequences were investigated. It was found that most of the casein kinase 2 potential sites found in sequences of enzymes are accessible for modification. Four of the 5 structures studied have CK2 consensus sites that may definitely influence the activity of the enzyme upon phosphorylation. Some of the potential "CK2-sites" has amino acid contents characteristic for physiological substrates of casein kinase 2 in eukaryotes. The main point of the elaborated method and the structural evidence for existence of a putative casein kinase E. coli predecessor or a protein with similar kinase activity are discussed. Physiological, biochemical, structural and evolutionary aspects of the existence of the putative predecessor are considered. PMID- 10099139 TI - The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. AB - BACKGROUND: To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. METHODS: North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic regression analysis was used to adjust for other factors known to be associated with vertical transmission. RESULTS: The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. CONCLUSIONS: The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine. PMID- 10099140 TI - Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. AB - BACKGROUND AND METHODS: We compared propranolol therapy and endoscopic ligation for the primary prevention of bleeding from esophageal varices. This prospective, controlled trial included consecutive eligible patients who had large varices (>5 mm in diameter) that were at high risk for bleeding. The patients were assigned to either propranolol therapy, at a dose sufficient to decrease the base-line heart rate by 25 percent, or variceal ligation, to be performed weekly until the varices were obliterated or so reduced in size that it was not possible to continue treatment. RESULTS: Of the 89 patients, 82 of whom had cirrhosis of the liver, 44 received propranolol and 45 underwent variceal ligation. The mean (+/ SD) duration of follow-up in each group was 14+/-9 and 13+/-10 months, respectively. The mean time required to achieve an adequate reduction in the heart rate was 2.5+/-1.7 days; the mean number of sessions needed to complete variceal ligation was 3.2+/-1.1. After 18 months, the actuarial probability of bleeding was 43 percent in the propranolol group and 15 percent in the ligation group (P=0.04). Twelve patients in the propranolol group and four in the ligation group had bleeding. Three of the four in the ligation group had bleeding before their varices had been obliterated. Nine patients in the ligation group had recurrent varices, a mean of 3.7 months after the initial treatment. Five patients in each group died; bleeding from the varices was the cause of death of four patients in the propranolol group and of three in the ligation group. There were no serious complications of variceal ligation; in the propranolol group, treatment was stopped in two patients because of side effects. CONCLUSIONS: In patients with high-risk esophageal varices, endoscopic ligation of the varices is safe and more effective than propranolol for the primary prevention of variceal bleeding. PMID- 10099141 TI - Annexin II and bleeding in acute promyelocytic leukemia. AB - BACKGROUND: Acute promyelocytic leukemia (APL) is associated with a hemorrhagic disorder of unknown cause that responds to treatment with all-trans-retinoic acid. METHODS: We studied a newly described receptor for fibrinolytic proteins, annexin II, in cells from patients with APL or other leukemias. We examined initial rates of in vitro generation of plasmin by tissue plasminogen activator (t-PA) in the presence of APL cells that did or did not have the characteristic translocation of APL, t(15;17). We also determined the effect of all-trans retinoic acid on the expression of annexin II and the generation of cell-surface plasmin. RESULTS: The expression of annexin II, as detected by a fluorescein tagged antibody, was greater on leukemic cells from patients with APL than on other types of leukemic cells (mean fluorescence intensity, 6.9 and 2.9, respectively; P<0.01). The t(15;17)-positive APL cells stimulated the generation of cell-surface, t-PA-dependent plasmin twice as efficiently as the t(15;17) negative cells. This increase in plasmin was blocked by an anti-annexin II antibody and was induced by transfection of t(15;17)-negative cells with annexin II complementary DNA. The t(15;17)-positive APL cells contained abundant messenger RNA for annexin II, which disappeared through a transcriptional mechanism after treatment with all-trans-retinoic acid. CONCLUSIONS: Abnormally high levels of expression of annexin II on APL cells increase the production of plasmin, a fibrinolytic protein. Overexpression of annexin II may be a mechanism for the hemorrhagic complications of APL. PMID- 10099142 TI - Early inhaled glucocorticoid therapy to prevent bronchopulmonary dysplasia. AB - BACKGROUND: The safety and efficacy of inhaled glucocorticoid therapy for asthma stimulated its use in infants to prevent bronchopulmonary dysplasia. We tested the hypothesis that early therapy with inhaled glucocorticoids would decrease the frequency of bronchopulmonary dysplasia in premature infants. METHODS: We conducted a randomized, multicenter trial of inhaled beclomethasone or placebo in 253 infants, 3 to 14 days old, born before 33 weeks of gestation and weighing 1250 g or less at birth, who required ventilation therapy. Beclomethasone was delivered in a decreasing dosage, from 40 to 5 microg per kilogram of body weight per day, for four weeks. The primary outcome measure was bronchopulmonary dysplasia at 28 days of age. Secondary outcomes included bronchopulmonary dysplasia at 36 weeks of postmenstrual age, the need for systemic glucocorticoid therapy, the need for bronchodilator therapy, the duration of respiratory support, and death. RESULTS: One hundred twenty-three infants received beclomethasone, and 130 received placebo. The frequency of bronchopulmonary dysplasia was similar in the two groups: 43 percent in the beclomethasone group and 45 percent in the placebo group at 28 days of age, and 18 percent in the beclomethasone group and 20 percent in the placebo group at 36 weeks of postmenstrual age. At 28 days of age, fewer infants in the beclomethasone group than in the placebo group were receiving systemic glucocorticoid therapy (relative risk, 0.6; 95 percent confidence interval, 0.4 to 1.0) and mechanical ventilation (relative risk, 0.8; 95 percent confidence interval, 0.6 to 1.0). CONCLUSIONS: Early beclomethasone therapy did not prevent bronchopulmonary dysplasia but was associated with lower rates of use of systemic glucocorticoid therapy and mechanical ventilation. PMID- 10099144 TI - The expanding spectrum of G protein diseases. PMID- 10099145 TI - Management of sickle cell disease. PMID- 10099146 TI - Elective cesarean delivery to reduce the transmission of HIV. PMID- 10099147 TI - Primary prevention of bleeding from esophageal varices. PMID- 10099148 TI - "Annexinopathies"--a new class of diseases. PMID- 10099149 TI - Bronchopulmonary dysplasia--no simple solution. PMID- 10099151 TI - Synthesis of theophylline-polyrotaxane conjugates and their drug release via supramolecular dissociation. AB - Theophylline-polyrotaxane conjugates were synthesized by coupling theophylline with alpha-cyclodextrins (alpha-CDs) in the polyrotaxane. The polyrotaxane is a molecular assembly in which many alpha-CDs are threaded onto a poly(ethylene glycol) (PEG) chain capped with L-phenylalanine (L-Phe). Theophylline-7-acetic acid was activated by coupling with 4-nitrophenol, and then ethylenediamine was allowed to react with the active ester in order to obtain N-aminoethyl theophylline-7-acetoamide. This derivative was coupled with a 4-nitrophenyl chloroformate-activated polyrotaxane to obtain the theophylline-polyrotaxane conjugates. The conjugates formed a specific association under physiological conditions, depending upon interactions between the theophylline molecules and/or the terminal l-Phe moiety in the conjugates. In vitro degradation of the conjugates revealed that theophylline-immobilized alpha-CDs were completely released by hydrolysis of the terminal peptide linkage in the polyrotaxane. This result indicates that the association of the conjugates does not induce the steric hindrance but rather enhances the accessibility of enzymes to the terminal peptide linkages. It is suggested that our designed drug-polyrotaxane conjugates can release the drugs via the dissociation of the supramolecular structure without steric hindrance of enzymatic accessibility to the terminal peptide linkages. PMID- 10099153 TI - Release of 5-amino salicylic acid from acrylic type polymeric prodrugs designed for colon-specific drug delivery. AB - New acrylic type polymeric systems having degradable ester or amide bonds linked to the bioactive agent 5-amino salicylic acid (5-ASA), were prepared and evaluated as materials for colon-specific drug delivery. Methacryloyloxyethyl 5 amino salicylate (MOES), and N-methacryloylaminoethyl 5-amino salicylamide (MAES) were prepared as the polymerizable derivatives of 5-ASA using activated ester methodology. The drug-containing monomers were free radically copolymerized with methacrylic acid or hydroxyethyl methacrylate, utilizing azobisisobutyronitrile as initiator. The polymer bearing 5-ASA units as side substituents of the acrylic backbone were obtained in the form of poly pendent esters or poly pendent amides. The drug release studies were performed by hydrolysis in buffered solutions (pH 1, 7.2, 8.5), or simulated intestinal fluid containing pancreatin to measure the chemical degradation expected to occur in the intestinal tract. The release profiles indicated that the hydrolytic behavior of polymers strongly depends on their degree of swelling, type of comonomer, and the nature of hydrolyzable bond. Implication of the results for use of these polymers for colon targeting are discussed. PMID- 10099152 TI - Development of nonionic surfactant/phospholipid o/w emulsion as a paclitaxel delivery system. AB - Paclitaxel is an anticancer agent with low aqueous solubility. More extensive clinical use of this drug is somewhat delayed due to lack of appropriate delivery vehicles. An attempt was made to adopt an o/w emulsion as the drug carrier which incorporated paclitaxel in the triacylglycerol stabilized by a mixed-emulsifier system. A suitable formulation was found in this study: 0.75 mg/ml paclitaxel, 10% (w/v) oil blend, 4% (w/v) EPC, 3% (w/v) Tween 80 in 2.25% (w/v) glycerol solution. The formulated emulsion has very good stability when stored at 4 degrees C, and the paclitaxel containment efficiency can be maintained above 95% and the mean emulsion diameter around 150 nm for at least 3 months. Paclitaxel emulsion displayed cytotoxicity against HeLa cells with IC50 at 30 nM. The average life span of ascitic-tumor-bearing mice was prolonged significantly by the treatment of paclitaxel-emulsion (P<0.05). The formulated emulsion is a promising carrier for paclitaxel and other lipophilic drugs. PMID- 10099154 TI - Flow cytometric and optical microscopic evaluation of poly(D, L-lactide-co glycolide) microspheres phagocytosis by pig alveolar macrophages. AB - The phagocytosis of fluorescent poly(D,L-lactide-co-glycolide) microspheres by fresh and frozen pig alveolar macrophages was investigated by optical microscopy on adherent cell culture and by flow cytometry with cell suspension. The kinetic of phagocytosis was studied on a 360 min period as a function of the ratio between microspheres and macrophages (MS:AM ratio from 1:1 to 10:1). No difference of phagocytosis between fresh and frozen macrophages was observed whatever the MS:AM ratio following flow cytometric evaluation while a significant phagocytosis pattern was noticed following optical microscopic evaluation for the highest ratio. The intensity of phagocytosis was dependent on the duration of incubation and dependent, but not proportionally, to the MS:AM ratio showing that the highest efficiency was obtained with the MS:AM ratio of 1:1. Flow cytometry analysis has shown a correlation between cell population and fluorescent events suggesting that phagocytosis of nonfluorescent antigen-loaded particles with different characteristics could be investigated. PMID- 10099155 TI - The potential use of mixed films of pectin, chitosan and HPMC for bimodal drug release. AB - Polyelectrolyte complex (PEC) formation between pectin USP and chitosan was investigated by examining the viscosities of supernatant solutions after removal of the precipitated complex. The amount of pectin, relative to chitosan, required for optimal PEC formation increased as the pH of the solution was reduced. At pH values of less than 1.3, there was no evidence for the formation of the PEC. Swelling studies conducted on pectin/chitosan films, showed minimal swelling occurring when the pectin:chitosan weight ratio was optimal for PEC formation, suggesting the formation of the PEC in situ. The permeability of the films to paracetamol as a model compound was dependent on film composition and was markedly increased after exposure to pectinolytic enzymes, used to mimic conditions in the colon. It may be implied from the results that similar formulations, applied as a film coat to tablets, could be used to achieve bimodal drug release with colonic conditions acting as a trigger for an increased rate of release. PMID- 10099156 TI - Modulated release of IdUrd from poly (D,L-lactide-co-glycolide) microspheres by addition of poly (D,L-lactide) oligomers. AB - This paper reports the release characteristics of a radiosensitizer, 5-iodo-2' deoxyuridine (IdUrd), from poly (D,L-lactide-co-glycolide) 50: 50 (PLGA) microparticles obtained by a phase separation technique. Poly (D,L-lactide) oligomers (D,L-PLA) were incorporated into the PLGA matrix in order to accelerate the overall drug release rate and regulate the triphasic release profile exhibited by the standard PLGA microparticles. For D,L-PLA (800), the burst effect was large and the IdUrd release was complete between 28 and 35 days. These results were attributed to rapid pore formation on the periphery of the microsphere in the early stages of incubation, due to hydrosolubility of the smallest oligomers (D,L-PLA (800)). In the case of D,L-PLA (1,100), drug release occurred over a six week period, the standard time course of conventional radiation therapy. The period during which the radiosensitizer was incorporated in human brain tumor cell nuclei after its entrapment in biodegradable microspheres was determined by using an organotypical tissue culture. The presence of radiosensitizer in the DNA of tumor cell nuclei was detected by immunohistochemical labelling of tumor fragments. IdUrd release from standard microspheres (7+/-0.5 weeks) was longer than from oligomer-containing batches. For D,L-PLA (800)-containing microspheres, the radiosensitizer was entirely released within 4. 5+/-0.5 weeks. The microspheres containing D,L-PLA (1,100) allowed an IdUrd release over a 5 to 6 week period. The ex vivo data were consistent with the in vitro findings in terms of release duration. PMID- 10099157 TI - An analysis of solute structure-human epidermal transport relationships in epidermal iontophoresis using the ionic mobility: pore model. AB - This study sought to examine the extent the ionic mobility-pore model, used to describe epidermal iontophoretic structure-permeability relationships, could describe a range of published iontophoretic data. The model incorporates, as determinants of iontophoretic transport, solute size, solute mobility, total current applied, presence of extraneous ions, determined by conductivities of both donor and receptor solutions, permselectivity of the epidermis, as well as a solute pore interaction term which together provided an excellent regression for iontophoretic permeability. The 'pore' radii for solute transport estimated from literature iontophoretic permeabilities using the model ranged from 6.8 to 17 A depending on the degree of hydration and conformation of solute assumed. The pore size range is consistent with transport through the polar intercellular and transappendageal pathway for transport. The pore restriction form of the model better describes the data obtained to date than other models described previously (Yoshida, N.H., Roberts, M.S., Solute molecular size and transdermal iontophoresis across excised human skin. J. Control. Release 25 (1993) 177-195). PMID- 10099158 TI - Adsorption of serum albumin to thin films of poly(lactide-co-glycolide). AB - Protein adsorption has been implicated in the variability of drug release from biodegradable microspheres. We used optical reflectometry to measure the extent and kinetics of bovine serum albumin (BSA) adsorption to smooth spin-cast films prepared from two poly(lactide-co-glycolide) (PLG) samples that have different end-groups, one being a hydrophilic carboxylic end group and the other a hydrophobic ester end group. One of us has previously shown that these end-groups influence microsphere degradation (Tracy et al. , 1998, Factors affecting the degradation rate of poly(lactide-co-glycolide) microspheres in vivo and in vitro. Biomaterials: submitted for publication.). Both films were moderately hydrophobic, and their wettability was independent of the type of end-group. BSA adsorbed readily to both native PLG films, attaining as much as 50% surface coverage by area and was insensitive to the type of end-group. Aging the films in water for 24 h prior to BSA exposure decreased the hydrophobicity of the films and this in turn correlated with a significant decrease in the initial BSA adsorption rate. This was consistent with the often-observed trend that surface hydrophobicity favors protein adsorption. In spite of the lower adsorption affinity revealed by this decreased initial adsorption rate, the final adsorbed amounts on the aged films exceeded those attained on native films, presumably due to the increase in total surface area produced by partial PLG erosion. PMID- 10099159 TI - The percutaneous penetration of prostaglandin E1 and its alkyl esters. AB - The percutaneous delivery of PGE1 and its alkyl esters in alcoholic saline solution through hairless mouse skin was compared. The quantification of alkyl esters was based on the same principle as that for PGE1, which was converted to PGB1 to enhance the sensitivity and minimize the interference. Results showed that it was PGE1 that appeared in the receiver compartment for all alkyl esters examined. The flux of all alkyl esters of PGE1 in the same concentration was higher than PGE1 itself at most of saline vehicle with various fractions of alcohol. The maximal flux for a fixed concentration of each alkyl ester appeared at different fractions of alcohol. When the fractions of alcohol was kept constant, the alkyl ester that showed the maximal flux at this concentration appeared to have a longer chain length with increasing the fraction of alcohol. But isopropyl ester deviated from this order. It was concluded that the alkyl ester derivatives promoted the penetration of PGE1 mainly as a result of enhancing the drug partitioning into the stratum corneum. The alcohol fraction that needed to achieve the maximal flux at the same concentration increased with the increase of alkyl chain length, which resulted in the decrease of solubility parameter. It is necessary to optimize the fraction of alcohol in the saline solution in order to achieve the maximal flux at a fixed concentration for these alkyl esters with different alkyl chain length. PMID- 10099160 TI - FTIR characterization of the secondary structure of proteins encapsulated within PLGA microspheres. AB - A commonly used technique for protein encapsulation in microspheres is the double emulsion method wherein an initial water-in-oil (w/o) emulsion of protein and polymer is formed via sonication, and then a second emulsion (w/o)/w is formed by dispersion in an aqueous phase via homogenization. This approach is often used to produce microspheres of biodegradable poly(lactic-co-glycolic acid) (PLGA). The harsh processing associated with this method can cause denaturation of the encapsulated protein. Herein, we have used Fourier transform infrared (FTIR) spectroscopy to determine the secondary structures of two model proteins, bovine serum albumin (BSA) and chicken egg-white lysozyme, within PLGA microspheres. The alpha-helix content of both proteins in the microspheres was about a third lower than in the lyophilized state, indicating conformational changes upon protein entrapment within the microspheres. BSA microspheres containing the stabilizing excipient trehalose have a higher alpha-helix content than those without excipient, suggesting that trehalose partially prevents the denaturing effects incurred during processing. In addition, BSA released from microspheres is improved by incorporation of trehalose: analysis of the protein released from the microspheres indicates that there is less BSA dimer formation in the trehalose containing microspheres than in those without trehalose. PMID- 10099161 TI - Therapeutic ultrasound. AB - Therapeutic ultrasound has been in use for many years. Early applications were those for which tissue heating was the goal, and so it was used for soft tissue injuries such as may be incurred during sport. More recently, attention has been drawn both to high intensity focused beams that may be used for thermal ablation of selected regions, and also to low intensity fields that appear to be able to stimulate physiological processes, such as tissue repair, without biologically significant temperature rises. Ultrasonic tools are used for therapeutic effect in dentistry and are being investigated for use in thrombolysis. This paper reviews the various therapeutic applications of ultrasound. PMID- 10099162 TI - Preliminary results of a phase I dose escalation clinical trial using focused ultrasound in the treatment of localised tumours. AB - OBJECTIVE: The primary aim of this phase I trial was to assess the tolerance of cancer patients to focused ultrasound (FUS) treatment in a variety of different sites and to document any associated acute or delayed toxicity. This would appear to be the first time that treatment has been given without sedation or anaesthesia. METHODS: Patients with advanced and/or metastatic disease were eligible for entry into this study. Previous work has established that an in situ ablative intensity (AI) of 1500 W/cm2 Isp for 1 s achieves coagulative necrosis at the focal spot. Ultrasonic exposures of 25-100% of AI for 1 s were delivered to preselected tissue volumes. Pain questionnaires recording any side effects were completed by the patient and the investigator separately. Ultrasound images of the target volume were taken before, immediately after, and 1 week after treatment. RESULTS: A total of 14 patients have been entered into this study to date. Seven patients were treated at their primary site and seven received treatment to one of their metastases. No treatment needed to be stopped because of pain. Eight of the 14 patients did not complain of any side effect during or after the treatment. One patient complained of mild, and two of moderate pain during the week following treatment. One patient developed an asymptomatic blister on the skin. CONCLUSION: Focused ultrasound is a safe, well-tolerated and non-invasive method of delivering ablative thermal energy to selected tumours. More clinical trials are needed to assess the role of this modality in the treatment of cancer. PMID- 10099163 TI - Noninvasive surgery of prostate tissue by high intensity focused ultrasound: an updated report. AB - OBJECTIVE: To establish clinical efficacy and safety of High Intensity Focused Ultrasound (HIFU) for the treatment of benign prostatic hyperplasia (BPH) in a multiple site clinical study. METHODS: Seven clinical sites were set up for the studies, five in the USA, one in Canada and one in Japan respectively. Sixty two patients were enrolled in these three studies. Transrectal ultrasound probes made to produce sufficient acoustic power required for focused ultrasound surgery of the prostate as well as to perform imaging of the prostate, were employed in the study. The probes ware made of 2.5, 3.0, 3.5, 4.0 and 4.5 cm focal length transducers to treat varying prostate sizes and shapes and operated at 4 MHz frequency for both imaging and treatment. The employed ultrasound device produced both transverse and longitudinal images of the prostate on the same display. The images were used for selection of tissue volume, treatment planning and monitoring of tissue during the HIFU treatment cycle. The patients in the USA and Canada were followed for two years and those in Japan were followed for one year on a regular interval. The results were evaluated for changes in the peak flow rate (Qmax in ml/s), quality of life (QOL) and International Prostate Symptom Score (IPSS). RESULTS: The average pre / post treatment results at 180 days were significantly different for Qmax, QOL and IPSS 8.5/14.2 (ml/s), 4.7/2.1 and 22/10 respectively. CONCLUSION: Under this protocol, HIFU was found safe and efficacious for the treatment of BPH. The HIFU treatment produced statistically significant results for the parameters measured with least complications. Additionally, the HIFU treatment was found to be durable. PMID- 10099164 TI - Treatment of localised prostate cancer with transrectal high intensity focused ultrasound. AB - With the advent of PSA dosing, an increasing number of prostate cancers are being detected at a local stage. Since 1989, our group has been developing a research project with the aim of establishing treatment of localised prostate cancer by means of HIFU. The treatment is performed transrectally, using ultrasound imaging guidance only. The quality of HIFU treatment depends on four factors: the intensity of the transmitted pulse, the exposure time, the signal frequency, and the time between two firing bursts. The lesions are created by a thermal effect. Their slightly conical form is due to the absorption of ultrasound by tissue, enhanced by cavitation bubbles. Results obtained since 1993 demonstrate that transrectally administered HIFU treatment achieves local control of localised prostate cancer in 80% of cases, with 70% complete success and 30% partial response. The use of an annular array probe with variable focus and frequency should significantly improve results in the future. Finally, real time visual display of the damaged tissue via differential imaging of the attenuation coefficient should give the surgeon an instant appreciation of the result of the sequence. It would thus be possible to repeat treatment of insufficiently covered zones in the same session. PMID- 10099165 TI - Ultrasonic thrombolysis: catheter-delivered and transcutaneous applications. AB - Ultrasonic thrombolysis has been proved to be an efficient and safe modality for the treatment of acute arterial occlusions in vitro and in vivo in animal studies. There have been and are ongoing parallel improvements in ultrasound technology and adjuvant pharmacological treatments for therapeutic applications. Thus therapeutic ultrasound for thrombolysis holds great promise in overcoming the limitations of current available therapies. PMID- 10099166 TI - High intensity focused ultrasound in benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is an extremely common condition and represents a major health issue in terms of patient numbers and treatment cost. Traditionally, the choice of treatment has been between watchful waiting and surgery, however, the side effects of surgery lead to reluctance for treatment in many men, other than those with severe symptoms and complications. In the last 2 decades there has been a rapid expansion in the number of treatments being offered and the number of patients submitting to novel therapies. Medical management has evolved to achieve a central role in the management of BPH. Heat based treatments are also being investigated with considerable interest. Transrectal high intensity focused ultrasound (HIFU) is one such treatment, which allows radiation-free treatment, without the need for intra-urethral manipulation. Imaging can be performed during treatment and treatment results in symptomatic improvement, which is retained with medium-term follow-up. It involves a brief hospital stay and post-operative complications are few. The use of HIFU has also been extended to the treatment of renal, prostatic and bladder tumours and the results in these areas suggest further expansion of its role in urological practice. PMID- 10099167 TI - Theoretical design of a spherically sectioned phased array for ultrasound surgery of the liver. AB - GOAL: The theoretical explanation of the limits of an array transducer to coagulate large tissues volumes. METHODS: A theoretical model is used to illustrate the focal limitations of a spherically sectioned array designed for the treatment of deep seated tissue, e.g. liver. The design optimizes the acoustic dose as a function of the focal depth and available acoustic aperture with the goal of coagulating large volumes in a single sonication period. A quantitative measure of the possible region of focal necrosis is modeled as a function of array parameters with the limiting criteria being near field heating and patient pain. RESULTS: Acoustic simulations show that the maximum distance to produce continuous necrosis between foci in a multiple focus pattern and in a temporally multiplexed pattern is approximately 50% larger than the distance needed between sequential foci. CONCLUSION: Multiple focus patterns or rapidly scanned single foci are significantly advantageous to sequential sonications of a single focus transducer. PMID- 10099168 TI - A comparison of ultrasonic beams for thermal treatment of ocular tumors. AB - OBJECTIVE: This study examined the relative merits of different ultrasonic beams and exposure modalities for treating ocular melanomas. METHODS: Simulations were conducted to evaluate temperature patterns and lesion shapes induced by intense ultrasound treatment of ocular tumors. In-vitro insonification experiments were conducted in bovine lenses. RESULTS: Simulated hyperthermia exposures did not effectively treat tumor margins because of thermal conduction into nearby fluid like media. Standard high-intensity focused beams produced narrow lesions during 2-s exposures. A high-intensity, multi-lobed beam, produced by a transducer with strip electrodes, generated asymmetric lesions with a single large dimension; this lesion shape could expedite the production of lesion matrices within large tumors. In-vitro cataract shapes were consistent with simulation results for focused high-intensity beams. CONCLUSIONS: Thermal conduction and perfusion can cause underheating of tumor margins during hyperthermia unless special beam designs are used. The strip-electrode transducer configuration promises to expedite treatment of extended tumor volumes. PMID- 10099169 TI - Hemostasis using high intensity focused ultrasound. AB - High intensity focused ultrasound (HIFU) has been shown to be an effective method of hemostasis, in animal studies, for both solid organs and blood vessels. Two distinct effects of HIFU, thermal and mechanical, appear to contribute to hemostasis. Acoustic hemostasis may provide an effective method in surgery and prehospital settings for treating trauma and elective surgery patients. A review of the methodology is given. PMID- 10099170 TI - Vascular occlusion using focused ultrasound surgery for use in fetal medicine. AB - OBJECTIVE: Focused ultrasound surgery (FUS) is being developed clinically for the non-invasive treatment of soft tissue tumours of the prostate, bladder, liver, kidney, muscle and breast. In the work described in this paper, the application of FUS is extended to investigate the potential to induce vascular occlusion, with the aim of applying the technique to problems in fetal medicine and oncology. METHODS: In this feasibility study the occlusion of femoral blood flow in vivo is demonstrated using an array of multiple single exposures of 1.7 MHz focused ultrasound. These were placed in two rows of four lesions at a focal depth of 5 mm. The 4660-W cm-2 (free field spatial peak intensity) 2-s exposures were placed 2 mm apart. Vascular patency was assessed using a Siemens Vision (1.5T) magnetic resonance (MR) imaging scanner with an extremity coil, and intravenous gadolinium contrast agent. FLASH and FISP MR sequences were used to obtain full 3D data sets providing information on soft tissue damage and perfusion. RESULTS AND CONCLUSION: Total vascular occlusion was achieved in four of nine cases and significant vascular disruption in five of nine cases. Refinement of the FUS technique and long-term studies are now indicated prior to initial clinical application in fetal medicine. PMID- 10099171 TI - IBUS guidelines for the ultrasonic examination of the breast. IBUS International Faculty. International Breast Ultrasound School. PMID- 10099172 TI - pTRIDENT, a novel vector family for tricistronic gene expression in mammalian cells. AB - We constructed tricistronic expression vectors for the simultaneous and coordinated expression of three independent genes in mammalian cells. One single promoter allows high level and, in some vectors, adjustable transcription of all three cistrons. Whereas the first cistron is translated in a cap-dependent manner, the subsequent ones utilize intercistronic regions of viral origin such as the internal ribosomal entry site of poliovirus or the cap-independent translation enhancer of encephalomyocarditis virus for enhanced translation. Three multiple cloning sites with a total of up to 18 unique restriction sites allow sequential cloning of the genes of interest. The modular structure of this pBluescript(R)-based high copy number vector system allows straightforward movement of individual cistrons among members of the pTRIDENT family, and facilitates their combination with existing expression vectors. PMID- 10099173 TI - Protein-protein and protein-salt interactions in aqueous protein solutions containing concentrated electrolytes. AB - Protein-protein and protein-salt interactions have been obtained for ovalbumin in solutions of ammonium sulfate and for lysozyme in solutions of ammonium sulfate, sodium chloride, potassium isothiocyanate, and potassium chloride. The two-body interactions between ovalbumin molecules in concentrated ammonium-sulfate solutions can be described by the DLVO potentials plus a potential that accounts for the decrease in free volume available to the protein due to the presence of the salt ions. The interaction between ovalbumin and ammonium sulfate is unfavorable, reflecting the kosmotropic nature of sulfate anions. Lysozyme lysozyme interactions cannot be described by the above potentials because anion binding to lysozyme alters these interactions. Lysozyme-isothiocyanate complexes are strongly attractive due to electrostatic interactions resulting from bridging by the isothiocyanate ion. Lysozyme-lysozyme interactions in sulfate solutions are more repulsive than expected, possibly resulting from a larger excluded volume of a lysozyme-sulfate bound complex or perhaps, hydration forces between the lysozyme-sulfate complexes. PMID- 10099174 TI - Extraction of equine chorionic gonadotrophin from pregnant mare plasma by direct adsorption on chromatographic media. AB - Equine chorionic gonadotrophin (eCG) is a hormone of practical value in veterinary medicine and animal production. Here we report a novel preparation procedure based on its direct adsorption onto anionic-exchange resins in a batch wise mode. The active plasma is previously conditioned to reduce pH and ionic strength to required levels. After the adsorption stage, a 90% recovery of the initial eCG is achieved, with a concentration factor of about 50 and an enrichment factor around 500, with high preservation of biological activity. Further purification is carried out by cation-exchange column chromatography. The recovery for the whole process is higher than 70%, and the final potency of the preparation is close to 4000 IU/mg. The process is well suited for its application to the industrial scale. PMID- 10099175 TI - Modification of ultrafiltration membrane with gelatin protein. AB - A dye-binding procedure was developed for the analysis of protein attached to the membrane, with bound and adsorbed forms of attachment being distinguished. The relationship between modification procedure and protein attachment was explored and related to flux, streaming potential, and rejection with variation of pH. The effects of attaching four different types of gelatin to the membrane were studied. Assessment was made of modifications for improvement of flux and selectivity in the presence of protein foulants. PMID- 10099176 TI - Respirometric assay for biofilm kinetics estimation: parameter identifiability and retrievability AB - Currently, no fast and accurate methods exist for measuring extant biokinetic parameters for biofilm systems. This article presents a new approach to measure extant biokinetic parameters of biofilms and examines the numerical feasibility of such a method. A completely mixed attached growth bioreactor is subjected to a pulse of substrate, and oxygen consumption is monitored by on-line measurement of dissolved oxygen concentration in the bulk liquid. The oxygen concentration profile is then fit with a mechanistic mathematical model for the biofilm to estimate biokinetic parameters. In this study a transient biofilm model is developed and solved to generate dissolved oxygen profiles in the bulk liquid. Sensitivity analysis of the model reveals that the dissolved oxygen profiles are sufficiently sensitive to the biokinetic parameters-the maximum specific growth rate coefficient (insertion markMU) and the half-saturation coefficient (Ks)-to support parameter estimation if accurate estimates of other model parameters can be obtained. Monte Carlo simulations are conducted with the model to add typical measurement error to the generated dissolved oxygen profiles. Even with measurement error in the dissolved oxygen profile, a pair of biokinetic parameters is always retrievable. The geometric mean of the parameter estimates from the Monte Carlo simulations prove to be an accurate estimator for the true biokinetic values. Higher precision is obtained for insertion markMU estimates than for Ks estimates. In summary, this theoretical analysis reveals that an on line respirometric assay holds promise for measuring extant biofilm kinetic parameters. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099177 TI - Optimizing seeding and culture methods to engineer smooth muscle tissue on biodegradable polymer matrices. AB - The engineering of functional smooth muscle (SM) tissue is critical if one hopes to successfully replace the large number of tissues containing an SM component with engineered equivalents. This study reports on the effects of SM cell (SMC) seeding and culture conditions on the cellularity and composition of SM tissues engineered using biodegradable matrices (5 x 5 mm, 2-mm thick) of polyglycolic acid (PGA) fibers. Cells were seeded by injecting a cell suspension into polymer matrices in tissue culture dishes (static seeding), by stirring polymer matrices and a cell suspension in spinner flasks (stirred seeding), or by agitating polymer matrices and a cell suspension in tubes with an orbital shaker (agitated seeding). The density of SMCs adherent to these matrices was a function of cell concentration in the seeding solution, but under all conditions a larger number (approximately 1 order of magnitude) and more uniform distribution of SMCs adherent to the matrices were obtained with dynamic versus static seeding methods. The dynamic seeding methods, as compared to the static method, also ultimately resulted in new tissues that had a higher cellularity, more uniform cell distribution, and greater elastin deposition. The effects of culture conditions were next studied by culturing cell-polymer constructs in a stirred bioreactor versus static culture conditions. The stirred culture of SMC-seeded polymer matrices resulted in tissues with a cell density of 6.4 +/- 0.8 x 10(8) cells/cm3 after 5 weeks, compared to 2.0 +/- 1.1 x 10(8) cells/cm3 with static culture. The elastin and collagen synthesis rates and deposition within the engineered tissues were also increased by culture in the bioreactors. The elastin content after 5-week culture in the stirred bioreactor was 24 +/- 3%, and both the elastin content and the cellularity of these tissues are comparable to those of native SM tissue. New tissues were also created in vivo when dynamically seeded polymer matrices were implanted in rats for various times. In summary, the system defined by these studies shows promise for engineering a tissue comparable in many respects to native SM. This engineered tissue may find clinical applications and provide a tool to study molecular mechanisms in vascular development. PMID- 10099178 TI - Recombinant production and purification of novel antisense antimicrobial peptide in Escherichia coli. AB - A fusion protein was genetically engineered that contains an antimicrobial peptide, designated P2, at its carboxy terminus and bovine prochymosin at its amino terminus. Bovine prochymosin was chosen as the fusion partner because of its complete insolubility in Escherichia coli, a property utilized to protect the cells from the toxic effects of the antimicrobial peptide. This fusion protein was purified by centrifugation as an insoluble inclusion body. A methionine linker between prochymosin and the P2 peptide enabled P2 to be released by digestion with cyanogen bromide. Cation exchange HPLC followed by reversed-phase HPLC were used to purify the P2 peptide. The recombinant P2 peptide's molecular mass was confirmed by mass spectrometry to within 0.1% of the theoretical value (2480.9 Da), and the antimicrobial activity of the purified recombinant P2 against E. coli D31 was determined to be identical to that of the chemically synthesized peptide (minimal inhibitory concentration of 5 mg/mL). Although the yield of the fusion protein after expression by the cells was high (16% of the total cell protein), the percentage recovery of the P2 peptide in the inclusion bodies was relatively low, which appears to be due to losses in the cyanogen bromide digestion step. PMID- 10099179 TI - Plasmid stability of recombinant Pseudomonas sp. B13 FR1 pFRC20P in continuous culture. AB - Plasmid stability of recombinant Pseudomonas sp. B13 FR1 pFRC20P, a strain capable of mineralizing 3- and 4-chlorobenzoate and 4-methylbenzoate, was investigated in continuous culture. The hybrid cosmid pFRC20P enables the strain to mineralize 4-methylbenzoate. Rapid plasmid loss was observed under nonselective conditions using 3-chlorobenzoate as the substrate. Plasmid stability decreased with increasing dilution rate. Despite the growth advantage of the generated plasmid free cells a total depletion of plasmid bearing cells was not observed. After approximately 50 generations the fraction of plasmid bearing cells reached a constant level of 10%, which was stably maintained during the next 25 generations. Cells from this stage were used to inoculate a new culture that resulted in a stable level of 50% plasmid bearing cells. By a temporary substrate change to selective conditions (4-methylbenzoate), this level could be further increased to 70%. Literature models on plasmid stability could not be applied to describe the experimental data. Therefore, a new but unstructured model was developed to describe the experimental results. The model is based on the existence of three subpopulations: a plasmid free one, an original plasmid bearing one with a growth disadvantage compared to plasmid free cells, and a second plasmid bearing subpopulation with increased stability that is generated from the original one and has a growth rate comparable to the plasmid free cells. PMID- 10099180 TI - Proposed mechanism of acetate accumulation in two recombinant Escherichia coli strains during high density fermentation. AB - The productivity of Escherichia coli as a producer of recombinant proteins is affected by its metabolic properties, especially by acetate production. Two commercially used E. coli strains, BL21 (lambdaDE3) and JM109, differ significantly in their acetate production during batch fermentation at high initial glucose concentrations. E. coli BL21 grows to an optical density (OD, 600 nm) of 100 and produces no more than 2 g/L acetate, while E. coli JM109 grows to an OD (600 nm) of 80 and produces up to 14 g/L acetate. Even in fed-batch fermentation, when glucose concentration is maintained between 0.5 and 1.0 g/L, JM109 accumulates 4 times more acetate than BL21. To investigate the difference between the two strains, metabolites and enzymes involved in carbon utilization and acetate production were analyzed (isocitrate, ATP, phosphoenolpyruvate, pyruvate, isocitrate lyase, and isocitrate dehydrogenase). The results showed that during batch fermentation isocitrate lyase activity and isocitrate concentration were higher in BL21 than in JM109, while pyruvate concentration was higher in JM109. The activation of the glyoxylate shunt pathway at high glucose concentrations is suggested as a possible explanation for the lower acetate accumulation in E. coli BL21. Metabolic flux analysis of the batch cultures supports the activity of the glyoxylate shunt in E. coli BL21. PMID- 10099181 TI - Evaluation of Alcaligenes eutrophus cells as an NADH regenerating catalyst in organic-aqueous two-phase system. AB - A soluble NAD-dependent hydrogenase contained in Alcaligenes eutrophus was evaluated as a coenzyme regenerating catalyst in an organic-aqueous two-phase (predominantly organic) system. The horse-liver alcohol-dehydrogenase (HLADH) catalyzed reduction of cyclohexanone to cyclohexanol was used as a model reaction. The impact of different solvents (selected to span a large variety of principal properties) on the stability and activity of the HLADH, using substrate driven regeneration, was studied. Solvents suitable for the HLADH were then selected for an evaluation of the hydrogenase-driven coenzyme regeneration. Hydrophobic solvents such as heptane, toluene, and 1,1,1-trichloroethane were found to be suitable for the coupled reactions catalyzed by HLADH and hydrogenase. Nonimmobilized cells, permeabilized with cetyl-trimethyl-ammonium bromide, were the most efficient preparation for the regeneration of NADH. The use of this preparation in heptane (10% water) was optimized with respect to the yield obtained in the HLADH-catalyzed reduction of cyclohexanone. Using the optimized conditions, yields of 99% cyclohexanol were obtained. PMID- 10099183 TI - The influence of impeller type in pilot scale xanthan fermentations AB - The rheological complexity of Xanthan fermentations presents an interesting problem from a mixing viewpoint, because the phenomena of poor bulk blending and low oxygen mass transfer rates inherent in highly viscous fermentations (and their consequences) can be systematically investigated, even at the pilot plant scale. This study in a 150 L fermentor compares the physical and biological performance of four pairs of impellers: a standard Rushton turbine, a large diameter Rushton turbine, a Prochem Maxflo T, and a Scaba 6SRGT. Accurate in fermentor power measurements, essential for the comparison of impellers in relation to operating costs are also reported. It is demonstrated that the agitator performance in Xanthan fermentations is very specific and the choice of which impeller to use in bioreactors to obtain enhanced performance is dependant on the applied criterion. None of the criterion favored the use of the standard Rushton turbine, therefore suggesting that there are strong grounds for retrofitting these impellers with either large diameter impellers of similar design or with novel agitators. In addition, fluid dynamic modeling of cavern formation has clearly highlighted the importance of a well mixed and oxygenated region for providing the capacity for high microbial oxygen uptake rates which govern Xanthan productivity and quality. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099182 TI - Intracellular compounds quantification by means of flow cytometry in bacteria: application to xanthan production by Xanthomonas campestris. AB - The use of flow cytometry (FCM) to quantitatively analyze intracellular compounds is studied. FCM is a very useful technique for individual cell studies in microbial systems, and gives access to information which cannot be obtained in any other way. Nevertheless, it provides data in arbitrary units, that is, relative data. This analytical technique could be employed for kinetic modeling of microbial systems and even for internal phenomena analysis, but for this purpose, absolute data-that is concentration of intracellular compounds-must be used. In this work, relative flow cytometry data are transformed into absolute data by means of calibrations employing the same fluorochromes with another technique: spectrofluorymetry. Calibrations of DNA, RNA, and protein intracellular concentrations are presented for the bacteria, Xanthomonas campestris. Other analytical methods, based on biochemical determinations, were also employed to quantify intracellular compounds, but the results obtained are very poor compared with those achieved by means of spectrofluorymetry (SFM). Calibration equations and data obtained by both techniques are given. Evolutions of protein and nucleic acids during Xanthomonas campestris growth and xanthan gum production are shown. PMID- 10099184 TI - Ionic interactions in nanofiltration of beta casein peptides AB - Nanofiltration (NF) membrane technology shows interesting potentials for separating organic components on the basis of solute charge and size in the range of 300-1000 g mol-1. Separation properties of two inorganic NF membranes were studied with a set of 10 small peptides (molecular mass range: 300-900 g mol-1; 3 < pI < 10) contained in a well-characterized tryptic beta casein hydrolysate. Peptides transmission strongly depended on ionic interactions in the system. Physicochemical conditions such as ionic strength and especially pH were crucial to the separation, because the membrane and peptides showed amphoteric properties. Thus, the three categories of peptides (acid, basic, neutral) were separated according to their pI because of presumed concentration gradients of charged peptides at the membrane: positive for basic peptides and negative for acid peptides. At optimum pH 8 this led to high transmissions of basic peptides (even over 100%), intermediate transmissions for neutral peptides, and low transmissions for acid peptides. The addition of multicharged cationic and anionic species in the hydrolysate induced a markedly enhanced selectivity when the polyelectrolyte was a membrane coion and a complete reversion of selectivity when it was a membrane counterion. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099185 TI - Microfabricated immunoisolating biocapsules. AB - A microfabricated silicon-based biocapsule for the immunoisolation of cell transplants is presented. The biocapsule-forming process employs bulk micromachining to define cell-containing chambers within single crystalline silicon wafers. These chambers interface with the surrounding biological environment through polycrystalline silicon filter membranes. The membranes are surface micromachined to present a high density of uniform pores, thus affording sufficient permeability to oxygen, glucose, and insulin. The pore dimensions, as small as 20 nm, are designed to impede the passage of immune molecules and graft borne viruses. The underlying filter-membrane nanotechnology has been successfully applied in controlled cell culture systems (Ferrari et al., 1995), and is under study for viral elimination in plasma fractionation protocols. Here we report the encouraging results of in vitro experiments investigating the biocompatibility of the microfabricated biocapsule, and demonstrate that encapsulated rat neonatal pancreatic islets significantly outlive and outperform controls in terms of insulin-secretion capability over periods of several weeks. These results appear to warrant further investigations on the potential of cell xenografts encapsulated within microfabricated, immunoisolating environments for the treatment of insulin-dependent diabetes. PMID- 10099186 TI - Effect of salt hydrate pair on lipase-catalyzed regioselective monoacylation of sucrose. AB - Sucrose monoesters of a fatty acid were synthesized by using lipase in a solvent free system. When lipase from Mucor miehei was used as a catalyst with capric acid as the donor and sugar as the acceptor, sucrose 6-monocaprate was predominantly produced in a yield of 25.3%. The yield of product was significantly increased by the direct addition of a suitable pair of solid salt hydrates to the reaction mixture to control the water activity (aw). Among the salt hydrate pairs investigated, the barium hydroxide, 8/1H2O pair resulted in the highest yield of the product. This salt addition method was also successfully employed for acylation of primary hydroxyl groups in various unprotected mono- and disaccharides such as glucose, galactose, fructose, trehalose, mannose, maltose, and lactose. PMID- 10099187 TI - Dynamic determination of anaerobic acetate kinetics using membrane mass spectrometry AB - A small, stirred, 14.4-mL tank reactor was designed to serve as a measurement cell for short-term investigation of microbial kinetics. A mass spectrometer membrane probe allowed the measurement of the dissolved gases of hydrogen, methane, oxygen, and carbon dioxide. pH was measured by an electrode and controlled by addition of acid or alkali. The highly sensitive measurement of gases with low solubility allowed rapid measurements at very low conversion. In kinetic experiments, a stepwise increase of substrate concentration (method A) and continuous feed of substrate (method B) were used, allowing quick estimation of substrate kinetics. Acetate conversion in mixed culture biofilms from a fluidized bed reactor was investigated. Substrate inhibition was found to be negligible in the concentration range studied. Experiments at various pH values showed that the undissociated acid form was the kinetic determinant. Kinetic parameters for Haldane kinetics of protons were KSH = 1.3 x 10(-5) mol m-3 and KIH = 8.1 x 10(-3) mol m-3. With free acid (HAc) as the rate determining species, the kinetic parameters for method A were KSHAc = 0.005 mol m-3 and KIHAc = 100 mol m-3 and for method B were KSHAc = 0.2 mol m-3 and KIHAc = 50 mol m-3. The maximum biomass activity occurred at around pH 6.5. Acetate was exclusively converted to methane and CO2 at pH > 6. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099188 TI - Influence of biomass accumulation on bed expansion characteristics of a down-flow anaerobic fluidized-bed reactor. AB - This article describes the bed expansion characteristics of a down-flow anaerobic fluidized bed reactor treating a synthetic wastewater. Experiments were carried out in a 0.08 m diameter and 1 m length PVC column. The carrier used was ground perlite (an expanded volcanic rock). Particles characteristics were 0.968 mm in diameter, specific density of 213 kg x m-3 and Umf (minimal fluidization velocity): 2.3 m x h-1. Experimental data of terminal velocities and bed expansion parameters at several biofilm thicknesses were compared to different models predicting the bed expansion of up-flow and down-flow fluidized beds. Measured bed porosities at different liquid superficial velocities for the different biofilm thicknesses were in agreement with the Richardson-Zaki model, when Ut (particle terminal velocity) and n (expansion coefficient) were calculated by linear regression of the experimental data. Terminal velocities of particles at different biofilm thicknesses calculated from experimental bed expansion data, were found to be much smaller than those obtained when Cd (drag coefficient) is determined from the standard drag curve (Lapple and Sheperd, 1940) or with others' correlations (Karamanev and Nikolov, 1992a,b). This difference could be explained by the fact that free-rising particles do not obey Newton's law for free-settling, as proposed by Karamanev and Nikolov (1992a,b) and Karamanev et al. (1996). In the present study, the same free-rising behavior was observed for all particles (densities between 213 and 490 kg x m-3). PMID- 10099189 TI - Influence of hydrodynamic conditions on naphthalene dissolution and subsequent biodegradation. AB - The influence of hydrodynamic conditions on the dissolution rate of crystalline naphthalene as a model polycyclic aromatic hydrocarbon (PAH) was studied in stirred batch reactors with varying impeller speeds. Mass transfer from naphthalene melts of different surface areas to the aqueous phase was measured and results were modeled according to the film theory. Results were generalized using dimensionless numbers (Reynolds, Schmidt, and Sherwood). In combined mass transfer and biodegradation experiments, the effect of hydrodynamic conditions on the degradation rate of naphthalene by Pseudomonas 8909N was studied. Experimental results were mathematically described using mass-transfer and microbiological models. The experiments allowed determination of mass-transfer and microbiological parameters separately in a single run. The biomass formation rate under mass transfer limited conditions, which is related to the naphthalene biodegradation rate, was correlated to the dimensionless Reynolds number, indicating increased bioavailability at increased mixing in the reactor liquid. The methodology presented in which mass transfer processes are quantified under sterile conditions followed by a biodegradation experiment can also be adapted to more complex and realistic systems, such as particulate, suspended PAH solids or soils with intrapartically sorbed contaminants when the appropriate mass-transfer equations are incorporated. PMID- 10099190 TI - Analysis of endogenous process behavior in activated sludge. AB - In this article, an autonomous four-compartment model that describes the endogenous respiration in an aerobic biodegradation process is proposed and analyzed theoretically. First, the multi-time scale of the system's behavior, to be taken into account in subsequent analyses, is emphasized. Then, an identifiability and observability study, given measurements of MLVSS (mixed liquor volatile suspended solids) and respiration rate, is performed for use under practical circumstances, such as in state and parameter estimation. It appears that the process is observable, but not fully identifiable. Hence, for the identification of some of the model parameters, additional measurements or experiments, also indicated here, have to be performed. Furthermore, it is shown that, under quasi-steady state conditions which, in general, appear shortly after initialization of an endogenous respiration experiment, the model can be reduced significantly. Finally, results of parameter estimation from available data are presented and discussed. PMID- 10099191 TI - Growth factor and bcl-2 mediated survival during abortive proliferation of hybridoma cell line. AB - Cultures of the CRL-1606 hybridoma (ATCC) have been reported to undergo continuous proliferation with simultaneous death during nutrient limited fed batch fermentations. The bcl-2 proto-oncogene has been shown to prevent cell death under a variety of otherwise death inducing conditions. We were interested in elucidating the nature of the massive death observed in cultures of CRL-1606, specifically with respect to the possible environmental causes, and the ability of overexpressed human bcl-2 (hbcl-2) to mitigate cell death. Abortive proliferation, or continuous proliferation in the presence of continuous death, could be induced in serum free cultures of CRL-1606 through the withdrawal of insulin provided the culture was competent for cell proliferation. Culture competency for proliferation was found to be solely determined by the presence of cell culture nutrients. Abortive proliferation was defective in cultures transfected with hbcl-2 and the enhanced viability observed resulted from an increased viable cell population and at the expense of the nonviable cell population normally found in untransfected cultures. Abortive proliferation was also observed in serum containing cultures upon serum shiftdowns. Like the insulin-supplemented serum free culture system, hbcl-2 transfected cultures exhibited defects in the abortive proliferation process. These results suggest that the massive death observed during nutrient-limited fed-batch fermentation originate, in part, from growth or survival factor limitations. Hence, approaches to design cell culture media that account for the cell's proliferation requirements without accounting for the cell's survival requirements may represent a cell death sentence. Given the transformed nature of the hybridomas, we conclude that the abortive proliferation of CRL-1606 is a consequence of inappropriate cell cycle entry in a survival factor limited environment. PMID- 10099192 TI - Effect of extracellular glutamine concentration on primary and secondary metabolism of a murine hybridoma: an in vivo 13C nuclear magnetic resonance study. AB - The effect of changes in extracellular glutamine level on metabolism of a murine hybridoma was examined with in vivo nuclear magnetic resonance (NMR) spectroscopy. Cells were cultured in a hollow-fiber bioreactor at high cell density to allow intracellular metabolite levels to be determined on a metabolically relevant time scale. Steady infusions of [1-13C] glucose were used to label glycolytic and tricarboxylic acid cycle intermediates, which permitted continuous monitoring with NMR spectroscopy during changes in environmental glutamine level. Samples of the extracellular medium were also analyzed to determine the effect of glutamine on other metabolites associated with primary and secondary metabolism. The changes in glutamine concentration had several effects on primary and secondary metabolism, depending on the rate the changes were made. For a brief reduction in feed glutamine concentration from 4 to 0 mM (which produced a rapid change from 0.67 to approximately 0 mM in residual glutamine), large changes were observed in the rate of consumption of metabolites normally associated with energy production. Antibody synthesis was strongly stimulated and nitrogen metabolism was significantly altered. For a more prolonged reduction from 2.4 to 1.2 mM (which produced a slower reduction from 0.30 to 0. 08 mM in residual glutamine), much smaller changes were observed even though the concentration of glutamine at the reduced feed level was very low. Energy metabolism did not appear to be limited by glutamine at 0.08 mM, which suggests that significant futile cycling may occur in energy producing pathways when excess glucose and glutamine are available. However, this concentration of extracellular glutamine appeared to affect some anabolic pathways, which require amino groups from glutamine. PMID- 10099193 TI - Efficiency of sunlight utilization: tubular versus flat photobioreactors AB - The light saturation effect imposes a serious limitation on the efficiency with which solar energy can be utilized in outdoor algal cultures. One solution proposed to reduce the intensity of incident solar radiation and overcome the light saturation effect is "spatial dilution of light" (i.e., distribution of the impinging photon flux on a greater photosynthetic surface area), but consistent experimental data supporting a significant positive influence of spatial light dilution on the productivity and the photosynthetic efficiency of outdoor algal cultures have never been reported. We used a coiled tubular reactor and compared a near-horizontal straight tubular reactor and a near-horizontal flat panel in outdoor cultivation of the cyanobacterium Arthrospira (Spirulina) platensis under defined operating conditions for optimum productivity. The photosynthetic efficiency achieved in the tubular systems was significantly higher because their curved surface "diluted" the impinging solar radiation and thus reduced the light saturation effect. This interpretation was supported by the results of experiments carried out in the laboratory under continuous artificial illumination using both a flat and a curved chamber reactor. The study also showed that, when the effect of light saturation is eliminated or reduced, productivity and solar irradiance are linearly correlated even at very high diurnal irradiance values, and supported findings that outdoor algal cultures are light-limited even during bright summer days. It was also observed that, besides improving the photosynthetic efficiency of the culture, spatial dilution of light also leads to higher growth rates and lowers the cellular content of accessory pigments; that is, it reduces mutual shading in the culture. The inadequacy of using volumetric productivity as the sole criterion for comparing reactors of different surface-to-volume ratio and of the areal productivity for evaluating the performance of elevated photobioreactors operated outdoors is stressed; it is furthermore suggested that the photosynthetic efficiency achieved by the culture also be calculated to provide a suitable parameter for comparison of different algal cultivation systems operated under similar climatic conditions. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099194 TI - Agitator speed and dissolved oxygen effects in xanthan fermentations AB - Agitation speed affects both the extent of motion in Xanthan fermentation broths because of their rheological complexity and the rate of oxygen transfer. The combination of these two effects causes the dissolved oxygen concentration and its spatial uniformity also to change with agitator speed. Separating these complex interactions has been achieved in this study in the following way. First, the influence of agitation speeds of 500 and 1000 rpm has been investigated at a constant nonlimiting dissolved oxygen concentration of 20% of air saturation using gas blending. Under these controlled dissolved oxygen conditions, the results demonstrate that the biological performance of the culture was independent of agitation speed as long as broth homogeneity could be ensured. With the development of increasing rheological complexity lending to stagnant regions at Xanthan concentrations >20 g/L, it is shown that the superior bulk mixing achieved at 1000 rpm, compared with 500 rpm, leading to an increased proportion of the cells in the fermentor to be metabolically active and hence higher microbial oxygen uptake rates, was responsible for the enhanced performance. Second, the effects of varying dissolved oxygen are compared with a control in each case with an agitator speed of 1000 rpm to ensure full motion, but with a fixed, nonlimiting dissolved oxygen of 20% air saturation. The specific oxygen uptake rate of the culture in the exponential phase, determined using steady-state gas analysis data, was found to be independent of dissolved oxygen above 6% air saturation, whereas the specific growth rate of the culture was not influenced by dissolved oxygen, even at levels as low as 3%, although a decrease in Xanthan production rate could be measured. In the production phase, the critical oxygen level was determined to be 6% to 10%, so that, below this value, both specific Xanthan production rate as well as specific oxygen uptake rate decreased significantly. In addition, it is shown that the dynamic method of oxygen uptake determination is unsuitable even for moderately viscous Xanthan broths. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099195 TI - Induction of catalytic activity in proteins by lyophilization in the presence of a transition state analogue. AB - The induction of catalytic activity in proteins by lyophilization in the presence of a transition state analogue (biomolecular imprinting) has been attempted. It was shown that proteins which were freeze-dried with n-isopropyl-4-nitrobenzyl amine (a transition state analogue for the reaction of dehydrofluorination of 4 fluoro-4-[p-nitrophenyl] butan-2-one) displayed higher beta-elimination activity as compared to their-non-imprinted counterparts. It was also found that native bovine serum albumin has a high dehydrofluorination activity towards the above substrate with kinetic parameters rather similar to those of a catalytic antibody prepared by Shokat et al. (1989). A comparison of the kinetic parameters determined in this study with those obtained for analogous catalytic antibodies and imprinted polymers was made. PMID- 10099196 TI - Bilayer permeability-based substrate selectivity of an enzyme in liposomes. AB - Liposomes were prepared from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), which contained the water soluble proteinase alpha-chymotrypsin. This liposome entrapped enzyme showed selectivity for externally added substrates in that only small substrates (benzoyl-l-Tyr-p-nitroanilide or acetyl-l-Phe-p-nitro anilide)-for which the liposome bilayer was permeable-were transformed into products. Large substrates (succinyl-l-Ala-l-Ala-l-Pro-l-Phe-p-nitroanilide or casein) could not penetrate from the external aqueous phase into the liposomes, and were not hydrolyzed. This substrate selectivity is entirely based on the compartimentation and permeability properties of the liposome microreactor. PMID- 10099197 TI - Polycyclic aromatic hydrocarbon oxidation by the white-rot fungus Bjerkandera sp. strain BOS55 in the presence of nonionic surfactants. AB - The effect of nonionic surfactants on the polycyclic aromatic hydrocarbon (PAH) oxidation rates by the extracellular ligninolytic enzyme system of the white-rot fungus Bjerkandera sp. strain BOS55 was investigated. Various surfactants increased the rate of anthracene, pyrene, and benzo[a]pyrene oxidation by two to fivefold. The stimulating effect of surfactants was found to be solely due to the increased bioavailability of PAH, indicating that the oxidation of PAH by the extracellular ligninolytic enzymes is limited by low compound bioavailability. The surfactants were shown to improve PAH dissolution rates by increasing their aqueous solubility and by decreasing the PAH precipitate particle size. The surfactant Tween 80 was mineralized by Bjerkandera sp. strain BOS55; as a result both the PAH solubilizing activity of Tween 80 and its stimulatory effect on anthracene and pyrene oxidation rates were lost within 24 h after addition to 6 day-old cultures. It was observed that the surfactant dispersed anthracene precipitates recrystallized into larger particles after Tween 80 was metabolized. However, benzo[a]pyrene precipitates remained dispersed, accounting for a prolonged enhancement of the benzo[a]pyrene oxidation rates. Because the endogenous production of H2O2 is also known to be rate limiting for PAH oxidation, the combined effect of adding surfactants and glucose oxidase was studied. The combined treatment resulted in anthracene and benzo[a]pyrene oxidation rates as high as 1450 and 450 mg L-1 d-1, respectively, by the extracellular fluid of 6-day-old fungal cultures. PMID- 10099198 TI - Synthesis of alkane hydroxylase of Pseudomonas oleovorans increases the iron requirement of alk+ bacterial strains. AB - The alk genes enable Pseudomonas oleovorans to utilize alkanes as sole carbon and energy source. Expression of the alk genes in P. oleovorans and in two Escherichia coli recombinants induced iron limitation in minimal medium cultures. Further investigation showed that the expression of the alkB gene, encoding the integral cytoplasmic membrane protein AlkB, was responsible for the increase of the iron requirement of E. coli W3110 (pGEc47). AlkB is the non-heme iron monooxygenase component of the alkane hydroxylase system, and can be synthesized to levels up to 10% (w/w) of total cell protein in E. coli W3110 (pGEc47). Its synthesis is, however, strictly dependent on the presence of sufficient iron in the medium. Our results show that a glucose-grown E. coli alk+ strain can reach alkane hydroxylase activities of about 25 U/g cdw, and are consistent with the recent finding that catalytically active AlkB contains two, rather than one iron atom per polypeptide chain. PMID- 10099199 TI - Expression of the membrane protein glycophorin A as a fusion with the antibiotic resistance protein neomycin phosphotransferase II. AB - The gene for the integral membrane protein glycophorin A (GPA) was cloned in frame to the 5' end of the antibiotic resistance gene, neomycin phosphotransferase II (NPT). Protein expression was achieved in Escherichia coli as well as in mammalian cells. In case of Chinese hamster ovary cells (CHO) the resistant populations were analyzed 2 weeks after transfection; the amount of GPA NPT fusion protein produced was constant from experiment to experiment. Neomycin resistance was directly correlated with GPA expression, thus allowing the direct selection for a stable GPA-expressing cell population without the need of a cloning step. The amount of GPA-NPT produced was further increased by weakening the specific NPT enzymatic activity via site-directed mutagenesis. Detection was simplified by the fact that all different fusion proteins could be detected by the same anti-NPT antibody. This approach may be also applicable to other membrane proteins. PMID- 10099200 TI - Simple approach to reducing proteolysis during secretory production of human parathyroid hormone in Saccharomyces cerevisiae. AB - A gene coding for human parathyroid hormone (hPTH) was synthesized and cloned into a yeast expression and secretion vector containing the mating factor alpha pre-pro leader sequence and the galactose-inducible promoter, GAL10. The intact hPTH(1-84) was found to be secreted into the culture medium. As observed in the previous reports on the secretory production of hPTH in yeast, however, the proteolytic cleavage occurred as the culture proceeded, resulting in a significant loss of the intact hPTH. Attempts were therefore made to reduce the extent of proteolysis by simply controlling the culture conditions. The proteolytic cleavage was significantly reduced by the addition of an excess amount of l-arginine (>/=0.2M) to the culture medium, which resulted in a marked improvement in the yield of intact hPTH. To examine whether l-arginine affects the activities of intracellular proteases such as KEX2 endoproteinase or extracellular proteases, the proteolysis experiments were performed by incubating the commercial intact hPTH in a yeast host culture supernatant. The results demonstrated that l-arginine at high concentrations reduced the rate of hPTH proteolysis by inhibiting extracellular proteases. PMID- 10099201 TI - Multiplicity and stability analysis of microorganisms in continuous culture: effects of metabolic overflow and growth inhibition AB - Metabolic overflow (enhanced uptake of substrate and secretion of intermediates) is a phenomenon often observed for cells grown under substrate excess. Growth inhibition by substrate and/or product is also normally found for this kind of culture. An effort is made in this work to analyze the dynamic behavior of a continuous culture subject to metabolic overflow and growth inhibition by substrate and/or product. Analysis of a model system shows that in a certain range of operating conditions three nonwashout steady state solutions are possible. Local stability analysis indicates that only two of them are stable thus leading to multiplicity and hysteresis. Further analysis of the intrinsic effects of different terms describing the metabolic overflow and growth inhibitions reveals that for the model system and the parameters considered, the combined effects of product inhibition and an enhanced formation rate of product under substrate excess cause the multiplicity and hysteresis. Growth inhibition by substrate and/or an enhanced substrate uptake appear not to be necessary conditions. The combined effects of enhanced product formation and product inhibition can also lead to unusual dynamic behavior such as a prolonged time period to reach a steady state, oscillatory transition from one steady state to another, and sustained oscillations. Using the occurrence of multiplicity and oscillation as criteria, the operating regime of a continuous culture can be divided into four domains: one with multiplicity and oscillation, one with unique steady state but possible oscillatory behavior, the other two with unique and stable steady state. The model predictions are in accordance with recent experimental results. The results presented in this work may be used as guidelines for choosing proper operating conditions of similar culture systems to avoid undesired instability and multiplicity. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099202 TI - The primary production of an infectious recombinant Herpes Simplex Virus vaccine. AB - The production and extracellular release of a recombinant Herpes Simplex Virus (type 2) from monolayers of infected complementing Vero cells (CR2) are addressed. Growth and virus production conditions are identified that provide adequate virus titers with cell seeding densities and viral multiplicities of infection that could be reasonably handled in manufacturing. Harvesting by sonication of cell monolayers is shown to give the highest recovery of infectious virus (to 2.5 x 10(6) pfu/mL) but leads to process stream contamination by cellular proteins through the rupturing of cells (to 28 pg protein/pfu). By comparison, freeze-thaw cycles and osmotic rupture by hypotonic saline or glycerol shock procedures yield only low virus recovery (typically <10% of that by sonication), and are accompanied by yet higher levels of protein contamination (up to 30-fold higher pg protein/pfu). Addition of the polyanionic polymers, heparin or dextran sulphate to a harvest using either hypotonic saline, glycerol shock or isotonic phosphate buffered saline increased the yield of infectious virus in the supernatant. By contrast, addition of polycationic poly-L-lysine resulted in negligible increase in the supernatant virus titer. The highest virus titers (4.7 x 10(7) pfu/mL) were achieved following treatment of roller bottle cultured cells displaying a high cytopathic effect with heparin at 50 microg/mL for at least 3 h post harvest. This procedure also gave the lowest levels of protein contamination (<2 pg protein/pfu). The fivefold lower yield of infectious virus from cultures displaying a low cytopathic effect (<70% CPE) indicates the importance of cell physiological state at harvest. PMID- 10099203 TI - Mobilization of broad host range plasmid from Pseudomonas putida to established biofilm of Bacillus azotoformans. I. Experiments. AB - A strain of Pseudomonas putida harboring plasmids RK2 and pDLB101 was exposed to a pure culture biofilm of Bacillus azotoformans grown in a rotating annular reactor under three different concentrations of the limiting nutrient, succinate. Experimental results demonstrated that the broad host range RSF1010 derivative pDLB101 was transferred to and expressed by B. azotoformans. At the lower concentrations, donor mediated plasmid transfer increased with increasing nutrient levels, but the highest nutrient concentration yielded the lowest rate of donor to recipient plasmid transfer. For transconjugant initiated transfer, the rate of transfer increased with increasing nutrient concentrations for all cases. At the lower nutrient concentrations, the frequency of plasmid transfer was higher between donors and recipients than between transconjugants and recipients. The reverse was true at the highest succinate concentration. The rates and frequencies of plasmid transfer by mobilization were compared to gene exchange by retrotransfer. The initial rate of retrotransfer was slower than mobilization, but then increased dramatically. Retrotransfer produced a plasmid transfer frequency more than an order of magnitude higher than simple mobilization. PMID- 10099204 TI - Mobilization of broad host range plasmid from Pseudomonas putida to established biofilm of Bacillus azotoformans. II. Modeling. AB - A strain of Pseudomonas putida that harbors plasmids RK2 and pDLB101 was exposed to a pure culture biofilm of Bacillus azotoformans grown in a rotating annular reactor. Transfer of the RK2 mobilizable pDLB101 plasmid to B. azotoformans was monitored over a 4-day period. Experimental results demonstrated that the broad host range, RSF1010 derivative pDLB101 was transferred to and expressed by B. azotoformans. In the companion article to this work, the rate of plasmid transfer was quantified as a function of the limiting nutrient, succinate, and as a function of the mechanism of transfer. A biofilm process simulation program (AQUASIM) was modified to analyze resultant experimental data. Although the AQUASIM package was not designed to simulate or predict genetic events in biofilms, modification of the rate process dynamics allowed successful modeling of plasmid transfer. For the narrow range of substrate concentrations used in these experiments, nutrient level had only a slight effect on the rate and extent of plasmid transfer in biofilms. However, further simulations using AQUASIM revealed that under nutrient poor conditions, the number of transconjugants appearing in the biofilm was limited. PMID- 10099205 TI - Activity and stability of a recombinant plasmid-borne TCE degradative pathway in suspended cultures. AB - The retention and expression of the plasmid-borne, TCE degradative toluene-ortho monooxygenase (TOM) pathway in suspended continuous cultures of transconjugant Burkholderia cepacia 17616 (TOM31c) were studied. Acetate growth and TCE degradation kinetics for the transconjugant host are described and utilized in a plasmid loss model. Plasmid maintenance did not have a significant effect on the growth rate of the transconjugant. Both plasmid-bearing and plasmid-free strains followed Andrews inhibition growth kinetics when grown on acetate and had maximum growth rates of 0.22 h-1. The transconjugant was capable of degrading TCE at a maximum rate of 9.7 nmol TCE/min. mg protein, which is comparable to the rates found for the original plasmid host, Burkholderia cepacia PR131 (TOM31c). The specific activity of the TOM pathway was found to be a linear function of growth rate. Plasmid maintenance was studied at three different growth rates: 0.17/h, 0.1/h, and 0.065/h. Plasmid maintenance was found to be a function of growth rate, with the probability of loss ranging from 0.027 at a growth rate of 0.065/h to 0.034 at a growth rate 0.17/h. PMID- 10099206 TI - Measurement of autolysis in submerged batch cultures of Penicillium chrysogenum. AB - The process of cellular autolysis was studied in an industrial strain of Penicillium chrysogenum by a range of methods, including assessment of biomass decline, NH+4 release, changes in culture apparent viscosity, and by means of a quantitative assessment of changes in micromorphology using a computerized image analysis system. The pattern of total intracellular proteolytic and beta-1, 3 glucanolytic activity in the culture was also examined. The overall aim was to identify a suitable method, or methods, for examining the extent of autolysis in fungal cultures. Autolysis was studied in submerged batch processes, where DOT was maintained above 40% saturation (non-O2-limited), and, under O2-limited conditions. Both N and O2 limitation promoted extensive culture autolysis. Image analysis techniques were perhaps the most sensitive method of assessing the progress of autolysis in the culture. Autolytic regions within some hyphae were apparent even during growth phase, but became much more widespread as the process proceeded. The early stages of autolysis involved continued energy source consumption, increased carbon dioxide evolution rate, degradation of penicillin, and decreased broth filterability. Later stages involved widespread mycelial fragmentation, with some regrowth (cryptic growth) occurring in non-O2-limited cultures. Intracellular proteolytic activity showed two peaks, one during the growth phase, and the other during autolysis. Autolysis was also associated with a distinct peak in beta-1,3-glucanolytic activity, indicating that degradation of cell wall matrix polymers may be occurring during autolysis in this strain of P. chrysogenum. PMID- 10099207 TI - Bacterial milking: A novel bioprocess for production of compatible solutes. AB - A novel biotechnological process called "bacterial milking" has been established for the production of compatible solutes using the Gram-negative bacterium Halomonas elongata. Following a high-cell-density fermentation which provided biomass up to 48 g cell dry weight per liter, we applied alternating osmotic shocks in combination with crossflow filtration techniques to harvest the compatible solutes ectoine and hydroxyectoine. H. elongata, like other halophilic or halotolerant microorganisms, produces compatible solutes in response to the salinity of the medium. When transferred to a low salinity medium (osmotic downshock), H. elongata cells rapidly released their solutes to achieve osmotic equilibrium. Subsequent reincubation in a medium of higher salt concentration resulted in resynthesis of these compatible solutes and-after a defined regeneration time-the procedure could be repeated. By repeatedly performing this "bacterial milking" process (at least nine times) we were able to produce large amounts of ectoines with a biomass productivity of 155 mg of ectoine per cycle per gram cell dry weight. Further purification of the products was achieved by a simple two-step procedure based on cation exchange chromatography and crystallization. The principles described in this article may also be useful for the production of other low-molecular-weight compounds. PMID- 10099208 TI - Optimization of Phaffia rhodozyma continuous culture through response surface methodology. AB - Response surface methodology was applied to optimize the growth of the yeast Phaffia rhodozyma in continuous fermentation using peat hydrolysates as substrate. A second-order, complete, factorial design of the experiments was used to develop empirical models providing a quantitative interpretation of the relationships between the two variables studied, dilution rate and pH. Maximum biomass concentration in the fermentor was obtained by employing the following predicted optimum fermentation conditions: a dilution rate of 0.017/h and a pH level of 7.19. A verification experiment, conducted at previously optimized conditions for maximum biomass volumetric productivity (a dilution rate of 0.022/h, and a pH level of 6.90), produced values for biomass concentration, residual substrate concentration, biomass yield, and biomass volumetric productivity that were very close to the predicted values, indicating the reliability of the empirical model. The concentration of the pigment astaxanthin produced by the yeast under the optimized growth conditions was found to be 544 mg astaxanthin/kg dry cell biomass. PMID- 10099209 TI - Growth and product formation of Aspergillus oryzae during submerged cultivations: verification of a morphologically structured model using fluorescent probes. AB - A morphologically structured model is well suited for obtaining a good description of growth and product formation of filamentous fungi for use in a process model, for example. This article describes a new morphologically structured model and its application to an alpha-amylase producing strain of Aspergillus oryzae. The model is based on a division of the fungal hyphae into three different regions: an extension zone, representing the tips of the hyphae; an active region, which is responsible for growth and product formation; and an inactive hyphal region. Two metamorphosis reactions describing branching and inactivation are included in the model, and the kinetics of branching and tip extension are based on known experimentally verified models of fungal microscopic morphology. To verify the structure of the model a double-staining method, based on a combination of fluorescence microscopy and automated image analysis, has been developed for measuring the fraction of active cells. The method employs the fluorescent dye 3, 3'-dihexyloxocarbocyanin to stain organelles inside the hyphae and Calcoflour White to stain the cell wall. The ratio between the projected areas of the organelles and of the entire hyphal element is then taken to be proportional to the fraction of active cells. When applied to chemostat and fed batch experiments, the double-staining method seemed to confirm the basic morphological structure of the model. The model is able to produce accurate simulations of steady-state and transient conditions in chemostats, of batch cultivations, and even the formation of a single hyphal element from a spore, all with the same values of the model parameters. PMID- 10099210 TI - Modeling brewers' yeast flocculation AB - Flocculation of yeast cells occurs during the fermentation of beer. Partway through the fermentation the cells become flocculent and start to form flocs. If the environmental conditions, such as medium composition and fluid velocities in the tank, are optimal, the flocs will grow in size large enough to settle. After settling of the main part of the yeast the green beer is left, containing only a small amount of yeast necessary for rest conversions during the next process step, the lagering. The physical process of flocculation is a dynamic equilibrium of floc formation and floc breakup resulting in a bimodal size distribution containing single cells and flocs. The floc size distribution and the single cell amount were measured under the different conditions that occur during full scale fermentation. Influences on flocculation such as floc strength, specific power input, and total number of yeast cells in suspension were studied. A flocculation model was developed, and the measured data used for validation. Yeast floc formation can be described with the collision theory assuming a constant collision efficiency. The breakup of flocs appears to occur mainly via two mechanisms, the splitting of flocs and the erosion of yeast cells from the floc surface. The splitting rate determines the average floc size and the erosion rate determines the number of single cells. Regarding the size of the flocs with respect to the scale of turbulence, only the viscous subrange needs to be considered. With the model, the floc size distribution and the number of single cells can be predicted at a certain point during the fermentation. For this, the bond strength between the cells, the fractal dimension of the yeast, the specific power input in the tank and the number of yeast cells that are in suspension in the tank have to be known. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099211 TI - Methanogenic population dynamics during start-up of anaerobic digesters treating municipal solid waste and biosolids. AB - An aggressive start-up strategy was used to initiate codigestion in two anaerobic, continuously mixed bench-top reactors at mesophilic (37 degrees C) and thermophilic (55 degrees C) conditions. The digesters were inoculated with mesophilic anaerobic sewage sludge and cattle manure and were fed a mixture of simulated municipal solid waste and biosolids in proportions that reflect U.S. production rates. The design organic loading rate was 3.1 kg volatile solids/m3/day and the retention time was 20 days. Ribosomal RNA-targeted oligonucleotide probes were used to determine the methanogenic community structure in the inocula and the digesters. Chemical analyses were performed to evaluate digester performance. The aggressive start-up strategy was successful for the thermophilic reactor, despite the use of a mesophilic inoculum. After a short start-up period (20 days), stable performance was observed with high gas production rates (1.52 m3/m3/day), high levels of methane in the biogas (59%), and substantial volatile solids (54%) and cellulose (58%) removals. In contrast, the mesophilic digester did not respond favorably to the start-up method. The concentrations of volatile fatty acids increased dramatically and pH control was difficult. After several weeks of operation, the mesophilic digester became more stable, but propionate levels remained very high. Methanogenic population dynamics correlated well with performance measures. Large fluctuations were observed in methanogenic population levels during the start-up period as volatile fatty acids accumulated and were subsequently consumed. Methanosaeta species were the most abundant methanogens in the inoculum, but their levels decreased rapidly as acetate built up. The increase in acetate levels was paralleled by an increase in Methanosarcina species abundance (up to 11.6 and 4.8% of total ribosomal RNA consisted of Methanosarcina species ribosomal RNA in mesophilic and thermophilic digesters, respectively). Methanobacteriaceae were the most abundant hydrogenotrophic methanogens in both digesters, but their levels were higher in the thermophilic digester. PMID- 10099212 TI - Biodegradation kinetics of naphthalene in nonaqueous phase liquid-water mixed batch systems: comparison of model predictions and experimental results. AB - A model is formulated to describe dissolution of naphthalene from an insoluble nonaqueous phase liquid (NAPL) and its subsequent biodegradation in the aqueous phase in completely mixed batch reactors. The physicochemical processes of equilibrium partitioning and mass transfer of naphthalene between the NAPL and aqueous phases were incorporated into the model. Biodegradation kinetics were described by Monod's microbial growth kinetic model, modified to account for the inhibitory effects of 1,2-naphthoquinone formed during naphthalene degradation under certain conditions. System parameters and biokinetic coefficients pertinent to the NAPL-water systems were determined either by direct measurement or from nonlinear regression of the naphthalene mineralization profiles obtained from batch reactor tests with two-component NAPLs comprised of naphthalene and heptamethylnonane. The NAPLs contained substantial mass of naphthalene, and naphthalene biodegradation kinetics were evaluated over the time required for near complete depletion of naphthalene from the NAPL. Model predictions of naphthalene mineralization time profiles compared favorably to the general trends observed in the data obtained from laboratory experiments with the two-component NAPL, as well as with two coal tars obtained from the subsurface at contaminated sites and composed of many different PAHs (polycyclic aromatic hydrocarbon compounds). The effects of varying the NAPL mass and the naphthalene mole fractions in the NAPL are discussed. It was observed that the time to achieve a given percent removal of naphthalene does not change significantly with the initial mass of naphthalene in a fixed volume of the NAPL. Significant changes in the mineralization profiles are observed when the volume (and mass) of NAPL in the system is changed. PMID- 10099213 TI - Consecutive reaction kinetics involving distributed fraction of methanogens in fluidized-bed bioreactors. AB - A kinetic model involving the distributed fractions of acidogens and methanogens is proposed. To determine the fluxes and biochemical reaction rates of the substrate sucrose and its intermediates, volatile fatty acids (VFAs) in bulk liquid and within the biofilm, a kinetic model was developed by combining the solid-phase model with the liquid-phase model. The predicted substrate removal efficiencies of the conventional and tapered fluidized-bed bioreactors (CFB, TFBs) are in good agreement with the experimental results. The biofilm thickness in TFBs are thicker than that in CFB, resulting in performance enhancement with TFBs. The simulated results obtained from the kinetic model show that methanogenesis is the rate-limiting step of degradation of the simple organic compound (sucrose), and the chemical oxygen demand (COD) concentration in the effluent is mainly contributed by the intermediates VFAs. The distributed fractions of acidogens and methanogens determined experimentally are 0.4 and 0.6, respectively. PMID- 10099214 TI - Chemical treatment of Escherichia coli. II. Direct extraction of recombinant protein from cytoplasmic inclusion bodies in intact cells. AB - A method is presented for the direct extraction of the recombinant protein Long R3-IGF-I from inclusion bodies located in the cytoplasm of intact Escherichia coli cells. Chemical treatment with 6M urea, 3 mM EDTA, and 20 mM dithiothreitol (DTT) at pH 9.0 proved an effective combination for extracting recombinant protein from intact cells. Comparable levels of Long-R3-IGF-I were recovered by direct extraction as achieved by in vitro dissolution following mechanical disruption. However, the purity of directly extracted recombinant protein was lower due to contamination by bacterial cell components. The kinetics of direct extraction are described using a first-order equation with the time constant of 3 min. Urea appears important for permeabilization of the cell and dissolution of the inclusion body. Conversely, EDTA is involved in permeabilization of the cell wall and DTT enhances protein release. pH proved to be important with lower levels of protein release achieved at low pH values (<9). Cell concentration also had a minor effect on Long-R3-IGF-I release and caused an observable increase in viscosity. Advantages of the direct extraction method include its speed, simplicity, and efficiency at releasing product. PMID- 10099216 TI - A mathematical model for the generation and control of a pH gradient in an immobilized enzyme system involving acid generation. AB - An optimal pH control technique has been developed for multistep enzymatic synthesis reactions where the optimal pH differs by several units for each step. This technique separates an acidic environment from a basic environment by the hydrolysis of urea within a thin layer of immobilized urease. With this technique, a two-step enzymatic reaction can take place simultaneously, in proximity to each other, and at their respective optimal pH. Because a reaction system involving an acid generation represents a more challenging test of this pH control technique, a number of factors that affect the generation of such a pH gradient are considered in this study. The mathematical model proposed is based on several simplifying assumptions and represents a first attempt to provide an analysis of this complex problem. The results show that, by choosing appropriate parameters, the pH control technique still can generate the desired pH gradient even if there is an acid-generating reaction in the system. PMID- 10099215 TI - A theoretical equation describing the time evolution of the concentration of a selected range of substrate molecular weights in depolymerization processes mediated by single-attack mechanism endo-enzymes. AB - Monitoring the time evolution of the concentration of a selected range of molecular weights of substrate, referred to as "detectable" substrate, has been used to determine endo-enzymic activities in polysaccharide depolymerizing processes. In the methodologies based on the use of dye-labeled substrates, the "detectable" substrate extends from a given molecular weight threshold downward. On the contrary, in the fluorescent probe-flow injection analysis methodology, initially developed to determine (1 --> 3)-(1 --> 4)-beta-D-glucanase activities, the "detectable" substrate extends from a given molecular weight threshold upward. Assuming that the time evolution of the molecular weight distribution of the substrate follows the most probable distribution (the enzymic attack is random and its mechanism is single attack), a theoretical equation describing the time evolution of the concentration of "detectable" substrate (from a given molecular weight threshold upward or downward) has been deduced. This equation, Wd = Wo. (1 + alphat). e-alphat, where Wd is the concentration of "detectable" substrate, Wo is the initial concentration of the substrate, t is the depolymerization time, and alpha is a parameter correlated through a hyperbola with the initial concentrations of enzyme and substrate and the Michaelis-Menten constant, Km, has been tested against different (1 --> 3)-(1 --> 4)-beta-D glucan/(1 --> 3)-(1 --> 4)-beta-D-glucanase systems using the fluorescent probe flow injection analysis methodology and Calcofluor as the fluorescent probe. The most important predictions of the theoretical equation, which allow accurate determination of both endo-enzymic activities and kinetic constants, have been experimentally confirmed. PMID- 10099217 TI - Effects of dissolved oxygen tension and mechanical forces on fungal morphology in submerged fermentation. AB - The effects of dissolved oxygen tension and mechanical forces on fungal morphology were both studied in the submerged fermentation of Aspergillus awamori. Pellet size, the hairy length of pellets, and the free filamentous mycelial fraction in the total biomass were found to be a function of the mechanical force intensity and to be independent of the dissolved oxygen tension provided that the dissolved oxygen tension was neither too low (5%) nor too high (330%). When the dissolved oxygen concentration was close to the saturation concentration corresponding to pure oxygen gas, A. awamori formed denser pellets and the free filamentous mycelial fraction was almost zero for a power input of about 1 W/kg. In the case of very low dissolved oxygen tension, the pellets were rather weak and fluffy so that they showed a very different appearance. The amount of biomass per pellet surface area appeared to be affected only by the dissolved oxygen tension and was proportional to the average dissolved oxygen tension to the power of 0.33. From this it was concluded that molecular diffusion was the dominant mechanism for oxygen transfer in the pellets and that convection and turbulent flow in the pellets were negligible in submerged fermentations. The biomass per wet pellet volume increased with the dissolved oxygen tension and decreased with the size of the pellets. This means that the smaller pellets formed under a higher dissolved oxygen tension had a higher intrinsic strength. Correspondingly, the porosity of the pellets was a function of the dissolved oxygen tension and the size of pellets. Within the studied range, the void fraction in the pellets was high and always much more than 50%. PMID- 10099218 TI - Kinetic evidence for pentachlorophenol-dependent growth of a dehalogenating population in a pentachlorophenol- and acetate-fed methanogenic culture. AB - A method was developed to evaluate growth of a reductively dechlorinating bacterial population within a pentachlorophenol (PCP)- and acetate-fed, mixed, methanogenic culture. In 6- to 12-day experiments, a computer-monitored/feedback controlled bioreactor was used to maintain constant pH, temperature, and acetate concentration, while transformation of multiple PCP additions was monitored. The potential at a platinum electrode, EPt, was not controlled externally, but was maintained constant at -0.25 +/- 0.002 V (vs. SHE) by iron sulfides in the medium and the activity of the culture. PCP was reductively dechlorinated at the ortho position, yielding 3, 4,5-trichlorophenol (3,4,5-TCP) via 2,3,4,5 tetrachlorophenol (2,3,4, 5-TeCP). Below an initial PCP concentration of 0.5 microM, PCP was transformed to 3,4,5-TCP within 3 to 6 h. Biomass concentration changes were small during this period, and PCP and 2,3,4,5-TeCP transformations were modeled as pseudo-first-order reactions. Increases in pseudo-first-order rate constants for PCP and 2,3,4, 5-TeCP were directly related to the amount of PCP transformed to 3,4, 5-TCP, suggesting enrichment of a PCP-catabolizing population. Moreover, rate constant increases were independent of the amount of acetate consumed, changes in the overall volatile suspended solids (VSS) concentration, and the experimental duration. When PCP was added to the reactor at increasingly shorter time intervals in an exponential pattern, pseudo-first order rate constants increased exponentially. An average rate constant doubling time of 1.7 days (1. 4 to 2.3 d) was estimated. While the VSS concentration of the culture increased 60% in an 8-day period, pseudo-first-order rate constants increased by a factor of approximately 6. This large increase in transformation rate constants suggests growth of a bacterial population capable of using PCP and 2,3,4,5-TeCP as terminal electron acceptors. PMID- 10099219 TI - Effects of glucose and glycerol on gamma-poly(glutamic acid) formation by Bacillus licheniformis ATCC 9945a. AB - Bacillus licheniformis ATCC 9945a is one of the bacterial strains that produce gamma-poly(glutamic acid) (gamma-PGA). The use of carbohydrate medium components for gamma-PGA production was explored. Cells were grown in shake flasks or in controlled pH fermentors using medium formulations that contain different carbon sources. During the cultivations, aliquots were removed to monitor cell growth, carbon utilization, polymer production, and polymer molecular weight. Glucose was a better carbon source than glycerol for cell growth. Furthermore, glucose was utilized at a faster rate than glycerol, citrate, or glutamate. However, by using mixtures of glucose and glycerol in medium formulations, the efficiency of gamma PGA production increased. For example, by increasing the glycerol in medium formulations from 0 to 40 g/L, the gamma-PGA broth concentration after 96 h increased from 5.7 to 20.5 g/L. Considering that glycerol utilization was low for the glucose/glycerol mixtures studied, it was unclear as to the mechanism by which glycerol leads to enhanced product formation. Cell growth and concomitant gamma-PGA production (12 g/L) at pH 6.5 was possible using glucose as a carbon source if trace amounts (0.5 g/L each) of citrate and glutamate were present in the medium. We suggested that citrate and glutamate were useful in preventing salt precipitation from the medium. In addition, glutamate may be preferred relative to ammonium chloride as a nitrogen source. The conversion of glucose to gamma-PGA by the strain ATCC 9945a was believed to occur by glycolysis of glucose to acetyl-CoA and tricarboxylic acid (TCA) cycle intermediates that were then metabolized via the TCA cycle to form alpha-ketoglutarate, which is a direct glutamate precursor. PMID- 10099220 TI - External versus internal source of calcium during the gelation of alginate beads for DNA encapsulation. AB - Alginate gels produced by an external or internal gelation technique were studied so as to determine the optimal bead matrix within which DNA can be immobilized for in vivo application. Alginates were characterized for guluronic/mannuronic acid (G/M) content and average molecular weight using 1H-NMR and LALLS analysis, respectively. Nonhomogeneous calcium, alginate, and DNA distributions were found within gels made by the external gelation method because of the external calcium source used. In contrast, the internal gelation method produces more uniform gels. Sodium was determined to exchange for calcium ions at a ratio of 2:1 and the levels of calcium complexation with alginate appears related to bead strength and integrity. The encapsulation yield of double-stranded DNA was over 97% and 80%, respectively, for beads formed using external and internal calcium gelation methods, regardless of the composition of alginate. Homogeneous gels formed by internal gelation absorbed half as much DNAse as compared with heterogeneous gels formed by external gelation. Testing of bead weight changes during formation, storage, and simulated gastrointestinal (GI) conditions (pH 1.2 and 7.0) showed that high alginate concentration, high G content, and homogeneous gels (internal gelation) result in the lowest bead shrinkage and alginate leakage. These characteristics appear best suited for stabilizing DNA during GI transit. PMID- 10099221 TI - Activity of glutamate dehydrogenase is increased in ammonia-stressed hybridoma cells. AB - The effect of added ammonia on the intracellular fluxes in hybridoma cells was investigated by metabolic-flux balancing techniques. It was found that, in ammonia-stressed hybridoma cells, the glutamate-dehydrogenase flux is in the reverse direction compared to control cells. This demonstrates that hybridoma cells are able to prevent the accumulation of ammonia by converting ammonia and alpha-ketoglutarate into glutamate. The additional glutamate that is produced by this flux, as compared to the control culture, is converted by the reactions catalyzed by alanine aminotransferase (45% of the extra glutamate) and aspartate aminotransferase (37%), and a small amount is used for the biosynthesis of proline (6%). The remaining 12% of the extra glutamate is secreted into the culture medium. The data suggest that glutamate dehydrogenase is a potential target for metabolic engineering to prevent ammonia accumulation in high-cell density culture. PMID- 10099222 TI - Propionic acid production by extractive fermentation. I. Solvent considerations. AB - Solvent selection for extractive fermentation for propionic acid was conducted with three systems: Alamine 304-1 (trilaurylamine) in 2-octanol, 1-dodecanol, and Witcohol 85 NF (oleyl alcohol). Among them, the solvent containing 2-octanol exhibited the highest partition coefficient in acid extraction, but it was also toxic to propionibacteria. The most solvent-resistant strain among five strains of the microorganism was selected. Solvent toxicity was eliminated via two strategies: entrapment of dissolved toxic solvent in the culture growth medium with vegetable oils such as corn, olive, or soybean oils; or replacement of the toxic 2-octanol with nontoxic Witcohol 85 NF. The complete recovery of acids from the Alamine 304-1/Witcohol 85 NF was also realized with vacuum distillation. PMID- 10099223 TI - Development of microbial mercury detoxification processes using mercury hyperresistant strain of Pseudomonas aeruginosa PU21. AB - A mercury-hyperresistant strain of Pseudomonas aeruginosa PU21 harboring plasmid Rip64 was utilized to develop bioprocesses able to detoxify and recover soluble mercuric ions in aquatic systems. The kinetics of mercury detoxification was investigated to determine the parameters needed for the design of the bioprocesses. Batch, fed-batch, and continuous bioreactors were utilized to evaluate the efficiency and feasibility of each mode of operation. The results showed that the specific mercury detoxification rate was dependent on cell growth phases, as well as the initial mercury concentrations. Cells at the lag growth phase exhibited the best specific detoxification rate of approximately 1.1 x 10( 6) microg Hg/cell/h, and the rate was optimal at an initial mercury concentration of 8 mg/L. In batch operations with initial mercuric ions ranging from 2 to 10 mg/L, the mercuric ions added were rapidly volatilized from the media in less than 2-3 h. With periodic feeding of 3 or 5 mg Hg/L at fixed time intervals, the fed-batch processes had mercury removal efficiencies of 2.9 and 3.3 mg Hg/h/L, respectively. For continuous operations, the effluent cell concentration (Xe) was essentially invariant at 527 and 523 mg/L with the dilution rates (D) of 0.18 and 0.325 h-1, respectively. The increase in mercury feeding concentrations (Hgf) from 1.0 to 6.15 mg Hg2+/L did not affect the steady-state cell concentration (Xe) but forced the effluent mercury concentration (Hge) to increase. The decrease in the dilution rate, however, resulted in lower Hge values. It was also found that sequential mercury vapor absorption columns recovered over 80% of the Hg degrees released from the bioreactor while the residual mercury vapor was subsequently immobilized by an activated carbon trap in the down stream of the absorption column. PMID- 10099224 TI - Soil immobilization: new concept for biotreatment of soil contaminants. AB - A new concept for the development of microbial consortia for the degradation of persistent soil pollutants and for pollutant treatment is proposed. The concept defined as "soil immobilization" is based on the entrapment of soil particles, showing microbial activity in degrading the target pollutant, into a solid membrane with a large pore size distribution. The particular hydrodynamic and mass transfer properties of this system result in a very efficient process. A new type of bioreactor is proposed for carrying out the immobilized soil process. The performance of the system was tested by developing a microbial system for the mineralization of pentachlorophenol (PCP). The results show that the volumetric efficiency of the process for PCP mineralization in the immobilized soil bioreactor is 1-3 orders of magnitude higher than reported literature values. Chlorine and carbon atoms of PCP are both nearly completely (99%) mineralized. PMID- 10099225 TI - Genetic engineering of Serratia marcescens with bacterial hemoglobin gene: effects on growth, oxygen utilization, and cell size. AB - The bacterial hemoglobin from Vitreoscilla has been shown to increase growth yield and yield of genetically engineered product in Escherichia coli. To test the generality of this phenomenon, the approximately 560-bp bacterial (Vitreoscilla) hemoglobin gene (vgb) (including the native promoter), cloned into the vector pUC8 in two constructs containing about 1650 and 850 bp, respectively, of Vitreoscilla DNA downstream of vgb, was transformed into Serratia marcescens. After several transfers of the transformants on selective media, both plasmids became stable in this host and the resulting strains produced hemoglobin. Both transformants were compared, regarding growth in liquid Luria-Bertani (LB) medium, with untransformed S. marcescens and S. marcescens transformed with pUC8. The vgb-bearing strains had about 5 times lower maximum viable cell numbers than the strains without hemoglobin, but the former also had late log or early stationary phase cells that were 5-10 times larger than those of the latter. Further, on a dry cell mass basis the presence of vgb inhibited cell growth in liquid media. In contrast, growth of the vgb-bearing strains on LB plates based on cell mass (determined from colony size) was markedly enhanced compared with that of the pUC8 transformant. Respiration of the vgb-bearing strains was lower than that of the strains without vgb on a cell mass basis. These results show that the presence of vgb can have idiosyncratic effects and is not always an aid to cell growth so that its use for genetic engineering must be tested on a case by case basis. PMID- 10099226 TI - Quantitative analysis of protein synthesis inhibition and recovery in CRM107 immunotoxin-treated HeLa cells. AB - Previously a mathematical model was proposed that quantitatively related protein synthesis inhibition kinetics of antitransferrin receptor-gelonin immunotoxins to the cellular trafficking of the targeting agent. That work is here extended to describe protein synthesis inhibition kinetics of immunotoxins containing the diphtheria toxin mutant CRM107. CRM107 differs from gelonin in both translocation and ribosomal inactivation mechanisms. Targeting agents used were antitransferrin monoclonal antibodies 5E9 and OKT9, OKT9Fab, and transferrin. CRM107 conjugates inhibited protein synthesis at substantially lower concentrations than gelonin conjugates; this effect was attributed to substantially higher translocation rates for CRM107. However, under certain conditions, CRM107 immunotoxin-treated cells were able to recover completely; this behavior was never observed with gelonin immunotoxins. To quantitatively capture this phenomenon, extracellular and cytosolic degradation of the toxin as well as growth-related recovery from toxin-induced damage were incorporated into the mathematical model. Translocation and cytosolic degradation rate constants were determined for each immunotoxin. Unlike the gelonin conjugates, the translocation rate of CRM107 conjugates depended on the targeting molecule. This provided indirect evidence that CRM107 remains disulfide linked to the targeting agent for at least part of the translocation process. Although the CRM107 conjugates all had higher translocation rates and inhibited protein synthesis at lower concentrations than the gelonin conjugates, the cells' ability to recover from protein synthesis inhibition at low immunotoxin concentrations limits the utility of CRM107 conjugates for targeted cell killing. PMID- 10099228 TI - Quantitative enzymatic production of 6-O-acylglucose esters AB - Selective production of emulsifiers from glucose and fatty acids has been achieved using an immobilized Candida antarctica lipase. Optimization of process selectivity considers the solubilities of the sugar and its monoesters in acetone at different temperatures, the percentage of this organic solvent in the reaction mixture, and the reaction temperature. The solvent (acetone) is both easily eliminated and accepted by the European Community for use in the manufacture of foods and/or food additives. Different fatty acids with a longer length chain than that of caprylic acid may be employed. For saturated fatty acids longer than lauric acid, continuous precipitation of the monoester as it is formed at 40 degrees C permits nearly complete conversion (98%) of glucose to the monoester within 2-3 days. The procedure does not require total dissolution of the sugar, and precipitation of the monoester permits selective conversion of charges of glucose higher than 100 mg/mL solvent. A scaleup of the process under the optimum conditions gives high yields of 6-O-lauroyl glucose, which may be readily prepared on a gram scale. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099227 TI - Continuous biological waste gas treatment in stirred trickle-bed reactor with discontinuous removal of biomass. AB - A new reactor for biological waste gas treatment was developed to eliminate continuous solvents from waste gases. A trickle-bed reactor was chosen with discontinuous movement of the packed bed and intermittent percolation. The reactor was operated with toluene as the solvent and an optimum average biomass concentration of between 5 and 30 kg dry cell weight per cubic meter packed bed (m3pb). This biomass concentration resulted in a high volumetric degradation rate. Reduction of surplus biomass by stirring and trickling caused a prolonged service life and prevented clogging of the trickle bed and a pressure drop increase. The pressure drop after biomass reduction was almost identical to the theoretical pressure drop as calculated for the irregular packed bed without biomass. The reduction in biomass and intermittent percolation of mineral medium resulted in high volumetric degradation rates of about 100 g of toluene m-3pb h-1 at a load of 150 g of toluene m-3pb h-1. Such a removal rate with a trickle-bed reactor was not reported before. PMID- 10099229 TI - Retention and regeneration of native NAD(H) in noncharged ultrafiltration membrane reactors: application to L-lactate and gluconate production. AB - NAD(H) was retained in a noncharged ultrafiltration membrane reactor for the simultaneous and continuous production of L-lactate and gluconate with coenzyme regeneration. Polyethyleneimine (PEI), a 50-kDa cationic polymer, achieved coenzyme retentions above 0.8 for PEI/NAD(H) molar ratios higher than 5. The ionic strength of the inlet medium caused a decrease of NAD(H) retention that can be counterbalanced by an initial addition of 1% bovine serum albumin (BSA). Continuous reactor performance in the presence of PEI and BSA showed that NAD(H), glucose dehydrogenase, and lactate dehydrogenase were retained by 10-kDa ultrafiltration membranes; L-lactate and gluconate were produced at conversions higher than 95%. PEI enhanced the thermal stability of the enzymes used and increased the catalytic efficiency of glucose dehydrogenase, while no effect was found on the kinetic parameters of lactate dehydrogenase. A model that implements the kinetic equations of the two enzymes describes the reactor behavior satisfactorily. In brief, the use of PEI to retain NAD(H) is a new interesting approach to be widely applied in continuous synthesis with the large number of known dehydrogenases. PMID- 10099230 TI - Ammonium ion and glucosamine dependent increases of oligosaccharide complexity in recombinant glycoproteins secreted from cultivated BHK-21 cells. AB - The effect of different ammonium concentrations and glucosamine on baby hamster kidney (BHK)-21 cell cultures grown in continuously perfused double membrane bioreactors was investigated with respect to the final carbohydrate structures of a secretory recombinant glycoprotein. The human interleukin-2 (IL-2) mutant glycoprotein variant IL-Mu6, which bears a novel N-glycosylation site (created by a single amino acid exchange of Gln100 to Asn), was produced under different defined protein-free culture conditions in the presence or absence of either glutamine, NH4Cl, or glucosamine. Recombinant glycoprotein products were purified and characterized by amino acid sequencing and carbohydrate structural analysis using matrix-assisted laser desorption ionization time of flight mass spectrometry, high-pH anion-exchange chromatography with pulsed amperometric detection, and methylation analysis. In the absence of glutamine, cells secreted glycoprotein forms with preponderantly biantennary, proximal fucosylated carbohydrate chains (85%) with a higher NeuAc content (58%). Under standard conditions in the presence of 7.5 mM glutamine, complex-type N-glycans were found to be mainly biantennary (68%) and triantennary structures (33%) with about 50% containing proximal alpha1-6-linked fucose; 37% of the antenna were found to be substituted with terminal alpha2-3-linked N-acetylneuraminic acid. In the presence of 15 mM exogenously added NH4Cl, a significant and reproducible increase in tri- and tetraantennary oligosaccharides (45% of total) was detected in the secretion product. In glutamin-free cultures supplemented with glucosamine, an intermediate amount of high antennary glycans was detected. The increase in complexity of N-linked oligosaccharides is considered to be brought about by the increased levels of intracellular uridine diphosphate-GlcNAc/GalNAc. These nucleotide sugar pools were found to be significantly elevated in the presence of high NH3/NH4+ and glucosamine concentrations. PMID- 10099231 TI - Characterization of bacteriophage lambda Q- mutant for stable and efficient production of recombinant protein in Escherichia coli system. AB - We previously demonstrated that the lambda system integrated into the host chromosome can overcome the instability encountered in continuous operations of unstable plasmid-based expression vectors. High stability of a cloned gene in a lysogenic state and a high copy number in a lytic state provide cloned-gene stability and overexpression in a two-stage continuous operation. But the expression by the commonly used S- mutant lambda was only twice as high as that of the single copy. To increase the expression in the lambda system, we constructed a Q- mutant lambda vector that can be used in long-term operations such as a two-stage continuous operation. The Q- mutant phage lambda is deficient in the synthesis of proteins involved in cell lysis and lambda DNA packaging, while the S- mutant is deficient in the synthesis of one of two phage proteins required for lysis of the host cell and liberation of the progeny phage. Therefore, it is expected that the replicated Q- lambda DNA containing a cloned gene would not be coated by a phage head and would remain naked for ample expression of the cloned gene and host cells would not lyse easily and consequently would produce larger amounts of cloned-gene products. The beta galactosidase expression per unit cell by the Q- mutant in a lytic state was about 30 times higher than that in a lysogenic state, while the expression by the commonly used S- mutant in a lytic state was twice as high as that in a lysogenic state. The optimal switching time of the Q- mutant from the lysogenic state to the lytic state for the maximum production of beta-galactosidase was 5.3 h, which corresponds to an early log phase in the batch operation. PMID- 10099232 TI - Oscillation characteristics of biofilm streamers in turbulent flowing water as related to drag and pressure drop. AB - Mixed population biofilms consisting of Pseudomonas aeruginosa, P. fluorescens, and Klebsiella pneumoniae were grown in a flow cell under turbulent conditions with a water flow velocity of 18 cm/s (Reynolds number, Re, =1192). After 7 days the biofilms were patchy and consisted of cell clusters and streamers (filamentous structures attached to the downstream edge of the clusters) separated by interstitial channels. The cell clusters ranged in size from 25 to 750 microm in diameter. The largest clusters were approximately 85 microm thick. The streamers, which were up to 3 mm long, oscillated laterally in the flow. The motion of the streamers was recorded at various flow velocities up to 50.5 cm/s (Re 3351) using confocal scanning laser microscopy. The resulting time traces were evaluated by image analysis and fast Fourier transform analysis (FFT). The amplitude of the motion increased with flow velocity in a sigmoidal shaped curve, reaching a plateau at an average fluid flow velocity of approximately 25 cm/s (Re 1656). The motion of the streamers was possibly limited by the flexibility of the biofilm material. FFT indicated that the frequency of oscillation was directly proportional to the average flow velocity (u(ave)) below 9.5 cm/s (Re 629). At u(ave) greater than 9.5 cm/s, oscillation frequencies were above our measurable frequency range (0.12-6.7 Hz). The oscillation frequency was related to the flow velocity by the Strouhal relationship, suggesting that the oscillations were possibly caused by vortex shedding from the upstream biofilm clusters. A loss coefficient (k) was used to assess the influence of biofilm accumulation on pressure drop. The k across the flow cell colonized with biofilm was 2.2 times greater than the k across a clean flow cell. PMID- 10099233 TI - Enzyme array-amperometric detection in carbohydrate analysis. AB - The introduction of an enzyme array-electrochemical detection method for carbohydrate analysis is demonstrated by using two complex and one high mannose N linked oligosaccharides. Instead of measuring the remaining uncleaved oligosaccharides in enzymatic digestion, released monosaccharides are directly quantified by pulsed amperometric detection at a gold electrode. The measured monosaccharide concentrations in combination with the enzyme array analysis provide structural characterization of oligosaccharides. The enzyme array electrochemical detection method does not require any separation procedure or any prior labeling of oligosaccharides. However, this method is limited by the use of purified oligosaccharide samples and the nature of the enzyme array. The development of more sophisticated enzyme arrays relies upon the introduction of a bank of highly specific (bond, arm, aglycon) exoglycosidases. PMID- 10099234 TI - Thermobarostability of alpha-chymotrypsin in reversed micelles of aerosol OT in octane solvated by water-glycerol mixtures. AB - Thermostability of alpha-chymotrypsin at normal pressure in reversed micelles depends on both an effective surfactant solvation degree and glycerol content in the system. The difference in alpha-chymotrypsin stability in reversed micelles at various glycerol concentrations [up to 60% (v/v)] was more pronounced at high surfactant degrees of solvation, R >/= 16. After a 1-h incubation at 40 degrees C in "aqueous" reversed micelles (in the absence of glycerol), alpha-chymotrypsin retained only 1% of initial catalytic activity and 10, 22, 59, and 48% residual activity in glycerol-solvated micelles with 20, 30, 50, and 60% (v/v) glycerol, respectively. The explanation of the observed effects is given in the frames of micellar matrix structural order increasing in the presence of glycerol as a water-miscible cosolvent that leads to the decreasing mobility of the alpha chymotrypsin molecule and, thus the increase of its stability. It was found that glycerol or hydrostatic pressure could be used to stabilize alpha-chymotrypsin in reversed micelles; a lower pressure is necessary to reach a given level of enzyme stability in the presence of glycerol. PMID- 10099235 TI - Metabolic modeling of polyhydroxybutyrate biosynthesis. AB - A mathematical model describing intracellular polyhydroxybutyrate (PHB) synthesis in Alcaligenes eutrophus has been constructed. The model allows investigation of issues such as the existence of rate-limiting enzymatic steps, possible regulatory mechanisms in PHB synthesis, and the effects different types of rate expressions have on model behavior. Simulations with the model indicate that activities of all PHB pathway enzymes influence overall PHB flux and that no single enzymatic step can easily be identified as rate limiting. Simulations also support regulatory roles for both thiolase and reductase, mediated through AcCoA/CoASH and NADPH/NADP+ ratios, respectively. To make the model more realistic, complex rate expressions for enzyme-catalyzed reactions were used which reflect both the reversibility of the reactions and the reaction mechanisms. Use of the complex kinetic expressions dramatically changed the behavior of the system compared to a simple model containing only Michaelis Menten kinetic expressions; the more complicated model displayed different responses to changes in enzyme activities as well as inhibition of flux by the reaction products CoASH and NADP+. These effects can be attributed to reversible rate expressions, which allow prediction of reaction rates under conditions both near and far from equilibrium. PMID- 10099236 TI - Escape of autocrine ligands into extracellular medium: experimental test of theoretical model predictions. AB - We have developed an experimental system for testing mathematical model predictions concerning escape of autocrine ligands into the extracellular bulk medium. This system employs anti-receptor blocking antibodies against the epidermal growth factor receptor (EGFR)/transforming growth factor alpha (TGFalpha) receptor/ligand pair. TGFalpha was expressed under the control of a tetracycline-repressed promoter, together with a constitutively expressed human EGFR in B82 mouse fibroblast cells. This expression system allowed us to vary TGFalpha synthesis rates over a roughly 300-fold range by adjusting tetracycline concentration. TGFalpha accumulation in the extracellular bulk medium was then measured as a function of cell density, TGFalpha synthesis rate, and anti-EGFR blocking antibody concentration. Consistent with model predictions, amounts of ligand in the medium on a per cell basis were found to diminish as cell density was increased but with reduced dependence on cell density at higher ligand synthesis rates. Similarly consistent with model predictions, higher ligand synthesis rates also decreased the effect of anti-receptor blocking antibodies. Our investigation has established that we can successfully analyze and understand autocrine ligand secretion behavior from the basis of our theoretical model. PMID- 10099237 TI - Growth and morphology of anchorage-dependent animal cells in a liquid/liquid interface system. AB - In general, anchorage-dependent animal cells cultivated on a solid culture substrate, such as polystyrene, are collected by trypsin treatment. This treatment may have detrimental effects such as the proteolysis of the cell membrane proteins. To avoid these effects, cell cultivation using a liquid/liquid interface system has been investigated. In this cultivation method, the cells grow at the interface between a culture medium and a hydrophobic liquid. In this study, various fluorocarbons (FC-40, FC-70, KPF-91, KPF-102, and KPF-142) were used as substrates for the interface, and the cultivation of fibroblast cells (L 929; the mouse-derived cell line) at the interfaces was investigated. Early in the cultivation period, the growth of L-929 cells depended on the substrate type. Although cell cultivation at the interfaces was possible, it was slower than that at the polystyrene surface. Cell spreading at the interfaces was relatively small, which indicates that cell adhesion at the interfaces may be weak. In particular, the cells at the MEM/FC-70 interface anchored with one another and formed multicellular hemispherical aggregations shaped like spheroids. The difference in the adhesions to the interfaces appears to be dependent on the contaminants contained in the fluorocarbons because the physical properties of the fluorocarbon did not affect the cell growth and adhesion. Moreover, subcultivation from the interfaces to the same interface was possible without trypsin treatment. In this case, the delay of the growth at the interfaces did not occur because the cells were not affected by trypsin treatment. PMID- 10099238 TI - Improved protein refolding using hollow-fibre membrane dialysis. AB - We have used a cellulose acetate, hollow-fibre (HF) ultrafiltration membrane to refold bovine carbonic anhydrase, loaded into the lumen space, by removing the denaturant through controlled dialysis via the shell side space. When challenged with GdnHCl-denatured carbonic anhydrase, 70% of the loaded protein reptated through the membrane into the circulating dialysis buffer. Reptation occurred because the protein, in its fully unfolded configuration, was able to pass through the pores. The loss of carbonic anhydrase through the membrane was controlled by the dialysis conditions. Dialysis against 0.05 M Tris-HCl for 30 min reduced the denaturant around the protein to a concentration that allowed the return of secondary structure, increasing the hydrodynamic radius, thus preventing protein transmission. Under these conditions a maximum of 42% of carbonic anhydrase was recovered (from a starting concentration of 5 mg/mL) with 94% activity. This is an improvement over refolding carbonic anhydrase by simple batch dilution, which gave a maximum reactivation of 85% with 35% soluble protein yield. The batch refolding of carbonic anhydrase is very sensitive to temperature; however, during HF refolding between 0 and 25 degrees C the temperature sensitivity was considerably reduced. In order to reduce the convection forces that give rise to aggregation and promote refolding the dialyzate was slowly heated from 4 to 25 degrees C. This slow, temperature controlled refolding gave an improved soluble protein recovery of 55% with a reactivation yield of 90%. The effect of a number of additives on the refolding system performance were tested: the presence of PEG improved both the protein recovery and the recovered activity from the membrane, while the detergents Tween 20 and IGEPAL CA-630 increased only the refolding yield. PMID- 10099239 TI - Enhanced secretion of human granulocyte colony-stimulating factor directed by a novel hybrid fusion peptide from recombinant Saccharomyces cerevisiae at high cell concentration. AB - The synthesis and secretion of recombinant human granulocyte colony-stimulating factor (rhG-CSF) are investigated in fed-batch cultures at high cell concentration of recombinant Saccharomyces cerevisiae, and some important characteristics of the secreted rhG-CSF are demonstrated. Transcription of the recombinant gene is regulated by a GAL1-10 upstream activating sequence (UASG), and the rhG-CSF is expressed in a hybrid fusion protein consisting of signal sequence of Kluyveromyces lactis killer toxin and N-terminal 24 amino acids of human interleukin 1beta. The intracellular KEX2 cleavage leads to excretion of mature rhG-CSF into extracellular culture broth, and the cleavage process seems to be highly efficient. In spite of relatively low copy number the plasmid propagation is stably maintained even at nonselective culture conditions. The rhG CSF synthesis does not depend on galactose level, whereas the production of extracellular rhG-CSF was significantly enhanced by increasing the inducer concentration above a certain level and also by supplementing the nonionic surfactant to the culture medium, which is notably due to the enhanced secretion efficiency. Various immunoblotting analyses demonstrate that none of the rhG-CSF is accumulated in the cell wall fraction and that a significant amount of intracellular rhG-CSF antibody-specific immunoreactive proteins is located in the ER. A core N-glycosylation at fused IL-1beta fragment is likely to play a critical role in directing the high-level secretion of rhG-CSF, and the O glycosylation of secreted rhG-CSF seems nearly negligible. Also the extracellular rhG-CSF is observed to exist as various multimers, and the nature of molecular interaction is evidently not the covalent disulfide bridges. The CD spectra of purified rhG-CSF and Escherichia coli-derived standard show that the conformations of both are similar and are almost identical to that reported for natural hG-CSF. PMID- 10099240 TI - Identification and control of oxidative metabolism in Ssaccharomyces cerevisiae during transient growth using calorimetric measurements. AB - The objective of this study was to characterize the dynamic adaptation of the oxidative capacity of Saccharomyces cerevisiae to an increase in the glucose supply rate and its implications for the control of a continuous culture designed to produce biomass without allowing glucose to be diverted into the reductive metabolism. Continuous cultures subjected to a sudden shift-up in the dilution rate showed that the glucose uptake rate increased immediately to the new feeding rate but that the oxygen consumption could not follow fast enough to ensure a completely oxidative metabolism. Thus, part of the glucose assimilated was degraded by the reductive metabolism, resulting in a temporary decrease of biomass concentration, even if the final dilution rate was below Dcrit. The dynamic increase of the specific oxygen consumption rate, qO2, was characterized by an initial immediate jump followed by a first-order increase to the maximum value. It could be modeled using three parameters denoted qjumpO2, qmaxO2, and a time constant tau. The values for the first two of the parameters varied considerably from one shift to another, even when they were performed under identical conditions. On the basis of this model, a time-dependent feed flow rate function was derived that should permit an increase in the dilution rate from one value to another without provoking the appearance of reductive metabolism. The idea was to increase the glucose supply in parallel with the dynamic increase of the oxidative capacity of the culture, so that all of the assimilated glucose could always be oxidized. Nevertheless, corresponding feed-profile experiments showed that deviations in the reductive metabolism could not be completely suppressed due to variability in the model parameters. Therefore, a proportional feedback controller using heat evolution rate measurements was implemented. Calorimetry provides an excellent and rapid estimate of the metabolic activity. Satisfactory control was achieved and led to constant biomass yields. Ethanol accumulated only up to 0.49 g L-1 as compared to an accumulation of 1.82 g L-1 without on-line control in the shift-up experiment to the same final dilution rate. PMID- 10099241 TI - Protein refolding by reversed micelles utilizing solid-liquid extraction technique. AB - This article reports that a reversed micellar solution is useful for refolding proteins directly from a solid source. The solubilization of denatured RNase A, which had been prepared by reprecipitation from the denaturant protein solution, into reversed micelles formulated with sodium di-2-ethylhexyl sulfosuccinate (AOT) has been investigated by a solid-liquid extraction system. This method is an alternative to the ordinary protein extraction in reversed micelles based on the liquid-liquid extraction. The solid-liquid extraction method was found to facilitate the solubilization of denatured proteins more efficiently in the reversed micellar media than the ordinary phase transfer method of liquid extraction. The refolding of denatured RNase A entrapped in reversed micelles was attained by adding a redox reagent (reduced and oxidized glutathion). Enzymatic activity of RNase A was gradually recovered with time in the reversed micelles. The denatured RNase A was completely refolded within 30 h. In addition, the efficiency of protein refolding was enhanced when reversed micelles were applied to denatured RNase A containing a higher protein concentration that, in the case of aqueous media, would lead to protein aggregation. The solid-liquid extraction technique using reversed micelles affords better scale-up advantages in the direct refolding process of insoluble protein aggregates. PMID- 10099242 TI - Molecular cloning of extremely thermostable esterase gene from hyperthermophilic archaeon Pyrococcus furiosus in Escherichia coli. AB - A genomic library of the hyperthermophilic archaeon Pyrococcus furiosus was constructed in Escherichia coli using pBluescript II SK(+) as a cloning vector. One positive clone exhibiting thermophilic ester-hydrolyzing activity was directly detected by an in situ plate assay using the chromogenic substrate 5 bromo-4-chloro-3-indolyl-acetate. The plasmid isolated from the clone contained a 3.8 kb HindIII fragment from P. furiosus. Expression of active thermostable esterase in E. coli was independent of isopropyl-beta-D-thiogalactopyranoside, suggesting that the archaeal esterase gene was heterologously controlled by its own promoter sequence, not by the vector-located lac promoter. Assays of esterase activity in heat-treated extract of the recombinant E. coli showed the highest temperature optimum (100 degrees C) and thermostability (a half-life of 50 min at 126 degrees C) among esterases reported to date. PMID- 10099243 TI - Two-phase bioconversion product recovery by microfiltration I. Steady state studies. AB - Recovery of an aqueous bioconversion product from complex, two-phase Pseudomonas putida broths containing 20% (v/v) soybean oil presents a significant challenge for downstream processing. Although not used before in multiple-phase separation for complex biotech products, crossflow filtration employing ceramic filters is one of the most attractive options which allow the design of integrated, continuous bioconversion processes. As a first attempt, we studied multichannel, monolithic ceramic membranes of different nominal pore sizes and lumen diameters under steady-state conditions. The best performance was obtained with 0.2-microm pore/3-mm-lumen membrane, which completely rejected both cells and oil droplets from the permeate, creating a clear aqueous product stream. Although the same separation was achieved, the 50K molecular weight cut-off (MWCO) ultrafilter showed greater irreversible but similar reversible resistance, in addition to an order-of-magnitude higher membrane resistance. Larger nominal pore microfilters, such as 0.45 and 1.0 microm, experienced both cell and oil leakage even at low transmembrane pressure (10 psig). Attributed to greater shear at the same recirculation rate, smaller lumen filters did provide greater permeate flux. However, for practical purposes, the 0. 2-microm-pore/4-mm-lumen ceramic membrane was chosen for further evaluation. Transmembrane pressures up to 50 psig provided only marginal gains in filtration performance, whereas increasing shear rate resulted in linear increases in steady-state flux, presumably due to formation of shear-sensitive, complex gel/oil/cell layer near the membrane surface. A nominal shear rate of 9200 s-1 and 20 psig transmembrane pressure were chosen as optimal operating conditions. Additional studies in a clean system revealed that as low as 5% (v/v) soybean oil in deionized (DI) water resulted in an order-of-magnitude decline in steady-state permeate flux. Breakthrough of oil droplets occurred at 35 psig transmembrane pressure. The severe fouling and breakthrough phenomena disappeared in the presence of washed cells for transmembrane pressure up to 43 psig, implying an oil/cell layer coating the membrane surface, thus preventing oil penetration. Serious membrane fouling was also experienced in microfiltration of oil-free, cell-free supernatant and oil-free whole broth. Consequently, soluble proteins/surfactants were suspected to be the major membrane foulants. Interestingly, soybean oil up to 30% (v/v) enhanced the flux, presumably through complicated interactions with the major foulants. Regeneration of membrane was best achieved with protease and hot caustic/bleach treatments, supporting the hypothesized fouling mechanisms mentioned above. This work provides process and system information for batch microfiltration runs in the future, to be reported elsewhere as Part II of this work. PMID- 10099244 TI - Determinants and rate laws of growth and death of hybridoma cells in continuous culture. AB - Experimental data from six hybridoma cell lines grown under diverse experimental conditions in both normal continuous and perfusion cultures are analyzed with respect to the significance of nutrients and products in determining the growth and death rates of cells and with respect to their mathematical modeling. It is shown that neither nutrients (glucose and glutamine) nor the common products lactic acid, ammonia, and monoclonal antibody can be generally assumed to be the clear-limiting or inhibiting factors for most of the cultures. Correspondingly, none of the unstructured models existing in the literature can be generally applied to describe the experimental data obtained over a relatively wide range of cultivation conditions as considered in this work. Surprisingly, for all cultures the specific growth rate (mu) almost linearly correlates with the ratio of the viable cell concentration (NV) to the dilution (perfusion) rate (D). Similarly, the specific death rate (kd) is a function of the ratio of the total cell concentration (Nt) to the dilution (perfusion) rate. These results strongly suggest the formation of not yet identified critical factors or autoinhibitors that determine both the growth and death rates of hybridoma cells. Based on these observations, simple kinetic models are developed for mu and kd which describe the experimental data satisfactorily. Analysis of the experimental data with the kinetic models reveals that under the current cultivation conditions the formation rate of the autoinhibitor(s) or the sensitivity of cell growth and death to the autoinhibitor(s) is mainly affected by the medium composition. Irrespective of the cell lines, cells grown on serum-containing media have almost the same model parameters, which are distinctively different from those of cells grown on serum-free media. Furthermore, in contrast to the prevailing view, kd is shown to positively correlate with mu if the effects of cell concentration and dilution (perfusion) rate are considered. Several important implications of these findings are discussed for the optimization and control of animal cell culture. PMID- 10099245 TI - A sensitivity study of the key parameters in the interfacial photopolymerization of poly(ethylene glycol) diacrylate upon porcine islets. AB - A method has been defined to interfacially photopolymerize poly(ethylene glycol) diacrylates (PEG diacrylates) to form a crosslinked hydrogel membrane upon the surfaces of porcine islets of Langerhans to serve as an immune barrier for allo- and xenotransplantation. A sensitivity study of six key parameters in the interfacial photopolymerization process was performed to aid in determination of the optimal encapsulation conditions, leading to the most uniform hydrogel membranes and viable islets. The key parameters included the concentrations of the components of the initiation scheme, namely eosin Y, triethanolamine, and 1 vinyl 2-pyrrolidinone. Other parameters investigated included the duration and flux of laser irradiation and the PEG diacrylate molecular weight. Each parameter was doubled and halved from the standard conditions used in the encapsulation process while holding all the remaining parameters at the standard conditions. The effects of changing each parameter on islet viability, encapsulation efficiency, and gel thickness were quantified. Islet viability was sensitive to the duration of laser illumination, viability significantly increasing as the duration was reduced. Encapsulation efficiency was sensitive to the concentrations of eosin Y, triethanolamine, and 1-vinyl 2-pyrrolidinone, to the laser flux, and to the PEG diacrylate molecular weight. Increasing the concentration of eosin Y significantly improved the encapsulation efficiency, while decreasing the concentration of 1-vinyl 2-pyrrolidinone and increasing the concentration of triethanolamine had the greatest effects in significantly reducing the encapsulation efficiency. Gel thickness was sensitive to the concentrations of triethanolamine and 1-vinyl 2-pyrrolidinone, to the duration of laser illumination, and to the PEG diacrylate molecular weight. Increasing the PEG diacrylate molecular weight significantly increased the gel thickness, while decreasing the concentration of 1-vinyl 2-pyrrolidinone and increasing the concentration of triethanolamine had the greatest effects in significantly reducing the gel thickness. From this sensitivity study, conditions were determined to encapsulate porcine islets, resulting in greater than 90% islet viability and greater than 90% encapsulation efficiency. PMID- 10099246 TI - Nucleation and growth of microbial lipase crystals from clarified concentrated fermentation broths. AB - Bulk crystallization is emerging as a new industrial operation for protein recovery. Characterization of bulk protein crystallization is more complex than protein crystallization for structural study where single crystals are grown in flow cells. This is because both nucleation and crystal growth processes are taking place while the supersaturation falls. An algorithm is presented to characterize crystallization using the rates of the two kinetic processes, nucleation and growth. The values of these rates allow ready comparison of the crystallization process under different operating conditions. The crystallization, via adjustment to the isoelectric pH of a fungal lipase from clarified fermentation broth, is described for a batch stirred reactor. A maximum nucleation rate of five to six crystals formed per microliter of suspension per second and a high power dependency ( approximately 11) on the degree of supersaturation were found. The suspended protein crystals were found to grow at a rate of up to 15-20 nm/s and also to exhibit a high power dependency ( approximately 6) of growth rate on the degree of supersaturation. PMID- 10099247 TI - Long-term competition between sulfate reducing and methanogenic bacteria in UASB reactors treating volatile fatty acids. AB - The competition between acetate utilizing methane-producing bacteria (MB) and sulfate-reducing bacteria (SRB) was studied in mesophilic (30 degrees C) upflow anaerobic sludge bed (UASB) reactors (upward velocity 1 m h-1; pH 8) treating volatile fatty acids and sulfate. The UASB reactors treated a VFA mixture (with an acetate:propionate:butyrate ratio of 5:3:2 on COD basis) or acetate as the sole substrate at different COD:sulfate ratios. The outcome of the competition was evaluated in terms of conversion rates and specific methanogenic and sulfidogenic activities. The COD:sulfate ratio was a key factor in the partitioning of acetate utilization between MB and SRB. In excess of sulfate (COD:sulfate ratio lower than 0.67), SRB became predominant over MB after prolonged reactor operation: 250 and 400 days were required to increase the amount of acetate used by SRB from 50 to 90% in the reactor treating, respectively, the VFA mixture or acetate as the sole substrate. The competition for acetate was further studied by dynamic simulations using a mathematical model based on the Monod kinetic parameters of acetate utilizing SRB and MB. The simulations confirmed the long term nature of the competition between these acetotrophs. A high reactor pH (+/-8), a short solid retention time (<150 days), and the presence of a substantial SRB population in the inoculum may considerably reduce the time required for acetate-utilising SRB to outcompete MB. PMID- 10099249 TI - Transformation of 3,5-dimethoxy,4-hydroxy cinnamic acid by polyphenol oxidase from the fungus Trametes versicolor: product elucidation studies. AB - Sinapic acid (SA), 3,5-dimethoxy,4-hydroxy cinnamic acid, was incubated with a crude polyphenol oxidase from the fungus Trametes versicolor. Some products of this transformation were isolated and their structures identified using mass spectrometry, nuclear magnetic resonance and Fourier transform infrared spectroscopy, and X-ray crystallography. It was found that the enzymatic oxidation of SA includes two distinct phases. In the initial phase SA is enzymatically transformed to r-1H-2c,6c-bis-(4'-hydroxy-3', 5'-dimethoxyphenyl) 3,7-dioxabicyclo-[3,3,0]-octane-4,8-dione, dehydrodisinapic acid dilactone. The mechanism of this reaction may involve coupling of two phenoxy radicals by the beta-beta mode and subsequent intramolecular nucleophilic attack. In the second phase dehydrodisinapic acid dilactone is transformed by polyphenol oxidase into several intermediate products, including 4-(4-(3, 5-dimethoxy-4-oxo-2,5 cyclohexadienyliden)-1, 4-dihydroxy-(E)-2-butenylidene)-2,6-dimethoxy-2, 5 cyclohexadien-1-one. The final product of the overall transformation of SA is 2,6 dimethoxy-p-benzoquinone. The obtained results were used to propose a part of the transformation pathway for the enzymatic oxidation of SA by polyphenol oxidase. PMID- 10099248 TI - Multinuclear NMR study of enzyme hydration in an organic solvent. AB - Multinuclear NMR spectroscopy has been used to study water bound to subtilisin Carlsberg suspended in tetrahydrofuran (THF), with the water itself employed as a probe of the hydration layer's physicochemical and dynamic characteristics. The presence of the enzyme did not affect the intensity, chemical shift or linewidth of water (up to 8% v/v) added to THF, as measured by 17O- and 2H-NMR. This finding suggests that hydration of subtilisin can be described by a three-state model that includes tightly bound, loosely bound, and free water. Solid-state 2H NMR spectra of enzyme-bound D2O support the existence of a non-exchanging population of tightly bound water. An important implication is that the loosely bound water is the same as free water from an NMR viewpoint. This loosely bound water must also be the water responsible for the large increase in catalytic activity observed in previous hydration studies. PMID- 10099250 TI - In vitro degradation of natural insoluble lignin in aqueous media by the extracellular peroxidases of Phanerochaete chrysosporium. AB - The lignin peroxidases (LIP) and manganese peroxidases (MNP) of Phanerochaete chrysosporium catalyze a wide range of lignin depolymerization reactions with lignin models and synthetic lignins in solution. However, their ability to degrade insoluble natural lignin in aqueous media has not been demonstrated. Insoluble isolated poplar lignin similar to natural lignin was treated in vitro in aqueous media for 12 h with LIP, MNP, and both. Treatment with MNP alone slightly increased the solid mass and produced measurable amounts of lignin derived 2,6-dimethoxyhydroquinone and 2-methoxyhydroquinone but did not appreciably decrease the total lignin content. Treatment with LIP alone did not decrease the mass but produced measurable amounts of lignin-derived p hydroxybenzoic acid and slightly decreased the lignin content. Finally, treatment with LIP and MNP together decreased the solid mass by 11%, decreased the lignin content by 5%, and released low-concentration compounds with mass spectra containing the typical lignin-derived electron-impact fragments of mass 107, 137, 151, 167, and 181. These results suggest that MNP increases the effectiveness of LIP-mediated lignin degradation. PMID- 10099251 TI - A new combined differential-discrete cellular automaton approach for biofilm modeling: application for growth in gel beads. AB - The theoretical basis and quantitative evaluation of a new approach for modeling biofilm growth are presented here. Soluble components (e.g., substrates) are represented in a continuous field, whereas discrete mapping is used for solid components (e.g., biomass). The spatial distribution of substrate is calculated by applying relaxation methods to the reaction-diffusion mass balance. A biomass density map is determined from direct integration in each grid cell of a substrate-limited growth equation. Spreading and distribution of biomass is modeled by a discrete cellular automaton algorithm. The ability of this model to represent diffusion-reaction-microbial growth systems was tested for a well characterized system: immobilized cells growing in spherical gel beads. Good quantitative agreement with data for global oxygen consumption rate was found. The calculated concentration profiles of substrate and biomass in gel beads corresponded to those measured. Moreover, it was possible, using the discrete spreading algorithm, to predict the spatial two- and three-dimensional distribution of microorganisms in relation to, for example, substrate flux and inoculation density. The new technique looks promising for modeling diffusion reaction-microbial growth processes in heterogeneous systems as they occur in biofilms. PMID- 10099252 TI - Polysaccharide production by plant cells in suspension: experiments and mathematical modeling. AB - Symphytum officinale L cells were grown in Erlenmeyer flasks at four different temperatures: 15, 20, 25, and 30 degrees C. A mathematical model of the culture growth is presented. The intracellular and extracellular products are considered in separate equations. An interrelation between fresh weight, dry weight, and viability is considered in the balances. The model includes a description of the changes in time of wet and dry biomass, cell viability, substrate concentration and polysaccharide concentration, both intra- and extracellular. The model was tested by fitting the numerical results to the data obtained. PMID- 10099253 TI - Molecular-modeling calculations of enzymatic enantioselectivity taking hydration into account. AB - A new molecular-modeling methodology has been applied to explain enzymatic enantioselectivity in water. This methodology, which combines vacuum molecular mechanics and the continuum solvation method, should provide a more realistic view of the solvent-enzyme and solvent-substrate interactions than the heretofore used approaches involving the vacuum molecular mechanics only. The methodology described herein has been validated using the experimental data on alpha chymotrypsin's enantioselectivity in the hydrolysis of four chiral substrates. The reasons why the vacuum molecular mechanics, although not taking hydration into account, still in most cases provide a satisfactory approximation of reality are discussed. PMID- 10099254 TI - On enzymatic activity in organic solvents as a function of enzyme history. AB - Catalytic activities of alpha-chymotrypsin and subtilisin Carlsberg in various hydrous organic solvents were measured as a function of how the enzyme suspension had been prepared. In one method, lyophilized enzyme was directly suspended in the solvent containing 1% water. In another, the enzyme was precipitated from its aqueous solution by a 100-fold dilution with an anhydrous solvent. In most cases, the reaction rate in a given nonaqueous enzymatic system strongly (up to an order of magnitude) depended on the mode of enzyme preparation. The magnitude of this dependence was markedly affected by the nature of the solvent and enzyme. A mechanistic hypothesis proposed to explain the observed dependencies was verified in additional experiments in which the water contents and enzyme history were further varied. PMID- 10099255 TI - Applicability of competitive and noncompetitive kinetics to the reductive dechlorination of chlorinated ethenes. AB - Reductive dechlorination of chlorinated ethenes has typically been modeled using standard Michaelis-Menten kinetic equations, implying that each dechlorination step is catalyzed by a unique biological factor. An alternative kinetic model is based on the assumption that all steps are mediated by a single factor. These two options are considered in the context of chlorinated ethene degradation by a previously characterized anaerobic culture. Competitive kinetics afford better chi-squared and visual fits of the data set tested. PMID- 10099256 TI - Continuous culture dynamics for aniline metabolism by Pseudomonas sp. CIT1. AB - Inhibition by toxic substrates enables multiple steady states to arise in biodegradation systems. This phenomenon was investigated for the continuous metabolism of aniline by Pseudomonas sp. CIT1. Differences of various metabolic parameters between the two growth regimes (uninhibited and inhibited) and the transient response to a step-up in dilution rate were determined. Regulatory mechanisms consistent with the experimental evidence are proposed. Aniline is the transcriptional inducer of a metabolic pathway that converts aniline to TCA cycle intermediates. The suite of enzymes is coordinately expressed from a single promoter. We followed the level of the pathway mRNA using a fragment containing the catechol 2,3 dioxygenase gene (andioxB) and monitored the pathway enzyme activity using catechol 2,3 dioxygenase (C23D). The inhibited regime resulted in a 60% lower growth yield, near constant levels of C23D monomer, but a 50% reduction in the specific activity of C23D, increased RNA synthesis rates (total and aniline pathway mRNA), and elevated RNA decay rates. Elucidation of regulatory mechanisms indicates that C23D is noncompetitively inhibited by aniline and subject to feedback inhibition by 2-hydroxymuconic semialdehyde (HMS). During uninhibited growth regime operation, metabolism of HMS is the rate limiting step; in contrast, conversion of aniline to catechol limits growth in the inhibited regime. PMID- 10099257 TI - Expert system for control of anaerobic digesters. AB - Continuous anaerobic digesters are systems that present challenging control problems including the possibility that an unmeasured disturbance can change the sign of the steady-state process gain. An expert system is developed that recognizes changes in the sign of process gain and implements appropriate control laws. The sole on-line measured variable is the methane production rate, and the manipulated input is the dilution rate. The expert system changes the dilution rate according to one of four possible strategies: a constrained conventional set point control law, a constant yield control law (CYCL) that is nearly optimal for the most common cause of change in the sign of the process gain, batch operation, or constant dilution rate. The algorithm uses a t test for determining when to switch to the CYCL and returns to the conventional set-point control law with bumpless transfer. The expert system has proved successful in several experimental tests: severe overload; mild, moderate, and severe underload; and addition of phenol in low and high levels. Phenol is an inhibitor that in high concentrations changes the sign of the process gain. PMID- 10099258 TI - Removal of proteoglycans increases efficiency of retroviral gene transfer. AB - We have previously shown that medium conditioned by virus producer cells inhibits retrovirus transduction, and that a portion of the inhibitory activity is sensitive to chondroitinase ABC. In this study, we have quantitatively evaluated the fraction of the inhibitory activity that is due to chondroitinase ABC sensitive material and partially characterized the inhibitors. The kinetics of chondroitinase ABC digestion of glycosaminoglycans and virus inhibitory activity in cell culture medium were measured, and the results used to estimate the amount of the chondroitinase ABC-sensitive virus inhibitory activity that was initially in the medium. We found that up to 76% of the inhibitory activity of medium conditioned by packaging cells derived from NIH 3T3 cells is sensitive to chondroitinase ABC. The remainder of the inhibitory activity is not sensitive to other glycosaminoglycan lyases (heparitinase I or heparinase I), which suggests that substances other than glycosaminoglycans or proteoglycans are present in virus stocks and inhibit transduction. To further characterize the inhibitors, proteoglycans from conditioned medium were purified by batch anion exchange and size exclusion chromatography. Two major size groups (100 kDa and 950 kDa) of proteoglycans were isolated. Transduction was inhibited 50% by 0.6 microg/mL of the high-molecular-weight proteoglycan or by 1.7 microg/mL of the low-molecular weight proteoglycan. Significantly, the proteoglycans, because of their large size and poor sieving properties, coconcentrated with virus particles concentrated by ultrafiltration and prevented any significant increases in transduction efficiency. Transduction efficiencies of virus stocks were increased more than tenfold by ultrafiltration, but only when the concentrated virus was treated with chondroitinase ABC. PMID- 10099259 TI - Examination of protein adsorption in fluidized bed and packed bed columns at different temperatures using frontal chromatographic methods. AB - The influences of various experimental parameters on the dynamic adsorption capacity (DAC) and the dynamic adsorption rate (DAR) of a biomimetic affinity silica-based adsorbent in fluidized and packed bed columns operated under plug flow conditions and at different temperatures have been investigated with different inlet concentrations of hen egg white lysozyme (HEWL) and human serum albumin (HSA). The DACs as well as the DARs of both the fluidized and packed beds were examined at 10% saturation (i.e., at the QB value) and the experimental data compared with the corresponding data obtained from batch equilibrium adsorption procedures. Parameters examined included the fluid superficial velocity and protein concentration and their effect on the binding capacity and column efficiency. Consistent with various results reported from this and other laboratories on the behavior of biospecific affinity adsorbents derived from porous silica and zirconia particles, adsorbents prepared from Fractosil 1000 were found to exhibit appropriate rheological characteristics in fluidized bed systems under the experimental conditions. Moreover, changes in temperature resulted in a more significant effect on the breakthrough profiles of HSA compared to HEWL with the immobilized Cibacron Blue F3G-A with Fractosil 1000 adsorbent. This result suggests that temperature effects can possibly be employed profitably in some processes as part of a strategy to enhance column performance with fluidized bed systems for selective recovery of target proteins. At relatively low superficial velocities of the feed, the DARs with HEWL and HSA were similar for both the fluidized and packed bed column systems, whereas, at high superficial velocities, the DARs for these proteins were larger with the packed bed columns. PMID- 10099260 TI - Yeast suspension filtration: flux enhancement using an upward gas/liquid slug flow-application to continuous alcoholic fermentation with cell recycle. AB - This study deals with the use of an upward gas/liquid slug flow to reduce tubular mineral membrane fouling. The injection of air into the feedstream is designed to create hydrodynamic conditions that destabilize the cake layer over the membrane surface inside the filtration module complex. Experimental study was carried out by filtering a biological suspension (yeast) through different tubular mineral membranes. The effects of operating parameters, including the nature of the membrane, liquid and gas flowrates, and transmembrane pressure, were examined. When external fouling was the main limiting phenomenon, flux enhancements of a factor of three could be achieved with gas sparging compared with single liquid phase crossflow filtration. The economic benefits of this unsteady technique have also been examined. To investigate the possibility of long-term operation of the two-phase flow principle, dense cell perfusion cultures of Saccharomyces cerevisiae were carried out in a fermentor coupled with an ultrafiltration module. The air injection allowed a high and stable flux to be maintained over 100 h of fermentation, with a final cell concentration of 150 g dry weight/L. At equal biomass level, a twofold gain in flux could be attained compared with classical steady crossflow filtration at half the cost. PMID- 10099261 TI - Affinity extraction of proteins with a reversed micellar system composed of Cibacron Blue-modified lecithin. AB - Crude soybean lecithin was used as a novel surfactant to form reversed micelles in n-hexane. Cibacron Blue F-3GA (CB) was directly immobilized to the reversed micelles by a two-phase reaction. The reversed micellar system without CB showed low solubilizing capacity for low molecular weight proteins, lysozyme, and cytochrome c due to the weak electrostatic interactions. The introduction of CB significantly increased the solubilization of lysozyme because of its affinity binding to CB but showed no effect on the solubilization of cytochrome c since it did not bind to CB. Although bovine serum albumin had an affinity for CB, it was not extracted to the reversed micelles containing CB because its high molecular weight resulted in a significant steric hindrance effect. Thus the reversed micellar system had a high selectivity resulting from both biospecific and steric hindrance effects. The extraction yield of lysozyme decreased significantly with increasing ionic strength. Therefore, the back extraction of lysozyme was carried out using a stripping solution with an ionic strength of 0.865 mol/L. The overall recovery yield of lysozyme after back extraction could be increased to 87% by stripping for 2 h. The recovered lysozyme exhibited an activity equivalent to native lysozyme, and its secondary structure was also unchanged. PMID- 10099262 TI - Establishment of an apoptosis-resistant and growth-controllable cell line by transfecting with inducible antisense c-Jun gene. AB - F-MEL cells were transfected with the c-jun antisense gene located downstream of a glucocorticoid-inducible MMTV promoter, and the obtained cells were named c-jun AS cells. When the c-jun AS cells were treated with dexamethasone (DEX) in DMEM supplemented with 10% serum, the growth of the cells was completely suppressed for a duration of 16 days with a high cell viability exceeding 86%. The c-jun expression in the c-jun AS cells was suppressed moderately in the absence of DEX and strongly in the presence of DEX. The c-jun AS cells grew well and reached a density of 10(6) cells/mL without supplementation of any serum components. Viability was greater than 80% after the cells had been cultured for 8 days in the absence of DEX. The c-jun AS cells stayed at a constant cell density and high viability above 80% for 8 days when they were cultured in the presence of DEX under serum deprivation. In contrast, the wild type F-MEL cells were unable to grow and died by apoptosis in 3 days under serum deprivation. Internucleosomal cleavage of DNA, a landmark of apoptosis, was clearly detectable. Thus the c-jun AS cell line that is resistant to apoptosis induced by serum deprivation and can reversibly and viably be growth-arrested was established. A dual-signal model was proposed to explain the experimental result, the interlinked regulation of apoptosis, and growth by c-jun. PMID- 10099263 TI - Characterization of chimeric antibody producing CHO cells in the course of dihydrofolate reductase-mediated gene amplification and their stability in the absence of selective pressure. AB - Recombinant Chinese hamster ovary (CHO) cells expressing a high-level of chimeric antibody against S surface antigen of hepatitis B virus were obtained by co transfection of heavy and light chain cDNA expression vectors into dihydrofolate reductase (dhfr)-deficient CHO cells and subsequent gene amplification in medium containing stepwise increments in methotrexate (MTX) level such as 0.02, 0.08, 0.32, 1.0, and 4.0 microM. The highest producer (HP) subclone was isolated from each MTX level and was characterized with respect to cell growth and antibody production in the corresponding level of MTX. The specific growth rate of the HP subclone was inversely proportional to the MTX level. On the other hand, its specific antibody productivity (qAb) rapidly increased with increasing MTX level up to 0.08 microM, and thereafter, it gradually increased to 20 microg/10(6) cells/day at 4 microM MTX. Southern blot analysis showed that the enhanced qAb at higher MTX level resulted from immunoglobulin (Ig) gene amplification. The stability of the HP subclones isolated at 0.02, 0.08, 0.32, and 1.0 microM MTX in regard to antibody production was investigated during long-term culture in the absence of MTX. The qAb of all subclones significantly decreased during the culture. However, the relative extent of decrease in qAb was variable among the subclones. The HP subclone isolated at 1 microM MTX was most stable and could retain 59% of the initial qAb after 80 days of cultivation. Southern blot analysis showed that this decrease in qAb of the subclones resulted mainly from the loss of Ig gene copies during long-term culture. Despite the decreased qAb, the HP subclone isolated at 1 microM MTX could maintain high volumetric antibody productivity over three months because of improved cell growth rate during long term culture. PMID- 10099264 TI - Enhanced TGFbeta1 maturation in high five cells coinfected with recombinant baculovirus encoding the convertase furin/pace: improved technology for the production of recombinant proproteins in insect cells. AB - One important limitation of the widely used insect baculovirus overexpression system is its inefficiency to properly process heterologous proteins which are initially biosynthesized as larger inactive precursor proteins. One example is transforming growth factor beta 1 (TGFbeta1), a 25-kDa homodimeric protein with pleiotropic functions. As many growth factors, the inactive TGFbeta1 precursor molecule needs to be proteolytically cleaved C-terminal to a basic sequence to yield the mature and active homodimer. In insect cells, a large proportion of overexpressed TGFbeta1 was found in an inactive precursor form suggesting that the levels of endogenous convertases are limiting for the production of mature and bioactive TGFbeta1 in this system. We have demonstrated that furin, a member of a novel family of mammalian prohormone convertases (PCs) can efficiently process TGFbeta1 precursor resulting in the production of the mature and active growth factor. Taking advantage of this observation, we have developed an improved overproduction system for TGFbeta1 by coexpressing prohTGFbeta1 and human furin convertase in High Five cells. Using this system, the production of mature active TGFbeta1 increased in a dose-dependent fashion reaching up to 7. 8 fold the amount obtained with the growth factor only. Thus, eliminating the rate limiting step in recombinant TGFbeta1 production maximizes its processing efficiency and the yield of the mature active growth factor. Such simple and efficient technology could be useful for large scale production of other proproteins which undergo similar maturation processes and share furin recognition sequences at the junction between the proregion and the mature polypeptide. PMID- 10099265 TI - Growth characteristics of Escherichia coli HB101[pGEc47] on defined medium. AB - This paper shows that differences in growth behavior of Escherichia coli strain HB101 and strain HB101[pGEc47] can be related to yeast extract-enriched medium rather than plasmid properties. An optimal medium for growth of E. coli HB101[pGEc47] was designed based on the individual yield coefficients for specific medium components (NH4+ 6 g g-1, PO43- 14 g g-1, SO42- 50 g g-1). The yield coefficient for L-leucine depends on the glucose content of the medium (20 g g-1 for 3% glucose, 40 g g-1 for 1% glucose) and the yield coefficient for L proline depends on the cultivation mode (20 g g-1 for batch cultivation, 44 g g-1 for continuous cultivation). Growth on defined medium after medium optimization is as rapid as on complex medium (0. 42-0.45 h-1). The critical dilution rate (DR) in the defined medium above which undesired production of acetic acid occurs is in the range of 0.23-0.26 h-1. PMID- 10099267 TI - Macroporous chitin affinity membranes for lysozyme separation PMID- 10099266 TI - Mathematical modeling of biofilm structure with a hybrid differential-discrete cellular automaton approach. AB - A hybrid differential-discrete mathematical model has been used to simulate biofilm structures (surface shape, roughness, porosity) as a result of microbial growth in different environmental conditions. In this study, quantitative two- and three-dimensional models were evaluated by introducing statistical measures to characterize the complete biofilm structure, both the surface structure and volume structure. The surface enlargement, coefficient of roughness, fractal dimension of surface, biofilm compactness, and solids hold-up were found to be good measures of biofilm structure complexity. Among many possible factors affecting the biofilm structure, the influence of biomass growth in relation to the diffusive substrate transport was investigated. Porous biofilms, with many channels and voids between the "finger-like" or "mushroom" outgrowth, were obtained in a substrate-transport-limited regime. Conversely, compact and dense biofilms occurred in systems limited by the biomass growth rate and not by the substrate transfer rate. The surface complexity measures (enlargement, roughness, fractal dimension) all increased with increased transport limitation, whereas the volume measures (compactness, solid hold-up) decreased, showing the change from a compact and dense to a highly porous and open biofilm. PMID- 10099268 TI - Cyclodextrin effects on the ex-situ bioremediation of a chronically polychlorobiphenyl-contaminated soil AB - The possibility of enhancing the intrinsic ex-situ bioremediation of a chronically polychlorinated biphenyl-contaminated soil by using cyclodextrins was studied in this work. The soil, contaminated with a large array of polychlorinated biphenyls and deriving from a dump site where it has been stored for about 10 years, was found to contain indigenous cultivable aerobic bacteria capable of utilising biphenyl and chlorobenzoic acids. The soil was amended with inorganic nutrients and biphenyl, saturated with water, and treated in aerobic batch slurry- and fixed-phase reactors. Hydroxypropyl-beta-cyclodextrin and gamma cyclodextrin, added to both reactor systems at the concentration of 10 g/L at the 39th and 100th days of treatment, were found to generally enhance the depletion rate and extent of the soil polychlorobiphenyls. Despite some abiotic losses could have affected the depletion data, experimental evidence, such as the production of metabolites tentatively characterized as chlorobenzoic acids and chloride ion accumulation in the reactors, indicated that cyclodextrins significantly enhanced the biological degradation of the soil polychlorobiphenyls. This result has been ascribed to the capability of cyclodextrins of enhancing the availability of polychlorobiphenyls in the hydrophilic soil environment populated by immobilised and suspended indigenous soil microorganisms. Both cyclodextrins were metabolised by the indigenous soil microorganisms at the concentration at which they were used. Therefore, cyclodextrins, both for their capability of enhancing the biodegradation of soil polychlorobiphenyls and for their biodegradability, can have the potential of being successfully used in the bioremediation of chronically polychlorinated biphenyl-contaminated soils. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099269 TI - Biotransformation of octane by E. coli HB101[pGEc47] on defined medium: octanoate production and product inhibition. AB - E. coli HB101[pGEc47], which is able to convert octane to octanoate, but cannot oxidize octanoate further, was grown on defined medium with glucose as carbon source in batch and continuous culture. The biomass yield on glucose decreased from 0.32 +/- 0.02 g g-1 in aqueous cultivations to 0.25 +/- 0.02 g g-1 in the presence of octane. Maximal octanoate productivities of 0.6 g L-1 h-1 were the same as found in cultivations on complex medium. The glucose-based carbon recovery in these experiments was 99 +/- 4% (in extreme, between 90% and 105%). An increase of the octane feed from 1% to 2% (v/v) or more led to washout of cells. This effect was reversible when the octane feed was decreased to its initial value of 1%. Analysis of experimental data by model simulation strongly suggested that washout was due to inhibition by octanoate only. Pulses of octanoate to a continuous culture grown on aqueous media were applied to analyze the inhibition further. Inhibition by acetate was not significant, but its presence in the medium reflected a physiological state that made the cells more sensitive to octanoate inhibition. Model simulation with linear inhibition kinetics could perfectly predict glucose consumption and the resulting glucose concentration. The linear type of inhibition was confirmed by a variety of batch experiments in the presence of different concentrations of octanoate. The glucose based specific growth rate, mu, decreased linearly with increasing concentrations of octanoate and became zero at a threshold concentration pmax of 5.25 +/- 0.25 g L-1. PMID- 10099270 TI - Chemically stabilized trypsin used in dipeptide synthesis. AB - Bovine pancreatic trypsin was treated with ethylene glycol bis(succinic acid N hydroxysuccinimide ester). Approximately 8 of 14 lysines per trypsin molecule were modified. This derivative (EG trypsin) was more stable than native between 30 degrees and 70 degrees C: T50 values were 59 degrees C and 46 degrees C, respective. EG trypsin's half-life of 25 min at 55 degrees C was fivefold greater than native's. EG trypsin had a decreased rate of autolysis and retained more activity in aqueous mixtures of 1,4-dioxan, dimethylformamide, dimethylsulfoxide, and acetonitrile. EG trypsin had lower Km values for both amide and ester substrates; its kcat values for two amides (benzoyl-L-arginine p-nitroanilide and benzyloxycarbonyl glycyl-glycyl-arginyl-7-amino-4-methyl coumarin) increased, whereas its kcat value for an ester (thiobenzoyl benzoyloxycarbonyl-L-lysinate) decreased slightly. The specific activity (kcat/Km) of EG trypsin was increased for both amide and ester substrates. EG trypsin gave higher yields and reaction rates than native in kinetically controlled synthesis of benzoyl argininyl leucinamide in acetonitrile and in t-butanol. Highest peptide yields occurred with EG trypsin in 95% acetonitrile, where 90% of the substrate was converted to product. No peptide synthesis occurred in 95% DMF with either form of trypsin. PMID- 10099271 TI - Sucrose enhances the recovery and activity of ribonuclease A during reversed micelle extraction. AB - We have investigated the effect of two simple sugars, glucose and sucrose, on the extraction of ribonuclease A by AOT-isooctane reversed micelles. Including the sugars at concentrations up to 0.75 M in the feed solution resulted in moderate improvements in the forward transfer efficiency. The greatest effects were seen observed in the backward transfer step where both the protein recovery yield and the activity of the protein were greatly increased. Protein transfer and activity yields were also dependent on the AOT concentration. We suggest that the presence of sucrose, which was solubilized into the reversed micelles, results in preferential hydration of ribonuclease A, reducing the protein-surfactant interactions. PMID- 10099272 TI - Deactivation and conformational changes of cutinase in reverse micelles AB - Deactivation data and fluorescence intensity changes were used to probe functional and structural stability of cutinase in reverse micelles. A fast deactivation of cutinase in anionic (AOT) reverse micelles occurs due to a reversible denaturation process. The deactivation and denaturation of cutinase is slower in small cationic (CTAB/1-hexanol) reverse micelles and does not occur when the size of the cationic reverse micellar water-pool is larger than cutinase. In both systems, activity loss and denaturation are coupled processes showing the same trend with time. Denaturation is probably caused by the interaction between the enzyme and the surfactant interface of the reversed micelle. When the size of the empty reversed micelle water-pool is smaller than cutinase (at W0 5, with W0 being the water:surfactant concentration ratio) a three-state model describes denaturation and deactivation with an intermediate conformational state existing on the path from native to denaturated cutinase. This intermediate was clearly detected by an increase in activity and shows only minor conformational changes relative to the native state. At W0 20, the size of the empty water-pool was larger than cutinase and the data was well described by a two-state model for both anionic and cationic reverse micelles. For AOT reverse micelles at W0 20, the intermediate state became a transient state and the deactivation and denaturation were described by a two-state model in which only native and denaturated cutinase were present. For CTAB/1-hexanol reverse micelles at W0 20, the native cutinase was in equilibrium with an intermediate state, which did not suffer denaturation. 1-Hexanol showed a stabilizing effect on cutinase in reverse micelles, contributing to the higher stabilities observed in the cationic CTAB/1-hexanol reverse micelles. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099273 TI - Transition probability cell cycle model with product formation. AB - A cell cycle population model based on the transition probability model of Smith and Martin (1973) has been extended to include product synthesis and export. The model handles two probable mechanisms. In the direct production model, the product is the protein. In the transcription model, the product is the specific mRNA. The protein is synthesized by translation of the specific mRNA and subsequently exported. In either case, the cell density is jointly distributed in the primary product and maturity age in the cell cycle. This extended model also is capable of describing a large range of conditions, including substrate dependent batch and continuous cultures. With the use of unity maturity-velocity (but the transition rate a function of limiting substrate), the model is shown to exhibit a negative growth association between the specific productivity of monoclonal antibodies from hybridomas and the dilution rates of a chemostat. Possibilities of maturity age dependent transcription and translation are considered, and the results show that these features can amplify the specific productivity negative association with specific growth rate. While this model may provide a partial elucidation of monoclonal antibody productivity in a chemostat, the present work provides a proper framework with which probable cell cycle dependent product formation can be analyzed rigorously with a comprehensive computational model. PMID- 10099274 TI - Influence of biomass production and detachment forces on biofilm structures in a biofilm airlift suspension reactor AB - The influence of process conditions (substrate loading rate and detachment force) on the structure of biofilms grown on basalt particles in a Biofilm Airlift Suspension (BAS) reactor was studied. The structure of the biofilms (density, surface shape, and thickness) and microbial characteristics (biomass yield) were investigated at substrate loading rates of 5, 10, 15, and 20 kg COD/m3. day with basalt concentrations of 60 g/L, 150 g/L, and 250 g/L. The basalt concentration determines the number of biofilm particles in steady state, which is the main determining factor for the biofilm detachment in these systems. In total, 12 experimental runs were performed. A high biofilm density (up to 67 g/L) and a high biomass concentration was observed at high detachment forces. The higher biomass content is associated with a lower biomass substrate loading rate and therefore with a lower biomass yield (from 0.4 down to 0.12 gbiomass/gacetate). Contrary to general beliefs, the observed biomass detachment decreased with increasing detachment force. In addition, smoother (fewer protuberances), denser and thinner compact biofilms were obtained when the biomass surface production rate decreased and/or the detachment force increased. These observations confirmed a hypothesis, postulated earlier by Van Loosdrecht et al. (1995b), that the balance between biofilm substrate surface loading (proportional to biomass surface production rate, when biomass yield is constant) and detachment force determines the biofilm structure. When detachment forces are relatively high only a patchy biofilm will develop, whereas at low detachment forces, the biofilm becomes highly heterogeneous with many pores and protuberances. With the right balance, smooth, dense and stable biofilms can be obtained. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099275 TI - Denitrification and nitric oxide reduction in an aerobic toluene-treating biofilter. AB - The presence of significant denitrification activity in an aerobic toluene treating biofilter was demonstrated under batch and flow-through conditions. N2O concentrations of 9.2 ppmv were produced by denitrifying bacteria in the presence of 15% acetylene, in a flow-through system with a bulk gas phase O2 concentration of >17%. The carbon source for denitrification was not toluene but a byproduct or metabolite of toluene catabolism. Denitrification conditions were successfully used for the reduction of 60 ppmv nitric oxide to 15 ppmv at a flow rate of 3 L min-1 (EBRT of 3 min) in a fully aerated, 17% v/v O2 (superficially aerobic) biofilter. Higher NO removal efficiency (97%) was obtained by increasing the toluene supply to the biofilter. PMID- 10099276 TI - Protein sorption and recovery by hydrogels using principles of aqueous two-phase extraction. AB - Use of the thermodynamic principles of aqueous two-phase extraction (ATPE) to drive protein into a crosslinked gel is developed as a protein isolation and separation technique, and as a protein loading technique for drug delivery applications. A PEG/dextran gel system was chosen as a model system because PEG/dextran systems are widely used in aqueous two-phase extraction and dextran gels (Sephadex(R)) are common chromatographic media. The effects of polymer concentrations and molecular weights, salts, and pH on the partitioning of ovalbumin matched ATPE heuristics and data trends. Gel partition coefficients (Cgel/Csolution) increased with increasing PEG molecular weight and concentration and decreasing dextran concentration (increased gel swelling). The addition of PEG to the buffer solution yielded partition coefficients more than an order of magnitude greater than those obtained in systems with buffer alone, or added salt. A combined salt/PEG system yielded an additional order of magnitude increase. For example, when ovalbumin solution (2.3 mg/mL) was equilibrated with Sephadex(R) G-50 at pH 6.75, the partition coefficients were 0.13 in buffer, 0.11 in buffer with 0.22M KI, 2.3 in 12 wt% PEG-10,000 and 32.0 in 12 wt% PEG-10, 000 with 0.22M KI. The effect of anions and cations as well as ionic strength and pH on the partitioning of ovalbumin also matched ATPE heuristics. Using the heuristics established above, partition coefficients as high as 80 for bovine serum albumin and protein recoveries over 90% were achieved. In addition, the wide range of partition coefficients that were obtained for different proteins suggests the potential of the technique for separating proteins. Also, ovalbumin sorption capacities in dextran were as high as 450 mg/g dry polymer, and the sorption isotherms were linear over a broad protein concentration range. PMID- 10099277 TI - Systematic errors in data evaluation due to ethanol stripping and water vaporization. AB - Systematic errors due to the neglect of water and/or ethanol partition between liquid and gaseous phases are discussed for bioreactors equipped with or without a condenser. Both water vapor and ethanol vapor are present in the off-gas leaving the condenser. Presence of residual water vapor largely influences the gas measurements by dilution. As a consequence, the oxygen consumption rate can be overestimated by a factor of 3 if calculations are not corrected for water vapor content or if no additional device is implemented after the condenser to completely dry the off-gases. The mass balance and partition equations predict that the condenser has only a small effect on reduction of the ethanol vapor content of the off-gas. The reason is the high ethanol concentration of the condensate droplets on the condenser wall in contact with the off-gases. Model predictions as well as experimental results show that ethanol evaporation represents a large fraction of the ethanol production rate and influences greatly the elemental recoveries. For a reactor working at 30 degrees C without condensation of the vapors and for a volumetric aeration rate of 0.63vvm, stripping of ethanol resulted in a gaseous dilution rate of 0.016 h-1 for ethanol. The dilution rate by stripping was reduced to 0.014 h-1 when a condenser at 12 degrees C was implemented. The fraction of ethanol that is stripped is mainly dependent on the ratio D/vvm (liquid to gaseous flow rates), and the effect is only slightly influenced by low condenser temperature. The evaporation of ethanol may account for more than 20% of the ethanol formation rate. Therefore, the condenser does not succeed to reflux all ethanol to the reactor broth. In terms of a unit operation, ethanol vapor can be efficiently reduced by absorption instead of condensation. To demonstrate the feasibility, a simple modification of the reactor was tested for continuous cultures: the feed port was changed from the top-plate to the top of the condenser, which was used as an absorption column. Ethanol stripping was reduced by a factor of 4 as compared to the condensation setup (at 12 degrees C): it accounted for 2% of the ethanol production rate as compared to 8.2% at D = 0.19 h-1 and 0.63vvm. PMID- 10099278 TI - Increase of xylitol production rate by controlling redox potential in Candida parapsilosis. AB - The effect of redox potential on xylitol production by Candida parapsilosis was investigated. The redox potential was found to be useful for monitoring the dissolved oxygen (DO) level in culture media, especially when the DO level was low. An increase in the agitation speed in a 5 L fermentor resulted in an increased culture redox potential as well as enhanced cell growth. Production of xylitol was maximized at a redox potential of 100 mV. As the initial cell concentration increased from 8 g/L to 30 g/L, the volumetric productivity of xylitol increased from 1.38 g/L. h to 4.62 g/L. h. A two-stage xylitol production strategy was devised, with stage 1 involving rapid production of cells under well aerated conditions, and stage 2 involving cultivation with reduced aeration such that the culture redox potential was 100 mV. Using this technique, a final xylitol concentration of 180 g/L was obtained from a culture medium totally containing 254.5 g/L xylose in a 3,000 L pilot scale fermentor after 77 h fermentation. The volumetric productivity of xylitol during the fermentation was 2.34 g/L. h. PMID- 10099279 TI - On-line estimation of biomass through pH control analysis in aerobic yeast fermentation systems. AB - The amount of acid or base consumed in yeast cultures has been recently assigned to the pathway of nitrogen assimilation under respiratory conditions with no contribution by carbon metabolism (Castrillo et al., 1995). In this investigation, experiments under respirofermentative conditions have shown that production or consumption of ethanol does not contribute significantly to the specific rate of proton production (qH+), thus extending the previously obtained relationships for all aerobic conditions in which other major acid/base contributions are not involved. Tests in batch and chemostat culture confirm the validity of qH+ as a formal control parameter in aerobic fermentations. PMID- 10099280 TI - Protein-protein and protein-salt interactions in aqueous protein solutions containing concentrated electrolytes PMID- 10099281 TI - Reactor heterogeneity with saccharopolyspora erythraea airlift fermentations AB - Bioreactor heterogeneity has been studied in a multiconfigurable pilot-scale airlift reactor (0.25 m3) which created different degrees of heterogeneity. The impact of the two sparger configurations, i.e. in the draft tube or the annulus, in conjunction with a marine propeller fitted at the base of the downcomer, on the physiology of Saccharopolyspora erythraea was studied. Cellular growth, morphology, and productivity were compared between airlift and stirred tank reactors. Dissolved oxygen tension heterogeneity caused by differences in dissolved oxygen tension around the vessel did not affect growth, but the reduction of heterogeneity improved the specific erythromycin production rate and final specific production. Erythromycin production was shown to be proportional to the energy dissipation rate. The enhancement of bubble coalescence with increasing apparent viscosity led to the reduction of the sectional gas holdups and the improvement of liquid mixing. The extent of the changes with increasing apparent viscosity was dependent on the broth morphology, reactor configurations, and operating conditions. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099282 TI - Specific heat flow rate: an on-line monitor and potential control variable of specific metabolic rate in animal cell culture that combines microcalorimetry with dielectric spectroscopy. AB - One of the requirements for enhanced productivity by the animal culture systems used in biotechnology is the direct assessment of the metabolic rate by on-line biosensors. Based on the fact that cell growth is associated with an enthalpy change, it is shown that the specific heat flow rate is stoichiometrically related to the net specific rates of substrates, products, and indeed to specific growth rate, and therefore a direct reflection of metabolic rate. Heat flow rate measured by conduction calorimetry has a technical advantage over estimates for many material flows which require assays at a minimum of two discrete times to give the rate. In order to make heat flow rate specific to the amount of the living cellular system, it would be advantageous to divide it by viable biomass. This requirement has been fulfilled by combining a continuous flow microcalorimeter ex situ with a dielectric spectroscope in situ, the latter measuring the viable cell mass volume fraction. The quality of the resulting biosensor for specific heat flow rate was illustrated using batch cultures of Chinese hamster ovary cells (CHO 320) producing recombinant human interferon gamma (IFN-gamma) during growth in a stirred tank bioreactor under fully aerobic conditions. The measuring scatter of the probe was decreased significantly by applying the moving average technique to the two participant signals. It was demonstrated that the total metabolic rate of the cells, as indicated by the specific heat flow rate sensor, decreased with increasing time in batch culture, coincident with the decline in the two major substrates, glucose and glutamine, and the accumulation of the by-products, ammonia and lactate. Furthermore, the specific heat flow rate was an earlier indicator of substrate depletion than the flow rate alone. The calorimetric-respirometric ratio showed the intensive participation of anaerobic processes during growth and the related IFN-gamma production. Specific heat flow rate was monotonically related to specific cell growth rate and associated with specific IFN-gamma production. Specific heat flow rate is potentially a valid control variable for the growth of genetically engineered cell lines producing target proteins. PMID- 10099283 TI - Intrinsic kinetic parameters of the pellet forming fungus aspergillus awamori AB - Fungi like Aspergillus awamori may spontaneously form pellets, which introduces an extra oxygen transfer resistance and influences the activity of the microorganism. Consequently, dramatic variations of apparent kinetics are reported in literature, due to variations in culture conditions, e.g., oxygen bulk concentration and pellet morphology. True intrinsic growth parameters like maximum growth rate and biomass yield, are important for process modelling and design. Values for these parameters may be obtained from observed kinetics by properly accounting for the anaerobic activity of the fungus. The true aerobic carbon yield for A. awamori of 0.6 mol Cx/mol Cs could be determined from the observed biomass yield after macroscopic monitoring of the anaerobic activity, and correction for the ethanol production by the fungal pellets. The true maximum growth rate was obtained from artificially immobilised A. awamori. In such well defined system, transport is only diffusive and the morphology is not influenced by the stirring conditions. A maximum growth rate of 0.4 h-1 at pH 4.5 could be established in gel beads after microscopic monitoring of the oxygen penetration with microelectrodes. The developing biomass concentration profiles in these beads may be inferred from an adequate theoretical description of the oxygen profiles in course of time. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099284 TI - A single step purification, immobilization, and hyperactivation of lipases via interfacial adsorption on strongly hydrophobic supports AB - A number of bacterial lipases can be immobilized in a rapid and strong fashion on octyl-agarose gels (e.g., lipases from Candida antarctica, Pseudomonas fluorescens, Rhizomucor miehei, Humicola lanuginosa, Mucor javanicus, and Rhizopus niveus). Adsorption rates in absence of ammonium sulfate are higher than in its presence, opposite to the observation for typical hydrophobic adsorption of proteins. At 10 mM phosphate, adsorption of lipases is fairly selective allowing enzyme purification associated with their reversible immobilization. Interestingly, these immobilized lipase molecules show a dramatic hyperactivation. For example, lipases from R. niveus, M. miehei, and H. lanuginosa were 6-, 7-, and 20-fold more active than the corresponding soluble enzymes when catalyzing the hydrolysis of a fully soluble substrate (0.4 mM p nitrophenyl propionate). Even higher hyperactivations and interesting changes in stereospecificity were also observed for the hydrolysis of larger soluble chiral esters (e.g. (R,S)-2-hydroxy-4-phenylbutanoic ethyl ester). These results suggest that lipases recognize these "well-defined" hydrophobic supports as solid interfaces and they become adsorbed through the external areas of the large hydrophobic active centers of their "open and hyperactivated structure". This selective interfacial adsorption of lipases becomes a very promising immobilization method with general application for most lipases. Through this method, we are able to combine, via a single and easily performed adsorption step, the purification, the strong immobilization, and a dramatic hyperactivation of lipases acting in the absence of additional interfaces, (e.g., in aqueous medium with soluble substrate). Copyright 1998 John Wiley & Sons, Inc. PMID- 10099285 TI - Factorial optimization of a six-cellulase mixture AB - A factorial experimental design approach was used to optimize mixtures of six cellulases (five Thermomonospora fusca cellulases and plus/minus Trichoderma reesei CBHI along with beta-glucosidase) so as to maximize the glucose produced from filter paper. Optimized mixture A and mixture B produced glucose at 25 and 8.3 MUmol glucose/MUmol enzyme/min, respectively, which are 8 and 1.5 times higher than the sum of the activity of the individual cellulases. In both mixtures, the glucose yield depended on the ratio and the cellulases used. Most enzymes showed synergistic interactions that increased the glucose yield. The yield of glucose with the optimum mixtures depended on the total enzyme concentration. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099286 TI - Genetically structured mathematical modeling of trp attenuator mechanism. AB - A genetically structured mathematical model of the trp attenuator in Escherichia coli based on known coupling mechanisms of the transcription of the trp leader region and translation of the trp leader peptide region is proposed. The model simulates, both qualitatively and quantitatively, the effects of tryptophan on the repression of cloned gene products. It shows that repression by attenuation mechanism alone operates over a narrow trp concentration range of 1 to 5 microM compared with 1 to 100 microM for trp repressor mechanism. This implies that attenuation by transcription termination is not relaxed until tryptophan starvation is severe. Simulation results show that the attenuator starts to derepress when the repressor is about 40% repressed, and becomes significantly derepressed only when the repressor repression decreased to about 20%. Unlike the case of repressor-operator interaction, the operating range of tryptophan concentration in the attenuator mechanism is not sensitive to plasmid copy number. PMID- 10099287 TI - Removal of nitrate from industrial wastewaters in a pilot plant by nitrate tolerant klebsiella oxytoca CECT 4460 and arthrobacter globiformis CECT 4500 AB - Two strains, a gram-negative bacterium Klebsiella oxytoca CECT 4460 and a gram positive, mycelium-forming bacterium Arthrobacter globiformis CECT 4500, tolerant to up to 1 M nitrate, were isolated from the grounds of a munitions factory. Under strict aerobic conditions and with appropriate C-sources, growth of these bacteria took place when the nitrate concentration in the medium was below 150 mM. Optimal growth conditions regarding the culture medium composition for the biological removal of nitrate were established in batch cultures. Then, the system was scaled up to a 40-L pilot plant and operated under continuous conditions in a factory with direct waste streams from dinitroethylene glycol production after appropriate dilution with nontreated groundwaters. The level of nitrate in the effluent was below 0.5% of the initial N-load. Nitrite and ammonium were undetectable and the level of the C-source in the effluent was below 50 mg per L. On the basis of these results, we conclude that the system worked on site satisfactorily. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099288 TI - Analysis of cell cycle activity and population dynamics in heterogeneous plant cell suspensions using flow cytometry. AB - Flow cytometry was used to measure cell cycle parameters in Solanum aviculare plant cell suspensions. Methods for bromodeoxyuridine (BrdU) labeling of plant nuclei were developed so that cell cycle times and the proportion of cells participating in growth could be determined as a function of culture time and conditions. The percentage of cells active in the cell cycle at 25 degrees C decreased from 52% to 19% within 7.6 d of culture; presence of a relatively large proportion of non-active cells was reflected in the results for culture growth. While the maximum specific growth rate of the suspensions at 25 degrees C was 0.34 d-1 (doubling time: 2.0 d), the specific growth rate of active cells was significantly greater at 0.67 d-1, corresponding to a cell cycle time of 1.0 d. A simple model of culture growth based on exponential and linear growth kinetics and the assumption of constant cell cycle time was found to predict with reasonable accuracy the proportion of active cells in the population as a function of time. Reducing the temperature to 17 degrees C lowered the culture growth rate but prolonged the exponential growth phase compared with 25 degrees C; the percentage of cells participating in the cell cycle was also higher. Exposure of plant cells to different agitation intensities in shake flasks had a pronounced effect on the distribution of cells within the cell cycle. The proportion of cells in S phase was 1.8 times higher at a shaker speed of 160 rpm than at 100 rpm, while the frequency of G0 + G1 cells decreased by up to 27%. Because of the significant levels of intraculture heterogeneity in suspended plant cell systems, flow cytometry is of particular value in characterizing culture properties and behavior. PMID- 10099290 TI - Optimized release of recombinant proteins by ultrasonication of E. coli cells. AB - The release kinetics of beta-galactosidase protein have been determined during small-scale ultrasonication of E. coli cells. Among several studied parameters, ionic strength and cell concentration have the least influence on the rate of protein recovery, whereas sample volume and acoustic power dramatically affect the final yield of soluble protein in the cell-free fraction. The analysis of these critical parameters has prompted us to propose a simple model for E. coli disintegration that only involves acoustic power and sample volume, and which allows prediction of optimal sonication times to recover significant amounts of both natural and recombinant proteins in a given set of relevant conditions. PMID- 10099289 TI - A novel biotinylated degradable polymer for cell-interactive applications. AB - We describe the development of a novel biodegradable polymer designed to present bioactive motifs at the surfaces of materials of any architecture. The polymer is a block copolymer of biotinylated poly(ethylene glycol) (PEG) with poly(lactic acid) (PLA); it utilizes the high-affinity coupling of the biotin-avidin system to undergo postfabrication surface engineering. We show, using surface plasmon resonance analysis (SPR) and confocal microscopy that surface engineering can be achieved under aqueous conditions in short time periods. These surfaces interact with cell surface molecules and generate beneficial responses as demonstrated by the model study of integrin-mediated spreading of endothelial cells on polymer surfaces presenting RGD peptide adhesion sequences. PMID- 10099291 TI - On-line study of fungal morphology during submerged growth in a small flow through cell. AB - A flow-through cell is designed to measure the growth kinetics of hyphae of Aspergillus oryzae grown submerged in a well controlled environment. The different stages of the growth process are characterized, from the spore to the fully developed hyphal element with up to 60 branches and a total length lt up to 10,000 micrometer. Spore swelling is found to occur without change in the form of the spore (circularity index constant at about 1.06) and the spore volume probably increases exponentially. The germ tube appears after about 4 h. The branching frequency and the rate of germ tube extension is determined. After about 10 h growth at a glucose concentration of 250 mg L-1, 6-7 branches have been set, and both the total hyphal length lt and the number of tips increase exponentially with time. The specific growth rate of the hyphae is 0. 33 h-1 while the average rate of the extension of the growing tips approaches 55 micrometer h-1. The growth kinetics for all the branches on the main hypha have also been found. The main hypha and all the branches grow at a rate which can be modeled by saturation kinetics with respect to the branch length and with nearly equal final tip speeds (160 micrometer h-1). Branches set near the apical tip of the main hypha attain their final tip speed in the shortest time, i.e., the value of the saturation parameter is small. Finally, the influence of substrate (glucose) concentration cs on the values of the morphological parameters has been determined. It is found that saturation type kinetics can be used to describe the influence of cs on the growth. Experiments with recirculation of effluent from the cell back to the inlet strongly suggest that the fungus secretes an inducer for growth and branching. PMID- 10099292 TI - Directed evolution of an esterase for the stereoselective resolution of a key intermediate in the synthesis of epothilones. AB - The directed evolution of an esterase from Pseudomonas fluorescens using the mutator strain Epicurian coli XL1-Red was investigated. Mutants were assayed for their ability to hydrolyze a sterically hindered 3-hydroxy ester, which can serve as a building block in the synthesis of epothilones. Screening was performed by plating esterase producing colonies derived from mutation cycles onto minimal media agar plates containing indicator substances (neutral red and crystal violet). Esterase-catalyzed hydrolysis of the 3-hydroxy ester (ethyl or glycerol ester) was detected by the formation of a red color due to a pH decrease caused by the released acid. Esterases isolated from positive clones were used in preparative biotransformations of the ethyl ester. One variant containing two mutations (A209D and L181V) stereoselectively hydrolyzed the ethyl ester resulting in 25% ee for the remaining ester. PMID- 10099293 TI - Metabolism analysis and on-line physiological state diagnosis of acetone-butanol fermentation. AB - Fermentation equations for acetone-butanol (AB) were applied in a metabolic analysis of the reaction network under various conditions; that is, at different pHs and a high NADH2 turnover rate using methyl viologen, in a Clostridium acetobutylicum culture. The results disclosed variations in the pattern of rate changes that reflected changes in the physiological state. A linear relationship was found to exist between NADH2 generation and butanol production rate. By coupling an automated measurement system with the fermentation model, on-line estimation of the culture state was accomplished. Based on the AB fermentation model, new parameters were defined for on-line diagnosis of the physiological state and determination of the best timing for amplifying NADH2 generation by the addition of methyl viologen to obtain a high level of butanol productivity. A potential means of achieving optimal control for a high level of solvent production, involving the correlation of certain rates, is proposed. PMID- 10099294 TI - Solubilization of subtilisin in CO2 using fluoroether-functional amphiphiles. AB - Carbon dioxide is a naturally abundant, environmentally benign solvent whose use, like water, in a process is not regulated by either EPA or FDA. Unfortunately, polar compounds such as amino acids and proteins are essentially insoluble in carbon dioxide. Further, alkyl-functional surfactants, which have been shown to allow extraction of proteins into conventional organic solvents, exhibit very poor or negligible solubility in CO2 at pressures below 50 MPa. Consequently, highly CO2-soluble fluoroether-functional surfactants have been generated and used to solubilize subtilisin Carlsberg from aqueous buffer and cell culture medium into CO2, with recovery accomplished by depressurization. Both the amount of protein solubilized in the emulsion and the extent of activity retention by the protein following recovery are functions of the initial protein concentration in the buffer. This, plus the observation that the presence of protein affects the stability of the emulsion, suggests that some of the protein is sacrificed to act as a stabilizer in these systems. In addition to solubilization via an inverse emulsion, it has also been shown that one can strip protein-surfactant aggregates from a middle phase emulsion using pure CO2, suggesting an ion-pairing type mechanism. PMID- 10099296 TI - A membrane bioreactor for biotransformations of hydrophobic molecules AB - The Membrane Bioreactor for Biotransformations (MBB) is based on the aqueous/organic two-phase system, and uses a tubular silicone rubber membrane to separate the two liquid phases. This avoids the key problem associated with direct contact two-phase processes, specifically, product emulsification. The baker's yeast mediated reduction of geraniol to citronellol was used as a model biotransformation to demonstrate MBB operation. Values for the overall mass transfer coefficient were determined for geraniol, (2.0 x 10(-5) ms-1), and for citronellol, (2.1 x 10(-5) ms-1) diffusion across the silicone rubber membrane. Using these values, and the specific activity of the biocatalyst (5 nmols-1g biomass-1), a suitable membrane surface area: biomass ratio was determined as 2.4 x 10(-3) m2g biomass-1. The bioreactor was operated at this surface area: biomass ratio and achieved a product accumulation rate 90-95% that of a conventional direct contact two-phase system. The slight reduction in product accumulation rate was shown not to be due to mass transfer limitations with respect to reactant delivery or product extraction. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099295 TI - Microporous microparticles designed as stable immunoadsorbents. AB - We have developed a solid-phase immunoadsorbent based on encapsulated goat anti apolipoprotein B polyclonal antibodies previously crosslinked with a 0.25% glutaraldehyde solution, and designed to remove by immunoaffinity the excess of apolipoproteins B from the plasma of patients affected by familial hypercholesterolemia. Compared to a classical immunoadsorbent prepared by activation of Sepharose CL-4B with cyanogen bromide, the resulting immunoadsorbent exhibits both optimal adsorption capacity and stability over the entire range of chemical and biochemical conditions during its practical handling. This approach will serve as a model system to demonstrate the applicability of microparticles as immunoadsorbents, which can be achieved for other encapsulated crosslinked proteins. PMID- 10099297 TI - The effects of turbulent jet flows on plant cell suspension cultures AB - Cell suspensions of Morinda citrifolia were subjected to turbulent flow conditions in a submerged jet apparatus, to investigate their hydrodynamic shear susceptibility. The suspensions were exposed to repeated, pressure-driven passages through a submerged jet. Two nozzles, of 1 mm and 2 mm diameter, were employed. Average energy dissipation rates were in the range 10(3)-10(5) W/kg and cumulative energy dissipation in the range 10(5)-10(7) J/m3. System response to the imposed conditions was evaluated in terms of suspension viability (determined using a dye exclusion technique) and variations in both chain length distribution and maximum chain length. Viability loss was well-described by a first-order model, and a linear relationship was identified between the specific death rate constant and the average energy dissipation rate. This relationship was consistent with results obtained using the same suspension cultures in a turbulent capillary flow device. Morphological measurements indicated that exposure to the hydrodynamic environment generated in the jet resulted in a significant reduction in both the average and maximum chain lengths, and the reduction in the maximum chain length was identified as an appropriate measure of sustained damage. Analysis of both viability and chain length in terms of cumulative energy dissipated revealed good agreement with results reported by other authors for morphologically different plant cell systems. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099298 TI - Modeling of biomass productivity in tubular photobioreactors for microalgal cultures: effects of dilution rate, tube diameter, and solar irradiance AB - A macromodel is developed for estimating the year-long biomass productivity of outdoor cultures of microalga in tubular photobioreactors. The model evaluates the solar irradiance on the culture surface as a function of day of the year and the geographic location. In a second step, the geometry of the system is taken into account in estimating the average irradiance to which the cells are exposed. Finally, the growth rate is estimated as a function of irradiance, taking into account photoinhibition and photolimitation. The model interconnects solar irradiance (an environmental variable), tube diameter (a design variable), and dilution rate (an operating variable). Continuous cultures in two different tubular photobioreactors were analyzed using the macromodel. The biomass productivity ranged from 0.50 to 2.04 g L-1 d-1, and from 1.08 to 2. 76 g L-1 d 1, for the larger and the smaller tube diameter photobioreactors, respectively. The quantum yield ranged from 1.1 to 2.2 g E-1; the higher the incident solar radiation, the lower the quantum yield. Simultaneous photolimitation and photoinhibition of outdoor cultures was observed. The model reproduced the experimental results with less than 20% error. If photoinhibition was neglected, and a growth model that considered only photolimitation was used to fit the data, the error increased to 45%, thus reflecting the inadequacy of previous outdoor growth models that disregard photoinhibition. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099299 TI - Biooxidation capacity of the extremely thermoacidophilic archaeon metallosphaera sedula under bioenergetic challenge AB - The biooxidation capacity of an extremely thermoacidophilic archaeon Metallosphaera sedula (DSMZ 5348) was examined under bioenergetic challenges imparted by thermal or chemical stress in regard to its potential use in microbial bioleaching processes. Within the normal growth temperature range of M. sedula (70-79 degrees C) at pH 2.0, upward temperature shifts resulted in bioleaching rates that followed an Arrhenius-like dependence. When the cells were subjected to supraoptimal temperatures through gradual thermal acclimation at 81 degrees C (Han et al., 1997), cell densities were reduced but 3 to 5 times faster specific leaching rates (Fe3+ released from iron pyrite/cell/h) could be achieved by the stressed cells compared to cells at 79 degrees C and 73 degrees C, respectively. The respiration capacity of M. sedula growing at 74 degrees C was challenged by poisoning the cells with uncouplers to generate chemical stress. When the protonophore 2,4-dinitrophenol (5-10 MUM) was added to a growing culture of M. sedula on iron pyrite, there was little effect on specific leaching rates compared to a culture with no protonophore at 74 degrees C; 25 MUM levels proved to be toxic to M. sedula. However, a significant stimulation in specific rate was observed when the cells were subjected to 1 MUM nigericin (+135%) and 2 MUM (+63%); 5 MUM levels of the ionophore completely arrested cell growth. The ionophore effect was further investigated in continuous culture growing on ferrous sulfate at 74 degrees C. When 1 MUM nigericin was added as a pulse to a continuous culture, a 30% increase in specific iron oxidation rate was observed for short intervals, indicating a potential positive impact on leaching when periodic chemical stress is applied. This study suggests that biooxidation rates can be increased by strategic exposure of extreme thermoacidophiles to chemical or thermal stress, and this approach should be considered for improving process performance. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099300 TI - Plasmid maintenance in Escherichia coli recombinant cultures is dramatically, steadily, and specifically influenced by features of the encoded proteins. AB - A set of eight closely related plasmid constructs carrying CI857-controlled recombinant genes has been used as a model to study plasmid stability in Escherichia coli, in the absence of antibiotic selection. Plasmid loss rates and relative interdivision times of plasmid-bearing cells and plasmid-free cells have been analyzed throughout prolonged cultures. Whereas the calculated plasmid loss rates are not consistent for a given plasmid and set of conditions, the relative growth fitness of plasmid-bearing cells is highly reproducible. In the absence of gene expression, plasmid maintenance is influenced by the length of the cloned segment, the growth temperature, and the plasmid copy number, but not by the plasmid size. At high, inducing temperatures, the effects of the metabolic burden are eclipsed by the toxicity exhibited by the different proteins produced, which is determined by structural features. Despite the multifactorial nature of the negative pressures acting independently on plasmid-bearing cells, the relative cell fitness in a mixed cell population is very reproducible for a given vector, resulting in a monotonous spread of the plasmid-free cells in recombinant cultures. PMID- 10099301 TI - Characterization of gas transfer and mixing in a bubble column equipped with a rubber membrane diffuser AB - Gas transfer and mixing were characterized in a 32-L bubble column reactor equipped with a commercially available rubber membrane diffuser. The performance of the membrane diffuser indicates that the slits in the membrane are best described as holes with elastic lids, acting as valves cutting off bubbles from the gas stream. The membrane diffuser thus functions as a one-way valve preventing backflow of liquid. Our design of the bottom plate of the reactor enabled us to optimize the aeration by changing the tension of the membrane. We thereby achieved mass transfer coefficients higher than those previously reported in bubble columns. A strong dependence of mass transfer on gas holdup and bubble size was indicated by estimates based on these two variables. The microalga, Rhodomonas sp. , sensitive to chemical and physical stress, was maintained for 8 months in continuous culture with a productivity identical to cultures grown in stirred tank reactors. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099302 TI - Improvement of interferon-gamma sialylation in Chinese hamster ovary cell culture by feeding of N-acetylmannosamine. AB - Because the presence of sialic acid can extend circulatory lifetime, a high degree of sialylation is often a desirable feature of therapeutic glycoproteins. In this study, the incomplete intracellular sialylation of interferon-gamma (IFN gamma), produced by Chinese hamster ovary cell culture, was minimized by supplementing the culture medium with N-acetylmannosamine (ManNAc), a direct intracellular precursor for sialic acid synthesis. By introducing 20 mM ManNAc into the culture medium, incompletely sialylated biantennary glycan structures were reduced from 35% to 20% at the Asn97 glycosylation site. This effect was achieved without affecting cell growth or product yield. The intracellular pool of CMP-sialic acid, the nucleotide sugar substrate for sialyltransferase, was also extracted and quantified by HPLC. Feeding of 20 mM ManNAc increased this intracellular pool of CMP-sialic acid by nearly thirtyfold compared with unsupplemented medium. When radiolabeled ManNAc was used to trace the incorporation of the precursor, it was found that supplemental ManNAc was exclusively incorporated into IFN-gamma as sialic acid and that, at 20 mM ManNAc feeding, nearly 100% of product sialylation originated from the supplemental precursor. PMID- 10099303 TI - Selective separation of trypsin from pancreatin using bioaffinity in reverse micellar system composed of a nonionic surfactant. AB - Selective separation of trypsin from a mixture involving many kinds of contaminating proteins, i.e., pancreatin, was achieved using trypsin inhibitor immobilized in the reverse micelles, which were composed of a nonionic surfactant, tetra-oxyethylene monodecylether. To determine the efficient operations throughout the whole separation process we examined the operating conditions, which affect the immobilization efficiency of trypsin inhibitor and also the forward and backward extractions of trypsin. Fifty percent of the recovery of trypsin from pancreatin was realized with no loss of activity of the recovered trypsin. PMID- 10099304 TI - Testing for diffusion limitations in salt-activated enzyme catalysts operating in organic solvents. AB - The dramatic activation of serine proteases in nonaqueous media resulting from lyophilization in the presence of KCl is shown to be unrelated to relaxation of potential substrate diffusional limitations. Specifically, lyophilizing subtilisin Carlsberg in the presence of KCl and phosphate buffer in different proportions, ranging from 99% (w/w) enzyme to 1% (w/w) enzyme in the final lyophilized solids, resulted in biocatalyst preparations that were not influenced by substrate diffusion. This result was made evident through use of a classical analysis whereby initial catalytic rates, normalized per weight of total enzyme in the catalyst material, were measured as a function of active enzyme for biocatalyst preparations containing different ratios of active to inactive enzyme. The active enzyme content of a given biocatalyst preparation was controlled by mixing native subtilisin with subtilisin preinactivated with PMSF, a serine protease inhibitor, and lyophilizing the enzyme mixture in the presence of different fractions of KCl and phosphate buffer. Plots of initial reaction rates as a function of percent active subtilisin in the biocatalyst were linear for all biocatalyst preparations. Thus, enzyme activation (reported elsewhere to be as high as 3750-fold in hexane for the transesterification of N-Ac-L-Phe-OEt with n-PrOH) is a manifestation of intrinsic enzyme activation and not relaxation of diffusional limitations resulting from diluted enzyme preparations. Similar activation is reported herein for thermolysin, a nonserine protease, thereby demonstrating that enzyme activation due to lyophilization in the presence of KCl may be a general phenomenon for proteolytic enzymes. PMID- 10099305 TI - Activity losses among T4 lysozyme variants after adsorption to colloidal silica. AB - Maintaining a specific molecular conformation is essential for the proper functioning of an enzyme. A substantial loss of catalytic activity can occur from the displacement caused by even a single amino acid substitution. Activity may also be lost as an enzyme undergoes a conformational change during adsorption. In this study, we investigated the effect of thermostability on the activities of three T4 lysozyme variants after adsorption to 9 nm colloidal silica particles. Less-stable T4 lysozyme variants lost more activity after adsorption than did more stable variants, apparently because they experienced more extensive structural alteration. PMID- 10099306 TI - Effect of yeast extract supplementation in leach solution on bioleaching rate of pyrite by acidophilic thermophile acidianus brierleyi AB - The bioleaching rate of pyrite (FeS2) by the acidophilic thermophile Acidianus brierleyi was studied at 65 degrees C and pH 1.5 with leach solutions supplemented with yeast extract. In the absence of yeast extract supplementation, A. brierleyi could grow autotrophically on pyrite, and the leaching percentage of pyrite particles (25-44 MUm) reached 25% for 7 d. The bacterial growth and consequent pyrite oxidation were enhanced by the addition of yeast extract between 0.005 and 0.25% w/v: the pyrite particles were completely solubilized within 6 d. The bioleaching rate was enhanced by a factor of 1.5 when the yeast extract concentration was changed from 0.005 to 0.05% w/v. However, there was only a slight effect on the leaching rate at the yeast extract concentrations of 0.05 to 0. 25% w/v, suggesting that the organic supplement level was in large excess in the pyrite bioleaching. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099307 TI - A new addition to the combinatorial library. PMID- 10099308 TI - Murine macrophage behavior on peptide-grafted polyethyleneglycol-containing networks. AB - Polyethyleneglycol-based networks were employed as substrates to graft bioactive peptides to study macrophage interactions with materials. Our overall objective was to utilize biologically active factors to stimulate certain macrophage function on materials suitable for implantation in connective tissues. In this study, we sought to explore the bioactivity of several peptides derived from extracellular matrix adhesion proteins and macrophage-active proteins that are normally soluble. The candidate peptides examined corresponded to residues 63 to 77 of complement component C3a (C3a(63-77)), residues 178 to 207 of interleukin-1 beta (IL1beta(178-207)), residues 1615 to 1624 of fibronectin (FN(1615-1624)), endothelial-macrophage activating polypeptide II, complement component C5a inhibitory sequence, macrophage inhibitory peptide, and YRGDG; materials lacking peptides were used as negative controls. An established murine cell-line IC-21 was employed as a macrophage model, and human dermal fibroblasts were used for comparison. Our results showed that the substrates without grafted peptides were free from artifactual cell adhesion associated with the adsorption of serum or cellularly secreted proteins for long duration of culture. Of all grafted samples, IL1beta(178-207)- and C3a(63-77)-grafted surfaces supported higher adherent macrophage densities. C3a(63-77)- and FN(1615-1624)-grafted surfaces supported higher adherent fibroblast densities. From competitive inhibition studies, cell adhesion was determined to occur in a receptor-peptide specific manner. The presence of grafted YRGDG in addition to IL1beta(178-207), C3a(63 77), or FN(1615-1624) synergistically increased macrophage and fibroblast adhesion. Materials grafted with IL1beta(178-207) or C3a(63-77) co-grafted with or without YRGDG did not support the formation of multinucleated giant cells from the fusion of adherent macrophages in vitro. PMID- 10099309 TI - Theoretical analysis of cell separation based on cell surface marker density. AB - A theoretical analysis was performed to determine the number of fractions a multidisperse, immunomagnetically labeled cell population can be separated into based on the surface marker (antigen) density. A number of assumptions were made in this analysis: that there is a proportionality between the number of surface markers on the cell surface and the number of immunomagnetic labels bound; that this surface marker density is independent of the cell diameter; and that there is only the presence of magnetic and drag forces acting on the cell. Due to the normal distribution of cell diameters, a "randomizing" effect enters into the analysis, and an analogy between the "theoretical plate" analysis of distillation, adsorption, and chromatography can be made. Using the experimentally determined, normal distribution of cell diameters for human lymphocytes and a breast cancer cell line, and fluorescent activated cell screening data of specific surface marker distributions, examples of theoretical plate calculations were made and discussed. PMID- 10099310 TI - Operation of mixed-culture immobilized cell reactors for the metabolism of meta- and para-nitrobenzoate by comamonas sp. JS46 and comamonas sp. JS47 AB - The treatment of meta- and para-nitrobenzoic acid in an industrial wastestream by Comamonas sp. JS46 and Comamonas sp. JS47 is investigated. The most important feature of the wastestream is the constantly changing concentration ratio of the two isomers. The most extreme occurrence is considered here: the complete change in feed carbon source from one isomer to the other. A series of immobilized cell airlift reactor experiments are described to examine the operation and response of the system to these changes in the feed carbon source. Separate reactors containing each species immobilized are compared with a reactor containing both species immobilized within the same bead, and to a reactor containing both species with each species confined to separate beads. On the basis of response time necessary to recover the appropriate activity, the reactor containing both species immobilized within the same bead offers the most effective arrangement. Interactions occurring between the two organisms in the coimmobilized system, mediated by the nitrobenzoate metabolites, are discussed relative to the improved response of this arrangement. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099311 TI - Fluxes and enzyme activities in central metabolism of myeloma cells grown in chemostat culture. AB - Activities of enzymes in glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, and glutaminolysis have been determined in the mouse myeloma SP2/0.Ag14. Cells were grown on IMDM medium with 5% serum in steady-state chemostat culture at a fixed dilution rate of 0.03 h-1. Three culture conditions, which differed in supply of glucose and oxygen, were chosen so as to change catabolic fluxes in the central metabolism, while keeping anabolic fluxes constant. In the three steady-state situations, the ratio between specific rates of glucose and glutamine consumption differed by more than twentyfold. The specific rates of glucose consumption and lactate production were highest at low oxygen supply, whereas the specific rate of glutamine consumption was highest in the culture fed with low amounts of glucose. Under low oxygen conditions, the specific production of ammonia increased and the consumption pattern of amino acids showed large changes compared with the other two cultures. For the three steady states, activities of key enzymes in glycolysis, the pentose phosphate pathway, glutaminolysis, and the TCA cycle were measured. The differences in the in vivo fluxes were only partially reflected in changes in enzyme levels. The largest differences were observed in the levels of glycolytic enzymes, which were elevated under conditions of low oxygen supply. High activities of phosphoenolpyruvate carboxykinase (E.C. 4.1.1.32) in all cultures suggest an important role for this enzyme as a link between glutaminolysis and glycolysis. For all enzymes, in vitro activities were found that could accommodate the estimated maximum in vivo fluxes. These results show that the regulation of fluxes in central metabolism of mammalian cells occurs mainly through modulation of enzyme activity and, to a much lesser extent, by enzyme synthesis. PMID- 10099312 TI - Modeling trichloroethylene degradation by a recombinant pseudomonad expressing toluene ortho-monooxygenase in a fixed-film bioreactor AB - Burkholderia cepacia PR123(TOM23C), expressing constitutively the TCE-degrading enzyme toluene ortho-monooxygenase (Tom), was immobilized on SIRANtrade mark glass beads in a biofilter for the degradation and mineralization of gas-phase trichloroethylene (TCE). To interpret the experimental results, a mathematical model has been developed which includes axial dispersion, convection, film mass transfer, and biodegradation coupled with deactivation of the TCE-degrading enzyme. Parameters used for numerical simulation were determined from either independent experiments or values reported in the literature. The model was compared with the experimental data, and there was good agreement between the predicted and measured TCE breakthrough curves. The simulations indicated that TCE degradation in the biofilter was not limited by mass transfer of TCE or oxygen from the gas phase to the liquid/biofilm phase (biodegradation limits), and predicts that improving the specific TCE degradation rates of bacteria will not significantly enhance long-term biofilter performance. The most important factors for prolonging the performance of biofilter are increasing the amount of active biomass and the transformation capacity (enhancing resistance to TCE metabolism). Copyright 1998 John Wiley & Sons, Inc. PMID- 10099313 TI - Kinetics of denitritification and denitratification in anoxic filters AB - Denitritification and denitratification in anoxic filters were performed to generate experimental data. Also, a kinetic model of denitratification that accounts for intrinsic biokinetics and hydrodynamic behavior of the biofilter is proposed. In denitritification, the simulated results are in good agreement with the experimental data; and a higher nitrite influent concentration gives a higher nitrite reduction efficiency if the denitrifying loading is kept the same. In denitratification, the intermediate nitrite tends to accumulate, and a higher denitrifying loading results in a higher nitrite effluent concentration. By inserting biological and physical parameter values into the kinetic model, the variations in distributed fractions of nitrate-reductase (f) and nitrite reductase (1-f) with different denitrifying loadings can be estimated by fitting in experimental data. The estimated f increased with an increase in denitrifying loading, implying that a higher denitrifying loading results in a higher nitrite effluent concentration. From parametric sensitivity analyses, the parameter f is more sensitive than other biological and physical parameters. Accordingly, the proposed kinetic model of denitratification can be used to predict the treatment performance of anoxic filters appropriately. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099314 TI - Use of potato tuber nucleotide pyrophosphatase to synthesize adenosine 5' monophosphate methyl ester: evidence that the solvolytic preferences of the enzyme are regulated by pH and temperature. AB - Nucleotide alkyl esters are pharmacologically important as potential (ant)agonists of purinoceptors and inhibitors of enzymes. Potato nucleotide pyrophosphatase (PNP) was compared with snake venom phosphodiesterase (SVP) as a catalyst to synthesize nucleotide alkyl esters. In methanol-water mixtures, the methanolysis/hydrolysis ratio of PNP, but not SVP, changed with pH and temperature, being optimal at high pH and low temperature. In a semi-preparative experiment, a crude PNP preparation produced 0.17 mM AMP-O-methyl ester (AMP-OMe) from 1 mM diadenosine 5',5"'-P1,P2-diphosphate (AppA) and 5M methanol, at pH 9 and 0 degrees C. Drawbacks to large-scale use are: low rates inherent to low temperatures, ATP unsuitability as a substrate for alcoholysis, and high cost of AppA. Advantages of PNP vs. SVP are cheapness, non-toxicity, and availability of the enzyme source. PMID- 10099315 TI - Effect of water and enzyme concentration on thermolysin-catalyzed solid-to-solid peptide synthesis. AB - We have studied a thermolysin-catalyzed solid-to-solid dipeptide synthesis using equimolar amounts of Z-Gln-OH and H-Leu-NH2 as model substrates. The high substrate concentrations make this an effective alternative to enzymatic peptide synthesis in organic solvents. Water content was varied in the range of 0 to 600 mL water per mol substrate and enzyme concentration in the range of 0.5 to 10 g/mol of substrates. High yields around 80% conversion and initial rates from 5 to 20 mmol s-1 kg-1 were achieved. The initial rate increases 10-fold on reducing the water content, to reach a pronounced optimum at 40 mL water per mol substrate. Below this, the rate falls to much lower values in a system with no added water, and to zero in a rigorously dried system. This behavior is discussed in terms of two factors: At higher water contents the system is mass transfer limited (as shown by varying enzyme content), and the diffusion distances required vary. At low water levels, effects reflect the stimulation of the enzymatic activity by water. PMID- 10099316 TI - Use of aqueous two-phase systems for in situ extraction of water soluble antibiotics during their synthesis by enzymes immobilized on porous supports. AB - Yields of kinetically controlled synthesis of antibiotics catalyzed by penicillin G acylase from Escherichia coli (PGA) have been greatly increased by continuous extraction of water soluble products (cephalexin) away from the surroundings of the enzyme. In this way its very rapid enzymatic hydrolysis has been avoided. Enzymes covalently immobilized inside porous supports acting in aqueous two-phase systems have been used to achieve such improvements of synthetic yields. Before the reaction is started, the porous structure of the biocatalyst can be washed and filled with one selected phase. In this way, when the pre-equilibrated biocatalyst is mixed with the second phase (where the reaction product will be extracted), the immobilized enzyme remains in the first selected phase in spite of its possibly different natural trend. Partition coefficients (K) of cephalexin in very different aqueous two-phase systems were firstly evaluated. High K values were obtained under drastic conditions. The best K value for cephalexin (23) was found in 100% PEG 600-3 M ammonium sulfate where cephalexin was extracted to the PEG phase. Pre-incubation of immobilized PGA derivatives in ammonium sulfate and further suspension with 100% PEG 600 allowed us to obtain a 90% synthetic yield of cephalexin from 150 mM phenylglycine methyl ester and 100 mM 7-amino desacetoxicephalosporanic acid (7-ADCA). In this reaction system, the immobilized enzyme remains in the ammonium sulfate phase and hydrolysis of the antibiotic becomes suppressed because of its continuous extraction to the PEG phase. On the contrary, synthetic yields of a similar process carried out in monophasic systems were much lower (55%) because of a rapid enzymatic hydrolysis of cephalexin. PMID- 10099317 TI - Determination of pollutant diffusion coefficients in naturally formed biofilms using a single tube extractive membrane bioreactor. AB - A novel technique has been used to determine the effective diffusion coefficients for 1,1,2-trichloroethane (TCE), a nonreacting tracer, in biofilms growing on the external surface of a silicone rubber membrane tube during degradation of 1,2 dichloroethane (DCE) by Xanthobacter autotrophicus GJ10 and monochlorobenzene (MCB) by Pseudomonas JS150. Experiments were carried out in a single tube extractive membrane bioreactor (STEMB), whose configuration makes it possible to measure the transmembrane flux of substrates. A video imaging technique (VIT) was employed for in situ biofilm thickness measurement and recording. Diffusion coefficients of TCE in the biofilms and TCE mass transfer coefficients in the liquid films adjacent to the biofilms were determined simultaneously using a resistances-in-series diffusion model. It was found that the flux and overall mass transfer coefficient of TCE decrease with increasing biofilm thickness, showing the importance of biofilm diffusion on the mass transfer process. Similar fluxes were observed for the nonreacting tracer (TCE) and the reactive substrates (MCB or DCE), suggesting that membrane-attached biofilm systems can be rate controlled primarily by substrate diffusion. The TCE diffusion coefficient in the JS150 biofilm appeared to be dependent on biofilm thickness, decreasing markedly for biofilm thicknesses of >1 mm. The values of the TCE diffusion coefficients in the JS150 biofilms <1-mm thick are approximately twice those in water and fall to around 30% of the water value for biofilms >1-mm thick. The TCE diffusion coefficients in the GJ10 biofilms were apparently constant at about the water value. The change in the diffusion coefficient for the JS150 biofilms is attributed to the influence of eddy diffusion and convective flow on transport in the thinner (<1-mm thick) biofilms. PMID- 10099318 TI - In hybridoma cultures, deprivation of any single amino acid leads to apoptotic death, which is suppressed by the expression of the bcl-2 gene. AB - The transfection of murine hybridomas with the apoptosis suppressor gene bcl-2 has been reported to result in the extension of batch culture duration, leading to significant improvements in culture productivity. In the present study, the effect of deprivation, individually, of each amino acid found in culture medium was examined to characterize the chemical environment of the culture in terms of its propensity to induce apoptosis. When cells were deprived of each amino acid, individually for 48 h, the majority of cell deaths in each case occurred by apoptosis, with essential amino acids being clearly most effective. For nearly all the amino acids, the viability of the bcl-2 cell line cultures was greater than 70% after 48 h, representing a substantial improvement in viability over control cell line cultures. Time course studies revealed that the induction of death could be divided into two phases. Initially, following the deprivation of a single essential amino acid, there was a period of time during which all the control cell line cultures retained high viability. The duration of this phase varied from 15 h in the case of lysine deprivation, through to 40 h in the case methionine deprivation. In the second phase of deprivation, the cultures exhibited an abrupt and rapid collapse in viability. The time taken for the viability to fall to 50% was similar for each amino acid. In every case, the duration of both phases of the bcl-2 cultures was considerably extended. Specific utilization rates were increased during the control cultures relative to the bcl 2 cultures for both the growth phase (ranging between 2% and 57% higher than the bcl-2 cultures) and the death phase (ranging between 172% to 1900% higher than the bcl-2 culture). PMID- 10099319 TI - Kinetic models for the growth of Escherichia coli with mixtures of sugars under carbon-limited conditions. AB - In natural environments, heterotrophic microorganisms encounter complex mixtures of carbon sources, each of which is present only at very low concentrations. Under such conditions no significant growth could be expected if cells utilized only one of the available carbon compounds as suggested by the principle of diauxic growth. Indeed, there is much evidence that microbial cells utilize many carbon sources simultaneously. In order to predict bacterial growth under such conditions we developed a model describing the specific growth rate as a function of the individual concentrations of several simultaneously utilized carbon substrates. Together with multisubstrate models previously published, this model was evaluated for its ability to describe growth of Escherichia coli during the simultaneous utilization of mixtures of sugars in carbon-limited continuous culture. Using the micromax and Ks constants determined for single substrate growth with six different sugars, the model was able for most experiments to adequately describe the specific growth rate of the culture, i.e., the experimentally set dilution rate, from the measured concentrations of the individual sugars. The model provides an explanation why bacteria can still grow relatively fast under environmental conditions where the concentrations of carbon substrates are usually extremely low. PMID- 10099320 TI - Advantages in using immobilized thermophilic beta-glycosidase in nonisothermal bioreactors. AB - Catalytic membranes, obtained by immobilizing thermophilic beta-glycosidase onto nylon supports, were used in a nonisothermal bioreactor to study the effect of temperature gradients on the rate of enzyme reaction. Two experimental approaches were carried out to explain the molecular mechanisms by which the temperature gradients affect enzyme activity. The results showed that the thermophilic enzyme behaved as the mesophilic beta-galactosidase, exhibiting an activity increase which was linearly proportional to the transmembrane temperature difference. The efficiency of the system proposed was determined by calculating two constants, alpha and beta, which represent respectively the percentage increase of enzyme activity when a temperature difference of 1 degrees C or a temperature gradient of 1 degrees C cm-1 were applied across the catalytic membrane. The increase of enzyme activity in nonisothermal bioreactors entailed a proportional reduction of production times. The advantages in using thermophilic enzymes immobilized in nonisothermal bioreactors are also discussed. PMID- 10099321 TI - The dynamical analogy between microbial growth on mixtures of substrates and population growth of competing species. AB - There is a similarity between the metabolic dynamics of a microbial species growing on a mixture of two substrates and the dynamics of growth of two competing populations. Specifically, the enzymes catalyzing the uptake and catabolism of substrates exhibit phenomena analogous to extinction and coexistence."Extinction" of the enzymes associated with one of the substrates results in sequential utilization of the substrates (diauxie) (Monod, 1942). "Coexistence" of the enzymes associated with the substrates results in simultaneous utilization of the substrates (Egli, 1995). Here, we formulate a simple model that shows the basis for this dynamical similarity: The equations describing the evolution of the enzyme levels are dynamical analogs of the Lotka Volterra model for two competing species. The analogy suggests ways of capturing the experimentally observed preculture-dependent growth patterns, i.e., growth patterns that vary depending on the physiological state of the preculture. PMID- 10099322 TI - Lipase-enhanced activity in flavour ester reactions by trapping enzyme conformers in the presence of interfaces AB - In order to improve the lipase-catalyzed synthesis of flavour esters, we have used the reported strategy of interfacial activation-based molecular (bio)imprinting [Mingarro et al. 1995. Proc. Natl. Acad. Sci. U.S.A. 92: 3308], later called trapping in the presence of amphiphile interfaces (TPI) [Mingarro et al. 1996. Biochemistry 35: 9935]. Five lipases of fungal and mammalian origin typically used for esterification process have been explored to improve production by TPI treatment. A marked enhancement of enzymatic activity has been observed in all TPI-treated lipases assayed and the activation factor obtained was up to 90-fold. The dependence on chain length of acyl donors in the esterification of geranyl alcohol has been investigated, showing clear differences between activated and nonactivated lipase. The results indicate that this rational approach leads to conversion yields that are remarkably higher, not only than its counterpart pH-optimized control lipase, but also the "protected" lipase by conventional methods (lyoprotectans or salts). We propose this strategy as a promising tool to be used in more industrial biotransformations. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099323 TI - Bacterial milking: A novel bioprocess for production of compatible solutes PMID- 10099324 TI - Quantification of microbial productivity via multi-angle light scattering and supervised learning. AB - This article describes the use of chemometric methods for prediction of biological parameters of cell suspensions on the basis of their light scattering profiles. Laser light is directed into a vial or flow cell containing media from the suspension. The intensity of the scattered light is recorded at 18 angles. Supervised learning methods are then used to calibrate a model relating the parameter of interest to the intensity values. Using such models opens up the possibility of estimating the biological properties of fermentor broths extremely rapidly (typically every 4 sec), and, using the flow cell, without user interaction. Our work has demonstrated the usefulness of this approach for estimation of yeast cell counts over a wide range of values (10(5)-10(9) cells mL 1), although it was less successful in predicting cell viability in such suspensions. PMID- 10099325 TI - Probing residue-level unfolding during lysozyme precipitation. AB - We have employed nuclear magnetic resonance (NMR) measurements of hydrogen exchange to identify residue-level conformational changes in hen egg white lysozyme (HEWL) as induced by salt precipitation. Deuterated HEWL was dissolved into a phosphate (H2O) buffer and precipitated at pH 2.1 upon addition of solid KSCN or (ND4)2SO4, allowing isotope labeling of unfolded regions. After 1 h, each precipitate was then dissolved at pH 3.8 to initiate refolding and preserve labeling and subsequently purified for NMR analysis. HEWL precipitated by 1.0 M KSCN exhibited increased hydrogen exchange at 14 residues out of 42 normally well protected in the native state. Of the affected residues, 9 were situated in the beta-sheet/loop domain. A similar, though less extensive, effect was observed at 0.2 M KSCN. Precipitation by 1.2 M (ND4)2SO4 resulted in none of the changes detected with KSCN. The popularity of ammonium sulfate as a precipitant is thus supported by this observed preservation of structural integrity. KSCN, in comparison, produced partial unfolding of specific regions in HEWL due most likely to known preferential interactions between -SCN and proteins. The severity of unfolding increased with KSCN concentration such that, at 1.0 M KSCN, almost the entire beta-sheet/loop domain of HEWL was disrupted. Even so, a portion of the HEWL core encompassed by three alpha-helices remained intact, possibly facilitating precipitate dissolution. PMID- 10099326 TI - Resistance of biofilms to the catalase inhibitor 3-amino-1,2, 4-triazole. AB - Consortia of catalase positive bacteria consisting of Pseudomonas aeruginosa, Pseudomonas fluorescens, and Klebsiella pneumoniae, in both the planktonic form and as biofilms, disproportionate hydrogen peroxide into oxygen and water. The biofilm, however, continued to disproportionate the hydrogen peroxide in the presence of the catalase inhibitor, 3-amino-1,2,4-triazole, while the planktonic organisms did not. While the bacterial catalase-peroxidase-dismutase system was probably responsible for the disproportionation of hydrogen peroxide in both cases, biofilms resisted inhibition of this enzyme system. PMID- 10099327 TI - Alcohol inhibition and specificity studies of lipase B from candida antarctica in organic solvents AB - Alcohol inhibition of the lipase B from Candida antarctica has been studied through two different approaches: using the same inhibitor (1-butanol) in different organic solvents and using different inhibitors (differing in chain length) in the same solvent. The competitive inhibition constant values obtained in each case correlate with the calculated activity coefficients of the substrate, suggesting that desolvation of the alcohol is the major force changed. Data dispersion observed using the second approach has been interpreted to come from contributions of enzyme-inhibitor interactions to the binding energy. On the other hand, deacylation has been found to be much less influenced by the solvent variation than the acylation step, despite of the fact that solvation of the substrate involved in this step (the alcohol) is expected to change more than for the ester. Concerning the specificity behavior of the enzyme, a bimodal pattern was observed for the deacylation rate dependence on the alcohol chain length, with the highest values for hexanol (C6) and decanol (C10). With regard to the ester specificity, ethyl caproate (C6) is the preferred one. These results have been confronted with those reported for the lipase from Candida rugosa. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099328 TI - Enantioselective hydroxylation of 4-alkylphenols by vanillyl alcohol oxidase AB - Vanillyl alcohol oxidase (VAO) from Penicillium simplicissimum catalyzes the enantioselective hydroxylation of 4-ethylphenol, 4-propylphenol, and 2-methoxy-4 propylphenol into 1-(4'-hydroxyphenyl)ethanol, 1-(4'-hydroxyphenyl)propanol, and 1-(4'-hydroxy-3'-methoxyphenyl)propanol, respectively, with an ee of 94% for the R enantiomer. The stereochemical outcome of the reactions was established by comparing the chiral GC retention times of the products to those of chiral alcohols obtained by the action of the lipases from Candida antarctica and Pseudomonas cepacia. Isotope labeling experiments revealed that the oxygen atom incorporated into the alcoholic products is derived from water. During the VAO mediated conversion of 4-ethylphenol/4-propylphenol, 4-vinylphenol/4 propenylphenol are formed as side products. With 2-methoxy-4-propylphenol as a substrate, this competing side reaction is nearly abolished, resulting in less than 1% of the vinylic product, isoeugenol. The VAO-mediated conversion of 4 alkylphenols also results in small amounts of phenolic ketones indicative for a consecutive oxidation step. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099329 TI - Optimising fed-batch production of recombinant proteins using the baculovirus expression vector system. AB - Fed-batch culture can offer significant improvement in recombinant protein production compared to batch culture in the baculovirus expression vector system (BEVS), as shown by Nguyen et al. (1993) and Bedard et al. (1994) among others. However, a thorough analysis of fed-batch culture to determine its limits in improving recombinant protein production over batch culture has yet to be performed. In this work, this issue is addressed by the optimisation of single addition fed-batch culture. This type of fed-batch culture involves the manual addition of a multi-component nutrient feed to batch culture before infection with the baculovirus. The nutrient feed consists of yeastolate ultrafiltrate, lipids, amino acids, vitamins, trace elements, and glucose, which were added to batch cultures of Spodoptera frugiperda (Sf9) cells before infection with a recombinant Autographa californica nuclear polyhedrosis virus (AcNPV) expressing beta-galactosidase (beta-Gal). The fed-batch production of beta-Gal was optimised using response surface methods (RSM). The optimisation was performed in two stages, starting with a screening procedure to determine the most important variables and ending with a central-composite experiment to obtain a response surface model of volumetric beta-Gal production. The predicted optimum volumetric yield of beta-Gal in fed-batch culture was 2.4-fold that of the best yields in batch culture. This result was confirmed by a statistical analysis of the best fed-batch and batch data (with average beta-Gal yields of 1.2 and 0.5 g/L, respectively) obtained from this laboratory. The response surface model generated can be used to design a more economical fed-batch operation, in which nutrient feed volumes are minimised while maintaining acceptable improvements in beta-Gal yield. PMID- 10099330 TI - Analysis and simulation of complex interactions during dynamic microfiltration of Escherichia coli suspensions. AB - Microfiltration is an important unit operation in downstream processing. However, due to the influence of membrane fouling, prediction of the filtration performance for biological suspensions is difficult. This paper describes a modeling approach that allows a comprehensive description of filtration performance. On the basis of experimental data and linguistic information, a specific artificial neural network was developed that predicts the process behavior within a certain range of parameters. This approach allows us to analyze influences of fermentation on filtration. By using extensive simulations, the interactions of 17 parameters were examined and the fouling causes determined. The model was developed for cell harvesting of Escherichia coli through a shear enhanced module. The method can be applied to any cross-flow filtration process. PMID- 10099331 TI - Catabolite repression mutants of Saccharomyces cerevisiae show altered fermentative metabolism as well as cell cycle behavior in glucose-limited chemostat cultures. AB - In glucose-limited continuous cultures, a Crabtree positive yeast such as Saccharomyces cerevisiae displays respiratory metabolism at low dilution rates (D) and respiro-fermentative metabolism at high D. We have studied the onset of ethanol production and cell cycle behavior in glucose-limited chemostat cultures of the wild type S. cerevisiae strain CEN.PK122 (WT) and isogenic mutants, snf1 (cat1) and snf4 (cat3) defective in proteins involved in catabolite derepression and the mutant in glucose repression mig1 (cat4). The triggering of fermentative metabolism was dependent upon catabolite repression properties of yeast and was coincident with a significant decrease of G1 length. WT cells of the strain CEN.PK122 displayed respiratory metabolism up to a D of 0.2 h-1 and exhibited longer G1 lengths than the snf1 and snf4 mutants that started fermenting after a D of 0.1 and 0.15 h-1, respectively. The catabolite derepression mutant snf4 showed a significant decrease in the duration of G1 with respect to the WT. An increase of 300% to 400% in the expression of CDC28 (CDC28-lacZ) with a noticeable shortening in G1 to values lower than approximately 150 min, was detected in the transformed wild type CEN.SC13-9B in glucose-limited chemostat cultures. The expression of CDC28-lacZ was analyzed in the wild type and isogenic mutant strains growing at maximal rate on glucose or in the presence of ethanol or glycerol. Two- to three-fold lower expression of the CDC28-lacZ fusion gene was detected in the snf1 or snf4 disruptants with respect to the WT and mig1 strains in the presence of all carbon sources. This effect was further shown to be growth rate-dependent exhibiting apparently, a threshold effect in the expression of the fusion gene with respect to the length of G1, similar to that shown in chemostat cultures. At the onset of fermentation, the control of the glycolytic flux was highly distributed between the uptake, hexokinase, and phosphofructokinase steps. Particularly interesting was the fact that the snf1 mutant exhibited the lowest fluxes of ethanol production, the highest of respiration and correspondingly, the branch to the tricarboxylic acid cycle was significantly rate-controling of glycolysis. PMID- 10099332 TI - Quantitating secretion rates of individual cells: design of secretion assays. AB - To observe events occurring in the microenvironment surrounding individual cells, a mathematical framework has been developed describing the behavior of a compound following its secretion by a single cell. This description is based on the diffusional and binding processes taking place in the vicinity of the cell surface. It allows prediction of the rate of capture and accumulation of a secreted compound around a single cell. This concept provides the basis for the design of two experimental assays for measuring single-cell secretion rates: (1) Cells are immobilized in hydrogel microbeads which contain capture sites for the secreted compound; and (2) artificial receptors are bound directly to the cell surface which are capable of binding molecules secreted by individual cells. This general methodology is developed in the specific case of the model organism Saccharomyces cerevisiae secreting a heterologous protein, but can be applied to any cell/secreted protein combination. Binding studies have shown that approximately 2 x 10(5) of these artificial receptors can be attached to the surface of a single yeast cell. At this surface density of a putative artificial receptor, it is predicted that single-cell secretion rates of 47 molecules/cell/sec of a 150 kDa protein can be detected. Simulations indicate that a microbead loaded with 5 x 10(6) capture antibodies will result in detection of secretion of this protein at rates as low as 4 molecules/cell/sec. PMID- 10099333 TI - Metabolic capacity of Bacillus subtilis for the production of purine nucleosides, riboflavin, and folic acid. AB - We developed a stoichiometric model of Bacillus subtilis metabolism for quantitative analysis of theoretical growth and biochemicals production capacity. This work concentrated on biochemicals that are derived from the purine biosynthesis pathway; inosine, guanosine, riboflavin, and folic acid. These are examples of commercially relevant biochemicals for which Bacillus species are commonly used production hosts. Two previously unrecognized, but highly desirable properties of good producers of purine pathway-related biochemicals have been identified for optimally engineered product biosynthesis; high capacity for reoxidation of NADPH and high bioenergetic efficiency. Reoxidation of NADPH, through the transhydrogenase or otherwise, appears to be particularly important for growth on glucose, as deduced from the corresponding optimal carbon flux distribution. The importance of cellular energetics on optimal performance was quantitatively assessed by including a bioenergetic efficiency parameter as an unrestricted, ATP dissipating flux in the simulations. An estimate for the bioenergetic efficiency was generated by fitting the model to experimentally determined growth yields. The results show that the maximum theoretical yields of all products studied are limited by pathway stoichiometry at high bioenergetic efficiencies. Simulations with the estimated bioenergetic efficiency of B. subtilis, growing under glucose-limiting conditions, indicate that the yield of these biochemicals is primarily limited by energy and thus is very sensitive to the process conditions. The maximum yields that can reasonably be expected with B. subtilis on glucose were estimated to be 0.343, 0.160, and 0.161 (mol product/mol glucose) for purine nucleosides, riboflavin, and folic acid, respectively. Potential strategies for improving these maximum yields are discussed. PMID- 10099334 TI - Metabolic design: how to engineer a living cell to desired metabolite concentrations and fluxes. AB - A biotechnological aim of genetic engineering is to increase the intracellular concentration or secretion of valuable compounds, while making the other concentrations and fluxes optimal for viability and productivity. Efforts to accomplish this based on over-expression of the enzyme, catalyzing the so-called "rate-limiting step," have not been successful. Here we develop a method to determine the enzyme concentrations that are required to achieve such an aim. This method is called Metabolic Design Analysis and is based on the perturbation method and the modular ("top-down") approach-formalisms that were first developed for the analysis of biochemical regulation such as, Metabolic Control Analysis. Contrary to earlier methods, the desired alterations of cellular metabolism need not be small or confined to a single metabolite or flux. The limits to the alterations of fluxes and metabolite concentrations are identified. To employ Metabolic Design Analysis, only limited kinetic information concerning the pathway enzymes is needed. PMID- 10099335 TI - Generating controlled reducing environments in aerobic recombinant Escherichia coli fermentations: effects on cell growth, oxygen uptake, heat shock protein expression, and in vivo CAT activity. AB - The independent control of culture redox potential (CRP) by the regulated addition of a reducing agent, dithiothreitol (DTT) was demonstrated in aerated recombinant Escherichia coli fermentations. Moderate levels of DTT addition resulted in minimal changes to specific oxygen uptake, growth rate, and dissolved oxygen. Excessive levels of DTT addition were toxic to the cells resulting in cessation of growth. Chloramphenicol acetyltransferase (CAT) activity (nmoles/microgram total protein min.) decreased in batch fermentation experiments with respect to increasing levels of DTT addition. To further investigate the mechanisms affecting CAT activity, experiments were performed to assay heat shock protein expression and specific CAT activity (nmoles/microgram CAT min.). Expression of such molecular chaperones as GroEL and DnaK were found to increase after addition of DTT. Additionally, sigma factor 32 (sigma32) and several proteases were seen to increase dramatically during addition of DTT. Specific CAT activity (nmoles/microgram CAT min. ) varied greatly as DTT was added, however, a minimum in activity was found at the highest level of DTT addition in E. coli strains RR1 [pBR329] and JM105 [pROEX-CAT]. In conjunction, cellular stress was found to reach a maximum at the same levels of DTT. Although DTT addition has the potential for directly affecting intracellular protein folding, the effects felt from the increased stress within the cell are likely the dominant effector. That the effects of DTT were measured within the cytoplasm of the cell suggests that the periplasmic redox potential was also altered. The changes in specific CAT activity, molecular chaperones, and other heat shock proteins, in the presence of minimal growth rate and oxygen uptake alterations, suggest that the ex vivo control of redox potential provides a new process for affecting the yield and conformation of heterologous proteins in aerated E. coli fermentations. PMID- 10099336 TI - A review of experimental measurements of effective diffusive permeabilities and effective diffusion coefficients in biofilms. AB - Experimental measurements of effective diffusive permeabilities and effective diffusion coefficients in biofilms are reviewed. Effective diffusive permeabilities, the parameter appropriate to the analysis of reaction-diffusion interactions, depend on solute type and biofilm density. Three categories of solute physical chemistry with distinct diffusive properties were distinguished by the present analysis. In order of descending mean relative effective diffusive permeability (De/Daq) these were inorganic anions or cations (0.56), nonpolar solutes with molecular weights of 44 or less (0.43), and organic solutes of molecular weight greater than 44 (0.29). Effective diffusive permeabilities decrease sharply with increasing biomass volume fraction suggesting a serial resistance model of diffusion in biofilms as proposed by Hinson and Kocher (1996). A conceptual model of biofilm structure is proposed in which each cell is surrounded by a restricted permeability envelope. Effective diffusion coefficients, which are appropriate to the analysis of transient penetration of nonreactive solutes, are generally similar to effective diffusive permeabilities in biofilms of similar composition. In three studies that examine diffusion of very large molecular weight solutes (>5000) in biofilms, the average ratio of the relative effective diffusion coefficient of the large solute to the relative effective diffusion coefficient of either sucrose or fluorescein was 0.64, 0.61, and 0.36. It is proposed that large solutes are effectively excluded from microbial cells, that small solutes partition into and diffuse within cells, and that ionic solutes are excluded from cells but exhibit increased diffusive permeability (but decreased effective diffusion coefficients) due to sorption to the biofilm matrix. PMID- 10099337 TI - I. Study of protein aggregation due to heat denaturation: A structural approach using circular dichroism spectroscopy, nuclear magnetic resonance, and static light scattering. AB - The objective of this study was to investigate the relationship between oxidized RNase A protein structure and the occurrence of protein aggregation using several spectroscopic techniques. Circular dichroism spectroscopy (CD) measurements taken at small temperature intervals were used to determine the protein's melting temperature, Tm, of approximately 65 degrees C in deionized water. A more detailed examination of the protein structure was undertaken at several temperatures around Tm using near- and far-UV CD and one-dimensional nuclear magnetic resonance (NMR) measurements. These measurements revealed the presence of folded structures at 55 degrees C and below, while denatured structures appeared at 65 degrees C and above. Concurrent static light scattering (SLS) measurements, employed to detect the presence of RNase A aggregates, showed that RNase A aggregation was observed at 65 degrees C and above, when much of the protein was denatured. Subsequent NMR time-course data demonstrated that aggregates forming at 75 degrees C and pH 7.8 were indeed derived from heat denatured protein. However, aggregation was also detected at 55 degrees C when the spectroscopic data suggested the protein was present predominantly in the folded configuration. In contrast, heat denaturation did not lead to RNase A aggregation in a very acidic environment. We attribute this phenomenon to the effect of charge-charge repulsion between the highly protonated RNase A molecules in very acidic pH. PMID- 10099338 TI - II. Electrostatic effect in the aggregation of heat-denatured RNase A and implications for protein additive design. AB - In the previous study (part I), heat-denatured RNase A aggregation was shown to depend on the solution pH. Interestingly, at pH 3.0, the protein did not aggregate even when exposed to 75 degrees C for 24 h. In this study, electrostatic repulsion was shown to be responsible for the absence of aggregates at that pH. While RNase A aggregation was prevented at the extremely acidic pH, this is not an environment conducive to maintaining protein function in general. Therefore, attempts were made to confer electrostatic repulsion near neutral pH. In this study, heat-denatured RNase A was mixed with charged polymers at pH 7.8 in an attempt to provide the protein with excess surface cations or anions. At 75 degrees C, SDS and dextran sulfate were successful in preventing RNase A aggregation, whereas their cationic, nonionic, and zwitterionic analogs did not do so. We believe that the SO3- groups present in both additives transformed the protein into polyanionic species, and this may have provided a sufficient level of electrostatic repulsion at pH 7.8 and 75 degrees C to prevent aggregation from proceeding. PMID- 10099339 TI - Leader peptide efficiency correlates with signal recognition particle dependence in Saccharomyces cerevisiae. AB - Secretion of bovine pancreatic trypsin inhibitor (BPTI) in Saccharomyces cerevisiae was examined with four different leader peptides: the invertase signal peptide, the mfalpha1 signal peptide, a synthetic signal peptide, and a synthetic pre pro leader. BPTI secretion from a low-copy CEN plasmid varies from 1.8 to 10.4 microgram/mL among these constructs. Secretion titers correlate with dependence on signal recognition particle (SRP), with greatest secretion from the most SRP-dependent construct. Examination of co- vs post-translational translocation pathways and overall translocation efficiency by ubiquitin translocation assay (UTA) does not provide insight into the variation in BPTI secretion efficiency, perhaps due to alteration in translocation kinetics from the additional polypeptide fusion required by the assay. BPTI translocation efficiency (as measured by UTA) is found to drop markedly upon depletion of Srp54p, prior to any observable growth defect. Subsequent to stress response induction and the onset of slow growth (15-h doubling time), BPTI translocation efficiency recovers to the level observed prior to SRP depletion. PMID- 10099340 TI - A cell adhesion peptide from foot-and-mouth disease virus can direct cell targeted delivery of a functional enzyme. AB - The G-H loop of foot-and-mouth disease virus is a disordered protrusion of the VP1 protein exposed on the virion surface. This short stretch includes an arginine-glycine-aspartic acid tripeptide, a recognized integrin-binding motif, which is responsible for cell attachment and infection. Eight copies of a peptide reproducing the amino acid sequence of this FMDV ligand have been displayed in solvent-exposed regions on an enzymatically active recombinant beta galactosidase. This viral peptide segment enables the chimeric enzyme to bind mammalian cell lines with different efficiencies, probably depending on the number of suitable cell receptors present on each of them. Moreover, it also promotes the internalization of the attached enzyme, which is transiently active inside the cells. These results suggest further exploration of the potential use of short adhesion peptides of viral origin as cell attachment tags to direct the targeted delivery of both genes and enzymes, instead of whole, infectious viruses. PMID- 10099341 TI - Microelectrode measurements of local mass transport rates in heterogeneous biofilms. AB - Microelectrodes were used to measure oxygen profiles and local mass transfer coefficient profiles in biofilm clusters and interstitial voids. Both profiles were measured at the same location in the biofilm. From the oxygen profile, the effective diffusive boundary layer thickness (DBL) was determined. The local mass transfer coefficient profiles provided information about the nature of mass transport near and within the biofilm. All profiles were measured at three different average flow velocities, 0.62, 1.53, and 2.60 cm sec-1, to determine the influence of flow velocity on mass transport. Convective mass transport was active near the biofilm/liquid interface and in the upper layers of the biofilm, independent of biofilm thickness and flow velocity. The DBL varied strongly between locations for the same flow velocities. Oxygen and local mass transfer coefficient profiles collected through a 70 micrometer thick cluster revealed that a cluster of that thickness did not present any significant mass transport resistance. In a 350 micrometer thick biofilm cluster, however, the local mass transfer coefficient decreased gradually to very low values near the substratum. This was hypothetically attributed to the decreasing effective diffusivity in deeper layers of biofilms. Interstitial voids between clusters did not seem to influence the local mass transfer coefficients significantly for flow velocities of 1.53 and 2.60 cm sec-1. At a flow velocity of 0.62 cm sec-1, interstitial voids visibly decreased the local mass transfer coefficient near the bottom. PMID- 10099342 TI - Mathematical model for liquid-gas equilibrium in acetic acid fermentations AB - An experimental study was conducted to propose an adequate mathematical model for liquid-gas equilibrium in acetic acid fermentations. Three operation scales (laboratory, pilot plant, and industrial plant) were employed to obtain the sets of experimental data. The proposed model, based in the UNIFAC method for the estimation of activity coefficients of a solution consisting of several components, takes into account the effect of temperature. However, in the set of equations, it has been necessary to put in the degree of equilibrium (epsilon). This coefficient adequately reflects the physical conditions of fermentation equipment. The experimental and numerical results help to define the fundamental mechanisms for liquid-gas equilibrium in these systems and demonstrate the model validity in the three tested scales. It was also found that in an industrial setting, closed systems are those with lowest evaporation losses. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099343 TI - Activity and stability of a recombinant plasmid-borne TCE degradative pathway in biofilm cultures AB - The activity and stability of the TCE degradative plasmid TOM31c in the transconjugant host Burkholderia cepacia 17616 was studied in selective and non selective biofilm cultures. The activity of plasmid TOM31c in biofilm cultures was measured by both TCE degradative studies and the expression of the Tom pathway. Plasmid loss was measured using continuous flow, rotating annular biofilm reactors, and various analytical and microbiological techniques. The probability of plasmid loss in the biofilm cultures was determined using a non steady-state biofilm plasmid loss model that was derived from a simple mass balance, incorporating results from biofilm growth and plasmid loss studies. The plasmid loss model also utilized Andrew's inhibition growth kinetics and a biofilm detachment term. Results from these biofilm studies were compared to similar studies performed on suspended cultures of Burkholderia cepacia 17616 TOM31c to determine if biofilm growth has a significant effect on either plasmid retention or Tom pathway expression (i.e., TCE degradation rates). Results show that the activity and expression of the Tom pathway measured in biofilm cultures was significantly less than that found in suspended cultures at comparable growth rates. The data obtained from these studies fit the plasmid loss model well, providing plasmid loss probability factors for biofilm cultures that were equivalent to those previously found for suspended cultures. The probability of plasmid loss in the B. cepacia 17616-TOM31c biofilm cultures was equivalent to those found in the suspended cultures. The results indicate that biofilm growth neither helps nor hinders plasmid stability. In both the suspended and the biofilm cultures, plasmid retention and expression could be maintained using selective growth substrates and/or an appropriate plasmid-selective antibiotic. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099344 TI - An experimental and modeling study on the removal of mono-chlorobenzene vapor in biotrickling filters AB - Removal of mono-chlorobenzene (m-CB) vapor from airstreams was studied in a biotrickling filter (BTF) operating under counter-current flow of the air and liquid streams. Experiments were performed under various values of inlet m-CB concentration, air and/or liquid volumetric flow rates, and pH of the recirculating liquid. Conversion of m-CB was never below 70% and at low concentrations exceeded 90%. A maximum removal rate of about 60 gm-3-reactor h-1 was observed. Conversion of m-CB was found to increase as the values of liquid and air flow rate increase and decrease, respectively. The effects of pH and frequency of medium replenishment on BTF performance were also investigated. The process was successfully described with a detailed mathematical model, which accounts for mass transfer and kinetic effects based on m-CB and oxygen availability. Solution of the model equations yielded m-CB and oxygen concentration profiles in all three phases (airstream, liquid, biofilm). It is predicted that oxygen has a controling effect on the process at high inlet m-CB concentrations. From independent, suspended culture, experiments it was found that m-CB biodegradation follows Andrews inhibitory kinetics. The kinetic constants were found to remain practically unchanged after the culture was used in BTF experiments for 8 months. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099345 TI - Effect of some operating variables on citrate recovery from model solutions by electrodialysis AB - The effect of pH and temperature (straight theta) on the overall performance indicators (i.e., solute recovery, rho, and Faraday, eta, efficiencies; specific energy consumption, epsilon, solute, JS, and water, JW, fluxes) of batch electrodialytic recovery of citric acid from model solutions was assessed at different values of feed solute concentration (cSf) and electric current density (j). Regardless of the initial feed concentration used, rho and JS were found to be independent of straight theta; eta and JW exhibited a positive trend with respect to straight theta, while epsilon a negative one. At the maximum temperature tested (33 degrees C), as the pH of the feed solution was varied from 3 to 7, rho increased from 0.90 +/- 0.08 to 0.97 +/- 0.02, eta grew from 0.09 +/- 0.02 to 0.50 +/- 0.01, JS practically doubled, epsilon reduced about 8 times, but JW increased from 3 to 4 times. So, the optimal conditions for this technique are to be determined by balancing the savings in the investment and maintenance costs against the energy costs. Copyright John Wiley & Sons, Inc. PMID- 10099346 TI - High-density perfusion culture of insect cells with a biosep ultrasonic filter. AB - The baculovirus/insect cell expression system has provided a vital tool to produce a high level of active proteins for many applications. We have developed a very high-density insect cell perfusion process with an ultrasonic filter as a cell retention device. The separation efficiency of the filter was studied under various operating conditions. A cell density of over 30 million cells/mL was achieved in a controlled perfusion bioreactor and cell viability remained greater than 90%. Sf9 cells from a high-density culture and a spinner culture were infected with two recombinant baculoviruses expressing genes for the production of human chitinase and monocyte-colony inhibition factor. The protein yield on a cell basis from infecting high-density Sf9 cells was the same as or higher than that from the spinner Sf9 culture. Virus production from the high-density culture was similar to that from the spinner culture. The results show that the ultrasonic filter did not affect insect cells' ability to support protein expression and virus production following infection with baculovirus. The potential applications of the high-density perfusion culture for large-scale protein expression from Sf9 cells are also highlighted. PMID- 10099347 TI - Stability and activity modulation of chymotrypsins in AOT reversed micelles by protein-interface interaction: interaction of alpha-chymotrypsin with a negative interface leads to a cooperative breakage of a salt bridge that keeps the catalytic active conformation (Ile16-Asp194). AB - The stability of alpha-chymotrypsin and delta-chymotrypsin was studied in reversed micelles of sodium bis(2-ethylhexyl)sulfosuccinate (AOT) in isooctane. alpha-Chymotrypsin is inactivated at the interface and at the water pool, while delta-chymotrypsin is inactivated only at the water pool. The mechanism of inactivation at the interface is related to the interaction of N-terminal group alanine 149 (absent in delta-chymotrypsin) with the negative interface. The dependence of enzyme activity on water content of these two enzymes in reversed micelles of AOT is also related with the interface interaction, since delta chymotrypsin does not have a bell-shaped curve as observed for alpha chymotrypsin. PMID- 10099348 TI - Mass transfer studies on immobilized alpha-chymotrypsin biocatalysts prepared by deposition for use in organic medium. AB - Mass transfer limitations were studied in enzyme preparations of alpha chymotrypsin made by deposition on different porous support materials such as controlled pore glasses, Celite, and polyamides of different particle sizes. It is the onset of mass transfer limitations that determines the position of the activity optimum with respect to enzyme loading on each support. The evidence of various experiments indicates that internal diffusional limitations are the important mechanism for the observed mass transfer limitations. External diffusion was not found to play an important role under the conditions used, and it was also found that when immobilizing multilayers of enzyme the buried enzyme molecules are active to a large extent. An extreme situation is observed on Celite at very high loadings. Under these conditions, this support is expected to have its pores completely filled with packed enzyme molecules, and then it is the diffusion within the enzyme layer that determines the observed rate. As the enzyme loading increases, the area of contact between the deposited enzyme layers and the liquid solution inside the pores diminishes, causing a decrease on the observed rate of an intrinsically fast reaction which apparently is incongruous with the presence of more enzyme in the system. This work shows that mass transfer limitations can be an important factor when working with immobilized enzymes in organic media, and its study should be carried out in order to avoid undesired reduced enzyme activities and specificities. PMID- 10099349 TI - Prevention of marine biofouling using a conductive paint electrode AB - Conductive paint electrode was used for marine biofouling on fishing nets by electrochemical disinfection. When a potential of 1.2 V vs. a saturated calomel electrode (SCE) was applied to the conductive paint electrode, Vibrio alginolyticus cells attached on the electrode were completely killed. By applying a negative potential, the attached cells were removed from the surface of the electrode. Changes in pH and chlorine concentration were not observed at potentials in the range -0.6 approximately 1.2 V vs. SCE. In a field experiment, accumulation of the bacterial cells and formation of biofilms on the electrode were prevented by application of an alternating potential, and 94% of attachment of the biofouling organisms was inhibited electrically on yarn used for fishing net coated with conductive paint. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099350 TI - Improvement of heterologous protein productivity using recombinant Yarrowia lipolytica and cyclic fed-batch process strategy. AB - A cyclic fed-batch bioprocess is designed and a significant improvement of rice alpha-amylase productivity of recombinant Yarrowia lipolytica is illustrated. A bioprocess control strategy developed and reported here entails use of a genetically stable recombinant cloned for heterologous protein, use of optimized media for cell growth and enzyme production phases, and process control strategy enabling high cell-density culture and high alpha-amylase productivity. This process control can be achieved through maintaining a constant optimal specific cell growth rate at a predetermined value (i.e., 0.1 h-1), controlling medium feed rate commensurate with the cell growth rate, and maintaining a high cell density culture (i.e., 60-70 g/L) for high productivity of cloned heterologous protein. The volumetric enzyme productivity (1, 960 units/L. h) achieved from the cyclic fed-batch process was about 3-fold higher than that of the fed-batch culture process (630 units/L. h). PMID- 10099351 TI - An Escherichia coli host strain useful for efficient overproduction of secreted recombinant protein. AB - Periplasmic secretion of overexpressed Bacillus stearothermophilus alpha-amylase was analyzed in batch and fed-batch cultivations of Escherichia coli MG1655:pCSS4 p and the mutant strain CWML2:pCSS4-p. Under all conditions investigated, growth and product formation of MG1655:pCSS4-p were severely impaired by heterologous protein expression and/or processing, while E. coli CWML2:pCSS4-p was found to be more robust and to accumulate 2- to 3-fold higher maximum alpha-amylase levels. While this strain is itself potentially interesting for applications, its properties also illustrate the potential of the selection procedure that was employed to obtain it from its progenitor MG1655 (Weikert, C., Sauer, U., Bailey, J. E., 1997. Microbiol. 143: 1567-1574. Application of this procedure to existing industrial strains may lead to significantly improved process organisms. PMID- 10099352 TI - Biodegradation of 1,1,1-trichloroethane by a carbon tetrachloride-degrading denitrifying consortium AB - A denitrifying consortium capable of degrading carbon tetrachloride (CT) was shown to also degrade 1,1,1-trichloroethane (TCA). Fed-batch experiments demonstrated that the specific rate of TCA degradation by the consortium was comparable to the specific rate of CT degradation (approximately 0.01 L/gmol/min) and was independent of the limiting nutrient. Although previous work demonstrated that 4-50% of CT transformed by the consortium was converted to chloroform (CF), no reductive dechlorination products were detected during TCA degradation, regardless of the limiting nutrient. The lack of chlorinated TCA degradation products implies that the denitrifying consortium possesses an alternate pathway for the degradation of chlorinated solvents which does not involve reductive dechlorination. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099353 TI - Fed-batch cultivation of an oxygen-dependent inducible promoter system, the nar promoter in Escherichia coli with an inactivated nar operon. AB - The nar promoter of Escherichia coli is maximally induced under anaerobic or microaerobic conditions in the presence of nitrate. We previously demonstrated in batch experiments that the intact nar promoter of E. coli cloned into a pBR322 based plasmid serves as a high-level expression system in a nar mutant of E. coli (Lee et al., 1996b). In this study, we extend characterization of the nar promoter expression system to the fed-batch culture mode, which is widely used in industrial-scale fermentation. From these experiments, it was found that the specific beta-galactosidase activity expressed from the lacZ gene fused to the nar promoter was maximal when host cells were grown under aerobic conditions [dissolved oxygen, (DO) = 80%] to absorbance at 600 nm (OD600) = 35 before induction of the nar promoter by lowering DO to 1-2% with alternating microaerobic and aerobic conditions. Approximately 15 h after induction, the OD600 of the culture reached 135 and the specific beta-galactosidase activity increased to 40,000 Miller units, equivalent to approximately 35% of the total cellular proteins. The specific beta-galactosidase activity before induction was approximately 1,000 Miller units, giving an induction ratio of approximately 40. Based on these results, we conclude that the nar promoter provides a convenient and effective high level expression system under conditions of fed-batch culture. PMID- 10099355 TI - Benefits from tween during enzymic hydrolysis of corn stover AB - Corn stover is a potential substrate for fermentation processes. Previous work with corn stover demonstrated that lime pretreatment rendered it digestible by cellulase; however, high sugar yields required very high enzyme loadings. Because cellulase is a significant cost in biomass conversion processes, the present study focused on improving the enzyme efficiency using Tween 20 and Tween 80; Tween 20 is slightly more effective than Tween 80. The recommended pretreatment conditions for the biomass remained unchanged regardless of whether Tween was added during the hydrolysis. The recommended Tween loading was 0.15 g Tween/g dry biomass. (The critical relationship was the Tween loading on the biomass, not the Tween concentration in solution.) The 72-h enzymic conversion of pretreated corn stover using 5 FPU cellulase/g dry biomass at 50 degrees C with Tween 20 as part of the medium was 0.85 g/g for cellulose, 0.66 g/g for xylan, and 0.75 for total polysaccharide; addition of Tween improved the cellulose, xylan, and total polysaccharide conversions by 42, 40, and 42%, respectively. Kinetic analyses showed that Tween improved the enzymic absorption constants, which increased the effective hydrolysis rate compared to hydrolysis without Tween. Furthermore, Tween prevented thermal deactivation of the enzymes, which allows for the kinetic advantage of higher temperature hydrolysis. Ultimate digestion studies showed higher conversions for samples containing Tween, indicating a substrate effect. It appears that Tween improves corn stover hydrolysis through three effects: enzyme stabilizer, lignocellulose disrupter, and enzyme effector. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099354 TI - Optimization and stability of glucoamylase production by recombinant strains of Aspergillus niger in chemostat culture. AB - When grown on a medium containing 5 g maltodextrin L-1, Aspergillus niger transformant N402[pAB6-10]B1, which has an additional 20 copies of the glucoamylase (glaA) gene, produced 320 +/- 8 mg (mean +/- S.E.) glucoamylase (GAM) L-1 in batch culture and 373 +/- 9 mg GAM L-1 in maltodextrin-limited chemostat culture at a dilution rate of 0.13 h-1. These values correspond to specific production rates (qp) of 5.6 and 16.0 mg GAM [g biomass]-1 h-1, respectively. In maltodextrin-limited chemostat cultures grown at dilution rates from 0.06 to 0.14 h-1, GAM was produced by B1 in a growth-correlated manner, demonstrating that a continuous flow culture system operated at a high dilution rate is an efficient way of producing this enzyme. In chemostat cultures grown at high dilution rates, GAM production in chemostat cultures was repressed when the limiting nutrient was fructose or xylose, but derepressed when the limiting nutrient was glucose (qp, 12.0), potassium (6.2), ammonium (4.1), phosphate (2.0), magnesium (1.5) or sulphate (0.9). For chemostat cultures grown at a dilution rate of 0.13 h-1, the addition of 5 g mycopeptone L-1 to a glucose mineral salts medium resulted in a 64% increase in GAM concentration (from 303 +/ 12 to 496 +/- 10 mg GAM L-1) and a 37% increase in specific production rate (from 12.0 +/- 0.4 to 16.4 +/- 1.6 mg GAM [g biomass]-1 h-1). However, although recombinant protein production was stable for at least 948 h (191 generations) when A. niger B1 was grown in chemostat culture on glucose-mineral salts medium, it was stable for less than 136 h (27 generations) on medium containing mycopeptone. The predominant morphological mutants occurring after prolonged chemostat culture were shown to have selective advantage in the chemostat over the parental strain. Compared to their parental strains, two morphological mutants had similar GAM production levels, while a third had a reduced production level. Growth tests and molecular analysis revealed that the number of glaA gene copies in this latter strain (B1-M) was reduced, which could explain its reduced GAM production. Shake-flask cultures carried out with the various morphological mutants revealed that in batch culture all three strains produced considerably less GAM than their parent strains and even less than N402. We show that physiological changes in these morphological mutants contribute to this decreased level of GAM production. PMID- 10099356 TI - Rapid biocatalytic polytransesterification: reaction kinetics in an exothermic reaction AB - Biocatalytic polytransesterification at high concentrations of monomers proceeds rapidly and is accompanied by an increase in the temperature of the reaction mixture due to liberation of heat of reaction during the initial phase. We have used principles of reaction calorimetry to monitor the kinetics of polymerization during this initial phase, thus relating the temperature to the extent of polymerization. Rate of polymerization increases with the concentration of monomers. This is also reflected by the increase in the temperature of the reaction mixture. Using time-temperature-conversion contours, a differential method of kinetic analysis was used to calculate the energy of activation ( approximately 15.1 Kcal/mol). Copyright 1998 John Wiley & Sons, Inc. PMID- 10099357 TI - Degradation of perchloroethylene and dichlorophenol by pulsed-electric discharge and bioremediation AB - Pulsed electric discharge (PED) and bioremediation were combined to create a novel two-stage system which dechlorinates the halogenated pollutants, 2,4 dichlorophenol and perchloroethylene, with repetitive (0.1-1 kHz), short pulse ( approximately 100 ns), low voltage (40-80 kV) discharges and then mineralizes the less chlorinated products with aerobic bacteria. A 6.1 mM aqueous dichlorophenol sample was cycled through the PED reactor (60 kV of applied pulsed voltage and 300 Hz) 6 times, resulting in the release of 55% of the initial dichlorophenol chloride ions (1 mM Cl- removed each cycle). The respective average specific efficiency is 0.4-0.6 keV/(Cl- molecule). Pseudomonas mendocina KR1, which grows in minimal medium supplemented with phenol but not with dichlorophenol, increased in cell density in all cultures supplemented with the PED-treated DCP samples and yielded a maximum of two-fold additional Cl- released compared to the PED-related alone. The number of PED-treatment cycles, voltage, and frequency were also varied, showing that both cell densities and overall dichlorophenol dechlorination were highly dependent upon the number of PED-treatment cycles, rather than the tested voltages and frequencies. Using this two-stage treatment system, PED released 31% of the initial chloride ions from dichlorophenol (after three cycles at 40-45 kV and 1.2 kHz) while P. mendocina KR1 in the second stage increased dechlorination to 90%. These results were corroborated by the 35% additional chloride release found with activated sludge cultures. Perchloroethylene (0.6 mM) was similarly treated in a first-stage PED reactor (80% chloride removal after four cycles) followed by biodegradation of the dechlorinated products with a recombinant toluene o-monooxygenase-expressing Pseudomonas fluorescens strain. Gas chromatographic analysis showed that the PED reactor created less-chlorinated byproducts (i.e., trichloroethylene) that were removed (74%) upon exposure to the recombinant bacterium. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099358 TI - Antisense strategies for glycosylation engineering of Chinese hamster ovary (CHO) cells. AB - Novel glycoproteins, inaccessible by other techniques, can be obtained by metabolic engineering of the oligosaccharide biosynthesis pathway. Furthermore, alteration of cell-surface oligosaccharides can change the properties of receptors involved in cell-cell adhesion. Sialyl Lewis X (sLex) is a cell-surface oligosaccharide determinant which is specifically expressed on granulocytes and monocytes and which interacts with selectins to influence leukocyte trafficking, thrombosis, inflammation, and cancer. Antisense technology targeting fucosyltransferase VI (Fuc-TVI), an enzyme necessary for the synthesis of the sLex in engineered Chinese hamster ovary (CHO) cells, has reduced Fuc-TVI activity, sLex synthesis, and adhesion to endothelial cells. Antisense methodology to reduce targeted activity in oligosaccharide biosynthesis or other pathways is an important addition to CHO cell metabolic engineering capabilities. PMID- 10099359 TI - Analysis of protein fouling during ultrafiltration using a two-layer membrane model. AB - Protein fouling can significantly alter both the flux and retention characteristics of ultrafiltration membranes. There has, however, been considerable controversy over the nature of this fouling layer. In this study, hydraulic permeability and dextran sieving data were obtained both before and after albumin adsorption and/or filtration using polyethersulfone ultrafiltration membranes. The dextran molecular weight distributions were analyzed by gel permeation chromatography to evaluate the sieving characteristics over a broad range of solute size. Protein fouling caused a significant reduction in the dextran sieving coefficients, with very different effects seen for the diffusive and convective contributions to dextran transport. The changes in dextran sieving coefficients and diffusive permeabilities were analyzed using a two-layer membrane model in which a distinct protein layer is assumed to form on the upstream surface of the membrane. The data suggest that the protein layer formed during filtration was more tightly packed than that formed by simple static adsorption. Hydrodynamic calculations indicated that the pore size of the protein layer remained relatively constant throughout the adsorption or filtration, but the thickness of this layer increased with increasing exposure time. These results provide important insights into the nature of protein fouling during ultrafiltration and its effects on membrane transport. PMID- 10099360 TI - Contribution of protein charge to partitioning in aqueous two-phase systems. AB - Protein partitioning in aqueous two-phase systems based on phase-forming polymers is strongly affected by the net charge of the protein, but a thermodynamic description of the charge effects has been hindered by conflicting results. Many of the difficulties could be because of problems in isolating electrochemical effects from other interactions of phase components. We explored charge effects on protein partitioning in poly(ethylene glycol)-dextran two-phase systems by using two series of genetically engineered charge modifications of bacteriophage T4 lysozyme produced in Escherichia coli. The two series, one in the form of charged-fusion tails and the other in the form of charge-change point mutations, provided matching net charges but very different polarity. Partition coefficients of both series were obtained and interfacial potential differences of the phase systems were measured. Multi-angle laser light scattering measurements were also performed to determine second virial coefficients. A semi-empirical model accounting for the roles of both charge and non-charge effects on protein partitioning behavior is proposed, and the results predicted from the model are compared to the results from the experiments. PMID- 10099361 TI - Colloidal gas aphrons: A novel approach to protein recovery. AB - Sebba (1987) defined colloidal gas aphrons (CGA) as microbubbles stabilized by surfactant layers, which are created by stirring surfactant solutions at speeds greater than a critical value. A high shear impeller is used for stirring and critical values for the impeller speed must be exceeded to create these stable gas liquid dispersions (typically >5000 rpm). Although there have been no previous reports of direct protein recovery using CGA, it is likely that, with appropriate choice of surfactant, proteins should adsorb to these surfactant bubbles by means of electrostatic and/or hydrophobic interactions. This is the basis of this study, in which the use of CGA for protein recovery from aqueous solution is considered. A surfactant which has been characterized previously for generation of CGA was chosen (Jauregi et al., 1997), i.e., the anionic surfactant sodium bis-(2-ethyl hexyl) sulfosuccinate (AOT). Lysozyme, a well-characterized protein, was chosen as the protein to be recovered. Lysozyme was recovered successfully from aqueous solution using CGA generated from AOT. At optimum conditions, lysozyme recovery, enrichment ratio, and separation ratio were 95%, 19 and 302 respectively, with enzyme activity maintained. These results indicate the exciting potential of this technique. A wide range of process conditions including initial concentration of protein and surfactant, surfactant/protein molar ratio, pH, and ionic strength were considered. High recoveries and enrichments were generally obtained at protein concentrations 0.11 mg/mL. However, at high ionic strength (0.29M) poor separation and recoveries were obtained at low protein concentrations (counter-ions diminishing electrostatic interactions between protein and aphrons at this condition). In general, (ns/np)a was determined to be between 10 and 16 for experiments in which high levels of recovery/separation parameters were found. For most conditions, protein precipitation was observed; however, this precipitate could be resolubilized without loss of enzyme activity. PMID- 10099362 TI - Surfactant-enhanced biodegradation of high molecular weight polycyclic aromatic hydrocarbons by stenotrophomonas maltophilia AB - The objectives of this study were to isolate and evaluate microorganisms with the ability to degrade high molecular weight polycyclic aromatic hydrocarbons (PAHs) in the presence of synthetic surfactants. Stenotrophomonas maltophilia VUN 10,010, isolated from PAH-contaminated soil, utilized pyrene as a sole carbon and energy source and also degraded other high molecular weight PAHs containing up to seven benzene rings. Various synthetic surfactants were tested for their ability to improve the PAH degradation rate of strain VUN 10,010. Anionic and cationic surfactants were highly toxic to this strain, and the Tween series was used as a growth substrate. Five nonionic surfactants (Brij 35, Igepal CA-630, Triton X 100, Tergitol NP-10, and Tyloxapol) were not utilized by, and were less toxic to, strain VUN 10,010. MSR and log Km values were determined for fluoranthene, pyrene, and benzo[a]pyrene in the presence of these nonionic surfactants and their apparent solubility was increased by a minimum of 250-fold in the presence of 10 g L-1 of all surfactants. The rate of pyrene degradation by strain VUN 10,010 was enhanced by the addition of four of the nonionic surfactants (5-10 g L 1); however, 5 g L-1 Igepal CA-630 inhibited pyrene degradation and microbial growth. The specific growth rate of VUN 10,010 on pyrene was increased by 67% in the presence of 10 g L-1 Brij 35 or Tergitol NP-10. The addition of Brij 35 and Tergitol NP-10 to media containing a single high molecular weight PAH (four and five benzene rings) as the sole carbon source increased the maximum specific PAH degradation rate and decreased the lag period normally seen for PAH degradation. The addition of Tergitol NP-10 to VUN 10,010 cultures which contained a PAH mixture (three to seven benzene rings) substantially improved the overall degradation rate of each PAH and increased the specific growth rate of VUN 10,010 by 30%. Evaluation of the use of VUN 10,010 for degrading high molecular weight PAHs in leachates from surfactant-flushed, weathered, PAH-contaminated sites is warranted. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099363 TI - Large-scale preparation of (Z)-3-hexen-1-yl acetate using candida antarctica immobilized lipase in hexane AB - A kilogram-scale synthesis of (Z)-3-hexen-1-yl acetate, in hexane, on direct esterification of (Z)-3-hexen-1-ol with acetic acid in the presence of 2% (w/w reactants) of an immobilized lipase from Candida antarctica (Novozym 435) is reported. Conversion yields ranging from 92 to 96% were obtained after optimization of various parameters. In that respect, elimination of the water proved crucial. Using at both the laboratory large scale (preparation of 200-400 g of ester) and the pilot scale (1-5 kg) a "reflux" rotary evaporator equipped with a graduated decantation flask, we were able to trap the water evolved during esterification while at the same time monitor the time course of the reaction. As a consequence of both an efficient water trapping and of a gentle dispersion of the immobilized lipase into the reaction medium, the lifetime of the enzyme was significantly prolonged. At the laboratory large scale (LLS), the yield was still >/=90% after seven consecutive utilizations whereas at the pilot scale (PS), it reached 93% after reusing the enzyme four times. In those conditions, the amount of immobilized enzyme necessary to produce 1 kg of (Z)-3-hexen-1-yl acetate was 18 g (1. 8%) and 60 g (6%) at the LLS and the PS, respectively. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099364 TI - Production of carotenoids by phaffia rhodozyma growing on media made from hemicellulosic hydrolysates of eucalyptus globulus wood AB - Phaffia rhodozyma NRRL Y-17268 cells were proliferated in xylose-containing media made from Eucalyptus wood. Wood samples were subjected to acid hydrolysis under mild operational conditions, and hydrolysates were neutralized with lime. Neutralized hydrolysates were treated with charcoal for removing inhibitors and then supplemented with nutrients to obtain culture media useful for proliferation of the red yeast P. rhodozyma. A set of experiments carried out in orbital shakers proved that hydrolysates containing 16.6 g xylose/L supplemented only with 3 g peptone/L performed well as fermentation media. At the end of experiments, xylose was depleted and 10.5 g cells/L were obtained. Biomass was highly pigmented and volumetric carotenoid concentrations up to 5.8 mg carotenoids/L (with 4.6 mg astaxanthin/L) were reached. Further experiments in batch fermentors using concentrated hydrolysates (initial xylose concentrations within 16.6 and 40.8 g/L) led to good biomass concentrations (up to 23.2 g cells/L) with increased pigment concentration (up to 12.9 mg total carotenoids/L, with 10.4 mg astaxanthin/L) and high volumetric rates of carotenoid production (up to 0.079 mg/L.h). Copyright 1998 John Wiley & Sons, Inc. PMID- 10099365 TI - Dynamic modeling of meta- and para-nitrobenzoate metabolism by a mixed co immobilized culture of comamonas spp. JS46 and JS47 AB - A model describing the transient activity of a mixed immobilized culture of Comamonas spp. JS46 and JS47 growing on mixed substrates is presented. The transient periods considered are those following changes in the feed carbon source, which alternated between meta- and para-nitrobenzoate. The feed profile alternately starved one of the species in the mixed culture. The response of the system, as quantified by the reactor effluent substrate concentrations, is dictated by the activity of the biomass and the appropriate biochemical pathway. As detailed mechanistic pathway information is not available, respirometry has been used to characterize both facets of activity. Two parameters were introduced: Psi representing pathway activity and Gamma representing biomass activity; a detailed description of the analysis is included. The model is compared to experimental investigation of the system and describes the reactor response well. The agreement between model and experiment suggests the usefulness of oxygen kinetics as global measurements to describe complex systems when mechanistic detail is not available. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099366 TI - Stability of a single-chain Fv antibody fragment when exposed to a high shear environment combined with air-liquid interfaces. AB - The effect of shear on the antigen binding activity of a recombinant scFv antibody fragment was investigated in the presence of air-liquid interfaces using a stirred vessel that was incompletely filled. Changes in binding activity of the scFv to its antigen were monitored using an optical biosensor which had been sensitized with hen egg lysozyme (the antigen). The biosensor response was used as a measure of scFv binding activity. In buffer solution (mean velocity gradient approximately 20,000 s-1), loss of binding activity followed a first-order model with a mean rate constant of 0.83 h-1. In unstirred buffer solution, no such loss was observed. Similarly, in sheared fermentation broth there was no loss of binding activity and protective effects were attributed to the antifoam PPG. PMID- 10099367 TI - Alteration of the substrate range of haloalkane dehalogenase by site-directed mutagenesis. AB - We attempted to expand the range of chlorinated solvents degraded by Xanthobacter autotrophicus GJ10 to include trichloroethylene by the rational modification of the enzyme haloalkane dehalogenase. The amino acids Phe164, Asp170, Phe172 and Trp175 were individually replaced with alanine by site-directed mutagenesis. All substitutions produced enzymes with lower than wild type activity with 1,2 dichloroethane. The Phe164Ala and Asp170Ala mutants were 3 and 2 times more active than was the wild type enzyme in dechlorinating 1,6-dichlorohexane. The Asp170Ala mutant resembled the wild type enzyme in its relative activity against longer chain substrates. No mutant was active with trichloroethylene. PMID- 10099368 TI - Influence of morphology and rheology on the production characteristics of the basidiomycete Cyathus striatus. AB - The influence of the pellet morphology of the basidiomycete Cyathus striatus on the production of the antibiotics striatals A, B, and C was investigated. The main operating parameters in fermenters of different sizes were the tip speed and the volumetric power input. Different methods were developed for quantification of morphological characteristics. The apparent viscosity of the suspension was measured with a cylinder rheometer. Sediment density was measured with a sedimentation apparatus. Particle size distributions were recorded with an image analysis system. By means of the presented measuring methods, morphological characteristics could be determined and enabled an early assessment of the fermentation course and the antibiotics production. During the exponential growth phase of the fungus the relative sediment height correlated with the biomass concentration. The pellet morphology at this stage influenced the later production of striatals. The yield of the striatals was markedly influenced by pellet size and sediment density. Since these morphological characteristics determine the rheological properties of the culture the measurement of the apparent viscosity of the culture in the production phase allowed predictions of the production yield. PMID- 10099369 TI - Stirred culture of peripheral and cord blood hematopoietic cells offers advantages over traditional static systems for clinically relevant applications. AB - The ability to culture hematopoietic cells in readily characterizable and scalable stirred systems, combined with the capability to utilize serum-free medium, will aid the development of clinically attractive bioreactor systems for transplantation therapies. We thus examined the proliferation and differentiation characteristics of peripheral blood (PB) mononuclear cells (MNC), cord blood (CB) MNC, and PB CD34(+) cells in spinner flasks and (control) T-flask cultures in both serum-containing and serum-free media. Hematopoietic cultures initiated from all sources examined (PB MNC, CB MNC, and PB CD34(+) cells) grew well in spinner vessels with either serum-containing or serum-free medium. Culture proliferation in spinner flasks was dependent on both agitator design and RPM as well as on the establishment of critical inoculum densities (ID) in both serum-containing (2 x 10(5) MNC/mL) and serum-free (3 x 10(5) MNC/mL) media. Spinner flask culture of PB MNC in serum-containing medium provided superior expansion of total cells and colony-forming cells (CFC) at high ID (1.2 x 10(6) cells/mL) as compared to T flask controls. Serum-free spinner culture was comparable, if not superior, to that observed in serum-containing medium. This is the first report of stirred culture of PB or CB MNC, as well as the first report of stirred CD34(+) cell culture. Additionally, this is the first account of serum-free stirred culture of hematopoietic cells from any source. PMID- 10099370 TI - Kinetic, dynamic, and pathway studies of glycerol metabolism by Klebsiella pneumoniae in anaerobic continuous culture: III. Enzymes and fluxes of glycerol dissimilation and 1,3-propanediol formation. AB - The initial steps of glycerol dissimilation and 1,3-propanediol (1, 3-PD) formation by Klebsiella pneumoniae anaerobically grown on glycerol were studied by quantifying the in vitro and in vivo activities of enzymes in continuous culture under conditions of steady state and oscillation and during transient phases. The enzymes studied included glycerol dehydrogenase (GDH), glycerol dehydratase (GDHt), and 1,3-propanediol oxidoreductase (PDOR). Three conclusions can be drawn from the steady-state results. First, glycerol concentration in the culture is a key parameter that inversely affects the in vitro activities (concentrations) of all three enzymes, but has a positive effect on their in vivo activities. Growth rate significantly affects the ratio of in vitro and in vivo enzyme activities under low glycerol concentrations, but not under glycerol excess. Second, whereas the flux through the oxidative pathway of glycerol dissimilation is governed mainly by the regulation of in vivo enzyme activity on a metabolic level, the flux through the reductive pathway is largely controlled by the synthesis of enzymes. Third, GDHt is a major rate-liming enzyme for the consumption of glycerol and the formation of 1,3-PD in K. pneumoniae at high glycerol concentrations. Results from oscillating cultures revealed that both in vitro and in vivo activities of the enzymes oscillated. The average values of the in vitro activities during an oscillation cycle agreed well with their corresponding values for nonoscillating cultures under similar environmental conditions. Experiments with step changes in the feed concentration of glycerol demonstrated that growth and product formation are very sensitive to changes of substrate concentration in the culture. This sensitivity is due to the dynamic responses of the genetic and metabolic networks. They should be considered when modeling the dynamics of the culture and attempting to improve the formation of 1,3-PD. PMID- 10099371 TI - Large acceleration of alpha-chymotrypsin-catalyzed dipeptide formation by 18 crown-6 in organic solvents AB - The effects of 18-crown-6 on the synthesis of peptides catalyzed by alpha chymotrypsin are reported. Lyophilization of the enzyme in the presence of 50 equivalents of 18-crown-6 results in a 425-fold enhanced activity when the reaction between the 2-chloroethylester of N-acetyl-L-phenylalanine and L phenylalaninamide is carried out in acetonitrile. Addition of crown ether renders the dipeptide synthesis in nonaqueous solvents catalyzed by alpha-chymotrypsin possible on a preparative scale. The acceleration is observed in different solvents and for various peptide precursors. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099372 TI - Expulsion of proteins from water-in-oil microemulsions by treatment with cosurfactant AB - A quick and simple method has been developed for the recovery of proteins from water-in-oil microemulsions (w/o-MEs), which is needed to further the use of liquid-liquid extraction in bioseparations. By adding a small portion (0.1 v/v or less) of cosurfactant (e.g., 1-alkanol) to w/o-ME solution, proteins were readily expelled, sometimes as solids, while most or all of the surfactant (Aerosol OT) remained in solution. The release of proteins increased with the further addition of cosurfactant and was greater when the molar ratio of protein to w/o-ME or fractional occupancy (f) was high. However, protein expulsion was also significant when f was small. The addition of cosurfactant released ribonuclease, lysozyme, alpha-chymotrypsin, pepsin, bovine serum albumin (BSA), and catalase from w/o-ME solution, but the expulsion was greater for BSA relative to chymotrypsin and lysozyme. Protein expulsion also increased with cosurfactant chain length for the homologous series of 1-alkanols starting at 1-butanol; however, water was also coexpelled in significant amounts. An exception to the latter rule was 1-butanol, which readily promoted the release of protein, but not encapsulated water. The addition of 1-butanol to a w/o-ME solution containing alpha-chymotrypsin and BSA selectively released the former protein, with chymotryptic activity occurring in the recovered protein. Possible mechanisms for the cosurfactant-mediated release of protein are discussed. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099373 TI - Serum-free production of recombinant proteins and adenoviral vectors by 293SF-3F6 cells. AB - This article describes the step-wise approach undertaken to select a serum-free medium (SFM) for the efficient production of a recombinant adenoviral vectors expressing beta-galactosidase (Ad5 CMV-LacZ), in the complementing human embryonic kidney 293S cells. In the first step, a 293S-derived transfectoma, secreting a soluble epidermal growth factor receptor sEGFr (D2-22), was used to estimate the potential of selected serum-free formulations to support the production of a recombinant protein as compared to serum-containing medium. Assays showed that only one among six commercial serum-free formulations could support both sEGFr production and cell growth in static or suspension culture. In commercially available calcium-containing serum-free formulations, the cell aggregates reached up to 3 mm in diameter. In the second step, 293S cells were gradually adapted to a low-calcium version of the selected medium (LC-SFM). Cells were cloned, then screened according to their ability to grow at a rate and an extent comparable to parental cells in serum-containing medium (standard) as single cells or small aggregates. The 293SF-3F6 clone, first adapted to and then cloned in the selected serum-free medium, was selected for further experiments. Bioreactor run performed with the 293SF-3F6 clone showed similar growth curve as in the shake-flask controls. In the final step, the recombinant viral vector productivity of the 293S cells and the 293SF-3F6 clone was tested. The 293SF-3F6 cells infected by Ad5 CMV-LacZ in 3 L-scale bioreactor maintained the specific productivities of both beta-galactosidase and adenoviral vector equivalent to the shake-flask controls in suspension culture. Results from this study clearly demonstrate that the 293SF-3F6 cell line thus selected may be used either for establishing stable transfected cell line or for the production of adenoviral vectors required for gene therapy studies. PMID- 10099374 TI - Morphological change and enhanced pigment production of monascus when cocultured with saccharomyces cerevisiae or aspergillus oryzae AB - When a Monascus isolate, a producer of Monascus pigments, was cocultured with either Saccharomyces cerevisiae or Aspergillus oryzae in a solid sucrose medium, there were significant morphological changes in Monascus culture. Cocultures exhibited cell mass increases of 2 times and pigment yield increases of 30 to 40 times compared to monocultures of Monascus. However, enhanced cell growth, an increase in pigment production, and morphological change did not occur in coculture with Bacillus cereus. Saccharomyces cerevisiae was more effective at enhancing pigment production than Asp. oryzae. Enhanced cell growth and increased pigment production occurred only in conjunction with morphological changes. Culture filtrates of S. cerevisiae were also effective in inducing morphology change in Monascus, similar to culture broths of S. cerevisiae. The hydrolytic enzymes produced by S. cerevisiae, such as amylase, and chitinase, are thought to be the effectors. The commercial enzymes alpha-amylase and protease from Asp. oryzae both caused a morphological change in Monascus and were effective in enhancing pigment production. However, lysozyme, alpha-amylase and protease from Bacillus species, protease from Staphylococcus, and chitinase from Streptomyces were not effective. The hydrolytic enzymes which cause a morphological change of Monascus culture and enhancement of pigment production are thought to be capable of degrading Monascus cell walls. An approximate 10-fold increase in pigment production was observed in liquid cocultures with S. cerevisiae. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099375 TI - Hydrophobilization of an esterase by genetic combination with polyproline at the carboxyl terminal AB - Polyproline, which is an amphiphilic polypeptide, was incorporated into the carboxyl terminal of an esterase by the recombinant DNA technique. The hydrophobicity of the esterase increased with increasing chain length of polyproline without inducing significant conformational changes. The mutant esterase catalyzed the hydrolysis of long-chain carboxylic acid ester more efficiently than the native esterase. It is considered that the alteration of substrate specificity is due to enhanced access of the mutant esterases to hydrophobic substrates. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099376 TI - Growth kinetics of Pseudomonas putida G7 on naphthalene and occurrence of naphthalene toxicity during nutrient deprivation. AB - The objectives of this work were (1) to demonstrate how the chemostat approach could be modified to allow determination of kinetic parameters for a sparingly soluble, volatile substrate such as naphthalene and (2) to examine the influence of the interactions of various nutrients on possible growth-inhibitory effects of naphthalene. Pseudomonas putida G7 was used as a model naphthalene-degrading microorganism. Naphthalene was found to be toxic to P. putida G7 in the absence of a nitrogen source or oxygen. The death rate of cells grown on minimal medium plus naphthalene and then exposed to naphthalene under anoxic conditions was higher than that observed under oxic conditions in the absence of a nitrogen source. The presence of necessary nutrients for the biodegradation of PAH compounds is indicated to be important for the survival of microorganisms that are capable of PAH degradation. The amounts of ammonia and oxygen necessary for naphthalene biodegradation and for suppression of naphthalene toxicity were calculated from growth yield coefficients. A chemostat culture of P. putida G7 using naphthalene as a carbon and energy source was accomplished by using a feed augmented with a methanol solution of naphthalene so as to provide sufficient growth to allow accurate evaluation of kinetic parameters. When naphthalene was the growth-limiting substrate, the degradation of naphthalene followed Monod kinetics. Maximum specific growth rate (micrometer) and Monod constant (Ks) were 0.627 +/- 0.007 h-1 and 0.234 +/- 0.0185 mg/L, respectively. The evaluation of biodegradation parameters will allow a mathematical model to be applied to predict the long-term behavior of PAH compounds in soil when combined with PAH transport parameters. PMID- 10099377 TI - Secondary metabolite scale-up to minimize homolog impurity levels AB - A mutant strain of Streptomyces hygroscopicus was found to produce up to 9.0 units/L of an immunoregulant precursor, immunomycin, with up to 3.5% of a lower homolog impurity under either dual fed-batch or batch conditions. Glycerol and valine were key nutrients influencing productivity and impurity levels. Soybean oil was successfully substituted for glycerol as a carbon source to minimize shot additions to batch culture. The remainder of the production medium was composed largely of defined components with the exception of yeast extract. Valine limitation increased lower homolog formation while decreasing higher homolog formation; excess valine decreased lower homolog formation below 2-3% while increasing higher homolog formation. Higher homolog formation in the presence of valine seemed to be slower than lower homolog formation in the absence of valine. Valine was believed to be the major butyrate precursor; consequently its availability influenced the impurity profile. A preliminary cost analysis suggests that elimination of added valine from the cultivation and replacement of glycerol with soybean oil can result in a 6.6-fold reduction in media costs relative to the original fed-batch process. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099378 TI - Elemental balancing of biomass and medium composition enhances growth capacity in high-density Chlorella vulgaris cultures. AB - The basic requirements for high-density photoautotrophic microalgal cultures in enclosed photobioreactors are a powerful light source and proper distribution of light, efficient gas exchange, and suitable medium composition. This article introduces the concept of balancing the elemental composition of growth medium with biomass composition to obtain high-density cultures. N-8 medium, commonly used for culturing Chlorella vulgaris was evaluated for its capacity to support high-density cultures on the basis of elemental stoichiometric composition of C. vulgaris. This analysis showed that the N-8 medium is deficient in iron, magnesium, sulfur, and nitrogen at high cell densities. N-8 medium was redesigned to contain stoichiometrically balanced quantities of the four deficient elements to support a biomass concentration of 2% (v/v). The redesigned medium, called M-8 medium, resulted in up to three- to fivefold increase in total chlorophyll content per volume of culture as compared to N-8 medium. Further experiments showed that addition of each of the four elements separately to N-8 medium did not improve culture performance and that balanced supplementation of all four deficient elements was required to yield the improved performance. Long-term (24 d) C. vulgaris culture in M-8 medium showed continuous increase in chlorophyll content and biomass throughout the period of cultivation. In contrast, the increase in chlorophyll content and biomass ceased after 7 and 12 d, respectively in N-8 medium, demonstrating the higher capacity of M-8 medium to produce biomass. Thus, the performance of high cell density photobioreactors can be significantly enhanced by proper medium design. The elemental composition of the biomass generated is an appropriate basis for medium design. PMID- 10099379 TI - The use of flow cytometry to study the impact of fluid mechanical stress on Escherichia coli W3110 during continuous cultivation in an agitated bioreactor. AB - Continuous culture fermentations of Escherichia coli W3110 have been carried out at controlled dissolved oxygen levels of 40% and 10% of saturation. Satisfactory and reproducible results were obtained. Agitation speeds of 400 and 1200 rpm at an aeration rate of 1 vvm have been used as well as an aeration rate of 3 vvm at 400 rpm. The upper levels of these variables represent much higher agitation and aeration intensities than those normally used in practical fermentations. The fermentations were monitored by mass spectrometry and optical density, and cell samples were studied by flow cytometry, SEM, and TEM. Protocols were developed so the state of both cell membranes and cell size could be measured by flow cytometry. Under all the conditions of agitation and aeration, flow cytometric analysis indicated that both cell membranes were intact and that a cytoplasmic membrane potential existed; also the cell size did not change, results confirmed by SEM and TEM. There were no detectable changes in off-gas analysis or optical density during the continuous fermentation nor in the cell structure as revealed by SEM or TEM, except at the highest agitation intensity. Under the latter conditions, after 7 h, the outer polysaccharide layer on the cell was stripped away. It is concluded that any changes in biological performance of this E. coli cell line due to variations in agitation or aeration intensity or scale of operation cannot be attributed to fluid dynamic stresses associated with the turbulence generated by impellers or with bursting bubbles. PMID- 10099380 TI - Hydrolysis of microcrystalline cellulose by cellobiohydrolase I and endoglucanase II from Trichoderma reesei: adsorption, sugar production pattern, and synergism of the enzymes. AB - Microcrystalline cellulose (10 g/L Avicel) was hydrolysed by two major cellulases, cellobiohydrolase I (CBH I) and endoglucanase II (EG II), of Trichoderma reesei. Two types of experiments were performed, and in both cases the enzymes were added alone and together, in equimolar mixtures. In time course studies the reaction time was varied between 3 min and 48 h at constant temperature (40 degrees C) and enzyme loading (0.16 micromol/g Avicel). In isotherm studies the enzyme loading was varied in the range of 0.08-2.56 micromol/g at 4 degrees C and 90 min. Adsorption of the enzymes and production of soluble sugars were followed by FPLC and HPLC, respectively. Adsorption started quickly (50% of maximum achieved after 3 min) but was not completed before 60-90 min. For CBH I a linear relationship was observed between the production of soluble sugars and adsorption, showing that the average activity of the bound CBH I molecules does not change with increasing saturation. For EG II the corresponding curve levelled off which is explained by initial hydrolysis of loose ends on Avicel. The enzymes competed for binding sites, binding of EG II was considerably affected by CBH I, especially at high concentration. CBH I produced more soluble sugars than EG II, except at conversions below 1%. At 40 degrees C when the enzymes were added together they produced 27-45% more soluble sugars than the sum of what they produced alone, i.e. synergistic action was observed (the final conversion after 48 h of hydrolysis was 3, 6, and 13% for EG II, CBH I, and their mixture, respectively). At 4 degrees C, on the other hand, when the conversion was below 2.5%, almost no synergism could be observed. Molar proportions of the produced sugars were rather stable for CBH I (11-15%, 82-89%, and <6% for glucose, cellobiose, and cellotriose, respectively), while it varied considerably with both time and enzyme concentration for EG II. The observed stable but high glucose to cellobiose ratio for CBH I indicates that the processivity for this enzyme is not perfect. EG II produced significant amounts of glucose, cellobiose, and cellotriose, which are not the expected products of a typical endoglucanase activity on a solid substrate. We explain this by hypothesizing that EG II may show processivity due to its extended substrate binding site and the presence of its cellulose binding domain. PMID- 10099381 TI - Two-coat systems for encapsulation of spathoglottis plicata (Orchidaceae) seeds and protocorms AB - Complex coacervation of alginate-chitosan and alginate-gelatin were used to develop two-coat systems for the encapsulation of Spathoglottis plicata seeds and protocorms (top-shaped structures formed after seed germination of orchids). Both the seeds and the protocorms could withstand the encapsulation treatments with high viability. About 54% of seeds and 40% of large protocorms (1.6-2.0 mm) were able to tolerate a 6-h desiccation treatment. However, viability of the small protocorms (0.7-0.9 mm) was greatly reduced if they were desiccated before encapsulation. Encapsulation after desiccation significantly increased the percentage viability of seeds and protocorms. Treatment with abscisic acid (ABA, 10(-5) M) before desiccation and encapsulation resulted in high percentage viability in seeds and large protocorms whereas the small protocorms were found to be less tolerant to the treatments. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099382 TI - Metabolic engineering of Serratia marcescens with the bacterial hemoglobin gene: alterations in fermentation pathways. AB - Serratia marcescens was transformed with plasmid vector pUC8 or pUC8 containing the bacterial (Vitreoscilla) hemoglobin gene (vgb) on either a 2.3-kb fragment (pUC8:15) or 1.4-kb fragment (pUC8:16) of Vitreoscilla DNA. The vgb-bearing strains were compared with the pUC8 transformant and untransformed S. marcescens with respect to growth in Luria-Bertani (LB) broth supplemented with glucose or casein acid hydrolysate. Growth (on a viable cell basis) was similar to that in unsupplemented LB. Total acid excretion (as estimated by medium pH) was similar for all strains in both LB plus 2% casein acid hydrolysate and LB without additions. Acid excretion in LB plus 2% glucose was somewhat greater at up to 10 h in culture for the two vgb-bearing strains; from 10 to 26 h in culture, the pHs of these cultures continued to decrease (to 4.1-4.2), whereas those of the non vgb-bearing strains returned to near the starting pH (7.4-7.8). Concomitantly, after 26 h of culture in LB plus 2% glucose, the non-vgb-bearing strains had produced about 15 times as much acetoin and about three to four times as much 2,3 butanediol as the vgb-bearing strains. In general, for all strains, much more acetoin and 2,3-butanediol were produced in LB plus 2% glucose than in unsupplemented LB. The exception was acetoin production by the strain bearing vgb on plasmid pUC8:15; after 26 h of culture in LB without supplementation it was between three and four times that of the other strains, and about 50% higher than its level in LB plus 2% glucose. When grown with the 2% casein acid hydrolysate supplement, the strain bearing vgb on plasmid pUC8:15 produced much more acetoin and 2,3-butanediol than the other strains after 26 hours in culture. The results confirm that vgb can significantly alter carbon metabolism and suggest that the use of vgb technology for directed metabolic engineering may be a complicated process, depending in part on medium composition. PMID- 10099383 TI - Nonflocculent versus total biomass ratio as a criterion for starting the biomass separation process AB - We introduce the ratio of nonflocculent versus total biomass as a criterion for starting cell separation from the medium. This criterion can be applied for the automation of the process regardless of the process dynamics. Its minimum indicates the optimum period of time for the start of the separation process with regard not only to nonflocculent cell concentration, but also medium attributes. In contrast to the concentration of nonflocculent cells, which has two minima, first at the beginning of the process and another broader one in the period during which maximum flocculation is present, the ratio has a single minimum and can therefore be implemented as a criterion for cell separation. To calculate the ratio value, in addition to an on-line method for nonflocculent biomass measurement described elsewhere, an on-line method for the total biomass of flocculent yeast is proposed. It is based on the absorbency measurement of the cell biomass, previously deflocculated by EDTA. Therefore, it can be applied in bioprocesses with transparent media and yeast that can be deflocculated by EDTA. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099384 TI - Adsorption and enzyme (beta-galactosidase and alpha-chymotrypsin): immobilization properties of gel fiber prepared by the gel formation of cellulose acetate and titanium iso-propoxide AB - We prepared a new composite gel fiber by the gel formation of cellulose acetate and titanium iso-propoxide. The fiber is harder than alginate gel; it is also stable in common solvents, phosphate solution, and electrolyte solutions over a wide range of pH from 3 to 10. The fiber shows amphoretic adsorption properties depending on pH, namely, it acts anionic with decreasing pH and cationic with increasing pH. However, the fiber had no adsorption property for a pyrogen endotoxin. The beta-galactosidase and alpha-chymotrypsin not retained in alginate gel were immobilized on the fibers by this method. The pH, temperature, and repeated run stabilities of the immobilized enzyme were compared to those of the native one. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099385 TI - Construction and characterization of F plasmid-based expression vectors. AB - A low-copy expression vector has been constructed from a 9 Kbp region of the Escherichia coli F plasmid containing the oriV and oriS origins of replication. This plasmid carries the beta-lactamase gene (Apr) and the araBAD promoter/araC regulator for arabinose-inducible gene expression. A derivative which carries a lacZ reporter gene was found to be stably maintained for at least 150 generations. A related multi-copy plasmid was stably maintained in arabinose-free medium, but no plasmid-bearing segregants remained after 60 generations when lacZ expression was induced. Induced expression resulted in 27% (multi-copy) and 12% (low-copy) decreases in growth rate. The uninduced levels of beta-galactosidase were 200 units (multi-copy) and 15 units (low-copy). PMID- 10099386 TI - mRNA stability and plasmid copy number effects on gene expression from an inducible promoter system. AB - The effects of mRNA stability and plasmid copy number on gene expression in Escherichia coli were evaluated by constructing multicopy (pMB1-based) and low copy (F-based) plasmids containing an arabinose-inducible promoter system, the lacZ reporter gene, and mRNA-stabilizing 5' hairpin structures. Product formation and cell growth were evaluated under a number of inducer concentrations. The introduction of a 5' hairpin into the untranslated region of the mRNA resulted in significantly higher gene expression from the multicopy plasmids at low inducer concentrations and increased gene expression from the low-copy plasmids across all inducer concentrations investigated. With high inducer concentrations, expression from high-copy plasmids significantly slowed cell growth, whereas expression from the low-copy plasmids had little effect on growth rate. At inducer concentrations between 1 x 10(-4) and 4 x 10(-4)%, the productivity of low-copy plasmids containing the 5'-hairpin was equal to or greater than that from multicopy plasmids. Together, these two gene expression strategies may find important use in metabolic engineering and heterologous gene expression. PMID- 10099387 TI - Synthesis and excretion of alpha-amylase in vgb+ and vgb- recombinant Escherichia coli: a comparative study. AB - Synthesis and excretion of alpha-amylase is investigated in batch cultures of Escherichia coli JM103[pMK57] (vgb-) and E. coli JM103[pMK79] (vgb+). While total production and excretion of alpha-amylase were promoted in Luria broth (LB) (excretion being as high as 87%), cell-mass-specific production of the enzyme was promoted in M9 in bioreactor cultures and in LB in shake flask cultures. Low aeration and agitation rates and presence of starch were conducive to alpha amylase synthesis in E. coli JM103[pMK79]. Two-stage bioreactor operating strategies that will improve alpha-amylase production are proposed. The potential of these strategies is demonstrated via two-stage shake flask cultures. PMID- 10099388 TI - Automated production of cultured epidermal autografts and sub-confluent epidermal autografts in a computer controlled bioreactor. AB - The objective of this work was to engineer an automated system for the production of cultured epidermal autografts and sub-confluent cultured epidermal autografts. Human epidermal cells were grown directly on a transparent FEP film, which was held in place and surrounded by a polycarbonate growth chamber. The growth chambers were stacked to accommodate various surface area requirements. To monitor the development of the grafts, the upper-most growth chamber in the stack was periodically placed on a standard phase contrast microscope. The growth chambers were connected to a multi-channel peristaltic pump, which was controlled automatically to manage fluid-handling operations. Sub-confluent graft production involved removing the epidermal-film composite from the growth chambers and cutting desired graft geometries. Producing cultured epidermal autografts involved (1) removing the confluent epidermal-film composite from the growth chambers, (2) treating the composites with dispase, and (3) clipping the detached cultured epidermis to a synthetic support. Twelve to fifteen days were required to produce sub-confluent grafts (total surface area 3500-4500 cm2 50% confluent) and 18 to 24 d were required to produce standard cultured epidermal autografts (total surface area 3500-4500 cm2). The system reduces the tedious manual labor associated with producing cultured epidermal autografts. PMID- 10099389 TI - Lipase-catalyzed transesterification in organic media: solvent effects on equilibrium and individual rate constants. AB - The kinetics of the immobilized lipase B from Candida antarctica have been studied in organic solvents. This enzyme has been shown to be slightly affected by the water content of the organic media, and it does not seem to be subject to mass transfer limitations. On the other hand, some evidence indicates that the catalytic mechanism of reactions catalyzed by this lipase proceeds through the acyl-enzyme intermediate. Moreover, despite the fact that the immobilization support dramatically enhances the catalytic power of the enzyme, it does not interfere with the intrinsic solvent effect. Consequently, this enzyme preparation becomes optimum for studying the role played by the organic solvent in catalysis. To this end, we have measured the acylation and deacylation individual rate constants, and the binding equilibrium constant for the ester, in several organic environments. Data obtained show that the major effect of the organic solvent is on substrate binding, and that the catalytic steps are almost unaffected by the solvent, indicating the desolvation of the transition state. However, the strong decrease in binding for hydrophilic solvents such as THF and dioxane, compared to the rest of solvents, cannot be easily explained by means of thermodynamic arguments (desolvation of the ester substrate). For this reason, data have been considered as an indication of the existence of an unknown step in the catalytic pathway occurring prior to formation of the acyl-enzyme intermediate. PMID- 10099390 TI - Affinity precipitation of alpha-amylase inhibitor from wheat meal by metal chelate affinity binding using cu(II)-loaded copolymers of 1-vinylimidazole with N-isopropylacrylamide AB - A method for purifying alpha-amylase inhibitor from wheat meal based on immobilized metal affinity with a thermosensitive copolymer is developed. The studies represent the thermoprecipitation properties of the copolymers of N isopropylacrylamide (NIPAM) with iminodiacetic acid (IDA) and 1-vinylimidazole (VI), respectively. The polymer which is obtained by the copolymerization of 1 vinylimidazole and N-isopropylacrylamide, charged with Cu(II), exhibited specific interaction of the metal ions to the protein inhibitor. The precipitation was induced by salt and the recovery of the amylase inhibitor was achieved by dissolving the inhibitor-polymer complex in imidazole buffer and subsequent precipitation of the polymer. A single family of the alpha-amylase inhibitor was recovered from the polymer with 89% yield and about fourfold purification. The SDS-PAGE pattern showed significant purification of the inhibitor. The binding of the inhibitor to the Cu(II)-polymer conjugate depends upon the Cu(II) concentration in the copolymer and also upon the concentration of the protein. The recovered polymer could be reused with reasonable efficiency. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099391 TI - Light/dark cycles in the growth of the red microalga porphyridium sp AB - The effect of light/dark cycles on the growth of the red microalga Porphyridium sp. was studied in a tubular loop bioreactor with light/dark cycles of different frequencies and in two 35-L reactors: a bubble column reactor and an air-lift reactor. Photon flux densities were in the range of 50 to 300 MUE m-2 s-1, and flow rates were 1 to 10 L min-1. Under conditions of low illumination and high flow rates, similar results were obtained for the bubble column and air-lift reactors. However, higher productivities-in terms of biomass and polysaccharide were recorded in the air-lift reactor under high light intensity and low gas flow rates. The interactions of both photosynthesis and photoinhibition with the fluid dynamics in the bioreactors was taken as the main element that allowed us to interpret the differences in performance of the bubble column and the air-lift reactor. It is suggested that the cyclic distribution of dark periods in the air lift reactor facilitates better recovery from the photoinhibition damage suffered by the cells. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099392 TI - Oxygen supply without gas-liquid film resistance to xanthomonas campestris cultivation AB - Alternative methods of oxygen supply are of crucial importance, especially in viscous fermentations and shear-sensitive fermentations. A method of oxygen supply that completely eliminates the gas-liquid transport resistance has been presented. The method involves a need-based liquid-phase decomposition of hydrogen peroxide to provide the necessary oxygen. When Xanthomonas campestris was cultivated (viscous cultivation) using this method of oxygen supply, dissolved oxygen (DO) levels were maintained above the setpoint of 50% throughout the cultivation, whereas the conventional cultivation was able to meet culture oxygen demand only for about 6 h in a 72-h fermentation. Furthermore, the maximum specific growth rate and xanthan yields in the novel cultivation were 89% and 169%, respectively, of those obtained in conventional cultivation. A mathematical model was also developed to simulate and predict results in fermentations employing the presented methodology. In addition, studies with HOCl pretreatments indicated that monofunctional catalase may be responsible for the decomposition of H2O2 supplied externally to cells; HOCl pretreatments also increased the tolerance of cells to H2O2. The decomposition kinetics of externally supplied H2O2 was Michaelis-Menten in nature with vmax = 1.196 x 10(-6) M s-1 and Km = 0.21 mM. The catalase concentration was estimated to be 3.4 x 10(-10) mol/g of cells. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099393 TI - Modeling pH effects on microbial growth: a statistical thermodynamic approach. AB - This paper applies a statistical thermodynamic approach to the kinetics of microbial growth influenced by pH. A general equation is developed and shown to provide a good theoretical basis for the existing pH models that have been widely used to describe the effects of pH on microbial growth kinetics. Four experimental data sets are used to test the general equation developed. The four data sets exhibited a variety of functional curve shapes, for example, symmetrical and asymmetrical bell-shaped, when the specific growth rate of microorganisms is plotted as a function of pH. All four data sets are found to be well represented by the general equation. The existing pH model was, however, found to represent only one out of four data sets, i.e., the symmetrical case. PMID- 10099394 TI - A unified model describing the role of hydrogen in the growth of desulfovibrio vulgaris under different environmental conditions AB - A unified model for the growth of Desulfovibrio vulgaris under different environmental conditions is presented. The model assumes the existence of two electron transport mechanisms functioning simultaneously. One mechanism results in the evolution and consumption of hydrogen, as in the hydrogen-cycling model. The second mechanism assumes a direct transport of electrons from the donor to the acceptor, without the participation of H2. A combination of kinetic and thermodynamic conditions control the flow of electrons through each pathway. The model was calibrated using batch experiments with D. vulgaris grown on lactate, in the presence and absence of sulfate, and was verified using additional batch experiments under different conditions. The model captured the general trends of consumption of substrates and accumulation of products, including the transient accumulation and consumption of H2. Furthermore, the model estimated that 48% of the electrons transported from lactate to sulfate involved H2 production, indicating that hydrogen cycling is a fundamental process in D. vulgaris. The presence of simultaneous electron transport mechanisms might provide D. vulgaris with important ecological advantages, because it facilitates a rapid response to changes in environmental conditions. This model increases our ability to study the microbial ecology of anaerobic environments and the role of Desulfovibrio species in a variety of environments. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099395 TI - Regioselective synthesis of ethoxylated glycoside esters using beta-glucosidase in supersaturated solutions and lipases in organic solvents AB - Three ethoxylated glycosides, tetraethylene glycol beta-D-glucoside, tetraethylene glycol beta-D-xyloside, and methoxy triethyleneglycol beta-D glucoside, were prepared via almond beta-glucoside-catalyzed (trans)glycosylation carried out in supersaturated solutions of glucose or p-nitrophenyl beta-D xyloside and the respective polyethylene glycols. The products were isolated and further modified by enzymatic esterification with Candida antarctica and Mucor miehei lipases. The latter enzyme showed a much greater selectivity for the primary hydroxyl group on the polyethylene glycol chain of the glucoside substrate, thus enabling us to obtain exclusively the corresponding monoester, omega-O-oleoyl tetraethylene glycol beta-D-glucoside. Novozyme was used for the preparative synthesis of two other monoesters, 6-O-oleoyl (methoxy triethyleneglycol) beta-D-glucoside and omega-O-oleoyl tetraethylene glycol beta D-xyloside. Two diesters, di-oleoyl tetraethylene glycol beta-D-glucoside and tetraethylene-bis(6-0-oleoyl glucoside) were also synthesized in good yields using this lipase. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099396 TI - Optimization of polyphosphate degradation and phosphate secretion using hybrid metabolic pathways and engineered host strains AB - Polyphosphate degradation and phosphate secretion were optimized in Escherichia coli strains overexpressing the E. coli polyphosphate kinase gene (ppk) and either the E. coli polyphosphatase gene (ppx) or the Saccharomyces cerevisiae polyphosphatase gene (scPPX1) from different inducible promoters on medium- and high-copy plasmids. The use of a host strain without functional ppk or ppx genes on the chromosome yielded the highest levels of polyphosphate, as well as the fastest degradation of polyphosphate when the gene for polyphosphatase was induced. The introduction of a hybrid metabolic pathway consisting of the E. coli ppk gene and the S. cerevisiae polyphosphatase gene resulted in lower polyphosphate concentrations than when using both the ppk and ppx genes from E. coli, and did not significantly improve the degradation rate. It was also found that the rate of polyphosphate degradation was highest when ppx was induced late in growth, most likely due to the high intracellular polyphosphate concentration. The phosphate released from polyphosphate allowed the growth of phosphate-starved cells; excess phosphate was secreted into the medium, leading to a down regulation of the phosphate-starvation (Pho) response. The production of alkaline phosphatase, an indicator of the Pho response, can be precisely controlled by manipulating the degree of ppx induction. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099397 TI - Dependence of penicillium chrysogenum growth, morphology, vacuolation, and productivity in fed-batch fermentations on impeller type and agitation intensity AB - The influence of the agitation conditions on the growth, morphology, vacuolation, and productivity of Penicillium chrysogenum has been examined in 6 L fed-batch fermentations. A standard Rushton turbine, a four-bladed paddle, and a six-bladed pitched blade impeller were compared. Power inputs per unit volume of liquid, P/VL, ranged from 0.35 to 7.4 kW/m3. The same fermentation protocol was used in each fermentation, including holding the dissolved oxygen concentration above 40% air saturation by gas blending. The mean projected area (for all dispersed types, including clumps) and the clump roughness were used to characterize the morphology. Consideration of clumps was vital as these were the predominant morphological form. For a given impeller, the batch-phase specific growth rates and the overall biomass concentrations increased with agitation intensity. Higher fragmentation at higher speeds was assumed to have promoted growth through increased formation of new growing tips. The mean projected area increased during the rapid growth phase followed by a sharp decrease to a relatively constant value dependent on the agitation conditions. The higher the speed, the lower the projected area for a given impeller type. The proportion by volume of hyphal vacuoles and empty regions decreased with speed, possibly due to fragmentation in the vacuolated regions. The specific penicillin production rate was generally higher with lower impeller speed for a given impeller type. The highest value of penicillin production as well as its rate was obtained using the Rushton turbine impeller at the lowest speed. At given P/VL, changes in morphology, specific growth rate, and specific penicillin production rate depended on impeller geometry. The morphological data could be correlated with either tip speed or the "energy dissipation/circulation function," but a reasonable correlation of the specific growth rate and specific production rate was only possible with the latter. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099398 TI - The effect of protein impurities on lysozyme crystal growth. AB - While bulk crystallization from impure solutions is used industrially as a purification step for a wide variety of materials, it is a technique that has rarely been used for proteins. Proteins have a reputation for being difficult to crystallize and high purity of the initial crystallization solution is considered paramount for success in the crystallization. Although little is written on the purifying capability of protein crystallization or of the effect of impurities on the various aspects of the crystallization process, recent published reports show that crystallization shows promise and feasibility as a purification technique for proteins. To further examine the issue of purity in macromolecule crystallization, this study investigates the effect of the protein impurities, avidin, ovalbumin, and conalbumin at concentrations up to 50%, on the solubility, crystal face growth rates, and crystal purity of the protein lysozyme. Solubility was measured in batch experiments while a computer controlled video microscope system was used to measure the ?110? and ?101? lysozyme crystal face growth rates. While little effect was observed on solubility and high crystal purity was obtained (>99.99%), the effect of the impurities on the face growth rates varied from no effect to a significant face specific effect leading to growth cessation, a phenomenon that is frequently observed in protein crystal growth. The results shed interesting light on the effect of protein impurities on protein crystal growth and strengthen the feasibility of using crystallization as a unit operation for protein purification. PMID- 10099399 TI - From detergent additive to semisynthetic peroxidase-simplified and up-scaled synthesis of seleno-subtilisin AB - A simplified and up-scaled synthesis of the semisynthetic peroxidase seleno subtilisin was developed. Highly purified to technical grade subtilisin preparations from Bacillus licheniformis and Bacillus amyloliquefaciens were applied as starting materials. Activation of Ser 221 with phenylmethanesulfonyl fluoride, nucleophilic substitution by sodium hydrogen selenide, and oxidation to the seleninic acid with hydrogen peroxide completed the chemical active-site modification. The reactions were accomplished with a minimum of simple work-up procedures in 10 g scale. Kinetics and enantioselectivity of the preparations were tested using 1-phenylethyl hydroperoxide. For the first time, an up-scaled synthesis of a semisynthetic enzyme is available. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099400 TI - Adaptive pole placement control algorithm for DO-control in beta-lactamase production. AB - The dissolved oxygen (DO) is an important variable in aerobic fermentations and affects the cell growth and product formation. Dissolved oxygen control is difficult in batch fermentations because of the time-varying conditions, time delays, and the probe dynamics. Modeling of the various patterns of biological activity in fermentations and their impact on the DO process dynamics is essential to both achieve a satisfactory control and to track the aforementioned patterns. An adaptive pole placement algorithm with time-delay compensation was used for controlling the DO, coupled with system identification using recursively estimated autoregressive models with exogeneous inputs (ARX). The flow rate of O2 in a constant flow rate gas inlet mixture is used as the manipulated variable. Supervision and coordination techniques are applied to improve the control performance. The control performance is affected by the accuracy of the model prediction and the selected time delay. The effect of DO level on the productivity of beta-lactamase using Bacillus subtilis under oxygen-limited conditions is investigated. Beta-lactamase stability is improved under prolonged growth conditions with low DO levels. PMID- 10099401 TI - Medium chain length alkane solvent-cell transfer rates in two-liquid phase, pseudomonas oleovorans cultures AB - The oxidation of medium chain length alkanes and alkenes (C6 to C12) by Pseudomonas oleovorans and related, biocatalytically active recombinant organisms, in two-liquid phase cultures can be used for the biochemical production of several interesting fine chemicals. The volumetric productivities that can be attained in two-liquid phase systems can be, in contrast to aqueous fermentations, limited by the transport of substrates from an apolar phase to the cells residing in the aqueous phase and by toxic effects of apolar solvents on microbial cells. We have assessed the impact of these possible limitations on attainable productivities in two-liquid phase fermentations operated with mcl alkanes. Pseudomonas oleovorans grows well in two-liquid phase media containing a bulk n-octane phase as the sole carbon source. However, cells are also damaged, typically resulting in a cell lysis rate of about 0.08 to 0. 10 h-1. These rates could be lowered by 50 to 70% to 0.03 h-1 and substrate yields increased from 0.55 to 0.85 g g-1 by diluting octane in non-metabolizable long-chain hydrocarbon solvents. Transfer rates of medium chain length (mcl) alkanes from the apolar phase to the cells were determined by following growth and the rate at which carbon-containing metabolites accumulated in the different phases of the cultures. mcl-Alkane solvent-cell transfer rates of at least 79, 64, and 18 mmol per liter of aqueous medium per hour were determined for n-heptane, n-octane, and n-decane, respectively. Rates of up to 30 mmol L-1 h-1 were observed under octane limiting conditions in systems where the apolar substrate was dissolved to concentrations below 3% (v/v) in hexadecene. Based on low power input experiments, we estimated the maximum obtainable mass transfer rates in large scale processes to be in the range of 13 mmol L-1 h-1 for decane and higher than 45 mmol L-1 h-1 for octane and heptane. The results indicate that high solvent to cell mass transfer rates and minimized cell damage will enable high production rates in two-liquid phase bioprocesses, justifying ongoing efforts to attain high densities of catalytically, highly active cells in such systems. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099402 TI - In situ microscopy for on-line determination of biomass. AB - A sensor is presented, which allows on-line microscopic observation of microorganisms during fermentations in bioreactors. This sensor, an In Situ Microscope (ISM) consists of a direct-light microscope with a measuring chamber, integrated in a 25 mm stainless steel tube, two CCD-cameras, and two frame grabbers. The data obtained are processed by an automatic image analysis system. The ISM is connected with the bioreactor via a standard port, and it is immersed directly in the culture liquid-in our case Saccharomyces cerevisiae in a synthetic medium. The microscopic examination of the liquid is performed in the measuring chamber, which is situated near the front end of the sensor head. The measuring chamber is opened and closed periodically. In the open state, the liquid in the bioreactor flows unrestricted through the chamber. In closing, a defined volume of 2,2. 10(-8) mL of the liquid becomes enclosed. After a few seconds, when the movement of the cells in the enclosed culture has stopped, they are examined with the microscope. The microscopic images of the cells are registered with the CCD-cameras and are visualized on a monitor, allowing a direct view of the cell population. After detection, the measuring chamber reopens, and the enclosed liquid is released. The images obtained are evaluated as to cell concentration, cell size, cell volume, biomass, and other relevant parameters simultaneously by automatic image analysis. With a PC (486/33 MHz), image processing takes about 15 s per image. The detection range tested when measuring cells of S. cerevisiae is about 10(6) to 10(9) cells/mL (equivalent to a biomass of 0.01 g/L to 12 g/L). The calculated biomass values correlate very well with those obtained using dry weight analysis. Furthermore, histograms can be calculated, which are comparable to those obtained by flow cytometry. PMID- 10099403 TI - Mixing and phase hold-ups variations due to gas production in anaerobic fluidized bed digesters: influence on reactor performance AB - The influence of mixing and phase hold-ups on gas-producing fluidized-bed reactors was investigated and compared with an ideal flow reactor performance (CSTR). The liquid flow in the anaerobic fluidized bed reactor could be described by the classical axially dispersed plug flow model according to measurements of residence time distribution. Gas effervescence in the fluidized bed was responsible for bed contraction and for important gas hold-up, which reduced the contact time between the liquid and the bioparticles. These results were used to support the modeling of large-scale fluidized-bed reactors. The biological kinetics were determined on a 180-L reactor treating wine distillery wastewater where the overall total organic carbon uptake velocity could be described by a Monod model. The outlet concentration and the concentration profile in the reactor appeared to be greatly influenced by hydrodynamic limitations. The biogas effervescence modifies the mixing characteristics and the phase hold-ups. Bed contraction and gas hold-up data are reported and correlated with liquid and gas velocities. It is shown that the reactor performance can be affected by 10% to 15%, depending on the mode of operation and recycle ratio used. At high organic loading rates, reactor performance is particularly sensitive to gas effervescence effects. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099405 TI - Quantitative enzymatic production of 1,6-diacyl sorbitol esters AB - The enzymatic synthesis of several sorbitol diesters whose HLB values are similar to those of monoglycerides (the largest single type of food-grade emulsifiers) has been studied. The procedure is carried out by the simple addition of the polyol to a solution of the fatty acid and is based on continuous precipitation of the diester formed at a low temperature. A solvent of relatively low toxicity (acetone) was used. Pure fatty acids of different chain lengths (lauric and caprylic acids) were employed. The procedure was also tested using the acids obtained from total hydrolysis of olive oil, as an example of industrial feedstocks of fatty acids. This synthesis strategy gave complete conversion of sorbitol and >95% yields of the corresponding 1,6-diesters. In addition, a strategy to reduce the reaction time is reported. The enzymatic procedure permits minimization of the solvent/sugar ratio because it does not require complete dissolution of the sugar in the organic solvent. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099404 TI - Processing of transgenic corn seed and its effect on the recovery of recombinant beta-glucuronidase. AB - The tools of plant biotechnology that have been developed to improve agronomic traits are now being applied to generate recombinant protein products for the food, feed, and pharmaceutical industry. This study addresses several processing and protein recovery issues that are relevant to utilizing transgenic corn as a protein production system. The gus gene coding for beta-glucuronidase (rGUS) was stably integrated and expressed over four generations. The accumulation level of rGUS reached 0.4% of total extractable protein. Within the kernel, rGUS was preferentially accumulated in the germ even though a constitutive ubiquitin promoter was used to direct gus expression. Fourth-generation transgenic seed was used to investigate the effect of seed processing on the activity and the recovery of rGUS. Transgenic seed containing rGUS could be stored at an ambient temperature for up to two weeks and for at least three months at 10 degrees C without a significant loss of enzyme activity. rGUS exposed to dry heat was more stable in ground than in whole kernels. The enzyme stability was correlated with the moisture loss of the samples during the heating. Transgenic seed was dry milled, fractionated, and hexane extracted to produce full-fat and defatted germ fractions. The results of the aqueous extraction of rGUS from ground kernels, full-fat germ, and defatted-germ samples revealed that approximately 10 times more rGUS per gram of solids could be extracted from the ground full-fat germ and defatted-germ than from the kernel samples. The extraction of corn oil from ground germ with hot hexane (60 degrees C) did not affect the extractable rGUS activity. rGUS was purified from ground kernels and full-fat germ extracts by ion exchange, hydrophobic interaction, and size exclusion chromatography. Similar purity and yield of rGUS were obtained from both extracts. Biochemical properties of rGUS purified from transgenic corn seed were similar to those of E. coli GUS. PMID- 10099407 TI - Fed-batch production of thermomonospora fusca endoglucanase by recombinant streptomyces lividans AB - The factors affecting the production of a Thermomonospora fusca endoglucanase by a recombinant Streptomyces lividans strain were studied in a fermentor with glucose addition controlled by a pH-stat. The recombinant plasmid was stable for 35 generations with constant endoglucanase productivity. Glucose and peptone were used as the carbon and nitrogen sources. Addition of Tween-80 increased endoglucanase production twofold. A significant decrease in endoglucanase production was observed at low aeration. During fed-batch cultivation, pulse feeding (6 g/L) of a glucose-ammonium sulfate solution was optimal for endoglucanase production. With higher concentrations of glucose (15 g/L), a significant amount of organic acid, including acetic acid, was produced, which inhibited cell growth and endoglucanase production. Under optimum conditions, 1.7 U/mL of endoglucanase were produced. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099406 TI - Gene dosage effects on polyhydroxyalkanoates synthesis from n-alcohols in Paracoccus denitrificans. AB - Putative promoters of polyhydroxyalkanoate (PHA)-synthetic genes of Paracoccus denitrificans were identified. Gene dosage effects for PHA synthesis were investigated in recombinants of P. denitrificans with increased expression levels of each PHA synthetic enzyme. In the cultivation of shake flasks using ethanol or n-pentanol as carbon source, a self-cloning recombinant of the phaC-encoding PHA synthase showed the highest contents [(g PHA). (g total biomass)-1] and the highest rates of PHA accumulation [(g PHA). (g residual biomass)-1. h-1] among these recombinants. The PHA content and PHA accumulation rate (g PHA/g residual biomass. h-1) of the self-cloning recombinant was 2 and 2.7 times higher, respectively, than that of the wild strain. This result strongly suggests that the step of PHA synthase is limited in in vivo PHA synthesis from n-pentanol via 3-ketovaleryl-CoA through beta-oxidation, and from ethanol via acetyl-CoA. Studies on fed-batch cultures keeping the alcohol concentration constant (0.02%) in a 5-L bioreactor showed that the ability of PHA biosynthesis was improved by the gene dosage of PHA synthase, although the growth rate of cells during the growth-associated PHA synthesis phase was retarded. The molecular weight of the polymer isolated from the strain, dosed by the PHA synthase gene, was lower than that of the polymer from the wild strain, indicating that the amount of PHA synthase in vivo affects the molecular weight of the polymer. PMID- 10099408 TI - Flux enhancement for membrane filtration of bacterial suspensions using high frequency backpulsing. AB - A promising method for reducing membrane fouling during crossflow microfiltration of biological suspensions is backpulsing. Very short backpulses (0.1-1.0 s) have been used to increase the net flux for washed bacterial suspensions and whole bacterial fermentation broths. The net fluxes under optimum backpulsing conditions for the washed bacteria are approximately 10-fold higher than those obtained during normal crossflow microfiltration operation, whereas only a 2-fold improvement in the net flux is achieved for the fermentation broths. A theory is presented that is based on external fouling during forward filtration and nonuniform cleaning of the membrane during reverse filtration. The model contains an adjustable parameter which is a measure of the cleaning efficiency during backpulsing; the cleaning efficiency found by fitting the model to the experiments increases with increasing frequency and duration of the backpulses. The theory predicts an optimum backpulsing frequency, as was observed experimentally. An economic analysis shows that crossflow microfiltration with backpulsing has lower costs than centrifugation, rotary vacuum filtration, and crossflow microfiltration without backpulsing. PMID- 10099409 TI - Removal of U and Mo from water by immobilized Desulfovibrio desulfuricans in column reactors. AB - Intact cells of Desulfovibrio desulfuricans were immobilized in polyacrylamide gel and used to remove soluble U and Mo from water by enzymatically mediated reduction reactions in column reactors. Formate or lactate served as the electron donor and oxidized U(VI) and Mo(VI) species served as electron acceptors. Greater than 99% removal efficiencies were achieved for both metals with initial concentrations of 5 mg/L U and 10 mg/L Mo. Hydraulic residence times in the columns were between 24 and 36 h. Sulfate concentrations as high as 2000 mg/L did not inhibit reduction of U or Mo in the columns. However, nitrate inhibited uranium reduction at concentrations near 50 mg/L and inhibited molybdenum reduction at concentrations near 150 mg/L. The results indicate that enzymatic reduction of U and Mo by immobilized cells of D. desulfuricans may be a practical method for removing these contaminants from solution in continuous-flow reactors. PMID- 10099410 TI - Biomass growth monitoring using pressure drop in a cocurrent biofilter AB - The possibility of following the biomass growth by pressure drop measurement was investigated in an aerated cocurrent upflow fixed-bed bioreactor continuously fed with wastewater containing industrial organic pollutants. The experiments were carried out in a biological filtration oxygenated reactor (Biofor) pilot plant packed with expanded clay balls (Biolite) of 2.7-mm diameter, which served as biomass carriers. The column was equipped for on-line pressure drop measurements. Correlation between pressure drop measurements and Reynolds numbers of air and water were determined in experiments carried out without biomass. Under operating conditions with biomass, it was demonstrated that column clogging and the operating time between washing cycles can be predicted depending on the volumetric organic load for a given total organic carbon inlet concentration. The biological activity of the fixed biomass was estimated from the oxygen consumption rate per unit time and carrier area. The oxygen consumption rate measurements demonstrated that the biological activity depends on the inlet substrate concentration, and that the Biofor column was most efficient between 75 and 100 g m-3 of total organic carbon inlet concentration. In the course of the wastewater treatment, using pressure drop measurements, the equivalent diameter of the Biolite particles, the reduced column macroporosity, and the biofilm thickness were calculated. An expression correlating biofilm density and biofilm thickness, as determined from the pressure drop measurements, was proposed. Good agreement was found between the fixed biomass in the reactor, determined as volatile suspended solids, and the biologically active biomass, estimated by respirometry. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099411 TI - A monte carlo simulation of the depolymerization of linear homopolymers by endo enzymes exhibiting random-attack probability and single-attack mechanism: application to the (1-->3), (1-->4)-beta-D-glucan/endo-(1-->3),(1-->4)-beta-D glucanase system AB - A Monte Carlo simulation of the depolymerization of linear homopolymers by specific endo-enzymes exhibiting random-attack probability and a single-attack mechanism has been developed. The program simulates the "real" depolymerization versus time of a polydisperse sample of substrate by a specific endo-enzyme. Given the initial mass distribution and concentration of the substrate, the initial concentration of the enzyme, and its Michaelis-Menten constant, the program simulates the evolution of the mass distribution of the substrate with the depolymerization time. When tested against experimental data from the depolymerization of barley (1-->3),(1-->4)-beta-D-glucan by malt endo-(1-->3), (1 ->4)-beta-D-glucanase, monitored using the Calcofluor-FIA method with fluorescent detection, excellent results were obtained. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099412 TI - On the performance of a hollow-fiber bioreactor for acidolysis catalyzed by immobilized lipase AB - The present communication describes the chemical modification of anhydrous butterfat by interesterification with oleic acid catalyzed by a lipase of Mucor javanicus. Two reactor configurations were tested, a batch-stirred tank reactor containing suspended lipase and a batch-stirred tank reactor in combination with a hollow-fiber membrane module containing adsorbed lipase. The goal of this research was to assess the advantage of using a (hydrophobic) porous support to immobilize the lipase in attempts to engineer butterfat with increased levels of unsaturated fatty acid residues (oleic acid) at the expense of medium-to-long chain saturated fatty acids (myristic and palmitic acids). Reactions were carried out at 40 degrees C in the absence of solvent under controlled water activity, and were monitored by chromatographic assays for free fatty acids. The results obtained indicate that the rate of interesterification using the proposed reactor configuration is enhanced by a factor above 100 relative to that using suspended lipase, for the same protein mass basis. Although hydrolysis of butterfat occurred to some degree, the enzymatic process that uses the hollow-fiber reactor was technically superior to the stirred tank system. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099414 TI - Resistance of biofilms to the catalase inhibitor 3-amino-1,2, 4-triazole PMID- 10099413 TI - DNA protection from extracapsular nucleases, within chitosan- or poly-L-lysine coated alginate beads. AB - DNA was immobilized within alginate matrix using an external or an internal calcium source, and then membrane coated with chitosan or poly-L-lysine. Membrane thickness increased with decreasing polymer molecular weight and increasing degree of deacetylation (chitosan). Beads were exposed to a 31,000 molecular weight nuclease to determine the levels of DNA protection offered by different membrane and matrix combinations. Almost total hydrolysis of DNA was observed in alginate beads following nuclease exposure. Less than 1% of total double-stranded DNA remained unhydrolyzed within chitosan- or poly-L-lysine-coated beads, corresponding with an increase in DNA residuals (i.e. double- and single-stranded DNA, polynucleotides, bases). Chitosan membranes did not offer sufficient DNA protection from DNase diffusion since all of the double-stranded DNA was hydrolyzed after 40 min of exposure. Both chitosan and poly-L-lysine membranes reduced the permeability of alginate beads, shown by enhanced retention of DNA residuals after DNase exposure. The highest level of DNA protection within freshly prepared beads was obtained with high molecular weight (197,100) poly-L lysine membranes coated on beads formed using an external calcium source, where over 80% of the double-stranded DNA remained after 40 min of DNase exposure. Lyophilization and rehydration of DNA beads also reduced permeability to nucleases, resulted in DS-DNA recoveries of 60% for chitosan-coated, 90% for poly L-lysine-coated, and 95% for uncoated alginate beads. PMID- 10099415 TI - Detection of functional groups and antibodies on microfabricated surfaces by confocal microscopy. AB - Fluorescence confocal microscopy was used to characterize micron-sized microfabricated silicon particles and planar oxide surfaces after silanization and immobilization of IgG antibody. Surfaces treated with amino- and mercaptosilanes were tested for the presence of amine and sulfhydryl groups by labeling with specific fluorescein probes. In addition, human antibody (IgG) was immobilized to the thiol-coated microparticles using the heterobifunctional crosslinker succinimidyl 4-(N-maleimidolmethyl)-cyclohexane-1-carboxylate. Estimates of the surface density of IgG were consistent with 8.3% of a monolayer of covalently-bound antibody. Confocal images confirmed uniform layers of both silanes and antibodies on the microparticles. The sensitivity limit for the confocal measurements was determined to be as low as 1.5 x 10(-5) fluors per nm2. PMID- 10099416 TI - Application of the redox potential for controling a sulfide oxidizing bioreactor AB - The investigations described show that the formation of elemental sulfur from the biological oxidation of sulfide can be optimized by controling the redox state of the solution. The nonsoluble sulfur can be removed by gravity sedimentation and re-used as a raw material, i.e., in bioleaching processes. It was shown that, by supplying an almost stoichiometrical amount of oxygen to the recirculated gas phase, the formation of sulfate is minimized. The redox potential is mainly determined by the sulfide concentration because this compound has a high standard exchange current density with the platinum electrode surface. By maintaining a particular redox setpoint value, in fact, the reactor becomes a "sulfide-stat." It was shown that in a sulfide-oxidizing bioreactor the measured redox potential, using a polished redox electrode, is kinetically determined rather than thermodynamically. The optimal redox value for sulfur formation is between -147 and -137 mV (H2 reference electrode, 30 degrees C, pH 8). The presented results are currently used for controling several full-scale installations, which desulfurize biogas and high-pressure natural gas. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099417 TI - Enhancement of Candida rugosa lipase production by using different control fed batch operational strategies. AB - Simulation studies have predicted that maximum lipase activity is reached with fed-batch operation strategies. In this work, two different fed-batch operational strategies have been studied: constant substrate feeding rate and specific growth rate control. A constant substrate feeding rate strategy showed that maximum aqueous lipolytic activity (55 U/mL) was reached at low substrate feeding rates, whereas lipase tends to accumulate inside the cell at higher rates of substrate addition. In the second fed-batch strategy studied, a feedback control strategy has been developed based on the estimation of state variables (X and mu) from the measurement of indirect variables such as CER by means of mass spectrometry techniques. An on-off controller was then used to maintain the specific growth rate at the desired value by adjusting the substrate feeding rate. A constant specific growth rate strategy gave higher final levels of aqueous lipolytic activity (117 U/mL) at low specific growth rates. At higher specific growth rates the enzyme remained accumulated inside the cell, as was observed with a constant feeding fed-batch strategy. With a constant specific growth rate strategy, lipase production by Candida rugosa was enhanced 10-fold compared to a batch operation. Purification studies have demonstrated that lipolytic and esterasic specific activity ratios of Candida rugosa isoenzymes can be modified by using different operational conditions. These studies have also showed that the isoenzymes obtained in a controlled growth rate strategy are around three- to four-fold more active than those obtained in a constant feeding rate strategy. PMID- 10099418 TI - Modeling the exponential growth of filamentous fungi during batch cultivation AB - In certain conditions, filamentous fungi are observed to grow exponentially during batch submerged growth. It is shown for three cases, with simple mechanistic models, that an exponential growth assumption is reasonable. The basis of these models is the identification of a growth unit, and a mechanism for its doubling with a constant generation time. The importance of the variation of morphological properties within populations is demonstrated by the comparison of computer simulations of simplified models using average values and either experimental data or computer simulations of detailed stochastic models. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099419 TI - Simple generic model for dynamic experiments with Saccharomyces cerevisiae in continuous culture: decoupling between anabolism and catabolism. AB - The dynamic behavior of a continuous culture of Saccharomyces cerevisiae subjected to a sudden increase in the dilution rate has been successfully modelled for anaerobic growth on glucose, and for aerobic growth on acetate, on ethanol, and on glucose. The catabolism responded by an immediate jump whereas biosynthesis did not. Thus catabolism was in excess to anabolism. The model considers the decoupling between biosynthesis and catabolism, both types of reactions being modelled by first-order kinetic expressions evolving towards maximal values. Yield parameters and maximal reaction rates were identified in steady state continuous cultures or during batch experiments. Only the time constant of biosynthesis regeneration, tauX, and the time constant of catabolic capacity regeneration, taucat, had to be identified during transient experiments. In most experiments tauX was around 3 h, and taucat varied between 2 and 2.5 h for the different metabolisms investigated. PMID- 10099420 TI - Enzymatic transformations in supersaturated substrate solutions: I. A general study with glycosidases. AB - The results of an initial study of enzymatic catalysis in metastable supersaturated solutions of carbohydrates are presented. It has been shown that such solutions, formed in the presence of small amounts of water and alcohol as plasticizers, are sufficiently stable under ambient conditions to enable enzymatic transformations of substrates. A partial phase diagram for a system consisting of glucose, water, and (poly)ethylene glycol was constructed to identify the regions which are most suitable for biotransformations. It was confirmed that the glass transition in this system occurred below the reaction temperature at any given composition of the constituent components. Several glycosidases were found to be catalytically active in this medium and the activity of beta-glucosidase from almond was determined at several compositions of the reaction mixture and related to the corresponding regions of the phase diagram. The synthetic utility of the system was illustrated by glucosylation of several alpha,omega-alkyldiols, short-chain polyethylene glycols, and hydroxyalkyl and glyceryl monoacrylates. PMID- 10099421 TI - Enzymatic transformations in supersaturated substrate solutions: II. Synthesis of disaccharides via transglycosylation. AB - Enzymatic transglycosylation in supersaturated solutions of substrates was investigated using crude glycosidase preparations from barley, snail, and coffee beans. It was shown that the use of supersaturated glycoside solutions as media for transglycosylation reactions offers considerable advantages over conventional aqueous systems. These advantages include higher yields, more efficient use of the donor glycosides and improved volumetric productivity, especially in the case of poorly water-soluble substrates. The regioselectivity of the glycosylation was not significantly affected by high concentrations of acceptor glycosides. It was also shown that the regioselectivity of transfer could be directed towards secondary hydroxyl groups by the use of methyl 6-O-acetyl-alpha-galactopyranoside as acceptor. The value of these approaches was demonstrated by the synthesis of methyl 3- and 4-O-beta-D-galactopyranosyl-alpha-D-galactopyranosides and methyl 3 O-beta-D-galactopyranosyl-alpha-L-fucopyranoside on a preparative scale. PMID- 10099422 TI - Immobilization of manganese peroxidase from Lentinula edodes and its biocatalytic generation of MnIII-chelate as a chemical oxidant of chlorophenols. AB - Manganese peroxidase (MnP) purified from commercial cultures of Lentinula edodes was covalently immobilized through its carboxyl groups using an azlactone functional copolymer derivatized with ethylenediamine and 2-ethoxy-1 ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) as a coupling reagent. The tethered enzyme was employed in a two-stage immobilized MnP bioreactor for catalytic generation of chelated MnIII and subsequent oxidation of chlorophenols. Manganese peroxidase immobilized in the enzyme reactor (reactor 1) produced MnIII-chelate, which was pumped into another chemical reaction vessel (reactor 2) containing the organopollutant. Reactor 1-generated MnIII-chelates oxidized 2,4-dichlorophenol and 2,4, 6-trichlorophenol in reactor 2, demonstrating a two-stage enzyme and chemical system. H2O2 and oxalate chelator concentrations were varied to optimize the immobilized MnP's oxidation of MnII to MnIII. Oxidation of 1.0 mM MnII to MnIII was initially measured at 78% efficiency under optimized conditions. After 24 h of continuous operation under optimized reaction conditions, the reactor still oxidized 1.0 mM MnII to MnIII with approximately 69% efficiency, corresponding to 88% of the initial MnP activity. PMID- 10099423 TI - Modeling and measurements of fungal growth and morphology in submerged fermentations. AB - Generalizing results from fungal fermentations is difficult due to their high sensitivity toward slight variation in starting conditions, poor reproducibility, and difference in strains. In this study a mathematical model is presented in which oxygen transfer, agitation intensity, dissolved oxygen tension, pellet size, formation of mycelia, the fraction of mycelia in the total biomass, carbohydrate source consumption, and biomass growth are taken into account. Two parameters were estimated from simulation, whereas all others are based on measurements or were taken from literature. Experimental data are obtained from the fermentations in both 2 L and 100 L fermentors at various conditions. Comparison of the simulation with experiments shows that the model can fairly well describe the time course of fungal growth (such as biomass and carbohydrate source concentrations) and fungal morphology (such as pellet size and the fraction of pellets in the total biomass). The model predicts that a stronger agitation intensity leads to a smaller pellet size and a lower fraction of pellets in the total biomass. At the same agitation intensity, pellet size is hardly affected by the dissolved oxygen tension, whereas the fraction of mycelia decreases slightly with an increase of the dissolved oxygen tension in the bulk. All of these are in line with observations at the corresponding conditions. PMID- 10099424 TI - Effect of Escherichia coli biomass composition on central metabolic fluxes predicted by a stoichiometric model. AB - The amino acid composition of proteins and the fatty acid composition of the cell membranes were measured in Escherichia coli growing exponentially in batch culture on glucose, succinate, glycerol, pyruvate, and acetate, and growing under continuous culture conditions on glucose at dilutions rates equivalent to the growth rates of the batch cultures. Although the fatty acid composition of the membranes did change significantly with carbon source and dilution rate, the amino acid content of proteins did not change significantly under either condition. A previously developed stoichiometric model of metabolism was used to calculate the fluxes through the metabolic reactions and to determine their sensitivity to changes in fatty acid and amino acid composition. PMID- 10099425 TI - Increased agitation intensity increases CD13 receptor surface content and mRNA levels, and alters the metabolism of HL60 cells cultured in stirred tank bioreactors. AB - Flow cytometry and Northern blotting were used to examine the effects of hydrodynamic forces in stirred tank bioreactors on CD13 receptor surface content and mRNA levels of HL60 (human promyelocytic leukemia) cells. A step increase in agitation rate from 80 to 300 or 400 rpm reduced the apparent HL60 growth rate in a dose-dependent manner. This step increase in agitation rate (to 300 or 400 rpm) also increased the CD13 receptor surface content on averge by 30% and 100%, respectively. This increase in CD13 receptor surface content was correlated with a 10% and a 60% increase in CD13 mRNA levels. We also observed a significant and very reproducible drop in CD13 expression over the course of a batch bioreactor run (80 rpm). Although we have no explanation for this, we show that the decrease in CD13 receptor surface content can be (at least partially, if not fully) explained by the corresponding decrease in CD13 mRNA. HL60 cell cultures agitated at 300 and 400 rpm exhibited glucose consumption and lactate production rates that were approximately 40% and 90% greater than values of the cultures agitated at 80 rpm. The physiological and practical implications of these results are discussed. PMID- 10099426 TI - Effects of methocel A15LV, polyethylene glycol, and polyvinyl alcohol on CD13 and CD33 receptor surface content and metabolism of HL60 cells cultured in stirred tank bioreactors. AB - Flow cytometry was used to examine the effect of hydrodynamic forces in a stirred tank bioreactor on the CD13 and CD33 receptor surface content of HL60 (human promyelocytic leukemia) cells. A step increase in agitation rate from 80 to 400 rpm reduced the HL60 cell apparent growth rate and increased the CD13 receptor surface content per cell, on average, by 95%. In contrast, this step increase in agitation rate to 400 rpm decreased the CD33 receptor surface content per cell, on average, by 10%. The protective effects of 0.1% Methocel A15LV, polyethylene glycol (PEG), and polyvinyl alcohol (PVA) on CD13 and CD33 receptor surface content were examined under agitation at 300 rpm in parallel 2 L bioreactor runs. The average CD33 receptor surface content was unaffected by the presence of Methocel A15LV or PEG, while PVA had a slight protective effect. In contrast, in terms of CD13 receptor content, HL60 cells agitated at 300 rpm with Methocel A15LV, PEG, or PVA behaved like cells agitated at 80 rpm with no media additives (McDowell and Papoutsakis, 1998). That is, Methocel A15LV, PEG, and PVA prevented the transduction of mechanical forces which affect CD13 cell content. HL60 cells cultured with 0.1% A15LV, PEG or PVA under conditions of mild agitation (60 rpm) in spinner flasks exhibited glucose consumption and lactate production rates that were approximately 20% lower than values of cultures containing no additive. Under conditions of agitation at 300 rpm in the 2 L bioreactor, the presence of A15LV, PEG, and PVA reduced the HL60 glucose consumption and lactate production rates by approximately 50%. Thus, media additives can dramatically reduce lactate accumulation in agitated bioreactors due to cell growth, in addition to providing protection from cellular injury. PMID- 10099428 TI - Effect of post-induction nutrient feeding strategies on the production of bioadhesive protein in Escherichia coli. AB - The effect of post-induction nutrient feeding strategies on the production of bioadhesive protein using an IPTG inducible expression system in Escherichia coli was investigated. Cells were cultured in an exponential fed-batch mode to the OD600 of ca. 100 (48 gDCW/L) prior to induction. Six different post-induction nutrient feeding strategies (pH-stat, exponential, constant and linear change in feeding rate with three different slopes) were then applied, and bioadhesive protein production was examined. It was found that post-induction cell growth was independent of nutrient feeding rate. However, bioadhesive protein production was significantly affected by post-induction feeding strategies. Linearly changing post-induction feeding rate with a suitable slope allowed production of bioadhesive protein up to 5.3 g/L, which was higher than that obtained by the other post-induction feeding strategies. PMID- 10099427 TI - Serum increases the CD13 receptor expression, reduces the transduction of fluid mechanical forces, and alters the metabolism of HL60 cells cultured in agitated bioreactors. AB - The effects of serum medium concentration on the CD13 receptor surface content and mRNA levels of HL60 (human promyelocytic leukemia) cells were examined using flow cytometry and Northern blotting. Increasing the serum concentration from 2.5% to 10% and from 5% to 10% increased the CD13 receptor surface content of HL60 cells by 100% and 25%, respectively, in spinner flasks agitated at 60 rpm. In bioreactors at 80 rpm, increasing the serum concentration from 2.5% to 10% and from 5% to 10% increased the CD13 receptor surface content by 60% and 35%, respectively. This increase in CD13 receptor surface content was correlated with a 30% and a 20% increase in CD13 mRNA levels. Increasing serum concentrations also increased the average HL60 cell size under non-damaging conditions (60 rpm in spinner flasks, 80 rpm in bioreactors). Under conditions of agitation at 300 rpm in 2 L bioreactors, increasing serum concentrations (2.5% vs. 10%, 5% vs. 10%) allowed for higher HL60 apparent growth rates, but decreased the CD13 receptor surface content and mRNA levels. In view of our earlier findings on the effects of agitation on the CD13 antigen, these data suggest that serum reduces the transduction of mechanical forces that affect CD13 expression. At 300 rpm, HL60 cells cultured in 10% serum exhibited glucose consumption and lactate production rates that were approximately 50% and 60% lower than the values of cells cultured in 5% and 2.5% serum, respectively. PMID- 10099429 TI - A pH-controlled fed-batch process can overcome inhibition by formate in NADH dependent enzymatic reductions using formate dehydrogenase-catalyzed coenzyme regeneration. AB - The NAD-dependent, formate dehydrogenase-catalyzed oxidation of formate anion into CO2 is known as the method for the regeneration of NADH in reductive enzymatic syntheses. Inhibition by formate and inactivation by alkaline pH-shift that occurs when oxidation of formate is carried out at pH approximately 7.0 may, however, hamper the efficient application of this NADH recycling reaction. Here, we have devised a fed-batch process using pH-controlled feeding of formic acid that can overcome enzyme inhibition and inactivation. The reaction pH is thus kept constant by addition of acid, and formate dehydrogenase is supplied continuously with substrate as required, but the concentration of formate is maintained at a constant, non- or weakly inhibitory level throughout the enzymatic conversion, thus enabling a particular NADH-dependent dehydrogenase to operate stably and at high reaction rates. For xylitol production from xylose using yeast xylose reductase (Ki,Formate 182 mM), a fed-batch conversion of 0.5M xylose yielded productivities of 2.8 g (L h)-1 that are three-fold improved when contrasted to a conventional batch reaction that employed equal initial concentrations of xylose and formate. PMID- 10099430 TI - Characterization of the diffusive properties of biofilms using pulsed field gradient-nuclear magnetic resonance AB - The mobility of water in intact biofilms was measured with pulsed field gradient nuclear magnetic resonance (PFG-NMR) and used to characterise their diffusive properties. The results obtained with several well-defined systems, viz. pure water, agar, and agar containing inert particles or active bacteria were compared to glucose diffusion coefficients measured with micro-electrodes and those calculated utilising theoretical diffusion models. A good correspondence was observed indicating that PFG-NMR should also enable the measurement of diffusion coefficients in heterogeneous biological systems. Diffusion coefficients of several types of natural biofilms were measured as well and these results were related to the physical biofilm characteristics. The values had a high accuracy and reflected the properties of a sample of ca. 100 biofilms, while non uniformity or non-geometrical shapes did not negatively influence the results. The monitored PFG-NMR signal contains supplementary information on e.g. cell fraction or spatial organisation but quantitative analysis was not yet possible. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099431 TI - Kinetics of combined pressure-temperature inactivation of avocado polyphenoloxidase. AB - Irreversible combined pressure-temperature inactivation of the food quality related enzyme polyphenoloxidase was investigated. Inactivation rate constants (k) were obtained for about one hundred combinations of constant pressure (0.1 900 MPa) and temperature (25-77.5 degrees C). According to the Eyring and Arrhenius equation, activation volumes and activation energies, respectively, representing pressure and temperature dependence of the inactivation rate constant, were calculated for all temperatures and pressures studied. In this way, temperature and pressure dependence of activation volume and activation energy, respectively, could be considered. Moreover, for the first time, a mathematical model describing the inactivation rate constant of a food quality related enzyme as a function of pressure and temperature is formulated. Such pressure-temperature inactivation models for food quality-related aspects (e.g., the spoilage enzyme polyphenoloxidase) form the engineering basis for design, evaluation, and optimization of new preservation processes based on the combined effect of temperature and pressure. Furthermore, the generated methodology can be used to develop analogous kinetic models for microbiological aspects, which are needed from a safety and legislative point of view, and other quality aspects, e.g., nutritional factors, with a view of optimal quality and consumer acceptance. PMID- 10099432 TI - Spray-drying performance of a bench-top spray dryer for protein aerosol powder preparation. AB - The objective of this work was to improve a bench-top spray dryer's efficiency in both production recovery and throughput for preparing protein aerosol powders. A Buchi mini-spray dryer was used to prepare the powders of recombinant humanized anti-IgE antibody. The resulting powder's physical properties such as particle size, residual moisture, and morphology, along with its recovery and production rate was the basis of this development work. Mass balance suggests that approximately 10-20% of powder was lost in the exhaust air, consisting primarily of particles less than 2 micrometer. Also, significant loss (20-30%) occurred in the cyclone. Attempts were made to improve product recovery in the receiving vessel using dual-cyclone configurations, different cyclone designs, cyclones with anti-static treatment, and different receiver designs. System modifications such as replacing the original bag-filter unit with a vacuum system effectively reduced drying air flow resistance, allowing the protein to be dried at a lower inlet air temperature and the production scale to be increased. We concluded that the modified spray-drying system is advantageous over the original bench-top spray dryer. This improvement will be beneficial to early-stage research and development involving high-valued protein powders. PMID- 10099433 TI - Uptake of phenylacetic acid by two strains of Penicillium chrysogenum. AB - Uptake of phenylacetic acid, the side-chain precursor of benzylpenicillin, was studied in Penicillium chrysogenum Wisconsin 54-1255 and in a strain yielding high levels of penicillin. In penicillin fermentations with the high-yielding strain, 100% recovery of phenylacetic acid in benzylpenicillin was found, whereas in the Wisconsin strain only 17% of the supplied phenylacetic acid was incorporated into benzylpenicillin while the rest was metabolized. Accumulation of total phenylacetic acid-derived carbon in the cells was nonsaturable in both strains at high external concentrations of phenylacetic acid (250-3500 microM), and in the high-yielding strain at low phenylacetic acid concentrations (2. 8-100 microM), indicating that phenylacetic acid enters the cells by simple diffusion, as concluded earlier for P. chrysogenum by other authors. However, at low external concentrations of phenylacetic acid saturable accumulation appeared in the Wisconsin strain. HPLC-analyses of cell extracts from the Wisconsin strain showed that phenylacetic acid was metabolized immediately after entry into the cells and different [14C]-labeled metabolites were detected in the cells. Up to approximately 50% of the accumulated phenylacetic acid was metabolized during the transport-assay period, the conversion having an impact on the uptake experiments. Nevertheless, accumulation of free unchanged phenylacetic acid in the cells showed saturation kinetics, suggesting the possible involvement of a high-affinity carrier in uptake of phenylacetic acid in P. chrysogenum Wisconsin 54-1255. At high concentrations of phenylacetic acid, contribution to uptake by this carrier is minor in comparison to simple diffusion and therefore, of no importance in the industrial production of penicillin. PMID- 10099434 TI - Interaction between CO2-mass transfer, light availability, and hydrodynamic stress in the growth of phaeodactylum tricornutum in a concentric tube airlift photobioreactor AB - The microalga Phaeodactylum tricornutum was grown in a concentric tube airlift photobioreactor. A maximum specific growth rate of 0. 023 h-1 was obtained using a superficial gas velocity around 0.055 m/s. Lower or higher gas flow rates limited the culture performance. To establish if the observed limitation was due to CO2 or to the photosynthetically active irradiance, characteristic times for mixing, mass transfer and CO2 consumption, and the photon flux absorbed by the culture were analyzed. The CO2-gradients in the culture were shown to be responsible for the limitation during the exponential growth phase, and both CO2 and light irradiance were limiting in the linear growth phase. The decrease in specific growth rate relative to the maximum was found to be related to the specific gas-liquid interfacial area, the length scale of the microeddies and the shear rate. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099435 TI - Minimal aerobic sludge retention time in biological phosphorus removal systems AB - The methodology for determination of the minimally required aerobic sludge retention time (SRTminaer) in biological phosphorus removal (BPR) systems is presented in this article. Contrary to normal biological conversions, the BPR process is not limited by a SRTmin resulting from the maximum growth rate of the organisms. This is because the aerobic SRT should be long enough to oxidize the amount of poly-hydroxy-alkanoates (PHA) stored in the anaerobic phase. This means that the SRTminaer will primarily depend on the PHA conversion kinetics and the maximal achievable PHA content in the cell (storage capacity). The model for the prediction of the minimally required aerobic SRT as a function of kinetic and process parameters was developed and compared with experimental data used to evaluate several operational aspects of BPR in a sequencing batch reactor (SBR) system. The model was proved as capable of describing them satisfactorily.Copyright 1998 John Wiley & Sons, Inc. PMID- 10099436 TI - Expanded and packed bed albumin adsorption on fluoride modified zirconia. AB - The expanded bed characteristics of 75-103microm fluoride-modified zirconia (FmZr) particles synthesized by a fed batch oil emulsion process were investigated. These particles are distinguished from commercially available expanded-bed adsorbents by virtue of their high density (2.8 g/cc) and the mixed mode protein retention mechanism which allows for the retention of both cationic and anionic proteins. The linear velocity versus bed porosity data agree with the Richardson-Zaki relationship with the terminal velocity in infinite medium of 2858.4 cm/h and a bed expansion index of 5.1. Residence time distribution (RTD) studies and bovine serum albumin (BSA) adsorption studies were performed as a function of the height of the settled bed to the column diameter (H:D) ratio and degree of bed expansion with superficial velocities of 440 to 870 cm/h. The settled bed, a 2x expanded bed, and a 3x expanded bed were studied for the H:D ratios of 1:1, 2:1, and 3:1. The dynamic binding capacity (DBC) at 5% breakthrough was low (2-8 mg BSA/mL settled bed) and was independent of the H:D ratio or the degree of bed expansion. The saturation DBC was 32.3 +/- 7.0 mg BSA/mL settled bed. The adsorption-desorption kinetics and intraparticle diffusion for protein adsorption on FmZr (38-75 micrometer) were investigated by studying the packed bed RTD and BSA adsorption as a function of temperature and flow rate. The data show that the adsorption-desorption kinetics along with intraparticle diffusion significantly influence protein adsorption on FmZr. Low residence times ( approximately 0.8 min) of BSA result in a DBC at 5% breakthrough which is 3.5-fold lower compared to that at 6-fold higher protein residence time. At low linear velocity (45 cm/h) the breakthrough curve is nearly symmetrical and becomes asymmetrical and more dispersed at higher linear velocity (270 cm/h) due to the influence of slow adsorption-desorption kinetics and intraparticle diffusion. Bioeng 60: 333-340, 1998. PMID- 10099438 TI - Insertion of microscopic objects through plant cell walls using laser microsurgery AB - A detailed protocol is presented for precisely inserting microscopic objects into the periplasmic region of plant callus cells using laser microsurgery. Ginkgo biloba and Agrobacterium rhizogenes were used as the model system for developing the optical tweezers and scalpel techniques using a single laser. We achieved better than 95% survival after plasmolyzing G. biloba cells, ablating a 2-4-MUm hole through the cell wall using a pulsed UV laser beam, trapping and translating bacteria into the periplasmic region using a pulsed infrared laser beam, and then deplasmolyzing the cells. Insertion of bacteria is also described. A thermal model for temperature changes of trapped bacteria is included. Comparisons with other methods, such as a reverse-pressure gradient technique, are discussed and additional experiments on plants using laser microsurgery are suggested. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099437 TI - Serum-free ex vivo expansion of CD34(+) hematopoietic progenitor cells. AB - In an effort to obtain defined culture conditions for ex vivo expansion of hematopoietic stem and progenitor cells which avoid the supplementation of serum, we cultured human CD34(+) hematopoietic progenitor cells in a chemically defined, serum-free medium in the presence of hematopoietic growth factors (HGFs), stem cell factor (SCF), interleukin (IL)-1beta, IL-3, IL-6, and erythropoietin (EPO). A medium, SFM-1, was prepared according to a protocol previously optimized for semisolid progenitor cell assays containing Iscove's Modified Dulbecco's Medium (IMDM) plus cholesterol, bovine serum albumin, transferrin, nucleotides and nucleosides, insulin, and beta-mercaptoethanol. In static cultures seeded with CD34(+)-enriched progenitor cells isolated from human peripheral blood, a mean 76.6-fold expansion of total nucleated cells and a mean 4.6-fold expansion of colony-forming cells (CFC) was recorded after 14 days. Morphological analysis of the expanded cells revealed formation of myeloid, erythroid, and megakaryocytic cells. Flow cytometric analysis indicated that CD34(+) antigen expressing cells were maintained to a limited degree only, and cell populations expressing surface markers for myeloid (CD33, CD14, and CD15) and megakaryocytic (CD41a) lineages predominated. Within SFM-1, bovine serum albumin (BSA), cholesterin, and transferrin represented the most critical components needed for efficient total cell and CFC expansion. Addition of autologous patient plasma (APP) or fetal calf serum (FCS) to SFM-1 resulted in inferior cell amplification and CFC formation compared to controls in SFM-1, indicating that the components used in SFM-1 could replace exogenous serum. Four commercially available serum-free media resulted in either comparable or lower total cell and CFC yields as SFM-1. The transplantation potential of CD34(+) cells after culture in SFM-1 was assayed using limiting dilution analysis on preformed irradiated bone marrow stroma and revealed maintenance of long-term bone marrow culture initiating cell (LTCIC) levels during the culture period. These data indicate that HGF-supported multilineage ex vivo expansion of human CD34(+) hematopoietic progenitor cells is feasible using an IMDM-based culture medium which contains a restricted number of additives, resulting in analogous or improved yields of both primitive and differentiated cells compared to previously established protocols. We suggest that this culture protocol is of advantage when working with pharmaceutical-grade preparations under serum-free conditions. PMID- 10099439 TI - Optimized enzymatic synthesis of methyl benzoate in organic medium. Operating conditions and impact of different factors on kinetics AB - Enzyme-catalyzed synthesis of methyl benzoate is reported. It is the first example of direct esterification of benzoic acid which provides good yields. The reaction was performed in a heterogeneous medium by Candida rugosa lipase powder suspended in a hexane/toluene mixture. The impact of some factors was examined. Benzoic acid does not inhibit the lipase until 100 mM. Above 90 mM, methanol inhibits the enzyme. This inhibition is partially eliminated by increasing benzoic acid concentration. Below 90 mM, methanol mainly interacts with the water adsorbed on the biocatalyst. A minimum water content is necessary to activate the biocatalyst. Water must be provided proportionally to the lipase content. Toluene, necessary for benzoic acid solubilization, also acts negatively on reaction kinetics. This is attributed to a modification of benzoic acid partition between the biocatalytic and the organic phases. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099440 TI - Water activity control: a way to improve the efficiency of continuous lipase esterification. AB - During continuous lipase-catalyzed oleic acid esterification by ethanol in n hexane, the oleic acid conversion, initially at 95%, decreases to 20% after 2 h. This decrease is caused by the accumulation of the water produced in the course of the reaction in the packed-bed reactor (PBR). In order to improve the PBR efficiency, it is necessary to evacuate the water produced. In this study, different approaches have been tested to control the water content in the PBR during continuous esterification. The first approach consisted in improving the water solubility by increasing the reaction medium polarity. The addition of polar additives to n-hexane, the use of more polar solvents, and the use of solvent-free reaction medium were tested as a means to favor the water evacuation from the PBR. First of all, the use ofn-hexane supplemented with acetone (3 M) or 2-methyl-2-propanol (1 M) enabled the conversion to be maintained at higher values than those obtained in pure n-hexane. The replacement of n-hexane by a more polar solvent, like the 5-methyl-2-hexanone, resulted in the same effect. In all cases, conversions at steady-state were always less than 95%, as obtained in pure n-hexane. This is explained by a decrease in the enzyme activity due to the increase in the medium polarity. Nevertheless, an increase in enzyme quantity allowed 90% conversion to be maintained during 1 week using 3 M acetone amended n hexane. Good results (a steady-state conversion of about 80%) were obtained when esterification was carried out in a solvent-free reaction medium containing 2 M 2 methyl-2-propanol as a polar additive. The second approach consisted in the evaporation of the accumulated water by use of an intermittent airflow. Although this process did not enable constant esterification rate to be maintained, it did enable the initial conversion (95%) to be restored intermittently. PMID- 10099441 TI - Synthesis of rotavirus-like particles in insect cells: comparative and quantitative analysis. AB - When the three major structural proteins, VP2, VP6, and VP7, of rotavirus are co expressed in insect cells infected with recombinant baculoviruses, they self assemble into triple-layered virus-like particles (VLPs) that are similar in morphology to native rotavirus. In order to establish the most favorable conditions for the synthesis of rotavirus VLPs, we have compared the kinetics of 2/6/7-VLP synthesis in two different insect cell lines: High Five cells propagated in Excell 405 medium and Spodoptera frugiperda 9 cells in Excell 400 medium. The majority of VLPs produced in both cell lines were released into the culture medium, and these released VLPs were predominantly triple-layered and were found to be stable for the period of six or seven days examined. The optimal synthesis of VLPs depended upon the cell line and the culture medium used as well as the time of harvesting infected cell cultures. The highest yield of VLPs was obtained from High Five cultures in the late phase of infection when the yield was at least 5-fold higher than that from S. frugiperda 9 cultures on a per cell basis. Our results demonstrate the usefulness of High Five cells for the production of VLPs as potential rotavirus subunit vaccines. PMID- 10099442 TI - Characterization of fluid-flow resistance in root cultures with a convective flow tubular bioreactor AB - Agrobacterium transformed root cultures of Hyoscyamus muticus were grown in a recirculating 2 L tubular bioreactor system. Performance of this convective flow reactor (CFR) was compared to a bubble column (BC) reactor of the same geometry: replicated CFR experiments produced an average tissue concentration of 556 +/- 4 grams fresh weight per liter in 30 d whereas the bubble column produced only 328 +/- 5 grams per liter corresponding to 25.3 +/- 0.0 and 14.3 +/- 0.5 grams dry weight per liter, respectively. Because media nutrient levels were maintained sufficiently high to saturate growth rate, the improved performance of the CFR is attributed to enhanced convective mass transfer. The pressure drops observed for flow through roots grown within the reactors were more than an order of magnitude higher than previously obtained by placing roots grown in shake culture into defined geometries. The experimentally observed flow resistance was much higher than would be predicted from correlations using the root diameter as the characteristic diameter for flow resistance. Several lines of evidence suggest that root hairs are a substantial contributor to the observed high flow resistance in these transformed root cultures. Pressure drop increased nonlinearly with velocity which could not be adequately described by a modified form of the Ergun equation. Kyan et al's (1970) equation, although predicting such curvature, relies almost exclusively on an empirical packing deflection term to describe the hydrodynamic behavior. Implications of these results to the design of submerged reactor systems for root culture are discussed. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099443 TI - A novel approach to biotransformations in aqueous-organic two-phase systems: enzymatic synthesis of alkyl beta-[D]-glucosides using microencapsulated beta glucosidase. AB - A novel approach to enzymatic biotransformations in aqueous-organic two-phase systems was developed where the aqueous phase was contained within permeable polymeric capsules suspended in organic solvent. Microencapsulated beta glucosidase, used as a model enzyme, was shown to retain its catalytic activity for a considerable time and was repeatedly used in batch experiments after recharging the microcapsules with solid glucose. The reaction conditions for the synthesis of hexyl beta-[D]-glucopyranoside were optimized with regard to the polymer composition of the microcapsules, pH, and the volume ratio of aqueous to organic phases. The potential for further improvement in the efficiency of the system was demonstrated by designing a bioreactor which incorporated units for product recovery and recycling of the organic solvent. Other advantages of the proposed methodology include facile control over the size and composition of the microcapsules, and mild reaction conditions during their preparation. PMID- 10099444 TI - Batch phenol degradation by candida tropicalis and its fusant AB - Phenol degradation by Candida tropicalis and its fusant, which is produced using protoplast fusion as a selective technique, is evaluated under batch and high concentration conditions. The respirometric data show that oxygen uptake activities of both yeast strains peak at pH 7.0 and 32 degrees C, but the fusant is more active than the control strain. Although the data show that both yeast strains are capable of sustaining discernible degradation in the presence of phenol inhibition, however, the C. tropicalis fusant is capable of attaining better phenol degradation than the control strain and it is less susceptible to phenol inhibition. Under the conditions tested, C. tropicalis is completely inhibited at phenol concentrations >/=3,300 mg/L, whereas for the C. tropicalis fusant complete inhibition is absent until phenol concentrations are >/=4, 000 mg/L. The observed cell yields of both yeast strains are virtually identical and remain fairly constant at approximately 0.5 mg MLVSS/mg C6H5OH (MLVSS: mixed liquor volatile suspended solids). Copyright 1998 John Wiley & Sons, Inc. Biotechnol Bioeng 60: 391-395, 1998. PMID- 10099445 TI - Effect of nonionic surfactants on naphthalene dissolution and biodegradation. AB - The effect of six nonionic surfactants, Igepal CA-720, Tergitol NPX, Triton X 100, PLE4, PLE10, and PLE23, on the dissolution rate of solid naphthalene was studied in stirred batch reactors. Results showed increased mass-transfer rates with increased surfactant concentrations up to 10 kg m-3. Dissolution experiments were adequatly described by a mechanistic mass-transfer model. Partitioning of naphthalene into the micelles and the diffusion coefficients of the micelles affected the dissolution rate most significantly. Combined dissolution and biodegradation experiments with Triton X-100 or PLE10 with naphthalene showed that the biomass-formation rate of Pseudomonas 8909N (DSM No. 11634) increased concomitantly with the mass-transfer rate under naphthalene-dissolution limited conditions up to surfactant concentrations of 6 kg m-3. PMID- 10099446 TI - Optimization of the production of virus-like particles in insect cells. AB - In this work the maximal operational hydrodynamic conditions (agitation and aeration rate) that cause no adverse effect in Sf-9 cells growth in SF900II serum free medium were determined. Shear stresses higher than 1 N m-2 and aeration rates higher than 0.04 vvm affect cell growth and when these conditions increase to 1.5 N m-2 and 0.11 vvm, cell growth is completely inhibited with significant cell morphology changes and a strong decrease in viability. Although the pO2 did not show a significant effect upon cell growth in the range from 10 to 50%, cell infection and specific productivity were dramatically affected. The production was optimal at a pO2 of 25% with decreases higher than 50% being observed when the pO2 decreased to 10 or increased to 50%. The maximum product quality, i.e., the percentage of product in the form of high molecular weight particles, is not coincident with maximum product titer. Although the highest Pr55gag particle titer was obtained at 96 hours post infection (hpi) and at pO2 of 25%, the best product quality (defined by gel filtration chromatography and Western immunoblot) was obtained at 48 hpi, independently of the pO2 used. The effect of overcritical conditions upon productivity was also studied. As obtained for cell growth, cell infection is affected by shear stresses above 1 N m-2 and by aeration rates higher than 0.04 vvm, with decreases in Pr55gag particle titer higher than 70%, even when the overcritical values are still far from the limit at which cell death occurs. The results obtained and the optimization strategy used allowed the maximization of the oxygen supply without damaging the cells, with important consequences on the scale-up of a production process involving this insect cell/baculovirus expression system. PMID- 10099447 TI - The synthesis of sub-micron magnetic particles and their use for preparative purification of proteins. AB - A novel one-step protocol for the preparation of sub-micron magnetic particles as small as 30 nm in diameter has been developed. The surface of the particles was functionalized with carboxyl groups ( approximately 1 COOH per 15A2) to facilitate the attachment of affinity ligands. The high surface area of the resulting beads, combined with the high density of functional groups on the surface, makes them ideally suited for the preparative purification of proteins as was demonstrated by the efficient isolation of trypsin (36 mg per gram of particles) from pancreatic extract. PMID- 10099448 TI - Probing the morphological developmental path of plant embryos by image tracking AB - An image analysis and pattern recognition system was applied to track the morphological changes of individual plant somatic embryos during the course of their development into mature embryos. A Fourier descriptor was used to transform the morphological information into quantitative features (Fourier features), which are amenable to mathematical and statistical analysis. At a given time point, the status of each developing embryo is represented by a point in the multidimension feature space spanned by these Fourier features. Connecting each point representing the individual embryos over time gives a trajectory which depicts the embryos' developmental "path" or history. Large variations in embryo development were observed, which is consistent with the population heterogeneity seen in batch embryo cultures. The rate at which each embryo progresses in the feature space was measured by a developmental vector. For embryos in a given class or developmental stage, the magnitude of the developmental vector exhibited a wide distribution. The results revealed that embryos with a higher developmental rate during the early stage of development had a higher chance of reaching the mature stage in a relatively short time. This single embryo tracking method is potentially a valuable tool in developing a correlation between the embryo's morphological features during the early stage of development and its eventual developmental fate. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099449 TI - Adsorptive control of water in esterification with immobilized enzymes: I. Batch reactor behavior. AB - Reducing the influence of an undesired product in an enzymatic reaction could have a significant impact on the productivity of such systems. Here, we focus on the removal of water formed during an enzymatic esterification in a batch reactor. A commercial immobilized lipase preparation, known as Lipozyme, is used as the biocatalyst and propionic acid and isoamyl alcohol dissolved in hexane are the substrates. In this system, the water formed will partition between the catalyst and the medium. As the more polar reactants are converted into the less polar ester product, the water is partitioned more towards the biocatalyst and the accumulation of water eventually causes lower reaction rates. Addition of a strong-acid cation exchange resin in sodium form is found to control the water accumulation on the biocatalyst without stripping the essential water needed for the enzyme to function and substantial improvements in conversion are achieved. A mathematical model is developed to describe the batch reaction behavior with and without added absorbent, which successfully predicts the behavior of water and its effects. PMID- 10099450 TI - Adsorptive control of water in esterification with immobilized enzymes: II. fixed bed reactor behavior. AB - Experimental and theoretical studies are conducted to understand the dynamic behavior of a continuous-flow fixed-bed reactor in which an esterification is catalyzed by an immobilized enzyme in an organic solvent medium. The experimental system consists of a commercial immobilized lipase preparation known as Lipozyme as the biocatalyst, with propionic acid and isoamyl alcohol (dissolved in hexane) as the reaction substrates. A complex dynamic behavior is observed experimentally as a result of the simultaneous occurrence of reaction and adsorption phenomena. Both propionic acid and water are adsorbed by the biocatalyst resulting in lower reaction rates. In addition, an excessive accumulation of water in the reactor leads to a rapid irreversible inactivation of the enzyme. A model based on previously-obtained adsorption isotherms and kinetic expressions, as well as on adsorption rate measurements obtained in this work, is used to predict the concentration and thermodynamic activity of water along the reactor length. The model successfully predicts the dynamic behavior of the reactor and shows that a maximum thermodynamic activity of water occurs at a point at some distance from the reactor entrance. A cation exchange resin in sodium form, packed in the reactor as a selective water adsorbent together with the catalyst particles, is shown to be an effective means for preventing an excessive accumulation of water formed in the reaction. Its use results in longer cycle times and greater productivity. As predicted by the model, the experimental results show that the water adsorbed on the catalyst and on the ion exchange resin can be removed with isoamyl alcohol with no apparent loss in enzyme activity. PMID- 10099451 TI - Production of D-phenylglycine from racemic (D,L)-phenylglycine via isoelectrically-trapped penicillin G acylase. AB - Penicillin G acylase (PGA) is exploited for producing pure D-phenylglycine from a racemate mixture, via an acylation reaction onto a cosubstrate, the ester methyl 4-hydroxyphenyl acetate. The reaction, when carried in a batch, is severely hampered by the reverse process, by which the product, 4-hydroxyphenylacetyl (L)phenyl glycine, upon consumption of L-phenylglycine, is converted by the enzyme back into free substrate and 4-hydroxyphenyl acetic acid via lysis of the amido bond. To prevent this noxious reaction, a multicompartment electrolyzer with isoelectric membranes (MIER) is used as enzyme reactor, operating in an electric field. PGA is trapped between pI 5.5 and pI 10.5 membranes, together with an amphoteric, isoelectric buffer (lysine). As the 4-hydroxyphenylacetyl (L)phenyl glycine product is formed, it vacates the reaction chamber by electrophoretic transport and is collected close to the anode, in a chamber delimited by pI 2.5 and 4.0 membranes. The same fate occurs to the free acid 4 hydroxyphenyl acetic acid, formed upon spontaneous (and enzyme-driven) hydrolysis of the methyl ester in the reaction chamber. These combined processes leave behind, in the enzyme reaction chamber, the desired product, pure D phenylglycine. The advantages of the MIER reactor over batch operations: the consumption of the L-form in the racemate is driven to completion and the enzyme is kept in a highly stable form, maintaining 100% activity after one day of operation, during which time the PGA enzyme, in the batch reactor, has already lost >75% catalytic activity. PMID- 10099452 TI - Local macromolecule diffusion coefficients in structurally non-uniform bacterial biofilms using fluorescence recovery after photobleaching (FRAP). AB - Pure culture Pseudomonas putida biofilms were cultivated under controlled conditions to a desired overall biofilm thickness, then employed within classical half-cell diffusion chambers to estimate, from transient solute concentrations, the effective diffusion coefficient for several macromolecules of increasing molecular weight and molecular complexity. Results of traditional half-cell studies were found to be erroneous due to the existence of microscopic water channels or crevasses that perforate the polysaccharidic gel matrix of the biofilm, sometimes completely to the supporting substratum. Thus, half-cell devices measure a composite transfer coefficient that may overestimate the true, local flux of solutes in the biofilm polysaccharide gel matrix. An alternative analytical technique was refined to determine the local diffusion coefficients on a micro-scale to avoid the errors created by the biofilm architectural irregularities. This technique is based upon the Fluorescence Return After Photobleaching (FRAP), which allows image analysis observation of the transport of fluorescently labeled macromolecules as they migrate into a micro-scale photobleached zone. The technique can be computerized and allows one to map the local diffusion coefficients of various solute molecules at different horizontal planes and depths in a biofilm. These mappings also indirectly indicate the distribution of water channels in the biofilm, which was corroborated independently by direct microscopic observation of the settling of fluorescently labeled latex spheres within the biofilm. Fluorescence return after photobleaching results indicate a significant reduction in the solute transport coefficients in biofilm polymer gel vs. the same value in water, with the reduction being dependent on solute molecule size and shape. PMID- 10099453 TI - Growth and energy metabolism in aerobic fed-batch cultures of Saccharomyces cerevisiae: simulation and model verification. AB - A kinetic model of overflow metabolism in Saccharomyces cerevisiae was used for simulation of aerobic fed-batch cultivations. An inhibitory effect of ethanol on the maximum respiration of the yeast was observed in the experiments and included in the model. The model predicts respiration, biomass, and ethanol formation and the subsequent ethanol consumption, and was experimentally validated in fed-batch cultivations. Oscillating sugar feed with resulting oscillating carbon dioxide production did not influence the maximum respiration rate, which indicates that the pyruvate dehydrogenase complex is not involved as a bottleneck causing aerobic ethanol formation. PMID- 10099454 TI - Start-up and the effect of gaseous ammonia additions on a biofilter for the elimination of toluene vapors. AB - Biotechnological techniques, including biofilters and biotrickling filters are increasingly used to treat air polluted with VOCs (Volatile Organic Compounds). In this work, the start-up, the effect of the gaseous ammonia addition on the toluene removal rate, and the problems of the heat accumulation on the performance of a laboratory scale biofilter were studied. The packing material was sterilized peat enriched with a mineral medium and inoculated with an adapted consortium (two yeast and five bacteria). Start-up showed a short adaptation period and an increased toluene elimination capacity (EC) up to a maximum of 190 g/m3/h. This was related to increased CO2 outlet concentration and temperature gradients between the packed bed and the inlet (Tm-Tin). These events were associated with the growth of the microbial population. The biofilter EC decreased thereafter, to attain a steady state of 8 g/m3/h. At this point, gaseous ammonia was added. EC increased up to 80 g/m3/h, with simultaneous increases on the CO2 concentration and (Tm-Tin). Two weeks after the ammonia addition, the new steady state was 30 g/m3/h. In a second ammonia addition, the maximum EC attained was 40 g/m3/h, and the biofilter was in steady state at 25 g/m3/h. Carbon, heat, and water balances were made through 88 d of biofilter operation. Emitted CO2 was about 44.5% of the theoretical value relative to the total toluene oxidation, but accumulated carbon was found as biomass, easily biodegradable material, and carbonates. Heat and water balances showed strong variations depending on EC. For 88 d the total metabolic heat was -181.2 x 10(3) Kcal/m3, and water evaporation was found to be 56.5 kg/m3. Evidence of nitrogen limitation, drying, and heterogeneities were found in this study. PMID- 10099455 TI - Inulase-secreting strain of Saccharomyces cerevisiae produces fructose. AB - The gene encoding inulase of the yeast Kluyveromyces marxianus (INU1Km) was cloned and expressed in the inulin-negative yeast Saccharomyces cerevisiae. Cells of S. cerevisiae transformed with the INU1Km gene have acquired extracellular inulase activity and were able to grow in the medium with inulin as a sole carbon source. The S. cerevisiae strain was constructed that is capable of heterologous expression of secreted K. marxianus inulase and is defective in fructose uptake due to null-mutations of the hexokinase structural genes HXK1 and HXK2. When grown in inulin-containing media, this strain is capable of accumulating at least 10% glucose-free fructose in the culture liquid. PMID- 10099456 TI - Acetate production from whey lactose using co-immobilized cells of homolactic and homoacetic bacteria in a fibrous-bed bioreactor. AB - Acetate was produced from whey lactose in batch and fed-batch fermentations using co-immobilized cells of Clostridium formicoaceticum and Lactococcus lactis. The cells were immobilized in a spirally wound fibrous sheet packed in a 0.45-L column reactor, with liquid circulated through a 5-L stirred-tank fermentor. Industrial-grade nitrogen sources, including corn steep liquor, casein hydrolysate, and yeast hydrolysate, were studied as inexpensive nutrient supplements to whey permeate and acid whey. Supplementation with either 2.5% (v/v) corn steep liquor or 1.5 g/L casein hydrolysate was adequate for the cocultured fermentation. The overall acetic acid yield from lactose was 0.9 g/g, and the productivity was 0.25 g/(L h). Both lactate and acetate at high concentrations inhibited the homoacetic fermentation. To overcome these inhibitions, fed-batch fermentations were used to keep lactate concentration low and to adapt cells to high-concentration acetate. The final acetate concentration obtained in the fed-batch fermentation was 75 g/L, which was the highest acetate concentration ever produced by C. formicoaceticum. Even at this high acetate concentration, the overall productivity was 0.18 g/(L h) based on the total medium volume and 1.23 g/(L h) based on the fibrous-bed reactor volume. The cells isolated from the fibrous-bed bioreactor at the end of this study were more tolerant to acetic acid than the original culture used to seed the bioreactor, indicating that adaptation and natural selection of acetate-tolerant strains occurred. This cocultured fermentation process could be used to produce a low cost acetate deicer from whey permeate and acid whey. PMID- 10099457 TI - Elevated glutamate dehydrogenase flux in glucose-deprived hybridoma and myeloma cells: evidence from 1H/15N NMR. AB - The glutamine metabolism was studied in glucose-starved and glucose-sufficient hybridoma and Sp2/0-Ag14 myeloma cells. Glucose starvation was attained by cultivating the hybridoma cells with fructose instead of glucose, and the myeloma cells with a low initial glucose concentration which was rapidly exhausted. Glutamine used in the experiments was labeled with 15N, either in the amine or in the amide position. The fate of the label was monitored by 1H/15N NMR analysis of released 15NH+4 and 15N-alanine. Thus, NH+4 formed via glutaminase (GLNase) could be distinguished from NH+4 formed via glutamate dehydrogenase (GDH). In the glucose-sufficient cells a small but measurable amount of 15NH+4 released by GDH could be detected in both cell lines (0.75 and 0.31 micromole/10(6) cells for hybridoma and myeloma cells, respectively). The uptake of glutamine and the total production of NH+4 was significantly increased in both fructose-grown hybridoma and glucose-starved myeloma cells, as compared to the glucose-sufficient cells. The increased NH+4 production was due to an increased throughput via GLNase (1.6 1.9-fold in the hybridoma, and 2.7-fold in the myeloma cell line) and an even further increased metabolism via GDH (4.8-7.9-fold in the hybridoma cells, and 3.1-fold in the myeloma cells). The data indicate that both GLNase and GDH are down-regulated when glucose is in excess, but up-regulated in glucose-starved cells. It was calculated that the maximum potential ATP production from glutamine could increase by 35-40 % in the fructose-grown hybridoma cells, mainly due to the increased metabolism via GDH. PMID- 10099459 TI - Malcolm lilly PMID- 10099458 TI - Use of dextrans as long and hydrophilic spacer arms to improve the performance of immobilized proteins acting on macromolecules. AB - New dextran-agarose supports, suitable for covalent immobilization of enzymes and proteins acting on macromolecular substrates, were prepared. The thick internal fibers of agarose gels were covered by a low-density layer of long, flexible, hydrophilic, and inert dextran molecules. Rennin and protein A were immobilized on these novel supports and the resulting derivatives exhibited a very high capacity for biological recognition of soluble macromolecular substrates. Caseinolytic activity of this immobilized enzyme was 15-fold higher than activity of directly immobilized rennin, through short spacer arms, on agarose gels. Similarly, the new derivatives of immobilized protein A were able to adsorb up to 2 molecules of immunoglobulin per each molecule of immobilized protein A. When the immobilized proteins were secluded away from the support surface by using these new long and hydrophilic spacer arms, they exhibit minimal steric hindrances that could be promoted by the proximity of the support surface. PMID- 10099460 TI - UCL biochemical engineering. PMID- 10099461 TI - Kinetic modeling of omega-transamination for enzymatic kinetic resolution of alpha-methylbenzylamine. AB - A kinetic model for omega-transaminase from Bacillus thuringiensis JS64 was developed by using the King-Altman method to simulate the kinetic resolution of alpha-methylbenzylamine (alpha-MBA). Starting from a ping-pong bi-bi mechanism, a complete kinetic model including substrate inhibition only in the reverse reaction (i.e., transamination between acetophenone and L-alanine) was developed. The asymmetric synthesis of (S)-alpha-MBA proved to be difficult due to a much lower maximum reverse reaction rate than the maximum forward reaction rate, thermodynamically exergonic forward reaction (i.e., transamination between (S) alpha-MBA and pyruvate), and the severe product and substrate inhibition of the reverse reaction. Experimental values for kinetic parameters show that the product inhibition constant of (S)-alpha-MBA is the most important parameter on determining the resolution reaction rate, suggesting that the resolution reaction rate will be very low unless (S)-alpha-MBA strongly inhibits the reverse reaction. Using the kinetic model, the kinetic resolution of alpha-MBA in aqueous buffer was simulated, and the simulation results showed a high degree of consistency with experimental data over a range of reaction conditions. Various simulation results suggest that the crucial bottleneck in the kinetic resolution of alpha-MBA lies mainly in the accumulation of acetophenone in reaction media as the reaction proceeds, whereas L-alanine exerts a little inhibitory effect on the reaction. The model predicts that removing acetophenone produced during the reaction can enhance the reaction rate dramatically. Indeed, the biphasic reaction system is capable of extracting acetophenone from the aqueous phase, showing a much higher reaction rate compared to a monophasic reaction system. The kinetic model was also useful in predicting the properties of other, better enzymes as well as the optimal concentrations of amino acceptor and enzyme in the resolution reaction. PMID- 10099462 TI - A proposed transient model for cometabolism in biofilm systems. AB - A dynamic model was developed to describe the behaviour of primary and secondary substrates in a biofilm reactor. The model incorporates structured kinetics to describe the generation and consumption of reducing power in the catabolic and respiratory subsystems, respectively. Secondary substrate transformation through oxygenolytic or reductive mechanisms can be modelled under either single or dual limitation of the electron donor and electron acceptor substrates. An example simulation of a theoretical biofilm system was performed. PMID- 10099463 TI - The expression of recombinant genes from bacteriophage lambda strong promoters triggers the SOS response in Escherichia coli. AB - The production of several non-related heterologous proteins in recombinant Escherichia coli cells promotes a significant transcription of recA and sfiA SOS DNA repair genes. The activation of the SOS system occurs when the expression of plasmid-encoded genes is directed by the strong lambda lytic promoters, but not by IPTG-controlled promoters either at 37 or at 42 degrees C, and it is linked to an extensive degradation of the proteins after their synthesis. The triggering signal for the SOS response could be an important arrest of cell DNA replication observed within the first hour after the induction of recombinant gene expression. The stimulation of this DNA repair system can partially account for the toxicity exhibited by recombinant proteins on actively producing E. coli cells. PMID- 10099464 TI - Double inhibition model for degradation of phenol by Pseudomonas putida Q5. AB - A semiempirical model, based on the presence of an inhibitory intermediate metabolite excreted to the broth, was developed to better predict the dynamic responses to shock loadings of Pseudomonas putida Q5 degrading phenol. Compared to the Haldane equation, the new model exhibited better prediction capabilities for a broad range of inlet concentration and dilution rate step changes. The experiments were performed at 10 degrees and 25 degrees C and ranged from stable responses to washouts. The time delays observed experimentally were successfully predicted with the dual-inhibition model and a very good agreement with the observed phenol profile also was found in a pulse experiment. A possible intermediate metabolite was detected by HPLC analyses based on the high correlation shown with the predicted inhibitory intermediate metabolite in the model. PMID- 10099465 TI - Preparation of a new thermo-responsive adsorbent with maltose as a ligand and its application to affinity precipitation. AB - A thermo-responsive polymer on which maltose was covalently immobilized as an affinity ligand was newly synthesized for purification of thermolabile proteins from the crude solution by affinity precipitation. Among the thermo-responsive polymers synthesized as carriers for adsorbent, poly(N-acryloylpiperidine) cysteamine (pAP) has a lower critical solution temperature (LCST) of around 4 degrees C, at which its solubility exhibits a sharp change. Adsorbent for affinity precipitation was prepared by combining pAP with maltose using trimethylamine-borane as a reducing reagent. This adsorbent (pAPM) obtained showed a good solubility response: pAPM in the basal buffer (pH 7.0) became soluble below 4 degrees C and was completely insoluble above 8 degrees C. The affinity precipitation method using pAPM consisted of the following four steps: adsorption at 4 degrees C, precipitation of the complex at 10 degrees C, desorption by adding the desorption reagent at 4 degrees C, and recovery of a target protein at 10 degrees C. In the affinity precipitation of Con A from the crude extract of jack bean meal, 82% of Con A added was recovered with 80% purity by addition of 0.2 M methyl-alpha-D-mannopyranoside as a desorption reagent. In the repeated purification of Con A from the crude extract, pAPM could be satisfactorily reused without decrease in the affinity performance. Moreover, when pAPM was used for the purification of thermolabile alpha-glucosidase from the cell-free extract of Saccharomyces cerevisiae, 68% of total activity added was recovered and the specific activity per amount of protein of the purified solution was enhanced 206-fold higher than that of the cell-free extract without thermal deactivation of the enzyme. PMID- 10099466 TI - Use of soybean oil and ammonium sulfate additions to optimize secondary metabolite production. AB - A valine-overproducing mutant (MA7040, Streptomyces hygroscopicus) was found to produce 1.5 to 2.0 g/L of the immunoregulant, L-683,590, at the 0.6 m3 fermentation scale in a simple batch process using soybean oil and ammonium sulfate-based GYG5 medium. Levels of both lower (L-683,795) and higher (HH1 and HH2) undesirable homolog levels were controlled adequately. This batch process was utilized to produce broth economically at the 19 m3 fermentation scale. Material of acceptable purity was obtained without the multiple pure crystallizations previously required for an earlier culture, MA6678, requiring valine supplementation for impurity control. Investigations at the 0.6 m3 fermentation scale were conducted, varying agitation, pH, initial soybean oil/ammonium sulfate charges, and initial aeration rate to further improve growth and productivity. Mid-cycle ammonia levels and lipase activity appeared to have an important role. Using mid-cycle soybean oil additions, a titer of 2.3 g/L of L 683,590 was obtained, while titers reached 2.7 g/L using mid-cycle soybean oil and ammonium sulfate additions. Both higher and lower homolog levels remained acceptable during this fed-batch process. Optimal timing of mid-cycle oil and ammonium sulfate additions was considered a critical factor to further titer improvements. PMID- 10099467 TI - Chinese hamster ovary cells with constitutively expressed sialidase antisense RNA produce recombinant DNase in batch culture with increased sialic acid. AB - Under some cell culture conditions, recombinant glycoprotein therapeutics expressed in Chinese hamster ovary (CHO) cells lose sialic acid during the course of the culture (Sliwkowski et al., 1992; Munzert et al., 1996). A soluble sialidase of CHO cell origin degrades the expressed recombinant protein and has been shown to be released into the culture fluid as the viability of the cells decreases. To reduce the levels of the sialidase and to prevent desialylation of recombinant protein, a CHO cell line has been developed that constitutively expresses sialidase antisense RNA. Several antisense expression vectors were prepared using different regions of the sialidase gene. Co-transfection of the antisense constructs with a vector conferring puromycin resistance gave rise to over 40 puromycin resistant clones that were screened for sialidase activity. A 5' 474 bp coding segment of the sialidase cDNA, in the inverted orientation in an SV 40-based expression vector, gave maximal reduction of the sialidase activity to about 40% wild-type values. To test if this level of sialidase would lead to increased sialic acid content of an expressed recombinant protein, the 474 antisense clone was employed as a host for expression of human DNase as a model glycoprotein. The sialic acid content of the DNase produced in the antisense cultures was compared with material made in the wild-type parental cell line. About 20-37% increase in sialic acid content, or 0.6-1.1 mole of additional sialic acid out of a total of 3.0 mole on the product, was found on the DNase made in the antisense cell lines. PMID- 10099468 TI - Monitoring recombinant human interferon-gamma N-glycosylation during perfused fluidized-bed and stirred-tank batch culture of CHO cells. AB - Chinese hamster ovary cells producing recombinant human interferon-gamma were cultivated for 500 h attached to macroporous microcarriers in a perfused, fluidized-bed bioreactor, reaching a maximum cell density in excess of 3 x 10(7) cells (mL microcarrier)-1 at a specific growth rate (mu) of 0.010 h-1. During establishment of the culture, the N-glycosylation of secreted recombinant IFN gamma was monitored by capillary electrophoresis of intact IFN-gamma proteins and by HPLC analysis of released N-glycans. Rapid analysis of IFN-gamma by micellar electrokinetic capillary chromatography resolved the three glycosylation site occupancy variants of recombinant IFN-gamma (two Asn sites occupied, one Asn site occupied and nonglycosylated) in under 10 min per sample; the relative proportions of these variants remained constant during culture. Analysis of IFN gamma by capillary isoelectric focusing resolved at least 11 differently sialylated glycoforms over a pI range of 3.4 to 6.4, enabling rapid quantitation of this important source of microheterogeneity. During perfusion culture the relative proportion of acidic IFN-gamma proteins increased after 210 h of culture, indicative of an increase in N-glycan sialylation. This was confirmed by cation-exchange HPLC analysis of released, fluorophore-labeled N-glycans, which showed an increase in the proportion of tri- and tetrasialylated N-glycans associated with IFN-gamma during culture, with a concomitant decrease in the proportion of monosialylated and neutral N-glycans. Comparative analyses of IFN gamma produced by CHO cells in stirred-tank culture showed that N-glycan sialylation was stable until late in culture, when a decline in sialylation coincided with the onset of cell death and lysis. This study demonstrates that different modes of capillary electrophoresis can be employed to rapidly and quantitatively monitor the main sources of glycoprotein variation, and that the culture system and operation may influence the glycosylation of a recombinant glycoprotein. PMID- 10099469 TI - Site-directed and random immobilization of subtilisin on functionalized membranes: activity determination in aqueous and organic media. AB - Kinetic comparisons have been made between a randomly immobilized and a site specifically immobilized subtilisin BPN' on microfiltration membranes of varying hydrophilicities in both aqueous and organic media. Site-directed mutagenesis was employed to introduce a single cysteine into the amino acid sequence of subtilisin at a location away from the active site. Immobilization of this mutant enzyme was then carried out using the single cysteine residue to orient the active site of the enzyme away from the membrane surface. Kinetic comparison of the immobilized mutant enzyme with the randomly immobilized wild-type enzyme in aqueous media showed an activity enhancement on both hydrophilic silica containing and hydrophobic poly(ether)sulfone membranes. Higher loading efficiencies were observed for the site-directed enzyme on immobilization. Optimal enzyme loading values were calculated for the randomly immobilized enzyme. An enhancement of activity was also observed for the site-directed immobilized systems using nearly anhydrous hexane as the solvent. PMID- 10099470 TI - Kinetic, dynamic, and pathway studies of glycerol metabolism by Klebsiella pneumoniae in anaerobic continuous culture: IV. Enzymes and fluxes of pyruvate metabolism. AB - The activities of pyruvate kinase (PK), pyruvate: formate-lyase (PFL), pyruvate dehydrogenase (PDH), and citrate synthase (CS) involved in the anaerobic glycerol conversion by Klebsiella pneumoniae were studied in continuous culture under conditions of steady states and sustained oscillations. Both the in vitro and in vivo activities of PK, PFL, and PDH are strongly affected by the substrate concentration and its uptake rate, as is the in vitro activity of CS. The flux from phosphoenolpyruvate to pyruvate is found to be mainly regulated on a genetic level by the synthesis rate of PK, particularly at low substrate concentration and low growth rate. In contrast, the conversion of pyruvate to acetyl-CoA is mainly regulated on a metabolic level by the in vivo activities of PFL and PDH. The ratio of in vitro to in vivo activities is in the range of 1 to 1.5 for PK, 5 to 17 for PFL and 5 to 80 for PDH under the experimental conditions. The regulation of in vivo activity and synthesis of these enzymes is sensitive to fluctuations of culture conditions, leading to oscillations of both the in vitro and in vivo activities. In particular, PFL is strongly affected during oscillations; its average in vitro activity is only about half of its corresponding steady-state value under similar environmental conditions. The average in vitro activities of PDH and PK under oscillations are close to their corresponding steady-state values. In contrast to all other enzymes measured for the glycerol metabolism by K. pneumoniae PFL and PDH are more effectively in vivo utilized under oscillations than under steady state, underlining the peculiar role of pyruvate metabolism in the dynamic responses of the culture. PMID- 10099471 TI - Hydrodynamic characteristics and gas-liquid mass transfer in a biofilm airlift suspension reactor. AB - The hydrodynamics and mass transfer, specifically the effects of gas velocity and the presence and type of solids on the gas hold-up and volumetric mass transfer coefficient, were studied on a lab-scale airlift reactor with internal draft tube. Basalt particles and biofilm-coated particles were used as solid phase. Three distinct flow regimes were observed with increasing gas flow rate. The influence of the solid phase on the hydrodynamics was a peculiar characteristic of the regimes. The volumetric mass transfer coefficient was found to decrease with increasing solid loading and particle size. This could be predominantly related to the influence that the solid has on gas hold-up. The ratio between gas hold-up and volumetric mass transfer coefficient was found to be independent of solid loading, size, or density, and it was proven that the presence of solids in airlift reactors lowers the number of gas bubbles without changing their size. To evaluate scale effects, experimental results were compared with theoretical and empirical models proposed for similar systems. PMID- 10099472 TI - Flotation characteristics of cyanobacterium Anabaena flos-aquae for gas vesicle production. AB - Cyanobacterium Anabaena flos-aquae was cultivated in photobioreactors for production of intracellular gas vesicles (GVs), as potential oxygen microcarriers. Natural flotation of the buoyant culture was investigated as a potential means of cell harvesting, because filtration and centrifugation tended to destroy the vesicles. Best flotation was found with actively growing culture and when conducted in the dark. The flotation-related cell properties, including the specific GV content, vesicle-collapsed filament density, and intracellular carbohydrate content, were measured to understand the phenomena. During the batch culture, the specific GV content remained relatively constant at 370 microL/(g dry cells) but the filament density (ranging 1.02 to 1.08 g/cm3) showed a decrease-then-increase profile. The increase began when the growth slowed down because of the reduced light availability at high cell concentrations. The dark flotation was studied with both actively growing (mu approximately 0.2 day-1) and stationary-phase cultures. The specific GV content of the stationary-phase culture remained relatively constant while that of the growing culture increased slightly. The intracellular carbohydrate content of the growing culture decreased much faster and more significantly, from 57 to 10 mg/(g dry cells) in 80% pure, and were utilized directly for high throughput screening in antibacterial assays. Several active wells were found, and the activity was verified by solution-phase synthesis of analytically pure material, indicating that the system described herein is an efficient means for the parallel synthesis of compounds for lead discovery. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099495 TI - Genetic optimization of combinatorial libraries AB - Most agrochemical and pharmaceutical companies have set up high-throughput screening programs which require large numbers of compounds to screen. Combinatorial libraries provide an attractive way to deliver these compounds. A single combinatorial library with four variable positions can yield more than 10(12) potential compounds, if one assumes that about 1000 reagents are available for each position. This is far more than any high-throughput screening facility can afford to screen. We have proposed a method for iterative compound selection from large databases, which identifies the most active compounds by examining only a small fraction of the database. In this article, we describe the extension of this method to the problem of selecting compounds from large combinatorial libraries. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099496 TI - Analysis of 9-fluorenylmethoxycarbonyl (FMOC) loading of solid-phase synthesis resins by gas chromatography AB - Base-catalyzed cleavage of the 9-fluorenylmethoxycarbonyl (FMOC) group and subsequent analysis by UV spectrophotometry is commonly employed to measure the "loading" of functional groups on solid support. Recent work suggests that 1,8 diazabicyclo[5.4. 0]undec-7-ene (DBU) may be superior to piperidine (the most commonly used base for the cleavage) for quantitative analysis by UV. We have compared deprotection of FMOC-bearing compounds by both DBU and piperidine, and have observed by GC-MS the formation of a dibenzofulvene-piperidine adduct (piperidine deprotection), and the formation of unassociated dibenzofulvene (DBU deprotection). We have further been able to use GC analysis of dibenzofulvene produced in the DBU deprotection mixture in a quantitative analysis of resin loading, which gave results comparable to UV methods. Sample preparation for this method has been automated using the Nautilus 2400 organic synthesizer to reduce the amount of operator time and increase throughput of sample analysis. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099497 TI - High-throughput screening of historic collections: observations on file size, biological targets, and file diversity. AB - At Pfizer Central Research, high-throughput screening has been an important source of new leads for drug discovery for a decade. Our experience with over 150 high-throughput screens can address questions about necessary file size, how well particular biological targets fare (with particular reference to protein-protein interactions), and what file diversity means in practice. PMID- 10099498 TI - Patents in combi-space: patent challenges in combinatorial chemistry AB - Patent protection of inventions relating to combinatorial chemistry is attended by special challenges. The "breakthrough" nature of the field together with the always complex and often arcane chemical manipulations, apparatus, and strategies which suffuse this field make it difficult to describe the inventions adequately. It can be a challenge to communicate effectively with official authorities charged with patent examination. Extraordinary effort is called for in clarifying such inventions such that their patentability can be appreciated. The utility of some types of inventions in this field may be open to question; clear statements of at least one acceptable utility-even if only a minor utility-is beneficial. Because a principal product of many aspects of combinatorial chemistry is information, e.g., the identification of a lead compound, offshore "piracy" is a risk. Domestic claim tie-ins may improve the ability to abate such piracy. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099499 TI - Solid-phase synthesis supports are like solvents PMID- 10099500 TI - Novel non-viral vectors for gene delivery: synthesis of a second-generation library of mono-functionalized poly-(guanidinium)amines and their introduction into cationic lipids. AB - The development of new gene delivery technologies is a prerequisite towards gene therapy clinical trials. Because gene delivery mediated by viral vectors remains of limited scope due to immunological and propagation risks, the development of new non-viral gene delivery systems is of crucial importance. We have synthesized a secondary library of mono-functionalized poly-(guanidinium)amines generated from a library of mono-functionalized polyamines applying the concept of "libraries from libraries." The method allows a quick and easy access to mono functionalized geometrically varied poly-(guanidinium)amines. The new building blocks were introduced into cationic lipids to obtain novel poly (guanidinium)amine lipids, which are potential DNA vectors for gene delivery. PMID- 10099501 TI - Development of chloromethylated SynPhasetrade mark crowns and their use in Pd(0) mediated cross-coupling reactions AB - We report the convenient generation of chloromethylated polystyrene surfaces (Merrifield linker)3 on SynPhasetrade mark crowns. It was demonstrated that these novel surfaces can be successfully employed for peptide chemistry as well as Pd(0) mediated cross-couplings. Copyright 1998 John Wiley & Sons, Inc. PMID- 10099502 TI - A novel parallel distributor for dispensing of IRORItrade mark RF-encoded tags to microkans in 96-well format AB - A novel parallel radio-frequency (RF) tag distributor has been developed which allows for distribution of RF tags into Irori microkans in 96-well format. The distributor has a holding capacity of approximately 1000 RF tags and distributes RF tags in groups of 12. Using the distributor, a block of 96 microkans can be filled with RF tags in less than 30 sec resulting in significant time savings over one-at-a-time manual RF tag distribution. The distributor may also be of utility as a solid-phase synthesis tool for dispensing resin enclosed in capsules (which have the same shape as RF tags). Copyright 1998 John Wiley & Sons, Inc. PMID- 10099503 TI - Solution-phase library generation: methods and applications in drug discovery. AB - Solution-phase high throughput synthesis has emerged as a powerful method for the rapid generation of chemical libraries. The success of this approach is largely due to the development of novel synthetic methodologies that expedite the preparation of compounds. Several isolation/purification techniques have also been developed to eliminate the time-consuming purification procedures often associated with solution-phase chemistry. These methods are amenable to parallel synthesis and combinatorial strategies and can be fully automated. In addition, the compound libraries generated using solution-phase high throughput synthesis have been used to accelerate both lead identification and lead optimization programs at various companies. PMID- 10099504 TI - Are porphyrin mixtures favorable photodynamic anticancer drugs? A model study with combinatorial libraries of tetraphenylporphyrins. AB - Reported here is the preparation of tetraphenylporphyrin libraries via efficient combinatorial solution-phase syntheses, their purification, and preliminary results from a bioorganic study on their uptake in liposome membranes. Libraries with up to 666 components were prepared with substituents including Br, CF3, Cl, CN, CO2Me, Et, F, OAc, and Ph. Further, a first example for the synthesis of more diverse libraries via a "latent libraries" approach is presented. This involves masking polar groups with lipophilic protecting groups. After purification of the latent library, the masking protecting groups are removed in a quantitative reaction that produces the library compounds as the only non-volatile components. Libraries were characterized by laser desorption time-of-flight mass spectrometry, NMR, and UV-vis spectroscopy. In vitro uptake into membranes of small sonicated liposomes was measured, both in terms of total porphyrin incorporation and in terms of structure-incorporation relationships. The latter were determined from isotopically-resolved laser-desorption mass spectra under conditions that yield quantitative results. Smaller libraries showed increased uptake of porphyrins bearing OH and CF3 substituents and lower uptake of ester-, alkyl-, and halide-bearing porphyrins. This structure-dependent selectivity disappears for larger libraries, however, where uniformly high uptake is observed, i.e., at a constant lipid:porphyrin ratio the total porphyrin incorporation is higher for libraries than for single compounds of similar polarity. We propose that the decreased concentration of individual compounds in large libraries is responsible for this effect. Membrane incorporation has previously been shown to correlate with photodynamic activity in vitro and in vivo.16 Therefore, these results may help to explain why photodynamic therapy of tumors, a modern anti-cancer treatment modality, is successfully performed with a complex mixture of porphyrins. PMID- 10099505 TI - Solution-phase simultaneous addition of functionalities (SPSAF) and chemical transformation to prepare N,N'-disubstituted piperazine libraries. AB - Several piperazine libraries were prepared using solution phase simultaneous addition of functionalities methodology as well as the "library from library" concept. The resulting piperazine libraries displayed antimicrobial activity against both gram-positive and gram-negative bacteria. PMID- 10099506 TI - Applications of mass spectrometry in combinatorial chemistry. AB - This article describes the use of two mass spectrometric techniques, matrix assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) mass spectrometry, toward a variety of challenging problems in drug discovery and identification. Quantitative ESI was used to screen for inhibitor activity of two different enzymatic glycosylation reactions resulting in the identification of the most effective inhibitors and the determination of their IC50 (inhibitor concentration at 50% inhibition). Also described is a combinatorial extraction method used with automated MALDI mass spectrometry to improve upon the clinical analysis of the immunosuppressant drug cyclosporin A (CsA). Optimization was performed by generating an array of solvent systems which were screened (by MALDI MS) for the most efficient extraction of CsA from whole blood. Ultimately a 70/30 hexane:CHCl3 mixture was identified as the most efficient binary solvent system for such extractions. In addition it was demonstrated that peptides and carbohydrates, covalently linked to a polymeric support (through a photolabile linker), can be directly analyzed by MALDI in a single step which requires no pretreatment of the sample to induce cleavage from the support. The UV laser light in the MALDI experiment was used to simultaneously promote the analyte's photolytic cleavage from the solid support and its gas phase ionization for subsequent mass spectral analysis. Overall, the strength of mass spectrometry lies in its versatility, making it a powerful analytical technique with which to characterize the diversity of compounds found in combinatorial libraries. PMID- 10099507 TI - Kinetics and modeling of autotrophic thiocyanate biodegradation. AB - The biokinetic parameters for autotrophic systems are difficult to obtain and are often mistakenly determined because the size of the autotrophic population in mixed (i.e., heterotrophic and autotrophic) cultures cannot be accurately estimated. This article presents a systematic approach, combining bioenergetic calculations and experimental data, to obtain values of the biokinetic parameters pertinent to the aerobic, autotrophic biodegradation of thiocyanate. Nonlinear regression techniques were employed using both initial thiocyanate utilization rate data and single thiocyanate depletion curves. Both types of data were necessary to overcome the problems arising from the linear nature of the substrate depletion curves and the high correlation of the biokinetic model parameters inherent in nonlinear regression analysis. The aerobic biodegradation of thiocyanate followed a substrate inhibition pattern that was successfully described by the Haldane-Andrews model. Although regression analysis did not yield unique biokinetic parameter estimates, the following parameter value ranges were obtained: maximum specific substrate utilization rate (k), 0.26 to 0.44 mg SCN-/mg biomass h; half-saturation coefficient (Ks), 2.3 to 7.1 mg SCN-/L; and inhibition coefficient (Ki), 28 to 109 mg SCN-/L. Based on the estimated biokinetic parameter values, a design and operation diagram was constructed that depicts the steady-state thiocyanate concentration as a function of solids retention time for a completely mixed, continuous-flow reactor. PMID- 10099508 TI - Production of reovirus type-1 and type-3 from Vero cells grown on solid and macroporous microcarriers. AB - Two strains of reovirus were propagated in Vero cells grown in stationary or microcarriers cultures. Vero cells grown as monolayers on T-flasks or in spinner cultures of Cytodex-1 or Cultispher-G microcarriers could be infected with reovirus serotype 1, strain Lang (T1L), and serotype 3, strain Dearing (T3D). A regime of intermittent low speed stirring at reduced culture volume was critical to ensure viral infection of cells in microcarrier cultures. The virus titre increased by 3 to 4 orders of magnitude over a culture period of 150 h. Titres of the T3D reovirus strain were higher (43%) compared to those of the T1L strain in all cultures. Titres were significantly higher in T-flask and Cytodex-1 microcarrier cultures compared to Cultispher-G cultures with respect to either reovirus type. The viral productivity in the microcarrier cultures was dependent upon the multiplicity of infection (MOI) and the cell/bead ratio at the point of infection. A combination of high MOI (5 pfu/cell) and high cell/bead loading (>400 for Cytodex-1 and >1,000 for Cultispher-G) resulted in a low virus productivity per cell. However, at low MOI (0.5 pfu/cell) the virus productivity per cell was significantly higher at high cell/bead loading in cultures of either microcarrier type. The maximum virus titre (8.5 x 10(9) pfu/mL) was obtained in Cytodex-1 cultures with a low MOI (0.5 pfu/cell) and a cell/bead loading of 1,000. The virus productivity per cell in these cultures was 4,000 pfu/cell. The lower viral yield in the Cultispher-G microcarrier cultures is attributed to a decreased accessibility of the entrapped cells to viral infection. The high viral productivity from the Vero cells in Cytodex-1 cultures suggests that this is a suitable system for the development of a vaccine production system for the Reoviridae viruses. PMID- 10099509 TI - Kinetic studies on the enzyme (S)-hydroxynitrile lyase from hevea brasiliensis using initial rate methods and progress curve analysis AB - (S)-Hydroxynitrile lyase (EC 4.1.2.39) from Hevea brasiliensis(rubber tree) catalyzes the reversible cleavage of cyanohydrins to aldehydes or ketones and prussic acid (HCN). Enzyme kinetics in both directions was studied on a model system with mandelonitrile, benzaldehyde, and HCN using two different methods initial rate measurements and progress curve analysis. To discriminate between possible mechanisms with the initial rate method, product inhibition was studied. Benzaldehyde acts as a linear competitive inhibitor against mandelonitrile whereas HCN shows S-linear I-parabolic mixed-type inhibition. These results indicate an Ordered Uni Bi mechanism with the formation of a dead-end complex of enzyme, (S)-mandelonitrile and HCN. Prussic acid is the first product released from the enzyme followed by benzaldehyde. For progress curve analysis, a kinetic model of an Ordered Uni Bi mechanism including a dead-end complex, enzyme inactivation, and the chemical parallel reaction was set up, which described the experimental values very well. From the reaction rates obtained the kinetic constants were calculated and compared with the ones obtained from the initial rate method. Good agreement could be achieved between the two methods supporting the suggested mechanism. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099510 TI - Design of reactive porous polymer supports for high throughput bioreactors: poly(2-vinyl-4,4-dimethylazlactone-co-acrylamide- co-ethylene dimethacrylate) monoliths. AB - Enzymatic bioreactors with both high flow characteristics and mechanical stability based on macroporous poly(2-vinyl-4, 4-dimethylazlactone-co-acrylamide co-ethylene dimethacrylate) monoliths have been prepared. Covalent immobilization of trypsin on these support is achieved in a single reaction step using the azlactone functional groups. Optimization of hydrophilic/hydrophobic properties of the monolith affords a support that does not shrink in water and leads to immobilized enzyme that shows high activity in the hydrolysis of both low and high molecular weight substrates such as L-benzoyl arginine ethyl ester and casein. The catalytic activity of the monolithic reactor is maintained even at a flow velocity of 180 cm/min, which substantially exceeds those reported in the literature for packed bed reactors. PMID- 10099511 TI - Modeling of enzymatic reactions in vesicles: the case of alpha-chymotrypsin. AB - The kinetic behavior of the alpha-chymotrypsin-catalyzed hydrolysis of the two p nitroanilide substrates succinyl-L-Ala-L-Ala-L-Pro-L-Phe-p-nitroanilide (Suc-Ala Ala-Pro-Phe-pNA) and benzoyl-L-Tyr-p-nitroanilide (Bz-Tyr-pNA) was modeled and simulated for two different systems, namely for an aqueous solution and for a vesicle system, which was composed of phospholipid vesicles containing entrapped alpha-chymotrypsin. In the case of the vesicles, the substrate was added to the bulk, exovesicular aqueous phase. The experimentally determined time-dependence of product (p-nitroaniline) formation was modeled by considering the kinetic behavior of the enzyme and-in the case of vesicles-the substrate permeability across the bilayer membrane. In aqueous solution-without vesicles-the kinetic constants kcat and KS (respectively KM) were determined from fitting the model to experimental data of batch product concentration-time curves. The results were in good agreement with the corresponding values obtained from initial velocity measurements. For the vesicle system, using the phospholipid 1-palmitoyl-2-oleoyl sn-glycero-3-phosphocholine (POPC), simulation showed that the substrate permeation across the bilayer was rate limiting. Using experimental data, we could obtain the substrate permeability coefficient for Bz-Tyr-pNA by parametric fitting as 2. 45 x 10(-7) cm/s. PMID- 10099512 TI - A patch coating method for preparing biocatalytic films of Escherichia coli. AB - A method has been developed for immobilizing viable but nongrowing Escherichia coli in highly uniform patches. The patches consist of a thin layer of bacteria in acrylate vinyl acetate covered with a thin layer of the same polymer devoid of bacteria and sealed by the edges. This method permits study of immobilized cell physiology in biocatalytic films by the assay methods used for suspended cells. Large numbers of patches of immobilized E. coli can be generated on metal or polyester sheets. Those described here are 12.7 mm in diameter; in them the cell layer is 30 microm thick and contains more than 5 x 10(8) viable cells. The method allows the cell-plus-polymer layer and the polymer sealant to be varied in thickness from 5 to 60 microm and from 7 to 80 microm, respectively. No leakage of cells was detected from 87% of the patches during 15 days of rehydration. Culturability of the immobilized cells, released by shaking the cells out of the porous polymer layer, was 80% of pre coating culturability. E. coli beta galactosidase activity and measurements of total RNA and DNA from immobilized and suspended cells indicated that cells immobilized in the thin polymer layer have higher specific beta-galactosidase activity and a slower total RNA degradation rate than suspended cells over 15 days. PMID- 10099513 TI - Mixed-valence compound-based biosensor. AB - A cobalt(II)hexacyanoferrate-based biosensor has been prepared simply by codeposition of an enzyme, together with the electrochemical formation of a cobalt (II)hexacyanoferrate compound electrochemically. The compound can be generated at a constant potential of -0.05 V (vs. Ag/AgCl). This compound possesses the catalytic property of reducing hydrogen peroxide to water at the operating potential of 0.0 V vs. Ag/AgCl. The mixed-valence compound-based biosensor possesses an unique interference-independent feature, which is important for biomedical application; this feature is attributed to the low overvoltage characteristic of cobalt (II)hexacyanoferrate. The electrochemical glucose biosensor responds to a series of glucose injections with linearity up to 5 mM (with correlation coefficient R = 0.9999) and the sensitivity of the linear portion is 733 nA/(cm2 x mM). The detection limit is 2 x 10(-6)M (S/N = 3). Both the potential-dependent electron transfer rate constant and the apparent Michaelis-Menten constant were studied in rotating disk experiments. The apparent Michaelis-Menten constant, Km' calculated from the slope of the "Lineweaver Burke" type reciprocal plot is 28 mM. A fast-response characteristic is observed in the rotating disk experiment and the 95% response time is 14.5 sec. No response was observed from the addition of either 2 x 10(-4)M galactose, acetaminophen, ascorbic acid, uric acid, cysteine, tyrosine, dopamine, or 1,4 dihydroxyquinone in the absence and/or in the presence of 5 x 10(-4)M glucose. PMID- 10099514 TI - Terminal settling velocity and bed-expansion characteristics of biofilm-coated particles. AB - Fluid dynamic behavior of biofilm-coated particles in ambient water has been investigated. New experimental results are presented and compared with published data. From experimental measurements of the single particle terminal settling velocity the corresponding drag coefficient was found to be larger (by a factor of 1.6) than that for a smooth, rigid sphere at the same Reynolds number. A new simple correlation describing this finding is suggested. For multiparticle systems the Richardson-Zaki equation, derived empirically for rigid particles, provided a satisfactory description of biological beds. Of the two numerical parameters characterizing the expansion law, i. e. the slope n and the extrapolation to voidage equal one ui, the first was found to be similar to that suggested by Richardson and Zaki (1954), whereas ui gave results smaller than the single-particle terminal settling velocity, in contrast with the mentioned work but in agreement with more recently published behavior. PMID- 10099515 TI - Prediction of dissolved oxygen and carbon dioxide concentration profiles in tubular photobioreactors for microalgal culture AB - A model is developed for prediction of axial concentration profiles of dissolved oxygen and carbon dioxide in tubular photobioreactors used for culturing microalgae. Experimental data are used to verify the model for continuous outdoor culture of Porphyridium cruentum grown in a 200-L reactor with 100-m long tubular solar receiver. The culture was carried out at a dilution rate of 0.05 h-1 applied only during a 10-h daylight period. The quasi-steady state biomass concentration achieved was 3.0 g. L-1, corresponding to a biomass productivity of 1.5 g. L-1. d-1. The model could predict the dissolved oxygen level in both gas disengagement zone of the reactor and at the end of the loop, the exhaust gas composition, the amount of carbon dioxide injected, and the pH of the culture at each hour. In predicting the various parameters, the model took into account the length of the solar receiver tube, the rate of photosynthesis, the velocity of flow, the degree of mixing, and gas-liquid mass transfer. Because the model simulated the system behavior as a function of tube length and operational variables (superficial gas velocity in the riser, composition of carbon dioxide in the gas injected in the solar receiver and its injection rate), it could potentially be applied to rational design and scale-up of photobioreactors. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099516 TI - High-level secretory production of intact, biologically active staphylokinase from Bacillus subtilis. AB - Staphylokinase is a promising blood-clot dissolving agent for the treatment of patients suffering from a heart attack. It would be desirable to produce this protein in large quantities for biochemical characterization and clinical trials. Production of intact, biologically active staphylokinase from bacterial expression systems has been a challenge because of N-terminal microheterogeneity, plasmid instability, or low-production yield. By using a seven-extracellular protease deficient Bacillus subtilis strain, WB700, intact staphylokinase can be produced via secretion. However, native staphylokinase gene (sak) in a high-copy number plasmid was found to be unstable in B. subtilis. To optimize the production and the stability of the expression vectors, both the promoter and the signal sequence of sak were replaced by B. subtilis promoters (P43, a constitutively expressed promoter; Pamy, a stationary-phase promoter; and PsacB, a sucrose-inducible promoter) and the levansucrase-signal sequence, respectively. This overcame the plasmid instability problem. To enhance transcription from the sacB promoter, degQ encoding a transcriptional activator for sacB and other protease genes was also installed in the expression vector. The use of WB700 as the expression host allowed enhanced production of staphylokinase from the sucrose-inducible plasmid without causing any obvious degradation of staphylokinase. Both the P43 and PsacB (with DegQ) promoters worked well. Over 90% of staphylokinase synthesized can be secreted effectively. With the optimization of both the culture media and the fermentation conditions, production of staphylokinase reached a level of 337 mg/L, and staphylokinase could be purified to homogeneity by a simple three-step purification scheme. Secreted staphylokinase did not show any N-terminal heterogeneity. This presents an attractive system for the production of staphylokinase in both high quality and quantity. PMID- 10099517 TI - The kinetics of taxoid accumulation in cell suspension cultures of Taxus following elicitation with methyl jasmonate. AB - Cell suspension cultures of Taxus canadensis and Taxus cuspidata rapidly produced paclitaxel (Taxol) and other taxoids in response to elicitation with methyl jasmonate. By optimizing the concentration of the elicitor, and the timing of elicitation, we have achieved the most rapid accumulation of paclitaxel in a plant cell culture, yet reported. The greatest accumulation of paclitaxel occurred when methyl jasmonate was added to cultures at a final concentration of 200 microM on day 7 of the culture cycle. The concentration of paclitaxel increased in the extracellular (cell-free) medium to 117 mg/day within 5 days following elicitation, equivalent to a rate of 23.4 mg/L per day. Paclitaxel was only one of many taxoids whose concentrations increased significantly in response to elicitation. Despite the rapid accumulation and high concentration of paclitaxel, its concentration never exceeded 20% of the total taxoids produced in the elicited culture. Two other taxoids, 13-acetyl-9-dihydrobaccatin III and baccatin VI, accounted for 39% to 62% of the total taxoids in elicited cultures. The accumulation of baccatin III did not parallel the pattern of accumulation for paclitaxel. Baccatin III continued to accumulate until the end of the culture cycle, at which point most of the cells in the culture were dead, implying a possible role as a degradation product of taxoid biosynthesis, rather than as a precursor. PMID- 10099518 TI - A tunable switch to regulate the synthesis of low and high molecular weight microbial polyesters. AB - The addition of poly(ethylene glycol) (Mn = 200 g/mol) (PEG-200) to the fermentation media of Alcaligenes eutrophus and Alcaligenes latus at various stages of growth resulted in the synthesis of poly(3-hydroxybutyrate) (PHB) with bimodal molecular weight distributions. The presence of 2% w/v-PEG-200 did not have deleterious effects on PHB volumetric yields and cell productivity. In general, the Mn values of the high (H) and low (L) fractions showed little variability as a function of the time at which PEG-200 was added to the cultures. By this approach, the H:L ratios (w/w) of the PHB synthesized by A. eutrophus and A. latus were varied from 9:91 to 76:24 and from 16:84 to 88:12, respectively. It is believed that the H fractions were formed prior to the addition of PEG-200 to the cultures. Also, once PEG-200 was made available to the cells, PEG-200 acted as a switch so that the reduced molecular weight fraction was formed. In addition, a necessary requirement for the above is that the frequency of transesterification reactions during polymer synthesis was small. The efficiency that PEG-200 reduced the molecular weight of the PHBs formed by both bacteria appears similar. Indirect evidence suggests that the PHB L fractions formed by A. latus subsequent to PEG-200 addition consist primarily of chains that have PEG terminal groups. This terminal chain structure was not observed for PHB formed by A. eutrophus. PMID- 10099519 TI - Decolorization of molasses and a dye by a newly isolated strain of the fungus Geotrichum candidum Dec 1. AB - A fungus, Geotrichum candidum Dec 1, newly isolated as a dye-decolorizing microorganism, was used to decolorize molasses and an anthraquinone dye in shaken flasks. A degree of decolorization of molasses of 87% was achieved after 12 days of cultivation, and the maximum rate of decolorization of the dye in the culture broth was obtained in 7 days. The apparent activity of peroxidase in the molasses, which is responsible for dye decolorization, was significantly lower than that of purified peroxidase, due to the inhibition by molasses, but the inhibition was reduced after the fungus was fully grown. As two ultrafiltered fractions of molasses were similarly decolorized by Dec 1, Dec 1 apparently degraded colored substances of a wide range of molecular weights. When Dec 1 was cultivated in a medium in which sucrose in the molasses was hydrolyzed with invertase, the degree of decolorization of molasses, and rate of decolorization of the dye were similar to these obtained above. PMID- 10099520 TI - Application of hypoosmolar medium to fed-batch culture of hybridoma cells for improvement of culture longevity. AB - Cell culture longevity in fed-batch culture of hybridomas is often limited by elevated medium osmolality caused by repeated nutrient feeding. Shotwise feeding of 10x Dulbecco's modified Eagle's medium (DMEM) concentrates elevated the osmolality of medium up to 540 mOsm/kg at the end of fed-batch culture of S3H5/gamma2bA2 hybridoma which is known to be lethal to most hybridomas. S3H5/gamma2bA2 hybridoma has been shown to grow without significant growth depression at 219 mOsm/kg in DMEM supplemented with 10% fetal bovine serum. To improve culture longevity in fed-batch cultures of S3H5/gamma2bA2 hybridoma, a hypoosmolar medium (223 mOsm/kg) was used as an initial basal medium. The use of hypoosmolar medium delayed the onset of severe cell death resulting from elevated osmolality and allowed one more addition of 10x DMEM concentrates to the culture. As a result, a final antibody concentration obtained was 121.5 microg/mL which is approximately 1.5-fold higher compared to fed-batch culture using a standard medium (335 mOsm/kg). When compared to batch culture, a more than 5-fold increase in the final antibody concentration was achieved. Taken together, the use of hypoosmolar medium as an initial medium in fed-batch culture improved culture longevity of S3H5/gamma2bA2 hybridoma, resulting in a substantial increase in the final antibody concentration. PMID- 10099521 TI - Understanding the influence of temperature change and cosolvent addition on conversion rate of enzymatic suspension reactions based on regime analysis. AB - It is a commonly held belief that enzymatic conversions of substrate in aqueous suspensions can be speeded up by raising the temperature or adding organic solvents to promote dissolution of the substrate. To quantify the impact of such changes, we studied the alpha-chymotrypsin-catalyzed hydrolysis of dimethyl benzylmethylmalonate as a model system. It was found that, upon addition of organic cosolvents, longer process times were actually required, even though the substrate solubility increased severalfold as expected. Upon raising the temperature from 25 degrees C to 37 degrees C, on the other hand, both the substrate solubility, the substrate dissolution rate, and the enzymatic reaction rate increased, leading to shorter process times. A dissolution-reaction model incorporating the kinetics of enzyme deactivation could be developed. A simple relation for the prediction of the overall process time was established by evaluating the time constants for the subprocesses: substrate dissolution; enzymatic conversion; and enzyme deactivation. Using regime analysis, rules of thumb for the optimization of an enzymatic suspension reaction were derived. PMID- 10099522 TI - Genetic engineering of protein-peptide fusions for control of protein partitioning in thermoseparating aqueous two-phase systems. AB - Genetic engineering has been used for the fusion of peptides, with different length and composition, on a protein to study the effect on partitioning in aqueous two-phase systems containing thermoseparating polymers. Peptides containing 2-6 tryptophan residues or tryptophan plus 1-3 lysine or aspartate residues, were fused near the C-terminus of the recombinant protein ZZT0, where Z is a synthetic IgG-binding domain derived from domain B in staphylococcal protein A. The partitioning behavior of the peptides and fusion proteins were studied in an aqueous two-phase system composed of dextran and the thermoseparating ethylene oxide-propylene oxide random copolymer, EO30PO70. The zwitterionic compound beta alanine was used to reduce the charge-dependent salt effects on partitioning, and to evaluate the contribution to the partition coefficient from the amino acid residues, Trp, Lys, and Asp, respectively. Trp was found to direct the fusion proteins to the EO-PO copolymer phase, while Asp and Lys directed them to the dextran phase. The effect of sodium perchlorate and triethylammonium phosphate on the partitioning of the fusion proteins was also studied. Salt effects were directly proportional to the net charge of the fusion proteins. Sodium perchlorate was found to be 3.5 times more effective in directing positively charged proteins to the EO-PO copolymer phase compared to the effect of triethyl ammonium phosphate on negatively charged proteins. An empirical correlation has been tested where the fusion protein partitioning is a result of independent contributions from unmodified protein, fused peptide, and salt effects. A good agreement with experimental data was obtained which indicates the possibility, by independent measurements of partitioning of target protein and fusion peptide, to approximately predict the fusion protein partitioning. PMID- 10099523 TI - Immunochromatographic membrane strip assay system for a single-class plasma lipoprotein cholesterol, exemplified by high-density lipoprotein cholesterol measurement. AB - In assessing risk factors of coronary heart disease, a membrane immunochromatographic system that minimizes requirements of instrument and reagent handling was investigated by utilizing high-density lipoprotein (HDL) cholesterol (HDL-C) as model analyte. The system is composed of four functional membrane strip pads connected in sequence as follows (from the bottom): immunoseparation based on the biotin-streptavidin reaction; catalytic conversion of cholesterol to hydrogen peroxide; production of a colorimetric signal; and induction of a continuous wicking of medium. For immunochromatography, a monoclonal antibody, specific to apolipoprotein B100 that is present on the surfaces of low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL), with a high binding constant (5 x 10(10) L/mol), was raised and chemically conjugated to streptavidin. The conjugate was first reacted with lipoprotein particles, and this mixture was absorbed by the capillary action into the biotin pad of the system. After being transferred by medium, immunocapture of LDL and VLDL particles onto the biotin pad took place, and in situ generation of a colorimetric signal in proportion to HDL-C occurred consecutively. The capture was selective as well as effective (minimum 88% of LDL and VLDL in clinical concentration ranges), and the detection limit of the HDL-C was far lower than 20 mg per 100 mL. The same concept may also be applicable to LDL cholesterol measurement provided suitable antibodies specific to HDL and VLDL are available. PMID- 10099524 TI - Site-protected fixation and immobilization of Escherichia coli cells displaying surface-anchored beta-lactamase. AB - Bacteria displaying heterologous receptors or enzymes on their surface hold great potential as whole-cell adsorbents and biocatalysts, respectively. For industrial applications, such surface-engineered cells need to be killed and chemically fixed to prevent disintegration and leakage of the displayed proteins under process conditions. It is also highly desirable to couple the chemically stabilized cells onto a solid support matrix for additional mechanical stability, flexibility in reactor choice, and easy separation from processed medium. Recently, we described the development of a readily scalable methodology for cell killing, fixation, and outer membrane stabilization via glutaraldehyde fixation followed by secondary crosslinking (Freeman, A., Abramov, S. and Georgiou, G. 1996. Biotechnol. Bioeng. 52: 625-630). Glutaraldehyde treatment was also found, however, to reduce the specific activity of a model enzyme, beta-lactamase displayed on the surface of E. coli. Here, we show that crosslinking carried out in the presence of beta-lactamase inhibitors, namely phenyl boronic acid or sodium borate, protects the active site from chemical modification resulting in up to threefold higher specific activities without affecting the cell-stabilizing effect of the glutaraldehyde treatment. To prepare an immobilized whole cell biocatalyst, residual unreacted surface aldehyde groups were employed to immobilize covalently the fixed bacteria onto chitosan-coated cellulose powder. The binding of the bacteria onto chitosan-coated cellulose was quantitative up to cell loading of 83 mg dry cell weight/g of support. Cell immobilization did not introduce mass transfer limitations and created only a modest reduction in Vmax. Thus, chemical crosslinking, affected in presence of reversible active-site inhibitors and coupled with cell immobilization on chitosan-coated cellulose represents a widely useful methodology for the process application of recombinant bacteria displaying surface-anchored heterologous proteins. PMID- 10099525 TI - Reductive dechlorination of chlorinated ethene DNAPLs by a culture enriched from contaminated groundwater. AB - A microbial culture enriched from a trichloroethene-contaminated groundwater aquifer reductively dechlorinated trichloroethene (TCE) and tetrachloroethene (PCE) to ethene. Initial PCE dechlorination rate studies indicated a first-order dependence with respect to substrate at low PCE concentrations, and a zero-order dependence at high concentrations. Studies of TCE and vinyl chloride (VC) dechlorination indicated a first-order dependence at all substrate concentrations. VC had little or no effect on the initial rate of TCE dechlorination. With subsaturating concentrations of chlorinated ethenes, nearly stoichiometric amounts of the toxic intermediate vinyl chloride accumulated prior to its dechlorination to ethene. In contrast, under saturating conditions, in which a dense, nonaqueous-phase liquid existed in equilibrium with the aqueous phase, the chlorinated ethene was dechlorinated to ethene, at a rapid rate, with the accumulation of relatively small amounts of chlorinated intermediates. PMID- 10099526 TI - Increasing extracellular matrix production in regenerating cartilage with intermittent physiological pressure. AB - Isolated equine chondrocytes, from juveniles and adults, were cultured in resorbable polyglycolic acid meshes for up to 5 weeks with semicontinuous feeding using a custom-made system to intermittently compress the regenerating tissue. Assays of the tissue constructs indicate that intermittent compression at 500 and 1000 psi (3.44 and 6.87 MPa, respectively) stimulated the production of extracellular matrix, enhancing the rate of de novo chondrogenesis. Constructs derived from juvenile cells contained concentrations of extracellular matrix components at levels more like that of native tissue than did constructs derived from adult cells. With intermittent pressurization, however, even adult cells were induced to increase the production of extracellular matrix. At both levels of intermittent pressure, the concentration of sulfated glycosaminoglycan in constructs from juvenile cells was found to be up to ten times greater than concentrations in control (nonpressurized) and adult cell-derived constructs. Whereas collagen concentrations in the 500 psi and control constructs were not significantly different for either juvenile or adult cell-derived constructs, intermittent pressurization at 1000 psi enhanced the production of collagen, suggesting that there may be a minimum level of pressure necessary to stimulate collagen formation. PMID- 10099527 TI - Human interleukin-2 production in insect (Trichoplusia ni) larvae: effects and partial control of proteolysis. AB - Many eukaryotic proteins have been successfully expressed in insect cells infected with a baculovirus in which the foreign gene has been placed under the control of a viral promoter. This system can be costly at large scale due to the quality of virus stock, problems of oxygen transfer, and severity of large-scale contamination. To circumvent this problem, we have investigated the expression of a foreign protein, human interleukin-2 (IL-2), in insect larvae, Trichoplusia ni, infected with the baculovirus Autographa californica nuclear polyhedrosis virus (AcNPV). The IL-2 gene was placed under control of the p10 promoter so that the polyhedra remained intact for efficient primary infection. From our results, it was clear that early infection limited larval growth and late infection delayed product production until near pupation, hence infection timing was important. Also, the harvest time was crucial for obtaining high yield, because IL-2 production had a sharp optimal peak with a time of occurrence dependent on both temperature and the initial amount of infection virus. Specifically, we found that, by raising the infection temperature to 30 degrees C, we more than doubled the protein productivity. Furthermore, a significant concern of the larvae/baculovirus expression system has been the large amount of protease produced by the larvae, which adversely affects the protein yield. Therefore, we screened several protease inhibitors and characterized the larval protease specificity and timing to attenuate their impact. This report elucidates and delineates the factors that most directly impact protein yield in the larvae expression system, using IL-2 as a model. PMID- 10099528 TI - Oxygen mass transfer characteristics in a membrane-aerated biofilm reactor. AB - Immobilization of pollutant-degrading microorganisms on oxygen-permeable membranes provides a novel method of increasing the oxidation capacity of wastewater treatment bioreactors. Oxygen mass transfer characteristics during continuous-flow steady-state experiments were investigated for biofilms supported on tubular silicone membranes. An analysis of oxygen mass transport and reaction using an established mathematical model for dual-substrate limitation supported the experimental results reported. In thick biofilms, an active layer of biomass where both carbon substrate and oxygen are available was found to exist. The location of this active layer varies depending on the ratio of the carbon substrate loading rate to the intramembrane oxygen pressure. The thickness of a carbon-substrate-starved layer was found to greatly influence the mass transport of oxygen into the active biomass layer, which was located close to, but not in contact with, the biofilm-liquid interface. The experimental results demonstrated that oxygen uptake rates as high as 20 g m-2 d-1 bar-1 can be achieved, and the model predicts that, for an optimized biofilm thickness, oxygen uptake rates of more than 30 g m-2 d-1 bar-1 should be possible. This would allow membrane aerated biofilm reactors to operate with much greater thicknesses of active biomass than can conventional biofilm reactors as well as offering the further advantage of close to 100% oxygen conversion efficiencies for the treatment of high-strength wastewaters. In the case of dual- substrate-limited biofilms, the potential to increase the oxygen flux does not necessarily increase the substrate (acetate) removal rate. PMID- 10099529 TI - Reversible denaturation of carbonic anhydrase provides a method for its adsorptive immobilization. AB - Palmityl-substituted sepharose 4B has been used for adsorptive immobilization of heat-denatured carbonic anhydrase. The native form of this enzyme does not show any affinity for binding to this hydrophobic support. However, through the process of denaturation-renaturation performed by heating and subsequent cooling of an enzyme solution in the presence of the matrix, it was possible to obtain a catalytically active immobilized preparation, which was used successfully in continuous catalytic transformations. It is suggested that this simple procedure may provide a convenient method of immobilization for proteins, which are not normally adsorbed on hydrophobic supports. PMID- 10099530 TI - Inhibitory effects and biotransformation of acrylic acid in computer-controlled pH-stat CSTRs. AB - In this study, the inhibitory effects and anaerobic biotransformation of acrylic acid in computer-controlled pH-stat completely stirred tank reactors (CSTRs) with two different cultures, namely unacclimated and acrylate-acclimated acetate enriched Methanosarcina and homogenized (crushed) granular cultures, were investigated. The microbial acclimation, influent concentration, and loading rate of acrylic acid were studied in the experiments. The experimental results revealed that methanogenic cultures at a concentration of 3200 +/- 80 mg/L as volatile suspended solids (VSS) could be acclimated to acrylic acid up to a loading rate of 220 mg/L per day (0.068 g acrylic acid/g VSS per day) in the presence of a constant acetate concentration of 2000 +/- 200 mg/L as the primary substrate after 300 days of acclimation. The same cultures (680 +/- 80 mg/L as VSS), after 80 days of acclimation to acrylic acid as the sole carbon source, transformed acrylic acid up to the loading rate of about 200 mg/L per day (0.29 g acrylic acid/g VSS per day) almost completely (>99%) to acetic and propionic acid, but could not effectively metabolize these intermediate products. Acrylate acclimated homogenized granular cultures (6900 +/- 80 mg/L as VSS) effectively metabolized 2200 mg/L per day (0.32 g acrylic acid/g VSS per day) of acrylic acid, as the sole carbon source, after 50 days of severe inhibition. PMID- 10099531 TI - A simple, two-component buffer enhances use of chromatofocusing for processing of therapeutic proteins. AB - To extend the feasibility of chromatofocusing to industrial use, we have developed a simple chromatofocusing buffer system capable of generating a smooth pH gradient without the use of an external gradient maker. Using two cationic buffering components, an internal pH gradient is produced on appropriate chromatography media over a broad pH range (9.5 to 5.0). The utility of this buffer system is demonstrated with PBE94 and DEAE Sepharose fast flow ion exchangers, as well as with experimental fast flow chromatofocusing gels. Using a rapid flow rate, we evaluated this buffer system for recovery of a therapeutic protein from a bacterial cell extract. The simplicity of the buffer system requiring no external gradient maker, coupled with the use of fast flow chromatographic media to produce broad-range pH gradients, improves the scalability of chromatofocusing for processing of therapeutic proteins. PMID- 10099532 TI - Biomass control in waste air biotrickling filters by protozoan predation. AB - Two protozoan species as well as an uncharacterized protozoan consortium were added to a toluene-degrading biotrickling filter to investigate protozoan predation as a means of biomass control. Wet biomass formation in 23.6-L reactors over a 77-day period was reduced from 13.875 kg in a control biotrickling filter to 11.795 kg in a biotrickling filter enriched with protozoa. The average toluene vapor elimination capacity at 1 g/m3 toluene and 64 m3/(m3. h) was 31.1 g/(m3. h) in the control and 32.2 g/(m3. h) in the biotrickling filter enriched with protozoa. At higher toluene inlet concentrations, toluene degradation rates increased and were slightly higher in the biotrickling filter enriched with protozoa. The lower rate of biomass accumulation after the addition of protozoa was due to an increase of carbon mineralization (68% as compared to 61% in the control). Apparent biomass yield coefficients in the control and enriched trickling filter were 0.72 and 0.59 g dry biomass/g toluene, respectively. The results show that protozoan predation may be a useful tool to control biomass in biotrickling filters, however, further stimulation of predation of the biomass immobilized in the reactor is required to ensure long-term stability of biotrickling filters. PMID- 10099533 TI - Enzymatic synthesis of alpha-butylglucoside lactate: a new alpha-hydroxy acid derivative. AB - An alpha-hydroxy acid derivative, alpha-butylglucoside lactate, was successfully prepared by enzymatic transesterification of alpha-butylglucoside with a lactate alkyl ester in a non-aqueous medium using immobilized lipase as biocatalyst. Ester synthesis in organic solvent was optimized. Solvent choice was made on the basis of substrate solubility and enzyme stability in the medium. A solvent-free reaction using butyllactate as lactate donor led to the highest yields. In the presence of 0.5M alphabutylglucoside and 100 g/L Novozym(R), a 67 % yield could be obtained within 40 h at 50 degrees C. However, the presence of butanol by product limited the reaction to a maximum that could not be exceeded in closed systems. The elimination of the alcohol under reduced pressure resulted in the complete equilibrium shift of the transesterification reaction in favor of synthesis; below 15 mbars, more than 95% of 0.5M alpha-butylglucoside could be converted within 30 h. Moreover, simultaneous evaporation of water allowed hydrolysis of butyllactate to be eliminated. Consequently, a very high alpha butylglucoside lactate concentration (170 g/) could be obtained in a single batch reaction. A single purification procedure, consisting of butyllactate extraction with hexane, enabled the product to be obtained at a purity above 95% (w/w). 1H and 13C NMR analysis later demonstrated that lactic acid was exclusively grafted onto the primary hydroxyl group of alphabutylglucoside. PMID- 10099534 TI - Engineered isoprenoid pathway enhances astaxanthin production in Escherichia coli. AB - The isoprenoid pathway is a versatile biosynthetic network leading to over 23,000 compounds. Similar to other biosynthetic pathways, the production of isoprenoids in microorganisms is controlled by the supply of precursors, among other factors. To engineer a host that has the capability to supply geranylgeranyl diphosphate (GGPP), a common precursor of isoprenoids, we cloned and overexpressed isopentenyl diphosphate (IPP) isomerase (encoded by idi) from Escherichia coli and GGPP synthase (encoded by gps) from the archaebacterium Archaeoglobus fulgidus. The latter was shown to be a multifunctional enzyme converting dimethylallyl diphosphate (DMAPP) to GGPP. These two genes and the gene cluster (crtBIYZW) of the marine bacterium Agrobacterium aurantiacum were introduced into E. coli to produce astaxanthin, an orange pigment and antioxidant. This metabolically engineered strain produces astaxanthin 50 times higher than values reported before. To determine the rate-controlling steps in GGPP production, the IDI-GPS pathway was compared with another construct containing idi, ispA (encoding farnesyl diphosphate (FPP) synthase in E. coli), and crtE (encoding GGPP synthase from Erwinia uredovora). Results show that the conversion from FPP to GGPP is the first bottleneck, followed sequentially by IPP isomerization and FPP synthesis. Removal of these bottlenecks results in an E. coli strain providing sufficient precursors for in vivo synthesis of isoprenoids. PMID- 10099535 TI - A simple method to determine the water activity of ethanol-containing samples AB - The water activity (aw) of microbial substrates, biological samples, and foods and drinks is usually determined by direct measurement of the equilibrium relative humidity above a sample. However, these materials can contain ethanol, which disrupts the operation of humidity sensors. Previously, an indirect and problematic technique based on freezing-point depression measurements was needed to calculate the aw when ethanol was present. We now describe a rapid and accurate method to determine the aw of ethanol-containing samples at ambient temperatures. Disruption of sensor measurements was minimized by using a newly developed, alcohol-resistant humidity sensor fitted with an alcohol filter. Linear equations were derived from aw measurements of standard ethanol-water mixtures, and from Norrish's equation, to correct sensor measurements. To our knowledge, this is the first time that electronic sensors have been used to determine the aw of ethanol-containing samples. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099536 TI - Protein purification with vapor-phase carbon dioxide. AB - Gaseous CO2 was used as an antisolvent to induce the fractional precipitation of alkaline phosphatase, insulin, lysozyme, ribonuclease, trypsin, and their mixtures from dimethylsulfoxide (DMSO). Compressed CO2 was added continuously and isothermally to stationary DMSO solutions (gaseous antisolvent, GAS). Dissolution of CO2 was accompanied by a pronounced, pressure-dependent volumetric expansion of DMSO and a consequent reduction in solvent strength of DMSO towards dissolved proteins. View cell experiments were conducted to determine the pressures at which various proteins precipitate from DMSO. The solubility of each protein in CO2-expanded DMSO was different, illustrating the potential to separate and purify proteins using gaseous antisolvents. Polyacrylamide gel electrophoresis in sodium dodecyl sulfate (SDS-PAGE) was used to quantify the separation of lysozyme from ribonuclease, alkaline phosphatase from insulin, and trypsin from catalase. Lysozyme biological activity assays were also performed to determine the composition of precipitates from DMSO initially containing lysozyme and ribonuclease. SDS-PAGE characterizations suggest that the composition and purity of solid-phase precipitated from a solution containing multiple proteins may be accurately controlled through the antisolvent's pressure. Insulin, lysozyme, ribonuclease, and trypsin precipitates recovered substantial amounts of biological activity upon redissolution in aqueous media. Alkaline phosphatase, however, was irreversibly denaturated. Vapor-phase antisolvents, which are easily separated and recovered from proteins and liquid solvents upon depressurization, appear to be a reliable and effective means of selectively precipitating proteins. PMID- 10099537 TI - Enzymatic synthesis of carbonate monomers and polycarbonates. AB - Diphenyl carbonate is an attractive monomer for copolymerization with Bisphenol-A to produce the strong, high melting polycarbonate, Bisphenol-A Polycarbonate. Diphenyl carbonate is an ideal candidate for this polymerization as the phenols constitute good leaving groups during polymerization. Industrially, diphenyl carbonate is produced via the phosgenation of a phenolic sodium salt. Using phosgene creates additional safety hazards as well as concerns in treating or disposing of the reaction by-products. The enzymatic synthesis of diphenyl carbonate via alcoholysis of dimethyl carbonate by phenol is presented. While the process is environmentally benign and eliminates the considerable safety issues related to the use of phosgene, phenol is a poor nucleophile and conversion to diphenyl carbonate is limited. Enzyme catalyzed condensation polymerization of carbonate monomers and diols is a more feasible and direct enzymatic route to polycarbonate. We describe an AA-BB condensation polymerization to make polycarbonates using enzymes at ambient conditions. Molecular weights of up to 8, 500 MW are achieved. Unlike the industrial polymerization, this process is performed without the use of acid catalysts, significant energy input, or high temperature or pressure. PMID- 10099538 TI - pH gradients in immobilized amidases and their influence on rates and yields of beta-lactam hydrolysis. AB - The pH gradients developing within immobilized biocatalysts during hydrolysis of penicillin G and glutaryl-7-aminocephalosporanic acid have been estimated both theoretically and experimentally. For the latter a fluorimetric method for the direct measurement of the average pH value within the carrier during reaction has been developed using the pH-dependent fluorescence intensity of an enzyme-bound fluorophore determined with a fiber bundle. The theoretical calculations were based on a model for the hydrolysis with immobilized enzymes using a kinetic expression with five pH-dependent, measurable kinetic and equilibrium constants. The transport reaction differential equation which considers the laminar boundary layer has been solved numerically for the key component. The calculated values agreed well with the experimental data. Under the typical reaction conditions of penicillin G hydrolysis the average pH value in the carrier was 1 and 2.5 pH units below the bulk pH (=8) with and without buffer, respectively. The corresponding changes for the hydrolysis of glutaryl-7-aminocephalosporanic acid at bulk pH 8 in the presence of buffer was 0.5. This demonstrates the existence of considerable pH gradients in carriers during hydrolytic reactions, even in buffered systems with negligible mass transfer resistance. The low pH value causes suboptimal reaction rates, reduced equilibrium conversion, and reduced enzyme stability. These pH gradients can be minimised by using buffers with pK values approximately equal to the bulk pH used for the hydrolysis. The prediction quality of the model has been tested applying it to fixed bed reactor design. The reduction in rate and yield due to concentration and pH gradients can be overcome with simple measures such as high initial pH value and pH adjustments in segmented or recycling fixed bed reactors. Thus, enzymatic conversions with high yield and high operational effectiveness are achieved. PMID- 10099539 TI - Continuous foaming for protein recovery: part I. Recovery of beta-casein. AB - Foam separation is known to have potential for separation of biological molecules with a range of surface activities. A statistical study (factorial design) was carried out to establish the optimum operating conditions for the continuous foam separation of beta-casein. Maximum values of enrichment of beta-casein into the foam phase were found for low levels of initial feed protein concentration, gas flow rate, feed-flow rate, and high foam heights. Maximum values of protein recovery, were generally found at high levels of initial feed protein concentration, gas-flow rate, feed-flow rate, and low foam heights. The highest values obtained for enrichment and separation ratio were 54.7 and 181.3, respectively, with a simultaneous protein recovery of 62%; thus, illustrating the potential effectiveness of this technique. The effect of foaming on protein conformation is also important, and in this study protein structure was analyzed before and after foam separation experiments. Techniques used were: native polyacrylamide gel electrophoresis (PAGE), UV absorbance spectroscopy, circular dichroism, and fluorescence. Native PAGE showed no detectable changes in protein structure. However, absorbance scanning, fluorimetry, and circular dichroism revealed some conformational changes over a range of concentration effects. PMID- 10099540 TI - Continuous foaming for protein recovery: part II. Selective recovery of proteins from binary mixtures. AB - Foam separation may have potential for protein recovery. However, for foam separation to be a viable protein recovery technique it is important to demonstrate, not only that high enrichments and recoveries can be achieved for single proteins, but also that high enrichments and recoveries, together with selectivity of partition, can be achieved for recovery from multi-component mixtures. Most process streams which require purification are indeed complex multi-component mixtures, for example, fermentation broths. In this study, three binary protein mixtures were chosen for continuous foam separation: beta casein:lysozyme; Bovine serum albumin (BSA):lysozyme and beta-casein:BSA (mixtures 1, 2, and 3, respectively). For each of these mixtures, the expected outcome of each experiment, based on a previous knowledge and determination of relevant protein physical properties, was that the first protein should be preferentially separated into the foam phase. On the basis of results reported in Part I of this study for the continuous foam separation of beta-casein, conditions found to favor maximum enrichment were selected. For each mixture a range of concentrations of both proteins was considered. For mixture 1, maximum protein recoveries in the foam phase were 85.6% and 25% for beta-casein and lysozyme, respectively; and for mixture 2, maximum recoveries of 77. 6% and 18.9% were obtained for BSA and lysozyme, respectively. Maximum enrichment ratios in the foam phase were 79.4 and 2.5 for beta-casein and lysozyme respectively in mixture 1; and 74.0 and 1.4 for BSA and lysozyme respectively in mixture 2. Selective partitioning of beta-casein and BSA into the foam phase was obtained in mixtures 1 and 2, respectively, particularly for protein concentrations at which dilute protein films are known to form at the gas-liquid interface in the foam. Maximum partition ratios for mixtures 1 and 2 were 31.8 and 52.8, respectively. For mixture 3, both BSA and beta-casein were enriched into the foam phase. Maximum enrichments were 42.9 and 24.7 for BSA and beta-casein, respectively; however, selective partitioning in mixture 3 was limited (maximum partition ratio being 1.8). PMID- 10099541 TI - High yield refolding and purification process for recombinant human interleukin-6 expressed in Escherichia coli. AB - Recombinant human interleukin-6 (hIL-6), a pleiotropic cytokine containing two intramolecular disulfide bonds, was expressed in Escherichia coli as an insoluble inclusion body, before being refolded and purified in high yield providing sufficient qualities for clinical use. Quantitative reconstitution of the native disulfide bonds of hIL-6 from the fully denatured E. coli extracts could be performed by glutathione-assisted oxidation in a completely denaturating condition (6M guanidinium chloride) at protein concentrations higher than 1 mg/mL, preventing aggregation of reduced hIL-6. Oxidation in 6M guanidinium chloride (GdnHCl) required remarkably low concentrations of glutathione (reduced form, 0.01 mM; oxidized form, 0.002 mM) to be added to the solubilized hIL-6 before the incubation at pH 8.5, and 22 degrees C for 16 h. After completion of refolding by rapid transfer of oxidized hIL-6 into acetate buffer by gel filtration chromatography, residual contaminants including endotoxin and E. coli proteins were efficiently removed by successive steps of chromatography. The amount of dimeric hIL-6s, thought to be purification artifacts, was decreased by optimizing the salt concentrations of the loading materials in the ion-exchange chromatography, and gradually removing organic solvents from the collected fractions of the preparative reverse-phase HPLC. These refolding and purification processes, which give an overall yield as high as 17%, seem to be appropriate for the commercial scale production of hIL-6 for therapeutic use. PMID- 10099542 TI - Effect of oxygen transfer on lipase production by Acinetobacter radioresistens. AB - The influence of oxygen on alkaline lipase production by Acinetobacter radioresistens was studied under two operating modes: controlled dissolved oxygen (DO) concentration and controlled aeration rate. Compared with cell growth, the lipase production depended more extensively on oxygen. The intrinsic factor determining cell growth and lipase production was oxygen transfer rate (OTR) rather than DO concentration. Improvements in OTR, either by aeration or agitation, resulted in an increase in lipase yield and/or a reduction in fermentation time. The formation of A. radioresistens lipase could be described by a mixed-growth-associated model, and the enzyme was mainly a growth-associated product. The overall productivity for the lipase, which depended more strongly on agitation than aeration, could be related with kLa. DO concentration could not be employed in this correlation, though it has been useful as a criterion for ensuring no oxygen limitation in an aerobic fermentation. PMID- 10099543 TI - Higher intracellular levels of uridinemonophosphate under nitrogen-limited conditions enhance metabolic flux of curdlan synthesis in Agrobacterium species. AB - Changes of intracellular nucleotide levels and their stimulatory effects on curdlan synthesis in Agrobacterium species were investigated under different culture conditions. Under nitrogen-limited conditions where curdlan synthesis was stimulated, intracellular levels of UMP were as high as 87 and those of AMP were 78 nmol/mg of cellular protein, while those under nitrogen-sufficient conditions were lower than 45 nmol/mg-protein. The levels of other nucleotides such as UDP, UTP, UDP-glucose, ADP, ATP, and ADP-glucose were lower than 30 nmol/mg-protein under both nitrogen-limited and sufficient conditions. The time profiles of curdlan synthesis and cellular nucleotide levels showed that curdlan synthesis had a positive relationship with intracellular levels of UMP and AMP. After the ammonium concentration in the medium fell below 0.1 g/L, intracellular levels of UMP and AMP increased, followed by curdlan synthesis. However, no significant changes in the specific activities of UMP kinase, UDP kinase, and UDP-glucose pyrophosphorylase were observed during cultivation. In vitro enzyme reactions for the synthesis of UDP-glucose, which serve as a precursor for curdlan synthesis, demonstrated that the synthesis of UDP-glucose increased with the increase of UMP concentration. In contrast, AMP had no effect on UDP-glucose synthesis at all. Addition of UMP in the medium increased the curdlan synthesis, whereas curdlan synthesis was inhibited in the presence of AMP. From these results, we concluded that only the higher intracellular UMP levels caused by nitrogen limitation in the medium enhance the metabolic flux of curdlan synthesis by promoting cellular UDP-glucose synthesis. PMID- 10099544 TI - Metabolism of peptide amino acids by Chinese hamster ovary cells grown in a complex medium. AB - Metabolic flux analysis is a useful tool for unraveling relationships between metabolism and cell function. Material balancing can be used to provide estimates of major metabolic pathway fluxes, provided all significant metabolite uptake and production rates are measured. Potential sources of metabolizable material in many serum-free media formulations are low molecular weight digests of biological material such as yeast extracts and plant or animal tissue hydrolysates. These digests typically contain large amounts of peptides, which may be utilized as amino acids. This article demonstrates the need for accounting for amino acids liberated from peptides in order to accurately estimate pathway fluxes in Chinese hamster ovary cells grown in a complex (hydrolysate containing) medium. A simplified model of central carbon metabolism provides the framework for analyzing external metabolite measurements. Redundant measurements are included to ensure the consistency of data and assumed biochemistry by comparing redundant measurements with their predicted values from a minimum data set, and by expressing the degree of agreement using a statistical "consistency index." The consistency index tests whether redundancies are satisfied within expected experimental error. For chemostat steady states of CHO cultures grown in a hydrolysate-supplemented medium, consistent data were obtained only when amino acids liberated from peptides were taken into account. PMID- 10099546 TI - The effect of process conditions on the alpha-amylolytic hydrolysis of amylopectin potato starch: An experimental design approach. AB - The hydrolysis of amylopectin potato starch with Bacillus licheniformis alpha amylase (Maxamyl) was studied under industrially relevant conditions (i.e. high dry-weight concentrations). The following ranges of process conditions were chosen and investigated by means of an experimental design: pH [5.6-7.6]; calcium addition [0-120 microg/g]; temperature [63-97 degrees C]; dry-weight concentration [3-37% [w/w]]; enzyme dosage [27.6-372.4 microL/kg] and stirring [0 200 rpm]. The rate of hydrolysis was followed as a function of the theoretical dextrose equivalent. The highest rate (at a dextrose equivalent of 10) was observed at high temperature (90 degrees C) and low pH (6). At a higher pH (7.2), the maximum temperature of hydrolysis shifted to a lower value. Also, high levels of calcium resulted in a decrease of the maximum temperature of hydrolysis. The pH, temperature, and the amount of enzyme added showed interactive effects on the observed rate of hydrolysis. No product or substrate inhibition was observed. Stirring did not effect the rate of hydrolysis. The oligosaccharide composition after hydrolysis (at a certain dextrose equivalent) did depend on the reaction temperature. The level of maltopentaose [15-24% [w/w]], a major product of starch hydrolysis by B. licheniformis alpha-amylase, was influenced mostly by temperature. PMID- 10099545 TI - Metabolic effects on recombinant interferon-gamma glycosylation in continuous culture of Chinese hamster ovary cells. AB - Asparagine linked (N-linked) glycosylation is an important modification of recombinant proteins, because the attached oligosaccharide chains can significantly alter protein properties. Potential glycosylation sites are not always occupied with oligosaccharide, and site occupancy can change with the culture environment. To investigate the relationship between metabolism and glycosylation site occupancy, we studied the glycosylation of recombinant human interferon-gamma (IFN-gamma) produced in continuous culture of Chinese hamster ovary cells. Intracellular nucleotide sugar levels and IFN-gamma glycosylation were measured at different steady states which were characterized by central carbon metabolic fluxes estimated by material balances and extracellular metabolite rate measurements. Although site occupancy varied over a rather narrow range, we found that differences correlated with the intracellular pool of UDP-N acetylglucosamine + UDP-N-acetylgalactosamine (UDP-GNAc). Measured nucleotide levels and estimates of central carbon metabolic fluxes point to UTP depletion as the cause of decreased UDP-GNAc during glucose limitation. Glucose limited cells preferentially utilized available carbon for energy production, causing reduced nucleotide biosynthesis. Lower nucleoside triphosphate pools in turn led to lower nucleotide sugar pools and reduced glycosylation site occupancy. Subsequent experiments in batch and fed-batch culture have confirmed that UDP-sugar concentrations are correlated with UTP levels in the absence of glutamine limitation. Glutamine limitation appears to influence glycosylation by reducing amino sugar formation and hence UDP-GNAc concentration. The influence of nucleotide sugars on site occupancy may only be important during periods of extreme starvation, since relatively large changes in nucleotide sugar pools led to only minor changes in glycosylation. PMID- 10099547 TI - Investigations on protein adsorption to agarose-dextran composite media. AB - A new stationary phase for protein purification was investigated with regard to its performance during capture of selected model proteins. The commercially available matrix consists of a porous agarose backbone, to which dextran is covalently attached. The dextran carries ion-exchange ligands, thus providing a binding space of high ligand density. Breakthrough of various proteins during frontal application to packed beds was measured and the experiments were analyzed in terms of equilibrium and breakthrough capacity. A significant increase of static capacity, as compared with conventional porous matrices, was found. Good dynamic properties allowed utilization of a high percentage of the equilibrium capacity at 10% breakthrough. For all proteins, a decreasing ratio of breakthrough to equilibrium capacity was detected with increasing feed concentration. This observation suggested a significant contribution of solid diffusion to the transport of proteins into the adsorbent particles. The specific architecture of the stationary phase, where the agarose base structure is derivatized with ion-exchange ligand-bearing dextran, may lead to this behavior. PMID- 10099548 TI - Enhancement of enzyme reaction of magnetically anisotropic polyacrylamide gel rods immobilized with ferromagnetic powder and beta-D-galactosidase in an alternating magnetic field. AB - An immobilized polyacrylamide gel containing beta-D-galactosidase and Sr-Ba ferrite was magnetized in a static magnetic field. The gel rods (10 mm long, O 2 mm) exhibiting magnetic anisotropy could move at lower than 100 Hz but not at higher than 250 Hz in an alternating magnetic field of 200 Oe. In case of immovability of gel rods, the apparent enzymic activity increased 3 times higher under exposure of an alternating magnetic field of 500 Oe (570 Hz). It could be explained that the ferromagnetic powder inside the gel might vibrate under the influence of elasticity of gel in the alternating magnetic field of 100 or 500 Oe and 0.2-12 kHz. This might facilitate faster diffusion of the substance inside the gel and transportation of the substrate and the product through the surface of gel. Consequently, the enzyme reaction was apparently activated. PMID- 10099549 TI - Kinetics of inactivation of Bacillus subtilis spores by continuous or intermittent ohmic and conventional heating. AB - Bacillus subtilis spores were suspended in 0.1% NaCl solution (ca. 10(7) CFU/mL) and treated by conventional or ohmic heating under identical temperature histories. Temperatures tested were in the range of 88 to 99 degrees C. Survival curves and calculated D values showed significantly higher lethality for spores by ohmic than conventional heating. The z or Ea values corresponding to the two heating methods, however, were not significantly different. Spores of B. subtilis were suspended in nutrient broth and treated with conventional and ohmic heating through a single- or a double-stage treatment. In case of double-stage treatment, heating was interrupted by a 20 min of incubation at 37 degrees C to induce a Tyndallization effect. Spore inactivation during double-stage treatment was greater for ohmic than conventional heating. The enhanced spore inactivation by ohmic, compared with conventional, heating resulted from a greater rate of spore death during the first stage of heating and greater decrease in count of viable spores immediately after the incubation period that intervened the heating process. Thus it is concluded that spore inactivation during ohmic heating was primarily due to the thermal effect but there was an additional killing effect caused by the electric current. PMID- 10099550 TI - Metabolite and isotopomer balancing in the analysis of metabolic cycles: I. Theory. AB - Proper analysis of label distribution in metabolic pathway intermediates is critical for correct interpretation of experimental data and strategic experimental design. While, for example, 13C nuclear magnetic resonance (NMR) spectroscopy is usually limited to the measurement of degrees of 13C enrichment, more information about metabolic fluxes can be extracted from the fine structure of NMR spectra, or molecular weight distributions of isotopomers of metabolic intermediates (measured by gas chromatography-mass spectrometry). For this purpose, rigorous accounting for the contribution of all pathways to label distribution is required, especially contributions resulting from multiple turns of metabolic cycles. In this paper we present a mathematical model developed to analyze isotopomer distributions of tricarboxylic acid cycle (TCA) intermediates following the administration of 13C (or 14C) labeled substrates. The theory presented provides the basis to analyze 13C NMR spectra and molecular weight distributions of metabolites. In a companion paper (Park et al., 1999), the theory is applied to the analysis of several cases of biological significance. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099551 TI - A method of graphically analyzing substrate-inhibition kinetics. AB - A model of substrate inhibition for enzyme catalysis was extended to describe the kinetics of photosynthetic production of ethylene by a recombinant cyanobacterium, which exhibits light-inhibition behavior similar to the substrate inhibition behavior in enzyme reactions. To check the validity of the model against the experimental data, the model equation, which contains three kinetic parameters, was transformed so that a linear plot of the data could be made. The plot yielded reasonable linearity, and the parameter values could be estimated from the plot. The linear-plot approach was then applied to other inhibition kinetics including substrate inhibition of enzyme reactions and inhibitory growth of bacteria, whose analyses would otherwise require nonlinear least-squares fits or data measured in constrained ranges. Plots for three totally different systems all showed reasonable linearity, which enabled visual validation of the assumed kinetics. Parameter values evaluated from the plots were compared with results of nonlinear least-squares fits. A normalized linear plot for all the results discussed in this work is also presented, where dimensionless rates as a function of dimensionless concentration lie in a straight line. The linear-plot approach is expected to be complementary to nonlinear least-squares fits and other currently used methods in analyses of substrate-inhibition kinetics. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099552 TI - Recovery of aroma compounds from a wine-must fermentation by organophilic pervaporation. AB - This study investigates the recovery of a wine-must aroma profile, formed by Saccharomyces cerevisiae during a muscatel wine-must fermentation, using organophilic pervaporation. Experiments were carried out along two independent, but organoleptically similar, fermentations. The wine-must samples and the aroma concentrates obtained were characterized organoleptically by a sensory panel and analytically with regard to eight major wine-must components: four alcohols; three esters; and one monoterpenic compound. Pervaporation performance was studied under fermentation conditions, and the permeate concentration, partial fluxes, and enrichment of the respective compounds were determined. The muscatel wine-must aroma profile was recovered purely and faithful to its origin between wine-must densities of 1075 and 1055 g L. At the beginning of the fermentation, too few aromas were present in the must for recovery. Toward the end of the fermentation, high ethanol concentrations in the wine-must caused a dramatic enrichment of two esters in the permeate, whereas other components investigated seemed unaffected. This shift resulted in an unbalanced aroma. In conclusion, it was shown that organophilic pervaporation can be highly suitable for the continuous recovery of very complex and delicate aromatic profiles produced during microbial fermentation. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099553 TI - A method for the decrease of phenolic content in commercial canola meal using an enzyme preparation secreted by the white-rot fungus Trametes versicolor. AB - An enzymatic process for upgrading the quality of canola meal (CM) by decreasing its phenolic content was investigated. The new method was based on the addition of the enzyme preparation from white-rot fungus Trametes versicolor to the meal buffer slurry. A 98% decrease in the concentration of SAE was observed after 1 h of the treatment. The following process variables were considered for optimizing the process: pH, temperature, enzyme, meal, and oxygen concentrations. It was found that: (1) the natural buffering capacity of CM resulted in a negligible effect of the pH of the buffer, which was used as the continuous phase in the process, on the extent of decrease in sinapic acid esters (SAE); (2) the system was saturated with the enzyme when its concentration was 4 nkat/mL of the continuous phase; and (3) the optimum temperature was 50 degrees C. The process could be carried out even at higher temperatures due to the protective action of CM, which resulted in an increase in the thermal stability of the enzyme. The particle size influenced the extraction of the SAE from the meal, indicating that, at lower SAE concentrations, the process became diffusion limited. This result, together with those showing no effect of the intensity of agitation, indicated that the enzymatic process can be characterized by high Biot numbers. During the enzymatic process, the molar concentration of available oxygen can become a limiting factor when it is more than four times lower than the molar concentration of phenolics in the treated meal. The new enzymatic method was compared with other methods reported in the literature for the decrease in the phenolic content of rapeseed meals. It was found that, among the methods tested, the enzymatic treatment was the most effective, followed by the lime treatment. The enzymatic process did not reduce the quality of the protein isolates prepared from the CM. After the addition of a simple acetone-washing step, the isolate from the enzymatically treated meal had even better properties. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099554 TI - Effects of agitation intensity on mycelial morphology and protein production in chemostat cultures of recombinant Aspergillus oryzae. AB - The effects of agitation on fragmentation of a recombinant strain of Aspergillus oryzae and its consequential effects on protein production have been investigated. Constant mass, 5.3-L chemostat cultures at a dilution rate of 0.05 h-1 and a dissolved oxygen level of 75% air saturation, have been conducted at 550, 700, and 1000 rpm. These agitation speeds were chosen to cover a range of specific power inputs (2.2 to 12 kW m-3) from realistic industrial levels to much higher values. The use of a constant mass chemostat linked to a gas blender allowed variation of agitation speed and hence gas hold-up without affecting the dilution rate or the concentration of dissolved oxygen. The morphology of both the freely dispersed mycelia and clumps was characterized using image analysis. Statistical analysis showed that it was possible to obtain steady states with respect to morphology. The mean projected area at each steady state under growing conditions correlated well with the 'energy dissipation/circulation" function, [P/(kD3tc)], where P is the power input, D the impeller diameter, tc the mean circulation time, and k is a geometric constant for a given impeller. Rapid transients of morphological parameters in response to a speed change from 1000 to 550 rpm probably resulted from aggregation. Protein production (alpha-amylase and amyloglucosidase) was found to be independent of agitation speed in the range 550 to 1000 rpm (P/V = 2.2 and 12.6 kW m-3, respectively), although significant changes in mycelial morphology could be measured for similar changes in agitation conditions. This suggests that mycelial morphology does not directly affect protein production (at a constant dilution rate and, therefore, specific growth rate). An understanding of how agitation affects mycelial morphology and productivity would be valuable in optimizing the design and operation of large scale fungal fermentations for the production of recombinant proteins. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099555 TI - Selenium reduction by a denitrifying consortium. AB - A denitrifying bacterial consortium obtained from the Pullman, Washington wastewater treatment facility was enriched under denitrifying conditions and its ability to reduce selenite and selenate was studied. Replicate experiments at two different experimental conditions were performed. All experiments were performed under electron-acceptor limiting conditions, with acetate as the carbon source and nitrate the electron acceptor. In the first set of experiments, selenite was present, whereas, in the second set, selenate was added. A significant lag period of approximately 150 h was necessary before selenite or selenate reduction was observed. During this lag period, nitrate and nitrite use was observed. Once selenite or selenate reduction had started, nitrate and nitrite reduction was concomitant with selenium species reduction. Trace amounts of selenite were detected during the selenate reduction study. Analysis of the data indicates that, once selenium species reduction was induced, the rate of reduction was proportional to the selenium species concentration and to the biomass concentration. Furthermore, at similar biomass and contaminant concentrations, selenite reduction is approximately four times faster than selenate reduction. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099556 TI - Chloroperoxidase-catalyzed enantioselective oxidation of methyl phenyl sulfide with dihydroxyfumaric acid/oxygen or ascorbic acid/oxygen as oxidants. AB - The chloroperoxidase catalyzed oxidation of methyl phenyl sulfide to (R)-methyl phenyl sulfoxide was investigated, both in batch and membrane reactors, using as oxidant H2O2, or O2 in the presence of either dihydroxyfumaric acid or ascorbic acid. The effects of pH and nature and concentration of the oxidants on the selectivity, stability, and productivity of the enzyme were evaluated. The highest selectivity was displayed by ascorbic acid/O2, even though the activity of chloroperoxidase with this system was lower than that obtained with the others. When the reaction was carried out in a membrane reactor, it was possible to reuse the enzyme for several conversion cycles. The results obtained with ascorbic acid/O2 and dihydroxyfumaric acid/O2 as oxidants do not seem to be compatible with either a mechanism involving hydroxyl radicals as the active species or with the hypothesis that oxidation occurs through the initial formation of H2O2. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099557 TI - Effect of scale-up on average shear rates for aerated non-Newtonian liquids in external loop airlift reactors. AB - Average shear rates have been estimated experimentally in a 700-dm3 external loop airlift reactor. Aqueous pseudoplastic carboxymethylcellulose and xanthan gum solutions were used to simulate non-Newtonian behavior of biological media. Average shear rates of non-Newtonian solutions were found by analogy with Newtonian glycerol solutions using downcomer liquid velocity as the measurable parameter. Due to the complexity of local shear rate measurement, an average shear rate was assumed to exist and is proportional to superficial gas velocity. The data from this work and those in the literature were used in producing a new correlation for estimating average shear rates as a function of superficial gas velocity, geometry, and dispersion height. Wall shear rates were found to be significant. The ratio of wall shear rates to bulk shear rates were varied from 5% to 40%. Furthermore, it has been found that shear rates generated in airlift loop reactors are lower than those generated in bubble columns. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099558 TI - Sterilization-in-place of concentrated nutrient solutions AB - Sterilization-in-place (batch sterilization) behavior of concentrated nutrient solutions was quantified for various nutrient solutions of fermentation processing interest. Experimental observations of sterilization temperatures and corresponding pressures suggested that sterilization pressures were substantially lower for concentrated nutrient solutions than for water. This effect was believed to be directly related to the lower vapor pressure and lower activity coefficient of these concentrated nutrient solutions. Using thermodynamic data for the specific nutrient, pressures and temperatures, calculated as a function of nutrient concentration, compared favorably with observed values. This method permits estimation of the expected sterilization pressure for concentrated nutrients for which no experimental observations have yet been made at the sterilization temperature of interest. Estimate accuracy, ranging from 0.006 to 0.06 bar, can be enhanced if one set of experimental temperature/pressure values is known at the expected sterilization scale. The potential impact of the nature of concentrated nutrient solutions on steam-in-place vessel headspace temperature distributions, D-values of B. stearothermophilus, and overall sterilization effectiveness is also discussed. The low vapor pressure of concentrated nutrient solutions was hypothesized to directly impact air removal effectiveness and sterilization performance during batch sterilization. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099559 TI - Influence of polymolecular events on inactivation behavior of xylose isomerase from Thermotoga neapolitana 5068. AB - The inactivation behavior of the xylose isomerase from Thermotoga neapolitana (TN5068 XI) was examined for both the soluble and immobilized enzyme. Polymolecular events were involved in the deactivation of the soluble enzyme. Inactivation was biphasic at 95 degrees C, pH 7.0 and 7.9, the second phase was concentration-dependent. The enzyme was most stable at low enzyme concentrations, however, the second phase of inactivation was 3- to 30-fold slower than the initial phase. Both phases of inactivation were more rapid at pH 7.9, relative to 7.0. Differential scanning calorimetry of the TN5068 XI revealed two distinct thermal transitions at 99 degrees and 109 degrees C. The relative magnitude of the second transition was dramatically reduced at pH 7.9 relative to pH 7.0. Approximately 24% and 11% activity were recoverable after the first transition at pH 7.0 and 7.9, respectively. When the TN5068 XI was immobilized by covalent attachment to glass beads, inactivation was monophasic with a rate corresponding to the initial phase of inactivation for the soluble enzyme. The immobilized enzyme inactivation rate corresponded closely to the rate of ammonia release, presumably from deamidation of labile asparagine and/or glutamine residues. A second, slower inactivation phase suggests the presence of an unfolding intermediate, which was not observed for the immobilized enzyme. The concentration dependence of the second phase of inactivation suggests that polymolecular events were involved. Formation of a reversible polymolecular aggregate capable of protecting the soluble enzyme from irreversible deactivation appears to be responsible for the second phase of inactivation seen for the soluble enzyme. Whether this characteristic is common to other hyperthermophilic enzymes remains to be seen. PMID- 10099560 TI - Maximum production strategy for biodegradable copolymer P(HB-co-HV) in fed-batch culture of Alcaligenes eutrophus. AB - A novel strategy for the maximum production of a biodegradable copolymer, poly(3 hydroxybutyric-co-hydroxyvaleric) acid, P(HB-co-HV), was developed, based on the kinetic parameters obtained from fed-batch culture experiments of Alcaligenes eutrophus. The effects of various culture conditions such as mole ratio of carbon:nitrogen in feed medium (C/N); total fatty acids concentrations; and addition ratio of fatty acids on cultivation properties such as the specific rates of cell formation, mu (h-1), P(HB-co-HV) production, rho[g.P(HB-co HV)/g.cell/h], production yield from fatty acids [g.P(HB-co-HV)/g.fatty acid], and mole fraction of monomeric units in the copolymer [mol.(HV)/{mol.(HB) + mol.(HV)}], were investigated. When nitrogen supply was sufficient for cell growth; that is, C/N (mol.nitrogen atom/mol.carbon atom) was low, mu was high, but rho and the production yield were low, because fatty acids were used mainly for energy formation and anabolic reactions in the cells. On the other hand, when nitrogen supply was limited for cell growth-that is, C/N was high-rho was high. The highest value of rho was obtained when C/N was 75. As the mole ratio of valeric acid (VA) to butyric acid (BA) in the feed medium was increased, the mole fraction of HV units in P(HB-co-HV) increased linearly. When the ratio of BA to VA in the feed medium was kept at a constant value, but C/N was increased, the mole fraction of HV units decreased. In particular, when C/N was >12, the mole fraction of HV units decreased linearly as C/N increased. When VA was utilized as the sole carbon source and C/N was fixed at 4, P(HB-co-HV) with the highest mole fraction of HV units (67 mol%) was achieved. From these results, it was shown that both C/N and the mole ratio of BA to VA in the feed medium should be well controlled for an optimal production of P(HB-co-HV) with the desired value of the mole fraction of HV units. When the addition ratio of butyric acid was 50 wt% of total fatty acids, a maximum production strategy for P(HB-co-HV) was developed and realized experimentally, which was based on a model of the relationship between mu and rho. PMID- 10099561 TI - Temperature effects and substrate interactions during the aerobic biotransformation of BTEX mixtures by toluene-enriched consortia and Rhodococcus rhodochrous. AB - A microbial consortium derived from a gasoline-contaminated aquifer was enriched on toluene (T) in a chemostat at 20 degrees C and was found to degrade benzene (B), ethylbenzene (E), and xylenes (X). Studies conducted to determine the optimal temperature for microbial activity revealed that cell growth and toluene degradation were maximized at 35 degrees C. A consortium enriched at 35 degrees C exhibited increased degradation rates of benzene, toluene, ethylbenzene, and xylenes in single-substrate experiments; in BTEX mixtures, enhanced benzene, toluene, and xylene degradation rates were observed, but ethylbenzene degradation rates decreased. Substrate degradation patterns over a range of BTEX concentrations (0 to 80 mg/L) for individual aromatics were found to differ significantly from patterns for aromatics in mixtures. Individually, toluene was degraded fastest, followed by benzene, ethylbenzene, and the xylenes. In BTEX mixtures, degradation followed the order of ethylbenzene, toluene, and benzene, with the xylenes degraded last. A pure culture isolated from the 35 degrees C enriched consortium was identified as Rhodococcus rhodochrous. This culture was shown to degrade each of the BTEX compounds, individually and in mixtures, following the same degradation patterns as the mixed cultures. Additionally, R. rhodochrous was shown to utilize benzene, toluene, and ethylbenzene as primary carbon and energy sources. Studies conducted with the 35 degrees C-enriched consortium and R. rhodochrous to evaluate potential substrate interactions caused by the concurrent presence of multiple BTEX compounds revealed a range of substrate interaction patterns including no interaction, stimulation, competitive inhibition, noncompetitive inhibition, and cometabolism. In the case of the consortium, benzene and toluene degradation rates were slightly enhanced by the presence of o-xylene, whereas the presence of toluene, benzene, or ethylbenzene had a negative effect on xylene degradation rates. Ethylbenzene was shown to be the most potent inhibitor of BTEX degradation by both the mixed and pure cultures. Attempted quantification of these inhibition effects in the case of the consortium suggested a mixture of competitive and noncompetitive inhibition kinetics. Benzene, toluene, and the xylenes had a negligible effect on the biodegradation of ethylbenzene by both cultures. Cometabolism of o-, m-, and p xylene was shown to be a positive substrate interaction. PMID- 10099562 TI - The affinity adsorptive recovery of an infectious herpes simplex virus vaccine. AB - The chromatographic purification of a recombinant Herpes Simplex Virus (type 2) from salt- and heparin-released harvests of infected complementing Vero (CR2) cells is addressed. Functionalized matrices and process operating conditions are identified that provide adequate virus titres in eluates that are significantly reduced in CR2 cell protein and DNA and possess a low level of HSV-2 protein. Virus from diluted salt-released harvests (0.14 M NaCl) was not appreciably adsorbed onto either heparin-Sepharose or Cellufine-heparin matrices but was virtually completely adsorbed onto Cellufine-sulfate and heparin-HP matrices. Virus was recovered by either a linear salt gradient elution (0.14-2 M NaCl) or by a single-step elution with 1.5 M NaCl in phosphate buffer. Recoveries of infectious virus with step elution were 21% and 89%, respectively, for these matrices. Virus from undiluted salt-released harvest (0.8 M NaCl) was substantially adsorbed onto Cellufine-sulfate gel (44% adsorption) and completely adsorbed onto heparin-HP matrices. This virus was recovered with high yield by either gradient or step elution with phosphate-buffered saline. Finally, heparin harvested virus was fed directly to these matrices and quantitatively adsorbed. The virus could be completely recovered from the heparin-HP matrix with 1.5 M NaCl buffer to provide a purified preparation containing only 0.05 pg protein/pfu and 1.2 x 10(-4) pg DNA/pfu. PMID- 10099563 TI - Efficient and economical recovery of poly(3-hydroxybutyrate) from recombinant Escherichia coli by simple digestion with chemicals. AB - A simple method for the recovery of microbial poly(3-hydroxybutyrate) [P(3HB)] from recombinant Escherichia coli harboring the Ralstonia eutropha PHA biosynthesis genes was developed. Various acids (HCl, H2SO4), alkalies (NaOH, KOH, and NH4OH), and surfactants (dioctylsulfosuccinate sodium salt [AOT], hexadecyltrimethylammonium bromide [CTAB], sodium dodecylsulfate [SDS], polyoxyethylene-p-tert-octylphenol [Triton X-100], and polyoxyethylene(20)sorbitan monolaurate [Tween 20]) were examined for their ability to digest non-P(3HB) cellular materials (NPCM). Even though SDS was an efficient chemical for P(3HB) recovery from recombinant E. coli, it is expensive and has waste disposal problem. NaOH and KOH were also efficient and economical for the recovery of P(3HB), and therefore, were used to optimize digestion condition. When 50 g DCW/L of recombinant E. coli cells having the P(3HB) content of 77% was treated with 0.2 N NaOH at 30 degrees C for 1 h, P(3HB) was recovered with purity of 98.5%. Using this simple recovery method, the effect of recovery method on the final production cost of P(3HB) was examined. Processes for the production of P(3HB) by recombinant E. coli from glucose with two different recovery methods, surfactant-hypochlorite digestion and simple digestion with NaOH, were designed and analyzed. By employing the fermentation process that resulted in P(3HB) concentration, P(3HB) content and P(3HB) productivity of 157 g/L, 77%, and 3.2 P(3HB) g/L-h, respectively, coupled with the recovery method of NaOH digestion, the production cost of P(3HB) was US$ 3.66/kg P(3HB), which was 25% less than that obtained by employing the surfactant-hypochlorite digestion method. PMID- 10099564 TI - Optimization of Pseudomonas cepacia lipase preparations for catalysis in organic solvents. AB - The activity of different lipase (from Pseudomonas cepacia) forms, such as crude powder (crude PC), purified and lyophilized with PEG (PEG + PC), covalently linked to PEG (PEG-PC), cross-linked enzyme crystals (CLEC-PC), and immobilized in Sol-Gel-AK (Sol-Gel-AK-PC) was determined, at various water activities (aw), in carbon tetrachloride, benzene and 1,4-dioxane. The reaction of vinyl butyrate with 1-octanol was employed as a model and both transesterification (formation of 1-octyl butyrate) and hydrolysis (formation of butyric acid from vinyl butyrate) rates were determined. Both rates depended on the lipase form, solvent employed, and aw value. Hydrolysis rates always increased as a function of aw, while the optimum of aw for transesterification depended on the enzyme form and nature of the solvent. At proper aw, some lipase forms such as PEG + PC, PEG-PC, and Sol Gel-AK-PC had a total activity in organic solvents (transesterification plus hydrolysis) which was close to (39 and 48%) or even higher than (130%) that displayed by the same amount of lipase protein in the hydrolysis of tributyrin one of the substrates most commonly used as standard for the assay of lipase activity-in aqueous buffer. Instead, CLEC-PC and crude PC were much less active in organic solvents (2 and 12%) than in buffer. The results suggest that enzyme dispersion and/or proper enzyme conformation (favored by interaction with PEG or the hydrophobic Sol-Gel-AK matrix) are essential for the expression of high lipase activity in organic media. PMID- 10099565 TI - Coupled cellular trafficking and diffusional limitations in delivery of immunotoxins to multicell tumor spheroids. AB - Immunotoxins have the potential to be powerful tools for selective cell killing, but their lack of clinical success against solid tumors indicates a need to better understand factors which limit immunotoxin transport in three-dimensional systems. In this work, a previously developed model which related immunotoxin toxicity to cellular trafficking in a single cell was coupled with a term accounting for diffusive transport of immunotoxin in a solid tumor sphere. This created a mathematical model which is capable of simulating the biological response of multicell tumor spheroids (MTS) to immunotoxin treatment. The model was used to predict the kinetics of protein synthesis inhibition in MTS treated with transferrin receptor-targeted immunotoxins as a function of immunotoxin concentration and toxin choice. HeLa cells were grown as MTS and treated with immunotoxins constructed from the anti-transferrin receptor antibody OKT9 and the toxins gelonin or CRM107, and the average protein synthesis inhibition and growth rates were measured. With no fitted parameters, the mathematical model quantitatively predicted the experimental observations. Immunotoxins were generally less effective against MTS than monolayer cells at equivalent conditions; for OKT9-gelonin at high concentrations this decrease in efficacy was attributed primarily to heterogeneous receptor distribution in MTS whereas for OKT9-CRM107 the decrease was caused primarily by a large barrier to penetration of the immunotoxin into the spheroid. The experimentally verified model was used to define the conditions which lead to large penetration barriers. In general, transport barriers in MTS become more important as immunotoxins become more effective against cells grown as monolayers. The proposed model is unique in its ability to predict toxicity in MTS directly, and is an important step toward understanding immunotoxin effect on tumors in vivo. PMID- 10099566 TI - Vancomycin production is enhanced in chemostat culture with biomass-recycle. AB - Production of the glycopeptide antibiotic vancomycin by Amycolatopsis orientalis ATCC 19795 was examined in phosphate-limited chemostat cultures with biomass recycle, employing an oscillating membrane separator, at a constant dilution rate (D= 0. 14 h-1). Experiments made under low agitation conditions (600 rpm) showed that the biomass concentration could be increased 3.9-fold with vancomycin production kinetics very similar to that of chemostat culture without biomass recycle. The specific production rate (qvancomycin) was maximal when the biomass recycle ratio (R) was 0.13 (D= 0.087 h-1). When the dissolved oxygen tension dropped below 20% (air saturation), the biomass and vancomycin concentrations decreased and an unidentified red metabolite was released into the culture medium. Using increased agitation (850 rpm), used to maintain the dissolved oxygen tension above 20% air saturation, maximum increases in biomass concentration (7.9-fold) and vancomcyin production 1.6-fold (0.6 mg/g dry weight/h) were obtained when R was 0.44 (D= 0.056 h -1) compared to chemostat culture without biomass-recycle. Moreover, at this latter recycle ratio the volumetric vancomycin production rate was 14.7 mg/L/h (a 7-fold increase compared to chemostat culture without biomass-recycle). These observations encourage further research on biomass-recycling as a means of optimising the production of antibiotics. PMID- 10099568 TI - Backward extraction of reverse micellar encapsulated proteins using a counterionic surfactant. AB - The back-extraction of proteins encapsulated in AOT reverse micelles was performed by adding a counterionic surfactant, either TOMAC or DTAB. This novel backward transfer method gave higher backward extraction yields compared to the conventional method with high salt and high pH of the aqueous stripping solution. The protein activity was maintained in the resulting aqueous phase, which in this case had a near neutral pH and low salt concentration. A sharp decrease of the water content was observed in the organic phase corresponding to protein back extraction using TOMAC. The backward transfer mechanism was postulated to be caused by electrostatic interaction between oppositely charged surfactant molecules, which lead to the collapse of the reverse micelles. The back extraction process with TOMAC was found to be very fast; more than 100 times faster than back-extraction with the conventional method, and as much as 3 times faster than forward extraction. The formation of 1:1 complexes of AOT and TOMAC in the solvent phase was observed, and these hydrophobic complexes could be efficiently removed from the solvent using adsorption onto Montmorillonite in order for the organic solvent to be reused. A second cationic surfactant, DTAB, confirmed the general applicability of counterionic surfactants for the backward transfer of proteins. PMID- 10099567 TI - Modelling of oligosaccharide synthesis by dextransucrase. AB - Dextransucrase catalyses the formation of dextran, but also of numerous oligosaccharides from sucrose and different acceptors, if appropriate conditions are chosen. Much experimental work has been carried out and a scheme of reactions and a mathematical model have been developed to describe the complex kinetic behaviour of the enzyme. A computer program was used to calculate the parameters of the model from a broad range of experimental data, investigating a large number of kinetic tests with the acceptors maltose and fructose. The results lead to design considerations for a continuous reactor system with immobilized dextransucrase to produce leucrose, a disaccharide of industrial interest. PMID- 10099569 TI - Investigation of a whole blood fluidized bed Taylor-Couette flow device for enzymatic heparin neutralization. AB - The use of clinical bioreactors will increase as more therapeutic proteins are being cloned, expressed, and produced at a reduced cost. The proposed use of an immobilized heparinase I reactor to make heparin anticoagulation a safer therapy is an example of how the specificity and high activity of an enzyme could be incorporated into a system to ultimately benefit a patient. However, the development of a safe and efficient bioreactor is important for the use of immobilized heparinase I and other therapeutic proteins designed for use in medical extracorporeal procedures. This study examined the possibility of using Taylor-Couette flow and "flow-induced" recirculation of the agarose beads as a way to fluidize agarose-bound heparinase in whole blood. Heparinase I was immobilized onto agarose beads via cyanogen bromide activation. A reactor based on Taylor-Couette flow was designed and modified with a tangential recirculation line. The reactor was tested for efficacy and safety in vitro in human blood. Visualization studies in water and 42% glycerol were used to determine the minimum rotation rate for efficient fluidization. The strategic placement of the recirculation line allowed recirculation of the agarose without the use of an external pump. The device removed 90% of the heparin activity within 2 min from 450 cc of human blood at a blood flow rate of 100 mL/min. Furthermore, the device maintained inlet and outlet clotting times of 269 +/- 10 and 235 +/- 6 s, respectively, demonstrating the potential for regional heparinization. Blood damage was a function of gel volume fraction and rotation rate of the inner cylinder. Hemolysis of the red cells is an important issue when Taylor vortices are combined with macroscopic solid particles such as agarose beads. A modified Taylor-Couette flow device was developed to treat whole blood and operational criteria were established to minimize hemolysis. PMID- 10099571 TI - Kinetic model for the co-action of beta-amylase and debranching enzymes in the production of maltose. AB - The kinetics of the hydrolysis of starch with beta-amylase and debranching enzymes was studied. The hydrolysis of the alpha-1, 6-glycoside bonds of the substrate by debranching enzymes does not create any new nonreducing ends, so debranching enzyme promotes the action of beta-amylase not by increasing the concentration of the substrate of beta-amylase but by increasing the linear linkage portion of the substrate. The introduction of an effective chain length function was used to formulate a kinetic model. PMID- 10099570 TI - A flow injection flow cytometry system for on-line monitoring of bioreactors. AB - For direct and on-line study of the physiological states of cell cultures, a robust flow injection system has been designed and interfaced with flow cytometry (FI-FCM). The core of the flow injection system includes a microchamber designed for sample processing. The design of this microchamber allows not only an accurate on-line dilution but also on-line cell fixation, staining, and washing. The flow injection part of the system was tested by monitoring the optical density of a growing E.coli culture on-line using a spectrophotometer. The entire growth curve, from lag phase to stationary phase, was obtained with frequent sampling. The performance of the entire FI-FCM system is demonstrated in three applications. The first is the monitoring of green fluorescent protein fluorophore formation kinetics in E.coli by visualizing the fluorescence evolution after protein synthesis is inhibited. The data revealed a subpopulation of cells that do not become fluorescent. In addition, the data show that single cell fluorescence is distributed over a wide range and that the fluorescent population contains cells that are capable of reaching significantly higher expression levels than that indicated by the population average. The second application is the detailed flow cytometric evaluation of the batch growth dynamics of E.coli expressing Gfp. The collected single-cell data visualize the batch growth phases and it is shown that a state of balanced growth is never reached by the culture. The third application is the determination of distribution of DNA content of a S. cerevisiae population by automatically staining cells using a DNA-specific stain. Reproducibility of the on-line staining reaction shows that the system is not restricted to measuring the native properties of cells; rather, a wider range of cellular components could be monitored after appropriate sample processing. The system is thus particularly useful because it operates automatically without direct operator supervision for extended time periods. PMID- 10099572 TI - Control of acetic acid concentration by pH-stat continuous substrate feeding in heterotrophic culture phase of two-stage cultivation of Alcaligenes eutrophus for production of P(3HB) from CO2, H2, and O2 under non-explosive conditions. AB - A-two stage culture method of hydrogen-oxidizing bacterium, Alcaligenes eutrophus, is used to produce poly-D-3-hydroxybutyrate, P(3HB) from CO2, O2, and H2 without using a very high oxygen transfer rate while maintaining the O2 concentration in gas phase below 6.9 (v/v)% to prevent detonation of the gas mixture. The two-stage method consists of a heterotrophic culture using fructose as carbon source for exponential cell growth and an autotrophic culture for P(3HB) accumulation. We investigated the use of acetic acid as a cheaper carbon source than fructose for the heterotrophic culture in the two-stage method. However, the acetate concentration in the culture system must be maintained at 1.0 g. dm-3 since its inhibitory effect on the cell growth is very strong. Then, high cell density cultivation of A. eutrophus was investigated by pH-stat continuous feeding of acetic acid to control acetate concentration. As a result, acetate concentration was automatically maintained around 1.0 g. dm-3 by using a feed with a composition in CH3COOH/CH3COONH4/KH2PO4 molar ratio of 5:1:0.084. Cell concentration increased to 48.6 g. dm-3 after 21 h of cultivation. The cell mass grown in the fed-batch culture on acetic acid was useful for P(3HB) production from CO2 in the subsequent autotrophic culture stage. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099573 TI - An efficient model development strategy for bioprocesses based on neural networks in macroscopic balances: Part II. AB - There is a need for efficient modeling strategies which quickly lead to reliable mathematical models that can be applied for design and optimization of (bio) chemical processes. The serial gray box modeling strategy is potentially very efficient because no detailed knowledge is needed to construct the white box part of the model and because covenient black box modeling techniques like neural networks can be used for the black box part of the model. This paper shows for a typical biochemical conversion how the serial gray box modeling strategy can be applied efficiently to obtain a model with good frequency extrapolation properties. Models with good frequency extrapolation properties can be applied under dynamic conditions that were not present during the identification experiments. For a given application domain of a model, this property can be used to considerably reduce the number of identification experiments. The serial gray box modeling strategy is demonstrated to be successful for the modeling of the enzymatic conversion of penicillin G In the concentration range of 10-100 mM and temperature range of 298-335 K. Frequency extrapolation is shown by using only constant temperatures in the (batch) identification experiments, while the model can be used reliable with varying temperatures during the (batch) validation experiments. No reliable frequency extrapolation properties could be obtained for a black box model, and for a more knowledge-driven white box model reliable frequency extrapolation properties could only be obtained by incorporating more knowledge in the model. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099574 TI - Monitoring biomass in root culture systems. AB - This paper presents a technique for accurate estimation of growth in root culture systems. Biomass correlations, were used to estimate fresh weight time course data in shake flasks and reactors based on a model of liquid nutrient uptake and osmolality, to account for changing specific water content of roots. This mass balance technique has been developed to permit accurate aseptic on-line estimation of dry weight (DW), fresh weight (FW), and liquid volume (V) in root cultures utilizing either refractive index or electrical conductivity of the liquid medium along with liquid medium osmolality. The ability to predict fresh weight is particularly important since this is proportional to the biomass volume fraction which determines mass transfer and other culture transport characteristics. The proposed model has been validated with time course information (DW, FW, and V) from 125 mL shake flasks and corroborated with data obtained from 2 L reactors. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099575 TI - Mass spectrometry for metabolic flux analysis. AB - Mass spectrometry in combination with tracer experiments based on 13C substrates can serve as a powerful tool for the modeling and analysis of intracellular fluxes and the investigation of biochemical networks. The theoretical background for the application of mass spectrometry to metabolic flux analysis is discussed. Mass spectrometry methods are especially useful to determine mass distribution of metabolites. Additional information gained from fragmentation of metabolites, e.g., by electron impact ionization, allows further localization of labeling positions, up to complete resolution of isotopomer pools. To effectively handle mass distributions in simulation experiments, a matrix based general methodology is formulated. The natural isotope distribution of carbon, oxygen, hydrogen and nitrogen in the target metabolites is considered by introduction of correction matrices. It is shown by simulation results for the central carbon metabolism that neglecting natural isotope distributions causes significant errors in intracellular flux distributions. By varying relative fluxes into pentosephosphate pathway and pyruvate carboxylation reaction, marked changes in the mass distributions of metabolites result, which are illustrated for pyruvate, oxaloacetate, and alpha-ketoglutarate. In addition mass distributions of metabolites are significantly influenced over a broad range by the degree of reversibility of transaldolase and transketolase reactions in the pentosephosphate pathway. The mass distribution of metabolites is very sensitive towards intracellular flux patterns and can be measured with high accuracy by routine mass spectrometry methods. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099576 TI - Effects of shear on two microalgae species. Contribution of pumps and valves in tangential flow filtration systems. AB - The circulation of microorganisms in tangential flow filtration systems induces perturbations and then the damage of brittle cells. This work is focused on the shearing of two marine microalgae species (Skeletonema costatum and Haslea ostrearia), both largely cultivated in western France (Region des Pays de la Loire). We have studied the effects of the circulation of these cells in pumps and valves. For the pumps, it is shown that shear stress is due to the type of pump, but that mechanical shear can have different effects even if the pumps and the number or frequency of loops are the same. Hence other intrinsic parameters of the pump must be taken into account: rotating velocity (omega), capacity (Cyl = output flow/rotating velocity) or internal leakage (K = inner volume/capacity). In throttling valves, the aim is to correlate the effect of shear to a parameter related to the inner geometry of the valve and to operating conditions. An overall parameter is then evaluated: the pressure drop coefficient Kv which integrates both the type of valve (ball valve or globe valve type) and its opening degree. Kv is derived from the relationship DeltaH = Kvu2/2g. The modelling of the shear effects is now conceivable: basic descriptive data used so far (type of pump, geometry or opening degree of the valve, etc.) being completed and partially substituted by quantitative parameters (rotating velocity, capacity, or internal leakage for the pumps, Kv coefficient for the valves). PMID- 10099577 TI - Dynamic reoptimization of a fed-batch fermentor. AB - Traditionally, fed-batch biochemical process optimization and control use complicated models and off-line optimizers with no on-line model adaptation and re-optimization. This work demonstrates the applicability, effectiveness, and economic potential, of a simple phenomenological model for modeling, and a novel optimizer for on-line re-optimization and control of an aerobic fed-batch fermentor. PMID- 10099578 TI - Multi-rate nonlinear state and parameter estimation in a bioreactor. AB - This paper concerns real-time, multi-rate, nonlinear state and parameter estimation in a pilot-scale biochemical reactor in which cultivation of mouse mouse hybridoma cells takes place. A multi-rate estimator is designed and implemented to estimate specific growth rate and concentrations of viable cells, total cells, glucose, glutamine, and monoclonal antibodies (MAb) in the reactor. These are estimated from frequent measurement (inferred values) of oxygen uptake rate (OUR) and infrequent and delayed measurements of the concentrations of viable cells, total cells, glucose, glutamine, and MAb. The infrequent measurements are available every 2 to 17 h with a time delay of 0.08 to 2.00 h, and OUR is inferred from dissolved oxygen concentration measurements that are available very 0.17 h. For each of the process variables, its infrequent measurement data and the profile of its estimate are presented to show the performance of the multi-rate estimator. PMID- 10099579 TI - Hydrolysis of menhaden oil by a Candida cylindracea lipase immobilized in a hollow-fiber reactor. AB - A lipase from Candida cylindracea immobilized by adsorption on microporous polypropylene fibers was used to selectively hydrolyze the saturated and monounsaturated fatty acid residues of menhaden oil at 40 degrees C and pH 7.0. At a space time of 3.5 h, the shell and tube reactor containing these hollow fibers gives a fractional release of each of the saturated and monounsaturated fatty acid residues (i.e., C14, C16, C16:1, C18:1) of ca. 88% of the corresponding possible asymptotic value. The corresponding coproduct glycerides retained over 90% of the initial residues of both eicosapentaenoic (EPA; C20:5) and docosahexaenoic (DHA; C22:6) acids. The half-life of the immobilized lipase was 170 h when the reactor was operated at the indicated (optimum) conditions. Rate expressions associated with a generic ping-pong bi-bi mechanism were used to fit the experimental data for the lipase catalyzed reaction. Both uni- and multiresponse nonlinear regression methods were employed to determine the kinetic parameters associated with these rate expressions. The best statistical fit of the uniresponse data was obtained for a rate expression, which is formally equivalent to a general Michaelis-Menten mechanism. After reparameterization, this rate expression reduced to a pseudo-first-order model. For the multiresponse analysis, a model that employed a normal distribution of the ratio of Vmax/Km with respect to the chain length of the fatty acid residues provided the best statistical fit of the experimental data. PMID- 10099580 TI - Main and interaction effects of acetic acid, furfural, and p-hydroxybenzoic acid on growth and ethanol productivity of yeasts. AB - The influence of the factors acetic acid, furfural, and p-hydroxybenzoic acid on the ethanol yield (YEtOH) of Saccharomyces cerevisiae, bakers' yeast, S. cerevisiae ATCC 96581, and Candida shehatae NJ 23 was investigated using a 2(3) full factorial design with 3 centrepoints. The results indicated that acetic acid inhibited the fermentation by C. shehatae NJ 23 markedly more than by bakers' yeast, whereas no significant difference in tolerance towards the compounds was detected between the S. cerevisiae strains. Furfural (2 g L-1) and the lignin derived compound p-hydroxybenzoic acid (2 g L-1) did not affect any of the yeasts at the cell mass concentration used. The results indicated that the linear model was not adequate to describe the experimental data (the p-values of curvatures were 0.048 for NJ 23 and 0.091 for bakers' yeast). Based on the results from the 2(3)-full factorial experiment, an extended experiment was designed based on a central composite design to investigate the influence of the factors on the specific growth rate (mu), biomass yield (Yx), volumetric ethanol productivity (QEtOH), and YEtOH. Bakers' yeast was chosen in the extended experiment due to its better tolerance towards acetic acid, which makes it a more interesting organism for use in industrial fermentations of lignocellulosic hydrolysates. The inoculum size was reduced in the extended experiment to reduce any increase in inhibitor tolerance that might be due to a large cell inoculum. By dividing the experiment in blocks containing fermentations performed with the same inoculum preparation on the same day, much of the anticipated systematic variation between the experiments was separated from the experimental error. The results of the fitted model can be summarised as follows: mu was decreased by furfural (0-3 g L 1). Furfural and acetic acid (0-10 g L-1) also interacted negatively on mu. Furfural concentrations up to 2 g L-1 stimulated Yx in the absence of acetic acid whereas higher concentrations decreased Yx. The two compounds interacted negatively on Yx and YEtOH. Acetic acid concentrations up to 9 g L-1 stimulated QEtOH, whereas furfural (0-3 g L-1) decreased QEtOH. Acetic acid in concentrations up to 10 g L-1 stimulated YEtOH in the absence of furfural, and furfural (0-2 g L-1) slightly increased YEtOH in the absence of acetic acid whereas higher concentrations caused inhibition. Acetic acid and furfural interacted negatively on YEtOH. PMID- 10099581 TI - Trichloroethene degradation in a two-step system by methylosinus trichosporium OB3b. Optimization of system performance: use of formate and methane. AB - The breakdown of dissolved TCE in a two-step bioremediation system is described. In the first reactor, the organism Methylosinus trichosporium OB3b is grown; in the second reactor, consisting of three 17-L column reactors in series, the cells degrade TCE. A special design allowed both for the addition of air (uG,s = 0.01 0. 04 mm s-1) in the conversion reactor to prevent oxygen limitation while minimizing stripping of TCE, and for the use of methane as exogenous electron donor. In two-step systems presented thus far, only formate was used (excess, 20 mM). We found formate additions could be reduced by 75% (15 degrees C), whereas small amounts of methane (0.02-0.04 mol CH4/g cells) could replace formate and led to equally optimal results. Example calculations show that up to 90% reduction in operating cost of chemicals can be obtained by using methane instead of formate. A model was developed to describe each of the conditions studied: excess formate and optimal methane addition, suboptimal formate addition and suboptimal methane addition. Using parameters obtained from independent batch experiments, the model gives a very good description of the overall TCE conversion in the two-step system. The system presented is flexible (oxygen/methane addition) and can easily be scaled up for field application. The model provides a tool for the design of an effective and low-cost treatment system based on methane addition in the conversion reactor. PMID- 10099582 TI - The effect of redox potential changes on reductive dechlorination of pentachlorophenol and the degradation of acetate by a mixed, methanogenic culture AB - The effect of changes in redox potential on methanogenesis from acetate, and on the reductive dechlorination of pentachlorophenol (PCP), was evaluated using a computer-monitored and feedback-controlled bioreactor. PCP was transformed via 2,3,4, 5-tetrachlorophenol (2,3,4,5-TeCP) to 3,4,5-trichlorophenol (3,4, 5-TCP). In 6- to 12-d experiments, pH, acetate concentration, and temperature were held constant; the redox potential, defined here as the potential measured at a platinum electrode (EPt), was maintained at different set points, while transformation of multiple PCP additions was monitored. Without redox potential control, the value of EPt for the culture was approximately -0.26 V (vs. SHE). The value of EPt was elevated from -0.26 V for periods up to 10 h by computer controlled addition of H2O2 or K3Fe(CN)6. Methanogenesis continued during a relatively mild shift of EPt to -0.2 V with H2O2, but was halted when EPt was raised to -0.1 V with either H2O2 or K3Fe(CN)6. Methanogenesis resumed when EPt returned to -0.26 V. During periods in which EPt was elevated significantly and methanogenesis stopped, transformation of PCP and 2,3,4,5-TeCP continued at progressively slower rates, but the rate of 2,3,4, 5-TeCP transformation was diminished to a greater extent. When a small volume of pure H2 was added to the reactor headspace, while EPt was maintained at -0.1 V, reductive dechlorination rates increased dramatically. Lower H2 concentrations during periods of oxidant addition, perhaps due to the effect of the oxidant on H2-producing bacteria, may contribute to decreased reductive dechlorination rates. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099583 TI - Use of thiobacillus ferrooxidans in a coupled microbiological-electrochemical system for wastewater detoxification AB - We have developed a mixed system, electrochemical-microbiological, that can be used for detoxifying organic compounds present in wastewater. In this system, organic matter oxidation takes place at the anode of an electrochemical reactor while ferric iron reduction takes place at the cathode. We have used a growing culture of Thiobacillus ferrooxidans to regenerate the ferric ions consumed. The culture is used as the catholyte (solution in the cathode compartment) of the system and is therefore permanently subjected to an electric field. We have verified that, under our working conditions, the culture is able to oxidize ferrous ions for long periods of time (up to 15 days) depending on the intensity of the applied current. We have checked the performance of this system in methanol oxidation. Our results show that it decreases the energy cost by 35% when com- pared with the pure electrochemical system traditionally used. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099584 TI - Phosphate release and heavy metal accumulation by biofilm-immobilized and chemically-coupled cells of a Citrobacter sp. pre-grown in continuous culture. AB - A heavy metal-accumulating Citrobacter sp. was grown in carbon-limiting continuous culture in an air-lift fermentor containing raschig rings as support for biofilm development. Planktonic cells from the culture outflow were immobilized in parallel on raschig rings by chemical coupling (silanization), for quantitative comparison of phosphatase activity and uranyl uptake by both types of immobilized cell. The flow rate giving 50% conversion of substrate to product (phosphate) in flow-through reactors was higher, by 35-40%, for the biofilm immobilized cells, possibly exploiting a pH-buffering effect of inorganic phosphate species within the extracellular polymeric material. Upon incorporation of uranyl ions (0.2 mM UO22+), both types of cell removed more than 90% of the input UO22+ at slow flow rates, but the chemically-coupled cells performed better at higher flow rates. The deposited material (HUO2PO4) subsequently removed Ni2+ from a second flow via intercalative ion exchange of Ni2+ into the crystalline HUO2PO4.4H2O lattice. This occurred irrespective of the method of coupling of the biomass to the support and suggested that uranyl phosphate accumulated by both types of cell has potential as a bio-inorganic ion exchanger-a potential use for the uranium recoved from primary waste treatment processes. PMID- 10099585 TI - An analysis of a trickle-bed bioreactor: carbon disulfide removal. AB - An analysis of the local processes occurring in a trickle-bed bioreactor (TBB) with a first-order bioreaction shows that the identification of the TBB operating regime requires knowledge of the substrate concentration in the liquid phase. If the substrate liquid concentration is close to 0, the rate-controlling step is mass transfer at the gas-liquid interface; when it is close to the value in equilibrium with the gas phase, the controlling step is the phenomena occurring in the biofilm. CS2 removal rate data obtained in a TBB with a Thiobacilii consortia biofilm are analyzed to obtain the mass transfer and kinetic parameters, and to show that the bioreactor operates in a regime mainly controlled by mass transfer. A TBB model with two experimentally determined parameters is developed and used to show how the bioreactor size depends on the rate-limiting step, the absorption factor, the substrate fractional conversion, and on the gas and liquid contact pattern. Under certain conditions, the TBB size is independent of the flowing phases' contact pattern. The model effectively describes substrate gas and liquid concentration data for mass transfer and biodegradation rate controlled processes. PMID- 10099586 TI - Biosynthesis and ultrasonic degradation of bacterial poly(gamma-glutamic acid). AB - A study of the production of poly(gamma-glutamic acid) (PGGA) by Bacillus licheniformis NCIMB 11709 grown on medium E in shake flasks at 30 degrees C is reported. The enantiomeric composition of PGGA was found to be highly sensitive to the concentration of Mn++, especially when the ion is present in small amounts (100 MUm) near the top of the bed consumed substrate at significantly lower rates per unit biomass than particles with thin biofilm (10-20 MUm) near the bottom of the bed, thereby suggesting that substrate mass-transfer resistance through biofilm may limit biodegradation rates in the upper portion of the FBB. Large agglomerates of biomass floc and sand, which formed at the top of the fluidized bed, and sand particles with thick biofilm were susceptible to washout from the FBB, causing operational and treatment instability. Radial injection of supplemental liquid feed near the top of the bed increased shear and mixing, thereby preventing formation and washout of agglomerates and thickly coated sand particles. Supplemental liquid injection caused the mean specific biomass loading on the sand to increase and also increased the total biomass inventory in the FBB. Rates of biodegradation in the FBB appeared to be limited by penetration of substrates into the biofilm and absorption of oxygen from air into the wastewater. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099588 TI - On-line monitoring of the progress of infection in Sf-9 insect cell cultures using relative permittivity measurements. AB - The use of on-line relative permittivity (epsilon') measurements for monitoring cultures of Sf-9 cells was evaluated in a batch culture and a batch infected with a baculovirus expressing beta-galactosidase. It was found that viable cell density and volume essentially accounted for all the variation in epsilon' in both non-infected and synchronously infected cultures, indicating that the epsilon' of a cell suspension was sensitive only to changes in the viable cell population. Additionally the parameter provided clearly defined signposts of the progress of the infection. PMID- 10099590 TI - Wine vinegar production using a noncommercial 100-litre bubble column reactor equipped with a novel type of dynamic sparger AB - This paper describes batch and semicontinuous acetic acid fermentations for wine vinegar production carried out with Acetobacter pasteurianus, and an industrial strain using a noncommercial 100-L bubble column reactor equipped with a novel type of gas-liquid dynamic sparger. Results showed acetification rates with this fermentor (i.e., an overall acetic acid productivity of 1. 8 g/L/h and yield of 94%) similar to that of the Frings acetator and higher as compared to others fermentors in current industrial use in Spanish wine vinegar factories, and a linear relationship between overall productivity and kLa with different operating conditions and fermentation scales. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099591 TI - On-line study of growth kinetics of single hyphae of Aspergillus oryzae in a flow through cell. AB - Using image analysis the growth kinetics of the single hyphae of the filamentous fungus Aspergillus oryzae has been determined on-line in a flow-through cell at different glucose concentrations in the range from 26 mg L-1 to 20 g L-1. The tip extension rate of the individual hyphae can be described with saturation type kinetics with respect to the length of the hyphae. The maximum tip extension rate is constant for all hyphae measured at the same glucose concentration, whereas the saturation constant for the hyphae varies significantly between the hyphae even within the same hyphal element. When apical branching occurs, it is observed that the tip extension rate decreases temporarily. The number of branches formed on a hypha is proportional to the length of the hypha that exceeds a certain minimum length required to support the growth of a new branch. The observed kinetics has been used to simulate the outgrowth of a hyphal element from a single spore using a Monte Carlo simulation technique. The simulations shows that the observed kinetics for the individual hyphae result in an experimentally verified growth pattern with exponential growth in both total hyphal length and number of tips. PMID- 10099592 TI - Enzymatic grafting of a natural product onto chitosan to confer water solubility under basic conditions AB - Chitosan is a natural biopolymer whose rich amine functionality confers water solubility at low pH. At higher pH's (greater than 6. 5), the amines are deprotonated and chitosan is insoluble. To attain water solubility under basic conditions we enzymatically grafted the hydrophilic compound chlorogenic acid onto chitosan. Despite its name, chlorogenic acid is a nonchlorinated phenolic natural product that has carboxylic acid and hydroxyl functionality. The enzyme in this study was tyrosinase, which converts a wide range of phenolic substrates into electrophilic o-quinones. The o-quinones are freely diffusible and can undergo reaction with the nucleophilic amino groups of chitosan. Using slightly acidic conditions (pH = 6), it was possible to modify chitosan under homogeneous conditions. When the amount of chlorogenic acid used in the modification reaction exceeded 30% relative to chitosan's amino groups, the modified chitosan was observed to be soluble under both acidic and basic conditions, and to have a pH window of insolubility at near neutral pH. 1H NMR spectra confirmed that chitosan was chemically modified, although the degree of modification was low. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099594 TI - Microbiological and kinetic aspects of a biofilter for the removal of toluene from waste gases AB - Microbiological and kinetic aspects of a biofilter inoculated with a consortium of five bacteria and two yeast adapted to remove toluene vapors were investigated. Initially the toluene sorption isotherm on peat and the effect of different environmental conditions on the toluene consumption rates of this consortium were measured. The fast start-up of the biofilter and the decay in the elimination capacity (EC) were reproduced using microcosm assays with toluene successive additions. Nutrient limitation and a large degree of heterogeneity were also detected. EC values, extrapolated from microcosms, were higher than biofilter EC when it was operating close to 100% efficiency but tended to relate better as the biofilter EC diminished. In studies on the microbial evolution in the biofilter, an increase in the cell count and variation in the ecology of the consortium were noted. Bacterial counts up to 10 x 10(11) cfu/gdry peat were found in 88 days, which corresponds to about a 10(4) increase from inoculum. Observations with SEM showed a nonuniform biofilm development on the support and the presence of an extracellular material. The results obtained in this work demonstrated that activity measurement in microcosms concomitant to the biofilter operation could be an important tool for understanding, predicting and improving the biofiltration performance. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099593 TI - Protein formulation and lyophilization cycle design: prevention of damage due to freeze-concentration induced phase separation. AB - Hemoglobin has been previously shown to unfold during freeze drying when lyophilized from formulations that undergo freeze-concentration induced phase separation (Heller et al. 1997. Biotechnol Prog 13:590-596). In this report, we show that such damage may be avoided using kinetic strategies to arrest the phase separation. By rapidly cooling samples during liquid nitrogen spray-freeze drying, the time that the formulation spends in temperature regimes (ca. -3 to 23 degrees C) in which phase separation is both thermodynamically favorable and kinetically realizable is minimized. Increased protein damage with decreasing cooling rates and/or longer annealing periods at -7 degrees C is observed by FTIR spectroscopy. Phase separation and concomitant protein damage may also be avoided by addition of mannitol at concentrations sufficient to cause crystallization. Mannitol crystals segregate the freeze concentrated solution into microscopic domains that block propagation and nucleation of phase separating events. Addition of noncrystallizing sugars, such as sucrose and trehalose, or nonionic surfactants, such as Tween 80 and Triton X-100, has little protective effect against phase separation induced damage during freezing drying. PMID- 10099595 TI - Computational and experimental investigation of flow and particle settling in a roller bottle bioreactor. AB - It is shown that cell settling is a key factor affecting the performance of roller bottle bioreactors. The two-dimensional cross-sectional flow at the center of a roller bottle is simulated using a finite difference method, and the settling behavior of cells is simulated using particle dynamics algorithms and validated experimentally using fluorescent particles. The settling behavior of particles in the roller bottle flow is studied using both steady and time dependent rotation rates. Under steady flow conditions the flow is divided into two regions: one where the particles settle to the wall and one where the particles remain suspended indefinitely. The relative size of these two regions depends on the ratio of the settling velocity to the rotation rate of the bottle. For unsteady flows generated by periodic changes of the bottle rotation direction, the settling of cells is accelerated significantly, leading to complete deposition in just a few turns of the bottle. PMID- 10099596 TI - Gas exchange is essential for bioreactor cultivation of tissue engineered cartilage. AB - Tissue engineered cartilage can be grown in vitro if the necessary physical and biochemical factors are present in the tissue culture environment. Cell metabolism and tissue composition were studied for engineered cartilage cultured for 5 weeks using bovine articular chondrocytes, polymer scaffolds (5 mm diameter x 2 mm thick fibrous discs), and rotating bioreactors. Medium pH and concentrations of oxygen, carbon dioxide, glucose, lactate, ammonia, and glycosoaminoglycan (GAG) were varied by altering the exchange rates of gas and medium in the bioreactors. Cell-polymer constructs were assessed with respect to histomorphology, biochemical composition and metabolic activity. Low oxygen tension ( approximately 40 mmHg) and low pH ( approximately 6.7) were associated with anaerobic cell metabolism (yield of lactate on glucose, YL/G, of 2.2 mol/mol) while higher oxygen tension ( approximately 80 mmHg) and higher pH ( approximately 7.0) were associated with more aerobic cell metabolism (YL/G of 1.65-1.79 mol/mol). Under conditions of infrequent medium replacement (50% once per week), cells utilized more economical pathways such that glucose consumption and lactate production both decreased, cell metabolism remained relatively aerobic (YL/G of 1.67 mol/mol) and the resulting constructs were cartilaginous. More aerobic conditions generally resulted in larger constructs containing higher amounts of cartilaginous tissue components, while anaerobic conditions suppressed chondrogenesis in 3D tissue constructs. PMID- 10099597 TI - Hyaluronate-alginate gel as a novel biomaterial: mechanical properties and formation mechanism. AB - With the aim of producing a biomaterial for surgical applications, the alginate hyaluronate association has been investigated to combine the gel-forming properties of alginate with the healing properties of hyaluronate. Gels were prepared by diffusion of calcium into alginate-hyaluronate mixtures, with an alginate content of 20 mg/mL. The hyaluronate source was shown to have significant effect on the aspect and the properties of the gels. The gels have viscoelastic behaviour and the transient measurements carried out in creep mode could be interpreted through a Kelvin-Voigt generalised model: experimental data led to the steady state hardness and a characteristic viscosity of the gel. Gels prepared from Na rooster comb hyaluronate with weight ratio up to 0.50 have satisfactory mechanical properties, and fully stable gels are obtained after a few days; on the contrary, use of lower molecular weight hyaluronate led to loose gels for hyaluronate contents over 0.25. Gel formation was investigated by measurements of the exchange fluxes between the calcium chloride solution and the forming gel, which allowed thorough investigations of the occuring diffusion phenomena of water, calcium ion and hyaluronate. Strong interactions of water with hyaluronate reduce significantly the rate of weight loss from the gel beads and allows higher water content in steady-state gels. Calcium content in the gel samples could be correlated to the actual alginate concentration, whatever the nature and the weight ratio of hyaluronate. PMID- 10099598 TI - Detoxification of organophosphate nerve agents by immobilized Escherichia coli with surface-expressed organophosphorus hydrolase. AB - An improved whole-cell technology for detoxifying organophosphate nerve agents was recently developed based on genetically engineered Escherichia coli with organophosphorus hydrolase anchored on the surface. This article reports the immobilization of these novel biocatalysts on nonwoven polypropylene fabric and their applications in detoxifying contaminated wastewaters. The best cell loading (256 mg cell dry weight/g of support or 50 mg cell dry weight/cm2 of support) and subsequent hydrolysis of organophosphate nerve agents were achieved by immobilizing nongrowing cells in a pH 8, 150 mM citrate-phosphate buffer supplemented with 1 mM Co2+ for 48 h via simple adsorption, followed by organophosphate hydrolysis in a pH 8, 50 mM citrate-phosphate buffer supplemented with 0.05 mM Co2+ and 20% methanol at 37 degrees C. In batch operations, the immobilized cells degraded 100% of 0.8 mM paraoxon, a model organophosphate nerve agent, in approximately 100 min, at a specific rate of 0.160 mM min-1 (g cell dry wt)-1. The immobilized cells retained almost 100% activity during the initial six repeated cycles and close to 90% activity even after 12 repeated cycles, extending over a period of 19 days without any nutrient supplementation. In addition to paraoxon, other commonly used organophosphates, such as diazinon, coumaphos, and methylparathion were hydrolyzed efficiently. The cell immobilization technology developed here paves the way for an efficient, simple, and cost-effective method for detoxification of organophosphate nerve agents. PMID- 10099599 TI - Production of glomus intraradices propagules, an arbuscular mycorrhizal fungus, in an airlift bioreactor AB - This work addresses the symbiotic culture of the arbuscular mycorrhizal (AM) fungus Glomus intraradices with Daucus carota hairy roots transformed by Agrobacterium rhizogenes, in two submerged culture systems: Petri dish and airlift bioreactor. AM fungi play an active role in plant nutrition and protection against plant pathogens. These fungi are obligate biotrophs as they depend on a host plant for their needs in carbohydrates. The effect of the mycorrhizal roots inoculum-to-medium volume ratio on the growth of both symbionts was studied. A critical inoculating condition was observed at approximately 0.6 g dry biomass (DW). L-1 medium, above which root growth was significantly reduced when using a low-salt minimal (M) liquid medium previously developed for hairy root-AM fungi co-culture. Below critical inoculum conditions the maximum specific root growth and specific G. intraradices spore production rates of 0.021 and 0.035 d-1, respectively, were observed for Petri dish cultures. Maximum spore production in the airlift bioreactor was ten times lower than that of Petri dish cultures and obtained with the lowest inoculum assessed (0.13 g DW. L-1 medium) with 1.82 x 10(5) +/- 4.05 x 10(4) (SEM) spores (g DW inoculum)-1 (L medium)-1 in 107 d. This work proposes a second-generation bioprocess for AM fungi propagule production in bioreactors. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099600 TI - Optimizing the salt-induced activation of enzymes in organic solvents: effects of lyophilization time and water content. AB - The addition of simple inorganic salts to aqueous enzyme solutions prior to lyophilization results in a dramatic activation of the dried powder in organic media relative to enzyme with no added salt. Activation of both the serine protease subtilisin Carlsberg and lipase from Mucor javanicus resulting from lyophilization in the presence of KCl was highly sensitive to the lyophilization time and water content of the sample. Specifically, for a preparation containing 98% (w/w) KCl, 1% (w/w) phosphate buffer, and 1% (w/w) enzyme, varying the lyophilization time showed a direct correlation between water content and activity up to an optimum, beyond which the activity decreased with increasing lyophilization time. The catalytic efficiency in hexane varied as much as 13-fold for subtilisin Carlsberg and 11-fold for lipase depending on the lyophilization time. This dependence was apparently a consequence of including the salt, as a similar result was not observed for the enzyme freeze-dried without KCl. In the case of subtilisin Carlsberg, the salt-induced optimum value of kcat/Km for transesterification in hexane was over 20,000-fold higher than that for salt-free enzyme, a substantial improvement over the previously reported enhancement of 3750-fold (Khmelnitsky, 1994). As was found previously for pure enzyme, the salt activated enzyme exhibited greatest activity when lyophilized from a solution of pH equal to the pH for optimal activity in water. The active-site content of the lyophilized enzyme samples also depended upon lyophilization time and inclusion of salt, with opposite trends in this dependence observed for the solvents hexane and tetrahydrofuran. Finally, substrate selectivity experiments suggested that mechanism(s) other than selective partitioning of substrate into the enzyme-salt matrix are responsible for salt-induced activation of enzymes in organic solvents. PMID- 10099601 TI - Structure of lysozyme dissolved in neat organic solvents as assessed by NMR and CD spectroscopies. AB - The structure of the model protein hen egg-white lysozyme dissolved in water and in five neat organic solvents (ethylene glycol, methanol, dimethylsulfoxide (DMSO), formamide, and dimethylformamide (DMF)) has been examined by means of 1H NMR and circular dichroism (CD) spectroscopies. The NMR spectra of lysozyme reveal the lack of a defined tertiary structure in all five organic solvents, although the examination of line widths suggests the possibility of some ordered structure in ethylene glycol and in methanol. The near-UV CD spectra of the protein suggest no tertiary structure in lysozyme dissolved in DMSO, formamide, and DMF, while a distinctive (albeit less pronounced than in water) tertiary structure is seen in ethylene glycol and a drastically changed one in methanol. A highly developed secondary structure was observed by far-UV CD in ethylene glycol and methanol; interestingly, the alpha-helix content of the protein in both was greater than in water, while the beta-structure content was lower. (Solvent absorbance in the far-UV region prevents conclusions about the secondary structure in DMSO, formamide and DMF.) PMID- 10099602 TI - Strain improvement of Aspergillus sp. and Penicillium sp. by induced mutation for biotransformation of alpha-pinene to verbenol. AB - Variants of Aspergillus sp. and Penicillium sp. obtained after treatment with colchicine, ethyl methanesulphonate (EMS), or ultraviolet (UV) irradiation indicated varying levels of significant increases in their efficiency to transform alpha-pinene to verbenol. In case of Aspergillus sp. the UV-induced variant was the best performer with a 15-fold increase in biotransformation efficiency compared to the wild type. In case of colchicine and EMS-induced variants the biotransformation increases were 2- and 8-fold, respectively. The UV induced variant of Penicillium sp. was capable of eight fold increase in efficiency while the colchicine- and EMS-induced variants were 1.5- and 2-fold, respectively. The variants were characterised with respect to changes in colony morphology, spore dimension, DNA content, and products formed, viz. verbenol and verbenone. PMID- 10099604 TI - Glycosylation of a recombinant protein in the Tn5B1-4 insect cell line: influence of ammonia, time of harvest, temperature, and dissolved oxygen. AB - Glycosylation is both cell line and protein dependent. Culture conditions can also influence the profile of glycoforms produced. To examine this possibility in the insect cell/baculovirus system, structures of N-linked oligosaccharides attached to SEAP (human secreted alkaline phosphatase), expressed under various culture conditions in BTI Tn5B1-4 cells, were characterized using FACE (fluorescence-assisted carbohydrate electrophoresis). Parameters varied were time of harvest, ammonia added during infection, dissolved oxygen, and temperature. It was found that glycosylation in the insect cell/baculovirus expression system is a robust, stable system that is less perturbed by variations in culture conditions than the level of protein expression. Addition of ammonia and low oxygen conditions affected SEAP expression, but not the oligosaccharide profile of SEAP. Time of SEAP harvest increased the amount of alpha-mannosidase resistant structures from 4.1% at 34 hours postinfection (h pi), to 5.0% at 100 h pi, and to 7.5% at 120 h pi. These structures were primarily sensitive to N acetylhexosaminidase digest, although a small amount was insensitive to both mannosidase and N-acetyl-hexosaminidase digests. Lowering the temperature from 28 degrees C to 24 degrees C or even 20 degrees C, resulted in a twofold increase in oligosaccharides containing terminal alpha(1,3)-mannose residues. This condition did not affect the amount of mannosidase-resistant structures. However, this could result in more complete glycosylation of recombinant proteins in the BTI Tn5B1-4 cell line, because more structures with the potential for further processing would be produced. PMID- 10099605 TI - Genetic manipulation to identify limiting steps and develop strategies for high level expression of penicillin acylase in Escherichia coli. AB - We have identified the bottleneck steps limiting expression of penicillin acylase (PAC) through comparison of the expression performance for various PAC-expression vectors constructed by genetically modulating the efficiencies of transcription and/or translation of the pac gene. To our knowledge, this is the first report demonstrating that expression of PAC could be limited by various steps, such as transcription, translation, and post-translational steps (i.e. translocation and periplasmic processing), depending on the host/vector systems. Results also indicate that the structure of the wild-type pac gene might not be optimal for direct use in production of PAC using recombinant DNA technology. To improve the gene expression, transcription was enhanced by manipulating certain DNA bases in the pac regulatory region, whereas translation was enhanced by enlarging the spacing between the ribosome binding site and the ATG initiation codon to increase the initiation efficiency. The information is useful in terms of developing genetic strategies for overproduction of recombinant PAC in Escherichia coli. PMID- 10099606 TI - Generalized linearization of kinetics of glucose isomerization to fructose by immobilized glucose isomerase. AB - The kinetic parameters of both glucose isomerization to fructose and immobilized glucose isomerase (GI) inactivation calculated under different conditions are compared and discussed. Utilizing these figures, the possibility of generalizing a linear model, previously proposed for the kinetics of glucose isomerization by immobilized glucose isomerase, is investigated, so as to apply them to whole ranges of temperature and concentrations of actual interest in industrial processes. The proposed model is a satisfactory approximation of the more involved Briggs-Haldane approach and substantially simplifies the problem of optimizing an industrial fixed-bed column for high-fructose corn syrup (HFCS) production. PMID- 10099607 TI - Use of an ethanol sensor for feedback control of growth and expression of TBV25H in Saccharomyces cerevisiae. AB - A process for production of a malaria transmission blocking vaccine candidate under the control of the ADH2 promoter in Saccharomyces cerevisiae was developed. Monitoring and controlling the ethanol concentration during the process is essential for successful expression of the recombinant protein. A simple sensor accomplishing this task has been developed, the principle of its operation is the following: air-flow through silicone tubing submerged in the media picks up ethanol, which is detected by an alcohol sensor that relays a signal to a controller regulating the amount of ethanol added to the culture. The sensor was used successfully in high cell density cultures of various scales. PMID- 10099608 TI - Virus-like particle analysis in yeast homogenate using a laser light-scattering assay. AB - Virus-like particles (VLPs) expressed intracellularly by the yeast S. cerevisiae have helped set the framework of a wide range of biologicals, particularly as carriers for viral antigens. This article investigates the use of dynamic light scattering (DLS) for the rapid evaluation of the concentration and purity of VLPs to aid the complex purification strategy. Development of the assay was performed in a high background process stream (yeast homogenate) and involved a change in the signal proportional to the VLP concentration by addition of antibodies that bind on the VLP surface and detection of that size change by DLS. Overall, the assay was found to provide a significant improvement of rapid monitoring alternatives for VLPs, exhibiting good sensitivity and speed of measurement. Data are given for the use of the DLS-based assay for optimization of VLP release during a yeast cell disruption treatment. PMID- 10099609 TI - Effect of ion binding on protein transport through ultrafiltration membranes. AB - Electrostatic interactions can have a significant impact on protein transmission through semipermeable membranes. Experimental data for the transport of bovine serum albumin (BSA) through a polyethersulfone ultrafiltration membrane were obtained in different salt solutions over a range of pH and salt concentrations. Net BSA charge under the same conditions was evaluated from mobility data measured by capillary electrophoresis. The results show that specific ionic composition, in addition to solution pH and ionic strength, can strongly affect the rate of protein transport through semipermeable ultrafiltration membranes. The effects of different ions on BSA sieving are due primarily to differences in ion binding to the protein, which leads to significant differences in the net protein charge at a given pH and ionic strength. This effect could be described in terms of an effective protein radius, which accounts for the electrostatic exclusion of the charged protein from the membrane pores. These results provide important insights into the nature of the electrostatic interactions in membrane systems. PMID- 10099610 TI - Kinetic modeling of oligosaccharide synthesis catalyzed by leuconostoc mesenteroides NRRL B-1299 dextransucrase AB - The kinetic behavior of soluble and insoluble forms of dextransucrase from Leuconostoc mesenteroides NRRL B-1299 was investigated with sucrose as substrate and maltose as acceptor. To study the parameters involved, a kinetic model was applied that was previously developed for L. mesenteroides NRRL B-512F dextransucrase. There are significant correlations between the parameters of the soluble form of B-1299 dextransucrase and those calculated for the B-512F enzyme; that is, their properties are comparable and differ from those of the insoluble form of B-1299 dextransucrase. Whereas the calculated parameters for high maltose concentrations describe the kinetic behavior very well, the time curves for low maltose concentrations were not described correctly. Therefore, the parameters were calculated separately for the two ranges. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099611 TI - Kinetics of enzymatic solid-to-solid peptide synthesis: intersubstrate compound, substrate ratio, and mixing effects. AB - A systematic study of thermolysin-catalyzed solid-to-solid peptide synthesis using Z-Gln and Leu-NH2 as model substrates was carried out. The aim was to extend the kinetic knowledge of this new reaction system involving highly concentrated substrate mixtures with little water (10% to 20% w/w). Preheating of the substrates, and ultrasonic treatment, as described in the literature, had no significant effect on our system. The formation of a third compound, the salt of the two substrates, was discovered during melting point experiments. This was associated with a very strong dependence of kinetics on the exact substrate ratio (e.g., twofold higher initial rate with 60% Leu-NH2 and 40% Z-Gln than with the equimolar substrate ratio). A model was developed to show how the composition and pH of the liquid phase depends on the substrate ratio, and seemed to explain the experimental rates. In addition, the influences of different mixing and water distribution methods are described. Finally, we can now summarize the major effects of the reaction system as a starting point for further research and scale up studies. PMID- 10099612 TI - Molecular modeling for the design of a biomimetic chimeric ligand. Application to the purification of bovine heart L-lactate dehydrogenase. AB - Molecular modeling was employed for the design of a biomimetic chimeric ligand for L-lactate dehydrogenase (LDH). This ligand is an anthraquinone monochlorotriazinyl dye comprising two moieties: (a) the ketocarboxyl biomimetic moiety, 2-(4-aminophenyl)-ethyloxamic acid, linked on the monochlorotriazine ring, mimicking the natural substrate of LDH, and (b) the anthraquinone chromophore moiety, linked also on the same monochlorotriazine ring via a diaminobenzenesulfonate group, acting as pseudomimetic of the cofactor NAD+. The positioning of the dye in the enzyme's binding site is primarily achieved by the recognition and positioning of the pseudomimetic anthraquinone moiety. The positioning of the biomimetic ketocarboxylic moiety is based on a match between the polar and hydrophobic regions of the enzyme's binding site with those of the biomimetic moiety of the ligand. The length of the biomimetic moiety is predetermined for the ketoacid to approach the enzyme catalytic site and form charge-charge interactions. The biomimetic chimeric ligand and the commercial nonbiomimetic ligand Cibacron(R) blue 3GA (CB3GA), were immobilized on crosslinked beaded agarose gel via their chlorotriazine ring. The two affinity adsorbents were evaluated for their purifying ability for LDH from six sources (bovine heart and pancreas, porcine muscle, chicken liver and muscle, and pea seeds). The biomimetic adsorbent exhibited approximately twofold higher purifying ability for LDH compared to the CB3GA adsorbent; therefore, the former was integrated in the purification procedure of LDH from bovine heart extract. The LDH afforded by this two-step purification procedure shows specific activity equal to 600 U/mg (25 degrees C) and a single band after SDS-PAGE analysis. PMID- 10099613 TI - Enzymatic synthesis of arginine-based cationic surfactants. AB - A novel enzymatic approach for the synthesis of arginine N-alkyl amide and ester derivatives is reported. Papain deposited onto solid support materials was used as catalyst for the amide and ester bond formation between Z-Arg-OMe and various long-chain alkyl amines and alcohols (H2N-Cn2, HO-Cn; n = 8-16) in organic media. Changes in enzymatic activity and product yield were studied for the following variables: organic solvent, aqueous buffer content, support for the enzyme deposition, presence of additives, enzyme loading, substrate concentration, and reaction temperature. The best yields (81-89%) of arginine N-alkyl amide derivatives were obtained at 25 degrees C in acetonitrile with an aqueous buffer content ranging from 0 to 1% (v/v) depending on the substrate concentration. The synthesis of arginine alkyl ester derivatives was carried out in solvent-free systems at 50 or 65 degrees C depending on the fatty alcohol chain length. In this case, product yields ranging from 86 to 89% were obtained with a molar ratio Z-Arg-OMe/fatty alcohol of 0.01. Papain deposited onto polyamide gave, in all cases, both the highest enzymatic activities and yields. Under the best reaction conditions the syntheses were scaled up to the production of 2 g of final product. The overall yields, which include reaction, Nalpha-benzyloxycarbonyl group (Z) deprotection and purification, varied from 53 to 77% of pure (99.9% by HPLC) product. PMID- 10099614 TI - Effect of temperature on the saccharide composition obtained after alpha amylolysis of starch AB - The hydrolysis of starch to low-molecular-weight products (normally characterised by their dextrose equivalent (DE), which is directly related to the number average molecular mass) was studied at different temperatures. Amylopectin potato starch, lacking amylose, was selected because of its low tendency towards retrogradation at lower temperatures. Bacillus licheniformis alpha-amylase was added to 10% [w/w] gelatinised starch solutions. The hydrolysis experiments were done at 50, 70, and 90 degrees C. Samples were taken at defined DE values and these were analysed with respect to their saccharide composition. At the same DE the oligosaccharide composition depended on the hydrolysis temperature. This implies that at the same net number of bonds hydrolysed by the enzyme, the saccharide composition was different. The hydrolysis temperature also influenced the initial overall molecular-weight distribution. Higher temperatures led to a more homogenous molecular weight distribution. Similar effects were observed for alpha-amylases from other microbial sources such as Bacillus amyloliquefaciens and Bacillus stearothermophilus. Varying the pH (5.1, 6.2, and 7.6) at 70 degrees C did not significantly influence the saccharide composition obtained during B. licheniformis alpha-amylase hydrolysis. The underlying mechanisms for B. licheniformis alpha-amylase were studied using pure linear oligosaccharides, ranging from maltotriose to maltoheptaose as substrates. Activation energies for the hydrolysis of individual oligosaccharides were calculated from Arrhenius plots at 60, 70, 80, and 90 degrees C. Oligosaccharides with a degree of polymerisation exceeding that of the substrate could be detected. The contribution of these oligosaccharides increased as the degree of polymerisation of the substrate decreased and the temperature of hydrolysis increased. The product specificity decreased with increasing temperature of hydrolysis, which led to a more equal distribution between the possible products formed. Calculations with the subsite map as determined for the closely related alpha amylase from B. amyloliquefaciens reconfirmed this finding of a decreased substrate specificity with increased temperature of hydrolysis. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099615 TI - Determination of the phosphorylated sugars of the Embden-Meyerhoff-Parnas pathway in Lactococcus lactis using a fast sampling technique and solid phase extraction. AB - An experimental procedure for the determination of intracellular concentrations of the phosphorylated sugars in the lactic acid bacterium Lactococcus lactis is presented. The first step of the procedure is a rapid sampling of a small volume of the growth medium into 60% (v/v) methanol precooled to -35 degrees C, bringing about a fast and complete stop of all metabolic activity. In contrast to yeast the metabolites leak out of the cells when these are brought into contact with methanol and are present in the medium and in the biomass after the quenching. A liquid-liquid extraction with chloroform at -25 degrees C ensures a total permeability of the cellular membrane towards the metabolites of interest as well as the inactivation of enzymes liable to alter their levels. The final step of the procedure consists in a solid phase extraction using columns with a high affinity for phosphorylated components. The internal standard was recovered to an extent of 85-95%. PMID- 10099616 TI - A comprehensive model of anaerobic bioconversion of complex substrates to biogas AB - A dynamic model describing the anaerobic degradation of complex material, and codigestion of different types of wastes, was developed based on a model previously described (Angelidaki et al., 1993). In the model, the substrate is described by its composition of basic organic components, i.e., carbohydrates, lipids, and proteins, the concentration of intermediates such as volatile fatty acids and long-chain fatty acids, and important inorganic components, i.e., ammonia, phosphate, cations, and anions. This allows dynamic changes of the process during a shift of substrate composition to be simulated by changing the input substrate data. The model includes 2 enzymatic hydrolytic steps, 8 bacterial steps and involves 19 chemical compounds. The model also includes a detailed description of pH and temperature characteristics. Free ammonia, acetate, volatile fatty acids, (VFA) and long-chain fatty acids (LCFA) constitute the primary modulating factors in the model. The model was tested with success in lab-scale reactors codigesting manure with glycerol trioleate or manure with gelatin. Finally, the model was validated using results from a full-scale biogas plant codigesting manure together with a proteinous wastewater and with bentonite bound oil, which is a waste with high content of lipids. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099617 TI - An expression system matures: a highly efficient and cost-effective process for phytase production by recombinant strains of Hansenula polymorpha. AB - An efficient process was developed for the low-cost production of phytases using Hansenula polymorpha. Glucose or glucose syrups, previously reported as repressive substrates, were used as main carbon sources during fermentation. Glucose was even the most productive substrate for high-level production of phytases. Compared with the process using glycerol, the standard carbon source used for this process until now, the use of glucose led to a reduction of more than 80% in the raw materials costs. In addition, exceptionally high concentrations of active enzyme (up to 13.5 g/L) were obtained in the medium, with phytase representing over 97% of the total accumulated protein. These levels greatly exceed those reported so far for any yeast-based expression system. Very efficient downstream processing procedures were developed with product recovery yields over 90%. Both the fermentation and downstream processing were successfully tested in pilot scale up to 2000 L. As a result, H. polymorpha can be used as a highly competitive system for low-cost phytase production. PMID- 10099618 TI - Solid-state fermentation in rotating drum bioreactors: operating variables affect performance through their effects on transport phenomena. AB - Aspergillus oryzae ACM 4996 was grown on an artificial gel-based substrate and on steamed wheat bran during solid-state fermentations in 18.7 L rotating drum bioreactors. For gel fermentations fungal growth decreased as rotational speed increased, presumably due to increased shear. For wheat bran fermentations fungal growth improved under agitated compared to static culture conditions, due to superior heat and mass transfer. We conclude that the effects of operational variables on the performance of SSF bioreactors are mediated by their effects on transport phenomena such as mixing, shear, heat transfer, and mass transfer within the substrate bed. In addition, the substrate characteristics affect the need for and the rates of these transport processes. Different transport phenomena may be rate limiting with different substrates. This work improves understanding of the effects of bioreactor operation on SSF performance. PMID- 10099619 TI - Expression of soluble and catalytically active plant (monocot) beta-glucosidases in E. coli. AB - Complementary DNAs encoding mature beta-glucosidase proteins Glu1 and Glu2 of maize were amplified by the polymerase chain reaction (PCR) and cloned into the expression vector pET21a. Both Glu1 and Glu2 isozymes were expressed in high yield ( approximately 3.8% of the total soluble protein and 32% of the total expressed protein) in E. coli. Recombinant enzymes were active on a variety of artificial and natural substrates at levels similar to those of their native counterparts isolated from maize seedlings. Western blot analysis confirmed that both recombinant isozymes were immunoreactive with maize anti-beta-glucosidase sera and their molecular sizes were identical to those of the native maize Glu1 and Glu2 isozymes. Zymogram assays in native gels revealed that recombinant enzymes had the same electrophoretic mobility and substrate specificity as their native counterparts. PMID- 10099620 TI - Kinetic model of biosurfactant-enhanced hexadecane biodegradation by Pseudomonas aeruginosa. AB - Many sites of environmental concern contain groundwater contaminated with nonaqueous phase liquids (NAPL). In such sites interfacial processes may affect both the equilibrium and kinetic behavior of the system. In particular, insoluble hydrocarbon partitioning and microbial biodegradation of insoluble hydrocarbon are influenced by the physicochemical and interfacial characteristics of the system. A mechanistic model describing the influence of biological surfactants on microbial biodegradation of liquid-phase insoluble hydrocarbon and subsequent reduction of nonaqueous-phase liquid hydrocarbon is presented. The model consists of six coupled differential equations which use lumped kinetic parameters to describe surfactant micelle formation and diffusion to the microbial cell, nonlinear kinetic expressions for microbial growth and degradation of insoluble hydrocarbon, kinetic spatial descriptions of the change in NAPL-phase droplet size and the organic phase volume fraction with time, as well as equilibrium partitioning expressions for hydrophobic organic contaminant partioning into the surfactant micelle. The model is validated by comparison to data obtained for hexadecane degradation in a well-mixed batch system by the biosurfactant producing microorganism Pseudomonas aeruginosa strain PG201 as well as for nonproducing mutants' growth and hexadecane biodegradation in the presence of exogenously added biosurfactant. Experimentally determined biological growth parameters, as well as physical parameters such as hydrocarbon droplet size, were applied in the kinetic model. Parameter sensitivity analysis was performed on the physical and biological parameters in the model. The parameter sensitivity analysis indicates that for the biological system examined the rate of hydrocarbon solubilization and micellar transport to the cell controls the rate at which cellular uptake and biodegradation of insoluble hydrocarbon occurs. Practical aspects relating to use of the model for support of surfactant-based bioremediation efforts are discussed. PMID- 10099621 TI - Oxygen, pH value, and carbon source induced changes of the mode of oscillation in synchronous continuous culture of Saccharomyces cerevisiae. AB - Oscillations of measured process parameters occur in continuous cultures of Saccharomyces cerevisiae owing to a partial synchronization of budding. Intentional changes of the oxygen concentration, pH value, and carbon source cause effects on the period length similar to those known from variations of the dilution rate. The generation times of parent and daughter cells frequently differ in synchronous culture. To analyze the oscillation the term mode IJ of oscillation is used, which is defined as the ratio IJ of the generation times of parent and daughter cells. When the dissolved oxygen concentration was reduced to zero, the mode of oscillation changed within two periods from mode 12 to mode 11, caused by a decrease of the generation time of daughter cells and an increase of that of the parent cells. When the pH value was slowly reduced from 5.0 to 3.9, a change from mode 112 to mode 13 was observed. Mode 13, representing one parent and three daughter cell populations (the start of budding of each of the three being delayed by one period), denotes an elongated generation time of the daughter cells compared to mode 112, marked by one parent and two different daughter cell classes. When the carbon source galactose was replaced by glucose a mode change from mode 12 to mode 11 was observed. This alteration of the mode was found to be dependent on the status of the cell cycle at the time when the carbon source is changed. The population distribution in batch cultures with glucose or galactose as a substrate was analysed by dyeing the DNA and counting the bud scars. Galactose provoked higher growth rates for the older cells. According to the model for stationary synchronous growth parameters like DO, pH value or the type of carbon source can be varied within a certain range without effecting the period length. If the variation imposes a certain stress, the culture switches to a new mode. These kinds of parameters therefore provide selective measures to influence the period lengths and the modes of oscillation. PMID- 10099622 TI - Biomass accumulation and clogging in biotrickling filters for waste gas treatment. Evaluation of a dynamic model using dichloromethane as a model pollutant. AB - A dynamic model is developed that describes the degradation of volatile acidifying pollutants in biotrickling filters (BTFs) for waste gas purification. Dynamic modelling enables the engineer to predict the clogging rate of a filter bed and the time it takes the BTF to adapt to changes in its inlet concentration. The most important mechanisms that govern the behaviour of the BTF are incorporated in the model. The time scale of the accumulation of biomass in a filter is investigated, and an approach is presented that can be used to estimate how long a BTF can be operated before its packing has to be cleaned. A three month experiment was carried out to validate the model, using dichloromethane (DCM) as a model acidifying pollutant. Valuable experimental data about biomass accumulation and liquid hold-up in the reactor were obtained with an experimental set-up that allows the continuous registration of the weight of the BTF. The results show that in BTFs eliminating DCM from a waste gas, clogging is not to be expected up to concentrations of several g/m3. Model calculations based on the measurements also suggest that the maximum carbon load that can safely be applied per unit void packing volume should not exceed 0.5-1.6 C mol/(m3. h), depending on the density of the biofilm formed. The model is a good predictor of the elimination of the pollutant in the system, the axial gas and liquid concentration profiles, the axial biomass distribution, and the response of the system upon a stepwise increase in the DCM inlet concentration. The influence of the buffer concentrations in the liquid phase upon the performance of the BTF is investigated. PMID- 10099623 TI - Membrane process for biological treatment of contaminated gas streams. AB - A hollow fiber membrane bioreactor was investigated for control of air emissions of biodegradable volatile organic compounds (VOCs). In the membrane bioreactor, gases containing VOCs pass through the lumen of microporous hydrophobic hollow fiber membranes. Soluble compounds diffuse through the membrane pores and partition into a VOC degrading biofilm. The hollow fiber membranes serve as a support for the microbial population and provide a large surface area for VOC and oxygen mass transfer. Experiments were performed to investigate the effects of toluene loading rate, gas residence time, and liquid phase turbulence on toluene removal in a laboratory-scale membrane bioreactor. Initial acclimation of the microbial culture to toluene occurred over a period of nine days, after which a 70% removal efficiency was achieved at an inlet toluene concentration of 200 ppm and a gas residence time of 1.8 s (elimination capacity of 20 g m-3 min-1). At higher toluene loading rates, a maximum elimination capacity of 42 g m-3 min-1 was observed. In the absence of a biofilm (abiotic operation), mass transfer rates were found to increase with increasing liquid recirculation rates. Abiotic mass transfer coefficients could be estimated using a correlation of dimensionless parameters developed for heat transfer. Liquid phase recirculation rate had no effect on toluene removal when the biofilm was present, however. Three models of the reactor were created: a numeric model, a first-order flat sheet model, and a zero-order flat sheet model. Only the numeric model fit the data well, although removal predicted as a function of gas residence time disagreed slightly with that observed. A modification in the model to account for membrane phase resistance resulted in an underprediction of removal. Sensitivity analysis of the numeric model indicated that removal was a strong function of the liquid phase biomass density and biofilm diffusion coefficient, with diffusion rates below 10(-9) m2 s-1 resulting in decreased removal rates. PMID- 10099624 TI - Effects of dissolved oxygen on the morphology of an arachidonic acid production by Mortierella alpina 1S-4. AB - Arachidonic acid (AA) production by Mortierella alpina 1S-4 was investigated using a 50-L fermentor. In order to optimize the dissolved oxygen (DO) concentration and to investigate the effect of DO on morphology, cultivation was carried out under constant DO at various levels in the range of 3-50 ppm. To maintain a DO concentration above 7 ppm, two methods, i.e., the oxygen-enrichment (OE) method (experimental range, 25-90% oxygen gas supplied) and the pressurization (PR) method (experimental range, 180-380 kPa headspace pressure), were used. As a result, the optimum DO concentration range was found to be 10-15 ppm. In this optimum DO concentration range, the AA yield was enhanced about 1.6 fold compared to that obtained at 7 ppm DO, and there was no difference in the AA productivity between the OE and PR methods. When the DO concentration was maintained at 20-50 ppm using the OE method, the morphology changed from filaments to pellets, and the AA yield decreased drastically because of stress due to the limited mass transfer through the pellet wall. When the DO concentration was maintained at 15-20 ppm using the PR method, the morphology did not change, and the AA yield decreased gradually. PMID- 10099625 TI - Wheat prolamine crosslinking through dityrosine formation catalyzed by peroxidases: improvement in the modification of a poorly accessible substrate by "indirect" catalysis AB - "Enzyme-assisted" oxidative polymerization of wheat gliadins was performed in an attempt to obtain new protein-based networks. Two plant peroxidases (soybean and horseradish) were used to induce the dimerization of tyrosine residues. The results show that tyrosines are poorly modified by these enzymes in an aqueous medium (dityrosine corresponded to 2% of the total amount of tyrosine). Two approaches were tested to overcome problems relating to accessibility to the target tyrosines: First, the efficiency of protein crosslinking via tyrosine tyrosine aromatic ring condensation was enhanced in water when the proteins were oxidized by a fungus peroxidase (manganese-dependent peroxidase from Phanerochaete chrysosporium), which acts according to an indirect catalysis mechanism (up to 12% of the total amount of tyrosine is recovered under a dimeric form). Second, when the gliadins were dispersed in a water/dioxane (3/1) mixed solvent system, the tyrosines were more accessible on the protein surface, and similar yields were obtained with both types of peroxidase. The two types of catalysis (contact and indirect) are considered from the standpoint of the accessibility of the target residues. Enzymatic oxidations were also performed on synthetic peptides mimicking the repeatitive domains of gliadins. The results show that exposure of tyrosine to the solvent may not be sufficient to induce dityrosine formation. The mechanical properties of some films obtained from peroxidase-treated gliadins were investigated to correlate protein crosslinking with a potential application. One effect of the enzymatic treatment was to increase the tensile strength of the films. Copyright 1999 John Wiley & Sons, Inc. PMID- 10099626 TI - Crosslinking of glucoamylases via carbohydrates hardly affects catalysis but impairs stability. AB - Mild oxidation of glucoamylases from Aspergillus niger (E.C.3.2.1.3. ) with periodate, followed by incubation with adipic acid dihydrazide, covalently linked enzyme molecules via their glycosyl groups. Size exclusion chromatography demonstrated and electron microscopy confirmed the formation of tetramers and octamers. Heat inactivation studies in the range of 60 degrees to 80 degrees C indicated that, in contrast to a priori expectations, crosslinking via the carbohydrates decreased rather than increased thermostability. The covalently linked species, even the octamers, displayed similar activity as the native forms toward maltose and soluble starch, but activity toward raw starch was completely lost. PMID- 10099627 TI - Relationship between recombinant activated protein C secretion rates and mRNA levels in baby hamster kidney cells. AB - Analysis of 12 baby hamster kidney (BHK) clones in exponential growth revealed a linear relationship between cell-specific recombinant activated protein C (APC) production rates and APC mRNA levels. This correlation indicated that mRNA levels limited APC productivity. Two strategies were employed to increase APC mRNA levels and APC productivity. First, sodium butyrate was added to increase mRNA levels by two- to sixfold in five APC-producing clones to obtain up to 2.7-fold increase in APC production rate. The second strategy was to retransfect an APC producing BHK cell line with a vector containing additional APC cDNA and a mutant DHFR. This mutant DHFR gene allowed the selection of retransfected clones in higher MTX concentrations. Over two-fold higher mRNA levels were obtained in these retransfected clones and the cell-specific APC production rate increased twofold. At the highest level of APC secretion, increases in mRNA levels did not result in higher rates of APC production. Analysis of the intracellular APC content revealed a possible saturation in the secretory pathway at high mRNA levels. The relation between mRNA level and APC secretion rate was also investigated in batch culture. The levels of total cellular RNA, APC mRNA, and beta-actin mRNA were relatively stable while cells were in the exponential growth phase, but rapidly decreased when cells reached the stationary phase. The decline of cell-specific APC mRNA levels correlated with a decline in APC secretion rates, which indicated that the mRNA levels continued to limit the rates beyond the exponential phase and into the declining growth and stationary phases of batch APC production. PMID- 10099628 TI - Inoculation and growth conditions for high-cell-density expansion of mammalian neural stem cells in suspension bioreactors. AB - Inoculation and growth conditions for the large-scale expansion of mammalian neural stem cells (NSC) have been determined. We examined suspension culture bioreactors of murine NSC, and concluded that the oxygen level should be kept high (20%), and the osmolarity of the medium should be kept low (below 400 mOsm/kg). The pH of the medium was found to have a large effect on cell proliferation, and the best growth characteristics were obtained within an optimum pH range of 7. 1 to 7.5. The inoculation conditions were also seen to have a large effect not only on the growth characteristics, but also on the number of cells that die in the initial stages of the culture. For large expansion of cells, low inoculum levels (10(4) cells/mL) and single-cell suspensions proved superior, whereas, for fast expansion of cells, higher inoculum levels (10(5) cells/mL) and spheroid inoculum forms were preferred. The inoculum temperature of the medium did not have a large effect on growth characteristics, but the pH greatly influenced cell proliferation. Inoculum pH levels should also be kept between 7.1 and 7.5. If these protocols are followed, high multiplication ratios and viabilities can be obtained in a 5-day batch suspension culture bioreactor run. A large number of cells could then be used in animal models for testing of neural drugs and in research and development toward cures for neurodegenerative disorders such as multiple sclerosis (MS) and Huntington's and Parkinson's disease. The results presented here also point the way toward studies on in vitro expansion of human neural stem cells. PMID- 10099629 TI - Predictive control of hollow-fiber bioreactors for the production of monoclonal antibodies. AB - The selection of medium feed rates for perfusion bioreactors represents a challenge for process optimization, particularly in bioreactors that are sampled infrequently. When the present and immediate future of a bioprocess can be adequately described, predictive control can minimize deviations from set points in a manner that can maximize process consistency. Predictive control of perfusion hollow-fiber bioreactors was investigated in a series of hybridoma cell cultures that compared operator control to computer estimation of feed rates. Adaptive software routines were developed to estimate the current and predict the future glucose uptake and lactate production of the bioprocess at each sampling interval. The current and future glucose uptake rates were used to select the perfusion feed rate in a designed response to deviations from the set point values. The routines presented a graphical user interface through which the operator was able to view the up-to-date culture performance and assess the model description of the immediate future culture performance. In addition, fewer samples were taken in the computer-estimated cultures, reducing labor and analytical expense. The use of these predictive controller routines and the graphical user interface decreased the glucose and lactate concentration variances up to sevenfold, and antibody yields increased by 10% to 43%. PMID- 10099630 TI - Concentration-dependent internalization of a cytokine/cytokine receptor complex in human hematopoietic cells. AB - Soluble steel factor (SF) is a potent stimulator of hematopoietic progenitor cell proliferation in vitro, and cytokine combinations that include SF can support extensive expansions of hematopoietic cells. Recently, we showed that very primitive progenitor cells from normal human bone marrow require exposure to very high concentrations of cytokines to maintain their primitive status while proliferating. These cells also display higher cell-specific cytokine uptake rates than more differentiated types of hematopoietic cells. As a first step toward identifying the mechanisms involved in mediating such cytokine dose dependent effects, we have now investigated the kinetics of SF receptor (c-kit) internalization by human Mo7e cells exposed to different extracellular concentrations of soluble SF. Transfer of Mo7e cells to a higher concentration of SF caused an initially rapid downregulation of cell surface c-kit which was accompanied by a rapid depletion of extracellular SF. Confocal microscopy showed a concomitant increase in the number and intensity of intracellular c-kit aggregates. After the first 30 min, the cells continued to deplete SF from the medium but at a much slower rate. During this period, there was a gradual recovery of expression of c-kit on the cell surface. A mathematical analysis of bulk medium to cell-surface SF-mass transport indicated that the cytokine depletion rates measured were not likely to have significantly depleted the SF concentration in the microenvironment of the cells. Taken together, these results underscore the importance of monitoring and appropriately regulating cytokine concentrations in hematopoietic cell expansion cultures. They may also help to explain the different biological responses exhibited by primitive hematopoietic cells exposed to different types and concentrations of cytokines for periods of days. PMID- 10099631 TI - Influence of water activity on the enantioselective esterification of (R,S) ibuprofen by Candida antarctica lipase B in solventless media. AB - The lipase-catalyzed enantioselective esterification of ibuprofen has been studied in a media, composed only of substrates. When racemic ibuprofen is used, the alcohol-chain length affects the esterification rates of individual enantiomers, but it does not affect the enantioselectivity. Water activity affects the esterification rates of (R)- and (S)-ibuprofen differently, leading to higher enantioselectivity at lower water activities. Experiments were also conducted at various (R)- to (S)-ibuprofen ratios. It appears that the esterification rate of (R)-ibuprofen is always proportional to its concentration, whereas at low water activity the esterification rate of (S)-ibuprofen shows a saturation at higher concentrations. Other 2-phenyl carboxylic acids were studied, and the increase in apparent enantioselectivity at low-water activity was not observed for the molecules tested. PMID- 10099632 TI - Should Third-World countries pay the tab for new drug development? PMID- 10099633 TI - Teaching commitments of clinical faculty. PMID- 10099634 TI - Free Internet access for community preceptors. PMID- 10099635 TI - Neutralizing the "clerkship-timing effect". PMID- 10099636 TI - One faculty's response to the patient-physician covenant. PMID- 10099637 TI - Physician leaders take aim: a sketch of an ideal medical culture. PMID- 10099638 TI - Health care reform: has it really begun? PMID- 10099639 TI - Clinical integration and new options for academic medical institutions in network development. AB - The author outlines two options, made possible by developments in antitrust law, that can create a favored role for academic health science centers as well as for stand-alone medical schools and teaching hospitals, using the unique strengths of these institutions that are often considered weaknesses by the marketplace. The first option is the development of clinically integrated collaborations that need not be either system-wide or necessarily governed by total quality management processes, or involve the characteristics of ownership typical of the usual integrated delivery systems. The second option is the development of new clinical "products." Each option encourages creative financing, legal, medical, and governance approaches and makes it possible for centers, medical schools, and teaching hospitals to build multi-provider collaborations that are in harmony with their missions and different from the less-compatible integrated delivery systems that they often seek to build. The author provides an extensive background on antitrust law to explain the two options and the criteria for crafting them within antitrust law. He then describes how antitrust law applies to multi-provider networks and in particular to academic health science centers and free-standing medical schools and teaching hospitals, and gives examples of the kinds of fruitful collaborations these institutions could engage in. He urges those institutions to realize that if they keep faith with their best characteristics in creative new ways (such as those suggested by his article), they will thrive in the years ahead. PMID- 10099640 TI - Scientific misconduct and correcting the scientific literature. AB - Journal editors are among those who must face the issue of when and how to correct the scientific literature when an allegation or finding of scientific misconduct occurs. The author describes an instructive incident of tainted data and a subsequent allegation of misconduct that involved a federally-sponsored study where some data had been fabricated. The journals that had published or were considering articles from that study were not told about the problem for almost four years after the initial allegations of misconduct. The author then provides information to throw light on such questions as: Who has the responsibility to ensure that a manuscript that may contain falsified or fabricated data is not published? Who has the responsibility to correct the literature when falsified or fabricated data have been published, and at what point should that correction be made? For example, should it be when the problem of data is suspected or when it is proven? And if proven, proven by whom? How is the larger scientific community to be notified about the problem? Where and when should the correction or retraction appear, and what should it tell readers about the basis for the retraction or correction? She also presents data from 25 cases to show the various lengths of time involved in correcting the literature after allegations of research misconduct had been made. The author concludes that the record shows how disconnected journal editors have been from the scientific misconduct process and that expectations differ regarding the obligations of authors, research institutions, and federal agencies about informing a journal when an allegation of scientific misconduct is made about a publication in its pages. The 25 cases show that substantial delays in notifying the journal and the public about allegations and findings of scientific misconduct are endemic, and that all parties have far to go in appreciating their roles in maintaining the integrity of the biomedical literature. PMID- 10099641 TI - Medical and scientific organizations and scientific evidence in U.S. trials: lessons from European legal theory. AB - Medical and scientific societies and organizations could help to solve the problem that the U.S. judicial system has with trials involving scientific evidence. This problem is exemplified by infamous trials in which opposing high paid experts present contradictory legal theories based on the same scientific facts. The conflicting conclusions of such experts often confuse rather than clarify the issues for the jury and even the judge. Dissatisfaction with these "battles of the experts" in both civil (e.g., breast-implant litigation) and criminal (e.g., forensic use of DNA evidence) trials ranges from concern to harsh criticism. Many critics identify as models for reform the European legal systems, where scientific evidence is presented in a relatively objective manner by experts appointed by the trial court. Since they are often selected from lists of the faculties of universities, European experts are more likely to represent prevailing views of the relevant scientific community. Most American judges are reluctant to appoint experts, but there are some examples of their increasing use, and legal mechanisms and procedures exist that would allow this approach. Professional organizations of scientists and physicians could serve an important role in fostering the forensic use of neutral expertise by developing lists of experts for the courts; this would at least provide the potential for unbiased experts in complex cases that involve scientific and medical evidence. Such expertise could help American courts in their quests for scientific and legal truths. PMID- 10099642 TI - Motivation in medical education: how theory can inform our practice. AB - Medical educators seek to understand and facilitate learners' motivations to acquire the skills, knowledge, values, and attitudes that will prepare them for life-times of learning and providing care to their patients and communities. Yet faculty are often challenged by experiences with learners who appear unmotivated, or who seem to value goals other than those the faculty espouse. Understanding what motivates learners may help educators appreciate the complex environment in which motivations are formed, and the sometimes-hidden influences upon motivation that may explain learners' attitudes and behaviors. In this brief essay, the author discusses some of the current theories about motivation and describes how they might relate to the education of physicians. She also explores the too frequent disparities between medical schools' stated goals for learners and what is actually taught or rewarded by faculty. Although motivation is multifaceted, involving learners and the entire learning environment, there are strategies that may be used to strengthen students' motivations to achieve important goals. PMID- 10099643 TI - "A world of knowledge at your fingertips": the promise, reality, and future directions of on-line information retrieval. AB - Medical knowledge resources are increasingly available in electronic form, particularly on the World Wide Web. The promise of this medium is that it offers a vast "world of knowledge at your fingertips." The reality, however, is somewhat different, as information systems are not well integrated into clinical practice, prove difficult to find specific information in, and contain content of varying quality. The continued evolution of the medium in the future should, however, be beneficial, as synthesized evidence-based resources become available and these resources are integrated into electronic medical record systems. PMID- 10099644 TI - The physician's role in a world of technology. AB - Technology has come to dominate the medical world over the past 100 years. Some of this technology has come from science and some has been imported from the world of business. Some technology exists in the form of physical objects; other technology takes the form of systems and organization. Technology to manage information has played a particularly critical role in changing how medicine is practiced. Those who choose to apply the latest technologies to patient care do so in ways that are not merely a reflection of some "objective" set of scientific data. Rather, the use of technology transforms both the clinical encounter and the technology itself, and in so doing reflects the values of those who created and those who use the technology. Despite the many ways that technology has come to be used for medical care over the course of the past century, the role of the physician has remained central. PMID- 10099645 TI - Community-based clinical education at the University of Birmingham Medical School. AB - Throughout the United Kingdom, medical schools have begun to make significant changes in the content and delivery of their undergraduate curricula in response to a number of social and educational forces. In particular, many schools have begun to focus increasingly on community-based education. This and other changes mirror developments that have taken place in other countries and in the context of other health care systems, with such forerunners as Harvard, Maastricht, and McMaster having had a fundamental influence. In this article, the authors describe the forces for curricular change in the United Kingdom and the specific recommendations for change made by the General Medical Council. They then discuss in detail the new curriculum at the University of Birmingham medical school, focusing in particular on a community medicine module, where students spend ten days per academic year learning in general medical practices in and around the city of Birmingham. PMID- 10099647 TI - Protecting patients, preserving progress: ethics in mental health illness research. PMID- 10099648 TI - Correlation of students' characteristics with their learning styles as they begin medical school. AB - PURPOSE: To investigate the relationship between learning styles (surface, strategic, and deep learning) and admission data for an incoming class of medical students. METHOD: In 1997, the Approaches and Study Skills Inventory (ASSIST) was administered to the University of Alberta Medical School's incoming class as part of their orientation. Ninety percent of the class completed the questionnaire, the results of which were correlated with prerequisite grade-point average (GPA), MCAT scores, number of years of premedical experience, and scores on autobiography, interview, and letters of reference. RESULTS: Higher surface learning scores correlated significantly with younger age at admission to medical school, as well as with higher GPA. There was a positive correlation between GPA and surface learning in the group of students with more than four years of premedical experience. CONCLUSIONS: The need to compete for grades in prerequisite courses may be a factor contributing to surface learning in new medical students. PMID- 10099649 TI - A job-satisfaction measure for internal medicine residency program directors. AB - PURPOSE: To develop a job-satisfaction measure that encompasses the multifaceted job of internal medicine residency program directors. METHOD: Questions were devised to measure program directors satisfaction with various facets of their jobs. In 1996, the authors surveyed all non-military internal medicine program directors in the United States. RESULTS: Of the program directors surveyed, 301 (78%) responded. More respondents than non-respondents held the title of department chairperson in addition to the title of program director (22% vs 7%). Factor analysis and correlation analysis yielded a multifaceted measure (termed PD-Sat) composed of 20 questions and six facets (work with residents, colleague relationships, resources, patient care, pay, and promotion) that made sense based on literature review and discussions with program directors (face validity). The PD-Sat had good internal reliability (Cronbach's alpha = .88), as had each of its six facets (Cronbach's alphas = .60-.90). The six facets correlated modestly with one another (Pearson's r2 = .12-.67), suggesting they were measuring different aspects of a common concept. The PD-Sat correlated significantly with an established four-question global job-satisfaction scale used in previous studies (Pearson's r2 = .33) demonstrating concurrent validity. Scores on the PD-Sat predicted whether program directors were considering, seeking, or making a job change (predictive validity). The PD-Sat performed comparably well in subsets of program directors who were and were not department chairs, suggesting that it might be applicable to different populations of program directors. CONCLUSION: The authors have developed a new facet-specific job-satisfaction measure that is reliable and valid for assessing the job satisfaction of internal medicine program directors. Because job descriptions for program directors in other specialties are similar, it may also be useful in these populations. PMID- 10099650 TI - Relationship between clinical competence and interpersonal and communication skills in standardized-patient assessment. AB - PURPOSE: To evaluate the relationship between clinical competence and interpersonal and communication skills, in an attempt to clarify current thinking about these two dimensions as measured with standardized-patient (SP) examinations. METHOD: Simple Pearson correlations were computed between total examination scores for clinical competence and interpersonal and communication skills. Three sets of different types of data involving 15 separate examinations were used to explore the generality of the findings. To control for a within-case halo effect and measurement error, corrected cross-half correlations and corrected cross-case correlations were also computed. RESULTS: The simple correlations and the corrected cross-half and cross-case correlations showed moderate and above relationships between these two dimensions in the clinical context. The simple correlations centered around .50, and the corrected cross half and cross-case correlations were slightly higher, centering around .65 and .70, respectively. CONCLUSION: The authors' thinking is that the moderate relationship between clinical competence and interpersonal and communication skills is not due to a flaw in the measurement of clinical competence, as has been suggested, but rather is a natural consequence of the clinical encounter, which exacts an interdependence of these two dimensions. At least, this possibility must be seriously considered so medical educators can think and act appropriately in the assessment of clinical performance. PMID- 10099651 TI - Consent documents, reproductive issues, and the inclusion of women in clinical trials. AB - PURPOSE: To describe language used in consent documents at one academic medical center to inform women participating in studies of potential reproductive and fetal risks. METHOD: The authors reviewed consent document language describing reproductive and fetal risks in 114 approved protocols. Protocols were identified as being of high, low, or unknown risk based upon FDA drug-risk and radiation risk categories. RESULTS: Although most consent documents advised women against participating for one or more pregnancy-related reasons, specific information about reproductive or fetal risks was included in fewer consent documents: 8 (73%) of the high-risk studies, 12 (40%) of the low-to-moderate-risk studies, and 29 (40%) of the unknown-risk studies. CONCLUSIONS: Investigators often omit fetal risk information from consent documents. Full disclosure of reproductive and fetal risks in consent documents and discussions can be taught and modeled during the research training period. The authors present a template with language that can be used in consent documents and recommend ongoing discussion of reproductive and fetal risks with women subjects throughout the study period. PMID- 10099652 TI - Part-time residency training in internal medicine: analysis of a ten-year experience. AB - PURPOSE: To evaluate a ten-year experience (1983-1993) with a part-time residency curriculum. METHOD: In 1994, the authors analyzed the curriculum through interviews with graduates of a part-time residency track, surveys of faculty and graduates of a full-time residency program, and a quantitative comparison of faculty evaluations of those part-time and full-time residents. RESULTS: Both participants and full-time residents supported the part-time track and reported no adverse effect on the residency program as a whole. Analysis of faculty evaluations found that part-time residents scored significantly higher with respect to clinical skills (p = .0005) and humanistic skills (p = .0001), while there was no difference between the groups in leadership or teaching skills. CONCLUSIONS: This part-time residency curriculum provided a highly useful program track for a group of internal medicine residents with concomitant obligations, allowing them to complete their training in an uninterrupted fashion. The part time structure did not adversely affect clinical competence and may have fostered humanistic attributes. The authors believe that this form of curriculum deserves wider consideration in residency training. PMID- 10099653 TI - The long-term effect of an innovative family physician curricular pathway on the specialty and location of graduates of the University of Washington. AB - PURPOSE: To report the specialty and rural/urban distribution a mean of 19 years after graduation for a cohort of students from a family physician curricular pathway. METHOD: Specialty and location information for medical students who had entered the University of Washington between 1968 and 1973 was obtained from the 1994 Physician Masterfile of the American Medical Association. RESULTS: Of the 239 family physician pathway graduates, 173 (72%) had intended family practice at graduation, and 136 (57%) were family physicians two decades later. The proportions of all graduates in family practice and of graduates serving rural Washington as family physicians had increased over that of a cohort of students who had entered the University of Washington prior to the introduction of the pathway curriculum. These proportions surpassed the goals set at the time the new curriculum was introduced. CONCLUSION: With early identification and support of students interested in family practice, an increased number entered the specialty and were still family physicians in mid-career. PMID- 10099654 TI - Medical students' education in the ambulatory care setting: background paper 1 of the Medical School Objectives Project. AB - The present article is the first MSOP Background Paper. In planning the Medical School Objectives Project (MSOP), the Association recognized that certain changes in medical students' education were occurring already in some schools, and that it would be important to gain insight into and monitor these changes to provide ideas and information to help schools design curricular changes to foster students' achievements of the objectives and recommendations set forth in the MSOP Reports published in 1998 and reprinted in Academic Medicine. This background paper provides an overview of the strategies being developed by medical schools to carry out education in the ambulatory care setting. This report is based on site visits in 1997 to 26 U.S. medical schools conducted by two of the authors (CEH and GAK), who also used information from 12 additional schools that were not visited and consulted individuals responsible for the evaluation of five grant programs dedicated to national curriculum reform. The authors define and discuss in detail the use of the three main strategies that their research uncovered: (1) longitudinal preceptorships, (2) multispecialty clerkships, and (3) activities that are community oriented and population based to provide medical students the kinds of educational experiences they need to understand and practice in the ambulatory care setting. The authors then discuss issues and challenges related to the implementation of these curricular changes: curricular management issues; developing and maintaining a network of practicing physicians willing to serve as preceptors; evaluating curricular innovations; and assessing students' performances. The authors conclude with general observations about the need for ambulatory care education, the difficulties that have been- and continue to be--met and overcome to implement it, and the recommendation that relevant learning experiences should be incorporated into existing course work or clinical experiences. PMID- 10099655 TI - Assessment of cardiac and pulmonary function in adult patients with Hodgkin's disease treated with ABVD or MOPP/ABVD plus adjuvant low-dose mediastinal irradiation. AB - We evaluated the long-term effects of combined modality therapy (CMT) with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) or mechlorethamine, vincristine, prednisone, procarbazine (MOPP)/ABVD plus adjuvant low-dose (< 30 Gy) involved-field radiation therapy (LDRT) on cardiac and pulmonary functions in adult patients with Hodgkin's disease (HD). Adjuvant LDRT (mean dose, 2340 cGy) to the mediastinum was administered to 24 patients after chemotherapy with MOPP/ABVD (n = 10) and ABVD (n = 14). The mean doses of doxorubicin and bleomycin were 233 mg/m2 and 92 IU/m2, respectively. Cardiac and pulmonary function tests were performed in all patients and, when available, were compared with pretreatment studies. After a median follow-up of 6.3 years, none of the patients had cardiac or pulmonary symptoms. A 4.7% overall decrease in left ventricular ejection fraction (LVEF) was observed (p = 0.03), but only one patient had a mildly decreased LVEF (47%). Diastolic function, LVEF, and left ventricular volume remained within the normal range in the other 23 patients. Mild pulmonary function study abnormalities occurred in 8 of 24 patients, 6 of whom were cigarette smokers. There were no significant changes in total lung capacity and forced vital capacity (FVC) values, but there was a 3% overall decrease in FEV1/FVC ratio (p = 0.05). In adult patients with HD, adjuvant LDRT after chemotherapy with ABVD or MOPP/ABVD did not result in a significant incidence of permanent pulmonary or cardiac toxicity after more than 6.3 years of median follow-up. Further studies are warranted to fully evaluate the impact of such therapy on cardiopulmonary function. PMID- 10099656 TI - Second-line chemotherapy with 96-hour infusional paclitaxel in refractory non small cell lung cancer: report of a phase II trial. AB - Advanced metastatic non-small cell lung cancer (NSCLC) that has progressed on initial cisplatin-based chemotherapy has a poor prognosis. Although paclitaxel is an active agent in the first-line therapy of NSCLC, 24-hr infusion of paclitaxel in patients with NSCLC failing first-line cisplatin-based regimens has shown minimal activity. Prolonged infusions of paclitaxel have shown activity in breast cancer patients who have failed short infusions of paclitaxel. In this study, 13 patients with refractory NSCLC who progressed on or after initial chemotherapy were treated with 96-hr paclitaxel (140 mg/m2 over 96 hr every 3 weeks) infusions as outpatients using a CADD infusion pump via a central catheter. Nine patients received only one or two cycles of treatment because of disease progression and had a median survival of 3 months (range, 1-5 months). Four patients had stabilization of disease for two to six cycles of treatment and had a median survival of 8 months (range, 8-12+ months). Grade 3-4 hematologic and nonhematologic toxicity occurred in < 10% of cycles, and no treatment-related hospitalizations occurred. Quality of life (QOL) assessments using the Functional Assessment of Cancer Therapy-Lung questionnaire were performed at baseline and with each treatment cycle. In conclusion, although no objective responses were seen, disease stabilization occurred in 31% of patients. Overall toxicity was tolerable with no major negative impact on QOL in those patients receiving two or more cycles of treatment. PMID- 10099657 TI - Effect of interferon alpha-2a on hormone receptor status in patients with advanced breast cancer. AB - The aim of this study was to assess the effect of recombinant interferon alpha-2a (rh-IFN) on estrogen (ER) and progesterone (PR) receptor expression in patients with advanced breast cancer and the evaluation of the effect of rh-IFN pretreatment on response to endocrine therapy with tamoxifen (TAM). Between June 1990 and November 1992, 20 patients with disseminated breast cancer and with metastatic skin nodules suitable for biopsy were entered into this study. Eighteen assessable patients underwent biopsy before and 2 weeks after treatment with rh-INF. rh-INF 3 x 10(6) IU were administered subcutaneously per day. Patients with ER expression at second biopsy were subsequently treated with 20 mg TAM daily. One patient had rapid disease progression and died before rebiopsy could be performed, and an additional patient refused second biopsy. All other patients were considered assessable. Thirteen patients showed ER expression before rh-IFN treatment, and 5 PR presented with expression. Rh-IFN increased ER expression in three patients and PR in four patients. No change was observed in 8 patients for ER and in 12 patients for PR. ER expression decreased in seven patients and PR expression decreased in two patients, respectively. Two patients showed a partial remission after subsequent treatment with TAM. Adverse reactions caused by rh-IFN were mainly flu-like symptoms. In this trial we found no systematic impact of rh-IFN on hormone receptor expression and, subsequently, on the response rate in patients with advanced breast cancer. PMID- 10099658 TI - A phase II trial of interferon alpha-2a and carboplatin in patients with advanced malignant mesothelioma. AB - We defined the antitumor activity, toxicity, and tolerability of a combined chemoimmunotherapy approach in patients with advanced malignant mesothelioma using daily low-dose interferon alpha-2a and carboplatin given every 4 weeks. This was a phase II study of 15 patients with surgically unresectable or metastatic malignant mesothelioma. All patients had measurable or assessable disease. No prior chemotherapy or immunotherapy was allowable. Carboplatin was given at 150 mg/m2 daily on days 1-3 and interferon alpha-2a at 3 million units subcutaneously daily throughout the study. Treatment was recycled every 28 days. Therapy was continued until disease progression. Fifteen patients were assessable for toxicity and 14 for response. One partial response (7%, 95% CI, 0-20%), with a response duration of 40 weeks, was seen. Most patients had early progression of disease. Toxicity was tolerable, and grade III/IV toxicity was uncommon. The median time to progression was 14 weeks (range, 1-52 weeks). The median survival was 25 weeks (range, 8-66 weeks). The combination of low-dose interferon alpha-2a and carboplatin did not result in greater antitumor activity than that reported for single-agent carboplatin in advanced malignant mesothelioma. Although toxicity was mild, carboplatin and low-dose interferon, given at this dose and schedule, cannot be recommended for this patient group. PMID- 10099659 TI - Prolonged severe 5-fluorouracil-associated neurotoxicity in a patient with dihydropyrimidine dehydrogenase deficiency. AB - 5-Fluorouracil (5-FU) is an analogue of pyrimidine nucleosides that is widely used in the treatment of head and neck, breast, ovarian, and colon cancer. Stomatitis, diarrhea, dermatitis, and myelosuppression are the main toxicities of 5-FU. A less frequent side effect that is becoming more recognized is neurologic toxicity. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-FU. DPD deficiency follows an autosomal recessive pattern of inheritance, and its prevalence is estimated to be 3%. Cancer patients who are receiving 5-FU treatment and are DPD deficient can develop severe side effects. The neurologic toxicity can vary from being mild to severe and prolonged. We describe the side effects of 5-FU in a colon cancer patient who suffered severe mucositis, desquamating dermatitis, prolonged myelosuppression, and neurologic toxicity that required admission to the intensive care unit. The patient remained hospitalized for 3 months. Recovery from the side effects was complete 4 months after the last 5-FU treatment. Subsequent testing revealed that this patient has an extremely low level of DPD activity (0.015 nmol/min/mg protein; mean, 0.189 nmol/min/mg protein). Because neurologic toxicity is becoming more recognized and DPD affects the catabolism of 5-FU, we discuss management issues and the use of new DPD inhibitors. We also discuss whether screening for DPD deficiency is warranted to identify patients at risk for severe toxicities from 5-FU treatment. PMID- 10099660 TI - Contemporary treatment of borderline ovarian tumors. AB - In conclusion, the prognosis for women with stage I borderline tumors is excellent. Surgery alone is the recommended treatment. For young patients, fertility-sparing surgery is optimal, with a small percentage eventually developing tumor in the contralateral ovary. For patients with advanced stage borderline tumors, 10-30% will relapse and approximately 10% will die of tumor. This risk is clearly higher for those with invasive peritoneal implants. Several controversies exist, including the classification of advanced stage serous borderline tumors and the issue of postoperative treatment. Future studies involving larger series and molecular biomarkers will hopefully elucidate the biologic behavior and optimal therapy for this interesting group of tumors. PMID- 10099661 TI - Locally advanced noninflammatory breast cancer. PMID- 10099663 TI - Role of radiation therapy in parameningeal rhabdomyosarcoma. AB - Radiation therapy plays a crucial role in the management of children with parameningeal rhabdomyosarcomas. Because of the close proximity to the skull base, most lesions are not amenable to complete surgical resection without mutilation, and treatment has primarily been chemoradiation. Adequate radiotherapy dose, coverage of the tumor, and knowledge of potential areas of invasion are of paramount importance as demonstrated by early data from the Intergroup Rhabdomyosarcoma Study Group. The timing, dose, and treatment volume for parameningeal rhabdomyosarcomas have evolved in the last 25 years in a continuous effort to find ways of maximizing local control while reducing possible late sequelae. Hyperfractionated radiation therapy is currently being tested against conventional dose radiation therapy for group III tumors. At present, approximately 70% of children treated for parameningeal rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Study are alive at 5 years compared with a 25% survival before the formation of multi-institutional cooperative group studies. PMID- 10099662 TI - Antimicrobial therapy in immunocompromised patients: infectious complications of solid tumors. PMID- 10099664 TI - Parameningeal rhabdomyosarcoma: major advances but no cigar! PMID- 10099665 TI - [A new organization of school health services: its twilight or renaissance?]. AB - Starting from the beginning of January 1998, school health service in Croatia became exclusively a preventive activity. This change provoked a lot of controversial discussions among general public and medical profession. This paper gives an outline of the historic course, the aims and content of school health in different countries. From its very beginning in the middle of the 19th century, school health started to develop as a preventive activity directed primarily towards organic etiology dominant in the morbidity of school children at that time (infectious diseases, tuberculosis, malnutrition). The morbidity has changed over time. Nowadays, the problems of psychosocial etiology have emerged into the first plane. Moreover, schooling has been prolonged. It covers a great part of childhood and almost the entire adolescence. The problems of adolescents are different and complex. Health care of school children and adolescents is functionally bound to the school as their natural environment. The most efficient health care is provided in close cooperation between medical personnel and teachers. Besides, the classical model of school health offers, particularly with respect to current problems, large possibilities for health promotion of children and adolescents, and in the long run, of the whole population. Health care of school children is not equally organized in different countries. The main difference depends on whether the school health team is directed only towards preventive and specific activities or towards comprehensive primary health care. In Croatia, traditionally, the integrated health care has developed. Beside preventive health care, the school doctors provided curative care for students in their schools. Within the reorganization of health care a new situation has arisen. Compulsory integration of preventive and curative activities at the school level is completely incompatible with the right to a free choice of primary care physician. However, by the strict interpretation of the principle of indivisibility of preventive and curative care, one school should cooperate with numerous personal doctors for its students. The essential principle of school health would be lost. The school represents a community which is exposed to the same health risks but keeps a great potential for health promotion. So, if this advantage is to be utilized, preventive care must be organized at the school level. This is the very nature of the reorganization in school health service which is performed in Croatia under the auspices of the Ministry of Health. Providing the preventive and specific health care for all school children and adolescents is the responsibility of school doctors who have become the employees of the Institutes of Public Health, while the curative care is provided by the personal physician of a student's or his parents' choice. PMID- 10099666 TI - [A clinico-experimental study of the functional morphology of hypophyseal adenomas]. PMID- 10099667 TI - [The HLA-DR phenotype in Croatian children with gluten enteropathy]. AB - Several studies of HLA and gluten enteropathy (GE) in European countries have found an association between this disease and certain DR phenotypes. However, no studies of DR phenotypes have been published in GE coming from Croatia. Therefore, we have studied HLA-A, B and DR specificities in 94 unrelated children with GE and in a group of healthy controls. In GE there was significant increase in the frequencies of A1 (61.70% v 24.50%; p < 0.0001) and B8 antigen (70.21% v 20.51%; p < 0.0001) compared with controls. The most frequent DR antigen was HLA DR3 (87.23% v 18.82% in controls) with the relative risk of 29.65. The distribution of DR phenotypes in GE showed that the most frequent one was DR3/other DR (54.26%) and in decreasing order DR3/DR7 (17.02%), DR3/X (15.96%) and DR5/DR7 (8.51%). These phenotypes account for 95.75% of patients studied. A further 3.19% have DR4/DR5 phenotype. However, due to the frequency of certain antigen in controls, only phenotypes DR3/DR7 (relative risk: 28.92), DR3/X (relative risk: 13.29) and DR3/ other DR (relative risk: 10.04) were significantly associated with GE. The present study emphasizes the importance of studying the HLA-DR phenotypes in patients with GE. PMID- 10099668 TI - [Incidence of breast feeding in the Bjelovar region]. AB - Without any doubt breastfeeding is the best diet for babies. Nevertheless, in Croatia little less than 40% of infants after the age of three months are breastfed. In order to asses the state, in Bjelovar region, data concerning the diet during infant period were collected for 4242 babies born in Bjelovar between January, 1991 and December, 1995. During the first month of infants life 37% of mothers weaned their children. 43.5% of mothers are nursing for three months, 13.6% longer then 6 months, and only 1.4% of mothers nurse for year. An average length of breast-feeding was 118.4 days. After weaning in a newborn period the majority of mothers decided to use industrial milk supplements. The activity of the whole community and not just medical staff is necessary to change the existing state. It is necessary to begin with breastfeeding promotion in elementary school. Media should pay more attention to breastfeeding. It is necessary to organize maternity hospitals by the "Baby-friendly hospital" principle. Already during the pregnancy period it is necessary to discuss with both parents all the aspects of breastfeeding. A systematic work of pediatricans, family doctors and visiting nurses is required to increase the number of mothers who are breastfeeding at least first 4-6 months. PMID- 10099669 TI - [Selection of phenotype characteristics in differentiation of various species of enterococci using an inductive mathematical program]. AB - In this paper a novel computer example-based learning system (Inductive learning by logic minimization) was used to determine the sufficient set of biochemical reactions and necessary conditions that have to be fulfilled for the correct identification of enterococci isolated from human specimens. Several combinations for accurate identification of Enterococcus faecalis and Enterococcus feacium from other enterococci were found. The simplest combination set for E. faecalis identification consists of 3 reactions: growth in 0.04% K-tellurite, mannitol acidification, failure to acidify raffinose. The simplest set for E. faecium differentiation from other enterococcal species is performed by the following 3 reactions: failure to acidify D-xylose and Na-pyruvate, and acidification of L arabinose. Only 4 tests are sufficient (acid from D-xylose, mannitol, L-arabinose and Na-pyruvate) for the correct identification of these two, the most frequently isolated species. If it is necessary to analyze all enterococcal species, then even three combinations of 9 tests for the correct differentiation of any of them, are available. PMID- 10099670 TI - [An approach to dyspepsia in primary health care]. AB - Dyspepsia is a common problem in primary health care and involves a great deal of physician's time, if we assume that the prevalence in general population is 25 50%. Since the definition of dyspepsia has been elusive, which has resulted in confusion about diagnosis and therapy, the need for management guidelines that would produce satisfactory results has been manifested. The International Gastro Primary Care Group has developed practical framework, which identifies the predominant symptom of dyspepsia as a guide in the selection of the most appropriate treatment, and is also used as a tool in dealing with common therapeutical dilemmas until new evidence become available. PMID- 10099671 TI - [The Internet in urology]. PMID- 10099673 TI - [Do we need written consent for transfusion therapy?]. PMID- 10099672 TI - [On the occasion of unveiling a memorial plaque to Dr. Bozidar Spisic]. AB - The first rehabilitation center was founded and organized in Zagreb, 1908, by prof. dr. Bozidar Sisic. Its importance was stressed through the history, as unique and first in this part of Europe. On the occasion of the 90th anniversary of its foundation, a memorial tablet was unveiled in the memory of prof. dr. Bozidar Sisic, the founder of croatian orthopedics, and medical and social rehabilitation. PMID- 10099674 TI - Effect of roughage type and concentrate supplementation on follicle numbers and in vitro fertilisation and development of oocytes recovered from beef heifers. AB - Increasing dietary energy tends to decrease the ovulatory response and produce fewer viable embryos following superovulation of beef cattle. Data in sheep indicate that high energy intake can decrease progesterone concentrations (P4), although effects in cattle are not as clear. The objectives were to evaluate the effects of roughage type and concentrate supplementation on P4 concentrations, follicle growth and subsequent oocyte fertilisation and embryo development in vitro. Forty-two beef heifers were allocated to 3 treatment groups: (i) silage ad libitum plus 6 kg concentrates (silage + conc.; n = 14); (ii) silage ad libitum (silage; n = 14) or (iii) hay ad libitum (hay; n = 14) for 40 days. Oestrus was synchronised using a controlled intravaginal progesterone releasing device (CIDR) for 7 days plus prostaglandin F2 alpha (15 mg luprostiol) administered 2 days before CIDR withdrawal. Ovaries were stimulated with 600 i.u. of follicle stimulating hormone (pFSH) administered in 6 equal doses at 12-h intervals, starting 12 days after CIDR withdrawal. Daily blood samples were collected from 3 days after CIDR insertion until CIDR withdrawal, and for another 3 days prior to pFSH, for P4 determination. Oocytes were recovered postmortem 12 h after the last pFSH injection, matured, fertilised and cultured in vitro. There was no overall effect of diet (P > 0.05) on P4 concentrations. The number of follicles grown in heifers on silage + conc (18.8 +/- 3.3), silage (23.5 +/- 3.4) or hay (18.1 +/- 2.6) were not affected by the dietary treatment (P > 0.05). The percentage of oocytes fertilised from heifers on hay (88%) was higher compared to oocytes from heifers on silage (79%; P < 0.05), but was not different (P > 0.05) compared to the proportion of oocytes from heifers on silage + conc. (86%). The percentage of fertilised oocytes that cleaved was higher from heifers on silage (94%; P < 0.01) compared with oocytes from heifers on hay (82%) or silage + conc. (86%). The proportion of embryos that developed to blastocyst was not different (P > 0.05) between groups of oocytes from heifers on silage + conc. (8%), silage (14%) or hay (15%). Heifers on silage produced numerically more blastocysts (silage: 19 from 14 heifers; silage + conc.: 8 from 14 heifers; hay: 12 from 14 heifers). These results suggest that dietary treatment used prior to oocyte recovery did not significantly influence the developmental competence of the oocytes in vitro. PMID- 10099675 TI - Low dietary protein during early pregnancy alters bovine placental development. AB - To determine if low dietary protein concentration in the first two trimesters of pregnancy alters placental development, genetically similar heifers from closed herd were fed diets containing different levels of protein in the first and second trimesters of gestation. There were four animals per treatment group, the groups being: L/L = fed a diet containing 7% crude protein (CP) (low protein) in the first and second trimesters; H/H = fed a diet containing 14% CP (high protein) in the first and second trimesters; L/H = fed low protein in the first trimester and high in the second trimester and vice versa for the H/L group. Low protein diets in the first trimester increased dry cotyledon weight at term. Trophectoderm' volume density increased in the H/L and L/H group compared to the L/L and H/H groups. Blood vessel volume and volume density in foetal villi decreased in the H/L and L/H groups compared with the H/H and L/L groups. There was no effect of diet treatment on cotyledon number, diameter or wet weight and no effect on the volume density of connective tissue or fibroblasts in the foetal villi. These results show that a low dietary protein concentration in the first trimester of pregnancy followed by increased protein in the second trimester enhanced placental development. Further, trophectoderm volume was highly correlated with birth weight. Early protein restriction in the pregnant cow may enhance foetal growth in part by stimulating placental growth and function. PMID- 10099676 TI - Ovarian responses to progesterone and oestradiol benzoate administered intravaginally during dioestrus in cattle. AB - This study examined the effects of administering progesterone and oestradiol benzoate (ODB) during mid-dioestrus, on ovarian follicular dynamics in cattle. Twelve cycling cows were used in a 4 x 4 latin square design, with the 4 treatments being initiated on Day 13 of the cycle (oestrus = Day 0) and comprising intravaginal insertion for 5 days of: (i) a progesterone releasing device (CIDR; 'P4'); (ii) a CIDR device with a gelatin capsule containing 10 mg ODB and 1 g lactose (CIDIROL; 'P4/ODB') attached; (iii) a placebo CIDR device with the 10 mg ODB capsule (ODB); and, (iv) a placebo CIDR device alone (CTRL). The ovaries of each cow were examined daily by transrectal ultrasonography from Day 7 of the cycle until subsequent ovulation. Blood samples were collected daily from Day 11, and at intervals of 2-4 h during the 24 h period either side of treatment initiation. The second dominant follicle (DF2) emerged on Day 10.7 +/- 0.2 (mean +/- SEM), and was 8.5 +/- 0.2 mm in diameter by Day 13. The DF2 developed through to ovulation (2-wave cycles) in half of the animals in the CTRL group; while in the other half of cases, the ovulatory follicle originated from the third follicle wave that emerged on Day 17.2 +/- 0.4. Administration of a CIDR device alone (P4 group) did not alter the 1:1 ratio of 2 and 3-wave cycles, but the third dominant follicle (DF3) in those cows with 3-wave cycles emerged earlier on Day 15.6 +/- 0.2. In contrast, the DF2 of every animal in the ODB and P4/ODB groups became atretic and was replaced by a DF3 which emerged 4.0 +/- 0.3 days later. The effects of ODB on luteal function were limited to an earlier decline in plasma progesterone concentrations from 2 to 4 days after device insertion and a reduction in diameter of the corpus luteum when administered concurrently with progesterone. Intravaginal administration of 10 mg ODB on Day 13 of the oestrous cycle, with or without progesterone, was effective in promoting follicle wave turnover. In the absence of ODB, progesterone administration alone (P4 group) did not alter the ratio of animals with 2 or 3 wave cycles from that observed in animals in the CTRL group, but did advance the timing of subsequent follicle wave emergence in those animals with 3-wave cycles. PMID- 10099677 TI - Effect of glucose availability on pulsatile luteinizing hormone release in rams before and after castration. AB - The hypothesis tested was that availability of glucose modulates the control of luteinizing hormone (LH) release. A second objective was to determine the role of testicular hormones in the control of pulsatile LH secretion during depressed blood glucose. Serial blood samples were collected at 15 min intervals for 8 h from intact pubertal Suffolk rams (n = 8; 7 months old) on consecutive days (Days 1, 2 and 3). Rams were castrated after sampling on Day 3 and samples were collected 3 weeks later on consecutive days (Days 4, 5 and 6). Insulin (120 units, iv) was given at Hour 4 of each of the six days to lower blood glucose. On Days 1 and 4, no other treatments were given (Control). On Days 2 and 5, LH releasing hormone (LHRH; 5 ng/kg, iv) was given at Hours 5, 6 and 7 to assess the ability of the pituitary to release LH. On Days 3 and 6, N-methyl-D,L-aspartate (NMA; 5 mg/kg, iv) was given at Hours 5, 6 and 7 to assess the ability of the hypothalamus to release LHRH. Insulin reduced plasma glucose by 52% for at least 3 h (P < 0.001). Insulin reduced the mean LH concentration (P < 0.05) and tended to reduce the LH response area (P < 0.10) in castrated animals during the control period. LHRH increased LH pulse number (P < 0.001) in intact rams and increased mean LH concentration (P < 0.01), LH pulse amplitude (P < 0.05) and LH response area (P < 0.01) in castrated animals compared to respective control periods. NMA increased mean LH concentration in intact rams (P < 0.0001) but did not affect mean LH in castrates. NMA increased LH pulse number in rams (P < 0.0001) but decreased number of pulses in castrates (P < 0.0001) compared to control periods. NMA increased LH pulse amplitude in both intact (P < 0.001) and castrated animals (P < 0.05). In conclusion, these results support the hypothesis that blood glucose concentrations influence the control of LH release in sheep. In addition, LH release in response to the LHRH secretagogue, NMA, is positively influenced by testicular hormones. PMID- 10099678 TI - Seasonal and management effects on fertility of the sow: a descriptive study. AB - This study was undertaken to determine management and seasonal effects on fertility in 1298 Finnish sow units over a 4-year period in 1992-1996. A multivariate analysis of the herd record data was undertaken to study the effect of various management factors on rebreeding rate. Factors found to have an effect were further subjected to time series plotting for seasonal effects. In addition, seasonal effects on the farrowing rate, age of gilts at first mating and littersize as well as the 3-week litterweight were studied. Year and month caused the most significant variation in the rebreeding rate. Moreover, geographical area, herd and way of breeding (mating vs. artificial insemination) were found to be significant determinants of rebreeding rate. Dry sows loosely housed were more likely to be rebred than sows housed in individual stalls. Sows receiving roughage feed (hay, straw) or bedding (straw) were less likely to require rebreeding. A significant seasonal fluctuation in farrowing rate was found with a nadir of 72.6% in August and a high of 80.9% in January. The average farrowing rate for the 4-year period was 77.7%. The age of gilts at first mating showed seasonal variation of 11 days (229.9 +/- 0.5 days in March and 241.4 +/- 0.5 days in November). In conclusion, this study indicates that group housing of dry sows increases the risk of rebreeding. In group housed sows, rebreeding more often occurs after an irregular oestrus-to-oestrus interval in summer-autumn whereas a not-in-pig seems to be a more common finding at late gestation in individually housed sows. PMID- 10099679 TI - Synthetic oviductal fluid and oviductal cell coculture for canine oocyte maturation in vitro. AB - The perfection of in vitro maturation in the bitch has yet to be achieved, and is an essential prerequisite for gamete salvage programmes in endangered canine species. In contrast to most mammals, the bitch ovulates an immature oocyte which undergoes meiotic maturation within the oviduct. A model of the oviductal environment may therefore be useful for performing in vitro maturation. This study was performed to investigate the effect of introducing an oviductal element to the culture environment, first with the use of a synthetic oviductal fluid (SOF), and secondly, using coculture with isolated canine oviductal epithelial cells, upon the rate of oocyte maturation in vitro. It was found that there was no difference in the proportion of oocytes undergoing germinal vesicle breakdown (GVBD) after 48 h in culture between SOF containing 0.3% bovine serum albumin (BSA, 45%), containing 4% BSA (36%) and control medium 199 (27%). There was also no difference in oocyte nuclear maturation to metaphase I/anaphase I/metaphase II (MI/AI/MII) after 48 h in culture between SOF containing 0.3% BSA (5%), containing 4% BSA (7%) and control medium 199 (6%). In addition, there was no difference in oocyte nuclear maturation to MI/AI/MII after 96 h between SOF containing 0.3% BSA (0), containing 4% BSA (7%) and control medium 199 (11%). In contrast, the proportion of oocytes undergoing GVBD after 96 h in culture was affected by the treatment used, with 27% in SOF + 0.3% BSA, 62% in SOF + 4% BSA and 63% in medium 199. It was found that there was no difference in the proportion of oocytes undergoing GVBD between the coculture treatments 199 (33%), 199 + cells (37%), coculture medium (30%) and coculture medium + cells (49%), and for oocyte nuclear maturation to MI/AI/MII, between medium 199 (2%), 199 + cells (0), coculture medium (6%) and coculture medium + cells (2%) after 48 h in culture. In addition, there was no difference in oocyte nuclear maturation to GVBD after 96 h between 199 (61%), 199 + cells (59%), coculture medium (65%) and coculture medium + cells (53%). In contrast, the proportion of oocytes maturing to MI/AI/MII after 96 h in culture was affected by the treatment used, with a significant difference between 199 (0), 199 + cells (9%), coculture medium (0) and coculture medium + cells (0). It was shown, therefore, that the culture of oocytes in the SOF improved oocyte nuclear maturation when supplemented with a high concentration of protein and that culture in the presence of oviductal epithelial cells improved oocyte maturation, but only after a prolonged period of time. PMID- 10099680 TI - Pulling the cart and enjoying the ride. AB - I was pleased to receive the invitation to write this prefactory chapter. In doing so, I join a number of physiologists whose work and writings I have often admired. There are two aspects of my experience in physiology that I discuss here. The first concerns my own research accomplishments. The second is my role in developing three departments of physiology and fostering the careers of others. While I take pleasure in the former, the overall contribution of the latter was undoubtedly greater. PMID- 10099681 TI - Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles. AB - Regulation of gastrointestinal (GI) motility is intimately coordinated with the modulation of ionic conductance expressed in GI smooth muscle and nonmuscle cells. Interstitial cells of Cajal (ICC) act as pacemaker cells and possess unique ionic conductances that trigger slow wave activity in these cells. The slow wave mechanism is an exclusive feature of ICC: Smooth muscle cells may lack the basic ionic mechanisms necessary to generate or regenerate slow waves. The molecular identification of the components for these conductances provides the foundation for a complete understanding of the ionic basis for GI motility. In addition, this information will provide a basis for the identification or development of therapeutics that might act on these channels. It is much easier to study these conductances and develop blocking drugs in expression systems than in native GI muscle cells. This review focuses on the relationship between ionic currents in native GI smooth muscle cells and ICC and their molecular counterparts. PMID- 10099682 TI - Ionic conductances in gastrointestinal smooth muscles and interstitial cells of Cajal. AB - Ion channels are the unitary elements that underlie electrical activity of gastrointestinal smooth muscle cells and of interstitial cells of Cajal. The result of ion channel activity in the gastrointestinal smooth muscle layers is a rhythmic change in membrane potential that in turn underlies events leading to organized motility patterns. Gastrointestinal smooth muscle cells and interstitial cells of Cajal express a wide variety of ion channels that are tightly regulated. This review summarizes 20 years of data obtained from patch clamp studies on gastrointestinal smooth muscle cells and interstitial cells, with a focus on regulation. PMID- 10099683 TI - Excitation-contraction coupling in gastrointestinal and other smooth muscles. AB - The main contributors to increases in [Ca2+]i and tension are the entry of Ca2+ through voltage-dependent channels opened by depolarization or during action potential (AP) or slow-wave discharge, and Ca2+ release from store sites in the cell by the action of IP3 or by Ca(2+)-induced Ca(2+)-release (CICR). The entry of Ca2+ during an AP triggers CICR from up to 20 or more subplasmalemmal store sites (seen as hot spots, using fluorescent indicators); Ca2+ waves then spread from these hot spots, which results in a rise in [Ca2+]i throughout the cell. Spontaneous transient releases of store Ca2+, previously detected as spontaneous transient outward currents (STOCs), are seen as sparks when fluorescent indicators are used. Sparks occur at certain preferred locations--frequent discharge sites (FDSs)--and these and hot spots may represent aggregations of sarcoplasmic reticulum scattered throughout the cytoplasm. Activation of receptors for excitatory signal molecules generally depolarizes the cell while it increases the production of IP3 (causing calcium store release) and diacylglycerols (which activate protein kinases). Activation of receptors for inhibitory signal molecules increases the activity of protein kinases through increases in cAMP or cGMP and often hyperpolarizes the cell. Other receptors link to tyrosine kinases, which trigger signal cascades interacting with trimeric G protein systems. PMID- 10099684 TI - The enteric nervous system and regulation of intestinal motility. AB - The enteric nervous system exerts local control over mixing and propulsive movements in the small intestine. When digestion is in progress, intrinsic primary afferent neurons (IPANs) are activated by the contents of the intestine. The IPANs that have been physiologically characterized are in the intrinsic myenteric ganglia. They are numerous, about 650/mm length of small intestine in the guinea pig, and communicate with each other through slow excitatory transmission to form self-reinforcing assemblies. High proportions of these neurons respond to chemicals in the lumen or to tension in the muscle; physiological stimuli activate assemblies of hundreds or thousands of IPANs. The IPANs make direct connections with muscle motor neurons and with ascending and descending interneurons. The circular muscle contracts as an annulus, about 2-3 mm in minimum oral-to-anal extent in the guinea pig small intestine. The smooth muscle cells form an electrical syncytium that is innervated by about 300 excitatory and 400 inhibitory motor neurons per mm length. The intrinsic nerve circuits that control mixing and propulsion in the small intestine are now known, but it remains to be determined how they are programmed to generate the motility patterns that are observed. PMID- 10099685 TI - Mechanisms of cardiac pain. AB - Angina pectoris often results from ischemic episodes that excite chemosensitive and mechanoreceptive receptors in the heart. Ischemic episodes release a collage of chemicals, including adenosine and bradykinin, that excites the receptors of the sympathetic and vagal afferent pathways. Sympathetic afferent fibers from the heart enter the upper thoracic spinal cord and synapse on cells of origin of ascending pathways. This review focuses on the spinothalamic tract, but other pathways are excited as well. Excitation of spinothalamic tract cells in the upper thoracic and lower cervical segments, except C7 and C8 segments, contributes to the anginal pain experienced in the chest and arm. Cardiac vagal afferent fibers synapse in the nucleus tractus solitarius of the medulla and then descend to excite upper cervical spinothalamic tract cells. This innervation contributes to the anginal pain experienced in the neck and jaw. The spinothalamic tract projects to the medial and lateral thalamus and, based on positron emission tomography studies, activates several cortical areas, including the anterior cingulate gyrus (BA 24 and 25), the lateral basal frontal cortex, and the mesiofrontal cortex. PMID- 10099686 TI - Desensitization of G-protein-coupled receptors in the cardiovascular system. AB - Multiple mechanisms exist to control the signaling and density of G-protein coupled receptors (GPRs). Upon agonist binding and receptor activation, a series of reactions participate in the turn off or desensitization of GPRs. Many GPRs are phosphorylated by protein kinases and consequently uncoupled from G proteins. In addition, many GPRs are sequestered from the cell surface and become inaccessible to their activating ligands. Both receptor:G protein uncoupling and receptor sequestration may involve the participation of arrestins or other proteins. A model for receptor regulation has been developed from studies of the beta-adrenergic receptor. However, recent studies suggest that other GPRs important in the cardiovascular system, such as the muscarinic cholinergic receptors that regulate heart rate, might be regulated by mechanisms other than those that regulate the beta-adrenergic receptors. This review summarizes our current understanding of the processes involved in the desensitization of GPRs. PMID- 10099687 TI - Regulation of natriuretic peptide secretion by the heart. AB - Secreted by the heart, more specifically by atrial cardiomyocytes under normal conditions but also by ventricular myocytes during cardiac hypertrophy, natriuretic peptides are now considered important hormones in the control of blood pressure and salt and water excretion. Studies on natriuretic peptide secretagogues and their mechanisms of action have been complicated by hemodynamic changes and contractions to which the atria are constantly subjected. It now appears that atrial stretch through mechano-sensitive ion channels, adrenergic stimulation via alpha 1A-adrenergic receptors, and endothelin via its ETA receptor subtype are major triggering agents of natriuretic peptide release. With several other stimuli, such as angiotensin II and beta-adrenergic agents, modulation of natriuretic peptide release appears to be linked to local generation of prostaglandins. In all cases, intracellular calcium homeostasis, controlled by several ion channels, is considered a key element in the regulation of natriuretic peptide secretion. PMID- 10099688 TI - Myoblast cell grafting into heart muscle: cellular biology and potential applications. AB - This review surveys a wide range of cellular and molecular approaches to strengthening the injured or weakened heart, focusing on strategies to replace dysfunctional, necrotic, or apoptotic cardiomyocytes with new cells of mesodermal origin. A variety of cell types, including myogenic cell lines, adult skeletal myoblasts, immoratalized atrial cells, embryonic and adult cardiomyocytes, embryonic stem cells, tetratoma cells, genetically altered fibroblasts, smooth muscle cells, and bone marrow-derived cells have all been proposed as useful cells in cardiac repair and may have the capacity to perform cardiac work. We focus on the implantation of mesodermally derived cells, the best developed of the options. We review the developmental and cell biology that have stimulated these studies, examine the limitations of current knowledge, and identify challenges for the future, which we believe are considerable. PMID- 10099689 TI - Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. AB - Molecular chaperones, including the heat-shock proteins (Hsps), are a ubiquitous feature of cells in which these proteins cope with stress-induced denaturation of other proteins. Hsps have received the most attention in model organisms undergoing experimental stress in the laboratory, and the function of Hsps at the molecular and cellular level is becoming well understood in this context. A complementary focus is now emerging on the Hsps of both model and nonmodel organisms undergoing stress in nature, on the roles of Hsps in the stress physiology of whole multicellular eukaryotes and the tissues and organs they comprise, and on the ecological and evolutionary correlates of variation in Hsps and the genes that encode them. This focus discloses that (a) expression of Hsps can occur in nature, (b) all species have hsp genes but they vary in the patterns of their expression, (c) Hsp expression can be correlated with resistance to stress, and (d) species' thresholds for Hsp expression are correlated with levels of stress that they naturally undergo. These conclusions are now well established and may require little additional confirmation; many significant questions remain unanswered concerning both the mechanisms of Hsp-mediated stress tolerance at the organismal level and the evolutionary mechanisms that have diversified the hsp genes. PMID- 10099690 TI - Genetic diseases and gene knockouts reveal diverse connexin functions. AB - Intercellular channels present in gap junctions allow cells to share small molecules and thus coordinate a wide range of behaviors. Remarkably, although junctions provide similar functions in all multicellular organisms, vertebrates and invertebrates use unrelated gene families to encode these channels. The recent identification of the invertebrate innexin family opens up powerful genetic systems to studies of intercellular communication. At the same time, new information on the physiological roles of vertebrate connexins has emerged from genetic studies. Mutations in connexin genes underlie a variety of human diseases, including deafness, demyelinating neuropathies, and lens cataracts. In addition, gene targeting of connexins in mice has provided new insights into connexin function and the significance of connexin diversity. PMID- 10099691 TI - Localized intracellular calcium signaling in muscle: calcium sparks and calcium quarks. AB - Subcellularly localized Ca2+ signals in cardiac and skeletal muscle have recently been identified as elementary Ca2+ signaling events. The signals, termed Ca2+ sparks and Ca2+ quarks, represent openings of Ca2+ release channels located in the membrane of the sarcoplasmic reticulum (SR). In cardiac muscle, the revolutionary discovery of Ca2+ sparks has allowed the development of a fundamentally different concept for the amplification of Ca2+ signals by Ca(2+) induced Ca2+ release. In such a system, a graded amplification of the triggering Ca2+ signal entering the myocyte via L-type Ca2+ channels is accomplished by a recruitment process whereby individual SR Ca2+ release units are locally controlled by L-type Ca2+ channels. In skeletal muscle, the initial SR Ca2+ release is governed by voltage-sensors but subsequently activates additional Ca2+ sparks by Ca(2+)-induced Ca2+ release from the SR. Results from studies on elementary Ca2+ release events will improve our knowledge of muscle Ca2+ signaling at all levels of complexity, from the molecule to normal cellular function, and from the regulation of cardiac and skeletal muscle force to the pathophysiology of excitation-contraction coupling. PMID- 10099692 TI - ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. AB - ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. By cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the receptors for sulfonylureas (SUR1 and SUR2), researchers have clarified the molecular structure of KATP channels. KATP channels comprise two subunits: a Kir6.0 subfamily subunit, which is a member of the inwardly rectifying K+ channel family; and a SUR subunit, which is a member of the ATP-binding cassette (ABC) protein superfamily. KATP channels are the first example of a heteromultimeric complex assembled with a K+ channel and a receptor that are structurally unrelated to each other. Since 1995, molecular biological and molecular genetic studies of KATP channels have provided insights into the structure-function relationships, molecular regulation, and pathophysiological roles of KATP channels. PMID- 10099693 TI - Adrenomedullin and the control of fluid and electrolyte homeostasis. AB - Two potent hypotensive peptides, adrenomedullin (AM) and proadrenomedullin N terminal 20 peptide (PAMP), are encoded by the adrenomedullin gene. AM stimulates nitric oxide production by endothelial cells, whereas PAMP acts presynaptically to inhibit adrenergic nerves that innervate blood vessels. Complementary, but mechanistically unique, actions also occur in the anterior pituitary gland where both peptides inhibit adrenocorticotropin release. In the adrenal gland both AM and PAMP inhibit potassium and angiotensin II-stimulated aldosterone secretion. Natriuretic and diuretic actions of AM reflect unique actions of the peptide on renal blood flow and tubular function. In the brain AM inhibits water intake and, in a physiologically relevant manner, salt appetite. Both AM and PAMP act in the brain to elevate sympathetic tone, effects that mirror the positive inotropic action of AM in the heart. Cardioprotective actions in the brain and heart may be important counter-regulatory actions that buffer the extreme hypotensive actions of the peptides when released in sepsis. Thus the biologic actions of the proadrenomedullin-derived peptides seem well coordinated to contribute to the physiologic regulation of volume and electrolyte homeostasis. PMID- 10099694 TI - Pathophysiology of endothelin in the cardiovascular system. AB - In this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states. PMID- 10099695 TI - Gene interactions in gonadal development. AB - The acquisition of a sexually dimorphic phenotype is a critical event in mammalian development. Although the maturation of sexual function and reproduction occurs after birth, essentially all of the critical developmental steps take place during embryogenesis. Temporally, these steps can be divided into two different phases: sex determination, the initial event that determines whether the gonads will develop as testes or ovaries; and sexual differentiation, the subsequent events that ultimately produce either the male or the female sexual phenotype. A basic tenet of sexual development in mammals is that genetic sex--determined by the presence or absence of the Y chromosome--directs the embryonic gonads to differentiate into either testes or ovaries. Thereafter, hormones produced by the testes direct the developmental program leading to male sexual differentiation. In the absence of testicular hormones, the pathway of sexual differentiation is female. This chapter reviews the anatomic and cellular changes that constitute sexual differentiation and discusses SRY and other genes, including SF-1, WT1, DAX-1, and SOX9, that play key developmental roles in this process. Dose-dependent interactions among these genes are critical for sex determination and differentiation. PMID- 10099696 TI - Synchronous activity in the visual system. AB - Synchronous activity among ensembles of neurons is a robust phenomenon observed in many regions of the brain. With the increased use of multielectrode recording techniques, synchronous firing of ensembles of neurons has been found at all levels in the mammalian visual pathway, from the retina to the extrastriate cortex. Here we distinguish three categories of synchrony in the visual system, (a) synchrony from anatomical divergence, (b) stimulus-dependent synchrony, and (c) emergent synchrony (oscillations). Although all three categories have been well documented, their functional significance remains uncertain. We discuss several lines of evidence both for and against a role for synchrony in visual processing: the perceptual consequences of synchronous activity, its ability to carry information, and the transmission of synchronous neural events to subsequent stages of processing. PMID- 10099697 TI - Timing in the auditory system of the bat. AB - Echolocating bats use audition to guide much of their behavior. As in all vertebrates, their lower brainstem contains a number of parallel auditory pathways that provide excitatory or inhibitory outputs differing in their temporal discharge patterns and latencies. These pathways converge in the auditory midbrain, where many neurons are tuned to biologically important parameters of sound, including signal duration, frequency-modulated sweep direction, and the rate of periodic frequency or amplitude modulations. This tuning to biologically relevant temporal patterns of sound is created through the interplay of the time-delayed excitatory and inhibitory inputs to midbrain neurons. Because the tuning process requires integration over a relatively long time period, the rate at which midbrain auditory neurons respond corresponds to the cadence of sounds rather than their fine structure and may provide an output that is closely matched to the rate at which motor systems operate. PMID- 10099698 TI - Synaptic mechanisms for coding timing in auditory neurons. AB - Neurons in the cochlear ganglion and auditory brain stem nuclei preserve the relative timing of action potentials passed through sequential synaptic levels. To accomplish this task, these neurons have unique morphological and biophysical specializations in axons, dendrites, and nerve terminals. At the membrane level, these adaptations include low-threshold, voltage-gated potassium channels and unusually rapid-acting transmitter-gated channels, which govern how quickly and reliably action potential threshold is reached during a synaptic response. Some nerve terminals are remarkably large and release large amounts of excitatory neurotransmitter. The high output of transmitter at these terminals can lead to synaptic depression, which may itself be regulated by presynaptic transmitter receptors. The way in which these different cellular mechanisms are employed varies in different cell types and circuits and reflects refinements suited to different aspects of acoustic processing. PMID- 10099699 TI - The role of timing in the brain stem auditory nuclei of vertebrates. AB - Vertebrate animals gain biologically important information from environmental sounds. Localization of sound sources enables animals to detect and respond appropriately to danger, and it allows predators to detect and localize prey. In many species, rapidly fluctuating sounds are also the basis of communication between conspecifics. This information is not provided directly by the output of the ear but requires processing of the temporal pattern of firing in the tonotopic array of auditory nerve fibers. The auditory nerve feeds information through several parallel ascending pathways. Anatomical and electrophysiological specializations for conveying precise timing, including calyceal synaptic terminals and matching axonal conduction times, are evident in several of the major ascending auditory pathways through the ventral cochlear nucleus and its nonmammalian homologues. One pathway that is shared by all higher vertebrates makes an ongoing comparison of interaural phase for the localization of sound in the azimuth. Another pathway is specifically associated with higher frequency hearing in mammals and is thought to make use of interaural intensity differences for localizing high-frequency sounds. Balancing excitation from one ear with inhibition from the other in rapidly fluctuating signals requires that the timing of these synaptic inputs be matched and constant for widely varying sound stimuli in this pathway. The monaural nuclei of the lateral lemniscus, whose roles are not understood (although they are ubiquitous in higher vertebrates), receive input from multiple pathways that encode timing with precision, some through calyceal endings. PMID- 10099700 TI - Timing of synaptic transmission. AB - Many behaviors require rapid and precisely timed synaptic transmission. These include the determination of a sound's direction by detecting small interaural time differences and visual processing, which relies on synchronous activation of large populations of neurons. In addition, throughout the brain, concerted firing is required by Hebbian learning mechanisms, and local circuits are recruited rapidly by fast synaptic transmission. To achieve speed and precision, synapses must optimize the many steps between the firing of a presynaptic cell and the response of its postsynaptic targets. Until recently, the behavior of mammalian synapses at physiological temperatures was primarily extrapolated from studies at room temperature or from the properties of invertebrate synapses. Recent studies have revealed some of the specializations that make synapses fast and precise in the mammalian central nervous system at physiological temperatures. PMID- 10099701 TI - Structure, strength, failure, and remodeling of the pulmonary blood-gas barrier. AB - The pulmonary blood-gas barrier needs to satisfy two conflicting requirements. It must be extremely thin for efficient gas exchange, but also immensely strong to withstand the extremely high stresses in the capillary wall when capillary pressure rises during exercise. The strength of the blood-gas barrier on the thin side is attributable to the type IV collagen in the basement membranes. However, when the wall stresses rise to very high levels, ultrastructural changes in the barrier occur, a condition known as stress failure. Physiological conditions that alter the properties of the barrier include intense exercise in elite human athletes. Some animals, such as Thoroughbred racehorses, consistently break their alveolar capillaries during galloping, causing hemorrhage. Pathophysiological conditions causing stress failure include neurogenic pulmonary edema, high altitude pulmonary edema, left heart failure, and overinflation of the lung. Remodeling of the capillary wall occurs in response to increased wall stress, a good example being the thickening of the capillary basement membrane in diseases such as mitral stenosis. The blood-gas barrier is able to maintain its extreme thinness with sufficient strength only through continual regulation of its wall structure. Recent experimental work suggests that rapid changes in gene expression for extracellular matrix proteins and growth factors occur in response to increases in capillary wall stress. How the blood-gas barrier is regulated to be extremely thin but sufficiently strong is a central issue in lung biology. PMID- 10099702 TI - Evolution of the vertebrate cardio-pulmonary system. AB - Vertebrate lungs have long been thought to have evolved in fishes largely as an adaptation for life in hypoxic water. This view overlooks the possibility that lungs may have functioned to supply the heart with oxygen and may continue to serve this function in extant fishes. The myocardium of most vertebrates is avascular and obtains oxygen from luminal blood. Because oxygen-rich pulmonary blood mixes with oxygen-poor systemic blood before entering the heart of air breathing fishes, lung ventilation may supply the myocardium with oxygen and expand aerobic exercise capabilities. Although sustained exercise in tetrapods is facilitated by septation of the heart and the formation of a dual pressure system, a divided cardio-pulmonary system may conflict with myocardial oxygenation because the right side of the heart is isolated from pulmonary oxygen. This may have contributed to the evolution of the coronary circulation. PMID- 10099703 TI - Mouse models of airway responsiveness: physiological basis of observed outcomes and analysis of selected examples using these outcome indicators. AB - The mouse is an ideal species for investigation at the interface of lung biology and lung function. As detailed in this review, there are well-developed methods for the quantitative study of lung function in mice. These methods can be applied to mice in both terminal and nonterminal experiments. Terminal experimental approaches provide more detailed physiological information, but nonterminal measurements provide adequate data for certain experiments. In this review, we provide two examples of how these models can be used to further understanding of the primary pathobiology of airway responsiveness in both the absence and the presence of induced airway inflammation. The first model is a dissection of chromosomal loci linked to the variance in airway responsiveness observed in the absence of any manipulation to induce airway inflammation. The second model explores the role of T-cell costimulatory signals in the induction of airway hyperresponsiveness. As the number of mice with targeted deletions of effector genes or insertion of informative transgenes grows, additional examples are likely to accrue. PMID- 10099704 TI - Sodium channels in alveolar epithelial cells: molecular characterization, biophysical properties, and physiological significance. AB - At birth, fetal distal lung epithelial (FDLE) cells switch from active chloride secretion to active sodium (Na+) reabsorption. Sodium ions enter the FDLE and alveolar type II (ATII) cells mainly through apical nonselective cation and Na(+) selective channels, with conductances of 4-26 pS (picoSiemens) in FDLE and 20-25 pS in ATII cells. All these channels are inhibited by amiloride with a 50% inhibitory concentration of < 1 microM, and some are also inhibited by [N-ethyl-N isopropyl]-2'-4'-amiloride (50% inhibitory concentration of < 1 microM). Both FDLE and ATII cells contain the alpha-, beta-, and gamma-rENaC (rat epithelial Na+ channels) mRNAs; reconstitution of an ATII cell Na(+)-channel protein into lipid bilayers revealed the presence of 25-pS Na+ single channels, inhibited by amiloride and [N-ethyl-N-isopropyl]-2'-4'-amiloride. A variety of agents, including cAMP, oxygen, glucocorticoids, and in some cases Ca2+, increased the activity and/or rENaC mRNA levels. The phenotypic properties of these channels differ from those observed in other Na(+)-absorbing epithelia. Pharmacological blockade of alveolar Na+ transport in vivo, as well as experiments with newborn alpha-rENaC knock-out mice, demonstrate the importance of active Na+ transport in the reabsorption of fluid from the fetal lung and in reabsorbing alveolar fluid in the injured adult lung. Indeed, in a number of inflammatory diseases, increased production of reactive oxygen-nitrogen intermediates, such as peroxynitrite (ONOO-), may damage ATII and FDLE Na+ channels, decrease Na+ reabsorption in vivo, and thus contribute to the formation of alveolar edema. PMID- 10099705 TI - Sodium-coupled transporters for Krebs cycle intermediates. AB - Krebs cycle intermediates such as succinate, citrate, and alpha-ketoglutarate are transferred across plasma membranes of cells by secondary active transporters that couple the downhill movement of sodium to the concentrative uptake of substrate. Several transporters have been identified in isolated membrane vesicles and cells based on their functional properties, suggesting the existence of at least three or more Na+/dicarboxylate cotransporter proteins in a given species. Recently, several cDNAs, called NaDC-1, coding for the low-affinity Na+/dicarboxylate cotransporters have been isolated from rabbit, human, and rat kidney. The Na+/dicarboxylate cotransporters are part of a distinct gene family that includes the renal and intestinal Na+/sulfate cotransporters. Other members of this family include a Na(+)- and Li(+)-dependent dicarboxylate transporter from Xenopus intestine and a putative Na+/dicarboxylate cotransporter from rat intestine. The current model of secondary structure in NaDC-1 contains 11 transmembrane domains and an extracellular N-glycosylated carboxy terminus. PMID- 10099706 TI - Modulation of vasopressin-elicited water transport by trafficking of aquaporin2 containing vesicles. AB - Vasopressin or AVP regulates water reabsorption by the kidney inner medullary collecting duct (IMCD) through the insertion and removal of aquaporin (AQP) 2 water channels into the IMCD apical membrane. AVP-elicited trafficking of AQP2 with the apical membrane occurs via a specialized population of vesicles that resemble synaptic vesicles in neurons. AQP2 vesicles and the IMCD apical membrane contain homologs of vesicle-targeting and signal transduction proteins found in neurons. Expression studies of AQP2, including human AQP2 mutants, suggest that the carboxyl-terminal domain of AQP2 is important in AQP2 trafficking, particularly as a site for cAMP-dependent protein kinase phosphorylation. These present data reveal that IMCD cells possess a complex integrated-signaling and vesicle-trafficking machinery that provides integration of AVP-elicited water transport with many other parameters within the IMCD cell as well as kidney. PMID- 10099707 TI - Electrogenic Na+/HCO3- cotransporters: cloning and physiology. AB - Bicarbonate and CO2 comprise the major pH buffer of biological fluids. In the renal proximal tubule most of the filtered HCO3- is reabsorbed by an electrogenic Na/HCO3 cotransporter located at the basolateral membrane. This Na+ bicarbonate cotransporter (NBC) was recently cloned. This review highlights the recent developments leading to and since the cloning of NBC: NBC expression cloning, protein features, clone physiology, isoforms and genes, mRNA distribution, and protein distribution. With the NBC amino acid sequence 30-35% identical to the anion exchangers (AE1-3), a superfamily of HCO3- transporters is emerging. Physiologically, NBC is electrogenic, Na+ dependent, HCO3- dependent, Cl- independent, and inhibited by stilbenes (DIDS and SITS). NBC clones and proteins have been isolated from several tissues (other than kidney) thought to have physiologically distinct HCO3- transporters. For example, NBC occurs in pancreas, prostate, brain, heart, small and large intestine, stomach, and epididymis. Finally, there are at least two genes that encode NBC proteins. Possible future directions of research are discussed. PMID- 10099708 TI - Electrophysiology of synaptic vesicle cycling. AB - Patch-clamp capacitance measurements can monitor in real time the kinetics of exocytosis and endocytosis in living cells. We review the application of this technique to the giant presynaptic terminals of goldfish bipolar cells. These terminals secrete glutamate via the fusion of small, clear-core vesicles at specialized, active zones of release called synaptic ribbons. We compare the functional characteristics of transmitter release at ribbon-type and conventional synapses, both of which have a unique capacity for fast and focal vesicle fusion. Subsequent rapid retrieval and recycling of fused synaptic vesicle membrane allow presynaptic terminals to function independently of the cell soma and, thus, as autonomous computational units. Together with the mobilization of reserve vesicle pools, local cycling of synaptic vesicles may delay the onset of vesicle pool depletion and sustain neuronal output during high stimulation frequencies. PMID- 10099709 TI - Genetics of synaptic vesicle function: toward the complete functional anatomy of an organelle. AB - Synaptic transmission starts with the release of neurotransmitters by exocytosis of synaptic vesicles. As a relatively simple organelle with a limited number of components, synaptic vesicles are in principle accessible to complete structural and functional genetic analysis. At present, the majority of synaptic vesicle proteins has been characterized, and many have been genetically analyzed in mice, Drosophila, and Caenorhabditis elegans. These studies have shown that synaptic vesicles contain proteins with diverse structures and functions. Although the genetic studies are as yet unfinished, they promise to lead to a full description of synaptic vesicles as macromolecular machines involved in all aspects of presynaptic neurotransmitter release. PMID- 10099710 TI - Reconstitution of regulated exocytosis in cell-free systems: a critical appraisal. AB - Regulated exocytosis involves the tightly controlled fusion of a transport vesicle with the plasma membrane. It includes processes as diverse as the release of neurotransmitters from presynaptic nerve endings and the sperm-triggered deposition of a barrier preventing polyspermy in oocytes. Cell-free model systems have been developed for studying the biochemical events underlying exocytosis. They range from semi-intact permeabilized cells to the reconstitution of membrane fusion from isolated secretory vesicles and their target plasma membranes. Interest in such cell-free systems has recently been reinvigorated by new evidence suggesting that membrane fusion is mediated by a basic mechanism common to all intracellular fusion events. In this chapter, we review some of the literature in the light of these new developments and attempt to provide a critical discussion of the strengths and limitations of the various cell-free systems. PMID- 10099711 TI - Mechanisms of hair cell tuning. AB - Mechanosensory hair cells of the vertebrate inner ear contribute to acoustic tuning through feedback processes involving voltage-gated channels in the basolateral membrane and mechanotransduction channels in the apical hair bundle. The specific number and kinetics of calcium-activated (BK) potassium channels determine the resonant frequency of electrically tuned hair cells. Kinetic variation among BK channels may arise through alternative splicing of slo gene mRNA and combination with modulatory beta subunits. The number of transduction channels and their rate of adaptation rise with hair cell response frequency along the cochlea's tonotopic axis. Calcium-dependent feedback onto transduction channels may underlie active hair bundle mechanics. The relative contributions of electrical and mechanical feedback to active tuning of hair cells may vary as a function of sound frequency. PMID- 10099712 TI - Ion channels of nociception. AB - Nociceptors are the first cells in the series of neurons that lead to the sensation of pain. The essential functions of nociceptors--transducing noxious stimuli into depolarizations that trigger action potentials, conducting the action potentials from the peripheral sensory site to the synapse in the central nervous system, and converting the action potentials into neurotransmitter release at the presynaptic terminal--all depend on ion channels. This review discusses recent results in the converging fields of nociception and ion channel biology. It focuses on (a) the capsaicin receptor and its possible role in thermosensation, (b) ATP-gated channels, (c) proton-gated channels, and (d) nociceptor-specific Na+ channels. PMID- 10099713 TI - Controversial issues in vertebrate olfactory transduction. AB - A number of controversial issues in olfactory transduction are discussed including the matter of multiple transduction pathways, with a new experiment proposed. Evidence is reviewed concerning the fact that cyclic AMP is the only pathway mediating olfactory transduction. Two knockout mice have been produced: a knockout for a cyclic nucleotide-gated channel and a G(olf) knockout. The results obtained with both mice are consistent with cyclic AMP being the only second messenger. The evidence for gaseous second channel messengers is also reviewed. Slow gating kinetics of the cyclic nucleotide-gated channel and the detection of single-odorant molecules are reviewed. A new phenomenon in which odorants can block odorant responses is discussed. PMID- 10099714 TI - Cellular mechanisms of taste transduction. AB - Taste receptor cells respond to gustatory stimuli using a complex arrangement of receptor molecules, signaling cascades, and ion channels. When stimulated, these cells produce action potentials that result in the release of neurotransmitter onto an afferent nerve fiber that in turn relays the identity and intensity of the gustatory stimuli to the brain. A variety of mechanisms are used in transducing the four primary tastes. Direct interaction of the stimuli with ion channels appears to be of particular importance in transducing stimuli reported as salty or sour, whereas the second messenger systems cyclic AMP and inositol trisphosphate are important in transducing bitter and sweet stimuli. In addition to the four basic tastes, specific mechanisms exist for the amino acid glutamate, which is sometimes termed the fifth primary taste, and for fatty acids, a so called nonconventional taste stimulus. The emerging picture is that not only do individual taste qualities use more than one mechanism, but multiple pathways are available for individual tastants as well. PMID- 10099715 TI - Trophic and tropic factors in the development of the central nervous system. PMID- 10099716 TI - Immunocytochemical localization of the AMPA receptor subunits in the mesencephalic trigeminal nucleus of the rat. AB - The mesencephalic trigeminal nucleus is composed of large (35-50 microns) pseudo unipolar neurons. Closely associated with them are small (< 20 microns) multipolar neurons. An unique peculiarity of the pseudo-unipolar perikarya is that they receive synaptic input from various sources, which sets them apart from the dorsal root and cranial nerves sensory ganglia neurons. Whereas glutamate is the best neurotransmitter candidate in pseudo-unipolar neurons, glutamatergic input into them has not yet been reported. AMPA glutamate receptors are implicated in fast excitatory glutamatergic synaptic transmission. They have been localized ultrastructurally at postsynaptic sites. This study demonstrates that the pseudo-unipolar neurons of the mesencephalic trigeminal nucleus express AMPA glutamate receptor subunits, which indicates that these neurons receive glutamatergic input. Serial sections from the rostral pons and midbrain of Sprague-Dawley rats were immunostained with antibodies against C-terminus of AMPA receptor subunits: GluR1, GluR2/3, and GluR4. The immunoreaction was visualized with avidin-biotin-peroxidase/DAB for light and electron microscopy. With GluR1 antibody only the smallest multipolar neurons were recognized as immunopositive within the mesencephalic trigeminal nucleus. GluR2/3 stained the pseudo-unipolar neurons intensely within the entire rostro-caudal extent of the nucleus. In addition the former antibody stained small multipolar neurons within the mesencephalic trigeminal nucleus, though with somewhat larger dimensions than those immunoreactive for GluR1. Whereas the overall staining with GluR4 antibody was scant, those pseudo-unipolar neurons that were stained, were strongly stained. Furthermore, a considerable number of microglial cells within and surrounding the mesencephalic trigeminal nucleus displayed very intense immunoreactivity for GluR4. These results are discussed in the light of the glutamate receptor subunit composition. PMID- 10099717 TI - Evidence for a possible glycinergic inhibitory neurotransmission in the midbrain and rostral pons of the rat studied by gephyrin. AB - The data on the glycinergic transmission in the rostral brainstem are both few and controversial. The present report provides evidence for a possible glycinergic transmission in Sprague-Dawley rats, based on observations of immunocytochemical labeling for gephyrin, a 93 kDa protein and a component of the functional glycine receptor. A monoclonal antibody against gephyrin was used, and the reaction product was visualized by means of avidin-biotin-peroxidase procedure. The reaction product in midbrain and rostral pons was found in neuronal perikarya and in proximal dendrites but in some cases the most distal dendritic branches were also labeled. The neuropil usually displayed a moderate staining with finely granulated reaction product. The most significant immunocytochemical signal was mainly encountered in large and medium-sized neuronal populations of the motor cranial nerve nuclei (III, IV, V), in the reticular formation (laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus, deep mesencephalic nucleus), in the red nucleus, in the intermediate and deep gray strata of the superior colliculus. Only in the substantia nigra and the inferior colliculus the parvocellular cell populations were mainly labeled. The present data suggest a significant inhibitory glycinergic neurotransmission in the rostral brainstem, probably mediated by interneurons. PMID- 10099718 TI - Calcium-calmodulin modulation of the activity of Na+/H+ exchanger in human platelets. AB - This study aimed at establishing the role of calmodulin in regulating pHi of human platelets under acid loads and in stimulated states. The response of human platelets to thrombin was an initial drop of pHi followed by a recovery with a significant increase above the pre-stimulation level in control experiments and a recovery to initial values in platelets maintained in the presence of 19 mmol/l TFP (trifluoperazine = 2 trifluoromethyl-10 [3'-(1 methyl-4-piperazinyl) propyl] phenothiazine). The change in pHi after 8 min was 0.130 +/- 0.030 in the control and 0.001 +/- 0.011 pH units in TFP (P < 0.05). The initial velocity of recovery from an acid load was reduced to 56.7 +/- 6% of the control (n = 6, P < 0.05) with 50 mumol/l W7 (N-(6 aminohexyl)-5-chloro-l-naphthalene sulphonamide), and to 29.7 +/- 4.3% of the control (n = 8, P < 0.05) with 19 mumol/l TFP. The initial velocity of recovery was significantly greater in recalcified platelets than in the preparations kept in the nominal absence of extracellular calcium (1.08 +/- 0.12 vs 0.66 +/- 0.12 pH units per min, P < 0.05). Lower concentration of TFP had an inhibitory effect only in the presence of calcium. The velocities of recovery reached similar values at higher TFP concentration. The significant interaction between Ca2+ and TFP concentrations indicates that the Ca-calmodulin complex, rather than an unspecified direct action of TFP, is responsible for the modulation of the Na+/H+ exchanger. These findings indicate that calcium calmodulin participates in both the recovery of pH after an acid load and the increase of pHi in stimulated states of human platelets. PMID- 10099720 TI - Striate, extrastriate and collicular processing of spatial disparity cues. AB - The spatial disparity sensitivity of single units in the primary visual cortex (17-18 border), in extrastriate area 19 and in the superficial layers of the superior colliculus of the cat brain were compared in the present study. Unit recordings were performed in paralyzed and anesthetized animals. Centrally located receptive fields were mapped, separated using prisms and then stimulated simultaneously using two luminous bars optimally adjusted to the size of the excitatory receptive fields. In the three regions studied, cells selective to spatial disparity were found and four classes of disparity sensitivity profiles emerged. Although the disparity sensitivity profiles of the cells in the three regions appeared to have the same general shape, selectivity was clearly different. Cells at the 17-18 border were sharply tuned, those of area 19 were not only less numerous but also less well tuned and collicular cells exhibited coarse selectivity. These differences in selectivity appear to be linked to the projection pattern of the X, Y and W systems to these regions and the roles that these cells might play in vision. PMID- 10099719 TI - Lack of effects of an acute hepatic vagotomy on insulin and catecholamine responses in rats following exercise. AB - The purpose of the present investigation was to evaluate the effects of an acute hepatic vagotomy on hormonal responses to hyperglycemic and hypoglycemic challenges in rats previously submitted to an exercise protocol. Two experiments were conducted. In a first experiment, 8-week trained (TR) and untrained (UNTR) rats, subdivided into acutely hepatic vagotomized (HV) and sham-operated (SHM) groups, were submitted to an intraperitoneal glucose tolerance test (0.5 g/kg) under anesthesia. Training was associated with a tendency (P = 0.07) for blood glucose levels to be less elevated (at time point 10 min), and with a significant (P < 0.01) lower glucose/insulin ratio following the glucose injection. The HV did not have any effects on these responses. In a second experiment, non exercised rats and a group of rats submitted to an acute bout of exercise (treadmill, 60 min, 26 m/min, 5% slope) 24 h before the experiment, each one of these two groups being subdivided into acutely HV and SHM groups, were submitted to an insulin-induced hypoglycemia protocol, under anesthesia. Blood glucose concentrations were decreased significantly (P < 0.01) to approximately 40 mg/dl in all groups 60 and 80 min after the insulin injection. Plasma adrenaline and noradrenaline levels were increased significantly (P < 0.01) in all groups. The catecholamine increase was not influenced by the HV or the acute exercise bout. The present results do not indicate an implication of the hepatic vagus nerve on hormonal responses to hyper and hypoglycemia following exercise. PMID- 10099721 TI - Time domain method to identify simultaneously parameters of the windkessel model applied to the pulmonary circulation. AB - Lumped models are frequently used to provide a satisfactory description of the hemodynamic properties of the pulmonary vasculature. The purpose of this study is to describe a method to identify simultaneously the parameters values of windkessel models components. The following equation was used to obtain R1 (characteristic resistance), R2 (peripheral resistance), C (total compliance) and L (inertance): [formula: see text] where ki are the following functions of L, R1, R2 and C: [formula: see text] To assess the accuracy of the method, estimates of R1, R2, and C were compared to characteristic impedance Rc, vascular resistance PVR and pulmonary arterial compliance Cd respectively computed from referenced methods. Comparison between R1 and Rc, PVR and R1 + R2, C and Cd were obtained in 5 anaesthetised pigs during basal conditions and after endotoxin-shock. The results indicate that in both conditions, comparisons evidenced highly significant correlations between values computed by the different approaches (p < 0.0001). Although our method yielded to consistently lower values than values provided by referenced methods, the results were concordant with respect to the expected response of pulmonary vasculature to endotoxin insult. We conclude that our method of identification is suitable for the assessment of lumped parameters windkessel model estimates. The main interest is that actual resistance and compliance values can be obtained easily and simultaneously by a global method approach. PMID- 10099722 TI - Seasonal variation of fatty acid content in natural microplankton from the Tumpat coastal waters of the South China Sea. AB - In the search for better understanding on the nutritional quality of natural tropical plankton, samples were collected from shallow coastal waters facing the South China Sea during the dry monsoon (May-September) and the wet monsoon (November-April) seasons from March 1993 to July 1994. The total fatty acid content of the predominantly phytoplankton communities (25-200 microns sieve nets) varied four to fivefold with the lowest value occurring during the dry monsoon when blue-green became predominant. Saturated fatty acid content (SAFA), polyunsaturated fatty acid (PUFA) and total omega 3 (sigma omega 3) showed the same seasonal pattern as the total fatty acid with high values in October to December 1993. When species of the dinoflagellate Peridinium and Ceratium were present in considerable amount, the docosahexaenoic acid DHA content was high, especially from March to May 1993. The maximum content of eicosapentaenoic acid EPA, total omega-3 fatty acid, PUFA and sigma omega 3 in phytoplankton occurred during the pre-monsoon period (October and November 1993) when the diatoms were present in large amounts. The larger fraction sample (> 200 microns sieve nets) which consisted predominantly of zooplankton had high amounts of PUFA from September to November 1993. PMID- 10099723 TI - [What is new in the treatment of COPD?]. PMID- 10099724 TI - [Effects of portable liquid oxygen therapy on walking]. AB - The effect on walking of portable liquid oxygen therapy (PLOT), which involves carrying a tank, remains unclear. Our aim was to evaluate the repercussion of PLOT on performance in the 6 minute walking test. We enrolled 30 patients receiving home oxygen therapy in a randomized crossover study, collecting data on arterial blood gases at baseline, spirometry, and performance on the 6 minute walking test at baseline and at later sessions with PLOT and with compressed air simulating oxygen. During the tests we measured peak heart rate, distance walked and time that oxygen saturation remained over 89%. For compressed air, no improvement over baseline values was observed for any of the parameters measured. During the PLOT tests, however, patients walked farther than at baseline and arterial oxygen saturation rose to the prescribed flow rate. Dyspnea was not significantly affected. PMID- 10099725 TI - [Lung transplantation at the Papworth Hospital: 9-year experience]. AB - OBJECTIVE: To review and compare our results for single lung transplantation (SLT) and double lung transplantation (DLT). METHODS: One hundred twenty-three patients transplanted between September 1988 and July 1997 (99 SLT and 24 DLT) were reviewed. Mean follow-up was 749 days. RESULTS: The following variables were significantly different for the two recipient populations: the most common indication was restriction for SLT and sepsis for DLT; mean ages were 50.3 +/- 9.2 and 40.6 +/- 14.3 for SLT and DLT, respectively; and nutritional status measured as body mass index was 21.5 +/- 4 for SLT and 18.6 +/- 2.7 for DLT. DLT patients experienced longer periods of ischemia during surgery (287 +/- 75 min versus 242 +/- 65 min for SLT, p = 0.01) and more of them required extracorporeal circulation (67% versus 37%, p = 0.005). Early postoperative morbidity after DLT was greater because of bleeding (1,046 +/- 848 ml versus 690 +/- 503 ml; p = 0.01) and time of intubation (9 hours, interquartile range 7 to 13 for DLT patients versus 5 hours, interquartile range 1 to 10 for SLT; p = 0.001). DLT recipients also suffered more respiratory infections during the first 3 months after surgery. Long term, DLT patients had greater pulmonary function capacity than did SLT patients, a difference that was maintained over the three years of follow-up. Readmission was more frequent among DLT patients because of infection (0.40 versus 0.26 readmissions per patient per 100 days; p < 0.02). CONCLUSIONS: Both unilateral and bilateral lung transplants are valid therapeutic options for patients with terminal phase lung disease. DLT offers more hope of long term functional recovery without negatively affecting survival. PMID- 10099726 TI - [Suberosis: involvement of bronchoalveolar +mastocytes in the genesis of interstitial involvement]. AB - Suberosis--the lung disease suffered by cork industry workers--may present in the form of either hypersensitivity pneumonitis (HP) or obstructive pulmonary disease (OPD) with asthma-like symptoms or chronic bronchitis. Mast cells play an important role in pulmonary inflammation and are particularly implicated in the rapid release of mediators in bronchoconstriction and the production of cytokines and mediators of fibroblast activity. Increased numbers of mast cells are present in bronchoalveolar lavage (BAL) fluid in interstitial lung diseases, suggesting that these cells also participate in chronic inflammatory processes and in pulmonary fibrosis. OBJECTIVES: To assess the participation of mas cells in interstitial pulmonary inflammation in cork industry workers by histochemically analyzing their presence in BAL fluid. Foreseeing the possible implication of bronchoalveolar mast cells in the pathogenesis of suberosis, we also studied their relation to various signs and symptoms of the disease, to respiratory function parameters and to degree of alveolitis. PATIENTS AND METHODS: Thirty-one cork industry workers with respiratory symptoms related to occupational exposure were enrolled. Occupational and case histories were taken. Physical examinations were complemented by chest X-rays, plethysmography/spirometry, fiberoptic bronchoscopy with BAL, and determination of carbon monoxide diffusing capacity (DLCO) and arterial blood gases at rest. Patient classification (20 with HP and 11 with OPD) was based on clinical and functional criteria and analysis of BAL fluid. Mast cells in cytospinned samples treated with two different stains [May Grunwald-Giemsa (MGG) and Toluidine Blue (Tol.Bl.)] were counted by two observers and the results were compared. MAIN RESULTS: Good correlation between the two staining methods was confirmed (rs = 0.86, p < 0.0001). Correlation between the two observers was also good (MGG rs = 0.86, Yol.Bl. rs = 0.87, p < 0.0001). The number of mast cells in BAL fluid was significantly higher in patients with HP [13.4 +/- 4.5 (x +/- SEM)] than in those with OPD (0.9 +/- 0.3; p < 0.002, Mann Whitney test). The subgroup of eight patients with poorer respiratory function (CV and/or DLCO < 80% of reference value) also had higher mast cell counts in BAL (19.9 +/- 7.7 versus 3.5 +/- 1.7; p = 0.002). We also saw a negative relation between mast cell counts in BAL fluid and lung function parameters: total lung capacity (rs = -0.68, p = 0.005) and DLCO (rs = -0.54, p = 0.008). Mast cell recovery from BAL fluid was positively related to severity of alveolitis in terms of total cell counts (rs = 0.62, p = 0.002), absolute lymphocyte counts (rs = 0.56, p = 0.006) and albumin levels (rs = 0.68, p = 0.003). CONCLUSIONS: Our findings suggest that mast cells participate in interstitial lung cell response to the inhalation of organic cork dust, particularly when HP is the form of presentation. Moreover, mas cell recruitment on the alveolar surface seems to be related to the intersity of lymphocytosis and interstitial pulmonary inflammation and to lung function deterioration in affected patients. PMID- 10099727 TI - [Usefulness of a gene amplification technique (LCx MTB) in the diagnosis of tuberculosis: preliminary results with different sputum samples]. AB - OBJECTIVE: To evaluate the use in non-sputum samples of a commercial molecular amplification kit (LCx MTB, Abbott Diagnostica) (LCx) for the diagnosis of tuberculosis. MATERIAL AND METHOD: Ninety-nine non-sputum samples from the same number of patients (bronchoalveolar, pleural and ascitic fluid, fecal samples, blood cultures, biopsies from different sites, cerebrospinal fluid, urine and gastric juices) and 14 sputum samples (10 from patients clinically suspected of having tuberculosis and 4 from patients diagnosed of tuberculosis and undergoing appropriate treatment for at least one month). All samples were LCx processed according to the manufacturer's instructions. The reference diagnosis was obtained by the Lowestein-jensen method and when results were inconsistent, we took into account the degree of clinical suspicion, response to treatment and histology. RESULTS: Seven of the 99 samples were positive by the LCx technique, and 6 of the 7 were also LJ positive; 1 could not be evaluated because of culture contamination. One LJ positive culture was LCx negative. Only one sample was positive by Ziehl-Neelsen (ZN) staining. Ninety-two samples were LCx negative, with 91 showing no growth at all. Sensitivity was 86% and specificity 98%. Atypical mycobacteria were detected in 4 cases, all of which were LCx negative. CONCLUSIONS: Diagnosis of tuberculosis by applying the LCx system to various types of samples other than sputum is simple, rapid, sensitive and specific. PMID- 10099728 TI - [Thoracic wounds: review of 90 cases]. AB - Our aim in reviewing all cases of chest wounds (CW) treated in our unit to analyze their causes, clinical characteristics and treatment. We performed a retrospective study of all CW patients admitted and/or treated by us between January 1986 and August 1997, studying causes, history, number and type of wounds, location, the association of chest and non-chest lesions, treatment, complications and length of hospital stay. The 90 CW patients treated in our unit accounted for 10.6% of all CW patients admitted during the study period. Eighty five (94.4%) were men and five were women (5.6%) and mean age was 33.87 years. Physical attack was the most common cause of CW, accounting for 74 cases (82.2%) and stab wounds (77 cases, 85.6%) were more common than gunshot wounds (13 cases, 14.4%). Sixty-one (67.%) were deep and most were to the left hemithorax (46 cases, 51.1%). Besides damage to skin and soft tissues of the chest wall, lesions most often affected the pleura (59 cases, 65.5%) and parenchyma (27 cases, 30%). Local treatment of the wound was sufficient for 31 patients (34.4%) but 29 (32.3%) also required drainage and 30 (33.3%) required surgery. Complications developed in 8 cases (8.9%) and one patient died while in surgery. Mean duration of hospital stay was 8.64 days. CW in our practice is seen most commonly in young men and is caused by physical aggression, usually involving knives. Most wounds are stabs, usually to the left hemithorax. The prognosis for firearm wounds is poorer. One third of patients require thoracic drains and another third require chest surgery in addition to local treatment of CW and other wounds. The patient's hemodynamic status was the parameter that indicated need for surgical treatment. PMID- 10099729 TI - [Pickwick or Pliny?]. PMID- 10099730 TI - [Current treatment of non-microcytic bronchopulmonary carcinoma and new TNM classification]. PMID- 10099731 TI - [The first simultaneous double unilateral lung transplantation in Spain: clinical course and results. Transplantation Group]. AB - Unilateral lung transplantation of two organs allows two patients to benefit from a single donor. We report the first and only such transplants--carried out simultaneously in the same surgical unit--to be performed in Spain to date. The diagnosis was idiopathic pulmonary fibrosis in both cases and the donor came from the same hospital. No complications developed during the subsequent hospital stay. Two years later, both patients are asymptomatic and carrying out normal activities with no limitations. PMID- 10099732 TI - [Treatment of sleep apnea-hypoapnea syndrome]. PMID- 10099733 TI - [Wegener granulomatosis. Bronchocentric variant]. PMID- 10099734 TI - [Pulmonary edema caused by nitrogen dioxide inhalation]. PMID- 10099735 TI - [Severe hypoglycemia secondary to localized pleural fibrous mesothelioma]. PMID- 10099736 TI - [Metastatic small-cell tumor of the lung with long survival]. PMID- 10099737 TI - [Positron emission tomography and pneumoconiosis]. PMID- 10099738 TI - The Barker hypothesis. An analysis. PMID- 10099739 TI - Management of choroid plexus cysts in the mid-trimester fetus. PMID- 10099740 TI - Calcium supplementation in nulliparous women for the prevention of pregnancy induced hypertension, preeclampsia and preterm birth: an Australian randomized trial. FRACOG and the ACT Study Group. AB - A multicentre, randomized controlled double-blind trial in 5 maternity hospitals in Australia assessed the effect of a daily supplement of calcium (1.8g oral calcium or an oral placebo) taken daily until delivery, from less than 24 weeks' gestation, on the frequency of pregnancy-induced hypertension, preeclampsia and preterm birth (< 37 weeks' gestation) in 456 nulliparas with a singleton pregnancy. Treatment with calcium reduced the risk of preeclampsia (relative risk 0.44 [95% CI, 0.21-0.90], p = 0.02) and the risk of preterm birth (relative risk 0.44 [95% CI, 0.21-0.90], p = 0.02). No significant differences were seen between the 2 groups in the frequency of pregnancy-induced hypertension, although the study only had statistical power to detect large differences in this outcome. An updated systematic review of the 9 randomized trials of calcium supplementation in pregnancy shows a significant reduction in the risk of hypertension and preeclampsia although no effect on preterm birth. Calcium supplementation during pregnancy reduced the risk of preeclampsia and preterm birth in this nulliparous population. The available evidence for systematic review of all the randomized trials of calcium supplementation shows benefit in reducing the risk of hypertension and preeclampsia. PMID- 10099741 TI - Quiet resting is not necessary prior to routine antenatal blood pressure measurement. AB - A premeasurement period of 5 minutes quiet resting is recommended prior to measuring blood pressure. The aim of this study was to determine the effect of this period of rest on the level of blood pressure in pregnant women. One hundred pregnant women had their blood pressure measured on a single visit using a QuietTrak ambulatory blood pressure monitor, used to remove human observer bias. Group 1 (n = 50) had blood pressure measured as soon as possible on entering the clinic room and again after 5 minutes rest. Group 2 were rested for 5 minutes on entry to the clinic room prior to the first blood pressure measurement and had the second measurement taken after a further 5 minutes rest. Results were compared in the 2 groups using ANOVA. In Group 1, the initial, mean systolic blood pressure was 116.6 versus 115.5 mmHg taken after 5 minutes quiet rest (p = 0.66). The corresponding diastolic values were 66.2 versus 64.1 (p = 0.40). In Group 2, the initial mean systolic blood pressure was 116.2 versus 115.6 taken after 5 minutes quiet rest (p = 0.85). The corresponding diastolic values were 68.5 versus 65.6 (p = 0.34). Blood pressure was as likely to rise as to fall after a period of quiet rest. It is not necessary to have pregnant women quietly resting during routine visits before having blood pressure measured. PMID- 10099742 TI - A survey of parturients using epidural analgesia during labour. Considerations relevant to antenatal educators. AB - The use of epidural analgesia (EA) during labour is increasing in Australasia. This highlights the need for improved educational and resource materials, current factual information about EA, and identification of consumer attitudes towards EA. In this survey, 350 parturients who had recently used EA for labour pain relief in a single maternity unit were asked to complete a questionnaire about their expectations and experience. The response rate was 90%. Prepartum information was most commonly derived from hearsay and least commonly from medical health professionals, 56% of respondents wanted pain to be made tolerable and 34% wanted complete pain relief. Almost half considered unrestricted mobility and delivery without obstetric assistance important. A minority were concerned about possible effects of EA on the baby or labour outcome. Anticipated pain during epidural placement was significantly greater than that experienced. Satisfaction with EA was high, although 36% described unpleasant or annoying effects associated with EA. Parent educators and epidural service providers should be aided by knowledge of where parturients obtain information and of consumer views about EA. PMID- 10099743 TI - Recurrent miscarriage, congenital heart block and systemic lupus erythematosus. AB - We report the obstetric history of a woman, who between 15 spontaneous abortions, gave birth to a child with congenital heart block. She later developed systemic lupus erythematosus, had antibodies to SS-A/Ro and SS-B/La but was repeatedly negative for antiphospholipid antibodies. PMID- 10099744 TI - Pregnancy in patients with systemic lupus erythematosus. AB - We reviewed the obstetrical performance and outcome of 15 pregnancies in patients with systemic lupus erythematosus (SLE) (study group) and compared them with 45 age and parity-matched normal pregnancies (control group). Eleven women (73.8%) were in remission phase and 4 (26.7%) had active disease at the time of conception. The time interval between disease diagnosis and the index pregnancy was 4.2 +/- 2.5 years. Two patients with renal involvement had lupus flare-up during the antenatal period. There was no case of lupus flare-up in the postpartum period. Gestational age at delivery was significantly lower in SLE patients (35.9 +/- 2.5 weeks) compared to the control group (37.4 +/- 2.2 weeks). The incidence of intrauterine growth retardation was significantly higher in the SLE patients (40%). There was no case of neonatal lupus or congenital heart block. PMID- 10099745 TI - Anaemia and perinatal outcome in Port Moresby. AB - In 1987, a computerized obstetric database was set up at the Port Moresby General Hospital. Between 1987 and 1992, 27,117 births took place. The mean haemoglobin value amongst the 83% of women in whom a haemoglobin value was tested was 10.0 +/ 1.7 g/dL. High stillbirth rates (94 per 1,000) were associated with a haemoglobin value < 6 g/dL. The stillbirth rate was slightly lower (14 per 1,000) in woman whose lowest haemoglobin value was in the range 10.0-10.9 g/dL than in those with a haemoglobin value > or = 11 g/dL (18 per 1,000). The stillbirth rate was increased in women with haemoglobin values > or = 14.0 g/dL. With respect to low birth-weight (< 2,500 g), the rates were also higher when the haemoglobin value was above 14.0 g/dL. The reason for these findings is not apparent and may be due to the impact of an uncharacterized confounding variable rather than the haemoglobin value. PMID- 10099746 TI - Cost consequences of implementation of an early obstetrical discharge programme in a military teaching hospital. AB - We evaluate the cost consequence of a voluntary early obstetrical discharge programme in a military teaching hospital. The study involved a control group of routine obstetrical discharge patients with uncomplicated vaginal delivery from March 1 to August 31, 1994 and the study group of early obstetrical discharge (24 48 hours) patients with uncomplicated vaginal delivery from March 1 to August 31, 1996. There were 1,042 total control patients with routine vaginal delivery totalling 2,668 hospital days with a mean number of hospital days of 2.56 per patient. The study group of early obstetrical discharge patients with uncomplicated vaginal delivery encompassed 1,050 patients with 1,965 hospital days with mean hospital days of 1.87 per patient (p < 0.05) without an increase in postpartum clinic or emergency room visits. The total cost of admissions (cost calculation of $1,221 per hospital day) fell from $3,257,628 in the routine discharge group to $2,399,625 in the early discharge cohort showing a total cost savings of $858,003 over the 6-months study period. The average cost per obstetrical admission for routine vaginal delivery fell from $3,126 per day to $2,285 per day without an increase in the postpartum paediatric adverse outcomes. Maternal postpartum readmission rates were statistically significantly increased (p < 0.05) in the study group at 0.6% with an OR[2.32(2.17, 6.92)] but all readmissions fell outside the 48-hour early discharge window. This programme showed significant cost savings without concomitant increase in paediatric or maternal adverse outcomes. PMID- 10099747 TI - Decrease in incidence of gestational diabetes mellitus in Far North Queensland between 1992 and 1996. AB - The pregnant population in Far North Queensland is at high risk of medical complications, such as diabetes, compared to the general Australian population (1,2). This retrospective observational study shows a true decline in the incidence of gestational diabetes mellitus (GDM) in this region over a 5-year period (1992-1996), contradicting the current belief that the incidence of GDM is increasing in non-Caucasian Australians. Although this change may be due to an improvement in medical and/or dietary intervention in this region, the real cause for the decline is yet to be recognized. PMID- 10099748 TI - The impact of leiomyomas on pregnancy. AB - In this retrospective case control investigation, 51 pregnant patients who were diagnosed by ultrasound with uterine myomas were compared to 102 randomly selected control patients to determine if the ultrasound diagnosis of one or more leiomyoma is associated with increased untoward pregnancy outcomes compared to controls. Women with uterine myomas were older (p = 0.001), more likely to be African American (p = 0.001), and undergo Caesarean delivery (p = 0.03) than controls. However, when women who underwent abdominal delivery for previous myomectomy (n = 5) were excluded from analysis, there was no significant difference in the incidence of Caesarean delivery. Overall, there was no difference in the incidence of obstetric complications between groups even when the data was stratified for large and/or multiple leiomyomas. The discovery of uterine leiomyomas by gestational ultrasound does not appear to place the patient at increased risk for preterm labour, early delivery, or other untoward pregnancy outcomes. PMID- 10099749 TI - Sexual behaviour during pregnancy. AB - The effects of pregnancy on sexuality were studied in 158 pregnant women. They were surveyed by questionnaire about sociodemographic variables and sexual behaviour. Dyspareunia was common in our study group during pregnancy. Pregnancy had a negative effect on orgasmic quality. Dyspareunia and orgasmic quality influenced coital frequency. Coital frequency declined as the month of the pregnancy increased. Pregnancy is a potent influence on sexuality irrespective of an individual's conditioning. PMID- 10099750 TI - Female genital mutilation--experience of The Royal Women's Hospital, Melbourne. AB - This study was performed to improve our knowledge and understanding of the needs of women affected by female genital mutilation. We looked at the types of complications of these practices which present to a large metropolitan women's hospital in order to determine how we can appropriately treat and support affected women. This was an observational study of women from countries with a high prevalence of female genital mutilation who presented to the Royal Women's Hospital between October, 1995 and January, 1997. Fifty-one patients with a past history of female genital mutilation who were attending the hospital for antenatal or gynaecological care consented to participate in the study. We found that 77.6% of women identified as having had female genital mutilation had undergone infibulation. More than 85% of the women in our study reported a complication of the procedure. The major complications were dyspareunia, apareunia and urinary tract infections; 29.4% of these women required surgery to facilitate intercourse. In our study group there was no difference in Caesarean section rates between the women who had previously delivered in Australia compared with those who had delivered in Africa. Women who have had a female genital mutilation procedure have specific needs for their care which present challenges to both their general practitioners and obstetrician/gynaecologists. These women have significant complications related to their procedure including social and psychosexual problems which require sympathetic management. PMID- 10099751 TI - The introduction of a woman-held record into a hospital antenatal clinic: the bring your own records study. AB - We report the introduction of a woman-held record into an antenatal clinic in a NSW teaching hospital using a randomized controlled trial. In 1997, 150 women were randomized to either retaining their entire antenatal record through pregnancy (women-held group) or to holding a small, abbreviated card, as was standard practice (control group). A questionnaire was distributed to women to measure sense of control, involvement in care and levels of communication. Availability of records at antenatal visits was also measured. Women in both groups were satisfied with their allocated method of record keeping, however, those in the women-held group were significantly more likely to report feeling in 'control' during pregnancy. Women in the control group were more likely to feel anxious and helpless and less likely to have information on their records explained to them by their caregiver. The number of records available at each clinic was similar in both groups. PMID- 10099753 TI - Transvaginal ultrasound appearances of the ovary in normal women and hirsute women with oligomenorrhoea. AB - The transvaginal ultrasound appearances of the ovary were determined in women with clinical and endocrine features of polycystic ovarian disease (PCOD) and apparently normal women. At scan the number of small follicles were counted and ovarian volume was calculated. The maximum width of the ovarian cortex was also measured. Blood was sent for measurement of LH, FSH and testosterone. The women with oligomenorrhoea were scanned at random and the normal women were seen within the first 5 days of the start of menstruation. There were significant differences between median values for the 2 groups in terms of number of small follicles, ovarian volume and stromal width; the ovaries of the hirsute women had more follicles, were of larger volume, and had greater stromal width. The 2 ranges for number of follicles did overlap, however. Four hirsute oligomenorrhoeic women had a normal number of follicles; all 4 had the several clinical and endocrine features indicative of PCOD. These data suggest that the classical ultrasound features of PCOD are not consistently present and that the absence of increased follicularity at scan should not necessarily deter clinicians from making the functional diagnosis of PCOD. PMID- 10099752 TI - Contraceptive use in Australia: evidence from the 1995 National Health Survey. AB - This paper analyses the patterns of contraceptive use among Australian women, using data from the 1995 National Health Survey. More than 44% of all women aged 18-49 years reported using a method of contraception. Among users, the 2 most commonly reported methods were the pill (60%) and condom (27%); IUD and natural methods accounted for less than 5% each. Sterilizing operations of the women/partner were the most frequently reported reasons for nonuse of contraception in women aged over 35 years, while among the younger women the most reported reasons were pregnancy or trying to get pregnant and not being sexually active. Among pill-users about a quarter were smokers, 20% overweight and 13% reported heart or circulatory disease. These figures were generally lower than in the general population but indicate a need for regular monitoring. The survey demonstrates the continuing evolution in the use of contraception among Australian women. PMID- 10099754 TI - Radical surgery for endometriosis. AB - Infiltrative endometriosis is an uncommon condition that may involve all pelvic organs and is associated with considerable morbidity. A small percentage of patients will have disease that is unresponsive to hormonal therapy and is unsuitable for conservative surgery. Presented is a review of 5 case reports of patients who required radical surgery for control of symptoms caused by endometriosis. Radical surgery was associated with minimal morbidity and a high rate of resolution of symptoms. Radical surgery should be considered as part of the treatment strategy particularly when there is evidence of endometriosis invading into the adjacent gastrointestinal tract or urinary tract. PMID- 10099755 TI - Hilus cell tumour of the ovary in a virilized, premenopausal woman. Case report and review of hyperandrogenism of ovarian origin. AB - A 35 year-old woman presented with virilization and was found to have elevated serum testosterone levels. Investigation revealed an 11 mm hilus cell tumour in the left ovary. After unilateral oophorectomy, serum testosterone levels rapidly returned to normal levels. The various ovarian tumours and conditions causing virilization are described and a clinical approach to the investigation of virilization is outlined. PMID- 10099756 TI - Vulvar vestibulitis syndrome: an often unrecognized cause of dyspareunia. AB - Vulvar vestibulitis syndrome (VVS) is an easily identifiable cause of entry dyspareunia. The aetiology is unknown although there is a strong association with Candida infection. The condition represents a focal area of hyperaesthesia within the vulvar vestibule. A management protocol for patients with this condition is presented; 230 patients with VVS were managed and followed-up over a 5-year period. Spontaneous resolution or improvement occurred in 21% of patients following initial explanation and use of simple local measures. In 21%, there were positive Candida cultures and long-term antifungal therapy resulted in a 71% cure. In Candida-negative patients, low-dose amitriptyline was used (up to 75 mg daily) with a 60% positive response rate. Carbamazepine was of little benefit (13% response). Surgical vestibulectomy was offered when conservative measures failed and this was performed in 22 patients (10%) with a beneficial result in 20 patients (91%). PMID- 10099757 TI - Contribution of the assisted reproductive technologies to fertility in males suffering spinal cord injury. AB - This study reviews 19 couples referred between 1990 and 1997 for fertility treatment for anejaculatory infertility in the male partner following spinal injury. Using sperm obtained by assisted ejaculation procedures, 14 of the 19 patients (74%) achieved at least 1 pregnancy. Pregnancy rates per treatment cycle were 12.0% for timed intrauterine insemination, 38.9% for gamete intra-Fallopian transfer and 19.2% for intracytoplasmic sperm injection followed by uterine embryo transfer. Choice of the appropriate assisted reproduction treatment to match the available semen quality results in a high level of success in such patients. PMID- 10099758 TI - Microlaparoscopic left upper quadrant entry in patients at high risk of periumbilical adhesions. AB - We performed a prospective study of microlaparoscopic direct entry in the left upper quadrant (LUQ) to determine the efficacy of this technique and the incidence and site of anterior abdominal wall adhesions in high-risk patients. Direct insertion of the MiniPort introducer was successful with 1 attempt in 16 patients and in 2 attempts with 1 patient. Overall, 12 patients (71%) had either bowel or omentum adherent to the anterior abdominal wall. Eight of the 12 patients (75%) with a previous midline abdominal wall incision were found to have subumbilical adhesions. Two patients were noted to have LUQ omental adhesions. Direct insertion of a 2 mm microlaparoscopic primary port in the LUQ appears to be simple, safe and quick to perform. It provides an excellent view of the peritoneal surface of the anterior abdominal wall and umbilical area. This procedure is likely to be the preferred method of peritoneal entry in high-risk patients in the future. PMID- 10099759 TI - Management of uterine leiomyosarcoma in Australia. AB - Uterine leiomyosarcoma is an uncommon malignancy for which the management varies widely between individual gynaecologists and gynaecological oncology units. We have performed a retrospective review of patients treated at both the Royal Women's Hospital in Melbourne (1970-1997) and King George V Hospital in Sydney (1987-1993). In addition we have performed a survey of Certified Gynaecological Oncologists (CGO's) to assess the current management of uterine leiomyosarcomas in Australia. The results show varied management practices exist in Australia, many of which are not supported by evidence in the current literature. Oophorectomy in the premenopausal patient appears unnecessary unless the ovaries are macroscopically involved. The role of pelvic lymphadenectomy is debatable. This practice was recommended by many CGO's, yet these nodes are rarely positive unless obvious extrauterine disease is present. Adjuvant chemotherapy appears not to have a role at present unless in a trial setting. Adjuvant radiotherapy does appear to have a potential palliative role as it prevents locoregional relapse, although survival is not prolonged. Until suitable phase 3 trials are available, gynaecological oncology units should be meticulous in prospectively recording the clinical course of their patients and critically analyzing their current management strategies. PMID- 10099760 TI - Pregnancy in women with diabetes and ischaemic heart disease. PMID- 10099761 TI - A case of aplastic anaemia in pregnancy. AB - Aplastic anaemia in pregnancy is an extremely rare condition with high maternal morbidity and mortality rates. Intensive haematological support remains the mainstay of therapy and a successful obstetric outcome can be best accomplished with the close clinical collaboration of the haematologist and the obstetrician as occurred with our patient reported here. PMID- 10099762 TI - Premature in utero closure of the ductus arteriosus following maternal ingestion of sodium diclofenac. PMID- 10099763 TI - Group B streptococcus infection, not birth asphyxia. AB - This case illustrates 2 main points. Firstly, fetal infection can mimic exactly both the immediate and delayed signs of perinatal asphyxia. Secondly, the placenta may hold the key to the diagnosis of sepsis which may be made difficult in the neonate by labour ward practices such as the use of intrapartum and immediate newborn antibiotics. We strongly support the recommendation that newborn blood and fetal membrane cultures should always be obtained in babies with a diagnosis of 'intrapartum asphyxia and fetal distress' (1). To this we would add the recommendation that placental histology be performed in these circumstances. PMID- 10099764 TI - Transplacental flecainide therapy for fetal supraventricular tachycardia in a twin pregnancy. AB - We present the case of a twin pregnancy in which 1 fetus developed hydrops secondary to supraventricular tachycardia at 30 weeks' gestation. Transplacental flecainide administration successfully treated the condition without evidence of maternal or fetal side-effects. The case raises ethical and possibly legal issues that present when 1 fetus in a twin pregnancy develops a condition the management of which could cause complications to the other twin and/or the mother. PMID- 10099765 TI - Rare delivery complication caused by an undiagnosed uterine septum. AB - The role of a uterine septum, and thus, metroplasty in an infertile woman is a debatable issue. A rare complication of fetal malpresentation and impaction in the uterine cavity due to undiagnosed uterine septum in a 24-year-old primigravida who conceived after 3 years of primary infertility is reported. This case highlights that uterine anomalies should be looked for in patients with infertility and reproductive failures, and should be corrected before conception by metroplasty in order to improve reproductive outcome. PMID- 10099766 TI - The incidence and management of failed Pipelle sampling in a general outpatient clinic. AB - A prospective audit was performed on 100 consecutive patients who underwent Pipelle endometrial sampling in a general outpatient clinic setting. The indications for sampling were abnormal menstrual bleeding (AMB, 65), intermenstrual or postcoital bleeding (IMB/PCB, 7), postmenopausal bleeding (PMB, 28). An insufficient sample was obtained in 33 women: (AMB 14, 21.5%); IMB/PCB, (0); PMB 19,68%). In 3 women the Pipelle was unable to be introduced through the cervix; in the remainder an insufficient sample for histological diagnosis was obtained. Registrars and resident doctors were more likely to sample insufficiently. In the AMB group all but 1 woman with an insufficient sample had further investigations or treatment but 7 of 19 (37%) of PMB patients had no further investigations. Where definitive histology was available, endometrial polyps or submucous fibroids were found in half of the cases with an inadequate Pipelle sample. Pipelle sampling detected only 1 of the 2 cases of endometrial cancer in this study. PMID- 10099767 TI - Antenatal diagnosis of transient abnormal myelopoiesis associated with Down syndrome. PMID- 10099768 TI - Embolic occlusion of the blood supply to uterine myomas: report of 2 cases. AB - Uterine myomas are the most common tumours of the female genital tract and with menorrhagia provide the most common indications for hysterectomy. Whilst myomectomy is a surgical alternative, it is associated with greater morbidity and a higher blood transfusion rate. Arterial embolization of myomas is a nonsurgical treatment option that can be performed as an outpatient procedure, is cheaper than myomectomy, permits preservation of reproductive potential, and may not only be associated with less morbidity than myomectomy but also may not cause adhesions which could compromise fertility. This paper details 2 cases treated by this technique. PMID- 10099769 TI - Endometrial balloon ablation under local analgesia and intravenous sedation. AB - We report a series of women (n = 16) with menorrhagia undergoing endometrial balloon ablation under local analgesia with light sedation. Ten women had significant, coexistent medical problems. The median duration of the procedure was 8.6 minutes (range 8.47-9.5 minutes). Postoperative assessment included pain scores assessed by linear analogue scale; requirement for opiate analgesia; length of postoperative stay and patient satisfaction with the procedure. The minimum postoperative follow-up was 6 months. The procedure was well-tolerated and in 80% of cases either no postoperative analgesia or simple analgesia only was required. Two women were admitted overnight, 1 for social reasons and the other for pain control. Three women ages 44, 54 and 55 years were amenorrhoeic at 6 months; 8 women were still menstruating but satisfied with the outcome and 5 women are seeking further treatment for menorrhagia. While the longer-term efficacy of the procedure remains to be established these results indicate that endometrial balloon ablation under local analgesia and light sedation, a simple and acceptable technique, may be a suitable alternative to more difficult procedures such as rollerball ablation. This is most likely to be the case in appropriately selected women who are willing to accept a reduction in menstrual flow rather than amenorrhoea as the treatment outcome. The main disadvantage of balloon ablation is the cost of the disposable balloons and the need for a dedicated electrosurgical unit. PMID- 10099770 TI - Chronic pain as the main presenting symptom of depression following hysterectomy in old age. PMID- 10099771 TI - Five-layer repair of rectovaginal fistula using a vaginal approach. A case report. AB - We present a case of a rectovaginal fistula which was revealed as an incidental finding at the time of posterior colporrhaphy. We describe a previously unreported 5-layer repair through a vaginal approach in preference to the more frequently reported approaches of endoanal flap or conversion to a fourth degree tear. The diagnosis and management of rectovaginal fistulas is discussed. PMID- 10099772 TI - Partial perforation of bladder by multiload. AB - A rare case of partial perforation of the wall of the bladder by an intrauterine contraceptive device (IUCD) in a puerperal woman and its subsequent laparoscopic removal is described. Cystoscopy revealed an intact bladder mucosa with the IUCD lying submucosally. This case demonstrates that an IUCD embedded in the wall of the bladder, whose mucosa is intact, can be safely removed through a laparoscope without resorting to laparotomy. PMID- 10099773 TI - Changes of resistance to activated protein C. PMID- 10099774 TI - Re: The sign of stress incontinence--should we believe what we see? PMID- 10099775 TI - Re: The sign of stress incontinence--should we believe what we see? PMID- 10099776 TI - Place of birth for preterm infants. PMID- 10099777 TI - Apoptotic signal transduction: emerging pathways. AB - Apoptosis is a counterbalance to mechanisms of cell proliferation and is critically important in regulation of the immune system, development, and normal tissue homeostasis. Mammalian signal transduction pathways affecting apoptosis are more complex than their counterparts in the nematode Caenorhabditis elegans, a valuable model system that has provided powerful initial insights into key molecules regulating apoptosis. Despite this complexity, substantial progress has been made in recent years towards defining the nature and detail of signalling pathways bringing about apoptosis in mammalian cells. In particular, the identity and precise substrate specificities of a large family of caspase enzymes, implicated as critical components of the apoptotic machinery, have been defined. In addition, the mechanism by which the cell surface Fas receptor mediates induction of apoptosis, via activation of caspases, has recently been elucidated. A prominent role for mitochondria in cell death pathways has also recently emerged, a clear theme being that mitochondria can trigger degradative events by the release of apoptogenic proteins (e.g., cytochrome c) from the intermembrane space to the cytosol. This review focuses on recent progress in these areas and discusses integration of this knowledge in our overall understanding of the processes that control apoptosis. PMID- 10099778 TI - G-actin conformational change and polymerization induced by paraquat. AB - Paraquat (1,1'-dimethyl-4,4'-bipyridilium dichloride) is a broad-spectrum herbicide that is highly toxic to animals (including man), the major lesion being in the lung. In mammalian cells, paraquat causes deep alterations in the organization of the cytoskeleton, marked decreases in cytoskeletal protein synthesis, and alterations in cytoskeletal protein composition; therefore, the involvement of the cytoskeleton in cell injury by paraquat was suggested. We previously demonstrated that monomeric actin binds paraquat; moreover, prolonged actin exposure to paraquat, in depolymerizing medium, induces the formation of actin aggregates, which are built up by F-actin. In this work we have shown that the addition of paraquat to monomeric actin results in a strong quenching of Trp 79 and Trp-86 fluorescence. Trypsin digestion experiments demonstrated that the sequence 61-69 on actin subdomain 2 undergoes paraquat-dependent conformational changes. These paraquat-induced structural changes render actin unable to completely inhibit DNase I. By using intermolecular cross-linking to characterize oligomeric species formed during paraquat-induced actin assembly, we found that the herbicide causes the formation of actin oligomers characterized by subunit subunit contacts like those occurring in oligomers induced by polymerizing salts (i.e., between subdomain 1 on one actin subunit and subdomain 4 on the adjacent subunit). Furthermore, the oligomerization of G-actin induced by paraquat is paralleled by ATP hydrolysis. PMID- 10099779 TI - Comparisons of the effects of temperature on the liver fatty acid binding proteins from hibernator and nonhibernator mammals. AB - Hibernating mammals rely heavily on lipid metabolism to supply energy during hibernation. We wondered if the fatty acid binding protein from a hibernator responded to temperature differently than that from a nonhibernator. We found that the Kd for oleate of the liver fatty acid binding protein (1.5 microM) isolated from ground squirrel (Spermophilus richardsonii) was temperature insensitive over 5-37 degrees C, while the rat liver fatty acid binding protein was affected with the Kd at 37 degrees C being about half (0.8 microM) that found at lower temperatures. This same trend was observed when comparing the specificity of various fatty acids of differing chain length and degree of unsaturation for the two proteins at 5 and 37 degrees C. At the lower temperature, ground squirrel protein bound long-chain unsaturated fatty acids, particularly linoleate and linolenate, at least as well as at the higher temperature and matched requirements for these fatty acids in the diet. The most common long-chain fatty acid, palmitate, was a more effective ligand for ground squirrel liver fatty acid binding protein at 5 degrees C than at 37 degrees C, with the opposite occurring in the eutherm. Rat protein was clearly not adapted to function optimally at temperatures lower than the animal's body temperature. PMID- 10099780 TI - Isolation and characterization of a mannose-binding lectin from leaves of the Chinese daffodil Narcissus tazetta. AB - A mannose-binding lectin was isolated from leaves of the Chinese daffodil Narcissus tazetta (family Amaryllidaceae) using a procedure that comprised extraction with aqueous buffer, ammonium sulfate precipitation, ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel Blue gel and mannose-agarose, and FPLC-gel filtration on Superose 12. The lectin was adsorbed on mannose-agarose and unadsorbed on DEAE-cellulose and Affi-gel Blue gel. It was an unglycosylated homodimer with a molecular mass of 26 kDa. Analysis of the N-terminal sequence of the N. tazetta lectin revealed considerable homology to lectins from the daffodil Narcissus pseudonarcissus, the snowdrop Galanthus nivalis (family Amaryllidaceae), the tulip Tulipa, and Kidachi aloe Aloe arborescens (family Liliaceae), and the orchid lectins (family Orchidaceae). The most striking likeness exists among the Amaryllidaceae lectins. The N. tazetta lectin exhibits hemagglutinating activity toward rabbit erythrocytes. PMID- 10099781 TI - Comparative study of free and bound glycolytic enzymes from sea scorpion brain. AB - Free and bound forms of hexokinase, pyruvate kinase, and lactate dehydrogenase were prepared from the brain of the sea scorpion (Scorpaena porcus) in a low ionic strength medium. Properties of the free and bound forms were compared to determine whether binding to particulate matter could influence enzyme function or stability in vivo. Changes in pH differently affected the activity of the free and bound forms of all three enzymes. Furthermore, bound forms of hexokinase and pyruvate kinase were more stable than the free enzymes to heating at 45 degrees C. Bound hexokinase showed higher affinity for substrates (ATP, glucose) than the free form and bound lactate dehydrogenase had greater affinity for pyruvate and NADH. Although the affinities of the two forms of pyruvate kinase for substrates were similar, Hill coefficients for phosphoenolpyruvate as well as inhibition by ATP differed between the two enzyme forms. Free and bound lactate dehydrogenase also showed differences in Hill coefficients and bound lactate dehydrogenase was less sensitive to substrate inhibition by high pyruvate concentrations. The possible physiological role of the binding of these glycolytic enzymes to subcellular structures is discussed. PMID- 10099782 TI - Developmental changes in hepatic metallothionein, zinc, and copper levels in genetically altered mice. AB - Using mice that either overexpress metallothionein 1 (MT-1*) or do not express metallothionein 1 and 2 (MT-null) and a control strain (C57BL/6), the essential metal storage function of hepatic metallothionein and its subcellular localization were investigated during development. Hepatic metallothionein, zinc, and copper levels were measured in all groups from gestational day 20 to 60 days of age. Hepatic metallothionein levels were maximal during the perinatal period in both MT-1* and C57BL/6 mice with levels approximately three times higher in MT 1* mice. MT-null mice had no detectable hepatic metallothionein throughout development. Hepatic zinc levels were highest in the neonatal period of MT-1* and C57BL/6 mice and declined to adult levels by 30 days of age, while hepatic zinc levels in MT-null mice did not vary markedly throughout development. Hepatic copper profiles were very similar in MT-1* and MT-null mice as compared with the C57BL/6 mice. Correlation analysis showed a strong positive correlation between hepatic metallothionein and zinc levels in MT-1* mice, moderate correlation between hepatic metallothionein and metals in C57BL/6 mice, but only a very weak correlation between hepatic metallothionein and copper levels in MT-1* mice. Immunohistochemical localization showed specific nuclear staining in both MT-1* and C57BL/6 mice during the neonatal period with a gradual shift to the cytoplasm. The results show that hepatic metallothionein is a major determinant of zinc but not copper levels during murine development. Additionally, hepatic metallothionein levels and localization are regulated in a similar manner in MT 1* and C57BL/6 mice. The MT-null mice maintain a basel level of zinc sufficient for development, which was found to be 15.9 micrograms/g. This value was similar to the levels of hepatic zinc that was not bound to metallothionein in MT-1* and C57BL/6 mice during development. PMID- 10099783 TI - Identification of the in vivo promoters of bacteriophages S13 and phi X174 and measurement of their relative activities. AB - Regions of bacteriophages phi X174 and S13 that contain putative promoter sequences were amplified by the polymerase chain reaction (PCR) and cloned into the reporter vector pKO-1. Assays of galactokinase activity revealed in vivo promoter activity in those constructs containing the promoter sequences with transcription initiation (+1) sites at nucleotide positions 45, 982, 1823, and 5211. These were identical in location to sequences with in vitro promoter activity and to the three known promoters PA, PB, and PD. P5211 is the location of a new, fourth, promoter. A site with a +1 position at nucleotide 4876, previously shown to initiate RNA synthesis in an in vitro run-off transcription assay, had no in vivo promoter activity. To investigate whether flanking sequences had effects on promoter activity, restriction fragments of phi X174 and S13 that encompass the in vivo promoters were cloned into the reporter vector pKO 1. The PA and P5211 promoter constructs showed dramatic effects with increases in activity of up to 7 times that shown with the PCR-generated promoter constructs. The phi X174 PB promoter construct had a 50% decrease in activity compared with the PCR-generated PB clone. While the data showed that in most instances promoter activity is affected by the flanking sequences in which the promoter is embedded, no general pattern correlating flanking sequences and promoter activity could be discerned. Additional evidence that the promoter sequence regions were active in vivo promoters was obtained by S1 nuclease mapping experiments. Initiation of RNA synthesis was shown at positions 45, 982, and 5211. PMID- 10099784 TI - Purification and kinetic characterization of 6-phosphogluconate dehydrogenase from Schizosaccharomyces pombe. AB - 6-Phosphogluconate dehydrogenase is the pivotal enzyme that links the gluconate route and the oxidative phase of the pentose phosphate pathway in Schizosaccharomyces pombe. The enzyme differs from the known 6-phosphogluconate dehydrogenases of other sources in that the Schizosaccharomyces enzyme is tetrameric having a subunit mass of 38 kDa, that it requires NADP+ obligatorily for activity, and that it can be activated by divalent metal ions such as Co2+ and Mn2+. Steady-state kinetic studies were undertaken. Initial rate and product inhibition results suggest that 6-phosphogluconate dehydrogenase from Schizosaccharomyces pombe catalyzes NADP(+)-linked oxidative decarboxylation of 6 phosphogluconate by an equilibrium random mechanism with two independent binding sites, namely one site for the nicotinamide coenzyme, NADP+/NADPH, and another site for 6-phosphogluconate-D-ribulose-5-phosphate and for CO2. Studies of pH dependence implicated a basic residue with a pK value of 7.4 in the binding of 6 phosphogluconate and an acidic residue with a pK value of 6.7 in the cation mediated interaction of NADP+ with the enzyme. PMID- 10099785 TI - Regulation of D-glucose-6-phosphate dehydrogenase from Schizosaccharomyces pombe. AB - D-Glucose-6-phosphate dehydrogenase is a regulatory enzyme of the oxidative pentose phosphate pathway in Schizasaccharomyces pombe. The enzyme is subject to negative cooperative regulation by D-glucose-6-phosphate as characterized by the Hill coefficient of 0.68 +/- 0.04. D-Glyceraldehyde-3-phosphate and D-ribulose-5 phosphate rectify the negative cooperativity as evidenced from a change in the Hill coefficients to 0.98 +/- 0.05 and 1.02 +/- 0.05, respectively. These pentose phosphate pathway intermediates also inhibit the enzyme competitively with respect to D-glucose-6-phosphate. Thus, D-glucose-6-phosphate dehydrogenase provides an avenue for regulating the partitioning of D-glucose between the redundant branches of the oxidative phosphate pathway in S. pombe. PMID- 10099786 TI - Topology of recombinant rat upstream binding factor. AB - Transmission electron microscopy and single particle electron crystallography were employed to reconstruct high-quality projection images of a recombinant, acidic tail deficient form of rat upstream binding factor. The upstream binding factor was found to be dimeric and approximately 10 nm in diameter with a central region of low density. Distinct nodes were observable, of size and spacing consistent with being HMG boxes 3 and 4. The dimerisation domain seemed most probably to be located in the internal region of the structure. PMID- 10099787 TI - A bioactive peptide from the transmembrane 5-intracellular loop 3 region of the human 5HT1a receptor. AB - 15 amino acid peptide from the transmembrane 5-intracellular loop 3 region of the human 5HT1a receptor produced concentration-dependent decreases in agonist binding. This result is consistent with a competitive interaction between peptide, receptor, and G protein at the receptor-G protein interface. Bombesin and a 13 amino acid peptide from the carboxyl terminus region of the receptor were inactive. Additionally, the peptide decreased forskolin-mediated cAMP elevation. Overall, these results suggest that amino acid residues from this region of the receptor are involved in receptor-G protein coupling and that G protein is activated by the receptor. PMID- 10099788 TI - Evidence of Trolox and some gallates as synergistic protectors of erythrocytes against peroxyl radicals. AB - The peroxidation of human erythrocytes induced by peroxyl radical initiator and its inhibition by several gallate esters (e.g., propyl, methyl, ethyl) and Trolox (a more polar analogue of vitamin E) have been studied. The antioxidant activity was determined on erythrocytes against hemolysis generated by a thermal activator, 2,2'-azobis-(2-amidinopropane)dihydrogenchloride. It was found that propyl gallate and its two analogues were more effective than Trolox in preventing cell lysis. However, the combination of gallate esters and Trolox produced a protective effect exceeding the arithmetic sum of their individual contributions. These perceived synergisms occur at more than one level of Trolox at a given level of a gallate ester. PMID- 10099789 TI - Characterization of a novel group of basic small heat shock proteins in Xenopus laevis A6 kidney epithelial cells. AB - In this study, we report the detection of a new group of five stress-inducible basic small heat shock proteins (BShsps) in Xenopus laevis kidney epithelial A6 cells by means of two-dimensional non-equilibrium pH gradient gel electrophoresis. These basic 30-kDa small hsps are distinct from the previously described X. laevis acidic hsp30 family on the basis of their charge and lack of cross-reactivity with an hsp30 antibody. Furthermore, at least two of the five BShsps were present constitutively, an observation that has not been made with the acidic hsp30 family. The heat inducibility of the BShsps was regulated at the level of transcription as indicated by their inhibited synthesis in the presence of the transcriptional inhibitor actinomycin D. Furthermore, the optimal temperature of BShsp induction, temporal pattern of synthesis, and induction of BShsps by other stressors such as herbimycin A and sodium arsenite were similar to those reported for the acidic hsp30 family. This study suggests that X. laevis contains at least two unique groups of small heat shock proteins that are coordinately expressed. PMID- 10099790 TI - Addressing a crisis. PMID- 10099791 TI - Teaching communication skills and obstetrics to residents. PMID- 10099792 TI - Internal schisms are bad medicine. PMID- 10099793 TI - Enough guidelines already. PMID- 10099794 TI - Drug-related illnesses cost a fortune. PMID- 10099795 TI - Erythema infectiosum (Fifth disease) and pregnancy. AB - QUESTION: One of my patients is currently 14 weeks pregnant. She is a teacher in grade 1, and there is an epidemic of Fifth disease in the school where she teaches. Can this disease affect her pregnancy and how should I care for her? ANSWER: Erythema infectiosum (Fifth disease) is usually a benign disease for children and mothers, but might have serious consequences for a fetus due to hemolytic anemia, although the risk is very low. You should evaluate the mother's immune status. If she is already immune (IgG positive), the risks are nil. If she is not immune (although the risk of the fetus's being affected is very low), fetal surveillance by repeated ultrasonographic examination and immune status reevaluation has been recommended. If a fetus is found to be affected, intrauterine evaluation and treatment are available at tertiary care centres. PMID- 10099796 TI - Ophthaproblem. Pterygium. PMID- 10099797 TI - Dermacase. Pityriasis versicolor. PMID- 10099798 TI - Play it safe. PMID- 10099799 TI - Practice tips. "Somersault" maneuver for a tight umbilical cord. PMID- 10099800 TI - Calcium supplementation during pregnancy reduces the risk of developing preeclampsia in nulliparous women. PMID- 10099801 TI - Levonorgestrel versus the "Yuzpe" regimen. New choices in emergency contraception. PMID- 10099802 TI - What's new in smoking cessation: Zyban. PMID- 10099803 TI - Obstetrics anyone? How family medicine residents' interests changed. AB - OBJECTIVE: To determine family medicine residents' attitudes and plans about practising obstetrics when they enter and when they graduate from their residency programs. DESIGN: Residents in each of 4 consecutive years, starting July 1991, were surveyed by questionnaire when they entered the program and again when they graduated (ending in June 1996). Only paired questionnaires were used for analysis. SETTING: Family medicine residency programs at the University of Toronto in Ontario. PARTICIPANTS: Of 358 family medicine residents who completed the University of Toronto program, 215 (60%) completed questionnaires at entry and exit. MAIN OUTCOME MEASURES: Changes in attitudes and plans during the residency program as ascertained from responses to entry and exit questionnaires. RESULTS: Analysis was based on 215 paired questionnaires. Women residents had more interest in obstetric practice at entry: 58% of women, but only 31% of men were interested. At graduation, fewer women (49%) and men (22%) were interested in practising obstetrics. The intent to undertake rural practice was strongly associated with the intent to practise obstetrics. By graduation, residents perceived lifestyle factors and compensation as very important negative factors in relation to obstetric practice. Initial interest and the eventual decision to practise obstetrics were strongly associated. CONCLUSIONS: Intent to practise obstetrics after graduation was most closely linked to being a woman, intending to practise in a rural area, and having an interest in obstetrics prior to residency. Building on the interest in obstetrics that residents already have could be a better strategy for producing more physicians willing to practise obstetrics than trying to change the minds of those uninterested in such practice. PMID- 10099804 TI - Satisfaction with obstetric care. Patient survey in a family practice shared-call group. AB - OBJECTIVE: To examine patients' satisfaction with their obstetric care in a family medicine shared-call group. DESIGN: A survey was given to a convenience sample of patients who came to see their doctors over a 6-week period. SETTING: Brameast Family Practice in Brampton, Ont, where eight doctors participate in a shared obstetrics call group with 16 other physicians, each taking call 1 day in 23 days. PARTICIPANTS: Mothers in the practice who had delivered in the previous 8 months. MAIN OUTCOME MEASURES: Demographic data, interventions during delivery, and satisfaction ratings. RESULTS: Of the 70% of women who responded, 96% were delivered by a doctor other than their own. Eighty-eight percent of these women were satisfied with their medical care at delivery and 96% were satisfied with their prenatal care. Nearly 79% said they would choose this shared-call group again. CONCLUSIONS: This pilot study demonstrated a high level of patient satisfaction with obstetric care, despite the fact that most patients were delivered by a doctor other than their own. Family practice groups sharing obstetric call offer a feasible alternative for physicians who wish to avoid the interference with lifestyle and office appointments that practising obstetrics usually entails. PMID- 10099805 TI - Maternity care calendar wheel. Improved obstetric wheel developed in British Columbia. AB - PROBLEM BEING ADDRESSED: Gestational calendar "wheels" are not well designed for routine prenatal care or for presenting the uncertainties of predicting date of delivery. OBJECTIVE OF PROGRAM: To design and pilot-test a new gestational calendar wheel that predicts the range of normal due dates in a way that reflects the biological realities of pregnancy. The calendar has prompts that could facilitate provision of antenatal care, support prenatal education, and guide the timing of induction for pregnancies past their due dates. MAIN COMPONENTS OF PROGRAM: The calendar sets out the key issues to be addressed with patients during pregnancy. It is designed to be photocopied while set to patients' dates: patients keep one copy; another is placed in their charts. The probability of delivering on a given date is presented graphically and as a percentage likelihood of giving birth during specified intervals. Twelve practising physicians, 12 residents, and 10 pregnant women pilot-tested and evaluated the wheel. Their responses were favourable. CONCLUSIONS: The Maternity Care Calendar wheel is a substantial advance on existing obstetric calendar wheels. It incorporates evidence-based information that should facilitate prenatal care, promote prenatal education, and foster realistic expectations about the likely timing of delivery. Early in the pregnancy, it can help establish the timing of induction for pregnancies past their due dates. Further testing of the calendar's effectiveness in improving patient outcomes is needed. PMID- 10099806 TI - Maternity Care Guidelines checklist. To assist physicians in implementing CPGs. AB - PROBLEM BEING ADDRESSED: Implementing the recommended clinical practice guidelines for prenatal care can be difficult for busy practitioners because the guidelines are numerous and continually being revised. OBJECTIVE OF PROGRAM: To develop a checklist outlining the current recommended activities for prenatal care to assist practitioners in providing evidence-based interventions to pregnant women. MAIN COMPONENTS OF PROGRAM: We reviewed guidelines for prenatal care from the Canadian Task Force on the Periodic Health Examination (CTFPHE) and from the report of the US Preventive Services Task Force (USPSTF). We searched MEDLINE for interventions commonly performed in pregnancy, but not reviewed by either task force. Interventions graded A or B are listed in bold type on the checklist. Interventions graded C by either task force or recommended by organizations not necessarily using the same rigorous criteria are listed in plain type. Recommended interventions are displayed along a time line under three headings: clinical maneuvers, investigations, and issues for discussion. Pilot testing by 12 practising physicians and 12 family practice residents showed that most respondents thought the checklist very useful. CONCLUSIONS: Providing a one page checklist summarizing recommended clinical maneuvers, investigations, and topics for discussion should help physicians with implementing the many clinical practice guidelines for prenatal care. PMID- 10099807 TI - Childbirth customs in Orthodox Jewish traditions. AB - OBJECTIVE: To describe cultural beliefs of Orthodox Jewish families regarding childbirth in order to help family physicians enhance the quality and sensitivity of their care. QUALITY OF EVIDENCE: These findings were based on a review of the literature searched in MEDLINE (1966 to present), HEALTHSTAR (1975 to present), EMBASE (1988 to present), and Social Science Abstracts (1984 to present). Interviews with several members of the Orthodox Jewish community in Edmonton, Alta, and Vancouver, BC, were conducted to determine the accuracy of the information presented and the relevance of the paper to the current state of health care delivery from the recipients' point of view. MAIN MESSAGE: Customs and practices surrounding childbirth in the Orthodox Jewish tradition differ in several practical respects from expectations and practices within the Canadian health care system. The information presented was deemed relevant and accurate by those interviewed, and the subject matter was considered to be important for improving communication between patients and physicians. Improved communication and recognition of these differences can improve the quality of health care provided to these patients. CONCLUSIONS: Misunderstandings rooted in different cultural views of childbirth and the events surrounding it can adversely affect health care provided to women in the Orthodox Jewish community in Canada. A basic understanding of the cultural foundations of potential misunderstandings will help Canadian physicians provide effective health care to Orthodox Jewish women. PMID- 10099809 TI - Routine prenatal HIV screening program launched. PMID- 10099808 TI - Childbirth customs in Vietnamese traditions. AB - OBJECTIVE: To examine and understand how differences in the cultural backgrounds of Canadian physicians and their Vietnamese patients can affect the quality and efficacy of prenatal and postnatal treatment. QUALITY OF EVIDENCE: The information in this paper is based on a review of the literature, supplemented by interviews with members of the Vietnamese community in Edmonton, Alta. The literature was searched with MEDLINE (1966 to present), HEALTHSTAR (1975 to present), EMBASE (1988 to present), and Social Sciences Abstracts (1984 to present). Emphasis was placed on articles and other texts that dealt with Vietnamese customs surrounding childbirth, but information on health and health care customs was also considered. Interviews focused on the accuracy of information obtained from the research and the correlation of those data with personal experiences of Vietnamese community members. MAIN MESSAGE: Information in the texts used to research this paper suggests that traditional Vietnamese beliefs and practices surrounding birth are very different from the biomedical view of the Canadian medical system. The experiences and beliefs of the members of the Vietnamese community support this finding. Such cultural differences could contribute to misunderstandings between physicians and patients and could affect the quality and efficacy of health care provided. CONCLUSIONS: A sensitive and open approach to the patient's belief system and open and frank communication are necessary to ensure effective prenatal and postnatal treatment for recent Vietnamese immigrants and refugees. Education and awareness of cultural differences are necessary for physicians to provide the best and most effective health care possible. PMID- 10099810 TI - Sudden infant death syndrome (SIDS). Canadian Foundation for the Study of Infant Deaths. Canadian Institute of Child Health. Canadian Paediatric Society. PMID- 10099811 TI - Hope for HIV patients. News from the 12th International Conference on HIV and AIDS. PMID- 10099813 TI - Laxatives. PMID- 10099812 TI - New treatment for hepatitis C. PMID- 10099814 TI - Intestinal permeability before and after ibuprofen in families of children with Crohn's disease. AB - BACKGROUND: Members of a subset of first-degree relatives of adults with Crohn's disease have been shown to have an increased baseline intestinal permeability and/or an exaggerated increase in intestinal permeability after the administration of acetylsalicylic acid. PURPOSE: To determine intestinal permeability in unaffected first-degree relatives of children with Crohn's disease before and after the administration of an ibuprofen challenge. METHODS: Lactulose-mannitol ratios, a measure of intestinal permeability, were determined in 14 healthy control families (41 subjects) and 14 families with a child with Crohn's disease (36 relatives, 14 probands) before and after ingestion of ibuprofen. An upper reference limit was defined using the control group as mean +/- 2 SD. RESULTS: The proportion of healthy, first-degree relatives with an exaggerated response to ibuprofen (20%, 95% CI 7% to 33%) was significantly higher than controls (P = 0.003). The exaggerated response was more common among siblings than among parents of pediatric probands. CONCLUSIONS: Members of a subset of first-degree relatives of children with Crohn's disease have an exaggerated increase in intestinal permeability after ibuprofen ingestion. These findings are compatible with there being a genetic link between abnormalities of intestinal permeability and Crohn's disease. PMID- 10099815 TI - Small bowel review: Part II. AB - In the past year there have been many advances in the area of small bowel physiology and pathology. In preparation for this review, over 500 papers were assessed; some have been selected and reviewed, with a particular focus on presenting clinically useful information for the practising gastroenterologist. PMID- 10099816 TI - Future directions in the treatment of patients with chronic hepatitis C virus infection. AB - Hepatitis C virus (HCV) infects over 170 million people worldwide. While interferon is currently the most used single agent therapy, this drug may result in a sustained loss of virus from the blood in only up to 15% of patients; new options for treatment are needed. With the release of ribavirin in North America and Europe, a viral clearance rate or 'cure' may be attained in up to 40% of patients. Developing successful antiviral therapy that prevents or delays the development of cirrhosis, liver failure and liver cancer as well as decreasing the demand for liver transplantation are clearly identified goals. Unfortunately, there is no complete in vitro model of HCV replication or translation. Due to the lack of an animal or cell culture model of HCV infection, in vitro translation screening systems to identify inhibitors of HCV protein translation are being evaluated by a large number of biotechnology companies. With advancing computer technology, high throughput screening processes are now possible and can be joined to specific in vitro model testing systems. Along with examining some of the information known about HCV therapy and the HCV genome, the present review discusses potential targets for new therapies and identifies therapeutic agents that are nearing clinical application. PMID- 10099817 TI - The Crohn's Disease Activity Index, its derivatives and the Inflammatory Bowel Disease Questionnaire: a review of instruments to assess Crohn's disease. AB - The Crohn's Disease Activity Index (CDAI) has been used to measure Crohn's activity for over a quarter of a century. The development of the CDAI is reviewed and its reliability and validity are examined. Instruments used to assess Crohn's disease that were developed subsequent to the CDAI, including the Harvey-Bradshaw Index, the Cape Town Index and a three-variable version of the CDAI (modified for survey research), are similarly reviewed. The most recent instrument to assess Crohn's disease, the Inflammatory Bowel Disease Questionnaire, which assesses patients in the domains of bowel, systemic, emotional and social function, is also discussed. PMID- 10099818 TI - Principles in the management of chronic hepatitis B viral infection. AB - Recently licensed and promising new experimental agents should have a profound impact on the treatment of patients with chronic hepatitis B virus (HBV) infection. However, certain management principles should remain unaltered. Recognizing the need for more urgent treatment in some individuals, being able to identify which patients require treatment and those who are most likely to respond to treatment, and selecting the optimal timing for treatment are clinical decisions that must continue to be addressed regardless of the antiviral agent 'of the month'. This review outlines general principles and provides a generic, timeless approach to the management of patients with chronic HBV infection. PMID- 10099819 TI - Malpractice and avascular necrosis: legal outcomes. AB - Every physician, but particularly specialists, have reason to be concerned about medical legal issues. Avascular necrosis has been established as a possible serious complication of steroid treatment in inflammatory bowel disease. Two specific Canadian cases illustrating the sequence of medical history, time, expert testimony and legal outcomes are presented. Awards plus costs in the order of $1 million or more were the result of these legal proceedings. The courts stated the major factors in finding liability against doctors were the failure to show the patient had been fully informed of treatment options. There was considerable weight given to expert testimony and the patient recollection of events to support their contentions. Adequate contemporaneous record keeping was absent to contradict evidence of the patients. The judges in both illustrative examples leaned heavily on Supreme Court of Canada guidelines whereby the patient must be informed at all stages of the medical process. PMID- 10099820 TI - Regulation of steroid receptor subcellular trafficking. AB - Cellular responses to external signals often reflect alterations in gene expression. The activation of cell surface hormone or growth factor receptors upon the binding of appropriate ligands mobilizes signal transduction cascades that can ultimately impact the activity of defined sets of transcription factors. The interpretation of hormonal signals can also be initiated intracellularly, as is the case for steroid hormone receptors. In addition to recognizing specific hormones, steroid hormone receptors also function as transcription factors and directly transduce hormonal signals to activation or repression of unique target genes. The delivery of activated steroid receptors to high-affinity genomic sites must be efficient to account for the rapidity and selectivity of many transcriptional responses to steroid hormones. Thus, the signal transduction capacity of steroid hormone receptors will be affected by the efficiency of receptor trafficking both between different subcellular compartments (i.e., the cytoplasm and nucleus) and within a specific compartment (i.e., the nucleus). This article will highlight the recent advances in our understanding of subcellular and subnuclear trafficking of steroid receptors. PMID- 10099821 TI - Differentiation between clathrin-dependent and clathrin-independent endocytosis by means of membrane fluidity measurements. AB - The fluorescence probe [1-(4-trimethylammonium]-6-phenyl-1,3,5-hexatriene (TMA DPH) displays properties relevant for both monitoring endocytosis kinetics and assessing membrane fluidity by fluorescence-anisotropy measurements (1). Thus, it is, possible with this probe to follow the evolution of membrane fluidity during endocytosis, from the very beginning of the process, i.e., the formation of endocytic vesicles. In most cases, endocytosis is known to start with clathrin coated vesicles. Still, there are more and more arguments in favor of a complementary endocytic pathway without clathrin. In this article we present membrane-fluidity data for very early endocytosis, which allow an upper limit to be determined for the contribution of a putative nonclathrin pathway. We show that this limit is markedly higher for bone marrow-derived macrophages than for mouse fibroblasts of the L929 cell line. PMID- 10099822 TI - Establishment of order in the flow of genetic information in cells. AB - The activities related to the flow of genetic information encoded in DNA in a cell are very orderly. This order, in a living cell, is achieved through specific, but noncovalent, interactions of varieties of structurally dynamic macromolecules under constantly changing physiological conditions. Hence, it is expected that there should be some force that can stabilize the multicomponent reaction processes and establish (or maintain) order in genetic regulatory functions under far-from-equilibrium conditions. The genetic regulatory functions in a cell, however, are believed to be energetically coupled. Expression of genes in a cell is often modulated under changing environmental conditions, raising the possibility of a state controlled nature of the genetic regulatory functions. Adenosine triphosphate (ATP) is the major free-energy contributor for these energy-consuming cellular activities. Enzymatic transfer of high-energy phosphate group from ATP to other reactive components is considered to be the chief mode of energy-transduction in a cell for various biosynthetic processes, as well as other activities related to the flow of information. In an effort to find a solution of the paradox, we assessed the contribution of physiological state of a cell in the process of maintaining order in genetic regulatory functions. As an approach, we systematically perturbed the normal energy flow of a cellular system (bovine aortic endothelial [BAE] cell) by a protein kinase inhibitor (staurosporine), and then followed the expression patterns of several constitutively-expressed protein-encoding genes to measure the effects. Staurosporine, as a function of its concentration, disintegrated the membrane structure of these cells, and eventually caused their death. These secondary consequences of staurosporine treatment offered two additional grossly altered physiological states of the cell to study. Under all of these dramatically altered energy states of the system, an extreme degree of functional coherence prevailed at every level of genetic regulatory function. Integrity at the level of gene transcription remained unaffected. Degradation rate of specific mRNA remained unaltered. Translational activities involving varieties of mRNA species continued in an well-ordered manner. Other state changes, resulting from nutrient and metabolic starvation, or inhibition of oxidative phosphorylation, in addition to the staurosporine treatments, also failed to disintegrate these ordered activities. The steady-state levels of specific mRNA underwent certain changes in these conditions, however, without maintaining any proportional relationships with the staurosporine concentrations applied or the ATP levels in the cell. These results thus led us to propose that the internal energy or a certain intrinsic property of the participating components, rather than the physiological state of the cell, acts as the dominant force in maintaining order and stability of genetic regulatory functions in a cell. Kinetic analyses under different energy states of the cell also supported the hypothesis, and further demonstrated the autoregulatory nature of the genetic order establishment. All of these results suggest a process of molecular self-organization as the fundamental principle for genetic regulation in a cellular system. PMID- 10099823 TI - Cathepsins as effector proteases in hepatocyte apoptosis. PMID- 10099824 TI - GLUT4 trafficking in insulin-sensitive cells. A morphological review. AB - In recent years, there have been major advances in the understanding of both the cell biology of vesicle trafficking between intracellular compartments and the molecular targeting signals intrinsic to the trafficking proteins themselves. One system to which these advances have been profitably applied is the regulation of the trafficking of a glucose transporter, GLUT4, from intracellular compartment(s) to the cell surface in response to insulin. The unique nature of the trafficking of GLUT4 and its expression in highly differentiated cells makes this a question of considerable interest to cell biologists. Unraveling the tangled web of molecular events coordinating GLUT4 trafficking will eventually lead to a greater understanding of mammalian glucose metabolism, as well as fundamental cell biological principles related to organelle biogenesis and protein trafficking. PMID- 10099825 TI - Calcineurin. Structure, function, and inhibition. AB - Calcineurin is a serine-threonine specific Ca(2+)-calmodulin-activated protein phosphatase that is conserved from yeast to humans. Remarkably, this enzyme is the common target for two novel and structurally unrelated immunosuppressive antifungal drugs, cyclosporin A and FK506. Both drugs form complexes with abundant intracellular binding proteins, cyclosporin A with cyclophilin A and FK506 with FKBP 12, which bind to and inhibit calcineurin. The X-ray structure of an FKPB12-FK506-calcineurin AB ternary complex reveals that FKBP12-FK506 binds in a hydophobic groove between the calcineurin A catalytic and the regulatory B subunit, in accord with biochemical and genetic studies on inhibitor action. Calcineurin plays a key role in regulating the transcription factor NF-AT during T-cell activation, and in mediating responses of microorganisms to cation stress. These findings highlight the potential of yeast genetic studies to define novel drug targets and elucidate conserved elements of signal transduction cascades. PMID- 10099826 TI - Erythropoietin is produced by tubular cells of the rat kidney. AB - The cellular site of erythropoietin (epo) production within the mammalian kidney is still not completely understood. In the present study, we examined the expression of epo mRNA in microdissected rat nephron segments by RT-PCR after induction of epo expression with cobalt chloride. Erythropoietin mRNA was not detected in nephron segments from saline injected rats. In cobalt chloride injected animals, epo mRNA was found in the majority of samples from the cortical region of the nephron, PCT, and CAL. Medullary tubule preparations (MCT and MAL) were mostly negative for epo mRNA, and glomeruli were uniformly negative. The induction of epo transcripts in tubular cells by cobalt chloride was paralleled by stimulation of the major transport enzyme in the kidney, namely, Na-K ATPase in a tubular profile similar to that of induction of epo transcripts. These results support some earlier findings that epo gene expression in response to cobalt salt stimulation of rat kidney occurs in transporting tubular epithelial cells. PMID- 10099827 TI - E2F-1 has properties of a radiosensitizer and its regulation by cyclin A kinase is required for cell survival of fibrosarcoma cells lacking p53. AB - Negative regulation of E2F-1 DNA binding function by cyclin A kinase represents part of an S-phase checkpoint control system that, when activated, leads to apoptosis. In this study, we examined the cellular sensitivity and resistance of isogenic mouse fibrosarcoma cell lines, differing primarily in their p53 status, to ectopic expression of wild-type (wt) E2F-1 and cyclin A kinase binding defective mutants of it. We found that E2F-1 (wt) potently affected the survival of p53+/+ tumor cells but not that of p53-/- cells. In contrast, expression of cyclin A kinase binding-defective E2F-1 species interfered with cell survival of fibrosarcoma cells irrespective of their p53 status. Finally, expression of E2F-1 (wt) in p53-/- fibrosarcoma cells enhanced the cytotoxic effect of ionizing radiation in vitro and in vivo in a mouse tumor model. These results suggest that E2F-1-dependent activation of an S-phase checkpoint is p53 independent and that E2F-1 possesses radiosensitizing properties in the absence of p53. PMID- 10099828 TI - Overproduction of MDM2 in vivo disrupts S phase independent of E2F1. AB - Expression of a beta-lactoglobulin (BLG)/mdm2 transgene (BLGmdm2) in the epithelial cells of the mouse mammary gland causes an uncoupling of S phase from M phase, resulting in polyploidy and tumor formation. The cell cycle defects are independent of interactions with p53. Because MDM2 also binds and activates the S phase-specific transcription factor E2F1, we hypothesized that increased E2F1 activity causes the development of the BLGmdm2 phenotype. We, therefore, generated BLGmdm2 mice that were null for E2F1. We observed no notable differences in histology or cyclin gene expression between BLGmdm2 and BLGmdm2/E2F1-/- mice, indicating that endogenous E2F1 activity was not required for the BLGmdm2 phenotype. Because, depending on the experimental system, either loss of E2F1 function or overexpression of E2F1 results in transformation, we also tested whether overexpression of E2F1 augmented the severity of the BLGmdm2 phenotype by generating mice that were bitransgenic for BLGmdm2 and BLGE2F1. We observed a unique mixture of the two single transgenic phenotypes histologically and found no significant changes in cyclin levels, indicating that overexpression of E2F1 had no effect on the BLGmdm2 transgenic phenotype. Thus, increased expression or absence of E2F1 does not affect the ability of MDM2 to disrupt the cell cycle. PMID- 10099829 TI - Dose-dependent effects of DNA-damaging agents on p53-mediated cell cycle arrest. AB - We examined the dose-dependent effects of DNA-damaging agents on G1 arrest in isogenic human cell lines differing in their p53 status. As expected, 5 or 20 Gy of ionizing radiation induced a p53-dependent G1 arrest. In contrast, UV light or actinomycin D induced a modest G1 arrest that was p53-dependent only at lower doses. At higher doses, cells were arrested in G1 in a p53-independent manner coinciding with inhibition of RNA synthesis and abolished cyclin E expression. Interestingly, expression of cyclin E was enhanced after exposure to moderate doses of UV light and actinomycin D, and this enhancement was suppressed by wild type p53. We propose that agents inducing transcription-blocking DNA lesions will at higher doses inhibit the progression of cells into S phase by a p53 independent mechanism involving the attenuation of E2F-mediated transcription of genes, such as cyclin E. PMID- 10099830 TI - Human melanoma cell line UV responses show independency of p53 function. AB - UV radiation-induced mutation of the p53 gene is suggested as a causative event in skin cancer, including melanoma. We have analyzed here p53 mutations in melanoma cell lines and studied its stabilization, DNA-binding activity, and target gene activation by UVC. p53 was mutated in three of seven melanoma cell lines. However, high levels of p53 were detected in all cell lines, including melanoma cells with wild-type p53, with the exception of one line with a truncated form. Upon UV induction, p53 accumulated in lines with wild-type p53, and p53 target genes p21Cip1/Waf1, GADD45, and mdm2 were induced, but the induction of p21Cip1/Waf1 was significantly delayed as compared with the increase in p53 DNA-binding activity. However, despite p53 target gene induction, p53 DNA binding activity was absent in one melanoma line with wild-type p53, and p53 target genes were induced also in cells with mutant p53. In response to UV, DNA replication ceased in all cell lines, and apoptosis ensued in four lines independently of p53 but correlated with high induction of GADD45. The results suggest that in melanoma, several p53 regulatory steps are dislodged; its basal expression is high, its activation in response to UV damage is diminished, and the regulation of its target genes p21Cip1/Waf1 and GADD45 are dissociated from p53 regulation. PMID- 10099831 TI - The cellular distribution and kinase activity of the Cdk family member Pctaire1 in the adult mouse brain and testis suggest functions in differentiation. AB - Pctaire1, a member of the family of cyclin-dependent kinases, has been shown to be particularly abundantly expressed in differentiated tissues such as testis and brain. However, very little is known about the cellular and subcellular distribution and function of Pctaire1 protein(s), which is the focus of this study. We show that Pctaire1 encoded two major proteins of M(r) approximately 62,000 and approximately 68,000, found predominantly in testis and brain. Within these two tissues, Pctaire1 was most abundant in the cytoplasm of terminally differentiated cells, notably, the pyramidal neurons in brain and elongated spermatids in testis. Immunoprecipitation experiments further showed that a kinase activity toward myelin basic protein was associated with Pctaire1 in the adult testis and brain and that its activity was potentially regulated through association with regulatory partner(s). These results suggest that Pctaire1 kinase might have an important role in differentiated cells such as postmitotic neurons and spermatogenic cells. PMID- 10099832 TI - Protein kinase C-epsilon plays a role in neurite outgrowth in response to epidermal growth factor and nerve growth factor in PC12 cells. AB - In this study, we examined the role of specific protein kinase C (PKC) isoforms in the differentiation of PC12 cells in response to nerve growth factor (NGF) and epidermal growth factor (EGF). PC12 cells express PKC-alpha, -beta, -gamma, delta, -epsilon, -mu, and -zeta. For PKC-delta, -epsilon, and -zeta, NGF and EGF exerted differential effects on translocation. Unlike overexpression of PKC-alpha and -delta, overexpression of PKC-epsilon caused enhanced neurite outgrowth in response to NGF. In the PKC-epsilon-overexpressing cells, EGF also dramatically induced neurite outgrowth, arrested cell proliferation, and induced a sustained phosphorylation of mitogen-activated protein kinase (MAPK), in contrast to its mitogenic effects on control cells or cells overexpressing PKC-alpha and -delta. The induction of neurite outgrowth by EGF was inhibited by the MAPK kinase inhibitor PD95098. In cells overexpressing a PKC-epsilon dominant negative mutant, NGF induced reduced neurite outgrowth and a more transient phosphorylation of MAPK than in controls. Our results suggest an important role for PKC-epsilon in neurite outgrowth in PC12 cells, probably via activation of the MAPK pathway. PMID- 10099833 TI - Rat embryo fibroblasts transformed by c-Jun display highly metastatic and angiogenic activities in vivo and deregulate gene expression of both angiogenic and antiangiogenic factors. AB - The comparative tumorigenicity in rats and nude mice of cell lines derived from FR3T3 and transformed by either c-jun, ras, SV40 lt, or bovine papilloma virus type 1 (BPV1) oncogenes was investigated. c-Jun-transformed cells were as tumorigenic and metastatic as Ras-transformed cells. Latencies were short, and numerous pulmonary metastases were observed in all injected animals. In contrast, tumors induced by s.c. injection of SV40-transformed cells developed slower, and none of the animals who received injections i.v. presented with metastases. BPV1 transformed cells had an intermediate tumorigenic and metastatic activity. Microvessels present in the different tumors were revealed by immunostaining with Griffonia (Bandeiraea) Simplicifolia lectin 1. Tumors obtained with c-Jun transformed cells exhibited more neovascularization than those induced by the other oncogenes. By comparison to FR3T3 cells or SV40- or BPV1-transformed cells, c-Jun-transformed fibroblasts repress the antiangiogenic thrombospondin-1 and SPARC genes, whereas we found that they express higher levels of gene expression of the angiogenic vascular endothelial growth factor. Finally, as compared with cells before passage in animals, thrombospondin-1, SPARC, and VEGF gene expression was also deregulated in cell lines isolated from primary tumors induced by BPV1-transformants. Our results indicate that the high transforming potential of c-Jun, evidenced as soon as transformation is established in vitro, correlates with deregulation of gene expression of both angiogenic and antiangiogenic factors leading to rapid neovascularization of tumors. PMID- 10099835 TI - Seizure-related opening of the blood-brain barrier produced by the anticholinesterase compound, soman: new ultrastructural observations. AB - Previous macroscopic and light microscopic observations established that the organophosphate soman, an irreversible inhibitor of cholinesterases, produces seizure-related opening of the blood-brain barrier (BBB) to proteins. In Wistar rats, this BBB alteration was found to be reversible. This alteration was greatest during the first hour of seizures, and was topographically limited to sensitive areas such as the thalamus. In contrast, the hippocampus remained free of any vascular leakage. The present study is an attempt to elucidate, in rat thalamus, the subcellular mechanisms involved in soman-induced BBB alteration. A combination of three ultrastructural approaches was used: examination of ultra thin sections, freeze-fracture, and post-embedding protein A-gold immunocytochemistry of the endogenous, normally exclusively blood-borne, albumin. Our findings show that soman-induced seizure activity produced no discernible structural change in the endothelial tight junctions, whereas it unambiguously increased the number of endothelial vesicles. Finally, immunolabelled albumin clearly crossed the endothelium, but was not systematically found inside the endothelial vesicles. Altogether, the present ultrastructural study confirms that soman can alter the integrity of the BBB, and demonstrates that the blood-to brain passage of proteins does not mainly derive from the opening of tight junctions. Although transcytosis is clearly increased through the cerebral endothelium, there is little evidence that blood-borne proteins penetrate the brain in this way. The actual mechanisms of transport thus remain to be clarified. PMID- 10099834 TI - Involvement of PKR in the regulation of myogenesis. AB - The involvement of the double-stranded RNA-activated protein kinase PKR in the regulation of the myogenic process was investigated. For this purpose, the murine myogenic cell line C2C12 was used. The cells were first cultivated in either growth medium or differentiation medium (DM), and the activation of PKR during differentiation was determined by monitoring its enzymatic activity and by immunoblot analysis. A significant increase in both parameters was detected already at 24 h in DM, whereas in cells grown in growth medium, the increase was evident only after 96 h, when spontaneous differentiation was observed in highly crowded cultures. Consequently, we established the direct effect of PKR activation on the myogenic process. C2C12 cells were transfected with an expression vector harboring a cDNA molecule encoding human PKR fused to the inducible metallothionein promoter. One of the clones (clone 8) expressing high levels of PKR was selected and further analyzed. In the presence of ZnCl2, which activates the promoter, the rate of cell growth of the transfected cells was clearly reduced compared to that of wild-type C2C12 cells transfected with only the neomycin-resistant gene (C2-NEO). In addition, altered morphology with partial fusion was observed. Biochemically, an increase in creatine kinase activity accompanied by an increased rate of expression of the myogenic protein troponin T and the myogenic transcription factors myoD and myogenin was detected in clone 8 cells exposed to ZnCl2. Most importantly, an induction in the level of cyclin-dependent kinase inhibitor p21WAF1 and an increase in the level of the underphosphorylated active form of the tumor suppressor protein pRb concomitant with the down-regulation of cyclin D1 and c-myc were also evident in the transfected clones. These changes were similar to those observed in normal C2C12 cells cultivated in DM. We conclude that PKR is an important regulatory protein participating in the myogenic process. PMID- 10099836 TI - Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. AB - The brain is partially protected from chemical insults by a physical barrier mainly formed by the cerebral microvasculature, which prevents penetration of hydrophilic molecules in the cerebral extracellular space. This results from the presence of tight junctions joining endothelial cells, and from a low transcytotic activity in endothelial cells, inducing selective permeability properties of cerebral microvessels that characterize the blood-brain barrier. The endothelial cells provide also, as a result of their drug-metabolizing enzymes activities, a metabolic barrier against potentially penetrating lipophilic substances. It has been established that in cerebrovascular endothelial cells, several families of enzymes metabolize potentially toxic lipophilic substrates from both endogenous and exogenous origin to polar metabolites, which may not be able to penetrate further across the blood-brain barrier. Enzymes of drug metabolism present at brain interfaces devoid of blood brain barrier, like circumventricular organs, pineal gland, and hypophysis, that are potential sites of entry for xenobiotics, display higher activities than in cerebrovascular endothelial cells, and conjugation activities are very high in the choroid plexus. Finally, xenobiotic metabolism normally results in detoxication, but also in some cases in the formation of pharmacologically active or neurotoxic products, possibly altering some blood-brain barrier properties. PMID- 10099837 TI - Expression and function of lymphocyte function associated antigen-3 (LFA-3) at the blood-brain barrier. AB - Lymphocyte function associated antigen-3 (LFA-3) is a cell surface glycoprotein involved in antigen independent T-cell activation and proliferation. The expression and function of LFA-3 at the blood-brain barrier were studied in an in vitro model consisting of primary cultures of human brain microvessel endothelial cells (HBMEC). Surface expression of LFA-3 was detected by immunogold silver staining and the presence of RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). Unstimulated HBMEC in primary culture constitutively express LFA-3 on their surface. Expression is only marginally upregulated following stimulation with tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN gamma). Similarly, LFA-3 RNA is present constitutively in unstimulated HBMEC with minimal increase after co-incubation with TNF-alpha and IFN-gamma. The function of LFA-3 as a costimulatory molecule on HBMEC was investigated by incubating purified CD4+ T-lymphocytes with resting or IFN-gamma treated HBMEC monolayers. Proliferation of alpha-CD3 activated CD4+ T-cells was significantly increased upon incubation with resting or activated endothelial cells. Monoclonal antibodies to LFA-3 consistently blocked the proliferative response by 64-76%. The ability of the cerebral endothelium to express LFA-3 and provide secondary signals for T-cell proliferation suggests that cerebral EC may be important in the initiation of inflammatory responses in the human central nervous system. PMID- 10099838 TI - Human brain pericytes as a model system to study the pathogenesis of cerebrovascular amyloidosis in Alzheimer's disease. AB - Cerebrovascular amyloidosis belongs to the pathological hallmarks of Alzheimer's disease brains. Although definite proof is still lacking, it is very well possible that the amyloid and its associated proteins are produced locally in the brain. In this paper we describe the development of a model system of cultured human brain pericytes to study the mechanisms of microvascular amyloid formation in vitro. These cultured cells may serve to study several aspects of cerebrovascular amyloidosis, which include the production of the amyloid precursor protein and of amyloid beta-protein-associated proteins as well as cytotoxic effects of amyloid beta-protein on perivascular cells. We demonstrated that pericytes produce and metabolize the amyloid precursor protein, and that they produce amyloid beta-protein-associated proteins, such as heparan sulfate proteoglycans, apolipoprotein E, and complement factor C1q. They are also prone to cellular degeneration after treatment with amyloid beta-protein, which is accompanied by increased expression of a number of amyloid beta-protein associated proteins. This may be an important mechanism to explain the cell death observed in vivo. Our data indicate that this cell culture model of human brain pericytes provides a useful and pathophysiologically relevant tool to study cerebrovascular amyloidosis. PMID- 10099839 TI - Intracellular protein glycation in cultured retinal capillary pericytes and endothelial cells exposed to high-glucose concentration. AB - There is now increasing evidence suggesting that non-enzymatic glycation (NEG) of proteins is involved in the pathogenesis of chronic diabetic complication. In this study we demonstrate that chronic exposure to high-glucose concentration leads to intracellular protein glycation in cultured bovine retinal capillary pericytes and endothelial cells. The level of intracellular protein glycation, as measured using a competitive enzyme-linked immunoabsorbant assay (ELISA), was found to increase in both pericytes and endothelial cells as function of time. As expected products of NEG were only detected when the Schiff base and the Amadori products were chemically reduced to glucitollysine by sodium borohydride. Despite the accumulation of early glycation products on cellular proteins there was no further rearrangement reaction into advanced glycation endproducts (AGEs), even after 12 days of incubation in high-glucose medium. Immunofluorescence microscopy demonstrated that the monoclonal antibody reacting with glucitollysine stains the cytoplasm of both pericytes and endothelial cells in a finely punctate pattern. Further studies using Western blot analysis suggested that a number of cellular proteins, including smooth muscle actin in pericytes, become rapidly glycated. The results from this in vitro study suggest that excessive accumulation of early products of non-enzymatic glycation in pericytes and endothelial cells may play an important role in the pathogenesis of diabetic retinopathy. PMID- 10099840 TI - Altered mRNA levels of antioxidant enzymes in pre-apoptotic pericytes from human diabetic retinas. AB - Because programmed cell death (PCD) is an important mode of pericyte dropout in human diabetic retinopathy, whether increased oxidative stress in cells with diminished antioxidant defenses plays a causative role in the PCD process in diabetic pericytes has been studied. Ten diabetic and eight non-diabetic eye-bank eyes from 5 diabetic and 4 non-diabetic patients were included in this study. From individual neural retinas pericytes were isolated by a newly developed immunomagnetic technique. Total mRNA of the purified pericytes was isolated for quantitative reverse transcriptase (RT)-PCR assay. mRNA levels of a death protease (CPP32), the major enzyme that initiates the proteolytic cascade leading to cell death, were determined in association with the expression of antioxidative enzymes including glutathione peroxidase (GSH-Px), glutathione reductase, CuZn superoxide dismutase (SOD), MnSOD and catalase genes in pericytes. In comparison with pericytes from non-diabetic retinas, pericytes from diabetic retinas highly expressed CPP32 genes (4 +/- 0.6 fold increase, p < 0.01, n = 9). In diabetic pericytes, up-regulation of glutathione peroxidase (GSH-Px) (8.2 +/- 0.9 fold increase, p < 0.01, n = 9) and down-regulation of glutathione reductase (Gr) (4.1 +/- 0.4 fold decrease, p < 0.05, n = 9) and CuZnSOD (2.1 +/- 0.7 fold decrease, p < 0.05, n = 9) were observed. mRNA levels of MnSOD and catalase of diabetic pericytes did not differ significantly from those of non diabetic pericytes. Overexpression of a member of interleukin-1 beta-converting enzyme (ICE) family, CPP32, indicated that the pericytes from diabetic retinas are in a "pre-PCD" state. This is the first evidence that the ICE family of death proteases is involved in pericyte dropout in diabetes. In these pre-PCD cells, the expression of antioxidant enzyme genes also was changed. Up-regulation of GSH Px indicates a compensation mechanism to meet the demand of excessive glutathione in reduced form. Decreased levels of both glutathione reductase and CuZnSOD, despite the oxidative stress in the diabetic condition, suggest the breakdown of the antioxidant defense in pericytes. Most importantly, the altered gene profile of scavenging enzymes under diabetic conditions, correlating with overexpression of the cell death protease gene, together suggest increased oxidative stress as an etiological agent of pericyte dropout in diabetic retinopathy. PMID- 10099841 TI - Angiogenic interaction between retinal endothelial cells and pericytes from normal and diabetic rabbits, and phenotypic changes of diabetic cells. AB - Retinal endothelial cells (ECs) and pericytes (PCs) were cloned and cultured from normal and diabetic rabbits to clarify the mechanism of diabetic proliferative retinopathy from the viewpoint of the interaction between ECs and PCs, and phenotypic changes of diabetic cells. PC-conditioned medium (PC-CM) from normal rabbits stimulated in vitro angiogenesis of diabetic ECs more than that of normal ECs. in vitro angiogenesis was also more stimulated in diabetic ECs than in normal ECs by basic fibroblast growth factor (bFGF) or transforming growth factor beta 1, indicating that diabetic ECs are different from normal ECs in terms of angiogenic potential. One mechanism of this property of diabetic ECs was the acceleration of cell proliferation but not of cell migration, because diabetic ECs grew more rapidly but did not migrate more than normal ECs in response to PC CM or bFGF. Moreover, PC-CM from diabetic PCs stimulated angiogenesis of normal ECs more than that from normal PCs, indicating that diabetic PCs secreted more angiogenic factor(s) than normal PCs. The angiogenic, mitogenic and migratory activities of PC-CM both from normal and diabetic PCs were similarly inhibited by an anti-bFGF antibody. Western blot analysis revealed this factor to be a bFGF like molecule. These data indicate that the interaction between ECs and PCs and the phenotypic changes of diabetic ECs and PCs both contribute to the proliferative retinopathy in diabetes. PMID- 10099842 TI - Distinct ICAM-1 forms and expression pathways in synovial microvascular endothelial cells. AB - Human synovial endothelial cell (HSE) intracellular adhesion molecule-1 (ICAM-1) is upregulated maximally by synergy of tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). Such synergy is not as pronounced in human umbilical vein endothelium (HUVE). ICAM surface staining and ELISA detection reflected similar levels on HUVE and HSE cells, yet mRNA levels were much higher in HSE cells in response to TNF alpha/IFN gamma. To correlate protein and mRNA levels of ICAM-1, both cell types were permeabilized and stained with a monoclonal antibody against ICAM-1. HSE cells displayed a distinct vesicular cytoplasmic staining for ICAM while HUVE cells were devoid of such stained vesicles upon staining with the antibody. ICAM-1 immunostaining of HSE cytoplasmic vesicles appeared enhanced in cells treated with TNF alpha/IFN gamma and monensin, an endosomal processing inhibitor. Monensin inhibited HSE cell surface expression of ICAM-1 routinely up to 70%, while HUVE cell expression was unaffected. In addition, monensin also inhibited soluble ICAM-1 release from HSE cells while not effecting HUVE cells. Immunoprecipitation of ICAM-1 followed by gel electrophoresis indicated that HUVE and HSE cell ICAMs are expressed in cell specific forms. These results define distinct forms and distinct secretory pathways for ICAM-1 in HSE cells and HUVE cells that indicate functional differences between these human endothelia. PMID- 10099843 TI - Pericytes of term human foeto-placental microvessels: ultrastructure and visualization. AB - Placental microvessels examined by transmission electron microscopy showed many pericytes and pericyte foot processes included in the basement membrane. The foot processes were distinct from the endothelial cell extensions because of their lighter staining, their content of reticulum endoplasmic, their scarcity of microfilaments and their separation from endothelial cells by basement membrane material. Some of these features were held in common with early villous perivascular cells and pericytes from other microvascular beds. Denudation of the villi by dissection allowed the microvascular basement membrane to be reached and pericytes to be identified by scanning electron microscopy as large cells with extensions apposed to microvessels. Similarly, a two-step collagenase-dispase digestion with an intermediate Percoll gradient separation progressively removed the trophoblast and the stroma down to the microvessels. Pericyte-like cells were observed lying over the microvessels that exhibited some terminal dilatations where endothelial cells were still surrounded by the basement membrane. The origin and the potential functions of the pericytes (contractility, basement membrane secretion, angiogenesis and phagocytosis) in the placental vascular bed are discussed. PMID- 10099844 TI - Immunostaining of vascular, perivascular cells and stromal components in human placental villi. AB - Fetal placental vessels develop and adapt in order to supply the fetus with nutrients. Immunostaining by antibodies against blood clotting factors, cell-cell and cell-matrix adhesion molecules, intermediate and contractile filaments, matrix components and enzymes give an overall view useful in assessing cell differentiation in placental villi. Endothelial cells stained positively for thrombomodulin, von Willebrand factor, CD34, CD31, cadherin-5, phalloidin and alpha 3-integrin. Trophoblastic cells were positive for cytokeratin, alpha 5 and alpha V integrins, L-prolyl hydroxylase and phalloidin. Myocytes from the media of stem villi exhibited positive vimentin, desmin, alpha-sm-actin and sm-myosin reactions but were CD26 negative. Myofibroblasts were vimentin, desmin, CD26, alpha-sm-actin and sm-myosin positive. Perivascular cells of intermediate and terminal villi were alpha-sm-actin, sm-myosin and anti-high molecular weight melanoma associated antigen (HMWMAA) positive. Trophoblastic and endothelial basement membranes were collagen IV positive. The most specific endothelial markers were cadherin-5, observed only at paracellular clefts, and von Willebrand factor. For perivascular cells, alpha-sm-actin, sm-myosin and HMWMAA provided a specific labeling. Differences in labeling intensity were noted along the cross section of the villous tree (vimentin, desmin, actin, myosin inward gradient). A continuity in the contractile function along the vessel length was indicated by alpha-sm-actin and sm-myosin positive cells, contrasting with the decreased von Willebrand reaction intensity. These data are discussed in relation to cell function and compared to cell culture results. PMID- 10099845 TI - Sodium-potassium pump inhibitor in the mechanism of one-kidney, one wrap hypertension in dogs. AB - Using ouabain sensitive 86Rb uptake by the vessel wall, we previously showed that sodium-potassium pump activity is decreased in the arteries and veins, and that the sodium-potassium pump inhibitor (SPI) is increased in the plasma of dogs with one-kidney, one wrap (1-K, 1W) hypertension, a low renin model of hypertension. We also showed in rats with a similar type of hypertension that the membrane potential of vascular smooth muscle cells in arteries is decreased, and that this decrease can be reproduced in arterial cells in arteries from normal rats by applying plasma from the hypertensive animals. One endogenous SPI in human plasma has been reported to be ouabain or its isomer. In this study, we used a newly available Dupont ouabain enzyme immunoassay kit to examine plasma and kidneys for SPI in dogs with 1-K, 1W hypertension. We also examined 1) the inhibiting activity of plasma of Na+, K(+)-ATPase obtained from normal kidneys, and 2) the Na+, K(+)-ATPase activity of the kidneys from these hypertensive animals. 1-K, 1W hypertension was produced in dogs by wrapping the left kidney in a silk bag and removing the right kidney. The removed kidney was kept at -70 degrees C till assayed. After 4 weeks of hypertension, the remaining kidney was removed and stored at -70 degrees C till assayed. Blood samples were drawn before and at weeks 3 and 4 of hypertension. Plasma levels of "ouabain" and Na+, K(+)-ATPase inhibitory activity were increased at weeks 3 and 4 of hypertension, compared to pre-hypertension levels. Renal tissue "ouabain" levels were also increased at week 4 of hypertension. However, renal Na+, K(+)-ATPase activity was unchanged. These findings, using two different assays, confirm our 1980 conclusion that SPI is elevated in the plasma of dogs with 1-K, 1W hypertension. The absence of renal Na+, K(+)-ATPase inhibition, despite increased plasma and renal SPI in these animals, may have important implications for the development of this type of hypertension. PMID- 10099846 TI - The role of the mesangial cell and its matrix in the pathogenesis of diabetic nephropathy. AB - Mesangial cells are pericyte-like cells which are found the glomeruli of the kidney. It is well known that they have important contractile and synthetic properties regulating the function of the glomerulus. During diabetes the synthesis of various extracellular matrix (ECM) components by mesangial cells are increased. In recent years it has been recognized that degradation of ECM may also be decreased in diabetes, contributing to the process of mesangium accumulation. The major enzymes responsible for ECM degradation are a large group of enzymes collectively known as matrix metalloproteinases (MMPs). The physiology of MMPs is complex and their activity is tightly regulated at many levels. The MMPs are synthesized as proenzymes and require activation via catalytic cleavage to become fully active. In this regard it is of importance that the mesangial cell and its pericellular matrix have a very active plasminogen cascade that can liberate plasmin locally to mediate matrix degradation both directly and indirectly, by activating the MMPs. In addition, the MMPs are regulated by transforming growth factor beta (TGF-beta). There is evidence that each of these pathways regulating the matrix degradation is affected by the diabetic environment and this will be the subject of this contribution. PMID- 10099847 TI - Expression of Glc3Man9GlcNAc2-PP-Dol is a prerequisite for capillary endothelial cell proliferation. AB - Protein N-glycosylation has been proposed to be intimately involved in the migration, proliferation and differentiation of endothelial cells. Using a synchronized, non-transformed capillary endothelial cell line from bovine adrenal medulla as a model, and the N-glycosylation inhibitor, tunicamycin, we have elucidated the molecular basis of the dolichol pathway in the angiogenic process. The synchronized culture required approximately 68 hrs. to complete one cell cycle, cells spending nearly 36 hrs. in G1 phase, 8 hrs. in S phase and 24 hrs. in G2 + M phase when maintained in 2% fetal bovine serum (heat-inactivated). The cell cycle however, was shortened due to a reduction of the G1 phase by 12-16 hrs. when the serum concentration was increased to 10%, or when beta FGF (1 or 10 nanogram) was added into the culture media containing 2% serum. Light microscopy and scanning electron microscopy both supported these proliferative responses. Serum concentration below 2% arrested cell proliferation and induced capillary lumen-like structure formation with 48 hrs. Expression of the blood clotting antigen factor VIII:C (a M(r) 270,000 dalton N-linked glycoprotein and a marker of our endothelial cells) preceded the endothelial cell proliferation and established a temporal relationship. Tunicamycin, an inhibitor of Glc3Man9GlcNAc2 PP-Dol biosynthesis, a prerequisite for N-linked protein glycosylation in the ER inhibited the cell growth and proliferation in a time and dose-dependent manner with a concomitant accumulation of immunopositive, non-glycosylated factor VIII:C in the conditioned media. Tunicamycin also caused surface blebbing and induction of programmed cell death (PCD)(apoptosis) within 32 hrs. Absence of cellular growth and proliferation, surface blebbing and the induction of PCD in the presence of tunicamycin, provided conclusive evidence that normal expression of Glc3Man9GlcNAc2-PP-Dol is an essential event for capillary proliferation during angiogenesis. PMID- 10099848 TI - How to assess and compare drugs in the management of migraine: success rates in terms of response and recurrence. PMID- 10099850 TI - How can PET scans help us understand headache mechanisms? PMID- 10099849 TI - Assessing new migraine therapies in Japan. PMID- 10099851 TI - Mechanisms of cluster headache. PMID- 10099852 TI - Appropriate migraine therapy for children and adolescents. PMID- 10099853 TI - The pioneer woman's view of migraine: Elizabeth Garrett Anderson's thesis "Sur la migraine". AB - This is a presentation of a doctoral thesis of 1870. The author was English but the thesis and the examinations were in French. Elizabeth Garrett Anderson, usually referred to as E.G.A., was the first woman in Britain to obtain the title of M.D., but not the first in Europe. Nadeshda Prokofevna Suslova, a Russian, received her M.D. in 1867 in Zurich, the most liberal university at that time, soon to be flooded by female students from Russia. E.G.A. had been applying to the few possible European universities but she settled for Paris after the Empress Eugenie had decided that she should be accepted there. This meant that she could succeed without having to be a Paris resident, just by writing a thesis and passing a series of examinations presided over by Paul Broca. This was important as she was already conducting private and dispensary practice, and could not find a locum (she insisted on a woman). E.G.A. had suffered many setbacks, for being a woman, as such being unacceptable in dissection rooms and operating theatres, and generally in a professional career where women were unheard of. She was finally permitted to receive her medical diploma from the Worshipful Society of Apothecaries of London. She wrote about her thesis: "I have chosen Headache as its subject. I had to find a subject which could be well studied without post-mortem observations, of which I can have but very few in either private or dispensary practice; and I wished also to take a large subject, one that demanded some insight into the harmony that exists between the main physiological functions." Marcia Wilkinson (M.W.), who worked in the Elizabeth Garrett Anderson Hospital in London for 35 years, heard there of E.G.A.'s thesis on migraine and sent for it from Paris. In 1966 she translated it into English from the original French, being interested both in the subject and in the person of this resolute and lucid woman. When H. Isler found the French thesis in the British Library he intended to translate it but, after discussion, we decided on a joint effort (95% of the translation is by M.W.; very few details were changed, and some footnotes added for better understanding). We think that E.G.A.'s text is a classic, showing profound understanding, sound practical advice, and also, in its theoretical part, the limits of neurophysiological knowledge in Paris when Brown-Sequard was "charge des cours" there. We may add that in her various examinations she had to answer questions, in French, on the use of footprints by the police, the general nature of fishes, toxic fishes, electric fishes, cod liver oil, and the secretion of tears. She earned much applause from the public, which consisted of male French students, and the overt appreciation of Paul Broca, head examiner, and Dr Wurtz, the Dean of the Faculte de Medecine. The impact of her thesis in the 19th century was modest. It appears to be rather marginal in the German literature of the early 20th century, but it has imprinted the management of migraine at the City of London Migraine Clinic in the last thirty years. The importance of nutrition, regular meals, regular habits, the need to supplement analgesics with antiemetics, and the treatment of the attack with rest, and great quantities of hot tea, were certainly related to E.G.A.'s doctrine. The internationally prevailing recommendation to give antiemetics, and then only analgesics, as well as the combination of both in one tablet, may thus be traced back to E.G.A. via the teachings of M.W. and Nat Blau. PMID- 10099854 TI - Sumatriptan is effective in the treatment of menstrual migraine: a review of prospective studies and retrospective analyses. AB - Menstrual migraine may be debilitating, long-lasting, and refractory to treatment. Because the efficacy and tolerability of abortive and prophylactic treatment options for menstrual migraine have generally not been evaluated in controlled clinical trials, treatment choices are often made on the basis of personal experience and anecdotal reports. This article reviews evidence from retrospective analyses and prospective studies showing that sumatriptan injection and tablets are effective and well tolerated in menstrual migraine. (1) Sumatriptan injection 6 mg was as effective in the treatment of menstrual migraine attacks as it was for nonmenstrual attacks in a retrospective analysis of data from two randomized, double-blind, placebo-controlled, parallel-group trials (n = 1104). In the menstrual migraine group, 80% of women treated with sumatriptan injection 6 mg compared with 19% of placebo-treated patients reported headache relief 1 h postdose (p < 0.001). (2) Sumatriptan injection 6 mg was effective in the acute treatment of menstrual migraine attacks in a prospective, double-blind, placebo-controlled, parallel-group, two-attack study (n = 226). Across the two attacks, 70-71% of patients treating menstrual migraine attacks with sumatriptan injection 6 mg compared with 22-24% of placebo-treated patients reported headache relief 1 h postdose (p < 0.001). (3) Sumatriptan tablets 100 mg were effective in the acute treatment of menstrual migraine attacks in a prospective, double-blind, placebo-controlled, crossover study in women diagnosed with menstrual migraine (n = 115). For menstrual migraine attacks, headache relief 4 h postdose was reported by 67% of sumatriptan-treated patients compared with 33% of placebo-treated patients. Sumatriptan injection and tablets were generally well tolerated in these studies, in which adverse events were characteristic of those typically observed in sumatriptan acute migraine clinical trials. These data demonstrate that sumatriptan injection and tablets are effective and well tolerated in the treatment of menstrual migraine. PMID- 10099855 TI - Search for mitochondrial DNA mutations in migraine subgroups. AB - It has been suggested that mitochondrial mutations cause migraine(-like) symptoms. The presence of mtDNA mutations (3243, 3271, 11084, and deletions) was investigated in three migraine subgroups (maternally transmitted migraine with and without aura, migrainous infarction, and nonfamilial hemiplegic migraine). No mutations were found. These mutations and deletions probably are not involved in the migraine subgroups studied, although an investigation of other material (e.g., muscle tissue) would have shown this with more certainty. PMID- 10099856 TI - Steady-state visual-evoked potentials in headache: diagnostic value in migraine and tension-type headache patients. AB - We tested the hypothesis that migraine and tension-type headache are separate disorders based on visual evoked potentials. We recruited 120 migraine without aura patients (MwoA), 64 tension-type headache patients (TTH), and 51 healthy controls. We performed discriminant analysis combined with a stepwise selection of predictors. Mean values of the F1 component were significantly increased over Fp1, C3, P4, O2 and O1 electrodes in MwoA and TTH patients compared with normal subjects. Only the control subjects were correctly distinguished. The increased brain response to visual stimulation detected in both MwoA and TTH may suggest a common neuronal dysfunction in the two headache subtypes. PMID- 10099857 TI - Does the antimigraine action of flunarizine involve the dopaminergic system? A clinical-neuroendocrinological study. AB - We have investigated the prolactin response to bromocriptine (BRC), a D2 dopamine receptor agonist in migrainous women before and after treatment with flunarizine. We evaluated whether this test was predictive of therapeutic efficacy of flunarizine treatment and whether the therapeutic response to flunarizine treatment was related to its effect on dopaminergic system at tuberoinfundibular level. Ten migrainous women underwent a BRC test in the late follicular phase before and after 1 and 3 months of treatment with flunarizine 10 mg at bedtime. Blood samples of prolactin (PRL), growth hormone, follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone were taken at basal condition. PRL was also evaluated 1 and 2 h after BRC (2.5 mg) administration. Each patient kept a daily headache diary for 1 month prior to the test and throughout the study. The level of PRL inhibition after BRC administration, observed before flunarizine treatment, was not predictive of the therapeutic response observed after 1 and 3 months of treatment. The effect of flunarizine on PRL level was not related to the therapeutic efficacy of the drug. These data suggest that flunarizine does not attenuate the activity of dopaminergic neurons in migrainous patients, and that the antimigraine effect of flunarizine does not seem related to its action on dopaminergic system at least at tuberoinfundibular level. PMID- 10099858 TI - Psychosocial factors in children and adolescents with migraine and tension-type headache: a controlled study and review of the literature. AB - We investigated 341 children and adolescents to evaluate the relevance of psychosocial factors in idiopathic headache. According to the criteria of the International Headache Society, 151 subjects had migraine and 94 had tension-type headache (TTH). Ninety-six subjects were headache-free controls. Psychosocial factors covered family and housing conditions, school problems, relations in the peer group, and several other items. We found that migraine patients did not differ from headache-free controls. Patients with TTH more often had divorced parents than the headache-free controls, and they had fewer peer relations than migraineurs and controls. In addition, migraine patients were significantly more often absent from school due to headache. All other psychosocial factors failed to discriminate between the three study groups. In conclusion, this controlled study in children and adolescents suggests that migraine is not related to family and housing conditions, school situation, or peer relations, whereas TTH is associated with a higher rate of divorced parents and fewer peer relations. PMID- 10099859 TI - Drug-induced headache: long-term results of stationary versus ambulatory withdrawal therapy. AB - Drug-induced headache is a well-known complication of the treatment of primary headache disorders, and its successful management is only possible by withdrawal therapy. However, it is unknown whether ambulatory or stationary withdrawal is the therapy preferred. We conducted a prospective study on the outcome of stationary versus ambulatory withdrawal therapy in patients with drug-induced headache according to the International Headache Society criteria. Out of 257 patients with the diagnosis of drug-induced headache during the study period, 101 patients (41 after ambulatory and 60 after stationary withdrawal therapy) could be followed up for 5.9 +/- 4.0 years. The total relapse rate after successful withdrawal therapy was 20.8% (14.6% after ambulatory and 25.0% after stationary withdrawal therapy, p < 0.2). The main risk factors for a relapse were male sex (OR = 3.9, CI = 1.3-11.6), intake of combined analgesic drugs (OR = 3.8, CI = 1.4 10.3), administration of naturopathy (OR = 6.0, CI = 1.2-29.3), and a trend to tension-type headache as the primary headache disorder (OR = 1.9, CI = 0.6-53.0). Our data suggest that neither the method of withdrawal therapy nor the kind of analgesic and other antimigraine drugs has a major impact on the long-term result after successful withdrawal therapy. Patients with risk factors according to our findings should be informed and monitored regularly, and combined drugs should be avoided. Furthermore, our data suggest that there is a need for research on individual psychological and behavioral risk factors for relapse after successful withdrawal therapy in drug-induced headache. PMID- 10099860 TI - Indirect costs of migraine in a managed care population. AB - Migraine is a highly prevalent condition that commonly affects individuals during their most productive years. The aggregate cost of providing healthcare for persons with migraine is substantial, but the economic consequences of lost and reduced productivity among this population are greater. This paper presents estimates of the annual indirect costs associated with migraine in a managed-care population. Our estimates include workplace and domestic productivity losses for persons employed outside the home as well as those persons engaged exclusively in domestic production or who are unable to work. We find that migraine is associated with annual indirect costs for men and women, respectively, of $4,548 and $4,897 in 1990 dollars, and that indirect costs increase with headache severity. Further research should continue to emphasize headache's effect on domestic production in order to avoid bias in measuring the economic effect of headache on women. PMID- 10099861 TI - Lamotrigine in the prophylactic treatment of migraine aura--a pilot study. AB - The aim of this study was to evaluate the efficacy of lamotrigine, a glutamate antagonist blocking voltage-sensitive sodium channels, in the prophylaxis of migraine aura symptoms. Glutamate is one of the main neurotransmitters involved in the development of cortical spreading depression. The study was conducted as an open longitudinal trial over 7 months, with a treatment phase of 4 months and a post-treatment period of 3 months. Thirteen patients suffering from migraine with aura and 2 patients with aura but without migraine were enrolled and treated with lamotrigine. The dose was gradually increased in steps of 25 mg up to 100 mg per day, depending on the patient's aura symptoms. Aura symptoms were reduced from baseline (an average of 1.3 aura episodes per month) to month 4 (0.1, p < 0.001). High statistical significance was also observed with regard to aura duration (23 min at baseline vs 4 min at 4 months, p < 0.001). In all 15 cases, increases in aura frequency (on average sevenfold, p < 0.001) and aura duration (minutes; on average more than threefold, p < 0.001) were evident following cessation of treatment. A number of mild to moderate adverse events without any medical consequences occurred. The study outcome suggests that lamotrigine is effective in preventing migraine aura symptoms and in influencing migraine headache frequency. PMID- 10099862 TI - Effectiveness of lamotrigine in the prophylaxis of migraine with aura: an open pilot study. AB - We report a small open pilot study to evaluate the efficacy of lamotrigine (100 mg/day) in the prevention of migraine with aura attacks. We studied 24 patients affected by migraine with aura with a high frequency of attacks. Following a 1 month run-in period, the patients took lamotrigine for 3 months. Mean attack number per month was reduced from 6.1 +/- 4.1 during the run-in period to 0.7 +/- 1.3 at the 3rd month of treatment (p < 0.0001). In 13 out of 21 patients who completed the study, the attacks were completely abolished at the 3rd month of treatment, while only one patient was completely unresponsive to the drug. Lamotrigine seems worthy of a controlled trial as prophylaxis of a migraine with aura. PMID- 10099863 TI - Pre-eclampsia and eclampsia headache: classification recommendation. PMID- 10099864 TI - Nifedipine, verapamil and diltiazem block shock-wave-induced rises in cytosolic calcium in MDCK cells. AB - Nifedipine and verapamil have been shown previously to protect against renal function alterations induced by shock wave lithotripsy (SWL) in humans and rats; however, the mechanism is unclear. This study was aimed to examine whether these drugs could protect cultured kidney cells following shock wave exposure (SWE). The effect of nifedipine, verapamil and diltiazem on Madin Darby canine kidney (MDCK) cells following SWE was examined by determining the release of glutamate oxalactate transferase (GOT) and lactate dehydrogenase (LDH) in cell suspensions; and also cytosolic Ca2+ concentration ([Ca2+]i). Immediately after SWE, there was a transient release of GOT and LDH (16% and 4 fold, respectively). In contrast, [Ca2+]i measured within 1-6 hr after SWE gradually increased by 15-156%. The Ca2+ entry blockers (1 or 10 microM) failed to inhibit the enzyme release; however, they abolished the progressive rises in [Ca2+]i. The Ca2+ entry blockers may protect the cells from damage of SWE via maintaining a low resting [Ca2+]i. PMID- 10099865 TI - The antioxidative property of green tea against iron-induced oxidative stress in rat brain. AB - The antioxidative property of green tea against iron-induced oxidative stress was investigated in the rat brain both in vivo and in vivo. Incubation of brain homogenates at 37 degrees C for 4 hours in vitro increased the formation of Schiff base fluorescent products of malonaldehyde, an indicator of lipid peroxidation. Auto-oxidation (without exogenous iron) of brain homogenates was inhibited by green tea extract in a concentration-dependent manner. Moreover, incubation with iron (1 microM) elevated lipid peroxidation of brain homogenates after 4-hour incubation at 37 degrees C. Co-incubation with green tea extract dose-dependently inhibited the iron-induced elevation in lipid peroxidation. For the in vivo studies: ferrous citrate (iron, 4.2 nmoles) was infused intranigrally and induced degeneration of the nigrostriatal dopaminergic system of rat brain. An increase in lipid peroxidation in substantia nigra as well as a decrease in dopamine content in striatum was observed seven days after the iron infusion. Intranigral infusion of green tea extract alone did not increase, and in some cases, even decreased lipid peroxidation in substantia nigra. Co-infusion of green tea extract prevented oxidative injury induced by iron. Both iron-induced elevation in lipid peroxidation in substantia nigra and iron-induced decrease in dopamine content in striatum were suppressed. Oral administration of green tea extract for two weeks did not prevent the iron-induced oxidative injury in nigrostriatal dopaminergic system. Our results suggest that intranigral infusion of green tea extract appears to be nontoxic to the nigrostriatal dopaminergic system. Furthermore, the potent antioxidative action of green tea extract protects the nigrostriatal dopaminergic system from the iron-induced oxidative injury. PMID- 10099866 TI - Ethyl isopropylamiloride downregulates Na,K-ATPase gene expression which confers cytotoxicity in primary proximal tubule cell cultures. AB - Our original attempt was to examine whether inhibition of Na/H exchange in proximal tubule would affect the expression of basolateral membrane protein Na,K ATPase. Three amiloride analogues were tested within the range of 10(-6) M to 10( 4) M in primary cultures of proximal tubule cells. Only ethylisopropyl amiloride (EIPA) dose-dependently downregulated Na,K-ATPase activity in cultured proximal tubule cells. The time course study revealed that EIPA (10(-4) M) significantly decreased Na,K-ATPase alpha- and alpha-mRNA abundance within 4 hr and suppressed Na,K-ATPase alpha- and beta-mRNA levels by 76.3 +/- 4.5% and 85.5 +/- 5.8%, respectively, within 24 hr. The decrease in Na,K-ATPase mRNA was followed by a decrease in Na,K-ATPase activity by 22.5 +/- 10.8% and 48.8 +/- 5.9% within 12 and 24 hr, respectively, which could be reflected by a coordinate decrease in levels of both alpha- and mature beta-protein. The cell viability was not affected until 20 hr of EIPA treatment, when an increase in LDH release and cell detachment was observed. Because EIPA rapidly decreased intracellular pH (pHi) to 6.7 within 2 hr and raising pHi to 6.6 by metabolic acidosis could not elicit changes in Na,K-ATPase activity, EIPA-induced downregulation of Na,K-ATPase should not be mediated through H+. In view of the time course of EIPA effects on Na,K-ATPase subunit mRNA, protein, activity and cell toxicity, the cytotoxic effect is likely resulted from a decrease in Na,K-ATPase activity. Take together, we conclude that EIPA induces downregulation of Na,K-ATPase expression via both pre- and post-translational mechanisms, which confers cytotoxic effects on proximal tubule cells. PMID- 10099868 TI - Increase of thyrotropin response to thyrotropin-releasing hormone (TRH) and TRH release in rats during pregnancy. AB - Regulation of thyrotropin (TSH) release by thyrotropin releasing hormone (TRH) in the anterior pituitary gland (AP) of pregnant rats was studied. The pregnant (day 7, 14, and 21) and diestrous rats were decapitated. AP was divided into 2 halves, and then incubated with Locke's solution at 37 degrees C for 30 min following a preincubation. After replacing with media, APs were incubated with Locke's solution containing 0, or 10 nM TRH for 30 min. Both basal and TRH-stimulated media were collected at the end of incubation. Medial basal hypothalamus (MBH) was incubated with Locke's medium at 37 degrees C for 30 min. Concentrations of TSH in medium and plasma samples as well as the cyclic 3':5' adenosine monophosphate (cAMP) content in APs and the levels of TRH in MBH medium were measured by radioimmunoassay. The levels of plasma TSH were higher in pregnant rats of day 21 than in diestrous rats. The spontaneous release of TSH in vitro was unaltered by pregnancy. TRH increased the release of TSH by AP, which was higher in pregnant than in diestrous rats. Maternal serum concentration of total T3 was decreased during the pregnancy. The basal release of hypothalamic TRH in vitro was greater in late pregnant rats than in diestrous rats. After TRH stimulation, the increase of the content of pituitary cAMP was greater in late pregnant rats than in diestrus animals. These results suggest that the greater secretion of TSH in pregnant rats is in part due to an increase of spontaneous release of TRH by MBH and a decrease of plasma thyroid hormones. Moreover, the higher level of plasma TSH in rats during late pregnancy is associated with the greater response of pituitary cAMP and TSH to TRH. PMID- 10099867 TI - Free radicals are involved in methylmethacrylate-induced neurotoxicity in human primary neocortical cell cultures. AB - Methylmethacrylate monomer (MMA), a highly volatile material, has been extensively used for the construction of complete or partial dental prostheses. While previous studies have indicated a variety of complications and untoward side-effects associated with its use, the possible neurotoxicity induced by this monomer has not been addressed. In this study, we have investigated the MMA produced neuronal injury in human neuron-enriched primary culture. Embryonic brain tissue (8-10 weeks postconception) was used for the primary neuron-enriched culture. Phase-contrast microscopy was used to evaluate morphological changes of cultured neurons. Extracellular concentrations of lactate dehydrogenase (LDH) and nitrite was measured from the culture medium to assess the magnitude of neuronal damage and nitric oxide formation, respectively. Neocortical neurons exposed to the monomer (1/200, Vmonomer/Vglycerol) for two days resulted in a significant increase in the LDH level but monomer (1/20000, 1/2000, or 1/200; Vmonomer/Vglycerol) failed to increase the nitrite level. Morphologically, the neurons subjected to monomer treatment exhibited irregular shrunken cell bodies with dystrophic and/or fragmented neurities, or even cell lysis. Moreover, superoxide dismutase plus catalase or vitamin C pretreatment protected against monomer-induced neurotoxicity. Our results suggest that this neurotoxicity can not likely be attributed to the cytotoxic effects of nitric oxide but may be mediated through the toxicity of superoxide and other free radicals. This is the first time, to our knowledge, that neurotoxicity induced by MMA has been demonstrated in human cortical neurons. PMID- 10099869 TI - Alteration in transcripting the gene encoding the delta-opioid receptor in rat brain is not underlying the development of tolerance to [D-Ala2,D-Leu5] enkephalin. AB - Previous study has demonstrated that chronic treatment of [D-Ala2,D-Leu5] enkephalin (DADLE) induces profound down-regulation of delta opioid receptor in rat brain. We further examined whether this down-regulation of receptor was due to a decrease in the transcription of gene encoding delta-opioid receptor (DOR 1). Rats received daily i.c.v. injection of DADLE for 1, 3, or 5 days and developed significant tolerance to the antinociceptive effect of DADLE after one day treatment. We measured the level of mRNA in rat brain tissues using in situ hybridization. No significant changes in the mRNA levels of the cortex, striatum, hippocampus, and thalamus on any examined days were found as compared to those of rats received sham operation only. There is only a transient decrease of DOR-1 mRNA level in midbrain region that occurred after a three-day treatment. Thus, the result of this study did not suggest that alteration in transcription of gene encoding delta-opioid receptor was responsible for the down-regulation of delta opioid receptor associated with the development of tolerance to DADLE. PMID- 10099870 TI - Pretraining infusion of DSP-4 into the amygdala impaired retention in the inhibitory avoidance task: involvement of norepinephrine but not serotonin in memory facilitation. AB - The present study investigated the involvement of amygdala noradrenergic (NE) and serotonergic (5-HT) systems in memory storage processing. Rats bearing chronic cannulae in the amygdala were trained on a one-trial inhibitory avoidance task and tested for retention 24 hrs later. Five days prior to training, rats received intra-amygdala infusion of vehicle or various doses of N-2-chloroethyl-N-ethyl-2 bromobenzylamine (DSP-4)-a NE-specific neurotoxin when given peripherally. Results showed that pretraining intra-amygdala infusion of 10.0 micrograms or 30.0 micrograms of DSP-4 impaired retention. Further, 30.0 micrograms of DSP-4 also abolished the memory enhancing effect of epinephrine (E) injected peripherally. However, local infusion of DSP-4 depleted not only NE but also 5-HT and DA substantially. Subsequent experiments found that the retention deficit induced by 30.0 micrograms of DSP-4 could be ameliorated by 0.2 microgram NE but not by 5-HT at a wide range of doses infused into the amygdala shortly after training, which ascribed the deficit to depletion of NE. After protecting the 5 HT terminals by a pretreatment of fluoxetine (15.0 mg/kg), pretraining intra amygdala infusion of 30.0 micrograms DSP-4 shifted the memory-enhancing dose of E from 0.1 mg/kg to 1.0 mg/kg. In contrast, pretraining intra-amygdala infusion of 15.0 micrograms 5,7-dihydroxytryptamine (5,7-DHT) or DSP-4 with a pretreatment of desipramine (DMI, 25.0 mg/kgx2) to protect NE terminals failed to impair retention or attenuate the memory enhancing effect of 0.1 mg/kg E injected peripherally. These findings, taken together, suggest that the memory modulatory effect of peripheral E involved, at least partially, the amygdala NE system. PMID- 10099871 TI - Effects of intraventricular norepinephrine on LH release in short- and long-term ovariectomized steroids-primed rats. AB - This study examined the noradrenergic mechanism in regulation of luteinizing hormone (LH) release in short- and long-term ovariectomized (OVX) steroids-primed rats. All rats were OVX on the diestrous day 1(D1) morning about 1000 h. After OVX, rats in the short-term OVX group were immediately primed with estradiol (E2, 0.1 mg/kg BW s.c.), fitted with atrial Silastic tubing, and a guide cannula in the right lateral cerebroventricle stereotaxically. Rats in the long-term OVX group received the same treatment (E2, atrial tubing and guide cannula implantation) three weeks later. Rats in both groups received progesterone (2 mg/rat s.c.) at 0930 h on the next day after E2. At 1000 h, intraventricular administration of norepinephrine HCl (NE, 0.01, 0.1, or 1.0 microgram in 2 microliters saline) was given. In short-term OVX-steroids-primed rats, NE did not alter LH levels in the peripheral plasma within 60 or 100 min. By contrast, in long-term OVX-steroids-primed rats, 1.0 microgram of NE gradually decreased plasma LH concentrations, which became significantly different from the initial value at the 60 min time point after treatment. On the other hand, intraventricular injection of 5 ng of the LH-releasing hormone (LHRH) elevated plasma LH concentrations within 10 min in both groups of rats, but at different efficacy: a brief release of LH in short-term OVX-steroids-primed rats and a prolonged release of LH in long-term OVX-steroids-primed rats. These results indicated that the interval after OVX plays a critical role in modulating the responsiveness to NE and LHRH in the steroids-primed OVX rats. PMID- 10099872 TI - Conformation of replicated segments of chromosome fibres in human S-phase nucleus. AB - Recent statistical analysis of the folding of G0/G1 chromosomes using fluorescence in situ hybridization (FISH) allowed development of a random walk/giant loop model of chromosome structure. According to this model there are two levels of organization of G0/G1 chromosome fibres. On the first level, the fibres are arranged in giant loops several Mbp in size, and within each loop the fibres are randomly folded. On the second level, the loop attachment sites form a chromosome backbone that also shows random folding. Newly replicated segments of mammalian chromosomes may be directly visualized at high resolution in S-phase nuclei using immunofluorescent methods and appear as worm-like fibres. In our earlier study, we analysed conformation of the fibres in human cells blocked for 16 h at the G1/S boundary with 5-fluorodeoxyuridine (FdU) and then released into S-phase by the addition of a DNA precursor. However, long treatment of cells with FdU induces very short replicons and may promote apoptosis. In this study we analysed conformation of the fibres in normally proliferating human cells that had not been blocked with FdU for a long time. It has been found that replicated chromosome fibres visualized just after 2 h of incubation of the cells with a non radioactively labelled DNA precursor behave as flexible polymer chains without major constraints, and that their local conformation in the range of several microns of their contour length may be considered as random. Confocal analysis of human X chromosomes visualized in HeLa cells using FISH with a specific painting probe shows that in S-phase the chromosomes occupy distinct nuclear territories and their apparent size does not differ from that in non-S-phase cells. This observation indicates that the second level of chromosome organization also exists in S-phase chromosomes. It appears, therefore, that the random walk/giant loop model developed earlier for G0/G1 chromosomes is also valid for S-phase chromosomes. PMID- 10099873 TI - Mapping the distribution of the telomeric sequence (T2AG3)n in the Macropodoidea (Marsupialia), by fluorescence in situ hybridization. I. The swamp wallaby, Wallabia bicolor. AB - Thylogale spp. (pademelons) retain the plesiomorphic (ancestral) 2n = 22 karyotype for the marsupial family Macropodidae (kangaroos and wallabies). The swamp wallaby, Wallabia bicolor, has the most derived macropodid karyotype with the lowest chromosome number (2n = 10 female, 11 male), and a multiple sex chromosome system (XX female, XY1Y2 male). All but one of the W. bicolor chromosomes are fusion chromosomes. Two of these chromosomes, the X chromosome and chromosome 1, are composed of three plesiomorphic Thylogale-like chromosomes. The distribution of the vertebrate telomeric sequence (T2AG3)n was examined by fluorescence in situ hybridization (FISH) in both species and a 'map' of non telomeric (T2AG3)n sites on W. bicolor chromosomes relative to Thylogale chromosomes was constructed. (T2AG3)n signals were observed at six fusion sites in the four fusions chromosomes examined, indicating that the (T2AG3)n sequence is consistently retained during fusions. The distribution of the interstitial signals on the long arm of chromosome 1 of W. bicolor and the X chromosome suggests how a combination of inversions, fusions and centromeric transpositions have resulted in interstitial telomeric sequence. PMID- 10099874 TI - Sequence of DNA replication in Allium fistulosum chromosomes during S-phase. AB - Bromodeoxyuridine pulse labelling and immunodetection were applied to synchronized Allium fistulosum cells to study sequential changes in the chromosome replication pattern during S-phase. The replication patterns were classified into five main types depending on the location of the replication signals: (1) over the whole chromosomes; (2) at proximal and interstitial regions; (3) at proximal, interstitial and distal regions; (4) at interstitial and distal regions; and (5) at distal regions. The frequencies of each pattern changed sequentially according to the timing of BrdU incorporation, demonstrating the temporal order of chromosome replication during S-phase. The distal regions that correspond to the major C-bands replicated throughout S-phase except for the earliest stage, but most intensely in late S-phase. The replication time of different chromosome sites overlapped, which is quite different from the biphasic mode of replication that occurs in mammalian chromosomes. PMID- 10099875 TI - Polymorphism of the nucleolus organizer regions (NORs) in Physalaemus petersi (Amphibia, Anura, Leptodactylidae) detected by silver staining and fluorescence in situ hybridization. AB - The nucleolus organizer regions (NORs) of both karyotypes I and II of Physalaemus petersi (Jimenez de la Espada, 1872) from the Brazilian Amazon were studied by Giemsa staining, and by the Ag-NOR method. Karyological group I specimens were also studied by the fluorescence in situ hybridization (FISH) technique. Multiple NOR-bearing chromosomes were detected in both karyotypes. The coincident results of the Ag-NOR and FISH methods rule out the occurrence of silent NORs in this anuran. There was no intraindividual NOR variability in either group, but interindividual variability of NORs was high in group I. Seven different patterns of active NOR distribution were definitely recognized among fifteen specimens. This was considered to be a NOR site polymorphism. These results, combined with the C-band polymorphism previously reported for P. petersi, demonstrate a high rate of chromosome evolution in this group. PMID- 10099876 TI - Molecular cytogenetic analysis of tetraploid and hexaploid Aegilops crassa. AB - The distribution of highly repetitive DNA sequences on chromosomes of tetraploid and hexaploid cytotypes of Aegilops crassa (Dcr1Xcr and Dcr1XcrDcr2 genomes) was studied using C-banding and in situ hybridization analyses with the pSc119, pAs1 and pTa794 DNA clones. In total, 14 tetraploid and five hexaploid accessions were examined. All chromosomes can be identified by their C-banding and ISH pattern with the pAs1 DNA clone. Only a few pSc119 hybridization sites were observed in the telomeric regions of several chromosomes. We found a high level of C-banding polymorphism and only minor variations in labeling patterns. The position of C bands generally coincided with the location of the pAs1 sequence. Three 5S rDNA loci were detected in tetraploid Ae. crassa, whereas five pTa794 ISH sites were observed in 6x Ae. crassa. All the hexaploid accessions differed from the tetraploids by a reciprocal non-centromeric translocation involving chromosomes A and N. Three additional translocations were detected in the accessions analyzed. The Dcr1 genome of 4x Ae. crassa is highly modified compared with the D genome of the progenitor species Ae. tauschii. Because of the large amount of chromosomal rearrangements, the origin of the Xcr genome remains unknown. The second Dcr2 genome of 6x Ae. crassa is different from the Dcr1 genome but is similar to the D genome chromosomes of Ae. tauschii, indicating that no additional large rearrangements occurred at the hexaploid level. PMID- 10099877 TI - Squash procedure for protein immunolocalization in meiotic cells. AB - Several techniques have been developed for protein immunolocalization in meiotic cells. However, most of them include treatments that lead to cell disruption and are only suitable for prophase-I cells. We describe a novel squash procedure of cell preparation for protein immunolabelling of different meiotic stages. This procedure is an alternative to both cryosectioning and whole spreading procedures. We present results obtained in mouse spermatocytes with three different antibodies: the MPM-2 mAb against mitotic phosphoepitopes, an anticentromere serum and a polyclonal serum against the SCP3 protein of the axial elements and lateral elements of the synaptonemal complex. The procedure was tested for single and double immunolabelling. With this technique a large number of cells at different meiotic stages can be analysed. Cell stages are easily identified and cell and chromosome structures are preserved. Thus, it allows the study of chromosome behaviour and the relationships between the different structural elements of the cell throughout meiotic divisions. Our procedure is also suitable for three-dimensional (3D) analyses and proved to be reliable in a wide range of systems including insects and mammals. In addition, the procedure may be interesting to obtain a rapid immunological diagnosis. PMID- 10099878 TI - Evolutionary conservation of whole homeologous chromosome arms in the Akodont rodents Bolomys and Akodon (Muridae, Sigmodontinae): maintenance of interstitial telomeric segments (ITBs) in recent event of centric fusion. AB - We have identified the almost complete correspondence of whole chromosome arms between the karyotypes of Bolomys lasiurus (2n = 33, 34) and Akodon montensis (2n = 24, 25) using comparative analysis of the GTG-banding patterns. To explain the karyotypic differentiation of the species, tandem and centric fusions, pericentric inversions, loss of telomeres and centromeres are required. Localization of telomere sequences using an (TTAGGG)n oligomere as a fluorescence in situ hybridization probe provided evidence of the maintenance of interstitial telomere sequences in a polymorphic centric fusion of recent origin in Bolomys lasiurus. The homeologies shared between the chromosomes of these two species and those of A. cursor (2n = 16), from previous work, are discussed. PMID- 10099879 TI - Identification of a new family of highly repetitive DNA, NTS9, that is located predominantly on the S9 chromosome of tobacco. PMID- 10099880 TI - Evolutionarily conserved telomeric location of BBC1 and MC1R on a microchromosome questions the identity of MC1R and a pigmentation locus on chromosome 1 in chicken. PMID- 10099881 TI - A drop technique for flatworm chromosome preparation for light microscopy and high-resolution scanning electron microscopy. PMID- 10099882 TI - Eight molecular markers from bovine syntenic groups U2, U5, U24, U14, U12, U28, X and Y were fluorescence in situ mapped to eight river buffalo chromosomes. PMID- 10099884 TI - Human ADP-ribosylation factor 4 (ARF4) gene. Map position 3p14.1. PMID- 10099883 TI - Dolphin interleukin-8 receptor. Map position 18q25-26. PMID- 10099885 TI - The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM. AB - BACKGROUND: The insertion-deletion (I/D) polymorphism of the angiotensin converting enzyme gene is a diallelic polymorphism that constitutes a genetic influence on the progression of renal diseases such as IgA nephropathy. Patients with the DD genotype have an accelerated progression towards end stage renal failure in these diseases. The role of the I/D polymorphism in the pathogenesis of diabetic nephropathy in IDDM is unresolved. PATIENTS AND METHODS: We therefore set out to study the contribution of the I/D polymorphism in 79 patients (age 39.5 +/- 7.6 years (mean +/- SD) with end stage renal failure due to diabetic nephropathy, who were recipients of a combined kidney-pancreas transplantation (n = 60), or who were on the waiting list for such a procedure (n = 19). The control series consisted of 82 patients (age 39.5 +/- 9.6 years) without microalbuminuria after fifteen years of IDDM. RESULTS: The ACE genotype distribution in patients was not in accordance with the Hardy-Weinberg equilibrium due to a significant overrepresentation of the DD genotype (X2 = 8.9, p = 0.01). This resulted in a significant increase of the D-allele frequency in the cases compared to controls (X2 = 4.9, p = 0.03). The presence of one D-allele did not increase the risk of end stage renal failure (odds ratio ID/II = 1.0, 95% CI 0.4-2.2). The presence of the DD genotype increased the risk of end stage renal failure twofold compared to the other genotypes (odds ratio 2.1, 95% CI 1.1-4.0). The risk estimate seemed slightly higher in patients with good metabolic control (odds ratio 2.6, 95% CI 1.0-7.1), than in patients with poor control (odds ratio 1.6, 95% CI 0.59-4.3). CONCLUSION: It is concluded that the risk of end-stage renal failure in patients with IDDM is twofold increased in patients with the DD genotype as compared to patients with other genotypes. PMID- 10099886 TI - Association of an insertion polymorphism of angiotensin-converting enzyme gene with the activity of lupus nephritis. AB - BACKGROUND: Lupus nephritis is a common manifestation of systemic lupus erythematosus (SLE). The pathogenesis of lupus nephritis has not been fully understood; however, immunological abnormalities have been considered in the development and activity of lupus nephritis. As angiotensin-converting enzyme (ACE) is implicated in various immunological phenomena, we investigated the correlation between insertion (I)/ deletion (D) polymorphism of the ACE gene and the activity of lupus nephritis. PATIENTS AND METHODS: Eighty-four patients with SLE and 100 healthy subjects were enrolled in this study. Following the extraction of genomic DNA from the peripheral blood, the ACE genotype was determined by the polymerase chain reaction. The patients were classified by the histological findings according to the WHO classification. In addition, the activity index and chronicity index were used to assess the severity of renal involvement. RESULTS: Individuals with II genotype showed a significantly increased activity of lupus nephritis. The allelic frequency was I/D = 0.84/0.16 in patients with WHO class IV renal lesions, and I/D = 0.36/0.64 in those with WHO class I lesions and 0.61/0.39 in patients with WHO class I or WHO class II. The difference in the allelic frequency between patients with WHO class IV and those with WHO class I or WHO class I + WHO class II was statistically significant (p = 0.00016 or p = 0.027, respectively). Moreover, lupus nephritis patients with II genotype showed significantly higher activity index than those with DD genotype (p = 0.0009). CONCLUSION: These results suggest that the insertion polymorphism of the ACE gene may correlate with the activity of lupus nephritis. PMID- 10099887 TI - Tonsillectomy does not prevent a progressive course in IgA nephropathy. AB - BACKGROUND: IgA nephropathy, or Berger's disease, is a primary mesangioproliferative glomerulonephritis, usually with a favourable prognosis. PATIENTS AND METHODS: To investigate the effect of tonsillectomy we conducted a retrospective investigation on renal outcome in 55 patients with IgA nephropathy in an outpatient university clinic between 1968 and 1994. Established risk factors for progressive IgA nephropathy were equally distributed in 16 patients subjected to tonsillectomy and in 39 patients without tonsillectomy. Renal survival and impact of risk factors were estimated by Kaplan-Meier analysis and Cox regression model. RESULTS: Seen in terms of the bivariate Kaplan-Meier analysis the probability of renal survival 10 years after biopsy was 0.37 for the 16 patients with tonsillectomy and 0.63 for the 39 patients without tonsillectomy (log-rank test p = 0.49, not significant). In the multivariate Cox regression model with 6 independent clinical covariates, initially high serum creatinine concentration had the strongest impact on renal outcome (p = 0.002), with a hazard ratio of 8.9 (95% CI: 2.3-35.0). Tonsillectomy had no significant influence in the Cox model (p = 0.37), displaying a hazard ratio of 1.7 (95% CI: 0.5-5.7). CONCLUSION: In conclusion, tonsillectomy does not reduce the risk of developing renal failure or prevent a progressive course of IgA nephropathy. PMID- 10099888 TI - Efficacy of oral immunotherapy on respiratory infections in hemodialysis patients: a double-blind, placebo-controlled study. AB - BACKGROUND: Hemodialysis (HD) patients suffer from several immune defects that make them prone to develop bacterial infections, in particular respiratory tract infections (RTIs). PATIENTS AND METHODS: As previous studies have shown that oral immunotherapy with an immunomodulating bacterial extract (IBE) is effective against RTIs, we decided to test its efficacy and safety in HD patients during a double-blind placebo-controlled prospective study. 40 HD patients with a documented history of RTIs in the previous year were treated for 24 weeks of the endemic season with one capsule daily of IBE (n = 21) or placebo (PL, n = 19). Clinical examinations, measurements of Mac-1 and gp150.95 on circulating phagocytes and routine laboratory evaluations were performed at week 0, 4, 12 and 24. Patients were also examined at each dialysis session allowing an accurate recording of any infectious episode, its treatment and of any untoward effect. RESULTS: During the last period of the study (weeks 13-24), IBE significantly reduced the number of patients with RTIs and consequently of antibiotic treatment courses as compared to PL (p = 0.018), whereas no difference was detected between IBE and PL during periods I (weeks 0-4) and II (weeks 5-12). There was no difference between IBE and PL for other, non respiratory infections. IBE was associated at several time points with an increased expression on phagocytes of adhesion molecules involved in phagocytosis (Mac-1 and gp150.95). However, the expression of these molecules was not predictive for the occurrence of RTI. IBE was on the whole as well tolerated as PL, 7 patients presented side effects (5 IBE, 2 PL, NS) which led to drop-out in 4 cases (3 IBE, 1 PL). No serious side effect was recorded, gastrointestinal upset being the most prevalent type. CONCLUSION: The results of this study indicate that immunomodulation with selected bacterial extracts constitutes a promising approach for the prevention of bacterial airway infections in groups at risk, such as HD patients. PMID- 10099889 TI - The features of psychological problems and their significance in patients on hemodialysis--with reference to social and somatic factors. AB - AIM: For the purpose of identifying the features of psychological problems and their significance in patients on hemodialysis, we analyzed how psychological problems are affected by social and somatic factors. SUBJECTS AND METHODS: The subjects all consisted of patients on hemodialysis at the Kidney Center of Fukuoka Red Cross Hospital between December 1994 and December 1996. We used the Cornell medical index health questionnaire on neurosis and the "easily upset or irritated", State-trait anxiety inventory to determine both state and trait anxiety, the Self rating Depression Scale on depression and divided into the patients who demonstrated each psychological problem and those who did not, and then analyzed the psychological problems between the two groups with reference to somatic and social factors which may have led the patients to develop their respective psychological problems. RESULTS: According to a chi-square analysis, neurosis, clinical trait anxiety and clinical state anxiety were all more closely related to somatic factors than to social factors. In contrast to neurosis and anxiety, more social factors than somatic factors were related with "easily upset or factors were related with" easily upset or irritated". "Easily upset or irritated" was significantly related to living with a spouse or with children. In addition, depression was related to various factors including both somatic and social factors. In a stepwise multiple logistic regression analysis, the presence of restless legs also correlated with all the psychological symptoms investigated in this study. The prevalence of depression was also related to the degree of awareness regarding the cause of renal failure (p < 0.01). CONCLUSION: Our results thus revealed the features of the psychological problems and their significance in patients on hemodialysis. PMID- 10099890 TI - Pathogenic role of glomerulo-tubular junction stenosis in glomerulocystic disease. AB - Glomerulocystic disease is an uncommon cystic renal condition characterized by cystic dilatation forming a glomerular cyst. The pathogenesis of this familial disease is unknown. We performed a serial section study using a biopsy specimen of a 16-year old female patient with glomerular cystic disease who had a family history of end stage renal failure. A total of 14 different glomeruli were analyzed, four of which exhibited a cystic appearance. Five glomerulotubular junctions were observed by serial sections, two of which had a stenotic appearance where glomerular cystic changes and periglomerular fibrosis were observed concomitantly. There were no such cystic glomerular changes in the other three glomeruli with non-stenotic glomerulo-tubular junctions. These findings suggest that the glomerular cystic lesion develops as a consequence of glomerulo tubular junctional stenosis probably caused by periglomerular fibrosis. PMID- 10099891 TI - Indinavir-induced nephropathy. AB - We report the case of a 38-year-old male who developed renal insufficiency while on the protease inhibitor, indinavir. This patient had an increase in serum creatinine over a period of approximately one year, along with persistently abnormal urinalysis. A renal biopsy was performed and showed marked tubular crystal deposition. The indinavir was discontinued, and after two months the patient's serum creatinine and urinalysis returned to normal. To our knowledge this is the second case of indinavir associated nephropathy. PMID- 10099892 TI - Severe cutaneous hypersensitivity requiring permanent icodextrin withdrawal in a CAPD patient. AB - We report a case of severe cutaneous hypersensitivity to icodextrin occurring in a CAPD diabetic patient. Icodextrin withdrawal was necessary to achieve cutaneous recovery. Although rare, this adverse event should be kept in mind. PMID- 10099893 TI - On the toxicity of valproic-acid. AB - Pancreatitis is a serious adverse effect of valproic acid (VPA). We report a case of VPA-induced pancreatitis in a dialysis patient. A brief review concerning VPA toxicity and acute pancreatitis in chronic renal patients is presented. We suggest that end-stage renal disease (ESRD) should be considered another risk factor for VPA-induced pancreatitis. PMID- 10099894 TI - Significantly high incidence and high morbidity of acute renal failure with respiratory tract involvement of p-ANCA-related angitis revealed in Kobe city and the environs after the Kobe earthquake in 1995. PMID- 10099895 TI - Importance of bone aluminum status in renal insufficiency and removal after kidney transplantation with low serum aluminum values. PMID- 10099896 TI - Myocardial abscess: an unusual complication of long-term hemodialysis line presence. PMID- 10099897 TI - Manidipine hydrochloride-induced chyloperitoneum in a patient with systemic lupus erythematosus. PMID- 10099898 TI - Formulation, stability, and delivery of live attenuated vaccines for human use. AB - The successful use of live attenuated viral and bacterial vaccines depends not only on the proper choice and delivery of the microorganisms, but also on maintaining the sufficient potency required for an immune response. The inherent lability of live organisms presents a particular formulation challenge in terms of stabilizing and preserving vaccine viability during manufacturing, storage, and administration. This review examines pharmaceutical approaches to the stabilization, formulation, and lyophilization of biological macromolecules in general, as well as the specific applicability of these principles to live attenuated viral and bacterial vaccines. Several formulation development case studies with live vaccines are presented. In addition, comparative stability data are summarized for many other live viral and bacterial preparations. Various pharmaceutical issues with conventional and novel delivery systems for administration of parenteral and oral live vaccines are also discussed. PMID- 10099899 TI - Enhancement of ocular drug penetration. AB - Although new drugs have recently been developed within the field of ophthalmology, the eye's various defense mechanisms make it difficult to achieve an effective concentration of these drugs within the eye. Drugs administered systemically have poor access to the inside of the eye because of the blood aqueous and blood-retinal barriers. And although topical instillation of drugs is very popular in ophthalmology, topically applied drugs are rapidly eliminated from the precorneal area. In addition, the cornea, considered a major pathway for ocular penetration of topically applied drugs, is an effective barrier to drug penetration, since the corneal epithelium has annular tight junctions (zonula occludens), which completely surround and effectively seal the superficial epithelial cells. Various drug-delivery systems have been developed to increase the topical bioavailability of ophthalmic drugs by enhancement of the ocular drug penetration. The first approach is to modify the physicochemical property of drugs by chemical and pharmaceutical means. An optimum promoiety can be covalently bound to a drug molecule to obtain a prodrug that can chemically or enzymatically be converted to the active parent drug, either within the cornea or after the corneal penetration. Along these same lines, the transient formation of a lipophilic ion pair by ionic bonding is also useful for improving ocular drug penetration. The second approach is to modify the integrity of the corneal epithelium transiently by coadministration of an amphiphilic substance or by chelating agents that act as drug-penetration enhancers. The third approach modifies the integrity of the corneal epithelium transiently by physical techniques including iontophoresis and phonophoresis. This paper reviews the absorption behavior and ocular membranes penetration of topically applied drugs, and the various approaches for enhancement of ocular drug penetration in the eye. PMID- 10099900 TI - Modifying breathing patterns in chronic heart failure. PMID- 10099901 TI - The ultimate follow-up. PMID- 10099902 TI - Magnesium treatment in acute myocardial infarction: an unresolved consensus. PMID- 10099903 TI - Cardiogenic shock: a failure in reperfusion. Time for a strategic change? PMID- 10099904 TI - Antibiotics for acute coronary syndromes: are we ready for megatrials? PMID- 10099905 TI - Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. PMID- 10099906 TI - Anthropometric, lifestyle and metabolic determinants of resting heart rate. A population study. AB - AIM: To clarify the determinants of resting heart rate at the population level in a random sample of the Belgian population. METHODS AND RESULTS: Data of 5027 men and 4150 women aged 25-74 years obtained from a Belgian nationwide survey were analysed. In multivariate analysis, blood pressure strongly correlated with heart rate in men (t = 12.4 for systolic; t = 8.8 for diastolic) and women (t = 12.0 for systolic; t = 7.7 for diastolic). Age (t = -3.4 in men; t = -8.1 in women) and height (t = -3.7 in men; t = -3.1 in women) correlated negatively with heart rate. Smoking raised heart rate in men (1-19 cigarettes.day-1, t = 6.1; > or = 20 cigarettes.day-1, t = 10.3) and women (> or = 20 cigarettes.day-1, t = 3.5). Serum phosphorus correlated negatively with heart rate (t = -3.5 in men; t = -8.3 in women). Serum log alkaline phosphatase (t = 6.7 in men; t = 7.2 in women) and serum protein (t = 5.3 in men; t = 4.4 in women) correlated positively with heart rate. CONCLUSION: At the population level, blood pressure, cigarette smoking, serum alkaline phosphatase and serum protein correlate independently, significantly and positively with heart rate, and age, height and serum phosphorus negatively. PMID- 10099907 TI - Decreases by magnesium of QT dispersion and ventricular arrhythmias in patients with acute myocardial infarction. AB - AIMS: Magnesium treatment suppresses ventricular arrhythmias in acute myocardial infarction and possibly mortality after infarction, but the underlying mechanisms are inadequately understood. We tested whether the effect of magnesium could be attributed to an influence on the autonomic control of the heart, changes in disturbed repolarization, relief of ischaemia or limitation of myocardial injury. METHODS AND RESULTS: Fifty-nine consecutive patients with acute myocardial infarction were randomized to receive 70 mmol of magnesium (n = 31) infused over 24 h or placebo (n = 26). Occurrence of ventricular arrhythmias and heart rate variability (SD of 5-min mean sinus beat intervals over a 24 h period, SDANN; low frequency/high frequency amplitude ratio, LF/HF ratio), and the number of ischaemic episodes on vectorcardiography were measured from the first day of treatment. QT dispersion corrected for heart rate was measured from the 12-lead ECG. Magnesium decreased the number of hourly ventricular premature beats (P < 0.001) and the number of ventricular tachycardias (P < 0.05). QT dispersion corrected for heart rate was decreased in both measurements at 24 h and 1 week (P < 0.001). SDANN and LF/HF ratio were unchanged. The number of ischaemic episodes on vectorcardiography were equal, and peak creatine kinase MB release did not differ between the groups. In testing the pathophysiological mechanisms, serum magnesium levels after infusion correlated with hourly ventricular premature beats (rs = -0.47; P < 0.01), ventricular tachycardias (rs = -0.26; P < 0.05), and QT dispersion corrected for heart rate (rs = -0.75; P < 0.001), but not with SDANN, LF/HF ratio or peak creatine kinase MB. QT dispersion corrected for heart rate correlated with hourly ventricular premature beats (rs = 0.48; P < 0.001) and ventricular tachycardias (rs = 0.27; P < 0.05). CONCLUSIONS: Magnesium suppresses early ventricular arrhythmias in acute myocardial infarction. The decreased arrhythmicity is related to enhancement of homogeneity in repolarization, but not to attenuation of prevailing ischaemia, improvement of autonomic nervous derangements or myocardial salvage. PMID- 10099908 TI - Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes. The final report of the ROXIS Study. AB - AIMS: Mounting evidence suggests infection, specifically Chlamydia pneumoniae, plays a role in atherosclerosis. We tested whether antibiotic treatment with the macrolide roxithromycin improves clinical outcome in patients with acute non-Q wave coronary syndromes. Preliminary reports revealed a reduction in events in the roxithromycin group at 30 days. We now report the long-term follow-up results. METHODS AND RESULTS: Sixty-four per cent of the initial 202 patients with unstable angina who were randomly assigned to receive either roxithromycin or placebo for 30 days completed the active treatment period. At day 30, the primary triple and double end-point rates were 9% and 4% in the placebo group compared to 2% and 0% in the roxithromycin group (unadjusted P = 0.032 and 0.058, respectively). The secondary triple and double end-point rates were again higher in the placebo group at day 90 (12.5% and 6.25% vs 4.37% and 0%, unadjusted P = 0.065 and 0.029, respectively), and at day 180 (14.6% and 7.29% vs 8.69% and 2.17%, unadjusted P = 0.259 and 0.17, respectively). Anti-C, pneumoniae IgG titres were unchanged in both groups while C-reactive protein levels decreased in both strategies, with a more significant decrease in the roxithromycin arm (P = 0.03). Elevated C-reactive protein levels predicted the need for revascularization. CONCLUSIONS: In this pilot trial, roxithromycin appears to extend the clinical benefit of preventing death and re-infarction for at least 6 months after initial treatment. PMID- 10099909 TI - Frequency and clinical outcome of cardiogenic shock during acute myocardial infarction among patients receiving reteplase or alteplase. Results from GUSTO III. Global Use of Strategies to Open Occluded Coronary Arteries. AB - AIMS: Reteplase has been reported to achieve better patency of the infarct artery than alteplase. As infarct artery patency is strongly associated with survival among patients with cardiogenic shock, we postulated that treatment with reteplase would improve outcomes among shock patients. METHODS: We compared 30 day mortality rates among patients in GUSTO-III who either presented with shock or developed shock after enrollment; all patients received either front-loaded alteplase or reteplase (two bolus doses of 10 MU, 30 min apart). RESULTS: Shock occurred in 260 (5.3%) of 4921 patients randomized to alteplase and 560 (5.5%) of 10,138 patients randomized to reteplase. Of these patients, 28 (10.8%) and 55 (9.8%) randomized to alteplase and reteplase, respectively, presented with shock. In-hospital, 35% and 37% of shock patients assigned to alteplase or reteplase, respectively, underwent coronary angiography, with similar rates of percutaneous (approximately 11-13%) or surgical (approximately 2-3%) revascularization procedures subsequently performed. Death within 30 days occurred in 169 (65%) and 353 (63%) shock patients randomized to alteplase and reteplase, respectively (P = 0.59). Of patients presenting with shock, 64% and 58% of patients randomized to alteplase or reteplase died within 30 days (P = 0.59). CONCLUSION: Compared with alteplase, reteplase did not improve outcome among patients who presented with shock or developed shock after receiving thrombolytics. The newer-generation thrombolytic agents remain of limited efficacy in the treatment and prevention of shock. PMID- 10099910 TI - Long-term survival in severe heart failure in patients treated with enalapril. Ten year follow-up of CONSENSUS I. AB - BACKGROUND: The CONSENSUS trial was the first study to show prognostic improvement by an ACE inhibitor. Patients in NYHA class IV heart failure were treated with enalapril or placebo. After study completion (average 183 days) all patients were offered open-label enalapril therapy. This paper reports on the survival at the 10-year follow up of the patients randomized in the CONSENSUS trial. METHODS: All 35 participating centres in CONSENSUS I were asked to complete a questionnaire on the survival status at 1 November 1996 of patients randomized in CONSENSUS. RESULTS: At 10-year follow up, one patient was lost to follow-up. Five patients, all in the enalapril group, were long-term survivors (P = 0.004). Averaged over the duration of the trial (double-blind plus open-label extension) the risk reduction was 30% (P = 0.008), with a 95% confidence interval of 11% to 46%. At the end of the double-blind study period, mortality was considerably higher among patients who did not receive open ACE inhibitor therapy compared to those who did. CONCLUSION: After a treatment period of, on average, 6 months, enalapril was shown to be effective. The effect was sustained for at least 4 years i.e. for another 3.5 years. The present follow-up is the first heart failure trial where the full life-cycle has been followed from randomization. In severe heart failure, mortality is significantly reduced by enalapril. On average, the beneficial effect is maintained for several years and overall survival time is prolonged by 50% (from 521 to 781 days). PMID- 10099911 TI - Mobile echoes on prosthetic valves are not reproducible. Results and clinical implications of a multicentre study. AB - AIMS: To test the hypothesis that inter-observer variability accounts for the wide variation in reported prevalences of fibrin strands on prosthetic heart valves and to develop criteria for their identification and reporting. METHODS AND RESULTS: A videotape with 30 sequences of prosthetic heart valves imaged by transoesophageal echocardiography and showing abnormalities such as strands, microbubbles, and spontaneous echocardiographic contrast, was assessed in 13 European and three American centres. There were three duplicated examples, unbeknown to the observers. Definitions and reported prevalence rates of the abnormalities were analysed, and inter- and intra-observer agreement estimated with the kappa statistic. Mobile echoes were identified in 40 to 80% of the sequences on the tape. The reported prevalence of mobile echoes correlated with the time spent reporting the tape. There was moderate inter-observer agreement for the identification of any mobile echoes (kappa = 0.38), but no agreement for their labelling (kappa = 0.22), in spite of similar definitions. Intra-observer reproducibility was good (agreement in 76% of the reduplicated sequences). CONCLUSIONS: The true prevalence and potential significance of mobile echoes on prosthetic heart valves cannot be assessed unless inter-observer consensus on echocardiographic criteria for identifying such echoes is reached. PMID- 10099912 TI - High and low pulmonary vascular resistance in heart transplant candidates. A 5 year follow-up after heart transplantation shows continuous reduction in resistance and no difference in complication rate. AB - BACKGROUND: In heart transplantation candidates, high pulmonary vascular resistance has been found to decrease promptly after heart transplantation without any further reduction during follow-up. Pulmonary hypertension has been described as associated with an increased peri- and postoperative complication rate and mortality. This study describes the evolution of pulmonary vascular resistance and the outcome for patients during 5 years following heart transplantation. METHODS AND RESULTS: Haemodynamic data, complication rate and mortality have been analysed during 5-year follow-up in all patients (n = 80) who were heart transplanted at Sahlgrenska University Hospital from 1988 through 1990. We found a significant and continuous reduction in pulmonary vascular resistance both in patients with a pre-operative high (> 3 Wood Units; n = 36), but reversible on nitroprusside, and pre-operative low (< or = 3 Wood Units; n = 44) pulmonary vascular resistance. A multivariate analysis showed that a pre operative high mean pulmonary artery and low mean pulmonary capillary wedge pressure predicted the decline in pulmonary vascular resistance during 5 years after heart transplantation. The need for a postoperative assist device, complication rate, and early and late mortality were independent of the pre operative level of pulmonary vascular resistance. CONCLUSIONS: A continuous reduction in pulmonary vascular resistance during 5 years following heart transplantation was found in patients with both high, but reversible, and low pre operative resistance levels. The outcome and survival were independent of the pre operative pulmonary vascular resistance level. PMID- 10099913 TI - Economics of myocardial perfusion imaging in Europe--the EMPIRE Study. AB - BACKGROUND: Physicians use myocardial perfusion imaging to a variable extent in patients presenting with possible coronary artery disease. There are few clinical data on the most cost-effective strategy although computer models predict that routine use of myocardial perfusion imaging is cost-effective. OBJECTIVES: To measure the cost-effectiveness of four diagnostic strategies in patients newly presenting with possible coronary artery disease, and to compare cost effectiveness in centres that routinely use myocardial perfusion imaging with those that do not. METHODS: We have studied 396 patients presenting to eight hospitals for the diagnosis of coronary artery disease. The hospitals were regular users or non-users of myocardial perfusion imaging with one of each in four countries (France, Germany, Italy, United Kingdom). Information was gathered retrospectively on presentation, investigations, complications, and clinical management, and patients were followed-up for 2 years in order to assess outcome. Pre- and post-test probabilities of coronary artery disease were computed for diagnostic tests and each test was also assigned as diagnostic or part of management. Diagnostic strategies defined were: 1: Exercise electrocardiogram/coronary angiography, 2: exercise electrocardiogram/myocardial perfusion imaging/coronary angiography, 3: myocardial perfusion imaging/coronary angiography, 4: coronary angiography. Primary outcome measures were the cost and accuracy of diagnosis, the cost of subsequent management, and clinical outcome. Secondary measures included prognostic power, normal angiography rate, and rate of angiography not followed by revascularization. RESULTS: Mean diagnostic costs per patient were: strategy 1: 490 Pounds, 2: 409 Pounds, 3: 460 Pounds, 4: 1253 Pounds (P < 0.0001). Myocardial perfusion imaging users: 529 Pounds, non-users 667 Pounds (P = 0.006). Mean probability of the presence of coronary artery disease when the final clinical diagnosis was coronary artery disease present were, strategy 1: 0.85, 2: 0.82, 3: 0.97, 4: 1.0 (P < 0.0001), users 0.93, non users 0.88 (P = 0.02), and when coronary artery disease was absent, 1: 0.26, 2: 0.22, 3: 0.16, 4: 0.0 (P < 0.0001), users 0.21, non-users 0.20 (P = ns). Total 2 year costs (coronary artery disease present/absent) were: strategy 1: 4453 Pounds/710 Pounds, 2: 3842 Pounds/478 Pounds, 3: 3768 Pounds/574 Pounds, 4: 5599 Pounds/1475 Pounds (P < 0.05/0.0001), users: 5563 Pounds/623 Pounds, non-users: 5428 Pounds/916 Pounds (P = ns/0.001). Prognostic power at diagnosis was higher (P < 0.0001) and normal coronary angiography rate lower (P = 0.07) in the scintigraphic centres and strategies. Numbers of soft and hard cardiac events over 2 years and final symptomatic status did not differ between strategy or centre. CONCLUSION: Investigative strategies using myocardial perfusion imaging are cheaper and equally effective when compared with strategies that do not use myocardial perfusion imaging, both for cost of diagnosis and for overall 2 year management costs. Two year patient outcome is the same. PMID- 10099914 TI - Pharmacological treatment for hyperlipidaemia--the best preventive measure? PMID- 10099915 TI - Weight, weight gain and coronary heart disease mortality. PMID- 10099916 TI - Measurement of coronary flow reserve: what does it tell us about myocardial viability? PMID- 10099917 TI - The value of the heart-rate corrected QT-interval for cardiovascular risk stratification. PMID- 10099918 TI - Is sinus bradycardia a factor facilitating overt heart failure? PMID- 10099919 TI - New perspectives on heart failure due to myocardial ischaemia. PMID- 10099920 TI - International economic analysis of primary prevention of cardiovascular disease with pravastatin in WOSCOPS. West of Scotland Coronary Prevention Study. AB - AIMS: The results of the West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated the clinical benefit of using pravastatin for the primary prevention of cardiovascular disease in hypercholesterolaemic men. To inform decision makers, who must also consider costs, this study assesses the economic efficiency of such an intervention in a broad range of countries. METHODS AND RESULTS: A generalized model of cardiovascular disease prevention was used to estimate the cost-effectiveness of primary prevention with pravastatin compared to diet alone. This model follows a cohort of hypercholesterolaemic men over a given period quantifying the effect in terms of the avoidance of cardiovascular disease based on treatment-specific risks derived from WOSCOPS data and extensive record linkage data on disease-specific survival. Country-specific costs are accounted for by expressing all such parameters in terms of the ratio of monthly treatment to that of managing a myocardial infarction. Over a broad range of inputs the cost-effectiveness ratios remain below $25,000 per life years gained, regardless of country. Subgroups with even better economic efficacy can be defined on the basis of higher baseline risk. CONCLUSIONS: In contrast to some previous reports, this analysis based on trial data demonstrates that pravastatin provides not only an effective means of primary cardiovascular disease prevention, but also an efficient one. PMID- 10099921 TI - Body weight and weight gain during adult life in men in relation to coronary heart disease and mortality. A prospective population study. AB - AIMS: To assess the risk of death from coronary disease, and all causes associated with body mass index and weight gain from age 20 to middle age. METHODS AND RESULTS: In this study, 6874 men aged 47 to 55 years at baseline and free of a history of myocardial infarction were followed with respect to mortality from coronary disease and from all causes over an average follow-up of 19.7 years, and with respect to non-fatal myocardial infarction for 11.8 years. High body mass index predicted death from coronary disease, but only at levels above 27.5 m.kg-2. Men with stable weight (defined as +/- 4% change from age 20) had the lowest death rate from coronary disease and the lowest risk of non-fatal myocardial infarction. Relative risk of coronary death increased with increasing weight gain, from 1.57 (1.14-2.15) (after adjustment for age, physical activity, and smoking) in the group who gained 4 to 10%, to 2.76 (1.97-3.85) in men with a weight gain of more than 35% (P for trend 0.0001), compared to men who remained stable. After further adjustment for serum cholesterol, systolic blood pressure, and diabetes, relative risks were reduced but still significantly elevated in all weight gain groups (P for trend 0.004). Data concerning non-fatal myocardial infarction were available for the first 11.8 years and showed a relative risk of 3.35 (2.05-5.47) after adjustment for age, physical activity, and smoking in men with a weight gain of more than 35%. CONCLUSION: Weight gain from age 20, even a very moderate increase, is strongly associated with an increased risk of coronary death and non-fatal myocardial infarction. PMID- 10099922 TI - Prolonged QT interval predicts cardiac and all-cause mortality in the elderly. The Rotterdam Study. AB - AIMS: To examine the association between heart-rate corrected QT prolongation and cardiac and all-cause mortality in the population-based Rotterdam Study among men and women aged 55 years or older and to compare the prognostic value of the QT interval, using different formulas to correct for heart rate. METHODS AND RESULTS: After exclusion of participants with arrhythmias or bundle branch block on the ECG, the study population consisted of 2083 men and 3158 women. The QT interval was computed by the Modular ECG Analysis System (MEANS). Data were analysed using Cox' proportional hazards model. Participants in the highest quartile of the heart-rate corrected QT interval had about a 70% age- and sex adjusted increased risk for both all-cause mortality (hazard ratio (HR) 1.8; 95% CI:1.3-2.4) and cardiac mortality (HR 1.7; 95% CI:1.0-2.7) compared to those in the lowest quartile. In women, the increased risk associated with prolonged QT for cardiac death was more pronounced than in men. These risk estimates did not change after adjustment for potential confounders, including history of myocardial infarction, hypertension and diabetes mellitus. CONCLUSION: A prolonged heart-rate corrected QT interval is an independent predictor for cardiac and all-cause mortality in older men and women. The risk associated with prolonged QT is hardly affected by the heart-rate correction formula used. PMID- 10099923 TI - Coronary blood flow reserve and wall motion recovery in patients undergoing angioplasty for myocardial infarction. AB - AIMS: The aim of this study was to evaluate the relationship between coronary flow reserve and the recovery of wall motion contractility in patients with recent myocardial infarction. METHODS AND RESULTS: Nineteen patients (55 +/- 8 years) undergoing balloon angioplasty for recent myocardial infarction were studied. After angioplasty, coronary flow reserve was lower in the infarct related artery than in a reference artery, 2.2 +/- 0.6 and 2.8 +/- 0.7, respectively, P < 0.05. There was no immediate correlation between coronary blood flow reserve measured after angioplasty and wall motion index. There was a negative correlation between coronary flow reserve and the number of necrotic segments (r = -0.43; P0.006). At the 4 month control angiogram, there was a significant increase in both left ventricular ejection fraction (59 +/- 14% vs 51 +/- 13%; P < 0.05) and wall motion index (-0.63 +/- 1.2 vs -1.94 +/- 0.9 units SD, P = 0.005). In patients in whom wall motion improved (> 1 unit SD), the immediate coronary flow reserve was higher (P < 0.05) than in patients without improved wall motion. In this group, the increase in wall motion index was correlated to the coronary blood flow reserve (r = 0.55; P < 0.02). CONCLUSION: These data show that after myocardial infarction, coronary flow reserve is associated with myocardial viability. PMID- 10099924 TI - Pulmonary venous flow in hypertrophic cardiomyopathy as assessed by the transoesophageal approach. The additive value of pulmonary venous flow and left atrial size variables in estimating the mitral inflow pattern in hypertrophic cardiomyopathy. AB - AIMS: This study was conducted to assess the characteristics of the pattern of pulmonary venous flow and to document the interaction of this flow and left atrial function with the pattern of mitral inflow in hypertrophic cardiomyopathy. METHODS AND RESULTS: Pulmonary venous and mitral flows were evaluated by the transoesophageal approach in 80 patients with hypertrophic cardiomyopathy. Left atrial size and function were measured by the transthoracic approach. Their values were compared with those obtained from 35 normal controls. Twelve patients showed significant (> 2+) mitral regurgitation. As a group, hypertrophic cardiomyopathy patients showed increased atrial reversal flow and longer deceleration time of the diastolic wave, but a wide variability of pulmonary venous flow patterns were observed. Thirty patients (37.5%) had pseudonormal mitral flow patterns. Stepwise multilinear regression analysis identified the ratio of systolic to diastolic pulmonary venous flow velocity, the ratio of velocity-time integrals of both flow waves at atrial contraction, the left atrial minimal volume and the systolic fraction as independent predictive variables of the mitral E/A wave velocity ratio (r = 0.82). By logistic regression, the former three variables were selected as independent predictive covariates of a pseudonormal mitral flow pattern (sensitivity: 83%, specificity: 90%). The ratio of velocity-time integrals of both atrial waves was the most important predictive variable in both analyses. CONCLUSIONS: The observed variability in the configuration of pulmonary venous flow velocity waveform is related to what occurs in transmitral flow in patients with hypertrophic cardiomyopathy. Significant mitral regurgitation is not an independent correlate of pseudonormal mitral inflow patterns in these patients. Our results further emphasize the complementary, additive value of the pulmonary venous flow velocity pattern and left atrial size in the interpretation of the mitral flow velocity pattern, and indirectly suggest the underlying increased left ventricular filling pressures of patients with hypertrophic cardiomyopathy and pseudonormal mitral flow patterns. PMID- 10099925 TI - Incidence and clinical relevance of coronary calcification detected by electron beam computed tomography in heart transplant recipients. AB - BACKGROUND: Patients treated by cardiac transplantation who survive beyond one year are at significant risk from fatal coronary artery disease. The development of coronary artery calcification in these patients is discussed and methods available to detect it are reviewed. OBJECTIVES: To assess the clinical importance of coronary artery calcium in heart transplant recipients. METHODS: In a cohort of 102 cardiac transplant recipients, electron beam computed tomography was used to measure calcium in the coronary arterial wall 63 days to 9.1 years (median 4.6 years) after transplantation. The results were compared with angiographic findings and with conventional coronary disease risk factors. The patients were followed for a mean of 2.12 years (1.2-4.02 years) to assess the relationship between these findings and future cardiac events. RESULTS: Forty-one (40.2%) had a stenosis of > 24% in one or more major coronary artery at angiography. Forty-six (45%) had a coronary calcium score > 0. The absence of calcium had a negative predictive value with respect to angiographic disease in any vessels of 87.5%. Logistic regression revealed that dyslipidaemia, systemic hypertension and organ ischaemic time were significant predictors of calcification. At follow-up, both an abnormal coronary angiogram and coronary calcium were found to be the only significant predictors of late events. Multivariate analysis suggested that the detection of coronary calcium did not offer any additional predictive information over that provided by the angiogram itself. CONCLUSION: Electron beam computed tomography is well suited to the assessment of calcium in the coronary arteries of heart transplant recipients, although the mechanisms of this calcification remain poorly understood. Calcium is detected more frequently than would be suggested by studies using intravascular ultrasound. It is associated with the presence of angiographic disease, and with some conventional risk factors for coronary disease. At follow up the presence of coronary calcium was associated with an adverse clinical outcome, as it is in conventional ischaemic heart disease. PMID- 10099926 TI - An echocardiographic study of right and left ventricular adaptation to physical exercise in elite female orienteers. AB - BACKGROUND: A considerable body of echocardiographic studies has described how athletic training induces morphological adaptation of the left ventricle in male endurance athletes, but only a few studies have described left ventricular adaptation in female endurance athletes. In contrast to changes in the left ventricle far less attention has been directed towards right ventricular changes due to extensive physical exercise. The purpose of this study was to obtain normal values and to determine if there are any differences in right and left ventricular cavity and wall dimensions between female orienteers and females with a mainly sedentary lifestyle. METHODS: Echocardiography was performed in 42 highly trained elite female orienteers and 32 healthy female students with a predominantly sedentary lifestyle. The 74 females had no history of cardiac disease, a normal electrocardiogram and showed no echocardiographic abnormalities. M-mode and two-dimensional measurements of the right and left ventricular cavity and wall were obtained in elite orienteers and sedentary females. For the right ventricle and wall, multiple cross-sections were used and measurements were obtained from the right ventricular inflow and outflow tract. RESULTS: The left ventricular end-diastolic cavity dimension and the left ventricular wall thickness were significantly greater in the athletes compared with the sedentary controls. The right ventricular inflow tract measurements were all significantly greater in the orienteers compared with the controls but the right ventricular outflow tract measurements were comparable in the study groups. The right ventricular wall thickness, calculated as the mean of three different wall measurements was an average of 13% greater in the athletes compared with the sedentary controls. CONCLUSION: This study suggests symmetrical cardiac enlargement with a concomitant increase in both the right and left ventricular wall, probably reflecting the increased haemodynamic loading in the female athletes. PMID- 10099927 TI - P-wave dispersion. PMID- 10099928 TI - Prophylactic anticoagulation in chronic atrial flutter. PMID- 10099929 TI - Cost effectiveness of coronary prevention. PMID- 10099930 TI - The secretory lectin ZG16p mediates sorting of enzyme proteins to the zymogen granule membrane in pancreatic acinar cells. AB - The recently established in vitro assay of condensation-sorting of pancreatic enzymes to the zymogen granule membrane (ZGM) (Dartsch, H., R. Kleene, H. F. Kern: In vitro condensation-sorting of enzyme proteins isolated from rat pancreatic acinar cells. Eur. J. Cell Biol. 75, 211-222 (1998)) was used to study the involvement of a novel secretory lectin, ZG16p, in the binding of aggregated proteins to ZGM. In isolated zymogen granules the lectin is predominantly associated with the membrane and can be removed to a large extent by bicarbonate treatment at pH 11.5. In the in vitro assay in which secretory proteins aggregate at pH 5.9 but only those bound to ZGM are sedimented into the pellet, ZG16p is significantly enriched in this pellet fraction, shown both by biochemical and fine structural analysis. Pretreatment of ZGM with anti-ZG16p antibody before their addition to the assay inhibits binding to the membrane by about 50%. Similarly, removal of ZG16p or prevention of its interaction with glycosaminoglycans (GAGs) in the submembranous matrix of ZGM by sodium bicarbonate treatment or chondroitinase digestion of ZGM also inhibits the binding efficiency of secretory proteins to ZGM to about the same extent. We conclude that ZG16p may act as a linker molecule between the submembranous matrix on the luminal side of ZGM and aggregated secretory proteins during granule formation in the TGN. PMID- 10099931 TI - Characterization of patocytosis: endocytosis into macrophage surface-connected compartments. AB - Previously, we described a unique macrophage endocytosis pathway in which aggregated low density lipoproteins and microcrystalline cholesterol induce and enter a labyrinth of membrane-bound compartments that remain connected to the cell surface. We now show that certain types of non-lipid particles such as polystyrene microspheres and colloidal gold also induce and enter macrophage surface-connected compartments (SCC), a process we call patocytosis. A common property among particles that stimulate patocytosis is their hydrophobic nature. Both aggregated LDL and microcrystalline cholesterol that we showed previously to stimulate patocytosis are hydrophobic. We now show that hydrophobic polystyrene microspheres and gold particles but not their hydrophilic counterparts triggered patocytosis. Uptake by patocytosis was limited to hydrophobic polystyrene microsphere particles less than 0.5 micron in diameter. Hydrophobic polystyrene microspheres greater than this size entered macrophages by phagocytosis. Actin independent capping of hydrophobic polystyrene microspheres on the plasma membrane preceded actin-dependent uptake of the microspheres into SCC. Sequential rounds of microsphere uptake into SCC over two successive days could occur. There was some mixing of initial and subsequently accumulated microspheres in SCC. SCC formed from plasma membrane invaginations that connected with spaces created by unfolding of stacks of internal microvilli. Microsphere transport from plasma membrane invaginations into these spaces was inhibited by primaquine. Patocytosis is a unique endocytic process in macrophages triggered by small hydrophobic particles that provides a mechanism to sequester large amounts of these materials within a labyrinth of SCC. PMID- 10099932 TI - Mutations in the pilz group genes disrupt the microtubule cytoskeleton and uncouple cell cycle progression from cell division in Arabidopsis embryo and endosperm. AB - Organised cell division and expansion play important roles in plant embryogenesis. To address their cellular basis, we have analysed Arabidopsis abnormal-embryo mutants which were isolated for their characteristic phenotype: mutant embryos are small, mushroom-shaped ("pilz") and consist of only one or few large cells each containing one or more variably enlarged nuclei and often cell wall stubs. These 23 mutants represent four genes, PFIFFERLING, HALLIMASCH, CHAMPIGNON, and PORCINO, which map to different chromosomes. All four genes have very similar mutant phenotypes although porcino embryos often consisted of only one large cell. The endosperm did not cellularise and contained a variably reduced number of highly enlarged nuclei. By contrast, genetic evidence suggests that these genes are not required for gametophyte development. Expression of cell cycle genes, Cdc2a, CyclinA2 and CyclinB1, and the cytokinesis-specific KNOLLE gene was not altered in mutant embryos. However, KNOLLE syntaxin accumulated in patches but no KNOLLE-positive structure resembling a forming cell plate occurred in mitotic cells. A general defect in microtubule assembly was observed in all mutants. Interphase cells lacked cortical microtubules, and spindles were absent from mitotic nuclei although in rare cases, short stubs of microtubules were attached to partially condensed chromosomes. Our results suggest that the cellular components affected by the pilz group mutations are necessary for continuous microtubule organisation, mitotic division and cytokinesis but do not mediate cell cycle progression. PMID- 10099933 TI - Putative involvement of a 49 kDa protein in microtubule assembly in vitro. AB - In higher plant cells, thus far only a few molecules have been inferred to be involved in microtubule organizing centers (MTOCs). Examination of a 49 kDa tobacco protein, homologous to a 51 kDa protein involved in sea urchin MTOCs, showed that it also accumulated at the putative MTOC sites in tobacco BY-2 cells. In this report, we show that the 49 kDa protein is likely to play a significant role in microtubule organization in vitro. We have established a system prepared from BY-2 cells, capable of organizing microtubules in vitro. The fraction, which was partially purified from homogenized miniprotoplasts (evacuolated protoplasts) by salt extraction and subsequent ion exchange chromatography, contained many particles of diameters about 1 micron after desalting by dialysis. When this fraction was incubated with purified porcine brain tubulin, microtubules were elongated radially from the particles and organized into structures similar to the asters observed in animal cells, and therefore also termed "asters" here. Since we could hardly detect BY-2 tubulin molecules in this fraction, the microtubules in "asters" seemed to be solely composed of the added porcine tubulin. Tubulin molecules were newly polymerized at the ends of the microtubules distal to the particles, and the elongation rate of microtubules was more similar to the reported rate of the plus-ends than that of the minus-ends in vitro. By fluorescence microscopy, the 49 kDa protein was shown to be located at the particles. Thus, its location at the centers of the "asters" suggests that the protein plays a role in microtubule organization in vitro. PMID- 10099935 TI - Proteolytic specificity of caspases is required to signal the appearance of apoptotic morphology. AB - The caspase family of cysteine proteases is essential for implementation of physiological cell death. Since a wide variety of cellular proteins is cleaved by caspases during apoptosis, it has been predicted that digestion of proteins crucial to maintaining the life of a cell is central to apoptosis. To assess the role of the proteolytic destruction during apoptosis, we introduced the non specific protease proteinase K into intact cells. This introduction led to extensive digestion of cellular proteins, including physiological caspase substrates. Caspase-3-like activity was induced rapidly, followed by morphological signs of apoptosis such as membrane blebbing and nuclear condensation. The caspase inhibitor Z-VAD-fmk inhibited the appearance of these morphological changes without reducing the extent of intracellular proteolysis by proteinase K. Loss of integrity of the cell membrane, however, was not blocked by Z-VAD-fmk. This system thus generated conditions of extensive destruction of caspase substrates by proteinase K in the absence of apoptotic morphology. Taken together, these experiments suggest that caspases implement cell death not by protein destruction but by proteolytic activation of specific downstream effector molecules. PMID- 10099934 TI - 2E4 (kaptin): a novel actin-associated protein from human blood platelets found in lamellipodia and the tips of the stereocilia of the inner ear. AB - Platelet activation, crucial for hemostasis, requires actin polymerization, yet the molecular mechanisms by which localized actin polymerization is mediated are not clear. Here we report the characterization of a novel actin-binding protein, 2E4, originally isolated from human blood platelets and likely to be involved in the actin rearrangements occurring during activation. 2E4 binds to filamentous (F)-actin by F-actin affinity chromatography and is eluted from F-actin affinity columns and extracted from cells with ATP. Its presence at the leading edge of platelets spread on glass and in the lamellipodia of motile fibroblasts suggests a role in actin dynamics. Using localization to obtain clues about function, we stained the sensory epithelium of the embryonic inner ear to determine whether 2E4 is at the barbed end of actin filaments during their elongation. Indeed, 2E4 was present at the tips of the elongating stereocilium. 2E4 is novel by DNA sequence and has no identifiable structural motifs. Its unusual amino acid sequence, its ATP-sensitive actin association and its location at sites of actin polymerization in cells suggest 2E4 plays a unique role in the actin rearrangements that accompany platelet activation and stereocilia formation. PMID- 10099936 TI - Analysis of NO synthase expression in neuronal, astroglial and fibroblast-like derivatives differentiating from PCC7-Mz1 embryonic carcinoma cells. AB - We studied the expression of the NO synthase isoforms in an in vitro model of neural development using RT-PCR, Western blot and immunohistochemistry. Murine PCC7-Mz1 cells (Jostock et al., Eur. J. Cell Biol. 76, 63-76, 1998) differentiate in the presence of all-trans retinoic acid and dibutyryl cAMP along the neural pathway into neuron-like, fibroblast-like and astroglia-like cells. Undifferentiated cells showed immunofluorescent staining for neuronal-type NOS I and endothelial-type NOS III. This expression pattern was retained in those cells differentiating into neurofilament- and tau protein-positive neuronal cells. Thymocyte alloantigen (Thy1.2/CD 90.2)-positive fibroblasts, appearing around day 3, and glial fibrillary acidic protein (GFAP)-positive astroglial cells, appearing after day 6 of differentiation, stained negative for any NOS isoform. Starting at day 6 of differentiation, expression of inducible-type NOS II could be stimulated with cytokines in a subset of cells, which may represent activated astrocytes. NOS II was always undetectable in non-induced cultures. These data indicate that the ability of stem cells to express NOS I and NOS III is only retained when the cells differentiate along the neuronal lineage, while a small subpopulation of cells acquires the ability to express NOS II in response to cytokines. PMID- 10099937 TI - Ectopic expression of alpha B-crystallin in Chinese hamster ovary cells suggests a nuclear role for this protein. AB - alpha B-crystallin (alpha B) is known to be a cytosolic, small heat shock-like multimeric protein that has anti-aggregation, chaperone-like properties. The expression of the alpha B-crystallin gene is developmentally regulated and is induced by a variety of stress stimuli. Importantly, alpha B-crystallin expression is enhanced during oncogenic transformation of cells, in a number of tumors, and most notably, in many neurodegenerative disorders, including Alzheimer's disease and multiple sclerosis. Other than its perceived role as a structural protein in the ocular lens, the actual function of alpha B-crystallin in cellular physiology remains unknown. We have stably transfected CHO cells with an inducible alpha B-cDNA-MMTV-promoter construct that allows the synthesis of recombinant alpha B-crystallin only upon exposure of these cells to dexamethasone. Using immunostaining and conventional and confocal microscopy, we have examined the subcellular distribution of the ectopically expressed alpha B crystallin. We find that in addition to being in the cytoplasm, the protein resides in the nuclear interior in the interphase nucleus. Double labeling with anti alpha B-crystallin and anti-tubulin, concanavallin, and wheat germ agglutinin, respectively, revealed that during cell division alpha B-crystallin is excluded from condensed chromatin and the nascent nuclei. However, the protein again appears in the newly formed nuclei after the completion of cytokinesis suggesting a conditional, regulatory role for alpha B-crystallin in the nucleus. PMID- 10099938 TI - Western nutrition and the insulin resistance syndrome: a link to breast cancer. AB - OBJECTIVE: The incidence of breast cancer in the Western world runs parallel to that of the major components of the insulin resistance syndrome- hyperinsulinaemia, dyslipidaemia, hypertension and atherosclerosis. Evidence is reviewed that the growth of breast cancer is favoured by specific dietary fatty acids, visceral fat accumulation and inadequate physical exercise, all of which are thought to interact in favouring the development of the insulin resistance syndrome. DESIGN: Clinical, epidemiological and experimental studies linking breast cancer risk with evidence of insulin resistance and its concomitants, were searched for in the MEDLINE database since 1985. RESULTS: Clinical and epidemiological evidence suggests that both breast cancer and the metabolic disorders comprising the insulin resistance syndrome are polygenic and multifactorial in origin. Experimental evidence suggests that hyperinsulinaemia and its concomitants can increase the promotion of mammary carcinogenesis and the mechanism is likely to involve increased bioactivity of insulin-like growth factor 1 (IGF-1). Case-control and cohort studies have shown that higher serum levels of IGF-1 are associated with increased breast cancer risk. Pharmacological agents which lower IGF-1 concentrations are under clinical trial for breast cancer prevention. CONCLUSIONS: Nutritional and lifestyle modifications that improve insulin sensitivity may not only decrease a tendency to atherosclerosis but also reduce breast cancer risk in women. In addition to a reduced fat intake, the dietary regimen might involve a reduced n-6/n-3 ratio of polyunsaturated fatty acids and should be associated with avoidance of obesity and regular physical exercise. Interventions to decrease breast cancer risk in first-degree relatives of breast cancer patients need to begin at an early age. PMID- 10099939 TI - Effect of one year residence in Antarctica on bone mineral metabolism and body composition. AB - OBJECTIVE: To evaluate the changes of the biochemical parameters of mineral metabolism and to assess the effect of these changes on the bone mass of young healthy men who voluntarily lived in the Antarctic Continent for one year. DESIGN: Lumbar spine and whole body bone mineral density (BMD) were measured pre- and post-campaign (14 months later). Serum and urinary biochemical parameters were measured every two months. Serum levels of calcium, phosphate, total alkaline phosphatase, parathormone (PTH) and 25-hydroxyvitamin D (250HD) were determined in blood fasting samples; and hydroxyproline, calcium and creatinine in 2 h fasting urine. The subjects received a dose of 100 i.u./d of vitamin D during May after obtaining the samples and then an average of 125 i.u./d from July to January. SUBJECTS: Seventeen healthy volunteers, who left Buenos Aires during the 1992 summer: ten arrived in the Belgrano II Base at the end of January and the other seven arrived in San Martin in March and stayed there up to summer 1993. RESULTS: BMD increased in lumbar spine (L2-L4), total body and the subarea of the legs but there were no differences between the pre- and post-campaign values in arms and pelvis. The percentage of fat mass decreased significantly after 1 y of residence in Antarctica, in comparison to the basal values. Most biochemical parameters remained unaltered and within the normal range during the whole study. PTH showed a nadir in March (end of the summer) when compared to initial levels (73.0 +/- 28.2 vs 39.9 +/- 32.7 pg/ml, P < 0.05), and recovered its initial value in spring. Calcium levels showed a significant decrease in March (9.5 +/- 0.4 vs 8.5 +/- 1.0 mg%, P < 0.01). 25OHD levels began to decrease in March (24.7 +/- 6.4 vs 18.7 +/- 5.3 ng/ml), reaching a minimum value whose difference approached statistical significance during the winter period (July: 16.4 +/- 8.2 ml, 0.05 < P < 0.06). No significant changes in serum phosphate, total alkaline phosphatase, urinary hydroxyproline/creatinine and calcium/creatinine ratios were found through the year. CONCLUSIONS: 25OHD levels decreased in autumn and winter (nadir in July) and recovered the initial levels by the end of the campaign. An unexplained marked diminution in PTH and serum calcium was found at the beginning of the campaign. In spite of the low vitamin D levels, bone mass in this group of young healthy men increased, probably because of their intense physical activity. PMID- 10099940 TI - Absorption and antioxidant effects of quercetin from onions, in man. AB - OBJECTIVE: To investigate the in vivo effects of quercetin following the ingestion of fried onions. DESIGN: Five healthy volunteers, three males and two females aged between 25 and 39 y, ingested 225 g of fried onions after an overnight fast and peripheral venous blood was collected 0, 2, 4, 24 and 48 h after consumption. Quercetin in the plasma, total antioxidant capacity and susceptibility of low density lipoproteins (LDL) to oxidation were measured. RESULTS: Following the onion meal, quercetin levels increased from baseline values (28.4 +/- 1.9 ng/ml) to peak after 2 h (248.4 +/- 103.9 ng/ml), decreasing to baseline again after 24 h (P > 0.05). This was accompanied by an increase in the total antioxidant activity of the plasma from baseline (1.70 +/- 0.04 mmol/l trolox equivalents) to 1.75 +/- 0.10 mmol/l trolox equivalents after 2 h and 1.76 +/- 0.08 mmol/l trolox equivalents after 4 h. There was no significant change in the susceptibility of the plasma or the isolated LDL to oxidation over the 48 h period after consumption of the fried onions. In view of these negative findings, we isolated LDL and other lipoproteins from plasma at each time point. Quercetin was not detected in either LDL or VLDL, but was present in the HDL fraction, although this fraction also contains other proteins including albumin. CONCLUSIONS: Quercetin can be absorbed in humans from dietary sources to high enough concentrations to increase the overall antioxidant activity of the plasma. Quercetin, however, has a strong affinity for protein and provides no direct protective effect during LDL oxidation. PMID- 10099941 TI - Evaluation of the effects of a new fermented milk product (Gaio) on primary hypercholesterolemia. AB - OBJECTIVE: To verify the effects on the lipid profile of a product of fermented milk (Gaio) in patients with mild to moderate primary hypercholesterolemia. DESIGN: The study was prospective, randomized, double-blinded and placebo controlled, with a crossover design. SUBJECTS: Thirty-two patients (21 women and 11 men) with ages ranging between 36 and 65 years old were included in the study. All of them were on a controlled diet for at least 8 weeks. INTERVENTION: Patients began, after clinical and laboratory analysis, in a randomized and double-blind manner to take 200 g daily of Gaio or its placebo. After 8 weeks blood was collected again for lipid profile evaluation and the crossover was made. After an additional 8 weeks blood was collected for another lipid profile determination. RESULTS: All patients included completed the study. Comparisons were made between means of lipid profile constituents after the placebo and active product periods. These showed significant mean reduction of 5.3% (P = 0.004) for total cholesterol, 6.15% (P = 0.012) for LDL-cholesterol and no significant variation for HDL-cholesterol and triglycerides. The majority of patients presented no variation or had a decrease in their total cholesterol level. However, during the active product period, three patients showed an increase in cholesterol level by more than 5%. CONCLUSION: The fermented milk (Gaio) produced a small but statistically significant decrease in total and LDL cholesterol mean. However, not all subjects seem to respond to the product, and a few subjects showed a cholesterol increment. Further investigations are necessary to clarify this aspect. PMID- 10099942 TI - Treatment for iron deficiency anaemia with a combined supplementation of iron, vitamin A and zinc in women of Dinajpur, Bangladesh. AB - OBJECTIVE: The study was set up to determine to what extent the addition of a supplement of vitamin A alone or in combination with zinc would improve standard iron treatment and correction of iron deficiency anaemia. DESIGN: 216 non pregnant anaemic women of 15-45 years of age with haemoglobin levels < or = 100 g/l were randomly assigned to three treatment groups. One group (A) received iron alone, a second group (B) received iron and vitamin A, and a third group (C) received iron, vitamin A and zinc. Every woman was given one iron capsule per day for 60 days as FeSO4 containing 60 mg of elemental iron. In addition, groups B and C received 200,000 i.u. of vitamin A, given as a supervised dose, on the first day of the treatment after collection of the blood sample. Group C received one zinc tablet per day for 60 days as zinc gluconate containing 15 mg of elemental zinc. SETTING: The north-western part of Bangladesh in the urban slums of Dinajpur district between February and August 1995. SUBJECTS: To select women with a haemoglobin level of < or = 100 g/l, all the women of four randomly selected municipal slums of the district in the targeted age group (328) were invited to take part in the study. Blood samples were analysed for haemoglobin, serum iron, total iron binding capacity (TIBC), ferritin, retinol and zinc. RESULTS: Out of the 328 women screened, 254 (77.5%) had a haemoglobin level < or = 100 g/l and 322 (98%) < or = 120 g/l. The three treatment schedules significantly increased haemoglobin levels and improved iron parameters, except for serum iron in the group who received iron alone. The group who received iron, vitamin A and zinc responded best with an increase in haemoglobin of 17.9 g/l as compared to the group receiving iron alone (13.4 g/l). Iron and vitamin A treatment gave an intermediate response of 15.9 g/l. However, these differences are only statistically significant only for the group who received iron, vitamin A and zinc and only for the increase in haemoglobin, P = 0.03. CONCLUSION: The results are suggestive that the addition of vitamin A and zinc to the treatment for anaemia can increase haemoglobin levels more than with iron alone. PMID- 10099943 TI - Relationship between overnight energy expenditure and BMR measured in a room sized calorimeter. AB - OBJECTIVE: The purpose of this study was to determine if overnight energy expenditure, the lowest energy expenditure sustained for 60 min during the night, measured and predicted basal metabolic rate are equivalent. DESIGN: Overnight energy expenditure (ON-EE), the lowest energy expenditure sustained for 60 min during sleep (LS-EE) and basal metabolic rate (BMR) were measured two to seven times in a room-sized indirect calorimeter in 69 adult subjects. Subjects' gender, age, weight and height were also used to predict BMR (FAO/WHO/UNU, 1985) (BMR-WHO). SETTING: Beltsville Human Nutrition Research Center, Beltsville, MD, USA. RESULTS: The results from calorimetry measurements (mean +/- s.d.) included: ON-EE (6.87 +/- 0.99 MJ/d), LS-EE (6.18 +/- 0.94 MJ/d) and BMR (6.87 +/- 0.99 MJ/d). Predicted BMR mean was: BMR-WHO, 6.95 +/- 1.03. The mean within-subject difference for the calorimetry measurements were: ON-EE, 0.21 MJ/d; LS-EE, 0.16 MJ/d; and BMR, 0.34 MJ/d. Results indicate there was no significant difference between ON-EE, BMR and BMR-WHO. LS-EE was significantly lower (P < 0.0001) than ON-EE, BMR and BMR-WHO. CONCLUSION: These results indicate that while metabolic rate drops significantly below BMR during sleep, overnight metabolic rate and BMR are equivalent. PMID- 10099944 TI - The potential use of maternal size in priority setting when combating childhood malnutrition. AB - OBJECTIVE: To devise a strategy for assessing the nutritional status of a household and specifying the major needs in combating childhood wasting, distinguishing between inadequate food availability, poor parental care and/or the need for improved public health measures. DESIGN: An evaluation of the relationship between children's wasting, stunting, or underweight and mothers' or adult women's body mass indexes (BMIs) in the same household. A household was designated as 'malnourished' on the basis of a single child's weight/height of < 2.0 s.d. or at risk of being malnourished if the Z-score was below--1.5. Adult women's BMI was taken to signify adequate household food availability. Sibling concordance of anthropometric measures was investigated. RESULTS: A wide variety of prevalence of severe (BMI < 16.0), moderate (BMI 16.0-16.9) and marginal (17.0 18.4) malnutrition existed in the various study areas. The worst condition was recorded in India, while 18% of the women in Zimbabwe were classified as obese. Similarly wide variation in the prevalence of child wasting and stunting was observed, with the Indian children again faring worst and those in Zimbabwe the best. The within-household analysis of concordance gave higher concordance for height than for weight between siblings. Mothers' BMI was highly correlated with the BMI of all other adult women in the same household and the BMI of all the women was found to be as useful as that of the mother for relating to children's anthropometry. Households with mothers of normal body weight but wasted children were designated as in need of public health measures and improved parental care rather than of enhanced food security. The distribution of households on this combined basis of maternal BMI and child nutritional status highlighted very diverse situations in the various study areas, with higher proportions of combined maternal and child malnutrition in India and in some areas of Ethiopia, while in Zimbabwe only 1-2% presented this condition. On this basis, the principal problem in India was food security; in Zimbabwe household security was rarely apparent, so public health measures and maternal care were designated as problems. In three Ethiopian communities there was a mixture of needs. CONCLUSIONS: A relatively simple household-based approach is proposed to discriminate the most pressing needs in combating childhood malnutrition, and a policy-making tool is suggested for setting priorities in community action. PMID- 10099945 TI - Difficulties in changing the diet in relation to dietary fat intake among patients with coronary heart disease. AB - OBJECTIVE: To study barriers in following nutritional advice among coronary heart disease patients in relation to dietary fat intake. DESIGN: A cross-sectional study using 4-day food records and a questionnaire with regard to barriers to or difficulties in following dietary advice. SUBJECTS: Altogether, 362 male subjects with coronary heart disease from two separate patient populations (91 + 271) were included in the study, with the mean age of 50 years and 60 years, respectively. The patients were classified into low (< or = 30 E%) or high (> 30 E%) fat intake groups. The patients with low dietary fat intake obtained on an average 10 E% less energy from fat as compared to the high dietary fat intake group. RESULTS: Overall, most patients with coronary heart disease reported difficulties in following nutritional advice when eating in social situations. Patients with high dietary fat intake reported more frequently than patients with low fat intake that they eat like other people without thinking about what they eat. On the other hand, there were no differences between the high and low fat intake groups in the barriers: eating at work, food price, shopping, taste or knowledge of nutrition. CONCLUSIONS: Our results suggest that the sensitivity to social influence is an important factor explaining noncompliance with dietary advice among patients with high dietary fat intake. PMID- 10099946 TI - Effect of 3 weeks of detraining on the resting metabolic rate and body composition of trained males. AB - OBJECTIVE: To examine the hypothesis that detraining decreases the resting metabolic rate (RMR) of long-term exercisers. DESIGN: Eight pairs of subjects were matched for age, mass and training volume. They were then randomly allocated to either a control group (continue normal training) or detraining group (stop normal training but continue activities of daily living). SETTING: Exercise Physiology Laboratory, The Flinders University of South Australia. SUBJECTS: Sixteen male subjects (age 23.1 +/- 4.7 y (s.d.); mass 73.73 +/- 8.9 kg; VO2max 60.2 +/- 6.3 ml. kg-1.min-1; height 180.3 +/- 5.0 cm; body fat 14.6 +/- 5.4%) were selected from a pool of respondents to our advertisements. INTERVENTIONS: Each pair of subjects was measured before and after a 3-week experimental period. RESULTS: Two (groups) x 3 (2-, 3-and 4-compartment body composition models) ANOVAs were conducted on the difference between the pre- and post-treatment scores for percentage body fat, fat-free mass (FFM) and relative RMR (kJ.kg FFM 1.h-1). No significant between-group differences were identified except for the detraining group's small decrease in FFM (0.7 kg, P = 0.05). The main effects for body composition model were all significant; but the overall differences between the multicompartment models and the 2-compartment one were less than their technical errors of measurement. No significant interaction (P = 0.51) resulted from a 2 x 2 ANOVA on the pre- and post-treatment absolute RMR data for the control (315.2 and 311.9 kJ/h) and detraining groups (325.4 and 325.5 kJ/h). CONCLUSIONS: 3-weeks detraining is not associated with a decrease in RMR (kJ/h, kJ.kg FFM-1.h-1) in trained males; hence, our data do not support a potentiation of the RMR via exercise training. The greater sensitivity of the multicompartment models to detect changes in body composition was of marginal value. PMID- 10099947 TI - New equations to estimate basal metabolic rate in children aged 10-15 years. AB - OBJECTIVE: To develop new equations for the estimation of basal metabolic rate in children aged 10-15 years, and to evaluate the impact of including pubertal stage into the equations. DESIGN: Mixed longitudinal. SETTING: The children were recruited from schools in Oxford, and the measurements were made in the schools. SUBJECTS: 195 school children, aged 10-15 years, were recruited in three cohorts. The gender distribution of the subjects was 40% boys and 60% girls. METHODS: Basal metabolic rate (BMR) was measured, by indirect calorimetry, at 6-monthly intervals for 3 years. Anthropometric data, height, weight, body breadths and skinfold measurements (biceps, triceps, subscapular, suprailiac and medial calf) were collected on each occasion. Fat and fat-free mass was calculated from the skinfold measurements. Pubertal development was also assessed on annually by paediatricians. Pubic hair (PH) and gonad (G) development was assessed in boys and breast (B) development in girls. The girls were questioned about menarche. Stepwise multiple regression analysis was used to develop and assess new formulae for BMR that also incorporate pubertal development. RESULTS: The mean BMR measured was 5.754 (s.d. 0.933) MJ/day (138 (s.d. 22) kJ/kg body wt/day) in the boys (n = 351) and 5.476 (s.d. 0.725) MJ/day (121 (s.d. 20) kJ/kg body wt/day) in the girls (n = 554). Weight was the most important factor in developing the regression equations for the calculation of BMR in both sexes (R2 = 0.61 and 0.52 for boys and girls, respectively). Stepwise multiple regression analyses, with independent variables such as gender, weight, height, puberty stage and skinfolds, allowed several BMR regression equations to be developed. The inclusion of the menarche status in the regression equations significantly (P < 0.05) improved BMR estimation in the pre-menarche girls. Boys, pubertal stage as assessed by Pubic Hair (PH) and Gonadal Stage (G) did not contribute to a significant improvement in BMR estimation, except for 11-year-olds. CONCLUSIONS: The inclusion of pubertal stage afforded only minor improvements in the derivation of regression equations for the estimation of BMR of children aged between 10 and 15 years. PMID- 10099948 TI - Intake of fatty acids in western Europe with emphasis on trans fatty acids: the TRANSFAIR Study. AB - OBJECTIVE: To assess the intake of trans fatty acids (TFA) and other fatty acids in 14 Western European countries. DESIGN AND SUBJECTS: A maximum of 100 foods per country were sampled and centrally analysed. Each country calculated the intake of individual trans and other fatty acids, clusters of fatty acids and total fat in adults and/or the total population using the best available national food consumption data set. RESULTS: A wide variation was observed in the intake of total fat and (clusters) of fatty acids in absolute amounts. The variation in proportion of energy derived from total fat and from clusters of fatty acids was less. Only in Finland, Italy, Norway and Portugal total fat did provide on average less than 35% of energy intake. Saturated fatty acids (SFA) provided on average between 10% and 19% of total energy intake, with the lowest contribution in most Mediterranean countries. TFA intake ranged from 0.5% (Greece, Italy) to 2.1% (Iceland) of energy intake among men and from 0.8% (Greece) to 1.9% among women (Iceland) (1.2-6.7 g/d and 1.7-4.1 g/d, respectively). The TFA intake was lowest in Mediterranean countries (0.5-0.8 en%) but was also below 1% of energy in Finland and Germany. Moderate intakes were seen in Belgium, The Netherlands, Norway and UK and highest intake in Iceland. Trans isomers of C18:1 were the most TFA in the diet. Monounsaturated fatty acids contributed 9-12% of mean daily energy intake (except for Greece, nearly 18%) and polyunsaturated fatty acids 3 7%. CONCLUSION: The current intake of TFA in most Western European countries does not appear to be a reason for major concern. In several countries a considerable proportion of energy was derived from SFA. It would therefore be prudent to reduce intake of all cholesterol-raising fatty acids, TFA included. PMID- 10099949 TI - A Swiss population-based assessment of dietary habits before and after the March 1996 'mad cow disease' crisis. AB - OBJECTIVE: To assess differences in dietary habits in the general population of Geneva, Switzerland, after the 1996 (BSE) crisis. DESIGN: Repeated population based survey during 1993, 1994, 1995 and 1996. SETTING: The Bus Sante 2000 epidemiological observatory of Geneva, Switzerland. SUBJECTS: A representative sample of 1190 men and 1154 women. MAIN OUTCOME MEASURE: Dietary habits assessed by a semi-quantitative food frequency questionnaire. RESULTS: The proportion of women who reported not having eaten beef was 7.7% in 1993-1995 and went up to 14.6% in 1996 (age-adjusted difference +6.4%, 95% CI +2.4 to +10.4). Among men, the proportion of non-beef-eaters remained constant (5%). There was a sharp increase of women who did not eat liver (+14.7%, +9.1 to +20.3) but less so in men (+2 5.1%, -0.7 to +10.8). Among women who ate meat, the amount of beef intake decreased by 120 g/month (95% CI -208 to -36). While chicken intake increased (+44 g/month, -2 to 88), overall intake of meat (including poultry but not fish) declined by 204 g/month (or 2.7 kg per year). In men the decrease in beef intake was not statistically significant (-48 g/month, -172 to 80), but consumption of chicken increased (+2 56g/month, +8 to +104). Fish intake was stable in both genders. The reduction in intake of animal protein (-3.5 g/day) in women and of retinol intake in both sexes (women -77 micrograms/day; men -56 micrograms/day) was statistically significant. CONCLUSIONS: The BSE crisis coincided with spontaneous differences in food habits, especially in women, that may have nutritional consequences at the population level. PMID- 10099950 TI - The development and differentiation of the parabronchial unit in quail (Coturnix coturnix). AB - The present study has been inspired by the conflicting data in the relevant literature concerning the embryogenesis of cell types of the parabronchial epithelium and the formation, discharge and distribution of trilaminar substance and lamellar bodies. Lung tissue from embryonic, newly hatched, immature and mature quail was subjected to standard processing for light and transmission electron microscopy. The parabronchial rudiments form shallow primitive atria on embryonic day 13. The precursors of granular cells differentiate with lamellar bodies in their cytoplasm. The residual population of non-granular epithelial cells is the common source for the differentiation of primitive squamous atrial and respiratory cells, the potential producers of trilaminar substance. The primitive squamous atrial cells sprout as branching infundibular canaliculi into the mesenchyme on embryonic day 14. The infundibular epithelium differentiates into the squamous respiratory cells that constitute with blood capillaries the blood-air barrier. Not until the time of hatching could the trilaminar substance be visualized being produced by squamous atrial and respiratory cells. In the late prehatching and early posthatching period the granular cells intensely escalate the production and discharge of lamellar bodies. The lamellar bodies form, together with sheets of trilaminar substance, mixed multilayered masses in atria. They disappear fast in the successive posthatching period. The formation of trilaminar substance in squamous atrial and respiratory cells is governed by the agranular endoplasmic reticulum, the cisternae of which take part in the formation of trilaminar units. The gas exchange tissue is predominantly represented by infundibula in immature quail. The posthatching growth of the gas exchange tissue of immature to mature quail occurs via intense multiplication of air and blood capillaries. PMID- 10099951 TI - Influence of anaesthetic agent on limb abnormalities observed following amniotic sac puncture. AB - In all of our previous studies into the effect of amniotic sac puncture (ASP) carried out on day 13 of pregnancy in mice, we have used intraperitoneal Avertin (tribromoethanol) as the general anaesthetic. In the present study, we used an inhalational anaesthetic (a mixture of halothane, oxygen and nitrous oxide in a ratio of 2:3:3). The principal difference between these two regimens is that even under optimal post-operative conditions when Avertin is used it can take between 45 and 90 min before complete recovery is achieved; when the inhalational anaesthetic is used, complete recovery is usually achieved within about 3-5 min. Because the experimental conditions were otherwise identical, this allowed the influence of the anaesthetic employed during ASP and the incidence of abnormalities induced on survival rate to day 19 of pregnancy to be studied. The survival rate was slightly higher when the inhalational anaesthetic was used, as was the incidence of limb abnormalities, although the overall incidence of gross abnormalities involving the palate, limbs and tail was not significantly different. The most marked difference, however, was in the incidence of syndactyly, which was significantly lower when the inhalational compared to the intraperitoneal anaesthetic was used: 26.6% v. 70.2% of the abnormal limbs analysed. A possible hypothesis is presented to explain this difference. PMID- 10099952 TI - A crossed projection from the optic tectum to craniocervical premotor areas in the brainstem reticular formation. An anterograde and retrograde tracing study in the mallard (Anas platyrhynchos L.). AB - The optic tectum in birds receives visual information from the contralateral retina. This information is passed through to other brain areas via the deep layers of the optic tectum. In the present study the crossed tectobulbar pathway is described in detail. This pathway forms the connection between the optic tectum and the premotor area of craniocervical muscles in the contralateral paramedian reticular formation. It originates predominantly from neurons in the ventromedial part of stratum griseum centrale and to a lesser extent from stratum album centrale. The fibers leave the tectum as a horizontal fiber bundle, and cross the midline through the caudal radix oculomotorius and rostral nucleus oculomotorius. On the contralateral side fibers turn to ventral and descend caudally in the contralateral paramedian reticular formation to the level of the obex. Labeled terminals are found in the ipsilateral medial mesencephalic reticular formation lateral to the radix and motor nucleus of the oculomotor nerve, and in the contralateral paramedian reticular formation, along the descending tract. Neurons in the medial mesencephalic reticular formation in turn project to the paramedian reticular formation. Through the crossed tectobulbar pathway visual information can influence the activity of craniocervical muscles via reticular premotor neurons. PMID- 10099953 TI - Effects of irradiation on facial development in mouse embryos. AB - The purpose of this study was to observe the effects of irradiation on the craniofacial development of NMRI mouse embryos. Two populations of pregnant mice were irradiated with a single dose of 2 Gray on day 8 of gestation for the first population (Po. 1) and on day 9 of gestation for the second population (Po. 2). On gestational days 9 to 17, embryos were submitted to histological and scanning electron microscope examinations. The two populations of embryos presented a high percentage of centro-facial hypoplasia (74.7% for Po. 1 and 75% for Po. 2) which was more pronounced in the latter one. Ocular anomalies were present in 16% of the first population. Cases of anencephaly, cleft palate and anomalies of the central nervous system were found in both populations. PMID- 10099954 TI - Changes of the lingual epithelium in Ambystoma mexicanum. AB - Changes in the lingual epithelium during ontogenesis and after induced metamorphosis in Ambystoma mexicanum are described as observed by light microscopy and scanning electron microscopy. The epithelium of the tongue is always multilayered in the larva as well as in the adult. It consists of a stratum germinativum with little differentiated basal cells and a stratum superficiale (superficial layer) with specialized superficial cells and goblet cells. Usually, there are more than two layers because of a stratum intermedium consisting of replacement cells. The apical cell membrane of the superficial cells is perforated by fine pores. Its most typical feature are microridges. Maturing superficial cells possess microvilli. Goblet cells occur in early larvae primarily in the centre of the tongue. They spread throughout the dorsal face of the tongue as their numbers increase during ontogenesis. The small apices of the goblet cells are intercalated in the wedges between the superficial cells. Leydig cells are not found on the larval tongue but on that of adults. Due to metamorphosis, the epithelium of the tongue changes. It is furrowed in its anterior part. The furrows house the openings of the lingual glands. The surface is further modulated by ridges which are densely coated by microvilli and which bear the taste buds. The villi of the tongue which lack extrusion pores show cilia and microvilli but lack microridges. The Leydig cells disappear during metamorphosis. In addition to the two types of goblet cells found in different regions of the glandular tubules, goblet cells occur in the caudal part. They secrete directly into the cavity of the mouth. The posterior part is characterised by a dense coat of cilia. PMID- 10099955 TI - The klapskate: an example of intermuscular coordination. PMID- 10099956 TI - Understanding quadrupedal locomotion. PMID- 10099957 TI - The mechanics of quadrupedal locomotion. 'How is the body propelled by muscles?'. PMID- 10099958 TI - Force-sharing among the primary cat ankle muscles. AB - Force-sharing measurements among the cat ankle extensors have been used for the past 20 years to elucidate the mechanisms underlying normal movement control and to study the force-sharing among synergistic muscles. Despite these efforts, many questions have eluded satisfactory explanation. Specifically, there has been great debate to what degree the soleus muscle is activated during low level locomotion, and whether the force-sharing among the ankle extensors is primarily caused by central or peripheral factors. We have measured the forces and corresponding electromyo-graphical activities in the soleus, gastrocnemius, plantaris, and tibialis anterior in more than 20 cats and for a variety of movements. Based on these measurements, and additional information obtained on the structural and functional properties of the cat ankle muscles, we conclude that the peak soleus forces are virtually maximal for all speeds of locomotion, despite an apparent submaximal level of activation at slow speeds. Furthermore, we found that the force-sharing among the soleus and gastrocnemius encompasses the entire possible range; from large soleus forces and zero gastrocnemius forces during still standing, to large gastrocnemius forces and no soleus forces during a high-frequency paw shake. Finally, we support the idea that shifts in force sharing from one muscle to the other are primarily caused by central factors; the peripheral factors, although appealing when considering the large differences in size, morphology, and fibre type distribution, are likely only of secondary importance. PMID- 10099959 TI - Use and fibre type composition in limb muscles of cats. AB - As a background for studies concerning the effects of training on the properties and fibre type composition of skeletal muscle, information is needed concerning the normal duration of muscle use per day. Data of this kind were collected from adult cats, using implanted electrodes for electromyographic recording from hindlimb muscles acting across the ankle joint: extensor digitorum longus (EDL), tibialis anterior (TA), peroneus longus (PL), lateral gastrocnemius (LG) and soleus (SOL). The accumulated duration of any recorded activity was expressed, for each electrode site, as a percentage of total sampling time ("duty time"). As measured intermittently across 24 h periods (4 min sampling per 30 min), these duty times were markedly and significantly different among the various muscles, averages varying from 1.9% for EDL up to 9.5% for posterior PL and 13.9% for SOL. The distribution of activity across the various muscles was markedly different between highly active periods (mid-day) and periods of rest (mid-night). The 24 h duty times were strongly and significantly correlated to duty times obtained for only mid-day activity but not to those for only mid-night activity. Following the end of the physiological measurements, the animals were sacrificed and the muscles were analyzed with regard to fibre type composition (histochemistry). There was a significant positive correlation between the 24 h duty time and the percentage of type I fibres ("slow"). In the Discussion, the present results from cats are briefly compared to previously published data for humans. PMID- 10099960 TI - The role of afferent feedback in the control of hamstrings activity during human gait. AB - In vertebrates, possibly also in man, the pattern of activation of muscles during locomotion can be generated by the spinal cord (locomotor CPG, central pattern generator). However, sensory feedback is crucial to adapt the functioning of the CPG to the external requirements during gait. It is postulated that afferent input from skin and muscles can contribute to the EMG activation patterns as observed in various limb muscles during gait. The activity of the hamstrings at end swing may be partially due to stretch reflexes of these muscles. At end stance the hamstring activity may be assisted by reflexes from natural skin activation from the dorsum of the foot. In addition, more specific actions are also incorporated. For example, sural nerve stimulation induces an activation of biceps femoris (BF) whereas a suppression is usually obtained for semitendinosus (ST), indicating that the induced activation is aimed at exorotation of the lower leg. Similarly, the preferential activation of medial versus lateral gastrocnemius (GM versus GL) in sural nerve induced reflexes could favor such exorotation. It is concluded that the present evidence points towards a possible contribution of various reflexes to the motor output seen during gait for movements both inside and outside the sagittal plane. PMID- 10099961 TI - Factors influencing the variable incidence of Y chromosome microdeletions in infertile patients. PMID- 10099962 TI - Surrogacy--a case for normalization. PMID- 10099963 TI - Money, morals and medical risks: conflicting notions underlying the recruitment of egg donors. PMID- 10099964 TI - The lipoprotein profile of women with hyperprolactinaemic amenorrhoea. AB - The aim of this study was to evaluate the lipoprotein profile in women with hyperprolactinaemic amenorrhoea and to establish whether effective dopamine agonist therapy might have a beneficial effect. Blood samples were collected from women with hyperprolactinaemic amenorrhoea and from controls matched for age, body mass index and smoking. Follow-up blood samples were collected from women on dopamine agonist therapy as treatment for their hyperprolactinaemia. Plasma cholesterol, high density lipoprotein cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein cholesterol, triglycerides, serum oestradiol and prolactin were measured. No statistically significant differences were found in the lipoprotein profile of the patient (n = 15) and control (n = 15) groups. During treatment with the dopamine agonist, bromocriptine (n = 9), significant reduction in total cholesterol [4.87 (3.98-5.87) versus 5.60 (4.55 6.61) mmol/l, P = 0.024] and LDL cholesterol [3.22 (2.01-4.23) versus 3.72 (2.59 4.93) mmol/l, P = 0.033] was noted. We conclude that beneficial alterations in the lipoprotein profile may occur in response to effective dopamine agonist therapy, presumably as a consequence of return of ovarian function and alleviation of oestrogen deficiency. Women with hyperprolactinaemic amenorrhoea should be encouraged to take effective therapy to improve their lipoprotein profile and potentially reduce their cardiovascular risk. PMID- 10099965 TI - A comparison of three gonadotrophin-releasing hormone analogues in an in-vitro fertilization programme: a prospective randomized study. AB - The use of gonadotrophin-releasing hormone analogues (GnRHa) has resulted in improved pregnancy rates in in-vitro fertilization (IVF) treatment cycles. Traditionally, short-acting analogues have been employed because of concerns over long-acting depot preparations causing profound suppression and luteal phase defects adversely affecting pregnancy and miscarriage rates. We randomized 60 IVF patients to receive a short-acting GnRHa, nafarelin or buserelin, or to receive a depot formulation, leuprorelin, all commenced in the early follicular phase and compared their effects on hormonal suppression and clinical outcome. We found that on day 15 of administration there was a significant difference in the suppression of oestradiol from initial concentrations, when patients on buserelin were compared with patients on nafarelin or leuprorelin (54 versus 72 and 65%; P < 0.05) and also in the number of patients satisfactorily suppressed, (80 versus 90 and 90%; P < 0.05), though there were no differences between the analogues by day 21. Similarly there was no difference in hormonal suppression during the stimulation phase or in implantation, pregnancy or miscarriage rates in comparing the three agonists. We conclude that with nafarelin and leuprorelin, stimulation with gonadotrophins may begin after 2 weeks of suppression and that long-acting GnRHa are as effective as short-acting analogues with no detrimental effects on the luteal phase. PMID- 10099966 TI - High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by 'prolonged coasting' of very hyperstimulated patients: a multicentre study. AB - In a multicentre trial, 65 in-vitro fertilization (IVF)-embryo transfer cycles were severely hyperstimulated. Instead of cancelling the cycle, gonadotrophins were withheld for a 'coasting period' until serum oestradiol concentrations had dropped below 10,000 pmol/l (mean 4.3 days), and then human chorionic gonadotrophin was administered. Four cycles were cancelled and there were 61 oocyte aspirations. A total of 103 fresh embryos was transferred to 53 patients, resulting in a pregnancy rate of 42% per started cycle (51% per embryo transfer), with an implantation rate of 31%. Only one patient developed severe ovarian hyperstimulation syndrome (OHSS). Four patients developed moderate OHSS. In all, two patients were hospitalized for OHSS. In order to optimize the coasting procedure, it seems important that each IVF centre identifies its appropriate cut off limits for serum oestradiol concentrations and follicle size for initiating and ending of the coasting period. Correctly handled, it seems to be a major advance in the search for improved stimulation policies for high-responders. PMID- 10099968 TI - Effect of antenatal dexamethasone therapy on maternal plasma human chorionic gonadotrophin, oestradiol and progesterone. AB - The aim of this study was to determine whether the current regimen of dexamethasone administration to induce fetal lung maturation affected the circulating concentrations of placental hormone. A standard regimen of dexamethasone that comprised two doses of 12-mg intramuscular injections, 12 h apart was administered to 12 pregnant women to promote fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation. Blood samples were collected before starting the dexamethasone therapy, 24 h, and 48 h after completing therapy for the measurement of the plasma concentrations of human chorionic gonadotrophin (HCG), oestradiol and progesterone. There was a progressive fall in the plasma concentrations of HCG following dexamethasone therapy (P = 0.049 and P = 0.034, 24-h and 48-h post therapy respectively). There was an initial fall in the plasma concentrations of oestradiol after dexamethasone therapy (z = 3.059; P = 0.002, 24-h post therapy), which recovered by 48 h (P = 0.239). There was no difference between the plasma concentrations of progesterone at the three time points. The effect of dexamethasone on HCG concentrations suggests that it has a direct inhibitory effect on placental hormone synthesis or secretion. Further studies are needed to define the mechanism of action of dexamethasone on placental HCG production. PMID- 10099967 TI - Evaluation of hypothalamic-pituitary-adrenal axis in amenorrhoeic women with insulin-dependent diabetes. AB - Diabetes is associated with a higher incidence of secondary hypogonadotrophic amenorrhoea. In amenorrhoeic women with insulin-dependent diabetes a derangement in hypothalamic-pituitary-ovary axis has been proposed. No data exist on hypothalamic-pituitary-adrenal function in these women. Gonadotrophin releasing hormone (GnRH), corticotrophin releasing hormone (CRH), metoclopramide and thyroid releasing hormone (TRH) tests were performed in 15 diabetic women, eight amenorrhoeic (AD) and seven eumenorrhoeic (ED). Frequent blood samples were taken during 24 h to evaluate cortisol plasma concentrations. There were no differences between the groups in body mass index, duration of diabetes, insulin dose and metabolic control. The AD women had lower plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, oestradiol, androstenedione and 17-hydroxyprogesterone (17-OHP) than the ED women. The responses of pituitary gonadotrophins to GnRH, and of thyroid stimulating hormone (TSH) to TRH, were similar in both groups. The AD women had a lower prolactin response to TRH and metoclopramide, and lower ACTH and cortisol responses to CRH, than the ED women. Mean cortisol concentrations > 24 h were higher in the amenorrhoeic group. Significant differences in cortisol concentrations from 2400 to 1000 h were found between the two groups. Insulin-dependent diabetes may involve mild chronic hypercortisolism which may affect metabolic control. Stress induced activation of the hypothalamic-pituitary-adrenal axis would increase hypothalamic secretion of CRH. This would lead directly and perhaps also indirectly by increasing dopaminergic tonus to inhibition of GnRH secretion and hence hypogonadotrophic amenorrhoea. Amenorrhoea associated with metabolically controlled insulin-dependent diabetes is a form of functional hypothalamic amenorrhoea that requires pharmacological and psychological management. PMID- 10099970 TI - Inhibitory effect of plasma obtained from hypophysectomized and control women on the assay of bioactive luteinizing hormone. AB - The purpose of this study was to determine the effect of components of female plasma on the value of bioactive luteinizing hormone (LH), especially in the presence of low immunological LH value. Using both an immunoradiometric assay (IRMA) and rat Leydig cell bioassay, immunoreactive (I) and bioactive (B) LH were assessed in plasma collected from women during a gonadotrophin releasing hormone (GnRH) test performed on day 7 of a spontaneous cycle. Two modes of response to an acute administration of GnRH were defined: normal production of gonadotrophins (group I) and excessive secretion (group II) associated with a significant difference in the B/I-LH ratio between the two groups. The B/I-LH ratio did not vary with sampling time during the test in either group. The addition of LH-free plasma collected from hypophysectomized women caused a 30% decrease in testosterone production compared to control values (in the presence or absence of hLH standard). A partial restoration of testosterone production was observed if plasma was first treated with PEG 12%. The inhibitory factor(s) was also present in plasma from ovulatory women, even after treatment by an antibody against the entire LH molecule. The effect of normal (A) or low I-LH plasma (B) on testosterone production varied strongly according to the plasma volume added to the bioassay, as well as to plasma treatments. Diethylether treatment caused a 50% decrease in testosterone secretion for plasma B (but not for A) whereas a diminution of the steroidogenesis is observed after a PEG treatment of plasma A (but not for B), suggesting that different inhibitory factors are present in plasmas A and B. Therefore the LH bioactivity measured in the rat Leydig cell assay, in terms of testosterone output, seems to represent a balance between the LH molecule and the presence of inhibitory factors in the plasma. PMID- 10099969 TI - The contributions of oestrogen and growth factors to increased adrenal androgen secretion in polycystic ovary syndrome. AB - Adrenal hyperandrogenism is prevalent in many women with polycystic ovary syndrome (PCOS), although the expression of this enhanced secretion may be heterogeneous. Since no single factor acts in isolation, this study was performed to assess the influence of oestradiol (total and unbound), insulin, insulin-like growth factor (IGF)-I, IGF-II and the binding proteins IGFBP-I, and IGFBP-3, on basal and adrenocorticotrophic hormone (ACTH) stimulated adrenal androgen secretion in 25 women with PCOS and 10 matched ovulatory controls. Women with PCOS exhibited elevations of all androgens as well as unbound oestradiol, insulin and non-IGFBP-1 bound IGF-I. Positive correlations were noted between oestrogen and basal and ACTH stimulated delta 5 adrenal androgens. Serum IGF-I was only correlated with basal dehydroepiandrosterone sulphate (DHEA-S), while insulin exhibited a strong correlation with the delta 4 pathway and androstenedione formation in particular. This correlation was also confirmed by dividing the PCOS group into those women with and without hyperinsulinaemia. The activity of 17,20 lyase favouring androstenedione was increased in the hyperinsulinaemic women. By multivariate analyses, body mass index did not influence these findings. Although there are inherent difficulties in making major conclusions based on correlative analyses, it is suggested that oestrogen may have a greater influence on enhancing delta 5 adrenal androgen secretion, and insulin a greater effect on the delta 4 pathway. In turn, the relative importance of these influences may contribute to the heterogeneous nature of adrenal hyperandrogenism in PCOS. PMID- 10099971 TI - Subfertile men with constitutive chromosome abnormalities do not necessarily refrain from intracytoplasmic sperm injection treatment: a follow-up study on 75 Dutch patients. AB - A follow-up study was performed to investigate the impact of the detection of a chromosome abnormality in infertile men who are candidates for intracytoplasmic sperm injection (ICSI) treatment. In this collaborative study between clinical genetics centres and fertility clinics in the Netherlands, 75 ICSI couples of which the male partners had a chromosome abnormality were included. All couples were extensively counselled on the risk of having a chromosomally unbalanced child. Forty-two out of 75 couples chose to proceed with the ICSI treatment. So far, treatment has resulted in a pregnancy in 11 cases. Four of them opted to have invasive prenatal diagnosis. Despite the genetic risks related to a chromosome abnormality in infertile men, a small majority (56%) of the couples did not refrain from the ICSI treatment. PMID- 10099972 TI - Morbidity and cost-effectiveness analysis of outpatient analgesia versus general anaesthesia for testicular sperm extraction in men with azoospermia due to defects in spermatogenesis. AB - The outcome and costs of testicular sperm extraction under outpatient local analgesia or general anaesthesia were compared in men with non-obstructive azoospermia. Nineteen consecutive patients were allocated to receive general anaesthesia, while the subsequent 21 consecutive patients received outpatient analgesia in the form of i.v. midazolam sedation, lignocaine spray, scrotal infiltration with local anaesthetic and spermatic cord block. Blood pressure, pulse rate and respiratory rate were determined. Sedation and testicular pain were assessed by subjective scoring. Both groups showed haemodynamic stability with little alteration in blood pressure, pulse rate and oxygen saturation. Toxic symptoms of local anaesthetic were not encountered in the outpatient group. No relationship was found between testicular size and the duration of the operation. The median postoperative pain intensity, sedation scores and analgesic requirements were significantly less in the outpatient group (P < 0.05). These advantages led to a shorter recovery time (P < 0.0001), 3-fold cheaper care and greater patient satisfaction (P < 0.0001) in the outpatient group. PMID- 10099973 TI - Fertility after laparoscopic management of deep endometriosis infiltrating the uterosacral ligaments. AB - The aim of this study was to evaluate fertility outcome after laparoscopic management of deep endometriosis infiltrating the uterosacral ligaments (USL). From January 1993 to December 1996, 30 patients who presented with no other infertility factors were treated using laparoscopic surgery. The overall rate of intrauterine pregnancy (IUP) was 50.0% (15 patients). Only one of these 15 pregnancies was obtained using in-vitro fertilization techniques (IVF). The cumulative IUP rate for the 14 pregnancies which occurred spontaneously was 48.5% at 12 months (95% confidence interval 28.3-68.7). The rate of spontaneous pregnancies was not significantly correlated with the revised American Fertility Society (rAFS) classification. The rate of IUP was 47.0% (eight cases) for patients with stage I or II endometriosis and 46.1% (six cases) for the patients presenting stage III or IV endometriosis (not significant). These encouraging preliminary results show that in a context of infertility it is reasonable to associate classic treatment for endometriosis (e.g. lysis, i.p. cystectomy, biopolar coagulation of superficial peritoneal endometriotic lesions) with resection of deep endometriotic lesions infiltrating the USL. Apart from the benefit with respect to the pain symptoms from which these patients suffer, it is possible to use laparoscopic surgery with substantial retroperitoneal dissection and enable half of the patients to become pregnant. These results also raise the question of the influence of deep endometriotic lesions on infertility. PMID- 10099974 TI - Gastrointestinal injuries during gynaecological laparoscopy. AB - A retrospective case review study was carried out on gastrointestinal injuries which occur during gynaecological laparoscopy. Fifty-six patients with 62 gastrointestinal injuries were identified. One-third of the complications (32.2%) occurred during the installation phase for laparoscopy. Four of the six complications attributed to electrosurgery were secondary to the use of monopolar coagulation. Diagnosis of these gastrointestinal injuries was made during surgery in only 20 patients (35.7%). The mean time before diagnosis was 4.0 +/- 5.4 (range 0-23) days. Treatment of these complications was performed by laparoscopic surgery in 16.1% of cases. Prevention relies on the surgeon's experience, strict observance of the safety rules, perfect familiarity with the physical properties of the instruments used, systematic use of bowel preparation for patients presenting a risk of bowel complications, systematic supervision of the route taken by the trocars, meticulous inspection on completion of surgery of all areas where bowel adhesiolysis has been used and, in case of any doubt, tests for leakage involving the rectosigmoid. For patients with a risk of bowel complications, the creation of a pneumoperitoneum and performing a mini laparoscopy in the left hypochondrium can be the judicious option. PMID- 10099976 TI - Propofol concentrations in follicular fluid during general anaesthesia for transvaginal oocyte retrieval. AB - Propofol (Diprivan) is an i.v. anaesthetic used for general anaesthesia. The purpose of this study was to measure the propofol concentration in arterial blood and follicular fluid in patients during transvaginal oocyte retrieval. After approval by the University Ethics Committee, 30 women participated in this prospective study. Following induction of anaesthesia with 0.5 mg alfentanil and 2 mg.kg-1 propofol i.v., a continuous infusion of propofol at 10 mg.kg-1.h-1 was used for maintenance of anaesthesia. Follicular fluid and arterial blood samples were aspirated simultaneously at fixed intervals during the surgical procedure and propofol assayed by high pressure liquid chromatography (HPLC). The mean follicular fluid concentration of propofol increased linearly with time from 0.10 +/- 0.02 microgram.ml-1 to 0.57 +/- 0.06 microgram.ml-1 and was strongly related to the cumulative dose of propofol administered. The absorption of propofol was time-dependent. There was no correlation between the concentration of propofol in the follicular fluid and the arterial blood concentration of the drug. In conclusion, a propofol-based anaesthetic technique resulted in significant concentrations of this agent in follicular fluid, related to the dose administered and to the duration of propofol administration. PMID- 10099975 TI - Relaxin secretion by human granulosa cell culture is predictive of in-vitro fertilization-embryo transfer success. AB - We have developed a cell culture system for human luteinizing granulosa cells which supports the timely and dynamic secretion of oestrogen, progesterone and relaxin in patterns that mimic serum concentrations of these hormones during the luteal phase of the menstrual cycle. There was a wide variation in the amount of relaxin secreted by the cultured cells for the 69 patients studied. As relaxin production was generally maximal by day 10 of culture, comparisons were made at this time point. It was observed that most of the conceptions occurred in patients with higher relaxin secretion in vitro. All cycles with relaxin > 800 pg/ml on day 10 had a term pregnancy while only 13% of cycles with relaxin < 200 pg/ml had term pregnancies. A limited number of cycles from donor/recipient cycles did not show similar results. Steroid concentrations were not predictive of conception. These results demonstrated that in-vitro production of relaxin is predictive of implantation success in in-vitro fertilization (IVF)-embryo transfer cycles. This supports the hypothesis that relaxin may be involved in implantation and that lowered relaxin concentrations may be a partial cause of poor pregnancy rates after IVF. PMID- 10099977 TI - The clinical efficacy of low-dose step-up follicle stimulating hormone administration for treatment of unexplained infertility. AB - The present study was designed to compare the clinical efficacy of low-dose step up follicle stimulating hormone (FSH) administration with conventional FSH protocol (FSH was injected daily starting with a dose of 150 IU), both combined with intrauterine insemination (IUI), for the treatment of unexplained infertility. A total of 97 unexplained infertility couples was randomly assigned to one or other of the two treatment groups, either conventional FSH with IUI (48 patients) or low-dose step-up FSH with IUI (49 patients), and only the first treatment cycle was evaluated in each protocol. The difference in pregnancy rates per cycle was not statistically significant between the low-dose FSH group and the conventional group [seven of 49 (14.3%) and seven of 48 (14.6%) respectively]. A significant reduction in the incidence of ovarian hyperstimulation syndrome (OHSS) was observed in the low-dose group (8.3% versus 27.1%, P < 0.05). The incidence of moderate OHSS requiring hospitalization was reduced significantly in the low-dose group (low-dose 0% versus conventional 16.7%, P < 0.01). However, the low-dose protocol did not completely prevent multiple pregnancies. Our results suggest that the low-dose step-up FSH treatment appeared to be useful for the treatment of unexplained infertility because of the high pregnancy rates and the significant decrease in the incidence of OHSS. PMID- 10099978 TI - Oocyte quality and treatment outcome in intracytoplasmic sperm injection cycles of polycystic ovarian syndrome patients. AB - Patients with polycystic ovarian syndrome (PCOS) have higher miscarriage rates. It is postulated that this is caused by a lower rate of mature oocytes, and a lower quality of embryos. Retrospectively we analysed 51 intracytoplasmic sperm injection (ICSI) cycles of 31 PCOS patients. These data were compared to age matched controls (105 cycles) during the same period. All patients of both groups received gonadotrophin-releasing hormone (GnRH) agonists prior to gonadotrophin treatment. The rate of metaphase II oocytes (MII) was not different. However, the mean absolute number of normally fertilized oocytes was significantly higher in PCOS patients (5.00 versus 3.56, P < 0.01), due to a higher number of oocytes retrieved. More embryos were transferred by cycle in the PCOS group (2.69 versus 2.17, P < 0.05), with a higher cumulative embryo score. The overall and multiple pregnancy rate showed no differences and the clinical abortion rate was lower (21 versus 41.67%, P < 0.05) in the controls. Our findings demonstrate that negative factors unconnected to oocyte morphology must be present in PCOS patients. It is possible that only cytoplasmic, not nuclear, maturity is influenced in these patients. PMID- 10099979 TI - Transrectal ultrasonography in the assessment of congenital vaginal canalization defects. AB - Our aim was to evaluate the reliability of transrectal ultrasonography in the preoperative assessment of congenital vaginal canalization defects. We studied nine patients, six with suspected Rokitansky syndrome and three with suspected complete transverse septum. Before corrective surgery all the patients underwent pelvic examination, transabdominal and transrectal ultrasonography. The ultrasonographic findings were compared with the surgical ones. Transrectal ultrasonography provided an accurate map of the pelvic organs showing the precise distances between the urethra and bladder anteriorly, rectum posteriorly, retrohymenal fovea caudally, and pelvic peritoneum cranially. Transrectal ultrasonography produced a picture that corresponded perfectly with the real anatomical situation. Conversely, abdominal ultrasonography provided inadequate images in six of our nine patients, and magnetic resonance imaging was responsible for a mistaken diagnosis in one patient with suspected transverse vaginal septum. In conclusion, if our results are confirmed in larger series, transrectal ultrasonography could be considered as a diagnostic procedure of choice in the assessment of vaginal canalization defects. PMID- 10099980 TI - Comparison between chromatin condensation and morphology from testis biopsy extracted and ejaculated spermatozoa and their relationship to ICSI outcome. AB - A significant association between male subfertility, imperfect spermiation and abnormal nuclear condensation has been suggested. The DNA content of spermatozoa might be responsible for inducing alterations in sperm morphology. The final nuclear shape, which is species-specific, depends on chromatin condensation during spermatogenesis as well as a precise organization of DNA within the nucleus. Many reports have described the association between disturbances in sperm chromatin condensation, morphology and male infertility. Chromatin condensation is achieved by gradual substitution of lysinerich somatic histones by testis-specific histone and finally by protamine. In this study two groups of patients were compared: the first consisted of 63 patients who had undergone intracytoplasmic sperm injection (ICSI) with freshly ejaculated spermatozoa whereas the second included 47 patients assigned to ICSI with testes biopsy extracted spermatozoa. In both groups chromatin condensation was assessed by aniline blue staining and morphology evaluated according to strict criteria. The condensed chromatin and morphology of spermatozoa were significantly (P < 0.0001) less in the second group compared to the first. However the fertilization, cleavage, implantation and pregnancy rates were almost the same in both investigated groups. There was no significant difference between the two groups with respect to ICSI outcome. The percentage of chromatin condensation (nuclear maturity) and morphologically-normal spermatozoa were significantly higher (P < 0.0001) in the ejaculated spermatozoa than in those from testis biopsy but the ICSI outcome (fertilization, cleavage, implantation and pregnancy rates) was the same. In view of these results the fertilization capability and the embryo quality obtained using testis biopsy extracted spermatozoa is not influenced by chromatin condensation and sperm morphology in testicular sperm extraction (TESE) ICSI programmes. Therefore, it could be said that neither chromatin condensation nor morphology of testis extracted sperm could predict the fertilization, implantation and pregnancy rate in TESE-ICSI programmes. PMID- 10099981 TI - Birth of a healthy neonate following the intracytoplasmic injection of testicular spermatozoa from a patient with Klinefelter's syndrome. AB - Klinefelter's syndrome is one of the known causes of azoospermia or cryptoazoospermia, and it may present in non-mosaic (47,XXY) or mosaic (47,XXY/46,XY) form. The likelihood of finding spermatozoa in the ejaculate or testicular tissue of patients with mosaic Klinefelter's syndrome is low, and with the non-mosaic form, even lower. We describe a patient with non-mosaic Klinefelter in whom initially non-motile spermatozoa were derived from searching the ejaculate. Ten mature oocytes were injected, but none was fertilized. Subsequently, testicular biopsy was undertaken in order to collect spermatozoa for oocyte injection. Fifteen motile sperm cells were found and injected. Nine oocytes were fertilized and cleaved; three embryos were transferred into the uterine cavity. The woman conceived and following a normal pregnancy delivered a healthy child. Genetic analysis of the neonate disclosed a normal 46,XY karyotype. Non-motile spermatozoa in the ejaculate did not prove their fertilization potential, but their presence did not exclude finding motile, fertile spermatozoa in the testicular tissue in a non-mosaic Klinefelter patient. This report is further evidence that normal spermatozoa with fertilization potential are produced in the testes of patients with Klinefelter's syndrome. PMID- 10099982 TI - The complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data. AB - Congenital bilateral absence of the vas deferens (CBAVD) is found in 1-2% of infertile males and in most male cystic fibrosis (CF) patients. CF and some of the CBAVD cases were found to share the same genetic background. In this study, 21 males with CBAVD had extensive physical and laboratory testing for symptoms of CF. Possible defective cellular chloride transport was measured by interstitial current measurement of rectal suction biopsies. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis was performed for 10 common CFTR mutations. CF-related symptoms were found in six men. On laboratory testing slightly abnormal liver and pancreatic function was found in seven patients. The sweat test was found to be abnormal in four patients; interstitial current measurement showed defective chloride excretion in 11 patients. CFTR gene mutations were found in 66% of the patients: eight were compound heterozygotes; in six, only one common mutation could be detected. The 5T allele in one copy of intron 8 was found in four men. CBAVD appears to be a heterogeneous clinical and genetic condition. A CFTR gene mutation was found in both copies of the allele or interstitial current measurement showed defective chloride excretion in 14/21 cases. Genetic counselling is clearly indicated for couples seeking pregnancy through epididymal or testicular sperm aspiration and intracytoplasmic sperm injection. PMID- 10099983 TI - Meiotic abnormalities and spermatogenic parameters in severe oligoasthenozoospermia. AB - The incidence of meiotic abnormalities and their relationship with different spermatogenic parameters was assessed in 103 male patients with presumably idiopathic severe oligoasthenozoospermia (motile sperm concentration < or = 1.5 x 10(6)/ml). Meiosis on testicular biopsies was independently evaluated by two observers. Meiotic patterns included normal meiosis and two meiotic abnormalities, i.e. severe arrest and synaptic anomalies. A normal pattern was found in 64 (62.1%), severe arrest in 21 (20.4%) and synaptic anomalies in 18 (17.5%). The overall rate of meiotic abnormalities was 37.9%. Most (66.7%) meiotic abnormalities occurred in patients with a sperm concentration < or = 1 x 10(6)/ml. In this group, total meiotic abnormalities were found in 57.8% of the patients; of these, 26.7% had synaptic anomalies. When the sperm concentration was < or = 0.5 x 10(6)/ml, synaptic anomalies were detected in 40% of the patients. In patients with increased follicle stimulating hormone (FSH) concentrations, total meiotic abnormalities occurred in 54.8% (synaptic anomalies in 22.6%). There were statistically significant differences among the three meiotic patterns in relation to sperm concentration (P < 0.001) and serum FSH concentration (P < 0.05). In the multivariate analysis, sperm concentration < or = 1 x 10(6)/ml and/or FSH concentration > 10 IU/l were the only predictors of meiotic abnormalities. PMID- 10099984 TI - Flow cytometry isolation and reverse transcriptase-polymerase chain reaction characterization of human round spermatids in infertile patients. AB - Flow cytometry coupled to cell sorting is proposed as a method to isolate round spermatids from testicular biopsies in obstructive azoospermic patients. The cells were separated on the basis of their size and density only. We obtained homogenous populations of alive round spermatids free of lymphocytes and diploid germ cells. The detection of protamine 1 gene (PRM1) and PRM2 expression in the sorted cells proves that these cells are round spermatids. On the contrary, neither the expression of CD3-delta, which is specific to lymphoid cells, nor that of MAGE1, which has been demonstrated in diploid germ cells, could be observed in the round spermatid population even after using a nested polymerase chain reaction (PCR) assay. The flow cytometry procedure failed to isolate round spermatids from ejaculates in non-obstructive azoospermic patients. In > 39 ejaculates tested by reverse transcriptase-PCR, only nine revealed the presence of some round spermatids, as demonstrated by the expression of PRM1. However, these round spermatids did not express PRM2. PMID- 10099985 TI - Flow cytometric method to isolate round spermatids from mouse testis. AB - The purpose of this study was to isolate pure populations of round spermatids from mouse testis by flow cytometry followed by cell sorting. Cell suspensions from mouse testis were enriched in germ cells by centrifugation on a discontinuous Percoll gradient, then analysed using a FACScalibur flow cytometer measuring the cell size and density. A large and well-delimited population of cells (R1) expected to contain round spermatids was observed on the dot plot diagram. Sorted R1 cells were very homogeneous in size (approximately 11 microns) and displayed the characteristic cytological aspect of round spermatids. Spermatid-specific gene expression was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) analysis of R1 cells using primers for protamine 2 gene (PRM2) and SP-10. A positive signal for SP-10 was obtained with a single cell using nested primers. The 5.5 kb transcript of c-kit, which is not expressed in spermatids, was not detected by nested RT-PCR, excluding a contamination with spermatogonia. Our results clearly established that flow cytometry followed by cell sorting allows the isolation of a highly homogeneous population of round spermatids from the testis. PMID- 10099986 TI - Induction of macrophage migration inhibitory factor in human ovary by human chorionic gonadotrophin. AB - The role of macrophage migration inhibitory factor (MIF) in human ovarian function remains obscure. The aim of this study was to investigate how MIF was related to ovulation by quantitative analysis of serum, follicular fluid and culture medium of granulosa cells obtained from in-vitro fertilization (IVF) and embryo transfer patients. Serum MIF concentrations in ovarian stimulation cycles for IVF-embryo transfer were higher at day 1 (median 92.6 ng/ml), which took place 35 h after human chorionic gonadotrophin (HCG) administration and just before the retrieval of oocytes, than those before day -6 (12.1 ng/ml), at day -5 to about day 0 (17.5 ng/ml) or at day 2 to about day 14 (8.2 ng/ml). MIF concentrations in the follicular fluid (113.4 ng/ml) obtained in ovarian stimulation cycles for IVF-embryo transfer were significantly higher than in serum (72.0 ng/ml) collected at the same time. MIF concentrations in the follicular fluid in natural cycles were higher in the ovulatory phase (51.6 ng/ml) than in the late follicular phase (13.8 ng/ml). MIF concentrations in the culture media of granulosa cells increased from 3.2 ng/ml to 7.2 ng/ml with HCG stimulation, and decreased from 2.4 ng/ml to 1.2 ng/ml when stimulation was withheld. These results indicate that HCG can induce the elevation of serum and follicular fluid MIF concentrations through the stimulation of ovarian cells, and that MIF is probably involved in the mechanism of ovulation. PMID- 10099987 TI - Vitrification of mouse germinal vesicle oocytes: effect of treatment temperature and egg yolk on chromatin and spindle normality and cumulus integrity. AB - The success rates for cryopreservation of immature oocytes from several species including human remain low, in contrast to major improvements with mature oocytes. In this study, a new approach has been developed using a short exposure ultra-rapid freezing protocol, examining the effect of temperature and egg yolk (two factors which may be expected to influence membrane flexibility) on the cryostability of immature mouse oocytes and cumulus complexes. These two factors were tested in various patterns for their cryoprotective effect using ethylene glycol as the principal cryoprotectant. The results showed that 37 degrees C pre- and post-freeze exposure significantly improved both survival and normal spindle configuration after in-vitro maturation. Egg yolk was found to produce further beneficial effects on both the oocyte and cumulus cell integrity, with the best effects being obtained at 37 degrees C with inclusion of egg yolk both before and after the freezing. This protocol produced > 80% normal survival post-thaw with intact and attached cumulus complex, 84% maturation rate and 45% normal metaphase configuration. In summary, a unique combination of high survival and meiotic normality together with good preservation of the attached cumulus cell mass has been achieved using a simple new vitrification procedure. PMID- 10099988 TI - Inhibin A and inhibin B reflect ovarian function in assisted reproduction but are less useful at predicting outcome. AB - To test the hypothesis that dimeric inhibin A and/or inhibin B concentrations represent improved markers of in-vitro fertilization (IVF) outcome over follicle stimulating hormone (FSH), 78 women who achieved pregnancy within three assisted reproduction treatment cycles were matched to 78 women who underwent at least three assisted reproductive treatment cycles and failed to achieve pregnancy. Baseline serum inhibin B and FSH were obtained between days 1 and 4 in a cycle prior to ovarian stimulation, and inhibin A and B were measured immediately before the ovulatory stimulus and in follicular fluid from the lead follicle. Comparing pregnant and non-pregnant subjects at baseline, younger age (34.0 +/- 0.5 versus 36.0 +/- 0.5 years; P < 0.003) and a combination of FSH lower than the median value (11.2 IU/l) and inhibin B higher than the median value (76.5 pg/ml) were associated with pregnancy (P < 0.03), but FSH (11.7 +/- 0.5 versus 12.9 +/- 0.9 IU/ml) and inhibin B (89.0 +/- 10.2 versus 79.7 +/- 7.7 pg/ml) were not independently associated. At the time of the ovulatory stimulus, serum inhibin A (52.8 +/- 3.8 versus 40.0 +/- 2.7 IU/ml; P < 0.004), inhibin B (1623.8 +/- 165.1 versus 859.2 +/- 94.8 pg/ml; P < 0.0009) and the number of oocytes retrieved (14.6 +/- 0.8 versus 10.1 +/- 0.6; P < 0.0001) were predictive of pregnancy when controlled for age. Inhibin A was correlated with the number of embryos (r = 0.4; P < 0.0001). However, neither inhibin A nor inhibin B provided additional information in predicting successful outcome over age and number of oocytes. We conclude that: (i) in patients undergoing assisted reproductive technology, age and number of oocytes retrieved are the strongest predictors of success; (ii) of the parameters available prior to cycle initiation, a combination of lower FSH and higher inhibin B was associated with a greater chance for a successful outcome but an absolute cut-off could not be defined; and (iii) during ovarian stimulation, higher concentrations of inhibin A and inhibin B in serum are associated with successful IVF and mark ovarian reserve as a measure of oocyte number and quality. PMID- 10099989 TI - Hyperreactio luteinalis associated with chronic renal failure. AB - Hyperreactio luteinalis is a rare benign condition characterized by bilateral ovarian enlargement associated with pregnancies where high concentrations of maternal serum human chorionic gonadotrophins are present. This condition may mimic the ovarian hyperstimulation syndrome. We report a case of a 34 year old woman with a history of chronic renal failure on haemodialysis who presented at 10 weeks' gestational age with hyperreactio luteinalis which was treated conservatively. Because of chronic renal failure, the presentation and course of the disease was different from that which has been previously reported. PMID- 10099990 TI - Species specificity of human and murine anti-ZP3 synthetic peptide antisera and use of the antibodies for localization and identification of ZP3 or ZPC domains of functional significance. AB - The mammalian zona pellucida has an important function in the fertilization process. The zona pellucida protein 3 (ZP3 or ZPC) is the ligand for primary sperm binding and induces the acrosome reaction. In various species, ZP3 primary structures are highly conserved as revealed by cDNA cloning. The objective of these studies was to localize ZP3 protein using antisera generated against defined synthetic peptides that are specific for mouse or for human ZP3. Immunohistochemistry and transmission electron microscopy were applied to murine and human ovary sections. Immunochemical studies were performed in hemizonae pellucidae from microbisected human oocytes. Using the competitive hemizona assay and various anti-ZP3 antibodies, we further intended to identify human ZP3 epitopes of functional significance. Our results showed that antiserum AS ZP3-9 (mouse specific) detected mouse ZP3 protein in mouse oocytes and in immunoblots, whereas AS ZP3-14 (human specific) detected human ZP3 protein in human ovary sections, native hemizonae pellucidae and in immunoblots. ZP3 material was also detected in cumulus cells by immunohistochemistry. Ultrastructural studies showed an equal distribution of ZP3 throughout the zona pellucida. The human competitive hemizona assay revealed that none of the anti-ZP3 synthetic peptide antisera affected sperm binding suggesting that those epitopes are not involved in primary sperm binding. Anti-porcine ZP3 beta protein antibodies (polyclonal) blocked human sperm-zona pellucida binding. In summary, these anti-ZP3 synthetic peptide antibodies specifically reacted with intact ZP3 protein (murine and human) but did not inhibit human sperm-zona pellucida binding; anti-ZP3 antibodies can therefore be used as biomarkers for ZP3 localization and function. PMID- 10099991 TI - Temporal and spatial aspects of fragmentation in early human embryos: possible effects on developmental competence and association with the differential elimination of regulatory proteins from polarized domains. AB - This study examined the relationship between blastomere fragmentation in cultured human embryos obtained by in-vitro fertilization and the effect of fragmentation on the distribution of the following eight regulatory proteins found to be: (i) localized in the mature oocyte in subplasmalemmal, polarized domains; and (ii) unequally inherited by the blastomeres during cleavage: leptin, signal transducer and activator of transcription 3 (STAT3), Bax, Bcl-x, transforming growth factor beta 2 (TGF beta 2), vascular endothelial growth factor (VEGF), c-kit and epidermal growth factor R (EGF-R). Four basic patterns of fragmentation were observed. The severity of the impact of each type of fragmentation on the affected blastomere(s) and the developmental competence of the embryo appeared to be a function of the unique temporal and spatial features associated with the particular fragmentation pattern(s) involved in each instance. The findings demonstrate that certain patterns of fragmentation can result in the partial or near total loss of the eight regulatory proteins from specific blastomeres and that the developmental potential of the affected embryo can be particularly compromised if it occurs during the 1- or 2-cell stages. In contrast, fragmentation from portions of a fertilized egg or a blastomere(s) in a 2-cell embryo that do not contain the protein domains, or the complete loss by fragmentation of a regulatory protein domain-containing blastomere after the 4 cell stage does not necessarily preclude continued development to the blastocyst, although the normality and developmental potential of the embryo may be compromised. The possible association between fragmentation and apoptosis was examined by annexin V staining of plasma membrane phosphatidylserine and TUNEL analysis of blastomere DNA. No direct correlation between fragmentation and apoptosis was found following the analyses of fragmented embryos with these two markers. However, while we suggest that changes in cell physiology unrelated to apoptosis are the more likely causes of fragmentation, we cannot exclude the possibility that fragmentation itself may be an initiator of apoptosis if critical ratios or levels of developmentally important proteins are altered by partial or complete elimination of their polarized domains. The findings are discussed with respect to the possible developmental significance of regulatory protein polarization in human oocytes and preimplantation stage embryos. PMID- 10099992 TI - The usefulness of a piezo-micromanipulator in intracytoplasmic sperm injection in humans. AB - Intracytoplasmic sperm injection (ICSI) has wide clinical application. In order to achieve good results with this method, it is important to restrict the possibility of oocyte injury as much as possible, and securely inject spermatozoa into the ooplasm. For this purpose, we clinically applied piezo-ICSI, which employs a micromanipulator with piezoelectric elements, to humans, and compared the results with those obtained by conventional ICSI. Conventional ICSI and piezo ICSI were used in 279 cycles and 335 cycles respectively. Piezo-ICSI showed significantly more favourable results, with a survival rate of 88.1% (conventional ICSI: 81.4, P < 0.001), a fertilization rate of 79.4% (conventional ICSI: 66.4%, P < 0.001), and a pregnancy rate of 23.1% (conventional ICSI: 14.9%, P < 0.05). In piezo-ICSI, the needle used is not sharpened and has a flat tip. However, deformation of the oocyte during insertion of the needle is restrained by vibration of the piezo, and the oolemma is punctured readily and securely by the piezo pulse, at the site where the spermatozoon is injected. Piezo-ICSI is a promising new technique for human ICSI that should improve the survival, fertilization and pregnancy rates after ICSI. PMID- 10099993 TI - Preliminary clinical experience with human blastocyst development in vitro without co-culture. AB - This preliminary analysis was designed to quantify blastocyst development of supernumerary embryos without the use of feeder cells, conditioned medium or whole serum. Embryos derived from in-vitro fertilization (IVF) that were not transferred or cryopreserved were included in this study. Ova were harvested for IVF after a standard ovarian stimulation with gonadotrophin-releasing hormone agonist/ human menopausal gonadotrophin (GnRHa/HMG) or follicle-stimulating hormone (FSH). Ova were collected and culture in 150 microliters droplets of P1 medium under mineral oil, in groups at 37 degrees C under 5% CO2, 5% O2, 90% N2 (group A) or under 5% CO2 in air (group B) environment. Embryo transfer was performed 72 h post-harvest. Viable embryos not transferred or cryopreserved were placed in blastocyst medium and cultured for an additional 48 h in 5% CO2 in air. Embryos that exhibited an expanded blastocoelic cavity and well-defined inner cell mass at 120 h were counted. Of 838 supernumerary embryos cultured, 448 (53.5%) reached the expanded blastocyst stage by 120 h of culture. Patients were given the option of cryopreservation at that time. The embryos were cryopreserved using a standard protocol with serial addition of glycerol. Embryos reaching the blastocyst stage after more than 120 h of culture were not included. There was no difference in the proportions of blastocyst development between group A, 217/410 (53.5%) and group B, 231/428 (54%). To date, 16 patients have each had up to three thawed blastocysts transferred, out of whom seven became pregnant. This report demonstrates that a simple system of sequential culture generated acceptable, viable blastocyst development (54%) with supernumerary embryos, without the use of feeder cells, conditioned medium or whole serum. Recognizing the differential metabolic requirements of early and late cleavage stage embryos has enabled the application of a glucose/phosphate-free simple culture medium (P1) for up to 72 h of culture and a complex, glucose-containing medium (blastocyst medium) for subsequent blastocyst development. PMID- 10099994 TI - Development of in-vitro-derived bovine embryos cultured in 5% CO2 in air or in 5% O2, 5% CO2 and 90% N2. AB - To evaluate the effects of a three gas mixture of 5% O2, 5% CO2 and 90% N2 (OCN) on preimplantation embryo development, bovine in-vitro fertilization (IVF) oocytes were cultured in a defined medium (mBECM) with various supplements either under 5% CO2 in air or under OCN. When cultured in mBECM alone, embryo development was significantly stimulated in OCN compared to 5% CO2 in air (experiment 1). In the OCN atmosphere, blastocyst formation was further increased after addition of fetal bovine serum (FBS; 10%) or FBS + cumulus granulosa cells (CGC) to mBECM. The ratio of blastocysts to 8-cell embryos, number of hatched blastocysts and embryo diameter were markedly increased, and zona thickness was decreased after FBS addition. However, development up to the morula stage was fully supported by mBECM alone. There was no significant effect of beta mercaptoethanol (ME; 10 microM) in OCN. In the 5% CO2 atmosphere, embryo development was significantly (P < 0.05) enhanced after addition of FBS + CGC + ME. In experiment 2, in OCN, FBS added at 60 h post-insemination was effective in stimulating blastocyst formation, but changes in medium volume per oocyte from 13.6 to 1.36 microliters had only a marginal effect. In conclusion, OCN gas mixture provides a suitable atmosphere for early embryo growth in vitro and mBECM + FBS in the optimal culture medium under this atmosphere. PMID- 10099995 TI - Effect of oxygen concentration on human in-vitro fertilization and embryo culture. AB - In this prospective randomized study on 1380 consecutive in-vitro fertilization (IVF) treatments, the results were compared of culture of human oocytes and embryos for the first 2 or 3 days of development in microdroplets of medium under oil using a gas phase containing either atmospheric (approximately 20%) or reduced (5%) O2 concentrations. No significant differences were found between the two groups cultured under either 5% or 20% O2 in rates of fertilization (60 versus 61%, respectively), embryo development at day 2 or 3, pregnancy (26.6 versus 25.4%, respectively), and implantation (13.4 versus 14.0%, respectively). Culture of surplus embryos under 5% O2 resulted in a significantly higher mean incidence of blastocyst formation per cycle as compared to the 20% O2 group (25.8 +/- 2.0 versus 20.4 +/- 1.9, respectively). The mean number of cells of embryos classified as blastocysts by microscopic observation of a blastocoel was significantly higher in the 5% O2 group as compared to the 20% O2 group, both in blastocysts fixed on day 5 (39.8 +/- 1.7 versus 31.9 +/- 1.9, respectively), as well as those fixed on day 6 (45.6 +/- 2.6 versus 33.7 +/- 3.4, respectively). This difference was due to the fact that significantly more blastocysts of the 20% O2 group had an abnormal low cell number of < 25 as compared to the 5% O2 group, both in blastocysts fixed on day 5 (39 versus 22%, respectively), as well as those fixed on day 6 (43 versus 22%, respectively). To conclude, although culture under 5% O2 leads to slightly improved preimplantation embryonic viability, this effect is either too marginal to result in higher pregnancy rates, or low O2 concentrations exert an effect during the later stages of preimplantation development only. PMID- 10099996 TI - Rapid visualization of metaphase chromosomes in single human blastomeres after fusion with in-vitro matured bovine eggs. AB - The present study was aimed to facilitate karyotyping of human blastomeres using the metaphase-inducing factors present in unfertilized eggs. A rapid technique for karyotyping would have wide application in the field of preimplantation genetic diagnosis. When cryopreserved in-vitro matured bovine oocytes were fused with human blastomeres, the transferred human nuclei were forced into metaphase within a few hours. Eighty-seven human blastomeres from abnormal or arrested embryos were fused with bovine oocytes in a preclinical study. Fusion efficiency was 100%. In 21 of the hybrid cells, no trace of human chromatin was found. Of the remaining 66, 64 (97%) yielded chromosomes suitable for analysis. The method was used to karyotype embryos from two patients with maternal translocations. One embryo which was judged to be karyotypically normal was replaced in the first patient, resulting in one pregnancy with a normal fetus. None of the second patient's embryos was diagnosed as normal, and hence none was transferred. The results of the present study demonstrated that the ooplasmic factors which induce and maintain metaphase in bovine oocytes can force transferred human blastomere nuclei into premature metaphase, providing the basis for a rapid method of karyotyping blastomeres from preimplantation embryos and, by implication, cells from other sources. PMID- 10099997 TI - Intracytoplasmic sperm injection into zona-free human oocytes results in normal fertilization and blastocyst development. AB - Zona-free human oocytes are frequently encountered in in-vitro fertilization (IVF) laboratories. The oocytes escape out of the zona pellucida, following zona fracture, which can occur during oocyte retrieval or manipulation, but occasionally may be the result of increased zona fragility. Some of the zona-free oocytes are mature and morphologically healthy; nevertheless, all are typically discarded. In this report, we demonstrate that zona-free oocytes can be fertilized normally using intracytoplasmic sperm injection (ICSI) and can subsequently develop without zona to the blastocyst stage in vitro. We therefore suggest that those mature and morphologically normal zona-free oocytes may be rescued, fertilized with ICSI and then cultured to the blastocyst stage for subsequent transfer or cryopreservation. PMID- 10099998 TI - Regression of endometrial hyperplasia after treatment with the gonadotrophin releasing hormone analogue triptorelin: a prospective study. AB - Endometrial hyperplasia is thought to be caused by the prolonged, unopposed oestrogenic stimulation of the endometrium. The regression of hyperplastic back to normal endometrium is the main purpose of any conservative treatment in order to prevent development of adenocarcinoma. The aim of this study was to evaluate the regression of hyperplastic to normal endometrium in patients with various forms of endometrial hyperplasia after treatment with the gonadotrophin-releasing hormone analogue (GnRHa) triptorelin for 6 months. Fifty-six patients with endometrial hyperplasia were enrolled in this trial; 39 patients (group I) presented simple hyperplasia, 14 (group II) complex hyperplasia and three (group III) atypical complex hyperplasia. All patients were treated with triptorelin for 6 months. Bleeding control during treatment was excellent. A post-treatment curettage for estimation of endometrial histology was performed on 54 out of 56 patients 100.1 +/- 44.7 days after the last triptorelin dose, following the restoration of pituitary function. Regression of hyperplastic to normal endometrium was observed in 32 (86.5%) out of 37 patients in group I and in 12 (85.7%) out of 14 in group II. Persistence of simple hyperplasia was found in five (14.5%) out of 37 patients in group I. Persistence of complex hyperplasia was found in 1 (7.1%) out of 14 patients and progression to atypical complex hyperplasia in another one (7.1%) woman in group II. In some of these cases, the presence of risk factors such as obesity, diabetes mellitus and ovulatory disturbances may contribute to the disease persistence despite therapy. On the other hand, in group III, none of the three patients had normal post-treatment endometrial histology. It seems, therefore, that in cases of endometrial hyperplasia without atypia, the administration of the GnRHa triptorelin is associated with high regression rates to normal endometrium. Conversely, the presence of atypia seems to be a poor prognostic factor. Treatment tolerance and bleeding control during therapy is excellent. PMID- 10099999 TI - Once-a-month treatment with a combination of mifepristone and the prostaglandin analogue misoprostol. AB - In this two centre study, the efficacy of 200 mg mifepristone orally followed 48 h later by 0.4 mg misoprostol orally for menstrual regulation was investigated. The dose of mifepristone was taken the day before the expected day of menstruation. Each volunteer was planned to participate for up to 6 months. A plasma beta human chorionic gonadotrophin (HCG) was measured on the day of mifepristone intake. The study was disrupted prematurely due to low efficacy. In 125 treatment cycles the overall pregnancy rate was 17.6% (22 pregnancies) and the rate of continuing pregnancies (failure) was 4.0%. Eight women discontinued the study due to bleeding irregularities which were seen in 15 cycles (12%). These effects on bleeding pattern made the timing of treatment day difficult. Late luteal phase treatment with a combination of mifepristone and misoprostol is not adequately effective for menstrual regulation. PMID- 10100000 TI - Low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome. AB - The present study was designed to investigate the effects of immunoglobulin G obtained from patients with antiphospholipid syndrome (APS) on in-vitro models of trophoblast invasiveness and differentiation. We tested the binding of affinity purified immunoglobulin G to human primary trophoblast cells. These antibodies affected the invasiveness and differentiation of cytotrophoblast cells after binding to the cell surface. In addition, we determined whether the drugs used to treat APS might be able to restore the trophoblast functions. Low-molecular weight heparin, in a dose-dependent manner, significantly reduced the immunoglobulin G binding to trophoblast cells and restored in-vitro placental invasiveness and differentiation. No effect was observed in the presence of acetylsalicylic acid. These observations may help in understanding the role of these treatments in women with APS. PMID- 10100001 TI - Are human placental bed giant cells merely aggregates of small mononuclear trophoblast cells? An ultrastructural and immunocytochemical study. AB - The ultrastructure of placental bed giant cells in early human pregnancies of 7 12 weeks gestational age is described. Their nature and function was further characterized by confocal immunofluorescence microscopy of paraffin sections labelled for cytokeratin, gap junction connexins (CX) 32 or 43, and placental hormones, alpha-human chorionic gonadotrophin (alpha-HCG) and human placental lactogen (HPL). Placental bed giant cells were observed with two phenotypes; as single large trophoblast cells containing one or more nuclear profiles in a voluminous cytoplasm, and as cell aggregates comprising mononuclear trophoblast cells in close apposition separated by narrow intercellular spaces. Cells within the aggregates are attached to one another by desmosomes, and also possess gap junctions as shown by immunolabelling for CX32 and CX43. By contrast, gap junctions were absent in the true multinucleated giant cells. Organelles present within the cytoplasm of the giant cells and their immunoreactivity for HPL and alpha-HCG suggest protein synthesis. PMID- 10100002 TI - Immunohistochemical localization of receptors for progesterone and oestradiol-17 beta in the implantation site of the rhesus monkey. AB - The aim of the present study was to examine the cellular basis of the involvement of oestradiol and progesterone in blastocyst implantation in the primate. To this end, the cellular distribution of receptors for oestradiol (ER) and progesterone (PR) in fetal trophoblast cells and in endometrial compartments of timed lacunar (pre-villous) and villous stages of placentation in primary implantation sites collected on days 13-22 of gestation were investigated in rhesus monkeys. Both in pre-villous stage tissue and in villous stage tissue, cytotrophoblast cells and syncytiotrophoblast cells and other trophoblast derived cells were PR positive, while they were generally ER negative. Maternal endometrial cells were ER negative, while epithelial cells, stromal cells and vascular endothelial cells in maternal endometrium showed heterogeneous staining patterns for PR depending on their relative location; these patterns, however, correlated well with glandular hyperplasia and differentiation, stromal-decidual transformation and vascular response seen during blastocyst implantation. PMID- 10100003 TI - Presence of uterine pinopodes at the embryo-endometrial interface during human implantation in vitro. AB - In order to study changes occurring on the surfaces of human endometrial epithelial cells in the presence of an implanted blastocyst, we used scanning electron microscopy for investigation of five endometrial biopsies and three human implantation sites obtained in vitro. All specimens showed areas with endometrial pinopodes, separated by cells displaying microvilli or cilia at the apical surface. Pinopode formation was more pronounced in endometrial biopsies than in cell cultures. All blastocysts adhered to pinopode presenting cells. Endometrial surface changes were not seen around the blastocysts. The results of this study demonstrate that cultured endometrial epithelial cells are capable of pinopode formation. Furthermore, endometrial epithelial pinopodes, generally considered as a marker of endometrial receptivity, seem to be directly involved in the adhesion of the blastocyst to the endometrial surface. PMID- 10100004 TI - Transcervical recovery of fetal cells from the lower uterine pole: reliability of recovery and histological/immunocytochemical analysis of recovered cell populations. AB - The aim of this work was to isolate, enumerate and attempt the identification of fetal cells recovered from the lower uterine pole. Immediately before elective termination of pregnancy at 7-17 weeks gestation, samples were recovered by transcervical flushing of the lower uterine pole (n = 108) or transcervical aspiration of mucus from just above the internal os (n = 187), and their contents examined using histological, immunohistochemical and molecular techniques. Syncytiotrophoblasts were identified morphologically in 28 out of 89 (31%) and 50 out of 180 (28%) flushings and aspirates respectively (mean 29%). Immunocytochemistry with monoclonal antibodies (mAbs) recognizing trophoblast or epithelial cell antigens on a smaller number of samples (n = 69) identified putative placental cells in 13 out of 19 (68%) and 25 out of 50 (50%) flushings and aspirates respectively (mean 55%). These included groups of distinctive cells with a small, round, hyperchromatic nucleus, strongly reactive with mAbs PLAP, NDOG1 and FT1.41.1. Smaller groups of larger, amorphous cells, usually containing multiple large, pale staining nuclei, reactive with mAb 340 and to a lesser degree with mAb NDOG5 were also observed. Taking cellular morphology and immunophenotype into consideration, the smaller uninucleate cells were likely to be villous mesenchymal cells, while the larger cells were possibly degrading villous syncytiotrophoblast. There was no significant difference in the frequency of fetal cells obtained by the two recovery methods. Squamous or columnar epithelial cells, labelled strongly with antibodies to cytokeratins or human milk fat globule protein, were observed in 97% (29 out of 30) of aspirates. The use of cervagem in a small number of patients prior to termination of pregnancy did not appear to influence the subsequent recovery of placental cells. Y-specific DNA was detected by polymerase chain reaction (PCR) in 13 out of 26 (50%) flushings and (99 out of 154) 64% aspirates analysed (mean 62%). In-situ hybridization (ISH) revealed Y-specific targets in 40 out of 69 (60%) of aspirates analysed. A comparison of PCR data obtained from transcervical recovered samples and placental tissues showed a concordance of 80% (76 out of 95), with 10 false positives. Comparing the PCR data from tissues with data derived by ISH from 41 aspirates gave a concordance of 90% with two false positives. Although syncytiotrophoblasts were much more likely to be present in samples containing immunoreactive placental cells, the detection rates of fetal-derived DNA were similar regardless of the morphological and/or immunological presence of placental cells. We conclude that the transcervical recovery of fetal cells, while promising, requires considerable additional effort being expended in further research and development, particular in the sampling procedure. PMID- 10100005 TI - Turner's syndrome and pregnancies after oocyte donation. AB - A total of 20 clinical pregnancies was achieved among 18 women with Turner's syndrome who were treated in an oocyte donation programme. The oocytes were donated by voluntary unpaid donors. A mean of 1.8 embryos per transfer was given to each recipient by way of 28 fresh and 25 frozen embryo transfers. With fresh and frozen embryos, 13 and seven pregnancies respectively were achieved. The clinical pregnancy rate per fresh embryo transfer was 46%, and the implantation rate 30%, being similar to the corresponding rates among our oocyte recipients with primary ovarian failure in general. The corresponding rates with frozen embryos were 28 and 19%. Of these pregnancies, 40% ended in miscarriage. This high rate may be explained by uterine factors. Six women were hypertensive during pregnancy, a rate comparable with that in other oocyte donation pregnancies. All these women delivered by Caesarean section. Pregnancy and implantation rates after oocyte donation were high in women with Turner's syndrome, but the risk of cardiovascular and other complications is high. Careful assessment before and during follow-up of pregnancy are important. Transfer of only one embryo at a time to avoid the additional complications caused by twin pregnancy is recommended. PMID- 10100006 TI - Characterization of human placental explants: morphological, biochemical and physiological studies using first and third trimester placenta. AB - The primary objective of this study was to characterize an in-vitro model of the human placenta using morphological, biochemical and physiological parameters. Placental villi were obtained from normal first trimester and term pregnancies. The villi were incubated with Dulbecco's modified Eagle's medium: Ham's F12 nutrient mixture in a shaking water bath at 37 degrees C for up to 310 min. The viability was determined by the production of beta human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH) and the incorporation of [3H]thymidine, [3H]L-leucine and L-[U14C]arginine, while ultrastructure was assessed by transmission electron microscopy. In the first and third trimester group, the release into the medium of the intracellular enzyme LDH remained unaltered throughout the experiment. By contrast, beta-HCG concentrations increased linearly and concentrations were higher in the first trimester than term villi (354.5 +/- 37.8 versus 107 +/- 8.1 IU/g villi protein; P < 0.001). Electron microscopy confirmed preservation of tissue viability for up to 4 h of incubation. The incorporation of thymidine (12.2 +/- 2.9 versus 5.2 +/- 0.5 nmol/g villi protein; P < 0.05), leucine (9.4 +/- 2.1 versus 1.9 +/- 0.4 nmol/g villi protein; P < 0.02) and arginine (17 +/- 4.4 versus 4.2 +/- 0.5 nmol/g villi protein; P < 0.05) were markedly higher in early than in term placenta. Furthermore, placental uptake of L-leucine by the first (9.4 +/- 2.1 versus 17 + 4.4 mol/g villi protein; P < 0.001) and third trimester placental villi (1.9 +/- 0.4 versus 4.2 + 0.5 mol/g villi protein; P < 0.001) was less than that of L arginine. This study describes a simple technique using placental explants to determine relative rates of uptake of substrate amino acids throughout gestation. PMID- 10100007 TI - Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat. AB - Successful pregnancy is strictly dependent on the trophoblast-decidual interaction and on an adequate blood supply to the implantation sites. Nitric oxide (NO) has been shown to play an important role during advanced gestation, although its role during early pregnancy is unclear. The aim of the present study in rats was to evaluate whether NO plays a role during the preimplantation [days 1-4 post coitum (p.c.)] and peri-implantation (days 6-8 p.c.) phases of pregnancy. The rats were treated with the non-specific nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), and the iNOS inhibitor aminoguanidine in the presence and absence of low-dose antiprogestin, onapristone, and evaluated on days 9 p.c. and 19 p.c., respectively. Before implantation, the treatments alone (L-NAME, aminoguanidine, onapristone) had little effect on pregnancy outcome. Conversely, aminoguanidine plus onapristone treatment completely prevented pregnancy, whereas L-NAME plus onapristone reduced the pregnancy rate to approximately 50%. In addition, both treatments drastically reduced decidualization. Oviductal flushing experiments revealed arrest of embryo development at around the 8-cell stage after aminoguanidine plus onapristone treatment on days 1-4 p.c. Similarly, treatment during the peri-implantation period with L-NAME, aminoguanidine, and onapristone each had only marginal effects on pregnancy. However, a combination of L-NAME and onapristone, and aminoguanidine plus onapristone prevented pregnancy in 71% and 42% of dams, respectively, as determined on day 19 p.c. These treatments also markedly inhibited the decidualization process. This study demonstrates synergistic effects of NOS inhibitors and an antiprogestin in preventing pregnancy. NOS, particularly the cytokine- and progesterone-inducible iNOS, may represent a new target for novel therapeutic agents capable of promoting or inhibiting pregnancy. PMID- 10100008 TI - Uterine artery embolization--a successful treatment to control bleeding cervical pregnancy with a simultaneous intrauterine gestation. AB - A case of a woman suffering from a bleeding heterotopic cervical pregnancy is described. The concurrent cervical pregnancy and intrauterine gestation were diagnosed by ultrasound and bleeding was initially controlled with selective fluoroscopic uterine artery embolization. A selective fetal reduction was done with ultrasound-guided intracardiac potassium chloride. Uterine artery embolization has been used successfully to control haemorrhage in cervical pregnancies when the main goal was to allow preservation of the uterus, thus maintaining potential fertility. This is the first report of arterial embolization used to control bleeding for maintaining a concurrent intrauterine heterotopic pregnancy in an in-vitro fertilization patient. Unfortunately, subsequent conservative measures led to undesired outcome. This procedure initially controlled the bleeding without disrupting the intrauterine fetal cardiac activity. PMID- 10100009 TI - Can nuchal cord cause transient increased nuchal translucency thickness? AB - When detected in a first trimester scan, an increased thickness of nuchal translucency (NT) may be associated with chromosomal, cardiac or genetic disorders. However, less attention has been devoted to the outcome of those fetuses who have confirmed normal anatomies and karyotyping, but have abnormal first trimester scans. Thus, a challenging new issue is how to counsel such cases of transient increased NT in which the translucency rapidly vanishes with no evidence of other underlying abnormalities. Two cases of transient increased thickness of NT are reported. In both, a nuchal cord was ultrasonographically demonstrated and a thorough work-up revealed chromosomally and anatomically normal fetuses. The pathophysiological theories behind these observations and their significance are discussed. Based on these observations, we suggest that transvaginal sonography combined with Doppler flow studies should be utilized for the presize detection of cord patterns to accomplish the work-up in cases of increased NT. PMID- 10100010 TI - Interleukin-8 potentiates the effect of interleukin-1-induced uterine contractions. AB - The aim of this research was to study the effect of exogenous interleukin (IL)-8, IL-1 and IL-8 + IL-1 on uterine contractions in rabbits. Four equal groups of non pregnant rabbits (n = 24) were investigated using either placebo or experimental drugs in the form of vaginal suppositories. The suppositories contained human recombinant IL-8 (200 ng), IL-1 (200 ng), IL-8 (200 ng) + IL-1 (200 ng) or vehicle Witepsol base, 500 microliters). Subsequently, the plasma concentration of prostaglandin (PG) E2 was estimated 3 h after the last dose of treatment. Neutrophil infiltration in the endometrial tissue was studied with anti-rabbit RT2 staining. Suppositories with IL-1 and IL-8 + IL-1 produced contractile responses with increased frequency (P < 0.003, P < 0.0005) and amplitude (P < 0.0001) in vivo, compared with vehicle. IL-1 and IL-8 + IL-1 also caused similar contractile effects with increased frequency (P < 0.01, P < 0.0007) and amplitude (P < 0.0001) in an in-vitro experiment than vehicle. The frequency and amplitude of uterine contractions were more significant with IL-8 + IL-1 than that of IL-1, both in vivo (P < 0.002, P < 0.05) and in vitro (P < 0.005, P < 0.01). IL-8 did not induce any contractions. Prostaglandin concentration was increased approximately 8-fold with IL-8 + IL-1 (P < 0.0001) and 2.5-fold with IL-1 treatment (P < 0.0001). Neutrophil numbers were significantly increased with IL-8 + IL-1 > IL-8 > IL-1 (P < 0.002, P < 0.0003 and P < 0.008) compared with vehicle. Our data suggest that IL-8 stimulates IL-1-induced uterine contractions through PGE2 production and could be an important process during labour and delivery. PMID- 10100011 TI - Fluctuations in CA 125 and CA 15-3 serum concentrations during spontaneous ovulatory cycles. AB - The aim of this study was to investigate cycle dependent changes of serum CA 125 and CA 15-3 concentrations during spontaneous ovulatory cycles. Twenty apparently healthy women with spontaneous menstrual cycles attending our infertility clinic were included. Of these women, 18 had occluded tubes as a result of sterilization. Ovulation was confirmed by luteinizing hormone test and ultrasonography and, to exclude endometriosis, a laparoscopy was performed. Serum samples for CA 125, CA 15-3, 17 beta-oestradiol and progesterone determinations were taken every second day starting on the 2nd day of the cycle until the 7th day of the next cycle. After correction for inter-individual variation in serum concentrations, highest CA 125 concentrations were found during the menstruation. During the follicular and peri-ovulatory phase CA 125 serum concentrations were lowest. For CA 15-3, serum concentrations were not statistically different throughout the cycle. CA 125 and oestradiol concentrations were negatively correlated, CA 15-3 and oestradiol concentrations were positively correlated. Absolute serum concentrations of both CA 125 and CA 15-3 vary among females. Within the female, fluctuations of CA 125 are phase related. In the population studied most of the patients had tubal obstruction and high CA 125 serum concentrations during menstruation, which revokes the theory that the menstrual rise of CA 125 is due only to retrograde menstruation. PMID- 10100012 TI - Leukaemia inhibitory factor expression in human follicular fluid. PMID- 10100013 TI - Deception by chimerism. PMID- 10100014 TI - Putting new drugs to good use. PMID- 10100015 TI - Selective cost of delayed childbearing. PMID- 10100016 TI - FRAXA premutations are not a cause of familial premature ovarian failure. PMID- 10100017 TI - Postmortem digoxin-like immunoreactive substances (DLIS) in patients not treated with digoxin. AB - Endogenous digoxin-like immunoreactive substances (DLIS) cross-react in immunoassays of digoxin. The postmortem rise in digoxin levels in patients treated with the drug may be due to its redistribution. It is unclear what is the contribution of DLIS to this increase and whether DLIS are present postmortem in patients not treated with digoxin. The objectives of this study were to determine whether DLIS are present after death in patients not treated with digoxin, whether a postmortem increase in DLIS is detectable and whether sampling site can affect DLIS concentrations. DLIS (measured as digoxin, TDx Abott) were determined in blood samples drawn antemortem from ICU patients; postmortem samples from femoral artery and cardiac chambers were taken at least 12 h after the death of these same patients. DLIS concentrations > or = 0.2 ng/ml were measured in 44 and 40% of patients antemortem and postmortem (femoral), respectively. No difference was found in DLIS levels between antemortem and postmortem femoral and cardiac samples. Age, ICU stay and postmortem sampling time did not affect the postmortem increase in DLIS. None of the levels was in the toxic range. DLIS may be present after death and their concentration does not increase postmortem. The interpretation of postmortem digoxin concentrations that fall in the therapeutic range should be done cautiously; such measurable levels do not necessarily indicate misuse or malicious intent even in patients who had not been treated with the drug. PMID- 10100018 TI - The selective cytotoxicity of cobra venom factor immunoconjugate on cultured human nasopharyngeal carcinoma cell line. AB - The selective cytotoxicity of a CVF immunoconjugate on human nasopharyngeal carcinoma cell line was reported. Cobra venom factor (CVF), a C3b-like glycoprotein, was linked to BAC5, a murine monoclonal antibody directed against a human nasopharyngeal carcinoma-associated membrane antigen, by a disulfide bond. The high affinity to cultured human nasopharyngeal cells (CNE2) and the complement activating potency retained in CVF immunoconjugate. Although the equimolar concentration of BAC5 or CVF alone was harmless to CNE2 cells, the CVF immunoconjugate in the presence of fresh human serum exhibited selective cytotoxicity on CNE2 cells in a concentration- (IC50 3.07 x 10(-7) mol/L) and time-dependent manner. No cytotoxicity occurred on either CNE1 (another human nasopharyngeal carcinoma cell line) or MGC-803 (human gastric carcinoma cell line) cells. Furthermore, direct lytic factor (DLF, cardiotoxin) separated from cobra venom, augmented CVF immunoconjugate-induced cytotoxicity significantly. These results indicate that the CVF immunoconjugate has complement-mediated selective cytotoxicity on CNE2 cells, which can be potentiated by DLF. PMID- 10100019 TI - Airway epithelial damage and release of inflammatory mediators in human lung parenchyma after sulfur mustard exposure. AB - This study was performed to evaluate the morphological effects of sulfur mustard on human lung parenchyma in vitro and to measure the metabolites of arachidonic acid which are released during acute exposure to the alkylating agent. Histological analysis of the tissue following exposure to sulfur mustard for a period of 45 min at 10 mM revealed the presence of paranuclear vacuoles in the epithelium, specifically, in the ciliated cells. The release of metabolites of arachidonic acid were determined in the bath fluids by an enzymo-immunoassay. The basal release of prostaglandin E2 (PGE2: 1.36 +/- 0.33 ng/g tissue) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha: 8.83 +/- 1.17 ng/g tissue) were not modified during tissue exposure to sulfur mustard (45 min, 0.1 mM). In addition, the basal release of cysteinyl-leukotriene E4 (LTE4: 1.55 +/- 0.44 ng/g tissue) was also not altered by challenge of the tissues with sulfur mustard. In contrast, when the human lung parenchyma was stimulated with anti human IgE (anti IgE) only the basal release of the metabolite of the 5-lipoxygenase pathway was significantly increased (LTE4: 6.84 +/- 1.57 ng/g tissue). These data suggest that sulfur mustard may produce morphological alterations in epithelial cells and at the time point studied (45 min exposure), this effect is not associated with a release of arachidonic acid metabolites. However, the increased release of LTE4 by anti-IgE suggests that the target cells for sulfur mustard and anti-IgE in the human lung may be different. PMID- 10100020 TI - A sheep model for continuous intrathecal infusion of test substances. AB - Pharmaceutical research and new drug development rely extensively on animal research. The development of novel agents for intrathecal administration requires preclinical studies of toxic effects in an animal model. We have developed a nonrodent animal model for this purpose. Our sheep model: 1 Is an animal whose neural axis is similar to the human 2 Allows for the percutaneous placement of intrathecal catheters 3 Has minimal possibilities of infection because the infusion system is totally implanted 4 Provides continuous infusion of the test agent 5 Generates behavioral, motor, neurological and histopathological information so that safety guidelines can be established prior to preclinical studies. PMID- 10100021 TI - Immunotoxicological examination of repeated dose combined exposure by dimethoate and two heavy metals in rats. AB - The immunotoxicity of 28 days combined oral exposure by dimethoate (DM) and two heavy metals (Pb or Cd) was investigated in male Wistar rats. Immunotoxic and no effect doses of DM (28.2 and 7.04 mg/kg) were combined with immunotoxic and no effect doses of CdCl2 (6.43 and 1.61 mg/kg) or lead acetate (80.0 and 20.0 mg/kg) in such a way that the high dose of each substance was given in combination with the no-effect dose of the other. To examine the interactions of these agents, general toxicological (body weight gain, organ weights), haematological (absolute and differential WBC, RBC, MCV, Ht. cell content of the femoral bone marrow), and immune function (splenic PFC number. DTH reaction) parameters were measured. Treatment with the combination of Pb or Cd and DM did not result in a reduction of humoral (PFC) and cellular (DTH) immune responses, whereas treatment with the substances alone did result in immune suppression. This protecting effect can probably be attributed to an effect on the kinetics of the compounds tested rather than on the immune system itself. Further interactions were found in both combinations, DM-Cd and DM-Pb, in the body weight gain and in the relative liver weight; the DM-Pb combination also affected the relative thymus weight and the MCV value. These findings show that the immunotoxic effects of the investigated materials, including their detectability and health consequences, can be modified in case of combined exposure. PMID- 10100022 TI - Species differences in hepatocyte induction of CYP1A1 and CYP1A2 by omeprazole. AB - Omeprazole, a proton pump inhibitor therapeutically administered for the treatment of gastric ulcers, induces the expression of cytochromes P4501A1/2 (CYP1A1/2) through transcriptional activation mediated by the Ah-dioxin) receptor. Primary cultures of hepatocytes isolated from rabbit, rat, mouse and human livers were compared for CYP1A1/2 mRNA inducibility by omeprazole (1 to 100 microM). Primary cultures of human hepatocytes were the most sensitive to the inducing effects of omeprazole. Rabbit hepatocytes were the only other cells studied that showed induced CYP1A1/2 mRNA expression from a concentration lower than 100 microM (i.e., 10 microM). Rat hepatocytes were the least sensitive to omeprazole induction. The response of mouse hepatocytes to omeprazole treatment was variable, with CYP1A1/2 mRNA expression being induced in only two of the three cultures examined. Differences in the time dependence of CYP1A1/2 mRNA expression were observed between species. In general, after treatment of hepatocytes with omeprazole the levels of CYP1A1 mRNA peaked prior to that of CYP1A2 mRNA. Due to the interspecific variability of CYP1A mRNA inducibility by omeprazole, we conclude that human hepatocytes in culture are probably the only appropriate animal model for prediction of CYP1A induction in humans. PMID- 10100023 TI - Different effects of (CIS+TRANS) 1,3-dichloropropene in renal cortical slices derived from male and female rats. AB - Nephrotoxic effects of 1,3-dichloropropene (cis and trans isomers mixture) was investigated in vitro by means of renal cortical slice model in male and female rats, including treatment with metabolism modifiers as an inducer of cytochrome P 450 1A class (beta-naphthoflavone), a reduced glutathione depleting (DL buthionine-[S,R]-sulfoximine), an inhibitor of gamma-glutamyl-transferase (AT 125) and inhibitor of cysteine conjugate beta-lyase (aminooxiacetic acid). Dose dependent decrease of p-aminohippurate uptake was observed in male renal cortical slices. Only the high doses (3.0 and 4.0 x 10(-4) M) caused a significant loss of organic anion uptake in females. beta-Naphthoflavone and alpha-amino-3-chloro-4,5 dihydro-5-isoxazoleacetic acid (AT-125) partially, but significantly, reduced organic anion loss in males. In females, DL-buthionine-[S,R]-sulfoximine significantly increased in females but in males loss of organic anion accumulation caused by 1,3-dichloropropene. Aminooxyacetic acid did not ameliorate 1,3 D effects in vivo and in vitro in male rats. It appeared very toxic for female rats (all rats died) after in vivo injection. Sensitivity to nephrotoxicity induced by 1,3-dichloropropene in vitro was about double in male than female rats. Reduced glutathione conjugation appeared involved in nephrotoxicity induced in males but in females, probably by means of a chloropropyl-cysteinylglycine-conjugate formation; slight toxicity in females is likely related to oxidative metabolism. PMID- 10100024 TI - The role of nitro-reduction and nitric oxide in the toxicity of chloramphenicol. AB - Recent work on the toxicology of chloramphenicol suggests that its propensity to cause damage to the blood forming organs may be related to its potential for nitro-reduction and the subsequent production of nitric oxide. In this study both aerobic and anaerobic nitro-reduction of chloramphenicol by human foetal and neonatal liver results in the production of the amine derivative. However intermediates of the reaction nitroso- or glutathionesulphinamido-chloramphenicol could not be detected by hplc. Perfusion of chloramphenicol through isolated lobules of human placentae caused a decrease in blood pressure at a time which coincided with a peak of nitric oxide production. However, although the pressure drop could be reversed by an inhibitor of nitric oxide synthetase, the nitric oxide profile remained the same. These observations suggest that involvement of the para-nitro group of chloramphenicol could cause both hemotoxicity and hypotension in susceptible individuals. PMID- 10100025 TI - Fatal multi-organ failure after suicidal overdose with MDMA, 'ecstasy': case report and review of the literature. AB - A 53-year-old prisoner died of multiorgan failure after a suicidal overdose with 3,4-methylenedeoxymethamphetamine (MDMA, 'Ecstasy'). Twelve hours after ingestion of MDMA, the patient became severely hyperthermic (107.2 degrees F) with evidence of rhabdomyolysis. He subsequently developed acute respiratory distress syndrome (ARDS), disseminated intravascular coagulopathy (DIC) and acute renal failure. At autopsy, plasma concentration of MDMA was 3.05 mg/L. This case shows that MDMA is still abused in our community and clinicians should know the symptoms of MDMA intoxication. In particular, MDMA should be considered when patients have symptoms or signs of increased sympathetic activity. The pathophysiology and treatment of MDMA-induced hyperthermia are discussed. PMID- 10100026 TI - BTS special symposium. In vitro toxicology--priorities for the year 2000. University of Surrey, 23 April 1998. Report of a symposium to discuss the BTS working party report on in vitro toxicology. PMID- 10100027 TI - Managed care and complementary and alternative medicine: lessons from the past and suggestions for the future. PMID- 10100028 TI - Carpal tunnel syndrome: clinical outcome after low-level laser acupuncture, microamps transcutaneous electrical nerve stimulation, and other alternative therapies--an open protocol study. AB - OBJECTIVE: Outcome for carpal tunnel syndrome (CTS) patients (who previously failed standard medical/surgical treatments) treated primarily with a painless, noninvasive technique utilizing red-beam, low-level laser acupuncture and microamps transcutaneous electrical nerve stimulation (TENS) on the affected hand; secondarily, with other alternative therapies. DESIGN: Open treatment protocol, patients diagnosed with CTS by their physicians. SETTING: Treatments performed by licensed acupuncturist in a private practice office. SUBJECTS: Total of 36 hands (from 22 women, 9 men), ages 24-84 years, median pain duration, 24 months. Fourteen hands failed 1-2 surgical release procedures. INTERVENTION/TREATMENT: Primary treatment: red-beam, 670 nm, continuous wave, 5 mW, diode laser pointer (1-7 J per point), and microamps TENS (< 900 microA) on affected hands. Secondary treatment: infrared low-level laser (904 nm, pulsed, 10 W) and/or needle acupuncture on deeper acupuncture points; Chinese herbal medicine formulas and supplements, on case-by-case basis. Three treatments per week, 4-5 weeks. OUTCOME MEASURES: Pre- and posttreatment Melzack pain scores; profession and employment status recorded. RESULTS: Posttreatment, pain significantly reduced (p < .0001), and 33 of 36 hands (91.6%) no pain, or pain reduced by more than 50%. The 14 hands that failed surgical release, successfully treated. Patients remained employed, if not retired. Follow-up after 1-2 years with cases less than age 60, only 2 of 23 hands (8.3%) pain returned, but successfully re-treated within a few weeks. CONCLUSIONS: Possible mechanisms for effectiveness include increased adenosine triphosphate (ATP) on cellular level, decreased inflammation, temporary increase in serotonin. There are potential cost savings with this treatment (current estimated cost per case, $12,000; this treatment, $1,000). Safe when applied by licensed acupuncturist trained in laser acupuncture; supplemental home treatments may be performed by patient under supervision of acupuncturist. PMID- 10100029 TI - Acupuncture for gastrointestinal and hepatobiliary disorders. AB - Acupuncture has been used for various gastrointestinal (GI) conditions. Voluminous data support the effect of acupuncture on the physiology of the GI tract, including acid secretion, motility, neurohormonal changes, and changes in sensory thresholds. Much of the neuroanatomic pathway of these effects has been identified in animal models. A large body of clinical evidence supports the effectiveness of acupuncture for suppressing nausea associated with chemotherapy, postoperative state, and pregnancy. Prospective randomized controlled trials have also shown the efficacy of acupuncture for analgesia for endoscopic procedures, including colonoscopy and upper endoscopy. Acupuncture has also been used for a variety of other conditions including postoperative ileus, achalasia, peptic ulcer disease, functional bowel diseases (including irritable bowel syndrome and nonulcer dyspepsia), diarrhea, constipation, inflammatory bowel disease, expulsion of gallstones and biliary ascariasis, and pain associated with pancreatitis. Although there are few prospective randomized clinical studies, the well-documented physiological basis of acupuncture effects on the GI tract, and the extensive history of successful clinical use of acupuncture, makes this a promising modality that warrants further investigation. PMID- 10100030 TI - Fatal and adverse events from acupuncture: allegation, evidence, and the implications. AB - In response to recent reviews in the literature that have focused on adverse events due to acupuncture treatment, this article reexamines the original reports from which they derive, particularly the fatalities allegedly caused by acupuncture. The article explores some important issues relating to the debate on risk and safety. Education and research strategies need to be developed so that the acupuncture profession can continue to minimize the likelihood of adverse events occurring in the future. PMID- 10100031 TI - Evidence of functional zinc deficiency in Parkinson's disease. AB - One of the primary areas of investigation in the pathophysiology of Parkinson's disease (PD) is the loss of the dopamine-producing cells in the melanized neurons of the substantia nigra, believed to be caused by oxidative stress resulting from excessive free radical activity. The cuprozinc enzyme, superoxide dismutase (SODCu2Zn2), catalyzes the dismutation of superoxide anions to hydrogen peroxide plus oxygen, and is normally found in high concentrations in the substantia nigra where it protects neurons by scavenging free radicals. Zinc supplementation has been shown to significantly increase SODCu2Zn2 in vitro. A novel oral zinc tally test (ZTT) used in the assessment of zinc status was administered to 100 PD patients and 25 controls. Patients with PD showed a significantly decreased zinc status as compared to controls (p < 0.001). Significance was also established for 3 self-reported health-related variables thought to be related to zinc status: vision problems, olfactory loss, and taste loss (p < 0.05). Relative risks for patients with PD for these variables were 1.51, 1.56, and 1.33, respectively. Zinc status as measured by the ZTT is negatively correlated with PD status. PD status is positively correlated with self-reported vision problems, and olfactory and taste loss. Further study of the role of zinc in the development and treatment of PD is warranted. PMID- 10100032 TI - Homeopathy and managed care: manageable or unmanageable. AB - Managed care presents a challenge to homeopaths and to consumers of homeopathic care. If homeopaths want to be a part of managed care, they will have to organize themselves to a higher level of professional order. Although the vast majority of practicing homeopaths are licensed in one of many conventional health professions, with the medical license being the most common, homeopaths need to develop more clearly defined educational standards and certification programs in the specialty of homeopathic medicine, and they need to have these programs certified by respected, independent agencies. The small number of homeopaths who are unlicensed will either have to become licensed or work with those who are and whose malpractice insurance would cover their care. This article notes that there is a small but significant body of clinical research and additional evidence that homeopathic care is cost effective. A recent increase in public and private research monies is leading to a larger body of evidence that homeopathic medicines are effective, and this will help it achieve greater acceptance and recognition from governmental bodies, medical professional associations, and managed care organizations. Reasons are given as to why managed care organizations will play a leading role in advocating that consumers learn to use homeopathic medicines for non-emergency self-care ailments as a way to empower them to take greater control over their health and to reduce doctor visits and hospitalizations. PMID- 10100033 TI - A single case report of healing through specific martial art therapy: comparison of MRI to clinical resolution in severe cervical stenosis: a case report. AB - OBJECTIVES: A 76-year-old patient with chronic and severe spinal cord compression secondary to cervical stenosis, a cervical osteophyte, and a herniated intervertebral cervical disk had lasting resolution of symptoms after completing a specific, martial art-based, physical therapy program. We wanted to determine if there were structural changes in the cervical spine that could account for the prompt resolution of symptoms. DESIGN: A 76-year-old female completed 8 weeks of a specific, martial art-based, physical therapy. The pretherapy and posttherapy cervical magnetic resonance images (MRIs) were compared. A follow-up evaluation was done at 1 year. RESULTS: The patient was symptom-free within 8 weeks of the start of therapy. She remained symptom-free at 1 year follow-up evaluation. There were no obvious structural differences in the pretherapy and posttherapy MRI studies. CONCLUSIONS: Resolution of symptoms was directly related to the specific martial art therapy. However, there were no changes in the pretherapy and posttherapy MRI studies, suggesting a significant adaptation to the spinal compression had occurred. These data suggest a viable option to surgery in elderly patients with chronic and severe cervical spinal stenosis. PMID- 10100034 TI - Dementia in Ayurveda. AB - The ancient Indian medical system, Ayurveda, included geriatrics as 1 of 8 medical divisions. Well-documented evidence exists for treating aging and age related disorders including dementia. Geriatrics was termed Rasayanatantra. Cognitive function was well recognized and Sanskrit terms existed such as Buddhi for intelligence and Cittanasa (Citta means mind, nasa means loss of) for dementia. A normal human life span was considered to be 100 years. It could be prolonged to 116-120 years through the use of preventive treatments, if they were started during late youth or middle age. Treatments included herbal preparations, diet, exercise, and attention to general mode of life and social behavior. Several herbal formulations are described, including details of their composition and preparation. The mode of action of antiaging drugs was believed to occur at 3 levels. Detailed descriptions of the mode of action of several herbs are provided, and recent research confirms some of this activity. PMID- 10100035 TI - Meeting of Commonwealth health related NGOs. Barbados November 12-15, 1998. PMID- 10100036 TI - Liabilities involved in conducting randomized clinical trials of CAM therapies in the absence of preliminary, foundational studies: a case in point. PMID- 10100037 TI - Treatment of periodontitis in the diabetic patient. A critical review. AB - Both type 1 and type 2 diabetes mellitus are associated with increased periodontal disease susceptibility. Conventional periodontal therapy appears to be effective in diabetic patients. It has not been demonstrated that chemotherapeutics are necessary for successful periodontal therapy in most diabetic patients. The effect of periodontal therapy on metabolic control of diabetes may not be clinically significant. PMID- 10100038 TI - An in-vitro evaluation of a dental subtraction radiography system using bone chips on dried human mandibles. AB - The aim of this in vitro study was to evaluate the ability of digital subtraction radiography to detect small differences in bone density between 2 dental images captured with the Digora radiographic imaging system. 5 dried human mandibles were held in a fixed position and cortical bone chips were superimposed on the alveolar bone between the 1st molar and 2nd premolar teeth. For each mandible, a reference image was obtained without bone chip placement. Subsequently, another image without a bone chip and a series of 10 images with bone chips ranging from 1.2 to 35.3 mg, were recorded. Each of the initial images of the 5 mandibles was then compared to the 11 subsequent images using digital subtraction radiography. The difference in density between the 2 images, at the site between the 1st molar and 2nd premolar, was calculated and represented as a volume equivalent of aluminium. Regression analysis demonstrated a close relationship between the weight of the bone chips and the aluminium equivalent density difference between the 2 radiographs (r2 = 0.96). Good results were obtained with the smaller bone chips that more closely resembled the dimensions of bone changes likely to be of clinical interest (1-8 mg). It is concluded that this subtraction radiography system is suitable for clinical investigations of localised small changes in alveolar bone and for the diagnosis and monitoring of destructive forms of periodontal diseases. PMID- 10100039 TI - The microbiota of periodontal pockets with different depths in therapy-resistant periodontitis. AB - This study presents the composition of the cultivable microbiota colonising periodontal pockets of different depths among 2 patient-groups classified as non responsive (NR-group; 11 participants) or responsive (R-group; 10 participants) to periodontal treatment. Microbiological samples from three types of pocket (< 4 mm deep A-samples; 4-5 mm B-samples; > 5 mm C-samples) were analysed by cultural methods for putative periodontitis pathogens, microbial groups constituting > or = 5% of the total cultivable flora and opportunistic pathogens. Actinomyces naeslundii, A. israelii, Bacteroides forsythus, Fusobacterium spp, Porphyromonas gingivalis, Prevotella intermedia, Peptostreptococcus micros, anaerobic streptococci and facultative anaerobic streptococci were most prevalent. Actinobacillus actinomycetemcomitans, Staphylococcus aureus, enteric rods and yeasts were less prevalent. The periodontitis pathogens Bacteroides forsythus, Fusobacterium spp, Porphyromonas gingivalis, Prevotella intermedia and Peptostreptococcus micros constituted together (on average) < or = 23% of the viable counts in the A- and B-samples of both patient groups and in the C-samples of the R-group. In the C-samples of the NR-group their mean counts were 45%. Correlations were found between smoking habits and the five pathogens in the C samples and in pooled pocket depth samples. The results show that groups of periodontopathogens should be considered a causal factor in therapy-resistant periodontitis. Further, smoking and deep pockets can enhance a shift in the balance of the subgingival microflora predisposing a site to disease and a susceptible host may be the pre-requisite to therapy-resistant periodontitis. PMID- 10100040 TI - Width/length ratios of normal clinical crowns of the maxillary anterior dentition in man. AB - The purpose of this investigation was to analyze the clinical crown of the 3 tooth groups of the maxillary anterior sextant of the permanent dentition of normal subjects with respect to (i) width, length and the width/length ratios and (ii) determine if there is a correlation between tooth dimensions or tooth group ratios and subject height. Subjects (> or = 20 y.o.) were recruited for this study if (i) the free gingival margin on the facial surface of teeth in the maxillary sextant was positioned apical to the cervical bulge, (ii) there was no evidence of attachment loss; as determined by lack of a detectable CEJ and (iii) the marginal tissue was knife edged in form, firm in consistency and coral pink in color. Teeth were excluded if (i) there was evidence of gingival alteration, i.e., gingival overgrowth/hyperplasia, inflammation, altered passive eruption, attachment loss, gingival recession or history of periodontal surgery, or (ii) there was evidence or history of incisal edge/proximal tooth alteration as in, i.e., restorative intervention, traumatic injury or occlusal wear into dentin. At least 1 suitable tooth from each tooth group of the maxillary anterior dentition had to be present. A maxillary impression was taken and poured in yellow die stone. The widest mesial-distal portion and the longest apical-coronal portion of the test teeth were measured. Gender, ethnicity and subject height (SH) were recorded for each participant. Due to a limited ethnic diversity only data from the Caucasian group were analyzed. The mean coronal tooth width (mm) of males versus females was CI: 8.59 versus 8.06, LI: 6.59 versus 6.13 and CA: 7.64 versus 07.15. The mean coronal tooth length (mm) of males versus females was CI: 10.19 versus 9.39, LI: 8.70 versus 7.79 and CA: 10.06 versus 8.89. All width and length measures were significantly greater for males than for females. The mean coronal tooth width/length ratios for males versus females was CI: 0.85 versus 0.86, LI: 0.76 versus 0.79 and CA: 0.77 versus 0.81. A comparison between genders of the width/length ratios of the CI and LI were found not to differ, however the CA ratio for females was significantly greater than for males. A statistically significant difference was found to exist between the mean (cm) SH for males versus females: 181.2 versus 164.0. A positive correlation (p < or = 0.0001 to 0.0691) was found to exist between tooth group width/height ratios within genders. No significant correlation was found between any of the tooth dimensions or tooth group ratios and SH. The results of this study indicate that within male and female Caucasians, the mean width/length ratio of the maxillary 3 anterior tooth groups is 0.81. As well, within both genders there is a positive correlation between tooth group width/length ratios. The significance of these findings with respect to periodontal mucogingival plastic surgical procedures is discussed. PMID- 10100041 TI - Non-surgical periodontal treatment with and without adjunctive metronidazole in smokers and non-smokers. AB - AIM: To determine whether adjunctive metronidazole therapy would compensate for the poorer treatment response to scaling and root planing reported in smokers. METHOD: A single-blind, randomised clinical trial of 28 smokers and 56 non smokers, stratified for periodontitis disease severity and randomly allocated to 3 treatment groups: (1) Scaling and root planing using an ultrasonic scaler with local anaesthesia (SRP), (2) SRP+ metronidazole tabs 200 mg tds for 7 days, (3) SRP + 2 subgingival applications of 25% metronidazole gel. Probing depths (PD) and attachment levels (AL) were recorded with a Florida probe at baseline, 2 months and 6 months post treatment by a single examiner who was unaware of the treatment modality. Results were analysed for all sites with baseline probing depths equal to or greater than Florida probe recordings of 4.6 mm using analysis of variance. RESULTS: Reductions in probing depth at 6 months were significantly less (p < 0.001) in the smokers (mean 1.23 mm, 95% confidence intervals = 1.05 to 1.40 mm) than in the non-smokers (1.92, 1.75 to 2.09 mm). Attachment level gains were approximately 0.55 mm and there was no statistically significant difference between smokers and non-smokers. There were no differences in any clinical measure in response to the three treatment regimens at 2 or 6 months for either smokers or non-smokers. A reduction in the proportion of spirochaetes was observed at 6 months which was less in smokers than in non-smokers (p = 0.034). Multiple linear regression analysis on probing depth at 6 months demonstrated that smoking was a significant explanatory factor (p < 0.001) for poor treatment outcome, whilst the presence or absence of adjunctive metronidazole was not (p = 0.620). CONCLUSION: This study confirms that smokers have a poorer treatment response to SRP, regardless of the application of either systemic or locally applied adjunctive metronidazole. PMID- 10100042 TI - Comparative antiplaque effectiveness of an essential oil and an amine fluoride/stannous fluoride mouthrinse. AB - The adjunctive use of antimicrobial mouthrinses to help control supragingival plaque and gingivitis has been shown to contribute significantly to patients' daily oral hygiene regimens. This controlled clinical study used an observer blind, randomized, cross-over design in a 4-day plaque regrowth model to determine the relative efficacies of an essential oil-containing mouthrinse (Listerine Antiseptic) and an amine fluoride/stannous fluoride-containing mouthrinse (Meridol) in inhibiting the development of supragingival plaque. A 0.1% chlorhexidine mouthrinse (Chlorhexamed-Fluid) was used as a positive control, and a 5% hydroalcohol solution was used as a negative control. Dosing for each of the test mouthrinses was based on the manufacturers' label directions. Because the volume and rinse time for each of the test mouthrinses were different, each test mouthrinse had its own negative control group. On day 1 of each test period, subjects received an oral soft and hard tissue examination and a dental prophylaxis to remove all plaque, calculus, and extrinsic stain. Starting the same day, subjects refrained from all mechanical oral hygiene procedures for the next 4 days and rinsed 2x daily under supervision with their randomly-assigned mouthrinse. On day 5, each subject received a plaque assessment as well as an oral examination to assess side effects. Each test period was separated by a 2-week washout period. 23 volunteers with a median age of 26 years completed the study. Compared to the respective placebos, the median percent plaque reductions at 5 days were 23.0%, 12.2%, and 38.2% for the essential oil, amine/stannous fluoride, and chlorhexidine rinses, respectively. The plaque reductions seen in the essential oil and chlorhexidine rinse groups were statistically significant (p < 0.001), while the plaque reduction in the amine/stannous fluoride rinse group was not statistically significant (p > 0.05). Additionally, the essential oil rinse was significantly more effective (p < 0.001) than the amine/stannous fluoride rinse in inhibiting plaque accumulation in this clinical model. PMID- 10100043 TI - Development and validation of a short-term clinical model for assessing calculus inhibitory agents. AB - The purpose of this project was to develop and validate an efficient, short-term clinical model for assessing topically-applied anticalculus agents. In this model, calculus development occurred within 14 days on both labial and lingual surfaces of the mandibular anterior teeth. Because of documented long-term clinical efficacy, pyrophosphate dentifrices were used to investigate the validity of the short-term calculus model for evaluating anticalculus agents. This paper provides the results of the final 3 studies conducted during the development of this model. For each study, the design consisted of two 14-day phases, i.e., a control phase and a treatment phase, separated by a 7-day washout phase. At the start of each phase, a prophylaxis was performed on the mandibular anterior teeth to remove all plaque and calculus. At the end of each phase, supragingival calculus formation on the labial and lingual surfaces of these same teeth was measured using the VMI scoring method. Twice a day during the control phase, subjects applied a control dentifrice undiluted to the test teeth with a custom-fitted toothshield and brushed only the exposed teeth with the same dentifrice. For the treatment phase, subjects were randomly assigned to groups balanced on the basis of control-phase calculus scores and then delivered the dentifrices using the toothshield as in the first phase. After 14 days, calculus formation occurred in all groups. However, the pyrophosphate dentifrice groups had significantly less calculus (16-30%) than the control dentifrice group. These studies demonstrated that this methodology permitted rapid formation of dental calculus, and by substantiating with anticalculus systems documented to have activity in long-term human trials, it is concluded that this short-term clinical model is valid for assessing anticalculus agents. PMID- 10100044 TI - The development and validation of an occlusal site-specific plaque index to evaluate the effects of cleaning by tooth brushes and chewing gum. AB - These studies sought to develop and validate an occlusal site-specific plaque index to be used to measure plaque removal by brushing or chewing gum. The index divides the occlusal surfaces into imaginary zones from which scores are apportioned on a 0-4 basis dependent on the perceived % plaque coverage of each zone. Examiner calibration was conducted over 2 studies assessing inter-examiner reproducibility and intra-examiner repeatibility, respectively. Study 1 involved 2 examiners who recorded scores from the same 3 groups of subjects who had suspended tooth cleaning for 4 days. Analyses for inter-examiner reproducibility showed no significant mean differences between examiners or no significant differences between variances of the 2 examiners scores. Study 2 involved the same 2 examiners individually scoring 3 groups of subjects 2 x (approximately 60 min apart) for occlusal plaque. Analysis for intra-examiner repeatability showed no significant mean differences between the 2 scorings of each examiner. Furthermore, there were no significant differences between the variances of each examiner's scores except for 1 examiner in the repeatability exercise for the 1st group of subjects. Study 3 involved groups of subjects at 2 separate clinical sites (Bristol, England and Berne, Switzerland) being scored for occlusal plaque before and after toothbrushing with water or after no toothbrushing. Data from individual examiners and examiners combined revealed a significant reduction in occlusal plaque with brushing compared to no brushing. Study 4 was the same as study 3 but occlusal plaque was scored before and after chewing gum or not chewing gum. The Bristol examiner recorded a significant reduction in plaque by chewing gum compared to not chewing gum but the Berne examiner did not. The latter may have resulted from a considerable disparity in the number of evaluable occlusal surfaces between the two study sites. The index could be employed as part of the overall assessment or oral hygiene or used in clinical trials to study mechanical and chemical plaque control agents. PMID- 10100045 TI - Relative proportions of mononuclear cell types in periodontal lesions analyzed by immunohistochemistry. AB - In this study, we investigated the relative proportions of infiltrating mononuclear inflammatory cells in sections of granulation tissue from periodontitis lesions in both adult periodontitis (AP) and early onset periodontitis (EOP) patients. We utilised a set of cluster of differentiation (CD) antigen-specific monoclonal antibodies to detect different cell types within the tissues. These included anti-CD 20 (B cells), anti-CD 3 (pan T cells) and anti-CD 45RO (memory T cells), anti-CD 4 (helper T cells) anti-CD 8 (suppressor T cells) and anti-CD 68 (monocyte/macrophage). Biopsies of granulation tissue were obtained from 9 patients with adult periodontitis (AP), from 10 patients with early onset periodontitis (EOP) and for comparative purposes, biopsies of gingival tissue from 4 patients with AP. A significantly greater number of T cells (p < 0.05) were observed in EOP and gingival sections than in AP sections. In addition, a greater number of B cells were observed in the granulation tissues than in the gingiva (p < 0.05). The relative numbers of B cells (CD 20). T cells (CD 3) and macrophages (CD 68) were expressed as a percentage of their combined total for each of the patient groups and indicated that the proportion of B lymphocytes was greater in AP sections than in EOP or gingival sections (p < 0.02). The proportion of T cells was lower in the AP periodontitis sections than in the EOP periodontitis sections (p < 0.05). There were no significant differences in the proportion of macrophages between the 3 categories of tissue specimens. The relative ratios of B cells (CD 20) to T cells (CD 3) and B cells (CD 20) to memory T cells (CD 45RO) and macrophages (CD 68) to T cells (CD 3) and memory T cells (CD 45RO) were analyzed and indicated that there was a significant increase in the B to T cell ratio in AP sections compared to EOP and gingival sections (p < 0.02). There was also a significant increase in the macrophage to T cell ratio in AP sections as indicated by CD 68 to CD 3 ratios (p < 0.05). There were no differences regarding the relative proportions of memory T cells or in the ratios of CD 4+ to CD 8+ T cells in the different disease categories. In conclusion, these differences in the relative proportions of B cells, T cells and macrophages may reflect a difference in the immunopathology of AP and EOP. PMID- 10100046 TI - Prediction and diagnosis of attachment loss by enhanced chemiluminescent assay of crevicular fluid alkaline phosphatase levels. AB - The current study aimed to apply a novel enhanced chemiluminescence assay in the analysis of gingival crevicular fluid (GCF) alkaline phosphatase (ALP) levels from patients with untreated adult periodontitis. 3666 sites in 25 patients were monitored prior to and after attachment loss was detected with a Florida disc probe. Parameters assessed were, relative attachment level, probing pocket depth, occurrence of bleeding on probing (single episode), GCF volume (microliter), total ALP levels (microIU/30 s sample time) and ALP concentration (IU/l). After recruiting patients to the study, all measures were taken at baseline and 3 months later, prior to the institution of non-surgical periodontal therapy at active sites. Thresholds for determining attachment loss were calculated using a modification of the tolerance method. The mesio-buccal sites of all teeth had GCF samples collected. The size of individual patient thresholds used to define whether attachment loss had occurred, was dependent upon the discomfort felt by that patient during electronic probing, with a positive correlation existing between discomfort on probing (10 cm visual analogue scale) and threshold size (R = 0.52, p < 0.049). A total of 274 sites (7.5%) experienced attachment loss of which 39 sites had GCF samples available for analysis. Total ALP levels were significantly higher at baseline for sites that progressed to attachment loss than paired controls (p < 0.003), but all other parameters showed no differences (p > 0.1). There were significant increases in total ALP levels and GCF volumes for active sites between baseline and 3 month measures (p < 0.01), but not for control sites or test site ALP concentration (p > 0.8). The diagnostic accuracy for GCF ALP as a predictor of future attachment loss (threshold 900 microIU/30 s) was 64%, with +ve and -ve predictive values of 62% and 68%. When a threshold of 1300 microIU/30 s was selected for ALP as a marker of recent or currently active disease, diagnostic accuracy and +ve/-ve predictive values were 77% and 77%/76%, respectively. These results indicate that total GCF ALP levels may serve as a predictor of future or current disease activity. PMID- 10100047 TI - Role of endothelin in the human craniofacial morphogenesis. AB - Human craniofacial morphogenesis is a complex biological event: it is mediated by several factors and different types tissue interaction. Recent studies on animal models have led to an improved understanding of human craniofacial malformations. In particular, the endothelins, peptides that are involved in various biological functions in many tissues and organs, have been shown to play a crucial role in the development of the first branchial-arch-derived structures in mice [Kurihara et al., Nature 368:703-710, 1994]. We previously reported the identification and localization of endothelin-1 (ET-1) and its receptors in human fetal jaw [Barni et al., Dev Biol 168:373-377, 1995]. In the present study, the gene expression of ET-1 and its receptors were demonstrated in human jaw from 11-12-week-old fetuses. By using in situ hybridization, mRNA for ET-1 was localized in the epithelial cells of the oral mucosa: mRNA for ET receptors (ETA and ETB subtypes) was expressed in the mesenchyme. In situ binding experiments confirmed the presence of ETA and ETB receptors in the cells involved in the osteogenesis of the mandible. Furthermore, ET-1 was able to stimulate thymidine uptake and the expression of the oncoprotein c-fos in the same cell types. Our results indicate that ET-1 may play a putative role in epithelium-mesenchyme interaction during human craniofacial morphogenesis. Our findings are in complete accord with those of the most recent works by Yanagisawa [Yanagisawa H et al., 1998] and Clouthier [Clouthier et al., Development 125:813-824, 1998]. They most probably confirm the primary role of ET-1 in the development of the pharyngeal arches. PMID- 10100048 TI - Craniofacial and otic capsule abnormalities in a transgenic mouse strain with a Col2a1 mutation. AB - Abnormal craniofacial features of a transgenic mouse model of chondrodysplasia with a type II collagen mutation (Gly574Ser) are described in this report. In addition to a shortened mandible and cleft palate, a misshapen otic capsule was observed. Interestingly, hearing impairment is often a component of the chondrodysplasia phenotype that results from mutations in COL2A1. To identify a potential mechanism in the hearing loss associated with type II collagen mutations, we examined the development of the otic capsule in the transgenic mice. It appeared to be smaller overall, relative to the skull proportions, and rather than the normal rounded dimensions, the transgenic capsule was flattened and elongated. We speculate that the cartilage of the developing otic capsule was less able to resist the mechanical forces from the developing brain and other tissues within the cranium and thus became deformed under pressure. We further speculate that the hearing loss associated with the chondrodysplasia phenotype is at least partially due to these defects in the developing cartilage matrix of the otic capsule. PMID- 10100049 TI - Altered expression of retinoic acid (RA) receptor mRNAs in the fetal mouse secondary palate by all-trans and 13-cis RAs: implications for RA-induced teratogenesis. AB - Retinoic acid (RA) is mandatory for various biological processes and normal embryonic development but is teratogenic at high concentrations. In rodents, one of the major malformations induced by RA is cleft palate (CP). RA mediates its effects by RA receptors (RARs), but the expression patterns of RARs in the developing palate are still unclear. We investigated the normal expression of RAR alpha, beta, and gamma messenger RNAs (mRNAs) in the fetal mouse secondary palate and the effects of all-trans and 13-cis RAs on the expression of RAR mRNAs by Northern blot analysis. RAR alpha (2.8, 3.8 kb), RAR beta (3.3 kb), and RAR gamma (3.7 kb) mRNAs were detected in the fetal palate on gestational days (GD) 12.5 14.5. The expression of RAR alpha and gamma mRNAs did not show apparent sequential changes, but that of RAR beta mRNA increased at GD 13.5. Treatment of pregnant mice with 100 mg/kg all-trans RA induced CP in 94% of the fetuses and elevated the levels of RAR beta and gamma mRNAs in the fetal palate. The up regulation of RAR beta mRNA by all-trans RA was more marked than that of RAR gamma mRNA. Treatment with 100 mg/kg 13-cis RA induced CP in only 19% of the fetuses. Although 13-cis RA elevated the RAR beta and gamma mRNA levels in fetal palates, its up-regulation was slower and less marked than that induced by all trans RA. These findings indicate that the induction of RAR beta mRNA in the fetal palate correlates well with the tissue concentration of all-trans RA after RA treatment, and RAR beta may be one of the most influential candidate molecules for RA-induced teratogenesis. PMID- 10100050 TI - Craniofacial manifestations in the Marfan syndrome: palatal dimensions and a comparative cephalometric analysis. AB - The purpose of this study was to determine how the craniofacial morphology, evaluated from dental casts and lateral cephalograms, in individuals affected by the Marfan syndrome diverge from healthy control groups. The high and narrow palatal vault as well as maxillary and mandibular retrognathy were strongly correlated to the syndrome. About 70% of the Marfan syndrome patients (n = 76) had been referred for orthodontic treatment, mostly because of crowded teeth or extreme maxillary overjet. In 36%, the orthodontic treatment was carried out before diagnosis or suspicion about the Marfan syndrome. In comparison to healthy orthodontic patients (n = 86), selected because of presence of high and narrow palatal vaults, crowding of teeth, extreme maxillary overjet, and open bite were much more prevalent in the Marfan syndrome patients than in the orthodontic control group. PMID- 10100051 TI - Components of soft tissue deformations in subjects with untreated angle's Class III malocclusions: thin-plate spline analysis. AB - While the dynamics of maxillo-mandibular allometry associated with treatment modalities available for the management of Class III malocclusions currently are under investigation, developmental aberration of the soft tissues in untreated Class III malocclusions requires specification. In this study, lateral cephalographs of 124 prepubertal European-American children (71 with untreated Class III malocclusion; 53 with Class I occlusion) were traced, and 12 soft tissue landmarks digitized. Resultant geometries were scaled to an equivalent size and mean Class III and Class I configurations compared. Procrustes analysis established statistical difference (P < 0.001) between the mean configurations. Comparing the overall untreated Class III and Class I configurations, thin-plate spline (TPS) analysis indicated that both affine and non-affine transformations contribute towards the deformation (total spline) of the averaged Class III soft tissue configuration. For non-affine transformations, partial warp 8 had the highest magnitude, indicating large-scale deformations visualized as a combination of columellar retrusion and lower labial protrusion. In addition, partial warp 5 also had a high magnitude, demonstrating upper labial vertical compression with antero-inferior elongation of the lower labio-mental soft tissue complex. Thus, children with Class III malocclusions demonstrate antero-posterior and vertical deformations of the maxillary soft tissue complex in combination with antero-inferior mandibular soft tissue elongation. This pattern of deformations may represent gene-environment interactions, resulting in Class III malocclusions with characteristic phenotypes, that are amenable to orthodontic and dentofacial orthopedic manipulations. PMID- 10100052 TI - Australian aborigines represent the first branch from Eurasian antecedents: odontometric evidence. AB - Most genetic data suggest that Australian aborigines and Southeast Asians associate, but their relative evolutionary relationship has remained obscure. Historically, the study of tooth crown variables has been important in establishing phylogenetic relationships. Through the quantification of whole tooth structure (GDP), including root, pulp, and enamel, a likely Eurasian phylogeny emerged from a canonical discriminant analysis of the microevolution among the populations. The analysis suggested that in modern human evolutionary history, Australian aborigines are the best representative extant population (first branch) from an unknown antecedent Eurasian founder population. The next branch from the Asian-based antecedent population was Caucasoids. Within the resident antecedent East Asian population, Southeast Asians then evolved, followed by a branch that lead to antecedent east Central Asians. Mongolians and all Native Americans independently evolved from this antecedent east Central Asian population. The relatively short morphogenetic separation between two areas that have been isolated for great periods of time, i.e., Australian aborigines and Native Americans, suggests that their association is not due to gene flow. PMID- 10100053 TI - Neural tube defects, methylenetetrahydrofolate reductase mutation, and north/south dietary differences in China. AB - There is a well-recognized correlation between methylenetetrahydrofolate reductase (MTHFR) C677T mutation homozygosity, elevated plasma homocysteine, and increased risk of neural tube defects (NTDs). This risk is modulated by maternal and fetal folate levels provided provided by diet or supplement. Although the frequencies of the C677T mutation are nearly identical between north and south China, the incidence of NTDs is nearly 5 times greater in the north than in the south. This dramatic difference appears related to the fact that dietary sources of folate are more plentiful and varied in South China. PMID- 10100054 TI - Prediction of cardiovascular damage in hypertensive patients: clinic or ambulatory blood pressures? PMID- 10100055 TI - Standardising blood pressure measurement in everyday practice: what's the gold standard? PMID- 10100056 TI - Baroreflex sensitivity changes with calcium antagonist therapy in elderly subjects with isolated systolic hypertension. AB - In order to study the effects of calcium-blocking therapy on cardiovascular homeostasis in elderly subjects with isolated systolic hypertension, we performed a randomised double-blind placebo-controlled crossover study of 6 weeks therapy with modified-release nifedipine or placebo. Changes with calcium-blocker treatment in clinic and 24-h blood pressure (BP), heart rate, BP variability, baroreflex sensitivity (BRS) by three methods (Valsalva manoeuvre, phenylephrine and sodium nitroprusside injection), and in baroreflex- and non-baroreflex mediated reflexes (tilt and cold face stimulus) were studied in 14 elderly subjects (mean age [+/- SEM] 70 +/- 1 years) with sustained isolated systolic hypertension (clinic BP 179 +/- 3/85 +/- 1 mm Hg). Clinic systolic BP, but not diastolic BP, was reduced with treatment (by 14 +/- 6 mm Hg, P = 0.03, diastolic BP 4 +/- 3 mm Hg, P = 0.16). Twenty-four hour BP was also reduced by nifedipine treatment (by 18 +/- 3/9 +/- 2 mm Hg, both P < 0.001). Clinic and 24-h heart rate, and daytime BP variability, were unchanged with treatment. BRS was significantly increased during nifedipine therapy by all three measurement methods (all P < 0.05). With 60 degrees tilt during active treatment, subjects exhibited a greater heart rate increase (P < 0.01), and a reduced fall in systolic (P < 0.05) and diastolic BP (P < 0.05). Thus despite the arteriosclerosis and reductions in large artery compliance described in elderly patients with isolated systolic hypertension, clinically important improvements in clinic and ambulatory BP and some aspects of cardiovascular homeostasis can be achieved with calcium-channel blocking therapy. PMID- 10100057 TI - Hypertension in black South Africans. AB - Hypertension is a major disease in the black populations of sub-Saharan Africa and the USA. The prevalence of hypertension varies from 1-30% in the adult population. Differences in blood pressure (BP) between black and white patients have been documented. In this review genetic, endocrine and environmental characteristics, renal physiology and cardiac function are reviewed. Racial differences in renal physiology and socio-economic status seem to account for BP differences. Black hypertensive patients in sub-Saharan Africa are prone to cerebral haemorrhage, malignant hypertension, leading to uraemia and congestive heart failure, whereas coronary artery disease is relatively uncommon. Responses to antihypertensive drugs like the beta-blockers and the angiotensin-converting enzyme (ACE) inhibitors are poor unless these agents are combined with a thiazide diuretic. Black hypertensive patients respond best to diuretics, vasodilators or calcium channel blockers. A profiled approach to the treatment of hypertension in black patients is suggested. PMID- 10100058 TI - Arm position is important for blood pressure measurement. AB - AIM: To test the effect of positioning the arm on the arm-rest of a common chair, below the officially recommended right atrial level, on the blood pressure (BP) readings in a group of out-patients. PATIENTS AND METHODS: A group of 69 patients (58 hypertensives; 39 males; mean +/- s.d. age 54.1 +/- 16.0 years) participated in the present study. BP and heart rate values obtained in each of the following two positions were compared: (1) sitting with the arms supported on the arm-rests of the chair and (2) sitting with the arms supported at the level of the mid sternum (the approximation of the right atrial level). BP was measured simultaneously at both arms, with a mercury sphygmomanometer at the right arm and with an automatic oscillometric device at the left arm. RESULTS: Both the systolic and diastolic BPs were significantly higher (P < 0.0001) when the arm was placed on the arm-rest of the chair than at the right atrial level. The same differences +/- s.d. in BP between the two positions were obtained with both measurement techniques: 9.7 +/- 9.4 mm Hg (systolic) and 10.8 +/- 5.8 mm Hg (diastolic) with the mercury sphygmomanometer and respectively 7.3 +/- 8.9 mm Hg and 8.3 +/- 6.0 mm Hg with the oscillometric device. No difference in the heart rate was found between the two positions. CONCLUSIONS: Placing the patient's arms on the arm-rest of the chair instead of at the reference right atrial level, BP measurement will result in spuriously elevated BP values. This may be of great importance for the diagnosis and the subsequent treatment decisions for patients with hypertension. PMID- 10100059 TI - Value of ambulatory intra-arterial blood pressure monitoring in the long-term prediction of left ventricular hypertrophy and carotid atherosclerosis in essential hypertension. AB - The aim of this study was to compare the abilities of clinic and ambulatory blood pressure (BP) to predict the long term occurrence of left ventricular hypertrophy and carotid atherosclerosis in uncomplicated hypertensive patients. Two hundred and ninety-five patients who had undergone 24-h ambulatory intra-arterial BP monitoring on the basis of an elevated clinic BP, attended follow-up at a mean of 10.2 (+/- 3.5) years later. This consisted of a history, physical examination, risk factor profile and serum cholesterol level. Echocardiography and carotid ultrasonography were also performed to determine left ventricular mass index and maximal intima-media thickness (IMTmax), a measure of carotid atherosclerosis severity. The factors most strongly correlated with both left ventricular mass index and IMTmax were age, 24-h mean pulse pressure and 24-h mean systolic BP. Age, 24-h mean systolic BP and body mass index were independent correlates of left ventricular hypertrophy (R2 = 17%), whereas age, 24-h mean pulse pressure and pack years were independent predictors of carotid atherosclerosis (R2 = 34%). Clinic BP did not feature in the final model for the long term prediction of cardiovascular end-organ damage. These findings promote a role for ambulatory BP monitoring in guiding aggressiveness of drug therapy in an attempt to limit potential target organ damage. PMID- 10100060 TI - The impact of blood pressure measurement methods on the assessment of differences in blood pressure levels between patients with normoalbuminuric type 1 diabetes and healthy controls. AB - The aim of the study was to investigate the impact of various blood pressure (BP) measurement methods on the assessment of differences in BP levels between patients with normoalbuminuric type 1 diabetes and healthy controls. We measured intra-arterial BP (i.a.), sphygmomanometric BP (sphygmo), 24-h ambulatory blood pressure (ABPM, auscultatory, Profilomat) and oscillometric BP (Dinamap) in 51 patients with normoalbuminuric type 1 diabetes (DP) with a mean diabetes duration of 8.4 years and 42 healthy controls (C). Results are expressed as mean +/- SE. There was no significant difference in i.a. BP between DP and C (systolic/diastolic BP and mean arterial pressure (MAP) 116.2 +/- 1.2/61.7 +/- 0.8 (82.8 +/- 0.9) mm Hg in DP vs 115.6 +/- 1.2/63.2 +/- 0.9 (83.4 +/- 1.1) in C). Sphygmo BP was 117.7 +/- 1.3/69.8 +/- 1.0 mm Hg in DP vs 116.5 +/- 1.5/67.8 +/- 1.3 in C (NS). Also, ABPM was not significantly different between both groups. Daytime BP between 10.00-23.00 h was 120.9 +/- 1.2/84.4 +/- 0.9 mm Hg in DP vs 120.4 +/- 1.5/83.7 +/- 1.0 in C (NS). Night-time BP between 01.00-07.00 h was 102.4 +/- 1.2/69.3 +/- 0.9 mm Hg in DP vs 103.4 +/- 1.5/69.1 +/- 1.3 in C (NS). In contrast, systolic Dinamap BP was higher in DP (118.6 +/- 1.3 in DP vs 113.4 +/- 1.4 mm Hg in C, P = 0.01) as was MAP (85.6 +/- 0.7 in DP vs 83.3 +/- 1.0 mm Hg in C, P = 0.05). Diastolic Dinamap BP was not significantly different (66.6 +/- 0.7 in DP vs 65.0 +/- 1.0 mm Hg in C). We conclude that intra-arterial BP was similar in patients with normoalbuminuric type 1 diabetes and healthy controls. Also, when using auscultatory BP devices there were no apparent differences in blood pressure. In contrast, using the oscillometric method (Dinamap), BP especially systolic, was higher in diabetic patients. Measurements with an oscillometric device (Dinamap) might therefore overestimate BP in patients with normoalbuminuric type 1 diabetes, thus confusing conclusions on the relationship between development of hypertension and microalbuminuria in the early phase of diabetes. PMID- 10100061 TI - Blood lead and blood pressure: evidence from the Health Survey for England 1995. AB - OBJECTIVES: To examine the relationship between blood lead and blood pressure (BP) and to estimate the possible effects of a decrease in blood lead on BP. METHODS: A 2-ml blood sample was collected from a sub-sample of those included in the Health Survey for England 1995, a cross-sectional survey of a nationally representative sample of the adult English population. Blood lead concentration was measured by atomic absorption spectrometry and three BP readings were taken under standardised conditions using the Dinamap 8100 monitor. Analyses were carried out using data on 2563 men and 2763 women aged 16 and over. RESULTS: In stepwise multiple regression analyses adjusting for various confounders--age, body mass index, smoking status, social class, region of residence and alcohol intake--blood lead was found to be significantly and positively associated with diastolic BP, and not systolic BP in men, but not in women. These findings were unaffected by the inclusion or exclusion of those on antihypertensive medication, by whether mean or median BP was used in the regression, or by the adjustment for alcohol consumption. A halving of currently prevalent blood lead levels is estimated to be associated with a decrease of between 0.8 to 1.1 mm Hg diastolic BP in men. CONCLUSION: These findings in the context of other published data are consistent with a small pressor effect of environmental lead levels on BP. They support recommendations for further efforts to reduce lead in the environment. PMID- 10100062 TI - Dissociation between albuminuria and insulinaemia in hypertensive and atherosclerotic men. AB - To better understand the links between circulating insulin and albuminuria in essential hypertension, the plasma insulin response t alpha a 75 gram glucose load and albuminuria were evaluated in 53 glucose-tolerant essential hypertensives and 12 controls. To allow any direct pressure-independent albuminuric effect of insulin to emerge more clearly, those same parameters were also evaluated in 20 glucose-tolerant normotensive patients with stable atherosclerotic peripheral vascular disease, a condition in which hyperinsulinaemia could be anticipated on the basis of previous reports. In response to glucose ingestion, hyperinsulinaemia was evident in both hypertensive and normotensive atherosclerotic patients, while, on average, urine albumin was elevated only in the former. When plasma insulin, systolic and diastolic blood pressure (BP) (by 24-h ambulatory BP monitoring), plasma glucose, triglycerides and body mass index were entered into a multiple regression analysis, only systolic BP appeared to exert an independent effect on urine albumin. Post glucose load plasma insulin did not differ between hypertensive patients with (n = 14) and without (n = 39) microalbuminuria (albuminuria > 20 micrograms/min). In further analyses, insulin and systolic BP values were divided in quartiles: albuminuria did not differ across insulin quartiles, while it was significantly higher in the top (n = 21) vs the bottom (n = 21) systolic BP quartile. Thus, hyperinsulinaemia and microalbuminuria were unrelated variables in these hypertensive and atherosclerotic patients. Blood pressure, particularly systolic, emerged as a primary predictor of urinary albumin excretion, although the importance of this parameter needs to be proved prospectively. PMID- 10100063 TI - Systolic Hypertension in Europe (Syst-Eur) trial phase 2: objectives, protocol, and initial progress. Systolic Hypertension in Europe Investigators. AB - The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5 25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts. PMID- 10100064 TI - Antihypertensive drug treatment: a comparison of usual care with self blood pressure measurement. AB - Blood pressure self-measurement is increasing in most communities and yet its role in the management of hypertension is poorly understood. This study was devised to evaluate the behaviour of doctors in general practice when treating patients with poorly controlled essential hypertension who use self-measurement. Patients, most of whom were already taking antihypertensive medications were commenced on perindopril or indapamide at their doctor's discretion and were randomly allocated to self-measurement (SM) using an OMRON HEM706 oscillometric device or a continuation of their usual care (UC) over an 8-week period. This was an observational study without any specific or set treatment goals for the doctor to follow. Sixty of 62 subjects completed the study and the two groups were equally matched for age, body mass index, gender, and blood pressure (BP). While additional perindopril or indapamide produced a significant fall in BP in both groups over the study period, the systolic pressure remained significantly higher in the SM group (sitting 148 +/- 3 compared with 142 +/- 3; 145 +/- 3 compared with 138 +/- 3 mm Hg respectively; P < 0.05). Twenty-four hour and daytime ambulatory monitor systolic pressures were also significantly higher in the SM group. Differences in diastolic BP were not statistically significant. Furthermore, SM patients were less likely to have their medications increased and more likely to have them reduced or ceased. Doctors and patients found self measurement convenient and useful. This study suggests that doctors prescribing decisions are influenced by evidence from self-measurement of BP with consequential increases in office BP related to reduced drug use. While self-BP measurement can offer reassurance about adequacy of control when away from a physicians office, our best evidence of understanding target blood pressures comes from large randomised studies using office blood pressures as an end-point. There is an urgent need for further study to provide arbitration between self measurement and office blood pressures although each measurement must contribute to the management of hypertension. PMID- 10100065 TI - The role of the hypertension specialists. ASH Working Committee. PMID- 10100066 TI - Antihypertensive treatment and the prevention of dementia: further insights from the Syst-Eur trial. PMID- 10100067 TI - How to assess glomerular function and damage in humans. AB - In human subjects, the assessment of renal function and of its changes by interventions is limited to the measurement of glomerular filtration rate (GFR), renal blood flow and the estimation of proteinuria. In humans, GFR can be determined exactly by measuring the clearance of an ideal filtration marker, such as inulin. The classic method of measuring inulin clearance in humans includes constant intravenous infusion of the compound and timed collections of urine. In order to avoid the need for timed urine collections, a number of alternative procedures have been devised. All these methods only use determinations of inulin in plasma or serum. From these, the total body inulin clearance is obtained using pharmacokinetic calculations. In order to measure total body clearance, usually called plasma clearance, inulin is either given as a constant intravenous infusion or as a bolus infusion. Both procedures overestimate GFR because of incomplete distribution of inulin during the study periods. The error may be minimized by using model-independent pharmacokinetic calculations. Unlike inulin, creatinine is not a perfect filtration marker. This is because the substance is not only eliminated by glomerular filtration but also by tubular secretion. The extent of tubular creatinine secretion is not constant in various individuals. Serum creatinine concentration is a commonly used measure of renal function in clinical practice. This parameter is determined both by the renal elimination and by the production of the compound. Differences in creatinine production among subjects and over time in a single individual may occur because of changes in muscle mass. Radioisotopic filtration markers can easily and accurately be measured in plasma and serum. Using this method, the plasma concentration-time curve of these compounds can easily be studied after intravenous bolus injection. From the plasma concentration-time curves obtained, the total body clearance (plasma clearance) of the substances can be calculated using pharmacokinetic models. Most frequently, 125l-iothalamate, 99mTc-diethylenethiaminepenta-acetic acid and 51Cr-ethylenediaminetetra-acetic acid are used for the estimation of GFR in humans. The total body clearance of all these filtration markers overestimates GFR. The error induced by this phenomenon is particularly relevant at low levels of GFR. In recent years, iohexol has been used as a filtration marker. The substance can be measured in plasma, serum and urine using high-performance liquid chromatography. So far, good agreement has been shown for GFR determined by the classic inulin clearance and by the iohexol plasma clearance. Screening for proteinuria is commonly performed using reagent test strips. Quantitative measurements of marker proteins can be used to estimate the extent and the site of damage in the nephron. These measurements may be used to estimate the progression of renal disease and the response to therapeutic interventions. Of particular interest is the degree of albuminuria which indicates nephropathy in diabetic patients and end-organ damage in patients with hypertension. PMID- 10100068 TI - Association of arginine vasopressin and arterial blood pressure in a population based sample. AB - BACKGROUND: The role of arginine vasopressin (AVP) in the development and maintenance of arterial hypertension is controversial. Furthermore, it remains unclear whether chronic treatment with antihypertensive agents modulates levels of AVP, with potential secondary effects on vascular tone and fluid homeostasis. OBJECTIVE: To investigate the relation between plasma AVP and arterial blood pressure in a population-based sample of 534 middle-aged subjects. RESULTS: Overall, levels of AVP were higher in hypertensive subjects (2.15 +/- 0.26 pg/ml; n = 289) than in normotensive subjects (1.45 +/- 0.15 pg/ml; n = 245; P < 0.05). (Hypertension was defined as systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 95 mmHg, or receiving antihypertensive medication.) In untreated individuals, plasma levels of AVP were found to be correlated with both systolic (r = 0.15, P = 0.002) and diastolic (r = 0.14, P = 0.005) blood pressure. The differences between the lowest and highest quartile of AVP levels were 5.1 mmHg (P = 0.03) and 2.6 mmHg (NS) for systolic and diastolic blood pressure, respectively, after adjustment for age and sex. Moreover, it appeared that the relation between AVP and blood pressure was particularly strong in subjects with low levels of renin (< 10 mU/l; n = 118; systolic blood pressure r = 0.24, P = 0.007; diastolic blood pressure r = 0.19, P = 0.03). Specifically, patients receiving monotherapy with diuretics (n = 39) or beta-blockers (n = 54) displayed elevated plasma levels of AVP (2.93 +/- 0.98 pg/ml and 2.74 +/- 0.74 pg/ml respectively); however, only in patients taking diuretics was this finding apparently independent of confounding variables. Other monotherapies with angiotensin-converting enzyme inhibitors (n = 9) or Ca(2+)-antagonists (n = 19) were not associated with levels of AVP. CONCLUSION: The data suggest that plasma levels of AVP display a discernible relationship with arterial blood pressure and hypertension, particularly when renin levels are low. In addition, with the exception of diuretics, no modulation of AVP levels is attributable to the intake of antihypertensive agents as it occurs in a population-based sample. PMID- 10100069 TI - Blood pressure in adults after prenatal exposure to famine. AB - BACKGROUND: Many studies have shown that low birth weight is associated with high blood pressure. The composition of the diet of pregnant women has also been found to affect blood pressure in their children. We assessed the effect of prenatal exposure to the Dutch famine of 1944-1945, during which the caloric intake from protein, fat and carbohydrate was proportionally reduced, on blood pressures in adults now aged about 50 years. METHODS AND RESULTS: We measured blood pressures at home and in the clinic among people born at term in one hospital in Amsterdam, The Netherlands, between November 1 1943 and February 28 1947, for whom we had detailed birth records. Blood pressures of people exposed to famine during late (n = 120), mid-(n = 109) or early gestation (n = 68) were compared with those of people born in the year before or conceived in the year after the famine (unexposed subjects, n = 442). No effect of prenatal exposure on systolic and diastolic blood pressure was observed. The mean systolic blood pressure taken in the clinic in those exposed in late gestation, and adjusted for sex and age, was 1.3 mmHg higher than in the unexposed group (95% confidence interval -1.9 to 4.4). The mean systolic blood pressure differed by -0.6 mmHg (95% confidence interval -3.9 to 2.7) for those exposed in mid-gestation and -1.7 mmHg (95% confidence interval -5.6 to 2.2) for those exposed in early gestation. People who were small at birth had higher blood pressures. A 1 kg increase in birth weight was associated with a decrease of 2.7 mmHg (95% confidence interval 0.3 to 5.1) in systolic blood pressure. Analyses of blood pressures measured at home gave similar results. CONCLUSION: High blood pressure was not linked to prenatal exposure to a balanced reduction of macronutrients in the maternal diet. However, it was linked to reduced fetal growth. We postulate that it might be the composition rather than the quantity of a pregnant woman's diet that affects her child's blood pressure in later life. PMID- 10100070 TI - Clinic-daytime blood pressure difference and cardiovascular damage. AB - OBJECTIVE: To investigate whether the clinic-daytime blood pressure difference can provide information on vascular reactivity to stress comparable to that of simple noninvasive stimuli such as a cold pressor test and isometric exercise, and whether there is any relationship between this blood pressure difference and noninvasive measurements of the left ventricular mass and carotid arterial wall. DESIGN: Patients with newly discovered, never-treated, sustained hypertension were included in the study after a 1 month run-in, during which time their blood pressure was measured three times at 2 week intervals. METHODS: Blood pressure was measured by a noninvasive procedure at rest and during a cold pressor test and an isometric exercise. The difference was calculated for systolic, diastolic and mean blood pressure as resting minus daytime ambulatory blood pressure. Parameters of the posterior wall and septal thickness of the left ventricle, aortic root and left atrium were studied by M-mode echocardiography. Carotid wall thickness and diameter were measured using ultrasound. RESULTS: The 90 patients enrolled in the study were divided into tertiles of clinic-daytime blood pressure difference. The composition of the groups differed in sex, since the majority of women were in the highest tertile, but was comparable for age, body mass index, renin-aldosterone axis and lipid and carbohydrate metabolism. Blood pressure responses to cold and isometric exercise were more pronounced in patients in the lowest tertile of blood pressure difference. No intergroup differences were detected in echocardiographic parameters of ventricular (left ventricular mass, tertiles I-III: 46.5 +/- 10, 42.3 +/- 8, 44.8 +/- 13 g/m2.7, respectively) and carotid (intima-media thickness, tertiles I-III 0.58 +/- 0.1, 0.54 +/- 0.1, 0.62 +/- 0.1 mm, respectively) structure. CONCLUSIONS: The present study indicates that the clinic-daytime blood pressure difference provides different information on cardiovascular reactivity compared with that obtained from the cold pressor test and isometric exercise. Moreover, it does not seem to have any relationship with ventricular hypertrophy and/or carotid wall thickening. PMID- 10100071 TI - Linkage of the Na,K-ATPase alpha 2 and beta 1 genes with resting and exercise heart rate and blood pressure: cross-sectional and longitudinal observations from the Quebec Family Study. AB - OBJECTIVE: To investigate whether genetic variations in the genes encoding the alpha and beta subunits of the Na,K-ATPase are linked with hemodynamic phenotypes. DESIGN AND PARTICIPANTS: Cross-sectional data based on 533 subjects (no antihypertensive medication) were obtained from 150 families of phase 2 of the Quebec Family Study, together with longitudinal data from 338 subjects (105 families) who had been measured 12 years earlier in phase 1 of the Quebec Family Study. MAIN OUTCOME MEASURES: Restriction fragment length polymorphisms were examined at the alpha 2 (exon 1 and exon 21-22 with BglII) and beta 1 (Msp I and Pvu II) loci of Na,K-ATPase. Hemodynamic phenotypes measured included systolic and diastolic blood pressure, heart rate and rate-pressure product at rest and during low-intensity exercise. RESULTS: Sib-pair analysis revealed relatively strong linkages (P = 0.0003-0.002) between the resting heart rate and rate pressure product and the alpha 2 exon 21-22 marker and alpha 2 haplotype. Moreover, the alpha 2 exon 21-22 marker showed suggestive linkages (P = 0.01 to 0.043) with resting systolic blood pressure and exercise diastolic blood pressure, heart rate and rate-pressure product, and the alpha 2 haplotype with exercise diastolic blood pressure and rate-pressure product and the 12-year change in resting systolic blood pressure (P = 0.03 to 0.05). Both the beta 1 Msp I marker and the beta 1 haplotype were linked with the resting rate-pressure product (P = 0.007 and 0.003, respectively), and all beta 1 markers showed linkage with the change in resting systolic blood pressure (P = 0.00005 to 0.024). In men, there was a significant (P = 0.01) interaction between the alpha 2 exon 21-22 genotype and the postglucose plasma insulin level with regard to resting systolic blood pressure. CONCLUSIONS: These data suggest that the alpha 2 and beta 1 genes of Na,K-ATPase contribute to the regulation of hemodynamic phenotypes in healthy subjects. PMID- 10100072 TI - Insertion/deletion angiotensin converting enzyme gene polymorphism affects the microvascular structure of the kidney in patients with nondiabetic renal disease. AB - OBJECTIVE: It has been reported that the deletion allele of the insertion/deletion polymorphism of the angiotensin I converting enzyme gene is associated with increased cardiovascular risk and progressive renal disease, including immunoglobulin A nephropathy. We therefore investigated the relationship between angiotensin converting enzyme polymorphism and intrarenal microvascular structure in 56 patients with nondiabetic renal disease. METHODS AND RESULTS: We determined various cardiovascular hormones of the renin angiotensin system and angiotensin converting enzyme gene polymorphism in 56 patients with nondiabetic renal diseases who underwent a renal biopsy. The patients were divided into three groups by angiotensin converting enzyme genotype (insertion/insertion, n = 21; insertion/deletion, n = 23; deletion/deletion, n = 12) using polymerase chain reaction methods. The angiotensin converting enzyme insertion/ deletion and deletion/deletion genotypes were associated with a significantly higher interlobular artery wall : lumen ratio than the insertion/insertion genotype (insertion/insertion 0.27 +/- 0.01, insertion/deletion 0.32 +/- 0.01, deletion/deletion 0.33 +/- 0.02; P < 0.05). Afferent arteriolar and tubulo-interstitial injury scores were similar among the three genotypes. Although serum angiotensin converting enzyme activity was higher in the deletion/deletion than in the other two genotypes (insertion/insertion 9.7 +/- 0.7, insertion/deletion 10.7 +/- 0.9, deletion/deletion 14.0 +/- 2.4 IU/I; P < 0.05), other factors of the renin-angiotensin system, including blood pressure and serum creatinine levels, were not different among the three groups. CONCLUSIONS: The angiotensin converting enzyme deletion/deletion genotype may be considered a risk factor for the development of microvascular wall thickening in nondiabetic renal diseases. PMID- 10100073 TI - Cyclosporine A and control of vascular tone in the human forearm: influence of post-transplant hypertension. AB - OBJECTIVE: The use of cyclosporine A after organ transplantation is associated with a high incidence of hypertension, but the underlying mechanisms for this process are not clear. We investigated the effects of blockade of basal release of endothelial nitric oxide and the effects of endothelium-independent and dependent vasodilators and vasoconstrictors in patients treated with cyclosporine A after heart transplantation. DESIGN: We measured blood pressure and forearm blood flow responses to brachial artery infusions of NG-monomethyl-L-arginine (L NMMA), sodium nitroprusside, acetylcholine, norepinephrine and vasodilating and vasoconstricting doses of endothelin-1 in eight patients early (< 3 months) and in 11 patients late (> 18 months) after transplantation. RESULTS: Diastolic blood pressure was higher late after transplantation, but calculated forearm vascular resistance was lower (P < 0.01). Thus, increased forearm vascular resistance does not contribute to the increase in blood pressure. The vasoconstrictor response to L-NMMA was similar in both groups but a reduced endothelium-dependent vasodilator response to acetylcholine was seen late after transplantation. However, impaired smooth muscle responsiveness to nitric oxide may have contributed to this finding, since the response to sodium nitroprusside tended to be reduced. Vasoconstrictor responses to norepinephrine and endothelin-1 were comparable but no vasodilation was seen with low doses of endothelin-1 late compared with early after transplantation (P < 0.05). CONCLUSIONS: The findings in the forearm circulation question the concept of generalized increases in vasoconstrictor responses or a disturbance of tonic, basal release nitric oxide in the pathogenesis of cyclosporine-A-induced hypertension. Although the forearm vasodilator responses to the stimulation of endothelial nitric oxide production and release by acetylcholine, and to low doses of endothelin-1, were impaired, these findings could be explained by the increase in blood pressure rather than cyclosporine A itself. PMID- 10100074 TI - Increased mechanosensitive currents in aortic endothelial cells from genetically hypertensive rats. AB - OBJECTIVE: To characterize and compare mechanosensitive cell currents in rat aortic endothelial cells from spontaneously hypertensive and Wistar-Kyoto rats. METHODS AND RESULTS: By use of the patch-clamp technique, we investigated whole cell currents of native rat aortic endothelial cells in the presence of mechanical stimulation elicited by hyposmotic cell swelling. In rat aortic endothelial cells, this hypotonic cell swelling induced a fourfold increase in outward-directed whole-cell currents carried by K+, leading to cell hyperpolarization and a small increase in inward-directed currents. Gadolinium, a blocker of stretch-activated cation channels, completely blocked hypotonic cell swelling-induced outward- and inward-directed whole-cell currents. Charybdotoxin, a blocker of Ca(2+)-dependent K+ channels, decreased hypotonic cell swelling induced outward-directed currents by up to 85%. Disruption of actin filaments by cytochalasin B and of microtubuli by nocodazole reduced the activation of hypotonic cell swelling-induced whole-cell currents by 91 and 71%, respectively. In experimental hypertension, hypotonic cell swelling-induced whole-cell conductance was significantly increased in spontaneously hypertensive rats (331 +/- 20 pS/pF) compared with normotensive controls (167 +/- 7 pS/pF, P < 0.01), whereas basal and agonist-induced cell conductances were not altered. CONCLUSIONS: Increased hypotonic swelling-induced currents in aortic endothelial cells from spontaneously hypertensive rats presumably reflect an increased density or mechanosensitivity of stretch-activated ion channels in experimental hypertension. The increased mechanosensitive whole-cell currents might indicate an altered endothelial mechanotransduction in experimental hypertension. PMID- 10100075 TI - Rapid regulation of adrenomedullin in metabolically compromised vascular smooth muscle cells. AB - OBJECTIVE: The prepro-adrenomedullin gene encodes the biologically active peptide adrenomedullin, which acts as a potent vasodilator as well as a modulator of vascular smooth muscle cell growth. We investigated the question of whether adrenomedullin is regulated in response to metabolic perturbations in vascular smooth muscle. MATERIALS AND METHODS: Acute inhibition of glycolysis, leading to partial depletion of cellular ATP, was produced in cultured rat aortic vascular smooth muscle cells by replacing glucose with 2-deoxyglucose. Solution hybridization/RNase protection analysis was used to quantitate changes in expression of the prepro-adreno-medullin messenger RNA and a specific radioimmunoassay was used to assess levels of secreted adrenomedullin. RESULTS: Acute incubation of rat aortic vascular smooth muscle cells with 2-deoxyglucose caused a rapid and sustained induction of low basal levels of adrenomedullin messenger RNA, which reached twice the control levels by 1 h and four times control levels by 6 h. The induction of adrenomedullin messenger RNA expression was dependent upon de-novo gene transcription and was reversed by the re introduction of glucose. Despite the sustained increase in adrenomedullin messenger RNA, secretion of immunoreactive-adrenomedullin from vascular smooth muscle cells was reduced by as much as 75% and paralleled the inhibition of radiolabeled amino acid incorporation into protein during glycolytic inhibition; both parameters recovered towards control levels following re-introduction of glucose. CONCLUSIONS: The rapid and reversible activation of the adrenomedullin gene and inhibition of adrenomedullin peptide release in response to metabolic inhibition suggest that adrenomedullin represents a novel localized mechanism that may modulate regional blood flow and vascular smooth muscle cell proliferation in response to perturbations of normal metabolism. PMID- 10100076 TI - Relationship between small-artery structure and systolic, diastolic and pulse pressure in essential hypertension. AB - OBJECTIVE: Studies of cerebral arterioles have suggested that pulse pressure may be a more important determinant of small-artery structure than systolic, diastolic or mean blood pressure in stroke-prone spontaneously hypertensive rats and in rats with an arterio-venous shunt. A study of small arteries has suggested that this is not the case in human essential hypertension. We therefore investigated the role of hemodynamic determinants on small-artery structure in hypertensive patients. DESIGN AND METHODS: To determine whether pulse pressure contributes to structural alterations in human essential hypertension, small arteries (lumen < 300 microns) were obtained from gluteal subcutaneous biopsies of 40 normotensive subjects aged 40.7 +/- 1.2 years and 45 untreated essential hypertensive humans aged 46.5 +/- 1.3 years. The relationship between the media: lumen ratio of the small arteries and levels of systolic, diastolic and mean blood pressure and pulse pressure was investigated. RESULTS: The media: lumen ratio (5.33 +/- 0.001%) of small gluteal subcutaneous arteries of normotensive subjects was significantly smaller and the lumen diameter (306 +/- 13 microns) significantly larger than in untreated hypertensive patients (7.42 +/- 0.001% and 244 +/- 9.7 microns respectively, P < 0.001). The media: lumen ratio of both groups examined together correlated with systolic blood pressure (r = 0.45, P < 0.001), diastolic blood pressure (r = 0.56, P < 0.001) and mean arterial pressure (r = 0.55, P < 0.001). The media: lumen ratio of vessels from hypertensive patients correlated with diastolic blood pressure (r = 0.22, P < 0.01) but not with systolic or mean blood pressure. There was no correlation between the media: lumen ratio of small gluteal subcutaneous arteries and pulse pressure in this population of normotensive and hypertensive subjects, examined together or separately. CONCLUSION: These results suggest that in 30- to 65-year-old humans with systolodiastolic essential hypertension, pulse pressure does not appear to be an important determinant of small-artery structure. PMID- 10100077 TI - U46619-mediated vasoconstriction of the fetal placental vasculature in vitro in normal and hypertensive pregnancies. AB - OBJECTIVES: To measure in-vitro responses to the thromboxane A2 (TxA2) mimetic U46619 in the fetal placental vasculature of human placentae from normotensive women and those with pre-eclampsia. Furthermore, to compare fetal vascular responses to endothelin-1,5-hydroxytryptamine, potassium chloride (KCl) and prostacyclin (PGI2) in placentae from normal or pre-eclamptic pregnancies. METHODS: Single placental lobules of intact placentae were bilaterally perfused in situ (fetal and maternal) with constant flows of Krebs' solution. Changes in fetal arterial perfusion pressure during intra-arterial infusion of vasoactive agents were recorded. Fetal placental vasoconstrictor concentration response curves were obtained to U46619 (0.01-300 nmol/l), endothelin-1 (0.4-160 nmol/l), KCl (3-300 mmol/l) and 5-hydroxytryptamine (0.03-30 mumol/l). In addition, vasodilator concentration response curves were obtained for PGI2 (1.2-350 nmol/l) in the fetal placental circulation during submaximal increases in perfusion pressure with prostaglandin F2 alpha (PGF2 alpha; 0.7-2.0 mumol/l). RESULTS: The maximum increase in perfusion pressure caused by U46619 in placentae from normotensive women was 194 +/- 25 mmHg. The maximum response to U46619 was significantly reduced in the placentae from women with pre-eclampsia (104 +/- 21 mmHg). In contrast, there were no differences in constrictor responses to endothelin-1,5-hydroxytryptamine and KCl, or in dilator responses to PGI2 in placentae obtained from either normotensive women or those with pre-eclampsia. CONCLUSION: TxA2 receptor-mediated vasoconstriction is reduced in the fetal vasculature of placentae from women with pre-eclampsia, possibly to compensate for the increased levels of TxA2 seen in these conditions. PMID- 10100078 TI - Angiotensin II type 1 and type 2 receptors bind angiotensin II through different types of epitope recognition. AB - OBJECTIVE: This study was designed to demonstrate that the principle of molecular recognition underlying high-affinity binding of angiotensin II to the type 2 (AT2) receptor is distinct from that of the type 1 (AT1) receptor. In general, the same functional pharmacophores in hormones are used to bind and activate different subtypes of cell surface receptors. However, the binding of angiotensin II to the AT2 receptor is distinct from that of the AT1 receptor. DESIGN AND METHODS: To systematically evaluate the effect of modification of angiotensin II side chains on binding to both the receptors, several analogs of angiotensin II were synthesized. Rat AT1 or AT2 receptors expressed in COS1 cell membranes were used to determine the affinity of analogs using radioligand competition binding experiments under equilibrium conditions. RESULTS: Modifications of all angiotensin II side chains affected binding to the AT2 receptor to nearly similar extents. In contrast, binding to the AT1 receptor was significantly affected by modifications at side chain positions 2, 4, 6 and 7. In accordance with previous observations that Tyr4- or Phe8-modified angiotensin II analogs antagonized vasoconstriction mediated exclusively by the AT1 receptor, binding to the AT1 receptor was significantly dependent on Tyr4 or Phe8 of angiotensin II whereas binding to the AT2 receptor was not. Rather surprisingly, the affinity profile of several angiotensin II analogs towards the AT2 receptor was similar to the measured affinity of the constitutively active N111G mutant AT1 receptor. CONCLUSIONS: These results suggest that the AT2-receptor pharmacophore is very distinct from that of the AT1 receptor. The AT1 receptor is in a constrained conformation and is activated only when bound to angiotensin II. In contrast, the AT2 receptor is 'relaxed' in that no single interaction is critical for binding, like the N111G mutant AT1 receptor, which is constitutively active. PMID- 10100079 TI - The effects of different types and doses of oestrogen replacement therapy on clinic and ambulatory blood pressure and the renin-angiotensin system in normotensive postmenopausal women. AB - OBJECTIVE: The effect on blood pressure of oral replacement' doses of exogenous oestrogen may depend on the type and dose of oestrogen administered. This study was designed to compare with placebo the effect of once daily treatment with a 'natural' oestrogen, piperazine oestrone sulphate, in two different doses and a semisynthetic oestrogen, ethinyloestradiol, on clinic and ambulatory blood pressure and the renin-angiotensin system in postmenopausal women. DESIGN AND METHODS: Twenty-four normotensive postmenopausal women (median age 54 years, range 47-60 years) participated in the study which used a double-blind crossover design. For each subject there were four randomized treatment phases, each lasting 4 weeks. The separate treatments administered once daily were 0.625 mg oestrone sulphate, 2.5 mg oestrone sulphate, 0.02 mg ethinyloestradiol and matching placebo. Clinic blood pressure, heart rate and weight were measured weekly with the mean values of weeks three and four of each phase used for analysis. Ambulatory blood pressure and biochemical measurements were performed in the final week of each phase. RESULTS: Twenty-four subjects entered and 22 completed the randomized phases of the study. Compared with the placebo phase, end-of-phase mean clinic diastolic blood pressure was reduced in subjects taking the semisynthetic oestrogen (P < 0.01) but was unchanged in those taking the 'low' and 'high' dose natural oestrogen. Mean clinic systolic blood pressure was also unchanged by any of the oestrogen treatments. Ambulatory night-time systolic, diastolic and mean arterial blood pressures were reduced with the low dose natural and semisynthetic oestrogen treatments compared with placebo (P < 0.01), whereas there was no significant effect of the oestrogen treatments on ambulatory daytime blood pressures. A reduction in clinic and ambulatory heart rate was observed with the high-dose oestrone and semisynthetic oestrogen treatments. There was a dose-dependent increase in plasma renin substrate and decrease in plasma renin concentration with all active treatments; however, there was no change in plasma renin activity or plasma aldosterone concentration. CONCLUSION: In normotensive postmenopausal women, replacement doses of natural and semisynthetic oestrogen reduce night-time ambulatory blood pressure with either no change or a small reduction in clinic blood pressure. Reduction in blood pressure is not explained by reduced activity of the renin-angiotensin system but could have a component of reduced central sympathetic drive consistent with the decreased heart rate. PMID- 10100080 TI - Withdrawal of hormonal therapy for 4 weeks decreases arterial compliance in postmenopausal women. AB - BACKGROUND: We demonstrated in a previous cross-sectional study that arterial compliance is elevated in postmenopausal women taking estrogen-containing hormonal therapy, which may partially account for the reduction in cardiovascular risk observed. OBJECTIVE: To investigate the effects of withdrawal and recommencement of hormonal therapy, each for 4 weeks, on arterial compliance. METHODS: Seventeen postmenopausal women [aged 56 +/- 4 years (mean +/- SD)] taking long-term hormonal therapy (+HT group) were studied at baseline, 4 weeks after withdrawal of hormonal therapy and again 4 weeks after recommencement. Systemic arterial compliance (SAC), pulse wave velocity (PWV) in the aorto femoral and femoral-dorsalis pedis regions, and hemodynamic variables were measured at baseline, and at the end of each study intervention. As a time control, seventeen postmenopausal women (aged 63 +/- 7 years) not taking hormonal therapy (-HT group) were also investigated. RESULTS: SAC significantly decreased from 0.47 +/- 0.06 to 0.40 +/- 0.05 arbitrary compliance units (mean +/- SEM; P < 0.05) after 4 weeks withdrawal from hormonal therapy. PWV in the femoral-dorsalis pedis region was elevated significantly by the withdrawal of hormonal therapy (8.4 +/- 0.4 to 9.4 +/- 0.5 m/s; P < 0.05), but PWV in the aortofemoral region did not change. After therapy had been recommenced for 4 weeks, SAC and PWV in the femoral-dorsalis pedis region were restored to baseline values. The -HT group showed no difference in SAC or PWV, and mean arterial pressure did not change in either group throughout the study period. CONCLUSION: These data suggest that hormonal modulation of distal arterial vascular tone may account for short-term changes in arterial compliance associated with estrogen-containing hormonal therapy. PMID- 10100081 TI - Adrenocorticotrophin-induced hypertension: effects of mineralocorticoid and glucocorticoid receptor antagonism. AB - OBJECTIVE: To examine whether the increase of blood pressure in adrenocorticotrophin-treated rats is mediated through mineralocorticoid or glucocorticoid receptors or corticosterone 6 beta-hydroxylation inhibition. DESIGN: Rats were randomly allocated to 14 treatment groups for 10 days. The treatments included sham injection (n = 35), adrenocorticotrophin (5, 100, 500 micrograms/kg per day, subcutaneously, n = 5, 15 and 15, respectively), spironolactone (100 mg/kg per day, subcutaneously, n = 15), standard-dose or high dose RU 486 (70 mg/kg every 3 days or 70 mg/kg per day, subcutaneously, n = 5 and 10, respectively), spironolactone + adrenocorticotrophin (100 micrograms/kg per day, n = 5, or 500 micrograms/kg per day, n = 10), standard-dose RU 486 + adrenocorticotrophin (500 micrograms/kg per day, n = 5), high-dose RU 486 + adrenocorticotrophin (100 micrograms/kg per day, n = 10), troleandomycin (40 mg/kg per day, subcutaneously, n = 5) and troleandomycin + adrenocorticotrophin (5 micrograms/kg per day, n = 5). Systolic blood pressure and metabolic parameters were measured every second day. RESULTS: Adrenocorticotrophin treatment increased systolic blood pressure dose-dependently (5 micrograms/kg per day: +14 +/- 2 mmHg; 100 micrograms/kg per day: +20 +/- 2 mmHg; 500 micrograms/kg per day: +28 +/- 2 mmHg, all P < 0.001). Adrenocorticotrophin at 100 and 500 micrograms/kg per day increased plasma sodium and decreased plasma potassium concentrations. Spironolactone did not block adrenocorticotrophin-induced systolic blood pressure changes but did block changes in plasma sodium and potassium levels. Standard-dose RU 486 did not modify the adrenocorticotrophin induced (500 micrograms/kg per day) systolic blood pressure rise but blocked the effect of adrenocorticotrophin on body weight. High-dose RU 486 partially blocked the adrenocorticotrophin-induced (100 micrograms/kg per day) systolic blood pressure increase (adrenocorticotrophin at 100 micrograms/kg per day: 143 +/- 3 mmHg; high-dose RU 486 + adrenocorticotrophin at 100 micrograms/kg per day: 128 +/- 5 mmHg, P < 0.001) and body-weight loss. Troleandomycin did not alter the development of adrenocorticotrophin-induced hypertension. CONCLUSIONS: Spironolactone and standard-dose RU 486 did not modify adrenocorticotrophin induced hypertension despite demonstrable antimineralocorticoid and antiglucocorticoid actions. High-dose RU 486 partially blocked adrenocorticotrophin-induced (100 micrograms/kg per day) hypertension, suggesting either a permissive effect of glucocorticoid on blood pressure or other antihypertensive actions of RU 486. Inhibition of glucocorticoid 6 beta hydroxylation by troleandomycin did not modify adrenocorticotrophin-induced hypertension, suggesting that effects of corticosterone 6 beta-hydroxylation in adrenocorticotrophin-induced hypertension are negligible. PMID- 10100082 TI - Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers. AB - OBJECTIVE: To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN: A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS: MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS: Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS: The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade. PMID- 10100084 TI - Effect of losartan on human platelet activation. AB - OBJECTIVE: Previous studies have demonstrated that losartan can block the thromboxane A2 receptor on the vascular wall. The aim of the present study was to assess the effect of losartan on human platelet activation. METHODS: Platelets were obtained from 15 healthy men, aged 26-40 years. Platelet activation was measured by changes in the light transmission of platelet-rich plasma stimulated by the thromboxane A2 analog U46619 (5 x 10(-6) mol/l) or ADP (10(-5) mol/l). RESULTS: U46619-stimulated platelet aggregation was significantly inhibited by losartan in a dose-dependent manner. Only a high dose of EXP 3174 (5 x 10(-5) mol/l), the in vivo active metabolite of losartan, was able to attenuate U46619 induced platelet activation. Captopril, an angiotensin I converting inhibitor, failed to modify U46619-induced platelet aggregation. Furthermore, the binding of [3H]-U46619 to platelets was competitively inhibited by losartan, whereas only a high dose of EXP 3174 reduced the binding of [3H]-U46619. Captopril failed to modify the binding of [3H]-U46619 to platelets. Losartan also reduced the platelet activation induced by ADP (10(-5) mol/l), a platelet agonist partially dependent on thromboxane A2. In addition, when thromboxane A2 generation was blocked by aspirin, ADP-induced platelet aggregation was inhibited to a similar degree to the inhibition induced by losartan. Exogenous angiotensin II did not elicit any modification of either U46619- or ADP-stimulated platelet aggregation. CONCLUSIONS: Losartan decreased platelet aggregation by a thromboxane A2 dependent mechanism. EXP 3174 was less potent than losartan in reducing thromboxane A2-dependent platelet activation. Captopril and exogenous angiotensin II had no effect on human platelet activation. These results suggest that losartan reduced thromboxane A2-dependent platelet activation independently of its effect on angiotensin II. PMID- 10100083 TI - Controlled study of the effect of angiotensin converting enzyme inhibition versus calcium-entry blockade on insulin sensitivity in overweight hypertensive patients: Trandolapril Italian Study (TRIS). AB - OBJECTIVE: The aim of this study was to evaluate the effect of trandolapril, an angiotensin converting enzyme inhibitor, on blood pressure, forearm blood flow and insulin sensitivity in comparison with nifedipine gastrointestinal therapeutic system. PATIENTS AND METHODS: This is a multicentre, two-way parallel group, open-label comparative study in 90 overweight hypertensive patients, who were randomly assigned to treatment for 8 weeks with either trandolapril or nifedipine. At baseline and after treatment, all patients underwent an oral glucose tolerance test, an evaluation of their metabolic profiles and a euglycaemic hyperinsulinaemic clamp test. In a subgroup of 18 patients, a forearm study was carried out. RESULTS: Blood pressure fell by the second week of treatment and remained significantly reduced compared with baseline in both treatment groups. Plasma triglyceride levels were also significantly reduced after trandolapril therapy, but no significant changes occurred in the other metabolic parameters during treatment with either drug. During the euglycaemic hyperinsulinaemic clamp, whole-body glucose use was similar in the two treatment groups at baseline, and a moderate but statistically significant increase in insulin sensitivity was observed after trandolapril treatment (trandolapril: 5.0 +/- 0.2 versus 4.5 +/- 0.2 mg/kg per min; nifedipine: 4.1 +/- 0.3 versus 4.2 +/- 0.3 mg/kg per min; P < 0.05, versus baseline and trandolapril versus nifedipine treatment). Skeletal muscle glucose uptake was significantly higher after trandolapril than after nifedipine therapy (5.0 +/- 0.7 and 3.0 +/- 0.4 mg/min, respectively; P < 0.01). As forearm blood flow was similar in the two treatment groups at baseline and was unchanged after 8 weeks of therapy, skeletal muscle glucose extraction was significantly greater in the ACE inhibitor treated-group than in the nifedipine comparative group (trandolapril: baseline 21 +/- 2, treatment 24 +/- 3 mg/dl; nifedipine: baseline 18 +/- 3, treatment 16 +/- 2 mg/dl; P < 0.05, trandolapril versus nifedipine treatment). CONCLUSIONS: During short-term treatment, ACE inhibition with trandolapril was able to moderately improve insulin sensitivity, in comparison with calcium blockade, and this effect appeared to be independent of the haemodynamic action of the drug. PMID- 10100085 TI - Dietary sucrose does not increase twenty-four-hour ambulatory blood pressure in patients with either essential hypertension or polycystic kidney disease. PMID- 10100086 TI - Arterial stiffness. AB - BACKGROUND: Arterial stiffness is an important determinant of pulse pressure, and of left ventricular load and coronary perfusion pressure. ASSESSMENTS OF STIFFNESS: Precise quantification is elusive, since stiffness is different in different arteries and even in the same artery at different pressures. Proximal elastic arteries and peripheral muscular arteries respond differently to aging change and to drugs. Various other terms are used to express stiffness, such as distensibility and compliance. Various indirect indices are also used, including pulse wave velocity, characteristic impedance and augmentation index. INCREASES IN STIFFNESS: While the literature is confusing, it is well established that stiffness of central arteries increases with aging and with elevated blood pressure. Effects of other diseases and of vasoactive agents are less clear-cut. PMID- 10100087 TI - The ethics of using placebo in hypertension clinical trials. AB - USE OF PLACEBO CONTROLS: Placebo controls can enhance the value of two types of hypertension trials: measurement of the blood pressure-lowering efficacy of antihypertensive treatment and determination of whether therapeutic interventions can affect clinical endpoints. However, the possibility of adverse outcomes in hypertensive patients allocated to placebo therapy raises ethical concerns. EFFICACY STUDIES: Placebo controls in efficacy studies are particularly helpful in thoroughly quantifying the effect of treatment. The hazard to patients can be minimized by exposing them to placebo for the least possible amount of time and, assuming that blood pressure is itself the primary variable, reducing the probability of cardiovascular events by excluding subjects with severe hypertension or major concomitant risk factors. ENDPOINT STUDIES: Endpoint studies present a more difficult challenge, for they are designed in anticipation of cardiovascular events and patients at high risk are often enrolled in order to more rapidly achieve the required number of endpoints for statistical analysis. In such circumstances, positive therapeutic controls, despite the complexities of analysis, must be preferred to placebo. EARLY-STAGE HYPERTENSION: Important questions regarding the management of early-stage hypertension remain, and despite official treatment guidelines recommendations, currently based chiefly on extrapolation and judgement, many physicians routinely withhold therapy in mild hypertension, even when other risk factors are present. With appropriate safeguards, placebo-controlled trials may be necessary to examine potential benefits of therapy in such patients. Indeed, resolving therapeutic uncertainty and creating well founded recommendations for the future management of the many patients with milder forms of hypertension can make placebo controls both ethical and appropriate. PMID- 10100088 TI - M235T angiotensinogen gene polymorphism and cardiovascular renal risk. AB - OBJECTIVE: In this meta-analysis, we attempted to derive pooled estimates for the putative associations between various cardiovascular-renal disorders and the M235T polymorphism of the angiotensinogen gene. METHODS: Case-control studies were combined, using the Mantel and Haenszel approach. Joint P values for continuous variables were calculated by Stouffer's method. Continuous measurements reported in different units were expressed on a percentage scale using the intrastudy mean of the MM genotype as denominator. RESULTS: The computerized database used for this analysis included 69 reports with an overall sample size of 27,906 subjects. Overall, possession of the T allele was associated with an increased risk of hypertension. In comparison with the MM reference group (number of studies, n = 32), the excess risk was 31% (P = 0.001) in TT homozygotes and 11% (P = 0.03) in TM heterozygotes. The sensitivity analysis showed that this association was present only in whites (T allelic frequency, f = 42.2%), but not in blacks (f = 77.0%) or Asians (f = 78.0%). Atherosclerotic complications (n = 12), renal microvascular disorders (n = 13), cardiomyopathy (n = 2) or diabetic retinopathy (n = 3) were not correlated with the M235T polymorphism. Publication bias was observed for hypertension, but not for coronary heart disease, including myocardial infarction, and for microvascular nephropathy. Furthermore, in comparison with the MM control group, the circulating angiotensinogen levels (n = 8) were raised by 11 and 7% (P = 0.01) in TT and TM subjects, respectively. In contrast, plasma levels of the angiotensin I converting enzyme (n = 4) and body mass index (n = 15) were not associated with the T allele. CONCLUSION: The T allele encoding angiotensinogen is not associated with atherosclerotic or microvascular complications, but in Caucasians behaves as a marker for hypertension. This association, which may have been inflated by publication bias, does not necessarily imply causality. PMID- 10100089 TI - Is the effect of low birth weight on cardiovascular mortality mediated through high blood pressure? AB - OBJECTIVE: To explore whether the inverse association between birth weight and mortality from circulatory diseases is mediated through blood pressure in men aged 50-75 years. DESIGN: Cohort study with retrospectively collected data on size at birth. SUBJECTS AND SETTING: The study included 1334 men born during 1920 1924, living in Uppsala, Sweden, who were examined at the ages of 50 and 60 years, and followed-up to the end of 1995. MAIN OUTCOME MEASURES: Mortality from circulatory diseases based on routine death registration. RESULTS: Birth weight showed a specific, inverse association with mortality from circulatory diseases: the rate ratio was 0.67 (95% confidence interval 0.50 to 0.89) per 1000 g increase in birth weight. This association was not appreciably affected by adjustment for sociodemographic characteristics or smoking, but was strengthened slightly by adjustment for body mass index at the ages of 50 and 60 years. Adjustment for systolic blood pressure at the age of 50 years only slightly reduced the strength of the inverse association between birth weight and mortality from ischaemic heart disease, and did not affect the inverse association between birth weight and mortality from stroke. Adjustments for systolic and diastolic blood pressure and hypertension treatment at the ages of 50 and 60 years did not reduce the strength of the association between birth weight and mortality from circulatory diseases at the age of 60-75 years. CONCLUSIONS: The inverse association between birth weight and mortality from circulatory diseases in men aged 50-75 years is independent of adult sociodemographic characteristics, smoking and adult obesity and does not seem to be mediated through an increased blood pressure in those with low birth weight. PMID- 10100090 TI - Heritability of plasma leptin levels: a twin study. AB - OBJECTIVE: To examine the influence of genetic factors on plasma leptin levels. SUBJECTS AND METHODS: We measured plasma leptin levels, body mass index and body fat distribution in healthy young female monozygotic (n = 19) and dizygotic (n = 14) twins. The twin zygosity was verified by determination of short tandem repeat and amplified fragment length polymorphism systems. The genetic analysis included analysis of variance-based and maximum likelihood-based methods. RESULTS: Plasma leptin levels were correlated significantly with body mass index (r = 0.59, P < 0.001), waist circumference (r = 0.54, P < 0.001) and hip circumference (r = 0.63, P < 0.001), but not with age (r = -0.17) or the waist:hip ratio (r = 0.02). The heritability estimates derived from intraclass correlations were significant for body mass index (P = 0.001), waist circumference (P = 0.004), hip circumference (P = 0.01) and plasma leptin levels (P = 0.005), but not for the waist:hip ratio (P = 0.22). In the maximum likelihood-based path analysis, heritability was estimated at 79% for body mass index and at 73% for plasma leptin levels. After adjustment for body mass index, the heritability estimate for leptin levels from the model-fitting approach was 55%. CONCLUSIONS: Genetic factors are major determinants of plasma leptin levels in humans and may account for as much as half of the variance in leptin levels. PMID- 10100091 TI - Association of Trp64Arg beta 3-adrenergic-receptor gene polymorphism with essential hypertension in the Sardinian population. AB - OBJECTIVE: To evaluate the possible association of three candidate gene polymorphisms with essential hypertension in the genetically homogeneous Sardinian population. SUBJECTS AND METHODS: We studied 494 unrelated, nondiabetic subjects, 213 (43.2%) with essential hypertension. All subjects underwent a 75 g oral glucose tolerance test with determination of glycemia and insulinemia and serum lipids. The polymorphisms evaluated comprised Trp64Arg of the beta 3 adrenergic receptor, Gly40Ser of the glucagon receptor gene and the insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene. RESULTS: Among the overall population studied, 48 (9.7%) were heterozygous carriers of the Trp64Arg polymorphism. The frequency of the Trp64Arg variant was significantly higher in hypertensives (13.6%) than normotensives (6.8%; chi 2 5.73, P = 0.017). The 48 subjects with the Trp64Arg variant had significantly higher (P < 0.049) serum triglyceride levels than the 446 with the Trp64Trp variant, while no significant differences were observed, either fasting or during the 75 g oral glucose tolerance test, in glycemia and insulinemia. No differences were found between hypertensive and normotensive subjects for ACE gene insertion/deletion polymorphism nor in the frequency of the Gly40Ser coding change in exon 2 of the glucagon receptor gene. CONCLUSIONS: Our results are consistent with the thesis that the Trp64Arg polymorphism of the beta 3 adrenergic receptor gene is associated more often with the condition of high blood pressure than with normal blood pressure. PMID- 10100092 TI - No linkage of the lipoprotein lipase locus to hypertension in Caucasians. AB - OBJECTIVE: A previous study has shown significant linkage of five markers near the lipoprotein lipase locus to systolic blood pressure, but not to diastolic blood pressure, in nondiabetic members of 48 Taiwanese families selected for noninsulin-dependent diabetes. However, lipoprotein lipase markers did not appear strongly linked to systolic blood pressure in a study of Mexican-Americans using a variety of selection schemes. The objective of the current study was to test whether markers near the lipoprotein lipase gene were linked to hypertension in Caucasians. DESIGN: To test for linkage of genetic markers in or near the lipoprotein lipase gene to hypertension in Caucasians, two sets of Caucasian hypertensive sibships were genotyped. The samples included 261 sibships (431 effective sibpairs) from four field centers of the National Heart, Lung and Blood Institute Family Heart Study and 211 sibships (282 effective sibpairs) from the Health Family Tree database in Utah. RESULTS: Two highly polymorphic markers in or near the lipoprotein lipase gene showed no evidence of excess allele sharing in either set of hypertensive sibships. Combining the two datasets resulted in 653 and 713 effective sibpairs for the two markers, sharing 0.495 +/- 0.30 and 0.486 +/- 0.28 alleles identical by descent compared to an expected sharing of 0.50. Multipoint analysis of the two loci also did not show linkage (P = 0.95). CONCLUSIONS: We conclude that the lipoprotein lipase locus and nearby regions do not appear to be linked to hypertension in Caucasians. PMID- 10100093 TI - Functional characterization of endothelin receptors in hypertensive resistance vessels. AB - OBJECTIVE: The physiological and pathophysiological functions of endothelin-1 in modulating the regional blood flow of normal and spontaneously hypertensive rats (SHR) were studied in the perfused mesenteric vascular bed, a useful model for investigating resistance vessels. DESIGN AND METHODS: We used 12-week-old SHR and Wistar-Kyoto (WKY) rats. Endothelin A (ETA) receptor responsiveness was evaluated by endothelin-1 (0.2-2 mumol/l) concentration-response curves, and repeated in the presence of indomethacin and the ETA and endothelin B (ETB) receptor antagonists BQ-485 and BQ-788, respectively. ETB receptor responsiveness was tested by sarafotoxin S6c concentration-response curves, obtained in the noradrenaline-precontracted mesenteric vascular bed, and repeated after treatment with BQ-788 and after endothelial denudation. RESULTS: In both groups, endothelin 1 induced concentration-dependent contraction; SHR exhibited a markedly increased maximal effect compared with WKY rats (P < 0.01). BQ-485 produced a shift to the right for endothelin-1 concentration-response curves in both groups, with a higher pA2 (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) value in SHR than in WKY rats (P < 0.01). The increase in the maximal effect produced by endothelin-1 in SHR was prevented by indomethacin, which also induced a significant increase in the endothelin-1 concentration producing the half-maximal response (EC50) in SHR (P < 0.05). Sarafotoxin S6c produced an ETB-dependent endothelium-mediated relaxant effect in WKY rats, which was not observed in SHR. CONCLUSIONS: The higher vasoconstriction induced by endothelin-1 in SHR may be related to a greater number of available ETA receptors, due to the presence of an ETA receptor subtype. This mechanism may be linked to the production of prostanoids that add to the direct endothelin-1 evoked vasoconstriction. These results, together with the lack of relaxation in response to sarafotoxin S6c in SHR, suggest that an imbalance in the endothelin-1 ability to induce both contraction and relaxation is present in SHR with sustained hypertension, manifesting as a greater contractile effect evoked in this strain. PMID- 10100094 TI - Effects of two calcium channel blockers on messenger RNA expression of endothelin 1 and nitric oxide synthase in cardiovascular tissue of hypertensive rats. AB - OBJECTIVE: The aim of this study was to investigate the effects of calcium channel blockers on messenger RNA expression of endothelin-1 and endothelial-type nitric oxide synthase in the cardiovascular tissue of stroke-prone spontaneously hypertensive rats (SHRSP). MATERIALS AND METHODS: The calcium channel blocker nilvadipine (1.0 or 3.2 mg/kg per day) was subcutaneously administered to two groups of SHRSP, from 4 or 8 weeks of age, for 8 weeks and 4 weeks, respectively. For comparison, nifedipine (3.2 mg/kg per day) was similarly administered to SHRSP from 4 weeks of age for 8 weeks. Kidney, heart, aorta and brain tissue samples were obtained when the rats were 12 weeks old. Messenger RNA expression of endothelin-1 and endothelial-type nitric oxide synthase was determined by reverse transcription-polymerase chain reaction followed by Southern blotting and a ribonuclease protection assay, respectively. Results were compared with those in untreated SHRSP and Wistar-Kyoto rats at 12 weeks of age. RESULTS: Both nilvadipine and nifedipine significantly decreased blood pressure in SHRSP. Although there were no changes in the weights of the kidney and brain, there was a significant decrease in the weight of the left ventricle of the groups treated with nilvadipine (1.0 mg/kg per day: mean +/- SEM 0.282 +/- 0.003 g; 3.2 mg/kg per day: 0.269 +/- 0.005 g) and nifedipine (1 mg/kg/day: 0.281 +/- 0.012 g) for 8 weeks compared with untreated SHRSP (0.301 +/- 0.004 g). Endothelin-1 messenger RNA expression, which was significantly increased by about twofold in the kidney, heart and brain of SHRSP compared with Wistar-Kyoto rats, was normalized by both calcium blockers. Endothelin-1 messenger RNA expression, which was decreased in the aorta of SHRSP, was further decreased by both calcium blockers. While there was no significant difference in endothelial-type nitric oxide synthase messenger RNA expression in the kidney, heart and aorta between the untreated SHRSP and Wistar-Kyoto rats, expression in the aorta was significantly increased in the group treated with these calcium blockers for 8 weeks from 4 weeks of age. CONCLUSIONS: These results suggest that, in addition to their potent antihypertensive effects, calcium channel blockers may exhibit cardiovasculoprotective and renoprotective effects by modifying mRNA expression of endothelin-1 and endothelial-type nitric oxide synthase in tissue. PMID- 10100095 TI - Effects of obstructive sleep apnea on endothelin-1 and blood pressure. AB - OBJECTIVE: To evaluate blood pressure and humoral vasoconstrictor responses to recurrent episodes of obstructive sleep apnea and the effects of therapy by means of continuous positive airway pressure. PATIENTS AND METHODS: We prospectively evaluated overnight changes in hemodynamics, oxygen saturation, the apnea hypopnea index, circulating endothelin-1, norepinephrine and plasma renin activity in 22 patients with severe obstructive sleep apnea before and after successful therapy using continuous positive airway pressure therapy (three measurements). Measurements of endothelin-1 and blood pressure were also obtained on three occasions, at similar times, in 12 healthy control subjects without sleep disturbances. RESULTS: Mean arterial pressure and endothelin-1 concentrations increased significantly after 4 h of untreated obstructive sleep apnea, and decreased after 5 h of continuous positive airway pressure. Changes in endothelin-1 levels were correlated with changes in mean arterial pressure (r = 0.44, P < 0.02) and with changes in oxygen saturation (r = 0.37, P < 0.05). Norepinephrine levels and plasma renin activity did not change significantly in patients with obstructive sleep apnea, and were not correlated with changes in blood pressure or oxygen saturation. In controls, blood pressure measurements at similar times during the night showed changes directionally opposite to that seen in obstructive sleep apnea, while endothelin-1 levels remained unchanged. CONCLUSIONS: Sleep apnea elicits increases in blood pressure and endothelin-1, with reductions in both after treatment. Vasoconstrictor and mitogenic effects of endothelin-1 may be implicated in increased cardiovascular risk in patients with obstructive sleep apnea. PMID- 10100096 TI - Mean arterial blood pressure and serum levels of the molar ratio of insulin-like growth factor-1 to its binding protein-3 in healthy centenarians. AB - OBJECTIVE: Healthy centenarians have a greater molar ratio of plasma insulin-like growth factor-1 to insulin-like growth factor binding protein-3 than that of aged subjects. We investigated the question of whether differences in mean arterial pressure and in this plasma ratio were related in healthy centenarians. SUBJECTS AND METHODS: We studied 52 subjects in total, 30 aged subjects (70-99 years) and 22 healthy centenarians (> 100 years) to determine differences in mean arterial pressure, endothelial function and intracellular cation levels. RESULTS: In the healthy centenarians, the molar ratio of fasting plasma insulin-like growth factor-1 to its binding protein-3 was significantly correlated with mean arterial pressure (r = -0.66, P < 0.001). Baseline (19.3 +/- 1.5 versus 27.6 +/- 2.2 mumol/l, P < 0.05) and L-arginine-stimulated percentage increases in the plasma total nitrate: nitrite ratio (67 +/- 3.4 versus 48 +/- 4.5%, P < 0.03) were greater in the healthy centenarians than in the aged subjects. An L-arginine bolus elicited an increase in forearm blood flow which was correlated with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.79, P < 0.001) and with the fasting erythrocyte magnesium concentration (r = 0.80, P < 0.001) in healthy centenarians. Both correlations remained significant (P < 0.01) after adjustment for sex, body mass index and the waist: hip ratio. Moreover, the fasting plasma molar ratio of insulin-like growth factor-1 to its binding protein 3 was correlated with the percentage increase in forearm blood flow (r = 0.59, P < 0.005) and with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.54, P < 0.009) in healthy centenarians. The centenarians had higher baseline total erythrocyte magnesium and lower calcium concentrations than the aged subjects. The addition of insulin growth factor-1 to the incubation medium increased the total intracellular erythrocyte magnesium content and decreased the calcium content in both groups of subjects. Nevertheless, the percentage increase in total erythrocyte magnesium (33 +/- 3.8 versus 12 +/- 3.4%, P < 0.03) and decline in intracellular calcium (17 +/- 2.8 versus 8 +/- 3.1%, P < 0.02) concentrations were greater in the healthy centenarians than the aged subjects. CONCLUSION: In healthy centenarians, insulin-like growth factor-1 may preserve endothelial function and modulate the intracellular cation content, thus contributing to a lower mean arterial pressure than that in aged subjects. PMID- 10100097 TI - Eicosanoids and membrane properties in arteries of aged spontaneously hypertensive rats. AB - OBJECTIVE: The arteries of aged spontaneously hypertensive rats (SHR) exhibit spontaneous electrical activity together with membrane depolarization. Vascular eicosanoid production is increased in SHR, which is further accelerated with aging. We tested the hypothesis that eicosanoids are involved in spontaneous electrical activity, membrane depolarization or both in mesenteric arteries of aged SHR. DESIGN AND METHODS: Membrane potentials were recorded with microelectrodes from the mesenteric arteries of aged (24 months and older) SHR, aged Wistar-Kyoto (WKY) rats and adult (6- to 8-month-old) SHR. RESULTS: The membrane potential was less negative in aged SHR (-38.5 +/- 0.9 mV) than in either aged WKY rats or adult SHR (-49.8 +/- 0.5 and -47.2 +/- 0.6 mV, respectively; P < 0.05 for both). Spontaneous electrical activity (5-20 mV, 1 7/min) was present only in arteries of aged SHR. Spontaneous electrical activity was not affected by phentolamine, atropine or tetrodotoxin, but was abolished by indomethacin, a cyclooxygenase inhibitor, and ONO-3708, a thromboxane A2/prostaglandin H2 receptor antagonist. Furthermore, indomethacin and ONO-3708 hyperpolarized the membrane by about 5 mV in aged SHR but not in the other two groups. Spontaneous electrical activity was enhanced by a thromboxane A2 analog and prostaglandin H2, and was abolished by a Ca2+ antagonist, nicardipine, and Ca(2+)-free solution. CONCLUSIONS: These findings suggest that cyclooxygenase dependent eicosanoids contribute importantly to both spontaneous electrical activity and membrane depolarization, presumably through activation of the thromboxane A2/prostaglandin H2 receptor, in mesenteric arteries of aged SHR, and that spontaneous electrical activity is mediated by a Ca2+ influx through voltage dependent Ca2+ channels. PMID- 10100098 TI - Renin-angiotensin system and fibronectin gene expression in Dahl Iwai salt sensitive and salt-resistant rats. AB - OBJECTIVE: The tissue renin-angiotensin system and extracellular matrix are involved in the cardiovascular hypertrophy and remodeling induced by hypertension. In this study, we examined the gene expression of the tissue renin angiotensin system and fibronectin in inbred Dahl Iwai salt-sensitive and salt resistant rats. MATERIALS AND METHODS: Eight pairs of 6-week-old male Dahl Iwai salt-sensitive and salt-resistant rats were fed either a low- or high-salt diet (0.3% or 8% NaCl, respectively) for 4 weeks. Activities of the circulating renin angiotensin system were measured by radioimmunoassay and the gene expression of tissue angiotensinogen, the angiotensin II type 1 receptor (AT1) and fibronectin were analyzed by Northern blot analysis. RESULTS: Salt loading significantly increased blood pressure and produced cardiovascular hypertrophy and nephrosclerosis in the salt-sensitive rats. Activities of the circulating renin angiotensin system were lower in salt-sensitive rats than in salt-resistant rats fed the low-salt diet, and salt loading lowered these activities in salt resistant rats but not in salt-sensitive rats. In salt-resistant rats, salt loading increased renal, cardiac and aortic angiotensinogen, AT1 and fibronectin messenger (m)RNA expression except for aortic fibronectin mRNA expression. In contrast, in the salt-sensitive rats, salt loading stimulated the expression of cardiac fibronectin and aortic angiotensinogen, AT1 and fibronectin mRNAs. Furthermore, the cardiac and aortic fibronectin mRNA levels in salt-sensitive rats were higher than those in salt-resistant rats when both strains were fed the high-salt diet. CONCLUSIONS: These results demonstrate that the expression of tissue angiotensinogen, AT1 and fibronectin mRNAs is regulated differently in Dahl Iwai salt-sensitive and salt-resistant rats, and indicate that salt-mediated hypertension activates the cardiac fibronectin gene independently of the tissue renin-angiotensin system and stimulates the aortic fibronectin gene with activation of the tissue renin-angiotensin system. PMID- 10100099 TI - Flow dependence of forearm noradrenaline overflow, as assessed during mental stress and sodium nitroprusside infusion. AB - OBJECTIVE: To evaluate the influence of blood flow on measurements of regional sympathetic nerve activity by radiotracer methodology ([3H]noradrenaline). DESIGN: Ten healthy men were studied under two conditions of elevated forearm blood flow: mental stress (Stroop colour word conflict test) and an intra arterial infusion of sodium nitroprusside. METHODS: Arterial blood pressure was measured invasively and forearm blood flow with strain-gauge plethysmography. Arterial and venous plasma adrenaline and noradrenaline were measured with high performance liquid chromatography, and regional and total noradrenaline spillover were calculated. RESULTS: During mental stress, mean arterial pressure increased by 17%, heart rate by 16 beats/min, forearm blood flow by 117%, while forearm vascular resistance decreased by 44% (P < 0.001 for all). Sodium nitroprusside increased forearm blood flow dose-dependently, but elicited only minor effects on systemic haemodynamics. Mental stress increased arterial plasma noradrenaline by 52% (P < 0.001), and total body noradrenaline spillover by 75% (P < 0.001). During sodium nitroprusside infusion, arterial plasma noradrenaline increased only slightly and total body noradrenaline spillover was unaffected Forearm noradrenaline overflow increased from 5.4 +/- 0.9 to 16.9 +/- 2.6 pmol/min per I (P < 0.001) during mental stress and from 6.6 +/- 0.8 to 16.9 +/- 3.7 pmol/min per I (P < 0.001) during the second dose-step of sodium nitroprusside infusion. By intra-individual comparisons of forearm noradrenaline overflow increases during mental stress and during sodium nitroprusside infusion, with similar forearm blood flow increases, the flow dependence of forearm noradrenaline overflow was estimated. During mental stress, about 60% (median value, range 29 112%) of the increase in forearm noradrenaline overflow was attributed to the increase in forearm blood flow, whereas 40% was considered to reflect increased sympathetic nerve activity. CONCLUSIONS: There seems to be a considerable flow dependence of the regional overflow of noradrenaline, that is, a component of simple wash-out of noradrenaline from the forearm tissues during vasodilation. However, the present results still indicate that sympathetic nerve activity in the forearm is increased during mental stress, justifying the radiotracer technique for semiquantitative measurements, also during vasodilation. PMID- 10100100 TI - Effect of postural changes on cardiovascular responses to static exercise in hypertensive human beings. AB - OBJECTIVE: In hypertensive patients, exaggerated increases in vascular resistance and arterial blood pressure have been reported on changing posture from supine to upright. In this study we tested the hypothesis that in hypertensive subjects, upright posture induces an increase in the vasoconstrictor and pressor responses to physical exercise. SUBJECTS AND METHODS: We studied 17 males with mild hypertension and 10 sex- and age-matched normotensives. Each performed three bouts of static handgrip at 30% maximum voluntary contraction for 2 min after 10 min of supine rest and, in sequence, after 10 min of sitting and 10 min of standing. Arterial pressure, heart rate and forearm vascular resistance were measured by Finapres and plethysmography, respectively. RESULTS: Exercise posture did not affect the mean arterial pressure and heart rate responses to static handgrip. No significant differences in these responses were observed between the hypertensives and the normotensives in any posture. In the hypertensives (n = 12), forearm vascular resistance did not change significantly from resting values during supine and sitting static handgrip but increased significantly during standing static handgrip. In the normotensives, forearm vascular resistance did not change significantly from resting values during static handgrip in any posture. The forearm vascular resistance response to the standing static handgrip was significantly greater in the hypertensives than the normotensives. The algebraic sum of forearm vascular resistance responses to postural change from sitting to standing plus that induced by sitting static handgrip (i.e. additive reflexes) was significantly less than the forearm vascular resistance response to the standing static handgrip (i.e. combined relexes), indicating a facilitatory interaction between exercise and orthostatic stimuli in hypertensives. In contrast, the algebraic sum of the heart rate responses to postural change from sitting to standing plus that induced by sitting static handgrip was significantly greater than the response to standing static handgrip, indicating an inhibitory interaction. CONCLUSIONS: In hypertensive patients, physiological orthostasis causes an increased vasoconstrictor response to static exercise, but this is opposed by an inhibitory influence on the heart rate response, with the result that the pressor response to static exercise is unaffected by upright posture. PMID- 10100101 TI - Losartan inhibits the post-transcriptional synthesis of collagen type I and reverses left ventricular fibrosis in spontaneously hypertensive rats. AB - OBJECTIVE: Previous studies have shown that as well as left ventricular hypertrophy, myocardial fibrosis develops early in rats with spontaneous hypertension (SHR). The present study was designed to investigate whether chronic treatment with the angiotensin II type 1 (AT1) receptor antagonist losartan modifies collagen type I metabolism and reverses left ventricular fibrosis in young SHR with left ventricular hypertrophy. DESIGN: The study was performed in 30-week-old normotensive Wistar-Kyoto (WKY) rats, untreated SHR and SHR treated with losartan (20 mg/mg per day, orally) for 14 weeks before they were killed. METHODS: Ventricular pro-alpha 1 (I) collagen messenger RNA was analyzed by Northern blot. Serum levels of the carboxy-terminal propeptide of procollagen type I (PIP) and the pyridoline cross-linked telopeptide domain of collagen type I (CITP) were determined by specific radioimmunoassays as markers of collagen type I synthesis and degradation, respectively. Collagen volume fraction was determined in the left ventricle by quantitative morphometry. RESULTS: Compared with WKY rats, SHR exhibited increased (P < 0.05) mean arterial pressure, pro alpha 1 (I) collagen messenger RNA, PIP and left ventricular collagen volume fraction, and similar CITP values. After the treatment period, mean arterial pressure was higher (P < 0.05) in losartan-treated SHR than in WKY rats. Compared with untreated SHR, treated SHR showed no left ventricular hypertrophy and diminished (P < 0.05) values of mean arterial pressure, PIP and left ventricular collagen volume fraction. No changes in pro-alpha 1 (I) collagen messenger RNA and CITP values were observed with treatment in SHR. No significant differences in the left ventricular collagen volume fraction were observed between treated SHR with normal blood pressure and treated SHR with abnormally high blood pressure at the end of the treatment period. CONCLUSIONS: These results suggest that chronic AT1 blockade with losartan decreases the post-transcriptional synthesis of fibril-forming collagen type I molecules in young SHR. This effect may be involved in the ability of this drug to reverse left ventricular fibrosis in young rats with genetic hypertension. Apart from its antihypertensive action, other mechanisms may mediate the antifibrotic effect of losartan in this animal model. PMID- 10100102 TI - Type A behavior is associated with an increased risk of left ventricular hypertrophy in male patients with essential hypertension. AB - OBJECTIVE: To determine whether type A behavior, which is associated with a risk of coronary heart disease, affects left ventricular hypertrophy in patients with essential hypertension. DESIGN: Cross-sectional study of 88 untreated patients with mild to moderate essential hypertension (33 men, mean +/- SEM age 54 +/- 1 years). METHODS: We measured the type A behavior score using a standardized questionnaire, left ventricular mass index using M-mode echocardiography and 24 h mean ambulatory blood pressure (recorded every 30 min). Beat-to-beat blood pressure was also measured using a Finapres device in patients at rest and during mental stress (counting backward) to determine the blood pressure response to stress. RESULTS: The left ventricular mass index was correlated with the type A behavior score (r = 0.214, P < 0.05), age (r = 0.266, P < 0.05), 24 h mean systolic and diastolic blood pressures (r = 0.391, P < 0.001, and r = 0.382, P < 0.001, respectively), systolic blood pressure both at rest and during stress (r = 0.255, P < 0.05, and r = 0.215, P < 0.05, respectively), and the variability of both systolic and diastolic blood pressures at rest (r = 0.253, P < 0.05, and r = 0.321, P < 0.01, respectively). Stepwise multiple linear regression analysis demonstrated that age was associated with an increase in the left ventricular mass index for both sexes (P = 0.004 for males, P = 0.003 for females). The type A behavior score predicted a greater increase in left ventricular mass index in men (P = 0.018) but not in women. The 24 h mean systolic blood pressure was associated with a greater increase in left ventricular mass index in women (P < 0.001) but not in men. CONCLUSION: Type A behavior is an independent risk factor for left ventricular hypertrophy in male patients with essential hypertension. PMID- 10100103 TI - L-arginine reverses severe nephrosclerosis in aged spontaneously hypertensive rats. AB - OBJECTIVE: Acute and prolonged effects of L-arginine on systemic and renal hemodynamics and on renal pathological changes were examined in 85-week-old spontaneously hypertensive rats (SHR). RESULTS: After 3 weeks of L-arginine administration (n = 9; 2 g/l in drinking water), mean arterial pressure remained unchanged, although the cardiac index increased (187 +/- 26 versus 263 +/- 15 ml/min per kg; P < 0.05) and total peripheral resistance decreased (1.15 +/- 0.18 versus 0.67 +/- 0.06 AU; P < 0.05); the glomerular filtration rate increased (0.41 +/- 0.07 versus 0.79 +/- 0.07 ml/min; P < 0.01). Control untreated, aged SHR (n = 10) demonstrated severe nephrosclerosis histologically, but those treated with L-arginine demonstrated a markedly reduced glomerular injury score (164 +/- 22 versus 83 +/- 9; P < 0.005), and their urinary protein excretion (39 +/- 5 versus 19 +/- 5 mg/100 g body weight per day; P < 0.05) and serum creatinine concentration (1.4 +/- 0.1 versus 0.9 +/- 0.1 mg/dl; P < 0.05) diminished. Intravenous L-arginine (300 mg/kg body weight) given to untreated SHR reduced mean arterial pressure, increased the cardiac index (+98 versus +1%; P < 0.05) and decreased total peripheral resistance (+56 versus +13%, P < 0.005); however, these variables remained unchanged after 3 weeks of L-arginine treatment. CONCLUSIONS: Three weeks of treatment with L-arginine improved systemic hemodynamics, renal function and renal histologic changes in aged SHR with naturally occurring nephrosclerosis. These data provide an important insight into the pathophysiology of nephrosclerosis in hypertension and with aging, which is seen clinically. PMID- 10100104 TI - The efficacy and tolerance of one or two daily doses of eprosartan in essential hypertension. The Eprosartan Multinational Study Group. AB - OBJECTIVE: The primary objective of this double-blind, parallel-group, placebo controlled, multicentre study was to compare the antihypertensive efficacy of one versus two daily doses of eprosartan, a novel nonbiphenyl, nontetrazole angiotensin II receptor antagonist, in 243 patients with mild to moderate hypertension (sitting diastolic blood pressure > or = 95 to < or = 114 mmHg). PATIENTS AND METHODS: The patients were randomized to titrated doses of eprosartan at 400-800 mg once a day, eprosartan at 200-400 mg twice a day, or placebo, with the incremental dose titrated over a 9-week period. Patients reaching target blood pressure (sitting diastolic blood pressure of < or = 90 mmHg) continued the fixed-dose treatment for 4 weeks. The primary efficacy measure was the mean change in trough sitting diastolic blood pressure from baseline to the study endpoint, determined on an intent-to-treat basis. RESULTS: By the end of the study, eprosartan had significantly reduced mean trough sitting systolic and diastolic blood pressure relative to baseline and to placebo. The mean +/- SD change from baseline in diastolic pressure was -9 +/- 8.4 mmHg for the single daily dose, -9 +/- 8.5 mmHg for two doses a day and -4 +/- 8.1 mmHg for placebo (P < 0.0001 versus placebo for both eprosartan regimens). Similarly, both eprosartan regimens significantly reduced mean trough standing systolic and diastolic blood pressure. At the end of the study, the response rate in the single daily dose group (46.8%) was significantly higher than in the placebo group (25.6%). There were no significant differences between the treatment groups in the number of patients whose blood pressure responded to treatment; 41.7% of those taking eprosartan once a day and 44.4% of those taking eprosartan twice a day, and who responded to treatment, were maintained on their original starting doses. The total daily dose required to achieve target blood pressure was comparable, whether eprosartan was administered once or twice a day. Both eprosartan regimens were well tolerated and the incidence of adverse events with eprosartan was similar to that of placebo. CONCLUSIONS: These results demonstrate that there was no significant difference in antihypertensive efficacy or tolerance between eprosartan taken in one or in two daily doses. Both dosing regimens provided significant and clinically meaningful reductions in blood pressure that were superior to placebo. Eprosartan in a single daily dose was shown to be an effective antihypertensive agent. Because of the good adverse effect profile and the simplicity of a single daily dose, eprosartan has the potential to improve patient compliance. PMID- 10100105 TI - Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators' Group. AB - OBJECTIVE: To compare the therapeutic coverage and safety of amlodipine and perindopril in patients with mild to moderate hypertension (diastolic blood pressure > or = 90 mmHg and < or = 109 mmHg). DESIGN: A double-blind, randomized, parallel-group, multicentre study. METHODS: Following a 2-week placebo wash-out period, the patients were randomly allocated to treatment with either amlodipine at 5-10 mg once a day or perindopril at 4-8 mg once a day, for 60 days. Trough: peak ratios were calculated by two different methods (global and individualized approaches) from 24 h ambulatory blood pressure recordings made after the placebo period and after the active treatment period. Residual lowering of blood pressure after single-blind, single-dose omission was also investigated with further 24 h ambulatory blood pressure monitoring. Safety assessments were made throughout the study. RESULTS: The placebo-adjusted, global, diastolic blood pressure trough: peak ratio was 0.80 in the amlodipine group (n = 47) and 0.81 in the perindopril group (n = 49) in an intent-to-treat analysis. The corresponding global systolic blood pressure trough: peak ratio was 0.83 for amlodipine and 0.68 for perindopril. Individual trough: peak ratios were non-normally distributed. Mean (+/- SD) individual trough: peak ratios (intent-to-treat analysis) for diatolic blood pressure were 0.50 +/- 0.69 for amlodipine (median 0.42) and 0.15 +/- 3.27 for perindopril (median 0.33). In the per protocol analysis, the corresponding values were 0.50 +/- 0.72 (median 0.34) for amlodipine and 0.01 +/- 3.90 for perindopril (median 0.21). Both treatments produced comparable decreases in clinic systolic and diastolic blood pressure between days 0 and 60. Forty-eight hours after the last dose, both systolic and diastolic blood pressure were lower in amlodipine-treated patients than perindopril-treated patients. Amlodipine and perindopril were generally well tolerated. The most frequently reported adverse event was leg oedema in amlodipine-treated patients (19.1%), and coughing in perindopril-treated patients (14.3%). CONCLUSIONS: These results showed no statistically significant difference in trough: peak ratios between amlodipine and perindopril. However, the ambulatory blood pressure trough: peak ratios showed very large variations. Determination of trough: peak ratios by the conventional approach or by an individual approach can yield disparate values. After omitting one dose, a condition imitating noncompliance, blood pressure was more effectively controlled with amlodipine than with perindopril. PMID- 10100106 TI - Is the use of placebo in antihypertensive drug studies ethical? PMID- 10100107 TI - Bicycle exercise blood pressure can be useful in a clinical practice. PMID- 10100108 TI - White-coat hypertension: a selection bias? PMID- 10100109 TI - Strain as a moderator of the relationship between work characteristics and work attitudes. AB - Research on the psychological effects of work characteristics has investigated their relationships with both work attitudes and psychological strain, with the latter 2 variables being treated as alternative or joint dependent variables. The focus of this article is to propose that strain moderates the relationship between perceptions of work characteristics and work attitudes. The proposition is tested on a maximum sample of 9,327 health care employees by using moderated multiple regression followed by subgroup comparisons. The results strongly support the moderating effect, showing that as strain increases, the strength of the relationship between perceptions of work characteristics and work attitudes decreases. PMID- 10100110 TI - Survival of the fittest: implications of self-reliance and coping for leaders and team performance. AB - Using a laboratory methodology, the authors sought to establish an association between self-reliance (based on attachment theory) and team performance and satisfaction. Three hypotheses (direct effect, mediator, and moderator) were tested. With a sample of 187 students, the authors compared leader self-reliance characteristics with group member self-reliance characteristics (group n = 50) as predictors of group performance and satisfaction. Only group member counterdependence was predictive of decreased performance. Further, the authors examined the possible mediating and moderating effects of coping on the self reliance-group effectiveness relationships. Coping did not mediate the relationship but did operate as a significant moderator in some instances. PMID- 10100111 TI - Work stress and self-reported alcohol use: the moderating role of escapist reasons for drinking. AB - This study examines the moderating role of escapist reasons for drinking alcohol in the job stress/self-reported alcohol use and problems relationship. It was hypothesized that higher levels of job stress would be associated with higher levels of self-reported drinking (H1) and drinking problems (H2) only for those who endorsed escapist reasons for drinking. For those who did not hold such beliefs, higher levels of job stress were predicted to be associated with lower self-reported alcohol intake (H3) and problems (H4). Survey data from white- and blue-collar workers employed across all paycodes and positions were collected randomly at a large manufacturing organization (62% response rate). Participants responded to questions concerning work stress, reasons for drinking, alcohol intake, and alcohol problems. Using only nonabstainers with complete data (N = 1,645), results from regression analyses generally supported all hypotheses. PMID- 10100112 TI - Rushed, unhappy, and drained: an experience sampling study of relations between time pressure, perceived control, mood, and emotional exhaustion in a group of accountants. AB - Experience sampling methodology was used to examine how work demands translate into acute changes in affective response and thence into chronic response. Seven accountants reported their reactions 3 times a day for 4 weeks on pocket computers. Aggregated analysis showed that mood and emotional exhaustion fluctuated in parallel with time pressure over time. Disaggregated time-series analysis confirmed the direct impact of high-demand periods on the perception of control, time pressure, and mood and the indirect impact on emotional exhaustion. A curvilinear relationship between time pressure and emotional exhaustion was shown. The relationships between work demands and emotional exhaustion changed between high-demand periods and normal working periods. The results suggest that enhancing perceived control may alleviate the negative effects of time pressure. PMID- 10100113 TI - Let's talk: patterns and correlates of social support among temporary employees. AB - The authors explored how temporary employees exchanged communications with supervisor, peers, and family and friends regarding positively job-related, negatively job-related, and non-job-related contents. The authors also examined roles of communication in coping with insecure job experiences. Survey results from 112 temporary employees working in various organizations provided evidence that communication contents were differentially related to work anxiety and life satisfaction for temporary employees. It was found that work anxiety increased when employees engaged in communication pertaining to negative job-related contents. Furthermore, the positive relationship between life satisfaction and positive communication with coworkers was observed only for the temporary employees who also had a permanent job. Implications for staffing temporary employees and suggestions for studying communication effects are discussed. PMID- 10100114 TI - Chronic fatigue syndrome, chronic fatigue, and psychiatric disorders: predictors of functional status in a national nursing sample. AB - Members of 2 nurses' associations (N = 71) were assessed using 2 mail questionnaires, a telephone questionnaire, the Diagnostic Interview Schedule, and medical records. Physicians reviewed participants to determine whether they met current criteria for chronic fatigue syndrome (CFS). Stepwise multivariate regression analyses were conducted to identify predictors of functional status scores. Impairments in physical, role, and social functioning increased as fatigue severity increased. Bodily pain increased as fatigue severity increased, and ratings of overall health increased as severity of fatigue decreased. Nurses with a current psychiatric diagnosis reported more impairments in emotional functioning than nurses with a lifetime diagnosis or no psychiatric diagnosis. Quality of life decreased as fatigue severity increased. Nurses with fatigue not meeting CFS criteria reported better quality of life than those with CFS or medical exclusions. PMID- 10100115 TI - Relationships between time management, control, work-family conflict, and strain. AB - This article incorporates recent research regarding time management into a model of work-family conflict. The authors hypothesized that 3 types of time management behavior would have both direct and indirect (through perceived control of time) relationships, with work interfering with family and family interfering with work. It was also hypothesized that both of these types of work-family conflict would be related to the strain outcomes of job dissatisfaction and health complaints. This model was tested with a sample of 522 workers. In general, the hypothesized relationships were supported. PMID- 10100116 TI - Effects of ipsilateral anterior thigh soft tissue stretching on passive unilateral straight-leg raise. AB - STUDY DESIGN: Randomized 3-group pretest-posttest with blind assessment of outcome. OBJECTIVES: The purpose of this study was to examine the effect of sagittal plane hold-relax exercise applied to the ipsilateral anterior thigh, and prone positioning on passive unilateral straight-leg raise measurements. BACKGROUND: Straight-leg raising has been viewed as a measurement for hamstring muscle length, but literature suggests that other structures may affect this measurement. METHODS AND MEASURES: Sixty subjects (45 men, 15 women) qualified for inclusion into the study based on a straight-leg raise measurement of < or = 65 degrees. Subjects were randomly assigned to one of three groups: control, static stretch, or sagittal plane hold-relax exercise. Pretest and posttest straight-leg raise measurements of the right lower extremity were performed for each subject. RESULTS: A 1-way ANOVA of the change scores showed a significant difference between groups. A Tukey post hoc analysis of the change scores showed that both treatment groups' means differed significantly from the control group and from each other, with the sagittal plane hold-relax group exhibiting the largest change (mean of 7.8 degrees +/- 2.8 degrees). CONCLUSIONS: The results of this study show that sagittal plane hold-relax exercise and passive prone results of this study show that sagittal plane hold-relax and passive prone positioning can significantly increase straight-leg raise range of motion, however the sagittal plane hold-relax stretching of the anterior thigh is more effective than passive prone positioning. PMID- 10100117 TI - Temperature change in human muscle during and after pulsed short-wave diathermy. AB - STUDY DESIGN: A time series design was used, with the dependent variable being gastrocnemius muscle temperature at a depth of 3 cm. OBJECTIVES: To determine the rate of temperature rise and the rate of post-treatment temperature decline in skeletal muscle following the application of pulsed short-wave diathermy (PSWD). BACKGROUND: Data on PSWD rate and longevity of heating are 20 years old and outdated. With the recent introduction of advanced diathermy equipment, results of our study would provide clinicians with much needed information regarding treatment duration. METHODS AND MEASURES: A 23-gauge thermistor was inserted into the center of the medial head of the anesthetized gastrocnemius muscle, 3 cm below the skin's surface of 20 subjects. The PSWD (27.12 MHz frequency) was applied using the following parameters: 800 bursts per second; 400 microseconds burst duration; 850 microseconds interburst interval; with a peak root mean square (RMS) amplitude of 150 W per burst and an average RMS output of 48 W. Temperature changes were documented every 5 minutes during the treatment and additionally at 5 and 10 minutes following treatment. RESULTS: The average baseline and peak temperatures were 35.84 +/- 0.93 degrees C and 39.80 +/- 0.83 degrees C, respectively. Mean temperature increases were: 1.36 +/- 0.90 degrees C (5 min); 2.87 +/- 1.44 degrees C (10 min); 3.78 +/- 1.19 degrees C (15 min); 3.49 +/- 1.13 degrees C (20 min). After the treatment terminated, intramuscular temperature dropped 0.97 +/- 0.68 degree C in 5 minutes and 1.78 +/- 0.69 degrees C in 10 minutes. CONCLUSIONS: PSWD is an effective modality if temperature elevation of deep tissue over a large area is the clinical objective. PMID- 10100118 TI - Neural and vascular anatomy of the menisci of the human knee. AB - STUDY DESIGN: Review of literature. OBJECTIVES: To review the general anatomy, vascular anatomy, healing potential, neural anatomy, and sensory functions of the menisci of the human knee. BACKGROUND: Recent research has revealed important roles and functions of the menisci of the human knee. METHODS AND MEASURES: A Medline search was performed using the following title and key words: menisci, meniscus, meniscal, vascular, blood, neural, nerve, anatomy, healing, sensory, mechanoreceptors, proprioception, nociceptors, surgery, meniscectomy, repair, and rehabilitation. The references from each article obtained were then reviewed in order to find additional articles not already located through the Medline search. RESULTS: In adults, the blood supply to the menisci of the knee reaches the outer 10% to 33% of the body of the menisci. This portion of the menisci is capable of inflammation, repair, and remodeling. Neural innervation with nociceptors and type I, II, and III mechanoreceptors reaches the outer 66% of the body of the menisci. The anterior and posterior horns of the menisci have a rich supply of both blood vessels and nerves. CONCLUSIONS: The menisci of the human knee are an important source of proprioceptive information regarding the position, direction, velocity, and acceleration and deceleration of the knee. Rehabilitation following injury or surgery to the menisci of the knee should, therefore, incorporate a proprioceptive retraining program that respects both the abilities and inabilities of different portions of the menisci to follow through with repair and remodeling. PMID- 10100119 TI - Role of scapular stabilizers in etiology and treatment of impingement syndrome. PMID- 10100120 TI - Intrarater reliability of selected clinical outcome measures following anterior cruciate ligament reconstruction. AB - STUDY DESIGN: Single group repeated measures following anterior cruciate ligament (ACL) reconstruction. OBJECTIVES: The purpose of this study was to evaluate the intrarater reliability of selected clinical outcome measures in patients having ACL reconstruction. BACKGROUND: Several investigations have reported the reliability of isokinetic testing and knee ligament arthrometry. Fewer studies have examined the reliability of lower extremity functional tests, with most of these studies evaluating normal subjects. METHODS AND MEASURES: Fifteen physically active males with unilateral ACL-reconstructed knees were evaluated with the KT-1000, Biodex isokinetic dynamometer, and 3 functional hop tests on 5 occasions. RESULTS: Intraclass correlation coefficients (ICCs) revealed good to high intrarater reliability (ICC > 0.80) of the functional hop tests and isokinetic peak torque values ICCs were higher for the involved limb than the uninvolved limb using the scores from the KT-1000 Manual Maximum Test. CONCLUSIONS: The outcome measures examined in this investigation have been shown to be reliable in patients with ACL reconstructions, and support previous investigations in nonimpaired populations. Further research is needed to examine the validity of these postoperative outcome measures in patients with ACL reconstructions. PMID- 10100121 TI - Error estimates in novice and expert raters for the KT-1000 arthrometer. AB - STUDY DESIGN: Single group repeated measures with multiple raters. OBJECTIVES: To determine the inter-rater reliability of KT-1000 measurements of novice and experienced raters and to provide error estimates for these raters. BACKGROUND: The KT-1000 arthrometer is often used clinically to quantify anterior tibial displacement. Few data have been documented, however, about the relative reliability of KT-1000 measurements obtained by novice compared with experienced users. METHODS AND MEASURES: Two novice and two experienced KT-1000 users performed measurements on 29 knees of 25 patients after anterior cruciate ligament (ACL) reconstruction or with a diagnosis of ACL deficiency. Measurements were performed at 131 N. Interrater and intertrial reliability coefficients (interclass correlation coefficient; ICC) and the standard error of measurement were calculated for expert and novice raters. RESULTS: The interrater ICC for novices was 0.65 and the interrate error was +/- 3.52 mm (90% confidence interval [CI]). The interrater ICC for experts was 0.79 and the interrater error was +/- 2.94 mm (90% CI). CONCLUSIONS: These results suggest that experience in using the KT-1000 is related to the interrater error of measurements and that training is an important consideration when using the KT-1000 arthrometer. PMID- 10100122 TI - Synthesis, conformational study, and spectroscopic characterization of the cyclic C alpha, alpha-disubstituted glycine 9-amino-9-fluorenecarboxylic acid. AB - A series of terminally blocked peptides (to the pentamer level) from L-Ala and the cyclic C alpha, alpha-disubstituted Gly residue Afc and one Gly/Afc dipeptide have been synthesized by solution method and fully characterized. The molecular structure of the amino acid derivative Boc-Afc-OMe and the dipeptide Boc-Afc-Gly OMe were determined in the crystal state by X-ray diffraction. In addition, the preferred conformation of all of the model peptides was assessed in deuterochloroform solution by FT-IR absorption and 1H-NMR. The experimental data favour the conclusion that the Afc residue tends to adopt either the fully extended (C5) or a folded/helical structure. In particular, the former conformation is highly populated in solution and is also that found in the crystal state in the two compounds investigated. A comparison with the structural propensities of the strictly related C alpha, alpha-disubstituted Gly residues Ac5c and D phi g is made and the implications for the use of the Afc residue in conformationally constrained analogues of bioactive peptides are briefly examined. A spectroscopic (UV absorption, fluorescence, CD) characterization of this novel aromatic C alpha, alpha-disubstituted Gly residue is also reported. PMID- 10100123 TI - A novel microtiter plate based method for identification of B-cell epitopes. AB - A new type of microtiter plate capable of binding biomolecules covalently in a one step procedure was used to map linear B-cell epitopes in two different proteins using a peptide-based solid phase immunoassay. The method was compared with a conventional immobilization method using passive adsorption to microtiter plates. An array of 15-mer peptides, overlapping by five amino acids, representing the entire sequences of ubiquitin and murine tumor necrosis factor alpha, respectively, was synthesized. The peptides were immobilized covalently using the new, specialized microtiter plates or non-covalently using conventional ELISA microtiter plates of the high binder type. Subsequently, specific antisera to ubiquitin or murine tumor necrosis factor-alpha were added to identify potential linear B-cell epitopes. All peptides, which were recognized on the conventional microtiter plates, were also recognized on the plates with the covalently bound peptides. In addition, the covalent immobilization method revealed epitopes that were not identified using the method for non-covalent binding although the peptides were in fact present on the non-covalent binding surface. The interaction with the hydrophobic surface of the conventional microtiter plate apparently interfered negatively with antibody recognition. The covalently binding microtiter plates described here could be useful for identification of new B-cell epitopes in protein antigens. PMID- 10100124 TI - The crystal structures of the synthetic C-terminal octa- and dodecapeptides of trichovirin. AB - The structures of two synthetic peptides with sequences corresponding to the C terminal region of the naturally occurring 14-residue peptaibol trichovirin have been determined. The crystal structures of 8- and 12-residue segments are presented and are compared with the structures of the tetrapeptide and of the 9 residue segment, which have been reported earlier. A comparison between these segments leads to the hypothesis that the three-dimensional structure of trichovirin is to a large extent determined by the properties of a periodically repeating -Aib-Pro- pattern in the sequence of the peptide. PMID- 10100125 TI - Total synthesis and membrane modifying properties of the lipopeptaibol trikoningin KB II and its analogues with acyl chains of different length at the N and C-termini. AB - Trikoningin KB II, a ten-amino acid residue lipopeptaibol blocked at the N terminus by the n-octanoyl group and at the C-terminus by the 1,2-amino alcohol L leucinol, and extracted from the fungus Trichoderma koningii, exhibits membrane modifying properties. We have synthesized by solution-phase methods trikoningin KB II and several analogues with acyl chains of different length at the N- and C termini. Permeability measurements showed that an appropriate length of the linear acyl chain is a more important characteristic for the onset of significant membrane-modifying activity than its position in the peptide chain. PMID- 10100126 TI - Heterotrimeric collagen peptides containing functional epitopes. Synthesis of single-stranded collagen type I peptides related to the collagenase cleavage site. AB - Synthetic collagen peptides containing larger numbers of Gly-Pro-Hyp repeats are difficult to purify by standard chromatographic procedures. Therefore, efficient strategies are required for the synthesis of higher molecular weight collagen type peptides. Applying the Fmoc/tBu chemistry, a comparative analysis of the standard stepwise chain elongation procedure on solid support with the procedure based on the use of the synthons Fmoc-Gly-Pro-Hyp(tBu)-OH and Fmoc-Pro-Hyp-Gly-OH was performed. The crude products resulting from the stepwise elongation procedure and from the use of Fmoc-Gly-Pro-Hyp(tBu)-OH clearly revealed large amounts of microheterogeneities that result from incomplete imino acid acylation as well as from diketopiperazine formation with cleavage of Gly-Pro units from the growing peptide chain. Conversely, by the use of the Fmoc-Pro-Hyp-Gly-OH synthon, the quality of the crude products was significantly improved; moreover, protection of the Hyp side chain hydroxyl function is not required using the Fmoc/tBu strategy. With this optimized synthetic procedure, relatively large collagen-type peptides were obtained in satisfactory yields as highly homogeneous compounds. PMID- 10100127 TI - Methods and measures: emerging strategies in women's health research. PMID- 10100128 TI - Birth trauma and the pelvic floor: lessons from the developing world. AB - Urinary incontinence, fecal incontinence, and pelvic organ prolapse are common stigmatizing conditions that afflict women far more often than they afflict men. It has been suggested that childbirth is the most likely factor to explain this great epidemiologic discrepancy between the sexes. Because the widespread availability of high-quality obstetric care through-out the industrialized world has led to precipitous drops in maternal mortality during the 20th century, many of the pathophysiologic mechanisms by which such injuries might arise are not as obvious as they were in times past. It is suggested that by looking at obstetric complications in the developing world, where the natural history of unrelieved obstructed labor is most obvious, it may be possible to shed new light on the pathophysiology of childbirth injury and its relationship to incontinence and prolapse. The spectrum of childbirth injuries resulting from obstructed labor in developing countries is surveyed, and the potential relevance of these findings to the more subtle forms of pelvic floor dysfunction seen in Western women is discussed. PMID- 10100129 TI - On the lack of correlation between self-report and urine loss measured with standing provocation test in older stress-incontinent women. AB - This study examined the association between the measured amount of urine lost during a standardized series of coughs in clinic (paper towel test) and questionnaire estimates of stress-related urine loss in 51 older women with mild to moderate urinary incontinence. It also examined the relationship between these questionnaire estimates and a 6-day urinary diary self-report of incontinence frequency and voiding episodes. Pearson's correlation coefficient and percent agreement were used to analyze the relationship between the variables. No significant correlations were found between the paper towel test results and questionnaire items reporting volume of urine loss. The relationship between urinary diary results and questionnaire items regarding the number of incontinence occurrences was weak but significant (r = 0.33, p = 0.045), with agreement in 53% of cases. Agreement was achieved in 68% of cases for number of voids per day recorded by urinary diary and reported by questionnaire (r = 0.65, p = 0.000). This study has quantified a weak correlation between objective and subjective measures of urine loss. These weak correlations could arise from either methodologic limitations in quantifying incontinence or the degree to which differences arise because different phenomena are being measured. PMID- 10100130 TI - Contraceptive introduction reconsidered: a new methodology for policy and program development. AB - Although new contraceptive technology has the potential for providing women with expanded options for fertility control, the historical record of international family planning shows that, in practice, introduction of new methods has not always broadened reproductive choice. Using the example of introduction of intrauterine devices into the Indian family planning program in the 1960s, we show that an exclusive focus on the technology itself is problematic and argue that methodologies are needed that relate introduction of new methods to user needs and program capacities. We summarize key findings from the Indonesian experience with Norplant introduction. Although an effort was made to address problems with previous approaches, major deficiencies in both the technical and interpersonal dimensions of care arose when the implants were made broadly available within the program. We subsequently present a methodology for contraceptive introduction developed by the World Health Organization. This methodology emphasizes the social and institutional context in which technology is used and suggests a participatory and research-based approach to program and policy development. We illustrate results from this new approach in its implementation in Vietnam and suggest areas for further evaluation. PMID- 10100131 TI - When is research participatory? Reflections on a reproductive health project in Brazil. AB - This article addresses women's participation in an organization development project designed to improve public sector family planning and reproductive health services in Brazil. Although community women collaborated in aspects of the intervention and research, the project nonetheless raises the basic question whether such involvement of community women does or does not correspond to what scientific writers consider to be the essence of participatory research. We review key project features in the context of recent literature and conclude that although the project is committed to the sharing of power and control, it does not fully correspond to the characteristics of participatory research. Moreover, we argue that given the project's central focus on reproductive health outcomes, complete adherence to the process-oriented, pure version of participatory research would have been inappropriate. PMID- 10100132 TI - Photovoice: a participatory action research strategy applied to women's health. AB - Photovoice is a participatory action research strategy that may offer unique contributions to women's health. It is a process by which people can identify, represent, and enhance their community through a specific photographic technique. Photovoice has three main goals: to enable people (1) to record and reflect their community's strengths and concerns, (2) to promote critical dialogue and knowledge about personal and community issues through large and small group discussion of their photographs, and (3) to reach policymakers. This report gives an overview of the origins, key concepts, methods, and uses of photovoice as a strategy to enhance women's health. PMID- 10100133 TI - Menstrual cycling and breast cancer: an evolutionary perspective. AB - This article attempts to bridge the disciplinary gap between evolutionary biology and clinical studies of women's health. The resulting dialogue is predicted to have useful implications for research aimed at the prevention of women's reproductive cancers. The specific focus is on the relationship between breast cancer and exposure to ovarian hormones during normal menstrual cycling. The clinician's view of normal cycling is radically different from that uncovered by evolutionary studies of noncontracepting populations. This point is illustrated by data on the Dogon of Mali, a traditional West African population with a mean of 8.6 +/- 0.3 live births per woman. The Dogon data include hormonal profiles (urinary estrone-3-glucuronide and pregnanediol-3-glucuronide) of 93 women (sampled twice weekly for 10 weeks) and a census of women's visits to menstrual huts (n = 736 days). Dogon women menstruated regularly only if they were sterile. Otherwise, women aged 20-34 years had a median of only two menses each over the 2 year study period. The median number of menses per lifetime was approximately 100, about a third as many as experienced by an American woman who had three live births. These results contribute to a growing body of evidence that women's bodies were designed by natural selection to spend most of the time in lactational amenorrhea and add support to the view that contraceptives can be made safer if they forego the hormonal swings associated with menstruation. This conclusion is further reinforced by evidence that menstrual bleeding serves no adaptive purpose. PMID- 10100134 TI - Modeling the involvement of the hypothalamic-pituitary-adrenal and hypothalamic pituitary-gonadal axes in autoimmune and stress-related rheumatic syndromes in women. AB - Autoimmune and stress-related rheumatic diseases are significantly more common in women than in men. Our group has focused on the role of two principal neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, in this increased susceptibility to rheumatic disease. We review the physiology of the HPA and HPG axes and discuss their reciprocal interactions. Mechanisms by which hormones of the HPA and HPG axes influence the immune system and modulate the course of autoimmune inflammatory diseases in animal models of rheumatic disease are described. In addition, we review the data suggesting the importance of these neurohormonal systems in rheumatic diseases. These data provide insights into why women may be at increased risk and how we might better understand the mechanisms that provoke expression of rheumatic diseases in women. To advance research in this area, it is critical to develop methods to evaluate the function of the neuroendocrine axes. Secretion of both HPA and HPG axis hormones, particularly the hormones of the hypothalamus and anterior pituitary, is largely by intermittent pulses. In addition, the HPA axis exhibits a profound circadian, or near 24-hour, variation, and HPG axis hormones fluctuate over the monthly cycle. These factors make meaningful analysis of these axes quite complex. We discuss models used in the analyses of neuroendocrine axes and the use of challenge testing to assess the integrity of neuroendocrine axes. PMID- 10100135 TI - Modeling adverse environmental impacts on the reproductive system. AB - When priority topics are being established for the study of women's health, it is generally agreed that one important area on which to focus research is reproduction. For example, increasing attention has been directed to environmental exposures that disrupt the endocrine system and alter reproduction. These concerns also suggest the need to give greater attention to the use of animal toxicologic testing to draw inferences about human reproductive risks. Successful reproduction requires multiple simultaneous and sequential processes in both the male and female, and the effect of toxicity on reproduction-related processes is time dependent. Currently, however, the risk assessment approach does not allow for the use of multiple processes or for considering the reproductive process response as a function of time. We discuss several issues in modeling exposure effects on reproductive function for risk assessment and present an overview of approaches for reproductive risk assessment. Recommendations are provided for an effective animal study design for determining reproductive risk that addresses optimization of the duration of dosing, observation of the effects of exposure on validated biomarkers, analysis of several biomarkers for complete characterization of the exposure on the underlying biologic processes, the need for longitudinally observed exposure effects, and a procedure for estimating human reproductive risk from the animal findings. An approach to characterizing reproductive toxicity to estimate the increased fertility risks in a dibromochloropropane (DBCP)-exposed human population is illustrated, using several reproductive biomarkers simultaneously from a longitudinal rabbit inhalation study of DBCP and an interspecies extrapolation method. PMID- 10100136 TI - Chemicals and menopause: effects on age at menopause and on health status in the postmenopausal period. AB - Menopause, a natural stage in women's lives, signals the cessation of fertility and causes changes in health status for many women. Chemical exposures may induce early or premature menopause and increase the risks of morbidity and mortality in the postmenopausal period. Chemicals that are toxic to follicles can lower the age of menopause by depleting the ovary of oocytes. Women may be exposed to these chemicals in the workplace, at home, and through exposure to contaminated drinking water near hazardous waste sites, as well as by direct or indirect exposure to cigarette smoke. PMID- 10100137 TI - A mechanistic-based approach for assessing chemical hazards to parturition. AB - Evaluations of environmental hazards to pregnancy often overlook the potential for chemicals to disrupt the final event, childbirth. There are relatively few epidemiologic studies on this topic and even fewer toxicologic investigations. Mechanistic-based approaches offset many of the difficulties that are anticipated with intact laboratory animals, such as interspecies variability in the initiating events, and may allow for rapid and relevant assessment of potential chemical hazards. In vitro systems based on knowledge of the cellular events that underlie parturition may, therefore, facilitate investigation of toxicologic aspects of parturition. Nonetheless, limitations of in vitro mechanistic-based approaches exist. Ultimately, the greatest understanding of risk to pregnancy from environmental chemicals is likely to result from the collaborative efforts of laboratory scientists and epidemiologists. PMID- 10100138 TI - Combining qualitative with quantitative approaches to study contraceptive pill use. AB - According to large-scale studies, oral contraceptive users become pregnant at rates that exceed ideal use failure rates. It is thought that a major cause is missed pills, but current research on consistent contraceptive pill taking is characterized by inadequate measures and a failure to investigate women's thinking about their own patterns of use. The purpose of this study was to gain some understanding about women's interpretations of consistency in their own pill taking through combining qualitative with quantitative data. The study was conducted in China, where contraception is free and widely available. Five urban and five rural oral contraceptive users were followed for up to three pill-taking cycles during 1996 for a total of 759 person-days. Consistency of pill taking was measured with electronic data obtained from a new blister package made by Anderson Clinical Technologies (Elmhurst, IL). Data from these devices were reviewed and interpreted by the study participants during in-depth private interviews. The users' reasons for missing pills included disruptions in their daily routines, their husband's absence, spotting, and trouble implementing the family planning program's instructions to take one pill per day for 22 days and start the next cycle on the fifth day of menses. One user gave these reasons for two cycles but denied missing numerous pills in her third cycle. Data from a series of four questionnaires showed that most demographic, psychosocial, and service system characteristics were not related to missed pills. However, results suggested that the daily routines of rural living may make consistent use more likely and that instructions for taking the pill may be associated with prolonged pill-free intervals and skipping pills during episodes of spotting. Three of the 10 women were at increased risk of pregnancy during the study period because of their pill-taking pattern. We concluded that the combination of qualitative with quantitative data enhances understanding of contraceptive use. Women themselves offer plausible reasons for their use behaviors. Listening to women could be useful in improving programs. PMID- 10100139 TI - Integrating quantitative and qualitative methods to study multifetal pregnancy reduction. AB - This study integrates quantitative and qualitative research methods to examine the psychologic repercussions of multifetal pregnancy reduction, a recently developed reproductive technology. Two theoretical vantage points, descriptive psychiatry and psychoanalytic theory, were used to understand the emotional impact of the medical intervention, which involves aborting some but not all of the fetuses in a multifetal pregnancy. Quantitative analysis of diagnostic interviews indicated that women who underwent pregnancy reductions were at no greater risk than controls for developing depressive disorder. Although multifetal pregnancy reduction posed no apparent mental health risk, women experienced it as stressful and distressing. Women's responses were organized and understood via qualitative analyses based on six contemporary psychoanalytic perspectives: drive theory, ego psychology, object relations theory, self psychology, interpersonal viewpoints, and developmental concepts. Some of the practical and philosophic implications of qualitative and quantitative strategies are considered. PMID- 10100140 TI - Using qualitative methods to elicit recall of a critical time period. AB - The period during and after puberty seems to be important for breast cancer initiation. Because experiences during that time are likely to be influenced by a woman's cultural background, we conducted a pilot study among Hispanic and Caucasian women to elicit their memories of early life events. These data were used to design culture-specific questionnaire modules for the retrospective assessment of peripubertal breast cancer risk factors, using specific strategies to trigger accurate recall. Study subjects were volunteer breast cancer survivors or relatives of survivors. In carrying out this work, we took methods from the social sciences and applied them to a research question in chronic disease epidemiology. We found both qualitative and quantitative differences in recall of peripubertal exposures and experiences between Hispanic and Caucasian subjects. Our preliminary data indicate that in contrast to Caucasian women, Hispanic women consider the church rather than school a touchstone for recalling past events. Under the domain "body development," Hispanic women are more likely to mention menstruation than Caucasian women but less likely to recall changes in body hair and breast development. Caucasian women cited team sports as an important physical activity during the peripubertal period, whereas Hispanic women listed more sedentary games and housework as the main activities. Results of our pilot study support the view that to enhance the validity of retrospective data on peripubertal breast cancer risk factors, it is important to take account of cultural differences. Our experience using qualitative methods to elicit data of this kind in the context of a larger epidemiologic research effort suggests that such innovative approaches are valuable. PMID- 10100141 TI - Soluble interleukin 2 receptor (sIL2R) in monitoring advanced lung cancer during chemotherapy. AB - STUDY OBJECTIVES: To evaluate the usefulness of measuring sIL2R for diagnostic and prognostic purposes and for monitoring disease during a 6-month period of chemotherapy, and to investigate the clinical significance of sIL2R serum concentrations. METHODS: The serum concentration of sIL2R, TPA and lymphocyte subsets CD4, CD8, CD25, CD16 were measured at diagnosis and then 1 and 6 months after the start of chemotherapy. PATIENTS: There were 39 patients (three females, 36 males; mean age 61.6 years) with lung cancer (LC), treated with chemotherapy and 22 control subjects (six females, 16 males; mean age 50.1 years) with non neoplastic lung diseases. RESULTS: No significant differences in sIL2R serum concentrations were observed at diagnosis between the control and LC group or when comparing the different histotypes, disease stages (IIIa-b vs IV) and survival (survival < or = 12 vs > 12 months). On comparing the sequential variations of the examined parameters a significant increase in sIL2R (P < 0.007) after 1 and 6 months versus basal value was observed only in patients surviving less than 12 months and in those who did not respond to chemotherapy. Moreover a negative correlation was observed between sIL2R serum concentrations and CD25+ and CD16+ lymphocyte subsets. Evaluation of survival curves of patients with basal sIL2R > or < or = 700 U/ml showed a slightly lower survival rate in the former group. CONCLUSIONS: The present results, confirming the poor utility of sIL2R in the diagnostic phase of the disease, show its usefulness in prognostic evaluation and in the clinical surveillance of patients with advanced lung cancer submitted to polychemotherapy. In this case any variations in sIL2R serum levels are likely to relate to the spread of the neoplasia rather than to the host immune response. PMID- 10100142 TI - The impact of surgical adjuvant thoracic radiation for different stages of non small cell lung cancer: the experience from a single institution. AB - A retrospective analysis is performed of 223 patients receiving radiotherapy after complete surgery or microscopic-positive resection margins for non-small cell lung cancer. All patients received a total dose of 55 Gy. For 98 stage II (T1, T2N1), a 5-year survival rate of 37% was found. First failure analysis showed 15% (15/98) local and 39% (38/98) distant failures. Patients with hilar positive lymph nodes had a 5-year survival rate of 32%, compared with 41% for lobar-positive nodes due to more distant failures. Patients with squamous histology had a better survival than non-squamous tumours. There were 48 patients with pN2 tumours. First failure analysis gave 23% (11/48) local and 39.5% (19/48) distant failures resulting in 35% 5-year survival. Patients with pT3N0 with microscopic-positive resection margins and pT3N1 tumours had 5-year survival rates of 21.5 and 17%. Postoperative radiotherapy should be advised in cases of positive hilar nodes, and in all cases of mediastinal-positive nodes. A combination schedule with chemotherapy seems necessary. PMID- 10100143 TI - Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer. AB - OBJECTIVES: We evaluated the effect of hyperfractionated accelerated radiotherapy combined with low dose radiosensitisers followed by standard dose chemotherapy in the treatment of unresectable stage III non small cell lung cancer (NSCLC). METHODS: Forty-seven patients received thoracic radiotherapy (1.5 bid x 5 days x 4 weeks) in combination with low dose daily (3-6 mg/m2) cisplatin +/- weekly vinblastine chemotherapy (step I), followed by three cycles of standard dose chemotherapy alone consisting of cisplatin (75-80 mg/m2) and vinblastine (8-16 mg/m2) given at 3-4 week intervals (step II). RESULTS: The overall response rate was 70% (21% CR). The progression free interval and the median survival duration were 10.4 months and 17.3 months, respectively. The 3 year survival rate was 21%. The site of first progression was local in 44%, distant in 41%, and simultaneous in 15% of patients. Levels of esophageal toxicity were significant but acceptable with the use of prophylactic therapy. Grade 3 or 4 esophageal toxicity was observed in 28 and 19% of patients during step I and II of the study, respectively. There were three deaths associated with esophageal toxicity. All occurred prior to the implementation of the prophylactic therapy for esophagitis. Acute pulmonary symptoms were reported in 25% of patients in step I, and pulmonary fibrosis, primarily asymptomatic, was observed in 51% of patients. Hematological toxicity was moderate. Two patients died of neutropenic sepsis/pneumonia. CONCLUSION: Concurrent chemotherapy and hyperfractionated accelerated radiotherapy followed by chemotherapy appears moderately effective in controlling tumour growth as measured by response rates and survival estimates. Toxicity is considerable but manageable and compatible with results from other combined modality studies. PMID- 10100144 TI - A phase II study with vinorelbine, gemcitabine and cisplatin in the treatment of patients with stage IIIb-IV non-small cell lung cancer (NSCLC). AB - In our phase II study an acceptable and effective agent like cisplatin was used in combination with vinorelbine and gemcitabine in patients with non-small cell lung cancer (NSCLC). These two new cytostatic drugs have demonstrated, when used as a single-agent treatment, effective response rates (vinorelbine) and minimum toxicity (gemcitabine). The following schedule was used: (i) vinorelbine 25 mg/m2 on days 1 and 8; (ii) gemcitabine 1000 mg/m2 on days 1 and 8; and (iii) cisplatin 75 mg/m2 on day 8. The schedule was repeated every 21 days, with a maximum of six cycles per patient. A total of 31 patients with a mean Karnofsky performance status of 90% were evaluated and 29 of them were finally eligible. Of the patients, five (16.1%) were at stage IIIb and the remainder (83.9%) were at stage IV. The overall response rate was 65% (20 patients); six patients (19.4%) had complete response (CR) and 14 (45.2%) had partial response (PR). Two patients (6.5%) had stable disease and seven (22.6%) had progressive disease. The most notable toxicity was hematologic. Leukoneutropenia was mainly revealed after the third or fourth cycle and granulocyte-colony stimulating factor (G-CSF) was administered in 24 patients (77.4%). Mild anemia was found in almost all patients after the third or fourth cycle (Hb 10-11 g/dl) and eight patients (25.8%) required erythropoietin (EPO). Thrombocytopenia was more often observed compared with other known chemotherapeutic regimens; six patients (19.4%) had grade I thrombocytopenia and therapy was delayed in another four patients (12.9%) due to this complication. Non-hematologic toxicity was mild and well tolerated and consisted of alopecia (54.8%), nausea and vomiting (12.9%), constipation (12.9%), peripheral neuropathy (9.6%), diarrhea (6.5%), stomatitis (3.2%) and local phlebitis (3.2%). The examined combination provides us with one of the best overall responses rates reported, however at the cost of remarkable hematologic toxicity. Therefore, it would be better applied in patients with good performance status. The high response rates give us hope of using this combination as a neoadjuvant regimen. PMID- 10100145 TI - Tumour response and radiation-induced lung injury in patients with recurrent small cell lung cancer treated with radiotherapy and concomitant interferon alpha. AB - The aim of this study was to determine whether either natural or recombinant interferon (IFN)-alpha can improve the response to radiotherapy (RT) in patients with small cell lung cancer (SCLC), and to assess the role of IFN in radiation induced lung injury. All patients had previously participated in a randomised trial of chemotherapy alone or in combination with IFN-alpha in three arms (arm O: no IFN, arm I: natural IFN-alpha, arm II: recombinant IFN-alpha). Patients with locally progressive disease in the lungs following chemotherapy were treated with RT and they continued with their concomitant IFN-alpha. The RT dose was 50 Gy. Radiation-induced lung injury was assessed by lung function tests, computed tomography and bronchoalveolar lavage fluid (BALF) analysis which included cell findings, Interleukin (IL)-1 alpha/-1 beta expression by alveolar macrophages and surfactant components. Seventeen patients were entered in the study, 16 of whom were evaluable. Response rates in Arms O, I and II were 50, 67 and 50%, respectively. Median survival was 18.5, 7 and 23 months respectively, and 1-year survival was 67, 29 and 75% respectively. Long-term survival as assessed by 2- and 3-year survival rates was 29% in patients receiving natural IFN-alpha as compared to 17% in patients not receiving IFN (not statistically significant findings). Every patient had abnormal results when assessed for radiation-induced lung injury. No statistically significant difference was found in toxicity between the treatment arms. A high surfactant protein (SP)-A/phospholipid ratio and a high level of SP-A in BALF before RT was associated with a high degree of radiation-induced lung injury measured by lung function tests and computed tomography in all arms of the study. Thus, we could not show that the combination of IFN-alpha and RT induced more lung toxicity than RT alone as we did in our previous study. The role of high SP-A/phospholipid ratios and high SP-A levels in BALF before RT as predictors of the development of lung injury after RT needs to be determined in the future. PMID- 10100146 TI - Thoracic solitary fibrous tumor: clinical and pathological diversity. AB - Fourteen cases (13 pleural and one intrapulmonary) of solitary fibrous tumors (SFTs) (the so-called fibrous mesothelioma) were studied. The lesions occurred more in females (nine cases) than males (five cases). The age of patients ranged from 44 to 73 years old (median 60 years). The tumors presented as cough with or without blood-tinged sputum, exertional dyspnea, chest pain, nausea, body weight loss, fever, or as asymptomatic masses detected by routine chest radiograph. Two patients with huge (tumor larger than 20 cm) malignant tumors had accompanying pleural effusion and one associated with hypoglycemia. Ten benign tumors measured 2-11 cm (median size 7 cm) while the remaining four histologically malignant ones measured 20-30 cm in size. All of them were well circumscribed and thinly encapsulated. Hemorrhage and necrosis were more frequently seen in the malignant tumors. Histologically, these lesions were characterized by 'patternless pattern' with occasional hemangiopericytic features (three cases). The tumor cells were all immunoreactive for vimentin, CD 34, and focally actin-positive in one case, but not for keratin, desmin, S-100 protein, carcinoembryonic antigen, alpha 1-ACT and F VIII-related antigen, supported a primitive mesenchymal origin. p53 protein was expressed in two of the malignant cases. Proliferating cell nuclear antigen stain was positive with 50 and 80% of the labeling index in the benign and malignant tumors, respectively, but retinoblastoma gene protein was negative in all tumors. This analysis confirmed the relationship between histological malignant SFTs and tumor size, cellularity, mitotic activity, necrosis and tumor suppressor gene expression. However, the clinical behavior was unpredictable. Complete respectability seemed to be the most important indicator of clinical outcome in the less aggressive tumors. PMID- 10100147 TI - Chromosome 3 imbalances are the most frequent aberration found in non-small cell lung carcinoma. AB - The chromosomal imbalances in nine cases of primary non-small cell lung cancer (NSCLC) and two cell lines derived from normal human bronchial epithelial (HBE) tissue were identified by comparative genomic hybridization (CGH). Gain of material from 3q and loss of 3p material were the most frequent changes in the primary tumors. Other commonly found imbalances included gain of material from 1q, 7p, 8q, 9q, 17q and 20q, and losses involving 4, 5q, 8p, 10 and 13q. High level gain was found in two cases, both encompassing the 3q23-q27 region. Loss of 3p was also found in both of the HBE cell lines suggesting that loss of one or more tumor supressor genes on 3p may be important for epithelial transformation and could be involved in the earlier stages of lung cancer development. PMID- 10100149 TI - Correspondence on brain metastases. PMID- 10100148 TI - Primary pulmonary collision tumor including squamous cell carcinoma and T-cell lymphoma. AB - We report a very rare occurrence of a primary collision tumor in the lung consisting of squamous cell carcinoma and T-cell lymphoma. A squamous cell carcinoma was diagnosed histologically following a transbronchial lung biopsy in a 71-year-old woman, but the other component was diagnosed histologically and immunohistochemically only on examination of the resection specimen. The malignant lymphoma was stained by the monoclonal antibody UCHL-1 (anti-D45RO) against T-lymphocytes but was not stained by the L26 (anti-CD20) antibody against B-lymphocytes. Immunostaining for CD3 was positive, confirming a T-cell lineage. Despite systemic chemotherapy, the patient died 7 months after operation, from progression of the lymphoma. Our case, which illustrates interesting attributes of collision tumors, consisted of an ordinary squamous cell carcinoma and a rare T-cell lymphoma arising in the lung, with the latter part of the combination dictating subsequent treatment and outcome. PMID- 10100150 TI - Highlights from the Second Cuneo Lung Cancer Conference. PMID- 10100151 TI - Age-associated alterations in cardiac and skeletal muscle glucose transporters, insulin and IGF-1 receptors, and PI3-kinase protein contents in the C57BL/6 mouse. AB - We investigated potential age-related changes in cardiac and skeletal muscle protein contents of glut-4 and glut-1 transporters, insulin and insulin-like growth factor-1 (IGF-1) receptors, and phosphatidylinositol 3-kinase (PI3-kinase) in the C57B1/6 mouse. Myocardial glut-4 content increased four- to five-fold between mid- to late-adulthood with no further age-related changes. Increases in myocardial glut-1 preceded the increase in glut-4 and was of a much smaller magnitude (25-40%). Skeletal muscle glut-4 was also increased (38-49%) and no further changes were noted between adulthood and old age. Cardiac insulin receptor and the p85 alpha subunit of PI3-kinase both declined by about 40%, whereas the skeletal muscle content of these two proteins were unaffected by aging. Cardiac (-23 to -24%) and skeletal muscle (-40 to -62%) IGF-1 receptor levels were decreased in adult and old animals with senescence being associated with a further decrease in cardiac IGF-1 receptor levels to 20% of controls. A two- to three-fold increase in both basal and maximal in vitro autophosphorylation of the cardiac insulin and IGF-1 receptors by their respective ligands was observed with senescence. It appears that cardiac and skeletal muscle demonstrate differential responses in terms of the magnitude and temporal responses of age-associated alterations in glucose transport related protein contents in the C57B1/6 mouse. PMID- 10100152 TI - Geroprotector effectiveness of melatonin: investigation of lifespan of Drosophila melanogaster. AB - The lifespan (LS) of Drosophila melanogaster was studied under the effect of melatonin at a concentration of 0.08% selected in preliminary experiments. The compound was introduced into a culture medium only at the stage of development. An inverse relationship was observed between the change in LS after the impact of the preparation and the value of LS in the corresponding control group (Spearman's rank correlation coefficient R = -0.83, P < 0.02). For a relatively low LS in a population from which the control and experimental groups were formed, the geroprotector effect of melatonin is the most distinct; for a relatively high LS, the effect of the hormone is either not detected or appears as a toxic reduction in LS (up to 10%) in the experimental group. Such nonuniform effects of melatonin are connected with fluctuating changes in viability in successive generations of D. melanogaster. The antioxidant mechanism of the geroprotector effect is also discussed. PMID- 10100153 TI - Effect of in vitro aging on the biosynthesis of glycosaminoglycans by human skin fibroblasts. Modulation by the elastin-laminin receptor. AB - The incorporation of a radioactive precursor 3H-glucosamine in glycoconjugates, essentially glycosaminoglycans (GAG) was evaluated in the culture medium and cell fraction of human skin fibroblasts. Using increasing passage numbers, we could estimate the effect of in vitro aging on these biosynthetic activities. The incorporation in different free (hyaluronan) and protein bound (proteoglycans) GAGs was evaluated after specific enzymatic digestion. Most newly synthesized GAGs were excreted in the extracellular medium. Incorporation of the tracer in hyaluronan, the major biosynthetic product, increased with passage number but its titratable concentration decreased with in vitro aging, suggesting a rapid post synthetic degradation. The proportion of chondroitin sulfates 4 (A) and 6 (C) and heparan sulfate decreased and that of dermatan sulfate increased with increasing passage number. We explored the modulation of these biosynthetic activities by the elastin laminin receptor. Using agonists (elastin peptides) and an antagonist (melibiose) of the receptor, their action on GAG biosynthesis was evaluated. Both elastin peptides and melibiose increased incorporation of the tracer in GAGs, but only melibiose inhibited post-synthetic degradation of hyaluronan, therefore increasing its concentration. The effect of passage number on the receptor mediated modulations was also investigated. PMID- 10100154 TI - Telomere shortening during aging of human osteoblasts in vitro and leukocytes in vivo: lack of excessive telomere loss in osteoporotic patients. AB - We have compared the telomere length, as assessed by Southern analysis, of telomere restriction fragments (TRFs) generated by RsaI/HinfI digestion of genomic DNA in: (i) in vitro cultured human trabecular osteoblasts undergoing cellular aging; and (ii) peripheral blood leukocytes (PBL) obtained from three groups of women: young (aged 20-26 years, n = 15), elderly (aged 48-85 years, n = 15) and osteoporotic (aged 52-81 years, n = 14). The mean TRF length in human osteoblasts undergoing aging in vitro decreased from an average of 9.32 kilobasepairs (kb) in middle-aged cells to an average of 7.80 kb in old cells. The rate of TRF shortening was about 100 bp per population doubling, which is similar to what has been reported for other cell types, such as human fibroblasts. Furthermore, there was a 30% decline in the total amount of telomeric DNA in senescent osteoblasts as compared with young cells. In the case of PBL, TRF length in the DNA extracted from young women was slightly longer (6.76 +/- 0.64 kb) than that from a group of elderly women (6.42 +/- 0.71 kb). A comparison of TRFs in the DNA extracted from the PBL from osteoporotic patients and from age-matched controls did not show any significant differences (6.47 +/- 0.94 versus 6.42 +/- 0.71 kb, respectively). Therefore, using TRF length as a marker for cellular aging in vitro and in vivo, our data comparing TRFs from osteoporotic patients and age-matched controls do not support the notion of the occurrence of a generalized premature cellular aging in osteoporotic patients. PMID- 10100155 TI - Age-dependent changes in rat liver microsomal membrane structure and functions under benzene treatment. AB - The influence of benzene on 3 and 24 months old rat liver microsomes was studied. Some structural and functional changes occur under benzene treatment in the cytochrome P-450 system which are more pronounced in 3 months old rat microsomes than in the 24 months ones. Glucose-6-phosphatase and glucose dehydrogenase activities indicate that 3 months old rat microsomal vesicles are more stable against benzene injury than those, of 24 months old ones. In vitro benzene hydroxylation activation by NADPH addition decreased disruptive xenobiotic's effect on 3 but not on 24 months old rat liver microsomal vesicles. This fact suggests that the rate of benzene hydroxylation is important for its membrane damaging action effect. Thus, age-related differences in xenobiotic action on liver microsomes could be related to the decrease of benzene metabolism rate with senescence. PMID- 10100156 TI - A low degree of fatty acid unsaturation leads to lower lipid peroxidation and lipoxidation-derived protein modification in heart mitochondria of the longevous pigeon than in the short-lived rat. AB - Birds have a maximum longevity (MLSP) much greater than mammals of similar metabolic rate and body size. Thus, they are ideal models to identify longevity characteristics not linked to low metabolic rates. In this investigation, we show that the fatty acid double bond content of total lipids and phosphatidylcholine, phosphatidylethanolamine and cardiolipin fractions of heart mitochondria is intrinsically lower in pigeons (MLSP = 35 years) than in rats (MLSP = 4 years). This is mainly due to a lower content of the most highly unsaturated docosahexaenoic acid (22:6n-3) and in some fractions arachidonic acid (20:4n-6). The lower double bond content leads to a lower sensitivity to in vitro lipid peroxidation, and is associated with a lower concentration of lipid peroxidation products in vivo, and a lower level of malondialdehyde-lysine protein adducts in heart mitochondria of pigeons than rats. These results, together with those previously obtained in other species or tissues, suggest that a low degree of fatty acid unsaturation is a general characteristic of longevous homeothermic vertebrate animals both when they have low metabolic rates (mammals of large body size) or high metabolic rates (small sized birds). This constitutive trait helps to protect their tissues and mitochondria against lipid peroxidation and oxidative protein modification and can be a factor contributing to their slow rate of aging. The results also show, for the first time in a physiological model, that lipid peroxidizability is related to lipoxidative protein damage. PMID- 10100157 TI - Interleukin-5 production by mononuclear cells from aged individuals: implication for autoimmunity. AB - It is well known that in the elderly a deterioration of immune functions may occur. Particularly, stimulation of T cells from aged individuals leads to different kind and/or size of responses if compared with the responses obtained from T cells from young individuals. At the same time, an increase in prevalence of autoantibodies occurs in elderly. The altered production of certain cytokines might explain this paradox of decreased responsiveness to foreign antigens in the face of an increased response to self-antigens. We and others have suggested that this kind of immune response might depend on an age-associated impairment of Th-1 type function that selectively affects production of cytokines involved in the control of cellular responses. In contrast, Th-2 type function is seemingly not affected in elderly, as suggested by normal in vitro production of cytokines involved in humoral responses. To strengthen this hypothesis, in this study we have analysed the influence of age on the ability of mitogen-stimulated cultures of peripheral blood mononuclear cells from human beings to produce another Th-2 type cytokine, i.e. interleukin-5 (IL-5). IL-5 content of both 24- and 48-h stimulated cultures from old individuals was greater than that of young ones, although this difference attained significance only at 48 h. We suggest that the decreased production of Th-1 type cytokines in the presence of a normal or even increased production of Th-2 type cytokines might account for the pattern of immune response which may be observed in elderly, i.e. a normal or increased humoral response, including an autoimmune one, in the face of a low cell mediated immune response. PMID- 10100158 TI - Effects of hindlimb suspension on contractile properties of young and old rat muscles and the impact of electrical stimulation on the recovery process. AB - The purpose of this study was to investigate the effects of hindlimb suspension (HS) on contractile properties of skeletal muscles of young and old rats and to determine the impact of electrical stimulation (ES) on the quality and degree of recovery of these muscles. After 21 days of HS, young soleus (SOL) muscle became faster, but there was no impact on young extensor digitorum longus (EDL) muscle. Twitch tension (Pt) decreased 61% in young and 70% in old SOL muscles. Specific tetanic tension (Po) decreased 53% in young and 64% in old SOL muscles, but again there was no impact on EDL muscle. After a 14-day period of recovery, contraction time (CT), half-relaxation time (RT1/2), Pt and Po returned to control group values in both young and old SOL muscles. Measurements of the contractile properties of young and old skeletal rat muscles showed ES sometimes to be beneficial but also sometimes to be harmful. A 14-day period of recovery, with or without ES, seemed sufficient for many variables to return to control group values. PMID- 10100159 TI - Guidelines on the implementation of diode in vivo dosimetry programs for photon and electron external beam therapy. AB - Semiconductor diodes offer many advantages for clinical dosimetry: high sensitivity, real-time readout, simple instrumentation, robustness and air pressure independence. The feasibility and usefulness of in vivo dosimetry with diodes has been shown by numerous publications, but very few, if any, refer to the utilization of diodes in electron beam dosimetry. The purpose of this paper is to present our methods for implementing an effective IVD program for external beam therapy with photons and electrons and to evaluate a new type of diodes. Methods of deciding on reasonable action levels along with calibration procedures, established according to the type of measurements intended to be performed and the action limits, are discussed. Correction factors to account for nonreference clinical conditions for new types of diodes (designed for photon and electron beams) are presented and compared with those required by older models commercially available. The possibilities and limitations of each type of diode are presented, emphasizing the importance of using the appropriate diode for each task and energy range. PMID- 10100160 TI - The treatment planning of segmental, conformal stereotactic radiosurgery utilizing a standard multileaf collimator. AB - Over a period of approximately 3 years, our institution has implemented and refined a system of Stereotactic Radiosurgery (SRS) which utilizes the standard multi leaf collimator (MLC) of the Scanditronix MM50 Racetrack Microtron and treats in an arrangement of segmental "pseudo-arcs." This system employs a commercial BRW based stereotactic frame which is mounted to the treatment table. With the exception of the table-mounted frame hardware there have been no modifications to the treatment machine to accommodate these treatments. By use of standard evaluation parameters (e.g., treatment time, planning time, dose conformance and dose heterogeneity ratios) this system compares quite favorably with reported data from institutions treating SRS with either a GammaKnife or a standard linear accelerator with tertiary collimators. PMID- 10100161 TI - Dosimetric advantages of enhanced dynamic wedge in small field irradiation for the treatment of macular degeneration. AB - Exudative macular degeneration is a process that affects the central retina and is the chief cause of blindness in people over 55 years old. Radiation appears to improve or stabilize visual acuity in some of these patients, although definitive clinical studies are ongoing. The delivery of radiation in patients with macular degeneration is unique and challenging because of the location of the surrounding structures, such as the lens and the opposite retina. The "standard" treatment technique has been an anterior oblique beam 20 degrees above lateral to limit dose to these structures. In preference to the undesirable hot spot caused by this single-beam technique, we have employed a superior and inferior oblique pair utilizing the Enhanced Dynamic Wedge (EDW). Couch rotation was used to establish the desired treatment angles. The anterior half of the fields were blocked with the asymmetric jaw (AJ). Studies were performed to determine the value of these methods in reducing lens dose. Although the peripheral dose measurements at Dmax using a 60 degrees metal wedge for > or = 10 cm square fields were higher than for an open field or the EDW, for the small retinal fields there was no lens-dose reduction attributable to the EDW. However, the steep wedge angles achievable with the EDW were useful for optimizing the dose distribution for the most desirable field angles. As expected, the independent collimator was more effective in reducing transmitted dose to the lens than a typical Cerrobend block. Measurements required to predict dose in and out of the field are discussed along with the dosimeters employed in evaluating small fields (less than 5 cm square) with the EDW. The technical challenges of positioning, immobilization, treatment planning and treatment delivery are presented. PMID- 10100162 TI - Use of segmental boost fields in the irradiation of inguinal lymphatic nodes. AB - En face electron fields to boost inguinal lymphatics have been used by oncologists for many years. With the introduction of multileaf collimators (MLC) and independent jaws, the practice of creating segmental fields to boost areas of interest has expanded. Typical anterior-posterior opposing field treatment of the pelvis may now be enhanced to include additional anterior segments to boost lymphatic tissue at a predetermined depth. This report illustrates the clinical implementation of one such segmental boost technique. Computer generated isodose plans utilize manual contour and CT-generated data for analysis of inguinal lymphatic depths. Potential areas of field overlap are discussed as well as the use of combined 6 and 15 MV photon energies to reduce areas of inhomogeneous dose. Technical details associated with MLC field size limits and other clinical factors are also discussed in relationship to smooth treatment delivery. PMID- 10100163 TI - Traditional and MLC based dose compensator design for patients with hip prostheses undergoing pelvic radiation therapy. AB - Perturbations in the dose distribution caused by a hip prosthesis when treating pelvic malignancies can result in unacceptable dose inhomogeneities within the target volume. Our results, obtained by in vivo exit dose measurements with diodes, showed a 55% reduction in the dose at the exit dmax of a lateral 15 MV photon beam after passing through a bilateral cobalt-chrome alloy hip prosthesis. Such an inhomogeneous dose distribution may decrease the curability. Solutions such as treatment techniques to avoid the prosthesis are often not the best choice as the dose to the rectum may be unacceptably high. In this work an alternative method of dose compensator is presented. Two types of dose compensators were designed based on a 3-D treatment planning system and CT images of a pelvic phantom containing a hip prosthesis: one was fabricated from a polyethylene-lead slab in the representation of step fringes and placed on a tray in the path of the beam while the other was produced by the use of several fields shaped with a multileaf collimator. The calculation procedures developed by the authors for generating the compensators are described. Results of film measurements performed in a phantom with and without the compensators in place are discussed. PMID- 10100164 TI - Essentials of radiation oncology chart design. AB - Medical Dosimetrists are commonly called upon to participate in the design of radiation oncology treatment records. The Medical Dosimetrist is uniquely qualified to provide input in the areas of treatment planning, simulation and delivery documentation. An idealized chart can facilitate the planning and delivery of quality patient care and lead the user to document such care. This publication outlines the essential minimum requirements for inclusion in a radiation oncology treatment chart. Conventional treatment record keeping has been by hard-copy documentation. Paperless treatment record models are presently being tested for efficacy. Either approach should seek to: maintain quality of patient care, enhance communication, and provide integrity in documentation. PMID- 10100165 TI - Diode verification of routine electron-beam treatments. AB - A platinum doped n type commercial silicon electron diode/electrometer system was evaluated for use in our comprehensive external beam radiotherapy quality assurance program. Directional dependence of diode response was investigated by positioning the diode at the radiation isocenter and recording the response versus beam incident direction. Dose rate response was examined by testing for nonidealities in inverse square law behavior. Energy dependence of response was explored using 6-21 MeV beams. Dose response linearity was investigated from 50 800 cGy. Radiation perturbation was measured using localization film. Finally, the system was evaluated for initial treatment quality assurance in a number of clinical cases (N = 34). The diode response exhibited +/- 5% variation within +/- 20 degrees of the detector's marked "preferred" direction for the 6 MeV beam. Higher energy electron beams exhibited much less directional dependence. Dose rate response was found constant from 178-326 cGy/min (or 96-130 cm SSD). Energy dependence of response was constant within +/- 5.5% from 6-21 MeV. Dose response was linear (r2 = 0.999). Radiation field perturbation was significant at the depth of dose maximum (dmax). The maximum perturbation measured was -12.5% at dmax using the 6 MeV beam. Clinical trials of the system demonstrated that the diodes could be utilized for initial treatment quality assurance. The system proved effective for routine initial treatment electron beam in vivo dosimetry when the directional and energy dependent limitations of the system were respected. PMID- 10100166 TI - Accuracy of numerically produced compensators. AB - A feasibility study is performed to assess the utility of a computer numerically controlled (CNC) mill to produce compensating filters for conventional clinical use and for the delivery of intensity-modulated beams. A computer aided machining (CAM) software is used to assist in the design and construction of such filters. Geometric measurements of stepped and wedged surfaces are made to examine the accuracy of surface milling. Molds are milled and filled with molten alloy to produce filters, and both the molds and filters are examined for consistency and accuracy. Results show that the deviation of the filter surfaces from design does not exceed 1.5%. The effective attenuation coefficient is measured for CadFree, a cadmium-free alloy, in a 6 MV photon beam. The effective attenuation coefficients at the depth of maximum dose (1.5 cm) and at 10 cm in solid water phantom are found to be 0.546 cm-1 and 0.522 cm-1, respectively. Further attenuation measurements are made with Cerrobend to assess the variations of the effective attenuation coefficient with field size and source-surface distance. The ability of the CNC mill to accurately produce surfaces is verified with dose profile measurements in a 6 MV photon beam. The test phantom is composed of a 10 degrees polystyrene wedge and a 30 degrees polystyrene wedge, presenting both a sharp discontinuity and sloped surfaces. Dose profiles, measured at the depth of compensation (10 cm) beneath the test phantom and beneath a flat phantom, are compared to those produced by a commercial treatment planning system. Agreement between measured and predicted profiles is within 2%, indicating the viability of the system for filter production. PMID- 10100167 TI - Selective in vivo dosimetry in radiotherapy using P-type semiconductor diodes: a reliable quality assurance procedure. AB - Since 1994, our center has conducted entrance dose measurements on selected patients receiving 6MV x-ray therapy by utilizing a commercial set of p-type semiconductor diodes. We report on three years results representing 386 patients having 1005 measurements and the usefulness of such a system in a radiotherapy department. The 386 patients represent approximately 20% of our total radical treatments. Minimal disruption to patient treatment was achieved. Measurements showed an average variation from expected dose of 0.5% +/- 2.2%. Specific treatment site groups were investigated. Our results show that in vivo dosimetry on a selected group of patients is an effective method of providing an independent verification of dose delivery accuracy. PMID- 10100168 TI - Interfacing a linear diode array to a conventional water scanner for the measurement of dynamic dose distributions and comparison with a linear ion chamber array. AB - A linear diode array was interfaced to a conventional water scanner for the measurement of dose distribution of dynamically wedged treatment fields. The system was validated by comparing the dose distribution of an open field measured with the system and with a scanning ionization chamber. The system was also compared with a commercial ion chamber array scanner for the measurement of dose distributions of dynamic wedges. The dose distributions of enhanced dynamic wedge fields measured with the two dosimetry systems agree well beyond the depth of maximum dose. However, in the buildup region, the measurements made with the linear diode array system differ by more than 10% from that of the ion chamber array scanner. PMID- 10100169 TI - Comparison of the transit dose components and source kinematics of three high dose rate afterloading systems. AB - High dose rate (HDR) afterloading systems are using a high activity Ir-192 source that stops at programmed dwell positions to deliver a prescribed dose. The treatment planning systems are based on the dose calculation model that does not take into account the transit part of a dose resulting from a source while in motion. In this presentation the transit dose components as well as the source kinematics of three commercially available HDR systems were examined using a previously established technique1 based on film dosimetry. The studied systems were: Nucletron-Oldelft, Omnitron 2000 and Gamma Med 12i. The optical density profiles permitted the observation and evaluation of such source kinematics features as velocity, acceleration, deceleration and the source movement between programmed dwell positions. The comparison of the transit dose components for all three HDR systems showed that the largest transit dose can be expected for the Omnitron system with the slowest speed source and the smallest transit dose component is on the Nucletron-Oldelft system with the fastest moving source. PMID- 10100170 TI - Lung compensator design using an electronic portal imaging device. AB - Using a liquid filled electronic portal imaging device (EPID) installed on a linear accelerator and a composite chest phantom, exit dose measurements were carried out to establish an empirical relationship between the pixel values of the imaging detector and the corresponding equivalent thickness of the overlying phantom material. Results for 6 and 10 MV photons show that the relationship depends on the so-called input/output characteristics of the imaging device for a particular photon energy. For a chest irradiation, an EPID image obtained under treatment geometry provides the pixel value information that is used to calculate the tissue deficit over the lung region. The compensators are made of lead whose thickness is calculated from the established empirical relationship to replace the tissue deficit over lungs. The effectiveness of the method is demonstrated with thermoluminescent dosimetry (TLD) for 6 and 10 MV beams. With compensators in place, the dose uniformity was found to be within +/- 5%. PMID- 10100171 TI - 103Pd loaded cartridge air kerma strength verification. AB - Using radioactive 125I or 103Pd seeds in large number to treat prostate cancer has become popular. This procedure's popularity translates to increased physicist and dosimetrist workloads with regard to performing source strength assays. In addition, radiation exposure to the physicists' and dosimetrists' hands as a result of source handling has increased significantly. As a result of these increases, a method of source calibration using applicator cartridges was developed to allow safe handling of sources and expedited source assays. The method uses a holder which allows a cartridge loaded with five to fifteen seeds to be placed in a standard well ionization chamber. Ionization readings are converted to air kerma source strengths which are compared with the manufacturer's stated activity. Excellent agreement between individual seed air kerma strength as well as comparison with the vendor's air kerma strength statement proves the validity of this assay technique. Absorption/geometry correction factors were experimentally derived during the development of this method. These factors allow accurate determination of air kerma source strength from a shipment of Iodine or Palladium seeds. PMID- 10100172 TI - Discovery and identification of estrogen. PMID- 10100173 TI - Exogenous and endogenous estrogens: an appreciation of biological complexity. PMID- 10100174 TI - Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. AB - OBJECTIVE: To investigate the effect of soy protein supplementation with known levels of phytoestrogens on cardiovascular disease risk factors and menopausal symptoms in perimenopausal women. METHODS: A randomized, double-blind crossover trial was conducted in 51 women consuming isocaloric supplements containing 20 g of complex carbohydrates (comparison diet), 20 g of soy protein containing 34 mg of phytoestrogens given in a single dose, and 20 g of soy protein containing 34 mg of phytoestrogens split into two doses. Women were randomly assigned to one of the three diets for 6-week periods and subsequently were randomized to the remaining two interventions to determine whether differences existed between the treatment diets for cardiovascular disease risk factors, menopausal symptoms, adherence, and potential adverse effects. RESULTS: Significant declines in total cholesterol (6% lower) and low density lipoprotein cholesterol (7% lower) were observed in both soy diets compared with the carbohydrate placebo diet. A significant decline in diastolic blood pressure (5 mm Hg lower) was noted in the twice-daily soy diet, compared with the placebo diet. Although nonsignificant effects were noted for a number of measures of quality of life, a significant improvement was observed for the severity of vasomotor symptoms and for hypoestrogenic symptoms in the twice-daily group compared with the placebo group. No significant effects were noted for triglycerides, high density lipoprotein cholesterol or frequency of menopausal symptoms. Adherence was excellent in all groups. CONCLUSIONS: Soy supplementation in the diet of nonhypercholesterolemic, nonhypertensive, perimenopausal women resulted in significant improvements in lipid and lipoprotein levels, blood pressure, and perceived severity of vasomotor symptoms. These data corroborate the potential importance of soy supplementation in reducing chronic disease risk in Western populations. PMID- 10100175 TI - Postmenopausal estrogen therapy and selected (less-often-considered) disease outcomes. AB - OBJECTIVE: To review the association between postmenopausal estrogen therapy and chronic conditions not usually considered in risk-benefit reviews. DESIGN: Ten year literature review (1989-1998) of case series and epidemiologic studies with risk estimates and 95% confidence intervals. RESULTS: Osteoarthritis and rheumatoid arthritis, the most extensively studied conditions, show no consistent association with hormone therapy. Two studies of systemic lupus erythematosus show a nearly three-fold increased risk apparent after 2 or more years of hormone therapy. Single studies suggest an increased risk of pancreatitis, asthma, and Raynaud's syndrome. Evidence for a reduced risk of diabetes mellitus is not compelling. Cataracts and migraine are either increased or decreased by hormone therapy. Among the associations considered here, only an increased risk of gallbladder disease and venous thromboembolic disease have been confirmed in clinical trials of hormone replacement therapy. CONCLUSIONS: Further studies are needed. PMID- 10100176 TI - Aromatase and estrogen receptor immunoreactivity in the coronary arteries of monkeys and human subjects. AB - OBJECTIVE: The objective of this study was to determine whether estrogen could be formed locally in the coronary arteries. DESIGN: Coronary arteries were examined from monkeys (Macaca fascicularis, one male and one female) and human subjects (one premenopausal woman, one postmenopausal woman, and one man) by immunocytochemistry, using purified antisera against human placental estrogen synthetase (aromatase) and ER alpha. The arteries were graded for the amount of atherosclerosis. RESULTS: There was clear immunopositivity for both aromatase and estrogen receptors in all arteries studied. Although all endothelial cells (CD31 positive) stained for both antigens, the staining in macrophages, fibroblasts, and smooth muscle cells was irregular. CONCLUSION: The present results provide the first evidence for the local formation of estrogen in the coronary arteries. In addition to complementing the evidence of a cardioprotective effect of estrogen on the coronary circulation, our results highlight the potential importance of local regulation of estrogen formation and the role of available precursor androgens in maintaining the cardiovascular system. PMID- 10100177 TI - Serum follicle-stimulating hormone and luteinizing hormone levels in women aged 35-60 in the U.S. population: the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). AB - OBJECTIVE: The objective of this study was to examine age-specific population based values for serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in women in the U.S. population. DESIGN: Data were collected from a nationally representative cross-sectional health examination survey that included measurements of follicle-stimulating hormone and luteinizing hormone and information from a personal interview. A total of 3388 women aged 35 to 60 years were examined during the third National Health and Nutrition Examination Survey, 1988-1994. RESULTS: Among U.S. women aged 35-60 years, median FSH and LH levels began to increase for women in their late 40s and reached a plateau for women in their early 50s. This study supports the previously reported association between serum FSH and age (i.e., serum FSH and LH levels increase with age) and smoking (i.e., current smoking was associated with an increased level of serum FSH). At FSH levels of > or = 15 IU/L or > or = 20 IU/L. 70 and 73% of women, respectively, were postmenopausal. Our study also found an interaction between age and oophorectomy. In addition, the present data suggest that women with only one ovary may have higher FSH levels than women with both of their ovaries. CONCLUSIONS: NHANES III provides population-based data that support previously reported associations between serum FSH level and age, smoking, and menopausal status. PMID- 10100178 TI - Influence of continuous combined estradiol-norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women. AB - OBJECTIVE: Estrogen-progestogen replacement therapy (HRT) may be associated with deterioration of insulin sensitivity in comparison to estrogens alone, which tend to improve insulin sensitivity in postmenopausal women. Insulin sensitivity with the use of continuous combined 17-beta estradiol/norethisterone acetate (E2/NETA) preparations has not been examined before in postmenopausal women. DESIGN: In a double-blind randomized parallel study, we evaluated the effect of 2 mg E2/1 mg NETA (high dose E2/NETA), 1 mg E2/0.5 mg NETA (low dose E2/NETA), or placebo (P) on the insulin sensitivity index (SI) in three groups (18 women/group) of postmenopausal nondiabetic women (follicle stimulating hormone [FSH] > 40 mIU/mL, mean +/- SD) aged 56 +/- 3 years, BMI 25 +/- 4 kg/m2, cholesterol 233 +/- 42 mg/dL, and triglycerides 87 +/- 36 mg/dL. Insulin sensitivity was measured by means of a two-step hyperinsulinemic euglycemic glucose clamp (insulin infusion rate, 0.25 and 1.0 mU/kg/min for 120 min each) at baseline and after 3 months of daily administration of high dose E2/NETA, low dose E2/NETA, or P. Analysis was performed assuming equivalence of start-end changes of insulin sensitivity among treatment groups (Anderson-Hauck test). RESULTS: SI was 7.7 +/- 2.9, 7.5 +/- 3.4, 6.8 +/- 2.2 at baseline and 6.3 +/- 3.0, 7.9 +/- 2.5, 7.1 +/- 3.1 mL/min/m2 per mu U/mL 3 months after the administration of high dose E2/NETA, low dose E2/NETA, and P, respectively. The low dose E2/NETA group had start-to-end changes of SI which were equivalent to the P group (0.4 [95% confidence interval [CI] -0.8; 1.7] vs. 0.4 [-0.3; 1.0]) (p = 0.02). For the high dose E2/NETA group, equivalence could not be shown with either the P (p = 0.89) or with the low dose E2/NETA group (p = 0.90). SI within the high dose E2/NETA group decreased by -1.5 (95% CI -2.7; -0.2) mL/min/m2 per mu U/mL. HbAlc decreased from 5.3 +/- 0.3 to 5.1 +/- 0.3% within the high dose E2/NETA group (p < 0.03) and remained unchanged within the low dose E2/NETA and P group. Fasting plasma glucose, fasting serum insulin, and C-peptide, as well as triglycerides and BMI were comparable among the groups at baseline and after 3 months. Total cholesterol decreased by 12% and 8% in women treated with high dose and low dose E2/NETA (p < 0.02), respectively, and remained unchanged within the P group. CONCLUSIONS: These results indicate that 3 months use of a low dose continuous E2/NETA preparation does not change insulin sensitivity in postmenopausal women. At high dose of E2/NETA, a modest decrease seems possible. The effects of E2/NETA on other parameters of carbohydrate and lipid metabolism are neutral or favorable. PMID- 10100179 TI - Hormone replacement therapy in perimenopause: effect of a low dose oral contraceptive preparation on bone quantitative ultrasound characteristics. AB - OBJECTIVES: Our aim was to assess the effects of a combined oral contraceptive (OC) preparation on bone quantitative ultrasound and biochemical markers of bone metabolism in perimenopausal women. DESIGN: Bone biochemical markers and bone quantitative ultrasound were evaluated in a longitudinal 2-year follow-up study conducted in healthy, normally menstruating perimenopausal women, perimenopausal oligomenorrheic women, and age-matched oral contraceptive-treated women (20 micrograms of ethinyl estradiol plus 0.15 mg desogestrel). The results were analyzed by factorial or repeated-measures analysis of variance, as appropriate. RESULTS: In normal women, there were no significant modifications in menstrual cycle, plasma FSH and estradiol levels, biochemical markers of bone turnover, and bone quantitative ultrasound. Conversely, in oligomenorrheic women, an increase in the cycle length with a concomitant rise in circulating plasma FSH and parallel decrease of plasma estradiol levels was evident. In this group, an increase in both urinary excretion of hydroxyproline and plasma osteocalcin levels paralleled a decrease in bone quantitative ultrasound. In perimenopausal OC-treated women, the pattern of osteocalcin and urinary excretion of hydroxyproline showed a slight decrease, whereas bone quantitative ultrasound did not show any significant modification. CONCLUSION: Perimenopausal OC administration can prevent the increase in bone turnover and the decrease in bone quantitative ultrasound that follow the perimenopausal impairment of ovarian function. PMID- 10100180 TI - Variations of cardiac performance and inotropism in healthy postmenopausal women treated with estroprogestin replacement therapy. AB - OBJECTIVE: The aim of the present study was to evaluate possible variations in cardiac hemodynamic parameters related to the natural changes of ovarian estrogen production. METHODS: Forty postmenopausal women aged 52.7 +/- 4.6 years, randomized into two groups (20 patients in each group) according to the administration (group A) or not (group B) of estroprogestin replacement therapy (ERT), were examined using thoracic electrical bioimpedence. RESULTS: After 6 months of therapy, we observed the following: (1) the mean end-diastolic index was significantly higher in group A than in group B (70.27 and 57.13 mL/m2, respectively) (p < 0.05); (2) the mean acceleration index, indicator of heart contractility, and the mean cardiac index rate, indicators of cardiac performance, were significantly higher in group A than in group B (mean, 1.35 vs. 0.76 s [p < 0.01] and mean, 3.22 vs. 2.34 L/min/m2 [p < 0.05], respectively); and (3) the patients treated with ERT showed systemic vascular resistance index values significantly lower than the controls (mean, 2280 vs. 3150 fOhm/m2 [p < 0.01]), achieving standard levels after 6 months of therapy. Furthermore, the acceleration index showed a significant increase, within group A, between the third and sixth month of ERT (0.91 vs. 1.35 s [p < 0.05]). CONCLUSIONS: Our findings suggest that postmenopausal women treated with a 6-month course of ERT have significantly improved end-diastolic index, heart contractility index, cardiac index, and systemic vascular resistance, whereas 3 months of ERT does not seem to induce the same effects. In our study, thoracic electrical bioimpedence was shown to be a sensitive and specific method of analysis with a very low cost of administration. PMID- 10100181 TI - Increased serum levels of growth hormone and insulin-like growth factor-I associated with simultaneous decrease of circulating insulin in postmenopausal women receiving hormone replacement therapy. AB - OBJECTIVE: Decreases in circulating growth hormone (GH) and its main biological messenger insulin-like growth factor-I (IGF-I) have been interpreted as part of the aging process. Because estrogens participate in modulating GH synthesis and secretion, hypoestrogenism in menopausal women may lead to GH deficiency. The aim of the present study was to determine the effect of hormone replacement therapy (HRT) on both GH and IGF-I levels as well as insulin concentrations in 50 menopausal women. DESIGN: Patients were assigned randomly into two treatment groups of 25 each; one group received three cycles of conjugated equine estrogen (CEE) 0.625 mg/day for 21 days, and the other, 1.25 mg/day during 21 days. Each also received chlormadinone acetate for 5 days. There was a control group consisting of regularly menstruating women. RESULTS: In the menopausal women, HRT increased significantly (p < 0.001) the low levels of GH and IGF-I; on the contrary the baseline insulin levels declined (p < 0.001) with HRT. A significant linear correlation (r = 0.90) was found between GH and IGF-I as well as with estradiol levels (r = 0.74) in the group of menopausal women receiving CEE 0.625 mg/day. This group of patients had a significant correlation (r = -0.63) between insulin and estradiol levels. No correlation was observed in the group receiving CEE 1.25 mg/day. CONCLUSIONS: HRT restored GH, IGF-I, and insulin levels to normal values in all women. Further research needs to be done to establish the beneficial effect of HRT regarding the prevention of the metabolic effects presumably caused by derangement in the somatotropic axis associated with aging. PMID- 10100182 TI - Why menopausal women do not want to take hormone replacement therapy. AB - OBJECTIVE: A survey was designed to determine why menopausal women do not take hormone replacement therapy (HRT). DESIGN: A sample of 3,600 women > 50 years old were randomly selected from six zip codes in northwest suburban Chicago. They received a maximum of three survey mailings. Those who did not respond were called and asked to respond over the phone. The data that were obtained included knowledge of, physician discussion about, use of, and reason for not currently taking HRT, menopausal status, last physician visit, and age grouping. RESULTS: A total of 1,966 (65%) women responded. Of these, 1,448 (74%) knew about HRT, 1,193 (61%) had discussed HRT with their physicians, and 815 (41%) had been treated with HRT in the past. A total of 552 women (28%) were currently being treated with HRT, of whom 419 (76%) had been treated for > 2 years. A total of 1,356 respondents were not being treated with HRT. Of these, 1,114 (82%) were menopausal, of whom 742 (67%) knew about HRT, 551 (50%) had discussed HRT with their physicians, 837 (75%) had seen their physician in the past year, and 236 (21%) had been treated with HRT in the past. Reasons for not taking HRT included the following: 49% no longer had menopausal symptoms, 45% did not want to take HRT, 33% were not offered it by their doctors, 28% were afraid to use it, and 27% were not menopausal. CONCLUSIONS: Seeing a physician in the past year did not ensure that these women understood the symptom course of menopause. Confirming women's knowledge about menopausal health or assisting physician education about menopausal health may offer opportunities both to assist women's decision making about HRT and to improve women's health care. PMID- 10100183 TI - Utilizing routine sonohysterography to detect intrauterine pathology before initiating hormone replacement therapy. AB - OBJECTIVE: To assess the utility of performing routine sonohysterography in conjunction with endometrial thickness measurement for detecting intrauterine pathology in asymptomatic postmenopausal women. DESIGN: Asymptomatic postmenopausal women (n = 60, mean age 52.7 +/- 4.5 years, amenorrhea > or = 6 months, follicle stimulating hormone > or = 40 mIU/mL) were evaluated with sonohysterography followed by endometrial biopsy before initiating hormone replacement therapy. RESULTS: Hyperplasia was detected in 5 of 22 (22.7%) patients with endometrial thickness of > 5 mm and in 0 of 38 (0.0%) patients with endometrial thickness of < or = 5 mm. When sonohysterography was performed, intracavitary pathology was discovered in 14 of 38 (36.8%) patients with endometrial thickness of < or = 5 mm (10 polyps, three submucosal myomas, and one septate uterus) and 14 of 22 (63.6%) patients with endometrial thickness of > 5 mm (nine polyps, four submucosal myomas, and one Asherman's syndrome). CONCLUSIONS: Endometrial thickness of < or = 5 mm excludes hyperplasia but does not eliminate other intrauterine pathology that may be discovered by sonohysterography. PMID- 10100184 TI - NAMS/Solvay Resident Essay Award. Relationship between estrogen, serotonin, and depression. AB - OBJECTIVE: A limited review of the medical literature was performed to determine whether there is an increase in the prevalence of depressive symptomatology in women undergoing menopause and whether this increase can be related to fluctuating levels of estrogen. In addition, we evaluate the possible effect that estrogen has on the concentrations of neurotransmitters, specifically serotonin, in the central nervous system and the subsequent impact on mood in peri- and postmenopausal women. Finally, we examine whether estrogen replacement therapy is efficacious in the treatment of depression during the climacteric. DESIGN: Limited MEDLINE review of the medical literature on depression in women, the evidence for a serotonergic role in depression, evidence linking estrogen to changes in serotonergic activity and evidence that estrogen therapy can improve depression. RESULTS: Depression is more common in women than in men and seems to be increased at times of changing hormone levels in women. The serotonergic system seems to play a major role in depression, although other neurotransmitters are also involved. Estrogen can alter not just serotonergic activity but also has an impact on the activity of several other neurotransmitters that might result in an antidepressant effect. At this time, estrogen therapy for the treatment of depression in peri- and postmenopausal women may be useful, but confirmatory studies are still lacking. CONCLUSIONS: There is suggestive evidence that estrogen therapy is appropriate treatment for mid-to-moderate depression in peri- and postmenopausal women. PMID- 10100185 TI - Transendothelial pathways in venular microvessels exposed to agents which increase permeability: the gaps in our knowledge. PMID- 10100186 TI - Endothelial gaps as sites for plasma leakage in inflammation. AB - OBJECTIVE: In 1961, Majno and Palade proposed that plasma leakage in acute inflammation caused by histamine, serotonin, or bradykinin results via gaps that form between endothelial cells of postcapillary venules. Now the relevance of endothelial gaps in plasma leakage is being questioned. The purpose of this review is to summarize experimental evidence from our studies showing that endothelial gaps participate in plasma leakage in inflammation. METHODS: Using neurogenic inflammation as a model of plasma leakage in acute inflammation, we compared five methods to determine whether endothelial gaps form in the microvasculature of the rat trachea. 1) Endothelial cells borders and gaps were stained with silver nitrate and visualized by light, scanning, and transmission electron microscopy. 2) The luminal surface of endothelial cells was examined by scanning electron microscopy. 3) The luminal surface of endothelial cells was stained with a biotinylated lectin and avidin-biotin-peroxidase histochemistry, and then was examined by differential interference contrast microscopy. 4) Endothelial junctions were reconstructed from serial sections photographed by transmission electron microscopy. 5) Leakage was measured after perfusion of lectins or tracers through aldehyde-fixed vessels in situ. RESULTS: The results from the five methods used in this system were consistent with the formation of gaps between endothelial cells. Endothelial gaps were rare or absent under baseline conditions, but appeared with the onset of plasma leakage and had a distribution that matched the distribution of leakage. Gaps had a complex morphology and were accompanied by fingerlike cell processes, which may anchor adjacent endothelial cells to one another and participate in gap closure. In contrast to normal vessels, vessels that were leaky in life continued to leak after aldehyde fixation, in evidence that, once formed, the leakage pathway did not require energy-dependent membrane movement or vesicle shuttling. Holes through endothelial cells were less than 1% as frequent as intercellular gaps. CONCLUSIONS: Taken together, the results show that endothelial gaps are a consistent feature of leaky vessels in the model system we studied, and are not an artifact of a particular method. The morphological complexity of the openings and accompanying fingerlike cell processes and overlapping endothelial cell borders make gaps difficult to distinguish from transcellular holes in thin sections viewed by transmission electron microscopy. However, scanning electron microscopic observations show that most of the openings in leaky venules are intercellular gaps, not transcellular holes. The formation and closure of gaps are likely to be energy-dependent, but the process of plasma leakage is not, provided there is adequate driving force for extravasation. The cellular mechanisms of gap opening and closure remain to be elucidated. PMID- 10100187 TI - Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. AB - OBJECTIVE: The goal of these studies was to define the anatomic pathways by which circulating macromolecules extravasate from the hyperpermeable microvessels that supply tumors and from normal venules that have been rendered hyperpermeable by vasoactive mediators. METHODS: Extravasation pathways of circulating macromolecular tracers were followed by several morphological techniques: light and fluorescence microscopy, transmission electron microscopy of routine as well as ultrathin and serial sections, computer-assisted three-dimensional reconstructions, and morphometry. RESULTS AND DISCUSSION: Macromolecules extravasated across tumor microvessels or across normal venules rendered hyperpermeable by VPF/VEGF, histamine, or serotonin by three primary pathways: 1) Vesiculo-vacuolar organelles (VVOs), clusters of cytoplasmic vesicles and vacuoles that span endothelial cytoplasm from lumen to ablumen; 2) trans endothelial cell (EC), pores, and 3) fenestrae. We also present data concerning the structure and function of VVOs as well as evidence that VVOs form as the result of linking together and fusion of caveolae-sized unit vesicles. Under suitable conditions VVOs also afforded a pathway for macromolecular transport in the reverse direction, i.e., from vascular ablumen to lumen. Finally, in addition to opening VVOs to the passage of macromolecules, mediators such as VPF/VEGF may also induce structural rearrangements of VVOs, transforming them into trans-EC pores or fenestrae. PMID- 10100188 TI - Openings through endothelial cells associated with increased microvascular permeability. AB - Rapid increases in microvascular permeability are associated with the appearance of openings in microvascular endothelium, which are believed to develop between the endothelial cells of venules. Reconstruction of these openings, from electron micrographs of serial sections of the endothelium reveal that many pass through the periphery of the endothelial cells close to intact intercellular junctions. Transcellular pathways are the principal type of opening induced in microvascular endothelium by the ionophore A23187, by VEGF, and by high transmural pressures. Some mediators induce the fusion of vacuoles with the luminal and abluminal surfaces of the endothelium, and it is suggested that the transcellular openings may develop from vacuolar channels. PMID- 10100189 TI - The influence of frequent and excessive intake of glucose on microvascular aging in healthy mice. AB - OBJECTIVE: The purpose of this study was to verify the following working hypothesis. Even in healthy individuals with normoglycemic adaptability, microvascular aging caused by the accumulation of advanced glycosylation end products (AGEs) in vascular walls would occur, when the blood glucose level is maintained intermittently high due to frequent and excessive sugar intake for a prolonged period. METHODS: Male BALB/c mice were divided into four groups: the S group raised with glucose-enriched feed and the C group with ordinary feed, as well as the SG group with the glucose-enriched feed and special drinking water supplemented with 0.25% aminoguanidine (AG), and the CG group with ordinary feed and this special drinking water. After 6 months, a mouse dorsal skinfold chamber was mounted on the skin of the back for the intravital-microscopic observations of microvasculature. RESULTS: Blood glucose levels were within normal ranges in all four animal groups, indicating their saccharometabolism to be normal. An autofluorescent AGE-positive ratio in the S group was 71.4%, and that in the C group was 33.3%. Mean caliber of arterial microvessels was smallest in the S group. The SG and CG group showed the caliber larger than the groups without AG. Vascular lesion indices were significantly larger in the S group than those of the groups with AG. The indices were particularly small in the SG group. A decrease of amplitudes in thicker vessels and an increase of vasomotor frequencies in thinner ones were demonstrated in the S group. The features of vasomotion differed in the groups with and without AG. CONCLUSIONS: Microvascular aging was clearly noticed in the S group. It has been concluded that vasomotor inhibition was generated in addition to hypertrophy and fragility in arterial microvessels of the group. It is further concluded that AG protects blood vessels from hypertrophy and fragility, but it downregulates vasomotion. PMID- 10100190 TI - Characterization of a transformed ovine lymphatic endothelial cell line. AB - OBJECTIVE: To develop a non-tumor-derived stable lymphatic endothelial cell line that exhibits rapid growth rate without serum and exogenous growth factors, while still maintaining key features characteristics of the non-transformed lymphatic endothelium. METHODS: Lymphatic endothelial cells were isolated from ovine mesenteric lymphatic vessels, grown to confluence and transfected with SV40 DNA using the calcium phosphate method. The resulting cell line was characterized using morphological, immunocytochemical, flow cytometric analysis, and immunoprecipatitation and Western blotting methods. RESULTS: The resulting cell line (sheep lymphatic endothelial transformed cell line, SLET-1) underwent rapid proliferation in the absence of growth factors and reduced concentrations of serum. In addition, key morphological and functional properties of the non transformed lymphatic endothelium were retained. These include the ability to form confluent monolayer cultures, the expression of the lymphatic endothelial specific VEGFR-3, FLT-4) tyrosine kinase receptor, the biosynthesis and secretion of von Willebrand factor and plasminogen activators. In addition, SLET-1 cells express cell surface antigens found on LEC that may act as antibody targets in various immune reactions. Monolayer cultures of the SLET-1 cells incubated with endothelial cell-growth factor formed tubular structures, indicating the retention of the capacity to differentiate. CONCLUSION: The SLET-1 cell line retained key morphological and functional properties characteristic of the non transformed lymphatic endothelium. The ability to form capillary-like tubular structures provides an important cell line for defining the role of specific proteins that are involved in the lymphagiogenic (formation of new lymphatic vessels) process. Thus, this transformed lymphatic endothelial cell line provides an in citro model that may have widespread utility in studying regulatory mechanisms of lymphatic endothelial cell function and differentiation. PMID- 10100191 TI - Immunolocalization of nitric oxide synthase and VEGF receptors in cultured lymphatic endothelial cells. PMID- 10100192 TI - Effects of denervation and hyperinnervation on dopamine and serotonin systems in the rat neostriatum: implications for human Parkinson's disease. AB - The research on central synaptic neurotransmission has greatly benefited from the use of the neurotoxin 2,4,5-trihydroxyphenylethylamine, or 6-hydroxydopamine (6 OHDA), that destroys catecholamine-containing neuronal cell bodies and nerve terminals. Refinements in the use of this neurotoxin led to the use of dopamine denervated animals as models of human Parkinson's disease, in which the loss of dopaminergic neurons is a prominent feature. Here we review structural, pharmacological, and biochemical studies carried out in the adult and neonatal 6 OHDA lesioned animals. These models have become useful and interesting paradigms to examine alterations in the expression of receptors and in their sensitivity to agonist drugs; some of these modifications may underlie the altered responsiveness of the dopamine-lesioned animals to dopamine, but also to other compounds, including serotoninergic drugs. We have also reviewed studies of amino acids as well as of monoamine metabolism and of uptake mechanisms that may underlie some of the behavioural alterations in these models that have become relevant for our understanding of the sprouting and plastic properties of spared neurons, and of the alternate neuronal projections that replace lesioned terminals, enabling compensatory adaptations. Although 6-OHDA-lesioned animals, that display some biochemical characteristics of Parkinson's disease in humans, do not express all of the neurological features exhibited by patients, the increasing knowledge that can be obtained from studies in simplified experimental models will undoubtedly lead to the development of innovative drugs and other replacement therapies for degenerative brain diseases. PMID- 10100193 TI - On the relationship between extracellular glutamate, hyperexcitation and neurodegeneration, in vivo. PMID- 10100194 TI - Acute effects of 3,4-methylenedioxymethamphetamine on brain serotonin synthesis in the dog studied by positron emission tomography. AB - The influence of an acute dose (2 mg/kg; i.v.; infused over 10 min) of 3,4 methylenedioxymethamphetamine (MDMA; Ecstasy) on the brain serotonin synthesis in the dog was assessed using alpha [11C]methyl-L-tryptophan and positron emission tomography. The rate of serotonin synthesis measured 1 h after injection of MDMA was six times greater than the base line (before MDMA) synthesis. Five hours after the MDMA injection, serotonin synthesis was about one half that at the base line, and about one thirteenth of the synthesis at 1 h after MDMA. A large increase seen 1 h after MDMA probably relates to the large release of serotonin by MDMA and reflects an attempt of the serotonergic system to replenish released serotonin. This probably correlates with the mood changes reported by humans after MDMA intake. Decrease observed 5 h after MDMA, in part, probably relates to the inhibitory effects of the released serotonin, which could act on the activity of tryptophan hydroxylase directly or indirectly via other monoaminergic systems (e.g. dopaminergic). PMID- 10100195 TI - Activity of phosphatidylethanolamine-N-methyltransferase in brain affected by Alzheimer's disease. AB - To determine whether phospholipid abnormality in Alzheimer's disease is associated with modification of phosphatidylethanolamine-N-methyltransferase, the activity of the enzyme was analysed in the frontal and occipital cortex of the brain from patients with Alzheimer's disease and from aged-matched control. The optimum pH for phosphatidylethanolamine-N-methyltransferase in human brain was 9.0. The enzyme activity was stimulated by detergent TWEEN 20 but inhibited by Triton X-100. Neither magnesium dependence nor chemical methylation was found. A decrease in activity of phosphatidylethanolamine-N-methyltransferase was observed in the frontal cortex of brain affected with Alzheimer's disease. The addition of exogenous phosphatidylethanolamine resulted in no modification in the methylation rate as compared with that of endogenous PE. The addition of phosphatidyl-N monomethylethanolamine and phosphatidyl-N,N-dimethylethanolamine resulted in significantly increased rates of methylation in brain tissues. However, the increased rate of phosphatidylethanolamine-N-methyltransferase activity stimulated by exogenous phospholipids was lower in the frontal cortex of brains with Alzheimer's disease when compared to the normals and there was no difference in the occipital cortex between Alzheimer's disease and the control. It is plausible that the decreased activity of phosphatidylethanolamine-N methyltransferase and its low compensating ability could relate to the modification of phosphatidylcholine in brain tissues from Alzheimer's disease patients. PMID- 10100196 TI - Dopamine and glutamate neurotoxicity in cultured chick telencephali cells: effects of NMDA antagonists, antioxidants and MAO inhibitors. AB - In a recent study, it was found that the intrastriatal administration to rats of the organophosphorous compound soman and kainic acid produced a rapid release not only of glutamate but also of dopamine in this brain region. Dopamine is a potent source of free radicals and is known to produce cytotoxic effects, per se. This raises the possibility that the released glutamate and dopamine act synergistically to produce the neurotoxicity found after soman administration. In order to investigate the feasibility of this hypothesis in an in vitro system, the effects of dopamine and glutamate upon cell survival were investigated using chick neurons (7 DIV) in serum-free primary culture. The neurons were treated with dopamine and/or glutamate for up to 24 h and cell toxicity was then assessed either by determination of cell densities, by the release of cytoplasmic LDH or by the MTT cytotoxicity assay. L-Glutamate produced a concentration-dependent cytotoxicity that was seen as early as after 30 min of exposure, and was accompanied by an increased level of lipid peroxidation. The L-glutamate toxicity could to a large extent by prevented by NMDA receptor antagonists and to a lesser extent by catalase, superoxide dismutase or glutathione ethyl ester added 30 min before the glutamate. Dopamine was also cytotoxic, and the cytotoxicity was reduced by the combination of catalase and glutathione ethyl ester but not by the MAO inhibitors clorgyline or L-deprenyl, or by the selective dopamine uptake inhibitor GBR 12783. The cytotoxic effects of dopamine and L-glutamate were additive rather than synergistic, regardless of the incubation time used. It is concluded that chick neurons in serum-free culture are a useful in vitro model system for the study of cell toxicity produced by oxidative stress and by glutamate. The cytotoxic effects of dopamine in this model are not due to the monoamine oxidase-mediated production of hydrogen peroxide but appear at least in part to be related to oxidative stress. PMID- 10100197 TI - The effect of hydrogen peroxide upon beta-adrenoceptor density and function in C6 rat glioma cells. AB - Hydrogen peroxide has been suggested to play an important role in the pathogenesis of Alzheimer's disease. In the present study, the effects of hydrogen peroxide upon the functional integrity of beta-adrenoceptors have been investigated in C6 glioma cells. Treatment of cells for 24 h with hydrogen peroxide in serum-free medium produced a concentration-dependent cell toxicity, seen both using cell counting and LDH release into medium as end point. There were no large nor consistent changes in either the density of cell surface beta 1, or beta 2-adrenoceptors, measured using the hydrophilic ligand [3H](-)-CGP 12177, nor in either basal, forskolin and isoprenaline-stimulated cAMP responses, following hydrogen peroxide treatment. It is concluded that the decreased adenylyl cyclase activity and responsiveness to Gs stimulation found in post mortem brain samples from Alzheimer's disease autopsy cases is unlikely to be mediated by hydrogen peroxide. PMID- 10100198 TI - Does the 'mystery of the extra glucose' during CNS activation reflect glutamate synthesis? AB - The hypothesis is proposed that the repeatedly demonstrated rise in local cerebral blood flow and glucose utilisation during neuronal activation, without a corresponding increase in oxygen utilisation, may reflect glutamine formation from glucose, followed by complete oxidative degradation of glutamate along complex and extended, but well described pathways, known to operate in the brain. The former process requires large amounts of glucose but little oxygen. The latter utilises oxygen but no additional glucose, is a prolonged process and so at any one time involves only a small increase in the rate of oxygen utilisation which is difficult to demonstrate experimentally. PMID- 10100199 TI - The existence of molecular water pumps in the nervous system: a review of the evidence. AB - Recently, the presence if both influx and efflux molecular water pumps (MWP's) in vertebrate cells has been reported. These appear to use a common mechanism; the intercompartmental cotransport of water uphill against a gradient as a hydrophylic osmolyte is transported down its own gradient, in a regulated fashion, by a membrane spanning cotransporter protein. In each case, the dwell time of the transported osmolyte is short in that it is metabolically converted and its products either eliminated or recycled, thereby maintaining the required high intercompartmental gradient. An influx water pump osmolyte has been identified as a sodium-glucose complex, and an efflux water pump osmolyte as N acetylhistidine. These osmolytes may also be archetypal representatives of many other osmolytes with similar functions in a variety of cells. When recycled, the osmolyte metabolites appear to be dewatered during high affinity binding that is associated with their active transport back across the membrane prior to intracellular resynthesis of the osmolyte. Since these cyclical systems result in the pumping of water, they also appear to create a previously unrecognized motive force which results in the establishment of unidirectional transcellular water flows between apical and basolateral cell membranes. As neurons represent highly specialized forms of animal cells, and cells which are also extremely sensitive to changes in osmotic pressure, the presence of these water pumps in the CNS could be significant. There would be connotations with regard to how neurons regulate water balance and transaxonal flow as well as to how these factors affect the integrated function of the nervous system. In this article, evidence of the presence of MWP's in the nervous system, and how they might relate to aspects of both normal and abnormal brain function is reviewed. PMID- 10100200 TI - Enhanced learning of proportional math through music training and spatial temporal training. AB - It was predicted, based on a mathematical model of the cortex, that early music training would enhance spatial-temporal reasoning. We have demonstrated that preschool children given six months of piano keyboard lessons improved dramatically on spatial-temporal reasoning while children in appropriate control groups did not improve. It was then predicted that the enhanced spatial-temporal reasoning from piano keyboard training could lead to enhanced learning of specific math concepts, in particular proportional math, which is notoriously difficult to teach using the usual language-analytic methods. We report here the development of Spatial-Temporal Math Video Game software designed to teach fractions and proportional math, and its strikingly successful use in a study involving 237 second-grade children (age range six years eight months-eight years five months). Furthermore, as predicted, children given piano keyboard training along with the Math Video Game training scored significantly higher on proportional math and fractions than children given a control training along with the Math Video Game. These results were readily measured using the companion Math Video Game Evaluation Program. The training time necessary for children on the Math Video Game is very short, and they rapidly reach a high level of performance. This suggests that, as predicted, we are tapping into fundamental cortical processes of spatial-temporal reasoning. This spatial-temporal approach is easily generalized to teach other math and science concepts in a complementary manner to traditional language-analytic methods, and at a younger age. The neural mechanisms involved in thinking through fractions and proportional math during training with the Math Video Game might be investigated in EEG coherence studies along with priming by specific music. PMID- 10100201 TI - Hemodynamic and metabolic changes following cerebral revascularization in patients with cerebral occlusive diseases. AB - Changes in cerebral hemodynamics and metabolism following cerebral revascularization were evaluated using positron emission tomography (PET). Ten patients who had received nonsurgical treatment for 3-6 months for minor completed stroke underwent superficial temporal artery to middle cerebral artery (STA-MCA) bypass surgery. All patients showed no extensive infarction on MR, and responsible vascular lesions were detected in the anterior circulation. A PET study of cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate for oxygen (CMRO2), and cerebral metabolic rate for glucose (CMRGlu) measurements was performed before and 1.5 months after surgery using a steady state technique. Angiographically, anastomotic sites were patent in all patients. Seven patients showed neurological improvement after surgery and the others showed no improvement. The decreases in CBF, CMRO2 and CMRGlu recovered to some extent not only on the lesion side but also on the contralateral side after surgery. The increase in OEF values on the lesion side subsequently decreased after surgery. CMRO2 and CMRGlu showed parallel changes. It is concluded that the metabolic improvement afforded by the cerebral revascularization resulted in the neurological improvement, and that PET study is a powerful method for evaluating patients with cerebral occlusive diseases. PMID- 10100202 TI - Geographical neurosurgery. AB - Disparities in manpower and facilities notwithstanding, neuroepidemiology might explain the observed differences in the mix of neurosurgical caseload in different parts of the world. The highest incidence rate of primary intracranial tumor was in Europe and the lowest rate in Africa. Glioma was more common in the West, teratoma in Japan and the Far East and meningioma in Africa. The lowest rates of childhood brain tumors were in South America, Africa and Asia. Stroke rates were very high in Finland and China. Blacks, Japanese and Chinese had more intracranial vascular occlusive disease while whites had more extracranial disease. Finland had a very high SAH incidence rate but the Middle East and Africa had low rates and a reversal of the aneurysm: AVM ratio. Highest incidence rates of neural tube defects occurred in countries where consanguineous marriages are common. Brain abscess, tuberculoma and other granulomas from infestations were preponderant in developing countries. Head injuries accounted for up to 40% of all neurosurgical admissions in some developing countries. Outside the USA and South Africa, civilian gunshot injuries were uncommon. PMID- 10100203 TI - Survival rates of malignant gliomas in Burgundy from 1990 to 1995. AB - The aim of this study was to provide current data on case-fatality rates of malignant gliomas in the area of Burgundy (1,300,000 inhabitants). The ascertainment was specific according to imaging and histologic criteria, and was exhaustive because of the existence of a single University Hospital allowing both imaging and histologic diagnosis from stereotaxic cerebral biopsy. During six full years we collected 161 cases of malignant gliomas grades II to IV, 93 men (57.76%) and 68 women (42.23%). The mean age was 61 years. In all the age groups, there were a male predominance. Headache, epilepsy and motor deficit were the most frequent symptoms at onset. In most cases, the gliomas were localized within the frontal area. The post-surgical Karnofsky score was up to 70 in 40% of the cases. There were 89 glioblastomas with grade IV, 37 anaplastic astrocytomas, 13 gliomatous tumors with grade II and IV and six anaplastic oligodendrogliomas. This grading explains the very low survival rates, with a negative effect induced by age. Among the most relevant contributions of this study to the clinical features of malignant gliomas is an analysis of case-fatality rates, evaluation of health care services and therapeutic trials. PMID- 10100204 TI - Differential regulation of AP-1 DNA-binding activity by D1 and D2 dopamine receptor antagonists in the rat caudate-putamen and globus pallidus following a unilateral 6-OHDA lesion of the medial forebrain bundle. AB - The effect of D1 and D2 dopamine receptor antagonists on the DNA-binding activity of the AP-1 transcription factor was studied in the rat caudate-putamen and globus pallidus following a unilateral 6-OHDA lesion of the medial forebrain bundle. In the caudate-putamen, vehicle-treated rats showed increased AP-1 DNA binding activity, which appeared to be reversed completely by treatment with the D1 receptor antagonist SCH23390 (1 mg kg-1 i.p.) and partially by the D2 antagonist sulpiride (50 mg kg-1 i.p.). In the globus pallidus, vehicle and sulpiride did not induce AP-1, while SCH23390 increased it significantly. This induction was much more prominent in the 6-OHDA-lesioned hemisphere than in the intact hemisphere. The present study suggests that in the caudate-putamen, dopamine-depletion induces long-lasting enhancement of AP-1 DNA-binding activity via activation of D1 receptors and the simultaneous activation of D2 receptors facilitate it. However, in the globus pallidus of the 6-OHDA-lesioned hemisphere, D1 but not D2 antagonism induces AP-1 in certain cell populations which may be distinct from those expressing AP-1 upon stimulation of D2 receptors. PMID- 10100205 TI - Simulation of therapeutic parent artery occlusion for basilar head aneurysms. Hemodynamic effect of occlusion sites and diameters of collateral arteries. AB - We simulated parent artery occlusion therapy for basilar head aneurysms to elucidate the hemodynamic changes induced by different occlusion sites and diameters of the posterior communicating arteries (PCom) as collateral pathways. A vascular model of the vertebrobasilar system with a basilar head aneurysm was constructed. Four types of occlusion were simulated: Basilar artery occlusion distal to (Type A), between (Type B) and proximal to (Type C) the superior cerebellar arteries, and bilateral vertebral artery occlusion (Type D). Glycerol solution was perfused into the model, and the half-life of the dye injected into the aneurysm was calculated and regarded as an index of stagnant flow in the aneurysm. The half-life was increased significantly and nonlinearly after parent artery occlusion, depending on the occlusion site and the ratio of two PCom diameters (diameter ratio). Intra-aneurysmal stagnation developed markedly in Type A and Type B in the diameter ratio higher than 0.70 and considerably in Type C in the ratio higher than 0.80. Additional P1 occlusion of the posterior cerebral artery enhanced the stagnation in Type A and B. Since the results are consistent with the published clinical data, the simulation study will be useful for speculating the efficacy of the therapeutic occlusion. PMID- 10100206 TI - Functional MR imaging with venography for neurosurgical identification of the central sulcus. AB - We evaluated the applicability of functional MR imaging overlaid onto brain images superimposed venography for neurosurgical identification of the central sulcus. In 20 volunteers and 12 patients with brain tumors located around the sensorimotor cortex, gradient echo and large flip angle functional MR image was performed to allow visualization of flow effect and susceptibility related changes in relative large vein by motor hand task. Functional MR image acquired was overlaid on 3D anatomical image with 3D venography. Based on the 3D mapping, intra-operative cortical somatosensory evoked potentials (SEPs) were recorded. The significant activation area obtained from functional MR imaging was projected on an ascending cortical vein in 16 volunteers (80%) and 10 patients (83%). Comparing the anatomical activation map with visual inspection of the exposed cortical surface made it easy to identify the activation area during surgery. The cortical veins in 9 of 10 were validated as a central vein by intra-operative cortical recording of SEPs. Combination of functional MR imaging overlaid onto 3D anatomical image with venography and intra-operative SEPs permitted rapid and accurate localization of the central sulcus during surgery. PMID- 10100207 TI - Suppression of acidic fibroblast growth factor-dependent angiogenesis by the antigrowth activity of 1,3,6-naphthalenetrisulfonate. AB - Growth factor-induced angiogenesis was studied using subcutaneously implanted gelatin sponges loaded with 10 mg ml-1 of acidic fibroblast growth factor (aFGF) in 20 micrograms ml-1 PBS heparin. The administration of 1,3,6 naphthalenetrisulfonate (NTS) directly into the sponge (20 mg ml-1) or intraperitoneally (200 mg kg-1) blocks invasion of the sponge by vasculature. Since angiogenesis is essential for tumor progression, the findings of the present study that NTS is an efficient inhibitor of neovascularization warrant further investigation of the potential clinical utility of this angiostatic agent for treating tumor growth and metastasis. PMID- 10100208 TI - Clinical evaluation of the effect of percutaneous transluminal angioplasty and intra-arterial papaverine infusion for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage. AB - The clinical efficacy of percutaneous transluminal angioplasty and intra-arterial papaverine infusion for treatment of vasospasm following subarachnoid hemorrhage was investigated. Between 1990 and 1993, 84 patients were treated for cerebral vasospasm in National Defense Medical College Hospital. Angioplasty was performed for asymptomatic vasospasm in 18 patients and for symptomatic vasospasm in 12 patients. Intra-arterial papaverine infusion was performed for asymptomatic vasospasm in 10 patients and for symptomatic vasospasm in four patients. The other 40 patients were treated with standard conservative therapy including hypervolemic and hypertensive hemodilution. The outcomes of these patients were analyzed using the Glasgow Outcome Scale. The outcome tended to be better for patients treated with angioplasty, but not for those treated with papaverine infusion, than for those treated conservatively. Recurrence of vasospasm was more frequent after papaverine infusion than after angioplasty. Undesirable complications such as abrupt development of unconsciousness were experienced during papaverine infusion but not during angioplasty. We conclude that percutaneous transluminal angioplasty is superior to intra-arterial papaverine infusion for prevention and treatment of vasospasm following aneurysmal subarachnoid hemorrhage. PMID- 10100209 TI - The significance of hypothermic acid-base management induced before ischemia in a rat model of transient middle cerebral artery occlusion. AB - We investigated the effects of acid-base management during pre- and intra ischemic hypothermia on regional cerebral blood flow (rCBF) and infarct volume using a transient focal cerebral ischemia model. Normal temperature was maintained in a group of 7 anesthetized rats, and hypothermia (30 degrees C) was maintained in two other groups of 7 anesthetized rats, in which alpha-stat (PaCO2 measured at 37 degrees C was maintained at 36 mmHg) and pH-stat (PaCO2 corrected for body temperature was maintained at 36 mmHg) conditions, respectively, were established. rCBF was monitored by laser-Doppler flowmetry in the ischemic penumbra. The middle cerebral artery (MCA) was occluded for 2 h and then reperfused. Infarct volume was measured after 24 h and expressed as a percentage of hemisphere volume. Pre-ischemic hypothermia reduced rCBF in the alpha-stat group and the pH-stat group to 52 +/- 2% and 86 +/- 7%, respectively (p < 0.01). After MCA occlusion, rCBF dropped in the control group, alpha-stat group, and pH stat group to 57 +/- 11%, 31 +/- 9%, 27 +/- 10%, respectively. Infarct volume in the alpha-stat group, and pH-stat group was significantly smaller (10 +/- 1% and 7 +/- 2%) than in the control group (42 +/- 7%, p < 0.01), but no differences were found between the hypothermic groups. Differences in acid-base management in the present study did not affect infarct volume, but pre-ischemic rCBF in the alpha-stat group was significantly lower than in the pH-stat group. The steeper fall in rCBF after MCA occlusion in the pH-stat group suggested that the autoregulatory response of the collateral pathways may have been reduced in this group. PMID- 10100210 TI - Early decrease of P-glycoprotein in the endothelium of the rat brain capillaries after moderate dose of irradiation. AB - In this study, we examined the degree of disruption of blood-brain barrier (BBB) in irradiated rat brains using P-glycoprotein, one of the functional molecules of BBB, as a marker. In the animal experiments, disruption of BBB has been mainly studied at the acute stage of brain edema caused by a lethal dose of irradiation. However, they do not mimic the clinical situation of radiotherapy for malignant brain tumors. Therefore, we examined effects of a clinically compatible dose of radiation on BBB. The rat hemisphere received a single application of 25 Gy of X rays, and P-glycoprotein was analyzed 5 days later by immunohistochemistry and Western blotting. Immunoreactivity of P-glycoprotein was found to be strong in endothelial cells of the brain of the nonirradiated rat as well as in the nonirradiated hemisphere of the irradiated rat. In contrast, very weak or no immunoreactivity was observed in the majority of endothelial cells in the irradiated hemisphere. Western blotting quantitatively showed that P-glycoprotein in the irradiated hemisphere decreased to nearly 60% that of the controls. The present study indicated that even a clinically applicable dose of radiation causes early disruption of BBB in the rat model. PMID- 10100211 TI - Near infrared spectroscopic monitoring of secondary cerebral energy failure after transient global hypoxia-ischemia in the newborn piglet. AB - The present study was done to establish whether the secondary cerebral energy failure could be reproduced in the newborn piglet subjected to transient global hypoxia-ischemia, and whether the evolution of secondary cerebral energy failure could be monitored by measuring the changes of Cyt aa3 using NIRS. Fifteen anesthetized, ventilated newborn piglets (< 3 day) were divided into 2 groups. Eight of hypoxia-ischemia (HI) group were induced transient HI by breathing 8% oxygen and complete occlusion of bilateral common carotid arteries for 30 min followed by release of occluders and reoxygenation and maintained for up to 48 h. Seven were given sham operation and maintained for 48 h also. Monitoring of cerebral Hb, HbO, HbT and Cyt aa3 were continued throughout the experiment using near infrared spectroscopy. Na+, K(+)-ATPase activity, lipid peroxidation products (conjugated dienes), tissue high energy phosphates (ATP and phosphocreatine) levels and brain glucose and lactate levels were determined biochemically in the cerebral cortex harvested at the termination of experiment. HbT as an index of a cerebral blood volume increased at 2 h after resuscitation significantly in HI group. During hypoxia-ischemia Cyt aa3 fell to -2.0 +/- 0.5 mu l-1 (p < 0.01), returned to baseline on resuscitation, but decreased again progressively from 33 h, and finally fell to -2.2 +/- 0.9 mumol l-1 (p < 0.01) at 48 h in spite of normal physiologic values. There were no changes in control animals. Cerebral level of ATP and PCr in HI group decreased significantly compared to control and ATP concentrations were correlated with the final levels of Cyt aa3. In HI group, cerebral Na+, K(+)-ATPase activity decreased, but the cerebral level of conjugated dienes, glucose, lactate was not different compared to controls. These findings suggest that secondary cerebral energy failure was successfully reproduced in the newborn piglets after transient hypoxia-ischemia and the continuous in vivo NIRS monitoring can be used as a useful tool for the monitoring of delayed cerebral injury. PMID- 10100212 TI - Propofol administration reduces hippocampal neuronal damage induced by kainic acid in rats. AB - The goal of this study was to determine whether propofol has protective effect against kainic acid (KA)-induced excitotoxicity. Administration of propofol (25 mg kg-1 i.p.) was done 2 h before KA (10 mg kg-1 i.p.), immediately after, and 2 h, 4 h, 6 h, and 12 h after the KA, and twice daily for an additional three days. Neuronal cell death in CA1 and CA3 subsector of hippocampus was evaluated quantitatively four days after KA. The KA and propofol-injected rats had a greater number of surviving neuronal cells than did KA (and vehicle)-injected rats. Our results suggest that propofol holds potential for the protection of neuronal cells against KA induced excitotoxicity. PMID- 10100213 TI - Combined transfrontal and endonasal endoscopic surgery of epidural abscess following frontal sinusitis. A case report. AB - A large epidural abscess secondary to frontal sinusitis in a previously healthy 19-year-old man was successfully treated with a small eyebrow incision using combined transfrontal and endonasal endoscopic technique. The abscess was resolved with concomitant pneumatization of the paranasal sinuses. The present case illustrates the promising use of endoscopy in the merging fields of neurosurgery and otorhinolaryngology. PMID- 10100214 TI - Radiosynthesis and autoradiographic evaluation of [11C]NAD-299, a radioligand for visualization of the 5-HT1A receptor. AB - The selective 5-HT1A receptor antagonist NAD-299 ([R]-3-N,N-dicyclobutylamino-8 fluoro-3,4- dihydro-2H-1-benzopyran-5-carboxamide) was labeled with the positron emitting radionuclide carbon-11. The radioligand was synthesized from NAD-195 ([R]-3-N,N-dicyclobutylamino-8-fluoro-5-trifluoromethylsulfonyl oxy-3,4- dihydro 2H-1-benzopyran) in two radiochemical steps. A palladium-catalyzed reaction of NAD-195 and [11C]cyanide was followed by hydrolysis of the carbon-11-labeled nitrile intermediate with basic hydrogen peroxide. The total radiochemical yield, based on [11C]CO2 and corrected for decay, was 20-40%. The specific radioactivity was 24 GBq/mumol (900 Ci/mmol) at end of synthesis, with a radiochemical purity better than 99% and a total synthesis time of 40-45 min. Autoradiographic examination of [11C]NAD-299 binding in human brain postmortem demonstrated high binding in hippocampus, raphe nuclei, and neocortex. The binding in the hippocampus was higher than in the neocortex. Within the hippocampus, the densest binding was observed in the CA1 region. [11C]NAD-299 binding was inhibited by addition of the 5-HT1A receptor ligands WAY-100635, pindolol, (+/-)-8-OH-DPAT, 5 HT, and buspirone, leaving a low background of nonspecific binding. The results indicate that [11C]NAD-299 binds specifically to 5-HT1A receptors in the human brain in vitro and is a potential radioligand for positron emission tomography (PET) examination of 5-HT1A receptors in vivo. PMID- 10100215 TI - Synthesis and in Vivo studies of [C-11]N-methylepibatidine: comparison of the stereoisomers. AB - The carbon-11-labelled nicotinic acetylcholine receptor (nAChR) agonist N methylepibatidine was evaluated in vitro and in vivo as a possible positron emission tomography (PET)-tracer for nicotinic receptors in the central nervous system (CNS). The racemic mixture and both enantiomers of N-methylepibatidine were compared. Biodistribution and metabolites for blood and brain of [C-11]N methylepibatidine were determined in mice. Whole body rat PET data were acquired for both stereoisomers. The regional distribution of the N-methyl-(-)-epibatidine in the brain was determined by a PET scan in a pig. Characteristic differences were found for the in vivo behavior of the stereoisomers of [C-11]N methylepibatidine. PMID- 10100216 TI - Radiosynthesis and preliminary evaluation of 5-[123/125I]iodo-3-(2(S) azetidinylmethoxy)pyridine: a radioligand for nicotinic acetylcholine receptors. AB - The radiochemical syntheses of 5-[125I]iodo-3-(2(S)-azetidinylmethoxy)pyridine (5 [125I]-iodo-A-85380, [125I]1) and 5-[123I]-iodo-A-85380, [123I]1, were accomplished by radioiodination of 5-trimethylstannyl-3-((1-tert-butoxycarbonyl 2(S)-azetidinyl)metho xy)pyridine, 2, followed by acidic deprotection. Average radiochemical yields of [125I]1 and [123I]1 were 40-55%; and the average specific radioactivities were 1,700 and 7,000 mCi/mumol, respectively. Binding affinities of [125I]1 and [123I]1 in vitro (rat brain membranes) were each characterized by a Kd value of 11 pM. Preliminary in vivo assay and ex vivo autoradiography of mouse brain indicated that [125I]1 selectively labels nicotinic acetylcholine receptors (nAChRs) with very high affinity and specificity. These studies suggest that [123I]1 may be useful as a radioligand for single photon emission computed tomography (SPECT) imaging of nAChRs. PMID- 10100217 TI - Synthesis of [11C] coenzyme Q-related compounds for in vivo estimation of mitochondrial electron transduction and redox state in brain. AB - We have studied the synthesis of [11C]2,3-dimethoxy-5-methyl-6-(10-hydroxy)-decyl 1,4-benzoquinone (idebenone) and [11C]2,3-dimethoxy-5-methyl-1,4-benzoquinone (CoQo) by methylation of their respective desmethyl precursors using [11C]CH3I for in vivo measurement of mitochondrial electron transfer and redox state. The [11C]idebenone was more lipophilic than [11C]CoQo; the latter became hydrophilic by reduction. Clearance of [11C]idebenone from mouse brain was more rapid than that of [11C]CoQo. The results indicated that modification of the isoprenoid side chain in [11C]CoQ is necessary to develop more suitable radiopharmaceuticals. PMID- 10100218 TI - (+)-p-([18F]fluorobenzyl)spirotrozamicol [(+)-[18F]spiro-FBT]: synthesis and biological evaluation of a high-affinity ligand for the vesicular acetylcholine transporter (VAChT). AB - (+)-1'-[4-Hydroxy-1-(4-fluorobenzyl)piperidin-3-yl]spiro[1H- indene-1,4'- piperidine] {(+)-Spiro-FBT}, a high-affinity vesicular acetylcholine transporter ligand, was labeled with fluorine-18, and evaluated in the rat and monkey. In the rat brain, (+)-[18F]Spiro-FBT accumulated preferentially in the striatum, hippocampus, and cortex, brains regions containing high-to-moderate densities of cholinergic terminals. However, due to rapid metabolism, no preferential accumulation of the radiotracer was observed in corresponding regions of the monkey brain. Consequently, rapid metabolism renders (+)-[18F]Spiro-FBT unsuitable for studying cholinergic function with positron emission tomography. PMID- 10100219 TI - Radioiodinated endothelin-1: a radiotracer for imaging endothelin receptor distribution and occupancy. AB - Endothelin (ET) is one of the most potent vasoconstrictors known. Recently, ET has been implicated in various diseases, e.g., acute renal failure and congestive heart failure, which present the possibility of treating such diseases with endothelin receptor antagonists. However, establishing the dosages for these antagonists may be difficult because no convenient physiologic indicator of action exists, and because of complexities in receptor function. Two receptor subtypes have been identified for which selective antagonists have been reported (e.g., BQ-123 for the ETA receptor and BQ-788 for the ETB receptor). Of the three natural peptide hormones (ET-1, ET-2, and ET-3), ET-1 exhibits high affinity for both subtypes of receptor. Using the selective peptide antagonists, and a nonpeptide antagonist with relatively balanced affinity for the two subtypes (L 749,329), we have characterized the interactions of [125I]ET-1 with its receptors in vivo (in rat). BQ-123, BQ-788, and L-749,329 inhibited binding consistent with binding to a single receptor site. However, the sum of inhibition by the selective antagonist was greater than 100% (as defined by inhibition with L 749,329), which suggests (a) lower in vivo selectivity than determined in vitro and/or (b) receptor subtype interactions. The latter explanation is supported, in part, by in vitro autoradiographic studies as well as studies in isolated tissues and cells. We synthesized ET-1 labeled with I-123 and obtained images of receptor distribution in both rat and rhesus monkey and have demonstrated our ability to visualize, via planar, noninvasive imaging, the occupancy of endothelin receptor by antagonists in both kidney and lung. [123I]ET-1 can therefore be used to determine clinical dosages of antagonist needed for receptor saturation. PMID- 10100220 TI - Synthesis of an I-123 analog of A-85380 and preliminary SPECT imaging of nicotinic receptors in baboon. AB - A radiosynthetic method to prepare the nicotinic acetylcholine receptor radioligand (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine, 5-IA, has been developed. The two-step sequence produced [123I]-5-IA in high radiochemical yield (52%), high radiochemical purity (98%), and high specific radioactivities (> 8,500 mCi/mumol). Preliminary single photon emission computed tomography studies with [123I]-5-IA in baboon demonstrated the appropriate regional localization for a high-affinity nicotinic radioprobe (thalamus > frontal cortex > cerebellum). Pretreatment with cytisine blocked [123I]-5-IA uptake in all brain regions (78 59% reduction), demonstrating the specificity of the radiotracer. PMID- 10100221 TI - In vitro and in vivo characterisation of [3H]ANSTO-14 binding to the sigma 1 binding sites. AB - N-(4-phenylbutyl)-3-hydroxy-4-azahexacyclo[5.4.1.0(2,6).0(3, 10).0(5,9) .0(8,11)]dodecane (ANSTO-14) showed the highest activity for the sigma 1 site (Ki = 9.4 nM) and 19-fold sigma 1/sigma 2 selectivity. The present study showed that [3H]ANSTO-14 binds to a single high-affinity site in guinea pig brain membranes with an equilibrium Ki of 8.0 +/- 0.3 nM, in good agreement with the kinetic studies (Kd = 13.3 +/- 5.4 nM, n = 4), and a Bmax of 3.199 +/- 105 fmol/mg protein (n = 4). The in vivo biodistribution of [3H]ANSTO-14 showed a high uptake in the diencephalon. Pretreatment of rats with sigma ligands including (+) pentazocine (sigma 1), ANSTO-14 (sigma 1), and DTG (sigma 1 and sigma 2) did not significantly reduce radiotracer uptake in the brain, but did in the spleen. A labelled metabolite was found in the liver and brain. Due to its insensitivity to sigma ligands, the accumulation of [3H]ANSTO-14 in the brain indicates high nonspecific binding. Therefore, [3H]ANSTO-14 is a suitable ligand for labelling sigma 1 sites in vitro but is not suitable for brain imaging of sigma binding sites in vivo. PMID- 10100222 TI - Neutral and stereospecific Tc-99m complexes: [99mTc]N-benzyl-3,4-di-(N-2 mercaptoethyl)-amino-pyrrolidines (P-BAT). AB - Technetium-99m-labeled radiopharmaceuticals are currently the most commonly used agents in nuclear medicine. To prepare binding site-specific small molecules containing a Tc-99m complexing core, it is important to consider a ligand system, which selectively forms only one stereoisomer. A novel series of bisaminoethanethiol (BAT) derivatives as a model system were prepared. Stereoisomers of N-benzyl-3,4-di(N-2-mercaptoethyl)-amino pyrrolidines (P-BAT): (3R,4R)-P-BAT (R,R-4) and (3,4)meso-P-BAT (8), the trans and meso isomer, respectively, as a chelating group were prepared successfully. The desired Tc-99m P-BAT complexes were obtained by using Sn(II)/glucoheptonate as the reducing agent for [99mTc]pertechnetate. As predicted, after complexation with [99mTc]Tc'O, the trans isomer, (3R,4R)-P-BAT (R,R-4), showed only one isomer; whereas the corresponding meso isomer, (3,4)meso-P-BAT (8), produced two distinctive complexes isolated readily by high performance liquid chromatography (HPLC). The [99mTc](R,S) meso-P-BAT (8) isomers showed a different lipophilicity (partition coefficient [P.C.] = 54.3 and 55.4 for peak A and peak B, respectively), as compared with that of the corresponding [99mTc](3R,4R)-P-BAT (R,R-4), trans isomer (P.C. = 163). Results of the biodistribution study in rats of these isomers show different heart and brain uptake, suggesting that the intrinsic differences in biodistribution are due to structural and stereospecific factors. Examples in this report confirm that it is possible to design stereospecific Tc-99m complexes based on the bisaminoethanethiol (N2S2, BAT) ligand system. Consideration on stereoselectivity of site-specific agents labeled with Tc-99m is likely an essential requirement on developing binding-site specific radiopharmaceuticals. PMID- 10100223 TI - Studies of technetium-99m nitridobisdithiocarboxylate leucocyte specific radiopharmaceutical: [99mTcN(DTCX)2], DTCX = CH3(CH2)8CS2. The cellular and subcellular distribution in human blood cells, and chemical behaviour. Synthesis of the analogous rhenium-188 radiopharmaceutical. AB - The distribution of the radiopharmaceutical ([99mTcN(DTCX)2], DTCX = CH3(CH2)8CS2) in the leucocyte population determined by a density separation with double gradient Polymorphprep was studied. Microautoradiographic analysis showed a subcellular distribution of the radiomarker in human blood cells. This technique confirmed the observed lymphocyte selectivity (69%) and revealed that the uptake was predominantly cytoplasmic around the nucleus. A labeling mechanism by passive endocytosis could be proposed involving a required lipophilicity of the radiopharmaceutical for lymphocyte targeting. Finally, we describe the new synthesis with an efficient yield and radiochemical purity of the analogous radiopharmaceutical [188ReN(DTCX)2]. PMID- 10100224 TI - Synthesis of heptadentate (N4O3) amine-phenol ligands and radiochemical studies with technetium-99m. AB - Heptadentate amine-phenol ligands with N4O3 donor atoms for coordination were synthesized by condensing tris(2-aminoethyl)amine with salicylaldehyde or acetophenone and reducing the Schiff bases formed with NaBH4. The ligands were characterized by 1H and 13C nuclear magnetic resonance spectroscopy. Radiochemical studies were carried out with no-carrier-added 99mTc and 99mTc spiked with 0.1-100 microM of 99Tc. Complexation yields were estimated from thin layer chromatography, paper electrophoresis, and solvent extraction studies. 99mTc complexes were formed in yields better than 90% with the amine-phenol ligands. The complexes were found to be neutral and lipophilic. Biodistribution studies of the 99mTc complexes showed that clearance was mainly through the hepatobiliary system. PMID- 10100225 TI - Labeling of phosphorothioate antisense oligonucleotides with yttrium-90. AB - Novel yttrium-90 (90Y)-labeled phosphorothioate antisense oligonucleotides were designed as a potential targeted radionuclide therapeutic agent for malignant tumors. A 15-mer phosphorothioate antisense oligonucleotide, which was complementary to the translation start region of the N-myc oncogene mRNA, was conjugated with isothiocyanobenzyl ethylenediamine tetraacetic acid (SCN-Bn EDTA), via a C-5-substituted deoxyuridine that had replaced a thymine in the oligonucleotide, and was then labeled with 90Y-acetate. Following purification, the radiochemical purity of the 90-Y-Bn-EDTA-phosphorothioate antisense oligonucleotides was estimated by 2.0% agarose gel electrophoresis, and the specific hybridization of 90Y-Bn-EDTA-phosphorothioate antisense oligonucleotide to a phosphorodiester sense oligonucleotide was investigated by 20% polyacrylamide gel electrophoresis in a cell-free system. Radiochemical purity was 98.7 +/- 0.4% at 72 h after labeling and 90.3 +/- 0.9% after 72-h incubation with human normal serum. The 90Y-Bn-EDTA-phosphorothioate antisense oligonucleotide hybridized specifically to a complementary phosphorodiester sense oligonucleotide. In conclusion, phosphorothioate antisense oligonucleotides can be labeled stably with 90Y using SCN-Bn-EDTA without loss of hybridization properties. PMID- 10100226 TI - An improved synthesis of [11C]L-703,717 as a radioligand for the glycine site of the NMDA receptor. PMID- 10100227 TI - Pyridostigmine, a carbamate acetylcholinesterase AChE inhibitor and reactivator, is used prophylactically against chemical warfare agents. PMID- 10100228 TI - [Nuclear medicine goes therapy?]. PMID- 10100229 TI - Differential diagnosis of metastases in bone scans: chemotherapy induced bone necrosis. AB - AIM: Influenced by the incorrect diagnosis of a bone metastasis caused by bone necrosis we evaluated reasons and frequency of bone necrosis in patients referred for bone scanning in follow-up of tumors. METHODS: Bone scans performed within two years on patients with primary bone tumors or tumors metastatic to bone were reviewed in respect to the final diagnosis bone necrosis. RESULTS: We found the cases of three young patients who presented the appearance of hot spots on bone scintigrams which were finally diagnosed as bone necrosis. In two cases the diagnosis was based on histological findings, in one case the diagnosis was made evident by follow-up. All the three patients had been treated by chemotherapy and presented no other reason for the development of bone necrosis. Enhanced tracer uptake in all sites decreased within eight weeks up to two years without therapy. CONCLUSION: Single and multiple hot spots after chemotherapy may be originated by bone necrosis but mimicry metastases. PMID- 10100230 TI - [Calculation of renal clearance by dynamic measurement of excreted activity]. AB - AIM: In this paper we present a new method to measure the renal slope-clearance of Tc-99m-MAG-3 in a single-shot model (Excretion-clearance). METHODS: A renal scintigraphy with Tc-99m-MAG-3 was performed in 22 patients. The excreted activity of the tracer in the kidneys and the bladder was dynamically measured using a double-head gamma-camera. Additionally the total absorption over the kidneys and the bladder was determined. The Excretion-clearance was calculated in a differential and an integral variant. Simultaneously the 2-compartment clearance (Sapirstein-clearance), the Oberhausen-clearance and the Bubeck clearance were calculated. RESULTS: The Sapirstein-clearance is considered as the "gold standard" in a single-shot model. The correlation of the Bubeck-clearance and the Oberhausen-clearance ranged from r = 0.96 to r = 0.97, the Excretion clearance (differential-method) correlated with r = 0.90. The absolute difference of the clearance-values was lowest comparing the Bubeck-clearance with the Sapirstein-clearance with an average difference of 11%, whereas the Excretion clearance revealed at least an average difference of 21% and the Oberhausen clearance of 24%. DISCUSSION: The Excretion-clearance requires a more complicated protocol measuring the clearance in comparison to the Bubeck-clearance. The results of the excretion-clearance differ more from the Sapirstein-clearance with regard to the examined patient population than the Bubeck-clearance. Regarding the theoretical basis of the methods, we expect advantages of the Excretion clearance compared with the Bubeck-Clearance in patients with compartmental disproportion or with a low clearance. We are going to prove this in combination with the above mentioned methodical improvements in a further study. PMID- 10100231 TI - Evaluation of scatter correction using a single isotope for simultaneous emission and transmission data. Phantom and clinical patient studies. AB - Photon scatter is one of the most important factors degrading the quantitative accuracy of SPECT images. Many scatter correction methods have been proposed. The single isotope method was proposed by us. AIM: We evaluate the scatter correction method of improving the quality of images by acquiring emission and transmission data simultaneously with single isotope scan. METHOD: To evaluate the proposed scatter correction method, a contrast and linearity phantom was studied. Four female patients with fibromyalgia (FM) syndrome and four with chronic back pain (BP) were imaged. Grey-to-cerebellum (G/C) and grey-to-white matter (G/W) ratios were determined by one skilled operator for 12 regions of interest (ROIs) in each subject. RESULTS: The linearity of activity response was improved after the scatter correction (r = 0.999). The y-intercept value of the regression line was 0.036 (p < 0.0001) after scatter correction and the slope was 0.954. Pairwise correlation indicated the agreement between nonscatter corrected and scatter corrected images. Reconstructed slices before and after scatter connection demonstrate a good correlation in the quantitative accuracy of radionuclide concentration. G/C values have significant correlation coefficients between original and corrected data. CONCLUSION: The transaxial images of human brain studies show that the scatter correction using single isotope in simultaneous transmission and emission tomography provides a good scatter compensation. The contrasts were increased on all 12 ROIs. The scatter compensation enhanced details of physiological lesions. PMID- 10100232 TI - [Onco-PET: lesion detection by monitor versus standardized film documentation]. AB - AIM: Lesion detection and localization of 2-[18F]fluoro-2-deoxy-D-glucose (F-18 FDG) Onco-PET-Investigations are usually performed on-line at the computer display. The aim of the present study was to evaluate the clinical efficacy of a standardized film documentation as an alternative approach. METHODS: 100 Onco-PET investigations without attenuation correction were analyzed with regard to number and localization of lesions suspicious of malignancy. A standardized documentation on film was developed including 1. transversal slices of the brain, 2. coronal slices and maximum-intensity-projections (MIPs) of the head/neck region and 3. of the trunk and 4. MIPs of the legs. These transparencies were analyzed at the light box. An additional analysis on the computer display was performed slice by slice in coronal, transversal and sagittal directions for the whole body. RESULTS: A total of 315 lesions were detected in 100 patients. In 96/100 patients the two modalities agreed both in number and localization of tumor-suspicious lesions. 7 lesions in the legs of 3 patients didn't show when interpreting the films (MIPs only). In 2/100 patients additional analysis on the computer display caused a change in the localization of 9/315 lesions. 8 of these were located in the legs. When adding coronal slices for the documentation of the lower extremities all the lesions were shown. Moreover, all lesions were localized correctly except one clinically non-relevant change of localization out of a total of 322 lesions. CONCLUSION: The newly developed standardized documentation supports the concept of film reading and reporting of onco-PET investigations, restricting an additional on-line analysis to rare cases only. Furthermore, the intention of the "Arbeitsgemeinschaft Standardisierung" (work group standardisation) are met, i.e. to ease analysis of follow-up studies acquired at different places. PMID- 10100233 TI - [Experimental determination of the lower energy discriminator level of positron emission tomographs]. AB - AIM: Using the continuous energy spectra of Compton scattered photons we measured the lower energy discriminator level of a positron emission tomograph (PET). METHODS: In PET scans, coincident photons with an energy between the lower and upper level of the energy discriminator (LLD/ULD) are acquired. Usually, the energy response of a detector is determined by measurements using various radiation sources with different energies. But this method is limited to the availability of the sources with the desired energies. The procedure described in this paper uses the energy spectrum from Compton scattered photons, providing a continuous energy spectrum for the direct measurement of the energy response of the detectors. For our measurements we used an activated Cu-64 point source (phi = 1 mm) which was positioned in an aluminium sphere (phi = 2 cm). RESULTS: The measured LLD values for a whole-body PET-scanner ECAT EXACT HR+ (CTI/Siemens) were systematically lower than the nominal values (327 keV instead of 350 keV) and confirm the results of C. Watson, recently found for line sources. CONCLUSION: This leads to an increased number of detected low energy photons (mainly scattered photons) and has to be taken into account within the scatter correction. PMID- 10100234 TI - Somatostatin receptor scintigraphy of a patient with a giant invasive prolactinoma. AB - A 41-year-old with a giant prolactinoma underwent in-111 pentetreotide (Octreotide) imaging showing very intense tracer uptake in the region of the anterior skull base. In contrast, there was no significant response to Octreotide therapy. Prediction of clinical responsiveness to Octreotide therapy in patients with pituitary adenomas may depend on the presence of somatostatin receptor subtype 5. Pentetreotide does not avidly bind to this receptor subtype and therefore, cannot be used clinically to predict therapeutic Octreotide responsiveness in patients with large prolactinomas. PMID- 10100235 TI - Pelvic and lumbar metastasis detected by bone scintigraphy in malignant pleural mesothelioma. AB - A case of a 43-year-old man suffering from pleural mesothelioma with distant bone metastasis is reported. The results of bone scintigraphy and NMR findings allowed the diagnosis. The current case describes a hematogenous metastasis to the pelvis and vertebral column from a malignant pleural mesothelioma that was detected initially by bone scintigraphy. PMID- 10100236 TI - Follow-up findings in regional cerebral blood flow (r-CBF)-SPECT in a case of idiopathic childhood hemidystonia. Functional neuroimaging and pathophysiological implications. AB - A 9 1/2-year-old girl suffered from intermitting tremor and jitteriness of her left hand and oral muscles every 4 to 6 weeks with long lasting episodes. Clinically myoclonias and dystonic positioning of the left arm, hand and facial muscles were seen. No evidence of trauma, infection or inborn errors of metabolism was found. Successful therapy with carbamazepine was initiated while L DOPA failed. An ictal 99m-Tc-HMPAO-SPECT showed severe asymmetry with focal hyperperfusion of the contralateral right thalamus and basal ganglia as well as of the bifrontal cortex, whereas no anatomical lesions were found by MRI. In contrast, an interictally performed 99m-Tc-HMPAO SPECT showed hypoperfusion of the right thalamus and normalisation of the frontal perfusion under medical treatment. These 99m-Tc-HMPAO-SPECT findings may provide new insights into the localisation and pathophysiological pathways of idiopathic childhood dystonia. PMID- 10100237 TI - Alternative opinions. PMID- 10100238 TI - Florida Advanced Registered Nurse Practitioners: on the road to controlled substance prescriptive authority. PMID- 10100239 TI - How old is old? The ethics of rationing. PMID- 10100240 TI - Using osteoporosis management to reduce fractures in elderly women. AB - Once regarded as an inevitable part of aging, osteoporosis and fracture risk are now recognized as preventable and treatable. Detecting fracture risk and preventing fractures are key intervention strategies. Comprehensive evaluation and treatment of individuals at risk include making the correct diagnosis, identifying correctable factors that can contribute to low bone mass and increased fracture risk, and treating at-risk patients with pharmacologic and nonpharmacologic therapies. Patients must employ sound nutrition practices and reduce the potential for injuries sustained in falls through exercise and environmental safeguards. PMID- 10100241 TI - Overview of common obstetric bleeding disorders. AB - Most bleeding occurring early in pregnancy is benign; occasionally, however, it can represent an abnormally developing fetus. Vaginal spotting occurs in about 25% of early pregnancies. Other common causes of bleeding during the first trimester of pregnancy are spontaneous abortion, ectopic pregnancy, and gestational trophoblastic disease. Second-trimester bleeding is usually related to an incompetent cervix. Third-trimester bleeding is most likely a sign of placental abnormalities. Most cases of bleeding after the first trimester need prompt referral. This article provides information to help clinicians diagnose, assess, and manage obstetric bleeding. Accurate diagnosis and prompt intervention are crucial in reducing the impact on maternal and perinatal morbidity and mortality. PMID- 10100242 TI - Varicella: the vaccine and the public health debate. AB - Since the March 1995 Food and Drug Administration approval of the varicella vaccine for the prevention of varicella and the early 1996 American Academy of Pediatrics recommendation for universal vaccination for all susceptible children age 12 months and older, controversy over the need for a universal vaccination has existed. This article reviews the pathogenesis and epidemiology of the varicella zoster virus, the historic development of the vaccine, and the benefits and barriers to adoption of a universal varicella vaccination schedule. It concludes with the public health perspective on this controversial vaccine and future research recommendations. PMID- 10100243 TI - Client characteristics and practice patterns of nurse practitioners and physicians. AB - This study's purpose was to describe the practice patterns of nurse practitioners (NPs) in Tennessee--specifically, the demographic characteristics and health problems of their clients and the therapeutic services they provide. A random sample of NPs practicing 20 or more hours per week in primary care in Tennessee provided data on a total of 680 clients seen during one selected day of care. An instrument adapted from the National Ambulatory Medical Care Survey (NAMCS) allowed comparison of the NP findings with a national survey of office-based physicians in five areas: client demographics, client health status, diagnostic tests ordered, therapeutic interventions provided, and client disposition. Although many similarities were seen, differences included the tendency of NPs to care for more younger and female clients, to perform fewer office surgical procedures, and to provide more health teaching/counseling interventions. PMID- 10100244 TI - Common questions about the newer fluoroquinolone antibiotics. PMID- 10100245 TI - Understanding peptic ulcer disease pharmacotherapeutics. AB - The implication that Helicobacter pylori is responsible for peptic ulcer disease (PUD) has revolutionized the pharmacotherapeutic management of PUD. There has been a shift from long-term therapy with antacids and histamine2 (H2) antagonists to short-term therapy with triple antimicrobials with or without an antisecretory agent or a double antimicrobial therapy with an antisecretory agent. A case of PUD in a 53-year-old woman and its management with double antimicrobial agents and an antisecretory agent is discussed. Research evidence suggests that a treatment regimen aimed at eradicating H. pylori without diagnostic testing enhances the ability to effectively manage suspected cases of PUD before complications arise and referrals to specialists are necessary. Discouraging the use of over-the-counter H2 antagonists, ruling out long-term use of nonsteroidal anti-inflammatory drugs before selecting the treatment regimen, and considering expected treatment compliance are important aspects of PUD management that emerged from this case. PMID- 10100246 TI - Low-dose aspirin therapy in the treatment of preeclampsia. PMID- 10100247 TI - Assessing the harm of silicone gel-filled breast implants. PMID- 10100248 TI - First, do no harm? PMID- 10100249 TI - Preoperative use of tissue plasminogen activator for large submacular hemorrhage. AB - BACKGROUND AND OBJECTIVE: Tissue Plasminogen Activator (TPA) has been used as an adjunct in the surgical removal of submacular hemorrhage. It is usually used intraoperatively, but may not provide enough time for effective fibrinolysis, especially for a large hemorrhage. The present study was conducted to evaluate the efficiency and safety of preoperative use of TPA for large submacular hemorrhages. METHODS: Five eyes with large submacular hemorrhage secondary to age related macular degeneration underwent subretinal injection of TPA in the office 24 hours before surgery. All hemorrhages were less than seven days old and at least 3 mm thick. RESULTS: Preoperative visual acuity ranged from counting fingers to hand motion (HM). Patient follow-up ranged from 3 months to 24 months (mean, 11 months). Final visual acuity ranged from 20/30 to HM. Four of the five eyes (80%) showed improved visual acuity after surgery and 3/5 (60%) attained visual acuity of 20/200 or better. CONCLUSION: Preoperative use of TPA for drainage of large submacular hemorrhage appears to be safe and may result in efficient clot removal. The true efficacy of TPA in the treatment of submacular hemorrhage can only be proven by a prospective randomized trial. PMID- 10100250 TI - Optic nerve sheath decompression for progressive central retinal vein occlusion. AB - OBJECTIVE: To review our results with optic nerve sheath decompression (ONSD) for progressive central retinal vein occlusions (CRVO). METHODS: Patients selected all had evidence of progressively worsening CRVO, a component of optic nerve swelling, and most were already monocular from prior disease in the contralateral eye. ONSD was performed using a nasal approach under retrobulbar anesthesia. RESULTS: Eight eyes from 8 patients with a mean follow-up of 12 months were analyzed. Six patients improved, 2 worsened. Mean preoperative visual acuity was 20/160, and mean final postoperative visual acuity was 20/70. No complications occurred. Nonischemic CRVOs, patients < 65 years old, and those undergoing ONSD within 3 months of presentation seemed to do better. CONCLUSION: ONSD may improve vision or stabilize visual loss in patients with progressive CRVO. PMID- 10100252 TI - Evaluation of cataract surgery in intermediate uveitis. AB - BACKGROUND AND OBJECTIVE: The authors analyzed the results of cataract surgery performed on patients with intermediate uveitis from January 1990 through January 1997. MATERIALS AND METHODS: Fifty-two eyes of 44 patients with intermediate uveitis underwent cataract surgery during this period. These patients were evaluated with respect to duration of intermediate uveitis, treatment regimen, intraoperative complications and final visual results. RESULTS: Visual acuity improved following surgery in 94.2% eyes and 71.2% eyes achieved a final visual acuity better than or equal to 20/60. Intraocular lens implantation accompanied the surgery in 24 eyes. Regional and systemic steroids were required for control of inflammation. The factors that limited visual recovery were severe cystoid macular edema, epiretinal membrane formation, and secondary retinal detachment. Recurrence of uveitis was noted in 6 cases. CONCLUSION: Absolute control of inflammation, atraumatic surgery, and regular postoperative follow-up can improve the results of cataract extraction. Intraocular lens implantation in selected cases is well tolerated with good visual results. PMID- 10100251 TI - The relationship between capsulorhexis size and anterior chamber depth relation. AB - BACKGROUND AND OBJECTIVE: To determine whether the diameter of the capsulorhexis has an effect on anterior chamber depth (ACD) following phacoemulsification surgery. PATIENTS AND METHODS: Fifty-one consecutive patients were selected for cataract extraction by phacoemulsification with intraocular lens (IOL) implantation. Twenty-two of 51 patients underwent 4 mm capsulorhexis, while the rest underwent 6 mm. All were implanted with a multi-piece polymethyl methacrylate posterior chamber IOL with 5.0 mm diameter biconvex optic and flexible haptic. They were followed 3 months postoperatively. The width of the capsulorhexis was assured according to the IOL optic implanted intraoperatively, and by the help of slit-lamp measurement after dilatation of the pupil on the first postoperative day. ACD and axial length (AL) of patients was obtained by ultrasonography on both the days before surgery, and the first and seventh postoperative days, and after 30, 60 and 90 days. RESULTS: Early significant increase of ACD and ACD/AL ratios were observed in only the 6 mm capsulorhexis group on the first day postoperatively (P = .012, and P = .018). On the 90th postoperative day, ACD increased significantly both in the 4 mm (P = .002) and the 6 mm capsulorhexis groups (P = .049) when compared to preoperative values. For the same period, meaningful increase in ACD/AL ratio in the eyes with both 4 mm and 6 mm capsulorhexis groups was also noted compared with preoperatively (P = .002 and P = .019). There was a statistical difference between the 90th day ACD values of 4 mm (3.73 +/- 0.32 mm, mean +/- standard deviation) and 6 mm capsulorhexis groups (3.50 +/- 0.33 mm) (P = .028). For the same period, ACD/AL ratio was also significantly different for both groups (0.152 +/- 0.01, and 0.142 +/- 0.01 respectively) (P = .004). The refractive error changes followed the ACD changes and showed meaningful differences between 1st and 90th days postoperative values of each group (P = .029, and P = .014, respectively). CONCLUSION: A 4 mm capsulorhexis results in a longer postoperative ACD than does a 6 mm capsulorhexis for the IOL type used in this study. PMID- 10100253 TI - Apraclonidine 0.5% versus brimonidine 0.2% for the control of intraocular pressure elevation following anterior segment laser procedures. AB - BACKGROUND AND OBJECTIVE: Both apraclonidine hydrochloride 0.5% and brimonidine tartrate 0.5% are potent alpha-2 agonists, effective in controlling the intraocular pressure (IOP) rise following argon laser trabeculoplasty (ALT). Brimonidine has recently become available commercially as a 0.2% solution. Our goal in this study was to compare the efficacy and side effect profile of 0.2% brimonidine to that of 0.5% apraclonidine in the prevention of IOP spikes following anterior segment laser procedures. PATIENTS AND METHODS: Patients undergoing argon laser trabeculoplasty, Nd:Yag peripheral iridectomy or posterior capsulotomy were prospectively randomized to receive either apraclonidine 0.5% or brimonidine 0.2%, approximately 10 minutes prior to laser surgery. Intraocular pressure was measured by a masked observer, using Goldmann applanation tonometry, before and 1 hour after the treatment. RESULTS: 51 ALTs, 21 peripheral iridectomies, and 13 posterior capsulotomies were performed. The incidence of an IOP rise greater than 5 mmHg was 3/43 (7.0%) in the brimonidine group and 0/42 (0%) in the apraclonidine group (P = 0.08, chi-squared). There were no IOP elevations greater than 8 mmHg. All IOP rises of greater than 5 mmHg occurred in the ALT sub-group, and within this sub-group, the mean change in IOP from pre- to post-op was -4.00 +/- 5.87 in the brimonidine group versus -4.29 +/- 3.86 in the apraclonidine group (P = 0.84). There was a statistically significant decrease in IOP from baseline in both drug groups (P < .0001). CONCLUSIONS: Both drugs are highly effective in controlling IOP spikes following anterior segment laser procedures. There is a tendency toward higher risk of IOP rise following argon laser trabeculoplasty with 0.2% brimonidine as compared to 0.5% apraclonidine, however, this was not statistically significant. PMID- 10100254 TI - Circumferential perilimbal anesthesia for combined cataract glaucoma surgery. AB - BACKGROUND AND OBJECTIVES: A topical-subconjunctival anesthesia technique named circumferential perilimbal anesthesia was tested in a consecutive series of 34 combined cataract and glaucoma cases to determine effectiveness in long duration anterior segment surgery. PATIENTS AND METHODS: The circumferential perilimbal technique for combined surgery involved administration of 4% topical Xylocaine drops and injection of 0.25 cc of 4% Xylocaine subconjunctivally 3-4 mm inferior to the limbus. The inferior subconjunctival anesthesia was then spread 360 degrees around the limbus circumferentially with a smooth forceps. The topical and local anesthetic was supplemented by intravenous preoperative and intraoperative sedative and analgesic medications. RESULTS: All patients had successful phacoemulsification cataract extraction with intraocular lens combined with trabeculectomy. Medical records and postoperative interviews of the combined cataract-glaucoma cases revealed an average surgery time of 46 minutes (range 35 minutes-60 minutes) and only one incident of patient intraoperative pain. CONCLUSION: The circumferential perilimbal technique was an effective anesthesia technique for long duration combined cataract and glaucoma surgery. PMID- 10100255 TI - The photic sneeze reflex and ocular anesthesia. AB - BACKGROUND AND PURPOSE: Intravenous sedation to minimize discomfort from local anesthetic injection has many potential complications including severe involuntary sneezing (i.s.). This prospective study evaluates the occurrence of i.s. and a history of photic sneezing (p.s.). METHODS AND MATERIALS: All patients receiving local anesthesia (retrobulbar or periocular injections) after intravenous thiopentone for eye surgery during eight months were asked about p.s. and observed for i.s. RESULTS: The 557 patients (40% males) had a mean age of 69.9 years and 14% recalled p.s. (29.5% males). I.s. developed in 5.2% of the 557. Only 7.6% of those with p.s. developed i.s. After periocular injections 23.8% developed as compared to 4.5% after retrobulbar injections. (P < 0.001). There was no relationship between p.s. and i.s. (p = 0.43). CONCLUSION: I.s. is not linked to p.s., with males and females at equal risk for either. I.s. is more common after periocular injections. PMID- 10100256 TI - Intraocular pressure fluctuations during strabismus operations and the postoperative period. AB - PURPOSE: To evaluate the intraocular pressure (IOP) variations which occur during and after strabismus surgery. METHOD: We measured the IOP in 34 eyes of 20 pediatric patients undergoing primary strabismus surgery under general anesthesia. Measurements were performed by the Tono-Pen (Mentor O&Q Inc. Norwell, MA) prior to surgery, immediately after suturing of the conjunctive, and 1 week and 4 weeks after surgery. All patients received the same local antibiotics and steroid solutions postoperatively. RESULTS: IOP decreased from baseline to the end of surgery by a mean of 8.26 +/- 1.8 mmHg and increased from baseline to 4 weeks after surgery by a mean of 3.6 +/- 1.8 mmHg. Thirty-eight percent of the eyes had an IOP of 21 mmHg or more during the postoperative period. CONCLUSION: IOP variations are prevalent during and after strabismus surgery. Careful postoperative measurements are recommended in order to identify individuals who may be prone to iatrogenically increased IOP. PMID- 10100258 TI - Sturge-Weber syndrome with bilateral congenital syndactyly: a previously undescribed association. AB - The Sturge-Weber syndrome consists of unilateral port-wine haemangioma of the face which may be associated with an ipsilateral intracranial haemangioma and choroidal angioma. The common derivation of the meningeal, choroidal and facial vessels may explain a congenital malformation of all three areas. I report the case of a child with typical Sturge-Weber syndrome who had a previously undescribed association with bilateral congenital syndactyly. PMID- 10100257 TI - The effects of compression sutures on filtering blebs in rabbit eyes. AB - PURPOSE: To investigate the effect of compression sutures on filtering bleb cellularity in rabbit eyes. METHODS: Six New Zealand rabbits had bilateral filtering surgery. In the study eye, on postoperative day 14 a 10-0 nylon suture was placed that compressed the bleb. Five-bromo-2'-deoxyuridine (BrdU) was injected intravenously on days 15, 16, and 18. On day 21 histologic sections of the blebs were obtained. The total cell count was compared to the number of actively dividing cells (marked by anti-BrdU antibody). RESULTS: Study eyes had higher total cell counts (P = .004) on postoperative day 21, but the proportion of proliferating cells was not significantly different (P = .11). CONCLUSION: In rabbit eyes, bleb compression sutures were associated with more cellular components in the bleb compared to control eyes, but did not induce a higher level of cellular proliferation. PMID- 10100259 TI - Surgical removal of a free floating cyst of the iris pigment epithelium causing disturbing visual symptoms. AB - Pigmented cysts in the anterior chamber, fixed or free floating, are considered to be unusual but not very infrequent. However, most of these cases usually do not need any treatment other than a periodic observation. We report the surgical removal of an iris pigment epithelial cyst floating freely in the anterior chamber. The reason for surgical removal was, disturbance in near vision being caused by movement of the cyst across the visual axis. This specific symptom of disturbed near vision, to the best of our knowledge, is a rare indication for surgery that has not been pointed out earlier. Histopathological confirmation of the clinical diagnosis was also obtained. PMID- 10100260 TI - Retinal venous macroaneurysm associated with premacular hemorrhage. AB - To report an unusual association of a retinal venous macroaneurysm with premacular hemorrhage in a 50-year-old man, using a case report method. The patient exhibited a dense premacular hemorrhage in the left eye. Fluorescein angiography demonstrated that the source of bleeding was an isolated retinal venous macroaneurysm. The anterior surface of the hematoma was opened with an argon green laser, resulting in rapid clearing of the premacular hemorrhage and improvement in vision. Treatment of the retina surrounding the macroaneurysm to prevent recurrence of bleeding was ineffective to achieve occlusion of the lesion. No recurrent hemorrhage occurred during the observation period. Retinal venous macroaneurysm, a quite rare condition, may be complicated by premacular hemorrhage. Argon green laser may be useful in treating such hemorrhage. Hemorrhagic detachment of the internal limiting membrane or subhyaloid hemorrhage in the macula may occur after retinal vessel rupture with physical exertion (Valsalva retinopathy) or in retinal vascular diseases, such as proliferative diabetic retinopathy, and retinal arterial macroaneurysm. Arterial macroaneurysms are a common, well-described retinal vascular disorder. In contrast to retinal arterial macroaneurysms, retinal venous macroaneurysms are quite rare. In this article we describe a patient who presented with premacular hemorrhage that was caused by a retinal venous macroaneurysm. The hematoma and the macroaneurysm were treated with argon green laser. PMID- 10100262 TI - A tarsal strip-periosteal flap technique for lateral canthal fixation. AB - Lateral canthal fixation is widely used. This article sought to determine if a periosteal flap used routinely in conjunction with a tarsal strip provides lasting lateral canthal fixation. This consecutive clinical series from two ambulatory surgery centers followed 79 patients who underwent 141 lateral canthal fixation procedures. Outcome was measured by the position of the lateral canthus. Correct positioning of the lateral canthus was achieved in 78 of 79 patients representing 139 of 141 procedures (98%). The failed case was a patient with floppy eyelid syndrome in whom the sutures tore through the tarsal strips. The tarsal strip-periosteal flap technique is a successful, technically direct method of lateral canthal fixation. It is promoted as an enhancement of the tarsal strip technique, and is especially helpful in patients with prominent eyes. PMID- 10100261 TI - A case of an intraocular foreign body due to graphite pencil lead complicated by endophthalmitis. AB - We report a case of an 8-year-old boy who presented with an intraocular foreign body composed of graphite pencil lead. The patient had been accidentally poked in the right eye with a graphite pencil. Primary care consisted of corneal suturing and lens extraction. Two pieces of the pencil lead remained in the vitreous cavity following surgery, and 2 days later the patient developed endophthalmitis. Pars plana vitrectomy was performed immediately and the intraocular foreign bodies were removed through the scleral wound. Cultures of the vitreous fluid revealed no bacterial organisms. X-ray fluoroscopic analysis of the vitreous detected 1 ppm of aluminum (a constituent of the pencil lead). Although the clinical presentation indicated probable bacterial endophthalmitis, the detection of elemental aluminum within the vitreous cavity also suggested the possibility of further retinal toxicity due to some dissolving of the pencil lead. PMID- 10100263 TI - A slit-lamp needling filtration procedure for uncontrolled glaucoma in pseudophakic and aphakic eyes. AB - In one aphakic and one pseudophakic patient without previous filtration surgery, a transconjunctival needling procedure similar to that used for failed filtration procedures was performed to create a filtering bleb. In both cases, intraocular pressure was successfully lowered for 6 months until the occurrence of bleb encapsulation, which was relieved by transconjunctival needling. There were no complications. In selected cases, this minimally invasive slit-lamp needling procedure provides successful filtration. PMID- 10100264 TI - New iris retractor for pupil dilatation during anterior vitrectomy: double-hook iris retractor. AB - To report a new iris retractor as a tool for pupillary dilatation in eyes with a small pupil. This instrument was designed to prevent the retractor from dropping out of corneal incision, especially during anterior peripheral vitrectomy requiring a scleral indentation. A new iris retractor was designed with the top in the form of a double-hook, based on the conventional flexible iris retractor. The new instrument was used in 16 eyes, and the conventional flexible iris retractor was used in 14 eyes, with proliferative retinopathy or proliferative diabetic retinopathy in cases in which anterior vitrectomy was performed. The number of times that the instrument has been replaced were recorded. The conventional flexible iris retractor was replaced at mean number of 4.2 times, while the new iris retractor was replaced a mean number of 0.3 times during vitreous surgery. The difference was statistically significant (P = 0.009, Mann Whitney test). The new iris retractor can easily hook onto the iris and is useful in anterior vitrectomy. PMID- 10100265 TI - Folding angle critical with hydrogel lens. PMID- 10100266 TI - Control of nausea and vomiting in children receiving combined cancer chemotherapy. PMID- 10100267 TI - Liposomal anthracyclines for brain tumors. PMID- 10100268 TI - Conducting pediatric psychosocial assessments: guiding treatment or creating blind spots. PMID- 10100269 TI - Pediatric oncology at the National Institute of Pediatrics in Mexico City. AB - The Instituto Nacional de Pediatria (National Institute of Pediatrics) is a referral, non-profit, teaching hospital. This government-funded institution is dedicated only and exclusively for clinical and research in pediatrics. In their 29 years, it has dictated the norms for patient care through a multitude of research projects in all fields of pediatrics. The purpose of our institution is to continue developing human professional resources in order to improve patient care across the country, especially in pediatric oncology, in which there is a tremendous shortage of professionals. We believe that all Mexican children with this disease have the right to have as good treatment and prognosis as the children from developed countries. PMID- 10100270 TI - Ondansetron and tropisetron in the control of nausea and vomiting in children receiving combined cancer chemotherapy. AB - Ondansetron (Zofron, Glaxo) and tropisetron (Navoban, Sandoz) are selective serotonin (5HT3) antagonists that have proven very effective in the prevention of vomiting and nausea in adults and children receiving cancer chemotherapy. This study compared the efficacy of the two agents in the prevention of vomiting and nausea in children receiving chemotherapy for solid tumors and blood malignancies. A total of 23 children were studied in 205 chemotherapeutic cycles (116 one-day regimens and 89 multiple-day regimens). In 102 chemotherapeutic cycles the children received ondansetron as an antiemetic agent in a dose of 5 mg/m2 30 min before chemotherapy was given and then 4 mg/m2 every 8 h i.v. (group A) and in 103 cycles they received tropisetron in one dose of 0.2 mg/kg 24 h-1 i.v. (max dose 5 mg) 30 min before cytotoxic drugs administration every day they received chemotherapy (group B). The response was defined as complete in the absence of nausea and vomiting per 24 h of chemotherapy, as partial given the presence of 1-4 events of vomiting and/or nausea less than 5 h per 24 h, and as failure if there were more than 4 events of vomiting and/or nausea for more than 5 h per 24 h of chemotherapy. The response of the two groups was studied independently and depending on the degree of emetogenicity of the chemotherapeutic agents, which were divided into mildly, moderately, and highly emetogenic. The comparison of the two groups not taking into consideration the emetogenicity of the chemotherapeutic agents showed that ondansetron was more effective in 1-day regimens (P = .023), whereas the two agents were equally effective in multiple-day regimens (P = .2). The statistical analysis depending on the emetogenicity of the chemotherapeutic agents showed increased efficacy of ondansetron in mild (P = .017) and moderately emetogenic chemotherapeutic agents, whereas there was no difference in the highly emetogenic drug group. Ondansetron is found to be more effective than tropisetron in controlling acute nausea and vomiting in children receiving mild and moderately emetogenic chemotherapeutic drugs, although there is no difference in the efficacy of both antiemetic agents when highly emetogenic drugs are administered. PMID- 10100271 TI - Expression of Wilms tumor gene (WT1) in children with acute leukemia. AB - Wilms tumor gene (WT1) expression occurs in various malignancies including adult leukemia. WT1 expression was studied in children with acute leukemia according to morphological types and immunophenotypes. RT-PCR was used to examine relative level of WT1 transcripts from the peripheral blood of 15 children diagnosed with acute leukemia: 12 acute lymphoblastic leukemias (ALLs) and 3 acute myelogenous leukemias (AMLs); 8 ALLs newly diagnosed, 2 ALLs in first marrow relapse, 2 ALLs in remission over 2 years, 2 AMLs newly diagnosed, and 1 AML in second marrow relapse. Six healthy adult volunteers were studied for controls. WT1 was detectable in 7 out of 10 ALLs and all 3 AMLs, but not in 2 ALLs in remission and the controls. The expression levels were higher for AMLs than for ALLs. According to the types of ALL, WT1 was detectable in 2 out of 2 non-T group II, 4 out of 6 non-T group III, but not in one CD20+ non-T group IV, while one T-ALL showed a relatively high level. WT1 expression was detectable more frequently in ALL-L2 than in ALL-L1 and with higher levels for ALL-L2. WT1 expression was frequently noted in children with acute leukemia. The results suggest that WT1 transcripts may prove to be a significant tumor marker, possibly as an MRD monitor in evaluating remission status and early relapse, and may also prove to be useful in predicting outcomes in acute leukemia in children. PMID- 10100272 TI - Hodgkin's disease in Turkish children: clinical characteristics and treatment results of 210 patients. AB - Although Hodgkin's disease (HD) is one of the common malignancies in childhood, there is limited information from developing countries in English literature. The aim of this study is to give epidemiologic features and treatment results of 210 previously untreated children with HD from a developing country. Between 1 June 1984 and 31 December 1992, all children seen who were younger than 18 years old with newly diagnosed, untreated, biopsy-proven Hodgkin's disease were included in this study. A clinical staging system was used to determine the dissemination of the disease. While patients with stage I-II disease received canape treatment protocol (three cycles COPP [cyclophosphamide, vincristine, procarbazine, prednisolone] or ABVD [doxorubicin, bleomycine, vinblastine, dacarbazine] plus low-dose involved-field radiotherapy), patients with stage III-IV disease were treated by sandwich protocol (six cycles COPP plus low-dose involved-field radiotherapy). A total of 210 patients with a median age of 8 years were eligible for this study. Male to female ratio was 3:1 and 37 (17.6%) were less than 5 years of age. The major histologic subtype was mixed cellularity (69.6%). Overall survival rates were 91.5 and 87.7%, and event-free survival rates were 71.5 and 70.5% at 5 and 10 years, respectively. No secondary malignancy has been observed so far. The prevalence of Hodgkin's disease in young children is higher and the distribution of histologic subtypes is also different from many Western countries. Canape and sandwich treatment protocols could be used safely in clinically staged childhood HD with tolerable toxicity. PMID- 10100273 TI - Liposomal daunorubicin (DaunoXome) in children with recurrent or progressive brain tumors. AB - Liposomal daunorubicin (DaunoXome = DNX) has been used in 14 children with recurrent or progressive growing brain tumor. DNX was given as a 1-h intravenous infusion with a dose of 60 mg/m2, once every 4 weeks, up to a cumulative dose of 600 mg/m2. At 3-month intervals the tumor process was evaluated on MRI or CT scan. Tumor response and toxicity of DNX were recorded according to the WHO guidelines. In 6 of the children a response has been established: 2 had complete responses, of which one relapsed again after 3 months; in 3 children a partial response was found. Two children showed stable disease. In 6 children the tumors grew progressively. In all responding children a remarkable subjective response was found. The toxicity of DNX at this dose was mild with a mild bone marrow depression and a slight but certain cardiotoxicity in 3 children. For the whole group the left ventricular function decreased with 13.8%. In 1 child the DNX treatment was stopped because of a decrease of the shortening fraction to 20%. In 4 children some hair loss was observed at the end of the treatment. In 3 children mental depression occurred that was associated with the administration of DNX. DNX is a well-tolerated and effective drug in the treatment of slowly progressive or recurrent brain tumors in children. PMID- 10100274 TI - Treatment of Hodgkin's disease in children with VAMP (vinblastine, adriamycin, methotrexate, prednisone) and VEPA (vinblastine, etoposide, prednisone, adriamycin). AB - Treatment of Hodgkin's disease in children should be directed at maximizing cures and minimizing the long-term effects of alkylating agents, anthracyclines, and bleomycin. In this study methotrexate and etoposide were used in the VAMP/VEPA regimens to treat 60 clinically staged pediatric patients with Hodgkin's disease. Twenty-nine patients with stages I-IIA received four courses of VAMP plus low dose radiotherapy. Thirty-one IIA bulky disease and IIB-IVB patients received four or six courses of VEPA plus low-dose radiotherapy. There were 6 partial remissions after the completion of chemotherapy and all of these patients relapsed, but 4 were successfully salvaged with ABMT. Two patients have died. The 3.1-year overall survival rate is 97% (100% VAMP, 94% VEPA) and the event-free survival rate is 88% (97% VAMP, 77% VEPA). These results suggest that VAMP is a reasonable treatment for low stages of Hodgkin's disease, but more advanced disease is not adequately treated by VEPA and low-dose radiotherapy. PMID- 10100275 TI - Serum levels and differential expression of intercellular adhesion molecule-1 in childhood leukemia and malignant lymphoma: prognostic importance and relationship with survival. AB - Serum levels and leukemic cell-tumor tissue expression of intracellular adhesion molecule-1 (ICAM-1/CD 54) were detected in 54 children with acute leukemia and malignant lymphoma. Serum samples were obtained from all patients before treatment and after cessation of the therapy from malignant lymphoma cases and during remission from leukemic patients. Twelve age-matched healthy children were included as a control group. The serum ICAM-1 levels were significantly higher in patients with acute lymphoblastic leukemia (ALL) or Hodgkin's disease (HD) than those in the control group (median values: 350.9, 286.4, and 138.4 ng/mL, respectively; P < .01 in each comparison). However, there were no significant differences concerning serum ICAM-1 levels between the control group and each of the acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), and Burkitt's lymphoma (BL) case groups (median values: 235.7, 222.7, 195.9, and 138.4 ng/mL, respectively; P > .05 in each comparison). Moreover, serum soluble ICAM-1 levels significantly declined in ALL or HD patients who were in complete remission (median values: 185.0 and 145.4 ng/mL, respectively; P < .05 in each comparison). In HD patients high levels of serum ICAM-1 could be correlated with high ESR (P < .01), whereas no statistically significant difference could be found when serum ICAM-1 titers were compared with stages, B symptoms, and histological subgroups, probably because of the inadequate number of patients in each group. Expression of ICAM-1 was mainly attributed to lymphocytes, vessels, and weakly to Hodgkin's cells, and this was significantly high in patients who were in advanced stages of disease. High serum sICAM-1 level was also associated with poor outcome and survival. Determination of serum level and/or tumor tissue expression of ICAM-1 in HD and ALL might represent an additional, but probably not independent, disease-associated marker to be used in the evaluation and/or monitoring of treatment response in patients with HD and ALL. PMID- 10100276 TI - Vitamin B12 absorption test and oral treatment in 14 children with selective vitamin B12 malabsorption. AB - Oral vitamin B12 (VB12) absorption was studied in 12 patients with selective VB12 malabsorption and in 6 age-matched healthy controls. Serum VB12 level was measured before and 3 h after oral administration of VB12 100 or 1000 micrograms. After administration of 1000 micrograms of VB12 an appreciable increase in the serum VB12 level was observed in patients as well as in controls. The mean of the increase in the serum VB12 level did not differ between patients and the controls (273 +/- 203 pg/mL, 180 +/- 71 pg/mL, respectively P > .05). Twelve patients previously treated by parenteral VB12 were switched to, and 2 newly diagnosed patients were started on, oral VB12 treatment of 1000 micrograms given every 2 weeks. Hematological parameters and serum VB12 levels remained stable after switching to oral therapy in the 12 patients. In the two newly diagnosed patients anemia was cured by orally administrated VB12. This study lends further support to the use of megadoses of VB12 as an alternative treatment for selective VB12 malabsorption. PMID- 10100277 TI - No response to recombinant human erythropoietin therapy in patients with congenital dyserythropoietic anemia type I. AB - Congenital dyserythropoietic anemia (CDA) type I is a rare inherited bone marrow disorder characterized by moderate to severe macrocytic anemia with pathognomonic cytopathology of nucleated red blood cells. Previous studies have suggested that serum erythropoietin levels in affected patients are lower than expected for the degree of anemia. An earlier study demonstrated a substantial increase in the number of CFU-E in CDA type I pattern on addition of exogenous erythropoietin. The present study reports on the response to recombinant human erythropoietin in 8 patients with CDA type I. Eighteen weeks of treatment, starting at 300 IU/kg twice a week and gradually increasing to 500 IU/kg three times a week, did not have a substantial effect on the mean hemoglobin value. These results indicate that recombinant human erythropoietin (rHuEpo) is not beneficial to patients with CDA type I and that the relatively low levels of serum erythropoietin probably play no major role in the pathogenesis of the disease. PMID- 10100278 TI - Clear cell sarcoma kidney: clinical features and outcome. AB - Clear cell sarcoma of kidney (CCSK) is a rare, highly malignant tumor. The clinical features and treatment outcome of 12 patients with CCSK are reported. From 1982 through December 1996, 12 cases of CCSK were seen at the Regional Cancer Centre, Trivandrum, India. Patients were staged according to NWTS III recommendation. They were treated with chemotherapy containing vincristine, actinomycin, and Adriamycin and radiotherapy. The survival curve was calculated by the Kaplan-Meier method. Mass and pain in the abdomen were the presenting symptoms. Male/female ratio was 3:1. Six had stage I, 4 had stage II, and 2 had stage III disease. Of the 12, 10 were evaluable, 6 are alive, and 3 recurred in 9 evaluable. Six patients are alive free of disease 10 to 108 months after diagnosis. The overall survival and disease-free survival of the 10 patients are 64 and 56%. It would appear that combined modality treatment can cure two thirds of children with CCSK. Effective treatment needs to be developed for children who fail after first line treatment. PMID- 10100279 TI - Acute spontaneous pneumomediastinum in a child with Hodgkin's disease and pulmonary fibrosis. AB - A case of acute spontaneous pneumomediastinum in a 13-year-old boy suffering from Hodgkin's disease and pulmonary fibrosis is reported. He was initially treated for Pneumocystis carinii but his respiratory function progressively deteriorated, and fibrosis secondary to bleomycin was suspected. The day before the admission to the Pediatric Intensive Care Unit the patient complained of anterior thoracic pain, and a chest x-ray revealed a left-sided small spontaneous pneumothorax and pneumomediastinum. Although air leak responded initially to conservative treatment, acute tension pneumomediastinum with cardiopulmonary decompensation recurred 6 days later, while the patient was on mechanical ventilation. Treatment with urgent evacuation of the accumulated air via subxiphoid drainage, using an old but ill-defined technique, resulted in complete resolution of pneumomediastinum and significant improvement of the hemodynamic condition. PMID- 10100280 TI - Down syndrome and juvenile myelomonocytic leukemia. PMID- 10100281 TI - Adverse effect of peritonitis on peritoneal membrane function in children on dialysis. AB - The effect of peritonitis on peritoneal membrane solute transport characteristics was determined as part of a multicenter study in children on continuous ambulatory/cycling peritoneal dialysis. Ninety-three children each underwent a 4 h peritoneal equilibration test (PET) with 1,100 ml/m2 2.5% Dianeal for determination of mass transfer area coefficients (MTAC), dialysate to plasma ratios (D/P) for creatinine and urea at 0, 30, 60, 120, 180, and 240 min and dialysate glucose levels at 0, 30, 60, 120, 180, and 240 min for calculation of D/Do. The mean age of the study cohort was 10.1 +/- 5.6 years (range 0.1-19 years). There were 162 historical episodes of peritonitis; at the time of the PET tests, 36 children had never had an episode of peritonitis (group I) while 57 children had a history of one or more episodes of peritonitis (group II). In group II children, the 4-h glucose D/Do was significantly lower and the 4-h D/P creatinine ratio, the creatinine MTAC, and the glucose MTAC were significantly higher (each P < 0.05) than in group I. In children with a history of peritonitis caused by Gram-negative organisms, the 4-h glucose D/Do (P < 0.05) and the creatinine MTAC (P < 0.05) were significantly lower and the glucose MTAC (P = 0.07) nearly significantly lower than in children without a history of peritonitis. Linear regression analysis did not demonstrate a correlation between any of the variables and duration of peritoneal dialysis, while the rate of peritonitis was weakly correlated with glucose MTAC (r = 0.34, P < 0.05) and with 4-h glucose D/Do (r = -0.222, P < 0.01). We conclude that children with a history of peritonitis have peritoneal membranes that are more permeable to glucose and creatinine than children without a history of peritonitis, and that the peritoneal membranes of children who have had peritonitis caused by Gram-negative organisms are also more permeable to creatinine and glucose. Such changes are likely to have an adverse effect on membrane function and could eventually contribute to ultrafiltration failure. PMID- 10100282 TI - Probucol for treatment of hyperlipidemia in persistent childhood nephrotic syndrome. Report of a prospective uncontrolled multicenter study. AB - In a prospective, uncontrolled multicenter study, we have evaluated the effects of probucol on hyperlipidemia, proteinuria, and glomerular filtration rate (GFR) in hyperlipidemic children with persistent nephrotic syndrome. Probucol was started for a total of 12 weeks in 8 children and for 24 weeks in 14 children. Lipoprotein profiles, serum malondialdehyde (MDA) levels, proteinuria, renal function, and electrocardiogram were monitored every 4 weeks. Side effects were recorded by questionnaire. Treatment was completed by 7 of 8 patients for 12 weeks and by 7 of 14 children for 24 weeks. After 12 weeks, the mean serum concentrations of triglycerides (-15%), total cholesterol (-25%), very low density lipoprotein-cholesterol (-27%), low-density lipoprotein-cholesterol ( 23%), and high-density lipoprotein-cholesterol (-24%), as well as apolipoprotein (apo) A-I (-19%), apo B (-21%), and MDA (-32%) were reduced. The positive effects of probucol on the lipoprotein profile persisted over 24 weeks; however, there was no significant effect on either proteinuria or GFR. In conclusion, probucol had beneficial effects on lipoproteins and lipid peroxidation, but improved neither proteinuria nor GFR. The drug was generally tolerated well, but had to be discontinued because of a prolonged QT interval in 4 of 22 patients. PMID- 10100283 TI - High incidence of focal segmental glomerulosclerosis in nephrotic syndrome of childhood. AB - In recent adult literature, there have been reports of an increasing incidence of focal segmental glomerulosclerosis (FSGS) among patients with nephrotic syndrome. To examine whether this observation is also relevant to the pediatric population we utilized our hospital computerized database to analyze the data on children with primary nephrotic syndrome seen first between the years 1984 and 1995. A questionnaire was also sent to all metropolitan Kansas City pediatricians to identify possible patients outside the database. The inclusion criteria were clinical nephrotic syndrome or proteinuria with a kidney biopsy. A total of 148 patients (group A) were identified; 86 of them from metropolitan Kansas City (group B). In group A the incidence of minimal change disease (MCD) and FSGS was 52.7% [95% confidence interval (CI) 44%-60%] and 23.0% (95% CI 16-29%), respectively and in group B 54.7% (95% CI 44%-65%) and 24.5% (95% CI 15%-33%), respectively. Those numbers were significantly different from the International Study of Kidney Disease in Children (IS-KDC) reported incidence of 76.4% for MCD and 6.9% for FSGS. Similar to the ISKDC, in our population children over 6 years had a higher incidence of FSGS than younger children (32.8% vs. 16.7%, P = 0.028). The annual incidence rate for nephrotic syndrome in group B was 2.2 cases/10(5) children per year, of which MCD comprised 1.22 cases/10(5) children per year and FSGS 0.5 cases/10(5) children per year. The annual incidence rates of both primary nephrotic syndrome (3.6) and FSGS (1.6) were significantly higher in African-Americans, than Caucasians (1.8 and 0.3 cases/10(5) children per year, respectively). Our study indicates nearly no change in the annual incidence of pediatric primary nephrotic syndrome, but a higher incidence of FSGS with reciprocal decline in the incidence of MCD. The possibility of primary nephrotic syndrome being caused by a non-MCD entity is further raised among African American and in children over 6 years. We conclude that our perception of primary nephrotic syndrome of childhood as a benign condition has to be carefully reexamined and a more-guarded prognostic approach adopted in our geographic area. PMID- 10100284 TI - Influence of serum albumin on renal function in nephrotic syndrome. AB - Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), determined by the clearances of inulin and para-aminohippuric acid, were evaluated in 119 children with different types of nephrotic syndrome and in different stages: the nephrotic stage (serum albumin < 25 g/l), recovery stage (25-35 g/l), and remission (> 35 g/l). GFR in the nephrotic stage was significantly lower than in remission and in controls, and was lowest at onset of the disease (84 +/- 6, 111 +/- 4, and 119 +/- 2 ml/min per 1.73 m2). ERPF was higher in the nephrotic stage than in recovery, especially in children with histological lesions. Thus the filtration fraction (FF) was greatly decreased in the nephrotic stage. In patients investigated both in the nephrotic and the remission phase, GFR and FF increased significantly. There was a direct correlation between the serum albumin concentration and FF and an inverse correlation between mean arterial pressure (MAP) and GFR and FF in all patients, a direct correlation between the serum albumin concentration and GFR in minimal change nephrotic syndrome patients, and an inverse correlation between ERPF and serum albumin in children with histological lesions. In conclusion, GFR and FF were decreased and ERPF increased in the nephrotic stage, normalizing in remission. The low GFR in the nephrotic stage was thus not dependent on hypoperfusion. We suggest that the low GFR is dependent on a very low ultrafiltration coefficient. The direct correlation between GFR and serum albumin and the indirect correlation between GFR and MAP suggest compensatory mechanisms that increase the ultrafiltration pressure to counteract the severely reduced ultrafiltration coefficient. PMID- 10100285 TI - One-center experience with cyclosporine in refractory nephrotic syndrome in children. AB - Uncontrolled or refractory nephrotic syndrome (NS), seen in a variety of glomerular disorders, leads to end-stage renal disease (ESRD). This study describes the use and efficacy of cyclosporine (CSA) for the treatment of refractory NS in 83 children seen over a 10-year period. The histological diagnosis leading to the NS was focal segmental glomerulosclerosis (FSGS) in 51% (n = 42), IgM nephropathy in 20% (n = 17), membranoproliferative glomerulonephritis in 10% (n = 8), lupus nephritis in 6% (n = 5), human immunodeficiency virus (HIV) nephropathy in 5% (n = 4), minimal change disease in 7% (n = 6), and membranous nephropathy in 1% (n = 1) of patients. During CSA therapy the mean proteinuria of the study population decreased from 5.14 g/24 h (4.80 g/m2 per 24 h) to 1.23 g/24 h (0.92 g/m2 per 24 h) (P < 0.001), the mean serum albumin increased from 2.13 g/dl to 3.53 g/dl (P < 0.001), the mean serum cholesterol decreased from 364 mg/dl to 223 mg/dl (P < 0.001), and the mean serum creatinine increased from 0.77 mg/dl to 1.2 mg/dl (P < 0.01). When analyzed by histological diagnosis, similar significant trends of reduction in proteinuria were seen in all but the lupus group. There was a rise in serum creatinine following the use of CSA in patients with FSGS, lupus nephritis, and HIV nephropathy; however the elevated serum creatinine was only significant in patients with FSGS. At the end of the study period, 20 patients had reached ESRD, of which 11 had FSGS, 5 had lupus nephritis, and 4 were patients with HIV nephropathy. Fifty-four patients were in remission at the end of the study period (48 with proteinuria < 100 mg/24 h and 6 with proteinuria < 500 mg/24 h). In conclusion, among children with refractory NS, CSA induced a remission in a large proportion. However toxicity, as noted by the rise in serum creatinine, was observed in several patients. Since this toxicity may be drug induced or a natural progression of the disease, careful monitoring and close follow-up are essential. PMID- 10100286 TI - Two-year cyclosporin treatment in children with steroid-dependent nephrotic syndrome. AB - We describe a prospective study of 2-year moderate-dose cyclosporin (CS) treatment in 13 children with steroid-dependent minimal change nephrotic syndrome (MCNS). CS treatment was commenced at 100-150 mg/m2 per day after remission was attained with prednisolone therapy, was adjusted to a target trough level of 100 ng/ml, and was administered for 2 years. The number of relapses during CS treatment significantly decreased compared with before CS treatment, all patients were able to discontinue prednisolone therapy, and steroid toxicity was reduced; 54% of patients remained in remission during CS treatment. Renal biopsies performed before CS treatment all showed MCNS without tubulointerstitial lesions. Creatinine clearance and urinary beta 2-microglobulin levels during CS treatment were normal in all patients, but renal biopsies performed after CS treatment revealed chronic CS nephrotoxicity in 7 patients. Clinical data, including CS dose and CS trough blood levels, were not significantly different between patients with and without nephrotoxicity. In conclusion, 2-year moderate-dose CS treatment in children with steroid-dependent MCNS is effective in preventing relapse and decreasing steroid toxicity. This treatment can, however, result in a high incidence of chronic nephrotoxicity. Renal function is not a reliable indicator of chronic CS nephrotoxicity. Renal biopsy is therefore necessary to monitor chronic CS nephrotoxicity. PMID- 10100287 TI - Mycoplasma pneumoniae-associated nephritis in children. AB - Mycoplasma pneumoniae infection is a rare cause of acute nephritis. Six children (2 girls) aged 5-10 years, admitted for nephritis, had serological tests showing recent Mycoplasma pneumoniae infection. The diagnosis of Mycoplasma pneumoniae infection was based on the presence of serum IgM, detected either by immunofluorescence (IF) (n = 1) or enzyme-linked immunosorbent assay (n = 5). Four children had a renal biopsy, with analysis of parenchymal Mycoplasma pneumoniae components by indirect IF and polymerase chain reaction. Extrarenal symptoms were: respiratory (n = 3), ear, nose and throat (n = 2), gastrointestinal (n = 3), hepatic (n = 1), neurological (n = 1), articular (n = 1), and hematological (n = 3). The patients presented with acute nephritis (1 had a nephrotic syndrome) or with acute renal failure and proteinuria. Pathological findings included type 1 membranoproliferative glomerulonephritis (MPGN, n = 1), proliferative endocapillary glomerulonephritis (n = 2) and minimal change disease (n = 1). The patient with type 1 MPGN progressed rapidly towards end-stage renal failure because of a congenital solitary kidney. Among the patients with endocapillary glomerulonephritis, 1 relapsed 6 months later and remained proteinuric, while the other recovered, as did the child with minimal change disease. The search for Mycoplasma pneumoniae antigens and nucleic acids in renal tissue was negative. However, the absence of the microorganism in the kidney is a common feature of post-streptococcal glomerulonephritis. We conclude that Mycoplasma pneumoniae is a rare yet potential cause of acute glomerulonephritis. PMID- 10100288 TI - Clinical guidelines and hospital discharges of children with acute urinary tract infections. AB - In order to evaluate the effect of the introduction of recent similar guidelines on the treatment of acute urinary tract infection (UTI) in children, and possible changes in its epidemiology, we analyzed the records of hospital discharge for acute UTI under the age of 15 years in England and Wales between 1979 and 1993 and in Finland between 1978 and 1994. Cases were defined by the ICD9 diagnostic codes 590.1 (acute pyelonephritis) and 599.0 (UTI, site not specified) for males and females according to three age groups (0-4, 5-9, and 10-14 years). We also compared the registry data on kidney transplants due to end-stage renal disease caused by recurrent pyelonephritis in the United Kingdom and Finland. In England the rate of attack of symptomatic UTI per 1,000 girls under 15 years increased from 0.74 (95% confidence interval 0.71-0.76) in 1987 to 1.32 (1.29-1.35) in 1993 (P < 0.001, test for trend). The respective figures for Finnish girls were 1.74 (1.62-1.86) in 1987 and 1.62 (1.51-1.74) in 1993 (P = 0.72). In English boys, the increase in the attack rate was from 0.38 (0.36-0.40) in 1987 to 0.70 (0.68-0.73) in 1993 (P < 0.001). In Finnish boys the respective figures were 0.74 (0.66-0.82) in 1987 and 0.88 (0.80-0.97) in 1993 (P < 0.02). The observed increases in the attack rates of UTI most probably relate to increased referral of acute UTI patients to hospitals for the recommended imaging studies rather than changing occurrence. Publication of guidelines for treatment of UTI in children, consolidating more-general awareness, may have contributed to this. The mean annual numbers of kidney transplants in the United Kingdom and Finland during 1989-1995 due to end-stage renal disease caused by pyelonephritis were of similar magnitude, i.e., 1.9 (1.6-2.3) transplants per million inhabitants in the United Kingdom and 2.8 (1.5-4.7) transplants per million inhabitants in Finland. The decreasing trend in these figures in both countries, although statistically significant only in the United Kingdom (P < 0.05, test for trend), suggests improved longterm outcome of these patients induced by better diagnosis and treatment of pyelonephritis and the diseases related to it, such as congenital malformations. According to our data, valid clinical guidelines are effective in changing clinical practice. PMID- 10100289 TI - Plasma ionized magnesium in tubular disorders with and without total hypomagnesemia. AB - Selective electrodes have been designed for determining plasma ionized magnesium. In kidney disease the relationship between ionized and total circulating magnesium is often altered. Hence plasma ionized magnesium (ETH 7025 membrane) was determined in 25 patients with primary renal tubular disorders; 6 patients had total hypomagnesemia. Total plasma magnesium was never reduced in the remaining 19 patients. Plasma ionized magnesium values were low in the 6 patients with total hypomagnesemia. In 18 of the 19 patients without total hypomagnesemia plasma ionized magnesium values were not reduced. Ionized hypomagnesemia was noted in a patient with normal total plasma magnesium in the context of hypercalciuric nephrocalcinosis of unknown origin. The study demonstrates an excellent concordance between plasma total and ionized magnesium in tubular disorders associated with total hypomagnesemia and a good concordance in tubular disorders that are not linked with total hypomagnesemia. The determination of circulating ionized magnesium is of little value in the diagnostic work-up of the vast majority of renal tubular disorders. The determination might perhaps disclose latent hypomagnesemia in nephrocalcinosis of unknown cause. PMID- 10100290 TI - A morbid course in a girl with mixed connective tissue disease. AB - We describe an 18-year-old girl with a 13-year history of mixed connective tissue disease whose clinical course was unique: she ultimately developed end-stage kidney and bowel disease that led to a protracted morbid clinical course. We report this case to alert pediatric nephrologists to the importance of early recognition of possible intestinal disease in these patients. Unfortunately, no therapy is currently known to reverse the pathological process in the bowel, but multiorgan transplantation might be an option if the numerous medical complications of end-stage bowel disease can be successfully controlled. PMID- 10100291 TI - Hypercalciuria and urolithiasis in a case of Costello syndrome. AB - Costello syndrome is characterized by postnatal growth deficiency, mental retardation, curly hair, coarse characteristic face, and loose skin of hands and feet. Patients with this syndrome have a high incidence of cardiac involvement, including arrhythmia, atrial septal defect, and hypertrophic cardiomyopathy. We report a 16-year-old adolescent female with Costello syndrome who presents with hypercalciuria and urolithiasis. PMID- 10100292 TI - White coat hypertension in two adolescents. AB - We describe two adolescent boys with white coat hypertension. Both patients had significantly high blood pressure documented on more than three occasions at clinic. No cause for hypertension or target organ damage was demonstrated. Twenty four-hour mean ambulatory blood pressure values were normal for height and sex, which led to the diagnosis. PMID- 10100293 TI - Ketorolac-induced irreversible renal failure in sickle cell disease: a case report. AB - Nonsteroidal anti-inflammatory drugs are often used in the management of those with acute pain secondary to sickle cell disease due to potent analgesic effects along with a lack of addictive potential, respiratory depression, and central nervous system effects, as may occur with narcotics. Caution should be observed in the use of nonsteroidal anti-inflammatory drugs in patients with compromised renal function. We present a case of a 17-year-old sickle cell disease patient with an acute painful episode and normal renal function indices who subsequently developed irreversible renal failure and a perirenal hematoma following the administration of ketorolac, despite adequate hydration. Due to its inhibitory effect on prostaglandin-mediated vasodilation, we advise caution in the use of ketorolac for the pain management of sickle cell painful episodes. We recommend following the administration guidelines for ketorolac for renal-compromised patients in those with painful episodes of sickle cell disease, and if used in this patient population, renal function must be very closely monitored. PMID- 10100294 TI - Enamel hypoplasia of primary teeth in chronic renal failure. AB - Chronic renal failure (CRF) in the first years of life is associated with developmental defects of enamel in the permanent dentition. We investigated if CRF also affects the primary (deciduous) dentition. Thirty-one children with CRF on conservative treatment (n = 12) or on renal replacement therapy (n = 19) underwent dental inspection. In addition, 18 CRF children provided an exfoliated deciduous tooth for microscopic examination. Enamel defects were detected in a total of 12 children (31%), either clinically or microscopically. Of the 7 children affected clinically, 6 (19% of all examined) presented localized hypoplasia of the primary canines, which was found only in 3% of healthy control children: 1 patient had generalized pitted enamel hypoplasia. By microscopy, 5 of 10 primary canines examined showed enamel hypoplasia localized exclusively in enamel formed after birth. The "birth line," a visible structure within the primary enamel, was always present, which excludes a prenatal onset of the defects. Of the 12 patients with an enamel defect, 9 had a documented onset of CRF within the first 7 weeks of life. We conclude that renal disease leading to CRF may affect enamel formation of primary teeth in early postnatal life, resulting in lesions different from those observed in the secondary dentition. PMID- 10100295 TI - Cerebral vascular complication and hyperhomocysteinemia in a cystinotic uremic child. AB - We report a 13-year-old girl with nephropathic cystinosis on chronic peritoneal dialysis who presented with two episodes of stroke. Laboratory evaluation showed severe hyperhomocysteinemia (108 mumol/l). Further testing revealed that she was homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) gene. Treatment with folic acid and vitamin B12 lowered plasma homocysteine to less than 20 mumol/l. No further episodes of stroke occurred over a follow-up of 12 months. Homocysteine levels should be measured in patients with chronic renal failure, since simple and safe treatment with folic acid and vitamin B12 is effective in lowering the plasma homocysteine level in patients with the thermolabile MTHFR allele. PMID- 10100296 TI - Should hyperlipidemia in children with the nephrotic syndrome be treated? AB - The pathogenesis, clinical significance, and treatment options of the disturbances in lipid metabolism in children with persistent nephrotic syndrome are reviewed. The lipoprotein profile is characterized by elevations of total plasma cholesterol and often triglycerides, elevated very low-density lipoprotein and low-density lipoprotein cholesterol, whereas high-density lipoprotein cholesterol levels are variable; plasma levels of the atherogenic and thrombogenic lipoprotein(a) are also elevated. The pathophysiology of nephrotic dyslipoproteinemia is multifactorial, including both an increased hepatic synthesis and a diminished plasma catabolism of lipoproteins. There is a rationale for treatment, since dyslipidemia may contribute to the development of atherosclerosis and the progression of chronic renal failure. However, the benefits of treatment with lipid-lowering drugs have not been proven. Short-term studies in adults with nephrotic syndrome have documented safety and efficacy of lipid-lowering drugs, including hydroxymethylglutaryl-CoA reductase inhibitors ("statins"), bile acid sequestrants, fibric acids, fish oil, and probucol. Statins are the most-effective mediation, resulting in a decrease of total cholesterol levels by about 30%-40%. Prospective controlled studies in children evaluating efficacy and safety of lipid-lowering drugs are needed. PMID- 10100297 TI - Prehepatic metabolism of drugs--a mechanism for low and variable oral bioavailability. PMID- 10100298 TI - Ureterocystoplasty in patients with small-capacity, non-compliant bladders. PMID- 10100299 TI - "5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter,". PMID- 10100301 TI - Subject-by-formulation interaction in determinations of individual bioequivalence: bias and prevalence. AB - PURPOSE: 1. To determine properties of the estimated variance component for the subject-by-formulation interaction (sigma D2) in investigations of individual bioequivalence (IBE), and 2, to evaluate the prevalence of interactions in replicate-design studies published by FDA. METHODS: Four-period crossover studies evaluating IBE were simulated repeatedly. Generally, the true bioequivalence of the two formulations, including sigma D2 = 0, was assumed. sigma D2 was then estimated in a linear mixed-effect model by restricted maximum likelihood (REML). The same method was applied for estimating sigma D2 for the data sets of FDA. RESULTS: 1. sigma D estimated by REML was positively biased. The bias and dispersion of the estimated sigma D increased approximately linearly with the estimated within-subject standard deviation for the reference formulation (sigma WR). Only a small proportion of the estimated sigma D exceeded the estimated sigma WR. 2. Distributions of the estimated sigma D were evaluated. At sigma WR = 0.30, a level of estimated sigma D = 0.15 was exceeded, by random chance, with a probability of about 25%. 3. Importantly, the behaviour of the sigma D2 values estimated from the FDA data sets was similar to that exhibited by the simulated estimates of sigma D2 which were generated under the conditions of true bioequivalence. CONCLUSIONS: 1. sigma D estimated by REML is biased; the bias increases proportionately with the estimated sigma WR. Consequently, exceeding a fixed level of sigma D (e.g., 0.15) does not indicate substantial interaction. 2. The data sets of FDA are compatible with the hypothesis of sigma D2 = 0. Consequently, they do not demonstrate the prevalence of subject-by-formulation interaction. Therefore, it could be sufficient and reasonable to evaluate bioequivalence from 2-period crossover studies. PMID- 10100300 TI - Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives. AB - Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance. PMID- 10100302 TI - The effect of hormones on the expression of five isoforms of UDP glucuronosyltransferase in primary cultures of rat hepatocytes. AB - PURPOSE: To investigate the direct effects of sex hormones, growth hormone, thyroid hormones and dexamethasone on the regulation of UDP glucuronosyltransferase (UGT). METHODS: Rat hepatocytes were cultured on matrigel and treated with various hormones. Northern blot analysis was carried out using cDNA probes to family 1 and family 2 isoforms. RESULTS: Treatment with 10(-5) M testosterone increased the mRNA levels of UGT 2B1 by 29% and UGT2B3 by 32%. Incubation of growth hormone (10 mU) with hepatocytes suppressed the expression of UGT2B1 and UGT2B3 by 17% and 38%, respectively. T3 administration resulted in a time and dose-dependent effect on the expression of UGT 1 isoforms, with increased UGT1A6 by 70%, and decreased UGT1A1 by 38% and UGT1A5 by 35%. All UGT isoforms except UGT 1A6 studied in this assay were up-regulated by dexamethasone, but to different degrees. The regulation of UGT1A1 and UGT2B1 by dexamethasone was dose and time dependent, and the induction of dexamethasone in the expression of UGT1A1 and UGT2B1 was blocked by cycloheximide but not dichloro-1-D ribofuranosylbenzimidazole. CONCLUSIONS: This study demonstrates that multiple hormones take part in the regulation of UGT mRNA expression in the rat and individual genes can be differentially modulated. PMID- 10100303 TI - Liposomes with incorporated MHC class II/peptide complexes as antigen presenting vesicles for specific T cell activation. AB - PURPOSE: The purpose of this study was to design a well-characterized liposomal carrier system for multivalent antigen presentation in order to activate T cells. METHODS: MHC class II molecules were loaded with peptide and subsequently reconstituted into liposomes. A FACS assay was developed to monitor peptide loading and MHC class II incorporation in the liposomes. For in vitro testing of the resulting MHC class II/peptide liposomes, a T cell hybridoma assay was employed. RESULTS: The FACS assay provided a qualitative means to visualize the amount of incorporated MHC class II and peptide molecules that were oriented in the appropriate way for antigen presentation to the T cells. Interestingly, when MHC class II molecules were loaded with the appropriate peptide prior to liposome incorporation, such liposomes were fully capable of inducing IL-2 production of a T cell hybridoma. CONCLUSIONS: This is the first article showing that MHC class II/peptide liposomes can serve as 'artificial antigen presenting cells' for activation of a CD4+ T cell hybridoma. As compared to soluble MHC class II/peptide complexes, the multivalency of liposomal complexes may be an important advantage when studying possible applications in immunotherapy. PMID- 10100304 TI - Prediction of membrane permeability to peptides from calculated dynamic molecular surface properties. AB - PURPOSE: To develop a theoretical method for prediction of transcellular permeability to peptides. METHODS: The dynamic molecular surface properties of 19 oligopeptide derivatives, divided into three homologous series were calculated. The dynamic molecular surface properties were compared with commonly used experimental predictors of membrane permeability such as partition coefficients. Relationships between the dynamic molecular surface properties and intestinal epithelial permeability, as determined in Caco-2 cell monolayers, were used to develop a model for prediction of the transmembrane permeability to the oligopeptide derivatives. RESULTS: A theoretical model was derived which takes both the polar and non-polar part of the dynamic molecular surface area of the investigated molecule into consideration. The model provided a strong relationship with transepithelial permeability for the oligopeptide derivatives. The predictability of transepithelial permeability from this model was comparable to that from the best experimental descriptor. CONCLUSIONS: To our knowledge, this is the first example of a theoretical model that gives a satisfactory relationship between calculated molecular properties and epithelial permeability to peptides by accounting for both the hydrogen bonding capacity and the hydrophobicity of the investigated molecule. This model may be used to differentiate poorly absorbed oligopeptide drugs at an early stage of the drug discovery process. PMID- 10100305 TI - Permeation of PEO-PBLA-FITC polymeric micelles in aortic endothelial cells. AB - PURPOSE: To determine aortic endothelial cells permeation ability and mechanisms of the aqueous block copolymeric micelles, poly(ethylene oxide)-poly (beta-benzyl L-aspartate) (PEO-PBLA) chemically conjugated with fluroescein isothiocyanate (FITC) by transport study and confocal laser scanning microscopy. METHODS: The block copolymers' PEO-PBLA-FITC was first synthesized and characterized by gel permeation chromatography (GPC) reflect index, UV, fluorescence detectors, and critical micelles concentrations (CMC), and atomic force microscopy (AFM). Permeation ability and mechanisms of polymeric micelles in aortic endothelial cells were evaluated by incubating with NaF, NaN3, wortmannin, cytochalasin B inhibitors, at 20 degrees C, and under reverse conditions. FITC and latex particles (40 nm) were also used for comparison of transport ability. The extent of localization of uptake polymeric micelles was established by confocal laser scanning microscopy. RESULTS: The size of the aqueous PEO-PBLA-FITC polymeric micelles was detected at around 56 nm with unimodal distribution by AFM. The CMC test revealed the fluorescence intensity increased to around 0.01-0.05 mg/ml. NaF, NaN3, wortmannin, cytochalasin B, 20 degrees C, and reverse experiments inhibited the absorption of polymeric micelles through aortic endothelial cells with apparent permeability coefficients (P) of 18.07 +/- 1.03 to 12.98 +/- 0.93, 11.31 +/- 0.77, 12.44 +/- 1.23, 6.40 +/- 0.23, 11.11 +/- 0.46, and 10.22 +/- 1.09 x 10(-7) cm/sec, respectively. Also, the permeation of FITC and latex on aortic endothelial cells was 70.02 +/- 4.71, and 2.05 +/- 0.41 x 10(-7) cm/sec, respectively. Confocal laser microscopy showed that fluorescent compounds were distributed in the intracellular cytoplasm and nucleus. CONCLUSIONS: PEO-PBLA FITC copolymeric micelles in an aqueous system were transported by energy dependent endocytosis with 18.07 x 10(-7) cm/sec penetrated range and were localized on intracellular and nucleus endothelial cells. PMID- 10100306 TI - Net secretion of furosemide is subject to indomethacin inhibition, as observed in Caco-2 monolayers and excised rat jejunum. AB - PURPOSE: To determine if intestinal secretion occurs for the poorly bioavailable diuretic, furosemide. METHODS: Jejunal segments of male Sprague-Dawley rats were mounted on diffusion chambers, and the permeation of furosemide was measured across the excised tissue in both directions. Studies were repeated using cultured epithelia from adenocarcinoma cells (Caco-2) grown on filter inserts mounted in 6-well plates. Temperature-dependence and chemical inhibition by indomethacin was also tested using the cell culture model. RESULTS: Net secretion from rat intestine of over 3-fold was observed for 20 microM furosemide. Net secretion of furosemide by Caco-2 cells was over 300% greater than for intestinal segments (10-fold vs. 3-fold). For both models, a decrease in furosemide transport in the direction of secretion was observed in the presence of indomethacin (100 microM), although only results using the Caco-2 cells showed in increase in the absorptive transport. Furosemide secretion from Caco-2 cells decreased with decrease in temperature from 37 degrees C to 4 degrees C, suggesting a carrier-mediated process. CONCLUSIONS: Furosemide appears to be secreted in the small intestine. These preliminary results indicate that furosemide bioavailability may be limited by an intestinal transporter. PMID- 10100307 TI - Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption- theoretical approach. AB - PURPOSE: To evaluate the effects of gut metabolism and efflux on drug absorption by simulation studies using a pharmacokinetic model involving diffusion in epithelial cells. METHODS: A pharmacokinetic model for drug absorption was constructed including metabolism by CYP3A4 inside the epithelial cells, P-gp mediated efflux into the lumen, intracellular diffusion from the luminal side to the basal side, and subsequent permeation through the basal membrane. Partial differential equations were solved to yield an equation for the fraction absorbed from gut to the blood. Effects of inhibition of CYP3A4 and/or P-gp on the fraction absorbed were simulated for a hypothetical substrate for both CYP3A4 and P-gp. RESULTS: The fraction absorbed after oral administration was shown to increase following inhibition of P-gp. This increase was more marked when the efflux clearance of the drug was greater than the sum of the metabolic and absorption clearances and when the intracellular diffusion constant was small. Furthermore, it was demonstrated that the fraction absorbed was synergistically elevated by simultaneous inhibition of both CYP3A4 and P-gp. CONCLUSIONS: The analysis using our present diffusion model is expected to allow the prediction of in vivo intestinal drug absorption and related drug interactions from in vitro studies using human intestinal microsomes, gut epithelial cells, CYP3A4-expressed Caco-2 cells, etc. PMID- 10100308 TI - Intracranial delivery of recombinant nerve growth factor: release kinetics and protein distribution for three delivery systems. AB - PURPOSE: Three different polymeric delivery systems, composed of either poly(ethylene-co-vinyl acetate) (EVAc) or poly(lactide-co-glycolide) (PLGA), were used to administer recombinant human nerve growth factor (rhNGF) intracranially in rats. METHODS: The delivery systems were characterized with respect to release kinetics, both in the brain and in well-stirred buffer solutions. RESULTS: During incubation in buffered saline, the delivery systems released rhNGF in distinct patterns: sustained (EVAc), immediate (PLGA1) and delayed (PLGA2). One 10-mg delivery system was implanted in each rat and an ELISA technique was used to determine the amount of rhNGF in 1-mm coronal brain slices produced immediately after removal of the delivery system. High levels of rhNGF (as high as 60,000 ng in a brain slice of approximately 50 microliters) were recovered from the brain tissue at 1, 2, and 4 weeks after implantation. With all three delivery systems, the amount of rhNGF in each brain slice decreased exponentially with distance from the implant site: the distance over which concentration decreased by 10-fold was 2-3 mm for all delivery systems. When rhNGF release was moderate (10 to 200 ng rhNGF/day), the total amount of rhNGF in the brain increased linearly with release rate, suggesting an overall rate of rhNGF elimination of 0.4 hr-1 or a half-life of 1.7 hr. With higher release rates (500 to 50,000 ng rhNGF/day), total amounts of rhNGF in the brain were considerably higher than anticipated based on this rate of elimination. CONCLUSIONS: Polymeric controlled release can provide high, localized doses of rhNGF in the brain. All of the experimental data were consistent with penetration of rhNGF through the brain tissue with a diffusion coefficient approximately 8 x 10(-7) cm2/s, which is approximately 50% of the diffusion coefficient in water. PMID- 10100309 TI - The acidic microclimate in poly(lactide-co-glycolide) microspheres stabilizes camptothecins. AB - PURPOSE: The camptothecin (CPT) analogue, 10-hydroxycamptothecin (10-HCPT) has been shown previously to remain in its acid-stable (and active) lactone form when encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres (1). The purpose of this study was to determine the principal mechanism(s) of 10-HCPT stabilization. METHODS: CPTs were encapsulated in PLGA 50:50 microspheres by standard solvent evaporation techniques. Microspheres were eroded in pH 7.4 buffer at 37 degrees C. The ratio of encapsulated lactone to carboxylate was determined by HPLC as a function of time, initial form of drug encapsulated, fraction of co-encapsulated Mg(OH)2, CPT lipophilicity, and drug loading. Two techniques were developed to assess the microclimate pH, including: i) measurement of H+ content of the dissolved microspheres in an 80:20 acetonitrile/H2O mixture and ii) confocal microscopy of an encapsulated pH sensitive dye, fluorescein. RESULTS: The encapsulated carboxylate converted rapidly to the lactone after exposure to the release media, indicating the lactone is favored at equilibrium in the microspheres. Upon co-encapsulation of Mg(OH)2, the trend was reversed, i.e., the lactone rapidly converted to the carboxylate form. Measurement of -log(hydronium ion activity) (paH*) of dissolved microspheres with pH-electrode and pH mapping with fluorescein revealed the presence of an acidic microclimate. From the measurements of H+ and water contents of particles hydrated for 3 days, a microclimate pH was estimated to be in the neighborhood of 1.8. The co-encapsulation of Mg(OH)2 could both increase the paH* reading and neutralize pH in various regions of the microsphere interior. Varying the drug lipophilicity and loading revealed that the precipitation of the lactone could also stabilize CPT. CONCLUSIONS: PLGA microspheres prepared by the standard solvent evaporation techniques develop an acidic microclimate that stabilizes the lactone form of CPTs. This microclimate may be neutralized by co-encapsulating a base such as Mg(OH)2, as suggested by previous work with poly(ortho esters) (2). PMID- 10100310 TI - Protein inhalation powders: spray drying vs spray freeze drying. AB - PURPOSE: To develop a new technique, spray freeze drying, for preparing protein aerosol powders. Also, to compare the spray freeze-dried powders with spray-dried powders in terms of physical properties and aerosol performance. METHODS: Protein powders were characterized using particle size analysis, thermogravimetric analysis, scanning electron microscopy, X-ray powder diffractometry, and specific surface area measurement. Aerosol performance of the powders was evaluated after blending with lactose carriers using a multi-stage liquid impinger or an Anderson cascade impactor. Two recombinant therapeutic proteins currently used for treating respiratory tract-related diseases, deoxyribonuclase (rhDNase) and anti IgE monoclonal antibody (anti-IgE MAb), were employed and formulated with different carbohydrate excipients. RESULTS: Through the same atomization but the different drying process, spray drying (SD) produced small (approximately 3 microns), dense particles, but SFD resulted in large (approximately 8-10 microns), porous particles. The fine particle fraction (FPF) of the spray freeze dried powder was significantly better than that of the spray-dried powder, attributed to better aerodynamic properties. Powders collected from different stages of the cascade impactor were characterized, which confirmed the concept of aerodynamic particle size. Protein formulation played a major role in affecting the powder's aerosol performance, especially for the carbohydrate excipient of a high crystallization tendency. CONCLUSIONS: Spray freeze drying, as opposed to spray drying, produced protein particles with light and porous characteristics, which offered powders with superior aerosol performance due to favorable aerodynamic properties. PMID- 10100311 TI - A polysorbate-based non-ionic surfactant can modulate loading and release of beta lactoglobulin entrapped in multiphase poly(DL-lactide-co-glycolide) microspheres. AB - PURPOSE: The goal of the present paper was to investigate the role of a surfactant, Tween 20, in the modulation of the entrapment and release of beta lactoglobulin (BLG) from poly (DL-lactide-co-glycolide) microspheres. METHODS: Poly(DL-lactide-co-glycolide) microspheres containing BLG were prepared by a water-in-oil-in-water emulsion solvent procedure. Tween 20 was used as a surfactant in the internal aqueous phase of the primary emulsion. BLG entrapment efficiency and burst release were determined. Displacement of BLG from microsphere surface was followed by confocal microscopy observations and zeta potential measurements, whereas morphological changes were observed by freeze fracture electron microscopy. RESULTS: Tween 20 was shown to increase 2.8 fold the encapsulation efficiency of BLG without any modification of the stability of the first emulsion and the viscosity of the internal aqueous phase. In fact, Tween 20 was shown to be responsible for removing the BLG molecules that were adsorbed on the particle surface or very close to the surface as shown by confocal microscopy and zeta potential measurements. Tween 20 reduced the number of aqueous channels between the internal aqueous droplets as well as those communications with the external medium. Thus, the more dense structure of BLG microspheres could explain the decrease of the burst release. CONCLUSIONS: These results constitute a step forward in the improvement of existing technology in controlling protein encapsulation and delivery from microspheres prepared by the multiple emulsion solvent evaporation method. PMID- 10100312 TI - Influence of crystal habit on trimethoprim suspension formulation. AB - PURPOSE: The role of crystal habit in influencing the physical stability and pharmacokinetics of trimethoprim suspensions was examined. METHODS: Different habits for trimethoprim (TMP) were obtained by recrystallizing the commercial sample (PD) utilizing solvent-change precipitation method. Four distinct habits (microscopic observation) belonging to the same polymorphic state (DSC studies) were selected for studies. Preformulation and formulation studies were carried out on suspension dosage forms containing these crystals. The freshly prepared suspensions were also evaluated for their pharmacokinetic behaviour on healthy human volunteers using a cross over study. RESULTS: Variation of crystallization conditions produces different habits of TMP. Among the different crystal habits exhibiting same polymorphic state, the most anisometric crystal showed best physical stability in terms of sedimentation volume and redispersibility. However, habit did not significantly affect the extent of TMP excreted in urine. CONCLUSIONS: Modification of surface morphology without significantly altering the polymorphic state can be utilized for improving physical stability of TMP suspensions. However, the pharmacokinetic profile remains unaltered. PMID- 10100313 TI - Evaluation of the feasibility and use of a prototype remote drug delivery capsule (RDDC) for non-invasive regional drug absorption studies in the GI tract of man and beagle dog. AB - PURPOSE: Evaluate a prototype Remote Drug Delivery Capsule (RDDC) for use in beagle dogs and human volunteers for non-invasive drug absorption studies in different regions of the gastrointestinal tract. METHODS: The device was dual radiolabeled and GI transit of the RDDC was monitored by gamma scintigraphy. Beagles were used initially to demonstrate the functional utility of the device where a solution of ranitidine hydrochloride (150 mg) was non-invasively delivered to the stomach, proximal small intestine and distal small intestine. A subsequent first time in human study enrolled twelve healthy male volunteers where the intended site of release was the stomach, early small bowel, distal small bowel or colon. RESULTS: Preliminary studies conducted in beagles indicated that the RDDC operated successfully and the onset of ranitidine serum levels were dependent on the time of capsule activation and site of drug release. Results from the human study showed that all twelve subjects swallowed the device with no discomfort. Mean gastric emptying of the RDDC was 1.50 +/- 1.28 h (range = 0.25 to 4.25 h), and total small intestine transit was 4.79 +/- 1.82 h (range = 2.00 to 8.25 h). The capsule was retrieved from the feces at 30.25 +/- 15.21 h (range = 14.12 to 74.25 h) and there were no reported adverse events. The prototype RDDC operated successfully in nine of the twelve human volunteers and the cause for the three failures was attributed to mechanical failure while the electronics assembly performed favorably. CONCLUSIONS: This prototype remote control capsule was shown to be well tolerated and functional to use in human volunteers as well as beagles. The application of the device coupled with gamma scintigraphy has the potential to be a valuable and rapid method to non-invasively evaluate regional drug absorption in the gastrointestinal tract under conditions that are both pharmaceutically and physiologically meaningful. PMID- 10100314 TI - The effect of in vivo dissolution, gastric emptying rate, and intestinal transit time on the peak concentration and area-under-the-curve of drugs with different gastrointestinal permeabilities. AB - PURPOSE: To theoretically investigate the impact of gastric emptying half-time, intestinal transit time and the time for 85% in vivo dissolution on the peak concentration and area-under-the curve of model drugs. METHODS: Simulations were performed using mathematical models of gastrointestinal physiology and pharmacokinetics of model drugs with different gastrointestinal permeability. They were used to investigate the effect of different permutations of gastric emptying times, intestinal transit times, dissolution rates and effective permeabilities on the maximum plasma drug concentration and the area-under-the curve of immediate release tablets relative to an oral solution (i.e., Cmax(tablet)/Cmax(solution) and AUC(tablet)/AUC(solution)). RESULTS: The higher the permeability of the drug, the more sensitive the Cmax ratio is to dissolution rate and gastric emptying rate. As the intestinal transit time becomes more rapid, the sensitivity to T85% dissolution time and gastric emptying half-time increases. There is less dependence for the AUC ratio on the gastric emptying time and dissolution rate. CONCLUSIONS: Under the assumptions of the models, the criterion of 85% dissolution in 15 minutes (T85%) for classifying a rapidly dissolving drug product is relatively conservative since the Cmax ratio exceeded 0.8 for a T85% dissolution time of one hour and a gastric emptying half-time faster than 0.2 hour over a wide range of permeabilities. PMID- 10100315 TI - Enantioselective synthesis and pharmacological evaluation of a new type of verapamil analog with hypotensive and calcium antagonist activities. AB - PURPOSE: The syntheses and evaluation for cardiovascular activity in the rat of both enantiomers of a verapamil analog in which the cyano group has been replaced by hydroxyl. METHODS: (+)- and (-)-alpha-[3-[[2-(3,4 Dimethoxyphenyl)ethyl]methylamino]propyl]- 3,4-dimethoxy-alpha-(1-methyl ethyl)benzyl alcohol were prepared from chiral sulfoxides produced by microbial biotransformations using Mortierella isabellina ATCC 42613 or Helminthsporium species NRRL 4671, and were examined for hypotensive and calcium antagonist activity using anaesthetized normotensive rats and isolated rat aorta and atria. RESULTS: The analogs showed a pharmacological profile similar to that exhibited by verapamil, possessing a remarkable hypotensive activity, accompanied by a significant bradycardia, in anaesthetized normotensive rats. In vitro, these analogs displayed clear inhibitory effects: in isolated rat aorta they inhibited, in a concentration-dependent fashion, the contractions and 45Ca2+ uptake induced by norepinephrine and high KCl, and in isolated rat atria the analogs considerably decreased the rate of contraction (negative chronotropic effects). No significant differences between the quantitative cardiovascular effects produced by the two enantiomers of the verapamil analogs were observed. CONCLUSIONS: The results suggest that, like that of verapamil, the cardiovascular activity exhibited by the new compounds seems to be due, at least in part, to a blockage of transmembrane calcium channels present in vascular smooth muscle cells. PMID- 10100316 TI - Pharmacokinetics of aminolevulinic acid after intravesical administration to dogs. AB - PURPOSE: To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. METHODS: Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. RESULTS: Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. CONCLUSIONS: These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation. PMID- 10100317 TI - Enhanced antinociception of the model opioid peptide [D-penicillamine] enkephalin by P-glycoprotein modulation. AB - PURPOSE: This study was conducted to examine the influence of P-glycoprotein (P gp) modulation on the pharmacodynamics of the model opioid peptide DPDPE. METHODS: Mice (n = 5-7/group) were pretreated with a single oral dose of the P-gp inhibitor GF120918 (25 or 250 mg/kg) or vehicle. 3H-DPDPE (10 mg/kg) or saline was administered 2.5 hr after pretreatment. Antinociception was determined, and blood and brain tissue were obtained, 10 min after DPDPE administration. RESULTS: A significant difference (p < 0.001) in DPDPE-associated antinociception was observed among mice pretreated with a 25- (83 +/- 16% MPR) or 250- (95 +/- 5% MPR) mg/kg dose of GF120918 in comparison to mice pretreated with vehicle (24 +/- 14% MPR) or mice receiving GF120918 without DPDPE (12 +/- 8% MPR). A significant difference (p < 0.01) in brain tissue DPDPE concentration also was observed among treatment groups [25 +/- 6 ng/g (vehicle), 37 +/- 11 ng/g (25 mg/kg GF120918), 70 +/- 8 ng/g (250 mg/kg GF120918)]. In contrast, blood DPDPE concentrations were not statistically different between groups (678 +/- 66, 677 +/- 130, and 818 +/- 236 ng/ml for vehicle, GF120918 [25 mg/kg], and GF120918 [250 mg/kg], respectively). A single 100-mg/kg i.p. dose of (+)verapamil increased the brain:blood DPDPE concentration ratio by approximately 70% relative to saline treated control mice (0.139 +/- 0.021 vs. 0.0814 +/- 0.0130, p < 0.01), a change in partitioning similar to that observed with the low dose of GF120918. These data provide further support for a P-gp-based mechanism of brain:blood DPDPE distribution. CONCLUSIONS: The present study demonstrates that GF120918 modulates blood-brain disposition and antinociception of DPDPE. Coadministration of a P-gp inhibitor with DPDPE may improve the pharmacologic activity of this opioid peptide. PMID- 10100318 TI - Estimation of intradermal disposition kinetics of drugs: I. Analysis by compartment model with contralateral tissues. AB - PURPOSE: The objectives of dermal application of drugs are not only systemic therapeutic, but also local ones. We would expect its intradermal kinetics to be dependent on its therapeutic purpose. To develop more efficient drugs for local or systemic therapeutics, it will be important to estimate quantitatively the intradermal disposition of drugs applied topically. We tried, therefore, to develop the compartment model to describe the intradermal disposition kinetics after topical application of drugs. METHODS: In vivo percutaneous absorption study for antipyrine, a model compound, was performed using rats with tape stripped skin, using the assumption that the stratum corneum permeability to drugs would be improved enough not to be a rate-limiting process. RESULTS: To analyze the results obtained, a 4-compartment model, composed of donor cell, viable skin, muscle, and plasma compartments, was applied. Although the fitting lines obtained could describe the concentration-time profiles of antipyrine in each compartment very well, the concentration profiles in the contralateral tissues were extensively overestimated. Therefore, we developed a 6-compartment model which included the viable skin and muscle in the contralateral site, and analysed the concentration-time curve of each compartment. The fitting curves were in good agreement with the experimental data for all the compartments including the contralateral viable skin and muscle, and thus, this model was recognized to be adequate for the estimation of intradermal kinetics after topical application. Judging from the obtained values of clearance from viable skin to plasma and from viable skin to muscle, about 80% of antipyrine penetrated into viable skin, which suggested it was absorbed into circulating blood and 20% was transported to muscle under viable skin. CONCLUSIONS: Pharmacokinetic analysis using the 6-compartment model would be very useful for the estimation of local and systemic availability after topical application of drugs. PMID- 10100319 TI - Effects of hyperlipidemia on the pharmacokinetics of nifedipine in the rat. AB - PURPOSE: The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. METHODS: Poloxamer 407 (P407) induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg-1 given i.v., i.p. and p.o.). Total plasma cholesterol levels increased from 0.82-2.02 to 5.27-11.05 mmol L-1 48 h post P407 administration (1 g kg-1, i.p.). Protein binding studies were conducted by an ultrafiltration method. RESULTS: Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and i.p. doses, respectively, thereby increasing AUC0-infinity, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0-infinity was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. CONCLUSIONS: The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out. PMID- 10100320 TI - Enhanced accumulation of sialyl Lewis X-carboxymethylpullulan conjugate in acute inflammatory lesion. AB - PURPOSE: E-selectin is a cell adhesion molecule that is specifically expressed in the inflammatory vascular endothelium in response to cytokines such as IL-1 beta and TNF-alpha, and interacts with specific ligands containing sialyl Lewis X (Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc-, SLex). In order to investigate the ability of E-selectin ligands to target the inflammatory site, the tissue distribution of carboxymethylpullulan (CMPul) modified with SLex was studied. METHODS: CMPul conjugates with various saccharides containing SLex and monovalent SLex were intravenously administered to mice with ear edema induced by arachidonic acid, and their distributions to the inflamed ear and other tissues were studied. To determine the microdistributions of these compounds, the inflamed ear was subjected to microautoradiography. RESULTS: After intravenous administration AUC0-24h of SLex-CMPul, which binds to E-selectin, in the inflamed ear was about 300-fold and 2.5-fold higher than that of monovalent SLex and CMPul conjugated with other saccharides, which can not serve as ligands for E-selectin. Microautoradiography also revealed SLex-CMPul accumulated at the microvessels in the inflammatory lesions. CONCLUSIONS: SLex-CMPul was found to have the potential to target drugs to the inflammatory lesion. PMID- 10100321 TI - Peptidoleukotriene (PLT) release and absorption from the airways of the isolated perfused guinea pig lung following chemical and antigenic challenge. AB - PURPOSE: To study the release and absorption of peptidoleukotrienes (PLTs) from the airways of the guinea pig lung following calcium ionophore A23187 (CI), benzalkonium chloride (BAC), ethylene diamine tetra-acetic acid (EDTA) or ovalbumin (OA) challenge. METHODS: PLT C4/D4/E4 were quantified in the perfusate of the isolated perfused guinea pig lung (IPGPL) following intratracheal administration of CI, BAC, EDTA or OA in different doses. The formation and airway-to-perfusate transfer kinetics of PLTs were analyzed by fitting mean data for cumulative PLT in perfusate vs. time to an A-->B-->C first-order release and transfer model, with dose-dependent transfer rate constants. RESULTS: CI induced apparent first order release of PLTs with a t1/2 approximately equal to 1.2 minutes. The amount of PLT released was CI dose-dependent, as was the airway-to perfusate transfer rate constant. These reached maxima of 0.254 microgram and 0.0557 min.-1, respectively, around a CI dose of 100 micrograms. In OA-sensitized IPGPL preparations, OA induced a similar dose-dependent release of PLTs, although the rates of PLT release were much greater and more variable than those seen with CI. In OA sensitized IPGPL preparations, at an OA dose of 1000 micrograms, the maximum amount of PLT released was 0.289 micrograms and the maximal airway-to perfusate transfer rate constant was 0.0229 min-1. BAC and EDTA failed to induce quantifiable PLT release from the airways. CONCLUSIONS: Rapid release of the inflammatory mediators, PLT C4/D4/E4, could be induced in the unsensitized IPGPL by CI, and in the sensitized IPGPL by OA. Transfer into perfusate occurred in both cases with dose-dependent t1/2 ranging from 12.4 through 57.8 minutes. PMID- 10100322 TI - Confocal imaging of peripheral regions of intact rat lungs following intratracheal administration of 6-carboxyfluorescein, FITC-insulin, and FITC dextran. AB - PURPOSE: This study compared the pulmonary disposition of 3 structurally diverse probe molecules following their intratracheal (i.t.) administration to anesthetized rats. METHODS: Following administration of 6-carboxyfluorescein (CF), FITC-insulin (FI) and FITC-dextran (FD), lungs were removed, inflated, perfused with a marker dye, and peripheral elements examined with confocal microscopy (CLSFM). RESULTS: At 5 min most of each probe remained within airspaces; the remainder distributed to interstitium, capillaries, Type II cells, and macrophages. At 60 min disposition differed significantly among probes. The smallest (CF, 376 Da) had almost completely exited air-spaces and was found primarily in extracellular interstitial spaces, often behind Type II cells. Disposition was consistent with both entry into peripheral lymphatics and association with peripheral fibers. FI and FD (6 and 10 kDa, respectively) were retained substantially longer within airspaces. In contrast to CF, FI appeared to localize along septal and peripheral fibers, but its disposition was inconsistent with the involvement of peripheral lymphatics. CONCLUSIONS: While all probes were < or = 10 kDa, there was considerable disparity among both their rates of absorption and subsequent disposition within peri-alveolar elements. CLSFM appears to be a useful ancillary tool for studying the pulmonary absorption of drugs and macromolecules. PMID- 10100323 TI - A new method for dissolution studies of lipid-filled capsules employing nifedipine as a model drug. PMID- 10100324 TI - Isradipine interacts with the open state of the L-type calcium channel at high concentrations. AB - Triple mutation of Tyr1485, Met1486 and Ile1493 in the IVS6 segment of alpha 1C-b subunit of the L-type calcium channel results in a loss of the high affinity inhibition by isradipine. The mutant channel (Ch30) yet exhibits a concentration dependent inhibition by isradipine with a 110-fold lower affinity. The mechanisms underlying the remaining low affinity block were investigated. Isradipine accelerated the current decay in Ch30 but not in wild type channel in a concentration dependent manner. Dependence of the current amplitude inhibition on holding potential was parallel in Ch30 and in wild type channels, while the acceleration of current decay in Ch30 was independent of the membrane potential. The recovery from voltage-dependent inactivation was biphasic in both channels and was slowed down by isradipine in the wild type but not in the Ch30 channel. The change of the charge carrier (Ba2+ or Ca2+) and calcium chelator (EGTA or BAPTA) did not affect the acceleration of current decay indicating that isradipine did not interact with the Ca(2+)-inactivated state of the channel. These results demonstrate that the mutations of Ch30 affect selectively the high affinity inhibition of an inactivated channel and unmask a low affinity interaction of isradipine with an open state of the channel. PMID- 10100325 TI - Cloning and characterization of 5'-end alternatively spliced human cholecystokinin-B receptor mRNAs. AB - We report here the cloning and characterization of a 5'-end alternatively spliced human cholecystokinin-B (CCK-B) receptor mRNA. The 5'-end of this CCK-B receptor transcript (termed CCK-BRtx) consisted of exon Ia, present in the ordinary full length CCK-B receptor mRNA (CCK-BRwt), and exon Ib, present in a previously described 5'-end alternatively spliced CCK-B receptor mRNA (CCK-BRt). A short open reading frame preceded the AUG translation initiation codon of the CCK-BRtx. Transfection of COS-7 cells with the CCK-BRtx or CCK-BRt cDNAs did not lead to the appearance of peptidergic and non-peptidergic binding sites. Cell free in vitro translation yielded proteins of approximately 44 kDa (CCK-B receptor) and 40 kDa (CCK-BRt receptor) whereas no 40 kDa product was detected from the cloned CCK-BRtx cDNA. Instead, a protein product of approximately 9 kDa was visualized, the size corresponding to the predicted protein encoded by the short open reading frame. The alternatively spliced CCK-B receptor transcripts were concomitantly expressed with the ordinary full-length CCK-B receptor mRNA in the brain, pancreas, and stomach. The possibility that such transcripts are translated in vivo into truncated CCK-B receptors is discussed. PMID- 10100326 TI - Influence of non-P region domains on selectivity filter properties in voltage gated K+ channels. AB - The selectivity filter in voltage-gated K+ channels is formed at the interface of the pore loops (S5-S6 loop) from four channel subunits. Whereas most K+ channels are essentially impermeable to Na+, the Kv2.1 K+ channel conducts Na+ relatively well in the absence of K+ and selects for K+ over Na+ at least partially by an affinity-based competition mechanism. To examine whether the ability of Kv2.1 to conduct Na+ reflected unique properties of either its S5-S6 loop or channel domains that held the S5-S6 loop in place (the scaffolding), we studied chimeras made from Kv1.3 (which is completely impermeable to Na+) and Kv2.1. Chimeras that contained either the S5-S6 loop from Kv1.3 inserted into the Kv2.1 scaffolding or vice versa both made highly selective K+ channels that conducted Na+ and displayed competition between Na+ and K+ for conduction through the pore: In channels that contained the S5-S6 loop from Kv2.1, concentration-dependent block of Na+ current by either external or internal K+ differed depending on whether Kv2.1 or Kv1.3 donated the scaffolding. These results indicate that neither the S5-S6 loop nor the scaffolding from Kv2.1 possess unique attributes that permit Na+ to conduct through the channel. Furthermore, these results indicate that the competitive interaction between K+ and Na+ at the selectivity filter is determined not only by the S5-S6 loop but also by the scaffolding that holds the S5-S6 loop. PMID- 10100327 TI - Mapping the binding site of the small intestinal peptide carrier (PepT1) using comparative molecular field analysis. AB - The present study was undertaken to examine the relationship between chemical structure (steric and electrostatic fields) and affinity for the small intestinal oligopeptide carrier (PepT1) using comparative molecular field analysis (CoMFA), a three-dimensional approach towards building quantitative structure-activity relationships. Various biological activity parameters (Kt, Jmax, Pc) and molecular descriptors (CoMFA fields, isobutylalcohol/water distribution coefficients) were examined. The resulting field map provides information on the geometry of the binding site cavity and the relative weights of various properties in different site pockets for each of the substrates considered. The results indicate that carrier permeability (Pc), calculated as the ratio of the half-maximal concentration (Kt) and the maximal carrier flux (Jmax), is sensitive to composition, size and hydrophobicity of the ligands. The best model obtained showed a high correlation between the carrier permeability (Pc) and the steric (76.3% contribution) and electrostatic (23.7% contribution) molecular fields with a cross-validated r2 (q2) of 0.754. The model fitted the experimental data with a correlation coefficient of 0.993 and a standard error of 0.041, while the regression line between experimental and calculated Pc had a slope of 0.994 with an intercept of 0.009. These results lead to a better understanding of the molecular requirements for optimal drug-carrier interactions with the intestinal peptide transporter and offers a useful visual aid for designing new potentially interesting structures with affinity for the oligopeptide transporter PepT1. PMID- 10100328 TI - Visualization of internalization and recycling of the gastrin releasing peptide receptor-green fluorescent protein chimera expressed in epithelial cells. AB - Gastrin releasing peptide (GRP) regulates critical gastrointestinal functions via the GRP receptor (GRPR). GRPR internalization and recycling have been proposed to play an important role in the cellular response to GRP. Our aim was to develop a direct method for investigating GRPR trafficking in living cells. A chimeric protein, consisting of GRPR fused to green fluorescent protein (GFP), was expressed in epithelial cells. Ligand and receptor interactions were examined with radiolabeled agonist and fluorescent imaging. In comparison with epithelial cells expressing wild-type GRPR, the GRPR-GFP expressing cells showed similar ligand binding affinity, GRP-stimulated Ca2+ signaling, and GRP-initiated internalization. In GRPR-GFP expressing cells treated with fluorescently labeled ligand, receptor and ligand trafficking was directly visualized. Upon ligand binding, the receptor-ligand complex coalesced into vesicles prior to internalization and migration to the perinuclear space. Whereas a portion of the receptors were observed to return to the plasma membrane, the ligand remained in the perinuclear space. Hyperosmolar solution prevented ligand and receptor internalization, and bafilomycin inhibited receptor recycling. We demonstrate that GRPR-GFP is physiologically similar to wild-type GRPR, and permits direct visualization of intracellular trafficking processes in individual living cells with minimal toxicity over several hours. PMID- 10100329 TI - An extensive and diverse gene family of nicotinic acetylcholine receptor alpha subunits in Caenorhabditis elegans. AB - Using reverse transcription-polymerase chain reactions the transcription of eight novel candidate nicotinic acetylcholine receptor (nAChR) alpha subunit genes has been demonstrated in the nematode Caenorhabditis elegans. Together with five other alpha subunit genes described elsewhere by ourselves (unc-38) and other workers (deg-3, acr-4, Ce21 and acr-6), this is now the largest known family of nAChR alpha subunit genes in a single species. By homology we have identified four groups of alpha subunits: DEG-3-like; ACR-16[Ce21]-like; UNC-38-like and ACR 8-like. Five C. elegans nAChR alpha subunits contain a modification in loop C of the ACh binding site in which the normally conserved Tyr-x-Cys-Cys, is replaced by a distinct motif (Tyr-x-x-Cys-Cys). Variation is also found in the channel lining M2 regions, including the replacement in four subunits of the highly conserved leucine at the 9' position by valine and most notably, the replacement in all ACR-8-like subunits of the highly conserved glutamic acid at the -1' position by histidine. Restrained molecular dynamics simulations have been used to generate homo-pentameric M2 helix bundle models for alpha subunits and possible functional implications examined. The calculated electrostatic potential energy profile for the M2 region of ACR-8 differs strikingly from that of ACR 16[Ce21] largely due to the presence of histidine at the -1' position, suggesting a possible perturbation of nAChR channel action permeability in the presence of this subunit type. PMID- 10100330 TI - Evaluation of a university course to promote physical activity: project GRAD. AB - Project GRAD (Graduate Ready for Activity Daily) evaluates a university course to promote physical activity. In a randomized study, 338 university seniors participated in either an intervention or control course for academic credit, and posttest data were collected on 321. The control course was knowledge-oriented. The intervention course taught behavior change skills in weekly lectures and peer led labs. Physical activity was assessed with 7-Day Physical Activity Recall interviews. The intervention had no significant effects on men. Among women, the intervention increased total physical activity during leisure, strengthening exercises, and flexibility exercise. This university course had the intended effects of promoting healthful patterns of physical activity among women, but no effects were observed on men, who were more active than women at baseline. PMID- 10100331 TI - A generalized rank-order method for nonparametric analysis of data from exercise science: a tutorial. AB - Frequent violations of the assumption that data are normally distributed occur in exercise science and other life and behavioral sciences. When this assumption is violated, parametric statistical analyses may be inappropriate for data analysis. We provide a rationale for using a generalized form of nonparametric analyses based on the Puri and Sen (1985) L treated as a chi 2 approximation. If data do not meet the assumption of normality, this nonparametric approach has substantial power and is easy to use. An advantage of this generalized technique is that ranked data may be used in standard parametric statistical programs widely available on desktop and mainframe computers, for example, regression, analysis of variance (ANOVA), multivariate analysis of variance (MANOVA) within BioMed, SAS, SPSS. Once the data are ranked and analyzed with these programs, the only adjustment required is to use a standard formula to calculate the nonparametric test statistic, L, instead of the parametric test statistic (e.g., F). Thus, rank order nonparametric models become parallel with their parametric counterparts allowing the researcher to select between them based on characteristics of the data distribution. Examples of this approach are provided using data from exercise science for regression, ANOVA (including repeated measures) and MANOVA techniques from SPSSPC. Using these procedures, researchers can easily examine data distributions and make an appropriate decision about parametric or nonparametric analyses while continuing to use their regular statistical packages. PMID- 10100332 TI - The effects of different knowledge of results spacing and summarizing techniques on the acquisition of a ballistic movement. AB - The present study crossed three knowledge of results summarizing techniques (single-trial KR, summary KR, and average KR) with two spacing conditions (KR on every fifth trial-20%- and KR on every trial-100%). Participants (n = 10 per group) performed 80 acquisition trials of a ballistic movement task involving both a temporal and spatial goal, followed by 30 immediate (10 min) and 30 delayed (2 days) no-KR transfer trials. For the spatial goal, performance was less accurate (absolute constant error) for the 20% spacing condition than the 100% condition during acquisition, but more accurate during delayed transfer. No effects were significant for variable error. For the temporal goal, performance was more accurate for the summary and average conditions than the single-trial KR condition; however, this effect was only present within the 20% spacing condition and only during Block 1 of acquisition. A similar effect held for variable error as well, except that the effect persisted for acquisition and transfer. It was concluded that the spacing of KR is more influential in promoting spatial accuracy than the summarizing of KR. PMID- 10100333 TI - The role of reduced frequency of knowledge of results during constant practice. AB - Two experiments were conducted to further examine the effects of reduced knowledge of results (KR) frequency on the learning of motor skills during constant practice. In Experiment 1, participants in five KR conditions (100% KR, 50% KR-fade, 50% KR-reverse fade, 50% KR-alternative, and 50% KR-random) practiced a movement timing task. In Experiment 2, participants in two KR conditions (100% KR and 50% KR-fade) practiced a waveform reproduction task. The results of both experiments failed to indicate that reduced KR frequency was more effective in promoting learning than the 100% KR conditions. The present study adds to the increasing number of experiments that do not find a benefit of reduced KR frequency on learning in constant practice. PMID- 10100334 TI - The "professional" work of experienced physical education teachers. AB - This study investigates whether experienced physical education teachers perceive the same frustrations and negative orientations as beginning teachers. Furthermore, it considers if the professionalization-deprofessionalization tension is a useful theoretical framework for analyzing the perspectives of experienced physical educators. In-depth interviews were conducted with 11 experienced physical education teachers. Data suggest that in many respects their working conditions and orientations are more supportive and positive than those reported for beginning physical educators. After presenting the teachers' perspectives in terms of their sense of commitment, competence, and power, it is concluded that the professional satisfaction of these experienced teachers can be instructive for improving the working conditions of all teachers. PMID- 10100335 TI - The effectiveness of the Canadian Quality Daily Physical Education program on school physical education. AB - The effectiveness of the Canadian Quality Daily Physical Education (QDPE) program in creating awareness, support, and influencing school based physical education programs was determined using quantitative and qualitative methodologies. Participants included teachers, principals and vice principals, school board officials and trustees, professional agencies and association, and provincial ministry of education officials. Findings showed this national initiative increased awareness and support of QDPE among all participants. Although the influence of this increased awareness and support on school physical education programming was limited, the greatest impact was in time committed to instruction, development of curricula, instruction of classes, delivery of intramural programs, professional development, and student response to physical education. The least impact was on hiring of physical education specialists, the number of staff, and funding for physical education. PMID- 10100336 TI - Description and process evaluation of a physical training program for obese children. PMID- 10100337 TI - MINI-LOGGER--reliability and validity for estimating energy expenditure and heart rate in adolescents. PMID- 10100338 TI - A comparison of peak heart rates elicited by the 1-mile run/walk and the progressive aerobic cardiovascular endurance run. PMID- 10100339 TI - Bandwidth knowledge of results enhances generalized motor program learning. PMID- 10100340 TI - Hrdlicka (1931) revisited: children who run on all fours. PMID- 10100341 TI - [The lung and the tropics]. PMID- 10100342 TI - [Exotic pulmonary mycoses]. AB - The so-called exotic pulmonary mycoses are imported diseases in France. They are infrequent or exceptional and for this reason can be underdiagnosed or recognized with delay. Nevertheless, they are easily treatable infections with available antifungal agents. As a rule, the site of primary infection is the lung with ensuing clearance or chronic local infection and/or dissemination. Immunocompromised hosts are more prone to develop severe forms or reactivation of the disease. PMID- 10100343 TI - [American pulmonary histoplasmosis caused by Histoplasma capsulatum]. AB - American pulmonary histoplasmosis is a deep mycosis imported from North America caused by the inhalation of Histoplasma capsulatum. It is endemic in several countries throughout the world and occasional cases have been reported in France, mainly imported from out lying French territories. The most frequent clinical forms observed in immunocompetent subjects are generally benign or silent and usually limited to a fortuitously discovered pulmonary nodule. Massive exposure may lead to an acute primary invasion producing a miliary aspect. Chronic forms simulating tuberculosis are exceptional. Inversely, opportunistic histoplasmosis in AIDS patients can produce an severe multiple organ disease. Ideally, mycelium should be isolated for diagnosis, a task which is easier in disseminated or operated nodular forms. More often, the epidemiological context, clinical and radiological features, the elimination of differential diagnoses and, retrospectively, serology are sufficient for diagnosis. The clinical course is usually favorable. Itraconazole is the treatment of choice for symptomatic or complicated forms. PMID- 10100344 TI - [Pulmonary parasitoses. General aspects]. AB - Parasite diseases of the lung comprise a wide group of nosological entities. The main parasite diseases of the lung (malaria, ambiasis, bilharziosis, distomatosis, hydatidiasis) as well as the eosinophilic lung will be discussed in specific articles in the journal. Other parasite diseases of the lung are discussed here after studying the general aspects of pulmonary parasite diseases. PMID- 10100345 TI - [Parasitic eosinophilic lungs]. AB - The eosinophilic lung is a term used to identify a heterogeneous group of parasitic diseases leading to common manifestations including alveolar or tissular pulmonary eosinophilia and, classically, radiological visible lesions of the lung. The different clinical presentations--Loffler's syndrome, larva migrans syndrome and tropical pulmonary eosinophilia are analyzed in this article and the particular features of the different causal parasites are discussed. Positive and differential diagnostic procedures in patients with pulmonary eosinophilia due to mycoses, drugs, vasculitis or an unknown cause are detailed. PMID- 10100346 TI - [Pulmonary manifestations associated with malaria]. AB - Pulmonary manifestations are frequently observed in children, pregnant women and travellers with malaria. The pathophysiology of these pulmonary manifestations is poorly understood but would appear to be secondary to an interaction between the parasitized red cells and the pulmonary capillary endothelium. Bronchitis and pneumonia do not directly compromise outcome but, left unrecognized, the delay in diagnosis and treatment may be fatal. Acute respiratory distress in children is the first cause of overmortality, coming before neurological involvement. The acute respiratory distress caused by severe malaria has no specific characteristics. Iatrogenic complications and pulmonary superinfections must be differentiated. The prevention of pulmonary manifestations associated with malaria can easily be accomplished by limiting water intake and carefully monitoring urinary output and weight. Treatment is the same as for acute flare ups in combination with symptomatic respiratory treatment when required. PMID- 10100347 TI - [Pleuropulmonary manifestations of amebiasis]. AB - Amibiasis is the third leading cause of death due to parasitic infections in the world. Amibiasis is endemic in the warm regions of the world with deficient hygiene and socio-economic situations. Entamoeba histolytica is the causal agent of invasive amibiasis, unlike Entamoeba dispar which is not a pathogen for humans. Amibian colitis and amibian abscess of the liver are the most frequent intestinal and extra-intestinal manifestations. Pleuropulmonary complications almost always occur in patients with a liver abscess, the intrathoracic contamination via transphrenic dissemination predominating. Respiratory signs are inaugural in 80% of the cases. Pleuropulmonary ambiasis designates the localization of the amibian infestation, but the clinical expression may vary: pneumonia, lung abscess, pleurisy, hepatobronchial fistulization and more infrequently pulmonary embolism. The preferential localization is the right hemithorax related to abscess in the right lobe of the liver. Left lobe abscesses lead to left-sided pleuropulmonary complications with the risk of rupture into the pericardium. Chocolate-colored pus from a pleural or abscess puncture or vomitus strongly suggests the diagnosis, which is confirmed by highly-positive serology. Metronidazole is the treatment of choice, providing cure without sequellae. In Africa, mortality and morbidity due to ambiasis are high. In Abidjan, 92% of cured patients have sequella, and mortality reaches 15%, the consequence of late diagnosis. PMID- 10100348 TI - [Pulmonary manifestations of schistosomiasis]. AB - Bilharziosis or schistosomiasis is the third leading endemic parasitic disease in the world, following malaria and ambiasis. More than 300 million individuals are infested. Schistomosomes are blood flukes which live in the perivisceral veins. Clinical signs result from ova migrations. Transmitted by urine and feces, the parasite cycle requires intermediary host, usually fresh water snails. Bilharsiosis is endemic in tropical zones where it is a major public health problem closely correlated with the socio-economic conditions. Liver, intestinal or urinary complications, depending on the species, lead to underestimated morbidity and mortality. Pulmonary lesions are attributed to 3 species: S. haematobium, S. mansoni and S. japonicum. Although the lung is mandatory step in the parasite cycle, pulmonary manifestations are limited. They can be acute or chronic depending on the phase of the cycle, but are the most frequent extradigestive localization for S. mansoni. Morbidity due to chronic manifestations is particularly severe and should be prevented whenever possible. PMID- 10100349 TI - [Paragonimiasis]. AB - Paragonimiasis is a helminthic disease of carnivorous animals. Man is infected accidentally. It has a worldwide distribution but is mainly encountered in Southeast Asia, particularly in Korea. Other endemic areas include Africa and South America. Cerebral paragonimiasis is not rare, but pleuropulmonary manifestations are the most prevalent. They include hemoptysis (frequently rusty colored), unilateral or bilateral pleural effusions, and pulmonary infiltrates or cavities. This constellation of symptoms often mimics those of tuberculosis. Cerebral and lung involvement has recently been investigated by CT-scan and NMR. The diagnosis is based on the identification of parasite eggs in sputum or feces, and on ELISA serology. The treatment of choice is praziquantel. PMID- 10100350 TI - [Pulmonary melioidosis]. AB - Melioidosis is most frequently encountered in pulmonary localization. Melioidosis is an infectious disease caused by Burkholderia pseudomallei first described by Whitmore in 1912 in Burma. B. pseudomallei is a Gram negative rod belonging to the Pseudomonadaceae family. Soil and water are the natural reservoirs for the germ which is a specific pathogen for several mammal species. Long endemic in Southeast Asia and several tropical zones, B. pseudomallei has recently been found in temperate zones, including France. Human contamination occurs via the transcutaneous route and often leads to dormant inapparent infection. Many conditions, such as diabetes, renal lithiasis, various circumstances of immunodepression or stress, facilitate clinical manifestations which vary greatly. Pulmonary manifestations may be acute and extensive, producing a torpid pseudo-tuberculous condition or a variety of clinical and radiological features mimicking other diseases. Bacteriological and serological tests may be negative. Exposure in an endemic zone, the notion of a favorable context, weight loss, cavitary images on successive chest x-rays and the presence of extra-pulmonary localizations may be suggestive. Ceftazidime or the amoxicillin-clavulanic acid combination are indicated, but mortality in acute forms still reaches 40%. Relapse can be expected if the treatment duration is too short. PMID- 10100351 TI - [Pulmonic plague]. AB - One hundred years after Yersin discovered Yersinia pestis during the plague epidemic in Hong Kong in 1894, human plague still has not been eliminated. The epidemic in 1994 in India, a country where no cases had been observed since 1996, raised great concern. Plague is an epizootic bacterial infection caused by a Gram negative coccobacillus, Y. pestis, transmitted by the bite of infected fleas. Bubonic plague is the most common form. Other clinical presentations include asymptomatic plague, abortive plague, pharyngeal plague, septicemic plague, meningeal plague, and primary or secondary pneumonic plague which is observed in 5 to 20% of cases. Plague is a highly communicable disease between humans despite antibiotic therapy which has reduced mortality by 80%. The prognosis depends on early diagnosis. Streptomycin and cyclines are the gold standard treatment. PMID- 10100352 TI - [Pulmonary anthrax]. AB - Anthrax is a zoonotic disease caused by Bacillus anthracis. Skin disease is the most common form in humans. Pulmonary anthrax related to the inhalation of airborne germs develops after a silent incubation period of several days and followed by acute respiratory distress. Diagnosis is a difficult task and generally based on demonstration of Bacillus anthracis on direct examination. Despite the sensitivity of B. anthracis to penicillin, treatment is rarely successful. PMID- 10100353 TI - [Respiratory manifestations of leptospirosis. A retrospective study of 91 cases (1978-1984)]. AB - Leptospirosis, an ubiquitous zoonotic disease, is a systemic infection usually producing fever with hepatorenal involvement, meningoenephalitis, and hemorrhage. Respiratory manifestations are less well known but have been described in certain regions such as Southeast Asia or the Reunion Island. From January 1978 through December 1994, 154 cases of documented leptospirosis were admitted to the South Reunion Hospital Center. Pulmonary involvement was observed in 91 of these cases (59.1%) with hemoptysis (37.4%) and radiological evidence of bilateral reticulonodular infiltration (40%). Extra-pulmonary manifestations in most cases suggested leptospirosis at admission. Thirteen consecutive patients underwent endoscopy explorations with bronchoalveolar lavage: intra-alveolar hemorrhage was evidenced in all cases. This highly typical pattern of cytolysis would emphasize (20.8%) when the classical extra-pulmonary signs are too discrete to suggest the diagnosis. In this series, 10 patients required ventilatory assistance and 2 were given corticosteroid boluses for massive hemoptysis. Mortality due to leptospirosis is two-fold higher in cases with pulmonary involvement. PMID- 10100354 TI - [Hantavirus and pulmonary pathology]. AB - The hantavirus pulmonary syndrome recognized in the United States in 1993 quickly brought the formerly little known virus into the limelight. Contrary to what has been written almost everywhere, this is not a "new" virus causing new "emerging" disease. Hantaviruses have been harbored in their natural hosts, three subfamilies of murine rodents, for millions of years. The phylogenetic classifications of these viruses follows that of their hosts, proving close adaptation and contradicting short-term emergence of American serotypes in Eurasia. Certain hantaviruses are the causal agents of renal diseases of variable severity grouped together under the term of hemorrhagic fever with a renal syndrome in Eurasia. Others cause acute respiratory distress syndrome, particularly in North America. Most cases occur in adults and the sex-ratio always favors men, probably due to exposure to airborne rodent ejections. No interhuman contamination is observed. A few dozen cases of hantavirus pulmonary syndrome are reported annually in North America and a few hundred cases in Europe. China is the only country were incidence has been high enough for hundreds of years to lead to an experimentation on vaccines. Hantaviruses are difficult to isolate and diagnosis in humans is based on serology. Improved diagnostic tools have led to a better assessment of the impact of this virus on public health. An epidemic in France in 1996 caused 230 cases while only 808 cases had been registered since 1977. Most of the cases occurred in Northeastern France and were focalized. PMID- 10100355 TI - [Metropolitan pneumologists and exotic diseases]. AB - Due to the increasingly widespread development of international exchanges, physicians, particularly pneumologists, working in metropolitan France may encounter patients with respiratory signs who have travelled or lived in tropical zones. In such cases, history taking, physical examination, imaging, bacteriological and parasitological explorations, pathology and immunology are all precious tools for diagnosis. All possible tropical diseases should be entertained, taking into account the geographical setting and the patient's lifestyle. The pneumologist must not forget that these exotic tropical diseases remain uncommon compared with cosmopolitan causes of lung disease: bacterial infections, tuberculosis, cancer. PMID- 10100356 TI - Degenerative changes of afferent neurons in the lumbosacral dorsal root ganglia following complete urethral obstruction in guinea pigs. AB - OBJECTIVE: The ultrastructural changes in the bladder afferent neurons were examined in the guinea pig following acute complete urethral obstruction. MATERIAL AND METHODS: Complete urethral ligation was carried out in nine guinea pigs under anaesthesia and the animals were sacrificed at 12, 24 and 48 h postoperatively. Three sham-operated animals were sacrificed at 48 h postoperatively as controls. The dorsal root ganglia (DRG) at L6, S1 and S2 spinal segments of the animals in each group were removed and processed for electron microscopic study. RESULTS: In the control groups, all the DRG neurons at L6-S2 segments appeared normal. At 12 h after urethral ligation, a few neurons in the DRG at various segments showed signs of structural changes, notably the mitochondria. Mitochondrial swelling was more pronounced at 24 h, and by 48 h most of them became vacuolated and lysed. It was estimated by semiquantitative study that 18.6% and 22% of DRG neuronal profiles at 24 and 48 h, respectively, displayed severe mitochondrial swelling and vacuolation. CONCLUSIONS: The observed degenerative changes in DRG neurons following complete urethral obstruction may be a cellular reaction in response to the axonal injury elicited by bladder overdistension. This may account for alterations in visceral sensation in patients with acute urinary retention. PMID- 10100357 TI - Morphometry and residual strain in porcine ureter. AB - Recent studies on blood vessels, the heart, trachea and esophagus have shown that these organs in the zero-stress state are not closed circular cross-sections of rings, but open sectors. Any analysis of stress and strain must begin with organs in the zero-stress state. This report presents data on morphometry of the zero stress and no-load states of the porcine ureter, and on residual strains and opening angles. The zero-stress state of the ureter is demonstrated by cutting the ureter into rings and cutting the rings into sectors; each sector is characterized by an opening angle. The outer and inner circumferences, the cross sectional area of the ureteral wall and the number of buckles showed axial variation, with the highest values proximally in the ureter. Residual strain in the circumferential direction was significant, but showed no axial variation. The opening angles were approximately 30 degrees at the most distal and proximal sites and approximately 90 degrees in mid-ureter. The opening angle showed positive correlation to the wall thickness in the zero-stress state, residual strain at the outer circumference and negative correlation to the length of the outer circumference in the zero-stress state. Residual strains must be taken into account when studying physiological problems in which the stresses and strains are important, e.g. the urine transport function of the ureter. PMID- 10100358 TI - Spontaneous subcapsular or perirenal haemorrhage caused by renal tumours. A urological emergency. AB - OBJECTIVE: Spontaneous perirenal haemorrhage is a rare abdominal emergency most commonly caused by solid renal tumours. The aim of this study was to evaluate the efficacy of different diagnostic methods and treatment modalities. MATERIAL AND METHODS: A total of 9 patients (5 women and 4 men) with spontaneous subcapsular or perirenal haemorrhage caused by renal tumours were treated at two Finnish central hospitals over a period of 20 years. RESULTS AND CONCLUSIONS: All the patients presented with flank pain, often severe and associated with a palpable mass and a reduced haemoglobin concentration. Ultrasonography was abnormal in all cases where it was used, but was able to show the tumour and haemorrhage correctly in only one case (13%). Computed tomography had a sensitivity of 71%. Seven patients underwent extrafascial nephrectomy (5 renal cell cancers, 1 malignant oncocytoma and 1 angiomyolipoma) and two with known tuberous sclerosis and bilateral renal angiomyolipomas were treated by superselective embolization. As these few cases were all individual and were collected over a long period of time, general statements about diagnosis and treatment must be approached critically. It may be concluded, however, that spontaneous perirenal haemorrhage is often a surgical emergency necessitating great efforts in terms of diagnosis and treatment. Computed tomography should be performed on all patients nowadays. If the bleeding is caused by a malignant tumour, extrafascial nephrectomy is the treatment of choice. For those with benign tumours selective embolization should be used. PMID- 10100359 TI - Reflex interaction between the proximal urethra and the bladder. A clinical experimental study. AB - OBJECTIVE: Animal experiments have shown that the bladder-cooling reflex is activated by cold stimulation of the bladder and urethra, causing a reflex bladder contraction. In this clinical experimental study, the bladder reflex responses to distension and cooling of the bladder neck and the proximal urethra were investigated. MATERIAL AND METHODS: Twenty-one patients with overactive bladders and documented positive ice water tests were studied. RESULTS: Three patients (14%) responded with reflex bladder contraction by urethral infusion of ice water only, and another 4 patients responded to urethral distension with both warm and cold water. In 4 patients, bladder contraction was induced by a catheter pulling on the bladder neck. CONCLUSION: This study supports the existence of a cold-sensitive reflex system in the human urethra. However, in the experimental situation, both cold and tension-mediated reflexes were more difficult to evoke from the urethra than from the bladder. PMID- 10100360 TI - Incidence and histological findings of unsuspected prostatic adenocarcinoma in radical cystoprostatectomy for transitional cell carcinoma of the bladder. AB - OBJECTIVE: The present study is designed to evaluate the incidence, histological features and significance of prostatic adenocarcinoma in patients undergoing cystoprostatectomy for Transitional Cell Carcinoma (TCC) of the bladder. PATIENTS, MATERIAL AND METHODS: From January 1990 to December 1996, 59 male patients (mean age 66.5 years), with no evidence of prostatic malignancy on preoperative clinical and biochemical assessment, underwent cystoprostatectomy for TCC of the bladder. The bladder was adequately sampled and the entire prostate sectioned at 5-mm intervals and examined histologically, in order to identify unsuspected prostatic cancer (PCa). RESULTS: Sixteen out of 59 patients (27%) were found to have PCa, which was multifocal in 5 cases (31.25%). The mean tumor size was 0.24 cm. The tumors were equally distributed in the anterior and posterior parts of the prostate and in the peripheral and transition zones, with uniform distribution in both prostatic lobes. In 5 patients (31.25%), the single focus of the tumor was in the apex. All were grade I tumors except one, and all were organ-confined with no capsular penetration. The follow-up ranged from 12-74 months (mean 39 months). Within this period, 7 patients died from metastatic bladder cancer. One patient with PCa localized in the prostatic apex had recurrent prostatic disease in the urethro-ileal anastomosis of an orthotopic bladder substitute; he is alive and on androgen deprivation. The remaining patients are relapse-free. CONCLUSIONS: Incidental PCa is quite a common finding in cystoprostatectomy specimens of bladder cancer patients. Its tendency to appear in the apex of the prostate demands careful and complete excision of the organ. PMID- 10100361 TI - Contact laser prostatectomy compared to TURP in prostatic hyperplasia smaller than 40 ml. Six-month follow-up with complex urodynamic assessment. AB - OBJECTIVE: To compare the efficacy and safety of contact laser vaporization (CLV) of the prostate and transurethral resection of the prostate (TURP). MATERIAL AND METHODS: Fifty patients with symptomatic prostatic hyperplasia with prostate volumes less than 40 ml were randomized to CLV or TURP treatment. All patients had infravesical obstruction confirmed preoperatively by pressure-flow studies. RESULTS: CLV lasted longer (51 +/- 13 min versus 34 +/- 12 min; p < 0.001), caused less bleeding (57 +/- 49 ml versus 175 +/- 133 ml; p < 0.001) and required longer bladder drainage time (4.3 +/- 6.1 versus 1.7 +/- 0.8 days; p < 0.01) than TURP. At 6-month follow-up, both treatments had improved objective urinary parameters and effectively reduced subjective symptoms. There were no significant differences between the study groups in symptoms scores (DanPSS-1), peak urinary flow rates (Qmax) and post-void residuals (PVR). Six months after treatment the detrusor pressure at peak urinary flow rate (PdetQmax) was 38.3 +/- 9.7 cm H2O in CLV patients and 31.3 +/- 9.9 cm H2O in TURP patients (NS). CLV treatment caused less retrograde ejaculation than TURP (1/16 potent CLV men versus 13/16 potent TURP men; p < 0.001). CONCLUSIONS: Contact laser prostatectomy proved to be a safe procedure which improved subjective and objective urinary parameters during 6-month follow-up as effectively as TURP in the treatment of symptomatic infravesical obstruction caused by minimal or moderate benign prostate enlargement. PMID- 10100362 TI - Distribution and elimination of the solute and water components of urological irrigating fluids. AB - OBJECTIVE: Irrigating fluids are used to dilate mucosal spaces and to remove blood and cut tissue from the operating field during endoscopic procedures. We have studied their disposition, since irrigating solutions are sometimes absorbed and may therefore be regarded as intravenous drugs. MATERIAL AND METHODS: The distribution and the rate of elimination of four irrigating fluids containing glycine, mannitol and sorbitol were studied after infusing 0.75 ml/kg/min of them over a period of 20 min in 10 male volunteers. Kinetic calculations were based on 12 blood samples collected over 120 min using traditional pharmacokinetics for the solutes and volume kinetics for the water component. RESULTS: The solutes had distribution half-lives of between 3 and 7 min; the elimination half-lives were 39 min (glycine), 97 min (mannitol) and 33 min (sorbitol). The volume of distribution during steady state was between 20 and 36 litres, while the volume of the body fluid space expanded by the water component of the irrigating fluids varied between 6 and 9 litres. Although the solutes became distributed over a much larger space than the infused fluid volume, the intersubject variation was smaller for the solute concentrations than for the dilution of the plasma fraction of the blood. CONCLUSIONS: The kinetics of the solute and water components of urological irrigating fluids can be analysed and compared using computer-based mathematical models. PMID- 10100363 TI - Italian multicentre open trial on DDAVP spray in nocturnal enuresis. AB - OBJECTIVE: The aim of the study was to compare the efficacy and safety of different doses of DDAVP spray treatment (20 to 40 mcg/day) in patients with primary monosymptomatic nocturnal enuresis (defined as three or more wet nights per week). MATERIAL AND METHODS: 237 patients (152 males, 75 females; age range 5 17 years), with no infections or organic abnormalities of the urinary apparatus and no neurological disorders, were admitted into the trial. The experimental design was planned as an "open study" with five different treatments schedules (5 groups). The daily doses of DDAVP at bedtime in groups 1 and 2 were 20 and 30 mcg, respectively, for 6 weeks. In groups 3 and 4 the daily doses for the first 2 weeks were 20 and 30 mcg, respectively, and then, after a washout period of 2 weeks, the daily doses for the two groups were 30 and 20 mcg, respectively. A dose-response study (20 to 40 mcg/day) was carried out in group 5. RESULTS: DDAVP spray therapy in primary monosymptomatic nocturnal enuresis was found to be resolutive in 70-75% of treated patients. No difference in response was found between the patients treated with the daily dose of 20 and those on 30 mcg. No important reactions were observed in patients treated with DDAVP spray at the different daily dose (20 to 40 mcg) or for different periods of time (up to 6 weeks). CONCLUSIONS: DDAVP spray therapy at a dose of 20 mcg/day was effective in 70-75% of primary monosymptomatic nocturnal enuretics. In non-responders the daily dose of DDAVP should be increased to 30 to 40 mcg. PMID- 10100364 TI - Daytime bladder dysfunction in therapy-resistant nocturnal enuresis. A pilot study in urotherapy. AB - OBJECTIVE: Bedwetting is the most common form of incontinence in children. Research in recent years suggests that there can be many different factors responsible for the problem of bed wetting, one of which is bladder dysfunction. The aim of this pilot study was to identify infrequent voiding ("hold pattern") and to investigate whether increasing the number of micturitions during the day can improve the nocturnal enuresis in children with several failed treatment attempts. MATERIAL AND METHODS: Twenty-two children with severe bedwetting were treated. Twelve of them had had no other treatment than increasing the number of regular micturitions during the day, while 10 patients had had enuresis alarm or desmopressin added. RESULTS: The number of wet nights after 1 month of treatment decreased in all children and the improvement continued in most of the children during the follow-up period. CONCLUSIONS: This study suggests that bladder training by increasing the number of micturitions during the day can be valuable in the treatment of nocturnal enuresis. PMID- 10100365 TI - Pediatric urinary tract reconstruction using intestine. AB - OBJECTIVE: To analyse the outcome of urinary tract reconstruction in children. MATERIAL AND METHODS: Fifteen children with bladder exstrophy or neurogenic bladder, 4-18 years old, were followed in accordance with a predetermined program for bladder augmentation (13 pat) or continent urinary reservoir (2 pat). The follow-up time was 1.7-6.3 years, median 3.7 years. RESULTS: All were dry, though one case had occasional leaks. Three bladder neck reconstructions, two artificial sphincters, one sling plasty and one fistula closure with subsequent bladder neck injection were required. Bladder volumes were adequate for age at low pressures. Reflux resolved in 12/13 ureters. A boy with preoperative renal insufficiency was transplanted. Total renal function remained otherwise stable despite acidosis in one case and some glomerular impairment in all. Progressive parenchymal lesions were seen in combination with abundant mucus, infections and calculi only. Growth and bowel function was unaffected. Bone mineral density showed overall increase; some low values were not consistent between investigations. CONCLUSIONS: Urinary tract reconstruction in children results in continence and regression of reflux. Growth, bone mineralization and renal function are unimpaired during the first years, but irrigation of the bladder is essential to minimize the risk of urinary tract infection. However, glomerular function might be affected and the possible risk of metabolic complications in later life can only be determined by continuous close monitoring over an extended period of time. ABBREVIATIONS: Voiding cystourethrogram (VCUG), dimercapto-succinic acid (DMSA), Chrome51 Ethylenediaminetetraacetic acid (Cr-EDTA), single photon absorption (SPA), bone mineral content (BMC), bone mineral density (BMD), dual photon x-ray absorption (DEXA), glomerular filtration rate (GFR), urinary tract infection (UTI), immunoglobulin G (IgG), clean intermittent catheterization (CIC) and subureteral teflon injection (STING). PMID- 10100366 TI - Acute and chronic effects of spirapril, alone or in combination with isradipine on kidney function and blood pressure in patients with reduced kidney function and hypertension. AB - In the present study we investigated the effect of a single dose, and 3 months of treatment with spirapril on kidney function, renin-angiotensin system, renal handling of sodium and blood pressure, in patients with reduced kidney function (serum creatinine 1.5-3 mg%) and hypertension. A single dose of 6 mg spirapril given at the beginning of the study did not affect glomerular filtration rate (GFR), renal plasma flow (RPF), angiotensin converting enzyme (ACE) activity, plasma renin activity (PRA) or renal handling of sodium. When the single dose of spirapril was given after 3 months of treatment with this agent, renal hemodynamics and PRA did not change. ACE activity, which was depressed by the previous spirapril treatment, decreased further (from 9.5 +/- 3.1 to 1.4 +/- 1.0 nmol/ml/min), (p < 0.05). Administration of 6 mg spirapril o.d. for 3 months did not have any effect on GFR or RPF. Serum ACE activity decreased from 92.1 +/- 8.0 to 5.1 +/- 2.6 nmol/ml/min (p < 0.05) and PRA increased from 1.4 +/- 1.2 to 4.1 +/- 3.6 ng/ml/min (p < 0.05). Plasma aldosterone did not change. Similar results were obtained when spirapril was combined with 5 mg isradipine in the initial and final single dose, or in the 3 months' treatment (5 mg o.d.). Blood pressure was normalized in 38% of the patients who received spirapril and in 71% of the patients who received spirapril and isradipine. Thus, (a) treatment with spirapril in patients with mild to moderate chronic renal insufficiency was not associated with deleterious effects on kidney function; (b) spirapril in a dose of 6 mg alone or in combination with 5 mg isradipine is effective in reducing blood pressure in hypertensive patients with reduced kidney function. PMID- 10100367 TI - Autosomal dominant polycystic kidney disease associated with familial sensorineural deafness. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by both renal and non-renal disorders. Extrarenal involvement includes noncystic manifestations such as cardiovascular abnormalities, colonic diverticula and intracranial aneurysms. Familial sensorineural hearing loss (SNHL) has been included in the definition of Alport's syndrome. However, other types of nephropathy have been occasionally associated with hereditary deafness. The association of ADPKD with hereditary SNHL has not been previously documented. We report a family with ADPKD associated with bilateral sensorineural deafness in a pedigree of four affected members in four generations. PMID- 10100368 TI - Complete pyelo-calyceal avulsion as a result of blunt abdominal trauma. AB - We present a rare case of complete avulsion of the kidney collecting system as a result of blunt abdominal trauma. Emergency celiotomy precluded radiographic studies. Perinephric hematoma was mild, the lesion was not detected and this later led to a nephrectomy. Pelvis disruption diagnosis is frequently delayed, and this compromises surgical reconstruction. PMID- 10100369 TI - Erectile dysfunction caused by sacral gun-shot injury. AB - A 22-year-old man suffering from isolated erectile dysfunction associated with damage to the right spinal nerve S2 caused by sacral gun-shot injury. He has no loss of bladder innervation. Treatment has been implantation of a penile prosthesis. PMID- 10100370 TI - Surgical management of chylous fistula after retroperitoneal lymph node dissection. AB - Conservative treatment with low-fat diet, medium-chain triglyceride or total parenteral nutrition, depending on the general condition of the patient, is the mainstay in the treatment of chylous ascites. In patients with persistent chylous fistula direct surgical closure is a valid treatment option. PMID- 10100371 TI - Transitional cell carcinoma of the bladder in children. AB - We present a case of transitional cell tumor of the urinary bladder in an 8-year old boy and discuss certain aspects of the epidemiology, aetiology, prognosis, treatment and follow-up. We review the published cases in the literature since 1992, and compare them with the classic series. PMID- 10100372 TI - Long arm deletion of chromosome 10 in a boy with monorchidism. AB - We report on a boy with long-arm deletion of chromosome 10 and compare this case to 10 previously reported patients. He had right cryptorchidism and absence of the left testis, but the size of his penis was normal. Cytogenetic analysis of the case showed the deficiency of 10q26.1-26.3 and the presence of 10qter. Four of 10 previously reported patients had an intersex phenotype, and all others had combinations of cryptorchidism, micropenis and hypospadias. These facts indicate that the terminal of chromosome 10q is strongly associated with abnormal male development. PMID- 10100373 TI - Quality of life with aphasia. AB - This article considers quality of life (QOL) with aphasia. The problems surrounding definition and measurement of QOL are reviewed. Dimensions of QOL that have been suggested include elements relating to physical problems, the toxicity dimension, body image and mobility, communication, and psychological, interpersonal, spiritual, and financial issues. These issues are placed in the context of wider dimensions of satisfaction and life quality related to individuality, culture, and philosophical and time elements. Research on the illness experience is related to QOL. Research on QOL after stroke and aphasia is reviewed. Clinical approaches that integrate models of betterment of life quality in aphasia are suggested. Notions of coping and of Aristos, "making the best of a given situation," are considered in the discussion of adjustment and accommodation to life with aphasia. PMID- 10100374 TI - The emotional impact of aphasia. AB - In this article we review the negative impact of aphasia on emotional well-being. Depression is the emotional response that has been examined most, and we examine the different causes of depression for people with aphasia. We discuss the relationships between recovery and emotional state and the clinical implications of these relationships, then review briefly issues of drug treatment for depression. We conclude that the emotional impact of aphasia can have a marked negative impact on recovery, response to rehabilitation, and psychosocial adjustment. PMID- 10100375 TI - Assessment of mood states in aphasia. AB - Depression is common in patients with stroke and other neurological conditions. Accurate assessment and diagnosis is critical in understanding the causes of mood disturbance in these patients and in establishing effective treatments. Examination of mood states, however, is difficult in patients with aphasia, impaired emotional expression, and other communication and cognitive difficulties. Most standardized measures of mood are inappropriate for this population due to the instruments' linguistic, attention, and other cognitive demands. The Visual Analog Mood Scales (VAMS) are psychometrically sound measures, developed specifically for neurologically impaired patients in general and aphasic patients in particular. These very brief scales assess eight mood states: sad, happy, tense, afraid, tired, energetic, confused, and angry. The utility of these scales in clinical practice is presented, as are specific recommendations and guidelines for the assessment of mood in patients with aphasia and other communication deficits. PMID- 10100376 TI - Perceptions of psychosocial adjustment to aphasia: applications of the Code- Muller Protocols. AB - We review research that has examined people's perceptions of likely psychosocial adjustment of aphasia. People's perceptions differ depending on whether they have aphasia themselves, are related closely to a person with aphasia, or work with the aphasic person in a professional capacity. In addition, people differ in what they perceive are the most important or relevant factors for psychosocial adjustment, and this too depends on whether they have aphasia themselves, are a relative or "significant other" in the aphasic person's life, or are a health professional working with the person with aphasia. Furthermore, there are marked differences in the way individuals predict likely psychosocial adjustment, and these perceptions can change over time. Most of this research has used the Code Muller Protocols (CMP) to examine these perceptions. This article describes the development and application of the CMP in aphasia. PMID- 10100377 TI - Psychosocial aspects of group communication treatment. Preliminary findings. AB - This article discusses preliminary psychosocial data from an efficacy study on the effects of group communication treatment in adults with chronic aphasia. Using a qualitative interview approach, participants with aphasia and their relatives/caregivers reported many positive psychosocial changes following treatment. The results suggest that group communication treatment had an impact on participants' home and community lives without direct treatment in those settings. Results are discussed in the context of managed care, group theory, and positive health. PMID- 10100378 TI - Group therapy for spouses of aphasic patients. AB - The setting, course, and results of a counseling and a therapeutic group for relatives of chronic aphasic patients are reviewed. Generally, providing and discussing information on the illness, its consequences, and medical and social services are greatly appreciated by group members. Counseling and group psychotherapy, as conducted by us, did not result in measurable improvements of relatives' perceptions of personal, social, and familial burdens. We assume, however, that group therapy does lead to more realistic attitudes toward burdensome and severely straining situations and may help with coping. Further research into psychotherapeutic strategies for relatives of disabled persons, who themselves suffer from psychological and social handicaps, is needed. PMID- 10100379 TI - Managing psychosocial adjustment to aphasia. AB - This article argues for incorporating psychosocial adjustment into treatment plans for people with aphasia. It proposes that rehabilitation is a social rather than a medical construct and that by adopting a broad range of intervention strategies, more effective approaches to reintegration can be adopted. Outcome measures relating to self-esteem are judged to be central to evaluating the efficacy of treatment. The role of social factors in managing psychosocial adjustment are considered alongside individual and family approaches to counseling. It is concluded that clinicians need to broaden their treatment program to include psychosocial adjustment in rehabilitation. PMID- 10100380 TI - History of prosthetic grafts. AB - The evolution of vascular surgery during the past five decades has established what was once controversial to be mandate, what was never dreamed of as debatable, and the vast body of knowledge yet to be unraveled--but requiring clinical application--as currently controversial. Controversy results when dissimilar therapies yield comparable outcomes, despite having been reached by different pathways. Scientific methods to dissect the precise mechanisms of cause/effect, and not reliance on associations, are necessary to resolve controversies that may contribute to inappropriate conclusions. Much effort has been expended by vascular surgeons in the search for an ideal vascular conduit. This edition of Seminars explores the status, past, present, and future, of a variety of graft materials. Future modifications and availability of the "ideal graft" will evolve as challenges are met. PMID- 10100381 TI - Physical and biomechanical issues in graft design. AB - New vascular grafts, stents, and stent grafts require designs that use known principles of bioadhesion and biomechanics, minimizing attachment strengths of blood-borne deposits or infecting microorganisms on their lumenal walls while maximizing tissue integration with the host vasculature. Critical surface tension (CST) is an easily measured material characteristic predictive of these outcomes. CST between 20 and 30 mN/m favors easy release and thromboresistance, whereas CST between 30 and 40 mN/m promotes strong bonding. PMID- 10100382 TI - Understanding and manipulating the biological response to vascular implants. AB - Wound healing is a very complex and dynamic process that involves both stimulation and inhibition of cells and bioactive substances, resulting in a stable scar. Although the histological aspects of this response are well understood, the regulation of wound healing on a molecular level has not been completely elucidated. An "appropriate" healing response is crucial after vascular graft implantation to permit a functioning patent conduit. If the biological response is unfavorable, graft failure ensues. Clearly, it has been shown that the patency for prosthetic vascular implants is less favorable than for autologous implants in certain anatomic positions. However, the factors that promote this failure have not been fully identified. This article reviews the normal biological response to vascular graft healing as we understand it and provides some alternatives to manipulate the cellular milieu in an attempt to promote a more favorable healing response to prosthetic implantation. PMID- 10100383 TI - Biomechanical factors as regulators of biological responses to vascular grafts. AB - Biomechanical forces have been implicated in the induction and progression of intimal hyperplastic thickening in vein, prosthetic, and endovascular bypass grafts. Graft implantation imposes significant alterations is shear and tensile forces. Such physical forces play an important role in modulating those cellular and molecular events that underlie regulation of vascular healing and adaptation. Characterization of such hemodynamic variables that induce perpetual medial vascular smooth muscle cell proliferation and migration will help in identification of those grafts at risk for occlusion and limited long-term patency and in design of therapeutic strategies that attenuate progressive intimal hyperplasia. PMID- 10100384 TI - Prosthetic above-knee femoropopliteal bypass. AB - One of the classic and as yet unresolved arguments in vascular surgery is whether using prosthetic for a first-time above-knee femoropopliteal bypass, to "save the vein" for a later, more distal bypass, is of net benefit. Most of the arguments supporting use of prosthetic for a first bypass in this situation are, in fact, not supported by the literature, whereas most of the arguments in favor of using vein first are. In addition, decision analysis shows that overall amputation-free survival and number of operative procedures required are clearly better if vein is used first under essentially all conditions--the overwhelmingly strongest determinant of outcome is patency of the first bypass, and the superior patency of initial bypass with vein mathematically outweighs the ability of the "preserved" vein to salvage failures after an initial bypass with prosthetic. Theoretical, empirical, and mathematical arguments all strongly favor preferential use of vein for a first bypass to the above-knee popliteal artery. PMID- 10100385 TI - Biological vascular grafts. AB - Biological bypass graft material has been used as an alternative to autogenous vein since the first lower extremity revascularization procedures were performed. Both immunogenicity and biodegradation can contribute to the failure of these grafts and must be addressed. Cryopreservation at ultralow temperatures (-196 degrees C) after pretreatment with dimethylsulfoxide has been successful in preserving viable vein graft endothelium. Both rejection and deterioration of the cellular elements may contribute to the relatively high failure rates. The umbilical vein graft has become an effective alternative to autogenous material. The glutaraldehyde tanning procedure increases tensile strength, masks antigenicity, and sterilizes the tissue. Recent results with excellent 5-year patency (67%) and cumulative limb salvage (80%) confirm the utility of this graft. PMID- 10100386 TI - Endothelial cell transplantation. AB - After more than 20 years of autologous endothelial cell transplantation, controversy is slowly giving way to consensus. The ongoing discussion regarding the optimal methods of creating an endothelial layer on synthetic vascular prostheses has been replaced by the realization that both in vitro endothelialization with cultured venous endothelial cells and mixed microvascular sodding result in equilibrated luminal tissue layers covered by a persistant endothelium. Clinical trials with almost 200 in vitro endothelialized prostheses are in their 10th year, and patency results are distinctly better than in nonendothelialized prostheses, particularly in below-the-knee grafts. PMID- 10100387 TI - Endovascular grafts. AB - The clinical application of endovascular grafts began with the work of Parodi in 1990, which fused intravascular stent and prosthetic graft technologies. These less invasive devices have been applied to the treatment of arterial aneurysm, long segment occlusive disease, and traumatic vascular injuries. A host of different systems have been developed that exploit the unique properties of balloon, superelastic metal, and vascular graft devices. PMID- 10100388 TI - The FDA and regulatory issues in graft development. AB - Regulatory issues in graft development range from mundane to complex because of the extensive diversity in graft technology. This article, describes the regulatory differentiation between types of grafts, incorporating a description of the system for classifying devices by the Food and Drug Administration (FDA). Information relating to the need for and the regulation of clinical investigations of grafts is included. This discussion includes a description of the current work by the International Organization of Standards on endovascular devices. Finally, a contrast between clinical studies sponsored by manufacturers and individual clinical investigators is provided. PMID- 10100389 TI - Structural failure of Dacron arterial grafts. AB - The ultimate test of a Dacron (polyethylene terephthalate or PET) arterial prosthesis depends on its ability to retain sufficient strength and durability to function properly for the life of the patient. Because graft recipients appear to be living longer, primarily because of improved medical and surgical treatment of cardiovascular disease, strength and durability of arterial prostheses have become increasingly important. From the time of implantation, all PET prostheses are continuously subjected to the cyclic stresses of pulsatile blood flow with mechanical fatiguing of yarns, as well as chemical and physical alterations associated with biodegradation. Notwithstanding the overall successful use of currently available prostheses, structural failure continues to occur sporadically and is especially noteworthy because of its potentially serious nature and usual occurrence 5 or more years after implantation, when the diagnosis may be overlooked or delayed. A review of the subject is provided based on the premise that timely recognition and appropriate management require a basic understanding of PET prostheses with respect to various fabric constructions and physical properties, graft healing, postoperative dilation, and known causes of structural failure. PMID- 10100390 TI - Word frequency, repetition, and lexicality effects in word recognition tasks: beyond measures of central tendency. AB - Response time (RT) distributions obtained from 3 word recognition experiments were analyzed by fitting an ex-Gaussian function to the empirical data to determine the main effects and interactive influences of word frequency, repetition, and lexicality on the nature of the underlying distributions. The ex Gaussian analysis allows one to determine if a manipulation simply shifts the response time (RT) distribution, produces a skewing of the RT distribution, or both. In contrast to naming performance, the lexical decision results indicated that the main effects and interactions of word frequency, repetition, and lexicality primarily reflect increased skewing of the RT distributions, as opposed to simple shifts of the RT distributions. The implications of the results were interpreted within a hybrid 2-stage model of lexical decision performance. PMID- 10100391 TI - A deficit in the short-term retention of lexical-semantic information: forgetting words but remembering a story. AB - This article examines the long-term memory of a patient, AB, who had previously been reported to have problems in the short-term retention of word meanings. The authors found that AB had a problem not only in the short-term but also in the long-term retention of lexical-semantic information. AB, however, had no problem in the long-term retention of other kinds of information (pictures, shapes, propositional information). This pattern of results was interpreted as evidence that lexical-semantic representations have their own specific memory resources that are involved in the retention of the corresponding representations across different time intervals (e.g., they are involved in short-term as well as long term retention). Implications for models of memory are discussed. PMID- 10100392 TI - Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. AB - Fifty-six heroin addicts and 60 age-matched controls were offered choices between monetary rewards ($11-$80) available immediately and larger rewards ($25-$85) available after delays ranging from 1 week to 6 months. Participants had a 1-in-6 chance of winning a reward that they chose on one randomly selected trial. Delay discounting rates were estimated from the pattern of participants' choices. The discounting model of impulsiveness (Ainslie, 1975) implies that delay-discounting rates are positively correlated with impulsiveness. On average, heroin addicts' discount rates were twice those of controls (p = .004), and discount rates were positively correlated with impulsivity as measured by self-report questionnaires (p < .05). The results lend external validity to the delay-discounting rate as a measure of impulsiveness, a characteristic associated with substance abuse. PMID- 10100394 TI - Spatial frequencies as a medium for guiding attention: comment on Lamb, Yund, and Pond (1999) AB - M. R. Lamb, E. W. Yund, and H. M. Pond (1999) question L. C. Robertson's (1996) earlier arguments that attention can be guided by spatial frequencies when searching for a target in complex visual patterns. The 2 major findings they report to argue against Robertson's conclusions are discussed and found inadequate for the purposes of abandoning this hypothesis. Instead, findings reported in the accompanying article in combination with previous findings reported by 2 of the same authors (M. R. Lamb & E. W. Yund, 1996) provide converging evidence to support spatial frequency as a medium for guiding attention. PMID- 10100393 TI - Is attentional selection to different levels of hierarchical structure based on spatial frequency? AB - Target identification is faster when the target level (global or local) is the same as that on the previous trial, presumably because attention is directed to the appropriate level. L. C. Robertson (1996) found that eliminating low spatial frequencies by contrast balancing eliminated this level repetition effect and concluded that attentional selection between different levels of structure is based on spatial frequency. In contrast, M. R. Lamb and E. W. Yund (1996a) found no effect of contrast balancing on the level repetition effect and thus concluded that attentional selection is not based on spatial frequency. In this study, the authors identified the procedural difference between the 2 studies responsible for this difference in results and replicated both findings. The data show that spatial frequency is not a necessary basis for attentional selection between global and local forms. Although it remains possible that spatial frequency is the basis of attentional selection under some circumstances, the data supporting this proposition are not yet compelling. PMID- 10100395 TI - [The pharmaco-economics of the treatment of arterial hypertension: data and controversies]. AB - The cost benefit ratio of antihypertensive therapy motivated many researches and discussions these last years. The treatment of this very frequent and chronic abnormality is of importance in this time of shortage of money available for health care. Its cost benefit ratio appears to decrease with age and the severity of hypertension: but these calculations rest on several hypotheses, that need scientific demonstrations by prospective data retrieval. PMID- 10100396 TI - [New methods on the subject of peroperative neurophysiological monitoring in vascular and orthopedic surgery]. AB - The neurological and neuropsychological complications of vascular and orthopedic surgery can be prevented by the early detection of the ischemic penumbra, that is, the stage at which the ischemic nervous structures are no more functional, but still alive and salvageable by reperfusion. This can be achieved by intraoperative neuromonitoring of the electroencephalogram and evoked potentials. We illustrate how these techniques led to improvement of the surgical strategy and patient outcome in carotid endarterectomies, descending aorta surgery and surgery performed under deep hypothermic circulatory arrest. PMID- 10100397 TI - The world of HIV and disease, and some new approaches to block it. PMID- 10100398 TI - [The role of chaperone proteins in the assembly of envelope proteins of hepatitis C virus]. AB - Formation of the viral envelope is an important step in the morphogenesis of enveloped viruses. Our data on the formation of hepatitis C virus (HCV) envelope indicate that endoplasmic reticulum (ER) chaperones play a role in the assembly of HCV envelope proteins (E1 and E2). We have shown that these glycoproteins interact with BiP, calreticulin and calnexin. However, among these chaperones, only calnexin is involved in the productive assembly of E1E2 complex. The other two chaperones interact with misfolded aggregates containing E1 and E2. Folding of HCV glycoproteins occurs in the context of intermediate complexes involving E1, E2 and calnexin. As soon as E1E2 heterodimers are properly folded, they separate from calnexin but don't leave the ER compartment. PMID- 10100399 TI - [Dose intensity in chemotherapy of ovarian carcinoma: to what degree?]. PMID- 10100400 TI - [23rd Congress of the European Society for Medical Oncology, 6-10 November 1998, Athens, Greece]. PMID- 10100401 TI - The chaotic component of human heart rate variability shows a circadian periodicity as documented by the correlation dimension of the time-qualified sinusal R-R intervals. AB - OBJECTIVE: This study investigates the hypothesis that the nonlinear component of human heart rate (HR) variability might show a periodic structure over the 24-h span. Such a postulate could explain how the chaotic component might coexist with the deterministic periodic variability of instantaneous HR in beat per minute. MATERIALS AND METHODS: The sinusal R-R intervals (sRRi) of the Holter EKG of 10 clinically healthy subjects (5 M, 5 F, 23-30 years) were analyzed per each hour of the day-night span according to two methods for the nonlinear chaotic variability, i.e., the correlation dimension method, and the linear periodic variability, i.e., periodic regression analysis. RESULTS: The hourly-qualified correlation integrals were found to show a significant circadian rhythm, with an acrophase located during the night in coincidence with the longest duration of the sRRi and the lowest rate of cardiac pulse. CONCLUSIONS: The rhythmic structure of the chaotic component of the human HR variability let us to think that a deterministic periodic chaos of fractal type regulates the nonlinear cardiac dynamics. Such a periodic structure allows the chaos to be compatible with the deterministic linear periodicity of circadian type which characterizes the within-day variability of human HR. PMID- 10100402 TI - Association between histological diagnosis of Helicobacter pylori and coronary heart disease: results of a retrospective study. AB - OBJECTIVE: Several epidemiological and clinical reports have investigated the relationship between Helicobacter pylori (H. pylori) infection and ischemic heart disease (IHD). All studies utilized for the diagnosis of H. pylori infection the antibody titre that is unable to distinguish an actual from a previous H. pylori infection. PATIENTS AND METHODS: We report a retrospective analysis on 149 subjects, who underwent an esophago-gastro-duodenoscopy, in whom the search for H. pylori was histologically performed. RESULTS: The prevalence of IHD is not significantly different from that observed in H. pylori free patients (26% vs 21%, p = 0.527). CONCLUSIONS: The mechanism underlying the possible role of H. pylori needs further investigation and prospective studies to further analyze the relationship between "active" H. pylori infection and ischemic heart disease were necessary. PMID- 10100403 TI - Lower 24-h blood pressure regimen in subjects with a familial genealogy of longevity. AB - OBJECTIVE: This study investigates the 24-h blood pressure (BP) pattern in longevous subjects and their progeny, in order to validate the hypothesis that the human beings who live beyond their longest expectancy of life should be protected from developing hypertension. Such a characteristic feature is supposed to be a biological aspect of human longevity which can be transmitted to the progeny. MATERIALS AND METHODS: The study was carried out on 92 elderly subjects, (45 M, 47 W, 76-102 years), and 28 firstborn descendants of the first (7 M, 7 W, 36-55 years) and second (7 M, 7 W, 16-26 years) generation, in clinical health. The control subjects were 308 clinically healthy individuals (154 M, 154 F, 16-75 years) of the common population, stratified by age. RESULTS: The longevous subjects were found to show a diastolic daily mean level less pronounced than expected, according to the BP age-related trend in the common population. Both the children and grandchildren of the longevous subjects were seen to show a systolic and diastolic daily mean level significantly less pronounced than in their coeval subjects of the common population. CONCLUSIONS: Because of the unexpected lower diastolic BP daily mean level in the very old subjects, the hypothesis that the longevous subjects might be protected from developing hypertension via the arteriolar vasoconstriction seems to be confirmed. Because of the lower systolic and diastolic BP in young and adult subjects with a positive familiarity for longevity, the hypothesis that the hemodynamic protection from senile hypertension might be an inheritable biological feature of the longevity seems to be acceptable. PMID- 10100404 TI - [Injectable progesterone in hormone replacement therapy in menopause]. AB - PURPOSE: To evaluate activity and tolerability of intramuscular administration of 17-alpha-hydroxyprogesterone caproate (Lentogest-Amsa) in hormone replacement therapy in menopause. PATIENTS AND METHODS: Intramuscular slow releasing 17-alpha hydroxyprogesterone caproate was given to 30 postmenopausal women. Patients were divided into two groups according to the number of monthly doses (1 or 2). RESULTS: In both groups of patients a regular monthly bleeding was obtained. Echographic assessment did not show abnormal endometrial thickness. CONCLUSIONS: The results of this study have pointed out the efficacy of intramuscular progesterone-caproate administration with a better compliance in the single dose group. PMID- 10100405 TI - [Philosophers, physicists and physicians in defense of the unity of the scientific method]. AB - The falsifiability of scientific knowledge is an acquired result of contemporary philosophy of science and yet there is not a universal consensus upon the idea of the unity of scientific method. Albeit there are differences in techniques of testing (methodics) hypotheses in the vast field of research, the author, following the critical rationalism of Karl Popper, favors the perspective of the unity of method in natural as well in social and philological sciences. PMID- 10100406 TI - Age related risk and prevention of postoperative complications. AB - Perioperative morbidity in elderly patients has decreased in last years, with the advent of newer surgical, anaesthetic and monitoring techniques, but is still important when compared with that of younger patients. Complications in the post operative show different frequencies and mainly depend: a) on age-related conditions of pulmonary, cardiovascular and renal functions, of C.N.S. and of nutritional status; b) on surgery and medication-related risk factors, inclusive of emergency, bedrest, analgesia and infusions, drugs and intensive care; c) on neoplastic or non-neoplastic disease, type of surgery and surgeon's experience. Appropriate surgical intervention, therefore, should not be deferred because the patient is elderly, but surgeon must look beyond measured indices to the qualities of vitality and motivation. PMID- 10100407 TI - [Therapy of breast carcinoma in elderly women]. AB - PURPOSE: To present an approach to the treatment of primary and metastatic breast cancer in the elderly. DESIGN: A large number of studies in elderly women with breast cancer have been reviewed. RESULTS: The studies reviewed demonstrate that the annual incidence of breast cancer increases with age, along with a longer life expectancy. Biennial mammography and annual physical examination are effective, but compliance with screening recommendations decreases with age. Most treatment decisions are based on studies that seldom include women over 65 years of age. With the exception of specific comorbid conditions that preclude anesthesia and surgery, older women tolerate breast surgery as well as younger women. Tamoxifen is the usual adjuvant systemic therapy given to older women. Metastatic breast cancer older women, in generally good condition, tolerate standard doses of chemotherapy as well as their younger counterparts. CONCLUSIONS: Future research should include clinical trials designed specifically for the elderly taking into account functional status and quality of life. PMID- 10100408 TI - [Gemcitabine in peritoneal mesothelioma: a case report]. AB - Malignant peritoneal mesothelioma is a rare tumor whose prognosis is poor. We report a case history of a 57-year old woman with large peritoneal masses and ascites refractory to several chemotherapeutic regimens. The patient benefited of a dramatic regression of disease with symptomatic improvement during chemotherapy with gemcitabine. Serum CA-125 values declined consensually to tumor regression. The duration of response was 12 months. The activity of gemcitabine in malignant mesothelioma has been already confirmed in phase II studies. Data are also available suggesting that better results can be obtained combining this agent with cisplatin, and a multicenter phase II study is now exploring the activity of this combination. PMID- 10100409 TI - [Development of cancer chemotherapy. The discovery of new active drugs. II]. PMID- 10100410 TI - In the teeth of the evidence: the curious case of evidence-based medicine. AB - For a very long time, evidence from research has contributed to clinical decision making. Over the past 50 years, however, the nature of clinical research evidence has drastically changed compared with previous eras: its standards are higher, the tools for assembling and analyzing it are more powerful, and the context in which it is used is less authoritarian. The consequence has been a shift in both the concept and the practice of clinical decision making known as evidence-based medicine. Evidence-based decisions, by definition, use the strongest available evidence, are often more quantitatively informed than decisions made in the traditional fashion; and sometimes run counter to expert opinion. The techniques of evidence-based medicine are also helpful in resolving conflicting opinions. Evidence-based medicine did not simply appear in vacuo; its roots extend back at least as far as the great French Encyclopedia of the 18th century, and the subsequent work of Pierre Louis in Paris in the early 19th century. The power of the evidence-based approach has been enhanced in recent years by the development of the techniques of systematic review and meta-analysis. While this approach has its critics, we would all want the best available evidence used in making decisions about our care if we got sick. It is only fair that the patients under our care receive nothing less. PMID- 10100411 TI - DNA vaccines for prophylactic or therapeutic immunization against hepatitis B virus. AB - DNA vaccines, with which the antigen is synthesized in vivo after direct introduction of its encoding sequences, offer a unique method of immunization that may overcome many of the deficits of traditional antigen-based vaccines. By virtue of the sustained in vivo antigen synthesis and the comprised stimulatory CpG motifs, plasmid DNA vaccines appear to induce strong and long-lasting humoral (anti-bodies) and cell-mediated (T-help, other cytokine functions and cytotoxic T cells) immune responses. In animal models, DNA vaccines against hepatitis B virus (HBV) give humoral and cell-mediated immunity superior to that of the current traditional antigen-based vaccines, indicating the possibility of a more effective prophylactic vaccine against HBV. Furthermore, DNA vaccines can overcome tolerance to and expression of HBV proteins in a transgenic mouse model of the HBV chronic carrier, opening up the possibility of an effective therapeutic DNA vaccine to treat chronic carriers of HBV. PMID- 10100412 TI - Current controversies in screening: cholesterol, breast cancer, and prostate cancer. AB - Physicians must make decisions in day-to-day practice even when the balance of benefit and harm is not yet known. Adopting a clinical policy about screening is a case in point. Three controversies in screening healthy adults illustrate different aspects of resolving a dispute when the evidence is incomplete. The major controversy in cholesterol screening is whether to screen young adults. There has never been a randomized trial of treatment, let alone a trial of screening, in young adults. However, a patchwork of evidence strongly suggests that, because the baseline risk of coronary heart disease (CHD) is very small in young adults, the absolute reduction in risk from treatment would be very small. In breast cancer screening, randomized trials do not show conclusively that periodic mammography for women aged 40-49 years reduces breast cancer mortality. A 7-10 year delay between the first mammogram and a reduction in deaths from breast cancer suggests the hypothesis that the only benefit of screening women aged 40-49 years occurs from mammograms performed after age 50. There is no high quality evidence that early detection and treatment reduce the death rate from prostate cancer. In lieu of randomized trial data, we must depend on a decision analysis that shows that screening middle-aged men is cost-effective relative to other preventive services. However, this result depends on using optimistic survival data in the decision model, and most organizations do not recommend routine screening. The best strategy is to discuss the harms and benefits, and let the patient decide. PMID- 10100413 TI - Complementary therapies and traditional Judaism. AB - In Jewish tradition, physicians are obligated to heal the sick and patients are obligated to seek healing from physicians. Judaism also sanctions certain complementary therapies such as prayers, faith healing, and amulets, when used as supplements to traditional medical therapy. Confidence in the healing powers of God through prayer and contrition is encouraged, provided that the patient uses prayer alongside traditional scientific medicine, not as a substitute for it. PMID- 10100414 TI - Colonic obstruction due to sigmoid muscular hyperplasia. AB - We report a case of acute colonic obstruction initially presumed to be secondary to acute diverticulitis, necessitating emergent surgical intervention. Pathologic examination failed to reveal evidence of inflammation, fibrosis or neoplasia. Marked hypertrophy of the sigmoid circular muscle layer was documented and thought to be the etiology of the colonic obstruction. PMID- 10100415 TI - Hepatocellular carcinoma with fibrolamellar pattern in a patient with autoimmune cholangitis. AB - A 75-year-old woman with a 15-year history of autoimmune cholangitis underwent orthotopic liver transplantation because of progressive liver decompensation. A clinically unsuspected hepatocellular carcinoma was found. A portion of the tumor showed fibrolamellar differentiation. Hepatocellular carcinoma, either with the usual pattern or with a fibrolamellar pattern, is rare in the setting of primary biliary cirrhosis, but has been seen in the setting of autoimmune hepatitis. Autoimmune cholangitis is a relatively recently recognized form of autoimmune liver disease whose association with hepatocellular carcinoma has yet to be determined. PMID- 10100416 TI - Cytomegalovirus infection in patients with HIV infection. AB - Cytomegalovirus (CMV) is responsible for the most common viral opportunistic infection in persons with acquired immunodeficiency virus syndrome (AIDS). Clinical disease due to CMV has been recognized in up to 40% of patients with advanced HIV disease. The most common presentation is retinitis, although colitis, esophagitis, pneumonitis and neurological disorders are also reported frequently. CMV retinitis is usually diagnosed clinically, and serological testing for CMV immunoglobulin is useful to support the diagnosis. Parts of the gastrointestinal tract (esophagus and colon) are the most common extraocular sites of CMV infection in AIDS patients. Therapy with systemic agents, including intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir, is effective. Ganciclovir is associated mainly with hematological toxicity, while foscarnet and cidofovir are nephrotoxic. Intravitreal injections with these antiviral agents are also effective, but inconvenient, and there is a need for repeated injections. Intraocular implants that slowly release ganciclovir have been effective for both acute therapy and long-term maintenance, but the occurrence of contralateral ocular and extraocular disease is a serious concern. New agents, as for example an anti-sense agent against CMV, appear promising. PMID- 10100417 TI - The importance of peritoneal imaging in the workup of genital edema in patients on continuous ambulatory peritoneal dialysis. AB - BACKGROUND: Genital edema is a well-reported complication of peritoneal dialysis. This phenomenon has been associated with extravasation of dialysate from the peritoneal cavity through a defect in the abdominal wall or through an wall or through an inguinal hernia (or patent processus vaginalis, persistent sac). In the first case, fluid tracks through the soft tissues of the abdominal wall and settles in the dependent genitalia. In the second, fluid tracks through the inguinal hernial defect and infiltrates into the tissues distal to the defect. It is difficult to precisely diagnose the etiology of many of these cases but it is obviously important. METHOD: We report a case of a patient who presented with penile and scrotal edema and was eventually found to have bilateral patent processus vaginalae. We used computed tomography and peritoneal scintigraphy in order to ascertain the diagnosis. RESULTS/CONCLUSIONS: We believe that computed tomography and peritoneal scintigraphy are extremely helpful in the workup of genital edema in patients on continuous ambulatory peritoneal dialysis. PMID- 10100418 TI - Mortality associated with concurrent strongyloidosis and cytomegalovirus infection in a patient on steroid therapy. AB - Disseminated strongyloidosis has been recognized with increasing frequency, often in patients who are immunocompromised or have received steroid therapy. In addition, disease due to cytomegalovirus (CMV) is noted in immunodeficient hosts. We report on a 55-year-old Puerto Rican man who received steroid treatment for orpharyngeal pemphigus vulgaris and developed abdominal symptoms with alternating constipation and diarrhea. The clinical work-up did not reveal specific abnormalities, but the patient died of cardiopulmonary failure. At the postmortem examination, the patient had evidence of strongyloidosis and CMV disease. This report reviews both this case and the literature, and discusses the overlapping infections of strongyloidosis and CMV disease in this patient who had received steroid therapy. PMID- 10100419 TI - [Posteroventral pallidotomy in Parkinson's disease]. PMID- 10100420 TI - [Pallidotomy in the treatment of complicated Parkinson's disease: clinical results at two years and analysis of prognostic factors]. AB - BACKGROUND: There is a renewed interest in pallidotomy as a treatment for complicated Parkinson's disease (PD). AIM: To present the clinical results as well as the analysis of prognostic factors obtained in 28 patients with PD and motor complications submitted to pallidotomy and followed by one year (n = 28) and 2 years (n = 12). RESULTS: The total motor score (Unified Parkinson's Disease Rating Scale [UPDRS]) in the off state improved by 33 and 23% at one and two years, respectively (p < 0.01). All the cardinal signs of the disease were significantly improved (p < 0.01): tremor (92%), rigidity (67%), bradykinesia (46%) and axial symptoms (21%). A slight tendency to worsening in axial symptoms was observed. Dyskinesias disappeared in all but one patient. The Schawb & England Scale in off was improved by 21%. No improvement in the non-operated side was observed. The subgroup of patients with an improvement of less than 30% in the UPDRS was older than the one with larger clinical benefit. The observed tendency to worsening in the total motor score was related mainly to the progression of the symptoms in the non-operated side. Complications were mild and transient. CONCLUSIONS: Pallidotomy is a relatively safe and effective therapeutic option for complicated PD patients. An adequate selection of patients is necessary, since efficacy is partial and limited to one hemibody. PMID- 10100421 TI - [Meningitis in subjects with human immunodeficiency virus infection]. AB - BACKGROUND: Neurological complications are frequently observed in HIV-1 patients. Lumbar puncture (LP) and LSF analysis are two key diagnostic procedures. AIM: To describe the etiology meningeal syndromes in a hospital series of HIV patients. RESULTS: In this study, we present the different meningeal complications from 198 HIV-1 patients referred, for the last five years, to the HIV Center of the Hospital of University of Chile. The diagnosis of HIV-1 was done clinically plus a positive ELISA test, and confirmed by Western blot and/or PCR. In all cases with a possible neurological complication (52/198), a LP was performed. Cytochemical and microbiological studies, were done in each CSF sample. Serum CD4/CD8 lymphocytes number were determined by flow cytometry, and brain CT scan and/or MRI were obtained. From the 52 patients in whom a LP was done, 24 showed an abnormal CSF, compatible with the diagnosis of meningitis. The most frequent etiology (11/24) was infection by Cryptococcus neoformans, followed by Treponema pallidum (7/24). There were 3 cases of HIV-1 meningitis, and 3 other cases with lymphoma, varicella zoster and cytomegalovirus meningitis. The frequency of cryptococcal infection was similar to that reported in the literature, but two interesting observations were the high frequency of neurosyphilis and the absence of TBC meningitis. In our country, the VDRL/FTA-ABS serum tests are mandatory in HIV patients. If these tests were positive a LP was performed, and this could partially explain the high number of cases coinfected with neurosyphilis. There is an important prevalence of lung TBC in our country, and as a consequence there is a policy of immunization to all newborn. It is possible that the high prevalence of TBC "promotes" a more actively search for TBC infection, with an early diagnosis and treatment of pulmonary TBC, and so a more frequent prophylaxis therapy in HIV patients, without the development of TBC meningitis. PMID- 10100422 TI - Current concepts of migraine and its treatment. PMID- 10100423 TI - [Is the lesion produced by oxidation a central part in the pathogenesis of Alzheimer's disease?]. AB - The two most striking features of Alzheimer's disease are: a) the multitude of abnormalities affecting essentially every system, and b) the strict age dependence. Recent work suggests that both features are linked to increased oxidative stress that damages lipids, proteins and nucleic acids and results in redox-active metal accumulations, mitochondrial damage and formation of advanced glycation endproducts. Interestingly, beta-protein precursor, amyloid-beta, presenilins and apolipoprotein E have all been linked to reactive oxygen species production or with apoptosis, a process intimately associated with oxidative stress. In therapeutics, the commonality between a number of efficacious agents appears to be oxidative stress reduction. Therefore, we contend that oxidative stress is the element that links the multitude of changes in Alzheimer's disease and that a reduction of oxidative stress will have a dramatic effect on reducing the incidence or progression of Alzheimer's disease. PMID- 10100424 TI - [Extradural thoracic arachnoid cyst]. PMID- 10100425 TI - [Compression of the sciatic nerve in uremic tumor calcinosis]. AB - Tumoral calcinosis is an uncommon and benign condition characterized by the presence of slow-growing calcified periarticular soft tissue masses of varying size. They are usually asymptomatic and nerve compression is rare. We describe the case of a 54-year-old female patient on long-term hemodialysis for chronic renal failure presenting sciatica in the left lower limb secondary to an extensive uremic tumoral calcinosis that affected the hip and thigh. The pathogenesis of uremic tumoral calcinosis as well as the treatment and clinical outcome are analyzed. The uncommon nerve compression due to tumoral calcinosis are reviewed. In conclusion, uremic tumoral calcinosis is a not previously reported infrequent cause of sciatic nerve compression. PMID- 10100426 TI - [Recurrent cerebral embolism as the main sign of atrial myxoma]. AB - Atrial myxomas (AM) are the most frequent cardiac tumors. Between 25-45% of the cases present neurologic manifestations, generally owing to cerebral embolic infarcts or intracranial haemorrhages. Cerebral embolism can precede cardiac or constitutional symptoms, but recurrent embolisms as the only disturbance are infrequent. We present the case of two patients with 66 and 70 years that suffered recurrent cerebral embolisms as the only manifestation of a left AM. Magnetic resonance (MR) studies showed several isquemic infarcts in different vascular territories. Echocardiagrams showed the presence of heterogeneous masses in left atrial that suggested AM. These were removed in both cases and the diagnosis of AM was confirmed by anatomopathologic exam. The presence of recurrent isquemic episodes in different cerebral territories must point the diagnosis to a cardioembolic source. AM must be taken into account in these cases, despite the lack of constitutional or cardiac symptoms, older age or concomitant carotid pathology. PMID- 10100427 TI - [Comment on "Respiratory failure secondary to disautonomy in lateral bulbar infarction"]. PMID- 10100428 TI - [Prion or prion?]. PMID- 10100429 TI - [Parkinsonian syndrome related to tacrine]. PMID- 10100430 TI - Psychoneuroendocrine aspects of temporolimbic epilepsy. Part I. Brain, reproductive steroids, and emotions. AB - The temporolimbic structures of the brain that subserve emotional representation are highly epileptogenic and play an important role in the modulation of hormonal secretion and mediation of hormonal feedback. Estrogen is highly epileptogenic and exerts energizing and antidepressant effects. Excessive estrogen influence produces anxiety, agitation, irritability, and lability. It can promote the development of anxiety manifestations (e.g., panic, phobias, and obsessive compulsive disorder). Progesterone and its metabolites inhibit kindling and seizure activity. They have potent anxiolytic effects, possibly by virtue of their GABAergic activity. Excessive progesterone influence produces sedation and depression. Testosterone has two major metabolites: estradiol, which can exacerbate seizures, and dihydrotestosterone, which blocks NMDA-type glutamate transmission and may be responsible for antiseizure effects. Testosterone has energizing effects and increases sexual desire in both men and women. In excess, however, it may promote aggressive, impulsive, and hypersexual behavior. Hormonal effects tend to be exaggerated or idiosyncratic in the setting of an abnormal or anomalous temporolimbic substrate, especially temporolimbic epilepsy. This may reflect altered neuronal responsivity to hormonal exposure perhaps by virtue of changes in the number of dendritic spines and receptors. PMID- 10100431 TI - Psychoneuroendocrine aspects of temporolimbic epilepsy. Part II: Epilepsy and reproductive steroids. AB - Reproductive dysfunction is unusually common among men and women with epilepsy. Reproductive endocrine disorders are also common and may be causal. The association between particular reproductive endocrine disorders and the laterality and focality of epileptiform discharges suggests an etiologic role for epilepsy. Gonadal steroids are neuroactive and influence seizure occurrence: estrogen is epileptogenic whereas progesterone has antiseizure effects. Fluctuations in the absolute and relative serum levels of these hormones may play a critical role in establishing three distinct patterns of catamenial epilepsy: 1) perimenstrual and 2) preovulatory in women with ovulatory cycles, and 3) entire luteal phase of the cycle in women with anovulatory cycles. Treatment with progesterone reduces seizure frequency by more than half. In men, testosterone effects may depend on the relative concentrations of two major testosterone metabolites that exert opposing influences on neuronal excitability: estrogen potentiates whereas dihydrotestosterone inhibits NMDA-mediated conductance. Combined therapy using an aromatase inhibitor along with testosterone improves sexual function and may reduce seizures in men with epilepsy. PMID- 10100432 TI - Psychoneuroendocrine aspects of temporolimbic epilepsy. Part III: Case reports. AB - Many reproductive steroids have neuroactive effects that can modulate neuronal excitability and influence emotions. Emotional disorders may result when 1) abnormal endocrine states interact with normal brain, 2) normal endocrine states interact with abnormal brain, and 3) abnormal endocrine states interact with abnormal brain. An understanding of these pathogenetic relationships and the potential therapeutic role of reproductive hormones should lead to a more effective and comprehensive management of women and men with anxiety and mood disorders. PMID- 10100433 TI - Depression and demoralization among Russian-Jewish immigrants in primary care. AB - The purpose of this study was to examine the levels and nature of psychological distress and depression among Russian-Jewish emigres in primary care. Fifty-seven consecutive patients at the primary care clinic were assessed with the Hamilton Depression Scale (Ham-D). The subjects completed self-rating scales, including the Beck Depression Inventory (BDI), Life Orientation Test, Beck Hopelessness Scale, Attributional Style Questionnaire, and Snaith-Hamilton Pleasure Scale. Data on demographics and physical complaints were collected and analyzed. Of the patients studied, 82.5% experienced psychological distress (BDI > or = 10), and 43.9% had clinically significant depressive symptoms (Ham-D > or = 17). BDI and Ham-D scores were significantly correlated with the number of psychosomatic complaints, hopelessness, lack of optimism, anhedonia, and dysfunctional attributional style. The distressed, but not depressed, patients had preservation of hedonic capacity. The authors found a high rate of depression based upon Ham-D scores among the Russian-Jewish emigres in primary care. The authors suggest that this high rate is attributable to a culturally specific tendency to express distress in somatic terms. The nature of distress was phenomenologically similar to demoralization. PMID- 10100434 TI - Should we train psychiatrists as primary care providers? AB - The author discusses the proposition that psychiatrists would be appropriate primary physicians for specific types of patients. The author reviews the arguments for and against psychiatrists as primary care providers, proposes questions that must be addressed in training for such a role, and describes current models of primary care education and practice for psychiatrists. The author believes that primary care may be an appropriate career track within psychiatry and suggests that the development of family medicine may provide useful guidance in incorporating primary care functions into psychiatry. PMID- 10100435 TI - Hypoactive delirium as a clinical symptom of intestinal perforation. PMID- 10100436 TI - HIV dementia presenting with somatic delusions and psychogenic polydipsia. PMID- 10100437 TI - [COPA (cuffed oropharyngeal airway). A new instrument for airway management]. PMID- 10100438 TI - [Utility of COPA (cuffed oropharyngeal airway) in anesthesia for colonoscopies]. AB - OBJECTIVE: To assess the usefulness of the cuffed oropharyngeal airway (COPA), a new device for airway control, in 45 patients scheduled for colonoscopy. PATIENTS AND METHODS: The patients were anesthetized with propofol and the COPA was applied following the manufacturer's recommendations. Positive pressure ventilation was provided at first, and later the patients were allowed to breathe spontaneously. RESULTS: The mean dose of propofol needed to place the COPA correctly was 2.3 +/- 0.3 mg.kg-1. "Free hands" anesthesia was possible in 43 procedures (96%). Placement had to be attempted several times in five patients (11%) before adequate ventilation was achieved. Two patients (4%) had to be switched to a smaller or larger size COPA. In two others (4%), the technique was abandoned because of inadequate ventilation. No hemodynamic changes were observed after placement, although systolic blood pressure tended to increase slightly during colonoscopy, while heart rate decreased. Spontaneous ventilation was possible in all cases and respiratory frequency and end-tidal CO2 increased significantly during colonoscopy. No cases of laryngospasm or sore throat were observed, although 10 patients (22%) coughed upon emergence from anesthesia. CONCLUSIONS: The COPA is a new alternative to intubation or other methods for controlling the airway during short procedures, making "free hands" anesthesia possible in most cases. Provided contraindications are respected, the number and seriousness of complications seems to be minimal. PMID- 10100439 TI - [Electron microscopic analysis of particles from surgical gloves and their possible introduction into the epidural space during epidural anesthesia]. AB - OBJECTIVE: Many publications have linked surgical glove powder to inflammatory reactions of the peritoneum, pleura, pericardium and meninges. Accidental contamination may also increase the likelihood of complications after spinal and epidural anesthesia. We aimed to analyze the morphological characteristics of microscopic particles adhering to surgical gloves and to analyze how likely such particles are to enter the epidural space during catheterization. MATERIAL AND METHOD: One hundred epidural catheters were studied in two groups (A and B) of 50. Group A catheters contained stylettes and the distal ends were open (Vygon). Group B catheters contained no stylettes and had closed distal ends and three side openings (Becton Dickinson). Continuous epidural anesthesia was simulated with half the catheters in each group (25) by touching the distal end of each line with the gloves and later inserting the catheter through a Tuohy needle. All catheters--those used in the simulation as well as the untouched ones--were then examined under a scanning electron microscope. The particles on the internal and external surfaces of the gloves had previously been identified under a microscope and analyzed by X-ray diffraction. RESULTS: Gloves: external glove surfaces carried particles measuring between 3 and 4 mu; their morphology was consistent with calcium carbonate. On internal surfaces we found larger particles, between 11 and 14 mu in diameter, shaped differently and of smooth appearance. Analysis of the latter showed them to contain traces of magnesium and to have characteristics consistent with organic molecules. The particles of one surface were never observed on the other. Catheters: the non-manipulated catheters in both groups contained no free particles matching those described above, whereas the outside surfaces of the catheters in contact with gloves contained particles consistent with those of external glove surfaces. The number of particles per square millimeter of surface was 2,598 (95% CI 2,200 to 2,900) in group A catheters and 2,340 (95% CI 2,000 to 2,600) in the group B catheters (p = NS). The differences in the number of particles adhering to catheters touched by gloves and those that had not been manipulated were statistically significant (p < 0.001). CONCLUSIONS: Particles adhering to gloves can be drawn into the epidural space during continuous epidural anesthesia. All unnecessary manipulation should therefore be avoided, and the portion of the catheter to be inserted into the epidural space should not be touched in order to prevent possible nonspecific meningeal inflammatory responses. PMID- 10100440 TI - [Comparative study of percutaneous tracheotomy and conventional surgical tracheotomy in patients with prolonged intubation]. AB - BACKGROUND: Percutaneous tracheotomy (PT) has become an alternative to conventional surgical tracheotomy (CST) in recent years. Our aim was to compare the advantages and disadvantages of the two techniques in our intensive care unit (ICU). PATIENTS AND METHODS: Two patient groups were compared. Sixty underwent PT and 47 underwent CST, and all were admitted to the ICU between May 1995 and August 1997. PT was performed in 49 by way of progressive dilations, and 11 were performed by Griggs' method using a dilator. Variables studied were age, sex, reason for admission, APACHE II upon admission to the ICU, duration of technique, and immediate and late complications. Statistical analysis was provided by applying a Student t test to contrast quantitative variables and a chi-squared test to compare proportions. RESULTS: The following variables were significantly different. APACHE II upon admission was 18 +/- 5 in the PT group and 15 +/- 6 in the CST group (p < 0.002). Duration of the procedure was 15 +/- 4 minutes in the PT group and 36 +/- 11 in the CST group (p < 0.005). Complications after tracheotomy in PT group patients consisted of 1 false line during a change of cannula and 1 late tracheoesophageal fistula. Complications in the CST group included 16 episodes of slight bleeding, 9 stoma infections, 3 cases of pneumothorax, 2 of bad scarring of the stoma and 1 late fistula (p < 0.005). Time of follow-up was 41 to 76 days for PT patients and 32 to 51 days for CST patients. CONCLUSIONS: PT is a fast, simple procedure that is easy to manage and requires fewer resources (operating theater, personnel and equipment) and causes fewer medium-term complications than does CST. PMID- 10100441 TI - [Utility of double burst stimulation in the detection of residual neuromuscular blockade]. AB - OBJECTIVE: To assess the usefulness of double burst stimulation (DBS) for detecting neuromuscular blockade caused by atracurium and vecuronium. PATIENTS AND METHODS: One hundred nineteen adult patients were randomly assigned to receive atracurium (n = 62) or vecuronium (n = 57), with electromyographic monitoring of the number of responses to train of four (TOF) stimuli, TOF-ratio (TR) and the amplitude of the first TOF response (T1) in the pollicis adductor and the response to neurostimulator DBS in the contralateral forearm. During recovery from neuromuscular blockade an independent anesthesiologist manually assessed two responses to DBS every minute as being clearly differentiated, doubtful or undifferentiated. The results were later compared to T1 and TR. RESULTS: Significant differences (p < 0.05) between groups were observed for TR in doubtful (0.27 +/- 0.18 and 0.34 +/- 0.17 for atracurium and vecuronium, respectively) and undifferentiated (0.34 +/- 0.22 and 0.43 +/- 0.18, respectively) responses to DBS, and for T1 with three TOF responses (26.0 +/- 13.6 and 33.1 +/- 14.2, respectively) or four responses (30.9 +/- 14.1 and 38.7 +/- 18.4, respectively). T1 values when TR was 0.75 (extubation criterion) were 68.1 +/- 23.8% and 60.5 +/- 17.4% for the atracurium and vecuronium groups, respectively (NS). CONCLUSIONS: Assuming that DBS reduces the risk of residual curarization and that a TOF-ratio greater than 0.75 indicates adequate recovery from neuromuscular blockade, manual assessment of DBS response as obtained in this study indicates curarization and equal responses do not guarantee its absence. The most reliable index of recovery from neuromuscular blockade is the TR obtained by electromyographic monitoring. PMID- 10100442 TI - [Remifentanyl. Indications in anesthesia]. AB - Remifentanil is a new opioid in the fentanyl family. Developed and marketed by Glaxo Wellcome Inc., it was approved by the U.S. Food and Drug Administration in July 1996 and has been available for use in Spain since the end of 1997. Remifentanil is an analog of fentanyl (4-piperidyl anilide) with a methyl-ester group that allows the molecule to be hydrolyzed by esterases in plasma and tissues. Rapid onset and metabolism make it an easy drug to control for achieving the desired depth of anesthesia, although these aspects are also the drug's main drawbacks given that the anesthesiologist must plan and initiate postoperative analgesia before surgery ends. Rapid onset and potency also mean that the use of this drug for either postoperative analgesia or monitored sedation in awake state with spontaneous breathing needs further study to assess safety. PMID- 10100443 TI - [Ventilation in prone decubitus in a patient with respiratory distress during heart surgery]. AB - Acute respiratory failure and adult respiratory distress syndrome are serious complications after heart surgery and are associated with a high mortality rate. We report the case of a 50-year-old man who developed severe respiratory distress after heart surgery with extracorporeal circulation and for whom oxygenation was possible with ventilation in prone decubitus position only after other therapeutic measured had failed. The physiological bases of ventilation in prone decubitus position, as well as the indications and contraindications of the technique are discussed. Early treatment, which is fundamental for managing these patients, facilitates a favorable outcome as is illustrated by the case we report. PMID- 10100444 TI - [Anesthesia in a patient with along-standing congenital heart malformation of the complete atrioventricular canal type for non-cardiac surgery]. AB - Atrioventricular canal defects are a class of malformation attributable to anomalies in embryonic development of the anterior and posterior endocardial cushions. In the absence of surgical correction, death usually ensues in the first few years of life. Defects as severe as those observed in our patient are rare in adults. We describe the anesthetic management (epidural anesthesia with spontaneous ventilation by laryngeal mask) for a 46-year-old woman with this malformation who underwent emergency laparotomy. PMID- 10100445 TI - [Impossibility of intubation due to angioedema secondary to an angiotensin converting enzyme inhibitor]. AB - Angioedema secondary to treatment of one year's duration with angiotensin converting enzyme inhibitor (ACEI) (lisinopril) in a 56-year-old man scheduled for elective cardiac surgery led unexpectedly to impossible intubation. Surgical access (tracheostomy) was required when airway control was threatened. We review the clinical course, etiology and treatment of angioedema secondary to ACEI therapy. This is a life threatening complication which, though rare, is becoming increasingly frequent with increased use of such drugs. PMID- 10100446 TI - [Prolonged neuromuscular blockade caused by mivacurium in a pediatric patient]. PMID- 10100447 TI - [Rupture of the obturator stylet of an intradural needle]. PMID- 10100450 TI - Is it true bacteremia or pseudobacteremia? PMID- 10100448 TI - [Anesthetic considerations on perioperative pulmonary aspiration]. PMID- 10100449 TI - [Use of rocuronium in a pateint with myasthenia gravis]. PMID- 10100451 TI - Localization of bleeding site in the small bowel using a combined diagnostic approach. AB - The difficulty in localizing a bleeding site in the small bowel with sufficient accuracy to define a therapeutic target is well known. Great strides have been made in the realms of angiography and endoscopy in finding and treating lesions above the Ligament of Treitz and below the ileocecal valve. Although not as common as these, lesions in the small bowel, frequently remain obscure as to their origin and are associated with significant morbidity and mortality. In a significant percentage of cases, a discreet lesion is not found. Angiography, endoscopy, fluoroscopy and surgical resection have each proved useful but used together can increase the yield in diagnosis and treatment. An approach utilizing all of the above techniques together, necessitated by the failure of endoscopic coagulation and angiographic embolization, will be presented, whereby the bleeding site due to angiodysplasia of the jejunum was identified and definitively resected surgically. PMID- 10100452 TI - Citalopram: another SSRI antidepressant. PMID- 10100453 TI - What is the nature of increased Stroop interference in schizophrenia? AB - In comparison to controls, patients with schizophrenia classically display (1) an overall slowing in response times (RTs) and (2) a disproportionate slowing in RTs in the conflict condition of the Stroop color/word interference task. These two effects appear repeatedly in the card version of the Stroop task but were not replicated in a number of studies using a computer item-by-item version of the task. The present study was aimed at understanding the exact nature of the increased interference classically found in the performance of patients with schizophrenia in the card version of the Stroop task. We used a computer trial-by trial version in which we investigated the effects of two major methodological differences between the two versions: (1) blocked (card version) versus mixed (computer version) presentation of the neutral, congruent and conflict conditions and (2) presence (card version) versus absence (computer version) of distractors in the spatial surrounding of the target. We found an overall slowing in performance and a disproportionate slowing in the conflict condition for patients with schizophrenia but only when the target was surrounded by distractors (in Experiments 2 and 3). The data are discussed in terms of a deficit in selective attention and inhibitory processes in schizophrenia. PMID- 10100454 TI - Averaging expectancies and perceptual experiences in the assessment of quality. AB - This study examines whether people integrate expectancy information with perceptual experiences when evaluating the quality of consumer products. In particular, we investigate the following three questions: (1) Are expectancy effects observed in the evaluation of consumer products? (2) Can these effects be viewed in cognitive processing terms? (3) Can a mathematical model based on the averaging of attribute information describe the effects? Participants in two experiments blindly evaluated (with the product names removed) consumer products from six sensory modalities: vision (computer printer output), tactile (paper towels), olfaction (men's cologne), taste (corn chips), auditory (audio cassette tapes), and tactile/medicinal (hand lotion). Participants in both experiments were asked to: (1) rate the overall quality of the product given arbitrary quality labels (High Quality, Medium Quality, or Low Quality); (2) rate the overall quality of the product without the labels, and (3) estimate the scale values for the quality labels alone. Group results revealed main effects of the quality labels in all product categories. The pattern of results could be described by an averaging model based on Information Integration Theory. These results have implications for placebo effects in consumer behavior and decision making. PMID- 10100455 TI - Brief foveal masking during scene perception. AB - In the present experiment, participants were exploring line drawings of scenes in the context of an object-decision task, while eye-contingent display changes manipulated the appearance of the foveal part of the image. Foveal information was replaced by an ovoid noise mask for 83 ms, after a preset delay of 15, 35, 60, or 85 ms following the onset of fixations. In control conditions, a red ellipse appeared for 83 ms, centered around the fixation position, after the same delays as in the noise-mask conditions. It was found that scene exploration was hampered especially when foveal masking occurred early during fixations, replicating earlier findings. Furthermore, fixation durations were shown to increase linearly as the mask delay decreased, which validates the fixation duration as a measure of perceptual processing speed. PMID- 10100456 TI - Temporal relationships between eye fixations and manual reactions in visual search. AB - Observers freely searched for, and manually responded to, the presence of a target in multistimulus displays. The stimuli were presented on a cinema screen such that each display subtended a large visual angle to encourage the use of eye movements. Times taken to initially fixate the target (T1Fs) were compared to manual response times (MRTs). The results of two experiments were qualitatively similar, despite different levels of difficulty between them. MRTs were a linear function of T1Fs, but only when fixations did not occur very early after the onset of the stimulus display. When fixations were made very soon after the onset of the display, T1Fs were independent of MRTs. The findings were described within the framework of a one-way synchronization model which was modified to accommodate attention effects in visual search. Finally, the methodology provides a novel means of quantifying the contributions of eye movements to manual acknowledgements in real-world vision-guided tasks. PMID- 10100457 TI - Anxiety and depression among law students: current knowledge and future directions. AB - Increased psychology-law collaboration has yielded great strides over the past 20 years. However, one area of research that remains overlooked involves the psychological well-being of law students. The purpose of this article is to review and evaluate the existing literature on anxiety and depression among law students. This literature suggests that self-reports of anxiety and depression are significantly higher among law students than among either the general population or medical students. Recommendations for advancing knowledge in this area include developing hypothesis-driven research, using measures that adequately discriminate between anxiety and depression, and testing alternative hypotheses regarding the origins of law student distress. PMID- 10100458 TI - Empirical research on the insanity defense and attempted reforms: evidence toward informed policy. AB - This paper addresses some common questions about the insanity defense and issues raised by commonly proposed "reforms." The first section begins with a brief description of the insanity defense and the reasons for its existence in the law. It then examines some of the popular myths and public misperceptions surrounding the insanity defense. The next three sections discuss proposed "reforms" and the empirical research that addresses their effect. These reforms, including various procedural changes in definitions, burden of proof, and expert testimony, the institution of a guilty but mentally ill verdict, and the abolition of the insanity defense itself, are reviewed, along with relevant research findings and policy issues. Finally, the development of sound conditional release programs for criminal defendants found not guilty by reason of insanity is proposed as a reform option which could serve the objectives of enhancing public safety and access to appropriate treatment while continuing to meet the objectives of the insanity defense within criminal jurisprudence. PMID- 10100459 TI - Coronary stents. Tiny tubes that help keep blood flowing. PMID- 10100460 TI - Health tips. Losing (or gaining) 1 pound in a week. PMID- 10100461 TI - 'NEAT' may make a difference in weight loss or gain. PMID- 10100462 TI - Ingredient in green tea kills prostate cancer cells, study finds. PMID- 10100463 TI - Alcohol and health. Weighing the benefits and risks of drinking. PMID- 10100464 TI - Idiopathic pulmonary fibrosis. Careful diagnosis is crucial. PMID- 10100465 TI - COX-2 inhibitors. New medication for arthritis pain. PMID- 10100466 TI - My father has developed "trigger finger." What is this? PMID- 10100467 TI - Why do boils occur, and what's the best way to treat them? PMID- 10100468 TI - Recent insights into neuroendocrine mechanisms of aging of the human male hypothalamic-pituitary-gonadal axis. PMID- 10100469 TI - Debate: is ICSI a genetic time bomb? No: ICSI is safe and effective. PMID- 10100470 TI - Debate: is ICSI a genetic time bomb? Yes. PMID- 10100471 TI - Exposure of human, boar, or bull sperm to a synthetic peptide increases binding to an egg-membrane substrate. AB - We evaluated the effects of in vitro exposure of sperm to synthetic FertPlus peptide, which represents a 60-amino acid sequence within rat prosaposin, using a microwell sperm-binding assay (SBA), in which an extract of hen's egg served as the binding substrate. Sperm suspensions were incubated with FertPlus peptide (six to eight concentrations; 0 and 20-1,280 pM) at 37 degrees C for 10 minutes, diluted > or = 20 times, and placed onto SBA plates. After 60 minutes at 37 degrees C, unbound sperm were washed away and the DNA of bound sperm was quantified. Percentage of sperm bound was independent of the percentage of motile sperm, but immotile sperm did not bind. For fresh human sperm (25 ejaculates), the percentage of sperm bound was increased by exposure to 640 pM peptide (P < 0.01). For 11 of 25 samples, the percentage of sperm bound for the aliquot exposed to 640 pM peptide was > or = 1.4 times the value for a 0 pM control aliquot. With frozen-thawed human sperm, for six of seven samples, binding was > or = 1.4 times greater after exposure to 640 pM peptide. For boar sperm held for approximately 24 hours at approximately 18 degrees C before use (28 ejaculates), there was a higher percentage of sperm bound for aliquots previously exposed to 1,280 pM peptide than there was for control aliquots (P < 0.01). For 16 of 28 samples, exposure to peptide increased the percentage of sperm bound by > or = 1.4 times. For frozen-thawed bull sperm, percentage of sperm bound was > or = 1.4 times greater for 4 of 10 samples that were briefly exposed to 160 pM peptide. Clearly, human, boar, and bull sperm were beneficially modified by brief in vitro exposure to FertPlus peptide, so that for many samples a greater percentage of sperm was bound in vitro. As presented in an accompanying paper, fertility of bull sperm was increased by brief exposure to FertPlus peptide. PMID- 10100472 TI - Exposure of thawed frozen bull sperm to a synthetic peptide before artificial insemination increases fertility. AB - We evaluated the effect on fertility of in vitro exposure of thawed frozen bull sperm to synthetic FertPlus peptide prior to artificial insemination (AI). The peptide represented a 60-amino acid sequence within rat prosaposin. Commercial cryopreserved semen was from three Holstein bulls. Onset of estrus in groups of Holstein nulliparous heifers was synchronized via injection of prostaglandin F2 alpha, and heifers were scheduled for AI 8-24 hours after estrus was detected. Semen was thawed, diluted to 2.4 x 10(6) sperm/ml with buffer, and split to provide control and exposed aliquots (0 or 30 microM peptide) that were incubated at 37 degrees C for 10 minutes and then were held at 32 degrees C. The two aliquots of semen then were used on an alternate basis 2-65 minutes later to inseminate females. Each AI (one per female) involved the deposit of approximately 250,000 sperm into each uterine horn. This procedure for AI was used to reduce the pregnancy rate with control semen to below the maximum value for a given bull and to facilitate detection of any beneficial effect of the peptide. For each bull, approximately 32 heifers were inseminated with control semen, and approximately 32 heifers were inseminated with peptide-exposed semen. Pregnancy was evaluated ultrasonically approximately 60 days after AI. After excluding one group of heifers with unusually low fertility, averaged across all animals, a 29% increase in pregnancy rate resulted from exposure of sperm to peptide (P < 0.04; one-tailed chi-square test; means were 48 vs. 62%). Pregnancy rates for the three bulls for control and peptide-exposed semen, respectively, were 42 and 62%, 44 and 64%, and 56 and 61%; means in the first two pairs of values tended to differ (P approximately equal to 0.10). These observations should be confirmed with sperm from other bulls used in a more conventional manner. However, with insemination of a limiting number of cryopreserved sperm, brief exposure of the thawed bull sperm to FertPlus peptide appeared to improve fertility dramatically. PMID- 10100473 TI - Motility potential of macaque epididymal sperm: the role of protein phosphatase and glycogen synthase kinase-3 activities. AB - Human and monkey ejaculated sperm contain protein phosphatase-1 (PP1), PP1 inhibitor 2 (12), and glycogen synthase kinase-3 (GSK-3). Inhibition of ejaculated human sperm protein phosphatase (PP) activity with calyculin-a (CL-A) significantly stimulates motility, implicating protein dephosphorylation in motility regulation. The present experiments were conducted to characterize and compare PP and GSK-3 activity in monkey caput and caudal epididymal sperm, to determine the cellular distribution of these enzymes, and to test the thesis that epididymal sperm PP activity is inversely related to motility. Caput epididymal sperm populations, (8.8% motile) contained levels of PP activity that were >3 times as high as those of caudal spermatozoa. This PP activity was further identified by inhibitor response profiles as PP1. In both caput and caudal sperm, the majority of this PP1 activity was localized in 100,000 x g soluble fractions. Western blot analysis indicated that a portion of this difference was the result of elevated amounts of PP1 in caput compared with caudal epididymal sperm. The presence of GSK-3 activity was undetectable in 100,000 x g insoluble fractions of epididymal sperm, whereas both caput and caudal sperm soluble fractions contained GSK-3 activity, which was approximately threefold higher in caput sperm compared with caudal populations. Treatment of caput epididymal sperm from the rhesus macaque with the PP inhibitor CL-A resulted in a significant, dose-dependent increase from 8 to 38% motile cells (without any effect on their path velocity). In contrast, CL-A had no significant influence on either percent motility or path velocity of caudal epididymal sperm. Cytosolic PP1 and GSK-3 activities appear to be inversely related to the motility of monkey epididymal sperm and may have a regulatory role in the development of the potential for motility in epididymal sperm. PMID- 10100474 TI - Hormonal regulation of inhibin B secretion by immature rat sertoli cells in vitro: possible use as a bioassay for estrogen detection. AB - The influences of follicle-stimulating hormone (FSH), gonadal steroids, and culture time were studied in relation to inhibin B production by Sertoli cells of immature rats cultured in vitro. Sertoli cell-enriched cultures were established from 18-day-old rats and were maintained in medium supplemented with insulin, transferrin, and epidermal growth factor at 34 degrees C. A recently developed ELISA for the measurement of inhibin B was used to assess the effects of recombinant human FSH (rh FSH), testosterone (T), and estradiol (E2) on inhibin B production and accumulation in the culture media of Sertoli cell-enriched cultures and to optimize the cell culture system to serve as a bioassay for the detection and quantification of estrogens and estrogenlike substances. Prolonging the incubation time (24, 48, or 72 hours) of Sertoli cells with control medium without rh FSH, T, or E2 resulted in a time-dependent increase of inhibin B production. Incubation with rh FSH (1, 2.5, 5, or 10 U/L) caused a dose- and time dependent increase of inhibin B production by Sertoli cells (but not by cultured Leydig cells), reaching a plateau at 5 U/L rh FSH. Addition of T in concentrations of 2.88, 5, or 50 ng/ml to medium without rh FSH and E2 significantly lowered the daily production rate of inhibin B (P < 0.05). In contrast, addition of E2 (0.01 and 0.1 ng/ml) caused a dose-responsive increase in inhibin B production after 24 and 48 hours. The relative increment of inhibin B production induced by E2 was maximal after 24 hours in the presence of 2.5 U/L rh FSH (acting synergistically) and in the absence of T. When these conditions are implemented, the Sertoli cell culture system may serve as a bioassay for estrogenic substances, and it may reflect the possibly harmful effect they may have on spermatogenesis. PMID- 10100475 TI - Spermatogenesis in early and chronic phases of experimental spinal cord injury in the rodent model. AB - A rodent model was used to study the degree and dynamics of potential spermatogenic alterations during both acute and chronic phases after experimental spinal cord injury (SCI). Sexually mature Sprague-Dawley rats underwent controlled impact SCI by exposure of the thoracic spine, T-10 laminectomy, and intraoperative somatosensory-evoked potential latency and amplitude. A 50 gm-cm SCI was produced in 35 experimental subjects. Sham surgery was performed on 16 control subjects through exposure of the dura without weight drop. SCI was verified by obliteration of the somatosensory-evoked potential following injury and subsequent neurologic assessment (modified hindlimb Tarlov scale) 4 weeks after injury. Flow cytometry with acridine orange as the DNA probe was used to measure potential spermatogenic alterations in testicular cell development and integrity of epididymal sperm chromatin structure between 2 and 20 weeks following SCI. Flow cytometric analysis revealed that nine of the 35 SCI animals demonstrated altered spermatogenesis; it is not clear whether these effects are specific or nonspecific stress related. These responder animals contributed to dramatic differences in relative percent testicular haploid cells (spermatids) and concurrent differences in percent diploid cells at 2, 4, 8, 12, and 16 weeks. Percentages within the three spermatid populations (round, elongating, and elongated) also differed at these time points. The sperm chromatin structure assay (SCSA) revealed significant epididymal sperm nuclear structure differences at 2, 4, and 12 weeks (P < 0.001). These findings are in concordance with our clinical observations of spermatogenesis in spinal cord injured men and suggest that significant spermatogenic deficit may occur, even in the early phase of injury. PMID- 10100476 TI - Effect of acute androgen withdrawal by GnRH antagonist on epididymal sperm motility and morphology in the cynomolgus monkey. AB - Hormonal male contraception requires an induction phase before azoospermia and contraceptive safety are achieved. The nature of spermatozoa that may be ejaculated during this induction phase was studied in a nonhuman primate. The GnRH antagonist Cetrorelix was administered daily to five cynomolgus monkeys to induce testicular regression, and the vehicle was given to five control animals. Within 16 days, the antagonist reduced androgens by 80% in the serum and by 50% in the epididymis. Sperm were obtained by mincing different epididymal regions and were examined for morphology (subjectively) and motility (objectively) after removal of the organs 16 and 25 days after continuous treatment. Spermatozoa entering the epididymis of monkeys undergoing regression differed from those of vehicle-treated controls in their greater susceptibility to disruption during preparation for morphological staining. The acquisition of motility by sperm in the epididymides attached to regressing testes occurred in the same epididymal region as controls but did not achieve the median velocities attained by sperm in controls during epididymal passage. Values for most sperm motion parameters developed as in the controls, and, during epididymal passage, sperm developed resistance to stresses encountered during preparation for morphological analysis. These observations suggest that spermatozoa ejaculated before spermatogenesis ceases may be potentially fertilizing because epididymal maturation continues in an androgen-deprived organ. From these preclinical studies, it can be concluded that in men, applying hormonal contraception precautions against pregnancy must be recommended before azoospermia is induced, since the epididymis can partially compensate for poor-quality sperm produced by a regressing testis even when levels of circulating androgens and tissue androgens are low. PMID- 10100477 TI - Evidence for the regulation of prostatic oxytocin by gonadal steroids in the rat. AB - Oxytocin and its receptor are present in the mammalian prostate, and the peptide has been shown to increase prostatic growth, 5alpha-reductase activity, and contractility. This study was performed to investigate whether local concentrations of the peptide were regulated by gonadal steroids in order to establish whether oxytocin has a physiological role in the prostate. Both intact and castrated adult Wistar rats were treated daily for 7 days with either testosterone propionate or the antiandrogen cyproterone acetate. Animals were then killed, and plasma hormone and prostatic oxytocin concentrations were measured. A separate group of rats was treated with the 5alpha-reductase inhibitor finasteride to investigate whether testosterone or dihydrotestosterone (DHT) was involved in regulating oxytocin concentrations. In a further series of experiments, rats were treated with diethylstilbestrol (DES) or the antiestrogen tamoxifen. Treatment with testosterone significantly decreased prostatic oxytocin, whereas reduction of androgens by castration or by administration of cyproterone acetate increased prostatic peptide concentrations without altering circulating levels of the peptide. Treatment with finasteride increased plasma testosterone but decreased DHT concentrations. Prostatic oxytocin concentrations were higher in finasteride-treated animals than in control animals with comparable testosterone levels. The data suggest that both testosterone and DHT are capable of decreasing prostatic oxytocin concentrations. Treatment with DES did not significantly alter prostatic oxytocin, but administration of tamoxifen decreased concentrations of the peptide, suggesting that low levels of estrogen may be necessary for oxytocin production. These data provide evidence that oxytocin is regulated by androgens, and we hypothesize that this regulatory mechanism may be involved in controlling prostatic growth. PMID- 10100478 TI - Determination of the steady-state intracellular chloride concentration in capacitated human spermatozoa. AB - Chloride channels participate in the mammalian sperm acrosome reaction (AR). However, the mechanism by which sperm regulate intracellular Cl- concentration ([Cl-]i) is not known. The steady-state [Cl-]i has also never been reported for mammalian spermatozoa. Therefore, using chloride-sensitive fluorescent dyes, we sought to determine the steady-state [Cl-]i of capacitated human spermatozoa by a null-point measurement technique. We found that the [Cl-]i was sufficiently elevated (a conservative estimate of > or = 41 mM) such that the opening of chloride channels should result in a Cl- efflux and, hence, in depolarization. Moreover, the [Cl-]i does not remain constant under varying extracellular Cl- concentrations ([Cl-]o). PMID- 10100479 TI - Inhibin B levels in plasma of the male rat from birth to adulthood: effect of experimental manipulation of Sertoli cell number. AB - Sertoli cells undergo important changes in their number and function at different ages in the rat and may be the primary source of circulating inhibin B. The aims of this study were 1) to establish the profile of inhibin B levels from birth to adulthood in normal rats and 2) to identify whether experimental manipulation of Sertoli cell numbers was able to alter this profile. Levels of inhibin B, measured by a specific two-site assay, increased fivefold in normal Wistar rats between day 3 and days 10-15, plateaued, and then declined in late puberty to reach adult levels which were approximately 60% of those observed on days 10-15. The increase in inhibin B levels in the neonatal period coincided with the period of Sertoli cell multiplication as indicated by incorporation of bromodeoxyuridine. Neonatal treatment of rats with a GnRH antagonist (GnRHa) reduced Sertoli cell number and adult testis weight by 48% and significantly reduced plasma levels of inhibin B at all ages through to adulthood. Induction of neonatal hypothyroidism in Sprague-Dawley rats by administration of propylthiouracil (PTU) up to day 25 of age increased final testis weight by 41% (indicative of increased Sertoli cell numbers) and resulted in elevation of plasma levels of inhibin B at all ages beyond 7 days of age. The degree of change in inhibin B levels in adult rats in the two experimental treatment groups was approximately proportional to the change in final testis weight. Plasma follicle stimulating hormone (FSH) showed changes opposite to inhibin B, with levels being lowered in PTU-treated rats and elevated (beyond day 25) in GnRHa-treated animals. The present results suggest that final Sertoli cell number per testis exerts an important effect on the circulating level of inhibin B (and FSH) in the rat. These findings are compared to the emerging data for the human male. PMID- 10100480 TI - Suppression of growth hormone does not affect ongoing spermatogenesis in rats. AB - Recent evidence suggests that growth hormone (GH) may enhance physiologic processes, such as spermatogenesis, in addition to causing classical anabolic effects. We have previously shown that testosterone restores spermatogenesis in rats that were made azoospermic by immunization against gonadotropin-releasing hormone (GnRH). In this study, we investigated whether suppression of GH affects spermatogenesis and the ability of testosterone to restore spermatogenesis following immunization against GnRH and/or growth hormone-releasing hormone (GHRH). Twelve rats were actively immunized against GnRH (anti-GnRH), twelve rats were actively immunized against GHRH (anti-GHRH), six rats were immunized against both GnRH and GHRH (anti-GnRH/GHRH), and six rats served as controls. Two weeks after the second booster, six rats each from the anti-GnRH and anti-GHRH groups as well as the six anti-GnRH/GHRH rats received 24-cm testosterone-filled Silastic implants (T), and the remaining six rats from each of these groups received empty Silastic implants. All rats were euthanized 2 months later. Weights of testes and testicular sperm counts were determined. Serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) concentrations were determined by radioimmunoassays. Serum GH and IGF-1 were suppressed in anti-GHRH rats. IGF-1 was partially restored by testosterone in anti-GHRH and in anti GnRH/GHRH rats, but GH was restored to control value in anti-GnRH/GHRH rats. Serum LH and FSH were suppressed in anti-GnRH and anti-GnRH/GHRH rats, but only FSH was partially restored by testosterone. Suppression of GH did not affect maintenance of spermatogenesis. However, because T partially restored GH and IGF 1 levels in anti-GnRH/GHRH rats and because spermatogenesis was found to be restored in these rats, we conclude that GH does not play a role in the maintenance of spermatogenesis in adult rats, but it may be required for the replenishment of germ cells in experimentally induced regressed rat testes. PMID- 10100482 TI - Modulation of insulin-like growth factor-1 in the seminal plasma of infertile men. AB - It has been suggested that insulin-like growth factor (IGF)-1 plays an important role in the regulation of spermatogenesis in the testes. In the present study, concentrations of total IGF-1 were determined in the seminal plasma of fertile (n = 44), male-factor infertile (n = 34), and immunoinfertile (n = 10) men in order to investigate the role of IGF-1 in male infertility. Levels of IGF-1 were expressed both as nanograms per milliliter and as nanograms per milligram of protein. IGF-1 was detected in the seminal plasma of both fertile and infertile men. IGF-1 levels differed significantly between fertile and immunoinfertile groups (P < 0.035 to P < 0.0001), whether expressed as nanograms per milliliter or as nanograms per milligram of protein. The immunoinfertile group showed a 31.3 37.9% increase in the mean IGF-1 concentration over the fertile group. There was no statistical difference in the mean or median levels of IGF-1 between the fertile and male-factor infertile groups, whether expressed as nanograms per milliliter or as nanograms per milligram of protein. However, when the male factor infertile subjects were divided into four subgroups based on which seminal parameter was defective, the subgroup having a low sperm count had IGF-1 levels that were significantly different from the fertile group, the immunoinfertile subgroup, and the other male-factor infertile subgroups. The low-sperm-count subgroup had the lowest mean and median IGF-1 levels of all the groups and subgroups tested. IGF-1 levels linearly correlated (r = 0.30-0.499) significantly (P = 0.023-0.027) with the total sperm count in the semen, whether analyzed with all groups together or in subgroups by condition. These findings suggest that IGF 1 has a role in fertility and that its derangement may be involved in male infertility, especially when mediated through low sperm count and immunologic factors. PMID- 10100481 TI - Testosterone-dependent restoration of spermatogenesis in adult rats is impaired by a 5alpha-reductase inhibitor. AB - Germ cell development (spermiogenesis in particular) in the adult rat is known to be testosterone dependent. Recently we proposed a role for the 5alpha reduction of testosterone to dihydrotestosterone (DHT) in the short-term restoration of round spermatid maturation when testicular testosterone levels are experimentally lowered. The current study aimed to further characterize the involvement of 5alpha-reductase in the restoration of spermatogenesis by investigating the short and long-term restoration of specific germ cell populations by testosterone in the presence or absence of a 5alpha-reductase inhibitor (L685,273). Spermatogenesis in adult rats was suppressed for 8 weeks using 3-cm testosterone and 0.4-cm estradiol silastic implants (testosterone-estradiol [TE] treatment); spermatogenesis was then restored by administration of increasing doses of testosterone with or without a competitive 5alpha-reductase inhibitor or with the androgen receptor antagonist flutamide. Animals were then killed after either 4 days or 6 weeks of treatment so that we could study the short- and long-term restorations of spermatogenesis. Stereological analysis showed that germ cell development between late pachytene spermatocytes to round spermatids in stage VII during either short- or long-term restoration was not affected by 5alpha reductase inhibition, but it was affected by flutamide. The conversion of round spermatids between stages VII and VIII was restored by testosterone treatment, but this restoration was prevented by flutamide. Both the short- and long-term restorations of this midspermiogenic event were significantly decreased when 5alpha-reductase was inhibited. After long-term restoration of spermatogenesis, elongated spermatids were restored to 42% of control but were significantly suppressed to 20% of control by coadministration of the 5alpha-reductase inhibitor because of a reduction in the number of round spermatids progressing between stages VII and VIII. The results demonstrate that the 5alpha-reduction of testosterone is particularly important for progression through midspermiogenesis, because this phase of germ cell development is more sensitive to withdrawal of androgens. We suggest that testicular 5alpha-reductase activity is important for the restoration or maintenance of low levels of sperm production in a hormonally based contraceptive setting. PMID- 10100483 TI - Evidence for the role of heterotrimeric guanine nucleotide-binding regulatory proteins in the regulation of the mouse sperm adenylyl cyclase by the egg's zona pellucida. AB - Sperm acrosomal exocytosis is the result of a complex set of signal transduction pathways activated physiologically by the egg's extracellular matrix, the zona pellucida. In the mouse, the zona pellucida has been demonstrated to induce an increase in sperm intracellular pH, Ca2+, and cyclic adenosine monophosphate (cAMP) concentrations as well as to activate proteins of the Gi class (G; guanine nucleotide-binding regulatory proteins). We recently reported that the mouse zona pellucida could activate the adenylyl cyclase of mouse sperm. It is not known, however, whether zona pellucida stimulation of adenylyl cyclase activity is mediated through G proteins. In the present study, we demonstrate that the sperm membrane-bound adenylyl cyclase activity is stimulated by the G protein activators guanosine-5'-O-thiotriphosphate (GTPgammaS) and mastoparan in a concentration-dependent manner. The maximal adenylyl cyclase activity measured with these two G protein activators is similar to the stimulation observed with the zona pellucida, but the effect of GTPgammaS is not additive or synergistic with the effects of mastoparan or the zona pellucida. Pertussis toxin treatment of sperm membranes inhibits the zona pellucida stimulation of adenylyl cyclase activity, while the basal or forskolin-induced activation of the enzyme is not affected. Partial inhibition of the stimulatory effect of the zona pellucida on the adenylyl cyclase activity is observed with guanosine-5'-O-thiodiphosphate (GDPbetaS), another G protein antagonist. To a reconstitution system containing Lubrol-PX, where zona pellucida or GTPgammaS stimulation of the sperm enzyme is not observed, addition of G protein betagamma subunits restores the activation of the sperm adenylyl cyclase by the zona pellucida and GTPgammaS without affecting the enzyme activity under basal or forskolin-stimulated conditions. These results support our hypothesis that mouse sperm adenylyl cyclase is stimulated by the zona pellucida through a pertussis toxin-sensitive pathway involving G proteins of the Gi class. PMID- 10100484 TI - Contrin, the human homologue of a germ-cell Y-box-binding protein: cloning, expression, and chromosomal localization. AB - Inactivation of germ-cell-specific molecules essential for the production of functional spermatozoa could lead to attractive new means for male contraception. The mouse protein MSY2 is the mammalian homologue of a class of Xenopus DNA/RNA binding proteins needed for the transcription of testis-specific genes and for translational repression (masking) of paternal mRNAs. In this report, we describe the human homologue for MSY2, Contrin. Sequence analysis of Contrin cDNAs predicts a protein highly similar to its mouse and Xenopus germ-cell Y-box protein homologues with a cold shock domain and four basic/aromatic islands. Contrin is highly basic and is rich in the amino acids arginine and proline. It contains seven putative casein kinase 2 phosphorylation sites and three putative protein kinase C phosphorylation sites, suggesting that Contrin could be highly phosphorylated in vivo. The predicted protein sequence contains two nuclear localization signals, consistent with its predicted role of shuttling between nucleus and cytoplasm. Contrin maps to human chromosome 17p11.2-13.1. By the criteria of northern and western blotting, Contrin appears to be testis specific and distinct from other mammalian Y-box-binding proteins. We predict that inactivation of Contrin function in mammalian germ cells would prevent the formation of functional male gametes. PMID- 10100485 TI - Immunocytochemical localization of the Ya, Yb1, Yc, Yf, and Yo subunits of glutathione S-transferases in the cauda epididymidis and vas deferens of adult rats. AB - Glutathione S-transferases (GSTs) are dimeric proteins grouped into five classes based on the degree of amino acid homology of their subunits. They are involved in cellular detoxification through the catalyzation of the conjugation of reduced glutathione with various electrophilic substances. In the present study, the distribution of Ya and Yc subunits from the alpha family, Yb1 and Yo subunits of the mu class, and the Yf subunit of the pi class were examined with light microscope immunocytochemistry in Bouin-fixed, paraffin-embedded tissue of different regions of the cauda epididymidis and vas deferens. In the cauda, principal cells showed high levels of expression of Ya, Yc, and Yo subunits, while in the vas deferens, staining decreased to moderate levels for the Ya and Yo subunits and to low levels for the Yc subunit. While Yf was maintained at low levels in principal cells of all cauda and vas deferens regions, Yb1 expression was more erratic, presenting a checkerboard-like staining pattern in the proximal vas deferens and showing moderate cytoplasmic but intense nuclear reactivity in all other regions. Basal cells in the cauda were intensely reactive for Yf, while in the vas deferens, they became unreactive. Conversely, basal cells were unreactive for Ya in the cauda and proximal vas deferens, while in the middle and distal vas deferens, they became moderately reactive. In the case of Yb1 and Yo, some basal cells were reactive while others appeared unreactive in all cauda and vas deferens regions. Yc elicited the display of both reactive and unreactive basal cells in the cauda regions, and while the cells were moderately reactive in the proximal vas deferens, they became intensely reactive in the middle and distal vas deferens. In summary, both principal and basal cells show varying degrees of GST expression in the different regions of the cauda and vas deferens, suggesting that these cells are subjected to a complex, changing environment of substrates. Furthermore, while expression often differs from principal to basal cells, the absence of reactivity of a given GST in one cell type is usually compensated for by expression in the other cell type in any given region of the cauda or vas deferens. Taken together, the data suggest that ample protection from harmful circulating electrophiles can be provided for sperm during their storage in the cauda and vas deferens. In addition, since principal cells of the vas deferens are involved in steroid synthesis, the presence of GSTs in these cells may also serve to bind steroids, or this presence may be involved in steroid isomerization. PMID- 10100486 TI - Principal cells of the vas deferens are involved in water transport and steroid synthesis in the adult rat. AB - Principal cells show marked structural differences in the proximal, middle, and distal regions of the vas deferens, reflective of diverse functional activities. In the present study, we performed electron microscopy to examine the structural features of principal cells using glutaraldehyde-fixed, Epon-embedded material, while functional parameters were examined using light microscopic immunocytochemistry on Bouin-fixed, paraffin-embedded material. In the proximal region, the cuboidal principal cells resembled those of the cauda epididymidis, but few clear cells and occasional narrow cells were present. In the middle region, principal cells often contained blebs of their apical cytoplasm containing vesicular and tubular profiles. These blebs extended far from the cell surface and appeared to be liberated into the lumen, suggesting an apocrine type of secretion. In the distal region, dilated intercellular spaces containing numerous membranous profiles of different shapes and sizes were noted between adjacent principal cells and overlying basal cells. The use of an anti-aquaporin 1 antibody revealed an intense reaction over the endothelial cells of numerous vascular channels in the lamina propria. Taken together, these observations suggested water transport from the lumen of the vas deferens via the dilated spaces to underlying vascular channels, the function of which may be to concentrate sperm. The infranuclear cytoplasm of principal cells of this region showed whorls of smooth endoplasmic reticulum (sER). Large intracytoplasmic cavities were found within the sER aggregates, and these contained membranous profiles that appeared to peel off from the surrounding sER elements. Various images of such cavities closely juxtaposed to the lateral plasma membrane suggested that the membranous profiles of the intercellular spaces were derived from them. Use of anti-3beta-hydroxysteroid dehydrogenase antibody revealed an intense reaction over principal cells of the vas deferens, as well as over the blebs in the lumen of the vas deferens, which is indicative of the steroid synthesis performed by these cells. The release of sER membranous profiles into the dilated spaces and the presence of blebs in the lumen may represent a means of transporting steroids that are destined for different sites out of the principal cells. Steroids in the blebs would be ultimately destined for utilization by luminal sperm, while those steroids in the dilated spaces are designed for utilization by muscle layers of the lamina propria. In summary, principal cells of the vas deferens appear to be involved in synthesis and secretion of steroids and in eliminating water from the lumen of the vas deferens. PMID- 10100487 TI - The diagnosis and management of soft tissue sarcomas of the extremities in the adult. AB - Soft tissue sarcomas are uncommon malignancies found in 2/100,000 Americans. The accurate early diagnosis, adequate surgical resection and radiation treatment is associated with a good prognosis in low-grade sarcomas and a fair prognosis in high-grade sarcomas. This monograph will discuss the principles of diagnosis, clinical presentation, adequate surgical management, radiation therapy principles and role of chemotherapy in adult patients with soft tissue sarcomas of the superficial trunk and extremities. Management of metastatic disease will also be discussed. PMID- 10100488 TI - Analytical methods for 3-nitrotyrosine as a marker of exposure to reactive nitrogen species: a review. AB - Nitric oxide (NO*) is a diatomic free radical which has recently been found to have a key role in both normal physiological processes and disease states. The presence of NO in biological systems leads to the formation of reactive nitrogen species (RNS) such as peroxynitrite which reacts avidly with tyrosine residues in proteins to form nitrotyrosine (NTYR). Since peroxynitrite has a very short half life at neutral pH, the presence of NTYR has been used as a marker of RNS production in various tissues. A number of methods for separation, detection, and quantitation of NTYR in biological samples have been developed. These methods include immunochemical techniques such as immunhistochemistry, ELISA, and Western blotting, high-performance liquid chromatography (HPLC) in combination with various detection systems including UV and electrochemical detection (ECD), gas chromatography (GC), gas chromatography-mass spectrometry (GC-MS), and electrospray mass spectrometry. In terms of sensitivity and specificity, it would appear that methods based on combinations of HPLC and various types of ECD are very versatile giving a limit of detection of 20 fmol per injection of protein hydrolysate. They are only limited by the sample quantity and the preparation that is required to achieve acceptable chromatograms. In addition to the detection of NTYR as a marker of RNS, its role in biological systems may be more subtle with nitration of key tyrosine residues likely to profoundly affect cellular function such as signaling cascades. Further advances are likely to be made in the localization of NTYR residues in peptide fragments using mass spectrometry. PMID- 10100489 TI - Neuronal-type NO synthase: transcript diversity and expressional regulation. AB - Of the three established isoforms of NO synthase, the gene for the neuronal-type enzyme (NOS I) is by far the largest and most complicated one. The genomic locus of the human NOS I gene is located on chromosome 12 and distributed over a region greater than 200 kb. The nucleotide sequence corresponding to the major neuronal mRNA transcript is encoded by 29 exons. The full-length open reading frame codes for a protein of 1434 amino acids with a predicted molecular weight of 160.8 kDa. However, both in rodents and in humans, multiple, tissue-specific or developmentally regulated NOS I mRNA transcripts have been reported. They arise from the initiation by different transcriptional units containing alternative promoters (at least eight in the human gene), cassette exon deletions or insertions, and/or the usage of alternate polyadenylation signals. Depending on the insertions and deletions, translation results in functional or nonfunctional proteins. The use of alternative promoters can influence gene expression by various means. Indeed, NOS I is not a static, constitutively expressed enzyme, but subject to expressional regulation by various compounds and conditions. The molecular mechanisms underlying these regulations are currently being studied in several laboratories including our own. PMID- 10100490 TI - Detection of 3-nitrotyrosine in human platelets exposed to peroxynitrite by a new gas chromatography/mass spectrometry assay. AB - A new sensitive and specific assay was developed and applied for the quantitative determination of 3-nitrotyrosine in proteins of human platelets. 3-Nitrotyrosine was quantitatively converted into a new pentafluorobenzyl derivative in a single step and detected as an abundant carboxylate anion at m/z 595 using negative ion chemical ionization gas chromatography/mass spectrometry. The internal standard, [13C6]-3-nitrotyrosine, was prepared via a new and efficient method using nitronium borofluorate dissolved in hydrochloric acid. The assay showed excellent linearity and sensitivity. Intact human platelets contained 1.4+/-0.6 ng of 3 nitrotyrosine per milligram of protein. Peroxynitrite increased 3-nitrotyrosine levels 4- to 535-fold at the concentration range of 10 to 300 microM. Decomposed peroxynitrite was without the effect. Nitrogen dioxide (43 microM) was also a potent tyrosine nitrating molecule, increasing the levels of 3-nitrotyrosine 153 fold. HOCl (50 microM) in the presence of nitrite (50 microM) increased the 3 nitrotyrosine levels 3-fold. Exposure of platelets to nitric oxide, nitrite, thrombin, adenosine diphosphate, platelet activating factor, and arachidonic acid had no effect on platelet 3-nitrotyrosine levels. PMID- 10100491 TI - Nitric oxide products degrade chondroitin sulfates. AB - Nitric oxide (NO) is a potent endogenous vasodilator that is elevated in response to inflammation. Inflammation also produces high levels of superoxide, which combines with NO to produce peroxynitrite (PN). We have previously reported that NO degrades heparin and heparan sulfate under acidic conditions and that PN degrades hyaluronan (HA) at neutral pH. Heparin and HA are glycosaminoglycans (GAGs) widely distributed in the extracellular matrix of tissues. Disruption of intestinal GAGs, particularly the chondroitin sulfates, were linked to inflammatory bowel diseases. Chondroitin sulfate A (CSA), chondroitin sulfate B (CSB), and chondroitin sulfate C (CSC) are constituents of the basement membranes of many tissues, including the intestine. The purpose of this study is to determine whether the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and PN can degrade chondroitin sulfates in vitro. The NO donor SNAP (2 mM, pH 4.0) or PN (5 mM, pH 7.4) was incubated for at least 1 week at 37 degrees C with CSA, CSB, or CSC. Breakdown of CSA, CSB, and CSC was assessed by gel filtration chromatography and compared with untreated controls. Percentage degradation was calculated based on the change in peak height compared to the control. SNAP treatment partially degraded CSB and CSC, whereas PN partially degraded all three chondroitin sulfates. Nitric oxide mediated degradation of GAGs, and particularly chondroitin sulfates, may be an important pathway of inflammatory tissue damage. PMID- 10100492 TI - Nitrate reductase alters 3-nitrotyrosine accumulation and cell cycle progression in LPS + IFN-gamma-stimulated RAW 264.7 cells. AB - Nitrite (NO2-), an end product of nitrogen radical metabolism, has recently been shown to increase tyrosine nitration by activated leukocytes indicating that nitrite modulates the immune response. We investigated the hypothesis that nitrite may increase nitration of molecular targets within activated cells leading to altered cell cycle progression. Intracellular nitrite was increased by transfection of murine macrophage-like RAW 264.7 cells with the nitrate reductase gene obtained from barley. Nitrate reductase facilitates the conversion of nitrate to nitrite; thus when extracellular nitrate is present, intracellular nitrite will be increased. Results show that addition of KNO3 increases NO2- production and intracellular nitrotyrosine accumulation in the transfectant but not the parent. Inhibition of nitric oxide synthesis with L-NAME during activation with IFN-gamma + LPS reduced NO2- production to the same extent in both cell lines; however, cellular accumulation of nitrotyrosine was reduced by only 25% in the transfectant (P = 0.21) and 49% in the parent cell line (P = 0.007), suggesting that intracellular nitrite increased nitrotyrosine accumulation through a pathway not requiring NO synthesis, i.e., myeloperoxidase system. Approximately 15% of the transfected cells had 4n DNA content 24 h postactivation compared to < 1% of the parent cells. Increased DNA copy number was correlated to nitrotyrosine accumulation. These findings show that intracellular nitrite can increase accumulation of nitrotyrosine and that nitration is linked to cell cycle perturbation. PMID- 10100493 TI - A new assay for the determination of low-molecular-weight nitrosothiols (nitrosoglutathione), NO, and nitrites by using a specific and sensitive solid state amperometric gas sensor. AB - Nitric oxide (NO) is generated in biological systems and plays an important role as a bioregulatory molecule. Its ability to bind hemoglobin and myoglobin is well known. Moreover, it may lose an electron forming the nitrosyl group involved in the formation of S-nitrosothiols. The main problem in analyzing NO is its extreme reactivity. We have tackled this task by using an amperometric sensor to determine free NO, S-nitrosothiols (such as S-nitrosoglutathione), and nitrite in cell-free systems and murine microglial cell cultures. The determination of nitrosothiols is of biochemical relevance and a difficult task particularly at low concentration values. In this article we describe a new method based on the reductive cleavage of the S-NO bond by cuprous ions followed by a solid-state amperometric determination. The system described by us is sensitive, rapid, does not require previous purification steps, is easy to perform, and is inexpensive. For this reason, we think that it may represent an important analytical improvement. It has been suggested that nitrosothiols may exert biological activity by acting as a reservoir of NO. We tested the production of nitrite and of RSNO in stimulated, cultured murine microglial cells and we have shown that nitrite accumulates in these conditions. GSNO also accumulates, provided that GSH is present in the medium. PMID- 10100494 TI - A novel apparatus for the exposure of cultured cells to volatile agents. AB - This article presents a novel exposure apparatus that allows the exposure of cultured cells to volatile chemicals, e.g., inhalation anesthetics. The apparatus consists of an exposure chamber and a tightly linked vaporizer unit with pumps and valves allowing adjustable fluxes of mixtures of test chemicals and carrier gas under open and closed-circuit conditions. The exposure chamber uses commercially available cell culture flasks and accommodates up to 12 flasks simultaneously. Both modules fit into a standard culture incubator. The exposure chamber may be mounted onto an oscillating axis to tilt the cultures periodically forth and back, thus allowing direct contact of the cells with test atmosphere. The vaporizer unit is connected to a personal computer which lets the experimenter set the "open" and "close" intervals of individual valves thereby controlling the composition and flow rate of the test gas mixture. The vapor concentration of test chemicals can be monitored at the inlet and outlet using infrared photodetectors or mass spectrometers. Computer-aided processing of exposure protocols allows unattended runs. Exposure protocols can be scripted and stored on disk, thus ensuring interexperimental reproducibility of complex exposure profiles. As an application example, the effect of three volatile anesthetics, halothane, enflurane, and isoflurane, on the viability of three commercially available cell lines (A549--human lung carcinoma, HTC-rat hepatoma, MDCK--Madin-Darby canine kidney) was investigated. After exposure to haloalkyl vapors (3%) for 6 and 24 h, respectively, significantly increased LDH levels versus controls, indicating cellular membrane damage, were detected in A549 and hepatoma cells after exposure for 24 h. Hepatoma cells showed a significant LDH release also after 6 h exposure to isoflurane. On the other hand, LDH release from MDCK cells was not significantly different from controls even after 24 h of continuous exposure to any of the tested anesthetics. PMID- 10100495 TI - A pharmacological validation of radiotelemetry in conscious, freely moving rats. AB - Two reference substances were used in the present study. d-Amphetamine is a direct catecholamine-releasing agent which has a marked stimulant effect upon locomotor activity at low to moderate doses and induces stereotypy at higher doses. (+/-)8-Hydroxy-2-(di-n-propylamino)-tetraline [(+/-)8-OH-DPAT] is a selective 5-HT1A receptor agonist which produces a well-defined behavioral syndrome and a dose-dependent hypothermia. The first aim of this study was to validate that the d-amphetamine-induced activity monitored by telemetry correlated to that concomitantly measured in automated cages and complement these measures with an ethologically based direct observational technique. d Amphetamine (2.5 and 5.0 micromol/kg s.c.) stimulated locomotion as assessed with radiotelemetry, in automatic cages and by observation. Accompanying these behavioral effects was a concurrent increase (assessed by radiotelemetry) in heart rate but not in blood pressure. The second part of this study examined the pharmacological effects of (+/-)8-OH-DPAT (0.09-6.1 micromol/kg s.c.) on behavior (observation and activity) and temperature and on the cardiovascular system. (+/ )8-OH-DPAT induced the classical serotonergic syndrome of lower lip retraction, forepaw treading, and flattened body posture (observation), and this was accompanied by a concomitant hypothermia (radiotelemetry). (+/-)8-OH-DPAT also induced a dose-dependent and significant decrease in heart rate for 50 min of the 1-h long observation period. This was not accompanied by an increase in blood pressure in spite of the increased activity as seen with all three methods. These results show that radiotelemetry can be used as a tool to measure activity, core temperature, and the cardiovascular parameters in animals that are less stressed than those that are restrained for similar more invasive measurements, and that this technique can be used in combination with others to produce a more complete ethogram of the animal's responses to pharmacological challenges. PMID- 10100496 TI - The up-and-down method substantially reduces the number of animals required to determine antinociceptive ED50 values. AB - As a consequence of an awareness of animal welfare concerns, one of the goals in biomedical research is to reduce, whenever possible, the number of laboratory animals used for experimentation. The up-and-down method is a procedure that has been confirmed to reduce the number of animals needed to determine LD50 values without compromising reliability. The purpose of the present study was to evaluate whether the up-and-down method could be applied to reduce the number of animals required to obtain the ED50 values of various antinociceptive agents. The ED50 values of morphine, heroin, fentanyl, codeine, meperidine, delta9-THC, CP 55,940, nicotine, and epibatidine for mice in the tail-flick test did not differ between the up-and-down method and a traditional dose-response procedure. Whereas a mean of 28 mice/drug were used in the dose-response procedure, only eight mice/drug were used in the up-and-down method. Moreover, the ED50 values calculated by both methods were highly correlated with each other (r = 0.99). Similarly, intracerebroventricular administration of either delta9-THC or CP 55,940 to rats resulted in nearly identical ED50 values for both methods. These results support the use of the up-and-down method as an effective procedure to reduce substantially the number of animals needed to determine ED50 values of a variety of antinociceptive drugs. PMID- 10100497 TI - Radiotelemetric versus externalized catheter monitoring of blood pressure: effect of vasopressin in spontaneous hypertension. AB - The changes in arterial pressure that follow withdrawal of a 3-h intravenous infusion of arginine vasopressin (AVP; 20 ng/kg/min) in spontaneously hypertensive rats (SHR) were monitored by radiotelemetry or conventional externalized femoral arterial catheters connected to pressure transducers. Baseline control arterial pressure was lower in the telemetry group compared to the externalized group. After withdrawal of the AVP infusion, blood pressure fell below preinfusion levels in both groups but the decrease was much less in the telemetry group. Strikingly, absolute blood pressure values recorded both during and after the vasopressin infusion were remarkably similar in the two groups. Responses in rats with externalized catheters implanted 7 days before infusion of AVP, a protocol similar to the telemetry group, were similar to those in rats with catheters implanted 24 h earlier. Blood pressure remained decreased in SHR infused with AVP for several days with complete recovery requiring 6-7 days. In contrast, physical activity decreased only on the first day following withdrawal of the infusion. Thus, the mechanism accounting for the blood pressure decrease must be of a long duration and unrelated to a change in gross physical activity. The results emphasize the value of radiotelemetry for recording blood pressure responses. PMID- 10100498 TI - Electrochemical detection of nitric oxide production in perfused pig coronary artery: comparison of the performances of two electrochemical sensors. AB - In situ direct measurement of nitric oxide (NO) in biological media is now possible by means of electrochemical detection. In the literature, there are principally two amperometric approaches based on the direct oxidation of NO either on a sensor made from platinum/ iridium (Pt/Ir) alloy coated with a three layered membrane or on a nickel porphyrin and Nafion-coated carbon fiber electrode. Nonetheless, the exact nature of the experimental amperometric signal obtained with the Pt/Ir system was never authenticated as being related to NO. This study compared responses of two sensors to the inhibition effect of Nomega nitro-L-arginine (L-NA) as the amperometric signals produced by 5 hydroxytryptamine (5-HT) on isolated pig coronary preparations. These amperometric signals could be attributed to NO only for the nickel porphyrin and Nafion-coated carbon fiber electrode. Indeed, voltammetric characterization of the electrochemical response demonstrated only variations of the baseline current upon additions of either SNAP or NO on the Pt/Ir electrode instead of anodic peak current displayed at 0.63-0.75 V for the other system. Nitrites induced baseline current variations with the Pt/Ir electrode, similar to those obtained with S nitroso-N-acetyl-dl-penicillamine (SNAP) or NO. This study highlights the potential hazards and pitfalls that may be associated with the use of a Pt/Ir sensor calibrated with SNAP solutions for the detection of NO production in various biological systems. PMID- 10100499 TI - A rat model of acute respiratory distress syndrome (ARDS): Part 1. Time dependency of histological and pathological changes. AB - The time course of histopathological changes in a rat lung lavage model of the acute respiratory distress syndrome (ARDS) was analyzed by sacrificing animals 10, 30, 60, 180, and 210 min after the last lung parenchyma lavage which was performed with physiological saline solution. This lavage depleted the lung from its natural surfactant resources leading into a pathophysiological cascade similar to that of the acute respiratory distress syndrome. Tracheotomized rats (12 animals per time point) were pressure-controlled ventilated (Siemens Servo Ventilator 900C) with 100% oxygen at a respiratory rate of 30 breaths/min, inspiration-expiration ratio of 1:2, peak inspiratory pressure of 28 cm H2O at positive end-expiratory pressure (PEEP) of 8 cm H2O. During the whole experimental period, the ventilation was not changed. Blood gases (partial arterial oxygen pressures [PaO2, mmHg] and partial arterial carbon dioxide pressures [PaCO2, mmHg]) were estimated before, directly after, and 10, 30, 60, 90, 120, 150, 180, and 210 min after the last lavage. For grading lung lavage induced histopathological changes associated with the time-dependent development of ARDS, slides were coded and evaluated without any knowledge of the sacrifice time. A semiquantitative grading was performed with respect to the severity of the following parameters: hyaline membrane formation (HM), interstitial and intraalveolar edema edema (E), and margination and infiltration of polymorphonuclear neutrophil leukocytes (PMNL) into the lung alveoli. The severity of these parameters showed a time-dependent increase after the last lavage. This was accompanied by a time-dependent decrease in partial arterial oxygen pressure (PaO2) values during the early postlavage period (up to 30 min). Thereafter, PaO2 levels remained fairly stable. The severity of intraalveolar and/or perivascular hemorrhages within the lung was not time dependent. The rat lavage model shows similarities to the pathophysiological sequelae occuring during the acute phase of the acute respiratory distress syndrome in humans. Most of the characteristic pathognomic histological changes seen in humans can be observed in this lung lavage model. This ARDS model is brief and easy in its experimental design, showed a good and homogeneous reproducibility of pathophysiological and histopathological parameters, and is therefore a useful model to estimate the influence of therapeutic pharmacological treatments of ARDS. PMID- 10100500 TI - An in vivo model of beta-adrenoceptor desensitization. AB - Chronic use of beta2-agonists and increased production of inflammatory mediators during the late allergic reaction after antigen challenge results in the desensitization of beta-adrenoceptors in the airways and the accompanying rise in nonspecific airway hyperresponsiveness. In this study, we established an in vivo model of beta2-adrenoceptor desensitization in guinea pig airways by administration of IL-1beta intratracheally or chronic albuterol by inhalation. In the establishment of beta-adrenoceptor desensitization in response to both beta agonist or inflammatory mediator, baseline pulmonary function responses were established to methacholine and isoproterenol-induced relaxation of methacholine bronchoconstriction. This was followed by the administration of IL-1beta (500 IU/d intratracheally for 2 days) or chronic albuterol (0.1 g/L by aerosol for 1 min three times a day for 10 days). After administration, the methacholine and isoproterenol-methacholine response was once again evaluated. Intratracheal administration of IL-1beta or chronic administration of albuterol significantly decreased (p < 0.05) the protective effect of isoproterenol on methacholine induced bronchoconstriction, eliciting beta-adrenoceptor desensitization in vivo. The in vivo model will be very useful in monitoring the effect of other potential drugs on beta-adrenoceptor function in the airways. PMID- 10100501 TI - A method of computationally enhanced detection of chromatogram regions with apparent high relative agonist activity. AB - An occasional but difficult problem arises in drug discovery during a chromatographic analysis in which high background activity is associated with the presence of most eluting molecular species. This makes the isolation of material of high relative activity difficult. A computational method is shown that clarifies the identification of regions of the chromatogram of interest. The data for bioactivity and absorbance are normalized to percent of maximal response, filtered to raise very small or zero values to a minimal level, and the activity/absorbance ratio is plotted per fraction. The fractions with relatively high activity become evident. This technique is a helpful adjunct to existing graphical methods and provides an objective relationship between the data sets. It is simple to implement with Visual Basic and spreadsheet data, making it widely accessible. PMID- 10100502 TI - Effects of gliquidone on D-glucose metabolism in rat pancreatic islets depend on hexose concentration. AB - The hypoglycemic sulfonylurea gliquidone, used at a 10 microM concentration, failed to affect the metabolism of D-glucose in rat pancreatic islets incubated in the presence of 5.6 mM, 8.3 mM or 16.7 mM D-glucose. However, at 2.8 mM D glucose, gliquidone increased D-[U-14C]glucose oxidation while decreasing the utilization of D-[5-3H]glucose and generation of radioactive acidic metabolites and amino acids from D-[U-14C]glucose. These dissociated effects could conceivably be attributable, respectively, to activation of FAD-linked glycerophosphate dehydrogenase as a result of an increase in cytosolic Ca2+ concentration and to a subsequent inhibition of phosphofructokinase as a result of an increase in cytosolic ATP concentration. The effect of gliquidone on the paired ratio between D-[U-14C]glucose oxidation and D-[5-3H]glucose utilization was indeed duplicated by repaglinide and suppressed in the absence of extracellular Ca2+ or at low temperature. The present findings thus provide a further illustration of the often contrasting effects of pharmacological and physiological insulinotropic agents on selected metabolic, cationic and functional variables in pancreatic islet cells. PMID- 10100503 TI - Changes in glycemia induced by exercise in rats: contribution of hepatic glycogenolysis and gluconeogenesis. AB - The participation of hepatic glycogenolysis and gluconeogenesis to the glycemic changes promoted by exercise was investigated. For this purpose, we employed swimming rats (2.5% body weight extra load attached to the tail, at 24 degrees C) using a favorable condition to measure hepatic glycogenolysis (fed rats) and a favorable condition to measure hepatic gluconeogenesis (fasted rats). This experimental approach permits us to compare the contribution of hepatic glycogenolysis and gluconeogenesis to glucose changes for a specific schedule of exercise. The animals were investigated at rest, after 5 minutes of swimming and after swimming to exhaustion. Our results show that hepatic glycogen has a crucial role to determine hyperglycemia during exercise. In contrast, hypoglycemia developed during exercise when glycogen was depleted. However, the ability of the liver to produce glucose from L-lactate, glycerol and L-glutamine was increased during exercise. Taken together, these findings suggest that the hepatic capacity to produce glucose from gluconeogenic substrates (except for L alanine) was increased when hepatic glycogen stores were depleted. Thus, the increased capacity to produce glucose shown by livers from exercising rats must to be an important metabolic adaptation to protect against severe hypoglycemia. PMID- 10100504 TI - Hepatic and intestinal first-pass effects of a new hepatoprotective agent, YH439, in rats. AB - First-pass effects of YH439 were evaluated after intravenous, intraportal, oral, and intraduodenal administration of the drug, 100 mg/kg body weight, to rats. The first-pass effects of YH439 in the lung and heart seemed to be negligible based on total body clearance values after intravenous and intraportal administration of the drug to rats compared with cardiac output in rats. Approximately 60% of orally and intraduodenally administered YH439 was not absorbed from rat gastrointestinal tract and the F values of YH439 were less than 0.22% after both administration of the drug to rats. Therefore, it could be concluded that approximately 40% of orally and/or intraduodenally administered YH439 could disappeared by hepatic and/or gastrointestinal first-pass effects. The hepatic first-pass effect of YH439 absorbed into the portal vein was approximately 45% (AUC difference between intravenous and intraportal administration) in rats. The AUC0-8hr values of YH439 after oral (18.7 microg min/ml) and intraduodenal (23.4 microg min/ml) administration were significantly smaller than that after intraportal administration (3260 microg min/ml), however, the values were not significantly different between oral and intraduodenal administration, suggesting that the gastric first-pass effect seemed to be negligible and intestinal first pass effect was considerable in rats. The low F of YH439 in rats could be mainly due to unabsorption (approximately 60%) and hepatic and intestinal first-pass effect (approximately 40%). PMID- 10100505 TI - The role of alpha1-adrenoceptors in the clonidine-induced contraction and relaxation of rat aorta. AB - Clonidine causes dilatation of the aorta in the presence of endothelium, while it causes contraction of the aorta in the absence of endothelium. The present study was carried out to clarify the role of alpha-1-adrenoceptors in the vascular action of clonidine. The aortic rings were suspended in Krebs-Henseleit (K-H) medium, and the effects of alpha-1- and alpha-2-adrenoceptor antagonists on the clonidine-induced contractions were measured. Moreover, the role of the phosphatidylinositol (PI) response was examined. The aortic slices were incubated in K-H medium containing, [3H]myo-inositol and clonidine. The formation of [3H]inositol monophosphate (IP1) was measured with a liquid scintillation counter. Clonidine caused contraction of the aorta in the absence of endothelium, in a dose-dependent manner. This contraction was inhibited by antagonists in the following order of the potency: prazosin > phentolamine > spiperone > urapidil = yohimbine > L-659066 > atipamezole. On the other hand, clonidine inhibited norepinephrine (NE)-induced contraction in the aorta in the absence and in the presence of endothelium. Clonidine enhanced IP1 accumulation in the aorta in the absence of endothelium, whereas it inhibited NE-induced IP1 accumulation in the aorta. The present results show that alpha-1-adrenoceptors are probably involved in the clonidine-induced contraction and relaxation of the rat aorta. PMID- 10100506 TI - Identification of non-acetylated metallothioneins induced in rat liver by zinc. AB - In addition to the usual two rat metallothionein (MT) isoforms (MT-I and MT-II), a third isoform of metallothionein (MT-II) is known to be induced by zinc in the liver of rats and mice, and by epidermal growth factors in cultured cells. Although the third isoform has been suggested to be similar and related to MT-II based on its behavior on size-exclusion and ion exchange HPLC columns, further characterization has not been performed. MT-II' was identified in the present study as the unacetylated isoform of MT-II based on mass spectrometric data obtained by matrix assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF MS) (i.e., MT-II' was 42 Da smaller than MT-II in its molecular mass). Chromatographic properties of MT-II' were consistent with this species being an unacetylated isoform of MT-II arising as a result on lack of acetylation rather than a post-translational deacetylation event (i.e., an isoform of MT-II not co-translationally acetylated, based on the change in its composition relative to MT-II and MT-I after induction of MT expression). Although MT-I' was not separated under the present conditions, the MT-I fraction gave a mass peak corresponding to a species 42 Da smaller than MT-I. This suggested that non-acetylated isoforms of both MT-1 and MT-II were present. PMID- 10100507 TI - Enhancement of tissue factor following ischemic-reperfusion injury in rats. AB - To evaluate the involvement of tissue factor (TF) in blood coagulation reflecting injury of the blood vessels induced by reperfusion following ischemic treatment in rat abdominal blood vessels in vivo, both TF expression and prothrombin time (PTT), which is used as a marker of coagulation, were measured after ischemic reperfusion treatment. TF expression was significantly increased at 0 and 5 min after reperfusion following a 30 min period of vessel ligation, while the PTT was significantly shortened at 5 and 10 min. On the other hand, the change of TF expression and PTT were not detected in the animals ligated vessel for 15 min. These results suggest that TF plays an important role in the injury after reperfusion following ischemia. PMID- 10100508 TI - Mechanisms of the preventive properties of some garlic components in the carbon tetrachloride-promoted oxidative stress. Diallyl sulfide; diallyl disulfide; allyl mercaptan and allyl methyl sulfide. AB - Previous studies evidenced that garlic extracts and/or garlic components were able to prevent against chemically induced tumors or acute toxic effects of chemicals (e.g. CCl4 induced liver injury). The chemopreventive potential of garlic has been attributed to the presence in it of several bioactive organosulfur compounds. Those components might act as antioxidants able to scavenge free radicals. In the present work we describe initial studies on the antioxidative-stress properties of some garlic components such as: diallyl disulfide (DDS), diallyl sulfide (DAS), allyl mercaptan (AMT) and allyl methyl sulfide (AMS). We found that DAS, DDS and AMT but not AMS were able to trap trichloromethyl and trichloromethylperoxyl free radicals. Further, DDS but not DAS or AMT also inhibited CCl4 promoted liver microsomal lipid peroxidation. DAS, but not DDS, AMT or AMS was able to react with free radicals arised during UVC activation of hydrogen peroxide or terbutyl hydroperoxide but not with those produced during UVC activation of terbutyl peroxide. However, all garlic components tested absorbed energy from UVC and became partially destroyed in the process. AMT, but not DDS, AMS or DAS was able to destroy 4-hydroxynonenal, a key reactive aldehyde produced during lipid peroxidation. AMT and DDS were also able to prevent UVC plus CCl4 promoted oxidation of albumin in vitro, but DAS and AMS failed to do so. Results suggest that the antioxidative stress properties of garlic might result from the contributions of its sulfur component in different steps and not necessarily from the contribution of only one of them. PMID- 10100509 TI - Antioxidant activity of nasunin, an anthocyanin in eggplant. AB - Delphinidine-3-(p-coumaroylrutinoside)-5-glucoside (nasunin), an anthocyanin was isolated as purple colored crystals from eggplant peels, Solanum melongena L. 'Chouja'. Using an electron spin resonance spectrometer and 5,5-dimethyl-1 pyrroline-N-oxide (DMPO), spin trapping, hydroxyl (.OH) or superoxide anion radicals (02*-) generated by the Fenton reaction or the hypoxanthine-xanthine oxidase system were measured as DMPO-OH or DMPO-OOH spin adducts. L-Ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetra-methyl-2-(4,8,12-trimethyltridecyl)-2 H-1-benzopyran 6yl-hydrogen phosphate] potassium salt (EPC-K1) and bovine erythrocyte superoxide dismutase (SOD) were used as standards for .OH and O2*-, respectively. Nasunin directly scavenged O2*- with a potency of 143+/-8 SOD-equivalent units/mg), and inhibited formation of DMPO-OH (0.65+/-0.07 EPC-K1 micromol/mg). A spectrophotometric study showed that nasunin formed an iron complex with a molar ratio of nasunin : Fe3+ of 2 : 1. Therefore, hydroxyl radical scavenging by nasunin is not due to direct radical scavenging but inhibition of .OH generation by chelating iron. Nasunin (1 microM) significantly protected against lipid peroxidation of brain homogenates (p<0.001) as measured by malonaldehyde and 4 hydroxyalkenals. These findings demonstrate that nasunin is a potent O2*- scavenger and iron chelator which can protect against lipid peroxidation. PMID- 10100510 TI - Liver-protective activities of aucubin derived from traditional oriental medicine. AB - The iridoid glycosides including aucubin (AU), catalpol (CA), swertimarin (SW), and gardenoside (GA) are frequently found as natural constituents of many traditional oriental medicinal plants including Chinese herbs. Among these iridoid glycosides, AU was systematically studied for its potent liver-protective activities using experimental systems of hepatic damage. AU showed high liver protective activity against carbon tetrachloride-induced hepatic damage in mice. Also AU showed significant protective activity against alpha-amanitin-induced hepatic damage in mice, and it prevented a depression of liver RNA biosynthesis caused by alpha-amanitin administration. Potent antidotal effects on mushroom poisoning in beagle dogs ingested with aqueous extract of Amanita virosa was observed; beagle dogs completely survived, even when AU administration was withheld for half an hour after mushroom poisoning. In addition, AU was found to suppress hepatitis B viral DNA replication in vitro. Conversion of AU to its aglycone form appeared to be a prerequisite step for an exhibition of such antiviral activity. PMID- 10100512 TI - Image-guided and computer-aided surgery in otology and neurotology: is there already a need for it? PMID- 10100511 TI - Characterization of muscarinic receptors in rat bronchial smooth muscle in vitro. AB - This study was undertaken to assess the important muscarinic receptor subtype in acetylcholine (ACh)-induced rat bronchial smooth muscle contraction. Ring smooth muscle strips of the left main bronchus were used. Isometrical contraction was measured in response to ACh in cumulative concentrations (10(-7)-10(-3) M) with and without preincubations with the muscarinic receptor antagonists, pirenzepine (an M1 antagonist), methoctramine (an M2 antagonist), and 4-diphenylacetoxy N methylpiperidine (4-DAMP; an M1/M3 antagonist). Preincubation with these antagonists resulted in concentration-dependent rightward shifts of the concentration-response curves to ACh. pA2 values (means+/-sem) were 8.80+/-0.10 for 4-DAMP, 7.03+/-0.06 for pirenzepine and 5.91+/-0.36 for methoctramine, indicating that the most important muscarinic receptor mediating ACh-induced contraction of rat bronchial smooth muscle is of the M3 type. PMID- 10100513 TI - Chronic inflammatory ear disease and cholesteatoma: creation of auxiliary attic aeration pathways by microdissection. AB - HYPOTHESIS: The attic compartments, except for Prussak's space, are aerated through the tympanic isthmus. The aim of this study was to develop aeration pathways that would bypass the isthmus in surgery for chronic inflammatory ear disease and cholesteatoma. BACKGROUND: Microdissection of the epitympanum has shown that the anterior attic and the supratubal recess are separated by the tensor fold, the excision of which creates a large new aeration pathway. METHODS: Earlier surgical experience was reexamined as to the access to the tensor fold. Twenty temporal bones were dissected to create clinically useful new surgical routes for tensor fold removal in the presence of an intact ossicular chain. RESULTS: An endaural atticotomy, extended to the supratubal recess, allows excision of the tensor fold; however, the excision must be performed blindly. Cutting the neck of the malleus to allow lateral lifting of the manubrium exposes the tensor tendon and allows rapid excision of the fold. The elasticity of the tendon assists in approximation of the cut edges. In canal wall up surgery, removal of the lateral attic bone until the root of the zygoma exposes the anterior surface of the head of the malleus and the lateral portion of the transverse crest. Drill-out of the crest leads directly to the posterior side of the tensor fold, allowing its excision under direct vision. Thinning of the attic bone lateral to the body and short process of the incus allows simultaneous removal of the lateral incudomalleal fold. CONCLUSIONS: When the ossicular chain is discontinuous, tensor fold resection can be made under direct vision. With an intact chain, cutting of the neck of the malleus used in tympanic glomus tumors causes no hearing changes, allows complete fold excision, and is adaptable to chronic ear surgery. The frontolateral attic route for removal of tensor fold, together with the lateral incudomalleal fold, can be used in the canal wall up surgery to improve attic aeration. PMID- 10100515 TI - Aural cholesteatoma: role of tumor necrosis factor-alpha in bone destruction. AB - HYPOTHESIS: The bone destruction in cholesteatoma is multifactorial. This study was undertaken to define the role of tumor necrosis factor-alpha (TNF-alpha) in bone destruction associated with cholesteatoma. BACKGROUND: Tumor necrosis factor alpha is an important inflammatory cytokine secreted by activated macrophages. It stimulates keratinocytes as an autocrine growth regulator. Few authors have localized TNF-alpha in aural cholesteatoma. An attempt was made in this study to show a correlation between TNF-alpha and cholesteatoma associated bone destruction by localizing TNF-alpha in cholesteatoma and measuring its serum level. METHODS: Serum TNF-alpha levels were measured in 20 patients with cholesteatoma of temporal bone and histochemical staining was used to localize TNF-alpha in pathologic tissue excised at surgery. RESULTS: Serum TNF-alpha levels in patients with cholesteatoma were significantly higher than in controls. In addition, TNF-alpha levels in patients with bone destruction were higher than in those without bone destruction. However, there was no correlation between age of the patient and serum TNF-alpha levels. The TNF-alpha was localized in various layers of cholesteatoma epithelium using indirect immunoperoxidase staining. CONCLUSION: TNF-alpha is one of the cytokines produced by cholesteatoma that may be an important mediator of bone destruction associated with cholesteatoma. TNF alpha has been localized in various layers of cholesteatoma and exerts a locally destructive effect on bone. Serum TNF-alpha levels are related to the extent of bone destruction. PMID- 10100514 TI - Infiltration of immunocompetent cells in the middle ear during acute otitis media: a temporal study. AB - HYPOTHESIS: The inflammatory response to acute otitis media (AOM) is a chain reaction involving, among others, macrophages, B lymphocytes, and T lymphocytes that vary in number on different days during the infection. The response is thought to eventually contribute to tympanosclerosis (TS). BACKGROUND: In humans, TS and myringosclerosis (MS) are obscure sequelae of chronic otitis media. MS is also commonly seen in children who have had acute purulent otitis media or secretory otitis media or after treatment with ventilation tubes in the tympanic membrane (TM). It causes hearing disability, especially if the ossicles or the inner ear are affected. No successful treatment is available. This study was performed to evaluate the inflammatory stages that may lead to TS or MS. METHODS: Sprague Dawley rats were exposed to a Pneumococcus type 3 solution into the middle ear. Groups of rats were killed at 3, 6, and 10 days after inoculation. Sections from the TM specimen were stained immunohistochemically according to the avidin-biotin method. Antibodies used were directed against macrophages, T cells, and B cells. Positive cells were counted and a mean value was estimated for each slide and section for each antibody in each rat. RESULTS: Results showed that macrophages, T cells, and B cells were presented time-dependently in the acute inflammatory response in AOM. At day 3, dendritic cells, macrophages, T cells, B cells, and other major histocompatibility complex (MHC)-restricted cells were richly expressed in the whole submucosal layer and especially in the annulus fibrosus. At day 6, the amount of all positive cells decreased except for B cells and other MHC-restricted cells, which slightly increased in number. At day 10, all of the cells were lower in number than at days 3 and 6. Macrophages and possible T cells could be detected in the TM, which has not been observed earlier. Large osteoclastlike cells were present close to the bone. CONCLUSIONS: Macrophages were the first cells to invade the tissue after AOM induction. Some cells were found in the TM. Large osteoclastlike cells could be seen adjacent to the bone in the submucosa. T cells and B cells were seen in the submucosa. PMID- 10100516 TI - Does otosclerosis occur only in the temporal bone? AB - HYPOTHESIS: Otosclerosis does not occur outside the temporal bone. BACKGROUND: The widely accepted assumption that otosclerosis is confined to the temporal bone has never been tested. It is important to investigate this issue, particularly because of evidence that otosclerosis may be a systemic (genetic) disease that could affect other bones. METHODS: Biopsies from 9 to 11 skeletal sites were obtained from 2 patients with clinical otosclerosis. Two hundred forty-one nontemporal bone sections were examined by light microscopy. RESULTS: No nontemporal skeletal bone section showed histologic evidence of otosclerosis. The data indicate, with 95% confidence, that the true prevalence of otosclerosis in the extratemporal skeleton of the 2 patients examined was < 3%. CONCLUSIONS: These findings suggest that otosclerosis is unlikely to occur outside the temporal bone. Factors unique to the otic capsule that may predispose it to otosclerosis are lack of bone remodeling and the presence of globuli interossei. PMID- 10100517 TI - Influence of CO2 laser application to the guinea-pig cochlea on compound action potentials. AB - HYPOTHESIS: Experiments in guinea pigs were performed to clarify which, if any, of the CO2 lasers in different modes (continuous wave [cw] and superpulse) can damage the inner ear on application of the laser parameters required for stapedotomy and to determine their application safety. METHODS: The laser effect connected with perforating the basal convolution of the guinea-pig cochlea (cochleostomy) was examined. Acoustic evoked potentials (compound action potentials [CAPs]) yielded information on inner-ear function. RESULTS: In cw mode, even single applications of an approximately four times higher power density (60,000 W/cm2) than necessary for stapedotomy at a pulse duration of 50 msec (energies up to 1 J) and 20-fold applications of effective parameters for a footplate perforation (power density 16,000 W/cm2; energy 0.2 J) did not cause CAP changes. Experimental studies with the CO2 superpulse laser used (peak pulse powers: ca. 300 W) have demonstrated that irreversible CAP alterations already occur in the effective laser range in > 40% of the animals. CONCLUSIONS: Because damage is expected only at much higher energies (> 2 J) than those used clinically, the CO2 laser in cw mode has a high application safety for laser stapedotomy. The application of the CO2 laser in superpulse mode with peak pulse powers of approximately 300 W in stapedotomy appears to be more unreliable and dangerous for the inner ear. PMID- 10100518 TI - Beta-2 transferrin assay in the identification of perilymph. AB - HYPOTHESIS: Western blot assay for beta-2 transferrin protein is a clinically useful method for the detection of human perilymph and should be used for the diagnosis of perilymph fistulas (PLFs). BACKGROUND: Considerable controversy exists regarding the diagnosis of PLF. Recent studies suggest that the detection of beta-2 transferrin protein may be useful in the identification of perilymph. METHODS: To evaluate the usefulness of the beta-2 transferrin assay for identifying human perilymph, paired perilymph samples and negative controls were collected on Gelfoam pledgets from 20 patients who had surgery that opened the inner ear. Blinded immunoelectrophoretic assay (Western blot) for beta-2 transferrin was performed on each specimen. RESULTS: Only one (5%) of the known perilymph samples and none of the control specimens were definitely positive for beta-2 transferrin. Combined with historical data, this assay has 29% sensitivity, 100% specificity, 100% positive predictive value, and 31% negative predictive value. CONCLUSIONS: These findings suggest that the beta-2 transferrin protein assay may not be a reliable method for detecting human perilymph when performed using this technique. PMID- 10100519 TI - Combined rupture of Reissner's membrane and round window: an experimental study in guinea pigs: experimental double-membrane rupture. AB - OBJECTIVE: Hearing loss caused by combined rupture of Reissner's membrane and the round window (RW) membrane (the double-membrane rupture) may differ depending on the site of the lesion on Reissner's membrane. The purpose of this experimental study was to reveal the relationship between the hearing impairment and the site of the lesion on Reissner's membrane. BACKGROUND: According to experimental studies on perilymphatic fistula (PLF), profound hearing loss is not induced by rupture of RW alone, but by the double-membrane rupture. However, the mechanism responsible for hearing loss in the double-membrane rupture remains unclear. METHODS: Compound action potentials (CAPs) of the cochlear nerve in response to tone pip stimuli (1, 2, 4, and 8 kHz) were recorded before the lesion, 90 minutes after the Reissner's membrane rupture, and 90 minutes after subsequent laceration of the RW. Reissner's membrane was ruptured at one of the four turns for comparison. RESULTS: The double-membrane rupture caused a more severe increase in CAP thresholds than seen with separate ruptures, when the Reissner's membrane was ruptured at the second turn. Such pronounced increase in threshold was not seen in ears with the rupture at other turns. CONCLUSIONS: The double-membrane rupture causes varying degrees of hearing loss depending on the site of the lesion of Reissner's membrane. When the Reissner's membrane was ruptured at the second turn, the most severe hearing loss was detected. PMID- 10100520 TI - Cochlear implantation in children with large vestibular aqueduct syndrome. AB - OBJECTIVE: This study describes the effectiveness of a multielectrode cochlear implant prosthesis (Cochlear; Cochlear Pty., Lane Cove, Australia) for providing hearing to children with deafness caused by large vestibular aqueduct syndrome (LVAS). STUDY DESIGN: The study design was a retrospective study. SETTING: All the children attended The Children's Cochlear Implant Center (NSW), which is a specialist center that provides audiologic testing, speech therapy, habilitation, and medical assistance for children with cochlear implants. PATIENTS: Ten children were studied who had profound hearing loss and radiologic evidence of a vestibular aqueduct larger than 2 mm in width in its intraosseous portion. INTERVENTION: The children received a multielectrode (Cochlear) cochlear implant prosthesis, and the associated programming of the device and habitation were performed postoperatively. No significant problems were encountered at any of the surgeries, although there was an initial gush of perilymph when the otic capsule was opened in 7 ears. MAIN OUTCOME MEASURES: Postoperative audiologic performance at six monthly intervals and school performance were assessed. RESULTS: The postoperative auditory performance was improved in all children. At 6 months, their average BKB score had increased from 31% to 79%; average word score, from 8% to 43%; and average phoneme score, from 38% to 70%. The older children were able to continue their education in their usual setting with less reliance on hearing support staff. CONCLUSION: Children with a deteriorating hearing loss caused by LVAS can derive considerable benefit from a cochlear implant. PMID- 10100521 TI - Successful cochlear implantation in a patient with MELAS syndrome. AB - OBJECTIVE: To describe methods of assessing cochlear implant candidacy in patients with potentially significant peripheral and central nervous system (CNS) degeneration. STUDY DESIGN: A patient with a degenerative CNS disease (MELAS syndrome) undergoing evaluation for cochlear implantation is described. SETTING: This study took place at a tertiary care center. PATIENT: A patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) who had cortical blindness and profound sensorineural hearing loss was evaluated and rehabilitated with cochlear implantation. INTERVENTIONS: Pure-tone audiogram, behavioral responses to promontory stimulation electrical auditory brainstem response, and electrically evoked middle-latency responses (MLRs) were used to assess eighth nerve, auditory brainstem, and cortical auditory pathways. Cochlear implantation with Cochlear Corporation mini 22 implant was performed. RESULTS: Repeatable electrically evoked MLRs and behavioral responses to promontory stimulation documented the presence of auditory cortical responses. Successful implantation resulted in open set speech recognition and communication using the auditory/oral mode. CONCLUSION: This report describes successful implantation in a patient with MELAS syndrome and demonstrates the ability to preoperatively confirm the integrity of brainstem and cortical auditory pathways despite significant CNS degeneration. PMID- 10100522 TI - Depth and quality of electrode insertion: a radiologic and pitch scaling assessment of two cochlear implant systems. AB - OBJECTIVE: To compare the depth of electrode insertion in two types of cochlear implants, and to assess the ability of the implantees in each group to place pitch during random electrical stimulation. STUDY DESIGN: This was a prospective clinical study. SETTING: This study was performed at an implant program within a university teaching hospital. PATIENTS: Five consecutive patients with the Clarion (Advanced Bionics, Symlar, CA, U.S.A.) device and 5 with the Nucleus-22 (Cochlear Corporation, Sydney, Australia) implants were enrolled. All 10 implantees had fully active and functioning electrodes. INTERVENTIONS: The depth of insertion was determined using plain anteroposterior skull film and high resolution computed tomography (CT). The quality of electrode insertion was assessed by pitch scaling; electrodes were randomly stimulated to generate subjective pitch responses. OUTCOME MEASURES: The depth of electrode insertion was measured radiographically as degrees of angular rotation within the cochlea. For pitch scaling, the averaged responses to electrical stimulation was plotted against the "place" of the electrodes along the array. Pitch range, plateauing, and reversal of pitches were also noted. Insertion depth was correlated with the result of pitch scaling and open-set speech discrimination at 3 months. RESULTS: The mean insertion depth was 406 degrees for the Clarion device and 254 degrees for the Nucleus device. CT was used to confirm the intracochlear placement of the electrodes and their relationships to the cochleostomy site. It did not confer more information than the plain films unless kinking had occurred. Pitch perception was consistent with the tonotopic organization of the cochlea. The Nucleus-22 recipients displayed a broader range of pitches with less plateaus and reversals than the Clarion implants. The depth of insertion did not compare well with the outcome of pitch scaling or with open-set speech discrimination scores in either group of implantees. CONCLUSION: The preformed spiral array of the Clarion device allowed deeper electrode insertion compared to the Nucleus-22 device. However, depth of insertion did not translate into better pitch placement. PMID- 10100523 TI - Early results using the nucleus CI24M in children. AB - OBJECTIVE: To report early postimplantation speech recognition results in children who received Nucleus CI24M cochlear implants. STUDY DESIGN: The study group consisted of 19 consecutively implanted children. PATIENTS AND SETTING: Congenitally deaf children (20 months to 15 years old) were implanted with the Nucleus CI24M and followed-up at New York University Medical Center for a period of 3 to 12 months. MAIN OUTCOME MEASURES: Speech perception was evaluated preoperatively and postoperatively using the Early Speech Perception (ESP) test, the Glendonald Auditory Screening Procedure (GASP) word and sentence tests, Phonetically Balanced Kindergarten (PBK) monosyllabic word lists, Common Phrases test, the Multisyllabic and Lexical Neighborhood (MLNT, LNT) tests, and the Banford-Kowal-Bench (BKB) sentence test. RESULTS: One-way analyses of variance revealed significant improvement in open-set speech recognition in children able to perform measurement tasks. CONCLUSIONS: The Nucleus CI24M cochlear implant provides significant benefit to children after short-term use. PMID- 10100524 TI - Direct measurement of cerebrospinal fluid pressure through the cochlea in a congenitally deaf child with Mondini dysplasia undergoing cochlear implantation. AB - OBJECTIVE: Perilymph/cerebrospinal fluid (CSF) "gushers" may occur at cochleostomy during cochlear implant surgery, particularly in patients with congenital cochlear duct malformation in which CSF in the internal auditory meatus is in direct communication with the perilymphatic space in the cochlea. The object of the study was to measure the pressure and flow of a CSF gusher at cochleostomy. STUDY DESIGN: The design was a preoperative pressure measurement. SETTING: The setting was a multidisciplinary cochlear implant program. PATIENT: A 4-year-old girl with bilateral Mondini deformity undergoing cochlear implantation was studied. INTERVENTION: A size 23 FG intravenous cannula was inserted into the cochlea and connected to a pediatric drip set to form an improvised manometer. MAIN OUTCOME MEASURE: Intracochlear fluid pressure was measured at 14 cm H2O, equivalent to the normal CSF pressure that would be recorded in a child of this age at lumbar puncture. An indirect measurement of the likely size of the CSF/perilymph defect was made. RESULTS: This technique may allow better assessment of the risk of postoperative CSF leakage and meningitis. CONCLUSION: This simple technique of measuring the pressure in a perilymph gusher can be used to assess the need for careful sealing of the cochleostomy, to measure the reduction in pressure produced by head elevation or a spinal drain, and to assess the probable size of a defect in the lamina cribrosa. PMID- 10100525 TI - Intratympanic gentamicin for control of vertigo in Meniere's disease: vestibular signs that specify completion of therapy. AB - OBJECTIVE: To determine if a protocol of weekly intratympanic gentamicin injections administered until development of signs of unilateral vestibular hypofunction can alleviate vertigo while preserving hearing in patients with intractable vertigo caused by unilateral Meniere's disease. STUDY DESIGN: The study design was a prospective investigational protocol. SETTING: The study was performed in outpatients at a tertiary referral center. PATIENTS: Entry criteria included a diagnosis of "definite" Meniere's disease according to the 1995 report of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS), intractable vertigo despite optimal medical therapy, no symptoms suggestive of Meniere's disease in the contralateral ear and serviceable hearing in the contralateral ear. The outcomes of the first 34 patients who entered the protocol are reported. INTERVENTION: A buffered gentamicin solution was injected into the middle ear at weekly intervals until development of spontaneous nystagmus, head shaking-induced nystagmus, or head-thrust sign indicative of vestibular hypofunction in the treated ear. MAIN OUTCOME MEASURE: The 1995 AAO-HNS criteria for reporting treatment outcome in Meniere's disease were used. The effects of treatment were assessed in terms of control of vertigo, disability status, hearing level, and quantitative measurement of vestibular function with caloric and rotatory chair tests. RESULTS: Vertigo was controlled in 91% of the patients. Profound hearing loss occurred as a result of gentamicin injection in one patient (3%). Intratympanic gentamicin was significantly less effective in controlling vertigo in patients who had previous otologic surgery on the affected ear. Recurrence of vertigo > or = 6 months after initially complete control was noted in seven patients (22%). Vertigo in six of these patients was eliminated by additional intratympanic gentamicin injections. CONCLUSIONS: Ending weekly intratympanic gentamicin injections when clinical signs of unilateral vestibular hypofunction appear can control vertigo in most patients. Hearing loss directly attributable to gentamicin is uncommon. Treatment outcome is best in patients who have not had previous otologic surgery. PMID- 10100526 TI - Test-retest reliability of open-loop bithermal caloric irrigation responses from healthy young adults. AB - OBJECTIVE: To determine normal caloric responses and test-retest correlations of caloric responses in a group of otologically normal persons using an open-loop caloric irrigation system. STUDY DESIGN: An open-loop bithermal caloric irrigator was used to obtain maximum slow component speed caloric responses of healthy young persons with a repeat caloric test occurring- 1 week later. SETTING: The caloric examination took place in a university speech and hearing clinic. SUBJECTS: Twenty healthy young adults (10 men and 10 women, ranging in age from 18 to 33 years) who reported no history of dizziness or hearing loss were recruited at a university. They had thresholds of 25 dB HL or better for frequencies 250 of 8000 Hz and had passed an examination performed by an otologist. RESULTS: The mean unilateral weakness (UW) response was 1.73% with a standard deviation of 12.1%. Test retest correlations were 0.82 for UW and 0.80 to 0.90 for individual ear responses. CONCLUSIONS: The results indicate that a minimum of a 25% UW should be present when identifying a significant UW. Also the test-retest correlations were considerably higher using an open-loop irrigator than those obtained using a closed-loop irrigation system in a previously reported study. PMID- 10100527 TI - Saccular dysfunction in Meniere's disease. AB - OBJECTIVE: The aim of this study was to assess any dysfunction of the sacculus in patients with unilateral Meniere's disease by monitoring the vestibular evoked myogenic potentials (VEMPs) evoked by high level clicks on the Stemomastoid muscles (SCMs). STUDY DESIGN: The study was a retrospective analysis. SETTING: The study was performed in the E.N.T. department of the Lariboisiere Hospital. PATIENTS: Fifty-nine patients aged 18 to 74 years with well-established unilateral Meniere's disease were included in the study. INTERVENTIONS: Loud monaural clicks were delivered unilaterally, and the VEMPs were recorded with skin electrodes on the ipsilateral SCM. All the patients were also subjected to a pure tone audiometric test and bithermal caloric testing. The postural performances of 39 patients were analyzed using the Equitest. MAIN OUTCOME MEASURE: VEMP results were the main outcome measure. RESULTS: The saccular response was absent on the affected side in 54% of the patients with Meniere's disease. This absence was correlated with the degree of low frequency hearing loss but not with canal paresis. Finally, nonfalling patients with saccular dysfunction had a significantly poorer postural performance than those without such dysfunction in the condition 5. CONCLUSION: Patients with Meniere's disease could have a saccular dysfunction (54% in this series). This saccular impairment correlated with low frequency hearing loss but not with canal paresis. Patients without VEMPs had poorer postural performances in condition 5 than those with normal VEMPs. Therefore, VEMP testing is useful for detecting patients at risk: in patients with saccular lesion, the dynamic postural performances should be assessed on a movable platform to detect visually dependent patients and to orient vestibular rehabilitation. PMID- 10100529 TI - Origins of the short latency vestibular evoked potentials (VsEPs) to linear acceleration impulses. AB - OBJECTIVE: To verify the vestibular origin of the short latency (t < 12.5 msec) vestibular evoked potentials (VsEPs) in response to linear acceleration impulses (L-VsEPs) and to differentiate between the contributions of the otolith organs and the semi-circular canals (SCCs) to their initiation. DESIGN AND METHODS: L VsEPs (stimulus intensity, 3 g; rise time, 1.0 to 1.5 msec) were recorded in fat sand rats (Psammomys obesus) before and after unilateral labyrinthectomy, plugging of the SCCs in the remaining ear, and bilateral labyrinthectomy. Auditory nerve brainstem evoked responses (ABRs) and VsEPs to angular acceleration impulses (A-VsEPs) were also recorded. Wave amplitudes and latencies were statistically analyzed (MANOVA, repeated t-tests). RESULTS: In the intact animal, the linear VsEPs consisted of 5 to 6 waves, several mV in amplitude, with short latencies. The latency of the first wave was 2.0 msec. These waves were abolished after bilateral labyrinthectomy. Before and after plugging of the SCCs, linear acceleration VsEP wave latencies did not change, although amplitudes were slightly reduced. Similar results were obtained with respect to ABRs recorded from the same ear. Angular acceleration VsEPs were abolished after SCC plugging. CONCLUSIONS: These and other results confirm that the linear VsEPs are compound action potentials of the vestibular pathway, the first wave is the response of the vestibular nerve, and they are initiated mainly in the otolith organs. PMID- 10100528 TI - Three new surgeries for treatment of intractable Meniere's disease. AB - OBJECTIVE: This study aimed to describe the rationales for and preliminary results of three new types of surgery for the treatment of intractable Meniere's disease, all involving insertion of a capillary tube into the endolymphatic duct. This study also aimed to compare the contrasting surgical strategies of endolymphatic sac enhancement versus sac supplantation. STUDY DESIGN AND SETTING: The study design was a retrospective review of 129 surgeries conducted by the author at Chang Gung Memorial Hospital since 1993: 51 cases of Huang/Gibson inner ear shunt implantation, 52 cases of intraductal capillary tube implantation (ICTI), and 26 cases of ICTIin combination with endolymphatic sac ballooning surgery (ESBS). PATIENTS: This study is limited to patients with classic Meniere's disease whose vertiginous symptoms were disabling and refractory to dietetic and medical treatment. MAIN OUTCOME MEASURES: Comparison of preoperative and postoperative conditions (e.g., vertigo control, hearing, disability) using American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) 1985 criteria and chi-square statistical method was measured. RESULTS: After 1 year of follow up, use of the Huang/Gibson shunt resulted in a 94.1% vertigo control rate (complete or substantial) and fairly good hearing results, ICTI by itself resulted in an 88.5% rate of vertigo control and relatively unremarkable hearing results, and the ICTI in combination with ESBS (ICTI/ESBS) achieved a vertigo control rate of 96.1% in addition to good hearing results. CONCLUSIONS: The 1 year follow-up results for Huang/Gibson shunt implantation and sac-preserving ICTI/ESBS have approximately duplicated the excellent performance of the Arenberg implant after the same follow-up period, perhaps attributable in part to enhancement of endolymph flow through the endolymphatic duct. PMID- 10100530 TI - The growth of acoustic neuromas in volumetric radiologic assessment. AB - OBJECTIVE: The volumetric assessments of neuroma were applied for radiologic observation of tumor growth. The hypothesis that most of neuromas are stable or show only slight growth was tested. STUDY DESIGN: This was an observational study. SETTING: The study was performed in the university centers. PATIENTS: The study group included 27 patients with 15 unilateral tumors and 12 bilateral tumors. All patients had at least 2 magnetic resonance imaging (MRI) examinations, and the average interval between initial and control examinations was 11.4 months. MAIN OUTCOME MEASURE: Volume measurements were performed on T1- weighted MRI spin echo sequences after injection of gadolinium using special software. Growth of the tumors was estimated by comparison of the results of three measurements from the initial and control MRI examinations. RESULTS: The growth was confirmed in 17 of 27 tumors (63%). Growth was found in 10 of 12 neuromas of neurofibromatosis type 2 (83.7%). In 15 unilateral neuromas, growth was found in 7 (43%). Unilateral neuromas were observed for a shorter period of time (6.3 months) than bilateral tumors (14.7 months). The correlation between a neuroma volume gain and the follow-up period was statistically significant (p = 0.003, r = 0.544). CONCLUSIONS: The growth of tumors can be confirmed despite a short follow-up period. PMID- 10100532 TI - Facial neuromas in children: delayed or immediate surgery? AB - OBJECTIVE: The objective of this study was to investigate the clinical characteristics and outcome of facial nerve neuromas in children. To date, no specific study has focused on children, and the management of these tumors is not codified. DESIGN AND SETTINGS: A review of case series treated in a tertiary care center of pediatric otolaryngology. SUBJECTS: The treatment and outcomes for 7 children (4 infants and 3 adolescents) were analyzed. RESULTS: Six patients underwent complete removal of tumor and immediate restoration of the nerve continuity. The grade of facial palsy improved in 4 of the 6 children, but did not get better than grade 3 (House classification). The remaining patient was managed conservatively and remained stable clinically and radiologically after 9 years follow-up. CONCLUSIONS: These findings support the reasonable strategy of combining conservative assessment of these slow-growing tumors with regular clinical and radiologic evaluations and radical surgery using various procedures. The choice depends on the age of the child, the extent and growth rate of the tumor, the grade of facial palsy, and the hearing function. PMID- 10100531 TI - Case report and discussion of hearing preservation after translabyrinthine excision of small acoustic tumors. AB - OBJECTIVE: Since 1991, three separate reports have shown how hearing may be salvaged after translabyrinthine excision of small acoustic tumors. The authors submit yet another report of a complete translabyrinthine excision of a 1.4-cm intracanalicular acoustic tumor with modest hearing preservation. An attempt is made to retrace the steps of the operation and recognize and discuss what particular events may have safeguarded the viability of the cochlea. With the availability of cochlear implantation, there should be added incentive to preserve the cochlear neurones if hair cells cannot be saved. STUDY DESIGN: The study design was a retrospective case review. SETTING: The study was conducted at a primary care hospital. INTERVENTION: Therapeutic and rehabilitative measures were performed. MAIN OUTCOME MEASURES: Hearing preservation was measured. CASE REPORT: A 55-year-old woman presented with a left-sided hearing loss and a 1.4-cm left acoustic tumor completely filling the internal auditory canal (speech reception threshold [SRT] 30 dB, discrimination [Pb] 28%). A successful translabyrinthine excision of the tumor was performed in November 1995. A 1-year postoperative audiogram showed a mixed hearing loss in the left ear with SRT 85 dB and Pb 0%. Average pure-tone threshold for 500 Hz, 1 kHz, and 3 kHz was 50 dB and aided SRT 40 dB with Pb 64%. Postoperative magnetic resonance imaging confirmed complete excision of the tumor. CONCLUSION: An exceptional case of hearing preservation after translabyrinthine excision of a small acoustic tumor illustrates how it may be possible to preserve cochlear hair cells and neurones simultaneously in certain selected cases. A review of the surgical events shows the value of sealing the cochlear duct with bone wax, selectively removing the vestibular nerves with the tumor by sharp dissection, and safeguarding the meatal segment of the anterior inferior cerebellar artery by a limited dural incision. PMID- 10100533 TI - Imaging case of the month: recidivistic epidermoid tumor. PMID- 10100534 TI - Temporal bone histopathology case of the month: otosyphilis. PMID- 10100535 TI - A critical appraisal of spontaneous perilymphatic fistulas of the inner ear. AB - OBJECTIVE: This article provides an overview of relevant data supporting and refuting the existence of spontaneous perilymph fistula, as well as critically reviewing the literature pertaining to their evaluation and management. DATA SOURCES: Sources used were relevant English language clinical and basic science publications. STUDY SELECTION: A Medline search dating back to 1966 for articles concerning perilymphatic fistula, including both human and animal data, was performed. Articles were included if they contained relevant data or were significant reviews of the subject. A traditional bibliography search was then completed to acquire articles missed by the computerized search, including works published before 1966. DATA EXTRACTION: The data from each publication were critically reviewed. Emphasis on understanding the clinical features of surgically created perilymph fistulas was used to more objectively assess the data regarding spontaneous perilymph fistulas. DATA SYNTHESIS: The data were not amenable to formal meta-analysis or valid data summarization; however, when possible trends and contrasting data were emphasized. CONCLUSIONS: Spontaneous perilymph fistulas are very rare occurrences and the majority are likely incited by a pressure-altering event. Current methodologies do not provide sufficient specificity and sensitivity to accurately diagnose perilymph fistulas. The results of endoscopic studies of the middle ear in the evaluation of perilymphatic fistula suggest a low incidence compared with the large number of fistulas reported in the literature. A high index of suspicion must be maintained, and appropriate preoperative counseling should reflect the current controversies. Questions must continue to be asked and further research pursued to help distinguish reality from myth. PMID- 10100536 TI - Hepatitis B and hemodialysis: the impact of universal precautions in preventing the transmission of bloodborne viruses. PMID- 10100537 TI - Risk of tuberculosis transmission in an adult day-care center. PMID- 10100538 TI - Level of suspicion of pulmonary tuberculosis over a 4-year period in a teaching hospital. PMID- 10100539 TI - Tuberculosis contact tracing among healthcare workers: source-case selection, method of tracing, and outcome of follow-up. PMID- 10100540 TI - Vancomycin-intermediate Staphylococcus epidermidis: curio or omen? PMID- 10100541 TI - The emergence of decreased susceptibility to vancomycin in Staphylococcus epidermidis. AB - BACKGROUND: Coagulase-negative staphylococci (CNS) are the major cause of nosocomial bloodstream infection. Emergence of vancomycin resistance among CNS is a serious public health concern, because CNS usually are multidrug-resistant, and glycopeptide antibiotics, among which only vancomycin is available in the United States, are the only remaining effective therapy. In this report, we describe the first bloodstream infection in the United States associated with a Staphylococcus epidermidis strain with decreased susceptibility to vancomycin. METHODS: We reviewed the hospital's microbiology records for all CNS strains, reviewed the patient's medical and laboratory records, and obtained all available CNS isolates with decreased susceptibility to vancomycin. Blood cultures were processed and CNS isolates identified by using standard methods; antimicrobial susceptibility was determined by using minimum inhibitory concentration (MIC) and disk-diffusion methods. Nares cultures were obtained from exposed healthcare workers (HCWs) to identify possible colonization by CNS with decreased susceptibility to vancomycin. RESULTS: The bloodstream infection by an S. epidermidis strain with decreased susceptibility to vancomycin occurred in a 49-year-old woman with carcinoma. She had two blood cultures positive for CNS; both isolates were S. epidermidis. Although susceptible to vancomycin by the disk-diffusion method (16 17 mm), the isolates were intermediate by MIC (8-6 microg/mL). The patient had received an extended course of vancomycin therapy; she died of her underlying disease. No HCW was colonized by CNS with decreased susceptibility to vancomycin. CONCLUSIONS: This is the first report in the United States of bloodstream infection due to S. epidermidis with decreased susceptibility to vancomycin. Contact precautions likely played a role in preventing nosocomial transmission of this strain, and disk-diffusion methods may be inadequate to detect CNS with decreased susceptibility to vancomycin. PMID- 10100542 TI - The prevalence of colonization with vancomycin-resistant Enterococcus at a Veterans' Affairs institution. AB - OBJECTIVE: To study vancomycin-resistant Enterococcus (VRE) prevalence, risk factors, and clustering among hospital inpatients. DESIGN: Rectal-swab prevalence culture survey conducted from February 5 to March 22, 1996. SETTING: The Veterans' Affairs Medical Center, Atlanta, Georgia. PATIENTS: Hospital (medical and surgical) inpatients. RESULTS: The overall VRE prevalence was 29% (42/147 patients). The VRE prevalence was 52% (38/73 patients) among patients who had received at least one of six specific antimicrobials during the preceding 120 days, compared with only 5% (4/74) among those who had not received the antimicrobials (relative risk, 9.6; P<.001). The longer the period (up to 120 days) during which antimicrobial use was studied, the more closely VRE status was predicted. Among 67 hospital patients in 28 multibed rooms, clustering of VRE among current roommates was not found. CONCLUSIONS: At this hospital with relatively high VRE prevalence, VRE colonization was related to antibiotic use but not to roommate VRE status. In hospitals with a similar VRE epidemiology, obtaining cultures from roommates of VRE-positive patients may not be as efficient a strategy for identifying VRE-colonized patients as obtaining screening cultures from patients who have received antimicrobials. PMID- 10100543 TI - Management of a Sabia virus-infected patients in a US hospital. AB - OBJECTIVE: To describe the hospital precautions used to isolate a Sabia virus (arenavirus: Arenaviridae)-infected patient in a US hospital and to protect hospital staff and visitors. DESIGN: Investigation of a single case of arenavirus laboratory-acquired infection and associated case-contacts. SETTING: A 900-bed, tertiary-care, university-affiliated medical center. PATIENTS OR OTHER PARTICIPANTS: The case-patient became ill with Sabia virus infection. The case contacts consisted of healthcare workers, coworkers, friends, and relatives of the case-patient. INTERVENTION: Enhanced isolation precautions for treatment of a viral hemorrhagic fever (VHF) patient were implemented in the clinical laboratory and patient-care setting to prevent nosocomial transmission. The enhanced precautions included preventing aerosol spread of the virus from the patient or his clinical specimens. All case-contacts were tested for Sabia virus antibodies and monitored for signs and symptoms of early disease. RESULTS: No cases of secondary infection occurred among 142 case-contacts. CONCLUSIONS: With the frequency of worldwide travel, patients with VHF can be admitted to a local hospital at any time in the United States. The use of enhanced isolation precautions for VHF appeared to be effective in preventing secondary cases by limiting the number of contacts and promoting proper handling of laboratory specimens. Patients with VHF can be managed safely in a local hospital setting, provided that appropriate precautions are planned and implemented. PMID- 10100544 TI - Surgical-site complications associated with a morphine nerve paste used for postoperative pain control after laminectomy. AB - OBJECTIVE: To identify risk factors that might explain a sudden increase in the rate of surgical-site complications following laminectomy. DESIGN: Retrospective cohort study. PATIENTS AND SETTING: Patients who underwent laminectomy at a 120 bed hospital from August 1 through October 15, 1996 (the epidemic period). A case patient was defined as a patient with postoperative surgical-site complications (surgical-site drainage, edema, or swelling) requiring surgical debridement. RESULTS: Of the 148 patients who underwent a laminectomy during the epidemic period, 17 (11%) met our case definition. The rate of postoperative surgical debridement was 7.6-fold higher during the epidemic period than the preceding 19 month period (17/148 vs 15/995, P<.001). Development of surgical-site complications was associated with intraoperative receipt of morphine nerve paste (relative risk [RR], 11; P<.001), preoperative shaving by nurses rather than surgeons (RR, 6.6; P=.006), procedures done by a certain surgeon (RR, 3.1; P=.022), or receipt of iodine rather than povidone-iodine for preoperative skin antisepsis (RR, 5.1; P=.002). In multivariate analysis, only receipt of morphine nerve paste remained as a risk factor (RR, 18; P=.011). The paste was used to control postoperative pain and was applied directly to exposed dura and surrounding tissues. At the time of surgical debridement (median, 24 days postsurgery), the original surgical sites showed residual paste and a lack of healing. Ten of 16 cultures from surgical sites were positive; all but three grew skin commensals. Histological examination of surgical specimens showed a foreign body reaction, but no marked acute inflammation. CONCLUSIONS: The intraoperative use of morphine nerve paste may delay wound healing and increase postoperative morbidity. When new products are introduced, standardized protocols should be developed for their use, and systematic surveillance should be done to monitor for potential adverse outcomes. PMID- 10100545 TI - Epidemiology of device-associated infections related to a long-term implantable vascular access device. AB - OBJECTIVE: To examine risk factors for, and determine the incidence of, device associated infections among patients with an implantable vascular access device. SETTING: Grady Health System, including a 1,000-bed, inner-city, public, teaching hospital and human immunodeficiency virus (HIV), oncology, and sickle cell clinics in Atlanta, Georgia. PATIENTS: 123 consecutive patients who received a PAS-Port implantable venous access device between January 1 and June 30, 1995. DESIGN: Retrospective cohort study with follow-up > or = 1 year following device implantation. RESULTS: Underlying illnesses included HIV infection in 66 patients (median CD4 count, 24.4 cells/mm3), malignancy in 51, and sickle cell disease in 6. Mean age of patients was 43.7 years, 50% were male, and 74% were black. Thirty one (25%) of 123 patients developed a primary or device-associated bloodstream infection (BSI), and 3 of the 31 patients experienced two separate episodes of infection. The overall rate of infection was 1.23 primary BSIs per 1,000 device days. Patients with cancer had a lower rate of infection than those with HIV infection, but the difference was not statistically significant (0.96 vs 1.50 BSIs/1,000 device days; relative risk, 0.58; 95% confidence interval, 0.27-1.26). Subgroup analysis of patients with different malignancies indicated that infection rates differed according to type of cancer, and there was a trend for heterogeneity across the different cancer strata (P=.06). Gram-positive pathogens accounted for 60% of the pathogens recovered. Six (19%) of 31 patients who developed an infection did so within the first 14 days after implantation. In 11 (32%) of the 34 BSIs, the port required removal; two patient deaths were attributed to device-associated bacteremias (0.072 deaths/1,000 device days). CONCLUSIONS: Approximately one fourth of patients who had a vascular access device implanted developed a primary BSI, but the overall infection rate (per 1,000 device days) was relatively low, even among those with HIV infection. Primary BSI rates in patients with vascular access devices appeared to differ according to the specific underlying illness. PMID- 10100546 TI - Long-lasting contamination of a vitrectomy apparatus with Serratia marcescens. AB - OBJECTIVE: To investigate the contamination of a vitrectomy apparatus with Serratia marcescens. DESIGN: Descriptive microbiological and molecular environmental study. SETTING: An 1,800-bed university hospital. RESULTS: S. marcescens was found inside the vitrectomy apparatus at the pressure transducer. Molecular typing by randomly amplified polymorphic DNA-automated laser fluorescence analysis and pulsed-field gel electrophoresis identified a single pattern for all strains isolated from the apparatus. Surprisingly, the contaminating strain was identical to two strains of S. marcescens isolated nearly 2 years earlier from two patients who were involved in a small outbreak of acute postoperative endophthalmitis following cataract surgery at another hospital. The emergency vitrectomies in these patients were performed at our hospital with the same apparatus that was found to be contaminated 2 years later. CONCLUSION: Performing a systematic environmental search for the assumed bacterial reservoir within the system of the vitrectomy apparatus finally made it possible to find and eliminate the nidus for the gram-negative rod. Molecular typing demonstrated that all isolates belonged to a single genotype, and revealed unexpectedly a link to two vitrectomies performed 2 years earlier. The data support the hypothesis that the source of the contamination was one of these patients, and thus contamination of the apparatus was present for almost 2 years. PMID- 10100547 TI - Evaluation of the SENIC risk index in a Spanish university hospital. AB - OBJECTIVE: To assess the performance of the Study of the Efficacy of Nosocomial Infection Control (SENIC) risk index for the evaluation of the risk of surgical site infection (SSI) in a country other than the United States, having a different health system. SETTING: 350-bed university hospital in Spain belonging to the National Health System (Insalud). DESIGN: Observational cohort study of 1,019 patients who underwent consecutive surgery from January to December 1992. Surgical-infection risk factors assessed by the traditional wound-classification system (clean, clean-contaminated, contaminated, and dirty-infected wound) and by the SENIC risk index (length of intervention more than 2 hours, more than three discharge diagnoses, abdominal surgery, and contaminated or dirty-infected wound) were compared by forward logistic regression. RESULTS: The SENIC risk index showed a greater ability to predict SSI than the traditional wound-classification system. The study carried out in our institution reproduced the estimators provided by the SENIC study in the United States. The SENIC risk index provided a stepwise increase in SSI rates, according to the number of factors present, for every traditional wound-classification group. In the case of clean wounds, the incidence of surgical infection (per 100 interventions) increased (1.5, 2.4, 5.3, and 50; P<.001) for patients having from zero to three risk factors of the SENIC risk index. CONCLUSIONS: This study shows that the SENIC risk index results are reproducible, and the index can be used to compare rates of wound infection across countries with different health systems than the United States. PMID- 10100548 TI - Evaluation of a handwashing intervention to reduce respiratory illness rates in senior day-care centers. AB - To decrease respiratory infections in senior day care, staff were educated on viral transmission and the value of hand washing. Fanny packs with alcohol foam supplemented hand washing and were alternated monthly between centers. Infection rates were unchanged with alcohol foam use. The intervention year's infection rate was significantly lower than the previous 3 years, suggesting a benefit of education. PMID- 10100549 TI - Regional dissemination and control of epidemic methicillin-resistant Staphylococcus aureus. Manitoba Chapter of CHICA-Canada. AB - A methicillin-resistant Staphylococcus aureus (MRSA) strain introduced into the largest tertiary-care teaching hospital in Manitoba in 1993 led to a sustained outbreak with secondary outbreaks at one community hospital, two large long-term care facilities, and nosocomial transmission at a second teaching hospital. Control measures were consistent at each institution and were coordinated on a province-wide basis. MRSA is not currently endemic in any facility in the province. PMID- 10100550 TI - Nosocomial infections with ceftazidime-resistant Pseudomonas aeruginosa: risk factors and outcome. AB - Prospective studies were conducted for nosocomial Pseudomonas aeruginosa infections from February 1, 1994, to October 30, 1995. Of 97 P. aeruginosa isolates from 97 patients, 35 were resistant to ceftazidime. Logistic regression revealed previous cephalosporin or piperacillin use as independent risk factors for nosocomial ceftazidime-resistant P. aeruginosa infection. Pulsed-field gel electrophoresis revealed that four nosocomial ceftazidime-resistant P. aeruginosa infections were caused by cross-infection, probably through medical personnel. PMID- 10100551 TI - The effect of frequency of chart review on the sensitivity of nosocomial infection surveillance in general surgery. AB - OBJECTIVE: To assess the sensitivity of different frequencies of nosocomial infection surveillance (NIS) in general surgery. DESIGN: Data obtained with a prospective daily NIS are compared with those of hypothetical cross-sectional studies carried out with different frequencies (from one weekly visit up to one visit every other day). SETTING: General surgery services at three hospitals. MAIN OUTCOME MEASURE: Sensitivity in the detection of nosocomial infection (overall and stratified by site), compared to a gold standard of prospective surveillance of every patient's complete medical record daily from the first day after surgery until discharge and once more after discharge. PATIENTS: 5,859 patients. RESULTS: 837 nosocomial infections were detected by the gold standard (58.8% were surgical-site infections [SSI]). The sensitivity of weekly NIS for all infections was 74.5% (95% confidence interval [CI95], 71.4%-77.5%) and varied from 65.1% (CI95, 56.2%-73.3%) for urinary tract infection to 83.3% (CI95, 62.6% 95.3%) for respiratory tract infection; it was 76.4% (CI95, 72.4%-80.1%) for SSI. As expected, sensitivity increased with the frequency of NIS. Performing NIS every 4 days improved sensitivity significantly, to 82.3% (CI95, 79.5%-84.8%) for all infections and 83.3% (CI95, 79.7%-86.5%) for SSI. One visit every other day increased the sensitivity for all infections by another 4.9%, mainly due to increased detection of urinary tract and other less severe infections. CONCLUSIONS: The sensitivity of two visits a week exceeded that of one weekly visit by approximately 8%, and one visit every other day added another 5% increase. Results varied according to duration of infection and postdischarge hospital stay. PMID- 10100553 TI - Ifosfamide and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma. AB - We treated 40 patients with poor prognosis lymphomas. Patients with non-Hodgkin's lymphoma (NHL, n = 14) received MINE chemotherapy (mesna, ifosfamide 1330 mg/m2 and etoposide 65 mg/m2 by i.v. infusions on days 1-3, mitoxantrone 8 mg/m2 i.v. on day 1), and those with Hodgkin's disease (HD, n = 26) received VIM chemotherapy (mesna, ifosfamide 1200 mg/m2 by i.v. infusion on days 1-5, etoposide 90 mg/m2 by i.v. infusion on days 1, 3 and 5, and methotrexate 30 mg/m2 i.v. on days 1 and 5). Chemotherapy was followed by G-CSF (10 or 16 microg/kg in two divided doses daily) to mobilize PBSC. We performed 134 aphereses (median three leukaphereses per patient) starting on either day 13 (median; VIM) or day 12 (median; MINE). The median yield was 9.9x10(6) CD34+ cells/kg and 53.2x10(4) CFU-GM/kg for VIM, and 13.5x10(6) CD34+ cells/kg and 53.4x10(4) CFU-GM/kg for MINE. Except for predictable myelosuppression, no serious toxicity was seen. Response rate using MINE was 63% (18% CR, 45% PR) and using VIM 50% (17% CR, 33% PR). We conclude that VIM and MINE are effective and well-tolerated salvage regimens in patients with lymphomas and, followed by G-CSF, they also exhibit good capacity to mobilize stem cells in a predictable time interval. PMID- 10100554 TI - Mobilization of peripheral blood stem cells with docetaxel and cyclophosphamide (CY) in patients with metastatic breast cancer: a randomized trial of 3 vs 4 g/m2 of CY. AB - The purpose of this study was to develop a regimen of docetaxel, cyclophosphamide (CY) and filgrastim for mobilization of peripheral blood stem cells (PBSC) in patients with metastatic breast cancer (n = 66). A phase I trial of CY 2, 3 or 4 g/m2 with docetaxel 100 mg/m2, in consecutive cohorts of four patients each, did not reveal any dose-limiting toxicities and subsequent patients were randomized to receive 3 or 4 g/m2 of CY. The median yield of CD34+ cells from all patients was 11.06x10(6)/kg (range, 0.03-84.77) from a median of two aphereses (range, 1 7); 6.52x10(6) CD34+ cells/kg/apheresis (range, 0.01-52.07). Target CD34+ cell doses > or =2.5 and > or =5.0x10(6)/kg were achieved in 89% and 79%, respectively. There were no statistically significant differences in CD34+ cell yields or target CD34+ cell doses achieved following 3 or 4 g/m2 of CY. Patients with only one prior chemotherapy regimen yielded a median of 12.82x10(6) CD34+ cells/kg/apheresis compared to 5.85 for those receiving > or =2 regimens (P = 0.03). It was concluded that the combination of docetaxel, 100 mg/m2, CY 3 g/m2 without mesna could be administered with acceptable toxicity with collection of adequate quantities of PBSC from the majority of patients. PMID- 10100555 TI - Ifosfamide in combination with paclitaxel or doxorubicin: regimens which effectively mobilize peripheral blood progenitor cells while demonstrating anti tumor activity in patients with metastatic breast cancer. AB - For patients with metastatic breast cancer (MBC) who undergo high-dose therapy with autologous peripheral blood progenitor cell (PBPC) transplantation, an important prerequisite is a mobilization regimen that efficiently mobilizes PBPCs while producing an effective anti-tumor effect. We prospectively evaluated ifosfamide-based chemotherapy for mobilization efficiency, toxicity and disease response in 37 patients. Patients received two cycles of the ifosfamide-based regimen; ifosfamide (5 g/m2 with conventional-dose cycle and 6 g/m2 with mobilization cycle) with either 50 mg/m2 doxorubicin (if limited prior anthracycline and/or progression more than 12 months after an anthracycline-based regimen) or 175 mg/m2 paclitaxel. For the mobilization cycle, all patients received additional G-CSF (10 microg/kg SC, daily) commencing 24 h after completion of chemotherapy. The target yield was >6x10(6) CD34+ cells/kg, sufficient to support the subsequent three cycles of high-dose therapy. The mobilization therapy was well tolerated and the peak days for peripheral blood (PB) CD34+ cells were days 10-13 with no significant differences in the PB CD34+ cells mobilization kinetics between the ifosfamide-doxorubicin vs. ifosfamide paclitaxel regimens. The median PBPC CD34+ cell content ranged from 2.9 to 4.0x10(6)/kg per day during days 9-14. After a median of 3 (range 1-5) collection days, the median total CD34+ cell, CFU-GM and MNC for all 44 individual sets of collections was 9.2x10(6)/kg (range 0.16-54.9), 37x10(4)/kg (range 5.7-247) and 7.3x10(8)/kg (range 2.1-26.1), respectively. The PBPC target yield was achieved in 35 of the 37 patients. The overall response rate for the 31 evaluable patients was 68% with 10% having progressive disease. Thirty-three patients have subsequently received high-dose therapy consisting of three planned cycles of high-dose ifosfamide, thiotepa and paclitaxel with each cycle supported with PBPCs. Rapid neutrophil and platelet recovery has been observed. Ifosfamide with G-CSF in combination with doxorubicin or paclitaxel achieves effective mobilization of PBPC and anti-tumor activity with minimal toxicity. PMID- 10100556 TI - Autologous stem cell transplantation for T and null cell CD30-positive anaplastic large cell lymphoma: analysis of 64 adult and paediatric cases reported to the European Group for Blood and Marrow Transplantation (EBMT). AB - Anaplastic large cell lymphoma (ALCL) is a heterogeneous family of lymphoid tumours, among which the T and null cell types were recently listed in the REAL classification as a distinct entity. Reports on autologous stem cell transplantation (ASCT) in this group are only occasional. Sixty-four patients with T and null cell ALCL from 25 European centres had been registered with the European Group for Blood and Marrow Transplantation (EBMT) at the onset of this study. The median age was 25 years (range 3.2-53.0). Thirty of the 64 patients (47%) were in complete remission (CR), 18 (28%) in partial remission (PR), and the remaining 16 (25%) had a more advanced or chemotherapy-refractory disease at transplant. Eighty-one percent of the patients were conditioned with chemotherapy alone and 75% received marrow stem cells. All the patients transplanted in first CR (15), except one, maintained the CR over time; six of 15 transplanted in CR subsequent to first, six of 18 transplanted in PR and 14 of 16 transplanted in refractory or relapsed disease progressed. Actuarial overall survival (OS) at 10 years is 70%. Multivariate analysis showed that good status at transplant, younger age, absence of B symptoms and absence of extranodal disease indicated a better prognosis. These data suggest that ASCT should be considered as a possible treatment for chemosensitive patients in CR or PR. However, definitive conclusions cannot be drawn from this study and a prospective randomised trial between ASCT and conventional chemotherapy may be indicated. PMID- 10100557 TI - Prevention of graft-versus-host disease in high risk patients by depletion of CD4+ and reduction of CD8+ lymphocytes in the marrow graft. AB - From March 1994 to September 1997, 30 patients with hematological malignancies (12 ANLL, 10 CML, four ALL and four multiple myeloma) received HLA-identical allogeneic bone marrow transplants with the marrow graft selectively depleted of CD4+ lymphocytes and the CD8+ cell content adjusted to 1x10(6)/kg. Total depletion of CD4+ and partial depletion of CD8+ lymphocytes was carried out by an immunomagnetical method. All patients were considered as having high risk for developing GVHD by at least one of the following criteria: patient age >35 years; donor age >35 years; donor multiparity or marrow from an unrelated donor. Twenty four cases received marrow from an identical sibling and six from an unrelated donor. In order to assess the role of methotrexate (MTX) in addition to cyclosporin A (CsA) after transplant, patients were randomly assigned to received either CsA alone (n = 15) or CsA plus a short course of MTX (n = 15). No case of primary graft failure was observed, but two patients developed late graft failure. Six patients presented grade II acute GVHD and no case of severe III-IV GVHD was seen. The actuarial probability of developing grade II-IV acute GVHD was 25.9+/-9.6% for the entire population. Patients receiving post-transplant CsA + MTX had significantly less probability of acute GVHD than those receiving CsA exclusively (6.7+/-6.4% vs. 50.5+/-17.8%, P = 0.03) and the schedule of post transplant immunosuppression was the only factor associated with the incidence of acute GVHD in a multivariate analysis. The actuarial incidence of chronic GVHD for the entire population was 31.8+/-12.5, and there was no significant difference between both groups with additional prophylaxis. Four patients with CML and three with ANLL relapsed: the actuarial probability of remaining in complete remission for all patients was 53.6+/-17.3%. For patients with acute leukemia, the probability of remaining in complete remission did not differ significantly between those transplanted in first complete remission and those receiving a transplant in more advanced phases of the disease (87.5+/-11.6% vs. 72.9+/-16.5%; P = 0.44). The incidence of mixed chimerism assessed by PCR was 34%. Nineteen patients are alive between 2 and 43 months post-transplant, the probability of overall survival being 57.8+/-10.4%. Our data indicate that this method of selective T cell depletion is very effective in preventing acute GVHD in high risk patients, particularly when used in combination with post-transplant CsA + MTX. PMID- 10100558 TI - Immune reconstitution after bone marrow transplantation for combined immunodeficiencies: down-modulation of Bcl-2 and high expression of CD95/Fas account for increased susceptibility to spontaneous and activation-induced lymphocyte cell death. AB - We have studied the regeneration of T cell subsets and function after BMT in 21 children affected by combined immunodeficiency after BMT. In the first months, the striking predominance of CD4+ cells displayed the primed CD45R0+ phenotype and a high number of activated (HLA-DR+) T cells were observed. Regeneration of naive CD4+CD45RA+ cells correlated with the recovery of proliferative responses to mitogens (r = 0.64, P<0.001). Peripheral blood lymphocytes circulating after BMT undergo an increased process of in vitro cell death, resulting from two mechanisms: spontaneous apoptosis (SA), a consequence of defective production of IL-2 and down-regulation of Bcl-2 (P = 0.02 vs. healthy controls), and high susceptibility to activation-induced cell death (AICD) after restimulation with mitogens. In accordance with the role of CD95/Fas in this latter process, we have observed a high level of CD95 expression (P<0.001 vs. healthy controls), correlated with AICD (P<0.001) but not with SA, and decreasing with time after BMT (P<0.001). Both SA and AICD levels correlated with the presence of activated T cells and decreased with the progressive recovery of T cell proliferative response. Therefore, the lymphocyte hyperactivated status might explain their susceptibility to apoptosis and contribute to the genesis of immunodeficiency that follows BMT. PMID- 10100559 TI - Short-term toxicity in pediatric marrow transplantation using related and unrelated donors. AB - The use of volunteer, unrelated donors has substantially increased the number of potential donors for pediatric marrow transplantation during the past few years. We describe our single institution experience of short-term toxicity after pediatric marrow transplantation using sibling or unrelated donors. Fully matched (A, B and DR loci) donors were employed in 94% of the cases in both groups. Conditioning of similar intensity and uniform supportive care were employed in the two groups. Both primary non-engraftment and secondary graft failure were more common among recipients of unmanipulated URD grafts. Clinically significant (grades III-IV) acute GVHD and toxic mortality during the immediate post transplant period were also higher in this group of patients. Pediatric marrow transplantation using volunteer, unrelated donors appears to be associated with an increased incidence of procedure-related toxic complications. PMID- 10100560 TI - Evaluation of uroprotective efficacy of amifostine against cyclophosphamide induced hemorrhagic cystitis. AB - The role of amifostine in the prevention of cyclophosphamide-induced hemorrhagic cystitis (HC) was evaluated in the rat model. Urinary bladders from control rats that received no drugs (group I) were compared with those from rats receiving cyclophosphamide alone at a dose of 150 mg/kg (group II), and two other groups receiving amifostine at 100 mg/kg (group III) and 200 mg/kg (group IV), 15 min prior to cyclophosphamide. Bladders were assessed macroscopically and histologically at 24 h and after 7 days. All the animals that received cyclophosphamide alone developed severe HC. On the basis of the scores of macroscopic and histologic changes, animals that received amifostine showed excellent uroprotection. Only 2/6 rats in group III and 1/6 rats in group IV developed mild HC at 24 h. None of the rats in either of these groups showed any evidence of HC at 7 days. It is concluded that amifostine protects the urothelium against cyclophosphamide-induced HC. PMID- 10100561 TI - Varicella zoster virus infection associated with high-dose chemotherapy and autologous stem-cell rescue. AB - A retrospective evaluation of 215 consecutive recipients of high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) was conducted to ascertain the incidence, temporal course, and outcome of varicella zoster virus (VZV) infection. Herpes zoster was identified in 40 individuals at a median of 69 days following ASCR. Six of these cases occurred at a median of 33 days prior to ASCR but following the initiation of high doses of stem cell mobilization chemotherapy. Twenty-five percent of patients demonstrated cutaneous or systemic dissemination and 32.5% required medical intervention for post-herpetic neuralgia. All except two individuals received antiviral chemotherapy. One patient with active VZV infection died of multiorgan failure 39 days after ASCR. Multivariate analysis of risk factors disclosed the significance of prophylactic acyclovir use in Herpes simplex virus seropositive individuals in reducing the risk of VZV infection. Moreover, the use of busulfan, thiotepa and carboplatin as the conditioning chemotherapy regimen was associated with an increased risk of subsequent VZV infection. The incidence of VZV reactivation after HDC and ASCR is similar to that observed following bone marrow transplantation but has an earlier onset. This may be related to an earlier induction of immunosuppression by stem cell mobilization chemotherapy administered prior to ASCR. We demonstrated a marked reduction in the proliferative and synthetic capacities of peripheral blood mononuclear cells obtained prior to and following stem cell mobilizing chemotherapy. Moreover, greater than 80% of VZV infections occurred within 6 months following ASCR and late cases were seldom observed compared to allogeneic and autologous bone marrow transplantation. The role of antiviral chemoprophylaxis during the period of maximum immunocompromise needs to be studied further in the HDC-ASCR setting. PMID- 10100562 TI - Increasing mixed haematopoietic chimaerism after BMT with total depletion of CD4+ and partial depletion of CD8+ lymphocytes is associated with a higher incidence of relapse. AB - In this study we analysed the incidence and clinical impact of the persistence of host haemopoiesis (mixed chimaerism, MC) after allogeneic BMT in 35 consecutive patients with haematologic malignancies using a total CD4+ cell-depleted graft with an adjusted dose of CD8+ cells (1x10(8)/kg). Chimaerism was assessed by PCR amplification of VNTRs in 30 evaluable patients: 19 non-CML and 11 CML cases which were also evaluated for the BCR-ABL transcript by RT-PCR. All but one had complete engraftment with a donor profile early post-BMT. At the end of the study period, 12 of 30 patients displayed MC (40%). The overall disease-free survival for MC patients was clearly unfavourable when compared to those who exhibited a donor profile (24.7% vs. 100%, P = 0.005). However, we found that only two of five patients with MC in the non-CML group relapsed, whereas a clear correlation could be made between MC and relapse in CML (seven showed MC, preceding cytogenetic or haematological relapse in six of them, which displayed a prior BCR ABL mRNA positivity). In addition, a quantitative-PCR approach enabled us to demonstrate that increasing amounts of MC are invariably associated with subsequent relapse, whereas a low stable level of host or complete donor haemopoiesis is consistent with clinical complete remission. Although these results suggest that the clinical impact of MC may depend on the underlying disease, it is compatible with the concept that the graft-versus-leukaemia effect against CML is mainly exerted by donor CD4+ lymphocytes. Elimination of this cellular subset may be responsible for the inability of the graft to prevent a progressive increase in the tumor cell burden. PMID- 10100563 TI - Interferon alpha for chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation. AB - Interferon alpha (IFN alpha) induces cytogenetic responses in patients with chronic myeloid leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT). The purpose of this study was to analyze the therapeutic role of IFN alpha in this setting. The experience of a single institution and the published results on this topic were evaluated. We have included patients who received IFN alpha as a single agent, excluding those patients who received previous or simultaneous donor leukocyte infusions. The outcomes of 11 patients treated in our center and those of 108 previously reported patients have been analyzed. Five out of 11 patients treated in our institution obtained a complete cytogenetic response (CGR). Two patients continue in complete cytogenetic response 3.5 and 8.2 years later, and the qualitative RT-PCR is negative for bcr abl RNA. The CGR has been transient in one patient, and follow-up is short in the other two. Secondary effects have been acceptable, with myelosuppression as the main toxic effect. Graft-versus-host disease did not occur. The literature review identified 108 patients treated with IFN alpha as sole therapy for relapsed CML. Cytogenetic response and CGR seem to be better in patients with cytogenetic relapse, as compared to patients with hematologic relapse (61% vs. 45% and 45% vs. 28%, respectively). Several patients remained in CGR for more than 5 years. This overview also suggests that CGR is more frequent when IFN alpha is used in patients relapsing after non T-depleted BMT. IFN alpha induces complete cytogenetic response in nearly half of the patients with CML who relapse after allogeneic BMT, with acceptable toxicity. We believe that these results using IFN alpha as a front-line therapy for CML relapsing after BMT warrant a randomized comparison with donor lymphocyte infusions. PMID- 10100564 TI - Retrospective survival analysis and cost-effectiveness evaluation of second allogeneic bone marrow transplantation in patients with acute leukemia. Gruppo Italiano Trapianto di Midollo Osseo. AB - The therapeutic options for patients with acute leukemia who relapse after the initial transplant include second bone marrow transplantation (2BMT) and conventional chemotherapy (CC). In this work, we conducted an analysis of published survival data and we evaluated the cost-effectiveness of 2BMT in comparison with CC. We retrieved survival information on 167 patients treated with 2BMT and 299 patients treated with CC. Survival figures were derived from individual patient data and were compared between 2BMT and CC. The mean lifetime survival (MLS) was estimated for each of the two patient cohorts using standard techniques of survival-curve extrapolation. The cost data of patients given 2BMT or CC were estimated from published data. Our analysis of individual survival data showed that 2BMT improved survival at levels of statistical significance (survival gain = 19.6 months per patient). Using an incremental cost of $90000 per patient, the cost-effectiveness ratio of 2BMT in comparison with CC was calculated as $52215 discounted dollars per discounted life year gained. Our results indicate that, in patients with acute leukemia who relapse after their first transplant, 2BMT significantly prolongs survival in comparison with CC and seems to have an acceptable cost-effectiveness profile. PMID- 10100565 TI - Primitive hematopoietic progenitors within mobilized blood are spared by uncontrolled rate freezing. AB - Uncontrolled-rate freezing techniques represent an attractive alternative to controlled-rate cryopreservation procedures which are time-consuming and require high-level technical expertise. In this study, we report our experience using uncontrolled-rate cryopreservation and mechanical freezer storage at -140 degrees C. Twenty-eight PBPC samples (10 cryovials, 18 freezing bags) from 23 patients were cryopreserved in a cryoprotectant solution composed of phosphate-buffered saline (80%, v/v) supplemented with human serum albumin (10%, v/v) and dimethylsulfoxide (10%, v/v). The cryopreservation procedure required on average 1.5 h. The mean (+/- s.e.m.) storage time of cryovials and bags was 344+/-40 and 299+57 days, respectively. Although cell thawing was associated with a statistically significant reduction of the absolute number of nucleated cells (vials: 0.3x10(9) vs. 0.2x10(9), P< or =0.02; bags: 14x10(9) vs. 11x10(9), P< or =0.0003), the growth of committed progenitors was substantially unaffected by the freezing-thawing procedure, with mean recoveries of CFU-Mix, BFU-E, and CFU-GM ranging from 60+/- 29% to 134+/-15%. Mean recoveries of LTC-IC from cryovials and bags were 262+/-101% and 155+/-27% (P< or =0.2), respectively. In 14 out of 23 patients who underwent high-dose chemotherapy and PBPC reinfusion, the pre-and post-freezing absolute numbers of hematopoietic progenitors cryopreserved in bags were compared. A significant reduction was detected for CFU-Mix (11 vs. 7.4x10(5)), but no significant loss of BFU-E (180 vs. 150x10(5)), CFU-GM (400 vs. 290x10(5)) and LTC-IC (15 vs. 16x10(5)) could be demonstrated. When these patients were reinfused with uncontrolled-rate cryopreserved PBPC, the mean number of days to reach 1x10(9)/l white blood cells and 50x10(9)/l platelets were 9 and 13, respectively. In conclusion, the procedure described here is characterized by short execution time, allows a substantial recovery of primitive and committed progenitors and is associated with prompt hematopoietic recovery following myeloablative therapy even after long-term storage. PMID- 10100566 TI - Cord blood banking: volume reduction of cord blood units using a semi-automated closed system. AB - Clinical evidence indicates that placental/umbilical cord blood (CB) is an alternative source of haematopoietic stem cells for bone marrow reconstitution. To establish a CB bank large panels of frozen, HLA-typed CB units need to be stored. Cryopreserved, unprocessed CB units require vast storage space. This study describes a method, using the Optipress II Automated Blood Component Extractor (Opti II) from Baxter Healthcare Corporation, to reduce the volume of the CB collection, preserving the quantity and quality of the progenitor cells, in a closed system. The CB collection was transferred to a triple bag system, centrifuged to produce a buffy coat layer and processed using a standard Opti II protocol to separate the whole blood into three components: plasma, buffy coat and buffy coat-depleted red cell concentrate. The buffy coat volume was standardised to 25 ml; mean reduced volume of 24.5 ml (s.d. 1.5 ml) with 53% red cell depletion. Good recovery of cells was observed: 92%, 98%, 96% and 106% recovery of nucleated, mononuclear, CD34+ and total colony-forming cells, respectively. Using this method for processing CB units reduces storage requirement by two-thirds but preserves the quantity and quality of the progenitor cells. PMID- 10100567 TI - Pulmonary enterovirus infections in stem cell transplant recipients. AB - In recent years, it has been recognised that the community respiratory viruses are a frequent cause of upper and lower respiratory tract infections in immunocompromised hosts such as bone marrow transplant recipients. By contrast, infections by non-polio enteroviruses have rarely been reported after stem cell transplantation. We present four cases of acute respiratory illness with enterovirus isolated as the sole pathogen from bronchoalveolar lavage. All four patients developed pneumonia and three died of progressive pneumonia, which reflects the severity of this complication. We conclude that enteroviral pulmonary infections may be a cause of severe pneumonia in immunocompromised hosts. PMID- 10100568 TI - Bilateral basal ganglial necrosis after allogeneic bone marrow transplantation in a child with Kostmann syndrome. AB - A 6-year-old girl underwent allogeneic BMT from a matched sibling donor for the treatment of Kostmann syndrome. She suddenly became drowsy on day 30 after BMT, and lost consciousness 2 days later. Cranial CT scan showed symmetrical lesions suggesting bilateral necrosis in the basal ganglia. Clinical and laboratory investigations failed to reveal any evidence of neurometabolic disease. PMID- 10100569 TI - Disseminated nocardiosis in a bone marrow transplant recipient with chronic GVHD. AB - We describe a case of disseminated nocardiosis in a 53-year-old male allogeneic marrow recipient with chronic GVHD, 15 years post BMT. Six months prior to admission he was treated for recurrent chronic GVHD with corticosteroids with a good response. He deteriorated subsequently while still on steroids requiring admission for fever, anorexia, weight loss, productive cough and progressive dyspnoea. On admission he had multiple nodular lesions on chest roentgenogram and subsequently grew Nocardia farcinica in blood culture. N. farcinica is rare post BMT, has a high mortality, is resistant to various antibiotics and needs prolonged antimicrobial therapy. We report the successful management of our patient with single agent trimethoprim-sulphamethoxazole. PMID- 10100570 TI - Vaginal stenosis following allogeneic bone marrow transplantation for acute myeloid leukaemia. AB - We report the unusual complication of vaginal stenosis occurring after allogeneic bone marrow transplantation (BMT) for leukaemia. This was in all likelihood a manifestation of chronic graft-versus-host disease (cGVHD), although the patient has no other stigmata of this and suffered little acute graft-versus-host disease (aGVHD) after BMT. Other risk factors for vaginal stenosis were considered and appear to be absent in this patient, although the total body irradiation used as part of her conditioning therapy may play a role. We suggest that vaginal stenosis may be under-reported, since female patients suffer a number of gynaecological complications after BMT, and that regular questioning and examination may aid in making an earlier diagnosis, allowing speedier instigation of therapy and thus improving quality of life. PMID- 10100571 TI - Non-invasive ventilatory support in the management of respiratory failure after autologous peripheral blood stem cell transplantation. PMID- 10100572 TI - Busulphan level and early mortality in thalassaemia patients after BMT. AB - The aim of the study was to correlate busulphan (BU) levels of thalassaemia patients with outcome of allogeneic transplant. BU levels were measured by gas chromatography mass fragmentography. All patients received a standardised dose of BU 16 mg/kg, and cyclophosphamide 150 or 200 mg/kg. For area-under-the-curve analysis (AUC), blood samples were obtained at 0, 1, 2, 3, 4 and 6 h after the first and fifth dose for all patients, and additional levels were measured after ninth and/or 13th dose in most patients. Outcome parameters examined included veno-occlusive disease of liver (VOD), idiopathic interstitial pneumonitis, chimerism, and day 90 survival. Twenty consecutive thalassaemia patients who underwent haematopoietic stem cell transplantation were studied. The median age at transplant was 11.2 years (range 3-21 years). Mean BU AUC levels were correlated with age at transplant (r = 0.58, P = 0.007). Nine patients developed VOD and six had mixed chimerism, but these did not correlate with mean BU AUC level. Four patients died before day 50 from VOD and interstitial pneumonitis. Patients with BU AUC levels greater than the median (908 micromol x min/l) had significantly lower probability of survival at day 90 (60%), whereas patients with BU AUC level less than the median all survived beyond day 90. No patient had graft rejection. In conclusion, a high BU AUC level was associated with a higher treatment-related mortality in thalassaemia patients after transplant. PMID- 10100573 TI - A phase I study of paclitaxel for mobilization of peripheral blood progenitor cells. AB - We conducted a phase I trial to determine the dose and schedule of paclitaxel, when given together with filgrastim, which would optimally promote mobilization of stem cells with tolerable toxicity. Dose escalation began at 275 mg/m2 3 h infusion. Dose-limiting neuropathy was observed at the 300 mg/m2 dose level. A second dose escalation was conducted utilizing 24 h infusion schedules, beginning at 225 mg/m2. Dose escalation was continued by 25 mg/m2 increments to 300 mg/m2, at which dose neuropathy was again dose-limiting. The recommended dose and schedule of paclitaxel for the purpose of mobilization of stem cells, when given together with filgrastim, are 275 mg/m2 as a 24 h infusion. The median stem cell yield after this dose of paclitaxel was 6.6 x 10(6) CD34+ cells/kg/apheresis (range 3.6 x 10(6)-7.7 x 10(6)). PMID- 10100574 TI - Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma. AB - We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77 patients received two cycles of VAD (n = 62) and/or two cycles of i.v. IDM 70 mg/m2 (n = 15) combined with G-CSF. PBSC were harvested after the first IDM, successfully in 87% of patients. Patients with a response to induction received myeloablative therapy with PBSCT (n = 50) followed by IFN maintenance or allo-BMT (n = 11). Seventy-two per cent of patients achieved a response after VAD which increased to 85% after IDM. Of patients who received PBSCT and allo-BMT, 24% and 45% achieved CR, respectively. Toxicity of induction consisted mainly of bone marrow suppression after IDM (median 8 days) with prolonged aplasia in 11% of patients after the second IDM. Only six infections WHO grade 3 occurred during induction. Treatment-related mortality of PBSCT and allo-BMT was 6% and 18%, respectively. Median time of follow-up is 44 months, and 50% of patients after PBSCT and 60% of patients after allo-BMT are still in remission. Survival rates of all patients were 82%, 75% and 63%, and for transplanted patients 86%, 79% and 68% after 12, 24 and 36 months. Well known prognostic factors, including alpha-IFN maintenance after PBSCT, were not significant for response or survival although patients in CR after allo-BMT had a strong tendency for better outcome. VAD/IDM is an effective and safe induction therapy for autologous and allogeneic stem cell transplantation. Based on these observations a phase III trial was started in October 1995 comparing IFN maintenance with PBSCT and allo-BMT after response to induction with VAD and IDM. PMID- 10100575 TI - Cells with clonal light chains are present in peripheral blood at diagnosis and in apheretic stem cell harvests of primary amyloidosis. AB - In primary systemic amyloidosis, small numbers of bone marrow plasma cells secrete monoclonal light chains that form extracellular fibrils (amyloid) in various organs. Evidence limited to a few cases suggests that rare clonal elements can also be found in the peripheral blood (PB), and this may be relevant in PB stem cell autotransplantation. Since up to 40% of amyloid clones do not synthesize heavy chains, in order to detect tumor cells with high specificity and sensitivity we developed a seminested allele-specific oligonucleotide polymerase chain reaction for tumor light chains. Clone-related sequences were detected in DNA and/or cDNA from the PB cells of eight of 10 patients at diagnosis and from apheretic collections of three of four cases undergoing PB progenitor autotransplantation. Since there are experimental data suggesting that circulating tumor cells may be involved in the growth of the amyloidogenic clone and may be chemoresistant, these findings are relevant to the use of leukapheresis purging strategies for PB progenitor autotransplantation in amyloidosis. PMID- 10100576 TI - Long-term follow-up of allogeneic bone marrow transplantation in patients with poor prognosis non-Hodgkin's lymphoma. AB - Relapsed or very aggressive high-grade NHL and refractory low-grade NHL have a poor clinical outcome. Autologous BMT may be used but is of limited efficacy in these cases. Allogeneic BMT offers the advantage of tumour-free bone marrow and a possible GVL effect. Between 1987 and 1996, 13 patients (median age 31 years) suffering from lymphoid malignancies underwent allo-BMT. Four patients had low grade NHL, three intermediate-grade and six high-grade NHL. Three patients were grafted with evolutive disease, four were in partial remission after several courses of chemotherapy, two were in CR2 and four were in CR1 after initial therapy. The mean number of prior treatments was 2.7 (1-6). Median time from diagnosis to BMT was 25 months (4-90). The conditioning regimen consisted of cyclophosphamide (120 mg/kg/day for all, plus VP16 in one case) and total body irradiation. Five out of the seven patients who were not in CR at the time of transplantation entered CR after BMT. Eight patients developed acute GVHD grade > or = II and four had chronic GVHD. Nine patients are alive, eight in CR with a median follow-up of 49.8 months post BMT (2-125). Overall survival is 67.3% and the median time for EFS is 102 months. Two patients with low-grade NHL relapsed 61 and 102 months post BMT and were treated with DLI. One patient with a stage IV SLL had a partial remission and one with multiple cutaneous localisation of FL entered CR after grade IV acute GVHD. Allo-BMT is a highly effective treatment for advanced poor prognosis lymphoid malignancies with acceptable toxicity. Moreover, DLI can be effective in relapsing patients. PMID- 10100577 TI - Immune reconstitution following allogeneic peripheral blood stem cell transplants. AB - Growth factor-mobilized peripheral blood stem cells (PBSCs) engraft rapidly in myeloablated recipients compared to conventional BM, but this procedure also mobilizes mature lymphocytes and monocytes which can impact immune reconstitution and GVHD. Hence, we serially evaluated immune reconstitution and cytokine expression in PBSCT recipients in the first year. Engraftment of neutrophils and monocytes stabilized early but NK cells, B cells and CD4+ T cell numbers were significantly (P < 0.05) low with persistently reversed CD4:CD8 ratios. NK function remained low throughout the first year. The quantitative decrease in CD4+ T cells resulted in significantly decreased proliferation in response to mitogens and alloHLA antigens. Yet, a qualitative analysis of T cell function measured by Ca++ influx after T cell activation with antiCD3 as well as T dependent polyclonal Ig secretion by mitogen-stimulated B cells was preserved even early post transplant. TNF alpha mRNA was detected in almost all recipients in the first year. IL-10 mRNA was detected in 77%, IL-2 in 22% and IFN gamma in 44% of recipients in the first 6 months. Only 30% expressed IL-10 in the second 6 months post transplant while expression of IL-2 and IFN gamma was detected in 38% and 46% respectively. Thirty-seven percent of PBSCT recipients developed grades II-IV acute GVHD but 72% went on to develop chronic extensive GVHD at a median of 120 days. Sixty-two percent developed CMV viremia and 5.4% developed overt CMV disease in the first year post PBSCT. Lymphocyte engraftment is quantitatively delayed but CD4 functions are preserved while NK numbers and function are compromised post PBSCT. IL-10 expression decreases after the first 6 months post transplant while TNF alpha is continually expressed. The balance between quantitative lymphocyte reconstitution and qualitative lymphocyte functions as well as changes in lymphokine patterns may influence infection and GVHD and thus the clinical outcome post PBSCT. PMID- 10100578 TI - Effective T cell regeneration following high-dose chemotherapy rescued with CD34+ cell enriched peripheral blood progenitor cells in children. AB - The ex vivo enrichment for the CD34+ cell fraction of PBPC, while it retains the capacity to restore haematopoiesis and potentially reduces a contamination by tumour cells, implements a depletion of T cells. To test whether such a setting adversely affects T cell reconstitution, we monitored T cells in four paediatric patients after CD34+ selected PBPC transplantation. The dose of CD34+ cells, which were enriched to 74%, median, was 7.1 x 10(6)/kg, median, that of T cells was 0.071 x 10(6)/kg, median. The patients were homogenous with respect to features with a potential to effect T cell reconstitution (low median age, (35 years); stage IV malignant tumours in first CR, uncomplicated post-treatment course). The results of sequential FACS analyses showed that by 9 months after treatment all four patients had recovered (1) a normal T cell count (CD3+ cells 1434/microl, median); (2) a normal CD4+ cell count (816/microl, median), while CD8+ cells were recovered (>330/microl) already by 3 months; (3) a normal CD4/CD8 ratio (1.8, median), as a result of an augmented growth of CD4+ cells between 3 and 6 months (increase of CD4+ cells 4.9-fold, median, CD8+ cells 1.1-fold, median). Expansion of cells with a CD45RA+ phenotype (thymus-derived T cells) predominated; from 3 to 6 months the increase of CD4+/CD45RA+ T cells was 130 fold, that of CD4+/CD45RO+ cells was 1.7-fold; CD8+/CD45RA+ cells increased 9 fold, CD8+/CD45RO+ cells increased 2.1-fold, indicating effective thymopoiesis. The findings demonstrate that in paediatric patients the setting of HD-CTX rescued with autologous CD34+ selected PBPC per se is not predictive of an impaired T cell recovery. High thymic activity may be a key factor for the rapid restoration of T cells. PMID- 10100579 TI - A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin. AB - Transplantation of solid organs including heart, kidney, and liver is associated with rapid bone loss and increased rate of fracture; data on bone marrow transplantation recipients (BMT) are scarce. The purpose of the present study was to examine the magnitude, timing, and mechanism of bone loss following allogeneic BMT, and to study whether bone loss can be prevented by calcium with or without calcitonin. Sixty-nine patients undergoing allogeneic BMT for malignant blood diseases were enrolled into the study. Forty-four (22 women, 22 men) completed 6 months, and 36 patients 1 year follow-up. They were randomized to receive either no additional treatment (n = 22), or oral calcium 1 g twice daily for 12 months (n = 12) or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months (n = 10). Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward's triangle) was measured by dual-energy X-ray absorptiometry (DXA). Bone turnover rate was followed with markers of bone formation and resorption (serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal (PICP) and aminoterminal propeptide (PINP), serum type I collagen carboxyterminal telopeptide (ICTP)). Serum testosterone was assayed in men. Calcium with or without calcitonin had no effect on bone loss or bone markers; consequently the three study groups were combined. During the first 6 post-transplant months BMD decreased by 5.7% in the lumbar spine and by 6.9% to 8.7% in the three femoral sites (P < 0.0001 for all); no significant further decline occured between 6 and 12 months. Four out of 25 assessable patients experienced vertebral compression fractures. Markers of bone formation reduced: B-ALP by 20% at 3 weeks (P = 0.027), PICP by 40% (P < 0.0001) and PINP by 63% at 6 weeks (P < 0.0001), with a return to baseline by 6 months. The marker of bone resorption, serum ICTP was above normal throughout the whole observation period, with a peak at 6 weeks (77% above baseline, P < 0.0001). In male patients serum testosterone decreased reaching a nadir (57% below baseline) at 6 weeks (P = 0.0003). In conclusion, significant bone loss occurs after BMT. It results from imbalance between reduced bone formation and increased bone resorption; hypogonadism may be a contributing factor in men. Bone loss can not be prevented by calcium with or without calcitonin. PMID- 10100580 TI - Rejection of an MHC class II negative tumor following induction of murine syngeneic graft-versus-host disease. AB - Cyclosporin A (CsA) has been used clinically to induce graft-versus-host disease following autologous bone marrow transplantation in an attempt to destroy residual leukemia cells and reduce relapse. To analyze the antitumor potential of murine syngeneic graft-versus-host disease (SGVHD), C3H/HeN mice were lethally irradiated, reconstituted with T cell-depleted syngeneic bone marrow (ATBM) and treated with CsA for 21 days. Graft-versus-leukemia activity was assessed by challenging groups of olive oil-treated control ATBM (OO-ATBM) and CsA-treated (CsA-ATBM) mice 1 week after CsA therapy with graded doses of the syngeneic 38C13 B cell lymphoma. Following CsA treatment, up to 70% of CsA-ATBM developed SGVHD and more than 70% of the animals injected with 500 38C13 cells exhibited long term survival (MST >80 days). In contrast, none of the OO-ATBM control mice developed SGVHD, and more than 75% of these mice died following injection of 500 38C13 tumor cells (MST = 34 days). Long-term survivors were not resistant to tumor challenge suggesting that tumor-specific immunity did not develop. Finally, class II negative 38C13 cells cultured in IL-4 or IL-10 were not inducible for MHC class II molecules, demonstrating that class II-independent antitumor mechanisms exist in SGVHD mice. PMID- 10100581 TI - Conclusions of a national multicenter intercomparative study of in vitro cultures of human hematopoietic progenitors. AB - With the aim of developing a standardized program of clonogenic cultures, a multicenter intercomparative study of human CFU-GM, BFU-E and CFU-GEMM cultures was conducted. Aliquots of fresh mononuclear cord blood cells, as well as uniform culture materials and instructions for cell culture and for colony scoring were distributed to 28 national laboratories involved in hematopoietic research and transplantation. High interlaboratory coefficients of variation (CV) in the reported number of progenitors were found in our first intercomparative study (range 67-231%). To investigate the relevance of colony scoring in variations of the reported colony numbers, participants were invited to attend a meeting where a single culture dish was scored. In this case, the CVs ranged from 31% to 81%. A subsequent intercomparative assay was then conducted, and significant reductions in the inter-laboratory CVs were obtained with respect to the first study (CVs for colonies grown with two different media: CFU-GMs, 48% and 55%; BFU-Es, 70% and 62%; CFU-GEMMs, 70% and 51%; respectively). In most instances CVs were not significantly different from those obtained in the single plate scoring study, suggesting that the scoring process was the most relevant parameter accounting for variations in the reported colony numbers. PMID- 10100582 TI - Stem cell component therapy: supplementation of unmanipulated marrow with CD34 enriched peripheral blood stem cells. AB - Eleven patients with hematologic malignancies and two with aplastic anemia were treated using unmanipulated marrow and immunoselected CD34+ blood cells. Donors began G-CSF (10 microg/kg) injections 1 day after undergoing bone marrow harvest. Blood stem cells were collected on day 5 of G-CSF. Peripheral blood lymphocytes were depleted via CD34-positive selection. If, after marrow and blood harvest, less than 2.0 x 10(6) CD34 cells/kg were mobilized, leukapheresis was repeated on day 6. Median time to an absolute neutrophil count greater than 500 microl was day 10; transfusion-independent platelet count greater than 20,000/microl was day 13; average hospital discharge was day 14; and average inpatient hospital charges were 101,870 US dollars. Acute GVHD grade II occurred in five of 13 patients. No patient developed grade III or IV acute GVHD. At a median follow-up of 10 months, no patient has developed extensive chronic GVHD. Allografts of unmanipulated bone marrow supplemented with G-CSF-mobilized and CD34 immunoselected blood cells may prevent an increased risk of GVHD while preserving the rapid engraftment kinetics of peripheral blood. Supplementation of marrow with CD34 enriched blood cells appears to result in rapid engraftment, early hospital discharge, lower inpatient charges, decreased regimen-related toxicity, and no apparent increase in GVHD. PMID- 10100583 TI - CD34+ cell enumeration in peripheral blood and apheresis samples, using two laboratory diagnostic kits or an institutional protocol. AB - In order to prepare the substitution of a commercially available diagnostic kit, ProCOUNT (Becton Dickinson) or Stem-Kit (Coulter Immunotech), for our institutional protocol, we compared the three techniques for the numeration of CD34+ progenitor cells in 50 peripheral blood and 51 apheresis samples, obtained from cancer patients or healthy donors. We show here that the three techniques yield results of the same order of magnitude. Although statistical analyses demonstrate significant differences between the three methods, these differences turned out to be clinically insignificant in most situations. Observed differences mostly affect samples with the highest content of CD34+ cells, while the three assays provide equivalent results for values that are close to clinically relevant thresholds (20 x 10(3) CD34+ cells/ml in peripheral blood to start apheresis, and accumulated number above 3 x 10(6) CD34+ cells/kg to stop apheresis). This study also supports the view that institutional protocols can provide a highly reliable determination of CD34+ cells counts and percentages. However, because institutional protocols often use research reagents and vary from institution to institution, the use of diagnostic kits may be prefered as one way to improve quality assurance in the practice of cell therapy. PMID- 10100584 TI - Effects of long-term cryopreservation on hematopoietic progenitor cells in umbilical cord blood. AB - There is considerable interest in developing banks of frozen umbilical cord blood cells for transplants but it is uncertain how long frozen cells survive. Our objective was to determine the recovery of frozen umbilical cord blood cells. We quantitated recovery of hematopoietic progenitor cells (CFU-GM, BFU-E, and CFU GEMM) from frozen umbilical cord blood cells stored for up to 12 years. Decay rates of CFU-GM, BFU-E and CFU-GEMM (d, expressed as percent of viable cells recovered (95% confidence interval) were 0.9930 (0.9889-0.9970), 0.9840 (0.9769 0.9911) and 0.9817 (0.9707-0.9927). Time-dependent recoveries, calculated by the formula d(k), (k = frozen storage interval in years) were >90% at 10 years. We conclude that frozen cord blood cells can be stored safely for prolonged intervals without substantial loss in hematopoietic progenitor cells. PMID- 10100585 TI - Myasthenia gravis and polymyositis as manifestations of chronic graft-versus-host disease. AB - Myasthenia gravis and polymyositis are each a rare manifestation of immune dysregulation in chronic graft-versus-host disease (cGVHD). We report a 4-year old boy with idiopathic acquired aplastic anemia who developed myasthenia gravis 22 months and polymyositis 69 months after an allogeneic BMT (5/6 matched, MLC nonreactive). The occurrence of both syndromes in one patient is unique. Autoimmune dysfunction may be associated with the development of cGVHD as demonstrated by the high incidence of prior aplastic anemia in BMT patients presenting with myasthenia gravis and polymyositis. Recognition of these neurologic manifestations is important in the diagnosis and treatment of cGVHD. PMID- 10100586 TI - Progressive multifocal leucoencephalopathy with peripheral demyelinating neuropathy after autologous bone marrow transplantation for acute myeloblastic leukemia (FAB5). AB - Progressive multifocal leucoencephalopathy is an opportunistic JC virus-related pathology occurring in immunocompromised patients. We report a case of severe cellular immunodeficiency in a patient who underwent autologous bone marrow transplantation for acute myeloblastic leukemia, and who subsequently developed progressive multifocal leucoencephalopathy, an unusual pathology in this context. Progressive multifocal leucoencephalopathy was preceded by a peripheral demyelinating neuropathy. We discuss the possible link between these two neuropathies, the possible aggravation or activation from CMV infection, as well as the possible contribution of bone marrow purging in the resultant cellular immunodeficiency. PMID- 10100587 TI - Successful human umbilical cord blood stem cell transplantation without conditioning in severe combined immune deficiency. AB - A 2-month-old girl with severe combined immunodeficiency (SCID), presented with mild staphylococcal skin infection, lymphopenia, low T cell number, absence of B cells, high number of NK cells, and a negligible response to mitogens. Since her older brother died as a result of SCID 2 years earlier, cord blood was harvested from a sister born 2 1/2 years earlier, who was normal and fully matched both by serology and molecular typing. In view of her clinical condition and in spite of a high number of NK cells with normal activity, HUCBT without preparative conditioning was performed. No G-CSF was administered. Engraftment with mixed chimerism was evident 3 weeks post transplantation. There were no peritransplantation complications. Eighteen months post transplantation, the girl is in excellent condition, blood counts are normal, T cell engraftment is complete, B cell engraftment is proceeding gradually, and the mitogen stimulation tests are normal. Due to the unique nature of HUCB hematopoietic cells, engraftment without conditioning may be possible in patients with SCID with fully matched donors. This is the first HUCBT performed without conditioning. PMID- 10100588 TI - Successful treatment of cerebral toxoplasmosis in a marrow transplant recipient: contribution of a PCR test in diagnosis and early detection. AB - We report successful treatment of cerebral toxoplasmosis in an unrelated donor marrow transplant recipient. The clinical diagnosis was confirmed by polymerase chain reaction (PCR) amplification for T. gondii-DNA performed both on cerebrospinal fluid and blood leukocytes. Retrospective testing of stored blood samples demonstrated positive leukocyte PCR signal detected up to 52 days prior to onset of clinical symptoms. This case highlights the value of PCR in the diagnosis and early detection of cerebral toxoplasmosis. PMID- 10100589 TI - In vitro interactions of a new derivative of spicamycin, KRN5500, and other anticancer drugs using a three-dimensional model. AB - PURPOSE: KRN5500 is a new derivative of spicamycin produced by Streptomyces alanosinicus and is known to have a wide range of antitumor activities against human cancer cell lines. Because of its unique structure, this compound seems to have a different mode of action from other antitumor drugs and nonoverlapping toxicities. Therefore, KRN5500 is expected to be a suitable candidate for combination chemotherapy. METHODS: We investigated the effects of combinations of KRN5500 and other anticancer drugs on the growth of a human non-small-cell lung cancer cell line, PC14, using a revised three-dimensional model. RESULTS: Synergism was observed when KRN5500 and cisplatin were combined at concentrations in the ranges 0.005 to 0.25 microg/ml and 0.025 to 0.25 microg/ml, respectively. In combination with carboplatin, an analog of cisplatin, and etoposide, a marked synergistic interaction was also found. CONCLUSION: These results suggest the usefulness of combinations of KRN5500 with cisplatin, carboplatin or etoposide for chemotherapy for non-small-cell lung cancer. PMID- 10100590 TI - Comparative brain tissue distribution of camptothecin and topotecan in the rat. AB - PURPOSE: The primary objective of this investigation was to compare the extent of brain distribution of the lactone and the carboxylate forms of camptothecin (CPT) and topotecan (TPT) in awake freely moving rats. METHODS: The plasma concentration-time profiles of the lactone and the carboxylate forms of CPT and TPT were determined simultaneously after a single i.v. administration of the lactone form of each drug. Also, the brain extracellular fluid (ECF) concentration-time profiles were characterized utilizing the microdialysis technique. This technique allowed serial sampling of the brain ECF in awake rats. RESULTS: CPT-lactone in plasma declined biexponentially with a terminal half-life of 102+/-25.2 min. During the elimination phase, the plasma concentration of CPT carboxylate was approximately ten times the concentration of CPT-lactone. The brain ECF to plasma distribution ratio measured as the ratio of the AUC in the brain ECF to the AUC in plasma was 0.51+/-0.08 for CPT-lactone, and 0.26+/-0.21 for CPT-carboxylate. The terminal half-life for TPT-lactone was 64.0+/-9.4 min. During the elimination phase, the TPT-carboxylate concentration was higher than that of TPT-lactone but the carboxylate to lactone concentration ratio was much lower than that of CPT. The brain ECF to plasma distribution ratio was 0.38+/ 0.12 for TPT-lactone, and 0.21+/-0.06 for TPT-carboxylate. CONCLUSIONS: CPT and TPT are distributed to the brain ECF most probably by passive diffusion across the blood-brain barrier. Although the brain ECF to plasma distribution ratio for CPT-lactone was higher than that for TPT-lactone, the brain ECF concentrations of TPT-lactone were significantly higher than the CPT-lactone brain ECF concentrations. The relatively high brain ECF to plasma distribution ratio of these two drugs makes them potential candidates for first-line treatment of CNS tumors. PMID- 10100591 TI - The bisindolylmaleimide protein kinase C inhibitor, Ro 32-2241, reverses multidrug resistance in KB tumour cells. AB - Ro 32-2241 is a bisindolylmaleimide that selectively inhibits protein kinase C (PKC) as compared with other protein kinases. Experiments were carried out to examine its potential as a multidrug resistance-reversing agent. Ro 32-2241 inhibited efflux, and increased accumulation, of [3H]-daunomycin in multidrug resistant (MDR) KB-8-5 and KB-8-5-11 cells and had no effect on drug-sensitive KB 3-1 cells. Ro 32-2241 completely reversed the doxorubicin resistance of KB-8-5 and KB-8-5-11 cells, showing no effect on the sensitivity of drug-sensitive KB-3 1 cells. The potency of Ro 32-2241 was comparable with that of cyclosporin A and better than that of verapamil, known modulators of multidrug resistance. Ro 32 2241 also completely reversed the taxol resistance of KB-8-5 cells and partially reversed the resistance of KB-8-5-11 cells. Vinblastine resistance was also partially reversed. Mechanistic experiments were carried out to determine whether Ro 32-2241 interacted with P-glycoprotein (Pgp) directly. Increased efflux of [14C]-Ro 32-2241 was seen with the more resistant KB-8-5-11 cells (although the percentage effluxed was very low as compared with [3H]-daunomycin), suggesting that Ro 32-2241 can act as a substrate for Pgp. Direct interaction of Ro 32-2241 with Pgp was confirmed by demonstration that it inhibited binding of [3H] azidopine to Pgp in KB-8-5-11 membranes. In conclusion, Ro 32-2241, acting directly on Pgp (rather than, or in addition to, an effect on PKC), is effective in reducing or reversing resistance to doxorubicin, taxol and vinblastine in human tumour cells with a clinically relevant degree of MDR. However, results of in vivo experiments conducted to investigate the effects of Ro 32-2241 on resistance to doxorubicin suggest that it may not be possible to achieve sufficiently high levels of Ro 32-2241 in vivo to modulate MDR. PMID- 10100592 TI - A comparative study of administration methods of granisetron injection used to treat nausea/vomiting induced by cancer chemotherapy without cisplatin in tumors of hematopoietic organs. Keihanshin Study Group of Hematological Malignancies. AB - PURPOSE: The antiemetic effect of granisetron injection at a dose of 40 microg/kg used in the treatment of nausea/vomiting induced by multidrug combined cancer chemotherapy excluding cisplatin in patients with tumors of hematopoietic organs was evaluated by comparing a 30-min infusion and a slow intravenous injection given over 30 s. METHODS: A two-group random-allocation comparative study was performed with the cooperation of multiple institutions using a central registration system. RESULTS: In the treatment of acute clinical symptoms, appetite was described as "similar to that during good health" by 61.1% of patients (55/93) in the instillation group and by 47.3% (44/93) in the slow injection group, a significant advantage in the infusion group. However, no significant differences in the number of episodes of vomiting, the severity of nausea or clinical efficacy were found. In the final clinical evaluation and assessment of usefulness based on the subjective judgement of physicians throughout the entire therapeutic period, no differences were discernible. No side effects were reported for either method and there was no indication of a sex difference concerning efficacy. However, the efficacy in patients with an anemic tendency was slightly inferior. CONCLUSIONS: The maintenance of appetite during the administration of anticancer drugs is very important to maintain patients' daily activities and quality of life. The present results support the usefulness of infusion of granisetron as an administration method during chemotherapy for malignant hemopathy. PMID- 10100593 TI - A phase I study of oral uracil/ftorafur (UFT) plus leucovorin and bis-acetato ammine-dichloro-cyclohexylamine-platinum IV (JM-216) each given over 14 days every 28 days. AB - PURPOSE: To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil/ftorafur (UFT) coadministered as a 14 consecutive-day every 28-day schedule. METHODS: Of 20 patients enrolled in this investigation, 17 on the following dose escalation scheme were evaluable for toxicity and/or response: I UFT 300 mg/day, JM-216 5 mg/day (three patients), II UFT 300 mg/day, JM-216 10 mg/day (four patients), III UFT 300 mg/day, JM-216 20 mg/day (ten patients). RESULTS: All 17 evaluable patients were evaluable for toxicity. At dose level III dose-limiting nausea and emesis were observed in one patient despite maximal antiemetic support. Importantly, neurotoxicity and nephrotoxicity were not observed at the JM-216 dose levels examined in this study. This observation is consistent with results seen with single agent JM-216. CONCLUSION: For JM-216 and UFT administered at 20 mg/day and 300 mg/day over 14 days, nausea and emesis were observed as the principal dose-limiting toxicities. These doses are considerably below the maximally tolerated doses of single agent JM-216 and UFT. Shorter administration schedules should be explored in an attempt to increase the dose intensity and minimize the toxicity of this combination oral regimen. PMID- 10100594 TI - Sonodynamically induced effect of rose bengal on isolated sarcoma 180 cells. AB - PURPOSE: The ultrasonically induced effect of rose bengal (RB) on isolated tumor cells was investigated. METHODS: Sarcoma 180 cells were suspended in air saturated phosphate-buffered saline and exposed to ultrasound in standing wave mode for up to 60 s in the presence and absence of RB. Cell viability was determined by the ability to exclude trypan blue. RESULTS: The rate of inducing cell damage by ultrasound was enhanced two to three times with 160 microM RB. while no cell damage was observed with RB alone. This enhancement was significantly inhibited by histidine. CONCLUSIONS: Ultrasonically induced in vitro cell damage was significantly enhanced by RB. A sonochemical mechanism may be suggested since the enhancement was significantly inhibited by an active oxygen scavenger. PMID- 10100595 TI - Combination effects of TAS-103, a novel dual topoisomerase I and II inhibitor, with other anticancer agents on human small cell lung cancer cells. AB - PURPOSE: TAS-103 [6-((2-(dimethylamino) ethyl)amino)-3-hydroxy-7H-iindeno(2,1 c)quinolin-7-one dihydrochloride] is a newly synthesized dual inhibitor of topoisomerase I and II. Since anticancer drugs are used in combination with other drugs for effective chemotherapy, we investigated the cytotoxic effect of TAS-103 in combination with other conventional anticancer agents, such as cisplatin, vindesine, doxorubicin, 5-fluorouracil, and the antitopoisomerase inhibitors SN 38 and etoposide in vitro. METHODS: Inhibition of the growth of the human small cell lung cancer cell line SBC-3 was evaluated using the tetrazolium dye (MTT) assay. Drug interactions were evaluated by isobologram analysis and the determination of combination indices supplemented by a three-dimensional model. RESULTS: Simultaneous use of TAS-103 and cisplatin had a supraadditive effect, but combinations of TAS-103 with other drugs had an additive or marginally subadditive effect. Three-dimensional model analysis added more information about the synergistic concentration ranges of two drugs (cisplatin 200-400 nM and TAS 103 7 10 nM). Sequential use of TAS-103 and cisplatin had only an additive effect. CONCLUSION: These results suggest that the concomitant use of TAS-103 and cisplatin has a greater cytotoxic effect on cancer cells than single drug use, and may provide a beneficial effect in the treatment of small-cell lung cancer. PMID- 10100596 TI - Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft. AB - PURPOSE: Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide; SR 4233) is a bioreductive agent that exhibits relatively selective cytotoxicity towards cells under hypoxic conditions and can enhance the antitumor activity of many standard oncolytics. In the present study we examined the interaction between tirapazamine in vivo with paclitaxel and paraplatin in two- and three-way combination studies using the MV-522 human lung carcinoma xenograft model. METHODS: Agents were administered as a single i.p. bolus, with tirapazamine being given 3 h prior to paclitaxel, paraplatin, or their combination. Tumor growth inhibition (TGI), final tumor weights, partial and complete responses, and time to tumor doubling were determined after drug administration. RESULTS: Tirapazamine as a single agent was ineffective against this human lung tumor model. A substantial increase in TGI was seen in animals treated with the triple-agent regimen (tirapazamine paclitaxel-paraplatin) compared to animals treated with double-agent regimens that did not include tirapazamine. The addition of tirapazamine to paclitaxel paraplatin therapy resulted in a 50% complete response rate; there were no complete responses seen when only the paclitaxel-paraplatin combination was administered. Time to tumor doubling was also significantly improved with the addition of tirapazamine to the paclitaxel and paraplatin combinations. Tirapazamine did not increase the toxicity of paclitaxel, paraplatin, or their combinations as judged by its minimal impact on body weight and the fact that no toxic deaths were observed with tirapazamine-containing regimens. CONCLUSIONS: These results are important since recent studies have suggested that the combination of paclitaxel and paraplatin may be particularly active in patients with advanced stage non-small-cell lung cancer. Since tirapazamine can significantly improve efficacy, but does not appear to enhance the toxicity of paclitaxel and paraplatin, its evaluation in future clinical trials in combination with paclitaxel-paraplatin-based therapy appears warranted. PMID- 10100597 TI - A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees C whole body hyperthermia. AB - PURPOSE: To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min. PATIENTS AND METHODS: Nine patients with refractory cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatment courses. Three patients were treated at TNF dose level I (50 microg/m2) and six patients were treated at TNF dose level II (100 microg/m2). TNF was delivered as a 24-h intravenous infusion, 48 h prior to the combination of L-PAM and WBH; L-PAM was given over 10 min at target temperature at a dose of 17.5 mg/ m2 based on a previous phase I WBH/L-PAM trial. WBH was administered with an Aquatherm radiant heat device. RESULTS: Myelosuppression was the major toxicity associated with therapy, but there were no instances of bleeding or neutropenic fevers. Grade 3 thrombocytopenia was seen with 15% of treatments. Regarding absolute neutrophil count, 15% of treatments were associated with grade 3 toxicity, and 45% with grade 4 toxicity, and regarding white blood cell count, 50% of treatments were associated with grade 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed was equivalent to that seen in our earlier phase I study of WBH and L-PAM (without TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with <25% of treatments and included nausea, vomiting, diarrhea, fevers, and headache. There were no instances of hypotension. There was no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments; these included nausea, vomiting, and herpes simplex I. Responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF dose level I). CONCLUSION: We conclude that the combination of TNF, L-PAM, and WBH is well tolerated at the dose levels studied. The clinical results justify further clinical investigation for this trimodality treatment approach. PMID- 10100598 TI - Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates. AB - PURPOSE: The antiviral nucleoside analogue ganciclovir is a potent inhibitor of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompromised patients. Ganciclovir is also used in cancer gene therapy studies that utilize the herpes simplex virus thymidine kinase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and children have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir. We studied the pharmacokinetics of ganciclovir in plasma and CSF in a nonhuman primate model that is highly predictive of the CSF penetration of drugs in humans. METHODS: Ganciclovir, 10 mg/kg i.v., was administered over 30 min to three animals. Ganciclovir concentrations in plasma and CSF were measured using reverse-phase HPLC. RESULTS: Peak plasma ganciclovir concentrations ranged from 18.3 to 20.0 microg/ml and the mean plasma AUC was 1075+/-202 microg/ml x min. Disappearance of ganciclovir from the plasma was biexponential with a distribution half-life (t(1/2)alpha) of 18+/-7 min and an elimination half-life (t(1/2)beta) of 109+/-7 min. Total body clearance (ClTB) was 9.4+/-1.6 ml/min/kg. The mean CSF ganciclovir AUC was 168+/-83 microg/ml x min and the mean peak CSF concentration was 0.7+/-0.3 microg/ml. The ratio of the AUCs in CSF and plasma was 15.5+/-7.1%. CONCLUSIONS: Ganciclovir penetrates into the CSF following i.v. administration. This finding will be useful in the design of gene therapy trials involving the HSV-TK gene followed by treatment with ganciclovir in CNS or leptomeningeal tumors. PMID- 10100599 TI - Pharmacology of N-benzyladriamycin-14-valerate in the rat. AB - PURPOSE: N-Benzyladriamycin-14-valerate (AD 198) is a semisynthetic anthracycline analogue superior to doxorubicin (DOX) both in vitro and in experimental rodent tumor models, and with differing mechanistic properties from those of the parental antibiotic agent. In the present study, we examined the metabolic fate and hematotoxicity of AD 198 in rats, with a view to determining whether some of the therapeutic properties observed for this drug might be due to a DOX prodrug effect. METHODS: Samples of plasma, bile and urine were obtained at various times following intravenous (i.v.) [14C]-AD 198 administration to rats and were analyzed by reversed-phase HPLC with flow-fluorescence detection and complementary liquid scintillography. In other animals, red blood cell and white blood cell (WBC) counts were determined for blood obtained by retrobulbar sampling on selected days from groups of animals receiving either AD 198 or DOX at several dose levels, as well as from vehicle controls. RESULTS: Following a single iv dose of [14C]-AD 198 (5 mg/kg; equivalent to the optimal murine antitumor dose) in anesthetized rats, a triphasic plasma decay pattern for parental drug was evident with extremely rapid alpha and beta phases followed by a very long terminal elimination phase. Principal plasma products included N benzyladriamycin (AD 288) and N-benzyladriamycinol (AD 298) together with very low levels of DOX and doxorubicinol (DOXOL). Analysis of bile from anesthetized and conscious animals receiving AD 198 revealed DOX to be the principal biliary fluorescent species together with low levels of AD 288, AD 298 and DOXOL; no parental drug was seen. By contrast, AD 288 was the principal urinary product, together with low levels of AD 298 and DOX; again, no parental drug was evident. Dose recovery (8 h) in the respective bile and urine of anesthetized rats was 12.4% and 13.2% based upon total fluorescence versus 1% and 15.3% of the administered radiolabel. In conscious animals, 13.4% of drug fluorescence was recovered in the bile (48 h), while in urine 16.6% and 77.1% of drug fluorescence and radiolabel, respectively, were eliminated over 72 h. The discrepancy between recovery of drug fluorescence and 14C was due to the production of nonfluorescent hippuric acid (benzoylglycine) and N-benzyl daunosamine as a consequence of hepatic and renal drug metabolism. In the separate hematotoxicity studies, AD 198 (24.6 mg/ kg i.v.; equivalent to the murine LD50 dose), produced a 45% reduction (nadir day 3-5) in WBC count, with recovery by day 10. By contrast, DOX (10 mg/kg i.v.; equivalent to the mouse highest nonlethal dose) produced an 80% decline in WBC with only partial recovery by day 17. CONCLUSIONS: By virtue of the low systemic DOX levels and low hematotoxicity observed in rats receiving AD 198, the in vivo therapeutic superiority of AD 198 cannot be attributed to substantial intracellular DOX generation. The conclusion that the therapeutic superiority of AD 198 compared to DOX results from the mechanistic differences between these two drugs is further supported by recent observations on their biochemical differences with regard to protein kinase C and topoisomerase II inhibition. PMID- 10100600 TI - A pharmacokinetic model and the clinical pharmacology of cis-platinum, 5 fluorouracil and mitomycin-C in isolated pelvic perfusion. AB - PURPOSE: An isolated pelvic perfusion technique using multiple agents was used both in patients with unresectable recurrent pelvic neoplasms and as a preoperative therapy for advanced pelvic malignancy. METHODS: The technique consisted of vascular occlusion via transfemoral balloon catheters, circulation and drug infusion using standard hemodialysis technology, and a 45-min isolation period. Blood and urine samples were analyzed for the levels of cis-platinum (17 patients, 21 courses of therapy, 50-100 mg/m2, infusion 0-10 min), 5-fluorouracil (12 patients, 14 courses, 1500 mg/m2, infusion 1/3 dose 0-1 min, 2/3 dose 1-20 min) and mitomycin-C (11 patients, 14 courses, 10-20 mg/m2, infusion 10-20 min). An empirical, four-compartment pharmacokinetic model was developed to establish drug distribution curves for the pelvic and systemic circulations and to yield valid estimates of the pharmacokinetic parameters. RESULTS: Pelvic isolation of drug was demonstrated by the pelvic-systemic drug exposure ratios of 6.0:1 for cis-platinum, 8.4:1 for 5-fluorouracil and 9.0:1 for mitomycin-C. Isolation at the L3-4 interspace resulted in minor urine drug elimination during isolation (cis-platinum 7.2% of drug, 5-fluorouracil 2.4% and mitomycin-C 2.5%). Because drug infusion was limited to the first 20 min of isolation, drug levels at the end of the isolation period were reduced to the extent that no extracorporeal drug removal mechanism was needed. CONCLUSION: These pharmacokinetic results indicate that this isolation technique has the potential to provide increased therapeutic indices and is a suitable system for evaluating fast-acting highly toxic experimental drugs to human pelvic cancers which are poorly responsive to conventional clinical protocols. PMID- 10100601 TI - A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa cyclophosphamide regimen. AB - PURPOSE: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. METHODS: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model). in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin thiotepa-cyclophosphamide combination). RESULTS: The measured mean AUC in our population was 4.1 min x mg/ml (median 3.9, range 1.9 6.3, SD 1.0 min x mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min x mg/ml (median 4.2, range 2.4-8.4, SD 1.2 min x mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. CONCLUSION: Although easy and attractive to use, the Ghazal Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations. PMID- 10100602 TI - A function for the vitamin E metabolite alpha-tocopherol quinone as an essential enzyme cofactor for the mitochondrial fatty acid desaturases. AB - A critical analysis of the changes in fatty acid patterns and their metabolism elicited by vitamin E deficiency leads to the proposal that a major role of dietary RRR-alpha-tocopherol (alpha-TOC) is as an enzymatic precursor of alpha tocopherolquinone (alpha-TQ) whose semiquinone radical functions as an essential enzyme cofactor for the fatty acid desaturases of the recently elucidated carnitine-dependent, channeled, mitochondrial desaturation-elongation pathway; a detailed mechanism for its function is proposed. Pathophysiological states produced by vitamin E deficiency and alpha-TOC transfer protein defects, such as ataxia, myopathy, retinopathy, and sterility are proposed to develop from the effects of impaired alpha-TQ-dependent desaturases and the resulting deficiency of their polyenoic fatty acid products. PMID- 10100603 TI - The nuclear protein PH5P of the inter-alpha-inhibitor superfamily: a missing link between poly(ADP-ribose)polymerase and the inter-alpha-inhibitor family and a novel actor of DNA repair? AB - Poly(ADP-ribose)polymerase is a nuclear NAD-dependent enzyme and an essential nick sensor involved in cellular processes where nicking and rejoining of DNA strands are required. The inter-alpha-inhibitor family is comprized of several plasma proteins that all harbor one or more so-called heavy chains designated H1 H4. The latter originate from precursor polypeptides H1P-H4P whose upper two thirds are highly homologous. We now describe a novel protein that includes (i) a so-called BRCT domain found in many proteins involved in DNA repair, (ii) an area that is homologous to the NAD-dependent catalytic domain of poly(ADP ribose)polymerase, (iii) an area that is homologous to the upper two thirds of precursor polypeptides H1P-H4P and (iv) a proline-rich region with a potential nuclear localization signal. This protein now designated PH5P points to as yet unsuspected links between poly(ADP-ribose)polymerase and the inter-alpha inhibitor family and is likely to be involved in DNA repair. PMID- 10100604 TI - Caspase-3 inhibits growth in Saccharomyces cerevisiae without causing cell death. AB - Caspase-3, a member of the caspase family of cell death proteases, cleaves cytoplasmic and nuclear substrates and promotes apoptotic cell death in mammalian cells. Although yeast homologs of apoptotic genes have not been identified, some components of apoptotic pathways retain function in yeast. Here we show that the expression of caspase-3 delays cell growth in Saccharomyces cerevesiae without causing cell death. Mutation of the caspase-3 QACRG active site abolished effects on yeast growth. Co-expression of caspase inhibitors alleviated growth inhibition in yeast as did the tripeptide caspase inhibitor ZVAD-fmk. These results suggest that substrates for caspase-3 are present in S. cerevesiae and may participate in the normal cell growth and division processes. PMID- 10100605 TI - Effect of magnetic resonance imaging on human respiratory burst of neutrophils. AB - It is known that low intensity magnetic fields increase superoxide anion production during the respiratory burst of rat peritoneal neutrophils in vitro. We investigated whether the high intensity magnetic fields (1.5 T) during magnetic resonance imaging can influence the human neutrophil function under in vivo conditions. Blood samples were obtained from 12 patients immediately before and after magnetic resonance imaging (mean time 27.6(+/-11.4 min)). The induced respiratory burst was investigated by the intracellular oxidative transformation of dihydrorhodamine 123 to the fluorescent dye rhodamine 123 via flow cytometry. The respiratory burst was induced either with phorbol 12-myristate 13-acetate, Escherichia coli, N-formyl-methionyl-leucylphenylalanine or priming with tumor necrosis factor followed by FMLP stimulation. There was no significant difference between the respiratory burst before and after magnetic resonance imaging, irrespective of the stimulating agent. Short time exposure to a high intensity magnetic field during magnetic resonance imaging seems not to influence the production of radical species in living neutrophils. PMID- 10100606 TI - Coordinate changes of polyamine metabolism regulatory proteins during the cell cycle of normal human dermal fibroblasts. AB - In human dermal fibroblasts, brought to quiescence (G0) by serum starvation, the S phase peaked 24 h and G2/M phases 36 h after serum re-addition. Under the same conditions, ornithine decarboxylase mRNA peaked at 12 h, decreased markedly in S phase and remained low until 48 h. Conversely, ornithine decarboxylase antizyme transcript dropped to its lowest level at 12 h, while reaching its highest values between 24 and 48 h. Ornithine decarboxylase activity followed essentially the pattern of its mRNA, but relative changes were much greater. S-Adenosylmethionine decarboxylase transcript and enzyme activity also peaked at around 12 h, decreasing thereafter. Spermidine/spermine N1-acetyltransferase mRNA and activity reached the highest values at 36-48 h. Putrescine concentration increased up to 18 h and fell dramatically in the S phase, remaining low thereafter. Both spermidine and spermine reached peaks at 18 h and decreased in the S phase, but not nearly as much as putrescine. We discuss how this comprehensive study may help to understand the involvement of polyamines in the control of cell proliferation. PMID- 10100607 TI - Isolation of a highly active PSII-LHCII supercomplex from thylakoid membranes by a direct method. AB - We have developed a simple and novel method to isolate a highly pure and active photosystem (PS) II complex, directly from thylakoid membranes. This complex is a discrete particle and contains all the proteins of the oxygen evolving complex and a set of chlorophyll alb binding proteins. The intactness of both the donor side and the acceptor side has resulted in a very high oxygen evolution activity and therefore offers a superior experimental system to that of PSII enriched membrane fragments in which there is heterogeneity in activities and biochemical composition. PMID- 10100608 TI - Stoichiometry of dipalmitoylphosphatidylcholine-DNA interaction in the presence of Ca2+: a temperature-scanning ultrasonic study. AB - DNA-DPPC complexes can be prepared by means of a single step procedure of mixing DNA solution and aqueous lipid dispersion in the presence of calcium ions. Interaction between DPPC and DNA brings about a biphasic shape of melting curves corresponding to the free lipid and the strongly bound one. The amount of the strongly bound lipid is 5 molecules per nucleotide which is close to the size of the first lipid monolayer around DNA molecule. PMID- 10100609 TI - The L2 loop peptide of RecA stiffens and restricts base motions of single stranded DNA similar to the intact protein. AB - The L2 loop in the RecA protein is the catalytic center for DNA strand exchange. Here we investigate the DNA binding properties of the L2 loop peptide using optical spectroscopy with polarized light. Both fluorescence intensity and anisotropy of an etheno-modified poly(dA) increase upon peptide binding, indicate that the base motions of single-stranded DNA are restricted in the complex. In agreement with this conclusion, the peptide-poly(dT) complex exhibits a significant linear dichroism signal. The peptide is also found to modify the structure of double-stranded DNA, but does not denature it. It is inferred that strand separation may not be required for the formation of a joint molecule. PMID- 10100610 TI - Interaction of tissue transglutaminase with nuclear transport protein importin alpha3. AB - Tissue transglutaminase is a multifunctional enzyme which has been involved in the regulation of cell growth, differentiation, and apoptosis. Recently, nuclear localization of tTG has been reported indicating the potential of active nuclear transport. In this study we use the yeast two-hybrid assay and co immunoprecipitation to show that tTG interacts with the nuclear transport protein importin-alpha3. Using electron microscopy we demonstrate that nuclear expression of tTG in a non-small cell lung cancer cell line is induced by retinoic acid (RA). These data suggest that importin-alpha3 could mediate active nuclear transport of tTG which may be important for the regulation of critical cellular processes. PMID- 10100611 TI - A stable interaction between syntaxin 1a and synaptobrevin 2 mediated by their transmembrane domains. AB - The proteins synaptobrevin (VAMP), SNAP-25 and syntaxin 1 are essential for neuronal exocytosis. They assemble into a stable ternary complex which is thought to initiate membrane fusion. In vitro, the transmembrane domains of syntaxin and synaptobrevin are not required for association. Here we report a novel interaction between synaptobrevin and syntaxin that requires the presence of the transmembrane domains. When co-reconstituted into liposomes, the proteins form a stable binary complex that cannot be disassembled by NSF and that is resistant to denaturation by SDS. Cleavage of synaptobrevin with tetanus toxin does not affect the interaction. Furthermore, the complex is formed when a truncated version of syntaxin is used that contains only 12 additional amino acid residues outside the membrane anchor. We conclude that the interaction is mediated by the transmembrane domains. PMID- 10100612 TI - First synthesis of a fully active spin-labeled peptide hormone. AB - For the first time in the electron spin resonance (ESR) and peptide synthesis fields, a fully active spin-labeled peptide hormone was reported. The ESR spectra of this alpha-melanocyte stimulating hormone (alpha-MSH) analogue (acetyl-Toac0 alpha-MSH) where Toac is the paramagnetic amino acid probe 2,2,6,6 tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid, suggested a pH independent conformation and a more restricted movement comparatively to the free Toac. Owing to its equivalent biological potency in a skin pigmentation assay as compared to the native alpha-MSH and its unique characteristic (paramagnetic, naturally fluorescent and fully active), this analogue is of great potential for investigation of relevant physiological roles reported for alpha-MSH. PMID- 10100613 TI - Biodegradative mechanism of the brown rot basidiomycete Gloeophyllum trabeum: evidence for an extracellular hydroquinone-driven fenton reaction. AB - We have identified key components of the extracellular oxidative system that the brown rot fungus Gloeophyllum trabeum uses to degrade a recalcitrant polymer, polyethylene glycol, via hydrogen abstraction reactions. G. trabeum produced an extracellular metabolite, 2,5-dimethoxy-1,4-benzoquinone, and reduced it to 2,5 dimethoxyhydroquinone. In the presence of 2,5-dimethoxy-1,4-benzoquinone, the fungus also reduced extracellular Fe3+ to Fe2+ and produced extracellular H2O2. Fe3+ reduction and H2O2 formation both resulted from a direct, non-enzymatic reaction between 2,5-dimethoxyhydroquinone and Fe3+. Polyethylene glycol depolymerization by G. trabeum required both 2,5-dimethoxy-1,4-benzoquinone and Fe3+ and was completely inhibited by catalase. These results provide evidence that G. trabeum uses a hydroquinone-driven Fenton reaction to cleave polyethylene glycol. We propose that similar reactions account for the ability of G. trabeum to attack lignocellulose. PMID- 10100614 TI - Hypoxia increases the association of 4E-binding protein 1 with the initiation factor 4E in isolated rat hepatocytes. AB - Incubation of hepatocytes under hypoxia increases binding of translation initiation factor eIF-4E to its inhibitory regulator 4E-BP1, and this correlates with dephosphorylation of 4E-BP1. Rapamycin induced the same effect in aerobic cells but no additive effect was observed when hypoxic cells were treated with rapamycin. This enhanced association of 4E-BP1 with eIF-4E might be mediated by mTOR. Nevertheless, only hypoxia produces a rapid inhibition of protein synthesis. Although hypoxia might be signalling via the rapamycin-sensitive pathway by changing eIF-4E availability, such a pathway is unlikely to be responsible for the depression in overall protein synthesis under hypoxia. PMID- 10100615 TI - A pseudoknot-compatible universal site is located in the large ribosomal RNA in the peptidyltransferase center. AB - The RNA secondary structure is not confined to a system of the hairpins and can contain pseudoknots as well as topologically equivalent slipped-loop structure (SLS) conformations. A specific primary structure that directs folding to the pseudoknot or SLS is called SL-palindrome (SLP). Using a computer program for searching the SLP in the genomic sequences, 419 primary structures of large ribosomal RNAs from different kingdoms (prokaryota, eukaryota, archaebacteria) as well as plastids and mitochondria were analyzed. A universal site was found in the peptidyltransferase center (PTC) capable of folding to a pseudoknot of 48 nucleotides in length. Phylogenetic conservation of its helices (concurrent replacements with no violation of base pairing, covariation) has been demonstrated. We suggest the reversible folding-unfolding of the pseudoknot for certain stages of the ribosome functioning. PMID- 10100616 TI - Transport of organic anions by the lysosomal sialic acid transporter: a functional approach towards the gene for sialic acid storage disease. AB - Transport of sialic acid through the lysosomal membrane is defective in the human sialic acid storage disease. The mammalian sialic acid carrier has a wide substrate specificity for acidic monosaccharides. Recently, we showed that also non-sugar monocarboxylates like L-lactate are substrates for the carrier. Here we report that other organic anions, which are substrates for carriers belonging to several anion transporter families, are recognized by the sialic acid transporter. Hence, the mammalian system reveals once more novel aspects of solute transport, including sugars and a wide array of non-sugar compounds, apparently unique to this system. These data suggest that the search for the sialic acid storage disease gene can be initiated by a functional selection of genes from a limited number of anion transporter families. Among these, candidates will be identified by mapping to the known sialic acid storage disease locus. PMID- 10100617 TI - Evidence that carnitine palmitoyltransferase I (CPT I) is expressed in microsomes and peroxisomes of rat liver. Distinct immunoreactivity of the N-terminal domain of the microsomal protein. AB - Mitochondria, microsomes and peroxisomes all express overt (cytosol-facing) carnitine palmitoyltransferase activity that is inhibitable by malonyl-CoA. The overt carnitine palmitoyltransferase activity (CPTo) associated with the different fractions was measured. Mitochondria accounted for 65% of total cellular CPTo activity, with the microsomal and peroxisomal contributions accounting for the remaining 25% and 10%, respectively. In parallel experiments, rat livers were perfused in situ with medium containing dinitrophenyl (DNP) etomoxir in order to inhibit quantitatively and label covalently (with DNP etomoxiryl-CoA) the molecular species responsible for CPTo activity in each of the membrane systems under near-physiological conditions. In all three membrane fractions, a single protein with an identical molecular mass of approximately 88,000 kDa (p88) was labelled after DNP-etomoxir perfusion of the liver. The abundance of labelled p88 was quantitatively related to the respective specific activities of CPTo in each fraction. On Western blots the same protein was immunoreactive with three anti-peptide antibodies raised against linear epitopes of the cytosolic N- and C-domains and of the inter-membrane space loop (L) domain of the mitochondrial enzyme (L-CPT I). However, the reaction of the microsomal protein with the anti-N peptide antibody (raised against epitope Val-14-Lys-29 of CPT I) was an order of magnitude stronger than expected from either microsomal CPTo activity or its DNP-etomoxiryl-CoA labelling. This suggests that the N terminal domain of the microsomal protein differs from that in the mitochondrial or peroxisomal protein. This conclusion was confirmed using antibody back titration experiments, in which the binding of anti-N and anti-C antibodies by mitochondria and microsomes was quantified. PMID- 10100618 TI - Contributions of the ionization states of acidic residues to the stability of the coiled coil domain of matrilin-1. AB - The pKa values of eight glutamic acid residues in the homotrimeric coiled coil domain of chicken matrilin-1 have been determined from 2D H(CA)CO NMR spectra recorded as a function of the solution pH. The pKa values span a range between 4.0 and 4.7, close to or above those for glutamic acid residues in unstructured polypeptides. These results suggest only small favorable contributions to the stability of the coiled coil from the ionization of its acidic residues. PMID- 10100619 TI - Secondary structure of the C-terminal domain of the tyrosyl-transfer RNA synthetase from Bacillus stearothermophilus: a novel type of anticodon binding domain? AB - The tyrosyl-tRNA synthetase catalyzes the activation of tyrosine and its coupling to the cognate tRNA. The enzyme is made of two domains: an N-terminal catalytic domain and a C-terminal domain that is necessary for tRNA binding and for which it was not possible to determine the structure by X-ray crystallography. We determined the secondary structure of the C-terminal domain of the tyrosyl-tRNA synthetase from Bacillus stearothermophilus by nuclear magnetic resonance methods and found that it is of the alpha+beta type. Its arrangement differs from those of the other anticodon binding domains whose structure is known. We also found that the isolated C-terminal domain behaves as a folded globular protein, and we suggest the presence of a flexible linker between the two domains. PMID- 10100620 TI - Regulation of c-fos gene transcription and myeloid cell differentiation by acute myeloid leukemia 1 and acute myeloid leukemia-MTG8, a chimeric leukemogenic derivative of acute myeloid leukemia 1. AB - Both acute myeloid leukemia 1 and c-Fos are regulatory factors of hematopoietic cell differentiation. We identified that the c-fos promoter contains an acute myeloid leukemia 1 binding site at nucleotide positions -6-+14. c-fos promoter activity was induced by transient overexpression of acute myeloid leukemia 1 in Jurkat T-cells, but not by that of the short form of acute myeloid leukemia 1 MTG8, a chimeric acute myeloid leukemia 1 protein. In 32Dcl3 myeloid cells, stable overexpression of acute myeloid leukemia 1-MTG8 blocked the c-fos gene transcription and cell differentiation, but that of acute myeloid leukemia did not. These data suggest that acute myeloid leukemia 1 and acute myeloid leukemia 1-MTG8 reciprocally regulate the myeloid cell differentiation, possibly by the way of regulating c-fos gene transcription. PMID- 10100621 TI - Role of tyrosine phosphorylation of phospholipase C gamma1 in the signaling pathway of HMG-CoA reductase inhibitor-induced cell death of L6 myoblasts. AB - Our previous studies have shown that the HMG-CoA reductase (HCR) inhibitor (HCRI), simvastatin, kills L6 myoblasts by involving Ca2+ mobilization from the Ca2+ pool in the cells but not by influx from extracellular space. More recently, we found that HCRI induced tyrosine phosphorylation of several cellular proteins, followed by apoptotic cell death of L6 myoblasts. The present study was aimed to elucidate the molecular target(s) of these tyrosine phosphorylations induced by HCRI and demonstrated that simvastatin induces tyrosine phosphorylation of phospholipase C (PLC) gamma1. This tyrosine phosphorylation of PLC-gamma1 caused the increment of the intracellular inositol triphosphate (IP3) levels in L6 myoblasts. Pretreatment of the cells with herbimycin A, a specific inhibitor of protein tyrosine kinase, inhibited a simvastatin-induced increase in IP3 level in the cells as well as tyrosine phosphorylation of PLC-gamma1. Interestingly, pretreatment of the cells with U-73122, a specific inhibitor of PLC, prevented simvastatin-induced cell death. Thus, these results strongly suggest that simvastatin-induced tyrosine phosphorylation of PLC-gamma1 plays, at least in part, an important role for the development of simvastatin-induced cell death. PMID- 10100622 TI - Characterization of phosphotyrosine containing proteins at the cholinergic synapse. AB - Tyrosine phosphorylation has been associated with several aspects of the regulation of cholinergic synaptic function, including nicotinic acetylcholine receptor (AChR) desensitization as well as the synthesis and clustering of synaptic components. While some progress has been made in elucidating the molecular events initiating such signals, the downstream targets of these tyrosine kinase pathways have yet to be characterized. In this paper we have used molecular cloning techniques to identify proteins which are tyrosine phosphorylated at the cholinergic synapse. Phosphotyrosine containing proteins (PYCPs) were isolated from the electric organ of Torpedo californica by anti phosphotyrosine immunoaffinity chromatography. Peptide sequencing and expression cloning then identified the isolated proteins. The proteins identified included heat shock protein 90, type III intermediate filament from Torpedo electric organ, alpha-fodrin, beta-tubulin, actin and rapsyn. These tyrosine phosphorylated proteins may play a role in the regulation of synaptic function by tyrosine kinases. PMID- 10100623 TI - Discovery of a receptor related to the galanin receptors. AB - We report the isolation of a cDNA clone named GPR54, which encodes a novel G protein-coupled receptor (GPCR). A PCR search of rat brain cDNA retrieved a clone partially encoding a GPCR. In a library screening this clone was used to isolate a cDNA with an open reading frame (ORF) encoding a receptor of 396 amino acids long which shared significant identities in the transmembrane regions with rat galanin receptors GalR1 (45%), GalR3 (45%) and GalR2 (44%). Northern blot and in situ hybridization analyses revealed that GPR54 is expressed in brain regions (pons, midbrain, thalamus, hypothalamus, hippocampus, amygdala, cortex, frontal cortex, and striatum) as well as peripheral regions (liver and intestine). In COS cell expression of GPR54 no specific binding was observed for 125I-galanin. A recent BLAST search with the rat GPR54 ORF nucleotide sequence recovered the human orthologue of GPR54 in a 3.5 Mb contig localized to chromosome 19p13.3. PMID- 10100624 TI - Alpha4 protein as a common regulator of type 2A-related serine/threonine protein phosphatases. AB - The catalytic activity of the C subunit of serine/threonine phosphatase 2A is regulated by the association with A (PR65) and B subunits. It has been reported that the alpha4 protein, a yeast homolog of the Tap42 protein, binds the C subunit of serine/threonine phosphatase 2A and protein phosphatase 2A-related protein phosphatases such as protein phosphatase 4 and protein phosphatase 6. In the present study, we showed that alpha4 binds these three phosphatases and the association of alpha4 reduces the activities of these phosphatases in vitro. In contrast, PR65 binds to the C subunit of serine/threonine phosphatase 2A but not to protein phosphatase 4 and protein phosphatase 6. These results suggest that the alpha4 protein is a common regulator of the C subunit of serine/threonine phosphatase 2A and protein phosphatase 2A-related protein phosphatases. PMID- 10100625 TI - Cell membrane dynamics and the induction of apoptosis by lipid compounds. AB - To investigate the induction of apoptosis by some lipid compounds which are a potent inducer of apoptosis, the plasma membrane fluidity of U937 cells was measured using the fluorescent probe, pyrene. The increase of the membrane fluidity was observed immediately after the treatment of cells with lipid inducers. We also found that the trigger of apoptosis was pulled within 30 min after treatment. Data from the dynamic light scattering experiment indicated that lipid inducers were dissolved to form the emulsion. At the very early stage of apoptosis, possibly, the well-controlled transfer of lipid inducers from the emulsion to the lipid layer of cells can bring about the increase of membrane dynamics which might lead to the induction of apoptosis. PMID- 10100626 TI - Ultrasensitive glycogen synthesis in Cyanobacteria. AB - Cyanobacter ADPglucose pyrophosphorylase exhibits a ultrasensitive response in activity towards its allosteric effector 3-phosphoglycerate, elicited by orthophosphate and polyethyleneglycol-induced molecular crowding. The ultrasensitive response was observed either when the enzyme operates in the zero or first order region for its physiological substrates. The ultrasensitivity exhibited maximal amplification factors of 15-19-fold with respect to 1% of the maximal system velocity. Only a 2.4-3.8-fold increase in 3PGA concentration was necessary to augment the flux from 10% to 90% through AGPase as compared with 200 fold required for the control. The results are discussed in terms of finely tuned regulatory mechanisms of polysaccharide synthesis in oxygenic photosynthetic organisms. PMID- 10100627 TI - Role of ERK1/ERK2 and p70S6K pathway in insulin signalling of protein synthesis. AB - The signalling pathways by which insulin triggers protein synthesis were studied using an antisense strategy to deplete ERK1/ERK2 and rapamycin to inhibit the p70S6K pathway. The results indicated that ERK1/ERK2 principally regulated the amount of the protein synthesis machinery available in the cell while the p70S6K pathway contributed to modulating its activation in response to insulin. ERK1/ERK2 also mediated in a small proportion of insulin-stimulated protein synthesis which included the induction of c-fos protein. When c-fos induction was blocked the majority of insulin-stimulated protein synthesis still occurred and thus did not require transcriptional regulation of c-fos or its targets. PMID- 10100628 TI - Structural changes in the recombinant, NADP(H)-binding component of proton translocating transhydrogenase revealed by NMR spectroscopy. AB - We have analysed 1H, 15N-HSQC spectra of the recombinant, NADP(H)-binding component of transhydrogenase in the context of the emerging three dimensional structure of the protein. Chemical shift perturbations of amino acid residues following replacement of NADP+ with NADPH were observed in both the adenosine and nicotinamide parts of the dinucleotide binding site and in a region which straddles the protein. These observations reflect the structural changes resulting from hydride transfer. The interactions between the recombinant, NADP(H)-binding component and its partner, NAD(H)-binding protein, are complicated. Helix B of the recombinant, NADP(H)-binding component may play an important role in the binding process. PMID- 10100629 TI - Localization of the site for the nucleotide effectors of Escherichia coli carbamoyl phosphate synthetase using site-directed mutagenesis. AB - Replacement by alanine of Ser-948, Thr-974 and Lys-954 of Escherichia coli carbamoyl phosphate synthetase (CPS) shows that these residues are involved in binding the allosteric inhibitor UMP and the activator IMP. The mutant CPSs are active in vivo and in vitro and exhibit normal activation by ornithine, but the modulation by both UMP and IMP is either lost or diminished. The results demonstrate that the sites for UMP and IMP overlap and that the activator ornithine binds elsewhere. Since the mutated residues were found in the crystal structure of CPS near a bound phosphate, Ser-948, Thr-974 and Lys-954 bind the phosphate moiety of UMP and IMP. PMID- 10100630 TI - Activation of recombinant human SK4 channels by metal cations. AB - The effects of metal cations on the activation of recombinant human SK4 (also known as hIK1 or hKCa4) channels, expressed in HEK 293 cells, were tested using patch clamp recording. Of the nine metals tested, cobalt, iron, magnesium, and zinc did not activate the SK4 channels when applied, at concentrations up to 100 microM, to the inside of SK4 channel-expressing membrane patches. Barium, cadmium, calcium, lead, and strontium activated SK4 channels in a concentration dependent manner. The rank order of potency was at Ca2+ > Pb2+ > Cd2+ > Sr2+ > Ba2+. PMID- 10100631 TI - Murine 12(R)-lipoxygenase: functional expression, genomic structure and chromosomal localization. AB - A cDNA, recently cloned (by Krieg et al. (1998)) from mouse skin, was shown to encode a 12(R)-lipoxygenase. When expressed in HEK cells, the recombinant protein converted methyl arachidonate into the corresponding 12-HETE ester which was shown to be the R-enantiomer by chiral phase chromatography. Neither arachidonic acid nor linoleic acid were substrates for the recombinant protein. The structure of the 12(R)-lipoxygenase gene is unique among all animal lipoxygenases in that it is divided into 15 exons and 14 introns spanning approximately 12.5 kb. By interspecific backcross analysis, the 12(R)-lipoxygenase gene was localized to the central region of mouse chromosome 11. PMID- 10100632 TI - In vivo operation of the pentose phosphate pathway in frog oocytes is limited by NADP+ availability. AB - Evolution of CO2 from labelled glucose microinjected into frog oocytes in vivo may be ascribed to the pentose-P pathway, as measured by radioactive CO2 production from [1-(14)C] and [6-(14)C]glucose. Coinjection of NADP+ and [14C]glucose significantly stimulated 14CO2 production. The effect depends on the amount of NADP+ injected, half maximal stimulation being obtained at 0.13 mM. The increase in CO2 production was also observed with microinjected glucose-1-P, glucose-6-P or fructose-6-P used as substrates. Phenazine methosulfate, mimicked the effects of NADP+. A high NADPH/NADP+ ratio of 4.3 was found in the cells, the intracellular concentration of NADP+ being 19 microM. PMID- 10100633 TI - Reconstitution of an electrogenic auxin transport activity mediated by Arabidopsis thaliana plasma membrane proteins. AB - Plasma membrane proteins from Arabidopsis thaliana leaves were reconstituted into proteoliposomes and a K+ diffusion potential was generated. The resulting ionic fluxes, determined in the presence of the plant hormone auxin (indole-3 acetic acid), showed an additional electrogenic and saturable component, with a K(M) of 6 microM. This flux was neither detected in liposomes in the presence of indole-3 acetic acid, nor in proteoliposomes in the presence of an inactive auxin analog and was completely inhibited by 3 microM naphtylphthalamic acid, a specific inhibitor of the auxin efflux carrier. The efficiency of the reconstituted carrier and the mechanism of its regulation by naphtylphthalamic acid are discussed. PMID- 10100634 TI - Binding of neuronal ELAV-like proteins to the uridine-rich sequence in the 3' untranslated region of tumor necrosis factor-alpha messenger RNA. AB - Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that is involved in the pathogenesis of several human CNS disorders. The AU-rich element (ARE) in the 3'-untranslated region (UTR) of TNF-alpha mRNA is implicated in post transcriptional control of TNF-alpha. In this study, we showed that a human neuronal ELAV-like protein binds to the ARE in the 3'-UTR of TNF-alpha mRNA. The protein binds to the uridine stretch in AUUUA pentanucleotides inside the ARE in the 3'-UTR of TNF-alpha mRNA. The TNF-alpha mRNA-binding region in the protein appears to be identical to the c-myc and IL-3 mRNA-binding regions. Moreover, this study showed that in vitro treatment of neuroblastoma cells with interleukin 4 (IL-4), which inhibits TNF-alpha production, reduced the expression of the neuronal ELAV-like proteins. These results suggest that the expression of neuronal ELAV-like proteins may be closely associated with the expression of TNF alpha in neuronal cells. PMID- 10100635 TI - Distribution of exogenous 25-hydroxycholesterol in Hep G2 cells between two different pools. AB - Binding of [26,27-(3)H]25-hydroxycholesterol (25HC) to human hepatoma Hep G2 cells was saturated within 120 min. Two intracellular pools of 25HC were identified in a pulse-chase experiment: (i) an exchangeable pool which was in dynamic equilibrium with 25HC in the medium (t(1/2) of reversible exchange 15 min) and (ii) an unexchangeable pool which remained in cells during incubation in medium containing LPDS. 25HC from the exchangeable pool inhibits cholesterol biosynthesis, decreases the HMG CoA reductase mRNA level and stimulates cholesterol acylation. 25HC from the unexchangeable pool was partially bound to cytosolic proteins and apparently utilized for metabolic transformation. Incubation of Hep G2 cells with [26,27-(3)H]25HC in the presence of a 30-fold molar excess of 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one was found to cause (i) 2-fold decrease in the binding of [26,27-(3)H]25HC to cytosolic proteins (sedimentation constant of radioactive complex was 4-5 S) and (ii) the 35% inhibition of 25HC transformation to polar metabolites. PMID- 10100636 TI - The interaction of ubiquinone-3 with phospholipid membranes. AB - The effects of ubiquinone-3 (UQ) on dipalmitoylphosphatidylcholine (DPPC) membrane were studied by surface monolayer, differential scanning calorimetry (DSC) and fluorescence techniques. DPPC and UQ are proved to be freely miscible in the mixed monolayer at an air/water interface, and to be partially miscible in bulk phase, i.e. bilayer and solid phase. There is a condensing interaction between UQ and DPPC in the UQ/DPPC mixed monolayers. The solubility of UQ in the DPPC is about 20 mole% and the solubility of DPPC in UQ is about 10 mole%. The membrane fluidity of DPPC was increased by the addition of UQ and the phase transition temperature was decreased. PMID- 10100637 TI - Requirement of the carboxy-terminal domain of RNA polymerase II for the transcriptional activation of chromosomal c-fos and hsp70A genes. AB - The carboxy-terminal domain of the large subunit of mouse and human RNA polymerase II contains 52 repeats of a heptapeptide which are the targets for a variety of kinases. We have used an alpha-amanitin resistant form of the large subunit of pol II to study the role of the carboxy-terminal domain in the expression of chromosomal genes. The large subunit of RNA polymerase II and deletion mutants thereof, which contain only 31 (LSdelta31) and 5 (LSdeltaS) repeats, were expressed in 293 cells. Subsequently, the endogenous large subunit of RNA polymerase II was inhibited by alpha-amanitin and the induction of chromosomal c-fos and hsp70A genes was determined. Cells expressing the large subunit of RNA polymerase II and LSdelta31 were able to transcribe the c-fos and hsp70A genes after treatment with the phorbolester TPA and after heat-shock, respectively. In contrast, cells expressing LSdelta5 failed to induce expression of both genes. PMID- 10100638 TI - Identification of the catalytic triad in the haloalkane dehalogenase from Sphingomonas paucimobilis UT26. AB - The haloalkane dehalogenase from Sphingomonas paucimobilis UT26 (LinB) is the enzyme involved in the gamma-hexachlorocyclohexane degradation. This enzyme hydrolyses a broad range of halogenated aliphatic compounds via an alkyl-enzyme intermediate. LinB is believed to belong to the family of alpha/beta-hydrolases which employ a catalytic triad, i.e. nucleophile-histidine-acid, during the catalytic reaction. The position of the catalytic triad within the sequence of LinB was probed by a site-directed mutagenesis. The catalytic triad residues of the haloalkane dehalogenase LinB are proposed to be D108, H272 and E132. The topological location of the catalytic acid (E132) is after the beta-strand six which corresponds to the location of catalytic acid in the pancreatic lipase, but not in the haloalkane dehalogenase of Xanthobacter autotrophicus GJ10 which contains the catalytic acid after the beta-strand seven. PMID- 10100639 TI - Mutational analysis of two Arabidopsis thaliana cyclin-dependent kinases in fission yeast. AB - We have analyzed five mutant alleles of two cyclin-dependent kinases from Arabidopsis thaliana, CDC2aAt and CDC2bAt, in Schizosaccharomyces pombe. Two of the five mutant alleles produced similar phenotypes for both cyclin-dependent kinases. The other three mutants caused phenotypes dependent on the particular cyclin-dependent kinase. Of all the mutant alleles, only two were found to possess a detectable kinase activity. Our mutational analysis lends further support for CDC2aAt being the true orthologue of the yeast cdc2. CDC2bAt, even though quite divergent from S. pombe cdc2, still retains the ability to interact with at least some essential cell cycle regulators, suggesting some functional homology with the yeast protein. Additionally, we demonstrated that the three amino acid deletion in the DL50 mutants results in the loss of the ability to interact with the suc1/CKS1 proteins. PMID- 10100640 TI - The BAH (bromo-adjacent homology) domain: a link between DNA methylation, replication and transcriptional regulation. AB - Using sensitive methods of sequence analysis including hydrophobic cluster analysis, we report here a hitherto undescribed family of modules, the BAH (bromo adjacent homology) family, which includes proteins such as eukaryotic DNA (cytosine-5) methyltransferases, the origin recognition complex 1 (Orc1) proteins, as well as several proteins involved in transcriptional regulation. The BAH domain appears to act as a protein-protein interaction module specialized in gene silencing, as suggested for example by its interaction within yeast Orc1p with the silent information regulator Sir1p. The BAH module might therefore play an important role by linking DNA methylation, replication and transcriptional regulation. PMID- 10100641 TI - Interaction of tumor and normal blood cells with ethylene oxide and propylene oxide block copolymers. AB - Ethylene oxide and propylene oxide block copolymers (pluronics) are widely known as agents that promote drug penetration across biological barriers. We have studied the interaction of normal and malignant blood cells with pluronics L61 and P85 that have different hydrophobicity. SP2/0 myeloma cells accumulated pluronics while normal cells adsorb most of the polymer on the surface. Interaction of pluronics with cells resulted in drastic changes of membrane microviscosity. Tumor cell membrane microviscosity decreased after pluronics adsorption, in contrast to normal cells, whose membrane microviscosity was enhanced. We suppose that sensitivity of tumor cell membrane microviscosity to the pluronics action correlates with its permeability for molecular substances. PMID- 10100642 TI - Polymerization of tau peptides into fibrillar structures. The effect of FTDP-17 mutations. AB - The peptides corresponding to the four repeats found in the microtubule binding region of tau protein were synthesized and their ability for self-aggregation in presence of heparin or chondroitin sulfate was measured. Mainly, only the peptide containing the third tau repeat is able to form polymers in a high proportion. Additionally, the peptide containing the second repeat aggregates with a very low efficiency. However, when this peptide contains the mutation (P301L), described in a fronto temporal dementia, it is able to form polymers at a higher extent. Finally, it is suggested to have a role for the first and fourth tau repeats. It could be to decrease the ability of the third tau repeat for self-aggregation in the presence of heparin. PMID- 10100643 TI - Post-translational processing of two alpha-amylase inhibitors and an arcelin from the common bean, Phaseolus vulgaris. AB - Mass spectrometric methods were used to investigate the proteolytic processing and glycopeptide structures of three seed defensive proteins from Phaseolus vulgaris. The proteins were the alpha-amylase inhibitors alphaAI-1 and alphaAI-2 and arcelin-5, all of which are related to the seed lectins, PHA-E and PHA-L. The mass data showed that the proteolytic cleavage required for activation of the amylase inhibitors is followed by loss of the terminal Asn residue in alphaAI-1, and in all three proteins, seven or more residues were clipped from the C termini, in the manner of the seed lectins. In most instances, individual glycoforms could be assigned at each Asn site, due to the unique masses of the plant glycopeptides. It was found that alphaAI-1 and alphaAI-2 differed significantly in their glycosylation patterns, despite their high sequence homology. These data complement the previous X-ray studies of the alpha1-amylase inhibitor and arcelin, where many of the C-terminal residues and glycopeptide residues could not be observed. PMID- 10100644 TI - Periorbital skin resurfacing using high energy erbium:YAG laser: results in 50 patients. AB - OBJECTIVE: To evaluate Erbium:YAG regional periorbital laser resurfacing clinically and histologically. STUDY DESIGN/MATERIALS AND METHODS: Photographic evaluation before and after Erbium:YAG resurfacing with histologic evaluation of depth of injury. SETTING: Group private single specialty practice. PATIENTS: Fifty patients in the age range of 35-62 years, Fitzpatrick skin types I-III were treated using Erbium:YAG for regional resurfacing of periorbital rhytides. OUTCOME MEASURES: Patients were seen at days 1, 2, 3, 7, 14, 28, and at six months and one year. Photographs were obtained prior to application of topical anesthesia and were utilized to judge improvement of rhytides at all time intervals. Additional photographs were taken at each follow-up visit and the results judged by an independent investigator. Results were graded into five categories at all treatment intervals: no improvement, mild (grade 1: up to 25%), moderate (grade 2: 25-50%), good (grade 3: 50-75%, or excellent (grade 4: 75 100%). For histologic evaluation of depth of ablation and thermal injury one, two, and three passes at 21.2 J/cm2 were performed on four patients. RESULTS: Re epithelization in the periorbital region was rapid with a mean duration of 2.65 days. Erythema ranged from a longest of six weeks to the shortest of seven days with a mean duration of 15.4 days. Evaluation of clinical results revealed that at two weeks mean improvement was 2.15 (between moderate and good). At four weeks further improvement was noted with a mean of 2.62. By six months, mean improvement score increased to 2.94. Minimal further improvement was noted between six months and one year with a mean improvement score of 3.02 (good to excellent). Histology revealed complete removal of the epidermis with one to three passes. Dermal ablation of 5-10 microns accompanied by small increases (5 10 microns) in dermal thermal injury occurred with each subsequent pass. CONCLUSIONS: We conclude that high energy Erbium:YAG periorbital resurfacing is a safe and effective modality which achieves substantial therapeutic effect. Most patients achieve approximately 75% improvement. Erythema fades quickly, reepithelization is rapid and side effects are minimal. PMID- 10100645 TI - Clinical and histologic evaluation of six erbium:YAG lasers for cutaneous resurfacing. AB - BACKGROUND: Several erbium:YAG lasers are currently available for cutaneous laser resurfacing. Although different laser systems are purported to produce equivalent laser energies to produce similar laser-tissue interactions, no comparative clinical or histologic studies have been performed to objectively demonstrate their relative efficacies. OBJECTIVE: The purpose of the present study was to examine the in vivo clinical and histopathologic effects of six different erbium:YAG resurfacing lasers. METHODS: A blinded, prospective study using six different erbium lasers (Candela, Continuum Biomedical, HGM, MDLT, SEO, Sharplan/ESC) was performed. The facial halves of 12 patients were randomly resurfaced with one of the six laser systems by using an identical laser technique at 5.0 J/cm2. Intraoperative skin biopsies were obtained after each of three laser passes in two patients for blinded histologic determination of tissue ablation level and presence of residual thermal damage. Clinical assessments of reepithelialization rates, severity and duration of erythema, side effects, and degree of clinical improvement were made at 0.5, 1, 2, 4, 12, 26, and 52 weeks postoperatively. RESULTS: Irrespective of the erbium laser system used, complete reepithelialization typically occurred at 0.5 weeks and resolution of erythema was noted within 1-2 weeks postoperatively. A mean clinical improvement of 50% was observed, with photodamaged skin showing greater improvement than scarred skin. The most common postoperative side effect was hyperpigmentation, with all affected patients having either darker skin tones or preceding dermal inflammation. Three laser passes were needed to effect total epidermal ablation when using any one of the erbium:YAG systems. CONCLUSIONS: Equivalent clinical and histologic results were seen after each of the six erbium:YAG lasers studied. Erbium:YAG laser resurfacing can be used to significantly improve mild cutaneous photodamage and atrophic scars. PMID- 10100646 TI - Histologic analysis of the thermal effect on epidermal and dermal structures following treatment with the superpulsed CO2 laser and the erbium: YAG laser: an in vivo study. AB - BACKGROUND AND OBJECTIVE: To compare the in vivo histologic effects of the carbon dioxide (CO2) and erbium:yttrium aluminum garnet (Er:YAG) lasers. To ascertain the effects of combining CO2 and Er:YAG laser modalities during a single treatment session. STUDY DESIGN/MATERIALS AND METHODS: Ten patients underwent laser treatment to four left preauricular sites 7 days prior to rhytidectomy as follows: CO2 alone, CO2/Er:YAG, Er:YAG alone, and Er:YAG/CO2. The right preauricular area was identically treated 1 hour prior to rhytidectomy. Laser treated skin was excised during rhytidectomy and was evaluated histopathologically in a blinded manner. RESULTS: After 7 days, all groups were reepithelialized and showed equal neo-collagen formation. After 7 days, CO2/Er:YAG and Er:YAG alone had the least collagen injury and thickest epidermis and papillary dermis of all groups. Specimens lased 1 hour prior to excision showed the least collagen injury and thermal necrosis when treated with CO2/Er:YAG and Er:YAG alone. Four passes with CO2 removed 250 microm of tissue, while eight passes with the Er:YAG removed 160 microm of tissue. CONCLUSIONS: Limiting CO2 laser passes and ending with Er:YAG produces less collagen injury, less thermal necrosis, and more robust epithelial and dermal fibrous tissue regeneration. CO2 followed by Er:YAG has similar thermal necrosis and collagen injury as Er:YAG alone, presumably due to Er:YAG removal of CO2 induced thermal injury. PMID- 10100647 TI - Effects of overlap and pass number in CO2 laser skin resurfacing: a study of residual thermal damage, cell death, and wound healing. AB - BACKGROUND: Newer CO2 laser systems incorporating short pulse and scanning technology have been used effectively to resurface the skin. As the number of resurfacing cases has increased, hypertrophic scarring has been reported more commonly. Previous dermabrasion and continuous wave CO2 studies have suggested that depth of injury and thermal damage are important predictors of scarring for a given anatomic region. To determine whether rapid overlapping of laser pulses/scans significantly altered wound healing, we examined residual thermal damage, cell death, and histologic and clinical wound healing in a farm pig. METHODS AND MATERIALS: Two popular CO2 systems were used, with a range of radiant exposures, degrees of overlap, and numbers of passes. Thermal damage was assessed by histology, and dermal cell viability was measured with nitrotetrazolium blue staining. Presence or absence of clinical scarring was determined by textural change and loss of skin markings. RESULTS: We observed that dermal thermal damage did not increase significantly with pass number when performed as in the normal clinical setting (for 2-4 passes); however, by delivering rapidly overlapping pulses and scans, residual thermal damage and cell death depth were increased as much as 100% over areas without immediate overlap of laser impacts. CONCLUSIONS: Immediate overlapping of CO2 laser pulses and scans is a significant risk factor in increasing thermal damage, cell death, and possibly scarring. PMID- 10100648 TI - CO2 laser physics and tissue interactions in skin. AB - BACKGROUND AND OBJECTIVES: The theoretical model of CO2 laser tissue interaction appeared to be too simplistic. To explain the reactions seen in skin, a more complex model was needed. We hoped to correlate the clinical-histologic patterns of CO2 laser tissue interactions. STUDY DESIGN/MATERIALS AND METHODS: The Ultrapulse CO2 laser was used on normal and pathologic skin conditions. Clinical observations were correlated with histologic examinations of biopsies. RESULTS: It was possible to demonstrate cavitation at the dermal-epidermal junction 2-3 diameters beyond the actual spot of CO2 laser contact with the skin. Dermal heat damage was seen as homogenization of collagen 1-2 diameters beyond the spot of laser contact. This flow of energy laterally at the dermal-epidermal junction and vertically down the skin follicles was both clinically beneficial and detrimental. Beneficially, superficial skin lesions separated at this junction and were easily removed. The heat coagulation of the dermis facilitated lesion removal without bleeding. The clinician had a better view of the pathology and could find focal zones of deeper pathology that could be easily re-treated. Detrimentally, this extended damage delayed wound healing and led to persistent erythema. CONCLUSION: These clinical-histologic correlations have provided a better understanding of CO2 laser tissue interactions in skin. It has been possible to take advantage of these findings to remove pathologic skin conditions more efficiently. PMID- 10100649 TI - Xanthelasma palpebrarum: treatment with the ultrapulsed CO2 laser. AB - BACKGROUND AND OBJECTIVE: Due to its delicate location near the eye and the high recurrence rate, the therapy of xanthelasma palpebrarum is a difficult surgical task. Besides chemical, physical, and surgical procedures, various laser systems have been used to treat these lesions (argon laser, pulsed dye laser, and CO2 laser). This study was designed to critically evaluate the use of the ultrapulsed CO2 laser for the treatment of xanthelasma palpebrarum. STUDY DESIGN/MATERIALS AND METHODS: We report about the standardized treatment of 23 patients (52 periorbital xanthelasmas) and the results obtained after one treatment with a new generation, ultrapulsed CO2 laser (COHERENT Ultrapulse 5000C, Palo Alto, CA; 250 500 mJ; 600-900 microsec; 10,600 nm). The followup time was 10 months. RESULTS: All lesions could be removed completely with a single laser treatment. As for side effects, only transient pigmental changes (4% hyperpigmentations, 13% hypopigmentations) and no visible scarring was observed. Three patients (13%) developed a recurrence of xanthelasma. CONCLUSIONS: The ultrapulsed CO2 laser is an effective and safe therapeutic alternative to the hitherto described approaches. PMID- 10100650 TI - Hair removal with a non-coherent filtered flashlamp intense pulsed light source. AB - BACKGROUND AND OBJECTIVE: To evaluate the effects on disruption of hair growth of the non-coherent filtered flashlamp intense pulsed light (IPL) source. MATERIALS AND METHODS: Twenty-eight sites on 23 patients with Fitzpatrick type I-III were enrolled using a single treatment IPL followed for three months post-treatment. Another 56 on 48 patients with Fitzpatrick skin types I-V randomly enrolled for two treatments one month apart and followed for six months. STUDY DESIGN: Prior to beginning treatment and at each follow-up visit hair counts were obtained by averaging three 1-cm2 areas on a clear acetate template placed over the skin. Repeat hair counts and photographs were obtained at 2, 4, 8, and 12 weeks for the single treatment protocol and at additional 4, 5, and 6 months for the double treatment protocol. Parameters utilized were a 2.8-3.2 millisecond pulse duration typically for three pulses with thermal relaxation intervals of 20-30 milliseconds with a total fluence of 40-42 J/cm2. RESULTS: For the double treatment protocol hair clearance of 64% was achieved immediately following the second treatment. By week 8 reduction of hair counts was 42%. At 6 months, hair counts were reduced by 33%. CONCLUSIONS: Non-coherent IPL is an effective modality for long-term hair removal. IPL is safe with minimal side effects of epidermal injury or pigmentation change. PMID- 10100651 TI - Use of an agent to reduce scattering in skin. AB - BACKGROUND AND OBJECTIVE: A method to increase light transport deeply into target areas of tissue would enhance both therapeutic and diagnostic laser applications. The effects of a hyperosmotic agent on the scattering properties of rat and hamster skin were investigated. STUDY DESIGN/MATERIALS AND METHODS: A hyperosmotic agent, glycerol, was applied in vitro and in vivo to rat and hamster skin to assess the changes in tissue optical properties. Changes in the reduced scattering coefficient after application of the agent in vitro to rat skin and after the skin has been rehydrated were assessed to evaluate the effect of the agent on tissue. RESULTS: Experimental results showed a transient change in the optical properties of in vitro rat skin. A 50% increase in transmittance and decrease in diffuse reflectance occurred within 5-10 min after the introduction of anhydrous glycerol. In addition, reduction of light scattering with this technique increased depth of visibility with optical coherence tomography. Injection of glycerol under the skin allowed in vivo visualization of blood vessels. CONCLUSIONS: The application of the agent reduces the amount of refractive mismatch found in the tissue and markedly reduces random scattering, thereby making the skin less turbid for visible wavelengths for a controlled period of time. PMID- 10100652 TI - Histological study of hair follicles treated with a 3-msec pulsed ruby laser. AB - BACKGROUND AND OBJECTIVE: Ruby laser energy at 694 mn is moderately absorbed by melanin and minimally absorbed by other skin chromophores. This property and its depth of penetration into dermis permit absorption into pigmented hair follicles, thus making it suited to photothermolysis of these appendages. Clinical reports of the efficacy of such lasers for removal of unwanted hair are emerging in large numbers, but scientific data regarding the exact mechanism of action is still lacking. This study aims to evaluate and define further the histological responses of hair follicles to 3-msec pulsed ruby laser light. STUDY DESIGN/MATERIALS AND METHODS: Twenty-four patients with brown or black axillary or groin hair were treated with a 3-msec ruby laser at fluences from 10 to 40 J/cm2 on one, two, or three occasions. Biopsies were taken at various intervals from immediately to 8 weeks after treatments. Biopsies were fixed and stained with either nitroblue tetrazolium chloride or hematoxylin and eosin for histological examination. RESULTS: One treatment induced changes typical of catagen followed by telogen at all fluences. The papillae always remained viable. Two and three treatments resulted in atypical telogen, with infundibular dilatation and plugging, and marked proliferation of the stem outer sheath. New anagen follicles were evident even after three treatments at 12- and then 8-week intervals and were biopsied 6 weeks later, but there were no hairs extending to or through the epidermis. CONCLUSION: There was no evidence of permanent follicle death after one ruby laser treatment. However, despite evidence of persistence of follicular elements after two and three treatments, it is possible that laser induced damage to the isthmus and upper stem may interfere with the interaction between dermal and epidermal germinative cells, thus inhibiting or altering the normal hair cycle. PMID- 10100653 TI - Modeling laser treatment of port wine stains with a computer-reconstructed biopsy. AB - BACKGROUND AND OBJECTIVE: The efficacy of laser treatment of port wine stains (PWS) has been shown to be highly dependent on patient-specific vasculature. The effect of tissue structure on optical and thermal mechanisms was investigated for different pulse durations by using a novel theoretical model that incorporates tissue morphology reconstructed tomographically from a PWS biopsy. STUDY DESIGN/MATERIALS AND METHODS: An optical-thermal numerical model capable of simulating arbitrarily complex, three-dimensional tissue geometries was developed. The model is comprised of (1) a voxel-based Monte Carlo optical model, (2) a finite difference thermal model, and (3) an Arrhenius rate process calculation to predict the distribution of thermal damage. Simulations based on previous computer-based reconstruction of a series of 6 microm sections from a PWS biopsy were performed for laser pulse durations (taup) of 0.5, 5.0, and 10.0 ms at a wavelength of 585 nm. RESULTS: Energy deposition rate in the blood vessels was primarily a function of vessel depth in skin, although shading effects were evident. Thermal confinement and selectivity of damage were seen to be inversely proportional to pulse duration. The model predicted blood-specific damage for taup = 0.5 ms, vascular and perivascular damage for taup = 5 ms, and widespread damage in superficial regions for taup = 10 ms. The effect of energy deposition in the epidermis was most pronounced for longer pulse durations, resulting in increased temperature and extent of damage. CONCLUSION: Pulse durations between 0.5 and 5 ms are likely optimal for the PWS analyzed. The incorporation of a tomographically reconstructed PWS biopsy into an optical thermal model represents a significant advance in numerical modeling of laser tissue interaction. PMID- 10100654 TI - Evaluation of carcass, live, and real-time ultrasound measures in feedlot cattle: I. Assessment of sex and breed effects. AB - Carcass and live-animal measures from 1,029 cattle were collected at the Iowa State University Rhodes and McNay research farms over a 6-yr period. Data were from bull, heifer, and steer progeny of composite, Angus, and Simmental sires mated to three composite lines of dams. The objectives of this study were to estimate genetic parameters for carcass traits, to evaluate effects of sex and breed of sire on growth models (curves), and to suggest a strategy to adjust serially measured data to a constant age end point. Estimation of genetic parameters using a three-trait mixed model showed differences between bulls and steers in estimates of h2 and genetic correlations. Heritability for carcass weight, percentage of retail product, retail product weight, fat thickness, and longissimus muscle area from bull data were .43, .04, .46, .05, and .21, respectively. The corresponding values for steer data were in order of .32, .24, .40, .42, and .07, respectively. Analysis of serially measured fat thickness, longissimus muscle area, body weight, hip height, and ultrasound percentage of intramuscular fat using a repeated measures model showed a limitation in the use of growth models based on pooled data. In further evaluation of regression parameters using a linear mixed model analysis, sex and breed of sire showed an important (P < .05) effect on intercept and slope values. Regression of serially measured traits on age within animal showed a relatively larger R2 (62 to 98%) and a smaller root mean square error (RMSE, .09 to 8.85) as compared with R2 (0 to 58%) and RMSE (.31 to 67.9) values when the same model was used on pooled data. We concluded that regression parameters from a within-animal regression of a serially measured trait on age, averaged by sex and breed, are the best choice in describing growth and adjusting data to a constant age end point. PMID- 10100655 TI - Evaluation of carcass, live, and real-time ultrasound measures in feedlot cattle: II. Effects of different age end points on the accuracy of predicting the percentage of retail product, retail product weight, and hot carcass weight. AB - Data from 970 feedlot steers and bulls were used to evaluate effects of different age end points on the accuracy of prediction models for percentage of retail product, retail product weight, and hot carcass weight. Cattle were ultrasonically scanned three to five times for fat thickness, longissimus muscle area, and percentage of intramuscular fat. Live animal measures of body weight and hip height were also taken during some of the scan sessions. Before development of prediction equations, live and ultrasound data were adjusted to four age end points using individual animal regressions. Age end points represented mean age at slaughter (448 d), mean age at the second-to-last scan before slaughter (414 d), mean age at the third-to-last scan before slaughter (382 d), and an age end point of 365 d. Ultrasound and live animal measures accounted for a large proportion of the variation in the dependent variables regardless of the age end point considered. For all three traits, final models based on independent variables adjusted to earlier ages of 365 and 382 d showed better or at least similar model R2 and root mean square errors than those based on independent variables adjusted to a mean slaughter age of 448 d. Validation of the models using independent data from 282 steers resulted in a mean across-age rank correlation coefficient of .78, .88, and .83 between actual and predicted values of the percentage of retail product, hot carcass weight, and retail product weight, respectively. Mean across-age rank correlation of breeding values for the corresponding traits were .92, .89, and .82. The results of this study suggest that live and ultrasound traits measured as early as 365 d could be used to predict end product traits as accurately as similar measures made before slaughter at age 448 d. PMID- 10100656 TI - Effects of implants on daily gains of steers wintered on dormant native tallgrass prairie, subsequent performance, and carcass characteristics. AB - Fall-weaned crossbred steer calves (n = 300; 184 +/- 2.9 kg) received either no implant (Control) or were implanted with Synovex-C (SC = 10 mg estradiol benzoate + 100 mg progesterone), Synovex-S (SS = 20 mg estradiol benzoate + 200 mg progesterone), or Revalor-G (RG = 8 mg estradiol-17beta + 40 mg trenbolone acetate) to determine the effects of implants on weight gain during winter grazing on dormant tallgrass prairie, subsequent grazing and finishing performance, and carcass characteristics. Steers grazed two dormant tallgrass prairie pastures from October 16, 1996, until March 29, 1997 (164 d), and received 1.36 kg/d of a 25% CP supplement that supplied 100 mg of monensin/steer. Following winter grazing, all steers were implanted with Ralgro (36 mg zeranol) and grazed a common tallgrass prairie pasture until July 17 (110 d). After summer grazing, all steers were implanted with Revalor-S (24 mg estradiol-17beta + 120 mg trenbolone acetate), and winter implant treatment groups were equally allotted to four feedlot pens. Steers were harvested November 17, 1997, after a 123-d finishing period. Daily gains during the winter grazing phase averaged .28, .32, .32, or .35 kg/d, respectively, for Control, SC, SS, or RG steers and were greater (P < .01) for implanted steers than for Controls. Summer daily gains were similar (1.05 +/- .016 kg/d; P > or = .61) for all treatment groups. Feedlot daily gains were also similar (1.67 +/- .034 kg/d; P > or = .21), with implanted steers weighing 14 kg more than Control steers (P = .05) at harvest, despite similar management during summer grazing and feedlot phases. Control steers tended (P = .06) to have lower yield grades. There were no differences (P = .99) in marbling between implanted and nonimplanted steers. Steers implanted during the wintering phase had increased skeletal and overall (P < .01) carcass maturities compared with nonimplanted steers, which resulted in more "B" and "C" maturity carcasses. Because carcass maturity score affects quality grade, the increased maturities of implanted steers resulted in a $9.04 decrease in carcass value/100 kg (P < .01) compared with Controls. The results of this study indicate that growth-promoting implants are efficacious for cattle wintered on dormant native range despite low daily gains. This increased weight is maintained through the summer grazing and feedlot phases; however, the benefit of the increased weight may be offset by decreased carcass quality grade and value due to increased carcass maturity. PMID- 10100657 TI - Production systems comparing early weaning to normal weaning with or without creep feeding for beef steers. AB - A 2-yr study was conducted to determine the effects of three weaning management systems on cow and steer performance. Cow-calf pairs were randomly assigned to one of three treatments, in which the steer calves were 1) early-weaned (yr 1, 177 +/- 9 d; yr 2, 158 +/- 21 d of age) and placed on a finishing diet (EW), 2) supplemented with grain for 55 d on pasture (yr 1, 177 to 231 d; yr 2, 158 to 213 d of age) while nursing their dams and then placed on a finishing diet (NWC), and 3) on pasture for 55 d while nursing their dams (yr 1, 177 to 231 d; yr 2, 158 to 213 d of age) and then placed on a finishing diet (NW). In yr 2, potential breed differences were evaluated using steers of three breed types: 1) Angus x Hereford (BRI); 2) Angus x Simmental (CON); and 3) Angus x Wagyu (WAG). In yr 1, EW steers gained 100% faster (P = .0001) than the average of NWC and NW steers, and NWC steers gained 32% faster (P = .02) than NW steers before weaning. In the feedlot, EW steers had lower intakes (7.70 vs 8.16 kg/d, P = .008) and better feed conversions (.170 vs .153, P = .002) than the average of NWC and NW steers. Marbling score was improved for EW steers compared with the average of NWC and NW steers (P = .003). In yr 2, EW steers had higher gains (P = .0006) during the entire study than the average of NWC and NW steers, and NWC steers had higher gains (P = .003) than NW steers. The EW steers had lower intakes (7.29 vs 7.68 kg/d, P = .0008) and better feed conversions (.160 vs .141, P = .0001) than the average of NWC and NW steers. The CON steers were heavier at slaughter than BRI steers (P = .01), and BRI steers were heavier than WAG steers (P =.0004). Early weaning improved the percentage of steers grading Average Choice or higher by 40%. The percentage of BRI steers grading Choice or greater was 21% higher and percentage of steers grading Average Choice or greater was 33% higher than CON. Cows with EW steers had higher ADG than cows with NW steers (.38 vs -.17 kg/d, P = .0001) before weaning. Cows with EW steers gained in body condition score (.23 vs .00, P = .04), and cows with NW steers did not change. Early weaning improved feed efficiency and quality grades of beef steers. PMID- 10100658 TI - Performance and carcass traits of early-weaned steers receiving either a pasture growing period or a finishing diet at weaning. AB - A 2-yr study was conducted to evaluate 1) steers fed ad libitum high concentrate after weaning (CONC), or 2) steers grown on pasture for 82 d, followed by high concentrate finishing (PAST), on the performance and carcass traits of 74 early weaned (117 d of age) steers. Potential breed differences were evaluated using crossbred steers of three types: 1) 3/4 Angus x 1/4 Simmental (BRI), 2) 3/4 Simmental x 1/4 Angus (CON), and 3) 1/2 Wagyu x 1/4 Angus x 1/4 Simmental (WAG). Steers were randomly assigned within breed to the two treatments. There was no interactions (P > .10), so the data were pooled over years. The CONC steers had an ADG that was .17 kg/d higher (P = .0001), intake 1.09 kg/d lower (P = .0001), and gain:feed ratio .013 unit better (.190 vs .177, P = .008) than PAST steers overall. Growing treatment did not affect total concentrate consumed (P = .97). The BRI steers required 31 d less than did CON steers (P = .008), and 23 d less than WAG steers (P = .05) when fed to a constant fat end point (1.1 cm). The BRI steers exhibited an ADG .16 kg/d higher (P = .0003), tended (P = .07) to have an ADG intake .49 kg/d higher, and exhibited gain:feed .01 unit better (.189 vs 180) than WAG steers. When compared with CON steers, BRI steers consumed 310 kg less total concentrate (P = .0003). No differences (P > .38) were observed between growing treatments for carcass characteristics or sensory attributes except that CONC steers tended (P = .11) to improve percentage of steers grading Average Choice or higher by 47% over PAST steers. The WAG steers had a 76-unit higher marbling score (1,000 = Small00, 1,100 = Modest00) (P = .006) than BRI steers, resulting in 19% more (P = .09) steers grading > or = Choice and 82% more (P = .03) grading > or = Average Choice. Liver (P = .15) and rumen (P = .01) weights as a percentage of hot carcass weight were reduced for CONC steers. The CONC steers had higher gain, lower intake, better efficiency, reduced liver and rumen weights, and consumed the same amount of total concentrate when compared with PAST steers. The BRI steers had less finishing days and lower daily intake compared with CON steers. The WAG steers had more days finishing, lower gain, lower intake, more undesirable efficiencies, consumed the same amount of total concentrate, and improved quality grades compared with BRI steers. PMID- 10100659 TI - Comparison of three weaning ages on cow-calf performance and steer carcass traits. AB - An experiment was conducted to compare three weaning ages on cow-calf performance and steer carcass traits. Crossbred steers (n = 168; 1/2 Simmental x 1/4 Angus x 1/4 Hereford) were randomly assigned to three treatments with eight pens per treatment: groups were 1) weaned at an average of 90 d of age (90 +/- 13 d) and placed in the feedlot, 2) weaned at an average of 152 d of age (152 +/- 13 d) and placed in the feedlot, and 3) weaned at an average of 215 d of age (215 +/- 13 d) and placed in the feedlot. The number of days steers were finished decreased by 55 and 38 d (linear, P = .0001) as weaning age increased when slaughtered at a constant fat end point (.81 cm). Weaning at an average of 90 and 152 d of age improved overall ADG by .15 and .07 kg/d, respectively, over weaning at an average of 215 d of age (linear, P = .005). Over the entire finishing period, intake increased (linear, P = .0006) and efficiency was poorer (linear, P = .004) as weaning age increased. Owing to differences in finishing days and intake, total concentrate consumed increased (linear, P = .03) as weaning age decreased. No differences (P > .21) were observed for carcass weight, longissimus muscle area, or yield grade. No differences (P > .19) were observed in marbling score or percentage of steers grading greater than or equal to Choice or Average Choice. Cow body condition score improved (linear, P = .0001) as weaning age decreased. Pregnancy rate improved 12 percentage units (linear, P = .15) for cows on the 90 d weaning treatment. In this study, early weaning improved gain and feed efficiency, but it increased total concentrate consumed. PMID- 10100660 TI - Genetic determination of individual birth weight and its association with sow productivity traits using Bayesian analyses. AB - Genetic association between individual birth weight (IBW) and litter birth weight (LBW) was analyzed on records of 14,950 individual pigs born alive between 1988 and 1994 at the pig breeding farm of the University of Kiel. Dams were from three purebred lines (German Landrace, German Edelschwein, and Large White) and their crosses. Phenotypically, preweaning mortality of pigs decreased substantially from 40% for pigs with < or = 1 kg weight to less than 7% for pigs with > 1.6 kg. For these low to high birth weight categories, preweaning growth (d 21 of age) and early postweaning growth (weaning to 25 kg) increased by more than 28 and 8% per day, respectively. Bayesian analysis was performed based on direct-maternal effects models for IBW and multiple-trait direct effects models for number of pigs born in total (NOBT) and alive (NOBA) and LBW. Bayesian posterior means for direct and maternal heritability and litter proportion of variance in IBW were .09, .26, and .18, respectively. After adjustment for NOBT, these changed to .08, .22, and .09, respectively. Adjustment for NOBT reduced the direct and maternal genetic correlation from -.41 to -.22. For these direct-maternal correlations, the 95% highest posterior density intervals were -.75 to -.07, and -.58 to .17 before and after adjustment for NOBT. Adjustment for NOBT was found to be necessary to obtain unbiased estimates of genetic effects for IBW. The relationship between IBW and NOBT, and thus the adjustment, was linear with a decrease in IBW of 44 g per additionally born pig. For litter traits, direct heritabilities were .10, .08, and .08 for NOBT, NOBA, and LBW, respectively. After adjustment of LBW for NOBA the heritability changed to .43. Expected variance components for LBW derived from estimates of IBW revealed that genetic and environmental covariances between full-sibs and variation in litter size resulted in the large deviation of maternal heritability for IBW and its equivalent estimate for LBW. These covariances among full-sibs could not be estimated if only LBW were recorded. Therefore, selection for increased IBW is recommended, with the opportunity to improve both direct and maternal genetic effects of birth weight of pigs and, thus, their vitality and pre- and postnatal growth. PMID- 10100661 TI - Effects of milk yield on biological efficiency and profit of beef production from birth to slaughter. AB - Effect of milk yield (MY) on biological efficiency and gross margin as an indicator of profit potential of beef production from birth to slaughter was determined. Data included 9 yr of spring-born single male calves. Biological efficiency was calculated as carcass weight/total feed energy intake, including nonlactating and lactating intakes of cow and creep and feedlot intakes of calf. Slaughter end point was finish constant at 9 mm of fat thickness. Gross margin was determined as returns minus feed costs. Three breeding systems were analyzed: purebred Hereford (HE), large rotational (LR), and small rotational (SR). Analyses were performed separately by breeding system when differences in the effect of MY among breeding systems were significant. Increased MY was associated with increased preweaning gain (P < .001), increased weight at start of feedlot trial (P < .001), and increased hot carcass weight (P < .05). No significant (P > .10) effect of MY on age at slaughter or on carcass weight per day of age at slaughter was found. Increased MY was associated with increased cow lactating energy intake (P < .10) and negatively associated with calf creep intake (P < .01). No effects of MY on intake of the cow during the nonlactating period, calf feedlot intake, or total feed intake were found. Increased MY was associated with a reduction in backfat thickness of the cow during the lactating period (P < .01) with no change in body weight. In the subsequent nonlactating period, increasing MY was associated with increased backfat thickness (P < .10) and body weight (P < .05). No effect of MY on change in backfat or weight of cow from calving to the end of the next nonlactating period was found. No effect of MY on biological efficiency to slaughter was detected. Milk yield was positively associated with gross margin from birth to slaughter (P < .05); results were similar when cow feed prices were reduced by 30%. Increased MY was associated with increased biological efficiency to weaning in HE (P < .01) and SR (P < .10), with no effect found in LR. When feeding cows to requirements, milk yield has a positive effect on the profit potential of beef production from birth to slaughter. PMID- 10100662 TI - Symposium introduction: What should animal science departments be doing to address contemporary issues? PMID- 10100663 TI - What are animal science departments doing to address contemporary issues? AB - Animal science departments are principle progenitors and disseminators of scientific information relating to the production of agricultural animals and their food products. The Land-Grant university missions of teaching, research, and extension are conduits designed to advance and enhance scientific knowledge within agriculture and to make this knowledge available to the public. I conducted an electronic survey to determine whether animal science departments are addressing contemporary issues through the traditional missions of the Land Grant university system, which issues they are addressing, and how they are addressing these issues. Sixty-three animal science department administrative heads (AH) were contacted through an E-mail listserve maintained through Michigan State University. An introductory letter described the goals of the survey and asked the AH to submit contact information for faculty coordinators of teaching, research, and extension within their departments. Forty-nine percent of the administrative heads responded and submitted contact information for 72 faculty members. Survey questions were sent to the identified faculty. The total survey return was 38.9%, 37.7% of the respondents answered questions for teaching, 31.1% for research, and 31.1% for extension. Animal waste, animal welfare, and food safety are examples of issues where all three missions have concentrated efforts. However, graduate student education on issues was identified as lacking emphasis. Animal science departments are responding to contemporary issues in all three of the Land-Grant mission components. PMID- 10100664 TI - What are the livestock industries doing, and what do they need from us? AB - Livestock industries are facing global competition and revolutionary changes. While facing this global competition, the similarities of many animal meat products require that they compete on a cost-of-production basis. Additional issues include the environmental impact of animal agriculture, the role of animal products in human nutrition, food safety and quality, biotechnology, animal welfare, and market access. Progressive producers are becoming more aware of the needs of their customers and are striving to improve product quality. Checkoff funds are used to finance promotion, research, and consumer information programs and are increasingly used to finance producer education. Industrialization trends in the livestock industries are changing the needs of constituencies, delivery mechanisms, and relationships with the people involved. Characteristics of closed operations include high production cost, outdated technology, smaller size, older operators, and lack of management focus. Successful operations tend to be growing in capacity, are system-oriented, maintain high throughput, keep accurate records, use outside consultants, and control production costs. Modern livestock production has lowered the cost of production by integrating new production and management technologies. In order for producers to be successful in the future, access to technology, capital, and timely information will be critical. Animal scientists have many common objectives with livestock industries. Their work in research, teaching, and extension is critical for continued progress. However, people in the industries sometimes have the perception that academic arrogance, discipline myopia, uncoordinated research, slow technology transfer, increasing research costs, and counter-productive tenure systems prevent animal scientists from being as relevant and responsive as they could be. Support from the industries is essential as animal scientists and academic departments seek political and funding support. This support can be attained by including integrated systems research, improving communication skills, achieving more efficient research budgets, rapidly publishing results, reducing the cost of information distribution, developing flexible research agendas, retraining scientists, acquiring modern methods, and emphasizing critical thinking, communication, and teamwork when teaching. PMID- 10100665 TI - What is the pharmaceutical industry doing, and what does the pharmaceutical industry want from animal science departments? AB - Perceived contemporary issues are 1) food safety and food healthfulness, 2) environment, 3) sustainability, 4) biotechnology, 5) animal well-being, 6) animals as food, and 7) research funding. Food safety is the paramount contemporary issue, and environment and sustainability issues can be considered as a single issue. Biotechnology, animal well-being, and animals as food are addressed in this paper as separate issues, but they can be considered as components of food safety and healthfulness. The pharmaceutical industry addresses these issues by providing safe and effective products to the livestock industry. These products are used to treat and prevent disease and to increase livestock production efficiency. These products contribute to a safe food supply, enhance protection of the environment, and increase the sustainability of animal agriculture through increased efficiency of livestock production. The pharmaceutical industry wants the following from animal science departments: 1) students skilled in deductive and inductive thinking and communicating to peers and the public; 2) regional research on food safety, such as irradiation, steaming of carcasses, E. coli contamination, antibiotic resistance, production facilities, and carcass contamination; 3) improved research to identify the food values of animal products and effective communication of that research to the public; 4) research on topics having the greatest potential to increase efficiency of animal production consistent with a positive impact on the environment and sustainability of animal production; 5) leadership in developing and using technologies such as biotechnology, not only as descriptors of biological processes, but as technologies to test hypotheses leading to new understandings of biology; 6) research on animal well-being and production facilities that foster animal well-being; 7) research and education on ethical and moral aspects of animals as food through encouragement of one or more staff members to become effective animal science department spokespersons; and 8) active participation in activities such as FAIR 95, Federation of Animal Science Societies, and multidepartmental and(or) interdisciplinary programs. PMID- 10100666 TI - From a philosopher's perspective, how should animal scientists meet the challenge of contentious issues? AB - This article reviews how professional ethics can be useful in helping animal scientists meet new responsibilities. The transition to a postindustrial period in animal production signals a shift in the nature of contentious issues that animal producers face. Whereas farm income was once the most controversial issue in animal production, producers and animal scientists now face complex risk issues that have overlapping constituencies. Animal scientists need to develop a professional ethic that will stress open and active debate on these issues. Discussion of these issues must take place in the animal science classroom. The new professional ethic should be based on core values required for scientific research. However, departments and professional societies must develop institutions that will permit the values and methods of rationality and truth seeking to be applied in areas where measurement and experimental method are unlikely to resolve disputes, (i.e., to controversial issues that require public discussion and debate). Several specific proposals for such institution building are discussed. PMID- 10100667 TI - Nutrient-specific preferences by lambs conditioned with intraruminal infusions of starch, casein, and water. AB - We hypothesized that lambs discriminate between postingestive effects of energy and protein and associate those effects with a food's flavor to modify food choices. Based on this hypothesis, we predicted that 1) lambs would acquire a preference for a poorly nutritious food (grape pomace) eaten during intraruminal infusions of energy (starch) or protein (casein) and that 2) shortly after an intraruminal infusion of energy or protein (preload), lambs would decrease their preferences for foods previously conditioned with starch or casein, respectively. Thirty lambs were allotted to three groups and conditioned as follows. On d 1, lambs in each group received grape pomace containing a different flavor and water was infused into their rumens as they ate the pomace. On d 2, the flavors were switched so each group received a new flavor and a suspension of starch (10% of the DE required per day) replaced the water infusion. On d 3, the flavors were switched again, and a suspension of casein (2.7 to 5.4% of the CP required per day) replaced the starch infusion. Conditioning was repeated during four consecutive trials. Lambs in Trial 1 had a basal diet of alfalfa pellets (e.g., free access from 1200 to 1700) and 400 g of rolled barley. Lambs in Trials 2, 3, and 4 received a restricted amount of alfalfa pellets (990 g/d) as their basal diet. After conditioning, all animals received an infusion of water, and, 30 min later, they were offered a choice of the three flavors previously paired with water, starch, or casein. On the ensuing days, the choice was repeated, but starch, casein, and barley replaced the water preload. The nutrient density of the infused preloads was increased during consecutive trials. Lambs preferred the flavors paired with starch > water > casein during Trial 1 (P < .05) and the flavors paired with starch > casein > water during Trials 2 (P < .05), 3 (P < .001), and 4 (P < .001). Preloads of casein decreased preferences for flavors previously paired with casein (P < .10 [Trial 2]; P < .001 [Trial 3], and increased preferences for flavors paired with starch (P < .05 [Trial 2]; P < .001 [Trial 3]). Preloads of energy (barley) had the opposite effect (P < .05 [Trial 3]). These results indicate that lambs discriminated between the postingestive effects of starch and casein and associated the effects with specific external cues (i.e., added flavors) to regulate macronutrient ingestion. PMID- 10100668 TI - Metabolism and morphology of brown adipose tissue from Brahman and Angus newborn calves. AB - The objective of this study was to compare adipocyte morphology and lipogenesis between breed types (Angus vs Brahman) in brown adipose tissue (BAT) and white adipose tissue (WAT) from newborn calves. The Brahman calves (n = 7) were born during the fall season, whereas the Angus calves were born in fall (n = 6) or the following spring (n = 4). At parturition, Brahman cows were lighter than fall Angus cows, but were heavier than spring Angus cows (P < .05). Birth weights and perirenal BAT weights were greater in spring-born, but not in fall-born Angus calves, than in Brahman calves (P < .05). Fall-born Angus BAT contained 63% more (P < .05) adipocytes/100 mg tissue and contained a greater proportion (P < .05) of adipocytes with mean diameters of 40 to 50 microm, and fewer adipocytes with diameters of 60 microm or greater, than Brahman BAT. Brahman BAT contained two-to three times as many beta-receptors as Angus BAT (P < .05), although the dissociation constant (Kd) was not different between breed types. Mitochondria in Brahman BAT were primarily spherical, whereas Angus BAT mitochondria were elongated, and mitochondrial cross-sectional area tended (P = .08) to be greater in Brahman BAT than in Angus BAT. The mitochondrial uncoupling protein (UCP) mRNA concentration (per 10(6) cells) was greater in Brahman BAT than in BAT from fall born Angus calves. Lipogenesis from acetate was greater in Angus BAT than in Brahman BAT (P < .05), and glucose and palmitate contributed a greater proportion of carbon to lipogenesis in Brahman BAT than in Angus BAT. These differences in lipogenesis between breed types were not observed in s.c. WAT. The WAT from both breed types contained adipocytes with distinct brown adipocyte morphology, suggesting an involution of BAT to WAT in utero. We conclude that differences in UCP gene expression cannot cause the greater peak thermogenesis of Angus calves; however, differences between breed types in lipid metabolism and(or) mitochondrial morphology may contribute to this phenomenon. PMID- 10100669 TI - Tenderness classification of beef: III. Effect of the interaction between end point temperature and tenderness on Warner-Bratzler shear force of beef longissimus. AB - The objectives of this experiment were to determine 1) whether end point temperature interacts with tenderness to affect Warner-Bratzler shear force of beef longissimus and 2) if so, what impact that interaction would have on tenderness classification. Warner-Bratzler shear force was determined on longissimus thoracis cooked to either 60, 70, or 80 degrees C after 3 and 14 d of aging from carcasses of 100 steers and heifers. Warner-Bratzler shear force values (3- and 14-d aged steaks pooled) for steaks cooked to 70 degrees C were used to create five tenderness classes. The interaction of tenderness class and end point temperature was significant (P < .05). The increase in Warner-Bratzler shear force as end point temperature increased was greater (P < .05) for less tender longissimus than more-tender longissimus (Tenderness Class 5 = 5.1, 7.2, and 8.5 kg and Tenderness Class 1 = 2.4, 3.1, and 3.7 kg, respectively, for 60, 70, and 80 degrees C). The slopes of the regressions of Warner-Bratzler shear force of longissimus cooked to 60 or 80 degrees C against Warner-Bratzler shear force of longissimus cooked to 70 degrees C were different (P < .05), providing additional evidence for this interaction. Correlations of Warner-Bratzler shear force of longissimus cooked to 60 or 80 degrees C with Warner-Bratzler shear force of longissimus cooked to 70 degrees C were .90 and .86, respectively. One effect of the interaction of tenderness with end point temperature on tenderness classification was to increase (P < .01) the advantage in shear force of a "Tender" class of beef over "Commodity" beef as end point temperature increased (.24 vs .42 vs .60 kg at 14 d for 60, 70, and 80 degrees C, respectively). When aged 14 d and cooked to 80 degrees C, "Commodity" steaks were six times more likely (P < .01) than "Tender" steaks to have shear force values > or = 5 kg (24 vs 4%). The end point temperature used to conduct tenderness classification did not affect classification accuracy, as long as the criterion for "Tender" was adjusted accordingly. However, cooking steaks to a greater end point temperature than was used for classification may reduce classification accuracy. The beef industry could alleviate the detrimental effects on palatability of consumers cooking beef to elevated degrees of doneness by identifying and marketing "Tender" longissimus. PMID- 10100670 TI - Effects of the halothane genotype and slaughter weight on texture of pork. AB - The objective of this study was to investigate the effects of the halothane (HAL) genotype, slaughter weight (SW), and the HAL x SW interaction on compositional and textural traits of raw and cooked pork. Pigs were bred to exhibit one of the three HAL genotypes (NN, Nn, and nn) with otherwise equivalent genomes. The nn halothane reactors are known to typically produce PSE pork, whereas NN pigs do not typically produce PSE pork. Pietrain x Large White gilts and boars, all with verified Nn genotype (by DNA test), were mated to obtain F2 littermates of the three HAL genotypes. These pigs were slaughtered at either 101 +/- 3 ("light") or 127 +/- 3 ("heavy") kg BW and were evaluated for longissimus muscle traits. The pH at .5 h after death (pH1) was 6.35, 6.13, and 5.68 in NN, Nn, and nn pigs, respectively. Sarcomere length was greater in nn than in NN and Nn pigs (1.94 vs 1.83 and 1.85 microm, respectively). Mechanical resistance was higher in nn than in NN pigs for both raw and cooked meat. Meat from nn pigs was judged by a trained panel to be less rough, more cohesive, harder, more fibrous, less granular, more elastic, and less easy to swallow than meat from NN pigs. For most traits under study, the heterozygotes were intermediate between the homozygotes but closer to NN than to nn pigs. Muscle from heavy pigs had longer sarcomeres and less moisture than muscle from light pigs. The n allele of the HAL gene unfavorably affects pork texture, and this effect is maintained throughout the range of 101 to 127 kg BW. PMID- 10100671 TI - Effect of postweaning feeding on the performance and energy balance of female rabbits at different physiological states. AB - The feeding of a high-fiber and low-energy diet to young rabbit does from weaning to the first kindling was used to modify their body reserves, stimulate their energy intake, and reduce the energy deficit during the first lactation. Rabbits (53 per group) were given ad libitum access to either a control or high-fiber diet (CP, 17.6 vs 15.8% of DM; crude fiber, 15.5 vs 19.9% of DM; digestible energy, 2,565 vs 2,261 kcal/kg of DM, respectively) from weaning to their first kindling. During lactation, both groups received the same diet, which contained 19.3% CP, 16.5% crude fiber, and 2,634 kcal/kg digestible energy (dry matter basis). Four comparative slaughters were performed to estimate the chemical and energy balance of rabbit does at different physiological states: at the beginning of the trial (12 rabbits, 45 d of age), at mating (10 rabbits per group, 136 d), at kindling (10 rabbits per group, 167 d), and at the end of lactation (12 and 11 rabbits for the control and the high-fiber group, 197 d). Large changes in body weight and composition were observed between slaughters. From 45 d to mating, doe body fat and energy increased 7.93 and 4.64 times the initial content, respectively. During pregnancy, body protein concentration decreased from 203 to 186 g/kg. At the end of lactation, body fat and energy concentration were reduced to values close to those measured at 45 d of age. Dietary treatment affected body chemical and energy balance during pregnancy and lactation but not reproductive and lactational performance. The high-fiber diet stimulated feed intake from weaning to the first kindling but not dietary energy intake. During lactation, the rabbits fed the high-fiber diet ate 10 kcal x d(-1) x kg live weight(-.75) more and lost less body fat (-405 vs -504 g) and body energy (-3,628 vs -4,294 kcal) than the does fed the control diet (P < .001). In the same period, all does showed water and protein retention (185 and 45 g, on average) regardless of dietary treatment. In conclusion, feeding young does a high-fiber diet until their first kindling reduced the chemical and energy body deficit at the end of the first lactation. PMID- 10100672 TI - Nutrient management procedures to enhance environmental conditions: an introduction. AB - The advent of concentrated, large animal production units presents a monumental challenge for the effective management of nutrients in animal manure. This symposium was organized to address the issue of the environmental impact of animal production and to offer suggestions on nutrient management procedures for reducing the environmental impact. There were four presentations on environmental concerns of animal manure that covered the topics of using the severe Dutch legislation that limits the amounts of nitrogen and phosphate in the manure allowed for application on cropland, potential for reducing odorous compounds in swine manure, alternatives to reduce the environmental impact of large swine production units, and, finally, perspectives on nutrient management procedures from a swine integrator's viewpoint. This introduction to the symposium highlights the major areas discussed within each of the four presentations. PMID- 10100673 TI - Potential for reduction of odorous compounds in swine manure through diet modification. AB - Recent public concern about air pollution from pork production units has prompted more research to develop methods to reduce and control odors. Masking agents, enzymes and bacterial preparations, feed additives, chemicals, oxidation processes, air scrubbers, biofilters, and new ventilation systems have been studied. Research relating the effects of the swine diet on manure odors has been scarce. Introducing feed additives to bind ammonia, change digesta pH, affect specific enzyme activity, and mask odors has been either costly or not consistently successful. Recent research emphasis has focused on manipulating the diet 1) to increase the nutrient utilization of the diet to reduce excretion products, 2) to enhance microbial metabolism in the lower digestive tract to reduce excretion of odor-causing compounds, and 3) to change the physical characteristics of urine and feces to reduce odor emissions. Primary odor-causing compounds evolve from excess degradable proteins and lack of specific fermentable carbohydrates during microbial fermentation. Reductions in ammonia emissions by 28 to 79% through diet modifications have been reported. Limited research on reduction of other odorous volatile organic compounds through diet modifications is promising. Use of synthetic amino acids with reduced intact protein levels in diets significantly reduces nitrogen excretions and odor production. Addition of nonstarch polysaccharides and specific oligosaccharides further alters the pathway of nitrogen excretion and reduces odor emission. Continued nutritional and microbial research to incorporate protein degradation products, especially sulfur-containing organics, with fermentable carbohydrates in the lower gastrointestinal tract of pigs will further control odors from manure. PMID- 10100674 TI - Alternatives to minimize the environmental impact of large swine production units. AB - Large swine production facilities have become controversial additions to the agricultural landscape as their numbers and sizes have increased. In addition to being larger enterprises, these units have involved greater specialization, the influx of outside capital, and the employment of labor without extensive investment in the enterprise. Major complaints have included water pollution and odors. Water pollution complaints have been related to surface and groundwater resources. Accidental spills, structural failure, and purposeful discharges have been noted. Odor problems are most often related to manure management techniques. Large anaerobic lagoons and irrigation of lagoon effluent have the potential to emit odors that travel long distances. Fortunately, technology and management alternatives exist to achieve higher levels of environmental acceptability. More effective water pollution and odor control alternatives generally increase construction and operating costs. Producers, regulatory officials, and the local public have an opportunity to interact to achieve progress in establishing acceptable compromises. This article identifies the range of existing and evolving alternative strategies and provides some assistance to producers and neighbors in achieving the necessary equilibrium. PMID- 10100675 TI - A swine integrator's perspective on nutrient management procedures. AB - The goal of pork producers is to operate in a sustainable manner that includes among other requirements, environmental soundness, social acceptability, and profitability. Gains in efficiency have reduced nutrient by-products per pig, but competitive forces have led to specialization, larger farms, and concentrated areas of production that have resulted in new opportunities related to nutrient management. Available technology uses on-farm processing or storage facilities, and manure is applied to the land as an organic fertilizer. Knowledge of nutrient content of soils and crop uptake of nutrients is incorporated into manure application and crop removal plans to prevent either runoff or nutrient buildup on the land. This is to ensure water quality protection. Existing systems are adequate but lack flexibility, require effective management, may not have been incorporated into older farms, and do not offer obvious solutions to odor concerns. Cost-effective alternatives should address those needs. Advancement in nutrient management procedures will likely accelerate the ongoing changes in the structure of the swine industry. PMID- 10100676 TI - Relations between body weight, feed intake, daily weight gain, and exocrine pancreatic secretion in chronically catheterized growing pigs. AB - The aim of this investigation was to develop models that would make it possible to correct exocrine pancreatic secretion data for the effect of BW and feed intake in growing pigs. In addition, the significance of exocrine pancreatic secretion for daily weight gain (DWG) was studied. Data were used from 10 pigs (16 to 32 kg BW) surgically fitted with chronic pancreatic catheters. The samples were collected under controlled conditions for two to five experimental days per animal (a total of 39 observations), during 2 h preprandially and during 2 h when feeding (postprandially). The exocrine pancreatic secretion traits included the hourly output of volume, the amount of protein, and trypsin and amylase activities. Multiple linear regressions were used to develop models to describe exocrine pancreatic secretion. The individual pig was the most important source of variation in the model. With increasing BW, 7 out of 10 pigs showed an increase in exocrine pancreatic secretion. However, the slopes of the regression lines differed between animals, which made it impossible to develop general models for the correction of secretion data for the effect of BW. Postprandial exocrine pancreatic secretion was always higher than preprandial secretion, but the amount of feed intake per se did not seem to affect secretion. Exocrine pancreatic secretion and DWG were positively correlated. We concluded that, under the present circumstances, expressing secretion per kilogram BW or kilogram feed intake was not feasible. Expressing secretion per hour was the best way to present the data. PMID- 10100677 TI - Supplemental cracked corn for steers fed fresh alfalfa: I. Effects on digestion of organic matter, fiber, and starch. AB - The effect of supplementation with different levels of cracked corn on the sites of OM, total dietary fiber (TDF), ADF, and starch digestion in steers fed fresh alfalfa indoors was determined. Six Angus steers (338 +/- 19 kg) fitted with cannulas in the rumen, duodenum, and ileum consumed 1) alfalfa (20.4% CP, 41.6% NDF) ad libitum (AALF); 2), 3), and 4) AALF supplemented (S) with .4, .8, or 1.2%, respectively, of BW of corn; or 5) alfalfa restricted at the average level of forage intake of S steers (RALF), in a 5 x 5 Latin square design. Total OM intake was lower (P < .01) in steers fed RALF than in those fed AALF but level of forage intake did not affect sites of OM, TDF, or starch digestion (P > .05). Forage OM intake decreased (P < .01) linearly (8,496 to 5,840 g/d) but total OM intake increased (P = .03) linearly (8,496 to 9,344 g/d) as corn increased from .4 to 1.2% BW. Ruminal apparent and true OM disappearance was not affected, but OM disappearing in the small intestine increased (P < .01) linearly with increasing levels of corn. Total tract OM digestibility (71.2 to 76.2%) and the proportion of OM intake that was digested in the small intestine (15.4 to 24.5%) increased (P < .01) linearly as corn increased. The TDF and ADF intakes decreased (P < .01) linearly as level of corn increased. Total tract TDF and ADF digestibilities were not different among treatments (average 62.9 and 57.8%, respectively). Starch intake and starch digested in the rumen and small and large intestine increased (P < .01) linearly with increasing corn level. Ruminal pH and VFA concentrations decreased and increased (P < .01), respectively, with increasing corn. Supplementation with corn increased OM intake, decreased forage OM intake, and increased the proportion of OM that was digested in the small intestine, but fiber digestion was not affected. PMID- 10100678 TI - Supplemental cracked corn for steers fed fresh alfalfa: II. Protein and amino acid digestion. AB - The effects of different levels of cracked corn on N intake, ruminal bacterial CP synthesis, and duodenal flows and small intestinal digestion of amino acids (AA) in steers fed fresh alfalfa indoors were determined. Angus steers (n = 6; average BW 338 +/- 19 kg) cannulated in the rumen, duodenum, and ileum were fed each of five diets over five periods in a Latin square design with an extra animal. Steers consumed 1) alfalfa (20.4% CP, 41.6% NDF) ad libitum (AALF); 2), 3), and 4) AALF supplemented (S) with three levels of corn (.4, .8, or 1.2% of BW, respectively), or 5) alfalfa restricted (RALF) to the average forage intake of S steers. Average N intake and duodenal flow of nonammonia N (NAN) were greater (P < .01) in S than in RALF steers. Greater duodenal flows of NAN in S compared with RALF were due to a trend toward higher (P = .06) flows of both bacterial and dietary N. Levels of corn decreased (P < .01) linearly N intake and increased (P < .01) linearly duodenal flow of NAN owing to a numerical linear increase in nonbacterial N (P = .15) with no increase in bacterial N flow. Duodenal NAN flows as percentages of N intake increased (P < .01) linearly (69.3 to 91.0%) as corn increased. Ruminal NH3 N concentration, ruminal CP degradability, and the proportion of bacterial N in duodenal NAN were decreased (P < .01) linearly as corn increased. Efficiency of net microbial CP synthesis was not affected (P > .05) by treatment (average 42.6 and 30.9 g N/kg of OM apparently or truly digested in the rumen, respectively). Small intestinal disappearance of total N and individual AA, except for threonine and lysine, and small intestinal digestibility of N and individual AA, except for methionine, histidine, and proline, increased (P < .01) linearly with level of corn and were greater (P < .01) in S than in RALF steers. Supplementing corn to steers fed fresh alfalfa reduced ruminal N losses and CP degradability and increased the duodenal flow and the small intestinal disappearance and digestibility of total N and total, essential, and nonessential AA. PMID- 10100679 TI - Fractionation of fiber and crude protein in fresh forages during the spring growth. AB - The composition of the fiber and CP of alfalfa, bromegrass, and endophyte-free and -infected tall fescue forages was compared during the spring growth from vegetative to reproductive stages. Forages were sampled from April 27 to June 6 in 1994, and from April 27 to June 11 in 1995, with 11 and 12 harvest dates, respectively. Total dietary fiber (TDF) was fractionated into insoluble and soluble fiber (SF). The CP of the forages was fractionated into nonprotein N (A), soluble CP (B1), insoluble CP that was soluble in neutral detergent (B2), CP insoluble in neutral detergent but soluble in acid detergent (B3), and CP insoluble in acid detergent (C). Effects of year, forage species, and harvest dates (day as a covariable) were included in the model. Across harvest dates, alfalfa (A) had lower (P < .01) TDF and higher (P < .01) SF concentrations than grasses (GR) (A: 49.9 and 14.4% and GR: 60.4 and 4.5% [OM basis] for TDF and SF, respectively). Alfalfa had higher (P < .01) CP (20.6% DM) than GR (15.3%). The rate of decrease in CP (% DM) across days was higher (P < .01) for bromegrass ( .4%/d) than for the other forages (-.29%/d). Fraction A (% of CP) was not different (P = .24) among forages (22.5%), but B1 was higher (P < .01) in A (17.1%) than in GR (13.2%). The B2 fraction (% of CP) was higher (P < .01) in A compared with GR (51.6 vs 45.9%, respectively). Alfalfa had lower (P < .01) B3 (3.0% of CP) than bromegrass (18.6%) and tall fescue (13.2%). Fraction C was not different (P = .23) among forages (3.8%). Fractions A, B1, and C (% of CP) did not change (P > .05) across days for all forages. Fraction B2 (% of CP) decreased across days in A (-.21%/d) but was not affected in GR. Fraction B3 (% of CP) increased (P < .05) in A (.1%/d), decreased in endophyte-infected tall fescue ( .20%/d), and did not change (P > .05) in the other forages. Crude protein and fiber composition were affected more by forage species than by maturity. The CP and NDF concentrations were more affected by maturity. Insoluble fractions but not soluble fractions of CP were affected by maturity. PMID- 10100680 TI - Degradation of two protein sources at three solids retention times in continuous culture. AB - Effects of solids retention times (SRT) of 10, 20, and 30 h on protein degradation and microbial metabolism were studied in continuous cultures of ruminal contents. Liquid dilution rate was constant across all retention times at .12 h(-1) (8.3 h mean retention time). Two semipurified diets that contained either soybean meal (SBM) or alfalfa hay (ALFH) as the sole nitrogen source were provided in amounts that decreased as SRT was increased. Digestion coefficients for DM, NDF, and ADF increased with increasing SRT. Digestion coefficients for nonstructural carbohydrates were higher in the SBM diet than in the ALFH diet but were not affected by SRT. Protein degradation in the ALFH diet averaged 51% and was unaffected by retention time. In the SBM diet, digestion of protein was 77, 78, and 96% at 10-, 20-, and 30-h retention times, respectively. Microbial efficiency decreased with increasing SRT and was greater for the SBM than for the ALFH diet. Efficiencies ranged from 30.6 to 35.7 and 20.8 to 29.2 g of N/kg of digested DM for the SBM and ALFH diets, respectively, as SRT decreased from 30 to 10 h. The diaminopimelic acid content of the microbes increased as SRT increased, indicating that changes in microbial species occurred owing to passage rates. From these results, we concluded that the digestibility decreases associated with increased ruminal turnover rates may be less for nonstructural carbohydrates and protein than for the fiber fractions. PMID- 10100681 TI - Cloning and characterization of the bovine somatostatin gene. PMID- 10100682 TI - Epidermal growth factor maps to pig chromosome 8. PMID- 10100683 TI - Identification of four highly polymorphic porcine microsatellite loci. PMID- 10100684 TI - Phosphoglycerate kinase 1 (PGK1) maps to Xq1.2 in the porcine genome. PMID- 10100685 TI - Androgen receptor (AR) maps to Xp1.1-q1.1 in the porcine genome. PMID- 10100686 TI - Overview of the Jackson Heart Study: a study of cardiovascular diseases in African American men and women. AB - The Jackson Heart Study is a partnership among Jackson State University, Tougaloo College, the University of Mississippi Medical Center and the National Institutes of Health's National Heart, Lung, and Blood Institute (NHLBI) and Office of Research on Minority Health. The purposes of the study are to: (1) establish a single-site cohort study to identify the risk factors for the development of cardiovascular diseases, especially those related to hypertension, in African American men and women; (2) build research capabilities in minority institutions by building partnerships; (3) attract minority students to careers in public health and epidemiology; and (4) establish an NHLBI Field Site in Jackson, Mississippi, similar to those established for the Framingham Heart Study and the Honolulu Heart Program. The study will consist of participants from the Jackson site of the Atherosclerosis Risk in Communities (ARIC) Study and a sample of residents from the Jackson metropolitan area. The study will have a sample size of approximately 6,500 men and women aged 35-84 years and will include approximately 400 families. Exam 1 is scheduled to take place in the spring of the year 2000. PMID- 10100687 TI - What is the role of obesity in hypertension and target organ injury in African Americans? AB - Hypertension is the most common reversible risk factor for cardiovascular disease. It is especially common in African Americans. One of the factors that may contribute to the high rates of hypertension and target organ injury in African Americans is obesity. Hypertension and obesity are common among African Americans. Obesity is particularly common in African American women. About 75% of African American women are obese. Regulation of both body weight and blood pressure are complex, involving an interaction of genetic and environmental factors. Most research thus far has focused on blood pressure control systems studied in other forms of hypertension, including the sympathetic nervous system, the renin angiotensin system, and metabolic factors-primarily insulin resistance. Proposed mechanisms that are unique to obesity-associated hypertension include: 1) intrarenal physical forces associated with obesity-induced changes in the renal medulla; 2) genetic/metabolic factors; and 3) metabolic effects of abdominal visceral fat. The Jackson Heart Study provides a unique opportunity to address unresolved questions in the relationship of body weight, blood pressure, and cardiovascular disease. PMID- 10100688 TI - What is the role of dietary sodium and potassium in hypertension and target organ injury? AB - There is substantial evidence from both observational epidemiology studies and randomized controlled trials that dietary intake of sodium and potassium is important in the etiology of hypertension. However, the direct evidence for a direct link between dietary sodium and potassium and risk of cardiovascular and renovascular events is limited. Epidemiological studies should be designed to examine the relationship between dietary intake of sodium and potassium and risk of stroke, coronary heart disease, left ventricular hypertrophy, and renal disease in a prospective manner. In these studies, dietary intake of sodium and potassium should be estimated using multiple 24-hour urine collections. These studies should be focused on African Americans because they are at a disproportionately high risk of developing hypertension and blood pressure related vascular disease. Moreover, this group has been underrepresented in most previous epidemiological studies. PMID- 10100689 TI - Why do we have a stroke belt in the southeastern United States? A review of unlikely and uninvestigated potential causes. AB - Although there is widespread recognition of a region with high stroke mortality in the southeastern United States that has persisted over the past 50 years (ie, the "stroke belt"), there is little agreement as to its underlying cause(s). Herein, we review data supporting 10 potential causes for the stroke belt, and assess: (1) the likelihood that each is the contributing factor to the excess mortality, and (2) areas of investigation where data are lacking and that require additional research efforts. PMID- 10100690 TI - Why is left ventricular hypertrophy so predictive of morbidity and mortality? AB - The prevalence, prognosis, and predictors of left ventricular hypertrophy (LVH) are reviewed, and theories of the pathogenesis of the relation between LVH and poor prognosis are summarized to highlight controversies in the field. In the Framingham Heart Study, which consists largely of white people, echocardiographic LVH has a prevalence of 14% in men and 18% in women. The prevalence of LVH is reported to be elevated in African Americans compared with whites, although the higher prevalence has been attributed to the increased prevalence of hypertension and obesity. Echocardiographic LVH is independently associated with a variety of cardiovascular endpoints, including coronary heart disease and stroke. Furthermore, after adjusting for other cardiovascular disease risk factors, LVH is associated with a doubling in mortality in both white and African American cohorts. Despite the intensive investigation of LVH, there remain many unanswered questions: To what extent do genetic or other factors account for the large portion of the variance in LVH that remains unexplained? What is the prognosis of LVH and left ventricular geometry in a population-based African American cohort? How does the development and progression of LVH relate to other risk factors and their treatment? What is the relation of LVH to poor prognosis? The proposed Jackson Heart Study will help address many important unanswered questions regarding LVH. PMID- 10100691 TI - Abnormalities of kidney function as a cause and a consequence of cardiovascular disease. AB - Hypertension, left ventricular hypertrophy (LVH), hypercreatininemia, and microalbuminuria (MA) are independent risk factors for cardiovascular disease (CVD). Hypertension increases the risk of CVD by two- to three-fold and LVH (especially concentric) is a risk factor for coronary heart disease, heart failure, stroke, and peripheral arterial disease. In people with hypertension, a serum creatinine level of 1.7 mg/dL or more may be an even stronger CVD risk factor than diabetes, smoking, LVH, or systolic blood pressure. Similarly, MA is a strong and independent predictor of CVD morbidity and mortality in people with and without diabetes and/or hypertension. Impaired renal sodium handling and sodium retention are physiological hallmarks of the very early stages of heart failure. Heart failure is a physiologically delicate condition that can decompensate with excess dietary salt intake or over diuresis, or compensate with cautious therapy designed to block the sodium retention and simultaneously interrupt excessively activated neurohumoral mechanisms. PMID- 10100692 TI - The role of hypertension, obesity, and diabetes in causing renal vascular disease. AB - The Jackson Heart Study will be an epidemiological study of African Americans in Jackson, Mississippi, to identify risk factors for development and progression of cardiovascular disease. One of the potential risk factors to be assessed in this study is renal vascular disease. Atherosclerotic renal vascular disease is a disease of the elderly, is predominantly seen in white people, and is strongly associated with diffuse atherosclerotic disease and high-grade hypertensive retinopathy. Patients with ischemic nephropathy may constitute up to 16% of new dialysis patients and die more quickly while on renal replacement therapy. Although often not present, hypertension is a commonly observed consequence (but probably not a cause) of renal vascular disease, and the control of blood pressure may not halt the progression of the disease. Approximately 20-25% of patients with moderate to severe renal artery stenosis will be diabetic. Diabetic patients fair less well with intervention and have a higher progression to end stage renal disease or death. Obesity is not commonly seen in patients with renal vascular disease. The Jackson Heart Study may be able to assess the true incidence of atherosclerotic renal vascular disease in African Americans and its impact of cardiovascular morbidity and mortality. PMID- 10100693 TI - Traditional coronary risk factors in African Americans. AB - The importance of traditional coronary artery disease risk factors in the development of coronary heart disease is well known. African Americans have a higher prevalence of such risk factors as hypertension, diabetes mellitus, obesity, cigarette smoking, and left ventricular hypertrophy, which might account for the disproportionate rate of coronary heart disease mortality in African Americans. Compelling data from randomized lipid-lowering trials show conclusively that lowering cholesterol levels, specifically low-density lipoprotein cholesterol, lowers coronary heart disease morbidity and mortality. Recent data has also demonstrated the beneficial effects of lowering blood pressure on cardiovascular mortality. Left ventricular hypertrophy, which results from elevated blood pressure, seems to raise coronary heart disease risks independently. Diabetes mellitus, cigarette use, physical inactivity, stress, and obesity play critical roles collectively and individually in increasing coronary heart disease, morbidity, and mortality. Clustering of coronary heart disease risk factors in African Americans must be strongly considered to play a critical role in the excess mortality from coronary heart disease seen in African Americans. New innovative approaches are required if the course of coronary heart disease is to be altered. PMID- 10100694 TI - Nontraditional cardiovascular risk factors. AB - A number of newer, "nontraditional" cardiovascular risk factors have been identified based on recent studies of the pathogenesis of atherosclerosis and atherothrombotic cardiovascular events. These include chronic inflammation and its markers, such as C-reactive protein; homocysteine; oxidative stress or endothelial dysfunction; lipoprotein Lp (a); psychosocial factors, such as environmental stress and responsiveness to stress; plasma insulin levels and markers of insulin resistance; and activation of the renin-angiotensin system, which is in part a function of polymorphisms in genes for components of the system, such as angiotensinogen and the angiotensin II type 1 receptor. The strength of the associations of the newer risk factors with cardiovascular therapy are currently being tested. This review will briefly discuss evidence that these risk factors are related to cardiovascular disease. PMID- 10100695 TI - The role of genetic and environmental factors in cardiovascular disease in African Americans. AB - Considerable interest has been focused over the years on estimating the relative importance of genetic and environmental factors on differences in rates of cardiovascular disease in blacks and whites. However, recent advances in molecular science have helped to illuminate the underlying complexity of this problem. Attempts to impute the genetic component from "what was left over" after control for a limited set of environmental exposures is increasingly recognized as naive. The requirements for a model that could account for interactions between genetic and environmental factors far exceeds the precision of our measurements. Although it is obvious that blacks experience not only unique environmental exposures, such as white racism, but more intense exposure to common factors, such as obesity, current methods make it very difficult to summarize these effects. Simpler models, using data from large samples, could provide greater precision and might illuminate the exposure-outcome relationships common to all groups. Meanwhile, efforts to identify genetic underpinnings of complex disorders will have to reach a much higher level of development before useful conclusions can be reached about the magnitude and variation of effects between racial and ethnic groups. PMID- 10100696 TI - On pushing the outer edge of the outer edge of paclitaxel's dosing envelope. PMID- 10100697 TI - Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. AB - Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen and permeability factor. Malignant human tumors have been shown to produce VEGF. Elevated levels of VEGF have been detected in sera of cancer patients, but its origin is unsettled. We analyzed VEGF concentrations in serum, plasma, whole blood, and peripheral blood mononuclear cells (PBMNCs) and platelets in 56 cancer patients and 52 healthy controls using ELISA. The VEGF concentrations in the lysed whole blood samples [blood VEGF (B-VEGF)] were higher in cancer patients than in healthy controls (median, 464 versus 298 pg/ml; P<0.0001). The highest B-VEGF values were found in disseminated cancer. In cancer patients, a high B-VEGF concentration was associated with a high peripheral blood leukocyte count (P = 0.0012) and platelet count (P = 0.019). In healthy individuals, a high B-VEGF was associated with a high leukocyte count (P = 0.0001) but not with the platelet count (P>0.1). The cancer patients regularly had higher B-VEGF concentrations than healthy individuals with comparable leukocyte or platelet counts. The VEGF content of isolated PBMNCs and platelets was severalfold higher in cancer patients than in healthy controls (median, 10.6 versus 0.9 pg per 10(6) PBMNCs, and median, 1.6 versus 0.5 pg per 10(6) platelets; P<0.0001 and P = 0.0008, respectively). Serum VEGF and B-VEGF correlated strongly (P<0.0001). Very little or no VEGF was found in the plasma. The results indicate that VEGF in the bloodstream is transported by blood cells, including leukocytes and platelets. The blood cells of cancer patients contain greatly elevated amounts of this major angiogenic growth factor, and this reservoir of VEGF may have a role in tumor angiogenesis and metastasis formation. VEGF in serum samples originates from blood cells, and the use of VEGF of whole blood or of isolated blood cells may improve the clinical value of VEGF measurements. PMID- 10100698 TI - Potent antitumor activity of 2-methoxyestradiol in human pancreatic cancer cell lines. AB - We examined the effect of 2-methoxyestradiol (2-ME) on the growth and tumorigenesis of human pancreatic cancer cells. 2-ME inhibited the growth of these cell lines (50-90%) in a dose- and time-dependent fashion, and terminal deoxynucleotidyl transferase staining showed that it induced apoptotic cell death. Flow cytometric analysis indicated that 2-ME-sensitive cells showed a prolonged S phase after 48 h of treatment. We used a mouse model for in vivo studies of lung metastasis and injected MIA PaCa-2 cells into the tail veins of nu/nu mice; lung colonies were formed. Mice given oral 2-ME showed 60% inhibition in the number of lung colonies compared with control, untreated animals. These results suggest that 2-ME may have clinical application for the treatment of pancreatic cancer. PMID- 10100699 TI - Acute encephalopathy: a new toxicity associated with high-dose paclitaxel. AB - The purpose of this study was to describe acute encephalopathy as a new toxicity associated with paclitaxel, when it is delivered at high doses (> or =600 mg/m2) with stem cell support. A total of 129 patients, included in clinical trials of paclitaxel-containing high-dose chemotherapy, were analyzed. A total of 114 patients received paclitaxel at a dose of > or =600 mg/m2. Six patients presented acute encephalopathy starting between 7 and 23 days after paclitaxel treatment; two of them had received prior whole-brain irradiation. Paclitaxel was given alone (one patient), with cyclophosphamide and cisplatin (two patients), and with cyclophosphamide and cisplatin plus 1,3-bis(2-chloroethyl)-1-nitrosourea (three patients). Central nervous system toxicity consisted of rapid obtundation and coma (five patients) and severe confusional picture with paranoid ideations (one patient). Brain magnetic resonance imaging showed diffuse white matter atrophy (one patient) or multiple small infarcts (one patient), or it was normal (four patients). Other complementary tests, including cerebrospinal fluid analysis and electroencephalography, were nondiagnostic. An effect from concomitant psychotropic medications or from other organ toxicities was excluded in all patients. Three patients recovered after 8-15 days, either spontaneously (two patients) or after high-dose steroids (one patient). Three patients died of irreversible coma. Necropsy, performed in two patients, showed generalized white matter atrophy and multiple brain parenchymal infarcts, respectively. No pharmacodynamic correlation between the occurrence of encephalopathy and a pharmacokinetic parameter of paclitaxel could be identified. Paclitaxel containing high-dose chemotherapy can cause severe acute encephalopathy. An aggravating effect from prior brain irradiation or concurrent 1,3-bis(2 chloroethyl)-1-nitrosourea seems possible. PMID- 10100700 TI - Measurement of DNA cross-linking in patients on ifosfamide therapy using the single cell gel electrophoresis (comet) assay. AB - The single cell gel electrophoresis comet assay has become established as a sensitive technique for measuring DNA strand breaks. The technique has been modified to allow the sensitive detection and quantitation of DNA interstrand cross-linking at the single cell level. Cells are irradiated immediately before analysis to deliver a fixed level of random strand breakage. After embedding of cells in agarose and lysis, the presence of cross-links retards the electrophoretic mobility of the alkaline denatured cellular DNA. Cross-links are, therefore, quantitated as the decrease in the comet tail moment compared with irradiated controls. Using this method, a linear response of cross-linking versus dose of chlorambucil over a wide dose range was demonstrated in human lymphocytes after drug treatment ex vivo. The method was also sensitive enough to determine cross-linking in clinical samples after chemotherapy. For example, crosslinking was observed in the lymphocytes of patients receiving ifosfamide (3 g/m2/day) as a continuous infusion for 3-5 days or as a 3-h infusion daily for 3 days. Cross links were detected in all patients within 3 h, with no evidence of DNA single strand break formation. In patients receiving continuous infusion, a plateau of cross-linking was reached by 24 h. In the patients receiving ifosfamide over 3 h, a clear decrease in the peak level of cross-linking was observed before subsequent infusions. PMID- 10100701 TI - Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions. AB - Tumor cells and associated stromal cells secrete matrix metalloproteinases (MMPs), contributing to invasion, angiogenesis, and metastasis. Batimastat (BB 94) is a broad-spectrum MMP inhibitor that causes resolution of ascites and/or tumor growth delay in animal models of breast, ovarian, and colorectal cancer. We recruited 18 patients with cytologically positive malignant pleural effusions into a Phase I study of intrapleural BB-94. Three patients received single doses of BB-94 at each dose level: 15, 30, 60, 105, 135, and 300 mg/m2. Two patients were retreated with a second course at 60 and 105 mg/m2. BB-94 was detectable in plasma 1 h after intrapleural administration, and peak levels of 20-200 ng/ml occurred after 4 h to 1 week. BB-94 persisted in the plasma for up to 12 weeks, at levels exceeding the IC50s for target MMPs. Peak values were higher, and persistence in the plasma was longer after higher doses of BB-94. The treatment was well tolerated. Toxic effects included low-grade fever for 24-48 h (6 of 18 patients, 33%) and reversible asymptomatic elevation of liver enzymes (8 patients, 44%). Toxicity seemed unrelated to BB-94 dose or plasma levels. Sixteen patients evaluable for response required significantly fewer pleural aspirations in the 3 months after BB-94 compared with the 3 months before. Seven patients (44%) required no further pleural aspiration until death/last follow-up. After 1 month, patients treated with 60-300 mg/m2 BB-94 had significantly better dyspnea scores, indicating improved exercise tolerance, compared with baseline scores the day after BB-94. The maximum tolerated intrapleural dose remains to be defined, but it is clear that intrapleural BB-94 is well tolerated, with evidence of local activity. PMID- 10100702 TI - Leukocyte O6-alkylguanine-DNA alkyltransferase from human donors is uniformly sensitive to O6-benzylguanine. AB - O6-Alkylguanine-DNA alkyltransferase (AGT) is the key DNA repair protein responsible for resistance to chloroethylating and methylating agents that attack at the O6 position of guanine. O6-Benzylguanine (BG), a potent inhibitor of AGT, has recently entered clinical trials. A number of point mutations and at least one human polymorphism within AGT are associated with AGT resistance to inactivation by BG. In this study, we evaluated AGT inhibition by BG in an in vitro assay of peripheral blood mononuclear cell AGT from 56 normal donors, 42 Caucasians, and 14 Japanese. AGT activity ranged from 2.7 to 21.9 fmol/microg DNA and was similar in Japanese and Caucasian donors. Depletion of AGT by BG was uniform in all donors with mean ED50s of 037 microM BG in Caucasians and 0.36 microM BG in Japanese. To determine whether the gly160arg AGT polymorphism described in the Japanese population, and recently shown to be BG resistant, could be detected by this assay, we mixed purified gly160arg AGT protein with blood mononuclear cell extract and measured in vitro BG inactivation. The ED50 for the mixture of the gly160arg AGT and mononuclear cell extract was 9 microM BG. On the basis of results in 56 donors, we conclude that BG-resistant AGT, defined as an ED50 in mononuclear cells of >1 microM BG, is present in 0 of 56 donors, (95% confidence interval, 0-6%), suggesting that polymorphisms producing AGT-resistant BG are unusual in humans. PMID- 10100703 TI - Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. AB - Dolastatin-10 (dola-10) is a potent antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and biological effects of dola-10 in patients with advanced solid tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 microg/m2. Dose-limiting toxicity of granulocytopenia was seen at 455 microg/m2 for minimally pretreated patients (two or fewer prior chemotherapy regimens) and 325 microg/m2 for heavily pretreated patients (more than two prior chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid drug distribution with a prolonged plasma elimination phase (t 1/2z = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 microg/m2 for patients with minimal prior treatment (two or fewer prior chemotherapy regimens) and 325 microg/m2 for patients who are heavily pretreated (more than two prior chemotherapy regimens). PMID- 10100704 TI - 67Cu-versus 131I-labeled Lym-1 antibody: comparative pharmacokinetics and dosimetry in patients with non-Hodgkin's lymphoma. AB - Antilymphoma mouse monoclonal antibody (MoAb) Lym-1, labeled with 67Cu or 131I, has demonstrated promising results in radioimmunotherapy (RIT) for lymphoma. Although 131I has played a central role in RIT thus far, some properties of 67Cu are preferable. A subset of our patients received both 67Cu- and 131I-labeled Lym 1, allowing a comparative evaluation of the two radiopharmaceuticals administered to a matched population of patients. Four patients with B-lymphocytic non Hodgkin's lymphoma that had progressed despite standard therapy entered trials of 67Cu- and 131I-labeled Lym-1, which were injected 3-26 days apart. Lym-1 was conjugated to 6-[p-(bromoacetamido)benzyl]-1,4,7,11-tetraazacyclotetradecane-N,N ',N",N'"-tetraacetic acid (BAT) via 2-iminothiolane (2IT) and radiolabeled with 67Cu to prepare 67Cu-2IT-BAT-Lym-1; 131I-Lym-1 was preparred by the chloramine-T reaction. Planar imaging was used to quantitate 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1 in organs and tumors daily for 3 days or longer. 67Cu-2IT-BAT-Lym-1 exhibited higher peak concentration in 92% (12 of 13) of tumors and a longer biological half-time in every tumor than 131I-Lym-1. The mean tumor concentration (%ID/g) of 67Cu-2IT-BAT-Lym-1 was 1.7, 2.2, and 2.8 times that of 131I-Lym-1 at 0, 24, and 48 h after injection, respectively. The mean biological half-times of 67Cu-2IT BAT-Lym-1 and 131I-Lym-1 in tumor were 8.8 and 2.3 days, respectively. Consequently, the mean tumor radiation dose delivered by 67Cu-2IT-BAT-Lym-1 was twice that of 131I-Lym-1, 2.8 (range 0.8-6.7), and 1.4 (range 0.4-35) Gy/GBq, respectively. 67Cu-2IT-BAT-Lym-1 delivered a lower marrow radiation dose than 131I-Lym-1; hence, the tumor:marrow therapeutic indices were 29 and 9.7, respectively. Radiation doses from 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 to normal tissues were similar except for liver, which received a higher dose from 67Cu-2IT BAT-Lym-1. Images obtained with 67Cu-2IT-BAT-Lym-1 were superior. Radiation dosimetry data for 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 agreed with corresponding data from the larger populations of patients from which the matched population for the current study was drawn. In conclusion, 67Cu-2IT-BAT-Lym-1 given to non Hodgkin's lymphoma patients in close temporal proximity to 131I-Lym-1 exhibited greater uptake and longer retention in tumor, resulting in higher radiation dose and therapeutic index than 131I-Lym-1. These as well as other factors suggest that 67Cu-2IT-BAT-Lym-1 may be superior to 131I-Lym-1 for RIT. PMID- 10100705 TI - Phase I targeted systemic exposure study of paclitaxel in children with refractory acute leukemias. AB - Clearance of anticancer drugs in children is highly variable, leading to wide variability in the systemic exposure associated with each dosage escalation in Phase I studies. The purpose of this Phase I study was to escalate targeted systemic exposure to paclitaxel, rather than dose, to attenuate the impact of pharmacokinetic variability at each escalation level. Children with recurrent acute leukemias received paclitaxel as 24-h infusions at escalating levels of paclitaxel systemic exposure [i.e., area under the concentration-versus-time curve (AUC)]. Plasma paclitaxel concentrations were measured by high-performance liquid chromatography-UV detection. A Bayesian algorithm using a two-compartment model with saturable distribution and saturable elimination was used to estimate clearance during the first 8 h of infusion; the infusion rate was adjusted 12 h after the start of infusion to achieve the target AUC. Toxicity and evidence of activity were assessed after each course. Six boys and one girl received eight courses of paclitaxel. The target AUC ranged from 31.5 to 45 microM x h. Five of the seven evaluable courses had AUCs between 75% and 125% of the target after adjustment (median, 100.2%; range, 51-151%), whereas none of the seven courses was projected to be in the target range had no change in dose been made (P = 0.021). The ratio of the achieved AUC to the target AUC was inversely related to clearance (r = -0.857; P = 0.014). Mucositis was the exposure-limiting toxicity, at AUCs lower than were expected based on Phase I studies in children with solid tumors. Pharmacokinetically-guided dosing strategies reduced variability in systemic exposure. Alternatives to traditional Phase I studies may be important in the setting of childhood leukemias because these patients show poor tolerance to Phase I therapy. PMID- 10100706 TI - Expression of cell cycle regulator p27Kip1 is correlated with survival of patients with astrocytoma. AB - p27Kip1 is a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation by mediating cell cycle arrest in G1. This study was undertaken to assess the prognostic value of p27Kip1 for astrocytomas. Tissue samples from 130 astrocytomas (WHO grade 1, 5 cases; grade 2, 23 cases; grade 3, 64 cases; grade 4, 38 cases), including 92 primary and 38 recurrent tumors, were examined immunohistochemically for Ki-67 and p27Kip1 expression. Patient charts were reviewed for clinical presentation, and survival was followed. The p27Kip1 labeling index (LI) ranged from 2.3 to 98.4%, with a mean value of 47.5% (+/ 23.4%). The p27Kip1 LI decreased with increasing tumor grade but did not correlate with other parameters. There was no correlation between Ki-67 LI and p27Kip1 LI. For patients with primary astrocytomas, the 50% survival times of those with low p27Kip1 LI (<50%) and those with high p27Kip1 LI (> or =50%) were 17.1 and 69.6 months, respectively. For patients with high-grade tumors, the 50% survival times were 13.1 months for those with low p27Kip1 LI and 33.7 months for those with high LI. On multivariate analysis, p27Kip1 was one of the most significant prognostic factors, indicating that low p27Kip1 LI was associated with poor prognosis (primary, risk ratio = 2.5, P = 0.0023; high-grade, risk ratio = 2.2; P = 0.0139). The expression of p27Kip1 was inversely related to tumor grade and positively related to favorable outcome of patients with astrocytoma, suggesting that p27Kip1 may be a candidate for prognostic factor for this tumor. PMID- 10100707 TI - Cathepsin B immunohistochemical staining in tumor and endothelial cells is a new prognostic factor for survival in patients with brain tumors. AB - The cysteine endopeptidase, cathepsin (Cat) B, and its endogenous inhibitor, stefin A, were found relevant for cancer progression of many neoplasms, including human brain tumors. Histological sections of 100 primary brain tumors, 27 benign and 73 malignant, were stained immunohistochemically for Cat B and stefin A. The immunohistochemical staining of Cat B in tumor cells, endothelial cells, and macrophages was scored separately from 0-12. The score in tumor and endothelial cells was significantly higher in malignant tumors compared with benign tumors (P<0.000). A significant correlation between immunostaining of Cat B (scored together for tumor and endothelial cells) and clinical parameters, such as duration of symptoms, Karnofsky score, psycho-organic symptoms, and histological score was demonstrated. Univariate survival analysis indicated that total Cat B score above 8 was a significant predictor for shorter overall survival (P = 0.003). In glioblastoma multiforme, intense Cat B staining of endothelial cells was a significant predictor for shorter survival (P = 0.003). Stefin A immunostaining was weak and detected only in a few benign and some malignant tumors, suggesting that this inhibitor alone is not sufficient in balancing proteolytic activity of Cat B. We conclude that specific immunostaining of Cat B in tumor and endothelial cells can be used to predict the risk of death in patients with primary tumors of the central nervous system. PMID- 10100708 TI - Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma. AB - The cellular pathways involved in the pathogenesis of hormone resistance remain unclear. Studies evaluating the role of changes in human androgen receptor (hAR) expression in the progression of prostatic tumors have been inconclusive. Androgenic influence over prostatic growth is mediated via the regulation of interactions between stromal and epithelial cells. We hypothesized that neoplastic transformation of the prostate would be associated with alterations in hAR expression in the adjacent stroma. Using immunohistochemical techniques, we determined hAR positivity in the epithelium and adjacent stroma of sections from 17 benign and 39 malignant prostatic glands. We found that whereas the expression of the receptor decreased in both cellular compartments as the tissues dedifferentiated, the depletion was more pronounced in the stromal nuclei (P<0.0001). However, in sections from both untreated and hormone-resistant prostate cancer tissues, although heterogeneity of hAR expression in malignant epithelia was increased, there appeared to be a unique field effect around the cancerous prostate glands that resulted in a decreased expression of the receptor in the adjacent benign glands and its total loss in the surrounding stroma. The loss of hAR in the stroma adjacent to malignant prostatic epithelium may play an important role in prostate cancer progression. Furthermore, the similarity of the lack of stromal hAR expression in newly diagnosed and hormone-resistant prostate cancer (P = 0.85) may be an indication that the mechanisms responsible for the acquisition of hormone independence are established early in the malignant transformation process. PMID- 10100709 TI - Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis. AB - The involvement of human papillomavirus (HPV) in the development of carcinomas of the uterine cervix has been firmly established. However, other genetic alterations also play an important role in the pathogenesis of cervical cancer. Therefore, we have investigated the role of several (onco)genes in cervical carcinoma. In tumors from 136 patients with stage I and II cancer of the uterine cervix, the expression of epidermal growth factor receptor (EGFR), c-erbB-2/neu, p53, and murine double minute 2 (MDM-2) was studied using immunohistochemistry. In 32 cases, amplification of EGFR, c-erbB-2/neu, MDM-2, and c-myc was studied by Southern blot hybridization. The expression levels of these proteins were correlated with HPV positivity, International Federation of Gynecologists and Obstetricians stage, lymph node metastases, tumor diameter, vessel invasion, and disease-free and overall survival. Moderate/strong expression of EGFR was observed in 54% of tumors. c-erbB-2/neu was focally positive in 12 cases. p53 showed moderate/strong expression in 32% of the tumors. Thirteen % of tumors showed a moderate/strong expression of MDM-2, and this expression was correlated to p53 expression (P<0.001). Only moderate/strong expression of EGFR was associated with reduced disease-free (P = 0.002) and overall survival (P = 0.003). In multivariate analysis, the association of EGFR overexpression with poor prognosis was independent from lymph node status. Gene amplification was found for EGFR (four cases), c-erbB-2/ neu (two cases), and c-myc (six cases). In two tumors, rearrangement of c-myc was found, probably due to the integration of HPV. In conclusion, overexpression of the EGFR is an independent predictor for prognosis in earlier stages (stage I and II) of cervical cancer. p53 and MDM-2 expression are correlated to each other and may play a role in the interaction with HPV. The importance of c-erbB-2/neu and c-myc amplification is relatively small in stage I and II cervical cancer. PMID- 10100710 TI - The prognostic significance of angiogenesis in epithelial ovarian carcinoma. AB - The molecular biology underlying the metastatic process in ovarian carcinoma remains poorly understood. For other neoplasms, the induction of angiogenesis by malignant cells has been shown to play a pivotal role in the process of tumor proliferation and metastasis. The purpose of this study was to characterize the degree of angiogenesis in epithelial ovarian malignancies and to determine whether the degree of neovascularization has prognostic significance for survival. Tissue sections obtained from 88 ovarian cancer patients were examined immunohistochemically for angiogenesis after staining with anti-human endothelial cell antibodies to von Willebrand factor and CD31. Light microscopy was performed, and individual microvessel counts were quantified at high power (x400). A chart review was completed, collating data regarding age, stage, grade, status of disease, and survival. Statistical exploratory methods were used to find potentially useful prognostic cutpoints for marker values of angiogenesis. Of the total 88 patients, tissue microvessel counts from 85 were evaluated via antibodies to von Willebrand factor and 87 for CD31. Overall, median survival was 2.7 years in women with cancers containing high microvessel counts versus 7.9 years in those with low microvessel counts (P = 0.03). A low microvessel count was associated with better 5-year survival in both early stage (I and II) and advanced stage (III and IV) disease. Our data suggest that the degree of neovascularization may have prognostic significance in epithelial ovarian carcinoma, especially for women with early-stage disease. In this group of women, the degree of angiogenesis may allow the selection of women at high risk for recurrence who may benefit from aggressive adjuvant therapy. PMID- 10100711 TI - Disseminated tumor cells in pancreatic cancer patients detected by immunocytology: a new prognostic factor. AB - Using an immunocytological approach, we previously showed that disseminated cancer cells are frequently found in peritoneal cavity and bone marrow samples of gastrointestinal and pancreatic cancer patients. Recently, we demonstrated that the detection of isolated tumor cells could serve as a new prognostic factor in gastric and colorectal cancer. Thus far, no conclusive data concerning the clinical implication of minimal residual disease in pancreatic cancer exist. In this study, we investigated peritoneal lavage and bone marrow samples of 80 pancreatic cancer patients to determine the predictive value of immunocytologically detected disseminated tumor cells. Therefore, immunocytological findings were correlated with the clinical follow-up data (median observation time, 10.7 months; range, 2-61 months), and the findings in peritoneal cavity and bone marrow samples were compared. Fifty-two % of the patients showed minimal residual disease at least in one compartment (39% positive lavage and 38% positive bone marrow samples). The detection rate of isolated tumor cells increased in parallel to the tumor stage. The presence of tumor cells in the peritoneal cavity significantly correlated with the survival time of the patients (P = 0.0035). In bone marrow samples, a strong trend was seen (P = 0.06). The evaluation of both compartments increased the number of positive patients and resulted in a highly significant correlation: all patients who were positive in at least one compartment died within 18 months, whereas negative patients showed a 5-year survival rate of 30% (P<0.0001). We recommend immunocytological investigation of peritoneal cavity and bone marrow samples as a new prognostic marker in pancreatic cancer patients. PMID- 10100712 TI - Rapid detection of MYCN gene amplification and telomerase expression in neuroblastoma. AB - Amplification of the MYCN gene and high telomerase activity predict a poor prognosis for the patients with neuroblastoma. We used PCR techniques for rapid detection of MYCN gene amplification and human telomerase reverse transcriptase (hTERT) expression in neuroblastoma specimens. The detection of MYCN gene amplification is based on differential PCR in which three primer pairs were used to coamplify a 178-bp fragment of target MYCN gene with two reference gene fragments, a 237-bp of p53 exon 7 and a 120-bp of beta-globin exon 3, in a single tube of 40 surgically resected tumor samples. MYCN amplification was identified by this differential PCR in all 10 samples carrying more than 10 copies (already known to have MYCN gene amplification by Southern blot analysis). There were no false-negative or false-positive cases, and the relative intensity of MYCN bands in the differential PCR correlated significantly with the copy number determined by Southern blot analysis (y = 0.99, P<0.0001). This protocol was also applicable in the biopsy or aspirated samples, as well as the paraffin-embedded tissues, and in detecting intratumoral heterogeneity. Using RT-PCR procedures, hTERT mRNA expression was detectable in all 13 tumors with high telomerase activity. These nonradioisotopic PCR-based protocols for detecting MYCN gene amplification and hTERT mRNA expression are rapid and reliable and are likely to be useful to determine the biological behavior of neuroblastoma. PMID- 10100713 TI - Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. AB - Rituximab is a chimeric antibody with human gamma-1 and kappa constant regions and murine variable regions. It recognizes the CD20 antigen, a pan B-cell marker. Therapeutic trials in patients with B-cell non-Hodgkin's lymphoma (NHL) have shown significant efficacy with a primary response rate of 50%, and a secondary response rate of 44% after repeat treatments in prior responders. The selection for proliferating tumor cells that no longer express CD20 may compromise repeated treatment. We have identified a patient who developed a transformed NHL that lost CD20 protein expression after two courses of therapy with rituximab. In a pretreatment lymph node biopsy, 83% of B cells (as defined by CD19 and surface immunoglobulin) expressed surface CD20. A biopsy from the recurrent tumor after two courses of rituximab revealed a diffuse large cell NHL where 0% of B cells expressed CD20 with no evidence of bound rituximab. Cytoplasmic staining showed no CD20 protein. Sequencing of immunoglobulin heavy chain cDNA identified identical variable sequences in the initial and recurrent lymphomas, confirming the association between the two tumors. Literature and database review suggests that approximately 98% of diffuse large cell lymphomas express CD20, which suggests that these tumors rarely survive without CD20. This is the first identified case of loss of CD20 expression in a lymphoma that has relapsed after rituximab therapy, although several other cases have since been identified. Considering the significant number of patients treated with anti-CD20 antibodies, this may occur only rarely and is unlikely to preclude recurrent therapy with anti-CD20 antibodies in the majority of patients. However, because many patients have relapsed after anti-CD20 antibody therapy and have not been biopsied to identify clones with down-regulated CD20 antigen, we do not currently know the true frequency of this phenomenon. When possible, patients should undergo evaluation for CD20 expression before repeated courses of anti-CD20 therapy. PMID- 10100714 TI - Detection of K-ras mutations of bronchoalveolar lavage fluid cells aids the diagnosis of lung cancer in small pulmonary lesions. AB - An increased prevalence of K-ras oncogene mutation in lung adenocarcinoma has been shown by PCR-primer-introduced restriction with enrichment for mutation alleles (PCR-PIREMA) experiments. In the present study we investigated whether this method is useful for the diagnosis of lung cancer in small pulmonary lesions, which are difficult to diagnose cytologically as lung cancer by bronchoscopic examination. We examined bronchoalveolar lavage fluid (BALF) cells from 33 patients with single nodular pulmonary lesions of less than 2 cm in diameter (measured on chest computed tomography scans) for K-ras (codon 12) mutation, by PCR-PIREMA. Transbronchial fiberscopic examinations had not revealed lung cancer cytologically in any of the patients. The final diagnoses for the 33 lesions were 20 adenocarcinomas, 5 cases of focal fibrosis, 5 cases of pneumonia, 1 case of tuberculosis, 1 hamartoma, and 1 case of lymph node swelling. BALF cell lysates were amplified and digested with a restriction enzyme to detect the K-ras oncogene. Only the normal K-ras was observed after the first amplification and digestion for each of the 33 patients. Three amplifications and digestions were performed for each sample. We detected mutation of K-ras in BALF cells from 15 (75%) of 20 lung cancer patients and in cells from only 4 (31%) of 13 patients with nonmalignant lesions. The detection rate of the K-ras mutation in lung cancer was significantly greater than that in nonmalignant lesions (P = 0.012). Our results indicate that the detection of the codon 12 K-ras mutation in BALF cells by PCR-PIREMA aids the diagnosis of lung cancer in patients with small pulmonary lesions with negative cytological findings. PMID- 10100715 TI - Mechanisms of methotrexate resistance in osteosarcoma. AB - High-dose methotrexate is a major component of current protocols for the treatment of osteosarcoma, but some tumors seem to be resistant. Potential mechanisms of resistance include decreased transport through the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR). To investigate methotrexate resistance, tumors were obtained from 42 patients with high-grade osteosarcoma. RFC and DHFR mRNA expression were studied by semiquantitative reverse transcription-PCR. The RFC and DHFR genes were studied for deletions and amplification by Southern blot. Thirteen of 20 (65%) osteosarcoma samples were found to have decreased RFC expression at the time of initial biopsy. At definitive surgery and relapse, 10 of 22 (45%) were found to have decreased RFC expression. Seventeen of 26 (65%) samples with a poor response to chemotherapy had decreased RFC expression, whereas 5 of 14 (36%) samples with a good response had a decrease (P = 0.03). None of the samples had an RFC gene deletion. Two of 20 samples (10%) showed increased DHFR expression at initial biopsy. The frequency of increased DHFR expression was significantly higher in metastatic or recurrent tumors (62%, P = 0.014). None of the samples showed evidence of DHFR gene amplification. The high frequency of decreased RFC expression in the biopsy material suggests that impaired transport of methotrexate is a common mechanism of intrinsic resistance in osteosarcoma. Increased DHFR expression in the pulmonary metastases may be a mechanism of acquired methotrexate resistance or a difference between primary and metastatic lesions. PMID- 10100716 TI - Clinical value of K-ras codon 12 analysis and endobiliary brush cytology for the diagnosis of malignant extrahepatic bile duct stenosis. AB - Extrahepatic biliary stenosis can be caused by benign and malignant disorders. In most cases, a tissue diagnosis is needed for optimal management of patients, but the sensitivity of biliary cytology for the diagnosis of a malignancy is relatively low. The additional diagnostic value of K-ras mutational analysis of endobiliary brush cytology was assessed. Endobiliary brush cytology specimens obtained during endoscopic retrograde cholangiopancreaticography were prospectively collected from 312 consecutive patients with extrahepatic biliary stenosis. The results of conventional light microscopic cytology and K-ras codon 12 mutational analysis were compared and evaluated in view of the final diagnosis made by histological examination of the stenotic lesion and/or patient follow-up. The sensitivities of cytology and mutational analysis to detect malignancy were 36 and 42%, respectively. When both tests were combined, the sensitivity increased to 62%. The specificity of cytology was 98%, and the specificity of the mutational analysis and of both tests combined was 89%. Positive predictive values for cytology, mutational analysis, and both tests combined were 98, 92, and 94%, whereas the corresponding negative predictive values were 34, 34, and 44%, respectively. The sensitivity of K-ras mutational analysis was 63% for pancreatic carcinomas compared to 27% for bile duct, gallbladder, and ampullary carcinomas. K-ras mutational analysis can be considered supplementary to conventional light microscopy of endobiliary brush cytology to diagnose patients with malignant extrahepatic biliary stenosis, particularly in the case of pancreatic cancer. The presence of a K-ras codon 12 mutation in endobiliary brush cytology per se supports a clinical suspicion of malignancy, even when the conventional cytology is negative or equivocal. PMID- 10100717 TI - Intracerebral adenovirus-mediated p53 tumor suppressor gene therapy for experimental human glioma. AB - Malignant gliomas of astrocytic origin are good candidates for gene therapy because they have proven incurable with conventional treatments. Although mutation or inactivation of the p53 tumor suppressor gene occurs at early stages in gliomas and is associated with tumor progression, many tumors including high grade glioblastoma multiforme carry a functionally intact p53 gene. To evaluate the effectiveness of p53-based therapy in glioma cells that contain endogenous wild-type p53, a clinically relevant model of malignant human glioma was established in athymic nu/nu mice. Intracerebral, rapidly growing tumors were produced by stereotactic injection of the human U87 MG glioma cell line that had been genetically modified for tracking purposes to express the Escherichia coli lacZ gene encoding beta-galactosidase. Overexpression of the p53 gene by adenovirus-mediated delivery into the tumor mass resulted in rapid cell death with the eradication of beta-galactosidase-expressing glioma cells through apoptosis. In long-term experiments, the survival of mice treated with the p53 adenoviral recombinant was significantly longer than that of mice that had received control adenoviral recombinant. During the observation period of 1 year, a complete cure was achieved in 27% of animals after a single injection of p53 adenoviral recombinant, and 38% of the animals were tumor free in the group receiving multiple injections of p53 adenoviral recombinant into a larger tumor mass. These experiments demonstrate that overexpression of p53 in gliomas, even in the presence of endogenous functional wildtype p53, leads to efficient elimination of tumor cells. These results point to the potential therapeutic usefulness of this approach for all astrocytic brain tumors. PMID- 10100718 TI - Thymidylate synthase level as the main predictive parameter for sensitivity to 5 fluorouracil, but not for folate-based thymidylate synthase inhibitors, in 13 nonselected colon cancer cell lines. AB - Thymidylate synthase (TS), a critical enzyme in the de novo synthesis of thymidylate, is an important target for fluoropyrimidines and folate-based TS inhibitors. In a panel of 13 nonselected human colon cancer cell lines, we evaluated the role of TS levels in sensitivity to 5-fluorouracil (5FU) and four folate-based TS inhibitors that have been introduced recently into the clinic: ZD1694 (Tomudex, Raltitrexed, TDX), GW1843U89 (GW), LY231514 (LY), and AG337 (Thymitaq, AG). Because the latter compounds have different transport and polyglutamylation characteristics, we also related these parameters with drug sensitivity, measured by the sulforhodamine B assay after 72 h of drug exposure. For 5FU, the IC50s varied from 0.8 to 43.0 microM. Leucovorin (LV) potentiated the activity of 5FU in only 4 of 13 cell lines. Sensitivity to folate-based TS inhibitors was variable; IC50s were in the range of: 5.3-59.0 nM TDX; 11.0-1570 nM LY; and 0.5-8.9 nM GW. Eleven of 13 cell lines had an IC50 for AG between 1.3 and 5.3 microM. Two cell lines were resistant to AG, Colo201 and SW1116, with IC50s of 27 and 29 microM, respectively. TS catalytic activity (conversion of dUMP to dTMP) varied from 62 to 777 pmol/h/10(6) cells. The number of FdUMP binding sites varied from 32 to 231 fmol/10(6) cells. Regression analysis showed a significant relation between TS catalytic activity and IC50s for 5FU and 5FU/LV. Kis for FdUMP showed a significant Spearman rank correlation with the IC50s of AG and GW. The role of antifolate transport, accumulation, and polyglutamylation was determined with [3H]methotrexate (MTX) as a reference compound. [3H]MTX influx via the reduced folate carrier varied from 18.6 to 150 fmol/10(6) cells/min. Folylpolyglutamate synthetase (FPGS) activity showed a range from 47 to 429 pmol/10(6) cells/h. A total of 24 h of [3H]MTX accumulation showed a 20-fold variation, from 1.2 to 21.8 pmol/10(6) cells. FPGS levels showed a Spearman rank positive correlation with cytotoxicity to TDX. In conclusion, in a heterogeneous nonselected human colon cancer cell line panel, the best predictor for sensitivity to 5FU and 5FU/LV was TS activity. Multiple sensitivity determinants were of importance for antifolate TS inhibitors, including FPGS activity and TS enzyme kinetics. PMID- 10100719 TI - Expression of p53 in cisplatin-resistant ovarian cancer cell lines: modulation with the novel platinum analogue (1R, 2R-diaminocyclohexane)(trans diacetato)(dichloro)-platinum(IV). AB - The compound (1R,2R-diaminocyclohexane)(transdiacetato)(dichloro)platinum(IV) (DACH-acetato-Pt) is a novel platinum-based antitumor agent with clinical potential against cisplatin-resistant disease that is under development in our laboratory. In view of the central role of the wild-type p53 tumor suppressor gene in drug-induced apoptosis, we evaluated the cytotoxicity of cisplatin and DACH-acetato-Pt in a panel of cisplatin-resistant ovarian tumor models with differing p53 status. Cisplatin was relatively more effective against mutant or null p53 cell lines (continuous drug exposure IC50, 1.2-3.3 microM) than it was against those harboring wild-type p53 (IC50, 2.8-9.9 microM). In contrast, DACH acetato-Pt was considerably more active in wild-type p53 models (IC50, 0.17-1.5 microM) than it was in mutant or null models (IC50, 2.7-11.3 microM). Inactivation of wild-type p53 function in OVCA-429 cells by the human papillomavirus type 16 (HPV 16) E6 plasmid increased resistance to DACH-acetato Pt by 3-5-fold, which confirmed the drug's dependence on wild-type p53 for its high cytotoxic potency. Differences between the two platinum agents were also evident in cell cycle studies: cisplatin arrested both wild-type and mutant p53 cells in G2-M, whereas DACH-acetato-Pt arrested wild-type p53 cells in G1 and mutant p53 cells in G2-M. The G1 arrest by DACH-acetato-Pt was abrogated in HPV 16 E6 transfectant clones of OVCA-429 cells. In agreement with effects on cell cycle progression, a 2-h pulse exposure to low concentrations (< or =25 microM) of DACH-acetato-Pt induced marked increases in p53 and p21Waf1/Cip1 expression in OVCA-429 cells. Cisplatin, in direct contrast, had no effect on expression of p53 or p21Waf1/Cip1 until the drug concentration was increased to 125 microM. In HPV 16 E6 transfectants of OVCA-429 cells, induction of p53 by the two agents was severely attenuated, and corresponding increases in p21Waf1/Cip1 were abrogated. This suggests that p21Waf1/Cip1 increases were p53 dependent. Collectively, the results demonstrate that DACH-acetato-Pt is very distinct from cisplatin. In particular, the greater activity of DACH-acetato-Pt in cisplatin-resistant wild type p53 ovarian tumor models can be ascribed to its ability to more efficiently induce p53 protein and activate p53 functions. PMID- 10100720 TI - Detection of poly(ADP-ribose) polymerase cleavage in response to treatment with topoisomerase I inhibitors: a potential surrogate end point to assess treatment effectiveness. AB - Cleavage of poly(ADP-ribose) polymerase (PARP) by caspases is a prominent characteristic of apoptosis or programmed cell death shown to be induced by topoisomerase (Topo) inhibitors. Because Topo I inhibitors have been shown to be effective in the treatment of some patients with colon cancer, we considered the possibility of using PARP cleavage as an early predictor of responsiveness to this class of agents. We show cleavage of PARP in response to treatment with Topo I inhibitors in colon cancer both in vitro and in vivo: (a) in vitro in SW480, HCT116, VACO5, VACO6, VACO8, VACO411, VACO425, and VACO451 human colon cancer cell lines treated with topotecan (TPT) or CPT-11; (b) in vivo in SW480, VACO451, and VRC5 colon cancer xenografts grown in athymic mice treated with TPT or CPT 11; and (c) in vivo in colon cancer samples from patients undergoing a Phase II clinical trial with CPT-11. Our results show a strong correlation between percentage of PARP cleavage and percentage of acridine orange-positive cells in colon cancer cell lines treated with 0.1 microM TPT for 24 and 48 h, confirming that PARP cleavage is a useful marker for programmed cell death in colon cancer cell lines. Results from experiments performed on colon cancer xenografts also show an association between PARP cleavage and response to treatment with TPT or CPT-11. The increase of PARP cleavage in xenografts and in clinical samples corresponding to treatment with Topo I inhibitors suggests that this procedure may have early predictive value to assess effectiveness of treatment. These results provide the basis for determining the validity of using PARP cleavage as an early marker of chemotherapeutic effectiveness in human samples. PMID- 10100721 TI - Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response. AB - Recently, cDNAs have been identified that encode four human proteins (MRP2-5) with structural similarity to the multidrug resistance protein (MRP). Preliminary studies have shown that levels of mRNAs encoding MRP2, MRP3, and MRP5, are increased in some drug-selected cell lines, but the correlation of MRP2-5 mRNA levels with drug resistance has not been examined. Using a collection of small cell lung cancer (SCLC) and non-SCLC patient samples and unselected cell lines established from patients at various stages of treatment, we examined the expression of MRP2, MRP3, MRP4, and MRP5, as well as MDR1 and MRP, by PCR. The levels of individual mRNAs were correlated with the sensitivity of these cell lines to doxorubicin (DOX), vincristine, VP-16, and cis diamminedichloroplatinum(II), as determined by a modified MTT assay. Using both SCLC and non-SCLC cell lines, we confirmed the previously observed correlation of MRP mRNA levels with resistance to DOX (B. G. Campling et al., Clin. Cancer Res., 3:115-122, 1997) and found a strong correlation of MRP3 mRNA levels with resistance of the cell lines to DOX. In addition, the mRNA levels of both MRP and MRP3 correlated with resistance of the cell lines to vincristine, VP-16, and cis diamminedichloroplatinum(II). These findings are consistent with the suggestion that MRP3, like MRP, may contribute to the drug resistance phenotype of lung cancer cells. PMID- 10100722 TI - Up-regulation of E-cadherin by an anti-epidermal growth factor receptor monoclonal antibody in lung cancer cell lines. AB - Many human epithelial carcinomas are characterized by the overexpression and constitutive activation of the epidermal growth factor receptor (EGF-R) via an autocrine signaling loop. We have investigated the effects of a ligand-blocking monoclonal antibody (mAb) against the EGF-R LA1 on selected parameters of human lung cancer cell lines (H322 and H661) and normal human bronchial epithelial (NHBE) cells. Using Western blot analysis, we show that H322 and NHBE cell lines express comparable levels of EGF-R/p170erbB-1. The LA1 mAb against EGF-R inhibits growth, induces differentiation to a more epithelial phenotype, reduces the constitutive activation of EGF-R, and upregulates epithelial cadherin glycoprotein expression in H322 and NHBE cells. In contrast, LA1 had no effect on either growth, differentiation, receptor tyrosine phosphorylation, or the expression of adhesion molecules in H661 cells, which is consistent with our finding that this cell line does not express detectable levels of EGF-R. These studies demonstrate that a blocking anti-EGF-R mAb can regulate proliferation, differentiation, and the expression of cell adhesion molecules in human bronchial epithelial cells. Our findings suggest possible therapeutic avenues for the treatment of invasive carcinomas via the blockade of EGF-R with antibodies. PMID- 10100723 TI - Enhancement of antitumor activity of polyethylene glycol-coated liposomal doxorubicin with soluble and liposomal interleukin 2. AB - Polyethylene glycol-coated liposomal doxorubicin (Doxil) has a sustained release profile and a mild myelosuppressive effect that may enable a beneficial interaction with lymphocyte-activating cytokines, such as interleukin 2 (IL-2). Previous studies have shown that liposome entrapment of IL-2 potentiates its immunomodulatory effects and reduces the need for frequent dosing. We assessed the therapeutic effect of Doxil (8 mg/kg) followed by free or liposomal IL-2 (50,000 Cetus Units x 3) in mice bearing M109 lung adenocarcinoma transplanted i.v. or i.p. Doxil was always administered i.v., whereas IL-2 was given i.v. in the i.v. M109 model and i.p. in the i.p. M109 model. The optimal combined treatment was significantly more effective than liposomal chemotherapy alone, producing tumor-free, long-term survivors in 100% (i.v. M109) and 94% (i.p. M109) of the mice, compared with 50% and 56%, respectively, for Doxil alone. The efficacy boost of IL-2 appeared to be formulation dependent, with free IL-2 and IL-2 in small unilamellar vesicles most active in the i.v. tumor model, and IL-2 in multilamellar vesicles most active in the i.p. tumor model. The combination of Doxil with free or liposomal IL-2 was devoid of any conspicuous toxicity. Cytokine treatment without chemotherapy was completely ineffective. Liposome based chemoimmunotherapy is a synergistic and highly efficacious approach to eradicate metastatic and regionally spread tumors. PMID- 10100724 TI - 1Alpha,25dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines. AB - The majority of men who die from prostate cancer (PC) have hormone-refractory disease. To date, chemotherapeutic agents have had little or no impact on the survival of such patients. To explore a new approach for the treatment of hormone refractory PC, we examined the combination effects of cis- or carboplatin with vitamin D. 1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its synthetic analogue, Ro 25-6760, have an antiproliferative effect on some prostate cancer cell lines. Consequently, the growth-inhibitory effects of the drugs were measured, both singularly and in combination with cis- or carboplatin, on PC cells. Our results show that although each of the drugs alone displayed antiproliferative activity, the growth inhibition of PC cells was further enhanced by the combination of 1alpha,25(OH)2D3 or Ro 25-6760 and either platinum agent. The greatest enhancement of inhibition occurred using smaller concentrations of the platinum compound in combination with higher concentrations of 1alpha,25(OH)2D3. Isobologram analysis revealed that 1alpha,25(OH)2D3 and platinum acted in a synergistic manner to inhibit the growth of PC cells. Our findings suggest that there is potential clinical value in combining 1alpha,25(OH)2D3 with platinum compounds for the treatment of advanced-stage human PC. PMID- 10100725 TI - Isolation of human lymphocyte antigens class I-restricted cytotoxic T lymphocytes against autologous myeloma cells. AB - Peripheral blood T cells from a patient with multiple myeloma in complete remission were selected in vitro against an autologous myeloma cell line (SBN-1), using a protocol designed for the selection of relatively rare precursor cytotoxic T cells (pCTL). Delayed addition (2 weeks) of interleukin 2 induced T cell proliferation, and a bulk culture (T-cell line) was obtained 2 days later. This T-cell line displayed cytotoxicity against SBN-1. A CD8+ CD4- cytotoxic T cell clone (CT5) was then obtained that recognized SBN-1 but not autologous EBV+ B-lymphoblastoid cells, autologous T PHA-blasts, or Daudi, Raji, K562, and 11 allogeneic myeloma cell lines. Moreover, CT5 cytotoxic activity against SBN-1 was blocked by monoclonal antibodies recognizing human lymphocyte antigen class I molecules. This seems to be the first demonstration of myeloma-specific pCTL in peripheral blood T cells of patients with multiple myeloma. PMID- 10100726 TI - Role of interleukin 10 and transforming growth factor beta1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopic implants in severe combined immunodeficiency mice. AB - Transfection of primary human prostate tumor cells (i.e., HPCA-10a, 10b, 10c, and 10d lines) with the transforming growth factor (TGF)-beta1 gene stimulated anchorage-independent growth and promoted tumor growth, angiogenesis, and metastasis after orthotopic implantation in severe combined immunodeficiency mice. In contrast, interleukin (IL)-10 transfected cells or cells cotransfected with these two genes exhibited reduced growth rates and significantly reduced angiogenesis and metastasis after 8, 12, and 16 weeks. Enzyme-linked immunosandwich assays confirmed that the respective tumors expressed elevated levels of TGF-beta1 and IL-10 in vivo. ELISAs further showed that TGF-beta1 expression induced matrix metalloproteinases-2 (MMP-2) expression, whereas IL-10 down-regulated MMP-2 expression while up regulating TIMP-1 in the transfected cells. Also, tumor factor VIII levels correlated with TGF-beta1 and MMP-2 expression and inversely with IL-10 and TIMP-1 levels. More importantly, mouse survival was zero after 4-6 months in mice bearing TGF-beta1- and MMP-2 expressing tumors and increased significantly in mice implanted with IL-10- and TIMP-1-expressing tumors (i.e., to >80% survival). Analysis of the metastatic lesions showed that they expressed TGF-beta1 and MMP-2 but barely detectable levels of IL-10 or TIMP-1, suggesting that IL-10 and TIMP-1 might normally block tumor growth, angiogenesis, and metastasis. PMID- 10100727 TI - Assessment of vascularity in histological sections: effects of methodology and value as an index of angiogenesis in breast tumours. AB - The aims of this study were to (a) determine how the quantification of blood vessels in histological sections (vascularity) is affected by the methodology used and (b) assess the value of vascularity as an index of angiogenesis by comparing tumour and normal breast tissue. Archival specimens of breast, lung and oral carcinoma, oral dysplasia and normal breast tissue were used to test the effects of the following experimental variables on vascularity: pretreatment of the sections (enzymatic digestion, heating), endothelial markers (von Willebrand factor and CD31 antibodies), method of quantification (highest microvascular density, average microvascular density and microvascular volume) and interobserver variations. All the variables examined significantly affected the estimated vascularity; this depended on the type of tissue and method used. The pretreatment of the sections before staining was the most important variable, altering the vascularity ranking of the tumours. Vascularity in breast tumours was similar to that of the normal breast intralobular stroma, suggesting that an area of high microvascular density in the tumour does not necessarily represent tumour-induced angiogenesis. Contradictory results have been published regarding the value of vascularity as a tumour prognostic factor. Our results suggest that statistically significant differences in vascularity values are most likely to arise from failure to optimize the staining protocol and from the method used to assess vascularity. PMID- 10100728 TI - Immunocytochemical characterization of lung macrophage surface phenotypes and expression of cytokines in acute experimental silicosis in mice. AB - The expression of the surface phenotypical profile and the cytokines TNF-alpha and IL-1beta from murine lung macrophages was studied in parenchymal lung tissue and bronchoalveolar fluid of mice, over a 2-week period, following a single intratracheal instillation of silica. The acute inflammatory reaction, confirmed by a significant augmentation of four times the control values of the number of macrophages recovered by lavage from experimental animals, was followed by organized granulomas in the interstitium. The immunohistochemical analysis of lung tissue sections after silica instillation demonstrated the increased alveolar and interstitial tissue expression of all surface antigens and cytokines studied, mainly Mac-1, F4/80 antigens, TNF-alpha and IL-1beta, which were occasionally observed in normal uninjected and saline-treated mice. These findings show that, after silica instillation, the expression of surface phenotypical markers of lung macrophages increased, and this change was concomitantly associated with an increased expression of the cytokines TNF-alpha and IL-1beta. These changes support the conclusion that an influx of the newly recruited and activated macrophage population, with a different phenotype, is induced by treatment during inflammation. The populational changes involve difference in functional activity and enhance TNF-alpha and IL-1beta expression. These cytokines, produced in the silicosis-induced inflammatory process, are associated with the development of fibrosis and may contribute to disease severity. PMID- 10100729 TI - Epidermal cell kinetics by combining in situ hybridization and immunohistochemistry. AB - Double labelling can serve as a useful tool for providing information about cell kinetics in normal and hyperproliferative tissues in general, and skin in particular. We have developed a double-labelling method that combines immunohistochemistry using the monoclonal antibody MIB1 and non-isotopic in situ hybridization using either a digoxigenin-labelled RNA probe specific for histone 3 mRNA sequences or a Fluorescein-labelled oligonucleotide probe specific for histone 2b, 3, 4 mRNA sequences. Double labelling was performed on normal, tape stripped normal skin and psoriatic skin. The three proliferation markers were also examined by single labelling. The ratio of cells in the S-phase (Ns) and the growth fraction (Ncy) was determined. In normal skin, psoriatic skin and tape stripped normal skin after 24 h and after 48 h, we calculated that 15%, 16%, 3% and 12% of growth fraction consisted of cells in the S-phase respectively. The S phase lasts approximately 10 h, so the cell cycle time in normal and psoriatic skin is approximately 62.5 h. At present, the MIB1/H3 digoxigenin or MIB1/H2b-H3 H4 Fluorescein double-labelling technique cannot be used routinely. Therefore, in order to understand the cell kinetic processes better, experiments are recommended to optimize these methods. From a practical point of view and for reasons of specificity and sensitivity, we prefer the Fluorescein-labelled oligonucleotide probe method. PMID- 10100730 TI - Association of cell and substrate adhesion molecules with connexin43 during intramembranous bone formation. AB - Prior studies in our laboratory have demonstrated an association of specific gap junction proteins with intramembranous bone formation in the avian mandible. The purpose of the present study was to extend these observations by determining if there was a relationship between the expression of one of the gap junction proteins examined previously (connexin43) and the expression of specific cell adhesion (CAM) and/or substrate adhesion (SAM) molecules [i.e. NCAM, A-CAM (N cadherin) and tenascin (tenascin-C)] that have previously been shown to be associated with bone formation. Immunohistochemical localization of connexin43, tenascin, NCAM and N-cadherin was performed on serial sections of mandibles of chick embryos from 6 to 12 days of incubation. Analysis of adjacent serial sections revealed that the NCAM and tenascin immunostaining that appeared initially on the lateral aspect of Meckel's cartilage preceded the overt expression of trabecular bone. At subsequent stages, NCAM and tenascin staining gradually overlapped the region of connexin43 expression. In contrast, the expression of N-cadherin was found to colocalize with that of connexin43 from the first appearance of connexin43 expression. Most significantly, although the domains of NCAM and tenascin expression were initially separate from that of connexin43, bone formation originated only in the region where these domains intersected. These findings suggest that, of the CAMs and SAMs examined, N cadherin appears to be associated with the establishment of cell contacts responsible for the presence and/or maintenance of connexin43-mediated gap junctional communication, while tenascin and NCAM appear to be associated, in a more specific manner, with processes that accompany the overt expression of the osteogenic phenotype. PMID- 10100731 TI - Improved cytochemical methods for demonstrating cell death using LR White as an embedding medium. AB - A series of techniques based on LR White resin are described, which permit the use of an anti-histone antibody for the in situ localization of DNA fragmentation characteristic of apoptosis at both the light and the electron microscope level. The methods, applied to an untreated squamous carcinoma of the pharynx, allow direct comparison of light microscopic localization of exposed nucleosomal histones using 3,3'-diaminobenzidine (DAB) and silver-enhanced techniques with a colloidal gold-based anti-histone technique at the electron microscope level. Parallel histochemical localization of acid phosphatase activity is also presented. PMID- 10100732 TI - Immunohistochemical distribution of epimorphin in human and mouse tissues. AB - A novel protein epimorphin has been identified as a mesenchymal signal factor. We reported previously ubiquitous expression of epimorphin in normal skin and a significant increased expression in diseased human skin. The present immunofluorescence study was conducted to determine systematically the distribution of epimorphin in adult human organs with an anti-epimorphin monoclonal antibody. Epimorphin was found to be widely distributed in all human organs examined. It was present in the connective tissue adjacent to or around various epithelial tissues, muscles and vessels. In particular, strong staining was present on the endomysium of muscles, the adventitia of blood vessels, along the sinusoidal lining of hepatocytes and connective tissue around epithelial cells, exocrine and endocrine glands. The results suggest that epimorphin may play a key role in maintaining normal tissue structure and interaction between mesenchymal tissue and epithelial tissue in vivo. PMID- 10100733 TI - The involvement of altered vesicle transport in redistribution of Ca2+, Mg2+ ATPase in cholestatic rat liver. AB - Vectorial sorting of plasma membrane protein-containing vesicles is essential for the establishment and maintenance of cell polarity. In the present study, the involvement of altered vesicle transport in the redistribution of membrane-bound Ca2+, Mg2+-ATPase resulting from cholestasis was investigated in hepatocytes. Cholestasis was induced in rat liver by common bile duct ligation. Ca2+, Mg2+ ATPase activity was demonstrated histochemically at the light and electron microscopical levels. Microtubules, an important factor for transcellular transport of vesicles, were studied in situ by immunofluorescence microscopy and electron microscopy in detergent-extracted preparations. The results showed that microtubules underwent significant changes after common bile duct ligation. The most pronounced alteration was focal accumulation of beta-tubulin in the cytoplasm of hepatocytes after 7 days of common bile duct ligation. At the electron microscopical level, the number of microtubules was increased considerably. In control livers, the activity of Ca2+, Mg2+-ATPase was localized only at the apical plasma membrane of hepatocytes, but it was also present at the basolateral plasma membrane after common bile duct ligation. The number of intracellular vesicles containing Ca2+, Mg2+-ATPase activity was increased strikingly, and some of them were associated with lateral membrane domains in which Ca2+, Mg2+-ATPase activity was found. It is concluded that common bile duct ligation induces the rearrangement of microtubules, which may disturb vectorial transport of Ca2+, Mg2+-ATPase-containing vesicles in hepatocytes, leading to the redistribution of Ca2+, Mg2+-ATPase. PMID- 10100734 TI - Histochemical demonstration of apoptotic cells in the chicken embryo using annexin V. AB - This study describes the use of biotinylated annexin V for the histochemical detection of apoptotic cells in cultured chicken embryos during gastrulation. This method is based on the Ca2+-dependent binding of annexin V to phosphatidylserine, a negatively charged phospholipid, located at the inner leaflet of the cell membrane in living cells. However, in the early stages of apoptosis, phosphatidylserine is translocated to the outer layer of the cell membrane and can then be recognized by annexin V. Applying this method in cultured chicken embryos during gastrulation, we obtained labelling of apoptotic cells in the three germ layers. In the epiblast and mesoblast, labelling was predominantly present in the region lateral to the primitive streak. At the level of the germinal crescent, labelled cells were also found in the epiblast. Labelled cells in the deep layer, which is a heterogeneous tissue layer composed of endophyll, sickle endoblast and definitive endoblast, were rather scarce. The distribution of cells, as observed in this study after labelling with annexin V in light microscopy and confocal laser scanning microscopy, is consistent with distributions reported by other authors using other approaches and with our previous observations made with the TUNEL technique and by electron microscopy after fixation in a tannic acid-based fixative. The main advantages of this method over other more sophisticated methods is its easiness and rapidity of execution and the fact that both early and late stages of apoptosis are detected. PMID- 10100735 TI - The relationship between electromagnetic field and light exposures to melatonin and breast cancer risk: a review of the relevant literature. AB - Worldwide, breast cancer is the most common malignancy accounting for 20-32% of all female cancers. This review summarizes the peer-reviewed, published data pertinent to the hypothesis that increased breast cancer in industrialized countries is related to the increased use of electricity [Stevens, R.G., S. Davis 1996]. That hypothesis specifically proposes that increased exposure to light at night and electromagnetic fields (EMF) reduce melatonin production. Because some studies have shown that melatonin suppresses mammary tumorigenesis in rats and blocks estrogen-induced proliferation of human breast cancer cells in vitro, it is reasoned that decreased melatonin production leads to increased risk of breast cancer. To evaluate this hypothesis, the paper reviews epidemiological data on associations between electricity and breast cancer, and assesses the data on the effects of EMF exposure on melatonin physiology in both laboratory animals and humans. In addition, the results on the effects of melatonin on in vivo carcinogenesis in animals are detailed along with the controlled in vitro studies on melatonin's effects on human breast cancer cell lines. The literature is evaluated for strength of evidence, inter-relationships between various lines of evidence, and gaps in our knowledge. Based on the published data, it is currently unclear if EMF and electric light exposure are significant risk factors for breast cancer, but further study appears warranted. Given the ubiquitous nature of EMF and artificial light exposure along with the high incidence of breast cancer, even a small risk would have a substantial public health impact. PMID- 10100736 TI - Protective effect of melatonin on indomethacin-induced gastric injury in rats. AB - The gastric injury associated with nonsteroidal anti-inflammatory drug (NSAID) therapy has been linked to the detrimental effects of the agents on the processes of prostaglandin synthesis, neutrophil (PMN) activation. and oxygen free radical generation. In the present study, we investigated the in vivo protective effects of melatonin on indomethacin-induced gastric lesions in the rat. Peroxidation of lipids and changes in the activities of related enzymes such as glutathione peroxidase (GSH-px) and myeloperoxidase (MPO), as a marker of PMNs infiltration, were also studied. Intraperitoneal (i.p.) injection of melatonin (0.25. 0.5, 1 mg kg(-1)) 30 min before indomethacin administration prevented gastric injury. The mean ulcer indices significantly (P < 0.05) decreased. Thiobarbituric acid (TBA) reactive substances in the gastric mucosa as an index of peroxidation, was increased after indomethacin administration and this increase was inhibited by melatonin. In addition, pretreatment with melatonin resulted in a significant increase of the enzymatic GSH-px activity up to the control levels; however, inhibition of ulceration by melatonin was not associated with a significant reduction in PMN infiltration. These results suggest that the protection afforded by the pineal hormone against indomethacin-induced gastric injury may be, in addition to other possible mechanisms, to its radical scavenging activity. PMID- 10100737 TI - Interactions of melatonin with membrane models: portioning of melatonin in AOT and lecithin reversed micelles. AB - The interaction of melatonin with water containing either sodium bis (2 ethylhexyl) sulfosuccinate (AOT) or soybean phosphatidylcholine (lecithin) reversed micelles has been investigated by UV absorption spectroscopy, at a molar ratio of melatonin:surfactant 1:800 for AOT and 1:400 for lecithin reversed micelles, and by varying the water:surfactant molar ratio (R). Our results suggest that in the presence of domains from apolar organic solvent to surfactant and to water, melatonin positions itself in the micellar phase, with a preferential location in the surfactant polar head group domain, independent of the nature of the surfactant and the amount of water encapsulated into the micellar core. Effects are due to the hydrophilic and lipophilic moieties of melatonin. The effectiveness of melatonin as an electron donor and free radical scavenger has been recently recognized. While supporting the hypothesis that melatonin may provide antioxidant protection without the benefit of receptors, present findings may suggest that the molecule could easily scavenge aqueous as well as lipophilic radicals. PMID- 10100738 TI - Melatonin receptor potentiation of cyclic AMP and the cystic fibrosis transmembrane conductance regulator ion channel. AB - We have used the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel as a model system to study the cAMP signal transduction pathways coupled to the Xenopus melatonin receptor. During forskolin (Fsk) stimulation, melatonin reduced the amplitude of the CFTR currents in oocytes injected with in vitro transcribed cRNAs for the Xenopus melatonin receptor and CFTR. Pertussis toxin (Ptx) treatment eliminated melatonin inhibition of Fsk stimulated CFTR currents. In oocytes injected with cRNA for melatonin receptors, serotonin receptors (5 HT7), and CFTR Cl- channels, application of melatonin together with serotonin (5 HT) activated an additional inward current showing potentiation of adenylyl cyclases by melatonin receptors. Subthreshold activation of 5-HT7 receptors was sufficient and necessary to permit activation of CFTR channels by melatonin. Preexposure to melatonin desensitized the melatonin receptor mediated response. Therefore, based on this model system, the effects of melatonin in vivo could be either positive or negative modulation of other neuronal inputs, depending on the mode of adenylyl cyclase stimulation. PMID- 10100739 TI - The effects of near-ultraviolet light on serotonin N-acetyltransferase activity in the chick pineal gland. AB - Effects of near-ultraviolet light (UV-A; 325-390 nm, peak at 365 nm) on the activity of the pineal serotonin N-acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthesis) were examined in chicks. Acute exposure of dark adapted animals to UV-A radiation produced a marked decline in NAT activity of the pineal gland. The magnitude of this suppression was dependent upon duration of the light pulse and the age of the animals. The decrease in the nighttime NAT activity evoked by a 5 min pulse of UV-A light applied during the fourth hour of the dark phase of the 12 hr light:12 hr dark cycle (LD) gradually deepened during the first 40 min after the return of animals to constant darkness, then the enzyme activity began to rise, reaching control values by 2 hr. Exposure of chicks to a 5 min pulse of UV-A light during the ninth hour of the dark phase produced a marked decline in pineal NAT activity, which was reversible after 15 min of darkness. Pretreatment of animals with an inhibitor of catecholamine synthesis, alpha-methyl-p-tyrosine (300 mg/kg, i.p.), or with a blocker of alpha2 adrenergic receptors, yohimbine (2 mg/kg, i.p.), antagonized the suppressive effect of UV-A light on nighttime NAT activity of the chick pineal gland. It is concluded that UV-A irradiation, similar to visible light, potently suppresses melatonin biosynthesis in the chick pineal gland, with an alpha2-noradrenergic signal playing the role of an intermediate in this action. PMID- 10100740 TI - Cloning and sequencing of the central region of the flagellin gene from the Gram positive bacterium Clostridium tyrobutyricum ATCC 25755. AB - The purpose of this study was to sequence the central part of the coding region of the Clostridium tyrobutyricum fiagellin gene to improve the immunoenzymatic counting of cells after milk filtration. The coding region was amplified by PCR, and the amplified products were cloned. A DNA sequence analysis of positive clones gave us 1,131 nucleotides with a partial calculated flagellin molecular mass of 40,143 Da. The flagellar filament protein sequence exhibited high levels of homology to sequences of flagellin protein from other bacteria in both N- and C-terminal parts, but little homology in the central domain. A PCR-restriction fragment length polymorphism analysis of amplified C. tyrobutyricum flagellin gene products confirmed the variability of the central domain. The flagellin mRNA was determined to be 1.1 kb in size, which suggests a monocistronic mRNA. Furthermore, the deduced protein flagellin contains eleven potential N glycosylation sites and one sequence rich in serine, which could be modified by O glycosylation. PMID- 10100741 TI - Intracellular Salmonella typhimurium induce lysis of human polymorphonuclear leukocytes which is not associated with the Salmonella virulence plasmid. AB - The interaction between Salmonella typhimurium and human polymorphonuclear leukocytes (PMNs) was analyzed in vitro. Three S. typhimurium strains, the wild type strain OU5043, its isogenic virulence plasmid-cured strain OU5048, and LT2, which represented the types that exhibited three mouse virulence levels, respectively, were used in this study. There was no correlation between the recovery of intracellular S. typhimurium from PMNs and the presence or absence of the virulence plasmid, or the strains' mouse virulence level. When the oxygen dependent response of PMNs upon phagocytosis of S. typhimurium was examined by checking the intracellular reduction of nitroblue tetrazolium (NBT), the fraction of PMNs that reduced NBT on phagocytosis of the three strains was around 80%, whereas it was 58% with Escherichia coli, 95% with phorbol 12-myristate 13 acetate and 15% with a negative control. Thus there were no significant differences among the three Salmonella strains in terms of their ability to induce the oxidative response in PMNs. Microscopic analysis of Salmonella infected PMNs indicated that the intracellular Salmonella induced lysis of PMNs. Both OU5043 and OU5048 exhibited a significant intracellular cytotoxic effect on PMNs after 24 hr of infection and this effect was not associated with the presence or absence of the virulence plasmid. On the other hand, lysis of PMNs was related to the intracellular survival of Salmnonella, as ofloxacin, an antibiotic, appeared to be able to protect human PMNs from Salmonella-induced cytotoxicity when this agent was added into the medium to inactivate the intracellular organism. The ability to induce lysis of PMNs by either wild-type or plasmid-cured strains of S. typhimurium may play a crucial role in the pathogenesis of non-typhoid Salmonella. The contribution of pSTV to human salmonellosis is likely to be limited. Furthermore, early institution of antibiotics with a high intracellular activity against Salmonella, such as fluoroquinolones, may be useful to prevent the dissemination of Salmonella infection. PMID- 10100742 TI - Growth conditions of and emetic toxin production by Bacillus cereus in a defined medium with amino acids. AB - The growth and emetic toxin (cereulide) production of Bacillus cereus strains in defined culture media were studied. We found that a fully synthetic medium (CADM) allowed the production of emetic toxin and the addition of glucose enhanced it. By subtracting each amino acid from CADM, we found that only three amino acids, valine, leucine and threonine, were essential for growth and toxin production by B. cereus. The addition of high levels (50 mM) of leucine, isoleucine and glutamic acid decreased the toxin production. Other amino acids had no effect at this concentration. PMID- 10100743 TI - The hsp operons are repressed by the hrc37 of the hsp70 operon in Staphylococcus aureus. AB - The heat-shock proteins are coded for the polycistronic operons hsp70 and hsp60 in Staphylococcus aureus. The hsp70 operon is comprised of five genes, hrc37, hsp20, hsp70, hsp40 and orf35, and the hsp60 is comprised of two genes, hsp10 and hsp60. The hsp70 operon transcribed five different sizes of mRNA from three promoters: P1, the most active promoter, transcribed 6.0 and 3.6 kb mRNAs; P2 transcribed a single 1.8 kb mRNA; and P3 transcribed 4.2 and 2.4 kb mRNAs. The hsp60 operon transcribed a single 2.1 kb transcript from only one promoter, P1. Both operons had a common structure of inverted repeat element (CIRCE, Controlling Inverted Repeat of Chaperon Expression) at the promoter region. All of the transcripts were heat (46 C) inducible. One of the unidentified genes, hrc37, was characterized. The disruptant of the hrc37 in the hsp70 operon enhanced the transcription of both operons at 37 C (derepression). Complementation of the disruptant with the cloned hrc37 plasmid recovered the repression of the transcription of both operons at 37 C. The product of hrc37, Hrc37, was found to bind to the CIRCE element. These findings indicated that Hrc37 from the hsp70 operon repressed the transcription of both the hsp70 and hsp60 operons by binding to the CIRCE element located at the promoter region. PMID- 10100744 TI - Secretion of hemolysin of Aeromonas sobria as protoxin and contribution of the propeptide region removed from the protoxin to the proteolytic stability of the toxin. AB - The sequence at the amino terminus region of the hemolysin ofAeromonas sobria is homologous with that of aerolysin of A. hydrophila. However, there is no homology between the two toxins in the sequence at the carboxy terminal region. It has been shown that aerolysin is secreted into culture supernatant as a protoxin. This proaerolysin is activated by the proteolytic removal of a carboxy terminal peptide. However, the role of the carboxy terminal region, which is removed in the activation process, has not been elucidated. In this study, we showed that hemolysin is also secreted as a protoxin into culture supernatant and that prohemolysin is cleaved by the protease of A. sobria between Ser-446 and Ala-447, resulting in the removal of a 42 amino acid peptide. The removal of the peptide converts the prohemolysin into active hemolysin. Subsequently, we mutated the hemolysin gene to delete the last several amino acid residues and expressed the genes in Escherichia coli, in order to examine the role of the carboxy terminal region of prohemolysin. The amounts of these mutant hemolysins accumulated in the periplasmic space of E. coli were very low compared with that of the wild-type. This observation indicated that the carboxy terminal region of prohemolysin contributes to the proteolytic stability of the toxin. PMID- 10100745 TI - Suppression by the DNA fragment of the motX promoter region on long flagellar mutants of Vibrio alginolyticus. AB - The axial length of the polar flagellum (Pof) of Vibrio alginolyticus is about 5 microm. We previously isolated mutants that make abnormally long flagella. The swarm sizes of these mutants in a soft agar plate are smaller than that of a wild type strain. We cloned a DNA fragment into the pMF209 plasmid that restored the swarming ability of the long-Pof strain V10578. The swimming speed and flagellar length of these transformants were almost equal to the wild-type values. The amounts of PF47 flagellin and PF60 sheath-associated protein, which increased in the long-Pof mutants, were retrieved to almost the wild-type level in the transformants. The plasmid pMF209 contained only a 143 bp chromosomal fragment whose sequence is about 80% similar to that of the motX promoter region of V parahaemolyticus. We speculate that this sequence interacts with a regulatory protein that controls Pof expression. The mutation causing the long-Pof phenotype may be in the gene encoding this protein or in the control region of a structural gene that is regulated by this protein. PMID- 10100746 TI - Experimental murine model for autoimmune enterocolitis using Klebsiella pneumoniae O3 lipopolysaccharide as a potent immunological adjuvant. AB - An experimental model for autoimmune enterocolitis was produced in mice by repeated immunization of homologous colon extract together with Klebsiella 03 lipopolysaccharide (KO3 LPS) as an immunological adjuvant. Histological changes in the intestinal lesions were characterized by infiltration with polymorphonuclear leukocytes in the lamina propria, muscularis mucosae and submucosa of repeatedly immunized mice. No such intestinal lesions were produced in mice receiving injections of colon extract alone or KO3 LPS alone. Development of the autoantibody and delayed-type hypersensitivity against colon extract were found in mice immunized with the mixture of colon extract and KO3 LPS. Distinct positive staining was detected specifically on the columnar epithelium of villi. Sera from hyperimmunized mice defined organ-specific antigens present in the intestine. Therefore, it was suggested that the intestinal lesions might be caused by an autoimmune mechanism. PMID- 10100747 TI - A 63 kDa tumor necrosis factor inhibitor released from a human monocytic leukemia cell line, THP-1. AB - A human monocytic cell line, THP-1-S, was cultured in a serum-free medium. The effect of the culture supernatant of THP-1-S on the cytotoxicity of rTNF-alpha to three kinds of cell lines and the binding of rTNF to its receptor were tested. The supernatant inhibited the cytotoxicity of rTNF-alpha when tested by the neutral red uptake method. In addition, the supernatant blocked the binding of 125I-rTNF-alpha to its receptor. Furthermore, following precipitation with PEG we detected complexes between rTNF-alpha and the inhibitory factor which formed during incubation with the culture supernatant from THP-1-S cells. However, the supernatant did not bind to or down-regulate the receptor for TNF-alpha on the cell surface of L-M-2d6 cells. This factor eluted with an apparent molecular mass of 63,000 Da by gel filtration and did not react with antibodies against p55 and p75 TNF receptors. These data suggest that human monocytic cells are capable of releasing an inhibitory factor against rTNF-alpha in serum-free culture conditions. PMID- 10100748 TI - Antisense macrophage migration inhibitory factor (MIF) prevents anti-IgM mediated growth arrest and apoptosis of a murine B cell line by regulating cell cycle progression. AB - Macrophage migration inhibitory factor (MIF) is involved in the generation of cell-mediated immune responses. Recently it has been reported that MIF also plays a role in cell proliferation and differentiation. In the present study, using a B cell line, WEHI-231, and its stable MIF-antisense transfectant, WaM2, as a representative transfectant, we investigated the mechanism underlying regulation of the cell growth by MIF. WaM2 cells produced less MIF than vector control or parental WEHI-231 cells. Reduced and increased proportions were seen in G1 and S phase cells, respectively, in WaM2 as compared with WEHI-231. Growth arrest and apoptosis after stimulation via surface Ig (sIg) were less prominent in WaM2 cells than those in WEHI-231. However, the addition of recombinant rat MIF did not reverse the inhibition of the growth arrest and apoptosis induced in WaM2 by cross-linking sIg. Almost the same amount of p27kip1 expression was detected in WaM2 cells as those in WEHI-231 and vector control cells. Cross-linking of sIg elevated the p27kip1 level equally in these cells irrespective of the MIF antisense expression. Taken together, it seems that MIF plays a role in inducing apoptosis in B cells upon IgM cross-linking by regulating the cell cycle via a novel intracellular pathway. PMID- 10100749 TI - Prolonged incubation period of salmonellosis in an outbreak of Salmonella enteritidis infection. AB - An outbreak of Salmonella enteritidis infections occurred in Otaru, Japan, in September 1997. A total of 143 cases of salmonellosis were reported to the local Public Health Center. In this outbreak, one case had a 214-hr incubation period. We investigated 5 isolates including this case by phage typing and pulsed-field gel electrophoresis (PFGE) to determine the genetic heterogeneity of S. enteritidis. Five isolates were phage typed as reacted, but did not conform (RDNC) with identical reaction patterns and had quite similar PFGE patterns. Thus, the prolonged incubation period may not be attributed to genetic heterogeneity of the organism but rather to other factors. PMID- 10100750 TI - Evaluation of an enzyme-linked immunosorbent assay based on binding inhibition for type-specific quantification of poliovirus neutralization-relevant antibodies. AB - To detect neutralization-relevant antibodies against 3 types of poliovirus (PV) without using tissue cultures and live viruses, an enzyme-linked immunosorbent assay (ELISA) based on monoclonal antibody-binding inhibition was evaluated using sera from 80 vaccinated Japanese children and 60 Pakistani poliomyelitis patients. Compared with the neutralization test, the sensitivity of the inhibition ELISA was 100% (111/111) for detection of anti-PV1 antibody, 98.3% (118/120) for anti-PV2, and 96.5% (82/85) for anti-PV3, and the specificity was 93.1% (27/29), 100% (20/20), and 92.7% (51/55), respectively. Thus, the inhibition ELISA showed excellent potential as a seroepidemiologic tool in both vaccinated and naturally-infected populations. PMID- 10100751 TI - The hemagglutinating action of Vibrio vulnificus metalloprotease. AB - Vibrio vulnificus protease (VVP), a 45-kDa zinc metalloprotease, consists of two functional domains: an N-terminal 35-kDa polypeptide having endoproteinase activity, and a C-terminal 10-kDa polypeptide that mediates the binding of VVP to the erythrocyte membrane. Therefore, VVP, but not its N-terminal endoproteinase domain alone, has agglutinating activity to rabbit erythrocytes. When a single zinc atom in the catalytic center was substituted by treatment with CuCl2 or NiCl2, proteolytic and hemagglutinating activities were reduced by Ni substitution but not by Cu substitution. Cu-treated 35-kDa polypeptide showed sufficient affinity of the catalytic center and weak binding ability to the erythrocyte membrane, but the Ni-treated polypeptide did not. These results suggest that the binding of endoproteinase domain to membrane is also necessary for hemagglutination. PMID- 10100752 TI - Expression of lymphotoxin gene inserted into Theiler's murine encephalomyelitis virus. AB - Theiler's murine encephalomyelitis virus (TMEV) belongs to the Picornaviridae genus. DA subgroup strains of this virus induce early, non-fatal polioencephalomyelitis followed by demyelination in the spinal cord, with virus persistence. We investigated the use of DA strain as a vector for the introduction of a foreign gene into the central nervous system. Human lymphotoxin (LT) gene was inserted in the L region, the most upstream part of the polyprotein coding region of DA genome. Expression of LT was demonstrated by an immunoblot and an enzyme-linked immunosorbent assay on BHK-21 cells that were infected with the recombinant virus. In addition, the expressed LT showed cytotoxicity against L-929 cells. PMID- 10100753 TI - Protective immunity induced by vaccination with SAG1 gene-transfected cells against Toxoplasma gondii-infection in mice. AB - To develop a vaccine by augmenting the protective cellular immunity against Toxoplasma gondii (T. gondii)-infection, T gondii SAG1 gene-transfectants were established by using RMA.S (H-2b), a murine transporter associated with the antigen processing (TAP) molecule-deficient lymphoma line, as a host antigen presenting cell (APC). Immunization of C57BL/6 mice with the SAG1-transfected RMA.S induced CD8+ cytotoxic T lymphocytes (CTL) specific for not only SAG1 transfected RMA.S but also T gondii-infected RMA.S, and elicited protective responses to infection with a virulent T. gondii strain, RH. PMID- 10100754 TI - Comparison of T-cell receptor Jbeta gene usage in spleen cells of different mouse strains. AB - To elucidate whether T-cell receptor Jbeta gene usage was affected by major histocompatibility complex haplotypes and other genetic backgrounds, we investigated such usage with Jbeta-specific probes in four different mouse strains. As a result, (a) frequent usage of Jbeta2.1 and Jbeta2.6, (b) infrequent usage of Jbeta1.3, Jbeta1.5 and Jbeta1.6, and (c) predominant usage of the Jbeta2 cluster compared to the Jbeta1 cluster were found. Importantly, these biases were common to almost all the tested Vbeta families of the four strains. Thus, TCR Jbeta usage would be independent of the major histocompatibility complex haplotypes and other genetic backgrounds. PMID- 10100755 TI - Specific inhibition of breast cancer cells by antisense poly-DNP oligoribonucleotides and targeted apoptosis. AB - Two membrane-permeable and RNase-resistant antisense poly-2'-O-(2,4 dinitrophenyl)-oligoribonucleotides (poly-DNP-RNAs) have been synthesized as inhibitors of human breast cancer, with nucleotide sequences complementary to the genes of RIalpha subunit of protein kinase A (RIalpha/PKA) and erbB-2, respectively. Both compounds inhibit the proliferation of SK-Br-3 breast cancer cells in culture above the concentration of 10 microg/ml, but have no effect on nontumorigenic MCF-10A breast cells. These antisense inhibitors also block the cell colony formation in methylcellulose medium, whereas the control poly-DNP-RNA with either random or sense sequence has no effect. RT-PCR data show that the antisense inhibition decreases the concentration of the mRNA. TdT-mediated dUTP nick-end labeling (TUNEL) fluorescence assay indicates that the targeted antisense inhibition by poly-DNP-RNAs leads to apoptosis of SK-Br-3 cells but does not affect nontumorigenic MCF-10A cells. The control poly-DNP-RNAs with random or sense nucleotide sequence are completely inactive. PMID- 10100756 TI - Enhanced levels of oleate-dependent and Arf-dependent phospholipase D isoforms in experimental colon cancer. AB - Phospholipase D (PLD) (EC 3.1.4.4) is one of the intracellar signal transduction enzymes and plays an important role in a variety of cellular functions. In order to clarify the role of PLD in proliferation and tumorigenesis of colon cancer, we investigated the activities of oleate-dependent and ADP-ribosylation factor (Arf) dependent types of PLD in experimental colon cancer of the rat. We produced colon cancer in Wistar rats by injecting the carcinogen, dimethylhydrazine dihydrochloride (DMH). The control rats were injected with physiological saline. Mucosal scrapings from the colon were homogenized and centrifuged to obtain the microsomal or membrane fraction. We measured the two types of PLD activities in these fractions using the transphosphatidylation reaction. Both oleate-dependent and Arf-dependent PLD activities were significantly higher in the colon cancer tissue than normal colonic mucosa. The mean specific activity of oleate-dependent PLD) in colon cancers was 1.66 +/- 0.75 (SD) nmol/min/mg whereas the value for normal colonic mucosa was 0.18 +/- 0.09 nmol/min/mg (P < 0.01; Mann-Whitney U test). On the other hand, the mean specific activity of Arf-dependent PLD in colon cancers was 76.36 +/- 29.37 pmol/min/mg whereas the value for normal colonic mucosa was 19.90 +/- 11.97 pmol/min/mg (P < 0.01; Mann-Whitney U-test). These results suggest that PLD is implicated in the proliferation and tumorigenesis of colon cancer. The present study provides the first evidence for the enhanced levels of two types of PLD in colon cancer and raises the possibility that these PLDs can be used as the potential target for the treatment of colon cancer. PMID- 10100757 TI - Expression of mucin genes and carbohydrate epitopes in 19 human colon carcinoma cell lines. AB - The levels of mRNA corresponding to the MUC1, MUC2, MUC5AC, MUC5B, and MUC6 genes were determined in 19 human colon adenocarcinoma cell lines by the reverse transcriptase-polymerase chain reaction method using specific primers in an attempt to correlate to the levels of cell surface carbohydrate epitopes. All 19 cell lines expressed MUC1 and MUC5B mRNA, whereas MUC2, MUC5AC, or MUC6 mRNA were only detected in 8, 3, or 2 of 19 cell lines, respectively. Sialyl Lewis a carbohydrates, identified by the monoclonal antibody (mAb) CA19-9, and sialyl Lewis X carbohydrates. identified by mAb KM93, were observed, with most of the cell lines expressing multiple mucin core polypeptide genes but with few cell lines expressing only MUC1 and MUC5B. Sialyl Tn epitopes identified by mAb B195.3R11 and by mAb TKH-2 were strongly expressed on both of two MUC6-positive cells, whereas only a small portion of MUC6-negative cells expressed these epitopes. Strict correlation between mucin gene expression and any carbohydrate epitopes examined was not observed. PMID- 10100758 TI - Microsatellite alterations at chromosomes 9p, 13q, and 17p in nonmuscle-invasive transitional cell carcinomas of the urinary bladder. AB - The clinical behavior of bladder cancer is difficult to predict and prognostic markers applicable to routinely processed tumor specimens clearly are needed. We screened 40 primary Ta and T1 bladder cancers for microsatellite alterations at 9p, 13q, and 17p with PCR, using nine polymorphic microsatellite markers. DNA was prepared after microdissection of paraffin-embedded transurethral resection specimens. PCR products were separated on sequencing gels, and allelic loss as well as band shifts was assessed by comparing alleles of control and tumor tissue. The results were correlated with grade, stage, and clinically documented tumor recurrence. Overall, allelic loss at 9p, 13q, and 17p was present in 35.1%, 25%, and 27.5% of cases, respectively. Whereas the frequency of allelic loss at 9p was nearly equally distributed throughout all tumor grades and stages, the occurrence of allelic loss at 13q and 17p correlated statistically significantly with higher grades and stage. Band shifts were observed in three cases. Of the 40 patients, 16 had tumor recurrence during a follow-up period of 3-49 months (median, 23 months). Kaplan-Meier analysis did not show any statistically significant correlation between allelic loss at either locus and tumor recurrence. The results confirm the role of alterations at 13q and 17p in the progression of bladder cancer. Allelic loss at 9p seems to be an early event in tumor development. However, the detection of alterations at the three chromosomal loci studied did not have any prognostic value regarding tumor recurrence in this group of patients. PMID- 10100759 TI - Microsatellite instability is infrequent in sporadic adult gliomas. AB - Microsatellite instability (MSI) is a form of genomic instability in tumors that may reflect mechanisms underlying carcinogenesis. Assessment of MSI in various types of sporadic tumors is therefore relevant to an understanding of molecular pathogenesis. In the case of sporadic adult gliomas, destabilization of mononucleotide, dinucleotide, and longer repeat sequences has been reported in high-grade tumors, though published estimates of the frequency of MSI vary widely. In the present work, we quantitated the frequency of length alterations at three microsatellite loci in 26 glioma/normal tissue pairs and at nine additional loci in 16 of the pairs. We analyzed di- and tetranucleotide markers, including five previously reported to be unstable in gliomas. and examined mostly high-grade tumors, both diploid and aneuploid. A large proportion of the tumor and normal brain specimens had no detectable activity of the DNA repair protein O6-methylguanine-DNA methyltransferase, a prevalent phenotypic trait in these tissues that we thought might be associated with MSI. We observed no length alterations in 222 sequence analyses, and estimate the frequency of MSI in our tumor sample as < 0.45% unstable sequences among all sequences examined, or < 3.9% gliomas with unstable sequences. We conclude that microsatellite length alterations are infrequent in our tumor population, and interpret currently available literature to indicate that the frequency of MSI is low in sporadic adult gliomas. PMID- 10100760 TI - Concentrations of the flame retardant 2,2',4,4'-tetrabrominated diphenyl ether in human adipose tissue in Swedish persons and the risk for non-Hodgkin's lymphoma. AB - Concentrations of the flame retardant 2,2',4,4'-tetrabrominated diphenyl ether (2,2',4,4'-TeBDE) in the adipose tissue of 77 individuals from Sweden were determined. The subjects were recruited during the time period 1995-97 and encompassed both men and women ranging from 28 to 85 years in age. Of the subjects included, 19 patients had non-Hodgkin's lymphoma (NHL), 23 patients had malignant melanoma, 8 patients had other cancers or in situ changes, and 27 persons had no cancer diagnosis. The mean concentration of 2,2',4,4'-TeBDE was 5.1 ng/g lipid (range 0.6-27.5) for the 27 persons without malignancies. For NHL patients the mean concentration was 13.0 ng/g lipid (range 1.0-98.2). A nonsignificantly elevated risk with dose response was found for NHL when the cases and controls were compared in the two highest concentration groups (2.05-< 5.43 ng/g lipid and > or = 5.43 ng/g lipid) with the lowest group (< 2.05 ng/g lipid) yielding odds ratio (OR) 1.9 with 95% confidence interval (CI) 0.3-14 and OR 3.8, CI 0.7-26, respectively. The results for the patients with malignant melanoma did not differ from the controls. PMID- 10100761 TI - Evaluation of a technique to occlude the internal carotid artery of horses. AB - OBJECTIVE: To evaluate an occlusion technique for the internal carotid artery of horses using an intravascular, detachable, self-sealing, latex balloon distally and ligatures proximally. STUDY DESIGN: Experimental study. ANIMALS: Six healthy adult horses. METHODS: In each horse, the left internal carotid artery was occluded by placement of an intravascular, detachable, self-sealing, latex balloon distally and two ligatures proximally. Radiographs were taken on days 2, 5, 10, and 30 after surgery to evaluate balloon inflation and position. Endoscopic examination of the left guttural pouch was performed 10 days after surgery to evaluate the integrity of the internal carotid artery and surrounding tissues. At 30 days, the left and right, common, internal, and external carotid arteries were examined grossly and then processed for histologic evaluation. RESULTS: Immediate and long-term occlusion of the left internal carotid artery was achieved in all horses. The surgical procedure was technically straightforward and no intraoperative or postoperative complications were encountered. The balloons remained inflated and in their original position throughout the study. Maturing to mature, organized thrombi were present in the left internal carotid artery in all horses at 30 days. The cerebral arterial circle and common carotid artery were patent at their junctions with the internal carotid artery in all horses. CONCLUSIONS: Use of an intravascular, detachable, self-sealing, latex balloon distally and ligatures proximally is an effective technique for occluding the internal carotid artery of horses. CLINICAL RELEVANCE: This technique may be useful for prevention of fatal hemorrhage in horses with lesions of the internal carotid artery. PMID- 10100762 TI - Surgical treatment of degenerative lumbosacral stenosis in dogs. AB - OBJECTIVE: To study the epidemiology, clinical findings, and long-term outcome of surgical treatment of degenerative lumbosacral stenosis (DLSS) in dogs. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: 131 client-owned dogs with DLSS. METHODS: The medical records of dogs with DLSS treated by dorsal laminectomy and dorsal fenestration were reviewed. The clinical diagnosis had been verified by diskography, epidurography or myelography, or a combination thereof. RESULTS: The German shepherd breed was over-represented (56.5%), and males were more often affected than females (2:1). Historically, reluctance or pain when jumping, rising from a prone position, or climbing stairs (92.4%) and signs of pain or stiffness during extensive physical activity (85.5%) were the most frequent concerns. The most common physical and neurologic examination findings were pain in the lumbosacral area during hyperextension (97.7%) and on direct digital palpation (84.7%). A total of 93.2% of the dogs were improved clinically within the follow-up period (mean 26 +/- 17 months). Recurrence of clinical signs resembling DLSS was reported by the owner or diagnosed by clinical examination in 17.6% of the dogs with a mean onset of signs at 18 +/- 13 months postoperatively. CONCLUSIONS: Surgical treatment of DLSS with dorsal laminectomy and fenestration generally resulted in good to excellent clinical outcome. PMID- 10100763 TI - Desmotomy of the accessory ligament of the superficial digital flexor tendon in the horse with use of a tenoscopic approach to the carpal sheath. AB - OBJECTIVE: To describe a tenoscopic approach to the carpal sheath for desmotomy of the accessory ligament of the superficial digital flexor tendon. STUDY DESIGN: The surgical procedure was developed with use of normal forelimbs from equine cadavers and experimental horses. ANIMALS OR SAMPLE POPULATION: Twelve equine cadaveric forelimbs, 4 forelimbs from 2 horses anesthetized for terminal surgical laboratories, and 10 forelimbs from five experimental horses were used. METHODS: The limbs were positioned lateral side up with the carpus slightly flexed. After distention of the carpal sheath, a portal was made approximately 2 cm proximal to the distal radial physis for arthroscope insertion. An instrument portal was made approximately 0.2 cm proximal to the distal radial physis. After flexion of the limb to 90 degrees, the accessory ligament of the superficial digital flexor tendon was palpated and desmotomy was performed. Cadaveric limbs were dissected to confirm complete desmotomy. Experimental horses were monitored for short- (perioperative) and long- (4 weeks) term postoperative complications. RESULTS: A tenoscopic approach to the carpal sheath provided adequate surgical access to the accessory ligament of the superficial digital flexor tendon for desmotomy. Most of the accessory ligament of the superficial digital flexor tendon could be easily seen within the sheath, except for the proximal 2 cm that could be readily palpated and subsequently transected. Important technical considerations were location of the arthroscope portal, adequate sheath distention, limb flexion to 90 degrees, and desmotomy location. It was beneficial, but apparently not essential, to avoid the proximal perforating vessel. Postoperatively, some horses had swelling but were not lame and had normal range of motion of the carpus. CONCLUSIONS: Desmotomy of the accessory ligament of the superficial digital flexor tendon could be performed by using a lateral tenoscopic approach to the carpal sheath. CLINICAL RELEVANCE: Desmotomy of the accessory ligament of the superficial digital flexor tendon by using a tenoscopic approach to the carpal sheath is an alternative technique to the medial incisional approach. PMID- 10100764 TI - Bilateral laparoscopic ovariectomy in standing mares: 22 cases. AB - OBJECTIVE: To describe a technique for laparoscopic bilateral ovariectomy in standing mares and report the outcome of 22 clinical cases. STUDY DESIGN: Prospective study. ANIMALS OR SAMPLE POPULATION: A total of 22 mares between 4 and 23 years of age, weighing between 360 and 600 kg. METHODS: Mares with normal ovaries, as determined by palpation per rectum, were restrained in standing stocks and sedated with detomidine (0.01 to 0.02 mg/kg intravenously [i.v.]) and butorphanol (0.01 to 0.02 mg/kg i.v.). The laparoscope and instrument insertion sites were infiltrated with 2% lidocaine before incision. One laparoscope portal and two instrument portals were located in each paralumbar fossa. Ovariectomy was accomplished by intracorporeal dissection and ligation of the ovarian pedicles. The two instrument portals in each flank were ultimately connected resulting in a 4 to 5 cm laparotomy to facilitate ovarian removal. RESULTS: No major operative or postoperative complications occurred. Minor complications included incomplete hemostasis of an ovarian pedicle with a single ligature (three mares), transient inappetence, pyrexia and incisional infection. Owner satisfaction and cosmetic results were considered excellent. CONCLUSIONS: Standing laparoscopic ovariectomy appears to eliminate many of the potential complications associated with traditional surgical methods for ovariectomy and avoids the risk of general anesthesia. CLINICAL RELEVANCE: This technique requires minimal laparoscopic instrumentation and will provide surgeons with an alternative approach for bilateral ovariectomy in mares. PMID- 10100765 TI - Standing surgical repair of cystorrhexis in two mares. AB - Two surgical techniques were used to evert the bladder into the vagina for observation and repair of bladder tears that were associated with parturition. One technique involved an incision through the vaginal floor into the peritoneal cavity just caudal to the cervix, and prolapse of the bladder into the vagina. The second technique involved a 3-cm incision through the urethra, 5 cm cranial to the urethral orifice, and digital exploration of the tear and finger traction to evert the bladder through the urethral incision. In both mares, the bladder defects were repaired in two layers, with use of 2-0 polyglycolic acid in a simple continuous pattern. After repositioning, the vaginal and urethral incisions were closed in single layers using absorbable suture material. A standing vaginal approach eliminates the need for general anesthesia and allows excellent observation and repair of bladder tears in adult mares. PMID- 10100766 TI - A stress-radiographic method to evaluate dogs for passive hip laxity. PMID- 10100767 TI - Determination of the minimum alveolar concentration of isoflurane in llamas. AB - OBJECTIVE: To determine the minimum alveolar concentration (MAC) of isoflurane (ISO) in llamas. STUDY DESIGN: Prospective study. ANIMALS: Eight adult neutered male llamas (9 +/- 1 years [x +/- SD], 177 +/- 29 kg). METHODS: Anesthesia was induced and maintained in otherwise unmedicated llamas with a mixture of ISO in oxygen administered through a standard small-animal, semi-closed circle system using an out-of-circle, agent-specific vaporizer. The time from mask placement to intubation was recorded. Inspired and end-tidal (ET) ISO was sampled continuously. At each anesthetic concentration, a constant ET ISO was maintained for at least 20 minutes before application of a noxious electrical stimulus (50 volts, 5 Hz, 10 ms for up to 1 minute). A positive or negative response to the stimulus was recorded, and ET ISO then increased (if positive response) or decreased (if negative response) by 10% to 20%. Individual MAC was the average of multiple determinations. Body temperature was maintained at 37 +/- 1 degrees C. Selected cardiopulmonary variables (heart rate [HR], respiratory rate [RR], arterial blood pressure [ABP]) and ET ISO were recorded at hourly intervals from first ISO. Arterial blood was collected for pH, PCO2, PO2 analysis and measurement of packed cell volume (PCV) and total protein (TP) at 2 hour intervals. Following MAC determination, the anesthetic was discontinued and llamas were allowed to recover. Duration and quality of recovery were noted. RESULTS: The time from start of induction by mask to completion of intubation took 19.1 +/- 4.8 minutes. The MAC of ISO corrected to one atmosphere at sea level (barometric pressure 760 mm Hg) in these llamas was 1.05 +/- 0.17%. Mean ABP increased from 70 +/- 26 mm Hg at the end of the first hour of anesthesia to 102 +/- 7 mm Hg measured at the end of the sixth hour of anesthesia. ET ISO decreased from 2.06 +/- 0.10% to 1.27 +/- 0.07% over the same time period, but MAC did not change with time. The duration from first ISO to discontinuation of ISO averaged 6.19 +/- 0.9 hours. Animals were able to support their heads in a sternal posture at 23 +/- 10 minutes, and stood 62 +/- 26 minutes following discontinuation of the anesthetic. CONCLUSION: The MAC for ISO is similar to, but slightly lower than, values reported for other species. CLINICAL RELEVANCE: Knowledge of MAC may facilitate appropriate clinical use and provide the basis for future investigation of ISO in llamas. PMID- 10100768 TI - The epidemiology of syphilis in the waning years of an epidemic: Houston, Texas, 1991-1997. AB - BACKGROUND: National and local syphilis rates have fallen since 1990. Accurate epidemiologic information about the distribution of syphilis during the waning years of an epidemic are important to health care organizations so that they can specifically target screening and intervention programs. GOALS: To describe the epidemiology of syphilis in Houston, Texas, from 1991 through 1997. STUDY DESIGN: Descriptive evaluation of morbidity surveillance data from the Houston Department of Health and Human Services. RESULTS: Between 1991 and 1997, rates for syphilis fell 61%. Rates for primary and secondary syphilis fell 90% among men and women in all race/ethnicity groups; early latent rates fell 81% among blacks, 57% among Hispanics, and 50% among whites. Late latent rates were stable among blacks and whites and increased among Hispanics. The proportion of total cases identified as late latent disease increased from 16% in 1991 to 63% in 1997. Congenital syphilis rates have remained at approximately 2 per 1,000 live births since 1993. CONCLUSION: Syphilis continues to be a problem in Houston. The medical community and HIV/STD prevention programs need to be vigilant in actively screening high risk individuals to identify syphilis at earlier stages of the disease and to prevent congenital syphilis. PMID- 10100769 TI - Prospective study of barrier contraception for the prevention of sexually transmitted diseases: study design and general characteristics of the study group. AB - BACKGROUND AND OBJECTIVES: The AIDS epidemic has brought barrier contraceptives to the forefront of public health research. A comprehensive evaluation of the efficacy of barrier contraceptive use in preventing sexually transmitted diseases (STDs), including AIDS, is necessary to inform both potential users and public health policy makers. This study was undertaken to evaluate the efficacy of condoms and vaginal spermicide products, used alone or in combination, in preventing gonorrhea and chlamydia among women attending an STD clinic. GOAL OF THIS STUDY: To describe the general characteristics of the study group and its follow-up experience. STUDY DESIGN: Women who met the eligibility criteria were invited to participate. The initial visit included an interview, a behavioral intervention promoting barrier methods, a physical examination, and instructions to complete a sexual diary. Participants received free barrier contraceptives and returned for six monthly follow-up visits. DESIGN RESULTS: Participants (n = 1,122) were low income, single (74%) black (89%) women with a median age of 24. The behavioral intervention led to the use of barrier protection in more than 70% of reported acts of vaginal intercourse. Barriers were used consistently (100% of sexual acts) during 51% of the months of follow-up. A total of 148 cases of gonorrhea (28 per 1,000 months) and 122 cases of chlamydia infection (23 cases per 1,000 months) were diagnosed during follow-up. CONCLUSION: This study represents a practical solution to a complex set of design considerations. The study protocol was successful in promoting consistent and proper use of barrier methods. PMID- 10100770 TI - Comparison of once-daily and twice-daily dosing of 0.75% metronidazole gel in the treatment of bacterial vaginosis. AB - BACKGROUND AND OBJECTIVES: Bacterial vaginosis is the most common cause of vaginal symptoms in women and has potential complications. Efforts to improve treatment of this disease process are warranted. GOAL OF THIS STUDY: The goal of this study was to compare the safety and efficacy of once-daily intravaginal administration of 0.75% metronidazole gel for 5 days to the established twice daily regimen in the treatment of bacterial vaginosis. STUDY DESIGN: Nonpregnant women with bacterial vaginosis diagnosed by accepted clinical criteria at 14 geographically diverse general gynecology clinics were enrolled in this prospective, randomized, investigator-blind, parallel study. They were treated with either once-daily or twice-daily 0.75% metronidazole gel 5 g intravaginally for 5 days and were reevaluated at 7 to 12 days and 28 to 35 days after completing treatment. Efficacy was determined by clinical criteria. Adverse drug reactions were monitored. RESULTS: Of the 514 evaluable women enrolled, bacterial vaginosis was cured at the first return visit among evaluable patients in 153 of 199 (77%) of those who received the once-daily and in 157 of 196 (80%) of those who received the twice-daily administration. Bacterial vaginosis was cured among evaluable patients at the final visit in 104 of 180 (58%) of those who received once-daily and 109 of 178 (61%) of those who received the twice-daily regimen. Intent-to-treat analysis showed cure at 1 month in 118 of 207 (57%) of those treated once daily and 129 of 209 (62%) of those treated twice daily. Side effects were mild, and none caused treatment discontinuation. CONCLUSIONS: Once daily dosing of 0.75% metronidazole gel 5 g for 5 days yields efficacy, safety, and tolerance equivalent to the currently used twice-daily dosing in the treatment of bacterial vaginosis, adding another competitive choice to the available therapeutic options for this condition. PMID- 10100771 TI - Lower genital tract infections among HIV-infected and high-risk uninfected women: findings of the Women's Interagency HIV Study (WIHS). AB - BACKGROUND AND OBJECTIVES: Few comparisons of factors associated with sexually transmitted diseases (STDs) and HIV are available for representative samples of American women. GOAL OF THE STUDY: To compare factors associated with STDs in a large sample of women infected with HIV and women not infected with HIV. STUDY DESIGN: A cross-sectional analysis of STDs in 2,058 women seropositive (HIV+) for HIV and 567 women seronegative (HIV-) for HIV. RESULTS: HIV + women were more likely than HIV- women to report previous STDs, with the exceptions of chlamydia and bacterial vaginosis. Both HIV status and CD4 lymphocyte count were associated with evidence of genital ulcerations, warts, and vaginal candidiasis (p <0.001 for all). HIV- women were more apt to report recent vaginal intercourse (p <0.001), a factor that was independently associated with the occurrence of bacterial and protozoan infections. CD4 lymphocyte depletion was the factor most closely associated with the expression of chronic viral infections. CONCLUSIONS: In this North American cohort, HIV+ women were more likely than HIV- women to report previous genital tract infections and symptoms. However, the HIV+ women reported less recent sexual activity and few gonococcal or chlamydial infections. PMID- 10100772 TI - STD syndrome packets: improving syndromic management of sexually transmitted diseases in developing countries. AB - OBJECTIVE: To design, introduce, and evaluate "STD syndrome packets" containing recommended drugs for each syndrome, four condoms, a partner treatment card, and a patient information leaflet, with the goal of improving sexually transmitted disease (STD) case management. METHODS: Packet design evolved around available packaging technology, informed by pilot testing with nurses working in primary care clinics, doctors in private medical practices, and patients with an STD, in Hlabisa, South Africa. Evaluation 1 year later included analysis of distribution records and interviews with 16 nurses and 64 patients. RESULTS: A cheap packet (2 U. S. cents each, excluding contents) compatible with current legislation was designed and introduced to six public sector clinics and as a short pilot to five private medical practices. Four thousand eighty-five packets were distributed to the clinics, equivalent to approximately 115% of the STDs reported over that period. All 16 nurses reported using the packets, but only 63% did so all the time because of occasional supply problems. All believed the packets improved treatment by saving time (75%), improving supply of condoms and partner cards (44%), and making treatment easier (56%). Patients also responded positively, and most said they would buy a packet (up to $5) at a pharmacy (84%) or store (63%) if available. CONCLUSIONS: The STD syndrome packets have the potential to improve STD syndromic management by standardizing therapy and improving the supply of condoms, partner cards, and information leaflets. Packets are popular with practitioners and patients, but consistent supply is essential for maximal impact. There may be scope for social marketing of the packets, which could further increase use. PMID- 10100773 TI - Conjugal transfer of the 3.05 beta-lactamase plasmid by the 25.2 Mda plasmid in Neisseria gonorrhoeae. PMID- 10100774 TI - Gonococcal infection of human fallopian tube mucosa in organ culture: relationship of mucosal tissue TNF-alpha concentration to sloughing of ciliated cells. AB - BACKGROUND AND OBJECTIVES: An experimental model consisting of gonococcal infection of human fallopian tube mucosa in organ culture has proven useful in studying the molecular pathogenesis of acute gonococcal salpingitis and postsalpingitis sequelae. Gonococcal infection of human fallopian tube mucosa in organ culture results in the sloughing of ciliated epithelial cells from the mucosa. This damage to the mucosa can be quantified on fallopian tube pieces by an assay of the percent of the periphery that has ciliary activity (PPCA) remaining at specific time points after infection. Although assay of the PPCA has been quite valuable, it is labor-intensive, somewhat subjective, and requires that the observers have training and experience. A more practical assay for genital mucosal damage is desirable for further investigations that employ the fallopian tube experimental model. Gonococcal infection of fallopian tube mucosa in organ culture also results in the production of easily quantified tumor necrosis factor-alpha (TNF-alpha) by the mucosa. Furthermore, treatment of the organ cultures with recombinant human TNF-alpha (rHuTNFalpha) alone also causes sloughing of ciliated cells from the mucosa. These findings strongly suggest that TNF-alpha is a mediator of the mucosal damage that attends gonococcal infection. GOALS OF THE STUDY: To determine: (1) whether the PPCA values and the TNF-alpha concentrations in fallopian tube mucosal tissues correlate closely enough to allow prediction of the PPCA from a measurement of the mucosal tissue TNF-alpha concentration; and (2) whether the correlation of the TNF-alpha mucosal tissue concentration with the sloughing of ciliated cells (measured by the PPCA) supports the hypothesis that induction of TNF-alpha by gonococcal infection, with resultant sloughing of ciliated cells, is likely to be a major pathogenic mechanism of gonococcal salpingitis and might mediate postsalpingitis infertility and ectopic pregnancy. STUDY DESIGN: A metaanalysis was performed on studies from three research groups (two laboratories in the United States and one in the United Kingdom, using identical techniques for quantifying the PPCA, TNF-alpha, or both. RESULTS: There was a close and statistically significant correlation between the TNF-alpha mucosal tissue concentration and the proportion of ciliated cells lost from the mucosa as measured by the PPCA (r = 0.95, p < 0.001). Therefore, as the mucosal tissue concentration of endogenous TNF-alpha increased, the loss of ciliated cells from the epithelium increased proportionately. CONCLUSIONS: During gonococcal infection of human fallopian tube mucosa in organ culture, the mucosal tissue concentration of TNF-alpha can be used to predict the PPCA, and therefore, the extent of mucosal damage. This finding should facilitate studies of the molecular pathogenesis of infectious diseases involving human genital mucosa. Further, the close correlation of mucosal TNF-alpha concentration with genital mucosal damage, evaluated by the PPCA, supports the hypothesis that induction of the proinflammatory cytokine, TNF-alpha, by gonococcal infection, with resultant inflammation and sloughing of ciliated cells, is an important pathogenic mechanism of gonococcal salpingitis and may mediate postsalpingitis infertility and ectopic pregnancy as well. PMID- 10100775 TI - Forgetting as a cause of incomplete reporting of sexual and drug injection partners. AB - BACKGROUND AND OBJECTIVES: Partner notification and social network studies of infectious disease often involve interviewing people to elicit their sexual and/or drug injection partners. Incomplete reporting of partners in these contexts would significantly hamper efforts to understand and control the spread of sexually transmitted diseases, HIV, and other infections. There are many reasons why individuals might not name their partners in interviews. This study provides a comprehensive assessment of forgetting as a cause of incomplete reporting of sexual and injection partners. STUDY DESIGN: One hundred fifty-six persons in Seattle, Washington, at presumed high risk for HIV recalled their sexual and/or injection partners in two interviews separated by 1 week or 3 months. RESULTS: Repeated, nonspecific prompting elicited, on average, 10% of all partners recalled in an interview. Subjects displayed substantial forgetting of partners across partner types, recall periods, and four independent measurement approaches, with up to 72% of partners forgotten. The number of partners recalled and subjective assessment of forgetting are moderate to good predictors of the number of partners forgotten. Recalled and forgotten partners do not differ dramatically on any of several partner variables. CONCLUSIONS: Forgetting is a primary factor in the incomplete reporting of sexual and injection partners. Interviewers should prompt repeatedly to maximize recall of partners. Reinterviewing is currently the best method available for identifying partners as completely as possible and should be focused on individuals who report many partners and/or sense they have other partners they cannot recall. PMID- 10100776 TI - Protective effect of a thermoreversible gel against the toxicity of nonoxynol-9. AB - BACKGROUND AND OBJECTIVES: One major problem associated with the use of nonoxynol 9 is that it can induce local inflammation and ulceration of the vaginal and cervical mucosa that might favor the entry of pathogens. With the aim of developing a gel formulation that could be effective in preventing sexually transmitted infections, the authors have evaluated the capacity of a polyoxypropylene/polyoxyethylene polymer to reduce or eliminate the toxicity of nonoxynol-9. STUDY DESIGN: The cytotoxicity of nonoxynol-9 alone or incorporated into the gel was investigated in human cervical and colon epithelial cells and after daily intravaginal application for 2 weeks in rabbits. RESULTS: In vitro experiments showed that nonoxynol-9 was highly toxic to human cervical and colon epithelial cells in a dose-dependent manner. However, the incorporation of the spermicide into the gel markedly reduced its toxicity under the same experimental conditions. In vivo studies showed that in animals treated with nonoxynol-9, the spermicide was very toxic to the vaginal and cervical mucosa as evidenced by the presence of bleeding, irritation, epithelial disruption, necrosis, the accumulation of leukocytes in the submucosa, and the loss of integrity of the epithelial cells. Of prime importance, the incorporation of nonoxynol-9 into the gel markedly reduced the toxicity of this potent spermicide/microbicide. CONCLUSION: The gel formulation could be used as an interesting approach to eliminate the toxicity of potent spermicides/microbicides such as nonoxynol-9. PMID- 10100777 TI - Assessment of health services for treatment of sexually transmitted infections among Nigerian adolescents. AB - BACKGROUND: The available evidence indicates that Nigerian adolescents use various health practitioners for the treatment of sexually transmitted diseases (STDs). However, the quality of the STD treatment used by adolescents has not been investigated previously. GOAL OF THIS STUDY: To investigate the quality of services provided by health practitioners for the treatment and prevention of STDs among adolescents in Benin City, Nigeria. STUDY DESIGN: In-depth interviews were conducted with 48 formal and informal sector health practitioners who were identified by key informants as being the main providers of STD treatment in the city. Their facilities were visited to evaluate the quality of services they provide for STD treatment. RESULTS: Health providers in the informal sector showed inadequate knowledge of the appropriate treatment methods for STDs. Although providers in the formal sector had better knowledge, they lacked appropriate management guidelines and were poorly oriented to the problems of STDs in adolescents. There was consensus among the health providers that adolescents most frequently use informal treatment for STDs. Nevertheless, among all providers, there was evidence of inadequate counseling of adolescents, a poor attitude toward the promotion of condom use, and inadequate use of referral opportunities. CONCLUSIONS: Comprehensive public health measures are needed to address these problems in Nigeria. These include the provision of reproductive health education for adolescents, the retraining of health providers, and the consolidation of services for the prevention and treatment of STDs. PMID- 10100778 TI - Laparoscopic management of complicated gallstone disease. PMID- 10100779 TI - Necrotizing pancreatitis. PMID- 10100780 TI - Risk scoring in surgical patients. AB - BACKGROUND: A large number of scoring systems for assessing a patient's risk of complications or death has been developed over recent years. This is a review of those that are of relevance to general surgeons. METHODS: A Medline literature search was performed to identify all articles concerning 'severity of illness', 'morbidity', 'mortality' and 'postoperative complications' in the field of surgery from 1966 to 1997. Further searches were performed to find papers about specific identified scoring systems, and relevant articles from the reference lists of these were also sought. RESULTS AND CONCLUSION: The advantages of an accurate assessment of a patient's risk include, on an individual level, the opportunity to give a more accurate prognosis and choose the most appropriate treatment. If the risk of an adverse outcome is known for a group of patients, the actual outcome can be compared with the predicted outcome, and comparison can be made between groups in different surgical units for the purposes of audit or research. The Physiological and Operative Severity Score for enUmeration of Mortality and morbidity (POSSUM) is the most appropriate of the currently available scores for general surgical practice. PMID- 10100781 TI - Treatment of colorectal liver metastases. AB - BACKGROUND: Surgical resection is the only potentially curative treatment for colorectal liver metastases, with 5-year survival rates approaching 40 per cent. However, at present only 20-25 per cent of such lesions are deemed resectable. This review examines developments in neoadjuvant and adjuvant treatments of colorectal liver metastases that aim to improve the results of surgical management of this disease. METHODS: A literature review was undertaken based on a Medline search from 1970 to May 1998. RESULTS: Further evolution in surgical technique is unlikely to lead to a dramatic increase in the resectability rate of colorectal liver metastases. Recent developments in neoadjuvant and adjuvant chemotherapy schedules, together with a range of interventional radiological procedures and interstitial lytic techniques, show promise in terms of extending the limits of resectability and decreasing recurrence rates associated with these lesions. Using multimodality regimens 5-year survival rates of 40 per cent are now being reported for lesions that were initially considered irresectable. CONCLUSION: Patients with colorectal liver metastases should be assessed in units that can offer all the specialist techniques necessary to deliver optimum care. Incorporation of newer neoadjuvant and adjuvant treatments into management strategies should occur in the setting of randomized trials. PMID- 10100782 TI - Cytolysis following chemoembolization for hepatocellular carcinoma. AB - BACKGROUND: Lipiodolized chemoembolization of hepatocellular carcinoma (HCC) can induce fever and cytolysis, defined as an increase in serum levels of liver transaminases, which is frequently assumed to result from tumour necrosis. This study aimed to assess the causes of this syndrome, reviewing preoperative data, intraoperative findings, tumour necrosis and the status of non-tumorous liver. METHODS: A retrospective study was undertaken of 29 patients treated by neoadjuvant lipiodolized chemoembolization before surgical resection of HCC. Tumour necrosis was assessed in the resected specimen and scored in four stages: absent, 50 per cent or less, more than 50 per cent, and complete. The status of non-tumorous liver parenchyma was classified as either fibrotic or cirrhotic. RESULTS: Cytolysis occurred following chemoembolization in 16 patients and was associated with fever in 11. Postchemoembolization cytolysis with or without fever was more likely to develop in patients with minor fibrotic changes than in those with cirrhosis (14 of 21 with fibrosis versus two of four with cirrhosis, P < 0.05). In contrast, the extent of tumour necrosis did not correlate with the occurrence of symptoms. CONCLUSION: These results suggest that fever and cytolysis following chemoembolization of HCC are an indication not of tumour necrosis but of injury to the non-tumorous liver. PMID- 10100783 TI - Value of magnetic resonance cholangiopancreatography in demonstrating major bile duct injuries following laparoscopic cholecystectomy. AB - BACKGROUND: Conventionally, recognition of bile duct injuries after laparoscopic cholecystectomy largely relies on endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC). However, these invasive procedures are not without risk. Preliminary experience with use of magnetic resonance cholangiopancreatography (MRCP) to identify these injuries is reported. METHODS: The medical records of five patients who had undergone laparoscopic cholecystectomy and had suspected major bile duct injuries were reviewed. All five patients underwent MRCP, followed by conventional cholangiography: either ERCP or PTC, or both. The findings of MRCP and conventional cholangiography were compared. RESULTS: Four patients had proven bile duct injuries. The remaining patient had gallstones dislodged into the common bile duct (CBD) during laparoscopic cholecystectomy, which presented as transient jaundice mimicking a bile duct injury. The MRCP images were of higher diagnostic value than conventional cholangiographic images in four patients with frank bile duct injury. For these patients, ERCP showed only the cut-off sign of the CBD, and PTC was needed to visualize the upper biliary system. MRCP, however, demonstrated the entire biliary system proximal and distal to the amputated or stenotic sites simultaneously. In the remaining patient with dislodged gallstones, the two techniques yielded similar diagnostic information. CONCLUSION: This preliminary study suggests that MRCP is an ideal diagnostic test whenever bile duct injury following laparoscopic cholecystectomy is suspected. PMID- 10100784 TI - Audit of methods of laparoscopic cholecystectomy. AB - BACKGROUND: The operation of laparoscopic cholecystectomy began the modern era of laparoscopic surgery. Refinements in technique continue to appear. The techniques currently favoured by British surgeons have been reviewed. METHODS: A questionnaire-based survey was carried out among surgeons with a special interest in minimal access surgery. The data collected were entered into a database and analysed. Current literature relating to surgical technique was reviewed. RESULTS: Many aspects were evaluated and the results have shown that there is no uniform approach. It is interesting that only 30.8 per cent of surgeons use the open (Hasson) technique for peritoneal access. In addition, the use of intraoperative cholangiography continues to vary, with 65.8 per cent using the technique in selected cases. Fascial repair is not undertaken by 12.2 per cent of surgeons. CONCLUSION: Some trends are clearly discernible. There is a greater willingness than previously to perform intraoperative cholangiography, but the consensus seems to be against performing it in all cases. Similarly, British surgeons seem to be largely unimpressed by the dangers of the Veress needle; the Hasson technique has not been widely adopted. The need to prevent port-site herniation seems to be generally accepted, with most surgeons performing fascial repair. PMID- 10100785 TI - Correlation between spiral computed tomography, endoscopic ultrasonography and findings at operation in pancreatic and ampullary tumours. AB - BACKGROUND: Spiral computed tomography (CT) allows high-resolution examination of the pancreas, surrounding vascular structures, lymph nodes and liver. Endoscopic ultrasonography (EUS) also allows high-resolution imaging of the pancreas and adjacent structures but is an invasive procedure. With the availability of spiral CT, the role of EUS in the investigation of patients with suspected pancreatic or ampullary tumours is unclear. METHODS: Forty-eight patients with clinical suspicion of a pancreatic or ampullary tumour underwent both spiral CT and EUS. Thirty-four patients had surgical exploration, of whom 17 underwent pancreatic resection and 17 had biliary and gastric bypass. The results of spiral CT and EUS were compared with the operative findings. RESULTS: The final histological diagnosis was ductal adenocarcinoma (24 patients), ampullary carcinoma (six), serous cystadenoma (two) and chronic pancreatitis (two). EUS demonstrated 33 and spiral CT 26 of the 34 primary lesions. EUS was particularly useful in the assessment of small resectable tumours missed by spiral CT. The sensitivity and specificity of EUS and spiral CT for detecting involvement by the tumour of the superior mesenteric vein, portal vein and lymph nodes were similar, but EUS was less effective at evaluating the superior mesenteric artery. CONCLUSION: EUS is an important additional investigation after spiral CT in patients with a suspected pancreatic or ampullary tumour. PMID- 10100786 TI - Evaluation of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose for the differentiation of chronic pancreatitis and pancreatic cancer. AB - BACKGROUND: The clinical presentation of patients with pancreatic cancer may resemble the clinical picture of chronic pancreatitis. A definitive preoperative diagnosis is not always obtained in patients with a history of chronic pancreatitis despite the use of modern imaging techniques. Operative strategy therefore remains unclear before operation in these patients. METHODS: Positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) was introduced recently into clinical oncology because of its ability to demonstrate metabolic changes associated with various disease processes. The impact of FDG PET on the differentiation of chronic pancreatitis and pancreatic cancer was investigated. FDG-PET was performed in 48 patients with chronic pancreatitis (n = 12), acute pancreatitis (n = 3) and pancreatic cancer (n = 27), and in controls (n = 6). Histological examination was undertaken in all cases except controls. The FDG-PET results were obtained without knowledge of results of other imaging procedures. The results were then compared with those of computed tomography, ultrasonography, endoscopic retrograde cholangiopancreaticography, operative findings and histology. PET images were analysed semiquantitatively by calculating a standard uptake value (SUV) 90-120 min after application of the tracer. RESULTS: Cut-off values were validated as follows: SUV greater than 4.0 for pancreatic cancer, SUV of 3.0-4.0 for chronic pancreatitis, and SUV of less than 3.0 for controls. Sensitivity and specificity of PET imaging were 0.96 and 1.0 for pancreatic cancer, and 1.0 and 0.97 for chronic pancreatitis. In five cases only FDG-PET led to the correct preoperative diagnosis. CONCLUSION: The results give further evidence that FDG-PET is an important non-invasive method for the differentiation of chronic pancreatitis and pancreatic cancer. Delayed image acquisition in the glycolysis plateau phase permits improved diagnostic performance. This imaging technique is extremely helpful before operation in patients with an otherwise unclear pancreatic mass, despite its costs. PMID- 10100787 TI - Assessment of potential donors for living related liver transplantation. AB - BACKGROUND: Living related liver transplantation has been developed as an important potential source of organs for treatment of children with acute and chronic liver disease. A single UK centre performing living related liver transplantation was established in 1993. METHODS: Parents who were potential donors for their children for living related liver transplantation were assessed for suitability according to a protocol based on one developed and published by the University of Chicago Transplant Group. Records kept by the transplant coordinators were retrieved and data were extracted. RESULTS: Of 64 potential donors for 32 potential recipients ten were excluded at a preliminary stage. Fourteen ultimately became donors. Of 54 parents who began evaluation 23 were finally considered to be suitable. There were 19 non-disease-related reasons for unsuitability: blood group mismatch (eight cases), size discrepancy (six), pregnancy (two), oral contraceptive medication (one), vascular anatomy variant (one) and age (one). Sixteen were unsuitable because disease was found, namely fatty liver (four), thyroid disease (two), hepatitis B positivity (two), cardiac murmur (one), anaemia (one), glucose-6-phosphate dehydrogenase deficiency (one), diabetes mellitus (one) and psychological problems (one), and three parents were affected by the same disorder as the child (Alagille syndrome, one; mitochondrial disorder, one; recurrent cholestasis, one). Three parents were rejected for more than one reason. Both parents were unsuitable for donation in 21 per cent of cases. CONCLUSION: Parents approach living related liver transplantation with enthusiasm. They should be advised of the high chance of unsuitability, including the finding of significant pathology. The limitation of living related liver transplantation as the major source of organs for children is recognized. PMID- 10100788 TI - Carotid endarterectomy before and after publication of randomized controlled trials. AB - BACKGROUND: In 1991, the European Carotid Surgery Trial (ECST) and the North American Symptomatic Carotid Endarterectomy Trial (NASCET) demonstrated that carotid endarterectomy (CEA), in addition to best medical therapy, significantly reduces ipsilateral stroke in patients with high-grade (70 per cent or more) carotid artery stenosis compared with best medical therapy alone. In 1995, the Asymptomatic Carotid Atherosclerosis Study demonstrated that CEA was of benefit in asymptomatic patients with stenosis greater than 60 per cent. The aim of this paper was to examine how the practice and outcome of CEA have changed since publication of these data. METHODS: A prospectively gathered computerized database comprising 634 consecutive CEAs was studied. Two time intervals were analysed: 1975-1991 inclusive (17 years) and 1 January 1992 to 1 May 1998 (6 years 4 months). RESULTS: Since 1991, there has been a fourfold increase in the number of CEAs performed annually for symptomatic disease. CEA is now performed almost exclusively for high-grade (more than 70 per cent) stenosis. There has been a significant reduction in the total peri-operative neurological event rate (12.5 versus 5.9 per cent, P < 0.05), and the 30-day combined major stroke (Rankin grade 3-5) and mortality rate has fallen to 2.0 per cent. The number of patients who have CEA for asymptomatic disease remains small with 16 of 30 being randomized within the Asymptomatic Carotid Surgery Trial. CONCLUSION: Publication of ECST and NASCET data has been associated with a major increase in the number of CEAs performed for symptomatic disease in this unit. Despite a greater proportion of high-risk patients, the results have improved progressively. PMID- 10100789 TI - Outcome of primary radiocephalic fistula for haemodialysis. AB - BACKGROUND: Patient characteristics may help select the most appropriate type of permanent vascular access for haemodialysis. The aim of this study was to assess the influence of patient-related variables on the outcome of radiocephalic fistulas. METHODS: Over 3 years 107 consecutive patients underwent formation of a radiocephalic fistula for permanent haemodialysis access. Patients receiving prosthetic, ulnar, brachial or secondary fistulas were excluded. Patients were followed prospectively until access failure, transplantation or death, or for a minimum of 6 months (median follow-up 24 months). RESULTS: Primary patency was 69 per cent at 12 months and 56 per cent at 24 months. Endovascular and surgical intervention led to limited improvement in secondary patency to 63 per cent at 24 months. Regression analysis showed that fistula failure was more common in women (P = 0.02), diabetics (P = 0.03) and young patients (P = 0.02). By life-table analysis, primary and secondary patency were significantly better (P = 0.01) for men and non-diabetics, while the outcome was similar for all age groups. CONCLUSION: One-third of radiocephalic fistulas fail irreversibly within 2 years. Failure is more likely in women and diabetic patients. PMID- 10100790 TI - Simultaneous aortic aneurysm repair and colonic surgery. PMID- 10100791 TI - Local and systemic effects of intraoperative whole-colon washout with 5 per cent povidone-iodine. AB - BACKGROUND: Segmental intraluminal instillation of several tumoricidal agents including povidone-iodine has been advocated to prevent anastomotic recurrence after colonic resection for colorectal cancer. The local and systemic effects of on-table whole-colon washout using 5 per cent povidone-iodine were assessed in patients undergoing elective surgery for colorectal cancer. METHODS: The local effect of 5 per cent povidone-iodine on the colonic mucosa and the effect of colonic mucosal damage by povidone-iodine on tumour take was first investigated in Fischer 344 rats. In 12 euthyroid non-allergic patients, on-table whole-colon lavage via the appendix was performed. Systemic (thyroid function) and local (mucosal damage assessed by repeat biopsies) effects were studied, as well as the in vitro tumoricidal effect of the final anal effluent on tumour cell suspensions. RESULTS: After 30 min of contact with povidone-iodine the rat colonic mucosa was severely injured, with detachment of the epithelial cell layer. Povidone-iodine-induced 'colitis' did not result in tumour development after inoculation of 10(6) Mtln3 carcinoma cells in ten rats. Epithelial desquamation was also observed, in all but one patient, 1 and 4 h after colonic lavage. However, epithelial restitution started within 1 day and no abnormality was revealed after 3-7 days. Urinary iodine excretion increased markedly and was not within normal values after 1 week. Levels of thyroid hormones decreased significantly but became normal within 1 week. The anal effluent containing povidone-iodine was found to be tumoricidal in vitro on a human colonic carcinoma cell line and on a tumour cell suspension produced from the patient's tumour. CONCLUSION: On-table whole-colon washout using 5 per cent povidone-iodine seems clinically feasible. This technique deserves further study as a substitute for preoperative bowel preparation and may help to prevent recurrent cancer due to implantation of viable exfoliated tumour cells. PMID- 10100792 TI - Hospital stay of 2 days after open sigmoidectomy with a multimodal rehabilitation programme. AB - BACKGROUND: Hospital stay after colonic surgery is usually between 5 and 10 days, limiting factors being pain, ileus, organ dysfunction and fatigue. Single modality intervention to reduce these factors with laparoscopic surgery usually requires a hospital stay of 5 days. This paper reports the results of a multimodal rehabilitation regimen after open sigmoidectomy. METHODS: Sixteen unselected patients scheduled for elective sigmoid resection (median age 71 years) underwent operation under combined spinal-epidural anaesthesia. After operation, epidural analgesia was continued for 48 h, with immediate oral nutrition and mobilization, and with planned discharge 2 days after surgery. RESULTS: The median postoperative hospital stay was 2 (range 2-6) days (48 h), patients being mobilized for a median of 5 h on the second postoperative day (24 48 h) and for 10 h on the third day (48-72 h). Within 48 h of operation 14 patients had an oral intake of 2000 ml or more and 15 had resumed defaecation. Fatigue and pain scores were low during the first 8-9 days after operation, with a median of 13 h of mobilization per day after discharge. There were no medical or surgical complications during 30 days of follow-up, except for two patients who suffered postspinal headache. CONCLUSION: Postoperative recovery after open colonic surgery may be accelerated by effective pain relief integrated into an accelerated rehabilitation programme. PMID- 10100793 TI - Minimizing recurrence after sigmoid volvulus. AB - BACKGROUND: This study was a retrospective review of a series of patients with sigmoid volvulus to identify risk factors for recurrence and recommend appropriate treatment. METHODS: Thirty-five patients with sigmoid volvulus were treated over 8 years. RESULTS: Six patients had emergency surgery for peritonitis. Twenty-eight of the other 29 patients had successful endoscopic decompression; 15 of these patients had elective surgery during the same admission. Twelve of the 14 patients who refused operation after endoscopic decompression developed recurrent volvulus, a median of 2.8 months later. Eight subsequently agreed to surgery and underwent elective operation following repeat decompression. Of 29 patients who had surgery, 27 had sigmoid colectomy (two were initial Hartmann procedures) and two had subtotal colectomy. Six patients who had sigmoid colectomy developed recurrent volvulus. Concomitant megacolon and megarectum at the time of initial surgery were significant predictors of recurrence. CONCLUSION: Subtotal colectomy, carried out as the primary procedure if there is concomitant megacolon or megarectum, might reduce the risk of recurrent sigmoid volvulus. PMID- 10100794 TI - Indicators of recurrence following cryotherapy for hepatic metastases from colorectal cancer. AB - BACKGROUND: This retrospective review aimed to assess the incidence of local recurrence at the cryosite, hepatic and extrahepatic recurrence and the corresponding disease-free intervals. Prognostic indicators following hepatic cryotherapy were also identified. METHODS: Eighty-five patients underwent complete cryotreatment of colorectal liver metastases between April 1990 and May 1997. Possible prognostic indicators were tested for their impact on the disease free interval at the cryosite, liver disease-free survival and overall disease free survival with univariate and multivariate analysis. RESULTS: At a median follow-up of 22 months 66 patients developed tumour recurrence: 18 in the liver only; 15 in the liver and lung; 22 in the liver and extrapulmonary areas; and 11 at extrahepatic sites only. Local recurrence at the cryosite occurred in 28 patients. Cryotreated metastases larger than 3 cm were associated with a shorter disease-free interval at the cryosite and liver disease-free survival; persistently raised serum carcinoembryonic antigen (CEA) levels after operation were associated with shorter liver disease-free and overall disease-free intervals in multivariate analysis. CONCLUSION: Improvements in probe placement and monitoring of the freezing process are required to allow successful treatment of large liver metastases. A failure in complete postoperative CEA response indicates that hepatic or extrahepatic disease was not detected before operation, which may be avoided with better staging procedures. PMID- 10100795 TI - Sequential hepatic and pulmonary resections for metastatic colorectal cancer. AB - BACKGROUND: Resection of pulmonary or hepatic colorectal metastases is associated with a 5-year survival rate of 25-40 per cent. This report analyses outcome following sequential resection of colorectal metastases to both organs. METHODS: Seventeen patients with histologically confirmed colorectal adenocarcinoma and resection of liver and lung metastases were identified from a prospective database. RESULTS: The median interval between resection of the primary tumour and first metastasis was 21 (range 0-64) months. The interval between resection of the first and subsequent metastases was 18 (range 1-74) months. No patient died in the postoperative period and there were two perioperative complications. The overall survival rate in 17 patients was 70 per cent at 2 years from resection of metastasis to the second organ, but the disease-free survival rate at 2 years was only 24 per cent. CONCLUSION: Although few long-term survivors were observed in this small series, sequential resection of hepatic and pulmonary metastases is warranted in a highly selected group of patients. PMID- 10100796 TI - Effect of radioimmunoscintigraphy on the management of recurrent colorectal cancer. AB - BACKGROUND: Radioimmunoscintigraphy (RIS) is being used increasingly as a new investigation in the diagnosis of recurrent colorectal cancer. This study assessed the efficacy of 99mTc-radiolabelled PR1A3 scanning in a cohort of patients with possible recurrent colorectal cancer and the effects of scan interpretation on subsequent clinical management. METHODS: The scans and case notes of patients scanned over a 3-year period were reviewed. RESULTS: Forty seven scans in 40 patients were available for analysis. In 39 instances in which scan interpretation could be verified accurately, sensitivity for recurrent colorectal cancer was 22 of 23 (96 per cent), specificity for recurrent colorectal cancer was eight of 16 (50 per cent), positive predictive value for recurrence was 22 of 30 (73 per cent) and negative predictive value for recurrence was eight of nine (89 per cent). In 16 of the 40 patients, scan interpretation strengthened a management decision or altered management. This was beneficial to ten patients and possibly detrimental to six. CONCLUSION: This study demonstrated that RIS is sensitive in the detection of recurrent colorectal cancer and benefited the patient in one-quarter of cases. For the majority of patients, accurate detection of recurrent disease cannot be followed by curative therapy, but there is an important subgroup of patients in whom RIS alters management beneficially. However, a randomized prospective study is needed to confirm this. PMID- 10100797 TI - Preoperative magnetic resonance staging of rectal cancer with an endorectal coil and dynamic gadolinium enhancement. AB - BACKGROUND: The aim of the study was to assess the value of endorectal coil magnetic resonance imaging (MRI) with gadolinium enhancement in the preoperative staging of rectal cancer. METHODS: In addition to standard evaluation, patients with rectal lesions were assessed by MRI obtained with a pelvic phased-array coil in combination with an endorectal coil. RESULTS: The study group comprised 29 patients with rectal cancer staged with an endorectal coil who had surgery without preoperative adjuvant therapy. In addition to standard T1- and T2 weighted images, dynamic contrast-enhanced images were acquired in all patients. Considerable interobserver variation was noted, particularly for pathological tumour stage pT1 or pT2 (kappa = 0.36). Compared with pathological findings, endorectal MRI correctly staged nine patients, overstaged 16 and understaged four. Whilst lymph node metastases were accurately detected in 70 per cent of patients, the positive predictive value was only 58 per cent. CONCLUSION: MR staging of rectal cancer with an endorectal coil and gadolinium enhancement is inaccurate for early tumours (stage T1 or T2) and is associated with a considerable degree of interobserver variation for individual scan sequences. PMID- 10100798 TI - Day-case haemorrhoidectomy. AB - BACKGROUND: Ligation excision haemorrhoidectomy is usually performed on an inpatient basis. This study was designed to assess the feasibility of day-case haemorrhoidectomy. METHODS: Patients fulfilling criteria for day surgery underwent ligation excision haemorrhoidectomy with the intention of a same-day discharge from hospital. A standardized protocol for anaesthesia, perioperative analgesia and antiemesis was followed. Patients received daily home nursing visits until they felt both comfortable and confident. Staff recorded pain and nausea scores on a visual analogue scale (range 1-10) until the first bowel action. Patient satisfaction was assessed independently after operation. RESULTS: Fifty-one patients underwent planned day-case haemorrhoidectomy. Forty-two (82 per cent) were discharged on the day of surgery. All patients were discharged within 26 h of surgery. Four patients required readmission, two with reactive bleeding, one with urinary retention and one for pain control. Pain and nausea were well controlled. Forty-four patients (86 per cent) were totally or very satisfied with their overall care. CONCLUSION: Ligation excision haemorrhoidectomy can be performed successfully as a day-case procedure. PMID- 10100800 TI - Colonic motility is abnormal before surgery for rectal prolapse. AB - BACKGROUND: Abdominal rectopexy remains the operation of choice for patients with rectal prolapse. Recurrence rates are low but the functional results are poor. Hindgut motility was measured before abdominal rectopexy to determine whether an underlying neuropathy might explain these poor results. METHODS: Seven women of mean(s.d.) age 56(10) years had a multilumen catheter inserted in the colon before abdominal rectopexy. Colonic intraluminal pressure was recorded for a mean(s.d.) of 19(3) h; the number of peaks over 5 and 50 mmHg, motility and high amplitude propagated contractions (HAPCs) were measured before and after a meal and compared with the findings in five controls. RESULTS: Patients had high numbers of contractions greater than 5 mmHg and high motility before meals. Controls responded to meals by increasing motility, unlike patients. HAPCs were seen in one patient but in all controls. CONCLUSION: These data show that patients with rectal prolapse have a hindgut motility abnormality before abdominal rectopexy, similar to that observed in spinal cord injury. This may explain the poor functional results after surgery, offering a rationale for colonic resection. PMID- 10100799 TI - Outcome of strictureplasty for duodenal Crohn's disease. AB - BACKGROUND: The outcome of strictureplasty for duodenal Crohn's disease has not been critically documented. The aim of this study was to assess the outcome of strictureplasty for duodenal Crohn's disease. METHODS: A retrospective review was undertaken of 13 patients who underwent strictureplasty (including four pyloroplasties) for obstructive duodenal Crohn's disease between 1974 and 1997. RESULTS: Ten patients underwent strictureplasty as the primary procedure, and in three strictureplasty was used as a revision procedure after previous bypass surgery. Two patients developed anastomotic breakdown and were treated either by Roux-en-Y duodenojejunostomy or partial gastrectomy. Symptoms of obstruction persisted in four patients after strictureplasty; three eventually resolved after prolonged nasogastric aspiration, but the other required gastrojejunostomy. In the long term, six patients developed restricture at the previous strictureplasty site. Five required repeat strictureplasty and the other patient underwent duodenojejunostomy. One patient who had repeat strictureplasty required a further strictureplasty because of restricture at the previous strictureplasty site. Overall nine of 13 patients required further surgery because of early postoperative complications or restricture at the strictureplasty site. CONCLUSION: Strictureplasty for duodenal Crohn's disease is associated with a high incidence of postoperative complications and restricture. PMID- 10100801 TI - Topical phenylephrine increases anal sphincter resting pressure. AB - BACKGROUND: Phenylephrine is an alpha1-adrenergic agonist which causes contraction of human internal anal sphincter muscle in vitro. Its intra-arterial administration in animals has been shown to increase resting sphincter pressure in vivo. In this study the effect of topical application of phenylephrine on resting anal pressure in healthy human volunteers was investigated. METHODS: Twelve healthy volunteers had measurements of maximum resting sphincter pressure (MRP) and anodermal blood flow taken before and after topical application of increasing concentrations of phenylephrine gel to the anus. To determine the duration of effect of the agent, readings were taken throughout the day after a single application. RESULTS: There was a dose-dependent rise in the resting anal sphincter pressure, with a small 8 per cent rise after 5 per cent phenylephrine (P = 0.012) and a larger 33 per cent rise with 10 per cent phenylephrine (mean(s.d.) MRP 85(12) cmH2O before versus 127(12) cmH2O after treatment, P < 0.0001). Thereafter no additional response was noted with higher concentrations of phenylephrine. The median duration of action of a single application of 10 per cent phenylephrine was 7 (range from 6 to more than 8) h. CONCLUSION: Topical application of 10 per cent phenylephrine gel to the anus produces a significant rise in the resting anal sphincter pressure in healthy human volunteers. This represents a potential novel therapeutic approach to the treatment of passive faecal incontinence associated with a low resting anal sphincter pressure. PMID- 10100802 TI - Investigation of oesophageal reflux symptoms after gastric surgery with combined pH and bilirubin monitoring. AB - BACKGROUND: Little is known about the role of bile in gastro-oesophageal reflux disease in patients with previous gastric surgery. This has partly been due to a lack of suitable techniques for identifying bile reflux objectively. METHODS: Some 28 patients with reflux symptoms and previous gastric surgery underwent oesophageal manometry, and 24-h ambulatory oesophageal pH and bilirubin monitoring. RESULTS: A wide variety of operations had been performed, most commonly Polya gastrectomy (seven patients), vagotomy and pyloroplasty (six) and vagotomy and gastrojejunostomy (four). Three patients had isolated acid reflux, eight had isolated bile reflux, six had combined acid and bile reflux, and 11 patients had no reflux. Two-thirds of heartburn symptoms were not associated with reflux. However, one-quarter were associated with acid reflux and only 7 per cent with bile reflux. Erosive oesophagitis was present in five patients: two with combined acid and bile reflux, and three with isolated bile reflux. CONCLUSION: Acid and/or bile reflux can be present after a wide variety of gastric operations. Symptoms are more frequently associated with acid reflux than with bile reflux. Erosive oesophagitis can occur in the presence of isolated bile reflux. Combined pH and bilirubin monitoring determines the nature of the refluxate, and may help in the management of these patients. PMID- 10100803 TI - Surveillance for Barrett's oesophagus in the UK. AB - BACKGROUND: Endoscopic screening for Barrett's oesophagus is being offered without evidence of efficacy Barrett's oesophagus is not an ideal candidate for a screening programme, as the natural history is unclear, uncertainties surround the indication for intervention and the treatment is associated with high morbidity and mortality rates. METHODS: To determine the practices that clinicians employ in the management of Barrett's oesophagus in the UK, postal questionnaires were sent in May 1997 to 297 randomly selected members of the British Society of Gastroenterology asking for details of their current practice. RESULTS: Of 152 respondents, 106 (70 per cent) performed surveillance for Barrett's oesophagus; 46 (30 per cent) did not carry out screening. There was no difference in the practices carried out by physicians or surgeons, teaching or acute general hospital clinicians, or those with an upper gastrointestinal interest. There was a wide disparity in screening interval: just over half (52 per cent) screen at yearly intervals. Only nine (8 per cent) took four quadrant biopsies per 2 cm of Barrett's oesophagus. Nearly half (49 per cent) manage mild dysplasia by increasing the frequency of endoscopy; only seven (7 per cent) prescribed patients a proton pump inhibiting agent. Faced with severe dysplasia, 33 (31 per cent) offered surgery immediately; 22 (21 per cent) simply followed the patient by endoscopy. Those not choosing to perform screening most frequently cited lack of evidence of efficacy as the reason behind their decision. CONCLUSION: There is wide variation in surveillance practices for Barrett's oesophagus. Some methods are ineffectual. The recommendations made by the Barrett's Oesophagus Working Party in 1991 are not followed, possibly because they are not practical. New workable guidelines based on available evidence and a consensus of expert opinion should be established; this was suggested by 38 per cent of respondents who performed screening. PMID- 10100804 TI - Prospective randomized controlled trial of preservation of the intercostobrachial nerve during axillary node clearance for breast cancer. PMID- 10100805 TI - Long-term clinical outcome of surgery for solitary rectal ulcer syndrome. PMID- 10100806 TI - Learning curve for oesophageal cancer surgery. PMID- 10100807 TI - Central venous pressure and its effects on blood loss during liver resection. PMID- 10100808 TI - The East Flanders Prospective Twin Survey (Belgium): a population-based register. AB - The East Flanders Prospective Twin Survey (EFPTS), started in 1964, is unique among the 17 major European twin registers because it is population based, the twins (and higher order births) are ascertained at birth, basic perinatal data are collected, chorion type is established and, when appropriate, genetic markers including DNA fingerprints, are determined. The total number of sets is 5089 twin, 158 triplet and 14 of higher order. Zygosity has been diagnosed on the basis of sex, placental structure and genetic markers in more than 95% of pairs. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early), the monochorionic-diamnionic pairs (intermediate), and the monochorionic-monoamnionic pairs (late). Methodology and basic results in twins are considered in this article; detailed studies will be reported later. The sex proportion in dizygotic (DZ) twins is the same as in singletons, whereas monozygotic (MZ) twins number more girls than boys. The difference in perinatal mortality between DZ and MZ twins is limited to the monochorionic MZ subgroup. Birth weight is highest in DZ twins and diminishes stepwise in MZ dichorionic and MZ monochorionic twins. Duration of pregnancy follows the same trend but is limited to a few days. Iatrogenic pregnancies are increasing to the point of representing almost 50% of the twin births in 1997. PMID- 10100809 TI - Effects of lifestyle, personality, symptoms of anxiety and depression, and genetic predisposition on subjective sleep disturbance and sleep pattern. AB - The effects on sleep pattern ('short-sleep' versus 'long-sleep') and subjective sleep disturbance of genotype, personality, symptoms of anxiety and depression, and lifestyle, were examined using survey data on a clinically unselected sample of adult Australian twin pairs, aged 17-88 years. When the effects of genotype, personality and symptoms were ignored, lifestyle variables appeared to account for roughly 4% of the variance in sleep disturbance, and 9% of the variance in sleep pattern. Significant genetic effects on sleep disturbance and sleep pattern were found, which were only partly explained by the effects of personality and symptoms of anxiety and depression. Much of the association between sleep disturbance and lifestyle appeared to be explained by separate effects of personality and symptoms of anxiety and depression on sleep and lifestyle ('genotype-risk-factor correlation'). There was little evidence for genetically determined differences in sensitivity to the lifestyle variables ('genotype x risk-factor interaction'). PMID- 10100810 TI - Time trends in twin perinatal mortality in northern England, 1982-94. Northern Region Perinatal Mortality Survey Steering Group. AB - The dynamics of perinatal mortality rates (PNMR) and causes of death in twin pregnancies over 13 years in the Northern Region of the National Health Service in England is described. All twin perinatal deaths occurring between 1982-1994 were identified from the Northern Region Perinatal Mortality Survey. The twinning rate increased from 9.9 per 1000 maternities in 1982 to 12.0 in 1994. There was a total of 10,734 twin pregnancies and of these 421 resulted in 530 perinatal deaths. The perinatal mortality rate in twins significantly decreased over time (1982-87, 55.4 per 1000; 1988-94, 44.4 per 1000; P = 0.01). The PNMR was significantly higher for twins from like-sexed than from unlike-sexed pairs (53.5 and 34.4 per 1000 respectively, P < 0.001). Despite no improvement in birthweight distribution in the twin population, birthweight-specific perinatal mortality rates for both like and unlike-sexed twins decreased for each birthweight category in 1988-94 compared with 1982-87. Twins with very low birthweight (< 1500 g) comprised 69%, and preterm twins (< 37 completed weeks of gestation) 74.9% of all twin perinatal deaths. The major immediate cause of early neonatal death was pulmonary immaturity (63%); antepartum anoxia caused 76.9% of antenatal deaths. Unexplained preterm labour and intrauterine death were the leading obstetric factors underlying death in twins. Despite a decrease over the 13 years, the perinatal mortality rate in twins in the Northern Region remains high. Continued monitoring of trends in twinning and mortality rates is needed to inform health care planning. PMID- 10100811 TI - How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins. AB - Molecular epidemiological studies confirm a substantial contribution of individual genes to variability in susceptibility to disease and death for humans. To evaluate the contribution of all genes to susceptibility and to estimate individual survival characteristics, survival data on related individuals (eg twins or other relatives) are needed. Correlated gamma-frailty models of bivariate survival are used in a joint analysis of survival data on more than 31,000 pairs of Danish, Swedish and Finnish male and female twins using the maximum likelihood method. Additive decomposition of frailty into genetic and environmental components is used to estimate heritability in frailty. The estimate of the standard deviation of frailty from the pooled data is about 1.5. The hypothesis that variance in frailty and correlations of frailty for twins are similar in the data from all three countries is accepted. The estimate of narrow sense heritability in frailty is about 0.5. The age trajectories of individual hazards are evaluated for all three populations of twins and both sexes. The results of our analysis confirm the presence of genetic influences on individual frailty and longevity. They also suggest that the mechanism of these genetic influences may be similar for the three Scandinavian countries. Furthermore, results indicate that the increase in individual hazard with age is more rapid than predicted by traditional demographic life tables. PMID- 10100812 TI - Maternal smoking and twinning. AB - In order to investigate a possible association between maternal smoking during pregnancy and twinning, information on 1,096,330 single births and 12,342 twin births in 1983-95 was obtained from the Swedish Medical Birth Registry (MBR). All odds ratios (OR) were estimated after stratification for year of birth and maternal age, parity, and educational level. Smoking women, compared with non smoking women, were at increased risk of having dizygotic (DZ) twins, but the risk increase was only evident among multiparas. A strong association between previous involuntary childlessness and dizygotic (DZ) twinning (especially in primiparas) was found. The strongest association between maternal smoking and DZ twinning was found among multiparas without any history of involuntary childlessness (OR: 1.35, 95%CI:1.22-1.49), whereas among women who had experienced involuntary childlessness, the opposite was seen (OR: 0.82, 95%CI:0.66-1.00, no difference between parity strata). Weinberg's differential method was used to estimate the number of monozygotic (MZ) twins, and a method of estimating stratified ORs among mothers of MZ twins was presented. No association was found between MZ twinning and maternal smoking (OR: 0.96, 95%CI:0.86-1.07), and no confounding by parity or previous involuntary childlessness was indicated. Several non-causal explanations to the positive association between DZ twinning and maternal smoking among multiparas were discussed, but homogeneity over strata indicated that maternal smoking may be a true risk factor for double ovulation. PMID- 10100813 TI - No paternal effect on monozygotic twinning in the Swedish Twin Registry. AB - Previous research has provided evidence for a genetic effect in monozygotic twinning, indicated by an increased risk for monozygotic women to have monozygotic offspring. However, since the biological mechanism for this trait is unknown, it is not clear if there exists a paternal inheritance. In this study we investigated twin pregnancies in offspring born in 1941-1996 to male twins in the Swedish Twin Registry and population controls born in 1926-1980. In total 4,225,331 offspring, of which 89,286 were twins, were studied. There was neither an increase in the probability for monozygotic men to have like-sexed twin offspring risk ratio (RR = 0.95; 95% CI = 0.77-1.13) nor an increase in the estimated number of monozygotic twin births. Thus, there is no evidence for a paternal effect on monozygotic twinning, suggesting that the gene(s) increasing the liability for division of the embryo are expressed in the mother and not in the fertilised egg. PMID- 10100814 TI - Nature vs nurture: are leaders born or made? A behavior genetic investigation of leadership style. AB - With the recent resurgence in popularity of trait theories of leadership, it is timely to consider the genetic determination of the multiple factors comprising the leadership construct. Individual differences in personality traits have been found to be moderately to highly heritable, and so it follows that if there are reliable personality trait differences between leaders and non-leaders, then there may be a heritable component to these individual differences. Despite this connection between leadership and personality traits, however, there are no studies of the genetic basis of leadership using modern behavior genetic methodology. The present study proposes to address the lack of research in this area by examining the heritability of leadership style, as measured by self report psychometric inventories. The Multifactor Leadership Questionnaire (MLQ), the Leadership Ability Evaluation, and the Adjective Checklist were completed by 247 adult twin pairs (183 monozygotic and 64 same-sex dizygotic). Results indicated that most of the leadership dimensions examined in this study are heritable, as are two higher level factors (resembling transactional and transformational leadership) derived from an obliquely rotated principal components factors analysis of the MLQ. Univariate analyses suggested that 48% of the variance in transactional leadership may be explained by additive heritability, and 59% of the variance in transformational leadership may be explained by non-additive (dominance) heritability. Multivariate analyses indicated that most of the variables studied shared substantial genetic covariance, suggesting a large overlap in the underlying genes responsible for the leadership dimensions. PMID- 10100815 TI - Report on the First International Workshop on the Genetic Epidemiology of Complex Traits using Twins and Sib-Pairs. PMID- 10100816 TI - Between-group psychotherapy outcome research and basic science. PMID- 10100817 TI - "Between-group psychotherapy outcome research and basic science" revisited. AB - Case studies involving the measurement of every plausibly causal variable and every important outcome variable and covering the widest possible range of cases in terms of these variables are the highest priority for psychotherapy research. Such case studies looked at together will give us the best initial understanding of what variables are probably causal and what treatments yield the best results for particular kinds of patients, therapists, and settings. The accumulation of such case studies will show us where we would benefit by doing comparative controlled experiments of distinct therapies or by employing optimum-seeking designs for a particular therapy. Collaboration by the practitioner community will be needed to do this. The truly difficult and necessary work of applied psychotherapy research still lies ahead of us, hardly touched. PMID- 10100818 TI - Psychotherapy research: basic or applied? AB - Borkovec and Miranda (1996) have argued that the "greatest progress in the development of increasingly useful interventions" (p. 14) will come from redefining comparative trials research on psychotherapy outcome as basic research. They foresee that such a reconceptualization will lead to the increased use of dismantling, parametric, and additive research strategies and that it will result in increasing collaboration with other basic researchers. The assumption that a redefinition will stimulate increased collaboration and specificity of causal mechanisms is questioned as are the assumptions that randomization, group comparison designs, and within therapist designs will lead inherently to more valid assessments of cause-effect relationships. Analyses of a randomized clinical trials study is used to illustrate how clinical research can be guided by theory to tease out causal relationships, within therapy, and within patient factors. Ultimately, a combination of research paradigms, including N = 1, clinical utility, and controlled research, will best provide answers to important questions of change mechanisms and treatment effectiveness. A simple reconceptualization, however, is not necessary to make this happen and belies the complexity and overlap of the problems to be addressed. PMID- 10100819 TI - Reconsidering "between-group psychotherapy outcome research and basic science:" applications to child and adolescent psychotherapy outcome research. AB - Borkovec and Miranda (1996) proposed that the purpose of controlled outcome studies is to increase our understanding of the change mechanisms associated with psychotherapy, and they suggested several ways that between-group outcome research establishes cause-and-effect relationships. Child psychotherapy outcome research presents special challenges for the issues raised by Borkovec and Miranda and four of these are discussed herein: (a) the multitude of influences on children and adolescents that affect their functioning and therapy outcomes, (b) accurately defining the referral problem, (c) identifying appropriate outcome measures and reliable informants of change in child and adolescent treatment, and (d) considering developmental processes that influence therapeutic effectiveness. It is suggested that transporting clinical trials methods to natural settings is of limited value in identifying cause-and-effect relationships, and an alternative methodology is proposed for advancing child therapy outcome research. This approach advocates developing a profile of the underlying causes that predict psychopathology and therapy outcome for individual children in real clinical settings and then aggregating the data for youth with similar profiles and outcomes. These data can then be used to generate hypotheses about what interventions work for specific children, and investigators can employ prospective studies of therapy outcome for youth with similar profiles. PMID- 10100820 TI - Summary: paradigms for psychotherapy outcome research. PMID- 10100821 TI - A study of Benjamin's eight-facet Structural Analysis of Social Behavior (SASB) model. AB - The study purpose was to evaluate the cluster, or facet, version of Benjamin's (1974, 1996b) Structural Analysis of Social Behavior (SASB) in independent samples of 133 normal participants and 182 psychiatric cases. We first tested for the presence of 3 circumplexes, Focus on the Other, Focus on the Self, and Introject in the 36 items that are hypothesized to define each of them. Next, intercorrelations of 8 item-based facet scales were assessed for internal consistency, factor structure, and circular order, with the expectation that the scales would be reliable, yield 2 higher-order factors, and demonstrate a circumplex structure. Principal components analysis was applied followed by varimax rotation. Data for both normal participants and patients uniformly confirmed the presence of 4 item-level factors and 2 cluster-based factors for each circle. Alpha coefficients for facet scales were typically high, but some were as low as .50. The principal difference between the normal participants and patients was that the circumplex was incomplete in the patient data with poor differentiation of the vertical and horizontal variables. PMID- 10100822 TI - Differential diagnosis of PTSD, schizophrenia, and depression with the MMPI-2. AB - This study used 102 male, veteran, psychiatric inpatients to describe patterns of MMPI-2 clinical and content scales that most accurately discriminate among patients diagnosed with PTSD, schizophrenia, and depression. Single scale accuracy classification using scales PK and PS was unacceptably low. Optimally weighted scales, including PK, Sc, BIZ, and ANX, correctly classified 70% of the patients. Suggestions for facilitating the use of formal decision rules are offered. PMID- 10100823 TI - Depersonalization, fantasies, and coping behavior in clinical context. AB - The main purpose of the present study was to determine the relation between specific dissociative experiences (depersonalization, fantasies) and self reported coping behavior in a clinical (depression, anxiety, schizophrenia) and nonclinical sample (normal adults). Dissociative experiences were assessed with the Questionnaire of Experiences of Dissociation (QED) of Riley (1988) and coping behavior with the Stress-Process Questionnaire (SPQ; Janke, Erdmann, & Boucsein, 1985). A factor analysis of the QED items revealed a two-factor extraction: Factor 1 "depersonalization" and Factor 2 "fantasies/daydreams." The clinical group scored higher on the QED factor "depersonalization" and had more passive forms of coping behavior (resignation, social isolation, self-compassion, self blame) than the normal adults. Similar correlation patterns were found for both groups: The QED factor "depersonalization" correlated highly with the coping behaviors "resignation," "social isolation," "self-blame," "self-compassion," and "rumination." No correlation between Factor 2 "fantasies/daydreams" and the coping behavior was found. Finally, correlations between depersonalization, trait anxiety, and personal need for structure were reported. PMID- 10100824 TI - Syndromes of schizophrenia and language dysfunction. AB - This study investigated the relationship between performance on word association and sentence construction tasks and the three-syndrome model of schizophrenic symptoms. Participants were 70 inpatients with a primary diagnosis of schizophrenia. Each participant was rated on positive and negative symptom scales, and ratings were grouped into three syndromal patterns (Reality Distortion, Psychomotor Poverty, and Disorganization). Among the syndromes, only symptoms of disorganization were significantly related to the ability to construct meaningful sentences using word associations. Results suggest that symptoms of disorganization, length of hospitalization, and premorbid adjustment are dimensions that are related to language disturbance in patients with schizophrenia. PMID- 10100825 TI - The relation of the MMPI-2 Pd Harris-Lingoes subscales to psychopathy, psychopathy facets, and antisocial behavior: implications for clinical practice. AB - Little is known concerning the correlates of the MMPI-2 Psychopathic deviate (Pd) Harris-Lingoes subscales. In four studies with undergraduates, Pd2 (Authority Problems) emerged as the most consistent marker of psychopathy and antisocial behavior and was the only Pd subscale to assess the callousness traditionally associated with psychopathy. Pd3 (Social Imperturbability) correlated highly with social potency and was the only Pd subscale to consistently assess low anxiety proneness. Pd1, Pd4, and Pd5 (Familial Discord, Social Alienation, and Self Alienation, respectively) correlated highly with externalization of blame but exhibited few differential correlates. Pd2 exhibited statistically significant levels of incremental validity above and beyond all other Pd subscales in the prediction of global psychopathy and antisocial behavior. These findings indicate that several Pd subscales assess markedly different facets of psychopathy and suggest that consideration of different Pd subscale elevations may hold important implications for clinical practice and assessment. PMID- 10100826 TI - Differential effects of treatment modality on psychosocial functioning of cocaine dependent men. AB - Changes in psychosocial functioning, including depression, anxiety, somatization, obsessive-compulsiveness, interpersonal sensitivity, confidence in the ability to resist taking drugs in different situations, and social adjustment are examined for male veterans entering treatment for cocaine dependence. The sample was comprised of African Americans (66%), Hispanics (8%), and Whites (26%) with a mean age of 35 years at intake. Participants were assessed at the end of 1 year and 2 years; during the follow-up period, participants utilized different combinations of treatment modalities. Paired t-tests showed significant improvement between intake and follow-up, both at the end of 1 year and 2 years, on the Beck Depression Inventory, on the depression, anxiety, obsessive compulsiveness, and interpersonal sensitivity scores of the Symptom Check List (SCL-58), and in four role areas of social adjustment on the Social Adjustment Inventory. There were no significant differences between intake and follow-up on the somatization subscale of the SCL-58 and on the Drug Taking Confidence Questionnaire (DTCQ). Measures taken at Year 2 were not significantly different from Year 1. Repeated measures analysis of variance revealed that treatment modality did not differentially affect psychosocial functioning on nearly all measures, except on somatization, confidence in the ability to resist taking drugs in different situations, and social adjustment involving leisure time. However, a combination of inpatient, high-intensity outpatient, and self-help group participation and a combination of outpatient and self-help group participation were better than a combination of inpatient, low-intensity outpatient, and self-help participation in increasing the confidence in the ability to resist cocaine use in different situations and to reduce symptoms of somatization. PMID- 10100827 TI - Emotional expression and feeling in schizophrenia: effects of specific expressive behaviors on emotional experiences. AB - The purpose of this study was to investigate the relationship between emotional expression and experience in schizophrenia by manipulating expressive behaviors directly and then assessing subsequent emotional feelings. In Study 1, facial expressions and bodily postures were manipulated in a sample of normals, the results of which replicate findings from previous studies of peripheral feedback effects on emotions. In Study 2, the same procedures were used with matched groups of outpatient schizophrenic men, patients with depression, and nonpsychiatric controls. Schizophrenia patients showed the usual effects from their facial expressions of sadness, fear, happiness, and surprise, but only from their postures of anger, whereas patients with depression showed the same effects only from their expressions and postures of sadness, and normal controls only from their expressions and postures of anger. These patterns may reflect those aspects of the emotional response system that are functional and dysfunctional in schizophrenia and depression. PMID- 10100828 TI - Psychological and neuropsychological predictors of coping patterns by patients with multiple sclerosis. AB - To determine the relative contribution of psychological and neuropsychological (NP) variables to the prediction of patterns of coping with disease-related stressors and satisfaction with their coping efforts, 56 patients with multiple sclerosis (MS) were administered the Ways of Coping Checklist, the Symptom Checklist-90-Revised, and a battery of NP tests chosen for their sensitivity to MS. Higher levels of psychological distress were associated with greater use of emotion-focused coping strategies and reduced perceived effectiveness of the coping strategies employed. Psychological distress was not related to the use of problem-focused strategies and NP variables did not predict coping style or effectiveness. MS patients who display heightened psychological distress may be good candidates for psychotherapeutic interventions aimed at improving perceived coping effectiveness. PMID- 10100829 TI - Self and observer reports of interpersonal problems in couples. AB - This study investigated self-partner agreement on a measure of interpersonal problems as well as the relationship between discrepancy in self-partner ratings and self-reported symptomatology. Both partners of 49 young adult couples rated themselves and their partners on the Inventory of Interpersonal Problems(IIP Horowitz, Rosenberg, Baer, Ureno, & Villasenor, 1988). The results demonstrated that couples generally evidenced significant agreement in characterizing the interpersonal problems of each target person, suggesting that the substantial self-partner agreement previously reported for personality traits generalizes to the domain of interpersonal problems. Results also indicated that the relationship between self-partner discrepancy and symptomatology depended on the target person's gender. Finally, the data provide preliminary evidence of the psychometric properties of an observer form of the IIP, including its circular structure. PMID- 10100830 TI - Emotion recognition in psychotherapy: impact of therapist level of experience and emotional awareness. AB - Accurately identifying another person's emotional state is an ability that may be necessary for a psychotherapist to empathize with a patient and that may be required for obtaining valid and reliable psychotherapy process ratings in research. Accuracy of identifying emotions and of rating emotional intensity expressed by a patient was studied in a comparison of 36 experienced therapists and 36 undergraduate psychology students who intended to become psychotherapists. Representative segments of a psychotherapy session were presented in one of three ways to tease apart the relative importance of verbal and nonverbal cues in making accurate ratings. Accuracy was judged against ratings supplied by two experienced and prestigious clinicians based on the same therapy sample. Results indicated that although therapists were more accurate than nontherapists in identifying emotions, they did not differ in the accuracy of rating emotional intensity. Moreover, accuracy of ratings was found to be less reliant on verbal cues among psychotherapists than among nontherapists. Finally, levels of participants' personal awareness of their own emotions had a positive impact on the accuracy of identifying specific emotions but not on the accuracy of rating their intensity. PMID- 10100831 TI - Codependency: predictors and psychometric issues. AB - This study examined the relationships between codependency and age, gender, self confidence, autonomy, and succorance, which is the quality of soliciting emotional support from others. The study also tested the validity of the Spann Fischer Codependency Scale (Fischer, Spann, & Crawford, 1991). Ninety-five undergraduates completed a demographic sheet, the Adjective Check List (Gough & Heilbrun, 1983), the Spann-Fischer Codependency Scale, the Co-Dependents Anonymous Checklist (Whitfield, 1991), and a questionnaire developed for this study based on the work of Hemfelt, Minirth, and Meier (1989). As predicted, codependency was negatively related to self-confidence and positively related to succorance. However, contrary to expectation, a negative relationship between codependency and autonomy was not found. In addition, low self-confidence was the strongest predictor of codependency. Finally, all three measures of codependency were strongly related, attesting to the convergent validity of the Spann-Fischer Codependency Scale. Future studies should further investigate the role of emotional autonomy and codependency and should begin to utilize an experimental approach, making predictions regarding the behavior of codependent and noncodependent persons in experimental situations. PMID- 10100832 TI - Interscorer reliability of the MMPI-2: should TRIN and VRIN be computer scored? AB - Some clinicians and researchers hand score their MMPI-2 protocols. Graham (1990) noted that TRIN and VRIN involve complex scoring that is best done by a computer. We examined the interscorer reliabilities of TRIN and VRIN and compared these results to the reliabilities of the other validity and clinical scales. Despite the high reliabilities (.97 to 1.00), clerical errors were common (i.e., 7% of the scales were scored inconsistently). Graham's caution about the inherent difficulty of scoring VRIN, but not TRIN, was supported. There were three times as many scoring disagreements for VRIN than any other scale (i.e., 27% of the protocols were in disagreement). PMID- 10100833 TI - Predicting discharge from Airforce basic training by pattern of affect. AB - We compared the efficacy of the state form of the MAACL-R (Zuckerman & Lubin, 1985) in predicting success in Air Force basic training. Results of discriminant functions analyses showed that the Anxiety, Depression, Hostility, Positive Affect, and Sensation Seeking scales of the state MAACL-R efficiently predicted success in basic training. The need to incorporate state measures into studies of prediction is discussed. PMID- 10100834 TI - Adult and geriatric normative data and validation of the profile of mood states. AB - The Profile of Mood States (POMS; McNair, Lorr, & Droppleman) is widely used to assess mood states. However, the utility of the POMS has been restricted by the lack of normative data from the general population. We report on our adult (N = 400) and geriatric (N = 170) POMS standardization samples. Both groups were age-, gender-, and race-stratified according to 1990 census data. We also report on convergent and discriminant validity of POMS scales, using a multitrait, multimethod paradigm. PMID- 10100835 TI - A two-factor model of the Depression Coping Questionnaire. AB - The original 11 factors reported for the 29-item Depression Coping Questionnaire (DCQ) unnecessarily limits its potential usefulness as a clinically interpretable self-report measure. Therefore, the goal of this study was to reduce the number of DCQ factors to equal the number of core dimensions of depression coping addressed by the measure. Study participants (N = 668) completed the original 29 item DCQ and the Center for Epidemiological Studies-Depression (CES-D) scale. The total sample was then split into two equal randomized subsamples. Using a factor loading value cutoff of .40, an initial LISREL exploratory factor analysis produced a 22-item, three-dimension model of positive (10 items), negative (8 items), and substance/sexual (4 items) depression coping behaviors. Because both the negative and substance/sexual dimensions addressed detrimental dimensions of depression coping, these factors were intercorrelated, however, the negative dimension accounted for greater variance. Consequently, given the stated goal of this study the model was then restricted to two core dimensions of positive and negative depression coping. Using the second split-half subsample, a LISREL confirmatory factor analysis produced a 17-item, two-factor model. One negative item (daydreaming) failed to maintain a loading value of .40 or higher and was deleted. The Goodness-of-Fit index for the 17-item, two-factor DCQ was .87 and the Root Mean Square Residual was .08. DCQ alpha coefficients were acceptable at .82 (positive) and .74 (negative). Significant CES-D subgroup differences and correlations were observed. PMID- 10100836 TI - Heaviness of abuse, drug preferences, and personality organization among drug abusers in Sweden. AB - In a case-finding sample of 1,824 substance abusers, personality organization (PO) was related to data on drug abuse. Heavy versus light abuse differentiated significantly between borderline PO (BPO) and neurotic PO (NPO), whereas psychotic PO (PPO) was characterized by inconsistent pattern of abuse in terms of heaviness. In terms of drug choice, all combinations with alcohol were associated with lower PO. PMID- 10100837 TI - A longitudinal study of the relationship of self-preoccupation with depression. AB - Self-preoccupation, the tendency to focus more on the self and to maintain self focused attention, is believed to be a vulnerability factor to depression. The present study investigated this hypothesis in a longitudinal design, using Japanese undergraduates. At Time 1, both self-preoccupation and depressive symptoms at that time, measured by the Zung Self-rating Depression Scale (SDS), were assessed. At Time 2, 3 months later, life events experienced from Time 1 to Time 2 and depressive symptoms at that time were assessed. Data from 169 undergraduates who scored less than 50 on the SDS in Time 1 were analyzed and the above hypothesis was suggested. When experiencing a greater number of negative events, those high in self-preoccupation became more depressed than those who were low in that tendency, though when there were a smaller number of negative events, this difference disappeared. PMID- 10100838 TI - Dimensions of the Beck Depression Inventory-II in clinically depressed outpatients. AB - To ascertain the dimensions of the Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) in clinically depressed outpatients, exploratory factor analyses were performed with the BDI-II responses of 210 adult (> or =18 years) outpatients who were diagnosed with DSM-IV depressive disorders. Two factors representing Somatic-Affective and Cognitive dimensions were found whose compositions were comparable to those previously reported by Beck, Steer, and Brown (1996) for psychiatric outpatients in general. A subsequent confirmatory factor analysis supported a model in which the BDI-II reflected one underlying second-order dimension of self-reported depression composed of two first-order factors representing cognitive and noncognitive symptoms. The clinical utility of using subscales based on these two latter first-order symptom dimensions was discussed. PMID- 10100839 TI - Trends in the use of selective serotonin reuptake inhibitors in nine Department of Veterans Affairs outpatient facilities. AB - The average daily dose and need for dose escalations for the drugs known as selective serotonin reuptake inhibitors (SSRIs) has frequently been a point of controversy. This study reports on the information gathered from nine Veterans Affairs hospitals over a two six-month periods. Average daily doses of fluoxetine, paroxetine, and sertraline started at 30.9 mg, 24.2 mg, and 87.8 mg and ended at 28.4 mg, 24.2 mg, and 89.8 mg, respectively. Cost, number of prescriptions, and dosage strength data is also presented. PMID- 10100840 TI - Initial validation of the Voris Cocaine Craving Scale: a preliminary report. AB - Although cocaine craving can persist for weeks after the last use and is thought to play a role in future relapses, few short, reliable, and valid instruments exist to measure craving. Therefore, we wished to examine the validity of the 4 item Voris Cocaine Craving Scale (VCCS), which was previously found reliable. A consecutive series of 41 recently withdrawn cocaine-dependent patients completed the 4-item VCCS and the Cocaine Craving Questionnaire (CCQ), which was used as the criterion measure. The VCCS items 1 "craving," 2 "mood," and 3 "health" were significant and highly correlated with the CCQ total craving score. The VCCS may prove to be useful in future outcome studies involving cocaine craving and in routine clinical treatment. PMID- 10100841 TI - Optimism and obesity treatment outcomes. AB - To examine the ability of the personality dimension dispositional optimism to predict short-term obesity treatment outcomes (weeks of program attendance and weight loss), 177 consecutive persons seeking outpatient treatment at a university-based weight management center completed the revised Life Orientation Test (LOT-R; Scheier, Carver, & Bridges, 1994) and underwent a comprehensive medically monitored weight loss program. The overall LOT-R and optimism subscales did not correlate with either attendance or weight loss. However, the pessimism subscale was positively associated with weeks of attendance. PMID- 10100842 TI - A possible role of di-leucine-based motifs in targeting and sorting of the syntaxin family of proteins. PMID- 10100843 TI - The structure of the antimicrobial active center of lactoferricin B bound to sodium dodecyl sulfate micelles. AB - Lactoferricin B (LfcinB) is a 25-residue antimicrobial peptide released from bovine lactoferrin upon pepsin digestion. The antimicrobial center of LfcinB consists of six residues (RRWQWR-NH2), and it possesses similar bactericidal activity to LfcinB. The structure of the six-residue peptide bound to sodium dodecyl sulfate (SDS) micelles has been determined by NMR spectroscopy and molecular dynamics refinement. The peptide adopts a well defined amphipathic structure when bound to SDS micelles with the Trp sidechains separated from the Arg residues. Additional evidence demonstrates that the peptide is oriented in the micelle such that the Trp residues are more deeply buried in the micelle than the Arg and Gln residues. PMID- 10100844 TI - cAMP-dependent induction of PDE5 expression in murine neuroblastoma cell differentiation. AB - The present study demonstrates, in both hybrid NG108-15 and mouse neuroblastoma N18TG2 cells, the presence and regulation of PDE5 mRNA during cell differentiation. PDE5 cDNA probes in Northern blot analysis recognize a approximately 9 kb transcript in bovine lung as well as in mouse neuroblastoma cells. Hybridization on total RNA extracted from dibutyryl-cAMP-treated NG108-15 cells shows a 5-fold increase of PDE5 9 kb mRNA: such an increase is not observed in N18TG2 although we observed a similar increase in the enzymatic activity of both cell lines. Our data demonstrate that PDE5 gene expression can be regulated by cAMP and suggest the existence of a complex regulatory system for PDE5 activity. PMID- 10100845 TI - Cloning of the mouse phospholipid hydroperoxide glutathione peroxidase gene. AB - 15-Lipoxygenases and phospholipid hydroperoxide glutathione peroxidases (PH-GPx) are counterparts in the metabolism of hydroperoxy lipids and a balanced regulation of both enzymes appears to be important for the cellular peroxide tone regulating the expression of redox sensitive genes. In contrast to lipoxygenases the molecular biology of PH-GPx is less well investigated. In this study we cloned the PH-GPx cDNA from a mouse fibroblast cDNA library and the PH-GPx gene from a mouse genomic library. The gene spans approximately 4 kb which includes 1 kb of 5'-flanking region and consists of seven exons and six introns. The immediate promoter region does not contain a TATA box but there are binding sites for several transcription factors which also occur in the porcine gene. Our investigations provide useful tools for future targeted gene disruption studies. PMID- 10100846 TI - Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. AB - In vitro evidence has suggested a change in the ability of tau bearing mutations associated with fronto-temporal dementia to promote microtubule assembly. We have used a cellular assay to quantitate the effect of both isoform differences and mutations on the physiological function of tau. Whilst all variants of tau bind to microtubules, microtubule extension is reduced in cells transfected with 3 relative to 4-repeat tau. Mutations reduce microtubule extension with the P301L mutation having a greater effect than the V337M mutation. The R406W mutation had a small effect on microtubule extension but, surprisingly, tau with this mutation was less phosphorylated in intact cells than the other variants. PMID- 10100847 TI - Regulation of Limulus skeletal muscle contraction. AB - Skeletal muscle contraction of Limulus polyphemus, the horseshoe crab, seemed to be regulated in a dual manner, namely Ca2+ binding to the troponin complex as well phosphorylation of the myosin light chains (MLC) by a Ca2+/calmodulin dependent myosin light chain kinase. We investigated muscle contraction in Limulus skinned fibers in the presence of Ca2+ and of Ca2+/calmodulin to find out which of the two mechanisms prevails in Limulus skeletal muscle contraction. Although skinned fibers revealed high basal MLC mono- and biphosphorylation levels (0.48 mol phosphate/mol 31 kDa MLC; 0.52 mol phosphate/mol 21 kDa MLC), the muscle fibers were fully relaxed at pCa 8. Upon C2+ or Ca2+/calmodulin activation, the fibers developed force (357+/-78.7 mN/mm2; 338+/-69.7 mN/mm2, respectively) while the MLC phosphorylation remained essentially unchanged. We conclude that Ca2+ activation is the dominant regulatory mechanism in Limulus skeletal muscle contraction. PMID- 10100848 TI - Hepoxilin signaling in intact human neutrophils: biphasic elevation of intracellular calcium by unesterified hepoxilin A3. AB - We have previously shown that the methyl ester of hepoxilin A3 causes a receptor induced rise in intracellular calcium through the release from intracellular stores in suspended human neutrophils. The corresponding free acid was devoid of activity. We now report that the action of the free acid form of hepoxilin A3 is dependent on the type of vehicle used, i.e. it is active in releasing calcium when used in an ethanol vehicle but not in DMSO. The methyl ester is equally active in either vehicle. The pattern of calcium release between the free acid and the methyl ester is qualitatively different. Both compounds show a biphasic pattern, i.e. an initial rapid phase followed by a slow decline in calcium levels but never reaching pre-hepoxilin A3 baseline levels. The methyl ester appears slightly more potent in the initial phase of calcium release than the free acid (methyl = 188+/-14 S.D., free acid = 135+/-11 S.D. nM, P < 0.0005). Both compounds appear to reach the same calcium levels at the plateau of the second prolonged phase (methyl = 88+/-8 S.D., free acid = 107+/-15 S.D. nM, not significant). Lanthanum chloride (an inhibitor of calcium influx) interfered with the second phase of the curve causing calcium levels to return to normal pre hepoxilin levels for both compounds. Addition of lanthanum chloride prior to the hepoxilin addition or carrying out the experiments in calcium-free medium, eliminated the second phase completely, with the calcium peak returning rapidly to normal baseline levels, suggesting that the second phase is due to calcium influx. Again the methyl ester is more active than the free acid (methyl, 189+/ 12; free acid, 145+/-6 S.D. nM, P<0.005). Additional experiments with tritium labelled methyl ester of hepoxilin A3 demonstrated that the compound is hydrolyzed into the free acid intracellularly. These experiments demonstrate that DMSO interacts with hepoxilin free acid, interfering with its entry into the cell while ethanol does not. Once inside the cell, hepoxilin interacts with its own receptor to release calcium rapidly from stores, but it also causes a more prolonged influx of calcium from the extracellular milieu. PMID- 10100849 TI - Protein phosphatase 1 is involved in the dissociation of Ca2+/calmodulin dependent protein kinase II from postsynaptic densities. AB - Autophosphorylation-dependent translocation of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) to postsynaptic densities (PSDs) from cytosol may be a physiologically important process during synaptic activation. We investigated a protein phosphatase responsible for dephosphorylation of the kinase. CaM kinase II was shown to be targeted to two sites using the gel overlay method in two dimensional gel electrophoresis. Protein phosphatase 1 (PP1) was identified to dephosphorylate CaM kinase II from its complex with PSDs using phosphatase inhibitors and activators, and purified phosphatases. The kinase was released from PSDs after its dephosphorylation by PP1. PMID- 10100850 TI - Complement component C8gamma is expressed in human fetal and adult kidney independent of C8alpha. AB - Human complement component C8gamma is an unusual complement factor since it shows no homology to other complement proteins but is a member of the lipocalin superfamily. So far, it has been found exclusively in plasma, covalently linked to C8alpha by disulfide bridging. We have used dot blot and Northern blot analyses of a large number of different human tissues to survey systematically the expression pattern of C8gamma. Our experiments clearly showed that besides in liver, this gene is also expressed in fetal and adult kidney. Renal expression of C8gamma is not dependent on C8alpha expression, since we could not detect C8alpha expression in kidney. Thus its physiological function is not restricted to a specific action in association with complement components. As a prerequisite for further characterization of the structure and binding activities of the uncomplexed C8gamma, we have expressed the encoding cDNA in Escherichia coli. To increase the probability for proper folding of the characteristic intramolecular disulfide bridge the recombinant protein was produced by secretion to the periplasm. PMID- 10100851 TI - Characterization of a cDNA encoding a precursor of Carassius RFamide, structurally related to a mammalian prolactin-releasing peptide. AB - We have characterized the cDNA encoding Carassius RFamide (C-RFa), which is structurally related to mammalian prolactin-releasing peptides (PrRPs), from the brain of the crucian carp. The deduced C-RFa precursor has been shown to comprise 117 amino acids, encoding a single C-RFa sequence. A comparative study of amino acid sequences has revealed that several sequences conserved in preproPrRPs are also found in the C-RFa precursor. Furthermore, the abundant presence of the C RFa mRNA in the telencephalon, optic tectum, medulla oblongata, and proximal half eye ball was demonstrated by Southern blot analysis of RT-PCR products. PMID- 10100852 TI - The chum salmon IGF-II gene promoter is activated by hepatocyte nuclear factor 3beta. AB - IGF-II plays an important role in growth and development of vertebrates and is highly expressed in adult salmon liver. In the present study, we demonstrate that a liver-enriched transcription factor, hepatocyte nuclear factor 3beta (HNF 3beta), is an activator of the chum salmon IGF-II gene. Multiple binding sites for HNF-3beta were identified within the 5'-UTR using electrophoretic mobility shift assays and mutation of these sites prevents binding of HNF-3beta. In transient transfection assays it was shown that mutation of the HNF-3beta binding sites results in a substantial decrease of HNF-3beta-activated salmon IGF-II gene expression. This is the first identified transcription factor that is functionally involved in the regulation of fish IGF-II expression. PMID- 10100853 TI - Central role of epidermal growth factor (EGF) receptor density in anchorage independent growth of normal rat kidney cells. AB - Epidermal growth factor (EGF) receptor levels are known to play a central role in density dependent growth regulation of normal rat kidney (NRK) fibroblasts. Here we show that EGF receptor expression is strongly decreased when NRK cells are cultured under anchorage independent conditions, and that expression is returned to original levels upon cell readherence. Agents that stimulate anchorage independent growth (AIG) of NRK cells in the presence of EGF are shown to upregulate both EGF receptor promoter activity and (125)I-EGF binding capacity. These data show that two aspects of phenotypic transformation of NRK cells, namely density arrest and AIG, can both directly be correlated to EGF receptor levels. PMID- 10100854 TI - The assumption that nitric oxide inhibits mitochondrial ATP synthesis is correct. AB - The assumption that reversible inhibition of mitochondrial respiration by nitric oxide (NO.) represents inhibition of ATP synthesis is unproven. NO. could theoretically inhibit the oxygen consumption with continued ATP synthesis, by acting as an electron acceptor from cytochrome c or as a terminal electron acceptor in stead of oxygen. We report here that NO. does reversibly inhibit brain mitochondrial ATP synthesis with a time course similar to its inhibition of respiration. Whilst such inhibition was largely reversible, there appeared to be a small irreversible component which may theoretically be due to peroxynitrite formation, i.e. as a result of the reaction between NO. and superoxide, generated by the mitochondrial respiratory chain. PMID- 10100855 TI - Unique topology of the internal repeats in the cardiac Na+/Ca2+ exchanger. AB - Hydropathy analysis predicts 11 transmembrane helices in the cardiac Na+/Ca2+ exchanger. Using cysteine susceptibility analysis and epitope tagging, we here studied the membrane topology of the exchanger, in particular of the highly conserved internal alpha-1 and alpha-2 repeats. Unexpectedly, we found that the connecting loop in the alpha-1 repeat forms a re-entrant membrane loop with both ends facing the extracellular side and one residue (Asn-125) being accessible from the inside and that the region containing the alpha-2 repeat is mostly accessible from the cytoplasm. Together with other data, we propose that the exchanger may consist of nine transmembrane helices. PMID- 10100856 TI - AlphaB-crystallin in the rat lens is phosphorylated at an early post-natal age. AB - We determined the developmental changes in the phosphorylation state of alphaB crystallin in lenses from rats at various post-natal ages by isoelectric focusing gel electrophoresis or sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a subsequent Western blot analysis of extracts of lenses using antibodies that recognized the carboxy-terminal sequence or each of the three phosphorylated serine residues (Ser-19, Ser-45 and Ser-59) in alphaB-crystallin. Phosphorylated forms of alphaB-crystallin were barely detected at birth but they became detectable at 3 weeks of age and reached plateau levels at 8 weeks of age. The phosphorylation of alphaB-crystallin at Ser-45 was observed preferentially. The active form of p44/42 MAP kinase, which is responsible for the phosphorylation of Ser-45 in alphaB-crystallin, also increased in a development-dependent manner. Thus we found that the developmental increase of the phosphorylation at Ser-45 of alphaB-crystallin in the rat lens was due to the developmental activation of p44/42 MAP kinase. PMID- 10100857 TI - Mapping of the MYCL2 processed gene to Xq22-23 and identification of an additional L MYC-related sequence in Xq27.2. AB - We report here the identification of a human genomic sequence from the q27.2 region of the X chromosome which shows a high homology to the L-MYC proto oncogene. This sequence is not the MYCL2 homology, previously mapped to the long arm of the X chromosome at q22-qter by Morton et al., as we located the MYCL2 processed gene in Xq22-23, using a panel containing a combination of hybrid DNA carrying different portions of the human X chromosome. Based on computer analysis, the MYC-like sequence (MYCL3) is 98.2% identical to a portion of exon 3 of the MYCL1 gene and maps to the Xq27.2 region, between the DXS312 and DXS292 loci. PMID- 10100858 TI - Identification and characterization of a 14 kDa human protein as a novel parvulin like peptidyl prolyl cis/trans isomerase. AB - A second member of the parvulin family of peptidyl-prolyl cis/trans isomerases was identified in a human lung cDNA library. The gene encoded a protein named hPar14 that has 131 amino acid residues and a molecular mass of 13676 Da. Sequence comparison showed 34.5% identity to E. coli Par10 and 34% identity to human Pin1 (hPar18) within a C-terminal region of 87 or 120 amino acid residues, respectively. In comparison to the E. coli Par10, hPar14 possesses a N-terminal extension of 41 amino acid residues. This extension does not contain a polyproline II helix-binding motif typical of the known eukaryotic parvulins. The hPar14 does not accelerate the cis to trans interconversion of oligopeptides with side chain-phosphorylated Ser(Thr)-Pro moieties as hPin1 did. In contrast, it showed preference of an arginine residue adjacent N-terminal to proline. Northern blot analysis revealed expression of the gene within various human tissues like heart, placenta, liver, kidney and pancreas. PMID- 10100859 TI - Absence in amphotericin B-spiked human plasma of the free monomeric drug, as detected by SERS. AB - Using surface enhanced Raman spectroscopy (SERS) which enables us to specifically detect traces of monomeric amphotericin B (AmB), we were able to show that in a 10(-5) M AmB suspension, the concentration of free drug was below 10(-8) M in the presence of low density lipoproteins (LDL) or plasma. The affinity constant of AmB for LDL determined from electronic absorption data, was found to be 4 x 10(6) M(-1). Therefore, since AmB appears to be in the majority bound to lipoproteins under in vivo conditions, its toxicity should not result from the induction of host-cell transmembrane permeability but rather from the internalization of the AmB-LDL complex. PMID- 10100860 TI - A novel dnaK operon from Porphyromonas gingivalis. AB - The nucleotide sequence of the dnaK operon cloned from Porphyromonas gingivalis revealed that the operon does not contain homologues of either dnaJ or grpE. However, there were two genes which encode small heat shock proteins immediately downstream from the dnaK and they were transcribed together with dnaK as one unit. The ATPase activity of the P. gingivalis DnaK was synergistically stimulated up to 40-fold in the simultaneous presence of Escherichia coli DnaJ and GrpE. These results suggest that the DnaK homologue of P. gingivalis, with its unique genetic structure and evolutionary features, works as a member of the DnaK chaperone system. PMID- 10100861 TI - TM7XN1, a novel human EGF-TM7-like cDNA, detected with mRNA differential display using human melanoma cell lines with different metastatic potential. AB - We have identified a novel 3845 bp cDNA differentially expressed in a human melanoma metastasis model. Northern blot analysis showed expression in the poorly and intermediately metastasizing cell lines and a marked downregulation in the highly metastatic cell lines. Using RT-PCR expression was also seen in several other tumor cell lines and normal cell types of human origin. cDNA sequence analysis revealed an ORF of 687 amino acids containing seven putative transmembrane domains C-terminally and a long N-terminus. The gene was mapped to 16q13. Highest homology was observed with members of the EGF-TM7 subfamily of the secretin/calcitonin receptor family. We propose the delineation of a subfamily of TM7 proteins, LN-TM7, containing seven transmembrane proteins with a long N terminal extracellular part. PMID- 10100862 TI - Surface display of functional fibronectin-binding domains on Staphylococcus carnosus. AB - The surface expression in Staphylococcus carnosus of three different fibronectin binding domains (FNBDs), derived from fibronectin binding proteins of Streptococcus dysgalactiae and Staphylococcus aureus, has been investigated. Surface localization of the chimeric proteins containing the FNBDs was demonstrated. All three surface-displayed FNBDs were demonstrated to bind fibronectin in whole-cell enzyme-linked binding assays. Furthermore, for one of the constructs, intranasal immunizations with the recombinant bacteria resulted in improved antibody responses to a model immunogen present within the chimeric surface proteins. The implications of the results for the design of live bacterial vaccine delivery systems are discussed. PMID- 10100863 TI - Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein. AB - Uric acid and ascorbic acid are important low molecular weight antioxidants in plasma. Their interactions and combined effect on Cu(2+)-catalysed oxidation of human low density lipoprotein were studied in vitro. It was found that uric acid alone becomes strongly prooxidant whenever it is added to low density lipoprotein shortly after the start of oxidation (conditional prooxidant). Ascorbic acid, which is present in human plasma at much lower concentrations (20-60 microM) than urate (300-400 microM), is in itself not a conditional prooxidant. Moreover, ascorbate prevents prooxidant effects of urate, when added to oxidising low density lipoprotein simultaneously with urate, even at a 60-fold molar excess of urate over ascorbate. Ascorbate appears to have the same anti-prooxidant effect with other aqueous reductants, which, besides their antioxidant properties, were reported to be conditionally prooxidant. Such interactions between ascorbate and urate may be important in preventing oxidative modification of lipoproteins in the circulation and in other biological fluids. PMID- 10100864 TI - Caffeine releases a glucose-primed endoplasmic reticulum Ca2+ pool in the insulin secreting cell line INS-1. AB - Caffeine mobilized an intracellular Ca2+ pool in intact fura-2-loaded INS-1 cells in suspension exposed to high (16 mM) [glucose], while a minor effect was observed with low (2 mM) [glucose]. Cells were kept in a medium containing diaxozide or no Ca2+ to prevent the influx of extracellular Ca2+. The caffeine sensitive intracellular Ca2+ pool was within the endoplasmic reticulum since it was depleted by the inhibitor of the reticular Ca2+ pumps thapsigargin and the InsP3-dependent agonist carbachol. No effect of caffeine was observed in the parent glucose-insensitive RINmF5 cells. In microsomes from INS-1 but not RINmF5 cells, the type 2 ryanodine receptor was present as revealed by Western blotting. It was concluded that the endoplasmic reticulum of INS-1 cells possesses caffeine sensitive type 2 ryanodine receptors Ca2+ channels. PMID- 10100865 TI - Molecular cloning of rat GADD45gamma, gene induction and its role during neuronal cell death. AB - To study the molecular mechanism of neuronal cell death, we carried out the screening of genes which were induced during the neuronal cell death of neuronal PC12. We cloned the cDNA of rat GADD45gamma, the third member of the GADD45 family. Induction of GADD45gamma mRNA was observed in the neuronal cell death caused by depletion of neurotrophic factor and Ca2+ ionophore treatment. Overexpression of GADD45gamma in superior cervical ganglion neurons caused cell death. These results suggest that GADD45gamma plays an important role in neuronal cell death. PMID- 10100866 TI - Prevention of alphaII(b)beta3 activation by non-steroidal antiinflammatory drugs. AB - We have studied the effect of non-steroidal antiinflammatory drugs (NSAIDs) on alphaII(b)beta3 integrin activation and platelet aggregation. NSAIDs such as meloxicam, piroxicam, indomethacin and aspirin, but not aceclofenac or diclofenac interfered with the activation state of alphaII(b)beta3. NSAIDs that inhibited alphaII(b)beta3 activation were also able both to partially inhibit platelet primary aggregation and to accelerate platelet deaggregation. These effects of NSAIDs were not dependent on cyclooxygenase inhibition. The results obtained indicate that some NSAIDs exert a specific action on alphaII(b)beta3 activation, and provide an additional mechanism that accounts for their beneficial effects in diseases in which platelet activation is involved. PMID- 10100867 TI - Dysfunctions of the epididymis as a result of primary carnitine deficiency in juvenile visceral steatosis mice. AB - The juvenile visceral steatosis mutant mice serve as an animal model of primary carnitine deficiency, classified as the sudden infant death syndrome. The defect in carnitine uptake was recently found to be due to a defect in the carnitine transporter gene. We herein report, for the first time, the characteristics of epididymal dysfunction in juvenile visceral steatosis mice. At 8-9 weeks of age, the epididymis was deformed and weight was significantly increased. Histologically, the duct of the proximal epididymis was dilated due to the accumulation of an unusually high level of spermatozoa. Spermatozoa were extravasated from the epididymal duct into the stroma. In contrast, the duct of the distal epididymis was constricted and contained no spermatozoa. Thus, the epididymal disorder causes obstructive azoospermia, leading to infertility. PMID- 10100868 TI - Interaction of heparin with annexin V. AB - The energetics and kinetics of the interaction of heparin with the Ca2+ and phospholipid binding protein annexin V, was examined and the minimum oligosaccharide sequence within heparin that binds annexin V was identified. Affinity chromatography studies confirmed the Ca2+ dependence of this binding interaction. Analysis of the data obtained from surface plasmon resonance afforded a Kd of approximately 21 nM for the interaction of annexin V with end chain immobilized heparin and a Kd of approximately 49 nM for the interaction with end-chain immobilized heparan sulfate. Isothermal titration calorimetry showed the minimum annexin V binding oligosaccharide sequence within heparin corresponds to an octasaccharide sequence. The Kd of a heparin octasaccharide binding to annexin V was approximately 1 microM with a binding stoichiometry of 1:1. PMID- 10100869 TI - The role of DnaK/DnaJ and GroEL/GroES systems in the removal of endogenous proteins aggregated by heat-shock from Escherichia coli cells. AB - The submission of Escherichia coli cells to heat-shock (45 degrees C, 15 min) caused the intracellular aggregation of endogenous proteins. In the wt cells the aggregates (the S fraction) disappeared 10 min after transfer to 37 degrees C. In contrast, the S fraction in the dnaK and dnaJ mutant strains was stable during approximately one generation time (45 min). This demonstrated that neither the renaturation nor the degradation of the denatured proteins was possible in the absence of DnaK and DnaJ. The groEL44 and groES619 mutations stabilised the aggregates to a lesser extent. It was shown by the use of cloned genes, dnaK/dnaJ or groEL/groES, producing the corresponding proteins in about 4-fold excess, that the appearance of the S fraction in the wt strain resulted from a transiently insufficient supply of the heat-shock proteins. Overproduction of the GroEL/GroES proteins in dnaK756 or dnaJ259 background prevented the aggregation, however, overproduction of the DnaK/DnaJ proteins did not prevent the aggregation in the groEL44 or groES619 mutant cells although it accelerated the disappearance of the aggregates. The properties of the aggregated proteins are discussed from the point of view of their competence to renaturation/degradation by the heat-shock system. PMID- 10100870 TI - Change in lactate production in Myc-transformed cells precedes apoptosis and can be inhibited by Bcl-2 overexpression. AB - As a result of Myc-dependent transcription of the LDH-A gene, Myc-transformed cells (Rat1-Myc) exhibit increased lactate production rates (LPR) even under aerobic conditions (the Warburg effect). Recently, the increased susceptibility to stress-induced apoptosis associated with Myc transfection has been linked to the overexpression of the LDH-A gene. In this report we demonstrate that the overexpression of the anti-apoptotic protein Bcl-2 in Rat1-Myc cells (Rat1-Myc Bcl-2) reduces the molar ratio of lactate production to glucose consumption (Y(L/G)). The Bcl-2 induced reduction in Y(L/G) may be associated with reduced expression of the LDH-A gene, or a decrease in LDH-A activity. Stimulation of apoptosis by staurosporine, a protein kinase C inhibitor, reduces the LPR in Rat1 Myc cells in a dose-dependent manner. The staurosporine effect on the LPR is rapid and precedes the execution phase of apoptosis as defined by caspase activation and PARP cleavage. This effect on LPR is completely blocked by Bcl-2 overexpression. Serum starvation alone does not affect the LPR of Rat1-Myc or Rat1-Myc-Bcl-2 cells; however, the effect of staurosporine on the LPR of Rat1-Myc cells is potentiated by serum starvation. These data demonstrate that Bcl-2 overexpression reduces the Y(L/G) in Rat1-Myc cells, perhaps via a reduction in the activity or expression of the LDH-A gene, and this reduction may desensitize cells to some pro-apoptotic stimuli. The reduction in LPR in response to staurosporine may be an early step in the induction of apoptosis in Rat1-Myc cells. By abolishing the reduction in LPR, Bcl-2 may protect Rat1-Myc cells from staurosporine-induced apoptosis. Moreover, the lack of effect by serum starvation on the LPR supports a model in which serum starvation induces apoptosis through a pathway distinct from that of the staurosporine and glucose-dependent apoptotic pathway(s) in Myc-transformed cells. PMID- 10100871 TI - DNA binding protein dbpA binds Cdk5 and inhibits its activity. AB - Progress in the cell cycle is governed by the activity of cyclin dependent kinases (Cdks). Unlike other Cdks, the Cdk5 catalytic subunit is found mostly in differentiated neurons. Interestingly, the only known protein that activates Cdk5 (i.e. p35) is expressed solely in the brain. It has been suggested that, besides its requirement in neuronal differentiation, Cdk5 activity is induced during myogenesis. However, it is not clear how this activity is regulated in the pathway that leads proliferative cells to differentiation. In order to find if there exists any Cdk5-interacting protein, the yeast two-hybrid system was used to screen a HeLa cDNA library. We have determined that a C-terminal 172 amino acid domain of the DNA binding protein, dbpA, binds to Cdk5. Biochemical analyses reveal that this fragment (dbpA(Cdelta)) strongly inhibits p35-activated Cdk5 kinase. The protein also interacts with Cdk4 and inhibits the Cdk4/cyclin D1 enzyme. Surprisingly, dbpA(Cdelta) does not bind Cdk2 in the two-hybrid assay nor does it inhibit Cdk2 activated by cyclin A. It could be that dbpA's ability to inhibit Cdk5 and Cdk4 reflects an apparent cross-talk between distinct signal transduction pathways controlled by dbpA on the one hand and Cdk5 or Cdk4 on the other. PMID- 10100872 TI - IS3 peptide-formed ion channels in rat skeletal muscle cell membranes. AB - A 22-mer peptide, identical to the primary sequence of domain I segment 3 (IS3) of rat brain sodium channel I, was synthesized. With the patch clamp cell attached technique, single channel currents could be recorded from the patches of cultured rat myotube membranes when the patches were held at hyperpolarized potentials and the electrode solution contained NaCl and 1 microM IS3, indicating that IS3 incorporated into the membranes and formed ion channels. The single channel conductances of IS3 channels were distributed heterogeneously, but mainly in the range of 10-25 pS. There was a tendency that the mean open time and open probability of IS3 channels increased and the mean close time decreased with the increasing of hyperpolarized membrane potentials. IS3 channels are highly selective for Na+ and Li+ but not for Cl- and K+, similar to the authentic Na+ channels. PMID- 10100873 TI - Aromatic ring cleavage of a non-phenolic beta-O-4 lignin model dimer by laccase of Trametes versicolor in the presence of 1-hydroxybenzotriazole. AB - The novel cleavage products, 2,3-dihydroxy-1-(4-ethoxy-3-methoxyphenyl)-1 formyloxypropane (II) and 1-(4-ethoxy-3-methoxyphenyl)-1,2,3-trihydroxypropane 2,3-cyclic carbonate (III) were identified as products of a non-phenolic beta-O-4 lignin model dimer, 1,3-dihydroxy-2-(2,6-dimethoxylphenoxy)-1-(4-ethoxy-3 methoxypheny l)propane (I), by a Trametes versicolor laccase in the presence of 1 hydroxybenzotriazole (1-HBT). An isotopic experiment with a 13C-labeled lignin model dimer, 1,3-dihydroxy-2-(2,6-[U-ring-13C] dimethoxyphenoxy)-1-(4-ethoxy-3 methoxyphenyl)propane (I-13C) indicated that the formyl and carbonate carbons of products II and III were derived from the beta-phenoxy group of beta-O-4 lignin model dimer I as aromatic ring cleavage fragments. These results show that the laccase-1-HBT couple could catalyze the aromatic ring cleavage of non-phenolic beta-O-4 lignin model dimer in addition to the beta-ether cleavage, Calpha-Cbeta cleavage, and Calpha-oxidation. PMID- 10100874 TI - On the barometric method for measurements of ventilation, and its use in small animals. AB - The barometric method is a common technique for measurements of pulmonary ventilation in unrestrained animals. It basically consists of recording the changes in chamber pressure generated during breathing. In fact, as the air inspired is warmed and humidified from the ambient to the pulmonary values, the total pressure in the animal chamber increases; the opposite occurs in expiration. The present commentary is an introduction to this method, briefly reviewing its historical development, the conceptual pitfalls, and potential sources of errors during practical applications. PMID- 10100875 TI - Whole-body plethysmography, does it measure tidal volume of small animals? AB - A whole-body plethysmograph was used for mice. The increase in pressure caused by each inhalation was equivalent to the increase that could be calculated to result from heating and humidification of the inhaled air. However, comprehending that a drop in temperature and humidity would cause an abrupt pressure decline during exhalation was difficult. Pressure changes in the plethysmograph were also studied with an artificial chest, modeling the respiratory mechanics, but without the "inhaled" air being heated or humidified. The "chest" consisted of a metal bellows oscillated by a stepper motor 25 to 175 times per minute. Hereby air (0.05 to 0.20 mL) moved in and out of the bellows. The air passed through a polyethylene tube, the length of which was proportional to "airway resistance" and varied from 5 to 35 cm. It was found that the pressure oscillation was affected not only by "tidal volume" of the mechanical chest but also by "respiratory rate" and by "airway resistance." We concur with previous investigators that the plethysmograph pressure reflects alveolar pressure and that fluctuations cannot be explained by changes in temperature and humidity. Accordingly, tidal volume can only be qualitatively and not quantitatively assessed. PMID- 10100876 TI - Estrogen administration, postexercise tissue oxidative stress and vitamin C status in male rats. AB - Estrogen can putatively act as an antioxidant and protect tissues from exercise induced oxidative stress. To test the in vivo efficacy of estrogen, the effects of 2 weeks of daily estrogen (40 microg x kg(-1) body weight beta-estradiol 3 benzoate) injection on indices of immediate postexercise oxidative stress and antioxidant status were determined in adult male rats, with and without 8 weeks of prior dietary vitamin E deprivation. The treadmill running protocol (60 min at 21 m x min(-1), 12% grade) induced significant oxidative stress as indicated by muscle glutathione status. Estrogen administration had little effect on postexercise tissue glutathione status, superoxide dismutase and glutathione peroxidase activity, and vitamin E levels. Estrogen administration induced significant reductions in muscle, liver, and heart vitamin C concentrations following exercise, as well as in unexercised male rats. Tissue vitamin C loss was not directly mediated through liver glycogen or glutathione status. Thus, estrogen administration generally did not appear to influence postexercise tissue indices of oxidative stress or antioxidant status and may have contributed to a decline in overall antioxidant protection by inducing losses in tissue vitamin C content. PMID- 10100877 TI - Modification of beta-adrenoceptors and adenylyl cyclase in hearts perfused with hypochlorous acid. AB - It is now well known that the signal transduction pathway involving beta adrenoceptors and adenylyl cyclase is altered in ischemic heart disease. Since leukocytes accumulate in the ischemic heart and produce hypochlorous acid (HOCl), we investigated the effects of HOCl upon beta-adrenoceptors and adenylyl cyclase activities by perfusing rat hearts with 0.1 mM HOCl for 10 min and isolating cardiac membranes. Marked depressions in both the density and affinity of beta1 adrenoceptors were observed, whereas no significant change in the affinity or density of beta2-adrenoceptors was seen in hearts perfused with HOCl. After treatment of hearts with HOCl, competition curves using isoproterenol, a beta adrenoceptor agonist, revealed a decrease in the proportion of high affinity binding sites. The adenylyl cyclase activities in the absence and presence of forskolin, NaF, Gpp(NH)p, or isoproterenol were depressed in hearts perfused with HOCl; however, the stimulatory effects of these agents on adenylyl cyclase were either unaltered or augmented. The presence of methionine in the perfusion medium prevented the HOCl-induced changes in beta1-adrenoceptors and adenylyl cyclase activity. These results suggest that HOCl may produce a defect in the beta adrenoceptor linked signal transduction mechanism by affecting both beta1 adrenoceptors and adenylyl cyclase enzyme in the myocardium. PMID- 10100878 TI - Effects of norepinephrine on lung liquid production by in vitro lungs from fetal guinea pigs. AB - Lungs from near-term fetal guinea pigs (61 +/- 2 days of gestation) were supported in vitro for 3 h; lung liquid production was monitored by a dye dilution method. Untreated control preparations produced fluid at 1.38 +/- 0.30 mL x kg(-1) body weight x h(-1), with no significant change (ANOVA; regression analysis); those given 1.24 x 10(-9) or 1.24 x 10(-8) M norepinephrine during the middle hour showed no significant change, but those given concentrations between 5.24 x 10(-8) and 1.24 x 10(-5) M all showed significant reductions or fluid reabsorption (based on 42 fetuses). The responses showed a linear relationship with the log concentration (r = 0.97). They appeared to involve alpha adrenoreceptors, since responses to 10(-7) M norepinephrine were unaffected by 10(-6) M propranolol, but those to 10(-7) and 1.24 x 10(-6) M norepinephrine were abolished by 10(-6) and 1.78 x 10(-5) M phentolamine, respectively (based on 48 fetuses). Activation was through alpha2-adrenoreceptors, since responses to 10( 7) and 10(-5) M norepinephrine were abolished by 10(-4) M yohimbine, but not by 10(-5) M prazosin (based on 60 fetuses). The results show that norepinephrine is able to reduce lung liquid production when at plasma levels present at birth, and that it can produce reabsorption; unlike epinephrine, there was no reduction in responses at high concentrations. This work reintroduces a neglected factor, norepinephrine, into possible controls of lung liquid reabsorption, and opens up the potential for neural controls. PMID- 10100879 TI - Caffeine and length dependence of staircase potentiation in skeletal muscle. AB - Skeletal muscle sensitivity to Ca2+ is greater at long lengths, and this results in an optimal length for twitch contractions that is longer than optimal length for tetanic contractions. Caffeine abolishes this length dependence of Ca2+ sensitivity. Muscle length (ML) also affects the degree of staircase potentiation. Since staircase potentiation is apparently caused by an increased Ca2+ sensitivity of the myofilaments, we tested the hypothesis that caffeine depresses the length dependence of staircase potentiation. In situ isometric twitch contractions of rat gastrocnemius muscle before and after 10 s of 10-Hz stimulation were analyzed at seven different lengths to evaluate the length dependence of staircase potentiation. In the absence of caffeine, length dependence of Ca2+ sensitivity was observed, and the degree of potentiation after 10-Hz stimulation showed a linear decrease with increased length (DT = 1.47 - 0.05 ML, r2 = 0.95, where DT is developed tension). Length dependence of Ca2+ sensitivity was decreased by caffeine when caffeine was administered in amounts estimated to result in 0.5 and 0.75 mM concentrations. Furthermore, the negative slope of the relationship between staircase potentiation and muscle length was diminished at the lower caffeine dose, and the slope was not different from zero after the higher dose (DT = 1.53 - 0.009 ML, r2 = 0.43). Our study shows that length dependence of Ca2+ sensitivity in intact skeletal muscle is diminished by caffeine. Caffeine also suppressed the length dependence of staircase potentiation, suggesting that the mechanism of this length dependence may be closely related to the mechanism for length dependence of Ca2+ sensitivity. PMID- 10100880 TI - Nimodipine inhibits the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb) in the rat. AB - Impaired nitric oxide (NO) activity is associated with an increase in blood pressure in rats. Voltage-regulated calcium channels are believed to participate in this hemodynamic event. To further test this hypothesis, we examined the effect of nimodipine and verapamil (calcium antagonists) on the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a well-known NO scavenger, in anesthetized rats. Nimodipine, the most potent of the two calcium antagonists used, was also tested against phenylephrine (alpha1-adrenoceptor agonist). The pressor effect of DCLHb was reduced markedly by nimodipine and verapamil, whereas that elicited by phenylephrine, particularly the tonic phase of its pressor response, was resistant to blockade by nimodipine. The bradycardia and tachycardia associated with the pressor effects of DCLHb and phenylephrine, respectively, were not affected by nimodipine. The pressor effect elicited by DCLHb and its alteration by nimodipine were also examined in rats pretreated with 100% O2. This treatment was found to potentiate the pressor effect of DCLHb. However, this synergism did not impair the inhibitory action of nimodipine towards the pressor activity of DCLHb. Altogether these results suggest that the pressor activity of DCLHb in our animal model might involve the participation of voltage-regulated calcium channels. PMID- 10100881 TI - Sodium nitrite, a potent relaxant of rat stomach fundus: in vitro evidence. AB - The effects of sodium nitrite (0.1, 1, 10 mM) on mechanical activity of isolated rat stomach fundus muscle and the influence of guanylate cyclase activity inhibitor (methylene blue) and channel inhibitors (tetrodotoxin, charybdotoxin, apamin) were studied. Nitrite evoked dose-dependent relaxation in the longitudinal and circular muscle layers. The lowest effective concentration of sodium nitrite was 0.1 mM, which is comparable with the NOAEL (no observed adverse effect level). Tetrodotoxin (1 microM) markedly inhibited electrically induced contraction and rebound relaxation, but did not influence the nitrite induced relaxation. Charybdotoxin (100 nM) decreased the relaxation evoked by 10 mM nitrite to 52.3 and 65.7% of control reaction in the circular and longitudinal muscle layer, respectively. Apamin (100 nM) did not influence the nitrite-induced relaxation. Methylene blue (10 microM) decreased relaxation induced by nitrite in the longitudinal and circular muscle layer, respectively, to 66.7 and 54.3% of the response to 1 mM nitrite alone. Relaxation induced by nitrite was decreased in the presence of L-cysteine (5 mM), and in the circular and longitudinal muscle layer reached 29.6 and 23.1%, respectively, of the response to 1 mM nitrite alone. We conclude that the relaxing effect of nitrite on gastric fundus results from its direct action on smooth muscle cells and probably the enteric nervous system is not involved in this action. The nitrite-elicited relaxation depends on activation of guanylate cyclase and high conductance Ca2+-activated potassium channels; however, activation of potassium channels might be a part of or might act in parallel with the mechanism involving the cyclic GMP system. Effects of nitrite observed in the presence of L-cysteine suggest that nitrosothiols are not responsible for nitrite-evoked activation of guanylate cyclase. PMID- 10100882 TI - Soy protein isolate in the presence of cornstarch reduces body fat gain in rats. AB - The objective of the present study was to determine the combined effects of dietary protein and carbohydrate sources on total body energy and protein and fat gains as well as on plasma insulin and glucose and tissue lipoprotein lipase activity in male Sprague-Dawley rats fed semipurified diets for 28 days. The diets varied in both protein and carbohydrate sources, namely, casein-cornstarch, casein-sucrose, soy protein isolate (SPI)-cornstarch, SPI-sucrose, cod protein cornstarch, and cod protein-sucrose. When SPI was combined with cornstarch, lower total body energy and fat gains were observed compared with the combination of either casein and sucrose, casein and cornstarch, or SPI and sucrose. Plasma glucose and insulin concentrations in addition to total and metabolizable energy intake and body weight gain were lower in rats fed the SPI-cornstarch diet than in those fed the casein-sucrose diet. Feeding the SPI-cornstarch diet compared with feeding either the casein-cornstarch or the SPI-sucrose diet also caused lower plasma glucose concentrations and a concomitant trend (p = 0.06) to reduced energy intake and body weight gain. Therefore, the reducing effects of the SPI cornstarch diet compared with the casein-cornstarch, the casein-sucrose, and the SPI-sucrose diets on body energy and fat gains may result from reductions in energy intake and in plasma glucose concentrations. PMID- 10100883 TI - Increased neural damage to global hemispheric hypoxic ischemia (GHHI) in febrile but not nonfebrile lipopolysaccharide Escherichia coli injected rats. AB - Experiments were conducted to compare the impact of febrile versus nonfebrile lipopolysaccharide (LPS) induced bacterial infection at the time of global hemispheric hypoxic ischemia (GHHI) on the neural damage evoked by the GHHI insult. In the first study acute intraperitoneal (i.p.) sterile saline (SS) or LPS Escherichia coli (60 microg/kg) was given to groups of male, conscious Long Evans rats, and core (colonic, Tc) temperatures were monitored over 6 h postinjection. Peak febrile response occurred approximately 5 h after the LPS E. coli was injected. Upon sacrifice 7 days later, no hemispheric or regional brain damage occurred in the saline or LPS-injected groups of this first study. In the second study, GHHI was applied (ligation of right common carotid artery + 35 min of 12% O2) in groups of anesthetized, male Long Evans rats previously given an acute i.p. injection of sterile saline or 60 microg/kg LPS E. coli 5 h earlier. Temperatures (Tc) were monitored before, during, and 1.5 and 24 h following GHHI. The LPS-injected group was subdivided into a febrile (Tc > 38 degrees C before and (or) after GHHI) and nonfebrile (Tc < 38 degrees C before and after GHHI) subgroups. A significant correlation was found between the peak temperature rise from preinjection control values following drug administration of either saline or LPS E. coli and the resultant hemispheric damage caused by GHHI. Moreover, upon sacrifice 7 days later ipsilateral hemispheric and regional (i.e., hippocampal, thalamic) damage to GHHI of the febrile LPS E. coli group was significantly increased from respective hemispheric, hippocampal, and thalamic damage of the saline and nonfebrile, LPS groups given the same ischemic insult. Results suggest that the heightened Tc of a LPS infection at the time of global ischemia exacerbated the neural damage of GHHI, a finding similar to that reported with heightened core temperatures induced by external heating. PMID- 10100884 TI - Inhibitory effect of gymnemic acid on intestinal absorption of oleic acid in rats. AB - Gymnemic acid, a mixture of triterpene glycosides extracted from the leaves of Gymnema sylvestre, is known to inhibit the intestinal absorption of glucose in human and rats. This work examined the effect of gymnemic acid on oleic acid absorption by the method of intestinal perfusion in rats. The results showed the following. (i) Gymnemic acid potently inhibited the absorption of oleic acid in intestine. (ii) This inhibition was dose dependent and reversible. (iii) The extent of inhibition and the recovery progress were extremely similar to that of glucose absorption. (iv) Taurocholate did not affect the inhibitory effect of gymnemic acid on oleic acid absorption, but lowering its concentration facilitated the recovery from the inhibition. (v) The absorption of oleic acid was not affected by other glycosides such as phloridzin, stevioside, and glycyrrhizin. These new findings are important for understanding the roles of gymnemic acid in therapy of diabetes mellitus and obesity. PMID- 10100885 TI - Ca2+-independent synergistic augmentation of O2- production by FMLP and PMA in HL 60 cells. AB - N-Formyl-Met-Leu-Phe (FMLP) and phorbol 12-myristate 13-acetate (PMA) caused a synergistic augmentation of superoxide anion (O2-) production in neutrophil-like HL-60 cells differentiated with dibutyryl cAMP. The present study was undertaken to investigate the mechanism of the synergistic augmentation of O2- production. FMLP increased intracellular free Ca2+ concentration ([Ca2+]i), which was slightly suppressed by PMA and completely inhibited by an intracellular Ca2+ chelating agent, O,O'-bis(2-aminophenyl)ethyleneglycol-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM). Although FMLP-induced O2- production was inhibited by BAPTA-AM, a major part of the synergistic augmentation of O2- production by FMLP and PMA remained after BAPTA-AM treatment, suggesting that a Ca2+-independent mechanism might be involved in the augmentation. FMLP and PMA caused an activation of phospholipase D (PLD) almost additively in a Ca2+ sensitive manner. The synergistic activation of mitogen-activated protein kinase (MAPK) was evoked by combined addition of PMA and FMLP in a BAPTA-AM resistant manner. However, PD98059, a MAPK kinase inhibitor, did not affect the synergistic augmentation of O2- production, although it potently inhibited the synergistic augmentation of tyrosine phosphorylation of MAPK. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, inhibited FMLP-induced O2- production, but it did not inhibit the synergistic augmentation of O2- production by PMA and FMLP. In contrast, staurosporine and GF109203X, protein kinase C inhibitors, reduced the synergistic augmentation induced by PMA and FMLP. In addition, pertussis toxin (PT) abolished the synergistic augmentation of O2- production. It is concluded that the synergistic augmentation of O2- production induced by PMA and FMLP is mediated through a PT-sensitive G protein and a protein kinase C in a Ca2+-independent manner. PMID- 10100886 TI - Effect of cycloheximide and tunicamycin on the gonadotrophin-releasing hormone stimulated distal glycosylation of luteinizing hormone by rat pituitary cells. AB - We have previously demonstrated that gonadotrophin-releasing hormone (GnRH) induces not only changes in quantity but also in quality on secreted luteinizing hormone (LH), by increasing [14C]Leu (translation) and [3H]Gal (distal glycosylation) incorporation into newly synthesized hormone. In the present report, we have further examined the GnRH-induced [3H]Gal-LH synthesis and release by treating anterior pituitary cells with polypeptide synthesis and glycosylation inhibitors (cycloheximide and tunicamycin, respectively). Pituitary cells from ovariectomized adult rats were cultured for 4 days and then incubated for different periods (0-5 h) in medium containing [14C]Leu plus [3H]Man or [14C]Leu plus [3H]Gal in the absence (basal) or presence of 10 nmol/L GnRH with or without (control) cycloheximide (1.0 and 4.0 microg/mL) or tunicamycin (0.5 and 2.0 microg/mL). At the end of each incubation period, the cells and the medium were separated and processed for DNA uptake and newly synthesized LH (labeled LH, by immunoprecipitation with a-betaLH) determinations. The velocity of synthesis and release (between 0 and 2 h, and between 2 and 5 h) was calculated by regression analysis and the statistical significance of differences was determined by the slope test. GnRH enhanced the rates of synthesis and release of [14C]Leu-, [3H]Man-, and [3H]Gal-LH to 157 and 237; 164 and 190; and 272 and 508% of basal values, respectively. Cycloheximide totally blocked synthesis and release of [14C]Leu-LH and greatly reduced those of [3H]Man-LH, resulting in the loss of cellular responsiveness to GnRH. Addition of tunicamycin to the pituitary cells inhibited the rates of synthesis and release of [3H]Man-LH which had been induced by GnRH, without altering those of [14C]Leu-LH. These findings indicate that glycosylation is not a condition for GnRH-stimulated LH translation. The GnRH-increased [3H]Gal-LH rates of synthesis and release were affected to a lesser extent by the inhibitors. Thus, GnRH stimulation of distal glycosylation can occur, albeit at a reduced rate, even though protein synthesis and glycosylation are blocked. In conclusion, the present results corroborate that GnRH stimulates the addition of galactose residues into LH molecule. This effect is not simply the consequence of stimulating LH polypeptide chain synthesis. In addition, it is shown that GnRH-increased LH translation is independent of glycosylation. PMID- 10100887 TI - Characterization of the isoform-specific differences in the gating of neuronal and muscle sodium channels. AB - Human heart (hH1), human skeletal muscle (hSkM1), and rat brain (rIIA) Na channels were expressed in cultured cells and the activation and inactivation of the whole-cell Na currents measured using the patch clamp technique. hH1 Na channels were found to activate and inactivate at more hyperpolarized voltages than hSkM1 and rIIA. The conductance versus voltage and steady state inactivation relationships have midpoints of -48 and -92 mV (hH1), -28 and -72 mV (hSkM1), and -22 and -61 mV (rIIA). At depolarized voltages, where Na channels predominately inactivate from the open state, the inactivation of hH1 is 2-fold slower than that of hSkM1 and rIIA. The recovery from fast inactivation of all three isoforms is well described by a single rapid component with time constants at -100 mV of 44 ms (hH1), 4.7 ms (hSkM1), and 7.6 ms (rIIA). After accounting for differences in voltage dependence, the kinetics of activation, inactivation, and recovery of hH1 were found to be generally slower than those of hSkM1 and rIIA. Modeling of Na channel gating at hyperpolarized voltages where the channel does not open suggests that the slow rate of recovery from inactivation of hH1 accounts for most of the differences in the steady-state inactivation of these Na channels. PMID- 10100888 TI - Effects of a nonpeptide bradykinin B2 receptor antagonist, FR167344, on guinea pig tracheal smooth muscle bradykinin receptors. AB - It is speculated that bradykinin may play an important role in asthma. Thus, bradykinin receptor antagonists may have therapeutic potential against asthma. Orally active bradykinin antagonists would be more desirable for the treatment of the disease. In the present study, we examined the effects of a novel, potent, selective, and orally active nonpeptide bradykinin B2 receptor antagonist, FR167344 (N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2 ,4 dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethylamin ocarbonyl)cinnamylamide hydrochloride), on guinea-pig tracheal smooth muscle bradykinin receptors. FR167344 inhibited [3H]bradykinin binding to bradykinin receptors in epithelium-denuded guinea-pig tracheal membrane with an IC50 of 2.1 nM and a Ki of 0.44 nM. This compound also inhibited bradykinin-induced contraction of epithelium-denuded guinea-pig trachea with a pK(B) of 10.8, but had no effect on carbachol-induced contraction of the trachea even at 10(-6) M. These results indicate that FR167344 has the specific antagonistic activity against guinea-pig tracheal smooth muscle bradykinin receptors. PMID- 10100889 TI - Analysis of the short wavelength-sensitive ("blue") cone mosaic in the primate retina: comparison of New World and Old World monkeys. AB - The distribution of short wavelength-sensitive (SWS or "blue") cone photoreceptors was compared in primates with dichromatic ("red-green colour blind") and trichromatic colour vision. We compared a New World species, the marmoset (Callithrix jacchus), with an Old World species, the macaque monkey (Macaca nemestrina). The SWS cones were identified by their immunoreactivity to an antiserum against the human SWS cone opsin. A single retina from a male capuchin monkey (Cebus apella) also was studied. The SWS cones make up less than 10% of all cone photoreceptors throughout the retina of all animals studied. In marmoset, the peak spatial density of SWS cones is close to 10,000/mm2 at the foveola. In macaque, the peak spatial density of SWS cones, close to 6,000/mm2, is at the fovea, but SWS cones are absent within 50 microm of the centre of the foveola. In both species, the density of SWS cones is higher on the nasal retinal axis than at corresponding eccentricities on the other retinal axes. The SWS cones in macaque are arranged in a semiregular array, but they are distributed randomly in marmoset. There is no difference in the spatial density or local arrangement of SWS cones between dichromatic and trichromatic marmosets. The results suggest that the SWS cone photoreceptor system is subject to different developmental and evolutionary constraints than those that have led to the formation of the red-green photoreceptor systems in primate vision. PMID- 10100890 TI - Differential distribution of isoforms of Leucophaea tachykinin-related peptides (LemTRPs) in endocrine cells and neuronal processes of the cockroach midgut. AB - Five isoforms of tachykinin-related peptides (TRPs), designated LemTRP-1-5, have been identified in the midgut of the cockroach Leucophaea maderae. These peptides have a conserved C-terminus hexapeptide (GFX1GX2Ramide; X1 and X2 are variable residues) and variable N-termini. Here, we address the question of whether these five isoforms are all colocalized in the two types of cells in the cockroach midgut, the endocrine cells and the neuronal processes. We also investigate whether the N-terminally extended isoforms LemTRP-2 and -3, which contain putative endoproteolytic cleavage sites, are expressed in intact form or are cleaved in the midgut cells. To this end, we used two approaches. (1) Extracts from portions of the midgut containing each of the cell types were subjected to reverse-phase high performance liquid chromatography (HPLC) and the fractions monitored in a radioimmunoassay (RIA) with an antiserum to the conserved C terminus of insect TRPs. (2) Antisera were raised to the variable N-termini of the extended LemTRP-2 and -3 and used for immunocytochemistry. The HPLC-RIA and immunocytochemical findings indicate that LemTRP-1 and 4-5 are present in the neuronal processes and in endocrine cells of the midgut proper and of the gastric cecae. The two extended forms LemTRP-2 and -3 display a differential distribution: LemTRP-2 was found in endocrine cells of midgut and gastric cecae, but not in neuronal processes, whereas LemTRP-3 was seen in neuronal processes and endocrine cells of the midgut proper, but not in the gastric cecae. LemTRP-3 and -4 have not been identified in the brain, suggesting further cell- and tissue specific expression of LemTRPs. The mechanisms behind the cell-specific expression of the LemTRPs are not yet understood, but the demonstration of differential distribution of the peptide isoforms provide a first indication that the isoforms may have different actions. PMID- 10100891 TI - Physiologic and morphologic properties of motoneurons and spindle afferents innervating the temporal muscle in the cat. AB - Little is known about physiology and morphology of motoneurons and spindle afferents innervating the temporalis and on synaptic connections made between the two. The present study was aimed at investigating the above issues at the light microscopic level by using the intracellular recording and horseradish peroxidase or biotinamide labeling techniques and by the use of succinylcholine (SCh) for the classification of spindle afferents in the cat. Temporalis motoneurons had dendritic trees that ranged from a spherical form to an egg-shaped form. The shape deformation was more prominent for the dendritic trees made by motoneurons located closer to the nuclear border. No axon collaterals of the motoneurons were detected. On the basis of the values for the dynamic index after SCh infusion, temporalis spindle afferents were classified into two populations: presumptive groups Ia and II. The spindle afferents terminated mainly in the supratrigeminal nucleus (Vsup), region h, and the dorsolateral subdivision (Vmo.dl) of the trigeminal motor nucleus (Vmo). The proportion of group Ia afferent terminals was lower in the Vsup than that of group II afferents. In the Vmo.dl, the proportion of group Ia afferent terminals was nearly even throughout the nucleus, but that of group II afferent terminals increased in the more outlying regions. The proportion of terminal distribution in the central region of Vmo.dl was higher for group Ia than group II. The frequency of contacts (presumptive synapses) made by a single spindle afferent on a motoneuron was higher for group Ia than group II. The present study provided evidence that the central organization of spindle afferent neurons is different between groups Ia and II. PMID- 10100892 TI - Spatial response properties of contralateral inhibited lobula plate tangential cells in the fly visual system. AB - This study describes the spatial response properties of a particular group of motion-sensitive and directionally selective neurons located in the lobula plate of the fly visual system. Their preferred motion direction is front-to-back (depolarization), and their null direction is back-to-front (hyperpolarization). They receive inhibitory input from the contralateral eye during pattern motion from back to front (regressive). In this study, we call these neurons regressive contralateral inhibited lobula plate tangential cells (rCI-LPTCs). Three physiologic groups of rCI-neurons (rCI-I, rCI-IIa, and rCI-IIb) can be distinguished on the basis of their ipsilateral pattern size dependence and their inhibitory contralateral input. rCI-I neurons depolarize during the motion of small ipsilateral patterns from front to back, but they become hyperpolarized by large ipsilateral patterns moving in the same direction. rCI-IIa and rCI-IIb neurons receive bidirectional inhibitory input from the contralateral eye. rCI IIa neurons respond best to small ipsilateral pattern sizes, but unlike rCI-I neurons, their net response to large patterns is positive. rCI-IIb neurons respond best to large ipsilateral patterns. The anatomical and physiologic variability of the rCI-neurons suggests that more than three types of rCI-neurons exist. The suggested physiologic groups might be preliminary. We recorded one neuron that could mediate the bidirectional inhibitory input that rCI-IIa and rCI IIb neurons receive from the contralateral eye. In the case of the rCI-IIa neurons at least one further contralateral inhibitory element has to be assumed. The tuning of rCI-IIa neurons to small ipsilateral pattern sizes is likely to be based on an on-center/off-surround organization of their synaptic input. PMID- 10100893 TI - Auditory nerve fiber responses following chronic cochlear de-efferentation. AB - The aim of the present study was to examine the role of the olivocochlear system in auditory processing by examining the long-term effects of cochlear de efferentation on auditory nerve response properties in adult chinchillas. Spontaneous rates, response thresholds, tuning curves, discharge rate-level functions, and adaptation of single auditory nerve fibers were measured in chinchillas with complete cochlear de-efferentation produced by sectioning the olivocochlear bundle in the internal auditory meatus. De-efferentation was verified as successful on the basis of acetylcholinesterase staining of surface preparations of the organ of Corti. Following chronic de-efferentation, there was a striking decrease in spontaneous rate, consistent with earlier observations in cats. In addition, the present study shows that complete de-efferentation results in: (1) increased driven discharge rates and decreased dynamic range of discharge rate-level functions, (2) larger onset-to-steady state ratio of discharge rate at moderate intensities, and (3) a hypersensitive tail of the tuning curve. These effects, largely confined to neurons that were most sensitive to frequencies between 2-8 kHz, indicate that the cochlear efferent system is important in maintaining normal function (e.g., frequency and intensity selectivity) of the auditory periphery by modulating auditory nerve fiber response properties. PMID- 10100894 TI - Typology, early differentiation, and exuberant growth of a set of cortical axons. AB - The corpus callosum interconnects both corresponding (homotopic) and noncorresponding (heterotopic) cortical sites of the two hemispheres. We have studied the axons that establish heterotopic connections from visual areas 17 and 18 (E axons) by using anterogradely transported biocytin and three-dimensional serial reconstructions in adult cats and in kittens. Their site of termination distinguished four types of axons. Type EI ends near the border between areas 19/21a or 7, and type EII near the PMLS/PLLS border (posteromedial and posterolateral lateral suprasylvian areas). Type EIII and EIV terminate the first near the PMLS/PLLS and PMLS/21a borders, and the second near the PMLS/PLLS and 19/21a or 7 borders. Taking into account the previously studied homotopic axons (O axons; Houzel et al. [1994] Eur. J. Neurosci. 6:898-917), it can be concluded that areas 17 and 18 are interhemispherically connected by at least five types of axons, three of which (O, EI, and EII) terminate near one areal border, the other two (types EIII and EIV), near two areal borders. All types terminate near representations of the vertical meridian of the visual field. The different types of axons can be identified already during the first postnatal week; at this age, unlike in the adult, they originate not only near the 17/18 border, but also, transiently, in area 17. This suggests that the developing cortex contains sets of neurons destined to send their axon to different targets; however, the axons grow beyond their sites of adult termination. Indeed, exuberant growth takes place at the stage of axonal elongation, and at subsequent stages of axonal differentiation, i.e., during subcortical branching, intracortical branching and synaptogenesis. The growth is progressively more constrained in its topographic distribution and the axons are subsequently reshaped by regressive events. PMID- 10100895 TI - Monkey somatosensory cerebrocerebellar pathways: uneven densities of corticopontine neurons in different body representations of areas 3b, 1, and 2. AB - We have studied the anatomic organization of corticopontine neurons in the monkey cytoarchitectonic areas 3a, 3b, 1, and 2. The purpose was to provide information about the composition of somatosensory cortical influence on cerebellar operations. Large tracer injections were made in the pontine nuclei. Retrogradely labeled neurons were confined to cortical layer 5, with the largest cell bodies located in area 3a and the smallest in area 3b. The distribution of labeled cells was quantitatively recorded and displayed in three-dimensional reconstructions and in flat maps. We have: (1) compared the average densities of labeled cells among the cytoarchitectonic areas, and (2) outlined the distribution of labeled cells within the cortical map of the body surface representation. The average density of labeled cells was considerably higher in areas 3a, 1, and 2, compared to area 3b. This finding suggests that areas 3a, 1, and 2 are more engaged in cerebellar operations than area 3b. We found marked density gradients of labeled cells within areas 3b, 1, and 2, but not within area 3a. When the density maps from areas 3b, 1, and 2 were superimposed on previously published somatotopic maps, we found higher average densities of corticopontine neurons in regions representing the trunk and proximal limbs, than in regions representing the distal forelimb. Thus, the distal forelimb representation, which is known to be strongly emphasized in terms of cortical volume, appears not to be correspondingly emphasized in the corticopontine projection. PMID- 10100896 TI - Merkel cells are responsible for the initiation of taste organ morphogenesis in the frog. AB - Taste organs in the frog have a distinctive cell type located exclusively in the basal portion. In the same fashion as type III cells in mammalian taste buds, these basal cells show immunoreactivity for serotonin antibody. Further, these cells are morphologically similar to epidermal Merkel cells. To determine the significance of these serotonergic basal cells, we examined the early development of taste organs during metamorphosis of the frog by focusing on the origin and possible roles of serotonergic basal cells. For convenience of description, five stages of development (metamorphic stage to climax stages A-D) are defined. In the metamorphic stage, a few noninnervated Merkel cells appear at the upper layer of the lingual epithelium. No neuronal elements are seen in the epithelium at this stage. At climax stages A-B, immature fungiform papillae become discernible in the dorsal surface of the tongue, where the Merkel cells are located. Merkel cells then move downward and extend their cytoplasmic processes toward the basal lamina. These cells are identified by their intense immunoreactivity for serotonin. During the later stages, many nerve fibers in the subepithelial connective tissue approach the epithelium containing Merkel cells. At climax stages C-D, Merkel cells extend cytoplasmic processes along the basal lamina toward the center of the newly forming fungiform papillae. The morphology of these Merkel cells exactly coincides with that of serotonergic basal cells in adult taste organs. Profuse exocytotic release of dense-cored granules of Merkel cells toward the nerve fibers through the basal lamina is frequently seen in these stages. The present study indicates that serotonergic basal cells are derived from intraepithelial Merkel cells, which act as target sites for growing nerves and may be responsible for the initiation of taste organ morphogenesis. PMID- 10100897 TI - Feasibility of using food-grade additives to control the growth of Clostridium perfringens. AB - Previously, it was demonstrated that the combination of sucrose laurate (SL) ethylenediaminetetraacetate (E) and butylated hydroxyl anisole (B) (SLEB) was an effective antimicrobial agent against both gram-negative (aerobes) and gram positive (facultative anaerobes) foodborne bacteria. This investigation examines the sensitivity of Clostridium perfringens to SLEB relative to: (1) the minimum inhibitory concentration (MIC) of SLEB required to inhibit the growth of C. perfringens and (2) the antibacterial effectiveness of different combination ratios of SLEB in fluid thioglycollate medium (FTM). Results indicated that the MIC of SLEB (1:1:1, v/v/v) against C. perfringens on tryptose sulfite cycloserine (TSC) agar was > 150 ppm at 37 degrees C. However, in FTM, a SLEB (1:1:1, v/v/v) concentration of > 100 ppm inhibited C. perfringens during an incubation (anaerobic) period of 196 h at 37 degrees C. The sensitivity of C. perfringens to different combination ratios was also investigated in FTM. The results showed that, when the concentrations of SL and E were held at 75 ppm in the SLEB combination, and the concentration of B increased from 0 to 75 ppm, C. perfringens growth increased initially during the first 24 h of incubation (37 degrees C) but remained constant during the next 48 h. Similarly, when concentrations of SL and E were held constant at 150 ppm in the SLEB combination and the B ratio increased from 50 to 150 ppm in FTM, C. perfringens viability decreased in all of the treated samples during 72-h incubation at 37 degrees C. The results indicated that SLEB was an effective inhibitor of C. perfringens growth activities, and the ratios of the components of SLEB can be adjusted to meet specific preservation needs. PMID- 10100898 TI - Characterization of Listeria monocytogenes from an ice cream plant by serotyping and pulsed-field gel electrophoresis. AB - One dominating strain of serotype 1/2b was found when serotyping and pulsed-field gel electrophoresis (PFGE) patterns were used for the characterization of 41 Listeria monocytogenes isolates originating from an ice cream plant. Samples were taken from the production environment, equipment and ice cream during the years 1990-1997. Serotyping divided the isolates into two serovars, 1/2b and 4b. Three rare-cutting enzymes (ApaI, AscI and SmaI) were used in the creation of PFGE patterns. AscI resulted in the best restriction enzyme digestion patterns (REDPs) for visual comparison. Eight different AscI REDPs were obtained, whereas ApaI produced six and SmaI seven banding patterns. When one-band differences are taken into account, 12 different PFGE types were distinguished based on information obtained with all three enzymes. The dominant PFGE type was found to have persisted in the ice cream plant for seven years. Improved and precisely targeted cleaning and disinfection practices combined with structural changes making for easier cleaning of the packaging machine, resulted in eradication of L. monocytogenes from this plant. PMID- 10100899 TI - Effect of bifidobacteria feeding on fecal flora and production of immunoglobulins in lactating mouse. AB - To elucidate the effects of probiotics on the stimulation of immunoglobulin production during lactation, feeding trials of bifidobacteria in lactating mice were conducted. Bifidobacteria appeared in feces at 9.67+/-0.17 log 10 number per gram levels. All bifidobacteria found in the feces were the administered strain. Mice fed bifidobacteria for 12 days showed significantly high levels of fecal total IgA compared to that of the control group (P < 0.05). The levels of anti beta-lactoglobulin IgA in milk as well as in fecal extracts were significantly higher in the bifidobacteria-fed group than that of the control group (P < 0.05). These results suggest that the intake of bifidobacteria can enhance local production of IgA in milk and the intestine, which may help to protect both pups and dams from exposure to food antigens. PMID- 10100900 TI - Serotypes and typability of Campylobacter jejuni and Campylobacter coli isolated from poultry products. AB - Campylobacter infection is one of the most common bacterial enteric pathogens. Campylobacter jejuni and Campylobacter coli infections are mostly food- and waterborne and especially poultry is often assumed to be an important source. The heat-stable serotyping system (the 'Penner' scheme) was used to study the serotype distribution of C. jejuni and C. coli isolated from different food products of poultry origin sampled from retail outlets in Denmark. A total of 156 isolates were serotyped, 85% of these were C. jejuni and 15% were C. coli. The most common C. jejuni serotypes were O:2 (30%), O:1,44 (12%) and the O:4-complex (8%). O:46 was the most frequent serotype among C. coli isolates. These serotypes are also common among Danish clinical isolates and isolates from broiler chickens and cattle. Differences in serotype distribution were seen for different kinds of poultry products. Isolates from chicken products covered a large selection of serotypes. In contrast, the majority of the isolates from other product groups (turkey, poussin, wild birds) were concentrated on 1-3 serotypes. Using the standard procedure for antigen preparation and serotyping, 25 of the 156 strains (16%) were nontypable. This rate of nontypable isolates is significantly higher than experienced for isolates from other sources than food products, i.e faecal samples from animals and humans. Subculturing and re-typing of the nontypable isolates improved the typability. After two, five and 10 subcultures 16, six and one isolate became typable, respectively. Only three isolates (2%) remained nontypable after 10 subcultures. PMID- 10100901 TI - Effect of ecological factors on the inhibitory spectrum and activity of bacteriocins. AB - The effect of food components and ecological factors on the activities of nisin, sakacin P and curvacin A was evaluated. Lactobacillus curvatus, Listeria innocua, Salmonella and Escherichia coli including E. coli O157:H7 were used as target organisms. Lecithin, casein, and divalent cations were antagonists of the bacteriocins at 0.1%, 0.1% and 10 mmol l(-1), respectively. A decrease in pH as well as the presence of EDTA, propyl-parabene or NaCl at concentrations of 0-1 mmol y(-1), 0-0.16 g l(-1), and 0-6% (w/w), respectively, increased the activity of all bacteriocins. These compounds as well as a pH < 5.5 rendered the Gram negative target organisms sensitive against bacteriocins. Of practical importance is the respective effect of NaCl at concentrations > 5% which are achieved in fermentation and ripening processes, e.g. in production of fermented sausages. A characteristic response was observed for each of the bacteriocins. It is suggested that bacteriocins of lactic acid bacteria are effective against a wide range of microorganisms including E. coli O157:H7 if applied in combination with other preservative principles prevailing in foods. PMID- 10100902 TI - Characterization of lactic acid bacteria isolated from a Thai low-salt fermented fish product and the role of garlic as substrate for fermentation. AB - Lactic acid bacteria (LAB) isolated from raw materials (fish, rice, garlic and banana leaves) and processed som-fak (a Thai low-salt fermented fish product) were characterized by API 50-CH and other phenotypic criteria. Lactococcus lactis subsp. lactis and Leuconostoc citreum were specifically associated with fish fillet and minced fish, Lactobacillus paracasei subsp. paracasei with boiled rice and Weisella confusa with garlic mix and banana leaves. In addition, Lactobacillus plantarum, Lactobacillus pentosus and Pediococcus pentosaceus were isolated from raw materials. A succession of aciduric, homofermentative lactobacillus species, dominated by Lb. plantarum/pentosus, was found during fermentation. In total, 9% of the strains fermented starch and 19% fermented garlic, the two main carbohydrate components in som-fak. The ability to ferment garlic was paralleled by a capacity to ferment inulin. An increased percentage of garlic fermenting strains was found during fermentation of som-fak, from 8% at day 1 to 40% at day 5. No starch fermenting strains were isolated during fermentation. Three mixed LAB cultures, composed of either starch fermenting Lc. lactis subsp. lactis and Lb. paracasei subsp. paracasei, or garlic fermenting Lb. plantarum and Pd. pentosaceus, or a combination of these strains were inoculated into laboratory prepared som-fak with or without garlic. In som-fak without garlic, pH was above 4.8 after three days, irrespective of addition of mixed LAB cultures. The starch fermenting LAB were unable to ferment som-fak and sensory spoilage occurred after three days. Fermentation with the combined mix of starch and garlic fermenting strains led to production of 2.5% acid and a decrease in pH to 4.5 in two days. The fermentation was slightly slower with the garlic fermenting strains alone. This is the first report describing the role of garlic as carbohydrate source for LAB in fermented fish products. PMID- 10100904 TI - Influence of pH on heat resistance of spores of Bacillus coagulans in buffer and homogenized foods. AB - The influence of pH of heating menstruum (McIlvaine buffer) on the heat resistance of Bacillus coagulans spores has been investigated and compared with the heat resistance in homogenized tomato and asparagus at pH 7 and 4 at a wide range of temperatures. Spores were less heat resistant in all menstrua at acid pH. The magnitude of this effect was greatest at the lowest heating temperatures tested. z values in buffer increased from 8.9 degrees C at pH 7 to 10.5 degrees C at pH 4. pH of menstrua was the main influencing factor, but media composition also influenced heat resistance: at pH 7 heat resistance was similar in all menstrua (D111 degrees C = 1.6 min) but at pH 4 the heat resistance in homogenized foods (D111 degrees C = 0.26 min in tomato and D111 degrees C = 0.28 min in asparagus) was lower than in buffer (D111 degrees C = 0.49 min). The reduced influence of the acidification of media on the heat resistance of B. coagulans at higher temperatures should be taken into account when a rise in the temperature of treatment for canned vegetables is considered to shorten duration of heat processes. PMID- 10100903 TI - Potentiation of hydrogen peroxide, nitric oxide, and cytokine production in RAW 264.7 macrophage cells exposed to human and commercial isolates of Bifidobacterium. AB - Bifidobacteria have been previously shown to stimulate immune function and this may be mediated by macrophages. The RAW 264.7 cell line was used here as a macrophage model to assess the effects of human and commercial Bifidobacterium isolates on the production nitric oxide (NO), hydrogen peroxide (H2O2) and the cytokines IL-6 and tumor necrosis factor (TNF)-alpha. Thirty three Bifidobacterium strains differentially stimulated the production of H2O2 NO, TNF alpha, and IL-6 in a dose-dependent manner in 24-h cultures. In the presence of lipopolysaccharide (LPS) the effects of bifidobacteria on NO and H2O2 were masked and were less pronounced at the later stage of incubation. Co-stimulation of macrophages with both LPS and Bifidobacterium increased the production of IL-6 synergistically. In contrast, LPS reduced the ability of the bifidobacteria induced macrophages to produce TNF-alpha. Our results demonstrated that both human and commercial Bifidobacterium strains can stimulate H2O2, NO, TNF-alpha, and IL-6 production, and this effect was strain-dependent. The in vitro approaches employed here should be useful in further characterization of the effects of bifidobacteria on gastrointestinal and systemic immunity. PMID- 10100905 TI - A model describing the relationship between regrowth lag time and mild temperature increase for Listeria monocytogenes. AB - In order to comply with the consumer demand for ready-to-eat and look 'fresh' products, mild heat treatment will be used more and more in the agrofood industry. Nonetheless there is no tool to define the most appropriate mild heat treatment. In order to build this tool, it is necessary to study and describe the response of a bacterial population to a mild increase in temperature, from the dynamic point of view. The response to a mild increase in temperature, defined by stress duration and temperature, consisted in a mortality phase followed by the lag time of the survivors and their exponential growth. The effect of the mild increase in temperature on the mortality phase was described in a previous paper (Breand et al., Int. J. Food Microbiol., in press). The effect of the stress duration on the lag was presented in a previous paper (Breand et al., Int. J. Food Microbiol. 38 (1997) 157-167). In particular, the biphasic relationship between the lag and the stress duration was observed and modelled with a four parameter nonlinear model: the primary model (Breand et al., Int. J. Food Microbiol. 38 (1997) 157-167). The study presented in this paper deals with the effect of the stress temperature on the biphasic relationship between the lag time and the stress duration. The secondary models describing the effect of the stress temperature on this biphasic relationship, were empirically built from our experimental data concerning Listeria monocytogenes. This work pointed out that the higher the stress temperature, the narrower the range of stress duration for which the lag time increased. Since the primary and the secondary models of the lag time were available, the global model describing the effect of the mild increase duration and temperature directly on the lag was fitted. This model allowed an improvement of the parameter estimator precision. The potential contribution in mild heat treatment optimization of this global model and the one built for the mortality phase (Breand et al., Int. J. Food Microbiol., in press) is discussed. PMID- 10100906 TI - Comparative survival of Salmonella typhimurium DT 104, Listeria monocytogenes, and Escherichia coli O157:H7 in preservative-free apple cider and simulated gastric fluid. AB - This study compared the survival of three-strain mixtures (ca. 10(7) CFU ml(-1) each) of Salmonella typhimurium DT104, Listeria monocytogenes, and Escherichia coli O157:H7 in pasteurized and unpasteurized preservative-free apple cider (pH 3.3-3.5) during storage at 4 and 10 degrees C for up to 21 days. S. typhimurium DT104 populations decreased by <4.5 log10 CFU ml(-1) during 14 days storage at 4 and 10 degrees C in pasteurized cider, and by > or =5.5 log10 CFU ml(-1) during 14 days in unpasteurized cider stored at these temperatures. However, after 7 days at 4 degrees C, the S. typhimurium DT104 populations had decreased by only about 2.5 log10 CFU ml(-1) in both pasteurized and unpasteurized cider. Listeria monocytogenes populations decreased below the plating detection limit (10 CFU ml( 1)) within 2 days under all conditions tested. Survival of E. coli O157:H7 was similar to that of S. typhimurium DT104 in pasteurized cider at both 4 and 10 degrees C over the 21-days storage period, but E. coli O157:H7 survived better (ca. 5.0 log10 CFU ml(-1) decrease) than S. typhimurium DT104 (> 7.0 log10 CFU ml(-1) decrease) after 14 days at 4 degrees C in unpasteurized cider. In related experiments, when incubated in simulated gastric fluid (pH 1.5) at 37 degrees C, S. typhimurium DT104 and L. monocytogenes were eliminated (5.5-6.0 log10 CFU ml( 1) decrease) within 5 and 30 min, respectively, whereas E. coli O157:H7 concentrations decreased only 1.60-2.80 log10 CFU ml(-1) within 2 h. PMID- 10100907 TI - Restriction fragment length polymorphisms analysis by pulsed-field gel electrophoresis for discrimination of Staphylococcus aureus isolates from foodborne outbreaks. AB - A number of outbreaks of disease due to Staphylococcus aureus occurring in Aichi ken, Japan, have provided the opportunity to investigate aspects of the molecular epidemiology of this and related organisms. Coagulase types, enterotoxin types, phage types, and restriction fragment length polymorphisms (RFLPs) as assessed by pulsed-field gel electrophoresis (PFGE) was performed for S. aureus infections diagnosed in the area of Aichi-ken. Among the 56 isolates of S. aureus from 30 outbreaks, 15 distinctive RFLP types were found by digestion with the restriction enzyme, SmaI. A total of 32 isolates from patients, foodstuffs and cooks on six occasions had the same RFLP types, coagulase types, enterotoxin types and phage types in the same outbreaks. Moreover, the coagulase and phage types could be separated in terms of RFLP. In one outbreak, ten isolates, which were derived from six patients, two foodstuffs and two cooks, had the same coagulase type, enterotoxin type, phage type, and RFLP type. This PFGE method may therefore prove useful for subclassifying S. aureus and differentiating isolates of the same coagulase types and phage types derived from sporadic cases and those derived from foodborne outbreaks. PMID- 10100908 TI - Bibliography of food microbiology. PMID- 10100909 TI - To what extent should papers submitted from drug companies be published in medical journals? PMID- 10100910 TI - A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms. AB - Combined data from double-blind risperidone studies were used to analyse the severity of extrapyramidal symptoms (EPS) associated with treatment in patients with chronic schizophrenia. Factors associated with maximum EPS severity were increasing risperidone dose (< or = 8 mg/day was similar to placebo), lower baseline EPS scores, and longer duration of psychotic symptoms, particularly in older patients. EPS severity was significantly greater in patients receiving haloperidol or other antipsychotics than in those receiving risperidone (4 to 8 mg/day) or placebo. Antiparkinsonian medications were required by significantly fewer patients treated with risperidone (4 to 8 mg/day) than by patients treated with haloperidol or other antipsychotics. Combined efficacy data showed that 4 to 8 mg/day was also the most efficacious dose range; there was no increase in efficacy with doses over 4 mg/day. Based on these data and post-marketing experience, 4 mg/day is an appropriate initial target dose for most patients with schizophrenia. Higher doses may be appropriate for patients with chronic illness, and lower doses may be appropriate for patients with a first psychotic episode or for elderly patients. PMID- 10100911 TI - Internal and external validity of the WHO Well-Being Scale in the elderly general population. AB - The objectives of this study were (i) to evaluate the validity of the WHO Well Being Scale in elderly subjects and (ii) to assess the influence of demographic variables on subjective quality of life. A sample of 254 elderly subjects completed the 22-item WHO Well-Being Scale. The scale had an adequate internal and external validity. However, the short 10-item and 5-item versions were equally valid. Low scores indicating decreased well-being were related to the presence of a psychiatric disorder or, independently, to poor living conditions. The Well-Being Scale and their short versions would appear to be useful instruments for identifying subjects with reduced subjective quality of life. PMID- 10100912 TI - Characteristics of psychiatric emergencies and the choice of intervention strategies. AB - The aim of this study was to describe the sociodemographic, contextual and clinical characteristics of a consecutive sample of 3611 psychiatric emergency visits to a Swiss university general hospital, and to investigate their associations with different intervention strategies. All consultations were documented by a questionnaire covering sociodemographic and diagnostic data as well as information about the consultation and the disposition decision. In a total of 1093 cases (30.3%) no further emergency intervention was required, in 1287 cases (35.6%) patients were offered out-patient crisis intervention, and in 1231 cases (34.1%) patients were hospitalized. Social integration and the presence of an easily recognizable precipitating stressor were associated with referral to out-patient crisis intervention. In logistic regression analyses, referral by the police or by health professionals (in contrast to self-referral or referral by relatives), current diagnosis of a psychotic disorder, and previous hospitalizations were the most powerful predictors of hospitalization. The presence of a precipitating stressor related to the patient's social network decreased the likelihood of hospitalization. The findings indicate a need for facilities offering brief admission, allowing for extended emergency assessments. PMID- 10100913 TI - Comparison of patient satisfaction with community-based vs. hospital psychiatric services. AB - OBJECTIVE: Previous work suggests that psychiatric patients are more satisfied with community-based than with hospital-based services, but it is not clear how far these findings can be generalized to routine services. The aim of this study was to compare the satisfaction of patients with psychosis between a hospital based service in London, UK and a community-based service in Verona, Italy. METHOD: The Verona Service Satisfaction Scale (VSSS) was used to measure satisfaction among patients with psychosis in Nunhead (London) and South Verona. RESULTS: Satisfaction across all dimensions was higher in South Verona than in Nunhead. Sociodemographic and service use differences between the two groups were insufficient to explain this difference. CONCLUSION: This study suggests that experimental findings that patients prefer community-based to hospital psychiatric services can be generalized to routine services. PMID- 10100914 TI - Outcomes and costs of a community support worker service for the severely mentally ill. AB - There has recently been an expansion of paraprofessional staff involved in the provision of care for the severely mentally ill. In this paper we shall evaluate the effects of a community support worker (CSW) service in South London. A sample of patients with severe mental illness receiving the service was assessed over a 6-month period in order to examine the effects of continuing use of CSWs on outcomes, service use and costs. During the study period there were improvements in outcome reflecting service satisfaction, needs, quality of life and social behaviour. Whilst provision of the CSW service did not lead to extra total service costs, service use and cost data suggest that CSWs are associated with the substitution of in-patient use by community-based services. PMID- 10100915 TI - The treatment received by substance-dependent male and female suicide victims. AB - Within a nation-wide psychological autopsy study we investigated use of treatment services and recognition of substance abuse problems among male and female substance-dependent suicide victims. Although during their final month half of the male subjects and two-thirds of the female subjects contacted health care services, in only one-sixth and one-third of cases, respectively, were substance abuse problems currently recognized. During their final year, 37% of the males and 67% of the females received psychiatric care. This was associated with Axis-I comorbid disorders among males, with lower socio-economic status and abuse of prescribed drugs among females, and with previous suicide attempts among both sexes. Due to their high psychiatric morbidity and tendency to have contacts with psychiatric services, the recognition, treatment and follow-up of subjects with substance use disorders in psychiatric care would appear to be of major importance for suicide prevention. PMID- 10100916 TI - Treatment received by alcohol-dependent suicide attempters. AB - The purpose of this study was to examine the clinical features of alcohol dependent suicide attempters and the treatment they received before and after the index attempt. A total of 47 subjects with current DSM-III-R alcohol dependence were identified from a systematic sample of 114 suicide attempters in Helsinki. All of them were comprehensively interviewed after the attempt, and the treatment they had received was established from psychiatric and other health-care records and follow-up interviews. Most had a history of psychiatric (83%) or substance abuse (83%) treatment. During the final month before the attempt, half of the subjects (51%) had been treated by health care services; 11% had received disulfiram-treatment and 6% had received psychotherapy. Subjects complied with recommended aftercare more often when they had been actively referred. After 1 month, 64% were being treated by health care services. However, only 14% were receiving disulfiram-treatment and 9% were receiving psychotherapy. These findings suggest that the quality and activity of treatment offered to suicide attempters with alcohol dependence should be improved. PMID- 10100917 TI - Depression Scale (DEPS) in schizophrenia. AB - OBJECTIVE: To explore the applicability of the Depression Scale (DEPS), a screening instrument for detecting depression in primary health care, in schizophrenia. METHOD: The DEPS was compared with the Calgary Depression Scale (CDS) among 63 patients with schizophrenia. RESULTS: Using the CDS as a gold standard, the positive and negative predictive values of the DEPS for the diagnosis of depression were 41% and 97%, respectively. The correlation between the total CDS scores and the total DEPS scores was 0.73. CONCLUSION: The DEPS appears to be useful for screening depression among schizophrenic patients, but the positive diagnosis must be confirmed with a clinical interview. PMID- 10100918 TI - Catatonia under medication with risperidone in a 61-year-old patient. AB - This report describes the case of a 61-year-old female schizophrenic patient with status post-frontal lobotomy some 35 years ago with prominent paranoid delusions. This woman developed severe catatonia under medication with a serotonergic/dopaminergic neuroleptic, risperidone, at a dose of up to 5 mg daily. The catatonic disorder was dose-dependent and subsided immediately after switching the medication to another atypical antipsychotic, clozapine. Given the negative history for catatonia in this patient, the temporal coincidence of administration of risperidone and catatonia is a novel finding. PMID- 10100919 TI - Bradykinin and its receptors in non-mammalian vertebrates. AB - The generation of bradykinin (BK) in blood by the action of the kallikrein-kinin system has been studied intensively in mammals but the system has received relatively little attention in non-mammalian vertebrates. The plasma of crocodilians and Testudines (turtles and tortoises) contains all the components of the kallikrein-kinin system found in mammals (prekallikrein activator, prekallikrein, kininogen, and kininases) and activation results in generation of [Thr6]-BK. Plasma of birds and snakes probably lacks a prekallikrein activator analogous to mammalian Factor XII but treatment with exogenous proteases (pig pancreatic kallikrein and/or trypsin) generates [Thr6, Leu8]-BK (chicken), [Ala1, Thr6]-BK (python) and [Val1, Thr6]-BK (colubrid snakes). The skins of certain frogs, particularly of the genus Rana, contain very high concentrations of BK related peptides but their pathway of biosynthesis involves the action of cellular endoproteinase(s) cleaving at the site of single arginyl residues rather than by the action of the kallikrein-kinin system. Evidence for a prekallikrein activator in fish plasma is lacking but treatment with exogenous proteases generates [Arg0, Trp5, Leu8]-BK (trout and cod), [Trp5]-BK (bowfin and gar), [Met1, Met5]-BK (sturgeon). The cardiovascular actions and effects upon gastrointestinal smooth muscle of these peptides in their species of origin differ markedly. For example, intra-arterial injections of the native BK peptides into unanesthetized fish produce transient hypertension in the cod, complex depressor and pressor responses in the trout and bowfin and hypotension in the sturgeon. Pharmacological studies in snakes and fish and with the recombinantally expressed chicken BK receptor have demonstrated that the BK receptors in the tissues of non-mammalian vertebrates have appreciably different ligand binding properties from the well-characterized mammalian B1 and B2 receptors. PMID- 10100920 TI - Structural motifs of pituitary adenylate cyclase-activating polypeptide (PACAP) defining PAC1-receptor selectivity. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) interacts with three types of PACAP/VIP-receptors. The PAC1-receptor accepts PACAP as a high affinity ligand but not vasoactive intestinal peptide (VIP) similarly binding to VPAC1- and VPAC2-receptors. To identify those amino acids not present in VIP defining PAC1-receptor selectivity of PACAP, radio receptor binding assays on AR4-2J cells were performed. It could be shown that PACAP(1-27) exhibited a distinct and much higher susceptibility to VIP-amino acid substitutions, compared to PACAP(1-38). Positions 4 and 5 seem to be most important for receptor binding of PACAP(1-27), whereas position 13 was identified to be crucial for maximal affinity of PACAP(1 38). PACAP(29-38) extension analogues of VIP revealed a stabilizing effect of the C-terminus of PACAP(1-38) on the optimal peptide conformation. The substitution analogues were also checked for their capacity to stimulate IP3 and cAMP formation in AR4-2J cells. Compared to PACAP(1-27) and PACAP(1-38), most analogues revealed potencies reduced congruously to their lower binding affinities. However, one of the analogues, PACAP(1-27) substituted in position 5, may represent a weak antagonist since this peptide was less potent in inducing second messengers than in label displacement. Our findings indicate that PACAP(1 27) and PACAP(1-38) differ in terms of their requirement of the amino acids in positions 4, 5, 9, 11 and 13 for maximal interaction with the PAC1-receptor. PMID- 10100921 TI - Biological activity of GLP-1-analogues with N-terminal modifications. AB - Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and improves glycemic control in type 2 diabetes. In serum the peptide is degraded by dipeptidyl peptidase IV (DPP IV). The resulting short biological half-time limits the therapeutic use of GLP-1. Therefore, various GLP-1 analogues with alterations in cleavage positions were synthesized. GLP-1-receptor binding was investigated in RINm5F cells. Biological activity of the GLP-1 analogues was investigated in vitro by measuring cAMP production in RINm5F cells. GLP-1 analogues with modifications in position 2 were not cleaved by DPP IV and showed receptor affinity and in vitro biological activity comparable to native GLP-1. Analogues with alterations in positions 2 and 8, 2 and 9 or 8 and 9 showed a significant decrease in receptor affinity and biological activity. In vivo biological activity was tested in pigs. GLP-1 analogues were administered subcutaneously followed by an intravenous bolus injection of glucose. Plasma glucose and insulin were monitored over 4 h. Compared to native GLP-1, analogues with an altered position 2 showed similar or increased potency and biological half-time. Other GLP-1 analogues were less active. Despite the lack of degradation of these GLP-1 analogues by DPP IV in vitro, their biological action is as short as that of GLP 1, except for desamino-GLP-1, indicating that other degradation enzymes are important in vivo. Alterations of GLP-1 in positions 8 or 9 result in a loss of biological activity without extending biological half-time. PMID- 10100922 TI - Molecular evolution of peptide tyrosine--tyrosine: primary structure of PYY from the lampreys Geotria australis and Lampetra fluviatilis, bichir, python and desert tortoise. AB - Peptide tyrosine-tyrosine (PYY) has been isolated from the intestines of two species of reptile, the desert tortoise Gopherus agassizii (Testudines) and the Burmese python Python molurus (Squamata), from the primitive Actinopterygian fish, the bichir Polypterus senegalis (Polypteriformes) and from two agnathans, the Southern-hemisphere lamprey Geotria australis (Geotriidae) and the holarctic lamprey Lampetra fluviatilis (Petromyzontidae). The primary structure of bichir PYY is identical to the proposed ancestral sequence of gnathostome PYY (YPPKPENPGE10/DAPPEELAKY20/YSALR HYINL30/ITRQRY). Tortoise and python PYY differ by six and seven residues, respectively, from the ancestral sequence consistent with the traditional view that the Testudines represent an earlier divergence from the primitive reptilian stock than the Squamates. The current views of agnathan phylogeny favor the hypothesis that the Southern-hemisphere lampreys and the holarctic lampreys arose from a common ancestral stock but their divergence is of a relatively ancient (pre-Tertiary) origin. The Geotria PYY-related peptide shows only two amino acid substitutions (Pro10-->Gln and Leu22-->Ser) compared with PYY from the holarctic lamprey Petromyzon marinus. This result was unexpected as Petromyzon PYY differs from Lampetra PYY deduced from the nucleotide sequence of a cDNA (Soderberg et al. J. Neurosci. Res. 1994;37:633 640) by 10 residues. However, a re-examination of an extract of Lampetra intestine revealed the presence of a PYY that differed in primary structure from Petromyzon PYY by only one amino acid residue (Pro10-->Ser). This result suggests that the structure of PYY has been strongly conserved during the evolution of Agnatha and that at least two genes encoding PYY-related peptides are expressed in Lampetra tissues. PMID- 10100923 TI - Chronic hypertension in ANP knockout mice: contribution of peripheral resistance. AB - Atrial Natriuretic Peptide (ANP) exerts a chronic hypotensive effect which is mediated by a reduction in total peripheral resistance (TPR). Mice with a homozygous disruption of the pro-ANP gene (-/-) fail to synthesize ANP and develop chronic hypertension in comparison to their normotensive wild-type (+/+) siblings. In order to determine whether alterations in basal hemodynamics underlie the hypertension associated with lack of endogenous ANP activity, we used anesthetized mice to measure arterial blood pressure (ABP) and heart rate (HR), as well as cardiac output (CO) by thermodilution technique. -/- (n = 7) and +/+ (n = 10) mice of comparable weight and age were used. Stroke volume (SV) and TPR were derived from CO, HR, and ABP by a standard formula. ABP (mm Hg) was significantly higher in -/- (132+/-4) (P < 0.0001) than in +/+ mice (95+/-2). CO (ml min(-1)), HR(beats min(-1))and SV (microl beat(-1)) did not differ significantly between -/- and +/+ mice (CO -/- = 7.3+/-0.5, +/+ = 8.3+/-0.6; HR /- = 407+/-22, +/+ = 462+/-21; SV -/- = 17.6+/-1.1, +/+ = 17.6+/-1.7). However, TPR (mm Hg ml(-1) min(-1)) was significantly elevated in -/- mice (18.4+/-0.7) compared to +/+ mice (12.3+/-1) (P = 0.0003). Autonomic ganglion blockade with a mixture of hexamethonium and pentolinium was followed by comparable percent reductions in CO (-/- = 28+/-4, +/+ = 29+/-3), HR (-/- = 9+/-4, +/+ = 16+/-4) and SV(-/- = 21+/-4, +/+ = 15+/-6) in both genotypes. However, the concomitant decrease in ABP (%) in -/- (41+/-2) was significantly greater than in +/+ (23+/ 4) mice (P = 0.0009) and was accompanied by a significant reduction in TPR. We conclude that the hypertension associated with lack of endogenous ANP is due to elevated TPR, which is determined by an increase in cardiovascular autonomic tone. PMID- 10100924 TI - Somatostatin and octreotide modulate the function of Kupffer cells in liver cirrhosis. AB - In our previous studies we have shown that somatostatin and octreotide modulate the function of peritoneal macrophages and Kupffer cells in noncirrhotic livers. However, the effects of somatostatin on the Kupffer cells in cirrhotic livers are not known. In the present study, Kupffer cells, obtained from male rats with carbon tetrachloride-induced cirrhotic livers, were treated in vitro with somatostatin or octreotide and their effects on the release of nitric oxide, tumor necrosis factor-alpha (TNF-alpha) and peroxide (H2O2) determined. At concentrations of 10(-13) or 10(-10) to 10(-6) M of somatostatin or 10(-12) to 10(-10) M, or 10(-6) M of octreotide, the amount of nitric oxide released by Kupffer cells was significantly suppressed relative to that of untreated cells. Kupffer cells treated with less than 10(-12) M or greater than 10(-12) M of somatostatin or octreotide released less TNF-alpha compared to the untreated controls. In addition, zymosan-induced H2O2 release by Kupffer cells treated with 10(-9) to 10(-7) M somatostatin or with 10(-15) to 10(-13) M and 10(-9) to 10(-7) M of octreotide was greater than that of the untreated controls. These findings demonstrate that somatostatin and octreotide modulate the release of nitric oxide, TNF-alpha and H2O2 by Kupffer cells in cirrhotic livers depending on the concentrations of hormones used. PMID- 10100925 TI - PYY immunoneutralization does not alter lipid-induced inhibition of gastric emptying in rats. AB - PYY is released from the distal ileum by fat and may be involved in mediating lipid-induced inhibition of gastric acid secretion and intestinal motility. The role of PYY in intestinal lipid-induced inhibition of gastric emptying in awake rats was investigated using a specific polyclonal antibody raised against PYY. METHODS: Gastric emptying of liquids was measured in awake rats fitted with a Thomas gastric cannula. Intralipid (total dose 50 or 100 mg) was perfused for 10 min (0.05 ml/min) into a duodenal (n = 11) or mid-intestinal cannula (60 cm from Ligament of Treitz; n = 8), and gastric emptying was measured over the 5-10 min period. Gastric emptying was measured 15 min after IP injection of PYY (1 nmol/rat). PYY antibody (20 mg) or a control antibody (anti-KLH; keyhole limpet hemocyanin) was injected ip 8-12 h before experiments. RESULTS: Exogenous PYY (1 nmol) inhibited gastric emptying and administration of PYY antibody blocked this response. Perfusion of lipid (50 and 100 mg) into the proximal intestine produced a 46% and 66% inhibition of gastric emptying respectively. Inhibition of gastric emptying in response to 50 mg lipid in the proximal small intestine was unaffected by administration of PYY antibody but was abolished by administration of the CCK A receptor antagonist devazepide (0.1 mg/kg ip). Perfusion of lipid into the distal intestine (50 and 100 mg) inhibited gastric emptying by 10% and 32% respectively. Inhibition of gastric emptying in response to 100 mg lipid in the distal intestine was unaffected by PYY antibody. CONCLUSIONS: Lipid perfused into either the proximal or distal intestine inhibits gastric emptying via a PYY independent mechanism. CCK is involved in proximal lipid induced inhibition of gastric emptying. PMID- 10100926 TI - Rat stomach ECL-cell histidine decarboxylase activity is suppressed by ergocalciferol but unaffected by parathyroid hormone and calcitonin. AB - The ECL cells are peptide hormone-producing cells, rich in histamine and chromogranin A (CGA)-derived peptides, that operate under the control of gastrin. Gastrin and the ECL cells form a functional unit, the gastrin-ECL-cell axis. The aims of the present study were to examine (1) if calcitonin (CT), parathyroid hormone (PTH) and vitamin D affect the gastrin-ECL-cell axis (by measuring the activity of the histamine-forming enzyme, histidine decarboxylase (HDC), and the expression of HDC mRNA and CGA mRNA in the ECL cells), and (2) if activation of the gastrin-ECL-cell axis affects the parathyroid glands (by measuring plasma PTH and mRNA expression). We also examined the possibility that the oxyntic mucosa harbours vitamin D receptors. Fasted rats received intravenous infusion of PTH and CT with or without gastrin. PTH raised the blood Ca2+ concentration, whereas CT infusion lowered it. Plasma PTH rose in response to CT, while serum gastrin remained unaffected. ECL-cell HDC was activated by gastrin but not by CT and PTH. Five daily subcutaneous injections of large amounts of ergocalciferol raised the blood Ca2+ concentration, while reducing the oxyntic mucosal HDC activity and the expression of HDC and CGA mRNA. The serum gastrin concentration was not affected. The findings are in line with the idea that the gastrin-ECL-cell axis can be suppressed by vitamin D or by vitamin D-dependent mechanisms. Western blot analysis revealed the presence of vitamin D receptor immunoreactivity and reverse transcription PCR detected vitamin D receptor gene expression in the rat oxyntic mucosa. Hypergastrinemia was induced by daily peroral treatment with the H+/K+ ATPase inhibitor, omeprazole, for 2 weeks or by continuous subcutaneous infusion of gastrin for 7 days. Elevated serum gastrin concentration was associated with increased HDC activity and increased HDC and CGA mRNA expression in the oxyntic mucosa. There was no elevation of plasma PTH or PTH mRNA expression in the parathyroid gland. PMID- 10100927 TI - Improvement of preservation with cardioplegia induced by heat stress is mediated by calcitonin gene-related peptide. AB - Previous studies have shown improvement of preservation with cardioplegia by calcitonin gene-related peptide (CGRP)-induced preconditioning. Therefore we examined the hypothesis that endogenous CGRP may be involved in the protection of heat stress against myocardial damages after prolonged cardioplegic arrest in isolated rat heart. Reperfusion after 4 h of hypothermic ischemia caused a decline of cardiac function and an increase of creatine kinase (CK) release. Heat stress induced by pretreatment with whole body hyperthermia (rectal 42 degrees C) for 15 min produced a significant increase in the plasma content of CGRP, an improvement of cardiac function and a decrease in the release of CK. However, after pretreatment with capsaicin (50 mg/kg, s.c.) to deplete CGRP in cardiac sensory nerves, the plasma concentration of CGRP was no longer increased and the cardioprotection afforded by heat stress was abolished. These findings suggest that improvement of preservation with cardioplegia by heat stress may be mediated by endogenous CGRP in the rat. PMID- 10100928 TI - Relaxing effect of insulin in renal arteries from diabetic rats. AB - Abnormal renal vasomotor tone exists in the early stages of diabetes mellitus. Insulin has been proposed to modulate renal function and to possess vasodilatory effects. The present study was initiated in order to evaluate the direct effect of insulin on isolated renal arteries. Twelve insulin-treated streptozotocine diabetic rats with diabetes for 50 days were compared with 15 weight-matched control rats. The contractile responses to 60 mM K+ and 10(-4) M noradrenaline, and the insulin- (0.8-6.4 I.U./ml) induced relaxation of vessels precontracted with noradrenaline, were similar in diabetic and control rats. There was a tendency towards greater relaxation in diabetic (71%) than in control rats (54%). Nw-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) given before noradrenaline tended to attenuate the insulin-induced relaxation, while addition of L-arginine (10(-6) M) to L-NAME attenuated the relaxation in diabetic but increased it in control rats (P < 0.05). The effect of insulin was tested further in control rats and was not influenced by administration of a single dose (10(-6) M) of indomethacin or propranolol given instead of L-NAME. The effect of a single dose of methylene-blue, given before noradrenaline, was tested in control rats in varying doses between 2 x 10(-6) and 2 x 10(-4) M. In the highest concentration it made no difference whether insulin was given or not and there was a similar relaxing effect in diabetic and control arteries. In conclusion, the present study showed that insulin per se has a relaxing effect on renal arteries. There was a tendency to greater relaxation in diabetic than in control rats, an effect which was attenuated by in-vitro-pretreatment with L-NAME as well as with L-NAME and L-arginine in diabetic vessels, while relaxation was increased in control vessels. This may indicate that the effect of insulin may be mediated through nitric oxide in diabetic but not in control rats. The effects of insulin in control vessels were not modified in vitro by indomethacin, propranolol or methylene-blue. PMID- 10100929 TI - CGRP 27-37 analogues with high affinity to the CGRP1 receptor show antagonistic properties in a rat blood flow assay. AB - CGRP Y0-28-37 is known as a selective CGRP1 receptor antagonist. We succeeded in optimising the CGRP1 receptor affinity of this fragment by multiple amino acid replacement. The analogues [p34, F35]CGRP 27-37 and [D31, p34, F35]CGRP 27-37 exhibit a 100-fold increased affinity compared to the unmodified segment. Receptor binding studies were performed with human neuroblastoma cells SK-N-MC, which selectively express the hCGRP1 receptor. Blood flow, which is increased by exogenous CGRP, was measured in the right femoral artery. Preincubation of the rats with [p34, F35]CGRP 27-37 and [D31, p34, F35]CGRP 27-37 led to a significant decrease in CGRP induced increase in vascular conductance indicating the antagonistic properties of these compounds. Interestingly, an exchange of the amino acid Asn31 to Asp31 in [p34, F35]CGRP 27-37 shortened the period of the antagonistic effect significantly, suggestive of a different rate of metabolism for the two ligands. Secondary structure investigations obtained by circular dichroism measurements revealed that an increase in ordered structure correlates with high binding affinity. PMID- 10100930 TI - Distinct effect of intracerebroventricular and intrathecal injections of nociceptin/orphanin FQ in the rat formalin test. AB - Nociceptin/orphanin FQ (nociceptin/OFQ), a newly discovered heptadecapeptide has been regarded as an endogenous ligand for orphan opioid receptor. The present study was designed to investigate the effect of nociceptin/OFQ on pain response and opioid analgesia in the rat formalin test. The results showed that intracerebroventricular injection of 1 microg nociceptin/OFQ enhanced the pain response, and 0.1 or 0.5 microg nociceptin/OFQ had no effect on formalin-induced pain. When 0.1 or 1 microg nociceptin/OFQ were used together with mu-, delta-, or kappa-opioid receptor agonists, endomorphin-1, DSLET or U50488H, respectively, it attenuated mu- and kappa- but not delta-receptor mediated analgesia. On the other hand, intrathecal injection of nociceptin/OFQ (0.1, 1 and 5 microg) reduced the pain response in the formalin test. In conclusion, nociceptin/OFQ potentiated formalin-induced pain response and antagonized opioid analgesia in the rat brain but inhibited pain response in the spinal cord. PMID- 10100931 TI - Effects of guanylin and uroguanylin on rat jejunal fluid and electrolyte transport: comparison with heat-stable enterotoxin. AB - The effects of rat guanylin, human guanylin, human uroguanylin and STa on net fluid and electrolyte transport in the closed jejunal loop were compared in anesthetized rats. STa administered into the lumen caused a concentration dependent (10(-8) to 10(-6) M) inhibition of net fluid and NaCl absorption in the jejunal loop. Uroguanylin had a similar but weaker effect than STa. Both rat and human guanylin inhibited fluid and NaCl absorption only at 10(-6) M. Their order of potency was STa > human uroguanylin > rat guanylin = human guanylin. Changing the luminal pH from 5 to 8 failed to affect the action of guanylin on fluid absorption. Both STa and uroguanylin, but not guanylin, increased the luminal pH by stimulating bicarbonate secretion. Pretreatment of the jejunal loop with guanylin (10(-6) M) 5 min before the instillation of STa (10(-7) M) significantly reduced the inhibitory effect of STa on fluid absorption. It is concluded that guanylin and uroguanylin administered into the rat jejunal lumen have an STa-like action on fluid and electrolyte transport. Guanylin may act as an endogenous antagonist of STa in the rat jejunum and prevent excessive fluid loss by STa. PMID- 10100932 TI - The effect of modelling and remodelling on human vertebral body architecture. AB - Vertebral bone strength is determined by several factors: cortical thickness, bone size, trabecular bone density, and microarchitecture. All these factors change with age as a result of the two dynamic processes: remodelling and modelling. When the changes become pronounced, osteoporotic fractures occur. There is a different aging pattern for men and women: 1. Men achieve a higher peak bone mass than women (mainly because of a larger cross-sectional area of their bones); 2. Men have no accelerated bone loss in middle age; and 3. Men seem to be able to compensate for their loss of cancellous bone strength by increasing their vertebral cross-sectional area with age. The general pattern, for both men and women is, though, that of an extreme (70-80%) decline in whole vertebral body strength during normal aging. The accompanying decline in bone density is much less pronounced (35-45%). This clearly illustrates the power relationship between bone density and strength. However, the role of changes in trabecular bone microarchitecture for vertebral bone strength during aging still needs to be determined. PMID- 10100933 TI - Is osteoporosis a matter of over-adaptation? AB - The stiffness and strength of cancellous bone depends on the amount of bone mineral (BMD) and on the three-dimensional distribution of the mineral (architecture). The relationship between mechanical properties and architecture, excluding confounding effects due to BMD can be studied using computer models of cancellous bone. It was shown that adaptation to mechanical deformation energy leads to an architecture which is an optimal or semi-optimal configuration with respect to maximal stiffness and minimal mass. Thus, the stiffness of the cancellous bone relative to the amount of bone (the bone density) can be considered as an optimality criterion. Based on these findings we assumed that the status of osteoporosis - or better fracture risk - could be related to how close this optimality criterion was met. In other words, we assumed that a higher fracture risk is simply related to a less optimal structure. This was tested for cancellous bone samples taken from post mortem vertebral bodies from two groups of subjects: one group with high fracture incidence during their lives and one group of "healthy" controls. It was found that the specimen from the high fracture incidence group had an architecture leading to a slightly stiffer structure relative to the BMD value. The conclusion is therefore that vertebral bone specimen from subjects with high fracture incidence are better optimized which was contradictory to what we expected. This finding indicates that bone specimen from the "healthy" control subjects had bone matrix at locations which are relatively unloaded. This tissue can be considered as not mechanically efficient or functional. A possible explanation of the present findings is that bone from subjects with increased fracture incidence is better adapted to mechanical stress, because it needs all bone material to carry the load. This stronger adaptation might be related to a compromised safety factor against bone loss, or diminished intrinsic matrix properties (e.g., microdamage). PMID- 10100934 TI - New architectural parameters derived from micro-MRI for the prediction of trabecular bone strength. AB - This article reviews recent progress in magnetic resonance microimaging of cancellous bone in vitro and in vivo from the perspective of the authors' laboratory. It is shown that in particular in vivo the key technical prerequisites to satisfy are: (i) achieving sufficient signal-to-noise ratio (SNR) to allow for adequate spatial resolution; (ii) the image processing algorithms have to be robust enough to provide accurate structural information in the limited spatial resolution regime, i.e., in the presence of inevitable partial volume blurring and noise. The practical lower limit of voxel size in vivo was found to be about 6 x 10(-3) mm3 in the radius, and about 10(-4) mm3 for small specimens in vitro with state-of-the-art equipment and scan times of 10 and 30 minutes, resp., and SNR approximately 10. Finally, data are presented highlighting the potential of these methods for predicting the bone's elastic modulus in vitro and fracture risk in vivo. PMID- 10100935 TI - A review of magnetic resonance (MR) imaging of trabecular bone micro architecture: contribution to the prediction of biomechanical properties and fracture prevalence. AB - Bone mineral density and three-dimensional trabecular structure play a significant role in predicting bone strength and biomechanical properties. MR is a non-invasive technique for determining trabecular architecture both in vivo and in vitro. In this paper we review the use of magnetic resonance imaging to obtain high resolution images of trabecular bone structure and quantify the three dimensional architecture of the trabecular bone network. Studies assessing the anisotropy of the trabecular architecture in human cadaveric specimens from the distal and proximal femur, and the thoracic and lumbar vertebrae, are reviewed. The contributions of the MR derived measures of 3D trabecular bone structure to the biomechanical strength of the specimen are presented. In vivo, the relationship between the high resolution MR derived trabecular bone structure parameters in the distal radius and calcaneus in patients with hip fractures, are compared to age matched normal controls. MR derived measures are compared to measures of trabecular bone mineral density (BMD) in the hip using dual X-ray absorptiometry (DXA). PMID- 10100936 TI - In vivo high resolution 3D-QCT of the human forearm. AB - In vivo examinations of bone microarchitecture have become available recently through high resolution computed tomography (3D-QCT) and magnetic resonance imaging. The spatial resolution of the resulting images, however, is not sufficient to depict individual trabeculae in their true shape. Nevertheless, structural indices such as relative bone volume, trabecular number, mean thickness and mean separation can be extracted with the help of a ridge detection algorithm. Precision of the procedure is of the order of 1%, accuracy is ascertained using a micro-CT based calibration. In this work we report first results of time serial examinations. Eighteen healthy postmenopausal women (no HRT) were measured at months 0, 6, and 12, and the temporal changes were analyzed. Examination site was the distal radius. The above mentioned structural indices, the average densities and the thickness of the cortical shell were determined. Of the 18 women 6 showed no significant bone loss of any kind, 5 lost primarily cancellous bone, 4 lost primarily cortical bone, and 3 had a substantial loss of cortical as well as cancellous bone. We conclude that even in a homogenous group such as postmenopausal women, there are considerable differences in the reason why bone is weakened and that high resolution 3D-QCT allows to differentiate between various types of bone loss. PMID- 10100937 TI - Three-dimensional in vivo morphometry of trabecular bone in the OVX rat model of osteoporosis. AB - This paper describes the application of synchrotron radiation microtomography to osteoporosis research. By taking advantage of the high intensity, collimation, and monochromaticity of synchrotron radiation, we have been able to image the three-dimensional trabecular bone structure in living rats, thus providing serial data on the earliest architectural changes that occur with estrogen loss. Results from these in vivo animal experiments demonstrate that one of the earliest manifestations of estrogen loss, in addition to a decrease in the amount of trabecular bone, is decreased connectivity. We demonstrate that estrogen replacement therapy, when initiated soon after significant changes have occurred, restores bone mass to baseline levels but does not recover the trabecular connectivity. Even without an associated recovery in trabecular connectivity, finite element calculations on the three-dimensional images suggest that estrogen recovers the original structural modulus of elasticity. We believe the recovery of the elastic properties is due to an increase in trabecular thickness above baseline values. PMID- 10100938 TI - Segmentation techniques for analysis of bone by three-dimensional computed tomographic imaging. AB - Improved methods for evaluation and quantification of the three-dimensional (3D) architecture of bone are needed in order to more fully understand the role of trabecular architecture in bone strength. Computed tomography (microCT) is capable of examining bone at resolutions below 30 microm (isotropic), with collection of a three-dimensional data set which can then be subjected to image analysis. In this paper, we discuss automated methods for important steps in this analysis, including methods for (1) segmenting the image into bone and background; (2) defining the volume of interest for determination of structural parameters; and (3) segmenting the bone into trabecular and cortical components. Evaluation of bone structure using these techniques provides new information about the 3D architecture of bone tissue, and may be useful for evaluation of structural changes in bone caused by aging, disease, or drug treatment. PMID- 10100939 TI - Applications of micro-CT and MR microscopy to study pre-clinical models of osteoporosis and osteoarthritis. AB - There is a tremendous unmet therapeutic need for the treatment of osteoporosis and osteoarthritis. The ovariectomized rat and the guinea pig are widely used animal models for the evaluation of new therapeutics for osteoporosis and osteoarthritis, respectively. We have utilized X-ray micro-CT techniques to quantitatively evaluate the differences in trabecular bone in the rat proximal tibia following ovariectomy and treatment with estrogen (17-B-estradiol). Results demonstrate a loss of trabecular bone and architecture following ovariectomy (p < 0.001), and a marked inhibition of trabecular bone loss in the estrogen treated group (p < 0.001). A similar change in architecture can be visualized in images obtained by high resolution MR microscopy. In addition, a good correlation was observed between the values of trabecular bone fraction (BV/TV) in the rat tibiae as obtained from 3-dimensional micro-CT data and 2-dimensional static histomorphometry (r = 0.89, 0.73, 0.79 for sham, OVX, and treated groups, respectively). Micro-CT images were also obtained from a set of lumbar vertebrae from sham operated and ovariectomized rats. Significant bone loss can be measured as early as 8 weeks following ovariectomy (p < 0.005). Micro-CT and MR images were also obtained to study age related changes in the stifle joint of the guinea pig. Significant boney changes can be seen in the tibia and femur from the animals at various ages. Changes in cartilage and joint space can also be visualized in the images. The utility of micro-CT imaging in evaluating the mouse skeletal system is illustrated by obtaining morphological and architectural details from high resolution images of the mouse hind limb and proximal tibia, respectively. The results demonstrate the advantages that multi-dimensional imaging techniques can offer in evaluating bone and joint related changes in animal models of osteoporosis and osteoarthritis. PMID- 10100940 TI - Measures of complexity for cancellous bone. AB - The problem of quantifying the structure of cancellous bone has been addressed in the past by histomorphometry and more recently by imaging techniques using X-ray attenuation. The current approaches compute and describe parts of the construction of the trabecular net. We developed a new technique which quantifies cancellous bone of human lumbar vertebrae as a whole. The interactions, transactions, and interrelationships of all parts of the structural composition of the trabeculae are accounted for and quantified. The method is based on the concept of structural complexity within the framework of nonlinear dynamics. The methodology was developed by using axial high resolution computed tomography images. The technique was transferred to quantitative computed tomography images and is based on the non-invasive assessment of 50 human L3 specimens. The value of Houndsfield units per pixel representing trabecular bone of the vertebrae was transformed into color-encoded and alphabet-encoded symbols. The procedure of transformation of the X-ray attenuation pixels into symbols was necessary as a basis on which measures of complexity were introduced to assess the composition of symbols within the images. The development of a generalization of symbolic dynamics, a mathematical method, to work with two-dimensional images was a prerequisite. The results of this study demonstrate that the structural composition of cancellous bone declines more rapidly than bone mineral density during the loss of bone. This outcome strongly suggests an exponential relationship between bone mineral density and the architectural composition of cancellous bone. Normal trabecular bone has a complex ordered structure. The structural composition during the osteopenic phase of bone loss is characterized by lower structural complexity and a significantly higher level of architectural disorder. A high grade of osteoporosis leads again to an ordered structure, although its structural complexity is minimal. PMID- 10100941 TI - Micro-CT examinations of trabecular bone samples at different resolutions: 14, 7 and 2 micron level. AB - Tomographic techniques are attractive for the investigation of trabecular bone architecture. Using either conventional X-ray sources or synchrotron sources currently allows the acquisition of 3D images in a wide range of spatial resolution that may be as small as a few micrometers. Since it is technically possible to examine trabecular architecture at different scales, a question is to know what type of information it is possible to get at each scale. For this purpose, a series of ten vertebrae samples from healthy females of different ages (33 to 90) was imaged at various resolutions on three different micro-CT systems (cubic voxel size respectively 14, 6.7 and 1.4 microm). The comparison of morphometric parameters extracted from the different images is in agreement with simulation results on the influence of spatial resolution on structure parameters. The conclusion is that a 14 microm voxel size gives a reasonably good parameterisation of trabecular architecture. Besides the synchrotron radiation 2 microm level images reveal interesting features on the irregularities and rupture of trabecular surface, and on remodeling zones. PMID- 10100942 TI - Micro-CT imaging of structure-to-function relationship of bone microstructure and associated vascular involvement. AB - We are exploring methods of quantitating the 3D microstructure of bone in a way that will provide quantitative information about the functional status of the bone. The basic strategy is to image the spatial distribution of a selected, local, marker of function (e.g., material properties or new bone formation) and relate this to the simultaneously imaged 3D anatomic microstructure. Many of these approaches are extensions of well-established 2D imaging techniques (e.g., use of fluorophores and autoradiography) to 3D micro-CT. Local stresses throughout the microstructure can be estimated from the 3D geometry (and change in that geometry in response to stress applied to the outside of the bones) and correlated to the local function. In addition to study of bone, we are also exploring calcification of arterial walls, both within the bone and outside the bone, such as coronary arteries. Arterial calcification in ovariectomised rats has been observed. PMID- 10100943 TI - Assessment of cancellous bone mechanical properties from micro-FE models based on micro-CT, pQCT and MR images. AB - Recently, new micro-finite element (micro-FE) techniques have been introduced to calculate cancellous bone mechanical properties directly from high-resolution images of its internal architecture. Also recently, new peripheral quantitative computed tomography (pQCT) and magnetic resonance (MR) imaging techniques have been developed that can create images of whole bones in vivo with enough detail to visualize the internal cancellous bone architecture. In this study we aim to investigate if the calculation of cancellous bone mechanical properties from micro-FE models based on such new pQCT and MR images is feasible. Three bone specimens were imaged with the pQCT scanning system and the MR-imaging system. The specimens were scanned a second time using a micro-CT scanner with a much higher resolution. Digitized reconstructions were made based on each set of images and converted to micro-FE models from which the bone elastic properties were calculated. It was found that the results of both the pQCT and the MR-based FE-models compared well to those of the more accurate micro-CT based models in a qualitative sense, but correction factors will be needed to get accurate values. PMID- 10100944 TI - Mechanical analysis of bone and its microarchitecture based on in vivo voxel images. AB - Prevention of osteoporotic fractures requires accurate methods to detect the increase in bone fragility at an early disease stage as well as effective therapies to reduce the risk of bone fractures. Presently the prediction of the patient-specific bone fracture risk is primarily based on bone density, since this is the only parameter which can routinely be measured in vivo. However, these predictions might not always be precise because the fracture risk is also determined by the bone microarchitecture and the bone's loading conditions. The aim of this paper is to introduce and evaluate new methods which could contribute to a better quantification of bone fracture risk. Recently, a new approach, combining computational engineering methods (finite element (FE) method) and 3D high-resolution imaging techniques, has been introduced which can account not only for bone density but also for microarchitecture and loading conditions. High resolution imaging techniques allow acquisition of 3D images of the bone microarchitecture, whereas FE methods applied to these images allow very precise calculation of the mechanical properties of bone. However, such a detailed FE analysis was not feasible for bone in vivo mainly because the resolution was not sufficient to measure the bone microarchitecture. It is shown here, from preliminary results, that the FE approach based on high-resolution images from a new CT scanner now allows prediction of the mechanical behavior of peripheral bones in vivo. It is expected that, eventually, the FE approach will lead to a better patient-specific fracture risk prediction than earlier methods based on bone density alone. Hence, with this new approach, it might be possible to detect the increase in bone fragility at an early stage of osteoporosis and it might also be possible to evaluate treatments more accurately. PMID- 10100945 TI - Mechanical properties of human trabecular bone lamellae quantified by nanoindentation. AB - Improved preventive and therapeutic strategies for skeletal diseases such as osteoporosis rely on a better understanding of the mechanical properties of trabecular bone and their influence on cell mediated adaptation processes. The mechanical properties of trabecular bone are determined by composition as well as structural (trabecular architecture), microstructural (trabecular packets) and nanostructural (lamellae) organization. Density is the major predictor of the mechanical properties of trabecular structures and has been extended to the concept of fabric to include architectural anisotropy and improve even further the power of prediction. Recent advances in QCT and MRI technologies allow for precise assessment of 3D trabecular architecture and the mechanical consequences of structural changes can be increasingly well quantified by the means of computational methods. While single trabeculae have been tested using various techniques with contrasting results, little is known about the intrinsic mechanical properties of trabecular bone lamellae on which these computational methods rely. For instance, water and mineral content have a significant effect on the elastic, viscous, yield and postyield properties of bone tissue. In addition, collagen fiber orientation affects the mechanics of single remodeling units. Variations in composition and organization determined by age, accumulated damage or disease may therefore reduce the mechanical integrity of trabecular bone and deserve more attention. The aim of this work was to utilize a nanoindentation technique to quantify elastic modulus and hardness of human trabecular bone lamellae. PMID- 10100946 TI - Micro-compression: a novel technique for the nondestructive assessment of local bone failure. AB - Many bones within the axial and appendicular skeleton are subjected to repetitive, cyclic loading during the course of ordinary daily activities. If this repetitive loading is of sufficient magnitude or duration, fatigue failure of the bone tissue may result. In clinical orthopedics, trabecular fatigue fractures are observed as compressive stress fractures in the proximal femur, vertebrae, calcaneus and tibia, and are often preceded by buckling and bending of microstructural elements. However, the relative importance of bone density and architecture in the etiology of these fractures is poorly understood. The aim of the study was to investigate failure mechanisms of 3D trabecular bone using micro computed tomography (microCT). Because of its nondestructive nature, microCT represents an ideal approach for performing not only static measurements of bone architecture but also dynamic measurements of failure initiation and propagation as well as damage accumulation. For the purpose of the study, a novel micro compression device was devised to measure loaded trabecular bone specimens directly in a micro-tomographic system. The measurement window in the device was made of a radiolucent, highly stiff plastic to enable X-rays to penetrate the material. The micro-compressor has an outer diameter of 19 mm and a total length of 65 mm. The internal load chamber fits wet or dry bone specimens with maximal diameters of 9 mm and maximal lengths of 22 mm. For the actual measurement, first, the unloaded bone is measured in the microCT. Second, a load-displacement curve is recorded where the load is measured with an integrated mini-button load cell and the displacement is computed directly from the microCT scout-view. For each load case, a 3D snap-shot of the structure under load is taken providing 34 microm nominal resolution. Initial measurements included specimens from bovine tibiae and whale spine to investigate the influence of the structure type on the failure mechanism. In a rod-like type of architecture as seen in the whale spine, structural failure was described by an initial buckling and bending of structural elements followed by a collapse of the overloaded trabeculae. In the more plate like bovine tibial architecture, buckling and bending could not be observed. Failure rather seemed to occur instantaneously. In conclusion, micro-compression in combination with 3D microCT allows visualization of failure initiation and propagation and monitoring of damage accumulation in a nondestructive way. We expect these findings to improve our understanding of the relative importance of density, architecture and load in the etiology of spontaneous fractures of the hip and the spine. Eventually, this improved understanding may lead to more successful approaches to the prevention of age-related fractures. PMID- 10100947 TI - A multi-well filtration assay for quantitation of inositol phosphates in biological samples. AB - The quantitation of inositol phosphates (IPs), mediators of certain signal transduction processes, typically involves laborious and time consuming conventional ion-exchange chromatography procedures. We have developed a high throughput microtiter plate-based IP assay that utilizes vacuum rather than gravitational flow and has significant advantages over existing methods. The response of recombinant HEK-293 cells expressing human LHRH receptor cDNA to LHRH agonists was used as a model system to develop the assay conditions. Cell lysates containing labeled IPs were applied in 96-well plates fitted with filtration discs containing regenerated Dowex AGI-X8 resin. Specifically bound inositol phosphates were eluted with 1 M ammonium formate in 0.1 M formic acid directly into a fresh 96-well plate and an aliquot of the eluate from each well is transferred into a 96-well plate and counted. The results were comparable to those obtained with the conventional column method and the variation among replicates was significantly improved. This assay facilitates rapid quantitation of inositol phosphates from a large number of samples with relative ease and reduced generation of radioactive waste. PMID- 10100948 TI - Determination of the thermogenesis curves and studies of the thermodynamics and thermokinetics of seed germination. AB - The thermogenesis curves of the germination of different rice and tree seeds were determined and studied by using a newly constructed microcalorimeter. The thermogenesis curves of the germination of the seeds demonstrate the existence of physiological triphasic patterns, which include imbibition, activation and growth stages in the germination process. The thermodynamics and thermokinetics of the main growth phase of the growth stage in the germination process have been studied. The growth heat effect (deltaH), the growth rate constant (k), the growth inhibitory factor (s) and deceleration rate constant (beta) have been determined and calculated, In addition, the experimental thermokinetic equations of the growth stage in the seed germination process have been established. PMID- 10100949 TI - A method for direct cross-linking of DNA bases containing aromatic amino groups to proteins. AB - A one step method to cross-link DNA bases containing aromatic amino groups directly to proteins was developed. No chemical modification of the base is required prior to conjugation, which is performed at neutral pH. Work focused on 8-oxoguanine and the carrier protein, bovine serum albumin. Conjugates were stable after sodium dodecyl sulfate (SDS)-induced protein denaturation and were characterized by UV spectroscopy, enzyme linked immunosorbent assay (ELISA), SDS polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analyses. This method is a viable alternative to existing procedures for generating DNA base protein conjugates for antibody characterization and affinity purification. PMID- 10100950 TI - An ESR assay for alpha-amylase activity toward succinylated starch, amylose and amylopectin. AB - The esterification of the three polysaccharides, starch, amylose and amylopectin was carried out in pyridine-DMSO by succinic anhydride. The carboxylic groups in the succinylated polysaccharides were measured by FT-IR spectroscopy. The succinic derivatives were tested as alpha-amylase (1,4-alpha-D-glucan glucano hydrolase, E.C. 3.2.1.1) substrates. A colorimetric assay of the alpha-amylase activity indicated that this enzyme is active on succinic esters of starch and amylose and that the activity shows a linear decrease with the number of succinic units introduced into the polysaccharide. Since the colorimetric test was not suitable for the detection of the alpha-amylase activity when succinylated amylopectin was the substrate, we set-up an assay based on the labeling by a paramagnetic probe of the free carboxylic groups of succinylated polysaccharides. The kinetics of the alpha-amylase reaction were monitored by ESR spectroscopy through the increase of the mobility of the paramagnetic probe. The spin label used was the commercially available 4-amino-tempo. By this method we demonstrated that alpha-amylase is active on succinylated amylopectin. The utility of the assay for monitoring alpha-amylase activity when other methods (i.e. colorimetric tests) fail, is discussed. PMID- 10100951 TI - Use of 13C conformation-dependent chemical shifts to elucidate the local structure of a large protein with homologous domains in solution and solid state. AB - In order to clarify the difference between solution NMR and X-ray diffraction analyses concerning the presence of alpha-helical structure in protein A, the 13C conformation-dependent chemical shifts of the 13C-labeled carbonyl carbons for selectively labeled protein A were used. In the 13C CP/MAS NMR spectra, the higher-field shifts of the carbonyl carbons of 13C-labeled Thr and Val residues compared with the random coil chemical shifts both in solution and solid state imply the presence of the third helix in the polypeptide chain, in contrast to the crystal structure of Fc-bound B-domain. Thus, a combination of selective isotope labeling and conformation-dependent chemical shifts will be a good Indicator to monitor the local structure of homologous protein in solution and solid state. PMID- 10100952 TI - A rapid method for the evaluation of the ionic permeabilities across epithelial cell membranes. AB - This short note presents a recipe for the calculation of the ionic permeabilities across epithelial cell membranes. The method requires the Goldman-Hodgkin-Katz formalism as well as the consideration of the equivalent electrical circuit for an epithelial cell. The equivalent electrical circuit is solved in terms of the equivalent electromotive forces coupled in series with the ionic resistances of both cell membranes (apical and basolateral). The present procedure is feasible for any leaky epithelial cell membrane with the condition that this membrane (apical or basolateral) does not contain primary or secondary mechanisms for active transport. PMID- 10100953 TI - 11-Tungstocobalto(II)phosphate as a useful standard for anionic colloid titration. PMID- 10100954 TI - Microcalorimetric study of antiviral effect of drug. PMID- 10100955 TI - A new epileptic seizure classification based exclusively on ictal semiology. AB - Historically, seizure semiology was the main feature in the differential diagnosis of epileptic syndromes. With the development of clinical EEG, the definition of electroclinical complexes became an essential tool to define epileptic syndromes, particularly focal epileptic syndromes. Modern advances in diagnostic technology, particularly in neuroimaging and molecular biology, now permit better definitions of epileptic syndromes. At the same time detailed studies showed that there does not necessarily exist a one-to-one relationship between epileptic seizures or electroclinical complexes and epileptic syndromes. These developments call for the reintroduction of an epileptic seizure classification based exclusively on clinical semiology, similar to the seizure classifications which were used by neurologists before the introduction of the modern diagnostic methods. This classification of epileptic seizures should always be complemented by an epileptic syndrome classification based on all the available clinical information (clinical history, neurological exam, ictal semiology, EEG, anatomical and functional neuroimaging, etc.). Such an approach is more consistent with mainstream clinical neurology and would avoid the current confusion between the classification of epileptic seizures (which in the International Seizure Classification is actually a classification of electroclinical complexes) and the classification of epileptic syndromes. PMID- 10100956 TI - Vigabatrin use in psychotic epileptic patients: report of a prospective pilot study. AB - OBJECTIVES: Evaluation of any possible behavioural reactions in epileptic patients during vigabatrin treatment. MATERIAL AND METHODS: Ten patients with refractory partial epilepsy, previous mental retardation and psychosis or other significant psychiatric morbidity treated with vigabatrin were submitted periodically to specific tests (to quantify any possible change in behavioural parameters) and also to EEG recordings. RESULTS: After 1 year of treatment 5/10 patients became seizure-free, 3/10 of them presented reduction of seizures by over 75%. None of the subjects presented episodes that could be interpreted as psychotic reactions and, moreover, some patients showed a reduction in stereotypies, instability and aggressiveness. In 66% of these patients an improvement in cognitive functions was observed. CONCLUSION: The onset of side effects can be prevented by a gradual introduction of vigabatrin and by the use of the drug in moderate doses. These data do not confirm the contraindication to treat with vigabatrin patients with a history of psychiatric disturbances. PMID- 10100957 TI - Plasmapheresis in myasthenia gravis. A comparative study of daily versus alternately daily schedule. AB - OBJECTIVES: The aim of this study was to compare the efficacy of different protocols of plasmapheresis in the treatment of myasthenia gravis (MG). MATERIALS AND METHODS: We treated 30 MG patients with plasmapheresis on either a daily or alternately daily schedule for 5 consecutive sessions. Acetylcholine receptor antibody (AchRAb), serum proteins including albumin, globulin, immunoglobulin G (IgG), IgA, and IgM, and MG score were measured before and after the course of plasmapheresis in each group of patients. RESULTS: The mean percent reductions of serum proteins including IgA (81.5% vs 69.7%), IgM (95.6% vs 87.1%), and globulin (63.2% vs 50.1%) were significantly higher in the daily group. There were no significant differences in AchRAb and IgG levels after treatment between these 2 groups. However, the reduction of MG score was greater in the daily group. All the patients tolerated plasmapheresis well except for 2.7% of them who experienced hypotension. CONCLUSION: Our results suggest that daily plasmapheresis may be more effective in the treatment of patients with advanced MG. PMID- 10100958 TI - Movement velocity dependent muscle strength in Parkinson's disease. AB - We measured isokinetic muscle strength of knee extension and flexion in 18 patients with Parkinson's disease who showed marked laterality in symptom severity and compared strength between the sides in the same patient. In all patient groups, the maximum peak torque of the more affected side was significantly less than for the less affected side at 15 revolutions per minute (r.p.m.) and 30 r.p.m. with the difference between the sides being larger at 30 r.p.m. than at 15 r.p.m., while at 5 r.p.m. there were no significant differences between sides. In the Yahr stage I group, the maximum peak torque in both extension and flexion at each velocity showed no significant difference between the sides. In contrast, in the stage II and III groups the maximum peak torque at 5 r.p.m. showed no significant difference between the sides, while at 15 r.p.m. and 30 r.p.m. these values showed a tendency and a significant difference between the sides, respectively, with the more affected side being weaker. These results suggest that muscle weakness in patients with Parkinson's disease increases with performance velocity, especially as the disease progresses. PMID- 10100959 TI - Infantile and juvenile presentations of Alexander's disease: a report of two cases. AB - We describe 2 new cases of Alexander's disease, the first to be reported in Belgium. The first patient, a 4-year-old girl, presented with progressive megalencephaly, mental retardation, spastic tetraparesis, ataxia and epilepsy: post-mortem examination showed widespread myelin loss with Rosenthal fibers (RFs) accumulation throughout the neuraxis. She was the third of heterozygotic twins, the 2 others having developed normally and being alive at age 5 years. The second patient developed at age 10 years and over a decade spastic paraparesis, palatal myoclonus, nystagmus, thoracic hyperkyphosis and thoraco-lumbar scoliosis with radiological findings of bilateral anterior leukoencephalopathy. Brain stereotactic biopsy at age 16 years demonstrated numerous RFs. With these 2 cases, we review the literature on the various clinico-pathological conditions reported as Alexander's disease. We discuss the nosology of this entity and the pathogeny of RFs formation and dysmyelination. Clues to the diagnosis of this encephalopathy in the living patient are briefly described. PMID- 10100960 TI - Dyscalculia in the early stages of Alzheimer's disease. AB - OBJECTIVE: To study mathematical deficits in the early stages of Alzheimer's disease (AD). METHODS: Sixty-eight patients with mild AD and 242 normal controls (NC) received a standardized battery (EC 301-R) assessing number processing and calculation abilities. AD patients also received testing for language, memory, visuo-spatial and executive-attentional domains. RESULTS: Sixty-four AD patients (94.1%) showed impaired performances on the EC 301-R. Mathematical deficits were evident both on calculation and number processing skills. Performance on the single tasks was related to attentional-executive resources and to impaired number representations. Heterogeneous patterns of preserved/impaired mathematical abilities were also observed in single cases. CONCLUSION: Dyscalculia is an early sign of AD. It should be included among the reliable clinical hallmarks for the diagnosis of AD. Identification of dyscalculic symptoms in these patients requires composite assessment procedure. PMID- 10100961 TI - Registry of first-ever stroke in Tartu, Estonia, 1991 through 1993: outcome of stroke. AB - OBJECTIVES: To provide information about the functional ability of the survivors of first-ever stroke in Estonia. PATIENTS AND METHODS: A population based epidemiological study 1991 through 1993 in Tartu. Herewith the data for 1991 and 1993 are presented. A total of 519 persons were registered; 82% of them were admitted (mean length 14 days), 66% were discharged home. RESULTS: During 6 months 41% of the patients died, the remaining 305 patients were interviewed about their living conditions, and functional ability using the Barthel ADL Index. Although 58% of patients responded to the questionnaire, no significant differences in several factors between the respondents and non-respondents were found. Thirty-eight percent of the patients were totally independent in ADL. CONCLUSION: The case-fatality rate at 6 months was high in Estonia and the proportion of totally independent patients 6 months after stroke is slightly lower compared to other studies. The short length of hospital treatment was possibly compensated by sufficient support by relatives after discharge. PMID- 10100962 TI - Effect of nimodipine on cerebral blood flow and cerebrovascular reactivity after subarachnoid haemorrhage. AB - The aim of the present study was to investigate the effect of nimodipine on autoregulation of cerebral blood flow (CBF), CO2 reactivity and cerebral oxygen metabolism (CMRO2) in patients with subarachnoid haemorrhage (SAH). Eight patients with severe SAH were studied with repeated CBF and CMRO2 measurements on the first day of the bleeding and after at least 12 h of treatment of nimodipine. An initial resting study, an autoregulation study and a hyperventilation study was performed. CBF was measured using the 133-Xenon intravenous method. CMRO2 was calculated as AVDO2 x CBF. Nimodipine did not significantly change CBF and CMRO2 in the initial resting study. After induced arterial hypotension intact autoregulation was found before as well as after treatment with nimodipine. Beneficial effects of nimodipine were found on CO2 reactivity and CMRO2 during hypotension that may be explained as a positive effect on cerebral ischaemia. PMID- 10100963 TI - Cerebrovascular reactivity in carotid artery occlusion: possible implications for surgical management of selected groups of patients. AB - OBJECTIVES: The aim of this study was to use transcranial Doppler ultrasonography to investigate cerebrovascular reactivity to hypercapnia in the middle cerebral arteries of patients with carotid occlusion with different outcomes. PATIENTS AND METHODS: Cerebrovascular reactivity to hypercapnia was calculated with the breath holding index (BHI). Patients with unilateral carotid occlusion were divided as follows: asymptomatic (20 patients), transient ischemic attack (TIA) (20 patients), minor (20 patients) and major stroke (14 patients). Values of BHI homolateral to the carotid occlusion were compared with those of 25 healthy subjects and 34 stroke patients without significant carotid stenosis. RESULTS: BHI values were comparable in healthy controls, non stenotic stroke patients and asymptomatic occluded patients. BHI values of patients with symptomatic occlusion were significantly lower than those of the above-mentioned groups (P<0.0001). Moreover, the reduction of BHI was significantly associated with the extent of the neurological impairment. In fact, BHI values were significantly higher in TIA than in minor and major stroke (P<0.0001) and in minor than in major stroke patients (P<0.02). Finally, we found that a BHI value homolateral to carotid occlusion of 0.69 can be considered the cut-point for distinguishing between symptomatic and asymptomatic patients. CONCLUSION: Prospective studies are needed to demonstrate if the presence of this threshold value may help in selecting a subset of patients with asymptomatic carotid occlusion or with transient or mild neurological deficit with the highest probability of benefiting from surgical therapy. PMID- 10100964 TI - Correlation between symptomatic, radiological and etiological diagnosis in acute ischemic stroke. AB - OBJECTIVES: The aim of this study was to correlate with the symptomatic, radiological and etiological diagnosis in acute ischemic stroke. SUBJECTS AND METHODS: Two hundred and fifty patients with first-ever ischemic stroke within 24 h of onset were prospectively studied with 3-step diagnoses: 1) symptomatic diagnosis based on the Oxfordshire Community Stroke Project criteria (OCSP), 2) radiological diagnosis (CT or MRI) and 3) etiological diagnosis based on the Lausanne Stroke Registry criteria. RESULTS: Most of the patients with symptoms of total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI) and posterior circulation infarcts (POCI) had corresponding lesions on CT or MRI, while only 68% of lacunar infarcts (LACI) patients had small subcortical infarction (SSI). More than 60% of patients with TACI were classified into cardioembolism in the third diagnosis, while the etiology of PACI was either CE or large-artery atherosclerosis (LAA) in equal numbers. Only 58% of LACI patients were classified into small-artery disease (SAD) and 29% of them (30 cases) into LAA, of which 23 patients had lesions other than SSI. The positive predictive value of SAD in the combination of LACI and SSI was 0.78. The etiology of POCI was variable. CONCLUSION: Except for LACI, the symptomatic classification by OCSP corresponds well to the radiological diagnosis. The etiological diagnosis can be predicted by OCSP in TACI and PACI, but it is hard in POCI, and a number of LACI are due to LAA. PMID- 10100965 TI - Wernicke's encephalopathy induced by hyperemesis gravidarum. AB - A report is presented on a patient with Wernicke's encephalopathy secondary to hyperemesis gravidarum. The 25-year-old female presented 11 weeks into pregnancy with prolonged vomiting. Neurological examination 8 weeks later demonstrated obtunded sensations, nystagmus and ataxia of gait. MR imaging revealed bilateral lesions in the mediodorsal nuclei of thalami, in the hypothalamus and in the periaqueductal gray matter (1). The neurological signs and the MRI findings pointed to a diagnosis of Wernicke's encephalopathy. The patient was treated with intramuscular vitamin B1 followed by oral thiamine until the end of pregnancy. The subsequent course of the pregnancy was uncomplicated, and resulted in the delivery of a healthy 2970 g male infant. A review of the literature published during the last 30 years revealed an additional 20 cases of Wernicke's encephalopathy induced by hyperemesis gravidarum. Only half of these pregnancies resulted in the birth of a normal infant. PMID- 10100966 TI - White matter hyperintensities on MRI in a patient with corticobasal degeneration. AB - We describe a patient who presented with the clinicopathological features of corticobasal degeneration (CBD). Over the course of 8 years, the patient developed myoclonus, dystonia, and supranuclear gaze palsy associated with an akinetic-rigid syndrome. To our knowledge, no previous report of a patient with CBD has described clear-cut regional white matter changes as revealed by magnetic resonance imaging (MRI) scans. In our patient, a T2-weighted MR image of the brain showed focal atrophy of the bilateral frontal cortex and asymmetric regional hyperintensities of the subjacent white matter. These signal changes seemed to primarily reflect the progression of neuronal degeneration, especially the demyelination secondary to axonal loss or change. PMID- 10100967 TI - Superior sagittal sinus obstruction and tuberculous abscess. AB - Intracranial tumours such as meningiomas may occasionally produce raised intracranial pressure by occluding a venous sinus. More uncommonly, midline tumours in the occipital regions of the skull can produce elevated intracranial pressure by non-thrombotic compression of the superior sagittal sinus. We present a case of raised intracranial pressure secondary to non-thrombotic obstruction of the superior sagittal sinus by a midline tuberculous abscess. PMID- 10100968 TI - Compression of the visual pathway by anterior cerebral artery aneurysm. AB - Visual failure is an uncommon presenting symptom of an intracranial aneurysm. It is even more uncommon in aneurysms arising from the anterior cerebral artery (ACA). We presented 2 patients with an aneurysm of the A1 segment of the anterior cerebral artery causing visual field defects. One patient presented with a complete homonymous hemianopia due to compression of the optic tract by a giant aneurysm of the proximal left A1 segment. The second patient had an almost complete unilateral anopia caused by compression of the optic nerve and chiasm by an aneurysm of the distal part of the A1 segment with a small chiasmatic hemorrhage and ventricular rupture. PMID- 10100969 TI - Scientific criteria and the selection of allergenic foods for product labelling. PMID- 10100970 TI - Cortical influences on the vestibular nuclei of the cat. AB - Our goal was to study potential substrates for cortical modulation of vestibular reflexes in the cat. In initial experiments, injections of wheat-germ-agglutinate horseradish-peroxidase into Deiters' nucleus and the rostral descending nucleus revealed bilateral colonies of retrogradely filled neurons in cortical areas 6, 2, and 3a (about 60 cells per colony). In cats anesthetized with chloralose urethane, we stimulated areas 2 and 3a with trains of pulses while recording from ipsilateral vestibular-nucleus neurons, which were characterized by their responses to sinusoidal tilts and tested for the presence of antidromic responses to stimulation of the upper cervical cord. A majority of the neurons was affected by cortical stimulation, showing either facilitation, inhibition, or a mixture of the two. Stimulation in area 2 was more effective than stimulation in area 3a. Despite the anatomic presence of direct cortico-vestibular projections, properties of facilitation and inhibition suggest that both were evoked by polysynaptic pathways. Cortical effects were broadly distributed to vestibular neurons without regard to responses of these neurons to sinusoidal tilts. There was no significant difference between effects on lateral and medial vestibulospinal tract neurons, but, as a group, vestibulospinal neurons were much more likely to be affected by cortical stimulation than neurons not antidromically activated from the C2 segment. We conclude that, by their influence on vestibulospinal neurons, neurons in cortical areas 2 and 3a should be able to modulate, in behaving animals, vestibular reflexes acting on the neck and limbs. PMID- 10100971 TI - Marked non-uniformity of fiber-type composition in the primate suboccipital muscle obliquus capitis inferior. AB - Obliquus capitis inferior (OCI) is a monoarticular suboccipital muscle linking the transverse process of the atlas (C1) to the spinous process of the axis (C2). Histochemical analysis of fiber-type composition showed that the muscle has a marked gradient of fiber-type distribution in which type I fibers comprise 95 100% of fibers in the deepest region but less than 10% of fibers in the superficial layer. Step-like changes in fiber-type proportions occurred between groups of fascicles. In most instances the boundaries between these fascicles did not exhibit different perimysial features from those fascicles with similar fiber type proportions. OCI contained large numbers of muscle spindles, which were concentrated in deep regions rich in type I fibers. The degree of nonuniformity in fiber-type distribution seen in OCI is unusually large when compared with patterns described in other primate muscles, and has implications for the way that the muscle is studied anatomically and physiologically. PMID- 10100972 TI - Recovery of synapses in axotomized adult cat spinal motoneurons after reinnervation into muscle. AB - Peripheral axotomy of adult cat spinal motoneurons induces a marked loss of synaptic boutons from the cell bodies and dendritic trees. The aim of the present study was to analyze the recovery of synaptic contacts in axotomized motoneurons following reinnervation into muscle. Adult cat spinal motoneurons were first deprived of their muscular contacts for 12 weeks and, then, allowed to reinnervate their target muscle. Two years later, regenerated motoneurons were labeled with horseradish peroxidase to allow quantitative ultrastructural analyses of the synaptic covering of the cell bodies and dendrites. Presynaptic boutons were classified according to their size and the shape of their synaptic vesicles. Results show that a recovery of synaptic covering occurs in the axotomized neurons after muscle reinnervation, but it affects various bouton types to different degrees. The number of S-type boutons synapsing with the soma was 70% higher after reinnervation than at 12 weeks after axotomy, while the number of F-type boutons had increased by only 13%. Compared with the normal situation, the number of S-type boutons synapsing with the proximal dendrites increased from 82% at 12 weeks after axotomy to 180% in the reinnervated state. In conclusion, in adult cat spinal motoneurons, the reestablishment of muscular contact is followed by a normalization of some of the synaptological changes induced by a prolonged state of axotomy. In certain respects restitution is incomplete, but in others it results in overcompensation. PMID- 10100973 TI - Psychophysical study of noxious and innocuous cold discrimination in monkey. AB - Psychophysical evidence shows that humans are better able to distinguish differences in the intensity of cutaneous temperature in the cool range than in the noxious cold range. In order to compare these human perceptual findings with physiological data from non-human primates, we performed similar psychophysical experiments of cold perception in monkeys. Two adult male rhesus monkeys were trained to detect cooling shifts from baseline temperatures between 0 degrees and 22 degrees C applied to the face with a 1-cm2 contact thermode. Detection thresholds were determined using the method of constant stimuli for one monkey and an adaptive psychophysical algorithm which insured constant behavioral performance for the other monkey. Results showed that both monkeys detected significantly smaller temperature decreases from innocuous cool baselines (i.e., 22 degrees and 16 degrees C) than from noxious and near-noxious baselines (10 degrees, 6 degrees, 0 degrees C). Similarly, the latencies for detecting the cooling shifts were shorter and less variable in the innocuous cool range than in the noxious cold range. The observation of more precise discrimination of innocuous cool than noxious cold temperatures in monkeys is consistent with human psychophysical data. Thus, these data suggest that differential patterns of neuronal activity evoked by cool and noxious cold cutaneous stimuli, observed in peripheral afferents as well as in the central nervous system of monkey and cat, probably also exist in the human. PMID- 10100974 TI - Adaptation of center of mass control under microgravity in a whole-body lifting task. AB - Human balance in stance is usually defined as the preservation of the vertical projection of the center of mass (COM) on the support area formed by the feet. Under microgravity conditions, the control of equilibrium seems to be no longer required. However, several reports indicate preservation of COM control in tasks such as arm or leg raising, tiptoe standing, or trunk bending. It is still unclear whether COM control is also maintained in complex multijoint movements during short term exposure to microgravity. In the current study, the dynamics of equilibrium control were studied in four subjects performing two series of seven whole-body lifting movements under microgravity during parabolic flights. The aims of the study were to examine whether the trajectory of horizontal COM motion during lifting movements changes in short-term exposure to microgravity and whether there is any sign of recovery after several lifting movements. It was found that, compared with control movements under normal gravity, the horizontal position of the COM was shifted backward during the entire lifting movement in all subjects. In the second series of lifting movements under microgravity, a partial recovery of the COM trajectory toward the normal gravity situation was found. Under microgravity, angles of the ankle, knee, hip, and lumbar joints differed significantly from the angles found under normal gravity. Recovery of joint angular trajectories in the second series of lifting movements mainly occurred for those angles that could contribute to a reduction of the backward COM shift. It is to be pointed out that COM control under microgravity is not redundant but functional. Persisting COM control under microgravity may be required for pure mechanical reasons, since rotational movements of the body are dependent on adequate control of the COM position with respect to external forces. It is shown that, from a mechanical perspective, subjects can benefit from a backward displacement of the COM in the downward as well as the upward phase of the lifting movement under microgravity. PMID- 10100975 TI - Localization of a seen finger is based exclusively on proprioception and on vision of the finger. AB - In a previous study we investigated how the CNS combines simultaneous visual and proprioceptive information about the position of the finger. We found that localization of the index finger of a seen hand was more precise (a smaller variance) than could reasonably be expected from the precision of localization on the basis of vision only and proprioception only. This suggests that, in localizing the tip of the index finger of a seen hand, the CNS may make use of more information than proprioceptive information and visual information about the fingertip. In the present study we investigate whether this additional information stems from additional sources of sensory information. In experiment 1 we tested whether seeing an entire arm instead of only the fingertip gives rise to a more precise proprioceptive and/or visual localization of that fingertip. In experiment 2 we checked whether the presence of a structured visual environment leads to a more precise proprioceptive localization of the index finger of an unseen hand. In experiment 3 we investigated whether looking in the direction of the index finger of an unseen hand improves proprioceptive localization of that finger. We found no significant effect in any of the experiments. The results refute the hypothesis that the investigated effects can explain the previously reported very precise localization of a seen hand. This suggests that localization of a seen finger is based exclusively on proprioception and on vision of the finger. The results suggest that these sensory signals may contain more information than is described by the magnitude of their variances. PMID- 10100976 TI - Pointing to remembered visual targets after active one-step self-displacements within reaching space. AB - We studied pointing movements to remembered visual targets in a completely darkened room with and without self-made step movements in order to investigate in which coordinate system and to what extent target representations relative to the body are updated for self-induced egomotion. A small red-light-emitting diode on the fingertip provided visual feedback about fingertip position at all times. We asked subjects to make pointing movements that started 2 s after disappearance of a visual target. In this interval of 2 s the subject did or did not make a step. The pointing errors without a step showed that subjects undershot faraway targets in a systematic way, whereas they sometimes overshot nearby targets. We found that the step causes larger pointing errors both in amplitude and direction with a bias in the direction of the step. We explored three different versions of a descriptive model in which polar coordinates were used to describe the pointing movement, and in which either Cartesian or polar coordinates were used to update target position relative to the shoulder for the step. The results suggest that incorporation of the step displacement in the new target position relative to the subject is done in a Cartesian frame of reference. Moreover, the amplitude of the step displacement tends to be underestimated by subjects. PMID- 10100977 TI - Reprogramming of grip aperture in a double-step virtual grasping paradigm. AB - The present study investigated the control of manual prehension movements in humans. Subjects grasped luminous virtual discs with the thumb and index finger, and we recorded the instantaneous grip aperture, defined as the 3-D distance between the thumb and index finger. Target size could remain constant (single step trials) or unexpectedly change shortly after target appearance (double-step trials). In single-step responses, grip aperture varied throughout the movement in a consistent fashion. Double-step responses exhibited distinct corrective modifications, which followed the target change with a latency similar to the normal reaction time. This suggests that visual size information has a fast and continuous access to the processes involved in grip formation. The grip-aperture profiles of single-step responses had a different shape when the target called for an increase than when it called for a decrease in the initial finger distance. The same asymmetry was observed for aperture corrections in double-step trials. These findings indicate that increases and decreases of grip aperture are controlled through separate processes, engaged equally by the appearance and by the size change of a target. Corrections of grip aperture in double-step trials had a higher peak velocity and reached their maximum as well as their final value earlier than the aperture profiles of single-step trials. Nevertheless, the total duration of double-step trials was prolonged. These response characteristics did not fit with either of the three corrective strategies previously proposed for double-step pointing movements, which could indicate that grasping and pointing movements are controlled by different mechanisms. However, more data are needed to substantiate this view. PMID- 10100978 TI - Resetting voluntary movement using peripheral nerve stimulation: influence of loading conditions and relative effectiveness. AB - The effect of peripheral nerve stimulation on voluntary rhythmic flexion extension movements at the wrist was studied in nine normal volunteers, and the results compared with the effect of cortical stimulation on the same task. In the first part of the study, magnetic stimulation was given over the inner aspect of the right arm at levels which, at rest, resulted in a wrist flexion twitch of at least 10 degrees. We were able to confirm that this form of (peripheral-nerve) stimulation is an effective means of phase-resetting voluntary wrist movements. In addition, and unlike magnetic stimulation applied over the contralateral motor cortex, changes in the standing torque load, against which the subjects moved, had little influence on the effectiveness of this form of stimulation. Similarly, the amplitude and direction of the averaged first post-stimulus position peak ("P1"), previously identified as important determinants of the resetting induced by a cortical stimulus, were largely independent of the loading torque. In a second part to the study, we directly compared, for a constant loading torque, the resetting induced by magnetic cortical stimulation with that following magnetic stimulation of peripheral nerves. The relationship between the amplitude of P1 and the associated resetting index was identical for both forms of stimulation. Our observations indicate that magnetic stimulation of peripheral nerves is an effective means of resetting voluntary movement. It differs from magnetic cortical stimulation in that the effects of peripheral nerve stimulation are little altered by changes in loading torque. When differences in the size of P1 are allowed for, both peripheral nerve and cortical stimulation are equally effective means of resetting voluntary rhythmical movement. PMID- 10100979 TI - Dynamic changes in corticospinal excitability during motor imagery. AB - We investigated temporal changes in the amplitudes of motor-evoked potentials (MEPs) induced by transcranial magnetic stimulation over the left motor cortex during motor imagery. Nine subjects were instructed to imagine repetitive wrist flexion and extension movements at 1 Hz, in which the flexion timing was cued by a tone signal. Electromyographs (EMGs) were recorded from the first dorsal interosseous, flexor carpi radialis and extensor carpi radialis muscles of the right hand, and magnetic stimulation was delivered at 0, 250, 500 and 750 ms after the auditory cue. On average, the evoked EMG responses were larger in the flexor muscle during the phase of imagined flexion than during extension, whilst the opposite was true for the extensor muscle. There were no consistent changes in the amplitudes of MEPs in the intrinsic hand muscle (first dorsal interosseous). The EMG remained relaxed in all muscles and did not show any significant temporal changes during the test. The H-reflex in the flexor muscle was obtained in four subjects. There was no change in its amplitude during motor imagery. These observations lead us to suggest that motor imagery can have dynamic effects on the excitability of motor cortex similar to those seen during actual motor performance. PMID- 10100980 TI - Effects of repetitive cortical stimulation on the silent period evoked by magnetic stimulation. AB - The effects of repetitive transcranial stimulation (rTMS) on brain activity remain unknown. In healthy subjects, we studied the effects of rTMS on the duration of the cortical silent period (SP). Repetitive stimuli were delivered with a Cadwell High Speed Magnetic Stimulator and a figure-of-eight coil placed over the hand motor area. rTMS was delivered in trains of 11 or 20 stimuli at frequencies of 3 and 5 Hz and at stimulation intensities of 110 and 120% of motor threshold. The SP was recorded from the forearm muscles during a voluntary contraction (20% of maximum effort). rTMS delivered at a frequency of 3 and 5 Hz and intensities of 110 and 120% motor threshold prolonged the duration of the SP, without modifying either the size or the latency of the muscle-evoked potentials (MEP). A conditioning train of 11 stimuli at 3 Hz had no effect on the duration of the SP evoked by a single magnetic shock delivered 600 ms after the train. These findings show that rTMS increases the duration of the cortical SP, but does so only during the train of stimuli. rTMS probably changes the duration of the SP by facilitating cortical inhibitory interneurons. PMID- 10100981 TI - Visual-vestibular interaction during transparent optokinetic stimulation in the rabbit. AB - Transparent motion is a visual stimulus condition that generates multiple motion vectors on the retina that can differ in speed, direction, and/or luminance. Transparent motion creates a conflict for retinal stabilization. In this study we investigated the effect of transparent visual motion on the oculomotor reflexes that provide retinal stabilization in the rabbit. In the first experimental condition, the animals were stationary. We presented one stationary and one oscillating visual pattern to the animals while varying the luminance of the patterns. We found that the optokinetic eye movement responses were fully determined by the luminance of the individual visual inputs, weighted for the total luminance. No effect of absolute stimulus intensity was found. In the second experimental condition we oscillated the animals, while using an identical visual stimulation paradigm. The contribution of the vestibulo-ocular reflex enhanced the response to the visual pattern, which was in agreement with the vestibular stimulus. This effect of vestibular stimulation was independent of the absolute intensity of the visual stimuli. From this result we conclude that the weighting process of the transparent visual patterns occurs upstream from the site of the visual-vestibular interaction. Both the visual weighting and the visual-vestibular interaction were dependent on stimulus frequency. In line with the properties of the visual and vestibular stabilization reflexes in isolation, the contribution of the vestibular system increased, whereas the influence of the optokinetic system decreased with increasing stimulus frequency. PMID- 10100983 TI - Correction: Alternative Medicine -- The Case of Herbal Remedies. PMID- 10100982 TI - Integration of visual and somatosensory target information in goal-directed eye and arm movements. AB - In this study, we compared separate and coordinated eye and hand movements towards visual or somatosensory target stimuli in a dark room, where no visual position information about the hand could be obtained. Experiment 1 showed that saccadic reaction times (RTs) were longer when directed to somatosensory targets than when directed to visual targets in both single- and dual-task conditions. However, for hand movements, this pattern was only found in the dual-task condition and not in the single-task condition. Experiment 1 also showed that correlations between saccadic and hand RTs were significantly higher when directed towards somatosensory targets than when directed towards visual targets. Importantly, experiment 2 indicated that this was not caused by differences in processing times at a perceptual level. Furthermore, hand-pointing accuracy was found to be higher when subjects had to move their eyes as well (dual task) compared to a single-task hand movement. However, this effect was more pronounced for movements to visual targets than to somatosensory targets. A schematic model of sensorimotor transformations for saccadic eye and goal-directed hand movements is proposed and possible shared mechanisms of the two motor systems are discussed. PMID- 10100984 TI - Dormant tumor-suppressor pathways in tumors. PMID- 10100985 TI - Raf-1 causes growth suppression and alteration of neuroendocrine markers in DMS53 human small-cell lung cancer cells. AB - Ras mutations are common in lung adenocarcinomas and squamous-cell cancers, which are non-small-cell lung cancers (NSCLCs). However, small-cell lung cancers (SCLCs) rarely have ras mutations, suggesting that ras activation may not confer a growth advantage in these cells. In one SCLC cell line DMS53, activated ras expression induced increased neuroendocrine differentiation and decreased cell proliferation. We show here that DMS53 cells undergo differentiation and G1 specific growth arrest in response to ras/raf/ mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway activation. To assess the consequences of activating the raf/MEK/MAPK pathway downstream of ras, we transfected a DMS53 cell line with DeltaRaf-1:ER, an activatable form of c-raf 1. DeltaRaf-1:ER activation suppressed cell proliferation and cloning on soft agar by 90% without evidence of apoptosis. Cell cycle analysis showed a reduced proportion of cells in S phase, and was associated with induction of the cyclin dependent kinase (cdk) inhibitor p16(INK4). Expression of the cell cycle-specific proteins pRb, Rb2/p130, p107, cyclin A, cdc-2, and E2F-1 was decreased after DeltaRaf-1:ER activation in DMS53 cells. The activity cdk4 and cdk2 was also reduced, as consistent with cell cycle arrest in cells with activated DeltaRaf 1:ER cells. In addition, DeltaRaf-1:ER reduced the expression of neuroendocrine markers, gastrin releasing peptide, and ret gene in DMS53:DeltaRaf-1:ER cells. These results provide further evidence that activation of the raf/MEK/ MAPK signaling pathway, which is associated with transformation in many circumstances, can reduce the growth of SCLC cells, and suggest that activation of this pathway might be clinically efficacious in some settings. PMID- 10100986 TI - Development of the innervation and airway smooth muscle in human fetal lung. AB - Human and porcine fetal airways have been shown to contract spontaneously from the first trimester, the latter also contracting in response to neural stimulation. Our object was to map immunohistochemically the innervation and its relationship to the airway smooth muscle (ASM) in the human fetal lung from early gestation to the postnatal period. Whole mounts of the bronchial tree were stained with antibodies to the pan-neuronal marker protein gene product 9.5, the Schwann cell marker S-100, and the ASM contractile protein alpha-actin, and imaged using confocal microscopy. By the end of the embryonic period (53 d gestation), the branching epithelial tubules in the primordial lung were covered with ASM to the base of the terminal sacs. An extensive plexus of nerve trunks containing nerve bundles, forming ganglia, and Schwann cells ensheathed the ASM. By 16 wk (canalicular stage), maturation of the innervation was advanced with two major nerve trunks running the length of the bronchial tree, giving rise to varicosed fibers lying on the ASM. An extensive nerve plexus in the mucosa was also present. The distal airways of infants who had died of Sudden Infant Death Syndrome were also covered with smooth muscle and were well innervated. Thus, an essentially complete coat of ASM and an abundant neural plexus ensheathing the airways are an integral part of the branching epithelial tubules from early in lung development. PMID- 10100987 TI - Lung fibrosis induced by silica particles in NMRI mice is associated with an upregulation of the p40 subunit of interleukin-12 and Th-2 manifestations. AB - Interleukin (IL)-12 is a cytokine produced principally by activated macrophages which is involved in control of the T-helper 1/T-helper 2 cell (Th1/Th2) polarization of immune responses. To examine its potential involvement in the development of lung fibrosis, we examined the expression (protein, messenger RNA [mRNA]) of IL-12 (p70) and of its subunits (p40 and p35) in lung homogenates, bronchoalveolar lavage fluid (BALF), and bronchoalveolar lavage (BAL) cell cultures in mouse models of resolutive alveolitis (RA) and fibrosing alveolitis (FA) induced by inorganic particles (manganese dioxide [MnO2] and crystalline silica, respectively). The administration of tungsten carbide (WC), which behaved as an innocuous dust for the lung, served as a negative control condition. The FA was specifically accompanied by a Th2-like polarization characterized by high levels of immunoglobulin (Ig)G1 in BALF and by a protracted overproduction of both p40 protein and mRNA, but not by the biologically active form of IL-12 (p70). In the RA model, the p40 response was only transient, and a Th1-like response was reflected by increased levels of interferon (IFN)-gamma and dominant levels of IgG2a in BALF. Taken together, these findings suggest that production of the p40 subunit of IL-12 and Th2 polarization play important roles in lung inflammatory and fibrotic responses to inhaled inorganic particles. PMID- 10100988 TI - Lysozyme expression during metaplastic squamous differentiation of retinoic acid deficient human tracheobronchial epithelial cells. AB - We previously reported (Gray, T. E., K. Guzman, C. W. Davis, L. H. Abdullah, and P. Nettesheim. 1996. Mucociliary differentiation of serially passaged normal human tracheobronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 14:104 112) that retinoic acid (RA)-deprived cultures of normal human tracheobronchial epithelial (NHTBE) cells became squamous, failed to produce mucin, and instead secreted or released large amounts of lysozyme (LZ). The purpose of the studies reported here was to elucidate the relationship between RA deficiency-induced squamous differentiation and increased LZ, and to determine what mechanisms were involved. We found that intracellular LZ began to accumulate in RA-deficient NHTBE cultures early during squamous differentiation. Between Days 10 and 18 of culture, cellular LZ levels were more than 10 times higher in RA-deficient than in RA-sufficient cultures. On Day 12, large numbers of cells began to exfoliate in RA-deficient cultures and extracellular LZ appeared at the apical surface, presumably released from the exfoliated cells. Metabolic labeling studies showed that the rate of LZ synthesis was not increased in RA-deficient cultures over that in RA-sufficient cultures; however, intracellular LZ half-life was much longer in RA-deficient cultures. We concluded that the increased accumulation of both intra- and extracellular LZ in RA-deficient cultures was due to increased LZ stability and was not the result of increased LZ synthesis. When RA-deficient cultures were treated on Day 7 with 10(-6) M RA, intracellular LZ levels did not substantially decrease until 3 d later, coinciding with a marked increase in mucin secretion. LZ messenger RNA levels were unchanged at 24 h, but were modestly increased (rather than decreased) at all subsequent time points. We concluded that RA does not directly regulate LZ, and that the excessive accumulation of LZ in RA-deprived NHTBE cells is a consequence of vitamin A deficiency-induced abnormal differentiation. PMID- 10100989 TI - alpha-smooth-muscle actin and microvascular precursor smooth-muscle cells in pulmonary hypertension. AB - Little is known of the molecular basis of smooth-muscle cell development in the microvessels of the adult lung in pulmonary hypertension (PH). Using quantitative and immunogold electron microscopy techniques we report the development of microvascular precursor smooth-muscle cells (PSMCs) expressing alpha-smooth muscle actin (alphaSMA), a first marker of smooth-muscle cell differentiation, in rats with hyperoxic PH. Increase in the frequency of distal (alveolar wall) vessels with alphaSMA cells preceded (Pchi2 < 0.02, Day 4) the increase in proximal (alveolar duct) vessels (Pchi2 < 0.02, Day 14). The smallest vessel with cells expressing alphaSMA (< 50 micrometer in diameter) increased most with time (Pchi2 < 0.001). Immunopositive PSMCs were rare in normal lung and frequent in hyperoxia. Well-developed filament arrays decorated with alphaSMA were detected in intermediate cells early in hyperoxia (Day 4). Similar filament networks were detected later in fibroblasts recruited to vessel walls (Days 7 to 14). By Day 28, cells derived from fibroblasts formed several layers in the vessel wall and expressed dense alphaSMA filament arrays, in either a central domain or mesh. Thus, intermediate cells are the source of cells expressing alphaSMA early in the microvessels in hyperoxic pulmonary hypertension and fibroblasts of cells in the late stage-the time of intense neomuscularization of the microvessels. PMID- 10100990 TI - Mucin gene expression during differentiation of human airway epithelia in vitro. Muc4 and muc5b are strongly induced. AB - Mucus hypersecretion is characteristic of chronic airway diseases. However, regulatory mechanisms are poorly understood. Human airway epithelial cells grown on permeable supports at the air-liquid interface (ALI) develop a mucociliary morphology resembling that found in vivo. Such cultures provide a model for studying secretory cell lineage, differentiation, and function, and may provide insight regarding events leading to mucus hypersecretion. The mucin gene expression profile of well-differentiated human airway epithelial cells in culture has not yet been established. We compared expression of all the currently described mucin genes in poorly differentiated (conventional cultures on plastic) and well-differentiated (ALI) human nasal and bronchial epithelial cells. Differentiation-dependent upregulation of MUC3, MUC5AC, MUC5B, and MUC6 messenger RNA (mRNA) was demonstrated using reverse transcriptase-polymerase chain reaction (RT-PCR). Northern blot analysis showed a similar increase for MUC4 and demonstrated that induction of MUC4 and MUC5B expression depended on retinoic acid. MUC1, MUC2, MUC7, and MUC8 mRNAs were also detected by RT-PCR, but these genes did not appear to be strongly regulated as a function of differentiation. Mucin gene expression was similar in bronchial and nasal cells. Thus, mucociliary differentiation of human airway epithelia in vitro entails upregulation of several mucin genes. PMID- 10100992 TI - Expression of cathepsin K in lung epithelial cells. AB - Alveolar and bronchial epithelial cells have been shown to have regulatory functions in the maintenance of lung structure and function. Recent evidence supports the premise that these cells can synthesize a variety of extracellular matrix components in vitro, suggesting an active participation in connective tissue remodeling. Their possible role in extracellular matrix degradation, however, is less clear. This study addresses the question of whether alveolar and bronchial epithelial cells express the highly collagenolytic and elastinolytic cysteine proteinase cathepsin K, which has recently been newly described. We provide evidence that the epithelial cell lines A549 and BEAS-2B are capable of expressing cathepsin K messenger RNA. Furthermore, we show that cathepsin K is expressed in normal bronchial epithelial cells. Western blot analyses of human lung-tissue lysates revealed specific immunoreactivity at molecular weights of 46 and 27 kD, corresponding to the procathepsin and the mature cathepsin K. Immunohistochemical analyses showed a pronounced staining of bronchial epithelial cells and in single alveolar epithelial cells. Using a specific fluorogenic cytochemical assay, the intracellular activity of the enzyme was localized. These findings demonstrate that bronchial and alveolar epithelial cells are capable of expressing cathepsin K, which could be of considerable importance for remodeling processes of the extracellular matrix in the lung. PMID- 10100991 TI - Ion composition and rheology of airway liquid from cystic fibrosis fetal tracheal xenografts. AB - The composition of airway surface liquid (ASL) is partly determined by active ion and water transport through the respiratory epithelium. It is usually stated that in cystic fibrosis (CF), CF transmembrane conductance regulator protein abnormality results in imbalanced ion composition and dehydration of ASL, leading to abnormal rheologic and transport properties. To explore the relationship between ion composition, water content, and viscosity of airway liquid (AL), we used a human xenograft model of fetal airways developed in severe combined immunodeficiency (SCID) mice. Six non-CF and six CF portions of fetal tracheas were engrafted subcutaneously in the flanks of SCID mice raised in pathogen-free conditions. AL accumulated in the closed cylindric grafts was harvested 9 to 17 wk after implantation. At the time of AL sampling, all tracheal grafts displayed well-differentiated pseudostratified surface epithelium and submucosal glands. The viscosity of AL was measured using a controlled-stress rheometer. The ion composition of AL was quantified by X-ray microanalysis. No significant difference was observed for AL viscosity between non-CF (0.6 +/- 0.5 Pa. s) and CF (0.2 +/- 0.1 Pa. s) samples. In AL from non-CF and CF samples, the ion concentrations were Na: 63.9 +/- 7.6, 79.7 +/- 11.6; Cl: 64.9 +/- 13.2, 82.6 +/- 15.7; Mg: 1.9 +/- 0.3, 2.2 +/- 0.4; S: 4.9 +/- 1. 3, 4.8 +/- 0.5; K: 2.4 +/- 0.5, 3.2 +/- 1.6; and Ca: 1.2 +/- 0.3, 2.6 +/- 0.8 mmol/liter, respectively. The ion composition of AL from CF versus non-CF xenografts was not significantly different. These results suggest that prior to inflammation and infection, the viscosity and ion composition of the fetal AL do not differ in CF and non-CF. PMID- 10100993 TI - Localization and distribution of endothelin receptor subtypes in pulmonary vasculature of normal and hypoxia-exposed rats. AB - To clarify the roles of two different endothelin (ET) receptors in the pulmonary vasculature, the localization and distribution of endothelin-A (ETA) and ETB receptors were investigated in rat lung under normal and hypoxic conditions by an immunohistochemical method. We also carried out in situ hybridization for ETB receptor. In normal rats, ETA receptor is localized in the media of the pulmonary artery and vein with predominant distribution in such proximal segments as elastic arteries and large muscular arteries. ETB receptor is expressed in the intima and media of pulmonary vessels. The distribution of ETB receptor in the media predominates in the distal segments of the pulmonary artery, whereas its distribution in the intima is greater in the proximal segments. Immunoreactivity for ETA receptor increases in the media of the distal segments of the pulmonary artery after exposure to hypobaric hypoxia. Semiquantitative evaluation showed immunoreactivity for ETA receptor in the pulmonary arteries accompanying the terminal bronchioles, respiratory bronchioles, and alveolar ducts to be increased by 2.5-, 5-, and 20-fold after 14 d exposure to hypoxia, respectively. The messenger RNA and immunoreactivity for ETB receptor increased significantly in the intima of the distal segments of pulmonary artery after 7 and 14 d exposure to hypoxia. These results suggest that the vasoconstrictive effects of ET-1 are exerted mainly through ETA receptor in the proximal segments of the pulmonary artery and vein, whereas its effects in the distal segments are mediated by ETA and ETB receptors in normal rats. ETA receptors that increase in resistance arteries after exposure to hypoxia appear to play an important role in the vascular remodeling associated with hypoxic pulmonary hypertension. Because ETB receptors in the endothelium mediate ET-1-induced vasodilatory effects, the increase in endothelial ETB receptors may counteract the development of hypoxic pulmonary hypertension. PMID- 10100994 TI - Cellular and biochemical response of the human lung after intrapulmonary instillation of ferric oxide particles. AB - Bronchoalveolar lavage (BAL) was used to sample lung cells and biochemical components in the lung air spaces at various times from 1 to 91 d after intrapulmonary instillation of 2.6 microm-diameter iron oxide particles in human subjects. The instillation of particles induced transient acute inflammation during the first day post instillation (PI), characterized by increased numbers of neutrophils and alveolar macrophages as well as increased amounts of protein, lactate dehydrogenase, and interleukin-8 in BAL fluids. This response was subclinical and was resolved within 4 d PI. A similar dose-dependent response was seen in rats 1 d after intratracheal instillation of the same particles. The particles contained small amounts of soluble iron (240 ng/mg) and possessed the capacity to catalyze oxidant generation in vitro. Our findings indicate that the acute inflammation after particle exposure may, at least partially, be the result of oxidant generation catalyzed by the presence of residual amounts of ferric ion, ferric hydroxides, or oxyhydroxides associated with the particles. These findings may have relevance to the acute health effects associated with increased levels of ambient particulate air pollutants. PMID- 10100995 TI - Inhibition of VCAM-1 expression in human bronchial epithelial cells by glucocorticoids. AB - We have demonstrated previously that cytokines induce surface expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on BEAS-2B bronchial epithelial cells in vitro. The present studies demonstrate glucocorticoid inhibition of cytokine-induced VCAM-1 expression as detected using flow cytometry and Northern blot analysis. Several commonly used inhaled glucocorticoids were tested for their ability to inhibit VCAM-1 and ICAM 1 expression. All glucocorticoids tested inhibited VCAM-1 expression in a dose dependent manner. No inhibition of ICAM-1 expression was observed. The most potent of the glucocorticoids tested for inhibition of VCAM-1 expression were mometasone furoate and fluticasone propionate (FP), which had IC50 values (i.e., concentrations at which each glucocorticoid produced 50% inhibition) of under 10 pM. Budesonide, triamcinolone acetonide, and beclomethasone dipropionate (BDP) had intermediate potency, and hydrocortisone and the BDP metabolite beclomethasone-17-monopropionate were the least potent of the steroids tested. Kinetic analysis of the ability of FP to inhibit VCAM-1 expression revealed that preincubation with FP for 3 h completely inhibited VCAM-1 expression induced by tumor necrosis factor-alpha (TNF-alpha). FP inhibited VCAM-1 expression by 50% even when added as late as 6 h after stimulation with TNF-alpha. Using Northern blot analysis, we confirmed inhibition of VCAM-1 and ICAM-1 messenger RNA (mRNA) expression by FP. Pretreatment with FP (10(-11) M to about 10(-7) M, 24 h) inhibited TNF-alpha-induced VCAM-1 mRNA expression in BEAS-2B in a dose-dependent manner, but did not inhibit expression of ICAM-1 mRNA. Studies with actinomycin D indicate that FP treatment accelerated the degradation of TNF-alpha-induced VCAM 1 mRNA. FP (10(-7) M) also inhibited VCAM-1 mRNA expression induced by TNF-alpha in primary human bronchial epithelial cells as assessed by reverse transcription polymerase chain reaction. These results suggest that suppression of epithelial VCAM-1 expression by glucocorticoids may contribute to their anti-inflammatory effects. PMID- 10100996 TI - Smooth-muscle myosin heavy-chain SM-B isoform expression in developing and adult rat lung. AB - The smooth-muscle cells composing the vasculature and airways of the lung display a variety of contractile protein phenotypes. To date, however, it has remained unclear how these phenotypes might contribute differentially to contractile activity. To address this issue, we made monospecific rabbit polyclonal antibodies against the difference peptide for the SM-B smooth-muscle myosin heavy chain (SMMHC) and used these to investigate the distribution of the SM-B isoform in lung. SM-B has a seven-amino acid insert in the head region that is known to result in a higher actin-activated adenosine triphosphatase activity and in vitro motility. During development, reactivity is first seen in the trachea and bronchi of saccular lung at the time of birth, when other SMMHC isoforms also are present. Immunoreactivity spreads distally through the airways as development proceeds, reaching the level of alveolar septae in the adult. Although the smaller vessels of the pulmonary vasculature react strongly with the SM-B antibody, reactivity is infrequently observed in large pulmonary vessels. Adult tracheal smooth muscle is highly and more uniformly reactive, commensurate with its relatively high maximal velocity of shortening. The differential expression of the SM-B isoform in vascular and airway smooth muscles demonstrated in this study may provide the molecular basis for functional differences between these smooth-muscle cell types and may provide one mechanism for adapting contractility in response to physiologic stresses in the lung. PMID- 10100997 TI - Estrogen acutely stimulates endothelial nitric oxide synthase in H441 human airway epithelial cells. AB - Nitric oxide (NO) is an important mediator of physiologic processes in the airway. Levels of exhaled NO are greatest and asthma symptoms are least in menstruating women during midcycle, when estrogen levels are highest. To better understand the role of estrogen in airway function, we tested the hypothesis that estrogen stimulates endothelial NO synthase (eNOS) in NCI-H441 human bronchiolar epithelial cells. eNOS activation was assessed by measuring conversion of [3H]L arginine to [3H]L-citrulline in intact cells. eNOS activity rose in the presence of estradiol-17beta (E2beta), with a maximum stimulation of 243% at 10(-8) M E2beta. This response was comparable to the 201% increase elicited by the calcium (Ca2+) ionophore A23187 (10(-5) M), and was evident as early as 5 min after such treatment. Actinomycin D had no effect on the response to E2beta, and eNOS abundance was similar in control and E2beta-treated cells. E2beta-stimulated eNOS activity was dependent on the influx of extracellular Ca2+, and was completely inhibited by the estrogen receptor (ER) antagonist ICI182,780. Messenger RNA and protein for the alpha isoform of ER (ERalpha) were evident in the H441 cells, and freshly isolated ovine airway epithelial cells also coexpressed eNOS and ERalpha. These findings indicate that estrogen acutely activates existing eNOS in H441 airway epithelial cells, through a process that involves the stimulation of epithelial ER and Ca2+ influx. This process may play a role in the hormonal modulation of airway function. PMID- 10100998 TI - Lung cancer and past occupational exposure to asbestos. Role of p53 and K-ras mutations. AB - Studies on somatic mutations in lung cancers associated with cigarette smoking and asbestos exposure are few. We investigated prevalence of mutations in the p53 and K-ras genes in lung tumors from smokers with and without asbestos exposure at work. For K-ras mutations, the study was an extension of an earlier analysis. Nearly all of the 105 consecutive patients examined were smokers and had non small-cell carcinoma of the lung with squamous-cell carcinoma or adenocarcinoma histology. Exposure to asbestos was estimated by pulmonary fiber counts and occupational histories. A pulmonary burden of >/= 1 x 10(6) asbestos fibers per gram of lung tissue, indicating work-related exposure, was found in 32% of the patients for whom fiber-analysis data were available (33 of 102 patients, all men). The statistical analysis showed pulmonary fiber count as the only significant predictor of adenocarcinoma histology, in contrast to squamous-cell carcinoma (smoking-adjusted odds ratio [OR] 3.0, 95% confidence interval [CI] 1.1 to 8.5). The frequency of p53 mutations was 39% (13 of 33) among the asbestos exposed cases, as compared with 54% (29 of 54) among the nonexposed cases; the difference was not significant, however. In male ever-smokers, a long duration of smoking was associated with p53 mutation (OR 3.2, 95% CI 1.2 to 8.8). In adenocarcinoma, p53 mutations were less prevalent (10 of 30, 33%) as compared with squamous-cell carcinoma (28 of 46, 61%; P = 0.02), whereas a strong and significant association was found between adenocarcinoma and K-ras mutation (OR 37, 95% CI 5.8 to 232, adjusted for smoking and asbestos exposure). Asbestos exposure alone was not significantly associated with increased occurrence of K ras mutations. In conclusion, the results may primarily reflect the observed excess of adenocarcinoma in the asbestos- exposed patients, and hence the decrease in p53 mutations and increase in K-ras mutations. PMID- 10100999 TI - Cloning and characterization of KPL2, a novel gene induced during ciliogenesis of tracheal epithelial cells. AB - To identify genes upregulated during the process of ciliated cell differentiation of airway epithelial cells, differential display was used to compare RNA from rat tracheal epithelial (RTE) cells cultured under conditions that inhibit/promote ciliated cell differentiation. Several partial complementary DNAs (cDNAs) were identified whose expression was regulated coordinately with ciliated cell differentiation. One of these, KPL2, detected a messenger RNA transcript of approximately 6 kb when used as a probe on Northern blots of RNA from ciliated cultures but was undetectable in RNA from nonciliated cultures. Sequencing of overlapping clones obtained by a modified rapid amplification of cDNA ends procedure generated a complete cDNA sequence that exhibited no significant homology to sequences in GenBank, indicating that KPL2 is a novel gene. Southern analysis demonstrated that KPL2 exists as a single-copy gene. KPL2 contains a long open reading frame predicted to code for a protein of > 200 kD. Several putative functional motifs are present in the protein, including a calponin homology domain, three nuclear localization signals, a consensus P-loop, and a proline-rich region, suggesting that KPL2 has a unique function. KPL2 was undetectable in heart and liver samples, but was expressed in brain and testis, tissues that contain axonemal structures. In seminiferous tubules of the testis, KPL2 expression was stage-specific and appeared to be highest in spermatocytes and round spermatids. During differentiation of RTE cells, the expression of KPL2 closely paralleled that of an axonemal dynein heavy chain. These results suggest that KPL2 plays an important role in the differentiation or function of ciliated cells in the airway. PMID- 10101000 TI - A cystic fibrosis tracheal gland cell line, CF-KM4. Correction by adenovirus mediated CFTR gene transfer. AB - Human tracheal gland serous (HTGS) cells are now considered one principal pulmonary target for the gene therapy of cystic fibrosis (CF). We developed a CF tracheal gland serous cell line, CF-KM4, obtained by the transformation of primary cultures of CF tracheal gland serous cells homozygous for the DeltaF508 mutation by using the wild-type SV40 virus. This cell line retained epithelial and secretory features of the native CF-HTGS cells in primary culture, namely, presence of cytokeratin, constitutive secretion of secretory leukocyte proteinase inhibitor, absence of responsiveness to carbachol and isoproterenol, and defective cyclic adenosine monophosphate-dependent chloride channel activity. Adenovirus-mediated CF transmembrane conductance regulator (CFTR) gene transfer into CF-KM4 cells corrected the defective chloride channel activity as well as the responsiveness to adrenergic and cholinergic agonists. In contrast, control transfection using adenovirus-mediated beta-galactosidase gene transfer was totally ineffective. In conclusion, these results present a stable CF tracheal gland cell line that has retained its epithelial and CF-specific defective secretory characteristics which are corrected after CFTR gene transfer. This cell line therefore appears to be a useful tool for large-scale molecular and cellular pharmacologic investigations designed to test potential therapies of the disease CF. PMID- 10101001 TI - Essential role of alveolar macrophages in intrapulmonary activation of NF-kappaB. AB - Acute inflammatory injury in rat lung induced by deposition of immunoglobulin G immune complexes requires expression of cytokines and chemokines as well as activation of the transcription factor nuclear factor (NF)-kappaB. There is little direct evidence regarding the role of alveolar macrophages in these activation events. In the present studies, rat lungs were depleted of alveolar macrophages by airway instillation of liposome-encapsulated dichloromethylene diphosphonate. These procedures, which greatly reduced the number of retrievable alveolar macrophages, suppressed activation of lung NF-kappaB in the inflammatory model. In addition, bronchoalveolar lavage levels of tumor necrosis factor-alpha (TNF-alpha) and the CXC chemokine, macrophage inflammatory protein-2, were substantially reduced. In parallel, upregulation of the lung vascular adhesion molecule, intercellular adhesion molecule-1, was greatly reduced by intrapulmonary instillation of phosphonate-containing liposomes. Neutrophil accumulation and development of lung injury were also substantially diminished. Lung instillation of TNF-alpha in alveolar macrophage-depleted rats restored the NF-kappaB activation response in whole lung. These data suggest that, in this inflammatory model, initial activation of NF-kappaB occurs in alveolar macrophages and the ensuing production of TNF-alpha may propagate NF-kappaB activation to other cell types in the lung. PMID- 10101002 TI - Breathing pattern response and epithelial labeling in ozone-induced airway injury in neutrophil-depleted rats. AB - To test the hypothesis that neutrophils enhance the repair of ozone (O3)-injured airway epithelium, we investigated breathing pattern responses and airway epithelial injury and repair in rats depleted of neutrophils using rabbit antirat neutrophil serum (ANS) and control rats treated with normal rabbit serum (NRS). Thirty-seven Wistar rats were exposed to O3 (1 ppm) or filtered air (FA) for 8 h followed by 8 h in FA. O3-exposed NRS- and ANS-treated rats showed similar progressive decreases in tidal volume and increase in breathing frequency, with maximal changes occurring at 8 h of exposure, whereas FA-exposed rats showed no significant changes. O3-exposed ANS-treated rats showed more epithelial necrosis in the nasal cavity, bronchi, and distal airways than did O3-exposed NRS-treated rats. Incorporation of 5-bromo-2-deoxyuridine (BrdU), a measure of cellular proliferation, was assessed using an optical disector to count BrdU- labeled terminal bronchiolar epithelial cells. O3-exposed ANS-treated rats had significantly less BrdU- labeled epithelial cells than did O3-exposed NRS-treated rats. We conclude that neutrophils contribute to the repair process by enhancing the proliferation of O3-injured airway epithelial cells. PMID- 10101003 TI - Characterization of chronic bronchopulmonary Pseudomonas aeruginosa infection in resistant and susceptible inbred mouse strains. AB - Chronic bronchopulmonary Pseudomonas aeruginosa infection, initiated by intratracheal instillation of 1 to 2 x 10(5) colony-forming units of a mucoid strain of bacteria trapped in agar beads, was characterized in resistant BALB/c mice and susceptible C57BL/6 (B6) mice through 28 d postinfection. B6 mice experienced a more severe infection than BALB/c mice as evidenced by significantly higher mortality and significantly greater weight loss during the first 14 d. Furthermore, B6 mice had significantly higher numbers of bacteria in the lungs through 21 d after infection. Overall, only 22% of these hosts cleared the infection. In contrast, 67% of BALB/c mice cleared the infection. These differences between resistant and susceptible mice were found to correlate with histopathologic differences in the type of inflammation and the extent of tissue damage. An acute, predominantly neutrophilic inflammation and extensive tissue damage were apparent in the lungs of susceptible B6 mice, whereas chronic, granulomatous inflammation and little or no tissue damage were visible in resistant BALB/c mice. The finding of acute inflammation in the lungs of infected B6 mice was confirmed by fluorescence-activated cell sorter (FACS) analyses, which demonstrated that these mice had significantly greater proportions of polymorphonuclear neutrophils in the lungs on Days 7 and 14 after infection than did BALB/c mice. FACS analyses also revealed significant and similar increases in CD3(+) lung cells in both strains as the infection progressed. The CD4/CD8 ratio was significantly greater in BALB/c mice by 21 d after infection when the majority of these animals, but not B6 mice, had cleared the infection. PMID- 10101004 TI - Expression of Bcl-2 and its homologues in human eosinophils. Modulation by interleukin-5. AB - The Bcl-2 family has been shown to be vital regulators of programmed cell death in numerous systems. To investigate the role of such proteins in the regulation of apoptosis of eosinophils, the expression of Bcl-2 and homologues Bcl-xL (death antagonists), Bax, and Bcl-xS (death agonists) were examined by immunoblot, flow cytometry, and reverse transcriptase-polymerase chain reaction analysis. Potential modulation of apoptosis-associated molecules during spontaneous apoptosis and in the presence of interleukin (IL)-5 was also investigated. Peripheral blood eosinophils were found to express constitutively Bax and Bcl-x, but Bcl-2 was absent. Analysis of mRNA revealed that the bcl-xL isoform predominated, although bcl-xS was also detectable. Spontaneous apoptosis due to culturing in the absence of cytokines for 24 h did not result in modulation of any of the Bcl-2 homologues examined. Culturing eosinophils in the presence of 100 pg/ml IL-5 for 24 h significantly reduced apoptosis (P < 0.01) to 10.7 +/- 2.6% compared with 46.8 +/- 7.4% in the absence of IL-5, and induced Bcl-2 mRNA and protein expression, with no detectable change in Bax, Bcl-x, or beta-actin as a control. This investigation indicates a specific profile of apoptotic molecules in eosinophils distinct from that of neutrophils, and indicates that survival enhancing IL-5 modulates the expression of Bcl-2 in vitro. PMID- 10101005 TI - Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum. AB - We evaluated the roles of proteinase 3 (PR3) and human neutrophil elastase (HNE), two neutrophil serine proteinases in the mechanisms leading to airway inflammation and hypersecretion in cystic fibrosis (CF). Using specific enzyme linked immunosorbent assay (ELISA), we found higher levels of PR3 than HNE in sputum from CF patients. Using two inhibitors, ICI (Imperial Chemical Industries) 200,355 (which inhibits both HNE and PR3) and secretory leukoproteinase inhibitor (SLPI) (which inhibits only HNE), we showed that PR3 was enzymatically active in sputum, and its activity, as assessed by SLPI-resistant serine proteinase activity, correlated highly with its antigenic concentration measured by ELISA. Interestingly, sputum pellet-associated serine proteinase activity was mostly due to HNE. PR3 purified from neutrophil azurophil granules triggered airway gland secretion, as measured by the release of radiolabeled molecules from cultured bovine tracheal serous cells pulse-labeled with Na235SO4. This secretory activity was inhibited by ICI 200,355. PR3 concentration in CF sputum was highly correlated with taurine concentration, a reliable marker of airway inflammation and respiratory scores (e.g., FEV1%), whereas no significant correlation was observed with HNE. We verified that Pseudomonas aeruginosa proteinases did not interfere with the assessment of PR3 and HNE. Indeed, the PR3/HNE ratio was greatest in patients chronically infected by P. aeruginosa. We suggest that PR3 may play a role in the hypersecretory process that is characteristic of CF. PMID- 10101006 TI - Role of a novel KCa opener in regulating K+ channels of hypoxic human pulmonary vascular cells. AB - Hypoxic pulmonary vasoconstriction (HPVC) is mediated, in part, via membrane depolarization and inhibition of K+ channels. We recently observed that the naturally occurring steroid dehydroepiandrosterone (DHEA) reversed and prevented HPVC in isolated perfused and ventilated ferret lungs. In the current study, we investigated the effects of DHEA on the major K+ channels of chronically hypoxic human pulmonary smooth-muscle cells (HPSMC). K+ channels were recorded by using the patch-clamp technique in whole-cell and single-channel configurations. Single channel recordings were performed in inside-out and outside-out excised patches, and in intact HPSMC in cell-attached configuration. Using whole-cell current recording, chronic hypoxia decreased the high-amplitude, high-noise, and charybdotoxin-sensitive Ca2+-dependent K+ channels (KCa). DHEA reversed the effect of chronic hypoxia on KCa, but had no effect on the low-amplitude, low noise, and 4-aminopyridine-sensitive delayed rectifying K+ channels. In the cell attached configuration, chronic hypoxia caused a decrease in KCa sensitivity to membrane potential (Em). DHEA reversed the effect of hypoxia on KCa sensitivity to Em and caused a mean of 40-mV left shift in voltage-dependent activation of KCa. DHEA increased KCa activation from both sides of membrane patches of hypoxic HPSMC via a cyclic adenosine monophosphate- and cyclic guanosine monophosphate independent pathway. We concluded that DHEA is a novel KCa opener of the human pulmonary vasculature. PMID- 10101007 TI - Prognostic role of cyclin D1 in lung cancer. Relationship to proliferating cell nuclear antigen. AB - We developed an immunohistochemical assay specific for cyclin D1 and suitable for formalin-fixed and paraffin-embedded sections, to evaluate cyclin D1 expression in a group of 135 surgically resected lung-cancer patients for the purpose of investigating the prognostic role of this protein in lung cancer. In addition, we compared cyclin D1 expression with the expression of proliferating cell nuclear antigen (PCNA), considered to be a reliable index of the proliferation rate. We found cyclin D1 expressed in more than 60% of the neoplastic cells in 26.5% of our specimens. A total of 24.5% of the specimens showed cyclin D1 expression in a percentage of cells ranging from 30 to 60%; 36.7% of the specimens expressed cyclin D1 in less than 30% of the cells; and 12.2% of the specimens expressed cyclin D1 in less than 1% of the evaluated cells. Western blot analyses confirmed the specificity of this assay by correlating statistically in a highly significant fashion with the immunohistochemical results (P = 0.0003). Furthermore, we found a direct relationship between cyclin D1 and PCNA immunodetection (P = 0.0004), which correlated cyclin D1 overexpression with a higher tumor proliferation rate. When we analyzed our data statistically, cyclin D1 expression was found to be a negative prognostic marker (P < 0.00005) whose expression correlates with a shorter patient survival time. PMID- 10101008 TI - Both Erk and p38 kinases are necessary for cytokine gene transcription. AB - A critical feature of sepsis-induced acute lung injury is the release of cytokines from endotoxin (LPS)- stimulated alveolar macrophages (AM). LPS is also known to activate various members of the mitogen- activated protein kinase (MAPK) family in other types of cells. In this study, we evaluated whether multiple members of the MAPK family regulate cytokine gene expression in LPS-stimulated AM. We found that LPS activates both the extracellular signal-regulated kinase (Erk) and p38 kinases, and that this activation is augmented when the cells are cultured in serum. Inhibition of either the Erk (with PD98059) or p38 (with SB203580) kinase pathway resulted in only a partial reduction in cytokine (interleukin-6 and tumor necrosis factor) messenger RNA accumulation and cytokine release, whereas inhibition of both pathways simultaneously resulted in a decrease in cytokine gene expression to near-control levels. Nuclear run-on assays showed that the effect of these MAPK pathways on LPS-induced expression of the cytokine genes was attributable, at least in part, to regulation of gene transcription. These findings suggest that activation of both the Erk and p38 kinase pathways is necessary for optimal cytokine gene expression in LPS stimulated human AM, and that the MAPK pathways play a critical role in the inflammatory response that occurs in sepsis-induced acute lung injury. PMID- 10101009 TI - Glycoprotein-340 binds surfactant protein-A (SP-A) and stimulates alveolar macrophage migration in an SP-A-independent manner. AB - Glycoprotein-340 (gp-340) was first identified as a surfactant protein (SP)-D binding molecule purified from lung lavage of patients with alveolar proteinosis (Holmskov, et al., J. Biol. Chem. 1997;272:13743). In purifying SP-A from proteinosis lavage, we isolated a protein that copurifies with SP-A and SP-D and that was later found by protein sequencing to be gp-340. We have shown that soluble gp-340 binds SP-A in a calcium-dependent manner independent of the lectin activity of SP-A. To examine the functional significance of this interaction, we tested the ability of soluble gp-340 to block SP-A binding to and stimulation of the chemotaxis of alveolar macrophages. We found that gp-340 does not affect the binding of SP-A to alveolar macrophages over a wide range of SP-A concentrations, nor does it inhibit the ability of SP-A to stimulate macrophage chemotaxis. We also found that gp-340 alone stimulates the random migration (chemokinesis) of alveolar macrophages in a manner independent of SP-A-stimulated chemotaxis. These results suggest that gp-340 is not a cell-surface receptor necessary for SP-A stimulation of chemotaxis, and show that gp-340 can directly affect macrophage function. PMID- 10101010 TI - Inhibition of pulmonary neutrophil trafficking during endotoxemia is dependent on the stimulus for migration. AB - In rat models of Gram-negative pneumonia, pulmonary emigration of neutrophils (polymorphonuclear leukocytes [PMNs]) is blocked when rats are made endotoxemic by an intravenous administration of endotoxin (lipopolysaccharide [LPS]). To test whether dysfunctional PMN migratory responses in the endotoxemic rat are specific for airway endotoxin, we gave rats intrapulmonary stimuli known to elicit different adhesion pathways for pulmonary PMN migration. Sprague-Dawley rats were treated intravenously with either saline or LPS and then instilled intratracheally with either sterile saline, LPS from Escherichia coli, interleukin (IL)-1, hydrochloric acid (HCl), zymosan-activated serum (ZAS), or lipoteichoic acid (LTA). Three hours later, accumulation of PMNs and protein in bronchoalveolar lavage fluid (BALF) were assessed. BALF PMN accumulation in response to intratracheal treatment with LPS (100%), IL-1 (100%), ZAS (40%), and LTA (58%) was inhibited by endotoxemia. In rats given intratracheal HCl, BALF PMN numbers were unaffected by intravenous LPS. The pattern of inhibition of migration suggests that intravenous LPS only inhibits migration in response to stimuli for which migration is CD18-dependent. In contrast to PMN migration, BALF protein accumulation was inhibited by intravenous LPS only when IL-1 or LPS was used as the intratracheal stimulus. To characterize further the differential responses to the various airway stimuli, the appearance in BALF of tumor necrosis factor-alpha (TNF-alpha) and the PMN chemokine macrophage inflammatory protein (MIP)-2 was measured. Accumulation of PMNs in BALF correlated with the BALF concentrations of MIP-2 (r = 0.846, P < 0.05) and TNF (r = 0.911; P < 0.05). The ability of intravenous LPS to inhibit pulmonary PMN migration correlated weakly with MIP-2 (r = 0.659; P < 0.05) and with TNF (r = 0.413; P > 0.05) concentrations in BALF. However, this correlation was strengthened for TNF (r = 0.752; P < 0.05) when data from IL-1-treated animals were excluded. Thus, the presence in BALF of inflammatory mediators that are known to promote CD18 mediated migration correlates with endotoxemia-related inhibition of PMN migration. Furthermore, the pattern of inhibition of pulmonary PMN migration during endotoxemia is consistent with the CD18 requirement of each migratory stimulus. PMID- 10101011 TI - Th1- and Th2-type cytokines regulate the expression and production of eotaxin and RANTES by human lung fibroblasts. AB - Eosinophils (Eos) and fibroblasts are known to play a major role in the pathogenesis of bronchial asthma and fibrotic lung disease. Therefore, we investigated whether Th1 and Th2 cytokines stimulate the production of Eo activating chemokines by lung fibroblasts. Analyses of the culture supernatant using multiple steps of high-performance liquid chromatography demonstrated that interleukin (IL)-4 preferentially stimulates lung fibroblasts to secrete a peak of eosinophil chemotactic activity (ECA) which, upon N-terminal analyses, showed similar sequence to eotaxin, whereas interferon (IFN)-gamma had negligible effect on the release of this chemokine. In contrast, tumor necrosis factor (TNF)-alpha stimulated lung fibroblasts to release two peaks of activity that were found to correspond to eotaxin and regulated on activation, normal T cells expressed and secreted (RANTES), respectively. Interestingly, IL-4 synergized with TNF-alpha to increase greatly the production of three biochemically distinct eotaxin forms. In contrast, IFN-gamma synergized with TNF-alpha to increase RANTES production. Neither IL-2, IL-5, IL-6 nor IL-10 had an effect on lung fibroblasts' capacity to express or release eotaxin and RANTES. Upon appropriate cytokine stimulation, lung fibroblasts were also found to express messenger RNA for monocyte chemotactic protein (MCP)-3 and MCP-4 but not eotaxin-2. However, no ECA like MCP 3 or MCP-4 was detected. These observations suggest that the release of Th1 or Th2 cytokines in the lung tissue polarizes lung fibroblasts to produce either RANTES or eotaxin as major Eo attractants. PMID- 10101012 TI - Role of very late adhesion integrins in mediating repair of human airway epithelial cell monolayers after mechanical injury. AB - Repair of the airway epithelium after injury requires that processes such as adhesion and cell migration occur in a defined order. Both of these processes depend on interactions between extracellular matrix (ECM) proteins and appropriate integrins. To study these interactions, we examined monolayer wound repair in a cultured human airway epithelial cell line, 16HBE14o-. Wounds created in confluent monolayers grown on either collagen-IV, laminin-1, or laminin-2 matrix closed quickly in response to 15 ng/ml epidermal growth factor (EGF). Concurrent treatment of cells grown on each matrix protein with EGF and a monoclonal antibody (mAb) to beta1-integrin inhibited wound closure. Treatment with a mAb to alpha2-, alpha3-, and alpha6-integrin blocked wound repair in monolayers grown on collagen-IV but did not do so in monolayers grown either on laminin-1 or laminin-2. Inhibition was not due to cell detachment or apoptosis. These data demonstrate that integrins expressed by airway epithelial cells mediate wound closure on different constitutive ECM proteins. These data suggest that beta1-integrin subunit function is required to permit migration and spreading of epithelial cells, and that alpha-integrin subunits alone do not mediate migration of epithelial cells grown on either laminin-1 or laminin-2. These differences may become important if the matrix protein composition of airway basement membrane changes in disease states such as asthma. PMID- 10101013 TI - Iron regulates hyperoxia-dependent human heme oxygenase 1 gene expression in pulmonary endothelial cells. AB - The endothelium of the lung is sensitive to the toxic effects of oxygen, and early evidence of toxicity is characterized by protein leak and extravasation of red blood cells. The overproduction of oxygen free radicals plays a critical role in the pathophysiology of a hyperoxic lung injury. Recently, heme oxygenase 1 (HO 1), the rate-limiting enzyme in the metabolism of heme, has been found to have a protective role in oxidant injury. Our laboratory and others have identified HO-1 as a hyperoxia-inducible protein. In this study, we characterized HO-1 expression and evaluated its regulation in human pulmonary endothelial cells. Hyperoxia results in a relatively small increase in HO-1 expression; however, this induction is potentiated by heme and dramatically potentiated in the presence of free iron. This is probably more reflective of the in vivo situation in which there is extravasation of heme and iron products. We also found that HO-1 expression depended on chelatable iron. The iron chelator desferrioxamine not only inhibited the iron- dependent potentiation of HO-1 in response to hyperoxia but also inhibited both hyperoxia and basal expression. On the basis of inhibitor studies and nuclear run-on assays, we demonstrated that this induction is transcriptionally dependent. We also evaluated 4.5 kb of the human HO-1 promoter region and demonstrated that this region has promoter activity to the stimulus heme; however, there was no evidence of promoter activity to either iron or hyperoxia. This diversity of promoter activity to heme, heavy metals, and hyperoxia is unique to the human HO-1 gene. PMID- 10101014 TI - Ultrastructural evaluation of lung maturation in a sheep model of diaphragmatic hernia and tracheal occlusion. AB - In fetuses with diaphragmatic hernia (DH) lung development is impaired, and pulmonary hypoplasia is one of the main factors responsible for the poor outcome of the disease. A possible treatment consists of occluding trachea during lung development to retain pulmonary fluid and to force the lung to expand. Although it appeared promising at first, this technique has recently been reported to decrease type II cell number and to induce surfactant deficiency. The aim of this study was to investigate lung maturation further through ultrastructural examination in a fetal lamb model of DH created at 85 d, followed or not by endoscopic balloon tracheal occlusion (TO) at 120 d of gestation. The proportion of alveolar epithelial type I and type II cells was altered by both treatments: the type I/type II cell ratio, which was about 2 in control lungs, was decreased 4.5-fold in DH lungs but was increased 4.5-fold in DH+TO lungs. The proportion of undifferentiated cells was increased in DH lungs. Indeterminate cells sharing features of type II and type I cells that were not observed in controls were seldom seen in DH lungs and were numerous in DH+TO lungs. The number of lamellar bodies per type II cell was decreased in both DH and DH+TO groups. In DH lungs, wall structure presented an immature appearance, with cellular connective tissue and poor secondary septation of saccules. In DH+TO lungs, primary septa appeared more mature, with reduced connective tissue, but secondary septa were still buds, although elastin was present at their tips. A single capillary layer was found in all three groups (control, DH, and DH+TO) with no sign of septal capillary pairing. This first investigation in DH and DH+TO lungs through transmission electron microscopy thus enabled us to show that compression and forced expansion of the lung are both responsible for alterations in type II cell differentiation and septal development. PMID- 10101015 TI - Expansion of interferon-gamma-producing lung lymphocytes in mouse silicosis. AB - Silicosis is characterized by mononuclear cell inflammation with macrophage activation, accumulation of lymphocytes, and fibrosis. Interferon-gamma (IFN gamma) is a lymphocyte cytokine with broad effects, particularly macrophage activation. Mice exposed to an aerosol of cristobalite silica (70 mg/m3, 12 d, 5 h/d) developed diffuse pulmonary pathologic changes with macrophage, lymphocyte, and neutrophil recruitment, and increased lung collagen. IFN-gamma messenger RNA (mRNA) was more abundant by semiquantitative reverse transcription-polymerase chain reaction in the lungs of silica-exposed mice than in control animals. IFN gamma mRNA transcripts were detected by in situ hybridization with digoxigenin labeled complementary DNA probes in normal mouse lung tissue within bronchial associated lymphoid tissues (BALT). In silica- exposed mice, mononuclear cells with IFN-gamma mRNA were more numerous in the silicotic lesions and enlarged BALT structures. Lung-cell suspensions were prepared by enzyme digestion, stained with fluorescent-labeled antibodies against intracellular cytokines, and enumerated by flow cytometry. The percentage of cells producing IFN-gamma was increased in silicotic mice (19% versus 11%). Interleukin (IL)-4 mRNA transcripts were less abundant in the lung tissue from silica-exposed mice than in control mice. Cells staining for IL-4 mRNA were found rarely in either the air-sham or the silica exposed mouse lungs, and almost all appeared to be within BALT structures. Approximately 3% of cells stained for IL-4 in the digested lungs from both groups. Similar cytokine patterns were observed in mediastinal lymph node/thymus and spleen tissues. The augmented IFN-gamma response, with IL-4 unchanged or decreased, in the lung lesions and lymphoid tissue of mice with silicosis suggests a Th-1-like lymphocyte-mediated immune-inflammatory response. PMID- 10101016 TI - Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. AB - We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several varieties of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after exposure to bleomycin or silica, respectively, for TNF and TNF receptor (TNFR) messenger RNA (mRNA), hydroxyproline content, and histopathology. Silica induced increased (over saline treated animals) expression of TNF mRNA in double TNFR knockout (Ko), C57BL/6, BALB/c, and 129/J mice. In contrast, bleomycin increased expression in all but BALB/c mice, which are resistant to the fibrogenic effects of this drug. mRNA expression of both receptors was constitutively expressed in all of the normal murine strains. Silica upregulated expression of the p75 receptor, but not the p55 receptor, in the C57BL/6, BALB/c, and 129/J mice. In comparison, bleomycin had little effect on either receptor in the bleomycin-resistant BALB/c mice. Hydroxyproline content of the lungs after treatment followed this same pattern, with significant increases caused by silica in the C57BL/6, BALB/c, and 129/J mice, whereas bleomycin caused no apparent increases in the BALB/c mice. Even though silica and bleomycin induced increases in TNF in the TNFR Ko mice, the mice were protected from the fibrogenic effects of these agents. This study supports the concept that TNF is a central mediator of interstitial pulmonary fibrosis. PMID- 10101017 TI - Leukemia inhibitory factor (LIF) and LIF receptor in human lung. Distribution and regulation of LIF release. AB - The distribution and regulation of leukemia inhibitory factor (LIF) and its receptor (LIFR) in human lung tissue is unknown. We recently found that LIF was immunolocalized to several cell types in human airways, and that exogenous LIF modulated neural and contractile responses of explanted airways. The present study aimed to determine the cellular distribution and regulation of gene transcripts for LIF and LIFR in human lung, and measured the release of LIF in response to anti-immunoglobulin (Ig)E, interleukin (IL)-1beta, and IL-6. Exposure of human lung to IL-1beta (100 pg/ml) resulted in the rapid induction of LIF messenger RNA (mRNA) (1 h) and subsequent protein release (6 h). Similar results were observed when lung tissue was exposed to anti-IgE (6 U/ml). Gene transcripts for LIF were observed in nine pulmonary cell types, with the greatest expression occurring in fibroblasts. LIFR transcripts were also widely expressed in these cell types. In cultures of nontransformed epithelial cells, lung fibroblasts, and airway smooth-muscle cells, IL-1beta (100 pg/ml) induced the rapid accumulation of LIF mRNA and protein release, with fibroblasts liberating the greatest amount. IL-6 also induced the expression of LIF mRNA and release of LIF in airway smooth muscle cells, whereas exogenous LIF itself had no effect. Expression of LIFR mRNA was not influenced by exposure to IL-1beta or LIF in any of the cell lines used. These results highlight the widespread distribution and rapid release of LIF in human lung tissue and, in conjunction with our previous report, suggest that this cytokine may play an important role in lung inflammatory processes and neuroimmune interactions. PMID- 10101018 TI - Keratinocyte growth factor stimulates CLC-2 expression in primary fetal rat distal lung epithelial cells. AB - Keratinocyte growth factor (KGF) is mitogenic for epithelial cells and induces cystic dilation of fetal lung explants through cystic fibrosis transmembrane conductance regulator-independent chloride channels. One candidate fetal lung chloride channel that is highly expressed on the apical surface of the respiratory epithelium and markedly downregulated after birth is CLC-2. We hypothesized that KGF regulates CLC-2 expression in the fetal lung. Primary fetal rat distal lung epithelial cell monolayers were grown in medium containing 10 ng/ml KGF for 48 h. CLC-2 protein was increased by Western blot analysis of whole cell lysates in KGF-treated cultures. Similarly, KGF stimulated CLC-2 messenger RNA (mRNA) by Northern blot analysis. This enhanced expression was dose-dependent and maximal at 48 h with 10 ng/ml KGF. Promoter-reporter gene experiments demonstrated that KGF did not stimulate gene transcription. By inhibition of new mRNA synthesis with actinomycin D, evidence was obtained that KGF stabilizes CLC 2 mRNA. We speculate that KGF may positively influence pulmonary chloride and fluid secretion by a secondary pathway affecting CLC-2 degradation. PMID- 10101019 TI - Cox-2-selective inhibitors: the new super aspirins. PMID- 10101020 TI - Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. AB - Phosphorylation of tau protein promotes stability of the axonal cytoskeleton; aberrant tau phosphorylation is implicated in the biogenesis of paired helical filaments (PHF) seen in Alzheimer's disease. Protein kinases and phosphatases that modulate tau phosphorylation have been identified using in vitro techniques; however, the role of these enzymes in vivo has not been determined. We used intraventricular infusions of antisense oligodeoxynucleotides (ODNs) directed against the major brain isoforms of the Ca2+/calmodulin-dependent phosphatase calcineurin to determine how reduced activity of this enzyme would affect tau dephosphorylation. Five-day infusions of antisense ODNs (5 and 10 nmol/day) in rats decreased immunoreactive levels and activity of calcineurin throughout the brain; sense ODNs, scrambled ODNs, and infusion vehicle alone had no effect. When neocortical slices were prepared from antisense ODN-treated rats and incubated for 1 to 2 h in vitro, tau protein remained phosphorylated as determined by using the phosphorylation-sensitive monoclonal antibodies AT-180 (Thr231) and AT-270 (Thr181). In contrast, AT-180 and AT-270 sites were completely dephosphorylated during incubation of neocortical slices from vehicle-infused controls and sense ODN-treated rats. Neocortical slices from antisense-treated rats were incubated with the phosphatase inhibitors okadaic acid (100 nM; 10 microM) and FK-520 (5 microM); these preparations showed enhanced tau phosphorylation, consistent with a significant loss of calcineurin activity. Thus, we conclude that phosphorylation of at least two sites on tau protein, namely, Thr181 and Thr231, is regulated by calcineurin. PMID- 10101021 TI - Domains determining ligand specificity for Ca2+ receptors. AB - The Ca2+ receptor is a G protein-coupled receptor that enables parathyroid cells and certain other cells in the body to respond to changes in the level of extracellular Ca2+. The Ca2+ receptor is a member of a family of G protein coupled receptors that includes metabotropic glutamate receptors (mGluRs), gamma aminobutyric acidB receptors, and putative pheromone receptors. As a family, these receptors are characterized by limited sequence homology and an unusually large putative extracellular domain (ECD). The ECD of the mGluRs is believed to determine agonist selectivity, but the functions of the structural domains of the Ca2+ receptor are not known. To identify structural determinants for cation recognition and activation of the Ca2+ receptor (and to further study the mGluRs), two chimeric receptors were constructed in which the large ECD of the Ca2+ receptor and the mGluR1 were interchanged. When expressed in Xenopus laevis oocytes, one of these chimeras, named CaR/mGluR1 [ECD of the Ca2+ receptor and transmembrane domain (TMD) of the mGluR1], responded to cation agonists (Gd3+, Ca2+, neomycin) of the Ca2+ receptor at concentrations similar to those necessary for activation of the native Ca2+ receptor. A reciprocal construct, named mGluR1/CaR (ECD of the mGluR1 and TMD of the Ca2+ receptor), was responsive to mGluR agonists but was much less sensitive to two of three cation agonists known to activate the Ca2+ receptor. A deletion construct of the Ca2+ receptor (DeltantCaR), which lacked virtually the entire ECD, was only activated by one of three agonists tested. These results suggest that the primary determinants for agonist activation of both the Ca2+ receptor and the mGluRs are found in the large ECD and that the Ca2+ receptor is possibly distinguished from the mGluRs in that it may contain sites in the TMD that permit activation by certain cation agonists. PMID- 10101022 TI - The negative regulation of the rat aldehyde dehydrogenase 3 gene by glucocorticoids: involvement of a single imperfect palindromic glucocorticoid responsive element. AB - Glucocorticoids repressed the polycyclic aromatic hydrocarbon-dependent induction of Class 3 aldehyde dehydrogenase (ALDH3) enzyme activity and mRNA levels in isolated rat hepatocytes by more than 50 to 80%, with a concentration-dependence consistent with the involvement of the glucocorticoid receptor (GR). No consistent effect on the low basal transcription rate was observed. This effect of glucocorticoids (GC) on polycyclic aromatic hydrocarbon induction was effectively antagonized at the mRNA and protein level by the GR antagonist RU38486. The response was cycloheximide-sensitive, because the protein synthesis inhibitor caused a GC-dependent superinduction of ALDH3 mRNA levels. This suggests that the effects of GC on this gene are complex and both positive and negative gene regulation is possible. The GC-response was recapitulated in HepG2 cells using transient transfection experiments with CAT reporter constructs containing 3.5 kb of 5'-flanking region from ALDH3. This ligand-dependent response was also observed when a chimeric GR (GR DNA-binding domain and peroxisome proliferator-activated receptor ligand-binding domain) was used in place of GR in the presence of the peroxisome proliferator, nafenopin. A putative palindromic glucocorticoid-responsive element exists between -930 and -910 base pairs relative to the transcription start site. If this element was either deleted or mutated, the negative GC-response was completely lost, which suggests that this sequence is responsible, in part, for the negative regulation of the gene. Electrophoretic mobility shift analysis demonstrated that this palindromic glucocorticoid-responsive element is capable of forming a specific DNA-protein complex with human glucocorticoid receptor. In conclusion, the negative regulation of ALDH3 in rat liver is probably mediated through direct GR binding to its canonical responsive element. PMID- 10101023 TI - Pyrrolidine dithiocarbamate prevents I-kappaB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs. AB - Lipopolysaccharide (LPS) is a key mediator of multiple organ injury observed in septic shock. The mechanisms responsible for LPS-induced multiple organ injury remain obscure. In the present study, we tested the hypothesis that the LPS induced injury occurs through activation of the transcription factor, nuclear factor-kappaB (NF-kappaB). We examined the effects of inhibiting NF-kappaB activation in vivo in the rat on LPS-induced: 1) gene and protein expression of the cytokine-inducible neutrophil chemoattractant (CINC) and intercellular adhesion molecule-1 (ICAM-1); b) neutrophil influx into lungs, heart, and liver; and c) increase in microvascular permeability induced by LPS in these organs. LPS (8 mg/kg, i.v.) challenge of rats activated NF-kappaB and induced CINC and ICAM-1 mRNA and protein expression. Pretreatment of rats with pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg, i.p.), an inhibitor of NF-kappaB activation, prevented LPS-induced I-kappaBalpha degradation and the resultant NF kappaB activation and inhibited, in a dose-related manner, the LPS-induced CINC and ICAM-1 mRNA and protein expression. Pyrrolidine dithiocarbamate also markedly reduced the LPS-induced tissue myeloperoxidase activity (an indicator of tissue neutrophil retention) and the LPS-induced increase in microvascular permeability in these organs. These results demonstrate that NF-kappaB activation is an important in vivo mechanism mediating LPS-induced CINC and ICAM-1 expression, as well as neutrophil recruitment, and the subsequent organ injury. Thus, inhibition of NF-kappaB activation may be an important strategy for the treatment of sepsis induced multiple organ injury. PMID- 10101024 TI - Post-transcriptional regulation of MyD118 and GADD45 in human lung carcinoma cells during 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2- naphthalene carboxylic acid induced apoptosis. AB - Recently, the novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2 naphthalene carboxylic acid (AHPN) has been shown to inhibit cell growth and induce apoptosis in several human carcinoma cell lines. To understand the mechanism of AHPN action, we identified, using the differential display method, several genes that are differentially regulated by AHPN. The sequence of one of these genes was highly homologous to mouse MyD118, a gene closely related to GADD45. Both of these genes have been reported to play a role in negative growth control and apoptosis. hMyD118 was expressed in a variety of tissues, including liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, and peripheral blood leukocytes. The levels of both hMyD118 and GADD45 mRNA was rapidly increased in a number of carcinoma cell lines after treatment with AHPN. This increase was specific for AHPN because retinoic acid, a retinoic acid receptor-selective retinoid, and an retinoid X receptor-selective retinoid were ineffective. These results suggest that this action of AHPN involves a novel mechanism that is independent of the nuclear retinoid receptors. AHPN increases the half-life of hMyD118 and GADD45 mRNA by >9-fold, indicating that it causes an increase in the stability of these mRNAs. The caspase inhibitor benzyloxycarbonyl Val-Ala-Asp fluoro-methylketone (ZVAD. fmk) had no effect on the induction of hMyD118, indicating that this increase occurred independently of caspase activation. Our study demonstrates that the inhibition of cell growth by AHPN is accompanied by an increase in hMyD118 and GADD45 mRNA, and that this enhancement is regulated at a post-transcriptional level. Our results support a role for MyD118 and GADD45 in the negative growth control by AHPN. PMID- 10101025 TI - Degradation of topoisomerase I induced by topoisomerase I inhibitors is dependent on inhibitor structure but independent of cell death. AB - DNA topoisomerase I (top I) is the target of the antitumor drug camptothecin (CPT) and its analogs. CPT induces dose- and time-dependent degradation of top I. Degradation of top I also occurs in a CPT-resistant cell line and, therefore, is not a consequence of cell death. Top I degradation is preceded by the appearance of a high molecular weight ladder of top I immunoreactivity and can be blocked by specific inhibitors of the proteasome. We compared the effects of five top I poisons [CPT, topotecan, 6-N-formylamino-12,13-dihydro-1, 11-dihydroxy-13-(beta-D glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3, 4-c]carbazole-5,7(6H)-dione (NB506), camptothecin-(para)-4beta-amino-4'-O-demethyl Epipodophyllotoxin (W1), and camptothecin-(ortho)-4beta-amino-4'-O-demethyl Epipodophyllotoxin (W2)] on cleavable complex formation and top I degradation. Although all five drugs induced cleavable complex formation, two of the drugs, NB506 and W1 did not induce top I degradation. PMID- 10101026 TI - Specific galpha11beta3gamma5 protein involvement in endothelin receptor-induced phosphatidylinositol hydrolysis and Ca2+ release in rat portal vein myocytes. AB - In this study, we identified the receptor subtype activated by endothelin-1 (ET 1) and the subunit composition of the G protein coupling this receptor to increase in cytosolic Ca2+ concentration in rat portal vein myocytes. We used intranuclear antisense oligonucleotide injection to selectively inhibit the expression of G protein subunits. We show here that the endothelin receptor subtype A (ETA)-mediated increase in cytosolic Ca2+ concentration was mainly dependent on Ca2+ release from the intracellular store. ETA receptor-mediated Ca2+ release was selectively inhibited by antisense oligonucleotides that inhibited the expression of alpha11, beta3, and gamma5 subunits, as checked by immunocytochemistry. Intracellular dialysis of a carboxyl terminal anti-betacom antibody and a peptide corresponding to the Gbetagamma binding region of the beta adrenergic receptor kinase-1 had no effect on the ETA receptor-mediated Ca2+ release. In contrast, a synthetic peptide corresponding to the carboxyl terminus of the alphaq/alpha11 subunit, heparin (an inhibitor of inositol 1,4,5 trisphosphate receptors), and U73122 (an inhibitor of phosphatidylinositol phospholipase C) inhibited, in a concentration-dependent manner, the ETA receptor mediated Ca2+ responses. Accumulation of [3H]inositol trisphosphate evoked by norepinephrine peaked at approximately 15 s, whereas that evoked by ET-1 progressively increased within 2 min. In myocytes injected with anti-alphaq antisense oligonucleotides, both amplitude and time course of the norepinephrine induced Ca2+ release became similar to those of the ET-1-induced Ca2+ response. We conclude that the ETA receptor-mediated Ca2+ release is selectively transduced by the heterotrimeric G11 protein composed of alpha11, beta3, and gamma5 subunits, and that a delayed stimulation of phospholipase C occurs via the alpha11 subunit. PMID- 10101027 TI - Transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N1-acetyltransferase show enhanced sensitivity to the polyamine analog, N1, N11-diethylnorspermine. AB - We have recently generated transgenic mice in which polyamine catabolism has been activated by overexpressing the rate-limiting enzyme of polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT). These animals have now been tested for their sensitivity to the polyamine analog N1,N11-diethylnorspermine (DENSPM), which is currently undergoing Phase I clinical trial. The analog is known for its ability to potently induce SSAT. Treatment for 4 days with a daily dose (125 mg/kg) of analog caused profound changes in polyamine metabolism in the transgenic animals. Liver SSAT activity was increased by approximately 800-fold while hepatic mRNA increased only 4-fold. Putrescine pools increased while spermidine and spermine pools nearly disappeared, resulting in a compensatory increase in ornithine decarboxylase activity. Similar but less profound changes were also seen in other tissues (spleen, intestine, and skin). This treatment also resulted in a 50% mortality in the transgenic animals, with no apparent histopathological changes in major organs. Nontransgenic animals exhibited no toxicity, and tissue SSAT activity was unchanged or only moderately increased. Polyamine pools were only slightly altered. Greater analog toxicity in transgenic animals may be attributable to higher tissue levels of DENSPM facilitated by SSAT mediated decreases in spermidine and spermine. To further confirm the enhanced sensitivity of the transgenic animals to the analog, groups of nontransgenic and transgenic animals were subjected to daily injections with DENSPM. On average, transgenic mice died approximately 3 days earlier than their nontransgenic litter mates. The findings indicate a contributing role for SSAT in whole animal toxicity by SSAT-inducing polyamine analogs. PMID- 10101028 TI - Antagonist pharmacology of metabotropic glutamate receptors coupled to phospholipase D activation in adult rat hippocampus: focus on (2R,1'S,2'R,3'S)-2 (2'-carboxy-3'-phenylcyclopropyl)glycine versus 3, 5-dihydroxyphenylglycine. AB - Metabotropic glutamate (mGlu) receptors coupled to phospholipase D (PLD) appear to be distinct from any known mGlu receptor subtype linked to phospholipase C or adenylyl cyclase. The availability of antagonists is necessary for understanding the role of these receptors in the central nervous system, but selective ligands have not yet been identified. In a previous report, we observed that 3, 5 dihydroxyphenylglycine (3,5-DHPG) inhibits the PLD response induced by (1S,3R)-1 aminocyclopentane-1,3-dicarboxylate in adult rat hippocampal slices. We now show that the antagonist action of 3, 5-DHPG (IC50 = 70 microM) was noncompetitive in nature and nonselective, because the drug was also able to reduce PLD activation elicited by 100 microM norepinephrine and 1 mM histamine. In the search for a selective and more potent antagonist, we examined the effects of sixteen stereoisomers of 2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG) on the PLD specific transphosphatidylation reaction resulting in the formation of [3H]phosphatidylethanol. The (2R,1'S,2'R,3'S)-PCCG stereoisomer (PCCG-13) antagonized the formation of [3H]phosphatidylethanol induced by 100 microM (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylate in a dose-dependent manner and with a much lower IC50 value (25 nM) compared with 3,5-DHPG. In addition, increasing concentrations of PCCG-13 were able to shift to the right the agonist dose response curve but had no effect when tested on other receptors coupled to PLD. The potent, selective, and competitive antagonist PCCG-13 may represent an important tool for elucidating the role of PLD-coupled mGlu receptors in adult hippocampus. PMID- 10101029 TI - Oxidative stress occurs in perfused rat liver at low oxygen tension by mechanisms involving peroxynitrite. AB - Ethanol increases free radical formation; however, it was recently demonstrated that it also causes extensive hypoxia in rat liver in vivo. To address this issue, it was hypothesized that peroxynitrite formed in normoxic periportal regions of the liver lobule has its reactivity enhanced in hypoxic pericentral regions where the pH is lower. Via this pathway, peroxynitrite could lead to free radical formation in the absence of oxygen. Livers from fed rats were perfused at low flow rates for 75 min. Under these conditions, periportal regions were well oxygenated but pericentral areas became hypoxic. Low-flow perfusion caused a significant 6-fold increase in nitrotyrosine accumulation in pericentral regions. During the last 20 min of perfusion, the spin-trap alpha-(4-pyridyl-1-oxide)-N tert-butylnitrone was infused and adducts were collected for electron-spin resonance analysis. A six-line radical adduct signal was detected in perfusate. Direct infusion of peroxynitrite produced a radical adduct with identical coupling constants, and a similar pattern of nitrotyrosine accumulation was observed. Retrograde perfusion at low rates resulted in accumulation of nitrotyrosine in periportal regions. Although the magnitude of the radical in perfusate was increased by ethanol, it was not derived directly from it. Both nitrotyrosine accumulation and radical formation were reduced by inhibition of nitric oxide synthase with N-nitro-L-arginine methyl ester, but not with the inactive D-isomer. Radical formation was decreased nearly completely by superoxide dismutase and N-nitro-L-arginine methyl ester, consistent with the hypothesis that the final prooxidant is a derivative from both NO. and superoxide (i.e., peroxynitrite). These results support the hypothesis that oxidative stress occurs in hypoxic regions of the liver lobule by mechanisms involving peroxynitrite. PMID- 10101030 TI - Flavone antagonists bind competitively with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) to the aryl hydrocarbon receptor but inhibit nuclear uptake and transformation. AB - Previous analyses suggested that potent aryl hydrocarbon receptor (AhR) antagonists were planar, with a lateral electron-rich center. To further define structural requirements and mechanism for antagonism, ten additional flavone derivatives were synthesized. Based on their ability to 1) compete with 2,3,7, 8 tetrachlorodibenzo-p-dioxin (TCDD) for binding to the AhR; 2) inhibit TCDD elicited binding of AhR to dioxin-responsive elements (DRE) in vitro; and 3) inhibit TCDD-induced transcription of DRE-dependent luciferase in stably transfected hepatoma cells, the most potent flavones contained a 3'-methoxy group and a 4'-substituent having one or more terminal atoms of high electron density ( N3, -NO2, or -NCS). Furthermore, these had low agonist activity as assessed by their inability to elicit AhR. DRE binding or to induce luciferase. Compounds containing bulkier 3' or 4'-substituents, or a 3'-OH group were less potent antagonists, and some were partial agonists. In rat liver cytosol, 3'-methoxy-4' azido- and 3'-methoxy-4'-nitroflavones bound competitively (with TCDD) to the AhR, indicating that they bind to the TCDD-binding site. When hepatoma cells were exposed to these flavones, AhR complexes were primarily immunoprecipitable from the cytosol and contained 90 kDa heat shock protein. In contrast, AhR in TCDD treated cells was primarily immunoprecipitated from nuclear extracts and was associated with Arnt but not 90 kDa heat shock protein. Immunocytofluorescence analysis in intact cells further indicated that the potent antagonist inhibited nuclear uptake of AhR and blocked TCDD-dependent down-regulation of AhR. Together, these data indicate that the most potent antagonists bind the AhR with high affinity but cannot initiate receptor transformation and nuclear localization. PMID- 10101031 TI - Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. AB - The endogenous nucleoside adenosine is thought to play a role in the pathophysiology of asthma by stimulating mast cells. We previously showed that the human mast cell line HMC-1 expresses A2A and A2B receptors, and that both receptors activate adenylate cyclase via Gs-protein but that only A2B receptors are also coupled to phospholipase C via Gq proteins. Stimulation of A2B but not A2A receptors induced production of interleukin-8 (IL-8) from HMC-1 cells. The mechanism by which adenosine promotes IL-8 synthesis has not been defined. In this study, we tested the hypothesis that mitogen-activated protein kinase (MAPK) signaling pathways are involved in this process. Stimulation of HMC-1 with the stable adenosine analog NECA (5'-N-ethylcarboxamidoadenosine) activated p21(ras) and both p42 and p44 isoforms of extracellular signal-regulated kinase (ERK). NECA (10 microM) induced a 1.9 +/- 0. 06-fold increase in ERK activity, whereas 10 microM of the selective A2A agonist CGS 21680 (4-((N-ethyl-5'-carbamoyladenos 2-yl)-aminoethyl)-phenylpropionic acid) had no effect. NECA, in parallel with the activation of ERK, also stimulated the p46 isoform of c-Jun N-terminal kinase (MEK) and p38 MAPK. Furthermore, the selective MAPK/ERK kinase 1 inhibitor PD 98059 (2'-amino-3'-methoxyflavone), and p38 MAPK inhibitors SB 202190 (4-(4 fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole) and SB 203580 (4-(4 fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H- imidaz ole) blocked A2B receptor-mediated production of IL-8. These results indicate that extracellular adenosine can regulate ERK, c-Jun N-terminal kinase, and p38 MAPK signaling cascades and that activation of ERK and p38 MAPK pathways are essential steps in adenosine A2B receptor-dependent stimulation of IL-8 production in HMC-1. PMID- 10101032 TI - Identification of protein kinase C phosphorylation sites involved in phorbol ester-induced desensitization of the histamine H1 receptor. AB - The histamine H1 receptor (H1R)-mediated signaling cascade is inhibited by phorbol ester-induced protein kinase C (PKC) activation. Cloning studies of the H1Rs have shown that several potential PKC phosphorylation sites are located in the third intracellular loop of H1R. To elucidate the molecular mechanism of PKC mediated desensitization, we identified amino acid residues that are involved in the desensitization of the H1R. Two amino acid residues (Ser396, Ser398) were determined to be PKC phosphorylation sites by in vitro phosphorylation studies using a series of synthetic peptides. Treatment with phorbol ester decreased histamine-induced accumulation of inositol phosphates in Chinese hamster ovary cells expressing the H1R with a rightward shift in the EC50 value, which implies the uncoupling of the receptor from the G protein. Site-directed mutagenesis studies showed that substitution of alanine for Ser398 but not for Ser396 markedly attenuated the effect of phorbol ester, which suggests that the Ser398 residue was primarily involved in PKC-mediated desensitization. PMID- 10101033 TI - Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney. AB - We have isolated a cDNA coding a new organic anion transporter, OAT-K2, expressed specifically in rat kidney. The OAT-K2 cDNA had an open reading frame encoding a 498-amino acid protein (calculated molecular mass of 55 kDa) that shows 91% identity with the rat kidney-specific organic anion transporter, OAT-K1. Reverse transcription-coupled polymerase chain reaction analyses revealed that the OAT-K2 mRNA was expressed predominantly in the proximal convoluted tubules, proximal straight tubules, and cortical collecting ducts. When expressed in Xenopus oocytes, OAT-K2 stimulated the uptake of hydrophobic organic anions, such as taurocholate, methotrexate, folate, and prostaglandin E2, although its homolog OAT-K1 transported methotrexate and folate, but not taurocholate and prostaglandin E2. In MDCK cells stably transfected with the OAT-K1 and OAT-K2 cDNAs, each transporter was localized functionally to the apical membranes and showed transport activity similar to that in the oocyte. Moreover, the efflux of preloaded taurocholate was also enhanced across the apical membrane in OAT-K2 transfectant. The taurocholate transport by OAT-K2-expressing cells showed saturability (Km = 10.3 microM). Several organic anions, bile acids, cardiac glycosides, and steroids had potent inhibitory effects on the OAT-K2-mediated taurocholate transport in the transfectant. These findings suggest that the OAT K2 participates in epithelial transport of hydrophobic anionic compounds in the kidney. PMID- 10101034 TI - Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4 trifluoromethylbenzoic acid. AB - The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy 4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2 hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated. PMID- 10101035 TI - Multiple mechanisms of resistance to polyglutamatable and lipophilic antifolates in mammalian cells: role of increased folylpolyglutamylation, expanded folate pools, and intralysosomal drug sequestration. AB - Chinese hamster ovary PyrR100 cells display more than 1000-fold resistance to pyrimethamine (Pyr), a lipophilic antifolate inhibitor of dihydrofolate reductase. PyrR100 cells had wild-type DHFR activity, lost folate exporter activity, and had a 4-fold increased activity of a low pH folic acid transporter. Here we report on the marked alterations identified in PyrR100 cells compared with parental cells: 1) approximately 100-fold decreased folic acid growth requirement; 2) a 25-fold higher glucose growth requirement in Pyr-containing medium; 3) a 2.5- to 4.1-fold increase in folylpolyglutamate synthetase activity; 4) a 3-fold increase in the accumulation of [3H]folic acid and a 3-fold expansion of the intracellular folate pools; 5) a 4-fold increase in the activity of the lysosomal marker beta-hexoseaminidase, suggesting an increased lysosome number/PyrR100 cell; and 6) a small reduction in the steady-state accumulation of [3H]Pyr and no evidence of catabolism or modification of cellular [3H]Pyr. Consequently, PyrR100 cells were markedly resistant to the lipophilic antifolates trimetrexate (40-fold) and AG377 (30-fold) and to the polyglutamatable antifolates 5,10-Dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) (26-fold) and AG2034 (14-fold). Resistance to these drugs was reversed in PyrR100 cells transferred into folate-depleted medium. In conclusion, these multiple resistance factors collectively result in a prominent increase in folate accumulation, an expansion of the intracellular folylpolyglutamate pool, and abolishment of the cytotoxic activity of polyglutamatable and lipophilic antifolates. The role of increased lysosome number per cell in sequestration of hydrophobic weak base drugs such as Pyr is also discussed as a novel mechanism of drug resistance. PMID- 10101036 TI - The formation of DNA interstrand cross-links by a novel bis-[Pt2Cl4(diminazene aceturate)2]Cl4.4H2O complex inhibits the B to Z transition. AB - We present data demonstrating that the cytotoxic compound [Pt2Cl4(diminazene aceturate)2]Cl4.4H2O (Pt-berenil) circumvents cisplatin resistance in ovarian carcinoma cells. The analysis of the interaction of Pt-berenil with linear and supercoiled DNA indicates that this compound induces the formation of a large number of covalent interstrand cross-links on DNA and that this number is significantly higher than that produced by cis-diamminedichloroplatinum(II) (cis DDP). Renaturation experiments, interstrand cross-link assays, and electron microscopy indicate that the kinetics of DNA interstrand cross-link formation caused by Pt-berenil binding is faster than that caused by cis-DDP at similar levels of platinum bound to DNA. Furthermore, the number of DNA interstrand cross links in Pt-berenil-DNA complexes is influenced by supercoiling. Circular dichroism experiments show that Pt-berenil strongly inhibits the B-DNA-to-Z-DNA transition of poly(dG-m5 dC). poly(dG-m5dC) at salt concentrations (3 mM MgCl2) at which the native methylated polynucleotide readily adopts the Z-DNA conformation, which suggests that the induction of interstrand cross-links by Pt berenil inhibits the Z-DNA transition. On the basis of these results, we propose that bis(platinum) compounds with structure similar to Pt-berenil may act as blockers of DNA conformational changes and may also display activity in cisplatin resistant cells. PMID- 10101037 TI - Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors: functional studies. AB - In radioligand binding studies, it has been reported that brucine, N-chloromethyl brucine, and brucine N-oxide increased the affinity of acetylcholine for M1, M3, and M4 muscarinic receptors, respectively, in a manner consistent with the predictions of the ternary complex allosteric model. We now demonstrate an equivalent ability of these three allosteric agents to modulate the actions of acetylcholine in functional studies in membranes and in whole cells. The enhancing actions of brucine and brucine N-oxide on acetylcholine (ACh) potency at M1 and M4 receptors respectively have been confirmed in guanosine-5'-O-(3 [35S]thio)triphosphate, GTPase, cAMP, and intracellular Ca2+ mobilization assays of function. In general, neither the basal nor the maximally stimulated response to ACh is affected. The subtype-selective allosteric effects of N-chloromethyl brucine on M2 and M3 receptors were shown to be qualitatively and quantitatively the same in guanosine-5'-O-(3-[35S]thio)triphosphate functional assays, in terms of both its affinity and cooperativity with ACh, as those found in binding assays. Neutral cooperativity of N-chloromethyl brucine with ACh on M4 receptor function was also observed, thereby demonstrating its "absolute subtype selectivity": a lack of action at any concentration at M4 receptors and an action at M2 and M3 receptors. The enhancing action of N-chloromethyl brucine on neurogenically released ACh binding at M3 receptors was also detected in whole tissue as an increased contraction of the isolated guinea pig ileum to submaximal electrical stimulation. In conclusion, these functional studies confirm that brucine analogs are allosteric enhancers of ACh affinity at certain muscarinic receptor subtypes. PMID- 10101038 TI - Word priming without awareness: A new approach to circumvent explicit memory contamination. AB - A major methodological limitation arising in the experimental study of implicit memory is that tasks that are characterized as implicit memory tests can be seriously contaminated by the use of covert explicit memory strategies. Given the evidence indicating that brief presentation of words (below the awareness threshold of subjects) can produce semantic priming, we wondered whether rapid visual presentation of primed words might provide an avenue to produce word priming without explicit memory contamination. Normal subjects were tested for word priming on a speeded category membership decision task. Explicit or implicit encoding procedures were used in four different experiments. Results demonstrated that brief presentation of words can indeed offer a means of producing word priming in absence of explicit recognition or recall of the primed words presented during the study phase. They also showed that such priming is equivalent in degree to the priming measured when using either a conventional implicit memory design or an explicit encoding procedure prior to the study of the primes. PMID- 10101039 TI - The role of stimulus factors in making categorical and coordinate spatial judgments. AB - We report three experiments which investigate the lateralization of categorical and coordinate processing. In all experiments, participants judged the position of a dot relative to a line. We manipulated display luminance (controlling for contrast), polarity (black-on-white versus white-on-black displays), and exposure duration (100, 150, and 200 ms). The results showed a left visual field-right hemisphere advantage for coordinate judgments, but only under highly prescribed conditions. We argue that stimulus and procedural factors are critical in determining the hemisphere by task interaction. PMID- 10101040 TI - Paradoxical facilitation of a free recall of nonwords in persons with traumatic brain injury. AB - Brain damage is usually associated with behavioral deficits. However, there is an increasing amount of evidence that lesions of some brain regions are associated with improvements instead of impairments of certain behaviors. We report the results of a study of free recall performance in subjects with traumatic brain injury. One-fourth of the subjects displayed above-normal performance in recall of nonwords. No such facilitation was found with nine lists of words. PMID- 10101041 TI - Lifelong estrogen exposure and cognitive performance in elderly women. AB - Fluctuating endogenous and exogenous estrogens influence cognition in women. In this study, cognitive functioning in elderly women was examined by applying methodology used in understanding the effects of chronic estrogen exposure on hormone-sensitive tissue other than the brain. An index, combining menstrual, reproductive, and physical markers associated with estrogen levels, was developed for elderly, nondemented, predominantly Caucasian women (n = 87). This index related to better performance on two verbal factors, one attentional and one global in nature. Findings suggest that estrogen exposure across the life span plays a role in brain aging. Possible physiological mechanisms for this effect are discussed. PMID- 10101042 TI - Adipocyte differentiation factor (ADF): a protein secreted by mature fat cells that induces preadipocyte differentiation in culture. AB - A factor that is released into the culture medium of mature adipocytes and promotes the differentiation (adipogenic conversion) of preadipocytes has been partially characterized. The factor acts in a dose-dependent manner on preadipocytes to produce up to a four-fold increase in triacylglycerol (triglyceride) content and a nine-fold increase in glycerol-3-phosphate dehydrogenase (GPDH) activity, a marker of the late phase of differentiation of preadipocytes. The material appears to be a protein, since it has a molecular weight (Superose-12 gel exclusion chromatography) of about 53 kDa, an isoelectric point (pl) of 4.7-4.9, and is inactivated by the proteases papain and chymotrypsin and extremes of pH (2 and 12). Considerations of molecular weight, isoelectric point, stability to specific proteases, and especially to the action of chemical agents [the adipogenic activity is not affected by either an oxidizing (KIO4) or a reducing agent (DTT)], lead to the conclusion that the differentiation factor is distinct from known cytokines. The authors suggest that the protein be designated adipocyte differentiation factor (ADF). ADF in vivo may act as a cytokine paracrine agent to regulate the differentiation of preadipocytes. PMID- 10101043 TI - A comparison of the anti-histone and Apop-Tag technique for demonstrating apoptosis with option for silver enhancement. AB - A novel immunocytochemical method is presented for the qualitative detection of DNA fragmentation in apoptosis. Anti-histone antibody is employed to localize exposed nucleosomal histones (H1, H2a, H2b, H3 and H4) rather than tagging the cut ends of fragmenting DNA as in conventional technique. The method was tested on squamous cell carcinoma of the larynx routinely fixed in formaldehyde and embedded in paraffin wax and compared with results obtained employing Apop-Tag kit (Oncor). PMID- 10101044 TI - Flow cytometric scoring of apoptosis compared to electron microscopy in gamma irradiated lymphocytes. AB - One of the early events occurring at the cell membrane during apoptosis is the translocation of phosphatidylserine from the inner side of the plasma membrane to the outer layer. These phosphatidylserine groups can be bound by fluorescein isothiocyanate (FITC)-labelled annexin V. The aim of this study was to evaluate the power of the annexin V flow cytometric assay in detecting apoptosis in gamma irradiated peripheral blood lymphocytes and in differentiating between apoptosis and primary necrosis in these cells. Therefore, 5 Gy and 20 Gy gamma irradiated peripheral blood mononuclear cells (PBMCs) were examined after a 24-h culture period. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique was performed as well. A comparison with an electron microscopic (EM) evaluation was made. EM is based on established morphological criteria allowing the classification of cells into four groups: viable, early apoptotic, secondary necrotic and primary necrotic cells. EM performed on annexin V positive sorted cells proved that a 5 Gy gamma irradiation of PBMCs mainly causes apoptosis, whereas a 20 Gy gamma irradiation mainly induces primary necrosis. Neither the annexin V flow cytometric assay nor the TUNEL assay were able to distinguish between primary and secondary necrotic cells. These results illustrate that if quantification of apoptosis is required, one should be careful in interpreting flow cytometric results obtained by annexin V or TUNEL staining in peripheral blood lymphocytes. Although in general primary necrotic cells show an increased forward scatter due to cellullar swelling, both early apoptotic and necrotic (primary or secondary) lymphocytes show a decreased forward scatter signal. Moreover, both primary and secondary necrotic lymphocytes are annexin V and propidium iodide (PI) positive and therefore indistinguishable. We conclude that if a new experiment focusing on apoptosis is set up, an initial EM evaluation is mandatory. If EM shows that the apoptosis inducing agent used in the design of the experiments is not causing primary necrosis, than the annexin V flow cytometric assay can provide rapid and quantitative information about apoptosis. PMID- 10101045 TI - Alterations in the growth and adhesion pattern of Vero cells induced by nutritional stress conditions. AB - The pattern of growth, adhesion and protein synthesis in Vero cells submitted to nutritional stress conditions was investigated. The control cells presented a characteristic pattern, with monolayer growth, while the stressed cells presented multilayered growth, with aggregate or spheroid formation which detached on the flask surface and continued their growth in another region. In the soft agar assay, with reduced amount of nutrients, only the stressed cells presented growth, indicating physical and nutritional independence. A 44-kDa protein was observed in stressed cells and was absent in non-stressed cells. The adhesion index and fibronectin synthesis and distribution were altered in stressed cells. After confluence, control cells presented fibronectin accumulation in lateral cell-cell contact regions, while this fibronectin accumulation pattern was not observed in stressed cells. These alterations may be responsible for the multilayered growth and decreased adhesion index observed in stressed cells which were transformed by nutritional stress conditions. PMID- 10101046 TI - Expression and cellular localization of the mRNA for the 25-kDa heat-shock protein in the mouse. AB - The 25-kDa heat-shock protein (Hsp25) is a member of the small heat-shock protein family but its function remains largely unknown. In the present study we examined the expression and cellular localization of Hsp25 mRNA in mice under physiological, unstressed conditions using Northern blot and in situ hybridization analyses with specific oligonucleotide probes. At the organ level, high amounts of Hsp25 mRNA were detected in the oesophagus, skin,eye, stomach, lung and urinary bladder, with moderate amounts in the heart, skeletal muscle, aorta, adrenal gland, ovary, testis, uterus, large intestine, and thymus. At the cellular level, intense to moderate signals for Hsp25 mRNA were localized in the muscle cells of smooth, heart and skeletal types, in the epithelial cells of stratified squamous and transitional types and of the oviduct, in the steroid endocrine cells of the adrenal cortex and corpus luteum, as well as in the spermatocytes of the testis. In contrast, the signal was scarcely detectable in the nervous tissues, lymphatic tissues, the columnar epithelial cells of the digestive tract, or the parenchymal cells of the liver, pancreas and kidney. These results suggest some significant role for Hsp25 in distinct populations of mouse cells under physiological conditions. PMID- 10101047 TI - Temporal-spatial expression of two Paracentrotus lividus cell surface proteins. AB - The temporal expression of two cell surface proteins, called BEP1 and BEP4, during Paracentrosus lividus embryonic development was studied. These proteins are found in both monomeric and dimeric forms in egg and embryos and we have established that their specific form is related to their being in the cytoplasm or on the cell surface. The spatial distribution of BEP1 and BEP4 proteins in eggs and embryos was established by whole mount immunohistochemistry. These proteins are located in the animal part of unfertilized and fertilized eggs; thereafter they are much less represented in structures derived from the vegetal cells of the embryo such as the micromeres of the 16 cell stage, the primary mesenchyme of blastula and the gut of gastrula. At the prism stage BEP1 and BEP4 proteins are present to some ectodermal parts and thereafter, at the pluteus stage, to the oral region. PMID- 10101048 TI - Osteogenic growth peptide enhances the rate of fracture healing in rabbits. AB - The discovery of growth factors, such as osteogenic growth peptide (OGP), that stimulate bone formation led to experiments to discover whether they can accelerate fracture healing. To determine whether OGP enhances the rate of healing in rabbits, fractures were made in the tibiae of New Zealand White rabbits and immobilized with either a plastic plate (unstable mechanical conditions), or a dynamic compression plate (stable mechanical conditions). OGP was administered to experimental animals by intravenous injection from day 4 until the day before sacrifice; control animals were not injected. After treatment with OGP, callus development under unstable mechanical conditions was accelerated. At 7 days, the cartilage in the centre of the callus was covered by bone and endochondral ossification had started; these events occur at 10 days in control fractures. Subsequently, endochondral ossification is completed earlier which allows the invasion of the fracture gap by cells, so that cortical union is complete by 21 to 28 days. In control fractures, bone is only beginning to form in the gaps at 28 days. There was no increase in the size of the callus in any of the experimental fractures compared to the untreated controls. Treatment with OGP has no observable effect on the rate of healing of fractures under stable mechanical conditions. These observations suggest that under unstable mechanical conditions only, the rate of callus formation and subsequent cortical healing is enhanced by treatment with OGP, but that the size of the callus is determined by mechanical and other factors. PMID- 10101049 TI - The oligomeric integrity of toposome is essential for its morphogenetic function. AB - Sea urchin embryos are uniquely suitable for the study of morphogenetic cell interactions. Efforts to identify the molecules responsible for morphogenetic cell adhesion led to the isolation of a 22S glycoprotein complex from Paracentrotus lividus sea urchin embryo, that has been called toposome. The biological activity of toposome in mediating cellular adhesion has been fully documented. Its function in determining positional guidance during the development of the sea urchin embryo has been proposed. Here studies on the molecular structure of toposome are reported showing that, under non-reducing conditions, it is resolved in sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) in a major band with an apparent molecular weight of 260 kDa, a doublet of 180-160 kDa and a lower band of 80 kDa. Digestion with EndoH endoglycosidase reduced the molecular sizes of the bands of 10%, 20% and 40%, respectively. In order to establish if the oligomeric integrity of toposome was essential for its function, the biological activity of each subunit on cells dissociated from sea urchin blastula embryos was tested. The resulting swimming embryoids were lacking skeleton, while reaggregating cells supplemented with native toposome developed into pluteus-like structures with skeletal elements. PMID- 10101093 TI - Effects of U-83836E on glutamate-induced neurotoxicity in dissociated rat cerebellar granule cells. AB - The effects of the lazaroid compound U-83836E on the glutamate-induced production of reactive oxygen species (ROS) were studied in dissociated rat cerebellar granule cells by flow cytometry. U-83836E completely inhibited ROS production with an estimated IC50 value of 21.7 +/- 9.1 nM. However, U-83836E did not inhibit the glutamate-evoked decrease in mitochondrial membrane potential (MMP). Nevertheless, U-83836E (10 nM to 10 microM) prevented cell death induced by 10 mM of glutamate. At concentrations above 10 microM, U-83836E by itself showed slight cytotoxicity, which was significant at a 100 microM concentration. U-83836E (25 to 200 microM) also increased the cytosolic calcium levels in a concentration dependent manner. Our results indicate that the cytotoxic effects found at micromolar concentrations of U-83836E could be explained by an increase in [Ca2+]i. Finally, since U-83836E did not prevent the MMP decrease evoked by glutamate, it is suggested that antioxidant pharmacotherapy would not be sufficient to block the neurotoxic effects of glutamate. PMID- 10101094 TI - Differential susceptibility of brain areas to cyanide involves different modes of cell death. AB - We have demonstrated that cyanide (KCN) induces selective degeneration of dopaminergic neurons in mice and apoptotic cell death in cultured neurons. In the present study the mode of cyanide-induced cell death was determined in the susceptible brain areas. Mice were treated with KCN (6 mg/kg ip) or vehicle (saline) twice daily for 1 to 12 days. After 3 days of KCN treatment, two separate lesions were observed in coronal brain sections. Widespread DNA fragmentation in parietal and suprarhinal regions of the motor cortex was observed by the in situ terminal deoxynucleotide transferase nick-end labeling (TUNEL) technique. Pyknosis and chromatin condensation, morphological hallmarks of apoptotic cells, were observed in TUNEL-positive regions. On the other hand, in the substantia nigra (SN), KCN produced a progressive, bilateral necrotic lesion that was evident by 3 days of treatment. The SN lesion was circumscribed by a prominent ring of glial infiltration, as determined by glial-acidic fibrillary protein (GFAP) immunostaining. The extent of the SN lesion steadily increased with treatment duration, and DNA fragmentation was not observed over the 1- to 12-day period. On the other hand, cortical apoptosis was not associated with necrotic cell loss or astrogliosis. Pretreatment of animals with the antioxidant alpha-phenyl-tert-butyl nitrone (PBN) for 7 days prior to and during 3 days of KCN administration markedly reduced cortical DNA fragmentation whereas the PBN treatment did not influence the SN necrosis or astrocytic gliosis. Except for moderate GFAP immunostaining in corpus callosum, other brain areas were not affected by cyanide. It is concluded that KCN-induced neuronal loss involves selective activation of necrosis or apoptosis in different neuronal populations, and involves divergent mechanisms and sensitivity to antioxidants. PMID- 10101095 TI - Activation of poly [ADP-Ribose] polymerase in endothelial cells and keratinocytes: role in an in vitro model of sulfur mustard-mediated vesication. AB - Although endothelial cells and keratinocytes appear to be the primary cellular targets of sulfur mustard (SM), the role of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) in SM-induced vesication has not been clearly defined. PARP is thought to play a crucial role in DNA repair mechanisms following exposure to alkylating agents like SM. Using a combination of fluorescence microscopy and biochemical assays, we tested the hypothesis that SM causes activation of PARP in endothelial cells and keratinocytes with subsequent loss of nicotinamide adenine dinucleotide (NAD) and depletion of adenosine triphosphate (ATP) levels. To determine if PARP activation accounts for SM-induced vesication, keratinocyte adherence and permeability of endothelial monolayers were measured as in vitro correlates of vesication. As early as 2 to 3 h after exposure to SM concentrations as low as 250 microM, dramatic changes were induced in keratinocyte morphology and microfilament architecture. Exposure to 500 microM SM induced a fourfold increase in PARP activity in endothelial cells, and a two- to threefold increase in keratinocytes. SM induced a dose-related loss of NAD+ in both endothelial cells and keratinocytes. ATP levels fell to approximately 50% of control levels in response to SM concentrations >/=500 microM. SM concentrations >/=250 microM significantly reduced keratinocyte adherence as early as 3 h after exposure. Endothelial monolayer permeability increased substantially with concentrations of SM >250 microM. These observations support the hypothesis that the pathogenic events necessary for SM-induced vesication (i.e., capillary leak and loss of keratinocyte adherence) at higher vesicating doses of SM (>/=500 microM) may depend on NAD loss with PARP activation and subsequent ATP-dependent effects on microfilament architecture. Vesication developing as a result of exposure to lower concentrations of SM presumably occurs by mechanisms that do not depend on loss of cellular ATP (e.g., apoptosis and direct SM-mediated damage to integrins and the basement membrane). PMID- 10101096 TI - Induction of altered hepatic foci by a mixture of dioxin-like compounds with and without 2,2',4,4',5,5'-hexachlorobiphenyl in female Sprague-Dawley rats. AB - The hepatic tumor-promoting activity of a mixture of polyhalogenated aromatic hydrocarbons (PHAHs) was studied in a medium term two-stage initiation/promotion bioassay in female Sprague-Dawley rats. The PHAH mixture contained 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7, 8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5 pentachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118), 2,3,3',4,4', 5-hexachlorobiphenyl (PCB 156), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) and covered >90% of the total toxic equivalents (TEQ) present in Baltic herring. To determine possible interactive effects of di-ortho-substituted PCBs, the PHAH mixture was tested with (PHAH+) and without (PHAH-) PCB 153. Rats were initiated by a diethylnitrosamine injection (30 mg/kg body wt i.p.) 24 h after a partial 23 hepatectomy. Six weeks after initiation, the PHAH mixtures were administered once a week by subcutaneous injections for 20 weeks. Treatment with the PHAH mixtures caused liver enlargement and an increased activity of the hepatic cytochrome P4501A1/2 and P4502B1/2. All PHAH exposure groups exhibited an increased occurrence of hepatic foci positive for the placental form of glutathione-S-transferase. In the PHAH-group dosed 1 microgram TEQ/kg body wt/week, the volume fraction of the liver occupied by foci was significantly lower compared to the TEQ equivalent dosed TCDD group (3.8 vs 8.7%). The volume fraction was significantly increased in the groups treated with 0.5, 1, or 2 micrograms TEQ/kg body wt/week of the PHAH+ mixture (4.5, 5.2, and 6.6%, respectively) compared to the corn oil group (2.0%), but to a lower extent than expected on basis of the TEQ doses. Overall, the TEQ-based administered dose overestimated the observed tumor-promoting effects of this PHAH mixture. The applicability of the toxic equivalency factor concept, the role of differences in toxicokinetic properties and interactive effects of PCB 153 on hepatic deposition of the dioxin-like congeners are discussed. PMID- 10101097 TI - Analysis of differential effects of Pb2+ on protein kinase C isozymes. AB - Protein kinase C has been implicated as a cellular target for Pb2+ toxicity. We have previously proposed that Pb2+ modulates PKC activity by interacting with multiple sites within the enzyme. In order to further characterize the Pb-PKC interactions we compared the effects of Pb2+ on the CA-dependent and -independent protein kinase C isozymes using recombinant human PKC-alpha, PKC-epsilon, and PKC zeta as well as the catalytic fragment of bovine brain protein kinase C, the PKC M. The results demonstrate that, whereas at pM concentrations Pb2+ activates PKC alpha half maximally (KAct approximately 2 pM), it has no effect on PKC-epsilon, PKC-zeta, or PKC-M activities. The activation of PKC-alpha by Pb2+ is additive with Ca2+ in a manner indicating interaction with half of the calcium activation sites. In the micromolar range of concentrations, Pb2+ inhibits all PKCs with estimated K0.5 of 1.0, 2.3, 28, and 93 microM for PKC-M, PKC-alpha, PKC-epsilon, and PKC-zeta, respectively. Examination of Pb2+ effects on PKC-M kinetics indicates a mixed type inhibition with respect to ATP and noncompetitive inhibition with respect to histone. Taken together with the results of our previous study (Tomsig and Suszkiw, J. Neurochem. 64, 2667-2673, 1995) and the evidence for the existence of two Ca2+ coordination sites Ca1 and Ca2 within the C2 domain (Shao et al., Science [Washington, D.C.] 273, 248-251, 1996), the results of the current study provide further support for a multisite Pb-PKC interaction scheme wherein lead (1) partially activates the enzyme through pM affinity interactions with the Ca1 site and inhibits the divalent cation dependent activity through nM-affinity interactions with Ca2 site in the C2 domain and (2) inhibits the constitutive kinase activity through microM-affinity interactions with the catalytic domain. The concentration dependence of the differential effects of Pb2+ on the calcium-dependent and -independent PKCs underscores the importance of the C2 motif as a high affinity molecular target for Pb2+. PMID- 10101098 TI - Induction of apoptosis and changes in nuclear G-actin are mediated by different pathways: the effect of inhibitors of protein and RNA synthesis in isolated rat hepatocytes. AB - Stressor-induced changes in the cytoskeleton, of which actin is a major component, may lead to apoptosis. The role of drug-induced changes in nuclear G actin and apoptosis was studied in freshly isolated hepatocytes. Several protein synthesis inhibitors, cycloheximide, puromycin, and emetine, induced 10 to 15% apoptosis in hepatocytes after 4 h, as was determined by changes in nuclear morphology and flow cytometric analysis of Annexin V-positive cells. Apoptosis induced by protein synthesis inhibition could be prevented by the caspase inhibitors Z-Val-Ala-DL-Asp fluormethylketone (zVAD-fmk) and Ac-Asp-Glu-Val-Asp aldehyde (DEVD-cho). Several (chemical) stressors cause a rapid increase in nuclear G-actin staining in hepatocytes or cell lines (Meijerman et al., Biochem. Biophys. Res. Commun. 240, 697-700, 1997). The protein synthesis inhibitors also increased G-actin staining in nuclei after 2 h; this could not be inhibited by zVAD-fmk or DEVD-cho. Changes in the cytosolic F-actin pattern did not occur until nuclear G-actin staining had already increased. The mRNA synthesis inhibitor actinomycin D, also increased nuclear G-actin staining, but did not induce apoptosis within the studied time frame. The results suggest that the induction of apoptosis and the increased nuclear staining of G-actin by protein synthesis inhibition are differently controlled. PMID- 10101099 TI - Antagonism of paraoxon intoxication by recombinant phosphotriesterase encapsulated within sterically stabilized liposomes. AB - This investigation effort is focused on increasing organophosphate (OP) degradation by phosphotriesterase to antagonize OP intoxication. For these studies, sterically stabilized liposomes encapsulating recombinant phosphotriesterase were employed. This enzyme was obtained from Flavobacterium sp. and was expressed in Escherichia coli. It has a broad substrate specificity, which includes parathion, paraoxon, soman, sarin, diisopropylfluorophosphate, and other organophosphorous compounds. Paraoxon is rapidly hydrolyzed by phosphotriesterase to the less toxic 4-nitrophenol and diethylphosphate. This enzyme was isolated and purified over 1600-fold and subsequently encapsulated within sterically stabilized liposomes (SL). The properties of this encapsulated phosphotriesterase were investigated. When these liposomes containing phosphotriesterase were incubated with paraoxon, it readily degraded the paraoxon. Hydrolysis of paraoxon did not occur when these sterically stabilized liposomes contained no phosphotriesterase. These sterically stabilized liposomes (SL) containing phosphotriesterases (SL)* were employed as a carrier model to antagonize the toxic effects of paraoxon by hydrolyzing it to the less toxic 4 nitrophenol and diethylphosphate. This enzyme-SL complex (SL)* was administered intravenously to mice either alone or in combination with pralidoxime (2-PAM) and/or atropine intraperitoneally. These results indicate that this carrier model system provides a striking enhanced protective effects against the lethal effects of paraoxon. Moreover when these carrier liposomes were administered with 2-PAM and/or atropine, a dramatic enhanced protection was observed. PMID- 10101100 TI - Sarin-like and soman-like organophosphorous agents activate PLCgamma in rat brains. AB - We report that there is a time-related change in the phospholipase C (PLC) activities of rat brain cytosol and membrane fractions after iv injection of a soman-like or a sarin-like organophosphorous agent (bis(isopropyl methyl)phosphonate [BIMP] and bis(pinacolyl methyl)phosphonate [BPMP]). PLCgamma was activated in the brain cytosol fraction from BPMP-injected rats. The phosphorylating activity of rat brain membrane fractions were enhanced by BPMP treatment. The brain membrane fractions from BPMP-treated rats phosphorylated several proteins, including supposedly PLCgamma in the brain cytosol fraction from control rats in vitro. These results suggest that soman and sarin may stimulate a membrane tyrosine kinase, including growth factor receptors, directly or indirectly. PMID- 10101101 TI - Tumor suppressor genes in rodent lung carcinogenesis-mutation of p53 does not appear to be an early lesion in lung tumor pathogenesis. PMID- 10101102 TI - Modeling the developmental neurotoxicity of chlorpyrifos in vitro: macromolecule synthesis in PC12 cells. PMID- 10101103 TI - Behaviour of migrating birds exposed to X-band radar and a bright light beam AB - Radar studies on bird migration assume that the transmitted electromagnetic pulses do not alter the behaviour of the birds, in spite of some worrying reports of observed disturbance. This paper shows that, in the case of the X-band radar 'Superfledermaus', no relevant changes in flight behaviour occurred, while a strong light beam provoked important changes. Large sets of routine recordings of nocturnal bird migrants obtained using an X-band tracking radar provided no indication of differing flight behaviour between birds flying at low levels towards the radar, away from it or passing it sideways. Switching the radar transmission on and off, while continuing to track selected bird targets using a passive infrared camera during the switch-off phases of the radar, showed no difference in the birds' behaviour with and without incident radar waves. Tracking single nocturnal migrants while switching on and off a strong searchlight mounted parallel to the radar antenna, however, induced pronounced reactions by the birds: (1) a wide variation of directional shifts averaging 8 degrees in the first and 15 degrees in the third 10 s interval after switch-on; (2) a mean reduction in flight speed of 2-3 m s-1 (15-30 % of normal air speed); and (3) a slight increase in climbing rate. A calculated index of change declined with distance from the source, suggesting zero reaction beyond approximately 1 km. These results revive existing ideas of using light beams on aircraft to prevent bird strikes and provide arguments against the increasing use of light beams for advertising purposes. PMID- 10101104 TI - In vivo locomotor strain in the hindlimb bones of alligator mississippiensis and iguana iguana: implications for the evolution of limb bone safety factor and non sprawling limb posture AB - Limb postures of terrestrial tetrapods span a continuum from sprawling to fully upright; however, most experimental investigations of locomotor mechanics have focused on mammals and ground-dwelling birds that employ parasagittal limb kinematics, leaving much of the diversity of tetrapod locomotor mechanics unexplored. This study reports measurements of in vivo locomotor strain from the limb bones of lizard (Iguana iguana) and crocodilian (Alligator mississippiensis) species, animals from previously unsampled phylogenetic lineages with non parasagittal limb posture and kinematics. Principal strain orientations and shear strain magnitudes indicate that the limb bones of these species experience considerable torsion during locomotion. This contrasts with patterns commonly observed in mammals, but matches predictions from kinematic observations of axial rotation in lizard and crocodilian limbs. Comparisons of locomotor load magnitudes with the mechanical properties of limb bones in Alligator and Iguana indicate that limb bone safety factors in bending for these species range from 5.5 to 10.8, as much as twice as high as safety factors previously calculated for mammals and birds. Limb bone safety factors in shear (3.9-5.4) for Alligator and Iguana are also moderately higher than safety factors to yield in bending for birds and mammals. Finally, correlations between limb posture and strain magnitudes in Alligator show that at some recording locations limb bone strains can increase during upright locomotion, in contrast to expectations based on size correlated changes in posture among mammals that limb bone strains should decrease with the use of an upright posture. These data suggest that, in some lineages, strain magnitudes may not have been maintained at constant levels through the evolution of a non-sprawling posture unless the postural change was accompanied by a shift to parasagittal kinematics or by an evolutionary decrease in body size. PMID- 10101105 TI - Comparative three-dimensional kinematics of the hindlimb for high-speed bipedal and quadrupedal locomotion of lizards AB - Although lizards have been model organisms for testing locomotor performance and in ecomorphological studies, the limb movements of lizards during high-speed locomotion are poorly understood. Thus, we quantified the three-dimensional kinematics of the hindlimb, body and tail for five morphologically distinct species of lizard during steady-speed locomotion near maximum sprinting speed (2 5 m s-1). The kinematics of different species had little multivariate overlap. More than half of the strides of all species had digitigrade foot posture, but the frequency of using digitigrade foot posture varied among species. The combination of digitigrade foot posture and large foot size of the lizards contributed substantially to the high values of hip height. For each species, different suites of kinematic variables distinguished bipedal from quadrupedal strides. Interspecific morphological variation did not correspond globally to variation in kinematics, although lizard species with elongated hindlimbs took longer strides than species with shorter hindlimbs. The Froude numbers and relative stride lengths of all lizards running near maximal speeds were large compared with those reported previously for other vertebrates. PMID- 10101106 TI - Monoamines and the isolated auricle of sepia officinalis: are there &bgr;-like receptors in the heart of a cephalopod? AB - Pharmacological examinations of isolated auricles from Sepia officinalis were carried out to analyze the putative role of the monoaminergic transmitter/receptor system in the control of auricle function. In conjunction with histofluorescence studies and HPLC analyses, evidence of a double excitatory serotonergic and noradrenergic innervation of the auricles was obtained. Serotonin-induced positive chronotropic and inotropic effects were blocked by mianserin (5-HT1 and 5-HT2) but not by cyproheptadine (5-HT2). It is assumed that the auricular serotonin (5-HT) receptor represents a 5-HT1-like subtype and is not identical to the ventricular 5-HT receptor. Noradrenaline, adrenaline and dopamine evoked mainly positive chronotropic reactions and less prominent positive inotropic reactions. The potency range (pD2 frequency: noradrenaline 6.65 >> adrenaline 5.69 > dopamine 5.34; pD2 amplitude: noradrenaline 6.09 (greater than or equal to) adrenaline 5.91 > dopamine 5.33) indicates out that noradrenaline might be the effective neurotransmitter in vivo. The &agr; mimetics clonidine ( &agr; 2) and phenylephrine ( &agr; 1) induced positive chronotropic and inotropic effects, while the &bgr;-mimetics albuterol (&bgr;2>&bgr;1) and dobutamine (&bgr;1) revealed only positive inotropic reactions. The &bgr;-agonist isoprenaline mimicked the positive chronotropic effects of noradrenaline and induced the strongest positive inotropic effects of all the agonists tested. Urapidil ( &agr; 1) or phentolamine ( &agr; 1 and &agr; 2) blocked only the positive chronotropic effects of noradrenaline and isoprenaline. The positive inotropic effects of isoprenaline could be blocked by the adenylate cyclase inhibitors MDL-12,330A or SQ-22, 536, which had no effect on the chronotropic effects of isoprenaline. These results suggest that two catecholaminergic receptors are present in the auricles of Sepia officinalis: an &agr; -like adrenoreceptor mediating mainly chronotropic effects, and a &bgr; like receptor which appears to mediate inotropic effects by activating the cyclic AMP pathway. These results suggest that the auricles exert a regulatory effect on ventricular performance. PMID- 10101107 TI - Identification and expression analysis of two developmentally regulated myosin heavy chain gene transcripts in carp (Cyprinus carpio). AB - Whilst developmentally regulated genes for the myosin heavy chain (MyoHC) have been characterised in mammalian, avian and amphibian species, no developmental MyoHC gene has previously been characterised in a species of fish. In this study, we identify two developmentally regulated MyoHC gene transcripts (named Eggs22 and Eggs24) in carp (Cyprinus carpio) and characterise their expression patterns during embryonic and larval development. The transcripts showed an identical temporal pattern of expression commencing 22 h post-fertilisation (18 degrees C incubation temperature), coincident with the switch from exclusive expression of genes for beta-actin to expression of genes for both beta- and alpha-actin, and continuing for 2 weeks post-hatching. No expression of these myosin transcripts was detected in juvenile or adult carp. Wholemount in situ hybridisation showed that both transcripts are expressed initially in the rostral region of the developing trunk and progress caudally. Both are expressed in the developing pectoral fin and protractor hyoideus muscles. However, the muscles of the lower jaw express only the Eggs22 transcript. No expression of either transcript was detected in cardiac or smooth muscle. A distinct chevron pattern of expression was observed in the myotomal muscle. This was shown to be caused by localisation of the mRNAs to the myoseptal regions of the fibres, the sites of new sarcomere addition during muscle growth, suggesting transport of MyoHC mRNA transcripts. The 3' untranslated region of the Eggs24 transcript contains a 10 base pair motif (AAAATGTGAA) which is shown to be also present in the 3' untranslated regions of MyoHC genes from a wide range of species. Possible reasons for the need for developmental isoforms of myosin heavy chain isoforms are discussed. PMID- 10101108 TI - Convective oxygen transport and tissue oxygen consumption in Weddell seals during aerobic dives. AB - Unlike their terrestrial counterparts, marine mammals stop breathing and reduce their convective oxygen transport while performing activities (e.g. foraging, courtship, aggressive interactions, predator avoidance and migration) that require sustained power output during submergence. Since most voluntary dives are believed to remain aerobic, the goal of this study was to examine the potential importance of the dive response in optimizing the use of blood and muscle oxygen stores during dives involving different levels of muscular exertion. To accomplish this, we designed a numerical model based on Fick's principle that integrated cardiac output (Vb), regional blood flow, convective oxygen transport (Q(O2)), muscle oxymyoglobin desaturation and regional rates of oxygen consumption (VO2). The model quantified how the optimal matching or mismatching of QO2 to VO2 affected the aerobic dive limit (ADL). We chose an adult Weddell seal Leptonycotes weddellii on which to base our model because of available data on the diving physiology and metabolism of this species. The results show that the use of blood and muscle oxygen stores must be completed at the same time to maximize the ADL for each level of VO2. This is achieved by adjusting Vb (range 19-94 % of resting levels) and muscle QO2 according to the rate of muscle oxygen consumption (VMO2). At higher values of VMO2, Vb and muscle perfusion must increase to maintain an appropriate QO2/VO2 ratio so that available blood and muscle oxygen stores are depleted at the same time. Although the dive response does not sequester blood oxygen exclusively for brain and heart metabolism during aerobic dives, as it does during forced submersion, a reduction in Vb and muscle perfusion below resting levels is necessary to maximize the ADL over the range of diving VO2 (approximately 2-9 ml O2 min-1 kg-1). Despite the reduction in Vb, convective oxygen transport is adequate to maintain aerobic metabolism and normal function in the splanchnic organs, kidneys and other peripheral tissues. As a result, physiological homeostasis is maintained throughout the dive. The model shows that the cardiovascular adjustments known as the dive response enable the diving seal to balance the conflicting metabolic demands of (1) optimizing the distribution and use of blood and muscle oxygen stores to maximize the ADL over the normal range of diving VO2 and (2) ensuring that active muscle receives adequate oxygen as VMO2 increases. PMID- 10101109 TI - Heart rates and diving behavior of leatherback sea turtles in the eastern pacific ocean AB - Heart rates and diving behavior of leatherback sea turtles (Dermochelys coriacea) were monitored at sea during the internesting interval. Instruments that recorded the electrocardiogram and the depth and duration of dives were deployed on six female leatherback turtles as they laid eggs at Playa Grande, Costa Rica. Turtles dived continually for the majority of the internesting interval and spent 57-68 % of the time at sea submerged. Mean dive depth was 19+/-1 m (mean +/- s.d.) and the mean dive duration was 7.4+/-0.6 min. Heart rate declined immediately upon submergence and continued to fall during descent. All turtles showed an increase in heart rate before surfacing. The mean heart rate during dives of 17.4+/-0.9 beats min-1 (mean +/- s.d.) was significantly lower than the mean heart rate at the surface of 24.9+/-1.3 beats min-1 (P<0.05). Instantaneous heart rates as low as 1.05 beats min-1 were recorded during a 34 min dive. The mean heart rate over the entire dive cycle (dive + succeeding surface interval; 19.4+/-1.3 beats min 1) was more similar to the heart rate during diving than to the heart rate at the surface. Although dive and surface heart rates were significantly different from each other, heart rates during diving were 70 % of heart rates at the surface, showing that leatherback turtles do not experience a dramatic bradycardia during routine diving. PMID- 10101110 TI - Kinematics of intraoral transport and swallowing in the herbivorous lizard uromastix acanthinurus AB - The kinematics of intraoral transport and swallowing in lizards of the species Uromastix acanthinurus (Chamaeleonidae, Leiolepidinae) were investigated using cineradiography (50 frames s-1). Additional recordings were also made using high speed (500 frames s-1) and conventional video systems (25 frames s-1). Small metal markers were inserted into different parts of the upper and lower jaw and the tongue. Cineradiographic images were digitised, and displacements of the body, head, upper and lower jaw and the tongue were quantified. Twenty additional variables depicting displacements and the timing of events were calculated. Multivariate analyses of variance indicated significant differences between feeding stages. Remarkably, only very few food-type-dependent differences were observed during intraoral transport, and no such differences could be demonstrated during swallowing. Using previously published data for the closely related insectivorous lizard Plocederma stellio, the effect of dietary specialisation in U. acanthinurus on the kinematic variables while eating locusts was examined. Species differed in a number of gape- and tongue-related variables. These differences may be related to differences in tongue structure between the species. Clearly, U. acanthinurus possesses a specialised gut and dental structure that allows them efficiently to cut pieces from whole leaves. However, a decrease in modulatory capacity seems to be a consequence of dietary specialisation in Uromastix acanthinurus. PMID- 10101111 TI - Impulse conduction in a sponge. AB - All-or-none propagated electrical impulses were recorded from the hexactinellid sponge Rhabdocalyptus dawsoni using suction electrodes attached to lumps of aggregated sponge tissue grafted onto the surface of pieces of the same sponge. Impulses were normally evoked by means of externally applied electrical shocks. Recorded externally using an a.c.-coupled amplifier, the electrical event was triphasic and lasted approximately 30 s; integration gave a diphasic waveform. A further integration to give the form of the membrane action potential produced a monophasic signal. Impulses propagated at 0.27+/-0.1 cm s-1 with an absolute refractory period of 29 s and a relative refractory period of approximately 150 s. Concurrent thermistor flow meter recordings confirmed that water flow through the sponge was arrested following the passage of an impulse, presumably as result of the cessation of beating of the flagella in the flagellated chambers. Tactile stimuli also evoked impulses, as did addition of particulate material to the incoming water stream. Impulses continued to propagate through the sponge during arrests, indicating that the conduction and effector systems were independent. Sponges lack nerves, and a variety of evidence indicates that the conducting tissues are the syncytial trabecular reticulum and pinacoderm layers. Na+ deficient solutions had little effect on the action potential, but propagation was blocked by 10 mmol l-1 Co2+, 1 mmol l-1 Mn2+ or 24 micromol l-1 nimodipine. Tetraethylammonium ions at 1-5 mmol l-1 also blocked propagation without prolonging the action potential. Impulse conduction in the sponge is discussed in relation to excitability and conduction in the protozoa and in plants and to non nervous conduction in more advanced animals. PMID- 10101112 TI - Cardiovascular and gill microcirculatory effects of endothelin-1 in atlantic cod: evidence for pillar cell contraction AB - Endothelin-1 (ET-1) has been shown to cause a considerable increase in the vascular resistance of fish gills. In trout, recent evidence suggest that this is the result of pillar cell contraction in the gill lamellae. Using epi illumination microscopy to observe the gill lamellae of anaesthetised Atlantic cod (Gadus morhua), we show that ET-1 (100 ng kg-1, injected into the ventral aorta) causes an increase in pillar cell diameter, consistent with pillar cell contraction, and a shift of intralamellar blood flow from the lamellar sheet to the outer marginal channels. Simultaneously, there was an increase in ventral aortic blood pressure, a reduction in cardiac output, an increase in gill vascular resistance and a reduction in the oxygen partial pressure of venous blood. All these effects were blocked by the ETA/ETB receptor antagonist bosentan (5 mg kg-1). Pillar cell contraction is likely to be a mechanism for matching the functional respiratory surface area with the instantaneous respiratory needs of the fish. PMID- 10101113 TI - Evidence for orientation using the e-vector direction of polarised light in the sleepy lizard tiliqua rugosa AB - Adult sleepy lizards (Tiliqua rugosa) were trained to orient in a predictable direction under natural sky light in outdoor pens. When tested under clear skies in the late afternoon, without a view of the sun, the lizards exhibited a symmetrical bimodal pattern of orientation with respect to the trained axis. Since the e-vector of polarised light provides an axial rather than a polar cue, the bimodal orientation exhibited by the lizards is consistent with the use of a celestial compass based on sky polarisation patterns. To confirm that the lizards could orient with respect to a polarisation pattern, lizards were trained in indoor pens to orient in a predictable direction under a linearly polarised light source. When tested in a circular arena illuminated by another polarised light source, the lizards used the e-vector direction of the polarised light source to orient along the trained axis. There was no evidence that the lizards were using any room-specific cues or brightness patterns to orient in the training direction. These results support the hypothesis that the lizards can use the e vector direction of polarised light in the form of a sky polarisation compass. PMID- 10101114 TI - Cis-regulatory elements of the mitotic regulator, string/Cdc25. AB - Mitosis in most Drosophila cells is triggered by brief bursts of transcription of string (stg), a Cdc25-type phosphatase that activates the mitotic kinase, Cdk1 (Cdc2). To understand how string transcription is regulated, we analyzed the expression of string-lacZ reporter genes covering approximately 40 kb of the string locus. We also tested protein coding fragments of the string locus of 6 kb to 31.6 kb for their ability to complement loss of string function in embryos and imaginal discs. A plethora of cis-acting elements spread over >30 kb control string transcription in different cells and tissue types. Regulatory elements specific to subsets of epidermal cells, mesoderm, trachea and nurse cells were identified, but the majority of the string locus appears to be devoted to controlling cell proliferation during neurogenesis. Consistent with this, compact promotor-proximal sequences are sufficient for string function during imaginal disc growth, but additional distal elements are required for the development of neural structures in the eye, wing, leg and notum. We suggest that, during evolution, cell-type-specific control elements were acquired by a simple growth regulated promoter as a means of coordinating cell division with developmental processes, particularly neurogenesis. PMID- 10101115 TI - Hindlimb patterning and mandible development require the Ptx1 gene. AB - The restricted expression of the Ptx1 (Pitx1) gene in the posterior half of the lateral plate mesoderm has suggested that it may play a role in specification of posterior structures, in particular, specification of hindlimb identity. Ptx1 is also expressed in the most anterior ectoderm, the stomodeum, and in the first branchial arch. Ptx1 expression overlaps with that of Ptx2 in stomodeum and in posterior left lateral plate mesoderm. We now show that targeted inactivation of the mouse Ptx1 gene severely impairs hindlimb development: the ilium and knee cartilage are absent and the long bones are underdeveloped. Greater reduction of the right femur size in Ptx1 null mice suggests partial compensation by Ptx2 on the left side. The similarly sized tibia and fibula of mutant hindlimbs may be taken to resemble forelimb bones: however, the mutant limb buds appear to have retained their molecular identity as assessed by forelimb expression of Tbx5 and by hindlimb expression of Tbx4, even though Tbx4 expression is decreased in Ptx1 null mice. The hindlimb defects appear to be, at least partly, due to abnormal chondrogenesis. Since the most affected structures derive from the dorsal side of hindlimb buds, the data suggest that Ptx1 is responsible for patterning of these dorsal structures and that as such it may control development of hindlimb specific features. Ptx1 inactivation also leads to loss of bones derived from the proximal part of the mandibular mesenchyme. The dual role of Ptx1 revealed by the gene knockout may reflect features of the mammalian jaw and hindlimbs that were acquired at a similar time during tetrapod evolution. PMID- 10101116 TI - her4, a zebrafish homologue of the Drosophila neurogenic gene E(spl), is a target of NOTCH signalling. AB - her4 encodes a zebrafish bHLH protein of the hairy-E(spl) family. The gene is transcribed in a complex pattern in the developing nervous system and in the hypoblast. During early neurogenesis, her4 expression domains include the regions of the neural plate from which primary neurons arise, suggesting that the gene is involved in directing their development. Indeed, misexpression of specific her4 variants leads to a reduction in the number of primary neurons formed. The amino terminal region of her4, including the basic domain, and the region between the putative helix IV and the carboxy-terminal tetrapeptide wrpw are essential for this effect, since her4 variants lacking either of these regions are non functional. However, the carboxy-terminal wrpw itself is dispensable. We have examined the interrelationships between deltaD, deltaA, notch1, her4 and neurogenin1 by means of RNA injections. her4 is involved in a regulatory feedback loop which modulates the activity of the proneural gene neurogenin, and as a consequence, of deltaA and deltaD. Activation of notch1 leads to strong activation of her4, to suppression of neurogenin transcription and, ultimately, to a reduction in the number of primary neurons. These results suggest that her4 acts as a target of notch-mediated signals that regulate primary neurogenesis. PMID- 10101117 TI - Developmental potential of mouse primordial germ cells. AB - There are distinctive and characteristic genomic modifications in primordial germ cells that distinguish the germ cell lineage from somatic cells. These modifications include, genome-wide demethylation, erasure of allele-specific methylation associated with imprinted genes, and the re-activation of the X chromosome. The allele-specific differential methylation is involved in regulating the monoallelic expression, and thus the gene dosage, of imprinted genes, which underlies functional differences between parental genomes. However, when the imprints are erased in the germ line, the parental genomes acquire an equivalent epigenetic and functional state. Therefore, one of the reasons why primordial germ cells are unique is because this is the only time in mammals when the distinction between parental genomes ceases to exist. To test how the potentially imprint-free primordial germ cell nuclei affect embryonic development, we transplanted them into enucleated oocytes. Here we show that the reconstituted oocyte developed to day 9.5 of gestation, consistently as a small embryo and a characteristic abnormal placenta. The embryo proper also did not progress much further even when the inner cell mass was 'rescued' from the abnormal placenta by transfer into a tetraploid host blastocyst. We found that development of the experimental conceptus was affected, at least in part, by a lack of gametic imprints, as judged by DNA methylation and expression analysis of several imprinted genes. The evidence suggests that gametic imprints are essential for normal development, and that they can neither be initiated nor erased in mature oocytes; these properties are unique to the developing germ line. PMID- 10101118 TI - Somatic signaling mediated by fs(1)Yb is essential for germline stem cell maintenance during Drosophila oogenesis. AB - Drosophila oogenesis starts when a germline stem cell divides asymmetrically to generate a daughter germline stem cell and a cystoblast that will develop into a mature egg. We show that the fs(1)Yb gene is essential for the maintenance of germline stem cells during oogenesis. We delineate fs(1)Yb within a 6.4 kb genomic region by transgenic rescue experiments. fs(1)Yb encodes a 4.1 kb RNA that is present in the third instar larval, pupal and adult stages, consistent with its role in regulating germline stem cells during oogenesis. Germline clonal analysis shows that all fs(1)Yb mutations are soma-dependent. In the adult ovary, fs(1)Yb is specifically expressed in the terminal filament cells, suggesting that fs(1)Yb acts in these signaling cells to maintain germline stem cells. fs(1)Yb encodes a novel hydrophilic protein with no potential signal peptide or transmembrane domains, suggesting that this protein is not itself a signal but a key component of the signaling machinery for germline stem cell maintenance. PMID- 10101119 TI - YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. AB - The Wilms' Tumour gene WT1 has important functions during development. Knock-out mice were shown to have defects in the urogenital system and to die at embryonic day E13.5, probably due to heart failure. Using a lacZ reporter gene inserted into a YAC construct, we demonstrate that WT1 is expressed in the early proepicardium, the epicardium and the subepicardial mesenchymal cells (SEMC). Lack of WT1 leads to severe defects in the epicardial layer and a concomitant absence of SEMCs, which explains the pericardial bleeding and subsequent embryonic death observed in Wt1 null embryos. We further show that a human derived WT1 YAC construct is able to completely rescue heart defects, but only partially rescues defects in the urogenital system. Analysis of the observed hypoplastic kidneys demonstrate a continuous requirement for WT1 during nephrogenesis, in particular, in the formation of mature glomeruli. Finally, we show that the development of adrenal glands is also severely affected in partially rescued embryos. These data demonstrate a variety of new functions for WT1 and suggest a general requirement for this protein in the formation of organs derived from the intermediate mesoderm. PMID- 10101120 TI - Novel guidance cues during neuronal pathfinding in the early scaffold of axon tracts in the rostral brain. AB - A scaffold of axons consisting of a pair of longitudinal tracts and several commissures is established during early development of the vertebrate brain. We report here that NOC-2, a cell surface carbohydrate, is selectively expressed by a subpopulation of growing axons in this scaffold in Xenopus. NOC-2 is present on two glycoproteins, one of which is a novel glycoform of the neural cell adhesion molecule N-CAM. When the function of NOC-2 was perturbed using either soluble carbohydrates or anti-NOC-2 antibodies, axons expressing NOC-2 exhibited aberrant growth at specific points in their pathway. NOC-2 is the first-identified axon guidance molecule essential for development of the axon scaffold in the embryonic vertebrate brain. PMID- 10101121 TI - Identification of mutations that cause cell migration defects in mosaic clones. AB - Cell movement is an important feature of animal development, wound healing and tumor metastasis; however, the mechanisms underlying cell motility remain to be elucidated. To further our understanding, it would be useful to identify all of the proteins that are essential for a cell to migrate, yet such information is not currently available for any cell type. We have carried out a screen for mutations affecting border cell migration in Drosophila. Mutations that cause defects in mosaic clones were identified, so that genes that are also required for viability could be detected. From 6000 mutagenized lines, 20 mutations on chromosome 2R were isolated that cause defects in border cell position. One of the mutations was dominant while all of the recessive mutations appeared to be homozygous lethal. This lethality was used to place the mutations into 16 complementation groups. Many of the mutations failed to complement cytologically characterized deficiencies, allowing their rapid mapping. Mutations in three loci altered expression of a marker gene in the border cells, whereas the remaining mutations did not. One mutation, which caused production of supernumerary border cells, was found to disrupt the costal-2 locus, indicating a role for Hedgehog signaling in border cell development. This screen identified many new loci required for border cell migration and our results suggest that this is a useful approach for elucidating the mechanisms involved in cell motility. PMID- 10101122 TI - Temporal and spatial regulation of symplastic trafficking during development in Arabidopsis thaliana apices. AB - Plasmodesmata provide symplastic continuity linking individual plant cells. However, specialized cells may be isolated, either by the absence of plasmodesmata or by down regulation of the cytoplasmic flux through these channels, resulting in the formation of symplastic domains. Maintenance of these domains may be essential for the co-ordination of growth and development. While cells in the center of the meristem divide slowly and remain undifferentiated, cells on the meristem periphery divide more frequently and respond to signals determining organ fate. Such symplastic domains were visualized within shoot apices of Arabidopsis, by monitoring fluorescent symplastic tracers (HPTS: 8 hydroxypyrene 1,3,6 trisulfonic acid and CF: carboxy fluorescein). Tracers were loaded through cut leaves and distributed throughout the whole plant. Confocal laser scanning microscopy on living Arabidopsis plants indicates that HPTS moves via the vascular tissue from leaves to the apex where the tracer exits the phloem and moves symplastically into surrounding cells. The distribution of HPTS was monitored in vegetative apices, and just prior to, during, and after the switch to production of flowers. The apices of vegetative plants loaded with HPTS had detectable amounts of tracer in the tunica layer of the meristem and in very young primordia, whereas the corpus of the meristem excluded tracer uptake. Fluorescence signal intensity decreased prior to the onset of flowering. Moreover, at approximately the time the plants were committed to flowering, HPTS was undetectable in the inflorescence meristem or young primordia. Later in development, after several secondary inflorescences and mature siliques appeared, inflorescence apices again showed tracer loading at levels comparable to that of vegetative apices. Thus, analysis of fluorescent tracer movement via plasmodesmata reveals there is distinct temporal and spatial regulation of symplastic domains at the apex, dependent on the developmental stage of the plant. PMID- 10101123 TI - Sensory activity affects sensory axon development in C. elegans. AB - The simple nervous system of the nematode C. elegans consists of 302 neurons with highly reproducible morphologies, suggesting a hard-wired program of axon guidance. Surprisingly, we show here that sensory activity shapes sensory axon morphology in C. elegans. A class of mutants with deformed sensory cilia at their dendrite endings have extra axon branches, suggesting that sensory deprivation disrupts axon outgrowth. Mutations that alter calcium channels or membrane potential cause similar defects. Cell-specific perturbations of sensory activity can cause cell-autonomous changes in axon morphology. Although the sensory axons initially reach their targets in the embryo, the mutations that alter sensory activity cause extra axon growth late in development. Thus, perturbations of activity affect the maintenance of sensory axon morphology after an initial pattern of innervation is established. This system provides a genetically tractable model for identifying molecular mechanisms linking neuronal activity to nervous system structure. PMID- 10101124 TI - Defects in thalamocortical axon pathfinding correlate with altered cell domains in Mash-1-deficient mice. AB - We have analyzed the pathfinding of thalamocortical axons (TCAs) from dorsal thalamus to neocortex in relation to specific cell domains in the forebrain of wild-type and Mash-1-deficient mice. In wild-type mice, we identified four cell domains that constitute the proximal part of the TCA pathway. These domains are distinguished by patterns of gene expression and by the presence of neurons retrogradely labeled from dorsal thalamus. Since the cells that form these domains are generated in forebrain proliferative zones that express high levels of Mash-1, we studied Mash-1 mutant mice to assess the potential roles of these domains in TCA pathfinding. In null mutants, each of the domains is altered: the two Pax-6 domains, one in ventral thalamus and one in hypothalamus, are expanded in size; a complementary RPTP(delta) domain in ventral thalamus is correspondingly reduced and the normally graded expression of RPTP(delta) in that domain is no longer apparent. In ventral telencephalon, a domain characterized in the wild type by Netrin-1 and Nkx-2.1 expression and by retrogradely labeled neurons is absent in the mutant. Defects in TCA pathfinding are localized to the borders of each of these altered domains. Many TCAs fail to enter the expanded, ventral thalamic Pax-6 domain that constitutes the most proximal part of the TCA pathway, and form a dense whorl at the border between dorsal and ventral thalamus. A proportion of TCAs do extend further distally into ventral thalamus, but many of these stall at an aberrant, abrupt border of high RPTP(delta) expression. A small proportion of TCAs extend around the RPTP(delta) domain and reach the ventral thalamic-hypothalamic border, but few of these axons turn at that border to extend into the ventral telencephalon. These findings demonstrate that Mash-1 is required for the normal development of cell domains that in turn are required for normal TCA pathfinding. In addition, these findings support the hypothesis that ventral telencephalic neurons and their axons guide TCAs through ventral thalamus and into ventral telencephalon. PMID- 10101125 TI - The Drosophila gene stand still encodes a germline chromatin-associated protein that controls the transcription of the ovarian tumor gene. AB - The Drosophila gene stand still (stil) encodes a novel protein required for survival, sexual identity and differentiation of female germ cells. Using specific antibodies, we show that the Stil protein accumulates in the nucleus of all female germ cells throughout development, and is transiently expressed during early stages of male germline differentiation. Changes of Stil subnuclear localization during oogenesis suggest an association with chromatin. Several mutant alleles, which are point mutations in the Stil N-terminal domain, encode proteins that no longer co-localized with chromatin. We find that Stil binds to many sites on polytene chromosomes with strong preference for decondensed chromatin. This localization is very similar to that of RNA polymerase II. We show that Stil is required for high levels of transcription of the ovarian tumor gene in germ cells. Expression of ovarian tumor in somatic cells can be induced by ectopic expression of Stil. Finally, we find that transient ubiquitous somatic expression of Stil results in lethality of the fly at all stages of development. PMID- 10101126 TI - Cerebellar histogenesis is disturbed in mice lacking cyclin D2. AB - Formation of brain requires deftly balancing primary genesis of neurons and glia, detection of when sufficient cells of each type have been produced, shutdown of proliferation and removal of excess cells. The region and cell type-specific expression of cell cycle regulatory proteins, such as demonstrated for cyclin D2, may contribute to these processes. If so, regional brain development should be affected by alteration of cyclin expression. To test this hypothesis, the representation of specific cell types was examined in the cerebellum of animals lacking cyclin D2. The loss of this cyclin primarily affected two neuronal populations: granule cell number was reduced and stellate interneurons were nearly absent. Differences between null and wild-type siblings were obvious by the second postnatal week. Decreases in granule cell number arose from both reduction in primary neurogenesis and increase in apoptosis of cells that fail to differentiate. The dearth of stellate cells in the molecular layer indicates that emergence of this subpopulation requires cyclin D2 expression. Surprisingly, Golgi and basket interneurons, thought to originate from the same precursor pool as stellate cells, appear unaffected. These results suggest that cyclin D2 is required in cerebellum not only for proliferation of the granule cell precursors but also for proper differentiation of granule and stellate interneurons. PMID- 10101127 TI - A novel ontogenetic pathway in hybrid embryos between species with different modes of development. AB - To investigate the bases for evolutionary changes in developmental mode, we fertilized eggs of a direct-developing sea urchin, Heliocidaris erythrogramma, with sperm from a closely related species, H. tuberculata, that undergoes indirect development via a feeding larva. The resulting hybrids completed development to form juvenile adult sea urchins. Hybrids exhibited restoration of feeding larval structures and paternal gene expression that have been lost in the evolution of the direct-developing maternal species. However, the developmental outcome of the hybrids was not a simple reversion to the paternal pluteus larval form. An unexpected result was that the ontogeny of the hybrids was distinct from either parental species. Early hybrid larvae exhibited a novel morphology similar to that of the dipleurula-type larva typical of other classes of echinoderms and considered to represent the ancestral echinoderm larval form. In the hybrid developmental program, therefore, both recent and ancient ancestral features were restored. That is, the hybrids exhibited features of the pluteus larval form that is present in both the paternal species and in the immediate common ancestor of the two species, but they also exhibited general developmental features of very distantly related echinoderms. Thus in the hybrids, the interaction of two genomes that normally encode two disparate developmental modes produces a novel but harmonious ontongeny. PMID- 10101128 TI - Cell cycle-dependent sequencing of cell fate decisions in Caenorhabditis elegans vulva precursor cells. AB - In Caenorhabditis elegans, the fates of the six multipotent vulva precursor cells (VPCs) are specified by extracellular signals. One VPC expresses the primary (1 degrees ) fate in response to a Ras-mediated inductive signal from the gonad. The two VPCs flanking the 1 degrees cell each express secondary (2 degrees ) fates in response to lin-12-mediated lateral signaling. The remaining three VPCs each adopt the non-vulval tertiary (3 degrees ) fate. Here I describe experiments examining how the selection of these vulval fates is affected by cell cycle arrest and cell cycle-restricted lin-12 activity. The results suggest that lin-12 participates in two developmental decisions separable by cell cycle phase: lin-12 must act prior to the end of VPC S phase to influence a 1 degrees versus 2 degrees cell fate choice, but must act after VPC S phase to influence a 3 degrees versus 2 degrees cell fate choice. Coupling developmental decisions to cell cycle transitions may provide a mechanism for prioritizing or ordering choices of cell fates for multipotential cells. PMID- 10101129 TI - Fine-scale transgenic mapping of the MyoD core enhancer: MyoD is regulated by distinct but overlapping mechanisms in myotomal and non-myotomal muscle lineages. AB - Skeletal muscle lineage determination is regulated by the myogenic regulatory genes, MyoD and Myf-5. Previously, we identified a 258 bp core enhancer element 20 kb 5' of the MyoD gene that regulates MyoD gene activation in mouse embryos. To elucidate the cis control mechanisms that regulate MyoD transcription, we have mutagenized the entire core enhancer using linker-scanner mutagenesis, and have tested the transcriptional activity of enhancer mutants using lacZ reporter gene expression in transgenic mouse embryos. In total, 83 stable transgenic lines representing 17 linker-scanner mutations were analyzed in midgestational mouse embryos. Eight linker-scanner mutations resulted in a partial or complete loss of enhancer activity, demonstrating that MyoD is primarily under positive transcriptional control. Six of these mutations reduced or abolished transgene expression in all skeletal muscle lineages, indicating that activation of MyoD expression in trunk, limb and head musculature is regulated, in part, by shared transcriptional mechanisms. Interestingly, however, two adjacent linker-scanner mutations (LS-14 and LS-15) resulted in a dramatic reduction in transgene expression specifically in myotomes at 11.5 days. At later stages, transgene expression was absent or greatly reduced in myotomally derived muscles including epaxial muscles (deep back muscles) and hypaxial muscles of the body wall (intercostal muscles, abdominal wall musculature). In contrast, head muscles, as well as muscles of the body derived from migrating muscle progenitor cells (e.g. limb, diaphragm), were unaffected by these mutations. In Pax-3-mutant mice, LS-14 and LS-15 transgene expression was eliminated in the body, but was unaffected in the head, yielding an identical expression pattern to the endogenous MyoD gene in mice mutant for both Myf-5 and Pax-3. These data support the hypothesis that LS 14 and LS-15 define the core enhancer targets for Myf-5-dependent activation of MyoD in myotomal muscles. PMID- 10101130 TI - Asymmetric cell division of thoracic neuroblast 6-4 to bifurcate glial and neuronal lineage in Drosophila. AB - In the development of the Drosophila central nervous system, some of the neuroblasts designated as neuroglioblasts generate both glia and neurons. Little is known about how neuroglioblasts produce these different cell types. NB6-4 in the thoracic segment (NB6-4T) is a neuroglioblast, although the corresponding cell in the abdominal segment (NB6-4A) produces only glia. Here, we describe the cell divisions in the NB6-4T lineage, following changes in cell number and cell arrangement. We also examined successive changes in the expression of glial cells missing (gcm) mRNA and protein, activity of which is known to direct glial fate from the neuronal default state. The first cell division of NB6-4T occurred in the medial-lateral orientation, and was found to bifurcate the glial and neuronal lineage. After division, the medial daughter cell expressed GCM protein to produce three glial cells, while the lateral daughter cell with no GCM expression produced ganglion mother cells, secondary precursors of neurons. Although gcm mRNA was present evenly in the cytoplasm of NB6-4T before the first cell division, it became detected asymmetrically in the cell during mitosis and eventually only in the medial daughter cell. In contrast, NB6-4A showed a symmetrical distribution of gcm mRNA and GCM protein through division. Our observations suggest that mechanisms regulating gcm mRNA expression and its translation play an important role in glial and neuronal lineage bifurcation that results from asymmetric cell division. PMID- 10101131 TI - Establishment of substratum polarity in the blastocoel roof of the Xenopus embryo. AB - The fibronectin fibril matrix on the blastocoel roof of the Xenopus gastrula contains guidance cues that determine the direction of mesoderm cell migration. The underlying guidance-related polarity of the blastocoel roof is established in the late blastula under the influence of an instructive signal from the vegetal half of the embryo, in particular from the mesoderm. Formation of an oriented substratum depends on functional activin and FGF signaling pathways in the blastocoel roof. Besides being involved in tissue polarization, activin and FGF also affect fibronectin matrix assembly. Activin treatment of the blastocoel roof inhibits fibril formation, whereas FGF modulates the structure of the fibril network. The presence of intact fibronectin fibrils is permissive for directional mesoderm migration on the blastocoel roof extracellular matrix. PMID- 10101132 TI - Hox genes differentially regulate Serrate to generate segment-specific structures. AB - Diversification of Drosophila segmental morphologies requires the functions of Hox transcription factors. However, there is little information describing pathways through which Hox activities effect the discrete cellular changes that diversify segmental architecture. We have identified the Drosophila signaling protein Serrate as the product of a Hox downstream gene that acts in many segments as a component of such pathways. In the embryonic epidermis, Serrate is required for morphogenesis of normal abdominal denticle belts and maxillary mouth hooks, both Hox-dependent structures. The Hox genes Ultrabithorax and abdominal-A are required to activate an early stripe of Serrate transcription in abdominal segments. In the abdominal epidermis, Serrate promotes denticle diversity by precisely localizing a single cell stripe of rhomboid expression, which generates a source of EGF signal that is not produced in thoracic epidermis. In the head, Deformed is required to activate Serrate transcription in the maxillary segment, where Serrate is required for normal mouth hook morphogenesis. However, Serrate does not require rhomboid function in the maxillary segment, suggesting that the Hox-Serrate pathway to segment-specific morphogenesis can be linked to more than one downstream function. PMID- 10101133 TI - Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation. AB - Blastocyst implantation requires molecular and cellular interactions between the uterine luminal epithelium and blastocyst trophectoderm. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) is induced in the mouse luminal epithelium solely at the site of blastocyst apposition at 16:00 hours on day 4 of pregnancy prior to the attachment reaction (22:00-23:00 hours), and that HB-EGF promotes blastocyst growth, zona-hatching and trophoblast outgrowth. To delineate which EGF receptors participate in blastocyst activation, the toxicity of chimeric toxins composed of HB-EGF or TGF-(&agr;) coupled to Pseudomonas exotoxin (PE) were used as measures of receptor expression. TGF-(&agr;) or HB-EGF binds to EGF-receptor (ErbB1), while HB-EGF, in addition, binds to ErbB4. The results indicate that ErbB1 is inefficient in mediating TGF-(&agr;)-PE or HB-EGF PE toxicity as follows: (i) TGF-(&agr;)-PE was relatively inferior in killing blastocysts, 100-fold less than HB-EGF-PE, (ii) analysis of blastocysts isolated from cross-bred egfr+/- mice demonstrated that HB-EGF-PE, but not TGF-(&agr;)-PE, killed egfr-/- blastocysts, and (iii) blastocysts that survived TGF-(&agr;)-PE were nevertheless killed by HB-EGF-PE. HB-EGF-PE toxicity was partially mediated by cell surface heparan sulfate proteoglycans (HSPG), since a peptide corresponding to the heparin-binding domain of HB-EGF as well as heparitinase treatment protected the blastocysts from the toxic effects of HB-EGF-PE by about 40%. ErbB4 is a candidate for being an HB-EGF-responsive receptor since RT-PCR analysis demonstrated that day 4 mouse blastocysts express two different erbB4 isoforms and immunostaining with anti-ErbB4 antibodies confirmed that ErbB4 protein is expressed at the apical surface of the trophectoderm cells. It is concluded that (i) HB-EGF interacts with the blastocyst cell surface via high affinity receptors other than ErbB1, (ii) the HB-EGF interaction with high affinity blastocysts receptors is regulated by heparan sulfate, and (iii) ErbB4 is a candidate for being a high-affinity receptor for HB-EGF on the surface of implantation-competent blastocysts. PMID- 10101134 TI - Discrete roles for secreted and transmembrane semaphorins in neuronal growth cone guidance in vivo. AB - From the initial stages of axon outgrowth to the formation of a functioning synapse, neuronal growth cones continuously integrate and respond to multiple guidance cues. To investigate the role of semaphorins in the establishment of appropriate axon trajectories, we have characterized a novel secreted semaphorin in grasshopper, gSema 2a. Sema 2a is expressed in a gradient in the developing limb bud epithelium during Ti pioneer axon outgrowth. We demonstrate that Sema 2a acts as chemorepulsive guidance molecule critical for axon fasciculation and for determining both the initial direction and subsequent pathfinding events of the Ti axon projection. Interestingly, simultaneous perturbation of both secreted Sema 2a and transmembrane Sema I results in a broader range and increased incidence of abnormal Ti pioneer axon phenotypes, indicating that different semaphorin family members can provide functionally distinct guidance information to the same growth cone in vivo. PMID- 10101135 TI - C. elegans MAC-1, an essential member of the AAA family of ATPases, can bind CED 4 and prevent cell death. AB - In the nematode Caenorhabditis elegans, CED-4 plays a central role in the regulation of programmed cell death. To identify proteins with essential or pleiotropic activities that might also regulate cell death, we used the yeast two hybrid system to screen for CED-4-binding proteins. We identified MAC-1, a member of the AAA family of ATPases that is similar to Smallminded of Drosophila. Immunoprecipitation studies confirm that MAC-1 interacts with CED-4, and also with Apaf-1, the mammalian homologue of CED-4. Furthermore, MAC-1 can form a multi-protein complex that also includes CED-3 or CED-9. A MAC-1 transgene under the control of a heat shock promoter prevents some natural cell deaths in C. elegans, and this protection is enhanced in a ced-9(n1950sd)/+ genetic background. We observe a similar effect in mammalian cells, where expression of MAC-1 can prevent CED-4 and CED-3 from inducing apoptosis. Finally, mac-1 is an essential gene, since inactivation by RNA-mediated interference causes worms to arrest early in larval development. This arrest is similar to that observed in Smallminded mutants, but is not related to the ability of MAC-1 to bind CED-4, since it still occurs in ced-3 or ced-4 null mutants. These results suggest that MAC-1 identifies a new class of proteins that are essential for development, and which might regulate cell death in specific circumstances. PMID- 10101136 TI - Improved reliability of the rapid microtiter plate assay using recombinant enzyme in predicting CYP2D6 inhibition in human liver microsomes. AB - A higher throughput method of screening for the inhibition of recombinant CYP2D6 using a microtiter plate (MTP) assay was evaluated using 62 new chemical entities and compared to data from the dextromethorphan O-demethylase assay in human liver microsomes (HLM). The IC50 values for the two assays closely matched for 53 compounds (85%). Six of the variant nine compounds had higher IC50 values with the recombinant enzyme, whereas three had lower IC50 values with the recombinant enzyme. When the inhibition with the recombinant enzyme was determined at various time points, the IC50 values increased as the duration of the incubation increased for the six compounds with higher IC50 values in the MTP assay. The IC50 values at 10 min matched more closely the IC50 values in HLM (95% compared with 85%). For three compounds that showed comparable IC50 values in the two assays, and the three compounds with lower IC50 values in the MTP assay, the IC50 values did not change over time. These results suggest that the six compounds that showed higher IC50 values in the MTP assay at 45 min are substrates for CYP2D6. Using known CYP2D6 substrates, a similar phenomenon was observed, i.e., inhibition curves shifted to higher IC50 values as incubation time increased. These results indicate that the higher throughput MTP assay is more comparable to HLM if the IC50 values are determined at 10 min rather than the recommended 45 min. Furthermore, data acquisition at multiple time points may indicate if a compound is a potential substrate or metabolism/mechanism-based inhibitor for the enzyme. PMID- 10101137 TI - Possible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats. AB - In our previous work, we found that the biliary excretion of the carboxylate form of irinotecan, CPT-11, on rat bile canalicular membrane consists of two components, the low-affinity one being canalicular multispecific organic anion transporter (cMOAT). In the present study, we have investigated the high-affinity component by studying the uptake in canalicular membrane vesicles. The ATP dependent uptake of the carboxylate form of CPT-11 was inhibited significantly by several substrates and/or modulators of P-glycoprotein, including PSC-833, verapamil, and cyclosporin A, at a substrate concentration of 5 microM, at which the high-affinity component is involved predominantly in CPT-11 transport. When the concentration of the carboxylate form of CPT-11 was 250 microM, at which the low-affinity component (cMOAT) is involved predominantly in its transport, the inhibitory effect of the above compounds was reduced greatly. Similarly, there was also much lower inhibition of the ATP-dependent uptake of S-(2,4 dinitrophenyl)-glutathione, a substrate of cMOAT, by the above compounds. Taurocholic acid, a substrate of canalicular bile acid transporter, failed to inhibit the uptake of CPT-11 at the substrate concentration of both 5 and 250 microM. These results suggest that P-glycoprotein may act as the high-affinity component in the biliary excretion of the carboxylate form of CPT-11 in rats. PMID- 10101138 TI - Bioavailability and metabolism of hydroquinone after intratracheal instillation in male rats. AB - The purpose of this study was to investigate the rate and extent of hydroquinone (HQ) absorption and first pass metabolism in the lungs of male rats in vivo. [14C]HQ in physiological saline was administered intratracheally via an indwelling endotracheal tube to simulate inhalation exposure to HQ dust. The bioavailability of HQ was determined by blood sampling simultaneously at arterial and venous sites beginning immediately after administration to conscious rats. Pulmonary absorption and metabolism, and systemic metabolism and elimination were determined by chromatographic analysis of parent compound and metabolites in blood samples after intratracheal administration of [14C]HQ at 0.1, 1.0, and 10 mg/kg. Pulmonary absorption of HQ was found to be very rapid with [14C]HQ detectable in arterial blood, and to a lesser extent in venous blood, within 5 to 10 s after dose administration. Only [14C]HQ was detected in the initial (5-10 s) arterial blood samples at all dose levels, indicating that pulmonary metabolism of HQ was not extensive. However, later blood samples (45-720 s) indicated rapid metabolism and elimination of the parent compound and metabolites after intratracheal absorption. The elimination half-life from the 0.1 mg/kg dose was allometrically scaled to human proportions and used to estimate the steady-state (maximum) human blood concentrations of HQ resulting from presupposed workplace exposures. The estimates indicated minimal levels of HQ in human blood after respiratory exposures of greater than 1 h at 0.1 or 2.0 mg/m3; these levels were less than background concentrations of HQ detected in human blood in previous studies. PMID- 10101139 TI - Effect of cyclosporine A on cytochrome P-450-mediated drug metabolism in the partially hepatectomized rat. AB - Despite its hepatotoxic potential, cyclosporine A (CsA) has been reported to positively influence compensatory liver growth. To probe the physiological consequences of CsA on the recovery of liver function, studies were initiated in the 2/3 partially hepatectomized (PHx) rat, taking the recovery of cytochromes P 450-dependent drug metabolism as primary outcome. CsA was administered at a dose of 3. 33 mg/kg/day for 10 days. Drug metabolism was evaluated by the recovery of 14CO2 after administration of isotopically labeled model drugs and by studying the expression of the P-450 transcripts involved in their biotransformation before and 24 to 96 h after PHx. Before PHx, neither the steady-state mRNA nor the in vivo disposition of caffeine (CYP1A2), erythromycin (CYP3A2 and 3A1), or aminopyrine (CYP2B1 and 2C11) were influenced by CsA. Studies 24 h after PHx revealed a 29 to 39% reduction in the elimination of [14C]aminopyrine and [14C]erythromycin, which was unaffected by CsA. Their metabolism at 48 to 96 h after PHx also remained unaffected by CsA. By contrast, postPHx, [14C]caffeine elimination decreased to a level closely proportional to the loss in liver mass. In addition, CsA accelerated the recovery and/or prevented the decrease of caffeine elimination 24 h after PHx but not at later time points, indicating an early, but unsustained, beneficial effect of CsA on the recovery of CYP1A2 mediated activities. These data show that at the critical time of greatest loss in liver mass, CsA has only a selective influence on the biotransformation of cytochrome P-450 protein-dependent activities and that its effect on the regeneration process does not translate into an overall accelerated recovery of the hepatic drug-metabolizing function. PMID- 10101140 TI - Characterization of metabolites of astaxanthin in primary cultures of rat hepatocytes. AB - The metabolism of the nonprovitamin A carotenoid astaxanthin was investigated in primary cultures of rat hepatocytes. In a time course study based on HPLC and gas chromatography-mass spectrometry analyses, one main metabolite, (rac)-3-hydroxy-4 oxo-beta-ionone, was found. This metabolite was conjugated mainly into glucuronides, as demonstrated by glusulase treatment of the conjugates under sulfatase-inhibiting conditions. Within 24 h more than 50% astaxanthin was metabolized and conjugated. Deconjugation of the polar conjugates with glusulase and analyses with HPLC and gas chromatography-mass spectrometry identified two metabolites, (rac)-3-hydroxy-4-oxo-beta-ionone and its reduced form (rac)-3 hydroxy-4-oxo-7,8-dihydro-beta-ionone, indicating that the former was reduced in the conjugated form. We confirmed that the ketocarotenoid astaxanthin induces xenobiotic-metabolizing enzymes in rat liver in vivo. However, there were no differences in the metabolism of astaxanthin in cultured hepatocytes from rats that were pretreated with astaxanthin and, thus, with induced cytochrome P-450 systems compared with control hepatocytes. Neither liver microsomes from astaxanthin-pretreated nor control rats metabolized astaxanthin. These results indicated that the cytochrome P-450 enzymes were not involved in the metabolism of astaxanthin in rat hepatocytes. We conclude that astaxanthin was metabolized in primary cultures of rat hepatocytes into (rac)-3-hydroxy-4-oxo-beta-ionone and its reduced form (rac)-3-hydroxy-4-oxo-7,8-dihydro-beta-ionone independent of the xenobiotic-metabolizing enzymes induced by astaxanthin. PMID- 10101141 TI - Comparative formation, distribution, and elimination kinetics of diphenylmethoxyacetic acid (a diphenhydramine metabolite) in maternal and fetal sheep. AB - Deamination to diphenylmethoxyacetic acid (DPMA) is the major route of diphenhydramine (DPHM) clearance in many species. In this study, we assessed the contribution of this pathway to nonplacental DPHM elimination and disposition of DPMA in maternal and fetal sheep. Paired maternal-fetal experiments were conducted in five chronically catheterized pregnant sheep (124-140 days gestation) with an appropriate washout period in between. Both maternal and fetal dosing experiments involved administration of an i.v bolus of deuterium-labeled DPMA ([2H10]-DPMA) combined with a 6-h infusion of DPHM (or a bolus of unlabeled DPMA with an infusion of deuterium-labeled DPHM). Maternal and fetal arterial plasma and urine samples were collected and analyzed for DPMA, [2H10]-DPMA, DPHM, and deuterium-labeled DPHM concentrations using gas chromatography-mass spectrometry. The preformed DPMA (or [2H10]-DPMA) had a substantially lower clearance (maternal: 0.55 +/- 0.18 versus 40.9 +/- 14.0 ml/min/kg; fetal: 0.37 +/ 0.11 versus 285. 6 +/- 122.2 ml/min/kg) and steady-state volume of distribution (Vdss, maternal: 0.10 +/- 0.02 versus 2.1 +/- 1.1 l/kg; fetal: 0.40 +/- 0. 06 versus 13.1 +/- 3.1 l/kg) as compared with the parent drug. The contribution of DPMA formation to maternal and fetal DPHM nonplacental clearance in vivo was 1.78 +/- 2.12% and 0.87 +/- 0.56%, respectively, indicating that DPMA formation is not a major route of DPHM clearance in fetal or maternal sheep. The recoveries of DPMA (or [2H10]-DPMA) in maternal urine were 88.0 +/- 6.5 and 92.1 +/- 7. 4% of the administered dose during maternal and fetal dosing experiments, respectively. Thus, this metabolite does not appear to be secondarily metabolized in fetal or maternal sheep. These findings are in contrast to other species (dog, rhesus monkey, human) where DPMA and its conjugates constitute approximately 40 to 60% of the total DPHM metabolites. PMID- 10101142 TI - Metabolism and disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) in rhesus monkeys. AB - Metabolism and disposition of the tobacco-specific N-nitrosamine, 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent rodent lung carcinogen, were studied in rhesus monkeys. In three males receiving a single i.v. dose of [5-3H]NNK (0.72 mCi; 4.6-9.8 microg/kg), urine was collected for 10 days. Within the first 24 h, 86.0 +/- 0.7% of the dose was excreted. NNK-derived radioactivity was still detectable in urine 10 days after dosing (total excretion, 92.7 +/- 0.7%). Decay of urinary radioactivity was biexponential with half-lives of 1.7 and 42 h. Metabolite patterns in urine from the first 6 h closely resembled those reported previously for patas monkeys; end products of metabolic NNK activation represented more than 50% of total radioactivity. At later time points, the pattern shifted in favor of NNK detoxification products (60-70% of total radioactivity in urine), mainly 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL) and its O-glucuronide conjugates. One female rhesus monkey received a single i.v. dose of [5-3H]NNK (1.72 mCi; 28.4 microg/kg) under isoflurane anesthesia; biliary excretion over 6 h (0.6% of the dose) was 10 times less than predicted by our previously reported rat model. No preferential excretion of NNAL glucuronide was observed in monkey bile. Collectively, these results suggest that the rhesus monkey could be a useful model for NNK metabolism and disposition in humans. PMID- 10101143 TI - Intestinal metabolism and transport of 5-aminosalicylate. AB - The purpose of this study was to determine the characteristics of intestinal absorption and metabolism of 5-aminosalicylic acid (5ASA). Regional perfusions of 5ASA in the anesthetized rat resulted in the appearance of N-acetyl-5 aminosalicylic acid in the intestinal lumen. Lumenal metabolite appearance was proportional to 5ASA permeability, which was 5-fold higher in the jejunum than in the ileum. Intestinal elimination significantly decreases 5ASA absorption at low lumenal drug concentrations and this process is saturated at high drug concentrations. Metabolite levels in intestinal tissue were higher than plasma levels at low perfusion drug concentrations, whereas the reverse was observed at high concentrations. Transport and metabolism of 5ASA was studied in Caco-2 monolayers. At low drug concentrations, 5ASA was preferentially transported in the basolateral (BL) to apical (AP) direction. With 5ASA incubation in either the AP or BL chamber, the N-acetyl metabolite appeared only in the AP compartment. Transport of N-acetyl-5-aminosalicylic acid was also exclusively observed in the BL to AP direction. Clinical data indicate that anti-inflammatory response to oral 5ASA correlates with the amount of 5ASA delivered to the intestinal tissue. This study shows that at lumenal levels below 200 microg/ml (concentrations that are typically achieved by controlled release dosage forms), intestinal secretion of 5ASA accounts for more than 50% of the total elimination and can significantly affect tissue levels and, therefore, may be an important factor in determining the response to 5ASA therapy. PMID- 10101144 TI - Biotransformation of curcumin through reduction and glucuronidation in mice. AB - Curcumin, the yellow pigment in turmeric and curry, has antioxidative and anticarcinogenic activities. In this study, we investigated the pharmacokinetic properties of curcumin in mice. After i.p. administration of curcumin (0.1 g/kg) to mice, about 2.25 microg/ml of curcumin appeared in the plasma in the first 15 min. One hour after administration, the levels of curcumin in the intestines, spleen, liver, and kidneys were 177.04, 26.06, 26.90, and 7.51 microg/g, respectively. Only traces (0.41 microg/g) were observed in the brain at 1 h. To clarify the nature of the metabolites of curcumin, the plasma was analyzed by reversed-phase HPLC, and two putative conjugates were observed. Treatment of the plasma with beta-glucuronidase resulted in a decrease in the concentrations of these two putative conjugates and the concomitant appearance of tetrahydrocurcumin (THC) and curcumin, respectively. To investigate the nature of these glucuronide conjugates in vivo, the plasma was analyzed by electrospray. The chemical structures of these metabolites, determined by mass spectrometry/mass spectrometry analysis, suggested that curcumin was first biotransformed to dihydrocurcumin and THC and that these compounds subsequently were converted to monoglucuronide conjugates. Because THC is one of the major metabolites of curcumin, we studied its stability at different pH values. THC was very stable in 0.1 M phosphate buffers of various pH values. Moreover, THC was more stable than curcumin in 0.1 M phosphate buffer, pH 7.2 (37 degrees C). These results, together with previous findings, suggest that curcumin-glucuronoside, dihydrocurcumin-glucuronoside, THC-glucuronoside, and THC are major metabolites of curcumin in vivo. PMID- 10101145 TI - Effect of its demethylated metabolite on the pharmacokinetics of unchanged TAK 603, a new antirheumatic agent, in rats. AB - A factor in the dose-dependent pharmacokinetics of ethyl 4-(3, 4-dimethoxyphenyl) 6,7-dimethoxy-2-(1,2, 4-triazol-1-yl-methyl)quinoline-3-carboxylate (TAK-603) in rats was shown to be due to the inhibition of metabolic clearance of unchanged TAK-603 by its major metabolite, M-I, in other words, product inhibition. The effect of M-I on the metabolic clearance of TAK-603 was studied using rats continuously infused i.v. with this metabolite at rates of 5.3 and 16.0 mg/h/kg. The total body clearance of TAK-603 was decreased remarkably in M-I-infused rats, and the decline of total body clearance depended on the steady-state plasma concentrations of M-I. The effect of M-I generated from the dosed parent drug on the plasma concentration-time profile of TAK-603 was investigated using bile cannulated rats after i.v. injection of 14C-labeled TAK-603 at doses of 1 and 15 mg/kg. Elimination rates of TAK-603 from rat plasma increased in the bile cannulated rats in which systemic M-I levels were reduced by interrupting its enterohepatic circulation. To express, simultaneously, the relationships between TAK-603 and M-I in plasma concentration-time profiles, a kinetic model based on the product inhibition was developed for the bile-cannulated rats. A good agreement between calculated curves and the observed concentrations of both TAK 603 and M-I was found at 1 and 15 mg/kg, and the calculated curves were drawn using constant parameters for the two dosages. These results show that the product inhibition by M-I is one factor responsible for the dose-dependent pharmacokinetics of TAK-603 in rats. PMID- 10101146 TI - Disposition and metabolism of 2-(2''(1'',3''-dioxolan-2-yl)-2- methyl-4-(2' oxopyrrolidin-1-Yl)-6-nitro-2h-1-benzopyran (SKP-450) in rats. AB - The disposition and metabolism of the new antihypertensive agent 2-(2"(1", 3" dioxolan-2-yl)-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-nitro -2H-1-benzopyran (SKP 450) were investigated in male rats after single oral and i.v. doses of 14C labeled compound. After an oral 2.0 mg/kg dose, mean radiocarbon recovery was 98.2 +/- 2.3% with 31.1 +/- 7.3% in the feces and 67.1 +/- 14.3% in the urine. Biliary excretion of radioactivity for the first 24-h period was approximately 40%, suggesting that SKP-450 is cleared either by hepatobiliary excretion or by renal excretion. SKP-450 was well absorbed; bioavailability calculated on the basis of radioactivity was 68 to 97%. Tissue distribution of the radioactivity was widespread with high concentrations in the liver and kidney but low central nervous system penetration. Radio-HPLC analysis of bile and urine from rats indicated the extensive metabolism of SKP-450 into oxidative metabolites. Oxidative metabolism of the dioxolanyl ring resulted in an aldehyde intermediate, subsequently confirmed in vitro, which was further oxidized to the corresponding carboxylic acid (M1) or reduced to the corresponding alcohol (M3). No parent drug was detected in the urine or bile. Glucuronide conjugate of M3 was also detected in urine and bile, accounting for 5.8 +/- 2.1 and 8.9 +/- 3. 7% of the excreted radioactivity, respectively. Quantitative data obtained from plasma samples suggest that the majority of circulating radioactivity was associated with metabolites. Our results suggest that the long duration of pharmacological activity of SKP-450 (>10 h) is largely attributable to its metabolites. PMID- 10101147 TI - Monospecific antipeptide antibody to cytochrome P-450 2B6. AB - To study cytochrome P-450 (CYP) 2B6 contribution to methoxychlor metabolism within human liver microsomes and to initiate an investigation of CYP2B6 protein expression, we developed a polyclonal antibody targeted to a 20-residue peptide within that protein. The antibody was found to be highly sensitive and monospecific for CYP2B6 on immunoblots. Although many immunological studies have described the absence or low expression of CYP2B6 in human livers, in the present investigation, we have found this not to be the case. We immunoquantified CYP2B6 apoprotein expression in a panel of 28 livers and found concentrations ranging from 2 to 82 pmol/mg protein, with a mean value of 25 pmol/mg protein. Five livers ( approximately 18%) displayed relatively high levels of CYP2B6 (>40 pmol/mg protein). There were no sex-related differences, although the highest level was observed in a 1-week postpartum donor given several medications. A marked diminution in variability was found in individuals aged 56 or older (n = 12), but there were no age-related trends in mean CYP2B6 content. We suggest that CYP2B6 represents a significant portion of total CYP in human liver. The exquisite sensitivity of this antibody (fmol quantities are detected easily on immunoblots) may explain our detection of CYP2B6 in 100% of livers versus its detection in a limited number of livers by certain other investigators. The antibody also was found to immunoinhibit CYP2B6-catalyzed N-demethylation of (S) mephenytoin in human liver microsomes by 68 to 79%. The utility of this antibody for determining human liver microsomal CYP2B6 contribution to the ortho hydroxylation of methoxychlor was demonstrated. PMID- 10101148 TI - Kinetics of drug metabolism in rat liver slices: IV. Comparison of ethoxycoumarin clearance by liver slices, isolated hepatocytes, and hepatic microsomes from rats pretreated with known modifiers of cytochrome P-450 activity. AB - To evaluate the theory that within precision-cut liver slices intercellular transport occurs in parallel with cellular metabolism and to illustrate the constraints this places on clearance predictions, the kinetics of ethoxycoumarin O-deethylation have been determined under varying conditions of hepatic cytochrome P-450 activity. Liver slices, isolated hepatocytes, and microsomes were obtained from rats treated with the inducers phenobarbital (PB) and beta naphthoflavone (betaNF) and the inhibitor aminobenzotriazole (ABT). In hepatocytes and microsomes, a two-site kinetic model with a high-affinity, low capacity site and an unsaturated low-affinity, high-capacity site described the hydroxycoumarin formation data. There were marked increases in Vmax (2- to 5-fold and 50- to 70-fold for PB and betaNF, respectively) in both systems and in CLint (3- and 9-fold for PB and betaNF, respectively) in hepatocytes and substantial decreases in both parameters (3-8 and 12-23% of control, respectively) in ABT hepatocytes and microsomes. A qualitatively similar response was evident in slices obtained from livers of rats treated with phenobarbital and ABT, but although slices from betaNF livers produced high metabolic rates (comparable to slices obtained from livers of rats treated with phenobarbital), these showed a linear increase with substrate concentration without indication of a high affinity site. The intrinsic clearance parameters were scaled to full liver capacity using hepatocellularities and microsomal recovery indices to allow direct comparison of these responses. The slice system consistently underestimated the effects of the modifiers. When compared with hepatocytes, estimates of 30, 15, and 1% for ABT, PB, and betaNF, respectively, were observed and the degree of underestimation was dependent on the magnitude of intrinsic clearance and was consistent with the above theory. PMID- 10101149 TI - Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S) ifosfamide in human liver microsomes. AB - The central nervous system toxicity of ifosfamide (IFF), a chiral antineoplastic agent, is thought to be dependent on its N-dechloroethylation by hepatic cytochrome P-450 (CYP) enzymes. The purpose of this study was to identify the human CYPs responsible for IFF-N-dechloroethylation and their corresponding regio and enantioselectivities. IFF exists in two enantiomeric forms, (R) - and (S) IFF, which can be dechloroethylated at either the N2 or N3 positions, producing the corresponding (R,S)-2-dechloroethyl-IFF [(R, S)-2-DCE-IFF] and (R,S)-3 dechloroethyl-IFF [(R,S)-3-DCE-IFF]. The results of the present study suggest that the production of (R)-2-DCE-IFF and (S)-3-DCE-IFF from (R)-IFF is catalyzed by different CYPs as is the production of (S)-2-DCE-IFF and (R)-3-DCE-IFF from (S)-IFF. In vitro studies with a bank of human liver microsomes revealed that the sample-to-sample variation in the production of (S)-3-DCE-IFF from (R)-IFF and (S)-2-DCE-IFF from (S)-IFF was highly correlated with the levels of (S) mephenytoin N-demethylation (CYP2B6), whereas (R)-2-DCE-IFF production from (R) IFF and (R)-3-DCE-IFF production from (S)-IFF were both correlated with the activity of testosterone 6beta-hydroxylation (CYP3A4/5). Experiments with cDNA expressed P-450 and antibody and chemical inhibition studies supported the conclusion that the formation of (S)-3-DCE-IFF and (S)-2-DCE-IFF is catalyzed primarily by CYP2B6, whereas (R)-2-DCE-IFF and (R)-3-DCE-IFF are primarily the result of CYP3A4/5 activity. PMID- 10101150 TI - Cellular distribution of cytochromes P-450 in the rat kidney. AB - The distribution of several cytochrome P-450 (P-450) isoenzymes between proximal tubular (PT) and distal tubular (DT) cells of the rat kidney was determined. Western blot analysis of microsomes prepared from liver and kidney cortical homogenates revealed that CYP2E1 protein was expressed in rat kidney microsomes at approximately 10% of hepatic levels. Microsomes from renal cortical, PT, and DT cells all expressed CYP2E1, with DT microsomes expressing slightly higher levels than PT microsomes. In contrast, chlorzoxazone hydroxylation activity was markedly higher in microsomes from PT cells than in those from DT cells. Northern blot analysis of total RNA from PT and DT cells exhibited a pattern of CYP2E1 mRNA distribution similar to that of CYP2E1 protein. CYP2C11 protein expression in renal cortical microsomes was approximately 10% of that in liver microsomes but was significantly higher in microsomes from PT cells than in those from DT cells. CYP3A1/2 was not detected in microsomes from either cortical, PT, or DT cells, but was detected in microsomes isolated from total liver or kidney cortical homogenates. CYP2B1/2 expression was detected in all tissues tested. The peroxisomal proliferator clofibrate enhanced the level of CYP2B1/2 in microsomes from both total liver and kidney cortical homogenates but not in microsomes from cortical, PT, or DT cells. CYP4A2/3 protein and CYP4A mRNA expression were detected in microsomes from total liver and kidney cortical homogenates and from renal cortical, PT, and DT cells using Western and Northern blot analyses, respectively. Lauric acid hydroxylation activity, an indicator of CYP4A, was comparable in PT and DT cells. Clofibrate elevation of CYP4A in cortical, PT, and DT microsomes was not as great as that detected in total kidney cortical microsomes. These results establish the distribution of several P-450 isoenzymes between different cell populations of the rat kidney. Furthermore, these results present evidence that the level of induction of certain P-450 isoenzymes in the kidney is cell type-specific. PMID- 10101151 TI - Tightly regulated and inducible expression of rabbit CYP2E1 using a tetracycline controlled expression system. AB - A tetracycline (Tc)-controlled gene expression system that quantitatively controls gene expression in eukaryotic cells () was used to express cytochrome P 450 2E1 (CYP2E1) in HeLa cells in culture. The rabbit CYP2E1 cDNA was subcloned into the Tc-controlled expression vector (pUHD10-3) and transfected into a HeLa cell line constitutively expressing the Tc-controlled transactivator, a positive regulator of expression in the absence of Tc. The expression of CYP2E1 was tightly regulated. There was a time-dependent induction of CYP2E1 after removal of Tc. In the absence of Tc, the enzyme was induced more than 100-fold and expressed about 18 pmol of CYP2E1/mg microsomal protein. At maximal levels of expression the enzyme catalyzed the formation of 158 pmol 6 hydroxychlorzoxazone/min/mg total cellular protein. In addition, the level of the enzyme could be modulated by the concentration of Tc in the media. In the absence of Tc, exposure of cells to N-nitrosodimethylamine caused a significant dose dependent decrease in cell viability. In contrast, menadione, a redox cycling toxicant, was less toxic to the cells after induction of CYP2E1 when compared with noninduced cells. Pulse-chase studies conducted 72 h after removal of Tc indicated a rapid turnover of CYP2E1 with a half-life of 3.9 h. Addition of the ligand, 4-methylpyrazole, and the suicide substrate, 1-aminobenzotrizole, decreased the degradation of CYP2E1. This cell line offers a useful system to examine the role of CYP2E1 in the cytotoxicity of xenobiotics and to investigate post-translational regulation of the enzyme. PMID- 10101152 TI - Larry Sandler: personal recollections. PMID- 10101153 TI - Genetic and physical maps of the Bacillus subtilis chromosome. AB - Sequencing of the complete Bacillus subtilis chromosome revealed the presence of approximately 4100 genes, 1000 of which were previously identified and mapped by classical genetic crosses. Comparison of these experimentally determined positions to those derived from the nucleotide sequence showed discrepancies reaching up to 24 degrees (approximately 280 kb). The size of these discrepancies as a function of their position along the chromosome is not random but, apparently, reveals some periodicity. Our analyses demonstrate that the discrepancies can be accounted for by inaccurate positioning of the early reference markers with respect to which all subsequently identified loci were mapped by transduction and transformation. We conclude (i) that specific DNA sequences, such as recombination hotspots or presence of heterologous DNA, had no detectable effect on the results obtained by classical mapping, and (ii) that PBS1 transduction appears to be an accurate and unbiased mapping method in B. subtilis. PMID- 10101154 TI - CYS3, a hotspot of meiotic recombination in Saccharomyces cerevisiae. Effects of heterozygosity and mismatch repair functions on gene conversion and recombination intermediates. AB - We have examined meiotic recombination at the CYS3 locus. Genetic analysis indicates that CYS3 is a hotspot of meiotic gene conversion, with a putative 5' 3' polarity gradient of conversion frequencies. This gradient is relieved in the presence of msh2 and pms1 mutations, indicating an involvement of mismatch repair functions in meiotic recombination. To investigate the role of mismatch repair proteins in meiotic recombination, we performed a physical analysis of meiotic DNA in wild-type and msh2 pms1 strains in the presence or absence of allelic differences at CYS3. Neither the mutations in CYS3 nor the absence of mismatch repair functions affects the frequency and distribution of nearby recombination initiating DNA double-strand breaks (DSBs). Processing of DSBs is also similar in msh2 pms1 and wild-type strains. We conclude that mismatch repair functions do not control the distribution of meiotic gene conversion events at the initiating steps. In the MSH2 PMS1 background, strains heteroallelic for frameshift mutations in CYS3 exhibit a frequency of gene conversion greater than that observed for either marker alone. Physical analysis revealed no modification in the formation of DSBs, suggesting that this marker effect results from subsequent processing events that are not yet understood. PMID- 10101155 TI - Suppressor analysis of the Saccharomyces cerevisiae gene REC104 reveals a genetic interaction with REC102. AB - REC104 is a gene required for the initiation of meiotic recombination in Saccharomyces cerevisiae. To better understand the role of REC104 in meiosis, we used an in vitro mutagenesis technique to create a set of temperature-conditional mutations in REC104 and used one ts allele (rec104-8) in a screen for high-copy suppressors. An increased dosage of the early exchange gene REC102 was found to suppress the conditional recombinational reduction in rec104-8 as well as in several other conditional rec104 alleles. However, no suppression was observed for a null allele of REC104, indicating that the suppression by REC102 is not "bypass" suppression. Overexpression of the early meiotic genes REC114, RAD50, HOP1, and RED1 fails to suppress any of the rec104 conditional alleles, indicating that the suppression might be specific to REC102. PMID- 10101156 TI - Analysis of mutations in the yeast mRNA decapping enzyme. AB - A major mechanism of mRNA decay in yeast is initiated by deadenylation, followed by mRNA decapping, which exposes the transcript to 5' to 3' exonucleolytic degradation. The decapping enzyme that removes the 5' cap structure is encoded by the DCP1 gene. To understand the function of the decapping enzyme, we used alanine scanning mutagenesis to create 31 mutant versions of the enzyme, and we examined the effects of the mutations both in vivo and in vitro. Two types of mutations that affected mRNA decapping in vivo were identified, including a temperature-sensitive allele. First, two mutants produced decapping enzymes that were defective for decapping in vitro, suggesting that these mutated residues are required for enzymatic activity. In contrast, several mutants that moderately affected mRNA decapping in vivo yielded decapping enzymes that had at least the same specific activity as the wild-type enzyme in vitro. Combination of alleles within this group yielded decapping enzymes that showed a strong loss of function in vivo, but that still produced fully active enzymes in vitro. This suggested that interactions of the decapping enzyme with other factors may be required for efficient decapping in vivo, and that these particular mutations may be disrupting such interactions. Interestingly, partial loss of decapping activity in vivo led to a defect in normal deadenylation-dependent decapping, but it did not affect the rapid deadenylation-independent decapping triggered by early nonsense codons. This observation suggested that these two types of mRNA decapping differ in their requirements for the decapping enzyme. PMID- 10101158 TI - The role of the mismatch repair machinery in regulating mitotic and meiotic recombination between diverged sequences in yeast. AB - Nonidentical recombination substrates recombine less efficiently than do identical substrates in yeast, and much of this inhibition can be attributed to action of the mismatch repair (MMR) machinery. In this study an intron-based inverted repeat assay system has been used to directly compare the rates of mitotic and meiotic recombination between pairs of 350-bp substrates varying from 82% to 100% in sequence identity. The recombination rate data indicate that sequence divergence impacts mitotic and meiotic recombination similarly, although subtle differences are evident. In addition to assessing recombination rates as a function of sequence divergence, the endpoints of mitotic and meiotic recombination events involving 94%-identical substrates were determined by DNA sequencing. The endpoint analysis indicates that the extent of meiotic heteroduplex DNA formed in a MMR-defective strain is 65% longer than that formed in a wild-type strain. These data are consistent with a model in which the MMR machinery interferes with the formation and/or extension of heteroduplex intermediates during recombination. PMID- 10101157 TI - Suppressor analysis of fimbrin (Sac6p) overexpression in yeast. AB - Yeast fimbrin (Sac6p) is an actin filament-bundling protein that is lethal when overexpressed. To identify the basis for this lethality, we sought mutations that can suppress it. A total of 1326 suppressor mutations were isolated and analyzed. As the vast majority of mutations were expected to simply decrease the expression of Sac6p to tolerable levels, a rapid screen was devised to eliminate these mutations. A total of 1324 mutations were found to suppress by reducing levels of Sac6p in the cell. The remaining 2 mutations were both found to be in the actin gene and to make the novel changes G48V (act1-20) and K50E (act1-21). These mutations suppress the defect in cytoskeletal organization and cell morphology seen in ACT1 cells that overexpress SAC6. These findings indicate that the lethal phenotype caused by Sac6p overexpression is mediated through interaction with actin. Moreover, the altered residues lie in the region of actin previously implicated in the binding of Sac6p, and they result in a reduced affinity of actin for Sac6p. These results indicate that the two mutations most likely suppress by reducing the affinity of actin for Sac6p in vivo. This study suggests it should be possible to use this type of suppressor analysis to identify other pairs of physically interacting proteins and suggests that it may be possible to identify sites where such proteins interact with each other. PMID- 10101159 TI - Suppressor analysis of mutations in the 5'-untranslated region of COB mRNA identifies components of general pathways for mitochondrial mRNA processing and decay in Saccharomyces cerevisiae. AB - The cytochrome b gene in Saccharomyces cerevisiae, COB, is encoded by the mitochondrial genome. Nuclear-encoded Cbp1 protein is required specifically for COB mRNA stabilization. Cbp1 interacts with a CCG element in a 64-nucleotide sequence in the 5'-untranslated region of COB mRNA. Mutation of any nucleotide in the CCG causes the same phenotype as cbp1 mutations, i.e., destabilization of both COB precursor and mature message. In this study, eleven nuclear suppressors of single-nucleotide mutations in CCG were isolated and characterized. One dominant suppressor is in CBP1, while the other 10 semidominant suppressors define five distinct linkage groups. One group of four mutations is in PET127, which is required for 5' end processing of several mitochondrial mRNAs. Another mutation is linked to DSS1, which is a subunit of mitochondrial 3' --> 5' exoribonuclease. A mutation linked to the SOC1 gene, previously defined by recessive mutations that suppress cbp1 ts alleles and stabilize many mitochondrial mRNAs, was also isolated. We hypothesize that the products of the two uncharacterized genes also affect mitochondrial RNA turnover. PMID- 10101160 TI - Distinct steps in yeast spore morphogenesis require distinct SMK1 MAP kinase thresholds. AB - The SMK1 mitogen-activated protein kinase is required for spore morphogenesis in Saccharomyces cerevisiae. In contrast to the multiple aberrant spore wall assembly patterns seen even within a single smk1 null ascus, different smk1 missense mutants block in a coordinated fashion at intermediate stages. One smk1 mutant forms asci in which the four spores are surrounded only by prospore wall like structures, while another smk1 mutant forms asci in which the spores are surrounded by inner but not outer spore wall layers. Stepwise increases in gene dosage of a hypomorphic smk1 allele allow for the completion of progressively later morphological and biochemical events and for the acquisition of distinct spore-resistance phenotypes. Furthermore, smk1 allelic spore phenotypes can be recapitulated by reducing wild-type SMK1 expression. The data demonstrate that SMK1 is required for the execution of multiple steps in spore morphogenesis that require increasing thresholds of SMK1 activity. These results suggest that quantitative changes in mitogen-activated protein kinase signaling play a role in coordinating multiple events of a single cellular differentiation program. PMID- 10101161 TI - Tempo and mode of Ty element evolution in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae genome contains five families of long terminal repeat (LTR) retrotransposons, Ty1-Ty5. The sequencing of the S. cerevisiae genome provides an unprecedented opportunity to examine the patterns of molecular variation existing among the entire genomic complement of Ty retrotransposons. We report the results of an analysis of the nucleotide and amino acid sequence variation within and between the five Ty element families of the S. cerevisiae genome. Our results indicate that individual Ty element families tend to be highly homogenous in both sequence and size variation. Comparisons of within element 5' and 3' LTR sequences indicate that the vast majority of Ty elements have recently transposed. Furthermore, intrafamily Ty sequence comparisons reveal the action of negative selection on Ty element coding sequences. These results taken together suggest that there is a high level of genomic turnover of S. cerevisiae Ty elements, which is presumably in response to selective pressure to escape host-mediated repression and elimination mechanisms. PMID- 10101162 TI - Suppression of a nuclear aep2 mutation in Saccharomyces cerevisiae by a base substitution in the 5'-untranslated region of the mitochondrial oli1 gene encoding subunit 9 of ATP synthase. AB - Mutations in the nuclear AEP2 gene of Saccharomyces generate greatly reduced levels of the mature form of mitochondrial oli1 mRNA, encoding subunit 9 of mitochondrial ATP synthase. A series of mutants was isolated in which the temperature-sensitive phenotype resulting from the aep2-ts1 mutation was suppressed. Three strains were classified as containing a mitochondrial suppressor: these lost the ability to suppress aep2-ts1 when their mitochondrial genome was replaced with wild-type mitochondrial DNA (mtDNA). Many other isolates were classified as containing dominant nuclear suppressors. The three mitochondrion-encoded suppressors were localized to the oli1 region of mtDNA using rho- genetic mapping techniques coupled with PCR analysis; DNA sequencing revealed, in each case, a T-to-C nucleotide transition in mtDNA 16 nucleotides upstream of the oli1 reading frame. It is inferred that the suppressing mutation in the 5' untranslated region of oli1 mRNA restores subunit 9 biosynthesis by accommodating the modified structure of Aep2p generated by the aep2-ts1 mutation (shown here to cause the substitution of proline for leucine at residue 413 of Aep2p). This mode of mitochondrial suppression is contrasted with that mediated by heteroplasmic rearranged rho- mtDNA genomes bypassing the participation of a nuclear gene product in expression of a particular mitochondrial gene. In the present study, direct RNA-protein interactions are likely to form the basis of suppression. PMID- 10101164 TI - Positive selection of novel peroxisome biogenesis-defective mutants of the yeast Pichia pastoris. AB - We have developed two novel schemes for the direct selection of peroxisome biogenesis-defective (pex) mutants of the methylotrophic yeast Pichia pastoris. Both schemes take advantage of our observation that methanol-induced pex mutants contain little or no alcohol oxidase (AOX) activity. AOX is a peroxisomal matrix enzyme that catalyzes the first step in the methanol-utilization pathway. One scheme utilizes allyl alcohol, a compound that is not toxic to cells but is oxidized by AOX to acrolein, a compound that is toxic. Exposure of mutagenized populations of AOX-induced cells to allyl alcohol selectively kills AOX containing cells. However, pex mutants without AOX are able to grow. The second scheme utilizes a P. pastoris strain that is defective in formaldehyde dehydrogenase (FLD), a methanol pathway enzyme required to metabolize formaldehyde, the product of AOX. AOX-induced cells of fld1 strains are sensitive to methanol because of the accumulation of formaldehyde. However, fld1 pex mutants, with little active AOX, do not efficiently oxidize methanol to formaldehyde and therefore are not sensitive to methanol. Using these selections, new pex mutant alleles in previously identified PEX genes have been isolated along with mutants in three previously unidentified PEX groups. PMID- 10101163 TI - Specific components of the SAGA complex are required for Gcn4- and Gcr1-mediated activation of the his4-912delta promoter in Saccharomyces cerevisiae. AB - Mutations selected as suppressors of Ty or solo delta insertion mutations in Saccharomyces cerevisiae have identified several genes, SPT3, SPT7, SPT8, and SPT20, that encode components of the SAGA complex. However, the mechanism by which SAGA activates transcription of specific RNA polymerase II-dependent genes is unknown. We have conducted a fine-structure mutagenesis of one widely used SAGA-dependent promoter, the delta element of his4-912delta, to identify sequence elements important for its promoter activity. Our analysis has characterized three delta regions necessary for full promoter activity and accurate start site selection: an upstream activating sequence, a TATA region, and an initiator region. In addition, we have shown that factors present at the adjacent UASHIS4 (Gcn4, Bas1, and Pho2) also activate the delta promoter in his4-912delta. Our results suggest a model in which the delta promoter in his4-912delta is primarily activated by two factors: Gcr1 acting at the UASdelta and Gcn4 acting at the UASHIS4. Finally, we tested whether activation by either of these factors is dependent on components of the SAGA complex. Our results demonstrate that Spt3 and Spt20 are required for full delta promoter activity, but that Gcn5, another member of SAGA, is not required. Spt3 appears to be partially required for activation of his4-912delta by both Gcr1 and Gcn4. Thus, our work suggests that SAGA exerts a large effect on delta promoter activity through a combination of smaller effects on multiple factors. PMID- 10101165 TI - Host genes that affect the target-site distribution of the yeast retrotransposon Ty1. AB - We report here a simple genetic system for investigating factors affecting Ty1 target-site preference within an RNAP II transcribed gene. The target in this system is a functional fusion of the regulatable MET3 promoter with the URA3 gene. We found that the simultaneous inactivation of Hir3 (a histone transcription regulator) and Cac3 (a subunit of the chromatin assembly factor I), which was previously shown by us to increase the Ty1 transposition rate, eliminated the normally observed bias for Ty1 elements to insert into the 5' vs. 3' regions of the MET3-URA3 and CAN1 genes. The double cac3 hir3 mutation also caused the production of a short transcript from the MET3-URA3 fusion under both repressed and derepressed conditions. In a hir3Delta single-mutant strain, the Ty1 target-site distribution into MET3-URA3 was altered only when transposition occurred while the MET3-URA3 fusion was actively transcribed. In contrast, transcription of the MET3-URA3 fusion did not alter the Ty1 target-site distribution in wild-type or other mutant strains. Deletion of RAD6 was shown to alter the Ty1 target-site preference in the MET3-URA3 fusion and the LYS2 gene. These data, together with previous studies of Ty1 integration positions at CAN1 and SUP4, indicate that the rad6 effect on Ty1 target-site selection is not gene specific. PMID- 10101166 TI - Removal of one nonhomologous DNA end during gene conversion by a RAD1- and MSH2 independent pathway. AB - Repair of a double-strand break (DSB) by homologous recombination depends on the invasion of a 3'-ended strand into an intact template sequence to initiate new DNA synthesis. When the end of the invading DNA is not homologous to the donor, the nonhomologous sequences must be removed before new synthesis can begin. In Saccharomyces cerevisiae, the removal of these ends depends on both the nucleotide excision repair endonuclease Rad1p/Rad10p and the mismatch repair proteins Msh2p/Msh3p. In rad1 or msh2 mutants, when both ends of the DSB have nonhomologous ends, repair is reduced approximately 90-fold compared to a plasmid with perfect ends; however, with only one nonhomologous end, repair is reduced on average only 5-fold. These results suggest that yeast has an alternative, but less efficient, way to remove a nonhomologous tail from the second end participating in gene conversion. When the removal of one nonhomologous end is impaired in rad1 and msh2 mutants, there is also a 1-hr delay in the appearance of crossover products of gene conversion, compared to noncrossovers. We interpret these results in terms of the formation and resolution of alternative intermediates of a synthesis-dependent strand annealing mechanism. PMID- 10101167 TI - Relative dependence of different outputs of the Saccharomyces cerevisiae pheromone response pathway on the MAP kinase Fus3p. AB - Fus3p and Kss1p act at the end of a conserved signaling cascade that mediates numerous cellular responses for mating. To determine the role of Fus3p in different outputs, we isolated and characterized a series of partial-function fus3 point mutants for their ability to phosphorylate a substrate (Ste7p), activate Ste12p, undergo G1 arrest, form shmoos, select partners, mate, and recover. All the mutations lie in residues that are conserved among MAP kinases and are predicted to affect either enzyme activity or binding to Ste7p or substrates. The data argue that Fus3p regulates the various outputs assayed through the phosphorylation of multiple substrates. Different levels of Fus3p function are required for individual outputs, with the most function required for shmoo formation, the terminal output. The ability of Fus3p to promote shmoo formation strongly correlates with its ability to promote G1 arrest, suggesting that the two events are coupled. Fus3p promotes recovery through a mechanism that is distinct from its ability to promote G1 arrest and may involve a mechanism that does not require kinase activity. Moreover, catalytically inactive Fus3p inhibits the ability of active Fus3p to activate Ste12p and hastens recovery without blocking G1 arrest or shmoo formation. These results raise the possibility that in the absence of sustained activation of Fus3p, catalytically inactive Fus3p blocks further differentiation by restoring mitotic growth. Finally, suppression analysis argues that Kss1p contributes to the overall pheromone response in a wild-type strain, but that Fus3p is the critical kinase for all of the outputs tested. PMID- 10101168 TI - The role of nucleotide binding and hydrolysis in the function of the fission yeast cdc18(+) gene product. AB - The fission yeast cdc18(+) gene is required for both initiation of DNA replication and the mitotic checkpoint that normally inhibits mitosis in the absence of DNA replication. The cdc18(+) gene product contains conserved Walker A and B box motifs. Studies of other ATPases have shown that these motifs are required for nucleotide binding and hydrolysis, respectively. We have observed that mutant strains in which either of these motifs is disrupted are inviable. The effects of these mutations were examined by determining the phenotypes of mutant strains following depletion of complementing wild-type Cdc18. In both synchronous and asynchronous cultures, the nucleotide-hydrolysis motif mutant (DE286AA) arrests with a 1C-2C DNA content, and thus exhibits no obvious defects in entry into S phase or in the mitotic checkpoint. In contrast, in cultures synchronized by hydroxyurea arrest and release, the nucleotide-binding motif mutant (K205A) exhibits the null phenotype, with 1C and <1C DNA content, indicating a block in entry into S phase and loss of checkpoint control. In asynchronous cultures this mutant exhibits a mixed phenotype: a percentage of the population displays the null phenotype, while the remaining fraction arrests with a 2C DNA content. Thus, the phenotype exhibited by the K205A mutant is dependent on the cell-cycle position at which wild-type Cdc18 is depleted. These data indicate that both nucleotide binding and hydrolysis are required for Cdc18 function. In addition, the difference in the phenotypes exhibited by the nucleotide-binding and hydrolysis motif mutants is consistent with a two-step model for Cdc18 function in which nucleotide binding and hydrolysis are required for distinct aspects of Cdc18 function that may be executed at different points in the cell cycle. PMID- 10101169 TI - Dna2 mutants reveal interactions with Dna polymerase alpha and Ctf4, a Pol alpha accessory factor, and show that full Dna2 helicase activity is not essential for growth. AB - Mutations in the gene for the conserved, essential nuclease-helicase Dna2 from the yeast Saccharomyces cerevisiae were found to interact genetically with POL1 and CTF4, which encode a DNA Polymerase alpha subunit and an associated protein, suggesting that Dna2 acts in a process that involves Pol alpha. DNA2 alleles were isolated that cause either temperature sensitivity, sensitivity to alkylation damage, or both. The alkylation-sensitive alleles clustered in the helicase domain, including changes in residues required for helicase activity in related proteins. Additional mutations known or expected to destroy the ATPase and helicase activities of Dna2 were constructed and found to support growth on some media but to cause alkylation sensitivity. Only damage-sensitive alleles were lethal in combination with a ctf4 deletion. Full activity of the Dna2 helicase function is therefore not needed for viability, but is required for repairing damage and for tolerating loss of Ctf4. Arrest of dna2 mutants was RAD9 dependent, but deleting this checkpoint resulted in either no effect or suppression of defects, including the synthetic lethality with ctf4. Dna2 therefore appears to act in repair or lagging strand synthesis together with Pol alpha and Ctf4, in a role that is optimal with, but does not require, full helicase activity. PMID- 10101170 TI - The relationship between DNA methylation and chromosome imprinting in the coccid Planococcus citri. AB - The phenomenon of chromosome, or genomic, imprinting indicates the relevance of parental origin in determining functional differences between alleles, homologous chromosomes, or haploid sets. In mealybug males (Homoptera, Coccoidea), the haploid set of paternal origin undergoes heterochromatization at midcleavage and remains so in most of the tissues. This different behavior of the two haploid sets, which depends on their parental origin, represents one of the most striking examples of chromosome imprinting. In mammals, DNA methylation has been postulated as a possible molecular mechanism to differentially imprint DNA sequences during spermatogenesis or oogenesis. In the present article we addressed the role of DNA methylation in the imprinting of whole haploid sets as it occurs in Coccids. We investigated the DNA methylation patterns at both the molecular and chromosomal level in the mealybug Planococcus citri. We found that in both males and females the paternally derived haploid set is hypomethylated with respect to the maternally derived one. Therefore, in males, it is the paternally derived hypomethylated haploid set that is heterochromatized. Our data suggest that the two haploid sets are imprinted by parent-of-origin-specific DNA methylation with no correlation with the known gene-silencing properties of this base modification. PMID- 10101171 TI - The posterior determinant gene nanos is required for the maintenance of the adult germline stem cells during Drosophila oogenesis. AB - In a variety of tissues in eukaryotes, multipotential stem cells are responsible for maintaining a germinal population and generating a differentiated progeny. The Drosophila germline is one such tissue where a continuous supply of eggs or sperm relies on the normal functioning of stem cells. Recent studies have implicated a possible role for the posterior determinant gene nanos (nos) in stem cells. Here, I report that nanos is required in the Drosophila female germline as well as in the male germline. In the female, nos is required for the functioning of stem cells. In nos mutants, while the stem cells are specified, these cells divide only a few times at the most and then degenerate. The loss of germline stem cells in nos mutant mothers appears to be due to a progressive degeneration of the plasma membrane. Furthermore, following germ cell loss, the germaria in the nos mutant mothers appear to carry on massive mitochondrial biogenesis activity. Thus, the syncytia of such germaria are filled with mitochondria. In the male germline, the male fertility assay indicates that nos appears to be also required for the maintenance of stem cells. In these mutant males, spermatogenesis is progressively affected and these males eventually become sterile. These results indicate novel requirements for nos in the Drosophila germline. PMID- 10101172 TI - Desiccation resistance in interspecific Drosophila crosses. Genetic interactions and trait correlations. AB - We used crosses between two closely related Drosophila species, Drosophila serrata and D. birchii, to examine the genetic basis of desiccation resistance and correlations between resistance, physiological traits, and life-history traits. D. serrata is more resistant to desiccation than D. birchii, and this may help to explain the broader geographical range of the former species. A comparison of F2's from reciprocal crosses indicated higher resistance levels when F2's originated from D. birchii mothers compared to D. serrata mothers. However, backcrosses had a resistance level similar to that of the parental species, suggesting an interaction between X-linked effects in D. serrata that reduce resistance and autosomal effects that increase resistance. Reciprocal differences persisted in hybrid lines set up from the different reciprocal crosses and tested at later generations. Increased desiccation resistance was associated with an increased body size in two sets of hybrid lines and in half sib groups set up from the F4's after crossing the two species, but size associations were inconsistent in the F2's. None of the crosses provided evidence for a positive association between desiccation resistance and glycogen levels, or evidence for a tradeoff between desiccation resistance and early fecundity. However, fecundity was positively correlated with body size at both the genetic and phenotypic levels. This study illustrates how interspecific crosses may provide information on genetic interactions between traits following adaptive divergence, as well as on the genetic basis of the traits. PMID- 10101173 TI - Genomic imprinting and position-effect variegation in Drosophila melanogaster. AB - Genomic imprinting is a phenomenon in which the expression of a gene or chromosomal region depends on the sex of the individual transmitting it. The term imprinting was first coined to describe parent-specific chromosome behavior in the dipteran insect Sciara and has since been described in many organisms, including other insects, plants, fish, and mammals. In this article we describe a mini-X chromosome in Drosophila melanogaster that shows genomic imprinting of at least three closely linked genes. The imprinting of these genes is observed as mosaic silencing when the genes are transmitted by the male parent, in contrast to essentially wild-type expression when the same genes are maternally transmitted. We show that the imprint is due to the sex of the parent rather than to a conventional maternal effect, differential mitotic instability of the mini-X chromosome, or an allele-specific effect. Finally, we have examined the effects of classical modifiers of position-effect variegation on the maintenance and the establishment of the imprint. Factors that modify position-effect variegation alter the somatic expression but not the establishment of the imprint. This suggests that chromatin structure is important in maintenance of the imprint, but a separate mechanism may be responsible for its initiation. PMID- 10101174 TI - Trans-acting factors required for inclusion of regulated exons in the Ultrabithorax mRNAs of Drosophila melanogaster. AB - Alternatively spliced Ultrabithorax mRNAs differ by the presence of internal exons mI and mII. Two approaches were used to identify trans-acting factors required for inclusion of these cassette exons. First, mutations in a set of genes implicated in the control of other alternative splicing decisions were tested for dominant effects on the Ubx alternative splicing pattern. To identify additional genes involved in regulation of Ubx splicing, a large collection of deficiencies was tested first for dominant enhancement of the haploinsufficient Ubx haltere phenotype and second for effects on the splicing pattern. Inclusion of the cassette exons in Ubx mRNAs was reduced strongly in heterozygotes for hypomorphic alleles of hrp48, which encodes a member of the hnRNP A/B family and is implicated in control of P-element splicing. Significant reductions of mI and mII inclusion were also observed in heterozygotes for loss-of-function alleles of virilizer, fl(2)d, and crooked neck. The products of virilizer and fl(2)d are also required for Sxl autoregulation at the level of splicing; crooked neck encodes a protein with structural similarities to yeast-splicing factors Prp39p and Prp42p. Deletion of at least five other loci caused significant reductions in the inclusion of mI and/or mII. Possible roles of identified factors are discussed in the context of the resplicing strategy for generation of alternative Ubx mRNAs. PMID- 10101175 TI - Preservation of duplicate genes by complementary, degenerative mutations. AB - The origin of organismal complexity is generally thought to be tightly coupled to the evolution of new gene functions arising subsequent to gene duplication. Under the classical model for the evolution of duplicate genes, one member of the duplicated pair usually degenerates within a few million years by accumulating deleterious mutations, while the other duplicate retains the original function. This model further predicts that on rare occasions, one duplicate may acquire a new adaptive function, resulting in the preservation of both members of the pair, one with the new function and the other retaining the old. However, empirical data suggest that a much greater proportion of gene duplicates is preserved than predicted by the classical model. Here we present a new conceptual framework for understanding the evolution of duplicate genes that may help explain this conundrum. Focusing on the regulatory complexity of eukaryotic genes, we show how complementary degenerative mutations in different regulatory elements of duplicated genes can facilitate the preservation of both duplicates, thereby increasing long-term opportunities for the evolution of new gene functions. The duplication-degeneration-complementation (DDC) model predicts that (1) degenerative mutations in regulatory elements can increase rather than reduce the probability of duplicate gene preservation and (2) the usual mechanism of duplicate gene preservation is the partitioning of ancestral functions rather than the evolution of new functions. We present several examples (including analysis of a new engrailed gene in zebrafish) that appear to be consistent with the DDC model, and we suggest several analytical and experimental approaches for determining whether the complementary loss of gene subfunctions or the acquisition of novel functions are likely to be the primary mechanisms for the preservation of gene duplicates. For a newly duplicated paralog, survival depends on the outcome of the race between entropic decay and chance acquisition of an advantageous regulatory mutation. Sidow 1996(p. 717) On one hand, it may fix an advantageous allele giving it a slightly different, and selectable, function from its original copy. This initial fixation provides substantial protection against future fixation of null mutations, allowing additional mutations to accumulate that refine functional differentiation. Alternatively, a duplicate locus can instead first fix a null allele, becoming a pseudogene. Walsh 1995 (p. 426) Duplicated genes persist only if mutations create new and essential protein functions, an event that is predicted to occur rarely. Nadeau and Sankoff 1997 (p. 1259) Thus overall, with complex metazoans, the major mechanism for retention of ancient gene duplicates would appear to have been the acquisition of novel expression sites for developmental genes, with its accompanying opportunity for new gene roles underlying the progressive extension of development itself. Cooke et al. 1997 (p. 362) PMID- 10101176 TI - High polymorphism at the human melanocortin 1 receptor locus. AB - Variation in human skin/hair pigmentation is due to varied amounts of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of eu- and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many mammals. We have sequenced the MC1R gene in 121 individuals sampled from world populations with an emphasis on Asian populations. We found variation at five nonsynonymous sites (resulting in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). Interestingly, the human consensus protein sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency (7%) in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. The MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon was sequenced to study the evolution of MC1R. The ancestral human MC1R sequence is identical to the human consensus protein sequence, while MC1R varies considerably among higher primates. A comparison of the rates of substitution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest. In addition, the nucleotide diversity at the MC1R locus is shown to be several times higher than the average nucleotide diversity in human populations, possibly due to diversifying selection. PMID- 10101177 TI - Suppression of intrachromosomal gene conversion in mammalian cells by small degrees of sequence divergence. AB - Pairs of closely linked defective herpes simplex virus (HSV) thymidine kinase (tk) gene sequences exhibiting various nucleotide heterologies were introduced into the genome of mouse Ltk- cells. Recombination events were recovered by selecting for the correction of a 16-bp insertion mutation in one of the tk sequences. We had previously shown that when two tk sequences shared a region of 232 bp of homology, interruption of the homology by two single nucleotide heterologies placed 19 bp apart reduced recombination nearly 20-fold. We now report that either one of the nucleotide heterologies alone reduces recombination only about 2.5-fold, indicating that the original pair of single nucleotide heterologies acted synergistically to inhibit recombination. We tested a variety of pairs of single nucleotide heterologies and determined that they reduced recombination from 7- to 175-fold. Substrates potentially leading to G-G or C-C mispairs in presumptive heteroduplex DNA (hDNA) intermediates displayed a particularly low rate of recombination. Additional experiments suggested that increased sequence divergence causes a shortening of gene conversion tracts. Collectively, our results suggest that suppression of recombination between diverged sequences is mediated via processing of a mispaired hDNA intermediate. PMID- 10101178 TI - Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. AB - We have used immunofluorescent localization to examine the distribution of MLH1 (MutL homolog) foci on synaptonemal complexes (SCs) from juvenile male mice. MLH1 is a mismatch repair protein necessary for meiotic recombination in mice, and MLH1 foci have been proposed to mark crossover sites. We present evidence that the number and distribution of MLH1 foci on SCs closely correspond to the number and distribution of chiasmata on diplotene-metaphase I chromosomes. MLH1 foci were typically excluded from SC in centromeric heterochromatin. For SCs with one MLH1 focus, most foci were located near the middle of long SCs, but near the distal end of short SCs. For SCs with two MLH1 foci, the distribution of foci was bimodal regardless of SC length, with most foci located near the proximal and distal ends. The distribution of MLH1 foci indicated interference between foci. We observed a consistent relative distance (percent of SC length in euchromatin) between two foci on SCs of different lengths, suggesting that positive interference between MLH1 foci is a function of relative SC length. The extended length of pachytene SCs, as compared to more condensed diplotene-metaphase I bivalents, makes mapping crossover events and interference distances using MLH1 foci more accurate than using chiasmata. PMID- 10101179 TI - A new Ac-like transposon of Arabidopsis is associated with a deletion of the RPS5 disease resistance gene. AB - The RPS5 and RFL1 disease resistance genes of Arabidopsis ecotype Col-0 are oriented in tandem and are separated by 1.4 kb. The Ler-0 ecotype contains RFL1, but lacks RPS5. Sequence analysis of the RPS5 deletion region in Ler-0 revealed the presence of an Ac-like transposable element, which we have designated Tag2. Southern hybridization analysis of six Arabidopsis ecotypes revealed 4-11 Tag2 homologous sequences in each, indicating that this element is ubiquitous in Arabidopsis and has been active in recent evolutionary time. The Tag2 insertion adjacent to RFL1 was unique to the Ler-0 ecotype, however, and was not present in two other ecotypes that lack RPS5. DNA sequence from the latter ecotypes lacked a transposon footprint, suggesting that insertion of Tag2 occurred after the initial deletion of RPS5. The deletion breakpoint contained a 192-bp insertion that displayed hallmarks of a nonhomologous DNA end-joining event. We conclude that loss of RPS5 was caused by a double-strand break and subsequent repair, and cannot be attributed to unequal crossing over between resistance gene homologs. PMID- 10101180 TI - Allele-specific interactions between ttg and gl1 during trichome development in Arabidopsis thaliana. AB - Trichome development in Arabidopsis thaliana is a well-characterized model for the study of plant cell differentiation. Two genes that play an essential role in the initiation of trichome development are GL1 and TTG. Mutations in either gene prevent the initiation of most trichomes. The GL1 gene encodes a myb-related transcription factor. Mutations in TTG are pleiotropic, affecting anthocyanins, root hairs, and seed coat mucilage in addition to trichomes. Six ttg alleles were examined and shown to form a hypomorphic series. The severity of all aspects of the ttg phenotype varied in parallel in this allelic series. The weakest allele, ttg-10, causes frequent clusters of adjacent trichomes, suggesting a role for TTG in inhibiting neighboring cells from choosing the trichome fate. This allele results from a mutation in the 5'-untranslated region of ttg and creates an out of-frame upstream AUG codon. The ttg-10 allele shows several unusual genetic interactions with the weak hypomorphic gl1-2 allele, including intergenic noncomplementation and a synthetic glabrous phenotype. These interactions are specific for the gl1-2 allele. The implication of these results for current models of trichome development is discussed. PMID- 10101181 TI - Bayesian mapping of multiple quantitative trait loci from incomplete outbred offspring data. AB - A general fine-scale Bayesian quantitative trait locus (QTL) mapping method for outcrossing species is presented. It is suitable for an analysis of complete and incomplete data from experimental designs of F2 families or backcrosses. The amount of genotyping of parents and grandparents is optional, as well as the assumption that the QTL alleles in the crossed lines are fixed. Grandparental origin indicators are used, but without forgetting the original genotype or allelic origin information. The method treats the number of QTL in the analyzed chromosome as a random variable and allows some QTL effects from other chromosomes to be taken into account in a composite interval mapping manner. A block-update of ordered genotypes (haplotypes) of the whole family is sampled once in each marker locus during every round of the Markov Chain Monte Carlo algorithm used in the numerical estimation. As a byproduct, the method gives the posterior distributions for linkage phases in the family and therefore it can also be used as a haplotyping algorithm. The Bayesian method is tested and compared with two frequentist methods using simulated data sets, considering two different parental crosses and three different levels of available parental information. The method is implemented as a software package and is freely available under the name Multimapper/outbred at URL http://www.rni.helsinki.fi/mjs/. PMID- 10101182 TI - Beneficial mutations, hitchhiking and the evolution of mutation rates in sexual populations. AB - Natural selection acts in three ways on heritable variation for mutation rates. A modifier allele that increases the mutation rate is (i) disfavored due to association with deleterious mutations, but is also favored due to (ii) association with beneficial mutations and (iii) the reduced costs of lower fidelity replication. When a unique beneficial mutation arises and sweeps to fixation, genetic hitchhiking may cause a substantial change in the frequency of a modifier of mutation rate. In previous studies of the evolution of mutation rates in sexual populations, this effect has been underestimated. This article models the long-term effect of a series of such hitchhiking events and determines the resulting strength of indirect selection on the modifier. This is compared to the indirect selection due to deleterious mutations, when both types of mutations are randomly scattered over a given genetic map. Relative to an asexual population, increased levels of recombination reduce the effects of beneficial mutations more rapidly than those of deleterious mutations. However, the role of beneficial mutations in determining the evolutionarily stable mutation rate may still be significant if the function describing the cost of high-fidelity replication has a shallow gradient. PMID- 10101183 TI - Animal mitochondrial genomes. AB - Animal mitochondrial DNA is a small, extrachromosomal genome, typically approximately 16 kb in size. With few exceptions, all animal mitochondrial genomes contain the same 37 genes: two for rRNAs, 13 for proteins and 22 for tRNAs. The products of these genes, along with RNAs and proteins imported from the cytoplasm, endow mitochondria with their own systems for DNA replication, transcription, mRNA processing and translation of proteins. The study of these genomes as they function in mitochondrial systems-'mitochondrial genomics'-serves as a model for genome evolution. Furthermore, the comparison of animal mitochondrial gene arrangements has become a very powerful means for inferring ancient evolutionary relationships, since rearrangements appear to be unique, generally rare events that are unlikely to arise independently in separate evolutionary lineages. Complete mitochondrial gene arrangements have been published for 58 chordate species and 29 non-chordate species, and partial arrangements for hundreds of other taxa. This review compares and summarizes these gene arrangements and points out some of the questions that may be addressed by comparing mitochondrial systems. PMID- 10101184 TI - Barminomycin forms GC-specific adducts and virtual interstrand crosslinks with DNA. AB - The sequence specificity of the binding of barminomycin (SN-07 chromophore) to DNA was investigated using an in vitro transcription assay. It was found that this compound formed blockages to transcription, and these blocks were highly selective for 5'-GC sequences. The half-lives of the first seven transcriptional blockages at 37 degrees C were 14-130 min, plus one site >>200 min, with widely varying levels of essentially permanent blockages at each site (0-100%; average of 40%), indicative of considerable dependence on flanking sequences of adducts stability at individual GC sites. Barminomycin was also shown to form DNA virtual (i.e. functional) interstrand crosslinks. Such crosslinks were also relatively heat stable, with 40% of the DNA remaining crosslinked after heating at 90 degrees C for 5 min. The barminomycin-DNA adducts and crosslinks appear to be essentially identical to those formed between adriamycin and DNA. Whereas adriamycin requires prior activation with formaldehyde in order to form adducts and crosslinks, barminomycin behaves in all respects as if it is a pre-activated form of adriamycin. PMID- 10101185 TI - Synthesis of 5-substituted 2'-deoxycytidine 5'-(alpha-P-borano)triphosphates, their incorporationinto DNA and effects on exonuclease. AB - Direct PCR sequencing with boronated nucleotides provides an alternative to current PCR sequencing methods. The positions of boranophosphate-modified nucleotides incorporated randomly into DNA during PCR can be revealed directly by exonuclease digestion to give sequencing ladders. Cytosine nucleotides, however, are especially sensitive to exonuclease digestion and provide suboptimal sequencing ladders. Therefore, a series of 5-substituted analogs of 2' deoxycytidine 5'-(alpha-P-borano)triphosphates (dCTPalphaB) were synthesized with the hope of increasing the nuclease resistance of deoxycytosine residues and thereby enhancing the deoxycytosine band intensities. These dCTP analogs contain a boranophosphate modification at the alpha-phosphate group in 2'-deoxycytidine 5'-triphosphate (dCTP) as well as a 5-methyl, 5-ethyl, 5-bromo or 5-iodo substitution for the 5-hydrogen of cytosine. The two diastereomers of each new dCTP derivative were separated by reverse phase HPLC. The first eluted diastereomer (putatively Rp) of each dCTP analog was a substrate for T7 DNA polymerase (Sequenase) and had an incorporation efficiency similar to normal dCTP and dCTPalphaB, with the 5-iodo-dCTPalphaB analog being the least efficient. Substitution at the C-5 position of cytosine by alkyl groups (ethyl and methyl) markedly enhanced the dCTPalphaB resistance towards exonuclease III (5-Et dCTPalphaB >5-Me-dCTPalphaB >dCTPalphaB approximately 5-Br-dCTPalphaB >5-I dCTPalphaB), thereby generating DNA sequences that better define the deoxycytosine positions. The introduction of modified dCTPalphaB should increase the utility of direct DNA sequencing with boronated nucleoside 5'-triphosphates. PMID- 10101186 TI - Identification and characterisation of the Drosophila melanogaster O6 alkylguanine-DNA alkyltransferase cDNA. AB - The protein O 6-alkylguanine-DNA alkyltransferase(alkyltransferase) is involved in the repair of O 6-alkylguanine and O 4-alkylthymine in DNA and plays an important role in most organisms in attenuating the cytotoxic and mutagenic effects of certain classes of alkylating agents. A genomic clone encompassing the Drosophila melanogaster alkyltransferase gene ( DmAGT ) was identified on the basis of sequence homology with corresponding genes in Saccharomyces cerevisiae and man. The DmAGT gene is located at position 84A on the third chromosome. The nucleotide sequence of DmAGT cDNA revealed an open reading frame encoding 194 amino acids. The MNNG-hypersensitive phenotype of alkyltransferase-deficient bacteria was rescued by expression of the DmAGT cDNA. Furthermore, alkyltransferase activity was identified in crude extracts of Escherichia coli harbouring DmAGT cDNA and this activity was inhibited by preincubation of the extract with an oligonucleotide containing a single O6-methylguanine lesion. Similar to E.coli Ogt and yeast alkyltransferase but in contrast to the human alkyltransferase, the Drosophila alkyltransferase is resistant to inactivation by O 6-benzylguanine. In an E.coli lac Z reversion assay, expression of DmAGT efficiently suppressed MNNG-induced G:C-->A:T as well as A:T-->G:C transition mutations in vivo. These results demonstrate the presence of an alkyltransferase specific for the repair of O 6-methylguanine and O 4-methylthymine in Drosophila. PMID- 10101187 TI - 5-(1-propargylamino)-2'-deoxyuridine (UP): a novel thymidine analogue for generating DNA triplexes with increased stability. AB - We have used quantitative DNase I footprinting and UV-melting studies to examine the formation of DNA triplexes in which the third strand thymines have been replaced by 5-propargylamino-dU (UP). The intra-molecular triplex A6-L-T6-L (UP)5T (L = two octanediol residues) shows a single UV-melting transition which is >20 degrees higher than that of the parent triplex A6-L-T6-L-T6at pH 5.5. Although a single transition is observed at all pHs, the melting temperature (Tm) of the modified oligonucleotide decreases at higher pHs, consistent with the requirement for protonation of the amino group. A similar intramolecular triplex with a longer overhanging duplex shows two melting transitions, the lower of which is stabilised by substitution of T by UP, in a pH dependent fashion. Triplex stability increases by approximately 12 K for each T to UP substitution. Quantitative footprinting studies have examined the interaction of three UP containing 9mer oligonucleotides with the different portions of the 17mer sequence 5'-AGGAAGAGAAAAAAGAA. At pH 5.0, the UP-containing oligo-nucleotides footprint to much lower concentrations than their T-containing counterparts. In particular (UP)6CUPT binds approximately 1000-fold more tightly than the unmodified oligonucleotide T6CTT. Oligonucleotides containing fewer UP residues are stabilised to a lesser extent. The affinity of these modified third strands decreases at higher pHs. These results demonstrate that the stability of DNA triplexes can be dramatically increased by using positively charged analogues of thymine. PMID- 10101188 TI - Nucleotide analogs facilitate base conversion with 3' mismatch primers. AB - We compared the efficiency of PCR amplification using primers containing either a nucleotide analog or a mismatch at the 3' base. To determine the distribution of bases inserted opposite eight different analogs, 3' analog primers were used to amplify four different templates. The products from the reactions with the highest amplification efficiency were sequenced. Analogs allowing efficient amplification followed by insertion of a new base at that position are herein termed 'convertides'. The three convertides with the highest amplification efficiency were used to convert sequences containing C, T, G and A bases into products containing the respective three remaining bases. Nine templates were used to generate conversion products, as well as non-conversion control products with no base change. We compared the ability of natural bases to convert specific sites with and without a preconversion step using nucleotide analog primers. Conversion products were identified by a ligation detection reaction using primers specific for the converted sequence. We found that conversions resulting in transitions were easier to accomplish than transversions and that sequence context influences conversion. Specifically, primer slippage appears to be an important mechanism for producing artifacts via polymerase extension of a 3' base or analog transiently base paired to neighboring bases of the template. Nucleotide analogs could often reduce conversion artifacts and increase the yield of the expected product. While new analogs are needed to reliably achieve transversions, the current set have proven effective for creating transition conversions. PMID- 10101189 TI - Nucleotide analogs and new buffers improve a generalized method to enrich for low abundance mutations. AB - A high sensitivity method for detecting low level mutations is under development. A PCR reaction is performed in which a restriction site is introduced in wild type DNA by alteration of specific bases. Digestion of wild-type DNA by the cognate restriction endonuclease (RE) enriches for products with mutations within the recognition site. After reamplification, mutations are identified by a ligation detection reaction (LDR). This PCR/RE/LDR assay was initially used to detect PCR error in known wild-type samples. PCR error was measured in low |Deltap K a| buffers containing tricine, EPPS and citrate, as well as otherwise identical buffers containing Tris. PCR conditions were optimized to minimize PCR error using perfect match primers at the Msp I site in the p53 tumor suppressor gene at codon 248. However, since mutations do not always occur within pre existing restriction sites, a generalized PCR/RE/LDR method requires the introduction of a new restriction site. In principle, PCR with mismatch primers can alter specific bases in a sequence and generate a new restriction site. However, extension from 3' mismatch primers may generate misextension products. We tested conversion of the Msp I (CCGG) site to a Taq I site (TCGA). Conversion was unsuccessful using a natural base T mismatch primer set. Conversion was successful when modified primers containing the 6 H,8 H -3, 4-dihydropyrimido[4,5 c ][1,2]oxazine-7-one (Q6) base at 3'-ends were used in three cycles of preconversion PCR prior to conversion PCR using the 3' natural base T primers. The ability of the pyrimidine analog Q6 to access both a T-like and C-like tautomer appears to greatly facilitate the conversion. PMID- 10101190 TI - Tissue-specific translational regulation of alternative rabbit 15-lipoxygenase mRNAs differing in their 3'-untranslated regions. AB - By screening a rabbit reticulocyte library, an alternative 15-LOX transcript of 3.6 kb (15-LOX mRNA2) was detected containing a 1019 nt longer 3'-untranslated region (UTR2) than the main 2.6 kb mRNA (15-LOX mRNA1). In anaemic animals, northern blotting showed that 15-LOX mRNA2 was predominantly expressed in non erythroid tissues, whereas 15-LOX mRNA1 was exclusively expressed in red blood cells and bone marrow. The 15-LOX 3'-UTR2 mRNA2 contained a novel 8-fold repetitive CU-rich motif, 23 nt in length (DICE2). This motif is related but not identical to the 10-fold repetitive differentiation control element (DICE1) of 19 nt residing in the 15-LOX UTR1 mRNA1. DICE1 was shown to interact with human hnRNP proteins E1 and K, thereby inhibiting translation. From tissues expressing the long 15-LOX mRNA2, two to three unidentified polypeptides with molecular weights of 53-55 and 90-93 kDa which bound to DICE2 were isolated by RNA affinity chromatography. A 93 kDa protein from lung cytosol, which was selected by DICE2 binding, was able to suppress translational inhibition of 15-LOX mRNA2, but not of 15-LOX mRNA1, by hnRNP E1. A possible interaction between DICE1/DICE2 cis / trans factors in translational control of 15-LOX synthesis is discussed. Furthermore, the 3'-terminal part of the highly related rabbit leukocyte-type 12 LOX gene was analysed. Very similar repetitive CU-rich elements of the type DICE1 (20 repeats) and DICE2 (nine repeats) were found in the part corresponding to the 3'-UTR of the mRNA. PMID- 10101191 TI - Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: hydration at the platinated site. AB - cis-diamminedichloroplatinum (II) (cisplatin) is a powerful anti-tumor drug whose target is cellular DNA. In the reaction between DNA and cisplatin, covalent intrastrand and interstrand cross-links (ICL) are formed. Two solution structures of the ICL have been published recently. In both models the double-helix is bent and unwound but with significantly different angle values. We solved the crystal structure at 100K of a double-stranded DNA decamer containing a single cisplatin ICL, using the anomalous scattering (MAD) of platinum as a unique source of phase information. We found 47 degrees for double-helix bending and 70 degrees for unwinding in agreement with previous electrophoretic assays. The crystals are stabilized by intermolecular contacts involving two cytosines extruded from the double-helix, one of which makes a triplet with a terminal G.C pair. The platinum coordination is nearly square and the platinum residue is embedded into a cage of nine water molecules linked to the cross-linked guanines, to the two amine groups, and to the phosphodiester backbone through other water molecules. This water molecule organization is discussed in relation with the chemical stability of the ICL. PMID- 10101192 TI - Comparative study of overlapping genes in the genomes of Mycoplasma genitalium and Mycoplasma pneumoniae. AB - Overlapping genes are defined, in this paper, as a pair of adjacent genes whose coding regions are partly overlapping. We systematically analyzed all overlapping genes in the genomes of two closely related species: Mycoplasma genitalium and Mycoplasma pneumoniae. Careful comparisons were made for homologous genes that are overlapped in one species but not in the other. This comparative analysis allows us to propose a model of how overlapping genes emerged in the course of evolution. It was found that overlapping genes were generated primarily due to the loss of a stop codon in either gene, in many cases, the absence of which resulted in elongation of the 3' end of the gene's coding region. More specifically, the loss of the stop codon took place as a result of the following events: deletion of the stop codon (64.4%), point mutation at the stop codon (4.4%), and frame shift at the end of the coding region (6.7%). Overlapping genes, in a sense, can be thought of as the results of evolutionary pressure to minimize genome size. However, our analysis indicates that many overlapping genes, at least in the genomes of M.genitalium and M.pneumoniae, are due to incidental elongation of the coding regions. PMID- 10101193 TI - Damage increases the flexibility of duplex DNA. AB - It is proposed that much of the recognition of specific types of damaged DNAs is based on accessible structural features, while much of the recognition of damaged DNAs, as a class, is based on flexibility. The more flexible a DNA the faster its diffusion rate. The diffusion rates of each member of a series of damaged duplex DNAs has been found to be significantly faster than that of the corresponding undamaged duplex DNA. The damaged sites studied include apurinic and apyrimidinic a basic sites, thymine glycol and urea. The presence of mismatched sites also increases the diffusion. Thus, damaged DNAs appear to have sufficient flexibility for recognition and the flexibility may allow damaged sites to act as a universal joint or hinge that allows distant sites on the DNA to come together. PMID- 10101194 TI - A conserved motif in group IC3 introns is a new class of GNRA receptor. AB - Terminal tetraloops consisting of GNRA sequences are often found in biologically active large RNAs. The loops appear to contribute towards the organization of higher order RNA structures by forming specific tertiary interactions with their receptors. Group IC3 introns which possess a GAAA loop in the L2 region often have a phylogenetically conserved motif in their P8 domains. In this report, we show that this conserved motif stands as a new class of receptor that distinguishes the sequences of GNRA loops less stringently than previously known receptors. The motif can functionally substitute an 11 nt motif receptor in the Tetrahymena ribozyme. Its structural and functional similarity to one class of synthetic receptors obtained from in vitro selection is observed. PMID- 10101195 TI - Reactivity of potassium permanganate and tetraethylammonium chloride with mismatched bases and a simple mutation detection protocol. AB - Many mutation detection techniques rely upon recognition of mismatched base pairs in DNA hetero-duplexes. Potassium permanganate in combination with tetraethylammonium chloride (TEAC) is capable of chemically modifying mismatched thymidine residues. The DNA strand can then be cleaved at that point by treatment with piperidine. The reactivity of potassium permanganate (KMnO4) in TEAC toward mismatches was investigated in 29 different mutations, representing 58 mismatched base pairs and 116 mismatched bases. All mismatched thymidine residues were modified by KMnO4/TEAC with the majority of these showing strong reactivity. KMnO4/TEAC was also able to modify many mismatched guanosine and cytidine residues, as well as matched guanosine, cytidine and thymidine residues adjacent to, or nearby, mismatched base pairs. Previous techniques using osmium tetroxide (OsO4) to modify mismatched thymidine residues have been limited by the apparent lack of reactivity of a third of all T/G mismatches. KMnO4/TEAC showed no such phenomenon. In this series, all 29 mutations were detected by KMnO4/TEAC treatment. The latest development of the Single Tube Chemical Cleavage of Mismatch Method detects both thymidine and cytidine mismatches by KMnO4/TEAC and hydroxylamine (NH2OH) in a single tube without a clean-up step in between the two reactions. This technique saves time and material without disrupting the sensitivity and efficiency of either reaction. PMID- 10101196 TI - A yeast-based bioassay for the determination of functional and non-functional estrogen receptors. AB - The response to endocrine therapy of breast cancer is not entirely predictable from hormone receptor status alone since some point mutated or splicing variants of the estrogen receptor (ER) show altered biological activities. In order to characterize the activities of all forms of ER in a heterogeneous breast tumor, a functional assay in Saccharomyces cerevisiae was developed. Total RNA isolated from breast cancer cells and one breast cancer specimen was reverse transcribed and the ER cDNA was amplified by PCR. The products were then cloned into an expression vector by in vivo homologous recombination in yeast. The yeast strain carries a reporter gene ( ADE2 ) coupled to an estrogen response element. Activation of the reporter by ER yielded white colonies whereas lack of ER activity produced red colonies. This permitted the testing for functionality of individual ER molecules and subsequent analysis by rescuing of the ER expression plasmids and complete DNA sequencing. This simple visual test allows discrimination between wild-type ER, constitutively active ER and inactive ER. PMID- 10101197 TI - Filamentous phage replication initiator protein gpII forms a covalent complex with the 5' end of the nick it introduced. AB - Rolling circle type DNA replication is initiated by introduction of a nick in the leading strand of the origin by the initiator protein, which in most cases binds covalently to the 5' end of the nick. In filamentous phage, however, such a covalent complex has not been detected. Using a suitable substrate and short reaction time, we show that filamentous phage initiator gpII forms a covalent complex with nicked DNA, which rapidly dissociates unless gpII is inactivated. A peptide-DNA complex was isolated from trypsin digest of the complex by ion exchange column chromatography and gel filtration, and its peptide sequence was determined. The result indicated that gpII was linked to DNA by the tyrosine residue at position 197 from the N-terminus. The mutant protein in which this tyrosine was replaced by phenylalanine did not show any detectable activity to complement gene II amber mutant phage in vivo. In vitro, the mutant protein recognized the origin and bent DNA as well as the wild-type does, but failed to introduce a nick and to relax the superhelicity of cognate DNA. PMID- 10101198 TI - Cloning and characterisation of mtDBP, a DNA-binding protein which binds two distinct regions of sea urchin mitochondrial DNA. AB - The cDNA for the sea urchin mitochondrial D-loop-binding protein (mtDBP), a 40 kDa protein which binds two homologous regions of mitochondrial DNA (the D-loop region and the boundary between the oppositely transcribed ND5 and ND6 genes), has been cloned. Four different 3'-untranslated regions have been detected that are related to each other in pairs and do not contain the canonical polyadenylation signal. The in vitro synthesised mature protein (348 amino acids), deprived of the putative signal sequence, binds specifically to its DNA target sequence and produces a DNase I footprint identical to that given by the natural protein. mtDBP contains two leucine zippers, one of which is bipartite, and two small N- and C-terminal basic domains. A deletion mutation analysis of the recombinant protein has shown that the N-terminal region and the two leucine zippers are necessary for the binding. Furthermore, evidence was provided that mtDBP binds DNA as a monomer. This rules out a dimerization role for the leucine zippers and rather suggests that intramolecular interactions between leucine zippers take place. A database search has revealed as the most significative homology a match with the human mitochondrial transcription termination factor (mTERF), a protein that also binds DNA as a monomer and contains three leucine zippers forming intramolecular interactions. These similarities, and the observation that mtDBP-binding sites contain the 3'-ends of mtRNAs coded by opposite strands and the 3'-end of the D-loop structure, point to a dual function of the protein in modulating sea urchin mitochondrial DNA transcription and replication. PMID- 10101199 TI - Pokeweed antiviral protein cleaves double-stranded supercoiled DNA using the same active site required to depurinate rRNA. AB - Ribosome-inactivating proteins (RIPs) are N-glycosylases that remove a specific adenine from the sarcin/ricin loop of the large rRNA in a manner analogous to N glycosylases that are involved in DNA repair. Some RIPs have been reported to remove adenines from single-stranded DNA and cleave double-stranded supercoiled DNA. The molecular basis for the activity of RIPs on double-stranded DNA is not known. Pokeweed antiviral protein (PAP), a single-chain RIP from Phytolacca americana, cleaves supercoiled DNA into relaxed and linear forms. Double-stranded DNA treated with PAP contains apurinic/apyrimidinic (AP) sites due to the removal of adenine. Using an active-site mutant of PAP (PAPx) which does not depurinate rRNA, we present evidence that double-stranded DNA treated with PAPx does not contain AP sites and is not cleaved. These results demonstrate for the first time that PAP cleaves supercoiled double-stranded DNA using the same active site that is required for depurination of rRNA. PMID- 10101200 TI - Cleavage of a 23S rRNA pseudoknot by phenanthroline-Cu(II). AB - Studying the intricate folding of rRNA within the ribosome remains a complex problem. Phenanthroline-Cu(II) complexes cleave phosphodiester bonds in rRNA in specific regions, apparently especially where the rRNA structure is constrained in some fashion. We have introduced phenanthroline-copper complexes into 50S Escherichia coli ribosomal subunits and shown specific cleavages in the regions containing nucleotides 60-66 and 87-100. This specificity of cleavage is reduced when the ribosome is heated to 80 degrees C and reduced to background when the ribosomal proteins are extracted and the cleavage repeated on protein-free 23S rRNA. It has been suggested that nucleotides 60-66 and 87-95 in E.coli 23S rRNA are involved in a putative pseudoknot structure, which is supported by covariance data. The paired cleavages of nearly equal intensity of these two regions, when in the ribosome, may further support the existence of a pseudoknot structure in the 100 region of 23S rRNA. PMID- 10101201 TI - Dye structure affects Taq DNA polymerase terminator selectivity. AB - All DNA sequencing methods have benefited from the development of new F667Y versions of Taq DNA polymerase. However, terminator chemistry methods show less uniform peak height patterns when compared to primer chemistry profiles suggesting that the dyes and/or their linker arms affect enzyme selectivity. We have measured elementary nucleotide rate and binding constants for representative rhodamine- and fluorescein-labeled terminators to determine how they interact with F667 versions of Taq Pol I. We have also developed a rapid gel-based selectivity assay that can be used to screen and to quantify dye-enzyme interactions with F667Y versions of the enzyme. Our results show that 6-TAMRA ddTTP behaves like unlabeled ddTTP, while 6-FAM-ddTTP shows a 40-fold reduction in the rate constant for polymerization without affecting ground-state nucleotide binding. Detailed mechanism studies indicate that both isomers of different fluorescein dyes interfere with a conformational change step which the polymerase undergoes following nucleotide binding but only when these dyes are attached to pyrimidines. When these same dyes are attached to purines by the same propargylamino linker arm, they show no effect on enzyme selectivity. These studies suggest that it may be possible to develop fluorescein terminators for thermocycle DNA sequencing methods for polymerases that do not discriminate between deoxy- and dideoxynucleotides. PMID- 10101202 TI - Human DNA topoisomerase I-mediated cleavage and recombination of duck hepatitis B virus DNA in vitro. AB - In this study, we report that eukaryotic topoisomerase I (top1) can linearize the open circular DNA of duck hepatitis B virus (DHBV). Using synthetic oligonucleotides mimicking the three-strand flap DR1 region of the DHBV genome, we found that top1 cleaves the DNA plus strand in a suicidal manner, which mimics the linearization of the virion DNA. We also report that top1 can cleave the DNA minus strand at specific sites and can linearize the minus strand via a non homologous recombination reaction. These results are consistent with the possibility that top1 can act as a DNA endo-nuclease and strand transferase and play a role in the circularization, linearization and possibly integration of viral replication intermediates. PMID- 10101203 TI - RNA binding specificity of Unr, a protein with five cold shock domains. AB - The human unr gene encodes an 85 kDa protein which contains five cold shock domains (CSD). The capacity of Unr to interact in vitro with RNA and its intracellular localization suggest that Unr could be involved in some aspect of cytoplasmic mRNA metabolism. As a step towards identification of Unr mRNA targets, we investigated the RNA-binding specificity of Unr by an in vitro selection approach (SELEX). Purine-rich sequences were selected by Unr, leading to the identification of two related consensus sequences characterized by a conserved core motif AAGUA/G or AACG downstream of a purine stretch. These consensus sequences are 11-14 nt long and appear unstructured. RNAs containing a consensus sequence were bound specifically by Unr with an apparent dissociation constant of 1 x 10(-8) M and both elements, the 5' purine stretch and the core motif, were shown to contribute to the high affinity. When the N-terminal and C terminal CSD were analyzed individually, they exhibited a lower affinity than Unr for winner sequences (5- and 100-fold, respectively) but with similar binding specificity. Two combinations of CSDs, CSD1-2-3 and CSD1*2-3-4-5 were sufficient to achieve the high affinity of Unr, indicating some redundancy between the CSDs of Unr for RNA recognition. The SELEX-generated consensus motifs for Unr differ from the AACAUC motif selected by the Xenopus Y-box factor FRGY2, indicating that a diversity of RNA sequences could be recognized by CSD-containing proteins. PMID- 10101204 TI - Age-associated increase in 8-oxo-deoxyguanosine glycosylase/AP lyase activity in rat mitochondria. AB - The mitochondrial theory of aging postulates that organisms age due to the accumulation of DNA damage and mutations in the multiple mitochondrial genomes, leading to mitochondrial dysfunction. Among the wide variety of DNA damage, 8-oxo deoxyguanosine (8-oxo-dG) has received the most attention due to its mutagenicity and because of the possible correlation between its accumulation and pathological processes like cancer, degenerative diseases and aging. Although still controversial, many studies show that 8-oxo-dG accumulates with age in the mitochondrial (mt) DNA. However, little is known about the processing of this lesion and no study has yet examined whether mtDNA repair changes with age. Here, we report the first study on age-related changes in mtDNA repair, accomplished by assessing the cleavage activity of mitochondrial extracts towards an 8-oxo-dG containing substrate. In this study, mitochondria obtained from rat heart and liver were used. We find that this enzymatic activity is higher in 12 and 23 month-old rats than in 6 month-old rats, in both liver and heart extracts. These mitochondrial extracts also cleave oligonucleotides containing a U:A mismatch, at the uracil position, reflecting the combined action of mitochondrial uracil DNA glycosylase (mtUDG) and mitochondrial apurinic/apyrimidinic (AP) endonucleases. The mtUDG activity did not change with age in liver mitochondria, but there was a small increase in activity from 6 to 23 months in rat heart extracts, after normalization to citrate synthase activity. Endonuclease G activity, measured by a plasmid relaxation assay, did not show any age-associated change in liver, but there was a significant decrease from 6 to 23 months in heart mitochondria. Our results suggest that the mitochondrial capacity to repair 8-oxo-dG, the main oxidative base damage suggested to accumulate with age in mtDNA, does not decrease, but rather increases with age. The specific increase in 8-oxo-dG endonuclease activity, rather than a general up-regulation of DNA repair in mitochondria, suggests an induction of the 8-oxo-dG-specific repair pathway with age. PMID- 10101205 TI - Ethanol-induced structural transitions of DNA on mica. AB - The effect of ethanol on the structure of DNA confined to mica in the presence of Mg2+was examined by varying the ethanol concentration and imaging the DNA by atomic force microscopy. Contour length measurements of the DNA show a transition from all-B-form at 0% ethanol to all-A-form at >25% ethanol. At intermediate ethanol concentrations, contour lengths suggest that individual molecules of air dried DNA are trapped with mixed compositions of A-form and B-form. The relative composition depends on the ethanol concentration. Fitting the length distributions at intermediate ethanol concentrations to a simple binomial model results in an upper bound estimate for the A-form and B-form domains of approximately 54 bp in the individual molecules. In addition to length changes, the apparent persistence length of DNA decreases with increasing ethanol concentration. At high concentrations of ethanol (>20%), DNA formed several higher order structures, including flower shaped condensates and toroids. PMID- 10101206 TI - Fast and simple purification of chemically modified hammerhead ribozymes using a lipophilic capture tag. AB - A new type of 5'-lipophilic capture tag is described, enabling the facile reverse phase HPLC purification of chemically modified hammerhead ribozymes (oligozymes) whilst still carrying the 2'-O-tert.-butyldimethylsilyl protection of the essential riboses. In its most convenient form, the capture tag consists of a simple diol, such as hexan-1,6-diol, which at one end is attached via a silyl residue to a highly lipophilic entity such as tocopherol (vitamin E) or cholesterol, and the other end is functionalized as a phosphoramidite. This lipophilic capture tag is added as the last residue in the solid-phase synthesis of chemically modified hammerhead ribozymes. Cleavage from the support and release of all protecting groups except for the silyl groups is achieved with ethanolamine/ethanol. The crude product is then loaded directly on to a reverse phase HPLC column. Separation of failure peaks from full length product is achieved easily using a short run time. The retarded product peak is collected, lyophilized, desilylated in the normal way and then desalted. This method removes the lipophilic capture tag yet leaves behind the hexanediol entity which helps protect the compound against degradation by 5'-exonucleases. The purity of the product as judged by analytical anion-exchange HPLC and capillary gel electrophoresis is generally better than 95% full-length, and yields of 2-4 mg from a 1 micromol scale synthesis are routine. In addition, the method can be readily scaled up, an important feature for the development of such chemically modified ribozymes as potential therapeutics. PMID- 10101207 TI - Cytogenetics of myelodysplastic syndromes. AB - This review focuses on karyotypic and molecular findings of myelodysplastic syndromes (MDS). Genetic entities are distinct on the basis of structural (deletions, translocations, inversions) or numerical chromosomal abnormalities (trisomies, monosomies). New information about the amount and nature of malignant cells in MDS, as well as of genes rearranging in specific translocations, recently provided by molecular cytogenetics, are analysed. Integration of clinical-haematological classifications with cytogenetic and molecular findings is discussed PMID- 10101208 TI - Prognostic scoring systems for risk assessment in myelodysplastic syndromes. AB - Clinical heterogeneity complicates therapy planning and makes it difficult to evaluate clinical trials in myelodysplastic syndromes (MDS). Thus, the development of a prognostic classification of MDS is of major clinical relevance, especially when considering the advanced age of most patients and the aggressiveness of the treatment modalities available. This review summarises the results of different studies focusing on prognostic factors in MDS and describes the relative advantages of the prognostic scoring systems that have been recently developed. This paper also discusses the prognostic factors of particular subtypes of patients. The percentage of marrow blasts, cytogenetic pattern and number and degree of cytopenias are the most powerful prognostic indicators in MDS. Although some limitations are evident, the recently developed scoring systems, and particularly the International Prognostic Scoring System, are extremely useful for predicting survival and acute leukaemic risk in individuals with MDS and should be incorporated into the design and analysis of therapeutic trials in these disorders. A risk-adapted treatment strategy is now possible and highly recommended for MDS patients. PMID- 10101209 TI - Pharmacological differentiation and anti-apoptotic therapy in myelodysplastic syndromes. AB - The haematological diversity of myelodysplastic syndromes (MDS) mandates that therapeutic strategies for this disease be guided by an understanding of the disease biology. Insights into the pathobiology of this disease have given rise to novel treatment strategies which exploit basic biological disturbances. Myelodysplastic bone marrow progenitors from patients with low leukaemia burden display an accelerated senescence phenotype which is characterised by impaired response to trophic signals and premature apoptotic death of primitive haematopoietic progenitors. Elaboration of aptogenic cytokines such as TNF-alpha and IL-1beta may reinforce this sequence by up-regulating cellular expression of fas ligand and its cognate receptor, suppressing responsiveness to growth factor stimulation, and accelerating apoptotic cell death. Inactivation of p15 or other tumour suppressor genes antedate disease progression and the emergence of blast populations with reduced capacity for fas mediated cell death. Herein we review the current understanding of the pathobiology of MDS and promising strategies for therapeutic intervention. PMID- 10101210 TI - Haematopoietic growth factors in the treatment of myelodysplastic syndromes. AB - There are several therapeutic options for myelodysplastic syndrome (MDS) patients but the potentially curative ones are only available for a minority of individuals. At present, in fact, the only two treatments that can prolong survival are allogeneic stem cell transplantation and intensive chemotherapy. The only two haematopoietic growth factors that can be useful in the treatment of selected MDS patients are recombinant human erythropoietin (rHuEpo) and G-CSF. Overall 15 to 20% of patients with MDS respond to rHuEpo treatment but the vast majority of responders are not transfusion-dependent and the doses required to achieve response are > 450 IU/kg per week. Factors predicting response include serum Epo levels <100 mU/ml, female gender and no or low need for transfusion. Recognising potential responders to rHuEpo can be extremely important in individual cases of MDS. G-CSF alone should be used only for short-term treatments. It may be administered to individual patients during an infective episode that does not respond to antibiotic therapy, particularly in the case of fungal infections. In addition, G-CSF may be employed for shortening the length of severe neutropenia following intensive chemotherapy. American and Scandinavian studies have shown that about 40% of MDS patients respond to a combined treatment of rHuEpo with G-CSF with amelioration of anaemia and that response can be maintained for a median duration of 24 months. Using pre-treatment serum Epo levels as a ternary variable (<100, 100-500 or > 500 U/l) and red blood cell transfusion need as a binary variable (<2 or > or =2 units per month), a predictive score for erythroid response to G-CSF plus rHuEpo can be obtained. This score can identify patients with a high probability of erythroid responses (about 75%). Due to the inadequacies of all current treatment modalities, participation in clinical trials should always be encouraged. PMID- 10101211 TI - Progress in intensive chemotherapy for high-risk myelodysplastic syndromes. AB - Substantial progress has been made in risk assessment for patients with myelodysplastic syndromes (MDS). The development of accurate prognostic classification systems allows a risk-adapted treatment strategy in the individual patient. Allogeneic haematopoietic stem cell transplantation (HSCT) was considered until recently as the only curative approach for MDS. Recent data suggest that intensive chemotherapy programs, such as those employed for patients with AML, may lead to prolonged disease-free survival in a low but significant fraction of patients with high-risk MDS. Intensive post-remission chemotherapy, with or without autologous HSCT, may constitute an appropriate alternative for those patients lacking a suitable sibling donor or for older patients who are in remission after intensive chemotherapy. In this review we will summarise the results and future perspectives of intensive chemotherapy for high-risk MDS patients. PMID- 10101212 TI - Stem cell transplantation in myelodysplastic syndromes. AB - The cornerstone of therapeutic management for most patients with myelodysplastic syndrome (MDS) is supportive care, mainly in view of the average advanced age in MDS and the poor response to therapy. Due to the lack of satisfactory therapies, allogeneic stem cell transplantation is today the treatment of choice in the majority of young patients with histocompatible siblings. Results of treatment with allogeneic stem cell transplantation varies considerably depending on the stage of disease at transplantation and various clinical factors, such as the presence of cytogenetic abnormalities, age, and the percentage of blasts in the bone marrow at transplantation. Most patients may benefit optimally from an allogeneic stem cell transplantation when the transplant is performed as soon as an HLA-identical family member has been identified. Progression to more advanced leukaemic conditions will be associated with a higher failure rate mainly due to an increased incidence of relapse after transplantation. Delay of the transplant may be justified in a minority of patients with refractory anaemia without cytopenias or complex cytogenetic abnormalities. Patients who lack an HLA identical family donor may be transplanted with either autologous stem cells or alternative allogeneic donors. The results are less compared to those obtained with histocompatible sibling transplantation due to an increased risk of relapse after autologous stem cell transplantation or a higher treatment-related mortality after transplantation with genotypically non-identical donors. PMID- 10101213 TI - Analysis of deprenyl metabolites in the rat brain using HPLC-ES-MS. AB - Methylamphetamine and amphetamine, the two major metabolites of deprenyl in the rat brain were analyzed using HPLC method combined with electrospray-mass spectrometer. (-)-Deprenyl and (+)-deprenyl were orally administered to rats either in a single dose of 10 mg/kg, or three times a week for three weeks. The metabolites were determined in four different parts of the rat brain, such as in the frontal cortex, corpus striatum, hippocampus, and hypophysis. The ratio of methylamphetamine to amphetamine was also compared after (-)-deprenyl and (+) deprenyl treatments. PMID- 10101214 TI - Glutathione S-transferases--a review. AB - The Glutathione S-transferases (GSTs) form a group of multi-gene isoenzymes involved in the cellular detoxification of both xenobiotic and endobiotic compounds. GSTs have been divided into a number of subclasses, alpha, mu, pi, and theta. The classification was made on the basis of sequence similarity and immunological cross-reactivity. GSTs show a high level of specificity toward GSH but the electrophilic second substrate can vary significantly both between and within the classes in spite of their sequence similarity. X-ray crystallography and site-directed mutagenesis studies have together elucidated the structure and mechanism of GSTs. Catalysis occurs by conjugation with glutathione (GSH) and the less toxic and more hydrophilic products can then be partially metabolised and excreted. This invaluable service is however disadvantageous during chemotherapy where GSTs have been associated with multi-drug resistance of tumour cells. Levels of expression of different isoforms of GSTs are tissue specific. The variations in expression between normal and tumour cells are of interest and in most cases the levels of GSTs are increased, especially p-GST. Understanding the complex role that GSTs play in drug resistance begins with determining the pattern of isoform expression and the substrate specificities of each isoform. The use of isozyme-specific, GSH analogues as inhibitors to modulate GST activity during chemotherapy is a promising strategy in the battle against cancer. This review attempts to provide a detailed overview of the literature concerning the different classes of GSTs, their function and mechanism and the use of GSTs as therapeutic targets for disease as current at the time of submission. PMID- 10101215 TI - The unique properties of dipeptidyl-peptidase IV (DPP IV / CD26) and the therapeutic potential of DPP IV inhibitors. AB - This review deals with the properties and functions of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). This membrane anchored ecto-protease has been identified as the leukocyte antigen CD26. The following aspects of DPP IV/CD26 will be discussed : the structure of DPP IV and the new family of serine proteases to which it belongs, the substrate specificity, the distribution in the human body, specific DPP IV inhibitors and the role of CD26 in the intestinal and renal handling of proline containing peptides, in cell adhesion, in peptide metabolism, in the immune system and in HIV infection. Especially the latest developments in the search for new inhibitors will be reported as well as the discovery of new natural substrates for DPP IV such as the glucagon-like peptides and the chemokines. Finally the therapeutical perspectives for DPP IV inhibitors will be discussed. PMID- 10101216 TI - PT523 and other aminopterin analogs with a hemiphthaloyl-L-ornithine side chain: exceptionally tight-binding inhibitors of dihydrofolate reductase which are transported by the reduced folate carrier but cannot form polyglutamates. AB - Nonpolyglutamatable antifolates are potentially of therapeutic interest for the treatment of tumors that are inherently refractory, or have become resistant, to classical antifolates as a result of decreased expression of the enzyme folylpolyglutamate synthetase. An interesting class of water-soluble nonpolyglutamatable analogs of aminopterin (AMT) have been developed, which are much more cytotoxic because they bind more tightly to dihydrofolate reductase (DHFR) and also utilize the reduced folate carrier (RFC) pathway more efficiently for influx into the cell. This review summarizes the in vitro and in vivo preclinical data on the initial lead compound, Nalpha-(4-amino-4-deoxypteroyl) Ndelta- hemiphthaloyl-L-ornithine (PT523). In addition, the synthesis and in vitro biochemical and biological properties of several types of second-generation analogs are discussed. Analogs modified in the B-ring of the pteridine moiety have been found to be of particular interest because their affinity for DHFR and their influx rate into cells via the RFC pathway are even greater than those of PT523. The hemiphthaloylornithine moiety, which is larger and more hydrophobic than the glutamate side chain of classical antifolates, appears to be chiefly responsible for the exceptionally high biological potency of PT523 and its B-ring analogs. PMID- 10101217 TI - Microbial models of mammalian metabolism of xenobiotics: An updated review. AB - The utilization of microbes as models for mammalian metabolism of xenobiotics has been well established since the concept was first introduced by Smith and Rosazza in the early seventies. The core assumption of this concept rests on the fact that fungi are eukaryotic organisms that possess metabolizing enzyme systems similar to those present in mammalian systems. Hence, the outcome of xenobiotic metabolism in both systems is expected to be similar, if not identical, and, thus, fungi can be used to predict the outcome of mammalian metabolism of various xenobiotics, including drugs. Utilizing microbial models offers a number of advantages over the use of animals in metabolism studies, mainly reduction in use of animals, ease of setup and manipulation, higher yield and diversity of metabolite production, and lower cost of production. In a continuation to our contribution to this field, this review will outline the results of studies that were conducted over the last seven years to emphasize the similarities between the microbial and mammalian metabolic pathways of xenobiotics through the endorsement of the concept of microbial models of mammalian metabolism . PMID- 10101218 TI - Recent advances in neurokinin receptor antagonists. AB - The structurally related neuropeptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), which belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems, influence the function of many tissues. SP and NKA have links to the following chronic diseases: asthma, inflammatory bowel disorders, rheumatoid arthritis, pain and psychiatric disorders. These peptides exert their effects through three G-protein coupled receptor subtypes, namely, the NK1, NK2, and NK3 receptors. Non-peptide antagonists of these receptors may provide opportunities for disease treatments. In this review, the very recent advances in nonpeptide neurokinin receptor antagonists will be described with an emphasis on structure-activity relationships which have been developed. PMID- 10101219 TI - 12-Lipoxygenase: classification, possible therapeutic benefits from inhibition, and inhibitors. AB - The metabolism of arachidonic acid can be catalyzed by either one of two enzyme families; the cyclooxygenases or the lipoxygenases. The family of lipoxygenases is divided into four subtypes according to tissue distribution; 5-, 8-, 12-, and 15-lipoxygenase. 12-lipoxygenase metabolites, such as 12(S) hydroxyeicosatetraenoic acid, have been found to play a central role in the various stages of the metastatic process in tumors and are, therefore, potential targets for anticancer treatment. A variety of lipoxygenase inhibitors already exist and can be classified into five major categories according to their mechanism of inhibition. These include antioxidants, iron chelators, substrate analogues, lipoxygenase-activating protein inhibitors, and, finally, epidermal growth factor-receptor inhibitors. PMID- 10101220 TI - Modulating apoptosis: current applications and prospects for future drug development. AB - Agents modulating apoptosis are of extraordinary promise for the treatment of several states of disease including cancer, AIDS, neurodegenerative and ischemic diseases. In this review a brief summary of cellular pathways relevant to programmed cell death first is given and potential therapeutic targets therein are emphasized. Current efforts in drug development are discussed from a mechanistic, biochemical point of view and pro- and anti-apoptotic strategies are related to the respective diseases. Therapeutic approaches addressed in this paper include the design and activity of novel low molecular weight agents (e.g. caspase inhibitors) as well as gene therapy (e.g. p53, adenovirus as vector in cancer treatment). In final sections, the latest findings in the field of apoptosis are highlighted and future applications are outlined. PMID- 10101221 TI - Manoalide. AB - Manoalide is a potent analgesic and antiinflammatory sesterterpene isolated in 1980 from a marine sponge. The antiinflammatory activity of manoalide is due to inhibition of PLA2, through irreversible binding to several lysine residues. The binding is realized by means of the two masked aldehyde functions present in the polar part of manoalide. Of the two aldehyde groups, only that present in the g hydroxybutenolide ring seems to be essential, since cacospongionolides, naturally occurring analogues lacking the second masked aldehyde group, were also shown to be irreversible PLA2 inhibitors. It appears that the minimum structural requirement for exhibiting manoalide-like PLA2 inhibition would be the presence in the inhibitor of functional groups able to seize the amino groups of PLA2 lysine residues with formation of stable covalent bonds. Many manoalide analogues have been isolated from marine sponges, most of them sharing PLA2 inhibitory properties. Other interesting bioactivities have also been reported for some of these compounds. PMID- 10101222 TI - Cadmium therapeutic agents. AB - Pollution of the environment with toxic metals has increased dramatically since the beginning of the industrial revolution. Cadmium is of particular concern because it accumulates in the human body with a half-life exceeding 10 years and has been linked with a number of health problems including renal tubular dysfunction, pulmonary emphysema, significant kidney damage, and possibly osteoporosis. Moreover, in 1993 the International Agency for Research on Cancer (IARC) classified cadmium and compounds containing cadmium as human carcinogens. The field of cadmium intoxication therapy has seen increases in interest due to its poignant toxicity in both humans and animals. Preliminary attempts to combat acute cadmium poisoning included the use of the chelating agents ethylenediaminetetraacetic acid (EDTA) and British anti-Lewisite (BAL). This review will focus on the chemistry, biology, and effectiveness of cadmium intoxication therapy to date. The toxicokinetics of cadmium mammals will be discussed briefly to understand the extent and severity of overexposure. An overview of cadmium chelation therapy will be given with an emphasis on the measurable effectiveness of each and significant structure activity relationships. Cadmium intoxication therapy will be reviewed by their indicated routes of action: direct (chelation and antagonism), indirect (induction), and symptom alleviation. The methods by which cadmium therapeutics are evaluated (in vivo, in vitro) are to be discussed. An evaluation of the clinical potential for promising therapeutics will be given. PMID- 10101223 TI - Interleukin-8: An autocrine inflammatory mediator. AB - Interleukin-8 (IL-8), a pro-inflammatory chemokine, induces trafficking of neutrophils across the vascular wall. The release of IL-8 is triggered by inflammatory signals from a large variety of cells. The diversity in the cellular source indicates pleiotropy of its functions. IL-8 plays a key role in host defense mechanism through its effects on neutrophil activation, but a continued presence of IL-8 in circulation in response to inflammatory conditions may lead to a variable degree of tissue damage. Like most of the peptide hormones or mediators, IL-8 transmits its signals through distinct cell surface receptors. The membrane spanning heptahelical IL-8 receptor is coupled with the effector enzyme(s) through the intermediacy of heterotrimeric GTP-binding regulatory proteins. A growing number of studies demonstrated regulation of IL-8 activity by pertussis toxin treatment, implying a role of pertussis toxin sensitive G proteins (Gi), in IL-8 induced effects. IL-8 induced activation of G-protein results in activation of phospholipase C b2 (PLCb2). This enzyme catalyzes the hydrolysis of membrane phosphoinositides to yield diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3), which in turn activates protein kinase C (PKC) and mobilizes the intracellular Ca2+, respectively. Neutrophils activation of phospholipase D (PLD) and superoxide generation in response to IL-8 have also been demonstrated. Furthermore, IL-8-mediated activation of mitogen activating protein kinase (MAPK) and tyrosine phosphorylation of cellular proteins have been observed. It appears that the signalling pathways induced by IL-8 are subject to fine modulations by the demand and presence of IL-8. The presence of IL-8 in various pathophysiological condition implies that blockade of its actions could be exploited for therapeutic purposes. PMID- 10101224 TI - 2-pyridylthioureas: novel nonpeptide somatostatin agonists with SST4 selectivity. AB - Somatostatin [somatotropin release-inhibiting factor (SRIF)] is a cyclic tetradecapeptide that is a potent inhibitor of growth hormone (GH) secretion from the anterior pituitary. In addition to the inhibitory effects on GH-release, SRIF 14 and SRIF-28, a 28-amino acid form of SRIF extended from the N-terminal end, inhibit the release of a variety of other peptides including glucagon, insulin, and gastrin, and both peptides act as neurotransmitters and neuromodulators in the central nervous system and the periphery. SRIF exerts its potent inhibitory effects following binding to high affinity SRIF receptors (ssts) that have been identified on target tissues. The recent cloning of five ssts has confirmed that the effects of SRIF are mediated by a family of G protein-coupled receptors (sst1 5). Based on structural and pharmacological properties sst2, sst3, and sst5 belong to the SRIF1 receptor subclass, and the sst1 and sst4 subtypes comprise the SRIF2 subclass. The major difference between these two subclasses is that SRIF1 receptors bind octapeptide and hexapeptide SRIF-14 analogs with high affinity, while SRIF2 receptors bind these analogs with drastically reduced affinity. A screening program was initiated to identify a lead nonpeptide with affinity for sst1-5 receptors. The search focused on a scaffold with the following attachments: (1) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mimic Phe7, and (3) a primary amine or other basic group to mimic the Lys9 residue of SRIF-14. Using these criteria, a novel thiourea (NNC 26-9100, 17) was discovered as a structural lead. The key fragments in this compound are a heteroaromatic moiety (pyridine), an aromatic group, and a basic imidazole group connected through a thiourea scaffold. Compound 17 exhibited a Ki = 6 nM at sst4 receptors with a 100-fold sst4/sst2 selectivity and was shown to be a full agonist at this receptor subtype. This article will review the literature on the design and development of nonpeptide somatostatin receptor ligands and the therapeutic potential of these agents. Furthermore, our work on the development of 2-pyridylthioureas as sst4 receptor agonists will be described. PMID- 10101225 TI - Prodrug approaches to the improved delivery of peptide drugs. AB - Undesirable pharmaceutical and biopharmaceutical properties, which include low water solubility, poor stability, and low permeability through biological membrane barriers, often hinder the clinical development of biologically active peptides. Finding solutions to these problems is a contemporary issue in developing clinically the vast number of biologically active peptides as drugs. In recent years, significant progress has been made in developing prodrug approaches for the improvement of the water solubility, stability, and membrane permeability of peptides. For improving water solubility, the focus has been on the bioreversible introduction of ionizable functional groups to peptides, which helps to increase the polarity and thus water solubility of the peptide drugs. For improving stability, efforts have focused on stabilizing peptides against exopeptidase-mediated hydrolysis by bioreversibly masking the terminal carboxyl and/or amino groups. For improving permeability through biological barriers, recent efforts have focused on both improving the lipophilicity of a peptide in order to facilitate its passive permeation through biological membranes and conjugation of a peptide to a carrier which allows for the active transport of the peptide-carrier conjugate. Many of the prodrug systems developed recently have the potential to be used clinically for the delivery of peptide drugs to the desired site of action. PMID- 10101226 TI - Overexpression of striatal enriched phosphatase (STEP) promotes the neurite outgrowth induced by a cAMP analogue in PC12 cells. AB - A cytoplasmic protein tyrosine phosphatase (PTPase) designated as striatal enriched phosphatase with a molecular weight of 46 kDa (STEP46) is highly expressed in striatal neurons with dopamine D1-receptors. To examine the hypothesis that STEP46 is involved in the neuronal functions modulated by the cyclic adenosine 3', 5'-monophosphate (cAMP)-signaling system, we introduced the complementary DNA of STEP46 into the pheochromocytoma cell line PC12, which exhibits neuronal differentiation characterized by neurite outgrowth in response to cAMP and nerve growth factor stimulation, and we established subclonal cell lines that constitutively overexpress STEP46 protein with PTPase activity. The subclones expressing STEP46 showed increased neurite outgrowth during differentiation induced by a cAMP analogue (dibutyryl cAMP). The positive regulatory role of STEP46 in the cAMP-induced neuronal differentiation of PC12 cells indicates that STEP46 may play a role in neuronal processes modulated by the cAMP-signaling cascade as a PTPase. PMID- 10101227 TI - Human c-Jun N-terminal kinase expression and activation in the nervous system. AB - Differential expression and localization of c-Jun N-terminal kinases (JNKs) in the human brain may reflect transduction of a variety of extracellular stimuli to selective cellular responses. Of the three JNKs, JNK1 and 2 are widely distributed in tissues and JNK3 is predominantly restricted to brain where it is expressed in neurons. Although there is considerable molecular conservation among all three JNKs, we distinguished expression of each by in situ hybridization, immunoblot analysis with a panel of antibodies, and stress-activation using c-Jun as substrate. In the human central nervous system (CNS), there are at least 10 isoforms: JNK3alpha1 and JNK1alpha1 were the major JNK isoforms expressed; JNK2 was not detected. On immunoblots of brain homogenates, antibody selectivity identified JNK3alpha1 as a 45-kDa protein, JNK1alpha1, a slightly lower band at 44 kDa, and a 50-kDa band of unknown specificity. Recombinant human JNK3alpha1, transfected either into CHO, COS-1, or Neuro2A (N2A) cells, was strongly expressed as a 45-kDa protein in each. Transfected JNK3alpha1, and endogenous JNK1, each immunoprecipitated from N2A cells, phosphorylated recombinant forms of human c-Jun. Kinase activity of each JNK was modestly stimulated in N2A cells by anisomycin but not by ceramide, UV irradiation, or heat shock. Endogenous JNK activation, especially at a low level, may reflect a chronic and cumulative stress process that contributes to hyperphosphorylation of cytoskeletal proteins such as those found in Alzheimer's disease (AD), and ultimately, induction of apoptosis. PMID- 10101228 TI - ERK MAP kinase activation is required for acetylcholine receptor inducing activity-induced increase in all five acetylcholine receptor subunit mRNAs as well as synapse-specific expression of acetylcholine receptor epsilon-transgene. AB - The AChR is a pentamer of four different subunits in a stoichiometry of alpha2betagammadelta in embryonic and alpha2betaepsilondelta in adult animals. Transcription of AChR subunit genes is most active in synaptic nuclei in adult skeletal muscle cells, and is regulated by neural factors such as ARIA. We report here that ARIA up-regulated specifically the expression of all five AChR subunits in C2C12 cells. The mRNA level of erbB2, erbB3, rapsyn, MuSK, SHP-2 and beta actin remained unchanged in response to ARIA stimulation in C2C12 cells. The ARIA induced increase in AChR subunit expression in C2C12 cells was inhibited by the erbB kinase inhibitor tyrphostin AG1478 and the MEK inhibitor PD98059, but not by the PI3 kinase inhibitor wortmannin, suggesting an important role of the erbB protein tyrosine kinases and MAP kinase in the regulation of the expression of the five different AChR subunits. To determine the signaling pathways in vivo, we studied the expression of reporter genes driven by the epsilon-promoter in injected muscles. The in vivo expression of the epsilon-transgene was inhibited by co-expression of dominant negative mutants of key components in the MAP kinase pathway including ras, raf and MEK, but not the dominant negative mutant of PI3 kinase. These results suggest that ERK MAP kinase activation is required for ARIA induced increase in all five AChR subunit mRNAs as well as synapse-specific expression of AChR epsilon-transgene. PMID- 10101229 TI - Absence of vasopressin expression by galanin neurons in the golden hamster: implications for species differences in extrahypothalamic vasopressin pathways. AB - In golden hamsters, there is a complete absence of the small diameter vasopressin (VP) neurons in the bed nucleus of the stria terminalis (BST) and medial amygdala (Me) which have been shown to exhibit steroid dependency and sexual dimorphism in many other rodent species. In rats, VP in the BST/Me is always colocalized with the neuropeptide galanin (GAL) and the sex difference in VP cell number appears to result from a sex difference in the number of GAL neurons which coexpress VP. Likewise, we reasoned that the species difference in extrahypothalamic VP pathways present in the golden hamster could result from a reduced coexpression of VP by GAL neurons in these regions. Here, we used in situ hybridization histochemistry to determine whether GAL mRNA expressing neurons are present in the BST and Me of golden hamsters despite the absence of VP expression in these regions. In addition, we have used slice binding and receptor autoradiography to identify specific GAL binding sites in the lateral septum, a probable target region of BST/Me neurons, and in situ hybridization to confirm that some of these binding sites correspond to the GALR1 GAL receptor subtype. Our findings indicate that the absence of VP expression in the BST/Me of golden hamsters results from a failure of extrahypothalamic GAL neurons to express the VP phenotype. Because GAL is expressed in the extended amygdaloid complex and GAL receptors are present in the septum of golden hamsters, GAL may play a role in modulating functions previously attributed to BST/Me pathways. PMID- 10101230 TI - Caspase inhibitors block the retinal ganglion cell death following optic nerve transection. AB - Retinal ganglion cells die by apoptosis following axotomy. The molecular mechanisms of the retinal ganglion cell death are not well understood. In the present study using RT-PCR and in situ hybridization techniques we demonstrated that levels of mRNA for Bcl-2 and Bcl-x decreased after axotomy. Bax levels remained high until 4 days after axotomy, decreased by day 7 and remained low up to day 10. CPP32 levels increased at day 7 and remained high after optic nerve cut. We studied whether inhibitors of CPP32/caspase would save the axotomy induced ganglion cell death. DEVD-CHO (Ac-Asp-Glu-Val-aspartic acid aldehyde) and DEVD-FMK (Z-Asp-Glu-Val-Asp-FMK), caspase inhibitors, when administered intraocularly at the time of optic nerve cut, at days 3 and 7 protect about 30 35% the ganglion cells from death. We further demonstrated that the number of reactive microglia decrease in the retina when the inhibitors were given as compared with retina where no inhibitors were given. The present data offers new avenues for studying the complex interactions between the retinal ganglion cell death and the activation of resident microglia/macrophages. PMID- 10101231 TI - Cultures of astrocytes and microglia express interleukin 18. AB - Interleukin 18 (IL-18 or interferon-gamma inducing factor) is a recently discovered pro-inflammatory cytokine and powerful stimulator of the cell-mediated immune response. IL-18 is produced by several sources including monocytes/macrophages, keratinocytes and the zona reticularis and zona fasciculata of the adrenal cortex. IL-18 occurs in brain but its cellular source in the CNS has never been investigated. The presence of IL-18 and its response to stimulation in the brain was tested with primary cultures of microglia, astrocytes and hippocampal neurons. IL-18 mRNA was present in astrocytes and microglia, but not in neurons. The endotoxin lipopolysaccharide (LPS) did not affect IL-18 in astrocytes, but LPS robustly increased IL-18 mRNA in microglia. IL-18 protein was constitutively expressed in astrocytes and induced in microglia by LPS. The levels of interleukin-1beta converting enzyme (ICE), an activating enzyme, and caspase 3 (CPP32), an inactivating enzyme, were assessed to investigate the presence of the appropriate processing enzymes in the cultured cells. ICE was present at constitutive levels in microglia and astrocytes suggesting that these cell types may produce and secrete matured IL-18. Active forms of CPP32 were not detectable in either cell type indicating the absence of a degradative pathway of IL-18. The present results demonstrate that microglia and astrocytes are sources of brain IL-18 and add a new member to the family of cytokines produced in the brain. PMID- 10101232 TI - Overexpression of NeuroD in PC12 cells alters morphology and enhances expression of the adenylate kinase isozyme 1 gene. AB - NeuroD, a basic helix-loop-helix transcription factor, plays an important role in neuronal differentiation. A rat NeuroD cDNA was obtained by the aid of reverse transcription-polymerase chain reaction (RT-PCR) and ligated to an expression vector having a CMV promoter. Transfection of the NeuroD-expression plasmid into PC12 cells, a rat pheochromocytoma cell line, induced morphological changes featured by neurite-like processes and synapse-like structures without a differentiation-inducing reagent such as NGF. In the transfected cells, the overproduced NeuroD was detected by Western blot analysis, and the expression of the gene encoding mid-sized neurofilaments, a neuron-specific marker, was demonstrated by RT-PCR. Adenylate kinase isozyme 1 (AK1) is an enzyme involved in the homeostasis of energy metabolism and appears specifically in neuronal cells during differentiation. The CAT reporter assay of the 5'-flanking region of the AK1 gene suggests that NeuroD activates the AK1 expression through E-boxes in the promoter region. RT-PCR analysis indicated the enhanced level of AK1 mRNA in NeuroD-producing PC12 cells. Electrophoretic mobility shift assays demonstrated that NeuroD was able to interact with a proximal E-box element of the AK1 promoter. The results indicated that NeuroD promoted the PC12 cells to differentiate into neuron-like cells with concomitant activation of the target genes including the AK1 and the neurofilament genes. PMID- 10101233 TI - Defensive conditioning-related increase in AP-1 transcription factor in the rat cortex. AB - In the studies reported herein, electrophoretic mobility shift assay (EMSA) and immunocytochemistry have been applied to document increased levels of AP-1 transcription factor, and its major component, c-Fos in the rat brain following behavioral training of two-way active avoidance. A single training session (50 trials) provoked elevation of AP-1 in the visual, sensory and limbic cortex but not in the hippocampus. A session following long term training (10 sessions, up to asymptotic level of performance) had much smaller effect on AP-1 levels in the visual cortex than single training session. The long term training was used to ensure that observed effects were related to acquisition of the reaction rather than simply to behavioral performance. Supershift EMSA analysis with antibodies directed at individual AP-1 components revealed that AP-1 extracted from the brains of trained as well as naive animals is composed of the same proteins, i.e., in order of relative level within the protein family: c-Fos, Fos B, Fra-2, and Jun D, Jun B, c-Jun. These studies reinforce the notion that transcription factors as regulators of gene expression-and AP-1 in particular-may respond to behavioral stimulation and furthermore may play a role in acquisition of behavioral reactions. PMID- 10101234 TI - RhoN, a novel small GTP-binding protein expressed predominantly in neurons and hepatic stellate cells. AB - A cDNA encoding a novel member of the small molecular weight GTP-binding protein (small G-protein) superfamily was cloned from rat spinal cord. The deduced amino acid sequence was highly homologous with those of so-far-known Rho proteins. Rho proteins were reported to alter many important cellular functions including formation of both actin stress fibers and focal adhesions. RNA blot hybridization and in situ hybridization analyses indicated that the novel small G-protein is expressed specifically in neurons in the brain and spinal cord and also in hepatic stellate cells. Based on the sequence similarity and neuron-specific expression in the brain, this protein was named RhoN. Unlike classical Rho proteins, RhoN was not susceptible to the ADP-ribosylation reaction by C3 botulinum toxin. Accordingly, RhoN seemed to be specifically involved in neuronal and hepatic functions as a C3 toxin-insensitive member of the Rho subfamily. Then, a mouse genomic DNA segment containing the RhoN gene was cloned. The locus was mapped on the mouse chromosome 11C-D. The sequence data showed that the protein-coding sequence for RhoN is divided by 4 introns, and that the defined 5 exons may encode intramolecular domains serving for different functions. PMID- 10101235 TI - Expression of norepinephrine and serotonin transporter mRNAs in the rat superior cervical ganglion. AB - We investigated the gene expression of three monoamine transporters (norepinephrine transporter, NET; serotonin transporter, SERT; and dopamine transporter, DAT) in the rat superior cervical ganglion (SCG). Most of principal ganglion neurons abundantly expressed NET mRNA. In addition, about 30% of principal ganglion neurons also expressed SERT mRNA. However, DAT mRNA expression was not observed there. These results suggest that serotonin as well as norepinephrine works as a neurotransmitter in a subset of principal ganglion neurons. PMID- 10101236 TI - Orofacial deep and cutaneous tissue inflammation differentially upregulates preprodynorphin mRNA in the trigeminal and paratrigeminal nuclei of the rat. AB - Preprodynorphin (PPD) and preproenkephalin (PPE) gene expression in a rat model of orofacial inflammation were examined in order to further characterize the neurochemical mechanisms underlying orofacial inflammation and hyperalgesia. Deep and cutaneous orofacial inflammation was produced by a unilateral injection of complete Freund's adjuvant (CFA) into the rat temporomandibular joint (TMJ) or perioral skin (PO), respectively. RNA blot analysis of the tissues including the spinal trigeminal complex revealed that the PPD mRNA level ipsilateral to TMJ inflammation was increased by 56.5+/-14.7% (n=4) when compared to the Naive group, and was significantly greater than the contralateral PPD mRNA level (p<0.05). The distribution of neurons that exhibited PPD mRNA after inflammation was localized by in situ hybridization (naive approximately 0). In TMJ-inflamed rats (n=6) PPD mRNA-positive neurons were found ipsilaterally in the medial portion of laminae I-II of the upper cervical dorsal horn (4.5+/-0.3), the dorsal portion of the subnucleus caudalis and caudal subnucleus interpolaris (5.2+/ 0.3), and the paratrigeminal nucleus (6.4+/-1.2). A very localized induction of PPD mRNA was also identified in a group of neurons in the intermediate portion of the subnucleus caudalis (2.4+/-0.4) in PO-inflamed rats (n=6). The distribution of these PPD mRNA-positive neurons was somatotopically relevant to the site of injury. There were no significant changes in PPE mRNA expression in both TMJ- and PO-inflamed rats. These results indicate that TMJ inflammation resulted in a more intense and widespread increase in PPD mRNA expression when compared to PO inflammation. These changes may contribute to persistent central hyperexcitability and pain associated with temporomandibular disorders. PMID- 10101237 TI - Antisense oligodeoxynucleotides against the muscarinic m2, but not m4, receptor supports its role as autoreceptors in the rat hippocampus. AB - Antisense oligodeoxynucleotides against muscarinic m2 and m4 receptors were used to investigate the role of these receptor subtypes as negative autoreceptors in the regulation of acetylcholine (ACh) release in the rat hippocampus. Following the continuous infusion of antisenses into the third ventricle (1 microgram microliter-1 h-1, 3 days), 3H-AF-DX 384/muscarinic M2-like binding was significantly decreased in the medial septum by the antisense against the m2 receptor whereas M2-like binding in the dorsal striatum was decreased by the antisense against the m4 receptor. In contrast, 3H-pirenzepine/muscarinic M1-like binding was unaffected by either antisense treatment in any of the brain areas investigated. When perfused into the hippocampus via a dialysis probe, the purported muscarinic M2 receptor antagonist AF-DX 384 (100 nM) increased hippocampal ACh release in freely moving rats. This effect of AF-DX 384 was significantly attenuated by the m2, but not the m4, receptor antisense treatment. Hippocampal choline acetyltransferase activity was not affected by either antisense treatments. Taken together, these results suggest that the molecularly defined muscarinic m2 receptor regulates hippocampal ACh release by acting as a negative autoreceptor. In contrast, the molecularly defined m4 receptor is unlikely to be directly involved in the negative regulation of ACh release in the rat hippocampus. Therefore, inhibiting muscarinic m2 receptor function may be an alternative approach to regulate the release of ACh in neurodegenerative diseases associated with impaired cholinergic functions. PMID- 10101238 TI - Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [35S]GTPgammaS binding responses. AB - The present study reports on G-protein activation by recombinant 5-HT receptors and by native 5-HT1A and 5-HT1B receptors in guinea-pig and rat brain using agonist-stimulated [35S]GTPgammaS binding responses mediated by a new 5-HT ligand, a dimer of sumatriptan. Dimerization of sumatriptan increased the binding affinity for h 5-HT1B (pKi: 9.22 vs. 7.79 for sumatriptan), h 5-HT1D (9.07 vs. 8.08) and also h 5-HT1A receptors (7.80 vs. 6.40), while the binding affinity for h 5-ht1E (6.67 vs. 6.19) and h 5-ht1F (7.37 vs. 7.78) receptors was not affected. Sumatriptan dimer (10 microM) stimulated [35S]GTPgammaS binding mainly in the superficial gray layer of the superior colliculi, hippocampus and substantia nigra of guinea-pig and rat coronal brain sections. This fits with the labelling by the 5-HT1B/1D receptor antagonist [3H] GR 125743. The observed [35S]GTPgammaS binding responses in the substantia nigra are likely to be mediated by stimulation of the 5-HT1B receptor subtype, since they were antagonized by the 5 HT1B inverse agonist SB 224289 (10 microM), and not by the 5-HT2A/1D antagonist ketanserin (10 microM). Quantitative assessment of the [35S]GTPgammaS binding responses in the substantia nigra of rat showed highly efficacious responses for both sumatriptan dimer and its monomer. In contrast, less efficacious agonist responses (51+/-10% and 35+/-13%, respectively) were measured in the guinea-pig substantia nigra. This may suggest that the G-protein coupling efficacy of 5-HT1B receptors is different between the substantia nigra of both species. In addition, the sumatriptan dimer also activated guinea-pig and rat hippocampal 5-HT1A receptors with high efficacy in contrast to sumatriptan. Therefore, dimerization of sumatriptan can be considered as a new approach to transform a partial 5-HT1A agonist into a more efficacious agonist. In conclusion, the sumatriptan dimer stimulates G-protein activation via 5-HT1B receptors besides 5-HT1A receptors in guinea-pig and rat brain. The magnitude of the 5-HT1B receptor responses is superior for sumatriptan and its dimer in rat compared to guinea-pig substantia nigra. PMID- 10101239 TI - Hippocampal neurotrophin and trk receptor mRNA levels are altered by local administration of nicotine, carbachol and pilocarpine. AB - Cholinergic receptor agonists nicotine (nicotinic), carbachol (nicotinic/muscarinic) and pilocarpine (muscarinic) were administered into the hippocampus and mRNA levels of neurotrophins and their receptors determined using in situ hybridisation. Drug doses were carefully chosen to avoid the potentially confounding effects of seizure and cell death. Nicotine caused a long-lasting increase in nerve growth factor (NGF) mRNA in all subfields of the hippocampus. The increase was evident from 24 h up to 72 h after drug administration. This increase was dependent on excitatory amino acid neurotransmission as it was blocked by administration of an AMPA or NMDA receptor antagonist. In contrast, carbachol and pilocarpine produced a transient increase in NGF mRNA levels present 4-8 h after drug administration. Pilocarpine caused a transient increase in hippocampal brain-derived neurotrophic factor (BDNF) levels, with carbachol and nicotine showing the same trend. Nicotine and carbachol caused transient decreases in NT-3 mRNA levels in dentate gyrus and CA2 with pilocarpine showing a similar trend. Increases in mRNA encoding full-length trkB were seen 8 h after nicotine, with nicotine also causing elevations in a mRNA encoding a truncated isoform (trkB.T2). TrkC mRNA was not altered by any of the conditions used. The study suggests that muscarinic and nicotinic receptor activation in the hippocampus causes transient changes in all of the neurotrophins, but that NGF levels are selectively up-regulated by nicotinic receptor stimulation. The reciprocal interaction between NGF and ascending cholinergic systems may be a component of the cognitive enhancing effects of nicotine. PMID- 10101240 TI - Transcriptional regulation of GABAA receptor gamma2 subunit gene. AB - We have cloned the promoter regions of the genes for the mouse and human gamma2 subunits of the type A receptors for gamma-aminobutyric acid (GABA). For the mouse, the two major transcription start sites were at +1 (by definition) and +43, as established by rapid amplification of cDNA ends (RACE) and primer extension. This numbering places the start methionine at +297. There was no TATA or CCAAT box. Both mouse and human sequences have a candidate neuron-restrictive silencer element (NRSE) site in the first intron (+956 in mouse). We made assorted mouse-based promoter/reporter (luciferase) constructs starting from a core extending from -331 to +136, varying sizes at both ends, and including and excluding the putative NRSE and more proximal sequences. These were tested by transient transfection in several neuron-like and non-neuronal cell lines. Both proximal and distal downstream elements appeared to help direct expression to neuron-like cells, the NRSE in the intron, by repression in non-neurons, and a 24 bp portion of the 5' untranslated region starting at +113 (named GPE1) by preferentially promoting expression in neuron-like cells. Cotransfected human NRSF (transcription factor for NRSE) reduced reporter expression in neuron-like cells for constructs containing the NRSE in two locations. In gel mobility shift assays, the mouse gamma2 NRSE and a consensus NRSE both bound in vitro translated NRSF very similarly, and the NRSF gave the same major shifted band with the mouse gamma2 NRSE as was observed with nuclear extracts. PMID- 10101241 TI - Time-dependent differences of repeated administration with Delta9 tetrahydrocannabinol in proenkephalin and cannabinoid receptor gene expression and G-protein activation by mu-opioid and CB1-cannabinoid receptors in the caudate-putamen. AB - The purpose of the present study was to examine the time-related effects of repeated administration of Delta9-tetrahydrocannabinol during 1, 3, 7 and 14 days on cannabinoid and mu-opioid receptor agonist-stimulated [35S]GTPgammaS binding, and CB1 cannabinoid receptor and proenkephalin gene expression in the caudate putamen. Repeated administration with Delta9-tetrahydrocannabinol produced a time related reduction in cannabinoid receptor synthesis and activation of signal transduction mechanisms in the caudate-putamen. Indeed, WIN-55,212-2-stimulated [35S]GTPgammaS binding decreased 24% on day 1 and then progressively decreased finding a 42% decrease on day 14. Similarly, CB1 cannabinoid receptor mRNA levels decreased (22%) on day 3, reaching 50% reduction on day 7. In contrast, a pronounced increase is detected in DAMGO-stimulated [35S]GTPgammaS binding and proenkephalin mRNA levels in the caudate-putamen. The highest degree of increase was reached on day 7 of the treatment (35% of proenkephalin mRNA levels and 62% of DAMGO-stimulated [35S]GTPgammaS binding) and then values slightly decreased on day 14. Taken together, the results of the present study indicate that, in the caudate-putamen, repeated administration with Delta9-tetrahydrocannabinol produces a time-related increase in proenkephalin gene expression and mu-opioid receptor activation of G-proteins, and a time-related decrease in CB1 cannabinoid receptor gene expression and reduction in CB1 cannabinoid receptor activation of G-proteins. These results also suggest a possible interaction between the cannabinoid and opioid systems in the caudate-putamen which may be potentially relevant in the understanding of the alterations of motor behavior that occur after prolonged exposure to cannabinoids. PMID- 10101242 TI - Protein kinase A linked phosphorylation mediates triiodothyronine induced actin gene expression in developing brain. AB - In the developing rat cerebra, triiodothyronine (T3) stimulates actin mRNA by acting predominantly at the level of transcription whereas tubulin mRNA is enhanced primarily by post-transcriptional regulation. We report here that in primary cultures of rat cerebra, the T3-induced actin gene expression is mediated by phosphorylation events. Inhibition of protein kinase A (PKA), but not of protein kinase C (PKC) or tyrosine kinase, totally blocked the induction of actin mRNA by T3. Under identical conditions, induction of tubulin mRNA by T3 was virtually unaffected by all the inhibitors. Activators of PKA, but not of PKC, potentiated the T3-induced actin gene expression, both at mRNA and protein level, by about 2-fold. In the absence of T3, neither the inhibitor nor the activator of PKA had any significant effect on this induction. The involvement of PKA in mediating the induction of actin mRNA by T3 was confirmed by transfecting primary cultures of rat cerebra with an expression vector encoding the protein kinase A inhibitor which totally abolished the induction. T3 is shown to enhance the phosphorylation of the thyroid hormone receptor, TRalpha, by about 2-fold but the level of phosphorylation of TRbeta remained virtually unaffected. PMID- 10101243 TI - Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol. AB - Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are differentially distributed in the brain and likely mediate different estrogen dependent processes. ERbeta is abundant in the bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus of the hypothalamus and the amygdala of the rat. In the paraventricular nucleus, which is devoid of ERalpha, ERbeta is colocalized with the neuropeptides, oxytocin and vasopressin, suggesting a potential functional role for ERbeta in the regulation of these peptides. We examined the regulation of ERbeta mRNA expression in the rat brain by 17beta-estradiol and the phytoestrogen, coumestrol. 17beta-Estradiol treatment decreased ERbeta mRNA in situ hybridization signal by 44.5% in the paraventricular nucleus of the hypothalamus (PVN), but had no effect in the bed nucleus of the stria terminalis (BnST) or the medial preoptic nucleus (MPA). In contrast, dietary exposure to coumestrol increased ERbeta mRNA signal by 47.5% in the PVN but had no effect in the BnST or the MPA. These data demonstrate that like ERalpha, ERbeta is down regulated by estrogen in a region specific manner in the rat brain. Furthermore, exposure to coumestrol may modulate ERbeta-dependent processes by acting as an anti-estrogen at ERbeta. This data contradicts results from cell transfection assays which suggest an estrogenic activity of coumestrol on ERbeta, indicating that the mode of action may be tissue specific, or that metabolism of dietary coumestrol may alter its effects. Because the highest concentrations of phytoestrogens are found in legumes, vegetables and grains, they are most prevalent in vegetarian and traditional Asian diets. Understanding the neuroendocrine effects of phytoestrogens is particularly important now that they are being marketed as a natural alternative to estrogen replacement therapy and sold in highly concentrated pills and powders. PMID- 10101244 TI - Differential regulation of apoptosis-related genes in resistant and vulnerable subfields of the rat epileptic hippocampus. AB - Animals exposed to kainic acid (KA) induced status epilepticus display a striking pattern of selective neuronal vulnerability in the hippocampus. Neurons in the hilus/CA3 and CA1 subfields appear particularly sensitive whereas dentate gyrus (DG) granule cells are resistant. The molecular basis for this differential susceptibility remains largely unknown. Recently, an involvement of nitric oxide, c-Jun amino-terminal kinases (JNK) and interleukin-1 beta converting enzyme (ICE) related proteases has been proposed in KA induced neuronal cell death. In the present study, we have determined the regional expression of transcripts for two modulating genes operating in these pathways, i.e., the endogenous protein inhibitor of neuronal nitric oxide synthase (PIN), and a cytoplasmic inhibitor of the JNK signal transduction pathway, designated JNK interacting protein-1 (JIP-1) and of the gene for the apoptosis-executing protease Caspase-3 in KA-treated animals. The expression of PIN and JIP-1 was found significantly upregulated in granule cells of the resistant DG. In contrast, an induction of the ICE-related protease Caspase-3 was observed in vulnerable hippocampal regions, i.e. CA1, CA3 and hilus. These results point towards PIN and JIP-1 as antiapoptotic factors contributing to selective resistance of granule cells, whereas Caspase-3 may be involved in cell death of hippocampal CA1, CA3 and hilar neurons in the kainate epilepsy model. PMID- 10101245 TI - The tyrosine kinase inhibitor genistein directly inhibits GABAA receptors. AB - The protein tyrosine kinase (PTK) inhibitor genistein has been widely used to examine potential effects of tyrosine phosphorylation on neurotransmitter function. We report here that genistein inhibits GABAA receptors through a direct effect. Extracellular application of genistein and GABA reversibly inhibited GABA activated currents recorded from HEK293 cells expressing rat alpha1beta2gamma2S or alpha1beta2 receptors, even when genistein was preequilibrated in the intracellular solution. Daidzein, an analog of genistein that does not block PTK, also inhibited GABA-activated current. Coapplication of lavendustin A, a specific inhibitor of PTK, had no effect on the GABA response. Our results demonstrate that genistein has a direct inhibitory effect on GABAA receptors that is not mediated via inhibition of tyrosine kinase. PMID- 10101246 TI - Arachidonic acid potentiates currents through Ca2+-permeable AMPA receptors by interacting with a CaMKII pathway. AB - The present study investigated the effect of arachidonic acid on the alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, presumably heteromeric receptors formed of GluR1, GluR2, and GluR3, expressed in Xenopus oocytes. Arachidonic acid (10 microM) potentiated currents through receptors expressing GluR1 and 3 (GluR1,3) to 170% of basal level during initial 20 min following application, being still evident at 60-min washing-out of the drug, while it never or little enhanced currents through receptors expressing GluR1 and 2 (GluR1,2) or GluR1, 2, and 3 (GluR1,2,3) (110% 30 min after treatment). The effect of arachidonic acid on GluR1,3 currents was not observed in Ca2+-free extracellular solution, and the potentiation was blocked by either KN-93, a selective Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor, or NP217, an active CaMKII inhibitor peptide, when co-expressed with the receptors. In contrast, the protein synthesis inhibitor, cycloheximide, the selective inhibitor of cAMP-dependent protein kinase (PKA), H-89, the selective inhibitors of protein kinase C (PKC), PKCI and GF109203X, the mitogen-activated protein (MAP) kinase kinase inhibitor, PD98059, or the inactive CaMKII inhibitors, KN-92 and NP218, had no effect on the currents. In the assay of intracellular calcium mobilizations, Ca2+ influx in response to receptor activation was greatest with receptors formed in oocytes expressing GluR1,3. The results of the present study indicate that arachidonic acid induces a long-lasting potentiation of GluR1,3 currents, possibly as a result of the interaction with a CaMKII pathway. PMID- 10101247 TI - Acute p-chloroamphetamine increases striatal preprotachykinin mRNA: role of the serotonin 2A/2C receptor. AB - Acute administration of p-chloroamphetamine (pCA) significantly increased (+90%) preprotachykinin (PPT) mRNA levels in the rat striatum. Administration of the serotonin2A/2C receptor antagonist, ritanserin, blocked the pCA-induced increase in PPT mRNA levels. alpha-Methyl-p-tyrosine pretreatment (alpha-MT, to reduce dopamine transmission) inhibited the pCA-induced increase in PPT mRNA levels. These results indicate that the pCA-induced increase in striatal PPT mRNA expression is mediated by serotonin2A/2C receptors but also requires dopamine tone. PMID- 10101248 TI - Prevalence of the GABAA receptor assemblies containing alpha1-subunit in the rat cerebellum and cerebral cortex as determined by immunoprecipitation: lack of modulation by chronic ethanol administration. AB - The anti-alpha1 antibody elicited higher immunoprecipitation (%) values of the [3H]flunitrazepam and [3H]muscimol binding activity in the rat cerebellum vs. cerebral cortex, whereas immunoprecipitation values for [3H]Ro 15-4513 and [3H]zolpidem were comparable in these brain regions. Chronic ethanol administration neither changed the radioligand binding to the immunoprecipitated pellet nor the percentage immunoprecip-itation values, thereby indicating that chronic ethanol did not result in down-regulation of the GABAA receptor assemblies containing alpha1-subunit. PMID- 10101249 TI - Vitamin D receptor 3'-untranslated region polymorphisms: lack of effect on mRNA stability. AB - Allelic variation at the 3'-end of the vitamin D receptor (VDR) gene has been associated with a 3-5-fold increased risk of developing prostate cancer and with differences in bone mineralization. This genetic diversity does not alter the VDR protein structurally, but instead may be a marker(s) of other, nearby polymorphisms that influence message stability or translation. The work reported here was instigated to identify additional VDR 3'-UTR polymorphisms that may have functional significance and to then test whether these genetic variants alter message stability. Initially, four novel, frequently occurring sequence variants were identified that associated with two common haplotypes that were described previously. These common sequence variants were not found within three message destabilizing elements that we mapped within the 3'-UTR of the vitamin D receptor mRNA. Furthermore, the two VDR 3'-UTR haplotypes conferred an identical half-life on a heterologous beta-globin reporter gene, in an in vitro assay. We therefore conclude that common polymorphisms within the VDR 3'-UTR do not influence message stability. PMID- 10101250 TI - The activation of ribonucleotide reductase in animal organs as the cellular response against the treatment with DNA-damaging factors and the influence of radioprotectors on this effect. AB - Cellular requirements for deoxyribonucleotide (dNTP) pools during DNA synthesis are related to ensuring of the accuracy of DNA copying during replication and repair. This paper covers some problems on the reactions of dNTP synthesis system in organs of animals against the treatment with DNA-damaging agents. Ribonucleoside diphosphate reductase (NDPR) is the key enzyme for the synthesis of dNTP, since it catalyses the reductive conversion of ribonucleotides to deoxyribonucleotides. The results obtained show that the rapid and transient increase in NDPR activity in animal organs occurs as cellular response against the treatment with DNA-damaging agents (SOS-type activation). We have also found the intensive radioprotector-stimulated activation of deoxyribonucleotide synthesis as well as DNA and protein synthesis in mice organs within 3 days after the administration of two radioprotectors, indralin and indometaphen, that provide the high animal survival. Our studies suggest that these effects are the most important steps in the protective mechanism of the radioprotectors and are responsible for the high animal survival. PMID- 10101251 TI - Human hepatitis B virus X protein is detectable in nuclei of transfected cells, and is active for transactivation. AB - Subcellular localization and transactivation of human hepatitis B virus X protein (HBx), a plausible causative factor for hepatocellular carcinogenesis, were studied in transiently transfected cells. The transactivation was detected not only by the cis-element driven chloramphenicol acetyltransferase (CAT) assay but also by immunostaining of CAT protein cotransfected into human hepatoma cell line HepG2. Scanning fluorescence microscopy showed the majority of immunological signals of HBx to be at the perinuclear region of transfected cytoplasm. HBx was also clearly detectable in the nucleus, though less intensely expressed. This was confirmed by Western analysis and coimmunoprecipitation of HBx with transcription factor IIB (TFIIB) in subcellular fractionations. The percentage of HBx-positive cells coincided with that of CAT-positive cells, and confocal laser microscopy revealed the coexistence of CAT signals in GFP-HBx positive cells. The SV40 large T antigen nuclear localization signal (NLS) appended HBx, regardless of whether NLS was added to the N- or C-terminus, transactivated all the examined X responsive elements (XRE) similarly as did wild-type HBx. Similar results were obtained in p53 negative Saos-2 cells. The detected nuclear HBx may be involved in modulating the transcription at the promoter level whereas the HBx in cytoplasm may be working through signal transduction pathways. PMID- 10101252 TI - Protein kinase C and amyloid precursor protein processing in skin fibroblasts from sporadic and familial Alzheimer's disease cases. AB - Non-amyloidogenic alpha-secretase processing of amyloid precursor protein (APP) is stimulated by protein kinase C (PKC). Levels and activity of PKC are decreased in sporadic Alzheimer's disease skin fibroblasts. We investigated whether alterations in PKC and PKC-mediated APP processing occur also in fibroblasts established from individuals with familial Alzheimer's disease APP KM670/671NL, PS1 M146V and H163Y mutations. These pathogenic mutations are known to alter APP metabolism to increase Abeta. PKC activities, but not levels, were decreased by 50% in soluble fractions from sporadic Alzheimer's disease cases. In contrast, familial Alzheimer's disease fibroblasts showed no significant changes in PKC enzyme activity. Fibroblasts bearing the APP KM670/671NL mutation showed no significant differences in either PKC levels or PKC-mediated soluble APP (APPs) secretion, compared to controls. Fibroblasts bearing PS1 M146V and H163Y mutations showed a 30% increase in soluble PKC levels and a 40% decrease in PKC mediated APPs secretion. These results indicate that PKC deficits are unlikely to contribute to increased Abeta seen with APP and PS1 mutations, and also that PS1 mutations decrease alpha-secretase derived APPs production independently of altered PKC activity. PMID- 10101253 TI - Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein. AB - The inherited metabolic disease propionic acidemia (PA) can result from mutations in either of the genes PCCA or PCCB, which encode the alpha and beta subunits, respectively, of the mitochondrial enzyme propionyl CoA-carboxylase. In this work we have analyzed the molecular basis of PCCA gene defects, studying mRNA levels and identifying putative disease causing mutations. A total of 10 different mutations, none predominant, are present in a sample of 24 mutant alleles studied. Five novel mutations are reported here for the first time. A neutral polymorphism and a variant allele present in the general population were also detected. To examine the effect of a point mutation (M348K) involving a highly conserved residue, we have carried out in vitro expression of normal and mutant PCCA cDNA and analyzed the mitochondrial import and stability of the resulting proteins. Both wild-type and mutant proteins were imported into mitochondria and processed into the mature form with similar efficiency, but the mature mutant M348K protein decayed more rapidly than did the wild-type, indicating a reduced stability, which is probably the disease-causing mechanism. PMID- 10101254 TI - Antioxidant mechanisms in apolipoprotein E deficient mice prior to and following closed head injury. AB - Apolipoprotein E deficient mice have distinct memory deficits and neurochemical derangements and their recovery from closed head injury is impaired. In the present study, we examined the possibility that the neuronal derangements of apolipoprotein E deficient mice are associated with oxidative stress, which in turn affects their ability to recover from close head injury. It was found that brain phospholipid levels in apolipoprotein E deficient mice are lower than those of the controls (55+/-15% of control, P<0. 01), that the cholesterol levels of the two mice groups are similar and that the levels of conjugated dienes of the apolipoprotein E deficient mice are higher than those of control mice (132+/-15% of P<0.01). Brains of apolipoprotein E deficient mice had higher Mn-superoxide dismutase (134+/-7%), catalase (122+/-8%) and glutathione reductase (167+/-7%) activities than control (P<0.01), whereas glutathione peroxidase activity and the levels of reduced glutathione and ascorbic acid were similar in the two mouse groups. Closed head injury increased catalase and glutathione peroxidase activities in both mouse groups, whereas glutathione reductase increased only in control mice. The superoxide dismutase activity was unaffected in both groups. These findings suggest that the antioxidative metabolism of apolipoprotein E deficient mice is altered both prior to and following head injury and that antioxidative mechanisms may play a role in mediating the neuronal maintenance and repair derangements of the apolipoprotein E deficient mice. PMID- 10101255 TI - Alteration of mannose transport in fibroblasts from type I carbohydrate deficient glycoprotein syndrome patients. AB - The aim of the present study was to explore how mannose enters fibroblasts derived from a panel of children suffering from different subtypes of type I carbohydrate deficient glycoprotein syndrome: seven carbohydrate deficient glycoprotein syndrome subtype Ia (phosphomannomutase deficiency), two carbohydrate deficient glycoprotein syndrome subtype Ib (phosphomannose isomerase deficiency) and two carbohydrate deficient glycoprotein syndrome subtype Ix (not identified deficiency). We showed that a specific mannose transport system exists in all the cells tested but has different characteristics with respect to carbohydrate deficient glycoprotein syndrome subtypes. Subtype Ia fibroblasts presented a mannose uptake equivalent or higher (maximum 1.6-fold) than control cells with a D-[2-3H]-mannose incorporation in nascent N-glycoproteins decreased up to 7-fold. Compared to control cells, the mannose uptake was greatly stimulated in subtype Ib (4.0-fold), due to lower Kuptake and higher Vmax values. Subtype Ib cells showed an increased incorporation of D-[2-3H]-mannose into nascent N-glycoproteins. Subtype Ix fibroblasts presented an intermediary status with mannose uptake equivalent to the control but with an increased incorporation of D-[2-3H]-mannose in nascent N-glycoproteins. All together, our results demonstrate quantitative and/or qualitative modifications in mannose transport of all carbohydrate deficient glycoprotein syndrome fibroblasts in comparison to control cells, with a relative homogeneity within a considered subtype of carbohydrate deficient glycoprotein syndrome. These results are consistent with the possible use of mannose as a therapeutic agent in carbohydrate deficient glycoprotein syndrome Ib and Ix. PMID- 10101256 TI - Protective effects of 5,6,7,8-tetrahydroneopterin against X-ray radiation injury in mice. AB - The protective effects of 5,6,7,8-tetrahydroneopterin (NH4) against radiation injury in mice were studied. (C57BL/6xA/J)F1 (B6A) mice received a single whole body irradiation dose of 200, 400, 700 or 800 cGy of X-rays. NH4 (30 mg/kg body weight) or phosphate-buffered saline (PBS) was injected intraperitoneally into irradiated mice 10 min before and after the irradiation and again after 6 h. All mice which received the 800 cGy radiation+PBS died between 8 and 11 days after the treatment. In contrast, those which also received NH4 demonstrated a significantly prolonged survival time and 40% lived more than 5 months. Total numbers of thymocytes and spleen cells on day 5 post-irradiation were dramatically reduced in line with the radiation dose. The survival was significantly enhanced by NH4 in treated mice. The proliferation of spleen cells in mice stimulated by concanavalin A (Con A) or lipopolysaccharide (LPS) was also greater in NH4 treated mice. The immune response of survivors 5 months after 800 cGy+NH4 treatments, against Con A, LPS, allogenic mouse, and sheep red blood cells had essentially recovered to the levels of normal mice. These results indicate that NH4 had an important role in modifying radiation injury. PMID- 10101257 TI - Quantitative trait loci that regulate plasma lipid concentration in hereditary obese KK and KK-Ay mice. AB - To identify quantitative trait loci (QTLs) responsible for regulating plasma lipid concentration associated with obesity, linkage analysis was carried out on the 190 F2 progeny of a cross between C57BL/6J female and KK-Ay (Ay allele at the agouti locus congenic) male. In F2 a/a (agouti locus genotype) mice, two QTLs were identified on chromosome 1 and a QTL on chromosome 3 for total-cholesterol. A QTL for HDL-cholesterol was identified on chromosome 1 and a QTL for NEFA on chromosome 9. In F2 Ay/a mice, two QTLs for HDL-cholesterol were found on chromosome 1. Loci for other lipids with suggestive linkage were also identified. In both F2 mice, one QTL on chromosome 1 for total- and HDL-cholesterol was mapped near D1Mit150, in the vicinity of the apolipoprotein A-II (Apoa2) locus. Seven nucleotide substitutions out of 309 nucleotide apolipoprotein A-II cDNA sequences were identified between KK and C57BL/6J. The Ay allele may be an indication of the plasma lipid levels, but its influence was less apparent than in the case of weight control. The loci for lipids were not on identical chromosomes with those previously identified for obesity, suggesting that hyperlipidemia in KK does not coincidentally occur with obesity. PMID- 10101258 TI - The effect of bile salts and calcium on isolated rat liver mitochondria. AB - Intact mitochondria were incubated with and without calcium in solutions of chenodeoxycholate, ursodeoxycholate, or their conjugates. Glutamate dehydrogenase, protein and phospholipid release were measured. Alterations in membrane and organelle structure were investigated by electron paramagnetic resonance spectroscopy. Chenodeoxycholate enhanced enzyme liberation, solubilized protein and phospholipid, and increased protein spin label mobility and the polarity of the hydrophobic membrane interior, whereas ursodeoxycholate and its conjugates did not damage mitochondria. Preincubation with ursodeoxycholate or its conjugate tauroursodeoxycholate for 20 min partially prevented damage by chenodeoxycholate. Extended preincubation even with 1 mM ursodeoxycholate could no longer prevent structural damage. Calcium (from 0.01 mM upward) augmented the damaging effect of chenodeoxycholate (0.15-0.5 mM). The combined action of 0.01 mM calcium and 0.15 mM chenodeoxycholate was reversed by ursodeoxycholate only, not by its conjugates tauroursodeoxycholate and glycoursodeoxycholate. In conclusion, ursodeoxycholate partially prevents chenodeoxycholate-induced glutamate dehydrogenase release from liver cell mitochondria by membrane stabilization. This holds for shorter times and at concentrations below 0.5 mM only, indicating that the different constitution of protein-rich mitochondrial membranes does not allow optimal stabilization such as has been seen in phospholipid- and cholesterol-rich hepatocyte cell membranes, investigated previously. PMID- 10101259 TI - In vivo modulation of rodent glutathione and its role in peroxynitrite-induced neocortical synaptosomal membrane protein damage. AB - Peroxynitrite, formed by the reaction between nitric oxide and superoxide, leads to the oxidation of proteins, lipids, and DNA, and nitrates thiols such as cysteine and glutathione, and amino acids like tyrosine. Previous in vitro studies have shown glutathione to be an efficient scavenger of peroxynitrite, protecting synaptosomal membranes from protein oxidation, the enzyme glutamine synthetase from inactivation, and preventing the death of hippocampal neurons in culture. The current study was undertaken to see if in vivo modulation of glutathione levels would affect brain cortical synaptosomal membrane proteins and their subsequent reaction with peroxynitrite. Glutathione levels were depleted, in vivo, by injecting animals with 2-cyclohexen-1-one (CHX, 100 mg/kg body weight), and levels of glutathione were enhanced by injecting animals with N acetylcysteine (NAC, 200 mg/kg body weight), which gets metabolized to cysteine, a precursor of glutathione. Changes in membrane protein conformation and structure in synaptosomes subsequently isolated from these animals were examined using electron paramagnetic resonance, before and after in vitro addition of peroxynitrite. The animals injected with the glutathione depletant CHX showed greater damage to the membrane proteins both before and after peroxynitrite treatment, compared to the non-injected controls. The membrane proteins from animals injected with NAC were comparable to controls before peroxynitrite treatment and were partially protected against peroxynitrite-induced damage. This study showed that modulation of endogenous glutathione levels can affect the degree of peroxynitrite-induced brain membrane damage and may have potential therapeutic significance for oxidative stress-associated neurodegenerative disorders. PMID- 10101260 TI - Cloning of the SmSPO-1 gene preferentially expressed in sporocyst during the life cycle of the parasitic helminth Schistosoma mansoni1. AB - Schistosomes are parasitic helminths with a complex life cycle in human and snail hosts. They express stage-specific genes that conceivably determine distinct properties of the parasite at different developmental stages. Here we report the stage-specific gene SmSPO-1, which is preferentially expressed in sporocysts residing in the snail host. The cDNA and the gene were cloned and sequenced. The cDNA, from cap site to the poly(A) addition site, is 498 bp long. It encodes a protein of 117 amino acids with a hydrophobic signal peptide of 18 residues, indicating that SmSPO-1 is a secreted or a membranal protein. In the gene the cDNA is split into four exons spread over 2.1 kb of chromosomal DNA. PMID- 10101261 TI - Differential potentiation of arachidonic acid release by rat alpha2 adrenergic receptor subtypes. AB - CHO transfectants expressing the three subtypes of rat alpha2 adrenergic receptors (alpha2AR): alpha2D, alpha2B, alpha2C were studied to compare the transduction pathways leading to the receptor-mediated stimulation of phospholipase A2 (PLA2) in the corresponding cell lines CHO-2D, CHO-2B, CHO-2C. The alpha2B subtype stimulated the arachidonic acid (AA) release after incubation of the cells with 1 microM epinephrine, whereas alpha2D and alpha2C gave no stimulation. Calcium ionophore A23187 (1 microM) increased the release by a factor of 2-4 in the three strains. When cells were incubated with both epinephrine and Ca2+ ionophore, the AA release differed greatly between cell lines with strong potentiation in CHO-2B (2-3 times greater than Ca2+ ionophore alone), moderate potentiation in CHO-2D, and no potentiation in CHO-2C. The three cell lines each inhibited adenylylcyclase with similar efficiencies when 1 microM epinephrine was used as the agonist. The potentiation depended on both alpha2AR and Gi proteins since yohimbine and pertussis toxin inhibited the process. Pretreatment of CHO-2B cells with MAFP which inhibits both cytosolic and Ca2+ independent PLA2, reduced the release of AA induced by epinephrine+Ca2+ ionophore to basal value, whereas bromoenol lactone, a specific Ca2+-independent PLA2 inhibitor, had no effect. Preincubation of the cells with the intracellular calcium chelator BAPTA gave a dose-dependent inhibition of the arachidonic acid (AA) release. In CHO cells expressing the angiotensin II type 1 receptor, coupled to a Gq protein, the agonist (10-7 M) produced maximal AA release: there was no extra increase when angiotensin and Ca2+ ionophore were added together. There was no increase in the amount of inositol 1,4, 5-triphosphate following stimulation of CHO-2B, -2C, -2D cells with 1 microM epinephrine. Epinephrine led to greater phosphorylation of cPLA2, resulting in an electrophoretic mobility shift for all three cell lines, so inadequate p42/44 MAPKs stimulation was not responsible for the weaker stimulation of cPLA2 in CHO-2C cells. Therefore, the stimulation of cPLA2 by Gi proteins presumably involves another unknown mechanism. The differential stimulation of cPLA2 in these transfectants will be of value to study the actual involvement of the transduction pathways leading to maximal cPLA2 stimulation. PMID- 10101262 TI - Transacylase formation of bis(monoacylglycerol)phosphate. AB - Recent work within our laboratory has focused on the enzymes we hypothesize are involved in the biosynthesis of bis(monoacylglycerol)phosphate from phosphatidylglycerol. Here we describe a transacylase, active at acidic pH values, isolated from a macrophage-like cell line, RAW 264.7. This enzyme acylates the head group glycerol of sn-3:sn-1' lysophosphatidylglycerol to form sn-3:sn-1' bis(monoacylglycerol)phosphate. Here we demonstrate that this enzyme uses two lysophosphatidylglycerol molecules, one as an acyl donor and another as an acyl acceptor, and that the acyl contributions from all other lipids tested are comparatively minor. This enzyme prefers saturated acyl chains to monounsaturates, 16 and 18 carbon fatty acids over 14 carbon fatty acids, and saturated acyl chains at the sn-1 position to monounsaturated acyl chains on the sn-2 carbon of lysophosphatidylglycerol. We present data which show the transacylase activity depends on the presence of a lipid-water interface and the lipid polymorphic state. PMID- 10101263 TI - Abnormal myo-inositol and phospholipid metabolism in cultured fibroblasts from patients with ataxia telangiectasia. AB - Ataxia telangiectasia (AT) is a complex autosomal recessive disorder that has been associated with a wide range of physiological defects including an increased sensitivity to ionizing radiation and abnormal checkpoints in the cell cycle. The mutated gene product, ATM, has a domain possessing homology to phosphatidylinositol-3-kinase and has been shown to possess protein kinase activity. In this study, we have investigated how AT affects myo-inositol metabolism and phospholipid synthesis using cultured human fibroblasts. In six fibroblast lines from patients with AT, myo-inositol accumulation over a 3-h period was decreased compared to normal fibroblasts. The uptake and incorporation of myo-inositol into phosphoinositides over a 24-h period, as well as the free myo-inositol content was also lower in some but not all of the AT fibroblast lines. A consistent finding was that the proportion of 32P in total labeled phospholipid that was incorporated into phosphatidylglycerol was greater in AT than normal fibroblasts, whereas the fraction of radioactivity in phosphatidic acid was decreased. Turnover studies revealed that AT cells exhibit a less active phospholipid metabolism as compared to normal cells. In summary, these studies demonstrate that two manifestations of the AT defect are alterations in myo inositol metabolism and phospholipid synthesis. These abnormalities could have an effect on cellular signaling pathways and membrane production, as well as on the sensitivity of the cells to ionizing radiation and proliferative responses. PMID- 10101264 TI - Macrophage-targeted CTP:phosphocholine cytidylyltransferase (1-314) transgenic mice. AB - CTP:phosphocholine cytidylyltransferase (CT) is a rate-limiting and complexly regulated enzyme in phosphatidylcholine (PC) biosynthesis and is important in the adaptation of macrophages to cholesterol loading. The goal of the present study was to use transgenesis to study the CT reaction in differentiated macrophages in vivo. We successfully created macrophage-targeted transgenic mice that overexpress a truncated form of CT, called CT-314. Sonicated homogenates of peritoneal macrophages overexpressing CT-314 protein demonstrated a two-fold increase in CT activity in vitro compared with homogenates from nontransgenic macrophages. CT-314 macrophages, however, demonstrated no increase in CT activity or PC biosynthesis in vivo. This finding could not be explained simply by intracellular mistargeting of CT-314, by the inability of CT-314 to associate with cellular membranes, or by substrate limitation. To further probe the mechanism, an in vitro assay using intact nuclei was developed in an attempt to preserve interactions between CT, which is primarily a nuclear enzyme in macrophages, and other nuclear molecules. This intact-nuclei assay faithfully reproduced the situation observed in living macrophages, namely, no significant increase in CT activity despite increased CT-314 protein. In contrast, CT activity in sonicated nuclei from CT-314 macrophages was substantially higher than that from nontransgenic macrophages. Thus, a sonication-sensitive interaction between excess CT and one or more nuclear molecules may be responsible for the limitation of CT activity in CT-314 macrophages. These data represent the first report of a CT transgenic animal and the first study of a differentiated cell type with excess CT. PMID- 10101265 TI - Analysis of the fatty acid components in a perchloric acid-soluble protein. AB - We had previously found that a perchloric acid-soluble protein (PSP1) occurs in rat liver, and that this novel protein inhibits protein synthesis in a rabbit reticulocyte lysate system (T. Oka, H. Tsuji, C. Noda, K. Sakai, Y.-H. Hong, I. Suzuki, S. Munoz, Y. Natori, J. Biol. Chem. 270 (1995) 30060-30067). In the present study, we analyzed lipid components bound to PSP1. Native PSP1 was purified from rat liver using Sephadex G-75, DE-52 cellulose and IgGPSP-affinity chromatography, and the lipid components were extracted. The components obtained from the purified PSP1 were shown to be free fatty acids by thin-layer chromatography. By GC-MS, six major fatty acids were identified as 14:0, 16:0, 18:0, 18:1, 18:2 and 20:4. 1 mol of PSP1 contained 1.26 mol of total fatty acid components. The fatty acid-binding assay of PSP1 showed that the Bmax was 1.25 mol fatty acid/mol PSP1 and the Kd value for palmitic acid was 6.03 microM. The concentration of PSP1 mRNA in rat liver increased 2.3-fold by the administration of peroxisome proliferator, bezafibrate. These findings show that PSP1 is a fatty acid-binding protein-like protein, which is involved in the intracellular metabolism of fatty acid and is quite different from the known fatty acid-binding proteins. PMID- 10101266 TI - Synthesis of mycolic acids of mycobacteria: an assessment of the cell-free system in light of the whole genome. AB - Mycolic acids are 70-90 carbon, alpha-alkyl, beta-hydroxy fatty acids constituting a major component of the cell envelope of Mycobacterium tuberculosis. The fact that the mycolic acid biosynthetic pathway is both essential in mycobacteria and the target for many first-line anti-TB drugs necessitates a detailed understanding of its biochemistry. A whole cell-free, but cell particulate- and membrane-containing enzyme preparation for mycolic acid biosynthesis was developed a few years ago and studied extensively. This system was shown to catalyze the synthesis of mature mycolic acids from [14C]acetate, but allows only minimal deposition into the cell wall proper. In the meantime the sequence of the entire genome of M. tuberculosis has been elucidated and its analysis using numerous protein sequence-based algorithms predicted cytoplasmic localization and a soluble, not a particulate, nature for the enzymes involved in the mycolic acid synthetic pathway. Accordingly, we re-assessed the 'cell-free' system for mycolic acid synthesis and concluded that it is probably due to the presence of unbroken cells, since viable cells were recovered from the cell wall preparation. The amount of whole cells depended upon the efficiency of the cell disruption method and conditions, and the amount of mycolic acid synthesized by the putative cell-free system correlated with the content of whole cells. Thus, accumulated results from the use of this 'cell-free' cell wall-based system should be re-evaluated in the light of these new data. PMID- 10101267 TI - Identification of the GGPS1 genes encoding geranylgeranyl diphosphate synthases from mouse and human. AB - E,E,E-Geranylgeranyl diphosphate (GGPP) is an important precursor of carotenoids and geranylgeranylated proteins such as small G proteins. In this study, we have identified mouse and human GGPP synthase genes. Sequence analysis showed that mouse and human GGPP synthases share a high level of amino acid identity (94%) with each other, and share a high level of similarity (45-50%) with GGPP synthases of lower eukaryotes, but only weak similarity (22-31%) to plant and prokaryotic GGPP synthases. Both of the newly identified GGPP synthase genes from mouse and human were expressed in Escherichia coli, and their gene products displayed GGPP synthase activity when isopentenyl diphosphate and farnesyl diphosphate were used as substrates. The GGPP synthase activity of these genes was also confirmed by demonstrating carotenoid synthesis after co-transformation of E. coli with a plasmid expressing the crt genes derived from Erwinia uredovora, and a plasmid expressing either the mouse or human GGPS1 gene. Southern blot analysis suggests that the human GGPS1 gene is a single copy gene. PMID- 10101268 TI - Functional expression and characterisation of a new human phosphatidylinositol 4 kinase PI4K230. AB - By constructing DNA probes we have identified and cloned a human PtdIns 4-kinase, PI4K230, corresponding to a mRNA of 7.0 kb. The cDNA encodes a protein of 2044 amino acids. The C-terminal part of ca. 260 amino acids represents the catalytic domain which is highly conserved in all recently cloned PtdIns 4-kinases. N terminal motifs indicate multiple heterologous protein interactions. Human PtdIns 4-kinase PI4K230 expressed in vitro exhibits a specific activity of 58 micromol mg-1min-1. The enzyme expressed in Sf9 cells is essentially not inhibited by adenosine, it shows a high Km for ATP of about 300 microM and it is half maximally inactivated by approximately 200 nM wortmannin. These data classify this enzyme as type 3 PtdIns 4-kinase. Antibodies raised against the N-terminal part moderately activate and those raised against the C-terminal catalytic domain inhibit the enzymatic activity. The coexistence of two different type 3 PtdIns 4 kinases, PI4K92 and PI4K230, in several human tissues, including brain, suggests that these enzymes are involved in distinct basic cellular functions. PMID- 10101269 TI - Subcellular localization of enzyme activities involved in the metabolism of platelet-activating factor in rainbow trout leukocytes. AB - The subcellular distribution of an alkyllyso-GPC: acetyl-CoA acetyltransferase (EC 2.3.1.67) and transacylase, two important enzyme activities involved in the remodeling pathway for the biosynthesis of platelet-activating factor (1-O-alkyl 2-acetyl-sn-glycero-3-phosphocholine, PAF) have been examined in leukocytes isolated from the pronephros of the rainbow trout, Oncorhynchus mykiss. Contrary to mammalian systems, in which the acetyltransferase is localized to intracellular membranes, the subcellular distribution of an acetyltransferase activity in rainbow trout leukocytes was localized to the plasma membrane. Analysis of the acetyltransferase products by thin-layer chromatography (TLC) and high performance liquid chromatography (HPLC) confirmed synthesis of two subclasses of PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine and 1-acyl-2 acetyl-sn-glycero-3-phosphocholine. The transacylase activity in this study was detected in membrane fractions in two domains of the intermediate density region which also contained the NADH dehydrogenase activity, a marker enzyme for the endoplasmic reticulum. Acylation of lysoPAF (1-O-alkyl-2-lyso-sn-glycero-3 phosphocholine) exhibited approximately 95% specificity for omega-3 fatty acids. Acylation patterns were not significantly different in either domain of the endoplasmic reticulum. A model is proposed herein for the metabolism of PAF in rainbow trout leukocytes. PMID- 10101270 TI - The influence of estrogen on hepatic cholesterol metabolism and biliary lipid secretion in rats fed fish oil. AB - Both estrogen and dietary n-3 polyunsaturated fatty acids are known to be hypocholesterolemic, but appear to exert their effects by different mechanisms. In this study, the interaction between dietary fish oil (rich in n-3 polyunsaturated fatty acids) and estrogen in the regulation of hepatic cholesterol metabolism and biliary lipid secretion in rats was studied. Rats fed a low fat or a fish oil-supplemented diet for 21 days were injected with 17alpha ethinyl estradiol (5 mg/kg body weight) or the vehicle only (control rats) once per day for 3 consecutive days. Estrogen-treatment led to a marked reduction in plasma cholesterol levels in fish oil-fed rats, which was greater than that observed with either estrogen or dietary fish oil alone. The expression of mRNA for cholesterol 7alpha-hydroxylase was decreased by estrogen in rats fed a low fat or a fish oil-supplemented diet, while the output of cholesterol (micromol/h/kg b.wt.) in the bile was unchanged in both groups. Cholesterol levels in the liver were increased by estrogen in rats given either diet, but there was a significant shift from cholesterol esterification to cholesteryl ester hydrolysis only in the fish oil-fed animals. Estrogen increased the concentration of cholesterol (micromol/ml) in the bile in rats fed the fish oil, but not the low fat diet. However, the cholesterol saturation index was unaffected. The output and concentration of total bile acid was also unaffected, but changes in the distribution of the individual bile acids were observed with estrogen treatment in both low fat and fish oil-fed groups. These results show that interaction between estrogen-treatment and dietary n-3 polyunsaturated fatty acids causes changes in hepatic cholesterol metabolism and biliary lipid secretion in rats, but does not increase the excretion of cholesterol from the body. PMID- 10101271 TI - Gp96/GRP94 is a putative high density lipoprotein-binding protein in liver. AB - We have previously shown that three high density lipoproteins (HDL)-binding proteins in liver, of 90, 110 and 180 kDa, are structurally related. In this study, these proteins are identified as gp96/GRP94. This protein is known to occur as a homodimer and has a dual subcellular localization: it is both an endoplasmic reticulum resident protein, where it is supposed to act as a chaperonin, and a plasma membrane protein, whose significance is unknown. In ultrastructural studies the plasma membrane localization of the homodimeric form was verified. The 90-kDa protein was abundantly present at the membranes of the endosomal/lysosomal vesicles as well as at the apical hepatocyte membranes, comprising the bile canaliculi. The monomeric protein is scarcely present at the basolateral membrane of the hepatocytes, but could be demonstrated in coated pits, suggesting involvement in receptor-mediated endocytosis. Labeling of the endoplasmic reticulum was virtually absent. Gp96/GRP94 was transiently expressed in COS-1 cells. However, the expressed protein was exclusively localized in the endoplasmic reticulum. Transfection with constructs in which the C-terminal KDEL sequence had been deleted, resulted in plasma membrane localized expression of protein, but only in an extremely low percentage of cells. In order to evaluate the HDL-binding capacities of this protein, stably transfected cells were generated, using several cell types. It appeared to be difficult to obtain a prolonged high level expression of gp96. In these cases, however, a marked increase of HDL-binding activity compared with the control cells could be observed. PMID- 10101272 TI - Perfluorooctanoic acid, a peroxisome-proliferating hypolipidemic agent, dissociates apolipoprotein B48 from lipoprotein particles and decreases secretion of very low density lipoproteins by cultured rat hepatocytes. AB - The hypolipidemic effect is evoked by various peroxisome proliferators. Modulation of gene transcription via peroxisome proliferator-activated receptor (PPAR) is generally responsible for this effect. In addition, we have found a PPAR-independent mechanism in which fibrates, known peroxisome proliferators, decrease hepatic secretion of very low density lipoproteins (VLDL) through inhibition of phosphatidylcholine synthesis via methylation of phosphatidylethanolamine (PE) (T. Nishimaki-Mogami et al., Biochim. Biophys. Acta 1304 (1996) 21-31). In the present study, we show a novel mechanism by which perfluorooctanoic acid (PFOA), a potent peroxisome proliferator and inhibitor of PE methylation, exerts its hypolipidemic effect. PFOA (100 microM) added to the medium rapidly decreased the secretion of triglyceride by cultured rat hepatocytes, which was independent of the activity of cellular PE methylation. Analysis of the density of apoB secreted into the medium showed that PFOA decreased apoB48 in VLDL, but increased apoB48 in the bottom d>1.21 fraction. This lipid-poor apoB48 was also generated by incubating medium that had been harvested from control cells with PFOA, indicating that PFOA has the ability to dissociate apoB48 from lipoprotein particles. Exposure of cells to PFOA for 2 h prior to the experiment was sufficient to generate lipid-poor apoB48, indicating that PFOA exerted its effect intracellularly. Taken together, the data suggest that a strong interaction of PFOA with apoB48 disturbs the association of apoB48 with lipids in the process of intracellular VLDL assembly, thereby inhibiting VLDL secretion. This study shows that the mechanisms of hypolipidemic effect caused by various classes of peroxisome proliferators are diverse. PMID- 10101273 TI - Intermediates of myocardial mitochondrial beta-oxidation: possible channelling of NADH and of CoA esters. AB - Adult rat heart mitochondria were isolated and incubated with [U-14C]hexadecanoyl CoA or unlabelled hexadecanoyl-CoA. The accumulating CoA and carnitine esters and [NAD+]/[NADH] ratio were measured by HPLC or tandem mass spectrometry. Despite minimal changes in the intramitochondrial [NAD+]/[NADH] ratio, 2, 3-unsaturated and 3-hydroxyacyl esters were observed as well as saturated acyl-CoA and acylcarnitine esters. In addition to acetylcarnitine, significant amounts of butyryl-, hexanoyl-, octanoyl- and decanoylcarnitines were detected and measured. Rat myocardial beta-oxidation is subject to control at the level of 3-hydroxyacyl CoA dehydrogenase but this control is not due to a simple lack of oxidised NAD. We hypothesise a pool of NAD in contact between the trifunctional protein of beta oxidation and complex I of the respiratory chain, the turnover of which is responsible for some of the control of beta-oxidation flux. In addition, short- and medium-chain acylcarnitine esters were detected whereas only small amounts of long-chain acylcarnitines were present. This may imply the presence of a mitochondrial carnitine octanoyl transferase or may reflect channelling of long chain CoA esters so that they are not available for carnitine palmitoyl transferase II activity. PMID- 10101274 TI - Molecular cloning and functional expression of a phospholipase D from cabbage (Brassica oleracea var. capitata). AB - We cloned and expressed a full-length cDNA encoding a phospholipase D of type alpha (PLDalpha) from cabbage. Analysis of the cDNA predicted an 812-amino-acid protein of 92.0 kDa. The deduced amino acid sequence of cabbage PLD has 83% and 80% identity with Arabidopsis PLDalpha and castor bean PLD, respectively. Expression of this cDNA clone in E. coli shows a functional PLD activity similar to that of the natural PLD. PMID- 10101275 TI - Halobacterial rhodopsins. AB - Following the discovery of the bacteriorhodopsin proton pump in Halobacterium halobium (salinarum), not only the halorhodopsin halide pump and two photosensor rhodopsins (sensory rhodopsin and phoborhodopsin) in the same species, but also homologs of these four rhodopsins in strains of other genera of Halobacteriaceae have been reported. Twenty-eight full (and partial) sequences of the genomic DNA of these rhodopsins have been analyzed. The deduced amino acid sequences have led to new strategies and tactics for understanding bacterial rhodopsins on a comparative basis, as summarized briefly in this article. The data discussed include (i) alignment of the sequences to qualify/characterize the conserved residues; (ii) assignment of residues that cause differences in function(s)/properties; and (iii) phylogeny of the halobacterial rhodopsins to suggest their evolutionary paths. The four kinds of rhodopsin in each strain are assumed, on the basis of their genera-specific distributions, to have arisen by at least two gene-duplication processes during evolution prior to generic speciation. The first duplication of the rhodopsin ancestor gene yielded two genes, each of which was duplicated again to give four genes in the ancestor halobacterium. The bacterium carrying four rhodopsin genes, after accumulating mutations, became ready for generic speciation and the delivery of four rhodopsins to each species. The original rhodopsin ancestor is speculated to be closest to the proton pump (bacteriorhodopsin). PMID- 10101276 TI - Inhibitory effects of catecholamines and anti-oxidants on the fluorescence reaction of 4,5-diaminofluorescein, DAF-2, a novel indicator of nitric oxide. AB - 4,5-Diaminofluorescein (DAF-2) is a newly developed indicator of nitric oxide (NO). Two amino groups of DAF-2 are oxidized by NO. We investigated the effects of reducers on the NO-induced oxidation of DAF-2. NOC-5 (0.1-10 microM), a NO donor, concentration-dependently elicited fluorescence with 10 microM DAF-2. The rate of the fluorescence reaction was dependent on the width of the excitation band path. The presence of catecholamines (1 microM), but not tyrosine or phenylephrine, attenuated the fluorescence induced by NOC-5. Ascorbate and other reducers like dithiothreitol, 2-mercaptoethanol, or glutathione (all 1 mM) abolished the fluorescence. These results suggest that reducers attenuate the NO induced fluorescence of DAF-2 mainly through an anti-oxidative action. PMID- 10101277 TI - Site-directed mutagenesis of a possible type 1 copper ligand of bilirubin oxidase; a Met467Gln mutant shows stellacyanin-like properties. AB - In our previous paper, we reported a mutant of recombinant Myrothecium verrucaria bilirubin oxidase, in which the Met467 residue was replaced by Gly [Shimizu, A. et al. (1999) Biochemistry 38, 3034-3042]. This mutant displayed a remarkable reduction in enzymatic activity and an evident decrease in the intensity of the absorption band around 600 nm (type 1 charge transfer transition). In this study, we report the preparation of three Met467 mutants (Met467Gln, Met467His, and Met467Arg) and characterize their enzymatic activities, midpoint potentials, and absorption and ESR spectra. Met467His and Met467Arg show no enzymatic activity and a great reduction in the intensity of the absorption band around 600 nm. Furthermore, their ESR spectra show no type 1 copper signal, but only a type 2 copper signal; however, oxidation by ferricyanide caused the type 1 copper signal to appear. On the other hand, Met467Gln as expressed shows both type 1 and type 2 copper signals in its ESR spectrum, the type 1 copper atom parameters being very different from usual blue copper proteins but very similar to those of stellacyanin. The enzymatic activity of the Met467Gln mutant for bilirubin is quite low (0.3%), but the activity for potassium ferrocyanide is similar (130%) to that of the wild type enzyme. These results indicate that Met467 is important for characterizing the features of the type 1 copper of bilirubin oxidase. PMID- 10101278 TI - Down-regulation of protein tyrosine phosphatase gene expression in lactating mouse mammary gland. AB - Detailed analysis of protein tyrosine phosphatase (PTP) expression in mouse mammary gland and mammary epithelial cells using a set of degenerate primers corresponding to the PTP core domain sequence revealed the presence of 16 different receptor-type and intracellular PTPs. Northern blot and RT-PCR analyses revealed that some PTPs were up-regulated during gestation, suggesting that these enzymes are involved in development of mammary gland. However, expression of most PTPs dramatically decreased during lactation, whereas the beta-casein gene expression was increased and remained at a high level. At the involution stage after weaning, most PTPs were up-regulated and their expression returned almost to the virgin level. Such up-regulation was also induced by forced weaning in lactating mother mice. These results suggest the possible contribution of PTPs to the development, involution, and remodeling of mammary gland and their possible inhibitory action on maintaining high expression of milk genes during lactation. PMID- 10101279 TI - Alkali-treated collagen retained the triple helical conformation and the ligand activity for the cell adhesion via alpha2beta1 integrin. AB - Alkaline treatment is a good method for extracting collagen with high recovery even from an aged animal specimen. However, the properties of collagen treated under alkaline conditions have not been well established yet. By the treatment with a solution of 3% sodium hydroxide and 1.9% monomethylamine, the isoelectric point of type I collagen was lowered from 9.3 to 4.8 because of the conversions of Asn and Gln to Asp and Glu. With the acidification of the pI, the denaturation temperature of the collagen was decreased from 42 to 35 degrees C after 20 d treatment, but the collagen-specific triple helical conformation was maintained. Human keratinocytes and fibroblasts adhered to the alkali-treated collagen via the collagen receptor integrin alpha2beta1. This indicates that the alkali treated collagen maintained its property as a biological adherent molecule. Unlike acid-soluble collagen, alkali-treated collagen lost the ability to form fibrils at neutral pH under physiological conditions. This ability was lost even after 4 h of alkaline treatment, when the denaturation temperature of the collagen did not change. On the other hand, the alkali-treated collagen formed a fibrous precipitate with a uniform diameter of 50-70 nm under acidic conditions at 30 degrees C. PMID- 10101280 TI - HPC-1/syntaxin 1A suppresses exocytosis of PC12 cells. AB - The membrane protein syntaxin (originally named HPC-1) is involved in vesicle trafficking and required for neurotransmitter release at nerve terminals. The presence of syntaxin on target membranes is hypothesized to confer specificity to targeting and fusion via interactions with complementary vesicle-associated proteins. To elucidate the function of syntaxin 1A in exocytosis, HPC-1/syntaxin 1A-reduced PC12h cells (PC12h/Deltasyx) that were stably transfected with a plasmid for antisense syntaxin 1A expression were constructed. Depolarizing stimulation of PC12h/Deltasyx enhanced dopamine release, compared with PC12h. There was a strong inverse correlation between syntaxin 1A protein expression and enhancement of dopamine release. Reduction of syntaxin 1A had no effect on increase of the cytoplasmic free Ca2+ concentration by depolarized stimulation. Moreover, PC12h/Deltasyx clones similarly enhanced of exocytosis by native secretagogues. These results indicate that syntaxin 1A has more than one function in exocytosis. PMID- 10101281 TI - Enzymatical properties of psychrophilic phosphatase I. AB - Phosphatase I purified from a psychrophile (Shewanella sp.) [Tsuruta et al. (1998) J. Biochem. 123, 219-225] dephosphorylated O-phospho-L-tyrosine and phospho-tyrosyl residues in phosphorylated poly(Glu4,Tyr1) random polymer (polyEY) and phosphorylated myelin basic protein (MBP) but not phosphoseryl and/or phosphothreonyl residues in phosphorylated histone H1, casein and phosphorylase a, indicating that the enzyme showed protein-tyrosine-phosphatase (PTPase, EC 3.1.3.48)-like activity in vitro. The enzyme was remarkably inhibited by diethylpyrocarbonate (DEPC), monoiodoacetic acid (MIAA), and monoiodoacetamide (MIAM). Binding of 1 mol of DEPC to 1 mol of the enzyme caused complete inhibition of the enzyme; and 0.88 mol of 1-carboxymethylated histidine per mole of the enzyme was found when 90% of enzyme activity was lost by modification with 14C-MIAA. These results indicated that this psychrophilic enzyme was a PTPase like enzyme with histidine as its catalytic residue. PMID- 10101282 TI - Functional expression of nitrile hydratase in Escherichia coli: requirement of a nitrile hydratase activator and post-translational modification of a ligand cysteine. AB - The nitrile hydratase (NHase) from Rhodococcus sp. N-771 is a photoreactive enzyme that is inactivated on nitrosylation of the non-heme iron center and activated on photo-dissociation of nitric oxide (NO). The nitrile hydratase operon consists of six genes encoding NHase regulator 2, NHase regulator 1, amidase, NHase alpha subunit, NHase beta subunit and NHase activator. We overproduced the NHase in Escherichia coli using a T7 expression system. The NHase was functionally expressed in E. coli only when the NHase activator encoded downstream of the beta subunit gene was co-expressed and the transformant was grown at 30 degrees C or less. A ligand cysteine, alphaCys112, of the recombinant NHase was also post-translationally modified to a cysteine-sulfinic acid similar to for the native NHase. Although another modification of alphaCys114 could not be identified because of the instability under acidic conditions, the recombinant NHase could be reversibly inactivated by nitric oxide. PMID- 10101283 TI - Structure-function relationship of model Aib-containing peptides as ion transfer intermembrane templates. AB - Peptaibols comprise a family of peptide antibiotics with high contents of 2 aminoisobutyric acid (Aib) residues and C-terminal amino alcohols. These peptides form alpha-helical structures leading to voltage-gated ion channels in lipid membranes. In the present study, amphiphilic helical Aib-containing peptides of various chain-lengths, Ac-(Aib-Lys-Aib-Ala)n-NH2 (n = 1-5), were designed to investigate the mechanisms of the aggregation and transmembrane orientation of helical motifs in lipid bilayer membranes. Peptide synthesis was performed by the conventional stepwise Fmoc solid-phase method. The crude peptides were obtained in high yields (66-85%) with high purities (69-95%). Conformational analysis of the synthetic peptides was performed by CD spectroscopy. It was found that these peptides take on highly helical structures, and the helicity of the peptides increases with an increase in chain-length. The longest peptide, Ac-(Aib-Lys-Aib Ala)5-NH2, self-aggregates and adopts a barrel-stave conformation in liposomes. Ac-(Aib-Lys-Aib-Ala)5-NH2 exhibited potent antimicrobial activity against Gram positive bacteria. Patch-clamp measurements revealed that this peptide can form well-defined ion channels with a long lifetime at relatively low transbilayer potentials and peptide concentrations. For this peptide, the single-channel conductance of the most frequent event is 227 pS, which could be related to a single-state tetrameric pore. PMID- 10101284 TI - Effect of the hemolytic lectin CEL-III from Holothuroidea Cucumaria echinata on the ANS fluorescence responses in sensitive MDCK and resistant CHO cells. AB - The addition of CEL-III to sensitive MDCK cells preincubated with 8-anilino-1 naphthalenesulfonate (ANS) caused an increase in the fluorescence intensity of the probe. The increase in the ANS fluorescence caused by CEL-III was Ca2+ dependent and strongly inhibited by 0.1 M lactose, indicating that Ca2+-dependent binding of CEL-III to specific carbohydrate receptors on the plasma membrane is responsible for this phenomenon. In contrast, no significant effect of CEL-III on the ANS fluorescence was observed in CHO cells, which are highly resistant to CEL III cytotoxicity. In MDCK cells, energy transfer from tryptophan residues to bound ANS molecules was observed in the presence of CEL-III, but not in CHO cells. Furthermore, the amount of ANS bound to MDCK cells increased as the concentration of CEL-III increased. Therefore, a simple interpretation is that the CEL-III-induced increase in ANS fluorescence is attributable to an increase of the hydrophobic region in the plasma membrane where ANS could bind. Immunoblotting analysis of proteins from cells treated with CEL-III indicated that CEL-III oligomers were irreversibly bound to the cells, and the amount of oligomer bound to MDCK cells was much greater than that bound to CHO cells under any conditions tested. The oligomerization may be accompanied by an enhancement of the hydrophobicity of CEL-III molecules, which in turn provides new ANS binding sites. The difference in susceptibility of MDCK and CHO cells to CEL-III cytotoxicity may be due to a difference in oligomerization of bound CEL-III. PMID- 10101285 TI - Characterization of the novel mitochondrial protein import component, Tom34, in mammalian cells. AB - Tom34 is a newly-found component of the mitochondrial protein import machinery in mammalian cells with no apparent counterpart in fungi. RNA blot and immunoblot analyses showed that the expression of Tom34 varies among tissues and differs from that of the core translocase component Tom20. In contrast to a previous report [Nuttal, S.D. et al. (1997) DNA Cell Biol. 16, 1067-1074], the present study using a newly-prepared anti-Tom34 antibody with a high titer showed that Tom34 is present largely in the cytosolic fraction and partly in the mitochondrial and membrane fractions after fractionation of tissues and cells, and that the membrane-associated form is largely extractable with 0.1 M sodium carbonate. The in vitro import of preproteins into isolated rat mitochondria was strongly inhibited by DeltahTom34 which lacks the NH2-terminal hydrophobic region of human Tom34 (hTom34). Import was also strongly inhibited by anti-hTom34. In pulse-chase experiments using COS-7 cells, pre-ornithine transcarbamylase (pOTC) was rapidly processed to the mature form. Coexpression of hTom34 resulted in a stimulation of pOTC processing, whereas the coexpression of hTom34 antisense RNA caused inhibition. The results confirm that Tom34 plays a role in mitochondrial protein import in mammals, and suggest it to be an ancillary component of the translocation machinery in mammalian cells. PMID- 10101286 TI - Molecular cloning and expression of the novel fungal beta-glucosidase genes from Humicola grisea and Trichoderma reesei. AB - A novel fungal beta-glucosidase gene (bgl4) and its homologue (bgl2) were cloned from the cellulolytic fungi Humicola grisea and Trichoderma reesei, respectively. The deduced amino acid sequences of H. grisea BGL4 and T. reesei BGL2 comprise 476 and 466 amino acids, respectively, and share 73.1% identity. These beta glucosidases show significant homology to plant beta-glucosidases belonging to the beta-glucosidase A (BGA) family. Both genes were expressed in Aspergillus oryzae, and the recombinant beta-glucosidases were purified. Recombinant H. grisea BGL4 is a thermostable enzyme compared with recombinant T. reesei BGL2. In addition to beta-glucosidase activity, recombinant H. grisea BGL4 showed a significant level of beta-galactosidase activity, while recombinant T. reesei BGL2 showed weak beta-galactosidase activity. Cellulose saccharification by Trichoderma cellulases was improved by the addition of recombinant H. grisea BGL4. PMID- 10101287 TI - Increases in ceramide levels in normal human mesangial cells subjected to different cellular stresses result from changes in distinct enzyme activities and can influence cellular responses to other stimuli. AB - Sphingolipids, ceramide in particular, have come to be regarded as having roles in cellular signaling, most recently being associated with stress and the cellular responses to stress. In the present study we first examined the mechanisms involved in the changes in cellular ceramide levels in normal human mesangial cells (NHMC) in the growth, quiescent, and senescent phases as well as those resulting from environmental stimuli. We found that in NHMC total ceramide levels increase in response to cellular stresses as a result of a combination of enzyme activities. Furthermore, different stresses cause different alterations in various enzyme activities, with age and growth influencing acidic enzymes, but cell density affecting neutral, resulting in final ceramide level increases which most likely are associated with distinct pools of ceramide. Secondly, we examined the influence of changes in ceramide levels on apoptosis induced by sphingosine and its methylated derivative N, N-dimethylsphingosine. We found that increases in cellular ceramide levels prohibited the apoptosis and caused a quiescent state in the cells. The data presented here provide additional insight into the roles of ceramide and related enzymes in cellular responses to stress and suggest a possible relevance to in vivo disease states. PMID- 10101288 TI - Specific and sensitive assay for alkaline and neutral ceramidases involving C12 NBD-ceramide. AB - A fluorescent analogue of ceramide, C12-NBD-ceramide, was found to be hydrolyzed much faster than 14C-labeled ceramide by alkaline ceramidase from Pseudomonas aeruginosa and neutral ceramidase from mouse liver, while this substrate was relatively resistant to acid ceramidase from plasma of the horseshoe crab. The radioactive substrate was used more preferentially by the acid ceramidase. It should be noted that C6-NBD-ceramide, which is usually used for ceramidase assays, was hardly hydrolyzed by any of the enzymes examined, compared to C12-NBD ceramide. For the alkaline and neutral enzymes, the Vmax and k (Vmax/Km) with C12 NBD-ceramide were much higher than those with 14C-ceramide. In contrast, for the acid enzyme these parameters with C12-NBD-ceramide were less than half those with the radioisotope-labeled substrate. It is noteworthy that the labeling of ceramide with NBD did not itself reduce the Km of the alkaline enzyme, but did that of the neutral enzyme. It was also found that C12-NBD-ceramide was preferentially hydrolyzed by the alkaline and neutral enzymes, but not the acid one, in several mammalian cell lines. This study clearly shows that the attachment of NBD, but not dansyl, increases the susceptibility of ceramide to alkaline and neutral enzyme, and decreases that to acid enzymes. Thus the use of this substrate provides a specific and sensitive assay for alkaline and neutral ceramidases. PMID- 10101289 TI - Cloning and expression of the Ca2+ channel alpha1C and beta2a subunits from guinea pig heart. AB - Complimentary DNA clones encoding the alpha1C and beta2a subunits of guinea-pig cardiac L-type Ca2+ channels were isolated using the PCR method. The open reading frame encoded 2,169 amino acids for the alpha1C and 597 amino acids for the beta2a subunit. The proteins showed 94.2 and 94.8%, respectively, identity to the respective subunit of the rabbit protein. The message size of the guinea pig alpha1C and beta2a subunits was 8.0 and 3.5/4.0 kb, respectively. RT-PCR analysis revealed that the alpha1C subunit is expressed exclusively in the heart, while the beta2a subunit is expressed in the heart, cerebellum, whole brain, and stomach. The alpha1C and beta2a subunits are transiently expressed in BHK (baby hamster kidney) cells, and the channel currents were studied using the whole-cell patch clamp technique in medium containing 30 mM Ba2+. In cells expressing alpha1C alone, the Ba2+ current was activated at -30 mV and more positive potentials and peaked at about 10 mV. The co-expression of beta2a with alpha1C did not affect the voltage-dependence of the current, but increased the peak current and accelerated current decay. In cells transfected with guinea pig alpha1C and rabbit beta1+alpha2/delta, a Ba2+ current comparable to those in native myocytes was observed. The Ba2+ current can be blocked completely by nifedipine and is enhanced 3-fold by Bay K 8644. On the other hand, neither forskolin nor okadaic acid affects the Ba2+ current, suggesting that cAMP mediated modulation is not easily reproduced in transfected cells, unlike that seen in native cardiac myocytes. PMID- 10101290 TI - Purification and characterization of cold-active L-glutamate dehydrogenase independent of NAD(P) and oxygen. AB - L-Glutamate dehydrogenase (GLDH) independent of NAD(P) and oxygen was first obtained from the psychrotrophic bacterium Aeromonas sp. L101, originally isolated from the organs of salmon (Oncorhynchus keta). GLDH was purified by a series of chromatography steps on DEAE-Sepharose, Superdex 200pg, Q-Sepharose, CM Sepharose, and Phenyl-Sepharose. The purified protein was determined to have a molecular mass of 110 kDa and a pI of 5.7. Maximum activity was obtained at 55 degrees C and pH 8.5. The activity of GLDH at 4 and 20 degrees C was 38 and 50%, respectively, of that at 50 degrees C. GLDH was coupled to cytochrome c and several redox dyes including 1-methoxy-5-methylphenazinium methylsulfate (1 Methoxy PMS), 2, 6-dichlorophenylindophenol (DCIP), 9 dimethylaminobenzo[alpha]phenoxazin-7-ium chloride (meldola's blue), 3,3'-[3,3' dimethoxy-(1,1'-biphenyl)-4, 4'-diyl]-bis[2-(4-nitrophenyl)-5-phenyl-2H tetrazolium chloride] (nitroblue tetrazolium; NBT), and 2-(4-iodophenyl)-3-(4 nitrophenyl)-5-phenyl-2H tetrazolium (INT). The presence of NAD(P) and oxygen gave no oxidation activity to GLDH. Spectroscopic profile and ICP data indicated a b-type cytochrome containing iron. PMID- 10101292 TI - Dynamin II is involved in endocytosis but not in the formation of transport vesicles from the trans-Golgi network. AB - Dynamins are a family of approximately 100-kDa GTPases that are thought to play a pivotal role in the formation of endocytic coated vesicles. There are three dynamin genes in mammals: dynamin I is neuron-specific, dynamin II shows ubiquitous expression, and dynamin III is expressed in testis, brain, and lung. However, most studies on the functions of dynamins to date have been restricted to dynamin I. In the present study, we show that, like dynamin I, dynamin II is involved in receptor-mediated endocytosis. While this study was in progress, Jones et al. [Jones, S.M., Howell, K.E., Henley, J.R., Cao, H., and McNiven, M.A. (1998) Science 279, 573-577] reported that dynamin II is localized in the trans Golgi network (TGN) and involved in the formation of constitutive transport vesicles and clathrin-coated vesicles from this compartment. However, immunofluorescence analyses and experiments using cells transfected with dominant negative dynamin II failed to show any evidence for localization of dynamin II in the TGN or for its involvement in vesicle formation from this compartment. Our data thus indicate that dynamin II is involved in endocytosis but not in the formation of transport vesicles from the TGN. PMID- 10101291 TI - Analysis of where and which types of proteinases participate in lysosomal proteinase processing using bafilomycin A1 and Helicobacter pylori Vac A toxin. AB - Lysosomal proteinases are translated as preproforms, transported through the Golgi apparatus as proforms, and localized in lysosomes as mature forms. In this study, we analyzed which subclass of proteinases participates in the processing of lysosomal proteinases using Bafilomycin A1, a vacuolar ATPase inhibitor. Bafilomycin A1 raises lysosomal pH resulting in the degradation of lysosomal proteinases such as cathepsins B, D, and L. Twenty-four hours after the withdrawal of Bafilomycin A1, NIH3T3 cells possess these proteinases in amounts and activities similar to those in cells cultured in DMEM and 5% BCS. In the presence of various proteinase inhibitors, procathepsin processing is disturbed by E-64-d, resulting in abnormal processing of cathepsins D and L, but not by APMSF, Pepstatin A, or CA-074. In the presence of Helicobacter pylori Vac A toxin, which prevents vesicular transport from late endosomes to lysosomes, the processing of procathepsins B and D occurs, while that of procathepsin L does not. Thus, procathepsins B and D are converted to their mature forms in late endosomes, while procathepsin L is processed to the mature form after its arrival in lysosomes by some cysteine proteinase other than cathepsin B. PMID- 10101293 TI - Characterization of imidazole as a DNA denaturant by using TGGE of PCR products from a random pool of DNA. AB - Perpendicular temperature gradient gel electrophoresis (TGGE) profiles were analyzed for PCR products from a random pool of DNA [60 nts random region flanked by two primer (20 nts) sites]. Besides a normal transition profile of a homoduplex, unique mobility transition profiles of two kinds of heteroduplex with a big internal loop were observed, representing the successive helix-coil transitions of the DNAs. As the appearance of the heteroduplex band is an estimator of the complexity of a random pool, it will be applicable to monitor the extent of the selection process in the in vitro selection method. When imidazole was added to the electrophoretic buffer, the transition pattern shifted to the low temperature side. At a concentration of 1 M, imidazole lowered the melting temperature (Tm) of DNA by 13+/-2 degrees C for all the three chain separation transitions observed. Thus imidazole is a stronger denaturant than urea, at least at dilute concentration. Dependence of Tm on concentration of imidazole and the mobility change suggested that imidazole binds to nucleotide in the single-stranded state. PMID- 10101294 TI - Genomic organization and promoter analysis of a mouse homeobox gene, Hex. AB - A homeobox gene, Hex, is mainly expressed in haematopoietic cells and hepatocytes. It is assumed to play a role in the early stage of differentiation of these cells. To understand the mechanisms involved in the regulation of the Hex gene expression in hepatocytes, we cloned and characterized the mouse Hex gene. The gene consists of four exons and three introns, and spans about 5.7 kb. All the exon-intron boundaries are consistent with the "GT-AG" rule. A single transcription start site was identified by primer extension and S1 mapping analyses. Although the 5'-flanking region is G/C rich (69%), it contains probable "TATA and CCAAT" boxes. Potential binding sequences for transcriptional regulatory proteins including Sp1 and AP-2 are also present in this region. Functional analysis of the Hex promoter was performed by transfecting MH1C1, HeLa, COS-7, and Caco-2 cells with Hex promoter region-luciferase constructs. We found three possible positive regulatory regions, comprising of nucleotides -199 and -172, -154 and -133, and -105 and -68, respectively, required for Hex gene expression in MH1C1 cells by analyses of a series of 5'-deletion constructs of the fusion genes. The activities of these constructs were extremely low in HeLa, COS-7, and Caco-2 cells suggesting that they possess cell-type specificity. Further analysis revealed two GC boxes, GC box1 and GC box2, at nucleotides -197 to -188 and -176 to -167, respectively, necessary for Hex gene expression. Thus, multiple regulatory elements contribute to the Hex gene expression in hepatocytes. PMID- 10101295 TI - Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. AB - A genetic polymorphism was identified in the 5'-flanking region of human CYP1A2 gene, and its effect on the transcriptional activation of the CYP1A2 gene was investigated. Nucleotide sequence analysis revealed the existence of a point mutation from guanine (wild type) to adenine (mutated type) at position -2964 in the gene. This point mutation was detected by a polymerase chain reaction restriction fragment length polymorphism method using DdeI or BslI restriction enzyme, and was proven to be genetically inherited. Allele frequency in 116 Japanese subjects showed 0.77 and 0.23 for the wild and mutated types of allele, respectively. The point mutation caused a significant decrease of CYP1A2 activity measured by the rate of caffeine 3-demethylation in Japanese smokers (p<0.05). Gel retardation analysis showed the existence of protein bound to the polymorphic locus. These results suggest that this polymorphism is a causal factor of decreased CYP1A2 inducibility. PMID- 10101296 TI - Recognition of multiple patterns of DNA sites by Drosophila homeodomain protein Bicoid. AB - Our previous studies demonstrated that the Drosophila homeodomain protein, Bicoid (Bcd), binds DNA cooperatively. In this study, we determined the patterns of adjacent DNA sites required for cooperative recognition by Bcd. Our in vitro selection and biochemical experiments demonstrated that Bcd binds preferentially to both head-to-head and tail-to-tail symmetric sites that are separated by short spacing. An increase in the spacing reduces the strict requirement of symmetric patterns of adjacent sites, permitting Bcd to recognize tandem repeat sites cooperatively. Our further experiments in vivo showed that the only pair of optimally spaced symmetric Bcd sites in a hunchback (hb) enhancer element contributes the most to transcriptional activation by Bcd, demonstrating the biological importance of the binding site patterns revealed by our in vitro selection studies. PMID- 10101297 TI - The human PMS2L proteins do not interact with hMLH1, a major DNA mismatch repair protein. AB - The human PMS2 gene encodes one of the bacterial mutL homologs that is associated with hereditary nonpolyposis colorectal cancer (HNPCC). One of the interesting features of the hPMS2 gene is that it is part of a multiple gene family which is localized on chromosome bands 7p22, 7p12-p13, 7q11, and 7q22. Here we report four newly identified hPMS2-like (PMS2L) genes. All four novel members of the PMS2L gene family encode relatively short polypeptides composed of the amino-terminal portion of hPMS2 and are expressed ubiquitously except in the heart. To clarify whether the PMS2L polypeptides contribute to the DNA mismatch repair (MMR) pathway through an interaction with hMLH1, we have performed a yeast two-hybrid assay and an immunoprecipitation study using an hPMS2 mutant cell line, HEC-1-A. Our results clearly indicate that hMLH1 does not interact with two representative PMS2Ls, whereas the carboxyl-terminal portion of hPMS2, not the amino-terminal portion, does interact with hMLH1. Thus, PMS2Ls are not likely to participate in the MMR pathway through association with hMLH1; they must play some other roles in the living cells. PMID- 10101298 TI - Identification and characterization of ligands for L-selectin in the kidney. III. Characterization of L-selectin reactive heparan sulfate proteoglycans. AB - L-Selectin, a leukocyte adhesion molecule, mediates leukocyte rolling on the endothelium and plays a critical role in leukocyte recruitment at inflammatory sites as well as in lymphocyte homing. We have previously shown that L-selectin reactive chondroitin sulfate and heparan sulfate proteoglycans (HSPGs) are both expressed in the distal tubules of the kidney and that versican is one of the chondroitin sulfate-type ligands. In the present study, we characterized the heparan sulfate-type ligand(s) in more detail. The molecular sizes of HSPGs were approximately 600 kDa with core protein sizes of 160 and 180 kDa. Western blotting analysis showed that L-selectin reactive HSPGs were neither agrin nor perlecan, major basement membrane HSPGs in the kidney. The binding to L-selectin was mediated by the lectin domain of L-selectin in a Ca2+-dependent manner and required heparan sulfate side chains, but not sialic acid. To our knowledge, this is the first biochemical characterization of the L-selectin reactive heparan sulfate proteoglycan(s) in the distal tubules of the kidney. PMID- 10101299 TI - Functional domain structure of human heterochromatin protein HP1(Hsalpha): involvement of internal DNA-binding and C-terminal self-association domains in the formation of discrete dots in interphase nuclei. AB - Human heterochromatin protein HP1(Hsalpha) possesses two evolutionarily conserved regions in the N- and C-terminal halves, so-called chromo and chromo-shadow domains, and DNA-binding domain in the internal non-conserved region. Here, to examine its in vivo properties, we expressed HP1(Hsalpha) as a fusion product with green fluorescent protein in human cells. HP1(Hsalpha) was observed to form discrete dots in interphase nuclei and to localize in the centromeric region of metaphase chromosomes by fluorescence microscopy. Interestingly, this dot-forming activity was also found in the N-terminal half retaining the chromo and DNA binding domains and in the C-terminal chromo-shadow domain. However, the chromo domain alone stained nuclei homogeneously. To correlate this dot-forming activity with self-associating activity in vitro, the chromo and chromo-shadow domain peptides were independently expressed in Escherichia coli, affinity purified, and chemically cross-linked with glutaraldehyde. In a SDS-polyacrylamide gel, the former mainly produced a dimer, while the latter produced a ladder of bands up to a tetramer. When passed through a gel filtration column in a native state, these peptides were exclusively separated as a dimer and a tetramer, respectively. These results suggested that the internal DNA-binding and C-terminal chromo shadow domains are both involved in heterochromatin formation in vivo. PMID- 10101300 TI - Molecular cloning and characterization of two zebrafish alpha(1,3)fucosyltransferase genes developmentally regulated in embryogenesis. AB - Some alpha(1,3)fucosylated oligosaccharides serve as counter receptors to lectin like adhesion proteins or are expressed with temporal precision during embryogenesis, and alpha(1, 3)fucosyltransferase is a key enzyme in the production of these oligosaccharides. Two alpha(1,3)-fucosyltransferase genes, designated zFT1 and zFT2, were cloned from zebrafish. Sequence comparisons with other genes indicated that zFT1 and zFT2 share about 30% amino acid sequence identity with human alpha(1, 3)fucosyltransferases. Although the alpha(1,3)fucosyltransferases cloned so far can be classified into three types myeloid, Lewis, and leukocyte-by virtue of their amino acid sequences, phylogenetic analysis indicated that neither zFT1 nor zFT2 belongs to any of these categories. The expression of zFT1 or zFT2 in mammalian cells induces alpha(1,3)fucosyltransferase activity to synthesize the Lewis x structure from pyridylaminated lacto-N-neotetraose; however, lacto-N-tetraose does not serve as a substrate. Reverse transcriptase-polymerase chain reaction analysis revealed that zFT1 is transcribed during a restricted period before hatching, whereas the mRNA for zFT2 was detected only after hatching. PMID- 10101301 TI - Characterization, cDNA cloning, and functional expression of mouse ileal sodium dependent bile acid transporter. AB - Mouse ileal sodium dependent bile acid transporter (ISBT) was characterized using isolated enterocytes. Only enterocytes from the most distal portion showed Na+ dependent [3H]taurocholate uptake. Northern blot analysis using a probe against mouse ISBT revealed the expression of mouse ISBT mRNA to be restricted to the distal ileum. The Km and Vmax for Na+-dependent [3H]taurocholate transport into isolated ileocytes were calculated as 27 microM and 360 pmol/mg protein/min, respectively. Uptake of [3H]taurocholate was inhibited by N-ethylmaleimide. We have cloned ISBT cDNA from mouse ileum. The cDNA included the entire open reading frame coding 348 amino acid protein with seven hydrophobic segments and two N glycosylation sites. COS-7 cells transfected with the expression vector containing this cDNA expressed Na+-dependent [3H]taurocholate uptake activity with a Km of 34 microM. PMID- 10101303 TI - 43rd Annual meeting of the GTH (Gesellschaft fur Thrombose- und Hamostaseforschung). Mannheim, Germany, February 24-27, 1999. Abstracts. PMID- 10101302 TI - Acute Leukemias VIII. Prognostic Factors and Treatment Strategies. Munster, Germany, 27 February-3 March, 1999. Abstracts. PMID- 10101304 TI - The Orr method in osteomyelitis, compound fractures and other infections. 1930. PMID- 10101305 TI - Introduction to adult posttraumatic osteomyelitis of the tibia. AB - The tibia is the most frequent site of an open fracture, and treatment of adult posttraumatic osteomyelitis of the tibia represents a significant clinical problem that has been recognized for centuries. Ancient modalities such as immobilization and debridement are still mainstays of therapy, and recent developments such as the use of antibiotics and muscle transfer have helped to improve outcome. Osteomyelitis is classified based on the Cierny-Mader system to provide prognostic and therapeutic information. Open fractures can be classified by the Gustilo system, again providing prognostic and therapeutic data. Gustilo Type III fractures have a high likelihood of having infection develop. Treatment principles include immobilization, thorough debridement, control of infection through antibiotic use, control of dead space, and soft tissue coverage. PMID- 10101306 TI - Adult posttraumatic osteomyelitis of the tibia. AB - Posttraumatic tibial osteomyelitis results from trauma or nosocomial infection from the treatment of trauma that allows organisms to enter bone, proliferate in traumatized tissue, and cause subsequent bone infection. The resulting infection is usually polymicrobial. The patient may be classified using the May and the Cierny-Mader classification systems. The diagnosis is based on the isolation of the pathogen(s) from the bone, or blood cultures. Appropriate therapy of posttraumatic tibial osteomyelitis includes adequate drainage, thorough debridement, obliteration of dead space, stabilization when necessary, wound protection, and specific antimicrobial therapy. PMID- 10101307 TI - Pathophysiology of posttraumatic osteomyelitis. AB - Understanding the pathophysiology of posttraumatic osteomyelitis is crucial as researchers attempt to meet the challenge of developing more effective strategies for the management and prevention of this infection. Some aspects of pathogenesis have been well described, including the important roles of the extent of soft tissue injury, bacterial attachment to necrotic bone and fixation devices, and bacterial contamination at the time of injury. More recently, the importance of early wound coverage in preventing osteomyelitis has been emphasized. Now some of the cellular interactions that promote infection and tissue damage are beginning to be understood. Trauma can have deleterious effects on host response to infection through its activation of certain cytokines. These cytokines, mainly produced by cells of the immune system, regulate the action of polymorphonuclear leukocytes, macrophages, and lymphocytes. Bacteria have been shown to use diverse tactics to initiate and maintain infection that lead to host defense impairment, decreased efficacy of antibiotics, and direct tissue damage. New insights into the pathophysiology of osteomyelitis may lead to the innovative therapeutic approaches needed to improve the standard of care for this infection. PMID- 10101308 TI - Adult posttraumatic osteomyelitis of the tibial diaphysis of the tibial shaft. AB - Osteomyelitis of the diaphysis of the tibia in adults is an uncommon but disabling condition. It occurs principally in patients with complex fractures of the tibial shaft in which devitalized bone becomes infected either with a single strain of a virulent organism or with multiple organisms. The outcome of treatment depends on the assessment and management of three interrelated factors, which are the vitality and stability of the bone, the virulence and antibiotic susceptibility of the infecting organism, and the condition of the soft tissues. The impact of the infection on the patient's vitality is of great importance. Successful management depends on control of inflammation, excision of dead bone, and stabilization of the skeleton. Interlocking nailing and local antibiotic treatment are particularly successful strategies. In the future, modification of the inflammatory response with local tissue mediators may become an important adjunctive therapy. PMID- 10101309 TI - Molecular diagnostics for the detection of musculoskeletal infection. AB - The last decade has seen the crossover of basic molecular research techniques toward clinical application. The use of molecular diagnostics originally was driven by the desire to identify unculturable or fastidious pathogens. Success in this setting has led to new applications aimed at identifying organisms involved in musculoskeletal infection. Recently, polymerase chain reaction techniques have been investigated as to their efficacy in diagnosing septic arthritis and periprosthetic infection. This paper will offer an introduction to molecular diagnostics, a brief review of several techniques, and update their status in the diagnosis of musculoskeletal infection. PMID- 10101310 TI - Antimicrobial treatment of chronic osteomyelitis. AB - Chronic osteomyelitis has been a difficult problem for patients and the treating physicians. Appropriate antibiotic therapy is necessary to arrest osteomyelitis along with adequate surgical therapy. Factors involved in choosing the appropriate antibiotic(s) include infection type, infecting organism, sensitivity results, host factors, and antibiotic characteristics. Initially, antibiotics are chosen on the basis of the organisms that are suspected to be causing the infection. Once the infecting organism(s) is isolated and sensitivities are established, the initial antibiotic(s) may be modified. In selecting specific antibiotics for the treatment of osteomyelitis, the type of infection, current hospital sensitivity resistance patterns, and the risk of adverse reactions must be strongly appraised. Antibiotic classes used in the treatment of osteomyelitis include penicillins, beta-lactamase inhibitors, cephalosporins, other beta lactams (aztreonam and imipenem), vancomycin, clindamycin, rifampin, aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, metronidazole, and new investigational agents including teicoplanin, quinupristin/dalfopristin, and oxazolidinones. Traditional treatments have used operative procedures followed by 4 to 6 weeks of parenteral antibiotics. Adjunctive therapy for treating chronic osteomyelitis may be achieved by using beads, spacers, or coated implants to deliver local antibiotic therapy and/or by using hyperbaric oxygen therapy (once per day for 90-120 minutes at two to three atmospheres at 100% oxygen). PMID- 10101311 TI - Culture results in open wound treatment with muscle transfer for tibial osteomyelitis. AB - Fifty-three patients who underwent a two-staged protocol of debridement and muscle flap coverage for chronic osteomyelitis of the tibia between 1991 and 1996 were evaluated. All patients underwent a thorough debridement of all nonviable tissue and bone at initial debridement. Multiple cultures were taken, including aerobic, anaerobic and fungal cultures from the pus, soft tissue, bone curettings and bone. All patients were treated with open wound management and dressing changes. Between 2 to 7 days, median 4 days, all patients underwent a second debridement with a complete set of identical cultures, and immediate soft tissue muscle transfer. There were 42 free vascularized and 11 local tissue transfers. The 53 patients were classified according to the Cierny-Mader classification for chronic osteomyelitis. Twenty-four patients had Stage IVA osteomyelitis, 10 patients had Stage IIIA osteomyelitis, nine patients had Stage IIIB osteomyelitis, eight patients had Stage IVB osteomyelitis, one patient had Stage IA osteomyelitis, and one patient had Stage IIB osteomyelitis. All 53 patients had positive cultures at the time of their initial debridement, and 14 of 53 (26%) had a positive culture at the time of the second debridement. Based on the results, it seems from a bacteriologic stand-point that the second debridement allows for the opportunity for redebridement and wound sterilization of organisms that still may be present. PMID- 10101312 TI - Bone repair techniques, bone graft, and bone graft substitutes. AB - This paper reviews the techniques and materials (bone graft and bone graft substitutes) that currently are used to treat nonunions and bone defects. The techniques reviewed are intramedullary nailing, plating, distraction osteogenesis, and electric stimulation. Bone graft and bone graft substitutes reviewed are as follows: vascularized bone transfers; autogenous bone graft; autogenous bone marrow; dimineralized bone matrix; growth factors; calcium sulphate; calcium phosphates; and allograft. The goal of management of fractures, nonunions, and segmental bony defects, is the return of function as quickly and completely as possible. Techniques and management strategies constantly are evolving to accomplish this goal. This paper reviews the history, indications, and limitations of bone repair techniques, methods of bone grafting, and materials available as bone graft substitutes. PMID- 10101313 TI - Osteomyelitis debridement techniques. AB - Debridement of chronic osteomyelitis can be technically demanding and difficult. The surgical principles that govern treatment of osteomyelitis involve an atraumatic approach and complete removal of all devitalized tissue and foreign material. Despite recent advances in medical science, the quality of surgical debridement remains the most critical factor in the successful management of chronic orthopaedic infections. Important areas discussed include thorough preoperative evaluation, the surgical philosophy, soft tissue aspects, bone considerations, and dead space management. PMID- 10101314 TI - Infected tibial nonunions (1981-1995). The evolution of change. AB - Between 1981 and 1995, 150 consecutive cases of middiaphyseal, infected nonunions of the tibia were treated prospectively on the author's osteomyelitis service. Thirty-nine (78%) of the 49 patients seen between 1981 and 1986 and 94 (93%) of the 101 patients seen 1986 through 1994 underwent successful salvage protocols with a minimum followup of 5 years. The difference in outcomes seen in the two groups eloquently reflects the emergence of specific pharmaceutic, technical, and biologic advances earmarking these two, distinct eras of care. PMID- 10101315 TI - Orthotic management for posttraumatic nonunion of the tibia complicated by osteomyelitis. AB - Frequently, patients undergoing complex bone reconstructions for the treatment of osteomyelitis complicating tibial nonunion require extended exoskeletal support. Once the need for strict, continuous cast immobilization has passed, the patient can be fitted with a removable orthosis. Although prefabricated ankle foot orthoses are available, the purpose of this paper is to highlight the sophisticated new custom orthotic options available to the physician for the patient. Difficult to fit limbs now can be accommodated. Access to a skilled orthotist is the sine qua non of success. PMID- 10101316 TI - Prosthetic options for below knee amputations after osteomyelitis and nonunion of the tibia. AB - Below the knee amputation after trauma is an appropriate option for many patients with recalcitrant infection and nonunion of the tibia. Patients who have had transtibial amputations have lower energy expenditure, heart rate, and oxygen cost when ambulating with their prostheses than when using a three-point gait with crutches without their artificial limb. Innovative prosthetists have improved each of the five essential components of the limb amputated below the knee: socket, insert, shaft and pylon, foot and ankle assembly, and suspension system. Prosthetists are integral members of the patient's healthcare team. Their recommendations and direct patient care are essential to optimizing the functional ability of patients who have had amputations. PMID- 10101317 TI - Autogenic versus allogenic bone grafts in anterior lumbar interbody fusion. AB - Between 1987 and 1993, 94 consecutive patients with painful spondylolisthesis underwent combined anterior and posterior fusion. The average age at operation was 40 years (range, 16-65 years). Posterior fusion was performed in all patients using pedicle screw systems, and anterior fusion was accomplished with autogenic or allogenic bone grafts. Patients retrospectively were assigned to two groups. In Group 1, anterior fusion was performed with autogenic bone grafts harvested from the iliac crest (n = 65; 146 segments) and in Group 2 allogenic bone grafts were taken from femoral heads (n = 39; 86 segments). The incidence of pseudarthrosis was evaluated on lateral tomograms 24 months after surgery. The mean clinical followup time was 4 years (range, 3-8 years). Pseudarthrosis was found in seven fused levels (3%) managed with autogenic bone grafts (Group 1) and in seven patients (8%) managed with allogenic bone grafts (Group 2). This incidence of pseudarthrosis was not significantly different between the two groups. Considering the possible complications associated with harvesting iliac crest bone, the use of allogenic bone appears justified. PMID- 10101318 TI - Treatment of congenital dislocated hip by arthroplasty with femoral shortening. AB - This was a retrospective study of 15 hips in 11 patients with complete congenital dislocation of the hip treated by total hip arthroplasty and femoral shortening with a subtrochanteric double chevron derotation osteotomy. The mean age at the time of surgery was 51 years (range, 21-74 years), and the mean followup was 5.5 years (range, 2-8.5 years). Functional evaluation using the modified Harris hip rating system showed an excellent result in five hips and a good result in seven hips (80% success rate). The location of the hip center was lowered by a mean of 8.3 cm (range, 5.7-10.4 cm). Leg length discrepancy in seven patients with unilateral involvement was reduced from a mean of 3.9 cm (range, 1.7-8.2 cm) before surgery to a mean of 1.4 cm at the latest followup (range, 0-4 cm). The Trendelenburg sign was assessed in 10 of 15 hips and was corrected from a positive preoperative status to a negative postoperative status in eight of these 10 hips. There were no cases of nonunion, dislocation, nerve palsy, or radiographic loosening. The only complications were a supracondylar fracture below the femoral component in a patient with severe osteoporosis 6 months after surgery and loosening of the cemented titanium metal backed acetabular component in the same patient 1.5 years after surgery. The current series showed that total hip arthroplasty in combination with a subtrochanteric double chevron derotation osteotomy has promising short to midterm results in the treatment of complete congenital dislocation of the hip in adults. PMID- 10101320 TI - Primary total hip arthroplasty with the AML total hip prosthesis. AB - Primary total hip arthroplasty using an uncemented AML total hip prosthesis (trispiked cup and a 4/5 porous coated stem) was performed in 50 patients (52 hips). The average age of the patients at the time of surgery was 47.6 years (range, 19-68 years), and the diagnosis was osteonecrosis of the femoral head in 18 hips, osteoarthritis in 16, fracture of the femoral neck in 14, osteoarthrosis secondary to childhood pyogenic arthritis in two, childhood tuberculous arthritis in one, and traumatic arthritis in one. The average followup was 11.3 years (range, 11-12 years). The average preoperative Harris Hip Score was 59 points, which improved to 90 points. Twenty-five (48%) hips had excellent results, 14 (27%) had good results, three (6%) had fair results, and 10 (19%) had poor results. The overall rate of revision was 15% (eight hips). The rate of revision of the femoral component was 2% (one hip), and the rate of revision of the acetabular component was 15% (eight hips). Twenty (38%) hips had acetabular and femoral osteolysis. Nine (17%) hips had femoral osteolysis only. Thirty-four (65%) hips had an average of 3.3 mm (range, 2-12 mm) of wear in the polyethylene liner. The average wear rate was 0.29 mm (range, 0.17 to 1.04 mm) per year. PMID- 10101319 TI - In vivo femoral intramedullary pressure during uncemented hip arthroplasty. AB - There is evidence in several animal and human studies that high intramedullary pressure in the femur is of causal significance for bone marrow release into the circulation, causing pulmonary fatty marrow embolization. A previous clinical study provided evidence that in uncemented hip arthroplasty, high intramedullary pressure and subsequent fat embolism with cardiorespiratory deterioration can occur. In this prospective clinical trial, the effect of five surgical techniques on the femoral intramedullary pressure was recorded intraoperatively in 36 patients during uncemented press fit hip arthroplasty. In Group A, the conventional surgical technique (slide hammer and femoral rasps) showed intramedullary hypertension during opening of the femoral canal, femur preparation, and prosthesis insertion. In Group B, a mechanical high frequency vibration rasp was used, instead of the slide hammer, and provided reduction of the intramedullary pressure peaks during opening of the femoral canal but could not prevent intramedullary hypertension during rasping and prosthesis insertion. In Group C, a modified surgical technique to prevent high intramedullary pressure reduced pressure peaks during opening of the femoral canal and resulted in a significant reduction of intramedullary pressure during femur preparation and prosthesis insertion compared with the conventional surgical technique used with Group A. In Group D the results of the modified surgical technique could be improved additionally by using the high frequency vibration rasp, instead of the slide hammer. In Group E conventional surgical technique in combination with a distal venting hole has not proven to be efficient in uncemented hip arthroplasty. Based on the results of this in vivo study, the proposed modified surgical technique in cementless hip arthroplasty can be recommended to avoid high intramedullary pressure peaks, which should minimize the risk of significant bone marrow release into the circulation and the risk for cardiorespiratory deterioration caused by fat embolism. PMID- 10101321 TI - Articular cartilage transplantation. Clinical results in the knee. AB - Between December 1983 and August 1991, 55 consecutive patients (55 knees) who underwent articular cartilage transplantation to their damaged knees were enrolled in the study. Average followup was 75 months (range, 11-147 months). Eight-two percent were younger than 45 years of age. Patients were evaluated through an 18-point scale, with 6 points each allocated to pain, range of motion, and function. An excellent knee was pain free, had full range of motion, and permitted unlimited activity. A good knee allowed full time employment and moderate activity. Eleven of 15 (73%) allografts transplanted 10 or more years ago were still good or excellent at the time of last followup. Overall, 45 of 55 (76%) knees that received the transplants were rated good or excellent. Specifically, 36 of 43 (84%) patients with unipolar transplants regained normal use of their resurfaced knee. The results after bipolar resurfacing were less encouraging, with only six of 12 (50%) knees rated good or excellent. The described technique of osteochondral shell allograft resurfacing of the knee capitalize on the different healing potentials of bone and cartilage by transplanting the viable articular cartilage organ in its entirety along with just enough of the underlying bone to allow for graft incorporation through creeping substitution. The results support the use of fresh osteochondral shell allograft transplantation for the treatment of large, full thickness articular cartilage defects to the medial or lateral femoral condyles and to the patella. PMID- 10101322 TI - Knee arthroplasty in hemophilic arthropathy. AB - Twenty-three total knee arthroplasties in 15 patients with severe hemophilia were performed between February 1974 and September 1988. Thirteen patients had Factor VIII deficiency and two had Factor IX deficiency. The mean followup period was 7.5 years, with a minimum of 4 years for patients who were alive (eight) at the time of this review. Seven patients had died before this report, and all were seropositive for the human immunodeficiency virus. Using the Hospital for Special Surgery knee scoring system, the result was excellent in one knee, good in three, fair in two, and poor in 17. One patient was seropositive for the human immunodeficiency virus at the time of the index procedure, and 12 were seropositive at the most recent followup; the human immunodeficiency status of three patients was unknown. There were two early and two late deep infections, all in patients who were seropositive for the human immunodeficiency virus. The most recent postoperative radiographs for all knees were reviewed using the Knee Society radiographic scoring system. Ten femoral components were well fixed, 11 were possibly loose, and two were probably loose. Eight tibial components were well fixed, 10 possibly loose, three probably loose, and two definitely loose. One knee had been revised for aseptic loosening. There are few published studies of the long term results of total knee arthroplasties in patients with hemophilia. In this series of 23 knees, there was a high rate of loosening and infection. Total knee arthroplasty may be a useful treatment for the relief of pain attributable to end stage hemophilic arthropathy, but there is a high rate of complications, especially in patients who are seropositive for the human immunodeficiency virus. PMID- 10101323 TI - The clinical significance of proximal tibial resection level in total knee arthroplasty. AB - Clinical and radiographic data were collected in 139 patients with 195 posterior cruciate retaining total condylar knee prostheses to evaluate the relationship of the proximal tibial resection level with long term results. Among the 139 patients were 75 patients with 106 total knee replacements observed for more than 8 years. All patients underwent biyearly routine examinations, including radiographs and clinical evaluations. The average medial tibial resection for the 139 patients with 195 total knee replacements was 2.95 mm, and in the subset of 75 patients (106 knees) observed for more than 8 years, it was 3.3 mm; both groups had a maximum of 14 mm. Sixty-three percent or 67 knees had medial resection levels of 3 mm or less. The average lateral tibial resection for the 195 knees was 5.48 mm and in the 106 knees was 5.71 mm, with a maximum of 22 mm. Fifty-one percent of 104 knees had lateral resection levels of 5 mm or less. Statistical analysis showed that there was no significant correlation between the level of proximal tibial resection and Knee Society knee score, range of motion, radiolucencies, or loosening or revision. These long term results suggest that minimal proximal tibial resection is not necessary for a successful arthroplasty, and problems associated with minimal resection, such as joint line elevation and thin polyethylene inserts, can be avoided. PMID- 10101324 TI - Prevention of stress fractures using custom biomechanical shoe orthoses. AB - In a prospective study of stress fractures the hypothesis that training with custom made biomechanical shoe orthoses could lessen the incidence of stress fractures in infantry recruits was tested. Recruits were assigned randomly to groups and given soft biomechanical orthoses or semirigid biomechanical orthoses and compared with a control group that did not train in biomechanical orthoses. All recruits wore infantry boots with soles designed like those of basketball shoes. Recruits were examined biweekly during 14 weeks of basic training. The incidence of stress fractures was 15.7% for the recruits with the semirigid biomechanical orthoses, 10.7% for the recruits with the soft biomechanical orthoses, and 27% for the control group. The soft biomechanical orthoses were tolerated better by the recruits than were the semirigid devices. Among trainees at high risk for stress fractures, prophylactic use of custom made biomechanical orthoses may be warranted. PMID- 10101325 TI - The relationship of heel pad elasticity and plantar heel pain. AB - Loss of heel pad elasticity has been suggested as one of the possible explanations of plantar heel pain. This hypothesis is evaluated by this blinded observer prospective study, using an age and weight matched control population. Hindfoot lateral radiographs of 73 patients with plantar heel pain, 29 of whom had bilateral involvement (102 feet), and who ranged in age from 20 to 60 years, were studied and compared with 120 healthy subjects (240 feet). Heel pad thickness and heel pad compressibility index were not significantly different in patients with plantar heel pain than in healthy subjects matched for age and weight. In patients with unilateral heel pain, heel pad thickness and heel pad compressibility index on the painful side were not significantly different from the opposite painless side. The contribution of the heel pad elasticity measured as a visual compressibility index for plantar heel pain is a matter of debate. PMID- 10101326 TI - Angiography for assessment of preoperative chemotherapy in musculoskeletal sarcomas. AB - Eleven abnormal findings of digital subtraction angiography were analyzed in 25 patients with bone sarcoma and in 23 patients with soft tissue sarcoma. The relation between digital subtraction angiographic findings and the histologic effect of chemotherapy was evaluated. Digital subtraction angiography was performed with the patient under local anesthesia with the Seldinger technique, using an ADVANT X unit. Contrast medium was injected at a rate of 4 to 6 ml per second, with the usual single bolus dose of approximately 6 to 8 ml. Eleven abnormal findings included tumor stain, hypervascularity, arterial distortion, vascular stretch, arterial dilatation, arteriovenous shunt, arterial encasement, occlusion, blood pool, caliber with irregular wall, and dilatation of draining vein. Each finding after preoperative chemotherapy was compared with that before chemotherapy and divided into three grades; Grade 1, not effective; Grade 2, effective; and Grade 3, very effective. Angiographic Grades 2 and 3 were defined as responders. The histologic effect was examined and scored according to the modified classification proposed by Huvos. Histologic Grades 1 and 2 were classified as nonresponders and Grades 3 and 4 as good responders. In bone sarcomas, hypervascularity and tumor stain were seen in all patients. In soft tissue sarcomas, tumor stain was shown in all 23 patients and hypervascularity was seen in 21 patients. Tumor stain, hypervascularity, vascular stretch, and arterial encasement were correlated closely with histologic findings and showed an accuracy equal to or greater than 70%. When these four findings changed to angiographic Grade 3 after preoperative chemotherapy, 90% of patients had good histologic outcome. PMID- 10101327 TI - Endoprosthetic reconstruction for malignant upper extremity tumors. AB - Between December 1980 and December 1992, 59 patients underwent 60 reconstructions with endoprostheses after resection of malignant tumors in the upper extremity. There were 32 male patients and 27 female patients, with a mean age of 33 years (range, 3-83 years). The type of reconstruction was based on the location of the primary tumor site. The histologic diagnoses included osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, soft tissue sarcoma, and fibrosarcoma of bone. Most of the patients had Stage IIB disease (N = 38), as established by the Musculoskeletal Tumor Society classification. An additional six patients had metastatic tumors to the upper extremity. Twenty seven of 59 patients died of disease progression. Two patients died of other causes (chronic leukemia, human immunodeficiency virus infection). The 30 survivors had a mean followup of 90 months (range, 60-170 months). The Musculoskeletal Tumor Society functional analysis for the patients with a minimum 2-year followup (N = 41) averaged 74%. Sixteen of the 59 (27%) patients had local complications. Problems related to mechanical failure and infection were managed successfully with second operation. Amputation was rare, occurring in three of 60 (5%) patients and was related only to local recurrence. Endoprosthetic reconstructions of the upper extremity after tumor resections have proven to be successful. PMID- 10101328 TI - Lymphoma presenting as a soft tissue mass. A soft tissue sarcoma simulator. AB - Lymphoma presenting as a soft tissue mass is rare and thus may be confused with the more common soft tissue sarcoma. No previous analysis of the clinical and radiologic features of lymphomas presenting as soft tissue masses is available because most of the cases reviewed are from the pathology literature. Four patients with diagnoses of extranodal lymphomas of the soft tissues were reviewed retrospectively with respect to their clinical features, primary tumor characteristics, stage, radiographic characteristics, treatment, and followup. Mean age was 72.5 years (range, 52-85 years). The soft tissue mass occurred in the thigh (three cases) and shoulder (one case). The median size of the soft tissue mass was 6.7 cm (range, 2-15 cm) in the largest dimension, as measured on magnetic resonance imaging. These patients each had evidence of lymphadenopathy at the time of diagnosis. Lactate dehydrogenase was increased significantly in two cases and increased slightly in two other cases. One case was Stage II(E) at presentation, one was Stage III(E), and two were Stage IV. All were B cell immunophenotype. All patients died between 2 and 24 months after diagnosis, despite the use of Cytoxan, vincristine, adriamycin, and prednisone chemotherapy in each case. Clinical and radiographic features that favor extranodal soft tissue lymphoma over sarcoma include pain and tenderness, lymphadenopathy (particularly when confluent radiologically), ipsilateral extremity swelling, and elevated lactate dehydrogenase. PMID- 10101329 TI - Surgical management of calcaneal unicameral bone cysts. AB - Unicameral bone cysts are not seen commonly in the calcaneus. Little is known about the etiology and natural history of these lesions. Calcaneal cysts often are symptomatic, although some of these lesions are detected as incidental findings. Treatment has been advocated based on the fear of pathologic fracture and collapse. Several published series have been divided in their favor for either open treatment or injection management. These series are small, and the optimal treatment is still in question. The current study compared the efficacy of methylprednisolone acetate injection treatment with curettage and bone grafting in the treatment of unicameral bone cysts of the calcaneus. All patients treated for unicameral bone cysts of the calcaneus during the past 7 years at two institutions were reviewed. Eleven patients met inclusion criteria. All diagnoses were confirmed radiographically or histologically. Demographic information, presenting complaints, diagnostic imaging, treatment modalities, and outcome were analyzed. Long term radiographic and subjective followup was obtained. Eighteen surgical procedures were performed on 11 patients with 12 cysts. Nine injections performed on six patients failed to show healing of the cyst. Nine cysts treated with curettage and bone grafting showed cyst healing. At mean followup of 28 months (range, 12-77 months), all 11 patients had no symptoms; there were no recurrences of the cyst in the nine patients who underwent bone grafting and persistence of the cyst in the two patients who underwent injection therapy. This review reports one of the largest series of cysts in this location. The results indicate that steroid injection treatment, although useful in other locations, may not be the best option for the management of unicameral bone cysts in the calcaneus. Curettage and bone grafting yielded uniformly good results. PMID- 10101330 TI - The effect of hyperbaric oxygen on medial collateral ligament healing in a rat model. AB - Hyperbaric oxygen has been shown to promote healing in bone and some soft tissues. This study was undertaken to determine its effect on ligamentous healing. Forty-eight Sprague-Dawley rats underwent a standardized surgical laceration of the right (divided) medial collateral ligament, whereas the left (undivided) medial collateral ligament was not surgically lacerated. A control group of 24 rats recovered without intervention. An experimental group consisting of the other 24 rats was exposed to hyperbaric oxygen at 2.8 atmospheres for 1.5 hours a day for 5 days after the surgery. Six rats from each group were euthanized at 2, 4, 6, and 8 weeks. The stiffness and final force to failure were recorded for the divided and undivided medial collateral ligaments. At 4 weeks, a statistically greater force was required to cause failure of the previously divided ligaments that had been exposed to hyperbaric oxygen than those that had not. The stiffness and force to cause failure of previously divided ligaments were statistically greater at 4 weeks than at 2 weeks, whether or not hyperbaric oxygen was used. No additional statistical increases in stiffness or force were observed at 6 weeks. PMID- 10101331 TI - Posterior cruciate ligament effects on the flexion space in total knee arthroplasty. AB - Twelve fresh frozen anatomic specimen knees were used in this study to measure changes in the tibiofemoral joint gaps after sacrificing the posterior cruciate ligament. Joint gap changes were measured using a motion tracking device in full extension and at 45 degrees and 90 degrees flexion. Tibiofemoral gaps were measured with no external compressive loads and under tension to define the flexion gap, the space available to be filled by components. After initial anterior cruciate ligament removal, meniscectomy, and a 1-cm tibial plateau cut, sacrifice of the posterior cruciate ligament caused significant differences in the flexion gap. At 90 degrees flexion the tibia distracted from the femur 5.26 +/- 1.9 mm (range, 3.2-9.1 mm) at rest and 6.4 +/- 2.5 mm under tension. No differences in the joint space were calculated in full extension under either loading case. The authors conclude that a major result of posterior cruciate ligament sacrifice is the creation of a larger flexion gap. This result provides insight into relative joint line changes that can occur after posterior cruciate ligament sacrifice. It also suggests the need for greater attention to flexion stability when sacrificing the posterior cruciate ligament and rethinking the role of posterior cruciate ligament release in the management of pure, primary flexion contracture. PMID- 10101332 TI - Racial, ethnic, and gender diversity and the resident operative experience. How can the Academic Orthopaedic Society shape the future of orthopaedic surgery? PMID- 10101333 TI - Maneuvers for reducing dislocated hips. A new technique and a literature review. AB - Twelve consecutive dislocated hip prostheses and one dislocated hip joint were reduced in the emergency room using the method described in this paper. This method has multiple advantages. It uses a lever and fulcrum technique and therefore is capable of producing substantial levels of force with less effort. The patient and physician are in relatively comfortable positions and little assistance is necessary. PMID- 10101334 TI - Knee pain in a 69-year-old woman. PMID- 10101335 TI - Stress fractures of the femoral neck. PMID- 10101336 TI - Relationship of the nerve with the iliac crest. PMID- 10101337 TI - An evidence based approach to diagnostic testing in emergency medicine. AB - Virtually all physicians involved in clinical practice are realizing that the delivery of highest caliber medical care requires a blend of appropriate training, adequate experience, the proper amount of "art," empathetic interpersonal skills, respect for patient preferences, and, more than ever, an evidence-based approach firmly grounded in methodologically sound scientific studies. This article provides an overview of the issue, explaining the evidence based approach to the many diagnostic studies discussed in the ensuing articles. PMID- 10101338 TI - Evaluation of the patient with closed head trauma: an evidence based approach. AB - This article approaches the subject of closed head trauma from the time-sensitive vantage point of the emergency physician. As the clinical scenario unfolds, he or she constantly evaluates the need for diagnostic tests as information is received from paramedics, nurses, and the history and physical examination. This article provides a synopsis and a critique of original clinical trials to aid the emergency physician in making an evidence based decision. PMID- 10101339 TI - Evaluation of the patient with spinal trauma and back pain: an evidence based approach. AB - The evaluation of spinal trauma and neck or back pain remains one of the most important and most common assessments in emergency medicine. This article provides an overview of an evidence based approach to this situation, and argues that appropriate use of imaging studies can reduce waste and better mitigate devastating outcomes to the patient. PMID- 10101340 TI - Evaluation of the patient with blunt chest trauma: an evidence based approach. AB - The patient who has sustained blunt trauma to the chest can present a diagnostic challenge to the emergency physician. There are several diagnostic modalities available for treating life-threatening injuries to these patients. The authors review published studies to support the use of these tests in diagnosing injuries from blunt thoracic trauma. The article focuses chiefly on two current areas of controversy, the diagnosis of blunt aortic and blunt myocardial injury. Finally, the authors make recommendations for the use of various tests based on the available evidence. PMID- 10101341 TI - Evaluation of the patient with blunt abdominal trauma: an evidence based approach. AB - Patients with blunt abdominal trauma present a special challenge to the emergency physician. Physical examination is often unreliable, even if the patient is awake, and the frequent co-existence of head injury exacerbates this problem. This article examines the evidence basis of three diagnostic modalities in evaluating blunt abdominal trauma: DPL (the time-honored test); CT scanning (the current standard of care); and abdominal sonography (the emerging standard- especially for examination conducted in the trauma room). A proposed algorithm for the appropriate use of these modalities is also presented. PMID- 10101342 TI - Evaluation of the patient with extremity trauma: an evidence based approach. AB - This article reviews relevant literature to provide evidence based guidelines for the evaluation of patients with extremity trauma in the emergency department. The development of clinical decision rules for extremity trauma in the ankle and knee, and guidelines for obtaining postreduction radiographs of shoulder dislocations and nursemaid's elbows are discussed. PMID- 10101343 TI - Evaluation of the infant with fever without source: an evidence based approach. AB - The infant with fever without an obvious source upon physical examination offers a challenging clinical problem. A combination of detailed history, physical examination, and selected laboratory tests allows the clinician to discern which infants are at lower risk for bacterial illness. Implications for management and future research are discussed herein. PMID- 10101344 TI - Evaluation of the patient with nontraumatic headache: an evidence based approach. AB - This article reviews the literature on the diagnostic tools available to make a cost-effective yet appropriate diagnosis in the patient with an atraumatic headache in the emergency setting. The tools addressed include a good history and physical examination alone, third-generation CT, lumbar puncture, and MR imaging. The epidemiology and characteristics of the more common primary and secondary causes of headache are also reviewed, allowing the clinician to develop a better pretest probability of disease, and make a more educated decision as to when additional diagnostic testing is needed. PMID- 10101345 TI - Evaluation of the patient with sore throat, earache, and sinusitis: an evidence based approach. AB - Sore throat, earache, and sinusitis are common presenting complaints in the emergency department, and all fall within the top ten in the United States. These complaints usually have a benign course but rarely can be a symptom of a serious disease process. This article provides an evidence-based review of the literature regarding the diagnosis of pharyngitis, otitis media, and sinusitis. PMID- 10101346 TI - Evaluation of the patient with syncope: an evidence based approach. AB - The cause of syncope often eludes the clinician despite extensive efforts to make a definitive diagnosis. In that group of patients for whom the cause has eluded the clinician, it is unclear which patients need a rapid inpatient work-up and which patients can be safely discharged for outpatient evaluation. The authors present the results of a systematic literature search to determine the diagnostic value of the emergency department work-up of the patient with syncope. PMID- 10101347 TI - Evaluation of the patient with seizures: an evidence based approach. AB - Statistics tell us that as many as 1 in 20 members of the population will suffer a seizure at some point in their lifetime, a figure which becomes even more likely if one lives to the age of 80. Thus, a careful evidence based approach to the patient with seizure is immensely useful to the emergency physician. The authors evaluate current studies on the subject, discuss seizures as they relate to specific patient groups, and, ultimately, make recommendations on this important subject. PMID- 10101348 TI - Evaluation of the patient with shortness of breath: an evidence based approach. AB - Shortness of breath is a common presenting complaint of emergency department patients, and may result from a number of different causes. Work-up to determine the etiology in a given patient may be challenging. The authors undertook a literature review limited to causes of dyspnea other than reversible airway disease. The results of this review are discussed herein, as well as recommendations for further research. PMID- 10101349 TI - Evaluation of the patient with gastrointestinal bleeding: an evidence based approach. AB - Gastrointestinal bleeding is a common and potentially life-threatening problem. The incidence of upper gastrointestinal bleeding (UGIB) is 40 to 150 episodes per 100,000 population per year. Mortality in large series is 6% to 10% for UGIB and has remained unchanged over the past 30 to 60 years. The incidence of hospitalization for acute lower gastrointestinal bleeding is about 20 to 27 episodes per 100,000 population per year, with a 200-fold increase with advancing age from the third to ninth decades. The mortality rate is 4% to 10% or higher. The evaluation of overt or acute gastrointestinal bleeding in the ED is reviewed here from the perspective of evidence-based medicine. PMID- 10101350 TI - Evaluation of the elderly patient with weakness: an evidence based approach. AB - Because of the altered physiology of the elderly population, either as a result of aging or as a result of other disease processes, many illnesses may present with features that are either atypical or nonspecific in nature. Difficult and nonspecific complaints such as weakness in an elderly patient must be handled in a judicious, cost-effective, comprehensive, and expeditious manner that benefits both the patient and the emergency department. This article addresses the evaluation of the elderly patient who presents to the ED complaining of weakness. PMID- 10101351 TI - [Quality measures in interventional radiology]. AB - The quality assurance of treatment measures is legally required but as yet not generally established in practice. For interventional radiology, the introduction of quality assurance for PTA of arteries of the lower limbs is planned for January 1999. It is reasonable to subject at least the most important and/or most frequently performed interventions to quality management. In the present article, the term quality in the management of diseases is defined and the system of total quality management discussed at the levels structure, process, and results. For its application, parameters of quality measurement in the form of standards, criteria, and characteristics values are necessary and must be laid down by a team of experts on the basis of subjective experience and/or results in the literature. Practical quality assurance takes place not only within a clinic but also externally by comparison with other centers. Data collection and evaluation requires high-performance software that will be continuously improved, expanded, and adapted to current needs during regular meetings between the various users. PMID- 10101352 TI - [Dental CT: image quality and radiation exposure in relation to scan parameters]. AB - PURPOSE: To develop a scan protocol for dental-CT which guarantees good image quality at the lowest possible radiation dose. METHODS: In an experimental investigation Dental-CT (HSA, GE, Milwaukee, USA) of the mandible of two human skeletons positioned in a water tank were performed in order to define the most advantageous scan protocol. Tube currents ranged from 40 to 200 mA and the scan technique was modified (axial mode or helical mode with pitches of 1 to 3 and corresponding increments of 0.4 to 1.0 mm). 39 patients underwent a dental-CT with decreased current (80 mA) in the helical scan mode (pitch 2, slice thickness 1 mm). Dose measurements were performed for two different scan protocols (A: axial, 130 mAs, B: helical, 80 mA, pitch 2). RESULTS: The preliminary investigations of image quality showed only a minor effect of the applied current. For the helical scan mode, pitches of more than 2 impaired image quality. A low increment had no advantages. There were no disadvantages in clinical practice using protocol B with decreased tube current. Absorbed radiation dose of dental CT performed with protocol B was decreased to one third in comparison to protocol A. CONCLUSIONS: A scan protocol with a low tube current (e.g., 80 mA, for a rotation time of 1 s) and a helical scan mode (e.g., for a slice thickness of 1 mm with a pitch of 2 and an increment of 1 mm) is recommended for performing dental-CT. PMID- 10101353 TI - [Independent radiologic prognostic factors for fatal outcome of ambulatory acquired pneumonia requiring inpatient treatment]. AB - PURPOSE: To evaluate the independent prognostic impact of the chest radiograph for mortality from community-acquired pneumonia requiring hospitalization. METHODS: Chest radiographs of 67 patients with hospital-treated community acquired pneumonia were analyzed with regard to the prognostic implications of radiographic patterns, extent and density of infiltrates, and its evolution during treatment. RESULTS: Non-survivors had a significantly higher extent of infiltrates (p = 0.008), density of infiltrates (p = 0.05), and radiographic spread during follow-up within 48-75 hours (p = 0.0001). In multivariate analysis, persistent or progressive infiltrates were associated with a 47-fold increase, and persistent or progressive density of infiltrates with an 18-fold increase in risk of mortality. The presence of both parameters could correctly predict 96% of survivors and 90% of non-survivors. CONCLUSIONS: The chest radiograph is an independent predictor of the severity of pneumonia. Both persistent or progressive infiltrates and persistent or progressive density of infiltrates are independently associated with mortality from community-acquired pneumonia. PMID- 10101354 TI - [Value of CT in diagnosis of respirator-associated pneumonia]. AB - PURPOSE: To analyse the diagnostic accuracy of computed tomography (CT) in ventilator-associated pneumonia (VAP). MATERIALS AND METHODS: 23 patients on mechanical ventilation with a new pulmonary abnormality on chest X-ray were examined with both spiral-CT and high-resolution CT. The diagnosis VAP was made according to prospectively defined criteria. Bronchoscopic specimen asservation with protected specimen brushing (PSB) served as gold standard. RESULTS: With PSB, 11 of 23 patients were found to have VAP. CT showed a sensitivity and specificity of 53% and 63%, respectively. Ground glass infiltrates appeared to have a 100% specificity but were found in only 5/11 patients. CONCLUSIONS: CT is not the method of choice for diagnosing VAP. Ground glass infiltrates seeming to be highly specific are only inconstantly found. PMID- 10101355 TI - [MRI diagnosis of cardiac myxomas: sequence evaluation and differential diagnosis]. AB - PURPOSE: To evaluate native and contrast enhanced T1-weighted spin (T1-SE), cine gradient echo (Cine-GE), and T2-weighted turbo spin (T2-TSE) sequences in the diagnosis and differential diagnosis of cardiac myxomas. METHODS: 15 patients with echocardiographically suspected cardiac atrial myxomas underwent 0.5 T-MR imaging of the heart with native T1-SE, contrast-enhanced T1-SE, Cine-GE, and T2 TSE sequences. MR images were evaluated for signal intensity (SI) and lesion's conspicuity. Results were confirmed histologically (14 x) or by follow-up (1 x). RESULTS: MRI revealed myxomas in 9 patients, sarcomas in three patients, and thrombi in three patients. Lesion conspicuity was better in Cine-GE and T2-TSE compared with native and contrast-enhanced T1-SE sequences. Myxomas were characterized by an intermediate SI similar to myocardium in T1-SE, high SI similar to water in T2-TSE, and low to moderately high enhancement (range 19-75%, mean 48%). CONCLUSION: Distinct SI characteristics together with anatomical topographical features (attachment to the interatrial septum, no infiltration of myocardium and vessels) are diagnostic for cardiac myxomas. Cine-GE and T2-TSE sequences are the sequences of choice for detection of myxomas and other atrial masses. T2-TSE and contrast-enhanced T1-weighted sequences are most useful for mass characterisation and differentiation between myxomas, malignant tumors, and thrombi. PMID- 10101356 TI - [Diagnosis of renal artery stenosis in 1.0 T using 3D phase contrast magnetic resonance angiography and dynamic contrast medium perfusion]. AB - PURPOSE: To assess renal artery stenosis (RAS) by 3D phase contrast (PC) MR angiography and dynamic perfusion imaging of the kidneys. METHODS: On a standard 1.0 T MR imaging system (Magnetom Expert, Siemens), 32 patients with angiographically proven unilateral RAS were examined using a 3D PC sequence (TR 40 ms/TE 9 ms/venc 30 cm/s). An ECG-gated Turbo-FLASH 2D sequence (TR 4.5 ms/TE 2.2 ms/TIeff. 400 ms) was applied to study the first pass of paramagnetic contrast agent (0.1 mmol Gd-DTPA/kg) through the kidneys. Signal intensity (SI) over time curves of the renal cortex were obtained and evaluated considering temporal relation and percentage of maximum SI compared to the aorta and normal kidneys. Analysis of the MRA was performed by two independent blinded readers. The gold-standard DSA was interpreted by consensus reading of two experienced radiologists. RESULTS: RAS was detected by 3D PC MRA with a sensitivity of 93% and specificity of 81% (ppv 82%, npv 93%, accuracy 87%, kappa = 0.61). Maximum SI in RAS was significantly decreased (p < 0.001-0.0001). A temporally delayed enhancement of 1.5 +/- 1.3 s was found for RAS > 75% (p < 0.002) but not for RAS < 75% (p > 0.1). CONCLUSIONS: 3D PC MRA is capable of detecting RAS in a high percentage of patients. Dynamic perfusion imaging of the kidneys, applied additionally, can confirm the diagnosis and give valuable information about the hemodynamic relevance of RAS in suspected unilateral disease. PMID- 10101357 TI - [Native spiral computerized tomography in patients with acute flank pain--sense or nonsense?]. AB - PURPOSE: To compare the diagnostic efficacy and costs of native spiral-CT and intravenous urography (IVU) in the management of patients with acute flank pain. METHOD: Native spiral-CT and IVU (following about 30 minutes after CT) were compared in 66 patients with acute flank pain followed by an IVU. The spiral-CT protocol was: 5-mm section thickness, 7.5-mm table feed and 3-mm increment. The analysis conducted independently by two radiologists entailed: (a) Morphology: presence of stone disease (yes-no), localization and size of calculi, periureteral and perirenal stranding, dilatation of the collecting system, and possible alternative diagnoses and (b) cost-effectiveness: direct and indirect costs. RESULTS: Fifty-two patients had urolithiasis. The detection rate of renal and ureteric calculi was significantly higher with native spiral-CT than with IVU (100% vs. 69%, respectively) (p < 0.05). A specific sign of ureteric calculi was the so-called soft tissue "rim sign" (sensitivity 82% and specificity 100%, respectively). In 13 of 14 patients with acute flank pain with no evidence of urolithiasis alternative diagnoses could be made by spiral-CT. Spiral-CT was significantly more cost-effective than IVU in management. CONCLUSION: Native spiral-CT is faster, more effective and less expensive than IVU in the management of patients with acute flank pain. Additionally, it poses less risk and has the capability for allowing alternative diagnoses. Therefore, unenhanced spiral-CT should be the first line modality in patients with acute flank pain. PMID- 10101358 TI - [Instability of spinal fractures--therapeutic relevance of different classifications]. AB - PURPOSE: To investigate if the assessment of spinal fracture stability according to the Magerl classification permits a better therapy decision than using the Denis 3-column model. MATERIAL AND METHODS: The X-ray and CT images of 99 consecutive patients treated for thoracolumbar spine fractures were analysed and the fractures were classified according to the above mentioned classifications. Using the 3-column model, the involvement of two or more columns was considered as unstable, whereas the fracture types A3.2, A3.3, B and C of the Magerl classification were defined as unstable. The stability evaluation was compared with the therapy decision and outcome. RESULTS: According to the 3-column model, 23 of 53 fractures which were classified as unstable were operated. Only five of the 30 conservatively treated unstable fractures showed a reduced healing process. The 46 stable fractures were treated conservatively with good results. Using the Magerl classification, 21 of the 28 unstable fractures were operated and 4 of the remaining 7 cases showed a reduced healing process. Of the 71 stable fractures only 2 were operated and in one patient minimal neurological symptoms occurred. CONCLUSION: The Magerl classification enables a more exact definition of stable and unstable spinal fractures. PMID- 10101359 TI - [Ultrasound appendix imaging in mucoviscidosis patients]. AB - PURPOSE: The aim of this study was to determine the presentation of the appendix in patients with cystic fibrosis (CF) compared to a healthy control group and patients with acute appendicitis using high resolution graded compression sonography. METHOD: 59 CF patients (mean age 11 years), 54 healthy children (mean age 9 years) and 322 patients with histologically proven acute appendicitis were evaluated by sonography. A blind ending tubular structure in longitudinal sections and a target-like figure in cross sections without peristalsis was considered as appendix. The maximum distance between the outer echolucent layers was calculated as diameter. RESULTS: In 20%, 67% and 90% of the cases, the appendix was identified in the CF-group, healthy children, and patients with acute appendicitis. The mean diameters were 9.8, 3.9, and 10.9 mm respectively. These differences were statistically significant (p < 0.001 and p < 0.012). CONCLUSION: The appendiceal mucocele in cystic fibrosis is an uncommon but important differential diagnosis of the acute appendicitis. PMID- 10101360 TI - [Comparison of radiation exposure of patients caused by selected interventional and angiography procedures--initial results]. AB - PURPOSE: To determine and judge patient doses caused by selected interventional and angiographic procedures using the "Multiskip" digital C-arm unit. MATERIALS AND METHODS: The dose-area product and the fluoroscopic time were measured for 71 percutaneous transluminal angioplasties (PTA), 33 PTA with stent implantation, and 37 embolizations; in addition, they were also measured for 285 digital subtraction angiographies (DSA). In the case of 13 PTA, 10 embolizations, and 33 DSA the number of radiographs was determined, and the dose-area product was divided into two parts, fluoroscopy and radiography, applying a computer programme. RESULTS: The median values of the dose-area product and the fluoroscopic time amounted to 36 Gy cm2 and 11.5 min for PTA, 131 Gy cm2 and 14.4 min for PTA with stent implantation, 197 Gy cm2 and 24.5 min for embolisation as well as 87 Gy cm2 and 3.7 min for DSA. For the relation between dose-area products caused by fluoroscopy and radiography and the number of radiographs, median values of 0.67 and 70 for PTA, 0.58 and 153 for embolisation as well as 1.35 and 135 for DSA were determined. CONCLUSIONS: To reduce the relatively high patient doses the modification of the C-arm unit is aspired to realize pulsed fluoroscopy and automatic filter selection. Also experimental investigations will be done related to additional filtration and reduction of the image intensifier input dose rate and dose per frame, respectively. Then, the effect of dose reduction caused by these measures will be confirmed in a comparable patient study. PMID- 10101361 TI - [Control of percutaneous biopsy with CT fluoroscopy]. AB - PURPOSE: Clinical evaluation of CT fluoroscopy and comparison with conventional CT guidance for monitoring of non-pulmonary percutaneous biopsy procedures. MATERIALS AND METHODS: 20 non-pulmonary CT-guided biopsy procedures were prospectively performed either with CT fluoroscopy or with conventional CT guidance. CT fluoroscopy was performed using 120 kV and 50, 70 or 90 mA at a frame-rate of three or six images per second. Number of punctures and biopsies, procedure times, radiation doses and histologic results were analyzed separately for conventional CT guidance and for CT fluoroscopy. RESULTS: With CT fluoroscopy, yield of biopsies was improved (p = 0.005, t-test) and procedure times were shorter than for conventional CT guidance (11.4 +/- 6.0 vs. 23.6 +/- 13.8 min; p = 0.03, t-test). Analysis of procedure related radiation exposure and histologic outcome showed no significant difference between conventional and fluoroscopic CT-guided procedures (p > 0.05, t-test). CONCLUSIONS: CT fluoroscopy facilitates guidance of percutaneous biopsy procedures. Compared to conventional CT assistance, procedure times are decreased while yield of biopsies is improved. PMID- 10101362 TI - [Ischemic complications in aortic dissection--percutaneous treatment with balloon fenestration and stent implantation]. AB - PURPOSE: To describe principles and results of percutaneous treatment of ischemic complications of aortic dissection. MATERIALS AND METHODS: In five cases (four patients) aortic dissection was clinically complicated by renal (n = 4), iliofemoral (n = 2) or mesenterial ischemia (n = 1). After evaluation by means of computed tomography, angiography, and manometry, treatment consisted of balloon fenestration of the intimal flap, stent placement or both. RESULTS: Eleven of 25 vascular beds were classified as ischemic. Treatment consisted of 11 balloon fenestration procedures in 3 patients, in one case supported by stent placement across the dissection membrane. Stents were placed in five renal arteries, one stent was placed in the true lumen of the aorta. One iliac artery was treated with balloon dilatation. One renal artery dissection became symptomatic after balloon fenestration and was treated successfully by stent placement. In all cases ischemia was resolved by endovascular treatment. All patients had persistent relief of symptoms. Mean follow-up time is 5.8 months. CONCLUSION: Ischemic complications of aortic dissection can be effectively and safely treated with stent placement and balloon fenestration. PMID- 10101363 TI - [Treatment of longitudinal femoropopliteal vascular lesions with stents--report of individual cases]. AB - PURPOSE: In a retrospective analysis the results of stent implantation in the superficial femoral and popliteal arteries were analysed. The stenoses were all larger than 10 cm in length. PATIENTS AND METHODS: In 16 patients (3 women, 13 men, mean age 74 years) 15 occlusions and 2 stenoses (average lesion length 13.9 cm) in the superficial femoral and popliteal arteries were treated with stents. Prior to treatment, 11 patients were in clinical stage 2 b, 1 in stage 3, and 5 in stage 4 according to Fontaine. In 15 cases a wall stent was implanted and in 2 a wall stent combined with a nitinol stent since a wall stent of ideal length was not available. The patients received heparin through a venous lock during the operation and as infusion for 24 hours after the operation, as well as ticlopidine for 4 weeks and acetylsalicylic acid as long-term medication. RESULTS: All 17 lesions were recanalized without residual stenoses. After stent implantation the arterial system was completely restored in 3 limbs, 8 patients were in stage 1, 2 in stage 2 a, 2 in stage 2 b, and 1 still in stage 4 according to Fontaine. 8 patients suffered from a stent thrombosis (within 1 week, after 3 weeks, and after 3 months). 4 stents were treated by angioplasty 4 and 5 months after implantation for suspected intimal hyperplasia. According to Kaplan-Meier the primary patency rate after 12 months was 85% (+/- 12 SD), the secondary rate 76% (+/- 10 SD). CONCLUSIONS: The primary treatment of longer femoropopliteal lesions with stents does not result in a satisfactory primary patency rate. The patency rate after 1 year can be increased to 76% by strict monitoring and reintervention. The method may be recommended, albeit with limitations, for patients in whom a bypass operation is not possible or not desired. PMID- 10101364 TI - [Results of "cross-over implantation of Palmaz-stents" with cross-over sheaths]. AB - PURPOSE: Presentation of technique of cross-over stent implantation of Palmaz stents using a cross-over sheath. MATERIAL AND METHODS: Between 1996 and March 1997 72 patients presenting symptoms of peripheral artery disease received 136 Palmaz stents, which were implanted in a cross-over technique with the aid of a cross-over sheath. RESULTS: As indications for stent implantation occurred: occlusion (n = 14), recoil (n = 11), distinctive calcification (n = 32), recurring stenosis/occlusion (n = 32), perforation (n = 3), dissection (n = 31), and aneurysms (n = 2). The cross-over technique with the aid of a cross-over sheath was successful in all 136 cases. Within the first 24 hours 3 acute reocclusions occurred (all femoral). For stents placed in the iliac artery the primary patency rate was 93.3% at 12 months and for stents placed in the femoral artery 72.0%. Furthermore, this techniques allows for simultaneous stenting of pelvic, femoral or lower leg arteries (n = 17). By using this technique, stenting of the distal external iliacal artery, common femoral artery (CFA) and proximal superficial femoral artery becomes either possible for the first time or easier. CONCLUSION: If Palmaz stents with a length of 2-7.8 cm should be implanted in the cross-over technique, the use of a cross-over sheath is recommended. PMID- 10101365 TI - [Experimental MRI-controlled cryotherapy of the brain with almost real-time imaging by radial k-space scanning]. AB - PURPOSE: To test radial k-space scanning by MR fluoroscopy to guide and control MR-guided interstitial cryotherapy of the healthy pig brain. METHODS: After MR tomographic planning of the approach, an MR-compatible experimental cryotherapy probe of 2.7 mm diameter was introduced through a 5 mm burr hole into the right frontal brain of five healthy pigs. The freeze-thaw cycles were imaged using a T1 weighted gradient echo sequence with radial k-Space scanning in coronal, sagittal, and axial directions. RESULTS: The high temporal resolution of the chosen sequence permits a continuous representation of the freezing process with good image quality and high contrast between ice and unfrozen brain parenchyma. Because of the interactive conception of the sequence the layer plane could be chosen as desired during the measurement. Ice formation was sharply demarcated, spherically configurated, and was free of signals. Its maximum diameter was 13 mm. CONCLUSIONS: With use of the novel, interactively controllable gradient echo sequence with radial k-space scanning, guidance of the intervention under fluoroscopic conditions with the advantages of MRT is possible. MR-guided cryotherapy allows a minimally-invasive, precisely dosable focal tissue ablation. PMID- 10101366 TI - [Lymph node imaging with ultra-rapid 3D MR angiography]. AB - PURPOSE: A report on observations of lymph node images obtained by gadolinium enhanced 3D MR angiography (MRA). METHODS: Ultrarapid MRA (TR, TE, FA-5 or 6.4 ms, 1.9 or 2.8 ms, 30-40 degrees) with 0.2 mmol/kg BW Gd-DTPA and 20 ml physiological saline. Start after completion of injection. Single series of the pelvis-thigh as well as head-neck regions by use of a phased array coil with a 1.5 T Magnetom Vision or a 1.0 T Magnetom Harmony (Siemens, Erlangen). We report on lymph node imaging in 4 patients, 2 of whom exhibited benign changes and 2 further metastases. In 1 patient with extensive lymph node metastases of a malignant melanoma, color-Doppler sonography as color-flow angiography (CFA) was used as a comparative method. RESULTS: Lymph node imaging by contrast medium enhanced ultrarapid 3D MRA apparently resulted from their vessels. Thus, arterially-supplied metastases and inflammatory enlarged lymph nodes were well visualized while those with a.v. shunts or poor vascular supply in tumor necroses were poorly imaged. CONCLUSIONS: Further investigations are required with regard to the visualization of lymph nodes in other parts of the body as well as a possible differentiation between benign and malignant lesions. PMID- 10101367 TI - [Repositioning of a central venous catheter with a guide wire with movable core]. AB - PURPOSE: A simple method to redirect malpositioned central venous catheters using a guide wire with movable core is described. METHODS: A 0.89 mm guide wire with movable core is inserted into the catheter. The core is withdrawn for a few centimeters producing a floppy wire tip segment, which follows the malpositioned course of the catheter. The core is then advanced in small steps, until the catheter tip flips into the correct vein. RESULTS: In 8 cases rapid repositioning of malpositioned catheters was accomplished with this technique, without moving the catheters at the entry site. CONCLUSIONS: The repositioning technique described is simple, fast, and inexpensive. Movement of the catheter at the entrance site is not necessary, thus not jeopardizing sterility, and without the need to solve the suture fixation. PMID- 10101368 TI - [Percutaneous removal of a brachiocephalic vein anchored venous catheter with wire loop and mini-laparoscopy scissors]. AB - PURPOSE: The use of mini-laparoscopy scissors to remove a central venous catheter inadvertently fixed to the wall of the brachiocephalic vein is described. PATIENT AND METHODS: During a rethoracotomy in a 15-year-old female patient, a central venous catheter preoperatively introduced in the left subclavian vein was inadvertently trapped by a suture and fixed to the wall of the left brachiocephalic vein. The foreign body was removed by use of a transjugularly introduced venous sheath, a catheter wire snare, and mini-laparoscopy scissors. RESULTS: The fixed catheter was freed from the wall of the vein under fluoroscopic control with the help of a mini-laparoscopy scissors. Since the intravasal end of the catheter had already been grasped during mobilization with the wire snare it could be completely removed subsequently without any problem. CONCLUSIONS: The percutaneous, intravascular use of mini-laparoscopy instruments may be considered for foreign body removal in special cases. PMID- 10101369 TI - [Patellar metastasis as an initial clinical-radiologic symptom of renal cell carcinoma]. PMID- 10101370 TI - [A fluoroscopy-controlled transcervical fallopian tube recanalization]. PMID- 10101371 TI - [Acute spinal epidural hematoma--comments on MRI diagnosis using fluid-attenuated inversion recovery sequence (FLAIR)]. PMID- 10101372 TI - Drug policy reform: societal and clinical perspectives. PMID- 10101373 TI - Harm reduction drug policies and practice: international developments and domestic initiatives. Overview of a symposium. March 22, 1995. PMID- 10101374 TI - Harm reduction: Australia as a case study. AB - This paper explicates the term, "harm reduction"; demonstrates that harm reduction has a long tradition; and uses one country, Australia, as a case study. Harm reduction can be understood as "policies and programs which are designed to reduce the adverse consequences of mood altering substances without necessarily reducing their consumption"; it is consistent with the best traditions of both medicine and public health. Although it is difficult to interpret trends in mortality from alcohol, tobacco, and illicit drugs to determine whether harm reduction in Australia "worked", the effectiveness of harm-reduction policies and programs in controlling HIV among injecting drug users (IDUs) seems extremely strong and suggests that benefits of harm-reduction programs for other drugs will become apparent in time. PMID- 10101375 TI - Methadone treatment by general practitioners in Amsterdam. AB - In Amsterdam, a three-tiered program exists to deal with drug use and addiction. General practitioners form the backbone of the system, helping to deal with the majority of addicts, who are not criminals and many of whom desire to be free of addiction. Distinctions are made between drugs with "acceptable" and "unacceptable" risks, and between drug use and drug-related crime; patients who fall into the former categories are treated in a nonconfrontational, nonstigmatizing manner; such a system helps prevent the majority of patients from passing into unacceptable, criminalized categories. The overall program has demonstrated harm reduction both for patients and for the city of Amsterdam. PMID- 10101376 TI - Recent developments in maintenance prescribing and monitoring in the United Kingdom. AB - After a brief historical review of British drug legislation and public and governmental attitudes, this paper describes the wide range of policies and practices that have appeared since the explosion of illicit drug abuse in the 1960s. The spectrum goes from a reluctance to prescribe at all to maintenance on injectable opiates. Comparisons are made with differing attitudes to the availability of abortion in public health services. Compared with 5 years ago, about three times more methadone is being prescribed. There is a steady increase in prescriptions for injectable methadone but heroin maintenance is still rare. The "British System" permits great flexibility in the choice of opiates for maintenance. Some amphetamine-prescribing programmes also exist. Hair analysis for drugs to monitor levels of both prescribed and unprescribed drugs is a welcome and promising alternative to undignified and often misleading urine tests. PMID- 10101377 TI - Harm reduction in Bern: from outreach to heroin maintenance. AB - In Switzerland, harm-reduction programs have the support of the national government and many localities, in congruence with much of the rest of Europe and in contrast with the United States, and take place in public settings. The threat of AIDS is recognized as the greater harm. This paper describes the overall national program and highlights the experience from one city; the program is noteworthy because it is aimed at gathering comparative data from controlled trials. PMID- 10101378 TI - When science and politics collide: the federal response to needle-exchange programs. PMID- 10101379 TI - Research on needle exchange: redefining the agenda. AB - Researchers studying needle-exchange programs in the United States pursue a two fold agenda that requires answers to these questions: (1) Do such programs successfully reduce HIV seroprevalence among injecting drug users? (2) Do they promote drug use? Several federal laws and regulations require convincing data on each question before the release of federal funds for needle exchange. Fears that needle exchange promotes drug use are at the core of federal concerns, and these fears are shared by community leaders, scientists, and public health professionals. Nonetheless, the manner in which the "drug use" question has been framed and addressed in scientific research has been given insufficient attention. This article aims to stimulate debate about current research, and restore a focus on HIV prevention, by addressing several methodological, logical, and ethical weaknesses that characterize the scientific inquiry into whether needle exchange promotes drug use. PMID- 10101380 TI - Developing communality: family-centered programs to improve children's health and well-being. AB - Despite decades of enormous investment in research and public programs, the United States continues to face pandemics of preventable health problems such as low birth weight, teenage pregnancy, drug abuse, and interpersonal violence. With some justification, these problems have been blamed on the failings of families. The reasons why families may function poorly in their child-rearing roles have not been coherently or vigorously addressed by our social policies; sometimes these policies have aggravated the problems. This paper provides background to allow a better understanding of families' role in the social determination of children's health, and argues for programs and policies that assist families through the creation of social supports embedded in communities that are characterized by trust and mutual obligation. PMID- 10101381 TI - Voluntary newborn HIV-1 antibody testing: a successful model program for the identification of HIV-1-seropositive infants. AB - Harlem Hospital in New York City has one of the highest HIV-1 newborn seroprevalence rates in the United States. We report the results of a program introduced in 1993 and designed to identify HIV-1-seropositive (HIV+) newborns at birth. All new mothers, independent of risk, received HIV counseling that emphasized the medical imperative to know the infant's HIV status as well as their own. Consent was obtained to test the infant; discarded cord blood samples were tested by enzyme-linked immunosorbent assay (ELISA), and when positive, Western Blot confirmation. We compared the number of HIV+ infants identified through voluntary testing with the number reported by the anonymous New York State Newborn HIV Seroprevalence Study. In 1993, 97.8% (91 of 93) of the number of HIV+ infants identified by the anonymous testing were identified through voluntary maternal and newborn testing programs. Eighty-five HIV+ infants were identified before nursery discharge: 50% (42/85) through newborn testing; 14% (12/85) through prenatal testing; 13% (11/85) presented to care knowing their status; 23% (20/85) were known because of a previous HIV+ child. Six additional HIV+ children were diagnosed after hospital discharge (mean age, 5.5 months; range 1.5 through 17 months); four presented with symptomatic disease. The optimal time for identification of the HIV+ pregnant woman is before or during pregnancy, but when this does not occur, voluntary newborn testing can identify many HIV+ infants who would otherwise be discharged undiagnosed from the nursery. PMID- 10101382 TI - The health impact of economic sanctions. AB - Embargoes and sanctions are tools of foreign policy. They can induce a decline in economic activity in addition to reducing imports and untoward health effects can supervene, especially among older persons and those with chronic illnesses. Often, violations of the rights of life, health, social services, and protection of human dignity occur among innocent civilians in embargoed nations. This paper examines the effects of embargoes and sanctions against several nations, and calls for studies to determine ways in which economic warfare might be guided by the rule of humanitarian international law, to reduce the effects on civilians. It suggests that the ability to trade in exempted goods and services should be improved, perhaps by establishing uniform criteria and definitions for exemptions, operational criteria under which sanctions committees might function, and methods for monitoring the impact of sanctions on civilian populations in targeted states, particularly with regard to water purity, food availability, and infectious-disease control. Prospective studies are advocated, to generate the data needed to provide better information and monitoring capacity than presently exists. PMID- 10101383 TI - Differential mortality in New York City (1988-1992). Part One: excess mortality among non-Hispanic blacks. AB - To determine the distribution of mortality for non-Hispanic blacks and non Hispanic whites in New York City, death certificates issued in New York City during 1988 through 1992, and the relevant 1990 US census data for New York City, have been examined. Age-adjusted death rates for blacks and whites by gender and cause of death were computed based on the US population in 1940. Also, standard mortality ratios and excess mortality were calculated using the New York City mortality rate as reference. The results showed that New York City blacks had higher age-adjusted death rates than whites regardless of cause, including stroke, AIDS, homicide, and diabetes. The rate for New York City blacks was also higher than the US total for both genders. Using New York City mortality rates as a reference, more than 80% of excess deaths in blacks occurred before age 65. Injury/poisoning was the leading cause of excess death (20.1%) in black males, while in black females, cardiovascular disease was the largest single cause of excess deaths (24.8%). The higher death rates, especially premature death, of blacks in New York City are related to conditions such as violence, substance abuse, and AIDS, for which prevention rather than medical care is the more likely solution, as well as to cardiovascular diseases, where both prevention through behavioral change, and health and medical care, can influence outcome. PMID- 10101384 TI - Differential mortality in New York City (1988-1992). Part Two: excess mortality in the south Bronx. AB - To display the extent of variations in mortality according to geographic regions in New York City, we have compared mortality in New York City as a whole with that of the South Bronx. Mortality records for 1988 to 1992 and 1990 US census data for New York City were linked. The 471,000 residents of the South Bronx were younger, less educated, and more likely to lack health insurance than other New Yorkers. Using age- and gender-stratified populations and mortality in New York City as standards, age-adjusted death rates and excess mortality in the South Bronx were determined. All-cause mortality in the South Bronx was 26% higher than the city as a whole. Mortality for AIDS, injury and poisoning, drug and alcohol abuse, and cardiovascular diseases were 50% to 100% higher in the South Bronx than in New York City; years of potential life lost before age 65 in the South Bronx were 41.6% and 44.2% higher for men and women, respectively, than in New York City; AIDS accounted for the largest single share of excess premature deaths (21.8%). In summary, inequalities in health status, reflected by higher mortality rates in the South Bronx, are consistent with, and perhaps caused by, lower socioeconomic status and deficient medical care among residents of this inner city community. PMID- 10101386 TI - Changes in patient problems, 1965 to 1995. A brief overview. PMID- 10101385 TI - Focus on adolescent pregnancy and childbearing: a bit of history and implications for the 21st century. AB - Early childbearing in the United States has roots in the past; is the focus of intense partisan debate at the present time; and will have demographic, social, and economic ramifications in the future. It is an extremely complex issue, for which its associated problems have no easy or simple answers. Early parenthood is viewed as a social problem that has defied public policy attempts to stem its growth. It has become the focus of concern primarily for three reasons: (1) sexual activity has increased sharply, most recently among the youngest teens; (2) out-of-wedlock childbearing has risen among all teenagers, regardless of age; and (3) the issue of welfare. A review of statistics highlights the problem and discussion focuses on means of mitigating the negative effects of early childbearing. PMID- 10101387 TI - The New York Eye and Ear Infirmary at 175 years. A historical review of the department of otolaryngology. PMID- 10101388 TI - Adult AIDS in New York City--risk categories. PMID- 10101389 TI - Epistemology of medicine. PMID- 10101390 TI - Keynote address. The Margaret E. Mahoney Lecture and Symposium on the State of the Nation's Health. PMID- 10101391 TI - Overview of challenges. PMID- 10101392 TI - Issues in children's health. PMID- 10101393 TI - Issues in employment and insurance. PMID- 10101394 TI - Evolution of managed health care. PMID- 10101395 TI - State initiatives in health policy. PMID- 10101396 TI - Margaret E. Mahoney Symposium on the State of the Nation's Health: questions from the audience. AB - The Symposium convened in the afternoon of March 22, 1995. Before a mid-afternoon pause in the proceedings, a question-and-answer session was held. An edited summary of that session follows. PMID- 10101397 TI - Commonwealth Fund Initiatives. PMID- 10101398 TI - Minority health. PMID- 10101399 TI - Patient-centered care. PMID- 10101400 TI - Women's health. PMID- 10101401 TI - Managed care: a national experiment. Unanswered questions and potential risks. PMID- 10101402 TI - A summary of the symposium. PMID- 10101403 TI - FDA-VMAC calls for increased regulation of new antimicrobials; animal groups question conclusion. PMID- 10101404 TI - No screwworms allowed. PMID- 10101405 TI - Believes USDA regulations needed for rats and mice. PMID- 10101406 TI - What is your diagnosis? Hypertrophic osteodystrophy (HOD). PMID- 10101407 TI - What is your diagnosis? Disruption of the caudal portion of the reciprocal apparatus in a horse. PMID- 10101408 TI - Theriogenology question of the month. Malignant teratoma of the ovary. PMID- 10101409 TI - Employment of male and female graduates of US veterinary medical colleges, 1998. PMID- 10101410 TI - Epidemiologic aspects, control, and importance of multiple-drug resistant Salmonella Typhimurium DT104 in the United States. PMID- 10101411 TI - Clinical outcome and associated diseases in dogs with leukocytosis and neutrophilia: 118 cases (1996-1998) AB - OBJECTIVE: To describe diseases, prognosis, and clinical outcomes associated with leukocytosis and neutrophilia in dogs. DESIGN: Retrospective study. ANIMALS: 118 dogs with leukocytosis and neutrophilia. PROCEDURE: Medical records from 1996 to 1998 were examined for dogs with WBC > or = 50,000 cells/microliter and neutrophilia > or = 50%. Signalment, absolute and differential WBC counts, body temperature, clinical or pathologic diagnosis, duration and cost of hospitalization, and survival time were reviewed. RESULTS: Mean age was 7.7 years, WBC count was 65,795 cells/microliter, and absolute neutrophil count was 53,798 cells/microliter. Mean duration of hospitalization was 7.4 days and cost of hospitalization was $2,028.00. Forty (34%) dogs were febrile, and 73 (62%) dogs died. Overall median survival time was 17 days. Dogs with neoplasia or fever were more likely to die than dogs that were hospitalized or had systemic or local infections. CLINICAL IMPLICATIONS: Leukocytosis and neutrophilia were associated with high mortality rate and have prognostic value. Given the mean duration and cost of hospitalization, frank discussion with an owner at first recognition of leukocytosis and neutrophilia may be warranted. PMID- 10101412 TI - Pulmonary aspergillosis in horses: 29 cases (1974-1997). AB - OBJECTIVE: To analyze medical records and identify factors that veterinarians can use to prevent pulmonary aspergillosis in horses or that would enable them to diagnose it as early as possible. DESIGN: Retrospective study. ANIMALS: 29 horses. PROCEDURE: Medical records were reviewed for horses with pulmonary aspergillosis diagnosed on the basis of characteristic postmortem findings. Information on history, clinical signs, disease progression, and postmortem findings was obtained. RESULTS: 25 of 29 (86.2%) horses had primary (n = 20) or secondary (5) disease compatible with loss of integrity of the gastrointestinal (GI) tract. The remaining 4 horses had a non-GI tract disorder; only 1 of these 4 had clinical signs associated with the respiratory tract (i.e., pleuropneumonia). Although 22 (75.9%) horses had various signs of respiratory tract disorders, an antemortem diagnosis of Aspergillus pneumonia was made in only 1 horse and was suspected in only 1 other. Fungal organisms were seen histologically in tissues other than the lung in 12 (41.4%) horses. CLINICAL IMPLICATIONS: Horses with enteritis, colitis, typhlitis, or other diseases of the GI tract that result in mucosal compromise, and horses with clinical signs of respiratory tract disease, particularly if the horse's condition is unresponsive to treatment with antimicrobial agents; should be considered at high risk of having pulmonary aspergillosis. Immunosuppression from debilitating disease may also predispose horses to aspergillosis. Because invasive pulmonary aspergillosis can be difficult to diagnose, clinicians should be aware of clinical and epidemiologic settings in which this disease would develop. PMID- 10101413 TI - Analysis of first gastric compartment fluid collected via percutaneous paracentesis from healthy llamas. AB - OBJECTIVE: To evaluate the safety and efficacy of percutaneous paracentesis for fluid collection from the first gastric compartment of healthy llamas and to describe characteristics of that fluid. DESIGN: Prospective study. ANIMALS: 10 healthy adult llamas. PROCEDURE: Physical examinations were performed prior to sample collection and for 14 days afterwards. A CBC was performed prior to sample collection and 5 days later. A 16-gauge, 7.5-cm stainless steel needle, positioned approximately 20 cm caudal to the costochondral junction of the last rib, was pointed in a dorsocraniomedial direction and pushed through the abdominal wall into the lumen of the first gastric compartment. Fluid was aspirated and analyzed immediately for color, odor, consistency, pH, methylene blue reduction (MBR) time, protozoa, and bacteria. RESULTS: Fluid samples were obtained from 9 of 10 llamas. Mean volume was 4.1 ml, mean pH was 6.67, and mean MBR time was 173 seconds. Odor was slightly acidic, color was light brown-green to light yellow-green, and consistency was moderate. Small protozoa with variable iodine staining and gram-negative bacteria were commonly detected. With few exceptions, results of physical examinations and CBC remained within reference ranges. CLINICAL IMPLICATIONS: Fluid samples from the first gastric compartment can be successfully obtained by percutaneous paracentesis. Fluid characteristics were similar to those of fluid collected via orogastric tube in llamas and cattle. PMID- 10101414 TI - Growth of suckling beef calves in response to parenteral administration of selenium and the effect of dietary protein provided to their dams. AB - OBJECTIVE: To determine whether parenteral administration of selenium (Se) to calves and the amount of forage and protein provided to their dams affects unadjusted body weight, adjusted 205-day body weight, and average daily gain (ADG) of suckling beef calves. DESIGN: Randomized controlled field trial. ANIMALS: 151 Hereford-Angus crossbred beef calves. PROCEDURE: Newborn calves, randomly assigned to 1 of 3 groups, served as untreated controls (n = 49) or were given Se (0.05 mg/kg [0.023 mg/lb] of body weight, SC) once within 2 days of birth (55) or within 2 days of birth and on days 70, 114, and 149 (47). Until day 149, cow-calf pairs were pastured in fields in which the amount of available forage was high or low and supplemental protein was or was not provided. Calves were weighed on days 1, 70, 149, and 209. On days 160 and 209, blood was obtained from 33 calves for measurements of Se concentration. RESULTS: Mean consumption of supplemental protein was 0.65 kg/dam/d. Between days 1 and 70, calves that received the first of 4 multiple injections of Se had significantly greater ADG than control calves. Average daily gain for calves given only 1 injection was not significantly different from controls. Between days 70 and 149, ADG of calves increased with dietary supplementation of protein to their dams. CLINICAL IMPLICATIONS: Strategic administration of Se to calves and dietary supplementation of protein to their dams may result in greater ADG in suckling beef calves during specific time intervals. PMID- 10101415 TI - Herd-level economic analysis of the impact of paratuberculosis on dairy herds. AB - OBJECTIVE: To perform a herd-level analysis of economic losses associated with paratuberculosis in dairy herds. DESIGN: Cross-sectional study. SAMPLE POPULATION: A multistage stratified random sample of 121 dairy herds in Michigan. PROCEDURE: A 2-part questionnaire was used to gather data on management practices, herd productivity, labor use, and expenditures. Blood samples were collected from a random sample of cows > or = 2 years old in each herd and tested for antibodies to Mycobacterium paratuberculosis. A herd was considered negative for paratuberculosis if results for all cows tested were negative. Multivariable linear regression was used to evaluate the data. RESULTS: A 10% increase in proportion of cows positive for paratuberculosis was associated with a 33.4 kg (73.5 lb) decrease in mean weight of culled cows. Mortality rate among herds positive for paratuberculosis was 3% higher than rate among herds negative for paratuberculosis. Herds positive for paratuberculosis did not have a significantly higher annual number of hours of labor per cow than did herds negative for paratuberculosis. CLINICAL IMPLICATIONS: For a herd of average size and cull rate, the reduction in mean weight of culled cows attributable to paratuberculosis represented a loss of approximately $1,150 annually for each 10% increase in herd prevalence of paratuberculosis. The increased mortality rate attributable to paratuberculosis represented a loss of between $1,607 and $4,400 on the basis of lost slaughter value and cost of replacement heifers. PMID- 10101416 TI - Use of a water hardness test kit to measure serum calcium concentration in cattle. AB - OBJECTIVE: To determine whether a commercially available water hardness test kit could be used to measure total serum calcium concentration and diagnose hypocalcemia in dairy cows. DESIGN: Prospective study. ANIMALS: 30 dairy cows from 19 commercial herds. PROCEDURE: Serum calcium concentration was determined using a water hardness test kit and a standard, laboratory-based method. Simple linear regression was used to determine whether there was a linear relationship between results of the 2 methods, and Spearman's rank correlation was used to calculate correlation between measurements. Sensitivity, specificity, and predictive values of using test kit-derived values for diagnosis of hypocalcemia (laboratory value < 8 mg/dl) were calculated. RESULTS: There was a high correlation and significant linear relationship between results of the 2 methods. Sensitivity, specificity, predictive value of a positive test result, and predictive value of a negative test result were 100, 73, 86, and 100%, respectively. Accuracy was improved by using a test kit-derived calcium concentration of 7 mg/dl as the cut-off for determining hypocalcemia. CLINICAL IMPLICATIONS: Results indicate that a commercially available water hardness test kit can be used as a rapid, inexpensive method of estimating serum calcium concentrations and diagnosing hypocalcemia in dairy cattle. However, the test is not practical for cow-side use, because blood samples must be centrifuged to obtain serum for use in the test kit. PMID- 10101417 TI - Adverse drug reaction reporting by general medical practitioners and retail pharmacists in Harare--a pilot study. AB - OBJECTIVE: The pilot study was undertaken to investigate whether doctors and pharmacists in the private sector are willing to undertake Adverse Drug Reaction (ADR) reporting, to analyse their perceptions with regard to ADR reporting and to determine whether the concept of sentinel reporters could be of value in Zimbabwe. DESIGN: An open, prospective study where a selected group of private general medical practitioners and community pharmacists were asked to report any suspected ADRs over a six month period and to complete a structured self administered questionnaire. SETTING: Private medical and pharmacy practices in Harare. SUBJECTS: General medical practitioners and community pharmacists. MAIN OUTCOME MEASURES: Number of ADR reports received at Medicines Control Authority (MCA) and questionnaire responses. RESULTS: 19 reports were received from participants (eight pharmacists and five doctors) accounting for 79.2% of ADR reports to the MCA, during the study period. Seventeen (89.5%) of the reports generated from the study came from doctors. The 19 reports involved 15 different drugs, three (20%) of which had been registered in the last three years. Twelve questionnaires were completed. Serious and unexpected reactions were more likely to be reported. Most respondents knew what was expected and were willing to report, although five (41.7%) felt they were too busy. Seventy five percent of the doctors had not known that a reporting scheme existed in Zimbabwe and none of the participants had ever sent in a report prior to the study. Medical journals and the drug manufacturers were the most important sources of information about ADRs. CONCLUSION: Simply having interested pharmacists and doctors on the look out for ADRs and increased reporting of ADRs to the MCA. There are willing health care personnel but there is a need for larger studies to see if sentinel reporting of ADRs is applicable on a country wide basis. PMID- 10101418 TI - Chronic lymphocytic leukaemia in the Bloemfontein academic hospitals. AB - OBJECTIVE: To study the clinical presentation, treatment and outcome of patients diagnosed with chronic lymphocytic leukaemia (CLL) in the Bloemfontein academic hospitals during the past 21 years. DESIGN: Descriptive, retrospective study of clinical records of all CLL patients diagnosed at the Haematology clinics of the Universitas and Pelonomi Hospitals in Bloemfontein from 1975 to 1996. METHODS: Age, sex and race distribution of CLL patients were analysed. The peripheral blood, bone marrow, clinical presentation and stage at time of diagnosis, were studied. Treatment modalities, response to treatment and survival of patients were also analysed. Categorical variables were summarised by frequencies and percentages, and numerical variables by means of percentiles. Subgroup comparisons were done by 95% confidence intervals (CI) for differences in percentages, medians or means. RESULTS: A total of 185 CLL patients were studied. There were more males (62.7%) than females and the mean age of the patients was 63 years (19 to 98 years). Eighty six percent of the patients were older than 50 years. Racial distribution was as follow: 106 White, 77 Black and two patients of mixed race. Black patients more often presented with advanced disease and higher lymphocyte counts. A response to therapy was noted for 118 (82.5%) of the 143 patients who received treatment. A complete remission or partial response was noted for 38 (32.2%) of the patients. CONCLUSIONS: The presentation of CLL in the Bloemfontein academic hospitals is similar to what is seen world-wide. This is the first study describing CLL in a large number of Black patients and demonstrates that although Black patients presented more often at a younger age and had high risk disease, their clinical course and progression according to stage, also correlated with what is described in the literature. PMID- 10101419 TI - Factors associated with missed opportunities to immunise with tetanus toxoid at a tertiary health institution in Nigeria. AB - OBJECTIVE: To determine the magnitude of and the reasons for missed opportunities to immunise with tetanus toxoid at a tertiary health institution in Nigeria. The information obtained would be used in developing an intervention strategy for eliminating missed opportunities in the future. DESIGN: Missed opportunity was assessed by using the Revised WHO/EPI protocol (WHO/EPI/MLM/91.7). Exit interviews were carried out on pregnant women visiting the antenatal (prenatal) clinic to register the present pregnancy. SETTING: A tertiary health institution in Nigeria. SUBJECTS: Pregnant women who attended the antenatal clinic for the purpose of registering the present pregnancy during the last two booking days in February, 1997 and the first booking day in March, 1997. MAIN OUTCOME MEASURES: Missed opportunities and contributory factors. RESULTS: The prevalence of missed opportunity was 66%. The factors responsible for missed opportunity were poor history taking, lack of knowledge of the current schedule of immunisation, dependence on physician referral for immunisation and inefficient immunisation record keeping system. CONCLUSION: The findings establish the need for providing physicians in antenatal settings with an update on current immunisation policy and practice and for improved documentation of immunisation histories. PMID- 10101420 TI - Visceral leishmaniasis in North West Saudi Arabia: a new endemic focus of L. donovani or further evidence of a changing pathogenic role for L. tropica? AB - OBJECTIVES: The objective of this study was to evaluate patients with VL from the city of Tabuk, Kingdom of Saudi Arabia, with particular reference to the possibility that a focus of VL exists in the North West Province of Saudi Arabia, an area where it had not previously been reported. SETTING: North West Armed Forces Hospital, Tabuk, Saudi Arabia. DESIGN: Retrospective evaluation of all cases of infantile visceral leishmaniasis diagnosed in Tabuk, Saudi Arabia between 1989 and 1994. RESULTS: 5 cases of infantile visceral leishmaniasis were reviewed. In four cases, no evidence of travel outside Tabuk could be identified, suggesting primary infection by viscerotropic Leishmanial organisms in this area of Saudi Arabia. CONCLUSIONS: Visceral leishmaniasis has been identified in an area previously not considered endemic for L. donovani. This observation may indicate either, a previously unrecognized focus of L. donovani or provide further evidence of a changing pathogenic role for L. tropica. PMID- 10101421 TI - Haemorrhagic varicella: a malignant variant of chicken pox. PMID- 10101422 TI - Bilateral massive galactoceles. An atypical presentation. AB - Two cases of atypical presentation of galactoceles are reported. Both young women were referred to Mulago Hospital, Department of Radiology for breast imaging because of painful enlargement of both breasts. Both were found to be young lactating mothers. Ultrasound and aspiration was done on both of them. Ultrasound showed cystic lesions in both women. A milky solution was aspirated in both cases. PMID- 10101423 TI - Rural thoracotomy that had to be done. PMID- 10101424 TI - Syndromic management of sexually transmitted diseases. Part 1--An overview. PMID- 10101425 TI - A preliminary study of stress levels among first year medical students at the University of Zimbabwe. AB - OBJECTIVE: To assess stress levels among first year medical students at the University of Zimbabwe. DESIGN: A cross sectional study using two questionnaires. SETTING: Department of Anatomy, Faculty of Medicine, University of Zimbabwe, Mount Pleasant, harare, Zimbabwe. SUBJECTS: First year medical students aged between 18 and 24 years who have spent about seven months in the medical school. RESULTS: A total of 109 out of 123 first year medical students were used in the study. The two questionnaires produced similar results with an average of about 35.5% normal and an average of 64.5% of the students being at various levels of stress and or depression. About 11% reported very high levels of stress while the majority of the stressed students fell within the middle bracket. The number of affected students decreased as the level of stress and depression increased and demonstrates the differences in the stress threshold of the individual students. Estimation of suicide tendencies from both questionnaires showed that about 12% of the students were at serious risk and about 20% at lesser risk of psychological and emotional depression. The stratification of group 2 of SRQ-20 was valuable in isolating those students seriously stressed and/or depressed. CONCLUSION: This study has demonstrated that a number of first year medical students of the University of Zimbabwe were at various levels of stress and/or depression. Those students in the extreme stress or depression group need serious attention. This state of psychological and emotional distress in the subsequent years of medical training and during the professional years may lead to serious social consequences. A system of identifying students with low stress threshold early in their training is recommended as well as a means of helping them to deal with the stress and its causes. PMID- 10101426 TI - Trends in caesarean sections at Tygerberg Hospital, South Africa: a 20 year experience. AB - OBJECTIVE: To investigate the caesarean section (CS) rate and the individual components thereof at Tygerberg Hospital; the trend and its relationship to the perinatal mortality rate. DESIGN: A retrospective study, using data from 1975 to 1994. SETTINGS: Tygerberg Academic Hospital (TBH) is the referral hospital for regional Midwife Obstetric Units (MOU) as well as the tertiary referral hospital for secondary hospitals in the former Cape Province, excluding the Eastern Cape. In the last year of the study there were 7,035 deliveries in TBH, 4,040 deliveries in the MOU and 28,596 in the secondary hospitals. SUBJECTS: 174,713 deliveries and 22,773 CS from 1975 to 1994. MAIN OUTCOME MEASURE: The individual components of the CS rate. RESULTS: The CS rate stayed constant at about 13%. The perinatal mortality rate declined from 34.7/1000 to 18.4/1000. CONCLUSION: A low, constant CS rate can be maintained without compromising the perinatal mortality rate. PMID- 10101427 TI - Distributional patterns of bacterial diarrhoeagenic agents and antibiograms of isolates from diarrhoeaic and non-diarrhoeaic patients in urban and rural areas of Nigeria. AB - OBJECTIVES: To determine the prevalence of bacteria that could cause diarrhoea in stool specimens of individuals with and without diarrhoea in both urban and rural areas of Nigeria. To ascertain the antibiotic susceptibilities of the bacterial diarrhoeagenic agents isolated. To document the predominant signs and symptoms associated with the various bacterial agents of diarrhoea. DESIGN: Prospective study. SETTING: Patients/individuals attending government and private clinics in Lagos, Edo and Cross-River States of Nigeria. SUBJECTS: A total of 1,200 stool samples were collected from patients with diarrhoea. Another total of 1,200 stool specimens were obtained from controls. RESULTS: For diarrhoea cases in urban areas Campylobacter spp. were more predominant (28%) and were followed by enteropathogenic Escherichia coli (EPEC) (28%) whereas in rural areas, EPEC were the most commonly isolated bacteria (18%), closely followed by Salmonella spp. (16%). Controls had a similar distribution pattern. Higher rates of isolation of these enteric bacteria were recorded among diarrhoea cases than in controls (p < 0.05). Diarrhoea due to Vibrio, Yersinia, Aeromonas, Plesiomonas and EPEC was mainly watery whereas it mainly consisted of blood/mucus for Shigella and Salmonella. All were associated with abdominal pain and fever. Results presented also indicate that over 80% of Shigella species, Salmonella, EPEC and P. shigelloides were susceptible to nalidixic acid and nitrofurantoin. Virtually all the enteropathogens were resistant to commonly used antibiotics such ampicillin, erythromycin, tetracyclines and streptomycin. CONCLUSION: Results show that distributional patterns of bacterial agents of diarrhoea may vary in urban and rural areas and have revealed the effectiveness of nalidixic acid, gentamicin and nitrofurantoin, in that order, against these enteropathogens. PMID- 10101428 TI - Syphilis in Murewa District, Zimbabwe: an old problem that rages on. AB - OBJECTIVE: To determine the prevalence of syphilis among pregnant women and women giving birth in health centres in a rural district and to identify problems associate with syphilis control in the same district. DESIGN: Cross sectional descriptive study. SETTING: Murewa District health facilities. SUBJECTS: Women attending health facilities in this district for antenatal care or delivery between February and May 1993. MAIN OUTCOME MEASURES: Syphilis sero-prevalence rate. Factors associated with poor syphilis control. RESULTS: Even though it is recommended that all women attending clinics for antenatal care (ANC) should be screened for syphilis at first visit only 308 (20%) out of 1,556 first visit attenders were screened during the study period. Three hundred and sixty six (33%) out of 1,096 women giving birth in health institutions were screened. The RPR/TPHA sero positivity rate for antenatal women was 9.2% while that for women delivering was 9.8%. A positive RPR was not significantly associated with the women's age, parity, infant's birth weight, sex or pregnancy outcome. Factors associated with poor syphilis control in this district included: lack of motivation and appreciation of the seriousness of syphilis in pregnancy; lack of transport to send specimens and receive results from Murewa District Hospital; poor record keeping; loss to follow up of women being tested or after starting treatment; lack of contact tracing and treatment of contacts and difficulties in implementing the 10 day neonatal regime and follow up of these infants. CONCLUSION: Syphilis remains poorly controlled in Murewa district and may be contributing significantly to high perinatal mortality rates. There is need to strengthen the syphilis control programme through motivation and training of health workers, decentralisation of testing and treatment of the condition and improved contact tracing. A repeat RPR test at delivery may not be cost effective. PMID- 10101429 TI - Severe envenomation by a "pet" vine snake. PMID- 10101430 TI - On the cause of the curvature of the basilar artery: a preliminary MRA study. PMID- 10101431 TI - Syndromic management of sexually transmitted diseases. Part 2--The management of genital discharge. AB - In men urethral discharge is commonly caused by Neisseria gonorrhoeae and Chlamydia trachomatis. Both organisms cause an acute anterior urethritis and infected men usually present with symptoms of urethritis. A proportion of men with urethral infection may remain asymptomatic. Amongst women the common cause of vaginal discharge is vaginitis caused by Trichomonas vaginalis, Candida albicans and anaerobic bacterial infection (bacterial vaginosis). However, cervicitis caused by N. gonorrhoeae and C. trachomatis also causes vaginal discharge. Cervicitis is the more serious cause of vaginal discharge as the aetiologic agents may lead to infection ascending above the internal os of the cervix resulting in pelvic inflammatory disease and other complications. PMID- 10101432 TI - Seroprevalence of human immunodeficiency virus type 1 infection in childhood malignancy in Zimbabwe. AB - OBJECTIVES: To determine the association between malignancy and the Human Immunodeficiency Virus type 1 (HIV-1) infection in children. DESIGN: Case series. SETTING: The Paediatric Oncology Unit at Parirenyatwa Teaching Hospital. SUBJECTS: 76 consecutive newly diagnosed cases of malignancy between May 15 and November 15 1997. MAIN OUTCOME MEASURES: HIV serostatus. RESULTS: 27 out of 64 children were HIV seropositive, giving a seroprevalance rate of 42.2% (95% CI 30.1 to 54.3%). The four commonest diagnosed malignancies were non-Hodgkin's lymphoma (22.4%), acute lymphoblastic leukemia (19.7%), Wilm's tumour (19.7%) and Kaposi's sarcoma (15.8%). These tumours accounted for 77.6% of all malignancies. Nine of a total of 17 patients with non-Hodgkin's lymphoma were HIV positive and all 12 patients with Kaposi's were also HIV positive. No cases of Burkitt's lymphoma were seen. Although there was increased incidence of non-Hodgkin's lymphoma (NHL) compared to previous years, there was no significant association with the HIV serostatus. A significant association between Kaposi's sarcoma (KS) and HIV serostatus was observed (p < 0.001). Children with KS were more likely to be HIV seropositive. Children with acute lymphoblastic leukemia (ALL) and Wilm's tumours (WT) were 83 and 88% less likely to be HIV seropositive, respectively. CONCLUSIONS: HIV has transformed the pattern of childhood malignancy in Zimbabwe. The two tumours mostly affected are NHL and KS. PMID- 10101433 TI - Nutritional status of HIV-1 seropositive patients in the Free State Province of South Africa--laboratory parameters. AB - OBJECTIVE: To evaluate the nutritional status of HIV-1 seropositive patients with regards to laboratory parameters; the correlation between nutrient intake and actual values of nutrients, as well as the relationship between malnutrition and disease progression. DESIGN: A cross sectional study. SETTING: The Immunology Clinic at the Pelonomi Hospital in Bloemfontein, South Africa. SUBJECTS: 90 HIV/AIDS patients in different stages of disease were recruited consecutively from January to May 1995. Sixteen patients were followed up in 1997. MAIN OUTCOME MEASURES: The patients were divided into three groups according to their CD4+ T cell counts, and blood levels of protein, albumin, cholesterol, ferritin, vitamin B12, magnesium, and phosphorus, as well as several micronutrients including vitamin E, vitamin C, beta-carotene and retinol which were determined using standard methods. These values were compared with the normal reference values used in the laboratory, and we tried to correlate these parameters with disease stage, as well as recorded nutrient intake in a subgroup of 35 patients. RESULTS: Abnormal values for several parameters, including plasma-retinol and serum protein were found, but no correlation between more advanced disease and micronutrient deficiencies could be demonstrated. CONCLUSIONS: HIV/AIDS patients from this population are deficient in several micronutrients, and for some patients this is mirrored by a low intake. Multivitamin/anti-oxidant supplementation of HIV/AIDS patients should be considered, as this could lead to improved immune function in these patients. PMID- 10101434 TI - In vivo testing of the therapeutic efficacy of chloroquine on falciparum malaria infections in Chirundu, Mashonaland West, Zimbabwe. AB - OBJECTIVE: To detect the level of the in vivo chloroquine efficacy in falciparum malaria infections, in order to assess the need for change in the management and treatment of uncomplicated malaria. DESIGN: Prospective descriptive study. SETTING: Chirundu Rural Clinic, Mashonaland West Province. SUBJECTS: 63 patients confirmed by a positive blood slide for P. falciparum who attended Chirundu clinic, who were eligible for the study and, who also agreed to participate. MAIN OUTCOME MEASURE(S): Frequency of treatment success, early treatment failure and late treatment failure in uncomplicated patients treated with chloroquine. RESULTS: Out of 63 cases enrolled and completely followed up, chloroquine treatment was effective in 54 cases (85.7%) and was not effective in nine cases (14.3%). All treatment failures were successfully treated with sulphadoxine + pyrimethamine (Fansidar) or quinine following the approved guidelines. CONCLUSIONS: Chloroquine remains highly effective in the treatment of malaria due to P. falciparum in the Zambezi Valley of Hurungwe district and therefore, has to remain the first line drug. Likewise, guidelines for the use of sulphadoxine + pyrimethamine (Fansidar) or quinine as second line drugs, are adequate to the local situation. Health workers directly supervised the patients when they were swallowing the tablets during the whole course, and this without doubt, indirectly increased the efficacy of chloroquine. It is vital to confirm the malaria diagnosis on the spot appointing microscopists or distributing a limited stock of Parasight-F test. PMID- 10101435 TI - Relationship between estimated body fat and some respiratory function indices. AB - OBJECTIVE: To find the relationship between estimated body fat and respiratory function indices. DESIGN: Cross sectional study of volunteers in the physiotherapy department. SUBJECTS: Physiotherapy patients with no respiratory or neuromascular diseases. MAIN OUTCOME MEASURES: Quetelet index (as measure of body fat), vital capacity and breath holding time. RESULTS: Their ages ranged from 20 year to 60 years with a mean 24.20 +/- 6.59 years and 29.72 +/- 14.18 years in males and females respectively. Subjects whose quetelet index was about 30 kg/m2 and above were classified as obese. None of the male subjects fell into the obese category, while six of the 50 female subjects fell into the obese category. Significant differences were observed in the mean of the Quetelet index, percent predicted vital capacity and the breath holding time between the normal female and the obese female subjects. A high but inverse relationship was found between estimated body fat and each percent predicted vital capacity and breath holding time in subjects whose Quetelet index was above 30 kg/m2. There was also a high and positive correlation between percent predicted vital capacity and breath holding time in subjects with Quetelet index above 30 kg/m2. CONCLUSION: These findings were attributed to the restrictive effect of excess adipose tissue located around the thorax and the abdomen. It was concluded that adequate caution should be taken during exercise therapy for patients with a Quetelet index value above 30 kg/m2 to enable them exercise safely and with respiratory efficiency. PMID- 10101436 TI - Traditional medicine in Nigeria and modern obstetric practice: need for cooperation. AB - OBJECTIVES: To determine the prevalent use of traditional medicine in pregnancy and labour and to find out if there is any association between the use of traditional medicine and obstetric outcomes. DESIGN: A cross sectional structured interview survey and case notes review. SETTING: Department of Obstetrics and Gynaecology, Ogun State University Teaching Hospital (OSUTH), Sagamu, Nigeria. SUBJECTS: 300 parturient mothers. MAIN OUTCOME MEASURES: a) Use or non-use of traditional medicines in pregnancy and labour. b) Maternal morbidity and mortality. c) Perinatal morbidity and mortality. RESULTS: 160 (53.3%) patients admitted to the use of traditional medicine in pregnancy and labour. The two groups (users and non-users) were similar with respect to age, parity and level of education. The three maternal deaths occurred in the users' group. The perinatal mortality was 91 per 1,000 among the users and 61.2 per 1,000 for the non-users. CONCLUSION: Mothers and neonates in the users' group fared worse than the controls. Delay in seeking hospital care was the major factor in the poorer outcomes for the users' group. Since the use of traditional medicine in pregnancy and labour is common among the population, efforts should be made by the two groups of physicians (traditional and Western) to co-operate. PMID- 10101437 TI - Pre-eclampsia/eclampsia: a literature review. AB - A review of literature on pre-eclampsia/eclampsia indicates that this is one of the commonest causes of high maternal and infant mortality and morbidity rates. Current information on the condition indicates that use of aspirin, phenytoin and magnesium sulphate are on the increase. However, in Malawi lytic cocktail and use of antihypertensives such as Hydralazine and, anticonvulsants such as Valium are currently in use. Even with this type of management, Malawi experiences high morbidity and mortality rates. This literature review was done to identify baseline data for a study to be carried out in some of the hospitals in Malawi to establish a protocol for effective management of pre-eclampsia and eclampsia in Malawi. It is hoped that after using low dose aspirin and magnesium sulphate, the morbidity and mortality caused by the disease will be reversed with time. PMID- 10101438 TI - Quality of published articles in CAJM. PMID- 10101439 TI - Syndromic management of sexually transmitted diseases. Part 3--The management of genital ulcers and inguinal buboes. PMID- 10101440 TI - [The effect of sodium fluoride on selected biochemical markers of bone turnover in ovariectomized rats]. AB - The aim of the study was to investigate the effect of fluoride on selected biochemical markers of bone remodelling in young growing rats and after ovariectomy performed on 12-weeks-old female Wistar rats. Seventy 6-weeks-old female Wistar rats were randomized into seven groups. The first baseline control group was sacrificed before the beginning of the experiment. Two groups served as controls receiving distilled water and the other groups received fluoridated water at different doses (two received 8 and two received 60 mgF-/l). 30 rats (ten from each group) were sacrificed after 6 weeks. Serum was then collected for measurement of fluoride concentration, serum total alkaline phosphatase activity (ALP) and concentration of telopeptide of rat type I collagen (ICTP). Last three groups (ten rats each) were ovariectomized and received than only distilled water to drink. After following six weeks all rats were sacrificed. After six weeks of experiment the group receiving 8 mg F-/l showed the lowest ICTP values and the smallest decrease of serum ALP activity compared to the baseline control group. The rats with higher plasma fluoride concentrations after ovariectomy demonstrated lower ICTP concentrations and higher ALP activity than animals with lower fluoride concentrations. PMID- 10101441 TI - [The influence of corticosteroid therapy on selected parameters of bone metabolism in children with nephrotic syndrome]. AB - The aim of the study was to evaluate the influence of prednisone therapy on selected parameters of bone metabolism [carboxyterminal propeptide of type I procollagen (PICP), carboxyterminal pyridinoline crosslinked telopeptide of type I collagen (ICTP), alkaline phosphatase (AP), parathormone (PTH), and calciuria (Cau) in children with nephrotic syndrome. Twenty patients (aged 4-15 years, mean: 9.2 years) were treated with prednisone. Blood and urine samples were taken: T0--before prednisone treatment; T1--after two weeks of treatment with prednisone 1-2 mg/kg/24 h; T2--after two weeks of treatment with prednisone 1-2 mg/kg/48 h; T3--after 3 months of treatment with prednisone; T6--in 6th month of treatment with prednisone, at dose 0.2-0.4 mg/kg/48 h. Mean values of PICP, ICTP, AP concentration, and PICP/ICTP ratio found in the T1 period were significantly lower, and mean Cau value was higher in comparison to means of these parameters observed before steroid treatment. After two weeks of prednisone administered every 48 hours mean values of PICP, ICTP concentrations and PICP/ICTP ratio were significantly higher than in the T1 period of treatment. There were no significant differences in mean concentrations of PTH before and during everyday doses of prednisone therapy. Mean value of PTH concentration decreased significantly during T2 in comparison with T1 period of prednisone treatment. Our data demonstrate that short-term treatment with high daily doses of prednisone in children with nephrotic syndrome is associated with increase of calciuria and suppression of serum markers of type I collagen's turnover. Changes of PICP, ICTP, and PICP/ICTP ratio depend on a method of steroid administration. Decreased PICP/ICTP ratio during daily steroid treatment may indicate stronger inhibition of bone formation than bone resorption, but significance of PICP/ICTP ratio in later phases of treatment needs further studies. Present study suggests that prednisone influences bone metabolism directly rather than by stimulating the parathyroids. PMID- 10101443 TI - [Densitometric evaluation of mineral deposits in children and young people with food sensitivity who were treated by diet therapy]. AB - Bone mineral content (BMC) and bone mineral density (BMD) of the whole skeleton were measured with dual energy x-ray absorptiometry (DEXA) using DPX-L bone densitometer (Lunar) in 240 caucasian subjects with food hypersensitivity, aged 2 18 years, fed milk-free diet (mean duration: 3.6 yrs). DEXA results were compared to the age and sex-matched reference population (n = 473) presenting normal consumption of milk and dairy products, Breast-feeding duration, social conditions and general physical activity did not differ in these groups. All subjects ranged between 3rd and 97th percentile for body weight and height and their nutritional status was similar in both groups, as assessed by means of anthropometric methods (BMI, skinfolds, midarm circumference). Mean values of total BMC and total BMD did not show significant differences between two groups of children, regarding to diet application. Although dietary calcium intake has a significant positive influence on the bone mineral content, our cross-sectional study suggests that the properly applied and controlled elimination diet should not disturb bone mass accumulation in children and adolescents with food allergy. PMID- 10101442 TI - [Vitamin D receptor gene polymorphism and the rate of bone loss of the femur neck and lumbar spine in hemodialized patients with chronic renal failure]. AB - It has been suggested that the vitamin D receptor (VDR) gene Bsml-polymorphism is a genetic determinant of bone metabolism. To test this hypothesis, the relationship between VDR genotypes, bone mineral density (baseline and after 18 months) and parameters of calcium metabolism and bone turnover were investigated prospectively in 136 haemodialyzed patients. Lumbar spine and femoral neck bone mineral density (BMD) were assessed by dual energy X-ray absorptiometry (DEXA). In addition calcium, phosphorus, 25(OH)D3, 1.25(OH)2D3, osteocalcin serum concentrations, bone alkaline phosphatase activity and intact 1, 84-PTH levels were measured. VDR genotype BB, Bb and bb were found in 24%, 46% and 30% of patients respectively. Initial BMD (g/cm2) of lumbar spine and femoral neck did not differ between genotypes, however the decrease of femoral neck BMD during 18 months of observation differ significantly (p < 0.02) between the particular genotype groups (femoral neck: BB -0.031 +/- 0.029; Bb -0.027 +/- 0.017; bb 0.017 +/- 0.019 g/cm2). Significantly lower serum level of 25OHD3 was found in patients with the BB genotype before and after 18 months of observation in comparison to the respective values obtained in bb genotype patients, (respectively, 21.0 +/- 16.8 ng/ml vs 30.8 +/- 17.9 ng/ml; p < 0.01 and 24.0 +/- 10.8 ng/ml vs 32.4 +/- 16.0 ng/ml; p < 0.02). BB genotype patients were also characterised by significantly lower serum level of 1.25(OH)2D3 both initially and after 18 month of the study (respectively in BB and bb patients 25.9 +/- 9.7 pg/ml vs 30.7 +/- 10.0 pg/ml; p < 0.02 and 18.4 +/- 12.3 pg/ml vs 24.3 +/- 13.0 pg/ml; p < 0.01). No significant differences were found in Ca, P, osteocalcin, iPTH serum concentrations and bone fraction of alkaline phosphatase activity between particular genotypes. Results from this study suggest that faster bone mineral loss and more exaggerated disturbances of vitamin D metabolism are present in haemodialyzed uraemic patients with BB than bb genotype of VDR. PMID- 10101444 TI - [Indices of mechanical strength of the distal radius in healthy women and women with Colles fracture]. AB - Wrist fractures (Colles) are one of the most frequently observed osteoporotic fractures in postmenopausal women. The aim of our study was the comparison of mechanical properties of distal radius of women with Colles fracture using a Stratec XCT 960 peripheral quantitative computed tomography (pQCT) in relation to age-pair controls without a wrist fracture. Using the pQCT method for estimation of SSI (Strength Strain Index), we found significant differences of SSI values in Colles subjects. In clinical practice, pQCT offers new diagnostic tools which cannot be provided by conventional densitometric methods. PMID- 10101445 TI - [Age-related changes of densitometric and strength parameters evaluated with QCT method in healthy women]. AB - In the present study the age-related changes of pQCT values in normal Polish women were examined. The volumetric bone mineral density, trabecular density, cortical density and Strength Strain Index was measured using peripheral quantitative computed tomography (Stratec XCT 960) in 459 healthy women aged 18 60 years. Bone mineral measurement of the distal and proximal radius may be useful in evaluation of age-related bone loss, fracture risk and for diagnosis of osteoporosis. PMID- 10101446 TI - [The influence of the height of body mass on ultrasound measurements of bones in healthy Polish women]. AB - Broadband ultrasound attenuation (BUA) and speed of sound (SOS) and stiffness index of the os calcis were measured in a sample of 407 normal sedentary women aged 40-60 years. Achieved results deliver reference data supporting measurement interpretation of physiologic as well pathologic conditions. Correlations were performed between ultrasound measurements and antropometric data. We observed that in women over 55 years there is a significant age related decline of BUA, SOS and stiffness. Significant correlations were also stated (p < 0.05) between body mass of woman aged 40-45, 46-50 i 51-55 and ultrasonic parameters of broadband ultrasound attenuation (BUA) (r = 0.26, 0.46, 0.43 respectively), considered as related to internal trabecular bone structure. In group of eldest woman (aged 56-60) such a correlations were not present, probably as an effect of intensive bone loss related to lack of protective effect of estrogens. PMID- 10101447 TI - [Analgetic treatment and rehabilitation in osteoporosis]. AB - Osteoporosis seems to be a component of body aging process. Through the years, muscles, ligaments, and fasciae loose their natural elasticity; degenerative changes form in joints; also, mechanical resistance of bones reduces. Involutive changes in central nervous system (CNS) cause disturbances in reciprocal transmission of impulses between CNS and muscles. This changes normal motion pattern, leading, consequently, to lasting stress of ligaments, muscles, joints and bones, what becomes a source of strong nociceptive impulses. One of first symptoms of this is pain, localized particularly in spine region. Pain is another cause of increased, abnormal tension of muscles and, thus, of their stress. Proper treatment of above situation must be necessarily consisted of simultaneous analgesia, correcting of muscle tension and relaxation. Therefore, guideline for the rehabilitation program needs to be supported by thorough clinical, biomechanical, roentgenographic and densitometrical case analysis. Rehabilitation works as prophylactics of formation and fixing of deformities. Therefore, this must be aimed to: pain relief, maintaining of proper patient's stance, rebuilding of normal muscle force, maintaining of normal motion range and increasing of daily motion activity, what would stimulate skeletal system. For practical reasons, forming of dysfunctions in motion system in course of osteoporosis is classified into three stages--I--early, II--advanced osteoporosis and III--late. PMID- 10101448 TI - [Cryotherapy in osteoporosis]. AB - Cryotherapy is use of temperature lower than -100 degrees C onto body surface, for 2-3 minutes, in aim to cause physiological reactions for cold and to use such adapting reactions. Organism's positive response to cryotherapy supports treatment of basic disease and facilitates kinesitherapy. Low temperature may be obtained by use of air flow cooled with liquid nitrogen; this could be applied either locally, over chosen part of the body, or generally, over the whole body, in cryosauna or in cryochamber. The most efficiently is applying cryotherapy twice a day, with at least 3 hours interval. Kinesitherapy is necessarily used after each cryotherapy session. Whole treatment takes 2 to 6 weeks, depending on patient's needs. Cryotherapy reduces pain and swellings, causes skeletal muscles relaxation and increase of their force, also, motion range in treated joints increases. Thus, cryotherapy seems to fulfill all necessary conditions for rehabilitation in osteoporosis. Cryotherapy represents numerous advantages: it takes short time for applying, being well tolerated by patient, also patient's status improves quickly. In addition, contraindications against cryotherapy are rare. All this makes cryotherapy a method for a broad use in prophylactics and treatment of osteoporosis. PMID- 10101450 TI - [Osteoporosis in developmental age: diagnostic and therapeutic problems]. AB - In children and the youth it is secondary osteoporosis (OP) rather than idiopathic one which occurs more often; its multidirectional pathogenesis is usually ascertainable. Secondary OP, mostly generalised, is diagnosed in the course of such hormonal disturbances as: primary hyperparathyroidism, hyperthyroidism, hyperadrenalocorticalism. Another group of diseases implicating OP are connective tissue pathologies: congenital (osteogenesis imperfecta, collagenopathies) and acquired (juvenile chronic arthritis). A serious problem for a paediatrician is the iatrogenic OP resulting from a long-term use of some medicines (glucocorticosteroids) or long-lasting immobilization for surgical and orthopaedic reasons, or from chronic general diseases. Osteoporosis accompanying pathological states of the skeletal and nervous systems (with paralyses and pareses) is particularly intensive and difficult for treatment. Osteoporosis in developmental age may cause disturbances in natural development of the skeleton, which leads to deformities in the skeletal system and to the formation of faulty postures. Lower body height is a frequent complication resulting from OP in children and the youth. In OP diagnostics the densitometry test is of the basic importance, the most common method is dual energy X-ray absorptiometry (DEXA) and the diagnosis criterion is the decrease of bone mineral density (BMD) greater than 2 SD. It should be taken into account also the X-ray and clinical symptoms, which are similar as those observed in adults. Osteoporosis biochemical markers, however are, less significant in children because for the most of then the reference values are not determined. The OP treatment is indispensable in developmental age and it should include pharmacological therapy and the proper diet and rehabilitation as well. PMID- 10101449 TI - [Genetic factors in osteoporosis]. AB - Osteoporosis is a widespread disease affecting more than 1/4th of the female and 1/10th of the male population. It is characterised by a low bone mass, which in turn leads to osteoporotic fractures. Bone mass can be described as bone mineral density (BMD). BMD in human population is subject to quite significant interpersonal variability, for 75 to 80% of which, the genetic factors are responsible. To investigate the dependence of BMD on genetic factors, a possible links between the BMD and the natural polymorphism of so called "candidate genes" are checked. The first candidate gene to be investigated was the gene coding for the receptor of the active form of vitamin D. A statistical linkage between the naturally occurring polymorphism of that gene and the BMD was found by many research centres. It was found that certain polymorphic variants of that gene are linked to higher BMD's than the other ones. This trend existed in different human races and various age groups in many countries including Poland. A batch of negative results which appeared in some papers can be explained either by high calcium consumption in the given population, or the existence of another gene affecting bone metabolism and closely coupled to the vitamin D receptor gene. Other investigated and promising genes are the genes coding for other receptors (e.g. oestrogen), regulatory proteins (e.g. IL-6) and structural proteins (e.g. type I collagen). PMID- 10101451 TI - [Estrogens and osteoporosis]. PMID- 10101452 TI - [Calcitonin -- 1998]. AB - Calcitonin is one of three most important factors involved in the regulation of systemic calcium homeostasis. Since its discovery in 1961 the structure of calcitonin from different species including human was established, synthetized and developed for use in human clinic. Up to now calcitonin is utilized in treatment of hypercalcemia, Paget disease, algodystrophy, primary and secondary osteoporosis and analgesia. Beside comparative studies aiming on selection of the most effective protocol of treatment and utilization, lately calcitonin is extensively studies for its antifracture potency in osteoporosis. One of the substantial therapeutical progress also appeared the utilization of intransal preparation of calcitonin. PMID- 10101454 TI - [Telomerase and gastrointestinal cancer]. AB - Activation of telomerase and stabilisation of telomeres are considered to be essential for the immortality of cancer cells. Telomerase activity is present in almost all carcinomas. It indicates that the detection of telomerase activity in tissues using a telomeric repeat amplification protocol (TRAP) is useful for cancer diagnosis. This review will describe the current state of knowledge of telomerase as it relates to gastrointestinal malignancies focussing primarily on published measurements of this enzymes activity in benign and malignant neoplasms of stomach, colon, pancreas and liver. Telomerase seems to be promising diagnostic and prognostic marker of gastrointestinal tumors which can be useful especially in early detection and even screening. Continuing research will determine its potential value in the control of cancer. PMID- 10101453 TI - [Pain as an important symptom in trauma, diseases and movement disorders]. AB - The author shows the importance of pain in motion organ diseases. He pointed out numerous orthopaedic conditions, such as inborn luxation of the hip joint, scoliosis, spondylolisthesis, at the preliminary stage of procedure, produce no pain. There are also diseases such as Perthes disease or osteoporosis, whose pain are untypical and appear at the moment of the fracture of the bone trabecules. Transitory pains are very often downplayed by patients and physicians, which may lead to serious mistakes in diagnosis. PMID- 10101455 TI - [Clinical analysis and therapeutic results of peripheral giant cell granuloma]. AB - The author presented clinical analysis and theraputic results of 105 cases of the peripheral giant cell granuloma treated in Division of Maxillofacial Surgery Regional Hospital in Rzeszow. In the 16 cases (15, 3%) this disease recurences in all prabability after non radical operation was observed. The author thinks that electrosurgical removal of the tumour is the treatment of choice. In the advanced stage of peripheral giant cell granuloma indicated excision tumour and the surrounding margin of healthy tissue with resection of the part of the alveolar process. Therapeutic indication to the extraction of the teeth neighbouring to the granuloma should be teken into consideration according to individual cases. PMID- 10101456 TI - [Local activation of blood coagulation in pancreatic tissue in chronic pancreatitis]. AB - Thromboembolic events may complicate clinical course of chronic pancreatitis. It is accepted that trypsin plays a role in the pathogenesis of these abnormalities. However there is a lack of information about local activation of blood coagulation in pancreatic tissue in chronic inflammation and contribution of tissue factor (TF) to this process. Immunohistochemistry was applied to AMeX fixed sections of tissues of ten cases of chronic pancreatitis to explore the presence and distribution of components of the coagulation system in situ. TF antigen was present in cells of ductules. Fibrinogen and fibrin were detected in the inflammatory infiltrates of the pancreatic tissue. The data suggest that there is local activation of blood coagulation in pancreatic tissue in chronic inflammation that depends on tissue factor. PMID- 10101457 TI - [The treatment of chronic duodenal ulcer with accompanying Helicobacter pylori infection]. AB - Three hundred seventy four patients with duodenal ulcers and Helicobacter pylori infections were given a four-week treatment of bismuth or ranitidin. In all patients two-week antibiotic therapy were given. Endoscopies with urease tests and histologic examinations were performed before initiation and four weeks after cessation of therapy. Four-week therapy with ranitidini and two-week therapy with amoxicillin and metronidasole is highly effective (89.6%) in duodenal ulcer healing and symptom improvement comparison to bismuth and antibiotic therapy. PMID- 10101458 TI - [The value of gastrointestinal antigens in the monitoring of patients with malignant head neoplasms]. AB - The authors present the results of examinations of test on the sensitivity of biochemical tumor marker (Ca 19-9) in a group of 35 patients with head malignant tumors. The sensitivity (SE) of Ca 19-9 was 22.9% in preliminary study. The values of Ca 19-9 changed from 22.9% to 25.9% in monitoring of tumors. Positive predictive value (PV+) and specify (SP) were 100% in preliminary study and in monitoring. Negative predictive value (PV-) was 50.9% in preliminary study and 51.6% in monitoring. In 25 patients we observed changes in examined parameters: SE--35%, SP--100%, PV(+)--100%, PV(-)--42.1% in monitoring. Our study indicates that serum levels of Ca 19-9 were higher in patients with head tumors than in control group. The surgical treatment of tumors didn't change the values of Ca 19 9. PMID- 10101459 TI - [Pigmented nevus in children as a diagnostic and treatment problem]. AB - Congenital and acquired nevi are common cutaneous malformation occurring in childhood. 315 children were cured in 1990-1995. 62% of nevi did not show any abnormalities of growth pattern and typical appearance. In 119 nevi there were danger signals present, that suggested unusual activity or possible malignant transformation. Changes of pigmentation were present in 36%, enlargement and abnormal texture in 21%, satellite nevi in 11%. Histologically, they were dermal in 28% and epidermodermal in 24%. Only in 3 children melanoma malignum was found, in 2 melanoma juvenile, in 4 dysplastic nevi. All of the children were operated. The very good final result was obtained in 289 children (92%). PMID- 10101460 TI - [Clinical symptomatology and laboratory diagnosis of 75 cases of ethylene glycol poisonings]. AB - Between 1991 and 1995 there were 75 cases of ethylene glycol poisoning (GE) hospitalised in the Clinic of Acute Poisoning of Institute of Occupational Medicine in Lodz, which comprised 0.9% of the total number of patients. The most common were cases of accidental antifreeze liquids consumption. On admittance to the clinic the state of 59% of the patients was diagnosed as severe and very severe. The main symptoms were: metabolic acidosis, which developed in 77% cases of poisoning, and its consequences--the central nervous damage and the cardiovascular system distributions. The average pH amounted to 7.06 while the base deficit to 22.42 mmol/l. Among complications the most commonly observed was the acute renal failure (84%) which developed during the first 24 hrs in all the 25 cases ending in deaths. Only in 16 out of 63 cases, in which the acute renal failure occurred, multiple hemodialyses proved necessary. Other complications accompanying the poisoning were as follows: anaemia, pneumonia, the irreversible central nervous system damage, the disseminated intravascular coagulation syndrome, and the hepatic damage. The comparative analysis (base on the chi2 and median test) of the deceased and cured patients has shown a significant difference (p < 0.05), among others, concerning the plasma osmolality, the frequency of the acute renal failure and the central nervous system damage occurrence. PMID- 10101461 TI - [Estrogen receptors in the malignant and benign neoplasms of the thyroid]. AB - The etiology of thyroid carcinoma is multifactoral. The examples of etiologic factors are: deficit of iodine, genetic predisposition's, female sex, older age, irradiate in childhood, thyroid growth stimulating factors, and epidermal growth factor. Epidemiological data suggested that differentiated thyroid carcinoma depends on sex hormones, especially estrogen. The author have immunohistochemically studied estrogen receptors (ER) in many benign and malignant thyroid tumours. The cases included 8 papillary, 4 follicular, 4 anaplastic, and 1 Hurthle cell carcinomas, 15 follicular adenomas, 4 Hurthle cell adenomas, 8 adenomatous goiter, and 12 parenchymal goiter. Incidences of ER positive cases were 4/8 in papillary carcinoma, 2/4 follicular carcinoma, 1/1 Hurthle cell carcinoma, 0/4 anaplastic carcinoma, 2/4 Hurthle cell adenoma, and 0/15 follicular adenoma, 0/8 adenomatous goiter, 0/12 parenchymal goiter. Estrogen receptors are commonly detectable in thyroid carcinomas (papillary carcinoma). Estrogens may play an important role as as a promoting factor in thyroid carcinoma. The results of future investigation will explain the possible role of hormones in thyroid pathology and the importance of the sex hormones receptors expression analysis for therapeutic detection. PMID- 10101462 TI - [Epidemiology of esophageal cancer]. AB - Authors describe the problems related to epidemiology of esophageal cancer in Poland and all over the world such as: incidence, mortality and morbidity, patients age, race and geographic differences. The paper particularly deals with the risk factors what can be very important for the further programs of the esophageal cancer treatment. PMID- 10101463 TI - [Activation of blood coagulation in patients with pancreatic cancer]. AB - The paper presents aspects of pancreatic cancer associated thrombosis. Prospects of anticoagulation as an adjutant modality in pancreatic cancer treatment are also discussed. PMID- 10101464 TI - [Selected problems concerning harmful effects of smoking on the upper segment of the alimentary tract]. AB - In the paper, on the basis of literature and of the authors own observations, the disorders resulting from smoking within the upper segment of the alimentary tract have been discussed. Tobacco has been identified as a factor substantially interfering in the motility of the upper segment of the alimentary tract and unfavourably influencing the gastric and duodenal mucosa. It explains its facilitating role in the pathogenesis of gastroesophageal reflux disease and a slower healing of peptic ulcers and also their more frequent relapse in smokers with a chronic peptic ulcer disease. PMID- 10101465 TI - [Results of treatment of the cancer of the large intestine in elderly patients]. AB - In the surgical management of colorectal cancer was disscussed and clinico pathological features of prognostic significance were undelined. PMID- 10101466 TI - [Contemporary methods of treatment of morbid obesity]. AB - Surgical treatment of morbid obesity appears to be more cost-effective than medical treatment. Moreover many medical treatments fail in the long term especially in cases with BMI > 40 kg/m2. That's why surgical treatment was introduced. Two kinds of procedures, gastric restrictive and gastric bypass, have resulted from these years of clinical investigation. Mentioned above surgical treatment produce efficient weight loss during several months after operations. Weight reduction surgery has been reported to improve several comorbid conditions. Minimal invasive procedures are waiting for randomised studies. PMID- 10101467 TI - [Marfan's syndrome: diagnosis and treatment]. AB - The Marfan syndrome is an autosomal dominant inherited disorder of connective tissue with pleiotropic manifestation involving mainly the cardiovascular, ocular, skeletal and pulmonary systems. Aortic root dilatation and heart valve lesions are particularly common and presage a reduced life expectancy. Over the ensuring 20 years, however, treatment to prevent or correct the cardiovascular complications of the syndrome has changed dramatically--life expectancy for patients with the Marfan syndrome has increased > 25%. Reasons for this dramatic increase may include (1) an overall improvement in population life expectancy, (2) benefits arising from cardiovascular surgery, and (3) greater proportion of milder cases due to increased frequency of diagnosis. Cardiovascular surgery, both prophylactic and emergent, has become accepted treatment for aortic aneurysm, and aortic dissection. In addition, beta-adrenergic receptor antagonists have gained wide acceptance as potential agents for delaying aortic expansion and progression to rupture or dissection. In conclusion, medical therapy is also associated with an increase in probable survival. PMID- 10101468 TI - [The syndrome of inappropriate TSH secretion of neoplastic origin (NIST)]. AB - The authors present clinical features, diagnostic approach and treatment of inappropriate TSH secretion syndrome. To data above 80 cases of this syndrome have been described. The main clinical features are thyrotoxicosis and vascular goiter present in the patient with pituitary adenoma. High concentrations of free thyroid hormones coexist with elevated TSH serum level. In some cases hyperproduction of other anterior lobe pituitary hormones was found. The molar ratio alpha subunit to TSH exceeds 1.0. In the management of inappropriate TSH secretion syndrome hypophysectomy, irradiation and long-acting somatostatin analog octreotide are applied. PMID- 10101469 TI - [Polish surgery in the anti-reformation period]. PMID- 10101470 TI - [Views on the use of calcium channel blockers in the treatment of heart ischemia and hypertension]. AB - Calcium-channel blockers differ in their molecular structure, their sites and modes of action. Based on rapport's about short acting calcium-channel blockers, several recent publications have questioned the safety of agents in this class, particularly nifedypine. It has been well documented that nifedypine can cause a precipitation uncontrollable drop in arterial blood pressure, which can be dangerous in the presence of ischemic heart disease, hypertension and other hemodynamically unstable situation. The cardiovascular risk for patients prescribed short-acting calcium channel blockers was eight times than for those taking, long-acting ones. Sustained-release preparations are the preferred form of therapy, as they appear, to be safer than short-acting agents. Most calcium channel blockers, including verapamil, diltiazem, amlodypine, felodipine, nitrendipine and nicardipine have been shown to be effective in reducing symptoms of myocardial ischemia, and all have been used successfully for lowering blood pressure in hypertensive patients. Data from trials of nondihydropyridines have not demonstrated increased mortality or myocardial infarction rates in patients with myocardial ischemia and good left ventricular function. In patients with coronary artery disease and in hypertensive patients with poor left ventricular function, amlodypine or felodipine may be relatively safe alternative. Particular attention should be paid to the benefits of werapamil in postinfarct patients. In patients with hypertension, calcium-channel blockers should be reserved for use when diuretics, beta-blockers or angiotensin-converting enzyme inhibitors have been used already or contraindicated or are not tolerated and when further blood pressure reduction is necessary. PMID- 10101471 TI - [Plasma adrenomodullin concentration in patients wtih essential hypertension]. AB - Adrenomedullin (ADM) is a novel peptide secretion from vascular smooth muscle, endothelial cells and other peripheral organs. It has potent and long-lasting vasodilatatory and natriuretic properties which could participate in regulating systemic blood pressure. To examine the pathophysiological role of ADM in hypertension the plasma concentrations of ADM were measured in patients with essential hypertension, before and after effective antihypertensive therapy, and in normotensive control group. Plasma ADM concentrations were increases in patients with severe hypertension and normal in patients with mild and moderate hypertension, and were decreased after effective therapy. In all hypertensive patients plasma ADM concentrations where not correlated with blood pressure, plasma renin activity, plasma endothelin-1,2, or plasma aldosterone. These results may suggest that ADM participates in defense mechanisms acting against the high elevation blood pressure in patients with hypertension. PMID- 10101472 TI - [Mean values of blood pressure and endothelin plasma concentration in patients with chronic renal failure]. AB - The aim of the present study was evaluation of correlation between big-endothelin concentration of the precursor substance of endothelin and mean values of blood pressure in 13 patients with compensates chronic renal failure. Their age ranged from 29 years to 55 years the mean age was 42.9 +/- 8.2 years. The patients were from the Consultational Nephrologic Outpatient Clinic. These patients were sent to the clinic after a hospital observation with recognised chronic renal failure (CRF), caused by chronic glomerulonephritis (without pathomorphological differentiation). The control group consistent of 10 healthy volunteers, an age ranged from 22 years to 49 years, a mean was 32.6 +/- 10.8 years. The following mean blood pressure values were found: in patient group a systolic pressure was 139.1 +/- 17.3 mm Hg and a diastolic pressure was 88.4 +/- 12.5 mm Hg and similar values in healthy control group were respectively: 118.6 +/- 4.0 and 72.4 +/- 5.9 mm Hg. Analogously the proendothelin concentration was 18.48 +/- 22.04 fmol/ml in patients with CRF and it was 4.67 +/- 0.27 fmol/ml in the control group. A positive correlation between mean blood systolic pressure values and the proendothelin concentration (r = 0.666, Y = 0.52X + 129.5; p < 0.05) in the was found patients group. PMID- 10101473 TI - [The dipyridamole test in coronary disease diagnosis]. AB - One of the coronary disease diagnostic methods of big sensitivity and specificity is perfusive effort scintrigraphy of myocardium by means of thallium-201. For few years the dipyridamole test has been applied instead of the effort test. Perfusive scintigraphy of myocardium after provocative treatment by means of dipyridamole and then selective coronary arteriography of coronary vessels, have been carried out at 25 patients with ischemia. These studies showed almost 100% of conformability with exposing the ischemia zones in scintigraphy and coronary arteriography in cases of coronary vessels contraction over 50%. The dipyridamole test also revealed the ischemzones in myocardium that are in agreement with coronary vascularization deficiency. That test can be utilized in revealing the coronary disease and is helpful in qualifying patients for coronary arteriography. At the same time studies that have been carried out prove that applying dipyridamole is absolutely contraindicated in treating of coronary disease of the organic background. PMID- 10101474 TI - [QT dispersion in patients with acute myocardial infarction]. AB - The aim of the study was the evaluation of the QT dispersion interval in patients with acute myocardial infarction, taking into consideration its location, treatment provided and coronary artery reperfusion. Investigations were performed in 75 patients treated because of acute myocardial infarction, including 57 men and 18 women, age 40-84 years. Acute myocardial infarction was recognised on a base of generally accepted criteria. At the reception standard 12-outputs ECG was performed. Next ECG testing was performed after 3 hours from the start of the thrombolytic therapy. In case of patients which were not qualified for thrombolytic therapy next ECG was applied within 3 hours after reception. For further observation of changes in QT dispersion ECG generally provided within 2, 3, 4 and 5 day of hospitalization were used. Taking as a location criterium of infarction the method of provided treatment and obtained reperfusion in the infarcted area, patients were classified to the one of 6 groups. To the first group (I)-patients with inferior wall infarction, treated thrombolytically with obtained reperfusion-15 patients were included, age 41-69 years. To the second group (II)-patients with inferior wall infarction, treated thrombolytically without obtained reperfusion-18 persons were included, age 43-84 years. To the third group (III)-patients with inferior wall infarction, not treated thrombolytically-9 patients were included, age 49-72 years. To the fourth group (IV)-patients with anterior wall infarction, treated thrombolytically with obtained reperfusion-9 persons were included, age 40-73 years. To the fifth group (V)-patients with anterior wall infarction, treated thrombolytically without obtained reperfusion-10 persons were included, age 47-78 years. To the sixth group (VI)-patients with anterior wall infarction, not treated thrombolytically 14 patients were included, age 44-81 years. Control group for the comparison of initial evaluation of the QT and QTc dispersion interval was group of 11 healthy persons, age 27-64 years. There was proved, that in patients with acute myocardial infarction, independently of its location, QT and QTc dispersion was increased. Thrombolytic therapy in patients with acute inferior wall myocardial infarction with reperfusion obtained causes extension of QT dispersion. In patients with acute anterior wall myocardial infarction thrombolytic therapy with obtained reperfusion causes reduction of QT and QTc dispersion. In patients not treated thrombolytically, which had anterior wall myocardial infarction, in first days of observation QT and QTc dispersion was increased. This effect was not observed in patients with inferior wall infarction. PMID- 10101475 TI - [Analysis of some exercise test parameters in patients 12 months after myocardial infarction]. AB - This study comprised 102 patients (70 men--32 women) in mean age 57 +/- 7.8 year after noncomplicated myocardial infarction. Thirty five patients were after anterior infarction (group I), 36 after inferior infarction (group II) and 31 after subendocardial infarction (non Q wave) (group III). Exercise tests were performed always in morning, on ergometer Medicor. This study was continued until restriction symptoms appeared or until the limit of 85% of the pulse rate adequate to the age. Assessment of effort and load tolerance as well as ST segment depression on ECG and the kind of effort pain, was performed. The minimal tolerance of effort in patients after non Q infarction has been found. Coronary efficiency was the worst in patients after inferior and non Q myocardial infarction. PMID- 10101476 TI - [The usefulness of echocardiography in prospective heart function evaluation in children on maintenance haemodialysis]. AB - Echocardiography evaluation of heart systolic and diastolic function is applied in monitoring of cardiovascular changes in end-stage renal disease children on maintenance haemodialysis. The aim of the study was the comparison of cardiac cavities diameters and heart walls thickness changes, as well as, indices of left ventricle (LV) function in 12 end-stage renal disease children before and after haemodialysis session, before (initial examination) and after half-year duration of maintenance haemodialysis treatment (control examination). In 5 dialysed children the comparison of above-mentioned parameters was done after 3 years of maintenance haemodialysis duration. In both examinations significant increase of relative wall thickness (RWT) of LV without the features of asymmetric hypertrophy and decrease of left atrium transverse diameter after haemodialysis session was noted. There was no progression of LV hypertrophy during the six months and three years of treatment. After 3 years of maintenance haemodialysis duration significant decrease of LV mass index was revealed in examined children. There was no significant change of cardiac cavity diameters and indices of LV function during the time of observation. PMID- 10101477 TI - [The improvement of echocardiographic assessment of the left ventricle by the use of perflenapent and harmonic imaging]. AB - Contrast echocardiography and harmonic imaging (HI) are promising new modalities applied in order to obtain improved visualisation of the left ventricle. Perflenapent (EchoGen, Abbott) is a new generation echocardiographic contrast agent that crosses the pulmonary capillary bed and produces long-term ventricle opacification. Our aim was to assess the left ventricle endocardial visualisation after perflenapent infusion and HI technique. We studied a pilot group of 10 patients (mean age 52.5 +/- 7.6, mean weight 76.9 +/- 10.1 kg, one female) with previously obtained sub-optimal non-contrast echocardiograms. Perflenapent was injected intravenously at dosis 0.05 ml/kg. Echocardiography was performed before perflenapent injection and during the time between injection and LV image disappearance. Images were assessed using four-point scale, 0 standing for the poorest and 3 for excellent visualisation. Perflenapent produced full chamber opacification in all pts. Contrast effect was observed for 550-15824 sec and myocardial enhancement was seen for 176-2116 sec after i.v. administration. After perflenapent administration, endocardial border was significantly better visible than before (1.9 +/- 0.57 vs. 2.9 +/- 0.31, p < 0.001). No hemodynamic effects were noted, as assessed by oxygen saturation, blood pleasure and heart rate. A mild, transient somnolence was seen in one pt. Perflenapent improved left ventricular function diagnostic capabilities, and provided enhanced visualisation of the myocardium. PMID- 10101478 TI - [The dependence of uroflowmetry on the size of the prostate gland]. AB - The authors studied dependence of weight of tissue obtained for open adenomectomy due to BPH on uroflowmetry parameters. They have made retrospective analysis of 388 patients. In this study the patients have been qualified for four groups in dependence on weight specimens. The average values of uroflowmetry parameters vary in particular groups but the differences are not statistically significant (p > 0.5). In conclusion parameters defined by uroflowmetry are independent on prostate size. PMID- 10101479 TI - [Variability of pathogenic bacterial flora as a cause of postoperative infection]. AB - The author discussed the results of investigations concerning pathogenic bacterial flora variation causing infection in a surgery ward. Data obtained in the period 1995-1996 were analysed. Covering 118 cases of postoperative infections and 72 cases of primary infections, treated surgically. To establish drug-sensitivity of the bacteria causing infections, the infected samples were taken from all these patients. It was found that different kinds of bacteria caused the postoperative and the primary infections. It was also noted that there was different progress in drug-resistance in each group. The author thing that drug-resistance monitoring in a surgery ward can make antibiotic choice easier in the case of infections, before establishing drug-sensitivity of infection-causing bacteria. PMID- 10101480 TI - [Excitatory amino acids and perspectives of epilepsy treatment]. AB - The main excitatory neurotransmitter in the brain is glutamate, which exerts its effects through multiple ionotropic and metabotropic receptors. Pharmacological and electrophysiological data point to essential role of glutamate receptors in seizure phenomena. Agonists of these receptors depolarize neurons and induce convulsions in various animal species. In contrast, glutamate receptor antagonists suppress seizure activity and may prevent development of an experimental epileptogenesis. Unfortunately, some of these drugs may evoke severe adverse effects such as, psychosis, impairment of memory and disturbance of motor functions. It is, however, believed that better understanding of molecular biology of glutamate receptors may help to design new anticonvulsants with good efficacy and safety profiles. Some aspects of excitatory amino acid neurochemistry and their therapeutic potential are critically discussed in this paper. PMID- 10101481 TI - [Platinum-based chemotherapy in renal transplant recipients with malignancies: a case report and review of literature]. AB - Authors present a case of renal transplant recipient treated with a carboplatin based chemotherapy for testicular embryonal carcinoma. The patient experienced severe treatment-related toxicity and died due to bone marrow aplasia 3 months after the diagnosis of cancer. The safety of platinum-based chemotherapy in renal transplant recipients is discussed with reference to the literature data. PMID- 10101482 TI - [Rapid clinical course of glomerulonephritis accompanying postinfectious reactive arthritis]. AB - A case of 17 years old patient, hospitalized for evaluation of bilateral ankle arthritis and polyarticular arthralgia, that developed soon after upper respiratory tract infection, was described. In few weeks of hospitalization, rapid progress of glomerulonephritis in course of reactive arthritis, was observed. In spite of treatment with antibiotics, steroids and immunosuppressive agents, patient's state showed no improvement. After 3 months extracorporeal dialysis became necessary. Now patient is waiting for renal transplantation. PMID- 10101483 TI - [Pregnancy and delivery in a pregnant woman with polycystic kidneys complicated by hypertension]. AB - The authors described the case of 21 years old hypertonic primipara with polycystic kidneys od hereditary origin. This disease was diagnosed in our ward by means of ultrasonographic examination. The pregnancy induced severe hypertension with preeclamptic symptoms in the 20th week. The intensive procedure resulted in blood pressure normalisation. The ultrasonographic examination of the feats kidneys "in utero" and after delivery didn't show the presence of cysts. The pregnancy was ended by caesarean section in the 37th week and a son of 2700 g with Apgar score 9 was delivered. PMID- 10101484 TI - [Cytoprotection of the endothelium cells in primary hypertension]. AB - Normal endothelium cells play a huge role in small blood vessels function. It's not only physical barrier between blood and surrounding structures, but also producers a lot vasodilatators and vasodepresors. It's controlled by blood humoral factors plaing important role on blood circulation physiology. Endothelium cells injury gives its function abnormality local and general as well. The main injury factor is hypertension, which provides to endothelium disfunction with vasopressors level growth which induces hypertension. Also primary endothelial injury induces hypertension and atherogenesis. PMID- 10101485 TI - [Bilateral testicular germ cell cancer]. AB - Actual problems of diagnosis and therapy bilateral testicular germ cell cancer are presented according to contemporary bibliography. PMID- 10101486 TI - [The role of neurohormonal mechanisms in the etiopathogenesis of essential hypertension]. AB - Outcomes of recently published studies showed that cause of primary hypertension may lay in dysregulation of one of physiological mechanisms. Accordingly to current knowledge one can state that disturbance of every of these mechanisms results in cascade of changes in function of sympathetic and endocrine systems with special impact in renin-angiotensin-aldosterone system. Better understanding of mechanisms underlying the pathogenesis of primary hypertension is crucial in development of such a treatment that not only reduces blood pressure but also prevents cardiovascular complications of hypertension. PMID- 10101487 TI - [Pharmacological treatment of lipid disorders according to present clinical studies]. AB - Hyperlipidemia beside hypertension, diabetes mellitus and smoking, is considered as the most serious factor of atherosclerosis. Studies performed in Poland indicated that only 28% of men and 32% of women has proper lipids concentration in blood serum. In 1992 the European Atherosclerosis Society (EAS) divided hyperlipoproteinemia into three types: hypercholesterolemia, hypertriglyceridemia and mixed hyperlipidemia, and each of them into mild and significant. Starting treatment attention should be paid not only on kind of lipid disorders, degree of its intensity, but also there should be evaluated other existing risk factors. Priority in treatment of hyperlipidemia consist of patients with established coronary heart disease and other forms of atherosclerotic disease. Clinical studies of last years for example like CARE, 4S, LCAS indicated plenty of advantages of lipid-lowering therapy in this group of patients, resulting in reduction total mortality coronary mortality, and recurrent coronary events. Second group consist of patients without clinical atherosclerotic disease, with high risk category. Advantages of lipid-lowering therapy in primary prevention resulting in reduction of coronary heart disease frequency proved between others study: LRC-CPPT, Oslo Study, WOSCOPS. Another groups consist postmenopausal women, in whose estrogen replacement therapy has an effect not only on improvement of lipides parameters, but also has beneficial effect on vassals endothelium and reduces risk of heart coronary disease down to 50%. Finally, there was described also problem of hypercholesterolemia treatment in young and older patients. New trends in treatment of lipid disorders were also presented. PMID- 10101488 TI - [Cardiopulmonary percutaneous support. Indications and methods. Part I]. AB - The artificial hearts and cardiopulmonary bypass replace hemodynamic cardiac work. Cardiopulmonary Percutaneous Support (PCSP) and "standby support" we use in the group of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) in the Hemodynamic Laboratory. Active compression-decompression cardiopulmonary resuscitation is a new method that improves cardiopulmonary hemodynamic function in animal-models and humans after cardiac arrest. PMID- 10101489 TI - [Neurological complications in patients with chronic renal failure]. AB - On the basis of current literature and their own experiences, the authors present the most common symptoms and syndromes of dysfunction of central and peripheral nervous system which appear in patients with chronic renal insufficiency. Current views on patomechanism of neural dysfunction due to renal failure in dialysed and non-dialysed patients are discussed. PMID- 10101490 TI - [Selenium and some antioxidants in blood of patients with chronic renal failure]. AB - Patients with chronic renal failure often have a reduced level of blood selenium. Decreased glutathione level, and the activity of glutathione peroxidase and superoxide dismutase are also lowered. As the effect of these alterations the concentration of malondialdehyde, a marker of the oxidative degradation of polyunsaturated fatty acids, is increased. In patients undergoing regular haemodialysis some of the above mentioned parameters are restored. In dialyzed patients with extremely low concentration of selenium, the administration of this element is recommended. PMID- 10101491 TI - [Advances in the treatment of algodystrophy]. AB - Current concepts about pathology, diagnosis and treatment of algodystrophy syndromes have been presenting. PMID- 10101492 TI - [Mammography or ultrasound in the breast cancer diagnosis]. AB - Indications to ultrasound examination and mammography are discussed in this article. Ultrasound is useful in women younger than 35 and mammography on the contrary after this age. As far as screening is concerned obly mammography is a proper tool for recognition. PMID- 10101493 TI - [On some controversies concerning "prions"]. PMID- 10101494 TI - [Education as a key successful continuous ambulatory peroneal dialysis program]. PMID- 10101495 TI - [Screening for renovascular hypertension in own material (1986-1998)]. AB - In 370 patients (pts) with hypertension(HT) in years 1986-1998 (168F + 202M, mean age 46 yrs) screening value of the following tests was evaluated: standard initial angioscintigraphy DTPA 99mTc(SA) in all pts(1-st screening group), significance of clinical suspicion on renovascular hypertension (RVHT) in the group of 74 pts (II-nd screening group). Captopril tests: renin captopril test(RCT) and isotopic captopril test (ICT) were performed in all 370 pts. Classical renal angiography as a reference test for renal artery stenosis (RAS) was performed in all pts suspected for RVHT on the basis of clinical anamnesis and or positive results of captopril tests. Results were as follows. Initial SA being abnormal in the whole group, appeared to be more significant for RAS only in the case of profound one side renal ischemia (GFR lower than 30% of total GFR). Resistance to three antihypertensive drugs, diastolic blood pressure > 120 mmHg and sudden onset of Ht, found in all 74 pts from the II-nd group, were the most significant clinical symptoms of RVHT, because critical RAS was found in 41, that is 55% of pts from the II-nd group. At least one positive CT was found in 37 from 42 pts with critical RAS in angiography with RTC being more sensitive and ICT more specific for hemodynamically significant RAS. The following screening protocol for RVHT was presented and discussed: precise clinical anamnesis followed by angiography or captopril tests according to the severity of clinical symptoms, aim of the study as well as accessibility and laboratory reproducibility of the captopril tests. PMID- 10101496 TI - [Significance of clinical anamnesis in the preliminary diagnosis of renovascular hypertension]. AB - Differences in the occurrence of renovascular hypertension (RVH) in the population of patients with arterial hypertension related to different preselection criteria induced us to analyse practical usefulness of clinical anamnesis for RVH. In 130 patients with arterial hypertension (72 women, 58 men, average age 48 years) and clinical suspicion on RVH, the initial renal angioscintigraphy (with 99m Tc-DTPA) was abnormal, demonstrating impairment of glomerular filtration rate. In the whole group captopril angioscintigraphy test (CAT) as well as captopril renin test (CRT) were simultaneously performed according to own protocol. In 24 cases highly suspected for RVH on the ground of clinical anamnesis the critical stenosis of renal artery (> 75% of the lumen) was found in the arteriography. The most significant signs of RVH in clinical anamnesis were the following: the diastolic blood pressure > 120 mm Hg (92% cases), resistance to 3 hypertensive drugs (92%), sudden onset and rapidly progressive course of hypertension (88%) and advanced hypertension retinopathy (79%). On the ground of these results, detailed clinical anamnesis is recommended as a cheap and easy preselection test for RVH in the hypertensive population. PMID- 10101497 TI - [Assessment of active renin instead of plasma renin activity in the renin captopril test]. AB - In the study usefulness of active renin (AR) measurement instead of plasma renin activity (PRA) in the diagnosis of reno-vascular hypertension(RVH) was evaluated. 42 patients with arterial hypertension (17F, 25M; mean age 45 + 12 years) and suspicion on RVH on the ground of the abnormal result of the preliminary renal angioscintigraphy were qualified to the study. Angioscintigraphic (SCT) and simultaneously renin captopril test (RCT) followed by renal arteriography or Doppler ultrasonography of renal arteries were performed in every case Haemodynamic significant stenosis of renal artery was revealed in 5 cases. The results of the examination in this group were as follows: in 3 patients positive RCT with PRA, in 4 patients positive RCT with R and in 2 patients positive SCT were found. The false positive results of RCT using PRA were obtained in 5 patients and only in 2 patients if using AR. There were no false positive results of SCT. The introduction of AR instead of PRA in RCT resulted in simplification and shortening of the diagnostic procedure. Furthermore, this modification increased detection of hemodynamically significant stenosis of renal artery from 2 cases revealed with SCT and 3 cases with PRAin RCT to 4 cases with AR. The successful preliminary results let us to introduce this modification of RCT to routine out-patients screening for RVH. PMID- 10101498 TI - [Continuous ambulatory peritoneal dialysis as a renal replacement therapy in blind diabetics with type 1 diabetes]. AB - Controversy around the place of CAPD in renal replacement therapy of blind Diabetics (BD) with type 1 Diabetes induced us to start CADP programme also in this group of patients. In yrs 95-98 we treated with CAPD 5 BD send to our Centre in IV/V phase of diabetic nephropathy (acc. to Mogensen). Duration of D up to 20 yrs, complete blindness in the last 2-10 yrs. Criteria of qualification for CAPD: standard medical +motivation of patient and family helper for self dialysis, unaided everyday life as well as blindness not before maturity. CAPD equipment: twin bag system with special modifications for BD. Own training programme of 2 weeks for patient/family helper modified for BD (without visual aids). We achieved full clinical and biochemical compensation of uremia; KT/Vurea > 1.9, weekly creatinine clearance > 60 1/1.73 sqm, UF > 400 ml. Peritonitis occurred in 2 of 5 patients with ratio 1:28 ptsmnths. IN CONCLUSION: for BD with type 1 Diabetes, leading unaided everyday life, the blindness doesn't seem to be limitation for CAPD, if patients are motivated for self dialysis and the training programme has been specially modified for them. PMID- 10101499 TI - [Evaluation of peritoneal solute transport parameters in diabetics treated with continuous ambulatory peritoneal dialysis]. AB - Increasing number of diabetics (D) on CAPD induced us to perform detailed kinetic evaluation of these patients. The purpose of the study was to characterize peritoneal solute transport parameters in diabetics and non-diabetics (ND) treated with CAPD and furthermore to assess clinical implications of eventual differences, especially with regard to programming the long-term CAPD in D. Twelve patients (7D and 5ND) on CAPD for 3-55 months were qualified to the investigation. They were clinically stable, with no impairment of ultrafiltration and free of peritonitis for at least 3 months. Four hours dwell studies with 2.0L of 3.86% glucose dialysis fluid were performed and mass transport coefficients (KBD) for glucose, potassium, sodium, total protein, urea and creatinine were calculated. No statistical differences for KBD between D and ND were found. However for every solute the average KBD values were higher in D that in ND. The observed differences do not justify any different treatment modality for D on peritoneal dialysis (PD). However high SD values, resulting from differences of peritoneal solute transport between patients, indicate the necessity of individualization of PD program. PMID- 10101500 TI - [Values of phase-contrast microscopy in the etiological diagnosis of hematuria in adults. Part I. Establishing individual norms for glomerular hematuria]. AB - In the cohort of 123 patients (average age 44 years) criteria for glomerular and nonglomerular hematuria (H) were established by phase-contrast microscopy (PCM). According to literature, hematuria was divided into glomerular, mixed or nonglomerular if: > 60%, 20-60% and < 20% dysmorphic erythrocytes (E) of fresh morning urine sediment were found. Diagnosis of glomerulonephritis was confirmed by renal biopsy in 54/57 glomerular H as well as in all 8 cases of mixed H. On the contrary, urological reasons for H were found in 55/58 cases of nonglomerular H with normal renal biopsy in the remaining 3 patients. Using value > 20% of dysmorphic E as a new norm for glomerular H, we found sensitivity and specificity of this test as 100% and 95% respectively. IN CONCLUSION: glomerular H should be suspected and renal biopsy recommended when > 20% dysmorphic E are found by PCM what means exclusion of the term "mixed H". PMID- 10101501 TI - [Value of phase-contrast microscopy in the etiological diagnosis of hematuria in adults. Part II: Analysis of factors modifying morphology of erythrocytes in urine sediment]. AB - In 41 patients with glomerular hematuria diagnosed by renal biopsy no correlation between intensity of tubulo-interstitial changes and range of dysmorphic erythrocytes (E) in phase-contrast microscopy (PCM) was found. However, such correlation existed in the case when acanthocytes in PCM were detected. From factors of potential influence on the morphology of E such as value of proteinuria, glomerular filtration rate, crystalluria, osmolarity and pH of urine, none had any significant role in changing the morphology of E of glomerular as well as of non-glomerular origin. PMID- 10101503 TI - [Influence of alphacalcidole on selected markers of the bone turnover in hemodialysed patients with secondary hyperparathyroidism]. AB - In 19 chronically hemodialysed patients (11M + 8F, mean age 52 +/- 15 yrs) with secondary hyperparathyroidism (sHP), selected markers of bone turnover in the course of pulsative treatment with alphacalcidol were evaluated. Alphakalcidol was given 3 times per week after hemodialysis. Every 3-rd month of therapy we measured serum concentration of procollagen type I carboxy-terminal propeptide PICP as a marker of bone formation as well as carboxy-terminal telopeptide type I collagen ICTP and iPTH as markers of bone resorption. The results were as follows. During 12 months of controlled treatment of sHP with alphacalcidol, statistically significant decrease of serum iPTH (from 393 +/- 145 pg/ml to 246 +/- 172 pg/ml) with simultaneous increase of serum PICP (from 235 +/- 168 mg/L to 414 +/- 168 mg/L) were obtained. Serum ICTP levels, although significantly increased in comparison to normal values, did not change under influence of alphacalcidol therapy. The mean weakly dosis of alphacalcidol of 2.27-2.39 mg successfully suppressed process of bone resorption evaluated by iPTH giving predominance to bone formation expressed by PICP. Serum levels of ICTP appeared to be of no value in monitoring treatment efficacy of alphacalcidol in hemodialysed patients with secondary hyperparathyroidism. PMID- 10101502 TI - [The value of urine sediment cytomorphology in the ambulatory differential diagnosis of hematuria]. AB - In order to improve early diagnosis of urotheliale neoplasms (UN) in nephrology outpatient clinic, 274 patients (221 male and 53 female, mean age 54 yrs), with recurrent hematuria (> 5 E/hpf) were investigated in years 1994-1998. The following examinations of fresh urine sediment were performed: in 114pts (group 1) erythrocytes of urine sediment examined with phase-contrast microscopy (PCM); in 129pts (group II) urine sediment examined with classical oncological cytology; in the III-rd group of 31pts (29M and 2F, aged 61-72), both methods were used because of high suspicion on UN on the ground of initial result of PCM, precisely clinical anamnesis as well as predominance of men in advanced age. Results were as follows. In the I-st group, in 6 from 42pts with urological hematuria in PCM, what means 5.2% of the whole group and 14% of the subgroup with urological hematuria, in further standard urological examination bladder carcinoma was found. In the II-nd group, positive result of urinary cytology (GI to GIII) was found in 7pts, what means 5.4% of the whole group. Results of urine cytology were confirmed later in the standard urological examination, which detected bladder carcinoma in all these patients. In the III-rd group, bladder carcinoma was found in all 22pts with urological hematuria in PCM. In 19 patients from this subgroup, urinary cytology was positive for UN (GI to GIII). In the remaining 3pts results of urinary cytology were false negative. False positive result of urinary cytology occurred in one from 9pts with glomerular hematuria and clinical or morphological (in renal biopsy) evidence of glomerulonephritis. On the results of the study, we propose--as an obligatory--in every case of recurrent hematuria of urological origin in PCM, examination of fresh urinary sediment with classical oncological cytology, especially if the patient belongs to the high risk group for urotheliale neoplasms. PMID- 10101504 TI - [Successful aorto-coronary bypass in the care of unstable heart ischemia in the course of irreversible renal failure treated by repeated hemodialyses]. AB - Cardiovascular diseases especially coronary heart diseases are responsible for high rate (about 50%) of deaths in the group of patients with irreversible renal failure treated with hemodialysis. Coronary artery bypass grafting is recommended as a method of choice in symptomatic patients with coronary heart disease being the candidate for renal transplantation. On the basis of recently observed patient successfully treated with coronary artery bypass grafting pre- and and postoperative dialysis protocol is presented and discussed with literature. PMID- 10101505 TI - [Acute intermittent porphyria: actual problems of clinical and laboratory diagnosis]. AB - On the case of 27 old woman with clinical symptoms of acute abdomen, severe electrolyte disturbances and attacks of grand mal seizures, different clinical masks and actual treatment guidelines of acute intermittent porphyria are presented. Among laboratory methods detecting precursors of hem in the urine, high-performance liquid chromatography (HPLC) as the most sensitive and specific method is recommended. Proper prophylaxis against new episodes of acute intermittent porphyria as well as long lasting ambulatory care of the patient are emphasized. Special attention should be paid to all close relatives of the patient, who need to be send to specialistic laboratories for exclusion of enzymatic defects of hem synthesis. PMID- 10101506 TI - [Retroperitoneal fibrosis with antiphospholipid syndrome: a coincidence or common autoimmunological etiology?]. AB - The term "retroperitoneal fibrosis" means pathophysiologically differentiated entities which are leading to development of pathological masses of connective tissue in retroperitoneal space. The etiology of the disease has not been clearly established up to now. Recently advanced hypothesis suggests that existence of the pathological masses of connective tissue in retroperitoneal space is a consequence of autoimmunological response to insoluble, oxidized lipoprotein of atheromatous plaque called ceroid, penetrating into periaortal space through atheromatic wall of aorta. On the basis of recently observed case of 43-years old woman with retroperitoneal fibrosis and antiphospholipid syndrome the possibility of common autoimmunological etiology of both entities is discussed. PMID- 10101507 TI - [Sulodexide in the treatment of right hand necrosis in diabetic patient performing exchanges of continuous ambulatory peritoneal dialysis (CAPD) by himself]. AB - The usefulness of sulodexide in the treatment of severe necrosis of right hand in 42 diabetic patient performing by himself CAPD exchanges is described. Very good results of this treatment, induced us to discuss clinical indications for this drug, which--according to our opinion--is particularly recommended for treatment of severe vascular complications in patients with diabetes and irreversible renal failure. PMID- 10101508 TI - [Therapeutic plasma exchanges with cyclophosphamide in the treatment of rapidly progressing glomerulonephritis]. AB - On the basis of two cases of rapidly progressive glomerulonephritis with over 50% crescents in percutaneous renal biopsy, anti-GBM antibodies in one case and progressive renal failure in both cases, successful treatment with plasma exchanges and aggressive immunosuppression according to our own protocol is presented and discussed with literature. PMID- 10101509 TI - [Alternative dialysis solutions in continuous ambulatory peritoneal dialysis]. AB - Not satisfactory enough long-term results of applying glucose in CAPD solutions as an osmotic agent were the reason of research on the alternative osmotic substances. The paper presents review of actually used solutions containing amino acids (Nutrineal) or polymer glucose (Icodextrin). The influence of these agents on metabolism of carbohydrate, lipids and nutrition of the organism as well as function and structure of peritoneum is reviewed and discussed. PMID- 10101510 TI - [Late ventricular potential as a risk factor for sudden cardiac death in chronically hemodialysed patients]. AB - Severe heart arrhythmias are common in patients with irreversible renal failure on chronic hemodialysis. Late ventricular potentials revealed on the signal averaged electrocardiogram were found to have predictive value of sudden cardiac death in general population of patients with coronary artery disease or nonischemic cardiomyopathy. The value of this method in hemodialysis patients is presented and discussed. PMID- 10101511 TI - [Advances of clinical diagnosis of osteodystrophy complicated by chronic renal failure]. AB - Renal osteodystrophy complicated chronic renal failure presents many clinical problems because of multiple pathogenetic factors, non specific clinical symptoms as well as not precisely enough methods evaluating progress and treatment efficacy of this complications. The paper is a review of such approved markers of bone turnover as intact PTH, bone specific alkaline phosphatase, calcium and phosphorus, bone biopsy and DEXA, as well as new bone turnover markers. Special references are referred to procollagen type I carboxyterminal (PICP) and aminoterminal (PINP), osteocalcin as new markers of bone formation process and to tartare resistant acid phosphatase pyridynoline, deoxypyridynoline and carboxyterminal telopeptide type I collagen (ICTP) as new markers of bone resorption process. PMID- 10101512 TI - [The use of leukotriene receptor antagonists and 5-lipoxygenase inhibitors in bronchial asthma treatment]. AB - Asthma is a chronic inflammatory disorder of airways. It is characterised by bronchoconstriction, oedema and airways mucus hypersecretion. The main clinical features of asthma are dyspnea, cough, wheezing and heaviness in the chest. The pathology of asthma is characterised by presence of many inflammatory mediators, where the most important are cysteinyl leukotriens. Leukotriens C4, D4 and E4 are 1000 times more potent than histamine in contracting airways smooth muscles. Inhibitors of arachidonic acid metabolism have been used in asthma treatment. They can block the 5-lipoxygenase enzyme and/or 5-lipoxygenase-activating proteine (FLAP), or can block the cysteinyl leukotriene receptors on the cell surface. Many inhibitors of arachidonic acid metabolism have been found during experimental trials. But only two are used as a drugs: zafirlukast and montelukast (leukotriene receptor inhibitors) montelukast and zileuton (5 lipoxygenase inhibitors) having the best efficacy in asthma treatment. Chronic treatment with these drugs results in a decrease of asthmatic symptoms, improvement of lung function (FEV1, PEF) and decreased usage of other medications -beta-adrenergic agonists and inhaled steroids. It has been proved that zafirlukast and zileuton show the high efficacy in mild-to-moderate asthma, exercise-induced asthma, allergen-induced asthma and aspirin-induced asthma. These oral drugs have been shown to course only mild adverse effects (such as temporary elevation in liver function tests, gastrointestinel disturbances, headache). Clinical usage of zafirlukast, montelukast and zileuton is limited in our country, they are hardly approachable on the market and the cost of treatment is high. PMID- 10101513 TI - [Analysis of circumstances of the development of chronic bronchitis in patients treated at Bydgoszcz Lung Disease Clinic in 1993-1996]. AB - The fact, that more than 10% people suffer from COPD /chronic obstructive pulmonary disease/, that number of COPD patients increases rapidly all over the world, and at the moment COPD is one from four the most frequent cause of death, makes us to search for effective methods of prevention and treatment. The number and variety of factors cooperating in pathogenesis and development of the disease in contrast to poor knowledge of them was the reason, that the retrospective analysis of some factors of 300 COPD patients, treated in our Clinic from severe exacerbations was carried out. There were analysed the following factors; age, gender, body mass index, profession, the length and duration of the disease, incidence of exacerbations and habits; alcohol drinking and cigarette smoking. The aim of these searches was to establish the factors which most commonly cooperate in initiation and development of COPD in the province of Bydgoszcz. There was established, that chronic bronchitis was more frequent in men. That deference is caused not only by exposure to occupational irritant factors. COPD was also more frequent in smokers /about 70%/, elders, blue collar workers, especially exposed to irritants and/or toxic effects by virtue of their work, persons living in industrialized Bydgoszcz. There were no correlation between COPD incidence and malnutrition or alcohol consumption, but the simple correlation between time of the disease and severity of airway obstruction was seen. The longer time of chronic bronchitis, the more increased airway obstructions, and more frequent respiratory insufficiency. In the course of the disease was growing; the number of malnutritioned patients and the number of exacerbations of chronic bronchitis. The longer time of disease, the shorter free of symptoms intervals. In alcohol consuming patients the exacerbations occurred significantly more frequent and more severe. There was correlation between alcohol and cigarette consumption. The exacerbations of chronic bronchitis in November, December and March were the most frequently seen. In observed group of chronic bronchitis patients the importance of risk factors unconnected with smoking was significantly great, that suggest the growing role of other factors in pathogenesis and development of COPD. PMID- 10101514 TI - [Difficulties in diagnosis of specific pneumonia: clinical and pathomorphological confrontation]. AB - Caseous pneumonia is one of acute kinds of tuberculosis. Difficulties in diagnosing of caseous pneumonia were described in this paper. Material contained 40 patients /28 men and 12 women/ mean age 53 +/- 16 years/ which died in The Hospital of Lung Diseases in Lodz. In this patients diagnosed caseous pneumonia. Analyse obtained many clinical parameters /age, sex, hospitalisation, period, investigation and medical, examination, results of bacteriological and radiological finding and autopsy diagnoses. Authors thought that the need of bacteriological examination and X-Ray examination in diagnosis of caseous pneumonia. Confrontation of clinical and pathomorphological diagnosis are very important. PMID- 10101515 TI - [Clinical analysis of pneumonia treated at the hospital]. AB - 104 cases of pneumonia, treated in Department of Pulmonary Diseases of Military Medical Academy in the years 1995-1997, were analysed. Patients were divided into two groups. In the first group were 58 patients which had acute symptoms of pneumonia and the treatment was started in our department without any treatment before. In the second group were 45 patients which had acute symptoms two or three weeks before admission to hospital. In this period these patients received one or more antibiotics. The bacteriological findings and the periods of the treatment were analysed in these both groups. PMID- 10101516 TI - [Peak expiratory flow (PEF) rates evaluation in 3-year-old children]. AB - In our study we examined 219 healthy 3-years old children. The children were exercised how to make a forced expiratory flow for about 7-10 days before the tests started. Subjects that had Chest Flexibility Index Rate equal 7.0 or higher were selected for further analysis. 174 (79.4%) children--131 from industrial region and 43 from control group--made PEF tests correctly. Use of three different peak flow meters ("Vitalograph"--Low Range model, mini-Wright--Low Range model, Personal-Best) made the results more reliable and determinant. Based on our results we concluded that the peak expiratory flow values obtained in 3 years old children can be used as reference values for assessment of PEF in healthy and ill children, the residents of an industrial region. PMID- 10101517 TI - [The way of nutrition and frequency of otitis media in hospitalized infants and 3 year-old children]. AB - It was made a comparison frequency of diagnosis of otitis media in hospitalized in the I Clinic of Children Diseases of Medical University of Lodz in 1975 and in 1995 infants and children under 2 depending on way of nutrition. It was shown and evident decreasing of frequency of otitis media from 22.6% in 1975 to 4.2% hospitalized in 1995. It was caused mainly by the change of a way of nutrition from artificial to natural and easy accessibility diets. It shows an allergic process as a probable source of otitis media in children. PMID- 10101518 TI - [Hyperplasia of pharyngeal lymphoid tissue in children]. AB - 40 children, aged 4-12, hospitalised in the III State Hospital of Children's Diseases and suffering from recurrent complaints of respiratory system with accompanying breathing disorders were subjected to clinical examination. In the analysed group 55% of children suffered from recurrent upper respiratory tract inflammations, 12.5% from recurrent otitis, 12.5%--increased neck nodules, 12.5% from hearing disorders, and 42.5% of children breathed by mouth. On the basis of allergic and immunological examinations, in 90.5% allergy was confirmed as the main cause of the complaints. In 7.5% of cases, above complaints were conditioned by accompanying infection. Increased total IgE level in serum was confirmed only in 37.5%. 17.5% of children showed peripheral blood eosinophilia. Some children were qualified for adenotomy and removed adenoid was examined histopatologically. Significant features of acute, subacute, and chronic inflammatory process leading to hypertrophy of the organ and causing obstruction in breathing were observed on the examination. Periodical dietetic treatment (the influence of nutritional allergy) and pharmacological treatment were recommended. PMID- 10101519 TI - [Food allergy in children with pollinosis in the Western sea coast region]. AB - Type and frequency of allergy to food was analysed in groups of children sensitized to grass pollens (170 children), birch pollen (142 children) and cereal pollens (158 children) in comparison with children being not sensitised to pollens (432 children). It has been disclosed that the most frequent food allergens in the whole studied group as well as among the children not sensitized to pollens are: milk, eggs, beef, chocolate, nuts and cereals (positive skin prick tests and allergy manifestations after food consumption). In 10-20% of children sensitised to grass pollens, it was revealed that the prick tests for carrot, celery, apple, tomato and nuts were positive. Manifestations after their consumption are evidenced by 30-70% of the studied subjects. In 20-40% of children sensitised to birch pollen there were positive skin prick tests for celery, carrot, potato, tomato, apple, peaches and grapes. The manifestations after their consumption appear in 20% of children. Eighty-five per cent of children sensitised to cereals pollens display positive skin prick tests for cereal grains. Half of them have signs of food allergy, most frequently after ingesting wheat and rye. PMID- 10101520 TI - [Analysis of food allergy incidence in children up to 5 years of age in the Wielikopolska region]. AB - The aim of this study was found the most frequent food allergens and analysis of food allergy incidence in children with food allergy from region Wielkopolska. 78 children in age from 2 months to 5 years of life with the first symptoms of food allergy: gastrointestinals symptoms and atopic dermatitis was examined. The specific IgE using the immunoenzymatic Quidel and AlaSTAT method to wheat, peanut, hazel nut, tomato, soya been, cow milk, egg, corn, orange and cod was percentage of the lymphocytes ThCD4+ in peripheral blood of allergy children was estimated. The normal results ranging from 29-42%. During the analysis established that in children from region Wielkopolska the most frequent allergen in each age was cow milk. Allergy to wheat found in 50% children with food allergy. It was observed increase allergy to new products as soya been, corn and nuts which are the more frequent used in our region. The causes apparent the food allergy among the children in age to 5 years are: so early given the cow's milk and other foreign protein to diet of infants, and infections the intestinal, airways and urine tracts. It is necessary breast-feeding the infants minimum up to 6 months of life and varying light diet without a big amounts of cow's milk or other foreign proteins during lactation and pregnancy. About a half of patients had a decreased number of lymphocytes T CD4+. Among the causes of food allergy the most important are in 40% the genetic factors but in 60% the infections factors and feedings defects. PMID- 10101521 TI - [Susceptibility of Pseudomonas aeruginosa isolated from hospital infections to antibiotics]. AB - A total of 674 clinical isolates of Pseudomonas aeruginosa were collected from 30 different hospitals located in 26 cities of Poland. These were 12 big regional hospitals, 7 large teaching hospitals, 4 specialised hospitals curing patients from the whole country, 6 small local hospitals and one regional paediatric hospital. The majority of strains were collected from patients hospitalised at ICUs (25.7%), surgical (21.7%), and internal medicine wards (9.9%). The isolates were recovered from different types of infections, mostly from respiratory tract infections (33.7%), wound infections (22.3%), and urinary tract infections (22.0%). All the isolates were subjected to antimicrobial susceptibility testing by MIC values evaluation. MICs of 13 different antibiotics (beta-lactams, aminoglycosides, chinolones) were determined by the agar dilution method. The general level of resistance of P.aeruginosa observed in the study was high, especially when compared to results of surveys obtained in other countries. Out of the antimicrobials used the highest activity in vitro was observed with meropenem, imipenem, piperacillin--tazobactam and ceftazidime. The high in vitro activity of ceftazidime was striking considering the long time of the use of this antibiotic in Polish hospitals. The highest levels of resistance were observed to some of the aminoglycosides. Populations of strains isolated in different wards or hospitals of different size were characterised by different susceptibility patterns. PMID- 10101522 TI - [Respiratory and skin diseases among school children in the industrial and rural regions]. AB - The studies were done among the school-children in 3 grammar schools (2 in the industrial and 1 in rural regions). Allergological examination (anamnesis, physical exam and skin prick tests with inhalants) were performed among the pupils suspected of the allergic disorders on the basis of the questionnaire analysis made in all school-children. The results were compared to the environmental air pollution in the school region. The frequency (4.9-7%) and the type of the allergic diseases were similar in all 3 schools. The most frequent allergens were pollen, mites and animal epithelia. In rural region familial predisposition to allergy was 2 times higher in pupils suffering from allergy. 70% of pupils suffering from allergy in the industrial regions had no familial predisposition to allergy. PMID- 10101524 TI - [Cromones in the therapy of food-induced allergic rhinitis, pharyngitis and laryngitis]. AB - Food allergy and rhinitis, pharyngitis and laryngitis are discussed in relation to actual bibliography. The role and place of cromones in therapy of this food induced allergic inflammations are presented. PMID- 10101523 TI - [Subclasses of IgG (IgG1-IgG4) in children during specific immunotherapy]. AB - The aim of this study was determination of IgG subclasses: IgG1, IgG2, IgG3 and IgG4 in children with atopic bronchial asthma and allergy rhinitis during long term specific immunotherapy. The results showed in crease of IgG1 at first and next IgG4 subclasses. In our opinion it's a positive reaction of specific immunotherapy. Decrease of IgG2 and in less degree of IgG3 must be very carefully observation and analyse general in children with recurrent infections in the respiratory tract during specific immunotherapy. PMID- 10101525 TI - [The effect of new H1-receptor antagonists on cardiovascular system]. AB - The authors present effects of new H1-receptor antagonists--terfenadine and astemizol on cardiovascular system in humans. The role of interactions between terfenadine and astemizol and other drugs is underlined. Effects of hepatic and heart diseases as well as astemizol and terfenadine overdose on their pharmacokinetics are also showed. PMID- 10101526 TI - [Clinical assessment of azelastine nasal spray in seasonal allergic rhinitis]. AB - The authors have studied the effect of azelastine nasal spray in the treatment of seasonal allergic rhinitis. The trial was a double-blind, placebo controlled study, with 33 allergic subjects (17 female, 16 male), 15-40 years old. The patients were randomized into two parallel groups, to receive daily 0.56 mg of azelastine intranasally or placebo during two weeks. Before and after treatment severity of nasal symptoms such as: sneezing, itching, nasal blockage, nasal discharge and general feeling were evaluated by patients according to VAS (visual analogue scale). At the same time the physician's evaluation of nasal oedema, nasal discharge and general patient's condition were performed (VAS). Additionally during the treatment patients noted possible adverse events. Patient's and physician's evaluations showed clinical efficacy in the azelastine group and no evident efficacy in the placebo group--between those two groups statistical significances were noted for all evaluated parameters (p < 0.001). The bitter taste in the mouth was the only serious side effect in some patients in azelastine group, although this was quite well accepted. Generally the treatment was well-tolerated. Azelastine nasal spray is an effective and well tolerated drug in the treatment of seasonal allergic rhinitis. PMID- 10101527 TI - [Efficacy and tolerance of fenspiride in adult patients with acute respiratory tract infections]. AB - Fenspiride is an antiinflammatory drug targeted for the respiratory tract. In our study clinical efficacy and tolerance of drug were evaluated in 392 adult patients with acute respiratory tract infections. According to clinical criteria all observed symptoms were classified as mild, moderate and severe. The most of observed patients were included into moderate symptom score. Cough and nose obturation were dominant symptoms. All noticed changes in the upper respiratory tract were decreased after fenspiride therapy in 7 days trial. In 168 observed patients systemic and in 60 local acting antibiotics were successfully applied. Excellent tolerance of fenspiride was documented in 59% and good tolerance --in 34% of patients. Observed adverse reactions were classified as mild and in 20 patients fenspiride was rejected. Authors suggest that fenspiride therapy is save and successful in patient with acute respiratory tract infection. Good results in patients with bronchitis in decreasing of bronchospasm indicate fenspiride as a good tool in bronchial infection. PMID- 10101528 TI - [Our experience in bronchiolitis obliterans organising pneumonia (BOOP): personal experience]. AB - BOOP is a disease with characteristic histology features which can occur as a secondary lung reaction to the various toxic agents or as a primary idiopathic disease. Idiopathic form of BOOP is a rare disease and may be found in 6-7 patients of 100,000 hospital admissions. We described 3 patients with idiopathic BOOP confirmed by the histologic lung examination. The time from the beginning of symptoms till the microscopical diagnosis ranged from 6 to 12 months. At the beginning of the disease the patients had symptoms compatible with the respiratory infection. In one of the patients the clinical course of the disease had a progressive character. In two patients spontaneous regression of radiological lung lesions was observed. This regression was however only temporary in one of them. In two cases treated by steroids regression of lung lesions was noticed. PMID- 10101529 TI - [Histiocytosis of Langerhans cells in the lung: case report]. AB - A case of a 21-year-old smoker has been described, clinically asymptomatic, in whom radiological examination revealed numerous diffused lesion in the lungs. On the basis of histological examination revealed numerous diffused lesions in the lungs. On the basis of histological examination of the lung biopsy specimen collected by means of videothoracoscopy, histiocytosis of pulmonary Langerhans cells has been diagnosed. The instituted treatment with prednisone and abstinence from nicotine lead to the remission of pulmonary lesions. Videothoracoscopy proved to be an effective method of collection of biopsy specimens from the lungs in diagnosis of diffused pulmonary lesions. PMID- 10101530 TI - [IgE mediated food allergy: pathomechanism, clinical picture and perspectives of new therapy]. AB - Diagnosis, pathomechanism and therapy of IgE mediated food allergy are discussed in aspects of new the rapentic problems. Stanworth's is noticed as a new tool for control of allergic IgE mediated reactions. PMID- 10101531 TI - [Allergy to cow's milk]. AB - Food allergy is presented with special focus on cow's milk induced reactions. Actual clinical diagnostic and therapeutical problems are discussed. PMID- 10101532 TI - [Maternal elimination diet during pregnancy and lactation, and the development of allergies in infants]. AB - The preventive value of the matemal dietary elimination during late pregnancy and lactation on the development of atopic disease in infancy was review. Despite continuing controversy it was documented that the maternal food-allergen avoidance mainly during lactation period protects against the development of allergic disease. PMID- 10101533 TI - Further prove on oxidative stress in alloxan diabetic rat tissues. AB - After intravenous administration of alloxan monohydrate (AL) diabetes developed in rats. Forty-eight hours after the injection the animals were sacrificed, their blood was collected in heparin containing tubes and the tissues were dissected and frozen (-70 degrees C) until their homogenization for pro- and antioxidant testing. Our results can be summarised as follows: (i) In the blood hemolysate the lipid peroxidation slightly elevated and the activity of antioxidant enzymes and reduced glutathione decreased. (ii) Similar phenomena could be observed in the different examined organ homogenates. The organs tested for pro- and antioxidant system were as follows: the liver, heart, skeletal muscle, kidney and pancreas. In our present work we attempt to confirm the data in support of the oxidative predominance over antioxidants in oxidative stress of AL diabetic rats. PMID- 10101534 TI - Isometric handgrip exercise-induced muscarinic vasodilation in the human skin microvasculature. AB - The existence of an active vasodilator system in the human skin microvasculature is well documented, but its physiological role and the underlying mechanisms are not completely understood. Cutaneous blood flow increases during isometric handgrip exercise. To examine whether this response is mediated by active vasodilation, isometric handgrip exercise testing was performed in nine healthy subjects. Local iontophoresis of atropine was applied to the forearm skin. Skin blood flow (SBF) monitoring by means of laser Doppler flowmetry was combined with continuous noninvasive blood pressure monitoring. SBF monitoring was performed at a site pretreated with atropine and an adjacent control area. Mean arterial pressure (MAP) was recorded noninvasively. Cutaneous vascular resistance (CVR) was calculated as MAP/SBF for the atropine treated and the control areas. Changes in CVR were expressed as percent deviation from the baseline (dCVR). Isometric handgrip exercise resulted in a marked reduction in CVR at the control site (dCVR: -66 +/- 4%). In contrast, the CVR was not significantly altered at the atropinetreated site (2.4 +/- 7%). It is concluded that isometric exercise induces an atropine-sensitive vasodilation which is mediated by muscarinic receptors in the human skin. PMID- 10101535 TI - Familial adult onset X-linked hypophosphataemic osteomalacia (report of a family; clinical and experimental studies). AB - From four patients (a great-grandmother, grandmother, her daughter and her grandson) suffering from a very severe form of familial X-linked hypophosphataemic osteomalacia (XLH), belonging to a 23-number-kindred of five generations, the youngest patient a 24-year-old man with an adult onset XLH was treated with phosphate and calcitriol for two years. Phosphate was given in increasing doses (500-6000 mg elemental phosphate) by mouth for a relatively short-term period and calcitriol in high doses per os combined with intermittent intravenous administration. Long-term treatment consisted of daily three grams of phosphate and 1.25 micrograms calcitriol by mouth combined with daily 2 micrograms calcitriol intravenously for one week every month. Dramatic clinical improvement occurred accompanied with definite radiological and scintigraphical changes. Serum phosphate increased from 0.525 +/- 0.478 mmol/l to 1.054 +/- 0.041 mmol/l (p < 0.001) in response to 3000 mg phosphate. A close correlation (r = 0.69) was found between serum phosphate and urinary phosphate excretions (p < 0.001) and an inverse correlation (r = -0.31) was found between serum phosphate and tubular reabsorption of phosphate (p < 0.01). Serum and urinary calcium values, parathormone as well as renal functions did not change. Administration of high doses of phosphate seemed to be an effective and probably safe form of treatment in XLH provided that development of hyperparathyroidism is prevented by the coadministration of high doses of calcitriol. PMID- 10101536 TI - Sensitization of rat gastrointestinal tract to acetylcholine and histamine produced by X-radiation. AB - Abdominal x-radiation produces both acute and chronic disturbances of gastrointestinal motility. Anaesthetized Albino-Oxford rats received one-session x-radiation (absorbed dose 10 Gy) of whole abdomen. Two hours after irradiation the rats were sacrificed and segments of their gastrointestinal tract (gastric fundus, jejunum, ileum and ascending colon, were mounted in isolated organ bath. Acetylcholine and 5-hydroxytryptamine produced tonic contractions of all gut segments, while histamine did so only with gastric fundus. While contractile effect of 5-hydroxytryptamine was not affected by x-radiation, the responses of all gut segments on acetylcholine were potentiated and shifted towards lower concentrations. After x-radiation histamine produced concentration-dependent tonic contraction of previously unresponsive jejunum and ascending colon. The results of our study suggest that x-radiation produces acute sensitization of rat gastrointestinal tract to acetylcholine and histamine. PMID- 10101537 TI - The effect of xylene inhalation on the rat liver. AB - In this study, 11,284 mg/m3 (2600 ppm) of xylene was administered for 8 hours a day to pregnant rats by means of inhalation, starting from the sixth day of their pregnancies. Furthermore, while a group of non-pregnant rats inhaled the same amount of xylene during the same period, the control group inhaled clean air. Consequently, in addition to the embryotoxic effects of xylene, the effects on the various tissues of the mothers and their litters were observed light and electron microscopes. No external anomalies were observed in any of the rats born at the end of the 21st day, and there were no macroscopic defects in their organs either. While following xylene inhalation no structural defects in the kidney and pancreas was found, expansions in the smooth endoplasmic reticulum of the liver tissues, increases in the lysosomes, and defective mitochondrion structures were found in the pregnant and non-pregnant rats. It was noticed that xylene in particular caused structural defects in the liver of the fetus. Compared to the control groups, increases were observed in the activities of the AST, ALT, ALP, and Arginase enzymes in the liver. PMID- 10101538 TI - Measurement of the residual urine index in insulin-dependent and non-insulin dependent diabetic men with and without neuropathy. AB - Value of the residual urine index was evaluated in 40 individuals both insulin dependent (IDDM) and non-insulin dependent (NIDDM) diabetic male patients with and without an objective evidence of neuropathy and in 20 age matched non diabetic men serving as controls using post void bladder ultrasonographic technique. These studies revealed striking results in the neuropathic group. Both IDDM and NIDDM diabetic patients with neuropathy exhibited a significant (P < 0.005) increase in residual-volume in comparison with the controls of the same age group and a direct correlation between residual urine retention and neurogenic bladder was found to be established thus suggesting a generalized massive hypotonia of the bladder in these patients. However, non of the two types of non-neuropathic diabetic patients showed significant difference in the above mentioned parameters compared to that their respective controls. A non significant association in the values of the study parameters between insulin dependent and non-insulin dependent diabetic men (with and without neuropathy) was also observed. These findings thus suggest a probable neuropathic involvement in the pathway of urinary tract in both IDDM and NIDDM diabetic men with neuropathy. The greater impairment of the values of residual urine index in these patients may be due to overall greater severity of neuropathy with sympathetic as well as parasympathetic damage irrespective of their type of diabetes. PMID- 10101539 TI - The effects of artificial tear solutions on wound healing in full thickness corneal incisions. AB - Carbopols (carbomer, polyacrylic acid) are appropriate for ophthalmic use as an artificial tear in the form of viscous aqueous solutions. Carbopol 940 preparations were developed as long-lasting artificial tears for the relief of dry eye syndrome and traumatic injury. We identified the 15 days local treatment effects of two artificial tear solutions by wound strength and histologic examination of the incision wounds of rabbit corneas by comparing these results with the controls. Three layers of control corneas were regular. The untreated but wounded corneas epithelium and stroma were completely irregular. Both treated eyes had thinner epithelization in the incision site compared to control unwounded eye. Wounds treated with A preparation (viscotiers) had vocuoles and numerous inflammatory cells and remarkable oedematous regions but B preparation (Thilo-Tears) treated wounds had inflammatory cells and oedematous regions less than the other group. The wound strengths of gel treated wounds were bigger than those of controls. A considerable result in wound strength and better wound healing was also obtained in B preparation treated group because of the arrangement of the pH and tonicity at the Thilo-tears gel preparation. PMID- 10101540 TI - Short-time predegenerated peripheral nerve grafts promote regrowth of injured hippocampal neurites. AB - Our previous studies revealed that predegenerated peripheral nerve grafts facilitated neurite outgrowth from the injured hippocampus and that this effect was particularly distinct when 7-, 28-, and 35-days predegenerated nerve grafts were used. It is recently known that a totally transected peripheral nerve exhibits biphasic neurite-promoting activity. The early phase lasts 7 days. The aim of the present study was to find whether short-time predegenerated (1-6 days) peripheral nerve grafts exert any neurotrophic effect and when this influence is maximal. Experiments were carried out on adult male Wistar rats. Sciatic nerves were totally transected and following 1, 2, 3, 4, 5 and 6 days their distal stumps were implanted into the hippocampus. Control animals were treated with non predegenerated sciatic nerve grafts. In all groups FITC-HRP was injected into the free end of graft six weeks following surgery. Special histochemic technique showed AChE-positive fibres inside the grafts of all examined groups. Fluorescence microscopic examination revealed the labeled cells in all examined groups, however their number was different in each group, depending on the predegeneration stage. They were most numerous at the fourth day of predegeneration. PMID- 10101541 TI - The effects of continuous light and darkness on the activity of monoamine oxidase A and B in the hypothalamus, ovaries and uterus of rats. AB - For assessing monoamine oxidase (MAO-A and -B) activities in the hypothalamus, ovaries and uterus, mature female rats were exposed to either continuous light or dark over 6 weeks. Confirming previous studies, continuous light induced constant estrus in all animals. The majority of animals kept under continuous dark during the six weeks remained mostly in diestrus with estrus appearing sporadically. The endocrinological function of the ovaries was disturbed by continuous light, which resulted in the development of polycystic ovaries, their morphological appearance being not significantly affected by continuous dark. Hypothalamic MAO-A activity was markedly reduced under the influence of both light (p < 0.05) and dark (p < 0.01). The activity of hypothalamic MAO-B was reduced only under the influence of dark (p < 0.01). In the ovaries, no significant differences were detected in either MAO-A or -B activity as a result of these environmental manipulations. In the uterus of rats exposed to continuous light which developed polycystic ovaries, MAO-A activity was significantly lower (p < 0.05) in comparison to either intact controls or rats exposed to continuous dark. These results demonstrate that chronic changes in photoperiodicity may considerably influence MAO-A activity and to a lesser extent MAO-B activity dependent on the tissue studied. PMID- 10101542 TI - The protective effect of Ginkgo biloba extract on CCl4-induced hepatic damage. AB - The aim of this study was to evaluate the protective effect of Ginkgo biloba extract on CCl4-induced hepatic damage in rats. Hepatic malondialdehyde, glutathione and hydroxyproline levels and histopathologic alterations in liver specimens were assessed. 200 mg/kg/day Ginkgo biloba extract were given orally to the animals for 10 days, then a single dose of 2 ml/kg b.w. carbon tetrachloride was, administered intraperitoneally. Ginkgo biloba extract treatment reduced hepatic malondialdehyde levels significantly (p < 0.05), but did not alter glutathione (p > 0.05) and hydroxyproline levels (p > 0.05). The light and electron microscopic findings showed that Ginkgo biloba extract limited the CCl4 induced hepatocyte necrosis and atrophy. These results suggest that this extract may protect the hepatocytes from carbon tetrachloride-induced liver injury. PMID- 10101543 TI - Academic medicine in Singapore. PMID- 10101544 TI - Abdominal surgery in human immunodeficiency virus (HIV) infected patients--early local experience. AB - The prevalence of human immunodeficiency virus (HIV) infection is increasing in Singapore. The surgical experience, however, remains limited. A retrospective review of 13 HIV-positive patients requiring abdominal surgery within Singapore was done. There were 4 females and 9 males with age ranging from 21 to 44 years. Operations included appendicectomy, colectomy, splenectomy, intestinal bypass, gastrostomy and exploratory laparotomy. Pathologic findings directly related to HIV infection were found in two-fifths (5 out of 13) of these patients. A low CD4+ count or signs of full-blown acquired immunodeficiency syndrome (AIDS) were not associated with a higher likelihood of HIV-related pathology; neither did it preclude a successful outcome. There were 2 early postoperative deaths, both with HIV-related pathology. Five of our patients who survived their abdominal surgery died on follow-up with a median survival of 17 months. In patients with typical surgical problems, e.g. appendicitis and torsion of the ovary, early surgery allows for rapid recovery similar to normal surgical patients. Care of these patients is best provided by surgeons with experience and interest in this condition together with infectious diseases physicians. Even palliative surgery offers a respite from acute and often severe problems and improves the quality of life significantly. Two patients with AIDS presented with sepsis and diffuse abdominal tenderness. Subsequent laparotomy revealed only primary bacterial peritonitis. For patients with AIDS and non-localizing abdominal signs, alternative non-invasive diagnostic modalities such as computed tomographic (CT) scan should be considered. PMID- 10101545 TI - Operative treatment of displaced talar neck fractures. AB - Twenty-two displaced talar neck fractures were treated by open reduction and internal fixation. Four open fractures were operated within 8 hours and 18 closed injuries were treated at an average interval of 13.8 hours after injury. Fractures were classified according to Hawkins' classification into 14 type II, 7 type III and 1 type IV. At an average follow up of 4.4 years, 18 cases obtained excellent or good results. Result was fair in 2 cases of delayed union and 1 case of avascular necrosis. Another case of avascular necrosis developed osteoarthritis of the ankle and had poor result. The overall incidence of avascular necrosis of the body of the talus was 9%. PMID- 10101546 TI - Stereotactic microelectrode-guided posteroventral pallidotomy and pallidal deep brain stimulation for Parkinson's disease. AB - Three patients underwent stereotactic posteroventral pallidotomy, and 1 patient underwent pallidal deep brain stimulation, for medically intractable symptoms of advanced Parkinson's disease, characterized by peak-dose levodopa dyskinesias, wearing-off fluctuations, tremor, rigidity and bradykinesia. Surgery was performed stereotactically under local anaesthesia, with eventual target coordinates derived from a combination of magnetic resonance imaging (MRI), coregistration with an electronic brain atlas, intraoperative microelectrode neuronal recordings and microstimulation before lesioning or placement of a deep brain stimulator was done. Assessment was made at baseline preoperatively and at 3-month intervals postoperatively, with Unified Parkinson's Disease Rating Scale (UPDRS) and Core Assessment Program for Intracerebral Transplantation (CAPIT) scoring. All patients improved in dyskinesia, tremor, rigidity and bradykinesia contralateral to the lesion side, but also on the ipsilateral side to a lesser extent. The improvement was largely seen in the 'off' state: UPDRS by 41%, and CAPIT by 19% on the contralateral side. 'On' freezing was not helped. There were no deaths and no visual complications, but there was one complication of a delayed contralateral upper limb dystonia after pallidotomy. The 1 patient with pallidal deep brain stimulation (DBS) obtained similar improvement as those with pallidotomy. Posteroventral pallidotomy and pallidal stimulation improves all the cardinal features of Parkinson's disease, and effectively ameliorates levodopa dyskinesias. PMID- 10101547 TI - Surgical results of open reduction and plating of humeral shaft fractures. AB - Thirty-five patients who sustained humeral shaft fractures were treated by open reduction internal fixation using AO techniques between 1992 and 1997. Open fractures occurred in 8 patients. Primary radial nerve palsy was present in 5 cases. In 16 patients an open fracture or multiple trauma, or both were indications for surgery. Eight osteosynthesis were performed after failed conservative treatment. The complications encountered were non-union (2 cases), osteomyelitis (2 cases), secondary radial nerve palsy (3 cases) and repeat surgery (4 cases). Bony union averaged 5.3 months radiographically. All cases of radial nerve palsy recovered eventually. Twenty-seven patients reported no pain. Twenty-six patients had full range of motion in the shoulder and elbow. Thirty three patients had full muscle strength. Open reduction internal fixation gives good results provided correct indications and principles of fixation are adhered, and is a good alternative to conservative treatment. We advocate operative reduction internal fixation and nerve exploration in fractures associated with radial nerve palsy. PMID- 10101548 TI - Anthropometry of anterior cruciate ligament in Singaporean Chinese. AB - Accurate reproduction of the anatomy of the anterior cruciate ligament during reconstructive surgery is paramount for obtaining good functional results. Graft size and length are important components of the reconstruction and the references we have used are Western figures. We feel that these Western figures do not apply to our local population. We performed an anthropometric study to test the hypothesis that the anterior cruciate ligament in the Singaporean Chinese is smaller than that quoted in Western literature. The study revealed that the anterior cruciate ligament in Singaporean Chinese is shorter and narrower. More importantly, the anterior cruciate ligament orientation in our study population is more vertical. This suggests that placement of the femoral tunnel in anterior cruciate ligament reconstruction has to be in a more vertical position to reproduce the physiometry of the anterior cruciate ligament. PMID- 10101549 TI - Is it feasible to use magnesium sulphate as a hypotensive agent in oral and maxillofacial surgery? AB - We report the results of a feasibility study using intravenous magnesium sulphate for deliberate hypotension in 16 ASA 1 patients undergoing major oral and maxillofacial surgery. All the patients received a standard nitrous oxide, oxygen, isoflurane, opioid and muscle relaxant anaesthetic. Magnesium sulphate was infused at 40 g/h until the mean arterial pressure reached 55 +/- 5 mmHg, followed by a maintenance dose of 5 g/h until 30 minutes prior to the end of surgery. The mean arterial pressure was significantly (P < 0.01) reduced by the magnesium sulphate when compared to baseline values. Control of the mean arterial pressure was satisfactory. No patient had reflex tachycardia, cardiac arrhythmia or rebound hypertension. In 14 patients the surgeons thought that the blood loss was less than when using other hypotensive anaesthetic techniques. In 2 patients the surgeons thought the blood loss was excessive. In another 2 patients, the surgeons thought that there was excessive facial swelling on completion of surgery. Postoperative muscle weakness and sedation were not problems clinically. Fourteen patients were extubated immediately after surgery and another 2 patients an hour later in the recovery room. Intraoperative urine output was well maintained. On completion of surgery, the prothrombin time was significantly increased (P < 0.05), and the partial thromboplastin time significantly decreased (P < 0.05) in all the patients (when compared to preoperative values); the clinical significance of this is unclear. The use of intravenous magnesium sulphate for deliberate hypotension is feasible in ASA 1 patients using a standard nitrous oxide, oxygen, isoflurane, opioid and muscle relaxant technique. This study forms the basis for a larger controlled study where the issues of postoperative sedation and weakness and coagulopathy can be dealt with in greater detail. PMID- 10101550 TI - Goldberger's triad in dilated cardiomyopathy--can it predict the severity of left ventricular dysfunction? AB - Goldberger's triad is a specific, but relatively insensitive, electrocardiographic sign for dilated cardiomyopathy. To study the correlation between the presence of this sign and the severity of left ventricular dysfunction, the electrocardiograms and echocardiographically-determined left ventricular parameters of 17 patients (mean age 59.3 +/- 11.8 years) with dilated cardiomyopathy were examined. Five of the patients had Goldberger's triad. We found that the mean left atrial diameter, the mean left ventricular internal diameters (both end-systolic and end-diastolic) and the mean left ventricular ejection fraction of the group of patients with Goldberger's triad did not differ significantly from the group without. Coronary angiography revealed occult coronary artery disease in 5 of 12 patients. A larger, prospective study is required to verify our finding. PMID- 10101551 TI - A study of idiopathic thrombocytopenic purpura (ITP) patients over a ten-year period. AB - Adult idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder caused by antiplatelet autoantibodies that cause platelet destruction by the reticuloendothelial system. The disease has been well-documented in the West. We studied 78 ITP patients diagnosed and followed up in a tertiary hospital, over a 10-year period, to give a profile of our local patients and their response to treatment. The majority of patients were females and fall in the 20 to 39 years age group. 21.8% were asymptomatic at presentation. The mean presenting platelet count was 31 x 10(9)/L. Complete response rate to steroid treatment was 46.7%. Thirty-seven patients (47.4%) underwent splenectomy with a success rate of 64.9%. 6.4% required multiple drugs to maintain a stable platelet count. There was no spontaneous, long-term remission in this series. 10.3% of our patients eventually developed an autoimmune disease. ITP has a variable clinical course and treatment has to be highly individualised. PMID- 10101552 TI - Drug treatment of hypercholesterolaemia. AB - We review the current drug treatment of hyperlipidaemia at our specialist out patient clinics between October 1995 and December 1995. During this period, 523 patients received one or more lipid-lowering drugs. Each patient was assessed for his vascular risk, the number of lipid measurements before and after treatment and the type, duration and outcome of drug treatment. Only 30% patients achieved the low-density lipoprotein cholesterol (LDL-C) targets recommended by the National Cholesterol Education Program II: 14%, 37% and 71% of the high, moderate and low risk patients achieved the targets respectively. Most patients (62.7%) were treated after only one lipid measurement and less than 50% of patients had a post-treatment lipid measurement within 3 months. Although the majority of patients did not achieve the recommended LDL-C targets, their LDL-C was significantly reduced by 20%. A greater reduction of LDL-C (32%) was achieved by simvastatin monotherapy. PMID- 10101553 TI - Computed tomographic and magnetic resonance imaging findings in paranasal sinus involvement in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) may spread to the paranasal sinuses. This retrospective study describes the features of paranasal sinus involvement in NPC on computed tomography (CT) and magnetic resonance imaging (MRI). One hundred and fourteen patients with histologically proven NPC underwent staging with both CT and MRI. Maxillary sinus infiltration was demonstrated on MRI in 10 patients; sphenoid sinus infiltration in 24 patients; and, ethmoid sinus involvement in 4 patients. CT could separate inflammatory changes from tumour in all maxillary sinuses but is less helpful in the sphenoid and ethmoid sinuses. Contrast enhanced MRI could differentiate tumour from inflammatory changes in all sinuses. Using MRI as the standard, the rates of CT separating tumour from inflammation are: maxillary sinus (100%), sphenoid sinus (43%) and ethmoid sinus (25%). Histological confirmation of tumour involvement in the paranasal sinuses is not available. It is important to separate sinusitis from tumour infiltration as prognosis and treatment planning may be affected. PMID- 10101554 TI - Reduction in retake rates and radiation dosage through computed radiography. AB - The availability of computed radiography has opened the possibility of using reduced dosage for radiographs in clinical settings and reducing the retake rate. A prospective controlled study was carried out over a period of four months comparing conventional X-rays and computed radiography. The aim was to assess if computed radiography at 50% normal dosage would result in films of adequate quality and a reduced retake rate compared to conventional radiography. The number and reason for retakes in each group were recorded. Film quality comparison using only chest X-rays (CXR) in one of three positions; erect posterior-anterior (PA), anterior-posterior (AP) sitting and supine was done by a panel of radiologists. A total of 6373 conventional and 4127 digital films were analysed. The overall retake rate was lower in the computed radiography group (4.6 vs 8.2% P < 0.001) as was the retake rate due to exposure factors (0.6% vs 3.2% P < 0.01). There was a higher proportion of optimal films in the computed radiography group for erect PA and sitting AP CXR (71% vs 61% P = 0.0015 and 64% vs 9% P = 0.0009 respectively) but no difference for supine films. Computed radiography resulted in a reduced retake rate due to exposure factors leading to a reduction in the overall retake rate. Despite 50% dosage reduction, films were of better or equal quality when compared to conventional radiography. PMID- 10101555 TI - The profile of hospitalised patients with Parkinson's disease. AB - The objective of this study was to provide a profile of patients with Parkinson's disease (PD) who required admission to hospital. We reviewed retrospectively all patients with PD who were admitted to our hospital in 1995. In our study, there were 260 admissions involving 173 PD patients. The average age was 74.7 years. Of these patients, 93 were males and 80 were females. There were 150 Chinese, 12 Indians, 9 Malays, and 2 of other races. The average duration of hospitalisation was 11.7 days. The main reasons for admissions were: 1) chest infections (22%), 2) falls (13%), 3) control of PD symptoms (10%), 4) general medical problems (9%) and 5) urinary dysfunction (8%). Nine per cent were classified as Hoehn and Yahr stage 2, 31% as stage 3, 31% as stage 4 and 24% as stage 5. Twenty-one per cent of our patients were first diagnosed with PD during their hospitalisation. Upon discharge, 26% required transfer to either a community hospital or nursing home. The current in-patient load of PD patients is expected to rise with the ageing population. A significant number of people within the community may have undiagnosed PD. These patients suffer multiple medical problems and need a multi disciplinary team approach to management. Greater resources will be required to support these patients in the community. PMID- 10101556 TI - Risk factors for predicting mortality in a paediatric intensive care unit. AB - Rapid advances in critical care technology and rising cost of medical care have spurred the development of outcome analysis including mortality risk prediction. The main objective of this study was to assess the risk factors contributing to mortality in our paediatric intensive care unit (PICU). This is a cohort study, consisting of consecutive admissions to the PICU from 1 January to 31 December 1997. The factors studied included multi-organ dysfunction syndrome (MODS), Pediatric Risk of Mortality III (PRISM III) scores in the first 24 hours (PRISM III-24), mechanical ventilation, renal replacement therapy, age, and diagnosis related groups. Univariate and multivariate statistical methods were used. Univariate analysis showed that need for mechanical ventilation, renal replacement therapy, presence of MODS involving 3 or more organs and PRISM III-24 scores were significantly associated with outcome (P < 0.0005). Relative risk of mortality in the presence of MODS and PRISM III-24 scores > or = 8 were 11.3 (95% CI: 3.3 to 38.3) and 15.8 (95% CI: 2.0 to 127.8), respectively. Using Cox Proportional Hazards model, the relative risk of mortality for any new admission could be calculated by the equation RR = e0.1032 x P, where P = PRISM III-24 scores. PMID- 10101557 TI - Glaucoma pattern amongst the elderly Chinese in Singapore. AB - Glaucoma is a major blinding condition and is more prevalent amongst the elderly. A population study of 479 elderly Chinese aged 60 years and older, and residing in Singapore was carried out to determine the prevalence of glaucoma. The overall glaucoma prevalence was 4.8% with normal tension glaucoma (61%) and primary angle closure glaucoma (26%) being the most prevalent forms of glaucoma. All cases were silent in presentation with 97% of cases previously undiagnosed. With the greying population in Singapore, the issue of screening the elderly for glaucoma should be considered. PMID- 10101558 TI - A descriptive study of the demography, symptomology, management and outcome of the first 300 patients admitted to an independent hospice in Singapore. AB - The aims of this study were: 1) to describe the demography, symptomology, investigations conducted, non-pharmacological interventions and outcome of patients admitted to an inpatient hospice and 2) to identify the nursing and medical needs of terminally ill patients. Case-notes of the first 300 patients admitted to Dover Park Hospice were studied retrospectively. There were 159 men and 141 women making up 325 admissions. The racial distribution was: Chinese 95.0%, Malays 3.0%, Indians 1.3% and Others 0.6%. Two-thirds of the men (64.2%) had spouses while 44.7% of the women were widowed. The mean age was 64.7 years. The 3 most common cancers were lung (21.7%), colorectal (14.6%) and hepatobiliary (12.5%). A proportion of patients (39.5%) were not known to have any metastases. Most patients were referred from hospitals and the home-care based Hospice Care Association. The commonest reason for admission was for "terminal care" (57.2%). At admission, only 38% of the patients were aware of their diagnoses and prognosis while 30% did not know either. The average length of stay was 25 days with 7.7% of patients having more than one admission. The most common symptoms were pain, anorexia, breathlessness, insomnia, constipation and dry skin. Non pharmacological interventions ranged from manual evacuation of the rectum to transfers to tertiary hospitals for surgery and other more invasive interventions. Many patients also attended day-care activities (23.1%). Outcome of the 325 admissions were as follows: went home 20%, died in the hospice 73.2%, went home to die 4.9% and others 1.8%. PMID- 10101559 TI - A review of pedestrian fatalities in Singapore from 1990 to 1994. AB - The authors reviewed 369 consecutive pedestrian fatalities, which occurred from 1990 to 1994. This represented 28.5% (range 23.3 to 37.2; 95% CI 26% to 31%) of all road accident autopsies during that time. The mean and median ages of this population were 51 (95% CI 48.63 to 53.37) and 54 years, respectively. There were 160 (43.3%) who were in the economically productive ages of 20 to 59 years. Of the 369 victims, 224 (60.7%) were males and 145 (39.3%) females, there being a preponderance of males across all age groups. Most of these accidents occurred during the hours of daylight and in conditions of good weather and visibility. It was estimated that pedestrian behaviour contributed, in part, to at least three quarters of these fatalities. The majority of these pedestrians died from multiple injuries (181; 49.1%) and closed head injury (146; 39.6%). The vast majority of subjects (357; 96.7%) had injury severity scores (ISS) > or = 16. A total of 100 subjects (27.1%) died at the sites of the accidents. Of these, 99 had ISS > or = 16, with 31 having had ISS = 75 (maximum score). Similarly, all 55 deaths that occurred in the A & E departments were associated with ISS > or = 16, with 6 having ISS = 75. This would imply that most of the deaths that had occurred on site and at A & E departments were not unexpected. Interestingly, no pedestrian aged < or = 12 years had an ISS < or = 16, suggesting that they may be more vulnerable to serious or life-threatening injury than adults. There were 46 (12%) victims who had detectable levels of ethanol in their blood samples, of whom, 10 had ISS = 75. However, the difference between the latter proportion and that of the rest of the pedestrian population who had no alcohol detected in their blood samples (31/323), was only marginally significant (95% CI 0.002 to 0.245). There was a high prevalence of pre-existing and intercurrent diseases, such as ischaemic heart disease (58.8%), hypertensive heart disease (30.4%), chronic obstructive airways disease (47.4%), bronchopneumonia (18.2%) and evidence of systemic hypertension (40.7%). It is submitted that the existence of these underlying conditions should be anticipated, or suspected, in the management of injured pedestrians, particularly the elderly, as they may influence the outcome of their critical care. PMID- 10101560 TI - A randomized trial of the use of print material and personal contact to improve mammography uptake among screening non-attenders in Singapore. AB - The Singapore Breast Screening Project was a nationwide study inviting a random sample of women between the ages of 50 and 64 years for mammography at one of two hospital-based screening centres over two years. The current study was undertaken to determine if (1) mailed health educational material alone, or (2) the same material delivered during a home visit made to the subject and her family would increase the uptake among Singapore women who had not responded to two previous invitations for mammographic screening as part of the Project. This randomized trial employed a standard second reminder letter (R), the same letter packaged with health education material designed for the project (RP) and the addition of a home visit to make contact with the woman and her family (RV). The outcome measure of interest was the proportion of women in each group subsequently attending for screening. The study population comprised 1500 non-attenders whose names appeared consecutively in the database of the larger screening centre in this Project. These were randomized into three groups of 500 each. In total, they broadly resembled the national population in ethnic composition (72.3% Chinese, 17.8% Malays, 9.0% Indians and 0.8% Others). By the end of the project, 7.0% of women in group R and 7.6% in group RP responded to the invitation. In group RV, 428 homes were visited at least once and contact was made with the subject and her family member in 306 (71.5%) cases. Subsequently, 13.3% of the women visited attended for screening. The rate ratio for attendance in group RP compared with group R was 1.09 (95% CI 0.70 to 1.70) and for group RV compared with R, 1.90 (1.27 to 2.84). When analyzed by groups originally assigned to, women in group RV remained significantly more likely to attend than those in groups R or RP. The marginal cost of a home visit, based on this study, was $25.04 per additional woman screened. Our results suggest that the response to a second reminder is generally low and that additional print material does not improve screening attendance in this group of initial non-attenders. Personal contact with the family through a home visit appears to increase uptake, and may be helpful particularly among women who have less frequent contact with the health care system. PMID- 10101561 TI - An overview of anaesthetic issues in phaeochromocytoma. AB - Recent developments in the anaesthetic management of phaeochromocytoma are reviewed. A brief summary of its pathophysiology and clinical features is also considered. The main anaesthetic issues involved in the assessment and preparation of these patients in light of the current information are then discussed. PMID- 10101562 TI - Case series of bronchoscopic removal of tracheobronchial foreign body in six adults. AB - Tracheobronchial foreign body is rare in adults. Diagnosis is difficult and requires a high index of suspicion. We report 6 cases of tracheobronchial foreign bodies in adults and their removal, as well as a literature review of this topic. Case records, chest radiographs and computed tomographies (CT) of the thorax were reviewed. There were 5 males and 1 female with a median age of 63.5 years. One patient could not protect his airway (tracheostomy). Foreign bodies were sutures (2), vegetable matter like peanuts, vegetables and popcorn (3), and a voice prosthesis. Main symptoms were cough, haemoptysis and breathlessness. There were few signs on physical examination and chest X-rays were not helpful in diagnosis. All patients had fibreoptic bronchoscopy although 3 subsequently required rigid bronchoscopy for foreign body removal. All foreign bodies were successfully removed without any complications. PMID- 10101563 TI - Creutzfeldt-Jakob disease presenting with visual blurring, diplopia and visual loss: Heidenhain's variant. AB - Focal electroencephalographic abnormalities as described in Heidenhain's variant of Creutzfeldt-Jakob disease are uncommon. We report a 73-year-old male presenting with visual symptoms, right hemianopia and rapidly progressive dementia. Myoclonus was synchronous with generalised periodic epileptiform discharges on electroencephalography (EEG). In addition, there were periodic focal sharp waves at the left occipital region. Diffusion-weighted magnetic resonance brain images showed slightly increased signal intensity in the occipital parasagittal area, left more than right. 14-3-3 protein was detected in the cerebrospinal fluid. The patient died within 5 months of presentation. PMID- 10101564 TI - Pericardial injury following severe sepsis from faecal peritonitis--a case report on the use of continuous cardiac output monitoring. AB - We report on a case of a 43-year-old man who developed reversible myocardial depression and pericarditis related to severe sepsis secondary to rectosigmoid colonic perforation. The management of this patient was aided by the use of a continuous thermodilution cardiac output catheter and monitor, recently introduced in clinical practice. PMID- 10101565 TI - A case report of neutrophilic eccrine hidradenitis in a patient receiving chemotherapy for acute myeloid leukaemia. AB - Neutrophilic eccrine hidradenitis (NEH) is a neutrophilic dermatosis primarily affecting the eccrine glands and occurs in patients undergoing chemotherapy. It must be distinguished from infections, drug eruptions, leukaemia cutis or other forms of skin diseases. As it is self-limiting, establishing the diagnosis will avoid unnecessary treatment for infections or changes in drug therapy. PMID- 10101566 TI - Sezary syndrome: a case report and a review of the molecular pathomechanism and management. AB - Sezary syndrome, one of the cutaneous T-cell lymphomas, is a rare cause of generalised exfoliative dermatitis. We report a case of Sezary syndrome in a 64 year-old man who had persistent erythroderma for four years and who subsequently developed inguinal lymphadenopathy and marked leukocytosis. We review the pathomechanism and management of this rare condition. PMID- 10101567 TI - Cutaneous polyarteritis nodosa: a case report and literature review. AB - Cutaneous polyarteritis nodosa (CPN) is an uncommon form of vasculitis. It exists as a separate entity, though bearing similar name with polyarteritis nodosa (PAN) which is an aggressive systemic vasculitis with multi-organ involvement. CPN runs a chronic but benign course. Its aetiology is unknown and it usually presents with painful nodules on the legs with mild constitutional symptoms, and extracutaneous features of arthralgias, arthritis, neuropathy and myopathy. No mortality has been reported thus far. It is therefore important to distinguish CPN apart from PAN. Symptomatic treatment with judicial use of systemic steroids and anti-inflammatory agents will suffice in most cases. PMID- 10101568 TI - Cryptococcal prostatic abscess in an immunocompromised patient: a case report and review of the literature. AB - A case of cryptococcal prostatic abscess in a 65-year-old Chinese man with immunosuppression from treatment of myasthenia gravis is presented. The patient was diagnosed to have cryptococcaemia when he presented with fever and urinary symptoms. Further investigations confirmed cryptococcal meningitis and imaging studies showed a hypodense lesion in the prostate. This proved to be an abscess and it was deroofed transurethrally. Histology of the prostatic tissue revealed the presence of Cryptococcus. The prostate can be a site of persistent cryptococcal infection and may take the form of an abscess. It should be drained transurethrally to prevent relapse. PMID- 10101569 TI - A case report of heparin resistance due to acquired antithrombin III deficiency. AB - A case of heparin resistance and its management during cardiopulmonary bypass is reported. A patient with a history of post-infarct angina and arrhythmias was treated with intravenous heparin infusion for five days prior to myocardial revascularisation surgery. He required 13,500 IU/kg of heparin to increase his activated clotting time to a therapeutic level for safe institution of cardiopulmonary bypass. This phenomenon of heparin resistance was postulated to be due to consumption of circulating antithrombin III as a result of prior heparinisation. Treatment with fresh frozen plasma restored heparin effectiveness. PMID- 10101570 TI - Mesothelial splenic cyst--a case report. AB - A 26-year-old male presented with a left upper abdominal mass of one year's duration. Ultrasonography revealed a cystic lesion arising from the lower pole of the spleen. Total splenectomy was done and pathological examination of the cyst confirmed a true cyst with mesothelial lining without squamous metaplasia. The epithelial linings of these true cysts ranged from flattened low cuboidal, low columnar to squamous type and unilayered or stratified. The pathogenetic hypotheses as well as clinicopathological features of this rare lesion, which is usually found in children and young adults, were reviewed. PMID- 10101571 TI - Effect of thyroxine on the contractile responses of the vas deferens to prostaglandin E2. AB - The effects of prostaglandin E2 (PGE2) on the contractile activity of thyroidectomized and thyroxine-treated albino rats were studied in vitro. Thyroidectomy totally inhibited the contractile response of the vas deferens to PGE2. Thyroxine treatment, on the other hand, significantly (P < .001) potentiated the response of vasa deferentia to PGE2, when compared to controls. It is suggested that thyroid hormones play a role in the contractile response of the vas deferens to PGE2. PMID- 10101572 TI - Expression and characterization of an epididymis-specific gene. AB - A truncated cDNA coding a rabbit epididymal protein (BE-20) was identified in a previous study. In the present study the full-length cDNA was isolated by the method of rapid amplification of cDNA ends. The BE-20 cDNA consisted of 585 bp with a poly(A) tail of 26 residues and an open reading frame composed of 369 bp encoding a deduced polypeptide containing 123 amino acid residues with a calculated molecular mass of 13 kDa. The N-terminus-contained a leucine-rich segment. BE-20 cDNA has about 76.8% homology with the HE4 gene of human epididymis. Northern blot analysis of mRNAs prepared from 17 different human tissues was performed using as probe a 0.5-kb DNA fragment corresponding to a segment of BE-20 cDNA. Positive reaction was elicited only with epididymal mRNA. A DNA fragment corresponding to a section of the open reading frame of BE-20 cDNA was cloned in Escherichia coli under the control of the T7 promoter. The cellular content of the expressed recombinant protein comprised about 55% of the total protein. The chromatographically purified bacterial product migrated as a single band with an estimated M(r) of 15 kDa on analysis by SDS-PAGE. In conclusion, BE 20 cDNA is expressed only in the epididymis. It is structurally related to the four-disulfide core family of extracellular proteinase inhibitors and may be involved in sperm maturation. PMID- 10101574 TI - Macro-orchidism in juvenile hypothyroidism. AB - A boy, aged 16 years, with absence of development of the secondary sex characteristics, inappropriately large testes for his stage of puberty, and short stature is described. The symptoms were secondary to long-standing prepubertal hypothyroidism. Following therapy with thyroxine, there was a rapid advancement in growth velocity, full development of the secondary sex characteristics, and reduction in the size of the testes. PMID- 10101573 TI - Molecular cloning and characterization of a novel testis-specific nucleoporin related gene. AB - A 20-kDa sperm membrane protein cDNA, designated as RSD-1, was isolated by epitope selection from a rat testis lambda gtll expression library. RSD-1 was used as a probe to screen a human testis lambda ZAPII cDNA expression library. A cDNA designated as BS-63 was isolated and found to consist of 1933 bp with an open reading frame of 1824 bp and assigned the accession number U64675 by GenBank. The deduced polypeptide consisted of 608 amino acid residues containing XFXFG or FG motifs that are characteristic of nuclear pore complex (NPC) proteins and act as potential binding sites for Ran. The N-terminal region has high homology with RanBP2/Nup358, a nucleoporin component, showing that BS-63 is a member of the NPC family. Northern blot analysis of mRNAs prepared from various human tissues shows that BS-63 is transcribed in two forms: 6.0 and 8.5 kb. The 8.5-kb transcript was present in low amounts in several somatic tissues, whereas the 6.0-kb transcript is expressed only in testis. In situ hybridization analysis of human testis sections showed that BS-63 mRNA is expressed only in germ cells at all stages of spermatogenesis. Sertoli cells did not transcribe the gene. PMID- 10101575 TI - XX-male syndrome bearing the sex-determining region Y. AB - The case of a 25-year-old man who presented for evaluation of infertility is described. The physical examination revealed testicular atrophy without gynecomastia. Repeated seminal analyses showed azoospermia, and serum hormonal levels suggested a state of a hypergonadotropic hypogonadism. Chromosomal analysis demonstrated 46XX. Polymerase chain reaction revealed the existence of a sex-determining region Y. The etiology of this rare sex reversal syndrome is discussed and cases reported in Japan are reviewed. PMID- 10101576 TI - Effect of progesterone on acrosome reaction, hypoosmotic swelling test, and DNA stability in human spermatozoa. AB - The association between different sperm parameters, an in vitro effect of progesterone, has not been studied satisfactorily. In this article, the effect of progesterone on acrosome reaction (AR), plasma membrane integrity, and chromatin stability has been assessed in human spermatozoa with normal morphology and motility. Semen samples were obtained by masturbation from 25 patients. Two criteria of classification were utilized in this study: high motility group and normal morphology group incubated with progesterone. The effect of progesterone on AR, plasma membrane integrity, and chromatin stability in human spermatozoa with normal morphology and motility was realized. The results suggest that only the subpopulation of spermatozoa with normal morphology is able to undergo the progesterone-induced AR. It is possible that in the reproductive female tract it takes place a high selection of sperm with chromatin stability determined and optimal plasma membrane to undergo the AR prerequisite for the fecundation. PMID- 10101577 TI - Spontaneous pregnancy following therapeutic approach of an infertile man with aspermia/obstructive azoospermia. AB - The combination of aspermia and obstructive azoospermia in the same infertile man is a rather rare entity. In the case reported here, all diagnostic criteria as well as subsequent recovery following two operations are compatible with an inflammatory origin. In such cases assisted reproduction should be recommended. However, in this case, an early spontaneous pregnancy rendered this unnecessary. PMID- 10101578 TI - Reverse zymography studies of protease inhibitors in the secretions of different lobes of rat prostate. AB - The purpose of this study was to determine whether protease inhibitors were a constituent of secretions from the different lobes of the rat prostate. A reverse zymography method was used employing gelatin substrate-SDS-polyacrylamide gel electrophoresis to detect inhibitors of trypsin in secretions of the ventral, lateral, and dorsal prostate lobes of the Sprague-Dawley rat. Inhibitors of approximately 34 and 63 kDa were detected in ventral prostate secretion and of about 63 and 73 kDa were found in lateral lobe secretion. However, no inhibitor activities were detected in secretions of the dorsal lobe. The protease inhibitors of ventral prostate secretion were partially purified by preparatory isolectric focusing and SDS-polyacrylamide gel electrophoresis. The 34-kDa (pI 5.6-6.4) inhibitor had a higher activity against trypsin, whereas the 63-kDa (pI 6.4-7.0) inhibitor was more active against chymotrypsin. The rat prostate appears to have a lobe-specific distribution of secretory serine protease inhibitors. PMID- 10101579 TI - Effect of nitric oxide releasers on some metabolic processes of rabbit spermatozoa. AB - The authors investigated the possible effect of nitric oxide (NO) releasers (the free radical form of nitrogen monoxide, which control some functions of many cells) on rabbit spermatozoa. A significant (P < .01) increment was found in the percentage of the acrosome reaction in rabbit spermatozoa incubated for 30-60 min in presence of the NO releasers sodium nitroprusside (SNP) and N-acetyl-S-nitroso cysteine (NACysSNO), but not with S-nitroso cysteine (CysSNO). This effect was reverted or lowered when the NO scavenger HbO2 was included in the medium. The effects of SNP and NACysSNO on acrosome reaction do not appear to be related to glucose utilization, viability, or lipid peroxidation. PMID- 10101580 TI - The immunopathogenesis of multiple sclerosis. AB - The aetiology of multiple sclerosis (MS) remains unknown. Evidence from clinical and animal studies strongly supports MS as an organ-specific autoimmune disease mediated by T helper 1 CD4+ autoreactive T cells. This chapter will review the evidence in favour of this theory, discuss central nervous system autoimmune hypotheses and outline the important inflammatory mechanisms involved in the immunopathogenesis of MS. The immunology applicable to the acute or isolated MS lesion is presented. Relevant clinical aspects of the disease are discussed to support and highlight potential inconsistencies in current thinking. Hypotheses are presented where parts of the immunopathogenic jigsaw puzzle remain incomplete, for example the mechanisms responsible for disease evolution. Where necessary, supportive evidence from the animal model experimental allergic encephalomyelitis is presented. PMID- 10101581 TI - Outcome measures in multiple sclerosis clinical trials. AB - Multiple sclerosis remains incurable. The urgency of this problem, together with the need to test an ever increasing number of promising therapeutic agents emerging from animal studies, has renewed interest in both the application and the development of efficient outcome measures for treatment trials. The selection and usage of instruments used to detect outcomes is probably the most important issue in treatment trial design. Thus, familiarity with them is essential not only for researchers, but also for clinicians who wish to interpret trial results critically. This chapter begins with a discussion of the properties of an ideal outcome instrument, then reviews the strengths and limitations of existing clinical, radiological and laboratory outcome measures. With this knowledge, the current consensus regarding appropriate outcome measure selection, as well as recommendations and future perspectives in trial design, are discussed. PMID- 10101582 TI - Spasticity, ataxia and fatigue in multiple sclerosis. AB - Multiple sclerosis frequently results in a wide range of symptoms which often coexist, creating a complex pattern of disability. Chief among these symptoms, both in relation to their frequency and their impact on the patient, are spasticity, ataxia and fatigue. This chapter discusses the pathological basis and current treatment of these symptoms and stresses the importance of a multidisciplinary approach to their management, producing a comprehensive care plan which incorporates these and any other coexisting problems. PMID- 10101583 TI - The cause and management of bladder, sexual and bowel symptoms in multiple sclerosis. AB - Neurological control of bladder, bowel and sexual function depends on intact innervation between cerebral controlling centres and the conus of the cord. It is probably the spinal cord disease in multiple sclerosis (MS) which is the main cause of the pelvic organ dysfunctions that occur. Essential to bladder management is understanding to what extent the patient has incomplete emptying while complaining predominantly of symptoms of bladder overactivity. Anticholinergic medication can be highly effective for treatment of detrusor hyperreflexia but if incomplete emptying is also part of the problem intermittent catheterization or some other means of improving emptying will be necessary. Although there is an increasing range of treatments available for erectile failure there is still little that can be done to help women with sexual dysfunction. However, patients of both sexes are likely to welcome the opportunity to discuss their problem. The prevalence of bowel dysfunction is higher in patients with MS than in the general population and there are a number of possible pathophysiological mechanisms for both the constipation and the faecal incontinence that occur. However, there are as yet few specific effective treatments. PMID- 10101584 TI - Treatment of multiple sclerosis with interferon beta 1b. AB - Interferon beta 1b is now an established therapeutic option for relapsing remitting multiple sclerosis. More recently, it has also been shown to slow down disease progression in secondary progressive multiple sclerosis. Interferon beta 1b's clinical effect is reflected in MRI studies demonstrating a dramatic effect in reducing disease activity. The drug is generally well tolerated, but its efficacy can be compromised in some patients by the emergence of neutralizing antibodies. This chapter will focus on interferon beta 1b (Betaseron) treatment for multiple sclerosis, its clinical and MRI effects, and its putative mechanism of action. PMID- 10101585 TI - Interferon beta 1a. AB - An improved understanding of the immunopathogenesis of multiple sclerosis (MS) has led to therapeutic attempts using immunoregulatory agents in patients with MS, including interferon beta. IFN-beta 1a has been tested in relapsing-remitting MS and its effectiveness in reducing exacerbation rate and in slowing sustained worsening of disability after 2 years has been shown. Magnetic resonance imaging results supported the clinical findings, showing a significant reduction in Gd enhancing lesion frequency and new lesion formation on T2-weighted images. This type of interferon is well tolerated and most adverse events are mild and transient. Further trials are in progress to amplify and clarify the observed benefits of IFN-beta 1a. PMID- 10101586 TI - Copolymer-1. AB - Copolymer 1 (Cop-1) is a mixture of synthetic polypeptides composed of four amino acids. Cop-1 was very effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Two principal mechanisms have been proposed to explain the suppressive activity of Cop-1 in EAE and in multiple sclerosis (MS): the induction of antigen-specific suppressor T cells and the interference with T-cell activation by competition with myelin antigens in binding to the major histocompatibility complex class II molecules. Clinical trials with Cop-1 have demonstrated that Cop-1 positively alters the course of relapsing-remitting multiple sclerosis (MS) by both reducing the relapse rate and slowing the progression of disability. In a 2-year multi centre, randomized, double-blind, placebo-controlled trial of 251 patients, Cop-1 was shown to reduce relapses by an average of 29% when compared with placebo. A preliminary study on patients with relapsing-remitting MS treated with Cop-1 showed a reduced number of new enhancing lesions on MRI as well as a reduced accumulation of lesion load during Cop-1 treatment. Antibodies to copolymer-1, which are found during Cop-1 treatment, do not interfere with its clinical effects. The side effects of Cop-1 are minimal and acceptable. In vitro and in vivo animal studies have shown a very good safety profile of Cop-1 which is devoid of teratogenic or mutagenic effects. Cop-1 joins interferon beta as a good candidate for treatment of relapsing-remitting MS. PMID- 10101587 TI - Other immunomodulatory therapies in multiple sclerosis. AB - This short review concentrates on immunomodulatory disease-modifying approaches that are under development for the treatment of multiple sclerosis based on present concepts of the immunopathogenesis of the disease that especially involve T-cells and macrophages as being prominently involved in inducing tissue destruction and on the advances that have been made in recent years by studying other treatment interventions that have been applied and that have been shown to be either successful (interferon beta, copolymer-1) or unsuccessful (many others). PMID- 10101588 TI - Remyelination in demyelinating disease. AB - In multiple sclerosis, partial remyelination is conspicuous in many lesions, and is thought to contribute significantly to lasting recovery from acute relapse. However, myelin repair ultimately fails during progression of the disease, as disability and handicap accumulate. In this chapter we explore the biological background to myelin repair in CNS demyelinating disease, and the reasons underlying the failure of more widespread and lasting remyelination in multiple sclerosis. Experimental studies provide clear evidence that therapies promoting myelin repair can be highly successful in the CNS, and we discuss the clinical approaches which might allow the translation of these laboratory studies to neurological practice, together with some of the potential hazards and pitfalls likely to arise. PMID- 10101589 TI - Human haptocorrin in hepatocellular carcinoma. AB - This study aimed to determine whether haptocorrin (HC), a vitamin B12 binder, is stored in hepatic cells and whether this storage is modified by hepatic carcinogenesis. It was carried out using immunohistochemistry on different liver tissues (normal liver and steatosis, N = 22; cirrhosis, N = 13; and hepatocellular carcinoma, N = 31). No significant immunostaining of HC was detected in noncancerous biopsies with the exception of in one case of cirrhosis. Hepatocellular carcinoma (HCC) sections showed a weak to moderate cytoplasmic staining of cancerous cells (93% of cases) and of noncancerous hepatocytes surrounding the tumor (95%) of cases. Sections with pseudoglandular structures showed a moderate to strong staining of their secretion products. These results and previous studies would seem to confirm the hypothesis that the raised HC serum level observed in HCC is due both to the increased hepatic synthesis of HC and to a decreased uptake by the liver of the particular isoform of this glycoprotein present in the serum of HCC patients. PMID- 10101590 TI - Understanding meta-analysis in cancer epidemiology: dietary fat and breast cancer. AB - Meta-analyses of the relationship between dietary fat and breast cancer risk using different methodologies have reported conflicting results. This investigation compares methodologic aspects of meta-analyses of patient data (MAP) with meta-analyses of data from the literature (MAL), and computes relative risk (RR) estimates from a random effects model using 28 published studies of dietary fat and breast cancer. MAP and MAL results compare closely when homogeneity is verified. When statistical homogeneity is rejected, a random effects model adjusting for study design and location is appropriate. The highest RR was found for case-control studies of European women (RR: 1.46), followed by North American case-control studies (RR: 1.25), case-control studies of women on other continents (RR: 1.23), cohort studies in Europe (RR: 1.20), and cohort studies in North America (RR: 1.02). The overall risk estimate in a MAL with heterogeneous studies should be interpreted only in a conditional model. PMID- 10101591 TI - Presystemic intestinal metabolism of N-nitrosodimethylamine in mouse intestine. AB - N-Nitrosodimethylamine (NDMA), a common food contaminant, is a potent liver carcinogen in rodents. A high presystemic intestinal metabolism has been shown for several nitrosamines including environmentally important compounds. We determined the metabolism of 1 micron [14C]-NDMA in isolated perfused mouse intestinal segments. We found NDMA to be equally distributed between the absorbed fluid and the perfusate. During a 2-h perfusion period, 0.13% of the radioactivity was converted to CO2. The formation of CO2 was decreased by pretreatment with diallylsulfide or addition of SKF 525A, and slightly increased by phenobarbital. Hydrophilic metabolites were found in the absorbate (0.9%) and perfusate (3.8%) of untreated mice. The amount of metabolites in the absorbate was increased by treatment with acetone or phenobarbital (8-fold), but not after starvation, with formaldehyde being present only in phenobarbital-treated animals. Treatment with diallylsulfide or addition of SKF 525A reduced the amount of metabolites in acetone-treated animals to control values. In conclusion, intestinal turnover does not significantly reduce the body burden of orally ingested NDMA and thus is not a first-line defense against this carcinogenic nitrosamine. NDMA metabolism has been attributed to the presence of cytochrome P450IIE1, which has not been detected in the intestine of untreated animals. The low turnover of NDMA, the induction by acetone and phenobarbital treatment, and the inhibition by diallylsulfide suggest the presence of low amounts of this or related cytochrome P450 isozyme(s) in mouse intestine. PMID- 10101592 TI - Mucosal expression of carcinoembryonic antigen and carbohydrate antigen 19-9 in patients with gastritis and gastric cancer. AB - Sixty-eight patients (45 males, 23 females) were studied in order to assess the usefulness of mucosal tissue concentrations of both carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in detecting patients at high risk for gastric cancer. CEA and CA19-9 were assayed on cytosol obtained from multiple endoscopic biopsies of 41 patients with chronic superficial gastritis, 18 with chronic atrophic gastritis, and 9 with gastric cancer. Mucosal tissue concentrations of both CEA and CA19-9 increased from chronic superficial gastritis to chronic atrophic gastritis and to gastric cancer (p = 0.005 and p = 0.002, respectively). Mucosal CEA levels in patients with intestinal metaplasia (IM) were significantly higher than in nonmetaplastic mucosa (p = 0.04). Epithelial dysplasia was associated with higher, though not significant, tissue concentrations of both CEA and CA19-9 when compared with IM. Finally, a correlation between serum levels and tissue concentrations was observed only for CA19-9 (Pearson's correlation coefficient = 0.7). In conclusion, these data indicate that gastric mucosa of patients with chronic atrophic gastritis and intestinal metaplasia express high levels of both CA19-9 and CEA. PMID- 10101593 TI - Lymphovascular and neural invasion in low-lying rectal carcinoma. AB - We have previously demonstrated that lymphovascular infiltration was correlated with an increased risk for developing lymph node metastasis in rectal adenocarcinomas confined within the submucosal layer. In another study, lymphovascular infiltration was also correlated with poor prognosis for patients with advanced rectal cancers. Considerations that low rectal tumors have an increased risk to develop recurrence and neural invasion have been recently implicated with a more localized pattern of tumor spread. We therefore assessed the lymphovascular and neural invasion in 65 specimens from patients with low rectal cancers who underwent curative operation to determine its implications in the treatment and prognosis. Lymphovascular invasion was noted in 60%, and neural invasion was found in 27% of the cases. Five-year survival rates (Kaplan-Meier method) were significantly decreased in patients with lymphovascular invasion (31 vs. 67%; p < 0.01) or neural invasion (30 vs. 58%; p < 0.01). Neither lymphovascular nor neural invasion was noted in Dukes' stage A tumors. There was no recurrence or distant metastasis in these patients. However, lymphovascular and neural invasion increased with tumor stage. Local recurrence and distant metastasis occurred respectively in three and four, and five and five patients with Dukes' B and C tumors, respectively. Both Dukes' B and C cases with local recurrence had a higher incidence of neural invasion as compared with the disease free group. These results suggest that postoperative assessment of venous and neural invasion may provide valuable information to better determine which patients with low rectal cancers would benefit from adjuvant treatment. PMID- 10101594 TI - Analysis of SAS gene and CDK4 and MDM2 proteins in low-grade osteosarcoma. AB - The region q13-15 of chromosome 12 contains SAS, CDK4, and MDM2 genes that are rearranged or amplified in a variety of human sarcomas. This study evaluated SAS gene amplification, and MDM2 and CDK4 protein expression in 20 tumor samples of central low-grade osteosarcoma (16 primary, 3 recurrences, 1 lung metastasis). SAS amplification was analyzed by quantitative polymerase chain reaction (PCR), while from the same paraffin-embedded samples, MDM2 and CDK4 protein expression was evaluated by immunohistochemistry. MDM2 and CDK4 proteins were found strongly expressed in 35% and 65%, respectively, of the samples. SAS was found amplified in 15% of the samples. These findings indicate that these genes may be involved in tumorigenesis and progression of low-grade osteosarcoma. PMID- 10101595 TI - Neoangiogenesis and squamous cell carcinoma of the tongue. AB - The relationship between neoangiogenesis and prognosis was investigated in 51 patients with surgically resected squamous carcinomas of the tongue. Twenty-six patients had lymph node metastases treated by radical neck dissection. Potential methodological sources of variation in vascular counts were examined. Vessels were immunolabeled for CD34, and the vessel counts (VC)--as well as the vessel counts adjusted for tumor area (VV)--were obtained in the most vascular parts of the carcinomas. Vascular hot spots were distributed throughout the carcinomas. The VC per hot spot increased with increasing size of carcinoma, and was higher in the resected carcinoma than in the diagnostic biopsy in four of eight cases. VC was not related to the growth pattern of the carcinoma or to metastasis, but patients with nodal metastases tended to have a lower VV than those with no metastases (p = 0.049). The tumor-specific survival of the whole group was 59%, and patients with nodal metastases had a shorter survival than those without metastases (p = 0.008). Cox's proportional hazards model demonstrated that carcinomas with a low VC tended to have a good prognosis (p = 0.023). The results from this relatively small series of cases support the hypothesis that some measures of neoangiogenesis are independent predictors of the spread and prognosis of lingual carcinomas. The variations in methodology among different studies currently preclude an accurate assessment of the prognostic significance of neoangiogenesis. PMID- 10101596 TI - p53 overexpression and mutation in endometrial carcinoma: inverted relation with estrogen and progesterone receptor status. AB - Overexpression and mutation of p53 in 46 primary endometrial carcinomas were determined comparatively with the status for estrogen receptor (ER) and progesterone receptor (PR). Immunohistochemically p53 overexpression was found in 9 of 46 cases (20%), while eight kinds of mutations in that gene were detected in 7 of 46 endometrial carcinomas (15%), using polymerase chain reaction single strand conformation polymorphism and subsequently direct sequencing method. Six of nine cases with p53 overexpression showed p53 mutation. All eight mutations showed single substitutions, and three cases in exon 4, one in exon 5, two in exon 6, and two in exon 7 were found. The cases with the p53 overexpression were significantly inversely related to that of ER or PR staining. Most endometrial carcinoma with p53 overexpression and/or mutation had a relatively poor prognosis and showed no reactivities of ER or PR. PMID- 10101597 TI - Prognostic significance of flow cytometric deoxyribonucleic acid analysis for patients with superficial bladder cancers: a long-term follow-up study. AB - Flow cytometric DNA ploidy analysis for human bladder cancers may provide significant diagnostic and prognostic potential. We have previously reported that combined use of histologic and flow cytometric parameters may offer additional information regarding the clinical outcome for bladder cancer patients. However, the evaluation included both superficial and muscle-invasive tumors. In the present manuscript, we present our study on whether flow cytometric determination yields significant prognosticators beyond the classical histologic evaluation only in the patient with superficial bladder cancer. A total of 217 patients with untreated bladder cancer were evaluated, using fresh bladder tumor specimens. Tumor grading (grade 1, 2, and 3) and stage (pTa + pT1a and pT1b) served as the histologic prognostic parameters. Multiple flow cytometric parameters assessed included DNA index, percentage S-phase cells, percentage G2/M-phase cells, and hypertetraploid cell presence. Multivariate survival analysis was performed using the SAS proportional hazard regression procedure to study statistical individual prognostic values of both the histologic and the flow cytometric parameters. Clinical follow-up of more than 60 months was required, with the mean follow-up being 116.3 +/- 18.6 months. Hypertetraploid cell presence was the single most important prognostic factor (p < 0.01; risk ratio: 14.3), with the second being tumor grade (p < 0.05; risk ratio: 4.6). No other parameters, including tumor stage, the DNA index, and cell phase fractions, contributed to the model. These results indicate that hypertetraploid cell presence found by flow cytometric determination may provide additional information regarding the clinical outcome for superficial bladder cancer patients, and can be used as an indicator for decision making in treatment of superficial bladder cancer patients. PMID- 10101598 TI - Biomarkers in monitoring for efficacy of immunotherapy and chemoprevention of bladder cancer with dimethylsulfoxide. AB - This study correlated biomarkers expressed in tumor and epithelial field with clinical response and recurrence. Of 25 bladder cancer patients, 11 received 6 weeks of intravesical Bacille Calmette-Guerin (BCG), and 14 were treated weekly with intravesical dimethylsulfoxide (DMSO) for 4 weeks to further modulate biomarker expression. G-actin, DNA aneuploidy, and p300 tumor antigen were evaluated by quantitative fluorescence image analysis on uroepithelial cells from bladder wash samples prior to and immediately following treatment. Excluding patients who did not respond to BCG (and who had persistently abnormal p300 and DNA markers), recurrence correlated with persistent abnormal G-actin findings. Of patients who were G-actin negative following therapy, only 25% recurred during follow-up in contrast to 67% in patients who were positive (p < 0.03 by Fisher's exact test). The odds ratio for recurrence was 6.00 (95% confidence interval: 1.3 28.6). Cytosolic G-actin levels can be an important intermediate end point marker for chemoprevention. PMID- 10101599 TI - Subcutaneous administration of interleukin-2 and interferon-alpha 2b in advanced renal cell carcinoma: long-term results. AB - Clinical data have supported the combination of subcutaneous r-interleukin-2 (rIL 2) and r-interferon-alpha (rIFN-alpha) as a promising combination for advanced renal cell carcinoma (RCC), with a reduced toxicity. We evaluated the activity and safety of this outpatient immunotherapy and report on the clinical results and the long-term survival analysis. Objective responses was observed in 9 of 50 (18%) patients, 6 of whom (12%) achieved a complete response. Overall median survival is 12 months, six patients were surviving at a median follow-up of 24 months, and three (6%) are still progression-free. PMID- 10101600 TI - Barrett's esophagus: are Caucasians the only ethnic group at risk? PMID- 10101601 TI - [Reflections of a neurobiologist on the origin of ethics]. PMID- 10101602 TI - [Induction of apoptosis in lymphocytes by glucocorticoids: between physiology and pharmacology]. AB - Glucocorticoids are physiological molecules that are also extensively used in clinics as anti-inflammatory, immunosuppressive or anti-tumoral agents. Glucocorticoids can induce apoptosis on normal lymphoid cells and play a key role in the physiology of thymic selection. In clinics these molecules are also used for their potencies in inducing apoptosis of malignant lymphoid cells. Glucocorticoids are mediating their effects after binding to an intracellular receptor belonging to the steroid receptor superfamily: the glucocorticoid receptor (GR). Once activated, the GR, can mediate his effects through direct binding on the DNA or via protein/protein interactions with transcription factors. Depending on the type of lymphocytes, the mechanism of apoptosis induced by glucocorticoids fall roughly in two categories: induction of "death genes" by the activated GR (I kappa B, c-jun) or repression of survival factors (AP-1, c Myc). In the case of thymic selection the mechanism is more subtle depending on the mutual repression of Nur77 and GR. PMID- 10101603 TI - [Apoptosis: molecular mechanisms]. AB - Apoptosis is a genetically programmed cell death that is required for morphogenesis during embryogenic development and for tissue homeostasis in adult organisms. In most cases, apoptosis involves cytochrome c release from mitochondria. In the cytosol, cytochrome c combines with APAF-1 in the presence of ATP to activate caspase-9 that, in turn, activates effectors caspases such as caspase-3. Bcl-2 and related proteins control cytochrome c release from the mitochondria whereas IAP (for Inhibitor of APoptosis) molecules modulate the activity of caspases. Plasma membrane receptors such as Fas (CD95, APO-1), characterized by a so-called "death domain" in their cytoplasmic domain, can activate the caspase cascade through adaptator molecules such as FADD (Fas Associated protein with a Death Domain). Dysregulation of the apoptotic machinery plays a role in the pathogenesis of various diseases and molecules involved in cell death pathways are potential therapeutic targets in immunologic, neurologic, cancer, infectious and inflammatory diseases. PMID- 10101604 TI - [Apoptosis and liver diseases]. AB - Regulation of homeostasic balance between cell proliferation and cell death, called apoptosis, is essential for development and maintenance of multicellular organisms. Recent research into the molecular mechanisms of apoptosis has revealed that apoptosis is a genetically and evolutionarily conserved process that can become deranged when the components of the cellular apoptotic machinery are mutated, perturbated by viral gene products or present in inappropriated quantities. Analysis of the regulatory apoptotic pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases or autoimmune diseases. Our understanding of the regulation of apoptosis in health and disease is far from complete and the use of understanding into new therapeutic modalities has only begun to be approached. PMID- 10101605 TI - [The origin of programmed cell death in the flow of evolution and its role in host-pathogen interactions]. PMID- 10101606 TI - [Cloning of prepronociceptin has led to the discovery of other biologically active peptides]. AB - Among the opioid receptors family, the cloning of the mu, kappa and delta receptors was followed by that of another member, named ORL1 (Opiate Receptor Like 1). In spite of obvious homologies with the mu, kappa and delta receptors, ORL1 does not display a relevant affinity for the endogenous ligands of these former receptors (beta endorphin, enkephalins, dynorphin A...). This observation has prompted to search for an endogenous ligand of ORL1. A heptadecapeptide which fulfils this function, with a nanomolar affinity, has been found. It was named either nociceptin or orphanin FQ. It demonstrates, according either to the dose or to the route of administration, hyperalgesic, allodynic, antiopioidergic or even analgesic effects. It displays also many behavioural effects, modifying especially locomotion, exploratory behaviour, motivation, anxiety, memory, food intake. Nociceptin results from the cleavage of a large precursor protein, prepronociceptin (PPNOC). In this latter, nociceptin is flanked on its C-terminal region by another peptide which may be regarded either as a heptadecapeptide (NocII), or a bidecapeptide (NocIII) according to the inclusion or not of a fragment constituted by 3 arginine residues. Investigating the functions modulated by NocII, we observed that it stimulates locomotor activity of mice and shortens the forepaws licking latency in the hot plate test (55 degrees C); these effects are not shared by NocIII. The simultaneous administration of NocII and nociceptin resulted in animals put on the hot plate to the appearance of their respective effects, not modified by the presence of the other. A 41 amino acid peptide flanks nociceptin on its N-terminal region in PPNOC. It may be cleaved to generate a heptadecapeptide, named nocistatin on account of its antagonist effect on the hyperalgesia/allodynia induced by nociceptin. Thus, the discovery of ORL1 has led to that of nociceptin, that of its precursor PPNOC, and thereby to that of NocII/NocIII and nocistatin. The functions modulated by these peptides are being investigated whereas their receptors are yet unknown. These multiple targets allow to expect new strategies to modulate their functions. PMID- 10101607 TI - [Function and therapeutic potential of the dopamine D3 receptor]. AB - The D3 receptor is recognized with high affinity by all antipsychotics and selectively expressed in limbic brain areas participating in the central of emotions, motivation and reward. In transfected cultured cells, stimulation of the D3 receptor inhibits cAMP formation and increases mitogenesis, which, in turn, is potentiated by activation of the cAMP cascade. This suggests that both opposite and synergistic interactions occur between the D3 receptor and the cydic AMP pathway, possibly underlying D1/D3 receptor interactions. In fact, D1 and D3 receptors colocalize in the islands of Calleja, in which they interact in opposition on c-fos mRNA expression, and in the shell of nucleus accumbens, in which they interact in synergy on substance P mRNA expression. The expression of the D3 receptor is highly dependent of the dopamine innervation: lesion of ascending dopamine neurons reduces D3 receptor mRNA and binding in the shell of nudeus accumbens, by deprivation of an unknown factor of dopamine neurons, distinct form dopamine and its cotransmitters. In agreement, expression of the D3 receptor in neurons during rat brain development starts after the settlement of dopamine innervation during the first postnatal week. However, in adult rats with a unilateral lesion of dopamine neurons, repeated treatment with levodopa rescues D3 receptor expression in the shell of nudeus accumbens and induces this expression in the dorsal striatum, a region controlling movements in which the D3 receptor is normally absent. This induction seems responsible for the behavioral sensitisation, i.e. increased responsiveness to levodopa. These observations suggest a role of the D3 receptor in the progressive increase in the therapeutic efficacy of levodopa in the initial treatment of Parkinson's disease, and/or its adversive motor and psychopathological effects during long-term treatment. Finally, various pharmacological and genetic data suggest a role of the D3 receptor in drug addiction and schizophrenia, the treatment of which could benefit from selective D3R agents. PMID- 10101608 TI - [Behavioral, cellular and molecular consequences of the dopamine transporter gene inactivation]. AB - Mice lacking the the plasma membrane dopamine transporter (DAT), following gene inactivation or knock out, show an increase in their spontaneous locomotor activity that is of the same magnitude than in normal mice treated with amphetamine or cocaine, known to increase levels of dopamine in the basal ganglia. Many adaptive responses have occurred in these animals than could not compensate for the hyper activity of the dopamine system. Surprisingly, while intracellular dopamine levels were of only 5%, extracellular dopamine levels were increased by 300%. We investigated the regulation of tyrosine hydroxylase (TH), the rate limiting enzyme of dopamine synthesis, and found that this enzyme is regulated at the levels of mRNA, protein, trafficking as well as in its regional, cellular and subcellular organization. Our results establish not only the central importance of the transporter as the key element controlling dopamine levels in the brain, but also its role in the behavioral and biochemical action of amphetamine, cocaine and morphine. In addition, these mice have provided key elements leading to possible clinical and social implications for illnesses such as Parkinson disease, attention deficit disorder and drug addiction. PMID- 10101610 TI - [Creation of a line of "depressed" mice from a selection of breeders exhibiting a behavioral helplessness]. AB - Antidepressants are used since 40 years. All presently used antidepressants have a slow onset of action and do not improve all patients; thus, there is an absolute need for new antidepressants. A variety of animal models, often based upon the monoaminergic theory of depressive disorders, has been used to screen the current antidepressants. In fact, the main focus of most of these animal models has been to predict the antidepressant potential i.e. to establish predictive validity. However, the evaluation of such animal models should also consider face validity, i.e. how closely the model resembles the human condition, and this should help to identify innovating medicines. Antidepressants, when taken by a healthy person, induce nothing more than side effects, unrelated to an action on mood, whereas they alleviate depressive symptomatology in depressed patients. We have speculated that genetically selected animal models would be closer to the human clinical situation than models based on standard laboratory strains. We have depicted here that marked differences exist between strains of mice in the amount of immobility i.e. "spontaneous helplessness" observed in the tail suspension test, a method used to screen potential antidepressants. We have studied the behavioural characteristics of mice selectively bred for spontaneous high or low immobility scores in the tail suspension test. Hopefully, these selectively bred lines will provide a novel approach to investigate behavioural, neurochemical and neuroendocrine correlates of antidepressant action. PMID- 10101609 TI - [Homozygote mice deficient in serotonin 5-HT1B receptor and antidepressant effect of selective serotonin reuptake inhibitors]. AB - We use the knockout mice strategy to investigate the contribution of the 5-HT1B receptor in mediating the effects of selective serotonin reuptake inhibitors (SSRI). Using microdialysis in awake 129/Sv mice, we show that the absence of the 5-HT1B receptor in mutant mice (KO 1B -/-) potentiated the effect of paroxetine on extracellular 5-HT levels in the ventral hippocampus, but not in the frontal cortex compared to wild-type mice (WT). Furthermore, using the forced swimming test, we demonstrate that SSRIs decreased immobility of WT mice, and this effect is absent in KO 1B -/- mice showing therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these findings suggest that 5-HT1B autoreceptors limit the effects of SSRI particularly in the hippocampus while postsynaptic 5-HT1B receptors are required for the antidepressant activity of SSRIs. PMID- 10101611 TI - [Effect of modafinil on electroretinograms of Lycosa tarentula in relation visual circadian rhythm (Araneae, Lycosidae)]. AB - Injections of modafinil, a drug able to induce in vertebrates an awakening effect via an effective central alpha 1-adrenergic tone, induce modifications of the amplitude and latency of electroretinograms (ERGs) in the spider Lycosa tarentula, during dark adaptation. Results of experiments are different from one eye type to another as circadian activity rhythms of the retinae also differ. Modafinil induces a decrease of diurnal amplitudes and has no effect on nocturnal amplitudes of ERGs of anterior-lateral eyes; in the case of posterior-median eyes, the amplitudes are increased in daytime as well as at night. Prazosin, antagonist of alpha 1-adrenergic receptors, injected after modafinil, induces a decrease of the amplitudes of ERGs in the same eyes. These results are discussed in relation to the visual activity of this species, both diurnal and nocturnal. The concepts of waking state versus sleep are not precisely characterized in arachnids, so that the effects of modafinil on L. tarentula may not be considered like those described in vertebrates. PMID- 10101612 TI - Reaching and enrolling drug users for HIV prevention: a multi-site analysis. AB - Since 1994, several sites have participated in a NIDA Cooperative Agreement for AIDS Community-based Outreach/Intervention Research Program to examine rates of HIV risk behaviors and evaluate HIV risk reduction interventions among out-of treatment drug injection and crack cocaine and heroin smokers. We studied the process and outcome of community outreach for recruitment of drug users in AIDS research and education projects in three metropolitan areas: St. Louis, MO; San Antonio, TX, and Durham and Wake Counties, NC. There were two primary areas of focus: (1) the level of accuracy among community health outreach workers (CHOWs) in identifying potentially eligible persons for HIV prevention, and (2) overall effectiveness in recruiting and enrolling persons in formal assessment and intervention studies. We found cross-site and within-site differences in levels of accuracy and in recruitment and enrollment yields. Drug users who had never been in treatment and drug users who had never been tested for HIV infection were underrepresented at all sites. We discuss the factors which may have contributed to cross-site and within-site differences. The findings suggest a need for continued study, refinement, and evaluation of community outreach strategies in order to enroll a broad spectrum of vulnerable groups in HIV prevention activities. PMID- 10101613 TI - Methadone-maintenance outcomes for Hispanic and African-American men and women. AB - Six-month methadone-maintenance response and outcome were examined for African American and Hispanic men and women in a large urban sample. A consistent pattern of improvement was indicated for both races and genders on the addiction severity index (ASI). There were virtually no statistically significant differences in ASI outcomes between Hispanics and African-Americans and men and women using conventional analysis of variance (ANOVA) procedures. Results from an additional equivalence analysis, however, indicated that baseline to 6-month changes for the different groups were generally not similar enough to consider them equivalent. Urine toxicologies obtained during the 6-month treatment period were also not statistically equivalent by race and gender. Evaluating outcomes by gender and race are discussed, as are the implications of using equivalence tests when examining group differences. PMID- 10101614 TI - Attentional functioning in abstinent cocaine abusers. AB - The effect of chronic cocaine use on attention is directly relevant to the treatment of cocaine dependence, since attention underlies most other cognitive processes, and thus the ability to profit from cognitively-based interventions. This paper reviews 17 studies examining attention in patients with cocaine abuse or dependence. Findings have been inconsistent, largely due to various methodological difficulties. There has been some suggestion of reduced cognitive speed, while focused and sustained attention have generally been unimpaired. Divided attention has been largely unexplored. Thus, there is insufficient evidence either to accept or reject the hypothesis of attentional dysfunction associated with chronic cocaine use. PMID- 10101616 TI - Trends in situational norms and attitudes toward drinking among whites, blacks, and hispanics: 1984-1995. AB - The purpose of this study was to explore trends in situational norms and attitudes toward drinking and to assess the associations of norms and attitudes with current drinking and frequent heavy drinking patterns among whites, blacks, and hispanics between 1984 and 1995. Data were obtained from two nationwide probability samples of US households. Results indicated that there were no broad trends in situational norms and attitudes toward drinking between 1984 and 1995 among whites, blacks, and hispanics in the US. The variations in norms and attitudes detected between 1984 and 1995 were ethnic and gender-specific. For all of the groups studied, situational norms and attitudes were highly predictive of both current drinking and frequent heavy drinking patterns. PMID- 10101615 TI - Prediction of treatment outcome in cocaine dependent males using quantitative EEG. AB - This study investigates the existence of outcome related neurophysiological subtypes within a population of abstinent cocaine dependent adults. We have previously reported and replicated the existence of a distinctive quantitative EEG (QEEG) profile in such a population, and demonstrated the persistence of this pattern at one and six month follow-up evaluations. This profile is characterized by significant deficits of absolute and relative delta and theta power, and excess of relative alpha power, as compared with age expected normal values. Abnormalities were greater in anterior than posterior regions, and disturbances in interhemispheric relationships were also observed. In the current study, 35 adult males with DSM-III-R cocaine dependence, were evaluated while residents of a drug-free residential therapeutic community, 5-15 days after last use of crack cocaine. Using multivariate cluster analysis, two neurophysiological subtypes were identified from the baseline QEEGs; Cluster 1 characterized by significant deficits of delta and theta activity, significant excess of alpha activity and more normal amounts of beta activity (alpha CLUS) and Cluster 2 characterized by deficits of delta, more normal amounts of theta and anterior excess of alpha and beta activity beta CLUS). No significant relationships were found between QEEG subtype membership and length of exposure to cocaine, time since last use of cocaine or any demographic characteristics. Further, no significant relationships were found between the commonly reported comorbid clinical features of depression and anxiety and subtype membership. However, a significant relationship was found between QEEG subtype membership and length of stay in treatment, with members of the alpha CLUS retained in treatment significantly longer than members of the beta CLUS. PMID- 10101617 TI - Predictors of increased condom use following HIV intervention with heterosexually active drug users. AB - Research with injection drug users (IDUs), at risk for acquiring and transmitting HIV, has focused primarily on their risky drug practices, with far less attention paid to their risky sex behaviors. The purpose of this study was to determine what variables were associated with an increase in condom use following an HIV intervention with 3357 IDUs in nine cities. Participants reported using condoms during 15% of their sexual encounters prior to the HIV intervention, and during 22% of their sexual encounters six months later. A logistic regression analysis indicated that individuals who increased their condom use were likely to be HIV seropositive (odds ratio OR = 2.49), to have received AIDS information prior to the intervention (OR = 1.28), to have multiple sex partners (OR = 2.14), to be single with multiple sex partners (OR = 1.34), or to have exchanged drugs or money for sex (OR = 1.33). Discussion focuses on the generally low incidence of condom use and the need for increased intervention, particularly among drug users in monogamous relationships and sex workers. PMID- 10101618 TI - Factors associated with coercion in entering treatment for alcohol problems. AB - Although the importance of coercion in entry to treatment for alcohol problems is recognized, few studies have focused on different types and levels of coercion among heterogeneous groups of clients entering treatment agencies. This paper describes demographic and problem characteristics associated with various sources and levels of coercion. More than 40% (n = 377) of individuals entering a representative sample of a county's HMO, public, and private indemnity-based non DUI alcohol treatment services (n = 927) indicated they received an ultimatum to enter treatment from at least one person. The most common source of an ultimatum to enter treatment was from family members (n = 222), followed by the legal system (n = 78), and healthcare professionals (n = 55). Respondents experiencing pressure to enter treatment reported that ultimatums from more than one source were common. Individuals entering treatment who were most likely to report being coerced were white, young adults (age 18-39), and married or living with a partner. When controlling for demographic characteristics and problem severity, family problem severity and legal problem severity predicted having received an ultimatum to enter treatment. Alcohol and drug problem severity were not related to receiving a treatment ultimatum. PMID- 10101619 TI - Contingent reinforcement sustains post-detoxification abstinence from multiple drugs: a preliminary study with methadone patients. AB - This study examined the efficacy of a urinalysis-based contingency management program for preventing relapse to abused drugs following a brief residential detoxification. Fourteen methadone maintenance patients who were chronic benzodiazepine users were enrolled in a 7-day inpatient benzodiazepine detoxification and randomly assigned to receive Contingency Management (N = 7) or Standard Care (N = 7) therapy upon return to outpatient methadone treatment. In the Contingency Management condition, a methadone take-home dose or a US $25 voucher (patient's choice) could be earned for each urine sample submitted on a Monday, Wednesday or Friday that was free of opiates, cocaine and benzodiazepines. Data analysis and interpretation focused on within-group post hoc differences due to group differences on employment and legal status, potentially confounding baseline variables. Repeated measures analysis of variance showed that Contingency Management patients submitted significantly more drug-free urine samples during the intervention compared to pre-detoxification (p < 0.01), whereas no significance changes were observed from pre- to post detoxification in the Standard Care patients. Employment and legal status of patients may have facilitated response to contingency management procedures, but did not prevent relapse when contingency management procedures were withdrawn. Overall, these preliminary results suggest that abstinence-based contingency management is a promising strategy for preventing relapse to multiple drugs of abuse in a subset of methadone maintenance patients when abstinence has been initiated through brief inpatient treatment. PMID- 10101620 TI - HIV prevalence and risk behaviors among new initiates into injection drug use over the age of 40 years old. AB - Injection drug users (IDUs) who have recently initiated an injecting career have high risk behaviors for HIV infection. The average age of an IDUs first injection is typically reported as 19-20 years, and some literature has reported 'maturing out' of drug use typically around 40 years old. The purpose of this study was to discriminate risk behaviors among newer injectors by age of initiation. This cross-sectional study includes volunteers enrolled using extensive community recruitment techniques in 1988 and 1989 in Baltimore, MD. Of the 722 injection drug users who had initiated injection within the prior six years, 124 were over 35 years old of whom 53 were 40 years and older. Rates of HIV were lower among those over 40 years (13.2%) than those who were 35-39 years (22.5%) or under 35 years old (20.9%). The behavioral characteristics of those aged 35-39 were similar to those under 35 years old, but those over 40 years old when compared with less than 39 years reported injecting at least daily less frequently (88.7% vs 76.5%, p = 0.042), using a needle from a sterile wrapper (19.0% vs 36.6%, p = 0.006), and injecting with their own works (52.6% vs 28.8%, p = 0.021). This study shows that people initiate injection drug use across a wide age range and that needle hygiene practices early after initiation tend to be safer in older compared to younger initiates. PMID- 10101622 TI - A case in point: exclusions and replacements for exclusions after randomization in clinical trials. PMID- 10101621 TI - Acute subjective effects of dynorphin A(1-13) infusion in normal healthy subjects. AB - Twelve healthy subjects with no history of substance abuse participated in a placebo-controlled single-blinded study of subjective response to acute i.v. administration of placebo and two doses of the natural shortened peptide sequence of the kappa-opioid agonist, dynorphin A(1-13) (low dose 120 micrograms/kg, high dose 500 micrograms/kg). Visual analog scales showed small but significant negative mood and positive drug effect 10 min post infusion in the high dose dynorphin compared to placebo infusion. The differences were no longer apparent at 30 min. These results show that dynorphin A(1-13), shown previously to have both neuroendocrine and modest analgesic effects, was well tolerated and produced modest transient subjective responses. PMID- 10101623 TI - Concurrent medication and the neuromuscular junction. PMID- 10101624 TI - Effect of caudal block on the plasma adrenaline and noradrenaline concentrations in paediatric patients undergoing ilioinguinal herniorrhaphy. AB - This study compared the effect of two anaesthetic techniques on the catecholamine levels in children undergoing ilioinguinal herniorrhaphy. Forty male paediatric patients ASA class I were allocated randomly to one of two groups: the control group (n = 20) received general anaesthesia including intravenous fentanyl; and the caudal group (n = 20) received caudal anaesthesia with bupivacaine 0.25% 1 mL kg-1 combined with general anaesthesia but without opioids. Plasma adrenaline and noradrenaline concentrations were measured at induction, at the end of surgery and in the post-anaesthesia care unit (PACU). In the caudal group, there were significant decreases in the adrenaline and noradrenaline concentrations at the end of surgery and in the PACU compared with baseline concentrations. In the control group, there was a significant increase in PACU concentrations of adrenaline and noradrenaline compared with baseline concentrations. These findings suggest that the addition of a caudal block to general anaesthesia in children undergoing ilioinguinal herniorrhaphy decreases significantly the neurohormonal responses to surgery. PMID- 10101625 TI - Temporal changes in airway protective reflexes elicited by an endotracheal tube in surgical patients anaesthetized with sevoflurane. AB - In order to elucidate temporal changes in airway reflex responses to prolonged tracheal intubation, 14 patients anaesthetized with sevoflurane were studied. In each spontaneously breathing patient with an endotracheal tube in place, the end tidal concentration of sevoflurane was slowly decreased from the initial value of 1.3% until signs of airway irritation were observed. The value of end-tidal sevoflurane concentration at which the airway reflexes occurred (T(ar)) and the types of airway reflex response elicited at onset of airway reflex response were determined during the periods immediately before (presurgical period) and after surgery (post-surgical period), with an interval ranging from 2 to 7 h between the two periods. There was no significant difference in the values of T(ar) between the presurgical period (0.6 +/- 0.3%, mean +/- SD) and the post-surgical period (0.7 +/- 0.1%). There was a considerable difference in the type of airway reflexes elicited during the two different periods; the initial responses during the presurgical period were the apnoeic reflex and/or forceful expiratory efforts, whereas the initial response during the post-surgical period, in the majority of patients, was the swallowing reflex. Our results indicate that there may be adaptation mechanisms responsible for temporal changes in airway protective reflexes after prolonged endotracheal intubation in surgical patients. PMID- 10101626 TI - Responders and non-responders to post-operative pain treatment: the loading dose predicts analgesic needs. AB - The study compares responders and non-responders to post-operative patient controlled analgesia (PCA) and evaluates factors that might differ between these two groups in order to identify non-responders during the early post-operative period. A prospective, randomized, double-blinded study design was used. Patients recovering from abdominal surgery were assigned to one of three treatment groups for a study period of 48 h. After titration of an individual loading dose, patients could self-administer 1 mL bolus doses (2 mg of morphine, 20 mg of tramadol or placebo) using a PCA device. Patients responding or not responding to the treatment were identified. In non-responders the escape medication was morphine. There were 96 responders and 65 non-responders. All responders showed similar pain scores, irrespective of the drug they received. Drug consumption of placebo responders was twice as high as that of opioid responders. Pain scores and analgesic consumption of non-responders were significantly higher compared with responders, although those patients received morphine. The loading dose correlated with subsequent analgesic consumption. Altogether, 89.2% of the non responders were identified after the loading dose. Size of loading dose and pain scores during the first 30 min are useful for assessing the overall response to post-operative pain management. These factors may be valuable for predicting individual pain management. PMID- 10101628 TI - Is evisceration of the eye more painful than enucleation? PMID- 10101627 TI - Effects of controlled hypotension with sevoflurane anaesthesia on hepatic function of surgical patients. AB - The effects of controlled hypotension induced with trimethaphan (TMP), nitroglycerin (TNG) or prostaglandin E1 (PGE1) during sevoflurane anaesthesia on hepatic function were studied in 28 patients undergoing spinal fusion surgery. Patients were randomly divided into three groups to receive TMP (group A, n = 10), TNG (group B, n = 10) or PGE1 (group C, n = 8). Anaesthesia was maintained with N2O and sevoflurane. The mean arterial blood pressure was maintained at 60 mmHg for 90 min. Measurements included arterial ketone body ratio (AKBR acetoacetate/3-hydroxybutyrate), SGOT, SGPT, LDH, blood glucose and blood gases were made. Measurements were taken before hypotension, 60 min and 90 min after starting hypotension, 60 min after recovery from hypotension and on the post operative day. AKBR showed no significant change. SGOT, SGPT and LDH were within normal limits. Controlled hypotension induced with TMP, TNG or PGE1 under sevoflurane anaesthesia in surgical patients did not cause hepatocellular damage. PMID- 10101629 TI - Effectiveness of Harpagophytum extract WS 1531 in the treatment of exacerbation of low back pain: a randomized, placebo-controlled, double-blind study. AB - Two daily doses of oral Harpagophytum extract WS 1531 (600 and 1200, respectively, containing 50 and 100 mg of the marker harpagoside) were compared with placebo over 4 weeks in a randomized, double-blind study in 197 patients with chronic susceptibility to back pain and current exacerbations that were producing pain worse than 5 on a 0-10 visual analogue scale. The principal outcome measure, based on pilot studies, was the number of patients who were pain free without the permitted rescue medication (tramadol) for 5 days out of the last week. The treatment and placebo groups were well matched in physical characteristics, in the severity of pain, duration, nature and accompaniments of their pain, the Arhus low back pain index and in laboratory indices of organ system function. A total of 183 patients completed the study. The numbers of pain free patients were three, six and 10 in the placebo group (P), the Harpagophytum 600 group (H600) and the Harpagophytum 1200 group (H1200) respectively (P = 0.027, one-tailed Cochrane-Armitage test). The majority of responders' were patients who had suffered less than 42 days of pain, and subgroup analyses suggested that the effect was confined to patients with more severe and radiating pain accompanied by neurological deficit. However, subsidiary analyses, concentrating on the current pain component of the Arhus index, painted a slightly different picture, with the benefits seeming, if anything, to be greatest in the H600 group and in patients without more severe pain, radiation or neurological deficit. Patients with more pain tended to use more tramadol, but even severe and unbearable pain would not guarantee that tramadol would be used at all, and certainly not to the maximum permitted dose. There was no evidence for Harpagophytum-related side-effects, except possibly for mild and infrequent gastrointestinal symptoms. PMID- 10101630 TI - Peripartum cardiomyopathy presenting after caesarean section. PMID- 10101631 TI - Retropharyngeal abscess: an unusual complication of tracheal intubation. AB - A 42-year-old man presented as an emergency to the ENT department with sore throat and complete dysphagia, having undergone an umbilical hernia repair under general anaesthesia with tracheal intubation 3 weeks previously at another institution. One course of antibiotics from his general practitioner improved the symptoms but, on discontinuation of the antibiotics, symptoms flared up leading to complete dysphagia. Indirect laryngoscopy showed a bulging of the retropharyngeal wall, which was confirmed as a widening of the retropharyngeal space on a lateral soft-tissue X-ray film of the neck. Surgical exploration confirmed a retropharyngeal abscess, which probably occurred as a complication of the original tracheal intubation. PMID- 10101632 TI - Masseter muscle rigidity after vecuronium. AB - Masseter muscle rigidity after suxamethonium, usually occurring in children induced with halothane, is associated with malignant hyperthermia. A case is reported in which masseter muscle rigidity occurred in an adult following vecuronium. From the limited data available, this and two similar reported cases, it appears that non-depolarizing muscle relaxants can, very rarely, cause masseter muscle rigidity in adults. This masseter muscle rigidity may complicate airway management, but is unlikely to progress to generalized rigidity and malignant hyperthermia. PMID- 10101633 TI - Hepatic encephalopathy--a physostigmine-reactive central anticholinergic syndrome? AB - This report describes an association between hepatic encephalopathy and central anticholinergic syndrome (CAS). A 60-year-old anaemic woman was admitted unconscious and with a delayed reaction to pain but with no focal neurological deficits. She had signs of portal hypertension and a history of non-alcoholic liver cirrhosis grade Child B. Suspecting upper gastro-intestinal bleeding, she was intubated for gastro-duodenoscopy and a fibrin-covered ulcer was revealed. Raised intra-abdominal pressure resulting from ascites caused cardiopulmonary failure, which required mechanical ventilation for 24 h, but extubation was possible after drainage of the ascites and blood volume replacement therapy. However, her neurological state remained unchanged despite normal blood ammonia concentration and no sedation. CAS was considered and physostigmine injected with immediate effect. The patient opened her eyes immediately and was fully orientated to personal and medical history. We suggest that hepatic encephalopathy may trigger CAS, although the significance of physostigmine in the treatment of hepatic encephalopathy remains to be addressed by controlled investigations. PMID- 10101634 TI - Comparison of intrathecal morphine and continuous femoral 3-in-1 block for pain after major knee surgery under spinal anaesthesia. PMID- 10101636 TI - MR imaging of musculoskeletal trauma to the pelvis and the lower limb. AB - Magnetic resonance imaging can be used in the trauma setting to detect fractures and associated soft tissue injuries of the musculoskeletal system. Magnetic resonance imaging complements plain radiography and CT for evaluating cancellous bone, cartilage and growth-plate injuries, and intra- and extraarticular supporting soft tissue structures. This review outlines typical applications and imaging consideration for injuries of the pelvis and lower extremity. PMID- 10101637 TI - Follow-up of musculoskeletal tumours. 2. Metastatic disease. AB - Both the prognosis and the morbidity of a patient with a primary malignant musculoskeletal tumour have improved over the past 25 years due to the advent of adjuvant chemotherapy and limb-sparing surgery. This has important implications for the role of imaging at the time of initial diagnosis and during follow-up. This pictorial essay reviews the imaging and pitfalls in the interpretation of musculoskeletal sarcoma metastases using a variety of radiological techniques. The optimal imaging strategy will be stressed. PMID- 10101638 TI - Real-time MR-guided joint puncture and arthrography: preliminary results. AB - The purpose of this study was to evaluate interactive MR-guided joint puncture with intra-articular application of contrast agent. MR-guided arthrography of the shoulder joint was successfully performed in three patients using an interactive guidance system implemented in an open-configuration MR system. Visualization of the needle pathway and contrast inflow was comparable to that with conventional X ray fluoroscopy. The position of the intra-articular needle tip was accurately confirmed and subsequent MR arthrography was diagnostic in all cases. PMID- 10101639 TI - Extramedullary hematopoiesis related to Paget's disease. AB - Extramedullary hematopoiesis usually occurs in hematological diseases but may also be found as an uncommon complication of Paget's disease, probably due to bone effraction mechanism. We present a case of intrathoracic extramedullary hematopoiesis related to Paget's disease. To our knowledge, this is the seventh case reported in the literature. We describe and correlate the conventional X ray, CT, MR imaging, and cytological findings. PMID- 10101640 TI - Diffuse metastatic infiltration of a carcinoma into skeletal muscle. AB - Skeletal muscle is one of the most unusual sites of metastasis from any malignancy. We report a patient with rapidly progressive contractures due to metastatic infiltration of a carcinoma of unknown origin into the skeletal muscle. This 61-year-old man presented with a 1-month history of rapidly evolving, painful restriction of mobility of his right arm and his legs. Computed tomography showed diffuse metastatic nodules in all muscles, particularly in the hip abductors. Muscle biopsy revealed extensive infiltration of the muscle with carcinoma cells. PMID- 10101641 TI - Clinical applications of functional MRI at 1.0 T: motor and language studies in healthy subjects and patients. AB - In this article we describe clinical applications of functional MRI (fMRI) at 1.0 T. All experiments were performed on a commercially available 1.0-T system (Magnetom Impact Expert, Siemens AG, Erlangen, Germany) using a blood oxygen level-dependent (BOLD)-sensitive multi-slice EPI technique (TE 66 ms, 4 mm slice thickness, 210 mm field of view, 64 x 64 acquisition matrix). Different paradigms for localization of the motor cortex and for language lateralization were tested in healthy subjects and patients. Methodological considerations concerning the development of the paradigms are also described. In all healthy subjects, motor activation elicited BOLD signal changes in the sensorimotor cortex, permitting identification of primary motor and sensory cortical areas. Furthermore, focal activation of different cortical areas by a language task was possible in 6 of 10 subjects. Nineteen motor studies were performed in 18 patients with supratentorial lesions, in most cases prior to neurosurgical procedures. In 14 studies, fMRI results demonstrated the localization of the motor hand areas relative to the lesion. The results proved valuable for preoperative planning and contributed to therapeutical decisions. We conclude that functional MRI for clinically relevant applications, such as localization of motor and language function, is feasible even at a field strength of 1.0 T without dedicated equipment. PMID- 10101643 TI - Preliminary experience with interactive guided brain biopsies using a vertically opened 0.5-T MR system. AB - The purpose of our study was to evaluate the feasibility and accuracy of brain biopsies performed within a vertically opened MR system. We worked with the interventional 0.5-T MR "SIGNA SP" (General Electric Medical Systems, Milwaukee, Wis.) with an integrated tracking device "Flashpoint Position Encoder" (Image Guided Technologies, USA). As a holding device for this instrument we constructed a special frame. The whole system allows an exact adjustment of an optimum biopsy direction and guidance of the biopsy in a non-stereotactic, interactive mode in near real-time. As biopsy tools we used MR-compatible aspiration and specially made side-cut needles (Daum, Germany; E-Z-EM, USA). We performed a prospective diagnostic brain biopsy study in 18 patients. Guidance of the needle was carried out using gradient-echo single-slice technique. The sample was taken after controlling the exact position of the needle tip on spin-echo images. In 12 cases an exact neuropathological diagnosis was possible. In 6 cases of negative biopsy (4 aspiration biopsies) the samples were not representative. Our results demonstrate the feasibility of interactive MR-guided minimally invasive brain biopsies in an open MR system. The best results were achieved using cut needles for biopsies of contrast-enhancing lesions visible on T1-weighted gradient-echo guidance sequence. PMID- 10101642 TI - Echo planar perfusion imaging with high spatial and temporal resolution: methodology and clinical aspects. AB - The purpose of the present study was to analyse specific advantages of calculated parameter images and their limitations using an optimized echo-planar imaging (EPI) technique with high spatial and temporal resolution. Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) was performed in 12 patients with cerebrovascular disease and in 13 patients with brain tumours. For MR imaging of cerebral perfusion an EPI sequence was developed which provides a temporal resolution of 0.68 s for three slices with a 128 x 128 image matrix. To evaluate DSC-MRI, the following parameter images were calculated pixelwise: (1) Maximum signal reduction (MSR); (2) maximum signal difference (delta SR); (3) time-to peak (Tp); and (4) integral of signal-intensity-time curve until Tp (SInt). The MSR maps were superior in the detection of acute infarctions and delta SR maps in the delineation of vasogenic brain oedema. The time-to-peak (Tp) maps seemed to be highly sensitive in the detection of poststenotic malperfused brain areas (sensitivity 90%). Hyperperfused areas of brain tumours were detectable down to a diameter of 1 cm with high sensitivity (> 90%). Distinct clinical and neuroradiological conditions revealed different suitabilities for the parameter images. The time-to-peak (Tp) maps may be an important advantage in the detection of post-stenotic "areas at risk", due to an improved temporal resolution using an EPI technique. With regard to spatial resolution, a matrix size of 128 x 128 is sufficient for all clinical conditions. According to our results, a further increase in matrix size would not improve the spatial resolution in DSC-MRI, since the degree of the vascularization of lesions and the susceptibility effect itself seem to be the limiting factors. PMID- 10101644 TI - 'Nonportal' splanchnic venous supply to the liver: abnormal findings on CT, US and MRI. PMID- 10101645 TI - CT of blunt trauma of the pancreas in adults. AB - In order to describe the CT findings in pancreatic injury and to evaluate the sensitivity of this technique, we performed a retrospective study. During a 5 year period (1993-1997), eight patients (five males and three females: age range 10-47 years) were investigated with CT. Endoscopicretrograde cholangiopancreatography (ERCP) was obtained in two patients, pre- and intra operatively, respectively. Among the standard laboratory tests obtained at admission, the value of serum amylase was reviewed. The imaging findings, especially those obtained with CT, were correlated with the surgical findings, when available (in seven of eight patients). At admission, diagnosis of pancreatic injury was missed at CT in three of eight patients (37.5%); thus, the sensitivity of CT for pancreatic injury was 62.5%. ERCP showed rupture of the pancreatic duct in the two cases in which it was performed. Serum amylase was elevated at admission in four of eight patients, resulting in a sensitivity of 50%. After surgery, an enterocutaneous fistula developed in one case, and was managed conservatively. One patient died from brain injury. Proper implementation of the CT technique and accurate film reading is mandatory to establish the diagnosis of pancreatic contusion. No correlation between CT features and type of outcome of surgical management could be established. On retrospective review of the CT examinations, it appeared that two of the three false-negative results could have been avoided. Therefore, proper CT technique and accurate film reading are mandatory in establishing the diagnosis of pancreatic injury. PMID- 10101646 TI - CT of hemodynamically unstable abdominal trauma. AB - This article is an appraisal of the use of CT in the management of patients with unstable abdominal trauma. We examined 41 patients with abdominal trauma using noncontrast dynamic CT. In 17 patients a postcontrast dynamic CT was also carried out. On CT, 25 patients had hemoperitoneum. Thirteen patients had splenic, 12 hepatic, 6 pancreatic, 8 bowel and mesenteric, 12 renal and 2 vascular injuries. Seven patients had retroperitoneal and 2 patients adrenal hematomas. All but five lesions (three renal, one pancreatic, and one splenic) were hypodense when CT was performed earlier than 8 h following the injury. Postcontrast studies (n = 17), revealed 4 splenic, 3 hepatic, 1 pancreatic, 3 renal, and 2 bowel and mesenteric injuries beyond what was found on noncontrast CT. Surgical confirmation (n = 21) was obtained in 81.81% of splenic, 66.66% of hepatic, 83.33% of pancreatic, 100% of renal, 100% of retroperitoneal, and 85.71% of bowel and mesenteric injuries. The majority of false diagnoses was obtained with noncontrast studies. Computed tomography is a remarkable method for evaluation and management of patients with hemodynamically unstable abdominal trauma, but only if it is revealed in the emergency room. Contrast injection, when it could be done, revealed lesions that were not suspected on initial plain scans. PMID- 10101647 TI - A case of bleeding gastric lipoma: US, CT and MR findings. AB - We report a case of gastric lipoma which manifested with an episode of acute gastrointestinal hemorrhage. Preoperative diagnosis was based on the US, CT, and MRI findings, as the results of gastrointestinal endoscopy were inconclusive. The role of current imaging methods, and particularly of MRI, is discussed. PMID- 10101648 TI - Multiple hepatic angiolipomas: a case report and review of literature. AB - Follow-up of two hepatic angiolipomas in a patient without evidence of tuberous sclerosis is reported. Initially, the lesions presented as homogenously enhancing masses, which were nearly isodense to normal liver tissue on plain CT scans. Focal nodular hyperplasia was assumed. One year later, fat was detected in the growing tumors and percutaneous core biopsy revealed hepatic angiolipomas. Natural history of these rare lesions is unknown, and this is to the best of our knowledge the first observation of fatty metamorphosis in such a benign, mesenchymal hepatic neoplasm. PMID- 10101649 TI - Update on diagnostic strategies of pulmonary embolism. AB - Acute pulmonary embolism is a frequent disease with non-specific findings, high mortality, and multiple therapeutic options. A definitive diagnosis must be established by accurate, non-invasive, easily performed, cost-effective, and widely available imaging modalities. Conventional diagnostic strategies have relied on ventilation-perfusion scintigraphy complemented by venous imaging. If the results are inconclusive, pulmonary angiography, which is regarded as the gold standard, is to be performed. Recently, marked improvements in CT and MRI and shortcomings of scintigraphy led to an update of the diagnostic strategy. Spiral CT is successfully employed as a second-line procedure to clarify indeterminate scintigraphic results avoiding pulmonary angiography. It can also be used as a first-line screening tool if service and expertise is provided. Venous imaging is indicated if CT is inconclusive. The MRI technique can be applied as an alternative second-line test if spiral CT is not available or is contraindicated. It has the greatest potential for further developments and refinements. Echocardiography should be used as a first-line bedside examination in critical patients. If inconclusive stabilized patients undergo spiral CT, unstable patients should be referred for pulmonary angiography. Chronic thromboembolic pulmonary hypertension is a rare sequela of acute pulmonary embolism which can be cured surgically. Morphology, complications, and differential diagnoses are better illustrated by spiral CT and MRA, whereas invasive acquisition of hemodynamic data is the sole advantage of angiography. PMID- 10101650 TI - Validity of pulmonary cine arteriography for the diagnosis of pulmonary embolism. AB - The aim of this study was to assess the interobserver variations in diagnosis of pulmonary embolism (PE) with cine technique and to compare the diagnostic accuracy of pulmonary arteriograms to final-outcome diagnosis. One hundred and seventy patients with clinical suspicion of acute PE were examined with ECG, laboratory tests, chest X-ray, pulmonary scintigraphy and selective pulmonary cine arteriography. The follow-up time was 6 months. Fifty-one arteriograms were interpreted as positive for PE. Two pulmonary emboli were missed when compared with the diagnosis as stated by the final-outcome committee. No arteriograms were considered as not of diagnostic quality. Mean interobserver agreement in lobar vessels was 100%, in segmental vessels 93% and in subsegmental vessels 63%. The mean interobserver agreement was 89%. Pulmonary cine arteriography produces high diagnostic accuracy and few inconclusive results in patients with suspected PE. PMID- 10101651 TI - Detection of pulmonary nodules with overlapping vs non-overlapping image reconstruction at spiral CT. AB - The aim of this study was to analyze whether overlapping image reconstruction increases numbers of pulmonary nodules detected at helical CT. Forty-eight helical CT scans (21 with a slice thickness of 10 mm; 27 with a slice thickness of 5 mm) of patients with known pulmonary nodules were reconstructed both with overlapping and non-overlapping image reconstruction. Two readers recorded number and size of pulmonary nodules as well as diagnostic confidence. With overlapping image reconstruction each reader diagnosed more pulmonary nodules (slice thickness 10 mm: +24.0 and +26.7%, both p < 0.01; slice thickness 5 mm: +9.5 and +11.9%, both not significant) and more "definite" nodules (slice thickness 10 mm: +20.3%, p < 0.05, and +30.8%, p < 0.005; slice thickness 5 mm: +18.0 and +17.0%, both p < 0.05). Nodules diagnosed with overlapping image reconstruction only were almost exclusively smaller than the slice thickness. The increase in number of nodules detected was not associated with a decrease in diagnostic confidence. Overlapping image reconstruction improves detection of pulmonary nodules smaller than the slice thickness at spiral CT. PMID- 10101652 TI - Exogenous lipoid pneumonia: high-resolution CT findings. AB - The aim of this study was to assess high-resolution computed tomography (HRCT) findings of exogenous lipoid pneumonia. High-resolution computed tomography was obtained in 25 patients with proven exogenous lipoid pneumonia resulting from aspiration of squalene (derived from shark liver oil). Diagnosis was based on biopsy (n = 9), bronchoalveolar lavage (n = 8), or sputum cytology and clinical findings (n = 8). The clinical history of taking squalene was confirmed in all patients. The CT findings were classified into three patterns: diffuse ground glass opacity, consolidation, and interstitial abnormalities. Distribution of the abnormalities, duration of taking squalene, predisposing factors for aspiration, and route of administration were analyzed. Ten patients showed diffuse ground glass opacity pattern. Seven of 10 patients had predisposing conditions such as unconsciousness, pharyngeal dysmotility, or motor disturbances, and 6 patients had a recent history of taking large amount of squalene through nasal route. Seven patients who had consolidation pattern had a history of taking squalene for several months and did not have any predisposing factor. All of the 5 patients who had a pattern of interstitial abnormalities had a history of taking squalene longer than 1 year and showed segmental distribution of interstitial thickening with interposing ground-glass opacities. Three patients simultaneously had two different patterns at different lobes of the lung. The HRCT findings of lipoid pneumonia are ground-glass opacities, consolidation, and interstitial abnormalities. These HRCT findings with appropriate inquiries could be useful for diagnosis of exogenous lipoid pneumonia. PMID- 10101653 TI - CT-guided intratumoral gene therapy in non-small-cell lung cancer. AB - The objective of this study was to prove the principle of CT-guided gene therapy by intratumoral injection of a tumor suppressor gene as an alternative treatment approach of incurable non-small-cell lung cancer. In a prospective clinical phase I trial six patients with non-small-cell lung cancer and a mutation of the tumor suppressor gene p53 were treated by CT-guided intratumoral gene therapy. Ten milliliters of a vector solution (replication-defective adenovirus with complete wild-type p53 cDNA) were injected under CT guidance. In four cases the vector solution was completely applied to the tumor center, whereas in two cases 2 ml aliquots were injected into different tumor areas. For the procedure the scan room had been approved as a biosafety cabinet. Gene transfer was assessed by reverse transcription and polymerase chain reaction in biopsy specimens obtained under CT guidance 24-48 h after therapy. Potential therapeutic efficacy was evaluated on day 28 after treatment using spiral CT. The CT-guided gene therapy was easily performed in all six patients without intervention-related complications. Besides flu-like symptoms, no significant adverse effects of gene therapy were noted. Three of the four patients with central injection exhibited gene transfer in the posttreatment biopsy. Gene transfer could not be proven in the two patients with multiple 2 ml injections. After 28 days, four of the six patients showed stable disease at the treated tumor site, whereas other tumor manifestations progressed. Computed tomography-guided injections are an adequate and easy-to-perform procedure for intratumoral gene therapy. PMID- 10101654 TI - CT angiography. AB - The advent of spiral (helical, volume) CT has revolutionised the performance of body CT and allowed the development of CT angiography (CTA). CT angiography is a non-invasive method of visualising the vascular system and in some instances can replace conventional angiography. In spiral CT a volume of data is obtained rapidly with no respiratory misregistration at peak vascular opacification following the peripheral injection of contrast. Appropriate timing will ensure that either the venous or arterial tree is visualised and from the volume of data multiple overlapping slices can be obtained to generate 2D and 3D images with no increase in radiation to the patient. CT angiography may be performed as a dedicated study or be undertaken retrospectively using post-processing of data from a conventional diagnostic spiral scan to provide additional information about the vascular tree. When undertaken as a dedicated study CTA is quicker, less invasive and less costly than a conventional angiogram with a decrease in the radiation dose to the patient; however, the spatial resolution is limited with vessels less than 2 mm not visualised and there is no contrast saving. PMID- 10101655 TI - Right aortic arch with aberrant left innominate artery: MR imaging findings. AB - A rare case of a 60-year-old man with a right aortic arch and aberrant left innominate artery is presented. This case had an unusual clinical presentation. The dysphagia appeared suddenly in adulthood, whereas vascular rings, when symptomatic, usually manifest early in childhood. To our knowledge, MR imaging findings of this anomaly have never been reported. The diagnosis was made by MR imaging and confirmed by surgery. Magnetic resonance imaging can replace angiography in the assessment of the aortic arch anomalies. PMID- 10101656 TI - Artefacts in spiral-CT images and their relation to pitch and subject morphology. AB - This qualitative study is intended to create awareness of artefacts that are associated with spiral-CT imaging. A simple description of spiral-CT reconstruction is used to explain how these artefacts depend on the pitch and subject morphology, and shows when these artefacts are likely to impair the diagnostic value of the acquired images. We scanned a cone and rod phantom with pitch 2, and used the acquired images to demonstrate how spiral data acquisition and interpolation leads to artefacts in the reconstructed images. We then demonstrated the effects of various pitches in scans of a human cadaver, whereas the slice thickness was kept constant. Some patient studies are presented in order to show the possible clinical consequences. Spiral acquisition may cause geometric distortions and apparent inhomogeneity of homogeneous structures. We were able to link these artefacts to the way in the acquisitions were done, and the reconstructions were performed. We have shown how these artefacts can be anticipated in clinical studies. When areas of low contrast, surrounded by hypo- or hyperdense structures, are scanned with a large pitch and viewed with a narrow window, spiral artefacts may influence the diagnostic quality of the images. These effects should be considered when choosing the pitch. PMID- 10101657 TI - Dose reduction in CT by on-line tube current control: principles and validation on phantoms and cadavers. AB - We investigated approaches to reducing the dose in CT without impairing image quality. Dose can be reduced for non-circular object cross-sections without a significant increase in noise if X-ray tube current is reduced at angular tube positions where the X-ray attenuation by the patients is small. We investigated different schemes of current modulation during tube rotation by simulation and phantom measurements. Both pre-programmed sinusoidal modulation functions and attenuation-based on-line control of the tube current were evaluated. All relevant scan parameters were varied, including constraints such as the maximum modulation amplitude. A circular, an elliptical and two oval water phantoms were used. Results were validated on six cadavers. Dose reduction of 10-45% was obtained both in simulations and in measurements for the different non-circular phantom geometries and current modulation algorithms without an increase in pixel noise values. On-line attenuation-based control yielded higher reductions than modulation by a sinusoidal curve. The maximal dose reduction predicted any simulations could not be achieved due to limits in the modulation amplitude. In cadaver studies, a reduction of typically 20-40% was achieved for the body and about 10% for the head. Variations of our technique are possible; a slight increase in nominal tube current for high-attenuation projections combined with attenuation-based current modulation still yields significant dose reduction, but also a reduction in the structured noise that may obscure diagnostic details. We conclude that a significant reduction in dose can be achieved by tube current modulation without compromising image quality. Attenuation-based on-line control and a modulation amplitude of at least 90% should be employed. PMID- 10101658 TI - Is there still a place for angiography in the management of renal mass lesions? AB - In recent years, the development of noninvasive imaging modalities for exploration of the kidney has markedly reduced the use of angiography in the evaluation of renal masses. Presently, it is not required in routine practice to evaluate renal masses. Ultrasound is the most efficient procedure in detecting renal tumor. It is acknowledged that arteriography has a limited diagnostic and staging value compared with CT and MRI for the assessment of renal cell carcinomas (RCC). Most urologists recommend partial nephrectomy or tumor enucleation in an effort to preserve as much as possible functioning renal tissue. In such cases a preoperative map of the renal vasculature is not needed. Information on the main renal artery(ies) and segmental renal arteries can be provided with spiral CT or dynamic MR angiography. Arteriography remains useful in exceptional situations. Interventional arteriography is becoming an important part. It is indicated by means of selective embolization for the treatment of potentially bleeding tumor (i.e. angiomyolipoma) or in emergency in cases of acute hemorrhage. Less frequently, it may be proposed as a palliative procedure for inoperable patients with huge renal tumor. Two other indications of interventional arteriography are acknowledged. Some urologists request preoperative embolization of the tumor-harboring kidney to decrease/avoid extensive blood loss during surgery and/or to facilitate surgery with huge renal tumors when the renal vessels are difficult to reach. The complications of nephron-sparing surgery (partial nephrectomy or tumor enucleation) related to bleeding or arteriovenous fistulas may be cured by arterial embolization. PMID- 10101659 TI - Cryptorchidism: strategies in detection. AB - Imaging evaluation of the patient with a non-palpable testis has evolved over recent decades. The rational explanation of imaging in these patients requires a clear understanding of the various causes of a non-palpable testis, and an appreciation of the utility and limitations of the available imaging modalities. This review describes the classification of non-palpable testis and discusses the role of modern imaging in evaluation. In particular, the relative accuracies of ultrasound, CT and MRI is reviewed. PMID- 10101660 TI - Hodgkin's lymphoma: an isolated case of involvement of the ureter. AB - We report the case of a man in which a Hodgkin's lymphoma involved the ureter as the very first clinical situs of the disease. Ureteral involvement in lymphomas is very rare (0.86%-7% and 1%-16%, found in two studies, respectively, of cases of patients with lymphoma examined post mortem) and when it does occur it is secondary to renal involvement or retroperitoneal adenopathies. It is by all means exceptional as an isolated situs of disease. Those cases reported in the literature as presenting lymphomatous involvement of the ureter have always been diagnosed as Non-Hodgkin's lymphomas. PMID- 10101661 TI - Internal carotid artery transposition: another cause of widening of the retropharyngeal space. AB - We present four cases of internal carotid artery (ICA) transposition which caused widening of the retropharyngeal soft tissues. Internal carotid artery transposition is a rare cause of retropharyngeal space enlargement, which can be accurately diagnosed in a non-invasive manner with spiral CT. Radiologists should be aware of this entity in the differential diagnosis of retropharyngeal space enlargement in symptomatic (dysphagia, pulsatile mass) and asymptomatic patients, and alert the clinician of its existence, due to the risk of massive bleeding if neck surgery is to be performed. PMID- 10101662 TI - Imaging breasts with silicone implants. AB - Over the last two decades, the use of breast implants both for breast augmentation and for breast reconstruction following mastectomy has increased substantially. It is estimated that around two million women have undergone breast augmentation, while hundreds of thousands have had breast reconstruction surgery. Different types of material have been used for breast implants, but silicone gel implants have been the dominating implant type. Many implants can lead to complications, such as hardening and rupture, and may therefore need in vivo evaluation by imaging, particularly if they lead to clinical symptoms. They can also pose problems in the assessment of surrounding breast tissue by conventional mammography. In this respect, imaging modalities such as ultrasound, computed tomography and magnetic resonance imaging offer greater possibilities to assess a failing implant, as well as surrounding breast tissue. Several factors, mainly of a psychological nature, lead to requests for breast implants. In this review article, only the imaging aspects of breasts with silicone gel implants will be dealt with. Each modality is concisely presented with its possibilities and limitations. PMID- 10101663 TI - Phyllodes tumors of the breast. AB - The aim of this study was to describe the clinical, mammographic, and sonographic findings of phyllodes tumor of the breast and correlate them to the benign or malignant pathological nature of the lesion and its clinical behavior. We retrospectively reviewed the clinical, radiologic, and pathologic findings of 12 cases of phyllodes tumors diagnosed in our hospital in the past 6 years, 6 of which were malignant. The surgical management and clinical course of the patients were also reviewed. Mammographically, soft tissue masses ranging from 2.5 to 15 cm were present in all patients. One patient had a mixed fat and water density mass and 2 patients had masses associated with coarse calcifications. At sonography, all tumors were well circumscribed; two of them were homogeneously hypoechoic, and the rest had heterogeneous internal echoes. Eight patients showed internal cystic areas. None of these characteristics proved to be useful in ascertaining the benign or malignant nature of the tumor. At surgery, 5 patients underwent mastectomy and 7 patients local excision of the tumor. Three of the later tumors, one benign and two malignant, recurred after several months. Fine needle aspiration biopsy suggested the diagnosis of phyllodes tumor in only 3 cases. After surgery, six tumors were classified as benign and six as malignant, three of which being of low-grade malignancy. None of the clinical or radiologic characteristics of the tumors were useful in predicting their histological nature or their behavior after surgery. Preoperative fine-needle aspiration biopsy often misdiagnosed the tumor as benign fibroadenoma. Only the histopathologic features of the excised mass proved to be helpful in assessing malignancy. PMID- 10101664 TI - Quiz case of the month. The diagnosis was the complete form of pachydermoperiostosis (primary hypertrophic osteoarthropathy). PMID- 10101665 TI - A point of view about "point of view". PMID- 10101666 TI - Tips for writing a scientific paper. PMID- 10101667 TI - Music! Music! Music! PMID- 10101668 TI - The role of music in physiologic accommodation. PMID- 10101669 TI - Human psychophysiological perception of musical scales and nontraditional music. PMID- 10101670 TI - The Lambdoma matrix and harmonic intervals. PMID- 10101671 TI - The infrared frequencies of DNA bases: science and art. PMID- 10101672 TI - Music for health: the five elements tonal system. PMID- 10101673 TI - The emerging field of sound training. PMID- 10101674 TI - The effects of vibroacoustic music on symptom reduction. PMID- 10101675 TI - The connection between rhythmicity and brain function. AB - Although rhythm and music are not entirely synonymous terms, rhythm constitutes one of the most essential structural and organizational elements of music. When considering the effect of music on human adaptation, the profound effect of rhythm on the motor system strongly suggests that the time structure of music is the essential element relating music specifically to motor behavior. Why the motor system appears so sensitive to auditory priming and timing stimulation can only be partially answered so far. The high-performance function of the auditory system regarding processing of time information makes good functional sense within the constraints of auditory sensory processing. Thus, the motor system sensitivity to auditory entrainment may simply be an evolutionary useful function of taking advantage of the specific and unique aspects of auditory information processing for enhanced control and organization of motor behavior; e.g, in the time domain. Unlike processes in the motor system, many other physiological processes cannot be effectively entrained by external sensory stimuli. For example, there is probably a very good protective reason why other cyclical physiological processes (e.g., autonomic processes such as heart rate) have only very limited entrainment capacity to external rhythmic cues. Some of the basic auditory-motor arousal connections may also have their basis in adaptive evolutionary processes related to survival behavior; e.g., in fight or flight reactions. Much of the "why" in auditory-motor interactions, however, remains unknown heuristically. In the absence of this knowledge, great care should be taken to not compensate for this lack of understanding of specific cause and effect processes by assigning anthropomorphic descriptions to the behavior of biological and physical systems. The unraveling of the perceptual, physiological, and neuroanatomical basis of the interaction between rhythm and movement has been, and continues to be, a fascinating endeavor with important ramifications for the study of brain function, sensory perception, and motor behavior. One of the most exciting findings in this research, however, may be the evidence that the interaction between auditory rhythm and physical response can be effectively harnessed for specific therapeutic purposes in the rehabilitation of persons with movement disorders. PMID- 10101676 TI - Is there a link between exposure to power-frequency electric fields and cancer? PMID- 10101677 TI - The Baltimore case. PMID- 10101678 TI - A proximal CCD imaging system for high-throughput detection of microarray-based assays. PMID- 10101679 TI - The Biomaterials Access Assurance Act of 1998. PMID- 10101680 TI - The role of CTLA-4 in the regulation of T cell immune responses. AB - Over the past few years a great deal of research has examined how T cell dependent immune responses are initiated and subsequently regulated. Ligation of the TCR with an antigenic peptide bound to an MHC protein on a professional APC provides the crucial antigen-specific stimulus required for T cell activation. Interaction of CD28 with CD80 or CD86 molecules on APC initiates a costimulatory or second signal within the T cell which augments and sustains T cell activation initiated through the TCR. However, recently it has become clear that T cell immune responses are a result of a balance between stimulatory and inhibitory signals. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface molecule that is expressed nearly exclusively on CD4+ and CD8+ T cells. Investigation into the role of CTLA-4 in the regulation of T cell immune responses has revealed that CTLA-4 is a very important molecule involved in the maintenance of T cell homeostasis. In the present review, evidence for the proposed inhibitory role of CTLA-4 is examined and a model suggesting a role for CTLA-4 in both early and late stages of T cell activation is presented. PMID- 10101681 TI - Expression of apoptotic regulatory molecules in renal cell carcinoma: elevated expression of Fas ligand. AB - Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO-1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated. PMID- 10101682 TI - Isolation and characterization of monoclonal antibodies directed against murine FRP-1/CD98/4F2 heavy chain: murine FRP-1 is an alloantigen and amino acid change at 129 (P<-->R) is related to the alloantigenicity. AB - Nineteen mAb directed against murine fusion regulatory protein-1 (mFRP 1)/4F2/CD98 were isolated and their biological properties were analysed. Intriguingly, mFRP-1 was found to be an alloantigen, namely, FRP-1.1 (DBA/2 and CBA mice type) and FRP-1.2 (BALB/c, C57BL/6 and C3H/He mice type). The nucleotide sequences of FRP-1.1 and FRP-1.2 were determined, demonstrating that amino acid change at 129 (P<-->R) is related to the alloantigenicity. mFRP-1 is expressed on thymocytes, on spleen cells, on peripheral lymphocytes and on blood monocytes, suggesting that the physiological role in vivo of murine FRP-1 is different from that of human FRP-1. The biological activities of antimFRP-1 mAbs showed by the present study are: (i) enhancement of Newcastle disease virus-induced cell fusion; (ii) suppression of HIVgp160-mediated cell fusion; and (iii) induction of aggregation and multinucleated giant cells of monocytes/macrophages. PMID- 10101683 TI - Physiological effects and adjuvanticity of recombinant brushtail possum TNF alpha. AB - The present paper describes the physiological properties of recombinant possum TNF-alpha and an adjuvant effect on antibody responses to the model protein antigen, keyhole limpet haemocyanin (KLH). For these studies recombinant possum TNF-alpha was produced in the yeast Pichia pastoris. The recombinant cytokine was secreted into the culture medium and purified by gel filtration. Possum TNF-alpha produced in this expression system was N-glycosylated and bioactive in two different assays. In a murine fibroblast L929 cytotoxicity assay, the possum TNF alpha had lower specific activity compared to human TNF-alpha, while in a possum specific assay, possum TNF-alpha enhanced the proliferation of PHA-stimulated possum thymocytes and was more active than human TNF-alpha. The physiological effect of the recombinant possum TNF-alpha was investigated in groups of possums administered doses of 6, 30 or 150 micrograms of cytokine. For each dose, TNF alpha caused profound effects on the numbers of circulating leucocytes characterized by a three-to-four-fold increase in neutrophil numbers at 6-24 h after injection and an initial sharp decrease in lymphocyte numbers. The efficacy of TNF-alpha as an immunological adjuvant was determined in possums administered KLH (125 micrograms) in an aqueous or Al(OH)3-based formulation with or without added recombinant TNF-alpha (150 micrograms). Serum antibody responses to KLH were monitored by ELISA. The TNF-alpha stimulated two-fold and four-fold increases in antibody levels in aqueous and Al(OH)3-based vaccine formulations, respectively. The strongest antibody responses were observed in the group of possums that received KLH formulated in Al(OH)3 with addition of TNF-alpha. PMID- 10101684 TI - Western blot analysis of bile or intestinal fluid from patients with septic shock or systemic inflammatory response syndrome, using antibodies to TNF-alpha, IL-1 alpha and IL-1 beta. AB - Septic shock or systemic inflammatory response syndrome (SIRS) often develops in patients following burns, traumatic injury, surgery or biliary obstruction. Although the inflammatory cytokines TNF-alpha and IL-1 have been strongly implicated in the development of these syndromes, treatment of patients by the systemic administration of inhibitors of TNF-alpha or IL-1 has shown limited effectiveness. Recent reports suggest that septic shock may be perpetuated by inflammatory cytokines secreted by the liver in response to bacterial translocation resulting from cytokine-induced gastrointestinal damage. The present study sought to demonstrate the presence of high levels of inflammatory cytokines in the bile or small intestine of patients suffering from septic shock or SIRS, with a view to the development of strategies for the reduction of gastrointestinal damage through intraduodenal administration of cytokine inhibitors. Western blot analysis of human bile or intestinal fluid using anti TNF-alpha antibodies resulted in the detection of a number of bands in samples from patients with septic shock or SIRS. However, these proteins differed antigenically from human recombinant TNF-alpha (rTNF-alpha) and showed no activity in a biological assay for TNF-alpha. Antibodies to IL-1 alpha and IL-1 beta detected several strong bands, some of which appeared to be identical to recombinant IL-1 alpha and IL-1 beta. It is concluded that proteins resembling several known inflammatory cytokines are present in the bile and intestine of septic shock patients, but it is suggested that further work is required to determine the nature and function of these molecules. PMID- 10101685 TI - Signalling by CD95 and TNF receptors: not only life and death. AB - Members of the TNF family of receptors play important roles in normal physiology and in defence. The recent rapid progress in the understanding of the mechanisms of apoptosis has been accompanied by assumptions that TNF family receptors such as CD95(Fas/APO-1) only have a role in regulating cell survival. While regulation of cell death is one important function of TNF family receptors, they are capable of activating signal transduction pathways that have many other effects. The present review will focus on signalling of some TNF family receptors in the immune system, not only for apoptosis, but also for survival or activation. PMID- 10101686 TI - Regulation of pro-apoptotic leucocyte granule serine proteinases by intracellular serpins. AB - Caspase activation and apoptosis can be initiated by the introduction of serine proteinases into the cytoplasm of a cell. Cytotoxic lymphocytes have evolved at least one serine proteinase with specific pro-apoptotic activity (granzyme B), as well as the mechanisms to deliver it into a target cell, and recent evidence suggests that other leucocyte granule proteinases may also have the capacity to kill if released into the interior of cells. For example, the monocyte/granulocyte proteinase cathepsin G can activate caspases in vitro, and will induce apoptosis if its entry into cells is mediated by a bacterial pore forming protein. The potent pro-apoptotic activity of granzyme B and cathepsin G suggests that cells producing these (or other) proteinases would be at risk from self-induced death if the systems involved in packaging, degranulation or targeting fail and allow proteinases to enter the host cell cytoplasm. The purpose of the present review is to describe recent work on a group of intracellular serine proteinase inhibitors (serpins) which may function in leucocytes to prevent autolysis induced by the granule serine proteinases. PMID- 10101687 TI - Targeted disruption of caspase genes in mice: what they tell us about the functions of individual caspases in apoptosis. AB - Cysteine proteases of the caspase family are crucial mediators of apoptosis. All mammalian cells contain a large number of caspases. Although many caspases are activated in a cell committed to apoptosis, recent data from caspase gene knockout mice suggest that individual caspases may be involved in the cell and stimulus-specific pathways of cell death. The gene disruption studies also establish the functional hierarchy between two structurally distinct classes of caspases. The present review discusses these recent findings and elaborates on how these mutant mouse models have helped the understanding of the mechanisms that govern programmed cell death in the immune and other systems. PMID- 10101688 TI - NK cells and apoptosis. AB - Natural killer (NK) cells are a cell of the innate immune system that play an important role in the early response to viral infections and tumours. Natural killer cells are cytolytic, and secrete cytokines that influence the developing antigen-specific immune response. In the present article the NK cell surface molecules regulating effector function, the NK cell effector mechanisms involved in apoptosis, and the role of NK cell effector mechanisms in immune responses are reviewed. PMID- 10101689 TI - Anti-viral strategies of cytotoxic T lymphocytes are manifested through a variety of granule-bound pathways of apoptosis induction. AB - Cytotoxic T cells and natural killer cells together constitute a major defence against virus infection, through their ability to induce apoptotic death in infected cells. These cytolytic lymphocytes kill their targets through two principal mechanisms, and one of these, granule exocytosis, is essential for an effective in vivo immune response against many viruses. In recent years, the authors and other investigators have identified several distinct mechanisms that can induce death in a targeted cell. In the present article, it is postulated that the reason for this redundancy of lethal mechanisms is to deal with the array of anti-apoptotic molecules elaborated by viruses to extend the life of infected cells. The fate of such a cell therefore reflects the balance of pro apoptotic (immune) and anti-apoptotic (viral) strategies that have developed over eons of evolutionary time. PMID- 10101690 TI - Does HIV cause depletion of CD4+ T cells in vivo by the induction of apoptosis? AB - The central pathogenic feature of AIDS is the dramatic loss of CD4+ lymphocytes. Despite more than a decade of intense research, the exact mechanism by which HIV causes this is still not understood. A major model for T cell depletion, proposed originally by Ameison and Capron in a report published in 1991, is that HIV sensitizes CD4+ T cells for activation-induced apoptosis. The apoptotic model of T cell depletion is discussed, and experiments that address the questions of whether apoptosis is restricted to infected cells or 'bystander' T cells, and whether T cell apoptosis requires participation of separate HIV-infected haematopoietic cell populations, are reviewed. PMID- 10101692 TI - [Theombolysis with GP IIb/IIIa-receptor blockader. Platelt aggregation inhibition: clear indications, new strategies]. PMID- 10101691 TI - MHC multimerization, antigen expression and the induction of APC amnesia in the developing immune response. AB - Class II multimer formation is an important event in immune recognition. Not only is multimerization a prerequisite for T cell activation, but it is a signal to APC. In the present article, we propose that multimerization can result in the specific removal of ligand complexes from the cell surface of the APC, an event which may influence the overall pattern of T cell reactivity. PMID- 10101693 TI - [Tegafur/uracil and oral calcium folinate in colorectal cancer]. PMID- 10101694 TI - Changes in public health policy related to fluoride concentrations in public water supplies. PMID- 10101695 TI - Fluoride--an element in good company. PMID- 10101696 TI - Oral functional limitation among dentate adults. AB - OBJECTIVES: The purpose of this study was to measure the prevalence of oral functional limitation in adults and to identify clinical and sociodemographic factors associated with that limitation. METHODS: The Florida Dental Care Study is a longitudinal study of risk factors for changes in oral health. Subjects (n = 873) with at least one tooth who were 45 years old or older participated in a baseline in-person interview and dental examination. Subjects were queried about oral functional limitations. RESULTS: Twenty-three percent of subjects reported difficulty chewing one or more foods using a five-item chewing index, and 10 percent reported difficulty speaking or pronouncing words because of problems with the mouth. The covariates in a multiple logistic regression identified as being significantly associated with chewing difficulty were fewer pairs of occluding anterior teeth, fewer pairs of occluding posterior teeth, more posterior teeth that are root tips, more anterior teeth that are mobile, reporting tooth pain, reporting bad breath, having but not wearing prosthetic appliances, reporting dry mouth, and being female. Having fewer anterior teeth, reporting a sore and/or broken denture, reporting unattractive teeth, and being black were significantly associated with speaking difficulty/difficulty pronouncing words because of problems with the teeth, mouth, or dentures. CONCLUSIONS: The findings in this study suggest a significant prevalence of oral functional limitation in dentate adults. Certain clinical and sociodemographic factors were strongly and independently associated with its presence. PMID- 10101697 TI - Descriptive models of restorative treatment decisions. AB - OBJECTIVES: This study developed descriptive models of dentists' restorative treatment decisions for individual teeth. Such models could be useful in personnel planning, in assessing the effects of dental treatment programs, and in furthering understanding of dentists' decision-making processes. METHODS: Logistic regression was used to construct models of the probability of individual teeth receiving a recommendation for restorative treatment. Independent variables for the models were data from epidemiologic oral examinations and self administered questionnaires of subjects who were seeking treatment at a dental school. Data for the dependent variable, the probability of treatment, were collected from multiple dentists' treatment plans of these subjects. Separate models were constructed for molar, premolar, and anterior teeth. An assessment of the models' utilities in a different population consisted of comparing the treatment probabilities estimated by the models with those actually experienced by a community sample of 317 individuals who visited dentists in the 18 months following our examination. RESULTS: Constructed models for molar, premolar, and anterior teeth returned kappa values of 0.60, 0.62, and 0.65, respectively, for the original data set. The models were less accurate in identifying which teeth received treatment among subjects in the community sample, with kappas of 0.10, 0.18, and 0.20, respectively. CONCLUSIONS: Models of dentists' restorative treatment decision making based on clinical and nonclinical data can determine the probability of treatment for individual teeth with reasonable accuracy. Hence, the approach holds promise for developing measures of normative treatment need. However, the models are not accurate predictors of dichotomous decisions by individual dentists regarding treatment interventions. Both differences in the subject samples used to develop and assess the models and individual dentist idiosyncrasies may contribute to this inaccuracy. PMID- 10101698 TI - Determinants for dental visit behavior among Hong Kong Chinese in a longitudinal study. AB - OBJECTIVES: The aim of this research was to study the major determinants for dental services utilization among middle-aged Hong Kong Chinese in a longitudinal study using an expanded Andersen and Newman model as the theoretical framework. METHODS: A random sample of 372 middle-aged Hong Kong Chinese were interviewed and clinically examined in an oral health survey. The findings were explained to the subjects and they were advised to seek care from their own dentist as appropriate. RESULTS: A total of 322 subjects were interviewed over the telephone after 12 months. About half had visited a dentist within the study period. Results of the bivariate analysis showed that proportionally more subjects who had dental benefit coverage, had prevention-oriented attitudes, were regular users of dental services, had received counseling from a dentist, or had more filled teeth at the baseline examination had visited a dentist within the study period. Logistic regression analysis produced a final model consisting of seven factors and three interaction terms that was able to classify 68 percent of the subjects into the correct user category. CONCLUSION: The expanded Andersen and Newman model was useful as a theoretical framework in studying the dental services utilization behaviors of the Hong Kong adults. PMID- 10101699 TI - Patterns of dietary fluoride supplement use during infancy. AB - OBJECTIVES: This paper reports on patterns of dietary fluoride supplement use during infancy. METHODS: Data were collected by mail for a birth cohort (n = 1,072) studied at 6 weeks and 3, 6, 9, and 12 months of age. RESULTS: Percentages using supplements were 13.7 at 6 weeks, 13.4 at 3 months, 16.5 at 6 months, 13.0 at 9 months, and 12.1 at 12 months. Among those receiving supplements, mean proportions of weeks that supplements were received during the different time periods varied from 0.59 to 0.80. Number of days per week receiving supplements averaged 4.8 to 5.0. Mean fluoride dosages when supplements were received were 0.22 mg to 0.24 mg. Estimated average daily fluoride ingestion per day (among those receiving supplements during that time period and factoring in those days and weeks that supplements were not received) was 0.11 mg at 6 weeks, 0.15 mg at 3 months, 0.12 mg at 6 months, 0.11 mg at 9 months, and 0.14 mg at 12 months. Among the subset of 129 children with complete data at all time points who used supplements sometime during their first year of life, mean annual daily supplement dosage was 0.07 mg fluoride, with 75 percent having less than or equal to 0.10 mg. Those infants with mothers and fathers with more education were more likely to receive supplements. CONCLUSIONS: Group average use of fluoride supplements was fairly consistent over the 12 months; however, individual patterns varied substantially. Estimated actual mean daily fluoride intake when including days that supplements were not received was substantially less than the recommended 0.25 mg per day. PMID- 10101700 TI - Preventive oral health behaviors among African-Americans and whites in Detroit. AB - OBJECTIVE: This study compared the preventive oral health behaviors of African Americans and whites. METHODS: Face-to-face interviews were conducted with a probability sample of 384 African-American and 358 white adults living in the greater Detroit area. Questions focused on brushing, flossing, and dental visits. RESULTS: More than 95 percent of both groups reported brushing daily; however, whites were more likely to brush all teeth, including parts that do not show. Frequency of flossing did not differ between groups. African-Americans, however, were less likely to floss all of their teeth. Whites were more likely than African-Americans to get dental check-ups at least once a year and much less likely to indicate they had never had a dental check-up. African-Americans tended to have less education and lower family income than whites and were more likely than whites to have Medicaid. Race differences in brushing thoroughness and annual check-ups were greatly reduced when income, education, and insurance were controlled statistically. CONCLUSIONS: African-Americans are less likely than whites to brush thoroughly, floss thoroughly, and get dental check-ups. These differences are partly traceable to differences in socioeconomic status and access to professional oral health care. PMID- 10101701 TI - Coverage and quality of oral cancer information in the popular press: 1987-98. AB - OBJECTIVES: National data show a lack of knowledge and misinformation about oral cancer and its early detection among the general public. A major source of health information is the popular press. For that reason this study reviewed coverage and quality of news items on the topic of oral cancer in the popular press. In addition, the number and types of tobacco advertisements in women and men's magazines were recorded for a one-year period. METHODS: Articles from magazines and newspapers were retrieved from the Magazine Index (1987 to April 1998), Newspaper Abstract (1989 to April 1998) and the Health & Wellness (1987 to April 1998) databases. The articles were analyzed both for adequacy of content and information. RESULTS: A total of 50 articles and news items including oral cancer were identified and analyzed, 18 from newspapers and 32 from magazines. Ninety four percent of the articles mentioned at least one risk factor for oral cancer. More than half of the articles (56%) identified spit tobacco (chewing tobacco or snuff) as the major risk factor for oral cancer, while far fewer mentioned either cigarettes (32%) or cigars (12%). Over 50 percent of the articles did not mention warning signs for oral cancers. Fourteen percent suggested clinical oral cancer examinations by a health professional; only 8 percent advised the use of self examination. A total of 417 tobacco advertisements (482 pages) were found among 22 magazines for the one-year period. They included 410 cigarette ads, seven cigar ads, and no spit tobacco ads. CONCLUSIONS: This study demonstrates the lack of coverage about oral cancer in the popular press in the past decade and provides a partial explanation of the public's lack of knowledge and misinformation about oral cancers. PMID- 10101702 TI - Colonization of mutans streptococci in 8- to 15-month-old children. AB - OBJECTIVE: The age at which a child becomes colonized with mutans streptococci (MS) is important for understanding early childhood caries. The aim of this study was to explore the relationship of age with MS colonization in infants. METHODS: Inner-city children (n = 149) between the ages of 8 months and 15 months, inclusive, who reportedly were still using a baby bottle, were sampled for MS. RESULTS: Evidence of MS colonization was seen as early at 10 months of age. For children 12 months old or younger (n = 80), 25 percent had detectable levels of MS; in the 15-month age group, 60 percent were colonized. CONCLUSION: This study suggests that prevention of MS colonization in some populations may need to be initiated prior to the child's first birthday. PMID- 10101703 TI - Can questionnaires replace clinical surveys to assess dental treatment needs of adults? AB - OBJECTIVE: The purpose of this study was to ascertain whether questionnaires can be used to replace clinical surveys by comparing normative and perceived caries status and treatment needs in a sample of adults living in East London, UK. METHODS: A cross-sectional study was conducted in two stages: a structured interview inquired about perceived dental caries status and treatment needs, and dental examinations were performed to determine oral health status and normative treatment needs. Perceived and normative assessments were compared for overall proportions, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), using the dental examination as a gold standard. RESULTS: Of 139 people examined, 122 were dentate. The PPVs for perceived caries and treatment need were 0.58 and 0.67, respectively. Overall agreement was 65.4 percent for the presence of caries and 64.7 percent for the presence of treatment need. However, no net error was found between the proportions of participants with decay, and a small net error (7.4%) was found between perceived and normative treatment need. CONCLUSIONS: Self-assessment is not useful to assess individual dental treatment need, but is of possible value in assessing the needs of adult communities. PMID- 10101704 TI - Clinical sealant retention following two different tooth-cleaning techniques. AB - OBJECTIVES: This study compared the effectiveness of two different tooth-cleaning techniques on clinical sealant retention. METHODS: Seventy-four children in second and third grades at an elementary school in the rural town of Waverly, Tennessee, had sealants applied to four, noncarious, fully erupted, first permanent molar teeth. The teeth had been cleaned using a brush attached to a rotary instrument with fluoridated prophy paste, versus a toothbrush without paste (dry brushing). A split-mouth design was used, whereby one side (upper and lower) of the mouth was subject to one tooth-cleaning technique while the opposite side received the other technique. RESULTS: Twelve months after a single application of pit and fissure sealant, 63 children were available for recall. Exactly 252 teeth were examined and overall retention was high, with approximately 98 percent of sealants retained. Although the greatest loss of sealant occurred with the rotary instrument technique, the difference in proportions of missing sealant between techniques was not statistically significant. CONCLUSIONS: In this study, the tooth-cleaning technique of dry brushing with a toothbrush as a preparatory step in the sealant procedure yielded high clinical sealant retention at 12 months. This retention was comparable to that observed with rotary instrumentation. This finding suggests that dry brushing by the operator may be an acceptable alternative to using a rotary instrument with brush and paste. PMID- 10101705 TI - [The foot--an important emphasis]. PMID- 10101706 TI - [Primary treatment of clubfoot]. AB - Our primary club foot therapy consists of a combination of plaster cast manipulation, physiotherapy and surgical correction. The initial plaster cast method of 4 to 6 weeks is followed by a functional mobilisation of the foot. The main aim being the reduction of the malpositioned talus in the ankle mortise. If there is residual deformity surgery is planned after six month. We use the Cincinnati approach with the possibility of the dorsal, medial and lateral release, enabling a correction of the hind-, mid- and forefoot. The main part of postoperative care is seen in the functional rehabilitation of the foot by physiotherapy, in order to achieve a cosmetic foot with good functions. Physiotherapy is advised until the child enters school in order to preserve function and form into adult life. A high frequency of satisfactory results can be expected using this protocol. PMID- 10101707 TI - [Recurrent club foot]. AB - About 25% of operated clubfeet will develop a recurrency or show a marked residual deformity. As main factor the failure of concentric reduction at the time of initial surgery has to be considered. Residual forefoot adduction and supination are the most common persistent deformities. Based on the experience with 94 recurrent/residual clubfeet (patients < 10 years) the surgical treatment at different age-groups is presented. As a general rule soft tissue release is applicable as a repeated procedure until the age of about eight to ten years. For revision in patients between two and eight years we recommend a closing wedge osteotomy of the cuboid and a tibialis transfer additional to repeated release procedures. In patients older than eight to ten years mid-tarsal osteotomies, correction according to llizarov with the external fixator or triple arthrodesis are to be considered as single or combined procedures. PMID- 10101708 TI - [Osteotomies of the mid- and back-foot in recurrent club foot]. AB - There are no clear guidelines on the treatment of relapsed clubfoot, which is a relatively frequent and difficult problem in paediatric orthopaedics. Numerous operative interventions are mentioned in the literature as suitable for correction of a residual deformity of the food. There are numerous soft tissue procedures (release operations, tendon extensions, tendon transfers and redressement by means of a fixateur externe) and osseous interventions (osteotomies, arthrodeses) that can be carried out in isolation or in combination. In the present article two types of osteotomy are described that make it possible to correct the most frequent forms of relapsed clubfoot: combined closing wedge cuboid and opening wedge cuneiform osteotomy for correction of adductus and supination of the forefoot and the calcaneal osteotomy after Dwyer for correction of varus position of the calcaneal part of the foot. The combined osteotomy in the midfoot involves shortening of the lateral ray with simultaneous lengthening of the medial ray, with the wedge out of the cuboid bone inserted into the medial cuneiform bone, which leads mainly to correction of the adductus, but does also make it possible to achieve partial correction of the supination with an osteotomy right through the cuneiform bone. In the case of rigid foot deformities it is advisable to carry out preliminary stretching by means of a fixateur externe, while in the case of a bean-shaped foot a combination of osteotomy and medial and lateral release is recommended. Results of a follow-up study of our own patients treated with this operation have shown that no revision operations were necessary in any of the patients with idiopathic clubfoot. Other types of osteotomy described in the literature as suitable for correction of residual forefoot adductus and supination are also mentioned in this paper. Thecalcaneal osteotomy after Dwyer, for which a lateral approach is always used, generally leads to satisfactory correction of varus position of the calcaneal part of the foot. It the calcaneus is found to have a short posterior part this osteotomy is modified so that instead of taking the form of a wedge osteotomy with lateral closing it is followed by a lateral displacement. In this way it is possible to prevent making the already short posterior calcaneus even shorter. Both the combined midfoot osteotomy and the calcaneal osteotomy after Dwyer can be performed alone or in combination with each other or with different operative interventions. PMID- 10101709 TI - [Polydactyly of the foot]. AB - Polydactyly may be preaxial or tibial (hallux-side), postaxial or ulnar (side of the little toe) and central (middle toes). The duplication may appear at the distal and medial phalanges or at the whole digit. The metatarsal bone may be part wise or completely duplicated, the accessory toes may share only one metatarsal. Surgical intervention may be indicated in shoe problems, for esthetic reasons or, especially in duplication of the metatarsales, because of secondary deviation of the toes and therefore shoe problems or plantar callosities. Preoperative analysis including x-ray is of great importance to achieve good functional and cosmetic results. PMID- 10101710 TI - [Abnormalities of the foot]. AB - A few selected++ metric and numeric malformations of the foot (Fibular deficiency, vertical talus, coalition, syndactylism, macrodactylism, metatarsal malformation, cleft foot, overriding fifth toe) are discussed to demonstrate, that concepts for their treatment should be developed as early as possible in order to allow for bringing those structures that are developed in optimum use. Besides function cosmetic aspects of the foot also deserve being respected. PMID- 10101711 TI - [Conservative treatment of neurogenic foot deformities]. AB - The lack of muscle control in neurological disorders often leads to deformities of the foot. The equinus (a contracture of the triceps surae muscle), the abduction and clubfoot deformity are the most common ones. The present paper describes the deformities and stresses the functional relevance for the patient. Therapeutic principles of the conservative orthopaedic means are described with special emphasis on the need of an adequate height of the aide and the foot position. Casting and the application of Botulinun toxine are described having a major side effect of muscle weakening. A combination of the different procedures, surgical interventions included, need to be selected for each patient offering the best management for each individual problem. PMID- 10101712 TI - [Soft tissue operations in neuromuscular foot deformities]. AB - The management of neuromuscular foot deformities in children and adolescents must be individualized because of differences in etiology and pathomechanics. If conservative treatment fails or reaches a plateau early soft tissue procedures are recommended. Treatment should focus not only at correction of the deformity but also at reestablishment of muscular balance. Early postoperative mobilisation is usually possible provided adequate orthotic control is maintained. Regular clinical follow-ups help to minimize postoperative problems. The general aim should be an optimization of functions and only rarely to achieve a normal foot. The basic principles of management can be described as correction of deformity, stabilization of unstable joints and balance of muscle power. PMID- 10101713 TI - [Flatfoot]. AB - Many parents are anxious because of the insufficient arch of the feet of their children. A true congenital deformity (congenital vertical talus) is extremely rare. In children the arch is physiologically flattened with a hypervalgus of the hindfoot. Those feet do not need treatment. If there is no medial recess in the footprint in a child over 3 years of age, then we are talking about a flexible flatfoot. When the load of the foot is more pronounced at the medial rather than at the lateral side, operative treatment can be indicated, such as a lengthening osteotomy of the calcaneum. If the flatfoot is rigid, the reason for it is usually a tarsal coalition. Operative transection of the osseous bridge with fat interposition can solve the problem. Flatfeet may also occur in neuromuscular diseases. Depending on the severity of the deformity, splints can be effective, or--in the more severe cases--operative treatment such as a triple arthodesis can be indicated. PMID- 10101714 TI - [Foot pain]. AB - Foot pain is a relatively common problem in children and adolescents. Most frequently the pain is localized at the heel, the mid- and forefoot are less common sites of discomfort. In this article we discuss the etiology of pain in those cases, where the foot has a normal clinical aspect. Sever's disease is most common in adolescents with strenuous athletic activity or with obesity. The calcaneal apophysis is overloaded. Usually the radiologic aspect of the calcis is normal. Treatment consists in reduction of the athletic activity, soft bedding of the heel in the shoes and reduction of weight. Avascular necrosis of the metatarsal head II or III (Freiberg's disease) is also relatively common, while necrosis of the navicular bone (Kohler's disease) is very rare. Treatment in these cases is always conservative. Pain can also originate from tarsal coalition. While in the beginning the foot has a normal aspect, lateron a rigid flatfoot can develop. In unclear cases stress fractures of the metatarsal bones, infections and tumors also have to be considered. PMID- 10101715 TI - [Drug therapy of rheumatoid arthritis]. PMID- 10101716 TI - Cytokines and antibody responses during Trypanosoma congolense infections in two inbred mouse strains that differ in resistance. AB - We studied IL-4, IL-10 and IFN-gamma secretion by splenocytes and the plasma levels of different isotypes of antibodies against various antigens of Trypanosoma congolense in highly susceptible BALB/c and relatively resistant C57BL/6 mice during the early course of infection with T. congolense. The patterns of appearance of cytokine spotforming cells in the spleens were essentially similar in the two mouse strains although higher numbers were detected in the spleens of BALB/c than C57BL/6 mice on some days post-infection. However, the amount of IL-4, IL-10 and IFN-gamma secreted into the culture fluids was dramatically different. From day 4 forward, splenocytes from BALB/c mice secreted very high levels of these cytokines. In contrast, splenocytes from infected C57BL/6 mice did not secrete detectable levels of IL-4 throughout the period tested. The secretion of IL-10 and IFN-gamma by C57BL/6 splenocytes only became appreciable on day 6 and was down-regulated by day 8, when the first wave of parasitaemia was being controlled. At days 6-8, splenocytes from infected C57BL/6 mice secreted two-fold higher amounts of IL-12 p40 than those from BALB/c mice. Infected BALB/c mice mounted an earlier IgM antibody response to variant surface glycoprotein (VSG), formalin-fixed T. congolense and whole T. congolense lysates than did infected C57BL/6 mice. However, they failed to make any detectable IgG3 and IgG2a antibody responses to these antigens whereas infected C57BL/6 mice made strong IgG3 and IgG2a responses. We speculate that enhanced resistance against T. congolense infections in mice may be mediated by IL-12 dependent synthesis of IgG2 antibodies to VSG and possibly also common trypanosomal antigens. PMID- 10101717 TI - Filarial antibody responses in Wuchereria bancrofti transmission area are related to parasitological but not clinical status. AB - In Wuchereria bancrofti transmission areas, three groups of individuals have been identified, according to the presence or absence of microfilariae or adult worm derived molecules in the blood compartment. These groups likely reflect individuals with different permissivity/resistance to the complete development of W. bancrofti cycle. The profile of filarial-specific immunoglobulins was analysed in W. bancrofti-exposed individuals in French Polynesia, according to the presence or absence of microfilariae (Mf) and adult worms, measured by Og4C3 circulating antigen. Individuals harbouring adult worms, have higher filarial specific IgG4 but lower IgG3 and IgE levels, than adult worm-free individuals, independently of the presence of Mf. Low filarial-specific IgG1 and IgG2 levels were associated with the presence of Mf but independent of the presence/absence of adult worms. The filarial antibody responses were associated with the parasitological status of individuals but not with clinical symptoms such as hydroceles or limb lymphangitis or elephantiasis. The reduction of filarial specific immunoglobulin levels was higher after treatment with diethylcarbamazine, than ivermectin, which likely reflects the better effect of the former on W. bancrofti adult worms. However, reduction of antibody levels was also observed in Mf-and adult worm-negative individuals. This could be due to the overall reduction of W. bancrofti transmission in the island where this study took place. PMID- 10101718 TI - IL-5 dominates cytokine responses during expression of protective immunity to Onchocerca lienalis microfilariae in mice. AB - In a model of protective immunity against Onchocerca microfilariae (mf), it has been demonstrated previously that immunocompetent mice clear a primary infection and are highly resistant to re-infection. This immunity correlates with CD4+ Th2 cells, is dependent on IL-5 but not IL-4, and can be transferred adoptively with spleen cells. In the current investigation, high levels of spontaneous proliferation and of IFN gamma production were observed in splenocyte cultures from immune mice, compared with cells from naive controls. Antigen-specific proliferation also occurred in immune cells, being vigorous following stimulation with adult worm antigen, but not with antigens from developing embryos or mf. Levels of IL-4, IL-5 and IFN gamma induced by the various antigens was similar, indicating that activation of alternate T helper cell sub-sets was unlikely to explain the lack of cellular responsiveness. After a primary inoculation with mf, spleen cells from infected mice co-produced IFN gamma and IL-5. In contrast, IFN gamma production was downregulated while IL-5 levels remained high during active elimination of a challenge infection. Significant levels of IL-4 production occurred only once parasite clearance had begun. These data confirm the importance of IL-5 in protection against Onchocerca mf in mice and question the role of IFN gamma in the expression of immunity. Production of high levels of IL 5 correlated with blood and tissue eosinophil mobilization during the clearance of a challenge infection. PMID- 10101719 TI - X-linked immunodeficiency affects the outcome of Schistosoma mansoni infection in the murine model. AB - The incidence of the X-linked immunodeficiency (Xid) on the outcome of Schistosoma mansoni infection has been evaluated through a comparative analysis of parasitological and immune parameters in two different mouse strains: control BALB/c and BALB. Xid mice which carry the Xid mutation and lack B1 (CD5+ B) cells. This study clearly demonstrates that infected B1 cell-deficient animals display a higher susceptibility to S. mansoni infection as revealed by an increase in the tissue egg loads and a significantly elevated mortality, as well as an increase in the granuloma densities. The analysis of the humoral and the cellular responses, conducted in the same experimental conditions, indicates differences in terms of cytokine production after specific antigenic stimulation of splenocytes. Larger amounts of IFN-gamma and IL-4 are observed in BALB. Xid mice while IL-10 production is reduced. In parallel, the study of the specific antibody isotype profiles shows higher amounts of specific IgE and IgG1 antibodies and lower amounts of IgM and IgA in BALB. Xid mice. Taken together, these observations support the idea that B cells are playing a role in the ability of mice to tolerate infection with Schistosoma mansoni. PMID- 10101720 TI - Comparison of antibody and protective immune responses against Trypanosoma cruzi infection elicited by immunization with a parasite antigen delivered as naked DNA or recombinant protein. AB - Immunization with naked DNA represents an attractive strategy for development of vaccines against a variety of infections including those caused by protozoan parasites. Recently, we have described that immunization with a plasmid containing the trans-sialidase (TS) gene induced protective immunity against Trypanosoma cruzi infection in BALB/c mice. The present study was aimed at examining and comparing the effectiveness of immunization using either plasmid or recombinant delivered antigens in a mouse strain highly susceptible to infection (A/Sn). Two plasmids were generated containing the coding region for the catalytic domain of TS. TS gene was inserted into pcDNA3 vector with or without the coding region for TS signal peptide. These two plasmids were found to be equally immunogenic at inducing antibodies to TS or inhibition of T. cruzi infection. A third plasmid, in which the TS gene was inserted into the vector VR1012, was as immunogenic as the two others. Immunization with a TS recombinant protein in alum generated a significantly higher antibody response as measured by ELISA or inhibition of TS enzymatic activity. Most relevant, this immunization reduced the mortality due to acute infection. PMID- 10101721 TI - Vaccination of mice with gamma-irradiated Schistosoma japonicum cercariae. AB - gamma-irradiated cercarial vaccines induce high levels of protection in mice against Schistosoma mansoni infection, however, the same has not been well established for S. japonicum. Here we describe vaccination studies in mice with gamma-irradiated S. japonicum cercariae testing the effectiveness of different irradiation doses, number of vaccinations, and mouse strains. In CBA/Ca mice, a single percutaneous exposure to 500 S. japonicum cercariae previously attenuated by 10, 20, 30, 40 or 50 krad gamma-irradiation induced significant, but comparable levels of protection (34-46%) against challenge infection. In a repeat experiment in C57Bl/6 mice, only groups vaccinated with 10 or 20 krad gamma irradiated cercariae showed statistically significant, but lower levels of resistance (20-24%). Multiple vaccination of CBA/Ca mice with 500 20 krad gamma irradiated cercariae did not improve the resistance level (40%). Analysis of IgG responses showed no clear correlation between antibody levels and levels of protection. Western blot analysis suggested that recognition of a 200-kDa antigen might be correlated with protection, that antigens of 42 and 50 kDa may be involved in the protection induced by single vaccination, but that different antigens might be protective in single vs multiple vaccinations. Sera from mice vaccinated with gamma-irradiated cercariae recognized many fewer antigens than more protective sera from mice vaccinated with UV-attenuated cercariae. These results suggest that the mouse may not be a suitable host for studies involving gamma-irradiated S. japonicum vaccines. PMID- 10101722 TI - Separation induced changes in squirrel monkey hypothalamic-pituitary-adrenal physiology resemble aspects of hypercortisolism in humans. AB - When separated from groups, squirrel monkeys respond with significant increases in plasma cortisol and adrenocorticotropic hormone (ACTH). While cortisol remains elevated above pre-separation levels, significant reductions occur in ACTH. Monkeys that respond with greater increases in cortisol subsequently exhibit greater reductions in ACTH, which suggests that reductions in ACTH are mediated by corticosteroid feedback. Monkeys that respond with greater increases in cortisol also tend to exhibit greater cerebrospinal fluid levels of the dopamine metabolite HVA, but not the norepinephrine metabolite MHPG, or corticotropin releasing factor (CRF). Attenuation of corticosteroid feedback with metyrapone results in significant increases in circulating ACTH, and in older monkeys increases plasma HVA. Similar findings in humans have been reported in clinical studies of hypercortisolism and major depression. PMID- 10101723 TI - Growth hormone response to baclofen in patients with seasonal affective disorder: effects of light therapy. AB - There is evidence for gamma-aminobutyric acid (GABA) dysfunction in the pathophysiology and treatment response of patients with major depression, but this has not been studied in seasonal affective disorder (SAD). Growth hormone (GH) response to a challenge with a GABAB receptor agonist, baclofen, is considered an in vivo index of hypothalamic GABAB receptor function in humans. To explore the role of GABAB receptor function in SAD, we compared the GH response to baclofen challenge in 15 patients with SAD and 20 matched healthy controls. Of the 15 patients with SAD, 14 had repeat baclofen challenge following 2-week treatment with light therapy. The results showed that baclofen administration led to a significant increase in GH release both in patients with SAD and normal controls. There was no significant difference in the GH response to baclofen between the two groups. Furthermore, 2-week treatment with light therapy did not significantly alter the baclofen-induced GH response in patients with SAD, in spite of a clear therapeutic effect. The results of this study suggest that hypothalamic GABAB receptor function, as measured by baclofen induced GH release, is not altered in patients with SAD or by light therapy. PMID- 10101724 TI - Thyrotropin stimulating hormone response to thyrotropin releasing hormone in patients with panic disorder. AB - OBJECTIVE: The aim of this study is to assess thyrotropin stimulating hormone (TSH) response to thyrotropin releasing hormone (TRH) in patients with panic disorder (PD). METHOD: The effects of TRH administration on the release of TSH were examined in 15 patients who met DSM-III-R criteria for PD and compared their test results with those of 15 normal control subjects. Blood samples were taken before TRH administration (baseline values) and at 15, 30 and 60 min. RESULTS: delta max TSH values were lower in the panic disorder patients than in the control subjects. Using the criterion of delta max TSH < or = 7 mlU/l, nine of the 15 panic disorder patients and four of the 15 control subjects had a blunted TSH response to TRH. CONCLUSIONS: These results confirm the findings from earlier reports that patients with PD show blunted TSH response to TRH which is similar to that seen in depressed patients. PMID- 10101725 TI - Estradiol facilitates performance as working memory load increases. AB - A water-escape version of the radial-arm maze was used to assess rat spatial working memory performance. Intact females and ovariectomized females receiving a physiologically low dose, physiologically moderate dose or no estradiol replacement were studied. Subjects were given seven trials a day for 12 days. Females receiving moderate dose estradiol made fewer errors than the other three groups during the latter portion of testing. As trials progressed within a session, the elements of information to be remembered increased. Assessment of individual trials revealed that when the demand on an animal's working memory system was limited to one to four elements of information, the three groups with estrogen (including intact females) maintained successful performance, whereas the ovariectomized females made more errors. However, when the demand on an animal's working memory system was increased to six elements of information, only the moderate dose estradiol females maintained successful performance. These data suggest that, although moderate levels of estradiol replacement are the most beneficial for working memory function, even low-dose estradiol replacement can act to protect working memory systems from the decline seen with the removal of ovarian hormones. PMID- 10101726 TI - Sex differences and menstrual cycle effects in human spatial memory. AB - A typical test of spatial memory requires subjects to relocate a number of objects in their original, previously studied positions. It has been argued that this test includes multiple separate processing components (Postma, A., De Haan, E.H.F., 1996. Quarterly Journal of Experimental Psychology 48A (1), 178-199; Postma, A., Izendoorn, R., De Haan, E.H.F., 1998. Brain and Cognition 36, 334 345). One has to encode the precise positions occupied, assign the various objects to the correct (relative) locations, and achieve an integration of both types of spatial information. The present study examined the presence of sex differences and the role of hormonal factors for these selective components of spatial memory. A computerised, immediate (working) memory version of the test was used, comparing 23 males and 34 females on three experimental conditions: positions only, object-to-position-assignment, and the combined condition, requiring integration of the other two components. In line with previous research (Postma et al., 1998) males showed a selective advantage for fine-grained, metric positional reconstruction (i.e. positions-only). Interestingly, a within-subjects comparison in the females only revealed a menstrual cycle effect for exactly the same dimension of spatial memory. In the nonmenstrual phase, females were better than during menstruation. This clearly implies a role for sex hormones in spatial memory, even though a subsequent analysis of testosterone samples in saliva did not reveal a significant correlation with measures of spatial memory in both males and females. PMID- 10101727 TI - Effect of the menstrual cycle stage on the melatonin suppression by dim white light. AB - Patients with bipolar disorder have been shown to have a supersensitive melatonin suppression to dim white light (200 and 500 lux) compared to normal healthy subjects. Previous studies suggest menstrual cycle dependent changes in the melatonin rhythm, but it is not known if the melatonin sensitivity to light changes during the menstrual cycle. The present study investigated the melatonin suppression to dim white light (200 lux) in different stages of the menstrual cycle. No significant differences in the percent suppression of melatonin were found across the stages of the menstrual cycle (p = .97). Our findings suggest that the menstrual cycle hormonal changes do not affect the melatonin sensitivity to dim light in healthy controls. PMID- 10101728 TI - Seasonal variation in plasma prolactin response to D-fenfluramine in healthy subjects. AB - To assess dynamically a seasonal variation in the functioning of the central serotonin (5-HT) system, we investigated the prolactin (PRL) response to the specific serotonergic agent D-fenfluramine (D-FEN) in the different seasons of the year. Thirteen healthy women and 11 healthy men (six for each season), aged 20-50 years, received PO 30 mg D-FEN and placebo, according to a randomized double-blind design. As compared to placebo, D-FEN induced a clear-cut increase in plasma PRL levels in all the seasons; this response was higher in fall than in spring and summer (p < .01 and < .05, respectively). In all the subjects, as a group, the hormone response to the 5-HT probe was inversely correlated with the body weight and age. These results document a seasonal variability in the PRL response to D-FEN, which suggests a seasonal fluctuation in central 5-HT transmission in healthy humans. PMID- 10101729 TI - Normative melatonin excretion: a multinational study. AB - The present study on overnight urinary melatonin was conducted on the most geographically dispersed population to date, over a 1 year period, also covering a broad age range (18-62 years). An inverse relationship between melatonin and age, as well as between melatonin and weight was observed for both genders. Females as a whole, had higher melatonin values than males. Furthermore, the excretion of melatonin exhibited a bimodal distribution, distinguishing two groups of individuals: low and high melatonin excretors. The cut-off point was set at 0.25 nmol/l for ages up to 40 years and at 0.20 nmol/l for subjects above this age. Since melatonin may be involved in several physiological and pathological processes, it could be of importance to detect the type of melatonin excretion that prevails in various conditions, using a simple noninvasive procedure such as the overnight urinary measurement. For that purpose, this large sample could serve as a worldwide reference databank across different ages and locations. PMID- 10101730 TI - Cortisol fluctuates with increases and decreases in negative affect. AB - Prior studies have reported cortisol secretion to be primarily influenced by negative affect, but less is known about cortisol activity during states of activation involving increased positive affect and decreased negative affect. On separate days, 30 healthy young men experienced: an activating and humorous video; a speech stressor; and a resting control period. Cortisol was measured in saliva before and after each 30-min mood induction. Positive affect (activation) was increased similarly by both the video and the speech compared to rest (p < .0001). Negative affect increased during the speech and decreased during the video (p < .001). Cortisol increased only during the speech (p < .0001). Following the video, however, cortisol was decreased significantly (p < .0001). Rest day cortisol revealed no differences across periods (p > .1). These results suggest that the hypothalamic-pituitary-adrenocortical axis is a dynamic system influenced by changes in negative affect irrespective of the experience of generalized activation. PMID- 10101731 TI - Benzodiazepine-induced chemotaxis is impaired in monocytes from patients with generalized anxiety disorder. AB - Peripheral benzodiazepine receptors (PBR) modulate chemotaxis and cytokine production of monocytes and lymphocytes. Since PBR are decreased in animal models of stress and in patients with anxiety disorders, in the present study we analyze the ability of monocytes obtained from patients suffering from generalized anxiety to migrate towards chemoattracting benzodiazepines. In these patients, the benzodiazepine-induced chemotaxis is completely abolished, while the response to the control chemoattractant formyl-leu-met-phe is still maintained. The chemotaxis responses are not restored after pharmacological treatment of the pathology. The decreased chemotactic response could be linked to a decreased number of PBR receptors present on monocytes of generalized anxiety disorder patients. PMID- 10101732 TI - Sexual differentiation modifies the allopregnanolone anxiolytic actions in rats. AB - The administration of progesterone (0.0, 1.0 and 2.0 mg/rat, s.c.) and allopregnanolone (5 alpha, 3 alpha dihydroprogesterone) (0.0, 0.5 and 1.0 mg/rat, s.c.) to both, males and females, produced a similar reduction in burying behavior. Only allopregnanolone showed a gender-dependent effect on burying behavior latency. Allopregnanolone actions were established in five groups of animals according to their neonatal hormonal manipulation: intact males and females, neonatally-testosterone propionate-treated female rats (TP, 30 and 120 micrograms/rat, s.c. at day 5) and neonatally (4-12 h after delivery) castrated males. Males and females showed a reduction in anxiety after treatment with allopregnanolone. Both neonatally-androgenized-females and -castrated males were completely insensitive to allopregnanolone anxiolytic action tested in both burying behavior and plus-maze paradigm. The virilizing action of neonatally administered TP was demonstrated by dose-dependent delayed vaginal opening, a persistent estrus in their vaginal smears and the presence of polifollicular ovaries. Results are discussed on the bases of the differences and similarities between males, females, androgenized females and neonatally castrated males to anxiolytic steroids and the underlying possible processes. PMID- 10101733 TI - Antagonism by pivagabine of stress-induced changes in GABAA receptor function and corticotropin-releasing factor concentrations in rat brain. AB - Pivagabine [4-(2.2-dimethyl-l-oxopropylamino) butanoic acid] (PVG) is a hydrophobic 4-aminobutyric acid derivative with neuromodulatory activity. The effects of subchronic treatment with PVG on stress-induced changes both on brain concentrations of corticotropin-releasing factor (CRF) and neurosteroids and on the function of the gamma-aminobutyric acid type A (GABAA) receptor complex were investigated in male rats. Subchronic treatment with PVG (100-200 mg/kg, i.p.) resulted in a dose-dependent inhibition of the foot shock-induced increase in the binding of t-[35S]butylbicyclophosphorothionate to unwashed membranes prepared from the cerebral cortex of rats killed immediately after stress; PVG treatment alone had no effect on this parameter. This antagonistic action of PVG was also shown in adrenalectomized-orchietomized rats. Foot-shock stress decreased by 74% and increased by 125% the CRF concentration in the hypothalamus and cerebral cortex, respectively. PVG prevented these effects of stress on CRF concentration in both brain regions; this drug per se reduced hypothalamic CRF concentration by 52% but had no effect in the cortex. Moreover, intracerebroventricular injection of CRF, like stress, induced a dose-dependent increase of [35S]TBPS binding to cerebral cortical membranes: an effect not prevented by subchronic treatment of PVG. Finally, PVG did not antagonize the stress-induced increases in the concentrations of neuroactive steroids in brain or plasma. These results suggest that the marked antistress action of PVG is mediated by antagonizing the effects of stress on GABA(A) receptor function and CRF concentrations in the brain, but not by altering the stress-induced increase in neurosteroid concentrations. PMID- 10101734 TI - Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat. AB - Social stress in rats is known to induce long-lasting, adverse changes in behaviour and physiology, which seem to resemble certain human psychopathologies, such as depression and anxiety. The present experiment was designed to assess the influence of individual or group housing on the vulnerability of male Wildtype rats to long-term effects of inescapable social defeat. Group-housed rats were individually exposed to an aggressive, unfamiliar male conspecific, resulting in a social defeat. Defeated rats were then either individually housed or returned to their group. The changes in their behaviour and physiology were then studied for 3 weeks. Results showed that individually housed rats developed long-lasting, adverse behavioural and physiological changes after social defeat. Their body growth was significantly retarded (p < .05) between 7 and 14 days after defeat. When individually and group-housed rats were exposed to a mild stressor (sudden silence) 2 days after defeat, both groups became highly immobile. However, when exposure was repeated at day 21, individually housed rats were still highly immobile compared to group-housed rats which regained their normal mobility after only 7 days. In an open field test, also regularly repeated, individually housed rats took significantly longer to leave their home base and were also significantly less mobile than group-housed rats over the entire 3-week test period as well as at specific timepoints. When the rats were placed in an elevated plus-maze 14 days after defeat, those that were individually housed were significantly more anxious than those that were group-housed. When tested at 21 days after defeat in a combined dexamethasone (DEX)/corticotrophin-releasing factor (CRF) test, results showed that the hypothalamic-pituitary-adrenocortical (HPA) activity in individually housed rats was higher. This was evidenced in the latter animals by the fact that DEX was significantly less able to suppress the secretion of ACTH and corticosterone, and by a significantly higher release of ACTH after administration of CRF. Although the weights of the spleen and testes of the two groups did not differ, the adrenals of individually housed rats were larger and the thymus and seminal vesicles were smaller. We conclude that when rats are isolated after defeat, they show long-lasting, adverse behavioural and physiological changes that resemble symptoms of stress-related disorders. In contrast, when familiar rats are housed together these effects of a social defeat are greatly reduced. These findings show that housing conditions importantly influence the probability of long-term adverse behavioural and physiological effects of social defeat in male Wildtype rats. PMID- 10101735 TI - Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats. AB - Peripheral (i.p.) and central (i.c.v.) injections of lipopolysaccharide (LPS) have been shown to induce brain expression of proinflammatory cytokines and to depress social behaviour in rats, increase duration of immobility and induce body weight loss. To determine if the anti-inflammatory cytokine, interleukin-10 (IL 10) is able to modulate these effects, recombinant rat IL-10 was injected in the lateral ventricle of the brain (30, 100, 300 ng/rat) prior to i.p. or i.c.v. injection of LPS (250 micrograms/kg or 60 ng/rat, respectively). Social exploration was depressed for 6 h after i.p. LPS injection. This effect was attenuated by IL-10 (30 and 100 ng) 2 h after injection, whereas the highest dose of IL-10 blocked the depression of social interaction for 6 h after LPS injection. IL-10 produced the same effects on the increase of immobility although the results did not reach significance. Social exploration was depressed 3 h after i.c.v. LPS injection, and this was accompanied by increased immobility. These effects were totally blocked by i.c.v. IL-10 (300 ng/rat). Rats lost body weight after i.c.v. LPS, and this effect was attenuated by i.c.v. IL-10. These results indicate that IL-10 is able to modulate the production and/or action of central proinflammatory cytokines. PMID- 10101736 TI - Dexamethasone blocks sleep induced improvement of declarative memory. AB - To investigate the role of glucocorticoids for effects of early and late nocturnal sleep on declarative and procedural memory, 2 mg dexamethasone (versus placebo) were administered to healthy men 7 h prior to retention sleep. The retention sleep interval covered either the early or late half of nocturnal sleep. Following placebo, recall of a paired associate list (declarative memory) benefitted more from early than late sleep and recall of mirror tracing skills (procedural memory) benefitted more from late than early sleep. Dexamethasone did not affect slow wave sleep dominating early sleep, but blocked the beneficial effect of early sleep on recall of paired associates. Conversely, dexamethasone reduced rapid eye movement sleep dominating late sleep, but did not affect late sleeps beneficial effect on mirror tracing skills. The natural inhibition of endogenous glucocorticoid secretion during early sleep seems to be essential for a sleep-related facilitation of declarative memory. PMID- 10101737 TI - Alpha 2-adrenoreceptor subtypes regulate ACTH and beta-endorphin secretions during stress in the rat. AB - The effect of different alpha 2-adrenoreceptor subtype agonists and antagonists on adrenocorticotrop hormone (ACTH) and beta-endorphin release induced by ether stress was examined. Ether inhalation-induced ACTH and beta-endorphin increase was inhibited by i.c.v. administration of 30 micrograms but not 1 and 10 micrograms clonidine (alpha 2-adrenoreceptor agonist). I.c.v. oxymetazoline (alpha 2A-adrenoreceptor agonist; 1-10-30 micrograms) or the alpha 1-agonist methoxamine (100 micrograms/rat) failed to inhibit the stress-induced rise. Pretreatment with the alpha 1/alpha 2B.C-antagonist prazosin (0.5 mg/kg, i.p.) prevented the effect of clonidine on the ether stress, while the alpha 1/alpha 2A antagonist WB-4101 (0.5 mg/kg, i.p.) was unable to counteract the inhibitory effect of clonidine. Prazosin alone had no effect on the ether-induced plasma ACTH and beta-endorphin elevation. These results suggest that noradrenaline in the central nervous system may inhibit the stress-induced hypothalamo-pituitary axis and pituitary beta-endorphin activation via alpha 2B.C-adrenoceptor subtypes and prazosin may antagonize its effect on these receptors. PMID- 10101738 TI - Effects of chronic mild stress (CMS) and imipramine administration, on spleen mononuclear cell proliferative response, serum corticosterone level and brain norepinephrine content in male mice. AB - There is increasing evidence that stress and emotional reactions produce changes in various immune processes. These changes may be due to alterations of the stress responses endocrine and for autonomic mediating mechanisms. In order to study such effects, the impact of chronic mild stress (CMS) application, and of subsequent imipramine administration were studied on the spleen mononuclear cell proliferative response period. OFI strain male mice were subjected to 4 or 7 weeks of CMS. The effects of these treatments on serum corticosterone levels and hypothalamic and hippocampal norepinephrine (NE) contents were also assessed. Subjects submitted to CMS had a higher spleen mononuclear cell proliferative response after either treatment duration. Imipramine treatment diminished this response enhancement in CMS exposed animals, but did not alter the proliferative responses of control subjects. Serum corticosterone levels, as well as hypothalamic and hippocampal nonrepinephrine contents did not significantly vary between groups. Taken together, these results suggest that CMSs effects on immune reactivity are not related to serum glucocorticoids or NE changes in these locations associated with the hypothalamic-pituitary- adrenocortical (HPA) axis. PMID- 10101739 TI - A determinant factor in the efficacy of GHRH administration in promoting sleep: high peak concentration versus recurrent increasing slopes. AB - A previous experiment indicated a greater efficacy of episodic than continuous growth hormone (GH)-releasing hormone (GHRH) administration in enhancing sleep. The greater efficacy of episodic administration could principally result from two factors, i.e. the greater peak concentration reached after episodic administration or the recurrence of increasing slopes in GHRH concentration. In order to investigate which factor essentially determines the pharmacodynamics of sleep promotion after GHRH, effects after a transient high peak in GHRH concentration were compared with those of repetitive increases in GHRH concentration. Sleep, plasma concentrations of GH, and GHRH were examined in healthy subjects after evening administration of a 'single' i.v. bolus of 50 micrograms GHRH, after five 'repetitive' boluses of 10 micrograms GHRH, and after placebo. Compared with placebo, single GHRH significantly increased time spent in stage 4 sleep (p < .01) and in stage 2 sleep, reduced time spent in wakefulness and onset latency of stage 4 sleep (p < .05, for each), while repetitive GHRH remained without effects. GH secretory activity also tended to be higher after single than repetitive GHRH. Thus, results suggest the relevance of a transiently high concentration of GHRH in blood as an essential factor in enhancing the central nervous sleep process. PMID- 10101740 TI - Inhibitory effect of loratadine on leukotriene B4 production by neutrophils either alone or during interaction with human airway epithelial cells. AB - Leukotriene B4 (LTB4), an inflammatory mediator, is a potent chemoattractant for neutrophils (PMN) that plays an important role in the late reaction in asthma. Human airway epithelial cells (HAEC) can interact with PMN to increase LTB4 production. The aim of this study was to determine the influence of loratadine, an antihistaminic drug, on the production of LTB4 by PMN either alone or during interaction with transformed HAEC. The effect of tumour necrosis factor-alpha (TNF-alpha) was also examined. LTB4 production was measured by RP-HPLC after cell stimulation with calcium ionophore. Loratadine (0.25-25 microM) induced a significant and dose-dependent decrease of LTB4 production by PMN alone whereas it was up-regulated by TNF-alpha. As reported by others, we confirmed the increase of LTB4 release when PMN were cocultured with HAEC as compared to PMN alone. Addition of loratadine to HAEC before co-culture with PMN induced a significant decrease of LTB4 formation by cell interaction. This effect was noted when HAEC were washed following incubation with loratadine, demonstrating a direct action of the drug on this cell type. Moreover, the TNF-alpha-induced stimulation of LTB4 release that we demonstrated in PMN-HAEC interaction was also inhibited by loratadine. These results indicate that loratadine might reduce inflammatory reaction by a direct effect on PMN LTB4 production but also through an influence on HAEC during interaction with PMN. PMID- 10101741 TI - Do parasympatholytic effects of long-acting beta 2-sympathomimetics contribute to their relaxant effects in airway smooth muscle cells? AB - To address the hypothesis of whether functional antagonistic effects of long acting beta 2-sympathomimetics (formoterol and salmeterol) might be supported by direct antagonistic effects on muscarinic acetylcholine receptors (mAChR), we performed radioligand binding experiments with 3H-quinuclidinyl-benzilate in membranes of airway smooth muscle cells (calf tracheal myocytes). beta 2 Sympathomimetics (short- and long-acting) were compared to catechol-ethanolamines and catechol-ethylamines. Tracheal myocytes were characterized by a high density of mAChR 1017 +/- 17 fmol/mg, which exceeds that of beta 2-adrenoceptors 20-fold. The affinities of drugs were determined by competition binding. Dissociation constants ?pKD-values) of formoterol (5.04 +/- 0.05) and salmeterol (5.24 +/- 0.04) matched that of ACh (5.37 +/- 0.03) and were significantly higher than that of the mAChR-agonist carbachol (4.65 +/- 0.03). pKD-values of mAChR-agonists were strictly dependent on GTP-concentration (> 50-fold difference between high- and low-affinity states), in contrast to those of formoterol, thereby characterizing formoterol as an mAChR-antagonist. A 10-fold lower affinity of the related compound fenoterol (3.94 +/- 0.02) hinted at the formyl-amino moiety of formoterol as a structural determinant of high-affinity whereas a 100-fold lower affinity of salbutamol as compared to salmeterol suggested the aliphatic side chain was a structural determinant of high affinity. The high affinity of dobutamine (4.96 +/- 0.02) and dopexamine (6.20 +/- 0.02) provided evidence that high affinity can be found not only for catechol-ethanolamines with long side chains but also for catechol-ethylamines. The question of whether high local concentrations after inhalation of long-acting beta 2-sympathomimetics could contribute to their therapeutical effects by antagonism with ACh on mAChR remains to be answered. PMID- 10101742 TI - Function of human alveolar macrophages after a 3-day course of azithromycin in healthy volunteers. AB - Azithromycin (AZM) is a new macrolide antibiotic with a high intracellular/extracellular concentration ratio. Immunomodulatory and antiinflammatory properties have been reported with other macrolides, especially erythromycin. The aim of the present study was to evaluate the effect of AZM on the production of proinflammatory mediators by alveolar macrophages (AM) up to 4 weeks after a 3-day course of AZM (500 mg, once a day). Nineteen non-smoking healthy male subjects were investigated with bronchoscopy and bronchoalveolar lavage. Group 1 received no treatment. Groups 2, 3, and 4 were bronchoscoped 1, 7 and 30 days, respectively, after AZM administration. AZM concentrations were simultaneously measured in plasma and in AM extracts. In serum, AZM levels were higher in group 2 (32.8 +/- 14.2 micrograms/l), at the lower limit of detection in group 3 (2.8 +/- 1.7 micrograms/l), and no longer detectable in group 4. In AM extracts, the highest concentrations were measured in group 2 (51.6 +/- 28.3 ng/microliter) and in group 3 (31.8 +/- 17.2 ng/microliter), and were detected up to 30 days after treatment in group 4 (2.9 +/- 2.3 ng/microliter). There was no significant differences between groups for blood or BAL proinflammatory cytokines levels (TNF-alpha, IL-1 beta, IL-6), and for superoxide generation by AM. We conclude that a 3-day course of AZM 500 mg/day in healthy subjects does not alter the proinflammatory cytokine profile in blood and in AM despite the prolonged tissue impregnation by this drug. PMID- 10101743 TI - Comparative effects of a fixed combination of reproterol hydrochloride and disodium cromoglycate with each agent alone on antigen-induced airway responses in sheep. AB - The purpose of this study was to compare the effectiveness of an eight day treatment with clinically relevant doses of a fixed combination of the beta 2 mimetic reproterol hydrochloride and disodium cromoglycate with each agent given alone against antigen-induced early (EAR) and late airway responses (LAR) as well as post-antigen-induced airway hyperresponsiveness (AHR) in allergic sheep. Animals were treated in a randomized fashion with either the inhaled combination (n = 6), reproterol hydrochloride alone (n = 6), disodium cromoglycate alone (n = 6), or placebo (n = 8). Treatments (two puffs from a metered dose inhaler) were given three times a day for 7 days and once on the 8th day 1 h before airway challenge with Ascaris suum antigen. In the placebo trial, antigen challenge resulted in EAR and LAR as measured by increases in specific lung resistance; these changes were followed 24h later by AHR to inhaled carbachol. With respect to the placebo trial, treatment with reproterol hydrochloride reduced the EAR (P < 0.05) and blocked the LAR (P < 0.05), but had no effect on the post-challenge AHR. Treatment with disodium cromoglycate also reduced the EAR (P < 0.05), blocked the LAR (P < 0.05), and blocked the post-antigen-induced AHR (P < 0.05). Treatment with the fixed combination reduced the EAR (P < 0.05), blocked the LAR (P < 0.05), and blocked the post-antigen-induced AHR (P < 0.05). Comparison of the different agents indicated that the fixed combination gave significantly increased protection against the EAR than either agent alone, gave slightly better (P < 0.05) protection against the late response than cromolyn sodium and gave better protection against post-antigen-induced AHR than reproterol hydrochloride alone. These results suggest that a fixed combination of a beta 2 mimetic and disodium cromoglycate provides some increased protection against antigen-induced airway responses when compared to either agent alone in a controlled laboratory setting. PMID- 10101744 TI - The effects of multiple dosing with zileuton on antigen-induced responses in sheep. AB - In a previous study, a single dose of zileuton (10 mg/kg, po) given 2 h before antigen challenge, had a minimal effect on the antigen-induced early airway response (EAR), although it was effective in blocking the late airway response (LAR). Because our previous data indicated that 5-lipoxygenase (5-LO) products contribute to the severity of the antigen-induced EAR in these animals, we hypothesized that the lack of effect of zileuton on the EAR may have had to do with inadequate tissue levels. Therefore, in this study, we determined if multiple dosing with zileuton, which theoretically could improve tissue levels, would provide protection against the antigen-induced EAR as well as the LAR. Each sheep was used in each of the three trials (> or = 15 days apart), the order of which was randomized. For trial 1, the sheep were treated with zileuton (10 mg/kg in 0.1% methylcellulose, p.o.) once a day for 4 days; for trials 2, the sheep were treated with zileuton (10 mg/kg, p.o.) for 2 days; and, for trial 3, the animals were treated with vehicle (0.1% methylcellulose) for 4 days as in trial 1. In all trials, antigen challenge followed 1 h after the last treatment. In the placebo trial, antigen challenge resulted in characteristic EAR (407 +/- 102%, increase over baseline) and LAR (335 +/- 75%, increase over baseline). The antigen-induced effects were completely blocked by the 4-day treatment (EAR = 24 +/- 3%; LAR = 17 +/- 3%, P < 0.05 vs. placebo). In the 2-day trial, the immediate increase in R1, after antigen challenge was only partially blocked (EAR = 163 +/- 16%, P < 0.10 vs. placebo and P < 0.05 vs. 4-day trial), but the late response was completely blocked (24 +/- 3%). The protection against the EAR obtained with the 4-day treatment was significantly better (P < 0.05) than that obtained with the 2-day treatment. The results of this study show that multiple dosing with the 5-LO inhibitor, zileuton, provides protection against the antigen-induced EAR as well as LAR. The effect on the EAR is dependent on the treatment time, with dosing 4 days before antigen challenge providing a more significant effect than either dosing 2 days before challenge (this study) or on the same day as antigen challenge as was seen by us previously. This effect may be related to increased tissue levels of the drug. PMID- 10101745 TI - Pituitary adenylate cyclase activating peptide induces cGMP-mediated relaxation in guinea-pig airways. AB - The mechanism of relaxation of the guinea-pig trachea induced by pituitary adenylate cyclase activating peptide (PACAP)-27 was investigated. We examined whether modulators of nitric oxide (NO) and carbon monoxide (CO) affect PACAP induced response of tracheal strips in vitro. Pretreatment with N omega-nitro-L arginine methyl ester hydrochloride (L-NAME) and L-arginine (L-arg) had no effect, while 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), haemoglobin and zinc protoporphyrin IX (ZnPP-9) partially abolished the PACAP-induced relaxation. PACAP-27 elevated cyclic GMP level in airway smooth muscle tissue. These results indicate that PACAP-27 not only induces cyclic AMP-mediated responses, but also cyclic GMP-mediated responses in the airway. In addition, CO is related to the PACAP-induced elevation of cGMP level in the tracheal tissue. PMID- 10101746 TI - The elimination half-life of urinary cotinine in children of tobacco-smoking mothers. AB - Exposure to environmental tobacco smoke (ETS) is strongly associated with childhood morbidity. Cotinine, the major metabolite of nicotine, is a useful marker of tobacco smoke exposure. Cotinine levels in infants are higher than in older children or adults exposed to the same reported quantity of ETS. One hypothesis to explain this difference is that the urinary elimination half-life of cotinine is different between infants and older children. Urine was collected at admission, 12, 24 and 48 h, cotinine levels were subsequently measured and then standardized by correcting for creatinine excretion. Urinary elimination half-life of cotinine was calculated in 31 infants and 23 older children. The median half-life was 28.3 h (range 6.3-258.5 h) in infants, and 27.14 h (range 9.7-99.42 h) in older children. A Mann-Whitney U test showed no significant difference in the median half-life of cotinine between the two age groups (P = 0.18). Multivariate linear regression analysis demonstrated no significant relationship between half-life of cotinine and corrected cotinine level (P = 0.24). Our results support the hypothesis that higher cotinine levels in infants is due to greater exposure, rather than slower metabolism of cotinine. PMID- 10101747 TI - A leukocyte elastase inhibitor reduces thrombin-induced pulmonary oedema in the rat: mechanisms of action. AB - The effect of a selective leukocyte elastase inhibitor, ICI 200,355, on thrombin induced pulmonary oedema was studied in rats. Thrombin administration produced an increase in lung weight (P < 0.05), wet weight/ dry weight ratio (P < 0.05), and relative lung water content (P < 0.05). The lung weight increase was reduced by the elastase inhibitor in doses of 2000, 200 and 20 micrograms/kg per h (P < 0.05), but not by 2 micrograms/kg per h. A dose of 20 micrograms/ kg per h seems to be optimal, since 10-fold and 100-fold increases in dose did not further improve the effect. Free elastase activity in lung tissue was higher after thrombin infusion than in controls, but was not depleted by the elastase inhibitor in vivo (P < 0.05). This elastase activity in the lung was, however, inhibited by the elastase inhibitor in vitro, indicating that the inhibitor can block extracellular, but not intracellular elastase activity. Thrombin infusion resulted in a significant decrease in plasma elastase inhibitory capacity (P < 0.05), which was depleted by the elastase inhibitor (20 micrograms/kg per h) (P < 0.05). Myeloperoxidase activity was significantly increased in lung tissue after thrombin infusion (P < 0.05). Lung myeloperoxidase activity 5 min after thrombin infusion was not affected by the elastase inhibitor, but the inhibitor induced a further increase in myeloperoxidase as seen 90 min after thrombin infusion, indicating that the effect of this inhibitor on pulmonary oedema is not due to reduction of leukocyte infiltration in the lungs, but may partly be exerted by prevention of neutrophil destruction. PMID- 10101748 TI - Selenium, glutathione peroxidase and superoxide dismutase in maltese asthmatic patients: effect of glucocorticoid administration. AB - Oxidative processes, mediated by free radical chemistry, are recognized to contribute significantly to the inflammatory pathology of bronchial asthma. This study analysed the degree of defence against reactive oxygen species in Maltese, asthmatic patients and in normal individuals, by measuring plasma selenium concentration, erythrocyte glutathione peroxidase (GSH-Px) activity and erythrocyte superoxide dismutase (SOD) activity, in order to determine their antioxidant status. The effect of glucocorticoids on the status of these antioxidants in patients was also investigated. The measurement of antioxidant status was carried out both in mild (n = 22) and severe (n = 37) asthmatics, as well as in healthy controls (n = 49). The same antioxidant profile was then investigated in a group of 16 severe asthmatics following treatment for 4 weeks with inhaled beclomethasone dipropionate (750 micrograms twice daily), and in a second group of 16 patients suffering from severe asthma, following 2-weeks treatment with oral prednisolone (15 mg daily during the first week and 10 mg daily during the second). No statistically significant difference was found in the plasma selenium concentrations and erythrocyte glutathione peroxidase activities between patients and controls. Both mild and severe asthmatics, however, exhibited a statistically significant lower erythrocyte superoxide dismutase activity than normal subjects (mild asthmatics: 62.9 (2.9) SOD 525 U/ml, severe asthmatics: 60.6 (1.9) SOD 525 U/ml, normal: 68.5 (1.1) SOD 525 U/ml, P < 0.01). Inhaled beclomethasone dipropionate exerted no effect on this antioxidant profile, while prednisolone caused a significant increase in plasma selenium concentration over pretreatment values (pretreatment: 118.3 (4.4) ng/ml, post-treatment: 138.1 (4.6 ng/ml, P < 0.01). It is thus suggested that asthmatic patients in Malta might be more susceptible to superoxide-induced damage than normal individuals. The reason for the prednisolone-induced augmentation of plasma selenium could not be determined from this study. It is postulated that the drug may decrease the excretion rate of the element, and may thus exert a positive antioxidant effect in individuals of established low selenium status. PMID- 10101749 TI - Carbon monoxide, a cyclic GMP-related messenger, involved in hypoxic bronchodilation in vivo. AB - Recent reports indicate the presence of two carbon monoxide (CO)-inducing enzymes, heme oxygenase (HO)-1 and -2 in airway smooth muscle. Generally HO-2 is considered to be a constitutive enzyme associated with various neuronal structures, whereas HO-1 can be induced by several factors, including hypoxia. Recent functional data indicate that exogenous CO can induce bronchodilation via a NO-independent, cyclic GMP-related mechanism. The aim of the present study was to investigate the potential role of CO as an endogenously produced airway messenger using an in vivo model of airway hypoxia. HO-1 and HO-2-like immunoreactivities were seen in airway smooth muscle along the bronchus and in the respiratory epithelium. The staining for HO-1 was relatively weak but consistent in all animals investigated. In contrast, the HO-2 staining was intense at all locations. After hypoxic stimulation, the staining for HO-1 and HO 2 was equally intense, indicating an up-regulation of the HO-1 expression. In another set up, anaesthetized, ventilated guinea-pigs were given a continuous infusion of histamine to increase total pulmonary resistance (R1). Hypoxic stimulation, induced by inhalation of 180 breaths of pure nitrogen (N2), resulted in a subsequent reduction in R1. Pretreatment with Rp-8Br-cGMPs, a cyclic GMP antagonist abolished more than 75% of this reduction, whereas L-NAME, an antagonist of NO synthesis, was without effect. Zinc protoporphyrin-IX (ZnPP), an inhibitor of HO, mimicked the effects of Rp-8Br-cGMPS. In conclusion, the present findings suggest a possible role for CO in the hypoxic regulation of airway tone. PMID- 10101750 TI - Current techniques in sentinel node mapping. AB - The prognosis for patients with breast cancer or melanoma largely depends on the involvement of nearby lymph nodes. This article examines techniques used to identify and assess sentinel nodes--those that drain the cancerous area. Such techniques may permit more conservative, node-sparing treatment. Studies evaluating the use of both radiopharmaceuticals and colored dyes are described. PMID- 10101751 TI - MQSA: the final rule. AB - On April 28, 1999, the final Mammography Quality Standards Act (MQSA) rule takes effect. On that date, the final regulations will replace the interim standards that have been in effect since October 1994. While the new guidelines are very similar to the interim guidelines, the final rule contains some important changes, particularly in the areas of personnel requirements and equipment standards. This article outlines modifications to the interim guidelines, with particular emphasis on requirements for radiologic technologists. PMID- 10101752 TI - Diagnosis and treatment of esophageal strictures. AB - Difficulty swallowing due to narrowing of the esophagus has many causes, both benign and malignant. This article examines the causes of esophageal stricture as well as its diagnosis and treatment. Radiographic examination, and in particular fluoroscopy, is key to a positive outcome for patients with this condition. PMID- 10101753 TI - Hantaviruses: an overview and radiographic correlation. AB - This article describes Hantaviruses and the infections they cause. Routes of transmission, disease phases and radiographic manifestations are discussed, along with recommendations for prevention and the radiologic technologist's role in prompt diagnosis. PMID- 10101754 TI - Internal mammary lymphoscintigraphy. PMID- 10101755 TI - Seizure after gadolinium administration. PMID- 10101756 TI - [The contribution of molecular genetics to the nosology and diagnosis of neurological disorders of childhood]. AB - INTRODUCTION: The recent spectacular development of molecular genetics has considerably amplified the role of genetics in classification and diagnosis, especially in degenerative diseases but also in other conditions such as developmental brain disorders and predisposition to some acquired diseases (e.g. infections and immunological maladies). OBJECTIVE: The aim of this article is not to review the ever growing list of disorders due to gene abnormalities but to present a few reflections on their consequences and to try to assess their impact on some of the basic concepts in clinical medicine. DEVELOPMENT: The main advantages attributable to the use of molecular genetics are the identification of clinical conditions with different clinical phenomena and due to a single cause and vice versa the existence of clinical conditions in which many different genetic abnormalities can be found. Its main drawbacks derive from its application for establishing nosologic classifications only on the basis of its findings, mainly due to the lack of congruence between phenotype and genotype. CONCLUSION: The information from molecular biology should be integrated with that of other sources in a significant profile, which is the intellectual basis of clinical medicine. PMID- 10101758 TI - [Advances in biochemistry in the understanding of neurometabolic disorders]. AB - The progress in the knowledge of neurometabolic diseases is due to the conjunction of innovations in several scientific and technological areas. Our review is focused in the biochemical aspects that we consider should be added systematically in the study of these diseases. 1. Analysis of sialotransferrin isoforms; 2. Analysis of specific acylcarnitines, and 3. Study of purine, pyrimidine and neurotransmitter metabolism. PMID- 10101757 TI - [New neurometabolic disorders: indicative clinical signs]. AB - Three groups of disorders are reviewed: the syndromes with carbohydrate deficient glycoproteins, congenital errors of metabolism involving purines and pyrimidines, and finally those of the neurotransmitters. Individually these disorders are rare, but as a group include many different pathological conditions. We list the clinical symptoms and laboratory data in patients with different enzyme deficiencies. Although some disorders have specific clinical characteristics, most have nonspecific clinical features which makes diagnosis difficult. PMID- 10101759 TI - [Approximation to the diagnosis of congenital metabolic disorders with neuroimaging]. AB - Inherited metabolic diseases (IMD) have a variable clinical and biological expression. In the last few years neuroimaging (MR, spectroscopic MR, PET, SPECT) have demonstrated the neurological impairment in some IMD. Biochemical analysis of the brain is possible due to spectroscopy MR. Neuroimaging in the IMD is not always definite but can frequently demonstrate an impairment in gray or white matter, basal ganglia, cerebellum or brain stem. In our article we analyze the different involvement of the central nervous system structures in IMD. On the other hand we review some brain malformations that can be related to IMD. PMID- 10101760 TI - [Usefulness of neurophysiological techniques in the diagnosis of metabolic disorders]. AB - OBJECTIVE: The author reviews the value of the electrophysiological techniques: electromyography (EMG), electroneurography or motor and sensitive nerve conduction velocity (MCV, SCV), brainstem auditory potentials (BAER), visual evoked potentials (VEP) and electroretinography (ERG), somatosensory evoked potentials (SEP), in the diagnosis of the different neurometabolic disorders. METHODS: In different tables are listed 52 neurometabolic diseases that give abnormalities of myopathic or neuropathic type (motor or sensitive, axonal or demyelinating), 59 diseases with ERG or VEP abnormalities, 34 diseases with altered function of peripheral or brainstem auditory ways (BAER), and 13 with SEP abnormalities. In each case the frequency and type of the specific sensory pathway abnormality is expressed in order to increase the usefulness in the differential diagnosis. CONCLUSION: Neurophysiological techniques often give an important help in the diagnosis of the neurometabolic disorders, making easier the selection of biochemical and histologic studies that will confirm the diagnosis. PMID- 10101761 TI - [Etiology of epilepsy in adolescents]. AB - OBJECTIVE: To review the etiology of epilepsies in adolescent patients treated at the Child Neurology Clinic, during the years 1995-1997. PATIENTS AND METHODS: All 13 years old patients, or older, were selected and considered adolescents. RESULTS AND CONCLUSIONS: A total of 863 patients with epileptic seizures were reviewed. Among them, 225 were epileptic adolescents and another 8 were adolescents with a single seizure or with several seizures clustering into a single event. Among the former, 163 suffered from partial epilepsy and 62 from generalized epilepsy. Partial epilepsies were distributed as: idiopathic (69), remote symptomatic (49) and cryptogenic (45). Generalized epilepsies were: idiopathic (22), cryptogenic (16) and cryptogenic-remote symptomatic (24). The latter included the Lennox-Gastaut syndrome, West syndrome, polymorphic epilepsy, etc. The etiology of these patients and related literature are reviewed in order to study the proper nosologic location of these entities. PMID- 10101762 TI - [Clinical features of epilepsy in adolescents]. AB - OBJECTIVE: The epilepsy is a common neurologic disorder in adolescence. Its prevalence is 1.5-2% in these ages. In this work the different epileptic types and syndromes that begin in adolescence are reviewed. DEVELOPMENT: Primary generalized epilepsies are the most frequent group. Its three syndromes, juvenile absences epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized with tonic-clonic seizures on awakening, have different clinical and electroencephalographic characteristic but also share a considerable overlapping among them. The partial epilepsies are frequently functional or idiopathic, but not so often as in childhood. The secondary generalized epilepsies are rare, and among them, the progressive myoclonic epilepsies are the main group. The clinical aspects of the different disorders are described. CONCLUSIONS: 19% of epilepsies have the onset in adolescence. There is a wide spectrum of clinical syndromes, with different symptoms and prognosis and also different of the corresponding syndromes that begin in childhood. PMID- 10101763 TI - [Psychological and social implications of epilepsy in adolescents]. AB - INTRODUCTION: Cognitive and behavioral disorders are more common among adolescents with epilepsy compared to non-epileptic, healthy adolescents or adolescents with other chronic, nonneurological disorders, but estimates of the scope of this problem vary widely, depending of the samples investigated. DEVELOPMENT: Normal adolescent behavior can be a complication for individuals with epilepsy. The most common psychological symptoms in the adolescent with epilepsy are attention problems and behavior disorders. The behavioral and cognitive events associated with epilepsy are the product of a complex interaction among neurological, psychosocial and medication variables. The most relevant neurological factors are: epileptic brain damage, associated brain lesions, subclinical discharges and long term effects of epileptic activity. CONCLUSIONS: This review is undertaken to summarize the literature on epilepsy in adolescents with respect psychopathological and social problems. PMID- 10101764 TI - [Factors modifying treatment of adolescents with epilepsy]. AB - We consider the factors which modify the treatment of epilepsy during adolescence: decision to start treatment, choice of the most suitable drug and its administration, the information which should be given to the adolescents and their families, the frequency, characteristics of follow-up visits whilst treatment is maintained and of its discontinuation, with particular emphasis on quality of life as the basic objective of the treatment of adolescents with epilepsy. PMID- 10101765 TI - [Various practical considerations in the management of movement disorders in children]. AB - Disorders of movement in children often cause semiological and diagnostic difficulties to the paediatricians concerned. Based on personal experience, the author analyzes aspects which are particularly useful in overcoming these problems. Epidemiology, rules for history taking, indications as to the interpretation of clinical signs and use of complementary studies are considered. PMID- 10101766 TI - [Molecular genetics of epilepsy: present and future implications in clinical practice]. AB - INTRODUCTION: Recent advances in mapping and isolating human epilepsy genes are having an increasing importance in the field of epileptology. DEVELOPMENT AND CONCLUSIONS: As the molecular bases of the genetic epilepsies are elucidated, more precise diagnoses and therapies are possible. Characterization of the genes responsible for several types of epilepsy will allow the clinician to increase diagnostic precision, offer more exact prognoses, and develop more efficient therapies. At the same time, the search for families with several affected members with some form of epilepsy has lead to the description of previously unnoticed epilepsies and epileptic syndromes. Both the precision in diagnosis and the description of new epilepsy syndromes should be of major importance for the development of the next version of the International Classification of Epilepsies and Epileptic Syndromes. Understanding the pathogenic mechanisms involved in different epilepsies may allow the rational development of 'design' antiepileptic drugs and, in the case of the poor-prognosis progressive myoclonus epilepsies, effective gene therapy treatments. Finally, the possibility of offering prenatal diagnosis and genetic counseling to families exposed to some forms of epilepsy may reduce their incidence in the future. PMID- 10101767 TI - [Clinical and genetic implications of dynamic mutations in neuropediatric practice]. AB - Dynamic mutations are a new type of genetic alteration identified in recent years. They are due to an increased number of repetitions of a particular trinucleotide and are associated with a particular group of neurological and/or neuromuscular disorders. They are characterized by intergenerational and intragenerational instability. There is an inversely proportional relationship between the number of repetitions and the age at which the first symptoms are seen (genetic anticipation). To date 13 disorders, due to this type of mutation, have been described. Some, such as sex-linked mental retardation (fragile X), myotonic dystrophy or Friedreich's ataxia involve an anomalous number of repetitions, reaching over a thousand of a given trinucleotide. Another group known as the polyglutamine disorders, since the CAG trinucleotide is repeated in all cases (dominant and familial ataxias, Huntington's disease) have an increased number of repetitions but there are less than a hundred of them. Finally, recently a third group has been described, oculo-pharyngeal dystrophy with less than a dozen repetitions. Why an increased number of repetitions of a trinucleotide found in or out of a gene is associated with a particular disorder is one of the questions raised by these mutations and which is starting to be discovered. PMID- 10101768 TI - [Congenital ataxias of genetic origin with structural anomalies of the cerebellum]. AB - Congenital ataxia is not a rare condition for who is involved in the practice of pediatric neurology. After a brief description on the normal development of the cerebellum, we present an extensive review on the neurological disorders due to malformations or metabolic disorders associated with hypoplasia of the cerebellum and congenital ataxia. PMID- 10101769 TI - [The phenomenon of genomic "imprinting" and its implications in clinical neuropediatrics]. AB - OBJECTIVE: We comment on the most important advances related to the phenomenon of genomic 'imprinting' in clinical paediatric neurology. DEVELOPMENT: Initially, we review the biological findings related to this subject and establish various concepts. Later, we attempt to clarify the different mechanisms of expression of the phenomenon 'imprinting' and its application in clinical practice. We give a detailed review of the various neurological disorders in which this genetic phenomenon has been involved to date. Finally, we attempt to determine when this genetic alteration should be suspected and which molecular biology techniques should be used to confirm the diagnosis. CONCLUSIONS: 1. Clinical diagnosis suspecting that the presence of genomic 'imprinting' may be the mechanism causing a particular pathology should be based on a family tree showing that both sexes and all generations are affected and that the severity of the same disease varies among different members of the same family; 2. Study strategy includes studying the methylation pattern of the DNA. If there are changes in this, PCR should be done to show the exact pattern of the alteration. PMID- 10101770 TI - [Paroxysmal disorders and episodic non-epileptic symptoms]. AB - INTRODUCTION: Non epileptic paroxysmal events (NEPE) are clinical disorders of usually sudden appearance, brief and originated by a cerebral disfunction of diverse causes with a common character to be no epileptic. DEVELOPMENT: The non epileptic paroxysmal events are more frequent than epileptic events. The 10% of the children have NEPE. The NEPE can to be confounded with epileptic fits. Careful and detailed history and wise valuation of the circumstances of occurrence and the characteristics and duration of the seizures are determined. The history include developmental milestones and search for possible causes of seizure disorders. A complete clinical examination and EEG are essentials in the differential diagnosis. More sophisticated techniques--polygraphy and video EEG monitoring--are of great value in selected and difficult cases. CONCLUSIONS: The NEPE are categorized: anoxic/hypoxia paroxysmal disorders, psychogenic paroxysmal events, paroxysmal events occurring during sleep, paroxysmal events of movements and other episodic symptoms. PMID- 10101771 TI - [Paroxysmal disorders caused by cerebral anoxia/hypoxia]. AB - INTRODUCTION AND DEVELOPMENT: Although the presentation of paroxystic episodes usually suggests epilepsy, there are many varied clinical conditions which occur periodically and paroxystically and are due to different causes. The pediatrician has to remember this in order not to make an erroneous diagnosis and so as to avoid unnecessary administration of antiepileptic drugs (which will be of no benefit), and also to avoid the repercussions which the diagnosis of epilepsy may have in family and social affairs. Paroxystic episodes related to anoxia/hypoxia are, amongst non-epileptic disorders, some of the commonest occurring in infancy and may have different degrees of importance: together with transitory, benign conditions such as apnea of crying there are serious and even potentially life threatening events such as some syncopes of cardiac origin. CONCLUSION: We review the main situations included in this section. PMID- 10101772 TI - [Psychogenic paroxysmal disorders in children]. AB - INTRODUCTION: Paroxystic psychic disorders which imitate organic disorders of the nervous system may have peripheral effects, present as changes in level of consciousness or appear as paroxystic behaviour changes. DEVELOPMENT AND CONCLUSIONS: The types of crises of psychological origin are: tantrums, panic attacks, crises of psychopathic rage, onanism or masturbation, epileptic pseudocrises or pseudoconvulsions and Munchausen's syndrome. In general psychic crises are not frequent in infancy: tantrums are commoner in small children and the other conditions usually occur after puberty or during adolescence. The anamnesis is the most important factor in the correct diagnosis of psychogenic paroxystic disorders. Complementary studies are done in doubtful cases, to rule out different pathological processes which might be causing the paroxystic disorder. Amongst these investigations, we emphasize the importance of the video EEG for differential diagnosis of paroxystic disorders in children. PMID- 10101773 TI - [Paroxysmal disorders and episodic non-epileptic symptoms related to sleep]. AB - INTRODUCTION: The paroxystical disorders and episodic symptoms not epileptics related to the sleep, constitute a great preoccupation motive for the parents as well as for all the professionals related to the Pediatrics, and defer in a way substantial of those which are gone to find in subsequent ages of the life. Development. A great number of they are bound to the development and have their maximum or exclusive incidence in the infantile age; and those which also occur in the adult age, have some special connotations in the infancy, with a thoroughly different therapeutic boarding to that of other ages therefore it is necessary an exhaustive knowledge of the same for their correct identification, by having a high incidence, and especially by the frequent mistakes that generate, since frequently they can carry to diagnostic of epilepsy those processes that it be not, with the social connotations that this implies, the countless complementary exams accomplishment and the possibility of certain drugs administration potentially toxic. CONCLUSIONS: It is discussed the need of a classification of the disorders of the sleep in the child and is accomplished a detailed description of the same emphasizing the important differential characteristics with other processes, taking into account to of the problems of the sleep that interests to consider in the pediatric age, the most important are found between those incidents associated with the stages of the sleep or the awake partial, recognized as parasomnias. Specific disorders are discussed. PMID- 10101774 TI - [Motor paroxysmal disorders]. AB - OBJECTIVE: In this paper we review and bring up to date non-epileptic paroxystic motor disorders, since knowledge of these is necessary to avoid confusion with epileptic crises. DEVELOPMENT: Particular attention has been paid to the etiopathogenesis, classification and treatment of tics, including Tourette syndrome. Familial paroxystic choreoathetosis and alterations of movement induced by drugs are considered in the light of new etiopathogenic concepts, such as hyperekplexy, spasmus nutans and Sandifer syndrome. We also mention the clinical aspects of shudders, paroxystic vertigo, continuous muscle activity, transitory cerebral ischemia and masturbation which should be remembered to avoid confusion with epileptic crises. PMID- 10101775 TI - [Rett syndrome as a hodogenesis disorder]. AB - In the last few years, Rett syndrome is conceived as a peculiar form of neurodevelopmental post-migrational disorder affecting dendritogenesis. In this article the clinical pathochronic pattern of classical forms is reviewed and the recent neurobiological and genetic evidences suggesting possible future explanations of its nature and origin are discussed. PMID- 10101776 TI - [Atypical forms of Rett's syndrome]. AB - INTRODUCTION: Females with Rett syndrome (RS) are actually known to present with a more heterogenous pattern of phenotypes than originally considered. DEVELOPMENT: This means that a number of clinical variants exist. These clinical variants are those patients who present some symptoms of the RS phenotype, but who show considerable variation in type and age of onset, severity of impairments and profile of clinical course. A correct delineation of atypical or variant RS cases is difficult but important. The following RS phenotype expressions are described: forme 'frustre' variant; early seizure type variant; late childhood regression variant; preserved speech variant; congenital RS. CONCLUSIONS: A model for inclusion criteria to be used for diagnosing as variants in school age has been suggested. The different RS variants are reviewed briefly. PMID- 10101777 TI - [Rett's syndrome in the Spanish population]. AB - INTRODUCTION AND OBJECTIVE: Rett syndrome was described in 1966 and became known through the English medical literature in 1983. There are typical and atypical forms. The objective of this study was to record the cases diagnosed in Spain and discover their clinical characteristics in order to describe its phenotype and geographical distribution. PATIENTS AND METHODS: We know of 207 cases and have obtained the records of 168 of these patients. A protocol and data collection programme has been developed giving the criteria for inclusion, and data which support or exclude this. Data collection was by post and the data for identification were the date of birth and the initials of the name and two surnames. With these variables, double-registering of patients was almost impossible. A statistical study with descriptive analysis and a study of continuous and alternating variables was immediately done. RESULTS AND CONCLUSION: The results gave the main characteristics, the differences between typical and atypical cases and a comparative study of variables. It has given clinical data which may be useful for prognosis of the condition in the future. PMID- 10101778 TI - [How to construct a neural tube: molecular genetics of neuro-embryological development]. AB - INTRODUCTION: The 'new neuroembryology' combines classical morphogenesis with new molecular genetic data on the programming of neural differentiation and the interactions of transcription products of various developmental genes. DEVELOPMENT: The neuroepithelium is generated from the primitive (Hensen's) node in birds and mammals, homologous with the dorsal lip of the amphibian gastula. The developing neural placode is 'induced' by the notochord, which initiates the differentiation of the floor plate, a ventral midline ependyma. This induction is effected by a gene called Sonic hedgehog, which also is a strong ventralizing influence and induces motor neuron differentiation. Various families of genes program neural tube differentiation with dorsoventral or ventrodorsal gradients, rostrocaudal gradients and mediolateral gradients. Genes that establish the primordial axes of differentiation are 'organizer genes' and those involved with the identity of specific structures are 'regulatory genes'. Some developmental genes continue to be expressed in adult life and preserve the unique identity of specific cellular types. The neural tube is divided into compartments or segments known as neuromeres (or rhombomeres in the hindbrain) with physical and chemical barriers that limit cell migration between segments; the entire spinal cord is formed from rhombomere 8. Both extrinsic and intrinsic mechanical factors contribute to bend the neural placode to form the neural tube [REV NEUROL 1999; 28: 110-6]. PMID- 10101779 TI - [Anatomic image of structural changes in the CNS]. AB - OBJECTIVE: To present a real classification of the cerebral midline and the posterior fossa malformations from a clinical, embryological, anatomical and imaging point of view. METHODS: They were considered personal criteria based in a wide experience, especially considering the clinical facts of the patients and their correlation with the magnetic resonance (MR) images and the anatomic findings as well as the contribution of the literature to this subject. RESULTS: It is able to distinguish several types of malformations that involve supratentorial or infratentorial zones or both in the same patient. Given the clinical, imaging and anatomical peculiarities, it is possible to differentiate isolated malformations and malformative syndromes involving zones of the cerebral midline or the posterior fossa. CONCLUSION: The clinical peculiarities are basic to suggest the presence of cerebral malformations, but the imaging study, especially the MR, is necessary in order to confirm the malformations. The differentiation between isolated malformation and malformative syndrome is nowadays necessary [REV NEUROL 1999; 28:116-29]. PMID- 10101780 TI - [The course of psychomotor development in different encephalic malformations]. AB - INTRODUCTION: Congenital malformations of the brain often are complex disorders which display a wide spectrum of neurological manifestations. The presence of this diversity makes it difficult to correlate clinical findings with neuropathological abnormalities or through neuroimaging studies. DEVELOPMENT: Furthermore, the complexity of the etiological problem creates difficulty to differentiate those disorders having a primary cause, usually implying a genetic origin, from those secondary to a intrauterine insult occurring during the developmental brain process. In this study we have made a approach to mental and motor development in patients with typical or isolated brain malformations. To provide focus, we purposely excluded patients with complex anomalies, neurological disease, chromosomal disorder, syndromic picture or those who had brain malformations secondary to a known insult. CONCLUSIONS: Our exposition come from our review of the current related literature and our own clinical experience, and we have chosen to classify the brain malformations into these three groups: those occurring before the 20th week of pregnancy, those occurring after the 20th week of pregnancy, and the malformations of the posterior fossa [REV NEUROL 1999; 28: 130-5]. PMID- 10101781 TI - [Epilepsy and CNS malformations]. AB - INTRODUCTION: Malformations of cortical development are currently considered to be one of the commonest causes of mental retardation and epilepsy. DEVELOPMENT: New neuroimaging techniques have helped diagnosis of these conditions during life and the recognition of new anatomo-clinical syndromes. Although the true incidence of these lesions as a cause of epilepsy is unknown, data from surgical patients indicate that this is the commonest pathology found in children operated on for intractable crises. Most of these patients have focal or generalized crises associated with mental retardation, with a wide range or severity. CONCLUSION: In this review we analyze the clinical features, electroencephalographic findings and the prognosis of epilepsy secondary to these malformations [REV NEUROL 1999; 28: 136-40]. PMID- 10101782 TI - [Muscular dystrophies due to alterations at extracellular space level: congenital muscular dystrophy caused by merosin deficiency]. AB - OBJECTIVE: This is an up-to-date analysis of congenital muscular dystrophies (CMD), especially merosin-deficient-CMD, we also present our center expertise. DEVELOPMENT: CMD are skeletal muscle degenerative hereditary diseases caused by abnormal synthesis of structural or functional muscle proteins. Severe hypotonia, joint deformities and muscle weakness at birth are the main features of CMD. A especial type of CMD caused by absence of alpha 2 chain (or merosin) of laminin 2, a tissue specific protein from muscle basement membrane which anchors extracellular matrix to dystrophin, is the paradigm of a muscular dystrophy produced by extracellular abnormalities. CMD merosin-negative locus was assigned to chromosome 6q2, where is localized the laminin alpha 2 chain gene (LAMA2). Recently, LAMA2 gene mutations producing the disease have been described. Floppy infant syndrome is its earliest symptom and CMD merosin-negative represents the most frequent cause of muscular origin. 40% of our CMD patients are completely merorin-deficient. They had marked delayed motor milestones and never became ambulant but their intelligence remainded normal. Nowadays we can perform a prenatal diagnosis by immunohistochemical analysis in trophoblast. CONCLUSION: CMD merosin-deficient represents a subset of patients with a potentially poor prognosis, thus an early diagnosis is highly convenient in order to establish a correct follow-up [REV NEUROL 1999; 28: 141-9]. PMID- 10101783 TI - [Sarcoglycanopathies]. AB - INTRODUCTION: Identification of several clinical pictures in relation to a deficit of various protein components of the sarcoglycan complex, has allowed a new classification to be established for muscular dystrophies, correlating the protein alpha, beta, gamma, sigma deficit with a type of girdle dystrophy ('Limb Girdle Muscular Dystrophy', LGMD) and the genomic identification respectively: 2D/17, 2E/4q12, 2C/13q12, 2E/4q12, 2F/5q33. The correlation between the various proteins and complexes and the dystrophin is known as Dystrophin Associated Glycoproteins (DAG) and Dystrophin Related Proteins (DRP). This interrelationship is fundamental to the study of the different components and the key to immunohistochemical study and evaluation amongst other things. Patients with alpha-sarcoglycan deficiency (LGMD 2D) show great clinical and genetic heterogeneity sometimes leading to severe degrees of muscular dystrophy similar to Duchenne muscular dystrophy. The mutation R77C is a recurrent mutation and the cause in over one third of the patients with this deficiency. Absence of gamma sarcoglycan is also a cause of severe muscular dystrophies with the Duchenne phenotype. It has been described in the Mediterranean region, Japan and Brazil. The delta 525T mutation is the commonest and also, as occurs with C283Y (specific to the gypsy race), is a foundational mutation. Deficit of beta-sarcoglycan (LGMD 2E) gives rise to different grades of clinical severity, frequently with cardiac involvement. At present the phenotype of sigma-sarcoglycan deficit (LGMD 2F) has yet to be described [REV NEUROL 1999; 28: 150-3]. PMID- 10101784 TI - [Dystrophin and dystrophin-associated proteins. Their evaluation at the neuromuscular pathology laboratory]. AB - OBJECTIVE: To describe the main techniques used to detect skeletal muscle proteins and to discuss the results regarding the new classification of limb girdle muscular dystrophies. MATERIAL AND METHODS: Over three hundred muscle biopsies with a suspected diagnosis of muscular dystrophy were immunostained for dystrophin, dystrophin-associated proteins, spectrin and utrophin. In one hundred and twenty of them, Western blot for different proteins was performed. RESULTS: Duchenne muscular dystrophy showed negative immunostaining and Western blot for dystrophin and dystrophin-associated proteins, and overexpression of utrophin. In Becker muscular dystrophy there is an abnormal dystrophin immunolabelling and molecular weight. Sarcoglycanopathies present decreased sarcoglycans and normal dystrophin. In some forms of congenital muscular dystrophy there is absence of merosin and alpha 2-laminin, with variable results on Western blot analysis. CONCLUSION: The immunohistochemical analysis of several cytoskeletal and transmembrane proteins as well as Western blot analysis, are necessary to elaborate a correct diagnosis of dystrophinopathies, sarcoglycanopathies and the different forms of congenital muscular dystrophy [REV NEUROL 1999; 28: 154-8]. PMID- 10101785 TI - [Alterations in functional proteins. Calpaine-3 deficiency]. AB - INTRODUCTION: Muscular dystrophies due to calpain deficiency are the first example of a muscular dystrophy due to the mutation of a gene codifying for a non structural enzymatic protein of unknown function and substrate. DEVELOPMENT: More than 70 mutations have been described in the gene structure, localized to chromosome 15. Although the time course and topography is fairly homogeneous, correlation between the different mutations and the phenotype has still to be analyzed. The age of onset of symptoms is usually between 8 and 14, with no difference between the sexes. There is a slow but uniformly progressive course starting in the pelvis and extending to the shoulder and the distal musculature. Almost all patients are confined to a wheelchair twenty years after onset of the disease. There is no facial, oculomotor or bulbar involvement and gemellar pseudohypertrophy is rare. However, a winged scapula and marked lumbar hyperlordosis is universal. No cardiac or cognitive changes have been observed. Muscle CT shows a pattern of atrophy, mainly of the posterior and medial muscle compartments and of the posterosuperficial group of the legs, which varies depending on the time the disorder has been present. This condition is the commonest etiological group of the dystrophy syndromes, especially of those of late infancy or juvenile onset, in the open populations studied to date. Muscle biopsy, stained by all methods available, is essential to rule out other types of progressive dystrophies secondary to deficiencies of structural proteins. PMID- 10101786 TI - [Mitochondrial encephalopathies: where are we going?]. AB - In few areas of medicine has progress been more spectacular than in the field of mitochondrial diseases, especially those related to mtDNA mutations. Much remains to be done, however, and this brief review discusses the following areas of research where progress has been more limited or data are still controversial: 1. The pathophysiology of mtDNA related disorders; 2. The molecular base of nDNA mutations; 3. The coenzyme Q10 deficiency; 4. Defects of translocases; 5. Defects of mitochondrial protein importation, and 6. Defects of intergemonic signalling. PMID- 10101787 TI - [Man-in-the-barrel syndrome]. PMID- 10101788 TI - [Idiopathic external hydrocephalus in childhood]. PMID- 10101789 TI - [Saddle block anesthesia syndrome with normal neuro-radiological findings]. PMID- 10101790 TI - [The use of carbamazepine in the treatment of secondary ADH deficit: on a letter titled SIADH and carbamazepine]. PMID- 10101791 TI - [Autosomal dominant nocturnal frontal lobe epilepsy]. PMID- 10101793 TI - [Teaching and research: increased fitness and competition. Reflections on a meeting]. PMID- 10101792 TI - [Treatment of thalamic tremor with gabapentine]. PMID- 10101794 TI - [Myopathy associated with neocarbimazole treatment]. PMID- 10101795 TI - [Late diagnosis of aneurysmal subarachnoid hemorrhage]. PMID- 10101796 TI - [Internal ophthalmoplegia: a rare complication of varicella]. PMID- 10101797 TI - Transcriptional regulation of the p53 tumor suppressor gene. AB - Transcriptional regulation of the p53 gene plays an important role in expression of wild type p53 and in elevated expression of mutant p53 genes in tumor cells. In addition, alterations in p53 transcription levels occur in response to changes in the cell cycle. The following review describes current knowledge regarding the structures of both the human and murine p53 transcriptional regulatory regions and the factors that have been demonstrated to regulate promoter activity. The potential role of defects in transcriptional regulation of the p53 gene in oncogenic transformation is discussed. PMID- 10101798 TI - p53-dependent cell cycle control: response to genotoxic stress. AB - p53 protein is involved in key responses to genotoxic stress. These functions underlie the role of p53 as the 'guardian of the genome'. In a simplified manner, upon low or repairable levels of DNA damage, p53 mediates the delay or arrest at checkpoints preceding cell replication (the G1/S checkpoint), and is involved in delaying damaged cells prior premitotic chromosome condensation (the G2 and pre meiotic check-points) and actual chromosome partition (the spindle check-point). During these delays, an opportunity is given to repair the DNA damage, before its fixation and propagation, that may lead to carcinogenesis. Upon high or irreparable DNA damage, p53 promotes the cells towards apoptosis. Here we review the known molecular pathways by which p53 controls the cell cycle, with a specific focus on the significance of p53-mediated checkpoint response for its 'tumor suppressor' function. The data reviewed is concerned with the in vivo mouse models including p53 knockout mice, transgenic mice harboring various mutant forms of p53 and mice knocked out for cell-cycle- and apoptosis-associated genes situated upstream or downstream from p53, that have been elaborated upon over the last few years. PMID- 10101799 TI - Mouse models dissect the role of p53 in cancer and development. AB - Mice lacking one or two copies of the p53 gene have provided invaluable insight into the process of tumorigenesis. The importance of apoptosis in suppression of tumorigenesis in vivo became evident from analysis of these mice. Moreover, the timing and kinds of tumors that develop in these mice are altered by the presence of additional inherited mutations, by strain differences, and by food intake. Developmental abnormalities are also visible in mice with loss of p53 and with overexpression of p53 suggesting that p53 levels are critical for normal cellular processes. While mice do not necessarily recapitulate all the tumor types found in inherited cancers, they offer the unique opportunity to decipher the critical pathways in tumorigenesis. These findings can then be applied to humans. PMID- 10101800 TI - Regulation of p53 downstream genes. AB - The p53 tumor suppressor is the most commonly mutated gene in human cancer. p53 protein is stabilized in response to different checkpoints activated by DNA damage, hypoxia, viral infection, or oncogene activation resulting in diverse biological effects, such as cell cycle arrest, apoptosis, senescence, differentiation, and antiangiogenesis. The stable p53 protein is activated by phosphorylation, dephosphorylation and acetylation yielding a potent sequence specific DNA-binding transcription factor. The wide range of p53's biological effects can in part be explained by its activation of expression of a number of target genes including p21WAFI, GADD45, 14-3-3 sigma, bax, Fas/APO1, KILLER/DR5, PIG3, Tsp1, IGF-BP3 and others. This review will focus on the transcriptional targets of p53, their regulation by p53, and their relative importance in carrying out the biological effects of p53. PMID- 10101801 TI - p53 and apoptosis. AB - One of the several biological functions attributed to p53 is the ability to induce apoptotic cell suicide. It has become clear that this apoptotic activity of p53 is central to its role as a tumor suppressor. A summary of current knowledge concerning the mechanisms of p53-mediated apoptosis is presented. The pivotal 'choice' between p53-induced viable growth arrest and apoptosis is discussed. PMID- 10101802 TI - Reactivation of mutant p53: a new strategy for cancer therapy. AB - The specific DNA binding activity of p53 is crucial for its tumor suppression function. Naturally occurring mutant forms of p53 are deficient for specific DNA binding. However, several studies have indicated that their specific DNA binding can be reactivated. Short peptides derived from the p53 C-terminus can reactivate at least some mutant p53 proteins and trigger a p53-dependent biological response. These results may provide the basis for the design of p53-reactivating anti-cancer drugs. PMID- 10101803 TI - Clinical implications of p53: effect on prognosis, tumor progression and chemotherapy response. AB - The p53 tumor suppressor gene is frequently mutated in most human malignancies. These mutations have been associated with clinical outcome for various cancer types. Since this gene's main function is to guard the integrity of the genome, its clinical relevance, i.e. its role in carcinogenesis and chemotherapy-drug resistance, have been extensively studied. These data and the p53 protein as a potential target for new treatment strategies, are reviewed based on acquired knowledge of the structure function of the p53 protein. PMID- 10101804 TI - Could p53 be a target for therapeutic suppression? AB - The function of p53 has been traditionally viewed in the context of its tumor suppressor activity. In fact, the p53-dependent growth arrest and apoptosis, occurring in response to a variety of stimuli, act to protect the organism from cancer by eliminating potential tumor precursors. However, the same functions of p53 could determine severe damage of normal tissues as a consequence of genotoxic stress associated with anti-tumor therapy. This makes p53 a potential target for therapeutic suppression with the purpose of rescuing normal tissues from the side effects of cancer treatment. We analyze the accumulated information regarding the role of p53 in acute and long-term consequences of genotoxic stress in vivo. Comparison of p53 wild type and p53-deficient mice indicates that p53, in fact, determines massive apoptosis occurring shortly after gamma irradiation in radiosensitive tissues. Sites of apoptosis match the tissue-specific pattern of p53 mRNA expression indicating that p53 regulation at mRNA level is a determinant of acute radiosensitivity of tissues. In the hematopoietic system, radiation induced death of both differentiating and stem cells strongly depends on p53, suggesting that p53 suppression would decrease damage and promote faster recovery of hematopoiesis after anti-cancer therapy. However, p53 does not effect the recovery of radiosensitive epithelia since their stem cells, in contrast to differentiating cells, die in a p53-independent manner. The validity and potential complications of therapeutic suppression of p53 in cancer treatment and under other stressful conditions are discussed in relation to the p53 functions in normal development. PMID- 10101805 TI - Oxidation and the spermatozoa. AB - The unusually high content of phospholipid-bound polyunsaturated fatty acids (PUFA) in the sperm plasma membrane drew attention to their potential physiological significance. Docosahexaenoic acid (22:6) is quantitatively the most important fatty acid. The high PUFA content of sperm membranes makes them vulnerable to peroxidative changes, since PUFA containing two or more double bonds are readily attacked by oxygen radicals. The effects of oxidation on sperm function have been suggested as detrimental as well as beneficial. Generation of reactive oxygen species (ROS) and peroxidation of sperm membrane can bring negative effects on motility, midpiece abnormalities, and sperm-oocyte fusion. ROS trigger sperm hyperactivation, and may support the capacitation of spermatozoa and fertilization. Spermatozoa are protected by various antioxidants and antioxidant enzymes in the seminal plasma or in spermatozoa itself. When the gametes are cultured in vitro, they become more susceptible to oxidative damage. Addition of antioxidants in the media brought beneficial effects in preventing loss of motility and inhibiting lipid peroxidation. Treating patients with antioxidants has shown to have a positive effect on improving fertilization in limited data. The mechanism of antioxidant effects on spermatozoa needs to be further studied. PMID- 10101806 TI - Free radicals in disease. AB - Partial reduction of molecular oxygen can generate reactive oxygen species (ROS), including the hydrogen peroxide, and the free radicals superoxide and hydroxyl. The formation of ROS is a feature of many degenerative diseases, such as atherosclerosis and neurodegeneration, Organisms contain a battery of defense mechanisms to prevent the formation of ROS, to scavenge them, and to repair the damage they cause. Free radicals are also involved in signal transduction pathways. For example, the free radical nitric oxide is involved in signal transduction in both the cardiovascular and central nervous systems. The interplay between nitric oxide and ROS has been a major focus of recent studies, as nitric oxide is an efficient radical scavenger. However, in some cases, such as in the formation of peroxynitrite from nitric oxide and superoxide, the product is potentially more deleterious that the parent radicals. This review describes the major chemical species involved in oxidative stress and free radical biochemistry, and gives a brief overview of their role in pathological conditions. PMID- 10101807 TI - Inflammation, lipids, and free radicals: lessons learned from the atherogenic process. AB - This review focuses on the question of how oxidative stress in cells populating atherosclerotic lesions stimulates gene expression, cell proliferation, and cell death, and how these events contribute to the initiation, progression, and destablization of the lesions. It is hypothesized that oxidative stress in endothelial cells, macrophages, and smooth muscle cells occurs as a result of the depletion of the cellular content of reduced glutathione. Glutathione becomes oxidized in response to the accumulation of oxidized lipids, the formation of reactive oxygen species released from the mitochondria and generated as part of the activation-induced respiratory burst, and the generation of nitric oxide, peroxynitrite, and thiol radicals. Both in vitro and in vivo evidence suggests that these cells can take up modified lipoproteins that become trapped within the artery wall leading to the overaccumulation of oxidized fatty acids and oxidized forms of cholesterol. The cells also generate oxidized lipids via the activity of lipoxygenases, cyclooxygenases, and myeloperoxidase. A sublethal oxidative stress can activate redox-sensitive kinase cascades and transcription factors such as NFB and AP-1, with resulting increases in the expression of factors associated with an inflammatory response and cellular proliferation. There is also accumulating evidence that suggests that oxidative stress may be associated with the induction of cell death either via stimulation of apoptosis and/or necrosis and that increased cell death contributes to the formation of a necrotic core, the hallmark of an advanced, unstable lesion. PMID- 10101808 TI - Endometriosis: a disease of oxidative stress? AB - Our central hypothesis proposes that oxidatively damaged red blood cells (RBCs), apoptotic endometrial cells or undigested endometrial tissue may signal the recruitment and activation of mononuclear phagocytes. Women with endometriosis are prone to respond to this stimulus with an inadequate macrophage scavenger receptor response although the secretory response is not impaired. Activated macrophages in the peritoneal cavity generate an oxidative stress, which consists of lipid peroxides, their degradation products, and products formed from their interaction with low-density lipoprotein (LDL) apoprotein and other proteins. The lipoproteins of the peritoneal fluid (interstitial fluid) have been shown to have lower vitamin E levels and to be more readily oxidized than plasma, so peritoneal fluid may actually contribute to the disease process actively rather than as a passive carrier of mediators of inflammation and growth. As a result of such a stress, a sterile, inflammatory reaction with secretion of growth factors, cytokines, and chemokines is generated, which is deleterious especially to successful reproduction. We propose that such a pro-oxidant environment (peritoneal fluid as well as activated macrophages) promotes growth of ectopic endometrium. The data presented in this review are just the beginning of exploring the role of oxidative stress in mediating the pathophysiology of endometriosis. Only by understanding the mechanisms involved in the pathogenesis of endometriosis can we develop the basis for new diagnostic and therapeutic approaches. PMID- 10101809 TI - Oxygen radicals, antioxidants, and lipid peroxidation. AB - Reactive oxygen species derived from molecular oxygen are highly reactive metabolites. These species can be generated by cellular or acellular mechanisms. They react with all biological molecules such as protein, lipid, and carbohydrates. The reaction of these species with lipids, called lipid peroxidation, is a very well-studied phenomenon. Compounds, which scavenge these molecules, are called antioxidants. The disruption of the delicate balance between pro- and antioxidants has been implicated in the pathophysiology of many chronic diseases such as, for example, atherosclerosis. This article presents an introduction to what reactive oxygen species are and their reactions with various metabolites. It deals with lipid peroxidation in detail and with methods for measuring lipid peroxidation. This article also outlines the importance of these species in the pathology of various gynecological diseases. PMID- 10101810 TI - Aging, menopause, and free radicals. AB - As women undergo menopause, circulating concentrations of estrogen decrease. The relative estrogen deprivation in postmenopausal women is associated with physiological changes and increased risk of several diseases, including cardiovascular disease. Studies in animals have shown that exogenous estrogen inhibits atherosclerosis, the underlying cause of cardiovascular disease. Ongoing clinical trials will soon provide data for the effect of exogenous estrogen on cardiovascular disease in postmenopausal women. Estrogen has a number of effects that could influence atherogenesis and cardiovascular disease. Estrogens have favorable effects on lipoproteins, but such effects can only account for part of the protection from cardiovascular disease that appears to be conferred by estrogen. Evidence suggests that estrogens can have both prooxidant and antioxidant effects. However, the available evidence suggests that in vivo physiological concentrations of estrogen may have a modest antioxidant activity, and prooxidant activity is unlikely. The antioxidant activity of estrogens and inhibition by estrogens of cellular processes that are thought to promote atherosclerosis are likely to be additional mechanism(s) by which estrogen inhibits atherosclerosis and cardiovascular disease, but more work is needed. Studies of some effects of estrogens on atherogenic processes in isolated cells need to be extended to the whole animal. The influence of estrogen receptors on inhibition of atherosclerosis by estrogen needs to be clarified. Future studies should be designed to investigate separately the estrogenic and antioxidant activities of estrogens and estrogen analogs. Investigations of the antioxidant activities of estrogens should include careful consideration of the interaction of estrogens with endogenous antioxidants and fatty acid saturation, and more attention should be paid to the potential for estrogens to inhibit intraarterial oxidation. PMID- 10101811 TI - Antioxidant and prooxidant actions of estrogens: potential physiological and clinical implications. AB - Oxidative stress and free radical-mediated cell death have been linked to diseases such as atherosclerosis, Alzheimer's disease, and cancer. Estrogens may promote, or offer protection against these conditions, by acting both as an antioxidant and prooxidant. Estrogens are converted to catecholestrogens via an oxidation step. Catecholestrogens are precursors of quinones that undergo a reversible oxidation-reduction reaction yielding semiquinones and reactive oxygen species. These semiquinones and reactive oxygen species may act as prooxidants and result in DNA and protein damage that may play a role in initiating tumor growth. Estrogen may also stimulate the peroxidase reaction, thereby promoting prooxidant reactions catalyzed by estrogen. Such reactions may be involved in enhancing the oxidizability of low-density lipoproteins (LDL). This mechanism of oxidation of LDL in plasma may actually lead to increased clearance of LDL by the liver and thereby contribute to estrogens' antiatherogenic action. On the other hand, participation of catecholestrogens in iron redox cycling may contribute to the antioxidant action of estrogens. This action might be important in sites such as the subendothelial space where estrogens are thought to inhibit LDL oxidation. Estrogens may also exert antioxidant effects by acting on genes with response elements for antioxidants. This may in turn inhibit expression of certain proteins involved in disease processes such as atherogenesis. Thus, by acting as an antioxidant and prooxidant, estrogen may produce both beneficial and adverse effects important in the prevention and pathogenesis of disease. PMID- 10101812 TI - Osteogenic protein versus autologous interbody arthrodesis in the sheep thoracic spine. A comparative endoscopic study using the Bagby and Kuslich interbody fusion device. AB - STUDY DESIGN: Using an in vivo interbody arthrodesis model, the efficacy of the Bagby and Kuslich (BAK) device packed with recombinant human osteogenic protein-1 (rhOP-1) was evaluated. OBJECTIVES: To compare the efficacy of osteogenic protein with that of autograft for interbody arthrodesis, with fusion success based on biomechanical, histologic, and radiographic analyses. SUMMARY OF BACKGROUND DATA: The use of recombinant human bone morphogenetic proteins (rhBMPs) as osteoinductive bone graft substitutes or expanders has recently gained considerable research interest, particularly when applied in posterolateral arthrodesis. However, whether these results can be extrapolated to a successful interbody spinal arthrodesis remains uncertain. METHODS: Twelve sheep underwent a multilevel thoracic spinal decompression by thoracoscopic approach. Three noncontiguous destabilization sites (T5-T6, T7-T8, T9-T10) were prepared and randomly treated as follows. Control group treatments were nonsurgical, destabilization alone, and empty BAK. Experimental groups were treated with autograft alone, BAK device packed with autograft, or BAK device packed with rhOP 1. Four months after surgery, interbody fusion status was quantified by biomechanical testing, computed tomography, microradiography, and histomorphometry. RESULTS: Results of biomechanical analysis showed statistically higher segmental stiffness levels when comparing the control and experimental groups with four of the five testing methods (P < 0.05). Computed tomography and microradiography characterized destabilization alone as producing one fusion in six preparations; the empty BAK, two in six;, autograft alone, four in eight; BAK with autograft, five in eight; and BAK with rhOP-1 group, six in eight-all evidenced by woven trabecular bone spanning the fusion sites. Histomorphometry yielded significantly more trabecular bone formation at the fusion sites in the three experimental groups than in the two control groups (P < 0.05). CONCLUSIONS: Interbody spinal fusions showing biomechanical and histomorphometric equivalency to autologous fusions have been achieved with rhOP-1. The functional unit stability and histologic osteointegration evidenced by the BAK/rhOP-1 complex shows this interbody arthrodesis technique to be a viable alternative toconventional autologous iliac crest, thereby obviating the need for an iliac crest donor site and associated patient morbidity. PMID- 10101813 TI - Osteoarthrosis of the facet joints resulting from anular rim lesions in sheep lumbar discs. AB - STUDY DESIGN: Facet joints from sheep lumbar spines were examined for histologic evidence of osteoarthrosis after anular incision. OBJECTIVES: To describe the sequence of changes in facet joints in an animal model of disc degeneration. SUMMARY OF BACKGROUND DATA: There are many studies with results showing a link between facet joint osteoarthrosis and disc degeneration, but the development of osteoarthrosis in facet joints has not been observed in a controlled study of disc degeneration. METHODS: Histologic features of facet joint degeneration were compared with established descriptions of human osteoarthrosis, and the sequence of changes was documented in a controlled prospective study of disc degeneration. RESULTS: Osteoarthrosis in sheep lumbar facet joints is similar to that described in human joints and develops in response to anular injury. Discs degenerate relatively soon after anular incision, but there is a long delay in the appearance of significant changes to the facet joints at the level of anular incision and adjacent levels. CONCLUSIONS: The results shows that facet joints in sheep undergo osteoarthrotic changes in response to disc degeneration and confirm the sheep as a suitable model for the study of degenerative spinal disorders. PMID- 10101814 TI - Headmaster collar restricts rheumatoid atlantoaxial subluxation. AB - STUDY DESIGN: A radiographic study of the effect of a modern orthotic device in the treatment of rheumatoid atlantoaxial subluxation. OBJECTIVE: To study the ability of a new open-type collar to restrict atlantoaxial subluxation. SUMMARY OF BACKGROUND DATA: Atlantoaxial subluxation is common in rheumatoid arthritis, and thus, the development of conservative treatments is important. It has been shown that a custom-made stiff collar significantly restricts atlantoaxial subluxation in approximately half of patients with unstable atlantoaxial subluxation. METHODS: In 30 successive patients with rheumatoid atlantoaxial subluxation, lateral view radiographs were taken in flexion, extension, and neutral positions without a collar and in flexion with the Headmaster collar. RESULTS: The mean atlantoaxial distance during flexion was 7.1 +/- 1.8 mm and during extension was 1.0 +/- 1.0 mm, and the mean instability was 6.1 +/- 2.3 mm. In the 20 cases with the greatest stabilizing effect, the mean atlantoaxial distance during flexion with a collar was 1.1 +/- 1.3 mm, whereas in 10 patients with lesser effect it was 6.7 +/- 2.5 mm (P < 0.0001). The lesser stabilizing effect was associated with the presence of atlantoaxial subluxation in the neutral position. CONCLUSION: The Headmaster collar is an effective and useful tool in the conservative treatment of simple unstable atlantoaxial subluxation, but an ordinary custom-made stiff collar is still often needed. These two collars are complementary, and their selection and use must be determined individually. PMID- 10101815 TI - Outcomes of surgical treatment for cervical myelopathy in patients more than 75 years of age. AB - STUDY DESIGN: Retrospective study on the results of surgical treatment of compressive cervical myelopathy in patients more than 75 years of age. OBJECTIVES: To investigate clinical features and surgical outcomes of compressive cervical myelopathy in aged patients and to discuss the role of surgical treatment. SUMMARY OF BACKGROUND DATA: There are few data focused on the outcomes of surgery in patients with cervical myelopathy who are more than 75 years of age. METHODS: Seventeen patients with compressive cervical myelopathy who underwent surgery were reviewed. The average age at the time of surgery was 77.2 years. Posterior decompression in 15 patients and anterior decompression in 2 patients were performed. Neurologic deficits before and after surgery were assessed using a scoring system proposed by the Japanese Orthopaedic Association (JOA score). Independence of daily living was evaluated. Radiologic features were examined with radiographs and magnetic resonance imaging. Clinical results were compared with those of patients less than 65 years old as a control. RESULTS: The preoperative mean JOA score was 6.1, the postoperative maximum JOA scores averaged 11.4, and the recovery rate was 48.4%. These were significantly inferior to scores in those less than 65 years of age. All seven of the patients who could not walk even with aids before surgery became independent in daily activities after surgery. At the final follow-up, the mean JOA score had decreased to 10.7 and the recovery rate to 39.1%. Five of nine patients whose follow-up periods were more than 5 years showed decreases in JOA score, although all patients were still ambulatory. CONCLUSIONS: Surgical decompression for cervical myelopathy appears to be beneficial, even in patients more than 75 years of age, in improving neurologic function and ability to engage in activities of daily living. PMID- 10101816 TI - Spinal growth and a histologic evaluation of the Risser grade in idiopathic scoliosis. AB - STUDY DESIGN: Thirty-four patients with idiopathic scoliosis who underwent anterior spinal surgery as part of the correction of spinal deformity were studied prospectively. Superior and inferior endplates were harvested and examined histologically for evidence of residual growth activity. This was then correlated with Risser grades, chronologic age, and pubertal status. OBJECTIVES: To clarify the correlation between Risser grade and vertebral endplate growth potential in patients with idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: The importance of longitudinal spinal growth in patients with idiopathic scoliosis and its correlation with curve progression and the crankshaft phenomenon after posterior fusion are well recognized. The Risser grade, which shows the extent of excursion of the iliac apophysis on serial plain radiographs, is commonly used to estimate residual spinal growth. However, the correlation between the Risser grade and vertebral endplate growth potential in patients with idiopathic scoliosis remains unclear. METHODS: Superior and inferior endplates were harvested from these patients and examined histologically for evidence of residual growth. This was correlated with Risser grade, chronologic age, and pubertal status. RESULTS: Risser Grade 5 was found to be the only indicator of cessation of vertebral growth in idiopathic scoliosis. Of the 14 patients with Risser Grade 4, 10 showed significant growth activity in the vertebral endplates. The reliability of Risser Grade 4 increases when combined with chronologic age and time since menarche in female patients. CONCLUSIONS: The crankshaft phenomenon is reported to occur only in patients with Risser Grade 2 or less, particularly those with open triradiate cartilages. Our findings of significant endplate growth activity, even in patients with Risser Grade 4, make it unlikely that the crankshaft phenomenon is caused purely by longitudinal spinal growth. PMID- 10101817 TI - The validity in persons with spinal cord injury of a self-reported functional measure derived from the functional independence measure. AB - STUDY DESIGN: A cross-sectional, mailed survey on impairment and function using 6361 respondents to the Spinal Cord Dysfunction National Veterans Survey who reported spinal cord injury as the sole cause of their spinal cord dysfunction. OBJECTIVES: To establish the concurrent and construct validities of a Self Reported Functional Measure appropriate for use in patients with spinal cord injuries. SUMMARY OF BACKGROUND DATA: Functional assessment is of increasing importance in clinical care, quality assurance, and national health-care planning. There is a conspicuous need for validated functional assessment measures that are rapid, reliable, and appropriate for use in the disabled population. METHODS: The correlation was examined of hours of personal assistance, number of affected limbs, amount of motor impairment, and amount of combined limb-motor impairment to Self-Reported Functional Measure response tertile (scores, 13-32, 33-45, 46-52; lower scores indicated worse function). RESULTS: There were statistically significant correlations between Self-Reported Functional Measure score and hours of personal assistance (P < 0.001), the number of affected limbs (P < 0.001), the amount of motor impairment (P < 0.001), and the amount of combined limbmotor impairment (P < 0.001). For example, 87% of people with the most limb-motor impairment (four affected limbs and no useful movement) were in the lowest Self-Reported Functional Measure tertile, compared with 3% of people in the least-affected category of limb-motor impairment. Furthermore, visual, sensory, or memory impairment did not influence the correlation between limbmotor impairment and Self-Reported Functional Measure score. CONCLUSION: The Self-Reported Functional Measure shows good concurrent and construct validities. PMID- 10101818 TI - Interaction between voluntary and postural motor commands during perturbed lifting. AB - STUDY DESIGN: An experimental study was conducted to evaluate the effect of an unexpected postural perturbation during a lifting task. OBJECTIVES: To investigate electromyographic responses in the erector spinae to a postural perturbation, simulating slipping, during an ongoing voluntary lifting movement. It was hypothesized that specific combinations of voluntary movement and postural perturbation present a situation in which injury caused by a rapid switch between conflicting motor commands can occur. SUMMARY OF BACKGROUND DATA: Studies of postural perturbations have mainly focused on behavior during static tasks such as quiet, upright standing. To date, there are no published studies of the effect of a perturbation during an ongoing voluntary lifting movement. METHODS: Subjects standing on a movable platform were exposed to random perturbations while lifting a 20-kg load. Muscle activity was recorded from flexor and extensor muscles of the trunk and hip. Trunk flexion angle in the sagittal plane was recorded with a video system. RESULTS: Perturbations forward were followed by an increased activity in erector spinae superimposed on the background activation present during the lift, indicating that both the voluntary and postural motor programs caused an activation of erector spinae. During backward perturbation, however, there was a sudden cessation of erector spinae activity followed by an extended period of rapid electromyographic amplitude fluctuations while the trunk was flexing, indicating an eccentric contraction of the erector spinae. CONCLUSIONS: This erratic behavior with large electromyographic amplitude fluctuations in the erector spinae after a backward slip during lifting may indicate a rapid switch between voluntary and postural motor programs that require conflicting functions of the back muscles. This may cause rapid force changes in load-carrying tissue, particularly in those surrounding the spine, thus increasing the risk of slip-and fall-related back injuries. PMID- 10101819 TI - A randomized prospective study of posterolateral lumbar fusion. Outcomes with and without pedicle screw instrumentation. AB - STUDY DESIGN: A prospective evaluation of the clinical and radiographic outcomes of 71 patients who underwent lumbar fusion, with or without transpedicular instrumentation. The patients completed a questionnaire that determined pain relief, medication use, return to work, and overall satisfaction with surgery. OBJECTIVES: To explore the effect, if any, of instrumentation on the outcome of lumbar fusion surgery, according to reports of the patients, and whether there is a correlation between the radiographic determination of a solid fusion and the same patient-reported outcome. SUMMARY OF BACKGROUND DATA: The literature on this topic reports pseudarthrosis rates from 0% to 57% and good to excellent results from 56% to 95%. These studies provide no clear-cut recommendations concerning the effect of added lumbar instrumentation on patient-reported outcome in a prospective manner using concurrent control subjects. METHODS: The patients were randomized to groups with and without instrumentation after deciding to undergo a lumbar fusion and consenting to enter the study. Radiographs were obtained and questionnaires filled out at 6 weeks, 6 months, 1 year, and 2 years after surgery. RESULTS: There was no statistical difference in patient-reported outcome between the two groups. There was a slight nonsignificant trend toward increased radiographic fusion rate in the group with instrumentation that did not correlate with an increased patient-reported improvement rate. CONCLUSIONS: These results do not provide data that indicate a benefit in outcome from added instrumentation in elective lumbar fusions. PMID- 10101820 TI - Patient outcomes after decompression and instrumented posterior spinal fusion for degenerative spondylolisthesis. AB - STUDY DESIGN: A retrospective study of patient outcomes after decompression and fusion for degenerative spondylolisthesis, using the SF-36 survey and a functional questionnaire. SUMMARY OF BACKGROUND DATA: In recent studies, patient outcomes have been examined more specifically; however, detailed functional outcomes are not available nor have widely used outcomes instruments been administered. METHODS: Thirty patients aged more than 40 years (average, 60.1 years) who had degenerative spondylolisthesis were evaluated after decompression and instrumented posterior fusion. Charts and radiographs were also reviewed. Questionnaires were administered by telephone, and consisted of the Medical Outcomes Study short form (SF-36) and 27 questions designed to evaluate function, quality of life, medication usage, and satisfaction with surgical results. RESULTS: Ninety-three percent of patient's were satisfied with their outcomes. Patients improved significantly in their ability to perform heavy and light activities, participate in social activities, sit, and sleep (P < 0.001) and also improved in pain, depression, and medication usage (P < 0.0001). SF-36 data showed significantly better overall assessment of health in all categories than that in a published cohort of patients with low back pain. The current study group also showed no difference in seven of eight categories when compared with the general population. Fusion rate was 93% at an average of 128 days. Three patients required reoperation: two for pseudarthrosis and one for a deep infection. A poorer outcome, scored by the SF-36, was associated with greater preoperative stenosis (P < 0.05) or occurrence of a complication (P < 0.05). CONCLUSIONS: Patients treated with decompression and fusion for degenerative spondylolisthesis had improved functional outcomes, when measured by a disease specific questionnaire and by widely used instruments. PMID- 10101821 TI - The outcome of lumbar discectomy in elite athletes. AB - STUDY DESIGN: An outcomes assessment of 14 elite college athletes who had undergone lumbar disc surgery was performed using the SF-36, a validated questionnaire that assesses quality of life. OBJECTIVES: To determine the outcomes and results of lumbar disc surgery in an elite group of athletes and compare the results with those in the general population and in age-matched control subjects. SUMMARY OF BACKGROUND DATA: Lumbar disc surgery is reported to be a highly successful procedure with excellent results. The outcome in elite athletes has not been assessed and compared with population norms and age-matched control subjects. METHODS: Fourteen athletes from schools in the National Collegiate Athletic Association with a mean age of 20.7, underwent lumbar discectomy for radiculopathy refractory to conservative treatment. Ten had a single-level microdiscectomy, three a two-level microdiscectomy, and one a percutaneous discectomy. Patients were evaluated at a mean follow-up of 3.1 years, underwent a detailed clinical evaluation, and filled out the SF-36 questionnaire. RESULTS: All 14 patients had improvement of pain with elimination of the radicular component, took less medication than before surgery, and returned to recreational sports. Nine patients, all with a single level microdiscectomy, returned to varsity sports. Five athletes prematurely retired from competitive sports because of continued symptoms. Three of the athletes who retired underwent two-level procedures, and one had a percutaneous discectomy. SF 36 scores for bodily pain, physical role, and social and mental health roles were significantly lower in those athletes who retired. Patient scores were also compared with those in a group of noninjured age-and sport-matched college athletes. There were no differences between injured and noninjured athletes, but both groups had scores significantly lower than normal values in an age-matched group for bodily pain, physical role, general health, and social function. CONCLUSIONS: All patients were satisfied with their surgeries, were greatly improved, and were pain free in activities of daily living. For a single-level microdiscectomy, the success rate in elite athletes is excellent, with 90% of athletes able to return to a high level of competition. Two-level disease may be associated with a less favorable outcome. PMID- 10101822 TI - Cervical spondylodiscitis after removal of a fishbone. A case report. AB - STUDY DESIGN: A case report of cervical spondylodiscitis after removal of a lodged fishbone. OBJECTIVES: To present a rare case of cervical spondylodiscitis and to inform the readers that a lodged fishbone can give rise to this complication after its removal. SUMMARY OF BACKGROUND DATA: In the literature, only one mention of this complication was found. METHODS: The literature, clinical presentation, technical examinations, and treatment are reviewed. RESULTS: Prolonged antibiotic treatment and immobilization of the cervical spine resulted in a cure of the spondylodiscitis. CONCLUSIONS: After removal of a lodged fishbone, a cervical spondylodiscitis is possible, but this is a very rare complication. In this patient, conservative treatment resulted in a cure of the infection. Successive magnetic resonance imaging investigations showed the extent of the destruction of the vertebral bodies and disc very well, as well as the curation of the spondylodiscitis after 5 months. PMID- 10101823 TI - Spontaneous regression of periodontoid pannus mass in psoriatic atlantoaxial subluxation. Case report. AB - STUDY DESIGN: A case report of a 41-year-old man with psoriasis who had cervical myelopathy caused by atlantoaxial subluxation and periodontoid pannus mass. OBJECTIVE: To describe the possible mechanism underlying the periodontoid pannus formation and the optimal treatment for such cases. SUMMARY OF BACKGROUND DATA: Atlantoaxial subluxation causing spinal cord compression at the craniocervical junction may develop in patients with rheumatoid or psoriatic arthritis. Periodontoid pannus formation plays an important role in compromising the anteroposterior diameter of the spinal canal and in causing neurologic deficits. Transoral transpharyngeal excision of the pannus is sometimes thought necessary for anterior decompression of the spinal cord. Spontaneous resolution of the periodontoid pannus after posterior atlantoaxial fusion and fixation has been documented in rheumatoid arthritis, but not in psoriatic arthritis. METHODS: The patient underwent posterior atlantoaxial fusion and Halifax fixation. RESULTS: The patient experienced clinical improvement. Regression of the periodontoid pannus mass was observed on magnetic resonance imaging. CONCLUSIONS: Posterior fusion and instrumentation resulted in spontaneous regression of the pannus mass and symptomatic relief. This report provides evidence that atlantoaxial instability may be the sine qua non for the formation of periodontoid pannus, and that amelioration of such instability leads to spontaneous resolution of the pannus mass. PMID- 10101824 TI - Pyogenic vertebral osteomyelitis caused by Campylobacter fetus subspecies fetus. A case report. AB - STUDY DESIGN: Clinical observation of a patient. OBJECTIVES: To present the clinical features of an unusual infection of the spine caused by Campylobacter fetus subspecies fetus and to suggest treatment. SUMMARY OF BACKGROUND DATA: This is only the second reported case of pyogenic vertebral osteomyelitis caused by Campylobacter fetus subspecies fetus. METHODS: A 66-year-old man had pain of the left lower extremity. Radiologic examination revealed an epidural mass associated with destruction of the L5-S1 vertebral bodies. RESULTS: Biopsy of the epidural mass was performed, and culture yielded Campylobacter fetus subspecies fetus. After intravenous antibiotics, oral doxycycline and erythromycin were given for 5 months. At 9 months after antibiotic treatment was completed, the patient's condition was stable. CONCLUSIONS: Prolonged oral administration of doxycycline and erythromycin was curative in this patient. PMID- 10101825 TI - Cranial nerve palsy as a complication of operative traction. AB - STUDY DESIGN: Case report. OBJECTIVE: This report documents one case of diplopia from abducens (sixth cranial) nerve palsy after spinal surgery using a Jackson table and cranial traction. SUMMARY OF BACKGROUND DATA: Cranial nerve deficits have frequently been described in the orthopedic literature after trauma, halo pelvic traction, and halo skeletal fixation. The theorized mechanism of injury to the abducens nerve involves stretch or traction force, which causes localized ischemia or a change in nerve position. An extensive literature search failed to show this type of injury using Gardner-Wells tongs in conjunction with the Jackson table. METHODS: This is a case report that included a chart review, examination of the patient, and a literature search. RESULTS: The patient had complete spontaneous resolution of abducens nerve dysfunction within 6 months. CONCLUSIONS: It is important for the surgeon to be aware of this potential complication and to inform patients who have diplopia that develops from abducens nerve palsy that most of these cranial nerve deficits spontaneously improve. PMID- 10101826 TI - Spondyloptosis of the cervical spine in neurofibromatosis. A case report. AB - STUDY DESIGN: Case report and literature review. OBJECTIVES: To review the English literature pertaining to spondyloptosis of the cervical spine in patients with Von Recklinghausen's disease and to present as an illustrative example the case of a 41-year-old woman with a spondyloptotic kyphotic curve of the spine at C5-C7 of more than 110 degrees. SUMMARY OF BACKGROUND DATA: Involvement of the cervical spine in neurofibromatosis has only rarely been documented, although the spine is the part of the skeleton mostly affected in this hereditary disease. Only a few cases with a cervical kyphotic curve exceeding 90 degrees or with cervical spondyloptosis have been reported until now. METHODS: A literature and chart review was conducted. The patient was first treated conservatively, but over time, the spontaneous neck pain increased to an intolerable level and progressive neurologic deficits developed in the four limbs. For these reasons, surgical intervention was undertaken, according to suggestions from the literature. RESULTS: Postoperative imaging showed improved realignment of the cervical spine with a residual kyphos of 30 degrees. At later follow-up stable bony fusion was obtained in the lower cervical spine. CONCLUSIONS: A successful one-stage anterior and posterior correction and fusion-stabilization procedure was performed with extension from the occiput to T1. PMID- 10101827 TI - Outcome in patients with cervical radiculopathy. Prospective, multicenter study with independent clinical review. AB - STUDY DESIGN: The Cervical Spine Research Society study is a prospective, nonrandomized, multicenter investigation of patients with cervical spondylosis and disc disease. In this analysis, only patients who had radiculopathy without myelopathy as the predominant symptom were considered. OBJECTIVES: To determine demographics, surgeon treatment practices, and outcomes in patients with symptomatic radiculopathy. SUMMARY OF BACKGROUND DATA: Current data on patient demographics and treatment practices of surgeons do not exist. There are no published prospective studies in which outcomes, including pain, function, neurologic symptoms, and ability to perform activities of daily living, are systematically quantified. METHODS: Patients were recruited by participating Cervical Spine Research Society surgeons. Demographic, symptomologic, and functional patient data were compiled from surveys of patients and physicians completed at the time of initial examination, and outcomes were assessed from surveys of patients completed after treatment. Data were compiled and statistically analyzed by a blinded third party. RESULTS: Of the 503 patients enrolled by 41 CSRS surgeons, 246 (49%) had radiculopathy. Patients had a mean duration of symptoms of 26.7 months (range, 8 weeks to > 352 months) and a mean age of 48.1 +/- 12.42 years; 44.7% were female. Surgery was recommended for 86 (35%) of these patients. Of the 155 patients on whom there were follow-up data, 51 (33%) underwent surgery, whereas 104 (67%) received medical treatment. Surgically treated patients had a significant improvement in pain, neurologic symptoms, functional status, and ability to perform activities of daily living. A significant number of patients who underwent surgery reported persistent excruciating or horrible pain on follow-up (26%). Patients treated medically also had significant improvement in pain and overall functional status. CONCLUSIONS: In summary, this study represents the first in-depth, prospective outcome analysis of patients with cervical spondylotic and discogenic radiculopathy. PMID- 10101828 TI - The optimal radiologic method for assessing spinal canal compromise and cord compression in patients with cervical spinal cord injury. Part I: An evidence based analysis of the published literature. AB - STUDY DESIGN: An evidence-based analysis of published radiologic criteria for assessing spinal canal compromise and cord compression in patients with acute cervical spinal cord injury. OBJECTIVES: This study was conducted to determine whether literature-based guidelines could be established for accurate and objective assessment of spinal canal compromise and spinal cord compression after cervical spinal cord injury. SUMMARY OF BACKGROUND DATA: Before conducting multicenter trials to determine the efficacy of surgical decompression in cervical spinal cord injury, reliable and objective radiographic criteria to define and quantify spinal cord compression must be established. METHODS: A computer-based search of the published English, German, and French language literature from 1966 through 1997 was performed using MEDLINE (U.S. National Library of Medicine database) to identify studies in which cervical spinal canal and cord size were radiographically assessed in a quantitative manner. Thirty seven references were included for critical analysis. RESULTS: Most studies dealt with degenerative disease, spondylosis, and stenosis; only 13 included patients with acute cervical spinal cord injury. Standard lateral radiographs were the most frequent imaging method used (23 studies). T1- and T2-weighted magnetic resonance imaging were used to assess spinal cord compression in only 7 and 4 studies, respectively. Spinal cord size or compression were not precisely measured in any of the cervical trauma studies. Interobserver or intraobserver reliability of the radiologic measurements was assessed in only 7 (19%) of the 37 studies. CONCLUSIONS: To date, there are few quantitative, reliable radiologic outcome measures for assessing spinal canal compromise or cord compression in patients with acute cervical spinal cord injury. PMID- 10101829 TI - The optimal radiologic method for assessing spinal canal compromise and cord compression in patients with cervical spinal cord injury. Part II: Results of a multicenter study. AB - STUDY DESIGN: A multicenter, retrospective study using computed tomographic and magnetic resonance imaging data to establish quantitative, reliable criteria of canal compromise and cord compression in patients with cervical spinal cord injury. OBJECTIVES: To develop and validate a radiologic assessment tool of spinal canal compromise and cord compression in cervical spinal cord injury for use in clinical trials. SUMMARY OF BACKGROUND DATA: There are few quantitative, reliable criteria for radiologic measurement of cervical spinal canal compromise or cord compression after acute spinal cord injury. METHODS: The study included 71 patients (55 men, 16 women; mean age, 39.7 +/- 18.7 years) with acute cervical spinal cord injury. Causes of spinal cord injury included motor vehicle accidents (n = 36), falls (n = 20), water-related injuries (n = 8), sports (n = 5), assault (n = 1), and farm accidents (n = 1). Canal compromise was measured on computed tomographic scan and T1- and T2-weighted magnetic resonance imaging, and cord compression at the level of maximum injury was measured on T1- and T2-weighted magnetic resonance imaging. All films were assessed by two independent observers. RESULTS: There was a strong correlation of canal compromise and/or cord compression measurements between axial and midsagittal computed tomography, and between axial and midsagittal T2-weighted magnetic resonance imaging. Spinal canal compromise assessed by computed tomography showed a significant although moderate correlation with spinal cord compression assessed by T1- and T2-weighted magnetic resonance imaging. Virtually all patients with canal compromise of 25% or more on computed tomographic scan had evidence of some degree of cord compression on magnetic resonance imaging, but a large number of patients with less than 25% canal compromise on computed tomographic scan also had evidence on magnetic resonance imaging of cord compression. CONCLUSIONS: In patients with cervical spinal cord injury, the midsagittal T1- and T2-weighted magnetic resonance imaging provides an objective, quantifiable, and reliable assessment of spinal cord compression that cannot be adequately assessed by computed tomography alone. PMID- 10101830 TI - Spectrophotometric determination of Sn(II) using palladium chloride in kits for 99mTc radiopharmaceuticals. AB - A method of quantitating Sn(II) suitable for the analysis of kits for 99mTc radiopharmaceuticals, based on a spectrophotometric determination using the Pd(II)-Sn(II) complex (yellow species) is described. The absorbance of the complex is measured at 410 nm and Beer's law is obeyed up to 250 micrograms Sn(II) in the aqueous phase. Several radiopharmaceutical kits were analyzed for their Sn(II) content. The investigation indicates that the procedure is simple, rapid and accurate for quantitative estimation of Sn(II) in various 99mTc labelling kits during development, manufacture and storage. PMID- 10101832 TI - The synthesis of (R)- and (S)-[N-methyl-11C]beta, beta-difluoromethamphetamine for the investigation of the binding mechanism of biogenic amines in vivo. AB - In an attempt to elucidate the contribution of the extent of nitrogen protonation on the in vivo binding of methamphetamine in the brain, the enantiomers of [N methyl-11C]beta, beta-difluoroamphetamine (4) were prepared for use in positron emission tomography (PET) studies. Thus, the enantiomers of beta, beta difluoroamphetamine were prepared from trans-beta-methylstyrene, via bromination, conversion into the azirine, fluorination and resolution as the tartrate salts. (R)- and (S)-beta, beta-difluoroamphetamine (3) were then each labelled with carbon-11 (tt/2 = 20.4 min) by N-methylation of the corresponding homochiral beta, beta-difluoroamphetamine with [11C]methyl iodide. The labelled products were each synthesised, purified and formulated in 35 min, starting from [11C]carbon dioxide in 15-16% decay-corrected radiochemical yield, with a radiochemical purity of > 99% and specific radioactivity of 50-150 GBq mumol-1 at end of synthesis. PMID- 10101831 TI - The use of clinoptilolite and its sodium form for removal of radioactive cesium, and strontium from nuclear wastewater and Pb2+, Ni2+, Cd2+, Ba2+ from municipal wastewater. AB - Three different samples of Iranian natural zeolites (clinoptilolite) and its sodium exchanged forms have been investigated for uptaking several different cations. Ion-exchange isotherms, have been given and discussed. PMID- 10101833 TI - NHS-MAS3: a bifunctional chelator alternative to NHS-MAG3. AB - This laboratory uses an N-hydroxysuccinimide derivative of S acetylmercaptoacetyltriglycine (NHS-MAG3) to conjugate amines for subsequent labeling with 99mTc. However, the synthesis from triglycerine is general and not restricted to this tripeptide. We had earlier selected a small number of alternative tripeptides and synthesized the corresponding NHS derivatives. Each was then evaluated in a search for bifunctional chelators with properties superior to NHS-MAG3, such as lower serum protein binding or improved stability to cysteine challenge. Based on these preliminary results, NHS-S acetylmercaptoacetyltriserine (NHS-MAS3) was selected for further investigation. We have now conjugated this bifunctional chelator to an biocytin and to an amine derivatized peptide nucleic acid (PNA). Both carriers were also conjugated with NHS-MAG3 under identical conditions and all were labeled with 99mTc at neutral pH and at boiling temperature while the conjugated PNAs were radiolabelled at neutral pH and at room temperature. Regardless of the chelator, reverse phase HPLC radiochromatograms of the labeled biotins and PNAs after purification showed a single peak. However, by size exclusion HPLC, the radiochromatograms always showed several peaks even after purification, but the MAS3 radiochromatograms were less complicated. For biotin and PNA both, radiolabeling via MAS3 showed improved 99mTc stability in 37 degrees C serum and in cysteine solution. The four preparations were administered to mice implanted in one thigh with avidin beads (biotins) or complementary PNA beads (PNAs). At 5 h post-administration, no significant differences were observed in the targeting of PNA beads between the two chelators, however the target thigh/normal thigh ratio was significantly higher for MAS3-biotin compared to MAG3-biotin. We conclude that labeling biocytin and amine-derivatized PNA with NHS-MAS3 compared to NHS-MAG3 provides simpler radiochromatographic profiles, improved stability of the label in serum and cysteine solution and can improve in vivo targeting. PMID- 10101834 TI - Dose assessment and behavior of tritium in environmental samples around Wolsong nuclear power plant. AB - For the estimation of the dispersion trend of tritium discharged from the Wolsung nuclear power plant, the present level of tritium in environmental samples in the vicinity of the Wolsong site has been studied. On the basis of tritium concentrations in environmental samples, the effective dose due to tritium has been estimated for an individual and population within a 16 km radius from the Wolsong site. The annual effective dose of tritium to an inhabitant around the Wolsong site ranged from 0.15 microSv y-1 to 1.3 microSv y-1. The dose level was negligible and much lower than some applicable standards, i.e. the limit on exposure from nuclear fuel cycle to the general public as recommended by ICRP (1 mSv y-1) or US EPA's limit (0.25 mSv y-1). The collective dose to the total population within a 16 km radius from the site, 1.2 x 10(-2) man.Sv y-1 was much lower than 1 man.Sv y-1, an applicable criterion for the so-called "exemption" of radiation sources and practices from regulatory control. PMID- 10101835 TI - Measurement of biodegradable substances using the salt-tolerant yeast Arxula adeninivorans for a microbial sensor immobilized with poly(carbamoyl) sulfonate (PCS) Part I: Construction and characterization of the microbial sensor. AB - A microbial biosensor based on the yeast Arxula adeninivorans LS3 has been developed for measurement of biodegradable substances. Arxula is immobilized in the hydrogel poly(carbamoyl) sulfonate (PCS). The immobilized yeast membrane is placed in front of an oxygen electrode with -600 mV versus Ag/AgCl. Arxula is salt tolerant; it can give a stable signal up to 2.5 M NaCl in sample (120 mM in measuring cell). The sensor's measurements are highly correlated to BOD5 measurements. It has a very high stability which can last for 40 day without any decrease in signal. The linear range of the sensor is up to a corresponding BOD value of 550 mg/l. PMID- 10101836 TI - Quartz crystal microbalance (QCM) as a device for the screening of phage libraries. AB - An immunosensing system based on a quartz crystal microbalance (QCM) is presented for the selection of both antigen specific recombinant antibodies and antigen specific human pancreatic secretory trypsin inhibitor (hPSTI) mutants isolated from large phage libraries. The QCM was integrated into a flow injection analysis system for the straightforward analysis of large sample numbers. Measurements were performed using a biotinylated antigen immobilized by streptavidin onto the gold surface of the quartz crystal and phages displaying recombinant antibodies or hPSTI mutants. The results obtained by the QCM were in accordance to those of a well established enzyme linked immunosorbent assay (ELISA). Therefore, the QCM is well suited for the detection of single high affinity clones isolated from large phage display libraries. PMID- 10101837 TI - Immobilization of histidine-tagged proteins on gold surfaces using chelator thioalkanes. AB - The reversible, oriented immobilization of proteins on solid surfaces is a prerequisite for the investigation of molecular interactions and the controlled formation of supramolecular assemblies. This paper describes a generally applicable method using a synthetic chelator thioalkane that can be self assembled on gold surfaces. The reversible binding of an anti-lysozyme F(ab) fragment modified with a C-terminal hexahistidine extension was monitored and the apparent dissociation constants determined using surface plasmon resonance. Infra red spectroscopy demonstrated that the secondary structure of the protein was unaffected by the immobilization process. The retention of functionality of the immobilized protein was also successfully demonstrated. Given the mild reaction conditions and reversibility, this method of oriented immobilization of proteins opens possibilities for the development of biosensors. PMID- 10101838 TI - Detecting staphylococcal enterotoxin B using an automated fiber optic biosensor. AB - The Man-portable Analyte Identification System (MANTIS), the first fully automated, self-contained, portable fiber optic biosensor, was utilized for the detection of Staphylococcal Enterotoxin B (SEB), a bacterial toxin produced by Staphylococcus aureus that commonly causes food poisoning. Because of its remarkable toxicity and stability, SEB is considered a prime threat as a biological weapon of mass destruction. The assay for SEB was used to evaluate the MANTIS' ability to function in the presence of various environmental interferents. The sensor could reliably detect SEB spiked into liquid samples containing a variety of smoke particles. However, substantial interference occurred when SEB was mixed into matrices capable of adsorbing SEB, such as 1% solutions of clay, topsoil, or pollen. Of equal importance, none of the interferents produced false positives in the MANTIS. The MANTIS demonstrated the capability to perform simultaneous immunoassays rapidly in the field with little or no user intervention. PMID- 10101839 TI - Characterisation of a thermophilic L-glutamate dehydrogenase biosensor for amperometric determination of L-glutamate by flow injection analysis. AB - Carbon paste wax electrodes incorporating thermophilic L-glutamate dehydrogenase, NADP and a polymeric toluidine blue O (poly-TBO) mediator have been characterised for the amperometric determination of L-glutamate at 313-318 K in a flow injection analysis (FIA) system. The biosensors exhibit good sensitivity, mechanical stability and reproducibilty, unlike carbon paste- or carbon wax-based electrodes under the same conditions. The carbon paste wax electrode responds linearly to L-glutamate up to 40 mM, the detection limit is 0.3 mM and the RSD (n = 10) for 5 mM L-glutamate was 7.6%. The response to some potential interferents has been quantified. Addition of finely ground hexaammineruthenium (III) trichloride ([Ru(NH3)6]Cl3) to the carbon paste wax electrodes decreases the FIA peak width and increases the peak current. The metal complex appears to accelerate the rate of oxidation of NAD(P)H by poly-TBO. PMID- 10101840 TI - Development of an automated microbial sensor system. AB - An automated whole cell biosensor system was developed by integration of immobilized microbial cells in a flow-through system with screen-printed flow through electrodes as detectors. The detectors used were thick-film Pt-electrodes in a 3-electrode configuration constructed as sandwich flow-through cells with a volume of about 36 microliters polarized at -900 mV. The measuring principle was the determination of oxygen consumption due to the microbial metabolism. Fructose was used as model analyte. The microorganisms were immobilized on cellulose acetate membranes and integrated into a newly created reaction chamber (membrane reactor). The microbial cells used were Rhodococcus erythropolis and Issatchenkia orientalis known to be suitable for the determination of biological oxygen demand. PMID- 10101841 TI - Needle-type lactate biosensor. AB - A needle-type lactate biosensor has been developed for continuous intravascular lactate monitoring. The sensor employs poly(1,3-phenylenediamine) as the inner layer on the platinum electrode in order to eliminate the interference from oxidizable physiological substances. Cross-linking with glutaraldehyde was used for enzyme immobilization. Dithiothreitol was used as the stabilizer of lactate oxidase. PVC (polyvinyl chloride) was chosen as the external diffusion control membrane. Sensor performance was evaluated in vitro and the sensor shows a sensitivity of 10-15 nA/mM, and a linear range from 1 mM to at least 15 mM lactate. Evaluation of the sensor response in blood plasma showed similar sensitivity and linear range as indicated by the calibration curves obtained in buffer solution. The sensor has a short response time of approximately 1 minute. The sensors were operated continuously for 7 days in phosphate buffer containing solution with a concentration at the physiological lactate level. No significant change in sensor sensitivity and its linear range has been observed. Sensors show a minimum change in its performance when stored in buffer at 4 degrees C for at least 9 months. PMID- 10101842 TI - Amperometric determination of lysine using a lysine oxidase biosensor based on rigid-conducting composites. AB - In this study, amperometric biosensors based on rigid conducting composites are developed for the determination of lysine. These lysine biosensors consist of chemically immobilized lysine oxidase membranes attached to either graphite methacrylate or peroxidase-modified graphite-methacrylate electrodes. The enzymatic degradation of lysine releases hydrogen peroxide, which is the basis of the amperometric detection. The direct oxidation of hydrogen peroxide is monitored at +1000 mV with a graphite-methacrylate electrode, while with the peroxidase-modified electrode reductive detection is performed. In addition, for the peroxidase-modified biocomposite electrode, both direct electron transfer and hydroquinone-mediated detection are studied. For the lysine biosensor based on the hydroquinone-mediated peroxidase biocomposite, the linear range is up to 1.6 x 10(-4) M, the sensitivity 11300 microA/M, the repeatability 1.8%, the detection limit 8.2 x 10(-7) M and the response time t95% is 42 s. The proposed biosensors are used to determine lysine in pharmaceutical samples. Results are consistent with those obtained with the standard method. PMID- 10101843 TI - Current awareness in biosensors & bioelectronics. PMID- 10101844 TI - Multi-bioassay approach for assessing the potency of complex mixtures of polycyclic aromatic hydrocarbons. AB - The chick embryotoxicity screening test (CHEST) and the Salmonella/microsome bioassay were used to evaluate embryotoxic and mutagenic endpoints from crude coal tar (CT) and its fractionated polycyclic aromatic hydrocarbon (PAH) mixtures (designated as A, B, C, D and E). In the CHEST assay, CT and PAH mixtures were injected into the egg yolk. A dose-dependent increase in embryo mortality was observed for all fractions. The E fraction resulted in 47% embryo mortality at a dose of 0.125 mg/kg and was more toxic than CT. At a dose of 1 mg/kg, 85-100% embryonic deaths occurred in fractions C and D and these two fractions were more potent than fractions A and B. The main visual toxic manifestations were liver lesions, discoloration of the liver, and edema. Both CT and fractionated PAH mixtures were also tested in the Salmonella/microsome plate incorporation assay with Salmonella typhimurium strain TA98 and were evaluated with and without metabolic activation at five dose levels. In the presence of S9, the CT and fractions C, D and E induced a dose-dependent positive response. Results from the Salmonella/microsome assay were in good agreement with findings from the CHEST assay suggesting that these two bioassays in combination may facilitate the rapid detection and ranking of complex PAH mixtures. PMID- 10101845 TI - Quantification of runoff in laboratory-scale chambers. AB - Many of the variables that control transport of agrochemicals and pathogens in the field are difficult to measure because parameters such as slope, soil and plant conditions, and rainfall cannot be adequately controlled in the natural environment. This paper describes the design, construction, operation and performance of a system useful for studying surface transport of agrochemicals and pathogens under controlled slope, rainfall and soil conditions. A turntable is used to support and rotate 4 soil chambers under oscillating dripper units capable of simulating rainfall intensities from 1 to 43 mm h-1. Chambers (35 x 100 x 18 cm i.d.) were constructed with an adjustable height discharge gate to collect runoff and three drains to collect leachate. Height adjustable platforms were constructed to support and elevate the chambers up to 20% slope. The chambers were uniformly packed with 35 to 45 kg of soil (bulk density 1.18-1.27 g cm-3) and initially saturated with two low intensity rain events. The coefficient of variation of the rainfall delivery over a range of 5 to 43 mm h-1 averaged 7.5%. An experiment to determine the variability between chambers in runoff amount and uniformity indicated that at least one runoff-equilibration cycle is needed to obtain steady state conditions for conducting runoff transport evaluations. Another experiment conducted to evaluate atrazine [2-chloro-4 (ethylamino)-6-(isopropylamino)-s-triazine] runoff under simulated crop-residue covered vs bare soil conditions indicated six times more runoff from bare than crop residue covered soil. The system is capable of precise application of simulated rain, the simultaneous collection of runoff and leachate at slopes up to 20% and can be easily modified to meet a wide range of research parameters. PMID- 10101846 TI - Mycotoxins of Aspergillus fumigatus in pure culture and in native bioaerosols from compost facilities. AB - Exposure to secondary metabolites of airborne fungi in waste handling facilities is discussed in regard to potential toxic impacts on human health. The relevance of mycotoxins has been intensely studied in connection with contamination of food and feed. Toxic secondary metabolites are expected to be present in airborne spores, but exposure to mycotoxins in bioaerosols has not been studied sufficiently. Aspergillus fumigatus is one of the most frequent species in the air of compost plants. A wide range of secondary metabolites was found in pure cultures of freshly isolated strains of A. fumigatus. Tryptoquivaline, a compound with tremorgenic properties, and trypacidin, for which no toxic properties are described, were found in native bioaerosols in a compost facility. The highly toxic metabolites gliotoxin and verruculogen were not found in the bioaerosols. PMID- 10101847 TI - Identification of the major urinary and fecal metabolites of 3,5-dinitrobenzamide in chickens and rats. AB - Colostomized chickens given oral doses of 3,5-dinitrobenzamide (nitromide) cleared nitromide predominantly through the urine (58% of dose) and feces (21% of dose). Rats cleared 52% of nitromide via urinary excretion and 44% via feces. Major urinary metabolites for both chickens and rats include: 3-amino-5 nitrobenzamide, 3-acetamido-5-nitrobenzamide, 3-acetamide-5-aminobenzamide, and 3,5-diacetamidobenzamide. The major fecal metabolite in chickens was 3-acetamido 5-nitrobenzamide (67% of fecal 14C) and 3-acetamido-5-aminobenzamide in rats (approximately 50%). PMID- 10101848 TI - An assessment of the environmental fate and exposure of benzene and the chlorobenzenes in Canada. AB - Systematic modelling of the fate of benzene and the chlorobenzenes is presented which follows a four-stage process of chemical classification, quantifying discharge rates and environmental concentrations, evaluative assessment of fate and regional mass balance modelling has been carried out for the southern Ontario region. The EQC model was applied to determine the principal transport and transformation processes experienced by this group of chemicals, which vary considerably in volatility and hydrophobicity. Observed environmental concentrations are in satisfactory agreement with the predictions of the steady state Level III ChemCAN model of chemical fate. A multiple pathway human exposure model which estimates intake of contaminants by residents of southern Ontario has been developed and applied to these chemicals. A novel method of deducing maximum tolerable environmental concentrations is presented. Results suggest that benzene and 1,4-dichlorobenzene are present in the environment at levels sufficient to cause exposures near allowable daily intake (ADI) levels for the general population, but the other substances are present at levels which result in exposure ranging from 1/10 to 1/1000 of the ADI. PMID- 10101849 TI - Modulation of metabolic activity prevents degradation of sorbed toluene. AB - The factors affecting the ability of a bacterial species to degrade different amounts of toluene (8.5 to 217 mg/g) sorbed to granular activated carbon (GAC), in an aqueous solution of mineral salts, were investigated. After 144 days the amounts of toluene remaining on one type of GAC ranged from 7.5 to 9.5 mg/g, and the aqueous concentrations of toluene ranged from 2 to 7 micrograms/L. Neither bacterial death nor an inhibition by accumulating by-products could explain why the remaining toluene had not been degraded. However, at these low concentrations of toluene, and probably because of cell starvation, bacteria were observed to be more than 100-times less efficient to degrade toluene than at high concentrations. We propose that this low degradation ability is responsible for the presence of residual toluene on the GAC, and that this mechanism may contribute to the persistence of low concentrations of sorbed pollutants in the environment. PMID- 10101850 TI - Effects of chlorides on emissions of toxic compounds in waste incineration: study on partitioning characteristics of heavy metal. AB - Chlorides derived from plastics and food residue content in MSW will affect the formation and partitioning of metal chlorides in the incineration discharges. Our study investigated the effects of waste-derived chlorides on the partitioning of heavy metals in a single-metal combustion system. The results indicate that the heavy metal partitioning behaviors are mainly affected by the presence of chloride, alkaline metals (i.e., Na, K) and moisture in the wastes. The configuration of the metal partitioning is determined by the availability of chlorine, hydrogen, and alkaline metals, or the extent to which the elements may divide from their compounds at a given combustion temperature. The effects of chlorides, including PVC, C2Cl4, FeCl3, NaCl and KCl, were also discussed. PMID- 10101851 TI - Biodeterioration of cardboard-based liquid containers collected for fibre reuse. AB - Liquid packaging board (LPB) collected in Germany is processed in Finland as recycled fibre and as plastic reject for incineration. The chemical, biological and physical changes occurring in recycled LPB bales were monitored during storage of six and 18 months. The moisture content in the core of the bales ranged from 7% to 53%, and pH values varied from 6.0 to 8.5. The average amount of mesophilic bacteria per container was 1.5 x 10(7) - 5 x 10(8), which means that recycled LPB pulp cannot be recommended for sanitary use. The concentration of CO2 inside the bale is an indicator of the activity of aerobic microorganisms and might be suitable for identifying deteriorated bales and removing them from the production line. Insects were found in some bales and the more deteriorated the bale was the more species of insects were found. The results showed the conversion of cellulose into humic acids to be clearly underway in some recycled LPB bales. The bale samples were extracted into hot water and into fulvic acids and humic acid (HA) fractions. The concentration of the humic acid fraction varied in the range 0.3-0.6% of the organic matter in fresh bales and 2.2% in one old bale. During aging nitrogen was enriched in all fractions. PMID- 10101852 TI - Polychlorinated naphthalenes in sediments from the Venice and Orbetello lagoons, Italy. AB - The purpose of this study was to evaluate the contamination caused by polychlorinated naphthalenes in two polluted Mediterranean lagoons. Surface sediment samples from Venice and Orbetello lagoons were analysed using HRGC-HRMS. The levels of the sum of mono- to octa-CN ranged from 0.03 to 1.51 ng/g. Differences in PCN levels were observed as a function of the sampling site, with levels at the industrial sites exceeding those at the control sites. Although the PCN patterns and profiles resembled one another in different sediment samples, they differed considerably when compared with those in the technical PCN formulation Halowax 1014. PMID- 10101853 TI - Study of dioxin sources in north Rhine-Westphalia. AB - This publication presents the results of the "Dioxins Measurement Programme of North Rhine-Westphalia" which has been initiated and sponsored by the Ministry of the Environment in North Rhine-Westphalia. Only 14 plants emitting more than 1 ng I-TEQ/m3 were found to account for almost the entire quantity emitted annually in North Rhine-Westphalia which according to the measurements amounted to 500 g I TEQ/a. For about 70% of the more than 50 plants included in the study which were thought to emit increased amounts of dioxins and furans this minitial assumption could not be confirmed; in these cases the concentrations were below 0.1 ng I TEQ/m3. Thus the entry of dioxins into the atmosphere was caused by few large plants and not by numerous small ones which would have been difficult to monitor. Immediately initiated abatement measures which instantly reduced the entry of PCDD/PCDF into the environment can be considered as the most important success of the programme. Moreover, the results on the measurement programme furnishes important information on the efficiency of waste gas cleaning methods and on the influence which input materials and operating conditions exert on the emissions of dioxins. PMID- 10101854 TI - Heavy metal deposition and variation in sedimentation rate within a sedimentary basin in Central Gulf of Finland. AB - In studies dealing with the chemical distribution of elements in marine soft sediments, variations in sedimentation rate within a basin can bias the interpretation of the data. A basin in the central part of the Gulf of Finland was sampled at nine sampling sites along a transect, 1.2 nautical miles long. Gravity cores of the topmost recent sediment were analysed for nitric acid leachable concentrations of heavy metals. Almost without exceptions the metal concentrations were lower in the surface sediment, indicating a decrease in pollution load during the last decade. The sedimentation rates within the basin differed substantially, from 2.5 mm a-1 to some 15 mm a-1. Without dating of the sediments, the comparison of different cores is almost impossible. Dating is essential, as is thorough investigation of the basins used in sediment monitoring. PMID- 10101855 TI - An in vitro study on the toxic effects of nonylphenols (NP) in mitochondria. AB - This paper is focused on alkylphenols, compounds which are formed by the biodegradation of polyethoxilatedalkylphenols detergents. Our experiments show that alkylphenols act not only as detergents, but also as uncouplers of the oxidative phosphorylation. This effect, can be observed at very low doses, thus suggesting that the preferential target of nonylphenols in living organisms are mitochondria. PMID- 10101856 TI - Degradation of nitrogen containing organic compounds by combined photocatalysis and ozonation. AB - The combination of TiO2-assisted photocatalysis and ozonation in the degradation of nitrogen-containing substrates such as alkylamines, alkanolamines, heterocyclic and aromatic N-compounds has been investigated. A laboratory set-up was designed and the influence of the structure of the N-compound, the TiO2 and ozone concentration on the formation of breakdown products were examined. The experimental results showed that a considerable increase in the degradation efficiency of the N-compounds is obtained by a combination of photocatalysis and ozonation as compared to either ozonation or photocatalysis only. The mineralization of the model substances was monitored by measurements of the TOC and ion-chromatographic determinations of the formed NO2- and NO3-. The temporal changes of concentrations of breakdown products, such as NH4+, short chain alkyl- and alkanolamines were determined by single column ion chromatography (SCIC) and as well as by electrospray mass spectrometry (EI-MS). PMID- 10101857 TI - Measuring the biodegradability of nonylphenol ether carboxylates, octylphenol ether carboxylates, and nonylphenol. AB - We examined the biodegradability of several metabolites of C8- and C9-alkylphenol ethoxylates, including nonylphenoxyacetic acid (NPEC1), nonylphenoxyethoxyacetic acid (NPEC2), octylphenoxyacetic acid (OPEC1), octylphenoxyethoxyacetic acid (OPEC2), and nonylphenol (NP). Using OECD method 301B (modified Sturm method), OPEC1 and OPEC2 are readily biodegradable: both compounds exceeded 60% of theoretical CO2 formation (ThCO2) by day 28, and required less than 10 days to go from 10% to 60% ThCO2. Also using method 301B, NPEC1 and NPEC2 exceeded 60% ThCO2 at day 28, but did not meet the 10 day window. Using OECD method 301F, the manometric respirometry method that measures oxygen consumption, approximately 62% of NP was biodegraded in 28 days, but required more than 10 days to go from 10% to 60% biodegradation. While the validity of the "10-day window" is currently being debated within OECD, the data show that the common metabolites of C8- and C9-APEs are rapidly degraded in the test systems used, which strongly suggests that they would not accumulate or persist in the environment. PMID- 10101858 TI - Polychlorinated biphenyls and some pesticides in perch (Perca fluviatilis) from inland waters of Latvia. AB - Polychlorinated biphenyls (PCBs), DDT-related substances, hexachlorocyclohexane (HCH) isomers and hexachlorobenzene (HCB) were analysed in perch (Perca fluviatilis) from Latvian lakes and rivers. DDE is present in the highest concentrations in all samples; 62-170 ng/g lipid weight in perch from rural areas and 460 ng/g in perch from the Riga area. Individual dominating PCB congeners were in the range 16-45 ng/g and 200-210 ng/g, respectively. The degree of contamination of rural areas in Latvia of these organohalogen substances is in the same range as in background areas in Sweden. Riga, the major urban area in Latvia, is shown to be more polluted with PCBs than other areas in Latvia. PMID- 10101859 TI - Ecotoxicity characterization of dinitrotoluenes and some of their reduced metabolites. AB - In the present study, the toxic effects of 2,4-dinitrotoluene (2,4-DNT), 2,6 dinitrotoluene (2,6-DNT) and a selection of their respective metabolites were examined and compared to 2,4,6-trinitrotoluene (TNT) using the 15-min Microtox (Vibrio fischen) and 96-h freshwater green alga (Selenastrum capricomutum) growth inhibition tests. All of the compounds tested were less toxic than TNT. Using the Microtox assay, 2,6-DNT was more toxic than 2,4-DNT and the order of toxicity for 2,6-DNT and its metabolites was: 2,6-DNT > or = 2A-6NT >> 2,6-DAT; whereas that for 2,4-DNT was: 4A-2NT > 2A-4NT > 2,4-DNT > 2,4-DAT. For the algal test, 2,4-DNT was more toxic than 2,6-DNT and the order of toxicity for 2,4-DNT and its metabolites was: 2,4-DNT > 2,4-DAT approximately equal to 4A-2NT = 2A-4NT. The order of toxicity for 2,6-DNT and its reduced metabolites using the algal test was very similar to the Microtox bioassay. These results demonstrate that the reduced metabolites of 2,6-DNT tested in this study were less toxic than that of the parent compound, but certain partially reduced metabolites of 2,4-DNT can be more toxic than the parent molecule. These data put into question the general hypothesis that reductive metabolism of nitro-aromatics is associated with a sequential detoxification process. PMID- 10101860 TI - Anaerobic incorporation of the radiolabeled explosive TNT and metabolites into the organic soil matrix of contaminated soil after different treatment procedures. AB - Four bioreactor designs were performed to evaluate the level of incorporation of 14C-labeled 2,4,6-trinitrotoluene (TNT) and metabolites into the organic soil matrix of different anaerobically treated contaminated soils. The contaminated soils were amended with molasses slivers (80:20% per weight) as auxiliary substrate to enhance microbial activity. After 5 weeks (bioreactors 1 and 2), 8 weeks (bioreactor 3) and 12 weeks (bioreactor 4) of anaerobic incubation, we determined 41%, 58%, 72%, and 54%, respectively, of the initially applied radioactivity immobilized in various soil fractions. After alkaline hydrolyses of the solvent-extracted soils, low quantities of radiolabel were found in the humic and fulvic acid fractions, whereas the bulk of 14C activity was found to be strongly bound to the humin fraction (solid soil residues). The amounts of solvent extractable radioactivity were 53%, 40%, 16%, and 29% for bioreactors 1, 2, 3, and 4, respectively. The level of TNT transformation at the end of the experiments was within 90-94%. Regarding the results presented in this study, we can assume that there is the possibility of high incorporation levels of TNT metabolites into the soil organic matrix mediated by microbial cometabolism under strictly anoxic conditions. PMID- 10101861 TI - Biogenic volatile organic compound emissions (BVOCs). I. Identifications from three continental sites in the U.S. AB - Vegetation composition and biomass were surveyed for three specific sites in Atlanta, GA; near Rhinelander, WI; and near Hayden, CO. At each research site emissions of biogenic volatile organic compounds (BVOCs) from the dominant vegetation species were sampled by enclosing branches in bag enclosure systems and sampling the equilibrium head space onto multi-stage solid adsorbent cartridges. Analysis was performed using a thermal desorption technique with gas chromatography (GC) separation and mass spectrometry (MS) detection. Identification of BVOCs covering the GC retention index range (stationary phase DB-1) from approximately 400 to 1400 was achieved (volatilities C4-C14). PMID- 10101862 TI - Biogenic volatile organic compound emissions (BVOCs). II. Landscape flux potentials from three continental sites in the U.S. AB - Landscape flux potentials for biogenic volatile organic compounds (BVOCs) were derived for three ecosystems in the continental U.S. (Fernbank Forest, Atlanta, GA; Willow Creek, Rhinelander, WI; Temple Ridge, CO). Analytical data from branch enclosure measurements were combined with ecological survey data for plant species composition and biomass. Other quantitative flux measurements at the leaf and landscape level were incorporated to scale the results from the enclosure measurements to the landscape level. Flux estimates were derived by using a one week ambient temperature and light record (30 min time resolution) and adjusting all emission rates to these conditions with temperature and light correction algorithms. PMID- 10101863 TI - Effect of liquid inhibitors on PCDD/F formation. Prediction of particle-phase PCDD/F concentrations using PLS modelling with gas-phase chlorophenol concentrations as independent variables. AB - Emissions of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) from municipal waste incineration are currently a subject of considerable public concern because of their extreme toxicity. PCDD/F formation in incineration processes is being studied widely, but little work has been done on their inhibition. We studied the effect of two liquid inhibitors, sodium ammonium hydrogen phosphate (NAHF) and urea (H2NCONH2), on PCDD/F formation in the combustion of liquid fuel doped with copper and chlorine using a pilot-scale plant. The inhibitors were injected into the flue gas stream at a temperature of 725 degrees C, whereupon both the chlorophenol and PCDD/F concentrations decreased. Particle-phase PCDD/F concentrations in particular decreased by up to 90% with NAHF and 70% with urea, but gas phase reduction took place only with urea. The results suggest that the formation of PCDD/Fs is hindered in the particle phase at the early stages of the PCDD/F formation chain, probably even before precursors such as chlorophenols have been formed. As a consequence, particle-phase PCDD/F concentrations can be predicted by a PLS (partial least squares) approach with the gas-phase chlorophenol concentrations as independent variables. The structure and partial charges of Cu(+)-urea complex were calculated by the HF/3-21G basis set. PMID- 10101864 TI - First evaluation of the Brazilian microorganisms biocatalytic potential. AB - The biocatalytic potential of two novel Brazilian strains of Aspergillus niger and Rhodotorula glutinis, revealed enantioselective epoxide hydrolase activity in the asymmetrization of meso-epoxide and monosubstituted epoxides respectively. These two types of oxirane derivatives are not usually good substrates for biocatalytic enantioselective conversion. PMID- 10101865 TI - Assessment of organic contaminant fate in waste water treatment plants. I: Selected compounds and physicochemical properties. AB - An extensive and comprehensive literature review has been conducted for compounds which we hypothesise could be present in sludge and maintain their integrity following application to agricultural land. The following compounds have been selected for review; chlorinated paraffins, quintozene, brominated diphenyl ethers, polychlorinated naphthalenes, polydimethylsiloxanes, chloronitrobenzenes, and a range of biologically active and pharmaceutical compounds. All have received interest as a result of their persistence and/or toxicity in environmental media. Physicochemical property information has also been compiled and/or calculated. In this way, an accompanying paper will attempt to predict compound fate in waste water treatment plants (WWTPs) and assess likely transfers from soil/plants to grazing livestock. These papers describe a first attempt to predict the fate of these classes of compounds in the environment and prioritise those of greatest concern. PMID- 10101866 TI - Quantitative structure-activity relationships for the toxicity of chlorophenols to mammalian submitochondrial particles. AB - The toxicity of a series of chlorophenols, determined by a short-term in vitro assay utilizing mammalian submitochondrial particles, was related to the physicochemical and structural properties of these compounds. Quantitative Structure-Activity Relationships were defined by correlating EC50 values with six molecular descriptors, chosen to represent lipophilic, electronic and steric effects: the n-octanol/water partition coefficient (log Kow), the constant of Hammett (sigma sigma), the acid dissociation constant (pKa), the first order valence molecular connectivity index (1 chi v), the perimeter of the efficacious section (sigma D) and the melting point (m.p.). The results of regression analysis showed that log Kow is the most successful descriptor, indicating that the ability of chlorophenols to partition into the lipid bilayer of the mitochondrial membrane has an important role in determining their toxic effects. These results are consistent with a molecular mechanism of uncoupling action based on the chemiosmotic theory and on the protonophoric properties of chlorophenols. The quality of the QSAR models confirms the suitability of the SMP assay as a short-term prediction tool for aquatic toxicity of environmental pollutants acting on respiratory functions. PMID- 10101867 TI - Levels of polychlorinated biphenyls in Patella piperata from the coast of Fuerteventura (Canary Islands, Spain). AB - Concentration of 51 PCB congeners were determined in the visceral mass of the endemic limpet Patella piperata, sampled in four stations in the coast of Fuerteventura (Canary Islands, Spain) during 1991-1995, and evaluated in order to assess the origin of their contamination and the possibility of this limpet being used as a bioindicator organism for PCB contamination. PCB extracted from samples were fractionated on Florisil columns and analysed by capillary gas chromatography with flame ionisation detector. Principal Component, Factor and Cluster Analysis were used to study the patterns and relationships among PCBs. PMID- 10101868 TI - Levels of dioxin-like compounds in sewage sludge determined with a bioassay based on EROD induction in chicken embryo liver cultures. AB - A bioassay for the detection of dioxin-like compounds was used to estimate levels in sewage sludge from Swedish sewage treatment plants (STPs). The sludge extracts were HPLC-separated into three fractions containing a) monoaromatic/aliphatic, b) diaromatic (e.g. polychlorinated biphenyls [PCBs], polychlorinated dibenzodioxins and polychlorinated dibenzofurans [PCDDs/Fs]), and c) polyaromatic compounds (e.g. polycyclic aromatic hydrocarbons [PAHs]). The bioassay, which is based on EROD (7-ethoxyresorufin O-deethylase) induction in cultured chicken embryo livers detected dioxin-like activity in all unfractionated extracts and in the di- and polyaromatic fractions of all sludge extracts, but not in the monoaromatic/aliphatic fractions. The levels ranged between 6 and 109 pg bio TEQ/g sludge (d.w.). In sediment samples from rural lakes in Sweden, levels of about 5 pg bio-TEQ/g (d.w.) have been found. The polyaromatic fractions of the sludge samples were potent in the bioassay, probably due to various PAHs and other polyaromatics in the sludge. The levels of six PAHs that are screened for in the sludge at Swedish STPs accounted for only 3-10% of the observed EROD induction by the polyaromatic fractions. Consequently, many other polyaromatic EROD-inducing compounds were present in the sludge. Inclusion of a biological test like the chicken embryo liver bioassay in the screening of sludge would improve the ability to detect the presence of bioactive dioxin-like compounds. A theoretical estimation of bio-TEQ concentrations in farm-soil following long-term application of sludge with bio-TEQ concentrations similar to those observed in this investigation indicated that the bio-TEQ levels in soil would increase very slowly over time. The chicken embryo liver bioassay proved useful in assessing levels of dioxin-like compounds in sewage sludge and it gives valuable complementary information to chemical analysis data. PMID- 10101869 TI - Ratio of the concentration of anthraquinone to anthracene in coastal marine sediments. AB - The ratio of the concentration of the oxidation product anthraquinone to that of its parent polycyclic aromatic hydrocarbon anthracene is reported for several coastal marine sediments. The ratio ranges from 0.317 in a highly contaminated industrialized harbor to 2.81 in a remote, less contaminated site. We hypothesize that differences in this ratio result from the input source of PAHs, with input from atmospheric deposition at remote sites resulting in a predominance of anthraquinone (ratio > 1), and direct discharge to highly contaminated industrialized harbors resulting in a predominance of anthracene (ratio < 1). To support this hypothesis, the fate of anthracene in the marine environment was investigated with respect to conversion to its oxidation product, anthraquinone. Once associated with sediments, anthracene is believed to be relatively persistent; however, it can potentially be subjected to oxidation via biological (microbial degradation) and chemical (chemical oxidation and photooxidation) processes. An assessment of the extent of oxidation of anthracene associated with sediments was conducted both under conditions simulating those found in the marine environment and under rigorous conditions by exposure to UV radiation. Results of this study show that while anthracene associated with marine sediments does not readily undergo oxidation to anthraquinone under conditions normally encountered in the marine environment, under extreme conditions anthracene is photooxidized by exposure to UV radiation. The extent of oxidation is influenced by sediment characteristics such as percent organic carbon, humic acid content and sediment surface area. The relative stability of anthracene under normal conditions may help to validate the use of the anthraquinone to anthracene ratio in marine sediments as an environmental marker of contaminant source. PMID- 10101870 TI - Expression of the neural cell adhesion molecule in mouse taste buds after denervation. AB - Expression of the neural cell adhesion molecule (NCAM) was studied by use of an immunocytochemical technique in the taste buds of mouse circumvallate papillae after bilateral transection of the glossopharyngeal nerves. In untreated mice, innervated type-III cells reacted with anti-NCAM antibody. After denervation the taste buds gradually decreased in number and size, and were practically absent within 11 days. In parallel, NCAM-reactive cells decreased at 3 and 8 days after surgery and at 11 days they were no longer found. Three days after denervation, synaptic contacts between type-III cells and nerve fibres were not found because of the disappearance of nerve fibres. However, remaining type-III cells, characterized with dense-cored vesicles, still maintained NCAM expression on their plasma membrane until day 8. PMID- 10101871 TI - IgG transcytosis is accelerated but its pathway is not disrupted by Brefeldin-A. AB - To see the action of Brefeldin-A (Bref-A) to transcytosis of the immunoglobulin G (IgG), we have examined the early stage of endocytosis and intracellular transport of IgG and transferrin (Tf) in epithelial cells of the rat yolk sac in culture with and without Bref-A. In the absence of Bref-A, the endocytosed IgG and Tf appeared in large apical endosomes during the first 5-15 min. At 15 min Tf recycling endosomes and IgG-transferring vesicles also appeared in the apical or basolateral cytoplasm, respectively. At 15 min in the presence of Bref-A, clouds of Tf-recycling endosomes accumulated in the apical cytoplasm, while distinct IgG transferring vesicles were distributed further to the basolateral cytoplasm. This differential action of Bref-A to IgG-transferring vesicles and Tf-recycling vesicles suggested an unexplored mechanism of sorting and basolateral transport of IgG. PMID- 10101872 TI - An ultrastructural study of age-related changes in mouse olfactory epithelium. AB - Transmission and scanning electron microscopic examinations were undertaken to detail changes in the olfactory epithelium (OE) resulting from the ageing process. Samples were prepared from 3% glutaraldehyde/1% formaldehyde perfused mice aged 6 months and 29-30 months. Compared to OE from young adults, a number of striking changes were apparent in tissue from older animals. The most obvious of these were extensive local accumulations of large inclusion bodies, totally disrupting the normal morphology of such affected areas of olfactory epithelium. Even in areas where these deposits were absent, other significant signs of ageing were noted in the seemingly unaffected OE of all older mice studied. Quantitative analysis of semi-thin resin sections revealed that the OE of aged mice was significantly reduced in thickness, and with significantly fewer olfactory sensory neurons, irrespective of whether or not inclusions were present. In addition, pale cells, which have been suggested to be a form of degenerating cells, were more abundant in aged OE. The straight, sharp boundary between respiratory and olfactory epithelia which is seen in young adults became irregular and disrupted with age due to an intermingling of the respiratory and olfactory cells. Such structural alterations may parallel olfactory dysfunction reputed to occur in older mammals. PMID- 10101873 TI - Detection of glycoconjugates by lectin gold labelling, silver enhancement, and scanning electron microscopy. AB - A method for detecting glycoconjugates on cell surfaces in scanning electron microscopy is described. Terminal saccharides were specifically recognized by a lectin conjugated to biotin, and, after incubation with an anti-biotin antibody conjugated to colloidal gold, silver enhancement was used to produce deposits large enough to be detected in standard scanning electron microscopes. Secondary electron images revealed the ultrastructure of the tissue investigated, while backscattered electron images showed the distribution of lectin binding sites. Using digital recording and processing, the two channels were combined in colour encoded images. The new method brings together lectin histochemistry and scanning electron microscopy and thus allows the three-dimensional distribution of glycoconjugates to be analysed at an ultrastructural level. PMID- 10101874 TI - Rethinking the value of choice: a cultural perspective on intrinsic motivation. AB - Conventional wisdom and decades of psychological research have linked the provision of choice to increased levels of intrinsic motivation, greater persistence, better performance, and higher satisfaction. This investigation examined the relevance and limitations of these findings for cultures in which individuals possess more interdependent models of the self. In 2 studies, personal choice generally enhanced motivation more for American independent selves than for Asian interdependent selves. In addition, Anglo American children showed less intrinsic motivation when choices were made for them by others than when they made their own choices, whether the others were authority figures or peers. In contrast, Asian American children proved most intrinsically motivated when choices were made for them by trusted authority figures or peers. Theoretical and practical implications of these findings are discussed. PMID- 10101875 TI - Catharsis, aggression, and persuasive influence: self-fulfilling or self defeating prophecies? AB - Does media endorsement for catharsis produce a self-fulfilling or a self defeating prophecy? In Study 1, participants who read a procatharsis message (claiming that aggressive action is a good way to relax and reduce anger) subsequently expressed a greater desire to hit a punching bag than did participants who read an anticatharsis message. In Study 2, participants read the same messages and then actually did hit a punching bag. This exercise was followed by an opportunity to engage in laboratory aggression. Contrary to the catharsis hypothesis and to the self-fulfilling prophecy prediction, people who read the procatharsis message and then hit the punching bag were subsequently more aggressive than were people who read the anticatharsis message. PMID- 10101876 TI - Reducing intergroup bias: elements of intergroup cooperation. AB - The authors examined the potentially separable contributions of 2 elements of intergroup cooperation, interaction and common fate, and the processes through which they can operate. The manipulation of interaction reduced bias in evaluative ratings, which supports the idea that these components are separable, whereas the manipulation of common fate when the groups were interacting was associated with lower bias in nonverbal facial reactions in response to contributions by in-group and out-group members. Whereas interaction activated several processes that can lead to reduced bias, including decategorization, consistent with the common in-group identity model (S. L. Gaertner, J. F. Dovidio, P. A. Anastasio, B. A. Bachman, & M. C. Rust, 1993) as well as M. Hewstone and R. J. Brown's (1986) group differentiation model, the primary set of mediators involved participants' representations of the memberships as 2 subgroups within a superordinate entity. PMID- 10101877 TI - The structure of Turkish trait-descriptive adjectives. AB - This description of the Turkish lexical project reports some initial findings on the structure of Turkish personality-related variables. In addition, it provides evidence on the effects of target evaluative homogeneity vs. heterogeneity (e.g., samples of well-liked target individuals vs. samples of both liked and disliked targets) on the resulting factor structures, and thus it provides a first test of the conclusions reached by D. Peabody and L. R. Goldberg (1989) using English trait terms. In 2 separate studies, and in 2 types of data sets, clear versions of the Big Five factor structure were found. And both studies replicated and extended the findings of Peabody and Goldberg; virtually orthogonal factors of relatively equal size were found in the homogeneous samples, and a more highly correlated set of factors with relatively large Agreeableness and Conscientiousness dimensions was found in the heterogeneous samples. PMID- 10101878 TI - Goal striving, need satisfaction, and longitudinal well-being: the self concordance model. AB - An integrative model of the conative process, which has important ramifications for psychological need satisfaction and hence for individuals' well-being, is presented. The self-concordance of goals (i.e., their consistency with the person's developing interests and core values) plays a dual role in the model. First, those pursuing self-concordant goals put more sustained effort into achieving those goals and thus are more likely to attain them. Second, those who attain self-concordant goals reap greater well-being benefits from their attainment. Attainment-to-well-being effects are mediated by need satisfaction, i.e., daily activity-based experiences of autonomy, competence, and relatedness that accumulate during the period of striving. The model is shown to provide a satisfactory fit to 3 longitudinal data sets and to be independent of the effects of self-efficacy, implementation intentions, avoidance framing, and life skills. PMID- 10101879 TI - Gender differences in autobiographical memory for childhood emotional experiences. AB - Research to date has paid remarkably little heed to gender differences in autobiographical memory. To redress this, the author examined memory for childhood events in adult men and women remembering back to childhood, and in children themselves. Five studies were conducted, and results revealed that females consistently recalled more childhood memories than males did and were generally faster in accessing the memories recalled. Furthermore, the gender difference observed was specific to memories of events associated with emotion and was apparent across a diverse range of emotions experienced by both the self and others. The overall pattern of findings obtained is consistent with the proposition that gender-differentiated socialization processes influence the content and complexity of representations of autobiographical emotional events in memory. To some extent, then, autobiographical memory appears to be a socially constructed phenomenon. PMID- 10101880 TI - The beta-lactamase cycle: a tale of selective pressure and bacterial ingenuity. PMID- 10101881 TI - [The loss of heterozygosity on the short arm of chromosome 3 in renal carcinoma]. AB - OBJECTIVE: Renal cancer accounts for 2% of tumors. The most common chromosome abnormality found in renal cancer is the loss of heterozygosity (LOH) on the short arm of chromosome 3 (3p), which suggests that near the gene responsible for von Hippel-Lindau disease, there may be one or more tumor suppressor genes between 3p14 and 3p21 with a relevant role in the development of renal cancer. METHODS: 41 patients with sporadic renal cancer were tested for three microsatellites mapped to the short arm of chromosome 3 (3p14.1-3p14.3, 3p21.2 3p21.3 and 3p25) by polymerase chain reaction. The results were compared with patient habits and tumor features. RESULTS/CONCLUSIONS: 43.9% of the patients showed LOH on at least one locus. Thirty-four percent showed LOH only on one locus, 4.9% on two loci and 7.3% on the three loci tested. All the patients who showed LOH on 3p21 had a tumor size greater than 25 mm. There is a risk 1.76 times higher of no loss in tumors less than 25 mm in size than in tumors greater than 25 mm (Cl 95% 1.33-2.33). PMID- 10101882 TI - [Surgical pathology of the scrotum. An analysis of a series of 56 cases]. AB - OBJECTIVE: To analyze the incidence and the clinical and histopathological features of non-inflammatory scrotal lesions with special reference to the non neoplastic lesions, which are the most common. METHODS: The cases of scrotal surgical pathology of the Hospital Nuestra Senora del Pino from 1988-1997 were reviewed. Skin biopsies for dermatological conditions, Fournier's gangrene, inflammatory-infectious lesions, hydroceles, lesions that could cause secondary involvement of the scrotal wall (e.g., spermatoceles) and invasive lesions from adjacent tumors were excluded from the study. RESULTS: 14 cases (4 neoplastic and 10 non-neoplastic lesions) were specifically analyzed. Of these 10 non-neoplastic lesions, 7 were epidermoid cysts (3 multiple) and 3 idiopathic calcinosis. The latter, which are discussed at length, presented in middle-aged patients (56, 45 and 42 years) as multiple nodules that had gradually appeared over several years (20 years in one of the cases) and had been invariably diagnosed as "sebaceous scrotal cysts". Their form of presentation and treatment are similar to those of true scrotal epidermoid cysts, with which they might be related. CONCLUSIONS: In our series, the most common primary scrotal lesions were non-neoplastic and comprised two types whose pathogenic relationship has as yet not been elucidated: simple epidermoid or epidermal cysts (half of which were multiple lesions) and less frequently idiopathic calcinosis of the scrotum. PMID- 10101883 TI - [The preoperative diagnosis of complex renal cystic masses]. AB - OBJECTIVE: To analyze the preoperative diagnostic methodology in a series of patients with complicated cystic renal masses in relation to the definitive anatomopathological findings. METHOD: 20 cases of asymptomatic complicated cystic renal masses in 19 patients submitted to surgical exploration are described. All cases were evaluated by US and CT. Fine needle punction-aspiration biopsy (FNPA) was done in 17 of the 20 masses and pre and postoperative anatomopathological analyses were performed. RESULTS: Following the Bosniak classification for complicated cystic masses, the US study showed two cases were type I, 5 type II, 10 type III, and 3 type IV, while the CT findings showed no type I, 8 type II, 9 type III and 3 type IV. The definitive anatomopathologic diagnosis was that of renal cell carcinoma in 11 cases. All but one (type II) of these 11 cases were Bosniak III or IV. Nine had a preoperative FNPA which showed malignant cells in two cases, while the remaining 7 were negative. The preoperative biopsy was negative in one of the 11 cases with renal cell carcinoma. The remaining 9 cases of complicated renal mass were simple cysts complicated by hemorrhage or infection. CONCLUSIONS: In our series, the use of the Bosniak classification system preoperatively highly correlated with the presumed benign or malignant nature of the lesion. FNPA biopsy, however, was not found to be very useful in the preoperative diagnosis of complicated cystic renal masses; it showed a sensitivity of 22% and a negative predictive value of 46.7%. Although the foregoing data have no statistical significance, a negative FNPA biopsy of a complicated cystic renal mass that raises reasonable doubts does not change the indication for a surgical exploration. PMID- 10101884 TI - [An assessment of prostatic weight by ultrasound]. AB - OBJECTIVE: To analyze the utility of transvesical ultrasound in the estimation of prostate weight. METHODS: A study was conducted on 50 patients with symptomatic prostatism, aged 54-82 years (mean 60). All the patients had a prostate volume estimation by ultrasound 15 days before surgery using the following formulas: AP x T x Cc x 0.52 cm; AP + T + Cc + 3 mm. All patients underwent surgery for benign obstructive prostatic disease; 25 by TURP and 25 by open surgery. The prostate tissue removed was compared with the US estimation. RESULTS: AP x T x Cc x 0.52 cm was found to be the most accurate formula for prostates weighing less than 50 gm and AP + T + Cc + 3 mm the most accurate for prostates greater than 50 gm. CONCLUSIONS: Our results show that not all formulas are applicable to all prostate sizes. PMID- 10101885 TI - [Brachytherapy results in prostatic cancer]. AB - OBJECTIVE: To analyze the 15-year results of external irradiation combined with radioactive gold grain implantation (Au198) in the treatment of adenocarcinoma of the prostate and to discuss the therapeutic perspectives. METHODS: The present study was conducted on 23 patients with localized prostate carcinoma (17 stage B; 6 stage C) that had been diagnosed and treated at our department from February 1981 to October 1986. The mean patient follow-up was 90.96 months. Au198 implantation (mean dose 3347.6 cGy) was performed through the abdominal approach prior to external irradiation (mean dose 39 Gy) with Co-60 (19 patients) or the 18-MV photon linear accelerator (4 patients). The mean fractionated dose was 180.43 cGy/day. RESULTS: Overall the 15-year locoregional control rate was 61% and disease-free survival was 38%. The overall survival rate was 25%, regardless of the cause of death. The tumor control rate was 61% for stage B and 83% for stage C lesions at 15 years. The disease-free survival rate was 40% for stage B and 50% for stage C tumors. The local control and disease-free survival rates were worse for patients in whom the diagnosis had been made by TUR (p = not significant). CONCLUSIONS: The locoregional tumor control and disease-free survival rates for this group of 23 patients who received combined therapy with external irradiation and radioactive gold grain implantation (Au198) were slightly lower than those obtained in another group of 104 patients treated at our Service of Radiotherapeutic Oncology with radical external radiation therapy and can be ascribed mainly to poor patient selection and inadequate radiation dose. PMID- 10101886 TI - [Marsupialization via minilaparotomy in the kidney transplant]. AB - OBJECTIVE: To describe the results of treatment of posttransplant lymphoceles by marsupialization through a mini-laparotomy. METHODS: From March 1996 to May 1998, 7 patients with a symptomatic lymphocele that had not been resolved by conservative treatment with drainage and povidone-iodine sclerosis underwent internal marsupialization to the peritoneal cavity through a minilaparotomy. RESULTS: All patients showed a good postoperative course and were discharged two days after the procedure. Recent US scans of 5 patients showed a renal graft with a normal appearance and no perineal collections. Two patients had a recurrence; one of them was symptomatic and required another treatment. Drainage and povidone iodine sclerosis resolved this condition. CONCLUSIONS: Marsupialization through a mini-laparotomy is an alternative to the laparoscopic approach and does not require new instruments or learning a new technique. PMID- 10101887 TI - [The usefulness of vaginal cones as a method of measuring perineal muscle strength. The RECOVA Group. REeducacion COnos VAginales]. AB - OBJECTIVE: To determine the utility of vaginal cones for the measurement of perineal muscle strength. METHODS: A study was conducted on 134 women (mean age 31.8 years) to determine the correlation between a clinical test for measuring perineal muscle strength and the number of vaginal cones retained by the patients. RESULTS: A correlation was found between the clinical test for measuring perineal muscle strength and the number of vaginal cones retained in 90% of the cases. This correlation increased to 96% in patients that had undergone rehabilitation of the perineal muscles with vaginal cones for a period of three months. CONCLUSION: Our results show that vaginal cones permit objective measurement of perineal muscle strength. PMID- 10101888 TI - [The therapeutic efficacy of vaginal cones in rehabilitating the perineal musculature. The RECOVA Group. REeducacion COnos VAginales]. AB - OBJECTIVE: To determine the utility of vaginal cones in the rehabilitation of the perineal muscles. METHODS: A study was conducted on 134 women (mean age 31.8 years). The control group comprised 51 women (38%) and study the group comprised 85 patients (62%) undergoing rehabilitation of the perineal muscles with vaginal cones for a period of three months. Both groups were adjusted for statistical analysis. RESULTS: The patients undergoing rehabilitation retained a vaginal cone 1.3-2.4 times more than the controls. The dropout rate was 29%. The patients who abandoned the study showed significant differences in comparison to those who completed the treatment for age, length of perineal muscle less than 3 cm, belonging to the control group and were followed by nurses. CONCLUSIONS: Rehabilitation using vaginal cones significantly improves the strength of the perineal muscles. PMID- 10101889 TI - [Fibroepithelial polyps of the upper urinary tract: their diagnostic evaluation and treatment in pediatrics]. AB - OBJECTIVE: To establish the diagnostic criteria, analyze the histological patterns of benign and malignant ureteral and renal pelvic polyps in pediatric patients and discuss the best treatment option based on the final diagnosis. METHODS/RESULTS: The literature is reviewed with special reference to the diagnostic and therapeutic aspects of fibroepithelial polyps of the upper urinary tract in pediatric patients. An additional case with benign cytological and radiological findings is described. The patient underwent partial pyeloureteral resection. Histological analysis of the surgical specimen confirmed a fibroepithelial polyp. CONCLUSIONS: We emphasize the importance of adequate preoperative evaluation, precise identification of the base of the lesion for a correct choice of the surgical approach, and the advantages of complete segmental resection and reanastomosis over simple excision of the polyp. PMID- 10101890 TI - [The webbed penis. A report of a new case]. AB - OBJECTIVE: To report an additional case of webbed penis or penis palmatus, an uncommon malformation caused by alterations that occur during the embryonic development of the external genitalia. METHODS: A 15-year-old by consulted for penile curvature. He was diagnosed as having webbed penis and phimosis, and was submitted to surgery. RESULTS/CONCLUSIONS: Z-plasty and circumcision achieved excellent results. He had no erectile anomalies following surgery. PMID- 10101891 TI - [Zoon's balanoposthitis. A preliminary note]. AB - OBJECTIVE: To review the different aspects of inflammatory disease of the glans penis and prepuce with special reference to Zoon's balanoposthitis. METHODS: The clinical history of patients that had been diagnosed and treated for Zoon's balanoposthitis are reviewed and discussed. RESULTS/CONCLUSIONS: Zoon's balanoposthitis is not a malignant lesion. Circumcision will suffice for the management and treatment of this condition. PMID- 10101892 TI - [An epidermal inclusion cyst located in the scrotum. A brief case report]. AB - OBJECTIVE: To describe a case of scrotal epidermal cyst with special reference to the differential diagnosis between cystic and tumoral lesions. METHODS/RESULTS: The clinical history of a patient with an epidermal cyst localized to the scrotum is presented and the literature is briefly reviewed. Scrotal epidermal cysts and pilonidal cysts are distinct. Their etiology (embryonic vs acquired) is discussed from an academic perspective. CONCLUSIONS: Pilonidal and epidermal cysts are benign lesions. Excisional biopsy using local anesthesia will generally suffice for the classification and treatment of these lesions. PMID- 10101893 TI - [Urethral foreign bodies. Apropos 2 cases]. AB - OBJECTIVE: To report two cases of urethral foreign body. Although this condition is not uncommon, few cases are reported in the literature. METHODS/RESULTS: Two cases of urethral foreign body are described: a 74-year-old male with mental disorder who presented with acute urinary retention arising from a fragment of a metal tube in the bulbous urethra and a 34-year-old female with intense micturition syndrome arising from a calcified electrical cable located in the urethra. Both patients required open surgery for foreign body removal. CONCLUSIONS: A wide variety of urethral foreign body has been described in the literature. In adults this is commonly caused by the insertion of objects used for masturbation and is frequently associated with mental disorder as in the two cases described herein. PMID- 10101894 TI - [An occult Leydig-cell tumor in a cryptorchid testis]. AB - OBJECTIVE: A case of Leydig cell tumor in a cryptorchid testis is described. METHODS: A 55-year-old man presented with no specific scrotal symptoms. A cryptorchid testis was discovered on physical examination and the patient was submitted to orchidectomy. RESULTS: A solid, well-circumscribed, round nodule of 0.8 cm in diameter was found in an atrophic testis. The histological examination showed a Leydig cell tumor with crystals of Reinke and immunostaining with vimentin. CONCLUSION: Leydig cell tumor may be related with cryptorchidism. PMID- 10101895 TI - [Renal leiomyosarcoma. Apropos a case]. AB - OBJECTIVE: To describe an additional case of leiomyosarcoma of the kidney in a patient that presented with nonspecific abdominal pain and a palpable mass. The clinical features, diagnosis and therapeutic aspects, as well as the prognostic factors of this tumor type are reviewed. METHODS: Patient evaluation included US, CT and MRI. The patient underwent a left radical nephrectomy and received adjuvant external radiotherapy. RESULTS: The patient is asymptomatic and has no local recurrence or metastasis 15 months postoperatively. CONCLUSIONS: Leiomyosarcoma of the kidney is an uncommon malignant mesenchymal tumor. To our knowledge, less than 100 cases have been reported in the literature. Its clinical features and the US, CT and MRI findings are not unlike those of renal adenocarcinoma. The treatment of choice is by radical nephrectomy. PMID- 10101896 TI - [Adult renal polycystosis as the causal entity of an intercostal hernia containing an intestinal loop: an unusual clinical case]. AB - OBJECTIVE: To describe a case of adult renal polycystosis causing intercostal hernia with intestinal segment. To our knowledge, no such case has been previously reported in the literature. METHODS/RESULTS: Diagnosis was by abdominal CT. Treatment was by bilateral nephrectomy and surgical repair of the diaphragmatic and intercostal hernia. CONCLUSIONS: Surgery is indicated in adult renal polycystosis if kidney size causes gastrointestinal involvement and above all, if the lungs are compromised by the intercostal diaphragmatic hernia. PMID- 10101897 TI - Urinary lithogen risk test: usefulness in the evaluation of renal lithiasis treatment using crystallization inhibitors (citrate and phytate). AB - OBJECTIVES: This paper presents the results of a test to globally determine the urinary risk factor of calcium stone formation in the evaluation of treatments using crystallization inhibitors, such as citrate and phytate. METHODS: Three groups of active calcium oxalate stone-formers have been selected. The lithogen urinary risk was determined using a specially designed disposable test before any medical treatment. After evaluation group I did not receive any treatment, group II was treated with potassium citrate and group III with a phytate-rich dietary complement. When 15 days had elapsed, the test to evaluate the risk of urinary calcium stone formation was applied again to the three groups. The main lithogenic biochemical parameters of each tested urine were also determined before and after treatment. RESULTS: An important number of calcium oxalate stone formers with high urinary risk factor (positive test) became negative after medical treatment (52% of the citrate-treated patients and 50% of the phytate treated patients), but only 7% of the untreated patients (1 patient) showed a decrease in their urinary risk factor for calcium stones (negative test) after 15 days had elapsed. When the treatment was not effective, in an important number of cases, the urine contained high levels of calcium or showed pH values greater than 6.5. CONCLUSION: From the obtained results it can be concluded that the test is useful to evaluate the efficacy of a given renal lithiasis medical treatment, and also the efficacy of the treatment of calcium oxalate renal lithiasis using crystallization inhibitors, such as citrate and phytate, in an important number of cases. PMID- 10101898 TI - DARG Report. PMID- 10101899 TI - The dental care of the disadvantaged child. PMID- 10101900 TI - The Odol man. PMID- 10101901 TI - Safety of adrenaline. PMID- 10101902 TI - Wide circulation. PMID- 10101903 TI - Patient care project. PMID- 10101904 TI - Pursuit of evidence. PMID- 10101905 TI - Briefing paper: oral aspects of dummy and digit sucking. AB - Dummy sucking usually ceases before permanent teeth erupt but digit sucking may persist beyond this stage producing a permanent disturbance and should be discouraged. PMID- 10101906 TI - Eating disorders and the dentist. AB - Dentists are likely to encounter patients who have eating disorders. The paper explains the various types and considers both the risk factors, and the psychological and medical complications. The effect on oral health and the principles of dental management are outlined. Dentists have an important part to play in the overall care of these patients. PMID- 10101907 TI - Dental erosion--the problem and some practical solutions. AB - There has been a clinical impression among dental practitioners, particularly those working with children, that the problem of dental erosion is increasing. Is this really the case or are we more aware of the problem? What is causing this increase, if it really exists? Perhaps more importantly, what can we do about it? This article looks at the prevalence, and aetiology of dental erosion, particularly in children, and makes some practical suggestions for possible control. PMID- 10101909 TI - A survey of dental practitioners on their use of electronic mail. AB - OBJECTIVES: To assess the feasibility of using electronic-mail as a tool for surveying dental practitioners; to determine both response rates and response times for this method; and provide baseline information on e-mail usage. METHOD: Self-administered questionnaire distributed by e-mail to 309 practitioners on Monday morning, 1 June 1998. RESULTS: 53.4% response rate within 1 month; 10.2% of replies were sent within 2 hours; and nearly half the replies were sent within 48 hours. Qualified dentists were more likely to respond early than undergraduates. The most popular point of access for e-mail was home (69.1%). The majority of responders (56.8%) use e-mail every day with 1 in 7 (14.2%) using it at least four times a day. 72.4% stated that they found e-mail useful for communicating with professional bodies, while 41.3% used it to communicate with colleagues about patients and patient referrals. 34.0% found e-mail useful for ordering goods, and supplies and 14.6% were using electronic mail to make patient appointments at least some of the time. CONCLUSIONS: Responses can be obtained at much greater speed than conventional postal techniques will allow, but response rates were only 53.4%. E-mail is predominately used at home and for inter professional communications, only a small proportion of responders use it for direct communication with patients. PMID- 10101908 TI - Medical emergencies in general dental practice in Great Britain. Part 2: Drugs and equipment possessed by GDPs and used in the management of emergencies. AB - OBJECTIVE: To ascertain the emergency drugs and equipment possessed by general dental practitioners (GDPs), the treatment provided and drugs used in management of the medical emergency events they reported. DESIGN: Postal questionnaire survey of a random sample of GDPs in Great Britain. SUBJECTS: 1500 GDPs, 1000 in England & Wales and 500 in Scotland. RESULTS: There was a 74% response. An aspirator, an airway, oxygen, adrenaline and an injectable steroid were possessed by about 90% of respondents; glucose, glyceryl trinitrate and a salbutamol inhaler by about 80%. Glucose was used in management of nearly one in ten of the events reported, an inhaler, glyceryl trinitrate and oxygen were the next most commonly used. Cardiopulmonary resuscitation (CPR) was carried out in management of 1.1-1.4% of events not associated with general anaesthesia (GA) and in 4.7-16% of events associated with GA, an average of once in 250 years of practice. CONCLUSIONS: Most respondents possessed drugs and equipment necessary to manage a medical emergency. Half the drugs recommended by the 'Poswillo report' to be available in every dental practice were not used in more than 8000 years of practice. PMID- 10101910 TI - The effects of socioeconomic status and dental attendance on dental caries' experience, and treatment patterns in 5-year-old children. AB - OBJECTIVE: To compare the dental caries' experience and treatment received by 5 year-old children registered with a GDP. DESIGN: Retrospective case note review of all 5-year-old children registered with seven GDPs. SETTING: The study was carried out in 1996/7 in Wirral and North Cheshire in the north west of England. SUBJECTS AND MATERIALS: Clinical, demographic and attendance data were collected from each practice using a common data abstraction form. Subjects were categorised according to regular/irregular attenders, and into five groups ranging from affluent to deprived using the Super Profiles geodemographic classification. The relationships between disease experience, treatment, attendance and socioeconomic status were compared using cross-tabulations, t tests and multiple linear regression. RESULTS: The dental records of 430 5-year old children were available for analysis. Irregular attenders had significantly higher dmft, dt and mt, and fewer filled teeth. Only 29% of disease experience of regular attenders was treated by restoration. Both socioeconomic status and visiting behaviour exerted significant independent effects on dmft, but dental attendance alone had a significant effect on ft. CONCLUSIONS: Significant inequalities remain in the disease experience and service use of young children. Regularly attending children have less than a third of their diseased teeth restored. Consensus is needed across the profession on the care of the diseased deciduous dentition. PMID- 10101911 TI - An analysis of an admissions system: can performance in the first year of the dental course be predicted? AB - The admissions process must be scrupulously fair and select the most suitable students. Data on applicants to the Manchester Dental School for the 1996/97 academic year were analysed. The aims of this project were to: describe the applicants using information from the UCAS (university entrance) form; to relate information from the UCAS form to interview performance and A-level results; and to evaluate whether these factors can predict performance during the first year of the course. PMID- 10101912 TI - 182-day pre-suit notice requirement. PMID- 10101913 TI - Hope is the bottom line. Leonard Marcus, PhD, brings passion to the table of health care negotiation. PMID- 10101914 TI - March is medical Alliance month. Physicians' spouses caring today for a healthy tomorrow. PMID- 10101915 TI - 1999 MSMS Foundation annual report. Doctors, you made a difference! PMID- 10101916 TI - For the record: addressing the questions of medical recordkeeping. PMID- 10101917 TI - Healing hands and generous hearts. MSMS recognizes volunteer efforts of physicians. PMID- 10101918 TI - Compliance programs. Do I really need one? PMID- 10101919 TI - New approaches to the treatment of phenylketonuria. AB - Phenylketonuria (PKU) is the most common of all aminoacidopathies and is caused by autosomal recessive deficiency of the hepatic phenylalanine hydroxylase system. The diagnosis of PKU should be multifactorial and based on a protein overload test that reveals increased plasma phenylalanine levels during the ingestion of a normal diet, a phenylalanine tolerance test, and in vitro and in vivo activity of the liver enzyme. An individualized diagnosis that characterizes the severity of the disease in each patient provides objective and effective criteria for the dietary treatment of each particular case. PMID- 10101920 TI - Biomarkers for establishing a tolerable upper intake level for vitamin C. AB - Dietary reference intakes (DRIs) for vitamin C for healthy U.S. populations are currently being formulated by the Panel on Dietary Antioxidants and Related Compounds of the Food and Nutrition Board of the Institute of Medicine. A major task of the Panel is to analyze the evidence of adverse effects of high-dose vitamin C intakes to derive, if appropriate, a Tolerable Upper Intake Level (UL) for vitamin C. The present report details current and past research examining potential adverse effects of supplemental vitamin C. The available data indicate that very high intakes of vitamin C (2-4 g/day) are well tolerated biologically in healthy mammalian systems. Currently, strong scientific evidence to define and defend a UL for vitamin C is not available. PMID- 10101921 TI - Green tea polyphenols and cancer: biologic mechanisms and practical implications. AB - Polyphenolic compounds in fruits and vegetables have been associated with lower risk of some diseases, including cancer. Recent research has shown that the polyphenolic antioxidants in green tea possess cancer chemopreventive effects. This review discusses the cancer chemopreventive effects associated with green tea and the molecular mechanisms that underlie the broad anticarcinogenic effect of polyphenols in green tea. PMID- 10101922 TI - The effects of potassium, magnesium, calcium, and fiber on risk of stroke. AB - Stroke mortality represents the third leading cause of death worldwide, after coronary artery disease and cancer. High blood pressure is a major risk factor for stroke. A recent study has identified potassium, magnesium, and fiber as significant modulators of stroke risk in men. The protective effects were particularly pronounced in hypertensive subjects. The observed protection may be due to direct and indirect effects of these nutrients on blood pressure and regulatory functions, such as endothelial function. A high intake of these nutrients, singularly or in combination, is associated with a more healthful overall lifestyle. The best strategy to achieve a high intake of these nutrients is a diet rich in fruits and vegetables. PMID- 10101923 TI - The role of oxidized low-density lipoprotein in the activation of peroxisome proliferator-activated receptor gamma: implications for atherosclerosis. AB - A molecular mechanism has been discovered that helps explain the formation of foam cells, which are components of atherosclerotic plaque. It involves the stimulation by oxidized low-density lipoprotein of its own uptake into macrophages through activation of the peroxisome proliferator-activated receptor gamma. PMID- 10101924 TI - [Frequency of appearance of antibodies to bovine serum albumin in children with diabetes type I]. AB - It has been suggested that antibodies to bovine serum albumin may participate in the autoimmune process leading to the destruction of pancreatic islets. In the present study the frequency of antibodies to bovine serum albumin (BSA-Ab) in 45 children with newly diagnosed diabetes type 1, 32 children with diabetes lasting from 1-10 years and 65 healthy children was evaluated. BSA-Ab were determined by fluoroimmunometric method. The average value of fluorescence intensity 19 children with newly diagnosed diabetes type 1, who feeding mother's milk was 2037 x 10(3) +/- 898 x 10(3) impulse of fluorescence per minute (IMF) and was significant lower than the average value of fluorescence intensity of children with newly diagnosed diabetes type 1, who feeding artificiality. Antibodies to bovine serum albumin were found in 10% of children with newly diagnosed diabetes type 1, who feeding at the first six months of their life mother's milk, in 42% of children with newly diagnosed diabetes type 1, who feeding artificially and 3% of healthy children. PMID- 10101925 TI - [Microalbuminuria as a risk factor for diabetic osteopathy in patients with IDDM and renal sufficiency]. AB - Disturbances in bone marrow vascularisation can be one of the causes of diabetic osteopathy. The aim of the study was to answers the question if microalbuminuria as a results of capillary injury can be a sign of bone mineralisation disorders in IDDM renal sufficient patients. We examined 60 IDDM patients (30 women without menstruation disturbances; 30 men; age 25-36 years old). All the observed subjects were divided into groups: I-30 normoalbuminuric patients (0-29 mg/24 h); II-30 microabuminuric patients (30-295 mg/24 h). Bone mineral density (BMD) of femoral neck, lumbar spine (L2-L4) and total body was measured by dual energy X ray absorptiometry (DEXA, Lunar). The biochemical parameters of bone turnover were measured both in serum and urine as follows: osteocalcine, total hydroxyproline (HPR, HPR/Cr), total alkaline phosphatase (AP) with bone fraction, total calcium (Ca, Ca/Cr) and inorganic phosphor (P). Microalbuminuric patients presented more severe bone turnover disturbances, shown by differences in: BMD and Z-score for femoral neck (p < 0.05), serum HPR (p < 0.05), AP (p < 0.05), AP (p < 0.01) and its bone fraction (p < 0.05). We proved the presence of statistically significant correlation coefficients for albuminuria and some densytometric and biochemical bone parameeters. Our results suggest that microalbuminuria can indirectly indicate the dynamic of bone turnover derangement in IDDM course. They are present mostly in the femoral neck, which because of the vascularisation type is particularly susceptible to subalimentation in the diabetic microangiopathy course. PMID- 10101926 TI - [Use of laser-doppler perfusion for evaluation of microcirculation in patients with diabetes type I]. AB - The purpose of this study was to investigate the foot skin microcirculation in type 1-diabetic patients. The study group comprised 67 patients divided into four subgroups: 13 women and 11 men healthy and had no family history of diabetes; 19 women and 24 men had type 1-diabetes. The studied measurements included 7 parameters determined during rest and post occlusive hyperaemia. They were performed with laser Doppler fluxmetry using surface probe localised in distal part of the lower limbs. The most significant data localised the probe in thumb. The maximum of hyperaemic response (MAX) was significantly lower in the diabetic patients as compared to the healthy subjects (p < 0.01). The time of peak flow (TM) was higher (p < 0.01) in diabetic patients as compared to the control subjects. The half time of hyperaemia (TH) was significant longer (p < 0.05) for diabetic groups. CONCLUSION: The laser Doppler method is helpful to identify patients with risk development diabetic complications. The most valuable data is MAX, TM and TH, the best localisation of the probe seems to be the most distal point of thumb. PMID- 10101927 TI - [Bone density in type 2 diabetes as related to obesity and adrenal function]. AB - The purpose of the study was to analyse bone density in patients with noninsulin dependent diabetes mellitus with respect to such factors as the magnitude of obesity, serum cortisol concentration and 17-ketosteroid excretion and insulinemia level. Bone density was measured by ultrasonography, insulin was determined by radioimmunoassay, and steroid level by using the method of Zimmerman. The patients had imminent and overt osteoporosis. The highest serum cortisol concentration was in groups with lower T-score significant negative correlation between cortisol and SOS index. The lowest 17-ketosteroid level was detected in the patients with the lowest T-score; a significant correlation was observed between 17-ketosteroids and BUA index. The present findings indicate an imbalance between bone protective and resorptive factors. This leads to osteopenia in patients with noninsulin-dependent diabetes mellitus despite a protective effect of obesity. PMID- 10101928 TI - [Some parameters of hemostasis and fibrinolysis in diabetic patients]. AB - The aim of our study was to estimate selected parameters of hemostasis and fibrinolysis in diabetic patients with vascular complications and obesity. The investigation was carried out in 23 type 1 diabetic subjects aged 17-56 ys, in 25 type 2 diabetic patients aged 41-69 ys and in 38 healthy persons: 16 "young"- aged 32.5 +/- 13.2 ys and 22 "old"--aged 56.2 +/- 9.4 ys. The following parameters were determined: glycaemia, HbA1c, blood level fibrinogen, euglobulin clot lysis time, plasminogen activator inhibitor (PAI-1) activity, microalbuminuria, triglyceride, total, HDL- and LDL-cholesterol concentration. Plasma fibrinogen level was elevated in type 2 diabetic subjects, and the highest concentrations were noted in patients with retinopathy or arterial hypertension, in overweight persons and--surprisingly--in type 1 diabetic subjects with nephropathy and coronary vascular disease (CVD). There were also positive correlations between fibrinogen level and systolic blood pressure (r = 0.3413, p < 0.02), diastolic blood pressure (r = 0.3809, p < 0.002) and microalbuminuria (r = 0.3552, p < 0.05). The mean euglobulin clot lysis time was prolonged in type II diabetics in comparison to the control group, especially in obese subjects. The highest activity of PAI-1 was found in overweight controls (28.87 +/- 6.24 Au/ml, p < 0.002). PAI-1 activity was also slightly increased in type 1 diabetic patients, especially with the symptoms of diabetic neuropathy, nephropathy or CHD, in comparison to the other groups. Our results seem to confirm the disturbed balance between coagulation and fibrinolysis--towards and increased risk of a prothrombotic state --in both--obese and diabetic patients--especially with advanced vascular complications. PMID- 10101929 TI - [Evaluation of nitric oxide metabolites concentration in patients with type I diabetes]. AB - Nitric oxide (NO) mainly known as a relaxing factor, serves a wide variety of other functions in different tissues. It is quickly metabolized to NO2- and NO3- in humans. The aim of the study was to estimate plasma nitrite anion (NO2-) concentration in type 1 diabetic patients. The study was performed in 30 well metabolically controlled patients (18 female and 12 male, aged 30.2 +/- 10.6 years, duration of diabetes 8.4 +/- 6.8 years. HbA1c 6.5 +/- 1.2%) (group A) and 20 poorly metabolically controlled patients (12 female and 8 male, aged 29.8 +/- 9.8 years, duration of diabetes 8.0 +/- 4.8 years, HbA1c 11.2 +/- 1.6%) (group B). The concentration of NO2- was measured with the use of a calorimetric micromethod, where nitrate reductase catalyses the conversion of NO3- to NO2-. The NO2- plasma concentration was significantly higher in diabetic patients in comparison to controls. The highest NO2- concentration was noticed in the group of well metabolically controlled diabetic patients (group A, group B, healthy subjects: 41.99 +/- 4.02, 33.33 +/- 2.44, 16.68 +/- 2.16 mumol/l, respectively, p < 0.05, p < 0.0001). The nitrite concentrations did not correlate with HbA1c (r = -0.03, p > 0.05). The results support the concept that metabolism of nitrite oxides in diabetes is disturbed independently from the degree of metabolic control. PMID- 10101930 TI - [The effect of an education and rehabilitation program for blind diabetics on the level of metabolic equalization]. AB - AIM: Evaluating efficiency of the education and rehabilitation programme for patients suffering from diabetes on the level of metabolic equalization. Two modules for patients have been introduced. The first is group education conducted in groups of 20 patients. This covers basic information concerning diabetes, self monitoring interventional actions and using the insulin-injector. The second model is repeated every three months: one-day observation in a room for daily basis patients, which is combined with an individual educational programme and evaluation of metabolic equalization. After 6 and 24 months the level of patients knowledge was checked with the test containing 12 questions and with application of 1-5 point scale. The state of metabolic equalization was also tested, by means of evaluating the average glycaemia, serum concentration of HbA1c and the dosage of insulin. The level of patients knowledge increased after 6 months from 39 +/- 18% to 44 +/- 19%, and after 24 months by 68 +/- 21. The average glycaemia was lowered from 14.04 +/- 9.32 to 8.10 +/- 5.05 mmol/l after 24 months. The average serum cholesterol level was lowered from 6.7 +/- 1.21 to 6.51 +/- 1.39 mmol/l. At the same time there was an increase in the fractions HDL from 1.26 +/- 0.32 to 1.34 +/- 0.46 mmol/l HbA1c from 10.1 +/- 1.4% to 8.5 +/- 1.2%. The daily dose of insulin was reduced from 58.6 +/- 29.3 units a day 44.2 +/- 22.1 +/- units a day. A positive body weight reduction was observed. BMI was lowered from 30.1 +/- 3.96 to 28 +/- 5 kg/m2. PMID- 10101931 TI - [Mortality of diabetic patients in Warsaw--22 year prospective observation (1973/74-1995). I. Mortality of diabetic patients with type 2 diabetes (non insulin-dependent-diabetes)]. AB - In the period 1973/74-1995 a prospective observation was carried out on 4420 diabetic patients (1990 males and 2430 females) aged 30-68 years, with type 2 (non-insulin dependent diabetes) of 1-10 years duration. During the 22-years period nearly 80% of initial cohort died. The risk of death were 2-times higher in diabetes than in the samples of general population observed at the same time. The death risk from cardiovascular disease were over 3-times higher than in general population. The relevant risk ratio has been found over 5-times higher for coronary heart disease, which were unlike to results from the differences in death ascertainment between diabetics and the city dwellers. The all-causes ratio of death and cardiovascular diseases were the same for women and men but it was selectively higher for females then males group for coronary heart disease and cerebrovascular diseases. Among diabetic cohort the risk of death was also higher for neoplasms, especially in women. PMID- 10101932 TI - [Mortality of diabetic patients in Warsaw--22 year prospective observation (1973/74-1995). II. Mortality of patients with type I diabetes (insulin-dependent diabetes)]. AB - During the follow-up 1973/74-1995 years 171 subjects with type 1 (insulin dependent diabetes) (105 males and 66 females) aged 18-30 years died 31.6% (32.4% males and 30.3% females). The relative risk of mortality for all causes in the compared to the general population was 5.0 (3.5 for men and 7.5 for women). Almost 30% deaths were from renal disease, 17% from ischemic heart disease, and 3 death in women from carcinoma of breast. PMID- 10101933 TI - [Adipocyte--endocrine organ?]. PMID- 10101934 TI - [Molecular genetic mechanisms and hereditary disease]. PMID- 10101935 TI - [Can we afford to perform autopsies?]. PMID- 10101937 TI - [Revolt among physicians against increased medical fees for patients]. PMID- 10101936 TI - [Unnecessary cardiac death--a challenge!]. PMID- 10101938 TI - [Strategic choices to prevent injuries]. PMID- 10101939 TI - [Injuries among children treated at emergency medical centers and in hospitals 1990-97]. AB - The Norwegian National Injury Sample Registry is a prospective case register of injuries occurring in the defined population of four cities. All injuries treated in hospitals and emergency wards are recorded in the registry. We used data from this registry to provide an epidemiologic overview of the incidence of injuries among children aged 0-14 in Norway. The study population consisted of approximately 61,500 children annually or approximately 492,000 children-years over the 1990-97 period. A total of 57,000 injuries were registered, or 116 injuries per 1,000 children-years. Approximately 2% of the injuries were classified as severe. 36% of all injuries occurred at home, 13% during sport activities and 13% were caused by accidents at school. Incidence was higher among boys than girls in all age groups. During their first 15 years of life, boys sustained on average 2.0 injuries and girls 1.5 injuries. Data from the Norwegian National Sample Injury Registry may provide useful information for prevention of and research on injuries among children. PMID- 10101941 TI - [Leukocoria (white pupil) among children--mother is always right]. AB - Leucocoria is a rare, but serious symptom in early childhood. It may be present at birth or develop during infancy. As in adults, infants usually display a black pupil, and upon shining a bright light into the pupil with the ophthalmoscope, an orange or red reflex emerges. The first person to see that something is wrong, is often the mother, but she cannot give a precise description. When the infant is crying it can be difficult to examine the red reflex, and the necessity of admitting the infant to an ophthalmologist, when the mother is worried, is discussed. In this paper we discuss two cases of retinoblastoma and one case of congenital cataract where the treatment was delayed due to late diagnosis of the leucocoria. The main conclusion is always to listen to the relatives when they are worried about the infant's eye, and to make sure that the infant is properly examined. PMID- 10101940 TI - [Mucosal malignant melanomas of the head and neck]. AB - Mucosal malignant melanomas in the head and neck are most frequently located in the nose and sinuses. The tumours are rare, the clinical course unpredictable and the prognosis poor. 13 patients were presented with malignant melanoma in nose and sinuses in the ENT department, Ulleval Hospital, in the course of 30 years. Average age at presentation was 72 years; there were eight women and five men. Ten patients were primarily operated, and two of these received postoperative irradiation. Three patients received only palliative treatment. Four patients are alive, observation time respectively ten, seven and approximately two years (two patients). Several of the dead patients had long observation periods before death and several had operations for recurrences. The longest observed survival was 19 years. All tumours had histological characteristics indicating aggressive growth. The material is too small and sampled over too long a period for conclusions to be drawn with regard to the effect of different treatment modalities. PMID- 10101942 TI - [Euthanasia and cancer]. AB - Euthanasia is clinical practice in several countries world-wide. Cancer patients' attitude in this field was focused through a review of case reports and questionnaire-based studies on Medline (1992-97). A total of nine publications including 459 cancer patients from USA, Canada and Holland were found. The majority of patients had poor performance status and advanced disease. At least one third reported themselves positive to euthanasia. Patients below 50 years of age, having superior performance status and not considering themselves religious, more frequently supported euthanasia. Psychological factors seem to be more significant than physical factors for support of euthanasia. Loss of control, being a burden on one's family and loss of dignity are the psychological factors most frequently reported. A "help to live" approach aimed at avoiding patient requests for help to die will mean that health care workers must allocate more of their time to these patients. Overcrowded hospitals with several patients in corridors and lack of nursing-homebeds do not make this situation easier to handle. PMID- 10101943 TI - [Nucleic acid based diagnosis in clinical microbiology]. AB - The introduction and increasing usage of nucleic acid based methods in clinical microbiology over the last years have contributed to better and earlier diagnosis of infectious diseases as well as more accurate monitoring of treatment. Various nucleic acid amplification methods such as the polymerase chain reaction and the ligase chain reaction are widely used in Norwegian clinical microbiological laboratories to detect fastidious or non-cultured infectious agents. The amplification methods combine an extremely high sensitivity with acceptable specificity. About 200,000 nucleic acid based examinations are now performed in clinical microbiological laboratories in Norway each year. PMID- 10101944 TI - [Guidelines for basic cardiopulmonary resuscitation of adult patients. European Resuscitation Council]. AB - In this article, 15 experts from six countries present an abridged version of the 1998 European Resuscitation Council guidelines for adult basic life support. Persons trained in advanced life support should use these guidelines together with the guidelines for advanced life support, also published in this journal. There are a few changes from the previous guidelines published in 1993. The ventilation tidal volume has been reduced to 400-600 ml, and the chest compression frequency has been increased to 100 min-1. In Norway, but not in the rest of Europe, the evaluation of the circulation by a pulse check has been eliminated in basic, but not in advanced cardiopulmonary resuscitation. This is due to reports that pulse checks performed by lay rescuers require much time with poor specificity and sensitivity. Finally, in evaluating the patient's own ventilation the differentiation between agonal gasps and regular breaths is stressed. PMID- 10101945 TI - [Guidelines for advanced cardiopulmonary resuscitation of adult patients. European Resuscitation Council]. AB - In this paper 16 experts from ten different countries present an abridged version of the 1998 European Resuscitation Council guidelines for advanced adult life support. There are few changes from the 1992 version, and they are mainly made for educational reasons. There is thus no convincing new scientific evidence that warrants changes in the guidelines. While there previously were three separate algorithms for ventricular fibrillation/ventricular tachycardia, asystole and electromechanical dissociation, there is now only one algorithm. The ventilation volume has been reduced to 400-600 ml, and the chest compression frequency has been increased to 100 min-1. For other rhythms than ventricular fibrillation/ventricular tachycardia, ventilation and chest compressions should now be performed for three minute periods, not one minute as used to be the rule. One minute is still the correct period for ventricular fibrillation/ventricular tachycardia. PMID- 10101946 TI - [Validation of causes of death by age]. AB - In Norway the percentage of autopsies has gradually decreased during the 1986 to 1994 period. As a consequence, the Cause of Death Registry has to rely to a greater extent on physicians' certificates only. The overall percent of autopsies was reduced from 13.8% in 1986 to 9.1% in 1994 (Haukeland Hospital, Bergen, not included). The frequency decreased with age, was lowest in women, and differed according to cause of death. In the examined age groups of 0 year, 1-59 years and 60 years and above the percentage changes were as follows in women: 69.9% to 48.9%, 35.8% to 27.2%; 11.5% to 5.7%. In men the changes were: 72.2% to 54.7%; 44.5% to 39.2%; 15.1% to 8.65%. Deaths due to cancer, congenital disorders and perinatal deaths were all validated if possible. About 40% of deaths due to accidents, poisoning and violence were validated. Myocardial infarctions were autopsied more frequently than stroke. The extent of validation of cause of death during this period is discussed. PMID- 10101947 TI - [Genomic imprinting and hereditary diseases]. AB - Clinical experience and molecular genetics have demonstrated several exceptions to Mendelian inheritance in man. Genomic imprinting is a mechanism that regulates expression or repression of genes according to their parental origin. The phenotypic expression of imprinted genes is therefore dependent on whether the gene was inherited from the father or the mother. More than 20 imprinted genes in man are recognized, and these genes tend to occur in clusters in the genome. The best characterized imprinted regions are the 15q11-13 region which involves Prader-Willi's syndrome and Angelman's syndrome and the 11p15 region involving Beckwith-Wiedemann's syndrome. The mechanism for disease expression in these two regions is discussed. PMID- 10101948 TI - [Complex hereditary diseases with psychiatric symptoms]. AB - Family and adoption studies indicate that genetic factors play a role in the development of many psychiatric disorders. A variable number of possible interacting genes giving a predisposition to the diseases is likely. The genetic dissection has been hampered by genetic complexity as well as by difficulties in defining the phenotypes. Genetic mapping efforts using sib pairs, twins and individual large families have revealed preliminary or tentative evidence of susceptibility loci for a number of psychiatric disorders. Illnesses described in this article include the prion disease familial fatal insomnia (FFI), alcoholism, anorexia nervosa, autism, bipolar affective disorder, dyslexia, enuresis nocturna, epilepsia, obsessive-compulsive disorders (OCD), schizophrenia, and the dementias, Alzheimer's disease and frontal lobe dementia. The genes and proteins related to the newly discovered transmitter in the central nervous system, nitric oxide (NO), and its genes and proteins are also reviewed. The number of mapped human genes now exceeds 30,000 of the estimated total number of 60,000 to 100,000 genes. This rapid development will facilitate gene mapping and efforts to isolate and identify the genes responsible for symptom susceptibility in many of the aetiologically unclear psychiatric diseases with complex genetic origin. PMID- 10101949 TI - [The basis for homeopathy as a therapeutic method]. PMID- 10101950 TI - [Development of medical fees depopulates the districts]. PMID- 10101951 TI - [University duties at Sentralsykehuset in Akershus]. PMID- 10101952 TI - Idiopathic constipation: too few stools and too little knowledge. AB - The precise abnormalities of colonic motility patterns in idiopathic constipation, and the alterations at the cellular, neural, myogenic and biochemical levels that underlie these patterns, are not yet understood. One promising approach in the treatment of constipation seems to be to design drugs that can stimulate GMCs to produce mass movements and consequently defaecation. This could possibly be achieved with the selective 5-HT4 receptor agonists prucalopride and SDZ HTF-919, which are currently in advanced clinical trials. Other mechanisms that provide a means to induce GMCs, such as NK1 receptor agonism, deserve further exploration. PMID- 10101953 TI - Selective COX-2 inhibitors: is the water becoming muddy? PMID- 10101954 TI - Agonist promiscuity: a positive twist. PMID- 10101955 TI - Inadequate career advice for students. PMID- 10101956 TI - Selective airway responsiveness in asthma. AB - Hyperresponsiveness of airway smooth muscle accounts for the susceptibility of asthmatic subjects to diverse bronchoconstrictor agents. It is widely presumed that hyperresponsiveness is not spasmogen selective. Hence, inhalation of methacholine is used routinely for clinical assessment of asthma and for evaluation of anti-asthma drugs. Comparative studies employing multiple spasmogens have revealed hyperresponsiveness to be markedly spasmogen selective. Because of this pronounced heterogeneity of hyperresponsiveness, sensitivity to methacholine cannot provide a reliable index of responsiveness. Development of exceptional hyperresponsiveness to bradykinin and to peptidoleukotrienes during allergic and other reactions could warrant the development of specific antagonists for asthma therapy. These issues are discussed here by Brian O'Connor, Simon Crowther, John Costello and John Morley. PMID- 10101957 TI - Recent advances in the pharmacological treatment of tinnitus. AB - Tinnitus is an extremely prevalent condition that impinges on the lives of sufferers to varying degrees. In some people, it is a fairly minor irritation but, for many, the tinnitus intrudes to such a degree that it affects their ability to lead a normal life, and in some very extreme cases has resulted in suicide. Insomnia, inability to concentrate and depression are commonly reported to accompany the condition. Relief can be reliably obtained using intravenous lignocaine, which indicates that pharmacology can provide a route for effective alleviation of the condition. In this article, Julie Simpson and Ewart Davies review the potential pharmacological therapies, and emphasize that clinical research has been hampered by the absence of a reliable objective assessment of the tinnitus and by the variable nature of the complaint. PMID- 10101958 TI - Opioids: first lessons from knockout mice. AB - Opioid receptors of the mu-, delta- and kappa-subtypes mediate the potent analgesic and addictive actions of opioid drugs. They also regulate responses to pain, stress and emotions when activated by endogenous opioid peptides. Recently, mice lacking opioid receptors or opioid peptides have been produced by gene targeting, providing molecular tools to study opioid function in vivo. Observations on mutant mice have shed new light on the mode of action of opioids, opioid receptor heterogeneity and interactions, and the involvement of each component of the opioid system in mouse physiology. In this article, Brigitte L. Kieffer reviews the first reported studies and discusses their therapeutic implications. PMID- 10101960 TI - The pharmacology of apoptosis. AB - Apoptosis is an area of intense scientific interest, which encompasses the study of and triggers mechanisms involved in mediating the cell biology of programmed cell death. A number of low molecular weight compounds have been used to inhibit or enhance this fundamental cellular process and so apoptosis has now become amenable to pharmacological manipulation. In this review Ross Kinloch, Mark Treherne, Mike Furness and Iradj Hajimohamadreza will focus on the current literature describing the pharmacology of apoptosis, with particular reference to the therapeutic potential that could arise from the development of pro- and anti apoptotic drugs. The pivotal role of apoptosis in such diverse pathological processes as tumour growth, the immune response and neurodegeneration suggests that an understanding of how apoptosis can be regulated by drugs will become increasingly important to the pharmaceutical industry. PMID- 10101959 TI - Kainate receptors: subunits, synaptic localization and function. AB - Although it is well established that kainate receptors constitute an entirely separate group of proteins from AMPA receptors, their physiological functions remain unclear. The molecular cloning of subunits that form kainate receptors and the ability to study recombinant receptors is leading to an increased understanding of their functional properties. Furthermore, the development of kainate receptor-selective agonists and antagonists over the past few years is now allowing the physiological roles of these receptors and, in some cases, specific subunits to be investigated. As a consequence, the synaptic activation of postsynaptic kainate receptors and the presence of presynaptic kainate receptors that serve to regulate excitatory and inhibitory synaptic transmission have been described, and will be discussed in this article by Ramesh Chittajallu, Steven Braithwaite, Vernon Clarke and Jeremy Henley. PMID- 10101961 TI - Neuropeptide Y feeding receptors: are multiple subtypes involved? PMID- 10101962 TI - Neuronal cell death: a demise with different shapes. PMID- 10101963 TI - Airway epithelium: more than just a barrier! PMID- 10101964 TI - The Vulcan kidney. AB - One can often gain new insights into a topic when approaching it from a new angle. The paradigm example involves the insights into histology that can be gained from studying pathology. For example, a rare cell type in the pituitary suddenly becomes very easy to recognize once a whole field of them can be seen in a tumour. Similarly, one can gain insights by looking at species other than our own. In this article, Doug Waud, using the kidney in Vulcans, takes this latter theme one step further to provide useful insights into renal physiology and pharmacology. PMID- 10101965 TI - Neurotrophins and depression. AB - Exogenous delivery of the neurotrophic factors, brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), promotes the function, sprouting and regrowth of 5-HT-containing neurones in the brains of adult rats. Similar infusions of BDNF into the dorsal raphe nucleus produce an antidepressant effect, as evaluated by several 'learned helplessness' paradigms. Environmental stressors such as immobilization induce depression and decrease BDNF mRNA. Antidepressants increase BDNF mRNA in the brain, via 5-HT2A and beta-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA. In this article, Tony Altar discusses how existing treatments of depression might work by increasing endogenous brain levels of BDNF or NT-3, which in turn could promote monoamine-containing neurone growth and function. Drugs that selectively stimulate the production of neurotrophins could represent a new generation of antidepressants. PMID- 10101966 TI - Are ion-exchange processes central to understanding drug-resistance phenomena? AB - Drug resistance in malarial parasites is arguably the greatest challenge currently facing infectious disease research. In addressing this problem, researchers have been intrigued by similarities between drug-resistant malarial parasites and tumour cells. For example, it was originally thought that the role of pfMDR (Plasmodium falciparum multidrug resistance) proteins was central in conferring antimalarial multidrug resistance. However, recent work has questioned the precise role of MDR proteins in multidrug resistance. In addition, recent ground-breaking work in identifying mutations associated with antimalarial drug resistance might have led to identification of yet another parallel between drug resistant tumour cells and malarial parasites, namely, intriguing alterations in transmembrane ion transport, discussed here by Paul Roepe and James Martiney. This further underscores an emerging paradigm in drug-resistance research. PMID- 10101967 TI - G protein regulation of adenylate cyclase. AB - Adenylate cyclase integrates positive and negative signals that act through G protein-coupled cell-surface receptors with other extracellular stimuli to finely regulate levels of cAMP within the cell. Recently, the structures of the cyclase catalytic core complexed with the plant diterpene forskolin, and a cyclase forskolin complex bound to an activated form of the stimulatory G protein subunit Gs alpha have been solved by X-ray crystallography. These structures provide a wealth of detail about how different signals could converge at the core cyclase domains to regulate catalysis. In this article, William Simonds reviews recent advances in the molecular and structural biology of this key regulatory enzyme, which provide new insight into its ability to integrate multiple signals in diverse cellular contexts. PMID- 10101968 TI - Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. AB - Chemokines constitute a growing family of structurally and functionally related small (8-10 kDa) proteins associated with inflammatory-cell recruitment in host defence. In addition to their well-established role in the immune system, recent data suggest their involvement in the maintenance of CNS homeostasis, in neuronal patterning during ontogeny and as potential mediators of neuroinflammation, playing an essential role in leukocyte infiltration into the brain. Chemokines and their G protein-coupled receptors are constitutively expressed at low-to negligible levels in various cell types in the brain. Their expression is rapidly induced by various neuroinflammatory stimuli, implicating them in various neurological disorders such as trauma, stroke and Alzheimer's disease, in tumour induction and in neuroimmune diseases such as multiple sclerosis or acquired immunodeficiency syndrome (AIDS). Here, F. Mennicken, R. Maki, E. B. De Souza and R. Quirion briefly summarize recent exciting findings in the field. PMID- 10101969 TI - Insight into adenosine receptor function using antisense and gene-knockout approaches. AB - The extensive role of adenosine in discriminating input from the extracellular environment is effected through a series of cell membrane-spanning proteins--the adenosine A1, A2A, A2B and A3 receptors. New genetic and epigenetic tools have emerged that facilitate the elucidation of the function of these receptors with greater specificity than is generally possible with traditional antagonist drugs. These tools include antisense oligonucleotides (epigenetic) and gene 'knockin' and 'knockout' mice (genetic) and are discussed in this article by Jonathan Nyce. PMID- 10101970 TI - Modeling DNA deformations induced by minor groove binding proteins. AB - Molecular modeling is used to demonstrate that the major structural deformations of DNA caused by four different minor groove binding proteins, TBP, SRY, LEF-1, and PurR, can all be mimicked by stretching the double helix between two 3' phosphate groups flanking the binding region. This deformation reproduces the widening of the minor groove and the overall bending and unwinding of DNA caused by protein binding. It also reproduces the principal kinks associated with partially intercalated amino acid side chains, observed with such interactions. In addition, when protein binding involves a local transition to an A-like conformation, phosphate neutralization, via the formation of protein-DNA salt bridges, appears to favor the resulting deformation. PMID- 10101971 TI - A light-harvesting antenna protein retains its folded conformation in the absence of protein-lipid and protein-pigment interactions. AB - The first study by nmr of the integral membrane protein, the bacterial light harvesting (LH) antenna protein LH1 beta, is reported. The photosynthetic apparatus of purple bacteria contains two different kinds of antenna complexes (LH1 and LH2), which consist of two small integral membrane proteins alpha and beta, each of approximately 6 kDa, and bacteriochlorophyll and carotenoid pigments. We have purified the antenna polypeptide LH1 beta from Rhodobacter sphaeroides, and have recorded CD spectra and a series of two-dimensional nmr spectra. A comparison of CD spectra of LH1 beta observed in organic solvents and detergent micelles shows that the helical character of the peptide does not change appreciably between the two milieus. A significantly high-field shifted methyl signal was observed both in organic solvents and in detergent micelles, implying that a similar three-dimensional structure is present in each case. However, the 1H-nmr signals observed in organic solvents had a narrower line width and better resolution, and it is shown that in this case organic solvents provide a better medium for nmr studies than detergent micelles. A sequential assignment has been carried out on the C-terminal transmembrane region, which is the region in which the pigment is bound. The region is shown to have a helical structure by the chemical shift values of the alpha-CH protons and the presence of nuclear Overhauser effects characteristic of helices. An analysis of the amide proton chemical shifts of the residues surrounding the histidine chlorophyll ligand suggests that the local structure is well ordered even in the absence of protein-lipid and protein-pigment interactions. Its structure was determined from 348 nmr-derived constraints by using distance geometry calculations. The polypeptide contains an alpha-helix extending from Leu19 (position of cytoplasmic surface) to Trp44 (position of periplasmic surface). The helix is bent, as expected from the amide proton chemical shifts, and it is similar to the polypeptide fold of the previously determined crystal structure of Rhodopseudomonas acidophila Ac10050 LH2 beta (S. M. Prince et al., Journal of Molecular Biology, 1997, Vol. 268, pp. 412-423). It is concluded that the polypeptide conformation of this region may facilitate assembly of the LH complex. PMID- 10101972 TI - Conformation in solution and dynamics of a structurally constrained linear insect kinin pentapeptide analogue. AB - The preferred conformations of the active diuretic insect kinin pentapeptide analogue Phe-Phe-Aib-Trp-Gly-NH2 were studied using nmr spectroscopy and molecular modeling. Structure sets consistent with rotating frame nuclear Overhauser effect spectroscopy distance constraints obtained by restrained simulated annealing in vacuo indicate a predominant population of a type II beta turn involving the Phe1-Trp4 region. An equilibrium between this type II and a type I beta-turn formed by residues Phe2 and Gly5 was observed in a 5 ns restrained molecular dynamics simulation using the implicit generalized Born solvent accessible surface area (GB/SA) solvation model. When subjected to 500 ps dynamics with explicit water both beta-turn folds were conserved throughout the simulations. The results obtained with implicit and explicit solvation models are compared, and their consistency with the nmr observations is discussed. The behavior of the linear pentapeptide in this study is in agreement with an earlier report on the consensus conformation of the insect kinin active core derived from analysis of cyclic active analogues. PMID- 10101973 TI - The 25th Bartlett Lecture. To act or not to act: perspectives on the representation of actions. AB - In this review, a description is offered of the way actions are represented, how these representations are built, and how their content can be accessed by the agent and by other agents. Such a description will appear critical for understanding how an action is attributed to its proper origin, or, in other words, how a subject can make a conscious judgement about who the agent of that action is (an agency judgement). This question is central to the problem of self consciousness: Action is one of the main channels used for communication between individuals, so that determining the agent of an action contributes to differentiating the self from others. PMID- 10101974 TI - Categorical perception of face actions: their role in sign language and in communicative facial displays. AB - Can face actions that carry significance within language be perceived categorically? We used continua produced by computational morphing of face-action images to explore this question in a controlled fashion. In Experiment 1 we showed that question--type--a syntactic distinction in British Sign Language (BSL)--can be perceived categorically, but only when it is also identified as a question marker. A few hearing non-signers were sensitive to this distinction; among those who used sign, late sign learners were no less sensitive than early sign users. A very similar facial-display continuum between "surprise" and "puzzlement" was perceived categorically by deaf and hearing participants, irrespective of their sign experience (Experiment 2). The categorical processing of facial displays can be demonstrated for sign, but may be grounded in universally perceived distinctions between communicative face actions. Moreover, the categorical perception of facial actions is not confined to the six universal facial expressions. PMID- 10101975 TI - Developmental surface dysgraphia: what is the underlying cognitive impairment? AB - The purpose of this study was to investigate the cognitive causes underlying spelling difficulties in a case of developmental surface dysgraphia, AW. Our results do not support a number of possibilities that could be the cause of AW's poor orthographic lexicon, including difficulties in phonological processing, phonological short-term memory, configurational visual memory, and lexical semantic memory. We have found instead that AW performs poorly in tasks that involve detection of the order of adjacent letters in a word or the order of adjacent units in strings of consonants or symbols. Finally, he performs poorly in tasks that involve reconstructing the order of a series of complex visual characters (Japanese and Hindi characters) especially when these are presented sequentially. We advance the hypothesis that AW's poor spelling and good reading skills stem from an underlying pattern of cognitive abilities where a very good visual configurational memory is coupled with a poor ability to encode serial order. This may have resulted in a holistic word-based reading strategy, which, together with the original problem of encoding order, may have had detrimental effects for the acquisition of spelling. PMID- 10101977 TI - Abuse of dextromethorphan. PMID- 10101978 TI - A clinical trial of hypertonic saline nasal spray. PMID- 10101979 TI - Report of the Council on Scientific Affairs. Use of restraints for patients in nursing homes. Council on Scientific Affairs, American Medical Association. AB - OBJECTIVE: To examine issues related to the use of restraints on nursing home patients, including regulations and guidelines, risks and benefits of restraint use, system problems, and measures to reduce restraint use, to determine when the use of restraints results in clinically desirable outcomes. METHODS: Sources of information included a review of published articles and reports, a survey of federal and state regulations and guidelines relating to restraint use in nursing homes, review of current legislative initiatives, and consultation with experts in the field. RESULTS: The data reveal that restraint use imposes more risk of falls and other undesirable outcomes than it prevents. In response to legislative initiatives and regulatory activities and by implementing alternatives, the prevalence of restraint use has decreased by 20% in recent years. In many states, facilities have created restraint-free environments or restraint-free policies and goals. The Council on Scientific Affairs finds that current federal and state regulations on the use of restraints have benefited the vast majority of nursing home patients. CONCLUSIONS: While guidelines are in place for the use of restraints when clinically necessary, the Council on Scientific Affairs recommends increased research to determine when the use of restraints results in desirable outcomes. Extraregulatory initiatives, such as widespread educational programs, are needed for professionals and consumers to improve awareness of the risks and benefits of restraints, as well as the rights of residents with respect to restraint use. PMID- 10101980 TI - Family dysfunction and Native American women who do not seek prenatal care. AB - OBJECTIVE: To test the hypotheses that, in a health system with few external barriers to care, women with no prenatal care (NPC) have higher rates of nuclear family dysfunction and disproportionate amounts of adverse neonatal outcomes compared with women with prenatal care. DESIGN: Case-control study. SETTING: Indian Health Service system. PATIENTS: Nuclear families of women not seeking prenatal care compared with those who did seek prenatal care. MAIN OUTCOME MEASURES: Dysfunctional outcome measures in nuclear families were children adopted, placed, or under protective surveillance; mothers denying pregnancy, being abused, or attempting suicide; and parents with alcoholism. Neonatal outcome measures were low birth weight and neonatal intensive care days. RESULTS: Dysfunctional markers occurred significantly more frequently in families of women with NPC than in families of women with prenatal care (57% of NPC and 12% of control families; McNemar odds ratio, 14; 95% confidence interval, 4.7-41.6). Neonatal outcome in this Native American population showed that women with NPC had only 2.6% (58/2222) of the total births but accounted for 11% of the low birth-weight infants (< 2500 g), 18% of the very-low-birth-weight infants (< 1500 g), and 24% of the level II and 41% of the level III newborn intensive care days. CONCLUSIONS: Women not seeking prenatal care in a system with few external barriers to care have significantly more family dysfunction (P < .001) than women seeking prenatal care. Infants of women with NPC generated a disproportionate amount of adverse neonatal outcome. The combination of NPC and family dysfunction was more predictive of adverse neonatal outcome than was NPC alone. PMID- 10101981 TI - Medication cost information in a computer-based patient record system. Impact on prescribing in a family medicine clinical practice. AB - BACKGROUND: Medications account for 8% of national health care expenditures, and prescription drugs are a focus of cost containment measures. Physicians have limited knowledge about drug costs, and no method of providing this information has demonstrated sustained cost reductions. OBJECTIVE: To determine the impact of cost information in a computer-based patient record system on prescribing by family physicians. METHODS: A yearlong, controlled clinical trial was conducted at the Family Medicine Center, Medical University of South Carolina, Charleston, a group practice staffed by attending physicians and residents. Prescription cost information was included in the computer-based patient record system used at the center. During a 6-month period, cost information was not displayed; during the subsequent 6-month intervention period, costs were displayed at the time of prescribing. An intention-to-treat analysis was used to compare prescription costs between the control and intervention periods for all medications prescribed, and stratified analyses for several medication and physician factors were performed. RESULTS: A total of 22,883 prescriptions were written during the 1-year study period. The mean +/- SD cost per prescription in the control period was $21.83 +/- $27.00 (range, $0.01-$510.00), and in the intervention period was $22.03 +/- $28.12 (range, $0.01-$435.96) (P = .61, Student t test). Increases in mean prescription cost and proportion of total costs were identified in 4 medication classes: antibiotics, cardiovascular agents, headache therapies, and antithrombotic agents. Decreases in mean prescription cost and proportion of total costs were identified in 5 medication classes: nonsteroidal anti inflammatory drugs, histamine type 2-receptor antagonists and proton pump inhibitors, ophthalmic preparations, vaginal preparations, and otic preparations. CONCLUSIONS: In this setting, the provision of real-time computerized drug cost information did not affect overall prescription drug costs to patients, although differences in individual medication classes were observed. The negative results of this study may reflect confounding due to the use of historical controls, suboptimal timing of the intervention in the prescribing process, susceptibility bias at the study site, or the insensitivity of prescribing habits to cost information. PMID- 10101982 TI - Biological, social, and behavioral factors associated with premenstrual syndrome. AB - OBJECTIVE: To investigate the influence of various biological, socioeconomic, and behavioral factors on premenstrual syndrome (PMS). DESIGN: Random-digit dialing technique. Of 7900 calls from all area codes, exchanges, and 2 digits known to be open in Virginia, with a pair of random digits, 1700 women were eligible for telephone interviews. A total of 874 women completed interviews, for a response rate of 67%. SETTING: State of Virginia. PATIENTS OR OTHER PARTICIPANTS: All women between the ages of 18 and 44 years and living in Virginia between August 1 and September 15, 1994, were eligible. MAIN OUTCOME MEASURES: Scores on Menstrual Distress Questionnaire, biological variables, lifestyle behaviors, socioeconomic status, and menstrual and reproductive history. RESULTS: Of the 874 women, 8.3% (95% confidence interval, 6.4%-10.2%) experienced PMS. Adjusted prevalence odds ratios for perceived stress and alcohol intake were 3.7 and 2.5, respectively, in women with PMS. Women with PMS were 2.9 times more likely to be physically active than women without PMS. Younger women, black women, and women with longer menses were more likely to have PMS. CONCLUSIONS: Scores on the stress scale and alcohol intake support the concept that PMS is stress related; intervention strategies to cope with stress may be effective. Further study will be required to determine the influence of race on PMS and whether women with PMS exercise more regularly than women without PMS because they believe exercise is effective in attenuating their symptoms. PMID- 10101983 TI - Barriers to follow-up of abnormal Papanicolaou smears in an urban community health center. AB - OBJECTIVE: To determine factors predictive of failure to return for colposcopy among women with significant abnormalities on Papanicolaou smears in a high-risk clinical population. DESIGN: Telephone survey. SETTING: An urban community health center. PARTICIPANTS: Two hundred seventy-nine women randomly selected from all women seen at the health center with abnormal Papanicolaou smears requiring colposcopy during 1993 to 1994. Six (2%) refused participation, and 19% could not be reached for inclusion. Subjects were mostly minority women receiving Medicaid. MAIN OUTCOME MEASURE: Completion of colposcopy. RESULTS: Of the 279 selected women, 79% were interviewed. The rate of adherence with colposcopy was 75% for the respondents. Women who did not know the results of their smear or who incorrectly understood their results were significantly less likely to return for colposcopy (P = .001). Younger women, especially teenagers, were less likely to return (P = .02). Socioeconomic status, education, primary language, health beliefs, fear of cancer, and clinician's gender or discipline were not associated with rate of follow-up. Barriers involving transportation, child care, and insurance also did not predict follow-up. CONCLUSIONS: Effective communication of results is the most important factor related to follow-up after abnormal Papanicolaou smear in this setting. In other settings, other factors may be of greater importance. PMID- 10101984 TI - Effects of physician awareness of symptom-related expectations and mental disorders. A controlled trial. AB - OBJECTIVE: To study whether physician awareness of symptom-related expectations and mental disorders reduces unmet expectations or improves patient satisfaction. DESIGN: Prospective, before-after trial, with control (n = 250) and intervention (n = 250) groups. Outcomes were assessed immediately after the index office visit, at 2 weeks, and at 3 months. SETTING: Ambulatory walk-in clinic. PARTICIPANTS: Five hundred adults with physical complaints. Exclusion criteria included upper respiratory tract infection and dementia. Follow-up was accomplished in 100% immediately after the visit, 92.6% at 2 weeks, and 82.6% at 3 months. INTERVENTIONS: Two-hour physician workshop followed by information provided before each visit on patient expectations, illness worry, and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) disorders. MEASUREMENTS: Symptom-related expectations, satisfaction with care, symptom improvement, functional status, physician-perceived difficulty of the encounter, visit costs, and use of health care services. RESULTS: Serious illness worry (64%), 1 or more specific expectations (98%), or a DSM-IV disorder (29%) were commonly present in study patients. Intervention patients were less likely to report unmet expectations (odds ratio, 0.52; 95% confidence interval [CI], 0.43 0.97) immediately after the visit and at 2 weeks, less likely to be perceived as difficult by their physician (odds ratio, 0.49; 95% CI, 0.24-0.98), and more likely to be fully satisfied at 2 weeks (odds ratio, 1.63; 95% CI, 1.14-2.00). By 3 months, groups were similar in terms of satisfaction and residual expectations. Symptom improvement occurred in most patients by 2 weeks (70.5%) and 3 months (81.2%), regardless of study group. There was also no difference in patients' serious illness worry during the follow-up. The intervention did not increase visit costs or use of health care services. CONCLUSION: Identifying symptom related expectations and mental disorders in patients presenting with physical complaints may improve satisfaction with care at 2-week follow-up and physician perceived difficulty of the encounter. PMID- 10101986 TI - Methods of reducing the financial risk of physicians under capitation. AB - In today's rapidly changing medical marketplace, managed care plans are not the only entities assuming risk for the care of enrollees through capitation. Increasingly, managed care plans are transferring this risk to their primary care and specialty physicians by paying them on a fully or partially capitated basis. Although capitation provides a strong incentive for physicians to provide cost effective care, there are concerns that capitation may place some physicians at considerable financial risk. Our purpose is to familiarize physicians with issues they will want to consider when they evaluate capitation options and methods that are available to reduce their financial risk. Specifically, we analyze 3 issues: the range of services that are capitated, who accepts the risk, and size of patient panel. We conclude with a discussion of 3 methods for reducing or limiting risk--reinsurance, "carve outs," and risk adjustment. PMID- 10101985 TI - Effects of ankle sprain in a general clinic population 6 to 18 months after medical evaluation. AB - OBJECTIVE: To assess the 1-year outcome of standard medical care of acute ankle sprains in a general clinic-based population. DESIGN: A self-administered survey was mailed to all adult patients who presented to a health system provider for evaluation of ankle sprain. SETTING: A regional primary care health system. PARTICIPANTS: Four hundred sixty-seven (66.5%) of 702 patients with ankle sprains evaluated by a system physician from April 1, 1995, to March 31, 1996. MAIN OUTCOME MEASURES: Prevalence and severity of self-reported ankle pain, swelling, perceived instability, and perceived weakness 6 to 18 months after medical evaluation. RESULTS: Most patients sought medical evaluation shortly after injury and were immobilized or braced; 32.7% reported formal or home-based physical therapy. Six to 18 months after injury, 72.6% reported residual symptoms. Of these, 40.4% reported at least 1 moderate to severe symptom, most commonly perceived ankle weakness; 40.3% were unable to walk 1 mile; and 43.3% were unable to jump or pivot on the ankle without symptoms. Factors associated with moderate to severe residual symptoms were reinjury of the ankle (odds ratio [OR], 7.21; 95% confidence interval [CI], 4.14-12.68), activity restriction longer than 1 week (OR, 2.04; 95% CI, 1.25-3.32), and limited weight bearing longer than 28 days (OR, 2.16; 95% CI, 1.28-3.63). CONCLUSIONS: Residual lifestyle-limiting symptoms are common 6 to 18 months after an ankle sprain. Ankle sprains may be more problematic than generally thought, or standard medical treatment may be inadequate. Further studies evaluating treatment regimens are needed to identify effective methods to reduce the long-term functional limitations of ankle sprain in general clinic populations. PMID- 10101988 TI - Frequently asked questions from clinical practice. What is the appropriate diagnostic approach for patients who complain of night sweats? PMID- 10101987 TI - Treating the obese patient. Suggestions for primary care practice. AB - Obesity is a major health problem in America. Weight loss is associated with improvements in obesity-related health complications, but patients and practitioners are frequently disappointed by the long-term results of weight control efforts. Recent research has yielded new findings concerning the causes of obesity, as well as new goals for obesity treatment. Traditionally, the goal of therapy has been reduction to ideal weight. Several scientific bodies, however, now recommend a more modest 5% to 15% reduction in initial weight. Current options for weight loss include behavioral or pharmacological management provided during primary care visits, self-help and commercial programs, hospital based interventions, and bariatric surgery. Regardless of the approach selected, long-term care usually is required to facilitate the maintenance of weight loss. PMID- 10101989 TI - Comparison of dermatologic diagnoses by primary care practitioners and dermatologists. A review of the literature. AB - BACKGROUND: Cost-containment efforts in the United States have led to a greater emphasis on health care delivery by primary care physicians as opposed to specialists, who are assumed to be more costly. With this approach, it is incumbent on the primary care physician to be able to accurately diagnose and treat common maladies, including skin disease. OBJECTIVE: To ascertain whether differences in performance were detectable between groups of physicians when presented with color slides or high-quality transparencies. DESIGN: We performed a critical review of published studies. RESULTS: Overall, dermatologists (93% correct) performed better than nondermatologists (52% correct) (P < .001). No difference was appreciable between dermatology residents (91% correct) and practicing dermatologists (96% correct) or between internal medicine residents (45% correct) and family practice residents (48% correct). In addition, family medicine attending physicians (70% correct) performed better than internal medicine attending physicians (52% correct) (P < .001). CONCLUSION: Primary care physicians should receive more training in the diagnosis of skin disease. PMID- 10101990 TI - Professionalism reconsidered. Priorities for physicians. PMID- 10101992 TI - Traditional healers face off with science. PMID- 10101991 TI - Fetal alcohol syndrome diagnosed by telelink in Manitoba. PMID- 10101993 TI - Smoking: an occupational hazard. PMID- 10101994 TI - Patients' pressure helps bring brachytherapy to BC. PMID- 10101995 TI - More than milk, eggs and orange juice. PMID- 10101996 TI - What causes chronic fatigue? PMID- 10101997 TI - What causes chronic fatigue? PMID- 10101998 TI - Relation between hospital surgical volume and outcome for pancreatic resection for neoplasm in a publicly funded health care system. AB - BACKGROUND: Recent studies from the United States have shown that institutions with higher numbers of pancreatic resection procedures for neoplasm have lower mortality rates associated with this procedure. However, minimal work has been done to assess whether the results of similar volume-outcome studies within a publicly financed health care system would differ from those obtained in a mixed public-private health care system. METHODS: A population-based retrospective analysis was used to examine pancreatic resection for neoplasm in Ontario for the period 1988/89 to 1994/95. Outcomes examined included in-hospital case fatality rate and mean length of stay in hospital. For each hospital, total procedure volume for the study period was defined as low (fewer than 22), medium (22-42) or high (more than 42). Regression models were used to measure volume-outcome relations. RESULTS: The likelihood of postoperative death was higher in low volume and medium-volume centres than in high-volume centres (odds ratio 5.1 and 4.5 respectively; p < 0.01 for both). Mean length of stay was greater in low- and medium-volume centres than in high-volume centres (by 7.7 and 9.2 days respectively, p < 0.01 for both). INTERPRETATION: This study adds to growing evidence that, for pancreatic resection for neoplasm, patients may have better outcomes if they are treated in high-volume hospitals rather than low-volume hospitals. PMID- 10101999 TI - Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. AB - OBJECTIVE: To analyse the evidence for the efficacy and potential harmful effects of benzodiazepines compared with other therapies in the treatment of acute alcohol withdrawal. DATA SOURCES: MEDLINE and the Cochrane Controlled Trials Registry were searched for English-language articles published from 1966 to December 1997 that described randomized controlled trials (RCTs) of benzodiazepines in the treatment of acute alcohol withdrawal. Key words included "benzodiazepines" (exploded) and "randomized controlled trial." Bibliographies of relevant articles were reviewed for additional RCTs, and manufacturers of benzodiazepines were asked to submit additional RCT reports not in the literature. STUDY SELECTION: Articles were considered for the meta-analysis if they were RCTs involving patients experiencing acute alcohol withdrawal and comparing a benzodiazepine available in Canada with placebo or an active control drug. Of the original 23 trials identified, 11 met these criteria, representing a total of 1286 patients. DATA EXTRACTION: Data were extracted regarding the participants, the setting, details of the intervention, the outcomes (including adverse effects) and the methodologic quality of the studies. DATA SYNTHESIS: The meta-analysis of benefit (therapeutic success within 2 days) showed that benzodiazepines were superior to placebo (common odds ratio [OR] 3.28, 95% confidence interval [CI] 1.30-8.28). Data on comparisons between benzodiazepines and other drugs, including beta-blockers, carbamazepine and clonidine, could not be pooled, but none of the alternative drugs was found to be clearly more beneficial than the benzodiazepines. The meta-analysis of harm revealed no significant difference between benzodiazepines and alternative drugs in terms of adverse events (common OR 0.67, 95% CI 0.34-1.32) or dropout rates (common OR 0.68, 95% CI 0.47-0.97). INTERPRETATION: Benzodiazepines should remain the drugs of choice for the treatment of acute alcohol withdrawal. PMID- 10102000 TI - Improved survival among HIV-infected patients after initiation of triple-drug antiretroviral regimens. AB - BACKGROUND: The efficacy of triple-drug antiretroviral regimens in the treatment of patients infected with HIV has been established in several randomized clinical trials. However, the effectiveness of these new regimens in patient populations outside clinical trials remain unproven. This study compared mortality and AIDS free survival among HIV-infected patients in British Columbia who were treated with double- and triple-drug regimens. METHODS: The authors used a prospective, population-based cohort design to study a population of HIV-positive men and women 18 years or older for whom antiretroviral therapy was first prescribed between Oct. 1, 1994, and Dec. 31, 1996; all patients were from British Columbia. Rates of progression from the initiation of antiretroviral therapy to death or to diagnosis of primary AIDS were determined for patients who initially received an ERA-II regimen (2 nucleoside analogue reverse transcriptase inhibitors [NRTIs] including lamivudine or stavudine, or both) and for those who initially received an ERA-III regimen (triple-drug regimen consisting of 2 NRTIs and a protease inhibitor [indinavir, ritonavir or saquinavir] or a non-NRTI [nevirapine]). RESULTS: A total of 500 men and women (312 receiving an ERA-III regimen and 188 an ERA-III regimen) were eligible. Patients in the ERA-III group survived significantly longer than those in the ERA-II group. As of Dec. 31, 1997, 40 patients had died (35 in the ERA-II group and 5 in the ERA-III group), for a crude mortality rate of 8.0%. The cumulative mortality rates at 12 months were 7.4% (95% confidence interval [CI] 5.9% to 8.9%) for patients in the ERA-II group and 1.6% (95% CI 0.7% to 2.5%) for those in the ERA-III group (log rank p = 0.003). The likelihood of death was more than 3 times higher among patients in the ERA-II group (mortality risk ratio 3.82 [95% CI 1.48% to 9.84], p = 0.006). After adjustment for prophylaxis for Pneumocystis carinii pneumonia or Mycobacterium avium infection, AIDS diagnosis, CD4+ cell count, sex and age at initiation of therapy, the likelihood of death among patients in the ERA-II group was 3.21 times higher (95% CI 1.24 to 8.30, p = 0.016) than in the ERA-III group. Cumulative rates of progression to AIDS or death at 12 months were 9.6% (95% CI 7.7% to 11.5%) in the ERA-II group and 3.3% (95% CI 1.8% to 4.8%) in the ERA-III group (log rank p = 0.006). After adjustment for prognostic variables (prophylaxis for P. carinii pneumonia or M. avium infection, CD4+ cell count, sex and age at initiation of treatment), the likelihood of progression to AIDS or death at 12 months among patients in the ERA-II group was 2.37 times higher (95% CI 1.04 to 5.38, p = 0.040) than in the ERA-III group. INTERPRETATION: This population-based cohort study confirms that patients initially treated with a triple-drug antiretroviral regimen comprising 2 NRTIs plus protease inhibitor or a non-NRTI have a lower risk of morbidity and death than patients treated exclusively with 2 NRTIs. PMID- 10102001 TI - HIV clinical trials are not enough. PMID- 10102002 TI - More procedures, better quality of care? Is there a case for regionalization of pancreatic resection for neoplasm? PMID- 10102003 TI - Diagnosis and management of acute alcohol withdrawal. AB - Alcohol abuse produces a considerable burden of illness in the Canadian population. The diagnosis of alcohol dependence and withdrawal can be difficult, particularly in the setting of covert intake or comorbidity. Two validated scales, the CAGE questionnaire to screen for alcohol abuse and dependence and the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scale to assess the severity of withdrawal, are valuable tools for clinicians to use on a regular basis. For the treatment of alcohol withdrawal, compelling anecdotal evidence supports the routine administration of thiamine, but not necessarily other vitamins. Phenytoin has not been shown to be superior to placebo for uncomplicated withdrawal seizures. Neuroleptics are not recommended for routine use. Sedation with benzodiazepines guided by the CIWA-Ar results is recommended. There is good evidence that the management of alcohol withdrawal can be improved with the routine use of the CIWA-Ar scale to assess severity, treatment with adequate doses of benzodiazepines and follow-up monitoring of patients in alcohol withdrawal. PMID- 10102004 TI - Prostate cancer: 12. The economic burden. PMID- 10102005 TI - Cost no object as new agency tries to restore blood system's credibility. PMID- 10102007 TI - Rural medicine needs cradle-to-grave strategy: blueprint. PMID- 10102008 TI - [Esophageal manometric studies in patients with an apoplectic stroke with/without oropharyngeal dysphagia]. AB - BACKGROUND AND OBJECTIVE: As many as 45% of all strokes can lead to permanent dysphagia, usually considered to be due to abnormal oropharyngeal coordination of contraction. It was the aim of the study to compare oesophageal motility in stroke patients with and without dysphagia. PATIENTS AND METHODS: The study group consisted of 36 patients (13 men, 23 women, mean age 74.1 +/- 11.3 years) who had sustained a stroke (19 [mean age 70.6 +/- 10.5 years] with and 17 [mean age 77.6 +/- 10.5 years] without dysphagia). All these patients underwent oesophageal manometry within 2 days after hospital admission. RESULTS: There were significant differences in the mean proportion of regular peristaltic waves in the distal oesophagus, 93.5 +/- 1.1% in patients without but in only 53.5 +/- 4.4% of those with dysphagia (P < 0.0001). Measurement of the proximal oesophagus showed 93.2 +/- 3.4% and 62.1 +/- 7.3% respectively. There was no significant difference between these two patient cohorts with regard to the resting pressure in the upper and lower oesophageal sphincters as well as in the amplitude and duration or speed of contraction in the region of the smooth and striated oesophageal muscles. CONCLUSIONS: In patients after a stroke who have dysphagia abnormalities of oesophageal motility are also of importance for their symptoms, being due less to pressure relations than to abnormal contraction patterns. PMID- 10102009 TI - [The rare differential diagnosis of a mediastinal space-occupying lesion]. AB - HISTORY AND CLINICAL FINDINGS: Two months before admission a 31-year-old man first noted a painless swelling on the right side of his neck without any associated symptoms. Physical examination revealed a painless right cervical node 4 cm in diameter. INVESTIGATIONS: Magnetic resonance imaging demonstrated a large right-sided cervical tumour which extended into a mediastinal mass 11 cm in diameter. The excised cervical node showed a Hodgkin's lymphoma. Further tests to stage the disease revealed a 1.5 cm tumour in the right testis. Removal of the latter showed a mixed testicular tumour. Mediastinoscopic biopsy confirmed Hodgkin's lymphoma of the mediastinal mass. TREATMENT AND COURSE: Standard chemotherapy of the Hodgkin's lymphoma was undertaken, followed by "extended field" radiation which has so far secured a remission of two years. CONCLUSION: Histological diagnosis is always essential in the case of an unusual tumour location so that a synchronous second tumour may be revealed. If there is a second tumour, exact histological classification with definitive staging of the tumours is necessary to ensure adequate treatment. PMID- 10102010 TI - [An unusual picture of insulinoma in type-2 diabetes mellitus and morbid obesity]. AB - HISTORY AND CLINICAL FINDINGS: Marked hyperinsulinism was demonstrated in the course of an oral glucose tolerance test (oGTT) in a 63-year-old woman with severe obesity (height 1.59 m, body weight 123 kg, body-mass index 46.4 kg/m2). The diabetic metabolic state, first diagnosed 12 years ago, had been replaced by a low plasma glucose level: she often had attacks of ravenous hunger. A reducing diet of 800 kcal had not been tolerated. She had not had any syncopes. She had continually gained weight since puberty, but her weight had remained relatively constant for the past 5 years during which she had been treated with L-thyroxine for a diffuse goitre (stage II). INVESTIGATIONS: In the course of an oGTT (75 g glucose) the basal insulin concentration (146 pmol/l) had risen to 1663 pmol/l at 30 min. The basal proinsulin level was 50 times normal (66 pmol/l vs. 1.418 pmol/l), while the initial plasma glucose level had fallen from 4.3 mmol/l to 3.8 mmol/l. Spiral computed tomography of the pancreas showed a 3 x 2.5 cm mass in the region of the tail of the pancreas. TREATMENT AND COURSE: At laparoscopy a 4 cm tumor was palpated in the region of the pancreatic tail. Left resection of the pancreas was performed. Histopathological examination of the surgical specimen confirmed an insulinoma. A repeat of oGTT 6 months postoperatively demonstrated a markedly diminished insulin level compared with the preoperative results, as well as a diabetic metabolic state. CONCLUSION: In case of dramatic improvement of diabetes mellitus in an obese patient without drug treatment or weight reduction an insulin-producing tumour should be considered in the differential diagnosis. There may be no typical hypoglycaemic symptoms because of insulin resistance associated with the obesity. PMID- 10102011 TI - [Dolly, Polly et al.: cloning by somatic cell nucleus transfer]. PMID- 10102012 TI - [The diagnosis of encephalopathy, neuropathy and myopathy in the critical patient]. PMID- 10102013 TI - [The demonstration of the efficacy of homeopathic drugs]. PMID- 10102014 TI - [The refusal of life-sustaining therapeutic measures in moribund patients]. PMID- 10102015 TI - [Modified triple therapies for Helicobacter pylori eradication]. PMID- 10102016 TI - Use of indomethacin in Langerhans cell histiocytosis. AB - BACKGROUND: Because prostaglandin (PG) E2 has been identified in the bone lesions of Langerhans cell histiocytosis (LCH), we speculated that indomethacin, a potent PG inhibitor, may be useful in patients with symptomatic LCH involving the bony skeleton. PROCEDURE: We used indomethacin to treat patients in whom we wanted to avoid steroids or chemotherapy, or in whom these treatments did not provide complete symptom relief. Ten children with bony LCH between 1984 and 1995 were treated; six had single-system bone disease and four had multisystem disease involving the bony skeleton and other organs. RESULTS: The dose of indomethacin ranged from 1 to 2.5 mg/kg/day (9-200 mg/day) in divided doses and was given for 1-16 weeks (mean, 6 weeks). Eight patients had a complete response to treatment, defined as complete resolution of symptoms for 4 weeks. One patient was withdrawn from treatment because of concern regarding the potential of indomethacin to induce seizures and a second patient, with suppurative skin lesions overlying a lytic skull defect, did not respond. CONCLUSIONS: Indomethacin is a useful therapy for LCH involving the bony skeleton and may have a role as first-line treatment in single-system bone disease. Whether it has a specific role in slowing disease progression or merely acts as an analgesic has not yet been established. PMID- 10102017 TI - Indeterminate-cell histiocytosis: immunophenotypic and cytogenetic findings in an infant. AB - BACKGROUND: The authors report the immunohistochemical, ultrastructural, and cytogenetic findings in a case of malignant histiocytic proliferation in an infant. PROCEDURE: The patient presented initially with bone lesions without skin or systemic involvement. Multiple biopsies were studied extensively by immunohistochemistry and electron microscopy. Cytogenetic studies of cell cultures supplemented with granulocyte-monocyte colony stimulating factor (GM CSF) were also performed. RESULTS: Morphologically, the cells resembled Langerhans cells, although with greater pleomorphism, as evinced by cells with usual polylobated nuclei. These cells expressed markers for macrophages and antigen presenting cells and were CD1a- and S-100-positive, but lacked Birbeck granules. The cells grown in culture supplemented with GM-CSF showed a unique combination of numerical and structural abnormalities affecting chromosomes 1, 6, 8, and 10. The disease followed a malignant course leading to the patient's demise despite aggressive chemotherapy and bone marrow transplant. CONCLUSIONS: The findings suggest a malignant hematopoietic stem-cell neoplasm with a capacity for macrophage or dendritic-cell differentiation. Morphology and immunophenotypic features place this neoplasm within the group recently conceptualized as indeterminate-cell histiocytosis. PMID- 10102018 TI - High incidence of treatment failure with vincristine, etoposide, epirubicin, and prednisolone chemotherapy with successful salvage in childhood Hodgkin disease. AB - BACKGROUND AND PROCEDURE: In an attempt to further reduce the long-term toxicity of chemotherapy for childhood Hodgkin disease (HD), the Australian and New Zealand Children's Cancer Study Group between 1990 and 1996 enrolled 53 children with biopsy-proven and imaging-staged HD into a chemotherapy-only treatment regimen using 5-6 courses of vincristine, etoposide, epirubicin, and prednisolone (VEEP). RESULTS: There were 23 events in these children with 3 progressive disease (PD), 8 partial remissions (PR), and 12 relapses. In the stage I patients, there were 8 events (35%). There was no association between the number of events and the stage of HD. Massive mediastinal disease at diagnosis was present in 16 patients, 11 of whom had an event with 3 PD, 3 PR, and 5 relapses. For all patients with an event at 6-24-month follow-up, all but two patients were salvaged with either alkylating agent-based chemotherapy alone or with irradiation and chemotherapy. The event-free survival for the whole group with median follow-up of 33 months was 59%, but only 31% for massive mediastinal disease. Disease-free survival was 78% and overall survival at 60 months was 92%, with one death due to drug-induced aplasia and another from acute myeloid leukemia. CONCLUSIONS: We conclude that VEEP chemotherapy in childhood HD used as the only treatment modality has an unacceptably high treatment failure rate in patients with massive mediastinal disease and 35% incidence of treatment failure in stage I disease. PMID- 10102020 TI - Prognostic importance of magnetic resonance imaging in bone marrow involvement of Hodgkin disease. AB - BACKGROUND: Determination of bone marrow involvement is important in staging Hodgkin disease (HD), so we compared the effectiveness of magnetic resonance imaging (MRI) with bone marrow biopsy in diagnosing bone marrow involvement in HD patients. PROCEDURE: Twenty-six patients with the diagnosis of HD were included in this study. The ages of the patients were between 4 and 24 years, with a median of 12. Eleven of them had stage III or IV disease and 15 had been previously diagnosed as having HD and were in relapse. They were evaluated by bone marrow biopsy and MRI of lumbar vertebrae. The biopsies were taken from the anterosuperior iliac spine with an age-appropriate Jamshidi biopsy needle. Within 14 days following biopsy, MRI of lumbar vertebrae was carried out. RESULTS: MRI revealed decreased signal intensity in T1-weighted images in 7 of 26 patients. On the other hand, bone marrow biopsies showed HD involvement in three out of seven patients. The remaining 19 patients who had normal bone MRI were negative for HD in their bone marrow biopsies. The patients with positive MRIs and negative biopsy for HD had bone pain. One of them had a femoral periosteal reaction on bone survey; the other two had height loss in their lumbar vertebral bodies. There was a statistically significant difference in the disease-free survival rates between MRI-positive and -negative patients in the following 24 months period (P < 0.0001). CONCLUSIONS: This study suggests that MRI is a useful method for diagnosing bone marrow involvement in HD, in that our MRI-positive patients had a higher relapse rate in the 24 months follow-up period than the MRI-negative patients. PMID- 10102019 TI - Improvement in CNS protective treatment in non-high-risk childhood acute lymphoblastic leukemia: report from the Japanese Children's Cancer and Leukemia Study Group. AB - BACKGROUND: Prevention of central nervous system (CNS) leukemia by early introduction of therapy to this sanctuary site is an essential component of modern treatment strategy for acute lymphoblastic leukemia (ALL). However, the optimal form of preventive CNS therapy remains debatable. PROCEDURE: To address this issue, we evaluated the efficacy of CNS preventive therapy for 572 children with ALL who achieved complete remission in the Children's Cancer and Leukemia Study Group (CCLSG) ALL874 (1987-1990) and ALL911 (1991-1993) studies. They received risk-directed therapy based on age and leukocyte count. In the ALL 874 study, the non-high-risk (low-risk [LR] + intermediate risk [IR]) patients were randomly assigned to the conventional cranial irradiation (CRT) regimen (L874A and I874A) and the high-dose methotrexate (HDMTX) regimen without CRT (L874B and I874B). The former patients received 18-Gy CRT plus 3 doses of intrathecal (i.t.) MTX and the latter patients received 3 courses of HDMTX at 2 g/m2 plus 13 doses of ITMTX (L874B) or 4 courses of HDMTX at 4.5 g/m2 plus 1 dose of ITMTX (I874B). RESULTS: The 7-year probabilities (+/- SE) of CNS relapse-free survival were 97.3% +/- 2.6% (L874A, n = 41) vs. 90.3% +/- 5.3% (L874B, n = 39) (P = 0.25) in the LR patients, and 100% (I874A, n = 55) vs. 78.5% +/- 6.5% (I874B, n = 54) (P = 0.002) in the IR patients. The corresponding disease-free survival (DFS) rates were 79.4% +/- 6.5% vs. 74.4% +/- 7.3% (P = 0.62) in the LR group and 63.3% +/- 6.8% vs. 58.3% +/- 7.2% (P = 0.66) in the IR group. Thus, the HDMTX regimen could not provide better protection of CNS relapse as compared with the CRT regimen, although their overall efficacy was not significantly different. In the ALL 911 study, intensive systemic chemotherapy with extended i,t, injections of MTX plus cytarabine achieved a high CNS relapse-free survival (98% +/- 1.9% at 7 years) and a favorable DFS (85.5% +/- 5% at 7 years) in the IR patients. The patients in the high-risk (HR) group in both ALL874 and ALL911 studies received the 18-Gy or 24-Gy CRT with intensive systemic chemotherapy. Their 7-year probabilities of CNS relapse-free survival ranged from 88% to 95%, among which the T-ALL patients had a risk of CNS leukemia, which was 3-4 times higher compared with B-precursor ALL patients. CONCLUSIONS: These results indicate that long-term intrathecal CNS prophylaxis as well as appropriate systemic therapy for the non-high-risk patients can provide protection against CNS relapse equivalent to that provided by cranial irradiation. PMID- 10102021 TI - Osteopenia in young adult survivors of childhood cancer. AB - BACKGROUND: Improved survival of children with malignant diseases is in part due to the application of intensive, multimodality therapies, including radiotherapy, surgery, glucocorticoids, and cytotoxic agents. Such interventions have the potential to induce complex hormonal, metabolic and nutritional effects that may interfere with skeletal mass acquisition during childhood and adolescence: it is possible that such childhood cancer survivors may therefore reach adulthood with diminished peak bone mass and be at increased risk for clinically significant osteoporosis later in their life. PROCEDURE: A bone mineral density (BMD) was measured in 26 unselected former cancer patients attending the Pediatric Long Term Clinic at M.D. Anderson Cancer Center. BMD was measured at the lumbar spine and the hip using dual X-ray absorptiometry (Hologic QDR-4500W). In addition, the patients' complete medical records were reviewed with particular attention to disease type, age modalities of treatment, and hormonal residual deficiencies. RESULTS: The median age of patients at the time of cancer diagnosis was 8 years (range, 0.3 to 16 years). Median age at BMD determination was 23 years (range, 18 to 41 years), and the median interval since cancer diagnosis and BMD was 18 years (range, 5 to 29). Overall, their BMD was decreased relative to peak bone mass at all sites: osteopenia was especially pronounced in patients with a history of cranial irradiation who had developed evidence of pituitary insufficiency during childhood or adolescence. Overall, the median BMD T-score was -1.41 at the lumbar spine, -1.04 at the femoral neck, and -1.06 for total hip. For patients with prior cranial irradiation, T-score at the lumbar spine was -2.18 (range, -4.06 to -0.98), at the femoral neck -1.92 (range, -4.11 to +1.10), and for total hip 1.67 (range, -4.79 to +0.56); BMD for irradiated patients was significantly lower than BMD of patients without cranial irradiation. We could not discern an independent impact of other disease characteristics or treatment modalities in this small group of patients. CONCLUSIONS: Osteopenia is a prominent finding in young adults who are survivors of childhood cancers; it is likely that antineoplastic treatments during childhood and adolescence impede peak bone mass acquisition. We suggest that systematic attention to this potential complication is needed in order to identify what subgroups of children may require regular surveillance and what interventions are required for its prevention or treatment. PMID- 10102022 TI - Limitation of ankle range of motion in survivors of acute lymphoblastic leukemia: a cross-sectional study. AB - BACKGROUND: The purpose of this study was to evaluate and determine the factors related to active and passive dorsiflexion range of motion (DF-ROM) in survivors of acute lymphoblastic leukemia (ALL), which is the most obvious impairment of musculoskeletal function in such children. PROCEDURE: The subjects included 54 survivors of ALL treated on Dana-Farber Cancer Institute protocols and 54 comparable healthy children. Bilateral active and passive DF-ROM were measured with the knee extended. RESULTS: The survivors of ALL had significantly less active and passive DF-ROM (6.4 vs. 16.8, 10.5 vs. 18.8 degrees, respectively, P < 0.001) than the comparison children. Weight for age at the time of assessment and change in height during treatment showed significant negative correlations with DF-ROM. Length of time-off treatment was not associated with DF-ROM. CONCLUSIONS: Multiple regression analyses identified the variables of age at diagnosis and gender as significant predictors of both DF-ROM measures following treatment. Children diagnosed at a younger age and females were at greater risk for restricted DF-ROM. Close monitoring and preventative therapy programs for this complication are warranted for children, especially young girls receiving treatment for ALL. PMID- 10102023 TI - Pretreatment, ultrasound-guided cutting needle biopsies in childhood renal tumors. AB - BACKGROUND: The current International Society of Paediatric Oncology (SIOP)-10 protocol does not allow pretreatment histological classification of low-stage renal tumors in children for fear of needle tract recurrences. The aims of this retrospective study were to evaluate the safety, sensitivity, and specificity of ultrasound-guided cutting needle biopsies (UCNB) performed at our institution in pediatric patients with renal tumors. PROCEDURE: Of 28 pediatric patients presenting with a renal tumor between 1988 and 1996, 25 underwent biopsy with the Biopty biopsy instrument (needle diameter 1.2 mm). The preoperative biopsy and nephrectomy slides were reviewed by a SIOP reference pathologist. The patients' hospital records were reviewed and biopsy complications were noted. RESULTS: At review of the nephrectomy slides, the diagnoses were: Wilms tumor (16 patients), with anaplasia in one case, rhabdoid tumor (2 patients), neuroblastoma (2 patients), mesoblastic nephroma (2 patients), clear cell sarcoma (1 patient), malignant teratoma (1 patient), and renal cell carcinoma (1 patient). No needle tract recurrence or other major complication was observed. The only complication was local pain at the biopsy site, which occurred in 24% (6/25) of the cases. The sensitivity of UCNB was 76% (19/25); five biopsies did not yield diagnostic material and one was not concordant. All cases of Wilms tumor were correctly diagnosed by UCNB, but only 33% (3/9) of the other tumors. CONCLUSIONS: In all cases of Wilms tumor a correct diagnosis was made. The overall sensitivity was 76%. UCNB proved to be a safe procedure that was not associated with needle tract recurrence or other serious complications. PMID- 10102024 TI - Meeting impossible psychosocial demands in pediatric oncology: creative solutions to universal challenges. PMID- 10102025 TI - Effective psychosocial intervention for children with cancer and their families. PMID- 10102026 TI - Neuroblastoma 4S with an unfavorable biological marker: what to do? PMID- 10102027 TI - Perforated lymphoma of the colon in an immunosuppressed child. PMID- 10102028 TI - Ovarian small cell carcinoma of the hypercalcemic type in a 14 month old: the youngest reported case. PMID- 10102029 TI - 13-cis-retinoic acid-induced eosinophilia following autologous bone marrow transplantation for neuroblastoma. PMID- 10102030 TI - Ectopic production of prolactin in an infant with non-Hodgkin lymphoma. PMID- 10102031 TI - Successful treatment of intracaval and atrial extension of rhabdomyosarcoma without surgical excision: an unusual presentation. PMID- 10102032 TI - Secondary acute promyelocytic leukemia after treatment with etoposide for Langerhans cell histiocytosis (LCH) PMID- 10102033 TI - Successful management of a child with asparaginase-induced hemorrhagic pancreatitis. PMID- 10102034 TI - Database of mouse strains carrying targeted mutations in genes affecting cellular responses to DNA damage: version 3. PMID- 10102035 TI - A full-length cDNA of hREV3 is predicted to encode DNA polymerase zeta for damage induced mutagenesis in humans. AB - DNA damage can cause mutations which in turn may lead to carcinogenesis. In the yeast Saccharomyces cerevisiae, DNA damage-induced mutagenesis pathway requires the REV3 gene. It encodes the catalytic subunit of DNA polymerase zeta that specifically functions in translesion DNA synthesis. We have cloned a cDNA of the human homologue of REV3 (hREV3), which consists of 10,716 bp and codes for a protein of 3130 amino acid residues (352,737 Da). Its C-terminal 755 amino acids show extensive homology with the yeast protein at the C-terminus: 43% identity and 74% similarity. This region contains the six highly conserved DNA polymerase motifs. Furthermore, we have identified four sequence motifs in the N-terminal region outside the polymerase domain that are conserved in DNA polymerase delta from various sources. Three of which are present in DNA polymerase zeta encoded by human, yeast, and plant REV3 genes, indicating that this protein is a member of the DNA polymerase delta family. DNA polymerases delta and zeta are structurally distinguished by the presence of a specific delta IV motif in the former and motifs zeta I and zeta II in the latter, respectively. Human DNA polymerase zeta is ubiquitously expressed in various tissues, consistent with the notion that the hREV3 pathway may be a fundamental mechanism of damage-induced mutagenesis in humans. PMID- 10102036 TI - RecBC and RecF recombination pathways and the induced precise excision of Tn10 in Escherichia coli. AB - Mitomycin C (MMC) treatment or mutations in uvrD enhance the frequency of Tn10 precise excision. We have shown previously that several repair-recombination genes, such as recA, ruv and recF are involved in the induced excision process. In this study, we find that other genes belonging to the RecBC and RecF sexual recombination pathways also participate in this process since mutations in recB, sbcB or recO diminish, though to different degrees, the frequency of Tn10 precise excision induced by MMC treatment or by uvrD mutants. Pairwise combinations of some of these mutations were also tested for Tn10 induced precise excision; most of these double mutants showed additive effects in reducing the frequency of the excision process. The results of these studies suggest that recombinational repair genes, particularly recF, sbcB and recO have different roles in the induced excision of Tn10 than in recombinational mating. PMID- 10102037 TI - Molecular cloning, expression and chromosomal localisation of the mouse Rev3l gene, encoding the catalytic subunit of polymerase zeta. AB - The REV3 gene of Saccharomyces cerevisiae encodes the catalytic subunit of DNA polymerase zeta which is involved in translesion synthesis. The mouse homolog of this gene, Rev3l, was cloned and sequenced. The gene encodes a putative protein of 3122 amino acids. The sequence conservation to its yeast counterpart is restricted to several regions. In the carboxy-terminal part of the protein all six domains are present that are characteristic for alpha-type DNA polymerases. In the amino-terminal part of the protein two regions can be identified with considerable similarity to the NT boxes of mouse polymerase delta. In addition, a region of 60 residues unique for the REV3 homologs can be found in the middle part of the protein. The mouse REV3L protein shows strong sequence conservation with the recently cloned human REV3L protein (86% identity overall). Northern blot analysis of various tissues of the mouse revealed that transcription of the Rev3l gene was highest in brain, ovaries and testis. The human REV3L gene was localised to the long arm of chromosome 6, region 21-22. The mouse equivalent maps to chromosome 10, distal to the c-myb gene, close to the Macs gene. PMID- 10102038 TI - Expression and nucleotide excision repair of a UV-irradiated reporter gene in unirradiated human cells. AB - It has been suggested that reactivation of damaged reporter genes introduced into cultured mammalian cells reflects transcription-coupled nucleotide excision repair. To evaluate this possibility directly, we introduced a UV-irradiated shuttle vector, pCMV beta, into unirradiated human cells and compared expression of the reporter gene (lacZ) with repair of cyclobutane pyrimidine dimers (CPDs). Expression of the irradiated reporter gene was more UV resistant in XPC cells, which are deficient in global genome repair, than in CSB cells, which are deficient in transcription-coupled repair. These results are consistent with the idea that repair of the reporter gene is primarily dependent upon transcription coupled repair. However, when the plasmid DNA was analyzed for removal of CPDs, no clear evidence was obtained for transcription-coupled repair either in XPC cells or in cells with normal repair capacity. PMID- 10102039 TI - Cisplatin-modification of DNA repair and ionizing radiation lethality in yeast, Saccharomyces cerevisiae. AB - Cis-diamminedichloroplatinum II (cisplatin) is a DNA inter- and intrastrand crosslinking agent which can sensitize prokaryotic and eukaryotic cells to killing by ionizing radiation. The mechanism of radiosensitization is unknown but may involve cisplatin inhibition of repair of DNA damage caused by radiation. Repair proficient wild type and repair deficient (rad52, recombinational repair or rad3, excision repair) strains of the yeast Saccharomyces cerevisiae were used to determine whether defects in DNA repair mechanisms would modify the radiosensitizing effect of cisplatin. We report that cisplatin exposure could sensitize yeast cells with a competent recombinational repair mechanism (wild type or rad3), but could not sensitize cells defective in recombinational repair (rad52), indicating that the radiosensitizing effect of cisplatin was due to inhibition of DNA repair processes involving error free RAD52-dependent recombinational repair. The presence or absence of oxygen during irradiation did not alter this radiosensitization. Consistent with this result, cisplatin did not sensitize cells to mutation that results from lesion processing by an error prone DNA repair system. However, under certain circumstances, cisplatin exposure did not cause radiosensitization to killing by radiation in repair competent wild type cells. Within 2 h after a sublethal cisplatin treatment, wild type yeast cells became both thermally tolerant and radiation resistant. Cisplatin pretreatment also suppressed mutations caused by exposure to N-methyl-N'-nitro-N nitrosoguanidine (MNNG), a response previously shown in wild type yeast cells following radiation pretreatment. Like radiation, the cisplatin-induced stress response did not confer radiation resistance or suppress MNNG mutations in a recombinational repair deficient mutant (rad52), although thermal tolerance was still induced. These results support the idea that cisplatin adducts in DNA interfere with RAD52-dependent recombinational repair and thereby sensitize cells to killing by radiation. However, the lesions can subsequently induce a general stress response, part of which is induction of RAD52-dependent error free recombinational repair. This stress response confers radiation resistance, thermal tolerance, and mutation resistance in yeast. PMID- 10102040 TI - Enhanced repair of benzo(a)pyrene-induced DNA damage in human cells treated with thymidine dinucleotides. AB - The small DNA fragment thymidine dinucleotide (pTpT) stimulates photoprotective responses in mammalian cells and intact skin. These responses include increased melanogenesis (tanning) and enhanced repair of DNA damage induced by ultraviolet (UV) light. Here we show that pTpT treatment of human keratinocytes enhances their repair of DNA damaged by the chemical carcinogen benzo(a)pyrene (BP), as determined by increased expression of a transfected BP-damaged reporter plasmid containing the chloramphenicol acetyltransferase (CAT) gene. The pTpT-enhanced repair of this BP-damaged plasmid is accomplished at least in part through activation of the p53 tumor suppressor protein and transcription factor, because p53-null H1299 cells showed enhanced repair only if previously transfected with a p53-expression vector. To elucidate the mechanism of this enhanced DNA repair, we examined the expression of p21 and proliferating cell nuclear antigen (PCNA), proteins known to be regulated by p53, as well as the XPA protein, which is mutated in the inherited repair-deficient disorder xeroderma pigmentosum (XP) group A and is necessary for the recognition of UV-induced DNA photoproducts. The p53, PCNA and XPA proteins were all up-regulated within 48 h after the addition of pTpT. Taken together, these data demonstrate that pTpT-enhanced repair of DNA damaged by either UV irradiation or chemical mutagens can be achieved in human cells by exposure to small DNA fragments at least in part through the activation of p53 and increased expression of p53-regulated genes. PMID- 10102041 TI - Swallowing and speech in infants following tracheotomy. AB - Tracheotomy in children has been associated with significant operative and post operative complications and disabilities. In this study, special attention was given to the post-operative effects on the ability to swallow and the development of speech in infants following tracheotomy. In 36 infants (19 boys, 17 girls) a tracheotomy was performed before the age of one year. Indications were: 1 severe upper airway obstruction (n = 25), 2. the requirement of prolonged mechanical ventilation (n = 10) and 3. intensive tracheal-broncheal suction (n = 1). In contrast of the absence of peri-operative complications, in the post-operative follow-up period we observed many complications and disabilities, partially attributable to several underlying disorders and to the tracheotomy itself. The swallowing ability was deteriorated in nearly all infants and the speech development was seriously delayed in 38% of all infants. Infants following tracheotomy require intensive care to minimize complications and to stimulate the ability to swallow and the development of speech. Some proposals for treatment of swallowing disorders and rehabilitation are proposed. PMID- 10102042 TI - Narrow and vacant internal auditory canal. AB - A case of unilateral congenital deafness revealing a narrow vacant internal auditory canal and a more anterior and superior second canal where the facial and vestibulocochlear nerves are well visualised is presented. Having reviewed the scientific and embryological data, the authors consider the mechanism of this malformation. PMID- 10102043 TI - Tonsillar lymphoma and AIDS. AB - A case of a patient presenting unilateral tonsillar enlargement, whereby non Hodgkin lymphoma (NHL) and AIDS were diagnosed, is presented. The clinical and pathological aspects of this pathology, its pathogenicity and treatment are reviewed. PMID- 10102044 TI - The Pharmacia & Upjohn International Symposia series on growth hormone and growth factors in endocrinology and metabolism. PMID- 10102045 TI - The transition from fetus to neonate--an endocrine perspective. AB - The transition from fetus to neonate involves three phases: late gestation, parturition and the processes needed to establish independent homoeostatic regulation after separation from the placenta. These phases are regulated by a series of fetal and placental endocrine events. Glucocorticoids have an important role in the preparation for birth, including involvement in lung and cardiac development, and the maturation of enzymes in a variety of pathways. Fetal cortisol production is, in turn, also under hormonal control. Parturition is a complex process, which is still poorly understood in humans. The final steps are largely dependent on the effect of prostaglandin F2 alpha on the myometrium associated with increased oxytocin activity. The transition to birth is accompanied by changes in respiration, circulation, glucose homoeostasis, and the onset of independent oral feeding and thermoregulation. Several examples of endocrine components of the transition from fetal to neonatal life are reviewed here: the role of prostanoids, the onset of thermogenesis, and changes in the thyroid hormone and growth hormone axes. The effects of hormone levels on prematurity and growth retardation are also discussed. PMID- 10102046 TI - Maternal endocrine adaptations to placental hormones in humans. AB - The remarkable endocrine alterations that are characteristic of human pregnancy are attributable to the placenta. In this tissue, steroid and peptide hormones are produced in extraordinary amounts. In addition, the haemomonochorioendothelial placentation of human pregnancy contributes to the unique distribution of products formed in trophoblasts into maternal and fetal compartments. In this review, the partial control exerted by the trophoblast on maternal metabolism is illustrated by the replacement in the maternal compartment of pituitary growth hormone (GH) with the trophoblast's own product, human placental GH. Placental GH differs from pituitary GH by 13 amino acids, has high somatogenic and low lactogenic activities and is secreted by the syncytiotrophoblast in a non-pulsatile manner. This continuous secretion appears to have important implications for the control of maternal levels of insulin-like growth factor I. Placental GH secretion is inhibited by glucose in vitro and in vivo, and is significantly decreased in the maternal circulation in cases of pregnancies with intrauterine growth retardation. PMID- 10102047 TI - Alterations of neonatal thyroid function. AB - Recent progress has been made in understanding the pathogenesis of neonatal thyroid disorders. Autosomal recessive inheritance of mutations of the thyroid peroxidase and thyroglobulin genes has been described in some patients with congenital hypothyroidism (CH) and a family history of CH. Autosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis. These discoveries are important for patients with CH diagnosed by neonatal screening, as these patients will have normal fertility. The molecular genetic analysis of mutations of the TSH gene in patients with familial and sporadic cases of isolated central CH, who are missed by TSH screening programmes, now enables rapid diagnosis and appropriate therapy in the neonate. In newborn infants with severe non-autoimmune hyperthyroidism, autosomal dominant gain-of-function mutations in the TSH receptor gene have been demonstrated. In these patients, molecular genetic studies are extremely helpful in therapeutic decision making, as early thyroid ablation is the only effective treatment that avoids the sequelae of long-term hyperthyroidism. Molecular genetic studies are therefore useful in the diagnostic work-up of neonatal thyroid alterations. PMID- 10102048 TI - Sexual dimorphism in the neonatal gonad. AB - The neonatal gonad has two distinct forms (i.e., is sexually dimorphic), as judged by morphological and endocrine characteristics. The dimorphic process begins early in embryogenesis. It is well established by the time of birth, by which time the genital ridge has developed into either a testis or an ovary. The mechanisms involved in sex determination involve the Y chromosome, autosomal genes, transcription factors and possibly other unidentified control networks. This review paper describes the morphological changes that occur and the endocrine functions in the developing gonads. It highlights a number of important differences in fetal and neonatal gonadal function. The testis has early histological definition, several determining genes, delayed germ cell maturation, early autonomous steroid secretion, luteinizing hormone (LH) receptor and steroid enzyme expression, high fetal testicular testosterone content, prominent postnatal Leydig and Sertoli cells and high postnatal serum testosterone levels. The ovary has a prolonged monomorphic state, probably one determining gene, germ cells in early meiotic arrest, delayed expression of LH receptor and aromatase, low ovarian oestradiol content, prominent postnatal follicles and low postnatal serum oestradiol levels. PMID- 10102049 TI - Mechanisms of in utero overgrowth. AB - Determination of the mechanisms that lead to in utero overgrowth has proved elusive. Recently, however, our knowledge has significantly expanded as a result of the generation of experimental mouse models, engineered to disrupt the expression of one or more genes (knockout mice), and by detailed molecular and genetic analyses of infants and children with overgrowth syndromes. Studies of knockout mice have largely defined the essential roles of the insulin-like growth factors (IGF-I and IGF-II), insulin and their receptors in embryonic and fetal growth, and have provided compelling evidence that increased IGF-II gene expression and/or abundance can stimulate excessive fetal somatic growth. The IGF II gene is usually expressed only by the paternally derived allele; however, when this imprinting is erased and IGF-II expression is biallelic, fetal overgrowth ensues. Such increased IGF-II expression would appear to explain the overgrowth in Beckwith-Wiedemann syndrome. Using the information gathered from knockout mice as a guide to human studies, detailed genetic investigations are likely to unravel the mechanisms behind other human overgrowth syndromes. PMID- 10102050 TI - Insulin-like growth factor binding proteins: a proposed superfamily. AB - The conventional concept is that the insulin-like growth factor binding proteins (IGFBPs) are cysteine-rich proteins, with conserved N- and C-domains, that are capable of binding insulin-like growth factors (IGFs) with high affinity. This dogma was recently challenged by the discovery of a group of cysteine-rich proteins that share important structural similarities with the IGFBPs, but have demonstrably lower affinity for IGFs. It is therefore proposed that these IGFBP related proteins (IGFBP-rPs) and the IGFBPs constitute an IGFBP superfamily. We speculate that the IGFBP superfamily is derived from an ancestral gene/protein that was critically involved in the regulation of cell growth and was capable of binding IGF peptides. Over the course of evolution, some members (IGFBPs) evolved into high-affinity IGF binders and others (IGFBP-rPs) into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means. PMID- 10102051 TI - Obesity: a growing problem. AB - Obesity, defined as a body mass index (BMI) of 30 kg/m2 or more, is common in many parts of the world, especially in the established market economies, the former socialist economies of Europe, Latin America, the Caribbean and the Middle Eastern Crescent. As many as 250 million people worldwide may be obese (7% of the adult population) and two to three times as many may be considered overweight. The prevalence of obesity seems to be increasing in most parts of the world, even where it used to be rare. Increased fatness, measured by a high BMI, a large waist circumference or a high waist/hip circumference ratio, is associated with many chronic diseases as well as with poor physical functioning. Assessments of the prevalence of obesity, and trends in this prevalence over time, are more difficult in children than adults, due to the lack of international criteria for classifying individuals as overweight or obese. The World Health Organization has now recommended the use of BMI-for-age percentiles, but the reference curves are still under development. France. The Netherlands, the UK and the USA are among the countries that have reported recent increases in the prevalence of obesity in children and adolescents. Although there are no accurate estimates of the components of energy balance and their changes over time, the available evidence suggests that the trends in obesity rates are related more to a reduction in energy expenditure than to an increase in caloric intake. Prevention of obesity through the promotion of a healthy lifestyle is among the important challenges for the new millennium, and should start in childhood. PMID- 10102052 TI - Leptin and the genetics of obesity. AB - The discovery of the Ob gene and its product, leptin, is a good example of the contribution made by molecular biology to the understanding of mechanisms initially hypothesized from classic physiological studies. Leptin is produced in adipose tissue and acts on the central nervous system to regulate multiple neuroendocrine secretions. In three rare cases of human morbid obesity, the discovery of mutations in the leptin and leptin receptor genes shows that leptin plays a crucial role in the control of weight and several endocrine functions (particularly reproduction). These studies also illustrate the limits of genetics in the investigation of monogenic forms of animal obesity, and the difficulties of linking molecular findings to the pathophysiology of complex diseases, such as human common obesity. Previous searches for mutations in the leptin and leptin receptor genes indicated that these are probably not major genes for common forms of human obesity. This review focuses on the recent molecular findings that have indicated a putative role for the leptin axis in human obesity. PMID- 10102053 TI - Neuroendocrine regulation of food intake. AB - Maintenance of appropriate stores of metabolic fuels depends on carefully matching caloric intake to caloric expenditure. Achieving such 'energy balance' is a product of complex interactions of peripheral hormones with effector systems in the central nervous system (CNS) that regulate food intake and energy expenditure. Leptin is a hormone that is made in the adipocytes, circulates in the blood and interacts with receptors in the CNS. These receptors can be found in two different types of systems. One effector system is termed 'anabolic' and is activated by low levels of leptin during negative energy balance. This system (exemplified by the hypothalamic neuropeptide Y system) increases food intake and decreases energy expenditure to facilitate the regaining of lost energy stores. The other effector system is termed 'catabolic' and is activated by high levels of leptin during positive energy balance. This system (exemplified by the hypothalamic melanocortin and corticotrophin-releasing hormone systems) decreases food intake and increases energy expenditure to facilitate the loss of excess energy stores. Further understanding of these systems is necessary to develop adequate treatments for disorders of energy balance, such as obesity and wasting. PMID- 10102054 TI - Insulin resistance in short children with intrauterine growth retardation. AB - Scientific evidence is accumulating for an association between intrauterine growth retardation (IUGR) and an increased risk of developing adult degenerative diseases, such as essential hypertension, non-insulin-dependent diabetes mellitus and ischaemic heart disease. A possible underlying mechanism for these conditions is insulin resistance. In this paper, mechanisms and methods of measurement of insulin resistance are briefly reviewed, and recent studies on the evaluation of insulin resistance in short children with IUGR are summarized. In our experience, short prepubertal children with IUGR show consistent insulin resistance, which becomes particularly evident during pubertal development. PMID- 10102055 TI - Evidence for an association between birth weight and blood pressure. AB - Evidence is presented to support the concept that there is an association between birth weight and blood pressure in humans. This relationship probably reflects an interaction between the genetic make-up of the individual and the environment. On average, a decrease in birth weight is associated with a rise in blood pressure in adult life. PMID- 10102056 TI - Final height of growth hormone-treated patients with growth hormone deficiency: the North American experience. AB - The results of treatment of growth hormone (GH)-deficient patients with recombinant GH are better than the results of treatment with pituitary GH. The reasons for this improvement include higher dosages, more consistent treatment, and daily administration. Under ideal circumstances, final height in patients with GH deficiency (GHD) can be within the normal range for adult height with GH treatment, and brought close to their target height. To achieve this result, it is important to diagnose and treat GHD early, use adequate doses of GH, and continue treatment until final height. PMID- 10102057 TI - Final height in idiopathic growth hormone deficiency: the KIGS experience. KIGS International Board. AB - Final height was evaluated in 369 patients with idiopathic growth hormone deficiency (IGHD) enrolled in KIGS--the Pharmacia & Upjohn International Growth Database. At the start of growth hormone (GH) therapy, the patients were 9.8 years of age, their mid-parental height SDS was -0.8, and their height SDS was 3.1. Of the 369 patients, 50% had multiple hormone deficiencies, and puberty was induced in 31%. Patients were 18 years of age at completion of GH therapy, and had received GH at a dose of 0.49 IU/kg/week (0.16 mg/kg/week), with a mean of 5.2 injections/week for 8.1 years. Final height SDS was -1.5, final minus initial height SDS was 1.7 and final minus mid-parental height SDS was -0.5. A Swedish subgroup (n = 69) received conventional GH therapy throughout at 0.65 IU/kg/week (0.22 mg/kg/week), with seven injections/week for a mean of 9.4 years. These patients achieved their genetic potential (final minus mid-parental height SDS, 0.03), with a normal final height SDS of -0.3. For the total group, the following variables were associated with final height: mid-parental height SDS (r = 0.62), injection frequency (r = 0.37), duration of GH treatment (r = 0.28), peak stimulated GH concentration (r = -0.25), age (r = -0.19) (all p < 0.001) and height velocity SDS in the first year of treatment (r = 0.20, p = 0.004). In conclusion, genetic potential, expressed as the mid-parental height, is the variable with the greatest identified influence on final height during GH treatment in IGHD. Current GH regimens will lead to a normal height and attainment of mid-parental height. However, higher dose, individualized GH regimens are likely to be necessary for patients with IGHD who are disadvantaged at the time of commencing GH therapy, such as those with short parents, those whose treatment began in late childhood or adolescence and those with less severe GHD. PMID- 10102058 TI - High-dose growth hormone (GH) treatment in prepubertal GH-deficient children. AB - Two clinical studies were conducted to determine the effect of different doses of growth hormone (GH) on prepubertal growth in GH-deficient boys. In one study, GH doses of 1.0 and 1.5 IU/kg/week (0.33 and 0.5 mg/kg/week) were given to groups of five children and compared with a conventional Japanese dose of 0.5 IU/kg/week (0.17 mg/kg/week) in 15 children. A significant dose-dependent increase in height velocity occurred in the first year of treatment, but differences between doses were not significant thereafter. In a second study, GH was administered to ten boys at a dose of 0.5 IU/kg/week for the first year, 0.75 IU/kg/week for the second year, 1.0 IU/kg/week for the third year and 0.5 IU/kg/week for the fourth and subsequent years (0.17, 0.25, 0.33 and 0.17 mg/kg/week, respectively). During the second and third years of GH treatment, these boys had significantly higher growth rates than controls, who were given GH at 0.5 IU/kg/week (0.17 mg/kg/week) throughout, indicating successful reduction in 'waning' of the treatment effect. At the end of the fourth year, the different protocols from the two studies had both resulted in a greater height SDS than the controls, and did not advance bone maturation. In conclusion, these protocols may be effective in increasing prepubertal height gain in children with GH deficiency. PMID- 10102059 TI - Effect of growth hormone (GH) during puberty in GH-deficient children: preliminary results from an ongoing randomized trial with different dose regimens. AB - This paper reports results from an ongoing, randomized, multicentre national trial. The aim is to elucidate whether a dose of growth hormone (GH) of 0.2 IU/kg (0.07 mg/kg), given either as once-daily or twice-daily injections during puberty, is more effective than a once-daily dose of 0.1 IU/kg/day (0.03 mg/kg/day) in improving final height in children with GH deficiency (GHD). The twice-daily regimen comes closer to the spontaneous GH secretion pattern in puberty. Ninety-two children with GHD who had been receiving GH therapy for at least 1 year, and with spontaneous puberty or who were prepubertal and due to be started on replacement therapy to induce puberty, were randomly assigned to receive GH as follows: group A, 0.1 IU/kg/day (0.03 mg/kg/day), administered once daily; group B, 0.2 IU/kg/day (0.07 mg/kg/day), administered once daily; and group C, 0.2 IU/kg/day (0.07 mg/kg/day), divided into two equal injections given at 12-hour intervals. Pubertal height gain was 0.7, 0.7 and 1.3 SDS for groups A, B and C, respectively. The gain in height during puberty was thus most marked in group C. Mean final height, when corrected for parental height, was between 0 and 1 SDS in all treatment groups. All but seven children reached a final height within +/- 2 SD of the general population. There was a wide range of final heights in all three treatment groups. This variation in response suggests the need to individualize treatment in order to achieve an appropriate final height for most individuals. PMID- 10102060 TI - When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue. AB - The effect of combined treatment with growth hormone (GH) and a luteinizing hormone-releasing hormone (LHRH) analogue, or GH alone, on pubertal height gain was assessed in an uncontrolled study in 15 boys and 10 girls with GH deficiency (GHD). Seven boys and six girls were treated with GH alone (group 1), and eight boys and four girls were treated with a combination of GH and an LHRH analogue during puberty (group 2). Mean ages (+/- SD) at the start of GH treatment and at the onset of puberty were significantly lower in group 2 (8.0 +/- 3.3 years and 11.2 +/- 0.8 years, respectively, in boys, and 6.3 +/- 1.6 years and 10.8 +/- 0.7 years in girls) than in group 1 (12.8 +/- 1.9 years and 13.7 +/- 1.4 years in boys, and 11.2 +/- 1.0 years and 12.5 +/- 1.2 years in girls). Height at the onset of puberty was less in group 2 than in group 1, but the difference was significant only for the boys. Combination treatment was started at a mean age of 11.7 +/- 1.2 years in boys and 11.5 +/- 1.0 years in girls. The duration of the combination treatment was 5.1 +/- 1.5 years in boys and 2.3 +/- 0.7 years in girls. The duration of the period between the onset of puberty and the end of GH treatment was significantly longer in group 2 (6.8 +/- 1.2 years in boys and 5.5 +/- 1.0 years in girls) than in group 1 (4.3 +/- 1.6 years in boys and 3.6 +/- 1.4 years in girls). The pubertal height gain was also significantly greater in group 2 (36.7 +/- 6.5 cm in boys and 29.0 +/- 8.3 cm in girls) than in group 1 (21.9 +/- 4.1 cm in boys and 18.6 +/- 4.1 cm in girls). Final height was significantly greater in group 2 than in group 1 in boys. Although there was no significant difference in final height between groups in the girls, the change in height SDS from the start of GH treatment until final height was significantly greater in group 2 (2.7 +/- 1.6 in boys and 4.5 +/- 0.5 SD in girls) than in group 1 (1.0 +/- 0.8 in boys and 1.8 +/- 0.9 SD in girls), in both boys and girls. In conclusion, it appears that combination of an LHRH analogue and GH may increase the pubertal height gain and the final height of children with GHD. The improvement is attributed to the prolongation of the treatment period, permitting slow bone maturation, and to the maintenance of height velocity. This combination treatment appears to be more effective in boys than girls. To fully assess this therapeutic approach, prospective controlled studies are needed. PMID- 10102061 TI - Growth in Crohn's disease. AB - Abnormal linear growth is frequent in children and adolescents with Crohn's disease. The typical pattern is of growth retardation associated with delayed skeletal maturation. Puberty is also frequently delayed. Over 50% of patients may have a subnormal height velocity, and approximately 25% will have short stature. The endocrine status is characterized by normal growth hormone secretion and a slightly subnormal serum level of insulin-like growth factor I, which is related to nutritional status. Principal therapeutic options are intestinal resection for localized disease, and enteral nutrition--using a polymeric diet--for more widespread disease, particularly involving the small intestine. Growth responses to both modalities are often excellent and produce considerable psychological benefit. Optimum therapy is achieved by close collaboration between gastroenterologists and endocrinologists, and by the use of auxological methods to document pre- and post-therapeutic management. PMID- 10102062 TI - Growth retardation in chronic diseases: possible mechanisms. AB - Multiple and complex mechanisms are likely to be involved in producing the growth retardation that occurs in children with chronic disease. The principal mechanisms in the pathway leading to growth arrest include too little substrate available to the child, excessive need for and over-consumption of substrate, and inefficient management of body components needed for growth. It is proposed that alterations in the growth hormone (GH)-insulin-like growth factor (IGF) system play a major role at each of the steps between insult from chronic disease and growth retardation. When substrate is insufficient, the production and action of IGF-I are attenuated at multiple points in the GH-IGF cascade. When over consumption of substrate occurs, a situation of 'internal starvation' probably develops--leading to events similar to those that take place when substrate supply is inadequate. Finally, conditions that cause inefficient management of body components needed for growth, as characterized by increased proteolysis, appear to be attenuated by GH and IGF-I. PMID- 10102063 TI - Can growth hormone counteract the effects of glucocorticoids on protein metabolism? AB - The size of the body's protein pool depends on the equilibrium between protein synthesis and breakdown. Glucocorticoids, the most potent catabolic hormones, act primarily by increasing protein breakdown, both in muscle and at the whole-body level. Growth hormone (GH) counteracts the catabolic effects of glucocorticoids by stimulating protein synthesis. Part of its effects are mediated via insulin like growth factor I (IGF-I). The effects of combined GH-IGF-I treatment are discussed. PMID- 10102064 TI - Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. AB - Severe growth retardation and profoundly altered body composition are observed in children treated with glucocorticoids for systemic forms of juvenile chronic arthritis. The aim of this study was to assess the effects of 1 year of treatment with growth hormone (GH) on height velocity and body composition, and the potential effects of such treatment on glucose tolerance. Fourteen children receiving steroid therapy for juvenile chronic arthritis were treated with GH, 1.4 IU/kg/week (0.47 mg/kg/week), for 1 year and were then followed up for 1 year after cessation of treatment. Baseline GH secretion and plasma levels of insulin like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were at the lower limit of normal, but increased with GH treatment. During the year of GH treatment, mean height velocity increased from 1.9 to 5.4 cm/year (p < 0.001), mean lean body mass increased by 12% (p < 0.01) and mean fat mass fell by 20% (p < 0.01) compared with baseline. Decreased glucose tolerance and increased glycosylated haemoglobin levels were also observed. This may have been a result of insulin resistance, as indicated by induced hyperinsulinaemia. Following the 1 year GH treatment period, height velocity fell to pretreatment values, and the height SDS at the end of the second year was lower (p < 0.01) than before treatment. Weight and fat mass increased markedly after cessation of GH treatment. These results suggest that GH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease. Long-term controlled studies are needed to determine the risks and benefits of GH therapy in such patients. PMID- 10102065 TI - Methodological considerations in the assessment of health-related quality of life in children. AB - Health-related quality of life (HRQL) can be described as the psychological and social aspects of a patient's health, and as the patient's view of his or her condition and its treatment. Doctors, parents and children have different views of a child's HRQL. This is not because one has the right perception and the others are wrong, but because they see different aspects of the child's HRQL. Only the children themselves can provide a subjective perception of their HRQL. The practical and conceptual considerations required when assessing children's HRQL are discussed. PMID- 10102066 TI - Peer relationships and quality of life. AB - Measures of peer relationships during childhood have been shown to be reliable predictors of several indicators of functioning during adulthood. Within each of these areas of functioning, children who have troubled peer relationships are more likely to show signs of distress than are other children. In addition, experiences with peers appear to provide a context for the development of many fundamental human capacities (e.g., moral judgment, conflict resolution skills, emotional regulation, etc.). Three interrelated levels of analysis can be used to assess a child's experiences with peers: the level of the individual (i.e., what the child is like); the level of the dyad (e.g., experiences with friends); and the level of the group (e.g., experiences with the set of individuals with whom the child typically associates). By determining a child's functioning at these three levels of analysis (using assessments from teachers, parents, and peers), it is possible to obtain a good assessment of a central portion of the quality of a child's life. Such measures have been used to assess the quality of life of children across the height spectrum and preliminary findings show that the peer experiences of children who are substantially shorter than their peers are remarkably similar to those of other children. PMID- 10102067 TI - Quality of life in Turner syndrome is related to chromosomal constitution: implications for genetic counselling and management. AB - Issues of self-appraisal, friendships and academic attainments are uniquely salient for all adolescents. For girls with Turner syndrome, social problems and learning difficulties often become more serious at this time, yet may be unacknowledged by those responsible for paediatric care because their focus is on growth and sexual maturation. Data on the social and educational adjustment of 110 45,X (monosomic) females aged between 6 and 25 years is presented. Detailed information on the patients' precise karyotype was used to demonstrate systematic differences in adjustment between those whose single X chromosome was maternally derived and those in whom it was paternal. Implications for educational support and parental guidance are discussed. PMID- 10102068 TI - Health-related quality of life in intersexuality. AB - Standardized methods for the assessment of health-related quality of life in patients with intersexuality are yet to be developed. This paper makes recommendations as to the kind of measures that should be included. PMID- 10102069 TI - Growth hormone therapy in hypochondroplasia. AB - Patients with hypochondroplasia present with variable phenotypes. Children with severe short stature and disproportion of the body segments usually have the mutation Asn540Lys. They respond to growth hormone (GH) therapy with an increase in spinal length and, coupled with a surgical leg-lengthening procedure, it is possible for some patients to achieve adult heights within the normal range. Some children who present with proportionate short stature and hypochondroplasia fail to increase their growth rate at puberty, although the growth spurt can be restored by GH therapy. Others, with an identical presentation, seem to grow normally during puberty. At present, there is no way of predicting who will undergo a normal pubertal growth spurt. We therefore monitor all patients during childhood and give GH treatment only to those patients who fail to develop a growth spurt at puberty. Severe cases may occasionally need treatment before puberty if their growth velocity is compromised, but these will probably also be candidates for a surgical leg-lengthening procedure. PMID- 10102070 TI - Molecular defects in achondroplasia and the effects of growth hormone treatment. AB - Achondroplasia is a common skeletal dysplasia with severe growth retardation. Recently, mutations in the fibroblast growth factor receptor 3 (FGFR3) were identified in patients with achondroplasia. In the present study, 70 of 75 Japanese patients with achondroplasia were found to have a G1138A mutation in FGFR3, and two patients had a G1138C mutation. Growth hormone therapy was given to 145 patients with achondroplasia. Significant dose-dependent effects on skeletal growth were obtained, with no long-term adverse effects. PMID- 10102071 TI - Human growth disorders: molecular genetics of the growth hormone-insulin-like growth factor I axis. AB - The critical role of the growth hormone-insulin-like growth factor I axis in controlling somatic growth in humans and other vertebrate species has been known for many years. Through molecular cloning and other related techniques many of the components of this axis have been characterized, with the most recent additions being key transcription factors required for pituitary development and for pituitary-specific gene expression. Several of these genes have been shown to be mutated in familial and sporadic human growth deficiency syndromes, thereby validating the central roles of the encoded proteins in the endocrine pathways regulating somatic growth. The purpose of this review is to highlight these recent advances from the perspective of the molecular genetics of human growth disorders. PMID- 10102072 TI - Natural history of growth hormone receptor deficiency. AB - This review discusses the natural history of growth hormone receptor deficiency (GHRD) in relation to epidemiology, mortality, growth, certain aspects of body composition, and intellectual development. The majority of affected individuals are of Semitic origin and 90% come from the Indian peninsula, the Middle East, or elsewhere in the Mediterranean. There is a twofold increased mortality before the age of 7 years for children with GHRD. Affected adults may have increased cardiovascular risk resulting from increased total cholesterol and low-density lipoprotein cholesterol, unrelated to adiposity or insulin resistance. Intrauterine growth is affected minimally, if at all. Within a genetically homogeneous population in Ecuador, postnatal growth effects are as variable as in a large genetically heterogeneous population. There is no influence of parental heights. Areal bone mineral density is reduced in adults with GHRD, but estimated volumetric bone density (bone mineral apparent density) is normal. Intellectual development is unaffected by GHRD. PMID- 10102073 TI - Relationship between phenotype and genotype in growth hormone insensitivity syndrome. AB - Growth hormone insensitivity syndrome (GHIS) of genetic origin is associated with many different mutations of the growth hormone receptor (GHR) gene and a recently described genetic defect of the insulin-like growth factor I (IGF-I) gene. Phenotypic and biochemical features were examined in a cohort of 82 patients with GHIS from 23 countries. The mean age of these patients was 8.3 years, their mean height SDS was -6.09 and their median IGF-binding protein-3 (IGFBP-3) SDS was 8.5. In total, 19 of the 82 patients (23%) were growth hormone-binding protein (GHBP)-positive (> 10%). The mean heights in GHBP-negative and GHBP-positive patients were -6.45 SDS and -4.89 SDS, respectively (p < 0.001). Sixteen different GHR gene mutations were identified in 27 patients with GHIS. All of these patients had homozygous mutations, except one who had a compound heterozygous mutation. There was no relationship between the type or site within the GHR gene of the mutation and the height SDS or IGFBP-3 SDS of the patients. GHIS is associated with a wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene alone. Other genes or environmental factors must contribute to the control of growth in patients with GHIS. PMID- 10102074 TI - Truncated growth hormone receptor isoforms. AB - Truncated forms of the growth hormone receptor (GHR) that lack the majority of the cytoplasmic domain have been identified in a number of human tissues. In vitro, these truncated receptors act as dominant-negative inhibitors of the growth hormone (GH) signal and also generate large amounts of growth hormone binding protein (GHBP). Mutations that lead to high levels of expression of the truncated GHR are associated with short stature and GH insensitivity. Thus, truncated GHRs may be important as a physiological regulator of GH signalling in addition to providing a mechanism for the production of GHBP. PMID- 10102075 TI - New growth hormone receptor exon 9 mutation causes genetic short stature. AB - A novel form of congenital growth hormone insensitivity syndrome (GHIS), which lacks the classic phenotype associated with this condition, is described. Dominant inheritance is shown to result from a heterozygous 876-1 G to C transversion of the 3' splice acceptor site preceding exon 9 in the growth hormone receptor (GHR) gene. The result of this mutation is a severely truncated cytoplasmic domain of the GHR, which is incapable of transmitting a signal. The mutant receptor is shown to form a heterodimer with the wild-type GHR, the activity of which is inhibited in a dominant-negative manner. PMID- 10102076 TI - Signal transduction defects in growth hormone insensitivity. AB - Growth hormone (GH) insensitivity is a heterogeneous condition that can result from mutations within the GH receptor (GHR) and that can be inherited as both an autosomal recessive and a dominant trait. However, evidence from a small number of growth hormone binding protein (GHBP)-positive families indicates that their GH insensitivity is independent of GHR mutations. Two of these families appear to have distinct abnormalities in GH signal transduction. Studies suggest that one family (classic Laron syndrome phenotype; designated family H) have a signalling defect close to the GHR, preventing activation of both the STAT and MAPK pathways, whereas the other family (less marked phenotype; family M) have a defect in activating MAPK but not the STAT pathway. The children studied here are specifically insensitive to GH and their defect must be exclusive to this signalling system. Thus, families with GHBP-positive GH insensitivity without GHR mutations are likely to be important models in which to study the specificity of GH signal transduction and the relationship between GH insensitive phenotype and signalling defect. PMID- 10102077 TI - Effects of insulin-like growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insensitivity syndrome. GHIS Collaborative Group. AB - Eight children with growth hormone insensitivity syndrome (GHIS) have been treated with injections of recombinant human insulin-like growth factor I (rhIGF I) for more than 5 years each. After good acceleration of growth in the first year of therapy, the growth rate decreased to an average of 5-6 cm/year. In general, growth with IGF-I therapy is less exuberant than that observed with growth hormone (GH) therapy in GH-deficient children. IGF is well tolerated, though there may be overgrowth of the lymphoid tissues and the kidneys. Bone mineral density is improved by treatment. The benefits of therapy appear to exceed the risks. PMID- 10102078 TI - Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity. AB - Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 micrograms/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly (p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs. PMID- 10102079 TI - Partial growth hormone insensitivity--idiopathic short stature is not always idiopathic. AB - Heterozygous growth hormone receptor (GHR) gene defects are not a common cause of idiopathic short stature. Although some of these GHR mutations may result in relative insensitivity to growth hormone (GH) in other studies, obligate heterozygotes did not present any clinical manifestations. Although patients with GH insensitivity and elevated GH binding protein (GHBP) levels have been described, it may be a reasonable approach to screen children who have growth failure, low levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, and low levels of GHBP. Whether the sensitivity of this screening approach can be increased by administering pharmacological doses of GH for a few days and measuring the resultant increase in serum IGF-I concentration remains to be determined by ongoing studies. PMID- 10102080 TI - Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH sensitive children. AB - The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from -1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGFBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS. PMID- 10102081 TI - Growth hormone insensitivity: our current understanding and future directions. PMID- 10102082 TI - The antiphospholipid (Hughes') syndrome: an entity to be expanded. PMID- 10102083 TI - Human leukocyte antigen-G: new roles for old? PMID- 10102084 TI - American Society for Reproductive Immunology report of the Committee for Establishing Criteria for Diagnosis of Reproductive Autoimmune Syndrome. PMID- 10102085 TI - Antiphospholipid antibodies and reproduction: the antiphospholipid antibody syndrome. AB - In women who have a diagnosis of APS (both clinical and laboratory criteria) the chance for successful pregnancy is reduced. In these cases, treatment appears to be a clear option, particularly in the case of prior thromboembolic events. The current preference of treatment for women with RPL and aPL antibodies is subcutaneous heparin and aspirin. This treatment should begin with a positive pregnancy test and continue postpartum. It is unclear, at this time, what treatment, if any, is required for women who do not meet all the criteria for diagnosis of APS, but who are known to have aPL antibodies. In some cases, these women were tested because of a prior false-positive test for syphilis, with subsequent identification of aPL antibodies. More recently, women undergoing IVF were tested and found to have an increased incidence of aPL antibodies. It was suggested that aPL antibodies are associated with infertility and failure to implant. However, a summary of published reports indicate that positive aPL antibodies in patients undergoing IVF do not influence ongoing pregnancy rates. This subject, however, remains an area of active investigation because aPL antibodies were shown to interact with the syncytiotrophoblast and cytotrophoblast layers and could, theoretically, after implantation. PMID- 10102086 TI - The expression of human leukocyte antigen-G on trophoblasts abolishes the growth suppressing effect of interleukin-2 towards them. AB - PROBLEM: We have shown the attenuated human leukocyte antigen (HLA)-G expression on trophoblasts and an aberrant expression of interleukin (IL)-2, a cytotoxic cytokine, in decidual tissue in preeclampsia, where deteriorated trophoblastic invasion into decidual layers may constitute a crucial pathogenesis. We hypothesized that the absence of HLA-G might make trophoblasts susceptible to compromise by IL-2. METHOD OF STUDY: We analyzed the growth of HLA-G-negative and positive cell lines, all of which possessed IL-2 receptors, in the culture with or without IL-2 supplementation. RESULTS: The proliferation of HLA-G positive trophoblastic cell lines (BeWo and JEG-3) was not influenced by the addition of IL-2, whereas a HLA-G-negative trophoblastic cell line (JAR) exhibited significantly decreased proliferation when cultured with IL-2. Interestingly, the transfection of JAR cells with HLA-G completely eliminates the growth-inhibitory effect of IL-2. CONCLUSION: The expression of HLA-G may commit trophoblasts to evade cell damage by IL-2, which may be relevant to maternal tolerance of the fetus during pregnancy and its derangement as exemplified by preeclampsia. PMID- 10102087 TI - Analysis of human leukocyte antigen-G polymorphism including intron 4 in Japanese couples with habitual abortion. AB - PROBLEM: The purpose of this study was to clarify whether there is a difference between the allele frequency of human leukocyte antigen (HLA)-G in healthy Japanese people and that of Japanese couples with habitual abortion. METHOD OF STUDY: Exons 2, 3, 4, and intron 4 of the HLA-G gene were analyzed in 20 couples with habitual abortion, using polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis. Intron 4 of the HLA-G gene was also analyzed in 54 healthy individuals. The nucleotide sequence of the PCR product of intron 4 was further determined by direct sequencing. RESULTS: Two kinds of nucleotide sequence were identified in intron 4 of the HLA-G gene, one of which was identical to that of HLA-G*01011, and the other was identical to that of HLA G*01012, G*01013, and G*0104. The frequency of each allele in affected women and their husbands did not significantly differ from that of healthy individuals, and no mutation was found in any affected couple. CONCLUSION: HLA-G allelic abnormality seemed to have little, if any, implication in the pathogenesis of habitual abortion. PMID- 10102088 TI - Interleukin-6 levels in co-culture of human in vitro fertilization embryos with Vero cells are not predictive of future successful development. AB - PROBLEM: In an attempt to predict successful embryo transfer and implantation, we measured interleukin (IL)-6 levels in culture supernatants of co-cultured preimplantation human embryos. We tested whether all in vitro fertilized human embryos in co-cultures do secrete IL-6, and whether there was any difference in such production between embryos that successfully reached the blastocyst stage and blocked embryos. We also addressed the question of IL-6 secretion by co culture support cells, namely Vero cells themselves. METHOD OF STUDY: Each fertilized oocyte was cultured individually and transferred in culture wells supplemented with a feeder layer of Vero cells at day 2. In vitro IL-6 production was measured by bioassay of the culture media. RESULTS: Because Vero cells themselves secrete IL-6, it became impossible, in co-culture, to quantify production of IL-6 by the sole embryos. On the other hand, the co-culture technique has shown us that embryos are likely to consume IL-6. There was no difference between blastocysts and blocked embryos. CONCLUSIONS: IL-6 levels in human embryo co-cultures do not correlate with future successful embryo transfer. PMID- 10102089 TI - Rupture of the distal biceps tendon. A report of 19 patients treated with anatomic reinsertion, and a meta-analysis of 147 cases found in the literature. AB - We present a series of 19 avulsions of the distal tendon of the biceps brachii muscle after a follow-up of 2 to 11 years. Ten patients with delayed diagnosis and treatment (3 weeks to 5 months) were compared with nine patients treated early (within 8 days after injury). Excellent or good results at follow-up were obtained in 9 of 10 patients in the delayed-treatment group and in all 9 patients in the early-treatment group. Nine of 10 patients in the delayed-treatment group and all patients in the early-treatment group had been able to return to their preinjury levels of activity. For reference, a meta-analysis of 147 cases reported previously was performed. Ninety percent of the patients treated with an anatomic reinsertion had excellent or good results after an average follow-up of 3 years, while similar results after 3 years were seen in 60% of the patients who had nonanatomic tendon reinsertion and in 14% of the patients who were treated nonoperatively. The delay of up to 3 years between injury and anatomic reinsertion had not compromised the result. From these data we concluded that anatomic reinsertion of the avulsed distal biceps tendon to the radius is the preferred treatment in acute as well as chronic injuries. PMID- 10102090 TI - Symptomatic thrower's exostosis. Arthroscopic evaluation and treatment. AB - A long-term follow-up was performed on 22 patients treated for a posterior glenoid osteophyte and symptomatic posterior shoulder pain during either the late cocking, acceleration, or follow-through phases of throwing. Arthroscopic evaluation of these patients revealed undersurface tearing of the rotator cuff in all but one. Fifteen patients also had tearing of the posterior labrum. Anterior labral fraying was noted in four patients. Treatment consisted of debridement of the rotator cuff and labral tears. The posterior glenoid osteophyte was removed arthroscopically in 11 patients. Eighteen of 22 throwers treated were available for long-term follow-up at a mean of 6.3 years (range, 1 to 12). Only 10 of 18 (55%) throwers evaluated had returned to their premorbid level of throwing. All 10 were asymptomatic and had maintained a high level of performance for a mean of 3.6 years (range, 1 to 8). At the time of latest follow-up, five players were still participating at the major league level and five had retired. One patient had recurrence of the exostosis 8 years after surgery. Among our patients a trend existed toward a poorer result and failure of return to activity with a posterior osteophyte greater than 100 mm2. A posterior glenoid exostosis, when identified in the symptomatic shoulder of the throwing athlete, can be considered a definite marker of internal impingement. PMID- 10102091 TI - A new pain provocation test for superior labral tears of the shoulder. AB - We prospectively evaluated the usefulness of a new pain provocation test to diagnose superior labral tears in 32 patients with diagnosed throwing injuries of the shoulder. Results of the pain provocation test were compared with findings on magnetic resonance arthrography (all 32 patients) and arthroscopic examination (15 patients). In 22 patients, detachment of the superior labrum was observed on arthrograms, and all of them had positive results on the new pain provocation test. Nine of the other 10 patients had negative results on the new pain provocation test. However, 1 of the 10 patients had a positive result. Eleven of 15 patients were found to have superior labral lesions arthroscopically, and all of them were classified as type II superior labral anterior posterior lesions. All the 11 patients had positive pain provocation tests. The other four patients without superior labral tears on arthroscopic findings had negative results on the new pain provocation test. The new pain provocation test identified all patients with detachment of the superior labrum confirmed by magnetic resonance arthrography, for a sensitivity of 100%, a specificity of 90%, and an accuracy of 97%. Results of the new pain provocation test were in accord with arthroscopic findings in the 15 patients who underwent arthroscopic examination. PMID- 10102092 TI - Subtalar subluxation in ballet dancers. AB - Ankle injuries frequently occur in dancers. Among these injuries, only a few cases of talar subluxation have been reported in the literature. In our series, we diagnosed and treated 25 subtalar subluxations over a 1-year period in the Ballet Bejart Lausanne company. The subluxations occurred after a grand plie on pointes or at the landing of a jump on demi-pointes, without any mechanism of ankle sprain. The dancer usually noted a sudden and sharp pain in the talonavicular joint and hindfoot with a feeling of "forward displacement" of the foot. At palpation, the talonavicular ligament, the anterior talofibular ligament, and the posteromedial part of the subtalar joint were painful. A limitation of the ankle extension and a clear hypomobility of the subtalar joint were noted. Under the effect of shearing forces on the midtarsal joint, a posteromedial subtalar subluxation occurred. Treatment consisted of a manipulation that reduced the subluxation. Continuous taping, which locks the talonavicular joint in the anterior direction, was recommended for 6 weeks. Dancing could be resumed in a swimming pool after 2 weeks, and on the ground after 3 to 4 weeks. We found that subluxation could recur, and that it could eventually become chronic. PMID- 10102093 TI - The effect of anterior cruciate ligament trauma and bracing on knee proprioception. AB - We studied the effect that chronic anterior cruciate ligament disruption, functional bracing, and a neoprene sleeve have on knee proprioception by measuring the threshold to detection of passive knee motion in all three conditions. The threshold to detection of passive knee motion was worse in knees with chronic anterior cruciate ligament insufficiency when compared with uninjured knees. This difference was small, on average an additional 0.28 degree of flexion-extension rotation was required for the anterior cruciate ligament deficient knee before the subject detected motion, and of questionable significance from a clinical and functional perspective. Wearing a functional brace or neoprene sleeve on the anterior cruciate ligament-deficient knee did not significantly change the threshold to detection of passive motion in comparison with the same knee without a brace, although improvements were observed. There was no relationship between the most common clinical means of characterizing altered biomechanics of the anterior cruciate ligament-deficient knee (that is, the magnitude of anterior-posterior knee laxity and the grade of pivot shift) and the threshold to detection of passive knee motion. PMID- 10102094 TI - Evaluation of knee stability before and after participation in a functional sports agility program during rehabilitation after anterior cruciate ligament reconstruction. AB - We sought to determine whether participation in a functional sports agility program as early as 4 weeks after anterior cruciate ligament reconstruction with autogenous patellar tendon graft would affect objective knee stability in 603 patients. The rehabilitation program prescribed a functional sports agility program at a mean of 5.1 +/- 1.0 weeks postoperatively when full knee hyperextension, knee flexion to 120 degrees, and quadriceps muscle strength of 60% of the normal leg had been achieved. The patients had KT-1000 arthrometer testing before beginning the program and at subsequent follow-up after they had performed the sport activity. The mean manual maximum KT-1000 arthrometer difference was 1.9 +/- 1.3 mm at initial testing and 1.9 +/- 1.2 mm at follow-up testing. The frequency distribution of the KT-1000 arthrometer scores revealed that 92.7% of patients at initial testing and 93.2% of patients at follow-up testing had displacement difference of 3 mm or less. The results of this study show that functional sports agility programs during the early rehabilitation period after anterior cruciate ligament reconstruction with a correctly placed autogenous patellar tendon graft do not cause a change in graft stability. PMID- 10102095 TI - Histologic evaluation of the glenohumeral joint capsule after the laser-assisted capsular shift procedure for glenohumeral instability. AB - Glenohumeral joint capsule obtained from 42 patients who had undergone an arthroscopic laser-assisted capsular shift procedure was evaluated histologically. A total of 53 samples from the anterior inferior glenohumeral ligament of the joint capsule were collected before and at various times after the procedure (range, 0 to 38 months). Despite glenohumeral instability, joint capsule of the patients before the procedure showed no significant histologic lesions. Laser treatment significantly altered the histologic properties of the tissue as evidenced by hyalinization of collagen and necrotic cells (time 0). Tissues sampled during the short-term period (3 to 6 months) after the procedure demonstrated fibrous connective tissue with reactive cells and vasculature. Collagen and cell morphology returned to normal in the middle- to long-term period (7 to 38 months) after the procedure, while the number of fibroblasts remained elevated. Joint capsule collected from the shoulders of six patients who experienced stiffness after the procedure showed persistent synovial, cellular, and vascular reaction even after 1 year postoperatively, the cause of which is unclear. This study revealed histologic evidence of robust tissue healing and maturation after thermal treatment by the laser-assisted capsular shift procedure, although mechanical and biochemical characterization of the tissue was not evaluated. Correlation with clinical follow-up must be performed to further clarify the advantages and disadvantages of this procedure. PMID- 10102096 TI - The effects of laser-induced collagen shortening on the biomechanical properties of the inferior glenohumeral ligament complex. AB - The purpose of this study was to determine the effects of laser-induced collagen shortening on the biomechanical properties of the inferior glenohumeral ligament complex. Fifty-seven bone-ligament-bone specimens underwent uniaxial tensioning to 10% strain. Approximately half of the specimens then underwent 10% shortening by lasing using a holmium:yttrium-aluminum-garnet laser. Both groups were again tensioned to 10% strain, and then loaded to failure. Ultimate strain and yield strain were significantly higher in the lased specimens than in the nonlased specimens. No significant difference was found for ultimate stress, yield stress, or elastic modulus between the two groups. Failure of the ligament did not appear to occur in the lased areas. The load-to-failure results suggested that the strength of the ligament complex was not significantly compromised by this lasing protocol. PMID- 10102097 TI - Increasing hamstring flexibility decreases lower extremity overuse injuries in military basic trainees. AB - The purpose of this intervention study was to prove that increasing flexibility of the hamstring musculotendinous unit would decrease the number of lower extremity overuse injuries that occur in military infantry basic trainees. Two different companies going through basic training at the same time were used. Hamstring flexibility was checked at the beginning and at the end of the 13-week infantry basic training course. The control company (N = 148) proceeded through normal basic training. The intervention company (N = 150) followed the same program but added three hamstring stretching sessions to their already scheduled fitness program. All subsequent lower extremity overuse injuries were recorded through the troop medical clinic. Hamstring flexibility increased significantly in the intervention group compared with the control group. The number of injuries was also significantly lower in the intervention group. Forty-three injuries occurred in the control group for an incidence rate of 29.1%, compared with 25 injuries in the intervention group for an incidence rate of 16.7%. Thus, in this study, the number of lower extremity overuse injuries was significantly lower infantry basic trainees with increased hamstring flexibility. PMID- 10102098 TI - Spinal injuries in skiers and snowboarders. AB - Spinal injuries are among the most devastating injuries associated with recreational sports. Snowboarding spinal injury patterns have not been described. During two seasons (1994 to 1995 and 1995 to 1996), 34 skiers and 22 snowboarders suffered serious spinal injuries (fracture or neurologic deficit or both) at two ski areas in British Columbia, Canada. Ski patrol records, the Provincial Trauma Database, and hospital records were reviewed. Injury rates were based on computerized lift-ticket data and a population estimate of 15% snowboarders (ski patrol observation). The incidence of spinal injury among skiers was 0.01 per 1000 skier-days, and among snowboarders was 0.04 per 1000 snowboarder-days. Mean age was 34.5 years for skiers and 22.4 years for snowboarders. Seventy percent of the skiers were men, whereas all of the snowboarders were men. Jumping (intentional jump > 2 meters) was the cause of injury in 20% of skiers and 77% of snowboarders. Neither age nor sex accounted for any significant portion of this difference. The rate of spinal injuries among snowboarders is fourfold that among skiers. Although jumping is the primary cause of injury, it is an intrinsic element of snowboarding. Until research defines effective injury-prevention strategies, knowledge of the risk of snowboarding should be disseminated and techniques for safe jumping should be taught. PMID- 10102099 TI - The natural history of the intercondylar notch after notchplasty. AB - Ten patients who underwent anterior cruciate ligament reconstruction by one surgeon using autologous patellar tendon grafts were evaluated. A standardized technique of performing a notchplasty was done to remove at least 5 mm of bone at the anterior outlet of the intercondylar notch. Computed tomography scans were done preoperatively, within 1 week postoperatively, and after 1 year of follow up. There were no statistically significant differences in the measured dimensions of the intercondylar notch between 1 week and 1 year postoperatively. While previous investigations have evaluated the relationship between intercondylar notch dimensions and risk of anterior cruciate ligament injury, we believe this is the first statistical study that addresses the natural history of the intercondylar notch in humans after bone resection. We believe that the data reported here may enhance our understanding and treatment of patients who have undergone previously failed anterior cruciate ligament reconstructions. PMID- 10102100 TI - Reconstruction of the anterior and posterior cruciate ligaments after knee dislocation. Results using fresh-frozen nonirradiated allografts. AB - We reviewed the results in 13 patients who underwent simultaneous allograft reconstruction of both the anterior and posterior cruciate ligaments after a knee dislocation (nine acute and four chronic injuries). Seven patients sustained related medial collateral ligament injuries and six patients had posterolateral complex injuries. Ligament reconstructions were performed using fresh-frozen Achilles or patellar tendon allografts. At follow-up evaluation (mean of 38 months), only one patient described the reconstructed knee as normal. Six patients had returned to unrestricted sports activities and four had returned to modified sports. The average extension loss was 3 degrees (range, 0 degree to 10 degrees) and average flexion loss was 5 degrees (range, 0 degree to 15 degrees). The KT-1000 arthrometer measurements at 133 N anterior-posterior tibial load showed a mean side-to-side difference of 4.5 mm (range, 0 to 10) at 20 degrees and 5.0 mm (range, 0 to 9) at 70 degrees. The mean Lysholm score was 88 (range, 42 to 100). International Knee Documentation Committee ratings were six nearly normal, five abnormal, and one grossly abnormal. Two patients required manipulations for knee stiffness. This study demonstrates that reconstruction of both cruciate ligaments can restore stability sufficient to allow sports activity in most patients with knee dislocations, but "normal" results are difficult to achieve. PMID- 10102101 TI - Surgical treatment for chronic lower-leg compartment syndrome in young female athletes. AB - Our experience in treating chronic lower-leg compartment syndrome suggests that women may be more susceptible to this injury than are men, an observation for which there is support in the literature. Furthermore, when we evaluated the 47 young female athletes (age range, 13 years 11 months to 21 years 10 months) from our practice on whom 78 separate surgeries were performed, we found a lower success rate than those generally reported in studies that combine male and female patients. We suspect, therefore, that for reasons as yet unclear, women may also respond less well than men to operative fasciotomy. PMID- 10102102 TI - A biomechanical analysis of matched bone-patellar tendon-bone and double-looped semitendinosus and gracilis tendon grafts. AB - Biomechanical testing was done on 15 matched pairs of central-third bone-patellar tendon-bone and double-looped semitendinosus-gracilis grafts harvested from 15 cadaveric knees. Load to failure, composite graft stiffness, and the modulus of elasticity were calculated for each graft. Specimens were from 2 female and 13 male donors (average age, 40 years; range, 17 to 53). Average load to failure for the patellar tendon grafts was 1784 N (+/- 580), compared with 2422 N (+/- 538) for the hamstring tendon grafts (significantly different). There was no statistically significant difference in stiffness between grafts (patellar tendon, 210 N/mm; hamstring tendon, 238 N/mm). The elastic modulus was 225 MPa (+/- 129) for the patellar tendon grafts and 145 MPa (+/- 58) for the hamstring tendon grafts (significantly different). The average cross-sectional area for the hamstring tendon grafts was 57 mm2, compared with the 45 mm2 for the patellar tendon grafts. The hamstring tendon grafts were significantly stronger than the matched central-third patellar tendon grafts, but the two grafts were similar in stiffness. The patellar tendon grafts had a higher modulus than the hamstring tendon grafts. PMID- 10102103 TI - Noncontrast magnetic resonance imaging of superior labral lesions. 102 cases confirmed at arthroscopic surgery. AB - Previous studies report that noncontrast magnetic resonance imaging is limited in the evaluation of the superior glenoid labrum. From our magnetic resonance imaging database of 2552 patients, we prospectively identified 104 patients with superior labral lesions who subsequently went on to arthroscopic surgery. Magnetic resonance images were assessed to identify fraying, flap tears, bucket handle tears, or displaced flap of fibrocartilage. The biceps tendon was also evaluated. Patients were categorized according to Snyder's classification, and the findings on the magnetic resonance images were correlated with surgical findings. One hundred of the 104 tears suspected on the images were confirmed at surgery. There were four false-positives and two false-negatives, the former reflecting one normal labrum, two meniscoid-type labra, and one sublabral foramen. With arthroscopic surgery as the standard, magnetic resonance imaging had a sensitivity of 98.0% (100 of 102), a specificity of 89.5% (34 of 38), and an accuracy of 95.7% (134 of 140) for detection of superior labral lesions. We concluded that high-resolution noncontrast magnetic resonance imaging can accurately diagnose superior labral lesions and aid in surgical management. PMID- 10102104 TI - Comparison of the Single Assessment Numeric Evaluation method and two shoulder rating scales. Outcomes measures after shoulder surgery. AB - The purpose of this study was to determine the correlation between the Single Assessment Numeric Evaluation method and the Rowe and American Shoulder and Elbow Surgeons scores. Between April 1993 and December 1996, 209 follow-up examinations were performed on 163 United States Military Academy cadets after shoulder surgery. These 209 examinations were divided into five follow-up categories: 3 months, 6 months, 1 year, 2 years, and greater than 2 years. The Rowe and American Shoulder and Elbow Surgeons scores from each subject's follow-up questionnaire were correlated with his or her Single Assessment Numeric Evaluation rating, which is determined by the subject's written response to the following question: "How would you rate your shoulder today as a percentage of normal (0% to 100% scale with 100% being normal)?" Correlation coefficients between the Single Assessment Numeric Evaluation and the two scores were 0.51 to 0.79 for the Rowe score and 0.46 to 0.69 for the American Shoulder Elbow Surgeons score. The results of this study indicate that the Single Assessment Numeric Evaluation correlates well with these two scores after shoulder surgery. This study suggests that this new evaluation method provides clinicians with a mechanism to gather outcomes data with little demand on their time and resources. PMID- 10102105 TI - Suturing versus immobilization of a muscle laceration. A morphological and functional study in a mouse model. AB - Muscle laceration remains a difficult problem for orthopaedic surgeons. Despite many studies related to the muscle's ability to regenerate after muscle degeneration, very few reports are available regarding structural and functional recovery after skeletal muscle laceration. We developed an animal model of muscle laceration in mice, where the gastrocnemius muscles were reproducibly transected. We compared the effect of a surgical repair versus a short period of immobilization (5 days) on the muscle healing. The natural course of muscle recovery was monitored at several points after injury using histologic, immunohistochemical, and functional testing. In the injured muscle, we observed a high number of regenerating myofibers and development of fibrotic scar tissue. Suturing the lacerated muscle immediately after injury promoted better healing of the injured muscle and prevented the development of deep scar tissue in the lacerated muscle; conversely, immobilization resulted in slower muscle regeneration and the development of a large area of scar tissue. Tetanus strength 1 month after injury was 81% of control muscles for the sutured muscles, 35% for the lacerated muscles with no treatment, and 18% for the immobilized muscles. Based on this study, suturing a muscle laceration with a modified Kessler stitch results in the best morphologic and functional healing. PMID- 10102106 TI - Atypical clinical and magnetic resonance imaging manifestations of meniscal cysts. A report of two cases and review of the literature. PMID- 10102107 TI - Posterior capsular avulsion in a college football player. PMID- 10102108 TI - Spontaneous shaft fracture of the tibia in weightlifting. A case report with dual energy X-ray absorptiometry and peripheral quantitative computed tomography measurements. PMID- 10102109 TI - Meniscus repair. PMID- 10102110 TI - Arthroscopy of the elbow. PMID- 10102111 TI - The clinical importance of the anaerobic energy system and its assessment in human performance. PMID- 10102113 TI - Hyperbaric oxygen therapy in sports. PMID- 10102112 TI - Fracture of the proximal tibia after Fulkerson anteromedial tibial tubercle transfer. A report of four cases. PMID- 10102114 TI - The effect of knee effusions on KT-1000 arthrometry: A cadaver study. PMID- 10102115 TI - The effect of knee effusions on KT-1000 arthrometry. PMID- 10102116 TI - Contact pressures at osteochondral donor sites in the knee. PMID- 10102117 TI - Little Leaguer's shoulder: a report of 23 cases. PMID- 10102118 TI - Reconstruction of the lateral collateral ligament of the knee with patellar tendon allograft. Report of a new technique in combined ligament injuries. PMID- 10102119 TI - Association between the menstrual cycle and anterior cruciate ligament in female athletes. PMID- 10102120 TI - Biomaterials in Urology II: future usage and management. AB - It seems likely, and indeed inevitable, that medical device usage will continue its rapid increase over the next 10 to 20 years and beyond. For surgeons, these new inventions will come in many forms but should take into account biocompatibility and resistance to encrustations and to microorganisms. This review focuses on research under way at present in vitro and in vivo on materials and coatings, use of bioelectrics, use of artificial organs and tissues, application of indigenous bacteria, and other alternative device management techniques, which could well become part of clinical practice in the future. By necessity, some of these citations are speculative, but supporting documentation for their inclusion is presented. PMID- 10102121 TI - Hand-assisted laparoscopic nephrectomy. AB - The introduction of hand-assisted laparoscopy should benefit every laparoscopic urologist. Hand assistance will shorten the learning curve for many urologists interested in performing laparoscopic renal procedures, including nephrectomy and nephroureterectomy. Advanced laparoscopists will be able to undertake more challenging procedures, including nephrectomies for inflamed, infected kidneys and live-donor nephrectomies. A step-by-step approach is presented for hand assisted laparoscopic nephrectomy. PMID- 10102122 TI - Direct percutaneous approach to the upper pole of the kidney: MRI anatomy with assessment of the visceral risk. AB - PURPOSE: In an attempt to determine the visceral risk secondary to a direct percutaneous puncture of the upper renal calix, the anatomic relations of the upper pole of the kidney were studied by magnetic resonance imaging. METHODS: Examination was performed on 25 normal volunteers placed successively in the right and left prone oblique position. The kidney axis and minimal distances from the cutaneous plane at the level of the upper and lower poles were measured. Axial and tangential simulated percutaneous approaches to the upper renal calix were compared in term of risk of damage to the pulmonary, splenic, and hepatic parenchyma. RESULTS: The transversal anteversion angle was statistically comparable for right and left kidneys, but the sagittal anteversion angle was significantly higher for right kidneys (p = 0.05). The minimal distance from the cutaneous plane was statistically comparable for the upper and lower poles. The lower pole was significantly deeper for left than right kidneys (p = 0.01). The visceral risk was statistically comparable for left and right kidneys and was significantly higher in case of an approach in the axis of the upper renal calix or through the 10th intercostal space compared to a puncture via the l1th space (p = 0.0001). CONCLUSION: A percutaneous puncture of the upper pole of the kidney above the 11th rib increases the risk of visceral damage. Preoperative evaluation, with the aid of CT scan or MRI, of the risk of pulmonary, splenic, or hepatic injury could be carried out in these cases. PMID- 10102123 TI - Endoscopic retrograde stenting for allograft hydronephrosis. AB - BACKGROUND AND OBJECTIVES: Ureteral obstruction occurs in 2% to 10% of all renal transplant recipients. Antegrade endourologic intervention has been the gold standard of therapy but carries significant morbidity. This study was designed to investigate the feasibility of retrograde stenting of these difficult ureters and to determine whether it can be performed with minimal morbidity without general or regional anesthesia. METHODS: Ninety-seven consecutive patients were found to have renal allograft hydronephrosis by ultrasonography, between August 1993 and March 1997. Of these, 61 (63%) had confirmation of obstruction by MAG-3 imaging, with equivocal results in 25 (26%). The remaining 11 patients had a rising creatinine concentration despite Foley catheter drainage. All patients had retrograde stenting attempted under local anesthesia followed by intravenous sedation if necessary. If stent placement was unsuccessful, the procedure was repeated under regional or general anesthesia. RESULTS: A total of 85 patients (88%) were managed successfully with retrograde stenting. Of these procedures, 24 (28%) were performed under local anesthesia alone, while 57 (67%) required both local anesthesia and intravenous sedation. Only 4 patients (5%) required general anesthesia. No patient suffered any morbidity associated with retrograde stenting. Of the 12 patients in whom retrograde stenting failed, 2 had renal allograft rupture and 10 had ureteral necrosis at surgical exploration. CONCLUSIONS: Retrograde stenting of the hydronephrotic renal allograft can be achieved with a high success rate and minimal morbidity, usually without general or regional anesthesia. If the ureter cannot be managed in a retrograde fashion, a high index of suspicion for a serious allograft complication should exist. PMID- 10102124 TI - Percutaneous nephrolithotomy with renal angiomyolipomas: a rare challenge. AB - Renal angiomyolipomas (AML) are vascular tumors associated with a risk of spontaneous bleeding. Renal trauma may also initiate such hemorrhage. We present a case in which we initially avoided direct puncture and the possible risk of bleeding through extensive renal AMLs and then subsequently performed a direct puncture through the tumors. A 21-year-old obese male patient with tuberous sclerosis and mental retardation presented to our institution with left renal colic and was found to have a staghorn calculus. A CT scan revealed extensive bilateral renal AMLs. The patient had previously undergone renal angioinfarction for an enlarging right-sided AML, and nuclear renography demonstrated 70% function from the left side. The patient had a nephrostomy access created on the morning of a scheduled percutaneous nephrolithotomy under three-dimensional CT guidance. There was no clinically significant bleeding. Intraoperatively, a second access site was required in order to render the patient stone free. This was done using standard biplanar fluoroscopic technique and traversed an AML. Both tracts were balloon dilated prior to placement of a 34F Amplatz sheath. Postoperatively, the patient had an uneventful recovery. A CT scan performed 1 day postoperatively revealed no retroperitoneal collection. This case demonstrates that renal access can be achieved with remarkable accuracy using 3D CT imaging. Furthermore, although this approach seems most prudent in the case of extensive renal AMLs, fluoroscopically guided renal access and dilation to 34F was not associated with bleeding in this patient. PMID- 10102125 TI - O'Brien peel-away sheath: an alternative for allograft percutaneous nephroscopy. AB - Percutaneous access and antegrade intervention remains the gold standard in the management of renal and ureteral complications in the renal transplant recipient. Current techniques with large nephrostomy sheaths and instrumentation carry significant morbidity in this patient population. We present our experience with a modification of the standard nephroscopic approach using a smaller (16F) O'Brien suprapubic peel-away introducer and sheath to access the allograft renal pelvis and allow manipulation with a smaller-caliber endoscope, with the purpose of attaining similar treatment outcomes with less morbidity in this subset of patients. Fourteen renal transplant patients with indications for antegrade management of renal or proximal ureteral complications had successful endoscopic intervention through the smaller sheaths without suffering any intraoperative or postoperative complications at a mean follow-up of 22 months (range 8-37 months). The mean operative time was 140 minutes (33-190 minutes), which is not significantly different from our operative time using standard instrumentation. PMID- 10102126 TI - A new generation of semirigid fiberoptic ureteroscopes. AB - BACKGROUND: Further advances in endoscope technology have allowed the development of a new generation of tightly packed fiberoptics encased within a rigid ureteroscope. The tips of these semirigid ureteroscopes measure between 5.0F and 11.9F, and their working channels measure between 1.8F and 5.5F, which allows passage of routine endoscopc instruments. Additionally, several manufacturers have recently produced straight-channel fiberoptic semirigid endoscopes with an offset lens which allow usage of rigid lithotripsy devices. New fiber-packing techniques provide numerous pixels within the image bundle. These ureteroscopes have varied distal lens systems, but all have excellent vision in the field of view. METHODS: Over the past 28 months, we have performed transurethral ureteroscopy in 187 patients, having utilized semirigid ureteroscopes in 158 patients for diagnostic procedures (8.7 %), stone manipulation (78.7 %), removal of migrated stents (4.4%), and surgery of stricture, tumor, or foreign bodies (8.2%). In more than 50% of our cases, ureteral dilation was not necessary, and the semirigid ureteroscope was passed to the area of interest without difficulty. RESULTS: We accessed the site of pathology in 96.2% of patients. Overall, complications occurred in 6.9% of patients. However, of these problems, 93.6% were small ureteral perforations (only three of which were caused by the semirigid ureteroscope itself), and all cases but one were managed successfully by a ureteral stent. No postoperative strictures were noted. CONCLUSION: This new generation of semirigid fiberoptic ureteroscopes represents another significant advance in the endourologic management of ureteral disease. PMID- 10102127 TI - Feasibility of total intravesical endoscopic surgery using mini-instruments in a porcine model. AB - BACKGROUND AND OBJECTIVES: The aim of minimally invasive approaches to vesicoureteral reflux, such as endoscopic trigonoplasty, is to lower the morbidity of open procedures without compromising the results. Initial successes have not been sustained, mainly because of trigonal splitting, which results in the ureteral orifices returning to their preoperative positions. This study was designed to address trigonal splitting by mobilizing the ureters before repositioning them and to evaluate the feasibility of accomplishing this intravesically with 2- to 3-mm endoscopic mini-instruments. METHODS: Bilateral vesicoureteral reflux was surgically created in 10 minipigs. After radiologic confirmation of success 4 weeks later, modified trigonoplasty was performed by endoscopic intravesical mobilization of both ureters and incision of the trigonal mucosa using 2-mm instruments. The ureteral orifices were then advanced toward the midline and sutured in place. The initial surgical techniques were modified to permit the entire procedure to be performed endoscopically in the last four minipigs. Cystograms and intravenous urograms were obtained 4 weeks later. RESULTS: Two minipigs died postoperatively. Six of the remaining eight had persistent reflux, including three of the four in the group treated completely by endoscopic means. None of the dissected ureters showed evidence of stricture or necrosis. CONCLUSIONS: Although the procedure was not successful in correcting reflux in this model, this study demonstrates the feasibility of endoscopic ureteral mobilization. With current instrumentation, there is no significant technical obstacle to complete intravesical endoscopic surgery, including ureteral reimplantation. PMID- 10102128 TI - Use of rigid hysteroscope for extraction of foreign bodies embedded in lower urinary tract. AB - PURPOSE: To introduce the use of the 20F rigid hysteroscope in urologic procedures. MATERIALS AND METHODS: The 20F hysteroscope was used to remove deeply embedded foreign bodies from the lower urinary tract of three patients in whom previous attempts with standard cystoscopic equipment were unsuccessful. RESULTS: In all three cases, the hysteroscope easily passed into the urethra and with the use of rigid instruments was able to remove the foreign bodies without complication. CONCLUSION: Situations may arise when the removal of embedded foreign bodies is not possible with standard cystoscopic equipment. The hysteroscope, which is available in most operating rooms, was able to extirpate even deeply embedded foreign bodies. PMID- 10102129 TI - Low-power v high-power KTP laser: improved method of laser ablation of prostate. AB - BACKGROUND AND OBJECTIVE: Current treatment technique for laser prostatectomy involve Nd:YAG wavelength at 60 to 80 W. Use of the KTP wavelength in addition to Nd:YAG allows for vaporization of more tissue, decreasing the amount undergoing coagulation necrosis. In this study, we compared 20 W and 40 W of KTP laser energy in conjunction with the Nd:YAG wavelength for the treatment of benign prostatic hyperplasia (BPH). PATIENTS AND MATERIALS: A total of 50 consecutive patients underwent laser ablation of the prostate, with 38 patients (Group I) receiving treatment with 20 W of the KTP and 60 W of the Nd:YAG wavelengths. The other 12 patients (Group II) underwent treatment with 40 W of KTP and 60 W of Nd:YAG laser energy. The patients had an initial evaluation consisting of American Urological Association (AUA) Symptom Score, uroflowmetry, transrectal ultrasonography for prostate volume measurement, and assay of prostate specific antigen (PSA) serum level. The patients were seen in follow-up at 1, 3, and 6 months. RESULTS: The mean symptom score decreased from 23.4 to 8.9 from Group I and from 18.2 to 3.5 for Group II at the 6-month follow-up. The mean peak urinary flow rate increased from 8.4 to 15.4 mL/sec Group I and from 8.3 to 16.5 mL/sec in Group II at the 6-month follow-up. CONCLUSIONS: The patients treated with the 40 W of KTP laser energy experienced a more rapid and sustained improvement in symptom score than those treated at 20 W. The improvement in peak urinary flow rate was approximately the same in the two groups. PMID- 10102130 TI - Interstitial thermometry in men undergoing electrovaporization of the prostate. AB - BACKGROUND AND OBJECTIVES: Transurethral electrovaporization of the prostate (TVP) has been utilized increasingly in the therapeutic management of benign prostatic hyperplasia (BPH). The temperature profile within both prostatic and periprostatic tissue has been presented as a parameter of safety in various preliminary studies. This prospective study measured interstitial temperature during TVP in both the prostate and the surrounding tissue of 18 men. METHODS: These 18 men undergoing TVP had three interstitial thermocouple probes placed under ultrasound guidance. Probes were positioned in the rectal wall and at the 5 and 7 o'clock position of the prostate capsule. A fourth probe was placed within 1 mm of the area of vaporization to determine "lesion" temperature. Temperature was measured at baseline and at 15-minute intervals as TVP was performed utilizing the VaporTrode at 240 to 280 W with a Valley Lab Force 40 generator. RESULTS: The maximum temperature variability was 1.9 degrees C. The temperature within 0.5 mm of the area of vaporization was >100 degrees C. These results were independent of the temperature of the irrigating solution. CONCLUSIONS: These results provide compelling evidence that high vaporization temperatures do not affect surrounding prostatic tissue. In theory, the risk of injury to either the rectum or the neurovascular bundle during TVP should be extremely low. PMID- 10102131 TI - Technology that will initiate future revolutionary changes in healthcare and the clinical laboratory. AB - Future trends in healthcare delivery will focus on preventive medicine that will require integration of molecular medicine with advanced information and computer technology. Molecular medicine will shift from costly intervention and treatment of established diseases to proactive prediction and prevention of disease risks. This approach will require new informatic systems that will link large scale databanks and special programs for data mining and retrieval in bioinformatics, cheminformatics, and population genetics. The clinical laboratory will soon be able to provide powerful new molecular diagnostic tools along with multianalytic assays for expression of genes and proteins in different patterns of diseases, disease progression, and predisposition to diseases. PMID- 10102132 TI - Perspective on the clinical laboratory: new uses for informatics. AB - Enhanced capabilities of modern information systems will have a major impact on the way that clinical laboratories generate diagnostic information and transmit that information to their physician clients. This article provides a perspective on how some of the most imminent changes in informatics are likely to alter laboratory practices and to create new roles for the clinical laboratory through the ability to manage vast quantities of information. The areas covered include utilization of laboratory services, process control in the laboratory, interpretation of test results, and laboratory economics. PMID- 10102133 TI - Antiphosphatidylserine antibodies in patients with autoimmune diseases and HIV infected patients: effects of Tween 20 and relationship with antibodies to beta2 glycoprotein I. AB - Antiphospholipid antibodies (aPL) react with negatively charged phospholipids, which may often be complexed with a protein cofactor such as beta2 glycoprotein (beta2GPI) and prothrombin. Cofactor requirements may be assessed by measuring antibodies to beta2GPI or by adding Tween 20 to some reagents in the assays for aPL (anticardiolipin and antiphosphatidyIserine). We have measured anticardiolipin antibodies (aCL), antiphosphatidylserine antibodies (aPS), and anti beta2 glycoprotein antibodies (abeta2GPI) in the serum of 10 normal subjects, 20 patients with systemic autoimmune diseases (SAD) diagnosed as having systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS), and 12 patients with HIV infection. Adding Tween 20 to aPS, the assay couldn't differentiate protein cofactor dependent from independent antibodies, but this can be done by measuring abeta2GPI (P= 0.0008). There was a significant correlation between aCL and a(beta)2GPI in the control group and in the patients with SAD, but not in the HIV-positive (HIV+) patients. After excluding the HIV+ patients, the best Spearman correlation was obtained between a(beta)2GPI and aCL (0.64, P< 0.0005). In 3 out of 7 patients with positive a(beta)2GPI and in 5 out of 6 patients with moderate or high positive aCL of the group of SAD, there was a history of venous thrombosis. The presence of moderate or high values of aCL either alone or together with a(beta)2GPI was significantly associated with a history of venous thrombosis (P < 0.05). Moderate or high aCL concentrations and their association with a(beta)2GPI seems to be useful for the assessment of the risk of venous thrombosis in unselected patients with SLE or APS. PMID- 10102134 TI - Clinical reliability of IgG, IgA, and IgM antibodies in detecting Epstein-Barr virus at different stages of infection with a commercial nonrecombinant polyantigenic ELISA. AB - We studied the diagnostic reliability of a modification of the Enzygnost EBV test (Behringwerke, Germany) for the detection of IgG, IgA, and IgM antibodies (Abs) in the diagnosis of Epstein-Barr virus (EBV) disease. One hundred and twenty three serum samples were studied: 14 asymptomatic subjects without EBV infection, 48 patients with primary infection, 46 subjects with past EBV infection (11 patients with other acute infections), 8 patients without EBV infection but with other viral infection, and 7 patients with probable acute clonal stimulation of B lymphocytes caused by different microorganisms. Enzygnost EBV is based on an ELISA test with a pool of viral antigens. In our series the reliability of IgM for the diagnosis of recent primary EBV infection was: sensitivity 100%, specificity 95%, positive predictive value 90.5%, and negative predictive value 100%. The IgG detection with Enzygnost was: sensitivity 98%, specificity 100%, positive predictive value 100%, and negative predictive value 91.7%. Only two subjects had positive IgA. The Enzygnost test is an efficient method for the diagnosis of EBV infection although a few IgM false positives can occur. PMID- 10102135 TI - Amplification of human genomic DNA sequences with polymerase chain reaction using a single oligonucleotide primer. AB - We present two examples of exponential nucleic acid amplification with the polymerase chain reaction (PCR) in the presence of only one amplification primer. Cloning and sequencing of the PCR products generated by amplification of human genomic DNA revealed that the amplified sequence contained only one primer and its complement, at the two ends of the PCR product. Although these experiments were performed with primers derived from the sequence of the prostate specific antigen (PSA) gene and the normal epithelial cell-specific 1 gene (NES1), the amplified sequences were novel and had no homology with either PSA or NES1 DNA. While both PSA and NES1 genes reside on chromosome 19q13.3-q13.4, the amplified sequences were found by mapping to reside on chromosome 5q12 and 5p15.1-p15.3, respectively. When we examined the mechanism of amplification by PCR using one primer in these two cases, we found that there was a high homology between the PSA primer or the NES1 primer and the two regions flanking the amplified sequence of chromosome 5q12 or 5p15. This indicated that the single PSA or NES1 primer could anneal on both strands of the DNA of that region, and mediate the exponential amplification. Since this phenomenon occurred to us twice with a limited number of different PCR reactions performed in our laboratory (< 20), we believe that it may represent a common artifact of PCR. Moreover, it appears that the palindromic primer binding sites can anneal to each other forming DNA cruciforms. PMID- 10102136 TI - Prostate specific antigen molecular forms in breast cyst fluid and serum of women with fibrocystic breast disease. AB - We have analyzed matched serum and breast cyst fluid samples for total PSA from 148 patients with fibrocystic breast disease. We have also determined the molecular forms of PSA (free PSA and PSA bound to alpha1-antichymotrypsin) in 78 breast cyst fluid samples. We found that total PSA can be detected in all cyst fluids and in about 75% of female sera. The median total PSA concentration in breast cyst fluid (bcf) is about 30 times higher than the median in the corresponding sera. Breast cyst fluid and serum PSA are not correlated with each other. Total serum PSA is inversely associated with patient age but the inverse association between bcf PSA and age is weak. Lower total PSA in bcf was seen in women who breast feed, and higher bcf PSA is associated with multiple cysts. Type I cysts (with a high K+/ Na+ ratio) tend to have higher total PSA than Type II cysts. All but three of the fractionated cyst fluids (75/78; 96%) had free PSA as the predominant molecular form. The most consistent finding of our study was the positive association between the cyst fluid K+/Na+ ratio and the free to bound PSA ratio. This association was confirmed by Spearman correlation as well as by Wilcoxon and chi-square analysis. Secretory/apocrine cysts (Type I) tend to have more total PSA and proportionally more free PSA than transudative/flattened cysts (Type II). PMID- 10102137 TI - Comparison of radial immunodiffusion and alkaline cellulose acetate electrophoresis for quantitating elevated levels of fetal hemoglobin (HbF): application to evaluating patients with sickle cell disease treated with hydroxyurea. AB - Radial immunodiffusion (RID), alkaline cellulose acetate electrophoresis, and high-performance liquid chromatography (HPLC) were compared for quantitating the elevated (> 10%) level of fetal hemoglobin (HbF) found in the red blood cells of sickle cell disease patients undergoing treatment with hydroxyurea. HPLC- and electrophoresis-determined values were comparable. The RID-determined values were higher, in many cases twofold higher. False high HbF values would be misleading in assessing the effectiveness of hydroxyurea therapy in sickle cell disease patients. We subsequently initiated an examination of the variation in HbF values due to the use of different HbF radial immunodiffusion QUIPlates and different positions within a single plate in an attempt to determine the cause of these discrepancies. Within-run precision studies indicated that significantly different size precipitin rings were obtained depending upon which area of the plate the hemolysate containing antigen (HbF) was applied. A common feature associated with poor precision plates was a marked difference in degree of coloration of gel throughout the plate. Spuriously high HF concentrations were obtained with antigen (HbF) placed in wells located in the lighter colored gel area while antigen placed in wells in the darker colored area of the agarose gel bed were more in agreement with the electrophoretically determined HbF concentrations. The variation in HbF values was significantly greater in the diluted (HbF QUIPlate Diluent) samples than in the neat samples even on plates of uniform gel coloration. As a result of this study, we will continue to monitor high HbF levels by densitometry following alkaline cellulose acetate electrophoresis. PMID- 10102138 TI - Measurement of adenylate cyclase activity in the minute bovine ciliary epithelial cells during the pharmacological stimulation of adrenergic and cholinergic receptors. AB - Although essential to the secretion of aqueous humor, little is known about the signal transduction underlying postreceptor adrenergic and cholinergic processes in the ciliary epithelium. We adopted a highly sensitive fluorometric assay technique in order to examine adenylate cyclase activity in minute membrane preparations made from the bovine ciliary epithelial cells. The protein concentration of the preparation was 3-5 mg/ ml. Norepinephrine (10(-7), 10(-6) and 10(-5) M) and carbachol (10(-7) and 10(-5) M) were incubated with 10 microl of membrane preparation to analyze the extent of the receptor-coupled influences on the adenylate cyclase activity. Meanwhile, forskolin (10(-5) M) was used to estimate the maximum adenylate cyclase activity. After the initial enzymatic destruction of noncyclic adenine nucleotides and phosphorylated metabolites, the diester linkage of cyclic AMP was cleaved and then converted to ATP. The ATP was enzymatically amplified to about 10,000 times of fructose-6-phosphate. The NADPH, formed when the fructose-6-phosphate was converted to 6-phosphogluconolactone, was measured fluorometrically. Basal and forskolin-stimulated maximum adenylate cyclase activities (pmol/mg protein/min) were 29.6+/-7.6 and 86.6+/-7.2 (mean+/ SE), respectively. Norepinephrine increased the adenylate cyclase activity in a dose-dependent manner, while carbachol hardly affected the activity. These results indicate that the adenylate cyclase activity can be measured in the minute ciliary epithelial cells and, moreover, that the current assay can be applied to assess the efficacy of newly available ophthalmic solutions or systemic drugs influencing adenylate cyclase activity in a discrete portion in the eye. PMID- 10102139 TI - The measurement of paediatric pain. PMID- 10102140 TI - Eating disorders in young women with type 1 diabetes: a cause for concern? PMID- 10102141 TI - Minimum time intervals for serial measurements of growth in recumbent length or stature of individual children. AB - A method is presented to estimate minimum time intervals for meaningful measurements of growth in recumbent length or stature on individual children. These intervals are based on the statistical features of growth, and consider the reliability of measurement, expected rates of growth, and variation in attained length or stature. Because of the assumptions used, the intervals should be considered as minima, except in some predictable cases. During the prepubescent period there are no differences in minimum intervals calculated for boys and girls. The intervals are shortest during the rapid growth attending infancy, and increase to 0.39 y (4.7 mo) at 8 y of age in boys and girls, and to 0.43 y (5.2 mo) at 10 y of age in boys. A reference curve of minimum intervals for length and stature during the prepubescent period is presented with an equation for more precise estimation of measurement intervals. To accommodate the pubescent growth spurt and its normal variation in timing, 0.5 y is recommended as the minimum interval during pubescence when the maturational timing of the child is unknown. These minimum measurement intervals should be appropriate for almost all individual children when growth in recumbent length or stature is measured serially. PMID- 10102142 TI - Composition of long chain polyunsaturated fatty acids in human milk and growth of young infants in rural areas of northern China. AB - The main source of fat in the diet in rural areas of northern China is soybean oil, therefore the pattern of essential fatty acids in human milk may be assumed to differ from that in milk from women in Western countries and to be similar to that of vegans. The concentrations of long chain polyunsaturated fatty acids in human milk and information on diet were analysed for 41 lactating women in rural areas of north China, and the growth of their infants was measured. The subjects were divided into two groups (group I, 1 mo postpartum; group II, 3 mo postpartum). The dietary intake of the mothers was high in carbohydrate and low in fat, protein and energy. The concentrations of linoleic acid (LA) and alpha linolenic acid (LNA) were high. The ratio of LA to LNA, (21.6), was higher than has been reported from other countries. The concentration of docosa-hexaenoic acid (DHA) was low and the ratio of arachidonic acid (AA) to DHA was much higher (2.8) than recommended and similar to that found in vegans. The concentrations of AA and DHA in the milk correlated positively with the infants' weight gain at the third month (p<0.05) and of DHA with length gain at the first and third months (p<0.01). Since the concentration of AA and, particularly, DHA in the milk declined during lactation, DHA deficiency may appear after 3-4 mo of age in breastfed Chinese rural infants. Further studies of Chinese rural mother-infant pairs are necessary to prove whether supplementation with suitable sources of AA and DHA, such as fish oil, should be recommended as lactation is lengthened to ensure optimal infant growth and development. PMID- 10102143 TI - A Danish adaptation of the Pain Coping Questionnaire for children: preliminary data concerning reliability and validity. AB - The aim of this study was to determine the reliability and validity of a Danish translation of the Pain Coping Questionnaire (PCQ) for children in Danish children. The PCQ was translated using a translation-back-translation method. The subjects were 352 healthy children and 40 children with juvenile arthritis (JA), aged 8-17 y. Sixteen of the JA children were divided into a high-pain group (n = 7) and a low-pain group (n = 9). The results were factor analysed using principal component analysis with varimax rotation. Clinical pain intensity was measured using visual analogue scales (VAS) from the Varni/Thompson Pediatric Pain Questionnaire. Experimental pain was induced using a cold pressor pain paradigm and outcome measures were pain intensity, pain discomfort and tolerance to cold pressor pain. A seven-factor solution emerged as the most consistent factor structure. Four subscales, Seeking Social Support (SSS), Cognitive Distraction (CD), Externalizing (EXT) and Internalizing/Catastrophizing (INT), corresponded with the parallel subscales proposed by Reid et al. (Pain 1998; 76: 83-96). Two subscales, Positive Self-Statements (PSS) and Behavioral Distraction (BD), were composed of four of the five items from the previously proposed subscales. One subscale, Information Seeking/Problem Solving (IP), consisted of items from two subscales proposed by Reid et al., i.e. Information Seeking and Problem Solving. Internal consistencies of the subscales were acceptable, with reliability coefficients ranging from 0.60 (BD) to 0.83 (IP) and with test-retest reliabilities between 0.59 and 0.78. Low-pain JA patients showed significantly higher levels of BD than High-pain JA patients (p<0.05). Greater utilization of PSS and BD was associated with less patient-reported present pain and less average everyday pain (p<0.05-0.01), and greater utilization of INT was significantly associated with higher experimental pain intensity (p<0.01). These preliminary findings provide support for the reliability and validity of the Danish modification of the PCQ in a Danish population and for the hypothesis that paediatric pain-coping strategies are associated with the intensity of clinical and experimental pain. PMID- 10102144 TI - Bone growth from 11 to 17 years: relationship to growth, gender and changes with pubertal status including timing of menarche. AB - The tempo and change in bone growth during puberty in relation to physical growth is described in a cohort of 56 boys and 52 girls. Distal forearm bone width, mineral content and volumetric density, anthropometry and pubertal status were measured at ages 11, 13, 15 and 17 y, and bone age at 17 y. Bone width and mineral content increased independently with age for each pubertal stage. Volumetric density fell during early puberty and then increased rapidly. Maximal increase of all bone variables occurred earlier in girls than in boys and earliest for bone width, then mineral content, then density. In girls most change occurred in the 12 mo before and after menarche. The degree of tracking was similar to that for height. Bone growth followed physical growth but at a slower tempo. By age 17 y boys had attained 86% of the reference adult bone mineral content and volumetric density; girls had attained 93% of the reference adult bone mineral content and 94% of volumetric density. Those skeletally mature at 17 y had greater mineral content and volumetric density. To maximize peak bone mass, modifiable environmental factors should be optimized before the onset of puberty and be maintained throughout this period of rapid growth and beyond attainment of sexual maturity. PMID- 10102145 TI - Gender differences in respiratory, nasal and skin symptoms: 6-7 versus 13-14-year old children. AB - ISAAC questionnaires were completed by the parents of 6432 children, aged 6-7 y and by themselves by 2864 children 13-14-y-old. Prevalence rates of respiratory and nasal symptoms and a diagnosis of asthma and hay fever were higher in 6-7-y old boys than in girls, while girls aged 13-14 y had higher rates for most symptoms, except asthma. Underdiagnosis of asthma in 13-14-y-old girls cannot be excluded as an explanation, but our data suggest under-reporting of respiratory and nasal symptoms in 13-14-y-old boys. PMID- 10102146 TI - Free secretory component as a standardization protein for nasopharyngeal specimens from children with upper respiratory tract infection. AB - Free secretory component (FSC) has been recommended as a reliable protein for correction of the unknown dilution in tracheal aspirate samples from preterm infants. To investigate whether FSC would also provide a valid standardization protein for samples of nasopharyngeal secretions, this study determined the intersubject variation and the alteration over time in the concentrations of FSC in nasal secretions from 35 children (median age 14 months) who participated in an antibiotic efficacy trial. Nasopharyngeal aspirates were obtained at enrolment and after 2-3 d. FSC in the specimens was quantified by a direct enzyme immunoassay. The concentrations of FSC in the nasal secretions ranged from 0.08 to 189.6 microg ml(-1) (median 12.3 microg ml(-1); the ratio of the highest to the lowest concentrations was 2370, the difference between the 90th and 10th percentile concentrations was 189-fold and the difference between the 75th and 25th percentile values was 26. FSC concentrations were significantly lower in children aged < or =12 months (median 2.2 microg ml(-1) than in the older children (median 21.5 microg ml(-1); p = 0.035). Between the first and the follow up specimens, 65% of the children had > or =2-fold difference in the levels of FSC in the secretions. Because an optimal standardization protein should show minimal variation between individuals and over time, FSC may not be a suitable protein for correction of the unknown dilution of nasopharyngeal specimens from children with upper respiratory tract infection. PMID- 10102147 TI - Double-blind, randomized, controlled trial of zinc or vitamin A supplementation in young children with acute diarrhoea. AB - In a double-blind, controlled trial with a factorial design, 684 patients (aged 6 months to 2 y; excludes 6 early dropouts) with acute watery diarrhoea of 3 d or less and some dehydration, who were attending a hospital, were randomly assigned to 4 groups to receive: (a) vitamin A 4500 microg retinol equivalent daily for 15 d; (b) 14.2 mg elemental zinc as acetate for the first 417 patients and 40 mg of the remaining 273 patients randomized to this group for 15 d; (c) both vitamin A 4500 microg retinol equivalent and zinc at the above doses daily for 15 d; or (d) placebo mixtures for 15 d. Patients were observed in the hospital for 24 h and followed up at home for 15 d. All received ascorbic acid 30 mg with each dose of medicine or placebo. Zinc supplementation was associated with a reduced duration of diarrhoea (13%, p = 0.03) and markedly reduced rate (43%, p = 0.017) of prolonged diarrhoea (>7 d). Vitamin A supplementation was associated with a nonsignificant trend for reduced rate of prolonged diarrhoea (p = 0.089). In conclusion, zinc supplementation as adjunct therapy had a substantial impact on the rate of prolonged diarrhoea and some impact on duration and may be beneficial in children with diarrhoea in developing countries. PMID- 10102148 TI - Killed oral Shigella vaccine made from Shigella flexneri 2a protects against challenge in the rabbit model of shigellosis. AB - The protective efficacy of an orally administered heat-killed virulent strain of Shigella flexneri 2a (5 weekly oral doses) was evaluated in 25 rabbits (14 immunized and 11 non-immunized controls) against challenge with the same strain of Shigella using the rabbit model of shigellosis. All 11 non-immunized rabbits developed bloody diarrhoea following challenge and 6 (54%) died. None of the 14 immunized rabbits developed diarrhoea (all had pellet stools) but 3 (21%) died from causes not associated with diarrhoea. Protection from diarrhoea and dysentery following oral immunization with a killed Shigella species was 100% and highly significant. Death following challenge was 2.5-fold higher in the non immunized group (p = 0.115) but was not significant. These promising results suggest that further studies should be undertaken to develop a killed oral vaccine against shigellosis. PMID- 10102149 TI - Helicobacter pylori gastritis in children: efficacy of 2 weeks of treatment with clarithromycin, amoxicillin and omeprazole. AB - Thirty-eight children with Helicobacter pylori gastritis diagnosed by histopathology, and/or bacteriological culture were treated with omeprazole, amoxicillin and clarithromycin. Follow-up endoscopy was performed in 34 children. Outcome was measured by negative histology and culture for H. pylori. Six patients were excluded. Of the 32 remaining children eradication was achieved in 75% (95% confidence interval 60-90%). PMID- 10102150 TI - Secular changes in anthropometric data in cystic fibrosis patients. AB - The aim of this study was to study the secular changes in anthropometric data over calendar time in patients with cystic fibrosis (CF). Growth curves were constructed for 270 patients based on height and weight registrations from the medical files. Height, body mass index (BMI), magnitude of pubertal peak height velocity (PHV) and age at PHV were analysed for possible secular changes from the 1960s to the 1990s. There was a significant change in height over calendar time in only 1 of 12 age groups. BMI showed a significant increase in 10- and 15-y-old boys and girls and in 5-y-old girls. The magnitude of PHV changed significantly over time, whereas age at PHV was constant. No significant changes in height and age at PHV over calendar time were observed; this was probably due to a selection bias since the oldest patients, who survived to be part of the present investigation, represented milder forms of the disease. The increase in BMI and change in magnitude of PHV over calendar time may reflect the improvement in treatment leading to a better survival and clinical status through puberty. The increase in BMI and change in magnitude of PHV were sufficient to overcome the selection bias from older patients with milder disease. PMID- 10102152 TI - Growth parameters in children with retinoblastoma. AB - The purpose of this study was to compare growth parameters of retinoblastoma patients with siblings and the normal Dutch population. Height, weight, head circumference and sitting height were measured in 67 patients and 63 controls. Target height was calculated based on the parental height of retinoblastoma patients. Standard deviation scores and population-based percentiles were calculated and used for statistical analysis. Retinoblastoma patients had larger head circumferences than the Dutch population and their siblings, and their weight was also higher than the Dutch population. Height and target height showed no differences from the Dutch population. Retinoblastoma patients had a greater sitting height than the Dutch population. Sample numbers were too small to reach statistical significance when comparing the sitting height of retinoblastoma patients with their siblings. No obvious explanations are available for these differences. PMID- 10102151 TI - Eating disorders in adolescent girls with insulin-dependent diabetes mellitus: a population-based case-control study. AB - In this study the prevalence of eating disorders in a population-based cohort of 89 female patients with type 1 diabetes, 14-18 y of age, was compared with that in age-matched healthy controls. Of all diabetic girls in the study area, 92% participated in the study. The majority were treated with multiple insulin injections and the mean HbA1c of the participants was 8.4%. On average, diabetic girls were 6.8 kg heavier than the controls. A two-stage design was used. The first consisted of a validated self-report questionnaire, the Eating Disorder Inventory (EDI). Girls who had high scores were then interviewed about eating habits and mental health using a semistructured interview, the BAB-T (Assessment of Anorexia-Bulimia - Teenager version). No cases of anorexia or bulimia nervosa were found, but 15 diabetic patients (16.9%) compared with 2 control girls (2.2%), p<0.01, had disturbed eating behaviour according to the questionnaire. In 6 of these 15 diabetic girls an eating disorder was confirmed at the interview, mainly binge eating and self-induced vomiting. None of the control girls showed an eating disorder. Overweight diabetic girls scored higher on EDI than non overweight diabetic girls (chi2 = 4.9; p = 0.038). No relationships were found between EDI scores and metabolic control (HbA1c), dose of insulin, frequency of hypoglycaemia or diabetic ketoacidosis. PMID- 10102153 TI - Myocardial function after autologous bone marrow transplantation in children: a prospective long-term study. AB - Early cardiac complications after autologous bone marrow transplantation (ABMT) were recorded for 49 children with haematological malignancies. There was no procedure-related mortality and only two cases of early post-transplant cardiac complications of clinical relevance, both of which were reversible. For 35 long time survivors (median follow-up 7 y) serial evaluations before and after ABMT included ECG, chest radiography, echocardiography and equilibrium radionuclide ventriculography (RVG). One patient had frequent supraventricular ectopic beats after ABMT, a finding not previously noted. The mean left ventricular diastolic diameter (LVDD) was 104% of expected before ABMT (95% confidence interval 99 110). During the first year post-transplant LVDD was about 110% of expected, but thereafter normalization occurred. The mean shortening fraction before ABMT was 31% (CI 29-34), compared with the mean value of 34% for healthy children in our laboratory, and it ranged between 29% and 33% during the follow-up period. Mean left ventricular ejection fraction determined by RVG was 65% (CI 61-69) and mean right ventricular ejection fraction was 46% (CI 43-49) before ABMT, and they did not change during follow-up. It is encouraging that these heavily pre-treated children could be autografted without serious cardiac complications or deterioration in myocardial performance in a 5-10-y prospect, but longer follow up is needed for a final evaluation. PMID- 10102154 TI - Assessment of terminal ileal and colonic inflammation in Crohn's disease with 99mTc-WBC. AB - We evaluated the sensitivity and specificity of Technetium-99m (99mTc)-white blood cell (WBC) for identifying terminal ileum inflammation in children with Crohn's disease (CD). In 40 children, total colonoscopy was done within a few days of a 99mTc-WBC scan carried out to evaluate the inflammation in children with CD. In 38 patients the intensity and the location of inflammation shown on the 99mTc-WBC scan of the colon were similar to the biopsy result of the colonoscopy. The sensitivity of the 99mTc-WBC scan was 97% in assessing colonic inflammation compared with colonoscopy. The 99mTc-WBC scan allowed evaluation of inflammation in the terminal ileum in 21 patients in whom the endoscopist did not cannulate the terminal ileum. Of the 19 patients in whom the terminal ileum was visualized endoscopically (14) or surgically (5), the 99mTc-WBC scan findings showed a similar degree of inflammation in 17. The 99mTc-WBC scan was abnormal in 10 of these 21 children in whom the gastroenterologist did not reach the terminal ileum. In these children with no ileoscopy the results of the 99mTc-WBC scan were consistent with the laboratory values, the gastroenterologist's clinical assessment and with long-term clinical follow-up. Finally, the 99mTc-WBC scan of 83 controls did not reveal any false-positive findings in the terminal ileum (colonoscopy result available in 30 controls). When total colonoscopy or ileoscopy is not performed or when contrast radiography is negative or unable to differentiate CD from lymphoid nodular hyperplasia, scintigraphy can demonstrate the presence of ileitis and/or colitis. PMID- 10102155 TI - A prospective audit of paediatric colonoscopy under general anaesthesia. AB - Colonoscopy in children is frequently performed using intravenous sedation. Traditionally, there have been few advocates of general anaesthesia and some have regarded colonoscopy conducted in this way as potentially more hazardous. The aim of this study was to undertake a prospective audit of paediatric colonoscopy carried out under general anaesthesia. The details of all children referred for colonoscopy during a 3.5-y period were collected prospectively and the safety and efficacy of performing colonoscopy under general anaesthesia were analysed. A total of 250 colonoscopies was performed in 215 children of median age 10.7 y (range 5 months to 16 y) and ileoscopy was carried out in 164 of these cases. An increasing proportion of patients was investigated as day-cases, including most of the 56 who had additional procedures carried out under the same anaesthetic. There were no complications from the colonoscopy (including the 18 patients who underwent polypectomy). Only one procedure-related complication occurred and this was avoidable. These results confirm the safety of paediatric colonoscopy under general anaesthesia and demonstrate the advantages and feasibility of such an approach. PMID- 10102156 TI - Breastfeeding patterns in exclusively breastfed infants: a longitudinal prospective study in Uppsala, Sweden. AB - Exclusive breastfeeding was studied among 506 infants in Uppsala, Sweden, based on daily recordings during the first 6 mo. The mothers had previously breastfed at least one infant for at least 4 mo. Most of the mothers considered that they breastfed on demand. Wide variations in breastfeeding frequency and suckling duration were found both between different infants and in the individual infant over time. At 2 wk, the mean frequency of daytime feeds (based on one 13-d record) between different infants ranged from 2.9 to 10.8 and night-time feeds from 1.0 to 5.1. The daytime suckling duration (based on one 24-h record) ranged from 20 min to 4h 35 min and night-time duration from 0 to 2h 8 min. At any given age, a maximum of only 2% of the infants were not breastfed during the night. At 4 mo, 95% of the infants were breastfeeding and 40% were exclusively breastfed at this age. Longer breastfeeding duration and longer duration of exclusive breastfeeding were both associated with higher frequency of breastfeeds, longer breastfeeding of the previous child and higher education. No gender differences were found. Maternal smoking was associated with shorter duration of exclusive breastfeeding, and pacifier use was associated with shorter duration of both exclusive breastfeeding and total breastfeeding. This study confirms that every mother-infant pair needs to be understood as a unique dyad throughout lactation. These data demonstrate a wide range of patterns among women who are exclusively breastfeeding and indicate that it would be inappropriate to put pressure on individual families to adopt preconceived patterns of infant feeding. PMID- 10102157 TI - Congenital hypothyroidism, seasonality and consanguinity in the West Midlands, England. AB - Seasonal variation in the incidence of congenital hypothyroidism (CHT) is reported by some centres. Also, the incidence of CHT varies with ethnic origin. We report our experience in the West Midlands, England. The overall incidence of CHT among 1128 632 neonates screened over 16 years in the West Midlands was 1:2924 live births, but was increased (1:2323; p<0.05) between October and December. In the city of Birmingham between 1981 and 1991, the incidence of CHT was 1:781, 1:5540 and 1:2257 in Pakistani, Indian and North-West European children, respectively; no cases were seen in those from other ethnic groups. Consanguinity among those of Pakistani descent could account for the increased incidence within this population. Identification of the cause of seasonal variation may aid development of preventative strategies. PMID- 10102158 TI - High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice. AB - A controlled study was conducted to assess the role of high-dose i.v. immunoglobulin (HDIVIG) therapy in neonatal immune haemolytic jaundice. Patients with ABO and/or Rh incompatibilities proved by significant hyperbilirubinaemia (>204 mmol l(-1)), positive direct antiglobulin test and high reticulocyte count (> or =10%) were randomly assigned to receive either conventional phototherapy alone or phototherapy with high-dose i.v. immunoglobulin (1 g kg(-1), over 4 h) as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded 290 mmol l(-1) and increased by more than 17 mmol l(-1) per h despite both treatment manoeuvres. Eight of 58 patients in the HDIVIG group required exchange transfusions, whereas it became necessary in 22 of 58 patients in the control group (p<0.001). The durations of phototherapy and hospitalization in terms of hours were significantly shorter in the HDIVIG group (p<0.05). No side effects of HDIVIG therapy were observed. In conclusion, HDIVIG therapy in newborns with ABO or Rh haemolytic diseases reduces haemolysis, serum bilirubin levels and the need for blood exchange transfusion, a procedure which has potential complications and carries a risk of mortality. PMID- 10102160 TI - Fucosidosis: immunological studies and chronological neuroradiological changes. AB - A 3.5-y-old boy of Arabic origin had the clinical features of both type 1 and type 2 fucosidosis, consistent with an intermediate form of the disease. The activity of his leucocyte alpha L-fucosidase was absent. He presented with recurrent sinopulmonary infection and otitis media in addition to paronychia and a periapical dental abscess. Investigation of his systemic immune function did not reveal a significant underlying defect, but subtle abnormalities, particularly of antibody production and secretory IgA, cannot be excluded. The cranial magnetic resonance images showed periventricular and subcortical white matter abnormalities and mild cortical atrophy in addition to globus pallidus changes. PMID- 10102159 TI - Confidential enquiry into deaths due to prematurity. AB - The aim of this study was to audit the management of neonatal respiratory distress syndrome (RDS) in a geographically defined population using a retrospective peer review of case notes. The subjects were 49 infants of 24-36 wk gestation with a birthweight >499 g, and dying as a consequence of prematurity at <1 y of age in Wales during 1996. Forty-four infants (90%) were delivered in a unit with staff experienced in the management of preterm birth. Of the 30 infants <30 weeks' gestation, 29 (97%) received neonatal intensive care on a (sub)regional unit. Predelivery corticosteroids were indicated in 34 cases and administered in 31 (91%). Resuscitation at birth was indicated in 47 infants and conducted satisfactorily in 42 (89%). Temperature on admission to the neonatal unit was not recorded in 7 infants; in the other 42 it was >35.5 degrees C in 21 (50%). Early surfactant therapy was administered to 31/34 (91%) infants still intubated 120 min after birth, but was given within 30 min to only 8 (24%). Mechanical ventilation was assessed in 41 infants and considered to be good in 23 (56%). Cardiovascular therapy was evaluated in 40 infants requiring active support and considered to be good in 31 (78%). We concluded that neonatal RDS was generally well managed, thermal care during resuscitation was poor, surfactant should be administered more promptly, and deficiencies in the management of ventilation were common and related mainly to poor anticipation and a slow response to problems. PMID- 10102161 TI - Italian guidelines for antiretroviral therapy in children with human immunodeficiency virus-type 1 infection. Italian Register for HIV Infection in Children. AB - Human immunodeficiency virus-type 1 (HIV-1) infection and its treatment are peculiar in children. Adherence and compliance must be carefully taken into account before initiating or changing therapy and in the choice of drugs. Even in the absence of paediatric-specific trial results and notwithstanding drug labelling notations, all antiretroviral drugs should be used when indicated. A combined therapy is compulsory. Therapy is highly recommended in category C or category 3 and recommended in category B children. Indications in categories N1, N2, A1 or A2 are limited. A triple association is recommended in category C or category 3 children or in those with a high viral load, when compliance is guaranteed. A step-down strategy is not advisable. Infants' treatment should be inserted into controlled studies. Therapy should be changed when serious side effects or poor tolerance (choose drugs with a different toxicity and greater tolerance), poor compliance (individualize the motives) or treatment failure (evaluate progression and adherence) occurs. PMID- 10102162 TI - Is it necessary to perform an endoscopy after the ingestion of liquid household bleach in children? PMID- 10102163 TI - "De-Nol test" for rapid diagnosis of Helicobacter pylori in childhood. PMID- 10102164 TI - Sarcoidosis in children. PMID- 10102165 TI - Methaemoglobinaemia in a premature infant secondary to prilocaine. PMID- 10102166 TI - Animal models of preeclampsia. AB - Some of the maternal symptoms of preeclampsia can be produced by uterine ischemia, although no quadriped spontaneously exhibits this disease. It may be that the combination of upright posture and uteroplacental ischemia are necessary for manifestation of the full syndrome. Chronic nitric oxide synthase inhibition in rats produces a pattern of change that resembles the symptoms of preeclampsia, and the preeclamptic-like response of rats with adriamycin nephropathy and hyperinsulinemia is associated with endothelial dysfunction. These models are definitely of use in preeclampsia research, but because this disease only occurs spontaneously in primates, the definitive studies on preeclampsia will, of necessity, be clinical. PMID- 10102167 TI - New insights into the genetics of preeclampsia. AB - Preeclampsia is familial. Pedigree analyses suggest that one or more common alleles may act as "preeclampsia susceptibility genes." The authors speculate that genes involved in blood pressure control, volume regulation, placental health, vascular disease, and vascular remodeling, underlie familial susceptibility to preeclampsia. Several candidate genes have been examined. These data suggest that a common mutation in the angiotensinogen promoter, A(-6), leads to elevated expression of this gene and pleiotropic effects, including abnormal spiral artery remodeling and failed hypervolemia of pregnancy. The factor V Leiden mutation, which predisposes women to thromboembolic disorders during pregnancy, has been implicated as another preeclampsia susceptibility gene. New insights into the genetics of preeclampsia will contribute to the understanding of this disease and should ultimately lead to improved diagnosis and treatment. PMID- 10102168 TI - The immunology of preeclampsia. AB - The immune maladaptation hypothesis of preeclampsia is concordant with cytokine mediated oxidative stress, chronology of endothelial activation, lipid changes, adverse effect of changing partners, and the protective effect of sperm exposure. Genetic factors may involve underlying hereditary thrombophilic disorders and hyperhomocysteinemia, essential hypertension and/or obesity, or control of the Th1/Th2 balance and thus affect the maternal response against fetal antigens. Placental ischemia and increased syncytiotrophoblast deportation are probably end stage disease phenomena. PMID- 10102169 TI - Vascular reactivity in preeclampsia. AB - It has long been known that vascular reactivity is altered in preeclamptic patients compared with normal pregnant women. This change even occurs weeks earlier than any clinical manifestation of the disease. Many investigators believe that the conditions for the development of preeclampsia are set as early as the first trimester. These changes in vascular reactivity appear to be independent of the blood pressure because they also occur in chronic hypertensive women destined to have preeclampsia. This review focuses on these changes in vascular reactivity reported in preeclampsia. Increased reactivity of the blood vessels in preeclampsia has been described in most, but not all, studies. The cause for the differences in reactivity between vessels from preeclamptic and normal pregnant women is not known. However, it cannot be attributed solely and with certainty to abnormalities in endothelium-dependent relaxation or the nitric oxide system because the study results published to date remain contradictory. In addition to functional differences, vessels from normal pregnant and preeclamptic women show distinct mechanical properties. PMID- 10102170 TI - Prediction of preeclampsia. AB - The onset of preeclampsia at or near to term is associated with low maternal and neonatal morbidity and mortality. In contrast, those patients (1%) who suffer early onset preeclampsia engender significant maternal and perinatal morbidity and mortality. Therefore, because of the lack of proven prophylaxis for preeclampsia, prediction of risk or identification of subclinical disease is desirable to identify patients for more intensive observation. There are certain at-risk groups of patients such as those with chronic hypertension, pregestational diabetes, multifetal gestation, and previous preeclampsia. These patients account for the majority of cases of preeclampsia in multiparas, yet only account for 14% of preeclampsia in nulliparous women. Thus, the majority of cases of preeclampsia arises from nulliparous women without medical complications at low risk. Differences in the time of onset, severity, and organ system involvement suggest there may be different underlying etiologies that ultimately lead to preeclampsia manifested as the triad of maternal hypertension, proteinuria, and edema. Distinct markers therefore may identify subgroups of at risk patients with separate underlying causes. These markers ultimately could be used for diagnosis of disease before the clinical appearance of maternal disease (hypertension, proteinuria, and edema). Based on data from patients with established disease, with the involvement of various organ systems, potential candidate markers would include renal function (kallikrein-creatinine); coagulation and fibrinolytic systems and platelet activation (platelet volume); markers of vascular function (fibronectin, prostacyclin, thromboxane) and oxidant stress (lipid peroxides, 8-isoprostane, antioxidants, anticardiolipin antibodies, hemoglobin, iron, transferrin, homocysteine, hypertriglyceridemia, albumin isoforms); placental peptide hormones (CRH, CRHbp, activin, inhibin, hCG); vascular resistance (uteroplacental flow velocity waveforms); genetic markers; insulin resistance; and glucose intolerance. Although cross-sectional studies have identified these potential markers, they need to be evaluated in prospective longitudinal studies with rigorous definition of outcome to determine if they are useful in predicting preeclampsia and whether they can identify different subgroups of patients. PMID- 10102171 TI - Prevention of preeclampsia. AB - Preeclampsia is a multisystem disorder of unknown cause. Efforts to prevent the disease or reduce its incidence have utilized pharmacological intervention as well as dietary supplementation. Recent, large, randomized trials have not shown a benefit from the use of aspirin. Calcium supplementation has also been studied extensively and found to be similarly ineffective in reducing the incidence or severity of preeclampsia in healthy women. The studies regarding the use of magnesium, zinc, and fish oils for the prevention of preeclampsia are fewer in number, but have also found minimal to no benefit. In the same respect, numerous randomized trials have been performed using antihypertensive agents, diuretics, and low-salt diet. Results of these studies have not shown any beneficial effect. Prevention of preeclampsia is unlikely as long as the underlying origin remains unknown. PMID- 10102172 TI - Prevention of eclampsia. AB - Eclampsia continues to be a major cause of maternal morbidity and mortality rates, especially in underdeveloped nations. Our data indicate that eclampsia may represent the end stage of at least two very different pathophysiological pathways: one in which cerebral perfusion is low because of vasospasm and another in which cerebral perfusion is increased because of abnormal autoregulation and a failure of the normal protective mechanisms. Magnesium sulfate has been extensively used in the management and prevention of eclamptic seizures in the United States and has been recently shown to be superior to both diphenylhydantoin and diazepam. We have shown that magnesium sulfate is a potent vasorelaxant and that its action may depend on improving cerebral perfusion. Nimodipine, a calcium channel blocker with selective cerebrovascular effect, is currently under investigation in severe preeclampsia. The data show that it is as effective as magnesium sulfate in preventing eclampsia, with less maternal and fetal side effects. Magnesium sulfate and nimodipine have opposite effects on the estimated cerebral perfusion pressure as determined with the Doppler ultrasound. We speculate that the estimated cerebral perfusion pressure may be used to determine the type of cerebrovascular abnormality and the most appropriate treatment in each individual patient with preeclampsia. PMID- 10102173 TI - Management of complicated preeclampsia. AB - The complicated preeclamptic patient represents a challenge for the clinician faced with her antepartum or postpartum care. The most serious sequelae of preeclampsia account for a significant portion of maternal morbidity and mortality. Severe preeclampsia also results in an appreciable portion of perinatal morbidity and mortality. In this review, developing trends in the treatment of severe preeclampsia are discussed. Expectant treatment of the patient remote from term, anesthesia choices, and delivery route are reviewed. Developing trends in the pharmacological approach to complicated preeclampsia are discussed. New concepts in the treatment of cerebrovascular preeclampsia and hepatic rupture are outlined and reviewed. PMID- 10102174 TI - Counseling for women with preeclampsia or eclampsia. AB - Preconception counseling may address issues such as nutrition, prevention and prediction of preeclampsia, utility of prenatal visits and fetal surveillance, risk of superimposed preeclampsia, recurrence risks for future gestation, diagnosis of underlying predisposing factors, and potential impact on future maternal and fetal health. Although certainty is lacking in medicine, it appears that minimal risk to either mother or fetus is attributable to mild chronic hypertension complicating pregnancy. Increased maternal and fetal morbidity is associated with superimposed preeclampsia. Unfortunately, we are unable to predict which of these gravidas will have superimposed preeclampsia and thus suffer added morbidity. There appears to be a greater than 50% chance of maternal or fetal morbidity for those women entering pregnancy with severe chronic hypertension in association with other renocardiovascular complications. Unfortunately, for the majority of women whose medical condition falls between these two extremes, the current predictive value remains vague. The best option is to review the existing literature with patients in a nondirective manner, allow them their decisions, and provide them the best available prenatal care. PMID- 10102175 TI - A comparison of transdermal fentanyl versus epidural morphine for analgesia in dogs undergoing major orthopedic surgery. AB - Postoperative analgesia provided by transdermal fentanyl was compared with that provided by epidural morphine in dogs undergoing major orthopedic surgery. Dogs randomly were assigned to receive either a 100 microg per hour transdermal fentanyl patch 24 hours prior to surgery (n=8) or epidural morphine (0.1 mg/kg body weight) administered following induction of anesthesia (n=10). Temperature, heart rate, respiratory rate, and pain score were recorded prior to surgery and zero, six, 18, 30, and 42 hours after surgery. Blood samples were collected from the dogs in the transdermal fentanyl group beginning 24 hours preoperatively to 42 hours postoperatively. Fentanyl concentrations were determined by radioimmunoassay. When all time periods after surgery were combined, dogs in the transdermal fentanyl group were experiencing significantly less pain after surgery than dogs given epidural morphine. The transdermal fentanyl provided analgesia after major orthopedic surgery greater than or equivalent to that of epidural morphine. PMID- 10102177 TI - Rectal ganglioneuroma in a dog. AB - An 18-month-old, spayed female Australian terrier cross was presented with a 10 month history of chronic large bowel diarrhea. Ulceration and two proliferative masses in the rectum were seen on colonoscopy. Surgical resection was performed to remove the masses, and the dog recovered without complications related to surgery. Histopathology was consistent with the diagnosis of ganglioneuroma. The dog had no clinical signs of disease within three months of surgery and was completely normal 2.5 years after diagnosis. This is the first report providing follow-up and successful outcome of a ganglioneuroma in the gastrointestinal tract of a dog. PMID- 10102176 TI - A retrospective study of canine house soiling: diagnosis and treatment. AB - A retrospective study was conducted to determine the relative frequency and type of elimination problem seen in dogs at a university referral practice and to evaluate the efficacy of the suggested treatments. Cases presented to the Animal Behavior Clinic at Cornell University between 1987 and 1996 were reviewed. Of 1,173 cases, 105 (9%) were house-soiling cases. Of these cases, the authors obtained outcome information from 70. Within the diagnosis of house soiling, incomplete housebreaking (n=59; 84%) were the most frequent referral cases, of which 48 cases (81%; 95% confidence interval, 69% to 90%) improved. Separation anxiety was considered the second most common underlying cause (n=27; 39%), of which 85% (n=23; 95% confidence interval, 66% to 96%) improved. Behavior modification was the most often suggested treatment (n=58), with 48 (83%) cases improving. Behavior modification consisted of accompanying the dog to the preferred elimination area, rewarding the dog for eliminating there, and punishing the dog only when caught in the act of house soiling. These results suggest that correct house training, behavior modification involving positive reinforcement, and appropriate punishment are essential to diminish house-soiling problems in dogs. PMID- 10102178 TI - Pythiosis of the digestive tract in dogs from Oklahoma. AB - Enteric pythiosis was diagnosed in nine dogs in Oklahoma. Eight dogs had anorexia and weight loss. Two of these dogs had diarrhea; two dogs exhibited vomiting and diarrhea; and one dog had vomiting. One dog presented with dysphagia. Seven dogs had either a palpable or radiographically visible abdominal mass. These seven dogs had localized regions of mucosal ulceration and thickened gastric or intestinal walls with some involvement of the adjacent mesentery or omentum. Two dogs had enlarged regional mesenteric lymph nodes. One dog that presented with dysphagia had an oropharyngeal mass involving the larynx and cranial esophagus. Microscopically, there was transmural chronic sclerosing and granulomatous to pyogranulomatous inflammation with arteritis. Pythium spp. were identified in all specimens by immunohistochemistry. PMID- 10102179 TI - Secondary hypoadrenocorticism associated with craniocerebral trauma in a dog. AB - An 11-month-old, neutered female miniature schnauzer presented with a severe head injury. The dog was treated for the acute effects of craniocerebral trauma and was hospitalized for just over a week. Several weeks later, she became weak and lethargic. A diagnosis of hypoadrenocorticism was confirmed with an adrenocorticotropin hormone (ACTH) stimulation test. An endogenous ACTH assay confirmed secondary hypoadrenocorticism. The dog was tested for hypopituitarism with canine thyroid-stimulating hormone and thyroxine serum assays and an insulin like growth factor assay. These tests could not confirm panhypopituitarism in this dog. The hypoadrenocorticism was treated with prednisone, and the dog remains controlled adequately three years later. PMID- 10102180 TI - Babesia gibsoni infections in dogs from North Carolina. AB - The recognition of canine babesiosis in North Carolina caused by Babesia gibsoni documents the expansion of the previously reported endemic area of this disease. Clinical signs ranged from severe hemolytic anemia and thrombocytopenia to subclinical infections. No infected dogs had traveled to endemic areas. Antibabesial treatment failed to eradicate the organism from infected dogs. PMID- 10102181 TI - Interlocking box jejunostomy: a new technique for enteral feeding. AB - A new jejunostomy tube placement technique is described and compared to traditional methods. The interlocking box technique was compared to a simple purse-string with jejunopexy and an inverting serosal tunnel (Witzel technique) with jejunopexy. Procedures performed in fresh canine cadavers were fluid pressure tested following tube removal. Mean+/-standard deviation (SD) intraluminal pressure necessary to induce leakage at the jejunopexy site of the interlocking box group (87.63+/-40.56 cm H2O) was significantly greater (p less than 0.001) than the simple purse-string (43.17+/-31.69 cm H2O) and serosal tunnel (46.33+/-23.60 cm H2O) groups. Significant differences were not identified between the latter groups. The interlocking box technique resisted leakage following acute removal better than conventional techniques and should be tested clinically. PMID- 10102182 TI - Cervical vertebral fractures in 56 dogs: a retrospective study. AB - The clinicopathological features of cervical fractures in 56 dogs were reviewed. "Hit by car" (HBC) was the most common inciting cause, and the axis and atlas were the vertebrae most frequently affected. Surgical treatment was associated with high (36%) perioperative mortality. However, all dogs that survived the perioperative period achieved functional recovery. Functional recovery was achieved in 25 (89%) of 28 nonsurgically treated dogs with adequate follow-up. Overall, severity of neurological deficits (nonambulatory status) and prolonged interval (five days or longer) from trauma to referral were associated with poorer outcome. Nonsurgical treatment is a viable therapeutic approach for many dogs with cervical fractures. Early neck immobilization and prompt referral are recommended, because delay in referral decreases the likelihood of functional recovery. PMID- 10102183 TI - Evaluation of joint stabilization for treatment of shearing injuries of the tarsus in 20 dogs. AB - Medical records of 20 dogs with 23 shearing injuries of the tarsus leading to joint instability were reviewed. A transarticular external skeletal fixation device or prosthetic ligament was used to stabilize the joints. The most common complications were fixator failure and implant infection. The median times for wound healing and maximal joint function were 10 and 12 weeks, respectively. Clinical outcome was excellent in 22%, good in 56%, and poor in 22%. Comparison of the two stabilization methods showed no statistically significant differences in healing time, time to regain function, or clinical outcome. PMID- 10102184 TI - Tarsometatarsal subluxation in dogs: partial arthrodesis by plate fixation. AB - In a retrospective study of tarsometatarsal joint subluxation in eight dogs, secondary fractures were identified in six dogs, particularly of the fourth tarsal bone and the proximal fifth metatarsal bone. Common causes of tarsometatarsal joint injury included jumping or falling and direct trauma to the foot. Partial tarsal arthrodesis, with the use of bone-plate stabilization and cancellous bone grafting of joint spaces after removal of articular cartilage, led to progressive bone healing in all dogs. Implant breakage did not occur in any dog. PMID- 10102185 TI - Intermuscular lipomas of the thigh region in dogs: 11 cases. AB - Ten dogs with intermuscular lipomas in the thigh region were treated by surgical resection. The masses were located predominantly between the semitendinosus and semimembranosus muscles and involved the full length of the femur. These lipomas were not infiltrative but located deep between the fascial planes of the associated muscles. These tumors can appear similar to soft-tissue sarcomas in this location, but they can be differentiated by cytology and histology. Differentiation from an infiltrative lipoma is predominantly determined at the time of surgery. No tumors recurred in the median follow-up period of 17 months. PMID- 10102186 TI - Partial colonic obstruction following ovariohysterectomy: a report of three cases. AB - Partial extramural obstruction of the descending colon was diagnosed in two dogs and a cat as a complication of elective ovariohysterectomy. In each case, the obstruction was caused by fibrous tissue that encircled or crossed the descending colon, severely restricting the organ's normal mobility and luminal diameter. Clinical signs secondary to obstipation were observed in two cases, five weeks and 27 months after elective ovariohysterectomy. In one dog without clinical signs, the adhesion was an incidental finding during a laparotomy performed nine years after the ovariohysterectomy. The fibrous adhesions were removed surgically in all three cases without additional complications. PMID- 10102187 TI - Percutaneous radiologic placement of peritoneal dialysis catheters. PMID- 10102188 TI - Distal migration of stent-grafts after endovascular repair of abdominal aortic aneurysms. AB - PURPOSE: To analyze patients after endovascular repair of abdominal aortic aneurysm (AAA) with respect to distal migration of stent-grafts and its underlying causes. MATERIALS AND METHODS: Sixty-five patients underwent endovascular repair between January 1994 and February 1997. There were seven women and 58 men, with a mean age of 71 years (range, 51-84 years). Three patients died in the perioperative period (one of myocardial infarction and two of multiorgan failure) and two patients died within 4 months of the procedure of non-procedure-related causes. In addition, two patients were followed at another hospital. The remaining 58 patients were followed up with spiral computed tomography scans at 1, 3, and 6 months, and biannually thereafter. Angiography was performed at 1 month and 1 year after the procedure and additionally when deemed clinically necessary. Mean follow-up was 29 months (range, 1-49). Migration more than 5 mm was considered significant. RESULTS: Twenty-six patients (45%) showed distal migration of stent-grafts during follow-up. Mean follow-up time at detection of migration was 13 months (range, 1-36 months). Thirteen cases of migration were ascribed to dilatation of the proximal aneurysmal neck during follow-up. Ten cases of migration were ascribed to causes other than neck dilatation or poor patient selection. In three cases, no obvious cause for the migration was found. The migration was complete in eight cases, leading to late conversion to open surgical repair. On two of these occasions, complete migration lead to aneurysm rupture. In addition, four patients received additional stent grafts as proximal extensions. CONCLUSIONS: Distal migration of stent-grafts after endovascular AAA repair occurred frequently in this series. Dilatation of the proximal aneurysmal neck is a major cause of distal migration of stent grafts. Improved proximal fixation is needed to secure long-term durability. PMID- 10102190 TI - Repair of junctional stent-graft leaks with use of a bare metal stent. PMID- 10102189 TI - Endoluminal treatment of infrarenal aortic aneurysms: clinical experience with the Talent stent-graft system. AB - PURPOSE: To evaluate the safety and efficacy of the Talent stent-graft (TSG) system in the endoluminal treatment of infrarenal abdominal aortic aneurysms (AAAs). PATIENTS AND METHODS: Endoluminal treatment of an AAA was attempted in 30 men with a mean age of 70.5 years (range, 51-83 years). Seven patients had AAAs suitable for treatment with a tube graft. In the other patients, treatment with a bifurcated TSG was planned. All procedures were performed as a combined surgical radiologic procedure in an angiographic room. RESULTS: Primary technical success was achieved in 25 of 30 patients (83%). Technical failures were due to misplacement of the TSG (n = 2) with proximal leakage as a consequence, inability to gain access via the iliac arteries (n = 1), and a distal leakage (n = 2). Secondary interventions (n = 2) and spontaneous thrombosis of a distal leak (n = 1) increased the secondary technical success rate to 93% (28 of 30). Two procedures were converted to open surgery (conversion rate = 6%). One patient died during the first 30 days after uncomplicated stent-graft insertion because of myocardial infarction (30-day mortality = 5%). No complications occurred during a mean follow-up of 15.4 months (range, 6-19 months). The maximum diameter of the AAA decreased in eight patients and remained unchanged in the remaining patients. No increase in diameter was observed. No late endoleak or migration of the TSG was observed. CONCLUSION: The TSG-system revealed satisfactory initial and early follow-up results. Treatment of AAAs with this stent-graft system is feasible. The technical success rate in carefully selected patients should be 90% or more. However, long-term observations are necessary to determine if the encouraging early results of this type of therapy can be preserved during long term follow-up. PMID- 10102191 TI - Slim graft: a low-profile method for deploying endovascular grafts. PMID- 10102192 TI - Hemodialysis graft mechanical thrombolysis with use of the Amplatz Thrombectomy Device: histopathologic evaluation of extracted myointimal tissue. AB - PURPOSE: To histopathologically evaluate material extracted from thrombosed hemodialysis access grafts by the Amplatz Thrombectomy Device (ATD). MATERIALS AND METHODS: Thrombosed hemodialysis access grafts were recanalized with use of crossed catheter technique with introduction of the ATD through 8-F sheaths. After removal of the ATD from the introducer sheath, the tip of the device was visually inspected. Discernible tissue in the impeller/housing mechanism was gently extracted with a hemostat and preserved in formalin. Specimens were evaluated histologically with hematoxylin-eosin and smooth muscle immunoperoxidase stains. RESULTS: The ATD was utilized in 18 patients with acutely thrombosed grafts. Sufficient tissue for pathologic evaluation was extracted from 10 devices. Histopathologic analysis yielded findings of fibrotic myointima in all 10 cases with positive smooth muscle stains. CONCLUSIONS: The unexpected, although consistent, finding of intimal and myointimal tissue fragments in the impeller/housing mechanism of the ATD raises questions with respect to the mechanism of tissue extraction and concerns regarding the use of the device in native vessels. Further studies are indicated to determine whether this apparent intimal injury will have a deleterious effect on vessel patency. PMID- 10102193 TI - Endovascular stent-grafts for superficial femoral artery disease: results of 1 year follow-up. AB - PURPOSE: To document a preliminary study to assess the deployment and outcomes of endoluminal stent grafting in the superficial femoral artery (SFA) with use of a prototype device. MATERIALS AND METHODS: Twenty patients with lifestyle-limiting intermittent claudication were selected for treatment with a balloon-mounted expansive polytetrafluoroethylene graft. All patients had angiographically proven SFA disease (median length, 17 cm) with normal arterial inflow and at least two calf vessels patent to the ankle. Follow-up was by means of ankle brachial pressure index (ABPI), duplex ultrasound, and angiography. RESULTS: Fourteen patients were successfully treated. Six patients were excluded: five by the study protocol and one because the procedure was a technical failure. ABPI rose from 0.6 before treatment to 1.0. The treated limbs became asymptomatic. Twelve-month primary, primary assisted, and secondary patency rates of treated patients were 29%, 50%, and 64%. CONCLUSION: Endovascular stent grafting of SFA lesions is technically feasible, but the patency rates obtained with this design are inferior to those obtained with conventional surgical bypass. PMID- 10102194 TI - Transcatheter arterial embolization for intractable epistaxis secondary to gunshot wounds. AB - PURPOSE: To evaluate the efficacy of transcatheter arterial embolization for intractable epistaxis secondary to gunshot wounds. MATERIALS AND METHODS: Seven patients with intractable epistaxis secondary to penetrating trauma (gunshot wounds) were studied with angiography and subsequently underwent embolization with particles (polyvinyl alcohol, gelatin sponge) and/or microcoils. Clinical follow-up included standard hemodynamic monitoring, serial hematocrit determinations, and clinical observation for recurrent bleeding. RESULTS: Diagnostic angiography demonstrated evidence of acute arterial injury in all patients. All patients subsequently underwent embolization to complete angiographic stasis. Two patients had persistent bleeding following embolization. One of these patients required maintenance of his nasal packing for 7 days after embolization; no blood products were required during this time. The second patient's bleeding resolved following correction of his coagulopathy. No complications occurred in any of the patients. CONCLUSIONS: Transcatheter arterial embolization for epistaxis secondary to gunshot wounds is efficacious in the acute setting when conservative management fails. PMID- 10102195 TI - Acute intraoperative embolic peroneal artery occlusion: treatment with suction embolectomy, angioplasty, and the transluminal extraction catheter. PMID- 10102196 TI - Diagnosis of pulmonary embolism: comparison of CT angiography and MR angiography in canines. AB - PURPOSE: To compare the sensitivity and specificity of helical computed tomographic angiography (CTA), CTA with multiplanar reconstructions (MPR)/three dimensional-shaded surface display (3D-SSD), and gadolinium-enhanced magnetic resonance angiography (MRA) for pulmonary embolism (PE) detection. MATERIALS AND METHODS: Gelatin sponge emboli were introduced into the femoral veins of seven dogs and conventional digital subtraction angiography (CA), CTA, and MRA performed. Images from CTA, CTA with MPR/3D-SSD, and MRA were reviewed for the presence of PE in lobar and segmental arteries, and subsegmental zones. Postmortem angiography and CA were the gold standard. RESULTS: There were 50 emboli in the 294 vessels/zones analyzed. The sensitivity of CTA for the two readers was 76% (95% confidence interval [CI]; 64%-88%) and 64% (95% CI; 50% 78%), and for the two MRA readers was 52% (95% CI; 38%-66%) and 48% (95% CI; 34% 62%). CTA was more sensitive than MRA when PE were subdivided by vessel caliber. Specificity was high for CTA and MRA among all readers (98.8%-99.6%). MPR/3D-SSD did not improve results of axial CT. MRA perfusion defects were 46% and 47% sensitive and 100% specific. Interobserver agreement was high for CTA and MRA (kappa 0.92 and 0.93, respectively). The average diameter of vessels with emboli was 3.7 mm +/- 1.06. CONCLUSION: Helical CTA is more sensitive than three dimensional gadolinium-enhanced MRA for the detection of PE. Both CTA and MRA are highly specific for PE detection and demonstrate high interobserver agreement. MPR/3D-SSD did not increase CTA performance over axial images alone. PMID- 10102197 TI - Massive hemorrhage complicating percutaneous endoscopic gastrostomy: treatment by means of transcatheter embolization of the right and left gastroepiploic arteries. PMID- 10102198 TI - The merits of percutaneous transluminal angioplasty of a superficial femoral artery stenosis via a retrograde popliteal artery approach. PMID- 10102199 TI - Effects of nitinol Strecker stent placement on vascular response in normal and stenotic porcine iliac arteries. AB - PURPOSE: This experimental study was conducted to evaluate neointimal thickness, lumen diameters, and histologic changes in normal and stenotic porcine iliac arteries following placement of self-expanding nitinol Strecker stents. MATERIALS AND METHODS: Neointimal trauma causing slight vascular stenosis was induced unilaterally within external iliac arteries of 12 swines by means of endothelial abrasion and high cholesterol diet. Nitinol Strecker stents were placed within the stenotic and the normal contralateral vascular segments. For histopathologic evaluation, the pigs were killed 12 or 24 weeks after stent placement and luminal diamters were evaluated angiographically. RESULTS: Excluding one occlusion, 15% narrowing of the lumen diameter was induced unilaterally (P = .002). Initial luminal gain after stent placement was greater for stenotic than for normal arteries. The amount of neointima thickness was not different between stenotic and normal vessels (P > .05). Comparing vascular diameters before stent placement and at follow-up, luminal loss due to neointima proliferation was 22% within normal arteries (P = .0002), while a luminal gain by 15% was found within the stenotic arteries (P = .008). Maturation of neointima and endothelial coverage were complete after 24 weeks. CONCLUSIONS: Even though nitinol Strecker stents induce excessive neointimal proliferation, stenotic arteries seem to profit from great early luminal gain resulting in 15% of vascular expansion at follow-up while slight stenosis is induced within normal iliac arteries. PMID- 10102200 TI - Portal vein embolization with use of a new liquid embolic material: an experimental study. AB - PURPOSE: To evaluate the efficacy and safety of a new liquid embolic material in portal vein embolization (PVE). MATERIALS AND METHODS: A new embolic material (Embol) was percutaneously injected into the left portal vein of 13 swine, using a balloon catheter to prevent reflux. The swine were killed immediately (n = 6), 2 weeks (n = 4), and 4 weeks (n = 3) after the PVE, and the volumes of the right and left lobes were measured. The changes in body temperature, aspartate aminotransferase (AST) (formerly SGOT), alanine aminotrasferase (ALT) (formerly SGPT), and bilirubin levels after the PVE were studied, and the histopathologic changes in the embolized and nonembolized lobes were examined with light microscopy. RESULTS: The average volume ratio of the right:left lobe immediately after the PVE was 55(+/-2):45(+/-1), and changed to 71(+/-3):29(+/-3) at 2 weeks and 82(+/-3):18(+/-3) at 4 weeks after embolization. There were only mild changes in AST, ALT, and bilirubin levels, and only one pig showed a significant elevation in body temperature after PVE. Microscopically, the embolized lobe showed contraction of hepatocyte without any sign of necrosis and the nonembolized lobe expansion of hepatocyte. CONCLUSIONS: The new embolic material seems effective and safe for PVE. PMID- 10102201 TI - Palliation of malignant dysphagia with expanding metallic stents. AB - PURPOSE: The authors describe their experience with expanding metallic stents for the palliation of malignant dysphagia. MATERIALS AND METHODS: During a 52-month period, 138 stents were inserted in 121 patients with malignant esophageal obstruction. The average age was 74 years; there were 78 men and 43 women. Data regarding the degree of initial dysphagia, presence of an esophago-respiratory fistula, effect of stent placement on swallowing ability, complications at the time of stent placement, and long-term survival were obtained. RESULTS: An improvement in dysphagia symptoms was recorded in more than 95% of patients. The average survival after stent placement was 24 weeks. Complications necessitating further intervention occurred in 26 patients. CONCLUSION: Insertion of self expanding metallic endoprostheses for the palliation of malignant esophageal obstruction is an effective therapy that can be carried out with relative ease. Successful palliation of symptoms can be expected in more than 95% of cases. PMID- 10102202 TI - Tuberculous stenosis of the left main bronchus: results of treatment with balloons and metallic stents. AB - PURPOSE: To assess the results of treatment with balloon dilation and metallic Z stents in patients with tuberculous stenosis of the left main bronchus. MATERIALS AND METHODS: Nineteen patients with tuberculous stenosis of the left main bronchus were treated with balloon (n = 15) and self-expanding metallic Z stents (n = 4). Respiratory status and pulmonary function tests were followed up for 2 90 months. RESULTS: In the balloon group, improvements in dyspnea occurred in 73% (11 of 15 patients) immediately, 73% after 1 month, 73% after 6 months, 64% after 1 year, 64% after 3 years, and 42% after 6 years (Kaplan-Meier method). Improvement of pulmonary function (FEV1 or FVC) was achieved in 62% (eight of 13) after 1 year. In the stent group, immediate improvements of dyspnea or pulmonary function occurred in all patients. However, fracture of the stents occurred in two patients, at 4 and 18 months, respectively. Occlusion of the lumen of the stent by granulation tissue occurred in another at 18 months. CONCLUSION: Balloon dilation can be an effective method for the treatment of tuberculous stenosis of the main bronchus. Metallic Z stents should be used cautiously because of their problems of mechanical durability and overgrowth of granulation tissue. PMID- 10102203 TI - Small-bowel obstruction caused by passage of a self-expanding hexagonal cell nitinol stent in the clinical setting of an inguinal hernia. PMID- 10102204 TI - Symptomatic spleno-mesenteric-portal venous thrombosis: recanalization and reconstruction with endovascular stents. AB - PURPOSE: To evaluate the safety and efficacy of portal reconstruction in patients with symptomatic spleno-mesenteric-portal venous thrombosis. MATERIALS AND METHODS: Portal reconstruction was attempted in 21 patients (seven women, 14 men; mean age, 53.6 years +/- 15.2) with chronic thrombosis of the portal vein alone (n = 8), splenic vein alone (n = 3), or portal, mesenteric, and splenic veins (n = 10). Indications for the procedure were bleeding varices (n = 15), ascites (n = 2), hypersplenism (n = 2), and enteropathy (n = 2). Sixteen procedures were started transhepatically and of these seven were converted to a transjugular intrahepatic portosystemic shunt (TIPS) after successful recanalization of the thrombosed vein. In six patients reconstructions were performed using an intrahepatic portal vein as outflow. Five procedures were performed primarily as TIPS. Wallstents dilated to 7-10 mm were used for reconstruction. The mean follow up period was 15.2 months +/- 15.9. RESULTS: Technical success of portal reconstruction was 85.7% (18 of 21). Thirty-day mortality was 14.3% (three of 21) but was not procedural related. The cumulative rates of survival, primary patency, and palliation at 43 months of follow-up were 61.2% +/- 13.5%, 63.5% +/- 15.3%, and 31.7% +/- 15.7%, respectively. Secondary patency was 79.1% +/- 13.8%. The only predictor of mortality was the presence of liver disease (P = .001, Cox regression). CONCLUSION: Portal reconstruction is a safe and effective treatment option for patients with symptomatic chronic portal thrombosis. Liver disease predisposes to a higher mortality. PMID- 10102205 TI - Massive hemoptysis secondary to bronchial collaterals: treatment with use of TIPS and embolization. PMID- 10102206 TI - Percutaneous mechanical declotting of dialysis grafts using a central approach: a summation of risks not acceptable in 1998. PMID- 10102207 TI - Optimal digital subtraction angiography of dorsalis pedis artery: effect of foot positioning on angiographic demonstration. PMID- 10102208 TI - Interventional radiology: a call to arms. PMID- 10102209 TI - Dislodgment and entrapment of a Greenfield filter. PMID- 10102210 TI - Complication of subclavian vein catheterization: treatment with coil embolization. PMID- 10102211 TI - Surgery for morbid obesity. Overview. AB - Obesity is a major health hazard in developed countries, and morbid obesity is associated with serious, debilitating and life-threatening sequelae. Medical treatments have been unsuccessful in the long run, if at all. Operations for massive obesity have developed over the last 40 years, based on malabsorption or gastric reduction, or a combination of both. These operations are being extended into the laparoscopic realm. Operation has been found to be the only method of achieving sustained significant weight loss, with reversal of the co-morbidities and rehabilitation, and with an acceptable complication rate, in the majority of these patients. PMID- 10102212 TI - Diseases and problems secondary to massive obesity. AB - Morbid obesity is a health hazard. It carries several health risks and decreases life expectancy. Individuals with morbid obesity may develop one or more complications. These are mainly cardiovascular, metabolic, respiratory, gastrointestinal, renal, genitourinary and gynaecological. Patients with morbid obesity also have a high surgical risk. This review analyses the most common complications of morbidly obese patients and their changes after surgically induced weight loss. PMID- 10102213 TI - Criteria for selection of patients for bariatric surgery. AB - International criteria for bariatric surgery and bariatric surgeons have been well-defined in terms of the current state of the art and are presented together with weight tables and a list of co-morbidities of morbid obesity. The bariatric surgeon should make the primary judgement concerning bariatric surgery using these criteria as guidelines only, not strict rules; others who use these criteria should govern themselves in a like, fair-minded, fashion. Medical insurers' and their agents' criteria, if excessively restrictive relative to the guidelines, may reflect an ingrained prejudice against the morbidly obese, manifesting itself in an unfair, unethical and immoral bias. It is the essence of humane and equitable behaviour on the part of all concerned that the morbidly obese receive non-discriminatory, appropriate treatment, care and medical insurer coverage for their disease and its comorbidities. PMID- 10102214 TI - Performance standards in bariatric surgery. AB - A bariatric surgeon is a fully trained general or gastrointestinal surgeon who has demonstrated specialized knowledge in the management of patients who suffer from morbid obesity and its complications. In addition to appropriate formal surgical training, preceptorships with experienced surgeons, preferably members of international bariatric societies, are highly desirable. Active participation in meetings of these societies, continuing medical education and knowledge of the current literature are necessary to maintain the required skills to treat these complex patients. Bariatric surgery should be performed at institutions that provide the necessary equipment, facilities and support systems for this particular population. When analysing outcomes of obesity surgery, long-term weight loss reports should include the number of patients followed and the time period of follow-up. Complications and re-operations should be presented, as well as modifications of techniques when various operations are compared. Weight loss should not be the only criterion used to define success or failure. Objective assessment of improvement in medical conditions related to obesity, and reliable measurements of quality of life after surgery should also be included in the final outcome analysis. PMID- 10102215 TI - Ileogastrostomy or jejunoileal bypass with drainage of the bypassed bowel into the stomach. AB - Ileogastrostomy was first performed for morbid obesity in 1982. In this review, the rationale and technique for the operation are described, and the results and complications discussed. An interesting aspect in a changing world is the lack of modification that has occurred in the surgery, and the possibility of long-term results which are rare in bariatric surgery. The techniques of wound closure have changed, however. The surgery is simple to perform and achieves excellent weight loss and reversal of co-morbid conditions such as non-insulin-dependent diabetes mellitus, but requires long-term follow-up. The principal long-term problem is calcium oxalate renal stones, with occasional patients having troublesome diarrhoea. PMID- 10102216 TI - Gastroplasty procedures, particularly vertical banded gastroplasty. AB - Vertical banded gastroplasty (VBG), the most frequently performed restrictive procedure to control severe obesity, was developed by Mason in 1982. The procedure evolved from experiential trials of earlier concepts and the timely availability of instrumentation to allow stapled vertical partition of the stomach. Success requires precise technical mastery and optimal patient compliance to provide permanent governance of satiety. The objective of weight control--to reverse co-morbidities of obesity, while causing minimal metabolic deficiencies--has been achieved in a wide selection of patients. The super-obese may be a group whose needs fall beyond the control of the VBG. Vertical ringed gastroplasty (VRG) performs similarly to VBG. Other types of gastroplasty have yet to prove reliable over time. Laparoscopic banded gastroplasty is reversible, adjustable and attractive to patients. Laparoscopic VBG must prove equivalent technical precision to that of open procedures before it can be useful. Deterrents to success such as staple-line failure, band erosion, behavioural backsliding, lack of teeth, large pouch syndrome and a super-obese candidate underscore the tenacity of severe obesity, the disease, as an adversary. Control, not cure, is possible. PMID- 10102217 TI - Gastric bypass procedures. AB - Surgical therapy to help the severely overweight has been performed for the past 40 years. As with every therapeutic modality, there have been changes, refinements and improvement as this therapy has evolved. Although the basic concept of gastric bypass remains intact, numerous variations are being performed at this time. Recent data compiled by the International Bariatric Surgery Registry have demonstrated that surgeons are moving from simple gastroplasty procedures, favouring the more complex gastric bypass procedures as the surgical treatment of choice for the morbidly obese patient. This review will discuss the evolution of the gastric bypass procedures, and the reasons for and results of the changes. Gastric bypass may represent the best surgical approach for the treatment of morbid obesity. PMID- 10102218 TI - Biliopancreatic diversion (doudenal switch procedure). AB - The physiological principle underlying biliopancreatic diversion (BPD) is attractive. It decreases food absorption and particularly that of fat. It preserves normal eating habits and is compatible with a good quality of life. Because weight loss is not a function of an imposed aversion to eating, it is more appealing to patients. Data are accumulating showing that BPD can permanently cure morbid obesity in a majority of patients and is remarkably well tolerated. While long-term systemic side-effects from decreased absorption continue to raise concerns, available results have already shown that, within 20 years, metabolic disturbances are well tolerated while weight loss and quality of life are maintained. Vitamin and mineral replacement therapy and periodic monitoring are essential. The original procedure described by Scopinaro with subsequent modifications will be presented, focusing on the duodeno-ileal switch procedure. PMID- 10102219 TI - Gastric banding for morbid obesity. AB - Recent advances in laparoscopy have renewed the interest in gastric banding techniques for the control of severe obesity. This method entails encircling the upper part of the stomach using bands made of synthetic materials, creating a small upper pouch that empties into the lower stomach through a narrow, non stretchable stoma. The reduced capacity of the pouch and the restriction caused by the band diminish caloric intake, depending on important technical details, thus producing weight loss comparable to vertical gastroplasties, without the possibility of staple-line disruption and lesser incidence of infectious complications. However, distension of the pouch, slippage of the band and entrapment of the foreign material by the stomach have been described. To reduce the likelihood of these occurrences, reviewing the literature of the past 20 years is important to surgeons new in the bariatric field. Understanding the development of this procedure helps in avoiding mistakes made during the evolutionary process. The simplicity and non-invasiveness of the technique, low morbidity, ease of revision, and especially its complete reversibility, make gastric banding a first-line choice in bariatric surgery. However, as in other pure restrictive methods, and perhaps more important than surgical refinements, patient compliance with the behavioural changes imposed by the procedure is critical for a successful outcome. PMID- 10102220 TI - An interval report on prospective investigation of adjustable silicone gastric banding devices for the treatment of severe obesity. AB - A review and updated report of an ongoing prospective investigation of two different adjustable silicone gastric banding devices is presented. One cohort of this study includes 40 subjects who have had a band placed by laparotomy. A second cohort includes 22 subjects who have had a newly designed adjustable silicone gastric band (ASGB) placed by laparoscopic or open technique. The goal of this investigation is to evaluate the achievement of sustained weight loss without the need for re-operation. Because of the frequent need for re-operation to correct life-threatening complications or ineffectiveness of ASGB devices, present clinical data indicate that improvements to the implantable system and the operative technique need to be made and verified by long-term study. At this point in development, ASGB remains an investigative procedure that has not fulfilled the scientific requirements of an accepted surgical treatment for severe obesity. PMID- 10102221 TI - Pathogenesis and medical therapy of primary sclerosing cholangitis. Any news? AB - Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intra- and extrahepatic bile ducts. Medical therapy has focused on anticholestatic, antiinflammatory and immunosuppressive drugs. Although inflammation, fibrosis and cholestasis may all occur at the same time, inflammation dominates the early phase and fibrosis and cholestasis the later stages. With inflammatory bowel disease and rheumatoid arthritis as stimulants, research on anti-inflammatory drugs is in a very active stage, with an emphasis on cytokines and cytokine antagonists. For patients with primary sclerosing cholestasis to fully benefit from these developments, it is necessary to define the early disease stage that constitutes a potential therapeutic window for these agents. PMID- 10102222 TI - Cytokines in acute pancreatitis--new pathophysiological concepts evolve. PMID- 10102223 TI - Does ursodeoxycholic acid mediate immunomodulatory and anti-inflammatory effects in patients with primary sclerosing cholangitis? AB - BACKGROUND AND OBJECTIVES: Therapy with ursodeoxycholic acid (UDCA) has been reported to be associated with improvements in abnormal serum biochemical liver tests in patients with primary sclerosing cholangitis (PSC). To evaluate further the effects of UDCA on this disease, we evaluated immunological markers and indices of inflammation during a one-year, prospective, open-label trial of UDCA therapy in patients with PSC. PATIENTS AND METHODS: Seventeen PSC patients were enrolled for one year of treatment with UDCA 12-15 mg/kg/day. Serum biochemical variables, immunological markers and indices of inflammation were compared before and at the end of therapy and 4 months after treatment had been withdrawn. Liver histology and immunohistochemistry for human leucocyte antigen (HLA) class I/II and intercellular adhesion molecule 1 (ICAM-1) expression were compared before and at the end of therapy. RESULTS: UDCA treatment was associated with significant improvements in serum biochemical liver tests, immunoglobulin levels and blood coagulation factors. Tumour necrosis factor alpha (TNF-alpha) production after in vitro whole-blood phytohaemagglutinin (PHA) stimulation was increased, but unaltered by UDCA therapy. Baseline serum levels of interleukin-6 (IL-6) and soluble IL-2 receptor were normal, and serum IL-8 levels were increased, but none of these variables was significantly affected by UDCA therapy. Liver histological stage/grade and HLA class I/II and ICAM-1 expression on biliary epithelial cells and hepatocytes were not markedly altered by UDCA therapy. CONCLUSIONS: UDCA therapy in PSC patients was associated with a decrease in cholestasis, but no consistent improvement in hepatic inflammation, fibrosis or histological stage of the disease. Immunomodulatory effects of UDCA in PSC do not appear to be HLA-restricted. PMID- 10102224 TI - Graded experimental acute pancreatitis: monitoring of a renewed rabbit model focusing on the production of interleukin-8 (IL-8) and CD11b/CD18. AB - OBJECTIVE: To establish and monitor a rabbit model of graded severity of acute pancreatitis to test the hypothesis that interleukin-8 (IL-8) and the adhesion molecule complex CD11b/CD18 are involved in the development of systemic complications in severe acute pancreatitis. METHODS: Acute pancreatitis induction in rabbits by duct ligation with or without infusion of 5.0% or 0.5% chenodeoxycholic acid or 0.9% saline. Control animals underwent laparotomy. The animals were monitored biochemically, histologically and immunohistochemically. RESULT: Increased serum levels of IL-8, tumour necrosis factor alpha (TNF-alpha), amylase and lipase were found in the chenodeoxycholic acid groups when compared with the saline, duct-ligated or control groups. Leukopenia, hypocalcaemia, and hyperglycaemia were marked in the 5.0% chenodeoxycholic acid group as compared to the saline, duct-ligated and control groups. Histologically, the 5.0% chenodeoxycholic acid group manifested a significant degree of pancreatic necrosis and neutrophil infiltration. The lungs of these animals showed acute lung injury and a significant up-regulation of CD11b/CD18. IL-8 was produced in pancreatic acinar and ductal cells. A significantly large output of ascitic fluid was seen in the 5.0% chenodeoxycholic acid group. CONCLUSION: The rabbit models of acute pancreatitis are reliable in that enzymatic and histological evidence of acute pancreatitis with or without systemic complications developed. IL-8 is produced locally in pancreatic acinar and ductal cells and significantly increased in peripheral blood during severe but not mild pancreatitis. The expression of the adhesion molecule complex CD11b/CB18 is significantly increased in lung tissue during severe acute pancreatitis with acute lung injury. IL-8 and CD11b/CB18 are involved in the pathogenesis of severe acute pancreatitis but not of mild oedematous pancreatitis. PMID- 10102225 TI - Thrombopoietic cytokines and reversal of thrombocytopenia after liver transplantation. AB - OBJECTIVES: Thrombopoietin (TPO), the key regulator of platelet production, is mainly produced by the liver and reduced expression of TPO could cause thrombocytopenia in liver cirrhosis. Reversal of thrombocytopenia by orthotopic liver transplantation seems to be mediated through an increase in TPO plasma levels after transplantation, but other cytokines with thrombopoietic activity could augment the actions of TPO on post transplant platelet recovery. DESIGN: Measurement of thrombopoietic cytokines before and for 14 days post liver transplantation in a cohort of thrombocytopenic liver transplant patients. METHODS: TPO, interleukin-3 (IL-3), IL-6, and IL-11 plasma levels as well as peripheral platelet count were analysed in thrombocytopenic patients with liver disease undergoing orthotopic liver transplantation (17 patients) and followed for 14 days after the intervention. RESULTS: Before liver transplantation, TPO plasma levels were undetectable and IL-3, IL-6, and IL-11 levels were normal. Sixteen out of 17 patients showed a significant rise of TPO levels within 2 days after transplantation, with a peak between days 4 and 6, while IL-3 and IL-6 levels did not show a significant rise. IL-11 levels remained normal. Platelet counts were significantly higher than pretransplantation levels by day 14 post transplantation. CONCLUSION: Restitution of normal TPO production by liver replacement seems to be of key importance for reversal of thrombocytopenia in liver disease. The early acting thrombopoietic factor IL-3 and the late acting factors IL-6 and IL-11 do not play a major role for recovery of peripheral platelet count after orthotopic liver transplantation. PMID- 10102227 TI - The 'artificial high pressure zone'. A non-invasive method to study in man the effect of the inhibitory innervation to the oesophagus. Validation study using a combined manometric--barostat technique. AB - OBJECTIVE: We previously developed a technique to study the effect of inhibitory innervation in the human oesophageal body, by creating an artificial high pressure zone (artificial HPZ) using an intra-oesophageal balloon. Swallowing provokes a fall in pressure in the artificial HPZ that precedes the peristaltic contraction. We aimed to prove that the swallow-induced fall in pressure in the artificial HPZ is due to relaxation of a segmental tonic contraction of the oesophageal wall at that level. METHODS: Studies were performed in five healthy subjects. Oesophageal pressures were measured at 5, 10 and 15 cm above the lower oesophageal sphincter. A rubber balloon opposite the middle pressure sensor was used to induce the artificial HPZ. A barostat bag was glued to the opposite side of the balloon. The pressure in the barostat bag was pre-set at 8 mmHg below the pressure measured in the artificial HPZ. We studied deglutition-induced variations in the barostat bag volume after single and multiple swallows. RESULTS: Immediately after single swallows and during multiple swallows, we observed a fall in pressure in the artificial HPZ and a significant increase in the barostat bag volume (254+/-67%) from 0.99 (0.37-1.93) to 3.74 (1.91-4.34) (P = 0.005) denoting oesophageal wall relaxation. CONCLUSION: The swallow-induced fall in pressure in the artificial HPZ represents a real relaxation of a segmental tonic contraction of the oesophageal wall due to deglutitive inhibition. The oesophageal artificial HPZ is a simple method that can be used to study inhibitory phenomena in the body of the human oesophagus. PMID- 10102226 TI - Regional bone mineral density after orthotopic liver transplantation. AB - OBJECTIVES: Although there is a fall in lumbar spine bone mineral density (BMD) after liver transplantation, little is known about femoral neck or total body BMD. Therefore we determined: (a) the proportion of patients with preexisting hepatic osteopenia before transplantation and (b) the effects of transplantation on global and regional BMD. DESIGN: Retrospective analysis of BMD measurements of patients before and up to 2 years after liver transplantation. METHODS: BMD was assessed by dual energy X-ray absorptiometry in 56 patients, before and at regular intervals after liver transplantation, for up to 24 months, to measure total body, lumbar spine (L2-L4) and femoral neck BMDs. RESULTS: Pre-transplant, 23% of patients had osteoporosis (a negative Z score > 2). Paired data before and after transplantation revealed no change in total body BMD. However, there was a fall in lumbar spine BMD (1.04+/-0.03 to 1.02+/-0.03 g/cm2; P < 0.04) at 1 month after transplantation. The reduction in lumbar spine BMD was seen up to 12 months, BMD at 18-24 months being similar to pre-transplant values. Femoral neck BMD also fell (0.96+/-0.06 to 0.83+/-0.04 g/cm2; P < 0.03), but only after 6-9 months, thereafter remaining below pre-transplant values until the end of the follow-up period. CONCLUSIONS: Although osteopenia is common in patients with liver disease, total bone density does not fall after transplantation. Nonetheless regional lumbar spine and femoral neck bone density does fall after transplantation with a risk period for femoral neck fracture which may extend for up to 2 years. PMID- 10102228 TI - The variability of the incremental postprandial portal vein flow response is partly caused by a relationship between fasting flow rate and phase activity of the migrating motor complex. AB - OBJECTIVE: Results from studies on portal flow rate (PFR) have demonstrated a considerable intra- as well as interindividual variability of the incremental integrated response (IIR). We hypothesized that part of the variation of the IIR might be related to variability of the fasting PFR caused by a relationship between PFR and characteristics of the migrating motor complex (MMC). DESIGN: We examined 12 healthy men and PFR was recorded by using the percutaneous colour Doppler technique. Gastric emptying (GE) was determined by scintigraphy and the meal consisted of an omelette of 100 g (1400 kJ; 60% fat, 20% protein, 20% carbohydrates) tagged with 99mTc sulphur colloids followed by 150 ml water mixed with 111In DTPA. The design included recording of PFR in phase II as well as in phase III of the MMC. Meal ingestion took place in the following duodenal phase I. Postprandial recordings of GE and PFR were performed at 10 min intervals for the following 2 h. RESULTS: Median (95% confidence limits) amount of solid emptied at 120 min was 68% (59-81%). PFR in phase III was significantly higher than in phase II (1.56 l/min (1.35-1.93 l/min) vs 0.96 l/min (0.84-1.12 l/min), P< 0.001). PFR increased after the meal and a peak flow of 2.19 l/min (1.58-2.46 I/min) was recorded 10 min after ingestion (P< 0.01 vs phase III). Based on these characteristics a difference in IIR is to be expected, and the calculations revealed that IIR is considerably higher in the phase II series than in the phase III series (50 l/min x 120 min (8-90 l/min) vs -26 l/min x 120 min (-55 to 1 l/min), P< 0.001). In both series a weak but significant inverse relationship was demonstrated between amounts emptied during a 20-min period and the corresponding IIR (n = 72; r = -0.27, P< 0.05 (III); r = -0.29; P< 0.05 (II)). CONCLUSION: We conclude that fasting PFR is related to phase activity of the MMC and characteristics of the postprandial IIR depend upon MMC activity at the time of recording of the fasting value. Future studies on PFR need to be performed with phase related recording of fasting flow and meal ingestion in relation to preselected characteristics of the MMC. PMID- 10102229 TI - Increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic, vascular permeability-enhancing cytokine with overexpression in various pathological disorders, including tumour growth, chronic inflammation and tissue repair. Recent studies have shown significantly increased serum levels of VEGF in patients with inflammatory bowel disease. The origin of the circulating VEGF is still unknown. The present investigation examines the VEGF production by peripheral blood mononuclear cells (PBMCs) in patients with inflammatory bowel disease. METHODS: VEGF levels were measured in culture supernatants of unstimulated PBMCs of 27 patients with inflammatory bowel disease and 10 healthy volunteers using a solid phase ELISA. In addition, VEGF serum levels were determined. RESULTS: PBMCs of both active Crohn's disease patients (1142.6+/ 483.9 pg/ml, P < 0.001, n = 12) and active ulcerative colitis patients (748.0+/ 637.6 pg/ml, P = 0.006, n = 4) produced significantly higher amounts of VEGF compared with PBMCs of healthy volunteers (113.4+/-101.8 pg/ml, n = 10). In addition, there was a significantly increased VEGF production by PBMCs of patients with active disease compared with PBMCs of patients with quiescent Crohn's disease (261.6+/-254.8 pg/ml, P < 0.001, n = 7) and inactive ulcerative colitis (147.7+/-100.3 pg/ml, P = 0.02, n = 4). There was no significant difference in VEGF release between patients with inactive inflammatory bowel disease and healthy controls. CONCLUSIONS: Significantly increased VEGF production by PBMCs was found in patients with active Crohn's disease and active ulcerative colitis. The study helps to clarify one of the origins of the significantly enhanced VEGF serum levels in patients with active inflammatory bowel disease observed in recent studies. PMID- 10102230 TI - Colonic wall thickening is related to age and not dose of high strength pancreatin microspheres in children with cystic fibrosis. AB - OBJECTIVE: Colonic fibrosis causing stricture is a recently described complication in cystic fibrosis (CF). Studies have suggested that ultrasound evidence of bowel thickening predicts this complication and that it is prevalent among children receiving large doses of high-strength pancreatin preparations. We performed ultrasound studies on our patients to look for evidence of bowel wall thickening or early stricture. METHOD: Detailed colonic ultrasounds were carried out in 33 children with CF including 25 who had been receiving high-strength pancreatin (Creon 25,000) continuously for 3 years at the time of study. RESULTS: Median lipase intake was 19 330 U/kg/day (range 0-59 880 U/kg/day) and median protease intake was 387 U/kg/day (range 0-1170 U/kg/day). The combined thickness of mucosa, sub-mucosa and muscle layers was measured in ascending, transverse and descending colon using a 7.5 MHz transducer. Measurements were also made in nine healthy controls. There was no relationship between enzyme dosage and colon thickness but simple regression identified a significant relationship (P < 0.001) between age and maximum colon thickness in all three areas. The colon of CF children was up to 50% thicker than in controls. CONCLUSIONS: Thickening of the order described elsewhere did not occur among any of the children studied. The results suggest that the most important factor determining the thickness of the CF colon is age. PMID- 10102231 TI - High prevalence of asymptomatic coeliac disease in Norway: a study of blood donors. AB - OBJECTIVE: The prevalence of symptomatic coeliac disease in Norway is 1:675. Coeliac disease has previously been reported in presumably healthy people. Our aim was to determine the prevalence of latent coeliac disease in apparently healthy (i.e. asymptomatic) Norwegian individuals. METHODS: Blood donor sera were tested for gluten antibodies (IgA, IgG). Positive samples (IgA AGA > 0.35, IgG AGA > 0.90) were further tested for endomysium antibodies (IgA EMA). EMA positive individuals were offered gastroenterological investigation. RESULTS: Of 2096 sera, 83 fulfilled the criteria for EMA testing (M/F = 55/28). Eight individuals were EMA positive. On biopsy, seven out of eight had villous atrophy (six subtotal, one partial). None of the patients had significant symptoms. Biochemical data showed iron deficiency (two), hypocalcaemia (one), and low serum zinc (five). All patients were treated with a gluten-free diet and followed up. CONCLUSION: The study indicates a prevalence of 1:340 among asymptomatic and presumably healthy people. This is in keeping with studies from other countries. Lack of symptoms does not exclude secondary deficiency conditions. PMID- 10102233 TI - Identification of factors that influence tolerance of upper gastrointestinal endoscopy. AB - OBJECTIVE: Unsedated gastroscopy is unpleasant for some patients. The identification of factors related to tolerance would permit the selection of patients for sedation. The aim of the present study was to identify these factors. METHODS: Five hundred and nine patients underwent diagnostic gastroscopy after the administration of topical pharyngeal anaesthesia, without sedation. Patients were grouped as to whether they had undergone prior examinations or not. Tolerance was assessed with a visual analogue scale and a questionnaire. RESULTS: Two hundred and seventy-three (54%) patients underwent gastroscopy for the first time, and 236 (46%) patients had prior experience. Patient tolerance was poor in 84 of 273 (31%) patients undergoing gastroscopy for the first time, and in 61 of 236 (26%) patients with prior experience. Logistic regression analysis identified the following variables related to poor tolerance: (a) in patients undergoing gastroscopy for the first time: presence of gag reflex (odds ratio (OR) = 3.42, 95% confidence interval (CI) 1.90-6.17), apprehension (OR = 2.57, CI 1.33-4.95), young age (OR = 0.95, CI 0.93-0.98) and high level of anxiety (OR = 1.91, CI 0.96 3.89); (b) in patients with prior experience: apprehension (OR = 4.21, CI 1.93 9.20), poor tolerance of prior examinations (OR = 4.92, CI 1.93-12.5) and female (OR = 2.23, CI 1.09-4.57). CONCLUSIONS: The above-mentioned factors are predictive of poor tolerance, and may enable the identification of those patients who might benefit more from sedation for gastroscopy. PMID- 10102232 TI - Basal and stimulated gastrin and pepsinogen levels after eradication of Helicobacter pylori: a 1-year follow-up study. AB - AIM: A decrease in gastrin and pepsinogen (PG) levels 1 month after Helicobacter pylori eradication has been described repeatedly, but the long-term progression of such a decrease has been scarcely studied. We therefore studied the effect of H. pylori eradication on basal and stimulated gastrin and PG levels for 1 year. Initially, the usefulness of measuring these parameters for the noninvasive diagnosis of H. pylori eradication was validated. Furthermore, an assessment was made of the association between H. pylori reinfection and a re-increase in gastrin and PG values. Finally, an evaluation was made of the variables influencing gastrin and PG concentration, with particular attention to H. pylori infection and histological lesions of gastric mucosa. METHODS: Two-hundred and twenty-two patients with duodenal ulcer were studied prospectively. Exclusion criteria were the administration of antibiotics, H2 antagonists, omeprazole or bismuth prior to endoscopy. In all patients serum basal levels of gastrin, PGI, and PGII were measured before and 1 month after completing eradication therapy. In the successfully eradicated patients, gastrin, PGI, and PGII were also measured at 6 and 12 months. In 80 patients stimulated measurements of gastrin (after ingestion of two beef cubes) and PGI (after injection of pentagastrin) were also performed. H. pylori-negative patients after therapy underwent a urea breath test at 6 and 12 months, and patients who had stimulated gastrin and PG concentration measured had also an endoscopy performed at 6 months. RESULTS: H. pylori was eradicated in 73% of patients. A histological improvement was observed 1 month after completing H. pylori eradication therapy, both at gastric antrum and body (P < 0.001), while a further improvement at antrum was demonstrated at 6 months (P < 0.01). With regard to the different cut-off points for decreased basal and stimulated measurements for diagnosing H. pylori eradication, the best results were obtained, respectively, with PGII (sensitivity of 90% and specificity of 76%) and PGI 30 min after stimulation (sensitivity and specificity of 82%), with an area under the ROC curve of 0.87 in both cases. In the multiple regressions analysis H. pylori status correlated with gastrin, PGI and PGII after therapy (P < 0.001), while histological lesions correlated only with gastrin levels (P < 0.05). A decrease in basal and stimulated serum parameters was demonstrated immediately after eradication (Wilcoxon test, P < 0.001), and an additional decrease (at 6 months) was observed just in PGI (Friedman test, P < 0.01). However, gastrin and PGII values remained unchanged after the first month post-eradication. Seven patients were reinfected with H. pylori during follow-up. Quantitation of basal and stimulated gastrin and PGI levels was not reliable as a reinfection marker. Regarding basal PGII, the parallelism was strong at 6 months (re-increase in all four reinfected patients), although only in one out of three with reinfection at 1 year did PGII rise at that stage. CONCLUSIONS: (1) Measurement of gastrin and PG levels (especially basal PGII values) is a useful non-invasive method to confirm H. pylori eradication after therapy. (2) H. pylori eradication is associated with a significant decrease in basal and stimulated gastrin levels and in basal PGII levels that is detected immediately (1 month) after finishing treatment, and remains unchanged for 1 year. However, the decrease in basal and stimulated PGI levels occurs progressively for 6 months, although such levels remain also unchanged afterwards. (3) Measurement of gastrin and PGI concentrations has a limited usefulness in the diagnosis of H. pylori reinfections after successful eradication, although PGII determination could be more useful in this situation. PMID- 10102234 TI - Multiple myeloma involving the stomach with vitamin B12 deficiency. AB - Involvement of the gastrointestinal tract by plasmocytoma is rare. In a 78-year old man with IgA lambda multiple myeloma stage IIIB, the evaluation of a megaloblastic anaemia revealed a subnormal vitamin B12 level. Urinary excretion of isotope-labelled vitamin B12 was reduced. Tests for gastric parietal cell and intrinsic factor antibodies were negative. There were no clinical signs of an insufficient absorption in the ileum. Biopsy specimens of the stomach showed a dense, diffuse infiltrate of malignant plasma cells in the lamina propria of fundus and corpus. A urease test for Helicobacter pylori was positive. There was a minor haematological improvement when vitamin B12 was given parenterally. Several combinations of cytostatic drugs had no effect on the manifestations of the multiple myeloma. In our patient the vitamin B12 deficiency may be related to a displacement or destruction of parietal cells by malignant plasma cells. PMID- 10102235 TI - Lymphatic fatty acid absorption profile during 24 hours after administration of triglycerides to rats. AB - In this study we determined in rats the complete 24-h lymphatic fatty acid profile after administration of either rapeseed oil (RO) or rapeseed oil interesterified with 10:0 (RO/C10) with special emphasis on the transition from absorptive to postabsorptive phase. Rats were subjected to cannulation of the main mesenteric lymph duct and the next day oils were administered through a gastric feeding tube. Lymph was collected in 1-h fractions for the following 24 h. The time for maximum lymphatic transport of fatty acids was at 4 h with fast changes in fatty acid composition from the fatty acids of endogenous origin to those of the administered oils. Seven to eight hours after administration the transport was significantly lower than maximum, indicating the change from absorptive to postabsorptive phase. At 24 h after administration of either oil the transport of total fatty acids, palmitic acid (16:0), and linoleic acid (18:2n-6) together with oleic acid (18:1 n-9) after RO had not returned to the transport at baseline. In contrast, the transport of decanoic acid (10:0) and alpha-linolenic acid (18:3n-3) returned to baseline values between 12 and 15 h. This indicated that the absorption of purely exogenous fatty acids (illustrated by 10:0 and 18:3n-3) was complete at 15 h and that the fatty acids transported between 15 and 24 h were derived mostly from endogenous stores. PMID- 10102236 TI - Dietary effects of conjugated octadecatrienoic fatty acid (9 cis, 11 trans, 13 trans) levels on blood lipids and nonenzymatic in vitro lipid peroxidation in rats. AB - The present study examined the antioxidant activity of conjugated octadecatrienoic fatty acid (9 cis,11 trans,13 trans-18:3), alpha-eleostearic acid, of karela seed (Momordica charantia), fed to rats for 4 wk. The growth pattern of rats and the effect on plasma cholesterol and high density lipoprotein (HDL) cholesterol and peroxidation of plasma lipid, lipoprotein, eryhrocyte membrane, and liver lipid were measured. Rats were raised on diets containing sunflower oil mixed with three different levels of conjugated trienoic fatty acid (9c,11t,3t-18:3) 0.5, 2, and 10% by weight; the control group was raised with sunflower oil as dietary oil as the source of linoleic acid (9c,12c-18:2). The growth pattern of the three experimental groups of rats showed no significant difference compared to the control group of rats, but the group with 10% 9c,11t,13t-18:3 had slightly higher body weight than the control group of rats. Concentrations of total cholesterol, HDL-cholesterol, and non-HDL-cholesterol in plasma were similar in all four groups. Plasma lipid peroxidation was significantly lower in the case of 0.5% 9c,11t,13t-18:3 group than the control group and the 2 and 10% 9c,11t,13t-18:3 dietary groups as well. Lipoprotein oxidation susceptibility test with 0.5, 2, and 10% 9c,11t,13t-18:3 dietary groups was significantly less susceptible to lipoprotein peroxidation when compared with sunflower oil dietary group, and the dietary group with 0.5% 9c,11t,13t-18:3 showed least susceptibility. There was significant lowering in erythrocyte ghost membrane lipid peroxidation in the 0.5, 2, and 10% 9c,11t,13t-18:3 dietary groups compared to the sunflower oil groups. Nonenzymatic liver tissue lipid peroxidation was significantly lower in the group of rats raised on 0.5% 9c,11t,13t-18:3, but the groups on 2 and 10% 9c,11t,13t-18:3 acid did not show any significant difference compared with the control group of rats. PMID- 10102237 TI - Dietary menhaden, seal, and corn oils differentially affect lipid and ex vivo eicosanoid and thiobarbituric acid-reactive substances generation in the guinea pig. AB - This investigation was carried out to characterize the effects of specific dietary marine oils on tissue and plasma fatty acids and their capacity to generate metabolites (prostanoids, lipid peroxides). Young male guinea pigs were fed nonpurified diet (NP), or NP supplemented (10%, w/w) with menhaden fish oil (MO), harp seal oil (SLO), or corn oil (CO, control diet) for 23 to 28 d. Only the plasma showed significant n-3 polyunsaturated fatty acid (PUFA)-induced reductions in triacylglycerol (TAG) or total cholesterol concentration. Proportions of total n-3 PUFA in organs and plasma were elevated significantly in both MO and SLO dietary groups (relative to CO), and in all TAG fractions levels were significantly higher in MO- than SLO-fed animals. The two marine oil groups differed in their patterns of incorporation of eicosapentaenoic acid (EPA). In guinea pigs fed MO, the highest levels of EPA were in the plasma TAG, whereas in SLO-fed animals, maximal incorporation of EPA was in the heart polar lipids (PL). In both marine oil groups, the greatest increases in both docosahexaenoic acid (22:6n-3, DHA) and docosapentaenoic acid (22:5n-3, DPA), relative to the CO group, were in plasma TAG, although the highest proportions of DHA and DPA were in liver PL and heart TAG, respectively. In comparing the MO and SLO groups, the greatest difference in levels of DHA was in heart TAG (MO > SLO, P < 0.005), and in levels of DPA was in heart PL (SLO > MO, P < 0.0001). The only significant reduction in proportions of the major n-6 PUFA, arachidonic acid (AA), was in the heart PL of the SLO group (SLO > MO = CO, P < 0.005). Marine oil feeding altered ex vivo generation of several prostanoid metabolites of AA, significantly decreasing thromboxane A2 synthesis in homogenates of hearts and livers of guinea pigs fed MO and SLO, respectively (P < 0.04 for both, relative to CO). Lipid peroxides were elevated to similar levels in MO- and SLO-fed animals in plasma, liver, and adipose tissue, but not in heart preparations. This study has shown that guinea pigs respond to dietary marine oils with increased organ and plasma n 3 PUFA, and changes in potential synthesis of metabolites. They also appear to respond to n-3 PUFA-enriched diets in a manner that is different from that of rats. PMID- 10102238 TI - Docosahexaenoic acid in the infant and its mother. PMID- 10102239 TI - Brain development and assessing the supply of polyunsaturated fatty acid. AB - Membrane lipids are necessary for structure and function of the developing nervous system. Rapid synthesis of brain tissue occurs during the last trimester of development of the human brain and the early postnatal weeks. This synthesis of brain structure involves the formation of complex lipids, many of which contain significant quantities of chain-elongated desaturated homologs of essential fatty acids. The present report discusses the implications of change in nutritional status on processes of brain development and metabolic events that involve lipids. PMID- 10102240 TI - Neonatal polyunsaturated fatty acid metabolism. AB - The importance of n-6 and n-3 polyunsaturated fatty acids (PUFA) in neonatal development, particularly with respect to the developing brain and retina, is well known. This review combines recent information from basic science and clinical studies to highlight recent advances in knowledge on PUFA metabolism and areas where research is still needed on infant n-6 and n-3 fatty acid requirements. Animal, cell culture, and infant studies are consistent in demonstrating that synthesis of 22:6n-3 involves C24 PUFA and that the amounts of 18:2n-6 and 18:3n-3 influence PUFA metabolism. Studies to show that addition of n 6 fatty acids beyond delta6-desaturase alters n-6 fatty acid metabolism with no marked increase in tissue 20:4n-6 illustrate the limitations of analyses of tissue fatty acid compositions as an approach to study the effects of diet on fatty acid metabolism. New information to show highly selective pathways for n-6 and n-3 fatty acid uptake in brain, and efficient pathways for conservation of 22:6n-3 in retina emphasizes the differences in PUFA metabolism among different tissues and the unique features which allow the brain and retina to accumulate and maintain high concentrations of n-3 fatty acids. Further elucidation of the delta6-desaturases involved in 24:5n-6 and 22:6n-3 synthesis; the regulation of fatty acid movement between the endoplasmic reticulum and peroxisomes; partitioning to acylation, desaturation and oxidation; and the effects of dietary and hormonal factors on these pathways is needed for greater understanding of neonatal PUFA metabolism. PMID- 10102241 TI - Assessment of long-chain polyunsaturated fatty acid nutritional supplementation on infant neurobehavioral development and visual acuity. AB - The aims of this paper are (i) to consider how best to examine effects of long chain polyunsaturated fatty acid nutritional supplementation or deficiency on infant neurobehavioral development, after controlling for other factors that might influence outcome, including maternal demographic, intellectual, and personality characteristics, and (ii) to present new findings on the relation between visual acuity and processing speed and the effects of prenatal alcohol exposure and visual acuity on infant information processing. The following topics are also addressed: (i) breastfeeding and intelligence, (ii) criteria for the selection and control of potential confounding variables, and (iii) new infant information processing measures. PMID- 10102242 TI - Effects of dietary polyunsaturated fatty acids on neuronal function. AB - Diets deficient in linoleic acid (18:2n-6), or that have unusual ratios of linoleic acid to alpha-linolenic acid (18:3n-3) induce changes in the polyunsaturated fatty acid (PUFA) composition of neuronal and glial membranes. Such changes have been linked to alterations in retina and brain function. These functional effects are presumed to follow from the biochemical consequences of modifying membrane PUFA content; known effects include modifications in membrane fluidity, in the activities of membrane-associated, functional proteins (transporters, receptors, enzymes), and in the production of important signaling molecules from oxygenated linoleic and alpha-linolenic acid derivatives. However, despite the demonstration that central nervous system function changes when dietary PUFA intake is altered, and that in general, membrane PUFA content influences membrane functions, little work has focused specifically on brain and retina to reveal the underlying biochemical bases for such effects. This review examines this issue, looking at known effects of dietary PUFA on neurons in both the central and peripheral nervous systems, and attempts to identify some approaches that might promote productive investigation into the underlying mechanisms relating changes in dietary PUFA intake to alterations in neuronal and overall nervous system functioning. PMID- 10102243 TI - Polyunsaturated fatty acid status and neurodevelopment: a summary and critical analysis of the literature. AB - The rationale for randomized trials designed to measure the effects of variable docosahexaenoic acid (DHA) status on neurodevelopment in human infants came from earlier studies of neurodevelopment in animals that were deficient in DHA owing to diets low in alpha-linolenic acid. The session on neurodevelopment looked at the results of these animal studies and discussed outcomes that appear to be analogous in human infants with variable DHA status. Presentations focused mainly on measures of development that may be attributed to more specific developmental domains (e.g., visual attention, recognition memory, problem-solving), some of which have been shown to be affected by long-chain polyunsaturated fatty acid (LCPUFA) status. This paper derives from discussions that took place during the session and reviews subsequent developments in this area. Although more difficult to interpret, global measures of infant development (e.g., the Bayley Scales of Infant Development, and Brunet-Lezine) can only suggest a relationship to specific developmental domains, but they have been applied in some randomized trials of LCPUFA and infant development. Those results are also summarized here. PMID- 10102244 TI - Polyunsaturated fatty acids and infant visual development: a critical appraisal of randomized clinical trials. AB - At the Consensus and Controversies Conference held in Barcelona in November 1996, one of the sessions focused on an evaluation of the effects of dietary polyunsaturated fatty acids (PUFA) on infant visual development. The intervention trials in preterm and term infants were reviewed and discussed in detail. Results of these trials, particularly those in term infants, were inconsistent; much discussion occurred concerning the causes of these diverse results. We attempt to reflect, rather than report exactly, the discussion relating to these issues and address the clinical trials according to recently published guidelines for conduct and reporting of randomized clinical trials (RCT). Compared with these recent guidelines, the published papers of RCT involving PUFA and visual function are often incomplete, making it difficult to assess if we can have a high degree of confidence in the reported effects (or lack of effects). Despite this, valuable data relating to the effect of diet on the visual development of infants were obtained. Our evaluation of the trials to date suggests that the definitive answer to the degree to which dietary long-chain PUFA is likely to influence visual development may only be resolved with impeccably conducted RCT. PMID- 10102245 TI - Statistical considerations in infant nutrition trials. AB - Infant nutrition trials usually require developmental follow-up, often to 18 mon, and sometimes beyond reading ability at age 7 yr. They are therefore logistically complex and costly, and should be conducted to a high statistical standard. With examples, we focus on: good practice in nutrition trials and the goal of a common protocol; how to set plausible trial targets and to work out trial size accordingly; statistical observations on assessing visual maturation; and methods of randomization, including the method known as minimization, which can be adapted to select more appropriately a comparison cohort of breast-fed infants. We end with discussion of analysis and reporting standards, including the give aways (or tell-tale signs) to be on the look out for. A Cochrane Collaboration for systematic review of randomized trials of infant nutrition is proposed. PMID- 10102246 TI - Long-chain polyunsaturated fatty acids and eicosanoids in infants--physiological and pathophysiological aspects and open questions. AB - Eicosanoids are highly active lipid mediators in physiologic and pathologic processes, with their effects ranging from cytoprotection and vasoactivity to modulation of inflammatory and proliferative reactions. Generation of eicosanoids can be affected by changes in the pools of their precursors, the long-chain polyunsaturated fatty acids (LCPUFA). Thus, dietary interventions such as supplementation of infant formula with specific n-3 and n-6 LCPUFA will alter formation as well as activity of the eicosanoids produced. This report summarizes the results and discussion of the workshop on "Eicosanoids and Polyunsaturated Fatty Acids in Infants." The intention of the workshop organizers was to give an overview of the role of eicosanoids in physiological and pathophysiological processes in infants, to discuss the implications that an increased n-3 and n-6 LCPUFA intake may have on eicosanoid generation, and to point out open questions and controversies for future research. PMID- 10102247 TI - Biological effects and safety issues related to long-chain polyunsaturated fatty acids in infants. AB - The purpose of this workshop at the American Oil Chemists' Society Symposium, "PUFA in Infant Nutrition: Consensus and Controversies," was to enumerate the safety issues raised by the prospect of supplementing infant formulas with long chain polyunsaturated fatty acids (LC-PUFA), to evaluate the evidence that these concerns are problematical, or theoretically problematical, and to identify the safety issues most in need of resolution. This was approached by reviewing briefly the known biological effects of LC-PUFA and how these effects might give rise to concerns about safety of LC-PUFA as components of infant formulas. Some of these issues were then discussed in more detail by invited participants, all of whom had submitted abstracts concerning the issue discussed. The pertinent aspects of all issues discussed during the workshop are summarized. In addition, since the symposium was held over 2 yr ago, an addendum summarizing additional data reported since the symposium that either support or refute issues discussed during the workshop also is included. PMID- 10102248 TI - Long-chain polyunsaturated fatty acids in diets for infants: choices for recommending and regulating bodies and for manufacturers of dietary products. AB - While the scientific evaluation of the physiologic effects, potential benefits, and risks of dietary preformed long-chain polyunsaturated fatty acids (LCPUFA) for infants have been discussed elsewhere, this manuscript addresses some of the resulting consequences and challenges of interpreting the available knowledge from the perspective of recommending and regulating bodies, and of manufacturers of dietary products and their ingredient materials. Traditionally human milk composition has served as a reference point for infant formula design. With respect to the use of LCPUFA in infant formula, much more emphasis than ever before invested for any other group of micronutrients has been put on clinical studies investigating the potential advantages and disadvantages of LCPUFA in infant foods, including growth, safety aspects, and a variety of other outcome measures. PMID- 10102249 TI - Effects of obesity and stable weight reduction on UCP2 and UCP3 gene expression in humans. AB - OBJECTIVES: The molecular determinants of energy expenditure are presently unknown. Recently, two uncoupling protein homologues, UCP2 and UCP3, have been identified. UCP2 is expressed widely, and UCP3 is expressed abundantly in skeletal muscle. Both could be important regulators of energy balance. In this paper, we investigated whether altered UCP2 and UCP3 mRNA levels are associated with obesity or weight reduction. RESEARCH METHODS AND PROCEDURES: UCP2, UCP3 long and short mRNA levels were examined in skeletal muscle and in white adipose tissue of lean, obese, and weight-reduced individuals by RNase protection assay. RESULTS: Expression of UCP2, UCP3S, and UCP3L mRNA in skeletal muscle was similar in lean individuals and in individuals with obesity at stable weight. In contrast, UCP3L and UCP3S mRNAs were decreased by 38% (p<0.0059) and 48% (p<0.0047), respectively, in 20% weight-reduced patients with obesity at stable weight. In contrast, UCP2 mRNA levels were increased by 30% in skeletal muscle of 20% weight-reduced subjects with obesity. In a different set of patients, mostly lean, UCP3L mRNA in skeletal muscle was decreased by 28% (p = 0.0425) after 10% weight reduction at stable weight. Expression of UCP2 mRNA in subcutaneous adipose tissue was similar in lean individuals and in individuals with obesity, and was increased by 58% during active weight loss. DISCUSSION: Stabilization at reduced body weight in humans is associated with a decrease in UCP3 mRNA in muscle. It is possible that reduced UCP3 expression could contribute to decreased energy expenditure in weight-stable, weight-reduced individuals. PMID- 10102250 TI - Serum leptin in elderly people: associations with sex hormones, insulin, and adipose tissue volumes. AB - OBJECTIVE: There are few data for associations of serum leptin with body fat, fat distribution, sex hormones, or fasting insulin in elderly adults. We hypothesized that the sex difference in serum leptin concentrations would disappear after adjustment for subcutaneous, but not visceral body fat. Serum leptin would not be associated with sex hormone concentrations or serum fasting insulin after adjusting for body fat and fat distribution. RESEARCH METHODS AND PROCEDURES: Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured using magnetic resonance imaging in a cross-sectional sample of 56 nondiabetic, elderly men and women aged 64 years to 94 years. Serum leptin, sex hormones (testosterone and estrone), sex hormone-binding globulin, and fasting insulin were also measured. Nine women were taking hormone replacement, and five men were clinically hypogonadal. RESULTS: Leptin was significantly associated with both SAT and VAT in each sex. Adjustment for SAT reduced the sex difference in leptin by 56%, but adjustment for VAT increased the difference by 25%. Leptin was not associated with serum estrone or hormone replacement therapy in the women, but had a significant, negative association with testosterone in the men that was independent of SAT, but not VAT. Leptin was significantly associated with fasting insulin in both sexes independent of age, sex hormones, sex hormone binding globulin, VAT and SAT. DISCUSSION: Sex difference in serum leptin is partly explained by different amounts of SAT. Studies including both men and women should adjust for SAT rather than total body fat that includes VAT. The sex difference in serum leptin is not due to estrogen, but may be partly explained by testosterone. Testosterone is negatively associated with leptin in men, but the association is confounded with VAT. Leptin is associated with fasting insulin in nondiabetic elderly men and women independent of body fat, fat distribution, or sex hormones. PMID- 10102251 TI - Birth weight, adulthood BMI, and subsequent weight gain in relation to leptin levels in Swedish women. AB - OBJECTIVE: Leptin seems to be involved in the regulation of energy balance, although little is known about the epidemiology of leptin with respect to prediction of weight gain and incidence of obesity-related diseases. The dual aim of this study is to document characteristics of leptin after long-term storage, and to describe its relation to body weight, from birth to old age, in an ongoing prospective study. RESEARCH METHODS AND PROCEDURES: A population-based sample of Swedish women was first examined at the ages of 38 to 60 and re-examined 24 years later. This study used 1358 frozen serum samples that had been stored 29 years for analysis of leptin concentrations and their relation to body weight history. RESULTS: Leptin values obtained from stored samples showed the same correlation with relative weight as that seen in a contemporary sample with similar demographic characteristics. Lower self-reported birth weight was associated with higher leptin levels in adulthood (p = 0.01), controlling for age and adult BMI. Prospective analyses revealed that high leptin in 38 to 46-year-olds predicted subsequent long-term weight gain (p = 0.003), although no significant associations were seen in women initially aged 50 or older. DISCUSSION: It is feasible to use frozen serum for studying leptin in relation to obesity and related developments many years later. High leptin level was a risk factor for subsequent weight gain in 38- and 46-year-old women. Retrospective analyses involving birth weight suggest that leptin resistance in adulthood might have fetal origins. PMID- 10102252 TI - Weight loss and leptin changes in individuals with type 2 diabetes. AB - OBJECTIVE: To identify variables associated with leptin change in subjects with type 2 diabetes after 3 weeks and 20 weeks of weight loss. RESEARCH METHODS AND PROCEDURES: Subjects with type 2 diabetes treated with diet or sulfonylureas (n = 54) were enrolled in a 20-week behavioral weight control program. Sulfonylureas were stopped > or =2 weeks before study entry. Seven subjects who restarted sulfonylureas after week 3 had their data analyzed separately after this point. RESULTS: Leptin, fasting plasma glucose, and insulin levels were measured at baseline and at 3, 10, and 20 weeks. After 3 weeks, subjects lost 2.7+/-2.0 kg (p<0.001), and had significant decreases in leptin (5.2+/-7.0 ng/mL, p<0.001), fasting plasma glucose (1.8+/-1.8 mmol/L, p<0.001), and insulin (23+/-60 pmol/L, p<0.03). Between week 3 and week 20, subjects lost an additional 6.3+/-4.4 kg (p<0.001), but had no further changes in leptin. The primary determinants of leptin change at all time-points were weight loss and initial leptin level. Changes in insulin were not related to changes in leptin after controlling for the effects of weight loss. At week 20, more recent weight loss (week 10 to week 20) was as strong a predictor of overall change in leptin as overall weight loss (baseline to 20 week). Subjects who restarted sulfonylureas had an increase in both leptin levels (+1.9+/-9.0 ng/mL, p<0.05) and insulin levels (+23+/-65 pmol/L, p<0.05), despite significant overall weight loss (-7.4+/-4.0 kg, p<0.01). Initial changes in leptin (0 weeks to 3 weeks) did not affect subsequent ability to lose weight. DISCUSSION: Both short- and long-term changes in weight had an effect on leptin changes in individuals with type 2 diabetes. Although physiological insulin changes did not independently influence changes in leptin concentration with weight loss, increases in insulin levels with sulfonylurea therapy were associated with increases in leptin levels despite weight loss. PMID- 10102253 TI - Is leptin concentration associated with the insulin resistance syndrome in nondiabetic men? AB - OBJECTIVE: Insulin resistance has been strongly associated with cardiovascular risk. Recently, leptin, a hormone that regulates appetite, has been associated with both obesity and insulin resistance. However, the possible relation of leptin to the insulin resistance syndrome has been controversial. RESEARCH METHODS AND PROCEDURES: To explore this issue, we examined the relation of leptin to blood pressure, lipid levels, low density lipoprotein (LDL) size, and glucose levels in 87 normoglycemic men. RESULTS: Leptin levels were significantly correlated with body mass index (BMI) (r = 0.494), fasting insulin (r = 0.576), whole-body glucose disposal rate (GDR) (r = -0.566), fasting glucose (r = 0.510) total triglycerides (r = 0.294), apolipoprotein B (r = 0.223), systolic blood pressure (r = 0.223), and LDL size (r = -0.244). After adjustment for BMI and GDR, leptin levels remained significantly correlated with fasting insulin, fasting glucose, triglyceride, apolipoprotein B, and systolic blood pressure. Leptin levels were also correlated with the number of metabolic risk factors (dyslipidemia, systolic blood pressure, and fasting glucose). DISCUSSION: We conclude that leptin concentrations may be associated with several cardiovascular risk factors related to insulin resistance syndrome. These associations are only partly explained by leptin's relationship with BMI and GDR. PMID- 10102254 TI - Two-year changes in lipids and lipoproteins associated with the maintenance of a 5% to 10% reduction in initial weight: some findings and some questions. AB - OBJECTIVE: This study assessed whether a 5% to 10% reduction in initial weight would be associated with as favorable long-term (i.e., 100 weeks) changes in lipids and lipoproteins, as have been observed on a short-term basis (i.e., 8 weeks). RESEARCH METHODS AND PROCEDURES: This was a prospective evaluation of 25 obese women, each of whom had lost > or =5% of initial weight during 48 weeks of treatment and had maintained a weight loss of this magnitude at 1-year follow-up (week 100). Lipids and lipoproteins were obtained at baseline and at weeks 8, 24, 48, and 100. All participants had a baseline total cholesterol > or =5.17 mmol/L (200 mg/dL). RESULTS: At the end of the first 8 weeks, weight fell an average of 11.7+/-2.8%, total cholesterol 20.6+/-7.5%, low-density-lipoprotein (LDL) cholesterol 23.0+/-18.1%, and triglycerides 26.0+/-20.1%. At week 48, weight had fallen to 20.1+/-7.0% below baseline, but total cholesterol and LDL cholesterol were reduced only 11.5+/-10.4% and 12.0+/-14.0% below baseline, respectively. These latter reductions were significantly (p<0.05) smaller than those observed at week 8, despite the larger weight loss at week 48. High-density-lipoprotein cholesterol declined significantly (p<0.05) during the first 8 weeks, but returned to baseline values by week 24. Patients gained 7.4+/-7.4 kg from weeks 48 to 100, during which time total and LDL cholesterol (but not triglycerides) rose significantly (p<0.05). Patients who, at week 100, maintained losses >10% of initial weight had significantly greater reductions in total and LDL cholesterol values than did patients who maintained losses of only 5% to 10% of initial weight. DISCUSSION: Results of this study underscore the importance of assessing long-term changes in weight-related health complications when patients have lost weight but are no longer dieting (and exercising) as aggressively as they did during the initial months of treatment. PMID- 10102255 TI - Weight control behaviors among adult men and women: cause for concern? AB - OBJECTIVES: To examine gender differences in weight control behaviors; their duration and the consistency of their use over a 3-year period; and variations of these behaviors by body mass index (BMI). RESEARCH METHODS AND PROCEDURES: The study population included 714 women and 229 men participating in a community based weight gain prevention program who completed surveys about their weight control behaviors annually for 3 years. General dieting behaviors (e.g., current, regular, and past dieting), dietary restraint (using Restrained Eating subscale of the Three-Factor Eating Questionnaire), and specific weight control practices (e.g., increasing exercise, skipping meals, and taking laxatives) were assessed. RESULTS: Women were more likely than men to report weight control behaviors, with particularly strong associations found between gender and "history of dieting" (odds ratio = 8.1) and "participation in an organized weight loss program" (odds ratio = 11.7). Among both genders, exercise was the most frequently reported specific weight loss practice (66% of women and 53% of men), followed by decreasing fat intake (62% of women and 48% of men). The use of at least one unhealthy weight control behavior over the past year was reported by 22% of the women and 17% of the men. Gender differences were not found for duration of use of most of the specific weight control practices over the past year, or for consistency of general dieting behaviors and dietary restraint over time. Although both gender and BMI were strongly associated with dieting behaviors, interactions between gender and BMI on prevalence rates of dieting were not significant. DISCUSSION: Although weight control behaviors were more prevalent among women than men, in general, large gender differences were not found in the types of behaviors used and the duration and consistency of their use. The high percentages of adults using healthy methods of weight control was encouraging. However, there is still cause for concern, in that unhealthy weight control practices were also reported by a significant percentage of the population. PMID- 10102257 TI - Psychological and behavioral predictors of body fat distribution: age and gender effects. AB - OBJECTIVE: Abdominal fat has been shown to be associated with several adverse outcomes including diabetes, cardiovascular disease, and hypertension. Risk factors for abdominal fatness include genetic effects, age, and gender. Most recently, it has been hypothesized that psychological factors, as well as behavioral factors, may play a part in where fat is distributed. The purpose of this study was to assess the longitudinal predictive power of psychological variables (cynicism, anger, anxiety, and depression) measured in 1987 on waist hip ratio (WHR) measured from 1992 to 1994 among different age and gender groups, as well as to test if alcohol consumption or smoking (measured in 1990) would mediate any of the relationships found. RESEARCH METHODS AND PROCEDURES: Data from the Swedish Adoption/Twin Study of Aging (n = 1392; average age: 58 years for middle-aged group and 74 years for older group; 58% female) were analyzed using a maximum-likelihood regression model where age, gender, and age by gender effects were assessed. RESULTS: Cynicism and anxiety predicted WHR in middle-aged subjects regardless of gender. Cynicism explained 2.5% of the variance in WHR and anxiety explained 1.7% of the variance in WHR. Anger predicted WHR in males regardless of age, explaining 4.0% of the variance; depression predicted WHR only in middle-aged females, explaining 2.0% of the variance. All analyses adjusted for body mass index, and neither alcohol consumption or smoking status mediated the relationships. DISCUSSION: These findings are suggestive with regard to the hypotheses that certain psychological states and behaviors may be associated with increased abdominal fatness. PMID- 10102256 TI - Sibutramine produces dose-related weight loss. AB - OBJECTIVE: Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. RESEARCH METHODS AND PROCEDURES: Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. RESULTS: Weight loss was dose-related and statistically significant vs. placebo (p<0.05) across all time-points for a 5 mg/day to 30 mg/day dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia. DISCUSSION: Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate. PMID- 10102258 TI - Effect of physical training and its cessation on percent fat and bone density of children with obesity. AB - OBJECTIVE: We determined the effect of 4-month periods of physical training (PT) and detraining on percent fat (percent fat) and bone density of children with obesity. RESEARCH METHODS AND PROCEDURES: Subjects were 79 7- to 11-year-old children with obesity; 34 were white, 44 were black, and 1 was Asian, 26 were male and 53 were female. They were randomly assigned to two groups: group 1 engaged in PT for the first 4 months, while group 2 engaged in PT during the second 4 months. Body composition was measured with dual energy absorptiometry, and diet was measured with 4 days of recall for each 4-month period. PT was offered 5 days/week for 40 minutes/session, heart rate monitors were worn, and no dietary information was given; mean attendance was 80%, and mean heart rate per session was 157 bpm. RESULTS: Group by time interactions across the three time points (from analysis of variance) were significant for percent fat (p = <0.001) and bone density (p = 0.045). Both groups declined in percent fat during the periods of PT, by an average of 1.6% fat units; in the 4 months after cessation of PT, group 1 increased by 1.3% fat. In both groups, bone density increased more during periods of PT (0.025 g/cm2) than during periods of no PT (0.010 g/cm2). No significant PT vs. no-PT differences were found for dietary intake of energy, macronutrients, or calcium. DISCUSSION: This study suggests that regular exercise, without dietary intervention, can enhance the body composition of children with obesity. PMID- 10102259 TI - Effects of weight cycling induced by diet cycling in rats differing in susceptibility to dietary obesity. AB - OBJECTIVE: Although the majority of evidence in rodents does not support the view that weight cycling (consisting of bouts of food restriction and refeeding) promotes obesity, the effects of weight cycling on body weight regulation remain controversial. We have previously demonstrated that some rats within a strain are more susceptible to develop obesity than others when given free access to a high fat diet. In this study, we tested the hypothesis that rats most susceptible to weight gain on a high-fat diet would also be most susceptible to weight gain as a consequence of weight cycling. RESEARCH METHODS AND PROCEDURES: Rats were provided a low-fat diet (12% corn oil) for 2 weeks, then given a high-fat diet (45% corn oil) for 2 weeks to identify those most (obesity prone) and least (obesity resistant) susceptible to weight gain. Half of each group was then subjected to three 30-day cycles of food restriction (10 days) and refeeding (20 days) [weight cycler (WC) rats]. The other half were allowed free access to the high-fat diet [control (CO) rats]. All rats were then followed for an additional 10 weeks, with free access to the high-fat diet. RESULTS: When considering the entire 160 days of the study, we found no evidence that WC rats relative to CO rats had increased body weight, increased body fat content, or elevated energy efficiency. We found no evidence that rats most prone to dietary obesity were also prone to weight gain after weight cycling. During the weight cycling phase (days 1 to 90), weight cycled groups consumed less energy and gained less weight than controls. During the follow-up phase, WC and CO rats did not differ significantly in weight gain or energy intake. DISCUSSION: In this study, weight cycling did not exacerbate the obesity produced by high-fat diet feeding. PMID- 10102260 TI - Use of preventive health care services by patients with obesity. PMID- 10102261 TI - The importance of timing and accurate interpretation of the benefits of weight reduction on plasma lipids. PMID- 10102262 TI - Bridge over troubled waters: sensing stress by disulfide bond formation. PMID- 10102263 TI - Regulation of membrane trafficking: structural insights from a Rab/effector complex. PMID- 10102264 TI - Global transcription regulators of eukaryotes. PMID- 10102265 TI - A sliding clamp model for the Rad1 family of cell cycle checkpoint proteins. PMID- 10102266 TI - Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching. AB - Many neurons in both vertebrates and invertebrates innervate multiple targets by sprouting secondary axon collaterals (or branches) from a primary axon shaft. To begin to identify molecular regulators of axon branch initiation or extension, we studied the growth of single sensory axons in an in vitro collagen assay system and identified an activity in extracts of embryonic spinal cord and of postnatal and adult brain that promotes the elongation and formation of extensive branches by these axons. Biochemical purification of the activity from calf brain extracts led to the identification of an amino-terminal fragment of Slit2 as the main active component and to the discovery of a distinct activity that potentiates its effects. These results indicate that Slit proteins may function as positive regulators of axon collateral formation during the establishment or remodeling of neural circuits. PMID- 10102267 TI - Slit is the midline repellent for the robo receptor in Drosophila. AB - Previous studies suggested that Roundabout (Robo) is a repulsive guidance receptor on growth cones that binds to an unknown midline ligand. Here we present genetic evidence that Slit is the midline Robo ligand; a companion paper presents biochemical evidence that Slit binds Robo. Slit is a large extracellular matrix protein expressed by midline glia. In slit mutants, growth cones enter the midline but never leave it; they abnormally continue to express high levels of Robo while at the midline. slit and robo display dosage-sensitive genetic interactions, indicating that they function in the same pathway. slit is also required for migration of muscle precursors away from the midline. Slit appears to function as a short-range repellent controlling axon crossing of the midline and as a long-range chemorepellent controlling mesoderm migration away from the midline. PMID- 10102268 TI - Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. AB - Extending axons in the developing nervous system are guided in part by repulsive cues. Genetic analysis in Drosophila, reported in a companion to this paper, identifies the Slit protein as a candidate ligand for the repulsive guidance receptor Roundabout (Robo). Here we describe the characterization of three mammalian Slit homologs and show that the Drosophila Slit protein and at least one of the mammalian Slit proteins, Slit2, are proteolytically processed and show specific, high-affinity binding to Robo proteins. Furthermore, recombinant Slit2 can repel embryonic spinal motor axons in cell culture. These results support the hypothesis that Slit proteins have an evolutionarily conserved role in axon guidance as repulsive ligands for Robo receptors. PMID- 10102269 TI - Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. AB - The olfactory bulb plays a central role in olfactory information processing through its connections with both peripheral and cortical structures. Axons projecting from the olfactory bulb to the telencephalon are guided by a repulsive activity in the septum. The molecular nature of the repellent is not known. We report here the isolation of vertebrate homologs of the Drosophila slit gene and show that Slit protein binds to the transmembrane protein Roundabout (Robo). Slit is expressed in the septum whereas Robo is expressed in the olfactory bulb. Functionally, Slit acts as a chemorepellent for olfactory bulb axons. These results establish a ligand-receptor relationship between two molecules important for neural development, suggest a role for Slit in olfactory bulb axon guidance, and reveal the existence of a new family of axon guidance molecules. PMID- 10102270 TI - Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. AB - Hedgehog (Hh) proteins play diverse organizing roles in development by regulating gene expression in responding cells. The Gli homolog Cubitus interruptus (Ci) is involved in controlling the transcription of Hh target genes. A repressor form of Ci arises in the absence of Hh signaling by proteolytic cleavage of intact Ci. We show that this cleavage is essential for limb patterning and is regulated by Hh in vivo. We provide evidence for the existence of a distinct activator form of Ci, which does not arise by mere prevention of Ci proteolysis, but rather depends on a separate regulatory step subject to Hh control. These different activities of Ci regulate overlapping but distinct subsets of Hh target genes. Thus, limb development is organized by the integration of different transcriptional outputs of Hh signaling. PMID- 10102271 TI - Discs Lost, a novel multi-PDZ domain protein, establishes and maintains epithelial polarity. AB - Polarization of epithelial cells depends on a hierarchical process whereby specific membrane-associated proteins become targeted to specialized membrane domains. Here, we describe a novel Drosophila protein, Discs Lost (DLT), that plays a crucial role in the polarization of embryonic epithelia during cellular blastoderm formation. At subsequent stages of development, DLT interacts with the apical determinant Crumbs (CRB) and the laterally localized protein Neurexin IV (NRX IV). Mutations in dlt or double-stranded RNA interference lead to aberrant localization of CRB and NRX IV and cause a concomitant loss of epithelial cell polarity. Hence, DLT is required to establish and maintain cell polarity and participates in different molecular complexes that define apical and lateral membrane domains. PMID- 10102272 TI - The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. AB - We have identified the Drosophila transmembrane molecule kekkon 1 (kek1) as an inhibitor of the epidermal growth factor receptor (EGFR) and demonstrate that it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase. During oogenesis, kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling. Consistent with our loss-of-function studies, we demonstrate that ectopic overexpression of kek1 mimics a loss of EGFR activity. We show that the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR, suggesting potential models for this inhibitory mechanism. PMID- 10102273 TI - Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. AB - Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/ threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene. PMID- 10102274 TI - Prion protein of 106 residues creates an artifical transmission barrier for prion replication in transgenic mice. AB - A redacted prion protein (PrP) of 106 amino acids with two large deletions was expressed in transgenic (Tg) mice deficient for wild-type (wt) PrP (Prnp0/0) and supported prion propagation. RML prions containing full-length PrP(Sc)produced disease in Tg(PrP106)Prnp0/0 mice after approximately 300 days, while transmission of RML106 prions containing PrP(Sc)106 created disease in Tg(PrP106) Prnp0/0 mice after only approximately 66 days on repeated passage. This artificial transmission barrier for the passage of RML prions was diminished by the coexpression of wt MoPrPc in Tg(PrP106)Prnp+/0 mice that developed scrapie in approximately 165 days, suggesting that wt MoPrP acts in trans to accelerate replication of RML106 prions. Purified PrP(Sc)106 was protease resistant, formed filaments, and was insoluble in nondenaturing detergents. The unique features of RML106 prions offer insights into the mechanism of prion replication, and the small size of PrP(Sc)106 should facilitate structural analysis. PMID- 10102275 TI - Transmembrane structure of an inwardly rectifying potassium channel. AB - Inwardly rectifying potassium channels (K(ir)), comprising four subunits each with two transmembrane domains, M1 and M2, regulate many important physiological processes. We employed a yeast genetic screen to identify functional channels from libraries of K(ir) 2.1 containing mutagenized M1 or M2 domains. Patterns in the allowed sequences indicate that M1 and M2 are helices. Protein-lipid and protein-water interaction surfaces identified by the patterns were verified by sequence minimization experiments. Second-site suppressor analyses of helix packing indicate that the M2 pore-lining inner helices are surrounded by the M1 lipid-facing outer helices, arranged such that the M1 helices participate in subunit-subunit interactions. This arrangement is distinctly different from the structure of a bacterial potassium channel with the same topology and identifies helix-packing residues as hallmark sequences common to all K(ir) superfamily members. PMID- 10102276 TI - Structural and functional analysis of the ARF1-ARFGAP complex reveals a role for coatomer in GTP hydrolysis. AB - The crystal structure of the complex of ARF1 GTPase bound to GDP and the catalytic domain of ARF GTPase-activating protein (ARFGAP) has been determined at 1.95 A resolution. The ARFGAP molecule binds to switch 2 and helix alpha3 to orient ARF1 residues for catalysis, but it supplies neither arginine nor other amino acid side chains to the GTPase active site. In the complex, the effector binding region appears to be unobstructed, suggesting that ARFGAP could stimulate GTP hydrolysis while ARF1 maintains an interaction with its effector, the coatomer complex of COPI-coated vesicles. Biochemical experiments show that coatomer directly participates in the GTPase reaction, accelerating GTP hydrolysis a further 1000-fold in an ARFGAP-dependent manner. Thus, a tripartite complex controls the GTP hydrolysis reaction triggering disassembly of COPI vesicle coats. PMID- 10102277 TI - Eye1 and Eye2: gene loci that modulate eye size, lens weight, and retinal area in the mouse. AB - PURPOSE: Vision is critically dependent on genetic factors that influence the rate and duration of eye growth. The genetic basis of variation in eye size in mice was explored, and genes that modulate eye weight, lens weight, and retinal area were mapped. METHODS: Eyes of approximately 700 mice were weighed. Data were corrected by regression analysis to eliminate effects of sex, age, and body weight. Interval mapping was used to locate quantitative trait loci (QTLs) using recombinant inbred strains and F2 intercrosses between strains C57BL/6J and DBA/2J. RESULTS: Major QTLs were discovered near the centromere of chromosome 5 (Eye1: genomewide P < 0.005) and on proximal chromosome 17 near the mast cell protease 6 gene (Eye2, P < 0.05). Both QTLs have significant effects on eye size, lens weight, and retinal area. The DBA/2J alleles at Eye1 and Eye2 are partially dominant and increase eye weight by as much as 1.0 mg. Analysis of 183 F2 progeny confirmed and refined the chromosomal assignments of both Eye1 and Eye2. CONCLUSIONS: Eye1 and Eye2 are the first loci known to control normal variation in eye size in any mammal. The hepatic growth factor gene (Hgf), a potent mitogen expressed in the retina, pigment epithelium, and choroid, is a strong candidate for Eye1. The human homolog of Eye2 should map to chromosome 6p, 16q13.3, or 19q13, whereas that of Eye1 should map to 7q. PMID- 10102278 TI - Human corneal ablation threshold using the 193-nm ArF excimer laser. AB - PURPOSE: To determine the human corneal threshold ablation energy density for the 193-nm ArF excimer laser, approximating clinical conditions. METHODS: The VISX Star (Santa Clara, CA) 193-nm argon fluoride excimer laser was used to ablate the cornea in human eye bank eyes under clinical conditions. Corneas were exposed to energy densities of 10, 20, 30, 35, 40, 45, and 140 to 160 mJ/cm2. Corneas were fixed for light and transmission electron microscopy immediately after laser exposure. RESULTS: Different ablation thresholds for various corneal structural elements were observed. The ablation threshold for the collagen in the corneal stroma was determined to be 30 mJ/cm2. Keratocytes had ablation thresholds of 40 mJ/cm2. These different ablation thresholds accounted for the production of stromal peaks and valleys, with the keratocytes atop the peaks. CONCLUSIONS: Different corneal structural elements have different ablation threshold energy densities. PMID- 10102279 TI - Activation of NADPH oxidase by docosahexaenoic acid hydroperoxide and its inhibition by a novel retinal pigment epithelial protein. AB - PURPOSE: In an earlier study, a novel retinal pigment epithelial protective protein (RPP) was described, which suppresses the superoxide generation of activated polymorphonuclear leukocytes (PMNs). In experimental autoimmune uveitis, docosahexaenoic acid hydroperoxide (22:6OOH) has been shown to be the major lipid peroxidation product in photoreceptors. This hydroperoxide was also found to be chemotactic to PMNs. This study was undertaken to evaluate the activation capability of 22:6OOH in resting PMNs and the possible inhibition of this activation by RPP. METHODS: The 22:6OOH was obtained from pure 22:6 and was purified by thin-layer and high-performance liquid chromatography. Intact rabbit peritoneal PMNs (7-8 X 10(5)) were coincubated with 0.5 microM formyl-methionyl leucyl-phenylalanine (fMLP), 1.3 microM 22:6OOH, or 5.0 microM 22:6. These systems were coincubated with and without 0.25 microg/ml RPP. From PMN cell-free preparations, the reconstitutes each containing 21 microg plasma membranes and 276 microg cytosolic factors were coincubated with arachidonate, 22:6OOH, or 22:6, each at 100 microM. The inhibition of superoxide production was estimated by adding 0.20 microg/ml RPP. Superoxide generation was measured by superoxide dismutase-inhibitable cytochrome C reduction. RESULTS: In 30 minutes, 22:6OOH activated PMNs produced 11.10 +/- 0.68 nanomoles superoxide, and production was suppressed 72% by RPP. Under the same conditions, fMLP induced production of 34.6 +/- 2.77 nanomoles superoxide, and RPP inhibited 60% of production. In the PMN cell-free systems, 100 microM 22:6OOH induced 74.7 nanomoles superoxide per milligram plasma membrane proteins per 5 minutes, and RPP suppressed 50% of production. These results were comparable with those generated by arachidonate, a known stimulator for this system. RPP was effective only when it was added before assembly of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. CONCLUSIONS: The inflammation-mediated retinal peroxidation product 22:6OOH significantly activates resting PMNs, either in intact cells or in cell-free preparations, to increase further the release of superoxide from PMNs, thus accelerating inflammation-mediated tissue damage. This profound amplification process seems to be effectively downregulated by an RPE-generated protein RPP. PMID- 10102281 TI - Asymmetry in optic disc parameters: the Blue Mountains Eye Study. AB - PURPOSE: To examine asymmetry in vertical optic disc parameters among subjects classified as normal, as having ocular hypertension (OH), and as having open angle glaucoma (OAG) in a population-based sample. METHODS: The Blue Mountains Eye Study examined 3654 people aged 49 to 97 years, including 2929 normal subjects, 118 with OH, and 79 with OAG in the groups of interest for the asymmetry study. Optic disc parameters were measured in a masked manner from stereo optic disc photographs. RESULTS: Vertical disc diameter asymmetry (the absolute value of left minus right disc diameters) was similar among normal, OH, and OAG groups (median, 0.07-0.08 mm). Vertical cup- disc ratio asymmetry was higher in patients with OAG (median, 0.11) than in normal subjects (median, 0.06; P < 0.0001) and in those with OH (median, 0.05; P < 0.0001) but was similar between normal subjects and patients with OH (P = 0.17). A cup- disc ratio asymmetry of 0.2 or more was found in 24% of patients with OAG, compared with 1% of patients with OH and 6% of normal subjects. Corresponding rates for cup- disc ratio asymmetry of 0.3 or more in these three groups were 10%, 0%, and 1%, respectively. Using multiple linear regression, cup-disc ratio asymmetry was associated with disc diameter asymmetry and intraocular pressure asymmetry. However, these two factors explained only 3% of the variability of cup- disc ratio asymmetry and 20% of cup diameter asymmetry. CONCLUSIONS: Despite differences between the OAG group and either the OH or normal groups, asymmetry alone was not useful in identifying patients with OAG. At all levels of asymmetry, subjects were more likely to be classified as normal than with OH or OAG. PMID- 10102280 TI - Expression of folate receptor alpha in the mammalian retinol pigmented epithelium and retina. AB - PURPOSE: Folic acid is essential for DNA, RNA, and protein synthesis, and deficiencies in folate can lead to nutritional amblyopia and optic neuropathy. The transport of folate from the choroidal blood supply to the retina is only now beginning to be understood. The reduced-folate transporter was reported recently to be present in cultured human retinal pigment epithelial (RPE) cells and is thought to be localized to the apical region of these cells. The authors hypothesize that the RPE plays a role in the vectorial transport of folate from the choroidal blood to the neural retina and uses not only the reduced-folate transporter but also the folate receptor alpha in mediating this transport. The purpose of the present study was to determine whether the folate receptor alpha was present in the RPE and, if so, whether it was distributed along the basolateral membrane of the RPE, supporting a role for the protein in the initial steps of folate transport into the RPE. METHODS: The expression of the folate receptor alpha in mouse RPE was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), functional assays, in situ hybridization, immunohistochemistry, and laser scanning confocal microscopy. RESULTS: RT-PCR analysis, cloning of the RT-PCR product, and subsequent sequencing established that folate receptor alpha mRNA transcripts are expressed in the mouse RPE/choroid and are expressed also in the neural retina. A heterologous functional expression assay using MTX(R)-ZR-75-1 cells showed that the folate receptor alpha cDNA obtained by RT-PCR from the RPE/choroid complex and the neural retina was functional as assessed by the binding of folic acid and by the uptake of N5-methyltetrahydrofolate. In situ hybridization localized the folate receptor alpha mRNA to the mouse RPE cells and to cells of the neural retina. The folate receptor alpha was detected immunohistochemically in the mouse and rat RPE and in several layers of the neural retina. Laser scanning confocal microscopy revealed the distribution of the folate receptor alpha along the basolateral region of the RPE and not the apical region. CONCLUSIONS: The present work represents the first analysis of the folate receptor alpha expression in intact mammalian retina. The receptor is present and functional in mouse RPE. It is distributed specifically along the basolateral surface of the RPE and is proposed to work in a coordinated manner with the reduced-folate transporter in the vectorial transport of folate from the choroidal blood to the neural retina. PMID- 10102282 TI - Characteristics of discrepancies between self-reported visual function and measured reading speed. Salisbury Eye Evaluation Project Team. AB - PURPOSE: Visual impairment is a risk factor for morbidity in the elderly and is often screened for by self-report. This study evaluates whether there are subsets for whom there is a discrepancy between self-reported and measured function. METHODS: The prevalence of a discrepancy between self-reported difficulty reading a newspaper and measured reading speed was determined in 2520 community-based men and women, aged 65 to 84 years, and the discrepant group characterized by polychotomous regression. RESULTS: Of subjects who reported minimal difficulty reading a newspaper, 10.8% (227/2107) read newsprint-sized text (0.21 degrees) more slowly than 80 words/min, a level previously shown to be necessary for sustained reading. Poor visual acuity, presence of psychiatric symptoms, and less satisfaction with vision were associated with being in the group that read slowly and reported difficulty with reading. Better cognition, better visual acuity, more years of education, white race, and fewer psychiatric symptoms were associated with being in the group that read more quickly and reported minimal difficulty. When reading the text size at which subjects read their fastest, only 2.6% of those with minimal difficulty remained discrepant. These individuals were more likely to have less education, be male, be African American, and have poorer cognitive status than those who did not remain discrepant. CONCLUSIONS: A subset of the elderly population have a substantial discrepancy between self-reported reading difficulty and measured reading speed. In some, this discrepancy may be based on underlying expectations and experiences, and in others it may represent a transition from no visual impairment to visual impairment. PMID- 10102283 TI - Perceived visual ability for independent mobility in persons with retinitis pigmentosa. AB - PURPOSE: To determine the distribution of perceived ability for independent mobility in people who are at various stages of retinitis pigmentosa (RP). METHODS: A questionnaire was developed to ask subjects to rate how difficult they found each of 35 mobility situations if they had no assistance. The scale was 1 (no difficulty) to 5 (extreme difficulty). In each of 127 subjects, the Rasch analysis, a latent trait analysis, was used to convert the ordinal difficulty ratings into interval measures of perceived visual ability for independent mobility. RESULTS: Content validity of the questionnaire was shown by good separation indexes (4.55 and 8.0) and high reliability scores (0.96 and 0.98) for the person and the item parameters. Construct validity was shown with model fit statistics. Criterion validity of the questionnaire was shown by good discrimination among mobility-related behavior such as "limit independent travel," "always ask for accompaniment," "use a mobility aid," and "have a fear of falling." The mobility situation shown to require the least visual ability was "moving about in the home"; the situation requiring the most was "walking at night." Bivariate regression analysis determined that for every decade of disease progression, perceived visual ability for mobility decreased by approximately 0.5 logit, which was slightly less than 10% of the total range in the study sample. A linear combination of the visual function measures, log minimum angle of resolution, log contrast sensitivity, and log retinal area accounted for 57% of the variability in the person measure. CONCLUSIONS: The patient-based assessment, developed to determine difficulty across a range of mobility situations, is a valid way to measure perceived ability for independent mobility. This latent trait varies systematically with the progression of RP and with visual function measures. PMID- 10102284 TI - Conjunctival epithelial cell differentiation on amniotic membrane. AB - PURPOSE: Amniotic membrane (AM)-reconstructed conjunctival surfaces recover the normal epithelial phenotype with a significantly higher cell density than the control. The present study was undertaken to examine how AM modulates rabbit conjunctival epithelial cell differentiation. METHODS: Rabbit conjunctival epithelial cells (RCEs) were cultured on the basement membrane side of dispase pretreated AM, with or without seeding rabbit conjunctival fibroblasts (RCFs) on the stromal side. After 7 to 12 days, half of the cultures were raised to the air liquid interface, and the remainder stayed submerged. A small group of air-lifted cultures containing RCFs was treated with retinoic acid. After 1, 2, and 4 weeks, cultures were terminated and processed for immunostaining with antibodies directed against distinct types of mucins (SMC and AM3), glycocalyx (AMEM2), keratin K3 (AE5), and K12 (AK2). Additionally, western blot analysis was performed for K3 keratin expression. Ultrastructural changes were evaluated by transmission electron microscopy. RESULTS: In general, RCEs grown on AM were uniformly small, negative to AE5 and AK2 antibodies, and positive to AMEM2 and ASPG1 antibodies. Epithelial stratification and cell polarity with prominent microvilli, tight junctions, and hemidesmosomes were more pronounced in air lifted cultures. RCEs cocultured with RCFs showed scattered AM3-positive goblet cells, which were not increased by retinoic acid. CONCLUSIONS: RCEs cultured on AM primarily exhibit a nongoblet conjunctival epithelial phenotype. Epithelial stratification and cell polarity, features essential for epithelial differentiation, are promoted by air-lifting. This culture model will be useful for studying how growth and differentiation of conjunctival epithelial cells can be modulated further. PMID- 10102285 TI - Differential inhibition of collagenase and interleukin-1alpha gene expression in cultured corneal fibroblasts by TGF-beta, dexamethasone, and retinoic acid. AB - PURPOSE: Expression of the genes for collagenase and interleukin-1alpha (IL 1alpha) are induced as stromal cells become activated to the repair fibroblast phenotype after injury to the cornea. This investigation examines the mechanisms whereby expression of these genes is inhibited by transforming growth factor-beta (TGF-beta), dexamethasone (DEX), or retinoic acid (RET A). METHODS: A model of freshly isolated cultures of corneal stromal cells and early passage cultures of corneal fibroblasts was used in these studies. This model reproduces the events of stromal cell activation in the corneal wound. RESULTS: In early passage cultures of corneal fibroblasts, expression of collagenase is under obligatory control by autocrine IL-1alpha. IL-1alpha controls its own expression through an autocrine feedback loop that is dependent on transcription factor NF-kappaB. TGF beta, DEX, and RET A were each effective inhibitors of collagenase gene expression in these cells. Furthermore, these agents have the capacity to inhibit expression of IL-1alpha and this was correlated with their ability to affect DNA binding activity of NF-kappaB. However, TGF-beta, DEX, and RET A were also effective inhibitors of the low level of collagenase expressed by freshly isolated corneal stromal cells that cannot express IL-1alpha. CONCLUSIONS: In cells with an active IL-1alpha autocrine loop there are at least two distinct signaling pathways by which collagenase gene expression can be modulated. The results of this study demonstrate that TGF-beta, DEX, and RET A differentially inhibit collagenase and IL-1alpha gene expression. This information will be useful in the design of therapeutic modalities for fibrotic disease in the cornea and other parts of the eye. PMID- 10102286 TI - Lysozyme sorption in hydrogel contact lenses. AB - PURPOSE: To examine the processes involved in formation of protein deposits on hydrogel contact lenses. METHODS: The adsorption and/or penetration of lysozyme on or into three types of contact lenses, etafilcon A, vifilcon A, and tefilcon, were investigated in vitro using a radiolabel-tracer technique, x-ray photoelectron spectroscopy, and laser scanning confocal microscopy. RESULTS: Binding of lysozyme to high-water-content, ionic contact lenses (etafilcon A and vifilcon A) was dominated by a penetration process. The extent of this penetration was a function of charge density of the lenses, so that there was a higher degree of penetration of lysozyme in etafilcon A than in vifilcon A lenses. In contrast, the binding of lysozyme to tefilcon lenses was a surface adsorption process. The adsorption and desorption kinetics showed similar trends to those found in human serum albumin (HSA) adsorption on lens surfaces. However, the extent of lysozyme adsorption on tefilcon is much higher than HSA adsorption, probably because of the self-association of lysozyme on the tefilcon lens surface. Furthermore, either penetration or adsorption of lysozyme involved reversible and irreversible processes and were both time dependent. CONCLUSIONS: Binding of lysozyme to hydrogel lenses involves surface adsorption or matrix penetration. These processes may be reversible or irreversible. The properties of the lens materials, such as charge density (ionicity) and porosity (water content) of the lenses, determine the type and rates of these processes. PMID- 10102287 TI - Matrix adhesion characteristics of corneal myofibroblasts. AB - PURPOSE: To investigate the adhesion characteristics of corneal myofibroblasts in a cell culture model. METHODS: Immunocytochemistry, immunoprecipitation, western blot analysis, and attachment assays were used to evaluate matrix adhesion characteristics of myofibroblasts. RESULTS: Myofibroblasts, defined by their expression of the smooth muscle isoform of alpha-actin, were evaluated and compared with fibroblasts. Myofibroblasts had larger vinculin-containing focal adhesions and expressed more of the classic fibronectin receptor (FNR) alpha5beta1 per cell. However, myofibroblasts had less surface expression of the higher molecular weight alpha4 subunit of another FNR, alpha4beta1, than did fibroblasts. Myofibroblasts adhered more avidly in an integrin-dependent manner to fibronectin than did fibroblasts. The attachment to fibronectin was actin dependent for both phenotypes, but the myofibroblasts' adhesion was more resistant to disruption by cytochalasin than were fibroblasts'. In addition to the previously described expression of a 135-kDa classic cadherin, myofibroblasts also expressed a 115-kDa mesenchymal cadherin, cadherin-11. CONCLUSIONS: Differentiation of corneal fibroblasts into myofibroblasts is associated with characteristics that would indicate that the latter have a special role in wound closure. The increase in focal and cell adhesion molecules that accompanies smooth muscle-specific actin expression provides the basis for the myofibroblasts' enhanced cell-fibronectin and cell-cell adhesion. PMID- 10102288 TI - Reactive oxygen species-induced apoptosis and necrosis in bovine corneal endothelial cells. AB - PURPOSE: The loss of corneal endothelial cells associated with aging and possibly other causes has been speculated to be related to exposure to reactive oxygen species (ROS). The current study was conducted to investigate, by use of photosensitizers, the underlying mechanisms involved in the death of bovine corneal endothelial cells (BCENs) caused by ROS. METHODS: BCEN cells in primary culture were treated with a photosensitizer (riboflavin or rose bengal) with light exposure. The patterns of cell damage and death were assessed using an acridine orange-ethidium bromide differential staining method, TdT-mediated dUTP nick-end labeling (TUNEL) assay, and transmission electron microscopy. The cytotoxicity was assayed by mitochondrial function using 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyl tetrazolium bromide (MTT) testing. Antioxidants, including catalase, L-histidine, salicylic acid, and superoxide dismutase, were used to determine the types of ROS involved. Activation of nuclear factor (NF)-kappaB was examined by fluorescent immunocytochemistry with anti-p65 antibody. RESULTS: Light-irradiated riboflavin or rose bengal resulted in a significant decrease in viability of BCEN cells. Chromosomal condensation and fragmentation were observed in apoptotic cells, and membrane lysis and damage of cell ultrastructures were observed in necrotic cells. Riboflavin induced apoptosis at 30 minutes and thereafter and induced necrosis after 2 hours. Rose bengal was shown to cause similar effects within half the time required for the effects of riboflavin. Catalase and salicylic acid were found to provide protection for BCENs from cytotoxic effects of riboflavin, and L-histidine was found to protect BCENs from cytotoxicity induced by rose bengal. Kinetic studies using immunocytochemistry showed that NF-kappaB was translocated into the nucleus within 15 minutes and 30 minutes after treatment with rose bengal and riboflavin, respectively. CONCLUSIONS: The cytotoxic effects of photo-irradiated riboflavin and rose bengal are shown to be mediated by two distinct but parallel pathways, one leading to apoptosis and the other to necrosis. Possible involvement of NF-kappaB in cell death is suggested. These findings provide potential leads for future investigation into the molecular mechanisms of loss of corneal endothelial cells related to aging, oxidative stress, and possibly other similar causes. PMID- 10102289 TI - Cone signal contributions to electroretinograms [correction of electrograms] in dichromats and trichromats. AB - PURPOSE: To find out how the different cone types contribute to the electroretinogram (ERG) by quantifying the contribution of the signal pathways originating in the long (L-) and the middle (M-) wavelength-sensitive cones to the total ERG response amplitude and phase. METHODS: ERG response amplitudes and phases were measured to cone-isolating stimuli and to different combinations of L and M-cone modulation. Conditions were chosen to exclude any contribution of the short wavelength-sensitive (S-) cones. The sensitivity of the ERG to the L and the M cones was defined as the cone contrast gain. RESULTS: In the present paper, a model is provided that describes the ERG contrast gains and ERG thresholds in dichromats and color normal trichromats. For the X-chromosome-linked dichromats, the contrast gains of only one cone type (either the L or the M cones) sufficed to describe the ERG thresholds for all stimulus conditions. Data suggest that the M-cone contrast gains of protanopes are larger than the L-cone contrast gains of deuteranopes. The response thresholds of the trichromats are modeled by assuming a vector summation of signals originating in the L and the M cones. Their L- and M-cone contrast gains are close to a linear interpolation of the data obtained from the dichromats. Nearly all trichromats had larger L- than M-cone contrast gains. Data from a large population of trichromats were examined to study the individual variations in cone weightings and in the phases of the cone pathway responses. CONCLUSIONS: The data strongly suggest that the missing cone type in dichromats is replaced by the remaining cone type. The mean L-cone to M-cone weighting ratio in trichromats was found to be approximately 4:1. But there is a substantial interindividual variability between trichromats. The response phases of the L- and the M-cone pathways can be reliably quantified using the response phases to the cone-isolating stimuli or using a vector addition of L- and M-cone signals. PMID- 10102291 TI - Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: protection is independent of IL-10-inducing activity. AB - PURPOSE: Experimental autoimmune uveoretinitis (EAU) is a cell-mediated model of retinal autoimmunity that is negatively regulated by interleukin (IL)-10. The antidepressant drug rolipram, a type IV phosphodiesterase inhibitor, enhances IL 10 production by monocyte/macrophages. The effect of rolipram on induction of EAU and its associated immunologic responses was investigated. METHODS: Mice were challenged for EAU induction by immunization with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP) or by adoptive transfer of uveitogenic T cells and were treated with rolipram. EAU severity and immunologic responses to IRBP were analyzed. In addition, the effect of rolipram added to the culture on antigen-driven responses of primed lymph node cells was tested. RESULTS: Rolipram treatment from days -1 to 7 after immunization (afferent phase) was not protective, but severity of EAU was reduced to 50% by treatment from days 8 to 16 after immunization or when EAU was induced by adoptive transfer (efferent phase). Antigen-specific proliferation and interferon (IFN)-gamma production ex vivo by lymph node cells of protected mice were not reduced. However, the addition of rolipram directly to the culture suppressed IRBP-driven proliferation and IFN-gamma production by primed lymph node cells. Freshly explanted lymph node cells of treated mice showed inhibition of IFN-gamma mRNA but no parallel enhancement of IL-10 mRNA by quantitative polymerase chain reaction. Rolipram inhibited EAU in IL-10 knockout mice equally well compared with controls and suppressed their primed lymph node cells in culture. CONCLUSIONS: Rolipram appears to inhibit the expansion and effector function of uveitogenic T cells, raising the possibility that it may be useful for treatment of established disease. Contrary to expectations based on in vitro studies, the protective effects in vivo appear to be independent of IL-10. The observation that suppression of antigen-specific responses is demonstrable only in the physical presence of the drug suggests that, in a clinical setting, continuous administration of rolipram might be needed to sustain its therapeutic effect. PMID- 10102290 TI - Latrunculin-A increases outflow facility in the monkey. AB - PURPOSE: To determine the effect of Latrunculin (LAT)-A, a macrolide that binds to G-actin, which leads to the disassembly of actin filaments, on shape, junctions, and the cytoskeleton of cultured bovine aortic endothelial cells (BAECs) and on outflow facility in living monkeys. METHODS: Latrunculin-A dose time-response relationships in BAECs were determined by immunofluorescence and phase contrast light microscopy, facility by two-level constant pressure anterior chamber perfusion. RESULTS: In BAECs, LAT-A caused dose- and incubation time- dependent destruction of actin bundles, cell separation, and cell loss. Cell-cell adhesions were more sensitive than focal contacts. Recovery was also dose- and time-dependent. In monkeys, exchange intracameral infusion and topical application of LAT-A induced dose- and time-dependent several-fold facility increases. The facility increase was completely reversed within several hours after drug removal. However, for at least 24 hours after a single topical LAT-A dose, perfusion with drug-free solution caused an accelerated increase in facility beyond that attributed to normal resistance washout. CONCLUSIONS: Pharmacological disorganization of the actin cytoskeleton in the trabecular meshwork by specific actin inhibitors like LAT-A may be a useful antiglaucoma strategy. PMID- 10102292 TI - AlphaB-crystallin selectively targets intermediate filament proteins during thermal stress. AB - PURPOSE: AlphaB-Crystallin is a small heat shock protein (sHsp) expressed at high levels in the lens of the eye, where its molecular chaperone functions may protect against cataract formation in vivo. The purpose of this study was to identify protein targets for the sHsp alphaB-crystallin in lens cell homogenates during conditions of mild thermal stress. METHODS: The authors report the use of a fusion protein, maltose-binding protein alphaB-crystallin (MBP-alphaB), immobilized on amylose resin as a novel method for isolating endogenous alphaB crystallin-binding proteins from lens cell homogenates after mild thermal stress. RESULTS: Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western immunoblot analyses showed selective interactions in lens cell homogenates between MBP-alphaB and endogenous alphaA- and alphaB-crystallins, the lens-specific intermediate filament proteins phakinin (CP49) and filensin (CP115), and vimentin during a mild 20-minute heat shock at 45 degrees C. No interactions were observed with the beta- or gamma-crystallins, or the cytoskeletal proteins actin, alpha-tubulin, and spectrin, although these proteins were present in lens cell homogenates. In contrast, gamma-crystallin and actin interacted with MBP-alphaB at 45 degrees C only in their purified states. The results obtained with MBP-alphaB were confirmed by immunoprecipitation reactions in which immunoprecipitation of native bovine alphaB-crystallin from heat-shocked lens cell homogenates resulted in the coprecipitation of phakinin and filensin. CONCLUSIONS: In the lens the sHsp alphaB-crystallin may selectively target intermediate filaments for protection against unfolding during conditions of stress. PMID- 10102293 TI - Oxidant-induced apoptosis in cultured human retinal pigment epithelial cells. AB - PURPOSE: To determine the mechanism of oxidant-induced cell death in cultured human retinal pigment epithelium (hRPE). METHODS: Cultured hRPE cells were treated with different concentrations of a chemical oxidant, t-butylhydroperoxide (tBH), for different periods of time. Apoptosis was determined with terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) and flow cytometry. Mitochondrial membrane potential (mtdelta psi) was measured by rhodamine 123 staining and subsequent flow cytometry. Release of mitochondrial cytochrome c (cyt c) and cleavage of procaspase 3 and caspase substrates were determined by western blot analysis. RESULTS: t-Butylhydroperoxide caused time- and dose-dependent activation of apoptosis in hRPE, indicated by characteristic morphologic changes; TUNEL-positive labeling; phosphatidylserine (PS) exposure; and procaspase 3, poly(ADP-ribose)polymerase, lamin, and tubulin cleavage. An early decrease of mtdelta psi was observed before caspase activation, together with the release of mitochondrial cyt c. CONCLUSIONS: Results indicate that tBH can induce apoptosis in hRPE, probably by triggering the mitochondrial permeability transition, which results in swelling and release of mitochondrial intermembrane proteins. PMID- 10102294 TI - Apoptosis and caspases after ischemia-reperfusion injury in rat retina. AB - PURPOSE: Extensive cell loss in the retinal ganglion cell layer (RGCL) and the inner nuclear layer (INL) was noted in a rat model of retinal ischemia reperfusion injury by transient elevated intraocular pressure (IOP). The possible involvement of apoptosis and caspases was examined in this model of neuronal loss. METHODS: Transient elevated IOP was induced in albino Lewis rats through the insertion of a needle into the anterior chamber connected to a saline column. Elevated IOP at 110 mm Hg was maintained for 60 minutes. Groups of animals were euthanatized at various times after reperfusion, and their retinas were evaluated by morphology, agarose gel electrophoresis of DNA, in situ terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling (TUNEL), immunohistochemistry of caspases II (ICH1) and III (CPP32), and morphometry. YVAD.CMK, a tetrapeptide inhibitor of caspases, was used to examine the involvement of caspases. RESULTS: A marked ladder pattern in retinal DNA gel analysis, typical of internucleosomal DNA fragmentation and characteristic of apoptosis, was present 12 and 18 hours after reperfusion. Labeling of nuclei in the RGCL and the inner nuclear layer (INL) by TUNEL was noted between 8 and 18 hours after reperfusion. Histologic and ultrastructural features typical of apoptosis were also observed in the inner retina after ischemia. YVAD.CMK administered during the ischemic period inhibited apoptotic fragmentation of retinal DNA and ameliorated the tissue damage. When administered intravitreally 0, 2, or 4 hours after reperfusion, YVAD.CMK was also effective in preserving the inner retina but had no significant effect when administered 6 or 8 hours after reperfusion. The inner retina showed transient elevated immunoreactivity of caspases II and III 4 and 8 hours after reperfusion. CONCLUSIONS: Retinal ischemia-reperfusion after transient elevated IOP induced apoptosis of cells in the retinal ganglion cell layer and the INL. Caspases may have a pivotal role in the early events of the apoptotic pathway(s). Rescue by using anti-apoptotic agents after ischemia-reperfusion is feasible. PMID- 10102295 TI - Interferon-gamma signaling in human retinal pigment epithelial cells mediated by STAT1, ICSBP, and IRF-1 transcription factors. AB - PURPOSE: Studies have shown that interferon (IFN)-gamma stimulates expression of intercellular adhesion molecule-1 (ICAM-1), major histocompatibility complex (MHC) class II, interleukin (IL)-6, and inducible nitric oxide synthase and inhibits replication of Toxoplasma gondii in human retinal pigment epithelial (HRPE) cells. The present study was undertaken to investigate the molecular mechanisms of IFN-gamma action. METHODS: RNA, whole-cell extracts, and nuclear extracts were prepared from HRPE cells cultured in the presence or absence of IFN gamma. Activation of IFN-gamma-responsive genes was analyzed by electrophoretic mobility shift assay, reverse transcription-polymerase chain reaction (RT-PCR), western blot analysis, and immunoprecipitation. RESULTS: HRPE cells constitutively expressed two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-1 and IRF-2. After exposure to IFN-gamma, transcription of IRF-1 and IFN consensus sequence binding protein (ICSBP) genes were induced; IRF-2 gene transcription was not upregulated. Activation of IFN gamma-responsive genes was mediated by tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)-1 factor. CONCLUSIONS: This study characterized the IFN-gamma signaling pathway in HRPE cells and identified IRF-1, ICSBP, and tyrosine-phosphorylated STAT1 as mediators of IFN-gamma action in these cells. ICSBP is thought to be exclusively used in immunologic responses and has previously been detected only in lymphoid cells. However, the current study shows that ICSBP expression is inducible in HRPE cells, suggesting that it may regulate gene transcription in RPE cells and possibly in other nonimmunologic cell types. PMID- 10102296 TI - The contribution of various NOS gene products to HIV-1 coat protein (gp120) mediated retinal ganglion cell injury. AB - PURPOSE: There is growing evidence that the neuronal pathology seen with HIV-1 is mediated, at least in part, through an excitotoxic/free radical pathway. Nitric oxide (NO) plays a critical role in the nervous system, in both normal and pathologic states, and appears to be involved in a variety of excitotoxic pathways. Whether isoforms of nitric oxide synthase (NOS) are involved in gp120 mediated neuronal loss in the retina was therefore explored. METHODS: To determine which (if any) of the various isoforms of NOS are critical in gp120 mediated damage in the retina, neuronal NOS-deficient [nNOS(-/-)], endothelial NOS-deficient [eNOS(-/ -)], and immunologic NOS-deficient [iNOS(-/-)] mice were subjected to intravitreal injections of gp120. RESULTS: Retinal ganglion cells in the nNOS(-/-) mouse were relatively resistant to gp120, manifesting attenuation of gp120-induced injury compared with wild-type mice. The iNOS(-/-) and eNOS(-/-) mice were as susceptible to gp120 toxicity as control animals. NOS inhibitors were protective against this toxicity. CONCLUSIONS: The presence of nNOS is a prerequisite for the full expression of gp120-mediated loss in the retina; eNOS and iNOS do not appear to play a significant role. PMID- 10102297 TI - Retinal TUNEL-positive cells and high glutamate levels in vitreous humor of mutant quail with a glaucoma-like disorder. AB - PURPOSE: To investigate whether retinal cell death observed in an avian glaucoma like disorder occurs by apoptosis and whether an increase in excitotoxic amino acid concentration in the vitreous humor is associated temporally with cell death in the retina. METHODS: Presumptive retinal apoptotic nuclei were identified by histochemical detection of DNA fragmentation (by TdT-dUTP terminal nick-end labeling [TUNEL]), and vitreal concentrations of glutamate and several other amino acids were determined by high-pressure liquid chromatography with fluorometric detection in the al mutant quail (Coturnix coturnix japonica) in which a glaucoma-like disorder develops spontaneously. RESULTS: TUNEL-labeled nuclei were located mostly in the ganglion cell layer (GCL) in the retina of mutant quails 3 months after hatching. However, labeled nuclei were also observed in the inner and outer nuclear layers. At 7 months, most TUNEL-positive nuclei were detected in the inner nuclear layer, whereas labeled cells in the GCL were reduced in number. No TUNEL-labeled nuclei were detected in the retina of control quails at any age. Vitreal concentrations of glutamate and aspartate were significantly increased in 1-month-old mutant quails compared with control animals. Concentrations decreased at 3 months, and no significant differences were observed between strains at 7 months. CONCLUSIONS: Presumptive apoptotic cell death is detected from 3 months after hatching in mutant quails and is not restricted to retinal ganglion cells. Cell death appears just after a significant increase in excitotoxic amino acid concentrations in the vitreous humor, suggesting a correlation between both events. PMID- 10102298 TI - Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26. AB - PURPOSE: To determine the chromosomal location and to identify the gene causing a type of retinitis punctata albescens, called Bothnia dystrophy, found in a restricted geographic area in northern Sweden. METHODS: Twenty patients from seven families originating from a restricted geographic area in northern Sweden were clinically examined. Microsatellite markers were analyzed in all affected and unaffected family members. Direct genomic sequencing of the gene encoding cellular retinaldehyde-binding protein was performed after the linkage analysis had been completed. RESULTS: Affected individuals showed night blindness from early childhood with features consistent with retinitis punctata albescens and macular degeneration. The responsible gene was mapped to 15q26, the same region to which the cellular retinaldehyde-binding protein gene has been assigned. Subsequent analysis showed all affected patients were homozygous for a C to T substitution in exon 7 of the same gene, leading to the missense mutation Arg234Trp. Analysis of marker haplotypes suggested that all cases had a common ancestor who carried the mutation. CONCLUSIONS: A missense mutation in the cellular retinaldehyde-binding protein gene is the cause of Bothnia dystrophy. The disease is a local variant of retinitis punctata albescens that is common in northern Sweden due to a founder mutation. PMID- 10102299 TI - Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. AB - PURPOSE: To determine the frequency and spectrum of mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein (CRALBP) in patients with hereditary retinal degeneration. METHODS: The single-strand conformation polymorphism (SSCP) technique and a direct genomic sequencing technique were used to screen the coding exons of this gene (exons 2-8) for mutations in 324 unrelated patients with recessive or isolate retinitis pigmentosa, retinitis punctata albescens, Leber congenital amaurosis, or a related disease. Variant DNA fragments revealed by SSCP analysis were subsequently sequenced. Selected alleles that altered the coding region or intron splice sites were evaluated further through segregation analysis in the families of the index cases. RESULTS: Four novel mutations were identified in this gene among three unrelated patients with recessively inherited retinitis punctata albescens. Two of the mutations were missense: one was a frameshift, and one affected a canonical splice donor site. CONCLUSIONS: Recessive mutations in the RLBP1 gene are an uncommon cause of retinal degeneration in humans. The phenotype produced by RLBP1 mutations seems to be a form of retinitis punctata albescens. PMID- 10102300 TI - Experimental induction of retinal ganglion cell death in adult mice. AB - PURPOSE: Retinal ganglion cells die by apoptosis during development and after trauma such as axonal damage and exposure to excitotoxins. Apoptosis is associated with changes in the expression of genes that regulate this process. The genes that regulate apoptosis in retinal ganglion cells have not been characterized primarily because previous studies have been limited to animal models in which gene function is not easily manipulated. To overcome this limitation, the rate and mechanism of retinal ganglion cell death in mice was characterized using optic nerve crush and intravitreal injections of the glutamate analog N-methyl-D-aspartate (NMDA). METHODS: To expose retinal ganglion cells (RGCs) to excitotoxins, adult CB6F1 mice were injected intravitreally in one eye with NMDA. In an alternative protocol to physically damage the axons in the optic nerve, the nerve was crushed using self-closing fine forceps. Each animal had one or the other procedure carried out on one eye. Loss of RGCs was monitored as a percentage of cells lost relative to the fellow untreated eye. Thy1 expression was examined using in situ hybridization. DNA fragmentation in dying cells was monitored using terminal transferase-dUTP nick-end labeling (TUNEL). RESULTS: RGCs comprise 67.5% +/- 6.5% (mean +/- SD) of cells in the ganglion cell layer (GCL) of control mice based on nuclear morphology and the presence of mRNA for the ganglion cell marker Thy1. One week after optic nerve crush, these cells started to die, progressing to a maximum loss of 57.8% +/- 8.1% of the cells in the GCL by 3 weeks. Cell loss after NMDA injection was dose dependent, with injections of 10 nanomoles having virtually no effect to a maximum loss of 72.5% +/- 12.1% of the cells in the GCL within 6 days after injection of 160 nanomoles NMDA. Cell death exhibited features of apoptosis after both optic nerve crush and NMDA injection, including the formation of pyknotic nuclei and TUNEL staining. CONCLUSIONS: Quantitative RGC death can be induced in mice using two distinct signaling pathways, making it possible to test the roles of genes in this process using transgenic animals. PMID- 10102301 TI - Effect of staurosporine on outflow facility in monkeys. AB - PURPOSE: To determine the effect of the serine-threonine kinase inhibitor staurosporine on outflow facility in living monkeys. METHODS: Total outflow facility was determined by two-level constant pressure perfusion of the anterior chamber bilaterally before and after intracameral infusion of staurosporine or vehicle in opposite eyes. RESULTS: Intracameral staurosporine dose-dependently doubled outflow facility, with 0.1 microM, 1 microM, and 10 microM being subthreshold, effective, and maximal doses, respectively. At 50 microM, intracameral staurosporine was less effective than 10 microM on facility and induced corneal toxicity. CONCLUSIONS: The broad-spectrum protein kinase inhibitor staurosporine increases outflow facility in living monkeys, perhaps by affecting the trabecular meshwork cytoskeleton. PMID- 10102302 TI - Mechanism of exercise-induced ocular hypotension. AB - PURPOSE: Although acute dynamic exercise reduces intraocular pressure (IOP), the factors that provoke this response remain ill-defined. To determine whether changes in colloid osmotic pressure (COP) cause the IOP changes during exercise, standardized exercise was performed after dehydration and hydration with isosmotic fluid. METHODS: Progressive cycle ergometer exercise to volitional exhaustion was performed after 4 hours' dehydration, and after hydration with 946 ml isosmotic liquid (345 mOsM). In each experiment, venous blood taken before and immediately after exercise was analyzed for hematocrit, plasma protein concentration, total plasma osmolality, and plasma COP. RESULTS: Exercise in both experiments significantly reduced IOP and elevated COP (each P < 0.01). Dehydration, compared with hydration, also significantly reduced IOP and elevated COP, when measured before and after exercise (P < 0.05). The correlation of mean IOP with mean COP, over the entire range created by varying exercise and hydration statuses, was statistically significant (r = -0.99; P < 0.001). In contrast, other indexes of hydration status, including hematocrit, total plasma osmolality, and plasma protein concentration, failed to change as IOP changed and failed to correlate with IOP, on either a group or individual basis, in conditions of varying levels of exercise and hydration. CONCLUSIONS: Acute dynamic exercise and isosmotic fluid ingestion each seem to change IOP through changes in COP. PMID- 10102303 TI - Effect of Ox-LDL on endothelium-dependent response in pig ciliary artery: prevention by an ET(A) antagonist. AB - PURPOSE: To investigate whether oxidized low-density lipoprotein (Ox-LDL) affects endothelium-dependent responses in isolated porcine ciliary arteries. METHODS: In a myograph system for isometric force measurements, quiescent vessels were incubated with 50 microg/ml, 100 microg/ml, or 200 microg/ml Ox-LDL; 100 microg/ml native LDL (n-LDL); 1 microM of the ET(A)- endothelin receptor antagonist BQ 123; 100 microg/ml Ox-LDL coadministered with 1 microM BQ 123; or 100 microg/ml Ox-LDL coadministered with 50 microM of the protein synthesis inhibitor cycloheximide. Vessels with nonfunctional endothelium (intentionally and mechanically damaged) were also exposed to 100 microg/ml Ox-LDL. Two hours later, vessels were washed, precontracted with the thromboxane A2 analog U 46619 (approximately 0.1 microM), and exposed to bradykinin (0.1 nM to 3 microM), an endothelium-dependent relaxing agent. RESULTS: In quiescent vessels, Ox-LDL evoked delayed contractions. In contrast, no contractions were observed after exposure to n-LDL, BQ 123, Ox-LDL with BQ 123, or Ox-LDL with cycloheximide. In vessels with nonfunctional endothelium, Ox-LDL did not evoke contraction. Bradykinin-induced relaxations were inhibited in a dose-dependent manner by Ox LDL, but not by n-LDL, BQ 123 alone, Ox-LDL with BQ 123, or Ox-LDL with cycloheximide. CONCLUSIONS: In porcine ciliary arteries, Ox-LDL affects endothelium-dependent responses through the activation of ET(A)- endothelin receptors. As Ox-LDL can accumulate in atherosclerotic plaques, such a mechanism might be involved in the occlusion of the ophthalmic circulation observed in patients with hypercholesterolemia and atherosclerosis. PMID- 10102304 TI - Increased susceptibility to constant light in nr and pcd mice with inherited retinal degenerations. AB - PURPOSE: To determine whether the degenerating photoreceptors in nervous (nr/nr) and Purkinje cell degeneration (pcd/pcd) mutant mice are more susceptible to the damaging effects of constant light than those in age-matched normal mice. METHODS: Beginning at two ages for each mutant, albino nr/nr and pcd/pcd mice were placed into constant fluorescent light at an illuminance of 115 foot-candles to 130 foot-candles for a period of 1 week. Age-matched (usually littermate) normal (+/-) mice were exposed at the same time. The degree of photoreceptor cell loss was quantified histologically by obtaining a mean outer nuclear layer thickness for each animal. The light-exposed mice were compared with age-matched mutant and normal mice that were maintained in cyclic light. RESULTS: The homozygous mutants at each age showed a significantly greater loss of photoreceptor cells caused by constant light exposure than did the normal +/- mice in the same period of light exposure. The nr/nr and pcd/pcd mutants lost two to three times the number of photoreceptor cells than did the +/- mice during the constant light exposure. CONCLUSIONS: It has long been thought that excessive light may be harmful to patients with inherited or age-related photoreceptor degenerations. The present data add to other experimental evidence suggesting that photoreceptors already undergoing inherited or other forms of degeneration may be particularly susceptible to the damaging effects of excessive light. PMID- 10102305 TI - Informed consent and general surgeons' attitudes toward the use of pain medication in the acute abdomen. AB - To determine general surgeons' attitudes about the use of pain medications in the acute abdomen, a questionnaire was mailed to all practicing general surgeons in Iowa. The questionnaire sought to determine the frequency with which pain medications were administered either before informed consent was obtained or before the patient with an acute abdomen was examined, and, in cases when pain medications were withheld, the reasons for withholding. The response rate was 72% (131 of 182). Seven percent of patients with an acute abdomen received pain medications by a general surgeon before being seen and 22% received pain medication by another physician in the emergency department (ED). Fifty-three percent of general surgeons responded that they believe pain medications preclude a patient from signing a valid informed consent; 78% reported that concerns about informed consent enter into their decision to withhold pain medications. Sixty seven percent agreed that pain medications interfere with diagnostic accuracy, and 82% consider diagnostic accuracy when deciding to withhold pain medication. PMID- 10102306 TI - Ultrasound for the detection of intraperitoneal fluid: the role of Trendelenburg positioning. AB - A prospective, observational study was performed to evaluate the role of Trendelenburg positioning in improving the sensitivity of the single-view ultrasound examination. Hemodynamically stable patients undergoing diagnostic peritoneal lavage (DPL) were assigned to one of two groups: supine or 5 degrees of Trendelenburg positioning. Baseline right intercostal oblique images of Morison's pouch were obtained followed by additional images for each 100 cc of lavage fluid instilled into the peritoneal cavity. The initial volume of fluid required to identify an anechoic stripe was recorded for each patient. Patients were excluded if they had (1) a positive DPL for hemoperitoneum (defined as 10 cc of gross blood or >100,000 red blood cells/microL), (2) positive baseline ultrasound study, (3) hemodynamic instability, or (4) lack of documentation (ie, baseline/subsequent hard copy images were not obtained or inadequately demonstrated anechoic stripe). The mean quantity of fluid for visualization of the anechoic stripe was 443.8 cc in the Trendelenburg group (n = 8) and 668.2 cc in the supine group (n = 11). These means were statistically different (P < .05, t test). The median amount of fluid needed for visualization of the anechoic stripe was 400 cc and 700 cc for the Trendelenburg and supine groups, respectively. PMID- 10102307 TI - Low- versus high-pressure irrigation techniques in Staphylococcus aureus inoculated wounds. AB - Current teaching emphasizes the importance of high-pressure (5 to 8 pounds per square inch [psi]) irrigation of traumatic wounds. The purpose of this study was to compare the irrigation efficacy, in an animal wound model, of the traditional higher-pressure, lower-volume (HPLV) syringe and catheter method of wound irrigation with a novel lower-pressure, higher-volume (LPHV) "port" method of irrigation. Experimental rat wounds were inoculated and incubated for 1 to 5 hours with a pathogenic strain of Staphylococcus aureus bacteria, then irrigated with one of the two methods. Irrigation times, mean irrigation pressures, and bacterial removal of the two techniques were compared. LPHV irrigation times were one third those of the HPLV. Mean irrigation pressures were 8.8 psi for HPLV and 1.6 psi for LPHV. HPLV and LPHV were found to be equally effective at washing out bacteria from the inoculated wounds at all times studied. PMID- 10102308 TI - Cervical spine injury in low-impact blunt trauma. AB - Few data are available regarding the incidence of cervical spine injuries following relatively low-impact blunt trauma. This prospective level II trauma center study of low-impact blunt trauma found a 1.30% incidence of cervical spine injury. Impressive differences were found in such parameters as population characteristics, modes of injury, elapsed times to emergency department evaluation, and Revised Trauma Scores between this study group and those reported in prospective level I high-impact blunt trauma series. Cervical spine injury in low-impact blunt trauma is significant and often presents less than dramatically, thus emphasizing a need for maintaining a high index of suspicion at all times. PMID- 10102309 TI - Helicopter transport of patients to tertiary care centers after cardiac arrest. AB - Air transport is commonly used to transfer survivors of cardiac arrest from rural hospitals to large tertiary-care centers, presumably to improve outcome. To examine this issue, a retrospective review of patients stabilized after a cardiac arrest was conducted; 157 transports were reviewed. The mean age of patients was 37.9 +/- 27.8 yrs, with a male to female ratio of 2.2:1. Survivors were significantly older than nonsurvivors. Thirty-one of 69 patients (45%) with primary cardiac disease were discharged alive from the hospital, 75% without neurological sequelae. Only a minority of patients with noncardiac medical illness (7%), electrical injury (33%), suffocation (15%), near-drowning (15%), and inhalation (0%) were discharged alive from the hospital. Outcomes for cardiac arrest in adult patients older than 65 years (32.3% survival) were similar to those for adult patients younger than 65 years (36.2% survival) (P = .887). These results show that survivors of a primary cardiac event have a favorable outcome when transferred by air to tertiary centers when compared with historical controls that were transported by ground. On the other hand, cardiac arrests from noncardiac medical illness, suffocation, near-drowning, and inhalation have a grim prognosis. Prospective studies should clarify the role of air transport in these patients. PMID- 10102310 TI - Cervical collar-induced changes in intracranial pressure. AB - Placement of a protective cervical collar is common in cases of acute head trauma. However, the effect of this collar on intracranial pressure is uncertain. This prospective study examined the change in measured cerebrospinal fluid pressure (CSFP) after the application of a rigid Philadelphia collar in 20 adult patients undergoing lumbar puncture. CSFP averaged 176.8 mm H2O initially and increased to an average of 201.5 mm H2O after collar placement (range 0 to 120). Although this difference of 24.8 mm H2O is statistically significant (P = .001), it is uncertain if this would be clinically important. Nonetheless, this small increment in pressure could be significant in patients who already have an elevated intracranial pressure. PMID- 10102311 TI - Toxicology training of paramedic students in the United States. AB - A 16-item survey was mailed to the directors of 618 paramedic training programs in the United States to determine (1) the number of lecture hours devoted to toxicology topics and (2) how often paramedic training includes a rotation in a poison control center. The response rate was 82%. Toxicology accounts for approximately 2% of paramedic students' total training. Cardiovascular drug toxicity and hazardous materials are discussed for over 60 minutes by more than 50% of paramedic training programs. Four paramedic programs have no lecture time on cyclic antidepressant overdoses and one program has no lecture time on carbon monoxide poisoning. Eighty-one percent (377 of 467) have access to a regional poison control center; 11% (42 of 377) use the poison control center as a paramedic training site. Some US paramedic training programs spend insufficient time covering topics that have significant out-of-hospital morbidity. Although poison control centers are often available, they are underutilized for paramedic training. PMID- 10102312 TI - Complications of emergency intubation with and without paralysis. AB - Expert and definitive airway management is fundamental to the practice of emergency medicine. In critically ill patients, rapid sedation and paralysis, also known as rapid-sequence intubation, is used to facilitate endotracheal intubation in order to minimize aspiration, airway trauma, and other complications of airway management. An alternative method of emergent endotracheal intubation, intubation minus paralysis, is performed without the use of neuromuscular blocking agents. The present study compared complications of these two techniques in the emergency setting. Sixty-seven intubations minus paralysis were prospectively compared with 166 rapid-sequence intubations. Complications were greater in number and severity in the nonparalyzed group and included aspiration (15%), airway trauma (28%), and death (3%). None of these difficulties were observed in the rapid-sequence group (P < .0001). These results show that rapid-sequence intubation when compared with intubation minus paralysis significantly reduces complications of emergency airway management and should be made available to emergency physicians trained in its use. PMID- 10102313 TI - Inhaled corticosteroids for asthma: are ED visits a missed opportunity for prevention? AB - Inhaled corticosteroids are effective but underused. This study evaluated the outpatient management of emergency department (ED) patients presenting with acute asthma and the relation of inhaled corticosteroid use to the patient's primary care provider (PCP) status. ED patients were interviewed by the hospital's asthma education program staff about their asthma. Overall, 85% (101 of 119) of asthmatics reported having a PCP. Although patients with a PCP and patients without a PCP both were using inhaled beta-agonists (93% v 89%, respectively; P = .54), patients without a PCP were less likely to be using inhaled corticosteroids (49% v 11%, P = .003). Controlling for age, acute asthma severity, and asthma hospitalizations during the past year, PCP status remained a significant predictor of inhaled corticosteroid use (odds ratio = 5.6; 95% confidence interval 1.1 to 27). Even among ED patients with a PCP, inhaled corticosteroids appear to be underused. ED asthma visits present an opportunity to initiate preventive measures such as inhaled corticosteroid use. PMID- 10102314 TI - Prehospital triage and communication performance in small mass casualty incidents: a gauge for disaster preparedness. AB - Because of their infrequency, disasters are difficult to train for. Emergency prehospital personnel frequently participate in small mass casualty incidents (MCIs) (3 to 50 victims). This study sought to examine prehospital performance in small MCIs in areas that are frequently mismanaged in disasters. Prospective data from the resource physician and retrospective data from tape recorded prehospital conversations were collected for a 9-month period. Clinical patient data, patient demographics, emergency medical services squad characteristics, and triage information were recorded. Forty-five consecutive MCIs were studied. Most of these were motor vehicle accidents. Prehospital providers included paid providers, nonpaid providers, and air and ground transport. The mean number of victims first identified (4.6%) was greatly different than the mean number of victims eventually transported from a scene (7.1%). Most patients were treated at a level 1 trauma center. Frequent errors included having multiple communicators on site (38%), misidentifying the number of victims (56%), and having unclear information for the resource physician (43%). Only 38% of events had prehospital triage information that was deemed appropriate in total. These results show that scene and triage errors are frequent in MCIs of small scale. This information can be used to assay a system's readiness for disasters. PMID- 10102315 TI - Patient ED turnaround times: a comparative review. AB - Patient turnaround times in emergency departments (EDs) are receiving increasing attention by patients, medical staff, hospital administrators, payers, and regulatory agencies. A retrospective study of ED turnaround times by hospitals identified by Modern Healthcare as being in the top 100 hospitals in the United States was undertaken. Five different categories of hospitals were studied. The shortest turnaround times occurred in rural hospitals with less than 250 beds and the longest times were in major academic centers with more than 400 beds. PMID- 10102316 TI - Outcomes of anticoagulated trauma patients. AB - Patients on warfarin are at high risk for potentially life-threatening hemorrhage even after relatively minor trauma. Outcomes of these patients and the potential complications of reversing the effects of anticoagulation have received little attention. This study was performed to determine the overall outcome of orally anticoagulated patients who sustained injury as well as to determine any untoward effects of reversing their anticoagulated states. A retrospective study of injured patients on warfarin was conducted on patients admitted to an urban, university, tertiary-referral, level I trauma center between 1/1/93 and 12/31/96. Surviving patients were followed for a period of at least 1 month. Injuries were grouped by anatomic site. Charts were reviewed for degree of anticoagulation on admission (ie, initial international normalized ratio [INR]), survival, adverse effects of reversal of anticoagulation, and reinstitution of warfarin therapy. Discharged patients were contacted at home for follow-up. Thirty-five consecutive patients, 18 men and 17 women, on warfarin therapy at the time of their injuries were reviewed. The mean age was 75 years, with a range of 39 to 96. The mean follow-up period was 12.7 months. Reasons for anticoagulation included atrial fibrillation, prosthetic heart valves, revascularized limb, hypercoagulable state, deep venous thrombosis, pulmonary embolism, phlebitis, and aortic stenosis. Mean admission INR was 3.2, with a range of 1.6 to 10.0. There were 8 in-hospital deaths. Intracranial hemorrhages accounted for the majority of injuries. Ten patients were not given reversal therapy. Four complications were attributable to reversal therapy (upper extremity hemiplegia, transient ischemic attack, deep venous thrombosis, arterial thrombosis). Twenty-one patients had their warfarin reinstituted. Follow-up of surviving patients ranged from 1.5 to 42 months. Patients on warfarin are at high risk for intracranial hemorrhage following trauma. Patients on warfarin may be reversed during the acute period following injury, but transient complications may arise. Further prospective studies need to be conducted to determine which anticoagulated trauma patients may not require reversal therapy. PMID- 10102317 TI - Pediatric scalp laceration repair complicated by skin staple migration. AB - Skin staples are ideal for pediatric scalp laceration closure because of their rapidity of placement and economy and ease of use. We report two cases of rotatory staple migration necessitating improvised removal techniques. Clinicians should be alert for this complication, which may result from a combination of staple design, local anatomic factors, superficial placement, and prolonged delay prior to removal. PMID- 10102318 TI - Transient peroneal nerve palsies from injuries placed in traction splints. AB - Two patients thought to have distal femur fractures presented to the emergency department (ED) of a level 1 trauma center with traction splints applied to their lower extremities. Both patients had varying degrees of peroneal nerve palsies. Neither patient sustained a fracture, but both had a lateral collateral ligament injury and one an associated anterior cruciate ligament tear. One patient had a sensory and motor block, while the other had loss of sensation on the dorsum of his foot. After removal of the traction splint both regained peroneal nerve function within 6 hours. Although assessment of ligamentous knee injuries are not a priority in the trauma setting, clinicians should be aware of this possible complication in a patient with a lateral soft tissue injury to the knee who is placed in a traction splint that is not indicated for immobilization of this type of injury. PMID- 10102319 TI - Emergency department presentations of cerebrovascular disease in children. AB - Five cases of children with cerebrovascular disease presentations to the emergency department (ED) were selected as a series to illustrate the variety of presentation of cerebrovascular disease in children. This series shows that although cerebrovascular disease in children is uncommon, it is likely that cases will occasionally present acutely to an ED. The emergency physician's role in the management of suspected acute strokes in children is that of immediate stabilization, imaging to rule out hemorrhage, other studies to rule out emergent acute disease, and timely consultation for further management. Computed tomography (CT) is useful to detect an acute hemorrhage or old ischemic lesion. Magnetic resonance imaging has superior image resolution over CT, but CT may be more practical initially. Magnetic resonance angiography is a useful part of the stroke workup in children. PMID- 10102320 TI - Asymptomatic dissection of the ascending aorta: diagnosis by transesophageal echocardiography. AB - A young man with marfanoid habitus underwent transesophageal echocardiography to evaluate an aortic root abnormality visualized on transthoracic echocardiography. Transesophageal echo demonstrated a type A aortic dissection traversing across the right sinus of Valsalva but not involving the aortic valve, right coronary artery, or pericardial sac. The aorta was not dilated. This is apparently the first reported case of an asymptomatic and uncomplicated aortic dissection localized to the sinus of Valsalva. PMID- 10102321 TI - Small ruptured abdominal aneurysm diagnosed by emergency physician ultrasound. AB - Ruptured abdominal aortic aneurysms currently have a high rate of both mortality and misdiagnosis. Aneurysms smaller than 4 cm are not commonly considered for surgical repair. This report describes the case of a ruptured abdominal aneurysm measuring less than 4 cm diagnosed by the emergency physician utilizing bedside ultrasound. Within 30 minutes of arrival at the emergency department the patient's abdominal pain resolved spontaneously after defecation. If the bedside ultrasound had not been performed it is possible the patient would have been discharged from the hospital without surgical intervention. Bedside ultrasound by emergency physicians may improve the diagnosis of ruptured aortic aneurysms, particularly if the presentation is atypical. PMID- 10102322 TI - Hypothyroidism presenting as acute cardiac tamponade with viral pericarditis. AB - This report describes the case of a young woman who presented to an emergency department with severe abdominal pain and shock. The patient was found to have pericardial tamponade due to a massive pericardial effusion. On further evaluation, the etiology of this effusion was considered to be secondary to hypothyroidism with concominant acute viral pericarditis leading to a fulminant tamponade. The presentation, differential diagnosis, and management of pericardial effusion and tamponade secondary to hypothyroidism and viral pericarditis are discussed. The diagnosis of hypothyroidism in conjunction with acute viral pericarditis should be considered in patients presenting with unexplained pericardial effusion and tamponade. PMID- 10102323 TI - Expeditious diagnosis of primary prosthetic valve failure. AB - Primary prosthetic valve failure is a catastrophic complication of prosthetic valves. Expeditious diagnosis of this complication is crucial because survival time is minutes to hours after valvular dysfunction. The only life-saving therapy for primary prosthetic valve failure is immediate surgical intervention for valve replacement. Because primary prosthetic valve failure rarely occurs, most physicians do not have experience with such patients and appropriate diagnosis and management may be delayed. A case is presented of a patient with primary prosthetic valve failure. This case illustrates how rapidly such a patient can deteriorate. This report discusses how recognition of key findings on history, physical examination, and plain chest radiography can lead to a rapid diagnosis. PMID- 10102324 TI - The electrocardiographic diagnosis of acute myocardial infarction in patients with ventricular paced rhythms. AB - The electrocardiographic diagnosis of ischemic heart disease is more difficult in the setting of ventricular-paced rhythms (VPR). ST segment/T wave configurations are changed by the altered intraventricular conduction associated with ventricular pacing. The anticipated, or expected, morphology in patients with VPR is one of QRS complex-ST segment/T wave discordance. An awareness of the anticipated ST segment morphologies of VPR is mandatory for the emergency physician. This knowledge is not dependent on additional diagnostic testing, medical records, or expertise in pacemaker function. Two cases are presented in which an analysis of the electrocardiogram in the setting of VPR assisted the treating physicians in establishing the correct diagnosis of acute myocardial infarction and arranging for urgent revascularization. PMID- 10102325 TI - Morbidity and mortality of hospitalized patients after the 1995 Hanshin-Awaji earthquake. AB - The objective of this study was to provide an overview of the morbidity and mortality of hospitalized patients during the Hanshin-Awaji earthquake. Medical records of 6,107 patients admitted to 95 hospitals (48 affected hospitals within the disaster area and 47 back-up hospitals in the surrounding area) during the initial 15 days after the earthquake were analyzed retrospectively. Patient census data, diagnoses, dispositions, and prognoses were considered. A total of 2,718 patients with earthquake-related injuries were admitted to the 95 hospitals included in our survey, including 372 patients with crush syndrome and 2,346 with other injuries. There were 3,389 patients admitted with illnesses. Seventy-five percent of the injured were hospitalized during the first 3 days. In contrast, the number of patients with illnesses continued to increase over the entire 15 day period after the earthquake. The mortality rates were 13.4% (50/372), 5.5% (128/2,346), and 10.3% (349/3,389) associated with crush syndrome, other injuries, and illness, respectively. The overall mortality rate was 8.6% (527/6,107 patients). Morbidity as well as mortality rates increased with age in patients with both injuries and illnesses. In the initial 15-day period, there was an unprecedented number of patients suffering from trauma, and they converged upon the affected hospitals. Subsequently an increased incidence of illness was observed. This survey underscores the need for adequate disaster response in such an urban situation. PMID- 10102326 TI - Renal abscess: early diagnosis and treatment. AB - The purpose of this study was to identify initial clinical characteristics that can lead to early diagnosis of renal abscess in the emergency department and predict poor prognosis. A retrospective review of 88 renal abscess patients, from April 1979 through January 1996, was conducted. Patients were categorized into two groups. In group 1, renal abscess was diagnosed by an emergency physician, whereas in group 2 renal abscess was not diagnosed by an emergency physician. Clinical characteristics included demographic data, predisposing medical problems, duration of illness before diagnosis, time spent in hospital diagnosis, initial signs and symptoms, laboratory tests, and radiology studies that may have been useful in the early diagnostic regimes. Clinical factors were also analyzed for their value in predicting poor prognosis. The mean age of 88 patients with renal abscess was 59.8 years. The most common predisposing disorder was diabetes mellitus, followed by renal calculi and ureteral obstruction. The duration of diagnosis by emergency physicians was shorter for group 1 patients (1.2 +/- .4 v group 2, 2.8 +/- 2.9 days; P < .01) and the blood urea nitrogen level was higher in group 1 (55.7 +/- 42.2 mg/dL, v group 2, 33.5 +/- 33.5 mg/dL; P = .02). In the early diagnosis of renal abscess, emergency physicians should focus on patients who have predisposing disorders, ie, diabetes mellitus, renal stones, immunosuppression, longer duration of symptoms of urinary tract infection, and renal failure, who should promptly be investigated with ultrasound in the emergency department. The cure rate after treatment with routine antibiotics plus percutaneous drainage was 64%. This therapy is recommended for initial treatment. Poor prognosis is associated with elderly patients with lethargy and with elevation of the serum blood urea nitrogen level. PMID- 10102327 TI - ED overcrowding in Taiwan: facts and strategies. AB - The objective of this study was to quantity the extent of emergency department (ED) overcrowding in Taiwan and to identify possible solutions. The ED log was reviewed for all patients who presented to the National Taiwan University Hospital's ED from January 16, 1996 through February 15, 1996. Charts from patients held longer than 72 hours were reviewed. Among 5,810 patients, 213 (3.6%) were held in the ED for more than 72 hours (7.1 patients per day). In 149 (70.0%) of them, admission was indicated but delayed (42 because more than one subspecialty were involved, 57 because of unavailability of bed, and 50 because of the disparity in admission priority between the emergency physicians and house staffs). Eighteen (8.4%) patients did not meet admission criteria (13 could have been treated in outpatient clinics, 3 needed placement in nursing homes, 2 because of personal problems). The others (22%) recovered while waiting. Significant overcrowding exists in EDs in Taiwan. Four solutions are proposed: (1) creation of a holding unit; (2) flexible ward assignment; (3) pre-established rules for admission priority-setting; and (4) active interfacility transfer. Only through these efforts can EDs in Taiwan guarantee an optimal level of care in the face of a growing patient demand. PMID- 10102328 TI - Utility of colorimetric end-tidal carbon dioxide detector for monitoring during prehospital cardiopulmonary resuscitation. AB - The purpose of this study was to evaluate a colorimetric end-tidal CO2 (ETCO2) detector (EASY CAP) as a monitor during prehospital cardiopulmonary resuscitation (CPR) without tracheal intubation. This detector was used for 121 patients during CPR with a laryngeal mask airway or face mask by authorized emergency lifesaving technicians. At 7 to 15 minutes after the initiation of CPR, ETCO was <0.5% in 30 cases (group A), 0.5% to 2.0% in 46 cases (group B) and >2.0% in 45 cases (group C). The rate of return of spontaneous circulation was 17% in group A, 24% in group B, and 48% in group C (groups A v C, P < .01). There was a significant difference in the rate of hospital admission between groups A and C. The ETCO2 value may be useful for monitoring during prehospital CPR with a laryngeal mask airway or face mask. PMID- 10102329 TI - Withholding pain medication in the ED because of legal fears--bad practice for a bad reason. PMID- 10102330 TI - Overcrowding in the ED: an international symptom of health care system failure. PMID- 10102331 TI - Effectiveness of mechanical versus manual chest compressions in out-of-hospital cardiac resuscitation. PMID- 10102332 TI - Diagnosing benign early repolarization. PMID- 10102333 TI - Treatment of capsaicin (Mace?) dermatitis. PMID- 10102334 TI - Redundancy of portable cervical spine films in the trauma suite. PMID- 10102335 TI - Myocardial infarction diagnosis by morphology of ventricular extrasystole. PMID- 10102336 TI - Lightning strike to the head of a helmeted motorcyclist. PMID- 10102337 TI - First-line management of paroxysmal supraventricular tachycardia. PMID- 10102338 TI - Utility of myoglobin in the evaluation of chest pain in the ED. PMID- 10102339 TI - Leukemic hyperleukocytosis-induced unstable angina and congestive heart failure. PMID- 10102340 TI - Pneumococcal meningitis with normal cerebrospinal fluid in an immunocompetent adult. PMID- 10102341 TI - Treatment of the cardiovascular manifestations of phosphine poisoning with trimetazidine, a new antiischemic drug. PMID- 10102342 TI - Crotalid antivenin availability during shortage. PMID- 10102343 TI - Cell-specific expression of the diphtheria toxin A-chain coding sequence under the control of the upstream region of the human alpha-fetoprotein gene. AB - BACKGROUND AND OBJECTIVES: Development of the system to express a suicide gene selectively in tumor cells is essential for gene therapy. We constructed a plasmid containing the diphtheria toxin A (DTA) fragment linked to human alpha fetoprotein (AFP) promoter and enhancer, and tested whether it can exert its cytocidal effect selectively on AFP-producing cells. METHODS: The chloramphenical acetyltransferase (CAT) reporter gene or DTA gene was linked to the 5' upstream region of the AFP gene. The plasmids were transfected into AFP-producing or non producing cells by the lipopolyamine-coated DNA method. Expression of CAT activity and effects on cell growth of transfected cells were assessed. RESULTS: When the AFP-producing cells HuH-7 or HepG2 were cotransfected with CAT reporter plasmid and pAF5.1DTA plasmid, the CAT activity was greatly suppressed. In contrast, cotransfection with pAF5.1DTA-R, the inversely inserted DTA gene, did not inhibit CAT activity. Furthermore, cell growth of HuH-7 cells transfected with pAF5.1DTA plasmid was significantly inhibited compared with HuH-7 cells transfected with DTA-R plasmid. CONCLUSIONS: Our results indicate that selective killing of AFP-producing cells will be attained by introducing the DTA gene linked to the promoter and enhancer region of AFP. PMID- 10102345 TI - Enhanced tumor targeting by an intratumoral injection of colloidal chromic 32P in two human tumors (AsPC-1 pancreas and Ls174T colon) in nude mice. AB - BACKGROUND AND OBJECTIVES: To find the mechanisms of the ongoing clinical trials in intralesional colloidal chromic 32P (32P-CP) brachytherapy, the cellular uptake of 32P-CP, changes in tumor interstitial fluid pressure (TIFP), and tumor blood flow (TBF) using two (AsPC-1, Ls174T) human tumors were measured. METHODS: After exposure to 32p-CP using exponential and plateau-phase cells, cells were trypsinized at various time intervals, then measured for the levels of radioactivity using a y-counter. Also measured were TIFP using the WIN technique and TBF with laser Doppler flowmetry. RESULTS: The plateau growth-phase of both tumors showed the maximal uptake of 32P-CP at approximately 100 min. TBF decreased within 10 min after an intratumoral (i.t.) injection of 32P-CP, and reached 75% of control value by 1 h. CONCLUSIONS: If 32P-CP was introduced i.t., it maintained highly efficient tumor targeting, mainly due to two physiological mechanisms: the high adherence of 32P-CP to the infused regions and the reduction in TBF by this therapeutic colloid. PMID- 10102344 TI - Prognostic evaluation of cutaneous malignant melanoma: a clinicopathologic and immunohistochemical study. AB - BACKGROUND AND OBJECTIVES: Depth of invasion and stage of the disease are established prognostic indicators in cutaneous malignant melanoma. The role of other parameters is still an open problem. METHODS: In 93 consecutive patients with cutaneous malignant melanoma, the level of invasion, tumor thickness, ulceration, vascular invasion, lymphoplasmocytic infiltrates, and mitotic index were evaluated by histology. Expression of Ki-67 and PCNA proliferative antigens together with vimentin, S100, and HMB 45 proteins were assessed by immunohistochemistry. RESULTS AND CONCLUSIONS: Disease-free and overall survival were correlated with tumor stage, tumor thickness, level of invasion, macroscopic pattern, ulceration, vascular invasion, expression of HMB 45, PCNA, and Ki 67/MIB1. Stage, HMB 45, and PCNA were independent prognostic factors for disease free survival, whereas tumor stage, tumor thickness, and expression of both proliferative antigens influenced overall survival independently. The variables studied demonstrated reciprocal correlation; therefore, analysis of many prognostic parameters in malignant melanoma could be recommended. PMID- 10102346 TI - Positive margins of breast biopsy: is reexcision always necessary? AB - BACKGROUND AND OBJECTIVES: Breast-conserving surgery requires excision of all gross tumor and subsequent radiation therapy. It is generally accepted that the presence of microscopically positive margins requires reexcision. The goal of this study was to identify characteristics that distinguish breast biopsy specimens with positive margins that when reexcised are free from residual tumor. This population of patients may benefit from breast irradiation only, without the need for another surgical procedure. METHODS: One hundred and fifteen of 395 cancer-proven biopsies had positive surgical margins and were treated with reexcision or mastectomy. Sixty-seven of these were negative for residual tumor and 48 were positive for residual tumor. Evaluation for tumor type, tumor size, grade, presence of vascular invasion, volume of the biopsy specimen, true positivity and the number of positive margins, multifocality of the tumor, and type of anesthesia was done by univariate and multivariate analysis. RESULTS: Univariate and multivariate analysis revealed that factors associated with a positive reexcision included margin status, method of detection, histologic appearance, and type of anesthesia used. CONCLUSION: These results suggest that small, clinically detectable unifocal tumors could be treated without the need for a further excision. Eradication of microscopic residual tumor could be done by irradiation only, sparing the patient an additional surgical procedure. PMID- 10102347 TI - Basal cell carcinoma of the vulva. AB - BACKGROUND AND OBJECTIVES: Vulvar basal cell carcinoma (BCC) accounts for 7% of all vulvar cancers at two hospitals in the south of Israel. The purpose of this study was to investigate the clinical findings, treatment and outcome of patients with vulvar BCC treated at these institutions. METHODS: Data from the files of eight patients with vulvar BCC who were managed at two regional hospitals in the south of Israel (Soroka Medical Center, Beer-Sheva and Kaplan Hospital, Rehovot) between January 1961 and December 1997 were evaluated. RESULTS: Mean age at diagnosis was 70.5 years. A history of other primary cancers was encountered in two patients. Prevailing presenting symptoms were vulvar lump, ulcer, itching, and bleeding. The tumor was most often located on the labium major and its mean size was 2.25 cm. Six patients had wide local excision, one had excisional biopsy, and one had hemivulvectomy. Two patients developed local recurrence and were treated by wide local reexcision and hemivulvectomy, respectively. At follow up, no patient developed regional and/or distant metastases, or died of BCC. CONCLUSIONS: Vulvar BCC is characterized by an indolent behavior with a very low propensity for metastatic spread. The treatment of choice is wide local excision. Because of a substantial risk of local recurrence and high frequency of other primary cancers, close long-term follow-up is essential. PMID- 10102348 TI - Inguinal lymph node metastases from rectal adenocarcinoma. AB - BACKGROUND AND OBJECTIVES: The prognosis of patients with inguinal lymph node metastases from rectal adenocarcinoma is poor. The purpose of this study is to analyze the clinical behavior and response to different therapies in a group of these patients. MATERIALS AND METHODS: The medical records of 32 patients with inguinal lymph node metastases from rectal adenocarcinoma, diagnosed between January 1985 and December 1996, were retrospectively analyzed. The cohort was divided into: Group A (synchronous), and Group B (metachronous), according to the time of diagnosis. RESULTS: There were 17 males and 15 females, with a mean age of 53.5+/-13.8 years. Bilateral inguinal lymph node metastases were diagnosed in 17 patients, and unilateral in 15 patients. Fourteen of 18 patients in Group A (78%) and 13 of 14 patients (93%) in group B, respectively, had concomitantly extrapelvic metastatic disease. Seventeen patients in Group A treated with colostomy + chemoradiotherapy (45 Gy/20 fractions to the pelvis and groin area + 5-fluorouracil 450 mg/m2/weekly) had a progressive metastatic disease; the remaining patient was lost to follow-up after an abdominoperineal resection plus superficial groin dissection. Median survival was 8 months (range, 4-30 months). Overall 5-year survival was 0%. Ten patients in Group B were treated with chemoradiotherapy (50 Gy/25 fractions + 5-fluorouracil 450 mg/m2 + leucovorin 30 mg/m2); three patients received supportive care only, and one patient was treated with a groin dissection. All of them died of disseminated metastatic disease at a median of 13 months (range, 6-57 months). Overall 5-year survival was 0%. CONCLUSION: The presence of inguinal metastases in patients with rectal cancer heralds systemic disease and, due to a poor response to the different therapies, only palliative treatment should be indicated. PMID- 10102349 TI - Use of omentum pedicled graft to protect great vessels in gastric transposition for pharyngoesophageal cancer. AB - BACKGROUND AND OBJECTIVES: Transmediastinal gastric transposition and pharyngogastric anastomosis is perhaps one of the most widely accepted methods for restoration of the alimentary continuity after pharyngoesophageal resection. The need of neck dissection, mediastinal tracheostomy, and previous radiotherapy may favor exposure and rupture of major vessels. Protection with omentum may prevent this complication. A comprehensive review of omentum flap use in surgery was undertaken. METHODS: A modified omentum pedicled flap was used in 6 out of 36 patients submitted to total pharyngolaryngoesophagectomy and gastric transposition (PLE>). RESULTS: None of the patients had major vessel rupture as compared with a 13% carotid and innominate artery rupture of a series of 30 patients previously operated on without omentum pedicled flap protection. CONCLUSIONS: The omental pedicled flap, performed as described, may provide reliable protection for carotid and innominate artery exposure, adding little time to the procedure. PMID- 10102350 TI - Multifocal soft tissue sarcoma: limb salvage following hyperthermic isolated limb perfusion with high-dose tumor necrosis factor and melphalan. AB - BACKGROUND AND OBJECTIVES: The prognosis for recurrent multifocal limb soft tissue sarcoma (STS) is dismal due to systemic spread. However, many of these patients undergo amputation due to ineffective local control. The purpose of the present study was to determine whether isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan permits limb salvage and palliation for such patients. METHODS: Of 53 STS patients treated with hyperthermic ILP with TNF (3-4 mg) and melphalan (1-1.5 mg/kg), 13 (25%) had multifocal STS and were candidates for amputation. RESULTS: The overall response rate was 92% (12/13) with 38% complete response and 54% partial response. Two patients died during the early postoperative period. Limb salvage was achieved in 85% of patients. One patient (8%) had only stable disease and underwent amputation. Local recurrence occurred in 38% but did not result in amputation. CONCLUSIONS: Although the number of patients in this study is too small to allow definitive conclusions, it seems that ILP/TNF offer limb salvage and palliation for recurrent multifocal STS patients. PMID- 10102352 TI - Primary pericardial synovial sarcoma: a case report and literature review. AB - Primary synovial sarcoma of the heart is a rare tumor, with only six previous cases having been reported in the literature. Treatment has included surgery with or without chemotherapy. We present the first case of a documented synovial sarcoma arising from the pericardium in a 19-year-old man. Molecular analysis for t(X; 18) SYT-SSX gene fusion was positive. Radiation treatment was given postoperatively to the entire heart with a boost to the area where the margins were positive. PMID- 10102351 TI - Kimura's disease: a case report and literature review. AB - Kimura's disease, which occurs endemically in the Far East and sporadically in the West, has so far eluded efforts to determine its exact pathogenesis. It presents as solitary or multiple benign swellings of the skin, has a predilection for the periauricular and scalp regions, and often is associated with regional lymphadenopathy. Morphologically, the lesions are characterized by proliferating blood vessels with rich eosinophilic infiltrate. Peripheral blood eosinophilia and raised serum IgE levels are signature features of the condition. The overall prognosis is good. When surgery is not possible, conservative treatment with either corticosteroids or radiation often can produce a favorable response. Complete surgical excision whenever feasible is the preferred treatment despite a high recurrence rate. Based on a recent case of Kimura's disease in a 55-year-old black woman, we discuss the pitfalls in the diagnosis of this chronic inflammatory disorder. PMID- 10102353 TI - What can we learn from the phenomenon of preferential lymph node metastasis in carcinoma? AB - Lymph nodes are the most common and earliest site of malignancies arising in epithelia. However, the reason for this pattern of preferential metastasis is not clear. This article reviews features of the metastatic process and lymph node microenvironment which might potentiate lymph node metastases. There is intriguing evidence that preferential lymph node metastasis is due to (1) the efficiency of lymph nodes as filters of the tumor cells which arrive there, and (2) the probability that adhesive interactions, normally governing the generation of different T-cell immune responses, are responsible for this efficiency and may also promote invasion and proliferation of tumor cells in the lymph node. Manipulation of the cytokine environment in a lymph node draining a primary epithelial tumor may alter both the expression of cell adhesion molecules within the node and the subsequent metastatic ability of the tumor cells arriving at it. PMID- 10102354 TI - Zinc finger proteins: watchdogs in muscle development. AB - The specificity of highly differentiated tissues is largely achieved through the action of cell- and stage-restricted transcription factors. The basic events in skeletal muscle development are triggered by a unique family of myogenic basic helix-loop-helix proteins - MyoD, Myf-5, myogenin and MRF-4. Binding sites for these factors are found in the promoter regions of many genes whose expression is restricted to muscle cells, but the tight regulation of gene expression is dependent on the interaction of different factors. In this respect zinc finger proteins seem to play an important role, not only in the establishment of muscle cells but also in the maintenance of muscle function. This review discusses several zinc finger proteins that have been characterized as regulators of muscle development and muscle-specific gene expression. PMID- 10102355 TI - Analysis of two chromosomal regions adjacent to genes for a type II polyketide synthase involved in the biosynthesis of the antitumor polyketide mithramycin in Streptomyces argillaceus. AB - Mithramycin is an aromatic antitumour polyketide synthesized by Streptomyces argillaceus. Two chromosomal regions located upstream and downstream of the locus for the mithramycin type II polyketide synthase were cloned and sequenced. Analysis of the sequence revealed the presence of eight genes encoding three oxygenases (mtmOI, mtmOII and mtmOIII), three reductases (mtmTI, mtmTII and mtmTIII), a cyclase (mtm Y) and an acyl CoA ligase (mtmL). The three oxygenase genes were each inactivated by gene replacement. Inactivation of one of them (mtmOII) generated a non-producing mutant, while inactivation of the other two (mtmOl and mtmOIII) did not affect the biosynthesis of mithramycin. The mtmOII gene may code for an oxygenase responsible for the introduction of oxygen atoms at early steps in the biosynthesis of mithramycin leading to 4 demethylpremithramycinone. One of the reductases may be responsible for reductive cleavage of an intermediate from an enzyme and another for the reduction of a keto group in the side-chain of the mithramycin aglycon moiety. A hypothetical biosynthetic pathway showing in particular the involvement of oxygenase MtmOII and of various other gene products in mithramycin biosynthesis is proposed. PMID- 10102356 TI - pBECKS2000: a novel plasmid series for the facile creation of complex binary vectors, which incorporates "clean-gene" facilities. AB - A new plasmid series has been created for Agrobacterium-mediated plant transformation. The pBECKS2000 series of binary vectors exploits the Cre/ loxP site-specific recombinase system to facilitate the construction of complex T-DNA vectors. The new plasmids enable the rapid generation of T-DNA vectors in which multiple genes are linked, without relying on the availability of purpose-built cassette systems or demanding complex, and therefore inefficient, ligation reactions. The vectors incorporate facilities for the removal of transformation markers from transgenic plants, while still permitting simple in vitro manipulations of the T-DNA vectors. A 'shuttle' or intermediate plasmid approach has been employed. This permits independent ligation strategies to be used for two gene sets. The intermediate plasmid sequence is incorporated into the binary vector through a plasmid co-integration reaction which is mediated by the Cre/loxP site-specific recombinase system. This reaction is carried out within Agrobacterium cells. Recombinant clones, carrying the co-integrative binary plasmid form, are selected directly using the antibiotic resistance marker carried on the intermediate plasmid. This strategy facilitates production of co integrative T-DNA binary vector forms which are appropriate for either (1) transfer to and integration within the plant genome of target and marker genes as a single T-DNA unit; (2) transfer and integration of target and marker genes as a single T-DNA unit but with a Cre/loxP facility for site-specific excision of marker genes from the plant genome; or (3) co-transfer of target and marker genes as two independent T-DNAs within a single-strain Agrobacterium system, providing the potential for segregational loss of marker genes. PMID- 10102357 TI - Cloning of the Escherichia coli endo-1,4-D-glucanase gene and identification of its product. AB - A plasmid (pYP17) containing a genomic DNA insert from Escherichia coli K-12 that confers the ability to hydrolyze carboxymethylcellulose (CMC) was isolated from a genomic library constructed in the cosmid vector pLAFR3 in E. coli DH5alpha. A small 1.65-kb fragment, designated bcsC (pYP300), was sequenced and found to contain an ORF of 1,104 bp encoding a protein of 368 amino acid residues, with a calculated molecular weight of 41,700 Da. BcsC carries a typical prokaryotic signal peptide of 21 amino acid residues. The predicted amino acid sequence of the BcsC protein is similar to that of CelY of Erwinia chrysanthemi, CMCase of Cellulomonas uda, EngX of Acetobacter xylinum, and CelC of Agrobacterium tumefaciens. Based on these sequence similarities, we propose that the bcsC gene is a member of glycosyl hydrolase family 8. The apparent molecular mass of the protein, when expressed in E. coli, is approximately 40 kDa, and the CMCase activity is found mainly in the extracellular space. The enzyme is optimally active at pH 7 and a temperature of 40 degrees C. PMID- 10102358 TI - Genetic interactions between Hsp90 and the Cdc2 mitotic machinery in the fission yeast Schizosaccharomyces pombe. AB - In Schizosaccharomyces pombe, wee1 encodes a tyrosine kinase that inhibits entry into mitosis by phophorylating Cdc2, the universal cyclin-dependent kinase (Cdk) that regulates the G2/M transition in all eukaryotic cells. A search for suppressors of the G2 arrest caused by overexpression of weel led to the isolation of a new allele of swo1 (named swo1-w1), the gene coding for chaperone Hsp90, which is required to stabilise Weel. The swo1-w1 allele carries a glycine to aspartic acid substitution at amino acid 155 that results in a partial loss of Hsp90 function. Cells bearing the swo1-w1 mutation in combination with the point mutation cdc2-33 or cdc2-M26 showed severe mitotic defects. Genetic interactions were not observed in combination with point mutations in other cdc genes, suggesting that Cdc2 specifically interacts with Hsp90. This synthetic lethal swo1-w1 cdc2-33 (or cdc2-M26) strain had normal levels of Cdc2 protein and histone H1 phosphorylation activity, indicating that Hsp90 is required to enable Cdc2 to interact with its mitotic substrates or regulators, rather than for its proper folding or stabilisation. In a wild-type background, swo1-w1 mutant cells were sensitive to temperature as well as to other stress agents, such as KCI, ethanol and formamide. Under these stressful growth conditions, the swo1-w1 cells displayed anaphase B arrest and aberrant septation patterns, indicating that a subset of proteins involved in mitosis and cytokinesis is highly dependent on chaperone Hsp90 for function. PMID- 10102359 TI - Cloning and characterisation of the sagA gene of Aspergillus nidulans: a gene which affects sensitivity to DNA-damaging agents. AB - Mutations within the sagA gene of Aspergillus nidulans cause sensitisation to DNA damaging chemicals but have no effect upon spontaneous or damage-induced mutation frequency. The sagA gene was cloned on a 19-kb cosmid-derived fragment by functional complementation of a sagA1 sagC3 double mutant; subsequently, a fragment of the gene was also isolated on a 3.9-kb genomic subclone. Initial sequencing of a small section of the 19-kb fragment allowed the design of primers that were subsequently used in RTPCR experiments to show that this DNA is transcribed. A 277-bp fragment derived from the transcribed region was used to screen an A. nidulans cDNA library, resulting in the isolation of a 1.4-kb partial cDNA clone which had sequence overlap with the genomic sagA fragment. This partial cDNA was incomplete but appeared to contain the whole coding region of sagA. The sagA1 mutant was shown to possess two mutations; a G-T transversion and a+ 1 frameshift due to insertion of a T. causing disruption to the C-terminal region of the SagA protein. Translation of the sagA cDNA predicts a protein of 378 amino acids, which has homology to the Saccharomyces cerevisiae End3 protein and also to certain mammalian proteins capable of causing cell transformation. PMID- 10102360 TI - Molecular characterisation and origin of the Coffea arabica L. genome. AB - Restriction fragment length polymorphism (RFLP) markers were used in combination with genomic in situ hybridisation (GISH) to investigate the origin of the allotetraploid species Coffea arabica (2n = 44). By comparing the RFLP patterns of potential diploid progenitor species with those of C. arabica, the sources of the two sets of chromosomes, or genomes, combined in C. arabica were identified. The genome organisation of C. arabica was confirmed by GISH using simultaneously labelled total genomic DNA from the two putative genome donor species as probes. These results clearly suggest that C. arabica is an amphidiploid formed by hybridisation between C. eugenioides and C. canephora, or ecotypes related to these diploid species. Our results also indicate low divergence between the two constituent genomes of C. arabica and those of its progenitor species, suggesting that the speciation of C. arabica took place relatively recently. Precise localisation in Central Africa of the site of the speciation of C. arabica, based on the present distribution of the coffee species, appears difficult, since the constitution and extent of tropical forest has varied considerably during the late Quaternary period. PMID- 10102361 TI - Molecular characterization of two light-induced, gamete-specific genes from Chlamydomonas reinhardtii that encode hydroxyproline-rich proteins. AB - Gametic differentiation in Chlamydomonas reinhardtii is a two-step process, which is controlled by the sequential action of the two extrinsic signals, nitrogen starvation and blue light. The gamete-specific genes GAS28 and GAS29 are expressed in the late phase of gametogenesis. Their light-induced expression is restricted to cells that have completed the first, nitrogen starvation-activated, phase of differentiation. A comparison of the two genes revealed striking similarities as well as differences. Their most prominent shared feature is an extended sequence homology of over 90% in their 5'-untranslated regions, suggesting a role in translational regulation. GAS28 and GAS29 both encode hydroxyproline-rich proteins (HRGPs) of very similar sizes that exhibit typical features of volvocalean cell wall constituents. GAS28 shows a high degree of homology with the Volvox pherophorin gene family, suggesting a relationship between these genes. PMID- 10102362 TI - Genetic analysis of mutant clones of Chlamydomonas reinhardtii defective in potassium transport. AB - Mutant clones of Chlamydomonas reinhardtii defective for potassium transport were isolated and characterized. Of the four genes identified, three - TRK1, TRK2 and TRK3 encode high-affinity transport functions, and one gene, HKR1, encodes a low affinity transport function. Characterization of the potassium dependence of recombinants possessing two mutant trk alleles suggests that the protein products of TRK2 and TRK3 interact functionally, and that TRK1 may serve a regulatory function. The mutant clone defective for a low-affinity potassium transporter was isolated by mutagenizing trk2-1 cells, which lack a functional high-affinity transporter, and screening surviving cells for dependence on very high potassium concentrations. The hkr1 phenotype is expressed only in the presence of trk2-1. PMID- 10102363 TI - The ukc1 gene encodes a protein kinase involved in morphogenesis, pathogenicity and pigment formation in Ustilago maydis. AB - The fungal phytopathogen Ustilago maydis alternates between budding and filamentous growth during its life cycle. This dimorphic transition, which is influenced by environmental factors and mating, is regulated in part by cAMP dependent protein kinase (PKA). We have recently identified a related protein kinase, encoded by the ukc1 gene, that also plays a role in determining cell shape. The ukc1 gene is homologous to several other protein kinase-encoding genes including the cot-I gene of Neurospora crassa, the TB3 gene of Colletotrichum trifolii, the orb6 gene of Schizosaccharomyces pombe, the warts tumor suppressor gene of Drosophila melanogaster and the myotonic dystrophy kinase gene in humans. Disruption of the ukc1 gene in U. maydis resulted in cells that were highly distorted in their morphology, incapable of generating aerial filaments during mating in culture and defective in their ability to cause disease on corn seedlings. In addition, the cells of ukc1 mutants became highly pigmented and resembled the chlamydospore-like cells that have been described for U. maydis. Overall, these results demonstrate an important role for the ukc1-encoded protein kinase in the morphogenesis, pathogenesis and pigmentation of U. maydis. PMID- 10102364 TI - An aureobasidin A resistance gene isolated from Aspergillus is a homolog of yeast AUR1, a gene responsible for inositol phosphorylceramide (IPC) synthase activity. AB - The AUR1 gene of Saccharomyces cerevisiae, mutations in which confer resistance to the antibiotic aureobasidin A, is necessary for inositol phosphorylceramide (IPC) synthase activity. We report the molecular cloning and characterization of the Aspergillus nidulans aurA gene, which is homologous to AUR1. A single point mutation in the aurA gene of A. nidulans confers a high level of resistance to aureobasidin A. The A. nidulans aurA gene was used to identify its homologs in other Aspergillus species, including A. fumigatus, A. niger, and A. oryzae. The deduced amino acid sequence of an aurA homolog from the pathogenic fungus A. fumigatus showed 87% identity to that of A. nidulans. The AurA proteins of A. nidulans and A. fumigatus shared common characteristics in primary structure, including sequence, hydropathy profile, and N-glycosylation sites, with their S. cerevisiae, Schizosaccharomyces pombe, and Candida albicans counterparts. These results suggest that the aureobasidin resistance gene is conserved evolutionarily in various fungi. PMID- 10102365 TI - Isolation of multicopy suppressors of the calcium sensitivity of a mutant lacking the bZIP transcription factor Atf1 in fission yeast. AB - In Schizosaccharomyces pombe, recent studies have uncovered a set of putative transcription factors of the basic leucine zipper (bZIP) type (e.g., Atf1, Pcr1, Pap1), which function downstream of the Sty1 mitogen-activated protein kinase (MAPK) cascade which is involved in stress-activated signal transduction. Accordingly, a delta atf1 mutant is known to exhibit osmosensitivity for growth, since one of the targets of Atf1 is the gpd1+ gene, which is responsible for the osmoadaptive glycerol production mediated by the Sty1 MAPK cascade. During the course of our studies on the osmotic response in S. pombe, we found that growth of a delta atf1 mutant is highly sensitive to the level of Ca2+ ions in the medium (but less sensitive to Mg2+ and Na+ ions). This phenotype seemed to be relevant to the osmosensitivity, because an delta gpd1 mutant showed a similar phenotype. An attempt was therefore made to isolate multicopy suppressors of the calcium sensitivity exhibited by the delta atf1 cells. Among such suppressors were several bZIP factors, including two known proteins (Atf21 and Pcr1), and two new ones (named Atf31 and Zip1). These factors were characterized further, in comparison to Atf1, with special reference to the Sty1 MAPK signaling pathway. PMID- 10102366 TI - Tissue- and environmental response-specific expression of 10 PP2C transcripts in Mesembryanthemum crystallinum. AB - Ten transcripts (Mpc1-10) homologous to protein phosphatases of the 2C family have been isolated from the halophyte Mesembryanthemum crystallinum (common ice plant). Transcripts range in size from 1.6 to 2.6 kb, and encode proteins whose catalytic domains are between 24% and 62% identical to that of the Arabidopsis PP2C, ABI1. Transcript expression is tissue specific. Two isoforms are present only in roots (Mpc1 and Mpc5), three in young leaves (Mpc6, 8 and 9), two in old leaves (Mpc6 and Mpc8), and two in post-flowering leaves (Mpc8 and Mpc9). Mpc2 is strongly expressed in roots and also in seeds, meristematic tissues and mature flowers. Mpc3 is specific for leaf meristems, and Mpc4 is found in root and leaf meristems. Mpc7 is restricted to meristematic tissues. Mpc10 is only present in mature flowers. Mpc2 (in roots and leaves), Mpc5 (in roots) and Mpc8 (weakly in leaves) are induced by salinity stress and drought conditions with different kinetics in different tissues, but other Mpcs are downregulated by stress. Cold stress (4 degrees C) leads to a decline in Mpc5 and Mp6, but low temperature provoked a long-term (days) increase in Mpc2 levels in leaves and a transient increase (less than 24 h) in roots. Four full-length transcripts have been obtained. In each case, after over-expression in E. coli, the isolated proteins exhibited (Mg2+-dependent, okadeic acid-insensitive) protein phosphatase activity, although activity against 32P-phosphocasein varied among different PP2Cs. Determination of tissue developmental and stress response specificity of PP2C will facilitate functional studies of signal-transducing enzymes in this halophytic organism. PMID- 10102367 TI - A molecular marker that segregates with sorghum leaf blight resistance in one cross is maternally inherited in another. AB - Leaf blight-resistant sorghum accession SC326-6 was crossed to the susceptible cultivar BTx623 to analyze the genetic basis for resistance. Field scoring of inoculated F2 progeny revealed that resistance was transmitted as a dominant single-gene trait. By combining the random amplified polymorphic DNA (RAPD) technique with bulked-segregant analysis, it was possible to identify PCR amplification products that segregated with disease response. Primer OPD12 amplified a 323-bp band (D12R) that segregated with resistance. Creation of longer primers, or SCARs (sequence characterized amplified regions) for D12R resulted in the amplification of a single major band of the predicted size from all the resistant F2 progeny and the resistant parent SC326-6, but not from BTx623 or 24 of 29 susceptible F2 progeny. The SCAR primers also amplified a single band with DNA from IS3620C, the female parent in a cross with BTx623 that has been used to produce a recombinant inbred population for RFLP mapping. An equivalent band was amplified from all 137 recombinant inbred progeny, indicating that organelle DNA is the amplification target in this cross. PMID- 10102368 TI - Differential expression of Listeria monocytogenes virulence genes in mammalian host cells. AB - We have used RT-PCR and GFP-mediated fluorescence to analyse the regulation of PrfA-dependent virulence genes of Listeria monocytogenes during proliferation in mammalian host cells. Our data show that most of the PrfA-regulated virulence genes are more efficiently expressed, as measured by transcript levels, when L. monocytogenes is grown in macrophages and macrophage-like cells rather than in epithelial cells, hepatocytes or endothelial cells. The promoters for hly and plcA are predominantly activated within the phagosomal compartment, while those for actA and inlC are predominantly activated in the host cell cytosol. Expression of actA and plcB precedes that of inlC after infection of epithelial cells and macrophages. Little transcription of inlA or inlB is observed in epithelial cells and there is only slightly more in macrophages. In both cell types the level of transcription of the inlAB operon is lower than is seen under extracellular growth conditions in rich media, which is compatible with the assumption that InlA and InlB are not required during intracellular growth of the bacteria. Activation of the PrfA-independent iap promoter is also low during intracellular growth, although the gene product (p60) is required for cell viability. The levels of the PrfA-dependent virulence gene transcripts do not correlate with the amount of prfA transcript present, which is low under all intracellular conditions analysed, suggesting that the prfA transcript is either highly unstable in bacteria that are growing intracellularly, or that the small amount of PrfA produced is highly activated by additional component(s). PMID- 10102369 TI - An alternative intronic promoter of the Bombyx A3 cytoplasmic actin gene exhibits a high level of transcriptional activity in mammalian cells. AB - Previous observations have indicated that the Bombyx mori gene for A3 cytoplasmic actin and vertebrate actin genes might make use of similar mechanisms for regulation of gene expression. To examine the suggested similarities, we have analyzed the expression of a LacZ reporter plasmid construct containing the 5' and 3' regulatory regions and the first intron of the A3 actin gene in a variety of vertebrate cell lines. We found that this silkworm expression cassette could drive expression of foreign genes in both mammalian and avian cell lines. Detailed analysis, however, indicated that neither the CArG box nor any of the promoter elements previously identified in the A3 actin gene were required for expression in mammalian cells. On the other hand, the first intron contained an efficient promoter, exhibiting in mouse cells a transcriptional activity comparable to that of the SV40 early promoter. The first intron of the A3 gene was also found to contain enhancer-like DNA elements that could stimulate the heterologous SV40 early promoter in mammalian cells. Promoter activity of the first intron of the A3 actin gene has not been observed previously. Recently however, we described a rare A3 actin mRNA isoform in B. mori cells, which initiates within the first intron. We suggest that the identified intronic promoter may be active not only in vertebrate cells but also in silkworm, and that it regulates the synthesis of the alternative A3 actin mRNA isoform. The characteristics of the 5' regulatory region of the A3 gene described here can also be exploited in the construction of bi-functional insect-mammalian expression vectors. PMID- 10102370 TI - YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae. AB - In this study, we utilized a genetic approach to identify genes which render yeast cells resistant to cerulenin (Cer), a potent and noncompetitive inhibitor of fatty acid synthase (FAS). Overexpression of the yeast transcription factor Yap1p was found to confer Cer resistance (CerR). This resistance was shown to be less pronounced in a strain deleted for YCF1, a multidrug resistance ABC transporter, supporting previous observations that implicated YCF1 in mediating CerR. However, isolation of YAP1 as a high-copy CerR gene in a ycf1delta strain suggested that YAP1-induced CerR was mediated by additional downstream effectors. Overexpression of neither glutathione reductase nor a predicted aryl alcohol dehydrogenase (the products of two YAP1-regulated genes involved in detoxification) conferred CerR. Overexpression of ATR1, another YAP1-regulated gene previously implicated in conferring resistance to a number of cytotoxic drugs, was also incapable of making cells resistant to Cer. In contrast, overexpression of Flr1p, a yeast transporter of the major facilitator superfamily which is also under the control of YAP1, was sufficient to confer CerR in an otherwise wild-type background. Moreover, CerR was markedly diminished in a strain deleted for FLR1. These findings implicate members of both of the transporter superfamilies involved in multiple drug resistance (MDR) in the acquisition of CerR in yeast. Furthermore, our studies indicate that yeast may be a useful model system in which to investigate the role of FAS in cancer biology and the effects of Cer on eukaryotic cell growth. PMID- 10102371 TI - Allelic variation at (TAA)n microsatellite loci in a world collection of chickpea (Cicer arietinum L.) germplasm. AB - A set of 12 randomly selected (TAA)n microsatellite loci of the cultivated chickpea (Cicer arietinum L.) were screened in a worldwide sample comprising 72 landraces, four improved cultivars and two wild species of the primary gene pool (C. reticulatum and C. echinosperum) to determine the level and pattern of polymorphism in these populations. A single fragment was amplified from all the accessions with each of 12 sequence-tagged microsatellite site markers, except for one locus where no fragment was obtained from either of the two wild species. There was a high degree of intraspecific polymorphism at these microsatellite loci, although isozymes, conventional RFLPs and RAPDs show very little or no polymorphism. Overall, the repeat number at a locus (excluding null alleles) ranged from 7 to 42. The average number of alleles per locus was 14.1 and the average genetic diversity was 0.86. Based on the estimates obtained, 11 out of the 12 frequency distributions of alleles at the loci tested can be considered to be non-normal. A significant positive correlation between the average number of repeats (size of the locus) and the amount of variation was observed, indicating that replication slippage may be the molecular mechanism involved in generation of variability at the loci. A comparison between the infinite allele and stepwise mutation models revealed that for 11 out of the 12 loci the number of alleles observed fell in between the values predicted by the two models. Phylogenetic analysis of microsatellite polymorphism in C. arietinum showed no relationship between accession and geographic origin, which is compatible with the recent expansion of this crop throughout the world. PMID- 10102372 TI - The fission yeast rpa17+ gene encodes a functional homolog of AC19, a subunit of RNA polymerases I and III of Saccharomyces cerevisiae. AB - Eukaryotic RNA polymerases I and III consist of multiple subunits. Each of these enzymes includes two distinct and evolutionarily conserved subunits called alpha related subunits which are shared only by polymerases I and III. The alpha related subunits show limited homology with the alpha-subunit of prokaryotic RNA polymerase. To gain further insight into the structure and function of alpha related subunits, we cloned and characterized a gene from Schizosaccharomyces pombe that encodes a protein of 17 kDa which can functionally replace AC19 - an alpha-related subunit of RNA polymerases I and III of Saccharomyces cerevisiae - and was thus named rpa17+. RPA17 has 125 amino acids and shows 63% identity to AC19 over a 108-residue stretch, whereas the N-terminal regions of the two proteins are highly divergent. Disruption of rpa17+ shows that the gene is essential for cell growth. Sequence comparison with other alpha-related subunits from different species showed that RPA17 contains an 81-amino acid block that is evolutionarily conserved. Deletion analysis of the N- and C-terminal regions of RPA17 and AC19 confirms that the 81-amino acid block is important for the function of the alpha-related subunits. PMID- 10102373 TI - The reversed SoxS-binding site upstream of the ribA promoter in Escherichia coli. AB - The ribA gene, encoding GTP cyclohydrolase II in Escherichia coli, is a member of the soxRS regulon, which is induced by superoxide-generating agents. By evaluating lacZ expression driven by the ribA promoter carrying different lengths of upstream region in a monolysogen, we found that the superoxide-responsive element resides between 56 and 94 nucleotides upstream of the transcriptional start site. Purified SoxS protein bound to this region and protected nucleotides between positions -80 and -58 from degradation by DNase I. This region contains a putative SoxS-binding sequence (soxbox) in reverse orientation. The SoxS protein interacted specifically with four guanine residues within the soxbox sequence, as demonstrated by methylation interference analysis. These results clearly indicate that SoxS binds to the reversed soxbox sequence in the ribA gene, while in other known genes of the soxRS regulon it binds to the normally oriented soxbox. Possible modes of interaction between SoxS and RNA polymerase are discussed. PMID- 10102374 TI - A novel simple satellite DNA is colocalized with the Stalker retrotransposon in Drosophila melanogaster heterochromatin. AB - In the T(1:2)dor(var7) multibreak rearrangement the distal 1A-2B segment of the X chromosome of Drosophila melanogaster is juxtaposed to an inverted portion of the heterochromatin of chromosome 2. Analysis of mitotic chromosomes by a series of banding techniques has permitted us precisely to locate the heterochromatic breakpoint of this translocation in the h42 region of 2R. Cloning and sequencing of the eu-heterochromatic junction revealed that the translocated 1A-2B fragment is joined to (AACAC)n repeats, which represent a previously undescribed satellite DNA in D. melanogaster. These repeated sequences have been estimated to account for about 1 Mb of the D. melanogaster genome. The repeats are located mainly in the Y chromosome and in the heterochromatin of the right arm of chromosome 2 (2Rh), where they are colocalized with the Stalker retrotransposon. PMID- 10102375 TI - Lic4, a nuclear phosphoprotein that cooperates with calcineurin to regulate cation homeostasis in Saccharomyces cerevisiae. AB - The target of the immunosuppressants cyclosporin A(CsA) and FK506 is calcineurin, a highly conserved protein phosphatase that is required for T-cell activation and the regulation of ion homeostasis in yeast. Here we identify two genes, PMR2B and LIC4 which, when overexpressed, suppress the cation-sensitive phenotype of yeast cells lacking calcineurin. PMR2B encodes a Na+/Li+-specific plasma membrane pump and is similar to PMR2A, whose expression is known to be regulated by calcineurin. LIC4 (lithium comvertas) encodes a novel 33-kDa protein with no identity to known proteins. LIC4 overexpression suppresses the Li+-sensitive phenotype of calcineurin mutants but not the defect in recovery from pheromone arrest or viability of calcineurin dependent mutants, indicating a specific role in cation homeostasis. Similarly, lic4 mutations increase the Li+ sensitivity of both wild-type and calcineurin mutant strains, and reduce expression of pmr2A in calcineurin mutant strains, indicating that calcineurin and Lic4 may regulate parallel cation homeostatic pathways. lic4 mutations also exacerbate the Li+ sensitive phenotype of hal3 mutant strains, and overexpression of either Lic4 or Hal3 suppresses the salt sensitivity of mutant strains lacking calcineurin, Hal3, or Lic4, either singly or in combination. Taken together, these observations suggest that calcineurin, Hal3, and Lic4 cooperatively regulate the response of yeast cells to cation stress. Lic4 is phosphoprotein in vivo and a calcineurin substrate in vitro. By indirect and direct immunofluorescence detection of HA- and GFP-tagged proteins, Lic4 is localized in the nucleus in wild-type cells but predominantly cytoplasmic in cells lacking calcineurin. Taken together, our findings support a model in which calcineurin and Lic4 are components of signalling cascades that regulate cation stress responses in yeast. PMID- 10102376 TI - Dbf2 is implicated in a Cbt1-dependent pathway following a shift from glucose to galactose or non-fermentable carbon sources in Saccharomyces cerevisiae. AB - Dbf2, a cell cycle-regulated protein kinase, has been shown recently to be part of the CCR4 transcriptional regulatory complex in the yeast Saccharomyces cerevisiae. We report here that temperature-sensitive (ts) dhf2-2 mutant cells can be rescued by overexpression of CDC14, which encodes a dual-specificity protein phosphatase, when grown on glucose-containing medium, as reported previously, but not on galactose. Screening of two S. cerevisiae cDNA libraries led to the identification of CBT1 as a gene which, if overexpressed simultaneously with CDC14, results in the rescue of the dbJ2-2 mutation at restrictive temperature on galactose-based medium, as well as on media containing non-fermentable carbon sources such as glycerol, lactate and acetate. Cbt1 has been shown previously to be essential for formation of cytochrome b in the mitochondria. On the other hand, the ts defects of ccr4delta and caf1delta mutants on glycerol medium at 37 degrees C (Ccr4 and Caf1/Pop2 are two other members of the CCR4 complex) could not be complemented by simultaneous overexpression of CBT1 and CDC14. CCR4 and CAF1 have been shown to play an essential role in activating the expression of genes for non-fermentative growth. Our results strongly suggest that, within the CCR4 complex, Dbf2 is directly involved in some mitochondrial function that depends on cytochrome b or on one of its main regulators, Cbt1. Therefore, Dbf2 may be required not only during mitosis but also during growth on non-fermentable carbon sources. PMID- 10102377 TI - High-throughput genetic mapping in Arabidopsis thaliana. AB - To facilitate rapid determination of the chromosomal location of novel mutations, we have improved current approaches to gene mapping using microsatellite length polymorphisms. The high-throughput linkage analysis method described here allows a novel gene to be tested for linkage against the whole genome of a multicellular eukaryote, Arabidopsis thaliana, in a single polyacrylamide gel. The procedure is based on the simultaneous co-amplification of 21 microsatellites in a single tube, using a multiplex PCR mix containing 21 primer pairs, each including one oligonucleotide labeled with one of three fluorescent dyes that have different emission wavelengths. The amplification products, which range in number from 21 to 42, depending on the genotype of the individual being tested, are electrophoresed in a single lane on a polyacrylamide gel. The use of an automated fragment analyzer makes it possible to perform linkage analysis on a one gel-one gene basis using DNA samples from 19 F2 individuals obtained from an outcross involving a mutant and a wild-type that is genetically polymorphic with respect to the ecotype in which the mutant was generated. Discrimination of the amplification products is facilitated not only by labeling with different fluorochromes, but also by prior testing of different sequences for the ability to prime the amplification of each microsatellite, in order to ensure that multiplex PCR yields compatible amplification products of non-overlapping size. The method is particularly useful in large-scale mutagenesis projects, as well as for routine mapping of single mutants, since it reveals the map position of a gene less than 24 h after the F2 individuals to be analyzed have become available. The concepts employed here can easily be extended to other biological systems. PMID- 10102378 TI - Novel ribosomal genes from maize are differentially expressed in the zygotic and somatic cell cycles. AB - We have isolated cDNAs representing more than 50 different genes from libraries of unfertilised egg cells and zygotes of maize, expression of which is up- or downregulated after in vitro fertilisation (IVF). Among the cDNAs isolated are seven which encode proteins that are probably involved in translation and two encoding proteins probably involved in DNA replication. The latter genes are strongly induced on fertilisation. This indicates that zygotic gene activation (ZGA) - the switch from maternal to embryonic control of development - occurs in the zygote shortly after fertilisation in higher plants - earlier than in animal systems so far investigated. Four novel transcripts for ribosomal proteins (S21A, S21B, L39, P0) involved in ribosome biosynthesis and translation were analysed in more detail. The expression of all four genes correlates with cell division activity and is strongly induced during the G1 phase of the somatic cell cycle. A different mode of regulation operates in the first embryonic cell cycle: relatively large amounts of transcript are stored in the unfertilised egg cells, and by 18 h after IVF, two ribosomal genes are induced while a third is downregulated. These results indicate that using the combination of single-cell culture techniques with novel molecular methods, it is possible to isolate and study numerous genes expressed in female gametes and zygotes of higher plants. The detailed analysis of the four ribosomal protein genes demonstrates that the zygotic and somatic cell cycles are differentially regulated. PMID- 10102379 TI - In vivo effect of 8-epi-PGF2alpha on retinal circulation in diabetic and non diabetic rats. AB - Retinal hemodynamic responses to a F2-isoprostane, 8-epi-PGF2alpha, were quantitated in vivo in non-diabetic and diabetic rats using a video fluorescein angiography system. Vascular diameters and retinal mean circulation time were determined before and after 5 microl intra-vitreous injection of 8-epi-PGF2alpha (10(-5) to 10(-3) M), 10(-4) M 8-epi-PGF2alpha, + 10(-3) M SQ29,548 or 10(-3) M LCB2853 (two inhibitors of TXA2 receptor), 10(4) M 9beta-PGF2alpha, or the carrier in non-diabetic animals. Diabetic rats received either 8-epi-PGF2alpha 10(-4) M, or the carrier. Compared to control animals, diabetic rats presented in the basal state a venous vasodilation (P<0.01), without modification of retinal mean circulation time or blood flow. After intravitreous injection of 8-epi PGF2alpha, a significant arterial vasoconstriction was observed in control but not in diabetic animals. This vasoconstriction was concomitant with increased retinal mean circulation time in control but not in diabetic rats, inducing an impaired reduction of blood flow. No vasoconstriction was observed after injection of either the carrier, 9beta-PGF2alpha or the isoprostane associated to the inhibitors of TXA2 receptors. This is the first direct observation that the isoprostane 8-iso-PGF2alpha is a potent vasoconstricting agent in the retina. It occurs at the arterial but not venous level, and is likely mediated through a TXA2-like receptor. Differences observed between control and diabetic animals suggest altered adaptative mechanisms toward vasoconstrictor substances (such as isoprostanes) in diabetic rats. PMID- 10102380 TI - Interaction between nitric oxide and prostaglandin E pathways in rat smooth muscle myometrial cells. AB - Previously, we demonstrated the presence of a nitric oxide (NO) prostaglandin (PG) pathway in myometrial cells obtained from uterine rat tissue. This pathway was modulated by estrogen and one possible function could be to modulate uterine relaxation. In the present study, we investigated the role of progesterone in the regulation of NO synthesis and the uterotonic PGE production by myometrial cells from uterine rat tissue. We worked with two groups of rats: (i) ovariectomizcd (OV) rats, without influence of sex hormones and (ii) OV rats injected with progesterone (4 mg) s.c. Myometrial uterine cells were obtained by a selective enzymatic digestion. In the incubation medium of these cells, nitrite concentration (as a measure of NO production) and PGE production were evaluated. To ensure a specific response, a competitive NOs inhibitor, N(G)-monomethyl-L arginine; L-NMMA (300 microM) was used. We found that at 48 h of the incubation period, cells obtained from progesterone-primed uterine tissue presented an increase in the nitrite concentration concomitant with a decrease in the PGE production. When L-NMMA was added to the cells, nitrite production and PGE synthesis returned to control values. The fact that this effect had not been observed in the group of cells obtained from OV rats suggests that progesterone was responsible for it. These data provide strong evidence that in spite of the fact that estrogen and progesterone modulate the NO-PG pathway in the uterine rat tissue, the two hormones have opposite effects. PMID- 10102381 TI - Fatty acid composition of phospholipids and neutral lipids from human diabetic small arteries and veins by a new TLC method. AB - It has been suggested that lipid peroxidation of polyunsaturated fatty acids (PUFA) may play a role in the pathogenesis of diabetic complications. To test this hypothesis, we aimed to compare PUFA composition of small arteries and veins (< 500 microm diameter) obtained from diabetic or non-diabetic Guadeloupean patients undergoing arterio-venous shunt surgery before renal dialysis. Small forearm subcutaneous vessels were analysed by a new TLC method which involved inclusion of vascular biopies directly in alveoles made in the TLC gel and lyophilization onto the plate. The TLC plate was then chromatographed and lipids were both extracted and eluted during this step. Fatty acid composition of phospholipid and neutral lipid fractions were determined. Similar fatty acid composition was obtained for arteries and veins from diabetic or non-diabetic subjects. In phospholipids from diabetic vessels, major changes consisted of a 20% decrease of arachidonic acid (20:4 n-6), a 40% decrease of its elongation product 22:4 n-6 and 30% increase of 18:2 n-6. In neutral lipids, 20:4 n-6 was also diminished by 60% whereas oleic acid increased by 15%. This loss of arachidonic acid in small diabetic vessels suggests impaired delta6-desaturase forming 20:4 n-6 or alternatively increased peroxide formation, in the vascular wall of small vessels in diabetic patients. PMID- 10102382 TI - Eicosatrienoic acid (20:3 n-9) inhibits the expression of E-cadherin and desmoglein in human squamous cell carcinoma in vitro. AB - Eicosatrienoic acid (ETA 5,8,11, n-9) is abnormally increased by essential fatty acid deficiency (EFAD), a condition associated with alterations of cell proliferation and differentiation. In comparison to certain EFAs, addition of ETA at a low concentration resulted in a reduction in the expression of the cell-cell adhesion molecule, E-cadherin, and to a lesser degree, of desmoglein, along with increased invasion of Matrigel by human squamous cell carcinoma (SCC) cells in vitro. At higher concentrations, ETA stimulated the growth of SCC cells. As previously shown, n-6 EFAs (mainly 18:3 n-6, GLA), up-regulated the expression of E-cadherin and desmoglein. This is the first report showing that the abnormal 20:3 n-9 (Mead's acid) is a down regulator of antimetastatic E-cadherin and desmoglein expression. PMID- 10102383 TI - Nitric oxide and endothelin relationship in intestinal ischemia/reperfusion injury. AB - Gastrointestinal mucosal blood flow is dependent on a balanced release of vasoactive substances from endothelium. Nitric oxide (NO) may increase the flow by vasodilatation and/or antiaggregation whereas endothelin (ET) may decrease it by vasoconstriction and aggregation. NO and ET may have counterbalancing effects on each other in tissue damage. In order to test this hypothesis, in this study on rats, L-arginine to increase NO levels and N(G)-nitro-L-arginine methyl esther (L-NAME) to decrease NO levels have been used in an intestinal ischemia/ reperfusion (I/R) injury model and portal vein ET response was evaluated. Lipid peroxidation product measurements and chemiluminescence (CL) studies were also carried out in ileal tissue samples. Intestinal I/R injury caused an increase in portal venous ET levels with levels of 9.4+/-0.5 fmol/ml in sham operation and 14.8+/-1.6 fmol/ml in I/R group. ET level of L-NAME-sh group was lower than that of sham-operated group and also ET level of L-NAME-I/R group was lower than that of I/R group. This yielded the conclusion that inhibition of NO synthesis decreases portal venous ET levels in this model. Increased NO production by L arginine caused increased ET levels in sham operated groups but this effect was not observed in I/R injury state. This study also showed that inhibition of NO synthesis has a protective role by reducing the reperfusion damage in this model. It is likely that NO and ET have a feedback effect on each other both under physiologic conditions and I/R injury. PMID- 10102384 TI - Effect of dexamethasone on leukotriene synthesis in DMSO-stimulated HL-60 cells. AB - Human leukemia (HL) 60 cells were differentiated by dimethylsulfoxide (DMSO) treatment to granulocyte-like cells, leukotriene (LT) synthesizing activity of which was increased in response to the differentiation of the cells. Four synthesizing enzymes, cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), LTA4 hydrolase and LTC4 synthase, and an enzyme associated protein, 5 lipoxygenase activating protein (FLAP) are involved in the generation of LTC4 and LTB4. We examined the expression of messenger RNA (mRNA) for these LT synthesizing enzymes and an associated protein in DMSO differentiated HL-60 cells by reverse transcriptase polymerase chain reaction (RT-PCR). The production of LTC4 and LTB4, measured by radioimmunoassay (RIA), was increased after the incubation with DMSO for more than 3 days. Messenger RNA abundance for 5-LO, LTC4 synthase and LTA4 hydrolase was increased, that for FLAP was stable, but that for cPLA2 was decreased. These results indicate that DMSO induced increase of LT synthesis is associated with the increase of mRNA expression of 5-LO, LTC4 synthase and LTA4 hydrolase, although the precise regulatory mechanisms of the increased mRNA expression are not determined. We also investigated an action of dexamethasone (DEX) on DMSO-induced enhancement of LT synthesis. DEX suppressed DMSO induced increase of LTC4 synthesis, but rather enhanced DMSO induced LTB4 production. The DEX attenuated the DMSO-induced increase of mRNA expression for LTC4 synthase, but showed no effect on that for LTA4 hydrolase. The inhibition of LTC4 synthesis is associated with the suppression of mRNA expression for LTC4 synthase. However, increased LTB4 synthesis by DEX is regulated by the mechanisms which are independent from mRNA level of LTA4 hydrolase. PMID- 10102385 TI - Modulation of rat liver lipid metabolism by prolactin. AB - The effect of chronic hyperprolactinemia on the delta6- and delta5-desaturation activity, total lipid and fatty acid composition, as well as fluorescence anisotropy, was studied in liver microsomes from anterior pituitary-grafted rats. We observed a depression in delta6-desaturation activity but no changes in the delta5-desaturation activity in the grafted animals. The microsomal fraction from the hyperprolactinemic rats contained significantly less amount of linoleic acid and a higher content of 20:4 n-6, 22:5 n-6 and 22:6 n-3 acids. Lipid rotational mobility was increased in microsomes as well as in liposomes obtained from the microsomes of transplanted animals. The fluidifying effect induced by PRL was located in the deepest zone of the membrane. The results obtained indicate that high levels of prolactin induce changes in polyunsaturated fatty acid distribution in liver microsomes, which regulates the lipid rotational mobility and hence membrane fluidity. PMID- 10102386 TI - Oxidant stress, anti-oxidants, nitric oxide and essential fatty acids in peptic ulcer disease. AB - In patients with duodenal ulcer (DU), the plasma levels of nitrite and lipid peroxides, the anti-oxidant content of red cells and plasma phospholipid fatty acid analysis were performed both before and after healing of the ulcer following treatment with lansoprazole, a proton pump inhibitor. These results showed that during the phase of active DU, the concentrations of antioxidants (superoxide dismutase, SOD, catalase and glutathione peroxidase) in red cells were low where as those of lipid peroxides and nitric oxide were high. Of the fatty acids measured, the concentration of palmitic acid (16:0) was increased during the active ulcer phase whereas those of arachidonic acid, alpha-linolenic acid and docosahexaenoic acid were low. These biochemical abnormalities reverted to normal following healing of the ulcer with lansoprazole. These results coupled with the observation that polyunsaturated fatty acids (PUFAs) can inhibit the growth of Helicobacterpylori and heal the ulcer suggest that free radicals, anti-oxidants, nitric oxide and PUFAs may play a significant role in the pathogenesis of DU. If this is true, it suggests that PUFAs can be exploited as potential anti-peptic ulcer drugs. PMID- 10102387 TI - Effects of DP-1904, a thromboxane synthetase inhibitor, on the antigen-induced airway hyperresponsiveness and infiltration of inflammatory cells in guinea-pigs. AB - The effect of DP-1904, a novel thromboxane (TX) synthetase inhibitor, on airway hyperresponsiveness was studied in actively sensitized guinea-pigs. Airway hyperresponsiveness to intravenous ACh was observed at 3 and 7 h after aerosolized antigen challenge. In the model, a significant correlation between increases of respiratory resistance and microvascular leakage was observed, corresponding to the elevation of TXB2 in bronchoalveolar lavage fluid (BALF) in the early phase. DP-1904, at doses of 3 mg/kg or higher given orally one hour prior to the antigen challenge, inhibited the TXB2 production and the development of airway hyperresponsiveness in the early phase. Further, DP-1904 significantly suppressed the accumulation of lymphocytes in BALF and airway hyperresponsiveness in the late phase, although it only slightly decreased the mobilization of eosinophils and neutrophils. The results suggest that TXA2 is possibly involved in the development of airway hyperresponsiveness, and DP-1904 prevented the airway hyperresponsiveness via inhibition of TXA2 production and regulation of inflammatory cells. PMID- 10102388 TI - Role of prostaglandins in the urinary bladder: an update. AB - Our knowledge of prostanoids is rapidly increasing. In this review we survey the factors governing the synthesis of prostanoids by the urinary bladder, their role in the maintenance of normal bladder function, the pattern of their secretion in bladder disease and the possible use of prostanoids in the treatment of bladder pathology. PMID- 10102389 TI - Correlation between arthroscopically observed changes and synovial light microscopic findings in osteoarthritic temporomandibular joints. AB - The aim of this study was to determine the correlation between arthroscopically observed (ASC) changes in the synovial membrane and other joint components and synovial light microscopic (LM) findings in the temporomandibular joint (TMJ). Synovial membrane biopsies were obtained during unilateral arthroscopy in forty patients. Thirty-one patients were diagnosed with TMJ osteoarthritis (OA) and nine patients with non-osteoarthritic conditions of their TMJs. Correlations between ASC and synovial LM findings were analyzed with Cohen's Kappa and Spearman's rank correlation tests. Values for Kappa of 0.6 and higher and values for a correlation coefficient of 0.7 and higher were considered satisfactory. No correlations were found in the retrodiscal tissue biopsies. In the anterodiscal tissue biopsies, ASC hypervascularity correlated with LM intima cell shape and cell density. ASC lowered attachment to the anterior slope of the articular eminence correlated with the LM presence of a fibrous intima matrix. In several TMJs, a high concurrence was observed between ASC and LM pathologic changes. The severity of pathologic changes as observed by LM was, however, often less than was suggested arthroscopically. PMID- 10102391 TI - Conservative treatment of unilateral condylar fractures in children: a long-term clinical and radiologic follow-up of 55 patients. AB - The purpose of this prospectively designed study was the long-term clinical and radiological evaluation of conservatively treated unilateral condylar fractures in children. Fifty-five children aged between 2 1/2 and 9 3/4 years, presenting with a singular unilateral fracture of the mandibular condyle, were treated in a nonsurgical-functional way using an intraoral myofunctional appliance. In the follow-up period, patients were investigated by standardized clinical examination and by evaluation of panoramic radiographs taken immediately post-traumatically, after 6, 12, 24, 48 and 72 weeks, and then yearly through the period of growth. With a satisfactory clinical course in all patients, there was no instance of functional disturbance or mandibular asymmetry after the respective follow-up periods. The radiographs showed a fairly good shape of the condyle (no or only slight condylar deformity) in the 47 patients of the 2-6 year age group. In the eight patients of the 7-10 year age group presenting with a class II or III condylar fracture, healing was characterized by incomplete condylar regeneration, resulting in a moderate condylar deformity in two cases, a definite reduction in condylar neck height in two cases, and a hypertrophic condylar deformity in four cases. The positive results of this study confirm the concept of a nonsurgical functional approach in children presenting with various types of unilateral fractures of the mandibular condyle. Condylar remodeling was the mode of fracture healing in instances of displaced and dislocated condylar fractures. PMID- 10102390 TI - Camouflage in head and neck region--a non-invasive option for skin lesions. AB - The technique of camouflage, a non-invasive procedure to correct flaws in the texture and colour of the facial skin, is presented. The acceptance and use of camouflaging by 52 patients with different diagnoses are presented. The advantages of camouflaging are discussed in comparison to medical tattooing. PMID- 10102392 TI - A review of quality of life assessment in oral cancer. AB - Quality of life is important in patients with oral and oropharyngeal cancer. The assessment of quality of life is complex and it is difficult to identify the studies and questionnaires previously reported that have dealt with quality of life assessment in patients with oral cancer. This article gives guidelines for choosing a questionnaire, provides a tabulated summary of 65 studies published in the English language from 1980 to 1997, and gives a brief description of 27 commonly used questionnaires. The review is of particular assistance to the clinician who is considering embarking upon quality of life research in oral cancer. PMID- 10102393 TI - Intra-tumor injection of an angiogenesis inhibitor, TNP-470, in rabbits bearing VX2 carcinoma of the tongue. AB - A semi-synthetic analogue of fumagillin, TNP-470, has been shown to be a potent angiogenesis inhibitor. In this study, we evaluated the anti-tumor efficacy of TNP-470 on rabbits bearing VX2 carcinoma of the tongue, by comparison of topical, intra-tumor (i.t.) injection with systemic, intra-venous (i.v.) administration. The i.t. injection of the angiogenesis inhibitor produced much stronger anti tumor effects, and almost complete tumor regression was achieved at doses of 10 mg/kg or 20 mg/kg. TNP-470 injected intra-tumorally significantly reduced expression of proliferating cell nuclear antigen (PCNA) and microvessel density in the VX2 carcinoma of the tongue. TNP-470 also halted the tumor-associated neovascularization in the rabbit cornea assay. These data suggest that i.t. injection of TNP-470 effectively inhibits tumor angiogenesis and disrupts microvasculature development, which may suppress tumor growth. In conclusion, the i.t. injection of TNP-470 provided remarkable anti-tumor effects on the VX2 carcinoma of the tongue and is expected to have promising therapeutic uses for oral cancer. PMID- 10102394 TI - Adenosquamous carcinoma of the mouth: a rare variant of squamous cell carcinoma. AB - Adenosquamous carcinoma is a rare tumour in the oral cavity and is characterised histologically by carcinomatous change in surface epithelium, in association with adenocarcinoma affecting the ducts of minor salivary glands. Only a dozen cases have previously been reported in the oral cavity, but all have shown an aggressive course with 60% of patients dying of disease. We report three further cases and review the literature, which suggests that this lesion should be regarded as a high-grade variant of squamous cell carcinoma. PMID- 10102395 TI - Surgical management of macroglossia due to primary amyloidosis. AB - A case of macroglossia due to primary amyloidosis is described, followed by a discussion of the various aspects of surgical intervention based on a literature review. PMID- 10102396 TI - Destruction of the glenoid joint fossa by a tenosynovial giant-cell tumour of the skull base: a case report. AB - A 63-year-old man is presented in whom a tenosynovial giant-cell tumour had destroyed the temporomandibular joint fossa and expanded intracranially. The lesion was not diagnosed for a period of at least two years. Treatment included wide resection including the surrounding bone, dura and condyle. PMID- 10102397 TI - Trichofolliculoma of the upper lip: report of a case. AB - A trichofolliculoma occurring in the mid-philtrum of the upper lip of a 17-year old boy is reported. It presented as an asymptomatic, 10 mm deep sinus and histology showed keratin-filled cysts or sinuses lined by stratified squamous epithelium. PMID- 10102398 TI - Multimodal strategy for reduction of homologous transfusions in cranio maxillofacial surgery. AB - The transfusion of homologous blood carries well-known risks that have prompted efforts to develop alternative techniques. Such measures are of particular interest to patients undergoing elective procedures. A total of 204 patients, out of 1470 patients who consecutively underwent major craniomaxillofacial procedures under general anesthesia over a two-year period, were enrolled in a prospective protocol to reduce homologous transfusion requirements when a blood loss in excess of 500 ml was anticipated. The data were compared with the results of a retrospective control group (n=2890) covering major procedures during the previous four years, when blood-saving measures were applied occasionally, but not based on a global strategy. Techniques for the reduction of homologous transfusions were acute normovolemic hemodilution, controlled moderate hypotension, cell saver and predeposit autologous blood. In addition, preoperative administration of human recombinant erythropoietin was introduced during the last year of the study. These techniques were applied individually or in combination, depending on contraindications specific for each technique, using invasive monitoring in order to maintain intraoperative hemodynamic stability. The goal of this study was to examine the extent to which homologous transfusions may be reduced with the systematic application of transfusion-sparing techniques. Of 204 patients qualifying for the transfusion-sparing protocol, 30 received homologous transfusions. In comparison to the control group, utilization of transfusion-sparing techniques had doubled. The overall reduction in the use of homologous transfusions was highly significant. When acute normovolemic hemodilution, controlled moderate hypotension and the cell saver were used in combination, a greater reduction in homologous transfusions was achieved than with the use of either a single modality or combination of any two. No transfusions were required in patients pretreated with erythropoietin. PMID- 10102399 TI - Age effects on ectopic bone formation induced by purified bone morphogenetic protein. AB - A mixture of heparin-Sepharose-purified bovine bone morphogenetic protein and type I atellocollagen was implanted in the subcutaneous tissues of 4-week, 10 month and 18-month-old rats. The implants were removed at 7, 14 and 21 days after implantation. The effects of rat age on ectopic bone formation were evaluated on the explants using haematoxylin-eosin staining, morphometric analysis, alkaline phosphatase activity and calcium content determination, as well as immunohistochemical staining of type IV collagen present in the basement membrane of blood vessels. On day 14 and 21, bone was observed in 4-week and 10-month-old rats, but the amount of bone formed in the latter was less than in the 4-week-old rats. In 18-month-old rats, bone was first found focally in very limited regions of the explants on day 21 and the amount of bone was much less than in 4-week-old rats. At all periods, alkaline phosphatase activity was higher in younger rats. On day 7, there were more blood vessels in the explants of 4-week-old rats than in those of 10-month or 18-month-old rats. On day 14 and 21, more blood vessels were found in the central regions of the explants in 4-week-old rats than in the same regions in 10-month or 18-month-old rats. The findings in the present study indicate that the rate and quantity of ectopic bone formation are reduced in aged rats, and suggest that the difference in blood vessel distribution is related to this reduction in ectopic bone formation. PMID- 10102400 TI - Alveolar ridge augmentation by distraction osteogenesis using titanium implants: an experimental study. AB - The left mandibular premolars were extracted from five adult dogs. After twelve weeks, a box-shaped osteotomy of the alveolar bone was carried out and two 10 mm implants were placed 5 mm into the transport alveolar segment, leaving 5 mm exposed. The alveolar bone was vertically augmented 5 mm by screwing the implants. After distraction, the implants were left to integrate into the bone. Histological and radiographical evaluations showed the lifting of the transport segment and the development of new bone in the distraction area. Although integration of implants within both the transport segment and the regenerated bone was observed, two of the ten implants failed and partial bone resorption of the transport segment was noted. PMID- 10102401 TI - The 49th Annual Meeting of the Arbeitsgemeinschaft fur Kieferchirurgie within the Deutsche Gesellschaft fur Zahn-, Mund- und Kieferheilkunde, together with the Arbeitskreis Oralpathologie within the Deutsche Gesellschaft fur Zahn-, Mund- und Kieferheilkunde, 21-23 May 1998, Bad Homburg, Germany. PMID- 10102402 TI - Autism in search of a home in the brain. PMID- 10102403 TI - Sympathetically maintained pain: has the emperor no clothes? PMID- 10102404 TI - Restless legs syndrome: a disease in search of identity. PMID- 10102405 TI - Autism: new data suggest a new hypothesis. PMID- 10102406 TI - Oculomotor evidence for neocortical systems but not cerebellar dysfunction in autism. AB - OBJECTIVE: To investigate the functional integrity of cerebellar and frontal systems in autism using oculomotor paradigms. BACKGROUND: Cerebellar and neocortical systems models of autism have been proposed. Courchesne and colleagues have argued that cognitive deficits such as shifting attention disturbances result from dysfunction of vermal lobules VI and VII. Such a vermal deficit should be associated with dysmetric saccadic eye movements because of the major role these areas play in guiding the motor precision of saccades. In contrast, neocortical models of autism predict intact saccade metrics, but impairments on tasks requiring the higher cognitive control of saccades. METHODS: A total of 26 rigorously diagnosed nonmentally retarded autistic subjects and 26 matched healthy control subjects were assessed with a visually guided saccade task and two volitional saccade tasks, the oculomotor delayed-response task and the antisaccade task. RESULTS: Metrics and dynamics of the visually guided saccades were normal in autistic subjects, documenting the absence of disturbances in cerebellar vermal lobules VI and VII and in automatic shifts of visual attention. Deficits were demonstrated on both volitional saccade tasks, indicating dysfunction in the circuitry of prefrontal cortex and its connections with the parietal cortex, and associated cognitive impairments in spatial working memory and in the ability to voluntarily suppress context-inappropriate responses. CONCLUSIONS: These findings demonstrate intrinsic neocortical, not cerebellar, dysfunction in autism, and parallel deficits in higher order cognitive mechanisms and not in elementary attentional and sensorimotor systems in autism. PMID- 10102407 TI - Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation. AB - BACKGROUND: Painful nerve and tissue injuries can be exacerbated by activity in sympathetic neurons. The mechanisms of sympathetically maintained pain (SMP) are unclear. OBJECTIVE: To determine the effect of cutaneous sympathetic activity on pain induced by primary afferent C-nociceptor sensitization with capsaicin in humans. METHODS: In healthy volunteers capsaicin was applied topically (n = 12) or injected into the forearm skin (n = 10) to induce spontaneous pain, dynamic and punctate mechanical hyperalgesia, and antidromic (axon reflex) vasodilatation (flare). Intensity of pain and hyperalgesia, axon reflex vasodilatation (laser Doppler), and flare size and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of high and low sympathetic skin activity induced by whole-body cooling and warming with a thermal suit. By this method sympathetic vasoconstrictor activity is modulated in the widest range that can be achieved physiologically. The degree of vasoconstrictor discharge was monitored by measuring skin blood flow (laser Doppler) and temperature (infrared thermometry) at the index finger. RESULTS: The intensity and spatial distribution of capsaicin-evoked spontaneous pain and dynamic and punctate mechanical hyperalgesia were identical during the presence of high and low sympathetic discharge. Antidromic vasodilatation and flare size were significantly diminished when sympathetic vasoconstrictor neurons were excited. CONCLUSIONS: Cutaneous sympathetic vasoconstrictor activity does not influence spontaneous pain and mechanical hyperalgesia after capsaicin induced C-nociceptor sensitization. When using physiologic stimulation of sympathetic activity, the capsaicin model is not useful for elucidating mechanisms of SMP. In neuropathic pain states with SMP, different mechanisms may be present. PMID- 10102408 TI - Striatal dopaminergic function in restless legs syndrome: 18F-dopa and 11C raclopride PET studies. AB - OBJECTIVE: To use PET to study striatal dopaminergic function in restless legs syndrome (RLS). BACKGROUND: RLS is a common disorder experienced by as much as 5% of the population. It has been suggested that this condition is associated with a disturbance of dopaminergic transmission. METHODS: The authors measured nigrostriatal terminal dopamine storage with 18F-dopa and striatal D2 receptor binding with 11C-raclopride PET in 13 RLS patients, five of whom were receiving treatment with L-dopa at the time of scanning. RLS results were compared with those of age-matched control subjects. RESULTS: Mean caudate and putamen 18F-dopa uptake were mildly reduced in the RLS patients compared with control subjects, and this reached significance (p = 0.04) in the putamen. Mean D2 binding was reduced in the caudate (p = 0.01) and the putamen (p = 0.008) in RLS patients compared with control subjects. Six of the 13 RLS patients had caudate and putamen D2 binding reduced below the control range. Three other RLS patients showed only reduced putamen D2 binding. There were no significant differences in striatal 18F-dopa uptake or D2 binding between L-dopa-naive and L-dopa-treated RLS patients. CONCLUSIONS: These PET findings support the hypothesis of central dopaminergic dysfunction in RLS. PMID- 10102409 TI - Restless legs syndrome improved by pramipexole: a double-blind randomized trial. AB - BACKGROUND: Restless legs syndrome (RLS) is characterized by leg paresthesia associated with an irresistible urge to move. Currently used dopaminergic agents, such as levodopa, pergolide, and bromocriptine, offer incomplete control of sensory and motor symptoms and induce severe side effects. OBJECTIVE: To assess the safety and efficacy of pramipexole, a full D3-receptor agonist, in the treatment of RLS. METHODS: Ten RLS patients were studied before and after two 1 month treatments (placebo and pramipexole) administered in a double-blind crossover fashion. The severity of sensory and motor manifestations was assessed by 1 week of home questionnaires and 2 consecutive nights of sleep laboratory recordings. The indexes of periodic leg movement during sleep (PLMS) and during wakefulness (PLMW) were used as primary outcome variables. RESULTS: Pramipexole dramatically reduced the PLMS index to normal values (Wilcoxon, p = 0.005). The PLMW index was also significantly reduced (Wilcoxon, p = 0.007). Pramipexole also alleviated leg discomfort at bedtime and during the night as measured by the home questionnaires. CONCLUSIONS: Pramipexole is the most potent therapeutic agent ever tested for RLS. Measures of both sensory and motor functions returned to normal values after treatment. Moreover, these results further support the hypothesis that D3 receptors play a major role in the physiopathology of this condition. PMID- 10102410 TI - A randomized controlled study of pergolide in patients with restless legs syndrome. AB - BACKGROUND: Open clinical trials indicate that low doses of pergolide, a long acting D1 and D2 dopamine agonist, lead to a reduction in the symptoms of restless legs syndrome (RLS) with subjective improvement in sleep quality. OBJECTIVE: To assess the therapeutic efficacy of pergolide in improving sleep and subjective measures of well-being in patients with idiopathic RLS using polysomnography and clinical ratings. METHODS: In a randomized, double-blind, placebo-controlled crossover design we enrolled 30 patients with idiopathic RLS according to the criteria of the International RLS Study Group. All patients were free of psychoactive drugs for at least 2 weeks before the study. Patients were monitored using polysomnography, clinical ratings, and sleep diaries at baseline and at the end of a 4-week pergolide or placebo treatment period. The initial dosage of 0.05 mg pergolide was increased to the best subjective improvement paralleled by 20 mg domperidone tid. RESULTS: At a mean dosage of 0.51 mg pergolide as a single daily dose 2 hours before bedtime, there were fewer periodic leg movements per hour of time in bed (5.7 versus 54.9, p < 0.0001), and total sleep time was significantly longer (373 versus 261 minutes, p < 0.0001). Ratings of subjective sleep quality, quality of life, and severity of RLS were improved significantly without relevant adverse events. CONCLUSION: Pergolide given as a single low-to-medium bedtime dose in combination with domperidone provides a well-tolerated and effective treatment of sensorimotor symptoms and sleep disturbances in patients with primary RLS. PMID- 10102411 TI - REM sleep behavior disorder and dementia: cognitive differences when compared with AD. AB - OBJECTIVE: To determine whether the dementia associated with REM sleep behavior disorder (RBD) differs from Alzheimer's disease (AD) and, if so, whether differences in cognitive performance between RBD/dementia and AD resemble reported differences between dementia with Lewy bodies (DLB) and AD. METHODS: This retrospective study compares neurocognitive performance between 31 patients with degenerative dementia and polysomnography-confirmed RBD and 31 patients without brainstem Lewy body pathology who met Consortium to Establish a Registry for Alzheimer's Disease (CERAD) clinical and neuropathologic criteria for AD. The patient groups did not differ in dementia severity (based on Global Deterioration Scale score) or duration. RESULTS: RBD preceded or coincided with the onset of cognitive decline in 94% of the patients. All but one patient with RBD/dementia had one or more of the following clinical features of DLB: visual hallucinations, extrapyramidal signs, or fluctuating cognition/alertness. The data revealed significantly worse performance on attention, perceptual organization, visual memory, and letter fluency for the RBD/dementia group, whereas the AD group showed significantly worse performance on confrontation naming and verbal memory. CONCLUSIONS: Patients with RBD and degenerative dementia demonstrate a significantly different pattern of cognitive performance from patients with AD. Most of the patients in the RBD/dementia sample also meet criteria for possible or probable DLB, and the pattern of cognitive differences from AD is similar to reported comparisons between DLB and AD. The cognitive and clinical data provide evidence to suggest that the dementia associated with RBD may represent DLB. PMID- 10102412 TI - Visual loss and getting lost in Alzheimer's disease. AB - BACKGROUND: AD causes patients to get lost in familiar surroundings, in part because of visuospatial disorientation from parieto-occipital involvement. Parieto-occipital cortex analyzes the radial patterns of visual motion that create optic flow and guide movements through the environment by showing one's direction of self-movement. OBJECTIVE: To determine whether AD patients are impaired in perceiving the visual patterns of optic flow, suggesting a perceptual mechanism of visuospatial disorientation. METHODS: We studied the ability of young normal subjects, elderly normal subjects, and AD patients to see and interpret visual patterns, including the radial motion of optic flow. Each person sat in front of a panoramic computer display and gave push-button responses to indicate their perception of the projected visual stimuli. Spatial navigation was tested by asking questions about a recently traversed path. RESULTS: Half of the AD subjects showed impaired optic flow perception that was associated with poor performance on the spatial navigation test, even though their perception of simple moving patterns was relatively preserved. Some AD subjects also showed a separate impairment in interpreting optic flow, so that they could not use those stimuli to judge their direction of self-movement. CONCLUSIONS: AD greatly impairs the ability to see the radial patterns of optic flow. This may interfere with the use of visual information to guide self-movement and maintain spatial orientation. PMID- 10102413 TI - Postmenopausal estrogen replacement therapy and risk of AD: a population-based study. AB - OBJECTIVE: To study the association between estrogen replacement therapy in postmenopausal women and AD using a case-control design. BACKGROUND: Studies of the effect of estrogen therapy on the risk of AD have been limited and have yielded conflicting results. METHODS: Case patients were all postmenopausal women who developed AD in the quinquennium 1980 through 1984 in Rochester, MN (n = 222). One control subject from the same population and free of dementia was matched to each case patient by age (+/-3 years) and length of enrollment in the records-linkage system (n = 222). Estrogen exposure was defined as any form of estrogen (oral, parenteral, topical, suppository) used for at least 6 months after the onset of menopause and before the onset of AD (or corresponding year in the matched control subject). Information on dose and duration of use was abstracted. Consistent with the matched design, analyses entailed conditional logistic regression. RESULTS: AD patients and control subjects had identical age at menarche (median: 13.0 versus 13.0 years) and age at menopause (median: 50.0 versus 50.0 years). The frequency of estrogen use was higher among control subjects than AD patients (10% versus 5%; odds ratio = 0.42; 95% confidence interval 0.18 to 0.96; p = 0.04). There was a significant trend of decreasing odds ratios with increasing duration of use. The inverse association between estrogen therapy and AD remained significant after adjustment for education and age at menopause. CONCLUSION: These results from a population-based study suggest that estrogen replacement therapy is associated with a reduced risk of AD in postmenopausal women. PMID- 10102414 TI - Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance. AB - OBJECTIVE: To assess the relationship between impaired glucose tolerance and both vascular dementia and AD. BACKGROUND: Diabetes and abnormalities of glucose metabolism have been associated with stroke and poor cognitive function. In addition, glycoproteins and glycosylation have been postulated to be associated with the development of neuritic plaques characteristic of AD. METHODS: A historical prospective cohort study of Japanese-American men (n = 3,774), who were examined at ages 45 to 68 (1965 through 1968) and again at ages 71 to 93 (1991 through 1993). Measurements were obtained by clinical and home examinations: assessment of glucose intolerance (nonfasting 1 hour after glucose load) from 1965 through 1968 and history of diabetes diagnosed by a physician at examinations given from 1965 through 1968 and from 1976 through 1978. At the 1991 through 1993 examinations, the Cognitive Assessment Screening Instrument (CASI) an instrument designed for use in cross-cultural settings combining features of the Folstein Mini-Mental State Examination, the Modified Mini-Mental State Examination, and the Hasegawa Dementia Screening Scale-was used. Diagnosis and classification of AD and vascular dementia were made by a consensus panel using neuropsychologic assessment data, a neurologist's evaluation, and information from a family informant. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised criteria were used to establish dementia, and subclassification by cause was based on other published criteria. RESULTS: No association between AD and diabetes, present either 25 or 15 years previously, was found after adjustment for age and education in a multiple regression model. A significant association was found between impaired glucose tolerance at baseline and vascular dementia (p < 0.01). CONCLUSIONS: These findings confirm expected relationships between impaired glucose tolerance and stroke-related dementia but do not support an association of disordered glucose metabolism with AD. PMID- 10102415 TI - The duration of symptoms in transient ischemic attack. AB - BACKGROUND: The majority of TIAs last from 2 to 15 minutes, although some may be of long duration. OBJECTIVE: We examined factors related to the duration of TIAs to identify the relationship to clinical characteristics. METHODS: We performed brain imaging studies as well as angiographic and cardiac examinations in 81 consecutive patients (64 men and 17 women, age 65.8+/-9.9 years) with carotid TIAs. We evaluated risk factors (hypertension, diabetes mellitus, hyperlipidemia, alcohol consumption, and smoking), potential cardiac sources of emboli, and arterial stenosis > or =50% in diameter in the carotid or middle cerebral arteries. Recent infarcts were assessed with CT or MRI. We correlated duration of symptoms with clinical data. RESULTS: The presence of emboligenic cardiac or arterial diseases was significantly related to the duration of symptoms. With sensitivity-specificity curve analysis for detecting such diseases, the duration of symptoms could be divided into short-duration TIAs (<60 minutes, n = 41) or long-duration TIAs (> or =60 minutes, n = 40). Patients with long-duration TIAs had emboligenic cardiac or arterial diseases more frequently than those with short-duration TIAs (86% versus 46%, p < 0.001). Recent infarcts were also more frequent in patients with long-duration TIAs than they were in patients with short-duration TIAs (45% versus 21%, p < 0.05). CONCLUSIONS: Short-duration and long-duration TIAs can be separated based on symptom duration of < 1 hour or > or = 1 hour. Patients with long-duration TIAs should be examined more closely for the presence of cardiac and arterial diseases than those with short-duration TIAs. PMID- 10102416 TI - Ischemia in the territory of a hypoplastic vertebrobasilar system. AB - BACKGROUND: Congenital variations in the configuration and size of the cerebral vessels may predispose to ischemic stroke. OBJECTIVES/METHODS: To illustrate that a hypoplastic basilar artery may lead to posterior circulation ischemia in adults, eight cases are reported from two university medical centers. RESULTS: Five men and three women with a mean age of 49.8 years are reported. Four of the patients had other conventional stroke risk factors. Two patients had brainstem strokes, and six had TIA. All patients had hypoplastic basilar arteries. Seven patients had at least one hypoplastic vertebral artery (bilateral in five cases), and six patients had both posterior cerebral arteries originating from the internal carotid arteries. CONCLUSIONS: A hypoplastic basilar artery is frequently accompanied by vertebral artery hypoplasia, and this can predispose adults to posterior circulation ischemia. This entity can be suspected on the basis of MR angiogram, but conventional angiography will provide definitive diagnosis. Optimal medical and surgical treatment of this condition is unresolved. PMID- 10102417 TI - Seasonal variation in stroke mortality rates. AB - OBJECTIVE: To identify possible contributors to the seasonal variation in stroke mortality. BACKGROUND: Stroke and respiratory disease mortality rates were calculated from vital statistics and census data for the United States from 1938 to 1988. State-specific average temperatures by month were derived from data obtained from the National Climatic Data Center for 1938 to 1987. METHODS: Each time series was decomposed into a trend, a seasonal effect, and a residual effect. Multiple regression was used to fit both a trend and a seasonal harmonic series. Cross-correlation was used to assess the relationship between the residual time series. RESULTS: There is a strong and consistent seasonal pattern of high stroke and respiratory disease mortality in the colder winter months. Stroke mortality was significantly and independently both positively associated with respiratory disease mortality and inversely associated with temperature. The sharp initial increases in both respiratory disease and stroke mortality in the late fall and early winter are synchronous, and the amplitudes are strongly associated, except for a saturation effect with extreme respiratory disease amplitudes. CONCLUSIONS: Seasonal change in stroke mortality is associated with seasonal variation in both respiratory disease and temperature. Respiratory disease and temperature may influence stroke mortality nonspuriously by affecting stroke case fatality, incidence, or both. PMID- 10102418 TI - MRI evidence of past cerebral microbleeds in a healthy elderly population. AB - BACKGROUND: Incidental foci of signal loss suggestive of past microbleeds are a frequent finding on gradient-echo T2-weighted MRI of patients with nontraumatic intracerebral hemorrhage and have been associated with bleeding-prone microangiopathy. If and to what extent such lesions may also occur in the normal population is unclear. OBJECTIVE: To determine focal hypointensities in asymptomatic elderly individuals and their relation to other clinical and morphologic variables. METHODS: T2-weighted MRI of the brain was performed in a consecutive series of 280 participants (mean age 60 years, range 44 to 79) of the Austrian Stroke Prevention Study. This cohort consisted of randomly selected individuals without history or signs of neuropsychiatric disorder. RESULTS: Past microbleeds ranging from one to five foci of signal loss were seen in 18 (6.4%) individuals. They were strongly associated with higher age, hypertension, and lacunes (p < 0.001), and extensive white matter damage was more frequently noted (p = 0.02). Hypertension was present in all individuals with focal hypointensities in the basal ganglia and infratentorially but in only 5 of 10 volunteers with microbleeds limited to cortico-subcortical sites (p = 0.04). CONCLUSIONS: MRI evidence of past microbleeds may be found even in neurologically normal elderly individuals and is related, but not restricted, to other indicators of small vessel disease. The predictive potential of this finding regarding the risk of intracerebral bleeding requires further investigation. PMID- 10102419 TI - Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. AB - OBJECTIVE: To determine whether the concentrations of the neuronal marker N acetylaspartate (NAA) and the choline-containing metabolites (Cho) are altered in the subcortical brain of HIV+ patients who are cognitively normal and clinically asymptomatic, and to determine whether these alterations are greater in the presence of cognitive impairments and clinical symptoms. BACKGROUND: Pathologic studies suggest that subcortical gray matter carries a heavy HIV load, and neuropsychological test results are consistent with involvement of subcortical and frontostriatal brain systems in HIV disease. Noninvasive proton magnetic resonance spectroscopy (1H MRS) suggests neuronal preservation and macrophage infiltration in the subcortical brain of clinically symptomatic and cognitively impaired HIV+ individuals. Improved 1H MRS methods may allow the early detection of metabolite alterations in the subcortical brain of asymptomatic HIV+ individuals. METHODS: Two-dimensional 1H MRS imaging was performed on 30 HIV- control subjects and 70 HIV+ patients with varying severities of systemic disease and neuropsychological impairments, but without cerebral opportunistic infections. RESULTS: Subcortical Cho was elevated in HIV+ patients compared with control subjects regardless of the presence or absence of cognitive impairment or clinical symptoms. Subcortical NAA was lower than control NAA only in severely cognitively impaired HIV+ subjects. Subcortical NAA correlated with performance on a variety of neuropsychological tests but not with Centers for Disease Control clinical stage, whereas high-thalamic Cho was associated with low CD4 lymphocyte counts. CONCLUSIONS: 1H MRS imaging detects higher Cho in subcortical brain early in HIV disease, when individuals are clinically and neuropsychologically asymptomatic, whereas lower NAA is only found in subcortical brain in individuals with severe neuropsychological impairments. Quantitative 1H MRS imaging may play a role in the objective assessment of the presence, magnitude, and progression of brain involvement in HIV infection. PMID- 10102420 TI - Bacterial meningitis in adults: demonstration of inner ear involvement using high resolution MRI. AB - OBJECTIVE: To visualize the sites involved in audiovestibular dysfunction during bacterial meningitis in adults and to relate these findings to the extent of hearing impairment and vestibular dysfunction. BACKGROUND: Hearing impairment is among the most frequent complications of bacterial meningitis. METHODS: High resolution MRI (HR-MRI) of the inner ear was performed in seven adult patients with hearing loss as a complication of bacterial meningitis. RESULTS: Five patients had unilateral (n = 1) or bilateral (n = 4) contrast enhancement of vestibulocochlear structures. The structures most frequently involved were the cochlear nerve (n = 9), the first cochlear turn (n = 9), the vestibulum (n = 9), and the semicircular canals (n = 7). There was a significant correlation between clinical and MRI findings: all nine ears with cochlear enhancement were deaf (hearing loss >90 dB), whereas none of the five ears with normal MRI findings had hearing losses of more than 90 dB (range, 30 to 70 dB; p = 0.0005). Vestibular dysfunction as revealed clinically and by quantitative vestibular function testing was found in six of seven patients (11 of 14 ears). Five of these patients (nine ears) also demonstrated enhancement of the vestibular organ on high-resolution MRI of the inner ear. CONCLUSIONS: High-resolution MRI can visualize the involvement of vestibulocochlear structures in bacterial meningitis in both cooperative and consciously impaired patients. These findings suggest a correlation between abnormalities on MRI and the extent of cochlear dysfunction. PMID- 10102421 TI - Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q) AB - OBJECTIVE: To report a family with X-linked Charcot-Marie-Tooth disease (CMTX) with proven connexin 32 (Cx32) mutation associated with deafness. METHODS: Twelve members of a CMTX family were examined clinically. Electromyography and sensory and motor conduction studies were performed in three men, two women, and a 7-year old boy. Audiometric testing was carried out in the three men, one woman, and an 8-year-old girl. Molecular genetic analysis was performed in six men and five women. RESULTS: The three men and the 7-year-old boy had the usual sensorimotor deficit and pronounced reduction of motor nerve conduction velocity. A 15-year old boy was asymptomatic and had only areflexia. The women had impairment of vibratory sensation and slight slowing of nerve conduction velocities. Sensorineural deafness was observed in the three men and in an 8-year-old girl without any motor or sensory deficit. Molecular genetic analysis revealed a new missense mutation located in codon 142 of the Cx32 gene leading to the substitution of an arginine by a glutamine. CONCLUSION: CMTX due to Cx32 mutations often shows interfamilial and intrafamilial phenotypic variation, which is also the hallmark of this family. The sensorineural deafness observed in this family suggests that Cx32 could play an important role in the auditory pathway. PMID- 10102422 TI - Calpain III mutation analysis of a heterogeneous limb-girdle muscular dystrophy population. AB - OBJECTIVE: To determine the frequency of calpain III mutations in a heterogeneous limb-girdle muscular dystrophy (LGMD) population. BACKGROUND: Mutations of the calpain III gene have been shown to cause a subset of autosomal recessive LGMDs. Patient populations studied to date have been primarily of French and Spanish origin, in which calpain III may cause 30% of autosomal recessive MDs. The incidence of calpain III mutations in non-French/Spanish MD patients has not been studied thoroughly. No sensitive and specific biopsy screening methods for detecting patients with abnormal calpain III protein are available. Thus, detection of patients relies on direct detection of gene mutations. METHODS: The authors studied the calpain III gene in 107 MD patient muscle biopsies exhibiting normal dystrophin. Muscle biopsy RNA was produced for each patient, and the entire calpain III complementary DNA was screened for mutations by reverse transcriptase PCR/single-strand conformation polymorphism using three different conditions. RESULTS: The authors identified nine patients (eight unrelated) with causative mutations. Six of the seven distinct mutations identified are novel mutations and have not been described previously. CONCLUSION: The results suggest that approximately 9.2% of patients in the heterogeneous population with an LGMD diagnosis will show mutations of the calpain III gene. Interestingly, two patients were heterozygous for a single mutation at the DNA level, whereas only the mutant allele was observed at the RNA level. This suggests that there are undetectable, nondeletion mutations that ablate expression of the calpain III gene. PMID- 10102423 TI - MRI abnormalities associated with partial status epilepticus. AB - OBJECTIVE: To report neuroimaging findings in patients with complex partial status epilepticus. BACKGROUND: During status epilepticus, neuroimaging may be used to exclude other neurologic conditions. Therefore, it is important to identify the neuroimaging features that are associated with status epilepticus. In addition, MRI characteristics may provide insight into the pathophysiologic changes during status epilepticus. METHODS: The history and neuroimaging examination results of three patients with complex partial status epilepticus were reviewed. Studies obtained during status epilepticus included diffusion weighted MRI (DWI), MR angiography (MRA), postcontrast T1-weighted MRI, T2 weighted MRI, and CT. Follow-up MRI was obtained in two patients, and autopsy results were available for the third. RESULTS: Some of the MRI and CT findings during partial status epilepticus mimicked those of acute ischemic stroke: DWI and T2-weighted MRI showed cortical hyperintensity with a corresponding low apparent diffusion coefficient, and CT showed an area of decreased attenuation with effacement of sulci and loss of gray-white differentiation. However, the lesions did not respect vascular territories, there was increased signal of the ipsilateral middle cerebral artery on MRA, and leptomeningeal enhancement appeared on postcontrast MRI. On follow-up imaging, the abnormalities had resolved, but some cerebral atrophy was present. CONCLUSIONS: The radiologic characteristics of status epilepticus resemble those of ischemic stroke but can be differentiated based on lesion location and findings on MRA and postcontrast MRI. The MRI abnormalities indicated the presence of cytotoxic and vasogenic edema, hyperperfusion of the epileptic region, and alteration of the leptomeningeal blood-brain barrier. These changes reversed, but they resulted in some regional brain atrophy. PMID- 10102424 TI - Visual discrimination after anterior temporal lobectomy in humans. AB - OBJECTIVE: To determine whether right anterior temporal lobectomy (RTL) results in perceptual deficits, and whether the perception of particular stimulus features (i.e., shape, motion, color) is affected differentially. BACKGROUND: RTL results in abnormal visual discrimination, recognition, and recall of pictorial material that cannot be easily specified verbally, such as designs and faces. It is unclear whether stimuli must be conceptually meaningful to elicit perceptual deficits. METHODS: Tests were constructed to assess a wide spectrum of basic visual discrimination abilities with simple, meaningless stimuli. The performance of nine patients who underwent left temporal lobectomy (LTL) and nine patients who underwent RTL were compared with that of normal control individuals. The mean excision size along lateral cortex was 3.7 cm for the LTL group and 5.6 cm for the RTL group; mean mesial excision size was 5.2 cm for LTL and 4.6 cm for RTL. RESULTS: Basic visual discrimination capacities were demonstrated to be essentially intact after LTL and RTL, except for a mild loss of blue color discrimination after RTL. CONCLUSIONS: There is little evidence that RTL produces perceptual impairments limited to the domain of pattern perception, or generalizable to nonmeaningful stimuli. The perceptual loss after RTL may be largely restricted to extraction of meaning, and related to the disruption of the circuits that connect the outcome of visual analysis to previously stored semantic information. PMID- 10102425 TI - Cerebral lateralization of language in normal left-handed people studied by functional MRI. AB - OBJECTIVE: To use functional MRI (fMRI) to further define the occurrence of left hemisphere, bilateral, and right-hemisphere language in a normal left-handed population. METHODS: A total of 100 healthy volunteers, consisting of 50 left handed subjects and a reference group of 50 right-handed subjects, were studied by fMRI of the frontal cortex during silent word generation. RESULTS: Ninety-six percent of right-handed subjects showed fMRI changes lateralized to the left hemisphere, whereas 4% showed a bilateral activation pattern. In contrast, left hemisphere lateralization occurred in 76% of left-handers, bilateral activation in 14%, and right-hemisphere lateralization in the remaining 10%. The predominance of right-hemisphere activation, however, was weak in these cases; only a single left-handed subject (2%) showed complete right-hemisphere lateralization. CONCLUSIONS: Silent word generation lateralizes to the left cerebral hemisphere in both handedness groups, but right-hemisphere participation is frequent in normal left-handed subjects. Exclusive right-hemisphere activation rarely occurred in the frontal lobe region studied. PMID- 10102426 TI - Physiology of perception: cortical stimulation and recording in humans. AB - OBJECTIVES: 1) To determine the effect of stimulus train duration (TD) on sensory perception using direct stimulation of somatosensory and visual cortices. 2) To investigate the occurrence of evoked potentials in response to stimulation that is subthreshold for perception. BACKGROUND: Studies of the mechanisms of conscious perception using direct cortical stimulation and recording techniques are rare. The clinical necessity to implant subdural electrode grids in epilepsy patients undergoing evaluation for surgery offers an opportunity to examine the role of stimulus parameters and evoked potentials in conscious perception. METHODS: Subjects included epilepsy patients with grids over somatosensory or occipital cortex. Single pulses (100 microseconds) and stimulus trains were applied to electrodes, and thresholds for perception were found. Evoked potentials were recorded in response to peripheral stimulation at intensities at, above, and below sensory threshold. RESULTS: During cortical stimulation, sensory threshold changed little for stimulus trains of 250 milliseconds and longer, but increased sharply as TD decreased below this level. Primary evoked activity was recorded in response to peripheral stimulations that were subthreshold for conscious perception. CONCLUSIONS: The results confirm a previous report of the effects of stimulus TD on sensory threshold. However, no motor responses occurred following somatosensory stimulation with short trains, as previously reported. The TD threshold pattern was similar in visual cortex. In agreement with the previous report, early components of the primary evoked response were not correlated with conscious sensory awareness. PMID- 10102427 TI - Interferon-alpha2a reduces MRI disease activity in relapsing-remitting multiple sclerosis. Norwegian Study Group on Interferon-alpha in Multiple Sclerosis. AB - OBJECTIVE: To evaluate the efficacy and safety of interferon-alpha2a (IFN alpha2a) in relapsing-remitting MS (RRMS). BACKGROUND: Several immune-modulating therapy regimens of IFN-alpha have shown varying results in MS. A recent pilot study suggested benefits from IFN-alpha2a. METHODS: Ninety-seven patients were randomized to receive subcutaneous injections of placebo (33 patients) or 4.5 million international units (mIU) (32 patients) or 9.0 mIU (32 patients) of IFN alpha2a three times weekly for 6 months, with a further 6 months of follow-up. Monthly gadodiamide-enhanced MRI was the primary method of evaluating efficacy. RESULTS: IFN-alpha2a treatment resulted in fewer new MRI lesions during the treatment period (p < 0.003). The probability of no new lesions during treatment was >2.5 times higher with 9.0 mIU IFN-alpha2a than with placebo (p < 0.005). The median number of lesions at the end of treatment was lower with IFN-alpha2a treatment than with placebo (p = 0.0004), but the difference disappeared during follow-up. The total number of lesions (mean) increased by 4.78 with placebo, 0.86 with 4.5 mIU IFN-alpha2a, and 0.28 with 9.0 mIU IFN-alpha2a during treatment (p = 0.030). No treatment effect on exacerbation rate, progression of disability, or quality of life was detected. Nine patients discontinued treatment, five because of adverse events. CONCLUSIONS: IFN-alpha2a treatment significantly reduced disease activity as measured by MRI, but the efficacy disappeared within 6 months after discontinuation of treatment. A long-term study of more patients using disability as a primary outcome measure is needed to evaluate the clinical impact. PMID- 10102428 TI - Brain weight in autism: normal in the majority of cases, megalencephalic in rare cases. AB - The brain weights of 21 postmortem autism cases (5 new and 16 previously published) were compared with normal brain weights from six autopsy studies. Of the 21 cases, 17 had normal brain weights and 1 was micrencephalic. Compared with the normal median (1,460 g), three autism cases were megalencephalic: two (1,810 g and 1,820 g) had been previously reported and one (1,880 g) was a new case. Brain weight is thus normal in most postmortem cases of autism. There are, however, rare cases of megalencephaly and possibly micrencephaly. PMID- 10102430 TI - Charcot-Marie-Tooth disease type 2 with restless legs syndrome. AB - In a series of 44 consecutive patients with Charcot-Marie-Tooth disease (CMT), we found restless legs syndrome (RLS) in 10 of 27 CMT type 2 (CMT2) patients (37%) and in none of 17 CMT type 1 patients (p = 0.004). In the CMT2 patients, RLS was associated with positive sensory symptoms (10/10 versus 10/17; p = 0.026). This finding supports the view that a disorder of sensory input plays a role in the pathogenesis of RLS. Symptomatic treatment may benefit these patients. PMID- 10102429 TI - Motor system excitability in patients with restless legs syndrome. AB - In 18 patients with idiopathic restless legs syndrome (RLS), intracortical inhibition by paired transcranial magnetic stimulation (TMS) was significantly reduced for both foot and hand muscles, suggesting that the entire motor cortex is disinhibited in RLS. Decreased intracortical facilitation in the foot muscle but not in the hand muscle may be due to subliminal activation of the symptomatic lower limbs. Motor excitability measurements of single TMS were not altered. These results support a subcortical origin of RLS. PMID- 10102432 TI - Effect of interferon beta on human myelin basic protein-specific T-cell lines: comparison of IFNbeta-1a and IFNbeta-1b. AB - The effect of interferon (IFN)beta-1a and IFNbeta-1b on human myelin basic protein-reactive T-cell lines was investigated. Both drugs inhibited proliferation and production of lymphotoxin (LT), whereas the production of interleukin-4 was not altered and interleukin-10 was induced. Comparing equal numbers of units IFNbeta-1a and -1b showed almost identical results. These in vitro data indicate that the immunomodulatory capacity of both interferons with respect to T cells paralleled their antiviral effect. PMID- 10102431 TI - (+)-alpha-[11C]Dihydrotetrabenazine PET imaging in familial paroxysmal dystonic choreoathetosis. AB - Clinical observations suggest a disturbance of striatal dopaminergic function in familial paroxysmal dystonic choreoathetosis (PDC). The authors used PET with [11C]dihydrotetrabenazine (DTBZ) to study striatal dopaminergic innervation in PDC. The results did not reveal abnormal DTBZ binding potential in PDC striatum. This suggests that dopaminergic abnormalities, if present, may be due to altered regulation of dopamine release or to postsynaptic mechanisms, rather than to an altered density of nigrostriatal innervation. PMID- 10102433 TI - A safety and pharmacokinetic study of intravenous natalizumab in patients with MS. AB - A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies. PMID- 10102434 TI - Subacute measles encephalitis in a young man immunosuppressed for ankylosing spondylitis. AB - Subacute measles encephalitis occurred 1 month after measles onset in a 26-year old HIV-negative man undergoing immunosuppressive treatment for ankylosing spondylitis. He had seizures, a decline in mental status, and progressive impairment of consciousness, with a fatal outcome. Despite severely deficient cellular immunity, the elevated antimeasles antibody titers and CSF findings indicated that humoral immunity was not impaired. Histologic, electron microscopic, and immunocytochemical studies revealed the typical intranuclear inclusions of paramyxovirus nucleocapsids, and measles virus antigen in neurons and oligodendrocytes. PMID- 10102435 TI - Neuroinvasion by human herpesvirus type 7 in a case of exanthem subitum with severe neurologic manifestations. AB - A 19-month-old girl presented with severe neurologic symptoms associated with exanthem subitum. Human herpesvirus type 7 (HHV-7) DNA was detected in the CSF and serum, and supported by serologic studies. The patient was diagnosed with encephalopathy due to an acute HHV-7 infection. Neuron-specific enolase in the CSF was strongly elevated during the acute stage of infection, suggesting that the encephalopathy was due to viral invasion of the brain. PMID- 10102436 TI - Single-day praziquantel versus 1-week albendazole for neurocysticercosis. AB - The efficacy of albendazole (15 mg/kg/d for 1 week) was compared with praziquantel (100 mg/kg in three divided doses at 2-hour intervals) for therapy of parenchymal brain cysticercosis. Ten patients were treated with albendazole and 10 patients with praziquantel. Although the total number of cysts was significantly reduced from 64 to 7 in patients treated with albendazole and from 59 to 24 in those treated with praziquantel, the number of patients improving with albendazole was not significantly different from those treated with praziquantel. PMID- 10102437 TI - Intra-arterial thrombolysis for perioperative stroke after open heart surgery. AB - Recent major surgery is an exclusion criterion for thrombolysis. Six patients with acute ischemic stroke underwent intra-arterial thrombolysis after recent open heart surgery without clinically significant bleeding complications, although one patient developed a small, asymptomatic cerebellar hemorrhage. Intra arterial thrombolysis may be an option for patients with cerebral embolism in the perioperative period. PMID- 10102438 TI - Resolution of early diffusion-weighted and FLAIR MRI abnormalities in a patient with TIA. AB - We report a patient with a clinical history and neurologic examination consistent with acute stroke. Diffusion-weighted and fast fluid-attenuated inversion recovery MRI obtained 4 hours after stroke onset detected focal abnormalities suggestive of acute ischemic brain damage. The neurologic deficit and the imaging abnormalities both resolved completely at follow-up. This patient illustrates complete resolution of early changes observed with diffusion-weighted MRI at the hyperacute phase in a TIA. PMID- 10102439 TI - CNS pseudovasculitis in a patient with pheochromocytoma. AB - The authors report a patient with angiographic findings resembling CNS vasculitis (CNS pseudovasculitis) who was found to have a pheochromocytoma. The angiographic changes resolved after surgical resection of the pheochromocytoma. Pheochromocytoma should be included in the differential diagnosis of angiographic findings suggestive of CNS vasculitis. PMID- 10102440 TI - Neurofilament protein levels in CSF are increased in dementia. AB - The neurofilament is the major cytoskeletal structure of myelinated axons. In this study, CSF levels of the light subunit of the neurofilament protein (NFL) were increased in patients with vascular dementia (VAD), AD, and frontotemporal dementia (FTD) compared with neurologically healthy individuals. Because NFL is localized mainly in myelinated axons, these results suggest that the degeneration of white matter in these disorders causes the increased CSF NFL levels. PMID- 10102441 TI - Radicular pain can be a symptom of elevated intracranial pressure. AB - We report two patients with leptomeningeal metastatic disease, one from breast cancer and the other from a spinal cord glioma, who developed episodic elevated intracranial pressure (ICP), each episode accompanied by the gradual onset of severe spine and radicular pain. Symptoms of pain promptly and completely resolved with opening of the on-off valve of each patient's ventriculoperitoneal shunt. It is theorized that the patients' radicular pain was caused by nerve root ischemia secondary to elevated ICP. PMID- 10102442 TI - Proper name anomia after left temporal lobectomy: a patient study. AB - A patient with a selective deficit in retrieving proper names after left temporal lobectomy is reported. He showed proper name anomia in conversation, in response to photographs, and in verbal descriptions, despite being able to provide semantic information about the people he was unable to name. This report provides evidence that the rostral part of the left temporal lobe plays a crucial role in processing proper names without involvement of other verbal functions. PMID- 10102443 TI - Isolated Echinococcus granulosus hydatid cyst in the CNS with severe reaction to treatment. PMID- 10102444 TI - Stroke prevention trials: how many enrollees can be expected by site? PMID- 10102445 TI - MRI follow-up of herpes simplex virus (type 1) radiculomyelitis. PMID- 10102446 TI - Mitochondrial G8363A mutation presenting as cerebellar ataxia and lipomas in an Italian family. PMID- 10102447 TI - Cerebrospinal fluid F2-isoprostanes are elevated in Huntington's disease. PMID- 10102448 TI - An MRI study of autism: the cerebellum revisited. PMID- 10102449 TI - Role of anticardiolipin antibodies in young persons with migraine and transient focal neurologic events. PMID- 10102450 TI - PET with 18fluorodeoxyglucose and hexamethylpropylene amine oxime SPECT in late whiplash syndrome. PMID- 10102451 TI - Herpes simplex virus encephalitis following corticosteroids and cranial irradiation. PMID- 10102452 TI - Facilitory paratonia and frontal lobe functioning. PMID- 10102453 TI - A longitudinal study of patients with venous malformations. PMID- 10102454 TI - Charcot-Marie-Tooth disease type 2 and P0 gene mutations. PMID- 10102455 TI - The clearance of thrombin-antithrombin and related serpin-enzyme complexes from the circulation: role of various hepatocyte receptors. PMID- 10102456 TI - Thrombomodulin gene defects in families with thromboembolic disease--a report on four families. AB - It has been suggested that an impaired thrombomodulin (TM) function could constitute an abnormality leading to thromboembolic disease (TED). The TM gene from 51 unrelated American patients with TED and 100 American blood donors was screened for mutations. Four heterozygous point mutations in the TM gene were detected. The mutations are distributed throughout the TM gene and predict amino acid changes 1) Pro483 to Leu, 2) Gly61 to Ala, 3) Asp468 to Tyr (earlier described) and 4) a silent mutation not predicting any amino acid change at Glu163. Family studies reveal that the occurrence of the different TM mutations is associated with a history of TED, but there are indications of multiple risk factors and no perfect co-segregation of the TM defects and TED. Among the controls. three individuals carried heterozygous TM variants predicting either a Pro477-Ser mutation (two cases) or an Asp468-Tyr mutation. Our results thus demonstrate that a previously undocumented abnormality in the protein C anticoagulant pathway, a defect in the TM gene, to a certain extent co-segregates with familial thrombophilia. Further studies are needed to prove the causality of these TM mutations. PMID- 10102457 TI - Is the prevalence of the factor V Leiden mutation in patients with pulmonary embolism and deep vein thrombosis really different? AB - INTRODUCTION: Previous investigations have suggested a lower prevalence of the factor V Leiden mutation in patients with pulmonary embolism, as compared to patients with deep leg vein thrombosis. METHODS: We studied unselected patients with pulmonary embolism, in whom we also assessed the presence of deep vein thrombosis by ultrasonography. We assessed the prevalence of heterozygosity for the factor V Leiden mutation and compared the outcome of patients with a normal ultrasound (primary pulmonary embolism) to those with an abnormal ultrasound (combined form of venous thromboembolism). Furthermore, we performed a literature search to identify all articles regarding the prevalence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and a combined form of venous thromboembolism. We calculated a (common) odds ratio for these 3 manifestations of venous thromboembolism, including the current findings. RESULTS: In 92 patients with proven pulmonary embolism, 25 (27%) had also an abnormal ultrasound. In these patients, the prevalence of the factor V Leiden mutation was 24% (95% CI 9%-45%), whereas the mutation was present in 5 of 67 patients with primary pulmonary embolism (7%; 95% CI 2%-16%). The literature analysis indicated the common odds ratio for the presence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and the combined form of venous thromboembolism to be 7.9 (95% CI 5-12), 3.5 (95% CI 2-6) and 6.8 (95% CI 3-14), respectively. CONCLUSION: In patients with primary pulmonary embolism the prevalence of the factor V Leiden mutation appears to be half of that reported in patients with primary deep vein thrombosis. The mechanism remains unclear. PMID- 10102458 TI - Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. AB - Gestational hypertension with or without proteinuria is a multifactorial disease in which the presence of a hypercoagulable state has been suggested. The prothrombin G20210A, the Factor V (FV) Leiden mutations, and the C677T 5-10 methylenetethrahydrofolate reductase (MTHFR) polymorphism were investigated in 140 women with gestational hypertension and in 216 normotensive women from Southern Italy. Nine controls (4.1%) and 16 cases (11.4%; OR: 2.96, 95% CI: 1.27 6.91) carried the prothrombin A20210 allele. FV Leiden mutation was observed in 4 controls (1.8%) and 11 cases (7.9%; OR: 4.53, 95% CI: 1.41-14.53). The TT MTHFR genotype was found in 36 controls (16.6%) and 34 cases (24.4%: OR: 1.61, 95% CI: 0.96-2.74). The impact of potential confounding variables was evaluated using a logistic regression analysis. Nulliparity, Factor V Leiden and prothrombin A20210 carrier status resulted to be independent risk factors of having gestational hypertension with or without proteinuria. Imbalance of haemostasis, through prothrombotic genetic factors, may predispose to the occurrence of gestational hypertension. PMID- 10102459 TI - Clinical prediction of deep vein thrombosis in patients with leg symptoms. AB - Symptoms and clinical signs individually are inaccurate for the diagnosis of DVT. However, when assessing patients with leg symptoms, clinicians have access to additional information, such as whether or not DVT risk factors are present that could improve the accuracy of clinical judgment. The purpose of this study was to identify which clinical variables best predict DVT, and to use these variables to create a clinical prediction index for DVT. We studied 271 university hospital patients with a first episode of symptomatic, clinically suspected DVT. The prevalence of DVT was 27%, of which 71% were proximal. At baseline, information was collected on demographic features, comorbidity, and symptoms and signs. A Bayesian model selection strategy was used to estimate the logistic regression model that best predicted DVT. Male sex [OR = 2.8 (1.5, 5.1)], orthopedic surgery [OR = 5.4 (2.2, 13.6)], warmth [OR = 2.1 (1.2, 3.9)] and superficial venous dilation on exam [OR = 2.9 (1.4, 5.7)] were independent predictors of DVT. Using the model, a clinical prediction index that categorized patients into different levels of DVT risk was created, and was useful in a theoretical strategy aimed to limit the need for contrast venography in patients with suspected DVT, such that 96% of study patients could have avoided contrast venography. This index should be evaluated prospectively in other patient populations. PMID- 10102460 TI - Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. AB - Forty-eight patients with acute proximal deep vein thrombosis (DVT) were randomised to intravenous infusions for 4 to 6 days with melagatran, a novel synthetic low molecular weight thrombin inhibitor, or unfractionated heparin adjusted by the activated partial thromboplastin time (APTT). The aim of the study was to investigate the pharmacokinetics, pharmacodynamics and the safety of melagatran therapy at three different doses. Steady-state plasma concentrations were rapidly achieved and maintained throughout the infusion period. The mean plasma concentrations in the low, medium and high dose groups were 0.17, 0.31 and 0.53 micromol/l, respectively. The prolongation of APTT was stable during the melagatran infusions and correlated to the plasma concentration. Phlebographically verified regression of thrombus size measured as decrease in Marder score was seen after 4 to 6 days in 8 of 12 patients, 6 of 12 patients and 5 of 11 patients in the low, medium and high dose groups of melagatran and in 5 of the heparin-treated patients. In the low dose group with melagatran, thrombus extension was seen in one patient. At the dose levels studied, melagatran was well tolerated with no clinically significant bleeding problems, suggesting that melagatran could safely be given to patients suffering from DVT. PMID- 10102461 TI - No indication for APTT screening in patients on oral anticoagulant therapy. AB - Patients on oral anticoagulant therapy (OAT) may bleed due to a very low factor IX level caused by a mutation at Ala-10 in the propeptide region of the factor IX gene. We evaluated screening of patients on OAT with an APTT to detect patients with this abnormality. In 734 patients an APTT was assessed. Twenty-three patients had a disproportionately prolonged APTT. In these patients the factor IX level, the mutation at Ala-10 and the frequency of bleeding complications were assessed. No severely lowered factor IX levels were found (1 patient with 5% factor IX). No mutations at Ala-10 were found and bleeding complications were not more frequent in these patients. CONCLUSION: Routine APTT screening of patients on OAT is not useful to detect patients with increased bleeding or with the Ala 10 mutation in the factor IX gene. PMID- 10102462 TI - A randomised, controlled study of the effects of aerobic exercise and dietary fish on coagulation and fibrinolytic factors in type 2 diabetics. AB - Type 2 diabetes is associated with disturbances in coagulation and fibrinolysis. Prospective studies show that increased tissue plasminogen activator (tPA) antigen increases the risk of cardiovascular mortality. The present study examined the hypothesis that combining a regime of moderate aerobic exercise with one daily fish meal as part of a low-fat diet (30% total energy) would improve coagulation and fibrinolytic factors in dyslipidaemic type 2 diabetic patients. In a randomised. controlled, 8-week trial, 55 sedentary type 2 diabetic subjects with serum triglycerides >1.8 mmol/l and/or HDL-C <1.0 mmol/l were randomly assigned to a low-fat diet (30% daily energy intake) with or without one fish meal daily (3.6 g omega3 fatty acids/day) and further randomized to a moderate (55-65% VO2max) or light (heart rate <100 bpm) exercise program. Plasma levels of fibrinogen, coagulation factor VIIc, tPA and plasminogen activator inhibitor (PAI 1) antigen were measured before and after intervention. In the 49 subjects who completed the study, the fish diet alone, moderate exercise alone and the combination of fish and moderate exercise all led to significant reductions in tPA antigen concentrations (-2.1 ng/ml, p = 0.02. -1.9 ng/ml, p = 0.03, -2.0 ng/ml, p = 0.01, respectively) compared to controls. In multivariate regression, changes in fasting blood glucose (positively) and erythrocyte omega3 fatty acid composition (inversely) were independent predictors of the change in tPA antigen. The fish diet alone contributed to a significant rise in coagulation factor VIIc compared to controls (4.9%, p = 0.02), which was prevented by moderate exercise. No significant effects on PAI-1 antigen and fibrinogen were seen. In view of recent epidemiological findings, the reduction in tPA antigen with both fish and moderate exercise in these dyslipidaemic type 2 diabetic patients could reflect a reduced thrombotic potential and decreased cardiovascular risk. Furthermore, a small, albeit significant, increase in coagulation factor VIIc associated with fish can be prevented by a concomitant programme of moderate exercise. PMID- 10102463 TI - Circulating platelets show increased activation in patients with acute cerebral ischemia. AB - Platelet activation plays a central role in acute arterial stenosis as has been shown in coronary heart disease. Likewise it can be assumed to be of importance in the evolution of acute cerebral ischemia (ACI), particularly in patients with large vessel disease. Flow cytometric detection of platelet adhesion molecules as a marker of platelet activation in a group of patients with ACI and different etiologies has not been evaluated. In 72 patients with ACI and 72 controls, the exposure of activation-dependent adhesion molecules was determined using flow cytometry after immunostaining with monoclonal antibodies against CD 62, CD 63 and thrombospondin. The extent of platelet activation differed as a function of the etiology of ACI: platelets from patients with atherosclerosis of brain supplying arteries expressed significantly more activation markers than did controls, whereas patients with cardioembolic stroke did not. By analyzing platelet adhesion molecules it is possible to describe platelet activation profiles in patients with acute cerebral ischemia. This diagnostic procedure will be useful for monitoring individualized anti-platelet therapy and may enable distinguishing different subgroups of stroke patients. PMID- 10102464 TI - Is a prolonged bleeding time associated with an increased risk of hemorrhage after liver biopsy? AB - Bleeding time determination is not advised as a general preoperative hemostasis screening test, but it might be useful in some patient groups. Patients referred for liver biopsy frequently have coagulation disturbances and are at risk of hemorrhage. In this prospective study 219 liver biopsies were carried out regardless of a prolonged bleeding time, but with minimum requirements for hemoglobin concentration, platelet count, and tests of the internal and external coagulation pathways. The bleeding time was prolonged in the case of 48 (22%) of the biopsies. Significant bleeding as defined by a hemoglobin decrease of > or =2.0 g/dl occurred in nine patients. Three of these patients were bone marrow transplanted. Patients with a prolonged bleeding time carried a five times higher risk of bleeding (odds ratio = 5.0; confidence interval = 1.1-21.8; p = 0.019). We conclude that the bleeding time may give additional information on the risk of bleeding in some patient groups undergoing liver biopsy. PMID- 10102465 TI - Genetic effects for plasma factor VII levels independent of and in common with triglycerides. AB - BACKGROUND: Coagulation factor VII has been demonstrated as a potential risk factor for cardiovascular disease. Both genes and non-genetic factors are related to plasma levels of factor VII. However, the extent to which genetic effects influence variability in plasma factor VII levels is unknown. Further, increased levels of plasma factor VII are associated with serum triglycerides, yet the reason for this association is not fully understood. METHODS AND RESULTS: Quantitative genetic analyses were applied to evaluate the relative importance of genetic and different environmental influences on plasma factor VII levels and to test the significance of genetic and environmental factors in common to factor VII and triglycerides in 215 pairs of middle-aged and elderly twins, of whom 104 were reared apart and 120 were women. Genetic influences were found to account for 57% of the individual differences in plasma factor VII levels, whereas shared rearing and residual-familial environmental factors were not significant. Furthermore, a significant genetic correlation of 0.38 was found between factor VII and triglycerides, but the environmental correlation between these two measures was not significant. Genetic factors in common to factor VII and triglycerides explain about 7% of the total variance for factor VII. CONCLUSION: The present study suggests that there are substantial genetic influences on plasma factor VII levels. Furthermore, genetic effects explain the phenotypic association between factor VII and triglycerides. PMID- 10102466 TI - Antibodies to factor XII associated with lupus anticoagulant. AB - Falsely low levels of factor XII (FXII) have been documented in patients who are lupus anticoagulant positive (LA+). In addition, we have previously noted a surprisingly high incidence (20.9%) of apparently true FXII deficiency in patients who were LA+. We have hypothesised that this may be partly due to the presence of antibodies to FXII. The aim of the present study was to investigate whether LA+ patient plasmas contain antibodies directed either against FXII or FXII in association with phospholipids. Plasma samples from 60 blood donors, all LA negative, and 51 LA+ patients were tested using ELISA assays employing purified FXII, phosphatidylserine (PS) and phosphatidylethanolamine (PE). We have identified seven patients whose plasma contained either IgG or IgM that reacted with purified FXII in the absence of PS or PE. When PS was included in the assay system four additional patient plasmas were shown to contain either IgG or IgM that reacted with FXII. The plasma of one patient contained IgG that reacted with FXII both in the presence and absence of PS. There was no reactivity to FXII with either IgG or IgM when PE was included in the assay system. Affinity purified IgG from three patients whose plasma reacted with FXII in the ELISA assay in the absence of PS, gave a positive reaction in an immunoblot assay. These results suggest that FXII antibodies are present in a significant proportion of LA+ patients and may lead to an erroneous diagnosis of FXII deficiency. PMID- 10102467 TI - Antithrombotic and anticoagulant activities of a low molecular weight fucoidan by the subcutaneous route. AB - Fucoidans (high-molecular-weight sulfated polysaccharides extracted from brown seaweeds) have anticoagulant and antithrombotic effects. They inhibit thrombin by catalyzing both serpins (antithrombin and heparin cofactor II) according to their chemical structures and origins. In this study, a low-molecular-weight (LMW) fucoidan of 8 kDa was obtained by chemical degradation of a high-molecular-weight fraction. The antithrombotic and anticoagulant activities of this new compound were compared to those of a low-molecular-weight heparin (LMWH), dalteparin, following subcutaneous administration to rabbits. This LMW fucoidan exhibited dose-related venous antithrombotic activity, with an ED80 of about 20 mg/kg, 2 h after a single subcutaneous injection. Its activity was comparable to that of dalteparin (close to 200 anti-Xa IU/kg) and was maximal 30 min after a single subcutaneous injection. The activity remained stable (about 70%) from 1 to 4 h after injection, but disappeared by 8 h. The antithrombotic activity was not associated with either a prolongation of the thrombin clotting time (TCT) or an increase in anti-Xa activity, contrary to dalteparin. A slight prolongation of APTT occurred with both compounds. This venous antithrombotic activity was associated with a decrease in ex vivo thrombin generation and with a significant increase in the lag phase in a thrombin generation test. LMW fucoidan thus has potent antithrombotic activity and a potentially weaker haemorrhagic effect (i.e. a smaller effect on coagulation tests and a smaller prolongation of the bleeding time) than dalteparin. PMID- 10102468 TI - Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. AB - The effect of dietary vitamin K intake on warfarin sensitivity is known only from case reports and few small clinical studies. We followed 50 patients commencing warfarin and consuming their regular diets (for 8 weeks) to study this relationship. A one-week recall dietary questionnaire was completed at weeks 2 and 8. Daily intake of nutrients and vitamin K was calculated from standard tables. Warfarin sensitivity index (WSI) was defined as final INR/final warfarin dose (mg/day/m2 of body surface area) (week 8). Vitamin K intake was 17-974 (median: 179) microg/day. Median WSI was 0.82 (0.31-4.47). A WSI value of 1.1 significantly separated excess (>250 microg/day) from normal (<250 microg/day) vitamin K consumers (16/18 vs. 15/32, respectively, p <0.01). The former had lower day 5 INR (median: 1.9 vs. 3.0, p <0.001), needed more warfarin to achieve INR > or =2.0 (32.0+/-9.2 mg vs. 25.4+/-6.4 mg, p = 0.009) and required a higher maintenance steady state warfarin dose (5.7+/-1.7 mg/day vs. 3.5+/-1.0 mg/day, p <0.001). We conclude that in 32% (16/50) of anticoagulated patients under usual dietary conditions sensitivity to warfarin is decreased by vitamin K intake > or =250 microg/day. PMID- 10102469 TI - Contribution of erythrocytes to thrombin generation in whole blood. AB - Thrombin generation (TG) initiated by diluted tissue-factor was investigated in whole human blood, in platelet-rich plasma (PRP), in platelet-poor plasma (PPP), and in PPP supplemented with red blood cells (RBCs). TG was characterized by the lag time preceding the thrombin burst and by the endogenous thrombin potential (ETP). RBCs at normal haematocrit were found to influence the lag time to the same extent as platelets. When TG was carried out in PRP or in PPP + RBCs, both the ETP and lag time were dependent on the platelet count or on the haematocrit, but the shapes of the dose-response curves were different. The inhibition of TG in PPP+ RBCs by two direct thrombin and factor Xa inhibitors: hirudin and DX 9065A, and two antithrombin III (AT)-dependent anticoagulants: heparin and SR 90107A was found to be similar to that previously described in PPP and in PRP: hirudin and DX 9065A only delayed TG whereas heparin and SR 90107A both delayed and decreased TG. FACscan analysis following labelling with FITC-annexin V or with phycoerythrin-labelled antiglycophorin A of samples taken in the course of TG initiated in PPP + RBCs showed that no significant haemolysis occurred and revealed that 0.51+/-0.075% (mean +/- sem, n = 3) of RBCs steadily exposed procoagulant phospholipids on their outer surface throughout the TG course. Furthermore, incubation of factors Xa and Va with washed RBCs sampled during TG in PPP +RBCs resulted in a significant and constant prothrombinase activity. Taken together, these data show for the first time that normal RBCs may participate in the haemostatic process through exposure of procoagulant phospholipids. PMID- 10102470 TI - Solvent effects on activity and conformation of plasminogen activator inhibitor 1. AB - We have studied effects of the solvent composition on the activity and the conformation of human plasminogen activator inhibitor-1 (PAI-1) from HT-1080 fibrosarcoma cells. Non-ionic detergents, includine Triton X-100, reduced the inhibitory activity of PAI-1 more than 20-fold at 0 degrees C, but less than 2 fold at 37 degrees C, while glycerol partly prevented the detergent-induced activity-loss at 0 degrees C. The activity-loss was associated with an increase in PAI-1 substrate behaviour. Evaluating the PAI-1 conformation by proteolytic susceptibility of specific peptide bonds, we found that the V8-proteinase susceptibility of the Glu332-Ser333 (P17-P16) bond, part of the hinge between the reactive centre loop (RCL) and beta-strand 5A, and the endoproteinase Asp-N susceptibility of several bonds in the beta-strand 2A-alpha-helix E region were increased by detergents at both 0 and 37 degrees C. The susceptibility of the Gin321-Ala322 and the Lys325-Val326 bonds in beta-strand 5A to papain and trypsin, respectively, was increased by detergents at 0 degrees C, but not at 37 degrees C, showing a strict correlation between proteinase susceptibility of beta strand 5A and activity-loss at 0 degrees C. Since the beta-strand 2A-alpha-helix E region also showed differential susceptibility to endoproteinase Asp-N in latent, active, and reactive centre-cleaved PAI-1, we propose that a detergent induced conformational change of the beta-strand 2A-alpha-helix E region influences the movements of beta-sheet A, resulting in a cold-induced conformational change of beta-strand 5A and thereby an increased substrate behaviour at low temperatures. These results provide new information about the structural basis for serpin substrate behaviour. PMID- 10102471 TI - Activation of plasminogen activator inhibitor-1 synthesis by phorbol esters in human promyelocyte HL-60--roles of PCKbeta and MAPK p42. AB - HL-60 cells treated by PMA develop the monocyte adherent phenotype and synthesize plasminogen activator inhibitor type-1 (PAI-1). We focused our study on the identification of the PMA-activated protein kinase C (PKC) isoform and its downstream transduction pathway activating PAI-1 synthesis. Acquisition of the monocytic phenotype was evidenced by cell adherence (90-95%) and a sharp increase of CD 36 and receptor for urokinase plasminogen activator (uPAR) surface expression. Ro 31-8220, a specific inhibitor of PKC, prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion. To identify the PKC isoform, we took advantage of the HL-525 cell line, an HL-60 cell variant deficient in PKCbeta gene expression. This defect prevents PMA to induce the differentiation process. HL-525 stimulated by PMA did not synthesize PAI-1 nor become adherent. However, in HL-525 cells either pretreated by retinoic acid that reinduces PKCbeta gene expression or transfected with PKCbeta cDNA, PMA significantly activated PAI-1 synthesis and adhesion of cells. Immunoblotting of active Mitogen Activated Protein Kinase (MAPK) p42/p44 in HL-60 cells showed a preferential and sustained activation of the p42 isoform by PMA over the p44 isoform. Ro 31-8220 significantly attenuated this activation. PD 098059 and U0126, both highly specific MEK inhibitors, efficiently prevented PMA-induced PAI 1 synthesis (mRNA and protein levels) and cell adhesion whereas SB203580, a specific inhibitor of stress-activated MAPK p38, did not. Results obtained from HL-60 and HL-525 cells indicate that the PMA-activated transduction pathway of uPAR expression involves a PKC isoform other than PKCbeta. In conclusion, we propose that the pathway PKCbeta-MEK-MAPK p42 is a potential linear route for PAI 1 synthesis leading to morphological changes and adherence linked to PMA-induced differentiation in HL-60 cells. PMID- 10102472 TI - The activation of plasminogen activator inhibitor-1 expression by IL-1beta is attenuated by estrogen in hepatoblastoma HepG2 cells expressing estrogen receptor alpha. AB - A low estrogen status in postmenopausal women is associated with elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1). In this study, the ability of estrogen compounds to regulate PAI-1 expression was determined in a hepatocyte HepG2 cell line made to stably express estrogen receptor alpha (ERalpha). In both the wild type and ER expressing HepG2 cells, estrogen had no effect on basal PAI 1 expression. However, in the ER expressing cells the ability of IL-1beta to increase PAI-1 mRNA and protein levels was attenuated by 17beta-estradiol, tamoxifen and twelve estrogen components of Premarin. In contrast, the mixed agonist/antagonist raloxifene had weak agonist activity and like the pure antagonist ICI 182780, it dose dependently blocked the effect of 17beta-estradiol on IL-1beta stimulated PAI-1 levels. These results suggest that estrogen agonists may lower PAI-1 levels in vivo by inhibiting cytokine activated PAI-1 expression by an ER dependent mechanism. PMID- 10102473 TI - Comparison of the effects of Apo(a) kringle IV-10 and plasminogen kringles on the interactions of lipoprotein(a) with regulatory molecules. AB - Lipoprotein(a) [Lp(a)] is associated with atherosclerosis and with disease processes involving thrombosis. Lp(a) contains apoprotein (a) [apo(a)], which has a sequence highly homologous to plasminogen. Hence, Lp(a) binds directly to extracellular matrix, cellular plasminogen receptors and fibrin(ogen) and competes for the binding of plasminogen to these regulatory surfaces. These interactions may contribute to the proatherothrombogenic consequences of high Lp(a) levels. These interactions are mediated by lysine binding sites (LBS). Therefore, we examined the role of apo(a) kringle IV-10 [the only apo(a) kringle demonstrated to exhibit lysine binding activity in the intact lipoprotein] in the interaction of Lp(a) with these regulatory molecules. We have compared directly apo(a) KIV-10 with plasminogen K4 to examine whether these highly structurally homologous kringle modules are also functionally homologous. Futhermore, because the plasminogen K5-protease domain (K5-PD) binds directly to fibrin, we have also examined the ability of this plasminogen fragment to inhibit the interaction of Lp(a) with these regulatory molecules and with extracellular matrix. Apo(a) KIV 10 competed effectively for the binding of 125I-Lp(a) to these surfaces but was less effective than either intact Lp(a), plasminogen K4 or plasminogen. Plasminogen KS-PD was a better competitor than apo(a) KIV-10 for 125I-Lp(a) binding to the representative extracellular matrix, Matrigel, and to plasmin treated fibrinogen. In contrast, plasminogen K5-PD did not compete for the interaction of Lp(a) with cells, although it effectively competed for plasminogen binding. These results suggest that Lp(a) recognizes sites in all of the regulatory molecules that are also recognized by apo(a) KIV-10 and that Lp(a) recognizes sites in extracellular matrix and in plasmin-modified fibrinogen that also are recognized by plasminogen K5-PD. Thus, the interaction of Lp(a) with cells is clearly distinct from that with extracellular matrix and with plasmin treated fibrinogen and the recognition sites within Lp(a) and plasminogen for these regulatory molecules are not identical. PMID- 10102474 TI - Platelet activation induced by combined effects of anticardiolipin and lupus anticoagulant IgG antibodies in patients with systemic lupus erythematosus- possible association with thrombotic and thrombocytopenic complications. AB - Antiphospholipid antibodies (aPL) are well known to be associated with arterial and venous thrombosis. In a series of 180 patients with systemic lupus erythematosus (SLE), the prevalence of arterial thrombosis was obviously higher in the patients who had both anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) (17/35, 48.6%, p<0.05) (Table 1) than in the other patients bearing aCL or LA alone or neither of them (2/145, 1.4%). Since a substantial fraction of the former group of patients with arterial thrombosis also had thrombocytopenia (12/17, 70.6%), there was a possibility that aCL and LA might have enhanced platelet activation and aggregation. To test this possibility, we studied the in vitro effects of aCL and LA on the enhancement of platelet activation by flow cytometric analysis using anti-CD62P and anti-CD41 monoclonal antibodies directed against platelet activation-dependent granule-external membrane (PADGEM) protein and platelet glycoprotein IIb (GPIIb), respectively. Platelet activation defined by the surface expression of CD62P was not induced by aCL+ x LA+ plasma only, but was significantly augmented by aCL+ x LA+ plasma in combination with adenosine diphosphate (ADP) at a low concentration that had only a modest effect on platelet activation. In contrast, aCL+ x LA-, aCL- x LA+ and aCL- x LA- plasma samples were incapable of enhancing platelet activation in the presence or absence of ADP stimulation. In addition to plasma samples, the purified IgG from aCL+ x LA+ plasma (aCL+ x LA+-IgG) also yielded apparent enhancement of platelet activation induced by ADP. Furthermore, platelet activation was generated by the mixture of aCL+ x LA--IgG and aCL- x LA+-IgG fractions prepared from individual patients, but not by each fraction alone. These results suggest that aCL and LA may cooperate to promote platelet activation, and may be involved, at least partially, in the pathogenesis of arterial thrombosis and thrombocytopenia in patients with SLE. PMID- 10102475 TI - Platelet contribution to leukotriene production in inflammation: in vivo evidence in the rabbit. AB - The contribution of platelets to arachidonic acid transcellular metabolism may represent an important pathway of leukotriene (LT) production. The aim of this study was to investigate the role of platelets on LT production in an acute inflammatory model in the rabbit. Preliminary experiments showed that rabbit whole blood (5 ml) stimulated in vitro with the calcium ionophore A23187 produced LTB4 (52.7+/-13.9 ng) and the mixed 5,12-DiHETE (7.25+/-0.75 ng). In A23187 stimulated thrombocytopenic blood, LTB4 was significantly reduced to 19.5+/-8.6 ng and 5,12-DiHETE was undetectable. Peptido-LTs were undetectable in both conditions. In experiments using washed cells, addition of thrombin-activated platelets to fMLP-activated PMN resulted in the appearance of 5,12-DiHETE and in more than twofold increase of LTB4 synthesis. When 3H-arachidonic acid-labelled platelets were mixed with unlabelled PMN and challenged with fMLP and thrombin, radioactive LTB4 and 5,12-DiHETE were produced, indicating that platelet-derived arachidonic acid was utilized by PMN 5-lipoxygenase. Intravenous infusion of fMLP (2.5 nmol/kg/min) in the rabbit induced marked granulocytopenia, thrombocytopenia and increased TxB2 plasma concentrations within 3 min. Electron microscopy of lungs showed morphologically activated and aggregated platelets occluding the capillary lumen. Activation and recruitment of circulating cells was accompanied by the production of LTB4 (peak levels at 1 min: 30.0+/-9.5 ng/ml) and LTE4 (peak levels at 10 minutes: 77.8+/-11.6 ng/ml). The areas under the blood concentration time curve (AUC, ng min/ml) corresponded to 812+/-182 and 3692+/-658 for LTB4 and LTE4, respectively. In immunologically thrombocytopenic rabbits, the AUC for LTB4 (86.0+/-23.0) and LTE4 (1165+/-542) were both significantly different from controls while in rabbits treated with an anti-leukocyte antiserum, both LTB4 and LTE4 were similar to controls. This experimental model provides in vivo evidence that platelets, involved in an acute inflammatory event contribute to the transcellular production of LTs. PMID- 10102476 TI - Induction of hypercoagulability condition by chronic localized cold stress in rabbits. AB - To evaluate the effect of cold-induced stress on renal and hepatic blood flow and coagulation parameters, rabbits' soles were exposed to ice pad (0 degrees C). Renal and hepatic blood flow was measured after 1 h and 15 days of cold stress. Coagulation parameters (0, 8th and 15th days of stress) and histological studies were performed. Renal and hepatic blood flow was significantly reduced after cold stress. Decreased platelet count, antithrombin III (AT III) activity, increased fibrinogen (Fbg) level, shortened activated partial thromboplastin time (aPTT) and prothrombin time (PT) was found after 8 and 15 days of cold-stress. Histology showed enlarged glomeruli with fibrin deposition in kidney, ischemic changes and fibrin deposition in liver and hemorrhagic necrosis in adrenal cortex. We conclude that undesirable localized cold induced sympathetic stimulation in daily life may be a predisposing factor for coagulopathy. PMID- 10102477 TI - Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/Perinatal Subcommittee. International Society on Thrombosis and Haemostasis. AB - TERMINOLOGY: Replace the term "Hemorrhagic Disease of the Newborn" (HDN) by "Vitamin K Deficiency Bleeding" (VKDB), as neonatal bleeding is often not due to VK-deficiency and VKDB may occur after the 4-week neonatal period. DEFINITION: VKDB is bleeding due to inadequate activity of VK-dependent coagulation factors (II, VII, IX, X), correctable by VK replacement. DIAGNOSIS: In a bleeding infant a prolonged PT together with a normal fibrinogen level and platelet count is almost diagnostic of VKDB; rapid correction of the PT and/or cessation of bleeding after VK administration are confirmative. WARNING SIGNS: The incidence of intracranial VKDB can be reduced by early recognition of the signs of predisposing conditions (prolonged jaundice, failure to thrive) and by prompt investigation of "warning bleeds". CLASSIFICATION: VKDB can be classified by age of onset into early (<24 h), classical (days 1-7) and late (>1 week <6 months), and by etiology into idiopathic and secondary. In secondary VKDB, in addition to breast feeding, other predisposing factors are apparent, such as poor intake or absorption of VK. VK-PROPHYLAXIS: BENEFITS: Oral and intramuscular VK (one dose of 1 mg) protect equally well against classical VKDB but intramuscular VK is more effective in preventing late VKDB. The efficacy of oral prophylaxis is increased with a triple rather than single dose and by using doses of 2 mg vitamin K rather than 1 mg. Protection from oral doses repeated daily or weekly may be as high as from i.m. VK. VK-PROPHYLAXIS: RISKS: VK is involved in carboxylation of both the coagulation proteins and a variety of other proteins. Because of potential risks associated with extremely high levels of VK and the possibility of injection injury, intramuscular VK has been questioned as the routine prophylaxis of choice. Protection against bleeding should be achievable with lower peak VK levels by using repeated (daily or weekly) small oral doses rather than by using one i.m. dose. BREAST FEEDING MOTHERS TAKING COUMARINS: Breast feeding should not be denied. Supervision by pediatrician is prudent. Weekly oral supplement of 1 mg VK to the infant and occasional monitoring of PT are advisable. CONCLUSION: VKDB as defined is a rare but serious bleeding disorder (high incidence of intracranial bleeding) which can be prevented by either one i.m. or multiple oral VK doses. PMID- 10102478 TI - Utilization of previously treated patients (PTPs), noninfected patients (NIPs), and previously untreated patients (PUPs) in the evaluation of new factor VIII and factor IX concentrates. Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. PMID- 10102479 TI - Rapid detection of factor XIII Val34Leu by allele specific PCR. PMID- 10102480 TI - A whole blood, multiplex PCR detection method for factor V Leiden and the prothrombin G20210A variant. PMID- 10102481 TI - Activated protein C (APC) resistance in young stroke patients. PMID- 10102482 TI - Prevalence of protein C deficiency in patients with cardiovascular problems in Japan. PMID- 10102483 TI - The elevated risk for venous thrombosis in persons with hyperhomocysteinemia is not reflected by the endogenous thrombin potential. PMID- 10102484 TI - Thrombomodulin in patients with Takayasu's arteritis. PMID- 10102485 TI - A monoclonal antibody against prothrombin fragment 1 behaves like a lupus anticoagulant. PMID- 10102486 TI - Interference with oral anticoagulant treatment by oestrogen--influence of oestrogen administration route. PMID- 10102487 TI - Is soluble P-selectin determination a more reliable marker of in vivo platelet activation than CD62P flow cytometric analysis? PMID- 10102488 TI - Soluble P-selectin in diabetes. PMID- 10102489 TI - Prevalence of factor VIII inhibitors in patients with hemophilia A in Brazil. PMID- 10102490 TI - Parvovirus B19 DNA contamination in coagulation factor VIII products. PMID- 10102491 TI - Snakebite? PMID- 10102492 TI - Antithrombin: facts and new hypotheses. AB - Antithrombin (AT) is an important inhibitor of the coagulation system, acting at many different levels of the coagulation cascade. This inhibitory action is enhanced several-fold by the glycosaminoglycan heparin. AT deficiency can be encountered in hereditary disorders, which are rare, or in acquired conditions, in which there is an excessive consumption of AT. Acquired AT deficiency is a common condition in sepsis, after major trauma or surgery, with or without associated disseminated intravascular coagulation (DIC). In these conditions, low levels of AT have been correlated with a poor outcome due to the development of multiple organ failure. Although supplementation with AT has been shown to attenuate the extent of organ failure in critically ill patients, it has not been possible to significantly improve the survival of these patients by administration of AT. An interesting new approach to AT treatment is based on the hypothesis that AT has specific effects that are independent of the coagulation cascade. Data from cell culture and animal experiments have demonstrated that AT can promote the endothelial production of prostacyclin and may therefore have anti-inflammatory actions. This effect is based on the interaction of AT with glycosaminoglycans in the cell membrane, and is independent of heparin. The role of AT in vessel wall antithrombogenicity is being increasingly appreciated. The concept of neointimal hyperplasia following vascular injury involves thrombin as an important mediator and thus, in addition to the anti-inflammatory effects of AT, new horizons in which AT may have an important role in the prevention of post traumatic hyperplastic response are also evolving. PMID- 10102493 TI - The mechanisms of action of alpha- and beta-isoforms of antithrombin. AB - Antithrombin (AT) is the most important physiological inhibitor of thrombin. This effect can be increased more than a 1000-fold by heparin and heparin-like glycosaminoglycans, which induce a conformational change in the molecule. Two isoforms of AT exist in plasma: alpha and beta. The beta-isoform lacks one of four carbohydrate side-chains that are present on the alpha-isoform. The beta isoform, which constitutes approximately 10% of plasma AT, has a higher affinity for heparin and heparin-like glycosaminoglycans than the alpha-isoform. In contrast to their distribution in plasma, the two isoforms of AT appear to be present in the same proportions in the vessel wall. After balloon injury of rabbit aorta, thrombin can be detected in the vessel wall, an effect that is inhibited by treatment with AT. The inhibitory effect of AT on thrombin coagulant activity in the injured vessel wall is attributable to the beta-isoform. The appearance of thrombin in the injured vessel wall can also be inhibited by heparin treatment, but this requires heparin to be circulating in plasma at the time of excision of the injured vessel wall. Thrombin has been suggested as a mitogen for smooth muscle cells. This effect of thrombin can be inhibited by AT, an inhibition that is increased by heparin in a concentration-dependent manner. The alpha-isoform of AT has a lower inhibitory capacity for the thrombin-induced proliferation of smooth muscle cells in the absence of heparin, compared with the beta-isoform, which is an effective inhibitor alone. This indicates that the beta isoform of AT may use glycosaminoglycans produced by smooth muscle cells as a cofactor. In conclusion, the beta-isoform of AT appears to be an effective inhibitor of the thrombin coagulant activity induced by vessel wall injury. It is also a more effective inhibitor of the thrombin-induced proliferation of smooth muscle cells than the alpha-isoform. PMID- 10102494 TI - The effect of antithrombin on the systemic inflammatory response in disseminated intravascular coagulation. AB - Sepsis and major trauma are the two most common causes of disseminated intravascular coagulation (DIC) and are characterized by a sudden increase in inflammatory mediators. In general, the outcome of the patient is determined by the degree of the inflammatory response. In severe cases of sepsis and trauma, cascade systems, such as the coagulation, fibrinolytic and complement systems, are activated beyond the capacity of the autoregulatory mechanisms. During DIC, plasma levels of antithrombin (AT)--a serine protease inhibitor that acts mainly on the serine proteases of the coagulation system--decrease due to the formation and subsequent elimination of complexes between AT and activated coagulation factors. The consumption of AT may start a vicious circle by facilitating further intravascular fibrin formation, followed by ischaemic tissue injury and accelerated activation of blood coagulation. Infusion of AT has an anti inflammatory effect through its ability to counteract microvascular thrombosis. Furthermore, AT induces the release of prostacyclin from the vessel wall by binding to glycosaminoglycans on the surface of endothelial cells. Prostacyclin has a marked anti-inflammatory effect as a result of its inhibitory effect on neutrophils, monocytes and platelets. PMID- 10102495 TI - Antithrombin substitution therapy. AB - Antithrombin (AT) is the most important inhibitor of the coagulation system. Due to the high cost of AT treatment, there must be rational arguments to justify its use. Established indications for AT substitution include hereditary homozygous AT deficiency in newborn babies and hereditary AT deficiency before or during certain situations, for example, surgery and pregnancy. AT substitution therapy can also be justified in the treatment of complex coagulation disorders, sepsis with disseminated intravascular coagulation and acute thromboembolic events with reduced AT activity. Administration of AT concentrates to patients with nephrotic syndrome or stable hepatopathy is not justified. To achieve an anti-inflammatory effect in patients with sepsis, it is thought that above-normal levels of AT activity (> 140% of the normal level) are probably needed. Although currently available data on the effect of AT in the treatment of sepsis are insufficient, results from controlled studies will soon become available and will show whether sepsis is an indication for AT substitution. PMID- 10102496 TI - Antithrombin: mechanism of action and clinical usage. Conclusion. PMID- 10102497 TI - Age-related synaptic changes in the central nucleus of the inferior colliculus of Fischer-344 rats. AB - The central nucleus of the inferior colliculus (ICc) is a major processing center for the ascending auditory pathways. Gamma-aminobutyric acid (GABA) and excitant amino acids (EAAs) are essential for coding many auditory tasks in the IC. Recently, a number of neurochemical and immunocytochemical studies have suggested an age-related decline in GABAergic inhibition in the ICc, and possibly excitant amino-acid-mediated excitation as well. The objective of this study was to compare quantitatively changes in the synaptic organization of the ICc among three age groups (3, 19, and 28 months) of Fischer-344 rats. Immunogold electron microscopic methods were used to determine if there were age-related changes in the density, distribution, or morphology of GABA-immunoreactive (+) and GABA immunonegative (-) synapses in the ICc. The data suggest similar losses of excitatory and inhibitory synapses in the ICc. There were significant reductions in the densities of GABA+ and GABA- synaptic terminals (approximately 30% and approximately 24%, respectively) and synapses (approximately 33% and approximately 26%, respectively) in the ICc of 28-month-old rats relative to 3 month-olds. The numeric values, which were adjusted to consider changes in volume of the IC with age, depict similar effects, although the effect magnitude for the adjusted values was reduced by approximately 9%. For both types of synapses, the decreases did not differ significantly from each other. The reductions in synaptic numbers appeared, to be related to a similar numeric decline in dendrites, in particular those with calibers of between 0.5 and 1.5 microm. The number and distribution of synaptic terminals on the remaining dendrites of GABA- neurons appeared not to undergo major age-related changes. GABA+ neurons, on the other hand, may have evolved patterns of synaptic and dendritic change during aging in which the distribution of synaptic terminals shifts to dendrites of larger caliber. In the 19-month group, the synaptic areas were elevated in terminals apposed to dendrites with calibers of 1.5 microm or less. However, this increase in synaptic size did not persist in the aged animals. No neuronal losses were detectable among the three age groups. Thus, the decrease in GABA and EAAs identified in the IC by previous studies may be attributable to synaptic and dendritic declines, rather than cell loss. PMID- 10102498 TI - Perirhinal cortex projections to the amygdaloid complex and hippocampal formation in the rat. AB - The differential efferent projections of the perirhinal cortex were traced by using anterograde and retrograde tracing techniques. The dorsal bank cortex (area 36) projected lightly to the lateral entorhinal cortex and more strongly to the lateral, posterolateral cortical, and posterior basomedial amygdaloid nuclei and amygdalostriatal transition zone. The ventral bank (dorsolateral entorhinal cortex) projected to the lateral entorhinal cortex, dorsal subiculum, and subfield CA1 and mainly targeted the basolateral amygdaloid nucleus. Corticocortical projections from the dorsal and ventral banks targeted different cortical areas. The fundus of the rhinal sulcus (area 35) projected to both lateral and medial entorhinal cortices, ventral subiculum, lateral and basolateral nuclei, and amygdalostriatal transition zone. Corticocortical projections targeted areas projected to by both dorsal and ventral banks and also by second somatosensory area, first temporal cortical area, and striate cortex. Neurons projecting to the lateral nucleus were distributed in all layers of the dorsal bank, wheras those projecting to CA1 and subiculum were found in superfical layers (mostly layer III) of the ventral bank. Projections to the basolateral nucleus arose from superfical layers (mostly layer II) of the fundus and deep layers of the ventral bank. Furthermore, projections to the amygdala mostly arose from rostral levels, whereas hippocampal projections primarily originated caudally. The rat perirhinal cortex is heterogeneous in its efferent connectivity, and distinct projections arise from the dorsal and ventral banks and fundus of the rhinal sulcus. The widespread cortical connectivity of the fundus suggests that only this part of the perirhinal cortex is similar to area 35 of the primate brain. PMID- 10102499 TI - Efferent projections of the ectostriatum in the pigeon (Columba livia). AB - The ectostriatum is a major visual component of the avian telencephalon. The core region of the ectostriatum (Ec) receives visual input from the optic tectum through thalamic nuclei. In the present study, the efferent projections of the ectostriatum were investigated by using the anterograde tracers Phaseolus vulgaris leucoagglutinin and biotinylated dextran amine. Projection patterns resulting from these tracers were confirmed by the retrograde tracer cholera toxin subunit B. When anterograde tracers were injected in Ec, primary projections were seen traveling dorsolaterally to the belt region of the ectostriatum (Ep) and the neostriatal area immediately surrounding Ep (Ep2). Neurons in Ep sent projections primarily to the overlying Ep2. The efferents of Ep2 traveled dorsolaterally to terminate in three telencephalic regions, from anterior to posterior: (1) neostriatum frontale, pars lateralis (NFL), (2) area temporo-parieto-occipitalis (TPO), and (3) neostriatum intermedium, pars lateralis (NIL). A part of the archistriatum intermedium and the lateral part of the neostriatum caudale also received somewhat minor projections. In addition, some neurons in Ec were also the source of direct, but minor, projections to the NFL, TPO, NIL, and archistriatum intermedium. The topographical relationship among the primary (Ec), secondary (Ep and Ep2), and tertiary (NFL, TPO, NIL) areas indicate that the neural populations for visual processing are organized along the rostral-caudal axis. Thus, the anterior Ec sent efferents to the anterior Ep, which in turn sent projections to anterior Ep2. Neurons in the anterior Ep2 sent projections to NFL and the anterior TPO. Similarly, the intermediate and posterior Ec sent projections to corresponding parts of Ep, whose efferents projected to intermediate and posterior Ep2, respectively. The intermediate Ep2 gave rise to major projections to TPO, whereas posterior Ep2 neurons sent efferents primarily to NIL. The organization of this neural circuit is compared with those of other sensory circuits in the avian telencephalon, as well as the laminar arrangement of the mammalian isocortex. PMID- 10102500 TI - Differential subcellular localization of forward and feedback interareal inputs to parvalbumin expressing GABAergic neurons in rat visual cortex. AB - In rat visual cortex, forward and feedback interareal pathways innervate both pyramidal and gamma-aminobutyric acid (GABA)ergic (Johnson and Burkhalter [1996] J. Comp. Neurol. 368:383-398). GABAergic neurons consist of different cell types of which the largest group expresses parvalbumin (PV; Gonchar and Burkhalter [1997] Cereb. Cortex 4:347-358). Here, we report that PV neurons in layers 2/3 are synaptic targets of forward and feedback projections between area 17 and the lateromedial area (LM) of rat visual cortex. In both forward and feedback pathways, approximately 90% of axon terminals in layer 2/3 labeled by tracing with biotinylated dextran amine formed synapses with PV-negative profiles. In both pathways, most of these profiles resembled dendritic spines. Although there were no differences in the innervation of PV-negative targets, the two pathways differed in the innervation of PV-positive neurons. In each pathway, approximately 10% of terminals formed synapses with PV-positive profiles. However, in the forward pathway, the size of the contacted PV-positive profiles was larger than in the feedback pathway. Moreover, in the forward pathway, axon terminals on PV-positive profiles were larger, contained more mitochondria and docked synaptic vesicles than feedback synapses on PV neurons. Our results show that PV neurons provide a major target for area 17 <-> LM forward and feedback pathways terminating in upper layers. In each pathway, the proportion of axons contacting PV neurons is similar. However, both pathways differ in the subcellular localization and morphology of synapses on PV neurons. These asymmetries may contribute to the inequality in the strength of disynaptic inhibition evoked by forward and feedback inputs (Shao and Burkhalter [1996] J. Neurosci. 16:7353-7365). PMID- 10102502 TI - Changes in the numbers of neurons and astrocytes during the postnatal development of the rat inferior olive. AB - In the developing nervous system, cell death is an important component of refining axonal projections. In the developing rat inferior olive, previous studies have demonstrated cell death as temporally incongruent with both initial axon-target interactions and subsequent axon collateral regression. Furthermore, these studies identified a late rise in neuron numbers that is concurrent with climbing fibre regression. As axonal regression has not previously been associated with increasing neuron numbers, and since immature neurons and glia have similar morphological characteristics, it was decided to reassess the timing of cell death within the inferior olive in animals in which neurons and glia had been differentially stained. Glia were identified by the presence of glial cytoskeletal proteins, S100, or glial fibrillary acidic protein, and stereological counts were made of both neurons and glia in the inferior olive from rats of ages 0, 5, 10, 15, and 30 days. The number of inferior olivary neurons was approximately 22,000 between birth and day 10, which decreased to about 17,500 by day 30 (P<0.05). In contrast, the number of glia rose from about 5,000 at birth to approximately 15,000 by day 10 (P<0.001), after which there was no further increase. The changes in neurons and glia caused the neuron-to-glia ratio to fall to approximately 1.5 by the time of functional maturation within the olive. These results confirm that there is neuronal death in the inferior olive but that it is temporally correlated with both climbing fibre regression and functional maturation of the olivocerebellar projection. PMID- 10102501 TI - Tenascin-C in the cochlea of the developing mouse. AB - Tenascin-C is a glycoprotein of the extracellular matrix that acts in vitro as both a permissive and a nonpermissive substrate for neurite growth. We analyzed, by immunocytochemistry, the distribution of tenascin-C along neural growth pathways in the developing mouse cochlea. In the spiral lamina, tenascin-C coexists in a region where nerve bundles arborize. In the organ of Corti, tenascin-C lines the neural pathways along pillar and Deiters' cells before and during the time of nerve fiber ingrowth. By embryonic day 16, tenascin-C is abundant on the pillar side of the inner hair cell but does not accumulate on the modiolar side until about birth, a time after the arrival of afferent fibers. The synaptic zones beneath outer hair cells are strongly labeled during the time when early events in afferent synaptogenesis are progressing but not during the time of efferent synaptogenesis. At the age when most neural growth ceases, tenascin-C immunoreactivity disappears. Faint tenascin-C immunolabeling of normal hair cells, strong tenascin immunolabeling in pathological hair cells of Bronx waltzer (bv/bv) mice, and staining for beta-galactosidase, whose gene replaces tenascin in a "knockout" mouse, indicate that hair cells supply at least part of the tenascin-C. The changing composition of the extracellular matrix in the synaptic region during afferent and efferent synaptogenesis is consistent with a role for tenascin in synaptogenesis. The presence of tenascin-C along the growth routes of nerve fibers, particularly toward the outer hair cells, raises the possibility that growth cone interactions with tenascin-C helps to guide nerve fibers in the cochlea. PMID- 10102503 TI - Ultrastructural anatomy of physiologically identified jaw-muscle spindle afferent terminations onto retrogradely labeled jaw-elevator motoneurons in the rat. AB - Neuronal microcircuits involving jaw-muscle spindle afferents and jaw-elevator motoneurons were studied via retrograde and intracellular labeling in rats. Initially, trigeminal motoneurons were retrogradely labeled from horseradish peroxidase (HRP) injections into the temporalis and masseter muscles. The intracellular response of jaw-muscle spindle afferent neurons was then characterized during palpation, ramp and hold, and sinusoidal stretching of the jaw-closing muscles. Biotinamide was injected into these neurons, and the tissue was processed for the visualization of HRP and biotinamide. The ultrastructure of 243 intracellularly stained jaw-muscle spindle afferent boutons located within the trigeminal motor nucleus (Vmo) was examined. Eighty-five of these boutons synapsed with motoneurons retrogradely labeled with HRP, and 158 boutons synapsed with unlabeled structures within the Vmo. All spindle afferent boutons contained clear, spherical synaptic vesicles. Although the majority of boutons were S type, a few labeled jaw-muscle spindle afferent boutons possessed a long, narrow cleft, with a subsynaptic cistern comparable to previous descriptions of C-type boutons. Sixty-eight percent of spindle afferent boutons synapsed with large or medium sized, retrogradely labeled motoneuron dendrites, and 32% synapsed with retrogradely labeled somata. In numerous instances, spindle afferent boutons synapsed with trigeminal motoneuron dendritic or somatic spines. Most of the synapses between spindle afferent boutons and trigeminal motoneuron dendrites were asymmetric, and the greatest percentage of axosomatic synapses between spindle afferents and trigeminal motoneurons were symmetric. Approximately 24% of spindle afferent boutons constituted the intermediate element of a axoaxodendritic or axoaxosomatic assemblage, implying that some jaw-muscle spindle afferent synapses with trigeminal motoneurons are presynaptically modulated. PMID- 10102504 TI - Autoradiographic study of alpha1- and alpha2-noradrenergic and serotonin1A receptors in the spinal cord of normal and chronically transected cats. AB - Serotoninergic and noradrenergic drugs have been shown to initiate and/or modulate locomotion in cats after spinal cord transection and in patients suffering from spinal cord injuries. To establish a firmer basis for locomotor pharmacotherapy, the distribution of alpha1- and alpha2-noradrenergic and serotonin1A (5-HT1A) receptors was examined in the spinal cord of control cats and of from animals with spinal cord transection at T13 some weeks or months previously. In control cats, the highest levels of alpha1-noradrenergic receptors, labeled with [3H]prazosin, were found in laminae II, IX, and X. The alpha2-noradrenergic receptors, labeled with [3H]idazoxan, were found mainly in laminae II, III, and X, with moderate densities in lamina IX. After spinal transection, both receptors did not change in segments above the lesion. At 15 and 30 days after spinal transection, binding significantly increased in laminae II, III, IV, and X for alpha2 and in laminae I, II, III, and IX for alpha1 receptors in lumbar segments. For longer survival times, binding densities returned to near control values. The 5-HT1A receptors, labeled with [3H] 8 hydroxy-dipropylaminotetralin, were found mainly in laminae I-IV and X. After spinal transection, binding significantly increased only in laminae II, III, and X of lumbar segments at 15 and 30 days. Thereafter, binding returned to control values. The pronounced upregulation of different monoaminergic receptors observed in the lumbar region in the first month after spinal transection suggests that these receptors may be important during the period when cats normally recover functions such as locomotion of the hindlimbs. PMID- 10102505 TI - Secondary motoneuron axons localize DM-GRASP on their fasciculated segments. AB - Cell surface adhesion molecules are thought to play a necessary role in axon guidance and fasciculation in the developing nervous system. We have studied a potential adhesion molecule using the zn-5 monoclonal antibody, which recognizes the surfaces of zebrafish spinal motoneurons. We show that zn-5 recognizes zebrafish DM-GRASP. DM-GRASP is a cell adhesion molecule of the immunoglobulin superfamily that mediates homophilic adhesion and neurite outgrowth in vitro. It is necessary for correct axon routing and fasciculation in the Drosophila visual system. In zebrafish, primary motoneurons pioneer the peripheral motor nerve pathways, and the axons of secondary motoneurons follow the routes established by the primary motoneuron axons. We show that, of the two classes of zebrafish spinal motoneurons, only the later growing secondary motoneurons express DM GRASP. The secondary motoneurons restrict DM-GRASP protein to their cell bodies and fasciculated segments of their axons. Expression of DM-GRASP is transient: The protein is present during the period of axonal growth and disappears after axons have reached their muscle targets. Thus, homophilic adhesion mediated by DM GRASP may play a role in fasciculation of secondary motoneuron axons but not in pathfinding by the pioneer axons of the primary motoneurons or in guidance of secondary motoneuron axons to their targets. PMID- 10102506 TI - Evidence-based practice: research and critical thinking. PMID- 10102507 TI - Critical thinking and clinical competence: a study of their relationship in BSN seniors. AB - National nursing organizations and nurses in the workplace identify critical thinking skills as essential to competent nursing practice. This study sets out to test the relationship between critical thinking skills and clinical competence because it seems that competent practice depends on critical thinking abilities. This study focuses on one school of nursing's response to the challenge of defining and measuring critical thinking and clinical competence and examining their relationship. An exploratory nonexperimental design was used with a heterogeneous sample consisting of two graduating nursing classes (N = 143). While the group of participants was able to think critically and practice competently according to set standards, there were no statistically significant correlations between critical thinking and clinical competence total scores. One conclusion for these findings is that critical thinking may not emerge as an associated factor with clinical competence until some time after nursing students become practicing nurses. PMID- 10102508 TI - Nursing education for critical thinking: an integrative review. AB - This integrative review summarizes 20 research studies reported from 1977 to 1995 that review change in the critical thinking abilities of professional nursing students. The Watson-Glaser Critical Thinking Analysis was used in 18 of 20 studies. The primary assumption was that critical thinking skills would increase during nursing education. However, the results of this review are mixed and contradictory. Possible reasons for these results are discussed. PMID- 10102509 TI - A triad of research roles: experiential learning in an undergraduate research course. AB - This article describes an innovative approach to teaching undergraduate research content directly involving students in a faculty research study, and a student research project undertaken in a nursing research course. Junior-level students participated as research subjects in a faculty study focusing on the health perceptions of baccalaureate nursing students, became data collectors in a related student project on the health perceptions of lay people, and became consumers of the research by analyzing the findings and clinical relevance of these studies. This strategy for teaching research assisted students to master undergraduate research content by participatory involvement in several distinct phases of the research process. The project generated considerable interest and served to foster positive attitudes toward nursing research while concurrently increasing students' comfort level with the total process. PMID- 10102510 TI - A survey of the ways master's level nursing students learn the research process. AB - Because of the need for advanced practice nurses to perform more outcome measurement, a survey was conducted in the fall of 1997 to determine how master's level students learned the research process. Three hundred four surveys were mailed to schools with master's programs, and 222 were returned for a return rate of 73%. Sixty-six percent of the programs surveyed required a thesis and/or a research project. However, there was great variation in the research projects. A comprehensive examination was used to measure research ability by 36 programs (16%), either in conjunction with a thesis or research project or alone. One hundred forty-six programs (66%) offered only one option, be it a thesis, research project, comprehensive examination, or the many other alternative activities described by respondents. Seventy-six programs (34%) offered a variety of options from which students could select. The major differences between the thesis and the research project were related to three issues: a) the nature of the supervision; b) whether the activity was an individual or group project; and c) the amount of participation of the students. Because of the variability of expectations and the ways students are taught research, it was recommended nurse educators determine whether master's level nurse graduates were prepared to conduct outcome measurement and whether the means used to teach the research process were effective considering that endeavor. PMID- 10102511 TI - Content validity exercises for nursing students. AB - In instrument development, the assessment of content validity is a critical step. However, content validation often is given superficial and cursory attention. Because the procedure involved in assessing content validity is not addressed in depth in research textbooks, nursing students may not fully understand or appreciate the intricacies required in this crucial process. The purpose of this article is to share some content validity exercises the author has developed for use with both undergraduate and graduate nursing students. These exercises involve an instrument, entitled the Postpartum Depression Screening Scale, which the author is currently developing. PMID- 10102512 TI - Teaching quantitative and qualitative analysis to undergraduate students. AB - Data analysis preparation for undergraduate nursing students conventionally has consisted of a required statistics course and a brief discussion of analysis strategies within an introductory research course. For students to view inquiry as integral to their practice, it is imperative that data analysis be taught in a manner whereby it may be incorporated into their repertoire of skills for nursing inquiry. This article describes an interdisciplinary, introductory course in quantitative and qualitative analysis taught in the context of three requisite inquiry courses: knowledge development, nursing inquiry, and nursing research. PMID- 10102513 TI - A longitudinal evaluation of baccalaureate nursing students' critical thinking abilities. PMID- 10102514 TI - Evaluation of critical thinking in a baccalaureate nursing program. AB - The assessment of critical thinking traditionally has been accomplished through observation of students by faculty in clinical settings and evaluation of written patient assessments and care plans. Quantitative measurement has become a current focus of nurse educators. The purpose of this cross-sectional study was to compare and contrast critical thinking abilities in beginning and graduating nursing students using the California Critical Thinking Skills Test (CCTST) and the California Critical Thinking Disposition Inventory (CCTDI). The CCTST revealed a significant difference in critical thinking from the sophomore year to the senior year. There also were significant differences between sophomores and seniors on the overall score for the CCTDI, with subtest differences in truth seeking, analyticity, self-confidence, and inquisitiveness. PMID- 10102515 TI - Incident of "human cloning" from Kyunghee University Medical Center. The Korean Academy of Medical Sciences. PMID- 10102516 TI - Peutz-Jeghers syndrome: a new understanding. AB - Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized by hamartomatous polyps in the small bowel and mucocutaneous pigmentation. Patients with Peutz-Jeghers syndrome often present as surgical emergencies with complications of the polyps, such as intussusception, bowel obstruction and bleeding. Furthermore, repeated operations may be needed in some patients, which may result in short bowel syndrome. Although early reports did not demonstrate a predisposition to cancer in patients with this syndrome, more recent studies have described an increased risk for both gastrointestinal and extra-gastrointestinal cancers. Women with the Peutz-Jeghers syndrome have the extremely high risk for breast and gynecologic cancer. Recently, Peutz-Jeghers syndrome susceptibility gene, encoding the serine threonine kinase STK11 (also called LKB1), was identified in families with Peutz-Jeghers syndrome. The identifications of germline mutations in families with Peutz-Jeghers syndrome could be a turning point in the management of Peutz-Jeghers syndrome. PMID- 10102517 TI - Inhibition of expression of P-selectin by antioxidant in cholesterol-fed rats. AB - Butylated hydroxytoluene (BHT) can inhibit experimental atherosclerosis in animals. Although the agent is an antioxidant, the exact mechanism of the reaction in atherosclerosis is still unknown. To investigate the effects of BHT on expression of P-selectin (PADGEM, GMP-140), intercellular adhesion molecule-1 (ICAM-1) and class II MHC (Ia) antigen, we proposed an experiment on rats. Male rats (n=18 per group) were fed either a normal cholesterol control diet, a normal cholesterol diet containing 0.5% BHT (BD), a high cholesterol diet containing 1.5% cholesterol and 0.1% sodium cholate (CD), or the CD diet containing 0.5% BHT (BCD). Rats were sacrificed after 3 days, and after 1, 2, 4, 10, and 17 weeks of dietary treatment. Although there was no gross or light microscopic atherosclerotic lesions, scanning electron microscopy revealed monocytic adhesion to aortic endothelium and mild endothelial injuries in CD and BCD groups. Immunohistochemically, the addition of BHT to a high cholesterol diet inhibited P selectin expression but not in ICAM-1 and Ia antigen. These findings suggest that in rats, high cholesterol diets induce expression of ICAM-1, P-selectin and Ia antigen. In addition, the antiatherogenic effect of BHT may play a role in the inhibition of P-selectin. PMID- 10102518 TI - Rapid and easy detection of Helicobacter pylori by in situ hybridization. AB - Various in situ hybridization (ISH) methods have been used to identify Helicobacter pylori, a causative organism responsible for chronic gastritis and peptic ulcer disease, but they were hard to perform and time consuming. To detect H. pylori in a rapid and easily reproducible way, we developed synthetic biotinylated oligonucleotide probes which complement rRNA of H. pylori. Formalin fixed and paraffin-embedded tissues from 50 gastric biopsy specimens were examined. Using a serologic test and histochemical stain (Warthin-Starry silver stain and/or Giemsa stain) as a standard, 40 of them were confirmed to be H. pylori-positive. Our ISH was quickly carried out within one hr and results were compared with those obtained from immunohistochemical stain. The ISH produced a positive reaction in 38 of 40 cases (95%). All H. pylori-negative cases failed to demonstrate a positive signal. The ISH has a sensitivity comparable to those of conventional histochemical and immunohistochemical stain, and has high specificity. In conclusion, ISH with a biotinylated oligonucleotide probe provides a useful diagnostic method for detecting H. pylori effectively in routinely processed tissue sections. PMID- 10102519 TI - Antifungal susceptibility testing of Candida species by flow cytometry. AB - The feasibility of flow cytometric antifungal susceptibility testing has been studied using the fluorescent anionic membrane potential probe, bis-(1,3 dibutylbarbituric acid) trimethine oxonol [DiBAC4(3)]. The in vitro antifungal susceptibility testing of amphotericin B was performed on 8 Candida isolates from clinical specimens and 2 ATCC strains by flow cytometry with the results compared to those of the National Committee of Clinical Laboratory Standards (NCCLS) M27 T, broth macrodilution method. The flow cytometric method is based on an increase of fluorescence given out by DiBAC4(3) in fungi when they are killed by antifungal agents. Minimum inhibitory concentration (MIC) of amphotericin B ranged from 0.25 to 1 microg/mL. All results agreed within +/-2 dilution between the flow cytometric method and the M27-T method. MIC with ATCC strains were within recommended ranges of M27-T. The new flow cytometric method revealed a clear and distinct reproducible test end point. A four hr of incubation was sufficient for the test. In conclusion, flow cytometry using DiBAC4(3) is a rapid and accurate in vitro antifungal susceptibility testing method. PMID- 10102520 TI - Morphological and biochemical analysis of anti-nuclear matrix protein antibodies in human sera. AB - Autoimmune sera have been used in the diagnosis of autoimmune diseases as well as the analysis of nuclear substructures. In an attempt to study the biological characteristics of the nuclear matrix, we screened human sera using immunofluorescent staining and immunoblot. We detected antibodies against nuclear matrix (NM), a remnant nonchromatin protein compartment after the treatment of detergent, salt and nuclease, in 212 out of 284 tested sera (74.6%) by immunoblot. Peptides with molecular weights of 70 kDa, 50 kDa and 25 kDa were detected in the order of frequency. Clinical informations of 198 out of 212 cases were available and went as follows: 38 cases were autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis; 132 non-autoimmune and non neoplastic diseases; 16 neoplastic diseases and 12 cases unclassified. The immunofluorescent staining intensity by anti-nuclear matrix protein (NMP) antibodies decreased variably, but fibrillogranular, speckled and nucleolar immunolocalization patterns were retained after in situ fractionation. Ku70 and La protein were detected by anti-NMP antibodies. Immunolocalization by anti-NMP antibodies indicates that the NMPs constitute a variety of characteristic nuclear substructures and may serve as autoantigens in diverse human diseases. In addition, the presence of Ku70 and La protein as NMPs suggests that the NM can be functionally active in association with DNA or RNA. PMID- 10102521 TI - Halothane effect on formalin-induced paw edema and flinching in rat. AB - The formalin test is a model of injury-produced inflammatory pain. Anesthetics, in clinically relevant concentrations, affect neutrophils and immune suppression. This study was to determine whether halothane reliably inhibits inflammatory reaction and formalin induced pain behavior or does not. Rats were exposed to 100% oxygen (control) or halothane, respectively for 30 min and then 24 hr later five percent formalin test was assessed. The base values of the paw's diameter were obtained earlier, and then formalin induced edema was assessed by measuring diameters of the injected paws at 5 min, 1 hr, 4 hr and 24 hr after the injection. Nociceptive behavior was quantified by counting the number of times with the paw flinched at 5 min intervals for 60 min. The diameters of edema in the halothane group lessened more than those in the oxygen group at 1 and 24 hr in each following of the injection (p<0.05). The rats pre-administered with oxygen or halothane were similar appearances in nociceptive behaviors. It suggests that halothane anesthesia might inhibit slightly the inflammatory reaction with the formalin-induced edema but might not inhibit the formalin induced pain behavior in the event of pre-administration halothane 24 hr earlier before the formalin test of rat. PMID- 10102522 TI - Presence of specific IgG antibody to grain dust does not go with respiratory symptoms. AB - A high prevalence of work-related symptoms in relation to grain dust exposure has been reported in grain dust workers, but the role of the specific IgG antibody is unknown. To study the possible role of specific IgG (sIgG) and specific IgG4 (sIgG4) in the development of work-related symptoms, sIgG and sIgG4 subclass antibodies against grain dust antigens were determined by ELISA in sera from 43 workers and 27 non-exposed controls. They were compared with results of specific IgE antibodies, exposure intensity and the presence of respiratory symptoms. SIgG and sIgG4 antibodies were detectable in almost all sera of exposed workers, and the prevalence were significantly higher than those of controls (p<0.05). Higher sIgG4 was noted in workers with specific IgE (p<0.05). The correlation between sIgG and exposure duration was significant (p<0.05). There was no association between the prevalence of sIgG and sIgG4 and the presence of respiratory symptoms, or work stations. In conclusion, these results suggest that the existence of sIgG and sIgG4 might represent a response to grain dust exposure and may unlikely play a role in the etiology of respiratory symptoms. PMID- 10102523 TI - Changes of neonatal mortality rate between 'pre' and 'post' surfactant period. AB - The objective of this study was to determine how the neonatal mortality rate has changed since surfactant (S) therapy was introduced in our Neonatal Intensive Care Unit (NICU), and to evaluate the efficacy of surfactant therapy in respiratory distress syndrome (RDS) patients. Incidences of risk babies such as outborns, prematurity, low birth weight infants and RDS, and neonatal mortality rates were compared between 'pre' (control, 1988 to 1991, n=4,861) and 'post' S period (study, 1993 to 1996, n=5,430). In RDS patients of 'post' S period, neonatal mortality rate was compared between S-treated and non-treated patients, and chest X-ray and ventilatory parameters were compared between pre- and post-72 hr of surfactant treatment. Surfactant therapy showed short term effects, judging by the decrease of early neonatal deaths and improvement of chest X-ray and ventilatory parameters in RDS patients. The overall neonatal mortality rate had a tendency to decrease in spite of increased incidences of risk babies in 'post' S period but it was less than expected. The reasons were thought to be that we had a high proportion of risk babies, and there was some bias in patient selection for surfactant therapy and its use. In conclusion, with the active prevention of risk baby delivery and appropriate use of surfactant, better results could be expected. PMID- 10102524 TI - Exogenous cysteamine increases basal pancreatic exocrine secretion in the rat. AB - To determine whether exocrine pancreatic secretion is regulated by endogenous somatostatin, somatostatin deficiency was induced by cysteamine. Rats were subcutaneously administered a single dose of cysteamine (30 mg/100 g body weight) 12 hr before experiment. Anesthetized rats were prepared with cannulation into bile duct, pancreatic duct, duodenum, and jugular vein and pancreatic juice was collected. For in vitro study, isolated pancreata of rats, pretreated with cysteamine, were perfused with an intraarterial infusion of Krebs-Henseleit solution (37 degrees C) at 1.2 mL/min, and pancreatic juice was collected in 15 min samples. In vivo experiment of the rat, the mean basal pancreatic secretions, including volume, bicarbonate, and protein output were significantly increased from 18.4+/-0.5 microL/30 min, 0.58+/-0.05 microEq/30 min, and 214.0+/-26.1 microg/30 min to 51.6+/-3.7 microL/30 min, 1.52+/-0.11 microEq/30 min, and 569.8+/-128.9 microg/30 min, respectively (p<0.05). In the isolated perfused pancreas, cysteamine also resulted in a significant increase in basal pancreatic secretion (p<0.05). Simultaneous intraarterial infusion of octreotide (10 pmol/hr) to isolated pancreata partially reversed the effect of cysteamine on basal pancreatic secretion. These findings suggest that endogenous somatostatin play an important role on the regulation of basal pancreatic exocrine secretion. PMID- 10102525 TI - Primary carcinoid tumor of the testis: immunohistochemical, ultrastructural and DNA flow cytometric study of two cases. AB - Primary testicular carcinoid tumor, occupying 0.23% of testicular neoplasm, is a rare and indolent neoplasm with the potential for distant metastasis. We present two cases of primary pure carcinoid tumor of the testis. Both patients were 36 years old. Physical examination revealed testicular mass with and without tenderness. The preoperative serum levels of beta-human chorionic gonadotropin and alpha-fetoprotein were normal and neither patient had carcinoid syndrome. The tumors measured 7.5x6x4 cm and 5.5x5x4 cm in size. Histologically, immunohistochemically and ultrastructurally, the tumors showed typical features of the carcinoid tumor. Case 1 showed extensive tumor necrosis and vascular invasion. DNA flow cytometric analysis showed aneuploidy with DNA index of 1.47 and S+G2M of 14.0% in case 1 and tetraploidy with DNA index of 1.96 and S+G2M of 22.1% in case 2. Both patients have been well without any signs of metastasis after operation for 24 months in case 1 and for 16 months in case 2. PMID- 10102526 TI - Intravenous immune globulin (i.v.IG) therapy in steroid-resistant atopic dermatitis. AB - Many trials have been done on steroid-resistant atopic dermatitis. Recently, intravenous immune globulin (i.v.IG) was reported to be effective in the treatment of steroid-dependent atopic dermatitis. The aim of this study was to clarify whether i.v.IG therapy is effective in steroid-resistant atopic dermatitis. Forty-one steroid-resistant atopic dermatitis patients were tested in this study. Patients who weighed less than 30 kg were administered 500 mg/kg of i.v.IG. Patients who weighed 30 kg or more were administered 15 g of i.v.IG. Patient evaluations and laboratory tests with peripheral bloods such as eosinophil percentages and serum IgE levels were performed at days 0, 1, 7, and 21. In the present study, patients who responded to i.v.IG therapy were classified as Group A. Twelve patients who showed transient effects with lower clinical significance were classified as Group B (29.3%). Remaining 12 patients (29.3%) in Group C showed no improvement at all. Serum IgE levels and blood eosinophil percentages were markedly decreased in Group A. I.v.IG therapy may be recommended in the treatment of atopic dermatitis with extremely high serum IgE levels. PMID- 10102527 TI - Comparison of relaxation responses of cavernous and trigonal smooth muscles from rabbits by alpha1-adrenoceptor antagonists; prazosin, terazosin, doxazosin, and tamsulosin. AB - Alpha1a-adrenergic receptor (AR) primarily mediates the contraction of the prostatic and cavernous smooth muscles. Among clinically available alpha1-AR antagonists for the medical management of benign prostatic hyperplasia (BPH), tamsulosin has a modest selectivity for alpha1A- and alpha1D- over alpha1B-ARs. To compare the effects of various alpha1-AR antagonists on relaxation responses of cavernous and trigonal smooth muscles, isometric tension studies with relatively selective (tamsulosin) and non-selective (prazosin, doxazosin, and terazosin) alpha1A-AR antagonists, were conducted in the cavernous and trigonal muscle strips of rabbits (n=10 each). Tamsulosin had the strongest inhibitory effect on contraction of trigonal smooth muscle among the various alpha1-AR antagonists, and the inhibitory activities of prazosin, doxazosin, and terazosin were not statistically different. All alpha1-AR antagonists caused concentration dependent relaxation of the cavernous muscle strips. Tamsulosin was shown to have greater potency than prazosin (more than 100-fold), doxazosin (more than 1000 fold), and terazosin (more than 1000-fold), in relaxation of cavernous smooth muscle. In conclusion, tamsulosin might be the most effective drug among the four commonly used alpha1-AR antagonists for the medical management of BPH. Tamsulosin might be a potential substitute for phentolamine in combination with vasoactive agents as an intracavernous injection therapy for patients with erectile dysfunction. PMID- 10102528 TI - Experimental autoimmune myasthenia gravis and CD5+ B-lymphocyte expression. AB - Myasthenia gravis is one of the typical organ specific autoimmune disease and the CD5+ B-lymphocytes are known to be associated with the secretion of autoimmune antibodies. The authors performed the study to establish an animal model of experimental autoimmune myasthenia gravis (EAMG) by immunizing the nicotinic acetylcholine receptor (AChR) and to understand CD5+ B-lymphocyte changes in peripheral blood of EAMGs. Lewis rats weighing 150-200 g were injected subcutaneously three times with 50 microg AChR purified from the electric organ of Torpedo marmorata and Freund's adjuvant. The EAMG induction was assessed by evaluating clinical manifestations. The CD5+ B-lymphocyte was double stained using monoclonal PE conjugated anti-CD5+ and FITC conjugated anti-rat CD45R antibodies and calculated using a fluorescence-activated cell sorter (FACS). In three out of ten Lewis rats injected with purified AChR, the EAMG models were established. The animals showed definite clinical weakness responded to neostigmine; they had difficulty in climbing the slope, or easily fell down from a vertical cage. The range of CD5+ B-lymphocytes of peripheral blood in the EAMG models was 10.2%-17.5%, which was higher than in controls. In conclusion, the EAMG models were successfully established and the CD5+ B-lymphocyte expression in peripheral blood increased in EAMGs. This provided indirect evidence of the autoimmune pathomechanism of human myasthenia gravis. PMID- 10102529 TI - Atypical pulmonary artery sling with diffuse-type pulmonary arteriovenous fistula. AB - The case of a cyanotic infant with a rare combination of atypical pulmonary artery sling, imperforate anus, absence of the left kidney, interruption of the inferior vena cava, left side hemihypertrophy and diffuse-type pulmonary arteriovenous fistula is described. The clinical features were confusing, because of compounding abnormalities involving the respiratory tract and pulmonary circulation. The diagnostic approach to the etiology of cyanosis is discussed and the embryonic origin of pulmonary artery sling is reviewed. PMID- 10102530 TI - Serologically diagnosed Lyme disease manifesting erythema migrans in Korea. AB - Lyme disease is a vector-borne infection, primarily transmitted by Ixodes ticks, and caused by Borrelia burgdorferi. It has a wide distribution in the northern hemisphere. In Korea, however, only one human case has been reported, although B. burgdorferi was isolated from the vector tick I. persulcatus in the region. A 60 year-old male and a 45-year-old female developed the clinical sign of erythema migrans. Each patients were bitten by a tick four weeks and five weeks, respectively, before entering the hospital. On serologic examination, significantly increased IgM and IgG antibody titers to B. burgdorferi were observed in consecutive tests performed at an interval of two weeks. They responded well to treatment with tetracycline. PMID- 10102531 TI - Behenoyl cytarabine-associated reversible encephalopathy in a patient with acute myelogenous leukemia. AB - We report a case of reversible encephalopathy syndrome in a 16-year-old girl with acute myelogenous leukemia (AML), who is undergoing during consolidation chemotherapy composed of BH-AC (N4-behenoyl-1-beta-D-arabinofuranosyl cytosine) and idarubicin. On the 6th day of chemotherapy, she was in a drowsy state following generalized tonic clonic seizure lasting 20 minutes. MR images revealed extensive cortical and subcortical white matter brain edema. Alertness returned over the 24 hr following by the discontinuation of BH-AC and intravenous administration of diphenylhydantoin, although she complained of intermittent headaches and visual disturbance. She gradually recovered from these symptoms during subsequent 7 days. Previously noted abnormal signal intensities have nearly disappreared on follow-up MRI obtained on the 22nd day after the first seizure. She was discharged without any neurologic sequela. This case suggests that BH-AC, a derivative of cytosine arabinoside (1-beta-D arabinofuranosylcytosine) could be a cause of reversible encephalopathy syndrome. PMID- 10102532 TI - von Willebrand disease with G4022A mutation (vWd Sungnam): a case report. AB - A 10-year-old male patient affected by type 2 von Willebrand disease (vWD) and his family members were investigated by hemostatic and molecular genetic studies. The propositus, who experienced frequent bleeding episodes, was characterized by a normal level of von Willebrand factor (vWF) antigen (54%), reduced vWF ristocetin cofactor activity (5%), decreased factor VIII clotting activity (25%) and absent high molecular weight multimers in the plasma. An exon 28 fragment coding for the A1 and A2 domains was amplified by polymerase chain reaction and sequenced. We found a heterozygous mutation (G4022A), producing an additional PstI restriction site, which resulted in the substitution of Arg578Gln. Family studies, including the parents and a brother, were negative for this mutation and vWF abnormalities were not observed. We confirmed that G to A mutation in the region of the platelet glycoprotein Ib binding domain of vWF causes the qualitative type 2 defect in von Willebrand disease. PMID- 10102533 TI - Two cases of common bile duct stone after liver transplantation. AB - Biliary complications after orthotopic liver transplants are a continuing cause of morbidity and mortality. Biliary stones and sludge are less well known complications of hepatic transplantation, although they have long been recognized. Recently we experienced two cases of biliary stones developed after liver transplantation. One 32-year-old male, who frequently admitted due to recurrent cholangitis, was treated with percutaneous transhepatic biliary drainage and choledochojejunostomy with cholecystectomy. The other 58-year-old male, who had stones in commone bile duct, was treated by endoscopic manipulation. They are in good condition without recurrent bile duct stones or its accompanying complications. Although stones and sludge are relatively infrequent after liver transplantation, surgical or interventional radiologic treatments are usually performed for treatment. PMID- 10102534 TI - Negative conversion of antimitochondrial antibody in primary biliary cirrhosis: a case of autoimmune cholangitis. AB - Autoimmune cholangitis is a clinical constellation of chronic cholestasis, histological changes of chronic nonsuppurative cholangitis and the presence of autoantibodies other than antimitochondrial antibody (AMA). It is uncertain whether this entity is definitely different from AMA positive primary biliary cirrhosis (PBC), though it shows some differences. We report a case of autoimmune cholangitis in a 59-year-old woman, who had been previously diagnosed as AMA positive PBC associated with rheumatoid arthritis, has been converted to an AMA negative and anticentromere antibody-positive PBC during follow-up. The response to ursodeoxycholic acid treatment is poor except within the first few months, but prednisolone was dropping the biochemical laboratory data. PMID- 10102536 TI - Flank ulcer in a patient with primary antiphospholipid syndrome. AB - A 32-year-old woman had a recurrent shallow ulcer on the flank. A biopsy specimen showed thromboses in the dermal vessels and she was found to have circulating antiphospholipid antibody with no associated systemic disease. A clean ulcer developed on the flank of a patient with primary antiphospholipid syndrome is considered to be a rarely encountered/unusual presentation of this syndrome. PMID- 10102535 TI - Metastasis-induced acute pancreatitis in a patient with small cell carcinoma of the lung. AB - Acute pancreatitis in cancer patients can be secondary to the malignant process itself or a complication of antineoplastic agent administration. However, acute pancreatitis caused by metastatic carcinoma of the pancreas is an uncommon condition with a poor prognosis. We report a case of a 63-year-old man with small cell carcinoma of the lung, who developed acute pancreatitis lately. Thirteen months earlier, he developed small cell carcinoma of the lung and received 6 cycles of chemotherapy. Abdominal CT scan showed swelling of the pancreas with multiple masses. The patient was managed conservatively and pancreatitis subsided. This case indicates that metastasis induced acute pancreatitis can be a manifestation of lung cancer, especially in small cell carcinoma. PMID- 10102537 TI - FHR Terminology. PMID- 10102538 TI - Treatment of pregnant women with GBS. PMID- 10102539 TI - New pedagogy for maternity nursing education. AB - Baccalaureate nursing faculty sought new ways to teach maternity nursing to expose health care practices that affect, define, and limit women's experiences of reproductive health care. By blending science, story, and spirituality within a feminist philosophy, the faculty created an atmosphere of chaos that transformed the classroom and clinical experiences of students. The students' awakened engagement with maternity nursing practice was evidenced by their connection to woman-centered care issues, and passing rates on the National Council Licensing Examination remained between 97-100%, indicating adequate learning of standard core content. PMID- 10102540 TI - Pastoral care for perinatal and neonatal health care providers. AB - Health care workers in the perinatal and neonatal environments experience many emotions as they encounter stressors day after day. The chaplain, one of many on the multidisciplinary team, can serve as a valuable resource for other team members. This article provides an overview of the various supportive roles the chaplain can assume. A case presentation highlights pastoral care of staff and family across the continuum from the perinatal to the neonatal units. PMID- 10102541 TI - Organic buildup and residual blood on infant stethoscopes in maternal-infant areas. AB - OBJECTIVE: To identify the presence of residual blood and organic matter on "clean" stethoscopes in maternal-infant units. DESIGN: In this retrospective, nonexperimental study, stethoscopes were tested using qualitative measurements. SETTING: Using a nonprobability sampling technique, 11 acute care hospitals in a three-state area of the southwestern United States were studied. PARTICIPANTS: All stethoscopes found on the maternal-infant units were included, for a total sample size of 97. INSTRUMENTS: A hand-held 10-power lens was used to visually rank the amount of organic buildup, and the phenolphthalein test was used to detect residual blood on the stethoscope. RESULTS: Of 97 clean infant stethoscopes, 80% of labor and delivery and 72% of nursery stethoscopes had organic buildup on the diaphragm. Both areas had similar rates of organic buildup, chi2 (1, N = 97) = 1.00, p = ns. Nursery areas did have significantly lower rates of residual blood than stethoscopes from labor and delivery, phi2 (1, N = 97) = 9.89, p = .002. Seventy-six percent of labor and delivery stethoscopes were positive for blood, as compared to 46% of nursery stethoscopes. CONCLUSIONS: Traditional methods for cleaning stethoscopes used in labor and delivery and nursery areas are ineffective in removing blood and other body fluids from the stethoscope. PMID- 10102542 TI - A baby has died: the impact of perinatal loss on family social networks. AB - OBJECTIVES: To describe the impact of a baby's death on the family's social network and to design nursing interventions to support families and their networks. DESIGN: Descriptive, with a qualitative approach. SETTING: An urban area of western Quebec. PARTICIPANTS: Twenty parents (mothers and fathers) who had experienced a perinatal loss (abortion, miscarriage, in-utero death, stillbirth, or death of a newborn within the 1st week of life) within the last 6 years. MAIN OUTCOME MEASURES: Self-administered questionnaires developed by the authors were completed by each parent. RESULTS: Family members' quality and quantity of ties with their network were profoundly affected by the perinatal loss. Some families experienced reinforcement of their bonds with their social network, but most suffered permanent losses of relationships with friends, colleagues, or extended family members. CONCLUSIONS: The quality and quantity of ties with one's network are associated with improved health status and life satisfaction. Considering the changes participants noted in their relationships within their network, further studies of the impact of these changes on family members' grieving process would be useful to guide nursing interventions. PMID- 10102543 TI - Parents' perception of skin-to-skin care with their preterm infants requiring assisted ventilation. AB - OBJECTIVE: To explore parents' perception of skin-to-skin care with their preterm infant who is on assisted ventilation, and to elucidate factors influencing the decision to continue or discontinue skin-to-skin care. DESIGN: Naturalistic inquiry, using open-ended, transcribed and audiotaped face-to-face and telephone interviews. SETTING: Tertiary neonatal care setting and homes of parents. PARTICIPANTS: Eight mothers and one father who participated in skin-to-skin care. INTERVENTIONS: Two 60-minute skin-to-skin care sessions. RESULTS: Three themes emerged: (a) ambivalence of parents toward skin-to-skin care, including subthemes of yearning to hold the infant and apprehension to do so; (b) need of a supportive environment; and (c) special quality of the parent-infant interaction, including subthemes of intense connectedness and active parenting. Perceptions of apprehension, need for a supportive environment, and active parenting differed between parents who continued skin-to-skin care during their infants' hospitalization and parents who did not. Three of the four parents who discontinued skin-to-skin care in the hospital resumed when their infants were home. CONCLUSIONS: Differences in narratives of parents highlighted the importance of individualizing the skin-to-skin experience to the needs of parent and infant. Parents who resumed skin-to-skin care at home valued the experience while their infant was hospitalized but needed intervention to alleviate their apprehension, enhance their feeling of autonomy, and modify the environment. PMID- 10102544 TI - Positively reframing perceptions of the menstrual cycle among women with premenstrual syndrome. AB - OBJECTIVE: To positively reframe perceptions of menstrual cycle experiences to diminish reports of negative perimenstrual symptoms among women with premenstrual syndrome (PMS). DESIGN/SAMPLE: A longitudinal quasi-experimental research design; data were collected on 28 women. SETTING: Treatment sessions were conducted in a university classroom in the northeastern United States. INTERVENTION: The intervention consisted of a health promotion program that provided social support and a psychoeducational intervention with a positive reframing psychotherapeutic maneuver. MAIN OUTCOME MEASURES: To describe (a) perceptions of biologic, psychologic, and social outcomes related to perimenstrual changes and (b) compare biologic, psychologic, and social outcomes of women participating in a health promotion intervention with women not participating. RESULTS: Negative perimenstrual symptom reports decreased for women in the experimental group. In addition, the participants' personal resources increased significantly. CONCLUSIONS: Participation in a peer support group that provides women with information on positive concomitants of the menstrual cycle can benefit women with PMS. PMID- 10102545 TI - Maternal fatigue: implications of second stage labor nursing care. AB - The parameters of fatigue have been studied in recent years in relation to women's health and the childbearing period. Less research emphasis has been placed on second stage labor, a period of time that can encompass considerable physiologic and psychologic fatigue. Consideration to minimizing second stage labor fatigue by altering conventional support practices is needed. This includes minimizing long periods of strong pushing or bearing down efforts in conjunction with sustained breath holding, particularly for women receiving epidural anesthesia. The potential sequelae of second stage labor fatigue, recommendations for practice changes, and new research directions are discussed. PMID- 10102546 TI - Longitudinal changes in fatigue and energy during pregnancy and the postpartum period. AB - OBJECTIVE: To describe perceived levels of fatigue and energy before, during, and after pregnancy in a group of healthy women experiencing uncomplicated pregnancies; and to examine relationships between their perception of fatigue and energy, parity, and physiologic indicators of sleep disturbances, thyroid function, and iron deficiency. DESIGN: Prospective, longitudinal. SETTING: Participants' homes. PARTICIPANTS: Convenience sample of 24 primiparous and 1 8 multiparous women. MAIN OUTCOME MEASURES: Change in fatigue and energy over time. Measures were obtained at follicular and luteal phases of the menstrual cycle before pregnancy, at each trimester, and at 1 and 3 months after delivery. RESULTS: Younger age and lower prepregnancy levels of iron, ferritin, and hemoglobin explained 1st trimester fatigue. Less total sleep was related to fatigue in the 3rd trimester. Postpartum fatigue was related to reduced amounts of sleep and low levels of ferritin and hemoglobin. CONCLUSIONS: With the exception of premenstrual (luteal) fatigue, progesterone levels were unrelated to fatigue. Neither paid employment nor family variables influenced perception of fatigue. Nurses working with childbearing populations should counsel women about significant 1st trimester fatigue so they can prepare their work and home environments in an attempt to achieve adequate rest. PMID- 10102547 TI - The fatigue experience for women with human immunodeficiency virus. AB - PURPOSE: To examine fatigue as a symptom experienced by women with human immunodeficiency virus (HIV). SAMPLE: A convenience sample of 100 women with HIV. ANALYSIS: Independent sample t-tests were used to test for mean differences in fatigue related to variables in the women's sociocultural and home environment (ethnicity, employment, marital status, and parenting). Pearson product moment correlations were used to examine significant relationships between fatigue and physiologic variables (age, CD4 cell count, and sleep). FINDINGS: Lower CD4 cell counts were related to more daytime sleep, higher evening fatigue, and higher morning fatigue. Morning fatigue was related to duration of wake episodes during the night, napping, and perception of sleep disturbance during the past week. The number of awakenings during the first night predicted the severity of fatigue the next evening. CONCLUSION: To understand the fatigue experienced by women with HIV, researchers and clinicians must focus on the relative contributions of sociocultural, home, and physiologic environments within which these women live. Additional research is ongoing to identify the strategies these women use to manage daily activities such that gender-relevant and culturally relevant interventions for alleviating fatigue can be tested in women with a variety of chronic illnesses, including HIV and acquired immune deficiency syndrome. PMID- 10102548 TI - Fatigue and other symptoms in patients with chronic obstructive pulmonary disease: do women and men differ? AB - OBJECTIVE: Describe the symptoms experienced by patients with chronic obstructive pulmonary disease (COPD), compare women and men with regard to their physical and psychologic symptoms, and determine the predictors of fatigue for the group as a whole and for women separately. DESIGN: Correlational, predictive. PARTICIPANTS: One hundred four (48 women/56 men) outpatients with severe COPD and a mean age of 60 years. MEASURES: Self-report of fatigue using the SF-36 energy/fatigue subscale and a "lack of energy" question. Self-report of dyspnea, general symptoms using the Memorial Symptom Assessment Scale, and psychologic symptoms using the Brief Symptom Inventory. Pulmonary function tests and arterial blood gas levels. RESULTS: Patients reported a moderate level of fatigue (mean of 44 on the SF-36), with no difference in the reports of men and women. When reporting their "lack of energy" during the past week, women reported more fatigue than did men. Other symptoms in descending order of reporting were dyspnea and cough. More women reported "don't look like myself" than did men. Women and men were similar in their psychologic symptoms except anxiety, which was higher in women (t = 2.64, p < .01). Predictors of fatigue (SF-36 subscale) for the group as a whole were found to be dyspnea and physical symptoms, predicting 42% of the variance. For the women alone, dyspnea and physical symptoms entered the equation, to predict 67% of the variance in fatigue. CONCLUSIONS: Predictors of fatigue were similar for women compared to the group as a whole, with symptoms having more of an impact on fatigue than did physiologic variables. PMID- 10102549 TI - Comparative clinical study of a bioabsorbable membrane and subepithelial connective tissue graft in the treatment of human gingival recession. AB - BACKGROUND: Connective tissue grafts and guided tissue regeneration (GTR) are the most current procedures in the treatment of gingival recession, but very few clinical comparative studies have been conducted. METHODS: The purpose of this study was to compare 2 types of treatment of gingival recession in the same patients. Fourteen pairs of Miller Class I defects were selected in 14 patients. In each pair, one recession was randomly assigned for treatment by GTR using a bioabsorbable membrane, and the other treated by subepithelial connective tissue graft (CTG). Height of recession (HR), clinical attachment level (CAL), probing sulcus depth (PSD), height of keratinized tissue (HKT), and distance from the cemento-enamel junction to the mucogingival junction (CEJ-MGJ) were recorded before surgery and 6 months postoperatively. RESULTS: The initial width and height of recession were, respectively, 3.73 mm (SD 0.56) and 3.85 mm (SD 1.15) for the CTG group, and 4.04 mm (SD 0.92) and 4.28 mm (SD 1.20) for the GTR group. The differences were not significant. CAL changes were not different. Both in the CTG group and in the GTR group, mean HR reduction was 2.89 mm (SD 1.18), representing a mean root coverage of 76% and 70.2%, respectively. The difference was not significant. HKT mean gain was significantly greater (P = 0.0001) with CTG (2.03 mm, SD 0.92) than with GTR (0.42 mm, SD 0.91). The GTR technique displaced the mucogingival junction significantly (P = 0.007) more coronally (2.35 mm, SD 1.44) than the CTG technique (0.78 mm, SD 1.23). CONCLUSIONS: Within the limits of this study, no difference could be found between subepithelial connective tissue graft and GTR with a bioabsorbable membrane with regard to root coverage, but the GTR technique did not increase the height of keratinized tissue and displaced the mucogingival junction more coronally at 6 months. PMID- 10102551 TI - Recombinant human bone morphogenetic protein-2 stimulation of bone formation around endosseous dental implants. AB - BACKGROUND: Successful endosseous implant placement requires that the implant be stable in alveolar bone. In certain cases, the implant can be stabilized in native bone but some part of the implant is not covered by bone tissue. This often occurs during placement of implants into extraction sites or in areas where bone resorption has occurred and the ridge width is not sufficient to completely surround the implant. In those cases, the clinician usually employs a procedure to encourage bone formation. These procedures typically include a bone graft and/or membrane therapy. Recent advances have led to the isolation, cloning, and production of recombinant human proteins that stimulate bone formation. One of these bone morphogenetic proteins (rhBMP-2) has been extensively studied in animal models and is currently being tested in human clinical trials. METHODS: In this study, rhBMP-2 was tested using a collagen sponge carrier to stimulate bone formation in defects in the canine mandible around endosseous dental implants. Six animals had a total of 48 implants placed. rhBMP-2 with the collagen carrier was implanted around 24 of these, the remainder having only the collagen carrier placed. Half the sites were covered with a nonresorbable expanded polytetrafluoroethylene membrane. Histologic analysis was performed after 4 and 12 weeks. The area of new bone formed, percentage of bone-to-implant contact in the defect area, and percentage fill of the defect was calculated. RESULTS: The addition of rhBMP-2 resulted in significantly greater amounts of new bone area and percentage of bone-to-implant contact and with more percentage fill after 4 and 12 weeks of healing. The area of new bone formed was reduced after 4 weeks when a membrane was present but after 12 weeks, there was no significant difference between membrane and non-membrane treated sites. In some specimens, new bone was found coronal to the membranes, with rhBMP-2-treated sites having greater amounts than non-rhBMP-2-treated sites. CONCLUSIONS: These data demonstrate that a bone differentiation factor significantly stimulates bone formation in peri-implant bone defects in the canine mandible. In addition, bone to-implant contact was significantly enhanced along the rough implant surface. Membrane-treated sites had less new bone formation after 4 weeks of healing but were similar to non-membrane sites after 12 weeks. These results demonstrate that rhBMP-2 can be used to stimulate bone growth both around and onto the surface of endosseous dental implants placed in sites with extended peri-implant osseous defects. PMID- 10102550 TI - Microbiota of successful osseointegrated dental implants. AB - BACKGROUND: The long-term survival of dental implants depends, in part, on control of bacterial infection in the peri-implant region. Periodontal pathogens colonized implants symptomatic through infection, whereas the microbiota of successful implants was similar to that of periodontal health. This study examined the impact on the peri-implant microbiota of crown restorations; implant type; length of time of loading; history of implant or periodontal infections; and whether implants replaced single or multiple teeth. It was of particular interest to evaluate implant colonization by species in a newly described red complex of periodontal pathogens, Porphyromonas gingivalis and Bacteroides forsythus. METHODS: This study sampled 43 partially edentulous subjects with successfully osseointegrated titanium root-form dental implants. Eighty-one (81) non-submerged and 20 submerged asymptomatic implants, 83 crowned, and 36 uncrowned teeth were sampled from peri-implant or subgingival sites. The microbiota of samples was evaluated using whole genomic DNA probes in a checkerboard assay to 23 subgingival species. RESULTS: Implants were colonized principally by oral streptococci, capnocytophagae, Veillonella parvula, Peptostreptococcus micros, and Fusobacterium nucleatum. The periodontal species, P. gingivalis, B. forsythus, Prevotella intermedia, Prevotella nigrescens, and Campylobacter rectus were detected in a few subjects. The microbiota around crowned implants and crowned teeth was similar. Streptococcus oralis, P. intermedia, and Selenomonas noxia were elevated in samples from uncrowned teeth compared to crowned teeth and implants. Microbial complexity increased as loading time increased, but colonization by periodontal pathogens, including red complex species, was higher in subjects with previous periodontal disease. No differences were observed in the microbiota of 1- and 2-stage implants, or between implants supporting single or multiple restorations. CONCLUSIONS: While presence of crowns had only a minor impact on the peri-implant microbiota, microbial changes were observed the longer the implants had been in function and in those patients with a history of periodontal or peri-implant infections. A history of periodontitis had a greater impact on the peri-implant microbiota than implant loading time. The major influence on the peri-implant microbiota was, however, the microbiota on remaining teeth. P. gingivalis and B. forsythus, red complex periodontal pathogens, colonized several implants, although all implants were successfully osseointegrated. PMID- 10102552 TI - Use of alendronate in peri-implant defect regeneration. AB - BACKGROUND: Previous studies have demonstrated an increase in bone mass and density with use of systemic alendronate sodium. This agent acts as an inhibitor of osteoclast activity, and is thought to result in more net osteoblastic activity. The objective of this study was to determine the effects of locally applied alendronate sodium on guided bone regeneration around dental implants. METHODS: Six adult mongrel dogs were divided into 2 groups: one group received alendronate-coated dental implants, and the other group served as control. Two types of dental implants were used in each dog: hydroxyapatite (HA)-coated and titanium machine-polished (TMP), for a total of 4 groups. Dental implants were placed immediately after extraction of the right and left second, third, and fourth mandibular premolars; a resorbable collagen membrane was secured over the implants and defects; and the flaps were closed primarily. Fluorescent labels were administered intravenously on days 0, 6, 12, and 22 to measure bone formation rate. Dogs were sacrificed on day 28. The specimens were sectioned and mounted, and bone formation rate was recorded with a computerized microscopic digitizer. Specimens were stained with Stevenel's blue and van Gieson's picric fuchsin. Bone-to-implant contact was recorded with a computerized microscopic digitizer. RESULTS: The results indicated a significant effect of locally applied alendronate (P < 0.0001) with both types of implants (HA and TMP), as well as the HA coating (P< 0.02) on increased bone formation rate. Additionally, alendronate had a significant effect on bone-to-implant contact, with an increase in the TMP model (P < 0.0001) and a decrease in the HA model (P < 0.0001 ). HA coating also had a significant effect on increasing bone-to-implant contact (P < 0.04). CONCLUSIONS: The results indicate that alendronate increases early bone formation rate around dental implants. Additionally, the local application as described resulted in greater bone-to-implant contact with TMP implants. PMID- 10102553 TI - Option-4 algorithm for third generation disc probe: agreement of selected site specific relative attachment level measurements and detection of longitudinal site-specific attachment level change. AB - BACKGROUND: Longitudinal site-specific attachment level change (SSAC), identified from serial relative attachment level measurements (RAL), is the principal indicator of progression/regression of periodontal diseases. Many variables confound RAL reproducibility and affect measurement error. The Option-4 algorithm was designed to reduce measurement error and improve accuracy and sensitivity of SSAC detection. The study aimed to evaluate the performance of the Option-4 algorithm. METHODS: A precalibrated clinician recorded full mouth RAL with a third generation disc probe on 4 occasions over 6 months in 16 subjects (mean age 48.1 years) with moderately advanced chronic adult periodontitis (2,312 sites). Option-4 allowed up to 4 RAL recordings per site per visit until 2 values had differences < or =1.0 mm and their mean was < or =1.0 mm from the previous visit mean: the clinician made the selection if these criteria were unfulfilled. RESULTS: Within-visit agreement < or =1.0 mm was > or =99.6%: all within-visit correlation coefficients = 0.98 (P<0.001). At each visit, mean difference in Option-4 values was < 0.05 mm, mean absolute difference (ignoring direction) was < or =.34 mm. Mean site-specific variances ranged from 0.092 mm2 to 0.097 mm2 across all visits. Subject thresholds for site-specific attachment level change (from estimated 95% confidence limits of visit 1 data) ranged from 0.52 mm to 0.67 mm. Linear SSAC (by linear regression) and between-visit patterns of SSAC were investigated. SSAC was detected in 100% subjects and at 51.0% measured sites. Linear SSAC (R2 > or =0.90: P < or =0.05) occurred at 105 sites (4.5%): 32 sites (1.4%) deteriorated, 73 sites (3.1%) improved. Between-visit SSAC occurred at 1,074 sites (46.5%): 391 sites (16.9%) deteriorated, 295 sites (12.8%) improved, and 388 sites (16.8%) showed exacerbation/remission patterns. CONCLUSIONS: The Option-4 algorithm produced high RAL agreement. Site-specific attachment level change was detected in both directions in 100% subjects and at 51.0% measured sites. PMID- 10102554 TI - Periodontal disease in patients with cleft palate and patients with unilateral and bilateral clefts of lip, palate, and alveolus. AB - BACKGROUND: Long-term health of the stomatognathic system, as well as esthetics, is the therapeutic goal in patients with facial clefts. The aim of this study was to analyze the periodontal situation of patients with cleft palate (CP) and cleft lip, palate, and alveolus (CLPA) to elicit the differing degrees and localization of periodontal disease. METHODS: In 30 patients with unilateral cleft lip, palate, and alveolus (UCLPA), 30 patients with cleft palate (CP), and 20 patients with bilateral cleft lip, palate, and alveolus (BCLPA), the gingival situation was identified and classified according to the sulcus bleeding index (SBI). Periodontal attachment loss and pathological loosening of teeth were noted for identification of periodontal lesions. The state of oral hygiene was recorded by the approximal plaque index (API). RESULTS: In general, poor oral hygiene was found in all patients. The SBI showed a high incidence of gingivitis in patients with cleft lip, palate, and alveolus. Patients with cleft palate had a minor extent of sulcus bleeding. Periodontal disease was found to a similar extent to that in the general population in patients with cleft palate, whereas patients with cleft lip, palate, and alveolus had a predisposition to deep periodontal destruction of teeth adjacent to the cleft. The registration of pathological loosening of teeth, a result of attachment loss, corresponded to the degree of periodontal disease shown by the attachment loss. CONCLUSIONS: A critical periodontal situation was found in patients with unilateral and bilateral cleft lip, palate, and alveolus, ultimately leading to tooth loss in the front tooth region. In contrast, patients with cleft palate exhibited periodontal situations similar to that found in the general population with additional damage, which may be attributed to orthodontic treatment. PMID- 10102555 TI - Polyamines found in the inflamed periodontium inhibit priming and apoptosis in human polymorphonuclear leukocytes. AB - BACKGROUND: Polymorphonuclear leukocytes (PMNs) are exposed to high concentrations of polyamines in the inflamed periodontium and possess a transport system for taking up these compounds. Previous studies suggest that polyamines are involved in priming of the PMN respiratory burst by tumor necrosis factor alpha (TNF-alpha) and can stabilize DNA against degradation. The purpose of this study was to determine whether exogenous polyamines can modulate priming by TNF alpha or delay nuclear changes associated with PMN apoptosis (programmed cell death). METHODS: Isolated human PMNs were incubated with putrescine or spermidine in vitro. Superoxide generation was measured with a cytochrome C reduction assay, and apoptotic changes were assessed by fluorescence microscopy (after cell staining with acridine orange and ethidium bromide). RESULTS: Incubation with 1 mM putrescine for 1 hour inhibited superoxide production by TNF-primed PMNs by 20%, but enhanced the production of superoxide by unprimed cells by 38%. Both effects were dose dependent and statistically significant (P <0.03, repeated measures ANOVA and Dunnett's test). Spermidine had no significant effects on PMN oxidative function. With regard to apoptosis, 1 mM putrescine or spermidine produced a statistically significant reduction in the proportion of apoptotic PMNs within 6 to 9 hours (P <0.05). In cells incubated for 7 hours with 300 microM putrescine or spermidine, the proportion of apoptotic cells was approximately 30% lower than in untreated controls (P <0.05, Dunnett's test). The delay of apoptosis by spermidine was less profound than that produced by TNF alpha and was not additive to the effects of this cytokine. CONCLUSIONS: Polyamines could potentially impair the priming of PMN oxidative function by TNF alpha at sites where this cytokine is present. In the absence of TNF-alpha, polyamines could enhance PMN superoxide release and enhance the maintenance of PMN function in the periodontal pocket. PMID- 10102556 TI - Periodontitis and anti-neutrophil cytoplasmic antibodies in systemic lupus erythematosus and rheumatoid arthritis: a comparative study. AB - BACKGROUND: This investigation was designed to determine and compare the distribution pattern of anti-neutrophil cytoplasmic antibodies (ANCA) in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in the presence or absence of periodontal disease. METHODS: Sera of 30 patients with SLE and 30 with RA were tested for ANCA utilizing an indirect enzyme immunosorbent assay (ELISA) directed to a neutrophil granular extract and 6 neutrophil granule proteins. A control group of 20 healthy individuals showing neither evidence of periodontal disease nor systemic compromise was also included in this study. RESULTS: For RA, the number of ANCA-positive sera was very low but was evenly distributed among patients with and without periodontitis. Conversely, a high number of ANCA-positive sera in SLE was found mostly in individuals presenting periodontal compromise. A statistically significant association between ANCA and periodontitis in SLE patients was found (P <0.005, chi square test). CONCLUSIONS: A marked difference in the number and distribution of ANCA with respect to periodontitis between RA and SLE was found. Hyperresponsiveness of B cells and polyclonal B activation to periodontopathic bacteria in SLE might be accountable for the high numbers of ANCA and the close association observed between those autoantibodies and periodontitis in SLE. PMID- 10102557 TI - Effects of cyclosporin A on alveolar bone: an experimental study in the rat. AB - BACKGROUND: There have been several investigations on the role of cyclosporin A (CSA) in gingival hyperplasia in both animals and humans. However, less attention has been given to the drug's effect on alveolar bone. This study used light microscopy to histologically and histometrically evaluate the effects of CSA on alveolar bone in the rat. METHODS: Sixty, 6-week-old Sprague-Dawley rats were separated into test and control groups. Animals in the test group received CSA in mineral oil (30 mg/kg body weight) daily by gastric feeding over the 6-week study. Control animals received only mineral oil. Ten animals from each group were sacrificed at weeks 2, 4, and 6. After histologic processing, the labial crest of the alveolar bone in the anterior mandible was evaluated by light microscopy. RESULTS: A distinct pattern of increased osteoclasia and reduced bone formation was observed in the CSA-exposed animals compared to the controls. Increased osteoclasia was observed in periodontal sites and decreased bone formation was observed in symphyseal sites. CONCLUSIONS: The results suggest that CSA has distinct effects on alveolar bone. PMID- 10102558 TI - Periodontitis in the house musk shrew (Suncus murinus): a potential animal model for human periodontal disease. AB - BACKGROUND: Our understanding of periodontal diseases has been facilitated greatly by the use of animal models. However, no animal model has been identified that truly reflects the disease seen in humans. Suncus murinus, a rat-sized laboratory house musk shrew, has received attention as a valuable animal model due to ease of handling. In the studies described here, periodontal conditions in Suncus murinus were evaluated to determine the usefulness of the shrew as an experimental model for understanding various aspects of periodontal diseases. METHODS: Periodontal tissues of 34 Suncus murinus (18 to 430 days old) were examined macroscopically, morphometrically, histologically, and ultrastructurally. RESULTS: Dentition pattern is I3/1, C1/1, P2/1, M3/3. Spontaneous gingival swelling with accumulation of plaque was observed in more than two-thirds of animals older than 200 days. Morphometric analysis of alveolar bone demonstrated a pattern of bone loss that correlated closely with animal age. Histologically, periodontal lesions varying from gingivitis to periodontitis, similar to those observed in humans, were noted. Marked infiltration of lymphocytes and plasma cells in the connective tissue was noted, usually not seen in periodontal lesions of rodents. Although osteoclastic alveolar bone resorption was noted, active bone resorption was not a frequent feature in specimens obtained from chronic inflammatory lesions. Ultrastructurally, degradation of collagen fibers in the inflamed area and ingestion of collagen fibrils by fibroblasts in the deeper connective tissue were often seen. CONCLUSIONS: These results indicate the potential utility of Suncus murinus as a model to study periodontal disease; e.g., chronic nature of the inflammatory periodontal lesions, similar to those in humans, as well as other advantages including size and ease of handling and housing of these animals. PMID- 10102559 TI - Gingival fibromatosis combined with cherubism and psychomotor retardation: a rare syndrome. AB - Gingival fibromatosis is frequently an isolated condition, but rarely associated with some uncommon syndromes. This paper describes an 11-year-old patient with pronounced gingival enlargement, cherubic facial appearance, and psychomotor retardation and discusses the major aspects of the case. The most striking finding orally was the presence of grossly hyperplastic gingiva, which completely covered all teeth except the occlusal surfaces of some teeth. The swelling in the lower part of the face and the appearance of sclera beneath the iris suggest cherubism. The diagnosis was confirmed by the detection of giant cell regenerative granuloma and perivascular eosinophilic particles and osteoclasts after biopsy of the mandible. In this case, surgery was the only effective way to treat the patient. A full-mouth gingivectomy procedure was performed under general anesthesia in 2 stages. The case was followed for 12 months and no recurrence was seen. An appropriate oral hygiene regimen was established. PMID- 10102560 TI - A long-term evaluation of composite-bonded natural/resin teeth as replacement of lower incisors with terminal periodontitis. AB - BACKGROUND: In patients with severe peridontitis, lower incisors are prone to terminal breakdown. This study assessed the longevity of composite-bonded resin/natural teeth (reinforced only with a stainless steel mesh) as replacements for periodontally lost lower incisors. METHODS: Besides the longevity of the restoration, the periodontal condition of the abutment teeth, and the general satisfaction of the patient were evaluated retrospectively via a phone interview, in combination with an analysis of the patient's clinical dental file. RESULTS: The cumulative proportion of survival rate of these composite restorations was 80% after 5 years of function. No statistically significant difference was found between the survival distribution of one- and two-pontic bridges (P = 0.66). The abutment teeth demonstrated stable probing depths and a negligible loss in attachment (0.1 mm/year). The satisfaction ratings were also favorable. CONCLUSIONS: The data seem to suggest that composite bonding of 1 or 2 teeth can be considered a semi-permanent rehabilitation for the replacement of 1 or 2 periodontally lost lower incisors. PMID- 10102561 TI - Spontaneous early exposure of submerged implants: I. Classification and clinical observations. AB - BACKGROUND: It is believed that during the osseointegration phase of submerged dental implants, complete mucosal coverage and isolation of the implant from the oral cavity avoids trauma and infection and establishes favorable conditions for osseointegration. Spontaneous early exposure is one of the complications that could adversely affect osseointegration of implants. METHODS: This study clinically classifies spontaneous early exposure and describes and analyzes this complication in a group of 148 patients treated with 372 submerged implants: 216 (58%) in the mandible and 156 (42%) in the maxilla. Edentulous sites were exposed by mid-crestal incisions and full thickness gingival flaps. Incisions were closed in an attempt to achieve complete closure and healing by primary intention. Measurements were taken to avoid mechanical trauma to the mucosa over the implants. Patients were followed up weekly and examined to identify early exposures. Perforations were classified according to the degree of exposure from 0 (no perforations) to 4 (complete exposure). RESULTS: Of the implants 51 (13.7%) presented spontaneous early exposure, (13%) in the mandible and 23 (14.7%) in the maxilla. Class 2 perforation was the most frequent, followed by Class 3, Class 1 and Class 4. Inflammation at the mucosal orifices of the perforations was minimal, but no objective index (bleeding, probing) was taken in order to avoid morphological changes of the lesions that were biopsied for histological examination. CONCLUSIONS: Early perforation and partial exposure of the implant's covering device are a focus for plaque accumulation which, if left untreated, may result in inflammation, damage to the peri-implant mucosa, and possible peri implant loss. PMID- 10102562 TI - Microorganisms and dental implants. PMID- 10102563 TI - Control of cell proliferation by Myc family genes. AB - The c-myc proto-oncogene was discovered as the cellular homologue of the transforming oncogene of several chicken retroviruses. It has become clear that c myc is a member of a small gene family; members of this family encode transcription factors of the Helix-loop-Helix family of transcription factors that can both activate and repress transcription. In vivo, these genes control both proliferation and apoptosis. This review will focus on recent progress in understanding how the encoded proteins exert their biological functions. PMID- 10102564 TI - Fragment E derived from both fibrin and fibrinogen stimulates interleukin-6 production in rat peritoneal macrophages. AB - Fibrin derived from fibrinogen after thrombin cleavage plays an essential role in forming blood clots. Fibrin as well as fibrinogen is also involved in the induction of platelet aggregation, leukocyte cell adhesion and phagocytosis. An additional biological role of fibrin and fibrinogen is presented in this study. One of the proteolytic peptides of fibrin/fibrinogen, fragment E, and not fragment D, was able to stimulate rat peritoneal macrophages to express interleukin-6 (IL-6). The stimulation of fibrin/fibrinogen fragment E on macrophages appeared to work in a dose- and time-dependent manner. Adherent fibrin fragment E was able to stimulate IL-6 expression as well as IL-6 protein production. The effect of fibrin fragment E was inhibited by the addition of an excess amount of GPRP tetrapeptide, but not by GHRP, which are the amino acids derived from the amino terminus of fibrin alpha and beta chains, respectively. These results suggest that fibrin as well as fibrinogen function as a stimulator to macrophages, and leukocyte integrin p150,95 (CD11c/ CD18), not Mac-I (CD11b/CD18), is involved in mediating fibrin stimulatory activity in macrophages. PMID- 10102565 TI - Particle bombardment mediated transformation and GFP expression in the moss Physcomitrella patens. AB - There are few plants facilitated for the study of development, morphogenesis and gene expression at the cellular level. The moss Physcomitrella patens can be a very useful plant with several advantages: simple life cycle containing a major haploid gametophyte stage, easy manipulation, small genome size (6 x 10(8) bp) and high similarities with higher plants. To establish the transformation system of mosses as a model for basic plant research, a series of experiments were performed. Mosses were cultured in cellophane overlaid BCD media, transformed by particle bombardment and selected by the choice of appropriate antibiotics. Initial transformants appeared 8 d or 14 d after selection, showing different sensitivities toward the antibiotics used. Heat treatment during the preparation of particles revealed that denaturing the DNA enabled a more efficient way to deliver a transgene into the chromosome. This was proven by the increase in the number of transformants by five times in the plants with denatured DNA. In the test for the repairing capacity of mosses, 154 and 195 transformants survived from 1 d and 3 d incubations, respectively, indicating that a longer period of incubation seemed to be recommendable for better survival. The selected transformants were further analyzed at the DNA and expression level. Transformed genes were confirmed by PCR where all the transformants showed the expected size of amplification. Histochemical beta-glucuronidase (GUS) and green fluorescent protein (GFP) expression also confirmed the integration of exogenous DNA. In a comparison of the two different forms of GFP, soluble-modified GFP (smGFP) expressed stronger signals than modified GFP (mGFP) due to its improved solubility. Confirmation of the transgene in the chloroplast transformation has improved the applicability of moss as a model system for the study of basic biological researches. PMID- 10102566 TI - Induction of uncoupling protein-2 (UCP2) gene expression on the differentiation of rat preadipocytes to adipocytes in primary culture. AB - We have examined uncoupling protein-2 (UCP2) gene expression in the adipose tissue of obese and normal rats and mice, and also in differentiated rat adipocytes in primary culture. Expression of the UCP2 gene was examined in rat and mouse adipose tissues using both RT-PCR and Northern blotting. Although the RT-PCR was not quantitative, the band corresponding to the UCP2 mRNA was stronger in white adipose tissue than in brown fat, regardless of the body weight of the rats. In agreement with the RT-PCR data, there was a higher level of UCP2 mRNA in the white adipocytes than in brown adipocytes, the level being greater in obese mice. Fibroblastic preadipocytes were obtained from the inguinal fat pad of suckling rats. Lipid droplets developed inside the cells upon differentiation and adipsin and UCP2 mRNAs were detected by Northern blotting. Both mRNAs were evident in the adipocytes at 4, 6, and 10 d after the induction of differentiation. There was no indication that the expression of UCP2 was markedly affected by the addition of leptin, dexamethasone or isoprenaline. PMID- 10102567 TI - Isolation of human anti-branched chain alpha-oxo acid dehydrogenase-E2 recombinant antibodies by Ig repertoire cloning in idiopathic dilated cardiomyopathy. AB - The generation of human monoclonal autoantibodies is critical for understanding humoral immune response in autoimmunity. In this study, Ig gene repertoire cloning was performed from a regional lymph node of a patient with idiopathic dilated cardiomyopathy (IDCM), and the resulting combinatorial IgG library was screened with bovine branched chain alpha-oxo acid dehydrogenase-E-2 (BCOADC-E2), one of the autoantigens in IDCM. After three rounds of affinity selection, we isolated three human recombinant IgG Fab molecules, named BC1, BC2 and BC3, that specifically react with BCOADC-E2 by ELISA. Interestingly, BC2 showed weak cross reactivity to pyruvate dehydrogenase complex-E2 (PDC-E2), another mitochondrial autoantigen found in primary biliary cirrhosis (PBC), and their kappa light chain genes have 95% homology with a light chain of the human anti-DNA antibody. Although the exact pathogenic effect of anti-BCOADC-E2 autoantibodies is still unknown in IDCM, the potential binding specificity and limited light chain gene usage of our recombinant IgG molecules may shed light on the initial mechanism as to how autoantibodies start developing in IDCM. PMID- 10102568 TI - Luteinizing hormone releasing hormone-RNase A conjugates specifically inhibit the proliferation of LHRH-receptor-positive human prostate and breast tumor cells. AB - Human prostate and breast tumor cells produce luteinizing hormone-releasing hormone (LHRH) receptors on their cell surface even when they have lost dependency on sex steroid hormones for growth. To investigate whether LHRH can be used as a cell-binding moiety to deliver toxin molecules into prostate and breast tumor cells, LHRH-bovine RNase A conjugates were constructed using the chemical cross-linking method. The treatment of the LHRH receptor-positive cells such as prostate LNCapFGC and breast MCF7 tumor cells with LHRH-RNase A conjugates resulted in a dose-dependent inhibition of growth. The cytotoxic activities of these conjugates were effectively reduced by the presence of exogenous LHRH. Either free RNase A or LHRH alone did not affect the proliferation of these cells. The LHRH-RNase A conjugates did not show cytotoxicity against FRTL5 and TM4 cells which do not express the LHRH receptors. These results suggest that LHRH can be used as a cell-binding molecule for the specific delivery of toxin molecules into the cells which express LHRH receptors on their surface. Thus, a new class of biomedicines that act as fusion proteins between LHRH and toxins will give us a new avenue for the treatment of human prostate and breast cancers, regardless of their steroid hormone dependency. PMID- 10102569 TI - Factors affecting human cytomegalovirus gene expression in human monocyte cell lines. AB - To understand the mechanisms for establishing and reactivating monocytes and macrophages from latency by human cytomegalovirus (HCMV), human monocyte cell lines were infected and HCMV gene expression was investigated. Indirect immunofluorescence assay (IFA) with monoclonal antibody to HCMV major immediate early (MIE) IE1 or IE2 proteins revealed that HCMV MIE genes were expressed at low levels in relatively more differentiated THP-1 cells with TPA treatment after virus infection (posttreatment). Less differentiated cells such as U937 or HL60 did not support MIE gene expression even after TPA treatment. If THP-1 cells were pretreated before virus infection with TPA and became differentiated at the time of HCMV infection, MIE gene expression increased by 5-6 fold. Therefore, the relative degree of monocyte cell differentiation appears to be an important factor for regulating HCMV gene expression. Further IFA studies using monoclonal antibodies specific for IE1 or IE2 proteins indicate that the sequence and general pattern of IE1 and IE2 gene expression in THP-1 cells treated with TPA were similar to those in permissive human fibroblast cells with some delay in time. Formation of the replication compartment detected with monoclonal antibody to HCMV polymerase accessory protein UL44 in THP-1 cells suggests a fully productive replication process of HCMV in these cells. Monocytes are known to be induced to differentiate by hydrocortisone (HC), tumor necrosis factor (TNF) alpha or interferon (IFN)-gamma. HC, which is known to stimulate HCMV replication in permissive human fibroblast (HF) cells, enhanced HCMV gene expression by 2-3 fold in TPA-pre or posttreated THP-1 cells, but TNF-alpha or IFN-gamma had little effect. Nitric oxide (NO) is released by immune cells in the defense against foreign stimuli and was shown to inhibit HCMV gene expression in HF cells. Increasing NO by nitroprusside significantly reduced HCMV gene expression in THP 1 cells. Therefore, it appears that the expression of HCMV immediate early genes in THP-1 cells treated with TPA closely resembles those in permissive HF cells. PMID- 10102570 TI - Expression, purification, characterization and crystallization of flap endonuclease-1 from Methanococcus jannaschii. AB - A gene coding for a protein homologous to the flap endonuclease-1 (FEN-1) was cloned from Methanococcus jannaschii, overexpressed, purified and characterized. The gene product from M. jannaschii shows 5' endo-/exonuclease and 5' pseudo-Y endonuclease activities as observed in the FEN-1 in eukaryotes. In addition, Methanococcus jannaschii FEN-1 functions effectively at high concentrations of salt, unlike eukaryotic FEN-1. We have crystallized Methanococcus jannaschii FEN 1 and analyzed its preliminary character. The crystal belongs to the space group of P2(1) with unit cell dimensions of a = 58.93 A, b = 42.53 A, c = 62.62 A and beta = 92.250. A complete data set has been collected at 2.0 A resolution using a frozen crystal. PMID- 10102571 TI - Isolation and characterization of the catalase gene from Rhizobium sp. SNU003, a root nodule symbiont of Canavalia lineata. AB - A catalase gene from Rhizobium sp. SNU003, a root nodule symbiont of Canavalia lineata, was cloned and its nucleotide sequence was determined. The Rhizobium DNA of about 280 bp was amplified using two PCR primers synthesized from the conserved sequences of the type I catalase gene. The nucleotide sequence of the amplified fragment revealed three regions that were conserved in the catalase, showing it as being part of the catalase gene. A genomic Southern hybridization using this fragment as a probe showed that the 5.5 kb PstI, 1.8 kb EcoRI, and 0.7 kb StyI fragments hybridized strongly with the probe. The Rhizobium genomic library constructed into the EMBL3 vector was screened, and one catalase clone was selected. The nucleotide sequence of the 5.5 kb PstI fragment from the clone revealed an open reading frame of 1455 bp, encoding a polypeptide of 485 amino acids with a molecular mass of 54,958 Da and a pI of 6.54. The predicted amino acid sequence of the catalase is 66.3% identical to that of Bacteroides fragilis, but was only 53.3% identical to the Rhizobium meliloti catalase. PMID- 10102572 TI - Distribution of gangliosides, GM1 and GM3, in the rat oviduct. AB - It is known that gangliosides, being ubiquitous membrane components, play important roles in cell-cell recognition, differentiation and transmembrane signalling. GM3, GM1 and GD1a were detected in the rat oviduct as major gangliosides by thin-layer chromatography (TLC) analysis. The total amounts of gangliosides from the oviducts at various times after hormone injection were not much changed. In order to identify their distribution and possible changes during ovulation, frozen sections of the rat oviducts were stained with specific monoclonal antibodies (MAbs) against the ganglio-series gangliosides. GM3 and GM1 were expressed in a different manner, but GD1a and other gangliosides were not immunohistochemically detected. In the ampullar region, GM3 was expressed in all the stroma and epithelial cells, but not GM1. GM1 was also not observed in epithelial cells. Staining by anti-GM1 monoclonal antibodies revealed long and minute thread-like structures in some of the stroma cells, whereas anti-GM3 monoclonal antibodies stained the entire cytoplasm, but not the nucleus, of all the stroma and epithelial cells. Other ganglio-series gangliosides, including GD1a, were not detected to some extent in the ampullar region by immunohistochemistry. Thus, these data suggest that GM3 and GM1 are oviduct specific gangliosides. PMID- 10102573 TI - Transcript titers of ecdysteroid receptor components vary between tissues and stages during Drosophila development. AB - In Drosophila, the ecdysteroids trigger the key regulatory cascades controlling the coordinated changes in the developmental pathway of molting and metamorphosis. Ecdysone action is mediated by a heterodimer consisting of the three ecdysone receptor (EcR) isoforms and the ultraspiracle proteins (USP). Heterodimers of these proteins bind to the ecdysone response element and ecdysone to modulate gene transcription. In this study, we developed a competitive reverse transcription polymerase chain reaction (RT-PCR) method to quantify the transcripts of functional ecdysone receptor components in individual tissues and for the whole body. The relatively small amount of variation in usp transcripts of the different tissues indicates that this gene does not perform a spatially restricted function in the late third instar wandering larvae while EcR isoforms were expressed in a more tissue-restricted pattern in the same stage. EcR-B1 was expressed at higher levels in larval tissues that are fated for histolysis, whereas EcR-A predominates in the imaginal discs. This result supports the hypothesis that a particular metamorphic response requires particular EcR isoforms. The transcript levels of the functional ecdysone receptor components fluctuate dramatically during development, suggesting that the regulations of the transcriptional and posttranscriptional levels of these genes play some role in ecdysteroid response during Drosophila development. PMID- 10102574 TI - Temperature sensitivity of catecholamine secretion and ion fluxes in bovine adrenal chromaffin cells. AB - The effects of temperature on ion fluxes and catecholamine secretion that are mediated by nicotinic acetylcholine receptors (nAChRs), voltage-sensitive calcium channels (VSCCs), and voltage-sensitive sodium channels (VSSCs) were investigated using bovine adrenal chromaffin cells. When the chromaffin cells were stimulated with DMPP, a nicotinic cholinergic agonist, or 50 mM K+, the intracellular calcium ([Ca2+]i) elevation reached a peak and decreased more slowly at lower temperatures. The DMPP-induced responses were more sensitive to temperature changes compared to high K+-induced ones. In the measurement of intracellular sodium concentrations ([Na+]i), it was found that nicotinic stimulation required a longer time to attain the maximal level of [Na+]i at lower temperatures. In addition, the VSSCs-mediated [Na+]i increase evoked by veratridine was also reduced as the temperature decreased. The measurement of [3H]norepinephrine (NE) secretion showed that the secretion within the first 3 min evoked by DMPP or high K+ was greatest at 37 degrees C. However, at 25 degrees C, the secretion evoked by DMPP, but not that by the 50 mM K+, was greater after 10 min of stimulation. This data suggest that temperature differentially affects the activity of nAChRs, VSCCs, and VSSCs, resulting in differential [Na+]i and [Ca2+]i elevation, and in the [3H]NE secretion by adrenal chromaffin cells. PMID- 10102575 TI - Molecular genetic analysis of the DiGeorge syndrome among Korean patients with congenital heart disease. AB - The DiGeorge syndrome (DGS) is a developmental defect of the third and fourth pharyngeal pouches, which is associated with congenital heart defects, hypoparathyroidism, cell-mediated immunodeficiency, velo-pharyngeal insufficiency and craniofacial dysmorphism. The aetiological factor in a great majority of DGS cases is monosomy for the chromosomal region 22q11. To analyze DGS at the molecular level, a new molecular probe (DGCR680) encompassing the ADU balanced translocation breakpoint was prepared. When 13 Korean patients with DGS-type congenital heart disease were analyzed with this probe, 9 turned out to have a deletion at this locus, and all of them except one exhibited a typical facial dysmorphism associated DGS. Though only 9 independent patients were detected to have a deletion at the locus using the commercial probe N25 (D22S75), which maps at about 160 kb from the ADU breakpoint to the telomeric end, results from fluorescence in situ hybridization revealed a deletion in all cases tested at this locus. Two patients who had a deletion at the locus D22S75 but not at DGCR680 did not exhibit any DGS-type facial abnormalities. This result implies that the 680 bp probe covering the ADU translocation breakpoint might be a candidate for a molecular marker that can distinguish a specific phenotype, such as facial features associated with the DiGeorge syndrome. This study also suggested that systematic approaches with several small DNA probes along the DGCR could help to dissect the complex phenotypes associated with the DiGeorge syndrome, such as cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia, etc. PMID- 10102576 TI - Polymorphism analysis of the CYP1A1 locus in Koreans: presence of the solitary m2 allele. AB - This study determined the complete genotype and the frequencies of all four mutations [T6235C (m1), A4889G (m2), T5639C (m3) and C4887A (m4)] of the CYP1A1 from 48 healthy Koreans and 17 Korean lung cancer patients. The mutations were analyzed by polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) and single stand conformation polymorphism (SSCP) simultaneously in order to improve accuracy as well as to screen for possible new alleles. Previously, the m2 mutation has always been linked to the m1 mutation. Also, the m1m2 double mutant allele (*2B) was thought to have a positive correlation with lung cancer susceptibility. Here we report the presence of the solitary m2 mutant allele without the m1 mutation (m1+m2) for the first time. This would be an evidence to support the theory of intragenic recombination in the CYP1A1 locus. The m1 mutation frequencies of healthy Koreans and lung cancer patients were 38.5% and 29.4%, respectively. The m2 mutation frequencies of healthy Koreans and lung cancer patients were 25.0% and 14.7%, respectively. Unlike the case for both Japanese and Caucasian lung cancer patients, neither m1 nor m2 mutations were overrepresented in Korean lung cancer patients. The m2 mutation frequency in Korean patients was significantly higher than those for Caucasians (2.7%) and the Japanese (19.8%). The African-American specific m3 mutation and m4 mutation found in Caucasians were not discovered in this study. The CYP1A1 allele with novel mutation was also not present. PMID- 10102577 TI - Characterization of two new channel protein genes in Arabidopsis. AB - Aquaporins, small channel proteins, found in a variety of organisms are members of the major intrinsic protein (MIP) superfamily and have been shown to facilitate water transport when expressed in Xenopus oocytes. We isolated two Arabidopsis cDNAs, SIMIP and SITIP, that encode protein homologues of the MIP superfamily. SIMIP exhibits a high degree of sequence homology to PIP3 and MIP1, and thus may belong to the plasmamembrane intrinsic protein (PIP) subfamily, whereas salt-stress inducible tonoplast intrinsic protein (SITIP) is highly homologous to VM23 and gamma-TIP, and therefore may belong to the TIP subfamily. Expression studies revealed that the two genes showed a different expression pattern. The SIMIP gene was expressed in a tissue-specific manner, for example, its highest transcript level is found in flowers, relatively low levels in siliques, and very low level in leaves and roots. In contrast, SITIP was expressed in nearly equal amounts in all the tissues we examined. Also, the expression of SIMIP and SITIP showed a temporal regulation pattern. For example, the highest expression level was at 1 week after germination. In addition, the transcript levels of SIMIP and SMTIP were increased upon NaCl and ABA treatments. The biological function of the 2 genes were investigated using two NaCl stress sensitive yeast mutant strains. The mutant yeast cells expressing these 2 genes were more resistant to high NaCl conditions. The results suggest that the proteins encoded by these genes may be involved in the osmoregulation in plants under high osmotic stress such as under a high salt condition. PMID- 10102578 TI - Reactive cysteine residue of bovine brain glutamate dehydrogenase isoproteins. AB - Protein chemical studies of glutamate dehydrogenase isoproteins (GDH I and GDH II) from bovine brain reveal that one cystein residue is accessible for reaction with thiol-modifying reagent. Reaction of the two types of GDH isoproteins with p chloromercuribenzoic acid resulted in a time-dependent loss of enzyme activity. The inactivation followed pseudo first-order kinetics with the second-order rate constant of 83 M(-1) s(-1) and 75 M(-1) s(-1) for GDH I and GDH II, respectively. The inactivation was partially prevented by preincubation of the glutamate dehydrogenase isoproteins with NADH. A combination of 10 mM 2-oxoglutarate with 2 mM NADH gave complete protection against the inactivation. There were no significant differences between the two glutamate dehydrogenase isoproteins in their sensitivities to inactivation by p-chloromercuribenzoic indicating that the microenvironmental structures of the GDH isoproteins are very similar to each other. Allosteric effectors such as ADP and GTP had no effects on the inactivation of glutamate dehydrogenase isoproteins by thiol-modifying reagents. By a combination of peptide mapping analysis and labeling with [14C] p chloromercuribenzoic acid, a reactive cystein residue was identified as Cys323 in the overall sequence. The cysteine residue was clearly identical to sequences of other GDH species known. PMID- 10102579 TI - Octamer motif is required for the NF-kappaB-mediated induction of the inducible nitric oxide synthase gene expression in RAW 264.7 macrophages. AB - The promoter of the mouse inducible nitric oxide synthase (iNOS) has a putative octamer motif (ATGCAAAA) which exists 24 bp upstream from the TATA box and is mismatched at a single residue from the consensus octamer motif. To examine whether this site is involved in iNOS expression, we constructed various deletions and site-directed mutants of the iNOS promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene, transfected the constructs into RAW 264.7 macrophages, and stimulated the cells with interferon-gamma (IFN gamma) and/or lipopolysaccharide (LPS). CAT activity was not induced by LPS in constructs containing only the octamer motif (-71 to +82), but was induced with constructs containing the octamer motif and the upstream sequences of the NF kappaB site (-91 to +82). However, a site-directed mutation of the octamer motif in the context of the -91 to +82 promoter construct or an extended promoter construct (-1542 to +82) abolished IFN-gamma and/or LPS-induced CAT activity. Similar results were obtained from site-directed mutants at either the NF-kappaB site or both the NF-kappaB site and octamer motif in these two constructs. In addition, we demonstrated that the conversion of the iNOS octamer motif into a consensus sequence increased CAT activity. Electrophoretic mobility shift assay (EMSA) performed with the NF-kappaB site or the octamer motif-containing oligonucleotide probe revealed that NF-kappaB binding was induced by LPS treatment, while the Oct-1 binding was constitutive. Competition assays performed with octamer-related oligonucleotide competitors derived from the immunoglobulin kappaB or SV40 promoter confirmed the identity of the iNOS promoter sequence as being a Oct-1 binding site. EMSA carried out using a probe containing both the NF kappaB site and the octamer motif identified two LPS-induced complexes. Competition assays with each NF-kappaB site or octamer motif competitor revealed that NF-kappaB and Oct-1 were present in these two complexes. These data suggest that, besides the NF-kappaB site, the octamer motif is essential for the maximal expression of the iNOS gene in murine macrophages, and the direct interaction of Oct-1 and NF-kappaB is important for the regulation of this gene. PMID- 10102580 TI - Release of copper ions from the familial amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutants. AB - Point mutations of Cu,Zn-superoxide dismutase (SOD) have been linked to familial amyotrophic lateral sclerosis (FALS). We reported that the Swedish FALS Cu,Zn-SOD mutant, D90A, exhibited an enhanced hydroxyl radical-generating activity, while its dismutation activity was identical to that of the wild-type enzyme (Kim et al. 1998a; 1998b). Transgenic mice that express a mutant Cu,Zn-SOD, Gly93 --> Ala (G93A), have been shown to develop amyotrophic lateral sclerosis (ALS) symptoms. We cloned the cDNA for the FALS G93A mutant, overexpressed the protein in E. coli cells, purified the protein, and studied its enzymic activities. Our results showed that the G93A, the D90A, and the wild-type enzymes have identical dismutation activity. However, the hydroxyl radical-generating activity of the G93A mutant was enhanced relative to those of the D90A and the wild-type enzyme (wild-type < D90A < G93A). These higher free radical-generating activities of mutants facilitated the release of copper ions from their own molecules (wild type < D90A < G93A). The released copper ions can enhance the Fenton-like reaction to produce hydroxyl radicals and play a major role in the oxidative damage of macromolecules. Thus, the FALS symptoms may be associated with the enhancements in both the free radical-generating activity and the releasing of copper ions from the mutant enzyme. PMID- 10102581 TI - Dentistry's social contract. PMID- 10102582 TI - Unfavorable splits in sagittal split osteotomy. PMID- 10102583 TI - Oral verrucous carcinoma. PMID- 10102584 TI - Oral and maxillofacial pathology. PMID- 10102585 TI - Critical systemic and psychosocial considerations in management of trauma in the elderly. AB - Traumatic injuries in the elderly are increasing commensurately with the activeness and healthiness of the lifestyles seen in our expanding geriatric population. Census data suggest that the elderly population will expand by 50% in future years and will represent a larger percentage of Americans by the year 2050. The annual occurrence of traumatic injuries in the elder cohort is reported to be as high as 29%. Perioperative management of acutely injured elderly patients is different from the care rendered to younger patients and is typically more complex. The purposes of this article are to (1) review factors related to aging that may have profound effects on the care and outcomes of senior citizens with craniofacial trauma, (2) consider the perioperative medical evaluation of the older patient, (3) discuss nutritional support and anesthetic management in the elderly, (4) discuss the unique physiological factors that may influence the treatment of craniofacial trauma in older patients, and (5) provide a rationale for facial trauma repair in the elderly that is influenced by the risk-benefit outcome of treatment planning decisions. PMID- 10102586 TI - Ischemic heart disease. AB - Imbalances between myocardial oxygen delivery and oxygen demand result in ischemic heart disease. Accurate stratification of risk for permanent myocardial injury and appropriate choice of therapy are critical in the successful management of ischemic heart disease. Dental therapy can be performed safely for most ambulatory patients with ischemic heart disease. PMID- 10102587 TI - Anesthetic efficacy and heart rate effects of the supplemental intraosseous injection of 2% mepivacaine with 1:20,000 levonordefrin. AB - OBJECTIVE: The purpose of this study was to determine the anesthetic efficacy and heart rate effects of a supplemental intraosseous injection of 2% mepivacaine with 1:20,000 levonordefrin. STUDY DESIGN: Through use of a repeated-measures design, 40 subjects randomly received 3 combinations of injections at 3 separate appointments. The combinations were as follows: inferior alveolar nerve (IAN) block (with 3% mepivacaine) + intraosseous injection of 1.8 mL of 2% mepivacaine with 1:20,000 levonordefrin; IAN block + intraosseous injection of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine (positive control); IAN block + mock intraosseous injection (negative control). Each first molar, second molar, and second premolar was blindly tested with a pulp tester at 2-minute cycles for 60 minutes after injection. Anesthesia was considered successful when 2 consecutive readings of 80 were obtained. Heart rate (pulse rate) was measured with a pulse oximeter. RESULTS: One hundred percent of the subjects had lip numbness with the IAN block + intraosseous mock technique and IAN block + intraosseous techniques. The anesthetic success rates for IAN block + mock intraosseous injection, IAN block + intraosseous lidocaine, and IAN block + intraosseous mepivacaine, respectively, were as follows: 80%, 100%, and 100% for the first molar; 90%, 100%, and 100% for the second molar; 77%, 97%, and 97% for the second premolar. For the first molar and second premolar, the differences were significant (P< .05) when the intraosseous mepivacaine and lidocaine techniques were compared with the IAN block + mock intraosseous injection. There were no significant differences between the intraosseous mepivacaine and lidocaine techniques. Eighty percent of the subjects had a mean increase in heart rate of 23-24 beats per minute with the intraosseous injection of the mepivacaine and lidocaine solutions; there were no significant differences between results with the 2 solutions. CONCLUSIONS: We concluded that intraosseous injection of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 2% mepivacaine with 1:20,000 levonordefrin, used to supplement an IAN block, significantly increased anesthetic success in first molars and second premolars. The 2 solutions were equivalent with regard to intraosseous anesthetic success rate, failure rate, and heart rate increase after IAN block. PMID- 10102588 TI - Increase in the threshold of pain and touch sensation in the human face with clonidine plus 30% nitrous oxide. AB - OBJECTIVE: This study was undertaken to assess the effects of clonidine combined with 30% nitrous oxide on tactile and pain sensations in the human face. STUDY DESIGN: Thirty-three subjects were involved in the study. The subjects were divided into 4 groups: 100% oxygen with placebo; 30% N2O with placebo; 100% oxygen with clonidine (0.075 mg), and 30% N2O with clonidine. Three tests for the threshold of pain sensation and tactile sensation were made at 60 minutes before and 0, 15, and 30 minutes during N2O or O2 inhalation. RESULTS: (1) The N2O with clonidine significantly increased the threshold of pain and tactile sensation in comparison with the other 3 treatments. (2) In terms of pain sensation, both N2O and clonidine showed significant increases in threshold of pain in comparison with the control values. CONCLUSIONS: These results indicate that the analgesic effects of 30% nitrous oxide are enhanced when use of the gas is combined with prior clonidine administration. PMID- 10102589 TI - Long-term histologic changes in the dental pulp after posterior segmental osteotomies. AB - OBJECTIVE: The purpose of this study was to examine pulp tissue for 18 months after segmental osteotomy in nonhuman primates. STUDY DESIGN: In this long-term experimental study, subapical, posterior, maxillary, and mandibular osteotomies were done in 26 baboons (Papio ursinus). Baboons were killed humanely immediately after operation and at 3, 6, 12, and 18 months, when tissues were perfusion fixed. Longitudinal step-serial sections of dental pulps were examined. RESULTS: There was a loss of the odontoblast layer as early as 3 months after surgery. Inflammatory cell infiltrate was most marked in the early postoperative stages, and the formation of osteodentin and secondary dentin was evident after 6 months. Foci of necrosis were present in the 3-month and 6-month groups but were replaced by pulp fibrosis in the 12-month and 18-month groups. All these changes were more frequent in experimental than control teeth. CONCLUSIONS: The histologic changes seen should not affect the prognosis of teeth in subapical osteotomy segments if clinicians are careful not to damage root apices and do regular, careful, clinical, and radiographic follow-up examinations. Because many pulps healed spontaneously in the study teeth, endodontic treatment should be delayed until it is clearly needed. PMID- 10102590 TI - Symptoms of unerupted mandibular third molars. AB - OBJECTIVE: The purpose of this study was to analyze the occurrence of symptoms in patients with unerupted mandibular third molars and to investigate the associated pathoses. STUDY DESIGN: Through a review of clinical records and periapical radiographs of completely unerupted and partially erupted mandibular third molars, a retrospective study was carried out. For each axial inclination, symptoms and pathoses associated with these teeth were analyzed. Statistical differences were tested by chi square analysis. RESULTS: Most of the patients were between 16 and 30 years of age. In 83% of cases, the mandibular third molars were partially erupted; in the other 17% of cases, the mandibular third molars were completely unerupted. Pain was the most frequent symptom in both groups. Pericoronitis was found mostly in third molar teeth with vertical and distal inclinations (P< .05), whereas caries was found mainly in mesially tipped third molars (P < .05). CONCLUSIONS: Most of the patients were in the third decade of life. Partially erupted mandibular third molars had more symptoms than completely unerupted teeth. Pain and pericoronitis were the most common problems in patients with unerupted third molars. PMID- 10102591 TI - Periodontal treatment and its effects on glycemic control: a review of the evidence. AB - Persisting poor glycemic control has been shown to be associated with the incidence and progression of diabetes-related complications. The bulk of oral health-related research has focused on the impact of diabetes on periodontal health, yet there are several lines of evidence to support the plausibility of the notion that periodontal infections contribute to problems with glycemic control. This article reviews the body of English-language literature containing reports of clinical research that has considered the relationship between treatment of periodontal diseases and improvement in glycemic control in humans. Although there is supportive clinical and epidemiologic evidence, equivocal and contrary evidence also exists. It is concluded from this review that the quantity, breadth, and strength of evidence-based knowledge are currently insufficient to establish periodontal therapy as influential in improving glycemic control in either type 1 or type 2 diabetes. Further rigorous, systematic study of the effects of treating periodontal infection on glycemic control is warranted. PMID- 10102592 TI - Disturbances in oral and dental structures in patients with pediatric lymphoma after chemotherapy: a preliminary report. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of chemotherapy on oral and dental structures and craniofacial growth in 30 survivors of childhood lymphoma. STUDY DESIGN: Eruption status, root malformations, premature apexification, agenesis, crown anomalies, soft tissue abnormalities, gingival and periodontal status, enamel defects and discolorations, and craniofacial growth status of the subjects were documented and compared with findings in 20 healthy children who served as controls. RESULTS: Statistically significant (P < .05) differences between the study and control groups were found for plaque index, enamel hypoplasias, discolorations, and agenesis. CONCLUSIONS: The results of the study suggest that antineoplastic therapy and/or childhood cancer can result in a higher prevalence of various malformations in teeth. Children treated in the early years of their lives displayed the most severe dental defects, suggesting that immature teeth are at a greater risk of developmental disturbances than fully developed teeth. PMID- 10102593 TI - Pyodermatitis-pyostomatitis vegetans: report of a case and review of the literature. AB - Pyodermatitis-pyostomatitis vegetans is a benign, rare disorder characterized by a pustular eruption in the oral mucosa and vegetating plaques involving the groin and axillary folds. Its association with inflammatory bowel disease is well established. We report the case of a 49-year-old-white man with ulcerative colitis who manifested a vegetating, annular plaque in the left inguinal region of 2 months' duration. Oral examination disclosed an erythematous mucosa with multiple painful pustules involving the labial and gingival mucosa. Histopathologic study demonstrated epidermal hyperplasia and an inflammatory infiltrate composed mostly of neutrophils and eosinophils, grouped into microabscesses within the epidermis and with a bandlike configuration in the upper dermis. Results of direct and indirect immunofluorescence studies were negative. We discuss the differential diagnosis between pyodermatitis pyostomatitis vegetans and pemphigus vegetans. PMID- 10102594 TI - Pyostomatitis vegetans associated with asymptomatic ulcerative colitis: a case report. AB - Pyostomatitis vegetans, a rare pustular disorder of the oral mucosa, is a highly specific marker for inflammatory bowel disease and may be difficult to treat. A case of pyostomatitis vegetans in a patient with long-standing asymptomatic ulcerative colitis is presented. Complete remission was achieved with topical steroids; no systemic treatment was required. PMID- 10102595 TI - Multiple sialoliths and a sialolith of unusual size in the submandibular duct: a case report. AB - A 49-year-old man with multiple sialoliths in the submandibular duct is described. One of the sialoliths was of remarkable size. This report is of interest because of the unusual size and weight of this sialolith and because of the patient's symptoms, which were relatively mild and of short duration. PMID- 10102596 TI - Intraosseous fibrous lesions of the jaws: a manifestation of tuberous sclerosis. AB - Four patients previously diagnosed with tuberous sclerosis are reported with intraosseous fibrous lesions of the jaws. Review of the literature revealed comparable pathosis occurring in extragnathic bones and several previous reports of similar lesions within the jaws. Therefore, these intraosseous fibrous proliferations are thought to represent an intraoral manifestation of tuberous sclerosis and not coincidental findings. In all 4 cases, the tumors demonstrated significant collagenization with numerous interspersed plump fibroblasts. Although histopathologically similar, the features of the lesions are not specific and also can be found in desmoplastic fibromas and simple odontogenic fibromas. The definitive diagnosis requires appropriate clinicopathologic correlation. PMID- 10102597 TI - A case of metastasizing pleomorphic adenoma. AB - The pleomorphic adenoma is the most common benign salivary neoplasm. A case is presented in which a palatal pleomorphic adenoma seeded a metastasis in the medullary cavity of the anterior maxilla, apparently by hematogenous spread after surgical manipulation. PMID- 10102598 TI - Multiple canalicular adenomas: a case report and review of the literature. AB - The canalicular adenoma is an uncommon, benign salivary gland tumor that most frequently occurs in the upper lip. Rarely, it manifests itself clinically and histologically as a multifocal lesion, a feature not generally seen with other intraoral salivary gland tumors. Here we report a case of canalicular adenoma that manifested itself with 13 clinically discrete tumor masses involving the upper lip and anterior buccal mucosa. In addition to the clinical nodules, there were microscopic foci of tumor cells in the adjacent normal-appearing salivary gland tissue surrounding the tumors. This article also reviews previously reported multifocal canalicular adenomas and discusses their features, emphasizing differences in the reported growth patterns of this unusual tumor. PMID- 10102599 TI - Bizarre parosteal osteochondromatous proliferation in the anterior maxilla: report of a case. AB - Bizarre parosteal osteochondromatous proliferations are a rare subgroup of the osteochondromatous lesions. They must be differentiated from reactive osteochondromatous proliferations, low grade parosteal osteogenic sarcoma, and chondrosarcoma. Their recognition is important from the point of view of management, which should be by simple excision. This article describes a case of bizarre parosteal osteochondromatous proliferation in a 2-year-old child; the lesion developed in the anterior maxilla, a previously unreported site. PMID- 10102600 TI - Massive osteolysis of the mandible: report of a case with multifocal bone loss. AB - Osteolysis of the jaws has been reported in association with infection, cysts, neoplasia, and metabolic, endocrine, or hematologic abnormalities. Rare cases of idiopathic osteolysis have also been recorded. We report the case of a 10-year old girl with mandibular basal and alveolar bone resorption that has continued over a period of 9 years. The patient has subsequently developed bilateral resorption of the ascending rami and condyles. The maxilla is uninvolved. Investigations included radiology, computerized tomography, scintigraphy, hematology, serum chemistry, endocrinology, histopathology, microbiology, and immunology. Neutrophil chemotaxis, chemiluminescence, and random migration values were low but within the normal range. These findings are interpreted as indicating an unusual variant of massive osteolysis. PMID- 10102601 TI - A comparison of 2 topical anesthetics on the discomfort of intraligamentary injections: a double-blind, split-mouth volunteer clinical trial. AB - OBJECTIVE: The purpose of this volunteer clinical trial was to compare the effects of 5% lidocaine ointment and EMLA cream on the discomfort associated with intraligamentary injections. STUDY DESIGN: A double-blind, split mouth study was conducted. Each of 10 healthy volunteers had 5% lidocaine and EMLA cream applied to the maxillary premolar buccal gingiva for 5 minutes before the administration of an intraligamentary injection. Discomfort during the injection was assessed through use of a visual analog scale. Data were analyzed by means of Student paired and unpaired t tests. RESULTS: Injection discomfort on the side on which EMLA cream was applied was significantly less than on the lidocaine side (t = 2.32, P < .05). CONCLUSIONS: EMLA cream reduced the discomfort associated with intraligamentary injections. PMID- 10102602 TI - Effect of chloroform, xylene, and halothane on enamel and dentin microhardness of human teeth. AB - OBJECTIVE: The purpose of this study was to assess in vitro the effect of commonly used gutta-percha solvents on the microhardness of human enamel and dentin. STUDY DESIGN: Crowns of human teeth were cut and treated with chloroform, xylene, and halothane. Treatment consisted of exposing the specimens for 5 or 15 minutes to the test solvents. Acid-treated and saline-treated specimens served as controls. After each treatment period, the specimens were rinsed, dried, and prepared for Vicker's microhardness analysis. Vicker's microhardness values for each specimen were recorded before and after treatment, and the differences were statistically compared. RESULTS: A statistically significant decrease in enamel and dentin microhardness was found in most solvent-treated groups; the amount of the decrease was directly related to the exposure time. CONCLUSIONS: Chloroform, xylene, and halothane may cause a significant softening effect on both enamel and dentin. This softening is already apparent after 5 minutes of treatment. PMID- 10102603 TI - 2-D and 3-D reconstructions of spiral computed tomography in localization of the inferior alveolar canal for dental implants. AB - OBJECTIVE: The purpose of this study was to compare and validate the accuracy of measurements on 2-dimensional and 3-dimensional reconstructions from spiral computed tomography in localization of the inferior alveolar canal. STUDY DESIGN: Four edentulous human cadaver heads with intact mandibles were imaged in a spiral computed tomography scanner. The data were transferred to a networked computer workstation to generate 2-dimensional orthoradially reformatted and 3-dimensional volumetric images. Linear measurements of the images were made from the superior border of the inferior alveolar canal to the alveolar crest. The specimens were then dissected at corresponding locations, and physical measurements were made. RESULTS: There were no statistically significant differences between the 2 dimensional computed tomography measurements and the physical measurements or between the 3-dimensional computed tomography measurements and the physical measurements. However, we did find a statistically significant difference between the 2-dimensional and 3-dimensional computed tomography measurements. CONCLUSIONS: 2-dimensional and 3-dimensional computed tomography images allow accurate measurements for localization of the inferior alveolar canal. PMID- 10102604 TI - Optimum dental radiography in bone marrow transplant patients. AB - OBJECTIVE: The purpose of this study was to establish an optimum radiographic examination regimen for patients undergoing bone marrow transplantation. Two radiographic examinations were compared: the panoramic radiograph and the full mouth series of radiographs. STUDY DESIGN: A prospective analysis of 65 consecutive patients undergoing bone marrow transplantation was undertaken. All patients were examined through use of both panoramic and full mouth series intraoral radiographs, including bitewings. Significant findings were recorded and compared by means of paired t test analysis for parametric data, such as caries, periapical inflammation and subgingival calculus, and by means of McNemar's test for nonparametric data, such as the presence or absence of severe periodontal disease. RESULTS: Acquired findings, such as caries, periodontal disease, and clinically significant faulty restorations, were detected more frequently from the full mouth series (P < .05). There was no significant difference in the detection of periapical pathosis. In 8 of 65 patients, clinically significant information, such as evidence of impacted wisdom teeth, neoplasms, and multiple myeloma, was better detected from the panoramic radiographs. CONCLUSIONS: The results suggest a combination of both modalities as the optimum means of radiologic survey in this "high-risk" patient population. PMID- 10102605 TI - Age and gender differences in temporomandibular joint radiographic findings before orthodontic treatment in adolescents. AB - OBJECTIVE: The purpose of this study was to determine whether there is a relationship between abnormal temporomandibular joint radiographic findings and age or gender in a sample of young preorthodontic patients. STUDY DESIGN: A total of 491 consecutive patients, aged 9 to 15 years, were referred for orthodontic records. Routine preorthodontic radiographs, including corrected sagittal tomographs, were taken for each patient and viewed by an observer blinded to clinical records. Temporomandibular joint radiographic findings were classified as normal or abnormal. For comparative purposes, the study population was divided into 2 age groups (9-11 years and 12-15 years). RESULTS: Frequency of abnormal findings ranged from 2.4% to 11.5% and was similar for both sides. Temporal component abnormalities correlated with abnormalities of condylar position, joint space, and condylar osseous morphology. The frequency of osseous abnormalities was higher in girls and highest in older girls. CONCLUSIONS: There are significant differences between genders for some temporomandibular joint radiographic abnormalities, and in our study sample the frequency of abnormalities was highest in 12-to-15-year-old girls. PMID- 10102606 TI - The effect of multiple examinations on the diagnosis of approximal caries and the restoration of approximal surfaces. AB - OBJECTIVE: The aim of this study was to determine the effect of multiple examinations on sensitivity and specificity in the diagnosis and restoration of approximal caries. STUDY DESIGN: In 2 studies, dentists examined bitewing radiographic films for approximal caries and the need for restoration. To model the clinical situation of multiple examinations over time, all groups of combinations of 2 to 10 dentists were constructed. Mean sensitivity and specificity were determined. In addition, 2 new variables were created: the first, "sensitivity any," was calculated by assigning a correct diagnosis for disease if any dentist in the group identified the diseased surface correctly; the second, "specificity all," was calculated by assigning a correct response only when all dentists in the group correctly identify a nondiseased surface. RESULTS: The sensitivity and specificity means were the same for all group sizes. The "sensitivity any" means increased monotonically from group size 1 to group size 10, whereas the "specificity all" means decreased continually. There was a statistically significant difference between sensitivity and "sensitivity any" and between specificity and "specificity all" for all group sizes in both studies. CONCLUSIONS: Multiple examinations increase the number of carious surfaces correctly diagnosed and the number of surfaces appropriately restored; however, multiple examinations also increase the number of sound surfaces diagnosed as carious and the number of intact surfaces receiving restorations. PMID- 10102607 TI - Predictors of recurrent dysplasia after a cervical loop electrocautery excision procedure for CIN-3: a study of margin, endocervical gland, and quadrant involvement. AB - Loop electrocautery excision procedure (LEEP) increasingly is being used for the treatment of cervical intraepithelial neoplasia (CIN). Few published studies address the possible correlation between the histologic findings of the LEEP cone biopsy and the incidence of residual/recurrent dysplasia We identified 248 patients with CIN-3 treated by LEEP at the University of North Carolina from September 1991 through September 1996. Computerized files of these patients were then reviewed through August 1997 for pathology follow-up results. Two hundred patients had pathology follow-up and interpretable material. LEEP cone slides were reviewed to confirm CIN-3 and to assess involvement of margins, endocervical glands, and multiple quadrants. Cytologic and histologic follow-up data were categorized as negative or positive, with the latter including high-grade squamous intraepithelial lesions, low-grade squamous intraepithelial lesions, and atypical squamous cells of undetermined significance. Fifty-five patients (27.5%) had residual/recurrent dysplasia, including 36 high-grade squamous intraepithelial lesions (66%), 14 low-grade squamous intraepithelial lesions (25%), and 5 atypical squamous cells of undetermined significance (9%). Greater recurrence rates were noted for cases with high-grade dysplasia involving margins (39% positive vs. 15% negative; P = .0001), endocervical glands (33% positive vs. 14% negative; P = .0044), and multiple quadrants (33% multiple vs. 14% single; P = .0036). In cases with negative margins, greater recurrence rates were still observed with high-grade dysplasia involving endocervical glands (20% positive vs. 9% negative; P = .0808) and multiple quadrants (20% multiple vs. 8% single; P = .0495). Positive margins, positive glands, and multiple quadrant disease are all predictors of residual/recurrent dysplasia after LEEP. Surgical pathology reports for LEEP cone biopsy specimens should include information on the presence of high-grade dysplasia involving margins, endocervical glands, and multiple quadrants. Continued close follow-up is especially warranted for patients whose LEEP cone biopsy specimens contain any of these histologic predictors of residual/recurrent dysplasia. PMID- 10102608 TI - Suppression of apoptosis does not foster neoplastic growth in Barrett's esophagus. AB - Esophageal adenocarcinoma often arises in association with metaplastic and dysplastic mucosa in Barrett's esophagus. Derangements in cell cycle control and apoptosis regulation might be responsible for the progression from metaplasia to dysplasia and adenocarcinoma We tested this hypothesis by performing cell cycle analysis, in situ detection of apoptosis, and evaluation for the immunohistochemical expression of proteins involved in proliferation (Ki-67), the control of apoptosis (bcl-2, bcl-x and bax), and cell cycle regulation (retinoblastoma and cyclin D1). We studied 17 randomly selected paraffin-embedded esophagectomy specimens that contained intestinal metaplasia without dysplasia, low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma Compared with gastric controls and intestinal metaplasia without dysplasia, high-grade dysplasia and esophageal adenocarcinoma demonstrated greater numbers of cells in S phase and G2 phase. Comparison of the proliferation index and the apoptotic rate in intestinal metaplasia without dysplasia, low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma showed a statistically significant trend that linked an increasing proliferation index and apoptotic rate with increasing histologic severity (P = .006 and P = .0002, respectively). A statistically significant linear association was found between bcl-x expression, bax expression, and the bcl-2-to-bax expression ratio versus increasing histologic severity (P = .0004, P = .007, and P = .03, respectively). These data support the hypothesis that neoplastic transformation of intestinal metaplastic epithelium in the esophagus might result from sequential changes in the expression of proteins involved in the control of apoptosis and the cell cycle. Furthermore, suppression of apoptosis does not seem to foster neoplastic growth in Barrett's esophagus. These observations will lead to a better understanding of the pathogenesis of esophageal adenocarcinoma and might contribute to enhancing the diagnostic accuracy when presented with dysplastic lesions. PMID- 10102609 TI - Overexpression of p53 protein associates decreased response to chemoradiotherapy in patients with esophageal carcinoma. AB - Induction chemoradiotherapy before esophagectomy for esophageal carcinoma seems to improve patient survival. Given the toxicity of this regimen, it would be useful to predict those patients likely to benefit. p53 is known to mediate apoptosis in response to DNA damage, but there are few data evaluating the relationship between p53 expression and chemoradiosensitivity in human tissues. We immunohistochemically evaluated p53 protein expression in 95 biopsy specimens from patients with esophageal carcinoma before chemoradiotherapy. p53 expression was correlated to the pathologic response identified in subsequent esophagectomy specimens. p53 immunoreactivity was recorded semiquantitatively using the following scale: neg, < 5%; 1+, 5-25%; 2+, 26-50%; 3+, 51-75%; 4+, > or = 76%. Pathologic response in esophagectomy specimens was categorized as overt residual tumor (ORT), minimal residual tumor, and no residual tumor. Of the 95 patients, 64 had adenocarcinoma, and 31 had squamous cell carcinoma. Of those with adenocarcinoma, 46 (72%) of 64 were positive for p53. Thirty-seven (80%) of 46 p53+ patients had ORT, compared with 4 (22%) of 18 p53- patients (P < .001). There was no correlation between the degree of p53 staining and pathologic response. Of those with squamous cell carcinoma, 13 (42%) of 18 were positive for p53. Three (23%) of 13 p53+ patients had ORT, compared with 4 (22%) of 18 p53- patients (P = .96). Our data indicate that overexpression of p53 protein is associated with decreased responsiveness to induction chemoradiotherapy in patients with esophageal adenocarcinoma but that no such association exists in patients with esophageal squamous cell carcinoma. PMID- 10102610 TI - Idiopathic fibroinflammatory (fibrosing/sclerosing) lesions of the mediastinum: a study of 30 cases with emphasis on morphologic heterogeneity. AB - The clinicopathologic and immunohistochemical findings in 30 cases of idiopathic fibroinflammatory lesions of the mediastinum are presented. There were 17 male and 13 female patients between 10 and 64 years of age; 19 were African-American, and 10 were Caucasian. Clinically, respiratory and/or systemic symptoms including cough, shortness of breath, and fever were present in 28 patients. Five patients also presented with evidence of superior vena cava syndrome. All of the lesions involved the anterior mediastinum with radiographic evidence of hilar and paratracheal involvement in nine and five patients, respectively. Histologically, the lesions were characterized by an inflammatory fibrosing process that showed three distinctive histologic patterns. On the basis of the histologic pattern, they were subdivided into three distinct groups (stages). Stage I demonstrated edematous fibromyxoid tissue with numerous spindle cells, eosinophils, mast cells, lymphocytes, plasma cells, and thin-walled blood vessels; Stage II showed thick glassy bands of haphazardly arranged collagen with focal interstitial spindle cells, lymphocytes, and plasma cells; and Stage III was characterized by dense acellular collagen with scattered lymphoid follicles and occasional dystrophic calcification. Immunohistochemical studies in 17 cases highlighted large numbers of vimentin- and actin-positive spindle cells and capillary-like vessels in Stage I lesions, with fewer numbers of vimentin-positive, actin negative spindle cells and vessels in Stage II lesions. Our findings suggest that "sclerosing mediastinitis" represents the final stage of an evolving, dynamic process with different morphologic appearances akin to abnormal wound healing. Thus, we propose the term fibroinflammatory lesion of the mediastinum to convey the true nature of the process. PMID- 10102611 TI - Clonal analysis of a solitary follicular nodule of the thyroid with the polymerase chain reaction method. AB - Solitary follicular nodules of the thyroid occasionally create a diagnostic problem, especially in the differential diagnosis between adenoma and nodular hyperplasia To obtain confident histologic parameters of clonal lesions, we analyzed DNA samples prepared from paraffin-embedded archival tissue from 20 solitary follicular nodules of the thyroid for clonality with the polymerase chain reaction (PCR) method. On the base of X chromosome inactivation mosaicism, we tested restriction fragment-length polymorphism of the phosphoglycerate kinase (PGK) gene and a highly polymorphic short tandem repeat of the human androgen receptor (HUMARA) gene. Of 18 informative cases, 10 were monoclonal, 7 were polyclonal, and 1 showed microsatellite instability. All of the five completely encapsulated nodules were monoclonal. Four of the five unencapsulated nodules showed polyclonality. Of the seven partially encapsulated nodules, four were monoclonal, and the others were polyclonal. The former showed 50% or more of encapsulation degree, whereas the latter showed less than 50%. The capsule tended to be thicker in monoclonal nodules (mean, 0.33 mm) than in polyclonal nodules (mean, 0.13 mm). Other histologic features of the nodules and surrounding parenchymal changes had no significance with respect to predicting clonality. This study suggests that the degree of encapsulation and capsular thickness are morphologically important for predicting the clonality of the thyroid nodule. PMID- 10102612 TI - The effect of fixation on detection of B-cell clonality by polymerase chain reaction. AB - It has been suggested that neutral buffered formalin (NBF)-fixed, paraffin embedded, or fresh specimens might provide satisfactory DNA templates for polymerase chain reaction (PCR) assays used in establishing the clonality and presumptive B-cell lineage of lymphoma. The suitability of other fixatives used by hematopathologists, such as B5, is still undetermined. Thirty cases were identified from the files of the Cleveland Clinic Foundation, Cleveland Ohio, that showed abnormal immunoglobulin heavy chain (IgH) rearrangement by Southern blot analysis (SBA). Corresponding paraffin-embedded tissue samples fixed in NBF (21 cases), B5 (18 cases), Hollande's fixative (17 cases), zinc formalin (ZF) (5 cases), and Bouin's fixative (3 cases) were studied. With use of consensus primers against the framework 3 (FR3) and FR2 regions of the VH gene, paired against JH primer(s), PCR analysis was performed. bcl-2/IgH translocation was also studied. Ten reactive lymphoid samples were used as controls, and 40 cases were evaluated. Successful amplification of a clonal proliferation was manifested as one or two discrete narrow bands in the appropriate size range. The sensitivity of detecting clonality was 95, 94, 67, 80, and 0% for NBF, Hollande's fixative, B5, ZF, and Bouin's fixative, respectively. Although NBF and Hollande's fixative were 100% specific, consistent false-positive results were a major problem with B5-fixed tissue. Paraffin-embedded tissue, fixed in NBF, Hollande's fixative, and ZF solutions, may be used for DNA extraction and PCR assays for establishing B-cell clonality. The precipitating fixative B5 and Bouin's solution should not be used for this purpose until the issue of false-positive results is resolved. PMID- 10102613 TI - Comparison of DNA ploidy, histologic, and immunohistochemical findings with clinical outcome in inflammatory myofibroblastic tumors. AB - Inflammatory myofibroblastic tumors (IMTs) are uncommon spindle cell proliferations that occur in the viscera and soft tissue of children and young adults. Their biologic potential is indeterminate: 25% of IMTs recur, and rare examples undergo malignant transformation (MT). This study investigates histologic features, DNA ploidy, and expression of apoptotic regulatory and oncogenic proteins in IMTs in an attempt to identify those deviances that might correlate with aggressive behavior or MT. Twenty-four formalin-fixed, paraffin embedded IMTs for which clinical outcome was known were evaluated for cellularity, cytologic atypia, mitoses, ganglion-like cells, inflammatory infiltrate, DNA ploidy by flow cytometric examination, and bax, bcl-2, p53, and c myc expression by immunohistochemical analysis. Sixteen (67%) of the IMTs did not recur, 6 (25%) recurred, and 2 (8%) underwent MT. Cellular atypia was observed in 69% of the cases without recurrence, 100% with recurrence, and 100% with MT. Ganglion-like cells were present in 56, 100, and 100% of the IMTs without recurrence, with recurrence, and with MT, respectively. There was no difference in the degree of cellularity, mitoses, or inflammatory infiltrate among the outcome groups. All of the tumors expressed bax, and none expressed c-myc. Two (8%) were immunoreactive for p53, one of which recurred and one of which underwent MT. bcl-2 expression was observed in 9 (37%) of the IMTs, with no difference among the three groups. Two IMTs were aneuploid, one of which underwent MT. Neither morphologic evaluation for cellularity, mitosis, or inflammatory infiltrate nor expression of bax or c-myc were useful for prediction of clinical outcome. The combination of atypia, ganglion-like cells, p53 expression and DNA ploidy analysis, however, might be useful to identify IMTs that might undergo MT or pursue a more aggressive clinical course with recurrences. PMID- 10102614 TI - Papillary transitional cell carcinoma of the breast: a report of five cases with distinction from eccrine acrospiroma. AB - Papillary carcinomas of the female breast exhibit a spectrum of morphologic appearances and might be mistaken for benign intraductal papillary lesions or papillary adnexal neoplasms. We report herein five cases of papillary carcinoma in which the epithelium closely resembled transitional cells of the urinary bladder. Grossly, the tumors had a nodular or papillary appearance, white, tan, or red in color. The microscopic features were those of an intraductal papillary proliferation of solid layers of epithelial cells overlying fibrovascular cores. The proliferating cells assumed a whorled or streaming growth pattern, with flattening of superficial cells. One case showed microinvasion. Comparison with a similar number of cases of the solid variant of papillary carcinoma of the breast showed a greater range of nuclear pleomorphism, mitotic counts, and a more varied immunohistochemical profile in the papillary carcinomas with transitional cell features. Eight cases of eccrine acrospiroma occurring in the female breast also displayed a solid or solid papillary pattern, with flattened superficial cells. These occurred in a younger age group, were located in the dermis or subcutis, and usually had zones of clear cells visible at low magnification. No evidence of recurrent or metastatic disease was found in the four patients for whom follow-up was available; the length of follow-up ranged from 18 months to 11 years. The stimulus for the development of this unusual phenotype is unclear, but the transitional-like variant seems to behave in a fashion similar to that of other types of papillary carcinoma of the breast. Distinction of this malignant lesion from various benign lesions that occur in the same region is mandatory. PMID- 10102615 TI - CD10 antigen expression correlates with the t(14;18)(q32;q21) major breakpoint region in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is a common morphologic term for a biologically diverse group of lymphomas. The chromosome translocation, t(14;18)(q32;q21), and its associated bcl-2 gene rearrangement are generally associated with follicular lymphomas. Some investigators, however, proposed that the presence of the t(14;18) in DLBCL suggests a possible follicle center cell origin and might correlate with a higher relapse rate after therapy. The CD10 antigen is expressed in a majority of follicular lymphomas but is also seen occasionally in DLBCLs. In this study, we examined 26 DLBCLs for CD10 expression by flow cytometric analysis and tested them for the t(14;18)(q32;q21) major breakpoint region by a polymerase chain reaction-based method. bcl-2 protein expression was analyzed by an immunoperoxidase method. Of the 26 DLBCLs, 9 (35%) were CD10 positive. bcl-2 protein was expressed in 7 (78%) of 9 CD10-positive cases and in 9 (53%) of 17 CD10-negative cases (P = .4). The t(14; 18) translocation was present in 6 (67%) of 9 CD10-positive cases but in only 2 (17%) of 12 CD10-negative cases (P = .03). Five cases did not yield amplifiable DNA for analysis. In summary, no difference in bcl-2 protein expression was seen in CD10 positive versus CD10-negative DLBCLs, but CD10-positive DLBCLs were significantly more likely than CD10-negative DLBCLs to harbor the t(14;18) translocation. This suggests that CD10 might be a marker of follicle center cell origin in DLBCL. PMID- 10102616 TI - Renal cell carcinoma of end-stage renal disease: an analysis of chromosome 3, 7, and 17 abnormalities by microsatellite amplification. AB - End-stage renal disease (ESRD) patients have an increased risk of carcinoma of the kidney, thought to result from development of a disproportionately high number of papillary renal cell carcinomas. This study was undertaken to discover whether these renal carcinomas have a deletion of the short arm of chromosome 3, which characterizes conventional (clear cell) carcinomas, or trisomies of chromosomes 7 and 17, which characterize the majority of sporadic papillary renal cell neoplasms. Archival specimens from 17 end-stage kidneys containing renal cell carcinomas were collected from 16 ESRD patients. DNA was extracted from paraffin blocks of tumor and nontumorous tissue. Microsatellites on the long and short arm of chromosomes 3, 7, and 17 were amplified in paired "normal" tumor samples. Heterozygous loci were analyzed for loss of heterozygosity, indicating a deletion, and for allele ratio differences, indicating a duplication. Successful microsatellite studies were obtained on 18 tumors (2 conventional carcinomas, 14 papillary carcinomas, 2 unclassified [solid, eosinophilic cell] carcinomas). Of the papillary carcinomas, none had a 3p deletion, five had trisomies of both chromosomes 7 and 17, six had no changes in chromosomes 7 and 17, and three had either trisomy 7 or trisomy 17 but not both. A 3p deletion was present in one of two conventional carcinomas. No chromosome 3, 7, or 17 changes were identified in the unclassified carcinomas. The genetic abnormalities in 6 of 18 ESRD tumors seemed to be the same as those found in sporadic papillary or conventional renal cell carcinomas. Nine of 14 papillary carcinomas did not show allelic duplications of chromosomes 7 and 17. This is uncharacteristic of the findings reported for most of the sporadic forms of the neoplasm and suggests that the genetic mechanism underlying the development of many papillary renal cell carcinomas in ESRD patients might be different than that of the general population. PMID- 10102617 TI - Chromophobe renal cell carcinoma: an immunohistochemical study of 21 Japanese cases. AB - Chromophobe renal cell carcinoma (RCC) is a newly established category of RCC composed histologically of characteristic "chromophobe" tumor cells. Although ultrastructural and immunohistochemical studies showed that these tumor cells present several features similar to those found in the intercalated cells of the collecting duct, immunohistochemical studies using antibody panels on a large number of cases are limited. We performed an immunohistochemical study of 21 Japanese cases of chromophobe RCC, along with cases of clear RCC and renal oncocytoma, to find hallmarks useful for precise differential diagnosis of these tumors. Chromophobe RCC was positive for epithelial membrane antigen but negative for vimentin. Cytokeratins did not show constant immunoreactivity in the three types of renal tumors. Furthermore, all of the chromophobe RCCs and renal oncocytomas were positive for E-cadherin but not for N-cadherin, whereas all of the clear RCCs were negative for E-cadherin, and 58% were positive for N cadherin. The Ki-67 labeling indices were significantly lower in cases classified as (pT1) or Grade 2 chromophobe RCC than in cases of clear RCC. Immunoreaction for E-cadherin was demonstrated to be useful for distinguishing chromophobe RCC from clear RCC, and a low Ki-67 labeling index might indicate a favorable prognosis, as reported in several previous studies. PMID- 10102618 TI - Prognostic value of thyroid transcription factor-1 in primary, resected, non small cell lung carcinoma. AB - Thyroid transcription factor-1 (TTF-1) is a 38-kDa nuclear protein expressed in thyroid follicular cells, in human fetal lung, and, after birth, in Type II epithelial cells of alveoli and in a subset of bronchial cells. Expression of TTF 1 was documented in neoplasms arising from cells that normally produce this transcription factor. In the present study, a series of surgically resected non small cell lung carcinomas (NSCLCs) was evaluated for the expression of TTF-1 protein, and the correlation between TTF-1 expression and patient survival was retrospectively tested. Ninety-six patients with primary NSCLC underwent surgical resection between 1987 and 1992. All of the tissue specimens from these patients were examined for TTF-1 protein expression by immunohistochemical analysis. Tumor immunoreactivity for TTF-1 was categorized into three groups (-, +, and ++), according to the percentage of reactive cells. The relationship between TTF-1 expression and postsurgical survival was analyzed for 88 patients [60 squamous cell carcinomas (SCCs) and 28 adenocarcinomas (ACs)]. TTF-1 stain was always limited to nuclei. Of the 96 specimens of NSCLC, 59 (61%) were scored as -, 20 (21%) as +, and 17 (18%) as ++. TTF-1 expression was significantly higher in ACs than in SCCs (P < .0001). Survival curves among the -, +, and ++ groups were significantly different (log rank test, P = .04). Multivariate analysis showed that NSCLCs in the ++ group were associated with a poor prognosis (P = .009), independent of node (P = .01) or stage status (P = .0006). When subsets of patients with SCC and with AC were separately analyzed, TTF-1 was found to have an independent prognostic value only in patients with SCC (P = .04). The results of this study suggest that immunoreactivity for TTF-1 in NSCLC closely relates to clinical outcome, especially in patients with SCC. PMID- 10102619 TI - Sarcoidosis with selective involvement of a second liver allograft: report of a case and review of the literature. AB - A case of sarcoidosis recurrent in a patient's second liver allograft is described. There was no granulomatous disease seen in the patient's first liver allograft. After the second orthotopic liver transplantation (OLT), the patient was successfully treated for acute rejection, aspergillus infection, and cytomegalovirus viremia. Approximately 2 months after the second OLT, the patient was treated with long-term interferon-alpha for recurrent hepatitis C. Five years after the operation, he experienced liver failure secondary to recurrent hepatitis and underwent a third OLT. This is only the second reported case of sarcoidosis recurrent in the liver parenchyma of a transplanted organ and the first in which interferon-alpha might have played a role. PMID- 10102620 TI - Benign nevus cell aggregates in the thymus: a case report. AB - Aggregates of benign nevus cells occurring in lymph nodes are a well-described incidental finding. Nevus cell aggregates (NCAs) can mimic foci of metastatic carcinoma or other disease processes, so the surgical pathologist should be familiar with this lesion. The purpose of this report is to describe the potential diagnostic difficulties created by benign NCAs within the thymus of a 32-year-old man with dysplastic nevus syndrome and malignant melanoma involving mediastinal lymph nodes and the right lung. Morphologically, the NCAs in this case elicited the differential diagnoses of metastatic melanoma and thymoma. Immunohistochemical studies helped to establish the correct diagnosis by demonstrating reactivity for S-100 protein and negative staining for keratin and HMB-45. Unlike malignant melanomas, NCAs show no p53 protein immunoreactivity, and low proliferative activity was detected by Ki-67 antigen immunostaining. Although melanocytic cells were rarely reported in thymic neoplasms, we are not aware of any previous reports of NCAs occurring in the normal thymus. PMID- 10102621 TI - Phosphorylation of p53 protein in response to ionizing radiation occurs at multiple sites in both normal and DNA-PK deficient cells. AB - The tumour suppressor gene product, p53, is involved in mediating cellular responses to DNA damage including growth arrest and/or apoptosis. The mechanism by which p53 protein senses the presence of damaged DNA is not understood. The possibility that p53 may be post-translationally modified by enzymes that are activated in response to DNA damage including DNA-dependent protein kinase (DNA PK), poly(ADP-ribose) polymerase and stress activated protein kinase has received considerable attention. Recent studies have indicated that DNA-PK is not required for the transactivation or apoptosis-promoting activities of p53 protein. However, the possibility that other functions of p53 may be dependent on phosphorylation by DNA-PK has not been explored. Here we describe a series of experiments that compares the expression, function and phosphorylation status of p53 protein in normal and DNA-PK-deficient scid cells. While several novel p53 phosphoforms are generated in response to DNA damage in normal cells, the same phosphoforms are observed in scid cells. PMID- 10102622 TI - Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. AB - The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identification of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and sufficient for production of pVHL18. pVHL18 can bind to elongin B, elongin C, and Hs-CUL2. When reintroduced into renal carcinoma cells that lack a wild-type VHL allele, pVHL18 suppresses basal levels of VEGF expression, restores hypoxia-inducibility of VEGF expression, and inhibits tumor formation in nude mice. These data strongly support the existence of two distinct VHL gene products in VHL tumor suppression. PMID- 10102623 TI - P53-dependent and -independent links between DNA-damage, apoptosis and mutation frequency in ES cells. AB - The hypothesis that p53 deficiency enhances the survival of DNA-damage bearing cells was investigated in wild-type and p53 mutant embryonic stem (ES) cells. Following UV-C irradiation, p53 is rapidly induced in wild-type cells and p53 dependent apoptosis follows within 8 h, resulting in the death of the majority of cells within 36 h. Increasing doses of UV-irradiation resulted in enhanced clonogenic survival of null cells as compared to wild-type. Amongst surviving clones, the Hprt mutation frequency was found to be dependent upon UV dose and influenced by p53 status. Treatment with ionizing radiation led to enhanced expression of p53 but resulted in little induction of apoptosis irrespective of p53 status. However, clonogenic potential was considerably reduced, particularly in wild-type cells which showed a tenfold lower survival than null cells. In contrast to the effects of UV-irradiation, the incidence of Hprt mutation did not differ significantly between wild-type and p53 null survivors. The data confirm that p53 restricts the numbers of cells bearing mutations that survive DNA damage induced by either agent, albeit by different mechanisms. PMID- 10102624 TI - Suppression of tumorigenicity in human ovarian cancer cell lines is controlled by a 2 cM fragment in chromosomal region 6q24-q25. AB - Multiple distinct regions of chromosome 6 are frequently affected by losses of heterozygosity in primary human ovarian carcinomas. We introduced a normal human chromosome 6 into HEY and SKOV-3 ovarian carcinoma cell lines using microcell mediated chromosome transfer techniques to further investigate the role of this chromosome in ovarian tumorigenesis. The exogenous chromosome was stably propagated in the recipient cells based on fluorescence in situ hybridization (FISH) analyses with a chromosome 6 painting probe. The tumorigenicity of HEY and SKOV-3 cells was completely suppressed after transfer of chromosome 6, but not after transfer of a chromosome 11q13-qter fragment used as control. Using 46 polymorphic microsatellite markers, the region bounded by D6S1649 and D6S1564 was found to be commonly deleted in HEY: chromosome 6 tumorigenic revertant clones. The boundaries of the commonly deleted region could be further narrowed down to a 2 cM (based on the Whitehead genetic map) or 0.36 megabase (based on gdb mapping data) region between D6S1637 and D6S1564 after transferring the exogenous chromosome from revertants into mouse L cells and performing allelic deletion mapping studies against this mouse background. We conclude that this region contains a tumor suppressor gene important for the control of ovarian tumor development. PMID- 10102625 TI - Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation. AB - Melanogenesis is a physiological process resulting in the synthesis of melanin pigments which play a crucial protective role against skin photocarcinogenesis. In vivo, solar ultraviolet light triggers the secretion of numerous keratinocyte derived factors that are implicated in the regulation of melanogenesis. Among these, tumor necrosis factor alpha (TNFalpha), a cytokine implicated in the pro inflammatory response, down-regulates pigment synthesis in vitro. In this report, we aimed to determine the molecular mechanisms by which this cytokine inhibits melanogenesis in B16 melanoma cells. First, we show that TNFalpha inhibits the activity and protein expression of tyrosinase which is the key enzyme of melanogenesis. Further, we demonstrate that this effect is subsequent to a down regulation of the tyrosinase promoter activity in both basal and cAMP-induced melanogenesis. Finally, we present evidence indicating that the inhibitory effect of TNFalpha on melanogenesis is dependent on nuclear factor kappa B (NFkappaB) activation. Indeed, overexpression of this transcription factor in B16 cells is sufficient to inhibit tyrosinase promoter activity. Furthermore, a mutant of inhibitory kappa B (IkappaB), that prevents NFkappaB activation, is able to revert the effect of TNFalpha on the tyrosinase promoter activity. Taken together, our results clarify the mechanisms by which TNFalpha inhibits pigmentation and point out the key role of NFkappaB in the regulation of melanogenesis. PMID- 10102626 TI - Immuno-histochemical detection of human telomerase catalytic component, hTERT, in human colorectal tumor and non-tumor tissue sections. AB - Human telomerase is expressed in germ tissues and in the majority of primary tumors. Cell renewal tissues and some pre-cancerous tissues also have weak telomerase activity. Yet, neither the exact location and frequency of telomerase positive cells nor the changes in telomerase expression during differentiation or carcinogenesis of individual cells are known. This paper reports on the expression of hTERT (telomerase reverse transcriptase) protein in tumor and non tumor colorectal tissues by Western blotting and tissue sections by immunohistochemistry using antibodies raised against partial peptides of hTERT. Though telomerase activity and hTERT expression at both mRNA and protein levels were generally higher in tumor part than in non-tumor part, these two were not always correlated: expression of hTERT did not always give rise to high telomerase activity. Colonic carcinoma cell nuclei were stained with anti-hTERT antibodies but not with antigen-preabsorbed antibodies. In normal mucosa, hTERT protein was expressed, though weaker than in carcinoma, in all colonic crypt epithelial cells except those at the tip; the expressing-cell distribution was much wider than that of Ki-67 positive cells which were located at the bottom of the crypt. Isolated crypt contained a significant level of hTERT protein revealed by Western blotting, while having very weak telomerase activity. Telomerase activity was detected in epithelial cells only at the bottom half of the crypt. Specific hTERT-staining was positive in tissue lymphocytes but negative in almost all other stromal cells. It is of interest to see whether a significant level of hTERT expression with low telomerase activity is characteristic of physiologically regenerating tissues containing stem cells. In situ detection of the hTERT protein will permit further analysis of cancer diagnosis and stem cell differentiation. PMID- 10102627 TI - CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes. AB - Previously, we have shown that nuclear extracts from cultured mouse keratinocytes induced to differentiate by increasing the levels of extra-cellular calcium contain Fra-1, Fra-2, Jun B, Jun D and c-Jun proteins that bind to the AP-1 DNA binding sequence. Despite this DNA binding activity, AP-1 reporter activity was suppressed in these cells. Here, we have detected the CREB family proteins CREB and CREMalpha as additional participants in the AP-1 DNA binding complex in differentiating keratinocytes. AP-1 and CRE DNA binding activity correlated with the induction of CREB, CREMalpha and ATF-1 and CREB phosphorylation at ser133 (ser133 phospho-CREB) in the transition from basal to differentiating keratinocytes, but the activity of a CRE reporter remained unchanged. In contrast, the CRE reporter was activated in the presence of the dominant-negative (DN) CREB mutants, KCREB and A-CREB, proteins that dimerize with CREB family members and block their ability to bind to DNA. The increase in CRE reporter activity in the presence of these mutants suggests that CRE-mediated transcriptional activity is suppressed in keratinocytes through protein-protein interactions involving a factor that dimerizes with the CREB leucine zipper. In experiments where the A-CREB mutant was co-transfected with an AP-1 reporter construct, transcriptional activity was also increased indicating that a CREB family member binds AP-1 sites and represses AP-1 transcriptional activity as well. Exogenous expression of the transcriptional repressor CREMalpha down regulated both CRE and AP-1 reporters in keratinocytes suggesting that this factor may contribute to the suppression of AP-1 transcriptional activity observed in differentiating keratinocytes. PMID- 10102628 TI - Expression of IkappaBalpha in the nucleus of human peripheral blood T lymphocytes. AB - According to current models the inhibitory capacity of I(kappa)B(alpha) would be mediated through the retention of Rel/NF-kappaB proteins in the cytosol. However, I(kappa)B(alpha) has also been detected in the nucleus of cell lines and when overexpressed by transient transfection. To gain better insight into the potential role of nuclear I(kappa)B(alpha) in a physiological context we have analysed its presence in the nucleus of human peripheral blood T lymphocytes (PBL). We demonstrate the nuclear localization of I(kappa)B(alpha) in PBL by different techniques: Western blot, indirect immunofluorescence and electron microscopy. Low levels of nuclear I(kappa)B(alpha) were detected in resting cells whereas a superinduction was obtained after PMA activation. The nuclear pool of I(kappa)B(alpha) showed a higher stability than cytosolic I(kappa)B(alpha) and was partially independent of the resynthesis of the protein. Unexpectedly, the presence of nuclear I(kappa)B(alpha) did not inhibit NF-kappaB binding to DNA and this phenomenon was not due to the presence of IkappaBbeta at the nuclear level. Immunoprecipitation experiments failed to demonstrate an association between nuclear I(kappa)B(alpha) and NF-kappaB proteins. Our results demonstrate that in resting and PMA-activated human PBL, I(kappa)B(alpha) is present in the nucleus in an apparently inactive form unable to disrupt NF-kappaB binding from DNA. PMID- 10102629 TI - The presence of the Rb c-box peptide in the cytoplasm inhibits p210bcr-abl transforming function. AB - In order to test if the carboxyl terminal polypeptide of the Retinoblastoma (Rb) tumor suppressor protein, could be used to suppress the growth factor-independent growth phenotype of p210bcr-abl positive myeloid cells, we introduced a truncated form of the 3' end of the Rb cDNA encoding its last 173 amino acid residues (Rb C box) which localize into the cytoplasm where the p210bcr-abl transforming protein is found, into myeloid cells (32D) which depends on the p210bcr-abl protein for IL3 growth factor-independent growth (32D-p210). The expression of the plasmid vectors carrying the Rb C-box cDNAs was shown to inhibit the abl tyrosine specific protein kinase activity of the p210(bcr-abl) oncoprotein and to suppress the IL3-independent growth phenotype of the 32D-p210 cells. The Rb C-box polypeptides did not suppress the growth of the untransfected 32D parental cell line in methylcellulose in the presence of IL3-conditioned medium. These results suggest that the cytoplasmic localization of the p210(bcr-abl) allows it to escape the effect of intranuclear proteins such as Rb which negatively regulate the p145(c-abl) kinase. PMID- 10102630 TI - FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts. AB - Friend virus-induced erythroleukemia involves two members of the ETS family of transcriptional regulators, both activated via proviral insertion in the corresponding loci. Spi-1/PU.1 is expressed in the disease induced by the original Friend virus SFFV(F-MuLV) complex in adult mice. In contrast, FLI-1 is overexpressed in about 75% of the erythroleukemias induced by the F-MuLV helper virus in newborn mice. To analyse the consequences of the enforced expression of FLI-1 on erythroblast differentiation and proliferation and to compare its activity to that of PU.1/Spi-1, we used a heterologous system of avian primary erythroblasts previously described to study the cooperation between Spi-1/PU.1 and the other molecular alterations observed in SFFV-induced disease. FLI-1 was found: (i) to inhibit the apoptotic cell death program normally activated in erythroblasts following Epo deprivation; (ii) to inhibit the terminal differentiation program induced in these cells in response to Epo and; (iii) to induce their proliferation. However, in contrast to Spi-1/PU.1, the effects of FLI-1 on erythroblast, differentiation and proliferation did not require its cooperation with an abnormally activated form of the EpoR. Enhanced survival of FLI-1 expressing erythroblasts correlated with the upregulation of bcl2 expression. FLI-1 also prevented the rapid downregulation of cyclin D2 and D3 expression normally observed during Epo-induced differentiation and delayed the downregulation of several other genes involved in cell cycle or cell proliferation control. Our results show that overexpression of FLI-1 profoundly deregulates the normal balance between differentiation and proliferation in primary erythroblasts. Thus, the activation of FLI-1 expression observed at the onset of F-MuLV-induced erythroleukemia may provide a proliferative advantage to virus infected cells that would otherwise undergo terminal differentiation or cell death. PMID- 10102631 TI - Different behavior of l-afadin and neurabin-II during the formation and destruction of cell-cell adherens junction. AB - We have recently isolated two novel actin filament-binding proteins, l-afadin and neurabin-II and shown that they are localized at cell-cell adherens junction (AJ) in epithelial cells. We found here that l-afadin, neurabin-II, ZO-1, and E cadherin showed similar and different behavior during the formation and destruction of cell-cell AJ in MDCK cells. In MDCK cells, the accumulation of both l-afadin and E-cadherin, but not that of ZO-1, changed in parallel depending on Rac small G protein activity. Dissociation of MDCK cells by culturing the cells at 2 microM Ca2+ caused rapid endocytosis of E-cadherin, but not that of l afadin or ZO-1. Addition of phorbol 12-myristate 13-acetate to these dissociated cells formed a tight junction-like structure where ZO-1 and l-afadin, but not neurabin-II or E-cadherin, accumulated. We furthermore found that, in non epithelial EL cells, which expressed E-cadherin and attached to each other, l afadin, neurabin-II, ZO-1 and E-cadherin were all localized at AJ. In cadherin deficient L cells, I-afadin was mainly localized at cell-cell contact sites, but ZO-1 was mainly localized at the tip area of cell processes. Neurabin-II did not accumulate at the plasma membrane area. Neither l-afadin nor neurabin-II significantly interacted with alpha-, beta-catenin, E-cadherin, ZO-1 or occludin. PMID- 10102632 TI - Autophosphorylation of KDR in the kinase domain is required for maximal VEGF stimulated kinase activity and receptor internalization. AB - We have previously reported the identification of four autophosphorylation sites on the KDR VEGF receptor. Two of these sites (tyrosines 951 and 996) are located in the receptor's kinase insert domain, and two (tyrosines 1054 and 1059) are located in the catalytic domain. In order to clarify the functional significance of these sites, we made DNA constructs in which tyrosine codons were replaced with those for phenylalanine, and expressed the DNA constructs in 293 cells. VEGF binding to cells expressing the native receptor led to a rapid increase in receptor and PLC-gamma phosphorylation, and a slower increase in the phosphorylation of p125FAK and paxillin. VEGF binding to KDR(Y951F) and KDR(Y996F) expressing cells resulted in phosphorylation of all cellular substrates tested, although the level of PLCgamma phosphorylation was decreased for KDR(Y996F). The decreased level of PLCgamma phosphorylation was not because PLCgamma-containing SH2 domains bind to the Y996 autophosphorylation site. We conclude that there exists receptor autophosphorylation sites not previously identified which allow for signaling via PLCgamma, as well as p125FAK and paxillin. VEGF binding to cells expressing KDR mutated at both tyrosine's 1054 and 1059 activated receptor autophosphorylation but at a level which was only 10% of that seen for cells expressing native receptor. Tyrosine phosphorylation of cell signaling proteins was not observed in KDR(Y1054,1059) expressing cells. Utilizing an in vitro assay which directly measures receptor catalytic activity allowed us to determine that the tyrosine kinase activity of the native receptor was significantly greater than that for the double mutant. We conclude from this result that VEGF-induced autophosphorylation at tyrosines 1054 and 1059 is a required step for allowing maximal KDR kinase activity. Maximal rates of receptor kinase activity is required for VEGF-induced receptor internalization, as internalization was delayed in the KDR(Y1054,1059F) expressing cells when compared to cells expressing native receptor. PMID- 10102633 TI - Overexpression of the wild type p73 gene in human bladder cancer. AB - p73, a first p53 relative, was recently identified and shown to be monoallelically expressed in a number of different human tissues. To determine the potential role of this gene in human bladder cancer, we investigated p73 expression levels, allelic expression patterns, and analysed p73 mutations in 23 unselected primary invasive bladder cancers with matched normal tissues and in seven bladder cancer cell lines. In a comparison between normal and tumor tissues using quantitative RT-PCR analysis, we found that p73 was overexpressed in 22/23 bladder cancers, sometimes as great as 20-fold. Allelic expression analysis using a C/T polymorphism in exon 2 and a newly identified T/C polymorphism in exon 5 revealed that p73 was biallelically expressed in both normal bladder and cancer tissues, suggesting that p73 is not imprinted in bladder tissue. Mutation screening of the p73 gene in bladder cancer DNAs using denaturing high performance liquid chromatography analysis and DNA sequencing revealed no tumor specific mutations in any coding exons of the p73 gene. These data suggest that the p73 is unlikely to be a tumor suppressor gene, but that overexpression of p73 may contribute to tumorigenesis in bladder cancer. PMID- 10102634 TI - Refinement of the LOH region 1 at 11q23.1 deleted in human breast carcinomas and sublocalization of 11 expressed sequence tags within the refined region. AB - Loss of constitutive heterozygosity at 11q23 has been detected in various human solid tumors. Here, we described the analysis of a series of normal and tumor pairs from 110 breast carcinomas for the presence of loss of heterozygosity at 11q23 loci. The overall frequency of LOH was 48%, confirming the importance of deletions at 11q23 in breast tumorigenesis. Previously, we have identified two independent regions of LOH at 11q23, the LOH region 1 at 11q23.1 and the LOH region 2 at 11q23.3. The most telomeric region was recently refined between loci D11S1345 and D11S1316, a region of about 1 Mb. However, the LOH region 1, most centromeric, was still not finely refined: the boundaries were defined by loci D11S2000 and D11S897, separated by about 8 Mb. Here, we refined its boundaries between loci D11S1347 and D11S927, a region of about 2 Mb. We have mapped 11 expressed sequence tags (ESTs) within this region and excluded another 20. This study represents a further step toward the identification of the putative tumor suppressor gene found within the LOH region 1 at 11q23.1. PMID- 10102635 TI - GTPase deficient mutant of G(alpha13) regulates the expression of Egr-1 through the small GTPase Rho. AB - The alpha-subunit of the heterotrimeric G protein G13 regulate cell growth, differentiation and apoptosis in different cell types. Expression of the constitutively activated mutant of G(alpha)13 (G(alpha13)QL) increases the expression of Egr-1, an immediate-early response gene that is identified to be involved in cell growth, differentiation, and apoptosis. Here we report that G(alpha13)QL activates the promoter of Egr-1 through specific sequence which includes the characteristic CArG boxes. We also demonstrate that the G(alpha13)QL activation of Egr-1 promoter is mediated by the Ras-like small GTPase Rho. PMID- 10102636 TI - A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3. AB - Smad proteins are essential components of the signalling cascade initiated by members of the Transforming Growth Factor-beta family. TGFbeta binding to heteromeric complexes of transmembrane Ser/Thr kinases induces Smad2 and Smad3 phosphorylation on their C terminus residues. This phosphorylation leads to oligomerization with Smad4, a common mediator of TGF-beta, activin and BMP signalling. The Smad complexes then translocate to the nucleus where they play transcription regulator roles. Even if they share 92% identity, the two TGFbeta/ restricted Smad2 and Smad3 are not functionally equivalent. As we have previously shown, Smad3 acts as a transcription factor by binding to a TGFbeta-responsive sequence termed CAGA box whereas Smad2 does not. Smad2 differs from Smad3 mainly in the N-terminal MH1 domain where it contains two additional stretches of amino acids that are lacking in Smad3. Here, we show that one of these domains corresponding to exon 3 is responsible for the absence of Smad2 transcriptional activity in CAGA box-containing promoters. Furthermore, in vitro studies indicate that this domain prevents Smad2 from binding to this DNA sequence. This suggests that Smad2 and Smad3 may have different subsets of target genes participating thus in distinct responses among TGFbeta pleiotropic effects. PMID- 10102637 TI - An ultrastructural study of amyloid intermediates in A beta1-42 fibrillogenesis. AB - Many attempts have been made to define early stages and intermediates in amyloid fibrillogenesis that may be susceptible to inhibition. We have developed an in vitro system, based on the use of A beta1-42 peptides, in which the development of prestages of protofilaments and protofilament and fibril formation could, for the first time, be followed by electron microscopy, supported by fluorescence spectrometry. The first recognizable ultrastructures after incubation of A beta1 42 peptides at 37 degrees C were globular subunits (4-5 nm in diameter) that gradually became organized into short protofilaments (30-100 nm), which in turn formed fibrils mainly by lateral association. At this stage, part of the protofilaments were seen first as collaterals protruding from the fibrils and then, as they were gradually incorporated, as buds on the fibril surface. A continuous growth of A beta1-42 fibrils was observed, seemingly originating from a nucleus, which appeared to consist of aggregates of amyloid intermediates. That protofilaments are intermediates also in the in vivo formation of amyloid was supported by the finding that AL fibrils isolated from amyloid tissues also exhibited radiating protofilaments. The demonstrated globular subunits and early formed protofilaments may be attractive targets for inhibition of fibril formation. PMID- 10102638 TI - How pre-existing, germline-derived antibodies and complement may help induce a primary immune response to nonself. AB - In the hypothesis that pre-existing, germline-encoded antibodies (naturally occurring antibodies, NAb) bind to conserved epitopes on invading nonself antigens, bound NAbs may initiate complement deposition and become targets of nascent C3b, which generates C3b-C3b-NAb complexes that remain associated with the nonself antigen (C3b-C3b-NAb...antigen). The inactivated form of these complexes (C3dg-C3dg-NAb...nonself antigen) may bind bivalently and thus firmly to B cells via CR2, a process stimulating antigen presentation. In some cases, CR2-bound 'C3dg-C3dg-NAb...antigen complexes' may further be recognized by immunoglobulin (Ig) determinants on B cells, whereby an immune response is elicited. As conserved epitopes on the nonself antigen are already complexed to NAbs, only B cells carrying Ig determinants specific for nonself epitopes may be stimulated. This hypothesis can explain directed affinity maturation towards nonself, protection from a strong immune response to conserved epitopes, down regulation of antibody formation and unresponsiveness to high-dose antigen. PMID- 10102639 TI - Administration of interleukin-12 prevents mite Der p 1 allergen-IgE antibody production and airway eosinophil infiltration in an animal model of airway inflammation. AB - The aim of the present study was to examine the in vivo effect of interleukin (IL)-12 on a murine model of asthma induced by Dermatophagoides pteronyssinus derived Der p 1 allergen. C57BL/6 mice immunized with Der p 1 allergen adsorbed to alum/pertussis toxin developed a T-helper type 2 (Th2)-dominant immune response characterized by the presence of IgE antibody, airway eosinophil infiltration and increased production of Th2 cytokine. Intraperitoneal injection of IL-12 (1 or 0.1 microg per day) for 5 days (day -1 to +3) simultaneously with each immunization, inhibited the production of IgE and IgG1 antigen-specific antibodies, whereas production of IgG2a was strongly enhanced. In addition, mice receiving both doses of IL-12 showed a strong inhibition of IL-5 but up regulation of IFN-gamma production by spleen cells stimulated with antigen. Administration of IL-12 also prevented antigen-induced eosinophil infiltration into the bronchoalveolar area in a dose-dependent manner and the primary inflammatory mediator serotonin in bronchoalveolar lavage (BAL) fluids was also reduced significantly. Taken together, the data indicate that IL-12 has a potent immunomodulatory effect on house-dust-mite-induced allergic disorders and may be used as an efficient agent for immunotherapy. PMID- 10102640 TI - Kinetics of cytokine release and expression of lymphocyte cell-surface activation markers after in vitro stimulation of human peripheral blood mononuclear cells with Streptococcus pneumoniae. AB - The aim of this study was to describe the kinetics of the cytokine release and the expression of activation markers on lymphocytes after stimulation of peripheral blood mononuclear cells (PBMC) with whole killed Streptococcus pneumoniae. The cytokine release and the expression of CD25 and HLA-DR on T cells, and CD69 on T cells, B cells and NK cells, were measured at different times. Our results show that tumour necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-10 and IL-12 reached maximal levels at 24 h, while IL-6, IL-8, TNF-beta and interferon (IFN)-gamma increased throughout the 1-week test period. The strains tested gave an increased expression of CD69 on all cell types, as well as an increase of CD25 and HLA-DR expression on T cells. The maximal CD69 expression was seen after 24 h on T cells and NK cells, while the B-cell expression of CD69 reached a plateau at the same time. All the cells still expressed CD69 on their surfaces after 1 week. In conclusion the results indicate that there was probably an early activation of monocytes leading to a polyclonal activation of lymphocytes. PMID- 10102641 TI - Modulation of the immune response by progesterone-induced lymphocyte factors. AB - Rat spleen and peripheral blood lymphocytes express progesterone receptors whose concentration is increased greatly during the early phase of pregnancy. After stimulation of progesterone the expression of receptors was augmented 2-3 times. When cells were cultured in the presence of progesterone they released a soluble factor that inhibited cellular immunoreactions (MLR, CRC) and cellular proliferation as measured by thymidine incorporation by spleen-cell culture. This factor also inhibited the synthesis of anti-DNP antibodies by a mouse hybridoma and diminished the proportion of cells in phase S. However, the percentage of asymmetric molecules produced by the hybridoma remained unaltered. These results support the hypothesis that soluble factors released by rat lymphocytes modulate the immune response of the mother and participate in the mechanism that protects the fetus against antipaternal antibodies. PMID- 10102642 TI - Structured reactions of serum IgM repertoires to immunization are dependent on major histocompatibility complex genes. AB - In normal animals, responses to immunization include alterations in the serum IgM antibody repertoire, as scored on autologous tissue antigens with no respect for the immunizing antigen. These immunogen-nonspecific antibody reactions were found previously to display specific structures dependent on strain and immunization protocols. Using major histocompatability complex (MHC)-congenic Lewis rats, we show that such IgM repertoire reactions are under the control of MHC-linked genes, including a class I locus. This strongly suggests the involvement of T cells restricted by both class I and class II MHC, in regulating serum IgM repertoires. Immunogen-nonspecific repertoire reactions to immunization may, therefore, represent degenerate, but prototypical, reactions or regulatory mechanisms embodying the natural repertoires of T- and B cells connected to autoantigens. Natural (auto)immunity could so serve to regulate the effector class of adaptive immune responses, particularly in order to avoid pathogenic autoreactivity following specific immunization with self-cross-reacting antigens. Appropriate analysis of nonspecific repertoire reactions could therefore contribute to the understanding of general structures of immune regulation and natural tolerance. PMID- 10102643 TI - Mechanisms involved in graft-versus-host disease induced by the disparity of minor histocompatibility M1s antigens. AB - In this study we investigated which type of T cells: high T-cell receptor (TCRhigh, cells of thymic origin) or intermediate TCR (TCRint, cells of extrathymic origin), expanded in the liver and other organs, resulting in the induction of graft-versus-host disease (GVHD) with minor lymphocyte stimulating (M1s) disparity. When 6.5 Gy-irradiated BALB/c (H-2d M1s-1b2a) mice were injected with interleukin-2 receptor beta-chain(-) (IL-2Rbeta(-)) CD3high cells purified from the spleen of B10.D2 (H-2d M1s-1b2b) mice, IL-2Rbeta(+)CD3high cells expanded in the liver and other organs of recipient mice. The majority of these cells were found to be IL-2Ralpha(-)Mel-14(-)CD4(+)Vbeta3(+) in GVHD mice. The CDR3 region in their TCR-alphabeta (i.e. N-Dbeta-N) was polyclonal, although there were skewed usages of Vbeta3 and Jbeta2.4. The majority of cells were confirmed to be of donor origin by the individual discrimination method, namely, they originated from isolated IL-2Rbeta(-)CD3high cells. Interestingly, these T cells lacked cytotoxicity against both a natural killer (NK)-sensitive target and thymocytes with M1s disparity and nondisparity. Another important finding was that activated granulocytes expanded at generalized sites in GVHD mice. The present results raise the possibility that M1s disparity is mainly recognized by TCRhigh cells with unique properties but that direct effector cells that induce GVHD might not be such T cells but rather accompanied granulocytes. PMID- 10102644 TI - Characterization of two infectious mouse mammary tumour viruses: superantigenicity and tumorigenicity. AB - Mouse mammary tumour virus (MMTV) is a type B retrovirus that causes mammary tumours in susceptible mice. MMTV encodes a superantigen (SAg) that has the property of stimulating T-cell populations expressing a particular variable region of the T-cell receptor (TCR) beta chain (Vbeta) and needs to be presented in the context of major histocompatibility complex (MHC) class II molecules. Previously, we described two exogenous MMTV, MMTV BALB14, which encodes a superantigen that induces the deletion of Vbeta14+ Tcells, and MMTV BALB2, which encodes a SAg that induces the deletion of Vbeta2+ Tcells. We now describe their biological activity: the deletions involve both CD4+ and CD8+ populations, are progressive and can be detected in blood, lymph nodes and spleen. Such deletions reflect, at least in part, those occurring during intrathymic development. Both BALB2 and BALB14 viral variants are capable of inducing a strong increase of Vbeta-specific T cells in BALB/c mice (I-A+, I-E+). However, when injected into the footpad, their initial stimulatory capacity differs in that the presence of MHC I-E molecules is essential only for the stimulation of Vbeta2+ T cells. Both viral variants are able to induce deletion even in the absence of the I-E molecule in which case, however, deletion appears later and is less pronounced. Both exogenous MMTVs induce, at the end of a year, 30-35% of pregnancy-dependent mammary adenocarcinomas. PMID- 10102645 TI - Distribution of TNF-alpha, TNF-R55 and TNF-R75 in the rheumatoid synovial membrane: TNF receptors are localized preferentially in the lining layer; TNF alpha is distributed mainly in the vicinity of TNF receptors in the deeper layers. AB - The expression of TNF-alpha and its receptors in the rheumatoid synovial membrane was investigated using immunohistochemistry and immunocytofluorescence. TNF alpha+ cells (< 10% of all cells) were found in all regions, predominantly in sublining and diffuse infiltrates. The highest percentage of TNF-R+ cells was found in the lining layer (50-90%), with a slight predominance of TNF-R55. In the sublining, fewer cells expressed TNF-R (approximately 50%), mostly TNF-R75. TNF R75+ cells were also detectable in diffuse infiltrates and lymphoid aggregates (10-50%). These contained only individual TNF-R55+ cells. In diffuse infiltrates, there were slightly more TNF-R55+ cells than in lymphoid aggregates (in both cases < 10%). In sequential sections, TNF-alpha+ cells localized mostly in the vicinity of TNF-R+ cells. Macrophage-like cells appeared to be the predominant TNF-R+ cell type. CD3+ T cells in lymphoid aggregates expressed exclusively TNF R75. Subsequently, the expression of membrane-bound TNF-alpha, TNF-R55 and TNF R75 was tested by FACS analysis in isolated RA synoviocytes (n = 7 patients). Only four specimens expressed mTNF-alpha, and that on a low percentage of cells (2 +/- 2.4%; mean +/- SD). In contrast, all specimens expressed higher percentages of TNF-R55 and TNF-R75 (21 +/- 1% and 14 +/- 7.1%, respectively). These results demonstrate that: (1) the percentage of cells expressing soluble/transmembrane TNF-alpha is greatly outnumbered by the percentage of cells expressing TNF receptors; and (2) TNF-alpha-expressing cells are localized in regions expressing substantial levels of TNF receptors. Therefore, the known pro inflammatory and pro-arthritic effects of TNF-alpha are probably mediated by local interactions between the receptors and their soluble and transmembrane ligands. PMID- 10102646 TI - The effects of CD40 ligation on peripheral blood mononuclear cell interleukin-12 and interleukin-15 production and on monocyte CD14 surface antigen expression in human immunodeficiency virus-positive patients. AB - Human immunodeficiency virus (HIV) infection causes dysregulation of surface phenotype, of accessory function and of cytokine production from peripheral blood mononuclear cells (PBMCs). As CD40 ligation induces several functional activities in these cells, this stimulation may partially mimic the situation occurring in vivo during an antigen-driven immune response. The aim of this study was to measure cytokine production and immunophenotypic changes induced by CD40 stimulation of PBMCs from HIV-positive patients. Under these experimental conditions, total and heterodimeric interleukin (IL)-12 production from PBMCs was similar, while IL-10 production was increased in HIV-positive patients compared with controls. On the contrary, CD40 ligation did not induce IL-15 production by PBMCs. Surface CD14 was down-modulated, as a consequence of CD40 stimulation, on monocytes from healthy controls but not on monocytes from HIV-positive patients. These data demonstrate that some of the CD40-mediated signals are disturbed in HIV-positive patients. These disturbances may contribute to the immune dysfunction seen in HIV infection. PMID- 10102647 TI - Peripheral blood T-cell receptor beta-chain V-repertoire in atopic dermatitis patients after in vitro exposure to Pityrosporum orbiculare extract. AB - The yeast Pityrosporum orbiculare belongs to the normal cutaneous flora but is also considered to be one of the factors that may contribute to atopic dermatitis (AD). In the present study we investigated the possibility that P. orbiculare can act with superantigen activity in AD. P. orbiculare-reactive T-cell lines (TCLs) were obtained after stimulation of peripheral blood mononuclear cells (PBMC) with P. orbiculare extract. T-cell receptor beta-chain V-segment (TCRBV) usage was investigated using monoclonal antibodies and flow cytometry. We could not find any difference in TCRBV usage between AD patients (n = 10) and healthy controls (n = 5), either in fresh PBMC or in P. orbiculare-reactive TCLs. Compared with their original PBMCs the P. orbiculare-reactive TCLs showed a decreased usage of several TCRBVs, although increased usage of certain TCRBVs could be seen in some of the individuals. Further analysis of the CDR3-length polymorphism exhibited a shift in CDR3-length distribution, indicating oligoclonal expansion of T cells specific to different antigens in the P. orbiculare extract. In conclusion we have not found any evidence for superantigen activity in P. orbiculare extract, but our data support the importance of classical major histocompatibility complex (MHC)-restricted allergens in P. orbiculare. PMID- 10102648 TI - Increased CD4+ T-lymphocyte senescence fraction in advanced human immunodeficiency virus type 1 infection. AB - Human immunodeficiency virus type 1 (HIV-1) infection is accompanied by peripheral CD4+ T-cell losses. CD4+ T-cell numbers often increase during antiviral treatment of acquired immune deficiency syndrome (AIDS), however, alterations in the CD4+ T-cell repertoire have not been completely corrected for these patients. Such individuals remain at increased risk of infection. Although senescence of the CD4+ T cells has not been adequately evaluated for advanced HIV 1 infection, hypothetically, replicative senescence could complicate therapeutic reconstitution of the CD4+ T cells in AIDS. In this study, correlates of replicative senescence, terminal restriction fragment (TRF) length and percentage short (< 5.0 kb) telomeric DNA (senescence fraction), were measured for the CD4+ T cells of HIV-1-infected patients with peripheral CD4+ T-cell counts of < 200/mm3. The results show that for advanced HIV-1 infection the TRF length of the CD4+ T cells is decreased (P < 0.01), and the senescence fraction increased (P < 0.05), when compared with uninfected controls. These findings suggest that cellular senescence may contribute to disruption of CD4+ T-cell diversity observed following the therapeutic, immunologic reconstitution of AIDS. PMID- 10102649 TI - Leishmania donovani infection of a susceptible host results in CD4+ T-cell apoptosis and decreased Th1 cytokine production. AB - The disease visceral leishmaniasis is caused by a protozoan parasite, Leishmania donovani and is characterized by depressed cell-mediated immunity (CMI) and unhindered parasite growth in a susceptible host. The opposite trend is observed in a resistant host. However, the mechanism of this loss of CMI during the progressive disease is unknown as yet. In this report, we demonstrate that more than 40% of CD4+ T cells from a susceptible host undergo apoptosis resulting in a significant decrease in interleukin (IL)-2 and interferon (IFN)-gamma secretion, leaving IL-4 secretion unaffected. These changes are not apparent in the case of CD4+ T cells derived from a resistant host. The data reported here suggest that experimental Leishmania donovani infection leads to selective deletion of the IL 2 and IFN-gamma-secreting cells but not Th2-like cells in a susceptible but not a resistant host. PMID- 10102650 TI - Some current controversies on nutritional requirements of full-term and pre-term newborn infants. AB - Many controversial topics have still to be resolved regarding the nutritional requirements of the newborn, and in particular of the pre-term infant. The term 'controversy' bears the connotation of prolonged dispute and such a situation has arisen for various reasons: (a) from inadequate research methodologies; (b) from the misinterpretation of, or bias within, the results of studies undertaken; (c) from not taking into account the multifactorial etiology of physiopathological situations or illnesses suffered by suckling neonates and newborn infants. Nevertheless, controversy as such is not always a negative factor, as investigation and discussion enable advances in therapeutic methods. PMID- 10102651 TI - Protein demand in the premature neonate and in the small for gestational age full term neonate. AB - From our analysis, it may be seen that from simple data it is possible to evaluate the protein and energy adequacy of very low weight neonates, which is crucial to help them achieve normal intellectual and somatic growth and development. PMID- 10102652 TI - Special formulas in infant nutrition: a review. AB - Special formulas should only be used by medical prescription and for those lactating infants with diagnosed nutritional problems. Lactose-free formulas or those based on soy are the logical choice when the exclusion of lactose from the diet is considered necessary. At present, there is no concensus on the appropriateness of soy formulas for the treatment and prevention of nutritional allergies and current opinion seems to favour hydrolyzed protein formulas. High degree protein hydrolysate formulas are used to treat lactating infants with an allergy to cow milk proteins or with serious nutritional problems. These formulas are not without risk, as they may contain residual epitopes capable of provoking a severe allergic reaction. Before using these formulas, allergenicity tests should be performed, particularly for highly sensitive infants. The unpleasant taste and high cost of these formulas, in addition to possible nutritional problems, limit their use in the prevention of atopic disease, although their efficacy is well established. Partially protein hydrolysate formulas are only used for preventive purposes and are not suitable for lactating infants with a proven allergy to cow milk. Although these formulas can reduce the incidence or delay the appearance of certain atopic symptoms, they have not been shown to prevent IgE-mediated allergic reactions to cow's milk and so their effectiveness is open to question. PMID- 10102653 TI - Percutaneous catheter use in newborn infants with parenteral nutrition. AB - The well known negative effect of infection on nutrition causes the cycle 'infection-malnutrition-infection'. Prolonged parenteral nutrition requires central venous catheterization. Due to the possibility of 'catheter related sepsis' (CRS) catheters should be used correctly to avoid septic complications. A very high percentage of central venous catheters (CVC) removed because of presumed infections are not infected when culture is done. In some patients infections are successfully treated with antibiotics without catheter removal. Removal of the line is recommended when catheter-associated sepsis is suspected or proven, but not for the extremely ill preterm infant or when such removal may be impractical. A therapeutic protocol is suggested to avoid future canalizations in the neonate, sometimes in a critical situation. Current literature referring to CRS in the newborn infant is reviewed. PMID- 10102654 TI - Biological roles of L-carnitine in perinatal metabolism. AB - Carnitine performs a crucial role in the energy supply of tissues during fetal life and in the neonatal period by controlling the influx of fatty acids into mitochondria. Carnitine also facilitates the oxidation of pyruvate and branched chain amino acids, and contributes to the protection of cells from the deleterious actions of acyl CoAs. Carnitine further acts as a secondary antioxidant, favouring fatty acid replacement within previously oxidatively damaged membrane phospholipids. Availability of L-carnitine is essential in the developing fetus for processes underlying fetal maturation. L-carnitine is also essential for development of hepatic ketone synthesis, a central pathway for neonatal energy metabolism. Ketone bodies inhibit the oxidation of both glucose and lactate, sparing these metabolic substrates for biosynthetic functions. PMID- 10102655 TI - Nutrition and fetal growth. AB - Essential factors for normal fetal growth include the correct utilization by the fetus of a suitable supply of energy and plastic nutrients, together with the adequate genic expression of the factors promoting tissue growth and an optimal hormonal framework. The nutritional state and welfare of the mother, the endocrine changes experienced and the uteroplacental function have all been related to the health of the fetus and the newborn infant, premature births, fetal nutritional disorders, certain diseases and even death. PMID- 10102656 TI - Maternal nutritional factors: significance for the fetus and the neonate. AB - The nutrition of the gestating woman and of the lactating mother has always been a matter of concern and is frequently the object of pharmacological supplementation. During gestation and lactation, nutritional requirements undergo considerable changes. Studies based on nutritional surveys have shown that the diet of the gestating woman in Spain is deficient mainly in iron, folates, zinc and pyridoxin, with an excessive proportion of lipids. These nutritional habits change during gestation, particularly in the final months. The consumption of milk, particularly of semi-skimmed milk, has increased since 1989. Although pharmacological supplements may not be a valid alternative for all situations, they would be applicable in situations of high nutritional risk when the dietary contribution is insufficient. For the rest of the population, it is only necessary to obtain a supplement from a diet suitably enriched with vitamins and minerals. PMID- 10102657 TI - The use of stable isotope techniques for nutritional and metabolic research in paediatrics. AB - Stable isotope methods are increasingly used in paediatrics for clinical diagnosis and research due to marked improvements in analytical technologies and better availability of suitable tracers. The safety of stable isotopes is of major importance for use in children. Large amounts of deuterium well above the doses applied under clinical conditions may induce adverse effects. In contrast, heavier stable isotopes such as 13C, 15N or 18O do not induce adverse effects even at the highest enrichments obtained, and they are safe. Breath tests with measurements of 13CO2 enrichment after oral application of a tracer can reliably evaluate helicobacter pylori infection and gastric emptying kinetics. Combined with an estimation of total CO2 production, 13CO2 breath tests allow estimation of the absorption and oxidation of 13C-labelled substrates, such as medium- and long-chain triglycerides, and demonstrates the beneficial effect of carnitine supplements on fat oxidation in primary carnitine deficiency. The study of metabolic processes may require the sampling of blood for isotopic analyses of metabolites of the applied tracer. Gas chromatography-isotope ratio mass spectrometry can detect tracer in individual components from small plasma samples. The high precision enabled us to utilize the small differences in natural 13C-enrichment between dietary fats to study fatty acid turnover in term infants, in whom the dietary fat source was switched to corn oil with a slightly higher 13C-content. With this approach we demonstrated active conversion of linoleic into arachidonic acid. We also applied biotechnologically produced, U 13C labelled linoleic and alpha-linolenic acids to infants and detected the conversion of these essential fatty acids to their longer chain polyunsaturated derivatives, with an apparent change of conversion activity with age. Moreover, it has become possible to measure tissue protein synthesis from small biopsy samples obtained in situ without surgery, such as forceps biopsies of rectal tumors. These few examples of recent developments demonstrate the great clinical and scientific potential of stable isotope methods in future paediatric applications. PMID- 10102658 TI - The role of dietary polyunsaturated fatty acids during the first 2 years of life. AB - The early dietary supply of long-chain polyunsaturated fatty acids (LCPUFA) might contribute to the higher developmental scores of children breast-fed as infants. Preterm infants' improved visual acuity and neurodevelopmental performance correlate with dietary supplementation of LCPUFA in amounts similar to those that breast-fed infants receive and studies of term infants report similar effects with LCPUFA supplementation. Whether term infants may benefit from LCPUFA unsupplemented formulas with higher amounts of alpha-linolenic acid (n - 3 LCPUFA precursor) is controversial. With the onset of weaning, the question of the exact quantity and quality of which dietary lipids to give for prevention purposes is still open. Early dietary intervention studies of weaned children under 2 years are in progress in populations at high risk for early cardiovascular disorders. Preliminary results indicate that these interventions, while preventing an age dependent increase in blood lipid levels, are safe for growth, but the balance of all the macronutrients should be carefully considered before general recommendations can be made. PMID- 10102659 TI - Fatty acid composition of plasma and erythrocytes in term infants fed human milk and formulae with and without docosahexaenoic and arachidonic acids from egg yolk lecithin. AB - Human milk contains small but nutritionally significant amounts of long-chain polyunsaturated fatty acids (LCP), such as arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-3) acids, which are not present in most infant formulae. In the present study, the fatty acid composition of plasma and erythrocytes was determined at birth and again at 7 days, 1 and 3 months in 49 healthy full-term infants (37-42 week's gestation). One group of infants was fed exclusively with human milk (n=16) and the others were randomly assigned to a standard term formula (F) (n=15) or the same formula with egg yolk lecithin providing DHA (0.15%) and AA (0.30%) (LCP-F) (n=18). Plasma and erythrocyte LCP values of the three dietary groups did not differ at 7 days of age, but the contents of DHA and AA in plasma and erythrocytes at 1 and 3 months were significantly lower (P<0.05) in infants fed non supplemented formula than in infants fed breast milk and supplemented formula. There were no differences in plasma or erythrocyte AA or DHA concentrations between the group fed breast milk and the group fed supplemented formula during the period studied. PMID- 10102660 TI - Influence of caesarean delivery and maternal factors on fat-soluble vitamins in blood from cord and neonates. AB - We measured plasma and erythrocyte vitamin E (VE) and plasma vitamin A (VA) profiles in 48 full-term and 8 preterm pairs of neonates and their mothers at birth and we determined whether there is any relationship between maternal and umbilical cord for the nutrients measured. At the same time, we assessed the influence of the delivery type and neonate anthropometric measurements on maternal and cord blood VA and VE levels. We measured vitamin levels in vein and arterial blood in order to establish differences due to fetal metabolism. To determine the influence of pregnancy on vitamin levels, we compared the maternal results with data from a group of 13 non-pregnant women. Cord blood had lower plasma VE (arterial 275.8+/-71.7 microg/dl and vein 282.89+/-64.4 microg/dl values), erythrocyte VE (arterial 256.96+/-50.41 microg/dl packet cells and vein 257.41+/-44.35 microg/dl values), and VA levels (arterial 26.72+/-11.83 microg/dl and 27.15+/-10.05 microg/dl values) and a lower vitamin E/total lipids ratio (VE/LT) (arterial 1.60+/-0.4 and vein 1.62+/-0.3 values) than maternal blood (1474.62+/-424.51 microg/dl, 305.94+/-54.75 microg/dl packet cells, 41.03+/-18.83 microg/dl, 2.34+/-0.5, respectively). VA levels were higher in preterm than full term neonates (P<0.05). Plasma and erythrocyte VE levels were not correlated in maternal blood but were correlated in neonates and infants (r>0.40; P<0.01). We found a good correlation between erythrocyte tocopherol of maternal and cord blood (r>0.40; P<0.01), although there was no correlation with plasma VE values. Cord vein plasma VE levels were higher than cord arterial blood measurements (P<0.01). The plasma VE and VE/LT of the mother and cord following vaginal delivery were higher than measurements from caesarean delivery (P<0.05), although erythrocyte levels were similar. The plasma VE level was higher in mothers at delivery than non-pregnant women. PMID- 10102661 TI - Neonatal dietary gangliosides. AB - Gangliosides are glycosphingolipids that are widely distributed in vertebrate tissues and body fluids and which are specially abundant in neural tissues. Milk from different species has a particular ganglioside content and profile. Human milk has a higher content of gangliosides than bovine milk. GD3 and GM3 are the predominant individual gangliosides in bovine milk. In human colostrum GD3 is also the main ganglioside whereas in human mature milk GM3 predominates over the other gangliosides. Human milk also contains GM1 and a number of highly polar gangliosides, which may play an important role in infant physiology. GM1 has been shown to inhibit Escherichia coli and Vibrio cholerae enterotoxins. We have found that a ganglioside-supplemented infant formula modifies the intestinal ecology of preterm newborns, increasing the Bifidobacteria content and lowering that of Escherichia coli. Although the exact mechanism by which dietary gangliosides reduce the fecal content of Escherichia coli is unknown, in vitro experiments suggest that they may act as false intestinal receptors for some strains of this bacteria. Since GD3 and other gangliosides have been involved in mechanisms of lymphocyte activation and differentiation, dietary gangliosides might have a function in intestinal immunity development. PMID- 10102662 TI - Evaluation of carnitine nutritional status in full-term newborn infants. AB - Carnitine supplements may be advisable not only in premature but also in artificially-fed full-term babies. The acyl-carnitine/free carnitine (AC/FC) and FC/total carnitine (FC/TC) ratios have been considered markers of "carnitine insufficiency" and "carnitine deficiency", respectively. Values of AC/FC>0.40 are considered abnormal and mean that FC has a low bioavailability to the cells and so reflects a "carnitine insufficiency". Values of FC/TC<0.7 indicate "carnitine deficiency". We analyze the validity of such ratios and the limits for them in three groups of full-term neonates (n=66): 22 breast-fed (BF), 22 with formula (F); and 22 fed with carnitine-supplemented formula. Several studies have shown the need to give supplements of carnitine to the neonate because of its "essentiality", but no one has demonstrated the adequate dosages. We therefore propose to establish new limit levels for these ratios to control carnitine nutritional status in neonates, based on the control of percentile ranges for normal BF infants (in this study: 97th percentile of AC/FC>0.83; 3rd percentile of FC/TC<0.54) and on evaluating the needs of neonates and dosages required to supplement F. The supplement of 2.2 mg of L-carnitine/100 ml in the cow's milk formula used in the present study produces a similar biochemical pattern of plasma carnitine and ACs to that observed in BF infants, together with a lower risk of developing "carnitine deficiency" or "carnitine insufficiency" than those babies fed with nonenriched F. Considering that human milk is the best source of nutrition for full-term infants, the limit established for AC/FC and FC/TC ratios at other ages of life seems to be "inadequate" for neonates. PMID- 10102663 TI - Protein in infant formulas. Future aspects of development. AB - Cow's milk protein intolerant infants (CMPI), shifted to a cow's milk protein hydrolysate based formula, often experience an improvement in signs of malabsorption; on the other hand, they also present a pattern of watery stools. In an attempt to find high levels of some gastrointestinal hormones that might induce hypermotility, motilin and neurotensin levels were studied in infants on starting formula and in cow's milk protein intolerant infants, on a cow's milk protein hydrolysate based formula. In 12 infants on unmodified cow's milk based formula (starting formula), motilin levels were: mean 71.66 pmol/L (s: 17); neurotensin 26.53 (s: 10.9). In 19 cow's milk protein intolerant infants on a cow's milk protein hydrolysate based formula, motilin levels were: mean 163.65 pmol/L (s: 70.06) (p<0.05); neurotensin: 31.76 pmol/L (s: 15.03) (p>0.05). Motilin (but not neurotensin) is higher in cow's milk protein intolerant infants on a cow's milk protein hydrolysate based formula. We conclude that high motilin levels can induce a different pattern of motility, and can be a pathogenetic factor in the persistence of loose and watery stools in infants with CMPI on a protein hydrolysate based formula. PMID- 10102664 TI - Bone mineralization status measured by dual energy radiographic densitometry in preterm infants fed commercial formulas. AB - We have studied the effect of two preterm commercial infant formulas with different calcium and phosphorus contents on the mineral balance and bone mineralization of 30 preterm infants at 1 month of age. Bone mineralization was measured by dual energy X-ray densitometry. The formula supplying a higher content of calcium and phosphorus promoted higher mineral retention (P<0.01) as well as higher bone mineral content (1.556 vs. 1.073 g, P<0.01) and bone mineral density (0.458 vs. 0.424 g/cm2, P<0.05), approaching values of the control group, which comprised a cohort of 15 preterm newborns whose gestational age was 4 weeks older than the subjects selected to be fed with the formulas. The intake of calcium correlated with retention (r=0.69); the phosphorus intake also correlated with phosphorus retention (r=0.95). Intakes of calcium and phosphorus correlated with the bone mineral content (r=0.65) and with bone mineral density (r=0.49). We conclude that formulas for preterm infants should not have a calcium content lower than 120 mg/100 kcal and should have a calcium/phosphorus ratio of about 2 to promote adequate bone mineralization. PMID- 10102665 TI - Low-dosage prophylactic vancomycin in central-venous catheters for neonates. AB - Neonatal infectious pathology remains one of the main causes of morbidity and mortality in this age group. The introduction of plasticized catheters for the administration of medication, fluidotherapy and parenteral nutrition was a significant advance in treatment of patients at risk, but also led to the appearance of infectious complications. Negative coagulase staphylococcus is the principal pathogen in most neonatal intensive care units. Recent studies have examined the prophylactic use of vancomycin in preterm babies receiving parenteral nutrition. We have evaluated the efficacy of this procedure, applied via the central venous catheters employed for all neonates, within the intensive care unit over a period of one year. Prophylactic vancomycin administered via the catheters significantly reduced the incidence of Gram-positive infections, despite the presence within this group of a greater number of septic risk factors than in the control group. PMID- 10102666 TI - Non-invasive assessment of brachial artery endothelial vasomotor function: the effect of cuff position on level of discomfort and vasomotor responses. AB - Non-invasive assessment of brachial artery flow-mediated dilation using cuff occlusion of the arm above or below the elbow to stimulate flow is emerging as a highly useful technique to examine endothelial vasomotor function in human subjects. In anticipation of a large-scale investigation, an important issue is the acceptability of the technique to participants. The purpose of this study was to determine the level of discomfort associated with the technique and compare it to the commonly used procedure of venipuncture. Flow-mediated dilation was determined using cuff occlusion of the arm above the elbow and a blood sample was obtained by standard venipuncture from 54 subjects. The level of discomfort for each procedure was assessed and compared using a visual analogue scale and was found to be extremely low. When the occlusion cuff was positioned above the elbow, the discomfort was slightly more severe (1.9+/-1.9 cm) than venipuncture (1.0+/-1.3 cm, p = 0.003). In 27 subjects, the effect of cuff position (above or below the elbow) was compared: the below the elbow position was associated with a reduction in the percentage increase in flow (570+/-280% versus 900+/-560%, p = 0.005), flow-mediated dilation (6.8+/-3.8% versus 9.8+/-5.7%, p = 0.008) and discomfort (1.6+/-0.8 versus 3.7+/-2.2 cm, p = 0.008). When the cuff was located below the elbow, the level of discomfort was equivalent to that associated with venipuncture. Thus, non-invasive assessment of flow-mediated brachial artery dilation is well tolerated and appears to be suitable for a large-scale study of endothelial function. PMID- 10102667 TI - Early development of deep-vein thrombosis following hip fracture surgery: the role of venous wall thickening detected by B-mode ultrasonography. AB - Deep-vein thrombosis (DVT) remains the most frequent complication following hip surgery. This study was designed in order to evaluate the development of DVT after hip fracture surgery, and to determine if venous wall thickening detected before surgery predisposes patients to postoperative DVT. Systematic ultrasound examinations were performed on 100 consecutive patients undergoing hip fracture surgery on the day preceding the operation, and then postoperatively on days 2, 5 and 10. A total of 12 proximal, 28 distal deep-vein and four saphenous vein thromboses were detected. Of the DVT, 19 (43%) were detected at day 2. Five out of eight patients with venous wall thickening had a previous history of DVT. Venous wall thickening was positively correlated with proximal DVT development (62.5% versus 8% incidence in the group of patients with and without venous wall thickening respectively; p<0.001, relative risk = 7.8). This study highlights the high frequency of early major thromboembolic events following hip fracture surgery. It is considered that patients with a previous history of venous thromboembolic disease should undergo B-mode ultrasonographic examination before hip fracture surgery. Patients in whom venous wall thickening is detected should have repeated postoperative ultrasonographic examinations enabling early detection of DVT. PMID- 10102668 TI - Atherosclerotic aneurysms of the superficial femoral artery: report of two ruptured cases and review of the literature. AB - Isolated arteriosclerotic aneurysms of the superficial femoral artery are rare. In citing the literature a total of 30 cases in 28 patients in the last 25 years were found. In addition to the above cases, two aged patients with ruptured aneurysms of the superficial femoral artery are reported; these were managed successfully with partial aneurysmectomy and restoration of the circulation of the extremity with a synthetic graft. The prognosis for this type of aneurysm following surgical therapy is good, despite the advanced age of the patients, and amputation is relatively rare, occurring in only two out of the 30 aneurysms (6.6%) reported. The risk of rupture is 46.6% (14/30) and is greater than that found in peripheral aneurysms. This, in association with the possibility of the creation of thrombosis (5/30; 16.6%) or embolization (1/30; 3.3%), threatens the extremity itself as well as the life of the patient, increasing the risk of complications and even death at a rate of 66.6% (20/30). Timely diagnosis, immediate surgical reconstruction and prompt mobilization, however, can guarantee a good prognosis for these aged patients. PMID- 10102669 TI - New developments in intravascular ultrasound. AB - Intravascular ultrasound (IVUS) is a dynamic imaging modality that provides real time in vivo visualization of atherosclerosis and other vascular pathology. The tomographic image presentation of IVUS permits detailed assessment of plaque morphology and its corresponding responses to interventional therapy. IVUS studies have confirmed vascular remodeling in vivo, have proposed a high-pressure stent implantation strategy and have shown two key mechanisms of restenosis after angioplasty: plaque proliferation and vessel shrinkage (negative remodeling). IVUS also provides accurate quantitative information regarding lumen size, vessel size and plaque burden. These observations, essential to achieving improved outcomes, have drastically changed the understanding of atherosclerotic artery disease and interventional procedures. IVUS has matured into an essential complement to daily peripheral and coronary interventional practice and is routinely incorporated as part of the interventional arsenal in the catheterization laboratory. A variety of new imaging techniques are currently being designed and tested. These include combined therapeutic devices, further miniaturization, 3-D applications and tissue characterization. These techniques may evolve to provide increased favorable clinical outcomes and more accurate information of vessel geometry and plaque composition. PMID- 10102670 TI - Diagnosis and treatment of chronic lower extremity ischemia. AB - Chronic lower extremity ischemia is due to progressive atherosclerosis of the aorto-iliac and/or infrainguinal arteries. This disease process is of great importance as millions of patients are affected by lower extremity arterial occlusive disease. Most of these patients are asymptomatic but a growing number of them are symptomatic, with complaints ranging from mild claudication to gangrene. The increasing number of patients affected by lower extremity atherosclerosis is, in part, due to the 'graying' of the general population and to the medical improvements of the past three decades that have allowed patients with generalized atherosclerosis to survive longer. Fortunately, the diagnosis and management of peripheral arterial occlusive disease has also significantly progressed leading to improved graft patency, limb salvage rates, and quality of life for patients. PMID- 10102671 TI - A systematic review of compression therapy for venous leg ulcers. AB - The aim of the study was to determine the relative effectiveness of compression therapies used in the treatment of venous leg ulcers. Randomized controlled trials (RCT) were sought using a search strategy that aimed to identify relevant RCT by searching eight electronic databases (including Medline, Embase and CINHAL), conference proceedings and hand searching key journals. In addition, citations within papers were scrutinized to identify any relevant studies. Suitability for inclusion in this review was determined by a critical appraisal of key determinants of the quality of the trials. Trials that included patients of mixed ulcer aetiology were excluded unless the results of patients with venous disease were reported separately. Data was extracted independently by two reviewers and synthesized quantitatively and qualitatively. Losses to follow up/withdrawals were assumed to be failures of treatment. A total of 132 articles were identified, and of these eight fulfilled the inclusion criteria. The remaining 126 trials were excluded due to trial design flaws, the inclusion of mixed/arterial aetiology ulcers or because they were non-RCT. Meta-analysis using a random-effects model showed the benefits of multi-layer and elastic compression bandages. It was concluded that more high-quality trials are required and that more emphasis should be placed on economic and quality of life data to try to ascertain the cost-effectiveness and utility of the treatment options available. PMID- 10102672 TI - Management of intracranial aneurysms. AB - Intracranial aneurysms are lesions commonly encountered by neurosurgeons, usually as a result of subarachnoid hemorrhage. The preferred treatment of these aneurysms is either surgical clipping or endovascular coiling, both of which eliminate the aneurysm from the normal circulation to prevent aneurysmal enlargement or additional hemorrhage. Despite advances over the last several decades in the understanding of intracranial aneurysms, morbidity from treatment of these lesions remains significant. This review will discuss the epidemiology, anatomy and pathophysiology, clinical and radiographic diagnosis, various treatment options, and potential complications from aneurysm treatment. PMID- 10102673 TI - Images in vascular medicine. Lymphoscintigraphy in congenital lymphedema. PMID- 10102674 TI - Immunomodulatory action of class mu-, delta- and kappa-opioid receptor agonists in mice. AB - Endogenous opioids exert a variety of functions outwith the central nervous system, including modulation of some murine lymphocyte functions. The results of this study indicate that mu-, delta- and kappa-receptor selective agonists are potent in vitro stimulators of mitogen-induced proliferation of murine T lymphocytes. Moreover, the observed enhancement of mitogen-induced proliferation was reversed by mu-, delta- and kappa-receptor class selective antagonists, beta funaltrexamine, ICI 174,864 and nor-binaltorphimine, respectively. An additional study has revealed that repeated administration (four injections) of the opioid receptor selective agonists DAGO, DPDPE and U-50488 also enhanced the concanavalin A-induced proliferation of lymphocytes. These results suggest that there are three classes of opioid receptors on T-lymphocytes and that all these receptor classes are involved in the stimulation of concanavalin A-induced proliferation. PMID- 10102675 TI - Expression of tyrosine hydroxylase, calcitonin gene-related peptide, substance P and protein gene product 9.5 in mouse islets transplanted under the kidney capsule. AB - Pancreatic islets transplanted to the kidney of syngeneic mice were stained for calcitonin gene-related peptide (CGRP), substance P (SP), tyrosine hydroxylase (TH), acetylcholinesterase and the pan-neuronal marker, protein gene product 9.5 (PGP). Nerve fibers expressing TH-like immunoreactivity (TH-LI) and CGRP-LI were rare for 4 days but increased 2 (CGRP) or 6 (TH) weeks after transplantation. In 1-year-old grafts the CGRP-LI innervation resembled that in situ, while TH-LI and PGP-LI innervations were increased. SP-LI fibers remained rare throughout. Perikarya intrinsic to the islets did not show CGRP-LI or SP-LI. The results indicate a progressive ingrowth of sensory fibers into the grafts and that the TH LI innervation becomes even more pronounced than in the pancreas. The post transplantation reaction of islet intrinsic neurons does not involve CGRP and SP, contrasting with previous observations for vasoactive intestinal polypeptide. PMID- 10102677 TI - Ontogenic development of prolactin immunoreactive neurons in the rat lateral hypothalamus. AB - The present study investigated the ontogenic expression of a prolactin-like substance (oPRL-ir) in rat hypothalamus from embryonic day (E) 17 to postnatal day (P) 29. By immunocytochemistry, the oPRL-ir peptide was only detected from P3. As in adults, labeled neurons were found exclusively in the lateral hypothalamic area. By in situ hybridization, with a cocktail of oligonucleotides complementary to the PRL mRNA, no labeling was observed in the hypothalamus, although dense labeling was obtained over the pituitary. With reverse transcriptase polymerase chain reaction, a 408 bp band, presumably corresponding to an oPRL mRNA, was detected from PO in the LHA, but also in other brain regions. These results suggest that the oPRL-ir neurons do not contain oPRL. The nature of the oPRL-ir peptide is still unknown, but its late onset of expression may be related to its putative involvement in feeding behavior. PMID- 10102676 TI - Neuropeptide secretion in exercise. AB - Plasma concentrations of atrial natriuretic peptide immunoreactivity (irANP) and brain natriuretic peptide immunoreactivity (irBNP) in elderly normal subjects (mean age 71.1, range 66-81 years, n = 10) were examined before (rest), during (peak of exercise) and after (3 min, 6 min) a treadmill exercise test (modified Bruce protocol). An attempt was also made to determine the effect of steady state exercise (30% and 50%) and posture (supine, sitting) on circulating levels of atrial natriuretic peptide and calcitonin gene-related peptide (CGRP) in man. The results suggest that exercise gives rise to increased levels of irANP and irCGRP, but not human BNP. The study also demonstrated a >40% rise in irCGRP and irANP levels at 50% steady state exercise compared with 30% steady state exercise. irCGRP was shown to decline in the upright position compared with the supine position, and irCGRP did not rise with exercise. Although ANP is normally stored in large concentration in the atria with much less in the ventricles and BNP is derived to a much greater extent from the ventricles, the differential release rate of these peptides may make BNP concentration a more sensitive indicator of left ventricular dysfunction than ANP. The observations obtained here also raise the possibility that the ANP system may not only help to eliminate intermittent overhydration, but also participate in the postural regulation of diuresis and natriuresis and perhaps even support the maintenance of excretory kidney function in the ageing subjects. PMID- 10102678 TI - Synthesis and opioid activity of novel tetrapeptides analogous to sequence (1-4) of dermorphin. AB - Seven new tetrapeptides analogous to (1-4) sequence of dermorphin were synthesized and evaluated for their opioid activity. The peptides were synthesized by the solution phase method. Their opioid activity revealed that peptides II and V were the most potent in the analgesia test as well as in the peripheral assays. Peptide II was most active in the guinea pig ileum assay, whereas peptide VI was 2763 times more selective for mu-receptors. PMID- 10102679 TI - Revised primary structures of rat pituitary gamma-lipotrophin and beta-endorphin. AB - In-depth investigations, by high performance liquid chromatographic purification, radio-immunoassay, mass spectrometry, tandem mass spectrometry, Edman sequencing and limited C-terminal ladder sequencing, were prompted by mass spectrometric charting experiments which suggested that the amino acid sequences for rat gamma lipotrophin and beta-endorphin require revision. The results for gamma lipotrophin identify a histidine for glutamine substitution at position 12, and heterogeneity in the expressed protein presumably due to partial dehydration. Partial dehydration for acidic joining peptide, previously reported by Toney et al was corroborated. The results for beta-endorphin confirm the presence of alanine at position 26 and provide no evidence for the expression of multiple forms of the hormone. PMID- 10102680 TI - Differential response to a stress stimulus of proenkephalin peptide content in immune cells of naive and chronically stressed rats. AB - Proenkephalin peptides produced by endocrine and nervous tissues are involved in stress-induced immunosuppression. However, the role of peptides produced by immune cells remains unknown. The present study examines the effect of acute and chronic foot-shock stress on proenkephalin peptide content in bone marrow (BMMC), thymus (TMC), and spleen (SMC) rat mononuclear cells. Proenkephalin was not processed to met-enkephalin in BMMC, while in TMC and SMC met-enkephalin represented 10% and 26% of total met-enkephalin-containing peptides, respectively. Naive rats receiving a stress stimulus showed a significant decrease of proenkephalin derived peptides in BMMC, TMC and SMC. However, in chronically stressed rats that already showed basal low peptide levels, a new stress stimulus produced a differential response in each immune tissue. That is, in BMMC peptide levels reached control rats values; in TMC remained unmodified; and in SMC, although precursors content increased, met-enkephalin levels were even lower than those observed in acutely stressed rats. Free synenkephalin content paralleled met-enkephalin changes in SMC of acutely and chronically stressed rats. The in vitro release of met-enkephalin and free synenkephalin increased in SMC of stressed rats. Met-enkephalin produced in SMC and partially processed proenkephalin peptides detected in BMMC, were only found in macrophages. However, met-enkephalin only appeared in bone marrow macrophages after at least 4 h of cell culture. Altogether, these results suggest that a stress stimulus induced proenkephalin peptide release from immune tissue macrophages. The differential response observed in chronically stressed rats suggest an alternative activation of heterogeneous proenkephalin-storing macrophage subpopulations. PMID- 10102681 TI - CaM kinase II: a protein kinase with extraordinary talents germane to insulin exocytosis. AB - CaM kinase II, a multifunctional Ca2+/calmodulin-dependent protein kinase, is expressed in the pancreatic beta-cell and is activated by glucose and other secretagogues in a manner correlating with insulin secretion. It is proposed that the activation of CaM kinase II mediates some of the actions of Ca2+ on the exocytosis of insulin secretory granules. This suggestion is supported by the localization of CaM kinase II to the insulin secretory granule and by the identification of two secretory-relevant proteins, MAP-2 and synapsin I, as endogenous substrates in the beta-cell. Mechanistically, CaM kinase II appears to be involved in secretory steps proximal to granule fusion at the plasmalemma, and may facilitate protracted secretion through control of the interaction of granules with the cell cytoskeleton and their mobilization from intracellular synthesis sites. Through its unique regulatory properties, however, CaM kinase II is predicted to serve in more specialized aspects of the secretory process. In particular, the ability of CaM kinase II to remain active after cell stimulation is suggested to represent a mechanism by which releasable pools of granules are replenished between stimuli. PMID- 10102682 TI - DNA demethylation during the differentiation of 3T3-L1 cells affects the expression of the mouse GLUT4 gene. AB - GLUT4 is the major glucose transporter in adipose tissue and skeletal and cardiac muscles. We examined the mechanisms underlying GLUT4 gene expression in 3T3-L1 cells, which express the gene during their differentiation from preadipocytes to adipocytes. In transient transfections, the activity of a mouse GLUT4 promoter extending to -100 bp in the 5'-flanking region did not differ significantly between 3T3-L1 preadipocytes and adipocytes. Promoter activity up to -590 bp in preadipocytes and adipocytes showed a 70% lower and 228% higher activity, respectively, than promoter activity extending to -100 bp. We also examined methylation status of the GLUT4 promoter. Up to -100 bp, there were five CpG sites at -11, -30, -58, -63, and -75 bp. Two CpG sites at -11 and -30 bp were highly methylated in preadipocytes (60 and 92%, respectively) and highly demethylated in adipocytes (28.6 and 25%, respectively). Conversely, three CpG sites at -58, -63, and -75 bp were highly demethylated in both preadipocytes and adipocytes (<12%). In gel mobility-shift assays, a fragment extending from -40 to -1 bp generated a methylation-sensitive band with nuclear extracts from both preadipocytes and adipocytes when the CpG sites were methylated. Southwestern analysis identified a protein of approximately 55 kDa that bound strongly to the methylated probe. Furthermore, methylation of the CpG sites inhibited promoters extending to -50 or -70 bp. These results suggest that in addition to cell type specific transcription factor, methylation of specific CpG sites and the methylation-sensitive transcription factor contribute to GLUT4 gene regulation during 3T3-L1 differentiation. PMID- 10102683 TI - Activation of protein kinase B and induction of adipogenesis by insulin in 3T3-L1 preadipocytes: contribution of phosphoinositide-3,4,5-trisphosphate versus phosphoinositide-3,4-bisphosphate. AB - Ectopic expression of activated protein kinase B (PKB) induces the differentiation of confluent 3T3-L1 preadipocytes into adipocytes. PKB is regulated by the lipid products of phosphoinositide 3-kinase (PI 3-kinase), phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2], and phosphatidylinositol-3,4,5 trisphosphate [PI(3,4,5)P3]. However, the relative contribution of each 3 phosphorylated phosphoinositide species in activating PKB remains unclear. Treatment of intact 3T3-L1 preadipocytes with synthetic 3-phosphorylated phosphoinositides revealed that only PI(3,4)P2 stimulated PKB activity. PKB was also activated by insulin, in a dose- and time-dependent manner. This activation was associated with an isolated rise in PI(3,4,5)P3, without any detectable change in PI(3,4)P2, demonstrating that this lipid was sufficient to activate PKB. Wortmannin and LY294002, inhibitors of PI 3-kinase, reduced insulin dependent activation of PKB, whereas rapamycin, an inhibitor of p70 S6 kinase, had no effect. Platelet-derived growth factor (PDGF), which is not adipogenic, stimulated the production of both 3-phosphorylated phosphoinositide species, and this was associated with a greater activation of PKB than that observed with insulin. A low dose of PDGF (1 ng/ml), which increased the production of only PI(3,4,5)P3 and mirrored the insulin effect, was unable to induce adipocyte differentiation. In summary, insulin and PDGF differ with respect to the accumulation of 3-phosphorylated phosphoinositides and to PKB activation in 3T3 L1 preadipocytes, but these responses do not themselves explain why insulin, but not PDGF, is adipogenic. PMID- 10102684 TI - Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor-gamma in human adipocytes. AB - Peroxisome proliferator-activated receptor (PPAR)-gamma is one of the key actors of adipocyte differentiation. This study demonstrates 1) that PPAR-gamma mRNA expression is not altered in subcutaneous adipose tissue (n = 44) or in skeletal muscle (n = 19) of subjects spanning a wide range of BMIs (20-53 kg/m2) and 2) that insulin acutely increases PPAR-gamma mRNA expression in human adipocytes both in vivo and in vitro. The effect of insulin was investigated in abdominal subcutaneous biopsies obtained before and at the end of a 3-h euglycemic hyperinsulinemic clamp. Insulin significantly increased PPAR-gamma mRNA levels in lean subjects (88 +/- 17%, n = 6), in type 2 diabetic patients (100 +/- 19%, n = 6), and in nondiabetic obese patients (91 +/- 20%, n = 6). Both PPAR-gamma1 and PPAR-gamma2 mRNA variants were increased (P < 0.05) after insulin infusion. In isolated human adipocytes, insulin induced the two PPAR-gamma mRNAs in a dose dependent manner, with half-maximal stimulation at a concentration of approximately 1-5 nmol/l. However, PPAR-gamma2 mRNA was rapidly (2 h) and transiently increased, whereas a slow and more progressive induction of PPAR gamma1 was observed during the 6 h of incubation. In explants of human adipose tissue, PPAR-gamma protein levels were significantly increased (42 +/- 3%, P < 0.05) after 12 h of incubation with insulin. These data demonstrate that PPAR gamma belongs to the list of the insulin-regulated genes and that obesity and type 2 diabetes are not associated with alteration in the expression of this nuclear receptor in adipose tissue. PMID- 10102685 TI - Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes. AB - Nitric oxide (NO), synthesized by the inducible isoform of nitric oxide synthase (iNOS), has been proposed as a mediator of immune-induced beta-cell destruction in type 1 diabetes. To evaluate the role of iNOS for beta-cell dysfunction and death, we investigated the sensitivity of beta-cells from mice genetically deficient in this enzyme (iNOS-/-, background C57BL/6x129SvEv, H-2b) both to interleukin (IL)-1beta-induced beta-cell dysfunction in vitro and to multiple low dose streptozotocin (MLDS)-induced diabetes in vivo. Exposure of islets isolated from C57BL/6 mice to IL-1beta for 24 h in vitro resulted in an induction of iNOS mRNA expression, an increase in nitrite formation, and a decrease in insulin release and proinsulin biosynthesis as compared with untreated C57BL/6 islets. IL 1beta failed to induce iNOS mRNA expression and increase nitrite formation by islets isolated from iNOS knockout mice (iNOS-/-), and no impairment in islet function was observed. The iNOS-/- mice showed a reduced incidence of hyperglycemia after treatment with MLDS as compared with wild-type C57BL/6 (H-2b) and 129 SvEv (H-2b) mice. On day 21 after the first streptozotocin (STZ) injection, 75% of the C57BL/6 mice and 100% of the 129SvEv mice had blood glucose levels >11 mmol/l, whereas the corresponding number for iNOS-/- mice was only 23%. This protection was not due to a delay in the onset of hyperglycemia, since no increase in number of hyperglycemic iNOS-/- mice was observed when the animals were followed up to 42 days. Moreover, islets isolated from iNOS-/- mice were susceptible to the in vitro deleterious effects of STZ. In conclusion, the present study provides evidence that iNOS may contribute to beta-cell damage after exposure to IL-1beta in vitro and treatment with MLDS in vivo. PMID- 10102686 TI - Glucose entrainment of high-frequency plasma insulin oscillations in control and type 2 diabetic subjects. AB - Regular high-frequency oscillations of insulin secretion are characteristic of normal beta-cell function. These oscillations are easily entrainable to an exogenous rhythm by small changes in glucose concentration in vitro. We tested whether high-frequency insulin oscillations in vivo would also be entrainable by glucose and whether a lack of entrainment would characterize the diabetic beta cell. We tested 13 control subjects and 11 patients with type 2 diabetes. Subjects underwent serial blood sampling at 1-min intervals for 60-120 min in the basal state or with small (15 mg/kg) boluses of glucose injected intravenously at exact 29-min intervals. Time series analysis was carried out using spectral analysis. Oscillations of basal plasma glucose concentrations were observed in both control and type 2 diabetic subjects, with a mean period of 11.3 +/- 3.1 and 11.6 +/- 2.0 min, respectively. These oscillations were entrained to mean periods of 15.0 +/- 0.6 and 14.2 +/- 0.9 min, respectively, by exogenous glucose. Regular high-frequency insulin oscillations were observed in control subjects; the mean period of basal plasma insulin oscillations was 10.7 +/- 1.2 min and was entrained to exogenously injected glucose, with a period of 15.2 +/- 0.1 min. In contrast, in the type 2 diabetic subjects, spontaneous insulin oscillations were unchanged by the glucose rhythm; the mean periods were 10.0 +/- 1.0 min during the basal period, and 10.1 +/- 0.0 min during glucose injections. These results demonstrate that spontaneous high-frequency insulin oscillations can be successfully entrained by glucose in control subjects. However, these oscillations in type 2 diabetic subjects are not similarly entrained. We conclude that loss of entrainment of spontaneous high-frequency insulin oscillations in type 2 diabetes is a highly sensitive manifestation of beta-cell secretory dysfunction. PMID- 10102687 TI - Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells. AB - Extracellular factors that regulate the growth and differentiation of cell lineages in the pancreatic primordia are poorly understood. Identification of these factors for pancreatic islet beta-cells could open new avenues for the treatment of insulin-dependent diabetes. We developed a low cell density serum free culture system for dissociated pancreatic cells from the 13.5-day mouse fetus and investigated the effects of extracellular matrix proteins on differentiation of islet cells. After 4 days in culture, total cell number decreased by two-thirds, but insulin-positive beta-cell number increased 10-fold. Both of collagens I and IV inhibited cell survival (by >50%), whereas fibronectin had no effect. In the presence of soluble laminin-1, however, the number of beta cells increased linearly by 60-fold without an increase in the total cell number; glucagon-positive cell number was unchanged, and somatostatin and pancreatic polypeptide-positive cells were not detected. The effect of laminin-1 was completely blocked by a monoclonal rat anti-laminin-1 antibody. In the presence of laminin-1, the thymidine analogue, BrdU, was incorporated into only 2.5% of cells, which were mainly insulin-negative at days 1-3. Laminin-1 appeared, therefore, to induce differentiation of beta-cells from precursor cells in day 13.5 fetal pancreas. Laminin-1 was shown to be expressed in the epithelial basement membrane of the 13.5- to 17.5-day fetal pancreas. These findings provide the first evidence of a role for laminin-1 to promote differentiation of pancreatic beta-cells. PMID- 10102688 TI - Interaction between genetic and dietary factors determines beta-cell function in Psammomys obesus, an animal model of type 2 diabetes. AB - The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studied the interaction between diet and diabetic predisposition for beta-cell function. A 4 day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold increase in serum glucose, insulin, and triglycerides, respectively, in diabetes-prone (DP) but not diabetes-resistant (DR) P. obesus. Hyperglycemia and concurrent 90% depletion of islet immunoreactive insulin stores were partially corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets. The HE diet augmented early and late insulin response in DR islets, whereas in DP islets, secretion progressively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P. obesus by a HE diet, concomitant with a decreased threshold for glucose and a 55% reduction in maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets. There were no differences in islet glucokinase (GK) and hexokinase (HK) Km; however, GK Vmax was 3.7- to 4.6-fold higher in DP islets, and HK Vmax was augmented 3.7-fold by the HE diet in DP islets. We conclude that the insulin-resistant P. obesus has an inherent deficiency in insulin release. In the genetically predisposed P. obesus (DP), augmented islet glucose phosphorylation ability and diet-induced reduction of the glucose threshold for secretion may lead to inadequate insulin secretion and depletion of insulin stores in the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptation to nutritional load seem to determine together the progression to overt diabetes in this species. It is hypothesized that similar events may occur in obese type 2 diabetic patients. PMID- 10102689 TI - Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. AB - The gerbil Psammomys obesus develops nutrition-dependent diabetes associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores. The contribution of changes in beta-cell turnover to insulin deficiency was investigated in vivo during transition to overt diabetes. Normo glycemic diabetes-prone P. obesus animals who were given a high-calorie diet developed hyperglycemia within 4 days, which was found to be associated with a progressive decline in pancreatic insulin content. This was accompanied by a transient increase in beta-cell proliferative activity and by a prolonged increase in the rate of beta-cell death, culminating in disruption of islet architecture. The hypothesis that "glucotoxicity" was responsible for these in vivo changes was investigated in vitro in primary islet cultures. Exposure of islets from diabetes prone P. obesus to high glucose levels resulted in a dose-dependent increase in beta-cell DNA fragmentation. In contrast, high glucose levels did not induce DNA fragmentation in rat islets, whereas islets from a diabetes-resistant P. obesus line exhibited a reduced and delayed response. Aminoguanidine did not prevent glucose-induced beta-cell DNA fragmentation in vitro, suggesting that formation of nitric oxide and/or advanced glycation end products plays no major role. Elevated glucose concentrations stimulated beta-cell proliferation in both rat and P. obesus islets. However, unlike the marked long-lasting effect in rat islets, only a transient and reduced proliferative response was observed in P. obesus islets; furthermore, beta-cell proliferation was inhibited after prolonged exposure to elevated glucose levels. These results suggest that hyperglycemia induced beta-cell death coupled with reduced proliferative capacity may contribute to the insulin deficiency and deterioration of glucose homeostasis in P. obesus. Similar adverse effects of hyperglycemia could play a role in the evolution of type 2 diabetes in genetically susceptible individuals. PMID- 10102690 TI - Gene transfer to human pancreatic endocrine cells using viral vectors. AB - We have studied the factors that influence the efficiency of infection of human fetal and adult pancreatic endocrine cells with adenovirus, murine retrovirus, and lentivirus vectors all expressing the green fluorescent protein (Ad-GFP, MLV GFP, and Lenti-GFP, respectively). Adenoviral but not retroviral vectors efficiently infected intact pancreatic islets and fetal islet-like cell clusters (ICCs) in suspension. When islets and ICCs were plated in monolayer culture, infection efficiency with all three viral vectors increased. Ad-GFP infected 90 95% of the cells, whereas infection with MLV-GFP and Lenti-GFP increased only slightly. Both exposure to hepatocyte growth factor/scatter factor (HGF/SF) and dispersion of the cells by removal from the culture dish and replating had substantial positive effects on the efficiency of infection with retroviral vectors. Studies of virus entry and cell replication revealed that cell dispersion and stimulation by HGF/SF may be acting through both mechanisms to increase the efficiency of retrovirus-mediated gene transfer. Although HGF/SF and cell dispersion increased the efficiency of infection with MLV-GFP, only rare cells with weak staining for insulin were infected, whereas approximately 25% of beta-cells were infected with Lenti-GFP. We conclude that adenovirus is the most potent vector for ex vivo overexpression of foreign genes in adult endocrine pancreatic cells and is the best vector for applications where high-level but transient expression is desired. Under the optimal conditions of cell dispersion plus HGF/SF, infection with MLV and lentiviral vectors is reasonably efficient and stable, but only lentiviral vectors efficiently infect pancreatic beta-cells. PMID- 10102691 TI - Glucose-dependent stimulatory effect of glucagon-like peptide 1(7-36) amide on the electrical activity of pancreatic beta-cells recorded in vivo. AB - The stimulatory effect of the glucagon-like peptide (GLP)-1(7-36) amide on electrical activity in pancreatic b-cells recorded in vivo was studied. The injection of GLP-1 produces a lengthening of the active phase with respect to the silent phase, leading to a stimulation of insulin release, which produces a secondary decrease in blood glucose concentration and eventually, to the hyperpolarization of the membrane at a blood glucose level of approximately 5 mmol/l. The injection of GLP-1 at a glycemic level <5 mmol/l does not stimulate electrical activity. This is in contrast to the effect of tolbutamide, which stimulates electrical activity at low glucose concentrations. These results demonstrate that in vivo, the stimulatory effect of GLP-1 on insulin secretion is at least partially mediated by its effect on beta-cell electrical activity. Furthermore, the glucose dependence of the effect confers to GLP-1, a security factor that supports its potential use in the treatment of type 2 diabetes. PMID- 10102692 TI - NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity. AB - Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis that, like glucagon-like peptide 1(7-36) amide (tGLP-1), has a functional profile of possible therapeutic value for type 2 diabetes. Both incretin hormones are rapidly inactivated in plasma by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study examined the ability of NH2 terminal modification of human GIP to protect from plasma degradation and enhance insulin-releasing and antihyperglycemic activity. Degradation of GIP by incubation at 37 degrees C with purified DPP IV was clearly evident after 4 h (54% intact). After 12 h, >60% of GIP was converted to GIP(3-42), whereas >99% of NH2-terminally modified Tyr1-glucitol GIP remained intact. Tyr1-glucitol GIP was similarly resistant to serum degradation. The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr1-glucitol GIP were examined in Wistar rats after intraperitoneal injection of either peptide (10 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly lower and insulin concentrations higher after both peptides compared with glucose alone. More importantly, individual glucose values at 15 and 30 min together with the areas under the curve (AUCs) for glucose were significantly lower after administration of Tyr1 glucitol GIP compared with GIP (AUC 255 +/- 33 vs. 368 +/- 8 mmol x l(-1) x min( 1), respectively; P < 0.01). This was associated with a significantly greater and more protracted insulin response after Tyr1-glucitol GIP than GIP (AUC 773 +/- 41 vs. 639 +/- 39 ng x ml(-1) x min(-1); P < 0.05). These data demonstrate that Tyr1 glucitol GIP displays resistance to plasma DPP IV degradation and exhibits enhanced antihyperglycemic activity and insulin-releasing action in vivo. PMID- 10102693 TI - Free fatty acids impair hepatic insulin extraction in vivo. AB - Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether FFAs impair hepatic insulin extraction (E(H)) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml x kg(-1) x min(-1)) plus heparin (0.44 U x kg(-1) x min(-1)) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol x kg(-1) x min(-1) for 150 min (period A, high insulin dose), and then at 2.4 pmol x kg(-1) x min(-1) for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol x kg(-1) x min(-1) for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 +/- 167, 1,491 +/- 240, 1,159 +/- 221 micromol/l (IH) and 221 +/- 44, 329 +/- 72, 176 +/- 44 micromol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 +/- 114, 126 +/- 12, 1,050 +/- 72 pmol/l for IH vs. 1,344 +/- 168, 96 +/- 4.2, 882 +/- 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E(H) were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 +/- 0.6, 12.0 +/- 0.9, 10.2 +/- 0.6 ml x kg(-1) x min(-1)) than with SAL (11.2 +/- 1, 13.6 +/- 0.7, 11.9 +/- 0.9 ml x kg(-1) x min(-1)) in periods A, B, and C. E(H) was also lower (P < 0.05) with IH (25 +/- 4, 40 +/- 5, 32 +/- 5%) than with SAL (30 +/- 2.8, 47 +/- 3, 38 +/- 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity. PMID- 10102694 TI - Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. AB - Impaired skeletal muscle glucose utilization under insulin action is a major defect in the etiology of type 2 diabetes. This is underscored by a new mouse model of type 2 diabetes generated by genetic disruption of one allele of glucose transporter 4 (GLUT4+/-), the insulin-responsive glucose transporter in muscle and adipose tissue. Male GLUT4+/- mice exhibited decreased GLUT4 expression and glucose uptake in muscle that accompanied impaired whole-body glucose utilization, hyperinsulinemia, hyperglycemia, and heart histopathology. To determine whether development of the diabetic phenotype in GLUT4+/- mice can be forestalled by preventing the onset of impaired muscle GLUT4 expression and glucose utilization, standard genetic crossing was performed to introduce a fast twitch muscle-specific GLUT4 transgene--the myosin light chain (MLC) promoter driven transgene MLC-GLUT4--into GLUT4+/- mice (MLC-GLUT4+/- mice). GLUT4 expression and 2-deoxyglucose uptake levels were normalized in fast-twitch muscles of MLC-GLUT4+/- mice. In contrast to GLUT4+/- mice, MLC-GLUT4+/- mice exhibited normal whole-body glucose utilization. In addition, development of hyperinsulinemia and hyperglycemia observed in GLUT4+/- mice was prevented in MLC GLUT4+/- mice. The occurrence of diabetic heart histopathology in MLC-GLUT4+/- mice was reduced to control levels. Based on these results, we propose that the onset of a diabetic phenotype in GLUT4+/- mice can be avoided by preventing decreases in muscle GLUT4 expression and glucose uptake. PMID- 10102695 TI - Inhibition of LDL oxidation in vitro but not ex vivo by troglitazone. AB - Diabetic subjects are at increased risk for developing coronary artery disease, in part because of increased oxidation of LDL, which promotes atherogenesis. Troglitazone, a new antidiabetic drug of the thiazolidinedione class, acts as an insulin sensitizer and improves hyperglycemia. Structurally, it contains a tocopherol moiety similar to vitamin E and has been shown to have antioxidant properties in vitro. Therefore, we evaluated whether troglitazone inhibited LDL oxidation both in vitro and in type 2 diabetic subjects ex vivo. Troglitazone inhibited oxidation of LDL induced by Cu2+ or 2'2'-azobis-2-amidinopropane hydrochloride (AAPH) with 50% inhibition at 1 micromol/l and 100% inhibition at 5 10 micromol/l troglitazone. The inhibition of LDL oxidation by troglitazone also was time dependent. In addition, troglitazone inhibited oxidation of 125I-labeled LDL and its subsequent uptake and degradation by macrophages. To determine whether troglitazone was incorporated into LDL particles or acted in the aqueous milieu, troglitazone was incubated overnight at 37 degrees C with LDL or plasma before LDL re-isolation. After re-isolation, LDL that was incubated with troglitazone was no longer protected from oxidation, compared with probucol treated LDL, which remained protected. Further, [14C]troglitazone did not get incorporated into LDL. This suggests that troglitazone exerts its antioxidant effect in the aqueous milieu of LDL. Consistent with this was the observation that the lag phases of copper-induced conjugated diene formation, a measure of the susceptibility in vivo, was similar for subjects taking troglitazone (76 +/- 5 min, n = 9) to subjects not taking the drug (77 +/- 3 min, n = 11; NS). Thus, troglitazone may be of value as an aqueous-phase antioxidant in addition to its effect on glucose homeostasis. PMID- 10102696 TI - Gluconeogenesis in very low birth weight infants receiving total parenteral nutrition. AB - Very low birth weight (VLBW) infants are dependent on total parenteral nutrition (TPN) to prevent hypoglycemia and provide a sufficient energy intake. However, diminished tolerance for parenteral glucose delivered at high rates frequently provokes hyperglycemia. We hypothesized that when their glucose supply is reduced to prevent hyperglycemia, VLBW infants can maintain normoglycemia via gluconeogenesis from glycerol and amino acids. Twenty infants born at 27 +/- 0.2 (mean +/- SE) gestational weeks and having a birth weight of 996 +/- 28 g, received lipids (1.6 +/- 0.1 mg x kg(-1) x min(-1)), protein (2.2 +/- 0.1 mg x kg(-1) x min(-1)), and glucose (3.1 +/- 0.1 mg x kg(-1) x min(-1) [17.1 +/- 0.2 micromol x kg(-1) x min(-1)]) parenterally over a period of 8-12 h on day 5.0 +/- 0.2 of life. Gluconeogenesis was estimated using [U-13C]glucose (n = 8) or [2 (13)C] glycerol (n = 6) and mass isotopomer distribution analysis (MIDA), or 2H2O (n = 6) and the rate of deuterium incorporation in carbon 6 of glucose. Blood glucose averaged 3.0 +/- 0.1 mmol/l; plasma glucose appearance rate (glucose Ra), 28.8 +/- 1.1 micromol x kg(-1) x min(-1); and glucose production rate (GPR), 10.7 +/- 1.0 micromol x kg(-1) x min(-1). The [U-13C]glucose and [2-(13)C]glycerol tracers provided similar estimates of gluconeogenesis, averaging 28 +/- 2 and 26 +/- 2% of glucose Ra and 72 +/- 5 and 73 +/- 9% of GPR, respectively. Glycerol contributed 64 +/- 5% of total gluconeogenesis. Gluconeogenesis measured by 2H2O, which does not include the contribution from glycerol, was comparable to the nonglycerol fraction of gluconeogenesis derived by the [2-(13)C]glycerol MIDA. We conclude that in VLBW infants receiving TPN, normoglycemia was maintained during reduced glucose infusion by glucose production primarily derived from gluconeogenesis, and that glycerol was the principal gluconeogenic substrate. PMID- 10102697 TI - Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats. AB - Insulin-dependent diabetes in rats is characterized by abnormalities of post binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the kidney capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes. PMID- 10102698 TI - Developmental damage, increased lipid peroxidation, diminished cyclooxygenase-2 gene expression, and lowered prostaglandin E2 levels in rat embryos exposed to a diabetic environment. AB - Previous experimental studies suggest that diabetic embryopathy is associated with an excess of radical oxygen species (ROS), as well as with a disturbance of prostaglandin (PG) metabolism. We aimed to investigate the relationship between these pathways and used hyperglycemia in vitro (embryo culture for 24-48 h) and maternal diabetes in vivo to affect embryonic development. Subsequently, we assessed lipid peroxidation and gene expression of cyclooxygenase (COX)-1 and -2 and measured the concentration of prostaglandin E2 (PGE2) in embryos and membranes. Both hyperglycemia in vitro and maternal diabetes in vivo caused embryonic dysmorphogenesis and increased embryonic levels of 8-epi-PGF2alpha, an indicator of lipid peroxidation. Addition of N-acetylcysteine (NAC) to the culture medium normalized the morphology and 8-epi-PGF2alpha concentration of the embryos exposed to high glucose. Neither hyperglycemia nor diabetes altered COX-1 expression, but embryonic COX-2 expression was diminished on gestational day 10. The PGE2 concentration of day 10 embryos and membranes was decreased after exposure to high glucose in vitro or diabetes in vivo. In vitro addition of NAC to high glucose cultures largely rectified morphology and restored PGE2 concentration, but without normalizing the COX-2 expression in embryos and membranes. Hyperglycemia/diabetes-induced downregulation of embryonic COX-2 gene expression may be a primary event in diabetic embryopathy, leading to lowered PGE2 levels and dysmorphogenesis. Antioxidant treatment does not prevent the decrease in COX-2 mRNA levels but restores PGE2 concentrations, suggesting that diabetes-induced oxidative stress aggravates the loss of COX-2 activity. This may explain in part the antiteratogenic effect of antioxidant treatment. PMID- 10102699 TI - Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. AB - We tested the hypothesis that insulin has effects on large artery stiffness in addition to its slow vasodilatory effect on resistance vessels in skeletal muscle, and whether such an effect might be altered in obesity. Eight nonobese (aged 25 +/- 1 years, BMI 22.7 +/- 0.4 kg/m2) and eight obese (aged 27 +/- 2 years, BMI 30.6 +/- 0.9 kg/m2) men were studied under normoglycemic hyperinsulinemic (sequential 2-h insulin infusions of 1 [step 1] and 2 [step 2] mU x kg(-1) x min(-1)) conditions, and another seven men participated in a saline control study. Central aortic pressure waves were synthesized from those recorded in the periphery using applanation tonometry and a validated reverse transfer function every 30 min. This allowed determination of augmentation (the pressure difference between early and late systolic pressure peaks) and the augmentation index (augmentation divided by pulse pressure), a measure of arterial stiffness. Whole-body glucose uptake was reduced by 48 (step 1) and 41% (step 2) (P < 0.01) in the obese subjects versus the nonobese subjects. Basal forearm blood flow averaged 2.5 +/- 0.2 and 2.6 +/- 0.2 ml x dl(-1) x min(-1) in the obese and nonobese subjects, respectively (NS). Insulin induced a significant increase in forearm blood flow after 2.5 h (3.6 +/- 0.4 ml x dl(-1) x min(-1), P < 0.05 vs. basal) in the nonobese subjects and after 4 h in the obese subjects (3.2 +/- 0.2, P < 0.05). In contrast to these slow changes in peripheral blood flow, augmentation and the augmentation index decreased significantly in the nonobese subjects after 1 h (-3.0 +/- 1.6 mmHg and -10.0 +/- 5.4%, respectively, P < 0.001 vs. basal), but remained unchanged until 3 h in the obese subjects. Percent fat (r = 0.86, P < 0.0001) and whole-body glucose uptake (r = -0.72, P < 0.01) correlated with the change in the augmentation index by insulin. These data demonstrate temporal dissociation in insulin's vascular actions. Insulin's effect to decrease arterial stiffness in nonobese subjects (a decrease in wave reflection) is observed under physiological conditions and precedes a slow vasodilatory effect in the periphery. In the obese subjects, insulin's normal effect to decrease central wave reflection is severely blunted. The degree of impairment in this novel vascular action of insulin is closely correlated with the degree of obesity and insulin action on glucose uptake. PMID- 10102700 TI - Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. AB - The decline of leptin (Ob protein) concentrations during fasting is implicated as a signal for increasing the expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamus. To test the hypothesis that the effects of food intake on arcuate nucleus NPY activation are mediated by leptin, we performed simultaneous triple in situ hybridization colocalization studies to determine whether the subset of NPY neurons that are activated by fasting preferentially expresses the long form of the leptin receptor (Ob-Rb). Thus, mRNAs encoding NPY and pro-opiomelanocortin (POMC) were colocalized in the arcuate nucleus of fed and fasted rats by fluorescence in situ hybridization in combination with isotopic in situ hybridization for Ob-Rb mRNA. In fed animals, 47% of arcuate nucleus neurons containing NPY mRNA also contained Ob-Rb mRNA, compared with 79% of POMC neurons (P < 0.01). After a 2-day fast, the number of arcuate nucleus neurons with NPY mRNA increased 50% (P < 0.05); the number of these that coexpressed Ob-Rb increased twofold (P = 0.013). Furthermore, Ob-Rb mRNA hybridization in individual NPY neurons increased by 64% (P < 0.02). In contrast, the number of POMC neurons that coexpressed Ob-Rb was unchanged. A significant interpretation of these findings is that the NPY neurons that do not express detectable levels of Ob-Rb mRNA are not activated by fasting, whereas the NPY neurons that are activated by fasting are the ones that express Ob-Rb. These data demonstrate a significant physiological difference between NPY neurons that express Ob-Rb and those that do not. The results support the conclusion that the effect of food intake on NPY neurons is mediated by the direct action of leptin via Ob-Rb receptors expressed by these NPY cells. The results also indicate that expression of Ob-Rb is a defining phenotypic characteristic of the subset of arcuate nucleus NPY neurons that are activated by fasting and play a central role in the adaptive response to negative energy balance. PMID- 10102701 TI - Effect of insulin on fat metabolism during and after normal pregnancy. AB - Whereas development of resistance to the action of insulin on glucose metabolism during gestation has been recognized, it is presently not known whether there is also resistance to the action of insulin on lipid metabolism. We have, therefore, examined the effect of physiological hyperinsulinemia (during euglycemic hyperinsulinemic clamping) on free fatty acid (FFA) turnover in seven nondiabetic overweight or obese women during and after pregnancy. Basal rates of FFA release, oxidation, and reesterification and basal plasma FFA concentrations were not significantly different from each other during the 2nd and 3rd trimester of pregnancy and postpartum. During euglycemic-hyperinsulinemic (approximately 500 pmol/l) clamping, however, lipolysis was significantly less inhibited during the 3rd trimester (from 7.0 +/- 0.9 to 4.9 +/- 0.9 micromol x kg(-1) x min(-1), -30%) than during the 2nd trimester (from 8.4 +/- 0.6 to 4.1 +/- 0.9 micromol x kg(-1) x min(-1), -51%) and postpartum (from 8.5 +/- 1.1 to 4.2 +/- 0.6 micromol x kg( 1) x min(-1), -51%). Similarly, fat oxidation was not inhibited at all (from 3.5 +/- 0.3 to 3.8 +/- 0.5 micromol x kg(-1) x min(-1)) during the 3rd trimester but was suppressed by 51% (from 3.9 +/- 0.2 to 1.9 +/- 0.3 micromol x kg(-1) x min( 1)) during the 2nd trimester and by 38% (from 2.6 +/- 0.7 to 1.6 +/- 0.5 micromol x kg(-1) x min(-1) postpartum. These data demonstrated that resistance to the action of insulin on lipolysis and on fat oxidation developed during late gestation and disappeared postpartum. PMID- 10102702 TI - Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. AB - Weight loss (WL) decreases regional depots of adipose tissue and improves insulin sensitivity, two parameters that correlate before WL. To examine the potential relation of WL-induced change in regional adiposity to improvement in insulin sensitivity, 32 obese sedentary women and men completed a 4-month WL program and had repeat determinations of body composition (dual-energy X-ray absorptiometry and computed tomography) and insulin sensitivity (euglycemic insulin infusion). There were 15 lean men and women who served as control subjects. VO2max was unaltered with WL (39.2 +/- 0.8 vs. 39.8 +/- 1.1 ml x fat-free mass [FFM](-1) x min(-1)). The WL intervention achieved significant decreases in weight (100.2 +/- 2.6 to 85.5 +/- 2.1 kg), BMI (34.3 +/- 0.6 to 29.3 +/- 0.6 kg/m2), total fat mass (FM) (36.9 +/- 1.5 to 26.1 +/- 1.3 kg), percent body fat (37.7 +/- 1.3 to 31.0 +/ 1.5%), and FFM (59.2 +/- 2.3 to 55.8 +/- 2.0 kg). Abdominal subcutaneous and visceral adipose tissue (SAT and VAT) were reduced (494 +/- 19 to 357 +/- 18 cm2 and 157 +/- 12 to 96 +/- 7 cm2, respectively). Cross-sectional area of low density muscle (LDM) at the mid-thigh decreased from 67 +/- 5 to 55 +/- 4 cm2 after WL. Insulin sensitivity improved from 5.9 +/- 0.4 to 7.3 +/- 0.5 mg x FFM( 1) x min(-1) with WL. Rates of insulin-stimulated nonoxidative glucose disposal accounted for the majority of this improvement (3.00 +/- 0.3 to 4.3 +/- 0.4 mg x FFM(-1) x min(-1)). Serum leptin, triglycerides, cholesterol, and insulin all decreased after WL (P < 0.01). After WL, insulin sensitivity continued to correlate with generalized and regional adiposity but, with the exception of the percent decrease in VAT, the magnitude of improvement in insulin sensitivity was not predicted by the various changes in body composition. These interventional weight loss data underscore the potential importance of visceral adiposity in relation to insulin resistance and otherwise suggest that above a certain threshold of weight loss, improvement in insulin sensitivity does not bear a linear relationship to the magnitude of weight loss. PMID- 10102703 TI - Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. AB - Detailed metabolic studies were carried out to compare major regulatory steps in glucose metabolism in vivo between 25 normal pregnant Latino women without and 150 pregnant Latino women with gestational diabetes mellitus (GDM). The two groups were frequency-matched for age, BMI, and gestational age at testing in the third trimester. After an overnight fast, women with GDM had higher fasting plasma glucose (P = 0.0001) and immunoreactive insulin (P = 0.0003) concentrations and higher glucose production rates (P = 0.01) but lower glucose clearance rates (P = 0.001) compared with normal pregnant women. During steady state hyperinsulinemia (approximately 600 pmol/l) and euglycemia (approximately 4.9 mmol/l), women with GDM had lower glucose clearance rates (P = 0.0001) but higher glucose production rates (P = 0.0001) and plasma free fatty acid (FFA) concentrations (P = 0.0002) than the normal women. These intergroup differences persisted when a subgroup of 116 women with GDM who were not diabetic < or = 6 months after pregnancy were used in the analysis. When all subjects were considered, there was a very close correlation between glucose production rates and plasma FFA concentrations throughout the glucose clamps in control (r = 0.996) and GDM (r = 0.995) groups. Slopes and intercepts of the relationships were nearly identical, suggesting that blunted suppression of FFA concentrations contributed to blunted suppression of glucose production in the GDM group. In addition to these defects in insulin action, women with GDM had a 67% impairment of pancreatic beta-cell compensation for insulin resistance compared with normal pregnant women. These results demonstrate that women with GDM have multiple defects in insulin action together with impaired compensation for insulin resistance. Our findings suggest that defects in the regulation of glucose clearance, glucose production, and plasma FFA concentrations, together with defects in pancreatic beta-cell function, precede the development of type 2 diabetes in these high-risk women. PMID- 10102704 TI - Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. AB - The transcriptional nuclear factor (NF)-kappaB can be activated by diverse stimuli such as cytokines, mitogens, oxidative stress, and lipids, leading to the transactivation of several genes that play important roles in the development of atherosclerosis. Because oxidative stress may play a key role in the pathogenesis of diabetic vascular disease, we have examined whether culture of porcine vascular smooth muscle cells (PVSMCs) under high glucose (HG) conditions (25 mmol/l) to simulate the diabetic state can lead to the activation of NF-kappaB, and also whether cytokine- or growth factor-induced NF-kappaB activation is altered by HG culture. We observed that PVSMCs cultured in HG showed significantly greater activation of NF-kappaB in the basal state compared with cells cultured in normal glucose (NG) (5.5 mmol/l). Treatment of the cells with cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1beta, or with growth factors, such as platelet-derived growth factor, insulin-like growth factor-I, and epidermal growth factor, all led to NF-kappaB activation in cells cultured in both NG and HG. However, their effects were markedly greater in HG. The augmented TNF-alpha-induced NF-kappaB activation in HG was associated with increased TNF-alpha-mediated transcriptional activation of the vascular cell adhesion molecule-1 promoter. Immunoblotting with an antibody to the p65 subunit of NF-kappaB indicated that the levels of this protein were higher in the nuclear extracts from cells cultured in HG compared with NG. Cells cultured in HG also produced significantly greater amounts of the reactive oxygen species superoxide. HG-induced NF-kappaB activation was inhibited by a protein kinase C inhibitor, calphostin C. These results suggest that hyperglycemia-induced activation of NF kappaB in VSMCs may be a key mechanism for the accelerated vascular disease observed in diabetes. PMID- 10102705 TI - Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs. AB - Only a minority of patients with type 1 diabetes develop diabetic nephropathy (DN). Poor glycemic control cannot fully explain DN risk, and family studies suggest genetic susceptibility factors. To understand familial DN concordance, we evaluated glomerular structure in families with type 1 diabetic sibling pairs. Kidney function and biopsy studies were performed in 21 probands (P) (first to develop diabetes) and 21 siblings (S) (second to develop diabetes), most with normal urinary albumin excretion rates (UAER). Glomerular structure was measured by morphometry. Intrafamilial correlation was estimated by one-way random-effects ANOVA and by mixed-effects ANOVA, adjusting for age and duration of diabetes. Diabetes duration was, by definition, longer in P than in S, while age and sex were similar. HbA1c over 5 years and blood pressure were not different in P and S and were without familial effect. UAER was greater in P than in S (P < 0.05), with strong familial effect (P = 0.03). A strong concordance among siblings for mesangial fractional volume (P < or = 0.01) remained significant after adjustment for diabetes duration and age (P = 0.04). Results were similar for mesangial cell (P = 0.01; adjusted P = 0.04) and mesangial matrix fractional volumes (P < 0.01; adjusted P = 0.06). There was also clustering of the patterns of glomerular lesions. For example, if P had relatively marked glomerular basement membrane thickening compared with mesangial matrix expansion, S had a similar pattern (chi2, P < 0.025). Strong concordance in severity and patterns of glomerular lesions in type 1 diabetic siblings, despite lack of concordance in glycemia, supports an important role for genetic factors in DN risk. PMID- 10102706 TI - Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. AB - The relationships between long-term intensive control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon) [carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0.001) and also of the secondary intervention cohort (P < 0.015-0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c). PMID- 10102707 TI - Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. AB - Aberrant neurofilament phosphorylation occurs in many neurodegenerative diseases, and in this study, two animal models of type 1 diabetes--the spontaneously diabetic BB rat and the streptozocin-induced diabetic rat--have been used to determine whether such a phenomenon is involved in the etiology of the symmetrical sensory polyneuropathy commonly associated with diabetes. There was a two- to threefold (P < 0.05) elevation of neurofilament phosphorylation in lumbar dorsal root ganglia (DRG) of diabetic rats that was localized to perikarya of medium to large neurons using immunocytochemistry. Additionally, diabetes enhanced neurofilament M phosphorylation by 2.5-fold (P < 0.001) in sural nerve of BB rats. Neurofilaments are substrates of the mitogen-activated protein kinase (MAPK) family, which includes c-jun NH2-terminal kinase (JNK) or stress-activated protein kinase (SAPK1) and extracellular signal-regulated kinases (ERKs) 1 and 2. Diabetes induced a significant three- to fourfold (P < 0.05) increase in phosphorylation of a 54-kDa isoform of JNK in DRG and sural nerve, and this correlated with elevated c-Jun and neurofilament phosphorylation. In diabetes, ERK phosphorylation was also increased in the DRG, but not in sural nerve. Immunocytochemistry showed that JNK was present in sensory neuron perikarya and axons. Motoneuron perikarya and peroneal nerve of diabetic rats showed no evidence of increased neurofilament phosphorylation and failed to exhibit phosphorylation of JNK. It is hypothesized that in sensory neurons of diabetic rats, aberrant phosphorylation of neurofilament may contribute to the distal sensory axonopathy observed in diabetes. PMID- 10102708 TI - Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue. AB - Plasminogen activator inhibitor 1 (PAI-1) is likely to play a role in vascular disease, primarily in subjects with android obesity. It has been demonstrated that PAI-1 is overexpressed in adipose tissue from obese subjects and that visceral adipose tissue produced more PAI-1 than subcutaneous fat. In the present study, the effect of insulin and glucocorticoids, which are key mediators of adipose tissue metabolism, was examined in relation to PAI-1 synthesis by human adipose tissue explants (HAT), collagenase isolated human adipocytes (IHA), cultured human stromal cells (cSC), and differentiated adipocytes from the murine clonal cell line 3T3-F442A. A significant increase in PAI-1 antigen release (1.5 fold) from HAT was detectable after 16 h of treatment with insulin concentrations of at least 10(-8) mol/l. This was associated with a PAI-1 mRNA increase. Concomitant addition of insulin (10(-8) mol/l) to forskolin (5 x 10(-5) mol/l) reversed the decrease in PAI-1 antigen caused by forskolin alone. No effect on PAI-1 antigen was observed when insulin was incubated with IHA or cSC. 3T3 F442A cells were sensitive to insulin with a four- and twofold increase in PAI-1 antigen and mRNA levels, respectively, after 16 h of stimulation with 10(-8) mol/l. Dexamethasone (DXM) significantly enhanced PAI-1 antigen and mRNA expression by HAT (1.5- and 2.5-fold increase, respectively) at concentrations of at least 10(-8) mol/l. A higher stimulation was observed with IHA (sevenfold increase) and with the differentiated 3T3 F442 cell line. Cortisol was found to be less potent than DXM. No effect was observed when glucocorticoids were incubated with cSC. Coincubation of HAT with insulin (10(-7) mol/l) and DXM (10( 7) mol/l) led to an additive effect on PAI-1 synthesis. These results support the hypothesis that PAI-1 expression in human adipose tissue is controlled by insulin and glucocorticoids and may help to explain the increase in plasma PAI-1 levels observed in patients with android obesity. PMID- 10102709 TI - Effect of glycemia on mortality in Pima Indians with type 2 diabetes. AB - The effect of plasma glucose concentration on overall and cause-specific mortality was examined in 1,745 Pima Indians (725 men, 1,020 women) > or = 15 years old with type 2 diabetes. During a median follow-up of 10.6 years (range 0.1-24.8), 533 subjects (275 men, 258 women) died; 113 of the deaths were attributable to cardiovascular disease, 96 to diabetes-related diseases (diabetic nephropathy for 92 of these), 249 to other natural causes, and 75 to external causes. After adjusting for age, sex, duration of diabetes, and BMI in a generalized additive proportional hazards model, higher baseline 2-h postload plasma glucose concentration predicted deaths from cardiovascular disease (P = 0.007) and diabetes-related diseases (P = 0.003), but not from other natural causes (P = 0.73). An increment of 5.6 mmol/l (100 mg/dl) in the 2-h plasma glucose concentration was associated with 1.2 times (95% CI 1.1-1.4) the death rate from cardiovascular disease, 1.3 times (95% CI 1.1-1.5) the death rate from diabetes-related diseases, and almost no change in the death rate from other natural causes (rate ratio = 1.0; 95% CI 0.94-1.1). In Pima Indians with type 2 diabetes, higher plasma glucose concentration predicts deaths from cardiovascular and diabetes-related diseases but has little or no effect on deaths from other natural or external causes. PMID- 10102710 TI - Pivotal role of nitric oxide in the control of blood pressure after leptin administration. AB - Leptin administration has been shown to increase renal, adrenal, and lumbar sympathetic nerve activity. However, this generalized sympathoexcitatory activity is not always followed by an increase in arterial pressure. The present study tested the hypothesis that leptin induces a release of nitric oxide (NO) that opposes the pressor effect of sympathoexcitation. The effect of intravenous administration of leptin (10, 100, and 1,000 microg/kg body wt) or vehicle on blood pressure (BP), heart rate (HR), and serum nitrite/nitrate concentrations of anesthetized Wistar rats was examined. At 90 min after injection, the three leptin doses tested increased serum NO concentrations 20.5, 33.1, and 89.5%, respectively (P < 0.001 vs. baseline). The effect of leptin on NO concentrations was significantly dose-dependent on linear trend testing (P = 0.0001). In contrast, leptin did not change serum nitrite/nitrate concentrations of fa/fa rats. Leptin administration to Wistar rats under NO synthesis inhibition (N(omega)-nitro-L-arginine methyl ester [L-NAME]) produced a statistically significant increase (P < 0.05) in both systolic BP and mean arterial pressure as well as in HR (P < 0.01). Injection of leptin into rats with pharmacologically induced ganglionic blockade (chlorisondamine) was followed by a decrease in BP and HR to values significantly lower (P < 0.01) than those observed with chlorisondamine treatment alone. The leptin-induced hypotension observed in the setting of ganglionic blockade was blocked by L-NAME. These findings raise the possibility that the leptin-induced release of NO may contribute to the homeostasis of BP. PMID- 10102711 TI - Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients. AB - There is evidence for genetic predisposition to diabetic nephropathy in type 1 diabetic patients. However, there are few studies on type 2 diabetic patients, and most of those have been conducted on ethnic minorities or Caucasian individuals. The aim of this study was to ascertain the presence of an inherited predisposition to diabetic nephropathy in a sample of Brazilian type 2 diabetic patients. Families with two or more type 2 diabetic siblings were identified. Subjects with the longest duration of known diabetes were considered probands. Some 90 probands and their 107 diabetic siblings were studied. Urinary albumin excretion rate was measured in a sterile 24-h urine sample on at least three different occasions. Probands and siblings were classified according to urinary albumin excretion rate as normo- (<20 microg/min), micro- (20-200 microg/min), or macroalbuminuric (>200 microg/min). Patients with end-stage renal disease were included in the macroalbuminuric group. Macroalbuminuria was identified in 5.2% of the siblings of normoalbuminuric probands and in 24.1% of the siblings of macroalbuminuric probands (P = 0.024). In multiple logistic regression, the presence of diabetic nephropathy in probands (micro- or macroalbuminuria and end stage renal disease) was significantly associated with the presence of sibling diabetic nephropathy (odds ratio = 3.75, 95% CI = 1.36-10.40, P = 0.011) adjusted for proband fasting plasma glucose and diabetes duration. Interpretation of these results should take into account the possibility that the families including siblings with diabetic nephropathy may have been overcounted and, on the other hand, that the siblings without diabetic nephropathy may have been undercounted. In conclusion, there is a familial aggregation of diabetic nephropathy in this sample of type 2 diabetic patients. PMID- 10102712 TI - Intermediate expansions of a GAA repeat in the frataxin gene are not associated with type 2 diabetes or altered glucose-induced beta-cell function in Danish Caucasians. AB - A variable expansion of a GAA repeat is present in the first intron of the frataxin gene, also termed FRDA1 or X25. Long repeat lengths (>66 repeats) are present in patients with Friedreich's ataxia, while an intermediate expansion (10 66 repeats) has recently been reported to be highly associated with type 2 diabetes. Using a polymerase chain reaction-based assay, we found that 32.4% (95%CI 29.9-34.9) of 636 Danish Caucasian type 2 diabetic patients were carriers of an intermediate expansion, whereas the frequency was 30.4% (26.4-34.4) among 224 matched glucose-tolerant control subjects (P = 0.6). In the control subjects, the values of serum insulin and C-peptide responses during an oral glucose tolerance test were similar between the 69 carriers and 155 noncarriers. Furthermore, we investigated a possible relationship between expansions of the FRDA1 gene and glucose-induced beta-cell function in 338 young Caucasians (33.7% [30.1-37.3] carriers) and in 215 glucose-tolerant subjects (31.0% [26.6-35.4] carriers) with a type 2 diabetic parent. In neither population did the carriers differ from noncarriers according to values of fasting plasma glucose, serum insulin, or C-peptide, acute serum insulin, or C-peptide responses after intravenous glucose. In conclusion, intermediate expansion of the frataxin trinucleotide repeat is not associated with type 2 diabetes or altered glucose induced insulin secretion in Danish Caucasians. PMID- 10102713 TI - Expression of naturally occurring variants in the muscle glycogen synthase gene. PMID- 10102714 TI - Allelic drop-out in exon 2 of the hepatocyte nuclear factor-1alpha gene hinders the identification of mutations in three families with maturity-onset diabetes of the young. PMID- 10102715 TI - Altered beta-cell characteristics in impaired glucose tolerant carriers of a GAA trinucleotide repeat polymorphism in the frataxin gene. AB - Friedreich's ataxia is associated with GAA trinucleotide repeat expansions in the frataxin gene. In the general population, these trinucleotide expansions are variable in length, and three types of expansions are seen: short, intermediate, and long repeats. Friedreich's ataxia patients are generally homozygous for the long repeats and exhibit diabetes as pronounced comorbidity. Ristow et al. recently reported an association between the intermediate-length normal allele in the frataxin gene and type 2 diabetes. We have investigated in 94 subjects with impaired glucose tolerance (IGT) as to whether the length of the GAA trinucleotide repeat polymorphism in the frataxin gene associates with parameters reflecting beta-cell function. A hyperglycemic clamp at 10 mmol/l glucose for 3 h was used to quantitate beta-cell characteristics. Carriers of one or two intermediate repeat alleles (n = 32) had a 50% higher median first- phase insulin response to glucose than the noncarriers. Furthermore, they needed less time to reach peak insulin. An analysis of the distribution of the various repeat lengths in elderly type 2 diabetic (n = 179) and control subjects (n = 183), with the same age and ethnic background, did not provide evidence for an association of the intermediate-length repeat allele with type 2 diabetes in Dutch Caucasians. PMID- 10102716 TI - Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. AB - Reactive oxygen species are involved in a diversity of biological phenomena such as inflammation, carcinogenesis, aging, and atherosclerosis. We and other investigators have shown that the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative stress, is increased in either the urine or the mononuclear cells of the blood of type 2 diabetic patients. However, the association between type 2 diabetes and oxidative stress in the pancreatic beta cells has not been previously described. We measured the levels of 8-OHdG and 4 hydroxy-2-nonenal (HNE)-modified proteins in the pancreatic beta-cells of GK rats, a model of nonobese type 2 diabetes. Quantitative immunohistochemical analyses with specific antibodies revealed higher levels of 8-OHdG and HNE modified proteins in the pancreatic beta-cells of GK rats than in the control Wistar rats, with the levels increasing proportionally with age and fibrosis of the pancreatic islets. We further investigated whether the levels of 8-OHdG and HNE-modified proteins would be modified in the pancreatic beta-cells of GK rats fed with 30% sucrose solution or 50 ppm of voglibose (alpha-glucosidase inhibitor). In the GK rats, the levels of 8-OHdG and HNE-modified proteins, as well as islet fibrosis, were increased by sucrose treatment but reduced by voglibose treatment. These results indicate that the pancreatic beta-cells of GK rats are oxidatively stressed, and that chronic hyperglycemia might be responsible for the oxidative stress observed in the pancreatic beta-cells. PMID- 10102717 TI - Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS prophylaxis. AB - PURPOSE: The purpose of this study was to develop, implement, and evaluate a practice guideline using ketoconazole for the prevention of the adult respiratory distress syndrome (ARDS) in critically ill patients. MATERIALS AND METHODS: In hospital A (study hospital), we developed a guideline for ketoconazole prophylaxis in patients at high risk of ARDS using evidence from two randomized trials. We prospectively implemented the guideline using intensive care unit (ICU) teaching sessions, in-services, informational posters, and patient-specific individual audit and feedback. ICU caregivers in hospital B (concurrent control hospital) did not participate in the guideline development or implementation and were unaware of the conduct of the study. RESULTS: Patients at risk of ARDS were similar in hospitals A and B. Implementation of the guideline was associated with a significantly higher use of ketoconazole use for ARDS prevention (P < .0001) and a significantly lower rate of ARDS (P < .05) in hospital A compared with hospital B. Mortality, duration of ventilation, and ICU stay were similar. CONCLUSION: Development and implementation of a prophylactic ketoconazole practice guideline for ICU patients at high risk of ARDS was associated with a higher prescription of ketoconazole and a lower rate of ARDS in the study hospital than in the control hospital. PMID- 10102718 TI - Relationship between blood lactate and early hepatic dysfunction in acute circulatory failure. AB - PURPOSE: The purpose of this study was to assess the influence of early hepatic dysfunction on lactate level in patients with acute circulatory failure in a retrospective study. MATERIALS AND METHODS: Blood lactate was compared between patients in acute circulatory failure (systolic blood pressure < or = 80 mm Hg despite fluid challenge) with or without early hepatic dysfunction (bilirubin > 60 micromol/L or SGOT > 100 IU/L during the first 48 hours). Univariate and multivariate analysis were performed to assess the effects of early hepatic dysfunction and other clinical and biological data on serum lactate levels in patients with acute circulatory failure. RESULTS: The study included 92 patients, mean age 64+/-15 years, mean simplified acute physiology score (SAPS) 18.4+/-4.1. Early hepatic dysfunction was identified in 29 patients (32%). Mean initial blood lactate was 5.54+/-4.78 mmol/L. Overall intensive care unit mortality was 67.3%. Although patients with and without hepatic dysfunction showed no significant difference in terms of mean SAPS, mean lowest systolic blood pressure, and mortality, serum lactate was higher in the group with hepatic dysfunction than in the group without hepatic dysfunction (8.24+/-6.49 mmol/L v4.29+/-3.09 mmol/L, P < .001). Factors independently associated with serum lactate were the existence of early hepatic dysfunction (P < .01), a nondistributive type of shock (P < .05), and the mean initial amount of epinephrine (P < .05). CONCLUSIONS: This study suggests that early hepatic dysfunction plays an important role in serum lactate elevation in acute circulatory failure. PMID- 10102719 TI - Effect of hospital-acquired ventilator-associated pneumonia on mortality of severe community-acquired pneumonia. AB - PURPOSE: The purpose of this article is to evaluate, using two pairwise case control studies, attributable mortality linked to hospital-acquired ventilator associated pneumonia (HA-VAP) complicating the intensive care unit (ICU) stay of patients exhibiting severe community-acquired pneumonia (CAP). MATERIALS AND METHODS: Over an 11-year period, 498 patients with severe CAP were collected. Among them, 43 exhibited HA-VAP. In a first case-control study, these patients were matched with control on the basis of six confounding variables known to be general ICU prognosis factors. In a second case-control study, six variables specifically linked to CAP prognosis were used for matching. RESULTS: In the two case-control studies, each case patient was matched with one control patient. In the first analysis, success of matching was achieved in 198 of 258 (77%) variables used for matching. In the second analysis, matching was successful for 242 of 258 (94%) confounding variables used. Eighteen patients died, compared with, respectively, 6 (P = .003) and 7 (P = .01) controls. Attributable mortality of HA-VAP was similar in the two pairwise analyses, respectively, 28% (risk ratio = 3.0; 95% confidence interval, 1.32 to 6.82) and 26% (risk ratio = 2.57; 95% confidence interval, 1.2 to 5.52). CONCLUSION: When confounding factors were controlled, HA-VAP appeared to increase mortality of severe CAP requiring ICU admission. PMID- 10102720 TI - Liquid ventilation attenuates pulmonary oxidative damage. AB - PURPOSE: Liquid perfluorochemicals reduce the production of reaction oxygen species by alveolar macrophages. We sought to determine whether the use of liquid perfluorochemicals in vivo during liquid ventilation would attenuate oxidative damage to the lung. MATERIALS AND METHODS: Healthy infant piglets (n = 16) were instrumented for mechanical ventilation and received intravenous oleic acid to create an acute lung injury. The animals were assigned to a nontreatment group receiving conventional mechanical ventilation or a treatment group receiving partial liquid ventilation with a liquid perfluorochemical. Following sacrifice, the bronchoalveolar lavage and lung parenchyma were analyzed for evidence of oxidative damage to lipids and proteins by determination of TBARS and carbonylated protein residues, respectively. RESULTS: Mortality in the control group was 50% at the completion of the study compared with no deaths in the partial liquid ventilation group (P = .025). The alveolar-arterial oxygen difference was more favorable following injury in the partial liquid ventilation group. The liquid ventilation group demonstrated a 32% reduction in TBARS (P = .043) and a 14% reduction in carbonylated protein residues (P = .061). CONCLUSION: These data suggest that partial liquid ventilation supports gas exchange and reduces mortality in association with a reduction in the production of reactive oxygen species and the concomitant attenuation of tissue damage during the early phase of acute lung injury. PMID- 10102721 TI - Katacalcin and calcitonin immunoreactivity in different types of leukocytes indicate intracellular procalcitonin content. AB - PURPOSE: Procalcitonin is a new marker of severity of nonviral, in particular, bacterial infections. In respect of sepsis its site of production remains unknown. This study was carried out to determine whether subsets of human leukocytes contain procalcitonin. MATERIALS AND METHODS: Blood samples of 17 patients who had demonstrated various degrees of serum procalcitonin levels on the day before evaluation were analyzed for serum procalcitonin by immunoluminometry and for intracellular reaction of monocytes, granulocytes, B-, and T-lymphocytes against katacalcin- or calcitonin-sensitive antibodies. Katacalcin and calcitonin are part of the procalcitonin molecule. Associations of these reactions with serum procalcitonin levels as well as differences between groups with a normal or elevated serum level were analyzed. RESULTS: Intracellular antibody reaction against katacalcin was demonstrated in all cell types. We also found a lower rate of intracellular antibody reaction against calcitonin. Associations of serum procalcitonin with the two antibody reactions were demonstrated. Differences in intracellular reactions in the group with elevated serum procalcitonin were seen with both antibodies compared with a normal control. CONCLUSION: Intracellular antibody reaction against katacalcin supports the notion that various types of leukocytes contain procalcitonin. PMID- 10102722 TI - Effect of gastric feeding on intragastric P(CO2) tonometry in healthy volunteers. AB - PURPOSE: The tonometric detection of a high intragastric regional P(CO2) (PrCO2) reflecting an elevated intramucosal P(CO2) can be helpful to diagnose mucosal ischemia, if acid secretion is suppressed to avoid intragastric CO2 production through buffering of acid by bicarbonate in the stomach. It is recommended to perform tonometry in the fasting state, but this may hamper feeding of the critically ill. On the other hand, postfeeding tonometry could serve as a diagnostic stress test because feeding increases mucosal blood flow demand, provided that the meal itself does not hamper diffusion of CO2 from mucosa to tonometer balloon and does not generate intragastric CO2, independently from intramucosal P(CO2). We therefore studied the effect of a standard meal on intragastric PrCO2 tonometry in healthy volunteers with suppression of meal stimulated gastric acid secretion and, presumably, with an adequate mucosal blood flow reserve. MATERIAL AND METHODS: The gastric juice pH and tonometric PrCO2 were measured in 14 human volunteers, after gastric acid secretion suppression by either ranitidine (100-mg bolus, followed by 25 mg/h i.v., n = 7) or by ranitidine plus pirenzepine (10-mg bolus, followed by 3 mg/h i.v., n=7) to suppress any residual meal-stimulated gastric acid secretion, before and at 30 minute intervals until 120 minutes after oral ingestion of a standard liquid test meal (Pulmocare [Abbott, the Netherlands]; 500 mL, 750 kcal, P(CO2) 5 mm Hg, pH 7.50). RESULTS: The gastric juice pH, which was >4.0 in all individuals throughout the study, and the PrCO2 did not depend on the regimen for gastric acid secretion suppression, and therefore the data were pooled. The PrCO2 (median [range]) after feeding was 69% (56% to 170%) of baseline (42 [37-51] mm Hg) from 0 to 30 minutes (P < .001), 85% (72% to 167%) of baseline from 30 to 60 (P < .05), 97% (57% to 193%) from 60 to 90 minutes, and 112% (97% to 189%) of baseline from 90 to 120 minutes with a rise above baseline in 10 of 14 patients. In vitro, the liquid test meal generated CO2 after adding bicarbonate but not after hydrochloric acid. CONCLUSION: We recommend intragastric tonometry to be performed in the fasting state and discourage tonometry after feeding as a stress test, because a single test meal changes tonometric PrCO2 in a time-dependent manner until 2 hours after gastric feeding of healthy volunteers. The fall in PrCO2 directly after feeding can be attributed to dilution, whereas a rise above baseline in some patients may have been caused, as supported by CO2 production after adding bicarbonate to the test meal in vitro, by CO2 production through buffering of meal-derived acid by gastric bicarbonate, in the absence of stimulated gastric acid secretion by feeding. PMID- 10102723 TI - Weaning from mechanical ventilation. AB - For most mechanically ventilated patients, weaning can be accomplished quickly and easily. However, there is a smaller group of ventilated patients who fail to wean and remain ventilator-dependent. These patients account for a significant amount of health care costs and pose a great challenge for clinicians. Detailed knowledge of the etiology and pathophysiology of weaning failure is very important for the "treatment" of difficult to wean patients, and is thoroughly presented in this article. Based on this physiological background, strategies and techniques are proposed that are useful for the gradual transition to spontaneous ventilation. PMID- 10102724 TI - Genetics and child psychiatry: I Advances in quantitative and molecular genetics. AB - Advances in quantitative psychiatric genetics as a whole are reviewed with respect to conceptual and methodological issues in relation to statistical model fitting, new genetic designs, twin and adoptee studies, definition of the phenotype, pervasiveness of genetic influences, pervasiveness of environmental influences, shared and nonshared environmental effects, and nature-nurture interplay. Advances in molecular genetics are discussed in relation to the shifts in research strategies to investigate multifactorial disorders (affected relative linkage designs, association strategies, and quantitative trait loci studies); new techniques and identified genetic mechanisms (expansion of trinucleotide repeats, genomic imprinting, mitochondrial DNA, fluorescent in-situ hybridisation, behavioural phenotypes, and animal models); and the successful localisation of genes. PMID- 10102725 TI - Genetics and child psychiatry: II Empirical research findings. AB - Key substantive findings from quantitative and molecular genetic research are reviewed in relation to affective disorder, schizophrenia, autism, hyperkinetic/attention deficit disorder, oppositional and conduct disorders, drug/alcohol problems, and Tourette's syndrome/chronic tics. PMID- 10102726 TI - Comorbidity. AB - We review recent research on the prevalence, causes, and effects of diagnostic comorbidity among the most common groups of child and adolescent psychiatric disorders; anxiety disorders, depressive disorders, attention deficit hyperactivity disorders, oppositional defiant and conduct disorders, and substance abuse. A meta-analysis of representative general population studies provides estimates of the strength of associations between pairs of disorders with narrower confidence intervals than have previously been available. Current evidence convincingly eliminates methodological factors as a major cause of comorbidity. We review the implications of comorbidity for understanding the development of psychopathology and for nosology. PMID- 10102727 TI - The treatment of the long-term sequelae of child abuse. AB - The literature on the long-term sequelae of sexual and physical abuse is reviewed. Abused children are at risk of long-term adverse psychological sequelae related to the abuse per se and not just as a consequence of other associated background factors. There is some specificity relating the type of psychological outcome to the type of abuse experienced. Physical abuse is just as traumagenic as sexual abuse in the long-term. Whatever the efficacy of specific psychological treatments, there are broad general service measures that will prevent both abuse and re-abuse and therefore impact on long-term sequelae. The studies on the effectiveness of intervention to prevent psychological sequelae of abuse are systematically appraised. There are few well-conducted and adequately controlled studies of the efficacy of treatment for abused children. Where a corpus of studies does exist, e.g. group therapy for sexually abused children, treatment for abused children appears to be as effective for children whose problems arise from other causes. Studies have also shown that abusive parenting can be changed by training. PMID- 10102728 TI - Neuroimaging in the developmental disorders: the state of the science. AB - The developmental disorders of childhood autistic, developmental language, reading (dyslexia), and attention deficit-hyperactivity disorders-manifest with deficits in the traditional behavioral domains of cognition, language, visual spatial function, attention, and socialization. However, none of these disorders has been associated with characteristic discrete focal lesions or recognized encephaloclastic processes. Developmental cognitive neuroscientists must therefore begin with the spectrum of sometimes divergent behaviors occurring within these disorders and work backward in an attempt to identify the responsible anomalous neural systems. Since the advent of "brain imaging" two decades ago, much effort has focused on identifying brain-behavior correlates in these disorders. The results of these neuropathologic, structural, and functional neuroimaging studies are presented and the reasons for the often divergent findings are discussed. As we approach the end of the Decade of the Brain, current neuroimaging techniques give us the technology for the first time to apply a fundamental cognitive approach to brain-behavior relationships in the developmental disorders, to eliminate the conglomeration of "apples and camels" phenomenon. Researchers are working together to create comparable protocols and to adhere to methods that can be replicated across sites. The future prospects for a greater understanding of the developmental disorders are now much brighter with neuroimaging technology. PMID- 10102729 TI - The adjustment of children with divorced parents: a risk and resiliency perspective. AB - This review addresses major questions about divorce, around which much contemporary research is oriented. These involve questions of the consequences of divorce for the adjustment of children and the vulnerability and resiliency of children in coping with divorce, whether children are better off in a conflictual intact family situation or a divorced family, and how mothers, fathers, and clinical or educational interventions can moderate the effects of divorce. Although research in the past decade has yielded considerable information about these questions, issues that need further investigation are also presented. PMID- 10102730 TI - Premature ventricular contractions during +Gz with and without pressure breathing and extended coverage anti-G suit. AB - BACKGROUND: High +Gz is known to provoke cardiac dysrhythmias. Pressure breathing during G (PBG) and extended coverage anti-G suits (ECGS) are used to enhance +Gz endurance and reduce fatigue during high +Gz flying. It is not known whether PBG in combination with ECGS increases the risk for premature ventricular contractions (PVC). HYPOTHESIS: PBG in combination with ECGS increases the risk of PVCs during high +Gz-loads. METHODS: Retrospective data were obtained from 14 subjects exposed to three different simulated aerial combat sorties each, in the centrifuge with a standard anti-G suit ensemble or with PBG in combination with ECGS. Each sortie consisted of a gradual onset G-exposure (GOR) and three simulated aerial combat maneuvers (SACM) containing four cycles of a +4.5 to +7 GzSACM; four cycles of +4 to +9 Gz tactical aerial combat maneuver (TACM) with several rapid transitions from +4 or +5 Gz to +8 or +9 Gz; and four cycles of +5 to +9 Gz SACM (5-9 SACM) with four cycles. ECG was recorded during the +Gz exposures to reveal any cardiac dysrhythmias. RESULTS AND CONCLUSIONS: No PVCs occurred during the GORs. During 4.5-7 SACMs, TACMs, and 5-9 SACMs there were 83, 50, and 24 PVCs with standard equipment, respectively, and 63, 54, and 39 PVCs with PBG and ECGS, respectively. There was no statistically significant difference between the equipment in any of the different types of +Gz exposures. No episodes of supraventricular tachycardia or relative bradycardia were found with either equipment. PMID- 10102731 TI - The heart is not necessarily empty at syncope. AB - BACKGROUND: Although extensively investigated, the mechanism(s) of post spaceflight orthostatic intolerance has not been elucidated. Several researchers have proposed that the "trigger" for syncope is an empty ventricle, initiated when a hypercontractile state, possibly due to a sudden surge in epinephrine, causes the walls of the left ventricle to touch leading to a profound sympatho inhibition and intense vagal stimulation. HYPOTHESIS: A markedly reduced left ventricular end systolic volume (LVESV) achieved during progressive, presyncopal limited lower body negative pressure (LBNP) is the trigger for syncope. METHODS: Eight healthy men, age 25.1+/-1.3 yr, volunteered for the study. Changes in left ventricular end-diastolic volume and LVESV were measured, using two-dimensional echocardiography, at each stage of LBNP from rest up to presyncope (PS). Plasma venous catecholamine concentrations were measured at the end of each stage by high performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: All subjects reached PS. Three men became bradycardic at presyncope while five remained tachycardic. LVESV decreased by 28% at PS with no evidence of ventricular cavity obliteration. Norepinephrine increased by 44% from rest to PS, but no epinephrine surge was detected (35% increase from rest to PS). CONCLUSION: These data indicate that it is possible to initiate syncope with only a 28% decrease in LVESV, and that sympatho-inhibition and bradycardia are not required elements for syncope to occur. PMID- 10102732 TI - Hoffmann-reflex is delayed during 6 degree head-down tilt with balanced traction. AB - BACKGROUND: Increased spinal height due to the lack of of axial compression on spinal structures in microgravity may stretch the spinal cord, cauda equina, nerve roots, and paraspinal tissues. HYPOTHESIS: Exposure to simulated microgravity causes dysfunction of nerve roots so that the synaptic portion of the Achilles tendon reflex is delayed. METHODS: Six healthy male subjects were randomly divided into two groups with three in each group. The subjects in the first group underwent horizontal bed rest (HBR) for three days. After a two week interval they underwent bed rest in a position of head-down tilt with balanced traction (HDT). So that each subject could serve as his own control, the second group was treated identically but in opposite order. Bilateral F waves and H reflexes were measured daily (18:30-20:30) on all subjects placed in a prone position. RESULTS: By means of ANOVA, differences between HDT and HBR were observed only in M-latency and F-ratio, not in F-latency, central latency, and H latency. Differences during the course of the bed rest were observed in M-latency and H-latency only. Tibial H latency was significantly lengthened in HDT group on day 2 and 3, although no significant difference between HDT and HBR was observed. CONCLUSION: The monosynaptic reflex assessed by H-reflex was delayed during 6 degree HDT with traction. The exact mechanism of this delay and whether the change was due to lengthening of the lower part of the vertebrae remain to be clarified. PMID- 10102733 TI - Quantitative phase contrast images to quantitate flow in a rat model of microgravity. AB - A magnetic resonance angiographic (MRA) technique for noninvasive measurement of flow in the inferior vena cava (IVC) was used to study blood flow changes in a simulated microgravity model. Microgravity was simulated in adult male Fischer 344 rats (n = 12, with each rat acting as its own control) using a tail harness to elevate the hindquarters, producing a non-weight bearing hindlimb (NWH) model. Quantitative phase contrast images of flow within the IVC were obtained initially and after a 2-week NWH protocol. Inferior vena cava blood flow was determined by converting the intensity at the respective magnetic resonance pixels into a corresponding flow by Doppler techniques. Average values for flow determined with MR angiography were 351.8 (SEM = 49) mm3 x s(-1) initially and 524.5 (SEM = 46) mm3 x s(-1) after exposure to 2 weeks of the NWH protocol. Post 2-week NWH flow increased 49.1% over the initial NWH value. Using a paired t-test, a significant difference was found between the rats' IVC flow values in the initial and post NWH groups (p < 0.004). The changes in IVC blood flow due to 45 degrees NWH may contribute to the overall changes observed in the cardiovascular system during simulated microgravity. PMID- 10102734 TI - Performance evaluation in analogue space environments: adaptation during an 8 month Antarctic wintering-over expedition. AB - BACKGROUND: This paper reports a study which examined the impact of long-term isolation and confinement on multiple-task performance. METHODS: A group of 10 scientists and 6 technicians from a French wintering-over expedition in the Antarctic participated in the 8-mo study. The group was tested 8 times on a computerized simulation of a complex life support system. The task environment allowed the measurement of primary and secondary task performance, system control activities and subjective operator state. RESULTS: No signs of serious performance decrements were observed but a number of subtle indications of hidden decrements emerged. The data also revealed strong differences in performance between the professional groups. Finally, the paper discusses the implications of the work for extended spaceflight. PMID- 10102735 TI - Maintenance of complex performance during a 135-day spaceflight simulation. AB - BACKGROUND: The maintenance of crew performance during extended space missions has been a major concern because of the problems associated with prolonged isolation and confinement. Previous research has failed to address this problem by not using appropriate performance tests. METHOD: Three Russian cosmonauts were tested on a PC-based simulation of a spacecraft's life support system during a 135-d simulation of a MIR spaceflight. A complex multiple-task environment was used to examine a comprehensive range of task management variables, including both primary and secondary task performance, control activity and information sampling behavior. Subjective state variables were also measured. RESULTS: The data suggested an overall successful adjustment to isolation and confinement, though some indications of temporary disruptions of some performance indicators were observed. Information sources were sampled less frequently with increasing mission length while system control activities showed a tendency to increase. CONCLUSION: Suggestions are made to address the problem of continuous learning during repeated testing sessions. Using well-designed computer simulations of complex task environments appears to be a promising approach for the evaluation of crew member performance. PMID- 10102736 TI - Gravitational changes affect tibial growth plates according to Hert's curve. AB - BACKGROUND: Microgravity significantly affects chondrocyte differentiation within the tibial epiphyseal growth plate of space flown rats. The changes produced in height and number of cells in different zones of the plate are associated with ultrastructural changes in the extracellular matrix. Given the importance of the growth plate in endochondral ossification, we began to assess the response of the plate to hypergravity, and the countermeasure value of excess G. METHODS: Rats of the strain used in Cosmos biosatellite missions were housed under conditions similar to Cosmos flights and subjected to continuous hypergravity (2 G) for 14 d, in a 12-ft radius centrifuge. RESULTS: Histomorphometrical analyses of tibial growth plates from these rats found the hypertrophic/calcification zone to be significantly reduced in both height and cell number, and the proliferation zone in cell number. CONCLUSIONS: These results, along with those of spaceflight and of studies using suspension-centrifugation, indicate that rat growth plate responds to gravitational changes according to Hert's curve: i.e., a) an increased baseline (minimal) loading reduces cartilage differentiation; and b) a reduced baseline loading may lead to increased cartilage differentiation but only within a range, beyond which lack of differentiation results. The plasticity of the plate, i.e., its ability to increase or decrease its activity in response to changes in gravity suggests the possibility of a range of G that will produce the load necessary to maintain normal growth of the plate, i.e., possible countermeasures to the effects of either hypo- or hyper-gravity. PMID- 10102737 TI - Plasma amino acids during human spaceflight. AB - BACKGROUND: The plasma amino acid distribution patterns were measured before, during and after flight on the Space Shuttle. The plasma samples were collected from the four payload crewmembers of the 1993 SLS-2 Columbia Shuttle mission. Samples were taken 45, 15 and 8 d before flight; inflight on days 2, 8 and 12 after launch; post-flight on the day of landing; and again 6, 14 and 45 d after landing. RESULTS: Most of the changes found pertained to the essential amino acids, particularly the branched chain amino acids (BCAA). The principle findings were: a) The plasma aminograms for inflight days 8 and 12 were very similar and both aminograms were very different from that of flight day 2. Flight day 2 was not different from the preflight ground control. b) With increasing time in space, there was an increase in the concentration of leucine and isoleucine in the plasma (p < 0.05). This increase occurred even though dietary BCAA intake was not increased inflight. c) The concentrations of the total essential amino acids and the branched chain amino acids (BCAA) in particular were decreased on the day of landing (p < 0.05). PMID- 10102738 TI - EEG topographical analysis of spatial disorientation. AB - BACKGROUND: We examined EEG topography while subjects experienced spatial disorientation (SD) such as vection and somatogravic illusion (SGI). METHODS: Five healthy male subjects were exposed to a rotating image evoking vection (Experiment 1) and to a 0.58 G linear forward acceleration evoking SGI (Experiment 2). The data were analog-to-digital converted with an epoch length of 1 s and a sampling frequency of 256 Hz. Polynomial coefficient vectors were calculated for the following analyses of EEG under the illusion: a) objective evaluation of topographical difference by two-way MANOVA; b) visual inspection of the power spectra maps; and c) logarithmic deviation ratio topography (log DRT). RESULTS: MANOVA demonstrated significant differences in EEG topography in the high alpha band while the vection was evoked. No significant difference was revealed in any bands for SGI. Characteristic patterns common to all subjects were hardly identified on the power spectra maps. By log DRT under vection, a decrease of power was observed in the centro-parietal area on the left side in one subject, on the right in another subject, and in the mid-right frontal area in a third subject compared with the control with eyes open. As for SGI, log DRT revealed a decrease of power in the occipital area in most of the trials as the magnitude was reduced by a visible horizon. CONCLUSIONS: MANOVA revealed a significant change in EEG topography while the subjects felt vection. Log DRT reflected characteristic patterns under vection and SGI. Thus EEG topography may be useful for the study of SD. PMID- 10102739 TI - Ataxia following exposure to a virtual environment. AB - BACKGROUND: Virtual environment (VE) technology has many promising applications in a variety of areas that may likely lead to widespread use as technology progresses and cost decreases. Recent research has demonstrated that simulator sickness, a well-established effect of simulator exposure, can occur with VE exposure as well. Because ataxia (postural unsteadiness) is known to occur following simulator exposure, it might also occur following VE exposure. Simulator sickness and after-effects, such as ataxia, pose severe safety risks and raise serious liability questions. METHOD: A PC-based VE system was used to investigate the occurrence of ataxic decrements in postural stability following a 20-min exposure to a commercially available game. There were 20 male and 20 female undergraduate students who served as participants. Postural stability was assessed using a sensitive, reliable measure of stance involving the velocity of head movement sway along the y-axis. Data on the occurrence of simulator sickness were also collected. Based on findings in other simulators, ataxia was hypothesized to occur. RESULTS: Ataxic decrements in postural stability were not found although simulator sickness did occur. CONCLUSIONS: Several possible factors possibly involved in the lack of ataxia were considered: statistical power; aspects of the postural test; participants' VE adaptation, exposure time, and immersion position; and the task performed. Ataxia may not be associated with short exposures to VEs for tasks which are not highly dynamic and individuals who are not experienced with the system. PMID- 10102740 TI - Analysis of cerebral bioelectrical activity during the compression phase of a saturation dive. AB - Considering previous studies on EEG brain mapping in the course of saturation dives, the authors studied the same standards of EEG performance during the compression phase of a saturation dive reaching -250 m. An increase of theta and beta rhythms was observed, especially in the midline anterior regions of the brain, during the entire compression period, while an increase of delta activity was noted only at -100 m. These results confirm our hypothesis that the compression profile is physiologically correct, because the EEG modifications decreased during the stay at maximum depth. PMID- 10102741 TI - The use of an independent visual background to reduce simulator side-effects. AB - BACKGROUND: Simulator sickness (SS) is a major problem which potentially limits interface applications that feature simulated motion. While display imperfections play a role, a large part of SS is motion sickness (MS). Sensory rearrangement theory holds that MS is related to conflicting motion cues; in the case of simulators, mainly a conflict between inertial cues (usually indicating no self motion) and visual stimuli from the display (indicating self-motion). It is suggested that MS does not arise from conflicting motion cues per se, but rather from conflicting rest frames selected from those motion cues. There is strong evidence that the visual rest frame is heavily influenced by the visual background. Providing an independent visual background (IVB) consistent with the inertial rest frame may reduce SS, even when the simulator's content-of-interest (CI) is not consistent with the inertial rest frame. METHODS: In two experiments, a circular vection stimulus was shown for 3-4.5 min in a head-mounted display, comparing see-through (i.e., IVB) to occluded (i.e., no IVB) modes. Measures included a standard SS questionnaire and a pre-exposure ataxia measure. Experiment 2 added a visual task which forced attention into the CI and a post exposure ataxia measure. In both experiments, subjects rated the CI as significantly more visible than the IVB. RESULTS: A large effect was found for the reduction of SS and ataxia in the first experiment, and for pre-exposure ataxia in the second. CONCLUSIONS: Future research will further test the IVB idea and examine applications to high-end simulators. PMID- 10102742 TI - Thermal and metabolic responses of women with high fat versus low fat body composition during exposure to 5 and 27 degrees C for 120 min. AB - BACKGROUND: Men with high fat body composition maintain higher core temperatures, and lower aerobic metabolic rates than their low fat counterparts thus, verifying the insulatory benefit of body fat. Females, on average have more body fat and less muscle mass than males, and may maintain rectal temperature (Tre) at a lower energy cost. METHODS: The present investigation dichotomized female subjects by percent fat (low fat; n = 3, LF = 19.2+/-3% vs. high fat; n = 4 HF: 29.9+/-3%) to elucidate the thermal and metabolic responses during acute exposure to 5 and 27 degrees C air for 120 min. An ANOVA was used to examine the following: Tre (degrees C), mean skin temperature (Tsk; degrees C), oxygen consumption (VO2; ml x kg(-1) x min(-1)) and tissue insulation (I; degrees C x m2 x W(-1)). For Tre, a significant fat x time interaction (p < 0.05) was demonstrated at both 5 and 27 degrees C, whereby Tre tended to be lower in the LF group than the HF group. VO2 at 5 degrees C demonstrated a main effect for time only. For I, a main effect for time was noted at 5 degrees C. Also for I, a trend (p = 0.06) toward a main effect of fat during exposure to 5 degrees C was noted while at 27 degrees C a main effect (p < 0.05) was demonstrated. RESULTS: From this data it appears that under these conditions, the HF group demonstrated higher Tre and I values than their LF counterparts that was not accompanied with a differential response with respect to aerobic metabolic rate. Thus, the impact of body composition on energy expenditure to maintain Tre differs between LF and HF males and females. PMID- 10102743 TI - A case study: are tonic-clonic seizures certifiable in airmen? PMID- 10102744 TI - Interexaminer reliability of the assessment of clinical furcation parameters as related to different probes. AB - The aim of this study was to investigate the interexaminer reliability of the assessment of clinical furcation diagnosis. Horizontal attachment level (PAL-H) measurements were obtained by 3 examiners in 6 molars in each of 10 patients with advanced periodontitis. In each patient, 3 molars were examined using a 3 mm incrementally marked Nabers probe, and 3 molars were examined using a pressure calibrated plastic probe (TPS). Assignment of the probe was random, and the schedule of examiners was changed for each patient. Clinical assessments were validated by intrasurgical measurements in 6 patients. Sixty molars with 152 furcations were investigated. Multifactorial analysis of variance revealed that PAL-H measurements were significantly influenced by examiner and furcation location, whereas type of probe and schedule of examination had no influence. The overall intraclass correlation coefficient was r = 0.695. The difference between clinical and intrasurgical PAL-H assessment was influenced by examiner and location but not by type of probe. Approximately 70% of the total variance of PAL H measurements was due to the variance of true values, whereas 30% of the variance may be explained by interexaminer and intraexaminer variance. The pressure-calibrated TPS probe failed to increase the interexaminer reliability of PAL-H measurements when compared to a Nabers probe. PMID- 10102745 TI - A clinical study of oral tori in southern Thailand: prevalence and the relation to parafunctional activity. AB - The objective of the present study was to investigate the relationship of oral tori and occlusal stress as indicated by parafunctional activity (clenching and grinding) and to report the prevalence of torus palatinus (TP) and torus mandibularis (TM) among patients attending a dental school hospital in southern Thailand. Six-hundred-nine individuals, 183 males and 426 females, were interviewed and examined for the presence of clenching and grinding habit. The presence of TP and TM was also examined in each individual and in the case of TM size was recorded. Tabulated analysis was carried out to find the crude relationships of the parafunction, age and sex to the presence of TP or TM. The relationships were then analyzed by logistic regression. Of these individuals, 376 (61.7%) had TP, whereas 182 (29.9%) had TM. The male:female prevalence ratios of TP and TM were 1:1.4 and 1:0.94, respectively. TP was, thus, more frequent in females. A strong association between clenching and grinding and the presence of TM was found. The presence of TM might be useful as a cue to look for signs of parafunction. PMID- 10102746 TI - LPS from Actinobacillus actinomycetemcomitans and the expression of beta2 integrins and L-selectin in an ex vivo human whole blood system. AB - Actinobacillus actinomycetemcomitans is assumed to be an important etiological agent in localized juvenile periodontitis (LJP) and to have the ability to invade periodontal tissues. This bacterium has also been noted for its potential to cause serious extraoral infections. In this study, the effect of lipopolysaccharides (LPS) extracted from A. actinomycetemcomitans on the expression of the leukocyte adhesion molecules CD11a/CD18, CD11b/CD18, CD11c/CD18 and L-selectin (CD 62L) were measured in an ex vivo whole blood system by use of fluorescent antibodies followed by flow cytometry. LPS from Escherichia coli, which is known to elicit a strong inflammatory response was used as a reference. The expression of the beta2 integrins CD11a/CD18, CD11b/CD18, and CD11c/CD18 were significantly upregulated in granulocytes and monocytes. This expression was dose dependent. The baseline levels of L-selectin was high on all three types of leukocytes, but on granulocytes and monocytes it decreased dramatically after stimulation with LPS. The LPS from A. actinomycetemcomitans was equally potent as LPS from E. coli in its ability to affect the expression of the leukocyte integrins and L-selectin. PMID- 10102747 TI - Effects of captopril and bradykinin on chorda tympani-induced salivation in cat. AB - The effects of captopril and bradykinin on chorda tympani-induced salivation were studied in the submandibular gland of anesthetized cat. Captopril and bradykinin, but not des-Arg9-bradykinin, increased salivation evoked by electrical stimulation of chorda tympani. These potentiated effects of captopril and bradykinin were suppressed by Hoe-140, a kinin B2 receptor antagonist, or by concomitant addition of N(G)-nitro arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and aspirin, a cyclooxygenase inhibitor. It appears that captopril potentiates chorda tympani-induced salivation through endogenously accumulated bradykinin, which acts on kinin B2 receptors, mediating production of nitric oxide and cyclooxygenase products. PMID- 10102748 TI - Development of the human temporomandibular joint. Computer-aided 3D reconstructions. AB - Computer-aided graphical three-dimensional reconstructions of histological serial sections of 12 human embryos and fetuses (25-250 mm Crown-rump length (CRL)) were used to trace the prenatal development of the elements of the human temporomandibular joint. The primordia of the condylar and coronoid processes could be identified as two bony peaks at the dorsal ends of the mandible at the stage of 25 mm CRL. The primordium of the temporal bone already existed at the stage of 37 mm CRL. The bone was apparent with a convex contour towards the condyle. The glenoid fossa was not yet visible. At 65 mm CRL, the osseous glenoid fossa could be distinguished at the enlarged temporal bone formation. The glenoid fossa developed posteriorly and medially from the condyle and extended in cranial and anterior direction. The glenoid fossa had various contours, changing from flat and slightly convex (65 mm CRL) to concave (250 mm CRL) with an articular tubercle. The distance between fossa and condyle increased proportionally. The lower joint cavity appeared at an earlier stage (65 mm CRL) than the upper joint cavity (70 mm CRL). Both cavities started development as isolated compartments fusing later on. The upper joint cavity followed the contour of the fossa, whereas the lower joint cavity followed the form of the condyle. The biconcave shape of the articular disc as well as the attachment of the lateral pterygoid muscle could be observed very early (70 mm CRL). PMID- 10102749 TI - Effect of masticatory function on the internal bone structure in the mandible of the growing rat. AB - The influence of changes in the masticatory function on bone mass, bone density and cortical thickness was analyzed in different functional units of the mandible of the growing rat. Young male albino rats were fed either a hard diet or a soft diet for 4 wk. Undecalcified coronal sections were selected from five mandibular regions and microradiographic images of the specimens alongside an aluminium stepwedge were obtained. Bone mass and density were measured at selected sites with a computer-aided image analysis system. Cortical thickness was measured on diagrams. The reduced masticatory function in the soft diet group produced different adaptive responses in the tested regions of the mandible. Some regions showed reduced cortical thickness (underneath the incisor and lateral to the first molar and some locations of the ramus), a few showed reduced bone density (medial to the first molar and in the ramus), and only one showed both (in the ramus). Reduced bone mass was associated mostly with thinner cortical bone rather than lower cortical bone density. Changes in cortical thickness and changes in bone density may be two different mechanisms for adjusting local mechanical properties in the mandible of the rat. Masticatory muscle function is a determinant for the amount and density of cortical and trabecular bone and may possibly influence results of orthodontic tooth movement and its possible relapse. PMID- 10102750 TI - Cholera toxin and forskolin stimulate formation of osteoclast-like cells in mouse marrow cultures and cultured mouse calvarial bones. AB - Osteoclasts are hematopoietic in origin and formed by proliferation, differentiation and fusion of osteoclast progenitor cells. However, the signal transducing mechanisms involved in generation of osteoclasts are not clear. We have used two well-known adenylate cyclase stimulators to examine the effect of cyclic AMP (cAMP) on the number of tartrate-resistant acid phosphatase (TRAP) positive multinucleated cells in cultured mouse calvarial bones and in mouse bone marrow cultures. The effects of forskolin and cholera toxin were compared with those of parathyroid hormone (PTH) and 1,25(OH)2vitaminD3 (1,25(OH)2D3). PTH, as well as forskolin and cholera toxin, increased the number of osteoclast profiles/mm bone in 24-h and 120-h cultures of mouse calvarial bones. In mouse bone marrow cultures, 1,25(OH)2D3 or PTH stimulated formation of TRAP-positive multinucleated cells. Moreover, forskolin or cholera toxin produced dose dependent stimulation of these cells at a range of concentrations correlating with their effect on cAMP production. The osteoclastic phenotype of the TRAP positive cells was demonstrated by autoradiography of 125I-labelled calcitonin binding and by the bone-resorbing activity of the cells. The sustained presence (0-9 d) of forskolin or PTH was required to obtain maximal formation of osteoclasts. However, the presence of 1,25(OH)2D3 was required only for the last 3 d of culture for maximal osteoclast formation. We conclude that PTH may stimulate osteoclast generation using the adenylate cyclase cAMP system as a signal transduction mechanism. PMID- 10102751 TI - Transmission electron microscopy of early plaque formation on dental materials in vivo. AB - This in vivo study describes the ultrastructural pattern of early plaque formation on various dental materials. Test pieces of amalgam, casting alloys, titanium, ceramics, glass polyalkenoate cement, composite resins, unfilled resins, and bovine enamel were attached to the buccal and lingual surfaces of the upper first molars in 3 subjects using removable intraoral splints. Specimens were exposed to the oral environment over a period of 24 h and subsequently processed for transmission electron microscopic evaluation. Only less pronounced variations could be detected in the ultrastructural appearance of the early plaque formed on the different material surfaces. However, electron microscopic observations revealed distinct differences in early biofilm formation between buccally and lingually mounted test pieces. While the bacterial colonization of specimens worn in the lingual position remained limited to the adherence of individual micro-organisms in the area of surface irregularities, a multi-layer adherence of micro-organisms was observed on all specimens carried in buccal areas. It is concluded that early plaque formation on solid surfaces is influenced predominantly by the oral environment rather than by material dependent parameters. These findings may be ascribed to the presence of the pellicle layer, which apparently masks any difference among materials, with regard to surface properties and biocompatibility. PMID- 10102752 TI - Influence of eugenol-containing temporary cement on efficacy of dentin-bonding systems. AB - Zinc oxide-eugenol (ZOE) cements are widely used as temporary filling materials. However, eugenol has earlier been shown to have a detrimental effect on both resin composites and dentin-bonding systems. The aim of the present in vitro study was to examine whether ZOE cement would also reduce the efficacy of relatively new dentin-bonding systems. This was done by determination of gap formation around resin composite fillings in dentin cavities and of bond strength of resin composite to enamel and dentin. The tooth surfaces involved were either freshly cut, or had been exposed to a ZOE cement (IRM) or to a non-ZOE cement (Cavit) for 7 d before application of a dentin-bonding system (Gluma CPS or Scotchbond Multi-Purpose Plus) and a resin composite (Z100). Gap formation was assessed in a light microscope on 20-min-old fillings and expressed as wall-to wall contraction (the width of the maximum marginal gap in % of the cavity diameter). Bond strength was measured in shear on 1-d-old specimens. The mean values of wall-to-wall contraction were 0.06-0.09% with Scotchbond Multi-Purpose Plus and 0.20-0.24% with Gluma CPS. The mean values of bond strength to enamel were 22-25 MPa for Scotchbond Multi-Purpose Plus and 20-23 MPa for Gluma CPS, and to dentin were 20-22 MPa for Scotchbond Multi-Purpose Plus and 13-14 MPa for Gluma CPS. The use of Scotchbond Multi-Purpose Plus resulted in higher bond strength to dentin and less wall-to-wall contraction than did Gluma CPS. No differences were found in either wall-to-wall contraction or in bond strength between the three groups for either dentin-bonding system. Thus, the ZOE cement did not influence the efficacy of two relatively new dentin-bonding systems. PMID- 10102753 TI - Fracture strength of intact and fragment-bonded teeth at various velocities of the applied force. AB - Bonding of a tooth fragment to the remaining tooth substance can restore crown fracture of an anterior tooth. In this study, sheep central incisors were used. The crowns were fractured transversely and the crown fragment was bonded to the remaining tooth structure. This technique involves acid etching, use of an experimental adhesive (Gluma+) and a BisGMA/TEGDMA resin. The mean fracture strength of the restored teeth was not significantly different from that of intact teeth when tested at a rather low crosshead speed (0.5 mm/min) but different and about 30% lower when tested at a higher crosshead speed (500 mm/min). In studies aiming to test resistance to forces which might cause trauma, it might be appropriate to use a high crosshead speed. PMID- 10102754 TI - The role of granulocyte-macrophage-colony stimulating factor, cortisol, and melatonin in the regulation of the circadian rhythms of peripheral blood cells in healthy volunteers and patients with breast cancer. AB - The circulating blood cells show highly reproducible circadian rhythms. However, the factors that regulate these rhythms are not well understood. In the current study, we examined the diurnal variations of peripheral blood cells (white blood cells, neutrophils, lymphocytes), granulocyte-macrophage-colony stimulating factor (GM-CSF), and melatonin levels, and considered the role of melatonin on these rhythms in healthy volunteers and in patients with early breast cancer. Fourteen premenopausal patients with early stage breast cancer (T2, N1 tumors) and 10 premenopausal healthy volunteers were included in the study. Blood samples were taken every 4 hr for a period of 24 hr. Peripheral blood cells were counted by automated analyser and also from peripheral blood films. GM-CSF levels were measured by ELISA and melatonin levels by radioimmunoassay (RIA). Serum melatonin, cortisol, and GM-CSF levels, and peripheral blood cell counts showed significant circadian rhythms in healthy volunteers. Except for GM-CSF, these circadian rhythms were found not to be suppressed in early breast cancer patients. While there were significant correlations of serum GM-CSF and cortisol levels with peripheral blood cell counts in healthy volunteers, only lymphocyte counts were found to be significantly correlated with serum GM-CSF and cortisol levels in patients with breast cancer. Serum melatonin levels were found to be significantly correlated with lymphocyte counts in both groups. Our results suggest that peripheral blood cells show significant circadian rhythms in both healthy volunteers and in patients with stage II (T2, N1) breast cancer, and GM CSF, cortisol, and melatonin may have a role in the regulation of peripheral blood cell counts. PMID- 10102755 TI - Circannual reproductive rhythm in the European hamster (Cricetus cricetus): demonstration of the existence of an annual phase of sensitivity to short photoperiod. AB - In the European hamster (Cricetus cricetus) short photoperiod (SP) is responsible for the transition between the breeding and the resting season and data obtained previously suggest that a circannual "clock" drives the annual rhythm of reproduction. This hypothesis implies the existence of a SP-sensitive phase of the circannual system that occurs independently of the photoperiodic regime perceived by the animals after their arousal from hibernation at the end of March. In control animals kept outside, testicular atrophy occurs in August. When the animals were transferred from outdoors to controlled SP conditions (LD 10:14 and ambient temperature Ta = 18+/-2 degrees C), immediately (Group II) or 2, 4, 6 wk after capture (Groups IV, V, VI, respectively), sexual arrest occurs at the same time between mid-June and mid-July. In the other groups, transfer from outdoors to SP either after 6, 8, 10, 12 or 14 wk (Groups VI, VII, IX, X, XI, respectively) after capture, is followed directly within 4 wk by the gonadal atrophy. When SP was applied from the beginning of August (Group XII) gonadal atrophy was observed after only 2 wk. In this last group, however, the rapid involution is the consequence of the already initiated decline in sexual activity induced by the short daylengths from July. When comparing the effect of SP in two different ambient temperatures (Ta: 18+/-2 degrees C vs 7+/-2 degrees C), immediately (Groups II vs III), 8 (Groups VII vs VIII) or 16 (Groups XII vs XIII) wk after capture, it appears that low temperature does not affect the physiological process described above. In the European hamster, after the gonadal regrowth at the end of hibernation, the animals do not need to experience increasing long days to react against SP. Gonadal inhibition is induced when, following our hypothesis, SP coincides with an endogenous period of sensitivity that extends from mid-May to at least July-August. The present findings complement and extend earlier evidence to support the existence of an endogenous circannual control of seasonal reproduction in the European hamster. PMID- 10102756 TI - Long-term exposure of hypothalamic explants to melatonin alters the release of gonadotrophin releasing hormone and the density of melatonin binding sites in the pars tuberalis of the male mink (Mustela vison). AB - To investigate the action of melatonin on the reproductive system, the effect of prolonged versus short-term exposure to melatonin on the release of gonadotrophin releasing hormone (GnRH) was examined in hypothalamic explants of male mink sacrificed in July, September or November. Mediobasal hypothalamic (MBH) explants including the pars tuberalis (PT) were incubated for 1 night with or without melatonin (10(-8) M) for 8 hr or 16 hr and the release of GnRH was then measured. The next day, the explants were incubated further but in a melatonin free buffer, and the release of GnRH was measured with increasing time. Half of the July and September explants had melatonin binding sites quantified by autoradiography. In November, a 16-hr exposure to melatonin induced a significant increase in the release of GnRH during the night, compared with control or 8-hr melatonin exposure. This increase persisted for at least 45 min after the withdrawal of melatonin, suggesting a stimulatory effect of melatonin on the synthesis of GnRH; this effect was apparent in July, September and November. In September, the density of melatonin binding in the PT was significantly lower in the explants incubated for 16 hr with melatonin, compared with those incubated for 8 hr. Thus, in vitro, a long exposure to melatonin, mimicking a single long night, stimulates the release and synthesis of GnRH in parallel with a decrease in the density of melatonin binding in the PT. These effects seem to depend heavily on the duration of exposure to melatonin. PMID- 10102757 TI - Perinatal development of circadian melatonin production in domestic chicks. AB - In contrast to the situation in mammals, in which circadian melatonin production by the pineal gland does not begin until some time after birth, the development of pineal gland rhythmicity is an embryonic event in the precocial domestic fowl. A distinct melatonin rhythm was found in 19-d-old chick embryos maintained under light:dark (LD) 16:8. No significant variation in melatonin levels was detected in embryos exposed to LD 8:16. The melatonin rhythm in the pineal gland and plasma of chick embryos incubated for 18 d in LD 12:12 persisted for 2 d in constant darkness indicating that melatonin production is under circadian control at least from the end of embryonic life. A 1-d exposure to a LD cycle during the first postembryonic day was sufficient to entrain the melatonin rhythm, and previous embryonic exposure to either LD or constant darkness (DD) neither modified this rapid synchronization nor did it affect the melatonin pattern during the two subsequent days in DD. It is suggested that, in contrast to the situation in mammals, the avian embryo has evolved its own early circadian melatonin-producing system because, as a consequence of its extrauterine development, it cannot use the system of its mother. PMID- 10102758 TI - Correlation between the circadian rhythm of melatonin, phagocytosis, and superoxide anion levels in ring dove heterophils. AB - A functional role for melatonin is its relationship to circadian timing mechanisms. In addition, there has recently been assumed to be a functional connection between the pineal gland and the immune system in mammals and birds, with some findings showing melatonin to be a free radical scavenger and general antioxidant. The present study investigates the possible relationship between the circadian rhythm of melatonin and the ingestion capacity as well as superoxide anion levels of ring dove (Streptopelia risoria) heterophils. In birds, heterophils, with their ability to ingest and kill different antigens, play a central role in the host defence mechanism. All determinations were made during 24 hr periods at 2 hr intervals. Radioimmunoassay showed an increase of melatonin serum levels during the dark period (from 20:00 to 07:00 hr) with a maximum at 04:00 hr, and a significant decline during the hours of light with a minimum at 16:00 hr. Similarly, the phagocytic index was enhanced during the night, with the maximum at approximately 04:00 hr and the minimum at approximately 18:00 hr. The same was the case in relation to phagocytic percentage. However, the superoxide anion levels were lower during darkness (minimum at 04:00 hr) and higher during the light period (maximum at 14:00 hr). In conclusion, our findings show that one pineal-mediated effect on the immune system may be a direct action of melatonin on phagocytosis and the phagocytic biochemical process, and that this neurohormone might act as an antioxidant. PMID- 10102759 TI - Melatonin receptors in neonatal pig brain and pituitary gland. AB - Summer infertility remains a major problem in domestic pigs. It has been proposed that sows which display this trait are inherent seasonal breeders. The influence of photoperiod on domestic pigs has been difficult to ascertain as significant diurnal fluctuations in blood levels of the pineal hormone, melatonin, which provide a direct neuroendocrine transduction of the ambient photoperiod in other species, remain questionable in adult pigs. To investigate whether the pig is potentially receptive to melatonin, central sites of action for this hormone were localized and characterized within the brain and pituitary of the neonatal pig by in vitro autoradiography using 2-((125)I)iodomelatonin. Specific binding was distributed over a number of discrete regions of the brain including the cerebral cortex, hypothalamus, thalamus, brainstem, and cerebellum. The choroid plexus, and the pars tuberalis and pars distalis of the pituitary were also specifically labeled. Specific binding was completely abolished in the presence of 10(-7) M melatonin, and inhibited in the presence of 10(-4) M GTPgammaS (guanosine-5-0-(3 thiotriphosphate)), a non-hydrolysable analogue of GTP, in all regions examined, indicating that binding is representative of a G-protein coupled receptor. Characterization studies showed that 2-((125)I)iodomelatonin binding was saturable with a dissociation constant (Kd) in the low picomolar range (approximately 30 pM). Competition studies with iodomelatonin, melatonin, N acetylserotonin and serotonin (5-HT) gave IC50 values similar to those previously characterized for the melatonin receptor in the ovine pars tuberalis. PMID- 10102760 TI - The effect of melatonin on cellular activation processes in human blood. AB - The pineal hormone melatonin, due to its lipophilic nature, has access to every cell and every part of a cell in the body, suggesting that it could exert effects on blood immune cells. The regulation of the activation of monocytes may be important in a number of diseases, especially pathophysiological conditions associated with inflammatory reactions. Considering this, a study on the effect of melatonin on monocytes in whole blood was carried out. Melatonin added at a final concentration of 5 ng/mL to whole blood in vitro reduced lipopolysaccharide (LPS)-induced tissue factor (TF) activity in monocytes by 55% in blood from a group of subjects with melatonin-sensitive cells. At even lower concentrations of melatonin (20-50 pg/mL) and in the physiological range, a trend of suppressed LPS induced TF activity by approximately 20% was seen. A further indication of a downregulation of LPS-stimulated monocytes by melatonin was shown by its reduction of LPS-induced tumor necrosis factor (TNF). Twenty to one hundred pg/mL melatonin caused a significant reduction of LPS-induced TNF production by approximately 25-30%. In contrast, melatonin at a final concentration of 10 pg/mL, added to whole blood incubated with LPS and also the phorbol ester, PMA, caused a significant rise of 25%; whereas 100 pg/mL enhanced LPS + PMA-induced TNF by approximately 80% as compared to LPS + PMA alone. These effects were not detectable during the winter darkness of Tromso (70 degrees N), probably due to the high content of melatonin in the blood even at daytime. These results show that melatonin may have a beneficial effect by suppressing the expression of TF activity in LPS-stimulated monocytes. Furthermore, the results indicate that LPS induced TF in monocytes of whole blood is independent of protein kinase C (PKC) activation. Melatonin is probably amplifying cellular activation reactions that are PKC-dependent. This may be physiologically important in upregulation of the immune system. PMID- 10102761 TI - Melatonin concentrations in the luminal fluid, mucosa, and muscularis of the bovine and porcine gastrointestinal tract. AB - Melatonin concentrations were measured in serum, luminal fluid, and tissues of the mucosa and muscularis of the entire bovine and porcine gastrointestinal tract (GIT). In both species, GIT levels profoundly exceeded serum levels. In pigs, melatonin was lowest in the luminal fluid and highest in the mucosa. No difference was found in various layers of bovine GIT. Compared to pigs, cows had higher melatonin levels in the stomach and ileum, but lower in the cecum and colon. There was no difference in melatonin levels between anterior and posterior segments of bovine GIT, whereas pigs exhibited several fold higher concentration of melatonin in the posterior segment (cecum and colon). Conversely, melatonin values in the anterior segment were significantly higher in cows, but in the posterior segments porcine values were higher. In cows, concentrations in the mucosa correlated with levels in the muscularis. Melatonin levels in the mucosa and muscularis were higher in the rumen and reticulum than in the omasum and abomasum. The species-specific levels and a distinct distribution of melatonin in the layers of the digestive tube indicates that this indole may be involved in the modulation of gastrointestinal function of monogastric as well as polygastric ungulates, albeit in a different capacity. PMID- 10102762 TI - Behavioral sensitization to nicotine is associated with behavioral disinhibition; counteraction by citalopram. AB - This study investigated the effects of repeated nicotine treatment on locomotor activity and behavioral inhibition, and the influence of citalopram on the behavioral effects obtained. Male rats received daily subcutaneous injections of vehicle + vehicle (veh + veh), citalopram (5.0 mg/kg) + vehicle (cit + veh), vehicle + nicotine (1.0 mg/kg; veh + nic) or citalopram + nicotine (cit + nic). Acutely, nicotine stimulated locomotor activity, and repeated daily nicotine injections sensitized veh + nic rats to the nicotine-induced locomotor stimulation after 5, 10 and 15 treatment days, whereas in cit + nic rats, the enhancement of nicotine-induced locomotion was suppressed. However, when challenged with nicotine after citalopram withdrawal (-36 h), the cit + nic treated animals were also observed to be sensitized. In the elevated plus-maze, repeated nicotine treatment produced behavioral disinhibition, measured as an increase of time spent in and entries made into open arms (%), and chronic citalopram treatment attenuated the expression of behavioral disinhibition. Moreover, the degree of nicotine sensitization correlated to the behavioral disinhibition observed. In summary, these findings suggest that behavioral sensitization to nicotine is associated with behavioral disinhibition and that chronic citalopram treatment counteracts the expression of both phenomena. Since citalopram is a highly selective serotonin reuptake inhibitor, the effects of citalopram may be due to a facilitation of serotonin neurotransmission caused by the chronic citalopram treatment. PMID- 10102763 TI - Enhanced conditioned inhibition following repeated pretreatment with d amphetamine. AB - We have shown that prior repeated exposure to d-amphetamine facilitates appetitive Pavlovian conditioning. However, animals sensitised in this manner also show elevated levels of stimulated activity. To investigate whether enhanced conditioning was dependent upon increased activity, a conditioned inhibition task was employed in the present study. Rats received d-amphetamine (2 mg/kg, i.p.) or vehicle once per day for 7 days. After a 7-day drug-free period, an activity assay confirmed that repeated d-amphetamine treatment markedly elevated the locomotor response to a subsequent challenge with 0.5 mg/kg d-amphetamine. Conditioning began 6 days later. In phase 1, stimulus A+ (light or tone) immediately preceded sucrose availability (excitatory conditioning). In phase 2, sucrose again was presented after A+ alone, but not after presentation of a compound of A+ with a second stimulus (AB-). Sensitisation enhanced the acquisition of conditioned approach behaviour to the excitatory stimulus A+ in phase 1. Furthermore, acquisition of conditioned inhibition to the stimulus compound, AB-, was also facilitated. Thus, sensitised rats showed reduced levels of responding to the stimulus compound far sooner than controls. Finally, a retardation test was carried out in stage 3, in which the inhibitory stimulus B- was paired alone with sucrose reward. Sensitised rats initially showed retarded acquisition of excitatory conditioned responding relative to controls, suggesting that B possessed stronger inhibitory associations in these animals. However, sensitised animals again exhibited higher levels of responding in later sessions, consistent with the enhanced excitatory conditioning shown in phase 1. These findings suggest that prior repeated d-amphetamine enhanced the acquisition of inhibitory and excitatory Pavlovian associations; a propensity not readily attributable to stimulated locomotor hyperactivity. PMID- 10102764 TI - Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report. AB - The administration of cytidine-5'-diphosphate choline (CDP-choline, citicoline) to animals increases the rate of membrane phospholipid synthesis and elevates brain dopamine levels. Because cocaine dependence has been associated with increases in brain phospholipid precursors, as well as depletion of dopamine within the central nervous system, the present outpatient study was conducted to assess the safety of citicoline (500 mg bid) and to determine if short-term treatment alters mood states and cocaine craving in subjects with a history of cocaine dependence. In addition, measures of drug craving and mood states after presentation of cocaine-related cues were collected on two occasions: before and after 14 days of double-blind treatment with either citicoline or placebo. Subjects did not experience any side effects and citicoline treatment was associated with decreases in self-reported mood states associated with cocaine craving. These preliminary data are encouraging and suggest that citicoline warrants further study as a promising potential treatment for cocaine abuse and dependence that is devoid of side effects. PMID- 10102765 TI - Effects of naltrexone with nicotine replacement on smoking cue reactivity: preliminary results. AB - Although several studies have examined the effects of opioid antagonists on smoking behavior, there have been no reports of the potentially therapeutic combination of naltrexone and nicotine replacement therapy. The primary objective of the present study was to determine whether naltrexone reduced reactivity to smoking cues among abstinent smokers treated with nicotine replacement. Twenty participants were instructed to abstain from smoking cigarettes for 9 h while using nicotine replacement therapy. Participants were subsequently treated with either naltrexone (50 mg) or placebo before being exposed to smoking cues. Results indicated that the smokers who received the placebo responded to smoking cue exposure with increases in urge to smoke and increases in negative affect. Participants who received naltrexone did not show any increase in urge or negative affect and showed a decrease in withdrawal symptoms after exposure to smoking cues. Although preliminary, the findings suggest that naltrexone may work in combination with nicotine replacement therapies to block the effects of smoking stimuli in abstinent smokers. PMID- 10102766 TI - Prolactin response to buspirone was reduced in violent compared to nonviolent parolees. AB - A neuroendocrine challenge procedure was carried out in male and female parolees. The parolees were divided into violent and non-violent groups based upon their criminal history. Buspirone (0.4 mg/kg), a 5-HT1a agonist, was used as the challenge agent and plasma prolactin levels were determined. The violent parolees had a blunted prolactin response compared to the non-violent parolees. While reduced serotonergic activity may account for this difference, the pharmacology of buspirone and control of prolactin release suggest a role for dopamine. A reduced serotonergic response would be consistent with a large body of data linking reduced serotonin function and aggressive behavior. While the mechanism is not definite, these data clearly provide evidence for an altered and blunted biological response in parolees with a history of violence. PMID- 10102767 TI - Manipulation of cigarette craving through rapid smoking: efficacy and effects on smoking behavior. AB - Craving is thought to play an important role in maintaining regular smoking patterns in current smokers, and in leading to relapse in smokers attempting to quit. Within the scientific community however, the concept is surrounded by controversy. In an effort to 1) identify interventions that can reliably influence cigarette cravings, and 2) assess the relationship between cigarette craving and smoking behavior, effects of aversive rapid smoking (up to nine cigarettes with puffs taken every 6 s) on self-reported craving and subsequent smoking behavior were compared to effects of self-paced smoking or no smoking. Subjects (n = 14) engaged in a rapid, self-paced or no smoking procedure at the start of three separate sessions. Craving levels, measured repeatedly during the next 3 h of no smoking, were significantly lower after rapid smoking than after either self-paced or no smoking. Measures of subsequent smoking behavior (latency to first cigarette, number of cigarettes, number of puffs) did not differ systematically across conditions. Thus, craving was reliably suppressed by aversive rapid smoking, but craving scores did not predict actual smoking behavior. PMID- 10102768 TI - Effects of central and peripheral nicotinic blockade on human nicotine discrimination. AB - Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg p.o.), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 microg/kg per min i.v.), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 microg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 microg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects. PMID- 10102769 TI - Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine induced enhancement of responding for conditioned reward. AB - Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect by investigating the effects of 5-HT agonists with differing affinities for 5-HT1 and 5-HT2 receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained to associate a light/tone stimulus (subsequently the CR) with water delivery. In a test phase, they were allowed access to a lever delivering the CR, and an inactive (NCR) lever. Responding on the CR lever was greater than responding on the NCR lever, indicating that the light/tone stimulus functioned as a CR. Responding for the CR was selectively potentiated by injections of d-amphetamine (10 microg) into the nucleus accumbens. This effect was reduced by injections into the nucleus accumbens of 5-CT (0.5 and 1 microg), RU24969 (10 microg), CP93,129 (1.25 and 2.5 microg) but not by DOI (10 microg) or 8-OH-DPAT (5 microg). The lower doses of 5 CT and CP93,129 did not reduce baseline responding for CR, or responding for water in a separate group of animals, indicating that the effects of these drugs were behaviourally selective. The higher doses abolished the CR effect, and in the case of 5-CT and RU24969 also reduced responding for water. All of the effective drugs share in common the ability to stimulate 5-HT1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5 HT1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the 5-HT(1B/1D) antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT1B receptors within the nucleus accumbens attenuates the effects of a dopamine-dependent behaviour, and that activation of these receptors can oppose the behavioural effects of elevated mesolimbic dopamine transmission. PMID- 10102770 TI - Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals. AB - The aim of the present study was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, olanzapine, in mice depleted of their dopamine by reserpine and alpha-methyl-DL-p-tyrosine pretreatment. Olanzapine (0.5, 1 and 2 mg/kg) dose-dependently increased locomotor activity, which was completely blocked by the selective dopamine D2 receptor antagonist, pimozide (0.5 mg/kg) but not by selective dopamine D1 receptor antagonist, SCH 23390 (0.5 and 1 mg/kg). Unlike olanzapine, the selective dopamine D2 receptor antagonists such as haloperidol (0.25 and 0.5 mg/kg) and pimozide (0.5 and 1 mg/kg), the selective 5-HT2A receptor antagonist, ritanserin (0.5 and 1 mg/kg) or the antimuscarinic agent scopolamine (0.5 and 1 mg/kg) failed to produce any locomotor stimulant effect. Olanzapine (1 and 2 mg/kg) and SCH 23390 (0.5 and 1 mg/kg) blocked hyperlocomotion and stereotypy induced by the selective dopamine D1 receptor agonist, SKF 38393 (10 and 25 mg/kg). Olanzapine (1 and 2 mg/kg) blocked hyperlocomotion and stereotypy induced by B-HT 920 (1 and 2 mg/kg), a selective dopamine D2 receptor agonist, whereas it blocked the hyperlocomotion but not stereotypy induced by the non-selective dopamine receptor agonist, apomorphine (0.5 and 1 mg/kg). The higher dose (4 mg/kg) of olanzapine blocked both stereotypy and hyperlocomotion induced by apomorphine. Olanzapine, in mice depleted of their dopamine stores, exhibited properties consistent with those of a D2 partial agonist having strong D1 antagonist property. The atypical nature of its clinical effect may be explained by a dual effect, partial agonistic-like action at D2 receptors and antagonist-like activity at D1 receptors, respectively. PMID- 10102771 TI - Escalating dose-binge stimulant exposure: relationship between emergent behavioral profile and differential caudate-putamen and nucleus accumbens dopamine responses. AB - Previous studies showed that treatment with high doses of amphetamine (8.0 mg/kg) administered according to an escalating dose-binge regimen, produced a unique behavioral profile that included a decrease in the duration of stereotypy and a pronounced increase in ambulation, characterized by a repeated bursting pattern of locomotion. This treatment regimen also resulted in differential dopamine response profiles in the caudate-putamen and nucleus accumbens: the dopamine response in the caudate-putamen exhibited a progressive within and between binge decline in peak levels, whereas the dopamine response in the nucleus accumbens was not significantly altered. The present study was designed to determine if this behavioral/dopamine response relationship was obtained under two additional conditions: first, in response to a relatively low dose amphetamine challenge (2.5 mg/kg) after withdrawal from escalating dose-binge treatment with either amphetamine or methamphetamine (6.0 mg/kg), and, second, during a lower dose (2.5 mg/kg amphetamine) escalating dose-binge regimen. Both the emergent behavioral profile and the regional differences in the dopamine response patterns were obtained under each set of conditions. These effects may be significantly implicated in the induction of stimulant psychosis, since the psychotogenic effects of amphetamine-like stimulants are most commonly associated with frequent, relatively high dose binge exposures. PMID- 10102772 TI - Antidepressant effects of nicotine in an animal model of depression. AB - Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg s.c.) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the alpha4beta2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the alpha7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders. PMID- 10102773 TI - Facilitation of sexual behavior in male rats following d-amphetamine-induced behavioral sensitization. AB - The present study investigated the effect of sensitization, induced by repeated injections of d-amphetamine, on sexual behavior in the naive male rat tested in a drug-free state. Injections of either d-amphetamine (1.5 mg/kg, i.p.) or saline were given every other day for a total of ten injections, and this regimen induced behavioral sensitization of locomotor activity in drug-treated rats. After a 3-week post-drug period, d-amphetamine-treated rats exhibited facilitated sexual behavior, as indicated by shorter latencies to mount and intromit, and a greater percentage of rats copulating. These rats also exhibited a general increase in the amount of copulation. Furthermore, sensitized rats displayed a facilitated acquisition of sexual behavior (i.e. mount and intromission latency <300 s for 3 consecutive days). After repeated sexual experience, rats pre treated with d-amphetamine also showed an augmented increase in level changes made in anticipation of the presentation of a receptive female. Finally, enhanced sexual behavior was independent of the environment in which repeated administration of d-amphetamine occurred, indicating that facilitation was not a consequence of conditioned associations between drug and test environment. These results demonstrate that behavioral sensitization due to repeated psychostimulant administration can "cross-sensitize" to a natural motivated behavior, such as sex. Furthermore, the subsequent facilitation of anticipatory sexual behavior (i.e. level changes) after repeated experience in rats previously treated with d amphetamine suggests that behavioral sensitization can influence incentive learning. PMID- 10102774 TI - The competitive NMDA receptor antagonist LY235959 modulates the progression of morphine tolerance in rats. AB - A rat warm-water tail-withdrawal procedure was used to examine the effects of chronic administration of the competitive NMDA receptor antagonist LY235959 in morphine tolerant rats. Morphine dose-dependently increased tail-withdrawal latencies from 55 degree C water. When morphine (10 mg/kg) was administered twice daily for 7 days, the morphine dose-effect curves shifted 0.3-0.5 log unit to the right. When morphine was administered for an additional 7 days, the morphine dose effect curve shifted 0.4 log unit further to the right. Co-administration of LY235959 (1, 3, 10 mg/kg) along with morphine prevented the development of tolerance observed during the second week of chronic morphine administration. Although the highest dose of LY235959 (10 mg/kg) partially reversed tolerance in five of seven rats, tolerance was not reversed by lower doses of LY235959. These data suggest that NMDA receptor antagonists may effectively prevent the progressive development of morphine tolerance at doses that are not sufficient to reverse pre-established morphine tolerance. PMID- 10102775 TI - Effects of histamine H3 receptor ligands in experimental models of anxiety and depression. AB - Histamine H3 receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H3 receptor function in experimental models of anxiety (elevated plus maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated i.p. with the histamine H3 receptor agonist R-alpha-methylhistamine (10 mg/kg) or the histamine H3 receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the i.p. administration of R alpha-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H3 receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-alpha-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-alpha-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2-10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H3 receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H3 receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied. PMID- 10102776 TI - Scopolamine slows the orienting of attention in primates to cued visual targets. AB - The cholinergic agonist nicotine facilitates visuospatial attention shifting, but the role of muscarinic cholinergic drugs in this behavior is unclear. In order to establish the generality of cholinergic action in attention shifting, we administered the muscarinic antagonist scopolamine to two rhesus monkeys trained to perform a cued target detection (Posner) task. In this task, monkeys signaled the detection of a peripheral visual target by releasing a switch and their reaction times were measured. The location of the target's appearance was preceded by a cue that was either valid (target and cue in the same spatial location), invalid (target and cue to opposite hemifields), spatially uninformative (cues in both hemifields, target to one hemifield), or omitted altogether. Scopolamine produced a dose-dependent increase in all reaction times and a decrease in accuracy. The slowing was most prominent for valid cues in either visual field. However, slowing did not occur in trials whose cues lacked spatial information, or in tasks in which attention was directed to events at the fixation point, whether or not peripheral distractors were present. These results provide additional support for the hypothesis that acetylcholine plays a key role in reflexive attention shifting to peripheral visual targets. PMID- 10102777 TI - Differential effects of ketamine on gating of auditory evoked potentials and prepulse inhibition in rats. AB - Schizophrenic patients suffer from deficits in information processing. Patients show both a decrease in P50 gating [assessed in the conditioning-testing (C-T) paradigm] and prepulse inhibition (PPI), two paradigms that assess gating. These two paradigms might have a related underlying neural substrate. Gating, as measured in both the C-T paradigm (the gating of a component of the auditory evoked potential (AEP)], and PPI can easily be measured in animals as well as in humans. This offers the opportunity to model these information processing paradigms in animals in order to investigate the effects of neurotransmitter manipulations in the brain. In order to validate the animal model for disturbances in AEP gating, d-amphetamine (0.5 and 1 mg/kg, i.p.) was administered. Gating of an AEP component was changed due to injection of d amphetamine (1 mg/kg) in the same way as seen in schizophrenic patients: both the amplitude to the conditioning click and the gating were significantly reduced. Next, the effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine (2.5 and 10 mg/kg, i.p.) was investigated to assess its effects in the two gating paradigms. It was found that ketamine (10 mg/kg) did not affect gating as measured with components of the AEP. However, ketamine (10 mg/kg) disrupted PPI of the startle response to the extent that prepulse facilitation occurred. Firstly, it is concluded that AEP gating was disrupted by d-amphetamine and not by ketamine. Secondly, PPI and the C-T paradigm reflect distinct inhibitory sensory processes, since both paradigms are differentially influenced by ketamine. PMID- 10102778 TI - Effects of nicotine administered via a transdermal delivery system on vigilance: a repeated measure study. AB - Fifteen 18- to 25-year-old male smokers were tested in a within-subjects design to determine the influence of a transdermal patch of 21 mg nicotine on vigilance. Subjects were tested on the RVIP test (Rapid Visual Information Processing test) 1.30, 3.00 and 6.30 h after patch application, to verify the involvement of the dose of nicotine on the performance. This study confirms and extends the increasing effects of nicotine on vigilance previously found with orally and transdermally given nicotine. Moreover, it showed that such performance was independent of the time of nicotine absorption (1.30, 3.00 and 6.30 h after patch application), which suggests that a relatively low dose of nicotine suffices to activate vigilance processing. Regarding motor performance, no convincing effect of nicotine was observed on reaction time. PMID- 10102779 TI - The effects of tryptophan depletion and loading on laboratory aggression in men: time course and a food-restricted control. AB - Some studies have shown that sharp reduction of L-tryptophan (Trp) concentration in plasma results in increases in laboratory-measured aggression. Conversely, raising plasma Trp has blunted aggression. These effects are presumably due to impaired or enhanced serotonin synthesis and neurotransmission in the brain. In this study, the laboratory-measured aggressive behavior of eight men under both Trp depletion (T-) and Trp loading (T+) conditions was compared to their aggressive behavior under food-restricted control conditions (overnight fast without an amino acid beverage). Subjects were provoked by periodic subtraction of money which was attributed to a fictitious other participant, and aggression was defined as the number of retaliatory responses the subject made ostensibly to reduce the earnings of the (fictitious) other participant. Following ingestion of the T- beverage, aggressive responding was significantly elevated relative to the food-restricted control condition, and this increased aggressive behavior became more pronounced across behavioral testing sessions on a time-course which paralleled previously documented decreases in plasma Trp concentrations. In contrast, no changes were observed in aggressive responding under T+ conditions relative to food-restricted conditions. These within-subject behavioral changes under depleted plasma Trp conditions support earlier indications of a role of serotonin in regulating aggression. PMID- 10102780 TI - Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization. AB - The mesolimbic dopamine (DA) system has been implicated in conditioned reward (CR), locomotor sensitization, and the reinforcing properties of psychomotor stimulants. Stimuli with formerly motivationally neutral properties that gain incentive properties by their predictive association with primary reinforcers are termed conditioned, or secondary, reinforcers. In these experiments, we investigated whether cocaine sensitization could potentiate augmented responding for CR produced by intra-accumbens amphetamine. After subjects were trained on the CR paradigm for 14 days, they received a regimen of cocaine sensitization or saline injections. On 2 test days, 8-10 days later, subjects were given amphetamine (6 microg/0.5 microl) or saline infusions into the nucleus accumbens (NAc) and responding for CR was measured using the "acquisition of a new response" paradigm. Responding on one novel lever resulted in the delivery of the conditioned stimulus (conditioned reinforcer, or CR lever), whereas responding on the other lever resulted in no CR stimulus presentation (NCR lever). Animals sensitized to cocaine showed increased responding on the CR lever after intra-NAc saline and potentiated CR lever responding after intra-NAc amphetamine. No differences in responding between the cocaine- and saline-treated groups on the NCR lever after the challenge were found. Locomotor sensitization under these conditions was confirmed in a separate group of subjects. These findings show that prior exposures to cocaine results in changes that potentiate the ability of intra-NAc amphetamine to enhance CR. Repeated stimulant drug use may induce long term neuronal adaptations that result in increased sensitivity to the behavioral, or incentive motivational, effects of stimulant drugs. PMID- 10102781 TI - Psychopathological, neuroendocrine and autonomic effects of 3,4 methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers. Results of an experimental double-blind placebo-controlled study. AB - The aim of this study was to contribute to the characterization of the entactogen (ecstasy) substance group. The psychopathological, neuroendocrine and autonomic effects of common recreational doses of the entactogen 3,4 methylenedioxyethylamphetamine (MDE), the hallucinogen psilocybin, the stimulant d-methamphetamine and placebo were investigated in a double-blind study with healthy volunteers (n = 32). Psychological effects of the drugs were assessed by means of standardized rating scales, self assessment inventories and free descriptions. The most characteristic effects of MDE were pleasant emotional experiences of relaxation, peacefulness, content and closeness to others. However, significant stimulant and hallucinogen-like effects were also present, although the latter were weaker than the effects of psilocybin. MDE elicited the strongest endocrine and autonomic effects among the three drugs, including robust rises of serum cortisol and prolactin, elevations of blood pressure and heart rate, and a moderate, but significant rise of body temperature. The apparent contrast between psychological and autonomic effects (subjective relaxation versus physical activation) was a unique feature of the MDE state. Our findings are in line with both users' reports and results from previous experimental studies, and support the view that entactogens constitute a distinct psychoactive substance class taking an intermediate position between hallucinogens and stimulants. PMID- 10102782 TI - Actions of the D1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L-dopa-primed common marmosets. AB - Common marmosets show parkinsonian motor deficits following 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D1 agonists A-77636 [(1R, 3S) 3-(1'-adamantyl)-1 aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] and A-86929 [(-) trans 9, 10-hydroxy-2-propyl-4, 5, 5a, 6, 7, 11b-hexahydro-3-thia-5-azacyclopent 1-ena[c]phenanthrene hydrochloride] possess potent antiparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stable motor deficits were treated with L-dopa plus carbidopa for 28 days to induce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 micromol/kg and then at 1.0 micromol/kg for a further 5 days. Several months later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally twice daily for 7 days, followed by A-77636 1 micromol/kg for 10 days, and then both A-77636 and L-dopa plus carbidopa were given concurrently for 3 further days. In these L-dopa-primed animals, A-86929 effectively reversed akinesia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behavioral tolerance was encountered, but antiparkinsonian activity was preserved and elicited behaviour was free of hyperkinesis and stereotypy and more naturalistic than that seen with L-dopa. After a week of twice-daily L-dopa dosing, administration of the long-acting D1 agonist A-77636 initially dramatically enhanced locomotion and reproduced dyskinesia with prominent dystonia, but after repeated administration of A-77636, dyskinesia and in particular chorea, gradually disappeared. Tolerance to locomotor stimulation greater than with A-86929 occurred, although activity remained significantly above baseline levels. There was a marked reduction in L-dopa-induced climbing, stereotypy and hyperkinesis and behaviour more closely resembled that of normal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A 77636 administration, dystonic, but virtually no choreic dyskinesias appeared and behaviour was once again free of stereotypy and hyperkinesis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesser liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subjects while maintaining effective antiparkinsonian activity and producing a more naturalistic motor response. The differential effects of A-77636 on chorea and dystonia, with suppression of chorea and stereotypy on co-administration with L-dopa, may reflect an altered balance of activity in the direct and indirect striatofugal pathways. These results suggest a possible role for D1 agonists in the treatment of Parkinson's disease. PMID- 10102783 TI - The impact of ergotamine-induced headache and ergotamine withdrawal on information processing. AB - Ergotamine abuse and subsequent ergotamine-induced headache is a common problem in the pharmacological treatment of migraine and other headache types; often, withdrawal therapy is necessary. This study investigated whether ergotamine abuse affects information processing and whether withdrawal therapy can lead to an improvement of information processing. We designed a standardized neurophysiological retrospective (ergotamine abuse) and prospective (ergotamine withdrawal) study in a supraregional headache outpatient clinic. Seventy-one patients abusing ergotamine derivatives with subsequent daily headache were enrolled and compared to 36 migraine patients without ergotamine intake and 36 healthy subjects. Information processing was evaluated by latencies and amplitudes of visually evoked event-related potentials (ERP) before and after ergotamine withdrawal therapy. P3 latency of the ERP was significantly increased in ergotamine abuse (442 +/- 45 ms) versus migraine (415 +/- 40 ms) and healthy subjects (410 +/- 33 ms), there was no difference between ergotamine tartrate and dihydroergotamine abuse. The migraine specific loss of habituation in information processing as measured by P3 latency could not be observed in migraine patients with ergotamine abuse. After successful withdrawal therapy in 36 patients, the abnormally prolonged P3 latency was significantly shortened (452 +/- 47 ms versus 433 +/- 30 ms; P < 0.004). Our findings imply that information processing is impaired by ergotamine abuse and can be improved but not normalized after withdrawal therapy. Furthermore, our data provide strong evidence that ergotamine, besides its peripheral effects, has a central mode of action. PMID- 10102784 TI - Peripheral hormonal responses to D-fenfluramine as a probe of central serotonergic function in humans. AB - We tested the hypothesis that D-fenfluramine (DFEN)-elicited cortisol (CORT) release in humans may be mediated by a direct effect on the adrenal gland by pretreating subjects with dexamethasone (DEX), to prevent release of ACTH from the pituitary, followed by a DFEN challenge test. Eight healthy subjects (four males; four female) (mean age = 38.1 +/- 8.4 years (SD)] were studied > 1 week apart (same phase of menstrual cycle) and testing order was randomised. On the with-DEX day (DEX+), subjects took 2 mg DEX orally at 10 p.m.; 30 mg DFEN was then given orally at 9 a.m. and samples were taken at 0-5 h for PRL and CORT. Peak hormone responses (delta values) were calculated by subtracting baseline values from the maximum levels post-DFEN administration. Peak and baseline hormonal values were compared between the two test conditions; DFEN-induced CORT and PRL responses were compared across all time points, with and without DEX. There was no significant difference in delta PRL between the two test conditions (DEX- and DEX+), but delta CORT values were significantly reduced after DEX: mean delta CORT DEX- = 68.4 +/- 26.3 nmol/l; DEX+ = 0.0 nmol/l (all blunted) (df 7,1; P = 0.03). The completely blunted peripheral cortisol response indicates that DFEN cortisol responses are of central origin only. PMID- 10102785 TI - Effects of adrenalectomy on 8-OH-DPAT induced hypothermia in mice. AB - Complex interactions exist between the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic system, and it has been suggested that these interactions may be fundamental to the pathophysiology and treatment of depressive illnesses. It has previously been found that chronic administration of corticosterone leads to adrenal suppression and an attenuation of somatodendritic 5-HT1A receptor function. Adrenalectomy (ADX) has been shown to cause an increase in postsynaptic 5-HT1A receptor numbers and possibly function. However, other reports have suggested that ADX does not alter somatodendritic 5-HT1A receptor mRNA or binding, though little is known of the effect of ADX on the function of somatodendritic 5-HT1A receptors. This study investigated the effect of markedly reducing corticosterone levels by ADX on 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced hypothermia in mice, an in vivo model of somatodendritic 5 HT1A receptor function. The degree of 8-OH-DPAT-induced hypothermia did not differ between control, sham, and ADX animals 14 days post operatively. Although repeated administration of corticosterone attenuates somatodendritic 5-HT1A receptor function, these data demonstrate that lowering of corticosteroid levels by ADX have no effect. This suggests that the effects of repeated corticosterone administration is not mediated by a secondary adrenal suppression. The difference in the effects of ADX on somatodendritic as opposed to postsynaptic 5-HT1A receptors may reflect the differential expression of corticosteroid receptor subtypes at postsynaptic and somatodendritic sites. PMID- 10102787 TI - Chronic morphine induces long-lasting changes in acetylcholine release in rat nucleus accumbens core and shell: an in vivo microdialysis study. AB - Previously, only in vitro studies have shown that chronic administration of morphine provokes long-lasting enhanced activity of accumbal cholinergic neurons, which may contribute to the behavioural sensitization, positive reinforcement and aversive effects associated with enhanced drug-seeking. The present study was aimed at clarifying whether these adaptive changes would also be supported by in vivo microdialysis measurements in freely moving rats, distinguishing between the accumbal substructures shell and core, and observing behavioural changes simultaneously. Acute administration of morphine dose-dependently decreased acetylcholine (ACh) release in the nucleus accumbens (NAc), with 10 mg/kg s.c. being most effective, 5 mg/kg ineffective. On day 5 of spontaneous abstinence from chronic morphine treatment (10-40 mg/kg morphine dose once daily for 5 days), when withdrawal symptoms were still present, even a lower morphine dose (5 mg/kg) was effective in decreasing ACh release in the NAc. During the later phase of abstinence, when no withdrawal symptoms were detectable, the opposite effect, i.e. an increase of ACh release was found. This later effect may represent a long lasting neuroadaptive effect of morphine. These adaptive effects seemed to be more prominent in the NAc shell. Concurrent with these changes in ACh release, morphine challenges produced marked behavioural stereotypes, possibly indicating behavioural sensitization. PMID- 10102786 TI - Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. AB - D4 dopamine receptors (DRs) are enriched in the primate prefrontal cortex, a brain region implicated in cognitive processes, and mesoprefrontal dopaminergic systems appear to be involved in modulating some cognitive functions of the prefrontal cortex. Despite anatomical localization of D4 DRs within the frontal cortex, the role of these receptors, specifically, in the regulation of cognition or behavior in primates is unknown. In these studies, we sought to learn whether specific antagonism of D4 DRs would affect performance of a task dependent on the frontostriatal system. The effects of NGD94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl) piperazin-1-yl)-methyl]-imidazol e dimaleate), a potent and selective D4 DR antagonist and haloperidol, a non-specific D2-like DR antagonist, on the performance of an object retrieval/detour task by monkeys were examined. The effects of these antagonists on the object retrieval task were evaluated in normal control monkeys and in subjects repeatedly exposed to phencyclidine (PCP), to induce frontal cortical dopaminergic and cognitive dysfunction. NGD94-1 (1-5 mg/kg) reversed the cognitive deficits of PCP pre-treated monkeys, whereas haloperidol (25 microg/kg) exacerbated PCP-induced performance impairments. A low dose of NGD94-1 failed to affect performance of control subjects, while both haloperidol and a high dose of NGD94-1 impaired control performance. These data show, for the first time, that D4 DRs modulate the cognitive functions of the frontostriatal system. PMID- 10102788 TI - Oxytocin as a possible mediator of SSRI-induced antidepressant effects. AB - The nonapeptide oxytocin is released into systemic circulation in situations of psychosocial interaction, and has been shown to be involved in mechanisms of social bonding and social recognition in laboratory studies. In view of disturbances in psychosocial relationships being a triggering factor for depression and anxiety, it is interesting to note that experimental studies have shown oxytocin to possess antidepressant- and anxiolytic-like actions. Thus. in the present study we examined effects of the SSRI citalopram (20 mg/kg i.p.) on plasma oxytocin, acutely and upon repeated administration, in adult male Sprague Dawley rats. Plasma oxytocin, and some functionally related peptides (CCK, gastrin, somatostatin and insulin), were measured by standard radioimmunoassay techniques. Acute citalopram administration produced a statistically significant increase in plasma oxytocin and CCK levels. Administration of citalopram for 14 days did not attenuate the oxytocin-releasing effect to a challenge dose of the SSRI zimeldine (20 mg/kg s.c.), whereas CCK levels were not increased after the subchronic citalopram treatment. Thus, the SSRI citalopram produces increased plasma oxytocin levels acutely, and there appears to be no or little tolerance to this effect upon repeated administration. There were no, or variable, effects on plasma levels of gastrin, somatostatin or insulin. It is suggested that oxytocin release is an important aspect of the pharmacological actions of SSRIs, and this could be an important contributory factor for the clinical profile of this group of antidepressants with particular efficacy in disorders of psychosocial origin. PMID- 10102789 TI - Effects of D1 dopamine receptor agonists on oral ethanol self-administration in rats: comparison with their efficacy to produce grooming and hyperactivity. AB - In order to study the potential efficacy of dopamine receptor agonists in the treatment of alcohol abuse, the present study investigated the effects of several dopamine D1 receptor agonists with different intrinsic activities on ethanol self administration in rats. In a separate experiment, the effects of two of the same compounds on saccharin self-administration were also studied. To investigate further the relationship between activity in reducing ethanol self-administration and efficacies to stimulate D1 receptors, the potencies of the agonists to reduce ethanol self-administration were compared with their potencies to produce hyperactivity and grooming, behaviors which are believed to involve stimulation of D1 receptors. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. Another group of rats was trained to self-administer a solution of saccharin (0.01% w/v) in a similar operant task. Pretreatment with full (R-6Br-APB, SKF 82958 and SKF 81297) and partial (SKF 38393 and SKF 77434) dopamine D1 receptor agonists dose dependently decreased responding for ethanol. SKF 82958 and SKF 38393 also decreased responding for saccharin. Comparison of potencies to decrease ethanol self-administration with potencies to produce locomotor activity and grooming revealed that reduction of ethanol self-administration by D1 full agonists occurs at doses similar to those which produce grooming and locomotor activity. However, the partial agonists (and in particular, SKF 38393) reduced responding for ethanol at doses lower than those producing hyperactivity. The present results underline the involvement of D1 dopamine receptors in reward processes. PMID- 10102790 TI - Involvement of protein kinase A in histamine-mediated inhibition of IL-2 mRNA expression in mouse splenocytes. AB - The release of histamine from mast cells and basophils during allergic reactions can regulate functions of T cells and may influence the nature of the immune response to a given antigen. The effects of histamine on T lymphocytes are associated with its binding to H2-receptors linked with adenylate cyclase, elevation of cAMP levels and activation of cAMP-dependent protein kinase (PKA). In this report we explore the role of PKA in histamine-mediated effects on IL-2 mRNA expression and IL-2 protein secretion. Fresh isolated mouse splenocytes (C57Bl/6) were pretreated with histamine (10(-4) M) for 1 h in the presence or absence of Rp-cAMPS (50 microM), an inhibitor of PKA regulatory subunit. The cells were then washed thoroughly and activated with plate-bound anti-CD3 (5 microg/ml), or PHA (1:100) or PMA + ionomycin (10 ng/ml, 1 microg/ml) for 6 h. Pretreatment with histamine inhibited IL-2 mRNA expression and secretion in cells activated with anti-CD3 or PMA, but not in cells activated with PMA + ionomycin. Rp-cAMPS prevented histamine-mediated suppression and did not itself affect IL-2 production. These results provide evidence that histamine affected IL-2 production when the cells were activated via the T cell receptor (TCR)/CD3 complex, but did not interfere with signal transduction pathways downstream of PKC leading to production of IL-2. These effects of histamine on IL-2 secretion and mRNA expression were mediated via PKA. PMID- 10102791 TI - PGG-glucan, a soluble beta-(1,3)-glucan, enhances the oxidative burst response, microbicidal activity, and activates an NF-kappa B-like factor in human PMN: evidence for a glycosphingolipid beta-(1,3)-glucan receptor. AB - PGG-Glucan, a soluble beta-(1,6)-branched beta-(1,3)-linked glucose homopolymer derived from the cell wall of the yeast Saccharomyces cerevisiae, is an immunomodulator which enhances leukocyte anti-infective activity and enhances myeloid and megakaryocyte progenitor proliferation. Incubation of human whole blood with PGG-Glucan significantly enhanced the oxidative burst response of subsequently isolated blood leukocytes to both soluble and particulate activators in a dose-dependent manner, and increased leukocyte microbicidal activity. No evidence for inflammatory cytokine production was obtained under these conditions. Electrophoretic mobility shift assays demonstrated that PGG-Glucan induced the activation of an NF-kappaB-like nuclear transcription factor in purified human neutrophils. The binding of 3H-PGG-Glucan to human leukocyte membranes was specific, concentration-dependent, saturable, and high affinity (Kd approximately 6 nM). A monoclonal antibody specific to the glycosphingolipid lactosylceramide was able to inhibit activation of the NF-kappaB-like factor by PGG-Glucan, and ligand binding data, including polysaccharide specificity, suggested that the PGG-Glucan binding moiety was lactosylceramide. These results indicate that PGG-Glucan enhances neutrophil anti-microbial functions and that interaction between this beta-glucan and human neutrophils is mediated by the glycosphingolipid lactosylceramide present at the cell surface. PMID- 10102792 TI - Effects of single intravenous doses of recombinant human interleukin-10 on subsets of circulating leukocytes in humans. AB - Recombinant human interleukin-10 (rhIL-10) is a potent and specific immunomodulatory agent which inhibits endotoxin-stimulated pro-inflammatory cytokine production by monocytes, blocks T-lymphocyte activation by antigen presenting cells, and modulates T(H)1/T(H)2 balance in immune responses. In previous clinical trials, rhIL-10 administered to healthy volunteers induced rapid and transient elevations of neutrophil and monocyte counts and reductions of lymphocyte counts in addition to suppression of endotoxin-stimulated whole blood cytokine synthesis. We sought to better characterize the effects of rhIL-10 on immunophenotypically defined subsets of circulating leukocytes that could be relevant to its immunomodulatory effects. Healthy volunteers were given single doses of 10 microg/kg rhIL-10 (n = 8) or equivalent placebo (n = 4) by intravenous injection. Significant changes of circulating leukocytes included transiently increased neutrophils and monocytes with parallel increases of CD33+ and CD14+ cells. Total lymphocytes as well as total CD3+, CD3+/CD4+ and CD3+/CD8+ cells transiently decreased. Mean fluorescence intensity of CD11a (integrin alpha chain subunit of lymphocyte function antigen-1, LFA-1) on lymphocytes transiently but significantly decreased, suggesting a mechanism for transient alteration of lymphocyte trafficking. In addition, mean fluorescence intensity of HLA-DR (major histocompatibility class II) on CD14+ cells (predominantly monocytes) transiently but significantly decreased, implying a possible alteration of antigen presenting function. Further study will be required to elucidate the immunomodulatory roles and potential clinical significance of these hematologic changes in therapeutic trials of rhIL-10 in patients with chronic inflammatory and autoimmune diseases. PMID- 10102793 TI - Endogenous mouse interleukin-10 is up-regulated by exogenously administered recombinant human interleukin-10, but does not contribute to the efficacy of the human protein in mouse models of endotoxemia. AB - In murine models of experimental endotoxemia, inflammatory cytokines as well as antiinflammatory interleukin-10 (IL-10) appear in the circulation after the injection of lipopolysaccharide (LPS). There is considerable experimental evidence to suggest that the major function of endogenously produced IL-10 is to down-regulate inflammatory cytokine production. Indeed, the protective effects of exogenously administered IL-10 against murine endotoxin lethality have been shown to correlate with its ability to inhibit the LPS-induced production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). While mouse IL-10 (mIL-10) has been used in the majority of studies in murine endotoxemia, we have found the human homolog to be equally effective in suppressing inflammatory cytokine production and in protecting mice from endotoxin lethality. However, we have recently observed that the LPS-induced endogenous IL-10 response is enhanced when mice are treated with recombinant human IL-10 (rhuIL-10). The upregulation of endogenous IL-10 by exogenously administered rhuIL-10 is particularly evident in mice that are primed with Corynebacterium partum (Proprionibacterium acnes). In the present study, we have examined the potential contributions of the increased circulating levels of mouse IL-10 to the inhibitory effects seen with rhuIL-10 on inflammatory cytokine production and endotoxin lethality. We show that pretreatment with a neutralizing anti-mouse IL-10 monoclonal antibody (mAb) has no effect on the ability of rhuIL-10 to suppress an LPS-induced inflammatory cytokine response in these mice. In contrast, the suppressive effects of the human protein on inflammatory cytokine responses are blocked completely by pretreating the animals with an anti-huIL-10 mAb. These data show that despite the up-regulated endogenous IL-10 response, it is the exogenously administered rhuIL-10 that is directly responsible for the suppressed inflammatory cytokine responses that are observed when the human protein is given to endotoxemic mice. PMID- 10102794 TI - Neurotensin stimulation of mast cell secretion is receptor-mediated, pertussis toxin sensitive and requires activation of phospholipase C. AB - Pretreatment of isolated rat serosal mast cells with U-73122, an aminosteroid inhibitor of phospholipase C, inhibited histamine secretion in response to neurotensin (NT). This inhibition reached a maximum after 1 h of pretreatment at 37 degrees C and was dependent upon the concentration of U-73122 (IC50 approximately 0.2 microM). The inactive analog, U-73343, had no effect on the secretory response to NT. Pretreatment of mast cells with U-73122 also blocked histamine secretion in response to substance P (SP), mastoparan (MP), compound 48/80, or amidated NT (NT-NH2). Stimulation of mast cells by NT was accompanied by a rise in the level of intracellular free calcium and a rapid (within seconds) increase in the level of inositol trisphosphate (IP3) which was inhibited by pretreatment of the cells with U-73122. Pretreatment of isolated mast cells with pertussis toxin (PTx) blocked histamine release in response to NT as well as to all peptides tested. PTx had no effect on histamine secretion elicited by anti IgE stimulation of sensitized mast cells. Pretreatment of mast cells with SR 48692, a NT-receptor antagonist, had no effect on histamine release induced by MP. At a high concentration (100 nM) SR 48692 partially inhibited the response to NT-NH2. These results, together with our earlier findings with SR 48692, indicate that the signal transduction pathway in mast cells activated by NT requires a specific NT-receptor, the activation of phospholipase C, and the involvement of a PTx sensitive G protein. The peptides SP and MP, and compound 48/80, while also requiring the activation of PLC and a PTx sensitive G protein, are not inhibited by the NT-R antagonist, SR 48692, suggesting that they exert their actions either via a different mast cell receptor or via a receptor-independent mechanism. PMID- 10102795 TI - Immunomodulatory effects of pharmacological elevation of cyclic AMP in T lymphocytes proceed via a protein kinase A independent mechanism. AB - The role of the cAMP pathway as an immunomodulatory system has been an area of intensive research. Pharmacological elevation of the cAMP pathway inhibits T lymphocyte proliferation and production of Th1-type cytokines. The effects of cAMP are thought to be mediated via activation of the intracellular receptor, protein kinase A (PKA). We investigated the inhibitory effects of cAMP elevation on human lymphocyte proliferation and function by utilising a range of selective inhibitors of PKA. Elevation of cAMP activity by dbcAMP, Sp-cAMPS and forskolin induced significant decreases of Con A stimulated PBMC proliferation. Co incubation with the selective PKA inhibitors HA1004, KT5720 and Rp-cAMPS showed these antiproliferative effects to persist, despite measurable PKA activity being inhibited to that of untreated cells or less. IL-2 production was also inhibited by dbcAMP in the presence of HA1004 and Rp-cAMPS. It has been demonstrated that the inhibitory effects of pharmacological elevations in cAMP on human T cell proliferation and IL-2 production do not require PKA activity. These observations indicate that control of lymphocyte proliferation and functional status by cAMP proceeds through PKA-independent events. Identification of the underlying mechanisms behind these effects would increase our understanding of the cAMP cascade and may provide a potentially novel target for immunomodulation. PMID- 10102796 TI - Lymphocyte activation and cytokine production by Pisum sativum agglutinin (PSA) in vivo and in vitro. AB - Mice spleen cells were incubated in vitro for 24 h with Pisum sativum agglutinin (PSA). The addition of these supernatants (SN) to macrophage cultures induced the production of nitric oxide (NO) by these cells in a dose-dependent manner. NO release was blocked in the presence of IFN gamma antibodies and partially inhibited by TNF alpha antibodies. The ability of PSA in inducing the production of IFN gamma and TNF alpha by spleen lymphocytes was confirmed assaying these cytokine levels in the SN. Spleen cells stimulated in vitro with PSA were highly activated showing an increased expression of the earlier activation marker, CD69, and a great proliferative response. On the other hand, spleen cells obtained from mice treated with PSA 24 h earlier, did not produce significant levels of IFN gamma or TNF alpha when incubated in vitro and showed a significantly lower proliferation rate when pulsed in vitro with PSA or Concanavalin A (ConA). The lower responsiveness to mitogens was also evident after 48 and 72 h after the treatment in vivo with the lectin. Nevertheless, the flow cytometric analysis of spleen lymphocytes obtained from PSA-treated animals showed a high degree of activation in cells CD3+. There was a decrease in the expression of L-selectin and VLA-4, when compared to controls, in parallel with a significant increase in the expression of CD69 and CD122 (IL-2R) in lymphocytes recovered from PSA injected animals. The data point to evidence that PSA induces immunomodulatory effects, activating spleen lymphocytes in vivo, which become unresponsive to a second stimulation in vitro. PMID- 10102797 TI - The inhibitory effect of polysaccharides isolated from Phellinus linteus on tumor growth and metastasis. AB - It was previously reported that polysaccharides (PL) isolated from Phellinus linteus strongly stimulated cell-mediated and humoral immunity. This study was undertaken to investigate the immunochemotherapeutic activity of PL against tumor growth and metastasis. PL alone significantly prolonged the survival rate of B16F10-implanted mice, inhibited tumor growth in NCI-H23-implanted nude mice, and reduced the frequency of pulmonary metastasis of B16F10 melanoma. Adriamycin significantly inhibited tumor growth, but only slightly inhibited metastasis. The combination therapy with PL and adriamycin was more effective in inhibiting tumor growth, but not metastasis. PL did not induce direct toxicity in cancer cells, which is characteristic of immunotherapeutics. In conclusion, PL might be of use in immunochemotherapy of cancer because of its effective activities on tumor growth and metastasis through the immunopotentiation of the patients without toxicity. PMID- 10102798 TI - Monophosphoryl lipid A, a derivative of bacterial lipopolysaccharide, fails to induce B1-receptor-dependent responses to (des-Arg9)-bradykinin in the rabbit in vivo. AB - OBJECTIVE: The aim of this study was to evaluate whether monophosphoryl lipid A (MLA) was able to induce a hypotensive response to (des-Arg9)-bradykinin in the rabbit in vivo, by inducing B1-receptor synthesis. MATERIALS AND METHODS: Arterial pressure was measured after intra-arterial administration of B1- and B2 receptor agonists and antagonists in control rabbits and in rabbits pre-treated 24 h earlier with MLA (100 microg kg(-1) i.v.) or lipopolysaccharide (LPS) (10 microg kg(-1) i.v.). RESULTS: Intra-arterial bradykinin administration induced a similar dose-dependent hypotension in all groups (BK 0.25 microg kg(-1), 36 +/- 3 mm Hg, BK 1 microg kg(-1), -39 +/- 3 mm Hg, p < 0.05 vs. control conditions) that was significantly antagonised by intra-arterial HOE 140 (2 microg kg(-1)) (-5 +/- 2 mm Hg, p < 0.05). Intra-arterial (des-Arg9)-bradykinin induced a hypotensive response in the LPS-pre-treated group (DBK 1 microg kg(-1), -6 +/- 1 mm Hg, DBK 10 microg kg(-1), -10 +/- 1 mm Hg, p < 0.05 vs. control conditions) that was totally abolished by intra-arterial (des-Arg9, Leu8)-bradykinin (10 microg kg(-1) min(-1)) (+1 +/- 2 mm Hg, p < 0.05). In the control and MLA-pre-treated groups, (des-Arg9)-bradykinin had no effect. CONCLUSION: MLA pre-treatment did not induce a hypotensive response to (des-Arg9)-bradykinin. We conclude that, in contrast to LPS, MLA does not induce B1-receptor synthesis, 24 h after its administration in the rabbit. Thus, the cardioprotective effects of MLA do not appear to be related to the kinin pathway. PMID- 10102799 TI - Effect of an atypical adrenergic beta3-agonist, GS-332: sodium (2R)-[3-[3-[2-(3 chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy] acetate, on urinary bladder function in rats. AB - We have developed an atypical adrenergic beta3-agonist, GS 332: Sodium (2R)-[3-[3 [2-(3 Chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy]acetate, which has an unique structure compared to other beta3 agonists. In vitro study, we compared effects of GS 332 on rat urinary bladder muscle strip contractility with those of clenbuterol hydrochloride (clenbuterol), an adrenergic beta2 agonist. GS-332 relaxed isolated rat urinary bladder strips in a concentration dependent manner with 50% effective concentration (EC50) of 15.7 nM, and the relaxant activity of GS 332 was as potent as that of clenbuterol(EC50; 30.8 nM). The concentration response curve of GS 332 on isolated rat urinary bladder was competed by a specific beta3-antagonist, SR59230A in a concentration-dependent manner, in which Schild slope was 1.1 and pA2 value of SR59230A was 7.1. In vivo study, cystometory investigated in anesthetized rats demonstrated that GS 332 was more potent in increasing the urinary storage volume than clenbuterol and less potent in inhibiting the contractile force of urinary bladder at micturition reflex than clenbuterol. These data demonstrate that GS 332, a new adrenergic beta3-agonist, may be more useful to maintain continence than clenbuterol, an adrenergic beta3 adrenergic agonist. PMID- 10102800 TI - Differences of antagonism for a selective alpha1D-adrenoceptor antagonist BMY 7378 in the rabbit thoracic aorta and iliac artery. AB - Based on the affinity of alpha1D adrenoceptor subtype for a selective antagonist BMY 7378, we studied its functional role in rabbit thoracic aorta and iliac artery, and evaluated the subtypes of the alpha1-adrenoceptors that are activated by phenylephrine (a full agonist) and tizanidine (a partial agonist). In thoracic aorta, the concentration response curves of phenylephrine and tizanidine were antagonized by BMY 7378 with low potency (pA2 values 6.68+/-0.06 and 6.67+/-0.06, slopes of Schild plot 1.06+/-0.04 and 1.01+/-0.04, respectively). On the other hand, in iliac artery concentration response curves for phenylephrine were potently antagonized by a low concentration of BMY 7378, and the slope (0.75+/ 0.02) of the Schild plot was significantly different from unity. In iliac artery, a concentration response curve of tizanidine was antagonized by BMY 7378 with low potency (pA2 value 6.64+/-0.08, slope of Schild plot 1.01+/-0.05). These results suggest that an alpha1D-adrenoceptor subtype contributes to alpha1-adrenoceptor mediating muscle contraction in iliac artery, but not in thoracic aorta of rabbit, and that it is activated by a full agonist phenylephrine but not by a partial agonist tizanidine. PMID- 10102801 TI - Relationship between global cytosolic Ca2+ concentration and Ca2+-activated K+ current in rabbit cerebral arterial myocyte. AB - In smooth muscle cells, the sarcoplasmic reticulum (SR) has been identified as the primary storage site for intracellular Ca2+. The peripheral SR is in close proximity with plasma membrane to make a narrow subsarcolemmal space. In this study, we investigated the regulation of subsarcolemmal [Ca2+] ([Ca2+]sl) and global cytosolic [Ca2+] ([Ca2+]c) of rabbit arterial smooth muscle using whole cell patch clamp technique and microspectrofluorimetry. The Ca2+-activated K+ current (IK(Ca)) and the ratio of fura-2 fluorescence (R340/380) were considered to reflect the [Ca2+]sl and [Ca2+]c, respectively. At a holding potential of 0 mV, extracellular application of 10 mM caffeine, a well known Ca2+-releasing agent, induced transient increase of IK(Ca) and R340/380 (IK(Ca)-transient and R340/380-transient, respectively). The increase and decay of IK(Ca) transient was faster than R340/380-transient. By repetitive application of caffeine, when the refilling state of SR was supposed to be lower than the control condition, IK(Ca) transient and R340/380 transient were suppressed to different levels; e.g. the second application 20 sec after the first could induce smaller IK(Ca) transient than R340/380-transient. Dissociation of IK(Ca)-transient and R340/380-transient was removed by sufficient (>3 min) washout of caffeine. Recovery from the dissociation was also dependent upon the membrane potential; faster recovery was observed at negative (-40 mV) holding potential than at depolarized (0 mV) condition. Dissociation of IK(Ca) from [Ca2+]c was also partially prevented by perfusion with Na+-free (replaced by NMDG+) extracellular solution. These results suggest that, 1) there is prominent spatial inhomogeneity of [Ca2+] in cerebral arterial myocyte, 2) [Ca2+]Sl is preferentially affected by the interference from nearby plasmalemmal Ca2+ regulation mechanism which is partly dependent upon extracellular Na+. PMID- 10102803 TI - Complexity in natural landform patterns AB - Patterns in nature, such as meandering rivers and sand dunes, display complex behavior seemingly at odds with their simplicity of form. Existing approaches to modeling natural landform patterns, reductionism and universality, are incompatible with the nonlinear, open nature of natural systems. An alternative modeling methodology based on the tendency of natural systems to self-organize in temporal hierarchies is described. PMID- 10102802 TI - Membrane properties and the neuro-effector transmission of smooth muscle cells in the canine internal anal sphincter. AB - The most distal part of the circular muscle layer functions as the internal anal sphincter, which constitutes a high pressure zone at rest, but maintains a relaxed state during defecation. To elucidate such sphincter mechanisms of the smooth muscle cells, the circular muscle layer in the canine anal canal was examined within 2 cm from the anal verge. Both the mechanical and intracellular electrical activities were recorded simultaneously. The examined region could be divided into three different regions according to the pattern of spontaneous activity and innervation and consisted of an upper region (20-15 mm from the anal verge), a transitional region (15-5 mm from the anal verge) and a lower region (within 5 mm from the anal verge), respectively. The spontaneous membrane activity was characterized by ongoing slow potential changes and each potential change was associated with a phasic contraction in the three regions. The mean frequencies of spontaneous electrical activity were 6.8, 15.9, and 24.1 c/min in the upper, transitional and lower regions, respectively. In the transitional and lower region, muscle tone generation was observed. Transmural field stimulation (0.4 msec in pulse duration) evoked membrane depolarization and contractions in the lower region. The application of an alfa adrenergic blocking agent completely suppressed the generation of excitatory responses, leaving a long lasting hyperpolarization associated with relaxation. In the transitional and upper region, stimulation consistently evoked membrane hyperpolarization with relaxation. The characteristics of this hyperpolarization response varied among the three regions. The total duration of hyperpolarization increased distally, while the time to peak hyperpolarization became decreases in a reverse direction. These regional differences in the characteristics of spontaneous membrane activity and innervation indicate that the transitional and lower region might therefore function as the internal anal sphincter. PMID- 10102804 TI - Complexity and climate AB - The climate that we experience results from both ordered forcing and chaotic behavior; the result is a system with characteristics of each. In forecasting prospective climate changes for the next century, the focus has been on the ordered system's responses to anthropogenic forcing. The chaotic component may be much harder to predict, but at this point it is not known how important it will be. PMID- 10102805 TI - Superradiance in a torus magnetosphere around a black hole AB - The coalescence of a neutron star and a black hole in a binary system is believed to form a torus around a Kerr black hole. A similarly shaped magnetosphere then results from the remnant magnetic field of the neutron star. In the strong-field case, it contains a cavity for plasma waves located between the barrier of the gravitational potential and the surrounding torus. This cavity may be unstable to superradiance of electromagnetic waves. Superradiant amplification of such waves, initially excited by turbulence in the torus, should inflate into a bubble in a time as short as approximately 0.75 (1 percent/&cjs3539;epsilon&cjs3539;2)(M/7M middle dot in circle) seconds approximately 0.15 to 1.5 seconds, assuming an efficiency &cjs3539;epsilon&cjs3539;2 = 0.5 to 5 percent and a mass M = 7M middle dot in circle. These bubbles may burst and repeat, of possible relevance to intermittency in cosmological gamma-ray bursts. The model predicts gamma-ray bursts to be anticorrelated with their gravitational wave emissions. PMID- 10102806 TI - Geochemical consequences of increased atmospheric carbon dioxide on coral reefs AB - A coral reef represents the net accumulation of calcium carbonate (CaCO3) produced by corals and other calcifying organisms. If calcification declines, then reef-building capacity also declines. Coral reef calcification depends on the saturation state of the carbonate mineral aragonite of surface waters. By the middle of the next century, an increased concentration of carbon dioxide will decrease the aragonite saturation state in the tropics by 30 percent and biogenic aragonite precipitation by 14 to 30 percent. Coral reefs are particularly threatened, because reef-building organisms secrete metastable forms of CaCO3, but the biogeochemical consequences on other calcifying marine ecosystems may be equally severe. PMID- 10102807 TI - Lateral variations in Compressional/Shear velocities at the base of the mantle AB - Observations of core-diffracted P (Pdiff) and SH (SHdiff) waves recorded by the Missouri-to-Massachusetts (MOMA) seismic array show that the ratio of compressional (P) seismic velocities to horizontal shear (SH) velocities at the base of the mantle changes abruptly from beneath the mid-Pacific (VP/VS = 1.88, also the value predicted by reference Earth models) to beneath Alaska (VP/VS = 1.83). This change signifies a sudden lateral variation in material properties that may have a mineralogical or textural origin. A textural change could be a result of shear stresses induced during the arrival at the core of ancient lithosphere from the northern Pacific paleotrench. PMID- 10102808 TI - High-resolution holocene environmental changes in the thar desert, northwestern india AB - Sediments from Lunkaransar dry lake in northwestern India reveal regional water table and lake level fluctuations over decades to centuries during the Holocene that are attributed to changes in the southwestern Indian monsoon rains. The lake levels were very shallow and fluctuated often in the early Holocene and then rose abruptly around 6300 carbon-14 years before the present (14C yr B.P.). The lake completely desiccated around 4800 (14)C yr B.P. The end of this 1500-year wet period coincided with a period of intense dune destabilization. The major Harrapan-Indus civilization began and flourished in this region 1000 years after desiccation of the lake during arid climate and was not synchronous with the lacustral phase. PMID- 10102809 TI - Clinoenstatite in alpe arami peridotite: additional evidence of very high pressure AB - Observations by transmission electron microscopy show that lamellae of clinoenstatite are present in diopside grains of the Alpe Arami garnet lherzolite of the Swiss Alps. The simplest interpretation of the orientation, crystallography, and microstructures of the lamellae and the phase relationships in this system is that the lamellae originally exsolved as the high-pressure C centered form of clinoenstatite. These results imply that the rocks were exhumed from a minimum depth of 250 kilometers before or during continental collision. PMID- 10102810 TI - Quantum phase interference and parity effects in magnetic molecular clusters AB - An experimental method based on the Landau-Zener model was developed to measure very small tunnel splittings in molecular clusters of eight iron atoms, which at low temperature behave like a nanomagnet with a spin ground state of S = 10. The observed oscillations of the tunnel splittings as a function of the magnetic field applied along the hard anisotropy axis are due to topological quantum interference of two tunnel paths of opposite windings. Transitions between quantum numbers M = -S and (S - n), with n even or odd, revealed a parity effect that is analogous to the suppression of tunneling predicted for half-integer spins. This observation is direct evidence of the topological part of the quantum spin phase (Berry phase) in a magnetic system. PMID- 10102811 TI - CH5+: the infrared spectrum observed AB - Protonated methane, CH5+, has unusual vibrational and rotational behavior because its three nonequivalent equilibrium structures have nearly identical energies and its five protons scramble freely. Although many theoretical papers have been published on the quantum mechanics of the system, a better understanding requires spectral data. A complex, high-resolution infrared spectrum of CH5+ corresponding to the C-H stretching band in the 3.4-micrometer region is reported. Although no detailed assignment of the individual lines was made, comparison with other carbocation spectra strongly suggests that the transitions are due to CH5+. PMID- 10102812 TI - Electrochemical defect-mediated thin-film growth AB - An electrodeposition technique is described that produces atomically flat epitaxial metal overlayers of quality similar to that obtained by ultrahigh vacuum techniques at elevated temperature. In this approach, a metal of interest such as silver is co-deposited with a reversibly deposited mediator metal. The mediator is periodically deposited and stripped from the surface, and this serves to significantly increase the density of two-dimensional islands of silver atoms, promoting a layer-by-layer thin-film growth mode. In situ scanning tunneling microscopy was used to demonstrate the growth process for the heteroepitaxial system silver/gold (111) with either lead or copper as the mediator. PMID- 10102813 TI - Strongly photonic macroporous gallium phosphide networks AB - A photo-assisted electrochemical etching technique to fabricate macropores in single-crystalline gallium phosphide (GaP) with variable porosity has been developed. Scanning electron microscopy and x-ray diffraction experiments confirm that the material consists of three-dimensional, interconnected random networks with pore sizes of about 150 nanometers. Optical transmission measurements demonstrate that the nonabsorbing disordered structures strongly scatter light. The photonic strength is controlled by filling the pores with liquids of different refractive indices. Macroporous gallium phosphide filled with air has the highest scattering efficiency for visible light. PMID- 10102814 TI - Multilineage potential of adult human mesenchymal stem cells. AB - Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential. PMID- 10102815 TI - Two distinct cytokines released from a human aminoacyl-tRNA synthetase. AB - Aminoacyl-tRNA synthetases catalyze aminoacylation of transfer RNAs (tRNAs). It is shown that human tyrosyl-tRNA synthetase can be split into two fragments with distinct cytokine activities. The endothelial monocyte-activating polypeptide II like carboxy-terminal domain has potent leukocyte and monocyte chemotaxis activity and stimulates production of myeloperoxidase, tumor necrosis factor alpha, and tissue factor. The catalytic amino-terminal domain binds to the interleukin-8 type A receptor and functions as an interleukin-8-like cytokine. Under apoptotic conditions in cell culture, the full-length enzyme is secreted, and the two cytokine activities can be generated by leukocyte elastase, an extracellular protease. Secretion of this tRNA synthetase may contribute to apoptosis both by arresting translation and producing needed cytokines. PMID- 10102816 TI - ROUGH SHEATH2: a Myb protein that represses knox homeobox genes in maize lateral organ primordia. AB - The regulation of members of the knotted1-like homeobox (knox) gene family is required for the normal initiation and development of lateral organs. The maize rough sheath2 (rs2) gene, which encodes a Myb-domain protein, is expressed in lateral organ primordia and their initials. Mutations in the rs2 gene permit ectopic expression of knox genes in leaf and floral primordia, causing a variety of developmental defects. Ectopic KNOX protein accumulation in rs2 mutants occurs in a subset of the normal rs2-expressing cells. This variegated accumulation of KNOX proteins in rs2 mutants suggests that rs2 represses knox expression through epigenetic means. PMID- 10102817 TI - The maize rough sheath2 gene and leaf development programs in monocot and dicot plants. AB - Leaves of higher plants develop in a sequential manner from the shoot apical meristem. Previously it was determined that perturbed leaf development in maize rough sheath2 (rs2) mutant plants results from ectopic expression of knotted1 like (knox) homeobox genes. Here, the rs2 gene sequence was found to be similar to the Antirrhinum PHANTASTICA (PHAN) gene sequence, which encodes a Myb-like transcription factor. RS2 and PHAN are both required to prevent the accumulation of knox gene products in maize and Antirrhinum leaves, respectively. However, rs2 and phan mutant phenotypes differ, highlighting fundamental differences in monocot and dicot leaf development programs. PMID- 10102818 TI - Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. AB - The ability of p53 to promote apoptosis in response to mitogenic oncogenes appears to be critical for its tumor suppressor function. Caspase-9 and its cofactor Apaf-1 were found to be essential downstream components of p53 in Myc induced apoptosis. Like p53 null cells, mouse embryo fibroblast cells deficient in Apaf-1 and caspase-9, and expressing c-Myc, were resistant to apoptotic stimuli that mimic conditions in developing tumors. Inactivation of Apaf-1 or caspase-9 substituted for p53 loss in promoting the oncogenic transformation of Myc-expressing cells. These results imply a role for Apaf-1 and caspase-9 in controlling tumor development. PMID- 10102819 TI - Phenotypic change caused by transcriptional bypass of uracil in nondividing cells. AB - Cytosine deamination to uracil occurs frequently in cellular DNA. In vitro, RNA polymerase efficiently inserts adenine opposite to uracil, resulting in G to A base substitutions. In vivo, uracil could potentially alter transcriptional fidelity, resulting in production of mutant proteins. This study demonstrates that in nondividing Escherichia coli cells, a DNA template base replaced with uracil in a stop codon in the firefly luciferase gene results in conversion of inactive to active luciferase. The level of transcriptional base substitution is dependent on the capacity to repair uracil. These results provide evidence for a DNA damage-dependent, transcription-driven pathway for generating mutant proteins in nondividing cells. PMID- 10102820 TI - Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. AB - Calcium-calmodulin-dependent protein kinase II (CaMKII) is thought to increase synaptic strength by phosphorylating postsynaptic density (PSD) ion channels and signaling proteins. It is shown that N-methyl-D-aspartate (NMDA) receptor stimulation reversibly translocates green fluorescent protein-tagged CaMKII from an F-actin-bound to a PSD-bound state. The translocation time was controlled by the ratio of expressed beta-CaMKII to alpha-CaMKII isoforms. Although F-actin dissociation into the cytosol required autophosphorylation of or calcium calmodulin binding to beta-CaMKII, PSD translocation required binding of calcium calmodulin to either the alpha- or beta-CaMKII subunits. Autophosphorylation of CaMKII indirectly prolongs its PSD localization by increasing the calmodulin binding affinity. PMID- 10102821 TI - The role of area 17 in visual imagery: convergent evidence from PET and rTMS. AB - Visual imagery is used in a wide range of mental activities, ranging from memory to reasoning, and also plays a role in perception proper. The contribution of early visual cortex, specifically Area 17, to visual mental imagery was examined by the use of two convergent techniques. In one, subjects closed their eyes during positron emission tomography (PET) while they visualized and compared properties (for example, relative length) of sets of stripes. The results showed that when people perform this task, Area 17 is activated. In the other, repetitive transcranial magnetic stimulation (rTMS) was applied to medial occipital cortex before presentation of the same task. Performance was impaired after rTMS compared with a sham control condition; similar results were obtained when the subjects performed the task by actually looking at the stimuli. In sum, the PET results showed that when patterns of stripes are visualized, Area 17 is activated, and the rTMS results showed that such activation underlies information processing. PMID- 10102822 TI - The human genus. AB - A general problem in biology is how to incorporate information about evolutionary history and adaptation into taxonomy. The problem is exemplified in attempts to define our own genus, Homo. Here conventional criteria for allocating fossil species to Homo are reviewed and are found to be either inappropriate or inoperable. We present a revised definition, based on verifiable criteria, for Homo and conclude that two species, Homo habilis and Homo rudolfensis, do not belong in the genus. The earliest taxon to satisfy the criteria is Homo ergaster, or early African Homo erectus, which currently appears in the fossil record at about 1.9 million years ago. PMID- 10102823 TI - Simple lessons from complexity AB - The complexity of the world is contrasted with the simplicity of the basic laws of physics. In recent years, considerable study has been devoted to systems that exhibit complex outcomes. This experience has not given us any new laws of physics, but has instead given us a set of lessons about appropriate ways of approaching complex systems. PMID- 10102824 TI - Complexity in chemistry. AB - "Complexity" is a subject that is beginning to be important in chemistry. Historically, chemistry has emphasized the approximation of complex nonlinear processes by simpler linear ones. Complexity is becoming a profitable approach to a wide range of problems, especially the understanding of life. PMID- 10102825 TI - Complexity in biological signaling systems. AB - Biological signaling pathways interact with one another to form complex networks. Complexity arises from the large number of components, many with isoforms that have partially overlapping functions; from the connections among components; and from the spatial relationship between components. The origins of the complex behavior of signaling networks and analytical approaches to deal with the emergent complexity are discussed here. PMID- 10102826 TI - Complexity and the nervous system. AB - Advances in the neurosciences have revealed the staggering complexity of even "simple" nervous systems. This is reflected in their function, their evolutionary history, their structure, and the coding schemes they use to represent information. These four viewpoints need all play a role in any future science of "brain complexity." PMID- 10102827 TI - Complexity, pattern, and evolutionary trade-offs in animal aggregation. AB - One of the most striking patterns in biology is the formation of animal aggregations. Classically, aggregation has been viewed as an evolutionarily advantageous state, in which members derive the benefits of protection, mate choice, and centralized information, balanced by the costs of limiting resources. Consisting of individual members, aggregations nevertheless function as an integrated whole, displaying a complex set of behaviors not possible at the level of the individual organism. Complexity theory indicates that large populations of units can self-organize into aggregations that generate pattern, store information, and engage in collective decision-making. This begs the question, are all emergent properties of animal aggregations functional or are some simply pattern? Solutions to this dilemma will necessitate a closer marriage of theoretical and modeling studies linked to empirical work addressing the choices, and trajectories, of individuals constrained by membership in the group. PMID- 10102828 TI - Ordeals for the fetal programming hypothesis. The hypothesis largely survives one ordeal but not another. PMID- 10102829 TI - Combined kidney and pancreatic transplantation. Ideal for patients with uncomplicated type 1 diabetes and chronic renal failure. PMID- 10102830 TI - Assessing operative skill. Needs to become more objective. PMID- 10102831 TI - Pleasing both authors and readers. A combination of short print articles and longer electronic ones may help us do this. PMID- 10102834 TI - Study confirms passive smoking increases coronary heart disease PMID- 10102835 TI - In brief PMID- 10102832 TI - Measuring the performance of public health agencies. Government, like doctors and hospitals, should meet quality standards. PMID- 10102836 TI - UK consultation rejects restriction of impotence treatment funding. PMID- 10102837 TI - Australia set for class action against tobacco industry. PMID- 10102838 TI - European commission proposes public health department. PMID- 10102839 TI - Outbreak of Japanese encephalitis hits Malaysia. PMID- 10102840 TI - Open letter disputes WHO hypertension guidelines PMID- 10102841 TI - Scientists develop vaccine strategy for peanut allergy PMID- 10102842 TI - UK government announces sex health strategy. PMID- 10102844 TI - UK proposes preclinical distance learning course. PMID- 10102843 TI - Australian hunger strike doctors urged to stop. PMID- 10102845 TI - Withdrawal of food supplement judged as misconduct. PMID- 10102846 TI - Health authority appeals on screening negligence. PMID- 10102847 TI - UK specialists urge the setting up of a national screening agency. PMID- 10102848 TI - Severity of heart attacks in US may be declining. PMID- 10102849 TI - UK consultants act to limit spiralling workload. PMID- 10102850 TI - Twins and maternal smoking: ordeals for the fetal origins hypothesis? A cohort study. AB - OBJECTIVE: To assess the direct and indirect effects of being a twin, maternal smoking, birth weight, and mother's height on blood pressure at ages 9 and 18 years. DESIGN: Longitudinal study. SUBJECTS: Cohort born in 1972-3. SETTING: Dunedin, New Zealand. MAIN OUTCOME MEASURE: Blood pressure at ages 9 and 18 years. RESULTS: Compared with singletons, twins had a systolic blood pressure 4.55 (95% confidence interval 1.57 to 7.52) mm Hg lower at age 9 after adjustment for direct and indirect effects of sex, maternal smoking, mother's height, socioeconomic status, and birth weight, as well as concurrent height and body mass index. Blood pressure in children whose mothers had smoked during pregnancy was 1.54 (0.46 to 2.62) mm Hg higher than in those whose mothers did not. The total effect of birth weight on systolic blood pressure at age 9 was -0.78 (-1.76 to 0.20) mm Hg and that for mother's height was 0.10 (0.06 to 0.14) mm Hg. Similar results were obtained for systolic blood pressure at age 18. The total effect of twins, maternal smoking, and birth weight on diastolic blood pressure was not significant at either age. CONCLUSIONS: Twins had lower birth weight and lower systolic blood pressure at ages 9 and 18 than singletons. This finding challenges the fetal origins hypothesis. The effect of maternal smoking was consistent with the fetal origin hypothesis in that the infants of smokers were smaller and had higher blood pressure at both ages. This may be explained by pharmacological rather than nutritional effects. The total effect of birth weight on systolic blood pressure, after its indirect effect working through concurrent measures of height and body mass index was taken into account, was small. PMID- 10102851 TI - Multicentre randomised controlled trial of nursing intervention for breathlessness in patients with lung cancer. AB - OBJECTIVE: To evaluate the effectiveness of nursing intervention for breathlessness in patients with lung cancer. DESIGN: Patients diagnosed with lung cancer participated in a multicentre randomised controlled trial where they either attended a nursing clinic offering intervention for their breathlessness or received best supportive care. The intervention consisted of a range of strategies combining breathing control, activity pacing, relaxation techniques, and psychosocial support. Best supportive care involved receiving standard management and treatment available for breathlessness, and breathing assessments. Participants completed a range of self assessment questionnaires at baseline, 4 weeks, and 8 weeks. SETTING: Nursing clinics within 6 hospital settings in the United Kingdom. PARTICIPANTS: 119 patients diagnosed with small cell or non-small cell lung cancer or with mesothelioma who had completed first line treatment for their disease and reported breathlessness. OUTCOME MEASURES: Visual analogue scales measuring distress due to breathlessness, breathlessness at best and worst, WHO performance status scale, hospital anxiety and depression scale, and Rotterdam symptom checklist. RESULTS: The intervention group improved significantly at 8 weeks in 5 of the 11 items assessed: breathlessness at best, WHO performance status, levels of depression, and two Rotterdam symptom checklist measures (physical symptom distress and breathlessness) and showed slight improvement in 3 of the remaining 6 items. CONCLUSION: Most patients who completed the study had a poor prognosis, and breathlessness was typically a symptom of their deteriorating condition. Patients who attended nursing clinics and received the breathlessness intervention experienced improvements in breathlessness, performance status, and physical and emotional states relative to control patients. PMID- 10102853 TI - Narrowing social inequalities in health? Analysis of trends in mortality among babies of lone mothers (abridged version 1). AB - OBJECTIVES: To examine trends in mortality among babies registered solely by their mother (lone mothers) and to compare these with trends in infant mortality for couple registrations overall and couple registrations subdivided by social class of father. DESIGN: Analysis of trends in infant death rates from 1975 to 1996 for the three groups. The data source was the national linked infant mortality file, containing all records of infant death in England and Wales linked to the respective birth records. SETTING: England and Wales. PARTICIPANTS: All live births (n=14.3 million) from 1975 to 1996; all deaths of infants from birth to 12 months of age over the same period (n=135 800). MAIN OUTCOME MEASURES: Death rates in the perinatal, neonatal, and postneonatal periods and for infancy overall. RESULTS: For the babies of lone mothers infant mortality has fallen to less than a third of the 1975 level, with a clear reduction in the gap between the mortality in these babies compared with all couple registrations: the excess mortality in solely registered births was 79% in 1975 reducing to 33% in 1996. Most of the narrowing of the sole-couple differential was associated with the neonatal period, for which there is now no appreciable gap. For couple registrations analysed by social class of father, infant death rates have more than halved in each social class from 1975 to 1996. The reductions in mortality were greater in the late 1970s and early 1990s. Infant death rates in classes IV V remained between 50% and 65% higher than in classes I-II. Differentials between social classes were largest in the postneonatal period and smallest in the perinatal and neonatal periods. The gap in perinatal and neonatal mortality between the babies of lone mothers and couple parents in social classes IV-V has disappeared. CONCLUSIONS: The differential in infant mortality between social classes still exists, whereas the differential between sole and couple registrations has decreased, showing positive progress in the reduction of inequalities. As the reduction in the differential was confined to the neonatal period these improvements may be more a reflection of healthcare factors than of factors associated with lone mothers' social and economic circumstances. PMID- 10102852 TI - Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics. AB - OBJECTIVE: To assess the impact of screening on the incidence of and mortality from cervical cancer. DESIGN: Comparison of age specific incidence and mortality before and after the introduction of the national call and recall system in 1988. SETTING: England. SUBJECTS: Women aged over 19 years. RESULTS: From the mid 1960s, the number of smears taken rose continuously to 4.5 million at the end of the 1980s. Between 1988 and 1994, coverage of the target group doubled to around 85%. Registrations of in situ disease increased broadly in parallel with the numbers of smears taken. The overall incidence of invasive disease remained stable up to the end of the 1980s, although there were strong cohort effects; from 1990 incidence fell continuously and in 1995 was 35% lower than in the 1980s. The fall in overall mortality since 1950 accelerated at the end of the 1980s; there were strong cohort effects. Mortality in women under 55 was much lower in the 1990s than would have been expected. CONCLUSIONS: The national call and recall system and incentive payments to general practitioners increased coverage to around 85%. This resulted in falls in incidence of invasive disease in all regions of England and in all age groups from 30 to 74. The falls in mortality in older women were largely unrelated to screening, but without screening there might have been 800 more deaths from cervical cancer in women under 55 in 1997. PMID- 10102854 TI - Narrowing social inequalities in health? analysis of trends in mortality among babies of lone mothers (abridged version 2) AB - Objectives: To examine trends in mortality among babies registered solely by their mother (lone mothers) and to compare these with trends in infant mortality for couple registrations overall and couple registrations subdivided by social class of father. Design: Analysis of trends in infant death rates from 1975 to 1996 for the three groups. The data source was the national linked infant mortality file, containing all records of infant death in England and Wales linked to the respective birth records. Setting: England and Wales. Participants: All live births (n=14.3 million) from 1975 to 1996; all deaths of infants from birth to 12 months of age over the same period (n=135 800). Main outcome measures: Death rates in the perinatal, neonatal, and postneonatal periods and for infancy overall. Results: For the babies of lone mothers infant mortality has fallen to less than a third of the 1975 level, with a clear reduction in the gap between the mortality in these babies compared with all couple registrations: the excess mortality in solely registered births was 79% in 1975 reducing to 33% in 1996. Most of the narrowing of the sole-couple differential was associated with the neonatal period, for which there is now no appreciable gap. For couple registrations analysed by social class of father, infant death rates have more than halved in each social class from 1975 to 1996. The reductions in mortality were greater in the late 1970s and early 1990s. Infant death rates in classes IV V remained between 50% and 65% higher than in classes I-II. Differentials between social classes were largest in the postneonatal period and smallest in the perinatal and neonatal periods. The gap in perinatal and neonatal mortality between the babies of lone mothers and couple parents in social classes IV-V has disappeared. Conclusions: The differential in infant mortality between social classes still exists, whereas the differential between sole and couple registrations has decreased, showing positive progress in the reduction of inequalities. As the reduction in the differential was confined to the neonatal period these improvements may be more a reflection of healthcare factors than of factors associated with lone mothers' social and economic circumstances. PMID- 10102855 TI - Social inequalities and health: ecological study of mortality in Budapest, 1980-3 and 1990-3. PMID- 10102856 TI - Science is seldom logical PMID- 10102857 TI - The doctor in the pulpit PMID- 10102858 TI - Effect of discussion and deliberation on the public's views of priority setting in health care: focus group study. AB - OBJECTIVE: To investigate the extent to which people change their views about priority setting in health care as a result of discussion and deliberation. DESIGN: A random sample of patients from two urban general practices was invited to attend two focus group meetings, a fortnight apart. SETTING: North Yorkshire Health Authority. SUBJECTS: 60 randomly chosen patients meeting in 10 groups of five to seven people. MAIN OUTCOME MEASURES: Differences between people's views at the start of the first meeting and at the end of the second meeting, after they have had an opportunity for discussion and deliberation, measured by questionnaires at the start of the first meeting and the end of the second meeting. RESULTS: Respondents became more reticent about the role that their views should play in determining priorities and more sympathetic to the role that healthcare managers play. About a half of respondents initially wanted to give lower priority to smokers, heavy drinkers, and illegal drug users, but after discussion many no longer wished to discriminate against these people. CONCLUSION: The public's views about setting priorities in health care are systematically different when they have been given an opportunity to discuss the issues. If the considered opinions of the general public are required, surveys that do not allow respondents time or opportunity for reflection may be of doubtful value. PMID- 10102860 TI - Curing a spasm PMID- 10102859 TI - Effect of UK national guidelines on services to treat patients with acute low back pain: follow up questionnaire survey. PMID- 10102861 TI - Acute urinary retention in men: an age old problem. PMID- 10102862 TI - The painful red foot-inflammation or ischaemia? PMID- 10102863 TI - Insult to cabbages PMID- 10102864 TI - ABC of labour care. Relief of pain. PMID- 10102865 TI - Sexuality and health: the hidden costs of screening for Chlamydia trachomatis. PMID- 10102866 TI - The World Bank and world health. Healthcare strategy. PMID- 10102867 TI - Times have changed PMID- 10102868 TI - Ductal carcinoma in situ of the breast. Has author carried out an audit? PMID- 10102869 TI - Selection to medical school in Great Britain. Admissions procedure at St Andrews is driven by purely academic criteria. PMID- 10102870 TI - Vitamin A for treating shigellosis. Study did not prove benefit. PMID- 10102871 TI - Rationing. Politicians, not doctors, must make the decisions about rationing. PMID- 10102872 TI - Effect on suicide rate of having reduced unemployment is uncertain. PMID- 10102873 TI - Trials of postoperative antiemetics need three arms. PMID- 10102874 TI - Guidelines for clinical guidelines should distinguish between national and local production. PMID- 10102875 TI - Guidelines in small countries and not translated into English may be ignored. PMID- 10102877 TI - Competency, consent, and the duty of care. PMID- 10102876 TI - Inherited predisposition to hypertension confounds the effect of low birthweight. PMID- 10102878 TI - When big may not be beautiful. PMID- 10102879 TI - Fluoroquinolone resistance in salmonellas and campylobacters from humans. PMID- 10102880 TI - Paediatric cardiac transplant surgery has improved. PMID- 10102881 TI - FDA approves drugs even when experts on its advisory panels raise safety questions. PMID- 10102882 TI - Oakley's case for using randomised controlled trials is misleading. PMID- 10102883 TI - Needs of teenagers with chronic disability. PMID- 10102884 TI - Cholesterol lowering diets and coronary heart disease. Diet alone substantially reduces cholesterol in hypercholesterolaemia. PMID- 10102885 TI - Michael bertrand devas PMID- 10102886 TI - Health service in ulster will be less bureaucratic PMID- 10102887 TI - Oxford handbook of Patients' welfare: A Doctor's guide to benefits and services PMID- 10102888 TI - The future of human reproduction: ethics, choice, and regulation PMID- 10102890 TI - Unauthorized freud: doubters confront A legend PMID- 10102889 TI - Sexually transmitted infections and AIDS in the tropics PMID- 10102891 TI - Opening eyes to child abuse PMID- 10102892 TI - Website of the week PMID- 10102894 TI - Another fine mess PMID- 10102893 TI - Is it part of the locum's job to whistleblow? PMID- 10102895 TI - Twins challenge the fetal origins hypothesis PMID- 10102896 TI - Reducing breathlessness in lung cancer can also reduce physical and emotional distress PMID- 10102897 TI - Cervical screening has reduced incidence of cancer and mortality PMID- 10102898 TI - Health gap narrows for babies of lone mothers PMID- 10102899 TI - The public's views differ systematically after discussion of healthcare priorities PMID- 10102900 TI - Guidelines on treating back pain have not improved GPs' services PMID- 10102901 TI - Reducing the impact of endogenous ribonucleases on reverse transcription-PCR assay systems. PMID- 10102902 TI - Novel molecular biological approaches for the diagnosis of preeclampsia. PMID- 10102903 TI - Nucleic acid detection technologies -- labels, strategies, and formats. AB - Currently, no consensus exists on assay formats, labels, or detection reactions for nucleic acid assays. New labels continue to be developed and tested, and recent candidates include acetate kinase, firefly luciferase, and genes for enzymes. An additional trend is toward nonamplification strategies (e.g., branched chain and dendrimer type assays) as alternatives to the popular PCR and related amplification strategies. The new wave of microanalytical devices (microchips, with nanoliter to microliter internal volumes), massively parallel simultaneous test arrays, and the desire to produce hand-held sensors present new challenges and requirements for nucleic acid detection methods (e.g., analysis of large arrays of micrometer-sized spots of nucleic acid with high resolution). Here I review selected developments and new directions in nucleic acid assays. PMID- 10102904 TI - Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study. AB - BACKGROUND: A38-year-old man presented with a history of fish odor (since age 5) and unusual muscle fatigue with increased serum creatine kinase. Our aim was to identify the metabolic error in this new condition. METHODS: We used 1H NMR spectroscopy to study serum and urine from the patient. RESULTS: The concentration of N, N-dimethylglycine (DMG) was increased approximately 100-fold in the serum and approximately 20-fold in the urine. The presence of DMG as a storage product was confirmed by use of 13C NMR spectroscopy and gas chromatography-mass spectrometry. The high concentration of DMG was caused by a deficiency of the enzyme dimethylglycine dehydrogenase (DMGDH). A homozygous missense mutation was found in the DMGDH gene of the patient. CONCLUSIONS: DMGDH deficiency must be added to the differential diagnosis of patients complaining of a fish odor. This deficiency is the first inborn error of metabolism discovered by use of in vitro 1H NMR spectroscopy of body fluids. PMID- 10102905 TI - Major interference from leukocytes in reverse transcription-PCR identified as neurotoxin ribonuclease from eosinophils: detection of residual chronic myelogenous leukemia from cell lysates by use of an eosinophil-depleted cell preparation. AB - BACKGROUND: The extraction of RNA from leukocytes for reverse transcription-PCR (RT-PCR) is time-consuming and contributes to variation in analysis of the Philadelphia (Ph1) chromosome of chronic myelogenous leukemia (CML) by RT-PCR. To detect residual CML after bone marrow transplantation, mRNA from at least 10(5) leukocytes should be analyzed, but the RNase activity of the cells precludes simple leukocytes lysis as an alternative to RNA extraction. We sought to identify the main source of RNase activity of leukocytes. METHODS: We used a three-step chromatographic process and amino acid sequence analysis. We selected eosinophil-free granulocytes by using a biotinylated CD16 antibody and selected mononuclear cells by fractionating the leukocytes with a Ficoll-Paque(R) density gradient. RESULTS: Chromatography and amino acid sequencing identified eosinophil derived neurotoxin (EDN) as the main source of leukocyte RNase. Depletion of eosinophils reduced the EDN content of cell lysates by approximately 90%, allowing a signal from a lysate of 50 K562 Ph1-positive cells mixed with 10(5) CD16(+) granulocytes that was equivalent to 77% of the signal in the absence of leukocytes. A similar lysate with mononuclear cells gave a signal equivalent to 53% of that without mononuclear cells. RNA extraction gave a signal equivalent to only 24% of the leukocyte-free control. CONCLUSION: The depletion of eosinophils during the preparation of leukocyte samples for RT-PCR efficiently reduces the risk of mRNA degradation by ribonucleases, enabling RT-PCR analysis directly from cell lysates with a better signal than can be obtained by RNA extraction. PMID- 10102906 TI - Multicenter trial of the quantitative BTA TRAK assay in the detection of bladder cancer. AB - BACKGROUND: Human complement factor H-related protein (hCFHrp) is produced by several bladder cancer cell lines and may be useful as a cancer marker. The aim of this study was to compare urinary hCFHrp and cytology for the detection of bladder cancer found by cystoscopy in patients with suggestive signs, symptoms, or preliminary test results. METHODS: The BTA TRAK assay, a quantitative enzyme immunoassay for the bladder tumor-associated antigen in urine, was compared with exfoliative cytology in 220 patients (155 men, 65 women; mean age, 64.2 years) presenting with signs, symptoms, or preliminary diagnostic results suggestive of this disease. Cystoscopy was the standard of detection. RESULTS: In the 100 patients found to have bladder cancer, the overall sensitivities of the BTA TRAK assay (at a previously determined decision threshold of 14 kilounits/L) and cytology were 66% (66 of 100) and 33% (33 of 100), respectively (P <0.001). The BTA TRAK assay proved to be statistically more sensitive than cytology for tumor grades I and II and for stage Ta and T1 tumors. In contrast, the overall specificity of the BTA TRAK assay in the 120 patients without cystoscopically confirmed bladder cancer was 69% (83 of 120) and that of cytology was 99% (119 of 120; P <0.001). The specificity of the BTA TRAK assay was higher in patients without benign or malignant genitourinary disease other than bladder cancer (76%; n = 89) than in patients with these conditions. When the BTA TRAK assay and cytology were used together such that a positive result in either test was scored as positive and the results compared with those of the BTA TRAK assay alone, increases in overall sensitivity and equivalent specificity were observed. CONCLUSION: Because of its relatively high sensitivity, the BTA TRAK assay could complement cytology as an adjunct to cystoscopy in the diagnosis and follow-up of most patients with bladder cancer. PMID- 10102907 TI - Near-patient test for C-reactive protein in general practice: assessment of clinical, organizational, and economic outcomes. AB - BACKGROUND: The benefits of near-patient, point-of-care tests have not been fully examined. We have assessed the clinical, organizational, and economic outcomes of implementing a near-patient test for C-reactive protein (CRP) in general practice. METHODS: In a randomized crossover trial during intervention periods, general practitioners (GPs) were allowed to measure CRP within 3 min, using NycoCard(R) CRP. During control periods, they had to mail blood samples for CRP measurements to the hospital laboratory and received test results 24-48 h later. Twenty-nine general practice clinics participated (64 GPs), and 1853 patients were included in the study. Results were evaluated at both the level of participating GPs and the level of included patients. RESULTS: For participating GPs, the overall use of erythrocyte sedimentation rates (ESRs) decreased by 8% (95% confidence interval, 1-14%) during intervention periods, and the number of blood samples mailed to the hospital laboratory decreased by 6% (1-10%). No reduction in the prescription of antibiotics was seen. The proportion of study patients having a follow-up telephone consultation was reduced from 63% to 53% (P = 0. 0001), and patients with CRP concentrations >50 mg/L had their antibiotic treatments started earlier when CRP was measured in general practices (P = 0.0161). CONCLUSION: The implementation of the near-patient CRP test was cost effective mainly on the basis of a reduction in the use of services from the hospital laboratory by GPs. If the implementation is followed by education and clinical guidelines, opportunities exist for additional reduction in the use of ESR and for a more appropriate use of antibiotics. PMID- 10102908 TI - Epitope analysis of a prostate-specific antigen (PSA) C-terminal-specific monoclonal antibody and new aspects for the discrepancy between equimolar and skewed PSA assays. AB - BACKGROUND: Immunoassays to measure prostate-specific antigen (PSA) often give different values for the same patient samples, and the calibrators among commercial immunoassays are not interchangeable. We developed three novel assays to quantify the free and complexed forms of PSA in serum. METHODS: We synthesized 46 peptides, which encompassed the entire PSA molecule, and determined the interactions between selected monoclonal antibodies (MAbs) and those peptides or the intact PSA molecule. RESULTS: MAb PA313 did not cross-react with human glandular kallikrein (hK2), which has 78% amino acid homology to PSA. This MAb bound with KD = 40 nmol/L to the C-terminal peptide of PSA and distinguished between a synthetic peptide derived from PSA (PSA46A: NH2-C-R226KWIKDTIVANP237 COOH) that differed from one derived from hK2 (PSA46B: NH2-C-R226KWIKDTAANP237 COOH) by a single amino acid. Only the MAb combination of PA313/PA121 showed equimolar reactivity with PSA and with PSA complexed with alpha1-antichymotrypsin (PSA-ACT). The free form of PSA (F-PSA) was determined by MAbs PA313/FPA503, and the amount of complexed PSA (C-PSA) in PSA-ACT was determined by alphaACT/PA313. The total PSA (T-PSA) measured by either of the equimolar assays (PA313/PA121 or Tandem-R) was consistent with the sum of F-PSA and C-PSA. In contrast, T-PSA by a skewed assay (IMx) was higher than F-PSA + C-PSA when the ratio of F-PSA to T-PSA (F/T) was >0.15. T-PSA measured by IMx was nearly equal to F-PSA/0.55 + C-PSA. The coefficient 0.55 reflected different reactivities of the IMx assay with PSA ACT and PSA. CONCLUSION: The discrepancy between the values measured by equimolar and skewed assays depends on the ratio of free to total PSA in the sample. PMID- 10102909 TI - Apolipoprotein E in cerebrospinal fluid: relation to phenotype and plasma apolipoprotein E concentrations. AB - BACKGROUND: Apolipoprotein (apo) E may be related to the development of Alzheimer disease, but data on apoE in cerebrospinal fluid (CSF) are limited. The aim of the present study was to measure apoE in CSF and relate its concentrations to apoE phenotype and CSF lipids. METHODS: We adapted an assay for CSF apoE sensitivity using an ELISA. It allowed us to measure CSF apoE with sufficient reproducibility and precision. RESULTS: The within- and between-run CVs were <7%, and the detection limit was 0.025 mg/L. No cross-reaction was found for other apolipoproteins. No significant differences related to sex or apoE phenotype were observed in the CSF apoE concentration. The mean CSF apoE concentration was significantly higher in the 0-5 year group (n = 6; 18.47 +/- 1.14 mg/L, mean +/- SD) than in the >5 year group (n = 34; 8.82 +/- 3.31 mg/L). The mean concentrations of total cholesterol (TC) and phospholipid (PL) in CSF were 2.68 +/- 2.16 and 6.50 +/- 2.84 mg/L (n = 52), respectively. Although no significant differences in TC or PL in the CSF were found with respect to sex or age, the concentrations in subjects with the apoE phenotype E4/E3 were significantly lower than in those with E3/E3 and E3/E2. The concentrations of apoE, TC, and PL in CSF did not correlate with those in plasma. The time-related fluctuations in CSF apoE were independent of those in total protein and IgG. CSF apoE was significantly correlated with TC and PL concentrations in the CSF, but not with the number of cells in the CSF. CONCLUSIONS: These findings support the idea that apoE and lipids are unable to cross the blood-brain barrier and that their concentrations in CSF may reflect production in central nervous tissue. PMID- 10102910 TI - Urinary cotinine and exposure to parental smoking in a population of children with asthma. AB - BACKGROUND: Studies of the effects of tobacco smoke often rely on reported exposure to cigarette smoke, a measure that is subject to bias. We describe here the relationship between parental smoking exposure as assessed by urinary cotinine excretion and lung function in children with asthma. METHODS: We studied 90 children 4-14 years of age, who reported a confirmed diagnosis or symptoms of asthma. In each child, we assessed baseline pulmonary function (spirometry) and bronchial responsiveness to carbachol stimulation. Urinary cotinine was measured by HPLC with ultraviolet detection. RESULTS: Urinary cotinine concentrations in the children were significantly correlated (P <0.001) with the number of cigarettes the parents, especially the mothers, smoked. Bronchial responsiveness to carbachol (but not spirometry test results) was correlated (P <0.03) with urinary cotinine in the children. CONCLUSION: Passive smoke exposure increases the bronchial responsiveness to carbachol in asthmatic children. PMID- 10102911 TI - A practical approach to determine cutoff concentrations for opiate testing with simultaneous detection of codeine, morphine, and 6-acetylmorphine in urine. AB - BACKGROUND: Both the Department of Defense (DoD) and the Department of Health and Human Services (DHHS) currently require two confirmation tests to verify use of heroin, one test for total morphine and a separate test for 6-acetylmorphine (6 AM). Our aim was to determine appropriate free-codeine, free-morphine, and 6-AM cutoff concentrations that could be substituted for total-morphine, total codeine, and 6-AM cutoff concentrations and to develop a less labor-intensive method for measuring codeine, morphine, and 6-AM. METHODS: Urine samples containing opiates were extracted, derivatized, and analyzed using gas chromatography-mass spectrometry with selective ion monitoring. RESULTS: The limits of detection for codeine, morphine, and 6-AM were 6, 5, and 0.5 microg/L, respectively. Recoveries were >90%. Quantification was linear over the concentration range of 6-1000 microg/L for codeine, 5-5000 microg/L for morphine, and 0.5-800 microg/L for 6-AM. Cutoff concentrations for confirmation of opiates were 100, 100, and 10 microg/L for free codeine, free morphine, and 6-AM. CONCLUSION: The proposed cutoff concentrations for free morphine and 6-AM provide better detection windows for morphine and heroin use than the cutoff concentrations for total morphine and 6-AM used at present. Detection of free codeine, instead of total codeine, simplifies interpretation of codeine use. The single-extraction method enables simultaneous, less labor-intensive analysis of morphine, codeine, and 6-AM. PMID- 10102912 TI - Assessment of serum thyroxine binding capacity-dependent biases in free thyroxine assays. AB - BACKGROUND: Free thyroxine (FT4) assays may exhibit biases that are related to serum T4 binding capacity (sBC). We describe two tests that can be used to assess the presence and magnitude of sBC-dependent biases in FT4 assays. METHODS: We used a direct equilibrium dialysis FT4 assay as the reference method and compared the results obtained with those of the FT4 assays under investigation, in patient sera having a wide range of sBC. We then compared the expected and observed FT4 results for sera diluted with an inert buffer. Because serum dilution causes a predictable decrease in sBC, an increasingly negative bias on progressive dilution is indicative of a sBC-dependent bias. RESULTS: The automated FT4 assay investigated (Vitros FT4) showed no demonstrable sBC-dependent bias by either test. CONCLUSION: These two tests can be used to screen for sBC-dependent biases in FT4 assays. PMID- 10102913 TI - Immunoradiometric assay for intact human osteocalcin(1-49) without cross reactivity to breakdown products. AB - BACKGROUND: Osteocalcin (Oc), a serum marker of bone turnover, circulates in several forms. We developed an assay for intact human Oc and investigated its clinical features. METHODS: We generated goat antibodies and N- and C-terminal Oc. The former was used on solid phase (polystyrene beads), and the latter was used as the tracer in an IRMA. RESULTS: The assay was linear with no cross reactivity to Oc(1-43), total imprecision (CV) of <10%, and recovery of 100% +/- 10%. Assay values for intact Oc in EDTA plasma samples were unchanged at 18-25 degrees C for 6 h. Values for intact Oc in serum, EDTA plasma, and heparin plasma samples did not change after storage on ice for 8 h. Serum samples from patients with various conditions were stored at -70 or -135 degrees C for up to 5 years and yielded z-scores comparable to an Oc(1-43) IRMA for all conditions except for renal failure. In renal failure, the Oc(1-43) assay values were increased, whereas the intact assay values were in the reference interval. CONCLUSION: Decreases in Oc assay values are inhibited by calcium chelation, and slowed by reduced temperatures. The described assay for intact Oc allows improved specificity for bone compared with an assay for Oc(1-43). PMID- 10102914 TI - Cross-reaction with luteinizing hormone beta-core is responsible for the age dependent increase of immunoreactive beta-core fragment of human chorionic gonadotropin in women with nonmalignant conditions. AB - BACKGROUND: The beta-core fragment of human chorionic gonadotropin (hCGbetacf), also termed "beta-core" and urinary gonadotropin peptide (UGP), has been reported to be present in the urine of healthy women and to increase in concentration after menopause. This could reflect cross-reaction with the equivalent metabolite of luteinizing hormone (LH), the beta-LH-core. METHODS: We measured immunoreactive LH, hCG, free alpha-subunit, and free beta-subunit hCG (hCGbeta), as well as beta-core, using the S504 RIA and Triton UGP enzyme immunoassay in 274 urine samples from women with nonmalignant gynecological conditions. The molar cross-reaction of each assay with purified beta-LH-core was determined. RESULTS: Cross-reaction with beta-LH-core was 100% in the LH and the S504 beta-core assay, 5% in the Triton UGP assay, and <0.1% in the hCG, free alpha-subunit, and free hCGbeta assays. Median urine concentrations of all analytes showed an age dependent increase. LH and free alpha-subunit concentrations were approximately 10(3) pmol/mol creatinine; hCG and S504 beta-core were approximately 10(2) pmol/mol creatinine; free hCGbeta and Triton UGP beta-core were in the tens of pmol/mol creatinine. The S504 beta-core concentrations were 10% of those of LH. S504 beta-core was strongly correlated with LH, but not with hCG or with free hCGbeta (LH, r2 = 0.45; hCG, r2 = 0.26; free hCGbeta, r2 = 0.03). The concentrations of beta-core detected by the Triton UGP assay, which has a 5% cross-reaction with beta-LH-core, were 2% of LH and 5% of the S504 beta-core concentrations. Triton UGP values correlated strongly with LH concentrations, but less well with S504 beta-core, intact hCG, and free hCGbeta (LH, r2 = 0.44; S504 beta-core, r2 = 0.33; hCG, r2 = 0.32; free hCGbeta, r2 = 0.19). CONCLUSIONS: Immunoreactive beta-core in women free of malignancies reflects cross-reaction with concentrations of the metabolite of LH, beta-LH-core, within the health related reference interval. PMID- 10102915 TI - 1H-NMR spectroscopy of body fluids: inborn errors of purine and pyrimidine metabolism. AB - BACKGROUND: The diagnosis of inborn errors of purine and pyrimidine metabolism is often difficult. We examined the potential of 1H-NMR as a tool in evaluation of patients with these disorders. METHODS: We performed 1H-NMR spectroscopy on 500 and 600 MHz instruments with a standardized sample volume of 500 microL. We studied body fluids from 25 patients with nine inborn errors of purine and pyrimidine metabolism. RESULTS: Characteristic abnormalities could be demonstrated in the 1H-NMR spectra of urine samples of all patients with diseases in the pyrimidine metabolism. In most urine samples from patients with defects in the purine metabolism, the 1H-NMR spectrum pointed to the specific diagnosis in a straightforward manner. The only exception was a urine from a case of adenine phosphoribosyl transferase deficiency in which the accumulating metabolite, 2,8 dihydroxyadenine, was not seen under the operating conditions used. Similarly, uric acid was not measured. We provide the 1H-NMR spectral characteristics of many intermediates in purine and pyrimidine metabolism that may be relevant for future studies in this field. CONCLUSION: The overview of metabolism that is provided by 1H-NMR spectroscopy makes the technique a valuable screening tool in the detection of inborn errors of purine and pyrimidine metabolism. PMID- 10102916 TI - Library of sequence-specific radioimmunoassays for human chromogranin A. AB - BACKGROUND: Human chromogranin A (CgA) is an acidic protein widely expressed in neuroendocrine tissue and tumors. The extensive tissue- and tumor-specific cleavages of CgA at basic cleavage sites produce multiple peptides. METHODS: We have developed a library of RIAs specific for different epitopes, including the NH2 and COOH termini and three sequences adjacent to dibasic sites in the remaining part of CgA. RESULTS: The antisera raised against CgA(210-222) and CgA(340-348) required a free NH2 terminus for binding. All antisera displayed high titers, high indexes of heterogeneity ( approximately 1.0), and high binding affinities (Keff0 approximately 0.1 x 10(12) to 1.0 x 10(12) L/mol), implying that the RIAs were monospecific and sensitive. The concentration of CgA in different tissues varied with the assay used. Hence, in a carcinoid tumor the concentration varied from 0.5 to 34.0 nmol/g tissue depending on the specificity of the CgA assay. The lowest concentration in all tumors was measured with the assay specific for the NH2 terminus of CgA. This is consistent with the relatively low concentrations measured in plasma from carcinoid tumor patients by the N-terminal assay, whereas the assays using antisera raised against CgA(210 222) and CgA(340-348) measured increased concentrations. CONCLUSION: Only some CgA assays appear useful for diagnosis of neuroendocrine tumors, but the entire library is valuable for studies of the expression and processing of human CgA. PMID- 10102917 TI - Within- and between-subject variation in commonly measured anthropometric and biochemical variables. AB - BACKGROUND: The biological variation of some commonly assessed metabolic variables in healthy subjects has not been studied extensively. The aim of the study was to assess, in 12 healthy subjects (6 male and 6 female; mean (SD) age; 22.7 (1.5) years) following an overnight fast, the day-to-day variation of body fat (impedance method), triglycerides, nonesterified fatty acid (NEFAs), glycerol, 3-hydroxybutyrate (3-OHB), lactate, glucose, insulin (RIA), C-peptide, and glucagon on 12 consecutive days. METHODS: Between- and within-subject coefficients of variation (CVG and CVW) were estimated using a random effects analysis of variance, and assay variation was subtracted to give the coefficient of within-subject biological variation (CVI). Individuality indices were calculated as CVW/CVG. RESULTS: The overall means, CVI, and individuality indices were as follows: for body fat, 24.2%, 10%, and 0.3; for triglycerides, 0.61 mmol/L, 21%, and 1.1; for NEFAs, 376 micromol/L, 45%, and 1.4; for glycerol, 48 micromol/L, 36%, and 0.8; for 3-OHB, 43 micromol/L, 61%, and 1.5; for lactate, 0.88 mmol/L, 31%, and 1.1; for glucose, 4.9 mmol/L, 4.8%, and 0.7; for insulin, 52 pmol/L, 26%, and 1.0; for C-peptide, 0.39 nmol/L, 24%, and 0.9; and for glucagon, 53 ng/L, 19%, and 0.8. CONCLUSIONS: The data presented here are necessary for the evaluation of several important metabolic variables in individual and group studies. The biological variation of some metabolites makes it difficult to characterize the status of healthy subjects with a single measurement. PMID- 10102918 TI - Beta-trace protein in serum: a new marker of glomerular filtration rate in the creatinine-blind range. PMID- 10102919 TI - Chronic lymphocytic leukemia cells may interfere in a glycated hemoglobin assay based on fluorescence quenching. PMID- 10102920 TI - Phenylalanine and tyrosine quantification by stable isotope dilution liquid chromatography-mass spectrometry from filter paper blood spots. PMID- 10102921 TI - Determination of hepatic iron concentration in fresh and paraffin-embedded tissue. PMID- 10102922 TI - Anthocyanins are detected in human plasma after oral administration of an elderberry extract. PMID- 10102923 TI - Measurement of protein carbonyls in plasma of smokers and in oxidized LDL by an ELISA. PMID- 10102924 TI - Technical evaluation of thyroid assays on the Vitros ECi. PMID- 10102926 TI - Limited linear range of the abbott AxSYM serum and erythrocyte folate methods PMID- 10102925 TI - Limited dynamic range of a new assay for serum folate. PMID- 10102927 TI - More on interference of N-acetylcysteine in measurement of acetaminophen PMID- 10102928 TI - Simple colorimetric procedures to determine smoking status PMID- 10102931 TI - Lemuel J. Bowie, PhD (1944-1998) PMID- 10102930 TI - Reliability of measurement of ionized magnesium in ultrafiltrate. PMID- 10102932 TI - Compiled by david E. Bruns, editor (dbruns@aacc.org) PMID- 10102933 TI - Functional and morphological correlates of connexin50 expressed in Xenopus laevis oocytes. AB - Electrophysiological and morphological methods were used to study connexin50 (Cx50) expressed in Xenopus laevis oocytes. Oocytes expressing Cx50 exhibited a new population of intramembrane particles (9.0 nm in diameter) in the plasma membrane. The particles represented hemichannels (connexin hexamers) because (a) their cross-sectional area could accommodate 24 +/- 3 helices, (b) when their density reached 300-400/microm2, they formed complete channels (dodecamers) in single oocytes, and assembled into plaques, and (c) their appearance in the plasma membrane was associated with a whole-cell current, which was activated at low external Ca2+ concentration ([Ca2+]o), and was blocked by octanol and by intracellular acidification. The Cx50 hemichannel density was directly proportional to the magnitude of the Cx50 Ca2+-sensitive current. Measurements of hemichannel density and the Ca2+-sensitive current in the same oocytes suggested that at physiological [Ca2+]o (1-2 mM), hemichannels rarely open. In the cytoplasm, hemichannels were present in approximately 0.1-microm diameter "coated" and in larger 0.2-0.5-microm diameter vesicles. The smaller coated vesicles contained endogenous plasma membrane proteins of the oocyte intermingled with 5-40 Cx50 hemichannels, and were observed to fuse with the plasma membrane. The larger vesicles, which contained Cx50 hemichannels, gap junction channels, and endogenous membrane proteins, originated from invaginations of the plasma membrane, as their lumen was labeled with the extracellular marker peroxidase. The insertion rate of hemichannels into the plasma membrane (80, 000/s), suggested that an average of 4,000 small coated vesicles were inserted every second. However, insertion of hemichannels occurred at a constant plasma membrane area, indicating that insertion by vesicle exocytosis (60-500 microm2 membranes/s) was balanced by plasma membrane endocytosis. These exocytotic and endocytotic rates suggest that the entire plasma membrane of the oocyte is replaced in approximately 24 h. PMID- 10102934 TI - Energetic and spatial parameters for gating of the bacterial large conductance mechanosensitive channel, MscL. AB - MscL is multimeric protein that forms a large conductance mechanosensitive channel in the inner membrane of Escherichia coli. Since MscL is gated by tension transmitted through the lipid bilayer, we have been able to measure its gating parameters as a function of absolute tension. Using purified MscL reconstituted in liposomes, we recorded single channel currents and varied the pressure gradient (P) to vary the tension (T). The tension was calculated from P and the radius of curvature was obtained using video microscopy of the patch. The probability of being open (Po) has a steep sigmoidal dependence on T, with a midpoint (T1/2) of 11.8 dyn/cm. The maximal slope sensitivity of Po/Pc was 0.63 dyn/cm per e-fold. Assuming a Boltzmann distribution, the energy difference between the closed and fully open states in the unstressed membrane was DeltaE = 18.6 kBT. If the mechanosensitivity arises from tension acting on a change of in plane area (DeltaA), the free energy, TDeltaA, would correspond to DeltaA = 6.5 nm2. MscL is not a binary channel, but has four conducting states and a closed state. Most transition rates are independent of tension, but the rate-limiting step to opening is the transition between the closed state and the lowest conductance substate. This transition thus involves the greatest DeltaA. When summed over all transitions, the in-plane area change from closed to fully open was 6 nm2, agreeing with the value obtained in the two-state analysis. Assuming a cylindrical channel, the dimensions of the (fully open) pore were comparable to DeltaA. Thus, the tension dependence of channel gating is primarily one of increasing the external channel area to accommodate the pore of the smallest conducting state. The higher conducting states appear to involve conformational changes internal to the channel that don't involve changes in area. PMID- 10102935 TI - Gating of cystic fibrosis transmembrane conductance regulator chloride channels by adenosine triphosphate hydrolysis. Quantitative analysis of a cyclic gating scheme. AB - Gating of the cystic fibrosis transmembrane conductance regulator (CFTR) involves a coordinated action of ATP on two nucleotide binding domains (NBD1 and NBD2). Previous studies using nonhydrolyzable ATP analogues and NBD mutant CFTR have suggested that nucleotide hydrolysis at NBD1 is required for opening of the channel, while hydrolysis of nucleotides at NBD2 controls channel closing. We studied ATP-dependent gating of CFTR in excised inside-out patches from stably transfected NIH3T3 cells. Single channel kinetics of CFTR gating at different [ATP] were analyzed. The closed time constant (tauc) decreased with increasing [ATP] to a minimum value of approximately 0.43 s at [ATP] >1.00 mM. The open time constant (tauo) increased with increasing [ATP] with a minimal tauo of approximately 260 ms. Kinetic analysis of K1250A-CFTR, a mutant that abolishes ATP hydrolysis at NBD2, reveals the presence of two open states. A short open state with a time constant of approximately 250 ms is dominant at low ATP concentrations (10 microM) and a much longer open state with a time constant of approximately 3 min is present at millimolar ATP. These data suggest that nucleotide binding and hydrolysis at NBD1 is coupled to channel opening and that the channel can close without nucleotide interaction with NBD2. A quantitative cyclic gating scheme with microscopic irreversibility was constructed based on the kinetic parameters derived from single-channel analysis. The estimated values of the kinetic parameters suggest that NBD1 and NBD2 are neither functionally nor biochemically equivalent. PMID- 10102936 TI - Novel gating mechanism of polyamine block in the strong inward rectifier K channel Kir2.1. AB - Inward rectifying K channels are essential for maintaining resting membrane potential and regulating excitability in many cell types. Previous studies have attributed the rectification properties of strong inward rectifiers such as Kir2.1 to voltage-dependent binding of intracellular polyamines or Mg to the pore (direct open channel block), thereby preventing outward passage of K ions. We have studied interactions between polyamines and the polyamine toxins philanthotoxin and argiotoxin on inward rectification in Kir2.1. We present evidence that high affinity polyamine block is not consistent with direct open channel block, but instead involves polyamines binding to another region of the channel (intrinsic gate) to form a blocking complex that occludes the pore. This interaction defines a novel mechanism of ion channel closure. PMID- 10102937 TI - Human ether-a-go-go-related gene K+ channel gating probed with extracellular ca2+. Evidence for two distinct voltage sensors. AB - Human ether-a-go-go-related gene (HERG) encoded K+ channels were expressed in Chinese hamster ovary (CHO-K1) cells and studied by whole-cell voltage clamp in the presence of varied extracellular Ca2+ concentrations and physiological external K+. Elevation of external Ca2+ from 1.8 to 10 mM resulted in a reduction of whole-cell K+ current amplitude, slowed activation kinetics, and an increased rate of deactivation. The midpoint of the voltage dependence of activation was also shifted +22.3 +/- 2.5 mV to more depolarized potentials. In contrast, the kinetics and voltage dependence of channel inactivation were hardly affected by increased extracellular Ca2+. Neither Ca2+ screening of diffuse membrane surface charges nor open channel block could explain these changes. However, selective changes in the voltage-dependent activation, but not inactivation gating, account for the effects of Ca2+ on Human ether-a-go-go-related gene current amplitude and kinetics. The differential effects of extracellular Ca2+ on the activation and inactivation gating indicate that these processes have distinct voltage-sensing mechanisms. Thus, Ca2+ appears to directly interact with externally accessible channel residues to alter the membrane potential detected by the activation voltage sensor, yet Ca2+ binding to this site is ineffective in modifying the inactivation gating machinery. PMID- 10102939 TI - Review article: antibiotic prophylaxis for endoscopic retrograde cholangiopancreatography (ERCP). AB - This review examines the evidence for antibiotic prophylaxis in endoscopic retrograde cholangiopan-creatography (ERCP), and provides detailed advice about suitable antibiotic regimens in appropriate high-risk patients. Ascending cholangitis and infective endocarditis are potential complications of endoscopic ERCP. The pathophysiology of these two complications is quite separate and different sub-groups of patients require prophylaxis with appropriate antibiotic regimens. Ascending cholangitis results from bacterial infection of an obstructed biliary system, usually from enteric Gram-negative microorganisms, resulting in bacteraemia. There is incomplete drainage of the biliary system after ERCP in up to 10% of patients who require stenting. Antibiotics started in these patients will probably reduce the frequency of cholangitis by 80%. If antibiotics are restricted to this group, approximately 90% of all patients having an ERCP will avoid antibiotics, but 80% of cholangitic episodes will be prevented. Infective endocarditis may result from the bacteraemia caused at the time of the ERCP in patients with an abnormal heart valve. Antibiotic prophylaxis, in particular covering alpha-haemolytic streptococci, should be started before the procedure in this defined high-risk group. PMID- 10102938 TI - Distinct transient outward potassium current (Ito) phenotypes and distribution of fast-inactivating potassium channel alpha subunits in ferret left ventricular myocytes. AB - The biophysical characteristics and alpha subunits underlying calcium-independent transient outward potassium current (Ito) phenotypes expressed in ferret left ventricular epicardial (LV epi) and endocardial (LV endo) myocytes were analyzed using patch clamp, fluorescent in situ hybridization (FISH), and immunofluorescent (IF) techniques. Two distinct Ito phenotypes were measured (21 22 degrees C) in the majority of LV epi and LV endo myocytes studied. The two Ito phenotypes displayed marked differences in peak current densities, activation thresholds, inactivation characteristics, and recovery kinetics. Ito,epi recovered rapidly [taurec, -70 mV = 51 +/- 3 ms] with minimal cumulative inactivation, while Ito,endo recovered slowly [taurec, -70 mV = 3,002 +/- 447 ms] with marked cumulative inactivation. Heteropoda toxin 2 (150 nM) blocked Ito,epi in a voltage-dependent manner, but had no effect on Ito,endo. Parallel FISH and IF measurements conducted on isolated LV epi and LV endo myocytes demonstrated that Kv1.4, Kv4.2, and Kv4.3 alpha subunit expression in LV myocyte types was quite heterogenous: (a) Kv4.2 and Kv4.3 were more predominantly expressed in LV epi than LV endo myocytes, and (b) Kv1.4 was expressed in the majority of LV endo myocytes but was essentially absent in LV epi myocytes. In combination with previous measurements on recovery kinetics (Kv1.4, slow; Kv4.2/4.3, relatively rapid) and Heteropoda toxin block (Kv1.4, insensitive; Kv4.2, sensitive), our results strongly support the hypothesis that, in ferret heart, Kv4.2/Kv4.3 and Kv1.4 alpha subunits, respectively, are the molecular substrates underlying the Ito,epi and Ito,endo phenotypes. FISH and IF measurements were also conducted on ferret ventricular tissue sections. The three Ito alpha subunits again showed distinct patterns of distribution: (a) Kv1.4 was localized primarily to the apical portion of the LV septum, LV endocardium, and approximate inner 75% of the LV free wall; (b) Kv4. 2 was localized primarily to the right ventricular free wall, epicardial layers of the LV, and base of the heart; and (c) Kv4.3 was localized primarily to epicardial layers of the LV apex and diffusely distributed in the LV free wall and septum. Therefore, in intact ventricular tissue, a heterogeneous distribution of candidate Ito alpha subunits not only exists from LV epicardium to endocardium but also from apex to base. PMID- 10102940 TI - Review article: Helicobacter pylori and gastro-oesophageal reflux disease clinical implications and management. AB - A significant proportion of patients with gastro-oesophageal reflux disease (GERD) have Helicobacter pylori infection, but it is unclear whether or not H. pylori should be treated in this clinical setting. The aim of this review was to critically assess the relationship between H. pylori and GERD and its potential implications for the management of GERD. Data for this review were gathered from the following sources up to April 1998-the biomedical database MEDLINE, a detailed review of medical journals, and a review of abstracts submitted to relevant international meetings. On average, 40% of GERD patients carry H. pylori infection, with a reported infection prevalence ranging from 16% to 88%. To date, there has been no reported controlled trial of effective H. pylori therapy in GERD. GERD has been reported to develop de novo following the cure of H. pylori in peptic ulcer disease. In the presence of H. pylori, proton pump inhibitor therapy appears to accelerate the development of atrophic corpus gastritis, a potentially precancerous condition. Conversely, proton pump inhibitor therapy seems to become less effective after cure of H. pylori. The mechanisms underlying these important contrasting phenomena are poorly understood. The relationship between H. pylori and GERD is complex, and it is difficult to give definitive guidelines on the management of H. pylori infection in GERD. Controlled trials of H. pylori therapy in GERD are urgently needed, as well as further long-term data on both the natural history of gastric histopathological changes in the H. pylori positive GERD patient treated with proton pump inhibitors, and the impact of H. pylori status on the clinical efficacy of antisecretory therapy. Pending these data, it is perhaps advisable to advocate cure of H. pylori in young patients with proton pump inhibitor-dependent GERD who, in the absence of anti-reflux surgery, are faced with the likelihood of long-term medical therapy. PMID- 10102941 TI - Review article: mechanisms and management of hepatotoxicity in ecstasy (MDMA) and amphetamine intoxications. AB - The social use of ecstasy (methylenedioxymethampheta-mine, MDMA) and amphetamines is widespread in the UK and Europe, and they are popularly considered as 'safe'. However, deaths have occurred and hepatotoxicity has featured in many cases of intoxication with amphetamine or its methylenedioxy analogues such as ecstasy. Recreational use of these drugs presents an important but often concealed cause of hepatitis or acute liver failure, particularly in young people. The patterns of liver damage and multiple putative mechanisms of injury are discussed. Recognition of the aetiological agent requires a high index of suspicion. Optimum management of the resultant liver damage, including the controversial role of liver transplantation for fulminant hepatic failure, is also discussed. PMID- 10102942 TI - Review article: the potential role of nitric oxide in chronic inflammatory bowel disorders. AB - The aetiology of the chronic inflammatory bowel diseases-ulcerative colitis and Crohn's disease-as well as 'microscopic colitis'-both collagenous (COC) and lymphocytic colitis (LC)-remains unknown. Autoimmune mechanisms, cytokine polymorphism, commensal bacteria, infectious agents and vascular impairment have all been proposed as playing important roles in the pathogenesis of this spectrum of diseases. A variety of proinflammatory mediators, including tumour necrosis factor alpha, interleukin-1beta, interferon gamma, leukotriene B4 and platelet activating factor, promote the adherence of phagocytes to the venular endothelium and extravasation of these cells into the colonic mucosa. In addition to large amounts of nitric oxide (NO), injurious peroxynitrite may be formed in the epithelium by the inducible nitric oxide synthase (iNOS), which is considered to elicit cytotoxicity by the generation of superoxide with reduced L-arginine availability. In active ulcerative colitis, and to a lesser extent in Crohn's disease, a greatly increased production of NO has been demonstrated by indirect and direct measurements. Surprisingly, even higher rates of production have been observed in COC-a condition which is never associated with injurious inflammation. The latter observation favours the notion that NO promotes mucosal integrity. Further evidence for a protective role of NO in chronic inflammatory bowel disorders is provided by the observation of increased susceptibility to the induction of experi mental colitis in 'knock-out' mice deficient in iNOS. Selective inhibitors of iNOS activity, as well as topical L-arginine, may therefore prove beneficial in inflammatory bowel disease by reducing the production of superoxide by iNOS, while only the former option may be expected to reduce diarrhoea in chronic inflammatory bowel disorders. Clearly, further experimental work needs to be done before testing topical L-arginine in human inflammatory bowel disease. PMID- 10102943 TI - Serum gastrin and chromogranin A during medium- and long-term acid suppressive therapy: a case-control study. AB - BACKGROUND: Serum chromogranin A (CgA) is regarded as a reliable marker of neuroendocrine proliferation. We previously described increased serum CgA levels during short-term profound gastric acid inhibition. AIM: To investigate serum gastrin and CgA levels in dyspeptic patients during continuous medium- (6 weeks to 1 year), or long-term (1-8 years) gastric acid suppressive therapy. PATIENTS AND METHODS: 114 consecutive dyspeptic patients referred for upper gastrointestinal endoscopy were enrolled in a cross-sectional, case-control study [62 patients on continuous antisecretory therapy, either with proton pump inhibitors (n = 47) or H2-receptor antagonists (H2RA) (n = 15) for gastro oesophageal reflux disease with or without Barrett's oesophagus or functional dyspepsia, and 52 age- and sex-matched patients without medical acid inhibition and with normal endoscopic findings (control group)]. Omeprazole doses ranged from 20 mg to 80 mg daily and ranitidine from 150 mg to 450 mg daily. Fasting serum CgA and serum gastrin levels were measured by radioimmunoassay (reference values: serum CgA < 4.0 nmol/L; serum gastrin < 85 ng/L). RESULTS: Fasting serum CgA levels positively correlated with serum gastrin in the entire study population (r = 0. 55, P = 0.0001). Median serum CgA values were higher in patients treated with a proton pump inhibitor than H2RA [2.8 (2.0-5.9) nmol/L vs. 2 (1.9-2.3) nmol/L, P < 0.002] and controls [2.8 (2.0-5.9) nmol/L vs. 1.8 (1.5 2.2) nmol/L, P < 0.0001) and did not differ between patients treated with H2RA or controls. Serum gastrin and CgA levels in patients on proton pump inhibitor therapy positively correlated with the degree and duration of acid inhibition. Patients on long-term proton pump inhibitor therapy had significantly higher fasting serum gastrin and CgA than those on medium-term proton pump inhibitor therapy [127 (73-217) ng/L vs. 49 (29-78) ng/L, P < 0.0001 and 4.8 (2.8-8) ng/L vs. 2.1 (1.9-2.6) ng/L, P < 0.001]. No such relation was found in patients on medium- vs. long-term H2RA. Overall, patients with positive Helicobacter pylori serology had higher serum gastrin and CgA levels than those with negative H. pylori serology [51 (27-119) ng/L vs. 27 (14-79) ng/L, P = 0.01, 2.4 (1.9-3.4) nmol/L vs. 2.0 (1.7-2.5) nmol/L, P = 0.05]. CONCLUSIONS: During long-term continuous proton pump inhibitor treatment, serum gastrin and CgA levels are significantly elevated compared to H2RA treatment and nontreated dyspeptic controls. H. pylori infection seems to affect gastric ECL cell secretory function. Increased serum CgA values during long-term profound gastric acid inhibition could reflect either gastric enterochromaffin-like cell hyperfunction or proliferative changes. PMID- 10102944 TI - Eradication of Helicobacter pylori increases gastric acidity in patients with atrophic gastritis of the corpus-evaluation of 24-h pH monitoring. AB - BACKGROUND: Recent studies have shown that the eradication of Helicobacter pylori results in a gastric acid secretion which decreases to normal levels in patients with duodenal ulcer disease. The aim of this study was to evaluate the effect of eradication of H. pylori in a 24-h study of gastric acidity in patients with atrophic gastritis of the corpus. METHODS: Intragastric acidity was measured by continuous 24-h pH monitoring, and the histology of the gastric antrum and corpus were evaluated in 14 H. pylori-positive patients with histologically proven atrophic gastritis of the corpus (10 men, 4 women; mean age, 57 years) before and 1 year after anti-H. pylori therapy. RESULTS: H. pylori was absent in 13 of 14 patients 1 year after treatment. Both gastritis and atrophy scores were significantly lower after eradication therapy (P < 0.01). The 24-h median pH and the percentage of 24-h pH readings above 4.0 units were significantly decreased after eradication therapy (from 5.12 +/- 0.36 to 2.69 +/- 0.21, and from 65.5 +/- 6.6% to 28.2 +/- 6.1%, P < 0.01, respectively.) CONCLUSION: Eradication of H. pylori increases 24-h gastric acidity in patients with atrophic gastritis of the corpus. Improvement of the histology of the gastric antrum and corpus may lead to the normalization of gastric acidity. PMID- 10102945 TI - Helicobacter pylori eradication with proton pump inhibitor-based triple therapies and re-treatment with ranitidine bismuth citrate-based triple therapy. AB - BACKGROUND: It has been suggested that short-term triple therapy comprising a proton pump inhibitor, plus clarithromycin and amoxycillin be used as first choice in treating H. pylori infection, while eradication failure patients should be further treated with a quadruple therapy. Nevertheless, conflicting results have been reported using these treatment regimens in different countries. METHODS: A total of 278 patients with H. pylori infection were randomised to receive one-week triple therapy, comprising clarithromycin 500 mg b.d., amoxycillin 1 g b.d., and either omeprazole 20 mg b.d. (OAC; 90 patients), or pantoprazole 40 mg b.d. (PAC; 95 patients), or lansoprazole 30 mg b.d. (LAC; 93 patients). H. pylori infection at entry, and eradication 4-6 weeks after therapy had ended, were assessed by rapid urease test and histology on biopsies from the antrum and the corpus. When eradication did not occur, patients were given a 2 week treatment comprising ranitidine bismuth citrate 400 mg b.d., tetracycline 500 mg t.d.s. and tinidazole 500 mg b.d. (RBTT). Eradication in these patients was assessed 4-6 weeks after conclusion of treatment by a further endoscopy. RESULTS: Six patients were lost to the follow-up. At the end of the first course of treatment, the overall H. pylori eradication rate was 78% (95% CI: 73-83) and 79% (95% CI: 75-84) at 'intention-to-treat' (ITT) and 'per protocol' (PP) analysis, respectively, without any statistically significant difference between treatment regimens, although a trend for better results with the omeprazole combination was observed. Moreover, H. pylori eradication was achieved in 82% (95% CI: 75-97) (ITT) and 86% (95% CI: 69-94) (PP) of 38 patients re-treated with RBTT regimen. CONCLUSIONS: Our data found that this short-term triple therapy is not a satisfactory treatment (< 80% eradication rate) for H. pylori infection. The 2-week triple therapy used as re-treatment in eradication failure patients yielded more promising results. PMID- 10102946 TI - Ranitidine bismuth citrate, tetracycline, clarithromycin twice-a-day triple therapy for clarithromycin susceptible Helicobacter pylori infection. AB - BACKGROUND: Although many combination therapies have been proposed, there is still interest in identifying simple, inexpensive, effective protocols that have high rates of success. AIM: To investigate the role of the new soluble form of bismuth, ranitidine bismuth citrate, in twice-a-day therapy for Helicobacter pylori infection. METHODS: Patients with histologically and culture proven H. pylori infection received ranitidine bismuth citrate 400 mg, tetracycline HCl 500 mg, and clarithromycin 500 mg, each b.d. for 14 days, followed by 300 mg ranitidine once a day for 4 additional weeks. Outcome was assessed 4 or more weeks after the end of antimicrobial therapy by repeat endoscopy with histology and culture (49 patients) or urea breath testing (14 patients). RESULTS: Sixty three patients completed the therapy, 59 men and four women (average age 56.7 years; range 31-75 years). All patients had clarithromycin-susceptible strains prior to therapy. H. pylori infection was cured in 94% (95% CI: 85-98%). There was a therapy failure in one patient who took the medicine for only 1 day and stopped because of side-effects. Three of the isolates from treatment failures were available post-failure; two were clarithromycin-resistant and one was susceptible. Side-effects were severe in two patients (3%) and moderate in three (primarily diarrhoea). CONCLUSIONS: Twice-a-day ranitidine bismuth citrate, tetracycline, clarithromycin triple therapy was well tolerated and effective for the treatment of H. pylori infection in patients with clarithromycin-susceptible H. pylori. PMID- 10102947 TI - Failure of a 1-day high-dose quadruple therapy for cure of Helicobacter pylori infection. AB - BACKGROUND: The optimal duration of treatment for eradication of Helicobacter pylori has still to be defined. A 1-day high-dose quadruple therapy with a combination of amoxycillin (or tetracycline), metronidazole, a bismuth salt and a proton pump inhibitor has led to eradication rates of 57-77%. In view of the high frequency of metronidazole-resistant strains of H. pylori in Europe, we hypothesized that by using clarithromycin in place of metronidazole and by increasing the dose of proton pump inhibitor, the efficacy of a 1-day high-dose quadruple therapy could be improved. METHODS: Patients were randomized to receive either amoxycillin 1000 mg b.d., clarithromycin 500 mg b.d. and lansoprazole 30 mg b.d. for 7 days, or amoxycillin 2000 mg q.d.s., clarithromycin 500 mg q.d.s., lansoprazole 30 mg t.d.s. and bismuth subcitrate 240 mg q.d.s. for 1 day. RESULTS: It was originally intended to include 100 patients. The first planned interim analysis performed after follow-up was completed for 30 patients revealed H. pylori eradication rates of 80% (12/15) in the 7-day triple therapy group and 20% (3/15) in the 1-day quadruple therapy group, the difference being highly significant (P = 0.003). Because the efficacy of the 1-day treatment was so low, the study was stopped for ethical reasons. Eleven patients who failed with the 1 day treatment were re-treated with the 7-day triple therapy: the eradication rate was 91% (10/11). CONCLUSIONS: One-day high-dose quadruple therapy with amoxycillin, clarithromycin, lansoprazole and bismuth subcitrate is dramatically less effective than the classic 7-day triple therapy with the same antibiotics. PMID- 10102948 TI - Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study. AB - BACKGROUND: Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing active duodenal ulcer. METHOD: This randomized, double-blind, multicentre study, conducted at 25 European sites, compared the efficacy and tolerability of rabeprazole and omeprazole in patients with active duodenal ulcers. One hundred and two patients with active duodenal ulcer received rabeprazole 20 mg and 103 patients omeprazole 20 mg once daily for 2 or 4 weeks, with ulcer healing monitored by endoscopy. RESULTS: After 2 weeks, complete ulcer healing was documented in 69% of patients given rabeprazole 20 mg and in 62% of patients given omeprazole 20 mg (N.S.). After 4 weeks, healing rates were 98% in the rabeprazole group and 93% in the omeprazole group (P = 0.083). Rabeprazole-treated patients had significantly greater improvement in daytime pain symptom relief than those treated with omeprazole at the conclusion of the study (P = 0.038). Both drugs were well tolerated over the 4-week treatment period. Mean changes from baseline to end point in fasting serum gastrin were significantly greater in the rabeprazole group, but at end-point mean values were well within normal limits for both groups. No clinically meaningful changes or other between-group differences were observed in laboratory parameters. CONCLUSION: In this study, rabeprazole produced healing rates equivalent to omeprazole at weeks 2 and 4, and provided significantly greater improvement in daytime pain. Both treatments were well tolerated. PMID- 10102949 TI - Protection of human gastric mucosa against aspirin-enteric coating or dose reduction? AB - BACKGROUND: Aspirin is widely used for cardiovascular prophylaxis. AIM: To compare the effectiveness of two widely-used strategies-dose reduction and enteric coating-for the minimization of gastric mucosal injury or toxicity. METHODS: Twelve healthy volunteers were studied. On four separate occasions each received, under blinded conditions, five daily doses of plain aspirin 300 mg, plain aspirin 75 mg, enteric-coated aspirin 300 mg or placebo. Ex vivo prostaglandin E2 synthesis was stimulated by the vortex mixing of gastric mucosal biopsies in Tris saline and measured by radioimmunoassay. Mucosal injury was quantified both by counting erosions and with a visual analogue scale. RESULTS: All three preparations reduced prostaglandin E2 synthesis by day five, by (median) 84% for plain aspirin 300 mg, by 80% for enteric coated aspirin 300 mg and by 63% for plain aspirin 75 mg. There was little mucosal injury prior to the start of each dose and period and no significant change with placebo. Plain aspirin caused a dose-dependent mucosal injury, with two (median, IQR 0-7) gastric erosions after five days of plain aspirin 75 mg, and 18 (2-26) after five days of plain aspirin 300 mg. With enteric-coated aspirin 300 mg there were 0 (0 1) gastric erosions (P = 0.003 compared to plain aspirin 300 mg P = 0.11, compared to plain aspirin 75 mg). CONCLUSION: Enteric coated aspirin reduces acute gastric mucosal injury to placebo levels, despite its inhibition of prostaglandin synthesis. Enteric coating is an appropriate strategy for the prevention of gastric mucosal damage induced by low-dose aspirin, which warrants systematic clinical evaluation. PMID- 10102950 TI - Indomethacin-induced gastric antral damage in hamsters: are neutrophils involved? AB - BACKGROUND: A direct role for neutrophils in the pathophysiology of indomethacin induced gastric damage is controversial. Therefore, such damage was evaluated in hamsters. METHODS: Gastric antral damage was evaluated 4 h after the oro-gastric administration of indomethacin (30 mg/kg). Prior to indomethacin, hamsters were treated with various pharmacological agents: rebamipide, methotrexate or anti neutrophil serum (ANS). The number of circulating neutrophils was determined from Wright-Giemsa stained blood smears. Myeloperoxidase (MPO) activity was measured as a marker of gastric antral neutrophil infiltration. RESULTS: Indomethacin caused primarily gastric antral damage. By histology, this damage did not penetrate the muscularis mucosa. A significant increase in gastric antral MPO activity was also found in indomethacin-treated hamsters. Rebamipide decreased macroscopic gastric antral damage in a dose-related fashion. Methotrexate treatment reduced the circulating blood neutrophil number by 38-44%, but did not affect gastric damage. ANS treatment resulted in near complete neutropenia, and also in a substantial reduction (84%) in gastric antral MPO activity. However, gastric antral damage was not significantly altered by ANS. CONCLUSIONS: Neutrophils are not directly involved in the pathophysiology of indomethacin induced damage to the hamster gastric antrum. PMID- 10102951 TI - Protective effects of zinc in indomethacin-induced gastric mucosal injury: evidence for a dual mechanism involving lipid peroxidation and nitric oxide. AB - BACKGROUND: Indomethacin causes gastric mucosal injury, although the pathogenesis is not fully understood. Zinc, is known to have gastroprotective effects in both humans and experimental animals. AIM: To determine (i) the protective effects of zinc in indomethacin-induced gastric mucosal injury in rats, and (ii) whether these cytoprotective effects are mediated by changes in gastric lipid peroxidation and/or nitric oxide synthase activity. METHODS: Gastric lesions were induced in rats by the intragastric administration of indomethacin. Morphological changes, lipid peroxidation (malondialdehyde levels) and nitric oxide synthase activity were determined in animals pre-treated with zinc sulphate and in controls. RESULTS: Indomethacin significantly increased malondialdehyde levels and decreased NOS activity. These effects were attenuated by pre-treatment with zinc (P < 0.005 and 0.0001, respectively). The protective effects of zinc were readily abolished in animals pre-treated with N-nitro-L-arginine methyl ester (L NAME). Morphologically, indomethacin induced large areas of mucosal ulcerations, which were completely prevented by zinc pre-treatment. CONCLUSIONS: Zinc provides protection against indomethacin-induced gastric mucosal injury. These protective effects result from the inhibition of lipid peroxidation and the preservation of mucosal nitric oxide synthase. PMID- 10102952 TI - Glucose metabolism and insulin sensitivity in inactive inflammatory bowel disease. AB - BACKGROUND: Inflammatory mediator concentration was found to be increased in active inflammatory bowel disease, and this could be related to an insulin resistant state. Moreover, glucocorticoids, which are widely used in the treatment of inflammatory bowel disease, are notoriously related to insulin resistance. AIM: To measure body composition, whole body glucose uptake and oxidation in Crohn's disease and ulcerative colitis patients with inactive disease. METHODS: All patients had clinical, ultrasound and biochemical assessment. Body composition was determined by isotopic dilution technique; basal metabolic rate and substrate oxidation were measured by indirect calorimetry. Insulin sensitivity was assessed by the euglycaemic hyperinsulinaemic clamp. Ten patients with inactive Crohn's disease (five males, aged 31.1 +/- 7.0 years) and 10 patients with inactive ulcerative colitis (five males, aged 33.4 +/- 8.8 years) participated in the study. Forty healthy subjects, matched for age and height were used as a control group. RESULTS: Crohn's disease patients showed lower BMI (P < 0.001), fat mass (P < 0.05) and respiratory quotient (P < 0.001) values compared to both ulcerative colitis and control subjects. No difference in peripheral glucose uptake (micromol/kg/min) was found between groups (respectively 42.5 +/- 6.78 in Crohn's disease, 40.2 +/- 8.00 in ulcerative colitis and 41.4 +/- 10.8 in control subjects). Glucose storage and oxidation did not differ between groups. CONCLUSION: Our data showed that inflammatory bowel disease patients in a remission phase of the disease activity had a whole body glucose uptake and oxidation similar to those of control subjects, probably due to fat-free mass preservation and low blood and tissue cytokine concentration. PMID- 10102953 TI - A cortisol suppression dose-response comparison of budesonide in controlled ileal release capsules with prednisolone. AB - AIM: To assess the systemic effect of oral budesonide, given as Entocort controlled ileal release capsules, over a dose range of 3-15 mg/day, compared with that of a moderate dose (20 mg/day) of prednisolone. METHODS: Twenty four healthy subjects were given 3, 9 or 15 mg budesonide or 20 mg prednisolone once daily, or 4.5 mg budesonide b.d., or placebo for 5 days in a randomized, double blind crossover study. The area under the curve (AUC) of plasma cortisol concentration and the amount of cortisol excreted in the urine were monitored. RESULTS: Both plasma and urine cortisol suppression showed a dose-response for the daily doses of budesonide. Prednisolone, 20 mg, suppressed plasma cortisol (AUC) statistically significantly more than 15 mg budesonide (P = 0.014), and 3 mg budesonide statistically significantly more than placebo (P = 0.010). No difference in AUC was detected between 9 mg and 4.5 mg budesonide b.d. Similar results for budesonide vs. placebo were obtained from urine cortisol excretion data. However, prednisolone affected urine cortisol less than it affected plasma cortisol. CONCLUSION: After 5 days of administration, budesonide controlled ileal release capsules, in both clinical (9 mg/day) and high doses (15 mg/day), affected plasma cortisol less than a moderate (20 mg/day) dose of prednisolone. PMID- 10102954 TI - Development of a new dyspepsia impact scale: the Nepean Dyspepsia Index. AB - BACKGROUND: There is not at present a suitable disease-specific health-related quality of life instrument for uninvestigated dyspepsia and functional (non ulcer) dyspepsia. AIM: To develop a new multi-dimensional disease-specific instrument. METHODS: The Nepean Dyspepsia Index (NDI) was designed to measure impairment of a subject's ability to engage in relevant aspects of their life and also their enjoyment of these aspects; in addition, the individual importance of each aspect is assessed. A 42-item quality of life measure was developed and tested, both in out-patients presenting to general practice with upper gastrointestinal complaints (n = 113) and in a randomly chosen population-based sample (n = 347). RESULTS: Adequate face and content validity was documented by an expert panel. Factor analysis identified four clinically relevant subscales: interference with activities of daily living, work, enjoyment of life and emotional well-being; lack of knowledge and control over the illness; disturbance to eating or drinking; and disturbance to sleep because of dyspepsia. These scales had high internal consistency. Both symptoms and the quality of life scores discriminated dyspepsia from health. CONCLUSION: The Nepean Dyspepsia Index is a reliable and valid disease-specific index for dyspepsia, measuring symptoms and health-related quality of life. PMID- 10102955 TI - Gastric emptying in hyperemesis gravidarum and non-dyspeptic pregnancy. AB - BACKGROUND: Emesis and hyperemesis are significant problems associated with early pregnancy. However, gastric emptying of solids has never been studied during early pregnancy in humans. AIM: To investigate gastric emptying of solids in patients recovering from hyperemesis gravidarum and in non-dyspeptic pregnant women and to compare these results with a group of healthy non-pregnant women. METHODS: Fourteen patients with hyperemesis gravidarum, 10 non-dyspeptic pregnant women and 36 non-pregnant women in the first half of the menstrual cycle underwent a gastric emptying study. Seven non-pregnant women repeated the test in the post-ovulatory period. RESULTS: Gastric emptying of solids was not significantly delayed in non-dyspeptic pregnant women compared with non-pregnant women. The emptying rate tended to be impaired in the post-ovulatory period of the menstrual cycle. Solid emptying was significantly accelerated in patients recovering from hyperemesis gravidarum, correlating well with thyroid function in the latter group. CONCLUSION: Pregnancy in humans is not associated with decreased solid gastric emptying. In subjects recovering from hyperemesis gravidarum, solid emptying is increased, correlating well with thyroid function abnormalities. Nausea and vomiting in hyperemesis are therefore probably not due to upper gastrointestinal disorders. PMID- 10102956 TI - The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. AB - BACKGROUND: The extract of medicinal plants containing curcumin is traditionally believed to have a positive contraction effect on the human gall-bladder. AIMS: To compare the effect of 20 mg curcumin or placebo on the gall-bladder volume of healthy volunteers. METHODS: A randomized, double blind and crossover design study was carried out in 12 healthy volunteers (seven males and five females). Ultrasonography examination was carried out serially to measure the gall-bladder volume. The data obtained was analysed by paired Student's t-test. RESULTS: The fasting gall-bladder volumes of 15.74 +/- 4.29 mL on curcumin and 15.98 +/- 4.08 mL on placebo were similar (P > 0.20). The gall-bladder volume was reduced within the period after curcumin administration. The percentage of gall-bladder volume reduction at 0.5, 1.0, 1.5 and 2.0 h after 20 mg curcumin administration were 11.8 +/- 6.9, 16.8 +/- 7.4, 22.0 +/- 8.5 and 29. 3 +/- 8.3%, respectively, which was statistically significant compared to placebo. CONCLUSION: On the basis of the present findings, it appears that curcumin induces contraction of the human gall-bladder. PMID- 10102957 TI - Combination therapy of pentoxifylline and TNFalpha monoclonal antibody in dextran sulphate-induced mouse colitis. AB - BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) has been suspected of playing an important role in the pathogenesis of inflammatory bowel diseases, and has become a target for the treatment of these diseases. Open-label, placebo controlled studies have shown that engineered CDP571 and chimeric anti-TNF antibody (cA2) provide a significant benefit in Crohn's disease. Since these antibodies have to be used repeatedly to maintain remission in inflammatory bowel disease, there is a concern that their use may compromise host defence and produce toxic side-effects. METHODS: We evaluated the combined use of mouse specific TNFalpha mab (25 microg/mouse, Endogen) and pentoxifylline (PF, 100 mg/kg/day, p.o., TNFalpha release inhibitor) in the DSS (3% dextran sulphate solution) model of mouse colitis. Colitis was induced by the feeding of 3% DSS for three cycles. The study groups were: Group I: single injection of rat anti mouse IgG, Group II: single injection of TNFalpha mab, Group III: daily PF for three cycles, Group IV: single injection of TNFalpha mab + PF for three cycles, Group V: TNFalpha mab at the beginning of each cycle (three injections) and Group VI: TNFalpha mab (three injections) + daily PF for three cycles. Daily disease activity (DAI) was measured throughout the study. At the end of each cycle, colon tissue was processed for histology, myeloperoxidase (MPO) and plasma TNFalpha. RESULTS: Mice treated with a single injection of TNFalpha alone or TNFalpha mab + PF showed significantly lower DAI, inflammation scores and ulcer index compared with the IgG treated group. Mice treated with TNFalpha mab + PF had no ulcers. Multiple injections of TNFalpha mab or TNFalpha mab + PF showed greater inhibition in DAI and cytokines in the first two cycles. However, in the third cycle, multiple injections of TNFalpha mab showed adverse proinflammatory effects. CONCLUSION: The simultaneous administration of pentoxifylline and TNFalpha mab may enhance therapeutic outcomes in inflammatory bowel disease and reduce the side-effects associated with the repeated use of TNFalpha mab. PMID- 10102958 TI - Polaprezinc protects gastric mucosal cells from noxious agents through antioxidant properties in vitro. AB - BACKGROUND: Polaprezinc has been shown to exert an anti-oxidant property in a tube experiment, protect gastric mucosa from experimental ulcerations in vivo, and accelerate the healing of gastric ulcer in humans. AIM: To examine a possible protective effect of polaprezinc on oxidant-mediated injury in primary monolayer cultures of rat gastric fundic mucosa. METHODS: Cytotoxicity was quantified by measuring 51Cr release. Whether or not polaprezinc exerts an antioxidant property was investigated by determining the effect of this agent on hydrogen peroxide (H2O2)-induced injury. The effects of polaprezinc on superoxide (O2-. ) generation as well as on ethanol (EtOH)-induced injury were also examined. Generation of O2-. was assessed by the reduction in cytochrome c. RESULTS: H2O2 caused a time- and dose-dependent increase in 51Cr release. The dose-response curve of 51Cr release by H2O2 shifted to the right in the presence of polaprezinc. Polaprezinc, at submillimolar concentrations, prevented H2O2-induced 51Cr release. EtOH also caused a dose-dependent increase in 51Cr release, which was prevented by the addition of polaprezinc. The incubation of cells with EtOH caused an increase in cytochrome c reduction, as the concentrations of EtOH increased. Polaprezinc inhibited EtOH-induced cytochrome c reduction. Protection by polaprezinc was microscopically associated with the prevention of monolayer disruption. CONCLUSIONS: Polaprezinc is antioxidative and directly protects gastric mucosal cells from noxious agents through its antioxidant properties in vitro. This finding may provide the theoretical basis for the usage of an antiulcer drug with antioxidant properties for the treatment of gastric inflammation, such as that induced by ethanol. PMID- 10102959 TI - Review article: current status of gastrointestinal carcinoids. AB - Carcinoid tumours are enigmatic, slow growing malignancies which occur most frequently (74%) in the gastrointestinal tract. In recent years, it has become apparent that the term 'carcinoid' represents a wide spectrum of different neoplasms originating from a variety of different neuroendocrine cell types. Carcinoid lesions are usually identified histologically by their affinity for silver salts, by general neuroendocrine markers, or more specifically by immunocytochemistry using antibodies against their specific cellular products. Within the gut, the most frequent sites are the small bowel (29%), the appendix (19%) and rectum (13%). Clinical manifestations are often vague or absent. Nevertheless, in approximately 10% of patients the tumours secrete bioactive mediators which may engender various elements of characteristic carcinoid syndrome. In many instances the neoplasms are detected incidentally at the time of surgery for other gastrointestinal disorders. The tendency for metastatic spread correlates with tumour size, and is substantially higher in lesions larger than 2.0 cm. An association with noncarcinoid neoplasms is ascribed in 8-17% of lesions. Treatment consists of radical surgical excision of the tumour, although gastric (type I and II) and rectal carcinoids may be managed with local excision. Overall 5-year survival is excellent for carcinoids of the appendix (86%) and rectum (72%), whereas small intestinal (55%), gastric (49%) and colonic carcinoids (42%) exhibit a far worse prognosis. PMID- 10102960 TI - The DU-MACH study: eradication of Helicobacter pylori and ulcer healing in patients with acute duodenal ulcer using omeprazole based triple therapy. AB - AIM: To investigate the efficacy of two omeprazole triple therapies for the eradication of Helicobacter pylori, ulcer healing and ulcer relapse during a 6 month treatment-free period in patients with active duodenal ulcer. METHODS: This was a double-blind, randomized study in 15 centres across Canada. Patients (n = 149) were randomized to omeprazole 20 mg once daily (O) or one of two 1-week b. d. eradication regimens: omeprazole 20 mg, metronidazole 400 mg and clarithromycin 250 mg (OMC) or omeprazole 20 mg, amoxycillin 1000 mg and clarithromycin 500 mg (OAC). All patients were treated for three additional weeks with omeprazole 20 mg once daily. Ulcer healing was assessed by endoscopy after 4 weeks of study therapy. H. pylori eradication was determined by a 13C-urea breath test and histology, performed at pre-entry, at 4 weeks after the end of all therapy and at 6 months. RESULTS: The intention-to-treat (intention-to-treat) analysis contained 146 patients and the per protocol (per protocol) analysis, 114 patients. The eradication rates were (intention-to-treat/per protocol): OMC-85% and 92%, OAC-78% and 87% and O-0% (O). Ulcer healing (intention-to-treat) was greater than 90% in all groups. The differences in the eradication and relapse rates between O vs. OMC and O vs. OAC were statistically significant (all, P < 0.001). Treatment was well tolerated and compliance was high. CONCLUSION: The OMC and OAC 1-week treatment regimens are safe and effective for eradication, healing and the prevention of relapse in duodenal ulcer patients. PMID- 10102961 TI - The influence of metronidazole resistance on the efficacy of ranitidine bismuth citrate triple therapy regimens for Helicobacter pylori infection. AB - AIM: To assess the influence of metronidazole resistance on the efficacy of ranitidine bismuth citrate-based triple therapy regimens in two consecutive studies. METHODS: In the first study, patients with a culture-proven Helicobacter pylori infection were treated with ranitidine bismuth citrate 400 mg, metronidazole 500 mg, and clarithromycin 500 mg, all twice daily for 1 week (RMC). In the second study, amoxycillin 1000 mg was substituted for clarithromycin (RMA). Susceptibility testing for metronidazole was performed with the E-test. Follow-up endoscopy was performed after >/= 4 weeks. Antral biopsy samples were taken for histology and urease test, and culture and corpus samples for histology and culture. RESULTS: 112 patients, 53 males, age 55 +/- 14 years (39 duodenal ulcer, 7 gastric ulcer and 66 gastritis) were treated with RMC, and 89 patients, 52 males, age 58 +/- 15 years (23 duodenal ulcer, 7 gastric ulcer and 59 gastritis) were treated with RMA. For RMC, intention-to-treat eradication results were 98% (59/60, 95% CI: 91-100%) and 95% (20/21, 95% CI: 76-100%) for metronidazole susceptible and resistant strains, respectively (P = 0.45). For RMA these figures were 87% (53/61, 95% CI: 76-94%) for metronidazole susceptible strains and 22% (2/9, 95% CI: 3-60%) for resistant strains (P = 0.0001). CONCLUSION: Both regimens are effective in metronidazole susceptible strains. However, in contrast to the amoxycillin-containing regimen, that containing clarithromycin is also effective in resistant strains. PMID- 10102962 TI - Triple therapy for Helicobacter pylori eradication is more effective than long term maintenance antisecretory treatment in the prevention of recurrence of duodenal ulcer: a prospective long-term follow-up study. AB - BACKGROUND: The effectiveness of Helicobacter pylori eradication treatment and long term acid suppression maintenance in the natural course of duodenal ulcer has not been directly compared. AIM: To compare in a prospective randomized study the effectiveness of H. pylori eradication on the prevention of recurrence of duodenal ulcer with long-term maintenance acid suppression therapy. METHODS: One hundred and fourteen duodenal ulcer patients were randomized to the treatment over a 12-month period. Fifty-seven of them received triple therapy consisting of 1 g sucralfate q.d.s. for 28 days, 300 mg metronidazole q.d.s. for 14 days and 250 mg clarithromycin q.d.s. for 14 days. Another 57 received 20 mg omeprazole q.d.s. for 12 months. An upper endoscopy was performed before treatment, at 6 weeks, and 2, 6 and 12 months after the first endoscopy. Side-effects were self recorded and clinical follow-ups were arranged for up to 4.25 years. RESULTS: The ulcer healing rate was 90.2% (95% confidence interval (95% CI): 79-97%) in the omeprazole group at 6 weeks as compared to 83.3% (95% CI: 70-93%) in the triple therapy group (P = 0.38). There was a higher success rate of pain control in the omeprazole group. Side-effects were more frequently reported and compliance was poorer in the triple therapy group during the first 4 weeks. During follow-up, more relapses were seen in the omeprazole group (9.8%, 95% CI: 3-21%) than the triple therapy group (4.2%, 95% CI: 1-13%) at 1 year (P = 0.44). All relapses were due to the persistence of H. pylori infection. At the 1 year follow-up, none of the patients who were H. pylori negative had an endoscopic relapse compared to 7 out of 56 patients who remained H. pylori positive (12.5%, 95% CI: 5-24%, P = 0.018). After a mean follow-up of 4.07 years, none of those who remained H. pylori negative had an ulcer relapse while the 11 out of 41 who remained H. pylori positive had an ulcer relapse (26.8%, 95% CI 14-43, P = 0. 0005). CONCLUSIONS: Both regimens were highly effective in healing ulcers. The eradication of H. pylori infection was associated with more side-effects and poor compliance but was more effective than the maintenance therapy in reducing the recurrence of duodenal ulcers. For the prevention of ulcer recurrence, testing of H. pylori status after triple therapy is more important than maintenance therapy. PMID- 10102964 TI - Furazolidone-containing short-term triple therapies are effective in the treatment of Helicobacter pylori infection. AB - BACKGROUND: A furazolidone-containing therapeutic regimen for Helicobacter pylori infection has attracted special interest in the face of a rising world-wide metronidazole resistant H. pylori, and the expense of currently used antimicrobial regimens. AIM: To evaluate the efficacy of furazolidone-containing regimens in eradicating H. pylori. METHODS: One-hundred and forty H. pylori positive patients with endoscopically confirmed duodenal ulcer or functional dyspepsia received one of four different regimens to eradicate H. pylori. In the first trial, the patients were randomly assigned to receive a 1-week course of furazolidone 100 mg b.d. and clarithromycin 250 mg b.d., with either tripotassium dicitrato bismuthate (TDB) 240 mg b.d. (FCB group) or lansoprazole 30 mg daily (FCL group). In the second trial, the patients were randomly assigned to receive a 1-week course of clarithromycin 250 mg b.d. and omeprazole 20 mg daily, with either furazolidone 100 mg b.d. (FCO group) or metronidazole 400 mg b.d. (MCO group). Endoscopy was repeated 4 weeks following completion of therapy with re assessment of H. pylori status on gastric biopsies by histology and culture. RESULTS: Four patients (1 in FCB, 1 in FCO and 2 in MCO groups) dropped out because they refused a follow-up endoscopy. Eradication rates of H. pylori on an intention-to-treat basis in the FCB, FCL, FCO and MCO groups were 91% (32/35, 95% CI: 82-99%), 91% (32/35, CI: 82-99%), 86% (30/35, CI: 74-97%) and 74% (26/35, CI: 60-89%) (all P > 0.05), respectively. Mild side-effects occurred in 15% of the 140 patients. In MCO group, the eradication rate in the patients infected with metronidazole-sensitive isolates of H. pylori was 86%, but dropped to 67% in those with metronidazole-resistance strains (P = 0.198). CONCLUSION: One-week regimens containing furazolidone and clarithromycin in combination with TDB or a proton pump inhibitor fulfil the criteria for successful H. pylori therapy. PMID- 10102963 TI - High cure rate of Helicobacter pylori infection using tripotassium dicitrato bismuthate, furazolidone and clarithromycin triple therapy for 1 week. AB - BACKGROUND: When metronidazole is used in bismuth-based or proton pump inhibitor based triple therapy, the cure rate of Helicobacter pylori is usually high. However, metronidazole-resistant H. pylori strains, which are increasing in frequency, are a major cause of failed H. pylori eradication. AIM: To evaluate the efficacy of non-metronidazole containing bismuth-based triple therapy for H. pylori infection. METHODS: One-hundred and eighty H. pylori-positive patients with endoscopically documented peptic ulcer disease or functional dyspepsia were randomly assigned to one of three 1-week regimens containing tripotassium dicitrato bismuthate (also called colloidal bismuth subcitrate) 240 mg b.d. and two antibiotics: furazolidone 100 mg b.d. plus clarithromycin 250 mg b.d. (Group A); or clarithromycin 250 mg b.d. plus amoxycillin 1000 mg b.d. (Group B); or furazolidone 100 mg b.d. plus josamycin 1000 mg b.d. (Group C). H. pylori status was assessed by rapid urease test, histology and culture of gastric biopsy specimens taken from both the antrum and corpus, both before and at least 4 weeks after completion of therapy. RESULTS: Thirteen patients dropped out (3 in group A, 5 in group B and 5 in group C). Based on an intention-to-treat analysis, the eradication rates achieved in groups A, B and C were 88% (53/60), 58% (35/60) and 77% (46/60), respectively. These differences were significant between groups A and B (P < 0.001), as well as between groups B and C (P < 0.05). Side-effects occurred in 7 (12%) patients in group A, 3 (5%) in group B and 8 (13%) in group C, and were mild, with the exception of vomiting in one patient (group C) that resulted in withdrawal from the study. CONCLUSION: One-week triple therapy, consisting of tripotassium dicitrato bismuthate, low-dose furazolidone and low dose clarithromycin, achieves a high cure rate of H. pylori. PMID- 10102965 TI - Eradication of Helicobacter pylori infection after ranitidine bismuth citrate, metronidazole and tetracycline for 7 or 10 days. AB - BACKGROUND: We assessed the efficacy, tolerance, and compliance of twice-daily triple therapy for Helicobacter pylori with ranitidine bismuth citrate, metronidazole and tetracycline for 7 or 10 days. METHODS: 105 subjects with H. pylori infection documented by the 13C-urea breath test were randomly assigned to a 7 or 10-day course of ranitidine bismuth citrate 400 mg b.d., metronidazole 500 mg b.d. and tetracycline 500 mg b.d. Subjects returned at the end of therapy for assessment of side-effects and pill count. A repeat 13C-urea breath test was obtained 4 or more weeks after completion of therapy and cure of infection was defined as a negative test result. RESULTS: Poor compliance (< 80% of medications) was seen in 2% of subjects randomized to 7 days of therapy and in 10% randomized to 10 days of therapy (P = N.S.). Intention-to-treat eradication rates were 56% for 7-day and 60% for 10-day therapy (P = N.S.). Per protocol eradication rates were 58% for 7-day and 61% for 10-day therapy (P = N.S.). The 10-day intention-to-treat eradication rate for males was 78% and 32% for females (P < 0.01) and per protocol eradication rates were 79% and 31%, respectively (P < 0.01). CONCLUSIONS: Despite excellent compliance and tolerance, neither 7 nor 10 days of therapy with twice-daily ranitidine bismuth citrate, metronidazole and tetracycline are adequate as a treatment of H. pylori infection. PMID- 10102966 TI - Is routine histological evaluation an accurate test for Helicobacter pylori infection? AB - AIM: To compare the diagnostic accuracy of routine histology for Helicobacter pylori infection, with histology by an expert pathologist, and to compare histology with the rapid urease test (RUT), 13C-urea breath test, IgG serology and culture of antrum and corpus specimens, in a consecutive series of untreated patients presenting for upper oesophago-gastro-duodenoscopy. MATERIALS AND METHODS: One-hundred and fifteen consecutive patients underwent multiple tests for H. pylori infection: rapid urease test, 13C-urea breath test, IgG serology and histology and culture on antrum and corpus biopsy specimens. Histology was first evaluated by the pathologists in a routine examination, and then blindly reviewed by an expert pathologist with a special interest in gastrointestinal pathology. The patients were considered to be H. pylori-positive if two or more tests were positive. RESULTS: Eighty-one patients (70.4%) were found to be H. pylori positive. 13C-urea breath test and IgG serology showed the best sensitivity and specificity (100%). Both the antral and body cultures, and the rapid urease test had the highest specificity (100%). Histological diagnosis after re-evaluation by an expert pathologist showed a high sensitivity (98. 8%) and specificity (100%), and was better than routine histology (sensitivity 92.6%; specificity 90.3%). The accuracy of the rapid urease test was greater than that of routine histology, and the combination of these two tests improved the sensitivity of H. pylori detection to up to 100%. CONCLUSION: All diagnostic tests usually utilised in clinical practice have a sensitivity higher than 90%. In patients who were not pre-treated with antisecretory agents or antibiotics, the sensitivity of histological diagnosis, however, seems to be influenced by the accuracy of the histological examination. The sensitivity of routine histology, but not of revised histological diagnosis, is improved by an additional rapid urease test. PMID- 10102967 TI - Mouse model of Helicobacter pylori infection: studies of gastric function and ulcer healing. AB - BACKGROUND: Helicobacter pylori infection in humans is a major risk factor for peptic ulcer, but studies on the relation between H. pylori infection and gastric pathology are limited due to a deficiency of convenient animal models resembling this infection in humans. METHODS: We studied the effects of inoculation of conventional BALB/c mice with CagA and VacA positive (type I) H. pylori or CagA and VacA negative H. pylori (type II) strains on gastric secretion and healing of chronic acetic acid-induced ulcers in mouse stomachs. The ulcer area, gastric blood flow, plasma interleukin (IL)-1beta and IL-12, as well as plasma gastrin and gastric luminal somatostatin were determined. Gastric mucosal biopsy samples were also taken for assessment of the presence of viable H. pylori using a rapid urease test, H. pylori-culture and the RT-PCR analysis of the signal for H. pylori CagA. RESULTS: Gastric acid and pepsin secretion was reduced by over 50% immediately after H. pylori inoculation and accompanied by a significant increment in plasma gastrin and fall in gastric luminal somatostatin content observed over all test days, particularly in mice infected with type I H. pylori. The area of ulcers in vehicle-treated controls decreased significantly starting from day 2 after ulcer induction and then continued to decline for a further 14 days to heal almost completely after 28 days. In contrast, the ulcers were present until day 28 in all mice infected with type I or type II H. pylori strains, being significantly larger, especially with type I H. pylori infection. The gastric blood flow at the ulcer margin and ulcer crater in vehicle-treated mice gradually increased with decreasing ulcer size, after 14 and 28 days reaching a value which was not significantly different from that in vehicle administered mice. In contrast, the gastric blood flow in type I H. pylori and, to a lesser extent, in type II H. pylori infected mice was significantly lower than in vehicle controls, both at the margin and at the crater of ulcers at all tested days. Histological changes such as oedema or congestion of surface epithelium were found after 7 days whereas mucosal inflammatory infiltration appeared after 14 days with a further increase after 28 days, especially in type I H. pylori and to a lesser extent in type II H. pylori infected mice. Plasma IL 1beta and IL-12 were significantly elevated at all tested days of ulcer healing and their increments were significantly higher in type I than in type II H. pylori infection. CONCLUSIONS: Conventional mice with gastric ulcers can be successfully infected by both toxigenic and nontoxigenic H. pylori strains, and this infection causes an immediate suppression of gastric secretion and markedly delays the healing of ulcers due to the fall in mucosal microcirculation in the ulcer region, cytokine release and an impairment in the gastrin-somatostatin link that appears to be independent of gastritis and more pronounced with infection of toxigenic than nontoxigenic strains. PMID- 10102968 TI - Effect of angiotensin II and telmisartan, an angiotensin1 receptor antagonist, on rat gastric mucosal blood flow. AB - BACKGROUND: Angiotensin II (ATII) has been suggested to contribute to shock induced dysfunction of the gastric circulation. AIM: To substantiate this conjecture, the effects on gastric mucosal haemodynamics and the hyperaemic response to acid back-diffusion of ATII and the angiotensin AT1 receptor antagonist, telmisartan, were examined in normal rats and in animals subjected to haemorrhage. METHODS: Gastric mucosal blood flow in phenobarbital-anaesthetized rats was recorded with the hydrogen clearance technique, and acid back-diffusion was induced by perfusing the stomach with ethanol (25%) in HCl (0.05 M). RESULTS: Intravenous infusion of ATII (0.3-10 nmol/min/kg) led to dose-dependent hypertension and a reduction of blood flow and vascular conductance in the gastric mucosa. The gastric hyperaemia caused by acid back-diffusion was attenuated by ATII (1 nmol/min/kg). These effects of ATII were antagonized by intravenous injection of telmisartan (1-10 mg/kg) which per se caused hypotension and dilated the gastric mucosal vasculature, but did not modify the gastric mucosal hyperaemia evoked by acid back-diffusion. Hypotension induced by haemorrhage (1.3 mL blood per 100 g body weight) failed to alter the hyperaemia due to acid back-diffusion, but caused gastric mucosal vasoconstriction, an effect that was left unaffected by telmisartan. CONCLUSIONS: ATII constricts the rat gastric microvasculature via an action involving AT1 receptors. The effects of telmisartan indicate that endogenous ATII contributes to the homeostatic regulation of gastric vascular tone but does not compromise the ability of the gastric microvasculature to react to influxing acid. These results negate the concept that ATII contributes to the gastric vascular perturbances in haemorrhagic shock. PMID- 10102969 TI - The systemic load and efficient delivery of active 5-aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine. AB - BACKGROUND: There have been reports of nephrotoxic reactions in patients with ulcerative colitis treated with 5-aminosalicylic acid (5-ASA) preparations. AIM: To compare the efficacy in delivery of active 5-ASA to the colon and the systemic load as the basis for potential long-term toxicity during treatment with olsalazine or mesalazine in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Fifteen patients with ulcerative colitis were treated with olsalazine or mesalazine, each for 7 days in an open, randomized, crossover design study. 5-ASA and acetyl-5-ASA (Ac-5-ASA) in plasma and urine were measured by high performance liquid chromatography. RESULTS: The plasma concentration of 5 ASA was 1.2 +/- 0.1 micromol/L (mean +/- S.E.M.) for olsalazine and 8.0 +/- 1.9 micromol/L for mesalazine, while the plasma concentration of Ac-5-ASA was 2.8 +/- 0.2 micromol/L for olsalazine and 10.8 +/- 1.6 micromol/L for mesalazine. The amount of 5-ASA excreted in the urine was 68 +/- 30 micromol/24 h for olsalazine and 593 +/- 164 micromol/24 h for mesalazine. The amount of Ac-5-ASA in the urine was 1260 +/- 102 micromol/24 h for olsalazine and 3223 +/- 229 micromol/24 h for mesalazine. The urinary recovery of total 5-ASA plus Ac-5-ASA (as a percentage of the given dose) was 23 +/- 2.1% for olsalazine and 39 +/- 3.6% for mesalazine. The ratio between the plasma concentrations of mesalazine and olsalazine differed significantly both for 5-ASA (5.1) and Ac-5-ASA (3.6); for 5-ASA (9. 9) and Ac-5 ASA (2.6) in urine, and for the urinary recovery of total 5-ASA plus Ac-5-ASA (1.7). Moreover, in the mesalazine group there was a large variation in the individual plasma concentrations of 5-ASA and Ac-5-ASA, with maximal values 5-6 fold higher than that in the olsalazine group. CONCLUSION: The systemic load of active 5-ASA is significantly higher for mesalazine than for olsalazine, when based on the dosages given and when calculated on an equimolar basis. Some of the patients in the mesalazine group showed unexpected high levels of plasma and urinary 5-ASA concentrations, a finding which may have long-term safety implications. PMID- 10102970 TI - Antioxidant effects of aminosalicylates and potential new drugs for inflammatory bowel disease: assessment in cell-free systems and inflamed human colorectal biopsies. AB - BACKGROUND: The therapeutic efficacy of 5-aminosalicylic acid in inflammatory bowel disease may be related to its antioxidant properties. AIM: To compare in vitro the antioxidant effects of conventional drugs (5-aminosalicylic acid, corticosteroids, metronidazole), with new aminosalicylates (4-aminosalicylic acid, balsalazide) and other potential therapies (ascorbate, N-acetylcysteine, glutathione, verapamil). METHODS: Compounds were assessed for efficacy in reducing the in vitro production of reactive oxygen species by cell-free systems (using xanthine/xanthine oxidase, with or without myeloperoxidase) and by colorectal biopsies from patients with ulcerative colitis using luminol-amplified chemiluminescence. RESULTS: 5-aminosalicylic acid and balsalazide were more potent antioxidants than 4-aminosalicylic acid or N-acetyl-5-aminosalicylic acid in cell-free systems. 5-aminosalicylic acid (20 mM) and balsalazide (20 mM) inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively, compared with only 59% inhibition by 4-aminosalicylic acid (20 mM). Hydrocortisone, metronidazole and verapamil had no significant effect on chemiluminescence in any system. Ascorbate (20 mM) inhibited chemiluminescence by 100% in cell-free systems and by 60% in rectal biopsies. N-acetyl cysteine (10 mM), and both oxidized and reduced glutathione (10 mM), completely inhibited chemiluminescence in cell-free systems, but not with rectal biopsies. CONCLUSIONS: The antioxidant effects of compounds varies between cell-free systems and inflamed colorectal biopsies. The effect of drugs on the chemiluminescence produced by these two assay systems is useful for screening potentially new antioxidant treatments for inflammatory bowel disease. Ascorbate seems worth further study as a novel therapy. PMID- 10102971 TI - Is maintenance therapy always necessary for patients with ulcerative colitis in remission? AB - BACKGROUND: The efficacy of sulphasalazine and mesalazine in preventing relapse in patients with ulcerative colitis is well known. It is less clear how long such maintenance should be continued, and if the duration of disease remission is a factor that affects the risk of recurrence. AIM: To determine whether the duration of disease remission affects the relapse rate, by comparing the efficacy of a delayed-release mesalazine (Asacol, Bracco S.p.A., Milan, Italy) against placebo in patients with ulcerative colitis with short- and long-duration of disease remission. METHODS: 112 patients (66 male, 46 female, mean age 35 years), with intermittent chronic ulcerative colitis in clinical, endoscopic and histological remission with sulphasalazine or mesalazine for at least 1 year, were included in the study. Assuming that a lower duration of remission might be associated with a higher relapse rate, the patients were stratified according to the length of their disease remission, prior to randomization into Group A (Asacol 26, placebo 35) in remission from 1 to 2 years, or Group B (Asacol 28, placebo 23) in remission for over 2 years, median 4 years. Patients were treated daily with oral Asacol 1.2 g vs. placebo, for a follow-up period of 1 year. RESULTS: We employed an intention-to-treat analysis. In Group A, whilst no difference was found between the two treatments after 6 months, mesalazine was significantly more effective than placebo in preventing relapse at 12 months [Asacol 6/26 (23%), placebo 17/35 (49%), P = 0.035, 95% Cl: 48-2.3%]. In contrast, in Group B no statistically significant difference was observed between the two treatments, either at 6 or 12 months [Asacol 5/28 (18%), placebo 6/23 (26%), P = 0.35, 95% Cl: 31-14%] of follow-up. Patients in group B were older, and had the disease and remission duration for longer, than those in Group A. CONCLUSIONS: Mesalazine prophylaxis is necessary for the prevention of relapse by patients with ulcerative colitis in remission for less than 2 years, but this study casts doubt over whether continuous maintenance treatment is necessary in patients with prolonged clinical, endoscopic and histological remission, who are at very low risk of relapse. PMID- 10102972 TI - A new mesalazine gel enema in the treatment of left-sided ulcerative colitis: a randomized controlled multicentre trial. AB - BACKGROUND: A new mesalazine rectal gel preparation (without propellant gas) has been recently developed to improve topical treatment in distal ulcerative colitis. AIM: To evaluate the efficacy, safety and patient tolerability of mesalazine gel enema compared with mesalazine foam enema in the treatment of patients with acute left-sided ulcerative colitis. METHODS: In a randomized multicentre investigator-blind parallel group trial, 103 patients with mild to moderate left-sided colitis or proctosigmoiditis were randomly allocated to mesalazine 2 g gel enema (n = 50 evaluable patients) and mesalazine 2 g foam enema (n = 53 evaluable patients) for 4 weeks. Clinical symptoms, endoscopic and histological findings were assessed at entry, 2 and 4 weeks. Patients' evaluation of treatment tolerability and acceptability was assessed at 2 and 4 weeks. RESULTS: After 4 weeks of treatment, clinical remission was achieved by 76% of mesalazine gel enema-treated patients and 69% of patients treated with mesalazine foam enema (P = 0.608). Endoscopic remission rates at week 4 were 51 and 52% for the mesalazine gel and foam enemas, respectively (P = 0.925). Histological remission was achieved by 30% of patients in both groups. Patients reported that the new mesalazine gel preparation was significantly better tolerated than the foam enema. Patients in the foam group had significantly more difficulty in retention (25% vs. 6%, P < 0.05), abdominal bloating (50% vs. 26%, P < 0.005) and discomfort during administration (48% vs. 26%, P < 0.05). CONCLUSION: The new mesalazine gel enema is efficacious and significantly better tolerated than the mesalazine foam enema. PMID- 10102974 TI - Prescription of acid-suppressing drugs in relation to endoscopic diagnosis: a record-linkage study. AB - BACKGROUND: Although widely used, few data are available on the appropriateness of prescribing of acid-suppressing drugs (ASDs), despite guidelines on the investigation and treatment of dyspeptic patients. METHODS: We created a database of 62 000 endoscopy examinations and record-linked these to a prescribing database. Endoscopic diagnoses were classified into peptic, nonpeptic and others. The H2-antagonists, omeprazole and misoprostol, were studied. RESULTS: 35 000 patients had one or more endoscopies during 1978-93; two-thirds were over 45 years of age at first endoscopy. A quarter of all patients who had been endoscoped had consistently normal examinations. Peptic oesophageal pathology was the commonest positive finding. A quarter of those prescribed ASDs between 1989 and 1993 had been endoscoped between 1978 and 1993. In those with a peptic diagnosis prescribed any ASD, the pathologies found were: oesophageal (42.9%), duodenal (36.3%) and gastro-pyloric (21.3%). Patients prescribed omeprazole were more likely to have undergone endoscopy than those prescribed other ASDs, and they were also more likely to have peptic oesophageal pathology. Long-term prescribing (>56 days per year) occurred in two-thirds of patients prescribed ASDs and 40% had at least one endoscopy. In those prescribed short-term ASDs, 20% had undergone at least one endoscopy. Peptic and nonpeptic endoscopic pathology was associated with increased ASD prescribing, but a normal endoscopy did not reduce prescribing. CONCLUSION: ASD prescribing appeared to be mainly symptom driven. Positive endoscopic findings increased the prescribing of ASDs, but normal findings did not reduce it. PMID- 10102973 TI - Depletion of colonic detoxication enzyme activity in mice with dextran sulphate sodium-induced colitis. AB - BACKGROUND: The increased risk of colonic malignancies in individuals with ulcerative colitis has prompted a search for early biomarkers of disease progression. AIM: To characterize Phase II detoxication enzyme expression during acute and chronic colitis. The mouse model of dextran sulphate sodium (DSS) induced colitis represents a relevant system with which to sequentially evaluate the spectrum of biochemical changes associated with colorectal cancer risk. METHODS: Acute and chronic colitis were induced in Swiss Webster mice by administering DSS in the drinking water (5%) for 1-4 cycles. Each cycle consisted of 7 days DSS and 14 days of water. The glutathione S-transferase (GST) activity, gamma-glutamylcysteine synthetase (gamma-GCS) activity and glutathione content of the colonic tissues were determined at various time points throughout the experiment. Alterations in GST isozyme expression were confirmed by Western and Northern blot. RESULTS: GST activity was reduced significantly in the colon by the end of Cycle 1 (84% of control values). Specific activities continued to decrease with subsequent cycles of DSS exposure. By the end of Cycle 4, glutathione levels and gamma-GCS activity had reached 29% and 56% of control, respectively. CONCLUSIONS: These data suggest that detoxication enzyme depletion is associated with both acute and chronic colitis and may be an important event in the progression of ulcerative colitis to colon cancer. PMID- 10102975 TI - Impact of food intake on the antisecretory effect of low-dose ranitidine and famotidine. AB - BACKGROUND: Over-the-counter status has recently been approved for low-dose H2 antagonists in several countries. Insufficient information is currently available on the effect of food in low-dose H2-antagonist therapy. AIM: Compare the antisecretory efficacy of low-dose ranitidine and famotidine in fasting and non fasting volunteers. METHODS: Twenty volunteers were randomized into a double blind, placebo-controlled, multiple-step crossover study comparing the antisecretory efficacy of 75 mg ranitidine, 10 mg famotidine and placebo over 12 h using intragastric pH-metry. Two standard meals were given after 4 h and 8 h of medication. Fifteen volunteers also participated in a second study comparing the antisecretory effect of both drugs, both with and without meals. RESULTS: In non fasting subjects, the percentage of time with pH > 4 was similarly elevated for both drugs compared with placebo over the first 8 h: ranitidine 39.3%, famotidine 29.5%, placebo 9.5% (P < 0. 001); but not for the last 4 h after the second meal (P > 0.05). Comparing the first 4-h period with the second, the percentage of pH > 4 was significantly reduced for both drugs in the second period in the subjects given food at the end of the initial 4-h period (ranitidine 56.9% vs. 26.6%, P = 0.005; famotidine 46.6% vs. 13.3%, P < 0.001). It remained more or less constant, however, for the second 4-h period in fasting subjects (ranitidine 41% vs. 28.1%, P = 0.46; famotidine 52.7% vs. 52.2%, P = 0.12). CONCLUSION: In non-fasting volunteers both low-dose H2-antagonists had comparable antisecretory effects and were superior to placebo over the first 8 h of therapy. Both drugs achieved a slightly higher antisecretory effect without food intake compared to with food intake. PMID- 10102976 TI - Low-dose lansoprazole provides greater relief of heartburn and epigastric pain than low-dose omeprazole in patients with acid-related dyspepsia. AB - AIM: To compare the relative efficacies of lansoprazole 15 mg o.m. and omeprazole 10 mg o.m. in relieving heartburn and epigastric pain in patients with acid related dyspepsia. In addition, the study compared the safety profiles of the two treatments. METHODS: This double-blind, parallel group, randomised, multicentre study was conducted in 52 general practices in the UK. A total of 609 patients was recruited, 562 of whom were eligible for inclusion in the intention-to-treat analysis. All of the patients had experienced at least mild heartburn or mild epigastric pain persistently on at least 4 of the previous 7 days; patients with severe symptoms were excluded. 283 patients received lansoprazole 15 mg and 279 received omeprazole 10 mg, both for 4 weeks. The main efficacy measure was relief of symptoms, based on physician assessments. RESULTS: In the intention-to-treat population, a complete relief of overall primary symptoms of dyspepsia was achieved after 2 weeks in 53% of patients receiving lansoprazole and in 41% of patients receiving omeprazole (P = 0.007). After 4 weeks, 59% of the lansoprazole group and 51% of the omeprazole group had achieved complete symptom relief (P = 0. 078). Antacids were taken for additional relief of symptoms in fewer patients given lansoprazole compared to the omeprazole group in the third and fourth weeks (P = 0.035) and also significantly fewer antacids were taken by patients in the lansoprazole group compared with patients in the omeprazole group (P = 0.033). The proportion of patients reporting adverse events was similar in both groups. CONCLUSION: Low-dose lansoprazole is more effective than low-dose omeprazole in the treatment of patients with mild heartburn or epigastric pain in general practice. PMID- 10102977 TI - Nitric oxide-releasing NSAIDs inhibit interleukin-1beta converting enzyme-like cysteine proteases and protect endothelial cells from apoptosis induced by TNFalpha. AB - BACKGROUND: Nitric oxide (NO)-releasing NSAIDs are a new class of NSAID derivatives with markedly reduced gastrointestinal toxicity. Although it has been demonstrated that NO-NSAIDs spare gastric mucosal blood flow, molecular determinants involved in this effect are unknown. AIM: To investigate the effect of aspirin, naproxen and flurbiprofen, and their NO-derivatives, on gastric apoptosis and endothelial cell damage induced by tumour necrosis factor-alpha (TNFalpha). In other systems, TNFalpha-induced apoptosis is mediated by caspases, a growing family of cysteine proteases similar to the IL-1beta converting enzyme (ICE), and so we have investigated whether NO-NSAIDs modulate ICE-like endopeptidases. METHODS: Rats were treated orally with aspirin, naproxen and flurbiprofen, or their NO-releasing derivatives in equimolar doses, and were killed 3 h later to assess mucosal damage and caspase activity. Endothelial cells (HUVECs) were obtained from human umbilical cord by enzymatic digestion. Caspase 1 and 3 activities were measured by a fluorimetric assay using selective peptides as substrates and inhibitors. Apoptosis was quantified by ELISA specific for histone-associated DNA fragments and by the terminal transferase nick-end translation method (TUNEL). RESULTS: In vivo NSAID administration caused a time dependent increase in gastric mucosal damage and caspase activity. NCX-4016, NO naproxen and NO-flurbiprofen did not cause any mucosal damage and prevented cysteine protease activation. NSAIDs and NO-NSAIDs stimulated TNFalpha release. Exposure to TNFalpha resulted in a time- and concentration-dependent HUVEC apoptosis, an effect that was prevented by pretreating the cells with NCX-4016, NO-naproxen, NO-flurbiprofen, SNP or Z-VAD.FMK, a pan-caspase inhibitor. The activation of ICE-like cysteine proteases was required to mediate TNFalpha induced apoptosis of HUVECs. Exogenous NO donors inhibited TNFalpha-induced cysteine protease activation. Inhibition of caspase activity was due to S nitrosylation of ICE/CPP32-like proteases. NO-NSAIDs prevented IL-1beta release from endotoxin-stimulated macrophages. CONCLUSIONS: NO-releasing NSAIDs are a new class of non-peptide caspase inhibitors. Inhibition of ICE-like cysteine proteases prevents endothelial cell damage induced by pro-inflammatory agents and might contribute to the gastro-protective effects of NO-NSAIDs. PMID- 10102978 TI - Clarithromycin-based triple therapies. PMID- 10102980 TI - Hypergastrinaemia with long-term omeprazole treatment. PMID- 10102984 TI - SUPPLEMENTARY MATERIAL: Solution structure of the B form of oxidized rat microsomal cytochrome b5 and backbone dynamics via 15N rotating frame NMR relaxation measurements: biological implications. PMID- 10102985 TI - Structural and energetic determinants of the S1-site specificity in serine proteases. AB - In recent years the number of determined three-dimensional structures of serine proteases that are accompanied by detailed mutational studies has grown rapidly. In particular, spatial structures have been described for enzymes involved in processes of critical medical significance, often related to severe pathophysiological diseases. There has also been significant progress in the understanding of the structural grounds for the substrate specificity of serine proteases. This review is concerned mainly with primary structural determinants of the S1 specificity, the crucial component of substrate selectivity, often in relation to more distant specificity elements, which cooperatively influence the S1 site. PMID- 10102986 TI - Functional analysis of O-linked oligosaccharides in threonine/serine-rich region of Aspergillus glucoamylase by expression in mannosyltransferase-disruptants of yeast. AB - The glaA gene encoding glucoamylase I (GAI) of Aspergillus awamori var. kawachi was heterologously expressed in mannosyltransferase mutants of Saccharomyces cerevisiae, in which the pmt1 gene and the kre2 gene were disrupted. The GAI enzymes expressed in these yeast mutant cells exhibited a lesser extent of O glycosylation. Secretion of GAI expressed in the pmt1-disruptant and in the kre2 disruptant, respectively, was almost the same as that of GAI expressed in wild type (wt) strains. The number of O-linked mannose in GAI from wt yeast strain ranged in size from one (Man1) to five (Man5). On the other hand, the O-linked oligosaccharides of GAI from the pmt1-disruptant ranged in size from Man1 to Man4. Man5 was not detected and Man2-Man4 were reduced in proportion to the reduction of Man1. The O-linked oligosaccharides of GAI from the kre2-disruptant ranged from Man1 to Man4, and the molar amount of Man4 was reduced to 27.3%, compared to that of the wt strain. The hydrolyzing abilities for soluble starch and the adsorbing abilities on raw starch were comparable between both disruptants and wt strains. However, the digesting abilities for raw starch of the disruptants were decreased to 70% of those of the wt strains. Stabilities of GAI of the disruptants were reduced toward extreme pH and high temperature, compared to those of the wt strains. These results demonstrate that the O-linked oligosaccharides of GAI are responsible for the enzyme stability and activity toward insoluble substrates but not for secretion. PMID- 10102987 TI - Binding and catalytic properties of the Cdc2 and Crp proteins of Dictyostelium. AB - Dictyostelium expresses at least two proteins of the cyclin-dependent kinase (Cdk) family, Cdc2 and Crp. Cdc2 levels remain relatively constant during differentiation, whereas the levels of Crp increase dramatically as differentiation progresses. Crp is highly related to the mammalian Cdk5, and p25 (a truncated form of p35, the activating subunit of Cdk5 from mammalian brain) stimulates the histone H1 kinase activity of GST-Crp by several fold. In contrast, p25 does not stimulate the histone H1 kinase activity of GST-Cdc2 or the Cdc2 activity present in cell extracts from vegetative Dictyostelium cells. GST-Cdc2, in vitro translated Cdc2 and Cdc2 from all stages of differentiation bind to p13suc1. In contrast, GST-Crp, in vitro translated Crp and the Crp protein present in cell extracts do not bind to p13suc1. We have confirmed a previous report by Arakane and Maeda [J. Plant Res. (1997) 110, 81-85] that there is a peak of p13suc1 bound histone H1 kinase activity during late development, but we found that there was no corresponding peak of p13suc1 bound Cdc2 protein that corresponds to this activity. Taken together, these data suggest that neither Cdc2 nor Crp is responsible for the late developmental peak of histone H1 kinase activity that binds to p13suc1. PMID- 10102988 TI - Equilibrium and transient intermediates in folding of human macrophage migration inhibitory factor. AB - Acid, guanidinium-Cl and urea denaturations of recombinant human macrophage migration inhibitory factor (MIF) were measured using CD and fluorimetry. The acid-induced denaturation was followed by CD at 200, 222, and 278 nm and by tryptophan fluorescence. All four probes revealed an acid-denatured state below pH 3 which resembled a typical molten globule. The pH transition is not two-state as the CD data at 222 nm deviated from all other probes. Urea and guanidinium-Cl denaturations (pH 7, 25 degrees C) both gave an apparent DeltaGU app H2O of 31 +/ 3 kJ.mol-1 when extrapolated to zero denaturant concentration. However, denaturation transitions recorded by fluorescence (at the same protein concentration) occurred at lower urea or guanidinium-Cl concentrations, consistent with an intermediate in the course of MIF denaturation. CD at 222 nm was not very sensitive to protein concentration (in 10-fold range) even though size-exclusion chromatogryphy (SEC) revealed a dimer-monomer dissociation prior to MIF unfolding. Refolding experiments were performed starting from acid, guanidinium-Cl and urea-denatured states. The kinetics were multiphasic with at least two folding intermediates. The intrinsic rate constant of the main folding phase was 5.0 +/- 0.5 s-1 (36.6 degrees C, pH 7) and its energy of activation 155 +/- 12 kJ.mol-1. PMID- 10102989 TI - Interaction of the DNA-binding antitumor antibiotics, chromomycin and mithramycin with erythroid spectrin. AB - The aureolic acid group of antitumor antibiotics, chromomycin A3 and mithramycin, are well established as transcription inhibitors, which bind reversibly to DNA at and above physiological pH, in the presence of divalent metal ions such as Mg2+. As part of our broad objective to elucidate their intracellular mode of action, other than association with DNA, we studied their interactions with the erythrocyte cytoskeletal protein, spectrin, in the absence and presence of magnesium. Different spectroscopic studies, such as absorbance, fluorescence and CD, have shown that both free chromomycin and mithramycin and their Mg2+ complexes bind to spectrin with an affinity higher than that reported for DNA. The affinity constants for the association of chromomycin and mithramycin (or their Mg2+ complexes) with spectrin are comparable with those for the association of spectrin with other cytoskeletal proteins, for example F-actin, ankyrin, protein 4.1, etc. The nature of the binding of the two antibiotics to spectrin is different. The mode of binding of the antibiotics with spectrin also changes in the presence of Mg2+. The interaction leads to a change in the tertiary structure of the protein. The relevance of the results to our understanding of the mode of action of the antibiotics is discussed. PMID- 10102990 TI - A novel form of human neuropsin, a brain-related serine protease, is generated by alternative splicing and is expressed preferentially in human adult brain. AB - We have cloned cDNAs encoding two isoforms of a human novel serine protease. They encoded sequences of 260 and 305 amino acids, and both showed significant homology to mouse neuropsin. Mouse neuropsin has been reported to be involved in hippocampal plasticity, therefore we designated the proteins as type 1 and type 2 neuropsin, respectively. The amino acid sequences of the two types of human neuropsin were identical, except that type 2 carried an insert of 45 amino acids at the C-terminus of the leader sequence. The essential three amino acids in the active site triad, His, Asp, and Ser, and the single putative N-glycosylation site were conserved in human and mouse neuropsin. Sequence analysis of the 946 bp genomic DNA spanning the region encoding the insertion sequence revealed that two isoforms were generated in human brain by alternative splicing. However, the mouse genomic sequence did not conserve the 3' acceptor consensus sequence at the corresponding position, suggesting that type 2 neuropsin was a species-specific splice variant. When the open reading frames of human neuropsin were expressed in insect cells, both types of neuropsin were detected in the conditioned media by western blot analysis using anti-human neuropsin serum. Northern blot hybridization and reverse transcription-polymerase chain reaction showed predominant expression of type 1 neuropsin in pancreas. Type 2 neuropsin was preferentially expressed in human adult brain and hippocampus, although both types were expressed in fetal brain and placenta in comparable amounts. Dot blot hybridization showed that neuropsin was expressed in various regions of adult brain, including the hippocampus and cerebral cortex, and also in various fetal tissues. These results suggest that human type 2 neuropsin may be important to the adult brain plasticity, although both types may be necessary for the development of the nervous system. PMID- 10102991 TI - Critical relationship between glycosylation of recombinant lutropin receptor ectodomain and its secretion from baculovirus-infected insect cells. AB - The lutropin receptor ectodomain overexpressed under the control of the powerful polyhedrin promoter in baculovirus-infected Sf9 insect cells, is mainly found in an inactive, intracellularly-aggregated form. It is secreted in an active form under the control of the P10 promoter, a somewhat weaker and earlier promoter, at the price of a lower production. The apparent molecular masses of the two species encoded by the same cDNA are 48 kDa and 60-68 kDa, respectively. The relationship between the extent and type of glycosylation and the extracellular targeting for the recombinant lutropin receptor ectodomains was investigated precisely with endoglycosidases, lectins of various specificities, and a glycosylation inhibitor, and tested with monoclonal and polyclonal antibodies. The results indicate that the strong polyhedrin promoter probably overwhelms the processing capacity of the ER in Sf9 cells, so that only a high-mannose precursor is expressed in large amounts. Only a minute amount of protein is secreted, which has been processed by Sf9 exoglycosidases/glycosyltransferases and bears complex/hybrid oligosaccharides. The weaker P10 promoter allows secretion of a mature and active receptor ectodomain, bearing complex glycosylation. An important O-linked glycosylation is also added post-translationally on this species. In particular, beta-galactose and sialic acid residues were specifically detected in the secreted species, evidence of the induction of the corresponding glycosyltransferases or of their genes. These results suggest that Sf9 cells should eventually be engineered with chaperones and glycosyltransferases in order to improve the production of demanding glycoproteins such as the porcine lutropin ectodomain, so as to open the way to resolution of the three-dimensional structures of these receptors. PMID- 10102992 TI - Chemical shift perturbation studies of the interactions of the second RNA-binding domain of the Drosophila sex-lethal protein with the transformer pre-mRNA polyuridine tract and 3' splice-site sequences. AB - The interactions of the second RNA-binding domain of the Drosophila melanogaster Sex-lethal protein (Sxl RBD2) with the oligoribonucleotides, GUUUUUUUU (GU8) and CUAGUG, representing the sequences surrounding an alternative 3'-splicing site of the transformer pre-mRNA (GU8CUAGUG), were studied using heteronuclear two dimensional NMR techniques. The 1H and 15N chemical shifts of the backbone amide resonances upon titration of Sxl RBD2 with each of these RNAs were recorded. It was found that Sxl RBD2 can bind not only to the polyuridine tract, GU8, but also to the downstream 3' splice-site sequence, CUAGUG, with similar affinities. In contrast, a nonspecific sequence, C8, did not bind to Sxl RBD2. This result is consistent with previous in vitro RNA-selection and UV-cross-linking results which indicated that the Sex-lethal protein binds to the uridine stretch and the AG dinucleotide in the consensus sequence, AUnNnAGU. In both cases, the chemical shift perturbations were significant for almost the same amino acid residues, including the two central beta-strands formed by the RNP2-motif and RNP1-motif with the two highly conserved aromatic residues (Y214 and F256) in the middle. As the first RNA-binding domain of Sex-lethal (Sxl RBD1) has a characteristic aliphatic residue at one of the two corresponding positions (I128 and F170), Y214 of Sxl RBD2 was replaced by Ile using site-directed mutagenesis. On the one hand, the 1H and 15N chemical-shift perturbations indicated that GU8 binds to the same interface of mutant Sxl RBD2 as of wild-type Sxl RBD2, although its binding affinity was decreased significantly. On the other hand, the specific binding of Sxl RBD2 to CUAGUG was abolished almost completely by the Y-->I mutation. Taken together, the present results indicate that the interface residues that bind with GU8 and CUAGUG are much the same, but the role of the Y214 residue is clearly different between these two target sequences. PMID- 10102993 TI - Examining the efficiency of receptor/G-protein coupling with a cleavable beta2 adrenoceptor-gsalpha fusion protein. AB - Reconstitution of high-affinity agonist binding at the beta2-adrenoceptor (beta2AR) expressed in Sf9 insect cells requires a large excess of the stimulatory G-protein of adenylyl cyclase, Gsalpha, relative to receptor [R. Seifert, T. W. Lee, V. T. Lam & B. K. Kobilka, (1998) Eur. J. Biochem. 255, 369 382]. In a fusion protein of the beta2AR and Gsalpha (beta2AR-Gsalpha), which has only a 1 : 1 stoichiometry of receptor and G-protein, high-affinity agonist binding and agonist-stimulated GTP hydrolysis, guanosine 5'-O-(3 thiotriphosphate) (GTP[S]) binding and adenylyl cyclase (AC) activation are more efficient than in the nonfused coexpression system. In order to analyze the stability of the receptor/G-protein interaction, we constructed a fusion protein with a thrombin-cleavage site between beta2AR and Gsalpha (beta2AR-TS-Gsalpha). beta2AR-TS-Gsalpha efficiently reconstituted high-affinity agonist binding, agonist-stimulated GTP hydrolysis, GTP[S] binding and AC activation. Thrombin cleaves approximately 70% of beta2AR-TS-Gsalpha molecules in Sf9 membranes. Thrombin cleavage did not impair high-affinity agonist binding and GTP[S] binding but strongly reduced ligand-regulated GTPase activity and AC activity. We conclude that fusion of the beta2AR to Gsalpha promotes tight physical association of the two partners and that this association remains stable for a single activation/deactivation cycle even after cleavage of the link between the receptor and G-protein. Dilution of Gsalpha in the membrane and release of activated Gsalpha into the cytosol can both prevent cleaved beta2AR-TS-Gsalpha from undergoing multiple activation/deactivation cycles. PMID- 10102994 TI - Low-temperature sensitivity and enhanced Bohr effect in red deer (Cervus elaphus) haemoglobin: a molecular adaptive strategy to life at high altitude and low temperature. AB - A study of the functional properties of haemoglobin from red deer (Cervus elaphus) whose habitat varies over a wide range of latitude, was performed. The oxygen-binding properties of the most common haemoglobin phenotype from the species living in Sardinia were examined with particular attention to the effect of pH, chloride, 2, 3-bisphosphoglycerate and temperature. Results indicate that red deer haemoglobin, like all haemoglobins from ruminants so far examined, is characterized by a low intrinsic oxygen affinity, with chloride being its main physiological modulator in vivo. The functional results and the low temperature sensitivity of the oxygen affinity are discussed in the light of the amino acid sequence of closely related ruminant haemoglobins. PMID- 10102995 TI - Differences in the ionic interaction of actin with the motor domains of nonmuscle and muscle myosin II. AB - Changes in the actin-myosin interface are thought to play an important role in microfilament-linked cellular movements. In this study, we compared the actin binding properties of the motor domain of Dictyostelium discoideum (M765) and rabbit skeletal muscle myosin subfragment-1 (S1). The Dictyostelium motor domain resembles S1(A2) (S1 carrying the A2 light chain) in its interaction with G actin. Similar to S1(A2), none of the Dictyostelium motor domain constructs induced G-actin polymerization. The affinity of monomeric actin (G-actin) was 20 fold lower for M765 than for S1(A2) but increasing the number of positive charges in the loop 2 region of the D. discoideum motor domain (residues 613-623) resulted in equivalent affinities of G-actin for M765 and for S1. Proteolytic cleavage and cross-linking approaches were used to show that M765, like S1, interacts via the loop 2 region with filamentous actin (F-actin). For both types of myosin, F-actin prevents trypsin cleavage in the loop 2 region and F-actin segment 1-28 can be cross-linked to loop 2 residues by a carbodiimide-induced reaction. In contrast with the S1, loop residues 559-565 of D. discoideum myosin was not cross-linked to F-actin, probably due to the lower number of positive charges. These results confirm the importance of the loop 2 region of myosin for the interaction with both G-actin and F-actin, regardless of the source of myosin. The differences observed in the way in which M765 and S1 interact with actin may be linked to more general differences in the structure of the actomyosin interface of muscle and nonmuscle myosins. PMID- 10102996 TI - Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of mitochondrial membranes, role of VDAC and ATP requirement. AB - Recent studies that attempt to explore the action of pro- and anti-apoptotic proteins of the bcl2 family demonstrate the crucial role of relocalization of cytochrome c from the mitochondrial intermembrane space to the cytosol. This early event of apoptosis can be mimicked in the yeast Saccharomyces cerevisiae following expression of bax. In mammalian mitochondria, the mechanism of relocalization is thought to involve the opening of the so-called permeability transition pore. We show in this paper: (a) that bax-induced release of cytochrome c in yeast does not involve any permeability transition of the inner mitochondrial membrane but involves a general alteration of the permeability of the outer mitochondrial membrane to macromolecules. This suggests that a permeability transition of the inner mitochondrial membrane is not an event required for the relocalization of cytochrome c in yeast. (b) The outer-membrane voltage-dependent anion channel (VDAC), a putative component of the permeability transition pore, is not involved in bax-induced release of cytochrome c or in the prevention of this release by bcl-xL. (c) Bax devoid of its C-terminal putative hydrophobic alpha-helix is as efficient as full-length bax to allow the relocalization of cytochrome c, demonstrating this segment of the protein is not required for membrane-targeting. (d) We finally observe that the action of bax on the outer mitochondrial membrane requires the presence of ATP both in vitro and in vivo, and it is shown that ATP directly increases the amount of bax inserted to mitochondria. PMID- 10102997 TI - Domain-domain interactions in high mobility group 1 protein (HMG1). AB - The high mobility group protein HMG1 is a conserved chromosomal protein with two homologous DNA-binding domains, A and B, and an acidic carboxy-terminal tail, C. The structure of isolated domains A and B has been previously determined by NMR, but the interactions of the different domains within the complete protein were unknown. By means of differential scanning calorimetry and circular dichroism we have investigated the thermal stability of HMG1, of the truncated protein A-B (HMG1 without the acidic tail C) and of the isolated domains A and B. In 3 mm sodium acetate buffer, pH 5, the thermal melting of domains A and B are identical (transition temperature tm = 43 degrees C and 41 degrees C, denaturation enthalpies DeltaH = 46 kcal.mol-1). The thermal melting of protein A-B presents two nearly identical transitions (tm = 40 degrees C and 41 degrees C, DeltaH = 44 kcal.mol-1 and 46 kcal.mol-1, respectively). We conclude that the two domains A and B within protein A-B behave as independent domains. The thermal melting of HMG1 is biphasic. The two transitions have a different value of tm (38 degrees C and 55 degrees C) and corresponding values of DeltaH around 40 kcal.mol-1. We conclude that within HMG1, the acidic tail C is interacting with one of the two domains A and B, however, the two domains A and B do not interact with each other. At 37 degrees C, one of the two domains A and B, within HMG1, is partly unfolded, whereas the other which interacts with the acidic tail C, is fully native. The interaction free energy of the acidic tail C is estimated to be in the range of 2.5 kcal.mol-1 based on simulations of the thermograms of HMG1 as a function of the interaction free energy. PMID- 10102998 TI - Molecular cloning, expression and characterization of a monkey steroid UDP glucuronosyltransferase, UGT2B19, that conjugates testosterone. AB - Although enzymatic processes involved in the formation of active steroids are well known, less information is available about the enzymes responsible for the metabolism of these hormones. Moreover, the expression of these catabolic enzymes, which include UDP-glucuronosyltransferases, may play a role in the regulation of the level and action of steroid hormones in steroid target tissues. Previous studies have shown that the cynomolgus monkey contains high levels of circulating androgen glucuronides, indicating that it represents the best animal model to study the glucuronidation of steroids in extrahepatic tissues. Two cDNA libraries were constructed from monkey liver and prostate mRNA, and a novel UDP glucuronosyltransferase UGT2B cDNA, UGT2B19, was isolated from both libraries. The UGT2B19 cDNA is 2108 bp in length and contains an open reading frame of 1584 bp encoding a protein of 528 residues. The UGT2B19 cDNA clone was transfected into HK293 cells and a stable cell line expressing UGT2B19 protein was established. The activity of UGT2B19 on 3alpha-hydroxy and 17beta-hydroxy positions of steroids was demonstrated. The enzyme also conjugates xenobiotics including eugenol, 1-naphthol and p-nitrophenol. Kinetic analysis revealed that UGT2B19 glucuronidates steroids with Km values of 1.6, 2.6 and 4.3 microm for testosterone, etiocholanolone and 5beta-androstane-3alpha,17beta-diol, respectively. UGT2B19 transcript was detected, by specific reverse transcriptase PCR analysis in the liver, ovary, prostate, colon, spleen, kidney, pancreas, brain, cerebellum, mammary gland and epididymis. The molecular characterization of simian UGT2B19 demonstrates relevance of using monkey as an animal model to study and understand steroid glucuronidation in extrahepatic target tissue. PMID- 10102999 TI - The active site of purple acid phosphatase from sweet potatoes (Ipomoea batatas) metal content and spectroscopic characterization. AB - Purple acid phosphatase from sweet potatoes Ipomoea batatas (spPAP) has been purified to homogeneity and characterized using spectroscopic investigations. Matrix-assisted laser desorption/ionization mass spectrometry analysis revealed a molecular mass of approximately 112 kDa. The metal content was determined by X ray fluorescence using synchrotron radiation. In contrast to previous studies it is shown that spPAP contains a Fe(III)-Zn(II) center in the active site as previously determined for the purple acid phosphatase from red kidney bean (kbPAP). Moreover, an alignment of the amino acid sequences suggests that the residues involved in metal-binding are identical in both plant PAPs. Tyrosine functions as one of the ligands for the chromophoric Fe(III). Low temperature EPR spectra of spPAP show a signal near g = 4.3, characteristic for high-spin Fe(III) in a rhombic environment. The Tyr-Fe(III) charge transfer transition and the EPR signal are both very sensitive to changes in pH. The pH dependency strongly suggests the presence of an ionizable group with a pKa of 4.7, arising from an aquo ligand coordinated to Fe(III). EPR and UV/visible studies of spPAP in the presence of the inhibitors phosphate or arsenate suggest that both anions bind to Fe(III) in the binuclear center replacing the coordinated water or hydroxide ligand necessary for hydrolysis. The conserved histidine residues of spPAP corresponding to His202 and His296 in kbPAP probably interact in catalysis. PMID- 10103000 TI - Functional differentiation in trematode hemoglobin isoforms. AB - The Hbs and the major electrophoretic Hb components (isoHbs) were isolated from three species of the trematodes, Explanatum explanatum (Ee), Gastrothylax crumenifer (Gc) and Paramphistomum epiclitum (Pe), that parasitise the common Indian water buffalo Bubalus bubalis. The Hbs are monomeric and resemble the so called nonfunctional mutant hemoglobins that have Tyr at B10 or E7 positions (replacing Leu and the His residues, respectively). However, they are capable of binding with O2 and CO. O2 equilibrium studies of trematode Hb isoforms reveal extremely high O2 affinities, with half-saturation O2 tension (P50) values up to 800 times lower than those of human hemoglobins. This correlates with Tyr residues at B10 and at the distal position (E7) that decrease the O2 dissociation rate by contributing hydrogen bonds (H-bonds) to the bound O2. These substitutions also increase the O2 association rates either due to orientation of E7-Tyr towards the solvent and/or by sterically hindering the entry of water molecules into the heme pocket. The latter may account for the low rate of autoxidation of trematode Hbs. The Hbs and their isoforms from different species exhibited pronounced variation in O2 affinity, which may relate to subtle differences in the structure of the heme pocket. The O2 affinities of the composite (unfractionated) Hbs were intermediate to those of the individual Hb isoform. The P50 values of Hbs here obtained by direct O2 equilibrium measurements differed from those calculated from kinetic data already published [Kiger, L., Rashid, A. K., Griffon, N., Haque, M., Moens, L.,Gibson, Q. H., Poyart, C., & Marden, M. C. (1998). Biophys. J. 75, 990-998.] Intermediate state(s) due to slow reorientation of E7-Tyr may account for this difference. Some Hb isoforms showed slight (either normal or reverse) Bohr effects. The hyperbolic O2 equilibrium curve, Hill coefficient (n) values near unity accord with a monomeric nature of trematode Hbs. In marked contrast to vertebrate Hbs, CO does not seem to compete effectively with O2 in trematode Hbs, as evident from partition coefficient values (M) below 1. PMID- 10103001 TI - Hydroxyl-radical production in physiological reactions. A novel function of peroxidase. AB - Peroxidases catalyze the dehydrogenation by hydrogen peroxide (H2O2) of various phenolic and endiolic substrates in a peroxidatic reaction cycle. In addition, these enzymes exhibit an oxidase activity mediating the reduction of O2 to superoxide (O2.-) and H2O2 by substrates such as NADH or dihydroxyfumarate. Here we show that horseradish peroxidase can also catalyze a third type of reaction that results in the production of hydroxyl radicals (.OH) from H2O2 in the presence of O2.-. We provide evidence that to mediate this reaction, the ferric form of horseradish peroxidase must be converted by O2.- into the perferryl form (Compound III), in which the haem iron can assume the ferrous state. It is concluded that the ferric/perferryl peroxidase couple constitutes an effective biochemical catalyst for the production of .OH from O2.- and H2O2 (iron-catalyzed Haber-Weiss reaction). This reaction can be measured either by the hydroxylation of benzoate or the degradation of deoxyribose. O2.- and H2O2 can be produced by the oxidase reaction of horseradish peroxidase in the presence of NADH. The .OH producing activity of horseradish peroxidase can be inhibited by inactivators of haem iron or by various O2.- and .OH scavengers. On an equimolar Fe basis, horseradish peroxidase is 1-2 orders of magnitude more active than Fe-EDTA, an inorganic catalyst of the Haber-Weiss reaction. Particularly high .OH-producing activity was found in the alkaline horseradish peroxidase isoforms and in a ligninase-type fungal peroxidase, whereas lactoperoxidase and soybean peroxidase were less active, and myeloperoxidase was inactive. Operating in the .OH producing mode, peroxidases may be responsible for numerous destructive and toxic effects of activated oxygen reported previously. PMID- 10103002 TI - A 42-kDa glycoprotein from chicken egg-envelope, an avian homolog of the ZPC family glycoproteins in mammalian Zona pellucida. Its first identification, cDNA cloning and granulosa cell-specific expression. AB - A glycoprotein with molecular mass of 42 kDa was identified as the major component of the chicken egg-envelope, the filamentous, extracellular matrix known as the perivitelline layer. By using a DNA probe amplified with degenerative primers derived from the protein's partial amino acid sequences, a cDNA clone encoding the egg-envelope 42-kDa glycoprotein (gp42) was isolated from a hen's ovary cDNA library. The gp42 open reading frame encoded 435 amino acid residues, including a putative signal peptide of 20 amino acids. The deduced amino acid sequence of gp42 showed significant similarity to egg-envelope glycoproteins of the ZPC family of several other vertebrate species, including human ZP3, mouse ZP3, Xenopus laevis gp43 and medaka (Oryzias latipes) ZI3 (LS F), which play important roles for sperm-egg interaction. A single N glycosylation site present in chicken gp42 is conserved among all five of these proteins: carbohydrate analysis of gp42 revealed the presence of a complex type glycan chain at this site. N-terminal sequence analysis of the mature polypeptide suggests that C-terminal processing of the pro-protein occurs during synthesis and secretion. The 1.4-kb gp42 transcript was detected only in follicles, and was found to be accumulated in granulosa cells in a manner dependent on ovarian follicular development. Furthermore, a metabolically radio-labeled gp42 was immunopreciptated from both cell lysate and culture supernatant of the granulosa cells with specific anti-gp42 antibody, suggesting granulosa cell-specific synthesis and secretion of the glycoprotein. PMID- 10103003 TI - FIRE3 in the promoter of the rat fatty acid synthase (FAS) gene binds the ubiquitous transcription factors CBF and USF but does not mediate an insulin response in a rat hepatoma cell line. AB - Several putative insulin-responsive elements (IRE) in the fatty acid synthase (FAS) promoter have been identified and shown to be functional in adipocytes and hepatocytes. Here we report on the insulin-responsiveness in the rat hepatoma cell line H4IIE of four cis-elements in the FAS promoter: the FAS insulin responsive elements, FIRE2 and FIRE3; the inverted CCAAT element, ICE; and the insulin/glucose-binding element, designated hepatic FIRE element, hFIRE, originally identified in rat hepatocytes. Using electrophoretic mobility shift assay (EMSA) competition experiments together with supershifts and in vitro transcription/translation we show that FIRE3 (-68/-58) binds not only the upstream stimulatory factors USF-1/USF-2 but also the CCAAT-binding factor CBF, also known as the nuclear factor Y, NF-Y. The putative IRE FIRE2, which shows sequence similarity to FIRE3, is located between -267 and -249. Gel retardation experiments indicate that USF-1 and USF-2 also bind to this element, which contains an imperfect E-box motif. Using the same approach we have shown that hFIRE binds the stimulatory proteins Sp1 and Sp3 in addition to CBF. Transient transfection experiments using FAS promoter constructs deleted for FIRE2 and FIRE3 demonstrate that neither of these elements mediates the insulin response of the FAS promoter in the rat hepatoma cell line H4IIE, however, ICE at -103/-87 is responsible for mediating the effect of the insulin antagonist cAMP. The hFIRE element located at -57/-34, in spite of its role in the glucose/insulin response in primary rat hepatocytes, is apparently not involved in the insulin regulation of the rat FAS promoter in H4IIE cells. The fact that the topology of the promoters of the FAS genes in rat, human, goose and chicken is conserved regarding CBF-binding sites and USF-binding sites implies an important role for these ubiquitously expressed transcription factors in the regulation of the FAS promoter. PMID- 10103004 TI - Properties of a subtilisin-like proteinase from a psychrotrophic Vibrio species comparison with proteinase K and aqualysin I. AB - An extracellular serine proteinase purified from cultures of a psychrotrophic Vibrio species (strain PA-44) belongs to the proteinase K family of the superfamily of subtilisin-like proteinases. The enzyme is secreted as a 47-kDa protein, but under mild heat treatment (30 min at 40 degrees C) undergoes autoproteolytic cleavage on the carboxyl-side of the molecule to give a proteinase with a molecular mass of about 36 kDa that apparently shares most of the enzymatic characteristics and the stability of the 47-kDa protein. In this study, selected enzymatic properties of the Vibrio proteinase were compared with those of the related proteinases, proteinase K and aqualysin I, as representative mesophilic and thermophilic enzymes, respectively. The catalytic efficiency (kcat/Km) for the amidase activity of the cold-adapted enzyme against succinyl AAPF-p-nitroanilide was significantly higher than that of its mesophilic and thermophilic counterparts, especially when compared with aqualysin I. The stability of the Vibrio proteinase, both towards heat and denaturants, was found to be significantly lower than of either proteinase K or aqualysin I. One or more disulfide bonds in the psychrotrophic proteinase are important for the integrity of the active enzyme structure, as disulfide cleavage, either by reduction with dithiothreitol or by sulfitolysis, led to a loss in its activity. Under the same conditions, aqualysin I was also partially inactivated by dithiothreitol, but the activity of proteinase K was unaffected. The disulfides of either proteinase K or aqualysin I were not reactive towards sulfitolysis, except under denaturing conditions, while all disulfides of the Vibrio proteinase reacted in absence of a denaturant. The reactivity of the disulfides of the proteins as a function of denaturant concentration followed the order: Vibrio proteinase > proteinase K > aqualysin I. The same order of reactivity was also observed for the inactivation of the enzymes by H2O2-oxidation, as a function of temperature. The order of reactivity observed in these reactions most likely reflects the accessibility of the reactive cystine or methionine side chains present in the three related proteinases, and hence a difference in the compactness of their protein structures. PMID- 10103005 TI - Molecular cloning, structural characterization and chromosomal localization of human lipoyltransferase gene. AB - Lipoyltransferase catalyzes the transfer of the lipoyl group from lipoyl-AMP to the lysine residue of the lipoate-dependent enzymes. We isolated human lipoyltransferase cDNA and genomic DNA. The cDNA insert contained a 1119-base pair open reading frame encoding a precursor peptide of 373 amino acids. Predicted amino acid sequence of the protein shares 88 and 31% identity with bovine lipoyltransferase and Escherichia coli lipoate-protein ligase A, respectively. Northern blot analyses of poly(A)+ RNA indicated a major species of about 1.5 kb. mRNA levels of lipoyltransferase were highest in skeletal muscle and heart, showing good correlation with those of dihydrolipoamide acyltransferase subunits of pyruvate, 2-oxoglutarate and branched-chain 2-oxo acid dehydrogenase complexes and H-protein of the glycine cleavage system which accept lipoic acid as a prosthetic group. The human lipoyltransferase gene is a single copy gene composed of four exons and three introns spanning approximately 8 kb of genomic DNA. Some alternatively spliced mRNA species were found by 5' RACE analysis, and the most abundant species lacks the third exon. The human lipoyltransferase gene was localized to chromosome band 2q11.2 by fluorescence in situ hybridization. PMID- 10103006 TI - Enzymatic properties of vesicle-reconstituted human cytochrome P450SCC (CYP11A1) differences in functioning of the mitochondrial electron-transfer chain using human and bovine adrenodoxin and activation by cardiolipin. AB - The recently reported heterologous expression and purification of both human cytochrome P450SCC and adrenodoxin [Woods, S.T., Sadleir, J., Downs, T., Triantopoulos, T., Haedlam, M.J. & Tuckey, R.C. (1998) Arch. Biochem. Biophys. 353, 109-115] has enabled us to perform studies with the membrane-reconstituted human enzymes to better understand the side-chain cleavage reaction in humans. Human P450SCC was successfully reconstituted into dioleoylphosphatidylcholine vesicles with and without cardiolipin and its enzymatic properties characterized in the membrane-bound state. Enhancement of the P450SCC activity and significant activation by cardiolipin were observed when human adrenodoxin instead of bovine adrenodoxin was used as electron donor. In the absence of cardiolipin, Km for cholesterol was decreased twice in the case of human adrenodoxin indicating enhanced cholesterol binding. On the other hand, in the presence of cardiolipin in the membrane both Km and V for cholesterol were decreased with human adrenodoxin as electron donor. Kinetic analysis of the interaction between human P450SCC and its redox partners provided evidence for enhanced binding of the human electron donor to human P450SCC indicated by both an increased V and decreased Kd for human adrenodoxin compared with the values with bovine adrenodoxin. Because no similar effects were observed in Tween 20 micelles, these results suggest that the phospholipid membrane may play an important role in the interaction of human adrenodoxin with human P450SCC. PMID- 10103007 TI - Selection-dominant and nonaccessible epitopes on cell-surface receptors revealed by cell-panning with a large phage antibody library. AB - To generate antibodies to defined cell-surface antigens, we used a large phage antibody fragment library to select on cell transfectants expressing one of three chosen receptors. First, in vitro panning procedures and phage antibody screening ELISAs were developed using whole live cells stably expressing the antigen of interest. When these methodologies were applied to Chinese hamster ovary (CHO) cells expressing one of the receptors for a neuropeptide, somatostatin, using either direct cell panning or a strategy of depletion or ligand-directed elution, many different pan-CHO-cell binders were selected, but none was receptor specific. However, when using direct panning on CHO-cells expressing the human membrane protein CD36, an extraordinary high frequency of antigen-specific phage antibodies was found. Panning on myoblasts expressing the rat homologue of CD36 revealed a similar selection dominance for anti-(CD36). Binding of all selected 20 different anti-(CD36) phage was surprisingly inhibited by one anti-(CD36) mAb CLB-IVC7, which recognizes a functional epitope that is also immunodominant in vivo. Similar inhibition was found for seven anti-(rat) CD36 that cross-reacted with human CD36. Our results show that, although cells can be used as antigen carriers to select and screen phage antibodies, the nature of the antigen target has a profound effect on the outcome of the selection. PMID- 10103008 TI - Phosphorylation of components of the ER translocation site. AB - In many eukaryotic cells, protein secretion is regulated by extracellular signalling molecules giving rise to increased intracellular Ca2+ and activation of kinases and phosphatases. To test whether components involved in the first step of secretion, the translocation of proteins across the endoplasmic reticulum (ER) membrane, are regulated by Ca2+-dependent phosphorylation and dephosphorylation, we have investigated the effect of Ca2+ on kinases associated with the rough ER. Using purified rough microsomes from dog pancreas we found that Ca2+-dependent isoforms of protein kinase C (PKC) are associated with the rough ER and phosphorylate essential components of the protein translocation machinery. Phosphorylation of microsomal proteins by PKCs increased protein translocation efficiency in vitro. We also found that proteins of the translocation machinery became phosphorylated in intact cells. This suggests a further level of regulation of protein translocation across the ER membrane. PMID- 10103009 TI - Half-of-the-sites reactivity of outer-membrane phospholipase A against an active site-directed inhibitor. AB - The reaction of a novel active-site-directed phospholipase A1 inhibitor with the outer-membrane phospholipase A (OMPLA) was investigated. The inhibitor 1-p nitrophenyl-octylphosphonate-2-tridecylcarbamoyl-3-et hanesulfonyl -amino-3-deoxy sn-glycerol irreversibly inactivated OMPLA. The inhibition reaction did not require the cofactor calcium or an unprotonated active-site His142. The inhibition of the enzyme solubilized in hexadecylphosphocholine micelles was characterized by a rapid (t1/2 = 20 min) and complete loss of enzymatic activity, concurrent with the covalent modification of 50% of the active-site serines, as judged from the amount of p-nitrophenolate (PNP) released. Modification of the remaining 50% occurred at a much lower rate, indicative of half-of-the-sites reactivity against the inhibitor of this dimeric enzyme. Inhibition of monomeric OMPLA solubilized in hexadecyl-N,N-dimethyl-1-ammonio-3-propanesulfonate resulted in an equimolar monophasic release of PNP, concurrent with the loss of enzymatic activity (t1/2 = 14 min). The half-of-the-sites reactivity is discussed in view of the dimeric nature of this enzyme. PMID- 10103010 TI - Effect of cations on purine.purine.pyrimidine triple helix formation in mixed valence salt solutions. AB - The effect of various monovalent, divalent and oligovalent cations on the reaction of triplex formation by GT and AG motif triplex-forming oligonucleotides, designed to bind to biologically relevant polypurine polypyrimidine sequences occurring in the promoters of the murine Ki-ras and human bcr genes, has been investigated by means of electrophoresis mobility shift assays (EMSA) and DNase I footprinting experiments. We found that in the presence of 10 mm MgCl2 the triple helices were progressively destabilized by adding increasing amounts of NaCl, from 20 to 140 mm, to the solution. We also observed that, while the total monovalent-ion concentration was constant at 100 mm, the exchange of sodium with potassium, but not lithium, results in a further destabilization of the triple helices, due to self-association equilibria involving the G-rich triplex-forming oligonucleotides. Potassium was found to destabilize triplex DNA even when the triple helices are preformed in the absence of K+. However, footprinting experiments also showed that the inhibitory effect of K+ on triplex DNA is partially compensated for by millimolar amounts of divalent transition metal ions such as Mn2+ and Ni2+, which upon coordinating to N7 of guanine are expected to enhance hydrogen-bond formation between the target and the third strand, and to reduce the assembly in quadruple structures of G rich triplex-forming oligonucleotides. Triplex enhancement in the presence of potassium was also observed, but to a lesser extent, when spermine was added to the reaction mixture. Here, the ion effect on triplex DNA is rationalized in terms of competition among the different valence cations to bind to triplex DNA, and differential cation stabilization of unusual quadruplex structures formed by the triplex-forming oligonucleotides. PMID- 10103011 TI - Solution structure of a conformationally constrained Arg-Gly-Asp-like motif inserted into the alpha/beta scaffold of leiurotoxin I. AB - A monoclonal antibody, AC7, directed against the RGD-binding site of the GPIIIa subunit of the platelet fibrinogen receptor, interacts with activated platelet. The H3 region (H3, RQMIRGYFDV sequence) of the complementarity-determining region 3 heavy chain of AC7 inhibits platelet aggregation and fibrinogen binding to platelet. H3 contains the arginine, glycine and aspartate residues, but in an unusual order. The solution structure of the decapeptide has been studied by proton NMR. The NMR data suggested a helical equilibrium. To test whether the helical structure of H3 was biologically relevant, a conformationally constrained peptide with the RGD-like motif was designed. The sequence of a scorpion toxin (leiurotoxin I) has been modified in order to constrain the H3 sequence in a rigid helical conformation. The structure of leiurotoxin I consists of a beta sheet and an alpha-helix, linked by three disulfide bridges. The structural feature of the chimeric peptide (H3-leiurotoxin) has been determined by standard two-dimensional NMR techniques. H3-Leiurotoxin structure closely resembles that of leiurotoxin I. PMID- 10103012 TI - Identification of positively charged residues of FomA porin of Fusobacterium nucleatum which are important for pore function. AB - FomA porin is the major outer-membrane protein of Fusobacterium nucleatum. It exhibits the functional properties of a general diffusion porin, but has no sequence similarity to other porins. According to the proposed topology model, each monomer of this trimeric protein is a beta-barrel consisting of 16 transmembrane segments with eight surface-exposed loops. Several conserved charged residues are proposed to extend from the beta-barrel wall into the aqueous channel lumen, and may contribute to a transverse electric field similar to that at the pore constriction of porins with known structure. The goal of our study was to identify particular basic residues contributing to such an electric field in FomA. Several arginines and lysines were replaced by negatively charged glutamates or uncharged alanines. The mutated FomA porins were expressed in Escherichia coli, and the effects on pore function were studied in vivo, by assaying the uptake rate of beta-lactam antibiotics, and in vitro after reconstitution of the purified proteins in lipid bilayer membranes. Some of the point mutations had a significant impact on the channel properties. The substitution R92A produced a 130% increased permeability of the zwitterionic beta lactam cephaloridine, and the cation selectivity of R92E increased by 70%. The effects of the R90E substitution on channel properties were similar. Most of the point mutations had a minor effect on the voltage gating of the FomA channel, resulting in an increased sensitivity, except for K78E, which showed a decreased sensitivity. The latter mutation had no effect on cation selectivity, but the K78A substitution improved the uptake rate of cephaloridine. The results presented here indicate that arginines 90 and 92 are probably part of the constriction zone of the FomA porin, and lysine 78 and arginines 115 and 117 are probably in close proximity to this region as well. PMID- 10103013 TI - Expression of receptors for human angiogenin in vascular smooth muscle cells. AB - Human angiogenin is a plasma protein with angiogenic and ribonucleolytic activities. Angiogenin inhibited both DNA replication and proliferation of aortic smooth muscle cells. Binding of 125I-angiogenin to bovine aortic smooth muscle cells at 4 degrees C was specific, saturable, reversible and involved two families of interactions. High-affinity binding sites with an apparent dissociation constant of 0.2 nm bound 1 x 104 molecules per cell grown at a density of 3 x 104.cm-2. Low-affinity binding sites with an apparent dissociation constant of 0.1 micrometer bound 4 x 106 molecules.cell-1. High-affinity binding sites decreased as cell density increased and were not detected at confluence. 125I-angiogenin bound specifically to cells routinely grown in serum-free conditions, indicating that the angiogenin-binding components were cell-derived. Affinity labelling of sparse bovine smooth muscle cells yielded seven major specific complexes of 45, 52, 70, 87, 98, 210 and 250-260 kDa. The same pattern was obtained with human cells. Potential modulators of angiogenesis such as protamine, heparin and the placental ribonuclease inhibitor competed for angiogenin binding to the cells. Together these data suggest that cultured bovine and human aortic smooth muscle cells express specific receptors for human angiogenin. PMID- 10103014 TI - Construction and characterization of a functional mutant of Synechocystis 6803 harbouring a eukaryotic PSII-H subunit. AB - A Synechocystis 6803 mutant carrying a chimaeric photosystem II (PSII), in which the Zea mays PsbH subunit (7.7 kDa calculated molecular mass) replaces the cyanobacterial copy (7.0 kDa), was constructed. With the exception of the N terminal 12 amino acid extension, which has a phosphorylatable threonine, the eukaryotic polypeptide is 78% homologous to its bacterial counterpart. Biochemical characterization of this mutant shows that it expresses the engineered gene correctly and is competent for photoautotrophic growth. Fluorescence analysis and oxygen evolution measurements in the presence of exogenous acceptors indicate that the observed phenotype results from a chimaeric PSII rather than from the absence of function associated with PsbH, suggesting that the heterologous protein is assembled into a functional PSII. Inhibition of oxygen evolution by herbicides belonging to different classes shows that the sensitivity of the mutant PSII is changed only towards phenolic compounds. This result indicates slight conformational modification of the QB/herbicide binding pocket of the D1 polypeptide caused by the bulky PsbH protein in the mutant, and also suggests close structural interaction of the D1 and PsbH subunits in the topological arrangement of PSII. PMID- 10103015 TI - Inhibition of the hydrolytic and transpeptidase activities of rat kidney gamma glutamyl transpeptidase by specific monoclonal antibodies. AB - Monoclonal antibodies (mAb) against the native form of rat kidney gamma-glutamyl transpeptidase (GGT) were isolated by screening hybridomas with rat kidney brush border membrane vesicles. They were directed against protein rather than sugar epitopes in that each recognized all GGT isoforms. All of them inhibited partially the enzyme activity of GGT. They were specific in that they inhibited the rat enzyme, but not the mouse or human enzyme. Kinetic analyses were carried out with free GGT and GGT-mAb complexes with d-gamma-glutamyl-p-nitroanilide in the presence or absence of maleate, or in the presence or absence of alanine, cysteine, cystine or glycylglycine as gamma-glutamyl acceptors. mAbs 2A10 and 2E9 inhibited the hydrolytic and glutaminase activities of GGT and had little effect on the transpeptidation activity of the enzyme, whereas mAbs 4D7 and 5F10 inhibited transpeptidation, but not hydrolytic or glutaminase activities. mAb 5F10 mimicked the effect of maleate on GGT, in that it inhibited transpeptidation, enhanced the glutaminase activity and increased the affinity of the donor site of GGT for acivicin. Such mAbs may be useful for long-term studies in tissue cultures and in vivo, and for the identification of GGT epitopes that are important for the hydrolytic and transpeptidase activities. PMID- 10103016 TI - Oligonucleotide aggregates bind to the macrophage scavenger receptor. AB - We have prepared a model receptor containing a Lys cluster (320-340) in the collagen-like domain of the bovine macrophage scavenger receptor, and have shown that it has a similar binding specificity to the native scavenger receptor. The native scavenger receptor is reported to bind the quadruplex structure of nucleotides. In this study, we analyzed the model receptor binding of nucleotides with various structures, random, parallel or antiparallel quadruplex and aggregate forms. This was carried out by direct binding assays using labeled oligonucleotides or surface plasmon resonance, and by an inhibition assay using Chinese hamster ovary (CHO) cells expressing the scavenger receptor. The results showed that the nucleotides forming the quadruplex structure did not exhibit any binding. Only the aggregate forms of the nucleotide could bind to the model receptor. They also inhibited the degradation of acetylated low density lipoprotein by CHO cells expressing the native scavenger receptor, whereas nucleotides that did not bind to the model receptor had no effect on cellular acetylated low density lipoprotein degradation. Our results suggest that the quadruplex structure is not essential but may be required for the formation of the nucleotide aggregates, which can interact with the scavenger receptor. PMID- 10103017 TI - Production in Escherichia coli and site-directed mutagenesis of a 9-kDa nonspecific lipid transfer protein from wheat. AB - The sequence encoding a wheat (Triticum durum) nonspecific lipid transfer protein of 9 kDa (nsLTP1) was inserted into an Escherichia coli expression vector, pET3b. The recombinant protein that was expressed accumulated in insoluble cytoplasmic inclusion bodies and was purified and refolded from them. In comparison with the corresponding protein isolated from wheat kernel, the refolded recombinant protein exhibits a methionine extension at its N-terminus but has the same structure and activity as demonstrated by CD, lipid binding and lipid transfer assays. Using the same expression system, four mutants with H5Q, Y16A, Q45R and Y79A replacements were produced and characterized. No significant changes in structure or activity were found for three of the mutants. By contrast, lipid binding experiments with the Y79A mutant did not show any increase of tyrosine fluorescence as observed with the wild-type nsLTP1. Comparison of the two tyrosine mutants suggested that Tyr79 is the residue involved in this phenomenon and thus is located close to the lipid binding site as expected from three dimensional structure data. PMID- 10103018 TI - Molecular cloning of human chondromodulin-I, a cartilage-derived growth modulating factor, and its expression in Chinese hamster ovary cells. AB - Bovine chondromodulin-I (ChM-I) purified from fetal cartilage stimulated the matrix synthesis of chondrocytes, and inhibited the growth of vascular endothelial cells in vitro. The human counterpart of this bovine growth regulating factor has not been identified. We report here the cloning of human ChM-I precursor cDNA and its functional expression in Chinese hamster ovary (CHO) cells. We first identified a genomic DNA fragment which encoded the N-terminus of the ChM-I precursor, and then isolated human ChM-I cDNA from chondrosarcoma tissue by PCR. The deduced amino acid sequence revealed that mature human ChM-I consists of 120 amino acids. In total, 16 amino acid residues were substituted in the human sequence, compared to the bovine counterpart. Almost of all the substitutions were found in the N-terminal hydrophilic domain. In the C-terminal hydrophobic domain (from Phe42 to Val120), the amino acid sequence was identical except for Tyr90, indicating a functional significance of the domain. Northern blotting and in situ hybridization indicated a specific expression of ChM-I mRNA in cartilage. We also successfully determined the cartilage-specific localization of ChM-I protein, using a specific antibody against recombinant human ChM-I. Multiple transfection of the precursor cDNA into CHO cells enabled us to isolate the mature form of human ChM-I from the culture supernatant. Purified recombinant human ChM-I stimulated proteoglycan synthesis in cultured chondrocytes. In contrast, it inhibited the tube morphogenesis of cultured vascular endothelial cells in vitro and angiogenesis in chick chorioallantoic membrane in vivo. PMID- 10103019 TI - Initiation of galactosaminoglycan biosynthesis. Separate galactosylation and dephosphorylation pathways for phosphoxylosylated decorin protein and exogenous xyloside. AB - By using various radiolabelled precursors, glycosylation and phosphorylation of decorin in a rat fibroblast cell line was investigated in the presence of increasing concentrations of p-nitrophenyl-O-beta-d-xylopyranoside. Decorin core protein glycanation was suppressed to approximately 25% of the normal level in the presence of 2 mm and 3 mm xyloside. Glycans/saccharides were released from the core protein and size-separated by gel chromatography. The intracellular decorin obtained from cells treated with 2 mm xyloside was substituted with Xyl and also with Gal-Xyl and Gal-Gal-Xyl, but not with longer saccharides. Only the trisaccharide contained an almost fully phosphorylated Xyl. We conclude that galactosylation of endogenous, xylosylated decorin and exogenous xyloside probably follow separate pathways or that xylosides and early decorin glycoforms are kept separated. At the addition of the first glucuronic acid the two pathways seem to merge and dephosphorylation of decorin takes place. Xyloside-primed and secreted galactosaminoglycan chains produced simultanously retained phosphorylated Xyl. Inadequate dephosphorylation could be due to excess substrate or to a short transit.time. As shown previously [Moses, J., Oldberg, A., Eklund, E. & Fransson, L.-A. (1997) Eur. J. Biochem. 248, 767-774], brefeldin A-arrested decorin is substituted with the linkage-region extended with an undersulphated and incomplete galactosaminoglycan chain. In cells treated with this drug, xylosides were unable to prime galactosaminoglycan synthesis and unable to inhibit glycosylation and phosporylation of decorin. PMID- 10103020 TI - Formation of lipoxygenase-pathway-derived aldehydes in barley leaves upon methyl jasmonate treatment. AB - In barley leaves, the application of jasmonates leads to dramatic alterations of gene expression. Among the up-regulated gene products lipoxygenases occur abundantly. Here, at least four of them were identified as 13-lipoxygenases exhibiting acidic pH optima between pH 5.0 and 6.5. (13S,9Z,11E,15Z)-13-hydroxy 9,11,15-octadecatrienoic acid was found to be the main endogenous lipoxygenase derived polyenoic fatty acid derivative indicating 13-lipoxygenase activity in vivo. Moreover, upon methyl jasmonate treatment > 78% of the fatty acid hydroperoxides are metabolized by hydroperoxide lyase activity resulting in the endogenous occurrence of volatile aldehydes. (2E)-4-Hydroxy-2-hexenal, hexanal and (3Z)- plus (2E)-hexenal were identified as 2,4-dinitro-phenylhydrazones using HPLC and identification was confirmed by GC/MS analysis. This is the first proof that (2E)-4-hydroxy-2-hexenal is formed in plants under physiological conditions. Quantification of (2E)-4-hydroxy-2-hexenal, hexanal and hexenals upon methyl jasmonate treatment of barley leaf segments revealed that hexenals were the major aldehydes peaking at 24 h after methyl jasmonate treatment. Their endogenous content increased from 1.6 nmol.g-1 fresh weight to 45 nmol.g-1 fresh weight in methyl-jasmonate-treated leaf segments, whereas (2E)-4-hydroxy-2-hexenal, peaking at 48 h of methyl jasmonate treatment increased from 9 to 15 nmol.g-1 fresh weight. Similar to the hexenals, hexanal reached its maximal amount 24 h after methyl jasmonate treatment, but increased from 0.6 to 3.0 nmol.g-1 fresh weight. In addition to the classical leaf aldehydes, (2E)-4-hydroxy-2-hexenal was detected, thereby raising the question of whether it functions in the degradation of chloroplast membrane constituents, which takes place after methyl jasmonate treatment. PMID- 10103021 TI - Structural characterization of l-aspartate oxidase and identification of an interdomain loop by limited proteolysis. AB - l-Aspartate oxidase is the first enzyme in the de novo biosynthesis of pyridinic coenzymes in facultative aerobic organisms. The enzyme is FAD dependent and it shares common features with both the oxidase and the fumarate reductase classes of flavoproteins. In this report we focused our attention on the supersecondary structure of the molecule by means of limited proteolysis studies. Moreover the polymerization state of the protein at different pH and the interactions with NAD and its analogues are described. The results suggest that l-aspartate oxidase is a monomer at pH values lower than 4.5 and a dimer at pH values higher than 6.5. The protein is organized in two major domains connected by a flexible loop located in the 120-140 region. The data obtained by limited proteolysis of the holo and the apo form in the presence and in the absence of substrates (fumarate and menadione), inhibitors (succinate) and NAD allows the proposition that both domains are involved in the binding of the flavin coenzyme. Moreover the data reported in this manuscript suggest that NAD inhibits l-aspartate oxidase activity by competing with the flavin for the binding to the enzyme. PMID- 10103022 TI - Phosphorylation of the alpha-subunits of the Na+/K+-ATPase from mammalian kidneys and Xenopus oocytes by cGMP-dependent protein kinase results in stimulation of ATPase activity. AB - Phosphorylation of Na+/K+-ATPase by cGMP-dependent protein kinase (PKG) has been studied in enzymes purified from pig, dog, sheep and rat kidneys, and in Xenopus oocytes. PKG phosphorylates the alpha-subunits of all animal species investigated. Phosphorylation of the beta-subunit was not observed. The stoichiometry of phosphorylation estimated for pig, sheep and dog renal Na+/K+ ATPase is 3.5, 2.2 and 2.1 mol Pi per mol alpha-subunit, respectively. Proteolytic fingerprinting of the pig alpha1-subunits phosphorylated by PKG using specific antibodies raised against N-terminus or C-terminus reveals that phosphorylation sites are located within the intracellular loop of the alpha subunit between the 35 kDa N-terminal and 27 kDa C-terminal fragments. Phosphorylation sites within the alpha1-subunit of the purified Na+/K+-ATPase do not appear to be easily accessible for PKG since incorporation of Pi requires 0.2% of Triton X-100. Administration of cGMP and PKG in the presence of 5 mm ATP, which prevents inactivation of the Na+/K+-ATPase by detergent, leads to stimulation of hydrolytic activity by 61%. Administration of 50 microm of cGMP or dbcGMP in yolk-free homogenates of Xenopus oocytes leads to stimulation of ouabain-dependent ATPase activity by 130-198% and to incorporation of 33P into the alpha-subunit without the detergent. Hence, PKG plays regulatory role in active transmembraneous transport of Na+ and K+ via phosphorylation of the catalytic subunit of the Na+/K+-ATPase. PMID- 10103023 TI - Expression of 3beta-hydroxysteroid dehydrogenase type I and type VI isoforms in the mouse testis during development. AB - Six isoforms of the enzyme 3beta-hydroxysteroid dehydrogenase (3betaHSD) have been identified in the mouse, each the product of a distinct gene. Two of these isoforms (type I and type VI) are detectable in the adult testis but changes in their expression during development are unknown. In this study we have examined changes in testicular expression and localization of mRNA encoding the type I and type VI isoforms of 3betaHSD. Total 3betaHSD (type I plus type VI) mRNA was measured by reverse transcription-polymerase chain reaction and showed a peak of expression at day 5 after birth followed by a decline and then a further rise after day 10 that continued up to adulthood. When each isoform was measured individually it was clear that the type I isoform was expressed at all ages from embryonic day 13 to adulthood. In contrast, the type VI isoform was only expressed at significant levels during fetal life on embryonic day 13 and then not again until after day 10 postnatally. Expression of the type VI isoform mRNA increased markedly after day 10 so that by adulthood it was the predominant 3betaHSD isoform present in the testis. Closer examination of the timing of type VI expression showed that the isoform mRNA was first detectable at a significant level on day 11. In-situ hybridization confirmed that the type I isoform is the only one expressed in the fetal/neonatal animal and showed that expression was limited to the interstitial tissue. In the adult, both type I and type VI expression was within the interstitial tissue. The timing of 3betaHSD type VI mRNA expression suggests, strongly, that this isoform is expressed only by adult type Leydig cells in the mouse testis and that this development starts shortly before day 11. The limited expression of the type VI isoform means that it will be a useful marker in studies of adult Leydig cell development. PMID- 10103024 TI - Mitogen-activated protein kinase (p38-, JNK-, ERK-) activation pattern induced by extracellular and intracellular singlet oxygen and UVA. AB - Ultraviolet A (UVA; 320-400 nm) radiation in human skin fibroblasts induces a pattern of mitogen-activated protein kinase (MAPK) activation consisting of a rapid and transient induction of p38 and c-Jun-N-terminal kinase (JNK) activity but not extracellular signal-regulated kinases (ERK). UVA activation of p38 can be inhibited by the singlet oxygen (1O2) quenchers azide and imidazole, but not by the hydroxyl radical scavengers mannitol or dimethylsulfoxide, pointing to the involvement of 1O2. The same effect has been shown for JNK. Like UVA, 1O2 generated intracellularly upon photoexcitation of Rose Bengal activates p38 and JNK but not ERK. p38 and JNK activation was also elicited by chemiexcitation for the intracellular generation of 1O2 by the lipophilic 1,4-endoperoxide of N,N' di(2,3-dihydroxypropyl)-1, 4-naphthalene dipropionamide. In contrast, extracellular generation of 1O2, by irradiation of Rose Bengal immobilized on agarose beads or by chemiexcitation employing the hydrophilic 1,4-endoperoxide of disodium 3,3'-(1,4-naphthylidene) dipropionate, was ineffective in activating p38 or JNK. These data suggest that the activation of p38 and JNK by 1O2 occurs only when the electronically excited molecule is generated intracellularly. PMID- 10103025 TI - Tissue expression and amino acid sequence of murine UDP-N-acetylglucosamine-2 epimerase/N-acetylmannosamine kinase. AB - Neuraminic acids are widely expressed as terminal carbohydrates on glycoconjugates and are involved in a variety of biological functions. The key enzyme of N-acetylneuraminic acid synthesis is UDP-N-acetylglucosamine-2 epimerase/N-acetylmannosamine kinase, which catalyses the first two steps of neuraminic acid biosynthesis in the cytosol. In this study we report the complete amino acid sequence of the mouse UDP-N-acetylglucosamine-2-epimerase/N acetylmannosamine kinase. The ORF of 2166 bp encodes 722 amino acids and a protein with a predicted molecular mass of 79.2 kDa. Northern blot analysis and in situ hybridization revealed that UDP-N-acetylglucosamine-2-epimerase/N acetylmannosamine kinase is expressed at early stages during development and in all tissues investigated with a maximal expression in the liver. PMID- 10103026 TI - Cobalt proteins. AB - In the form of vitamin B12, cobalt plays a number of crucial roles in many biological functions. However, recent studies have provided information on the biochemistry and bioinorganic chemistry of several proteins containing cobalt in a form other than that in the corrin ring of vitamin B12. To date, eight noncorrin-cobalt-containing enzymes (methionine aminopeptidase, prolidase, nitrile hydratase, glucose isomerase, methylmalonyl-CoA carboxytransferase, aldehyde decarbonylase, lysine-2,3-aminomutase, and bromoperoxidase) have been isolated and characterized. A cobalt transporter is involved in the metallocenter biosynthesis of the host cobalt-containing enzyme, nitrile hydratase. Understanding the differences between cobalt and nickel transporters might lead to drug development for gastritis and peptic ulceration. PMID- 10103027 TI - Mixed reconstitution of mutated subunits of HIV-1 reverse transcriptase coexpressed in Escherichia coli - two tags tie it up. AB - The active form of HIV-1 reverse transcriptase (RT) is a p66/p51 heterodimer, in which the p51 subunit is generated by C-terminal proteolytic cleavage of p66. A well-known problem of p66 recombinant expression is partial cleavage of a 15-kDa peptide from the C-terminus by host proteases that can not be completely suppressed. In order to analyse the contribution of specific residues to a particular function in one distinct subunit, an expression and purification system is required that selects for the combination of the two individual subunits with the desired substitutions. We reconstituted the p66/p51 heterodimer from subunits coexpressed in Escherichia coli as an N-terminal fusion protein of glutathione S-transferase (GST) with p51 and a C-terminally His-tagged p66, respectively. The two-plasmid coexpression system ensures convenience for gene manipulation while degradation is reduced to a minimum, as dimerization protects the protein from further proteolysis. The combination of glutathione-agarose, phenyl-superose and Ni/nitrilotriacetate affinity chromatography allows rapid and selective purification of the desired subunit combination. Truncated forms of p51 are efficiently removed. Mobility-shift assay revealed that the preparations are free of p66 homodimer. In a successful test of the novel expression system, mixed reconstituted RTs with p51 selectively mutated in a putative nucleic acid binding motif (the so called helix clamp) show reduced binding of dsDNA in mobility-shift assays. This indicates the p51 subunit has an active role in DNA binding PMID- 10103028 TI - The structure of the carbohydrate backbone of the core-lipid A region of the lipopolysaccharide from a clinical isolate of Yersinia enterocolitica O:9. AB - Yersinia enterocolitica O:9 strain Ruokola/71-c-PhiR1-37-R possesses mainly rough type lipopolysaccaride (LPS) and smaller amounts of S-form LPS. Structural analysis of the former is reported here. After deacylation of the LPS, the phosphorylated carbohydrate backbone of the inner core-lipid A region could be isolated by using high-performance anion-exchange chromatography. Its structure was determined by means of compositional and methylation analyses and 1H-, 13C-, and 31P-NMR spectroscopy as: [see text] in which L-alpha-D-Hep is L-glycero-alpha D-manno-heptopyranose, D-alpha-D-Hep is D-glycero-alpha-D-manno-heptopyranose, and Kdo is 3-deoxy-D-manno-oct-2-ulopyranosonic acid. All hexoses are pyranoses. PMID- 10103029 TI - Bacillus subtilis chorismate mutase is partially diffusion-controlled. AB - The effect of viscosogens on the enzyme-catalyzed rearrangement of chorismate to prephenate has been studied. The steady-state parameters kcat and kcat/Km for the monofunctional chorismate mutase from Bacillus subtilis (BsCM) decreased significantly with increasing concentrations of glycerol, whereas the 'sluggish' BsCM mutants C75A and C75S were insensitive to changes in microviscosity. The latter results rule out extraneous interactions of the viscosogen as an explanation for the effects observed with the wild-type enzyme. Additional control experiments show that neither viscosogen-induced shifts in the pH dependence of the enzyme-catalyzed reaction nor small perturbations of the conformational equilibrium of chorismate can account for the observed effects. Instead, BsCM appears to be limited by substrate binding and product release at low and high substrate concentrations, respectively. Analysis of the kinetic data indicates that diffusive transition states are between 30 and 40% rate determining in these concentration regimes; the chemical step must contribute to the remaining kinetic barrier. The relatively low value of the 'on' rates for chorismate and prephenate (approximately 2 x 106 m-1.s-1) probably reflects the need for a rare conformation of the enzyme, the ligand, or both for successful binding. Interestingly, the chorismate mutase domain of the bifunctional chorismate mutase-prephenate dehydratase from Escherichia coli, which has steady state kinetic parameters comparable to those of BsCM but has a much less accessible active site, is insensitive to changes in viscosity and the reaction it catalyses is not diffusion-controlled. PMID- 10103030 TI - A unique primary structure, cDNA cloning and function of a galactose-specific lectin from ascidian plasma. AB - The complete amino acid sequence of a galactose-specific lectin from the plasma of the ascidian Halocynthia roretzi has been determined by sequential Edman degradation analysis of peptide fragments derived by proteolytic fragmentation and chemical cleavage of the reductive S-pyridylethylated lectin. Peptide fragments were separated by reverse-phase HPLC. The N-terminal and C-terminal amino acid sequences were determined by Edman degradation and enzymatic digestion. The H. roretzi plasma lectin is a single-chain protein consisting of 327 amino acids and four disulfide bonds, one of which was found to be cross linked intramolecularly. A comparison of the amino acid sequence of the H. roretzi plasma lectin with the sequences of other proteins reveals that the H. roretzi lectin has a structure consisting of a twice-repeated sequence, a fibrinogen-related sequence and a C-type lectin-homologous sequence. The above amino acid sequence was verified by cDNA cloning of this lectin. Three cDNA clones that have single ORFs encoding the lectin precursor were isolated from an H. roretzi hepatopancreas cDNA library. The deduced amino acid sequences in the three cDNA clones contain the same sequence of the mature lectin molecule and the same putative signal sequence. In addition, it was demonstrated that this lectin can enhance phagocytosis by H. roretzi hemocytes. Thus, the plasma lectin is constructed into an oligomer structure via intermolecular disulfide bonds and plays a role in the biological defense of H. roretzi as a defense molecule. PMID- 10103031 TI - Characterization of the cardiac holotroponin complex reconstituted from native cardiac troponin T and recombinant I and C. AB - Cardiac troponin I (cTnI), the inhibitory subunit of cardiac troponin (cTn), is phosphorylated by the cAMP-dependent protein kinase A at two adjacently located serine residues within the heart-specific N-terminal elongation. Four different phosphorylation states can be formed. To investigate each monophosphorylated form cTnI mutants, in which each of the two serine residues is replaced by an alanine, were generated. These mutants, as well as the wild-type cardiac troponin I (cTnI WT) have been expressed in Escherichia coli, purified and characterized by isoelectric focusing, MS and CD-spectroscopy. Monophosphorylation induces conformational changes within cTnI that are different from those induced by bisphosphorylation. Functionality was assessed by measuring the calcium dependence of myosin S1 binding to thin filaments containing reconstituted native, wild-type and mutant cTn complexes. In all cases a functional holotroponin complex was obtained. Upon bisphosphorylation of cTnI-WT the pCa curve was shifted to the right to the same extent as that observed with bisphosphosphorylated native cTnI. However, the absolute values for the midpoints were higher when recombinant cTn subunits were used for reconstitution. Reconstitution itself changed the calcium affinity of cTnC: pCa50-values were higher than those obtained with the native cardiac holotroponin complex. Apparently only bisphosphorylation of cTnI influences the calcium sensitivity of the thin filament, thus monophosphorylation has a function different from that of bisphosphorylation; this function has not yet been identified. PMID- 10103032 TI - The carboxy-terminal sequence Asp427-Glu432 of beta-tubulin plays an important function in axonemal motility. AB - Flagellar motility is the result of specific interactions between axonemal microtubular proteins and the dynein motors. Tubulin, the main component of microtubule, is a very polymorphic protein resulting from the expression of several isogenes and from the existence of various post-translational modifications. In order to characterize tubulin isoforms and tubulin domains that are important for flagellar movement, we prepared monoclonal antibodies against axonemal proteins from whole sea-urchin sperm tails. The monoclonal antibodies obtained were screened for their potency to inhibit demembranated-reactivated sperm models and for their monospecific immunoreactivity on immunoblot. Among the different antibodies we obtained, D66 reacted specifically with a subset of beta tubulin isoforms. Limited proteolysis, HPLC, peptide sequencing, mass spectroscopy and immunoblotting experiments indicated that D66 recognized an epitope localized in the primary sequence Gln423-Glu435 of the C-terminal domain of Lytechinus pictus beta2-tubulin, and that this sequence belongs to class IVb. The use of synthetic peptides and immunoblotting analysis further narrowed the amino acids important for antibody recognition to Asp427-Glu432. Because the primary effect of this antibody on sperm motility is to decrease the flagellar beat frequency, we suggest that this sequence is involved in the tubulin-dynein head interaction. PMID- 10103033 TI - NMR studies on the 46-kDa dimeric protein, 3,4-dihydroxy-2-butanone 4-phosphate synthase, using 2H, 13C, and 15N-labelling. AB - 3,4-Dihydroxy-2-butanone 4-phosphate synthase catalyses the release of C-4 from the substrate, ribulose phosphate, via a complex series of rearrangement reactions. The cognate ribB gene of Escherichia coli was hyperexpressed in a recombinant E. coli strain. The protein was shown to be a 46-kDa homodimer by hydrodynamic analysis. A variety of protein samples labelled with different grades of 13C, 15N and 2H, i.e. one with 100% 2H and 15N, one with 75% 2H, 99% 13C, 15N, and one with 100% 2H, 99% 13C,15N were prepared. Despite the large molecular size, 2- and 3-dimensional NMR spectra of reasonable quality were obtained. Attempts at the assignment of individual 13C, 15N and 1H signals show, in principle, the feasibility of structure determination. The number of NMR signals shows unequivocally that the homodimeric protein obeys strict C2 symmetry. PMID- 10103034 TI - Structural and mechanistic aspects of transcriptional induction of cytochrome P450 1A1 by benzimidazole derivatives in rat hepatoma H4IIE cells. AB - The effect of several structurally different benzimidazole compounds on CYP1A1 expression at the transcriptional, mRNA and protein levels was investigated in the rat hepatoma H4IIE cell line. Omeprazole, thiabendazole, carbendazim, 2 mercaptobenzimidazole and 2-mercapto-5-methoxybenzimidazole caused a dose dependent increase in CYP1A1 protein levels that reached maximum effect at 250 microm, as measured by Western blot. In addition, hydroxyomeprazole, 2 aminobenzimidazole and 2-mercapto-5-nitro-benzimidazole caused a notable increase in CYP1A1 protein expression, whereas 5-O-desmethylomeprazole, 2 hydroxybenzimidazole, 2-benzimidazole propionic acid and 5-benzimidazole carboxylic acid were ineffective. Thus, benzimidazole substituted with a thiol or an amino group in the 2-position were active inducers. Northern blot analysis confirmed an extensive increase of CYP1A1 mRNA induced by omeprazole and 2 mercapto-5-methoxybenzimidazole which was 32% and 49% of maximal induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) respectively, whereas thiabendazole and carbendazim showed approximately 15% increase as compared to TCDD. Transient transfection of H4IIE cells, with a XRE-pGL3 reporter gene construct revealed a 2.3-4.3-fold induction by carbendazim, thiabendazole, and 2-mercapto-5 methoxybenzimidazole as compared to a 3.3- and 23-fold induction by omeprazole and TCDD, respectively. Thus, these data indicate that the benzimidazoles utilize the aryl hydrocarbon receptor-arnt-XRE-mediated signal-transduction pathway for induction of the CYP1A1 gene. PMID- 10103035 TI - Nucleoside diphosphate kinase activity in soluble transducin preparations biochemical properties and possible role of transducin-beta as phosphorylated enzyme intermediate. AB - Known nucleoside diphosphate kinases (NDPKs) are oligomers of 17-23-kDa subunits and catalyze the reaction N1TP + N2DP --> N1DP + N2TP via formation of a histidine-phosphorylated enzyme intermediate. NDPKs are involved in the activation of heterotrimeric GTP-binding proteins (G-proteins) by catalyzing the formation of GTP from GDP, but the properties of G-protein-associated NDPKs are still incompletely known. The aim of our present study was to characterize NDPK in soluble preparations of the retinal G-protein transducin. The NDPK is operationally referred to as transducin-NDPK. Like known NDPKs, transducin-NDPK utilizes NTPs and phosphorothioate analogs of NTPs as substrates. GDP was a more effective phosphoryl group acceptor at transducin-NDPK than ADP and CDP, and guanosine 5'-[gamma-thio]triphosphate (GTP[S]) was a more effective thiophosphoryl group donor than adenosine 5'-[gamma-thio]triphosphate (ATP[S]). In contrast with their action on known NDPKs, mastoparan and mastoparan 7 had no stimulatory effect on transducin-NDPK. Guanosine 5'-[beta, gamma imido]triphosphate (p[NH]ppG) potentiated [3H]GTP[S] formation from [3H]GDP and ATP[S] but not [3H]GTP[S] formation from [3H]GDP and GTP[S]. Depending on the thiophosphoryl group acceptor and donor, [3H]NTP[S] formation was differentially regulated by Mg2+, Mn2+, Co2+, Ca2+ and Zn2+. [gamma-32P]ATP and [gamma-32P]GTP [32P]phosphorylated, and [35S]ATP[S] [35S]thiophosphorylated, a 36-kDa protein comigrating with transducin-beta. p[NH]ppG potentiated [35S]thiophosphorylation of the 36-kDa protein. 32P-labeling of the 36-kDa protein showed characteristics of histidine phosphorylation. There was no evidence for (thio)phosphorylation of 17-23-kDa proteins. Our data show the following: (a) soluble transducin preparations contain a GDP-prefering and guanine nucleotide-regulated NDPK; (b) transducin-beta may serve as a (thio)phosphorylated NDPK intermediate; (c) transducin-NDPK is distinct from known NDPKs and may consist of multiple kinases or a single kinase with multiple regulatory domains. PMID- 10103036 TI - Towards minimized gonadotropins with full bioactivity. AB - Gonadotropins are highly complex glycoprotein hormones consisting of two noncovalently associated subunits, which are heavily glycosylated. Using the X ray structure of human choriogonadotropin and structure/activity relationships we aimed to design 'minimized' gonadotropins of reduced complexity. Our results show that it is possible to reduce the size of natural human choriogonadotropin by one third of its molecular weight while retaining its wild-type biopotency. To our knowledge, such 'mini'-human choriogonadotropins represent the smallest gonadotropins described so far with an lutropin/choriogonadotropin receptor affinity and in vitro biological activity comparable with that of natural human choriogonadotropin. It provides an important step towards the structure/function based design of small molecule drugs to the human gonadotropin receptors. PMID- 10103037 TI - A 75-kDa Na+,K+-ATPase competitive inhibitor protein isolated from rat brain cytosol binds to a site different from the ouabain-binding site. AB - A Na+,K+-ATPase inhibitor protein has been purified to homogeneity from rat brain cytosol by ammonium sulphate precipitation, DEAE anion-exchange chromatography and hydroxyapatite adsorption column chromatography. The purified protein migrates as a single polypeptide band of 75 kDa on 7.5% SDS/PAGE. Amino acid composition data shows the presence of a high number of acidic amino acids in the molecule in relation to the pI value of 4.6. The inhibitor binds Na+,K+-ATPase reversibly and blocks ATP binding sites at micromolar concentrations with an I50 of approximately 700 nm. As a result, formation of the phosphorylated intermediate of Na+,K+-ATPase is hindered in the presence of the inhibitor. It does not affect p-nitrophenylphosphatase activity. Tryptophan fluorescence studies and CD analysis suggest conformational changes of Na+,K+-ATPase on binding to the inhibitor. PMID- 10103038 TI - A molecular mechanism for the cleavage of a disulfide bond as the primary function of agonist binding to G-protein-coupled receptors based on theoretical calculations supported by experiments. AB - A model of the binding site of delta-opioids in the extracellular region of the G protein-coupled opioid receptor based on modelling studies is presented. The distance between Asp288 and the disulfide bridge (Cys121-Cys198) formed between the first and second extracellular loops was found to be short. This model is consistent with site-directed mutagenesis studies. The arrangement of the ligands found in the receptor led to the development of a reaction mechanism for the cleavage of the disulfide bond catalysed by the ligands. Semi-empirical quantum chemical PM3 and AM1 calculations as well as ab initio studies showed that the interaction between the carboxylic acid side chain of aspartic acid and the disulfide bond leads to the polarization of, and withdrawal of a proton from, the protonated nitrogen of the ligand to one of the sulfur atoms. A mixed sulfenic acid and carboxylic acid anhydrate is formed as an intermediate as well as a thiol. The accompanying cleavage of the disulfide bond may produce a conformational change in the extracellular loops such that the pore formed by the seven-helix bundle opens allowing entrance of the ligand, water and ions into the cell. Cleavage of the disulfide bond after opioid administration was demonstrated experimentally by flow-cytometric measurements employing CMTMR and monobromobimane-based analyses of membrane-located thiols. The suggested mechanism may explain, in a consistent way, the action of agonists and antagonists and is assumed to be common for many G-protein coupled receptors. PMID- 10103039 TI - Biosynthesis of ansatrienin (mycotrienin) and naphthomycin. Identification and analysis of two separate biosynthetic gene clusters in Streptomyces collinus Tu 1892. AB - The polyketide chains of the two ansamycin antibiotics, ansatrienin (mycotrienin) and naphthomycin produced by Streptomyces collinus are assembled using 3-amino-5 hydroxybenzoic acid (AHBA) as a starter unit. The gene encoding AHBA synthase, an enzyme which catalyzes the final step of AHBA biosynthesis in the recently discovered aminoshikimate pathway, has been used to identify two separate antibiotic biosynthetic gene clusters in S. collinus. In one of these clusters, analysis of approximately 20 kb of contiguous sequence has revealed both a cluster of six genes presumed to play a role in the AHBA pathway and the beginning of a polyketide synthase (PKS) gene containing an acyl ACP ligase domain. This domain is likely responsible for loading AHBA onto the PKS. This gene cluster also contains chcA, encoding the enzyme 1-cyclohexenylcarbonyl CoA reductase, which is essential for the biosynthesis of the cyclohexanecarboxylic acid moiety of ansatrienin from shikimic acid, and a peptide synthetase. This gene cluster thus seems to control the biosynthesis of ansatrienin, which contains a side chain of N-cyclohexanecarbonyl-d-alanine esterified to the macrocyclic lactam backbone. In the putative naphthomycin biosynthetic gene cluster approximately 13 kb of contiguous sequence has revealed a second set of the genes required for AHBA biosynthesis. In addition the end of a polyketide synthase and a gene putatively involved in termination of the chain extension process, formation of an intramolecular amide bond between the AHBA nitrogen and the carboxyl group of the fully extended polyketide chain, have been identified. Thus, despite commonality in biosynthesis, the ansatrienin and naphthomycin biosynthetic gene clusters show clear organizational differences and carry separate sets of genes for AHBA biosynthesis. PMID- 10103040 TI - Efficient screening for catalytic antibodies using a short transition-state analog and detailed characterization of selected antibodies. AB - One of the major obstacles to acquiring catalytic antibodies is that it requires labor-intensive procedures to select catalytic antibodies from huge repertories of antibodies. Here, we selected potential catalytic Abs by utilizing their affinity towards a short transition-state analog which contained only the transition-state structural element, and evaluated in detail its efficiency to enrich catalytic Abs. Hybridoma supernatants elicited against a phosphonate derivative, the TSA1, were screened by a three-step screening process: step 1, ELISA for TSA1-BSA; step 2, ELISA for the short TSA4; and step 3, competitive inhibition by the short TSA2. Only 22. 8% of positive mAbs from step 1 were found to be catalytic. The rate of catalytic Abs increased to 45.7% using screening steps 1 plus 2, and reached 83.3% using all three screening steps. This clearly suggests that our screening protocol is an efficient method to select potential catalytic Abs. Furthermore, we characterized the properties of both the catalytic Abs and the noncatalytic Abs in detail. The catalytic Abs tended to have lower Kd for TSA1 and the short TSA2 than noncatalytic Abs. It was also observed that catalytic Abs showed clear enantiospecificity toward substrate 6 containing d phenylalanine while noncatalytic Abs did not. The detailed analysis of kinetic and binding parameters for these antibodies gives us further insight into catalytic antibodies. PMID- 10103041 TI - Pen c 1, a novel enzymic allergen protein from Penicillium citrinum. Purification, characterization, cloning and expression. AB - A 33-kDa alkaline serine protease secreted by Penicillium citrinum strain 52-5 is shown to be an allergenic agent in this fungus. The protein, designated Pen c 1, was purified by sequential DEAE-Sepharose and carboxymethyl (CM)-Sepharose chromatographies. Pen c 1 has a molecular mass of 33 kDa and a pI of 7.1. The caseinolytic enzyme activity of this protein was studied. The protein binds to serum IgE from patients allergic to Penicillium citrinum. The cDNA encoding Pen c 1 is 1420 bp in length and contains an open reading frame for a 397-amino-acid polypeptide. Pen c 1 codes for a larger precursor containing a signal peptide, a propeptide and the 33-kDa mature protein. Sequence comparison revealed that Pen c 1 possesses several features in common with the alkaline serine proteases of the subtilisin family. The essential Asp, His, and Ser residues that make up the catalytic triad of serine proteases are well conserved. Northern blots demonstrated that mRNAs transcribed from this gene are present at early stages of culture. The allergen encoded by Pen c 1 gene was expressed in Escherichia coli as a fusion protein bearing an N-terminal histidine-affinity tag. The protein, purified by affinity chromatography with a yield of 130 mg of pure protein per liter of culture, was able to bind to both a monoclonal anti-Pen c 1 antibody and IgE from the serum of patients allergic to Penicillium. Recombinant Pen c 1 can therefore be expressed in E. coli in large quantities and should prove useful as a standardized specific allergen for immuno-diagnosis of atopic disorders. In addition, full caseinolytic enzyme activity could be generated in the purified recombinant protein by sulfonation and renaturation, followed by removal of the affinity tag, indicating that the refolded protein can assume the same conformation as the native protein. PMID- 10103042 TI - Thermal effects on an enzymatically latent conformation of coagulation factor VIIa. AB - Activation of the zymogen factor VII yields an enzyme form, factor VIIa, with only modest activity. The thermal effect on this low activity of factor VIIa and its enhancement by the cofactor tissue factor was investigated. Factor VIIa activity measured with a chromogenic peptide substrate is characterized by an unusual temperature dependency which indicates that the activated protease exists in an equilibrium between a latent (enzymatically inactive) and an active conformation. As shown by calorimetry and activity measurements the thermal effects on factor VIIa are fully reversible below the denaturation temperature of 58.1 degrees C. A model for factor VIIa has been proposed [Higashi, S., Nishimura, H., Aita, K. & Iwanaga, S. (1994) J. Biol. Chem. 269, 18891-18898] in which the protease is supposed to exist primarily as a latent enzyme form because of the poor incorporation into the protease structure of the N-terminal Ile153 released by proteolytic cleavage during activation of factor VII. Binding of tissue factor to factor VIIa is assumed to shift the equilibrium towards an active conformation in which the N-terminal Ile153 forms a salt bridge with Asp343. We corroborate the validity of this model by: (a) chemical modification of factor VIIa; this suggests that the thermal effect on the equilibrium between the active and inactive conformation is reflected in the relative accessibility of the active site and the N-terminal Ile153; (b) measurements of factor VIIa binding to tissue factor indicating that complex formation is favoured by stabilization of the active conformation; and (c) activity measurements of a cross-linked factor VIIa-tissue factor complex; this showed that cross-linking stabilized the active conformation of factor VIIa and essentially prevented its thermally-induced transformation into the inactive state. PMID- 10103043 TI - Characterization of a cDNA encoding a precursor polypeptide of a D-amino acid containing peptide, achatin-I and localized expression of the achatin-I and fulicin genes. AB - Achatin-I and fulicin, isolated from the ganglia and atria of the giant land snail Achatina fulica, are a tetrapeptide and pentapeptide containing a d-Phe and d-Asn at position 2, respectively. We succeeded in cloning a cDNA encoding a precursor of achatin-I from the Achatina ganglia, revealing that the d-Phe present in achatin-I is coded by a common l-Phe codon, TTT or TTC. The deduced polypeptide was found to comprise seven repeats of the achatin sequence GFAD and one analog GFGD flanked on both sides by the typical endoproteolytic site KR. Northern blot analysis of transcripts and Southern blot analysis of reverse transcription (RT)-PCR products demonstrated that achatin-I mRNA was localized in the subesophageal ganglia, whereas expression of fulicin mRNA was detected in the atrium as well as in the subesophageal ganglia. Furthermore, localization of the achatin gene transcript in the right and left pedal ganglia compartments was shown by in situ hybridization on sections of subesophageal ganglia, whereas the fulicin transcript was observed in the right and left parietal ganglia. These data suggested that achatin-I plays an essential role in the regulation of the heart as a neurotransmitter or neurohormone through production in the pedal ganglia and transport to the atrium, whereas fulicin serves not only as a neurotransmitter or neurohormone but also as a novel atrial hormone. PMID- 10103044 TI - Identification of chURP, a nuclear calmodulin-binding protein related to hnRNP-U. AB - In a screen for myosin-like proteins in embryonic chicken brain, we have identified a novel nuclear protein structurally related to hnRNP-U (heterogeneous nuclear ribonuclear protein U). We have called this protein chURP, for chicken U related protein. In this screen, chURP was immunoreactive with two myosin antibodies and, in common with the unconventional myosins, bound calmodulin in vitro in both the presence and absence of calcium ions. Determination of 757 amino acids of the chURP sequence revealed that it shares 41% amino acid identity with human and rat hnRNP-U, although chURP and hnRNP-U appear not to be orthologous proteins. ChURP is ubiquitously expressed in the nuclei of all chick tissues and, as one of a growing number of calmodulin-binding proteins to be identified in the nucleus, further highlights the potential of calmodulin as a regulator of nuclear metabolism. PMID- 10103045 TI - Two-dimensional electrophoresis of Malassezia allergens for atopic dermatitis and isolation of Mal f 4 homologs with mitochondrial malate dehydrogenase. AB - The yeast Malassezia furfur is a natural inhabitant of the human skin microflora that induces an allergic reaction in atopic dermatitis. To identify allergens of M. furfur, we separated a crude preparation of M. furfur antigens as discrete spots by 2-D PAGE and detected IgE-binding proteins using sera of atopic dermatitis patients. We identified the known allergens, Mal f 2 and Mal f 3, and determined N-terminal amino acid sequences of six new IgE-binding proteins including Mal f 4. The cDNA and genomic DNA encoding Mal f 4 were cloned and sequenced. The gene was mitochondrial malate dehydrogenase and encoded Mal f 4 composed of 315 amino acids and a signal sequence of 27 amino acids. We purified Mal f 4, which had a molecular mass of 35 kDa from a membrane fraction of a lysate of cultured cells. Thirty of 36 M. furfur-allergic atopic dermatitis patients (83.3%) had elevated serum levels of IgE to purified Mal f 4, indicating that Mal f 4 is a major allergen. There was a significant correlation of the Phadebas RAST unit values of Mal f 4 and the crude antigen, but not between Mal f 4 and the known allergen Mal f 2. PMID- 10103046 TI - Interaction of purified human proteinase 3 (PR3) with reconstituted lipid bilayers. AB - Proteinase 3 (PR3), the major target autoantigen in Wegener's granulomatosis is a serine proteinase that is normally stored intracellularly in the primary granules of quiescent neutrophils and monocytes. Upon cell activation, a significant portion of this antigen is detected on the cell surface membrane. The nature of the association of PR3 with the membrane and its functional significance are unknown. We investigated the interaction of purified human PR3 with mixtures of zwitterionic (dimyristoyl-L-alpha-phosphatidylcholine, DMPC) and anionic (dimyristoyl-L-alpha-phosphatidylglycerol, DMPG) phospholipids in reconstituted lipid bilayers using differential scanning calorimetry and lipid photolabeling, and measured the affinity of this interaction using spectrophotometry. Two other primary granule constituents, human neutrophil elastase (HNE) and myeloperoxidase (MPO) were investigated for comparison. In calorimetric assays, using lipid vesicles of mixed DMPC/DMPG, increasing PR3 concentrations (protein/lipid molar ratio from 0 to 1 : 110) induced a significant decrease of the main chain transition enthalpy and a shift in chain melting temperatures which is indicative of partial insertion of PR3 into the hydrophobic region of the lipid membranes. This was confirmed by hydrophobic photolabeling using liposomes containing trace amounts of the photoactivable [125I]-labeled phosphatidylcholine analog TID PC/16. The molar affinity of PR3, HNE, and MPO to lipid vesicles of different DMPC/DMPG ratios was then determined by spectrophotometry. At a DMPC/DMPG ratio of 1 : 1, molar affinities of PR3, Kd = 4.5 +/- 0.3 microm; HNE, 14.5 +/- 1.2 microm; and MPO, 50 +/- 5 microm (n = 3) were estimated. The lipid-associated PR3 exhibited two-fold lower Vmax and Km values, and its enzyme activity was slightly more inhibited (Ki) by the natural alpha1-proteinase inhibitor (alpha1-PI) or an autoantibody to PR3. PMID- 10103047 TI - In Saccharomyces cerevisae, feedback inhibition of homocitrate synthase isoenzymes by lysine modulates the activation of LYS gene expression by Lys14p. AB - Expression of the structural genes for lysine biosynthesis responds to an induction mechanism mediated by the transcriptional activator Lys14p in the presence of alpha-aminoadipate semialdehyde (alphaAASA), an intermediate of the pathway acting as a coinducer. This activation is reduced by the presence of lysine in the growth medium, leading to apparent repression. In this report we demonstrate that Saccharomyces cerevisiae possesses two genes, LYS20 and LYS21, encoding two homocitrate synthase isoenzymes which are located in the nucleus. Each isoform is inhibited by lysine with a different sensitivity. Lysine overproducing mutants were isolated as resistant to aminoethylcysteine, a toxic lysine analog. Mutations, LYS20fbr and LYS21fbr, are allelic to LYS20 and LYS21, and lead to desensitization of homocitrate synthase activity towards lysine and to a loss of apparent repression by this amino acid. There is a fair correlation between the I0.5 of homocitrate synthase for lysine, the intracellular lysine pool and the levels of Lys enzymes, confirming the importance of the activity control of the first step of the pathway for the expression of LYS genes. The data are consistent with the conclusion that inhibition by lysine of Lys14p activation results from the control of alphaAASA production through the feedback inhibition of homocitrate synthase activity. PMID- 10103048 TI - Structural analysis of the lipopolysaccharide oligosaccharide epitopes expressed by a capsule-deficient strain of Haemophilus influenzae Rd. AB - Structural elucidation of the lipopolysaccharide (LPS) of Haemophilus influenzae, strain Rd, a capsule-deficient type d strain, has been achieved by using high field NMR techniques and electrospray ionization-mass spectrometry (ESI-MS) on delipidated LPS and core oligosaccharide samples. It was found that this organism expresses heterogeneous populations of LPS of which the oligosaccharide (OS) epitopes are subject to phase variation. ESI-MS of O-deacylated LPS revealed a series of related structures differing in the number of hexose residues linked to a conserved inner-core element, L-alpha-D-Hepp-(1-->2)-L-alpha-D-Hepp-(1-->3) [beta-D-Glcp- (1-->4)-]- L-alpha-D-Hepp-(1-->5)-alpha-Kdo, and the degree of phosphorylation. The structures of the major LPS glycoforms containing three (two Glc and one Gal), four (two Glc and two Gal) and five (two Glc, two Gal and one GalNAc) hexoses were substituted by both phosphocholine (PCho) and phosphoethanolamine (PEtn) and were determined in detail. In the major glycoform, Hex3, a lactose unit, beta-D-Galp-(1-->4)-beta-D-Glcp, is attached at the O-2 position of the terminal heptose of the inner-core element. The Hex4 glycoform contains the PK epitope, alpha-D-Galp-(1-->4)-beta-D-Galp-(1-->4)-beta-D-Glcp while in the Hex5 glycoform, this OS is elongated by the addition of a terminal beta-D-GalpNAc residue, giving the P antigen, beta-D-GalpNAc-(1-->3)-alpha-D-Galp (1-->4)-beta-D-Galp-(1-->4)-D-Glc p. The fully extended LPS glycoform (Hex5) has the following structure. [see text] The structural data provide the first definitive evidence demonstrating the expression of a globotetraose OS epitope, the P antigen, in LPS of H. influenzae. It is noteworthy that the molecular environment in which PCho units are found differs from that observed in an Rd- derived mutant strain (RM.118-28) [Risberg, A., Schweda, E. K. H. & Jansson, P-E. (1997) Eur. J. Biochem. 243, 701-707]. PMID- 10103049 TI - Affinity labelling with MgATP analogues reveals coexisting Na+ and K+ forms of the alpha-subunits of Na+/K+-ATPase. AB - To test the hypothesis that Na+/K+-ATPase works as an (alpha beta)2-diprotomer with interacting catalytic alpha-subunits, tryptic digestion of pig kidney enzyme, that had been inactivated with substitution-inert MgATP complex analogues, was performed. This led to the demonstration of coexisting C-terminal Na+-like 80-kDa as well as K+-like 60-kDa peptides and N-terminal 40-kDa peptides of the alpha-subunit. To localize the ATP binding sites on tryptic peptides, studies with radioactive MgATP complex analogues were performed: Co(NH3)4-8-N3 ATP specifically modified the E2ATP (low affinity) binding site of Na+/K+-ATPase with an inactivation rate constant (k2) of 12 x 10-3.min-1 at 37 degrees C and a dissociation constant (Kd) of 207 +/- 28 microm. Tryptic digestion of the [gamma32P]Co(NH3)4-8-N3-ATP-inactivated and photolabelled alpha-subunit (Mr = 100 kDa) led, in the absence of univalent cations, to a K+-like C-terminal 60-kDa fragment which was labelled in addition to an unlabelled Na+-like C-terminal 80 kDa fragment. Tryptic digestion of [alpha32P]-or [gamma32P]Cr(H2O)4ATP - bound to the E1ATP (high affinity) site - led to the labelling of a Na+-like 80-kDa fragment besides the immediate formation of an unlabelled K+-like N-terminal 40 kDa fragment and a C-terminal 60-kDa fragment. Because a labelled Na+-like 80-kDa fragment cannot result from an unlabelled K+-like 60-kDa fragment, and because unlabelled alpha-subunits did not show any catalytic activity, the findings are consistent with a situation in which Na+- and K+-like conformations are stabilized by tight binding of substitution-inert MgATP complex analogues to the E1ATP and E2ATP sites. Hence, all data are consistent with the hypothesis that ATP binding induces coexisting Na+ and K+ conformations within an (alphabeta)2 diprotomeric Na+/K+-ATPase. PMID- 10103050 TI - Heme and acute inflammation role in vivo of heme in the hepatic expression of positive acute-phase reactants in rats. AB - Acute-phase protein synthesis in the liver during inflammation is regulated via cytokines and glucocorticoids. Using quantitative reverse transcription (RT)-PCR analysis and immunoassay, we explored, in the rat, the response of the acute phase protein, alpha-2 macroglobulin (A2M), after systemic inflammation induced by lipopolysaccharide (LPS) or localized inflammation induced by turpentine oil (TO). The results indicate that synthesis of A2M is higher following TO-induced inflammation than LPS-induced inflammation and is not correlated with interleukin (IL)-6 or glucocorticoid levels. We studied the putative role of heme in this differential A2M expression following localized vs. systemic inflammation; addition of heme during LPS-induced inflammation can boost the expression of A2M, whereas blocking heme synthesis (by succinyl acetone) or enhancing its consumption in parallel biosynthetic pathways (cytochrome P450 induction by phenobarbital) decreases A2M expression. This decrease was abolished by exogenous heme supplementation. Finally, we demonstrate that heme supplementation is also able to increase the A2M response in female rats to a level similar to that in male rats providing a new insight into the puzzling sexual dimorphism observed previously during localized inflammation. We propose that heme should be considered a new regulatory element in controlling liver A2M expression during inflammation. PMID- 10103051 TI - Engineering the disulphide bond patterns of secretory phospholipases A2 into porcine pancreatic isozyme. The effects on folding, stability and enzymatic properties. AB - Secretory phospholipases A2 (PLA2s) are small homologous proteins rich in disulphide bridges. These PLA2s have been classified into several groups based on the disulphide bond patterns found [Dennis, E. A. (1997) Trends Biochem. Sci. 22, 1-2]. To probe the effect of the various disulphide bond patterns on folding, stability and enzymatic properties, analogues of the secretory PLA2s were produced by protein engineering of porcine pancreatic PLA2. Refolding experiments indicate that small structural variations play an important role in the folding of newly made PLA2 analogues. Introduction of a C-terminal extension together with disulphide bridge 50-131 gives rise to an enzyme that displays full enzymatic activity having increased conformational stability. In contrast, introduction of a small insertion between positions 88 and 89 together with disulphide bridge 86-89 decreases the catalytic activity significantly, but does not change the stability. Both disulphide bridges 11-77 and 61-91 are important for the kinetic properties and stability of the enzyme. Disulphide bridge 11-77, but not 61-91, was found to be essential to resist tryptic breakdown of native porcine pancreatic PLA2. PMID- 10103052 TI - Enzymatic synthesis of alpha3'sialylated and multiply alpha3fucosylated biantennary polylactosamines. A bivalent [sialyl diLex]-saccharide inhibited lymphocyte-endothelium adhesion organ-selectively. AB - Multifucosylated sialo-polylactosamines are known to be high affinity ligands for E-selectin. PSGL-1, the physiological ligand of P-selectin, is decorated in HL-60 cells by a sialylated and triply fucosylated polylactosamine that is believed to be of functional importance. Mimicking some of these saccharide structures, we have synthesized enzymatically a bivalent [sialyl diLex]-glycan, Neu5Acalpha2 3'Lexbeta1-3'Lexbeta1-3'(Neu5Acalpha2-3'Lexbeta1-3Lexbe ta1-6')LN [where Neu5Ac is N-acetylneuraminic acid, Lex is the trisaccharide Galbeta1-4(Fucalpha1 3)GlcNAc and LN is the disaccharide Galbeta1-4GlcNAc]. Several structurally related, novel polylactosamine glycans were also constructed. The inhibitory effects of these glycans on two L-selectin-dependent, lymphocyte-to-endothelium adhesion processes of rats were analysed in ex-vivo Stamper-Woodruff binding assays. The IC50 value of the bivalent [sialyl diLex]-glycan at lymph node high endothelium was 50 nm, but at the capillaries of rejecting cardiac allografts it was only 5 nm. At both adhesion sites, the inhibition was completely dependent on the presence of fucose units on the sialylated LN units of the inhibitor saccharide. These data show that the bivalent [sialyl diLex]-glycan is a high affinity ligand for L-selectin, and may reduce extravasation of lymphocytes at sites of inflammation in vivo without severely endangering the normal recirculation of lymphocytes via lymph nodes. PMID- 10103053 TI - Aspects of the molecular structure and dynamics of neuropeptide Y. AB - Human neuropeptide Y (hNPY) and the Q34-->P34 mutant (P34-hNPY) have been characterized by CD spectroscopy. hNPY self-associates in aqueous solution with a dimerization constant in the micromolar range. The self-association correlates with an increase in secondary-structure content which was studied as a function of concentration, temperature and pH. The effects of temperature were measured in water (5-84 degrees C) and in ethanediol/water (2 : 1) (-90 degrees to +90 degrees C). A single-residue mutation, Q34-->P34, affects the pH, thermal and self-association properties of NPY. The CD results are correlated with photochemically induced dynamic nuclear polarization NMR experiments which show that the tyrosines at the interface between two monomer units present limited accessibility to a photoreactive dye. An equilibrium state is described, involving a PP-fold monomer form and a handshake dimer form, that accommodates the physicochemical properties of NPY. PMID- 10103054 TI - Uptake and fate of class B scavenger receptor ligands in HepG2 cells. AB - Class B scavenger receptors (SR-Bs) interact with native, acetylated and oxidized low-density lipoprotein (LDL, AcLDL and OxLDL), high-density lipoprotein (HDL3) and maleylated BSA (M-BSA). The aim of this study was to analyze the catabolism of CD36- and LIMPII-analogous-1 (CLA-1), the human orthologue for the scavenger receptor class B type I (SR-BI), and CD36 ligands in HepG2 (human hepatoma) cells. Saturation binding experiments revealed moderate-affinity binding sites for all the SR-B ligands tested with dissociation constants ranging from 20 to 30 microg.mL-1. Competition binding studies at 4 degrees C showed that HDL and modified and native LDL share common binding site(s), as OxLDL competed for the binding of 125I-LDL and 125I-HDL3 and vice versa, and that only M-BSA and LDL may have distinct binding sites. Degradation/association ratios for SR-B ligands show that LDL is very efficiently degraded, while M-BSA and HDL3 are poorly degraded. The modified LDL degradation/association ratio is equivalent to 60% of the LDL degradation ratio, but is three times higher than that of HDL3. All lipoproteins were good cholesteryl ester (CE) donors to HepG2 cells, as a 3.6-4.7-fold CE selective uptake ([3H]CE association/125I-protein association) was measured. M BSA efficiently competed for the CE-selective uptake of LDL-, OxLDL-, AcLDL- and HDL3-CE. All other lipoproteins tested were also good competitors with some minor variations. Hydrolysis of [3H]CE-lipoproteins in the presence of chloroquine demonstrated that modified and native LDL-CE were mainly hydrolyzed in lysosomes, whereas HDL3-CE was hydrolyzed in both lysosomal and extralysosomal compartments. Inhibition of the selective uptake of CE from HDL and native modified LDL by SR-B ligands clearly suggests that CLA-1 and/or CD36 are involved at least partially in this process in HepG2 cells. PMID- 10103055 TI - Acn9 is a novel protein of gluconeogenesis that is located in the mitochondrial intermembrane space. AB - Previous studies have indicated that the Acn9 protein is involved in gluconeogenesis. Yeast mutants defective in the ACN9 gene display phenotypes identical with mutants defective in metabolic enzymes required for carbon assimilation. These phenotypes include the inability to utilize acetate as a carbon and energy source, elevated levels of enzymes of the glyoxylate cycle, gluconeogenesis and acetyl-CoA mobilization, and a deficiency in de novo synthesis of glucose from ethanol. The ACN9 gene was isolated by functional complementation of the acetate growth defect of an acn9 mutant. The open reading frame corresponds to YDR511w, and encodes a protein of unknown function. Homologs have been identified in human, mouse, and nematode databases. Two mutant alleles were sequenced. The mutations altered amino acid residues that are conserved among members of the new gene family. ACN9 gene expression was slightly repressed by glucose, and the level of the transcript was approximately 100-fold lower than that of glyoxylate or tricarboxylic acid cycle enzymes. A functional epitope tagged form of Acn9 was expressed to study expression and the subcellular localization of the protein. The tagged protein was localized to the mitochondrial intermembrane space. PMID- 10103056 TI - Cloning and structural analysis of leydin, a novel human serine protease expressed by the Leydig cells of the testis. AB - We present the cloning and structural analysis of a novel member of the large family of trypsin-related serine proteases. Northern blot analysis shows that this protease, in adult tissues, is expressed almost exclusively in the human testis. In addition, a larger transcript was detected in relatively high abundance in several embryonic tissues, indicating different functions during embryonic and adult life. Sera raised against this protease was used to locate the expression in adult tissues to the testosterone producing cells of the testis, the interstitial Leydig cells. We therefore propose the name leydin for this novel protease. Leydin is clearly distinct from acrosin, the other testis specific serine protease which is expressed by the spermatocytes. Leydin is probably a two-chain protease such as acrosin, prostasin, and coagulation factor XI. The heavy chain consists of 246 amino acids, corresponding to a molecular mass of 27384 Da and a net charge of +10.76. The size of the light chain is between 9 and 18 amino acids depending on the site of proteolytic cleavage, which remains to be determined. The amino-acid residues surrounding the active site indicate a trypsin-like cleavage specificity. The presence of two dibasic sequences Arg-Arg and Lys-Arg at the N-terminus of the heavy chain indicate that one or more subtilisin-like endopeptidases are responsible for the processing of leydin. However, leydin may also be activated by a trypsin-like enzyme, possibly by auto catalysis. PMID- 10103057 TI - Solution properties of the free and DNA-bound Runt domain of AML1. AB - The Runt domain is responsible for specific DNA and protein-protein interactions in a family of transcription factors which includes human AML1. Structural data on the Runt domain has not yet become available, possibly due to solubility and stability problems with expressed protein fragments. Here we describe the optimization and characterization of a 140-residue fragment, containing the Runt domain of AML1, which is suitable for structural studies. The fragment of AML1 including amino acids 46-185 [AML1 Dm(46-185)] contains a double cysteine- >serine mutation which does not affect Runt domain structure or DNA-binding affinity. Purified AML1 Dm(46-185) is soluble and optimally stable in a buffer containing 200 mm MgSO4 and 20 mm sodium phosphate at pH 6.0. Nuclear magnetic resonance and circular dichroism spectroscopy indicate that the Runt domain contains beta-sheet, but little or no alpha-helical secondary structure elements. The 45 N-terminal residues of AML1 are unstructured and removal of the N-terminal enhances sequence-specific DNA binding. The NMR spectrum of AML1 Dm(46-185) displays a favorable chemical shift dispersion and resolved NOE connectivities are readily identified, suggesting that a structure determination of this Runt domain fragment is feasible. A titration of 15N-labelled AML1 Dm(46-185) with a 14-bp cognate DNA duplex results in changes in the 15N NMR heteronuclear single quantum coherence spectrum which indicate the formation of a specific complex and structural changes in the Runt domain upon DNA binding. PMID- 10103058 TI - Effects of divalent metal ions on the activity and conformation of native and 3 fluorotyrosine-PvuII endonucleases. AB - The activities of restriction enzymes are important examples of Mg(II)-dependent hydrolysis of DNA. While a number of crystallographic studies of enzyme-DNA complexes have also involved metal ions, there have been no solution studies exploring the relationship between enzyme conformation and metal-ion binding in restriction enzymes. Using PvuII restriction endonuclease as a model system, we have successfully developed biosynthetic fluorination and NMR spectroscopy as a solution probe of restriction-enzyme conformation. The utility of this method is demonstrated with a study of metal-ion binding by PvuII endonuclease. Replacement of 74% (+/- 10%) of the Tyr residues in PvuII endonuclease by 3-fluorotyrosine produces an enzyme with Mg(II)-supported specific activity and sequence specificity that is indistinguishable from that of the native enzyme. Mn(II) supports residual activity of both the native and fluorinated enzymes; Ca(II) does not support activity in either enzyme, a result consistent with previous studies. 1H- and 19F-NMR spectroscopic studies reveal that while Mg(II) does not alter the enzyme conformation, the paramagnetic Mn(II) produces both short-range spectral broadening and longer range changes in chemical shift. Most interestingly, Ca(II) binding perturbs a larger number of different resonances than Mn(II). Coupled with earlier mutagenesis studies that place Ca(II) in the active site [Nastri, H. G., Evans, P.D., Walker, I.H. & Riggs, P.D. (1997) J. Biol. Chem. 272, 25761-25767], these data suggest that the enzyme makes conformational adjustments to accommodate the distinct geometric preferences of Ca(II) and may play a role in the inability of this metal ion to support activity in restriction enzymes. PMID- 10103059 TI - Cleavage of transcription factor SP1 by caspases during anti-IgM-induced B-cell apoptosis. AB - Apoptosis is instrumental in the processes generating the diversity of the B-cell repertoire. Autoreactive B-cells are eliminated by anti-IgM crosslinking after encountering self-antigens, but precise mechanisms leading to B-cell apoptosis are still not well understood. We report here the cleavage of the transcription factor SP1 in the human Burkitt lymphoma cell line BL60 during anti-IgM-induced apoptosis. Western blot analysis revealed two cleavage products of approximately 68 kDa and 45 kDa after induction of apoptosis. Cleavage could be completely inhibited by zDEVD-fmk, an inhibitor specific for caspase 3-like proteases. In vitro cleavage of recombinant SP1 by recombinant caspase 3 (CPP32) or caspase 7 (Mch 3) results in similar cleavage products as those observed in vivo. Recombinant caspase 6 (Mch 2) primarily generates a 68-kDa cleavage product, as observed after calcium ionophore (CaI) induced B-cell apoptosis. In contrast, caspase 1 (ICE) did not cleave SP1 in vitro. The time course of SP1 cleavage during anti-IgM-induced apoptosis is paralleled by an increase of caspase activity measured by DEVD-p-nitroanilide (DEVD-pNA) cleavage. DNA band-shift assays revealed a decrease in the intensity of the full length SP1/DNA complex and an increase in the intensity of a smaller complex due to the binding of one SP1 cleavage product. By Edman sequencing we could identify a caspase 3 cleavage site after Asp584 (D584AQPQAGR), generating a 22-kDa C-terminal SP1 protein fragment which still contains the DNA binding site. Our results show the cleavage of the human transcription factor SP1 in vivo and in vitro, underlining the central role of caspase 3-like proteases during the process of anti-IgM-induced apoptosis. PMID- 10103060 TI - Characterization of low-molecular-mass trypsin isoinhibitors from oil-rape (Brassica napus var. oleifera) seed. AB - A new low-molecular-mass (6767.8 Da) serine proteinase isoinhibitor has been isolated from oil-rape (Brassica napus var. oleifera) seed, designated 5-oxoPro1 Gly62-RTI-III. The 5-oxoPro1-Gly62-RTI-III isoinhibitor is longer than the Asp2 Pro61-RTI-III and the Ser3-Pro61-RTI-III forms, all the other amino acid residues being identical. In RTI-III isoinhibitors, the P1-P1' reactive site bond (where residues forming the reactive site have been identified as PnellipsisP1 and P1'ellipsisPn', where P1-P1' is the inhibitor scissile bond) has been identified at position Arg21-Ile22. The inhibitor disulphide bridges pattern has been determined as Cys5-Cys27, Cys18-Cys31, Cys42-Cys52 and Cys54-Cys57. The disulphide bridge arrangement observed in the RTI-III isoinhibitors is reminiscent of that found in a number of toxins (e.g. erabutoxin b). Moreover, the organization of the three disulphide bridges subset Cys5-Cys27, Cys18-Cys31 and Cys42-Cys52 is reminiscent of that found in epidermal growth factor domains. Preliminary 1H-NMR data indicates the presence of alphaalphaNOEs and 3JalphaNH coupling constants, typical of the beta-structure(s). These data suggest that the three-dimensional structure of the RTI-III isoinhibitors may be reminiscent of that of toxins and epidermal growth factor domains, consisting of three-finger shaped loops extending from the crossover region. Values of the apparent association equilibrium constant for RTI-III isoinhibitors binding to bovine beta trypsin and bovine alpha-chymotrypsin are 3.3 x 109 m-1 and 2.4 x 106 m-1, respectively, at pH 8.0 and 21.0 degrees C. The serine proteinase : inhibitor complex formation is a pH-dependent entropy-driven process. RTI-III isoinhibitors do not show any similarity to other serine proteinase inhibitors except the low molecular mass white mustard trypsin isoinhibitor, isolated from Sinapis alba L. seed (MTI-2). Therefore, RTI-III and MTI-2 isoinhibitors could be members of a new class of plant serine proteinase inhibitors. PMID- 10103061 TI - A novel lipoprotein from the hemolymph of the cochineal insect, Dactylopius confusus. AB - A new type of insect lipoprotein was isolated from the hemolymph of the female cochineal insect Dactylopius confusus. The lipoprotein from the cochineal insect hemolymph was found to have a relative molecular mass of 450 000. It contains 48% lipid, mostly diacylglycerol, phospholipids and hydrocarbons. The protein moiety of the lipoprotein consists of two apoproteins of approximately 25 and 22 kDa, both of which are glycosylated. Both apolipoproteins are also found free in the hemolymph, unassociated with any lipid. Purified cochineal apolipoproteins can combine with Manduca sexta lipophorin, if injected together with adipokinetic hormone into M. sexta. This could indicate that the cochineal lipoprotein can function as a lipid shuttle similar to lipophorins of other insects, and that the cochineal insect apolipoproteins have an overall structure similar to insect apolipophorin-III. PMID- 10103062 TI - Organization and alternate splice products of the gene encoding nuclear inhibitor of protein phosphatase-1 (NIPP-1). AB - Nuclear inhibitor of protein phosphatase-1 (NIPP-1) is one of two major regulatory subunits of protein phosphatase-1 in mammalian nuclei. We report here the cloning and structural characterization of the human NIPP-1 genes, designated PPP1R8P and PPP1R8 in human gene nomenclature. PPP1R8P (1.2 kb) is a processed pseudogene and was localized by in situ hybridization to chromosome 1p33-32. PPP1R8 is an authentic NIPP-1 gene and was localized to chromosome 1p35. PPP1R8 (25.2 kb) is composed of seven exons and encodes four different transcripts, as determined from cDNA library screening, reverse transcriptase-PCR (RT-PCR) and/or EST (expressed sequence tag) database search analysis. NIPP-1alpha mRNA represents the major transcript in human tissues and various cell lines, and encodes a polypeptide of 351 residues that only differs from the previously cloned calf thymus NIPP-1 by a single residue. The other transcripts, termed NIPP 1beta, gamma and delta, are generated by alternative 5'-splice site usage, by exon skipping and/or by alternative polyadenylation. The NIPP-1beta/delta and NIPP-1gamma mRNAs are expected to encode fragments of NIPP-1alpha that differ from the latter by the absence of the first 142 and 224 residues, respectively. NIPP-1gamma corresponds to 'activator of RNA decay-1' (Ard-1) which, unlike NIPP 1alpha, displays in vitro and endoribonuclease activity and lacks an RVXF consensus motif for interaction with protein phosphatase-1. While the NIPP 1alpha/beta/delta-transcripts were found to be present in various human tissues, the NIPP-1gamma transcript could only be detected in human transformed B lymphocytes. PMID- 10103063 TI - DNA triple-helix formation on nucleosome core particles. Effect of length of the oligopurine tract. AB - We have used DNase I footprinting to examine the formation of intermolecular triplexes on DNA fragments which have been complexed with nucleosome core particles. We have prepared five DNA fragments, based on the 160-bp tyrT sequence, which contain different length oligopurine tracts (up to 25 bp) at two different positions along the fragment, and have examined their availability for triple-helix formation after reconstituting onto nucleosome core particles. These results are compared with the formation of shorter triplexes in the same regions. In general we find that increasing the length of the complex does not facilitate nucleosomal triplex formation and that the most important factor affecting triplex formation is the position of the target site within the nucleosome-bound fragment. In some instances we find that longer oligonucleotides inhibit triplex formation. Although successful triplex formation was achieved on the longest nucleosome-bound oligopurine tracts, this was accompanied by changes in cleavage pattern that suggest oligonucleotide-induced changes in nucleosome structure. PMID- 10103064 TI - Subcellular localization of the BtpA protein in the cyanobacterium Synechocystis sp. PCC 6803. AB - Photosystem I is a large pigment-protein complex embedded in the thylakoid membranes of chloroplasts and cyanobacteria. In the cyanobacterium Synechocystis sp. PCC 6803, the btpA gene encodes a 30-kDa polypeptide. Mutations in this gene significantly affect accumulation of the reaction center proteins of photosystem I in Synechocystis 6803 [Bartsevich, V. V. & Pakrasi, H. B. (1997) J. Biol. Chem. 272, 6372-6378]. We describe here the intracellular localization of the BtpA protein. Immunolocalization in Synechocystis 6803 cells demonstrated that the BtpA protein is tightly associated with the thylakoid membranes. Phase fractionation in the detergent Triton X-114 indicated that BtpA is a peripheral membrane protein. To determine which surface of the thylakoid membrane BtpA is exposed to, we used a two-phase polymer partitioning technique to develop a novel method to isolate inside-out and right-side-out thylakoid vesicles from Synechocystis 6803. Treatments of such vesicles with different salts and protease showed that the BtpA protein is an extrinsic membrane protein which is exposed to the cytoplasmic face of the thylakoid membrane. PMID- 10103065 TI - Pregnenolone esterification in Saccharomyces cerevisiae. A potential detoxification mechanism. AB - While studying the effect of steroids on the growth of the yeast Saccharomyces cerevisiae, we found that pregnenolone was converted into the acetate ester. This reaction was identified as a transfer of the acetyl group from acetyl-CoA to the 3beta-hydroxyl group of pregnenolone. The corresponding enzyme, acetyl CoA:pregnenolone acetyltransferase (APAT) is specific for Delta5- or Delta4-3beta hydroxysteroids and short-chain acyl-CoAs. The apparent Km for pregnenolone is approximately 0.5 microm. The protein associated with APAT activity was partially purified and finally isolated from an SDS/polyacrylamide gel. Tryptic peptides were generated and N-terminally sequenced. Two peptide sequences allowed the identification of an open reading frame (YGR177c, in the S. cerevisiae genome database) translating into a 62-kDa protein of hitherto unknown function. This protein encoded by a gene known as ATF2 displays 37% identity with an alcohol acetyltransferase encoded by the yeast gene ATF1. Disruption of ATF2 led to the complete elimination of APAT activity and consequently abolished the esterification of pregnenolone. In addition, a toxic effect of pregnenolone linked to the disruption of ATF2 was observed. Pregnenolone toxicity is more pronounced when the atf2-Delta mutation is introduced in a yeast strain devoid of the ATP-binding cassette transporters, PDR5 and SNQ2. Our results suggest that Atf2p (APAT) plays an active role in the detoxification of 3beta-hydroxysteroids in association with the efflux pumps Pdr5p and Snq2p. PMID- 10103066 TI - Purification, redox and spectroscopic properties of the tetraheme cytochrome c isolated from Rubrivivax gelatinosus. AB - The tetraheme cytochrome c subunit of the Rubrivivax gelatinosus reaction center was isolated in the presence of octyl beta-D-thioglucoside by ammonium sulfate precipitation and solubilization at pH 9 in a solution of Deriphat 160. Several biochemical properties of this purified cytochrome were characterized. In particular, it forms small oligomers and its N-terminal amino acid is blocked. In the presence or absence of diaminodurene, ascorbate and dithionite, different oxidation/reduction states of the isolated cytochrome were studied by absorption, EPR and resonance Raman spectroscopies. All the data show two hemes quickly reduced by ascorbate, one heme slowly reduced by ascorbate and one heme only reduced by dithionite. The quickly ascorbate-reduced hemes have paramagnetic properties very similar to those of the two low-potential hemes of the reaction center-bound cytochrome (gz = 3.34), but their alpha band is split with two components peaking at 552 nm and 554 nm in the reduced state. Their axial ligands did not change, being His/Met and His/His, as indicated by the resonance Raman spectra. The slowly ascorbate-reduced heme and the dithionite-reduced heme are assigned to the two high-potential hemes of the bound cytochrome. Their alpha band was blue-shifted at 551 nm and the gz values decreased to 2.96, although the axial ligations (His/Met) were conserved. It was concluded that the estimated 300 mV potential drop of these hemes reflected changes in their solvent accessibility, while the reduction in gz indicates an increased symmetry of their cooordination spheres. These structural modifications impaired the cytochrome's essential function as the electron donor to the photooxidized bacteriochlorophyll dimer of the reaction center. In contrast to its native state, the isolated cytochrome was unable to reduce efficiently the reaction center purified from a Rubrivivax gelatinosus mutant in which the tetraheme was absent. Despite the conformational changes of the cytochrome, its four hemes are still divided into two groups with a pair of low-potential hemes and a pair of high-potential hemes. PMID- 10103067 TI - Evidence of noncovalent dimerization of calmodulin. AB - Calcium-binding proteins, such as S-100, dimerize readily, and this phenomenon plays an important role in their regulation of target enzymes [Krebs, J., Quadroni, M. & Van Eldik, L.J. (1995) Nat. Struct. Biol. 2, 711-714; Kilby, P.M., Van Eldik, L.J. & Roberts, G. C. (1996) Structure 4, 1041-1052]. We have investigated by Fourier-transform ion cyclotron resonance (FTICR) MS the conformational states of the calcium-binding protein calmodulin, and present clear evidence for a calmodulin dimer formed as a result of noncovalent interactions between folded monomers. Ultra-high-resolution electrospray ionization (ESI) mass spectra for calmodulin, obtained with a 9.4 T FTICR mass spectrometer, are presented. With the use of denaturing solutions (1 : 1 acetonitrile/water + 1% formic acid), relatively high charge states (20 < z < 10) of monomeric calmodulin ions were detected, whereas when calmodulin was electrosprayed from buffer, monomers ions with only 5-10 charges were detected. CD measurements for calmodulin in buffered solution revealed that its alpha helical content was significantly higher than that for calmodulin in acetonitrile/water solutions, consistent with a proposition that changes in charge state distributions observed in the MS experiments reflect differing states of calmodulin folding. Under buffered conditions, noncovalently bound calmodulin dimers were observed by ESI FTICR MS. Analytical ultracentrifugation experiments carried out in the same solution conditions as those used in the MS experiments were consistent with the proposed calmodulin dimer-monomer equilibrium. The ultra-high mass resolution achieved with the 9.4 T FTICR mass spectrometer allowed unequivocal identification of the noncovalent, as opposed to covalent, character of the calmodulin dimer. PMID- 10103068 TI - A new approach to estimate the number, density and variability of receptors at central synapses. PMID- 10103069 TI - Functional role of the slow activation property of ERG K+ channels. AB - ERG (ether-a-go-go-related gene) K+ channels are crucial in human heart physiology (h-ERG), but are also found in neuronal cells and are impaired in Drosophila 'seizure' mutants. Their biophysical properties include the relatively fast kinetics of the inactivation gate and much slower kinetics of the activation gate. In order to elucidate how the complex time- and voltage-dependent activation properties of ERG channels underlies distinct roles in excitability, we investigated different types of ERG channels intrinsically present in cells or heterologously expressed in mammalian cells or Xenopus oocytes. Voltage-dependent activation curves were highly dependent on the features of the eliciting protocols. Only very long preconditioning times produced true steady-state relationships, a fact that has been largely neglected in the past, hampering the comparison of published data on ERG channels. Beyond this technical aspect, the slow activation property of ERG can be responsible for unsuspected physiological roles. We found that around the midpoint of the activation curve, the time constant of ERG open-close kinetics is of the order of 10-15 s. During sustained trains of depolarizations, e.g. those produced in neuronal firing, this leads to the use-dependent accumulation of open-state ERG channels. Accumulation is not observed in a mutant with a fast activation gate. In conclusion, it is well established that other K+ channels (i.e. Ca2+-activated and M) control the spike frequency adaptation, but our results support the notion that the purely voltage dependent activation property of ERG channels would allow a slow inhibitory physiological role in rapid neuronal signalling. PMID- 10103070 TI - GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization. AB - GABAB (gamma-aminobutyric acid)-receptors have been implicated in central nervous system (CNS) functions, e.g. cognition and pain perception, and dysfunctions including spasticity and absence epilepsy. To permit an analysis of the two known GABAB-receptor splice variants GABAB-R1a (GB1a) and GABAB-R1b (GB1b), their distribution pattern has been differentiated in the rat brain, using Western blotting and immunohistochemistry with isoform-specific antisera. During postnatal maturation, the expression of the two splice variants was differentially regulated with GB1a being preponderant at birth. In adult brain, GB1b-immunoreactivity (-IR) was predominant, and the two isoforms largely accounted for the pattern of GABAB-receptor binding sites in the brain. Receptor heterogeneity was pronounced in the hippocampus, where both isoforms occurred in CA1, but only GB1b in CA3. Similarly, in the cerebellum, GB1b was exclusively found in Purkinje cells in a zebrin-like pattern. The staining was most pronounced in Purkinje cell dendrites and spines. Using electron microscopy, over 80% of the spine profiles in which a synaptic contact with a parallel fibre was visible contained GB1b-IR at extrasynaptic sites. This subcellular localization is unrelated to GABAergic inputs, indicating that the role of GABAB-receptors in vivo extends beyond synaptic GABAergic neurotransmission and may, in the cerebellum, involve taurine as a ligand. PMID- 10103071 TI - Neuregulin is a mitogen and survival factor for olfactory bulb ensheathing cells and an isoform is produced by astrocytes. AB - The rat olfactory bulb is an exceptional CNS tissue. Unlike other areas of the brain, growing axons are able to enter the olfactory bulb and extend within this CNS environment throughout adult life. It appears that the glial cells of the olfactory system, known as olfactory bulb ensheathing cells (OBECs), may have an important role in this remarkable process of CNS neural regeneration. OBECs are unusual glial cells, possessing properties of both astrocytes and Schwann cells. In this study we show that astrocytes (in the form of astrocyte-conditioned medium; ACM) produce two critical regulatory functions for OBECs: mitogenic activity and a survival factor. Interestingly, the ACM-derived activity for OBECs appears to reside in a signalling protein(s) belonging to the neuregulin (NRG) family of growth factors, and specifically appears to coincide with one or more products of the nrg-1 gene. Our observations provide evidence for the following: recombinant human neu differentiation factors (NDFbeta1, -2 and -3) are mitogenic to OBECs; the activity in ACM can be neutralized by NDF antibodies; these same antibodies detect a 50-kDa, non-heparin binding protein in concentrated ACM; astrocytes express detectable nrg-1 transcripts; and OBECs express functional NRG receptors erbB2 and erbB4. PMID- 10103072 TI - ZFM1/SF1 mRNA in rat and gerbil brain after global ischaemia. AB - Cerebral ischaemia results in significant brain damage, but the molecular mechanisms associated with ischaemia-induced brain injury are not well defined. We have adopted an improved differential-display method to search for new ischaemia-related genes. Among the different cDNAs isolated following transient forebrain ischaemia in rat, PH3.3 was selected for further studies. The search for homologies revealed that it is the rat homologue to human zinc finger motif 1 (ZFM1), also called mammalian splicing factor 1 (SF1). With Northern blot, PH3.3 hybridized with three mRNA species of 2.3, 2.9 and 3.6 kb, significantly increased at 6 h and 5 days after the ischaemic insult. These findings were extended also to another animal model. In situ hybridization in ischaemic gerbils showed that PH3.3 mRNA was induced in the dentate gyrus as early as 4 h post ischaemia. Expression peaked at 2 days in the whole hippocampus and cortex, and then progressively decreased towards sham levels. By day 4, expression had disappeared almost entirely from the cells in the CA1 region of the hippocampus, concomitant with the degeneration of pyramidal neurons. Interestingly, ZFM1/SF1 has been recently identified as activated following p53-induced apoptosis. Several lines of evidence suggest that p53 may play two roles in the post ischaemic brain. The primary role of p53 is to activate DNA repair processes, but if repair fails, apoptosis will be initiated. Thus, ZFM1/SF1 may represent a relevant link between p53 and the neuroprotective/neurodegenerative processes which follow cerebral ischaemia. PMID- 10103073 TI - Activity-dependent regulation of alternative splicing patterns in the rat brain. AB - Alternative splicing plays an important role in the expression of genetic information. Among the best understood alternative splicing factors are transformer and transformer-2, which regulate sexual differentiation in Drosophila. Like the Drosophila genes, the recently identified mammalian homologues are subject to alternative splicing. Using an antibody directed against the major human transformer-2 beta isoform, we show that it has a widespread expression in the rat brain. Pilocarpine-induced neuronal activity changes the alternative splicing pattern of the human transformer-2-beta gene in the brain. After neuronal stimulation, a variant bearing high similarity to a male-specific Drosophila tra-2179 isoform is switched off in the hippocampus and is detectable in the cortex. In addition, the ratio of another short RNA isoform (htra2-beta2) to htra2-beta1 is changed. Htra2-beta2 is not translated into protein, and probably helps to regulate the relative amounts of htra2-beta1 to beta3. We also observe activity-dependent changes in alternative splicing of the clathrin light chain B, c-src and NMDAR1 genes, indicating that the coordinated change of alternative splicing patterns might contribute to molecular plasticity in the brain. PMID- 10103074 TI - SNARE complex at the ribbon synapses of cochlear hair cells: analysis of synaptic vesicle- and synaptic membrane-associated proteins. AB - Neurotransmitters are released via exocytosis of synaptic vesicles involving a fusion complex consisting of a set of highly conserved proteins, which form a multiprotein complex resulting in the docking of synaptic vesicles at the site of release. There are three major differences between cochlear hair cell synapses and CNS synapses: (i) hair cells have a specialized structure, the synaptic ribbon, to which synaptic vesicles are attached; (ii) hair cells can maintain high and sustained release of neurotransmitter; and (iii) hair cells lack synaptophysin and synapsin. These differences suggest that an unconventional mechanism of neurotransmitter release may be involved at ribbon synapses. In this study we used different and complementary approaches to determine whether or not ribbon-containing hair cells of the cochlea express any component of the core fusion complex found in conventional synapses. Syntaxin 1, the synaptic membrane synaptosome-associated protein (SNAP)-25 and vesicle-associated membrane protein (VAMP or synaptobrevin) were found to be present in the organ of Corti of both rat and guinea-pig, as shown by reverse transcription polymerase chain reaction and Western blotting. In situ hybridization and immunocytochemistry showed mRNA and protein expression, respectively, in both inner and outer hair cells. Synaptotagmins I and II, generally considered to play major roles in neurotransmitter release at central synapses, were not detected in the organ of Corti. PMID- 10103075 TI - The close homologue of the neural adhesion molecule L1 (CHL1): patterns of expression and promotion of neurite outgrowth by heterophilic interactions. AB - The close homologue of L1 (CHL1), a member of the L1 family of neural adhesion molecules, is first expressed at times of neurite outgrowth during brain development, and is detectable in subpopulations of neurons, astrocytes, oligodendrocyte precursors and Schwann cells of the mouse and rat. Aggregation assays with CHL1-transfected cells show that CHL1 does not promote homophilic adhesion or does it mediate heterophilic adhesion with L1. CHL1 promotes neurite outgrowth by hippocampal and small cerebellar neurons in substrate-bound and soluble form. The observation that CHL1 and L1 show overlapping, but also distinct patterns of synthesis in neurons and glia, suggests differential effects of L1-like molecules on neurite outgrowth. PMID- 10103076 TI - Properties of NMDA receptors in rat spinal cord motoneurons. AB - Postnatal development and properties of N-methyl-d-aspartate (NMDA) receptors were studied with whole-cell and outside-out patch-clamp techniques in interneurons and fluorescence-labelled motoneurons in rat spinal cord slices. Both the absolute amplitude of NMDA-induced currents and currents normalized with respect to the motoneuron capacitance increased significantly at postnatal days 10-13 when compared to the responses evoked at postnatal days 2-3. The mean amplitude of the responses to kainate also increased in motoneurons of postnatal days 10-13. Single-channel currents induced by low concentrations of glutamate, exhibited four distinct amplitude levels corresponding to 19.2 +/- 2.4 pS, 38.4 +/- 3.5 pS, 56.3 +/- 2. 4 pS and 69.6 +/- 3.7 pS. In contrast, the conductance of single channels, recorded under identical conditions, in rat spinal cord interneurons was less, 15.3 +/- 3.2 pS, 29.9 +/- 5.4 pS, 46.7 +/- 4. 8 pS and 62.4 +/- 3.9 pS. The high (56/70 pS) conductance single-channel openings in motoneuron patches were sensitive to NMDA receptor inhibitors D-2-amino-5 phosphonovalerate, 7-chlorokynurenic acid and ifenprodil. Whole-cell NMDA-evoked currents were blocked in a voltage-dependent manner by extracellular Mg2+ with an apparent dissociation constant for Mg2+ binding at 0 mV of 1.8 +/- 0.5 mm. The conductance and relative distribution of NMDA receptor channel openings induced by 1 micrometer glutamate in patches isolated from the motoneurons were independent of age from postnatal day 4 to 14. The results suggest that the properties of NMDA receptor channels in motoneurons differ from those in spinal cord interneurons and cells transfected with NR1/NR2 subunits. PMID- 10103077 TI - Adrenergic innervation of rat sensory ganglia following proximal or distal painful sciatic neuropathy: distinct mechanisms revealed by anti-NGF treatment. AB - Sympathetic axons invade dorsal root ganglia (DRG) following nerve injury, and activity in the resulting pericellular axonal 'baskets' may underlie painful sympathetic-sensory coupling. Sympathetic sprouting into the DRG may be stimulated by nerve growth factor (NGF). To test this hypothesis, we investigated the effect of daily anti-NGF administration on pain and on sprouting in the DRG induced by chronic sciatic constriction injury (CCI) or L5 spinal nerve ligation (SNL). These models have been shown to differ subtly in the onset of pain behaviours and adrenergic sprouting, and we now demonstrate a fundamental difference in the way sympathetic axons invade the DRG: after CCI, perivascular noradrenergic collaterals sprouted into the DRG in a manner dependent upon peripherally derived NGF. In contrast, after SNL, regenerating sympathetic axons were diverted towards the DRG from the spinal nerve by the obstructing ligature, and this effect was only moderately impeded by anti-NGF. The differential dependence on anti-NGF suggests that adrenergic innervation of the DRG after SNL and CCI may reflect regenerative and collateral sprouting, respectively. Pain behaviour was similarly affected: anti-NGF completely prevented CCI-induced thermal hyperalgesia and mechanoallodynia, but the same treatment only partly relieved these symptoms following SNL. These differences emphasize that although CCI and SNL may result in similar behavioural abnormalities, the underlying mechanisms may be governed by distinct processes, differentially dependent on peripheral NGF. These mechanistic differences will have to be considered in the development of appropriate treatment strategies for neuropathic pain produced by different types of pathology. PMID- 10103078 TI - Myelin-associated oligodendrocytic basic protein is essential for normal arrangement of the radial component in central nervous system myelin. AB - We previously reported that myelin-associated oligodendrocytic basic protein (MOBP) was abundantly expressed in the central nervous system (CNS) myelin, and shared several characteristics with myelin basic protein (MBP). In particular, a cluster of positively charged amino acids was considered to facilitate compaction of the cytoplasmic face of the myelin sheath, as in the case of MBP. However, the contribution of MOBP in forming and maintaining the myelin sheath still remains unclear. Recent investigations showed that one isoform of MOBP was expressed in the embryo prior to myelination, and MOBP isoforms were colocalized with the microtubular network and nucleus in vitro. To explore the role of MOBP in vivo, we generated MOBP-deficient mice and analysed the CNS myelin. Surprisingly, the compact myelin was formed, however, the myelin from MOBP-deficient mice exposed to hexachlorophene, a known dysmyelinating agent, showed widening of the major dense lines. These results suggest that MOBP is not essential for myelin formation, but reinforces the apposition of the cytoplasmic faces of the myelin sheath. A striking phenotype of MOBP-deficient mice was the presence of the straight 'condensed' radial component. This component has been described as a tight junction-like complex running radially and zig-zag through the CNS myelin sheath between inner and outer mesaxons. These results suggest that MOBP is essential for normal arrangement of the radial component. PMID- 10103079 TI - Callosal connections of the parabelt auditory cortex in macaque monkeys. AB - Auditory cortex of macaque monkeys is located on the lower bank of the lateral sulcus and the adjoining superior temporal gyrus. This region of cortex contains a core of primary-like areas surrounded by a narrow belt of associated fields. Adjacent to the lateral belt on the superior temporal gyrus is a parabelt region which contains at least two subdivisions (rostral and caudal). In previous studies we defined the parabelt region as cortex with topographic cortical connections with the belt areas surrounding the core, and connections with the dorsal and magnocellular divisions of the medial geniculate complex, but minimal connections with the core region and ventral division of the medial geniculate complex. The callosal connections of the parabelt auditory cortex were determined by placing injections, of up to six distinguishable tracers, into different locations of the parabelt region in each of four macaque monkeys. The results indicated that the strongest callosal projections arise from homotopic areas in parabelt cortex, and they roughly matched the rostrocaudal levels of the medial and lateral belt cortex. Weaker callosal inputs to the parabelt originate from the corresponding levels of the superior temporal gyrus and superior temporal sulcus. The core region does not contribute significant callosal projections to the parabelt region. The results provide further support for the conclusion that the parabelt region represents a third level of auditory cortical processing beyond direct activation by primary subcortical and cortical auditory structures. PMID- 10103080 TI - Ionotropic glutamate receptors in isolated horizontal cells of the rabbit retina. AB - With the use of the whole-cell voltage-clamp technique, we have recorded the currents induced by ionotropic glutamate receptor agonists on isolated axonless horizontal cells (HC) of rabbit retina. Bath application of the non-N-methyl-D aspartate receptor agonists: kainate (KA), alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) and L-glutamate (GLU) produced an increase in the conductance for non-selective cations. All the isolated horizontal cells responded to GLU, AMPA and KA. Responses elicited by GLU and AMPA but not KA exhibited a concentration-dependent desensitization. Application of N-methyl-D aspartate (NMDA) evoked no responses. The rank order affinities of the agonists as estimated from EC50 values were AMPA > GLU > KA. Whereas KA had the lowest affinity of the agonists tested, it produced the largest currents. Hill coefficients of the concentration-response data were near 1 for AMPA, and 2 for KA and GLU. Coapplication of AMPA with cyclothiazide (CTZ) blocks AMPA receptor desensitization, and enhanced its effects on conductance. However, CTZ did not change the KA -induced conductances. In all cells tested, 6,7-dinitroquinoxaline (DNQX) completely and reversibly blocked the effects of KA and AMPA. The KA- and AMPA-induced currents were also completely blocked by 1-(4-aminophenyl)-4-methyl 7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a selective AMPA receptor antagonist. These results indicate that the responses to glutamate agonists in HC were mediated almost exclusively by AMPA receptors. Our study indicates that AMPA receptors play a fundamental role in mediating the synaptic input into rabbit horizontal cells. PMID- 10103081 TI - CNS pattern of metabolic activity during tonic pain: evidence for modulation by beta-endorphin. AB - CNS correlates of acute prolonged pain, and the effects of partial blockade of the central beta-endorphin system, were investigated by the quantitative 2 deoxyglucose technique in unanaesthetized, freely moving rats. Experiments were performed during the second, tonic phase of the behavioural response to a prolonged chemical noxious stimulus (s.c. injection of dilute formalin into a forepaw), or after minor tissue injury (s.c. saline injection). During formalin induced pain, local glucose utilization rates in the CNS were bilaterally increased in the grey matter of the cervical spinal cord, in spinal white matter tracts and in several supraspinal structures, including portions of the medullary reticular formation, locus coeruleus, lateral parabrachial region, anterior pretectal nucleus, the medial, lateral and posterior thalamic regions, basal ganglia, and the parietal, cingulate, frontal, insular and orbital cortical areas. Pretreatment with anti-beta-endorphin antibodies, injected i.c.v., led to increased metabolism in the tegmental nuclei, locus coeruleus, hypothalamic and thalamic structures, putamen, nucleus accumbens, diagonal band nuclei and dentate gyrus, and in portions of the parietal, cingulate, insular, frontal and orbital cortex. In formalin-injected rats, pretreated with anti-beta-endorphin, behavioural changes indicative of hyperalgesia (increased licking response) were found, which were paralleled by a significant enhancement of functional activity in the anterior pretectal nucleus and in thalamo-cortical systems. A positive correlation was found between the duration of the licking response and metabolic activity of several forebrain regions. These results provide a map of the CNS pattern of metabolic activity during tonic somatic pain, and demonstrate a modulatory role for beta-endorphin in central networks that process somatosensory inputs. PMID- 10103082 TI - Episodic corticosterone treatment accelerates kindling epileptogenesis and triggers long-term changes in hippocampal CA1 cells, in the fully kindled state. AB - We tested the effect of episodic (approximately 10 days) corticosterone treatment on: (i) behavioural symptoms during kindling epileptogenesis; and (ii) electrical activity in the CA1 hippocampal area during epileptogenesis, and later on, in the fully kindled state. Male rats received a corticosterone-releasing pellet (100 mg/day) shortly before kindling was started, resulting in elevated hormone levels during the early and middle stages of epileptogenesis. The appearance of moderate behavioural signs of epilepsy and severe tonic-clonic seizures was significantly accelerated in corticosterone-treated animals compared to placebo controls. During epileptogenesis, corticosterone treatment did not affect the amplitude and paired-pulse characteristics of in vivo-recorded CA1 field responses, or the duration of the afterdischarge following tetanic stimulation of the Schaffer collaterals. However, other properties of CA1 cells studied in vitro, in the fully kindled state, were altered by the earlier episodic corticosterone treatment. Thus, in kindled rats, the amplitude of the population spike in the CA1 area was significantly enhanced after prior exposure to high corticosterone levels. Prior episodic steroid treatment resulted furthermore in a significantly increased amplitude of voltage-gated Ca currents, in kindled rats. At that time, corticosterone levels of animals which had received a corticosterone-releasing pellet earlier were no longer elevated compared to the placebo controls; the corticosteroid-treated rats did also not differ from the controls with respect to the mRNA expression levels for the two corticosteroid receptor subtypes in the hippocampus. The data suggest that exposure of animals to a period of stressful experiences during a critical phase in epileptogenesis could impose lasting deleterious effects on the course of epilepsy, even when CORT levels have been normalized again. PMID- 10103083 TI - c-Jun expression after axotomy of corneal trigeminal ganglion neurons is dependent on the site of injury. AB - The proto-oncogene c-Jun has been implicated in the control of neuronal responses to injury and in axonal growth during regenerative processes. We have investigated the expression of c-Jun during normal terminal remodelling in trigeminal ganglion neurons innervating the cornea and after acute injury of epithelial nerve terminals or parent axons. Remodelling and rearrangement, or damage limited to corneal epithelium endings, was not a trigger for activation of c-Jun expression. However, injury of parent axons in the stroma or in the orbital ciliary nerves induced c-Jun expression in 50% of the population of corneal neurons, which included all of the large myelinated and 20% of the small neuropeptide-containing corneal neurons. This suggests that c-Jun expression in trigeminal ganglion neurons is not associated with normal remodelling or regeneration of peripheral nerve terminals, and that it takes place only when parent axons are injured. A substantial number of damaged neurons do not express c-Jun, indicating that in primary sensory neurons, injury and regeneration may not always be coupled to the expression of this proto-oncogene. PMID- 10103084 TI - Organization of visual cortex in the northern quoll, Dasyurus hallucatus: evidence for a homologue of the second visual area in marsupials. AB - Two visual areas, V1 and V2 (first and second visual areas), appear to be present in the posterior neocortex of all eutherian mammals investigated so far. However, previous studies have not established whether an area homologous to V2 also exists in metatherian mammals (marsupials). Using electrophysiological techniques, we mapped the visual receptive fields of neurons in the striate and peristriate cortices of the northern quoll, an Australian marsupial. We found that neurons in a 2-mm-wide strip of cortex rostrolateral to V1 form a single, relatively simple representation of the complete contralateral hemifield. This area resembles V2 of eutherians in several respects: (i) neurons in the medial half of the peristriate area represent the lower visual quadrant, whereas those in the lateral half represent the upper visual quadrant; (ii) the vertical meridian of the visual field is represented adjacent to V1, while the visual field periphery is represented along the lateral and rostrolateral borders of the peristriate area; (iii) there is a marked anisotropy in the representation, with a larger magnification factor parallel to the V1 border than perpendicular to this border; and (iv) receptive fields of multiunit clusters in the peristriate cortex are much larger than those of cells in V1 at comparable eccentricities. The cortex immediately rostral and lateral to V2 did not respond to visual stimulation under our recording conditions. These results suggest that V1 and V2 together form a 'core' of homologous visual areas, likely to exist in all therian mammals. PMID- 10103085 TI - Suppression of epileptogenesis by modification of N-methyl-D-aspartate receptor subunit composition. AB - The effects of altered N-methyl-D-aspartate (NMDA) receptor subunit composition on seizure development in kindling epilepsy were assessed in transgenic mice expressing high neuronal levels of NR2D under control of the calcium/calmodulin kinase II alpha subunit (alphaCaMKII) promoter. The NR2D subunit is normally present at very low levels in the mature forebrain. Transgenic mice showed a marked reduction of amygdala kindling development. Spread of epileptic activity was retarded and generalized seizures appeared later in animals overexpressing NR2D compared with wild-type mice. The progressive lengthening of epileptiform activity, which normally occurs in kindling, was also dampened in transgenic animals. We conclude that NMDA receptor subunit composition determines the progression of experimental epilepsy. PMID- 10103086 TI - Spatiotemporal patterning of glutamate receptors in developing ferret striate cortex. AB - We have studied glutamate receptor levels during very early phases of cortical formation by using quantitative in vitro autoradiography to map the expression of NMDA, AMPA and kainate receptors in the developing primary visual cortex of the ferret. NMDA and non-NMDA receptors exhibit very different developmental profiles in primary visual cortex. NMDA receptor density is low at birth and increases throughout the first 2 postnatal months, rising between threefold (layers II/III) and ninefold (layer VI). In contrast, AMPA receptors are abundant at birth and their density remains constant for the first postnatal month, before rising by a maximum of 1.7-fold (layer I) at around the time of eye-opening (postnatal day 32). Kainate receptors are also present in high levels at birth and their expression levels rise in the early postnatal period by between 1. 5-fold (layer I) and threefold (layers V/VI) to a peak just after eye-opening. The proportion of the total ionotropic glutamate receptor binding contributed by NMDA receptors thus rises from 5% at birth to a maximum of 22% at 2 months of age, while the AMPA receptor contribution falls from 87% to 72% over the same period. Below cortex, all three glutamate receptor subtypes are expressed in the subplate region for the first 3 postnatal weeks. These developmental patterns, combined with the fact that AMPA receptors are densely expressed in the proliferative zones underlying presumptive area 17, indicate that non-NMDA receptor expression levels in primary visual cortex are mostly specified much earlier than those of NMDA receptors. PMID- 10103087 TI - Ontogeny of water transport in rat brain: postnatal expression of the aquaporin-4 water channel. AB - Brain water transport is poorly understood at the molecular level, and marked changes occur during brain development. As the aquaporin-4 (AQP4) water channel protein is abundant in brain, the expression levels and subcellular distribution of this protein were examined during postnatal development. This study focused on the cerebellum, which showed the same pattern of AQP4 development as the rest of the brain. Semiquantitative immunoblotting revealed very low levels of AQP4 in the first postnatal week. A pronounced increase was noted in the second week, from 2% of adult level at postnatal day 7 (PN7) to 25% at PN14. At PN1 and PN3 immunofluorescence microscopy revealed weak labelling, mainly in radial processes (Bergmann fibres) and at the pial surface. Between PN7 and PN14 the labelling underneath the pia showed a strong increase, and immunoreactivity also appeared around blood vessels throughout the cerebellum. High-resolution immunogold electron microscopy revealed that the subpial and perivascular labelling was restricted to glial end feet, notably to those plasma membrane domains that were apposed to the basal laminae. At no stage was there any evidence of neuronal AQP4 labelling, and AQP1, -2, -3 and -5 proteins were not detected in the neuropil. Riboprobes to AQP4 mRNA produced a particularly strong in situ hybridization signal in glial cells between PN7 and PN14, corresponding to the stage of the most rapid increase of AQP4 protein. The time course and pattern of AQP4 expression suggests that this aquaporin plays an important role in brain water and K+ homeostasis from the second week of development. PMID- 10103088 TI - Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. AB - The vanilloid receptor (VR1) protein functions both as a receptor for capsaicin and a transducer of noxious thermal stimuli. To determine the expression and targetting of this protein, we have generated antisera against both the amino and carboxy termini of VR1. Within the dorsal root and trigeminal ganglia of rats, VR1-immunoreactivity (VR1-ir) was restricted to small and medium sized neurons. VR1-ir was transported into both the central and peripheral processes of these primary afferent neurons, as evidenced by: (i) the presence of VR1-ir in nerve fibres and terminals in lamina I and lamina II of the superficial dorsal horn, and the association of VR1-ir with small diameter nerve fibres in the skin and cornea; (ii) the reduction of VR1-ir in the spinal cord after dorsal rhizotomy; and (iii) the accumulation of VR1-ir proximal to sciatic nerve ligation. At the ultrastructural level, VR1-ir was associated with plasma membranes of neuronal perikarya in dorsal root ganglia and nerve terminals in the dorsal horn. VR1-ir was also seen in nerve fibres and terminals in the spinal trigeminal nucleus and nucleus of the solitary tract. Within a large proportion of dorsal root ganglion neurons and the terminals of their axons, VR1-ir was colocalized with staining for the P2X3 purinoceptor, and with binding sites for the lectin IB4. Surprisingly, VR1-ir did not coexist substantially in nerve fibres and terminals that contain substance P and calcitonin gene-related peptide, suggesting complex mechanisms for the release of these neuropeptides in response to capsaicin application. PMID- 10103089 TI - Expression of Ras-GRF in the SK-N-BE neuroblastoma accelerates retinoic-acid induced neuronal differentiation and increases the functional expression of the IRK1 potassium channel. AB - Ras-GRF, a neuron-specific Ras exchange factor of the central nervous system, was transfected in the SK-N-BE neuroblastoma cell line and stable clones were obtained. When exposed to retinoic acid, these clones showed a remarkable enhancement of Ras-GRF expression with a concomitant high increase in the level of active (GTP-bound) Ras already after 24 h of treatment. In the presence of retinoic acid, the transfected cells stopped growing and acquired a differentiated neuronal-like phenotype more rapidly than the parental ones. Cells expressing Ras-GRF also exhibited a more hyperpolarized membrane potential. Moreover, treatment with retinoic acid led to the appearance of an inward rectifying potassium channel with electrophysiological properties similar to IRK1. This current was present in a large number of cells expressing Ras-GRF, while only a small percentage of parental cells exhibited this current. However, Northern analysis with a murine cDNA probe indicated that IRK1 mRNA was induced by retinoic acid at a similar level in both kinds of cells. Brief treatment with a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway reduced the number of transfected cells showing IRK1 activity. These findings suggest that activation of the Ras pathway accelerates neuronal differentiation of this cell line. In addition, our results suggest that Ras-GRF and/or Ras pathway may have a modulatory effect on IRK1 channel activity. PMID- 10103090 TI - Blockade of neurotensin receptors suppresses the dopamine D1/D2 synergism on immediate early gene expression in the rat brain. AB - A remarkable feature of dopamine functioning is that the concomitant activation of D1-like and D2-like receptors acts to intensify the expression of various dopamine-dependent effects, in particular the expression of the immediate-early genes, c-fos and zif268. Using non-peptide neurotensin receptor antagonists, including SR48692, we have determined that blockade of neurotensin receptors reduced the cooperative responses of direct acting D2-like (quinpirole) and partial D1-like (SKF38393) dopamine agonists on the expression of Fos-like antigens and zif268 mRNA. Pretreatment with SR48692 (3 and 10 mg/kg) reduced the number of Fos-like immunoreactive cells produced by the combined administration of SKF38393 (20 mg/kg) and quinpirole (1 mg/kg) in the caudate-putamen, nucleus accumbens, globus pallidus and ventral pallidum. High-affinity neurotensin receptors are likely to be involved in these D1-like/D2-like cooperative responses, as compounds structurally related to SR48692, SR48527 (3 mg/kg) and its (-)antipode, SR49711 (3 mg/kg), exerted a stereospecific antagonism in all selected brain regions. Pretreatment with SR48692 (10 mg/kg) also diminished Fos induction by the indirect dopamine agonist, cocaine (25 mg/kg), particularly at the rostral level of the caudate-putamen. In situ hybridization experiments in the caudate-putamen indicated that SR48692 (10 mg/kg) markedly reduced zif268 mRNA labelling produced by SKF38393 plus quinpirole in cells not expressing enkephalin mRNA, but was unable to affect the concomitant decrease of zif268 mRNA labelling in enkephalin-positive cells. Taken together, the results of the present study indicate that neurotensin is a key element for the occurrence of cooperative responses of D2-like and partial D1-like agonists on immediate-early gene expression. PMID- 10103091 TI - Scorpion alpha-like toxins, toxic to both mammals and insects, differentially interact with receptor site 3 on voltage-gated sodium channels in mammals and insects. AB - alpha-Like toxins, a unique group designated among the scorpion alpha-toxin class that inhibit sodium channel inactivation, are highly toxic to mice but do not compete for alpha-toxin binding to receptor site 3 on rat brain sodium channels. We analysed the sequence of a new alpha-like toxin, which was also highly active on insects, and studied its action and binding on both mammalian and insect sodium channels. Action of the alpha-like toxin on isolated cockroach axon is similar to that of an alpha-toxin, and the radioactive toxin binds with a high affinity to insect sodium channels. Other sodium channel neurotoxins interact competitively or allosterically with the insect alpha-like toxin receptor site, similarly to alpha-toxins, suggesting that the alpha-like toxin receptor site is closely related to receptor site 3. Conversely, on rat brain sodium channels, specific binding of 125I-alpha-like toxin could not be detected, although at high concentration it inhibits sodium current inactivation on rat brain sodium channels. The difficulty in measuring binding to rat brain channels may be attributed to low-affinity binding due to the acidic properties of the alpha-like toxins that also impair the interaction with receptor site 3. The results suggest that alpha-like toxins bind to a distinct receptor site on sodium channels that is differentially related to receptor site 3 on mammalian and insect sodium channels. PMID- 10103092 TI - X-ray kinematic analysis of shoulder movements during target reaching and food taking in the cat. AB - Co-ordinate movements around the shoulder are essential during reaching movements. We performed a quantitative kinematic analysis of movements of the shoulder girdle: three-dimensional X-ray frames (time resolution 20 ms) were recorded during the target-reaching and food-taking paradigm in five cats either sitting (n = 4) or standing (n = 1) in front of a food well. Movements of the scapula consisted of a flexion of the scapula (anteversion of the glenoid) followed by flexion of the gleno-humeral joint (decrease in the angle between the scapular spine and humerus). In the sitting animals, the gleno-humeral flexion reversed to extension some 120 ms before object contact, while in the standing animal flexion continued during the ongoing scapular flexion. In both cases, the scapula was nearly horizontal at the end of target reaching. The fulcrum for scapular movements was located near the vertebral border of the scapula at the medial elongation of the scapular spine. No major translational components of the fulcrum with respect to the trunk were found during reaching. Together with full flexion of the scapula, this reduces the number of degrees of freedom considerably and thereby probably simplifying the specification of the end-point of the limb chain. End-point specification is further supported by rotational movements of the scapula. In the sitting animal, the amplitude of inward rotation along the long axis of the scapula was around 20 degrees, while it was much more variable in the standing animal, reflecting more variable starting positions. We hypothesize that the glenoid is used to 'foveate' the target object. PMID- 10103093 TI - Vasopressin released within the septal brain area during swim stress modulates the behavioural stress response in rats. AB - The aim of the present study was to investigate the physiological significance of the neuropeptide arginine vasopressin (AVP) released within the septum, in the behavioural response of rats to stress. In the first experiment, rats were chronically implanted with a microdialysis probe aimed at the mediolateral or ventral septum to monitor the local release of AVP in response to 10 min of forced swimming in 20 degrees C warm water. Exposure to this stressor caused a significant increase in AVP release in both the mediolateral (174 +/- 21%, P < 0.01) and ventral septum (220 +/- 33%, P < 0.01). In contrast, microdialysates collected outside the mediolateral septum or in the lateral ventricle remained at prestress levels throughout the dialysis period. Furthermore, unstressed control animals failed to show significant alterations in vasopressin release in the mediolateral septum. In a second experiment, the introduction of the V1 receptor antagonist d(CH2)5Tyr(Me)AVP into the mediolateral septum via inverse microdialysis concomitant with stressor exposure caused the rats to spend an increased time floating and a reduced time swimming compared to vehicle-treated rats. This effect was acute and also detected 24 h after antagonist administration. Taken together, these findings demonstrate a significant activation of the septal vasopressinergic system in response to swim stress. Furthermore, our data support the view that AVP released within this brain area is involved in the generation of active behavioural strategies aimed at coping with new and challenging situations. PMID- 10103094 TI - Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns. AB - The cytoarchitecture of the human and the macaque monkey dorsolateral prefrontal cortex has been examined in a strictly comparative manner in order to resolve major discrepancies between the available segmentations of this cortical region in the human and the monkey brain. In addition, the connections of the dorsolateral prefrontal cortical areas were re-examined in the monkey. The present analysis showed that only a restricted portion of what had previously been labelled as area 46 in the monkey has the same characteristics as area 46 of the human brain; the remaining part of this monkey region has the characteristics of a portion of the middle frontal gyrus in the human brain that had previously been included as part of area 9. We have labelled this cortical area as 9/46 in both species. These two areas (i.e. 46 and 9/46), which constitute the lower half of the mid-dorsolateral frontal cortex, have a well-developed granular layer IV, and can easily be distinguished from area 9, on the upper part of the mid dorsolateral region, which does not have a well-developed granular layer IV. Area 9 has the same basic pattern of connections as areas 46 and 9/46, but, unlike the latter areas, it does not receive input from the lateral parietal cortex. Caudal to area 9, on the dorsomedial portion of the frontal cortex, there is a distinct strip of cortex (area 8B) which, unlike area 9, receives significant input from the prestriate cortex and the medial parietal cortex. The present results provide a basis for a closer integration of findings from functional neuroimaging studies in human subjects with experimental work in the monkey. PMID- 10103095 TI - Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal. AB - The activity of mesolimbic dopaminergic neurons was investigated in rats at various times after a chronic regimen of morphine, which produced, upon suspension, a marked somatic withdrawal syndrome. Single-cell extracellular recording techniques, coupled with antidromic identification from the nucleus accumbens, were used to monitor neuronal activity while behavioural observations allowed quantification of the somatic signs of morphine withdrawal. Temporal correlation of electrophysiological indices, such as firing rate and burst firing, with scores obtained through behavioural assessments proved negative, in that somatic signs were pronounced at 24 h after suspension of treatment and then subsided to control values at 72 h after the last morphine injection. In contrast, the firing rate and burst firing of mesolimbic dopaminergic neurons were found to be reduced at 1, 3 and 7 days after morphine withdrawal. After 14 drug-free days, electrophysiological analysis revealed an apparent normalization of various parameters. However, at this time, intravenous administration of morphine produced an increment of electrical activity which was significantly higher than that obtained in control (saline treated) rats. Further, administration of the opiate antagonist naltrexone, administered without prior morphine, at 3, 7 and 14 days after the last morphine administration, failed to alter dopaminergic neuronal activity. The results indicate: (i) that the activity of mesolimbic dopaminergic neurons remains reduced well after somatic signs of withdrawal have disappeared; (ii) after 14 days of withdrawal, the augmented magnitude of the electrophysiological response to exogenous morphine suggests an increased sensitivity of opiate receptors; and (iii) the lack of relationship between dopaminergic activity and somatic signs of withdrawal corroborates the notion that dopaminergic activity in the mesolimbic system does not participate in the neurobiological mechanisms responsible for somatic withdrawal. The present results may be relevant to the phenomenon of drug addiction in humans and consequent relapse after drug-free periods. PMID- 10103096 TI - Activation of reward circuitry in human opiate addicts. AB - The neurobiological mechanisms of opiate addictive behaviour in humans are unknown. A proposed model of addiction implicates ascending brainstem neuromodulatory systems, particularly dopamine. Using functional neuroimaging, we assessed the neural response to heroin and heroin-related cues in established opiate addicts. We show that the effect of both heroin and heroin-related visual cues are maximally expressed in the sites of origin of ascending midbrain neuromodulatory systems. These context-specific midbrain activations predict responses to salient visual cues in cortical and subcortical regions implicated in reward-related behaviour. These findings implicate common neurobiological processes underlying drug and drug-cue-related effects. PMID- 10103097 TI - Acetylcholinesterase and inhibitors: effects upon normal and regenerating nerves of the rat. AB - In peripheral nerves, the function of acetylcholinesterase (AChE) is not related to hydrolysis of acetylcholine. To test for a trophic role, AChE or its inhibitors were administered locally to normal and regenerating nerves of rats. In the normal nerve, neither AChE nor serum albumin affected the cytological pattern of the nerve. BW284c51, a specific inhibitor of AChE, resulted in demyelination, proliferation of Schwann cells and sprouting of axons after 5-7 days. Edrophonium or propidium, other specific inhibitors of AChE, did so to a much lesser extent. Vehicle, and iso-OMPA (inhibitor of pseudocholinesterases) did not affect the cytology of the nerve. Elongation of regenerating axons was evaluated at day 3 post-crush. Native AChE applied distal to the crush reduced the elongation of regenerating axons (- 36%), while serum albumin, heated AChE and filtered AChE did not. BW284c51, edrophonium or propidium enhanced the axonal elongation (33%) when they were administered for 2 days before, but not after, the crush. Iso-OMPA or vehicle administered before or after the crush were not effective. Thus, AChE reduces elongation of regenerating axons, while inhibition of AChE enhances elongation and affects the cytology of the normal nerve as well. We propose that AChE has a trophic role in mammalian peripheral nerves. PMID- 10103098 TI - Origins of the glycinergic inputs to the rat locus coeruleus and dorsal raphe nuclei: a study combining retrograde tracing with glycine immunohistochemistry. AB - The amino acid glycine is a major inhibitory neurotransmitter in the brainstem and is likely involved in the tonic inhibition of the monoaminergic neurons during all sleep-waking stages. In order to determine the neurons at the origin of the glycinergic innervation of the two principal monoaminergic nuclei, the locus coeruleus and the dorsal raphe of the rat, we applied a double-labelling technique, combining retrograde transport of cholera-toxin B subunit with glycine immunohistochemistry. Using this technique, we found that the locus coeruleus and dorsal raphe nuclei receive a common glycinergic innervation from the ventral and ventrolateral periaqueductal grey, including the adjacent deep mesencephalic reticular nucleus. Small additional glycinergic inputs to these nuclei originated from the lateral paragigantocellular nucleus and the rostral ventromedial medullary reticular formation. The potential role of these glycinergic inputs in the control of the excitability of the monoaminergic neurons of the locus coeruleus and dorsal raphe nuclei is discussed. PMID- 10103099 TI - Cytochrome c release and caspase-3 activation during colchicine-induced apoptosis of cerebellar granule cells. AB - The microtubule-disrupting agent colchicine is known to be neurotoxic toward certain neuronal populations including cerebellar granule cells (CGCs). In this study we investigated the involvement of cytochrome c release and caspase-3 activation during colchicine-induced CGC apoptosis. Treatment of rat CGCs with 1 micrometer colchicine (for up to 24 h) caused high molecular weight DNA fragmentation and nuclear condensation. An involvement of group II caspases (which includes caspase-3) was demonstrated by the proteolytic degradation of poly(ADP-ribose) polymerase (PARP) after 18 h exposure to colchicine. Colchicine induced a time-dependent increase in Ac-Asp-Glu-Val-Asp-alpha-(4-methyl-coumaryl 7-amide) (DEVD-MCA) cleavage activity in CGCs, which was blocked with a specific, peptide-based, aldehyde inhibitor of group II caspases, i. e. DEVD-CHO. We also observed a time-dependent proteolysis of caspase-3 as judged by the appearance of p17 which is one of the subunits of active caspase-3. Activation of caspase-3 during colchicine-induced apoptosis may be mediated by cytochrome c since there was a close correlation between the time courses of cytochrome c release from the mitochondria and of caspase-3 activation. Furthermore, colchicine-induced apoptosis, as assessed by propidium iodide visualization of the nuclei, could be blocked by the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (O-methyl) fluoromethyl ketone. PMID- 10103100 TI - The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons. AB - Neurotoxicity is one of the side-effects of the therapeutically useful antitumour agent, Ara-C (or 1-beta-d-arabinofuranosyl-cytosine, cytarabine). This agent is also reported to induce cell death of cultured neurons. In this study, we show that Ara-C-induced death of differentiating rat cerebellar granule neurons is prevented by cycloheximide at concentrations corresponding to its action in preventing protein synthesis. The death is accompanied by cleavage of the caspase substrate poly ADP ribose polymerase (PARP) and c-Abl-dependent activation of the stress-activated protein kinases c-Jun N-terminal kinase and p38. However, c-Jun levels do not rise and the activation of the stress-activated protein kinases is not required for this form of neuronal death. Cyclin-dependent kinase (cdk) activity and inappropriate cell-cycle re-entry have been implicated in some forms of death in differentiated neurons. Here we show that Ara-C-induced death of cerebellar granule neurons is prevented by an inhibitor of cdk4, whereas inhibition of cdk1, -2 and -5 mimics the death, and non-cdk4/6 cdks are inhibited by Ara-C treatment. Cdk1 and -2 are dramatically down-regulated during neuronal differentiation, and neither Ara-C nor inhibition of these cdks induces death in mature neurons. This mechanism could also play a significant role in the neurotoxicity associated with the therapeutic use of Ara-C, as cdk levels can be upregulated in stressed neurons of adult brain. We propose that the balance between cdk4/6 and cdk1/2/5 activity may determine the survival of early differentiating neurons, and that DNA-damaging agents may induce neuronal death by inhibiting cdk1/2/5 under conditions which require these activities for survival. PMID- 10103101 TI - AMPA-preferring receptors with high Ca2+ permeability mediate dendritic plasticity of retinal horizontal cells. AB - The synaptic complex formed by the cone photoreceptor pedicles and the dendrites of horizontal cells in the teleost retina undergoes structural changes during light adaptation. Numerous spinules are formed by the terminal dendrites, and they are subsequently retracted during dark adaptation. In a retina kept under continuous illumination, the retraction process can be initiated by analogues of the neurotransmitter glutamate acting at AMPA/kainate receptors. On the other hand, the retraction process depends on calcium influx and the subsequent activation of CaMkII. We show here that the retraction of spinules induced by AMPA or kainate is not impaired in the presence of cobalt, making an involvement of voltage-gated calcium channels unlikely. Using calcium imaging techniques with isolated horizontal cells, we demonstrate that AMPA and kainate, but not NMDA, increase [Ca2+]i in the presence of nicardipine, caffeine and thapsigargin. The increase of [Ca2+]i under these conditions depends on [Ca2+]o and on the agonist in a dose-dependent manner, suggesting that the increase of [Ca2+]i is largely due to calcium influx through the agonist-gated channel. Pharmacological studies were performed to determine whether AMPA- and/or kainate-preferring receptors mediate the calcium influx. The AMPA-preferring receptor antagonist LY303070 blocked glutamate- and kainate-evoked increases of [Ca2+]i in a concentration dependent manner, indicating that kainate-preferring receptors contributed little or nothing to the observed [Ca2+]i increase. This was supported by experiments where cyclothiazide (which blocks the desensitization of AMPA receptors) and concanavalin A (which potentiates responses mediated by kainate receptors) were applied. In all cases, LY303070 blocked the agonist-evoked increase of [Ca2+]i. The presence of AMPA-preferring receptors with high Ca2+ permeability on horizontal cells was also supported by measuring agonist-induced currents using whole-cell recording techniques. Furthermore, LY303070 was able to impair the retraction of spinules during dark adaption in the in vivo situation. PMID- 10103102 TI - The isolated mammalian brain: an in vivo preparation suitable for pathway tracing. AB - An in vitro preparation of complete brain is presented which allows successful tracing with fast axonal tracers for at least 2 days after in vitro preparation. A simple procedure is used, by which the isolated brain is submerged in oxygenated artificial cerebrospinal fluid, enabling maintenance of adequate integrity without perfusion the vascular system. The use of an isolated brain has many advantages: virtually all brain areas are easily accessible; tracer applications are possible without problems of animal survival; and the tracers are be translocated by blood circulation. The viability of this isolated brain preparation was validated by successful recording of extracellular field potentials 1 day later. PMID- 10103103 TI - Visual experience alters the molecular profile of NMDA-receptor-mediated sensory transmission. AB - N-methyl-D-aspartate (NMDA) receptors (NMDArs) may facilitate experience dependent changes in the visual system. Early sensory experience has an influence over the production of the molecular components from which NMDArs are assembled, and thereby alters the properties of functional receptors. Using the antagonists D-2-amino-5-phosphonovalerate (AP5) and 3-(2-carboxypiperazin-4-yl)-propyl-1 phosphonate (CPP), which have some selectivity for different variants of the NMDAr, we demonstrate that visual deprivation (by dark rearing) has functional consequences for NMDArs in the superior colliculus. An increase in the sensitivity of visual responses to AP5 in dark-reared rats indicated that NMDArs were more important for visual transmission in these individuals. We also observed a relative change in the efficacy of the antagonists against the visual responses of normal versus dark-reared rats. AP5 reduced the visual responses of both groups, but CPP was ineffective against visual responses after dark rearing. In the same neurons, CPP blocked NMDA induced activity indicating that molecular adaptations of NMDArs are specific to those synapses mediating visual activity. PMID- 10103104 TI - Ca2+ activation of hSlo K+ channel is suppressed by N-terminal GFP tag. AB - The human slow poke (hSlo) K+ channel was tagged with GFP (green fluorescent protein) at the N-terminus of its alpha-subunit. The fusion protein was expressed transiently in HEK293 cells; it formed functional voltage-gated channels as shown by whole cell patch-clamp measurements. However, the tag lowered the voltage dependence of gating and it suppressed the typical left-shift of gating by intracellular binding of Ca2+. The location of the GFP-tagged N-terminus was confirmed to be on the extracellular side by application of a monoclonal antibody to nonpermeabilized cells. Structural interpretations of the effects are discussed. PMID- 10103105 TI - Reduced function of L-AP4-sensitive metabotropic glutamate receptors in human epileptic sclerotic hippocampus. AB - Human temporal lobe epilepsy is characterized by strong synaptic reorganization that leads to abnormal recurrent excitatory synaptic connections among hippocampal neurons. In addition, electrophysiological studies show that synaptic activity of the main afferent input to the hippocampus, the perforant path, is prolonged and amplified by changes in postsynaptic glutamate receptors. The current view is that these morphological and physiological abnormalities contribute significantly to the hyperexcitability seen in the hippocampus of temporal lobe epilepsy. Recently, it was found that presynaptic inhibitory metabotropic glutamate receptors are an important negative feedback mechanism that controls synaptic release of glutamate in the hippocampus. In this study, we assessed the functionality of this feedback system by investigating the metabotropic glutamate receptor mediated depression of excitatory synaptic transmission in surgically removed hippocampi from patients with marked synaptic reorganization (Ammon's horn sclerosis group) and from patients without detectable reorganization (lesion group). We report here that this control of synaptic transmission is lost in hippocampi from the Ammon's horn sclerosis group whereas this control is preserved in hippocampi from the lesion group. The data presented here suggest that the loss of feedback inhibition mediated by metabotropic glutamate receptors could be a further, previously not recognized, mechanism in the pathophysiology of temporal lobe epilepsy. PMID- 10103107 TI - Reaction time performance following unilateral striatal dopamine depletion and lesions of the subthalamic nucleus in the rat AB - The akinesia resulting from Parkinson's disease or striatal dopamine depletion in experimental animals can be ameliorated or reversed by inactivation of the subthalamic nucleus. This inactivation might be effective by restoring balance to the basal ganglia motor circuits. Alternatively, new movement-related deficits might be introduced which mask the original impairments (e.g. hyperkinesia might replace hypokinesia). In the present study, striatal dopamine depletion was effected unilaterally, in order to dissociate generalized effects, e. g. hyperkinesia, from response-specific initiation effects. Rats were trained in a lateralized visual reaction time task and then assigned to one of four groups: striatal dopamine depletion; cell body lesion of the subthalamic nucleus; combined striatal dopamine depletion and subthalamic nucleus lesion; or control. As expected, rats with striatal dopamine depletion exhibited slower reaction time and a bias to respond to the ipsilateral side. The subthalamic nucleus lesion resulted in no reaction time change (in particular, there was no evidence of faster reaction times), but there was an increase in anticipatory responding. The group with the combined striatal dopamine depletion and subthalamic nucleus lesion had no reaction time impairment. This group showed an increase in anticipatory errors and a contralateral response bias. These data demonstrate that lesions of the subthalamic nucleus do not merely cancel the akinesia which follows striatal dopamine depletion by the addition of a hyperkinetic impairment. Rather, there appears to be a change in the balance of the motor system. PMID- 10103106 TI - Neuronal and behavioural abnormalities in striatal function in DARPP-32-mutant mice. AB - We investigated the role of the protein phosphatase inhibitor, dopamine- and cAMP regulated phosphoprotein of 32 kDa (DARPP-32), in the expression of striatal neuropeptides and in biochemical and behavioural responses to repeated cocaine administration, using DARPP-32 knock-out mice. The striatum of DARPP-32-mutant mice showed heightened substance-P-like immunoreactivity, but normal levels of other neuropeptides. Repeated cocaine administration increased levels of DeltaFosB, a Fos family transcription factor, in the striatum of wild-type mice, and this increase was abolished in DARPP-32-mutant mice. Cocaine (20 mg/kg) acutely induced the same level of locomotor activity in the mutant and wild-type mice, but the mutants showed a higher rate of locomotor sensitization to repeated cocaine exposures. These data show that DARPP-32 is involved in regulating substance P expression in the striatonigral pathway, and in biochemical and behavioural plasticity with chronic administration of cocaine. PMID- 10103108 TI - Direct comparison of projections from the central amygdaloid region and nucleus accumbens shell. AB - Certain neurochemical and connectional characteristics common to extended amygdala and the nucleus accumbens shell suggest that the two represent a single functional-anatomical continuum. If this is so, it follows that the outputs of the two structures should be substantially similar. To address this, projections from the caudomedial shell and central nucleus of the amygdala, a key extended amygdala structure, were demonstrated in Sprague-Dawley rats with different anterograde axonal tracers processed separately to exhibit distinguishable brown and blue-black precipitates. The caudomedial shell projection is strong in the ventral pallidum and along the medial forebrain bundle through the lateral preopticohypothalamic continuum into the ventral tegmental area, distal to which it thins abruptly. The central nucleus projects strongly to the bed nucleus of the stria terminalis and the sublenticular extended amygdala, but substantially to the lateral hypothalamus only at levels behind the rostral part of the entopeduncular nucleus. Innervation of the ventral tegmental area by the central amygdala is minimal, but the lateral one-third of the substantia nigra, pars compacta and an adjacent lateral part of the retrorubral field receive substantial central amygdala input. Central amygdaloid projections are robust in caudal brainstem sites, such as the reticular formation, parabrachial nucleus, nucleus of the solitary tract and dorsal vagal complex, all of which receive little input from the accumbens. The substantial differences in the output systems of the caudomedial shell of accumbens and central amygdala suggest that the two represent distinct functional-anatomical systems. PMID- 10103109 TI - Selective up-regulation of P- and R-type Ca2+ channels in rat embryo motoneurons by BDNF. AB - Cultured spinal cord motoneurons from day 15 rat embryos (E15) represent a useful model to study Ca2+ channel diversities and their regulation by neurotrophins. Besides the previously identified L-, N- and P-type channels, E15 rat motoneurons also express high densities of R-type channels. We have previously shown that the P-type channel is nearly absent in 60% of these cells, while the R-type contributes to approximately 35% of the total current. Here, we show that chronic preincubation of cultured rat motoneurons with high concentrations (20-100 ng/mL) of brain-derived neurotrophic factor (BDNF) caused a selective up-regulation of the P- and R-type current density available after blocking N- and L-type channels, with no changes to cell membrane capacitance. N- and L-type channels were either not affected or slightly down-modulated by the neurotrophin. The onset of BDNF up-regulation of P/R-type currents had a half-time of 12 h and reached maximal values of approximately 80%. High concentrations of nerve growth factor (NGF; 50-100 ng/mL) had no effect on P/R currents, while BDNF action was prevented by the kinase inhibitor K252a and by the protein synthesis inhibitor anisomycin. These results suggest that chronic applications of BDNF selectively up-regulates the Ca2+ channel types which are most likely to be involved in the control of neurotransmitter release in mammalian neuromuscular junctions. The signal transduction mechanism is probably mediated by TrkB receptors and involves the synthesis of newly functionally active P- and R-type channels. Our data furnish a rationale for a number of recent observations in other laboratories, in which prolonged applications of neurotrophins were shown to potentiate the presynaptic response in developing synapses. PMID- 10103110 TI - The interaction between F3 immunoglobulin domains and protein tyrosine phosphatases zeta/beta triggers bidirectional signalling between neurons and glial cells. AB - F3, a mouse glycosyl-phosphatidylinositol anchored molecule of the immunoglobulin superfamily, is known to influence axonal growth and fasciculation via multiple interactions of its modular immunoglobulin-like domains. We prepared an Fc chimeric molecule (F3IgFc) to identify molecules interacting with these domains and characterize the functional impact of the interactions. We affinity-isolated tenascin-C and isoforms of the proteoglycan-type protein tyrosine phosphatases zeta/beta (PTPzeta/RPTPbeta) from extracts of developing mouse brain. We showed that both PTPzeta/RPTPbeta and tenascin-C can bind directly to F3, possibly in an exclusive manner, with the highest affinity for the F3-PTPzeta/RPTPbeta interaction. We observed a strong binding of F3IgFc-coated fluorospheres to astrocytes in neural primary cultures and to C6 astrocytoma cells, and demonstrated, in antibody perturbation experiments, that F3-Ig binding on astrocytes depends on its interaction with PTPzeta/RPTPbeta. We also found by confocal analysis that tenascin-C and PTPzeta/RPTPbeta were colocalized on astrocytes which suggests a complex interplay of interactions between PTPzeta/RPTPbeta, tenascin-C and F3. We showed that the interaction between PTPzeta/RPTPbeta and F3-Ig-like domains can trigger bidirectional signalling. C6 glia-expressed PTPzeta/RPTPbeta stimulated neurite outgrowth by cortical and cerebellar neurons, whereas preclustered F3IgFc specifically modified the distribution of phosphotyrosine labelling in these glial cells. Both effects could be prevented and/or mimicked by anti-F3 and anti-6B4PG antibodies. These results identify F3 and PTPzeta/RPTPbeta as potential mediators of a reciprocal exchange of information between glia and neurons. PMID- 10103111 TI - GABAB-receptor-mediated control of GABAergic inhibition in rat histaminergic neurons in vitro. AB - The onset of slow wave sleep may require an inhibition of histaminergic neurons by GABAergic afferents from the ventrolateral preoptic area. We have utilized electrophysiological methods in an in vitro brain slice preparation to examine the role of GABAB receptor activation in GABAergic synaptic inhibition in histaminergic neurons of the tuberomammillary nucleus. Tetrodotoxin blocked evoked GABAergic IPSPs but not miniature IPSPs or IPSCs. Evoked IPSPs varied in amplitude and exhibited failures of transmission. Baclofen reduced the amplitude of evoked IPSPs in all experiments and often caused an increase in failures of transmission. Responses elicited by application of exogenous GABA were insensitive to baclofen treatment. The action of baclofen was blocked by CGP 35348 (100 microm), a GABAB receptor antagonist, which also enhanced the amplitude of evoked IPSPs. The frequency of spontaneous and miniature IPSPs and IPSCs was reduced by baclofen. However, the amplitude distribution of mIPSCs was not altered. We conclude that GABA release onto TM neurons is under presynaptic control via GABAB receptors. This presynaptic control of transmission to tuberomammillary neurons may reduce inhibition, increasing histamine release and enhancing wakefulness. PMID- 10103112 TI - Functional heterogeneity in dopamine release and in the expression of Fos-like proteins within the rat striatal complex. AB - The dorsolateral striatum, and the core and shell of the nucleus accumbens are three major anatomical regions of the striatal complex. The shell is considered as a part of the extended amygdala, and is involved in the control of motivation and reward. The core and the striatum are considered central to sensory motor integration. In this study we compared the responses of these three regions to mild stress and drugs of abuse by measuring extracellular dopamine (DA) concentrations and Fos-like immunoreactivity (Fos-LI). The results are summarrized as follows. (i) In unchallenged conditions, extracellular DA concentrations were highest in the dorsolateral striatum and lowest in the core, whereas Fos-LI was highest in the shell and lowest in the dorsolateral striatum. (ii) After challenges that increase DA by depolarizing DAergic neurons (injection stress or 2 mg/kg morphine), the shell presented the largest increase in DA levels and Fos-LI. (iii) After the administration of a DA-uptake blocker (15 mg/kg cocaine), the percentage increase in DA was still largest in the shell. However, the absolute increase in DA and Fos-LI in the shell and the dorsolateral striatum were similar. (iv) After a full D1 agonist (SKF82958), Fos-LI was highest in the shell and lowest in the dorsolateral striatum. In conclusion, the nucleus accumbens shell seems to be the area of the striatal complex most functionally reactive to stress and drugs of abuse. However, the dorsolateral striatum and the core appear functionally distinct, as for most of the parameters studied these two regions differed. PMID- 10103113 TI - Mobilization of intracellular calcium stores participates in the rise of [Ca2+]i and the toxic actions of the HIV coat protein GP120. AB - The HIV envelope glycoprotein, GP120, increases intracellular Ca2+ concentration and induces degeneration of human and animal neurons in culture. Using patch clamp recordings and Ca2+ imaging techniques, we have now examined the contribution of intracellular stores of calcium in the effects of GP120. We report that in rat hippocampal neuronal cultures, GP120 induces a dramatic and persistent increase in [Ca2+]i which is prevented by drugs that either deplete (caffeine, carbachol, thapsigargin) or block (dantrolene) Ca2+ release from intracellular stores. In contrast, N-methyl-d-aspartate (NMDA) receptors or voltage-dependent calcium channels do not participate in these effects, as: (i) the increase in [Ca2+]i was not affected by NMDA receptor antagonists or calcium channel blockers; and (ii) and GP120 did not generate any current in whole-cell recording. Dantrolene, a ryanodine stores inhibitor, also prevented neuronal death induced by GP120. Our results show that the GP120-induced rise in [Ca2+]i originates from intracellular calcium stores, and suggest that intracellular stores of calcium may play a determinant role in the pathological actions of GP120. PMID- 10103114 TI - Expression of TrkB and TrkC but not BDNF mRNA in neurochemically identified interneurons in rat visual cortex in vivo and in organotypic cultures. AB - The mammalian visual cortex contains morphologically diverse populations of interneurons whose neurochemical properties are believed to be regulated by neurotrophic factors. This requires the expression of neurotrophin receptors. We have analysed whether brain-derived neurotrophic factor (BDNF), its receptor trkB and the NT-3 receptor trkC are expressed in interneurons of rat visual cortex in vivo, and in organotypic visual cortex cultures, paying particular attention to the subsets of neuropeptidergic neurons. In situ hybridization in combination with immunofluorescence for calcium-binding proteins and neuropeptides revealed that BDNF is not expressed in interneurons in vivo or in vitro. For the neurotrophin receptors we found in vivo at postnatal day 70 (P70) that approximately 80% of the parvalbumin-immunoreactive (-ir), but only 50% of the intensely calbindin-ir, and only 20% of the calretinin-ir neurons express trkB. Double labelling with neuropeptides revealed that approximately 50% of the neuropeptide Y-ir and approximately 50% of the somatostatin-ir neurons express trkB in a laminar-specific way. Only 25% of the vasoactive intestinal polypeptide (VIP)-ir neurons coexpress trkB. The coexpression of neuropeptide Y with trkB, but not with BDNF or trkC, was confirmed with a double in situ hybridization. In contrast, the percentages differed in the immature cortex; at P14 70% of the NPY ir neurons and 46% of the calretinin-ir neurons revealed trkB expression, while the ratio for calbindin-ir cells was fairly constant (59%). From the interneuron populations studied, only 12% of the parvalbumin-ir neurons expressed trkC. A triple labelling revealed that some neurons coexpressed both trk mRNAs, while others had only trkC. The analysis of interneurons in organotypic cultures yielded very similar results. The results indicate that trkB ligands synthesized by pyramidal neurons influence neuropeptide or calcium-binding protein expression in a paracrine or transsynaptic manner. However, in contrast to current belief, in the adult only about half of all interneurons appear responsive to trkB ligands. Although the proportion is higher in the immature cortex, not all of the interneurons appear neurotrophin-receptive. With regard to the presence or absence of neurotrophin receptors, the molecular heterogeneity of GABAergic interneurons in the visual cortex is higher than currently assumed, and the responsiveness to neurotrophins changes with development in a cell type-specific way. PMID- 10103115 TI - N-cadherin expression in endothelial cells during early angiogenesis in the eye and brain of the chicken: relation to blood-retina and blood-brain barrier development. AB - The factors responsible for the induction and maintenance of blood-brain barrier properties are still undefined. The process of blood-brain barrier formation is thought to take place in a two-stage manner: the initial commitment of vascular sprouts by neuroectodermal cells may be followed by the stabilization of barrier properties. In the present study, we investigated the expression pattern of neural (N)-cadherin during early angiogenesis in the brain and the pecten oculi of the chicken. The pecten has been introduced previously as a model for the investigation of the formation and maturation of barrier properties in the central nervous system. Whereas perineural and choroid vessels remained immunonegative for N-cadherin, vascular sprouts invading both the brain and the pecten primordium acquired anti-N-cadherin immunoreactivity. Confocal laser scanning and immunoelectron microscopy indicated that the antigen was located at the ablumenal endothelial membrane in contact with subendothelial cells. With the onset of barrier differentiation as determined by junctional restriction of the tight junction protein occludin, N-cadherin labelling rapidly decreased. Specific intraneuroectodermal upregulation and decline of endothelial N-cadherin was confirmed by in situ hybridization and suggests that N-cadherin expression by cerebral and pecteneal endothelial cells represents an initial and transient signal which may be involved in the commitment of early blood vessels to express blood-brain and blood-retina barrier properties. PMID- 10103117 TI - Excitatory synaptic inputs to pyramidal neurons of the lateral amygdala. AB - Whole-cell patch clamp recordings were made from pyramidal neurons in the rat lateral amygdala (LA). Synaptic currents were evoked by stimulating in either the external capsule (ec), internal capsule (ic) or basolateral nucleus (BLA). Stimulation of either the ic, ec or BLA evoked a glutamatergic excitatory synaptic current (EPSC) which was mediated by both non-NMDA and NMDA (N-methyl-d aspartic acid) receptors. The ratio of the amplitude of the NMDA receptor mediated component measured at +40 mV to the amplitude of the alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component measured at -60 mV was similar regardless of whether EPSCs were evoked in the ec, ic or BLA. At resting membrane potentials, excitatory synaptic potentials evoked from either the ec or putative thalamic inputs were unaffected by application of the NMDA receptor antagonist APV. Spontaneous glutamatergic currents had two components to their decay phase. The slow component was selectively blocked by the NMDA receptor antagonist D-APV, indicating that AMPA and NMDA receptors are colocalized in spiny neurons. We conclude that pyramidal cells of the LA receive convergent inputs from the cortex, thalamus and basal nuclei. At all inputs, both AMPA/kainate and NMDA-type receptors are active and colocalized in the postsynaptic density. PMID- 10103116 TI - GDNF family ligands and receptors are differentially regulated after brain insults in the rat. AB - Expression of mRNAs for glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN) and their receptors was studied in adult rat brain using in situ hybridization after 40 kindling-evoked, rapidly recurring seizures or 10 min of global forebrain ischaemia. Following seizures, GDNF and NTN mRNAs were elevated in dentate granule cells, and c-Ret mRNA in hilar neurons and non-pyramidal cells in CA1 and CA3 regions. GFRalpha-1 mRNA levels showed more widespread increases in the dentate granule cell layer and hilus, CA1 and CA3 pyramidal layers, basolateral amygdala and parietal cortex. The expression of GFRalpha-2 mRNA increased in the piriform cortex and decreased in the CA1 region and basolateral amygdala. Forebrain ischaemia induced elevated expression of GDNF mRNA in dentate granule cells, GFRalpha-1 mRNA in the dentate granule cell layer, hilus and CA3 pyramidal layer, and GFRalpha-2 mRNA in the parietal cortex. The gene expression patterns observed here suggest that GDNF and NTN may act as target-derived factors, but also in an autocrine or paracrine manner. GFRalpha-1 can be coexpressed with GFRalpha-2 and c-Ret mRNAs in the same hippocampal or thalamic neurons, but other neurons contain GFRalpha-1 alone or together with c-Ret mRNA. The gene expression changes for the ligands, and the receptor components are region-, cell- and insult-specific, and occur independently of each other, mainly within 24 h after seizures or ischaemia. This dynamic regulation of GDNF and NTN circuits primarily at the receptor level may be important for the effectiveness of neuroprotective responses but could also trigger plastic changes, e.g. those underlying the development of epileptic syndromes. PMID- 10103118 TI - Categorization of complex visual images by rhesus monkeys. Part 1: behavioural study. AB - In order to study how visual categories are coded by the activities of single neurons, it is necessary to first demonstrate that the animal subjects can categorize the visual stimuli employed in the single-unit recordings. Thus, rhesus monkeys were trained in a visual categorization task designed to minimize rote learning of individual exemplars and to allow testing of transfer from old to novel exemplars of the category. The stimuli were presented during controlled fixation. The monkeys learned to distinguish complex colour images of trees from other objects and generalized from old to novel exemplars. An extensive series of tests with probe stimuli showed that simple form, colour and texture features had insufficient stimulus control to account for the categorization performance. Scrambling the images impaired categorization performance, suggesting that the configuration of stimulus components controlled the categorization. The animals also learned a fish/non-fish categorization, but more slowly than a tree/non-tree categorization. These results indicate that rhesus monkeys can learn to categorize socially neutral, complex, natural visual images and suggest that this categorization is based on a combination of low-level features. PMID- 10103119 TI - Categorization of complex visual images by rhesus monkeys. Part 2: single-cell study. AB - In order to investigate the neural coding of ordinate-level visual categories, single-cell recordings were made in the anterior temporal cortex of two rhesus monkeys performing a categorization of colour images of trees versus images of other objects. Neurons showed a high average degree of selectivity for these complex colour images. Although most neurons responded to trees and non-trees, about a quarter responded in a category-specific manner, e.g. to trees but not non-trees, and about one-tenth responded almost exclusively to exemplars of the trained category. The responses of these neurons were largely invariant for stimulus transformations, e. g. changes in position or size, and decreased with the degree of image scrambling, mimicking the behavioural results. However, the responses of single neurons were insufficiently stimulus invariant to accommodate the entire range of variability present in the features of exemplars within the same category. This strong within-category selectivity challenges the idea that a prototype is represented at the single neuron level, but suggests that ordinate level categorization is based on a population of neurons, each selective for a limited set of exemplars. PMID- 10103120 TI - Clusters of GABAA receptors on cultured hippocampal cells correlate only partially with functional synapses. AB - We describe a method to label gamma-aminobutyric acid (GABA)A receptors on the surface of living hippocampal neurons in primary culture, and we compare the distribution of receptors with that of active synapses. To visualize GABAA receptors, the affinity-purified antibody beta3(1-13), recognizing the extracellular N-termini of the GABAA receptor beta2- and beta3-subunits, was used in combination with fluorescent secondary antibodies. The beta2- and beta3 subunits belong to the predominant GABAA receptor subunits in the hippocampus. As expected for aggregates of GABAA receptors in the somato-dendritic plasma membrane, a patchy staining pattern similar to that seen by labelling neurons after fixation was obtained. An antiserum recognizing an intracellular epitope of GABAA receptor beta3-subunits did not label the receptors in living neurons. Whole-cell recordings of GABA-evoked Cl - currents were not affected after decorating GABAA receptors with antibody beta3(1-13). Combining the staining of GABAA receptors with the labelling of active presynaptic terminals with the fluorescent dyes FM1-43 or FM4-64, consistently resulted in the detection of GABAA receptor clusters that were not located at active synapses. These amounted to approximately 50% of all labelled GABAA receptor clusters. GABAA receptor clusters that were not associated with active presynaptic terminals partially colocalized with the synaptic vesicle marker protein sv2, while another fraction had no presynaptic counterpart at all. These findings suggest the presence of presynaptically silent GABAergic synapses in cultured hippocampal neurons. They also indicate that for the maintenance of GABAA receptor aggregates, the release of GABA from an opposing active terminal is not essential. PMID- 10103121 TI - Effects of excitotoxic lesions of the rat prefrontal cortex on CREB regulation and presynaptic markers of dopamine and amino acid function in the nucleus accumbens. AB - The present study investigated the effects of excitotoxic lesions of the prefrontal cortex (PFC) on dopamine (DA) and excitatory amino acid (EAA) function in the nucleus accumbens core using in vivo microdialysis in freely moving rats. As a postsynaptic marker of neuronal function, the nuclear levels of the transcriptional factor CREB and its active phosphorylated form, CREB-P, were measured in the ventral tegmental area (VTA), and in the core and shell subregions of the nucleus accumbens of sham and lesioned animals. PFC-lesioned animals exhibited a greater locomotor response to novelty and amphetamine administration (125-500 microg/kg i.v.). No change was observed in extracellular levels of glutamate or saturable d-aspartate binding (a marker for the high affinity EAA transporter) in the nucleus accumbens of PFC-lesioned animals. Extracellular levels of DA were comparable in sham and lesioned animals under tonic conditions, however, following amphetamine administration, DA efflux was significantly attenuated in lesioned animals. No correlation was observed between microdialysate levels of amino acids and the attenuated dopaminergic response to amphetamine in lesioned animals. Further, no effect of the lesion was found on nuclear CREB protein in saline- and amphetamine-treated rats. The density of CREB P immunoreactive nuclei, while remaining unchanged in the VTA, increased in the nucleus accumbens shell following amphetamine treatment in lesioned animals. The results show that an important modulatory role of the PFC on the behavioural response to novelty and amphetamine is associated with the level of immediate early gene regulation rather than levels of extracellular DA and amino acids in the ventral striatum. PMID- 10103122 TI - Absence of the dopamine D2 receptor leads to a decreased expression of GDNF and NT-4 mRNAs in restricted brain areas. AB - Neurotrophic factors (NTFs) control the metabolic and electrophysiological properties of dopaminergic neurons in the brain. At the level of the substantia nigra, NTFs have been proposed to control dopamine release by regulating the firing rate of dopaminergic cells. This function is normally controlled by presynaptic dopaminergic autoreceptors. Dopamine has also been proposed to regulate the expression of NTFs and their receptors in the nigrostriatal pathway. Thus, an interaction between the signalling cascades activated by NTFs and dopamine receptors might possibly influence the physiology of dopaminergic neurons. Among dopamine receptors, D2 receptors (D2R) are the most abundant on dopaminergic neurons, where they exert autoreceptor functions. To test for an interaction between the NTF and dopaminergic pathways we have analysed the expression of NTFs and their receptors in D2R-deficient (D2R -/-) mice. Our study shows that the mRNA levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 and their corresponding receptors are not modified in the dopaminergic system of D2R -/- adult mice compared with wild-type littermates. However, a marked reduction of glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-4 (NT-4) mRNAs is observed in the striatum and parietal cortex of D2R -/- mice, respectively. These results implicate dopamine, acting through D2 receptors, in the local control of specific NTF expression. The down regulation of GDNF and NT-4 expression might also contribute to the locomotor phenotype of D2R -/- mice. PMID- 10103123 TI - Androgen treatment of neonatal rats decreases susceptibility of cerebellar granule neurons to oxidative stress in vitro. AB - Oxidative stress has been implicated in various neurodegenerative diseases. There is substantial evidence indicating that gonadal hormones can affect neuronal cell survival via both a genomic as well as a non-genomic mode of action. In the present study, the potential protective activity of testosterone on neuronal cells was investigated by using an in vitro/ex vivo model. Cerebellar granule cells (CGC) were prepared from 7-day-old rats which had been treated with a single dose of oil or testosterone propionate on postnatal day 3. After 7 days in culture, cells were exposed to oxidative challenges, including hydrogen peroxide and the nitric oxide donor S-nitrosocysteine (SNOC), which can induce CGC death via apoptosis. Colchicine, which causes apoptosis via a different mechanism, was also used. The cells were monitored for apoptotic morphology by propidium iodide and TUNEL staining. Additionally, the presence of chromatin fragmentation was determined. CGC obtained from testosterone-treated rats were found to be more resistant to hydrogen peroxide and nitric oxide toxicity, as shown by a 75 and 45% decrease in apoptotic cells, respectively. In contrast, the susceptibility to colchicine was not modified. As CGC from testosterone-treated pups were selectively protected from oxidative stress, different components of the antioxidant defence systems were analysed. A twofold increase in the activity of catalase and superoxide dismutase was found in the CGC prepared from testosterone treated rats. These results suggest that in vivo treatment with androgens render CGC less vulnerable to oxidative stress-induced apoptosis by potentiating antioxidant defences. PMID- 10103124 TI - Contribution of endogenously formed arachidonic acid in the presynaptic facilitatory effects of NMDA and carbachol on dopamine release in the mouse striatum. AB - Arachidonic acid stimulated the release of [3H]-dopamine from striatal microdiscs in a concentration-dependent and partially calcium-dependent manner. Inhibitors of cytosolic and membrane-bound phospholipase A2 were used to determine whether endogenously formed arachidonic acid also contributes to the release of [3H]-DA (previously taken up in tissues or endogenously synthesized from [3H]-tyrosine) evoked by N-methyl-d-aspartate (NMDA) and carbachol alone or in combination. In the presence of magnesium, carbachol was found to remove the magnesium block of NMDA receptors and to facilitate the NMDA-evoked release of [3H]-DA from striatal microdiscs and synaptosomes. In addition, in the absence of magnesium, synergistic responses were induced by both agonists on microdiscs but not on synaptosomes. Responses induced by NMDA, carbachol or both agonists on microdiscs were reduced by phospholipase A2 inhibitors, the most striking effects being observed with mepacrine. Mepacrine was also shown to reduce the oxotremorine, but neither the nicotine- nor the potassium-evoked release of [3H]-DA. Tetrodotoxin decreased the release of [3H]-DA evoked by the co-application of NMDA and carbachol on microdiscs, but mepacrine still decreased this tetrodotoxin resistant response. Similarly, mepacrine still decreased the release of [3H]-DA evoked by NMDA and carbachol on synaptosomes. Altogether, these results indicate that arachidonic acid which is formed in striatal neurons, and to a lesser extent in DA fibres, under stimulation of NMDA and muscarinic receptors, partially contributes to the presynaptic facilitation of DA release evoked by NMDA and carbachol. PMID- 10103125 TI - Auditory activation of cortical visual areas in cats after early visual deprivation. AB - Auditory activation of the primary visual cortex (area 17) and two extrastriate visual cortical areas - the anterolateral lateral suprasylvian area (ALLS) and anteromedial lateral suprasylvian area (AMLS), was investigated in visually impaired cats. Impairment was accomplished shortly after birth by bilateral eyelid suturing (binocularly deprived cats, BD) or bilateral enucleation (binocularly enucleated cats, BE). In BE cats, the optic nerve and chiasm were entirely degenerated. No cortical atrophy or cytoarchitectural malformation was noticed in either BD or BE cats. In both normal and impaired cats we found auditory-responsive cells in the ALLS and AMLS, areas that are considered strictly visual. The most remarkable finding was an increase in the relative number of these auditory cells in the BD and BE cats, which was more prominent in the latter. Some auditory-responsive cells were also found in area 17 of BE cats. On the basis of formal calculation, it is tempting to suggest that the increase in relative number of auditory cells in these areas reflects the transformation of all the visual cells in the ALLS of BD and BE cats into auditory cells. In BE cats, all bimodal cells and an appreciable percentage of non-responsive cells also had transformed to auditory cells. In the AMLS of BD cats, it is primarily the bimodal cells that become auditory cells, whereas in BE cats all the visual and bimodal cells as well as non-responsive cells undergo this transformation. This assumption, however, is one possible interpretation of our results but not the only one. Other modes of neuronal plasticity that might yield similar results in the visually deprived cats can not be ruled out. PMID- 10103126 TI - Platelet-activating factor receptor is not required for long-term potentiation in the hippocampal CA1 region. AB - From pharmacological studies, platelet-activating factor (PAF) has been proposed as a retrograde messenger for long-term potentiation (LTP) in the hippocampal CA1 region. We re-examined a possible contribution of PAF to LTP with a more specific approach using mice deficient in the PAF receptor. The PAF receptor-deficient mice exhibited normal LTP and showed no obvious abnormality in excitatory synaptic transmission. We also performed pharmacological experiments on the wild type mice. Two structurally different antagonists of PAF receptors had no effects on LTP. Furthermore, the application of PAF itself caused no detectable changes in excitatory synaptic transmission. Thus, we conclude that the PAF receptor is not required for LTP in the CA1 region. Introduction PMID- 10103127 TI - Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala. AB - These experiments examined the involvement of glucocorticoid receptors (GRs or type II) located in the A2-noradrenergic cell group of the rat nucleus of the solitary tract (NTS) in modulating memory storage. Bilateral intra-NTS infusions (0.5 microL) of the specific GR agonist RU 28362 (11beta, 17beta-dihydroxy-6, 21 dimethyl-17alpha-pregna-4,6-trien-20yn-3-one), in doses ranging from 0.01 to 10.0 ng, immediately after inhibitory avoidance training produced a dose-dependent enhancement of 48 h retention performance. Infusions of 0.1 or 1.0 ng of the agonist enhanced retention, whereas lower or higher doses were ineffective. Post training infusions of the GR antagonist RU 38486 [17beta-hydroxy-11beta-(4 dimethylaminophenyl)-17alpha-(1-pr opynyl)-o estra-4,9-dien-3-one, 0.01-10.0 ng] into the NTS did not significantly affect retention performance, but shifted the dose-response effects of post-training systemic injections of the synthetic glucocorticoid dexamethasone to the right. These results indicate that activation of GRs in the NTS can influence memory formation for inhibitory avoidance training, and suggest that the effects of circulating glucocorticoids on memory are mediated, in part, by an activation of GRs in the NTS. Additionally, pretraining infusions of the beta1-adrenergic antagonist atenolol (0.5 microg in 0.2 microL) into the basolateral nucleus of the amygdala (BLA), a brain structure which receives noradrenergic projections from the NTS and is implicated in memory storage modulation, blocked the memory-enhancing effects of the GR agonist (1.0 ng) infused into the NTS. These findings provide evidence that memory storage is modulated by glucocorticoid binding to GRs in noradrenergic cell bodies in the NTS and suggest that these modulatory effects are conveyed by ascending projections to the BLA. PMID- 10103128 TI - Excitatory amino acids and synaptic transmission in embryonic rat brainstem motoneurons in organotypic culture. AB - We used brainstem motoneurons recorded in organotypic slice co-cultures maintained for more than 18 days in vitro, together with multibarrel ionophoretic applications of glutamate receptor agonists and bath applications of specific blocking agents, to study the responses of rat brainstem motoneurons to glutamate receptor activation, and the contribution of these receptors to synaptic transmission. Differentiated brainstem motoneurons in vitro are depolarized by glutamate, N-methyl-d-aspartate (NMDA) and dl-alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid (AMPA) iontophoresis, and express NMDA, AMPA and also specific kainate receptors, as evidenced by (+/-)2-amino-5-phosphonovaleric acid (APV)- and (-)1-(4-aminophenyl)-3-methyl-carbamoyl-4-methyl-7, 8-methylenedioxy 3,4-dihydro-5H-2,3-benzo-diazepine [GYKI 53784 (LY303070)]-resistant depolarizations. Electrical stimulations applied to the dorsal part of the explant trigger excitatory synaptic potentials with latencies distributed in three regularly spaced groups. Excitatory postsynaptic potentials (EPSPs) in the earliest group have a similar latency and time course and correspond to monosynaptic activation. EPSPs in later groups have more scattered latencies and time courses and correspond to polysynaptic activation. Monosynaptic EPSPs are insensitive to the specific NMDA blocker APV, and are completely and reversibly suppressed by the non-competitive AMPA receptor antagonist GYKI 53784 (LY303070). Detailed analysis of the spontaneous excitatory synaptic activity shows that APV decreases the frequency of spontaneous EPSPs without modifying their shape or amplitude. We conclude that excitatory synapses on brainstem motoneurons in vitro are mainly activated through AMPA receptors (AMPA-Rs). NMDA receptors (NMDA-Rs) are present in the membrane, but are located either at extrasynaptic sites or silent synapses, and are not directly involved in synaptic transmission on motoneurons. On the contrary, NMDA receptors contribute to synaptic transmission within the premotor interneuronal network. PMID- 10103129 TI - Distribution of synaptic vesicle proteins in the mammalian retina identifies obligatory and facultative components of ribbon synapses. AB - The mammalian retina contains two synaptic layers. The outer plexiform layer (OPL) is primarily composed of ribbon synapses while the inner plexiform layer (IPL) comprises largely conventional synapses. In presynaptic terminals of ribbon synapses, electron-dense projections called ribbons are present at the synaptic plasma membranes. Ribbons bind synaptic vesicles and guide them to the synaptic membrane for fusion. In this manner, ribbons are thought to accelerate the delivery of vesicles for continuous exocytosis. In recent years, a large number of synaptic proteins has been described but it is not known if these protein colocalize in the same types of synapses. In previous studies, several proteins essential for synaptic function were not detected in ribbon synapses, suggesting that the mechanism of synaptic vesicle exocytosis may be very different in ribbon and conventional synapses. Using confocal laser scanning microscopy, we have now systematically investigated the protein composition of ribbon synapses. Our results show that, of the 19 synaptic proteins investigated, all except synapsin and rabphilin are obligatorily present in ribbon synapses. For example, rab3 which was reported to be absent from ribbon synapses, was found in bovine, rat and mouse ribbon synapses using multiple independent antibodies. In addition, we found staining in these synapses for PSD-95 and NMDA receptors, which suggested a similar design for the postsynaptic component in ribbon and conventional synapses. Our data show that ribbon synapses are more conventional in composition than reported, that most synaptic proteins are colocalized to the same type of synapse, and that synapsin and rabphilin are likely to be dispensible for basic synaptic functions. PMID- 10103130 TI - Unexpected localization of the Na+/Cl--dependent-like orphan transporter, Rxt1, on synaptic vesicles in the rat central nervous system. AB - Numerous features of its primary structure demonstrate that the orphan transporter Rxt1 belongs to the Na+/Cl--dependent neurotransmitter plasma membrane transporter superfamily, which includes the dopamine, norepinephrine, serotonin and gamma-aminobutyric acid (GABA) transporters. Initial immunocytochemical investigations with affinity-purified antibodies have established that Rxt1 is localized, almost exclusively, in axon terminals of glutamatergic neurons and subsets of GABAergic neurons in the CNS. Further studies were carried out to determine its subcellular distribution. In a first series of experiments, PC-12 cells were transfected with plasmids encoding either the dopamine transporter or Rxt1. Immunofluorescence experiments showed that the dopamine transporter was expressed in these cells, and, as expected, addressed to their plasma membrane. Surprisingly, this was never the case with Rxt1, which was targeted to the same subcellular compartment as synaptophysin, a vesicular protein. In a second set of experiments, subcellular fractionation of rat striatum showed that Rxt1, but not the dopamine transporter, was relatively abundant in the purified synaptic vesicle fraction. Finally, electron microscopic immunocytochemistry with anti-Rxt1 antibodies showed peroxidase as well as pre- and post-embedding immunogold labelling confined to the intracellular compartment in various brain regions. Moreover, quantitative analysis of post-embedding experiments demonstrated that the immunogold particles corresponding to Rxt1 immunoreactivity were mostly localized to small synaptic vesicles. These data indicate that, in contrast with the other members of the Na+/Cl--dependent neurotransmitter transporter superfamily, which are targeted to the plasma membrane, Rxt1 is distributed as a vesicular protein in the CNS. PMID- 10103131 TI - Distribution of fibroblast growth factor-5 in rat hypothalamus, and its possible role as a regulator of feeding behaviour. AB - We previously reported that a transcript of fibroblast growth factor-5 (FGF-5) was more abundant in the brain of postnatal and adult mice than in the embryonic brain. This suggested that FGF-5 plays some role in the mature brain. Here, we have investigated the spatiotemporal expression and function of FGF-5 in the adult rat hypothalamus with the emphasis on feeding behaviour. In situ hybridization experiments demonstrated that, in both adequately fed and fasted (20 h) rats, FGF-5 transcripts were present within several nuclei in the hypothalamus (viz. the magnocellular part of the paraventricular nucleus, supraoptic nucleus, arcuate nucleus, median eminence, and ventromedial hypothalamic nucleus), but not in the lateral hypothalamic area. Quantitative detection of FGF-5 mRNA in the hypothalamus (especially in the paraventricular nucleus) indicated that food deprivation (20 h) reduced the expression of this gene to almost one-half of that seen in the control (fed) rats. The expression recovered to the control level after 1 h re-feeding, and this recovery persisted for several hours. Furthermore, FGF-5, when infused into the third ventricle, consistently reduced food intake, water intake and body weight gain, all in a dose-dependent manner. These results suggest that FGF-5 in the hypothalamus acts as a physiological regulator of feeding behaviour, and that its decreased expression during food deprivation may be important in stimulating appetite. PMID- 10103133 TI - Effects of unilateral cochlear removal on dendrites in the gerbil medial superior olivary nucleus. AB - For most neurons, dendrites serve as the major pathway for incoming activity from other neurons. It might therefore be expected that dendrites are particularly sensitive to variations in the level of afferent input they receive. In the auditory brainstem, this expectation has been confirmed in neurons of the medial superior olivary nucleus (MSO). The MSO is uniquely suited to studies of afferent influences on dendrites, as lateral and medial dendrites of MSO neurons receive inputs almost exclusively from the ipsilateral and contralateral ears, respectively. Thus, the effects of unilateral afferent manipulations may be compared between defined dendrites on the same neurons. We have used unilateral deafening (by surgical destruction of the cochlea) in immature [postnatal day 18 (P18)] and adult gerbils to study the late maturation and effect of peripheral deafferentation on the dendrites of MSO neurons. In semi-thin, frontal sections from unoperated animals, we found a change between P18 and adulthood from a lateral to a medial bias in the symmetry of MSO dendrites. Cochlear removal in adulthood led to a reduction in the density of dendritic profiles on the side of the ablation in both MSOs. Cochlear removal at P18 led to a rapid (< 3 days) and sustained dendritic atrophy that was most marked in the caudal part of the nucleus. Electron microscope (EM) measurements in the sagittal plane on MSO dendrite profiles of animals unilaterally deafened at P18 showed a reduction in the number, but not in the area, of profiles on the side of the deafened ear. These results demonstrate a developmental change in the symmetry of MSO medial and lateral dendrites, and a rapid and long-lasting reduction in the number of distal dendrites produced by unilateral deafening either in infancy or adulthood. PMID- 10103132 TI - Contralateral trigeminal nerve lesion reduces polyneuronal muscle innervation after facial nerve repair in rats. AB - Functional recovery after facial nerve surgery is poor. Axotomized motoneurons (hyperexcitable upon intracellular current injections, but unable to discharge upon afferent stimulation) outgrow supernumerary branches which are misrouted towards improper muscles. We hypothesized that alterations in the trigeminal input to axotomized electrophysiologically silent facial motoneurons might improve specificity of reinnervation. To test this we compared, in the rat, behavioural, electrophysiological, and morphological parameters after transection and suture of the buccal facial nerve (buccal-buccal anastomosis, BBA) with those after BBA plus excision of the ipsi- or contralateral infraorbital nerve (ION). After BBA, the mystacial vibrissae dropped and remained motionless until 18-21 days post operation (days PO). After BBA plus ipsilateral ION excision, there was no recovery of vibrissae whisking at all. Following BBA plus contralateral ION excision, full restoration of whisking occurred at 7-10 days PO. Electromyography of whiskerpad muscles showed normal waveform and amplitude was also most rapidly restored after BBA plus contralateral ION excision. Neuron counts after retrograde tracing showed that the intact buccal nerve contained axons of the superior (91%) and inferior (9%) buccolabial nerves. After BBA, the superior nerve comprised 56%, the inferior 21%, and 23% of the motoneurons projected within both nerves. After BBA plus ipsilateral ION excision, misdirection worsened and values changed to 48, 39 and 13%, respectively. After BBA plus contralateral ION excision, portions improved to 69, 23 and 8%. We conclude that, by reducing the redundant axon branching, lesion of contralateral ION provides the best conditions for recovery of vibrissae rhythmical whisking after reconstructive surgery on the facial nerve. PMID- 10103134 TI - The dopamine D2 receptor subfamily in rat retina: ultrastructural immunogold and in situ hybridization studies. AB - Dopamine, a major neurotransmitter in the vertebrate retina, is released from interplexiform cells and a restricted subset of amacrine cells. Dopamine effects vary between different retinal cell types, most likely due to differences in cell specific receptor subtype expression. Identification of cells expressing receptors of the D2-subfamily (D2R, D3R, D4R) on a light microscopical level has rendered equivocal results, and no information is as yet available concerning the subcellular distribution of receptor protein. In the present study, D2R and D2/3R subtype-specific antisera, and D2R-, D3R- and D4R-specific oligonucleotide probes were used for ultrastructural and in situ hybridization analyses of the receptor subtype distribution in the rat retina. Light and electron microscopy showed that in addition to the known localization of intense D2R-immunoreactivity in all dopaminergic cells immunoreactive for tyrosine hydroxylase (TH), homogeneous, less intense D2R-immunoreactivity was also seen throughout the inner plexiform layer (IPL). Ultrastructurally, many additional amacrine cell processes devoid of TH-immunoreactivity at all levels of the inner plexiform layer were immunoreactive. D2R-immunoreactivity was found mainly on intracellular vesicles, and immunoreactivity associated with the plasma membrane was always extrasynaptic. No D2R-immunoreactivity was found in amacrine cell somata postsynaptic to the so-called dopaminergic 'ring endings'. Many D2R-mRNA reactive cells were observed throughout the inner nuclear layer. Morphologically, labelled cells resemble amacrines and bipolars but not horizontal cells. Reactivity with splice variant-specific oligonucleotide probes suggested that the D2LR variant is the predominant if not the only D2R isoform in the rat retina. D2R-mRNA reactivity was not observed in other retinal layers, in particular not in photoreceptor inner segments, which displayed D4R-mRNA reactivity. D3R-mRNA reactivity was not detected. The results indicate that D2-like responses are mediated through the D2R subtype, by an autoreceptor mechanism in dopaminergic cells, and by volume transmission in non-dopaminergic cells of the inner retina. D2-like responses in photoreceptors probably represent D4R activation. PMID- 10103135 TI - Rhombomere origin plays a role in the specificity of cranial motor axon projections in the chick. AB - Guidance of cranial motor axons to their targets conforms to a segmental plan in the chick embryo. Trigeminal motor neurons lie within rhombomeres 2 and 3 and project via an exit point in rhombomere 2 to innervate the first branchial arch. Facial motor neurons lie within rhombomeres 4 and 5 and grow out via an exit point in rhombomere 4 to innervate the second branchial arch. We have investigated the axial level-specific matching of motor neurons and branchial arches using donor to host transplantation in avian embryos. Previous work has shown that rostrocaudal reversal of a single hindbrain segment (rhombomere 3) leads to misprojection of a contingent of trigeminal axons via the facial nerve exit point. Using the same experimental manipulation in chick embryos and quail chick chimaeras, we have analysed the pathways of these aberrant projections. We have found that in the majority of embryos analysed from stage 19 to 31, trigeminal axons from the transplanted rhombomere projected towards second branchial arch muscles, in addition to their normal first arch muscle targets. However, from stage 32 to 36, aberrant projections to second arch-derived muscles were detected only in a small minority of embryos. These experiments show that trigeminal motor neurons show a lack of specificity in their early projection into the periphery but that inappropriate projections may be later eliminated. This suggests that segmental mechanisms intrinsic to the hindbrain specify motor neurons with respect to their eventual innervation pattern. PMID- 10103136 TI - Conditioned enhancement and suppression in the developing auditory midbrain. AB - Neural responses in the adult central auditory system to binaural stimuli can be altered by preceding acoustic events, including auditory motion. To determine whether the juvenile auditory system also exhibits this feature, we have examined interaural level difference (ILD) processing in the developing gerbil. A long binaural stimulus was followed without interruption by modulation of the level difference (virtual acoustic motion), which in turn was followed smoothly by a new steady state ILD. Auditory responses of single neurons in the inferior colliculus (IC) were assessed for sensitivity to the final steady state ILD. The response of EI neurons (excited by contralateral stimulation and inhibited ipsilaterally) was examined at postnatal (P) days 17-18, P24-25, and in adult animals. In adult animals, a sudden reduction of the inhibitory stimulus level resulted in a long-lasting (median = 4.3 s) enhanced discharge rate (conditioned enhancement). In P17-18 animals, conditioned enhancement only lasted for 1.2 s. When the inhibitory stimulus level was suddenly increased, adult neurons often displayed a conditioned suppression of discharge rate (median = 4.5 s), whereas P17-18 neurons remained suppressed for a much briefer period (median = 1.2 s). Moreover, the difference between conditioned responses and control discharge rates was three-four times greater in adult neurons compared to those recorded in P17-25 animals. Because conditioned responses are sensitive to the relative balance of contralateral excitation and ipsilateral inhibition, we examined the relationship between excitatory and inhibitory thresholds. In adult animals, excitatory thresholds were an average of 12 dB lower than inhibitory thresholds, while at P17-25 excitatory and inhibitory thresholds were roughly the same. These results indicate that computational properties of juvenile and adult IC neurons differ quantitatively, and this may reflect an imbalance between excitation and inhibition. The developmental differences described herein may limit the ability of young animals to locate a sound source with the latency and accuracy of an adult. PMID- 10103137 TI - Cleavage of the TrkA neurotrophin receptor by multiple metalloproteases generates signalling-competent truncated forms. AB - The ectodomain of the neurotrophin receptor TrkA has been recovered as a soluble fragment from the culture media of cells by a process that involves endoproteolytic cleavage. This cleavage may be upregulated by several treatments, including NGF treatment or protein kinase C activation. In this report we have investigated the cellular site and proteolytic activities involved in TrkA cleavage, and the effects of ectodomain truncation on signalling. Cleavage occurs when the receptor is at, or near, the cell surface, and it can be prevented by agents that affect protein sorting. Cleavage generates several cell-bound fragments, and their generation can be differentially blocked by inhibitors, documenting the involvement of multiple plasma membrane metalloendoproteases. The major cell-bound receptor fragment (i) is tyrosine-phosphorylated in vivo; (ii) does autophosphorylate in vitro; and (iii) is able to associate with intracellular signalling substrates. Artificial deletion of the TrkA ectodomain results in an active receptor that induced neurite outgrowth in pheochromocytoma cells. Cleavage by this natural cellular mechanism appears thus to serve not only as an outlet of receptor binding fragments, but also to generate signalling competent cell-bound receptor fragments. In the nervous system this ligand independent receptor activation could play important roles in the development and survival of neurons. PMID- 10103138 TI - Regional distribution of Y-receptor subtype mRNAs in rat brain. AB - Molecular cloning techniques have recently led to the identification of a growing number of neuropeptide Y-receptor subtypes, suggesting possible subtype-specific involvement in different physiological processes. Here we report the first study which determines and compares the mRNA expression of all four cloned functional Y receptor subtypes (Y1, Y2, Y4 and Y5) in consecutive sections of the rat brain on a cellular level, using a uniform in situ hybridization technique. Our results demonstrate that Y-receptor subtype mRNA expression is widely distributed throughout the rat brain. Interestingly, coexpression of all four Y-receptors, at different levels, is particularly evident within the limbic system, including the hypothalamus, hippocampus, amygdala, piriform and cingulate cortices and tegmental areas, all of which are heavily involved in behaviour, emotion and homeostatic regulation. Particularly interesting is the demonstration that Y5 receptor mRNA expression always coincides with the presence of Y1-receptor mRNA (although not vice versa), possibly due to the overlapping organization and transcriptional control of their genes. However, it is also clear that several brain nuclei display preferential expression of one or a selective combination of Y-receptor subtype mRNAs. Furthermore, it is evident that there is regionalization of expression within certain loci which express all four receptor subtype mRNAs, particularly within the paraventricular and arcuate hypothalamic nuclei. Our results suggest that some of neuropeptide Y's (NPY) effects may be mediated through one particular subtype, whereas other physiological processes might require the coordinated action of different subtypes within the same or discrete areas. PMID- 10103139 TI - Biophysical properties of scorpion alpha-toxin-sensitive background sodium channel contributing to the pacemaker activity in insect neurosecretory cells (DUM neurons). AB - A scorpion alpha-toxin-sensitive background sodium channel was characterized in short-term cultured adult cockroach dorsal unpaired median (DUM) neurons using the cell-attached patch-clamp configuration. Under control conditions, spontaneous sodium currents were recorded at different steady-state holding potentials, including the range of normal resting membrane potential. At -50 mV, the sodium current was observed as unclustered, single openings. For potentials more negative than -70 mV, investigated patches contained large unitary current steps appearing generally in bursts. These background channels were blocked by tetrodotoxin (TTX, 100 nm), and replacing sodium with TMA-Cl led to a complete loss of channel activity. The current-voltage relationship has a slope conductance of 36 pS. At -50 mV, the mean open time constant was 0.22 +/- 0.05 ms (n = 5). The curve of the open probability versus holding potentials was bell shaped, with its maximum (0.008 +/- 0.004; n = 5) at -50 mV. LqhalphaIT (10-8 m) altered the background channel activity in a time-dependent manner. At -50 mV, the channel activity appeared in bursts. The linear current-voltage relationship of the LqhalphaIT-modified sodium current determined for the first three well resolved open states gave three conductance levels: 34, 69 and 104 pS, and reversed at the same extrapolated reversal potential (+52 mV). LqhalphaIT increased the open probability but did not affect either the bell-shaped voltage dependence or the open time constant. Mammal toxin AaHII induced very similar effects on background sodium channels but at a concentration 100 x higher than LqhalphaIT. At 10-7 m, LqhalphaIT produced longer silence periods interrupted by bursts of increased channel activity. Whole-cell experiments suggested that background sodium channels can provide the depolarizing drive for DUM neurons essential to maintain beating pacemaker activity, and revealed that 10-7 m LqhalphaIT transformed a beating pacemaker activity into a rhythmic bursting. PMID- 10103140 TI - Modelling the mosaic organization of rod and cone photoreceptors with a minimal spacing rule. AB - The mosaic of photoreceptors is regarded as a prime example of the precise control of cellular positioning in the vertebrate nervous system. This study was undertaken with the idea that understanding the intrinsic geometrical features of photoreceptor mosaics is a necessary step to unveil the biological mechanisms governing their formation. We show in the retina of the ground squirrel that the arrays of both the rods and S cones are non-random, but that nothing more than a simple minimal-spacing rule constraining receptor positioning is sufficient to account for the spatial organization of both mosaics. The size of this 'exclusion zone' is an intrinsic characteristic of each cell type, and it is simply the difference in the size of this domain that accounts for the regularity of the S cone array and the irregularity of the rod array at identical density. Consequently, regularity in receptor mosaics is produced by two independent biological events, one embodying the exclusion zone, and another specifying the local density of a given receptor type. PMID- 10103141 TI - Relationships between trait and state anxiety and the central benzodiazepine receptor: a PET study. AB - The central benzodiazepine receptor (cBZr) has long been implicated in anxiety disorders on the basis of: (i) the well-known anxiolytic and anxiogenic properties of cBZr agonists and inverse agonists, respectively; (ii) a possibly reduced sensitivity to benzodiazepines in anxious subjects; and (iii) a putative endogenous ligand. Thus, two main hypothesis have been advanced, namely changes in the concentration or properties of the latter, and changes in the GABAA complex conformation, which contains the cBZr. Neither postmortem studies nor appropriate animal models are available to investigate these ideas. We have used positron emission tomography (PET) to measure both the density and affinity of the cBZr in multiple brain regions in unmedicated patients and age- and sex matched healthy volunteers, and have looked for differences between groups as well as correlations between cBZr parameters and state and trait anxiety scores. We studied 10 unmedicated patients (sex ratio 1 : 1; mean age: 39 years), prospectively recruited using DSM III-R criteria, and 10 age- and gender-matched healthy unmedicated volunteers. Thanks to a PET procedure using two successive administrations of 11C-flumazenil (at high and low specific radioactivity) and previously validated by us, we estimated the Bmax, Kd and bound : free (B/F) ratios in 11 neocortical areas and in the cerebellum. Before and after the PET session, anxiety scores from Spielberger's and Covi's scales were obtained. There was no statistically significant difference in Bmax, Kd or B/F-values between the two groups for any region. Across the two groups, there were only a few marginally significant anxiety-score-PET correlations, suggesting chance findings. This is the first fully quantitative study to report on the relationships between cBZr parameters and anxiety. Using two independent approaches (i.e. group comparison and across-group correlations), we found no evidence for a link between anxiety trait or state and the cBZr in neocortex or cerebellum in this sample. These findings, if confirmed by studies on larger samples, have implications for the pharmacotherapy of anxiety disorders, and will need to be considered when designing new neurobiological models of anxiety. PMID- 10103142 TI - Adrenalectomy increases neurogenesis but not PSA-NCAM expression in aged dentate gyrus. AB - Ageing is accompanied by a decline in neurogenesis and in polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and by elevated basal levels of circulating corticosterone. In a companion study, we demonstrated that suppression of corticosterone by adrenalectomy increased neurogenesis and PSA-NCAM expression in the dentate gyrus of adult rats. Here we show that adrenalectomy increased neurogenesis in this structure in old rats, as measured by the incorporation of 5-bromo-2'-deoxyuridine in neuronal progenitors. This effect was prevented by corticosterone replacement. In contrast, PSA-NCAM expression remained unchanged in comparison with controls. Thus, in the aged brain, stem cells are still present and able to enter the cell cycle. This may point to ways of protecting or treating age-related cognitive impairments. PMID- 10103143 TI - Sprouting and regeneration after pyramidotomy and blockade of the myelin associated neurite growth inhibitors NI 35/250 in adult rats. AB - After a selective unilateral lesion of the corticospinal tract (CST) at the level of the brainstem (pyramidotomy) and neutralization of the myelin associated neurite growth inhibitors NI-35/250 with the monoclonal antibody (mAb) IN-1, we had previously observed a strong behavioural recovery in parallel with an enhanced structural plasticity of the lesioned as well as the unlesioned CST. The present study focuses on the regenerative response of the cut CST axons at the lesion site in these adult rats. The results show a strong enhancement of regenerative sprouting of CST fibres by treatment with the mAb IN-1. Successful elongation of these sprouts through the pyramidal decussation and into the cervical spinal cord was also dependent on the presence of this antibody. In the spinal cord, regenerating fibres were rarely found in the position of the former CST; most of the fibres were distributed seemingly randomly over the entire lateral extent of the spinal cord. PMID- 10103144 TI - [Evaluation of the results of treatment of cancer of the large intestine based on our clinical data]. AB - Results of the treatment of 225 patients operated between 1991-1995 on the colorectal carcinoma in the II Clinic of Surgery, Medical Academy Wroclaw are evaluated. The analysis of the own material covers the tumor site, age of the patients, histologic grade and clinical stage according to Dukes. The type of surgical procedure--curative or palliative and the evaluation of the survival, death and recurrence rate is presented. Curative procedures were possible only in approximately 60% of cases. The Dukes stage C and D was established in 55.5% of the operated patients. Authors believe that such a significant number of advanced cases was the reason of so poor results. In conclusion they suggest to introduce screening tests for early detection of colorectal carcinoma. PMID- 10103145 TI - [Activation of the immune system in colorectal carcinoma and its assessment]. AB - The immune system of the patients with colorectal cancer is activated. Urinary neopterin is an index of this systemic immune activation, reflecting the circulating activity of interferon-gamma. We have measured urinary neopterin excretion in 34 patients with colorectal cancer. This excretion was significantly higher in our patients compared to reference group (325 +/- 267 vs 169 +/- 62 mumol/mol creatinine, neopterin concentrations were considerably higher in Dukes' stage D disease compared with Dukes' stage B and C disease/561 +/- 372 vs 188 +/- 47 and 250 +/- 142 mu/mol creatinine. Increased neopterin detected the presence of metastatic disease with 90% sensitivity and 87.5% specificity. Authors conclude that urinary neopterin measurement may be useful in the staging of colorectal cancer. PMID- 10103146 TI - [CT-pneumocolon in the diagnosis of colorectal carcinoma]. AB - Accurate preoperative examination and early diagnosis of possible recurrence of the disease play an important role in successful therapy of colorectal carcinoma. At present, modifications of classical examination are being applied, too. In this paper the first experience in using the CT pneumocolon for diagnosing the colorectal cancer is presented. The method improves the diagnostic possibilities of the classical CT examination technique. It enables to image the morphology of the tumour in the air insufflated colon lumen, tumour infiltration outside intestinal wall, localization of organs in the presupposed operation field and possible infiltration of lymph-nodes or liver metastases. The examination has proved easy to be performed with minimal patient's discomfort. PMID- 10103147 TI - [Problems with continence after deep pelvic anastomoses in rectal carcinoma]. AB - Based on the complex evaluation of the continence by anorectal manometry, EMG examination of sphincters, transrectal sonography, defecography and Colonic Transit Time examination, the analysis of the group of 15 patients partially incontinent after operation of carcinoma of the lower part of the rectum has been done. In these patients the deep pelvic anastomosis or coloanal anastomosis was performed. In none of the patients any serious organic damage of sphincters was manifested, the causes were dominantly extrasphincteric and functional, solvable well by conservative methods. PMID- 10103148 TI - [Trans-sphincteric resection of the rectum]. AB - On the base of long time watching of 16 patients treated by transsphincteric resection of the rectum authors believe that this operation has even nowadays still its justification among operations preserving continention. They have dominant position namely in indications for benign disease, where only a small part of patients require a more extent performance. On the contrary, at rectum carcinoma the operating performance is highly elective. PMID- 10103149 TI - [An active approach to liver metastasis]. AB - The intravenous line together with port--Implantofix was placed into art. hepatica propria by laparotomic operation in 16 patients with hepatal metastases (with the main diagnosis either colorectal or breast carcinoma). At the same time there were: 1. visually detected hepatal metastases resected in extraanatomical lines in 4 patients 2. non-resectable metastases sclerotised with 96% ethylalcohol in 3 patients All 16 patients underwent locoregional chemotherapy via subcutaneous port. The medium survival length was 9-12 months. 11 patients were lost due to progression of the disease (lung metastases), five patients are still alive. PMID- 10103150 TI - [Immunotherapy as part of comprehensive therapy in abdominal reoperations with septic complications]. AB - On the base of literature and clinical experience indications of human immunoglobulins in the treatment of infections in surgical patients are presented. Besides prophylactic using in elective operations immunoglobulins were administered as a part of treatment in septic complications, postinjured infections, hospital acquired infections in ICU and immunosuppression. Application of immunoglobulins are regularly part of adjuvant therapy of sepsis in surgical patients. Intravenous immunoglobulins--Pentaglobin and Endobulin were administered postoperatively in patients with reoperations for postoperative peritonitis. For evaluation of effects of immunoglobulins there are presented some clinical and laboratory parameters of sepsis. PMID- 10103151 TI - [Personal experience with treatment of primary hyperparathyroidism]. AB - The primary hyperparathyreosis needs the interdisciplinary approach. The ideal term for surgical intervention is the period of the latent HPT, that means the time, when the signs of irreversibly damaged organs are not yet present. In the Czech Republic they are approximately 100-300 such cases per year with the primary diagnosed HPT. These patients should be sent to the departments, specialized for this type of surgery. PMID- 10103152 TI - [Laparoscopic cholecystectomy and its safety--observations after 2000 procedures]. AB - The authors experience with laparoscopic cholecystectomy in the group of 2200 patients operated on from March 1992 to September 1996 is discussed. The complications rate at the beginning and at the end of the study is expressed. In the last 100 cases there was conversion rate of 1%, no biliary injury was observed and the average postoperative hospital stay was 2.26 days. In the whole group of patients biliary injuries were observed in 0.18%. Lethality was 0.13%. The authors conclude, that laparoscopic cholecystectomy is a save method in the treatment of the gallstone disease, when certain rules are respected. PMID- 10103153 TI - [Biological and medical monitoring of persons with occupational exposure to fibrous materials]. AB - Health status indicators in 3 groups of workers professionally exposed to fibrous materials and 1 control group have been followed. In spite of the fact that asbestos as a compound of friction elements has been forbidden and replaced by non-asbestos materials, quite important changes in peripheral lymphocytes aberrations we found in persons working with these new materials. PMID- 10103154 TI - [Preparation trauma in stomatology]. AB - In this paper authors deal with the causes of preparation trauma in stomatology. They have studied effects of high temperature on human cells cultured in vitro. Based both on literature data and on their own experience they summarize basic principles of preparation which prevent preparation trauma. They summarize how to eliminate as much as possible factors that damage hard dental tissues and pulp. PMID- 10103155 TI - [Physical, chemical and biological aspects of treatment of pathological changes in hard dental tissues]. AB - The methods of preparation of dental tissues, treatment of the dentine wound and filling materials, which replace the hard dental tissues, are discussed to evaluate their features in toward the requirements for biological harmlessness. Based on the literature data, their own clinical and practical experiences, the authors have found that none of the currently used preparation methods as well as supports or filling materials are fulfilling the biological treatment requirements. Therefore, it is necessary to be aware of this fact, and adjust the medical procedures in such a way to avoid the harmful effects or to suppress then as much as possible until the ideal preparation procedures and filling materials will be developed. PMID- 10103156 TI - [Development of dipeptidyl peptidase IV (DPP IV) activity in postnatal differentiation of the submandibular gland in mice]. AB - The localization of a serine exopeptidase--DPP IV--in the male and female submandibular gland of the mouse during gland postnatal development was studied histochemically in the light microscopic level. The present results suggest that localization of DPP IV is closely related to the postnatal differentiation and maturation of acini and male granular convoluted tubules. Remarkable sex differences of DPP IV activity were detected in the submandibular gland of pubescent and adult animals. The possible physiological role of DPP IV in major salivary glands is also discussed in the paper. PMID- 10103157 TI - [Histochemical activity of dipeptidyl peptidase IV (DPP IV) in intracerebral transplantation of the submandibular gland in mice]. AB - Histochemical activity of DPP IV in the intracerebral homotransplants of submandibular gland of the newborn mouse was investigated in the course of a 5 month period after transplantation. Eight weeks after grafting, the enzyme pattern in the parenchyma of transplants was already comparable with the enzyme pattern of a fully mature mouse submandibular gland in situ. At this time, DPP IV was active in the apicolateral cell membranes of numerous acini of the gland transplants. Enzyme activity in apical cell cytoplasm of granular convoluted tubules was found only in transplants located in the brain of male recipients. PMID- 10103158 TI - [Growth of the neurocranium]. AB - The present study demonstrates the results of evaluation of growth changes of the neurocranium in a set of 98 human skulls of immature individuals aged 6-18/20/ years from the XIII.-XVIII. century. Craniometric values were matched with the corresponding values measured on the skulls of the same age groups from the IX. century and IX.-XII. centuries. PMID- 10103159 TI - [Effect of acute exposure to SO2 on cellular defense mechanisms in the lung (pilot study)]. AB - Sulphur dioxide is one of the most important and most frequent atmospheric pollutant of our environmental setting. In presented pilot-study we describe the influence of acute exposure to sulphur dioxide on alveolar macrophages of guinea pigs. The alveolar macrophages represent the main part of mononuclear phagocytic system, which is responsible for the defence of respiratory tract against foreign compounds. The experimental animals were exposed over three hours to sulphur dioxide with the concentration of about 400 ppm. After exposure we did not find significant changes in phagocytic activity of alveolar macrophages. PMID- 10103160 TI - [Modulation of wound healing in glaucoma filtration surgery]. AB - Authors evaluate application of mitomycin C (0.2-0.4 mg/ml) on the sclera during glaucoma filtering surgery. Mean follow up was 19.5 months in the group of 67 patients (75 eyes). The most serious complication was an early endophthalmitis in 2 cases with the loss of residual visual field and vision, 1x hemophthalmus followed with development of traction retinal detachment, 1x hypotonic maculopathy, 1x traction retinal detachment for progression of diabetic proliferative vitreoretinopathy of neovascular glaucoma. Higher rate of complications was noted in the group of mitomycin C 0.4 mg/ml. Visual acuity was better one line Snellen optotypes in 3 cases, and worse in 26 cases. Intraocular pressure compensation up to 20 mmHg was reached in 32 cases without therapy (45.1%), in 28 cases therapy (39.6%), Intraocular pressure above 20 mm Hg was in 11 cases (15.4) and the data are not known in 4 cases (5.4%). Intraocular pressure was compensated after mitomycin C application in 84.7%. PMID- 10103161 TI - [Chemical load in the population and its evaluation]. AB - Human health is determined by the interplay between heredity and the environment. Air, water, food and soil contain chemical, physical and biological agents some of which are known to be harmful to health. Chemical substances that pose the risk to human health and safety and to the environment are subject to governmental regulation. The regulatory decision-making process and regulatory actions are based on two distinct elements: risk assessment and risk management. Air pollution (outdoor, indoor) is a world problem afflicting densely populated urban centers and heavily industrialised areas. Industrialization and the widespread use of chemicals coupled with modern intensive agricultural practices have raised a global concern about the contamination of soil and water. Three categories of environmental chemical contaminants generally occur in food- natural and synthetic organic compounds and traces of toxic metals. Human health protection against chemical exposure can be realised in three ways. Environmental monitoring assesses exposure to a chemical agent by measuring its concentration in the environment (i.e., air, soil, food, water). Biological monitoring assesses internal exposure to a chemical agent by measuring the chemical, its metabolites or nonadverse biological response in body fluids, tissues, expired air or excreta. Health surveillance entails the periodic medical examinations of exposed humans with the purpose of protecting health and preventing disease. PMID- 10103162 TI - [Biological monitoring of chemical exposure]. AB - In this paper we described the biological monitoring as a capable exposure assessment tool that has provided important information used in public health decisions. Biological monitoring is based on determination of biological markers of exposure which are presented as the quantity of a chemical substance or its metabolites or as the deviation of biological parameters (enzyme activity etc.) induced by this substance in exposed humans. The greatest advantage of biological monitoring is the fact that the biological marker of exposure is more directly related to the adverse effects than any environment measurement. Another advantage of biological monitoring is based on the reality that the nonoccupational background exposure (leisure activity, residency, dietary habits, smoking, etc.) may also be expressed in the biological level. Biological parameters can be unfortunately affected by various factors that influence the fate of xenobiotic in vivo. The "BEL" (BTV-biological tolerance value for occupational exposures) is defined as the maximum permissible quantity of a chemical substance or its metabolites or the maximum permissible deviation from the norm of biological parameters during or after exposure. It should be subject to regular revision in the light of new scientific data. PMID- 10103163 TI - [A review of findings on chromium toxicity]. AB - Chromium belongs amongst highly industrially utilized elements. Its role, however, encompasses the physiologic function too. On the other hand, increased exposition to this element, either during its processing, production or in nature in a form of a toxic waste, can lead to the arising of the toxic effects. These toxic features of chromium have been in focus for many years and herein are given together with some new discoveries, such as the influence of chromium on apoptosis, or specific mutations in genes caused by chromium and their repair. PMID- 10103164 TI - [Immunoscintigraphy]. AB - Immunoscintigraphic methods present a great step forward in non-invasive diagnostics. They contribute not only in tumor diagnostic where monoclonal antibodies against tumorous antigens (TAG 72, CEA) are used but also in the sphere of inflammation diagnostic with the use of monoclonal antibody BW 250/183 which is bound onto non-specific cross reacting antigen NCA 95 of granulocytes. Another sphere of interest is the detection of heart muscle damage with the use of monoclonal antibody against myosin and detection of venous thrombosis with the use of monoclonal antibody against fibrin. Monoclonal antibodies are labelled with indium 111 or technecium 99m. PMID- 10103165 TI - [Practical remarks on publishing in international scientific journals]. AB - Differences in style of publishing in national and international scientific journals could negatively influence the acceptance of a manuscript. The article directs an attention of beginning authors to possible pitfalls and tries to give them advice how to reduce elementary mistakes and to enhance a chance for the acceptance of the manuscript. PMID- 10103166 TI - [Determination of the minimal erythema dosage and natural photoprotection of the skin in the population]. AB - Effects of ultraviolet radiation (UV) on the human skin are summarized in the introductory part from physical and biological point of view, especially photoaging and photocarcinogenesis. Special attention has been paid to skin phototype which characterizes the individual susceptibility to UV. The minimal erythema dose (MED) serves for establishment of this susceptibility. The mean MEDs for white population in other countries are also shown here. Mechanisms of natural photoprotection in connection with instructions how to increase artificial photoprotection are described here. The investigation of skin type incidence in our population and determining their mean MEDs for UV-B and polychromatic light was the aim of practical work. The UV-B MED is in average 23.4 mJ/cm2. The further work has been concentrated on the assessment of pigmentation response after irradiation and especially on the comparison of the minimal erythema doses before season and after it. We found mean double increase of the MED after sunlight exposition during summer season. We suggested, that double increasing of seasonal natural photoprotection does not represent definitive protection for most people and does not impair summer warning system in media which is based on winter MEDs. Some recommendations for improvement of protection of Czech population against UV radiation are proposed in conclusion. PMID- 10103167 TI - [Biophysical principals in radiotherapy of malignant tumors]. AB - The successfulness of tumour radiotherapy depends before all on achieving the maximal effect of radiation on the tumour with contemporary minimalization of the injury of normal tissues in its vicinity. Such selectivity of radiation action may be realized by utilization of physical (kind and energy of radiation, irradiation conditions) as well as biological (modification of radiation effects) factors. The aim of this publication is to give a survey of fundamental biophysical and radiobiological principles conditioning the differential action of ionizing radiation on tumorous and normal cell populations from the standpoint of the relevancy of experimental radiobiology (radiation effect on the proliferative capacity of the tumorous and normal tissue) to radiotherapy. More accent than customary in medical literature is put on the physical interactions of radiations in matter and dosimetry as well as microdosimetry of radiation. The importance of microdosimetry will perhaps increase in future in connection with the therapeutic usage of non-conventional kinds of radiation (neutrons, heavy charged particles, pi-mezons). Basic biophysical machanisms of radiation action on cells and cell populations are described and explained in terms of quantum radiobiology (single- and multihit theory, target theory, stochastics of radiation injury development, etc.) as well as the main principles of modification of radiation effects (oxygen effect, radiosensitizers, fractionation of the dose). A brief interpretation of the Strandquist model of isoeffect curves for the fractionated irradiation is presented enabling to relate mutually the total absorbed dose to the total irradiation time and the number of fractions. PMID- 10103168 TI - Fully automated measurement of total homocysteine in plasma and serum on the Abbott IMx analyzer. PMID- 10103169 TI - Simple colorimetric procedures to determine smoking status. PMID- 10103171 TI - Hypergastrinaemia with long-term omeprazole treatment. PMID- 10103172 TI - Complexity and the economy AB - After two centuries of studying equilibria-static patterns that call for no further behavioral adjustments-economists are beginning to study the general emergence of structures and the unfolding of patterns in the economy. When viewed in out-of-equilibrium formation, economic patterns sometimes simplify into the simple static equilibria of standard economics. More often they are ever changing, showing perpetually novel behavior and emergent phenomena. Complexity portrays the economy not as deterministic, predictable, and mechanistic, but as process dependent, organic, and always evolving. PMID- 10103173 TI - Aminoglycosides: activity and resistance. PMID- 10103174 TI - In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t butylglycylamido derivative of minocycline (GAR-936). AB - The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the N,N-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG MINO, with an MIC range of 0.25 to 0.5 microgram/ml, showed good activity against strains expressing tet(M) (ribosomal protection), tet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, < or = 0.5 microgram/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S. aureus including MRSA strains and strains containing tet(K) or tet(M) resistance determinants (median effective doses [ED50s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline sensitive E. coli strains as well as E. coli strains containing either tet(M) or the efflux determinant tet(A), tet(B), or tet(C) (ED50s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO. PMID- 10103175 TI - Bile salts: natural detergents for the prevention of sexually transmitted diseases. AB - The development of new, safe, topical microbicides for intravaginal use for the prevention of sexually transmitted diseases is imperative. Previous studies have suggested that bile salts may inhibit human immunodeficiency virus infection; however, their activities against other sexually transmitted pathogens have not been reported. To further explore the potential role of bile salts in preventing sexually transmitted diseases, we examined the in vitro activities and cytotoxicities of select bile salts against Chlamydia trachomatis, herpes simplex virus (types 1 and 2), Neisseria gonorrhoeae, and human immunodeficiency virus in comparison to those of nonoxynol-9 and benzalkonium chloride using both primary cells and cell lines derived from the human female genital tract. We found that taurolithocholic acid 3-sulfate and a combination of glycocholic acid and taurolithocholic acid 3-sulfate showed excellent activity against all of the pathogens assayed. Moreover, taurolithocholic acid 3-sulfate alone or in combination was less cytotoxic than nonoxynol-9 and benzalkonium chloride. Thus, taurolithocholic acid 3-sulfate alone or in combination warrants further evaluation as a candidate topical microbicidal agent. PMID- 10103176 TI - Efficacy of RD3-0028 aerosol treatment against respiratory syncytial virus infection in immunosuppressed mice. AB - RD3-0028, a benzodithiin compound, has antiviral activity against respiratory syncytial virus (RSV) in cell culture. We used a mouse model of RSV infection to determine the in vivo effect of RD3-0028. Cyclophosphamide (CYP)-treated, immunosuppressed mice were inoculated intranasally. The lungs of the mice were removed on day 4. The virus titers of the lungs of RD3-0028-treated mice were compared to the virus titers of the lungs of virus-inoculated, untreated control mice. In an effort to increase the therapeutic effectiveness of this compound, RD3-0028 was administered by aerosol to RSV-infected mice by using a head exposure system. Aerosols generated from reservoirs containing RD3-0028 (7 mg/ml) administered for 2 h twice daily for 3 days significantly reduced the pulmonary titer of RSV-infected mice. It is clear that the minimal effective dose of RD3 0028 for RSV-infected mice is significantly less than that of ribavirin, the only compound currently available for use against RSV disease. Furthermore, the RD3 0028 aerosol administration appeared to protect the lungs of infected, CYP treated mice against tissue damage, as evidenced by the preservation of the lung architecture and a reduction in pulmonary inflammatory infiltrates. RD3-0028 aerosol was not toxic for mice at the therapeutic dose. The present study demonstrates the effectiveness of aerosol administration of RD3-0028 for RSV infected mice. PMID- 10103177 TI - Recombinant bactericidal/permeability-increasing protein (rBPI21) in combination with sulfadiazine is active against Toxoplasma gondii. AB - The activity of recombinant bactericidal/permeability-increasing protein (rBPI21), alone or in combination with sulfadiazine, on the intracellular replication of Toxoplasma gondii was assessed in vitro and in mice with acute toxoplasmosis. rBPI21 markedly inhibited the intracellular growth of T. gondii in human foreskin fibroblasts (HFFs). Following 72 h of exposure, the 50% inhibitory concentration of rBPI21 for T. gondii was 2.6 micrograms/ml, whereas only slight cytotoxicity for HFF cells was observed at the concentrations tested. Subsequent mathematical analyses revealed that the combination of rBPI21 with sulfadiazine yielded slight to moderate synergistic effects against T. gondii in vitro. Infection of mice orally with C56 cysts or intraperitoneally (i.p.) with RH tachyzoites resulted in 100% mortality, whereas prolongation of the time to death or significant survival (P = 0.002) was noted for those animals treated with 5 to 20 mg of rBPI21 per kg of body weight per day. Treatment with rBPI21 in combination with sulfadiazine resulted in significant (P = 0.0001) survival of mice infected i.p. with tachyzoites but not of mice infected orally with T. gondii cysts. These results indicate that rBPI21 is active in vitro and in vivo against T. gondii and that its activity is significantly enhanced when it is used in combination with sulfadiazine. To our knowledge, this is the first report of the activity of rBPI21 against a protozoan parasite. PMID- 10103178 TI - Effects of azole antifungal drugs on the transition from yeast cells to hyphae in susceptible and resistant isolates of the pathogenic yeast Candida albicans. AB - Oral infections caused by the yeast Candida albicans are some of the most frequent and earliest opportunistic infections in human immunodeficiency virus infected patients. The widespread use of azole antifungal drugs has led to the development of drug resistance, creating a major problem in the treatment of yeast infections in AIDS patients and other immunocompromised individuals. Several molecular mechanisms that contribute to drug resistance have been identified. In C. albicans, the ability to morphologically switch from yeast cells (blastospores) to filamentous forms (hyphae) is an important virulence factor which contributes to the dissemination of Candida in host tissues and which promotes infection and invasion. A positive correlation between the level of antifungal drug resistance and the ability to form hyphae in the presence of azole drugs has been identified. Under hypha-inducing conditions in the presence of an azole drug, resistant clinical isolates form hyphae, while susceptible yeast isolates do not. This correlation is observed in a random sample from a population of susceptible and resistant isolates and is independent of the mechanisms of resistance. 35S-methionine incorporation suggests that growth inhibition is not sufficient to explain the inhibition of hyphal formation, but it may contribute to this inhibition. PMID- 10103179 TI - Cloning, sequence analyses, expression, and distribution of ampC-ampR from Morganella morganii clinical isolates. AB - Shotgun cloning experiments with restriction enzyme-digested genomic DNA from Morganella morganii 1, which expresses high levels of cephalosporinase, into the pBKCMV cloning vector gave a recombinant plasmid, pPON-1, which encoded four entire genes: ampC, ampR, an hybF family gene, and orf-1 of unknown function. The deduced AmpC beta-lactamase of pI 7.6 shared structural and functional homologies with AmpC from Citrobacter freundii, Escherichia coli, Yersinia enterocolitica, Enterobacter cloacae, and Serratia marcescens. The overlapping promoter organization of ampC and ampR, although much shorter in M. morganii than in the other enterobacterial species, suggested similar AmpR regulatory properties. The MICs of beta-lactams for E. coli MC4100 (ampC mutant) harboring recombinant plasmid pACYC184 containing either ampC and ampR (pAC-1) or ampC (pAC-2) and induction experiments showed that the ampC gene of M. morganii 1 was repressed in the presence of ampR and was activated when a beta-lactam inducer was added. Moreover, transformation of M. morganii 1 or of E. coli JRG582 (delta ampDE) harboring ampC and ampR with a recombinant plasmid containing ampD from E. cloacae resulted in a decrease in the beta-lactam MICs and an inducible phenotype for M. morganii 1, thus underlining the role of an AmpD-like protein in the regulation of the M. morganii cephalosporinase. Fifteen other M. morganii clinical isolates with phenotypes of either low-level inducible cephalosporinase expression or high-level constitutive cephalosporinase expression harbored the same ampC-ampR organization, with the hybF and orf-1 genes surrounding them; the organization of these genes thus differed from those of ampC-ampR genes in C. freundii and E. cloacae, which are located downstream from the fumarate operon. Finally, an identical AmpC beta-lactamase (DHA-1) was recently identified as being plasmid encoded in Salmonella enteritidis, and this is confirmatory evidence of a chromosomal origin of the plasmid-mediated cephalosporinases. PMID- 10103180 TI - Exposure to metronidazole in vivo readily induces resistance in Helicobacter pylori and reduces the efficacy of eradication therapy in mice. AB - The Helicobacter pylori SS1 mouse model was used to characterize the development of resistance in H. pylori after treatment with metronidazole monotherapy and to examine the effect of prior exposure to metronidazole on the efficacy of a metronidazole-containing eradication regimen. Mice colonized with the metronidazole-sensitive H. pylori SS1 strain were treated for 7 days with either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole once a day or three times per day (TID). In a separate experiment, H. pylori-infected mice were administered either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole TID for 7 days, followed 1 month later by either peptone trypsin broth or the mouse equivalent of 20 mg of omeprazole, 250 mg of clarithromycin, and 400 mg of metronidazole twice a day for 7 days. At least 1 month after the completion of treatment, the mice were sacrificed and their stomachs were cultured for H. pylori. The susceptibilities of isolates to metronidazole were assessed by agar dilution determination of the MICs. Mixed populations of metronidazole-resistant and -sensitive strains were isolated from 70% of mice treated with 400 mg of metronidazole TID. The ratio of resistant to sensitive strains was 1:100, and the MICs for the resistant strains varied from 8 to 64 micrograms/ml. In the second experiment, H. pylori was eradicated from 70% of mice treated with eradication therapy alone, compared to 25% of mice pretreated with metronidazole (P < 0.01). Mice still infected after treatment with metronidazole and eradication therapy contained mixed populations of metronidazole-resistant and -sensitive isolates in a ratio of 1:25. These results demonstrate that H. pylori readily acquires resistance to metronidazole in vivo and that prior exposure of the organism to metronidazole is associated with failure of eradication therapy. H. pylori-infected mice provide a suitable model for the study of resistance mechanisms in H. pylori and will be useful in determining optimal regimens for the eradication of resistant strains. PMID- 10103181 TI - In vitro antibacterial properties of pexiganan, an analog of magainin. AB - Pexiganan, a 22-amino-acid antimicrobial peptide, is an analog of the magainin peptides isolated from the skin of the African clawed frog. Pexiganan exhibited in vitro broad-spectrum antibacterial activity when it was tested against 3,109 clinical isolates of gram-positive and gram-negative, anaerobic and aerobic bacteria. The pexiganan MIC at which 90% of isolates are inhibited (MIC90) was 32 micrograms/ml or less for Staphylococcus spp., Streptococcus spp., Enterococcus faecium, Corynebacterium spp., Pseudomonas spp., Acinetobacter spp., Stenotrophomonas spp., certain species of the family Enterobacteriaceae, Bacteroides spp., Peptostreptococcus spp., and Propionibacterium spp. Comparison of the MICs and minimum bactericidal concentrations (MBCs) of pexiganan for 143 isolates representing 32 species demonstrated that for 92% of the isolates tested, MBCs were the same or within 1 twofold difference of the MICs, consistent with a bactericidal mechanism of action. Killing curve analysis showed that pexiganan killed Pseudomonas aeruginosa rapidly, with 10(6) organisms/ml eliminated within 20 min of treatment with 16 micrograms of pexiganan per ml. No evidence of cross-resistance to a number of other antibiotic classes was observed, as determined by the equivalence of the MIC50s and the MIC90s of pexiganan for strains resistant to oxacillin, cefazolin, cefoxitin, imipenem, ofloxacin, ciprofloxacin, gentamicin, and clindamicin versus those for strains susceptible to these antimicrobial agents. Attempts to generate resistance in several bacterial species through repeated passage with subinhibitory concentrations of pexiganan were unsuccessful. In conclusion, pexiganan exhibits properties in vitro which make it an attractive candidate for development as a topical antimicrobial agent. PMID- 10103182 TI - Emergence of fosfomycin-resistant isolates of Shiga-like toxin-producing Escherichia coli O26. AB - We evaluated the susceptibilities of 129 Shiga-like toxin-producing Escherichia coli (STEC) isolates to various antibiotics. The numbers of isolates for which MICs were high (> or = 128 micrograms/ml) were as follows: 5 for fosfomycin, 14 for ampicillin, 1 for cefaclor, 6 for kanamycin, 22 for tetracycline, and 2 for doxycycline. For two isolates of STEC O26 MICs of fosfomycin were high (1,024 and 512 micrograms/ml, respectively). Conjugation experiments and glutathione S transferase assays suggested that the fosfomycin resistance in these isolates was determined not by a plasmid but chromosomally. The amount of active intracellular fosfomycin in these STEC isolates was 100- to 200-fold less than that in E. coli C600 harboring pREFTT47B408 in the presence of either L-alpha-glycerophosphate or glucose-6-phosphate. Cloning, sequencing, and Northern blot analysis demonstrated that the transcriptional level of the murA gene encoding UDP-N-acetylglucosamine enolpyruvoyl transferase in these isolates was greater than that in E. coli C600. Our results suggest that the fosfomycin resistance in these STEC isolates is due to concurrent effects of alteration of the glpT and/or uhp transport systems and of the enhanced transcription of the murA gene. PMID- 10103183 TI - Nitrite reductase from Pseudomonas aeruginosa released by antimicrobial agents and complement induces interleukin-8 production in bronchial epithelial cells. AB - We have recently reported that nitrite reductase, a bifunctional enzyme located in the periplasmic space of Pseudomonas aeruginosa, could induce interleukin-8 (IL-8) generation in a variety of respiratory cells, including bronchial epithelial cells (K. Oishi et al. Infect. Immun. 65:2648-2655, 1997). In this report, we examined the mode of nitrite reductase (PNR) release from a serum sensitive strain of live P. aeruginosa cells during in vitro treatment with four different antimicrobial agents or human complement. Bacterial killing of P. aeruginosa by antimicrobial agents induced PNR release and mediated IL-8 production in human bronchial epithelial (BET-1A) cells. Among these agents, imipenem demonstrated rapid killing of P. aeruginosa as well as rapid release of PNR and resulted in the highest IL-8 production. Complement-mediated killing of P. aeruginosa was also associated with PNR release and enhanced IL-8 production. The immunoprecipitates of the aliquots of bacterial culture containing imipenem or complement with anti-PNR immunoglobulin G (IgG) induced twofold-higher IL-8 production than did the immunoprecipitates of the aliquots of bacterial culture with a control IgG. These pieces of evidence confirmed that PNR released in the aliquots of bacterial culture was responsible for IL-8 production in the BET-1A cells. Furthermore, the culture supernatants of the BET-1A cells stimulated with aliquots of bacterial culture containing antimicrobial agents or complement similarly mediated neutrophil migration in vitro. These data support the possibility that a potent inducer of IL-8, PNR, could be released from P. aeruginosa after exposure to antimicrobial agents or complement and contributes to neutrophil migration in the airways during bronchopulmonary infections with P. aeruginosa. PMID- 10103184 TI - 9-[2-(Phosphonomethoxy)propyl]adenine (PMPA) therapy prolongs survival of infant macaques inoculated with simian immunodeficiency virus with reduced susceptibility to PMPA. AB - Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a useful animal model of human immunodeficiency virus infection for the study of the emergence and clinical implications of drug-resistant viral mutants. We previously demonstrated that SIV-infected infant macaques receiving prolonged treatment with 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) developed viral mutants with fivefold reduced susceptibility to PMPA in vitro and that the development of these mutants was associated with the development of a K65R mutation and additional compensatory mutations in reverse transcriptase (RT). To study directly the virulence and clinical implications of these SIV mutants, two uncloned SIVmac isolates with similar fivefold reduced in vitro susceptibilities to PMPA but distinct RT genotypes, SIVmac055 (K65R, N69T, R82K A158S,S211N) and SIVmac385 (K65R, N69S, I118V), were each inoculated intravenously into six newborn rhesus macaques; 3 weeks later, three animals of each group were started on PMPA treatment. All six untreated animals developed persistently high levels of viremia and fatal immunodeficiency within 4 months. In contrast, the six PMPA treated animals, despite having persistently high virus levels, survived significantly longer: 5 to 9 months for the three SIVmac055-infected infants and > or = 21 months for the three SIVmac385-infected infants. Virus from only one untreated animal demonstrated reversion to wild-type susceptibility and loss of the K65R mutation. In several other animals, additional RT mutations, including K64R and Y115F, were detected, but the biological role of these mutations is unclear since they did not affect the in vitro susceptibility of the virus to PMPA. In conclusion, this study demonstrates that although SIVmac mutants with the PMPA-selected K65R mutation in RT were highly virulent, PMPA treatment still offered strong therapeutic benefits. These results suggest that the potential emergence of HIV mutants with reduced susceptibility to PMPA in patients during prolonged PMPA therapy may not eliminate its therapeutic benefits. PMID- 10103185 TI - Efficacy of doxycycline, azithromycin, or trovafloxacin for treatment of experimental Rocky Mountain spotted fever in dogs. AB - Dogs were experimentally inoculated with Rickettsia rickettsii (canine origin) in order to compare the efficacies of azithromycin and trovafloxacin to that of the current antibiotic standard, doxycycline, for the treatment of Rocky Mountain spotted fever. Clinicopathologic parameters, isolation of rickettsiae in tissue culture, and PCR amplification of rickettsial DNA were used to evaluate the response to therapy or duration of illness (untreated infection control group) in the four groups. Concentrations of the three antibiotics in plasma and blood cells were measured by high-performance liquid chromatography. Doxycycline and trovafloxacin treatments resulted in more-rapid defervescence, whereas all three antibiotics caused rapid improvement in attitudinal scores, blood platelet numbers, and the albumin/total-protein ratio. Based upon detection of retinal vascular lesions by fluorescein angiography, trovafloxacin and doxycycline substantially decreased rickettsia-induced vascular injury to the eye, whereas the number of ocular lesions in the azithromycin group did not differ from that in the infection control group. As assessed by tissue culture isolation, doxycycline resulted in the earliest apparent clearance of viable circulating rickettsiae; however, rickettsial DNA could still be detected in the blood of some dogs from all four groups on day 21 postinfection, despite our inability to isolate viable rickettsiae at that point. As administered in this study, trovafloxacin was as efficacious as doxycycline but azithromycin proved less efficacious, possibly due to the short duration of administration. PMID- 10103186 TI - Antiviral effect of hyperthermic treatment in rhinovirus infection. AB - Human rhinoviruses (HRV) are recognized as the major etiologic agents for the common cold. Starting from the observation that local hyperthermic treatment is beneficial in patients with natural and experimental common colds, we have studied the effect of brief hyperthermic treatment (HT) on HRV replication in HeLa cells. We report that a 20-min HT at 45 degrees C is effective in suppressing HRV multiplication by more than 90% when applied at specific stages of the virus replication cycle. Synthesis of virus proteins is not affected by HT, indicating that the target for treatment is a posttranslational event. The antiviral effect is a transient cell-mediated event and is associated with the synthesis of the 70-kDa heat shock protein hsp70. Unlike poliovirus, rhinovirus infection does not inhibit the expression of hsp70 induced by heat. The possibility that hsp70 could play a role in the control of rhinovirus replication is suggested by the fact that a different class of HSP inducers, the cyclopentenone prostaglandins PGA1 and delta 12-PGJ2, were also effective in inhibiting HRV replication in HeLa cells. Inhibition of hsp70 expression by actinomycin D prevented the antiviral activity of prostaglandins in HRV-infected cells. These results indicate that the beneficial effect of respiratory hyperthermia may be mediated by the induction of a cytoprotective heat shock response in rhinovirus-infected cells. PMID- 10103187 TI - LY303366 exhibits rapid and potent fungicidal activity in flow cytometric assays of yeast viability. AB - LY303366 is a semisynthetic analog of the antifungal lipopeptide echinocandin B that inhibits (1,3)-beta-D-glucan synthase and exhibits efficacy in animal models of human fungal infections. In this study, we utilized flow cytometric analysis of propidium iodide uptake, single-cell sorting, and standard microbiological plating methods to study the antifungal effect of LY303366 on Saccharomyces cerevisiae and Candida albicans. Our data indicate that an initial 5-min pulse treatment with LY303366 caused yeasts to take up propidium iodide and lose their ability to grow. Amphotericin B and cilofungin required longer exposure periods (30 and 180 min, respectively) and higher concentrations to elicit these fungicidal effects. These two measurements of fungicidal activity by LY303366 were highly correlated (r > 0.99) in concentration response and time course experiments. As further validation, LY303366-treated yeasts that stained with propidium iodide were unable to grow in single-cell-sorted cultures. Our data indicate that LY303366 is potent and rapidly fungicidal for actively growing yeasts. The potency and rapid action of this new fungicidal compound suggest that LY303366 may be useful for antifungal therapy. PMID- 10103189 TI - Molecular characterization of an antibiotic resistance gene cluster of Salmonella typhimurium DT104. AB - Salmonella typhimurium phage type DT104 has become an important emerging pathogen. Isolates of this phage type often possess resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline (ACSSuT resistance). The mechanism by which DT104 has accumulated resistance genes is of interest, since these genes interfere with treatment of DT104 infections and might be horizontally transferred to other bacteria, even to unrelated organisms. Previously, several laboratories have shown that the antibiotic resistance genes of DT104 are chromosomally encoded and involve integrons. The antibiotic resistance genes conferring the ACSSuT-resistant phenotype have been cloned and sequenced. These genes are grouped within two district integrons and intervening plasmid-derived sequences. This sequence is potentially useful for detection of multiresistant DT104. PMID- 10103188 TI - High-frequency, in vitro reversible switching of Candida lusitaniae clinical isolates from amphotericin B susceptibility to resistance. AB - Recent studies have revealed an increase in the incidence of serious infections caused by non-albicans Candida species. Candida lusitaniae is of special interest because of its sporadic resistance to amphotericin B (AmB). The present in vitro study demonstrated that, unlike other Candida species, C. lusitaniae isolates frequently generated AmB-resistant lineages form previously susceptible colonies. Cells switching from a resistant colony to a susceptible phenotype were also detected after treatment with either UV light, heat shock, or exposure to whole blood, all of which increased the frequency of switching. In some C. lusitaniae lineages, after a cell switched to a resistant phenotype, the resistant phenotype was stable; in other lineages, colonies were composed primarily of AmB susceptible cells. Although resistant and susceptible lineages were identical in many aspects, their cellular morphologies were dramatically different. Switching mechanisms that involve exposure to antifungals may have an impact on antifungal therapeutic strategies as well as on standardized susceptibility testing of clinical yeast specimens. PMID- 10103190 TI - Strength and regulation of the different promoters for chromosomal beta lactamases of Klebsiella oxytoca. AB - The two groups of chromosomal beta-lactamases from Klebsiella oxytoca (OXY-1 and OXY-2) can be overproduced 73- to 223-fold, due to point mutations in the consensus sequences of their promoters. The different versions of promoters from blaOXY-1 and blaOXY-2 were cloned upstream of the chloramphenicol acetyltransferase (CAT) gene of pKK232-8, and their relative strengths were determined in Escherichia coli and in K. oxytoca. The three different mutations in the OXY beta-lactamase promoters resulted in a 4- to 31-fold increase in CAT activity compared to that of the wild-type promoter. The G-->T transversion in the first base of the -10 consensus sequence caused a greater increase in the promoter strength of the wild-type promoter than the two other principal mutations (a G-to-A transition of the fifth base of the -10 consensus sequence and a T-to-A transversion of the fourth base of the -35 sequence). The strength of the promoter carrying a double mutation (transition in the Pribnow box and the transversion in the -35 hexamer) was increased 15- to 61-fold in comparison to that of the wild-type promoter. A change from 17 to 16 bp between the -35 and -10 consensus sequences resulted in a ninefold decrease of the promoter strength. The expression of the blaOXY promoter in E. coli differs from that in K. oxytoca, particularly for promoters carrying strong mutations. Furthermore, the blaOXY promoter appears not to be controlled by DNA supercoiling or an upstream curved DNA, but it is dependent on the gene copy number. PMID- 10103191 TI - The immune response modifier imiquimod requires STAT-1 for induction of interferon, interferon-stimulated genes, and interleukin-6. AB - Imiquimod is an oral inducer of interferon (IFN) and several other proinflammatory cytokines and has been successfully used topically as an antiviral agent for the treatment of genital warts. We have investigated the molecular mechanisms by which imiquimod induces the expression of IFNs, IFN stimulated genes (ISGs), and proinflammatory cytokines in vivo, using mice deficient in various components of the IFN signaling system. Mice deficient in the transcription factor interferon regulatory factor 1 (IRF-1) or in the serine/threonine protein kinase PKR responded normally to imiquimod, producing high levels of circulating IFN and induction of several ISGs. On the other hand, when mice deficient in STAT-1 were treated, a 32-fold reduction in the level of circulating IFN was observed, together with a lack of induction of 2-5 oligo adenylate synthetase (2-5 OAS) and IRF-1 genes. Interestingly, there was also a lack of induction of interleukin-6 (IL-6) gene expression, although tumor necrosis factor was induced and readily detected in serum. In mice deficient in the type I IFN receptor, imiquimod induced levels of IFN similar to those in control mice, but again, neither 2-5 OAS, IRF-1, nor IL-6 genes were induced in mutant mice. Our results suggest that STAT-1 plays a critical role in the mechanism of gene activation by imiquimod. Moreover, induction of IL-6 gene expression appears to be dependent on components of the IFN signaling cascade. PMID- 10103192 TI - Ampicillin-sulbactam and amoxicillin-clavulanate susceptibility testing of Escherichia coli isolates with different beta-lactam resistance phenotypes. AB - The activities of ampicillin-sulbactam and amoxicillin-clavulanate were studied with 100 selected clinical Escherichia coli isolates with different beta-lactam susceptibility phenotypes by standard agar dilution and disk diffusion techniques and with a commercial microdilution system (PASCO). A fixed ratio (2:1) and a fixed concentration (clavulanate, 2 and 4 micrograms/ml; sulbactam, 8 micrograms/ml) were used in the agar dilution technique. The resistance frequencies for amoxicillin-clavulanate with different techniques were as follows: fixed ratio agar dilution, 12%; fixed concentration 4-micrograms/ml agar dilution, 17%; fixed ratio microdilution, 9%; and disk diffusion, 9%. Marked discrepancies were found when these results were compared with those obtained with ampicillin-sulbactam (26 to 52% resistance), showing that susceptibility to amoxicillin-clavulanic acid cannot be predicted by testing the isolate against ampicillin-sulbactam. Interestingly, the discrimination between susceptible and intermediate isolates was better achieved with 4 micrograms of clavulanate per ml than with the fixed ratio. In contrast, amoxicillin susceptibility was not sufficiently restored when 2 micrograms of clavulanate per ml was used, particularly in moderate (mean beta-lactamase activity, 50.8 mU/mg of protein) and high-level (215 mU/mg) TEM-1 beta-lactamase producer isolates. Four micrograms of clavulanate per milliliter could be a reasonable alternative to the 2:1 fixed ratio, because most high-level beta-lactamase-hyperproducing isolates would be categorized as nonsusceptible, and low- and moderate-level beta lactamase-producing isolates would be categorized as nonresistant. This approach cannot be applied to sulbactam, either with the fixed 2:1 ratio or with the 8 micrograms/ml fixed concentration, because many low-level beta-lactamase producing isolates would be classified in the resistant category. These findings call for a review of breakpoints for beta-lactam-beta-lactamase inhibitors combinations. PMID- 10103193 TI - Impact of gyrA and parC mutations on quinolone resistance, doubling time, and supercoiling degree of Escherichia coli. AB - Isogenic mutants derived from quinolone-susceptible isolate WT by introducing gyrA (S83L, D87G) and parC (S80I, E84K) mutations associated with quinolone resistance were characterized with respect to quinolone resistance, growth rate, and degree of global supercoiling. The latter was determined by use of a pair of reporter plasmids carrying supercoiling-dependent promoters pgyrA and ptopA, respectively, transcriptionally fused to the reporter gene bla coding for TEM-1 beta-lactamase. The quotient (Qsc) of the beta-lactamase specific activity determined for a mutant carrying either plasmid was taken as a measure of the degree of global supercoiling. These Qsc data were comparable to results obtained from the separation of topoisomers of plasmid pBR322 on chloroquine-containing agarose gels and indicate a reduced degree of negative supercoiling in resistant mutants relative to the parent, WT. The S83L mutation in gyrA had the strongest influence on quinolone resistance while leaving other parameters nearly unaffected. The gyrA double mutation (S83L plus D87G) had an effect on quinolone resistance similar to that of a single mutation. Phenotypic expression of the parC mutation (S80I) was dependent on the presence of at least one gyrA mutation. Expression of high-level fluoroquinolone resistance (ciprofloxacin MIC, > 4 micrograms/ml) required a combination of the gyrA double mutation and one parC mutation (S80I or E84K). Such mutants showed considerable alterations of growth rate, global supercoiling, or both. Introduction of a parC mutation affected neither the doubling time nor the degree of supercoiling, while the presence of the gyrA D87G mutation was associated with a significant reduction in the degree of DNA supercoiling. PMID- 10103194 TI - Pharmacodynamics of vancomycin for the treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. AB - With the emergence of beta-lactam antibiotic resistance among strains of Streptococcus pneumoniae, vancomycin has assumed an important role in the treatment of bacterial meningitis. Using the rabbit meningitis model, we evaluated the pharmacokinetics and pharmacodynamics of vancomycin in this setting. Animals were given 80 mg/kg of body weight daily in two or four divided doses to determine the penetration and activity of vancomycin in cerebrospinal fluid (CSF); each regimen was administered with and without dexamethasone. Mean peak (2 h) concentrations in CSF that were four- to eightfold higher than the minimum bactericidal concentration (MBC; 0.5 microgram/ml) for the pathogen were adequate for bacterial clearance. In both groups concentrations in CSF remained higher than the MBC for greater than 80% of the respective dosing intervals, and the penetration of vancomycin into CSF was 20%. Mean concentrations in CSF at 24 to 36 h of therapy were lower than those achieved during the first 12 h, consistent with a decline in the level of antibiotic entry into CSF as inflammation wanes. Rates of bacterial clearance were similar for the two regimens, and for all animals cultures of CSF were sterile by 36 h. The coadministration of dexamethasone significantly reduced the penetration of vancomycin into CSF by 29% and significantly lowered the rate of bacterial clearance during the first 6 h in animals receiving 20-mg/kg doses of vancomycin. For animals receiving 40-mg/kg doses, therapeutic peak concentrations in CSF were obtained even with steroid use, suggesting that the effect of steroids may be circumvented by the use of larger daily doses of vancomycin. PMID- 10103195 TI - Clavulanate induces expression of the Pseudomonas aeruginosa AmpC cephalosporinase at physiologically relevant concentrations and antagonizes the antibacterial activity of ticarcillin. AB - Although previous studies have indicated that clavulanate may induce AmpC expression in isolates of Pseudomonas aeruginosa, the impact of this inducer activity on the antibacterial activity of ticarcillin at clinically relevant concentrations has not been investigated. Therefore, a study was designed to determine if the inducer activity of clavulanate was associated with in vitro antagonism of ticarcillin at pharmacokinetically relevant concentrations. By the disk approximation methodology, clavulanate induction of AmpC expression was observed with 8 of 10 clinical isolates of P. aeruginosa. Quantitative studies demonstrated a significant induction of AmpC when clavulanate-inducible strains were exposed to the peak concentrations of clavulanate achieved in human serum with the 3.2- and 3.1-g doses of ticarcillin-clavulanate. In studies with three clavulanate-inducible strains in an in vitro pharmacodynamic model, antagonism of the bactericidal effect of ticarcillin was observed in some tests with regimens simulating a 3.1-g dose of ticarcillin-clavulanate and in all tests with regimens simulating a 3.2-g dose of ticarcillin-clavulanate. No antagonism was observed in studies with two clavulanate-noninducible strains. In contrast to clavulanate. No antagonism was observed in studies with two clavulanate-noninducible strains. In contrast to clavulanate, tazobactam failed to induce AmpC expression in any strains, and the pharmacodynamics of piperacillin-tazobactam were somewhat enhanced over those of piperacillin alone against all strains studied. Overall, the data collected from the pharmacodynamic model suggested that induction per se was not always associated with reduced killing but that a certain minimal level of induction by clavulanate was required before antagonism of the antibacterial activity of its companion drug occurred. Nevertheless, since clinically relevant concentrations of clavulanate can antagonize the bactericidal activity of ticarcillin, the combination of ticarcillin-clavulanate should be avoided when selecting an antipseudomonal beta-lactam for the treatment of P. aeruginosa infections, particularly in immunocompromised patients. For piperacillin tazobactam, induction is not an issue in the context of treating this pathogen. PMID- 10103196 TI - Structure of In31, a blaIMP-containing Pseudomonas aeruginosa integron phyletically related to In5, which carries an unusual array of gene cassettes. AB - The location and environment of the acquired blaIMP gene, which encodes the IMP-1 metallo-beta-lactamase, were investigated in a Japanese Pseudomonas aeruginosa clinical isolate (isolate 101/1477) that produced the enzyme. In this isolate, blaIMP was carried on a 36-kb plasmid, and similar to the identical alleles found in Serratia marcescens and Klebsiella pneumoniae clinical isolates, it was located on a mobile gene cassette inserted into an integron. The entire structure of this integron, named In31, was determined. In31 is a class 1 element belonging to the same group of defective transposon derivatives that originated from Tn402 like ancestors such as In0, In2, and In5. The general structure of In31 appeared to be most closely related to that of In5 from pSCH884, suggesting a recent common phylogeny for these two elements. In In31, the blaIMP cassette is the first of an array of five gene cassettes that also includes an aacA4 cassette and three original cassettes that have never been described in other integrons. The novel cassettes carry, respectively, (i) a new chloramphenicol acetyltransferase encoding allele of the catB family, (ii) a qac allele encoding a new member of the small multidrug resistance family of proteins, and (iii) an open reading frame encoding a protein of unknown function. All the resistance genes carried on cassettes inserted in In31 were found to be functional in decreasing the in vitro susceptibilities of host strains to the corresponding antimicrobial agents. PMID- 10103197 TI - Biochemical characterization of the Pseudomonas aeruginosa 101/1477 metallo-beta lactamase IMP-1 produced by Escherichia coli. AB - The blaIMP gene coding for the IMP-1 metallo-beta-lactamase produced by a Pseudomonas aeruginosa clinical isolate (isolate 101/1477) was overexpressed via a T7 expression system in Escherichia coli BL21 (DE3), and its product was purified to homogeneity with a final yield of 35 mg/liter of culture. The structural and functional properties of the enzyme purified from E. coli were identical to those of the enzyme produced by P. aeruginosa. The IMP-1 metallo beta-lactamase exhibits a broad-spectrum activity profile that includes activity against penicillins, cephalosporins, cephamycins, oxacephamycins, and carbapenems. Only monobactams escape its action. The enzyme activity was inhibited by metal chelators, of which 1,10-o-phenanthroline and dipicolinic acid were the most efficient. Two zinc-binding sites were found. The zinc content of the P. aeruginosa 101/1477 metallo-beta-lactamase was not pH dependent. PMID- 10103198 TI - Fourteen-member macrolides inhibit interleukin-8 release by human eosinophils from atopic donors. AB - Macrolide antibiotics such as erythromycin have been reported to be effective for asthma. However, the precise mechanisms of this effect remain unclear. We studied the effect of erythromycin, clarithromycin, josamycin, and other antibiotics on the release by eosinophils of interleukin-8 (IL-8), a potent chemokine for inflammatory cells, including eosinophils themselves. Human eosinophils were isolated from atopic patients, and the effects of the drugs on IL-8 release were evaluated. Only 14-member macrolides (erythromycin and clarithromycin) showed a concentration-dependent suppressive effect on IL-8 release (control, 100%; erythromycin at 1 microgram/ml, 67.82% +/- 3.45% [P < 0.01]; clarithromycin at 5 micrograms/ml, 56.81% +/- 9.61% [P < 0.01]). The effect was found at therapeutic concentrations and appeared to occur at the posttranscriprtional level. In contrast, a 16-member macrolide (josamycin) had no significant effect. We suggest that 14-member macrolides inhibit IL-8 release by eosinophils and may thereby prevent the autocrine cycle necessary for the recruitment of these cells into the airways. PMID- 10103199 TI - Lipopolyamines: novel antiendotoxin compounds that reduce mortality in experimental sepsis caused by gram-negative bacteria. AB - The interactions of lipopolyamines, a class of structurally unique compounds currently being used as transfection (lipofection) agents, with lipopolysaccharide (LPS) have been characterized. Our studies have demonstrated that 1,3-di-oleoyloxy-2-(6-carboxyspermyl)-propylamide), available commercially as DOSPER, binds to purified LPS with an affinity of about 1/10 that of polymyxin B. This essentially nontoxic compound inhibits, in a dose-dependent manner, LPS induced activation of the Limulus clotting cascade and the production of tumor necrosis factor alpha (TNF-alpha) interleukin-6 (IL-6), and nitric oxide from LPS stimulated J774.A1 cells, a murine macrophage-like cell line. Cytokine inhibition is paralleled by decreased steady-state levels of TNF-alpha and IL-6 mRNA and inhibits the nuclear translocation of nuclear factor kappa B. These findings suggest that the lipopolyamine compound sequesters LPS, thereby blocking downstream cellular activation events that lead to the production of proinflammatory mediators. Administration of DOSPER to D-galactosamine-sensitized mice challenged either with LPS or with Escherichia coli organisms provided significant protection against lethality both with and without antibiotic chemotherapy. Partial protection is evident in LPS-challenged mice treated with DOSPER as late as 2 to 4 h following the endotoxin challenge. A greater degree of protection is observed in E. coli-challenged animals receiving ceftazidime than in those receiving imipenem, which is probably attributable to the higher levels of LPS released in vivo by the former antibiotic. Potent antiendotoxic activity, low toxicity, and ease of synthesis render the lipopolyamines candidate endotoxin sequestering agents of potential significant therapeutic value. PMID- 10103200 TI - Pharmacokinetics of beta-L-2',3'-dideoxy-5-fluorocytidine in rhesus monkeys. AB - beta-L-2',3'-Dideoxy-5-fluorocytidine (beta-L-FddC), a novel cytidine analog with an unnatural beta-L sugar configuration, has been demonstrated by our group and others to exhibit highly selective in vitro activity against human immunodeficiency virus types 1 and 2 and hepatitis B virus. This encouraging in vitro antiviral activity prompted us to assess its pharmacokinetics in rhesus monkeys. Three monkeys were administered an intravenous dose of [3H] beta-L-FddC at 5 mg/kg of body weight. Following a 3-month washout period, an equivalent oral dose was administered. Plasma and urine samples were collected at various times for up to 24 h after dosing, and drug levels were quantitated by high-pressure liquid chromatography. Pharmacokinetic parameters were obtained on the basis of a two-compartment open model with a first-order elimination from the central compartment. After intravenous administration, the mean peak concentration in plasma (Cmax) was 29.8 +/- 10.5 microM. Total clearance, steady-state volume of distribution, terminal-phase plasma half-life (t1/2 beta), and mean residence time were 0.7 +/- 0.1 liters/h/kg, 1.3 +/- 0.1 liters/kg, 1.8 +/- 0.2 h, and 1.9 +/- 0.2 h, respectively. Approximately 47% +/- 16% of the intravenously administered radioactivity was recovered in the urine as the unchanged drug with no apparent metabolites. beta-L-FddC exhibited a Cmax of 3.2 microM after oral administration, with a time to peak drug concentration of approximately 1.5 h and a t1/2 of 2.2 h. One monkey in the oral administration arm of the study had a significant delay in the absorption of the aqueous administered dose. The absolute bioavailability of orally administered beta-L-FddC ranged from 56 to 66%. PMID- 10103201 TI - A new resistance gene, linB, conferring resistance to lincosamides by nucleotidylation in Enterococcus faecium HM1025. AB - Resistance to lincomycin and clindamycin in the clinical isolate Enterococcus faecium HM1025 is due to a ribosomal methylase encoded by an ermAM-like gene and the plasmid-mediated inactivation of these antibiotics. We have cloned and determined the nucleotide sequence of the gene responsible for the inactivation of lincosamides, linB. This gene encodes a 267-amino-acid lincosamide nucleotidyltransferase. The enzyme catalyzes 3(5'-adenylation) (the adenylation of the hydroxyl group in position 3 of the molecules) of lincomycin and clindamycin. Expression of linB was observed in both Escherichia coli and Staphylococcus aureus. The deduced amino acid sequence of the enzyme did not display any significant homology with staphylococcal nucleotidyltransferases encoded by linA and linA' genes. Sequences homologous to linB were found in 14 other clinical isolates of E. faecium, indicating the spread of the resistance trait in this species. PMID- 10103202 TI - In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram positive bacteria. AB - The in vitro activities of two new ketolides, HMR 3647 and HMR 3004, were tested by the agar dilution method against 280 strains of gram-positive bacteria with different antibiotic susceptibility profiles, including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus spp. (group A streptococci, group B streptococci, Streptococcus pneumoniae, and alpha-hemolytic streptococci). Seventeen erythromycin-susceptible (EMs), methicillin-susceptible S. aureus strains were found to have HMR 3647 and HMR 3004 MICs 4- to 16-fold lower than those of erythromycin (MIC at which 50% of isolates were inhibited [MIC50] [HMR 3647 and HMR 3004], 0.03 microgram/ml; range, 0.03 to 0.06 microgram/ml; MIC50 [erythromycin], 0.25 microgram/ml; range, 0.25 to 0.5 microgram/ml). All methicillin-resistant S. aureus strains tested were resistant to erythromycin and had HMR 3647 and HMR 3004 MICs of > 64 micrograms/ml. The ketolides were slightly more active against E. faecalis than against E. faecium, and MICs for individual strains varied with erythromycin susceptibility. The MIC50s of HMR 3647 and HMR 3004 against Ems enterococci (MIC < or = 0.5 microgram/ml) and those enterococcal isolates with erythromycin MICs of 1 to 16 micrograms/ml were 0.015 microgram/ml. E. faecalis strains that had erythromycin MICs of 128 to > 512 micrograms/ml showed HMR 3647 MICs in the range of 0.03 to 16 micrograms/ml and HMR 3004 MICs in the range of 0.03 to 64 micrograms/ml. In the group of E. faecium strains for which MICs of erythromycin were > or = 512 micrograms/ml, MICs of both ketolides were in the range of 1 to 64 micrograms/ml, with almost all isolates showing ketolide MICs of < or = 16 micrograms/ml. The ketolides were also more active than erythromycin against group A streptococci, group B streptococci, S. pneumoniae, rhodococci, leuconostocs, pediococci, lactobacilli, and diphtheroids. Time-kill studies showed bactericidal activity against one strain of S. aureus among the four strains tested. The increased activity of ketolides against gram-positive bacteria suggests that further study of these agents for possible efficacy against infections caused by these bacteria is warranted. PMID- 10103203 TI - Development of resistance during antimicrobial therapy caused by insertion sequence interruption of porin genes. AB - We have demonstrated by using an in vitro approach that interruption of the OmpK36 porin gene by insertion sequences (ISs) is a common type of mutation that causes loss of porin expression and increased resistance to cefoxitin in Klebsiella pneumoniae. This mechanism also operates in vivo: of 13 porin deficient cefoxitin-resistant clinical isolates of K. pneumoniae, 4 presented ISs in their ompK36 gene. PMID- 10103204 TI - Comparison of activities of broad-spectrum beta-lactam compounds against 1,128 gram-positive cocci recently isolated in cancer treatment centers. AB - We report the in vitro activities of broad-spectrum beta-lactam antimicrobials tested against 1,128 gram-positive pathogens recently isolated from cancer patients. Cefepime and imipenem were more active than ceftazidime and ceftriaxone against these organisms. Only vancomycin demonstrated reliable activity against oxacillin-resistant staphylococci, Enterococcus spp., and Corynebacterium spp. The spectrum of gram-positive organisms against which cefepime and imipenem have activity provides an advantage over ceftazidime as empiric therapy for cancer patients, potentially reducing the need for the empiric addition of glycopeptides. PMID- 10103205 TI - Presence of mefA and mefE genes in Streptococcus agalactiae. AB - Eighteen unrelated clinical isolates of Streptococcus agalactiae with the M phenotype harbored an mef gene. DNA sequencing showed that one of nine strains contained mefA (producing one amino acid substitution), whereas the remaining eight carried mefE (identity, 100%). Restriction analysis of PCR products indicated that the nine other strains also contained mefE. PMID- 10103206 TI - Alterations in GyrA and ParC associated with fluoroquinolone resistance in Enterococcus faecium. AB - High-level quinolone resistance in Enterococcus faecium was associated with mutations in both gyrA and parC genes in 10 of 11 resistant strains. On low-level resistant strain without such mutations may instead possess an efflux mechanism or alterations in the other subunits of the gyrase or topoisomerase IV genes. These findings are similar to those for other gram-positive bacteria, such as Enterococcus faecalis. PMID- 10103207 TI - Protection by short-chain fatty acids against 1-beta-D-arabinofuranosylcytosine induced intestinal lesions in germfree mice. AB - In germfree mice, the administration of short-chain fatty acids (SCFA) protected the intestinal mucosa from damage produced by 1-beta-D-arabinofuranosylcytosine (Ara-C). Animals receiving SCFA and Ara-C had intestinal morphologies closer to normal than the control animals, which had severe intestinal lesions. We concluded that orally administrated SCFA reduce intestinal lesions, improving the mucosa pattern of the small intestine and colon. PMID- 10103208 TI - Mutations in the gyrA, parC, and parE genes associated with fluoroquinolone resistance in clinical isolates of Mycoplasma hominis. AB - Five clinical isolates of Mycoplasma hominis from three different patients were examined for resistance to fluoroquinolones; some of these isolates were probably identical. All five isolates harbored amino acid substitutions in the quinolone resistance-determining regions of both DNA gyrase (GyrA) and topoisomerase IV (ParC or ParE). Furthermore, the novobiocin MIC for three isolates showed a significant increase. This is the first characterization of fluoroquinolone resistant clinical mycoplasma isolates from humans. PMID- 10103209 TI - Molecular basis of AmpC hyperproduction in clinical isolates of Escherichia coli. AB - DNA sequencing data showed that five clinical isolates of Escherichia coli with reduced susceptibility to ceftazidime, ceftriaxone, and cefotaxime contain an ampC gene that is preceded by a strong promoter. Transcription from the strong promoter was 8- to 18-fold higher than that from the promoter from a susceptible isolate. RNA studies showed that mRNA stability does not play a role in the control of AmpC synthesis. PMID- 10103210 TI - Integron-mediated rifampin resistance in Pseudomonas aeruginosa. AB - A new rifampin resistance gene, arr-2, has been found in Pseudomonas aeruginosa. The ARR-2 protein shows 54% amino acid identity to the rifampin ADP-ribosylating transferase encoded by the arr gene from Mycobacterium smegmatis. This arr-2 gene is located on a gene cassette within a class I integron. PMID- 10103211 TI - Trovafloxacin in combination with vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model. AB - Trovafloxacin, a new fluoroquinolone, produced bactericidal activity (-0.33 +/- 0.13 delta log10 CFU/ml.h; intravenously [i.v.] administered dose, 15 mg/kg) comparable to that of vancomycin (-0.39 +/- 0.18 delta log10 CFU/ml.h; i.v. admininistered dose, 20 mg/kg) in the treatment of experimental meningitis in rabbits due to a pneumococcal strain highly resistant to penicillin (MIC of penicillin G, 4 micrograms/ml). The combination of both drugs significantly increased (P < 0.05) the killing rate (-0.60 +/- 0.23 delta log10 CFU/ml.h) compared to that produced by either monotherapy. These results were also confirmed in vitro. PMID- 10103212 TI - In vitro activities of 13 fluoroquinolones against Staphylococcus aureus isolates with characterized mutations in gyrA, gyrB, grlA, and norA and against wild-type isolates. AB - The in vitro activities of 13 fluoroquinolones (FQs) were tested against 90 Staphylococcus aureus clinical isolates: 30 wild type for gyrA, gyrB, grlA and norA and 60 with mutations in these genes. Clinafloxacin (CI-960), sparfloxacin, and grepafloxacin were the most active FQs against wild-type isolates (MICs at which 90% of isolates were inhibited, 0.06 to 0.1 microgram/ml). Mutations in grlA did not affect the MICs of newer FQs. grlA-gyrA double mutations led to higher MICs for all the FQs tested. Efflux mechanisms affected the newer FQs to a much lesser extent than the less recently developed FQs. PMID- 10103213 TI - Sequences of the genes for the TEM-20, TEM-21, TEM-22, and TEM-29 extended spectrum beta-lactamases. AB - The sequences of the blaTEM genes encoding TEM-20, TEM-21, TEM-22, and TEM-29 extended-spectrum beta-lactamases were determined. Analysis of the deduced amino acid sequences indicated that TEM-20 and TEM-29 were derived from TEM-1 and that TEM-21 and TEM-22 were derived from TEM-2. The substitutions involved were Ser 238 and Thr-182 for TEM-20; His-164 for TEM-29; Lys-104, Arg-153, and Ser-238 for TEM-21; and Lys-104, Gly-237, and Ser-238 for TEM-22. The promoter region of the blaTEM-22 gene was identical to that of blaTEM-3. High-level production of TEM-20 could result from a 135-bp deletion which combined the -35 region of the Pa promoter with the -10 region of the P3 promoter and a G-->T transition in the latter motif. PMID- 10103214 TI - Pharmacokinetics of oral zidovudine entrapped in biodegradable nanospheres in rabbits. AB - The pharmacokinetic profile of oral zidovudine entrapped in a 50:50 polyactide coglycolide matrix (nanospheres) was compared to those of standard oral and parenteral zidovudine formulations in rabbits. The bioavailability of zidovudine nanospheres at 50 mg/kg of body weight was 76%, and this dose achieved prolonged exposure to zidovudine compared to standard formulations without an increase in the drug's peak concentration. PMID- 10103215 TI - Potentiation of isoniazid activity against Mycobacterium tuberculosis by melatonin. AB - The limited number of effective antituberculosis drugs available necessitates optimizing current treatments. We show that melatonin, which is synthesized in the pineal gland, can cause at least a threefold increase in the efficacy of isoniazid. This suggests that tuberculosis chemotherapy can be improved by innate molecules such as melatonin. PMID- 10103216 TI - Effect of 3-hydroxyphthaloyl-beta-lactoglobulin on vaginal transmission of simian immunodeficiency virus in rhesus monkeys. AB - Heterosexual transmission of human immunodeficiency virus type 1 (HIV-1) is the major cause of the ongoing AIDS epidemic. Application of chemical barrier methods is expected to contribute to the worldwide control of this epidemic. Bovine beta lactoglobulin modified by 3-hydroxyphthalic anhydride (3-hydroxyphthalovyl-beta lactoglobulin [3HP-beta-LG]) was shown to inhibit HIV-1, HIV-2, simian immunodeficiency virus (SIV), herpes simplex virus type 1 and 2, and Chlamydia trachomatis infection in vitro. Here, we show that 3HP-beta-LG not formulated into any vehicle protected three of six rhesus monkeys against vaginal infection by SIV. Incorporation of the compound into an appropriate vehicle is expected to increase the degree of protection. 3HP-beta-LG may be effective as a vaginal inhibitor of HIV-1 infection in humans. PMID- 10103217 TI - Pseudomonas aeruginosa: a survey of resistance in 136 hospitals in Spain. The Spanish Pseudomonas aeruginosa Study Group. AB - We carried out a nationwide study with all of the isolates of Pseudomonas aeruginosa collected in a week in 136 hospitals in Spain. The data on 1,014 isolates included resistance to the following antimicrobials: piperacillin tazobactam, 7%; meropenem, 8%; amikacin, 9%; tobramycin, 10%; piperacillin, 10%; ticarcillin, 13%; imipenem, 14%; ceftazidime, 15%; cefepime, 17%; ciprofloxacin, 23%; aztreonam, 23%; ofloxacin, 30%; gentamicin, 31%. The most frequent serotypes were O:1 (25.1%), O:4 (21.6%), and O:11 (11.3%). PMID- 10103218 TI - In vitro activities of ketolides HMR 3647 [correction of HRM 3647] and HMR 3004 [correction of HRM 3004], levofloxacin, and other quinolones and macrolides against Neisseria spp. and Moraxella catarrhalis. AB - In vitro activities of the ketolides HMR 3647 [corrected] and HMR 3004 [corrected] against pathogenic Neisseria gonorrhoeae and N. meningitidis, saprophytic Neisseria isolates, and Moraxella catarrhalis were determined. The comparison of ketolide activities with those of the other macrolides shows a much better activity in the majority of species, with macrolide MICs at which 90% of the isolates are inhibited between 8- and 10-fold higher. PMID- 10103219 TI - The anti-influenza virus drug rimantadine has trypanocidal activity. AB - We report here that bloodstream forms of the African trypanosome, Trypanosoma brucei, are sensitive to the anti-influenza virus drug rimantadine (50% inhibitory concentration of 1.26 micrograms ml-1 at pH 7.4). The activity is pH dependent and is consistent with a mechanism involving inhibition of the ability to regulate internal pH. Rimantadine is also toxic to the trypanosomatid parasites Trypanosoma cruzi and Leishmania major. PMID- 10103220 TI - Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. AB - Recent evidence supports the contribution of a multidrug efflux mechanism to fluoroquinolone resistance in Streptococcus pneumoniae. In this paper I show that reserpine, an inhibitor of multidrug transporters in gram-positive bacteria, dramatically suppresses the in vitro emergence of ciprofloxacin-resistant variants of S. pneumoniae, suggesting that the combination of a fluoroquinolone with an inhibitor of multidrug transport may help preserve the efficacy of this class of antibiotics. PMID- 10103221 TI - Growth in the presence of salicylate increases fluoroquinolone resistance in Staphylococcus aureus. AB - Salicylate and acetylsalicylate slightly increased fluoroquinolone resistance in ciprofloxacin-susceptible and -resistant Staphylococcus aureus. Salicylate allowed a greater number of cells from ciprofloxacin-susceptible and -resistant strains to survive on high fluoroquinolone concentrations. Salicylate also increased the frequency with which a susceptible strain mutated to become more resistant to ciprofloxacin. PMID- 10103222 TI - New antimicrobial agents approved by the U.S. Food and Drug Administration in 1998 and new indications for previously approved agents. PMID- 10103223 TI - Fungal degradation of lipophilic extractives in eucalyptus globulus wood AB - Solid-state fermentation of eucalypt wood with several fungal strains was investigated as a possible biological pretreatment for decreasing the content of compounds responsible for pitch deposition during Cl2-free manufacture of paper pulp. First, different pitch deposits were characterized by gas chromatography (GC) and GC-mass spectrometry (MS). The chemical species identified arose from lipophilic wood extractives that survived the pulping and bleaching processes. Second, a detailed GC-MS analysis of the lipophilic fraction after fungal treatment of wood was carried out, and different degradation patterns were observed. The results showed that some basidiomycetes that decreased the lipophilic fraction also released significant amounts of polar extractives, which were identified by thermochemolysis as originating from lignin depolymerization. Therefore, the abilities of fungi to control pitch should be evaluated after analysis of compounds involved in deposit formation and not simply by estimating the decrease in the total extractive content. In this way, Phlebia radiata, Funalia trogii, Bjerkandera adusta, and Poria subvermispora strains were identified as the most promising organisms for pitch biocontrol, since they degraded 75 to 100% of both free and esterified sterols, as well as other lipophilic components of the eucalypt wood extractives. Ophiostoma piliferum, a fungus used commercially for pitch control, hydrolyzed the sterol esters and triglycerides, but it did not appear to be suitable for eucalypt wood treatment because it increased the content of free sitosterol, a major compound in pitch deposits. PMID- 10103224 TI - Formation of hydride-Meisenheimer complexes of picric acid (2,4, 6 trinitrophenol) and 2,4-dinitrophenol during mineralization of picric acid by Nocardioides sp. strain CB 22-2. AB - There are only a few examples of microbial conversion of picric acid (2,4,6 trinitrophenol). None of the organisms that have been described previously is able to use this compound as a sole source of carbon, nitrogen, and energy at high rates. In this study we isolated and characterized a strain, strain CB 22-2, that was able to use picric acid as a sole source of carbon and energy at concentrations up to 40 mM and at rates of 1.6 mmol. h(-1). g (dry weight) of cells(-1) in continuous cultures and 920 micromol. h(-1). g (dry weight) of cells(-1) in flasks. In addition, this strain was able to use picric acid as a sole source of nitrogen at comparable rates in a nitrogen-free medium. Biochemical characterization and 16S ribosomal DNA analysis revealed that strain CB 22-2 is a Nocardioides sp. strain. High-pressure liquid chromatography and UV visible light data, the low residual chemical oxygen demand, and the stoichiometric release of 2.9 +/- 0.1 mol of nitrite per mol of picric acid provided strong evidence that complete mineralization of picric acid occurred. During transformation, the metabolites detected in the culture supernatant were the [H-]-Meisenheimer complexes of picric acid and 2,4-dinitrophenol (H--DNP), as well as 2,4-dinitrophenol. Experiments performed with crude extracts revealed that H--DNP formation indeed is a physiologically relevant step in picric acid metabolism. PMID- 10103225 TI - Geographic distribution and genetic diversity of Ceanothus-infective Frankia strains. AB - Little is known about Ceanothus-infective Frankia strains because no Frankia strains that can reinfect the host plants have been isolated from Ceonothus spp. Therefore, we studied the diversity of the Ceonothus-infective Frankia strains by using molecular techniques. Frankia strains inhabiting root nodules of nine Ceanothus species were characterized. The Ceanothus species used represent the taxonomic diversity and geographic range of the genus; therefore, the breadth of the diversity of Frankia strains that infect Ceanothus spp. was studied. DNA was amplified directly from nodular material by using the PCR. The amplified region included the 3' end of the 16S rRNA gene, the intergenic spacer, and a large portion of the 23S rRNA gene. A series of restriction enzyme digestions of the PCR product allowed us to identify PCR-restriction fragment length polymorphism (RFLP) groups among the Ceanothus-infective Frankia strains tested. Twelve different enzymes were used, which resulted in four different PCR-RFLP groups. The groups did not follow the taxonomic lines of the Ceanothus host species. Instead, the Frankia strains present were related to the sample collection locales. PMID- 10103226 TI - Homofermentative production of D- or L-lactate in metabolically engineered Escherichia coli RR1. AB - We investigated metabolic engineering of fermentation pathways in Escherichia coli for production of optically pure D- or L-lactate. Several pta mutant strains were examined, and a pta mutant of E. coli RR1 which was deficient in the phosphotransacetylase of the Pta-AckA pathway was found to metabolize glucose to D-lactate and to produce a small amount of succinate by-product under anaerobic conditions. An additional mutation in ppc made the mutant produce D-lactate like a homofermentative lactic acid bacterium. When the pta ppc double mutant was grown to higher biomass concentrations under aerobic conditions before it shifted to the anaerobic phase of D-lactate production, more than 62.2 g of D-lactate per liter was produced in 60 h, and the volumetric productivity was 1.04 g/liter/h. To examine whether the blocked acetate flux could be reoriented to a nonindigenous L-lactate pathway, an L-lactate dehydrogenase gene from Lactobacillus casei was introduced into a pta ldhA strain which lacked phosphotransacetylase and D-lactate dehydrogenase. This recombinant strain was able to metabolize glucose to L-lactate as the major fermentation product, and up to 45 g of L-lactate per liter was produced in 67 h. These results demonstrate that the central fermentation metabolism of E. coli can be reoriented to the production of D-lactate, an indigenous fermentation product, or to the production of L-lactate, a nonindigenous fermentation product. PMID- 10103227 TI - Role of calcium in activity and stability of the Lactococcus lactis cell envelope proteinase. AB - The mature lactococcal cell envelope proteinase (CEP) consists of an N-terminal subtilisin-like proteinase domain and a large C-terminal extension of unknown function whose far end anchors the molecule in the cell envelope. Different types of CEP can be distinguished on the basis of specificity and amino acid sequence. Removal of weakly bound Ca2+ from the native cell-bound CEP of Lactococcus lactis SK11 (type III specificity) is coupled with a significant reversible decrease in specific activity and a dramatic reversible reduction in thermal stability, as a result of which no activity at 25 degrees C (pH 6.5) can be measured. The consequences of Ca2+ removal are less dramatic for the CEP of strain Wg2 (mixed type I-type III specificity). Autoproteolytic release of CEP from cells concerns this so-called "Ca-free" form only and occurs most efficiently in the case of the Wg2 CEP. The results of a study of the relationship between the Ca2+ concentration and the stability and activity of the cell-bound SK11 CEP at 25 degrees C suggested that binding of at least two Ca2+ ions occurred. Similar studies performed with hybrid CEPs constructed from SK11 and Wg2 wild-type CEPs revealed that the C-terminal extension plays a determinative role with respect to the ultimate distinct Ca2+ dependence of the cell-bound CEP. The results are discussed in terms of predicted Ca2+ binding sites in the subtilisin-like proteinase domain and Ca-triggered structural rearrangements that influence both the conformational stability of the enzyme and the effectiveness of the catalytic site. We argue that distinctive primary folding of the proteinase domain is guided and maintained by the large C-terminal extension. PMID- 10103228 TI - Development and characterization of a fluorescent-bacteriophage assay for detection of Escherichia coli O157:H7. AB - In this paper we describe evaluation and characterization of a novel assay that combines immunomagnetic separation and a fluorescently stained bacteriophage for detection of Escherichia coli O157:H7 in broth. When it was combined with flow cytometry, the fluorescent-bacteriophage assay (FBA) was capable of detecting 10(4) cells/ml. A modified direct epifluorescent-filter technique (DEFT) was employed in an attempt to estimate bacterial concentrations. Using regression analysis, we calculated that the lower detection limit was between 10(2) and 10(3) cells/ml; however, the modified DEFT was found to be an unreliable method for determining bacterial concentrations. The results of this study show that the FBA, when combined with flow cytometry, is a sensitive technique for presumptive detection of E. coli O157:H7 in broth cultures. PMID- 10103229 TI - Initial reactions in the biodegradation of 1-chloro-4-nitrobenzene by a newly isolated bacterium, strain LW1. AB - Bacterial strain LW1, which belongs to the family Comamonadaceae, utilizes 1 chloro-4-nitrobenzene (1C4NB) as a sole source of carbon, nitrogen, and energy. Suspensions of 1C4NB-grown cells removed 1C4NB from culture fluids, and there was a concomitant release of ammonia and chloride. Under anaerobic conditions LW1 transformed 1C4NB into a product which was identified as 2-amino-5-chlorophenol by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. This transformation indicated that there was partial reduction of the nitro group to the hydroxylamino substituent, followed by Bamberger rearrangement. In the presence of oxygen but in the absence of NAD, fast transformation of 2-amino-5-chlorophenol into a transiently stable yellow product was observed with resting cells and cell extracts. This compound exhibited an absorption maximum at 395 nm and was further converted to a dead-end product with maxima at 226 and 272 nm. The compound formed was subsequently identified by 1H and 13C NMR spectroscopy and mass spectrometry as 5-chloropicolinic acid. In contrast, when NAD was added in the presence of oxygen, only minor amounts of 5 chloropicolinic acid were formed, and a new product, which exhibited an absorption maximum at 306 nm, accumulated. PMID- 10103231 TI - Isolation and characterization of alfalfa-nodulating rhizobia present in acidic soils of central argentina and uruguay AB - We describe the isolation and characterization of alfalfa-nodulating rhizobia from acid soils of different locations in Central Argentina and Uruguay. A collection of 465 isolates was assembled, and the rhizobia were characterized for acid tolerance. Growth tests revealed the existence of 15 acid-tolerant (AT) isolates which were able to grow at pH 5.0 and formed nodules in alfalfa with a low rate of nitrogen fixation. Analysis of those isolates, including partial sequencing of the genes encoding 16S rRNA and genomic PCR-fingerprinting with MBOREP1 and BOXC1 primers, demonstrated that the new isolates share a genetic background closely related to that of the previously reported Rhizobium sp. Or191 recovered from an acid soil in Oregon (B. D. Eardly, J. P. Young, and R. K. Selander, Appl. Environ. Microbiol. 58:1809-1815, 1992). Growth curves, melanin production, temperature tolerance, and megaplasmid profiles of the AT isolates were all coincident with these characteristics in strain Or191. In addition to the ability of all of these strains to nodulate alfalfa (Medicago sativa) inefficiently, the AT isolates also nodulated the common bean and Leucaena leucocephala, showing an extended host range for nodulation of legumes. In alfalfa, the time course of nodule formation by the AT isolate LPU 83 showed a continued nodulation restricted to the emerging secondary roots, which was probably related to the low rate of nitrogen fixation by the largely ineffective nodules. Results demonstrate the complexity of the rhizobial populations present in the acidic soils represented by a main group of N2-fixing rhizobia and a second group of ineffective and less-predominant isolates related to the AT strain Or191. PMID- 10103230 TI - Integrative model for binding of Bacillus thuringiensis toxins in susceptible and resistant larvae of the diamondback moth (Plutella xylostella). AB - Insecticidal crystal proteins from Bacillus thuringiensis in sprays and transgenic crops are extremely useful for environmentally sound pest management, but their long-term efficacy is threatened by evolution of resistance by target pests. The diamondback moth (Plutella xylostella) is the first insect to evolve resistance to B. thuringiensis in open-field populations. The only known mechanism of resistance to B. thuringiensis in the diamondback moth is reduced binding of toxin to midgut binding sites. In the present work we analyzed competitive binding of B. thuringiensis toxins Cry1Aa, Cry1Ab, Cry1Ac, and Cry1F to brush border membrane vesicles from larval midguts in a susceptible strain and in resistant strains from the Philippines, Hawaii, and Pennsylvania. Based on the results, we propose a model for binding of B. thuringiensis crystal proteins in susceptible larvae with two binding sites for Cry1Aa, one of which is shared with Cry1Ab, Cry1Ac, and Cry1F. Our results show that the common binding site is altered in each of the three resistant strains. In the strain from the Philippines, the alteration reduced binding of Cry1Ab but did not affect binding of the other crystal proteins. In the resistant strains from Hawaii and Pennsylvania, the alteration affected binding of Cry1Aa, Cry1Ab, Cry1Ac, and Cry1F. Previously reported evidence that a single mutation can confer resistance to Cry1Ab, Cry1Ac, and Cry1F corresponds to expectations based on the binding model. However, the following two other observations do not: the mutation in the Philippines strain affected binding of only Cry1Ab, and one mutation was sufficient for resistance to Cry1Aa. The imperfect correspondence between the model and observations suggests that reduced binding is not the only mechanism of resistance in the diamondback moth and that some, but not all, patterns of resistance and cross-resistance can be predicted correctly from the results of competitive binding analyses of susceptible strains. PMID- 10103232 TI - Suppression of the biocontrol agent trichoderma harzianum by mycelium of the arbuscular mycorrhizal fungus glomus intraradices in root-free soil AB - Trichoderma harzianum is an effective biocontrol agent against several fungal soilborne plant pathogens. However, possible adverse effects of this fungus on arbuscular mycorrhizal fungi might be a drawback in its use in plant protection. The objective of the present work was to examine the interaction between Glomus intraradices and T. harzianum in soil. The use of a compartmented growth system with root-free soil compartments enabled us to study fungal interactions without the interfering effects of roots. Growth of the fungi was monitored by measuring hyphal length and population densities, while specific fatty acid signatures were used as indicators of living fungal biomass. Hyphal 33P transport and beta glucuronidase (GUS) activity were used to monitor activity of G. intraradices and a GUS-transformed strain of T. harzianum, respectively. As growth and metabolism of T. harzianum are requirements for antagonism, the impact of wheat bran, added as an organic nutrient source for T. harzianum, was investigated. The presence of T. harzianum in root-free soil reduced root colonization by G. intraradices. The external hyphal length density of G. intraradices was reduced by the presence of T. harzianum in combination with wheat bran, but the living hyphal biomass, measured as the content of a membrane fatty acid, was not reduced. Hyphal 33P transport by G. intraradices also was not affected by T. harzianum. This suggests that T. harzianum exploited the dead mycelium but not the living biomass of G. intraradices. The presence of external mycelium of G. intraradices suppressed T. harzianum population development and GUS activity. Stimulation of the hyphal biomass of G. intraradices by organic amendment suggests that nutrient competition is a likely means of interaction. In conclusion, it seemed that growth of and phosphorus uptake by the external mycelium of G. intraradices were not affected by the antagonistic fungus T. harzianum; in contrast, T. harzianum was adversely affected by G. intraradices. PMID- 10103233 TI - Location and survival of leaf-associated bacteria in relation to pathogenicity and potential for growth within the leaf AB - The growth and survival of pathogenic and nonpathogenic Pseudomonas syringae strains and of the nonpathogenic species Pantoea agglomerans, Stenotrophomonas maltophilia, and Methylobacterium organophilum were compared in the phyllosphere of bean. In general, the plant pathogens survived better than the nonpathogens on leaves under environmental stress. The sizes of the total leaf-associated populations of the pathogenic P. syringae strains were greater than the sizes of the total leaf-associated populations of the nonpathogens under dry conditions but not under moist conditions. In these studies the surface sterilants hydrogen peroxide and UV irradiation were used to differentiate cells that were fully exposed on the surface from nonexposed cells that were in "protected sites" that were inaccessible to these agents. In general, the population sizes in protected sites increased with time after inoculation of plants. The proportion of bacteria on leaves that were in protected sites was generally greater for pathogens than for nonpathogens and was greater under dry conditions than under moist conditions. When organisms were vacuum infiltrated into leaves, the sizes of the nonexposed "internal" populations were greater for pathogenic P. syringae strains than for nonpathogenic P. syringae strains. The sizes of the populations of the nonpathogenic species failed to increase or even decreased. The sizes of nonexposed populations following spray inoculation were correlated with the sizes of nonexposed, internal populations which developed after vacuum infiltration and incubation. While the sizes of the populations of the pathogenic P. syringae strains increased on leaves under dry conditions, the sizes of the populations of the nonpathogenic strains of P. syringae, P. agglomerans, and S. maltophilia decreased when the organisms were applied to plants. The sizes of the populations on dry leaves were also correlated with the sizes of the nonexposed populations that developed following vacuum infiltration. Although pathogenicity was not required for growth in the phyllosphere under high-relative-humidity conditions, pathogenicity apparently was involved in the ability to access and/or multiply in certain protected sites in the phyllosphere and in growth on dry leaves. PMID- 10103234 TI - Regional differences in production of aflatoxin B1 and cyclopiazonic acid by soil isolates of aspergillus flavus along a transect within the United States. AB - Soil isolates of Aspergillus flavus from a transect extending from eastern New Mexico through Georgia to eastern Virginia were examined for production of aflatoxin B1 and cyclopiazonic acid in a liquid medium. Peanut fields from major peanut-growing regions (western Texas; central Texas; Georgia and Alabama; and Virginia and North Carolina) were sampled, and fields with other crops were sampled in regions where peanuts are not commonly grown. The A. flavus isolates were identified as members of either the L strain (n = 774), which produces sclerotia that are >400 micrometer in diameter, or the S strain (n = 309), which produces numerous small sclerotia that are <400 micrometer in diameter. The S strain isolates generally produced high levels of aflatoxin B1, whereas the L strain isolates were more variable in aflatoxin production; variation in cyclopiazonic acid production also was greater in the L strain than in the S strain. There was a positive correlation between aflatoxin B1 production and cyclopiazonic acid production in both strains, although 12% of the L-strain isolates produced only cyclopiazonic acid. Significant differences in production of aflatoxin B1 and cyclopiazonic acid by the L-strain isolates were detected among regions. In the western half of Texas and the peanut-growing region of Georgia and Alabama, 62 to 94% of the isolates produced >10 microgram of aflatoxin B1 per ml. The percentages of isolates producing >10 microgram of aflatoxin B1 per ml ranged from 0 to 52% in the remaining regions of the transect; other isolates were often nonaflatoxigenic. A total of 53 of the 126 L strain isolates that did not produce aflatoxin B1 or cyclopiazonic acid were placed in 17 vegetative compatibility groups. Several of these groups contained isolates from widely separated regions of the transect. PMID- 10103235 TI - Effectiveness of chemometric techniques in discrimination of lactobacillus helveticus biotypes from natural dairy starter cultures on the basis of phenotypic characteristics AB - Lactobacillus helveticus is the dominant organism in natural starter cultures used for the production of typical Italian cheeses. In this study, 74 L. helveticus strains, isolated from grana and provolone cheese natural whey starters, were distinguished with respect to their origin by using both cell wall protein profiles and chemometric evaluation of some phenotypic parameters, such as the ability to acidify cultures and the presence of nonspecific proteolytic and peptidase activities. Cell wall protein patterns allowed L. helveticus strains to be distinguished with respect to their source of isolation. Among the different phenotypes studied, no single specific parameter permitted the two groups of strains to be separated. A good discrimination between the two groups of L. helveticus species was obtained by multivariate statistical techniques, which permitted the extraction of all of the discriminating information retained in the phenotypic activities. Associations between strain phenotype expression and dairy environmental ecosystem source are discussed. PMID- 10103236 TI - Identification of Cryptosporidium felis in a cow by morphologic and molecular methods. AB - Apicomplexan Cryptosporidium parasites infect a wide range of vertebrate hosts. While some species are limited to a single host group, such as Cryptosporidium baileyi, which infects chickens, other species of this genus, such as C. parvum, infect a wide range of mammalian species from mice to humans. During an investigation of Cryptosporidium infection in cattle on a farm in northern Poland, we identified an infection caused by C. felis, in addition to known infections with C. muris and C. parvum. This new infection was identified based on the size of the oocysts (mean size, 4.3 +/- 0.4 micrometer; range, 3.5 to 5.0 micrometer), as well as by analysis of the molecular sequence of the variable region of the small-subunit rRNA. This finding demonstrates the complex host specificity and circulation in the environment of Cryptosporidium species. PMID- 10103238 TI - Bacterivory rate estimates and fraction of active bacterivores in natural protist assemblages from aquatic systems AB - Unlike the fraction of active bacterioplankton, the fraction of active bacterivores (i.e., those involved in grazing) during a specified time period has not been studied yet. Fractions of protists actively involved in bacterivory were estimated assuming that the distributions of bacteria and fluorescently labeled bacteria (FLB) ingested by protists follow Poisson distributions. Estimates were compared with experimental data obtained from FLB uptake experiments. The percentages of protists with ingested FLB (experimental) and the estimates obtained from Poisson distributions were similar for both flagellates and ciliates. Thus, the fraction of protists actively grazing on natural bacteria during a given time period could be estimated. The fraction of protists with ingested bacteria depends on the incubation time and reaches a saturating value. Aquatic systems with very different characteristics were analyzed; estimates of the fraction of protists actively grazing on bacteria ranged from 7 to 100% in the studied samples. Some nanoflagellates appeared to be grazing on specific bacterial sizes. Evidence indicated that there was no discrimination for or against bacterial surrogates (i.e., FLB); also, bacteria were randomly encountered by bacterivorous protists during these short-term uptake experiments. These analyses made it possible to estimate the ingestion rates from FLB uptake experiments by counting the number of flagellates containing ingested FLB. These results represent the first reported estimates of active bacterivores in natural aquatic systems; also, a proposed protocol for estimating in situ ingestion rates by protists represents a significant improvement and simplification to the current protocol and avoids the tedious work of counting the number of ingested FLB per protist. PMID- 10103240 TI - Microbiology of the oil fly, Helaeomyia petrolei. AB - Helaeomyia petrolei larvae isolated from the asphalt seeps of Rancho La Brea in Los Angeles, Calif., were examined for microbial gut contents. Standard counts on Luria-Bertani, MacConkey, and blood agar plates indicated ca. 2 x 10(5) heterotrophic bacteria per larva. The culturable bacteria represented 15 to 20% of the total population as determined by acridine orange staining. The gut itself contained large amounts of the oil, had no observable ceca, and maintained a slightly acidic pH of 6.3 to 6.5. Despite the ingestion of large amounts of potentially toxic asphalt by the larvae, their guts sustained the growth of 100 to 1,000 times more bacteria than did free oil. All of the bacteria isolated were nonsporeformers and gram negative. Fourteen isolates were chosen based on representative colony morphologies and were identified by using the Enterotube II and API 20E systems and fatty acid analysis. Of the 14 isolates, 9 were identified as Providencia rettgeri and 3 were likely Acinetobacter isolates. No evidence was found that the isolates grew on or derived nutrients from the asphalt itself or that they played an essential role in insect development. Regardless, any bacteria found in the oil fly larval gut are likely to exhibit pronounced solvent tolerance and may be a future source of industrially useful, solvent-tolerant enzymes. PMID- 10103239 TI - Identification of aerobically and anaerobically induced genes in Enterococcus faecalis by random arbitrarily primed PCR. AB - Enterococci have emerged among the leading causes of nosocomial infection. With the goal of analyzing enterococcal genes differentially expressed in environments related to commensal or environmental colonization and infection sites, we adapted and optimized a method more commonly used in the study of eukaryotic gene expression, random arbitrarily primed PCR (RAP-PCR). The RAP-PCR method was systematically optimized, allowing the technique to be used in a highly reproducible manner with gram-positive bacterial RNA. In the present study, aerobiosis was chosen as a variable for the induction of changes in gene expression by Enterococcus faecalis. Aerobically and anaerobically induced genes were detected and identified to the sequence level, and differential gene expression was confirmed by quantitative, specifically primed RT-PCR. Differentially expressed genes included several sharing identity with those of other organisms related to oxygen metabolism, as well as hypothetical genes lacking identity to known genes. PMID- 10103241 TI - Cloning and nucleotide sequence analysis of gyrB of Bacillus cereus, B. thuringiensis, B. mycoides, and B. anthracis and their application to the detection of B. cereus in rice. AB - As 16S rRNA sequence analysis has proven inadequate for the differentiation of Bacillus cereus from closely related species, we employed the gyrase B gene (gyrB) as a molecular diagnostic marker. The gyrB genes of B. cereus JCM 2152(T), Bacillus thuringiensis IAM 12077(T), Bacillus mycoides ATCC 6462(T), and Bacillus anthracis Pasteur #2H were cloned and sequenced. Oligonucleotide PCR primer sets were designed from within gyrB sequences of the respective bacteria for the specific amplification and differentiation of B. cereus, B. thuringiensis, and B. anthracis. The results from the amplification of gyrB sequences correlated well with results obtained with the 16S rDNA-based hybridization study but not with the results of their phenotypic characterization. Some of the reference strains of both B. cereus (three serovars) and B. thuringiensis (two serovars) were not positive in PCR amplification assays with gyrB primers. However, complete sequencing of 1.2-kb gyrB fragments of these reference strains showed that these serovars had, in fact, lower homology than their originally designated species. We developed and tested a procedure for the specific detection of the target organism in boiled rice that entailed 15 h of preenrichment followed by PCR amplification of the B. cereus-specific fragment. This method enabled us to detect an initial inoculum of 0.24 CFU of B. cereus cells per g of boiled rice food homogenate without extracting DNA. However, a simple two-step filtration step is required to remove PCR inhibitory substances. PMID- 10103242 TI - Disaccharides as a new class of nonaccumulated osmoprotectants for Sinorhizobium meliloti. AB - Sucrose and ectoine (1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carboxylic acid) are very unusual osmoprotectants for Sinorhizobium meliloti because these compounds, unlike other bacterial osmoprotectants, do not accumulate as cytosolic osmolytes in salt-stressed S. meliloti cells. Here, we show that, in fact, sucrose and ectoine belong to a new family of nonaccumulated sinorhizobial osmoprotectants which also comprises the following six disaccharides: trehalose, maltose, cellobiose, gentiobiose, turanose, and palatinose. Also, several of these disaccharides were very effective exogenous osmoprotectants for strains of Rhizobium leguminosarum biovars phaseoli and trifolii. Sucrose and trehalose are synthesized as endogenous osmolytes in various bacteria, but the other five disaccharides had never been implicated before in osmoregulation in any organism. All of the disaccharides that acted as powerful osmoprotectants in S. meliloti and R. leguminosarum also acted as very effective competitors of [14C]sucrose uptake in salt-stressed cultures of these bacteria. Conversely, disaccharides that were not osmoprotective for S. meliloti and R. leguminosarum did not inhibit sucrose uptake in these bacteria. Hence, disaccharide osmoprotectants apparently shared the same uptake routes in these bacteria. Natural-abundance 13C nuclear magnetic resonance spectroscopy and quantification of cytosolic solutes demonstrated that the novel disaccharide osmoprotectants were not accumulated to osmotically significant levels in salt-stressed S. meliloti cells; rather, these compounds, like sucrose and ectoine, were catabolized during early exponential growth, and contributed indirectly to enhance the cytosolic levels of two endogenously synthesized osmolytes, glutamate and the dipeptide N acetylglutaminylglutamine amide. The ecological implication of the use of these disaccharides as osmoprotectants is discussed. PMID- 10103243 TI - Detection of cytolethal distending toxin activity and cdt genes in Campylobacter spp. isolated from chicken carcasses. AB - This study was designed to determine whether isolates from chicken carcasses, the primary source of Campylobacter jejuni and Campylobacter coli in human infections, commonly carry the cdt genes and also whether active cytolethal distending toxin (CDT) is produced by these isolates. Campylobacter spp. were isolated from all 91 fresh chicken carcasses purchased from local supermarkets. Campylobacter spp. were identified on the basis of both biochemical and PCR tests. Of the 105 isolates, 70 (67%) were identified as C. jejuni, and 35 (33%) were identified as C. coli. PCR tests amplified portions of the cdt genes from all 105 isolates. Restriction analysis of PCR products indicated that there appeared to be species-specific differences between the C. jejuni and C. coli cdt genes, but that the restriction patterns of the cdt genes within strains of the same species were almost invariant. Quantitation of active CDT levels produced by the isolates indicated that all C. jejuni strains except four (94%) had mean CDT titers greater than 100. Only one C. jejuni strain appeared to produce no active CDT. C. coli isolates produced little or no toxin. These results confirm the high rate of Campylobacter sp. contamination of fresh chicken carcasses and indicate that cdt genes may be universally present in C. jejuni and C. coli isolates from chicken carcasses. PMID- 10103244 TI - Characterization and heterologous expression of the genes encoding enterocin a production, immunity, and regulation in Enterococcus faecium DPC1146. AB - Enterocin A is a small, heat-stable, antilisterial bacteriocin produced by Enterococcus faecium DPC1146. The sequence of a 10, 879-bp chromosomal region containing at least 12 open reading frames (ORFs), 7 of which are predicted to play a role in enterocin biosynthesis, is presented. The genes entA, entI, and entF encode the enterocin A prepeptide, the putative immunity protein, and the induction factor prepeptide, respectively. The deduced proteins EntK and EntR resemble the histidine kinase and response regulator proteins of two-component signal transducing systems of the AgrC-AgrA type. The predicted proteins EntT and EntD are homologous to ABC (ATP-binding cassette) transporters and accessory factors, respectively, of several other bacteriocin systems and to proteins implicated in the signal-sequence-independent export of Escherichia coli hemolysin A. Immediately downstream of the entT and entD genes are two ORFs, the product of one of which, ORF4, is very similar to the product of the yteI gene of Bacillus subtilis and to E. coli protease IV, a signal peptide peptidase known to be involved in outer membrane lipoprotein export. Another potential bacteriocin is encoded in the opposite direction to the other genes in the enterocin cluster. This putative bacteriocin-like peptide is similar to LafX, one of the components of the lactacin F complex. A deletion which included one of two direct repeats upstream of the entA gene abolished enterocin A activity, immunity, and ability to induce bacteriocin production. Transposon insertion upstream of the entF gene also had the same effect, but this mutant could be complemented by exogenously supplied induction factor. The putative EntI peptide was shown to be involved in the immunity to enterocin A. Cloning of a 10.5-kb amplicon comprising all predicted ORFs and regulatory regions resulted in heterologous production of enterocin A and induction factor in Enterococcus faecalis, while a four-gene construct (entAITD) under the control of a constitutive promoter resulted in heterologous enterocin A production in both E. faecalis and Lactococcus lactis. PMID- 10103245 TI - Estimation of bacterial cell numbers in humic acid-rich salt marsh sediments with probes directed to 16S ribosomal DNA AB - The feasibility of using probes directed towards ribosomal DNAs (rDNAs) as a quantitative approach to estimating cell numbers was examined and applied to study the structure of a bacterial community in humic acid-rich salt marsh sediments. Hybridizations were performed with membrane-bound nucleic acids by using seven group-specific DNA oligonucleotide probes complementary to 16S rRNA coding regions. These included a general eubacterial probe and probes encompassing most members of the gram-negative, mesophilic sulfate-reducing bacteria (SRB). DNA was extracted from sediment samples, and contaminating materials were removed by a series of steps. Efficiency of DNA extraction was 48% based on the recovery of tritiated plasmid DNA added to samples prior to extraction. Reproducibility of the extraction procedure was demonstrated by hybridizations to replicate samples. Numbers of target cells in samples were estimated by comparing the amount of hybridization to extracted DNA obtained with each probe to that obtained with a standard curve of genomic DNA for reference strains included on the same membrane. In June, numbers of SRB detected with an SRB-specific probe ranged from 6.0 x 10(7) to 2.5 x 10(9) (average, 1.1 x 10(9) +/- 5.2 x 10(8)) cells g of sediment-1. In September, numbers of SRB detected ranged from 5.4 x 10(8) to 7.3 x 10(9) (average, 2.5 x 10(9) +/- 1.5 x 10(9)) cells g of sediment-1. The capability of using rDNA probes to estimate cell numbers by hybridization to DNA extracted from complex matrices permits initiation of detailed studies on community composition and changes in communities based on cell numbers in formerly intractable environments. PMID- 10103246 TI - Reduction of cell lysate viscosity during processing of poly(3-hydroxyalkanoates) by chromosomal integration of the staphylococcal nuclease gene in Pseudomonas putida. AB - Poly(3-hydroxyalkanoates) (PHAs) are biodegradable thermoplastics which are accumulated by many bacterial species in the form of intracellular granules and which are thought to serve as reserves of carbon and energy. Pseudomonas putida accumulates a polyester, composed of medium-side-chain 3-hydroxyalkanoic acids, which has excellent film-forming properties. Industrial processing of PHA involves purification of the PHA granules from high-cell-density cultures. After the fermentation process, cells are lysed by homogenization and PHA granules are purified by chemical treatment and repeated washings to yield a PHA latex. Unfortunately, the liberation of chromosomal DNA during lysis causes a dramatic increase in viscosity, which is problematic in the subsequent purification steps. Reduction of the viscosity is generally achieved by the supplementation of commercially available nuclease preparations or by heat treatment; however, both procedures add substantial costs to the process. As a solution to this problem, a nuclease-encoding gene from Staphylococcus aureus was integrated into the genomes of several PHA producers. Staphylococcal nuclease is readily expressed in PHA producing Pseudomonas strains and is directed to the periplasm, and occasionally to the culture medium, without affecting PHA production or strain stability. During downstream processing, the viscosity of the lysate from a nuclease integrated Pseudomonas strain was reduced to a level similar to that observed for the wild-type strain after treatment with commercial nuclease. The nuclease gene was also functionally integrated into the chromosomes of other PHA producers, including Ralstonia eutropha. PMID- 10103247 TI - Expression of the Corynebacterium glutamicum panD gene encoding L-aspartate-alpha decarboxylase leads to pantothenate overproduction in Escherichia coli. AB - The Corynebacterium glutamicum panD gene was identified by functional complementation of an Escherichia coli panD mutant strain. Sequence analysis revealed that the coding region of panD comprises 411 bp and specifies a protein of 136 amino acid residues with a deduced molecular mass of 14.1 kDa. A defined C. glutamicum panD mutant completely lacked L-aspartate-alpha-decarboxylase activity and exhibited beta-alanine auxotrophy. The C. glutamicum panD (panDC. g.) as well as the E. coli panD (panDE.c.) genes were cloned into a bifunctional expression plasmid to allow gene analysis in C. glutamicum as well as in E. coli. The enhanced expression of panDC.g. in C. glutamicum resulted in the formation of two distinct proteins in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, leading to the assumption that the panDC.g. gene product is proteolytically processed into two subunits. By increased expression of panDC.g. in C. glutamicum, the activity of L-aspartate-alpha-decarboxylase was 288-fold increased, whereas the panDE.c. gene resulted only in a 4-fold enhancement. The similar experiment performed in E. coli revealed that panDC.g. achieved a 41-fold increase and that panDE.c. achieved a 3-fold increase of enzyme activity. The effect of the panDC.g. and panDE.c. gene expression in E. coli was studied with a view to pantothenate accumulation. Only by expression of the panDC.g. gene was sufficient beta-alanine produced to abolish its limiting effect on pantothenate production. In cultures expressing the panDE.c. gene, the maximal pantothenate production was still dependent on external beta-alanine supplementation. The enhanced expression of panDC.g. in E. coli yielded the highest amount of pantothenate in the culture medium, with a specific productivity of 140 ng of pantothenate mg (dry weight)-1 h-1. PMID- 10103248 TI - Identification of four phage resistance plasmids from Lactococcus lactis subsp. cremoris HO2. AB - The bacteriophage-host sensitivity patterns of 16 strains of Lactococcus lactis originally isolated from a mixed strain Cheddar cheese starter culture were determined. Using phages obtained from cheese factory whey, four of the strains were found to be highly phage resistant. One of these isolates, Lactococcus lactis subsp. cremoris HO2, was studied in detail to determine the mechanisms responsible for the phage insensitivity phenotypes. Conjugal transfer of plasmid DNA from strain HO2 allowed a function to be assigned to four of its six plasmids. A 46-kb molecule, designated pCI646, was found to harbor the lactose utilization genes, while this and plasmids of 58 kb (pCI658), 42 kb (pCI642), and 4.5 kb (pCI605) were shown to be responsible for the phage resistance phenotypes observed against the small isometric-headed phage phi712 (936 phage species) and the prolate-headed phage phic2 (c2 species). pCI658 was found to mediate an adsorption-blocking mechanism and was also responsible for the fluffy pellet phenotype of cells containing the molecule. pCI642 and pCI605 were both shown to be required for the operation of a restriction-modification system. PMID- 10103249 TI - Microbiological and geochemical characterization of fluvially deposited sulfidic mine tailings AB - The fluvial deposition of mine tailings generated from historic mining operations near Butte, Montana, has resulted in substantial surface and shallow groundwater contamination along Silver Bow Creek. Biogeochemical processes in the sediment and underlying hyporheic zone were studied in an attempt to characterize interactions consequential to heavy-metal contamination of shallow groundwater. Sediment cores were extracted and fractionated based on sediment stratification. Subsamples of each fraction were assayed for culturable heterotrophic microbiota, specific microbial guilds involved in metal redox transformations, and both aqueous- and solid-phase geochemistry. Populations of cultivable Fe(III)-reducing bacteria were most prominent in the anoxic, circumneutral pH regions associated with a ferricrete layer or in an oxic zone high in organic carbon and soluble iron. Sulfur- and iron-oxidizing bacteria were distributed in discrete zones throughout the tailings and were often recovered from sections at and below the anoxic groundwater interface. Sulfate-reducing bacteria were also widely distributed in the cores and often occurred in zones overlapping iron and sulfur oxidizers. Sulfate-reducing bacteria were consistently recovered from oxic zones that contained high concentrations of metals in the oxidizable fraction. Altogether, these results suggest a highly varied and complex microbial ecology within a very heterogeneous geochemical environment. Such physical and biological heterogeneity has often been overlooked when remediation strategies for metal contaminated environments are formulated. PMID- 10103250 TI - Degradation of ciprofloxacin by basidiomycetes and identification of metabolites generated by the brown rot fungus Gloeophyllum striatum. AB - Ciprofloxacin (CIP), a fluoroquinolone antibacterial drug, is widely used in the treatment of serious infections in humans. Its degradation by basidiomycetous fungi was studied by monitoring 14CO2 production from [14C]CIP in liquid cultures. Sixteen species inhabiting wood, soil, humus, or animal dung produced up to 35% 14CO2 during 8 weeks of incubation. Despite some low rates of 14CO2 formation, all species tested had reduced the antibacterial activity of CIP in supernatants to between 0 and 33% after 13 weeks. Gloeophyllum striatum was used to identify the metabolites formed from CIP. After 8 weeks, mycelia had produced 17 and 10% 14CO2 from C-4 and the piperazinyl moiety, respectively, although more than half of CIP (applied at 10 ppm) had been transformed into metabolites already after 90 h. The structures of 11 metabolites were elucidated by high performance liquid chromatography combined with electrospray ionization mass spectrometry and 1H nuclear magnetic resonance spectroscopy. They fell into four categories as follows: (i) monohydroxylated congeners, (ii) dihydroxylated congeners, (iii) an isatin-type compound, proving elimination of C-2, and (iv) metabolites indicating both elimination and degradation of the piperazinyl moiety. A metabolic scheme previously described for enrofloxacin degradation could be confirmed and extended. A new type of metabolite, 6-defluoro-6-hydroxy deethylene-CIP, provided confirmatory evidence for the proposed network of congeners. This may result from sequential hydroxylation of CIP and its congeners by hydroxyl radicals. Our findings reveal for the first time the widespread potential for CIP degradation among basidiomycetes inhabiting various environments, including agricultural soils and animal dung. PMID- 10103251 TI - Variation in resistance of natural isolates of Escherichia coli O157 to high hydrostatic pressure, mild heat, and other stresses. AB - Strains of Escherichia coli O157 isolated from patients with clinical cases of food-borne illness and other sources exhibited wide differences in resistance to high hydrostatic pressure. The most pressure-resistant strains were also more resistant to mild heat than other strains. Strain C9490, a representative pressure-resistant strain, was also more resistant to acid, oxidative, and osmotic stresses than the pressure-sensitive strain NCTC 12079. Most of these differences in resistance were observed only in stationary-phase cells, the only exception being acid resistance, where differences were also apparent in the exponential phase. Membrane damage in pressure-treated cells was revealed by increased uptake of the fluorescent dyes ethidium bromide and propidium iodide. When strains were exposed to the same pressure for different lengths of time, the pressure-sensitive strains took up stain sooner than the more resistant strain, which suggested that the differences in resistance may be related to susceptibility to membrane damage. Our results emphasize the importance of including stress-resistant strains of E. coli O157 when the efficacy of a novel or mild food preservation treatment is tested. PMID- 10103252 TI - Production of poly(3-hydroxybutyric acid-co-4-hydroxybutyric acid) and poly(4 hydroxybutyric acid) without subsequent degradation by Hydrogenophaga pseudoflava. AB - A Hydrogenophaga pseudoflava strain was able to synthesize poly(3-hydroxybutyric acid-co-4-hydroxybutyric acid) [P(3HB-co-4HB)] having a high level of 4 hydroxybutyric acid monomer unit (4HB) from gamma-butyrolactone. In a two-step process in which the first step involved production of cells containing a minimum amount of poly(3-hydroxybutyric acid) [P(3HB)] and the second step involved polyester accumulation from the lactone, approximately 5 to 10 mol% of the 3 hydroxybutyric acid (3HB) derived from the first-step culture was unavoidably reincorporated into the polymer in the second cultivation step. Reincorporation of the 3HB units produced from degradation of the first-step residual P(3HB) was confirmed by high-resolution 13C nuclear magnetic resonance spectroscopy. In order to synthesize 3HB-free poly(4-hydroxybutyric acid) [P(4HB)] homopolymer, a three-stage cultivation technique was developed by adding a nitrogen addition step, which completely removed the residual P(3HB). The resulting polymer was free of 3HB. However, when the strain was grown on gamma-butyrolactone as the sole carbon source in a synthesis medium, a copolyester of P(3HB-co-4HB) containing 45 mol% 3HB was produced. One-step cultivation on gamma-butyrolactone required a rather long induction time (3 to 4 days). On the basis of the results of an enzymatic study performed with crude extracts, we suggest that the inability of cells to produce 3HB in the multistep culture was due to a low level of 4-hydroxybutyric acid (4HBA) dehydrogenase activity, which resulted in a low level of acetyl coenzyme A. Thus, 3HB formation from gamma-butyrolactone is driven by a high level of 4HBA dehydrogenase activity induced by long exposure to gamma-butyrolactone, as is the case for a one-step culture. In addition, intracellular degradation kinetics studies showed that P(3HB) in cells was completely degraded within 30 h of cultivation after being transferred to a carbon-free mineral medium containing additional ammonium sulfate, while P(3HB-co 4HB) containing 5 mol% 3HB and 95 mol% 4HB was totally inert in interactions with the intracellular depolymerases. Intracellular inertness could be a useful factor for efficient synthesis of the P(4HB) homopolymer and of 4HB-rich P(3HB-co-4HB) by the strain used in this study. PMID- 10103253 TI - Phylogenetic analysis of Cryptosporidium parasites based on the small-subunit rRNA gene locus. AB - Biological data support the hypothesis that there are multiple species in the genus Cryptosporidium, but a recent analysis of the available genetic data suggested that there is insufficient evidence for species differentiation. In order to resolve the controversy in the taxonomy of this parasite genus, we characterized the small-subunit rRNA genes of Cryptosporidium parvum, Cryptosporidium baileyi, Cryptosporidium muris, and Cryptosporidium serpentis and performed a phylogenetic analysis of the genus Cryptosporidium. Our study revealed that the genus Cryptosporidium contains the phylogenetically distinct species C. parvum, C. muris, C. baileyi, and C. serpentis, which is consistent with the biological characteristics and host specificity data. The Cryptosporidium species formed two clades, with C. parvum and C. baileyi belonging to one clade and C. muris and C. serpentis belonging to the other clade. Within C. parvum, human genotype isolates and guinea pig isolates (known as Cryptosporidium wrairi) each differed from bovine genotype isolates by the nucleotide sequence in four regions. A C. muris isolate from cattle was also different from parasites isolated from a rock hyrax and a Bactrian camel. Minor differences were also detected between C. serpentis isolates from snakes and lizards. Based on the genetic information, a species- and strain-specific PCR restriction fragment length polymorphism diagnostic tool was developed. PMID- 10103254 TI - beta-tubulin mRNA as a marker of Cryptosporidium parvum oocyst viability. AB - Determining the viability of waterborne Cryptosporidium parvum oocysts remains a technical challenge. rRNA and mRNA were evaluated in a reverse transcription (RT) PCR assay as potential markers of oocyst viability. The rationale for this approach is the rapid turnover and postmortem decay of cellular RNA. The beta tubulin mRNA and an anonymous mRNA transcript were chosen as potential markers because they are the only mRNA species in C. parvum known to possess introns. This feature facilitated the distinction between genuine RT-PCR products and PCR products originating from copurifying DNA. Prolonged incubation at room temperature of initially viable oocysts resulted in a gradual decrease in mRNA levels, which correlated with the loss of oocyst infectivity to neonatal mice. In contrast, oocysts stored at 4 degrees C for over 39 weeks maintained their infectivity and displayed no decrease in the level of beta-tubulin RT-PCR product. The postmortem decay of two mRNA species demonstrates that RT-PCR analysis can provide information on the viability of C. parvum oocysts. The methodological similarity between PCR detection and RT-PCR viability analysis could facilitate the development of a combined detection and viability assay. PMID- 10103255 TI - The alkene monooxygenase from Xanthobacter strain Py2 is closely related to aromatic monooxygenases and catalyzes aromatic monohydroxylation of benzene, toluene, and phenol. AB - The genes encoding the six polypeptide components of the alkene monooxygenase from Xanthobacter strain Py2 (Xamo) have been located on a 4.9-kb fragment of chromosomal DNA previously cloned in cosmid pNY2. Sequencing and analysis of the predicted amino acid sequences indicate that the components of Xamo are homologous to those of the aromatic monooxygenases, toluene 2-, 3-, and 4 monooxygenase and benzene monooxygenase, and that the gene order is identical. The genes and predicted polypeptides are aamA, encoding the 497-residue oxygenase alpha-subunit (XamoA); aamB, encoding the 88-residue oxygenase gamma-subunit (XamoB); aamC, encoding the 122-residue ferredoxin (XamoC); aamD, encoding the 101-residue coupling or effector protein (XamoD); aamE, encoding the 341-residue oxygenase beta-subunit (XamoE); and aamF, encoding the 327-residue reductase (XamoF). A sequence with >60% concurrence with the consensus sequence of sigma54 (RpoN)-dependent promoters was identified upstream of the aamA gene. Detailed comparison of XamoA with the oxygenase alpha-subunits from aromatic monooxygenases, phenol hydroxylases, methane monooxygenase, and the alkene monooxygenase from Rhodococcus rhodochrous B276 showed that, despite the overall similarity to the aromatic monooxygenases, XamoA has some distinctive characteristics of the oxygenases which oxidize aliphatic, and particularly alkene, substrates. On the basis of the similarity between Xamo and the aromatic monooxygenases, Xanthobacter strain Py2 was tested and shown to oxidize benzene, toluene, and phenol, while the alkene monooxygenase-negative mutants NZ1 and NZ2 did not. Benzene was oxidized to phenol, which accumulated transiently before being further oxidized. Toluene was oxidized to a mixture of o-, m-, and p cresols (39.8, 18, and 41.7%, respectively) and a small amount (0.5%) of benzyl alcohol, none of which were further oxidized. In growth studies Xanthobacter strain Py2 was found to grow on phenol and catechol but not on benzene or toluene; growth on phenol required a functional alkene monooxygenase. However, there is no evidence of genes encoding steps in the metabolism of catechol in the vicinity of the aam gene cluster. This suggests that the inducer specificity of the alkene monooxygenase may have evolved to benefit from the naturally broad substrate specificity of this class of monooxygenase and the ability of the host strain to grow on catechol. PMID- 10103256 TI - Cloning and partial characterization of endopolygalacturonase genes from Botrytis cinerea. AB - Botrytis cinerea is a plant-pathogenic fungus infecting over 200 different plant species. We use a molecular genetic approach to study the process of pectin degradation by the fungus. Recently, we described the cloning and characterization of an endopolygalacturonase (endoPG) gene from B. cinerea (Bcpg1) which is required for full virulence. Here we describe the cloning and characterization of five additional endoPG-encoding genes from B. cinerea SAS56. The identity at the amino acid level between the six endoPGs of B. cinerea varied from 34 to 73%. Phylogenetic analysis, by using a group of 35 related fungal endoPGs and as an outgroup one plant PG, resulted in the identification of five monophyletic groups of closely related proteins. The endoPG proteins from B. cinerea SAS56 could be assigned to three different monophyletic groups. DNA blot analysis revealed the presence of the complete endoPG gene family in other strains of B. cinerea, as well as in other Botrytis species. Differential gene expression of the gene family members was found in mycelium grown in liquid culture with either glucose or polygalacturonic acid as the carbon source. PMID- 10103257 TI - Surface-grafted, environmentally sensitive polymers for biofilm release. AB - Controlling bacterial biofouling is desirable for almost every human enterprise in which solid surfaces are introduced into nonsterile aqueous environments. One approach that is used to decrease contamination of manufactured devices by microorganisms is using materials that easily slough off accumulated material (i.e., fouling release surfaces). The compounds currently used for this purpose rely on low surface energy to inhibit strong attachment of organisms. In this study, we examined the possible use of environmentally responsive (or "smart") polymers as a new class of fouling release agents; a surface-grafted thermally responsive polymer, poly(N-isopropylacrylamide) (PNIPAAM), was used as a model compound. PNIPAAM is known to have a lower critical solubility temperature of approximately 32 degrees C (i.e., it is insoluble in water at temperatures above 32 degrees C and is soluble at temperatures below 32 degrees C). Under experimental conditions, >90% of cultured microorganisms (Staphylococcus epidermidis, Halomonas marina) and naturally occurring marine microorganisms that attached to grafted PNIPAAM surfaces during 2-, 18-, 36-, and 72-h incubations were removed when the hydration state of the polymer was changed from a wettability that was favorable for attachment to a wettability that was less favorable. Of particular significance is the observation that an organism known to attach in the greatest numbers to hydrophobic substrata (i.e., H. marina) was removed when transition of PNIPAAM to a more hydrated state occurred, whereas an organism that attaches in the greatest numbers to hydrophilic substrata (i.e., S. epidermidis) was removed when the opposite transition occurred. Neither solvated nor desolvated PNIPAAM exhibited intrinsic fouling release properties, indicating that the phase transition was the important factor in removal of organisms. Based on our observations of the behavior of this model system, we suggest that environmentally responsive polymers represent a new approach for controlling biofouling release. PMID- 10103258 TI - Ferrioxamine-mediated Iron(III) utilization by Salmonella enterica. AB - Utilization of ferrioxamines as sole sources of iron distinguishes Salmonella enterica serotypes Typhimurium and Enteritidis from a number of related species, including Escherichia coli. Ferrioxamine supplements have therefore been used in preenrichment and selection media to increase the bacterial growth rate while selectivity is maintained. We characterized the determinants involved in utilization of ferrioxamines B, E, and G by S. enterica serotype Typhimurium by performing siderophore cross-feeding bioassays. Transport of all three ferric siderophores across the outer membrane was dependent on the FoxA receptor encoded by the Fur-repressible foxA gene. However, only the transport of ferrioxamine G was dependent on the energy-transducing protein TonB, since growth stimulation of a tonB strain by ferrioxamines B and E was observed, albeit at lower efficiencies than in the parental strain. Transport across the inner membrane was dependent on the periplasmic binding protein-dependent ABC transporter complex comprising FhuBCD, as has been reported for other hydroxamate siderophores of enteric bacteria. The distribution of the foxA gene in the genus Salmonella, as indicated by DNA hybridization studies and correlated with the ability to utilize ferrioxamine E, was restricted to subspecies I, II, and IIIb, and this gene was absent from subspecies IIIa, IV, VI, and VII (formerly subspecies IV) and Salmonella bongori (formerly subspecies V). S. enterica serotype Typhimurium mutants with either a transposon insertion or a defined nonpolar frameshift (+2) mutation in the foxA gene were not able to utilize any of the three ferrioxamines tested. A strain carrying the nonpolar foxA mutation exhibited a significantly reduced ability to colonize rabbit ileal loops compared to the foxA+ parent. In addition, a foxA mutant was markedly attenuated in mice inoculated by either the intragastric or intravenous route. Mice inoculated with the foxA mutant were protected against subsequent challenge by the foxA+ parent strain. PMID- 10103259 TI - Biphasic extracellular proteolytic enzyme activity in benthic water and sediment in the northwestern mediterranean Sea AB - In this study, we used the fact that bacteria are able to cleave a fluorogenic substrate analog (L-leucine-7-amido-4-methylcoumarin) to determine the maximal ectoproteolytic activities (Vm) and affinities (Km) of natural benthic microbial communities by the multiconcentration kinetic method. This investigation was performed during the winter and summer of 1997 with a set of 36 samples of near bottom water and sediment collected from a coastal area and an offshore area in the western part of the Gulf of Lions. The existence of biphasic microbial ectoproteolysis was statistically confirmed for both the near-bottom water and the sediment, regardless of the spatial and seasonal conditions. Globally, 72.2% of the entire set of bacterial consortia collected at the water-sediment boundary layer showed biphasic microbial kinetics. A specific estimator of the biphasicity indicated that deep benthic bacterial consortia responded better with episodic nutrient supplies than shallower benthic bacterial consortia responded. PMID- 10103260 TI - Selection of clc, cba, and fcb chlorobenzoate-catabolic genotypes from groundwater and surface waters adjacent to the Hyde park, Niagara Falls, chemical landfill. AB - The frequency of isolation of three nonhomologous chlorobenzoate catabolic genotypes (clc, cba, and fcb) was determined for 464 isolates from freshwater sediments and groundwater in the vicinity of the Hyde Park industrial landfill site in the Niagara watershed. Samples were collected from both contaminated and noncontaminated sites during spring, summer, and fall and enriched at 4, 22, or 32 degrees C with micromolar to millimolar concentrations of chlorobenzoates and 3-chlorobiphenyl (M. C. Peel and R. C. Wyndham, Microb. Ecol: 33:59-68, 1997). Hybridization at moderate stringency to restriction-digested genomic DNA with DNA probes revealed the chlorocatechol 1,2-dioxygenase operon (clcABD), the 3 chlorobenzoate 3,4-(4,5)-dioxygenase operon (cbaABC), and the 4-chlorobenzoate dehalogenase (fcbB) gene in isolates enriched from all contaminated sites in the vicinity of the industrial landfill. Nevertheless, the known genes were found in less than 10% of the isolates from the contaminated sites, indicating a high level of genetic diversity in the microbial community. The known genotypes were not enriched from the noncontaminated control sites nearby. The clc, cba, and fcb isolates were distributed across five phenotypically distinct groups based on Biolog carbon source utilization, with the breadth of the host range decreasing in the order clc > cba > fcb. Restriction fragment length polymorphism (RFLP) patterns showed that the cba genes were conserved in all isolates whereas the clc and fcb genes exhibited variation in RFLP patterns. These observations are consistent with the recent spread of the cba genes by horizontal transfer as part of transposon Tn5271 in response to contaminant exposure at Hyde Park. Consistent with this hypothesis, IS1071, the flanking element in Tn5271, was found in all isolates that carried the cba genes. Interestingly, IS1071 was also found in a high proportion of isolates from Hyde Park carrying the clc and fcb genes, as well as in type strains carrying the clcABD operon and the biphenyl (bph) catabolic genes. PMID- 10103261 TI - Detection of small numbers of Campylobacter jejuni and Campylobacter coli cells in environmental water, sewage, and food samples by a seminested PCR assay. AB - A rapid and sensitive assay was developed for detection of small numbers of Campylobacter jejuni and Campylobacter coli cells in environmental water, sewage, and food samples. Water and sewage samples were filtered, and the filters were enriched overnight in a nonselective medium. The enrichment cultures were prepared for PCR by a rapid and simple procedure consisting of centrifugation, proteinase K treatment, and boiling. A seminested PCR based on specific amplification of the intergenic sequence between the two Campylobacter flagellin genes, flaA and flaB, was performed, and the PCR products were visualized by agarose gel electrophoresis. The assay allowed us to detect 3 to 15 CFU of C. jejuni per 100 ml in water samples containing a background flora consisting of up to 8, 700 heterotrophic organisms per ml and 10,000 CFU of coliform bacteria per 100 ml. Dilution of the enriched cultures 1:10 with sterile broth prior to the PCR was sometimes necessary to obtain positive results. The assay was also conducted with food samples analyzed with or without overnight enrichment. As few as 97% in order to quantify diversity. In all, 34 clusters containing two or more sequences were identified, and the largest group contained nine clones. A number of diversity, dominance, and evenness indices were calculated, and they all indicated that diversity was high, reflecting the low coverage of rDNA libraries achieved. Differences in diversity between sample types were not observed. Collector's curves, however, indicated that there were differences in the underlying community structures; in particular, there was reduced diversity of organisms of the alpha subdivision of the class Proteobacteria (alpha-proteobacteria) in improved soils. PMID- 10103274 TI - Wide distribution and diversity of members of the bacterial kingdom Acidobacterium in the environment. AB - To assess the distribution and diversity of members of the recently identified bacterial kingdom Acidobacterium, members of this kingdom present in 43 environmental samples were surveyed by PCR amplification. A primer designed to amplify rRNA gene sequences (ribosomal DNAs [rDNAs]) from most known members of the kingdom was used to interrogate bulk DNA extracted from the samples. Positive PCR results were obtained with all temperate soil and sediment samples tested, as well as some hot spring samples, indicating that members of this kingdom are very widespread in terrestrial environments. PCR primers specific for four phylogenetic subgroups within the kingdom were used in similar surveys. All four subgroups were detected in most neutral soils and some sediments, while only two of the groups were seen in most low-pH environments. The combined use of these primers allowed identification of a novel lineage within the kingdom in a hot spring environment. Phylogenetic analysis of rDNA sequences from our survey and the literature outlines at least six major subgroups within the kingdom. Taken together, these data suggest that members of the Acidobacterium kingdom are as genetically and metabolically diverse, environmentally widespread and perhaps as ecologically important as the well-known Proteobacteria and gram-positive bacterial kingdoms. PMID- 10103275 TI - Real-time monitoring of Escherichia coli O157:H7 adherence to beef carcass surface tissues with a bioluminescent reporter. AB - A method for studying bacteria that are attached to carcass surfaces would eliminate the need for exogenous sampling and would facilitate understanding the interaction of potential human food-borne pathogens with food animal tissue surfaces. We describe such a method in which we used a bioluminescent reporter strain of Escherichia coli O157:H7 that was constructed by transformation with plasmid pCGLS1, an expression vector that contains a complete bacterial luciferase (lux) operon. Beef carcass surface tissues were inoculated with the bioluminescent strain, and adherent bacteria were visualized in real time by using a sensitive photon-counting camera to obtain in situ images. The reporter strain was found to luminesce from the tissue surfaces whether it was inoculated as a suspension in buffer or as a suspension in a bovine fecal slurry. With this method, areas of tissues inoculated with the reporter strain could be studied without obtaining, excising, homogenizing, and culturing multiple samples from the tissue surface. Use of the complete lux operon as the bioluminescent reporter eliminated the need to add exogenous substrate. This allowed detection and quantitation of bacterial inocula and rapid evaluation of adherence of a potential human pathogen to tissue surfaces. Following simple water rinses of inoculated carcass tissues, the attachment duration varied with different carcass surface types. On average, the percent retention of bioluminescent signal from the reporter strain was higher on lean fascia-covered tissue (54%) than on adipose fascia-covered tissue (18%) following water washing of the tissues. Bioluminescence and culture-derived viable bacterial counts were highly correlated (r2 = 0.98). Real-time assessment of microbial attachment to this complex menstruum should facilitate evaluation of carcass decontamination procedures and mechanistic studies of microbial contamination of beef carcass tissues. PMID- 10103276 TI - Combined microautoradiography-16S rRNA probe technique for determination of radioisotope uptake by specific microbial cell types in situ. AB - We propose a novel method for studying the function of specific microbial groups in situ. Since natural microbial communities are dynamic both in composition and in activities, we argue that the microbial "black box" should not be regarded as homogeneous. Our technique breaks down this black box with group-specific fluorescent 16S rRNA probes and simultaneously determines 3H-substrate uptake by each of the subgroups present via microautoradiography (MAR). Total direct counting, fluorescent in situ hybridization, and MAR are combined on a single slide to determine (i) the percentages of different subgroups in a community, (ii) the percentage of total cells in a community that take up a radioactively labeled substance, and (iii) the distribution of uptake within each subgroup. The method was verified with pure cultures. In addition, in situ uptake by members of the alpha subdivision of the class Proteobacteria (alpha-Proteobacteria) and of the Cytophaga-Flavobacterium group obtained off the California coast and labeled with fluorescent oligonucleotide probes for these subgroups showed that not only do these organisms account for a large portion of the picoplankton community in the sample examined ( approximately 60% of the universal probe-labeled cells and approximately 50% of the total direct counts), but they also are significant in the uptake of dissolved amino acids in situ. Nearly 90% of the total cells and 80% of the cells belonging to the alpha-Proteobacteria and Cytophaga Flavobacterium groups were detectable as active organisms in amino acid uptake tests. We suggest a name for our triple-labeling technique, substrate-tracking autoradiographic fluorescent in situ hybridization (STARFISH), which should aid in the "dissection" of microbial communities by type and function. PMID- 10103277 TI - Counting and size classification of active soil bacteria by fluorescence in situ hybridization with an rRNA oligonucleotide probe. AB - A fluorescence in situ hybridization (FISH) technique based on binding of a rhodamine-labelled oligonucleotide probe to 16S rRNA was used to estimate the numbers of ribosome-rich bacteria in soil samples. Such bacteria, which have high cellular rRNA contents, were assumed to be active (and growing) in the soil. Hybridization to an rRNA probe, EUB338, for the domain Bacteria was performed with a soil slurry, and this was followed by collection of the bacteria by membrane filtration (pore size, 0.2 micrometer). A nonsense probe, NONEUB338 (which has a nucleotide sequence complementary to the nucleotide sequence of probe EUB338), was used as a control for nonspecific staining. Counting and size classification into groups of small, medium, and large bacteria were performed by fluorescence microscopy. To compensate for a difference in the relative staining intensities of the probes and for binding by the rhodamine part of the probe, control experiments in which excess unlabelled probe was added were performed. This resulted in lower counts with EUB338 but not with NONEUB338, indicating that nonspecific staining was due to binding of rhodamine to the bacteria. A value of 4.8 x 10(8) active bacteria per g of dry soil was obtained for bulk soil incubated for 2 days with 0.3% glucose. In comparison, a value of 3.8 x 10(8) active bacteria per g of dry soil was obtained for soil which had been air dried and subsequently rewetted. In both soils, the majority (68 to 77%) of actively growing bacteria were members of the smallest size class (cell width, 0.25 to 0.5 micrometer), but the active (and growing) bacteria still represented only approximately 5% of the total bacterial population determined by DAPI (4', 6 diamidino-2-phenylindole) staining. The FISH technique in which slurry hybridization is used holds great promise for use with phylogenetic probes and for automatic counting of soil bacteria. PMID- 10103278 TI - cumA, a gene encoding a multicopper oxidase, is involved in Mn2+ oxidation in Pseudomonas putida GB-1. AB - Pseudomonas putida GB-1-002 catalyzes the oxidation of Mn2+. Nucleotide sequence analysis of the transposon insertion site of a nonoxidizing mutant revealed a gene (designated cumA) encoding a protein homologous to multicopper oxidases. Addition of Cu2+ increased the Mn2+-oxidizing activity of the P. putida wild type by a factor of approximately 5. The growth rates of the wild type and the mutant were not affected by added Cu2+. A second open reading frame (designated cumB) is located downstream from cumA. Both cumA and cumB probably are part of a single operon. The translation product of cumB was homologous (level of identity, 45%) to that of orf74 of Bradyrhizobium japonicum. A mutation in orf74 resulted in an extended lag phase and lower cell densities. Similar growth-related observations were made for the cumA mutant, suggesting that the cumA mutation may have a polar effect on cumB. This was confirmed by site-specific gene replacement in cumB. The cumB mutation did not affect the Mn2+-oxidizing ability of the organism but resulted in decreased growth. In summary, our data indicate that the multicopper oxidase CumA is involved in the oxidation of Mn2+ and that CumB is required for optimal growth of P. putida GB-1-002. PMID- 10103279 TI - Use of green fluorescent protein to detect expression of an endopolygalacturonase gene of Colletotrichum lindemuthianum during bean infection. AB - The 5' noncoding region of clpg2, an endopolygalacturonase gene of the bean pathogen Colletotrichum lindemuthianum, was fused to the coding sequence of a gene encoding a green fluorescent protein (GFP), and the construct was introduced into the fungal genome. Detection of GFP accumulation by fluorescence microscopy examination revealed that clpg2 was expressed at the early stages of germination of the conidia and during appressorium formation both in vitro and on the host plant. PMID- 10103280 TI - Diversity of bacteroides fragilis strains in their capacity to recover phages from human and animal wastes and from fecally polluted wastewater. AB - Great differences in capability to detect bacteriophages from urban sewage of the area of Barcelona existed among 115 strains of Bacteroides fragilis. The capability of six of the strains to detect phages in a variety of feces and wastewater was studied. Strains HSP40 and RYC4023 detected similar numbers of phages in urban sewage and did not detect phages in animal feces. The other four strains detected phages in the feces of different animal species and in wastewater of both human and animal origin. Strain RYC2056 recovered consistently higher counts than the other strains and also detected counts ranging from 10(1) to approximately 10(3) phages per ml in urban sewage from different geographical areas. This strain detected bacteriophages in animal feces even though their relative concentration with respect to the other fecal indicators was significantly lower in wastewater polluted with animal feces than in urban sewage. PMID- 10103281 TI - Genomic relationships between Enterococcus faecium strains from different sources and with different antibiotic resistance profiles evaluated by restriction endonuclease analysis of total chromosomal DNA using EcoRI and PvuII. AB - Forty-seven Enterococcus faecium strains from different sources were evaluated by restriction endonuclease analysis (REA) of total chromosomal DNA. Strains from chicken, pork, and humans were clearly divided into separate clusters, whereas strains from different countries, strains with different antibiotic resistance profiles, or clinical and healthy-subject strains were not. PMID- 10103282 TI - Different strategies for molecular differentiation of Mycobacterium bovis strains isolated in Sardinia, Italy. AB - Different genetic markers were used to analyze 22 Mycobacterium bovis strains isolated from cattle in Sardinia and one human isolate. IS6110 DNA fingerprinting differentiated the strains into six patterns, whereas with enterobacterial repetitive consensus sequence primers produced seven clusters. PCR ribotyping followed by digestion with HaeIII and PvuII produced five and seven patterns, respectively. PCR with the (GTG)5 oligonucleotide primer showed the best discriminatory power, generating eight clusters among the strains analyzed. PMID- 10103283 TI - Quantitative selective PCR of 16S ribosomal DNA correlates well with selective agar plating in describing population dynamics of indigenous Pseudomonas spp. in soil hot spots. AB - We used a quantitative PCR method targeting 16S ribosomal DNA using competitive PCR for specific detection of indigenous Pseudomonas DNA in soil hot spots. The amount of Pseudomonas DNA corresponded to the number of culturable Pseudomonas bacteria on Gould's S1 agar. This represents the first use of PCR for quantification of indigenous bacteria in more than one sample of soil. PMID- 10103284 TI - Effects of nickel and cobalt on kinetics of methanol conversion by methanogenic sludge as assessed by on-line CH4 monitoring. AB - When metals were added in a pulse mode to methylotrophic-methanogenic biomass, three methane production rate phases were recognized. Increased concentrations of Ni and Co accelerated the initial exponential and final arithmetic increases in the methane production rate and reduced the temporary decrease in the rate. When Ni and Co were added continuously, the temporary decrease phase was eliminated and the exponential production rate increased. We hypothesize that the temporary decrease in the methane production rate and the final arithmetic increase in the methane production rate were due to micronutrient limitations and that the precipitation-dissolution kinetics of metal sulfides may play a key role in the biovailability of these compounds. PMID- 10103285 TI - A double-selective tissue culture system for isolation of wild-type poliovirus from sewage applied in a long-term environmental surveillance. AB - We describe a simple, cost-efficient, double-selective method for isolation of wild-type poliovirus from sewage samples containing vaccine polioviruses and other enteroviruses, with a detection limit of 18 to 50 PFU per 1 to 2 liters of sewage. By this method we were able to process 1,700 sewage samples collected between 1991 and 1996, from which 10,472 plaques were isolated, 41 of them being identified as wild-type polioviruses. PMID- 10103286 TI - Enhanced degradation of polyvinyl alcohol by Pycnoporus cinnabarinus after pretreatment with Fenton's reagent. AB - Degradation of polyvinyl alcohol (PVA) was investigated by using a combination of chemical treatment with Fenton's reagent and biological degradation with the white rot fungus Pycnoporus cinnabarinus. Inclusion of the chemical pretreatment resulted in greater degradation of PVA than the degradation observed when biological degradation alone was used. PMID- 10103287 TI - Isolation and characterization of a second subunit of molecular chaperonin from Pyrococcus kodakaraensis KOD1: analysis of an ATPase-deficient mutant enzyme. AB - The cpkA gene encoding a second (alpha) subunit of archaeal chaperonin from Pyrococcus kodakaraensis KOD1 was cloned, sequenced, and expressed in Escherichia coli. Recombinant CpkA was studied for chaperonin functions in comparison with CpkB (beta subunit). The effect on decreasing the insoluble form of proteins was examined by coexpressing CpkA or CpkB with CobQ (cobyric acid synthase from P. kodakaraensis) in E. coli. The results indicate that both CpkA and CpkB effectively decrease the amount of the insoluble form of CobQ. Both CpkA and CpkB possessed the same ATPase activity as other bacterial and eukaryal chaperonins. The ATPase-deficient mutant proteins CpkA-D95K and CpkB-D95K were constructed by changing conserved Asp95 to Lys. Effect of the mutation on the ATPase activity and CobQ solubilization was examined. Neither mutant exhibited ATPase activity in vitro. Nevertheless, they decreased the amount of the insoluble form of CobQ by coexpression as did wild-type CpkA and CpkB. These results implied that both CpkA and CpkB could assist protein folding for nascent protein in E. coli without requiring energy from ATP hydrolysis. PMID- 10103288 TI - Genetic analysis of biodegradation of tetralin by a Sphingomonas strain. AB - A strain designated TFA which very efficiently utilizes tetralin has been isolated from the Rhine river. The strain has been identified as Sphingomonas macrogoltabidus, based on 16S rDNA sequence similarity. Genetic analysis of tetralin biodegradation has been performed by insertion mutagenesis and by physical analysis and analysis of complementation between the mutants. The genes involved in tetralin utilization are clustered in a region of 9 kb, comprising at least five genes grouped in two divergently transcribed operons. PMID- 10103289 TI - Semiautomated metabolic staining assay for Bacillus cereus emetic toxin. AB - This paper describes a specific, sensitive, semiautomated, and quantitative Hep-2 cell culture-based 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay for Bacillus cereus emetic toxin. Of nine Bacillus, Brevibacillus, and Paenibacillus species assessed for emetic toxin production, only B. cereus was cytotoxic. PMID- 10103290 TI - Preventing neonatal group B streptococcal disease: cost-effectiveness in a health maintenance organization and the impact of delayed hospital discharge for newborns who received intrapartum antibiotics. AB - OBJECTIVES: To estimate the cost and health benefits of implementing a risk factor-based prevention strategy for early-onset neonatal group B streptococcal (GBS) disease, using baseline assumptions and costs from a health maintenance organization. With the risk factor-based strategy, intrapartum antibiotics (IPAs) would be provided to women with fever, prolonged rupture of membranes, or preterm labor. A second objective was to determine the impact of an increased length of stay for well term infants with mothers who received IPAs. METHODS: We used decision analysis to compare the costs and benefits of the prevention strategy with usual obstetric practice for a cohort of 100 000 women and their newborn infants. We derived baseline values from a previous study based on chart review and automated cost data from a health maintenance organization in Northern California. In sensitivity analyses, we varied baseline assumptions, including additional costs for observing well term infants who received IPAs. RESULTS: If adherence to guidelines were 100%, 17% of mothers would receive IPAs at a cost of $490,000; $1.6 million would be saved by preventing 66 GBS cases (64% reduction). The net savings would be $1.1 million and 61 life-years. The net cost is sensitive to the cost of caring for well infants who received IPAs. If each term infant of a mother who received IPAs had 1 more day of observation than other term infants, there would be a net cost of $8.1 million; the cost per GBS case prevented would be $120,000 and the cost per life-year saved would be $130,000. CONCLUSIONS: Implementation in a health maintenance organization of a risk factor based strategy to prevent neonatal GBS disease can prevent substantial disease and be cost saving. However, if the length of hospital stay were extended among well term infants whose mothers received IPAs, the strategy would be relatively costly compared with other medical interventions. PMID- 10103291 TI - The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. AB - CONTEXT: Despite growing concern over the escalating antimicrobial resistance problem, physicians continue to inappropriately prescribe. It has been suggested that a major determinant of pediatrician antimicrobial prescribing behavior is the parental expectation that a prescription will be provided. OBJECTIVES: To explore the extent to which parental previsit expectations and physician perceptions of those expectations are associated with inappropriate antimicrobial prescribing; and to explore the relationship between fulfillment of expectations and parental visit-specific satisfaction. DESIGN: Previsit and postvisit survey of parents and postvisit survey of physicians. SETTING: Two private pediatric practices, one community based and one university based. PARTICIPANTS: Ten physicians (response rate = 77%), and a consecutive sample of 306 eligible parents (response rate = 86%) who were attending sick visits for their children between October 1996 and March 1997. Parents were screened for eligibility in the waiting rooms of the two practices and were invited to participate if they spoke and read English and their child was 2 to 10 years old, had a presenting complaint of ear pain, throat pain, cough, or congestion, was off antimicrobial therapy for the past 2 weeks, and was seeing one of the participating physicians. MAIN OUTCOME MEASURES: Antimicrobial prescribing decision, probability of assigning a bacterial diagnosis, and parental visit-specific satisfaction. RESULTS: Based on multivariate analysis, physicians' perceptions of parental expectations for antimicrobials was the only significant predictor of prescribing antimicrobials for conditions of presumed viral etiology; when physicians thought a parent wanted an antimicrobial, they prescribed them 62% of the time versus 7% of the time when they did not think the parent wanted antimicrobials. However, physician antimicrobial prescribing behavior was not associated with actual parental expectations for receiving antimicrobials. In addition, when physicians thought the parent wanted an antimicrobial, they were also significantly more likely to give a bacterial diagnosis (70% of the time versus 31% of the time). Failure to meet parental expectations regarding communication events during the visit was the only significant predictor of parental satisfaction. Failure to provide expected antimicrobials did not affect satisfaction. CONCLUSIONS: The antibiotic resistance epidemic should lead to immediate replication of this study in a larger more generalizable population. If inaccurate physician perceptions of parent desires for antimicrobials for viral infections are confirmed, then an intervention to change the way physicians acquire this set of perceptions should be undertaken. PMID- 10103292 TI - Factors that predict preexisting colonization with antibiotic-resistant gram negative bacilli in patients admitted to a pediatric intensive care unit. AB - OBJECTIVE: To predict which patients hospitalized in a pediatric intensive care unit (ICU) are colonized with antibiotic-resistant gram-negative rods on admission. METHODS: Consecutive children admitted to a pediatric ICU over a 6 month period were entered into the study. A questionnaire soliciting information regarding the child's medical history and home environment was completed by the parent or guardian. Nasopharyngeal and rectal cultures were obtained on each of the first 3 days of ICU admission, and organisms resistant to ceftazidime or tobramycin were identified. Only clonally distinct organisms, as confirmed by pulsed field gel electrophoresis, were analyzed. The association between identification of colonization with an antibiotic-resistant gram-negative rod within 3 days of ICU admission and factors included in the questionnaire was tested by chi2 or t test. RESULTS. In 64 (8.8%) of 727 admissions, an antibiotic resistant gram-negative bacillus was isolated within the first 3 ICU days. More than half were identified on the day of admission. Colonization was associated with two factors related to the patient's medical history, namely, number of past ICU admissions (1.98 vs.87) and administration of intravenous antibiotics within the past 12 months (67.9% vs 28.2%). No association was found between colonization and exposure to oral antibiotics. In addition, factors related to the child's environment were also associated with presumed importation of an antibiotic-resistant gram-negative rod into the ICU. Specifically, residence in a chronic care facility was strongly associated with colonization (28.3% vs 2.6%); exposure to a household contact who had been hospitalized in the past 12 months also predicted colonization (41.7% vs 18.5%). CONCLUSIONS: These data suggest that a profile can be established characterizing children colonized with resistant gram-negative bacilli before admission to a pediatric ICU. Infection control measures may help to contain these potentially dangerous bacteria once they have been introduced into the unit. PMID- 10103293 TI - Cerebral magnetic resonance imaging and ultrasonography findings after neonatal hypoglycemia. AB - OBJECTIVE: The aim of this study was to investigate sequential neuroradiologic changes in the brains of infants after transient neonatal hypoglycemia. We used magnetic resonance imaging (MRI) and ultrasonography (US) head scans. METHODS: Eighteen symptomatic full-term infants whose serum glucose concentrations were 12 months of age were eligible if they were to be treated according to a standardized ED protocol for acute asthma with nebulized albuterol (2.5 mg/dose if weight <30 kg, otherwise 5 mg/dose) and oral prednisone or prednisolone (2 mg/kg up to 80 mg). Subjects were randomized to receive either ipratropium (250 microg/dose) or normal saline (1 mL/dose) with each of the first three nebulized albuterol doses. Further treatment after the first hour was determined by physicians blinded to subject group assignment. Records were reviewed to determine the length of time to discharge home from the ED, number of doses of albuterol given before discharge, and the number of patients admitted to the hospital. RESULTS: Four hundred twenty-seven patients were randomized to ipratropium or control groups; these groups were similar in all baseline measures. Among patients discharged from the ED, ipratropium group subjects had 13% shorter treatment time (mean, 185 minutes, vs control, 213 minutes) and fewer total albuterol doses (median, three, vs control, four). Admission rates did not differ significantly (18%, vs control, 22%). CONCLUSIONS: The addition of three doses of ipratropium to an ED treatment protocol for acute asthma was associated with reductions in duration and amount of treatment before discharge. PMID- 10103298 TI - Day care centers and respiratory health. AB - OBJECTIVE: To estimate the effects of the type of day care on respiratory health in preschool children. METHODS: A population-based cross-sectional study of Oslo children born in 1992 was conducted at the end of 1996. A self-administered questionnaire inquired about day care arrangements, children's health, environmental conditions, and family characteristics (n = 3853; response rate, 79%). RESULTS: In logistic regression controlling for confounding, children in day care centers had more often nightly cough (adjusted odds ratio, 1.89; 95% confidence interval, 1.34-2. 67), and blocked or runny nose without common cold (1.55; 1.07-1.61) during the past 12 months compared with children in home care. Poisson regression analysis showed an increased risk of the common cold (incidence rate ratio, 1.21; 1.12-1.30) and otitis media (1.48; 1.22-1.80), and the attributable proportion was 17.4% (95% confidence interval, 10.7-23.1) for the common cold and 32.4% (18. 0-44.4) for otitis media. Early starting age in the day care center increased the risk of developing recurrent otitis media. Also the lifetime risk of doctor-diagnosed asthma was higher in children who started day care center attendance during the first 2 years of life. CONCLUSIONS: Attendance to day care centers increases the risk of upper respiratory symptoms and infections in 3- to 5-year-old children. The starting age seems to be an important determinant of recurrent otitis media as well as asthma. The effect of day care center attendance on asthma is limited to age up to 2 years. This effect is most likely mediated via early respiratory tract infections that are substantially more common in children in day care centers compared with children in home care. PMID- 10103299 TI - Atypical chronic lung disease patterns in neonates. AB - OBJECTIVE: To determine, in the postsurfactant era, the incidence and clinical characteristics of infants with atypical versus traditionally defined bronchopulmonary dysplasia (BPD) among premature infants with birth weights <1251 g. DESIGN: Retrospective cohort study. SETTING: A single regional neonatal intensive care unit (level III/IV). PATIENTS: Two hundred thirty-two premature infants <1251 g at birth consecutively admitted during a 2-year period. MAIN OUTCOME MEASURE: Incidence of classic BPD and atypical chronic lung disease (CLD) (occurring without preceding respiratory distress or after recovery from respiratory distress). RESULTS: Among 177 infants <1251 g who survived to 28 days, 27 (15%) had atypical CLD and 61 (34.5%) had classic BPD. Atypical CLD infants were significantly heavier and more mature than classic BPD infants (mean birth weights, 922 +/- 152 g vs 854 +/- 173 g; and mean gestational age, 26.8 +/- 1.3 weeks vs 26.1 +/- 1.6 weeks). Median duration of ventilator support (31 days; range, 2 to 127 vs 42 days; range, 4-145 days) and oxygen therapy (30 days; range, 11 to 163 vs 48 days; range, 19-180 days) were shorter in atypical CLD infants than in classic BPD infants. CONCLUSION: Atypical CLD comprised 31% of total cases of CLD. Atypical CLD appears to be less severe than classic BPD. These data suggest that initial, acute lung injuries are not the sole antecedents of neonatal CLD. PMID- 10103300 TI - Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. AB - OBJECTIVES: To evaluate the relationship between the severity of necrotizing enterocolitis (NEC) and circulating concentrations of proinflammatory cytokines interleukin (IL)-1beta and IL-8 and counterinflammatory cytokines IL-1 receptor antagonist (IL-1ra) and IL-10. These cytokines have been associated with bowel injury or inflammation and may be released more slowly or later than previously examined cytokines. Also, to determine if any one of these cytokines will predict the eventual severity of NEC when measured at symptom onset. METHOD: Serial blood samples at onset, 8, 24, 48, and 72 hours were obtained from newborn infants with predefined signs and symptoms of NEC. Normal levels were defined from weight-, gestation-, and age-matched controls. Concentrations of the four cytokines were determined by enzyme-linked immunosorbent assay and compared throughout the time period by stage of NEC, using sepsis as a co-factor. Mean concentrations of each cytokine at onset were compared with the controls. Threshold values were obtained with the best combination of high sensitivity and high specificity for defining stage 1 NEC or for diagnosing stage 3 NEC at onset. RESULTS: There were 12 cases of stage 1, 18 cases of stage 2, and 6 cases of stage 3 NEC included in the study, as well as 20 control infants. Concentrations of IL-8 and IL-10 were significantly higher in infants with stage 3 NEC from onset through 24 hours compared with infants with less severe NEC. At onset, concentrations of all four cytokines were significantly higher in stage 3 NEC. To identify, at onset, the infants with a final diagnosis of stage 3 NEC, an IL-1ra concentration of >130 000 pg/mL had a sensitivity of 100% and a specificity of 92%. At 8 hours, an IL 10 concentration of >250 pg/mL had a sensitivity of 100% and a specificity of 90% in identifying stage 3 NEC in infants with symptoms suggestive of NEC at onset. CONCLUSIONS: The severity of NEC and its systemic signs and symptoms are not due to a deficiency of counterregulatory cytokines. In fact, mean concentrations of IL-1ra in NEC are higher than what has been reported in other populations. The cytokines IL-8, IL-1ra, and IL-10 are released later or more slowly after a stimulus and may be more useful in identifying, within hours of symptom onset, which infant will develop significant NEC. PMID- 10103301 TI - Primary prevention of childhood lead exposure: A randomized trial of dust control. AB - BACKGROUND: Dust control is recommended as one of the primary strategies to prevent or control children's exposure to residential lead hazards, but the effect of dust control on children's blood lead levels is poorly understood. OBJECTIVE: To determine the effectiveness of dust control in preventing children's exposure to lead, as measured by blood lead levels, during their peak age of susceptibility. DESIGN: A randomized, controlled trial. SETTING: Rochester, NY. PARTICIPANTS: A total of 275 urban children were randomized at 6 months of age, of whom 246 (90%) were available for the 24-month-old follow-up visit. INTERVENTIONS: Children and their families were randomly assigned to an intervention group (n = 140), which received cleaning equipment and up to eight visits by a dust control advisor, or a control group (n = 135). OUTCOME MEASURES: Geometric mean blood lead levels and prevalence of elevated blood lead levels (ie, >10 microg/dL, 15 microg/dL, and 20 microg/dL). RESULTS: At baseline, children's geometric mean blood lead levels were 2.9 microg/dL (95% confidence interval [CI] = 2.7, 3.1); there were no significant differences in characteristics or lead exposure by group assignment, with the exception of water lead levels. For children in the intervention group, the mean number of visits by a dust control advisor during the 18-month study period was 6.2; 51 (36%) had 4 to 7 visits, and 69 (49%) had 8 visits. At 24 months of age, the geometric mean blood lead was 7.3 microg/dL (95% CI = 6.6, 8.2) for the intervention group and 7.8 microg/dL (95% CI = 6.9, 8. 7) for the control group. The percentage of children with a 24-month blood lead >/=10 microg/dL, >/=15 microg/dL, and >/=20 microg/dL was 31% versus 36%, 12% versus 14%, and 5% versus 7% in the intervention and control groups, respectively. CONCLUSIONS: We conclude that dust control, as performed by families and in the absence of lead hazard controls to reduce ongoing contamination from lead-based paint, is not effective in the primary prevention of childhood lead exposure. PMID- 10103302 TI - Vagal nerve stimulation in epileptic encephalopathies. AB - OBJECTIVE: To study the effect of vagal nerve stimulation (VNS) in children with epileptic encephalopathies. METHODS AND MATERIALS: All children receiving VNS during a 2-year period at our center were studied prospectively for changes in seizure frequency, electroencephalogram (EEG), adaptive behavior, quality of life, and where appropriate, verbal/nonverbal performance. Assessments were made before and for at least 1 year after implant. RESULTS: Sixteen children were studied. One device was removed because of infection. Of the remaining 15 children, 4 had a >50% reduction and 2 had a >50% increase in seizure frequency at 1 year after implant. Median reduction in seizure frequency was 17%. There was no trend toward improvement of the EEG or adaptive behavior. Quality of life was unchanged in most areas, except in perceived treatment side effects and general behavior that were improved. In 6 children undergoing further assessment, there was a significant improvement in verbal performance; this did not correlate with reduction in seizure frequency. CONCLUSION: VNS did not significantly improve seizure frequency, severity, adaptive behavior, or the EEG during the first year of treatment for the group as a whole, although 4 children (27%) had a worthwhile reduction in seizure frequency. There were significant improvements in perceived treatment side effects and general behavior. PMID- 10103303 TI - A case-control study of necrotizing fasciitis during primary varicella. AB - OBJECTIVE: An increase in the incidence of necrotizing fasciitis (NF) occurring in previously healthy children with primary varicella was noted in the Washington State area between December 1993 and June 1995. Our objective was to investigate ibuprofen use and other risk factors for NF in the setting of primary varicella. METHODS: Case-control study. Demographic information, clinical parameters, and potential risk factors for NF were compared for cases and controls. Cases of NF were analyzed to identify potential determinants of NF complicated by renal insufficiency and/or streptococcal toxic shock syndrome. Multivariate logistic regression was used to evaluate the association between ibuprofen use and NF. A case was defined as a child with NF hospitalized within 3 weeks of primary varicella (n = 19). Controls were children hospitalized with a soft tissue infection other than NF within 3 weeks of primary varicella (n = 29). Odds ratios (ORs) of ibuprofen, as well as other potential risk factors were evaluated. In addition, demographic and clinical data as well as other potential risk factors were compared between cases and controls. RESULTS: After controlling for gender, age, and group A streptococcus isolation, cases were more likely than controls to have used ibuprofen before hospitalization (OR, 11. 5; 95% confidence interval, 1.4 to 96.9). In most children, ibuprofen was initiated after the onset of symptoms of secondary infection. Children with NF complicated by renal insufficiency and/or streptococcal toxic shock syndrome were more likely than children with uncomplicated NF to have used ibuprofen (OR, 16.0; 95% confidence interval, 1.0 to 825.0). Children with complicated NF also had a higher mean maximum temperature (40.9 degrees C vs 39.3 degrees C), and a longer mean duration of secondary symptoms (1.7 days vs 0.6 days) before admission than children with uncomplicated NF. CONCLUSION: Ibuprofen use was associated with NF in the setting of primary varicella. Additional studies are needed to establish whether ibuprofen use has a causal role in the development of NF and its complications during varicella. PMID- 10103304 TI - Neurocognitive sequelae of scaphocephaly. AB - OBJECTIVE: Early cranioplasty for scaphocephaly has become routine in most countries. In addition to normalizing the shape of the skull, it has been found to decrease intracranial hypertension. Whether corrective surgery benefits the child's cognitive outcome has been poorly documented. DESIGN: Eighteen children whose sagittal suture showed premature fusion at birth or soon thereafter were operated on at age 1 week to 7 months. All patients healed without complications and were followed-up at regular intervals. At the age of 7.8 to 16.3 years they were examined to clarify their neurocognitive development and to compare the results with their age- and gender-matched healthy controls. RESULTS: Originally scaphocephalic children, although operated on, had mild deficiencies in auditory short-term memory and language development when examined with the general comprehension, similarities, and digit span subscales of the Wechsler Intelligence Scale for Children-Revised. In all other respects their developmental outcome was equal to that of the controls. CONCLUSIONS: Despite relative early correction of the skull shape, originally scaphocephalic children's neurocognitive performances do not reach the same level in all of the neurocognitive domains as their matched controls at school age. Early operation (/=38.5 degrees C or complaint of vomiting, diarrhea, or decreased oral intake. The assessments were done during three periods: September 1997 through December 1997 (control), January 1998 through March 1998 (intervention), and April 1998 (washout). In the control and washout periods, physicians noted tests ordered on a list attached to each chart. In the intervention period, physicians noted tests ordered on a similar list that included standard hospital charges for each test. Records of each visit were reviewed to determine clinical and demographic information as well as patient disposition. In the control and intervention periods, families of nonadmitted patients were interviewed by telephone 7 days after the visit. RESULTS: When controlled for triage level, vital signs, and admission rates, in a multivariate model, charges for tests in the intervention period were 27% less than charges in the control period. The greatest decrease was seen among low-acuity, nonadmitted patients (43%). In telephone follow-up, patients in the intervention period were slightly more likely to have made an unscheduled follow-up visit to a health care provider (24.4% vs 17.8%), but did not differ on improved condition (86.7% vs 83.4%) or family satisfaction (93.8% vs 93.0%). Adjusted charges in the washout period were 15% lower than in the control period and 15% higher than in the intervention period. CONCLUSION: Providing price information was associated with a significant reduction in charges for tests ordered on pediatric ED patients with acute illness not requiring admission. This decrease was associated with a slightly higher rate of unscheduled follow-up, but no difference in subjective outcomes or family satisfaction. PMID- 10103326 TI - Pediatric injury control in 1999: where do we go from here? PMID- 10103327 TI - Immunization performance measurement in a changing immunization environment. AB - OBJECTIVE: The measurement of performance in the delivery of recommended vaccinations for children is used frequently as a marker for quality of care and as an outcome for studies of interventions to improve immunization coverage levels. The critical element of immunization performance measurement is the determination of immunization status. This methodologic review 1) discusses immunization status as a measure of quality of primary care for children, 2) describes immunization status measures used in immunization intervention studies, and 3) examines selected technical issues of immunization status measurement. METHODS AND TOPICS: 1) Description of the characteristics of immunization status measurements obtained by a systematic review of studies published between 1980 and 1997 on interventions to raise immunization coverage, and 2) illustration of technical considerations for immunization status measurement using one local database and one national database of immunization histories. Technical issues for immunization status measurement include 1) the need to use documented immunization histories rather than parental recall to determine immunization status, 2) the need to link records across providers to obtain complete records, 3) the sensitivity of immunization status to missing immunization data, and 4) the potential of measures incorporating combinations of immunizations to underestimate the degree of vaccination in a population. CONCLUSIONS: Immunization performance measurement has many characteristics of a robust quality of care measure, including high acceptance by primary care providers of routine vaccination, association of immunization status with the conduct of other clinical preventive services, agreed-on technical and programmatic standards of care, and legislative requirements for medical record documentation. However, it is not without challenges. Careful attention to technical issues has potential to improve immunization delivery health services research. PMID- 10103328 TI - Clerkship curricular revision based on the Ambulatory Pediatric Association and the Council on Medical Student Education in Pediatrics guidelines: does it make a difference? AB - OBJECTIVE: To compare general pediatric knowledge acquisition and clinical problem-solving skills by students pre- and postcurricular reform based on the 1994 Ambulatory Pediatric Association and the Council on Medical Student Education in Pediatrics (APA-COMSEP) curricular guidelines. SETTING: A large, urban academic medical center. SUBJECTS: Third-year medical students on a required clerkship in Pediatrics. INTERVENTION: Pre- and postcurricular revision, the students were given both the National Board of Medical Examiners (NBME) Pediatric Subject Examination and an objective examination, which was developed in-house, based on the APA-COMSEP guidelines (Pediatric Clerkship Examination [PCE]). Baseline data before curricular revision were obtained on 52 students from May 1995 to May 1996. After curricular redesign in May 1996, data were obtained on 42 students from May 1996 to May 1997. Curricular revision focused on the following: defining educational principles, selecting teaching strategies, defining learning objectives, implementing the curriculum, and evaluating the students with an examination. RESULTS: Before curricular revision, the average NBME score was 521 +/- 122. The average PCE score was 53.7% +/- 10.1%. After curricular revision, the average NBME score was 520 +/- 109, and the average PCE score was 67.7% +/- 8.4%. Content areas showing the greatest improvement were fluids and electrolytes, issues pertaining to the newborn, and health supervision. CONCLUSIONS: Our baseline data indicate that despite spending two thirds of the clerkship in the ambulatory setting, students did not acquire adequate general pediatric knowledge or clinical problem-solving ability. After broad clerkship revision based on the APA-COMSEP Core Curriculum, students' acquisition of general pediatric knowledge and clinical problem-solving improved significantly, as measured by the PCE. The overall NBME Pediatric Subject Examination scores did not reflect this increased acquisition of general pediatric knowledge. PMID- 10103330 TI - 1999 annual meeting of the ambulatory pediatric association PMID- 10103329 TI - Holistic pediatrics: a research agenda. AB - Increasing numbers of American families seek complementary and alternative medical care (CAM) for their children; at the same time health care organization and financing are undergoing radical changes. The combination of these factors provides a powerful incentive for research on the effectiveness and safety of CAM therapies and their role in treating children. This article describes a rationale, spectrum, priorities, and methodologies for a research agenda in holistic pediatrics. The top priorities are clinical research projects addressing the safety and effectiveness of alternative therapies used for vulnerable children suffering from serious illnesses. Additionally, major research questions involve the impact of the various definitions such as "alternative," "complementary," "folk," "integrative," and "holistic" medicine on perceptions of health care, professional education, and funding of products and services. Research efforts in alternative therapies need to address explicitly the tremendous heterogeneity between and among the practices, beliefs, and providers of professional and lay services. Qualitative ethnographic research is needed to understand the consequences of diverse explanatory models and meanings of health and illness for patient-provider communication, adherence with professional recommendations, and satisfaction with care. Health services researchers need to address questions related to the epidemiology of CAM practices, health manpower issues, practice characteristics and the process and content of health care and how discoveries about CAM care may enhance the quality of mainstream health services. A rationale is provided for prioritizing certain conditions and therapies within these efforts. PMID- 10103331 TI - Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. AB - OBJECTIVES: To describe the epidemiology of nosocomial infections in pediatric intensive care units (ICUs) in the United States. BACKGROUND: Patient and ICU characteristics in pediatric ICUs suggest the pattern of nosocomial infections experienced may differ from that seen in adult ICUs. METHODS: Data were collected between January 1992 and December 1997 from 61 pediatric ICUs in the United States using the standard surveillance protocols and nosocomial infection site definitions of the National Nosocomial Infections Surveillance System's ICU surveillance component. RESULTS: Data on 110 709 patients with 6290 nosocomial infections were analyzed. Primary bloodstream infections (28%), pneumonia (21%), and urinary tract infections (15%) were most frequent and were almost always associated with use of an invasive device. Primary bloodstream infections and surgical site infections were reported more frequently in infants aged 2 months or less as compared with older children. Urinary tract infections were reported more frequently in children >5 years old compared with younger children. Coagulase-negative staphylococci (38%) were the most common bloodstream isolates, and aerobic Gram-negative bacilli were reported in 25% of primary bloodstream infections. Pseudomonas aeruginosa (22%) was the most common species reported from pneumonia and Escherichia coli (19%), from urinary tract infections. Enterobacter spp. were isolated with increasing frequency from pneumonia and were the most common Gram-negative isolates from bloodstream infections. Device associated infection rates for bloodstream infections, pneumonia, and urinary tract infections did not correlate with length of stay, the number of hospital beds, or season. CONCLUSIONS: In pediatric ICUs, bloodstream infections were the most common nosocomial infection. The distribution of infection sites and pathogens differed with age and from that reported from adult ICUs. Device associated infection rates were the best rates currently available for comparisons between units, because they were not associated with length of stay, the number of beds in the hospital, or season. PMID- 10103332 TI - Primary care physicians' use of screening echocardiography. AB - OBJECTIVE: To survey primary care physicians to understand their reasons for using echocardiography to screen for congenital heart disease in children and to assess their understanding of the costs associated with cardiology services. DESIGN: A questionnaire. PARTICIPANTS: Eight hundred sixty-seven pediatricians and family physicians in our region were surveyed, 494 (57%) responded and 466 were used for the analysis. RESULTS: The majority of pediatricians and family physicians in our area do not know the relative costs associated with cardiology consultation and echocardiography. They also believe it likely that a cardiologist will routinely obtain an echocardiogram as part of their evaluation of a child with a murmur, although this is not the case. The availability and convenience of specialist appointments was found to significantly influence the decision to order an echocardiogram. Family physicians were significantly more likely than pediatricians to order an echocardiogram for a variety of clinical indications. CONCLUSIONS: Improving primary care physicians' knowledge of the costs associated with cardiology services and current cardiology practice patterns, in addition to improving the availability of cardiology referrals, may reduce the number of expensive and unnecessary echocardiograms. echocardiography, heart murmur, congenital heart disease, cost-effectiveness. PMID- 10103333 TI - Cranial ultrasound abnormalities identified at birth: their relationship to perinatal risk and neurobehavioral outcome. AB - OBJECTIVES: Minor cranial ultrasound abnormalities, such as mild ventricular enlargement, choroid plexus cysts, and subependymal cysts, have been identified in 3% to 5% of the newborn population. Although clinicians generally consider these abnormalities to be insignificant for the outcome of the newborn, few convincing data have been published to support this optimism. The objectives of this study were to identify potential risk factors associated with the identification of cranial ultrasound abnormalities at birth and to determine if the abnormalities were related to neurobehavioral sequelae in the newborn. METHODS: Three hundred eight women were enrolled in this prospective, longitudinal maternal-infant health and development study either at the time they entered the public health care system for prenatal care or at delivery if they had no prenatal care. Each woman participated in an in-depth psychosocial interview at the end of each trimester of pregnancy. Retrospective chart review by experienced medical personnel was used to compile data for the Hobel perinatal risk score for each study participant after delivery. Offspring underwent cranial ultrasound evaluation, the Amiel-Tison Neurologic Assessment, and the Brazelton Neonatal Behavioral Assessment Scale within 96 hours of birth by experienced examiners blinded to any maternal-infant history. RESULTS: Of the 308 women originally enrolled in the study, 301 delivered living infants. Of these, 266 infants (88%) underwent a cranial ultrasound evaluation and are the subject of this article. For the purposes of the current study, infants were divided into those with normal (n = 239) and those with abnormal (n = 27) ultrasound results. Abnormal ultrasound results included the following lesions: subependymal cyst (n = 13); mild ventricular enlargement (n = 6); choroid plexus cysts (n = 3); a combination of cysts and increased ventricular size (n = 2); a 7-mm midline cyst in the superior posterior portion of the third ventricle (n = 1); subependymal hemorrhage and ventricular enlargement (n = 1); and increased ventricular size, subependymal hemorrhage and cysts, and two small, right thalamic calcifications (n = 1). There were no significant differences between those with an abnormal ultrasound and those with a normal ultrasound for birth weight, length, gestational age, rate of prematurity, frequency of nulliparity, or frequency of small for gestational age infants. However, infants with an abnormal ultrasound had a significantly smaller mean head circumference than those with a normal ultrasound (34.5 +/- 1.9 cm vs 33.7 +/- 1.9 cm). The infants with an abnormal ultrasound had a higher median prenatal (50 vs 45), neonatal (14 vs 8), and total (94 vs 77) Hobel risk score but not a higher labor-delivery score. There were no significant differences when these groups were compared on additional risk factors not included in the Hobel scoring system such as race and socioeconomic status. In addition, mothers who used a greater number of drugs during the first trimester of pregnancy were more likely to have an infant with an abnormal ultrasound at birth such that the probability of having an abnormal ultrasound rose to 22% by the time the pregnant women were using four drugs. Neurologic examinations revealed no differences between the infants with normal and abnormal ultrasounds. There were also no group differences for five of the seven Brazelton cluster scores, the excitable or depressed clusters, or eight of the nine qualifier scores. However, infants with abnormal ultrasounds performed significantly better on the habituation (7.3 +/- 0.8 vs 6.6 +/- 1.5) and autonomic regulation (6.5 +/- 0.8 vs 6.0 +/- 1.0) clusters but more poorly on the cost of attention qualifier score (4.9 +/- 1.2 vs 5.5 +/- 1.2) on the Brazelton Neonatal Behavioral Assessment Scale. CONCLUSION: Infants with an abnormal cranial ultrasound at birth had higher perinatal risk scores. (ABSTRACT TRUNCATED) PMID- 10103334 TI - Zinc supplementation in malnourished children with persistent diarrhea in Pakistan. AB - OBJECTIVE: To evaluate the potential benefit of dietary supplementation of a rice lentil (Khitchri) and yogurt diet with 3 mg/kg/d of elemental zinc (as zinc sulfate) in hospitalized malnourished children (age 6-36 months) with persistent diarrhea for 14 days. METHODOLOGY: Randomized, double-blind placebo-controlled trial. SETTING: Nutrition Research Ward at the National Institute of Child Health, Karachi, Pakistan, where children were admitted for 14 days of inpatient supervised rehabilitation. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: overall weight gain by day 14. SECONDARY OUTCOMES: overall energy intake, stool output, time to diarrheal recovery and weight gain (>/=3 days), plasma zinc, copper, prealbumin, and insulin-like growth factor-1. RESULTS: Of 87 children randomized for supplementation with either zinc or placebo, the two groups were comparable at admission in terms of severity and duration of diarrhea, as well as nutritional and anthropometric parameters. The overall weight gain, stool volume, stool frequency, as well as the time taken for diarrheal recovery or steady weight gain, were comparable for both supplemented children and controls. Supplemented children had a significant improvement in plasma zinc levels and serum alkaline phosphatase by day 14 of therapy in comparison with controls. Plasma copper levels were low in both groups at admission and although an increase was seen in control children, levels decreased further after zinc supplementation. There was no significant difference between the two groups for hemoglobin, serum albumin, prealbumin, and plasma insulin-like growth factor-1 increments during the course of therapy. Evaluation of primary and secondary outcome criteria among the subset of children with plasma zinc levels <60 microg/d at admission did not reveal any significant differences. CONCLUSIONS: Although there was satisfactory recovery in malnourished children with persistent diarrhea receiving the Khitchri-yogurt diet, there was no evidence of improved weight gain or acceleration of recovery from diarrhea with zinc supplementation. In contrast, the reduction in plasma copper levels in zinc-supplemented malnourished children suggests that caution should be exercised in supplementing severely malnourished children with zinc alone. PMID- 10103336 TI - Thalidomide in children undergoing bone marrow transplantation: series at a single institution and review of the literature. AB - Thalidomide has one of the most notorious drug histories because of its teratogenicity. Its widespread use in the 1960s led to a worldwide epidemic of phocomelia in inborns; this in turn led to its complete ban in most of the world. However, it has now been licensed for selected indications including graft-versus host-disease (GVHD) after bone marrow transplantation, wasting associated with tuberculosis and human immunodeficiency virus infection, and leprosy. Little is known, however, about its use in children in these settings. Therefore, we report our experience and review the literature on thalidomide in children for GVHD after bone marrow transplantation. We studied 6 patients, 2 with chronic GVHD, 2 with acute GVHD, and 2 with acute GVHD progressing into chronic disease. One patient with chronic GVHD had a complete response, whereas the other had a partial response. Side effects consisted primarily of sedation and constipation, which are reported previously and well known side effects. None had neuropathy. One patient had rash, eosinophilia, and early pancreatitis that began shortly after initiation of thalidomide, persisted, and resolved only after discontinuation of thalidomide. Eosinophilia and pancreatitis are both previously unreported side effects or associated findings of thalidomide treatment. Review of the literature reveals three major studies of thalidomide in GVHD; of these two included children and adults together, and one in which age range of patients was not mentioned. In addition, four series of children receiving only thalidomide are reported. These series contained 1 to 14 patients each. Results show efficacy in at least 50% of children with chronic GVHD and little or no efficacy in children with exclusively acute GVHD. Side effects are similar to those reported in adults and consisted mostly of sedation and constipation, both of which subsided over time and resolved after discontinuing the drug. We speculate on the reasons for which thalidomide is more effective in chronic, compared with acute, GVHD in children, and make recommendations for future study. PMID- 10103335 TI - A comparison of ritalin and adderall: efficacy and time-course in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Very little research has focused on the efficacy of Adderall (Shire Richwood Inc, Florence, KY) in the treatment of children with attention deficit/hyperactivity disorder (ADHD), and no studies have compared it with standardized doses of Ritalin (Novartis Pharmaceuticals, East Hanover, NJ). It is thought that Adderall has a longer half-life than Ritalin and might minimize the loss of efficacy that occurs 4 or 5 hours after Ritalin ingestion. We compared two doses of Ritalin and Adderall in the treatment of ADHD in children in an acute study and assessed the medications' time courses. DESIGN: Within-subject, double-blind, placebo-controlled, crossover design lasting 6 weeks. As in our previous work, medication changes occurred on a daily basis in random order over days. SETTING: Eight-week, weekday (9 hours daily) summer treatment program at the State University of New York at Buffalo, using an intensive behavioral treatment program including a point system and parent training. STUDY PARTICIPANTS: Twenty-five children (21 boys and 4 girls) diagnosed as ADHD using standardized structured interview and rating scales, mean age 9.6 years, 88% Caucasian, of average intelligence, with no medical conditions that would preclude a trial of stimulant medication. Thirteen were comorbid for oppositional defiant disorder and another 8 for conduct disorder. INTERVENTIONS: Children received 10 mg of Ritalin, 17.5 mg of Ritalin, 7.5 mg of Adderall, 12.5 mg of Adderall, or placebo, twice a day (7:45 AM and 12:15 PM), in random order with conditions changing daily for 24 days. OUTCOME MEASURES: Daily rates of behaviors in recreational and classroom settings, and standardized ratings from counselors, teachers, and parents, were averaged across days within condition within child and compared. Within-subject relative sizes of the medication effects were computed by taking the placebo-minus-drug mean difference divided by the placebo standard deviation for each child, and were compared hourly between first daily ingestion (7:45 AM) and 5:00 PM to assess the time course of the two drugs. Measures were taken at 12:00 PM (recess rule violations) and at 5:00 PM (parent behavior ratings) to determine whether Adderall was still effective at times when the effects of Ritalin should have worn off. Parent ratings were also made for evening behavior to assess possible rebound, and side effects ratings were obtained from parents, counselors, and teachers. Parents, counselors, and teachers also rated their perceptions of medication status and whether they recommended the continued use of the medication given that day. Finally, a clinical team made recommendations for treatment taking into account each child's individual response. RESULTS: Both drugs were routinely superior to placebo and produced dramatic improvements in rates of negative behavior, academic productivity, and staff/parent ratings of behavior. The doses of Adderall that were assessed produced greater improvement than did the assessed doses of Ritalin, particularly the lower dose of Ritalin, on numerous but not all measures. This result suggests that the doses of Adderall used were functionally more potent than those for Ritalin. Adderall was generally superior to the low dose of Ritalin when the effects of Ritalin were wearing off at midday and late afternoon/early evening. The lower dose of Adderall produced effects comparable to those of the higher dose of Ritalin. Both drugs produced low and comparable levels of clinically significant side effects. Staff clinical recommendations for continued medication favored Adderall three to one. Almost 25% of the study participants were judged to be nonresponders by the clinical team, presumably because of their large beneficial response to the concurrent behavioral intervention and minimal incremental benefit from medication. CONCLUSIONS: This is the first investigation to assess comparable doses of Adderall and Ritalin directly. (ABSTRACT TRU PMID- 10103337 TI - Pediatricians' response to the demand for school health programming. AB - OBJECTIVE: Because of the broad and increasing interest in school health, the American Academy of Pediatrics (AAP) surveyed its members to determine their awareness of school health education/programs, their level of participation, their desire to participate, and their resource needs to participate more effectively. METHODS: Self-administered questionnaires were mailed to a randomized representative sample of AAP members (N = 1602). Overall response rate was 64.5%. Some responses were stratified for analysis by gender; age (>45 years or 70% wanted to become involved or more involved and needed information on how they may be able to participate. Only 25% believed they were adequately prepared. Two thirds believed school-based clinics were one of the best ways to reach underserved children and adolescents and should include preteens. CONCLUSION: AAP pediatricians want to become more involved with comprehensive school health programs. The ways in which they want to participate vary substantially. Most pediatricians thought they needed additional education. The AAP has developed recommendations for graduate medical education and continuing medical education for pediatricians to participate in integrated school health services. PMID- 10103338 TI - Variability in physician opinion on limiting pediatric life support. AB - OBJECTIVE: We conducted this study to investigate how physicians in a pediatric intensive care unit (ICU) currently make decisions to withdraw and withhold life support. Consultation with the patient's primary caregiver often precedes decisions about withdrawal and limitation of life support in chronically ill patients. In these scenarios, the patient's primary caregiver was the pediatric oncologist. To evaluate the influence of subspecialty training, we compared the attitudes of the pediatric intensivists and the oncologists using scenarios describing critically ill oncology patients. DESIGN: Cross-sectional survey. Each physician was randomly assigned 4 of 8 potential case scenarios. SETTING: A total of 29 American pediatric ICUs. PARTICIPANTS: Pediatric intensive care and oncology attendings and fellows. INTERVENTION: Systematic manipulation of patient characteristics in two hypothetical case scenarios describing 6-year-old female oncology patients presenting to the ICU after the institution of mechanical ventilator support for acute respiratory failure. Cases 1 through 4 described a patient who, before admission, had a 99% projected 1-year probability of survival from her underlying cancer and suffered from severe neurologic disabilities. Cases 5 through 8 described a patient who was neurologically normal before admission and had a <1% chance of surviving longer than 1 year because of her underlying cancer. Each physician was randomly assigned 2 cases from cases 1 through 4 and 2 cases from cases 5 through 8. Within each of these case scenarios, parental preferences (withdraw or advance support or look for guidance from the caregivers) and probability of survival (5% vs 40%) were manipulated. Before distribution, the survey instrument was pilot-tested and underwent a rigorous assessment for clinical sensibility. PRIMARY OUTCOME MEASURES: Physicians ratings of the importance of 10 factors considered in the decision to withdraw life support, and their decisions about the appropriate level of care to provide. Respondents were offered five management options representing five levels of care: 1) discontinue inotropes and mechanical ventilation but continue comfort measures; 2) discontinue inotropes and other maintenance therapy but continue mechanical ventilation and comfort measures; 3) continue with current management but add no new therapeutic intervention; 4) continue with current management, add additional inotropes, change antibiotics and the like as needed, but do not start dialysis; and 5) continue with full aggressive management and plan for dialysis if necessary. Respondents also were asked whether they would obtain an ethics consultation. RESULTS: A total of 270 physicians responded to our survey (165 of 198 potentially eligible pediatric intensivists and 105 of 178 pediatric oncologists for response rates of 83% and 59%, respectively). The respondents considered the probability of ICU survival and the wishes of the parents regarding the aggressiveness of care most important in the decision to limit life-support interventions. No clinically important differences were found when the responses of oncologists were compared with those of intensivists. In six of eight possible scenarios, the same level of intensity of care was chosen by less than half of all respondents. In three scenarios, >/=10% of respondents chose full aggressive management as the most appropriate level of care, whereas another >/=10% chose comfort measures only when viewing the same scenario. The most significant respondent factors affecting choices were professional status (attending vs fellow) and the self-rated importance of functional neurologic status. The majority of respondents (83%) believed that the intensive care and the oncology staff were usually in agreement at their institution about the level of intervention to recommend to the parents. (ABSTRACT TRUNCATED) PMID- 10103339 TI - A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection. AIDS Clinical Trials Group 330 Team. AB - OBJECTIVES: To evaluate the pharmacokinetic features, safety, and tolerance of abacavir, given alone and in combination with other nucleoside antiretroviral agents, in symptomatic human immunodeficiency virus (HIV)-infected children. METHODS: HIV-infected children discontinued prior antiretroviral therapy and were given abacavir orally, 4 mg/kg every 12 hours for 6 weeks, followed by 8 mg/kg every 12 hours for 6 weeks (n = 39); or 8 mg/kg every 12 hours for 12 weeks (n = 8). Children then were randomized to receive a second nucleoside antiretroviral agent (zidovudine, stavudine, didanosine, or lamivudine), plus abacavir. Pharmacokinetics, safety, tolerance, CD4(+) lymphocyte counts, and plasma HIV RNA concentrations were evaluated. RESULTS: At a dose of 8 mg/kg every 12 hours, area under the plasma concentration-versus-time curves and plasma half-life values were comparable with those reported for adults receiving abacavir at a dose of 300 mg twice daily. One case each of hypersensitivity reaction and peripheral neuropathy occurred during abacavir monotherapy. Three children experienced neutropenia while receiving abacavir in combination with another antiretroviral agent. Mean CD4(+) lymphocyte count and plasma HIV RNA concentration did not change when prior antiretroviral therapy was changed to abacavir monotherapy. CONCLUSIONS: Abacavir therapy is associated with good short-term tolerance and safety in HIV-infected children. Phase III studies are in progress to assess the antiviral activity of abacavir in children and adults. PMID- 10103340 TI - Lack of vancomycin-associated nephrotoxicity in newborn infants: a case-control study. AB - OBJECTIVE: The purpose of this study was to compare the incidence of nephrotoxicity, defined as doubling of baseline serum creatinine concentration, in newborn infants with peak vancomycin serum concentrations 40 microg/mL. A secondary objective was to correlate concomitant disease states and potentially nephrotoxic drug therapy with rises in serum creatinine in vancomycin recipients. METHODS: Newborn infants with culture-proven Staphylococcus aureus or coagulase negative staphylococcal septicemia who received vancomycin therapy for >3 days between 1985 and 1995 were identified from an existing database and a review of medical record. All 69 patients included in the study had serial serum creatinine determinations, including a baseline value within 48 hours of starting treatment with vancomycin, and serum vancomycin concentrations determined after at least three doses, with peak and trough concentrations determined 1 hour after a 60 minute infusion and 15 to 30 minutes before a dose, respectively. Infants with congenital renal or cardiac anomalies were excluded. Demographic characteristics, vancomycin dosing regimen, serum vancomycin concentrations and sample times, concomitant drug therapy, and disease states were recorded. Patients were divided into group A (peak vancomycin concentration 40 microg/mL). The change in serum creatinine concentration between the start and end of vancomycin therapy was determined. Nephrotoxicity was identified if serum creatinine doubled at any time from the start to the end of vancomycin therapy. Alternative definitions of nephrotoxicity (any rise in serum creatinine to >0.6 mg/dL or new abnormalities of urine sediment) were used in additional analyses. RESULTS: A total of 69 evaluable patients (gestational age, 28.9 +/- 3.0 weeks; birth weight, 1219 +/- 516 g) were identified, 61 in group A and 8 in group B. Six patients in group A underwent doubling of serum creatinine concentration during vancomycin therapy, whereas none in group B did so. Serum creatinine doubled to >0.6 mg/dL in only 3 infants (all in group A). Any increase in serum creatinine to >0.6 mg/dL was seen in 10 infants, 9 of whom were in group A. No confounding variable, including previous or concomitant underlying disease states associated with renal dysfunction or treatment with other potentially nephrotoxic agents, were associated with a significant rise in serum creatinine. CONCLUSION: Vancomycin-associated nephrotoxicity is rare in neonates, even with serum peak concentrations >40 microg/mL. PMID- 10103341 TI - Why do newborn infants have a high plasma creatinine? AB - BACKGROUND: Plasma creatinine (Pcr) levels at birth are greatly elevated in relation to the size (and the muscle mass) of the newborn infant and remain so for 1 to 2 weeks. Particularly intriguing is the fact that Pcr levels are higher in preterm than in term infants and for a longer postnatal period. The smaller the birth weight, the higher the Pcr. This cannot be explained by maternal transfer of Pcr or by the absolute and relative (to adult body surface area) reduced glomerular filtration rate of the newborn. Perhaps the renal handling of creatinine is involved. DESIGN: In 522 pairs of mothers and fetuses, maternal and fetal Pcr were compared from 16 weeks of gestation until term. Pcr was measured in 66 newborns of various birth weights and followed for 1 month. Creatinine clearance (Ccr) and inulin clearance (Cin) were measured simultaneously in adult (n = 8) and newborn (n = 20) New Zealand White rabbits. In the latter, nephrogenesis continues after birth and they are therefore a good animal model for the study of the renal function in premature infants. PATIENT: A case of a premature male infant is presented (gestation: 29 weeks; birth weight: 1410 g) suspected of having sepsis because of premature rupture of membranes and postpartum maternal fever. This suspicion was not confirmed. Blood chemistry evaluation showed a high Pcr at birth (0.85 mg/dL, 75 micromol/L), even higher than that of the mother (0.77 mg/dL, 68 micromol/L). The Pcr started to decrease after approximately 1 week but remained elevated throughout 1 month of follow-up. RESULTS: From the maternal-fetal Pcr measurements it was quite evident that during the second half of gestation the small molecular weight creatinine (113 dalton, 0.3 nm radius) of the mother and fetus equilibrates at all maternal Pcr levels. The newborn Pcr levels were not only high at the time of birth but remained so for more than 3 weeks. It was also shown that the smaller the infant the higher the Pcr levels. The results of the animal experimental data showed that adult rabbits had the normal physiologic pattern in which Ccr overestimates Cin (Ccr/Cin ratio >1.0). In contrast, the results in the newborn rabbits showed an unexpected underestimation of the Ccr vis-a-vis Cin (Ccr/Cin ratio <1.0). This means, as is explained at length in the "Discussion" of this article, that the preterm newborn infant reabsorbs creatinine along the renal tubule. CONCLUSION: The riddle of the high Pcr levels in term and particularly in preterm newborns seems to be solved. Once the umbilical cord is severed, the perfect intrauterine maternal-fetal biochemical balance is disturbed. Thereafter, the already transferred exogenous, adult-level creatinine will rapidly disappear in the first urine specimens passed by the now autonomous newborn infant. A new steady state is achieved in due time, based on independent neonatal factors. One of these factors is the unusual occurrence of tubular creatinine reabsorption. We hypothesize that this latter temporary phenomenon is attributable to back-flow of creatinine across leaky immature tubular and vascular structures. With time, maturational renal changes will impose a barrier to creatinine. From that point onwards, total body muscle mass, glomerular filtration rate, and tubular secretion will in health determine the Pcr level of the individual. plasma creatinine, tubular handling of creatinine, newborn, premature infants. PMID- 10103342 TI - Anaphylactic reaction to oral cefaclor in a child. AB - Adverse drug reactions are a common clinical problem. It has been estimated that 6% to 15% of hospitalized patients experience some sort of adverse drug reaction. Clinical manifestations of adverse drug reactions include skin rash; a serum sickness-like reaction; drug fever; pulmonary, hepatic, and renal involvement; and systemic anaphylaxis. Many of these adverse events are not immunologically mediated. Actual allergic or immunologic drug reactions probably account for <25% of adverse drug reactions overall. Antibiotics are one of the major contributors to drug hypersensitivity. Cefaclor, an oral second-generation cephalosporin with a beta-lactam ring, is used against various infectious diseases of the respiratory tract, especially in children. Several cases of cefaclor hypersensitivity have been reported. The most common presentations are either erythematous or papular eruptions, although serum sickness-like reactions have also been described. Anaphylactic reactions, although rare, have been observed in adults. Here we report a case of anaphylactic reaction to cefaclor in a 21/2-year old patient. PMID- 10103343 TI - Diagnostic testing unwarranted for children with blood lead 10 to 14 microg/dL. AB - BACKGROUND: Recent statements from the American Academy of Pediatrics and Centers for Disease Control and Prevention recommend diagnostic venous blood lead testing within 90 days of a marginally elevated screening test (10-14 microg/dL). OBJECTIVE: To evaluate the ability of a marginally elevated capillary (CScr) or venous (VScr) blood lead screening test to predict venous diagnostic (VPb) blood lead (taken within 90 days of the screening test) that would prompt environmental evaluation (>/=20 microg/dL). DESIGN: Population-based follow-up study comparing CScr and VScr with VPb drawn within 90 days of the screening sample. This study population was drawn from all children aged 0 to 4 years who were screened in Worcester County, Massachusetts, and Providence County, Rhode Island, with CScr and VScr during calendar year 1994. OUTCOME MEASURES: To evaluate predictive validity, CScr and VScr were correlated with VPb. CScr, VScr, and VPb results were then separated into the following categories: <10, 10 to 14, 15 to 19, and >/=20 microg/dL. CScr and VScr categories were cross-tabulated against VPb categories, and logistic regression analysis was used to evaluate categorical elevations of CScr and VScr as predictors of VPb >/=20 microg/dL. RESULTS: Of 31 904 children screened with CScr, 5450 (17.1%) were elevated and 1278 were followed up with VPb within 90 days. Of 14 623 children screened with VScr, 2979 (20.4%) were elevated and 614 were followed up with VPb within 90 days. CScr was only weakly correlated with VPb (r = 0.39), whereas VScr was more strongly correlated with VPb (r = 0.73). Compared with CScr <10 microg/dL, CScr in the 10 to 14 microg/dL range did not identify a higher percentage of children with VPb elevation in any category, and falsely misclassified as lead poisoned some 77% of children. Compared with VScr <10 microg/dL, VScr in the 10 to 14 microg/dL range identified higher percentages of children with VPb in the 10 to 19 microg/dL range but not with VPb >/=20 microg/dL, and falsely misclassified as lead poisoned 42% of children. Compared with screening tests <10 microg/dL, the odds of identifying a child with VPb >/=20 were no different from 1 for CScr of 10 to 14 microg/dL (adjusted odds ratio 1.4 [95% confidence interval 0.3, 6.6]), CScr of 15 to 19 microg/dL (3.2 [0.7, 15.7]), or VScr of 10 to 14 microg/dL (0.9 [0.3, 3.0]). CScr and VScr in the 15 to 19 microg/dL range were associated with significantly higher odds of having VPb >/=20 microg/dL when compared with screening tests <10 microg/dL. CONCLUSIONS: These data indicate that special diagnostic testing within 90 days for children with CScr and VScr in the 10 to 14 microg/dL range does not result in greater identification of VPb >/=20. Raising the set point for diagnostic testing to 15 microg/dL in this sample would eliminate the unnecessary follow-up of 5162 children, of whom 3360 were falsely misclassified as having undue lead exposure. PMID- 10103344 TI - Intravenous catheter blood cultures: utility and contamination. AB - OBJECTIVE: In pediatrics, blood cultures (BCs) are often drawn as intravenous (IV) catheters are placed. This routine minimizes the number of painful and often difficult punctures a child must undergo but results in the discarding of multiple BC bottles when these cultures are later determined to be unnecessary. If the contamination rate of BCs drawn through an indwelling IV did not exceed the contamination rate of BCs drawn at the time of IV placement, BCs could be drawn from the IV without subjecting the patient to another venipuncture. This study was done to compare the contamination rates of BCs drawn by these two methods. Additionally, we sought to determine if the collection of two BCs enhances pathogen recovery. METHODS: Prospective comparison of contamination and bacteremia rates of BCs drawn by two different methods: the first BC was drawn at the time of IV line placement and the second BC was drawn from the previously placed IV at a later time. Setting. Urban pediatric emergency department with an annual census of 40 000. PARTICIPANTS: One thousand five hundred sixty-four patients between the ages of 3 days and 22.1 years. The median age was 2.2 years. Sixty-four patients were excluded because we were unable to draw the second BC. Forty-six percent of eligible patients (n = 690) were girls. RESULTS: Fifty-seven (1.9%) of 3000 grew contaminants: 27 in the first and 30 in the second BC for contamination rates of 1.8% and 2.0%. Thirty-eight (1.3%) of 3000 BCs grew pathogens: 24 represent 12 patients with growth in two out of two cultures and 14 represent 14 patients with growth in one out of two cultures. Pathogen rates were 1.1% (16/1500) with one BC per patient and 1.7% (22/1500) with two BCs per patient. CONCLUSIONS: There is no difference in the contamination rates of two BCs drawn from the same site at two different times. The collection of two BCs per patient may enhance pathogen recovery. PMID- 10103345 TI - Neonatal necrotizing fasciitis: a report of three cases and review of the literature. AB - OBJECTIVE: Necrotizing fasciitis (NF) is a predominantly adult disorder, with bacterial infection of the soft tissue. In children, it is relatively rare and has a fulminant course with a high mortality rate. In the neonate, most cases of NF are attributable to secondary infection of omphalitis, balanitis, mammitis, postoperative complications, and fetal monitoring. The objective of this communication is to report 3 cases of neonatal NF and provide a literature review of this disorder. RESULTS: This review yielded 66 cases of neonatal NF. Only 3 cases were premature. There was no sex predilection and the condition rarely recurred. Several underlying conditions were identified that might have contributed to the development of neonatal NF. These included omphalitis in 47, mammitis in 5, balanitis in 4, fetal scalp monitoring in 2, necrotizing enterocolitis, immunodeficiency, bullous impetigo, and maternal mastitis in 1 patient each. The most common site of the initial involvement was the abdominal wall (n = 53), followed by the thorax (n = 7), back (n = 2), scalp (n = 2), and extremity (n = 2). The initial skin presentation ranged from minimal rash to erythema, edema, induration or cellulitis. The lesions subsequently spread rapidly. The overlying skin might later develop a violaceous discoloration, peau d'orange appearance, bullae, or necrosis. Crepitus was uncommon. Fever and tachycardia were frequent but not uniformly present. The leukocyte count of the peripheral blood was usually elevated with a shift to the left. Thrombocytopenia was noted in half of the cases. Hypocalcemia was rarely reported. Of the 53 wound cultures available for bacteriologic evaluation, 39 were polymicrobial, 13 were monomicrobial, and 1 was sterile. Blood culture was positive in only 20 cases (50%). Treatment modalities included the use of antibiotics, supportive care, surgical debridement, and drainage of the affected fascial planes. Two of the 6 cases who received hyperbaric oxygen therapy died. The overall mortality rate was 59% (39/66). In 12 cases, skin grafting was required because of poor granulation formation or large postoperative skin defects among the survivors. CONCLUSION: Neonatal NF is an uncommon but often fatal bacterial infection of the skin, subcutaneous fat, superficial fascia, and deep fascia. It is characterized by marked tissue edema, rapid spread of inflammation, and signs of systemic toxicity. The wound cultures are predominantly polymicrobial and the location of initial involvement depends on the underlying etiologic factor. High index of suspicion, prompt aggressive surgery, appropriate antibiotics, and supportive care are the mainstays of management in the newborn infant with NF. PMID- 10103346 TI - Technical report: urinary tract infections in febrile infants and young children. The Urinary Tract Subcommittee of the American Academy of Pediatrics Committee on Quality Improvement. AB - OVERVIEW: The Urinary Tract Subcommittee of the American Academy of Pediatrics Committee on Quality Improvement has analyzed alternative strategies for the diagnosis and management of urinary tract infection (UTI) in children. The target population is limited to children between 2 months and 2 years of age who are examined because of fever without an obvious cause. Diagnosis and management of UTI in this group are especially challenging for these three reasons: 1) the manifestation of UTI tends to be nonspecific, and cases may be missed easily; 2) clean voided midstream urine specimens rarely can be obtained, leaving only urine collection methods that are invasive (transurethral catheterization or bladder tap) or result in nonspecific test results (bag urine); and 3) a substantial number of infants with UTI also may have structural or functional abnormalities of the urinary tract that put them at risk for ongoing renal damage, hypertension, and end-stage renal disease (ESRD). METHODS: To examine alternative management strategies for UTI in infants, a conceptual model of the steps in diagnosis and management of UTI was developed. The model was expanded into a decision tree. Probabilities for branch points in the decision tree were obtained by review of the literature on childhood UTI. Data were extracted on standardized forms. Cost data were obtained by literature review and from hospital billing data. The data were collated into evidence tables. Analysis of the decision tree was used to produce risk tables and incremental cost-effectiveness ratios for alternative strategies. RESULTS: Based on the results of this analysis and, when necessary, consensus opinion, the Committee developed recommendations for the management of UTI in this population. This document provides the evidence the Subcommittee used in the development of its recommendations. CONCLUSIONS: The Subcommittee agreed that the objective of the practice parameter would be to minimize the risk of chronic renal damage within reasonable economic constraints. Steps involved in achieving these objectives are: 1) identifying UTI; 2) short term treatment of UTI; and 3) evaluation for urinary tract abnormalities. PMID- 10103347 TI - Child centered literacy orientation: a form of social capital? AB - OBJECTIVE: To describe the home literacy environment and to identify financial, human, and social capital variables associated with the presence or lack of Child Centered Literacy Orientation (CCLO) in families with young children who regularly attend pediatric primary care clinics. DESIGN: Cross-sectional case control analysis of structured parent interviews conducted in two hospital-based and four community-based pediatric clinics in New England. SUBJECTS: Parents of 199 healthy 1- to 5-year-old children whose mean age was 30 +/- 15 (SD) months were interviewed. Parents were primarily mothers (94%) with a mean age of 28 +/- 7 (SD) years 60% of whom were single. Educational levels of study parents varied: 43% had not graduated from high school, 29% had a high school equivalency, and 28% had at least a year of college or vocational training. This was a multiethnic parent group. Sixty-five percent were bilingual or non-English speaking. Fifty eight percent were born outside of the continental United States. Parents were primarily of low-income status with 85% receiving Women, Infant, and Children (WIC) food supplements, Aid to Families With Dependent Children, and/or Medicaid. RESULTS: Half of the parents interviewed reported that they rarely read books. Sixty percent of children had fewer than 10 books at home and two-thirds of these households contained fewer than 50 books total. When asked open-ended questions, 28% of parents said that sharing books with their child was one of their three favorite activities together, 14% said that looking at books was one of their child's three favorite things to do, and 19% reported sharing books at bedtime at least six times each week. Thirty-nine percent of families had at least one of these three literacy-related responses present and so were said to have a CCLO. A backwards stepwise multiple logistic regression on CCLO was performed with family financial, human, and social capital variables. Parents married or living together (odds ratio [OR] 2.56, 95% confidence interval [CI] = 1.21-5.42), higher adult-to-child ratios in the home (OR 1.92, 95% CI = 1.20-3.05), households speaking only English (OR 2.67, 95% CI = 1.24-5.76), parents reading books themselves at least a few times a week (OR 2.86, 95% CI = 1.38-5.91), and homes with more than 10 children's books (OR 3.3, 95% CI = 1.6-6.83), were all independently and significantly associated with the presence of CCLO. Older child age and higher parent education remain in the model but were not significant at the P <.05 level. Ethnicity and income status were dropped for lack of additional significance from this model, which described 24% of the variance in CCLO. CONCLUSION: Although two-parent families and higher adult-to-child ratios in the home appear to be social capital variables with protective effects, low-income, single-parent, and minority or immigrant families are at significant risk for lacking both children's books and a CCLO. We suggest that CCLO may itself be another form of social capital reflecting parental goals and expectations for their children. We speculate that interventions which provide children's books and information about reading with children to impoverished families with young children may facilitate more parent-child book sharing. Pediatricians and other primary care providers serving underserved populations may have a unique opportunity to encourage activities focusing on young children and promoting literacy. PMID- 10103348 TI - An advisory statement from the Pediatric Working Group of the International Liaison Committee on Resuscitation. AB - The International Liaison Committee on Resuscitation (ILCOR), with representation from North America, Europe, Australia, New Zealand, Africa, and South America, was formed in 1992 to provide a forum for liaison between resuscitation organizations in the developed world. This consensus document on resuscitation extends previously published ILCOR advisory statements on resuscitation to address the unique and changing physiology of the newly born infant within the first few hours after birth and the techniques for providing advanced life support. After careful review of the international resuscitation literature and after discussion of key and controversial issues, consensus was reached on almost all aspects of neonatal resuscitation, and areas of controversy and high priority for additional research were delineated. Consensus on resuscitation for the newly born infant included the following principles: Common or controversial medications (epinephrine, volume expansion, naloxone, bicarbonate), special resuscitation circumstances affecting care of the newly born, continuing care of the newly born after resuscitation, and ethical considerations for initiation and discontinuation of resuscitation are discussed. There was agreement that insufficient data exist to recommend changes to current guidelines regarding the use of 21% versus 100% oxygen, neuroprotective interventions such as cerebral hypothermia, use of a laryngeal mask versus endotracheal tube, and use of high dose epinephrine. Areas of controversy are identified, as is the need for additional research to improve the scientific justification of each component of current and future resuscitation guidelines. PMID- 10103349 TI - Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review. AB - BACKGROUND: Day-case surgery is of great value to patients and the health service. It enables many more patients to be treated properly, and faster than before. Newer, less invasive, operative techniques will allow many more procedures to be carried out. There are many elements to successful day-case surgery. Two key components are the effectiveness of the control of pain after the operation, and the effectiveness of measures to minimise postoperative nausea and vomiting. OBJECTIVES: To enable those caring for patients undergoing day-case surgery to make the best choices for their patients and the health service, this review sought the highest quality evidence on: (1) the effectiveness of the control of pain after an operation; (2) the effectiveness of measures to minimise postoperative nausea and vomiting. METHODS: Full details of the search strategy are presented in the report. RESULTS - ANALGESIA: The systematic reviews of the literature explored whether different interventions work and, if they do work, how well they work. A number of conclusions can be drawn. RESULTS-ANALGESIA, INEFFECTIVE INTERVENTIONS: There is good evidence that some interventions are ineffective. They include: (1) transcutaneous electrical nerve stimulation in acute postoperative pain; (2) the use of local injections of opioids at sites other than the knee joint; (3) the use of dihydrocodeine, 30 mg, in acute postoperative pain (it is no better than placebo). RESULTS-ANALGESIA, INTERVENTIONS OF DOUBTFUL VALUE: Some interventions may be effective but the size of the effect or the complication of undertaking them confers no measurable benefit over conventional methods. Such interventions include: (1) injecting morphine into the knee joint after surgery: there is a small analgesic benefit which may last for up to 24 hours but there is no clear evidence that the size of the benefit is of any clinical value; (2) manoeuvres to try and anticipate pain by using pre-emptive analgesia; these are no more effective than standard methods; (3) administering non-steroidal anti-inflammatory drugs (NSAIDs) by injection or per rectum in patients who can swallow; this appears to be no more effective than giving NSAIDs by mouth and, indeed, may do more harm than good; (4) administering codeine in single doses; this has poor analgesic efficacy. RESULTS-ANALGESIA, INTERVENTIONS OF PROVEN VALUE: These include a number of oral analgesics including (at standard doses): (1) dextropropoxyphene; (2) tramadol; (3) paracetamol; (4) ibuprofen; (5) diclofenac. Diclofenac and ibuprofen at standard doses give analgesia equivalent to that obtained with 10 mg of intramuscular morphine. Each will provide at least 50% pain relief from a single oral dose in patients with moderate or severe postoperative pain. Paracetamol and codeine combinations also appear to be highly effective, although there is little information on the standard doses used in the UK. The relative effectiveness of these analgesics is compared in an effectiveness 'ladder' which can inform prescribers making choices for individual patients, or planning day-case surgery. Dose-response relationships show that higher doses of ibuprofen may be particularly effective. Topical NSAIDs (applied to the skin) are effective in minor injuries and chronic pain but there is no obvious role for them in day-case surgery. RESULTS-POSTOPERATIVE NAUSEA AND VOMITING: The proportion of patients who may feel nauseated or vomit after surgery is very variable, despite similar operations and anaesthetic techniques. Systematic review can still lead to clear estimations of effectiveness of interventions. Whichever anti-emetic is used, the choice is often between prophylactic use (trying to prevent anyone vomiting) and treating those people who do feel nauseated or who may vomit. Systematic reviews of a number of different anti-emetics show clearly that none of the anti-emetics is sufficiently effective to be used for prophylaxis. (ABSTRACT TRUNCATE PMID- 10103354 TI - The making of leaders. PMID- 10103353 TI - Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses. PMID- 10103355 TI - Hospital library acts as internal consultant. PMID- 10103356 TI - To health care, with grateful affection. PMID- 10103357 TI - Customer service relies on strong communication skills. PMID- 10103358 TI - Teamwork leads to better operating room management. AB - Because the diversity of staff members who work in hospital operating rooms (ORs) can cause conflicts and lead to inefficiencies, a team approach must be used to ensure better management of resources. Administrators, financial managers, and materials managers can join with OR personnel to improve scheduling, reduce time spent preparing and cleaning ORs, and better handle human resources. In the long run, reviewing OR demands and resources controls costs and improves the delivery of care. PMID- 10103359 TI - Risk sharing: health care's latest challenge. AB - With pressure building to reduce healthcare costs, relations between providers and insurers in the years ahead increasingly will focus on risk sharing and utilization controls. Fixed price agreements and managed care plans are two approaches expected to come into wider use. To cope with coming utilization reviews and efforts to manage outpatient care, hospitals will need information systems allowing them to evaluate patient mixes and service intensities. PMID- 10103360 TI - Researchers say cost data spells survival for hospitals. PMID- 10103361 TI - Healthcare industry problems call for cooperative solutions. AB - The complexity of problems facing American health care--from extending health benefits to the uninsured to caring for people with acquired immune deficiency syndrome--require cooperative solutions involving providers, insurers, and policy makers. A spokesman for the health insurance industry presents ideas about the future of health care and discusses the role of insurers in meeting the challenges ahead. Among the items on the agenda: further growth of managed care; continued attempts to control costs and utilization; and sharing the burden of risk with consumers. PMID- 10103362 TI - HFMA outlines future healthcare environment. PMID- 10103364 TI - Scrutinize risk when investing in real estate. PMID- 10103363 TI - Relative costing eases clinical financial analysis. PMID- 10103365 TI - Supervision: learning from experience. PMID- 10103366 TI - An approach to nurse managerial reporting: an essential task. AB - Managerial reporting is an essential task for managers. It can become a useful tool for upward communication. If each nurse manager keeps the nurse administrator well informed about his or her unit, communication to the hospital chief executive officer regarding the nursing department as a whole will be enhanced. PMID- 10103367 TI - A new role-and-feedback system for the supervisor and the organization. AB - Changes in industry in general and in health care are forcing changes in organizational structures and in people. A new role for supervisors is being demanded as layers of management are reduced to cut costs and simplify operations. The new supervisor will have to be a leader and decisionmaker. The feedback system suggested here provides a mechanism for ensuring that supervisors' leadership is going in the right direction and that their decisions are having the desired effects. PMID- 10103368 TI - Assessing the need for supervisory training: use of performance appraisals. PMID- 10103369 TI - Developing the art of successful clinical supervision in health care programs. AB - Supervision is a dynamic and ever-changing process. Excellent employees can be trained to be outstanding supervisors if the competencies and skills of the supervisory process are clarified. Supervision is a successful art that can be learned and enhanced if appropriate supervisory skills are identified, taught, and learned. Supervision is too important in developing the future health care work force to be left to chance. PMID- 10103370 TI - Improving performance appraisal from the bottom up. PMID- 10103371 TI - Does your shop need a makeover? PMID- 10103372 TI - Bring on the "warm fuzzies": increasing sales through trust-building. PMID- 10103373 TI - Information, please! PMID- 10103374 TI - Paper prices up 8% and still climbing. PMID- 10103375 TI - Hospitals build regional plants to control costs. PMID- 10103376 TI - Therapeutic substitution and better purchasing significantly reduce hospital pharmacy costs. PMID- 10103377 TI - Results will earn materials managers respect, trust in '90s. PMID- 10103378 TI - Materials managers' pharmaceutical tracking responsibility limited to issuance and returns. PMID- 10103379 TI - Ohio mandates DRG refinement to measure patients' severity of illness. PMID- 10103380 TI - Acute and custodial care among impaired aged. AB - The authors surveyed a community-based population of 628 persons who were 65 and over and who lived either in a rural Maryland county or in Baltimore. For each subject, the number of different medical problems, the subject's capacity to perform physical tasks, and the ability to function were assessed. The number and type of medical problems tended to be the best predictors of whether or not hospital or physician's office care were used, and of the volume of physician's office visits for subjects who sought outpatient care. The subject's ability to function was the best predictor of whether or not the subject used a paid home aide and the volume of family caregiving. Implications for research on association between need and use of long-term care are discussed. PMID- 10103381 TI - New death list finds 196 "high outliers". PMID- 10103382 TI - Credit for good deeds. Golden rules of barter. PMID- 10103383 TI - Installing a patient care system physicians will use. PMID- 10103384 TI - Cholesterol screenings: is there a return on investment? AB - Community outreach programs like health screenings will face increasing scrutiny as attempts to reconcile expenses and revenues intensify. If you cannot supply evidence that a screening program can generate new revenue, that program might be written off as a loser. Providing the evidence is not as difficult as you might think; it requires planning and the resourceful use of software you may already have available. PMID- 10103385 TI - Using geodemographics to launch a telephone referral service. AB - Mercy Health Services, a diversified, $1.5 billion, 23-hospital system based in Indiana, Iowa, Michigan and New York, purchased a microcomputer-based marketing support system in November 1988. Two marketers affiliated with the hospital describe the system's use in determining the feasibility of developing a direct mail campaign for a referral service. PMID- 10103386 TI - What makes an effective administrator?. Interview by LaTresa Costello. AB - Bruce Grotewiel, EMT-P, director of the Jefferson City Ambulance Service in Missouri, was named 1989 EMS administrator of the year by the National Association of Emergency Medical Technicians (NAEMT). NAEMT bases its decision each year on a combination of community service, service to the EMS profession, and excellence as an EMS administrator. The National Society of EMS Administrators, a division within NAEMT, established the award in 1988. It is sponsored by Fitch and Associates, a Kansas City-based health-care-management consulting firm. Grotewiel became director of the hospital-based service in March 1988, after working as the assistant director for four years. As a result of his efforts, the service has expanded to include 40 EMS providers and seven ALS units, response time has been significantly reduced, and employee compensation and benefits have increased. What does it take to be a top administrator? EMS staff writer LaTresa Costello recently spoke with Grotewiel to find out. PMID- 10103387 TI - When the earth moved.... AB - Northern California directors & dietitians are still talking about where they were, what they were doing & what they learned when the most severe earthquake ever hit their region. The sights & sounds & the lessons revealed by a world turned upside down live on in the following recollections. PMID- 10103389 TI - Personalization pays off. PMID- 10103388 TI - For greater fund-raising success ... hire an art director. PMID- 10103390 TI - Facilities management in the 1990s demands job, building flexibility. PMID- 10103391 TI - Conducting a lighting audit at your facility. PMID- 10103392 TI - AHA: health facilities should reduce use of CFCs. PMID- 10103393 TI - Survey confirms boost in job responsibilities. PMID- 10103395 TI - '80s changes to continue--at a different pace. PMID- 10103394 TI - Power conversions save on maintenance, parts. PMID- 10103396 TI - Computer security: planning to protect corporate assets. PMID- 10103397 TI - Voice mail makes a difference. PMID- 10103398 TI - Promoting women's and children's services. PMID- 10103399 TI - A turning point. PMID- 10103400 TI - Policymakers put their money on medical effectiveness research. PMID- 10103401 TI - Is gender germane? PMID- 10103402 TI - How managers decide what their problems are. PMID- 10103403 TI - The case of the frozen embryos. PMID- 10103404 TI - Child abuse and neglect: breaking the cycle of violence. PMID- 10103405 TI - Systemic healthcare reform: is it time? Six proposals for universal coverage. PMID- 10103406 TI - Coping with closure. Consideration of legal issues in hospital closing can save precious time and considerable money. AB - From the legal perspective, closing a hospital can be as difficult as opening one. Whether a hospital is closing or downsizing, it should become familiar with the relevant legal issues before the process begins and develop a strategy for addressing them. Hospitals planning to discontinue services often must give advance notice to federal, state, and local governmental agencies, as well as to nongovernmental organizations such as the Joint Commission on Accreditation of Healthcare Organizations and to contractors. Failure to notify the applicable state licensing agency may violate the hospital licensing act and subject the hospital and its officers and directors to statutory sanctions. A hospital must carefully consider the closure's effect on its medical staff. If the medical staff brings legal action, the law in many states and the hospital's own corporate and medical staff bylaws may provide some defenses. A major consideration in any closure is the procedures for dealing with employee issues such as termination rights and benefits, access to personnel files, unemployment compensation benefits, severance pay and notice, transfer privileges, posttermination obligations, bargaining unit issues, preferential hiring, and communications. A hospital closure will also trigger issues concerning Medicare and Medicaid reimbursement, debt instruments, Hill-Burton grants, bankruptcy, and Joint Commission accreditation. A good community communications program is essential to a smooth closure or downsizing. If the hospital does not explain why it must take the action, the community may misinterpret its motives and react with hostility, which can influence government agencies. The hospital might retain a professional public relations consultant, especially if the community is complex or has been hostile to the hospital in the past. PMID- 10103407 TI - The business of ethics. Hospitals need to focus on managerial ethics as much as clinical ethics. AB - Business ethics begins with the recognition of the various values and "goods" involved in judgements of what to do. Four key values are individual rights, individual self-interest, the company's best interest, and the public good. Often a company has to choose which of these goals or values should be subordinated to another. Business ethics, then, must clarify priorities among these values and establish priority principles to resolve conflicts. One approach to contemporary business ethics emphasizes personal integrity, focusing on conflicts of interest; another approach stresses social responsibility, focusing on the effect of company policy on groups and individuals in society. In business, most of the attention to conflicts of interest focuses on the conflict between employee self interest and the firm's interest. Healthcare organizations may need to focus on potential conflicts between the patient's interest and the institution's or physician's interest. Physician referrals and pharmaceutical companies' marketing practices are two areas with potential conflicts. Not-for-profit organizations have been quicker than the business world to acknowledge social responsibility. In many ways, however, the social impact of healthcare policies and decisions has not been as carefully considered as it should be. Institutionalizing deliberation about clinical ethical issues has helped to raise awareness about the ethical dimensions of medical care. It would also be useful to institutionalize attention to business ethics in healthcare. PMID- 10103408 TI - Partners at work. Catholic social teaching demands that managers respect workers' rights. AB - For almost 100 years Catholic social teaching has demanded that workers be treated in accord with their dignity as persons created and loved by God. Numerous papal encyclicals, a statement by the 1971 Roman Synod of Bishops, and the U.S. bishops' 1986 pastoral letter all insist on workers' rights to just wages, healthful working conditions, appropriate ways of participation and freedom to form or join unions. Throughout this century the Church has taught that a just wage should provide workers and their families "a standard of living in keeping with the dignity of the human person." Just compensation should also include provisions for adequate healthcare, security for old age or disability, unemployment compensation, and other benefits. Workers should also be able to participate as fully as possible in the enterprise they are a part of. "Each person," Pope John Paul II has written, "is fully entitled to consider himself a part owner of the great workbench at which he is working with everyone else." Finally, Catholic social teaching has consistently defended the rights of all people to form or join unions. Although the existence of this right does not oblige Catholic institutions to give up what they perceive to be their own interests, it does oblige them to avoid adopting an adversarial stance toward unions and to openly acknowledge their employees' right to unionize. PMID- 10103410 TI - Union elections and the NLRB. The healthcare industry continues to challenge bargaining unit determinations. AB - In the healthcare industry today, unions and management must cope with a confused, contradictory, and often changeable body of law and National Labor Relations Board (NLRB) policy when unions attempt to establish themselves at a particular institution. More than 15 years ago, Congress amended the National Labor Relations Act to grant labor unions the right to organize employees of not for-profit hospitals and other healthcare organizations. An election to form a union cannot be held, however, until the NLRB determines which employee classifications constitute an "appropriate" collective bargaining unit. Since 1974, labor and management have fought over this basic question before Congress, the NLRB, and the federal courts. One paragraph of congressional instruction to the NLRB, which stipulates that the board prevent "proliferation of bargaining units in the health care industry," has over the years been construed in widely varying ways by the board and the courts. Management has argued that two units should be the maximum number allowed as appropriate whereas unions have argued for more. Last April the NLRB established a rule allowing for as many as eight bargaining units at a particular institution, but three months later a federal district court issued a permanent injunction against the rule. The board has appealed the injunction, and as both sides await a ruling, dozens of pending hospital union election cases have mounted up. Nor does a decision by a court of appeals promise to resolve the issue. PMID- 10103409 TI - The right choice. Two approaches to determining right and wrong. AB - What if your superior sent you on a recruiting trip and told you to misrepresent the institution, if necessary, to get more nursing staff? What would you do? Finding ways to do what is right is a challenge. But determining what is right is a prior and often a more difficult task, involving a choice of ethical perspectives. One perspective is utilitarianism--a form of consequentialism, whereby acts are right or wrong depending on their consequences. A second ethical approach is a respect-for-persons position, a form of deontology which holds that we have a duty to refrain from certain acts that are inherently disrespectful of persons. The utilitarian way to determine right from wrong is to look at an action's implications for people's happiness or unhappiness. Lies might be justified on a case-by-case basis if they tend to produce more happiness than any other option. An ethical alternative is a respect-for-persons view. Three broad tests can be applied to judge whether an action is respectful of persons: the tests of autonomy, promise keeping, and reciprocity. PMID- 10103411 TI - Support your local EAP? PMID- 10103412 TI - Spartanburg EMS takes the prize. PMID- 10103413 TI - Protect yourself. Avoiding the claim of abandonment. PMID- 10103414 TI - Honing skills for suicide intervention. PMID- 10103415 TI - The key-point method for EMS system appraisal: one approach to the gold standard. PMID- 10103416 TI - Prehospital i.v. therapy. Are we contributing to patient complications? PMID- 10103417 TI - PR at disaster drills. Don't be caught without it. PMID- 10103418 TI - 1990 EMS salary survey. PMID- 10103419 TI - Malpractice reform is doomed--and doctors are to blame. PMID- 10103420 TI - Your practice--get ready for 10 tough years. PMID- 10103421 TI - Personnel licensure: a raging issue that won't go away. PMID- 10103423 TI - 11 keys to quality management in the lab. PMID- 10103422 TI - A surprise visit from OSHA. PMID- 10103424 TI - AHM names new top officer. PMID- 10103425 TI - Calif. coalition wants insurance issue on ballot. PMID- 10103426 TI - The outlook for healthcare and hospitals in 1990. Roundtable discussion. PMID- 10103428 TI - Challenges of new decade demand break with tradition. PMID- 10103427 TI - Two hospitals may reopen in Chicago's strained system. PMID- 10103429 TI - Medical Care International's strategy for success puts its surgeons first. PMID- 10103430 TI - Money, power at stake in turf fight over HMOs. PMID- 10103431 TI - CEOs more involved in decision making. PMID- 10103432 TI - Mobile mammography tries to enhance its image and revenue through strategic ties. PMID- 10103433 TI - Not-for-profits restructure to avoid trouble. PMID- 10103434 TI - Death rates incomplete, misleading--studies. PMID- 10103435 TI - And what is your bid for this loyal admitter? Please, don't hold back. Healthcare's hidden costs. PMID- 10103436 TI - Daniel Drake Memorial survives scandal-stoked fires, takes on new identity. PMID- 10103437 TI - Independent peer review often too costly for clients. PMID- 10103438 TI - AIDS travel restriction policy challenged. PMID- 10103439 TI - Care Enterprises' credits revise plan. PMID- 10103440 TI - Bond surge not expected to last in 1990s. PMID- 10103441 TI - AMI might buy up to 10 hospitals in next 5 years. PMID- 10103442 TI - Epic reports first-year loss. PMID- 10103443 TI - NME reports record earnings. PMID- 10103444 TI - Five hospitals leave Adventist Great Lakes region to form system. PMID- 10103445 TI - Flu season crowds nation's emergency departments. PMID- 10103446 TI - Bargaining unit appeal heard. PMID- 10103447 TI - Cluster staffing promotes decentralized management. PMID- 10103448 TI - How a hospital uses "differentiated practice". PMID- 10103449 TI - Small & rural & surviving. PMID- 10103450 TI - Catering to community support. PMID- 10103451 TI - A good year for good health. PMID- 10103452 TI - Phone book covers list healthcare services. PMID- 10103453 TI - From scissors to software. PMID- 10103454 TI - Concierge concept eases family fears. PMID- 10103455 TI - Soothing the worried well. PMID- 10103456 TI - Turning a negative into ... a nothing. PMID- 10103457 TI - New name--new image. PMID- 10103458 TI - Checklist for a health program. PMID- 10103459 TI - Focus on women. PMID- 10103460 TI - 'Ease of mind' promotes breast care center. PMID- 10103461 TI - Teddy bear clinic. PMID- 10103462 TI - Cradling referrals from parents-to-be. PMID- 10103463 TI - Neonatal unit celebrates. PMID- 10103464 TI - Hugs 'n kisses make it better. PMID- 10103465 TI - Sex talk. PMID- 10103466 TI - A medical journal grows in Texas. PMID- 10103467 TI - Landslide response to handbook for kids. PMID- 10103468 TI - Candlelight march in Missouri heartland. PMID- 10103469 TI - Physician profiles on file. PMID- 10103470 TI - "I gave at the office". PMID- 10103471 TI - Meeting the individual needs of a changing population. PMID- 10103472 TI - A visit from the First Lady--the long shot that paid off. PMID- 10103473 TI - Reform of residential care gathers steam on Capitol Hill. PMID- 10103474 TI - Creative inservice training programs boost staff morale. PMID- 10103475 TI - A step-by-step approach to choosing an information system. PMID- 10103476 TI - The physician's appearance and professionalism. AB - The attire of 101 physicians in 24 Minnesota clinics was observed, and the relationships between appearance and 1) gender, 2) role, and 3) location were analyzed. Comparisons between resident and staff physicians revealed several significant differences. The results suggest that the physician's appearance affects how others view the physician as a professional. PMID- 10103477 TI - 1990 annual forecast. Hospitals. PMID- 10103478 TI - 1990 annual forecast. Nursing homes/elder care. PMID- 10103479 TI - Physician, heal thyself: because the cure, the Health Care Quality Improvement Act, may be worse than the disease. PMID- 10103480 TI - Mergers = cuts and consolidation. Reconciling service cuts with a hospital's mission can be painful. PMID- 10103481 TI - Physician recruitment for hospital governing boards. PMID- 10103482 TI - Primary care clinics meet community and hospital needs. PMID- 10103483 TI - Hospital mergers: thinning the antitrust thicket. PMID- 10103484 TI - Trustees should give thanks. PMID- 10103485 TI - Written executive compensation policies can ease the board's role. PMID- 10103486 TI - Congress seeks to ensure safe medical devices. PMID- 10103487 TI - Board chairman John Makel on cutting services versus diversification. Interview by Karen Gardner. AB - John Makel, chairman of the board of the Memorial Health Alliance of Mount Holly, NJ, and vice-president and regional trust office manager, First Fidelity Bank, NA New Jersey, Moorestown, began his tenure on the board of the Memorial Hospital of Burlington County, NJ, in 1975. He has been chairman of the alliance since 1983. Makel has been involved in diversification and divestment decisions since 1979, when the alliance was formed. It now includes a 402-bed acute care hospital--the Memorial Hospital of Burlington County--a 120-bed long-term care facility, and a home health care agency that makes approximately 70,000 home care visits a year The alliance's 30-member board, under the active leadership of a 13-member executive committee, governs each of the three affiliates. Recently, Trustee managing editor Karen Gardner talked with Makel to learn how the board has approached the difficult decisions involved in cutting services versus diversification. PMID- 10103488 TI - What every trustee should know about D&O liability. PMID- 10103489 TI - Keeping the record straight: guidelines for charting (Part II-Obstetrical documentation). Professional Liability Program, Farmers Insurance Group of Companies. PMID- 10103490 TI - Controlling outside legal costs. PMID- 10103491 TI - Quality of care defined. PMID- 10103492 TI - Perspectives. PROs: struggling to define the rules of the game. PMID- 10103493 TI - Perspectives. Is American health care ripe for reform? PMID- 10103494 TI - Perspectives. Drug testing on the job: seeking a delicate balance. PMID- 10103495 TI - Equal access to health care--patient dumping. NAHAM (National Association of Hospital Admitting Managers) position paper. AB - NAHAM's first position paper, "Equal Access to Health-Care-Patient Dumping," was prepared as part of the association's strategic planning process. This paper is the first in a series which will examine federal healthcare issues. This paper like the others to follow will increase membership awareness of healthcare issues, providing NAHAM with greater influence in the federal healthcare policy arena. PMID- 10103496 TI - Improving communication between admitting nurses and physicians. PMID- 10103497 TI - The physician and admitting partnership. PMID- 10103499 TI - Physician bonding: building a strong relationship. PMID- 10103498 TI - Inspector General v. Michael L. Burditt, M.D. PMID- 10103500 TI - Physician bonding: a new strategy in healthcare marketing. PMID- 10103501 TI - Cleveland Clinic CompreCare Affiliate Program: a comprehensive physician liaison program. PMID- 10103502 TI - Removal of obsolete regulations on limitation on federal participation for capital expenditures under Section 1122 of the Social Security Act--HCFA. Final rule. AB - This rule removes obsolete regulations governing the section 1122 capital expenditures review program. With the repeal of the comprehensive health planning authority, Title XV of the Public Health Service (PHS) Act, no funds were appropriated to support State capital expenditure review activities, or to administer the program. PMID- 10103503 TI - Assisted living with residents in mind. Conclusion of the national survey analysis. PMID- 10103504 TI - Laundry loads on the rise. Disposables backlash increases linen usage. PMID- 10103505 TI - Managers need varied skills. PMID- 10103506 TI - Reducing restraint reliance. PMID- 10103507 TI - Resident assessment under OBRA '87. AB - A resident assessment system that uniformly measures the functional, medical, mental and psychological status of nursing home patients upon admission and periodically thereafter will go into effect in all Medicare and Medicaid certified facilities in October, 1990. PMID- 10103508 TI - Few chances to buy; occupancy high. PMID- 10103509 TI - Practical methods to improve fee collections. AB - A medical practice's financial policies should be frankly discussed with patients and explained at the initial visit. At that time, health insurance coverage should also be discussed. This candid conversation not only opens the door to further communication regarding a once-sensitive subject but also facilitates collection of fees--especially important when high-priced procedures are contemplated. The author also discusses third-party payers (including Medicare) and the pros and cons of prepaid health plans. PMID- 10103510 TI - The networking standards evolution: toward a real electronic medical record. Interview by Carolyn Dunbar. AB - While converging networking standards have created short- and long-term options for healthcare IS planners, one strong goal is a "life-long, longitudinal electronic medical record" that includes data of all types--text, wave forms, voice, images and other pictorial data. Jack Harrington of Hewlett-Packard says these complex efforts are shaped by major forces that now speed progress toward multilateral acceptance of a uniform standard. PMID- 10103511 TI - ASTM (American Society for Testing and Materials) standards for medical computing. AB - One of the founders of the Healthcare Information Standards Coordinating Committee (HISCC), formed two years ago, discusses the need for and status of development of standards that allow incompatible systems to share healthcare data. IS standards underpin the entire concept of networking, which stands as a top priority for the 1990s. PMID- 10103512 TI - Beyond networking: moving from data exchange to information sharing. PMID- 10103513 TI - The northern California quake: an EMS perspective. PMID- 10103514 TI - Beating burnout. PMID- 10103515 TI - Health promotion, families, and the diagnostic process. PMID- 10103516 TI - Rural determinants in family health: considerations for community nurses. PMID- 10103517 TI - Family caregiving in a changing society: the effects of employment on caregiver stress. PMID- 10103518 TI - Design and implementation of a citywide breastfeeding promotion program: the New York City approach. PMID- 10103519 TI - A model program for enhancing services to chemically dependent infants: an interdisciplinary approach to serving infants in out-of-home placement. PMID- 10103520 TI - Living healthy with HIV. A patient education program whose time has come. PMID- 10103521 TI - U.S. nears start-up of malpractice data bank. PMID- 10103522 TI - Sharing a crisis. RNs & family physicians. PMID- 10103523 TI - Organizing and focusing the board's work: keys to effectiveness. PMID- 10103524 TI - Strong, effective boards: a necessity for the 1990s. PMID- 10103525 TI - Governance for whom? The dilemmas of change and effectiveness in hospital boards. PMID- 10103526 TI - New issues and expectations for governance. PMID- 10103527 TI - Activities of the Washington State Medical Disciplinary Board. Taking an extra step. PMID- 10103528 TI - The medical staff of the future. AB - Reinventing the medical staff is a process that has been hinted at, but not yet pursued in any full scale effort. Hospitals have the most to lose by maintaining the status quo and the most to gain by initiating a reconsideration of their relationships to physicians. This article explores the underlying need for change, examines alternative models and recommends action for implementing change within the medical staff. PMID- 10103529 TI - HCFA's mortality statistics boost teaching hospitals. PMID- 10103530 TI - Karl Bartscht develops transitional care units. Interview by Donald E.L. Johnson. PMID- 10103531 TI - Special report on patient care. "Voluntary" commitment of minors to private psychiatric hospitals: California's response. PMID- 10103533 TI - Her legacy: a future! PMID- 10103532 TI - How to develop a creative and self-motivated work team. AB - In summary, food service managers must use every available tool and resource to do their jobs. The development of self-motivated food service workers will help a great deal. Managers and dietitians must do a better job of dealing with employees as individuals and understanding the dynamics of the kitchen/service team. Good workers are those whose lives are generally healthy and crisis free. Take advantage of programs that will benefit your employees. Develop good delegation skills. It works for managers, it's good for employees. Finally, use the influence of the informal leader to the advantage of the department. They aren't going to go away--turn that man or woman into your ally. As individuals, we managers can't do it all. But, as a motivated team we can. PMID- 10103534 TI - Cafeteria promotion idea: the Coffee Mug Club (a case study). PMID- 10103535 TI - Fix up your fixturing! PMID- 10103536 TI - Words to the wise. PMID- 10103537 TI - Easter parade. PMID- 10103538 TI - Pharmacist-managed patient-care services and prescriptive authority in the U.S. Public Health Service. AB - The Indian Health Service (IHS), an agency of the US Public Health Service, instituted a broad range of clinical pharmacy services for ambulatory patients in the 1960s and early 1970s. One outgrowth of these services was that pharmacists were authorized to provide certain prescription legend drugs directly to patients without physician preauthorization. Also, pharmacists monitored patients' progress and were authorized to make therapeutic substitutions of drugs. Pharmacist prescribing privileges in these programs were defined by P & T Committee-approved protocols. Success with these programs led to expanding the pharmacist's role to include physical assessment and differential diagnosis of patients with specific diseases and to manage their care when that care consisted primarily of medications. The development and implementation of these programs and the results of a study of pharmacist prescribing within the IHS are described in this article, as is the IHS clinical pharmacy training program. PMID- 10103539 TI - U.S. hospital trends in the 1990s: fewer beds, less debt. PMID- 10103541 TI - NH hospital relocates main entrance, ED to reflect shift in care. PMID- 10103540 TI - The National Practitioner Data Bank: new informational duties for hospitals. PMID- 10103542 TI - 'Dynamic control' offers greater savings, comfort. PMID- 10103543 TI - CAD: asset-management as well as a design tool. PMID- 10103544 TI - Asbestos abatement requires prudent approach. PMID- 10103545 TI - ASHE survey: salaries increase as duties expand. PMID- 10103546 TI - Needs identification key to motivating workers. PMID- 10103547 TI - Court refuses to review discretionary decisions of hospital boards. PMID- 10103548 TI - Payment for prisoners' hospital care: a vexing issue. PMID- 10103549 TI - Hospitals' med-surg is 5% to 16% of operating budgets. PMID- 10103550 TI - Generic prices expected to fall 3%. PMID- 10103551 TI - Four materials managers create a "cookbook" for hospital capital equipment procurement. PMID- 10103552 TI - Medical-surgical prices continue to creep up. PMID- 10103553 TI - County and not-for-profit hospital mergers should avoid local government support. AB - A rural not-for-profit hospital is taking over a healthy facility that the county government operated as a county home for the aged. Questions have arisen as to the proper way to handle the transfer of property, including medical supplies. Also, there are accounting problems in connection with the continued operation of the facility as far as materials management is concerned. In this dialogue, Dr. Decker addresses these problems. PMID- 10103554 TI - Are you giving away too much care? PMID- 10103555 TI - How colleagues benefit from my work in a nursing home. PMID- 10103556 TI - Doctors are fighting back against bullying reviewers. PMID- 10103557 TI - Information management: an HMO essential. AB - Health maintenance organizations (HMO), with their diverse audiences and complex operations, offer the best proof that management information systems (MIS) are emerging as an essential and marketable business asset. Authors Paul Egerman and Susan Heineman offer many uses for a good MIS and why such a program is essential to an HMO's success. PMID- 10103558 TI - A frosty open enrollment season. PMID- 10103559 TI - Clarifying who decides. PMID- 10103560 TI - Current Michigan legislation. PMID- 10103561 TI - Trustees reveal advocacy plans. PMID- 10103562 TI - Causes of executive turnover. PMID- 10103563 TI - 'Health system overhaul shouldn't be top priority.'. PMID- 10103564 TI - Physicians vs. administrators: when a vote of no confidence forces the board to take sides. PMID- 10103565 TI - Cigna to acquire Equicor from HCA, Equitable. PMID- 10103566 TI - VHA sells stake in Partners. PMID- 10103567 TI - AHA advisory group to study financing, delivery system. PMID- 10103568 TI - Coalition of executives to push healthcare reform. PMID- 10103569 TI - Study examines role of hospital boards in physician evaluation. PMID- 10103570 TI - Hospital leaders predict decade's hurdles, solutions. PMID- 10103571 TI - Rehab facility's fund-raising letter sparks controversy. PMID- 10103572 TI - Technology scrutiny emerges as job task. PMID- 10103573 TI - Phone service faces privacy challenge. PMID- 10103575 TI - Columbia Hospital Corp. drops plans to buy system. PMID- 10103574 TI - Texas Hospital Assn. reports 15 closings in 1989. PMID- 10103576 TI - Marketers seek to divide and conquer. PMID- 10103577 TI - Baxter studies divestitures. PMID- 10103579 TI - Experts still betting on healthcare REITs. PMID- 10103578 TI - Beverly Enterprises ponders offering. PMID- 10103580 TI - FTC, 2 not-for-profits sign antitrust pact. PMID- 10103581 TI - Wilensky nomination clears Senate panel. PMID- 10103582 TI - Number of hospital bond downgrades declines. PMID- 10103583 TI - State of the Union cost-control focus fails to satisfy industry. PMID- 10103584 TI - Employer costs of group health benefits take 17% jump--survey. PMID- 10103585 TI - Trauma networks look for rescue. Hospitals dropping out as uncompensated costs mount. PMID- 10103586 TI - Emerging breed of exec helps hospitals embrace change. PMID- 10103587 TI - AHA board approves plan to write national health policy. PMID- 10103588 TI - A legal drama in 2 acts: why hospital execs should know the law in antitrust defense. PMID- 10103589 TI - Vanderbilt's stockless system relies on distributors as its materials managers. PMID- 10103590 TI - Single-room maternity care begets more utilization. PMID- 10103591 TI - Group questions reliability of financial data. PMID- 10103592 TI - Former VHAE chief exec challenges sale of Partners. PMID- 10103593 TI - National Heritage, Life Care Centers of America weigh merger. PMID- 10103594 TI - Sullivan's new role boosts chances for reforms--experts. PMID- 10103595 TI - The coming evolution in computer systems. Hospitals need flexibility to take advantage of new technologies. PMID- 10103596 TI - AmeriNet, largest shareholder break. PMID- 10103597 TI - Justice Dept. levels criminal antitrust charges. PMID- 10103598 TI - Allegheny: a tertiary titan with all the right moves. PMID- 10103599 TI - For-profit hospitals work to pick holes in recent study on mortality rates. PMID- 10103600 TI - Gain-sharing plans aim to boost productivity. PMID- 10103601 TI - Ponder remains no. 1 financial adviser. Chapman & Cutler top bond counsel. PMID- 10103602 TI - Wilensky confirmed as HCFA chief. PMID- 10103603 TI - JCAHO surgery/anesthesia scoring guidelines released. PMID- 10103604 TI - Informed consent: nurse as troubleshooter. PMID- 10103605 TI - Bipolar forceps misconnection hazardous. PMID- 10103606 TI - Radiation risk higher; but standards adequate. PMID- 10103607 TI - Ambulatory surgery unit needs own identity. PMID- 10103608 TI - Tissue transplants: the dilemma of the body's growing value. PMID- 10103609 TI - California hospitals launch purchasing support group. PMID- 10103610 TI - Solid-waste solutions aid operators, environment. PMID- 10103611 TI - Association of Surgical Technologists. Resource catalog. PMID- 10103612 TI - Changing the paradigm. "If what we are doing is nursing, why don't most nurses already know this stuff?" AST (Association of Surgical Technologists) Board of Directors. PMID- 10103613 TI - The AARP (American Association of Retired Persons) perspective. AB - To summarize, five areas have been targeted by the AARP for improvement: Market and price stability Geriatric training for medical and support staff Emphasis on preventive care and maintenance programs Integration of health care services with social services Provision of useful consumer information on quality of care as a marketing tool AARP is concerned about the universe of health care problems facing this nation. I do not for an instant suggest that these issues will be easily resolved or resolved quickly. We are all anxious to find solutions that work. One of the most promising solutions is with you, in your experience, commitment and willingness to forge new ground. HMOs and Social HMOs serving this older population are leaders in the health care industry. Many of you have demonstrated that HMOs can provide quality medical care for elderly patients. It is AARP's hope that working together we can create an environment in which HMOs adopt policies and practices that ensure comprehensive quality health for the elderly. PMID- 10103614 TI - How does your HMO handle the seasonal demand for school and camp physicals?. Interview by Susan B. Yox. PMID- 10103615 TI - The challenge of providing comprehensive care to the elderly. PMID- 10103616 TI - Efficacy of diabetes education: classroom versus individualized instruction. AB - A pilot study was conducted using the concerns based adoption model (CBAM) developed at the University of Texas-Austin. This model uses two diagnostic dimensions: stages of concern (SC) and levels of use (LU). Movement in these dimensions is an important determinant of self-motivated disease management. It is postulated that this self-motivation is the basis of long-term adherence to the patient's therapeutic regimen and results in the decreased use of medical services. Twenty patients who attended a series of formal diabetes education classes were compared with 20 patients who received individualized instruction. Classroom education was significantly more effective in increasing the SC about diabetes management. However, the increase in LU (technical skills) was not significantly different in either setting. At 2- to 3-month follow-up evaluation, results indicated that retention of skills and motivation are excellent and that SC and LU continued to improve. In summary, this study demonstrated that classroom education is technically equivalent, more cost-effective, and may be more conducive to learning than individualized instruction. PMID- 10103617 TI - National Conference on Comprehensive Care of the Elderly '89. The HMO approach. PMID- 10103618 TI - Mergers and reorganizations: Part II. Managing during a merger or consolidation. PMID- 10103619 TI - Coulter STKR. PMID- 10103620 TI - A hospital facsimile network improves patient care. PMID- 10103621 TI - The medical treatment guardian program. PMID- 10103622 TI - The role of patients/family members in the hospital ethics committee's review and deliberations. PMID- 10103623 TI - Resuscitation of patients: one medical center's new approach. Memorial Medical Center, Springfield, Illinois. PMID- 10103624 TI - Severity-of-illness systems produce cost, MD behavior changes, users say. PMID- 10103625 TI - Perspectives. Product liability reform: an uphill battle. PMID- 10103626 TI - Perspectives. Clean Air Act: ill wind for hospitals. PMID- 10103627 TI - EDI: the best in business partner cooperation. Part Two: HL7 is the Rosetta Stone of the healthcare systems industry. AB - This is the second of a three-part series on electronic data interchange (EDI) applications. Part One appeared in the October 1989 issue of USH. Part Two covers EDI applications within a hospital, from one computer system to another. It illustrates how the new HL7 standards will make "seamless" interfaces an economic reality for the first time. Part Three will focus on the paperwork reduction aspects of EDI, and the resultant cost savings. Through the use of permanent CD ROM storage, the day will come when a hospital's business transactions (purchase orders, invoices, checks) as well as medical records, will never be put on paper. PMID- 10103628 TI - Cost containment through productivity improvement. PMID- 10103629 TI - The interdependence of healthcare management and information technology. A look beyond financial information systems. PMID- 10103630 TI - Residency manpower trends. PMID- 10103631 TI - The Committee on Professional Liability. PMID- 10103632 TI - The Committee on Socioeconomic Issues. PMID- 10103633 TI - Utilization review: a report card. PMID- 10103634 TI - The city as patient. PMID- 10103635 TI - Indian Health Service; contract health services--PHS. Final rule. AB - This is a final rule clarifying the regulations governing receipt of contract health services from the Indian Health Service (IHS). Under this rule, IHS is specifically designated as payor of last resort for persons defined as eligible for IHS contract health services notwithstanding any State or local law to the contrary. PMID- 10103636 TI - Advisory council; establishment of the Commission on the National Nursing Shortage--HRSA. PMID- 10103637 TI - Sick about health. PMID- 10103638 TI - IG reports on abuse problems. PMID- 10103639 TI - OBRA provisions bring changes. PMID- 10103640 TI - HCFA re-examines self-administration of medications. PMID- 10103641 TI - Pressure reduction: the many choices. PMID- 10103642 TI - Infection control under OBRA '87. PMID- 10103643 TI - Don't let subpoenas catch employees by surprise. PMID- 10103644 TI - The effects of family structure and regular places of care on preventive health care for children. AB - Data from the 1982 National Access to Medical Care Survey were examined to answer questions on preventive health care received by children in families with one or two working parents and possible differences among their various regular sources of care. Evidence supports the general and expected conclusion that children of single female workers are most at risk. Children from these non-traditional families appeared to benefit most from care given in the offices and clinics of private physicians, while those of such families enrolled in health maintenance organizations benefitted least. When compared with HMO enrollees from the other two types of families (those where men were working and women stayed home, or where both parents worked), children of single parents were least likely to have received tine tests or DPT inoculations. Finding implications are discussed with suggestions for further research including investigating the effects of modifying hours of service and the provision of institutional supports for working parents. PMID- 10103645 TI - Utilization patterns and strategic implications in the 1990s. PMID- 10103646 TI - Metro hospital associations. Interview by Donald E. L. Johnson. PMID- 10103647 TI - Disposable versus reusable pillows: a case study. PMID- 10103648 TI - Specialty bed management: a success story. PMID- 10103649 TI - The role of the Pharmacy and Therapeutics Committee in materiel management. PMID- 10103650 TI - Price versus quality: the war in the jungle. PMID- 10103651 TI - Hospital ethics committees in transition. PMID- 10103652 TI - Infections in the hospitalized elderly. AB - Nosocomial infections are a particular problem among the elderly. Their cost is high mortality and a bill of $4 billion annually. The routine observation of a few simple aseptic practices will significantly blunt the impact of this health care concern in our hospitals and nursing homes. PMID- 10103653 TI - Results from the 1989 Member Employment Survey, Part II. PMID- 10103654 TI - Data sets and coding guidelines: sequencing vs. classification rules. PMID- 10103655 TI - Treatment decisions for the elderly. AB - Patients must be given the opportunity to make medical treatment choices. Based on legal and clinical precedents, guidelines must be established for determining the choice-making competency of persons unable to make their own decisions. PMID- 10103656 TI - Continuing Education Program Handbook on Maintenance of Certification. American Medical Record Association. PMID- 10103657 TI - American Medical Record Association. Standards for Maintenance of Certification. PMID- 10103658 TI - Making RBRVS and physician payment reform a reality. PMID- 10103659 TI - ASIM and the long road toward RBRVS. PMID- 10103660 TI - Medical outcome data and physician feedback: walls are coming down! AB - Physician study groups or task forces based at the local or state level can play an important role in monitoring and disseminating outcome data. Twelve states already have begun pilot projects to look at data on practice variations. PMID- 10103661 TI - What's ahead for the Public Health Service?. Interview by Janice C. Simmons. AB - Dr. Mason, who took over as head of the Public Health Service a year ago, talks about the agency's responsibilities in dealing with AIDS, health manpower shortages and medical treatment effectiveness. PMID- 10103662 TI - Facing up to the medical legacies of the 1980s. PMID- 10103663 TI - What's the next step for outcomes assessment? AB - A series of initiatives are being launched nationwide to provide health status and clinical information to physicians in a variety of settings. What needs to be done, though, to ensure their validity and clinical usefulness? PMID- 10103664 TI - Seeking effectiveness in health care: the federal perspective. AB - The former Health Care Financing Administration chief, now working at the White House, says that although it is important for the government to fund medical effectiveness research, input from practicing physicians is important. PMID- 10103665 TI - To the lighthouse. PMID- 10103666 TI - Common goals across oceans. PMID- 10103667 TI - Help from home. PMID- 10103668 TI - A workload shared. PMID- 10103669 TI - The standard bearer of Thatcherite policy? PMID- 10103670 TI - Facing up to demand. PMID- 10103671 TI - Waiting to be served. PMID- 10103672 TI - Plan ahead for the future. PMID- 10103673 TI - A sporting chance for health. PMID- 10103674 TI - Coded messages on a matter of principle. PMID- 10103675 TI - Healthcare data briefing: race and health. PMID- 10103676 TI - Treating the malaise in time. PMID- 10103677 TI - Slipping through the net. PMID- 10103678 TI - Stand up for patient rights. PMID- 10103679 TI - Home away from home. PMID- 10103681 TI - Tea and sympathy on wheels. PMID- 10103680 TI - Power to prevent. PMID- 10103682 TI - Waste for profit. PMID- 10103683 TI - Needs assessment made simple. PMID- 10103685 TI - The charity challenge. PMID- 10103684 TI - Escape the trap. PMID- 10103686 TI - Market for health. PMID- 10103687 TI - Data in the districts. PMID- 10103688 TI - Capturing accuracy. PMID- 10103689 TI - Rural hospital survival: an analysis of facilities and services correlated with risk of closure. AB - To test whether the facilities and services offered by rural hospitals can put them at risk of closure or protect against it, this study compares U.S. rural community hospitals that closed during the period 1980-1987, with a matched set of hospitals that remained open. Utilizing epidemiologic matched case-control methods and controlling for type of ownership, we found that (1) physical therapy, respiratory therapy, intensive care unit, computed tomography scanner, hospital auxiliary, and diagnostic radioisotope were negatively correlated with closure (i.e., had a protective effect); (2) the facilities and services correlated with risk of closure differed significantly between the pre-PPS (1980 1983) and post-PPS (1984-1987) periods; and (3) the presence of a skilled nursing or other long-term care unit was a significant risk factor during the period 1984 1987. Implications of these findings for hospital survival strategies and rural health care delivery under PPS are discussed. PMID- 10103690 TI - Intraoperative autotransfusion: a community program. AB - The Southern Arizona Regional Blood Program of the American Red Cross in cooperation with Tucson hospitals conducted a pilot program of the provision of intraoperative autologous transfusion services. The service provided instruments, staff, and disposables to salvage and wash red cells shed during scheduled and emergency surgical procedures. The lower cost and other efficiencies of providing this service through a regional blood center suggest that it may be more appropriate to offer this service on a regional basis than exclusively within a hospital. Hospitals and regional blood centers should consider offering this advanced form of hemotherapy to their communities. PMID- 10103691 TI - Control and support: what physicians want from hospitals. AB - It has been asserted that physicians hold the key to success in hospital efforts to increase admissions and contain costs. While there is a great need to forge a partnership with the medical staff in achieving mutual goals, little is known about what physicians want from hospitals. A survey was completed by 177 physicians in two Cleveland-area hospitals that assessed their preferences on issues concerning hospital governance and control, hospital services, and hospital employment of physicians. Results showed that physicians want greater involvement in hospital decision making and desire services that facilitate their practice of medicine. Responses varied significantly according to physician age, specialty, HMO participation, and multiple-staff membership. Greater effort on the part of hospital administrators to assess and understand medical staff needs is suggested. PMID- 10103692 TI - Public information on private practice: the availability of physician inpatient data. AB - Despite increased interest in information describing physicians and their hospitalized patients, little attention has been given to the availability of these data and the related policy issues. We surveyed the 20 states with a publicly mandated data system based on hospital discharge abstracts that included physician information. States vary considerably in their orientation toward the public availability of the information and in the ability to personally identify physicians from the data. Potential benefits and problems in using the information for health services research, in improving the quality of care, and in analyzing practice patterns are reviewed. The policy issues associated with the collection and use of publicly available data on physicians and their hospitalized patients are discussed. PMID- 10103693 TI - ROI (return on investment): its role in voluntary hospital planning. AB - Return on investment is the primary financial criterion used to evaluate the desirability of capital investment in investor-owned firms. Voluntary health care firms need to examine more carefully their return-on-investment levels. The potential loss of capital cost payment in the Medicare program and the removal of tax-exempt financing would raise the effective cost of capital to voluntary health care firms significantly. Many health care providers might find that they are no longer going concerns if capital costs increase much more. PMID- 10103694 TI - Diversification behavior of multihospital systems: patterns of change, 1983-1985. AB - Studies of diversification in the health care sector have typically focused on hospital-level activity. Little attention has been given to the broader organizational context in which many hospitals operate (multihospital systems, parent holding companies). This article empirically examines diversification behavior of 100 multihospital systems between 1983 and 1985 in order to assess how systems respond to resource constraints, uncertainty, and competitive pressures on inpatient care. Patterns of diversification are identified, and their implications for systems strategic behavior are discussed. PMID- 10103695 TI - Detection and prevention of ambulatory care pharmacy dispensing errors. AB - There have been few studies of errors committed in ambulatory care pharmacies. Errors can be classified as incorrect strength, wrong product, wrong dosage form, wrong quantity, incorrect or omitted labeling (such as directions, patient's name, prescriber's name, auxiliary label, drug name, or strength), dispensing deteriorated drugs, and dispensing in non-childproof containers. Errors can be prevented by possessing and using knowledge, by proper performance and by having good systems in effect to prevent and/or uncover errors. Some contributing factors, which cause errors, are distraction and interruption, poor work habits, thoughtless robot-like performance, workloads past the safety threshold, poor working conditions, poorly written and incomplete prescriptions. A prime system to prevent errors from reaching the patient is the old tried and true system of having work checked by another person. The use of patient profiles can aid in reducing errors. The activity of patient counseling can reduce errors. Suggestions are made to reduce the number of errors made. A simple quality assurance program is presented. Case studies of medication errors are presented. The future use of bar-coding should be an extremely useful tool for preventing medication errors. PMID- 10103696 TI - Evaluation of drug interaction microcomputer software: Dambro's Drug Interactions. AB - Dambro's Drug Interactions was evaluated using general and specific criteria. The installation process, ease of learning and use were rated excellent. The user documentation and quality of the technical support were good. The scope of coverage, clinical documentation, frequency of updates, and overall clinical performance were fair. The primary advantages of the program are the quick searching and detection of drug interactions, and the attempt to provide useful interaction data, i.e., significance and reference. The disadvantages are the lack of current drug interaction information, outdated references, lack of evaluative drug interaction information, and the inability to save or print patient profiles. The program is not a good value for the pharmacist but has limited use as a quick screening tool. PMID- 10103697 TI - Medication-related law suits against the hospital. PMID- 10103698 TI - Recognizing the job hunting pharmacist. PMID- 10103699 TI - Heparin versus saline flushing solutions in a small community hospital. AB - Since no nursing policy on flushing procedures existed in their small community hospital, the authors thought it would be useful to clarify recent reports of the equivalency of saline to heparin flushes in their patient group before establishment of such a policy. They conducted a 2 month double-blinded, cross over study of catheter failures when using either saline or heparin 10 units/mL flushing solutions. All medical and surgical floor patients were included in the study. Floor nurses were used as observers and characterized catheter failures as either loss of patency or phlebitis. Heparin was shown to cause more phlebitis than saline (p less than .025), but no difference was found between the two flushing solutions in loss of patency. Data revealed a statistically significant advantage to using saline flushes when both loss of patency and phlebitis were combined (p less than .05). They recommended adoption of a flushing procedure which did not contain heparin. PMID- 10103700 TI - Use of a personal computer to support an investigational drug service. AB - A description of the rationale for the computerization of an Investigational drug service, (IDS) including the potential for benefits in three major areas: (1) policy & procedure, (2) financial analysis, and (3) drug accountability. Through the use of readily available computer software, dispensing, and billing procedures have been streamlined. Software with spreadsheet capability facilitates analysis of the financial status of the IDS. A specially designed software package allows maintenance of the drug account-ability records for investigational protocols. PMID- 10103701 TI - Drug interaction micromputer software evaluation: RxTriage. AB - RxTriage was evaluated using general and specific criteria. The installation process, ease of learning and use, and technical support were rated excellent. The user documentation was good. The scope of coverage, frequency of updates and overall clinical performance were good. The quality of the clinical documentation, which included key drug interaction texts and primary references, was excellent. The primary advantages of the program are the quality of its data base and interaction information and the inclusion of decision support tables. The disadvantage is the relative high cost as compared to other available microcomputer programs. PMID- 10103702 TI - Development of an adverse drug reaction reporting program self-study module for nursing personnel. PMID- 10103703 TI - Dosing guidelines for common neonatal and pediatric emergency drugs. AB - In some instances, pediatric emergency drug use will be necessary in areas besides the neonatal intensive care unit, or emergency rooms of hospitals which treat children. It is essential in the non-specialized areas that an easily accessible, relevant, source of drug information be available for emergency drug use. Drug dosing guidelines and monitoring parameters for the pediatric population for 14 emergency drugs have been compiled into an easy-to-read compendia in order to assist physicians, residents, nurses, and pharmacists in instances when time is crucial. PMID- 10103704 TI - A review of MINSQ graphic software and APEX hospital pharmacy software. PMID- 10103705 TI - Quality management in a multi-hospital system: a single standard of care. PMID- 10103706 TI - The cost of a quality assurance program in a university hospital. PMID- 10103707 TI - The role of a policies and procedures coordinator for the department of surgical services. PMID- 10103709 TI - Information systems education for future health services administrators. PMID- 10103708 TI - Thresholds are traffic controls. PMID- 10103710 TI - The CIO's (chief information officer) location in the organizational structure: implications for health administration education. PMID- 10103711 TI - Technological glitter can't replace IS basics. PMID- 10103712 TI - Impact of technology in health care and health administration: hospitals and alternative care delivery systems. AB - Applications as outlined above and many more that have not yet even been identified--but that will be invented and developed--will have an enormous impact on the health care industry. Clearly, capital requirements to purchase this technology will go up and thus exert further pressure for the reduction of personnel. Computers and robots will replace a significant percentage of health care personnel; overall health care costs as a percent of gross national product will nevertheless probably continue to rise in spite of improvements in productivity. Added costs will be offset in part by the use of technology in areas that will impact efficiency. Because of these accelerating uses of sophisticated technology, future administrators will have a greater appreciation for what technology can offer. Practical uses of robotics, expert systems, and artificial intelligence will require administrators to be technologically proficient. PMID- 10103713 TI - An ideal curriculum model. PMID- 10103714 TI - Continuing education needs of board members, administrators, and health care personnel. AB - Our society is becoming more aware of the basic fact that education is a lifelong process. The dynamic world in which we live requires that we continually update our knowledge and skills. Educational institutions that have traditionally viewed their mission as one of providing a sequence of courses leading to a specific degree are now expanding their role to include postgraduate nondegree offerings. The MIS area certainly ranks high among those fields that have a dynamic characteristic. Institutions with particular academic strength in this area can provide a needed service--and at the same time create a market niche for themselves--by developing and presenting continuing education programs in the area of MIS. PMID- 10103715 TI - Are you high tech and no touch? A new medical term for you: customer. PMID- 10103717 TI - EMS comes of age. Views on the lessons of the '80s applied to the '90s. PMID- 10103716 TI - Trading places. Paramedics in the hospitals, nurses in the field. PMID- 10103718 TI - Barrier fabrics: the need for a standard strikethrough test. PMID- 10103719 TI - Medical waste quality monitoring: changing employee behavior. PMID- 10103720 TI - Selecting a medical waste disposal service. PMID- 10103721 TI - Medical waste disposal methods: one hospital's solution. PMID- 10103722 TI - Aeration of respiratory therapy items--are you really aerating? AB - Ethylene oxide vapor (EtO) may be contained inside sterlized packages, even after many hours of aeration if the items are not properly prepared. First, the items must be disassembled. Second, the items must be aerated for the minimum length of time specified by the product manufacturer, including those items specified for the types of packaging material used. This article presents results of testing respiratory therapy items for residual EtO, and makes recommendations for effective aeration. PMID- 10103723 TI - Pressure relieving beds. PMID- 10103725 TI - Wanted: risk takers and peacemakers. PMID- 10103724 TI - Who was that masked man...? PMID- 10103726 TI - Working safely with EtO. PMID- 10103727 TI - For three years, I treated the wrong patient. PMID- 10103728 TI - Why some colleagues' fees are sky-high. PMID- 10103729 TI - Groups are still bidding top dollar for the doctors they want. PMID- 10103730 TI - Improving productivity: the administrator's point of view. PMID- 10103731 TI - A sweeping QA program for a large hospital lab. PMID- 10103732 TI - Seeking (and finding) painless QA in a tiny lab. PMID- 10103733 TI - Making the most of site visits to choose a new LIS (laboratory information system). PMID- 10103734 TI - On-line laboratory section budgeting. PMID- 10103735 TI - Limited funding mutes minority project's applause. PMID- 10103736 TI - Allegheny General Hospital's tax-exempt status challenged. PMID- 10103737 TI - Construction & architects survey. More hospitals ready to rebuild. PMID- 10103738 TI - Drexel bankruptcy filing may hinder junk deals. PMID- 10103739 TI - Senate panel investigating healthcare auditors. PMID- 10103740 TI - Utilization review firms to establish voluntary accreditation commission. PMID- 10103741 TI - Measuring the performance of hospital governing boards. PMID- 10103742 TI - Weight-loss market's fat profits are fading. PMID- 10103743 TI - Self-insured employers limit AIDS benefits. PMID- 10103744 TI - A look inside X-ray film price increase shows the costs of 'extras' piling up. PMID- 10103745 TI - CFO award winner reports on Harvard. PMID- 10103746 TI - More workers striking over healthcare benefits. PMID- 10103747 TI - Antitrust probe delays proposed acquisition by San Jose system. PMID- 10103749 TI - Aggressive action changes community hospital's image to reflect profitability. PMID- 10103748 TI - Advertising pact scrutinized for possible antitrust violations. PMID- 10103750 TI - Healthcare's future found in outpatient alternatives. PMID- 10103751 TI - Hospital managed-care pact rewards quality. PMID- 10103752 TI - Cleveland Clinic to buy hospital in Ft. Lauderdale from HealthTrust. PMID- 10103753 TI - Hahnemann, Allegheny end discussions on affiliation. PMID- 10103754 TI - Charges stabilizing for inpatient rehab--study. PMID- 10103755 TI - Comparative data pressure providers to keep costs down. PMID- 10103756 TI - Selling receivables can be costly, beneficial. PMID- 10103757 TI - OBRA reform necessitates a conflict resolution process. PMID- 10103758 TI - What we need is a new attitude. PMID- 10103759 TI - "Adopt a Nursing School" program targets students. PMID- 10103760 TI - Training your staff can be a win-win position. PMID- 10103761 TI - The Social Accountability Budget: a tool for nonprofits. PMID- 10103762 TI - Long term care pharmacists to play a more proactive role. PMID- 10103763 TI - Wanderer security systems offer choices, diversity. PMID- 10103764 TI - Nurse assistant training. PMID- 10103765 TI - Dealing with disaster. PMID- 10103766 TI - Point/counterpoint: national health insurance. AB - In early November at the annual Board of Directors meeting of the Federation of American Health Systems, Chrysler Corporation's Walter B. Maher spoke for health care reform, stressing a need for a strong government solution. Humana Inc.'s George Atkins rose to the defense of the health care industry and countered Maher's ideas with his case for expansion of existing government programs coupled with a larger share of cost responsibility falling to employees. PMID- 10103767 TI - Voluntary guidelines for managed care. PMID- 10103768 TI - Universal access: debate goes national. PMID- 10103769 TI - Grass roots in Minnesota. PMID- 10103770 TI - The problem of the drug-exposed newborn: a return to principled intervention. PMID- 10103771 TI - Eliminating future tense. Stress and the healthcare manager. PMID- 10103772 TI - Magnetic resonance spectroscopy & spectroscopic imaging. PMID- 10103773 TI - The sequential encounter evaluation. A tool for quality assurance. AB - A technique for retrospective quality assurance studies is described. The radiologic imaging studies employed on a sampling of patients were retrospectively evaluated. Each encounter between the patient and the radiology department was reviewed and assessed to determine if the patient's workup was assisted by the encounter, unaffected by the encounter or adversely affected. A scoring system is described and criteria for appropriate utilization of radiologic studies suggested. PMID- 10103774 TI - The workstation in radiology. PMID- 10103775 TI - Restructuring hospital costs to improve solvency and prevent bankruptcy. AB - The authors present a framework, derived from successful experience with an actual hospital turnaround, for helping hospital management to restructure costs quickly and strategically under the pressure of losses. The framework isolates structurally inefficient hospital overheads into four distinct categories and prescribes very different corrective actions for each of them. Application of the framework to bankruptcy is also discussed. PMID- 10103776 TI - AOHA (American Osteopathic Hospital Association) members enter '90s in good financial health. PMID- 10103777 TI - Special report. Severity-of-illness systems produce cost, MD behavior changes users say. PMID- 10103778 TI - Agitation and falls in institutionalized elderly persons. AB - The occurrence of falls and the manifestations of three dimensions of agitation (aggressive behaviors, physically nonaggressive behaviors, verbal behaviors) were recorded in 408 nursing home residents during each of the three nursing shifts. Falls occurred most frequently during the busiest shift (the day shift) and least frequently during the night shift when most residents were sleeping and nursing staff were not as busy, a result that confirms previous reports. In comparison to residents who did not fall, residents who fell manifested significantly more physically nonaggressive behaviors, more aggressive behaviors, more verbally agitated behaviors, and overall, a greater total number of agitated behaviors. PMID- 10103779 TI - Working with the elderly: a one-year internship training program combining practice and theory. AB - The Golden Age Association, a 6,000-member senior center, provides educational, recreational, social, cultural, and physical activities to well, aged people. In 1983, a training program was developed to enable the center to offer new services and programs to a growing senior population during a time of budgetary restrictions. The importance of maintaining and increasing the quality of life of seniors was paramount. A program was designed to recruit and train intern/staff assistants for a practical and theoretical one-year course. They received hands on experience in the center and participated in an ongoing gerontology course. The center's goals were to provide high-caliber workers and generate a group of skilled people to work with seniors in the center and elsewhere in the community. This article focuses on recruitment, training, job assignment, and the evaluation process. The plausibility of this type of program is explored using a nontraditional adult education model and the "teachable moment" as well as staff intern-volunteer relationships. This program is an example of what can be done to provide service and simultaneously train future gerontology workers. PMID- 10103780 TI - Ohio community mental health center directors' perceptions of programming for older adults: an exploratory study. AB - This study of Ohio CMHC directors' perceptions examines three systems dimensions: how mental health services are provided to elders, levels of service needs and whether they are met, and barriers to service delivery. Two distinct types of centers are compared--those that do and do not have specialized geriatric components. Specialized programming efforts appear to be making a difference in bridging the gap between levels of service delivery and need. PMID- 10103781 TI - Assessing social welfare programs for the elderly: the specification of functional goals. AB - Social welfare planners have lacked clear, functional goals against which to evaluate the performance of social and health programs. The authors construct a model for assessing the extent to which a community's services are addressing the independence and behavioral functioning needs of its elderly residents. The model is evaluated using service data from a middle-income midwestern community. PMID- 10103782 TI - Aging in place: a dilemma for retirement housing administrators. AB - The phenomenon of aging in place poses fundamental questions for administrators and planners of housing for the elderly. Based on a planning study for one retirement facility in the upper Midwest, we reviewed current knowledge pertinent to aging in place and present the findings of interviews with 13 housing administrators and present some limited market analysis of the host community of the subject retirement facility. PMID- 10103783 TI - Perspectives. ProPAC & hospitals: agreeing to disagree. PMID- 10103784 TI - Upgrading medical helicopters. PMID- 10103785 TI - The effect of an airway algorithm on flight nurse behavior. AB - This study examined the effects of a clinical algorithm (based on Glasgow Coma Scale) on the airway management of patients transported from the scene of accident or illness by a helicopter emergency medical service staffed with two flight nurses. The year before institution of the algorithm was compared to the subsequent year. Patients from the two years were similar with regard to diagnoses and physiologic status. Patients transported after the introduction of the algorithm were over twice as likely to have had an airway maneuver attempted. An algorithm defining when airway maneuvers ought to be attempted in the field may assist flight nurses in more aggressively managing airways. PMID- 10103786 TI - The judiciary: surprising supporters of malpractice reform. AB - Are the judges surprising supporters of malpractice reform? What is the overall message of the ACOG survey of judges, and how can organized medicine use that message? On balance, the ACOG survey of judges shows that they agree with physicians who argue that the present system needs to be changed. The overall message is that the present tort system does not work very well in the area of expert witness testimony, the system of jury decision-making, or the awarding of damages. Since it does not work very well, the medical community must continue to advocate changes to the system, ones that are fair to society as a whole. The judges' opinions on what reforms would better serve society can be persuasive data to present to state and federal legislators. So it's not just lawyers vs. doctors anymore. After all, the judges are lawyers, too. And these lawyers seem to be on the doctors' side. PMID- 10103787 TI - Pediatric acquired immune deficiency syndrome (AIDS); health care demonstration projects--HRSA. Notice of availability of funds. AB - The Bureau of Maternal and Child Health and Resources Development (BNCHRD), Health Resources and Services Administration (HRSA) announces that Fiscal Year (FY) 1990 funds are available for grants for Pediatric AIDS Health Care Demonstration Projects, Pediatric AIDS Comprehensive Center Demonstration Projects, and National Issues of High Priority. Projects will be funded to demonstrate strategies and innovative models for intervention in pediatric AIDS and coordinated services for children, youth, and women of childbearing age with Human Immunodeficiency Virus (HIV) infection, AIDS or other related conditions, or those at risk for developing infection and its consequences. Funds were appropriated for this purpose by Public Law 101-166. PMID- 10103788 TI - Privacy Act of 1974; new routine use and system of records name change--HHS. Notification of a new routine use and system of records name change. AB - The Public Health Service (PHS) is publishing notice of a new routine use, responding to comments, changing the system name, providing the contractor's address, and making editorial clarifications for system of records: 09-15-0054, "Health Care Practitioner Adverse Credentialing Data Bank, HHS/HRSA/BHPr", now titled "National Practitioner Data Bank for Adverse Information on Physicians and Other Health Care Practitioners, HHS/HRSA/BHPr." PMID- 10103789 TI - Health care facilities demand reliable electrical distribution systems. AB - The electrical distribution system is the lifeline of a hospital. Redundancy, flexibility and reliability are key components to keep in mind during design. PMID- 10103790 TI - Standby power for critical areas: hospitals. AB - Selecting an emergency standby power system for critical areas is a task requiring a thorough knowledge of available systems and the loads that must be covered. PMID- 10103791 TI - A pediatric chronic illness transition unit. AB - A four-bed Chronic Illness Transition Unit (CITU) for the care and developmental support of children who require long-term hospitalization is described. The goal is to discharge patients to the home or the best alternative environment as expeditiously as possible. The layout, staffing, and equipment; the importance of regional coordination; and components that increase viability of such a program and unit are discussed. The costs of construction and the projected costs of service are reviewed. It is hoped that others can use this experience to establish pediatric transition units, thereby improving care, developmental stimulation, family support, and placement of children with severe chronic illnesses. PMID- 10103792 TI - Capturing new human services markets. A revenue-generating strategy. PMID- 10103793 TI - Positive stress for health care providers. PMID- 10103794 TI - Dealing with the difficult patient-family and remaining sane. PMID- 10103795 TI - The personal side of caring for persons with AIDS. PMID- 10103796 TI - Medicating home health patients. Considerations for the caregiver. PMID- 10103797 TI - An international perspective on home care. Trends and highlights in six countries. PMID- 10103798 TI - How to succeed in the home care business in the 1990s. PMID- 10103799 TI - Partners in accreditation. PMID- 10103800 TI - Patient representatives and the law. PMID- 10103801 TI - Risk management comes of age. PMID- 10103803 TI - CHA's new CEO. Interview by Henrik Bent Axel Andersen. PMID- 10103802 TI - Bridging the gaps. PMID- 10103804 TI - The decade takes shape: computers in healthcare for the 90's. AB - The healthcare industry in the 1990s will continue to be driven by the three primary issues that emerged in the '80s--the need to improve productivity, profitability and quality of care. The critical difference for the '90s, however, is that these issues will reach a crisis point that will demand resolution. PMID- 10103805 TI - Then and now: how far have we come? Part I. AB - The political, technological and economic forces of the turbulent '80s mandated changes in the way the American healthcare sector conducted the business of caring for people. In this first of a two-part series, Computers in Healthcare examines the evolution of healthcare computing in several key application areas. Part I will explore progress in laboratory, radiology, patient accounting, case mix and patient care systems. PMID- 10103806 TI - Voice entry in the lab. PMID- 10103807 TI - Case management in healthcare information systems. PMID- 10103808 TI - A new approach to decision support at Adventist Health Systems/Sunbelt. PMID- 10103809 TI - A wish list for the 1990's. PMID- 10103810 TI - Life extension, patient values & dietitians. PMID- 10103811 TI - Best of both worlds. PMID- 10103812 TI - Vital truths about managing your costs. AB - Four truths apply to every business situation: 1. It is essential to be a lower cost supplier. 2. To stay competitive, inflation-adjusted costs of producing and supplying products and services must trend downward. 3. The true cost and profit pictures for each product/market segment must always be known, and traditional accounting practices must not obscure them. 4. A business must concentrate as much on cash flow and balance-sheet strengths as it does on profits. In order to ascertain exactly what your costs are, you must carefully isolate and assign various costs to specific products, accounts, or markets. Managers often do this badly, working on the basis of "average" costs. This ignores important differences among products and the fact that different products, different markets, and different customers incur different overhead costs. Most manufacturing companies' most important expense categories are R&D, sales, and general and administrative costs, but surprisingly, they generally don't get the attention they should. Neither do two crucial ratios-gross margin and the percent of assets employed per dollar of sales. Gross margins should usually not be less than 40%, and for most manufacturing companies, assets should not be over 60% of annual sales. Wrong deviation from these ratios will undermine profit targets. Once your costs are known and clearly assigned to product lines, markets, and key customers, they should be widely shared in the organization so that everyone will feel committed to cost management and know when deviations occur. PMID- 10103813 TI - The state of American management. AB - Every year, the president of the United States offers his State of the Union address. Here, from one of the most respected managers in America, is a report on the State of American Management. The state of management, says Walter B. Wriston, is good. Despite the predictions of America's decline, our economy continues to prosper. That is because of this fundamental truth: the United States is the only country in the world that renews itself daily. This is the Age of Pluralism, and U.S. business is based on pluralism. The spirit of the entrepreneur has entered the mainstream of U.S. management, transforming bureaucracy and emphasizing leadership. Today's top executives need to be more like politicians than the number-crunchers of yesterday. At the same time, information is flowing more freely, so corporations are eliminating layers of managers who were really just transmission lines. And top managers are learning to listen to the people who are closest to the work. Everyone today is a knowledge worker. The accelerating pace of knowledge has put a greater premium than ever on talent. Globalization is a big part of this new world. From the manager's viewpoint, globalization means that "you're in a marketplace where you're suddenly waking up with a guy...from a country you're not too sure where it is, who's eating your lunch in your hometown." To understand global competition, managers in large and small companies need broad vision. Finally, to deal with change, U.S. managers must confront some issues at home. For instance, our accounting systems are obsolete, both in companies and in our national accounts.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10103814 TI - The staying power of the public corporation. AB - Has the publicly held corporation out-lived its usefulness? In HBR's September October 1989 issue, Michael C. Jensen of the Harvard Business School said "yes." The institutional shortcomings of the public corporation are so grave, he argued, that it must be considered fatally flawed. He described the emergence of a new form of enterprise-the LBO Association-that releases much of the untapped value and corrects many of the inefficiencies of large public companies. Alfred Rappaport, a professor and consultant who advises large public companies, joins the debate with a rebuttal to Jensen. Rappaport shares many of Jensen's criticisms of current strategic and financial practices among public companies. But he does not believe leveraged buyouts and other going-private transactions can replace the public corporation. This is so, he asserts, for two reasons: LBOs have a limited demand and a limited life. Rappaport argues that the publicly held corporation is worth saving. It is inherently flexible and self-renewing properties that are fundamental to stability and progress in a market-driven economy and that transitory organizations like LBOs cannot replicate. Rappaport advances a four-point program to overhaul strategic planning, compensation, and governance to maximize shareholder value in public companies: 1. Find the highest valued use for all assets. 2. Limit investment to opportunities with credible potential to create value. 3. Return cash to shareholders when such value creating investments are not available. 4. Establish incentives for managers and employees to focus on the critical business drivers that create value. PMID- 10103815 TI - An interview with: James Cuthbertson. PMID- 10103817 TI - Screening: a method to prioritize patient care. PMID- 10103816 TI - Getting disabled workers back on the job. PMID- 10103818 TI - Quality food service: developing a critical palate. PMID- 10103819 TI - Optimal utilization of clinical dietitians. PMID- 10103820 TI - Physicians as heroes: a dying breed? PMID- 10103821 TI - An idea whose time has come: AMRA has arrived in Washington, DC. PMID- 10103822 TI - Computerized medical records: the need for a standard. AB - Major concepts introduced in this paper are as follows. 1) Organization, with its attendant qualities of accuracy, consistency, legibility, completeness, and simplicity, is the heart of the medical record. Technology should not be allowed to obscure this goal. 2) The main function of the computerized medical record is data storage with the qualities of organization noted above. This function must be clearly separated from condensation, analysis, or other secondary manipulation of data. 3) Many aspects of data manipulation call for the judgment of a physician. This judgement may be aided by computer software, but not replaced by it. 4) Present technological barriers, most notably speed, permanent large storage, and voice input should not influence the design of the effective computerized record. Future technology will be able to service the carefully designed medical record. 5) Textual parts of the computerized medical record can follow a simple and machine independent outline format. All parts of the record should use a textual introduction emphasizing patient and record identification. 6) A patient profile is central to each patient file. Updating this profile as needed must be recognized as a primary function of the physician at every patient encounter. 7) Acceptance of a standard for the computerized medical record now, before technology has matured and software diversified, will avoid a pitfall commonly experienced in other fields and save substantial healthcare funds. This standard should be geared to the needs of physicians and patients, not to the constraints of technology. The future of medical computing is bright. Obstacles to the practical use of the computerized medical record exist, but we may expect these to vanish within a few years. The great challenge to physicians now is to take this opportunity to control a new technology, rather than to be driven by it. The soul of good medicine is not in the equipment available, but in the rational and carefully thoughtout use of those tools at hand. We must recognize now the need for a uniform style of computerized medical record before the technological establishment besieges us with a flood of specialized, non interchangeable, and expensive machines. Indeed, a bit of careful thought now as the foundation is laid can prevent the tangled confusion so typical of new technology. We have a golden opportunity to avoid a new round of escalating medical costs. PMID- 10103823 TI - The design and development of a satellite medical record center. AB - This article discusses the successful development of a medical record satellite through the collaboration of the Department of Medicine of the University of Rochester management and the Medical Record Department of Strong Memorial Hospital. PMID- 10103824 TI - Talent spotting in the theatre. PMID- 10103825 TI - A force to reckon with. PMID- 10103826 TI - Appliance of science. PMID- 10103827 TI - Eyes across the ocean. PMID- 10103828 TI - Breakthrough to help. PMID- 10103829 TI - Contracting data. PMID- 10103830 TI - Riding out the gale. PMID- 10103831 TI - Caring mutual support. PMID- 10103832 TI - Preventive measures. PMID- 10103834 TI - Small is beautiful: a profitable perspective. PMID- 10103833 TI - Break the legal chains. PMID- 10103835 TI - Bedtime buys. PMID- 10103836 TI - Achieving rational therapeutics through consensus-based protocols and follow-up. AB - In this exclusive Hospital Formulary interview, three key members of the therapeutics committee at Hartford Hospital, an 861-bed, private teaching hospital, discuss some of the techniques that they have used to ensure the development of a sound and effective formulary system within their institution. The committee emphasizes a policy-making approach that incorporates, up front, the expertise of key clinicians together with the best available information from the medical literature. Once committee policy has been set, implementation of drug use guidelines is largely automatic, and compliance is carefully monitored and reviewed. PMID- 10103837 TI - Treatment of intra-abdominal infections: cost comparison of ampicillin/sulbactam and clindamycin/gentamicin. AB - The cost of 2 g ampicillin/1 g sulbactam given IV piggyback qid was compared with 900 mg clindamycin admixed with 1.5 mg/kg gentamicin given IV piggyback tid for the treatment of perforated or gangrenous appendicitis in 116 patients. Fifty eight ampicillin/sulbactam-receiving patients incurred greater costs for IV supplies (+104.6/patient vs +67.9/patient) and nursing administration costs (+16.5/patient vs +10.7/patient). On the other hand, pharmacist and technician preparation costs were greater for the 58 clindamycin/gentamicin-receiving patients (+15.4/patient vs +13.3/patient). The clindamycin/gentamicin-receiving patients also incurred additional changes for laboratory fees and pharmacokinetic monitoring--+18.7/patient and +36.1/patient, respectively. When incorporating all cost parameters, there were no statistically significant differences in mean total drug therapy costs between the two treatment regimens--+433.3 +/- +58.5/patient for ampicillin/sulbactam and +373.8 +/- +86.2/patient for clindamycin/gentamicin. PMID- 10103838 TI - Unit dose pharmacy workload forecasting: validation of the pharmacy service unit model. AB - Departmental efficiency is a priority issue for hospital administration as third party payers maintain or reduce the level of reimbursement. This study validates the PHASU (PHArmacy Service Unit) model, which predicts the workload and productivity of a unit dose pharmacy. A PHASU equivalency system enabled the authors to develop a comparative standard for all pharmacy procedures. The procedure most reflective of workload is unit dose orders. Predicted productivity and staff requirements compare favorably to management engineering determinations. The PHASU model represents a reliable workload forecasting instrument that pharmacy managers can prospectively incorporate in the support of current and future pharmacy services. PMID- 10103839 TI - Physician-owned pharmacies under attack. PMID- 10103840 TI - Non-pharmaceutical JCAHO standards relating to pharmacy. PMID- 10103841 TI - Understanding how our own actions shape our world. Excerpts from a conversation with Peter Senge. PMID- 10103842 TI - Finding the right leverage point. PMID- 10103843 TI - Four examples of better problem-solving. PMID- 10103844 TI - A powerful tool for healthcare management. PMID- 10103845 TI - The learning laboratory. PMID- 10103846 TI - The megatrends--and the backlash. PMID- 10103847 TI - Niched. PMID- 10103848 TI - The perils of detachment. PMID- 10103849 TI - Hitting the target. PMID- 10103850 TI - Importing the Canadian plan. PMID- 10103851 TI - Healthcare system reform may be on the horizon. PMID- 10103852 TI - Hepatitis B: the silent epidemic. PMID- 10103853 TI - Home sweet homes. PMID- 10103854 TI - The renaissance of pastoral care. AB - Administrators are finding pastoral care has a future, and a vital one. Without question, the chaplaincy of the future will not be the same as the chaplaincy of the past. Its theology will remain a constant, and its roots will hold fast, but the services will change, along with the healthcare environment in which it operates. If it wants to be an integral part of the clinical team, pastoral care must address three critical areas: spirituality, outreach, and accountability. Healing is spiritual. The meaning and purpose patients find in life, as well as their involvement with the spiritual, are key healing indicators in their treatment. As the spirituality movement articulates its value within the practice of medicine, pastoral care departments are likely to be its principal catalysts. Pastoral care departments are reassessing their ability-and the need-to see every patient, and instead are identifying those patients who will most benefit from pastoral intervention. At the same time, pastoral care services are extending beyond the hospital and will be based in many other settings in the future. If pastoral care hopes to be indispensable in the healthcare setting, it must demonstrate that it makes a contribution and a difference. This requires developing and applying clinical standards to its ministry, as well as creating an empirical data base to substantiate the efficacy of pastoral care interventions. PMID- 10103855 TI - The professional chaplain. AB - In this technological age, when hospitals run the risk of becoming frightening and impersonal places, pastoral care departments have an obligation to ensure that they provide high-quality, professional service. One of the common themes of contemporary mission statements is the call for "holistic care"-- meeting the physical, emotional, social, and spiritual needs of patients. A second theme is the importance of providing high-quality care. In the past 20 years, the National Association of Catholic Chaplains has developed education and accreditation programs that have led to stronger, more effective pastoral care service and education. Although credentialing is not a panacea for all problems and conflicts, when persons work at developing personal, professional, and theological competencies, they are more successful in resolving conflict. In fact, well-prepared, certified chaplains enhance all aspects of the healthcare ministry. Finally, the effort to improve pastoral care provides an opportunity for all involved to "live the mission." Today's greater emphasis on team ministry allows the pastoral care department to be a model of community and dialogic relationship for the rest of the healthcare facility. PMID- 10103856 TI - The science of caring. AB - A downsizing crisis at Mount Carmel Medical Center, Columbus, OH, forced its Pastoral Care Department to begin thinking in terms of accountability. Trained in an intuitive style of chaplaincy, the staff distrusted a clinical approach to pastoral care. Nonetheless, when they found themselves scrambling to justify their existence, the entire department staff literally withdrew from the hospital for two days to redesign pastoral care. What evolved was a process of "focused care." It represented a radical departure from their traditional assumptions about chaplaincy in that henceforth they would (1) base their ministry on assessment of spiritual need, with primary attention to high-risk patient populations, (2) continue to provide eucharistic ministry through volunteers, but no longer rely on Catholic chaplains to carry out those duties, (3) no longer assume that a chaplain needed to be present at every death or medical crisis, and (4) no longer assume that the impact of a spiritual ministry could not be objectively measured. PMID- 10103857 TI - Pastoral partners. AB - To test the hypothesis that patients will receive a higher quality of holistic care through a "joint venture" of nurses and chaplains than they will from each individual working independently, a nursing unit of 30 medical/surgical beds was chosen for a six-month pilot study. Part of the experiment included the use of a small index card, which the nurse filled out with the patient's name, religion, and church. The card also included two questions. The first was directed to the patient: Do you want your church notified? The second was for the nurse: Would this patient benefit from a pastoral visit? The ward clerk gave the card to the assigned chaplain each day, and the chaplain saw those patients who the nursing staff believed would benefit from a visit. The nurses and chaplains developed a mutual respect for, and understanding of, each other's complementary role in the patients' care and, thus, became more competent in their approach to patients. The admissions clerk could become a part of the "joint venture" by asking the patient if he or she would like a church notified and wished to receive the sacraments (if Catholic). The nursing staff would then need only to assess whether the patient would benefit from a pastoral visit. Through this cooperation, the chaplain would be free to minister to patients with identified needs, especially to those most in need of care. PMID- 10103858 TI - Ministry in a climate of grief. AB - Chaplains are now being called on to minister in a climate of grief caused by organizational crises (e.g., downsizing, mergers, lay-offs). Such crises are disruptive and may cause panic and shock, as well as insecurity, for employees. The pastoral care department can play an important role in such a climate. To be effective, the department should have high status within the organization, with direct access to high-level executive, and it should be well regarded throughout the institution. The department should also be clearly visible. This includes participating on committees, visiting departments where the crisis is acute, and planning farewell receptions for employees being let go. Especially important is the chaplains' ability to listen to angry employees without feeling threatened or becoming defensive or judgmental. They must also speak up when problems surface, calling the organization to be accountable for issues of justice, ethics, values, and mission. PMID- 10103859 TI - Biomedical conflicts in the heartland. A systemwide ethics committee serves rural facilities. AB - Big-city medical research centers are not the only institutions facing ethical dilemmas. Bioethical conflicts occur regardless of community location or size. The Presentation Health Care System, Sioux Falls, SD, established a systemwide ethics committee. It owns, leases, or manages 15 rural institutions in four North Central states: South Dakota, North Dakota, Montana, and Minnesota. Of these facilities, 10 are hospitals and 5 are nursing homes. Most are located in small communities stretched along 1,100 interstate miles. The Presentation system began organizing its ethics committee in spring 1985. The ethics committee was to provide educational opportunities for its members, as well as for local facilities. These opportunities were to include subscriptions to appropriate publications, meetings with guest speakers, videos, and group "brainstorming" sessions. An annual ethics conference would provide community education and address the ethical issues confronting affiliates. Organizers scheduled a planning session at a systemwide leadership conference and invited anyone interested to attend. Eventually, 23 representatives of system affiliates were selected as members of the committee. The group meets twice a year. Since 1985, the committee has been holding ethics conferences on a regular basis. PMID- 10103860 TI - Pastoral care: attention to the sacred. PMID- 10103861 TI - Practitioner data bank to open soon. PMID- 10103862 TI - One man's triumph. PMID- 10103863 TI - Electrical safety testing of medical equipment in Japan. AB - In Japan, the manufacture and sale of medical electrical equipment requires the permission and license of the Ministry of Health and Welfare. Electrical safety tests must be conducted at an official institution. This paper presents the statistical results of a series of 404 safety tests of medical devices, reports the electrical safety problems encountered, and suggests electrical design considerations for safety. PMID- 10103864 TI - Making "management by objectives" work: the "QMPO" (quarterly management by priority objective) system. PMID- 10103865 TI - Escaping the charge of false imprisonment. PMID- 10103866 TI - How to write an RFP for automated systems. AB - There is no absolute formula for writing a good RFP. But materiel managers who want to utilize an RFP to facilitate selection of an automated system should: Plan and create the RFP with the cooperation of others. Direct the RFP only to vendors who survive an initial telephone screening. Clearly organize the document. Try to use questions that seek structured responses. Include all relevant information about the hospital the vendor will need to provide a meaningful response. Keep it simple. Be inclusive yet succinct. Use the RFP as a supplement to, not substitution for, communication with prospective vendors. PMID- 10103867 TI - Cleaning and decontaminating medical instruments. PMID- 10103868 TI - Contract administration: easy as "Lotus 1-2-3.". PMID- 10103869 TI - Advances in materiel management systems technology. AB - When evaluating materiel management systems for your needs into the 1990s, be aware that the hardware you choose could be just as important as the software. It should 1) provide flexibility for growth, 2) provide access to a unified database for departments on-site as well as in remote locations, and 3) be easily managed and maintained by those that need it for critical day-to-day information. Software developers are already incorporating the new technologies in their programs and systems designs for the 1990s. Being up-to-date on the new hardware and new software will help you evaluate the right materiel management information system. PMID- 10103871 TI - Workplace celebrations. PMID- 10103870 TI - Employee layoffs. PMID- 10103872 TI - The materiel cycle. PMID- 10103873 TI - Metropolitan and nonmetropolitan adolescents: differences in demographic and health characteristics. AB - The demographic and health characteristics of metropolitan and nonmetropolitan adolescents are examined based on a nationally representative sample of 15,181 randomly selected adolescents from the 1984 National Health Interview Survey. One third of all adolescents reside in nonmetropolitan areas of the United States. Nonmetropolitan youth differed from their metropolitan counterparts in race, population concentration in the South, poverty status, family composition, education of household head, and marital status. While the health status of metropolitan and nonmetropolitan youth were similar, their patterns of health services utilization and health insurance coverage were not. Nonmetropolitan adolescents made fewer physician visits and were more apt to delay seeking physician care than metropolitan youth. Adolescents in nonmetropolitan areas were also 39 percent more likely to be hospitalized and 30 percent more likely than metropolitan youth to be without any form of health insurance protection. Despite higher rates of poverty among nonmetropolitan adolescents, they were 20 percent less likely to be publicly insured. The delivery and financing implications of these distinct metropolitan and nonmetropolitan demographic and health characteristics are discussed. PMID- 10103875 TI - Ethics be damned! It's time to try contingency fees. PMID- 10103874 TI - The effects of area health education centers on primary care physician-to population ratios from 1975 to 1985. AB - The purpose of this study was to explore how the primary care (PC) physician-to population ratio changed from 1975 to 1985 in counties that were served by an Area Health Education Center (AHEC) in contrast to those counties that were not. The investigation attempted to determine whether any observed changes in this ratio were dependent upon either degree of urbanization or contiguity to a Standard Metropolitan Statistical Area (SMSA). The data source for this study was the Area Resource File. Results indicated that: (a) irrespective of AHEC status, increased degree of urbanization across counties was associated with relatively more PC physicians in both 1975 and 1985; (b) PC physician-to-population ratios increased from 1975 to 1985 for all American Medical Association (AMA) county code categories, regardless of AHEC versus non-AHEC designation; (c) AHEC counties demonstrated greater (or equivalent) absolute improvement for all AMA county code categories except for several categories which represented more urbanized counties; (d) for the least urbanized counties in the AMA code, the percentage improvement in PC physician-to-population ratios for AHEC counties ranged from 3 to 5 percent higher than corresponding percentage improvement in ratios for non-AHEC counties; and (e) AHEC counties showed greater absolute and percentage improvement in PC physician-to-population ratios than did non-AHEC counties for counties not contiguous to SMSAs. PMID- 10103876 TI - Nurses' salaries: how can doctors compete with hospitals? PMID- 10103877 TI - We've gone too far in letting patients make decisions. PMID- 10103879 TI - Heighten efficiency with an integrated bar code system. PMID- 10103878 TI - The flowering of managed care. PMID- 10103880 TI - We were guest stars at the science center for Lab Week. PMID- 10103882 TI - The future is your imagination. PMID- 10103881 TI - The evolution of regional health care systems: a look into the future. PMID- 10103884 TI - Trustee issues discussed from the national perspective. PMID- 10103883 TI - Doctors, hospitals: "Seize the day.". PMID- 10103885 TI - Hospitals go cold turkey on smoking. PMID- 10103886 TI - A decade for vision: the state of our health 1990. PMID- 10103887 TI - Auxilians of the future: dynamos or dinosaurs? PMID- 10103888 TI - Incentive plans used to attract and retain executive talent. PMID- 10103889 TI - The health care system is an idea whose time has come, again and again. PMID- 10103890 TI - Pepper Panel's healthcare blueprint omits funding, bipartisan support. PMID- 10103891 TI - For-profit chains look beyond the bottom line. PMID- 10103892 TI - Bill would provide AIDS relief. PMID- 10103893 TI - Caring for babies exposed to crack could cost $20 billion--government officials. PMID- 10103894 TI - Slower expansion helps second-tier chains leave troubles behind. PMID- 10103895 TI - Diversification strategy benefits innovative leader. PMID- 10103896 TI - As layoffs hit, Baxter tools for growth. PMID- 10103897 TI - Maxicare sues to reclaim payments. PMID- 10103898 TI - IRS crackdown may boost labor costs. PMID- 10103899 TI - IBM introduces bedside workstation. PMID- 10103900 TI - Rural elderly prefer urban care--study. PMID- 10103901 TI - Suppliers, vendors report increasing delays in getting their money from hospitals. PMID- 10103902 TI - Do mergers work? PMID- 10103903 TI - Merging hospitals learn costs of fighting antitrust challenge from Justice Dept. PMID- 10103904 TI - State's conditions guide merged hospital's actions. PMID- 10103905 TI - Justice lacks a credible case against some hospital mergers. PMID- 10103906 TI - Coalition to develop proposals to overhaul healthcare system. PMID- 10103907 TI - Major reforms urged for Louisiana hospital system. PMID- 10103908 TI - Proposed new 3rd-class rates would hike cost of direct mail. PMID- 10103909 TI - Radio station bars impotence ads. PMID- 10103910 TI - Healthcare bonds that violate covenants can be refinanced, but it's tricky. PMID- 10103911 TI - Nu-Med cancels hospital sales. PMID- 10103912 TI - VHA supplies to be checked for effects on environment. PMID- 10103913 TI - Physician antitrust case settled. PMID- 10103914 TI - Abbott chairman sues to keep job. PMID- 10103915 TI - Pasadena hospital to leave L.A. County trauma system. PMID- 10103916 TI - Senate committee approves bill providing aid for trauma systems. PMID- 10103917 TI - Hospitals stretch their creativity to motivate workers. PMID- 10103918 TI - Medical-injury study stirs malpractice debate. PMID- 10103919 TI - Failure to reach agreement may result in bankruptcy filing for four retirement centers. PMID- 10103920 TI - Nevada revenue-reduction law hasn't hurt hospitals. PMID- 10103921 TI - Study documents hospital's economic worth. PMID- 10103922 TI - Foundation sues over sale of French Hospital. PMID- 10103923 TI - Member drive aims to move union 'out front' in nurse organization. PMID- 10103924 TI - Junk bond woes likely to have few side effects. PMID- 10103925 TI - Parents help ease separation anxiety in ASC (ambulatory surgery center). PMID- 10103926 TI - Sources for statistics about surgery and operating rooms. PMID- 10103927 TI - House staff on-call scheduling: an intern's proposal. AB - House staff scheduling is currently one of the most important issues in graduate medical education. Proposals for regulation arose as a result of mistakes made by exhausted interns, and they involve doctors, hospitals, the public, and authorities. The New York State Department of Health recommendations include restricting work to less than 80 hours per week and shifts to less than 24 consecutive hours. PMID- 10103928 TI - Implementing a corporate quality management program: the AMI experience. PMID- 10103929 TI - Comprehensive quality measurement in the hospital emergency department. PMID- 10103930 TI - Quality assurance in outpatient medical records. PMID- 10103931 TI - Innovations and research review: the role of the ART (accredited record technician)--challenge and change. PMID- 10103932 TI - Incentives for completing medical records--the legal risks. PMID- 10103933 TI - Art therapy in Holland: defining a position in a hierarchical structure. PMID- 10103934 TI - How to live--or at least exist--with OSHA rules. PMID- 10103935 TI - Perspectives. Pepper watchers hopes dashed. PMID- 10103936 TI - EAPs (employee assistance programs): dawning of a new age. AB - New EAPs are being developed to cope with a wide range of employee problems. A plan focused on compassion can meet employees' needs and favorably affect the bottom line. PMID- 10103937 TI - All managers are HR (human resources) managers. AB - Employee frustration and turnover may be partly due to management's reliance on the HR staff. HR professionals should share their expertise with other managers, so they can effectively deal with some of their own staff problems. Find out how to help your organization's managers improve communications with their staff and, ultimately, improve the bottom line. PMID- 10103938 TI - Workplace flexibility. AB - Whether your organization is in a growth pattern or downsizing, you are probably facing change. To gain some insight into your options, here is an in-depth look at the problems and benefits of some flexible work arrangements from a just published study by Catalyst. PMID- 10103939 TI - Goliath had rights too. PMID- 10103940 TI - Setting up a temporary shop. AB - Instead of calling an agency to fill a temporary position, some companies especially in banking and health care, are taking care of the recruiting inhouse. Flexibility and quality seem to be the main reasons why companies are handling the extra responsibility. PMID- 10103941 TI - Compensation plan analysis. AB - Determining what share of the company's financial resources is used for compensation programs can be done through various mathematical processes. Some of the basic equations are discussed and examples are included in this article. PMID- 10103942 TI - Health screening goes to work. AB - On-site health risk assessment and screening can be more than just an employee relations gesture. These screenings at least have the potential to help control health care costs. PMID- 10103943 TI - How business is responding to the retiree dilemma. An HIAA/Johns Hopkins survey explores current status and future trends. PMID- 10103944 TI - Work-related accidents and deaths. National Safety Council. PMID- 10103945 TI - The trauma in trauma care. PMID- 10103946 TI - Cooperative agreements for minority community-based human immunodeficiency virus (HIV) prevention projects--HHS. Program announcement and availability of funds for fiscal year 1990. PMID- 10103947 TI - Position paper on occupational therapy in home care. The Canadian Association of Occupational Therapists. PMID- 10103948 TI - Assuring quality care and improving staff productivity through standard care plans. PMID- 10103949 TI - Pay-per-visit for staff. Saving money without sacrificing quality of care. AB - In summary, the VNA of Los Angeles has found that the pay-per-visit system provides tremendous costsavings and that it has eliminated visit productivity problems. Additionally, field staff have found that the system can improve their earning power. Although the development, initiation, and maintenance of the pay per-visit system requires a significant commitment of both time and effort, it is a system that we highly recommend to other home health organizations. PMID- 10103950 TI - Administrative priorities. Decisions and strategies that attract and retain quality staff. PMID- 10103951 TI - The physician's role in home care. A vital ingredient of quality assurance. PMID- 10103952 TI - Financial perspectives on hospice quality assurance. PMID- 10103953 TI - Rights of employees with AIDS. PMID- 10103954 TI - Measuring the quality of home health care--some important considerations. PMID- 10103955 TI - The outcome audit. Assuring quality care. PMID- 10103956 TI - Home care & public policy. PMID- 10103957 TI - Homemaker-home health aide training and competency-evaluation requirements: toward a national solution. PMID- 10103958 TI - Computer use in Canadian drug information centres. AB - In July 1988, a survey was conducted to determine the extent of computer use by Canadian drug information centres. A questionnaire, mailed to 36 major DI centres, yielded an 89% return. Computers were being used by 75% of the responding centres (65.6% personal computers, 9.4% mainframe). Word processing was the most popular computer application, followed by formulary maintenance, online literature searching, compiling workload statistics, pharmacokinetic calculations, storing answered requests, and storing journal article citations. Medline was the most common database accessed; the National Library of Medicine was the most popular vendor. Compact disc read only memory systems were used by 18.75% of centres. Some respondents reported developing internal programs for drug information. PMID- 10103959 TI - Tort law--scope of psychiatrist's liability for acts of released inpatients- Colorado Supreme Court holds psychiatrist liable under negligent release theory for violent act of involuntarily committed mental patient--Perreira v. State, 768 P.2d 1198 (Colo. 1989). PMID- 10103960 TI - Hedging opportunities in health care. AB - Medical care futures contracts offer new hedging opportunities to increase protection against unexpected price changes. Commodity futures contracts can be designed explicitly to hedge volatile group health insurance premiums and capitated hospital and physician prices. This article describes one way to design and use these hedging instruments. PMID- 10103961 TI - Approaches to medical practice valuations. PMID- 10103962 TI - Key strategic decisions and fine tuning for the 1990s. PMID- 10103963 TI - Turnaround owes success to new community strategy. PMID- 10103964 TI - Robert Davidge plans for growth of ambulatory care. Interview by Donald E.L. Johnson. PMID- 10103965 TI - Death and the health professional: organization and defense in health care. AB - Organizational and technological developments within the health care system have helped consolidate a power structure that dehumanizes clients and fosters defensiveness in professionals. Frequent exposure to death renders health professionals vulnerable to severe anxiety, which they may try to avoid through death denial, leaving them psychologically unable to support dying clients. Professional education, attitudes equating death with professional failure, organizational coping strategies among nurses, and staff burnout interact to perpetuate this atmosphere. As a model for learning, this article analyzes a pediatric case study to illuminate the manifestations of professional defensiveness. Finally, I consider three specific problem-solving strategies: improving morale, opening communication, and expanding professional education to include death studies and psychological study of the health organization. Bringing humanity back into the health care environment is possible to the extent that both the organization and its members are responsive and open to change. PMID- 10103966 TI - Guidelines to service quality control. PMID- 10103967 TI - Wanted: trust for a happy vision of the future. PMID- 10103968 TI - A role for doctors on the management scene. PMID- 10103969 TI - Change at the grass roots. PMID- 10103970 TI - A testing question. PMID- 10103971 TI - Ignored but still in need. PMID- 10103972 TI - Stick to the agenda. PMID- 10103973 TI - Keeping nurses mobile. PMID- 10103974 TI - A climate of trust. PMID- 10103975 TI - P&T Committee review of nifedipine GITS: new modality for angina and hypertension. AB - The nifedipine gastrointestinal therapeutic system (GITS) was recently approved for use in the treatment of angina and hypertension. According to the experts in this roundtable discussion, the GITS formulation provides continuous delivery of nifedipine, ensuring relatively constant drug levels and 24-hour efficacy with a once-daily dosage regimen. Nifedipine GITS also has a favorable side-effects and drug-interaction profile. This formulation will be useful for both inpatients and outpatients and may benefit patients in whom therapeutic levels previously could not be reached due to side effects. PMID- 10103976 TI - P&T Committee review of fluconazole: an effective alternative to antifungal therapy. AB - Fluconazole is a new antifungal agent available in both oral and parenteral formulations. According to the experts in this roundtable discussion, fluconazole represents a major clinical advance in the treatment of candidiasis and cryptococcosis in cancer patients, patients with AIDS, organ transplant recipients, and other patients at risk for opportunistic mycoses. The pharmacokinetic profile for fluconazole permits infrequent dosing and also makes it ideal for tissue site infections. Fluconazole's low toxicity gives it an advantage over currently available antifungal therapy and will permit prompt presumptive treatment of selected infections. PMID- 10103977 TI - Surgical staff resource management of the operating room. AB - Physician involvement in the resource decision-making process has become an increasingly important objective for administrations and boards. The clinical program budget approach was initiated in the operating room as a test case, combining elements of education, peer review and economic incentives. This trial was successful, resulting in greater awareness of costs as well as budget changes. The Victoria Hospital Corporation experience supports the future viability of clinical program budgeting. PMID- 10103978 TI - Evolution not revolution: health administration education for the 21st century. PMID- 10103979 TI - Health promotion: a life-long spectrum for health care facilities. AB - Although many traditional health care facilities were not called upon to contribute to health promotion and prevention in two statements from ministers of National Health and Welfare, many have well-established programs that complement treatment. As it is important to be able to measure the effectiveness of these activities, the author proposes that a Promotion and Prevention Index (PPI) be created within the health care system. The PPI, a percentage factor, would be applied to services and programs and, hopefully, provide a scale for formal recognition among traditional institutions. PMID- 10103980 TI - Hospital's child care center bolsters staff recruiting, retention. PMID- 10103981 TI - Subcommittees are key to better safety programs. PMID- 10103982 TI - Parking-facility design enhances safety, security. PMID- 10103983 TI - NFPA (National Fire Protection Association) proposes change in air-compressor rules. PMID- 10103984 TI - Survey: teaching facilities pay top CE salaries. PMID- 10103985 TI - Prepare HVAC equipment now for summer's heat. PMID- 10103986 TI - Health care construction boom to continue in '90. PMID- 10103987 TI - Antitrust decision focuses on sufficiency of evidence. PMID- 10103988 TI - Personnel faces the future. AB - Nic Seddon reflects on what the future holds for personnel staff in the NHS. His main concerns are the effects of the white paper, employment in the 1990s and the Single European Market. PMID- 10103989 TI - Private thoughts on public values. AB - Laurie MacMahon gives his views on why we should take care when applying private sector values to public-sector organisations like the NHS. PMID- 10103990 TI - Staff migration within the European community. AB - What will be the effects on the labour health market of 1992? Will there be a mass exodus of medical staff to other parts of Europe? Will Britain be flooded with doctors and nurses from abroad? Joanna Lyall reports. PMID- 10103991 TI - Mission statements. AB - With the move towards a far more business-oriented NHS, Lynne Carlisle looks at a private company whose efforts at staff communication could provide a useful lesson to health service managers. PMID- 10103992 TI - Training centre of excellence. AB - At Hensol Hospital in Mid Glamorgan a commercial conference centre has been set up to train staff in mental handicap services. As Alison Hyde reports, the centre's successes have not been just financial ones. PMID- 10103993 TI - Turning danger into opportunity. AB - Brian Edwards looks at the management of change required to pave the way for successful implementation of the white paper, and sees a challenging time ahead. PMID- 10103994 TI - Managing lawyers. PMID- 10103995 TI - Twisting and turning. PMID- 10103996 TI - Life, liberty and death. PMID- 10103997 TI - Redefining administrative liability. PMID- 10103998 TI - Surgical packs prices to rise 3%-7%. PMID- 10103999 TI - Hospitals vary in the amount of involvement materials managers have in capital equipment. PMID- 10104000 TI - Materials managers regard productivity and price competitiveness reports as essential to success. PMID- 10104001 TI - Materials managers must be wary of contract capacity in dealings with corporate suppliers. AB - Sometimes a hospital materials manager wonders if the parties with whom he contracts are really agreeing to the terms of the contract. Also occasionally there are facts which cause a question to arise as one's capacity to enter into a contract. These questions raise issues which are part of the foundation of our contract law. In this dialogue, Dr. Decker develops these basic issues. PMID- 10104002 TI - Managed care: ten leading trends for the 1990s. PMID- 10104003 TI - Flexible pay arrangements. The need for a systematic approach. AB - Regrading large numbers of staff is a difficult and sometimes painful exercise. Mike Palmer and Graham Martin describe how job evaluation was used in a restructuring of pathology staff and argue that the technique will be increasingly valuable when pay is settled at the local level. PMID- 10104004 TI - Setting standards in occupational therapy. PMID- 10104005 TI - Loaves & fishes by the sea. One answer to resource allocation. AB - How can community units ensure that services are provided on the basis of need rather than history? This article describes the efforts being made in Portsmouth and South East Hampshire (one of the country's largest health authorities) to meet this fundamental challenge. The approach taken is to match information on workloads, health care needs and neighbourhoods to facilitate effective resource management. PMID- 10104006 TI - Authority members and standards of clinical care. AB - Charlotte Williamson argues that in the post-white paper NHS authority members- and managers--will have to interest themselves more than they have previously in clinical care. In this first part of her article she defines individual and collective clinical care and non-clinical care, and discusses responsibility for standards in these different but overlapping aspects of care. In the second part of the article, to be published in our next issue, she will discuss setting standards locally. PMID- 10104007 TI - Dutch health reforms in the 1980s. AB - In the eighties most countries found it necessary to restrain or reduce health care expenditure, and it nowhere proved easy. Ute Ballay describes the consequences of efforts in the Netherlands to rationalise and control hospital budgets. PMID- 10104008 TI - Customer service and its role in health care. AB - "Customer service is an important constituent of marketing but it is not a substitute for marketing". Virginia Hayden explains what it is and why it is worth the money and effort. PMID- 10104009 TI - The context of health promotion in the NHS. AB - In connection with "Working for Patients" health authorities have been asked by the NHS Management Executive how they intend to perform their "core" functions. "Core" tasks for regions include: "monitoring and promoting the health of their populations (including the functions set out in HC(88)64), determining with districts and FPCs, the health needs of their resident populations; collecting and managing information which facilitates this. . ." ". . . District, in close collaboration with FPCs, will retain a key role in ensuring that the health needs of their populations are met; that there are effective services for the prevention and control of diseases and the promotion of health." Amanda Killoran reviews the context of health promotion in the NHS, and indicates the importance of developing nationally integrated programmes of disease prevention and health promotion. PMID- 10104010 TI - Who is likely to join a prepaid health care plan? A behavioral approach to identification. AB - The authors investigate the antecedents to intention to use a closed-panel prepaid health care plan. A diffusion model is applied to identify the significant antecedents to choice. The findings support the conclusion that consumer behavior models are suitable for studying health care consumers. PMID- 10104011 TI - Using condoms in the age of AIDS: a phenomenological study with marketing implications. AB - The authors examine respondents' potential reactions to the suggestion of condom usage by and to their sex partner. Results indicate that when a sex partner suggests condom use, individuals may react with a feeling of shared responsibility and/or look favorably upon the suggesting partner. In contrast, persons who suggest condom usage may be questioning their partner's past and envisioning a short-term relationship. The effects of individual-difference variables on feelings about condom usage are described and implications for marketing are delineated. PMID- 10104012 TI - Time preference, psychographics, and smoking behavior. AB - Following the lead of recent independent economic and consumer behavior theories in health behavior, the author investigates the link between three sets of variables and smoking status and intensity. Data from a nationwide survey show that consumer psychographic dimensions provide more meaningful and valid predictors of smoking intensity than consumer time preference and demographic characteristics. The time preference measures show that smoking decisions also involve economic-like choices. The three sets of predictive variables were able to discriminate smoking status (smokers, nonsmokers, and ex-smokers). Implications for public policy makers are discussed. PMID- 10104013 TI - Mergers in health care: can they be done? The lessons from Roanoke and Rockford. Interview by Michael B. Guthrie. PMID- 10104014 TI - Using mass transit public service advertising to market family planning. AB - To increase public awareness of family planning services in New Jersey, the Family Planning Program of the State Department of Health conducted an intermediary marketing campaign using free public service advertising on mass transit. In 1986, the year of the campaign, 237 calls were made to the advertised hotline, resulting in a like number of referrals to family planning service providers. Also, 2664 new patients examined in the state's family planning agencies in 1986 cited exposure to the media campaign as the reason for their visits. The results of the campaign and their implications for other public service agencies are discussed. PMID- 10104015 TI - Ethics in health care marketing: the Twin Cities perspective. AB - Do hospital-based marketers have a common perspective on what practices are ethical for the promotion of health services to consumers? Do they find adequate guidance in making ethical decisions on marketing practices from the mission statements of their institutions? The author sought answers to these questions through a survey of marketers and other health care professionals in the highly competitive Twin Cities health care environment. PMID- 10104016 TI - How patients evaluate the quality of ambulatory medical encounters: a marketing perspective. AB - Quality is becoming an important issue in marketing ambulatory medical services. Based on an empirical study, this article examines how consumers evaluate the quality of medical encounters and how providers can influence patients' perceptions of quality. PMID- 10104017 TI - Segmenting the mental health care market. AB - The authors report the results of a segmentation study of the mental health care market. A random sample of 387 residents of a western city were interviewed by telephone. Cluster analysis of the data identified six market segments. Each is described according to the mental health care services to which it is most sensitive. Implications for targeting the segments are discussed. PMID- 10104018 TI - The audit payoff: medical journal titles most in demand. PMID- 10104019 TI - Collection tactics that can get you sued. PMID- 10104020 TI - Here's an antidote for managed care. PMID- 10104021 TI - Physicians' families get shortchanged on care. PMID- 10104022 TI - Cut costs and improve care, too? These doctors did. PMID- 10104023 TI - Are you taking enough time off? PMID- 10104024 TI - CRAHCA (Center for Research in Ambulatory Health Care Administration) poised to lead group practice management research into the 1990s. PMID- 10104025 TI - The 'bundling of medicine' and creation of a new profession. PMID- 10104026 TI - HMO facts and fictions. PMID- 10104027 TI - Nursing's role in the ambulatory care setting. AB - The role of the nurse is taking on a new significance in the ambulatory care setting as new financial, technological and social trends occur in health care. Authors Mary Ann Moore and Anita Geving explain that because of all these trends, physicians are feeling pressure to adapt new practice patterns and as a result are becoming more aware of how nurses can support their practices as part of these changes. PMID- 10104028 TI - Maximizing nursing potential through use of assistive workers. PMID- 10104029 TI - Measuring and monitoring nursing intensity. AB - With the explosion in the volume and array of ambulatory services, Kathleen Parrinello believes that nurse managers must gain a better understanding of nursing care requirements and resources consumed if they want to provide effective and efficient health care. Parinello describes a system for evaluating the nursing care requirements of patients and fitting those requirements to the appropriate level of staff expertise. PMID- 10104030 TI - Innovative scheduling for maximum space use. PMID- 10104031 TI - Pursuing a clinical career in nursing. AB - Since the 1970s, health care employers have struggled with the increasing nationwide shortage of nurses. Janice Sosias and Susan Andrus detail how Colorado Kaiser Permanente, as the state's largest health care provider, developed nursing career paths as a way to recruit and retain registered nurses. PMID- 10104032 TI - Physician income distribution. PMID- 10104033 TI - Adventist Health/U.S. will dismantle system, form new association. PMID- 10104034 TI - IRS gives hospitals latitude in physician incentive plans. PMID- 10104035 TI - Hospitals cashing in on clean-up claims processing. PMID- 10104036 TI - Canada tabs Wash. hospital. PMID- 10104037 TI - Charter Medical head denies errors linked to SEC probe. PMID- 10104038 TI - Health Trust near agreement on bank debt refinancing. PMID- 10104039 TI - Alternative liability coverage still offers benefits. PMID- 10104040 TI - Study prompts debate over PROs' focus. PMID- 10104041 TI - Tax-supported hospital sued. PMID- 10104042 TI - TDS to introduce electronic patient record system. PMID- 10104043 TI - La. hospital affected by Drexel's fall. PMID- 10104044 TI - AMI planning asset sales in Denver. PMID- 10104045 TI - Financial viability lies in back-to-basics approach. PMID- 10104046 TI - Staff involvement key to successful employee relations. PMID- 10104047 TI - OBRA provides guidelines for quality assurance programs. PMID- 10104048 TI - Developing a contract to meet resident, facility needs. PMID- 10104049 TI - Why are my premiums so high? And other insurance questions. PMID- 10104051 TI - Beyond COBRA: the next emergency medicine battleground. AB - In 1985, the Consolidated Omnus Budget Reconciliation Act, COBRA, was passed by Congress. Designed to protect patients who present for emergency treatment regardless of their ability to pay for care, one aim of COBRA is to eliminate "patient dumping." The author emphasizes the need for physicians to become aware of their legal responsibilities to a patient and stresses the importance of physician involvement in health care legislation. PMID- 10104050 TI - Hospital demand for physicians. AB - This article develops a derived demand for physicians that is general enough to encompass physician control, simple profit maximization and hospital utility maximization models of the hospital. The analysis focuses on three special aspects of physician affiliations: the price of adding a physician to the staff is unobserved; the physician holds appointments at multiple hospitals, and physicians are not homogeneous. Using 1983 American Hospital Association data, a system of specialty-specific demand equations is estimated. The results are consistent with the model and suggest that physicians should be concerned about reduced access to hospitals, particularly as the stock of hospitals declines. PMID- 10104052 TI - Health policy reforms. Interview by Thomas G. Goodwin. PMID- 10104053 TI - Brand names for hospitals? PMID- 10104054 TI - "Voluntary" commitment of minors in private psychiatric hospitals: California's response. PMID- 10104055 TI - Utilization review--managing the reviewers. PMID- 10104056 TI - JIT (just-in-time)/stockless programs for hospitals. PMID- 10104057 TI - A comparison of Kentucky rural and urban hospitals. PMID- 10104058 TI - Trauma release. PMID- 10104059 TI - Profitability of acute care operations. PMID- 10104060 TI - Perspectives. Debating the quality of HHS leadership. PMID- 10104062 TI - Perspectives. U.S. health report card: mixed performance. PMID- 10104061 TI - Sullivan and Horner set HHS agenda. PMID- 10104063 TI - Perspectives. Chiropractors: AMA's bone of contention. PMID- 10104064 TI - Wilensky settles into HCFA job. PMID- 10104065 TI - 1989 accident review. Helicopter accidents set second lowest record in decade. PMID- 10104066 TI - Pertinent information on personal protective gear. PMID- 10104067 TI - Towers, lights and safety. PMID- 10104068 TI - Keep safe from tail rotor strikes. PMID- 10104069 TI - Children's hospitals face struggle for survival. PMID- 10104070 TI - Pioneer program gives infants a health start. PMID- 10104071 TI - Hospital-based program fights child abuse. PMID- 10104072 TI - Infant program bridges the gap between hospital and home. PMID- 10104073 TI - California Pediatric Critical Care Coalition tackles children's issues. PMID- 10104074 TI - Hospital food service challenges of the 90s. PMID- 10104075 TI - McDonald's joins Childrens Hospital of Los Angeles. PMID- 10104076 TI - National Commission on Children. Hope for the health of America's children. PMID- 10104077 TI - What's wrong with trauma care? PMID- 10104078 TI - Health Resources and Services Administration; statement of organization, functions and delegations of authority--PHS. PMID- 10104079 TI - Recruiting still a challenge. PMID- 10104080 TI - Latest tax act goes easy. No major impact foreseen for nursing homes. PMID- 10104081 TI - Progressive restraint release without additional staffing. Structuring group activities is the key. PMID- 10104082 TI - Drugs in the workplace: New York State is meeting the challenge. AB - Ms. Hodes outlines the magnitude of the workplace drug abuse problem and describes New York State's response to the situation. She shows that the New York program emphasizes education and rehabilitation and restricts drug testing. PMID- 10104083 TI - Response to "Cost reductions from a smoking policy". PMID- 10104084 TI - Smoking costs and policies updated: a response to James T. Golden. PMID- 10104085 TI - Putting outpatient costs on a low fat diet. PMID- 10104086 TI - Viral hepatitis. AB - Viral hepatitis is the most common serious contagious disease caused by viruses that attack the liver. Approximately 70,000 cases are reported to the Centers for Disease Control each year, representing only a fraction of U.S. cases. There are five types of viral hepatitis currently known: Hepatitis A--formerly called infectious hepatitis; Hepatitis B--formerly called serum hepatitis, and the most serious form; Hepatitis C--formerly called non-A, non-B hepatitis; Hepatitis D- formerly called delta hepatitis; Hepatitis E--formerly called enteric or epidemic non-A, non-B hepatitis. The following Open Forum, prepared by leading EMS experts, explores the differences among the types of hepatitis, signs and symptoms, and EMS implications. PMID- 10104087 TI - Lifecare. AB - Foodservice has become a major attraction in lifecare communities, the fastest growing segment of the senior citizens housing market. PMID- 10104088 TI - Childcare. PMID- 10104089 TI - Homecare. AB - With the help of volunteers from coast to coast, operators of homemeal delivery programs are helping needy seniors preserve their dignity, environments & cherished independence, providing nourishment for bodies & souls. PMID- 10104090 TI - Here come the 1990s--stand up & be counted. PMID- 10104091 TI - Determining customer satisfaction. PMID- 10104092 TI - Strong medicine for health costs. AB - Companies feeling blue--or in the red--over feverish employee medical expenses have found some relief. Just take an HMO and add a twist. PMID- 10104093 TI - Healthcare data briefing: AIDS predictions. PMID- 10104094 TI - Capital questions. PMID- 10104096 TI - Pounds, shillings and death. PMID- 10104097 TI - Myth and reality. PMID- 10104095 TI - Score on quality. PMID- 10104098 TI - Cope with calamity. PMID- 10104099 TI - Take the time to talk. PMID- 10104100 TI - Renovation cuts cost, speeds construction of psych group home. PMID- 10104101 TI - EPA-compliance options for underground tanks. PMID- 10104102 TI - EPA storage-tank rules include many exclusions. PMID- 10104103 TI - Use of key contract supplies declined in 1980s. PMID- 10104104 TI - Surgical instruments: the unmanaged asset. AB - Hundreds of thousands of dollars are invested in surgical instruments in hospitals. Materiel management and central service professionals should focus attention on managing this asset, just as we have done for supply and linen inventories. However, there are no performance standards against which to measure performance in this area; in fact, there are not even any commonly accepted indicators of surgical instrument inventories. The purpose of this article is to stimulate interest in the issue of surgical instrument inventory, so that materiel management and central service professionals will begin collecting data that will eventually allow definition of performance standards. Indicators of performance are suggested, specifically: 1. The number of "pars" of instruments in inventory, where one par equals the average amount of instruments used in one day. 2. The average of the value of instruments used per surgical procedure. Management of surgical instrument inventories could become a new source of both one-time savings (by reducing purchasing as inventories decrease) and ongoing annual savings (by decreasing the size of instrument trays in use). PMID- 10104106 TI - Analgesic infusion pumps. ECRI. PMID- 10104105 TI - Interacting with physicians. AB - The author describes the differences in the way physicians and managers think about their roles in the hospital and how understanding these differences can improve future interactions between these two groups of healthcare professionals. PMID- 10104107 TI - Endoscopes and equality. PMID- 10104108 TI - Managing for success--or failure? PMID- 10104109 TI - Prevention of occupational hepatitis B infections. PMID- 10104110 TI - Supplying crash carts. PMID- 10104111 TI - Patients who like to fool doctors. PMID- 10104112 TI - The rationing debate: a question of how--not whether? American College of Healthcare Executives. PMID- 10104113 TI - Will losing Jim Sammons help or hurt the AMA? PMID- 10104114 TI - Image, architecture, and costs of ambulatory care. PMID- 10104115 TI - The facility time bomb is ticking. PMID- 10104116 TI - Hospital daze: the chief executive of a smaller hospital recounts a typical day. PMID- 10104117 TI - Corporate ethics for hospitals--the challenge of the 1990s? PMID- 10104118 TI - Auxilians: a primer in writing your legislators. PMID- 10104119 TI - With no restraints, architects design the 'perfect' future. PMID- 10104120 TI - Former VHA exec continues push to thwart Partners sale. PMID- 10104121 TI - Pact would settle 'typing arrangement' charges. PMID- 10104122 TI - Stockless inventory: some say it's a hot new innovation, but skeptics don't put much stock in its claims. PMID- 10104123 TI - Vendors must make good on automated medical record. PMID- 10104124 TI - Providers rip investigation. PMID- 10104125 TI - Staffing firm accused of fraud. PMID- 10104126 TI - Anesthesia delivery buffeted by shortage, glut and rivalry. PMID- 10104127 TI - Equipment resale salvages cash. PMID- 10104128 TI - Truce can pay off in pooled financing. PMID- 10104129 TI - National health plan opposed. PMID- 10104130 TI - PPRC addresses reform implementation. PMID- 10104131 TI - Two hospitals change management. PMID- 10104132 TI - AMI's Denver assets spark interest. PMID- 10104133 TI - Sullivan offers little at border confab. PMID- 10104134 TI - Court rejects merger. PMID- 10104135 TI - Study finds higher prices in markets with more hospitals. PMID- 10104136 TI - Baxter announces restructuring. PMID- 10104137 TI - Bush's AIDS leadership criticized. PMID- 10104138 TI - Tracking America's two largest alliances: VHA and American Healthcare Systems. PMID- 10104139 TI - Humana wins Ky. vote. PMID- 10104140 TI - Workers strike S. Calif. Kaiser facilities. PMID- 10104141 TI - American Express silent on new system. PMID- 10104142 TI - Healthcare trade group executives well paid. PMID- 10104143 TI - Federal, state cooperation fosters antitrust probes. PMID- 10104144 TI - Linkup with vendor can stretch ad budget. PMID- 10104145 TI - JCAHO survey finds concern over standards. PMID- 10104146 TI - AHM (American Healthcare Management) may have trouble paying debts. PMID- 10104147 TI - Life Care to acquire National Heritage. PMID- 10104149 TI - Know general accounting--and survive. PMID- 10104148 TI - Financial ratios: clues to the big picture of a hospital's fiscal health. AB - With trustees, investors, regulatory agencies, and others paying close attention to hospital finances, healthcare financial managers must detect problems before they grow out of control. Liquidity, capital structure, activity, and profitability ratios can provide pieces to the puzzle. PMID- 10104150 TI - Bold companions. PMID- 10104151 TI - Targeting the depressed. PMID- 10104152 TI - Women asking for women physicians. PMID- 10104153 TI - Stalking the perfect practice physician. PMID- 10104154 TI - Physicians on film. PMID- 10104155 TI - Showcasing physician specialties. PMID- 10104156 TI - Award-winning brochure design. PMID- 10104157 TI - What's up, Doc? PMID- 10104158 TI - Pediatric patients--handle with care. PMID- 10104159 TI - "Drive through" clinic. PMID- 10104160 TI - "Lean Forever" gets fat response. PMID- 10104161 TI - Food for thought. PMID- 10104162 TI - "No waiting" sells ER. PMID- 10104163 TI - Waitless admissions. PMID- 10104164 TI - The way to treat a lady. PMID- 10104165 TI - Magazine replaces bundle of brochures. PMID- 10104167 TI - Retiring execs donate expertise. PMID- 10104166 TI - Who pays for the sick-poor? PMID- 10104168 TI - Reimbursement will ensure OBRA's focus on care outcomes. PMID- 10104169 TI - Moving ahead with the challenge: meeting the OBRA mandate. PMID- 10104170 TI - The movie moguls vs. grandma and grandpa. PMID- 10104171 TI - Selection of "talented" employees is no accident. PMID- 10104172 TI - Resident morale, facility image bolstered by family involvement. PMID- 10104173 TI - Use of outside company can increase operating efficiency. PMID- 10104174 TI - Evaluating psychotrophic drug use in the nursing home. PMID- 10104175 TI - Licensure and certification directors eye new process. PMID- 10104176 TI - The medical imaging technologist shortage in New Jersey: its extent and magnitude. AB - The medical imaging and radiation therapy communities in New Jersey were surveyed to: (1) quantify the personnel shortage, (2) determine the percentage of licensed technologists not employed in the field of medical imaging and radiation therapy, and (3) identify the medical facility type(s) most affected by the personnel shortage. The data supports the claim that a shortage of technologists in all areas of medical imaging and radiation therapy exists. Activities being conducted to address the shortage are presented. PMID- 10104177 TI - Construction alternatives for free-standing facilities. AB - Many hospitals are exploring free-standing facilities as an option for providing more efficient imaging services. Mr. Brown discusses the pros and cons of an emerging building technology, manufactured construction, in which building and site preparation are done simultaneously. He presents the criteria managers should use to make a knowledgeable decision. PMID- 10104178 TI - ACR survey results: diagnostic imaging scientists and engineers. AB - The American College of Radiology's Committee on Physics Resources of the Commission on Human Resources conducted a survey of diagnostic imaging scientists and engineers to assess who is providing radiologic physics and related services in diagnostic imaging departments. The survey forms were distributed through the members of the American Healthcare Radiology Administrators. Survey results showed a predominance of M.S. and Ph.D. degrees in physics and medical/radiological physics. Nearly all respondents had their time split between numerous categories of work, such as clinical and research, and between different modalities such as diagnostic x-ray, nuclear medicine and radiation oncology. To enhance physics services in important areas such as CT, which currently receive little time, support is needed for work prioritization, for training, and for positions for physics and physics-support personnel. PMID- 10104179 TI - Trends in radiology: Part I. AB - Trends in exam charges, procedure volume and workload are reported in this first part of the AHRA's "Trends in Radiology" survey. The author also provides comparisons of data from this survey with studies done in 1985 and 1987. PMID- 10104180 TI - JCAHO radiology survey performance. AB - In an effort to help radiology managers better understand JCAHO requirements, this article provides a synopsis of the rate of recommendations with contingencies in JCAHO inspections of radiology departments during 1988. This report has been prepared by the American College of Radiology using data provided by the JCAHO. PMID- 10104181 TI - What is private utilization review? PMID- 10104182 TI - The evolution of quality assurance and the role of the governing board. PMID- 10104183 TI - Financial future of hospitals, Part 2. Interview by Julie Johnson. PMID- 10104184 TI - The hospital legal checkup. PMID- 10104185 TI - Life after death: organ procurement programs in hospitals. PMID- 10104186 TI - What governing boards should expect of medical staff leaders. PMID- 10104187 TI - Changes in the AHA's volunteer arrangement. PMID- 10104188 TI - Meeting the needs of elderly patients. PMID- 10104189 TI - Ideal auxiliary recruits: hospital staff. PMID- 10104192 TI - HAVE (Hospital Awards for Volunteer Excellence) nominees exhibit innovation. PMID- 10104191 TI - Creative fund-raisers: case studies. PMID- 10104190 TI - Directions for a new decade. PMID- 10104193 TI - Quality management is the future. PMID- 10104194 TI - Volunteers vital to QA program. PMID- 10104195 TI - AIDS knowledge and attitudes for July-September 1989. Provisional data from the National Health Interview Survey. PMID- 10104196 TI - How a small firm competes for large projects. PMID- 10104197 TI - Perspectives. Federal benefits revisions: reform or cost control? PMID- 10104199 TI - Fund raising for libraries: a case study. AB - The present economic climate is forcing medical librarians to look at supplementary sources of income and actively to seek funds on behalf of their libraries outside their institutions. This paper looks at fund raising for medical libraries and describes the fund-raising activities of the Friends of the Library at the Royal College of Surgeons in Ireland. PMID- 10104198 TI - Goal-oriented evaluation as a program management tool. AB - Health promotion programs, like all human services activities, must be well managed in order to be effective. In an age of reduced financial resources to support new programs and sustain old ones, all program directors must be concerned with the efficiency with which available resources are used to meet program goals and objectives. In times such as these, competition is high for those resources that are available. Programs that can demonstrate both effectiveness in meeting their goals and operational efficiency in doing so are more likely to be successful in the competition for these scarce resources. In this article, practical suggestions for the use and presentation of evaluation data in the analysis of program effectiveness and efficiency are presented. The methodology is based on the contention that program evaluation should be useful to program directors as an integral part of their management of program resources in relation to program goals. PMID- 10104200 TI - The role of the British Library for medical and health information. Standing Conference of National and University Libraries (SCONUL). AB - This paper examines the role of the British Library in the provision of medical and health information in the U.K. Medicine--in both the public and private sector--is big business. The British Library is already heavily involved in the provision of information to the medical community but there is little planning for the most cost-effective allocation of resources for medical information across the nation. There is no focus for research and development in medical information policy and medical librarians do not readily identify with the British Library. This paper suggests that the British Library could help to develop a focus for medical information policy in the way the National Library of Medicine does for the USA. PMID- 10104201 TI - "Low income levels" for health professions and nursing programs--HRSA. PMID- 10104202 TI - Statement of organization, functions, and delegations of authority--FDA. PMID- 10104203 TI - Agency for Health Care Policy and Research; statement of organization, functions and delegations of authority--PHS. PMID- 10104204 TI - Gut issue. AB - Unions are willing to strike over it, and companies are ready to draw the line, too. Now both sides are turning to Congress to fix the health insurance mess. This is the first of two articles on responses to the growing health care crisis. A report on state efforts begins on p. 708. PMID- 10104205 TI - Palliative care ministry to families. PMID- 10104206 TI - Is there a need for Catholic hospitals? PMID- 10104207 TI - Mission effectiveness in Catholic health care facilities. PMID- 10104208 TI - Organizational culture: what is it? PMID- 10104209 TI - PC-based project management comes to healthcare. AB - While many hospitals are struggling to boost their return on IS investments, one large healthcare system has discovered that PC-based project management software can help ensure successful implementation. PMID- 10104210 TI - Applications: how far have we come? Part II. AB - In this second of a two-part look at the evolution of critical issues and application areas, Computers in Healthcare Associate Editor Ellen Pollock examines how far integration, nursing systems, executive decision support and expert systems have come during the 1980s. Her top industry sources discuss the outlook for these applications in the near-term future, as well. PMID- 10104211 TI - The key is teamwork: making medical records information systems succeed. AB - Problems within an existing hospital information system can often hamper efforts of medical records personnel to perform chart completion, clinical abstracting, tracking, deficiency analysis and other essential tasks. Years of experience have enabled Leslie Ann Fox, consultant for Care Communications, Inc., to collect observations, and through them, recommend key success factors to make the system work well. PMID- 10104212 TI - The electronic medical record is closer than you think! PMID- 10104213 TI - Charitable life insurance--the ideal deferred gift. AB - As financial pressures on non-profits rise, fund raisers are constantly searching for alternative income sources. Life insurance may be one of them. PMID- 10104214 TI - Life insurance for endowment--great concept or a booby trap? AB - Life insurance as a charitable gift is an attractive alternative. But first the fund raiser must check out the companies and the different types of policies available. PMID- 10104215 TI - Fitness and health promotion in Japan. AB - Health promotion efforts in Japan are progressing much as they are in the United States. However, as Japan has different health problems and a different business culture, health promotion efforts in Japan differ from those in the United States. This paper will examine the major causes of death in Japan, prevalent lifestyle problems, cultural differences, types of health promotion programs which are offered, and program effectiveness. By making comparisons between two culturally different countries health promotion professionals will be able to understand their own programs better and develop new ideas for future programming efforts. PMID- 10104216 TI - An exploratory study of health practices of American Catholic nuns. AB - American Catholic nuns represent a distinct segment of American women, yet little is known about their health practices. Assessment of health-related activities of these women was conducted by means of a self-report survey which was completed by 345 nuns in the midwestern United States. Although 53% had a complete physical examination in the last year, 11% had not had one for more than seven years, and 44% had not had a recent breast or pelvic examination. Thirty-seven percent did monthly breast self-examination (BSE), 37% examined themselves rarely, and 26% never performed BSE. Nuns performing BSE were more likely to have been examined by a health care provider in the past year (p less than .05). Nuns reporting a more positive health status said they got an adequate amount of sleep and participated in regular exercise, yet reported themselves to be overweight (p less than .05). Stress was reported by 74%, and an inverse relationship between perceived relaxation time and perceived stress level was noted (p less than .05). Overall, data reflected certain health educational and behavioral deficits. Because nuns comprise a chronologically older cohort than their secular counterparts, efforts that enable adoption of wellness practices and facilitate improved health care among these women seem to be warranted. PMID- 10104217 TI - Situational leadership for collaboration in health care settings. PMID- 10104218 TI - C.H.A.T.: The Community Health Awareness Team. PMID- 10104219 TI - Handling manipulation. PMID- 10104220 TI - Intuition, ethical decision making, and the nurse manager. PMID- 10104221 TI - Managing free agents in health care organizations: a supervisory challenge. PMID- 10104222 TI - Supervisory and managerial assessment centers in health care. PMID- 10104223 TI - The motivational impact of nonfinancial employee appreciation practices on medical technologists. PMID- 10104224 TI - The CEO hits the road (and other sales tales). AB - Kenneth Macke, CEO of Dayton-Hudson, the soft goods and discount store chain, often spends weekends prowling his own and competitors' stores, observing. Edwin Artzt, CEO of Procter & Gamble, once interrupted a global marketing jaunt to work with a division on its promotion plans. These are CEOs in the trenches, a place where they ought to spend a certain amount of their time so that they can learn how the business is going. "A desk is a dangerous place from which to view the world," says John le Carre, as quoted approvingly by the author. Mackay asserts that time spent on the road with the sales force is especially valuable. You will learn: Whether all the sales team knows its prospects and sets reasonable expectations. How much the salespeople know about the product, particularly in ways that differentiate it from the competition. Whether the sellers keep abreast of changes in customers' businesses. If the salespeople feel they have a stake in the business. As a rookie envelope salesman, Mackay was taken in tow by a veteran and shown the value of learning the competition's local customer base intimately. Later, as the CEO with a junior salesperson in tow, he demonstrated the value of learning not only the competition's moves but also the customers'. To close sales, salespeople and the CEO have to look over their customers' shoulders as well as their competitors'. PMID- 10104226 TI - The new pay programs. PMID- 10104225 TI - The business of innovation: an interview with Paul Cook. Interview by William Taylor. PMID- 10104227 TI - Pay-for-performance. PMID- 10104228 TI - Just how much am I worth? PMID- 10104229 TI - A unique opportunity. PMID- 10104230 TI - What the people say. PMID- 10104231 TI - Old values in New York. PMID- 10104232 TI - In the pursuit of good quality. PMID- 10104233 TI - P & T Committee perspectives: maintaining a successful formulary system in a private community hospital. AB - Institution of an effective formulary and P & T Committee is a difficult but critical task for many private hospitals. In this exclusive Hospital Formulary interview, Drs. Benner, Mykita, and Brown, members of Sutter Memorial Hospital's Pharmacy, Formulary, and Therapeutic Review Committee (their name for the P & T Committee) emphasize the need for a sound formulary system in order to survive the current changes in health care. Sutter Memorial is sophisticated in its delivery of healthcare services, which include advanced neonatology and state-of the-art heart transplantation. Although good patient care remains the foremost concern, these committee members acknowledge that care must be affordable as well as therapeutically sound. Key to their committee's success is the cooperative effort among the pharmacy, nursing, and medical staff. They foresee the issue of rational therapeutics as a major challenge in the 1990s. PMID- 10104234 TI - A description of a successful computerized adverse drug reaction tracking program. AB - The University of Illinois Hospital Drug Information Center recently began using a database software program (File Express, Version 4.0, Redmond, WA) for storing and retrieval of reported adverse drug reactions (ADRs). Important features of the software program include the capability of easily generating reports, rapid sorting of data, large storage capability, minimal startup cost, and a user friendly menu system. The number of reported ADRs increased from 24 in 1987 to 124 in 1988 due, in part, to increased educational efforts, revision of the ADR reporting form, and cooperation from the medical records department in identifying reported ADRs during chart review. Overall, pharmacists were found to report most of the ADRs. Retrospective analysis of the ADR reports may help identify trends in ADRs based on the drug and route of administration. A decrease in the incidence of some ADRs and, thus, improved patient care, may result as the information obtained from the computer-based ADR reporting system is shared among healthcare professionals. PMID- 10104235 TI - Multidisciplinary approach to cost reduction of C-section prophylaxis. AB - Runaway cefoxitin costs prompted a thorough usage evaluation by the P & T Committee, the antibiotic review subcommittee, and the pharmacy department at this 450-bed teaching hospital. C-section prophylaxis accounted for 25% of all cefoxitin usage. With the assistance of the ob/gyn department, a major campaign was initiated to alter prescribing habits and evaluate more cost effective prophylaxis. Single dose cefotetan replaced multidose cefoxitin regimen for a 6 month trial basis. Annualized cost savings for drug and supplies were approximately $49,086, and no change in morbidity was noted. The ob/gyn department then agreed, at the request of the antibiotic subcommittee, to conduct a trial comparing single dose cefotetan with single dose cefazolin in women undergoing C-section. The results indicated that both treatments were equally effective, consequently, cefazolin replaced cefotetan, producing an additional $10,384 annual savings. Overall, our approach to C-section cost reduction resulted in a total of $59,470 annual savings and demonstrated the effectiveness of an organized multidisciplinary approach. PMID- 10104236 TI - Antibiotic order form designed to educate, ease decision making. PMID- 10104237 TI - Informed consent revisited. PMID- 10104238 TI - Patient claims confidentiality breach. PMID- 10104239 TI - Outreach program for older adults: implications and opportunities. PMID- 10104240 TI - Meeting the mental health needs of the elderly community: a multifaceted challenge. PMID- 10104241 TI - Facility design with the elderly in mind. PMID- 10104242 TI - Financing ambulatory care services for the elderly. PMID- 10104243 TI - Informing and educating the electorate about AIDS. PMID- 10104244 TI - New physicians shun rural practices. PMID- 10104245 TI - Emergency AIDS funding bill approved by committee. PMID- 10104246 TI - Fewer hospitals close in '89 than in previous year--AHA. PMID- 10104247 TI - Shaping hospitals' capital spending decisions. PMID- 10104248 TI - IRS steps up scrutiny. PMID- 10104249 TI - Kaiser employees OK 3-year pact. PMID- 10104250 TI - Marketing must turn savage. PMID- 10104251 TI - System finds Shangri-La in the hills of South Carolina. PMID- 10104252 TI - Ex-employees sue hospital. PMID- 10104253 TI - Hospitals trying ventures with various businesses. PMID- 10104254 TI - Municipal bond volume declines in first quarter. PMID- 10104255 TI - Legality of NLRB rules upheld. PMID- 10104256 TI - Must that dropped package be discarded? PMID- 10104257 TI - What are an OR manager's primary ethical obligations? PMID- 10104258 TI - Ethics committee can be helpful to nurses. PMID- 10104259 TI - Procedures for disciplining employees. PMID- 10104260 TI - Leadership and the challenge of paradox. PMID- 10104261 TI - Access to care: the AHA's position on mandated employee health benefits. PMID- 10104262 TI - Providing quality leadership. PMID- 10104263 TI - Better days ahead for hospitals. Interview by Julie Johnsson. PMID- 10104264 TI - Peer review, privileges: MDs fear legal tangles. PMID- 10104265 TI - Health information centers provide a needed service. PMID- 10104266 TI - Providing competitive physician benefits within the law. PMID- 10104268 TI - Edward Linde on hospital construction and design. Interview by Karen Gardner. PMID- 10104267 TI - One man's cooperative venture is another man's antitrust suit. PMID- 10104269 TI - The image of mammography. PMID- 10104270 TI - Productivity and its effect on education. PMID- 10104271 TI - Selecting from the service menu. Part 1. PMID- 10104272 TI - Reason for being: measuring and improving patient satisfaction. PMID- 10104273 TI - The ACR-NEMA standards--developing an interface for image exchange. PMID- 10104274 TI - The day the lights went out. PMID- 10104275 TI - Balancing managerial responsibilities (are you having fun?). PMID- 10104276 TI - Equipment leasing. A guide for lessees. PMID- 10104277 TI - The manpower dilemma revisited. Part 2. PMID- 10104278 TI - The relative accessibility for health districts to regionally supplied specialist services. AB - This paper describes a study carried out in the North Western Health Region of England where it is policy to provide access to regionally supplied specialist services on an equal basis to all component Health Districts. The results, however, suggest substantial differences in uptake depending on the proximity of the District of residence of the patient to the location of such specialist service. Throwing light on this phenomenon proved difficult because many important Regional services are hard to disentangle from the 'normal' District services with which they are organisationally linked. Also diagnostic classification schemes do not always provide a clear indication of those patients who require the super-specialist service. PMID- 10104279 TI - Preliminary report on nurse job satisfaction on wards for the elderly, mentally ill. AB - The effect of Community Care Policies upon staffing levels within institutions is potentially problematic; wider job opportunities becoming available to nurses as community provision increases. The job satisfaction of nurses still working within institutions must, therefore, be an issue of importance in the maintenance of suitably qualified and experienced staff. This study examines the differing amounts of job satisfaction reported by a sample of 59 nurses all working on long stay wards for the elderly, mentally ill; located within three different institutions. The results show that the measures selected for use have high content and face validity for this population. The effects of institutional and staff management are highlighted as being major influences upon the degree of job satisfaction. PMID- 10104280 TI - Managing physician efficiency and effectiveness in providing hospital services. AB - Physicians control more than 80 percent of the decisions affecting health costs. Consequently, managing physician practice patterns is an important avenue to reducing health care costs. One approach to identifying inefficient practice patterns is demonstrated in this pilot study of physicians treating heart shock patients. Physicians are evaluated using data envelopment analysis (DEA), a relatively new linear-program-based efficiency evaluation tool. This approach (1) locates physicians using excess resources in treating patients, (2) estimates the amount of excess resources used, and (3) explicitly considers the quality of patient care in the overall assessment of the physician's practice patterns. Findings of physician inefficiency that are stable over time could be used to alter practice patterns and subsequently to assist in cost containment. PMID- 10104281 TI - The compatibility of general managers' activities and intentions in managing change in the NHS. AB - As Hales (1986) has observed, the problem of much of the managerial research to date has been the reluctance to ask why managers behave in the way they do. The behaviour of general managers in tackling organisational change in the NHS needs to be viewed not only with respect to what is done but also with respect to how personal and organisational objectives are construed. In other words, the implementation of organisational change ultimately rests on how general managers perceive the nature of this change and their role in structuring their own personal and organisational objectives into appropriate activities. Examining the compatibility of managerial activities and the underlying values and intentions which support them is of critical importance in any cognitively-based approach. These intentions provide an important link between perceptions (i.e. how the organisation is construed) and behaviour (i.e. what activities managers choose to perform). Understanding the conceptual frameworks which underpin managerial activities could have profound implications for assessing the performance of general managers. PMID- 10104282 TI - Supply-induced demand for hospital care. AB - Preliminary analysis of hospital utilization data indicates that Roemer's Law may still be operative in rural Iowa: counties with more hospital beds per capita have more hospital utilization per capita. However, when patient origin data are analyzed findings are entirely different. Bed supply is not related to utilization rates in Iowa counties. Instead, the number of unique hospital services is associated with higher utilization rates. The impact of this characteristic of hospital supply, however, is much weaker than the original Roemer effect. The contradiction of these findings with Roemer's Law is apparently a result of a methods effect: use of hospital utilization data which are not derived from actual population experience reveals a relationship which is a statistical artifact. The data also reveal that suburban counties have higher utilization rates than either rural or urban (MSA core) counties. PMID- 10104283 TI - Alternatives, agendas and outcomes: budget cutting in health care organizations. PMID- 10104284 TI - Neurology referral patterns. AB - To examine the indications for referral of patients to neurologists, a survey was conducted of 88 such referrals by general internists in an HMO. In approximately one third of all referrals, the neurologist's advice regarding diagnosis and treatment was of minor or no importance. Instead, such referrals were often responsive to patient and family demands or focused upon the necessity for neuroimaging, even when the likely diagnosis and required treatment were already evident. Referral rates in HMO practice are strongly influenced by the practice styles of primary care providers. The authors conclude that a case manager ("gatekeeper") mechanism in competitive medical plans that excludes patient self referrals may have a greater effect upon total (and surgical) specialty care, compared with the volume of services provided by medical specialists such as neurologists. PMID- 10104285 TI - Rheumatology referral patterns. AB - The authors studied the characteristics of patients referred for rheumatology consultation in a group model HMO. Six hundred twelve patients were evaluated in 1986. The ages ranged from 3 to 85 years, with an average of 52 years. Female patients outnumbered male patients almost 3:1. Only 44% of referrals had a presumptive diagnosis and more than one half of these diagnoses were changed by the consulting rheumatology specialist, suggesting a high value added from the HMO rheumatologic consultation. Internists referred at a slightly higher rate than family practitioners, and pediatricians referred children at one tenth of the adult rate. Comparison with other published data on fee-for-service rheumatology practices indicates that in one group model HMO, which prohibits patient self-referral, rheumatologic specialists see a higher percentage of patients with vague or difficult-to-manage conditions such as the connective tissue diseases and fibromyalgia and a lower percentage of osteoarthritis and gout. This finding suggests that the structure and incentives of HMOs alter medical referral and practice patterns in significant ways. PMID- 10104287 TI - Government as medical ethicist. PMID- 10104286 TI - Office efficiency in primary care. AB - Little has been written examining the issue of what contributes to efficiency in the primary care setting in HMOs. After a review of the literature, an informal study of primary care physicians at Group Health Cooperative of Puget Sound is described. Issues of physical space, telephone use, teamwork, the medical encounter, hospital rounds, charting, paperwork, and shifting gears when busy are addressed in the context of provider and patient satisfaction. PMID- 10104288 TI - Professional team development. PMID- 10104289 TI - A new approach to workload recording. A contemporary approach to staffing analysis. AB - The question of "How productive is our laboratory?" is one with which we wrestle constantly. The College of American Pathologists (CAP) Workload Recording Method (WLR) is somewhat familiar to most laboratorians. It is a system that could be better used in most laboratories. The recent introduction of a new approach to productivity analysis and of code numbers for nonworkloaded activities makes the system easier to use and more meaningful in analyzing staff productivity. Laboratory managers strive constantly to answer the question, "How do I show administration my real staffing needs?" Personnel productivity analysis is a benefit of using the CAP WLR method. PMID- 10104290 TI - Antrim Laboratory and Financial Systems. PMID- 10104291 TI - Impact of new technology on laboratory informatics. Bar codes, voice recognition, artificial intelligence, and CD ROMS. PMID- 10104292 TI - Networking with our colleagues. PMID- 10104293 TI - Meet the decade's biggest challenges by stemming the tide of turnover. AB - A 10 percent raise won't cut it for most of your top people, and salary demands are only one of the factors contributing to the turnover problem in I/S organizations. Here's how to keep your winners on board so projects stay on time and on budget. PMID- 10104294 TI - American Osteopathic Hospital Association 1989 annual report. A vision for the nineties. PMID- 10104295 TI - National practitioner data bank: how to exercise your rights. PMID- 10104296 TI - Do not resuscitate orders: a reappraisal. PMID- 10104297 TI - Ethics and human values committee survey: (AMI Denver Hospitals: Saint Luke's, Presbyterian Denver, Presbyterian Aurora: Summer 1989). A study of physician attitudes and perceptions of a hospital ethics committee. AB - By studying physician perceptions of the Hospital Ethics Committee (HEC), the committee can determine (1) what areas the committee should concentrate on, and (2) how it is perceived by the physician community. The topics covered by the study included whether or not a HEC is needed in any hospital system, as well as the specific need within AMI Denver hospitals. In addition, the physician participants discussed what departments should be represented on the HEC and what topics it should study and discuss. By discussing the perceived effectiveness and the ideal function of HECs the physicians were able to provide the committee with many concrete suggestions to improve its effectiveness and visibility within the hospital community. Most of the advice is captured in one physician's words: "Be Visible and Credible." PMID- 10104298 TI - The development of an ethics consultation service. PMID- 10104299 TI - Biomedical ethics and an ethics consultation service at the University of Virginia. PMID- 10104300 TI - National practitioner data bank: how to exercise your rights. PMID- 10104301 TI - Special report. Practitioner data bank promise: more work for hospitals, but fewer "bad doctor" surprises. PMID- 10104302 TI - Communications survey. PMID- 10104304 TI - Annual transport statistics. PMID- 10104303 TI - Product & service guide. PMID- 10104305 TI - Waste disposal in the NHS--the alternatives. PMID- 10104306 TI - Incineration--controlling the costs of environmental legislation. PMID- 10104307 TI - Application of condition monitoring techniques to machinery in arduous service. PMID- 10104308 TI - Medical waste legislation in California. PMID- 10104309 TI - Medical waste regulations: what lies ahead. PMID- 10104310 TI - AIDS quilt memorializes thousands of lives lost. PMID- 10104311 TI - Prioritizing medical care resources: lessons of 1989. PMID- 10104313 TI - CHPAC (California Hospitals Political Action Committee) achieves new standard of success. PMID- 10104312 TI - Sullivan hopeful on AB (Assembly Bill) 350 Task Force outcome. PMID- 10104314 TI - Medical biohazardous waste disposal challenges hospitals. PMID- 10104315 TI - Team up to meet child-care needs. AB - Recognizing the importance of child care is not the same as providing it. The options for many employees are limited, but some employers are trying to assist employees with their child-care needs. One option that benefits many small to medium-sized companies is a child-care consortium. PMID- 10104316 TI - Incentive effects of medical malpractice. The effects of malpractice litigation on physicians' fees and incomes. PMID- 10104317 TI - Experience rating: does it make sense for medical malpractice insurance? PMID- 10104318 TI - The medical liability crisis: the New York experience. AB - The past 15 years have not been easy for the doctors who manage Medical Liability Mutual. There have been many frustrations and setbacks, and at times the predictors of doom for MLMIC seemed to be correct. Despite all the difficulties, the board of directors has never deviated from its original basic principles: (1) to attempt to settle meritorious claims rapidly and to resist totally those claims without merit; (2) to invest funds with caution and prudence, while achieving the best possible return on that investment; (3) to reduce medical injury and enhance patient safety; and (4) to make every effort to change a system that does not serve the public and threatens our health care system. The next five years may well be even more hectic than the past 15 have been. We do not know the reasons for the recent apparent improvement, and the situation may well deteriorate again. It is to be hoped that major changes that will benefit the public as a whole will occur, and that in the future the concerns of professional liability will not consume as much of our time and resources as they do at present. PMID- 10104319 TI - Liability pilot survey examines claims, expert witnesses. PMID- 10104320 TI - New agency will promote quality of care. PMID- 10104321 TI - Love and let die. AB - When the very technology that can save lives is only prolonging death, how should a patient decide whether to stop treatment--or help death along? In the last days of a ravaging disease, patients and their families face all but unbearable decisions. Is there a right to die? To commit suicide? To be killed on request? As the private dilemmas multiply, they have become the public province of interest groups, policymakers and the U.S. Supreme Court. PMID- 10104322 TI - Valuing experience: how to keep older workers healthy. PMID- 10104323 TI - Getting the most out of case management. PMID- 10104324 TI - The uninsured: a dilemma. PMID- 10104325 TI - The European Business Council for Health. PMID- 10104326 TI - Data watch. How the work force is changing. PMID- 10104327 TI - The 1990 national executive poll on health care costs and benefits. AB - In its first annual survey, Business & Health polled corporate leaders nationwide. We asked how much companies are spending on health care, what benefits companies are offering now and what they plan to offer in the future, and how much emphasis firms are putting on managed care and wellness. We also asked what worries executives most about health benefits and who they blame for rising costs. Here's what we found out. PMID- 10104328 TI - Is fraud driving up your dental care costs? PMID- 10104329 TI - Massachusetts' universal health plan: who will pay the bill? PMID- 10104330 TI - Pepper Commission report released. PMID- 10104331 TI - Designation of medically underserved populations and areas--HRSA. Notice. AB - Under the provisions of section 330(b)(6) of the Public Health Service (PHS) Act, 42 U.S.C. 254c(b)(6), as amended by Pub. L. 99-280, the Governors of the States of Hawaii and Maine have asked the Secretary of Health and Human Services (HHS) to designate specific populations within their States as medically underserved populations (MUPs). Also, under section 330(b)(3) of the PHS Act, certain geographic areas in the States of Missouri, Nebraska, South Carolina, South Dakota, and Washington have been proposed for designation as medically underserved areas (MUAs). This notice provides an opportunity for State and local officials, State organizations representing Community Health Centers, and other interested parties in the above-mentioned States to provide recommendations and to comment on the proposals to designate as medically underserved the areas and populations described in this notice. PMID- 10104332 TI - Availability of funds to provide health services in the Pacific Basin--HHS. Notice of availability of funds. AB - The Health Resources and Services Administration (HRSA) announces that up to $331,000 is available under section 301 of the Public Health Service (PHS) ACT 42 U.S.C. 241, for funding public and non-profit private entities for projects to build capacity and improve health services and systems, particularly preventive health services, in the Commonwealth of the Northern Mariana Islands, American Samoa, Guam, the Federated States of Micronesia, the Republic of the Marshall Islands and the Republic of Palau and to provide technical assistance relative to such projects. In recognition of the extent of funding available, these funds will be available only to continue activities currently receiving funds under the section 301 Pacific Initiative grant authority. HRSA will entertain applications from current grantees for supplemental grants to modify project activities, and from eligible organizations for competing continuation grant awards to extend project activities. PMID- 10104333 TI - Federal assistance for rural hospitals for advancement and improvement of health care services and the enhancement of quality care--fiscal year 1990--HRSA. PMID- 10104334 TI - Statement of organization, functions, and delegations of authority; Indian Health Service--PHS. PMID- 10104335 TI - Statement of organization, functions, and delegations of authority; Indian Health Service--PHS. PMID- 10104336 TI - Availability of funds for grants to provide for the delivery of AIDS/HIV services within community health facilities--HRSA. Notice of available funds. AB - The Health Resources and Services Administration (HRSA) announces the availability of approximately $10.9 million in Fiscal Year (FY) 1990 for grants to community health facilities, including Community and Migrant Health Centers and local public hospitals and clinics, to provide comprehensive primary care services to persons with human immunodeficiency virus (HIV) infection. These grants will be awarded under the provisions of the Department of Health and Human Services Appropriations Act, FY 1990, Public Law 101-166. PMID- 10104337 TI - The forgotten elderly: inside America's prisons. PMID- 10104338 TI - Outlook for accessing capital. Lenders regroup to meet needs in the 1990s. Interview by Jim Bowe. PMID- 10104339 TI - Costs, coverage distinctions climb. PMID- 10104340 TI - Selectivity offset by greater eligibility. PMID- 10104341 TI - Abuse and neglect. A foundation for criminal liability. PMID- 10104342 TI - Three hundred sixty-five days post-HMO. AB - Carolina Medical Care was conceived as a physician-owned HMO. Two-and-a-half years later, it was declared insolvent and shut down. As a founding member of the HMO, a third of its 15,000 patients were capitated to the Mecklenburg Medical Group. This case study examines the efforts to keep those patients following dissolution of the HMO. PMID- 10104343 TI - Nursing salaries: a new strategy. AB - Salary inconsistencies in the nursing department of the Mecklenburg Medical Group were becoming a significant problem. This case study explains how the group implemented a system to bring nurses' salaries in line with the rest of the community. PMID- 10104344 TI - The advanced group practice model. AB - This professional paper reviews the market and medical economic forces at work which favor the group practice model, and investigate alternative structures in the group practice model that would appeal to the solo practitioner and two-man association. PMID- 10104345 TI - Does owning a nursing home fit into your medical group's future? AB - A savvy administrator must explore and implement ways to keep the medical group growing, but always to keep in perspective the monetary limitations. This professional paper provides a model to use in determining whether or not a medical group should consider branching out into the nursing home business. PMID- 10104346 TI - Organization and automation of the medical records department. AB - The Lewis-Gale Clinic, a 100-physician multispecialty group practice, needed to get its record systems more organized in order to provide the foundation necessary to continue patient growth objectives. The following case study describes how these goals were accomplished. PMID- 10104347 TI - Overcrowding: the ED's newest predicament. PMID- 10104348 TI - The politics of trauma. Will legislation save the systems? PMID- 10104349 TI - Will you still love me tomorrow? Lessons in loyalty. PMID- 10104350 TI - The economic burden of providing trauma care: what are the costs and who pays? PMID- 10104351 TI - Liabilities of regulatory noncompliance. PMID- 10104352 TI - The obstetrics market matures for LDRs/LDRPs (labor delivery recovery/post partum rooms). PMID- 10104354 TI - Hospital-based ambulatory care faces uncertain future. PMID- 10104353 TI - Pre-design facilities for change. AB - Medical facilities are changing to meet the demand for convenient out-patient healthcare, and hospitals are clearly following the market to deliver primary care services through ambulatory care facilities. Whether it is a satellite center for a hospital, an out-patient surgical center or any number of other specialty service clinics, a free-standing facility represents a major investment, filled with latent pitfalls. PMID- 10104355 TI - Planning indicators. Home health care services mix varies by type of ownership; long-term patients choose proprietary agencies for home health needs. PMID- 10104356 TI - Mt. Sinai Hospital enters new building phase. PMID- 10104358 TI - Disability management strategies focus on early rehab. PMID- 10104357 TI - AIDS report summarizes data for hospital managers. PMID- 10104359 TI - Building a regional medical center. Interview by Donald E.L. Johnson. AB - Allen P. Fletcher is president of a 372-bed community hospital that is between Atlanta and Birmingham and loses patients to hospitals in those cities more frequently than he likes. Northeast Alabama Regional Medical Center, Anniston, Alabama, runs an average daily census of about 165 patients and many of its 100 active physicians are so busy that they have waiting lists. Fletcher has been president of Northeast for six years. He holds an MHA from Georgia State University. In an interview with Donald E.L. Johnson, editor and publisher of Health Care Strategic Management, Fletcher talks about the small window of opportunity he sees for secondary hospitals. PMID- 10104360 TI - The hospice concept of care: facing the 1990s. AB - Although hospice is a widely accepted form of care for the terminally ill, there is still a misconception that hospice represents a place, rather than a form of care. Hospice is designed to address three major problems of dying: pain, loneliness, and loss of control. It also emphasizes the role of the family in the caregiving process. The greatest need today in hospice is the increased involvement of the medical profession. Hospice must also expand to include not only cancer patients, but anyone who is dying, including AIDS patients. The future of hospice is bright, but it needs our commitment, our time, and our prayers. PMID- 10104361 TI - Folk art reduces hospital stress. AB - A photographic story of one teaching hospital's innovative approach to alleviating patient anxiety. PMID- 10104362 TI - Interim targeting: a productivity improvement method that works. PMID- 10104363 TI - Same story, different words? PMID- 10104364 TI - Gaining perspective. PMID- 10104365 TI - Not so mobile a market. PMID- 10104366 TI - Cures at the touch of a key. PMID- 10104367 TI - Facing up to errors. PMID- 10104368 TI - A fresh start. PMID- 10104369 TI - On a downward gradient. PMID- 10104370 TI - Silence is not golden. PMID- 10104371 TI - IT's (information technology's) on to a good thing. PMID- 10104372 TI - The DGM's dilemma. PMID- 10104373 TI - Talent waiting to be tapped. PMID- 10104374 TI - Beyond old rivalries. PMID- 10104375 TI - Making the team work. PMID- 10104376 TI - Driving the NHS. PMID- 10104377 TI - The day trippers. PMID- 10104378 TI - Sharing in caring. PMID- 10104379 TI - Technology in transit. PMID- 10104380 TI - Using Monte Carlo simulation to make better capital investment decisions. AB - The financial analysis of a proposed capital investment typically involves estimating the project's expected cash flows and profitability and then perhaps looking at one or two alternative scenarios. However, this procedure provides incomplete information about a project's potential risk/return characteristics because it focuses on only a few possibilities; whereas, real-world investments can have an almost unlimited number of financial outcomes. Monte Carlo simulation can solve the incomplete information problem. In a Monte Carlo simulation, relatively certain input variables are specified by single values, while relatively uncertain variables are specified by probability distributions. The end result is a probability distribution that describes the project's full range of potential profitability. With a complete set of information concerning a project's risk/return characteristics, decision makers can better judge the financial impact of the investment and hence make better capital investment decisions. PMID- 10104381 TI - Evaluation of health care work environments via a social climate scale: results of a field study. AB - Health care organizations must be concerned with their work environment and its effect on their ability to function effectively. Areas such as medical protocol, professional education, and patient care receive constant attention, as they should; but perhaps training in traditional management may be lacking, especially among first-level and middle-level management. Due to a lack of in-depth management training and experience, some health care supervisors may not be fully aware of the work climate in their organization, or of the implications of that climate. This article addresses the concept of organization climate and suggests the use of a standardized scale--the Work Environment Scale (Moos 1986) for climate assessment. An example of its application in a hospital is provided. PMID- 10104382 TI - A bereavement program: good care, quality assurance, and risk management. AB - Oregon Health Sciences University Hospital implemented a proactive bereavement program based on a faculty research project demonstrating poor sensitivity to the families of deceased patients, their subsequent postdeath adjustment, and feelings about interactions at the hospital. The program has improved support to families at the time of death and established a follow-up system that refers families with adjustment difficulties to an appropriate provider. Educational programs have improved the skills and sensitivity of trainees and staff in responding to stressful patient-family situations concerning death and bereavement. Beyond providing optimal care, a bereavement program benefits quality assurance, risk management, and the community image of any hospital. PMID- 10104383 TI - Patient complaint strategies in a general hospital. AB - This study aimed to understand specific complaint behaviors of inpatients regarding perceived problems in the receipt of hospital services and to study the effect of provider responses to the different complaint strategies on patients' overall satisfaction with hospital services. The analysis was performed on 155 patients who had reported a problem in the receipt of services and had acted to elicit a change. Three complaint strategies were studied--formal, informal, and a combination of both. The use of these strategies was studied in relation to type of hospital service and the type of ward where the problem emerged. Two questions were investigated--what strategy leads to the best outcome for the patients? and how does each outcome affect overall satisfaction with hospital services? PMID- 10104384 TI - Intermountain Health Care: a multihospital system committed to rural health care. AB - This article describes Intermountain Health Care's experience in rural health care and outlines the accomplishments and problems that a multihospital system has experienced in maintaining its commitment to rural health care. Development of services in both administrative and clinical functions shared between referral centers and the corporate office with rural hospitals is explained and the amount of savings generated described. The challenge of maintaining hospitals with 20 beds or fewer is explained as well as how hospitals with 50 beds or more are breaking even because of the support from the system. Strategies are described to address decreasing revenues in the environment and alternatives of care available from Intermountain Health Care to the communities that cannot sustain an acute care facility are identified. PMID- 10104385 TI - Training improves productivity. PMID- 10104386 TI - The ABCs of selling. PMID- 10104387 TI - Pharmacy service to the nurseries. PMID- 10104388 TI - Disaster imminent--Hurricane Hugo. AB - Response to a disaster situation depends upon the type of circumstances presented. In situations where the disaster is the type that affects the hospital as well as a wide surrounding area directly, the hospital and pharmacy itself may be called upon to continue functioning for some period of time without outside assistance. The ability to function for prolonged periods of time requires the staff to focus on the job at hand and the administrative staff to provide security, compassion, and flexibility. Plans for a disaster of the nature of a hurricane require that attention be paid to staffing, medication inventories, supplies, and services being rendered. Recognition of the singular position occupied by a hospital in the community and the expectations of the local population require that hospitals and the pharmacy department have the ability to respond appropriately. PMID- 10104389 TI - Documenting concurrent clinical pharmacy interventions. AB - The documentation of clinical pharmacy activities is an important issue and the authors describe a relatively simple and easily implemented method of documenting concurrent clinical pharmacy interventions. This quality assurance measure was added to the quality assurance calendar of a tertiary care medical center/teaching hospital to: (1) document to the Joint Commission on Accreditation of Healthcare Organizations that the pharmacy department is involved in direct patient care, and (2) demonstrate to hospital administrators that pharmacists are an integral and necessary component of the health care team. At least 115 of 428 (27%) documented interventions during 1988 prevented patients from suffering potentially serious side effects and adverse drug reactions. Physicians and nurses initiated consultations by contacting pharmacists, either by phone or in person, and asking them to: (1) recommend dosages for renally impaired patients; (2) monitor patients receiving medications such as aminoglycosides, digoxin, and phenytoin; (3) suggest appropriate doses for specific indications; (4) recommend a formulary drug for a specific condition; and (5) provide drug information. Pharmacists initiated consultations by contacting physicians and nurses, either by phone or in person, to clarify an order or make recommendations regarding drug therapy. Nurses, pharmacists, and physicians initiated 37%, 33%, and 30% of the clinical interventions, respectively. Most of the physician (89%) and nurse (82%) initiated interventions were requests for drug information, whereas most of the pharmacist initiated interventions were order clarifications (51%). The daily documentation of clinical pharmacy interventions demonstrated that the quality of patient care and patient outcome was improved and served as an effective method of cost-justifying pharmacist positions in this era of fiscal constraints. PMID- 10104391 TI - 1989 annual survey--133 orphan drug products. PMID- 10104390 TI - Patient education: instruction cards for i.v. antibiotics. PMID- 10104392 TI - Developing mobile lithotripsy services. AB - Today's health care environment forces hospitals to seek competitive advantages over other providers in their area, yet circumstances and situations exist where cooperation among providers is the only way to ensure the effective and efficient provision of quality care to area residents. In the case of new and expensive medical technology, cooperation may be necessary to make state-of-the-art treatment modalities available to the patient population in an affordable manner. The role of outside consultants and legal counsel should not be overlooked. Independent consultants can be a valuable resource in dealing with planning agencies and in preparing a Certificate of Need. In addition, reputable firms can lend additional credibility to the conduct of feasibility studies and the preparation of financial projections. Continuity in terms of staffing and committee representatives is also extremely important. In a process that covered a three-and-one-half year time period, participants can lose sight of the original goals of the venture and even interest in the project. Hospitals and physicians in northeastern Pennsylvania combined to provide an alternative to surgical intervention for the removal of kidney stones. The process was a lengthy and complicated one, but one that resulted in a service which, above all, is of benefit to those affected by kidney stone disease. The delivery network currently includes seven facilities, five as partners and two on a fee-for-service basis, with an additional five making application to join the program in the future.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10104393 TI - Reviewing hospital-physician contracts: reading between the lines. PMID- 10104394 TI - Easy street. David Guynes designs real-life rehabilitation settings. PMID- 10104395 TI - AIDS hospice. PMID- 10104396 TI - Plus One. An exercise/health center in downtown New York designed by James Biber Architect. PMID- 10104397 TI - Playroom injury leads to hospital liability. PMID- 10104398 TI - The Employment Polygraph Protection Act of 1988: should hospitals be concerned? PMID- 10104399 TI - Price survey. Surgical instruments to rise 6% to 8%. PMID- 10104400 TI - More hospitals prefer to work with prime vendor distributors. PMID- 10104401 TI - Incentive programs. Safe Harbor regs will define legal discounts. PMID- 10104402 TI - Materials managers must respond quickly to improper shipped goods to avoid headaches. AB - The hospital placed an order by telephone for 1,000 envelopes printed with the hospital's logo on them. When the shipment arrived, it contained 100,000 envelopes with the logo on them. The printer said that a computer that handled the order and scheduled the printing caused the over shipment. In this dialogue, Dr. Decker discusses the issues involved in the transaction. PMID- 10104403 TI - Used medical equipment generates little cash for hospitals; old devices donated to charities. PMID- 10104404 TI - Productivity: "working smart" to cope with labor shortages. PMID- 10104405 TI - Super nursing units: one of 18 tactics for reducing hospital labor costs by the Health Care Advisory Board. PMID- 10104406 TI - A critical look at recent developments in tax exempt hospitals. PMID- 10104407 TI - Withholding consent for medical care of a child: the ultimate parental decision. PMID- 10104408 TI - A cure for the health care crisis. AB - To reduce medical costs while preserving access to quality care, try the good old marketplace, where consumers cast their dollar votes. PMID- 10104409 TI - The Mental Health Services Program for Youth. AB - This paper traces the development of The Robert Wood Johnson Foundation's Mental Health Services Program for Youth, a private initiative designed to improve the organization, financing, and delivery of service to seriously mentally ill youth. The rationale and structure of this five-year initiative are discussed. In July 1989, 12 one-year development grants were awarded under the program's first phase. All of the grantees propose to utilize a number of strategies to restructure their mental health financing systems. Other common features include: the development of central intake units, early identification mechanisms, stronger utilization review protocols, and unified client tracking mechanisms. PMID- 10104410 TI - Family-centered services: implications for mental health administration and research. AB - Efforts to move the system of care for children with serious emotional disorders toward community-based alternatives has prompted a growing recognition of the need for supportive services for families. This article examines the shifts in policy and administrative practice that are needed in order to move toward a family-centered system of care. Proactive administrative support is particularly important in this system shift. Four important barriers to a family-centered system of care are examined: (1) efforts have tended to focus on the child as the unit of services, rather than on the family; (2) efforts have tended to focus primarily on mental health services, rather than considering the full range of services needed by the child and family; (3) efforts have tended to emphasize formal services, often ignoring the support provided by informal networks; and (4) the resources and expertise of parents and other family members have not been used. New roles for parents--which involve working with administrators and researchers are discussed. PMID- 10104411 TI - Children's mental health: challenges for the nineties. AB - This article summarizes some of the progress made in serving children with emotional disorders and their families during the 1980s, and it provides an overview of the status of the children's mental health field as the decade ends. The article then proceeds to identify seven major challenges that the field faces as a new decade begins. These challenges relate to training and human resources development, funding for services, research, interagency collaboration, overall service system development, advocacy, and children at risk for developing serious emotional disorders. PMID- 10104412 TI - The role of individualized care in a service delivery system for children and adolescents with severely maladjusted behavior. AB - Individualized care is a total system of care that is tailored to a child with severely maladjusted behavior. The services are unconditional, flexible, child and family focused, and interagency coordinated. The services follow the child until the child is adjusting in a normalized, mainstream environment. Individualized care is illustrated through two different projects. One is the Alaska Youth Initiative where individualized care was used to return children from out-of-state, residential programs. The other is Project Wraparound where it was used to prevent children from being removed from their families. This paper begins with the principles of individualized care and then describes the ecological, multilevel assessment process that coincides with the delivery of services. A case example from Project Wraparound is provided for clarification. Following the case example is a discussion of the need for evaluation data with some suggested strategies for documenting effectiveness. The final section focuses on two barriers to the implementation of individualized care. One is the tendency to think in terms of component programs rather than individualized services. The other barrier is the competition for scarce resources. Strategies are presented for overcoming both barriers. PMID- 10104413 TI - Moving out: transition policies for youth with serious emotional disabilities. AB - Moving from the children's service system to the adult service system is a difficult process for youth with serious emotional disabilities. The fragmentation of services and entrance criteria-based age makes this transition difficult. This article examines how state-level policy can facilitate the orderly planning and delivery of transition services. Several types of transition policies currently in use by states are described, and nine important components of transition policy are identified. These components represent content which needs to be present in order for state level policy to adequately address the needs of transitioning adolescents with serious emotional disabilities. Mental health planners, state administrators and policy analysts can play an important role in initiating, reviewing, and coordinating state policy regarding transition. PMID- 10104414 TI - Ideas and inducements in mental health policy. AB - Between 1946 and 1963, federal officials sought to change the national practice of providing mental health care, away from state-run mental institutions and toward outpatient care based in local communities. These policy makers relied on two policy instruments, ideas and inducements. Both instruments contributed to unexpectedly significant changes in federal, state, and local policy. I conclude that a policy instrument framework helps to disentangle the strands of successful public management, and that it is useful to think of ideas as policy instruments that offer leverage on policy outcomes. PMID- 10104415 TI - Innovation in public sector human services programs: the implications of innovation by "groping along". AB - This paper examines innovation in seventeen human services programs cited by the 1986 Ford Foundation Awards Program for Innovations in State and Local Government. The sample is particularly useful for distinguishing between two models for successful innovation: a policy planning model and Behn's model of "groping along." The cases suggest that the "groping along" model best fits the way that innovation came about in these programs. Innovative ideas typically developed through practice; programs began operating very quickly; and programs, once operating, were repeatedly modified in response to operational experience. Translating the groping-along model into specific prescriptions for managers requires us to reconsider the role of analysis. The case examples suggest that analysis may be most valuable in helping managers learn from experience. PMID- 10104417 TI - Does advertising draw patients? PMID- 10104416 TI - Serials standards work: the next frontier. AB - Serials, one of the more complicated areas of library technical endeavors, has lacked the benefit of standards for a long time. Even now, with standards beginning to be available, the majority of institutions are not working within standard serials formats. A survey to determine the use of serials standards in libraries was conducted in 1988 by the American Library Association, Resources and Technical Services Division, Serials Section, Committee to Study Serials Standards. In the spring of 1988 a survey was sent to a group encompassing the Association of Research Libraries members, CONSER participants, United States Newspaper Program participants, Microform Project libraries, and some vendors and librarians who attended the Committee meetings on a regular basis. The survey questionnaire assessed the current level of serials standards awareness of librarians and vendors. Topics included the type of serials systems used, standards relevant to serials control and union listing and whether or not they are implemented, types and levels of training staff received in the application of standards, benefits of the standards, and areas where standards are most needed. PMID- 10104418 TI - Patient loyalty. You're doing something right. PMID- 10104419 TI - Malpractice: why fewer patients are out for blood. PMID- 10104420 TI - Your office: making things easier for patients pays off. PMID- 10104421 TI - The many faces of productivity measurement. PMID- 10104422 TI - AIDS precautions in practice. AB - Are labs taking appropriate measures to prevent HIV transmission? MLO's national survey indicates that efforts are admirable overall, although follow-up can be inconsistent. PMID- 10104423 TI - The risk of AIDS to laboratorians: an update. PMID- 10104424 TI - OSHA: new player in the battle against AIDS. AB - The Federal agency's far-reaching proposed standard on preventing exposure to HIV and HBV infection in the workplace will probably become final by next year. What prompted the standard and what does it call for? PMID- 10104425 TI - Continuing education work group: a useful strategy. PMID- 10104426 TI - Cholesterol screening. Part III. A lab-driven program for cholesterol testing. PMID- 10104427 TI - A spreadsheet for capital equipment financial modeling. PMID- 10104428 TI - Criminal price-fixing and the physician: what's going on here? AB - The Department of Justice has recently taken a keen interest in examining the activities of physicians for potential antitrust violations based on price-fixing agreements. Consequently, it is important for physicians and their counsel to become familiar with the applicable antitrust principles to avoid participation in questionable agreements. PMID- 10104429 TI - Medical malpractice and tort reform: a summary and look to the future. AB - In this article, the author describes the recent history and current status of tort reform in this country and provides an overview of various trends that are likely to shape the future of tort reform. PMID- 10104430 TI - Emerging trends in medical practice: primary practice revisited. AB - Following the failure of the diversification era, hospitals are returning to the roots of medicine. The result is a new focus on primary care, a beneficial outcome for both the medical and hospital communities. PMID- 10104431 TI - Health care litigation: recent trends in the law of noneconomic damages- emotional distress. AB - This article and an article to follow, the sixth and seventh in a series, will address the topic of noneconomic damages in medical malpractice cases. Pain and suffering, emotional distress, loss of consortium, loss of a chance, hedonic damages, and other forms of nonpecuniary damages have played a major role in the increased recovery of compensatory damages from health care providers. This article will provide an overview of the subject of noneconomic damages and an in depth discussion of the law regarding damages for emotional distress to third parties as it has evolved in the State of California. PMID- 10104432 TI - Exhausting administrative remedies in appeals of PRO contract bid rejections: a case study. AB - This article will discuss the procedures for filing an administrative appeal with the Comptroller General and the General Accounting Office. An actual case study of an appeal filed in a bid protest of a peer review organization contract award will be studied to illustrate the appeal process, and the resolution of this appeal will be examined. PMID- 10104433 TI - The physician-driven marketing program: what it means to the physician. AB - In this article, the author describes the benefit to hospitals of implementing physician-driven marketing programs and what implementation of such programs can mean to physicians. PMID- 10104434 TI - Bell v. Sharp Cabrillo Hospital: defining the hospital's level of corporate responsibility. PMID- 10104435 TI - Peer review--it's time for a change. PMID- 10104436 TI - Higher costs of pediatric AIDS care documented. PMID- 10104437 TI - Antitrust investigation of proposed Calif. hospital acquisition dropped. PMID- 10104438 TI - VHA Enterprises proxy supports Partners sale. PMID- 10104439 TI - 1990 benefits survey. PMID- 10104440 TI - New patient-dumping rules may stir up trouble between execs, physicians. PMID- 10104441 TI - NLRB prepares to implement new hospital bargaining rules. PMID- 10104442 TI - A simmering perception of inequality. PMID- 10104443 TI - Union election activity dwindles. PMID- 10104444 TI - Tennessee hospital finds it can reduce its costs by improving quality. PMID- 10104445 TI - Mich. first state to get Moody's rating update. PMID- 10104446 TI - Baptist CEO Struble resigns under fire. PMID- 10104447 TI - PacifiCare offers to buy Maxicare. PMID- 10104448 TI - HealthVest slashes value of portfolio. PMID- 10104449 TI - AHA joins appeal in antitrust case. PMID- 10104450 TI - Physicians offered stake in hospital. PMID- 10104451 TI - Healthcare Int'l cuts ties with top execs. PMID- 10104452 TI - Economic data from AHA suggest hospital industry's financial crisis is easing. PMID- 10104453 TI - Lawsuit seeks to block VHAE sale of Partners. PMID- 10104454 TI - Untangling management structures. AB - Hospital executives looking for ways to cut costs are finding that complex hospital management structures contribute to higher healthcare costs and cumbersome decisionmaking. Several hospitals are trying to undo the damage, while folks in Washington are doing their part to speed the slimming process. PMID- 10104455 TI - Squeezing out needless costs. Conference attendees debate symptoms and cures for waste. PMID- 10104456 TI - The team's time has come. AB - Hospital management became more diverse and talented in the 1980s to deal with the crush of change and financial pressure in the industry. But most hospitals haven't taken the extra step of developing management teams to take on the challenges of the '90s, says Don Arnwine. PMID- 10104457 TI - 1 merger case ends; 1 appealed. PMID- 10104458 TI - AIDS panel calls for emergency money. PMID- 10104459 TI - Diversifying into skill-nursing care. PMID- 10104460 TI - Selective nursing homes delay hospital discharges--studies. PMID- 10104461 TI - Hospitals taking a hard look at 'soft benefits'. AB - Hospitals buy systems for their "qualitative" benefits and not just to save money or cut costs. But these "soft" benefits can be nearly as elusive as hard-dollar savings, concluded a study conducted for Modern Healthcare by Coopers & Lybrand and Zinn Enterprises. Second in a series. PMID- 10104462 TI - Group Purchasing Alliance/USA disbands. PMID- 10104463 TI - Trade association receives funding. PMID- 10104464 TI - Physical-plant services offer programs to cut utility bills, source of capital funding. AB - Some hospitals are turning plant operations over to companies that design systems to reduce costs in return for a share of the savings. Some companies also pay for or finance capital improvements as part of the deal. PMID- 10104465 TI - Healthcare PACs give generously to senators. PMID- 10104466 TI - AHM cutting expenses, adding technology. AB - American Healthcare Management, emerging from bankruptcy protection is cutting corporate costs and expanding into new technology to attract more private-paying patients and lessen dependence on Medicare business. PMID- 10104467 TI - Two HealthTrust hospitals near sale. PMID- 10104468 TI - Caring for AIDS patients: cost issues. PMID- 10104469 TI - Caring for the homeless elderly. PMID- 10104470 TI - Ethical problems for physicians raised by AIDS and HIV infection: conflicting legal obligations of confidentiality and disclosure. PMID- 10104471 TI - A shared vision of hospital leadership. PMID- 10104472 TI - Implementing continuous quality improvement. PMID- 10104473 TI - The role of governance in the financially distressed hospital. PMID- 10104474 TI - CEO firings: the medical staff's role. PMID- 10104475 TI - Outpatient programs for oncology. PMID- 10104476 TI - Education is the key to a hospital's successful future. PMID- 10104477 TI - Ethics: trustees have the right stuff. PMID- 10104478 TI - Communication is high on Wilensky's HCFA agenda. PMID- 10104479 TI - Hilton Head Hospital trustee discusses hospital finance. Interview by Karen Gardner. AB - Hilton Head Hospital, a 64-bed acute care hospital in Hilton Head Island, SC, was built in 1975. During its early years, the hospital struggled to meet its payroll. For the last few years, the hospital's operating margin has been so healthy that this small, general hospital is now able to contribute substantially to maintaining its sophisticated services and equipment. As vice-chairman of the hospital's board of trustees, vice-chairman of the hospital's parent corporation, and chairman of the hospital's foundation, Frederick S. Donnelly, Jr., is well aware of the governing boards' decisions that have contributed to Hilton Head Hospital's financial turnaround. He recently talked with Trustee managing editor Karen Gardner about the hospital's finances. PMID- 10104480 TI - Trustees and ethical policymaking: leadership in values. PMID- 10104481 TI - Perception/reality. Selecting from the service menu. Part two. Keeping the customer satisfied. PMID- 10104482 TI - PACS mania. PMID- 10104483 TI - Hiring technologists as temporary workers--without annoying the IRS. PMID- 10104484 TI - Nursing home utilization in adults: a prospective population-based study. AB - Rates of nursing home utilization between 1972 and 1986 were determined for 1,302 men and women living in an upper-middle-class community in Southern California. Leading diagnostic reasons for admission were dementia, cancer, and stroke, and the leading nondiagnostic reason for admission was an inability to carry out activities of daily living. In this cohort, rates of nursing home utilization increased with age. Women at all ages used nursing homes at a higher rate than men, although their probability of survival once admitted was greater. Admission rates were higher over time or prior to death than when observed cross sectionally. Rates were highest in the year prior to death but declined at time of death. PMID- 10104485 TI - Medical care for the elderly: attitudes of medical caregivers. AB - Attitudes of medical caregivers toward treating the elderly were defined in reference to two aspects of quality of care: the technical and the psychosocial aspects. The correlation between these aspects was assessed using samples of first-year and third-year students, interns, and MDs who had graduated two or four years previously. Socioeconomic background and orientational characteristics were also entered in an elementary structural model predicting attitudes toward treating elderly patients. The results clearly indicated that the two aspects of attitudes toward treating elderly persons were so highly correlated that only one dimension defined these attitudes, except in the case of first-year students. Furthermore, only two orientational characteristics consistently explained these attitudes throughout the five groups, while background characteristics were excluded from the model in the graduate MD group. These results suggest that studies of the determinants of medical student attitudes toward treating the elderly should test for the number of dimensions before estimating the effect of a set of predictors. PMID- 10104486 TI - Age and patterns of HMO satisfaction. AB - Consumerism and increasing complexity in health care options highlight the importance of health care satisfaction. Patterns and sources of satisfaction are assessed for health maintenance organizations (HMOs), a relatively novel option, using national survey data. Particular attention is paid to age differences, because HMO Medicare coverage is a recent development and older people generally express little HMO familiarity or receptivity. Higher satisfaction is expressed by HMO members than by nonmembers for both younger and older persons. HMO satisfaction is higher for older than for younger members, a pattern at odds with nonmember attitudes about HMOs. Member satisfaction is a function of the nature of patient/provider ties and related attitudes, as it is among nonmembers. Importance of a "regular" provider is particularly evident among older HMO members. Patterns of HMO satisfaction among older members likely reflects both cohort differences and age-associated patterns of health and related attitudes. PMID- 10104487 TI - Patient age, visit purpose, and the ordering of consultations in a primary care clinic. AB - In this study we examine what factors determine whether patients seen in a Veterans Administration primary care clinic will be referred to specialty clinics. It is based on a 25% sample of all patients seen by the medical residents in one clinic over an 18-month period. Our dependent variable is whether the patient was referred for a consultation or not. We performed separate regression analyses for patients who visited the clinic with acute complaints, with chronic-flareup complaints, and with chronic-routine complaints. Within each of these three categories, we further subdivided our sample into patients under and over 65. In each of the six regression equations we controlled for the medical diagnosis and for each resident's work load, residency year, and training. Work load and residency year had opposite (and unpredicted) effects for patients over the age of 65 compared to those under the age of 65. Higher work loads were associated with higher consultation rates for patients over 65 and with lower rates for those under 65. Residency year had a negative effect on referrals for patients over 65 and a positive effect for patients under 65. PMID- 10104488 TI - Perspectives. Taking a cue from Britain's NHS. PMID- 10104489 TI - Perspectives. Oregon's recipe for health care rationing. PMID- 10104490 TI - The University of Michigan Medical Center patient services. PMID- 10104491 TI - New JCAHO patient complaint standards; 'no problem', report NAHAM members. PMID- 10104492 TI - The 'Admit Me' game. PMID- 10104493 TI - Caring through service at The Methodist Hospital, Houston. PMID- 10104494 TI - Perpetual water treatment without chemicals. PMID- 10104495 TI - City General Hospital, Stoke-on-Trent--new surgical accommodation. PMID- 10104497 TI - City General Hospital, Stoke-on-Trent--structural considerations. PMID- 10104496 TI - City General Hospital, Stoke-on-Trent--engineering services. PMID- 10104498 TI - Ultraviolet disinfection. PMID- 10104499 TI - Not enough for all. Oregon experiments with rationing health care. PMID- 10104500 TI - US laboratory staffing crisis. AB - In this article, the factors contributing to a shortage of qualified medical laboratory technologists in the US have been examined, and the Canadian perspective studied. Continued public relations programs, with special programs directed to high school, college and university students would seem to be the appropriate way to prevent similar problems from occurring and escalating in Canada. PMID- 10104501 TI - Applied principles of quality assurance and quality control in the histopathology laboratory. AB - The principles of quality assurance programs and quality control procedures as they are applied to the histopathology section of the laboratory are reviewed. The basic importance of the Standard Operating Procedure Manual is emphasized and the importance of accurate record keeping in tissue reception and accessioning is noted. A detailed look is taken at the quality control measures applied to the repetitive processing sequences involved in the production of stained tissue slides. The problems of the subjective nature of the final assessment of the finished slide are reviewed. PMID- 10104502 TI - Risk management and the laboratory. PMID- 10104503 TI - Guidelines for quality assurance programs in cytopathology. Canadian Society of Cytology. PMID- 10104504 TI - ART certification--an update. PMID- 10104505 TI - Codes put greater emphasis on life safety. AB - To meet today's life-safety needs in modern facilities engineers must follow exact code parameters. This is the only way to ensure that maximum life-safety needs are met. PMID- 10104506 TI - Sam Schultz and the University Hospital Consortium. Interview by Carolyn Dunbar. PMID- 10104507 TI - Bedside computing positively impacts patient care. AB - Experimenting with bedside patient care systems has turned up a valuable track record of experiences to shape nursing/physician utilization and future development. PMID- 10104508 TI - National cardiac registry allows outcomes comparison. AB - Quality, better patient outcomes and cost-containment are high on the healthcare agenda for the '90s. Comparison of clinical treatments over a broad range of episodes and variables can help physicians and researchers determine highly effective--and cost-effective--treatments. A national database, the Merged Cardiac Registry, has taken a big step toward that end. PMID- 10104509 TI - 1990--the age of the user? PMID- 10104510 TI - The quiet vacuum for critical hospital applications. PMID- 10104511 TI - Efficient soap systems help increase productivity of housekeeping staff. PMID- 10104512 TI - Crossroads catering by Irving Healthcare Systems. PMID- 10104513 TI - The U. of Iowa Hospitals & Clinics: atrium dining room & conference center. PMID- 10104514 TI - Musical motivation. PMID- 10104515 TI - Forging new ties: the Maryland experience. PMID- 10104516 TI - Cooperation and coordination between medical boards and hospitals. PMID- 10104517 TI - How to close the health care gap. PMID- 10104518 TI - What leaders really do. AB - Leadership is different from management, but not for the reasons most people think. Leadership isn't mystical and mysterious. It has nothing to do with having "charisma" or other exotic personality traits. It is not the province of a chosen few. Nor is leadership necessarily better than management or a replacement for it. Rather, leadership and management are two distinctive and complementary systems of action. Each has its own function and characteristic activities. Both are necessary for success in today's business environment. Management is about coping with complexity. Its practices and procedures are largely a response to the emergence of large, complex organizations in the twentieth century. Leadership, by contrast, is about coping with change. Part of the reason it has become so important in recent years is that the business world has become more competitive and more volatile. More change always demands more leadership. Most U. S. corporations today are overmanaged and underled. They need to develop their capacity to exercise leadership. Successful corporations don't wait for leaders to come along. They actively seek out people with leadership potential and expose them to career experiences designed to develop that potential. Indeed, with careful selection, nurturing, and encouragement, dozens of people can play important leadership roles in a business organization. But while improving their ability to lead, companies should remember that strong leadership with weak management is no better, and is sometimes actually worse, than the reverse. The real challenge is to combine strong leadership and strong management and use each to balance the other. PMID- 10104519 TI - CEO incentives-its not how much you pay, but how. AB - The arrival of spring means yet another round in the national debate over executive compensation. But the critics have it wrong. The relentless attention on how much CEOs are paid diverts public attention from the real problem-how CEOs are paid. The authors present an in-depth statistical analysis of executive compensation. The study incorporates data on thousands of CEOs spanning five decades. Their surprising conclusions are at odds with the prevailing wisdom on CEO pay: Despite the headlines, top executives are not receiving record salaries and bonuses. Cash compensation has increased over the past 15 years, but CEO pay levels are just now catching up to where they were 50 years ago. Annual changes in executive compensation do not reflect changes in corporate performance. For the median CEO in the 250 largest public companies, a $1,000 change in shareholder value corresponds to a change of just 6.7 cents in salary and bonus over a two-year period. With respect to pay for performance, CEO compensation is getting worse rather than better. CEO stock ownership-the best link between shareholder wealth and executive well-being-was ten times greater in the 1930s than in the 1980s. Compensation policy is one of the most important factors in an organization's success. Not only does it shape how top executives behave but it also helps determine what kind of executives an organization attracts. That's why it's so urgent that boards of directors reform their compensation practices and adopt systems that reward outstanding performance and penalize poor performance. PMID- 10104521 TI - Disaster planning: how hospitals withstood the 1989 San Francisco earthquake. PMID- 10104520 TI - Robert Shellow on psychological screening of security personnel. PMID- 10104522 TI - Gaining cooperation among members of hospital project teams. PMID- 10104523 TI - Stress and satisfaction among professionals who care for AIDS patients: an exploratory study. PMID- 10104524 TI - The Achilles heel of merit pay. PMID- 10104525 TI - Improving nursing's image will help end the shortage today and tomorrow. PMID- 10104526 TI - Hospital chief executive officer turnover. AB - This study indicates that the nationwide CEO turnover rate is lower than many people estimate but was still, in 1987, an uncomfortable 22 percent on average. Some of this turnover may help some hospitals, for example, those with incompetent administrators. Some turnover may be natural in that some CEOs may have retired or died. Other turnover is controlled, such as that in the investor owned sector where planned movement is expected. The analysis of the data in this study indicates that smaller hospitals experience higher turnover rates than do their larger counterparts. In 1987 Sun Belt and western hospitals experienced greater turnover than upper midwestern and eastern hospitals. As a group, however, the investor-owned sector led in turnover rates among hospital CEO turnover rates. PMID- 10104528 TI - Communication. PMID- 10104527 TI - Applying the Deming method in hospitals: Part 2. AB - The first article in this two-part series provided a brief history of W. Edwards Deming's influence on Japanese management and outlined the elements of his theories regarding continuous improvement of quality. This column more fully describes Deming's theories as set forth in his book Out of the Crisis (1986). It then gives examples of how they apply in hospitals. Readers will readily identify applications in their own management activities. PMID- 10104529 TI - An analysis of hospital union election activity: 1985-1987--by hospital ownership, size, and system, and employee organization and bargaining-unit size. AB - During the three-year period 1985-1987, there were 238 elections in nongovernmental, short-term hospitals to determine whether or not unions would represent the employees. Unions had a success rate of 47.1 percent, similar to that of earlier years. This study reports these election results by hospital and election characteristics. For hospitals, the analysis includes elections by census region, ownership, bed size, and multi-institutional characteristics. For elections, the analysis includes the nature and type of election, employee organization, and employee bargaining-unit-size characteristics. This study concludes that the number of union elections decline as hospital bed size increases, and the union success rate is curvilinear and higher in both small and very large hospitals; union success declines as bargaining-unit size increases. Investor-owned and nonprofit, religious hospitals that are members of multi institutional systems have lower union success rates than nonsystem hospitals do in their ownership category. However, unions are much more successful in multi union and decertification elections compared with single-unit elections and initial recognition elections. PMID- 10104530 TI - Selection and implementation of a bar-code-based record management system in ambulatory care. AB - How a large, university affiliated group practice selected and implemented a bar code record management system is described in this article. PMID- 10104531 TI - The Unified Medical Language System (UMLS) of the National Library of Medicine. AB - This article describes the rationale for a Unified Medical Language System (UMLS) being developed by the National Library of Medicine and relates the usefulness of the System for medical record practitioners. PMID- 10104532 TI - Guest editorial: what's happening? PMID- 10104533 TI - AMRA named to Joint Commission PTAC (Professional and Technical Advisory Committee). PMID- 10104534 TI - The legality of unlinked anonymous screening for HIV infection: the U.S. approach. AB - The purpose of this article is to describe the legal approach, and in particular, the specific statutory vehicle adopted by the U.S. with respect to unlinked anonymous screening, and to offer the U.S. approach as a possible model for those countries presently considering the implementation of unlinked HIV screening programs. Clear legal authorization for unlinked anonymous HIV testing is provided for by statute or regulation in the U.S. Federal regulations and various state laws specifically permit unlinked anonymous testing. Under these regulations and statutes, informed consent of a test subject is not required so long as testing is done for research purposes and the test results are not individually traceable to particular subjects. PMID- 10104535 TI - Future health care technology and the hospital. AB - The past decades have been a time of rapid technological change in health care, but technological change will probably accelerate during the next decade or so. This will bring problems, but it will also present certain opportunities. In particular, the health care system is faced with the need to spend its limited resources more effectively. The number of hospital beds is being reduced, and lengths of stay are falling. In the future, the health care system will have to care for an increasing number of elderly people, both with chronic disease and also with dependency because of frailty and functional problems. The hospital of the future will probably be smaller and more intensive in the nature of its care. In part, this is because many present and future clinical technologies can be delivered outside of the hospital setting. And communication technologies offer the possibility of tying the various parts of the health care system into one true system. This would mean that the future hospital would have a more active role in supervising technical care outside of the hospital, and in making specialized knowledge accessible in all parts of the health system. PMID- 10104536 TI - Hospital technology management: the Tao of clinical engineering. AB - Planning a profession's future is a formidable task that must be based on both what the members want to become and what is natural to the marketplace. The hospital industry, however, will not wait for clinical engineering to establish its profession. Competition will arise and push aside the unprepared. Clinical engineering's leadership has not created a clear vision of their profession's role in improving healthcare, nor have they helped others to internalize a sincere professional purpose and to share the responsibility for change. This paper examines the profession and articulates action that only clinical engineers can take to increase their value in the hospital industry. PMID- 10104537 TI - Controlling chemical exposure in healthcare facilities. AB - Employee exposures to toxic chemicals in the healthcare environment can best be managed through a process of exposure assessment, monitoring and control. A general approach for dealing with chemical exposures through an exposure control program is presented. The positive implications of an exposure control program for employee relations, regulatory affairs and legal affairs are discussed. PMID- 10104538 TI - Management of rented medical equipment. AB - Northern California Kaiser Foundation Hospitals' Biomedical Engineering developed a regional rental medical equipment management program in response to the revised 1989 Joint Commission's Health Care Organization Accreditation Standards. The program shifts the operational and safety responsibility for the equipment from the hospitals to the rental vendor. Rental vendors who agreed to Biomedical Engineering's performance standards became preferred vendors from which Kaiser Foundation Hospitals rented their equipment. This program has become a standard adopted by other hospitals that are members of BAMMI (Bay Area Managers of Medical Instrumentation). PMID- 10104539 TI - Physician misconduct: warning other hospitals and resulting corrective action. PMID- 10104540 TI - Health maintenance organization gatekeeping policies: potential liability for deterring access to emergency medical services. PMID- 10104541 TI - Cellular technology. Revolutionizing EMS communications. PMID- 10104542 TI - Maximizing prehospital radio communications. PMID- 10104543 TI - Prohibit free fishing trips. PMID- 10104544 TI - Care giving as work: how nurse's aides rate it. PMID- 10104545 TI - Food fair and wine tasting. PMID- 10104546 TI - Management excellence: agenda for the 1990s. PMID- 10104547 TI - Logical contradictions in feminist health care: a rejoinder to Peggy Foster. PMID- 10104548 TI - Symposium: trends in health planning and marketing. PMID- 10104549 TI - If marketing is everything, maybe it's nothing. PMID- 10104550 TI - Marketing practices of California hospitals: findings from recent research. PMID- 10104552 TI - Direct hospital marketing: an idea whose time has come. AB - Health care marketing has arrived swiftly and with significant impact upon the hospital scene. From the early days of rejection and suspicion of only a few years ago, it has now taken its place with other hospital management functions. Still, however, hospitals have not yet reached the degree of expertise that exists in other sectors. One of the reasons why hospitals have not fully emerged to the level of marketing expertise as many of their traditional business counterparts is that many of the areas of both the science and art of marketing have not been fully developed. One such area is direct mail marketing. Presented here is an overview of the advantages and functions of hospital direct mail marketing. A variety of examples are given with a more thorough case example being provided by Lee's Summit Community Hospital in Lee's Summit, Missouri. The successful direct mail marketing campaign there should be both an inspiration and a model for success for other hospitals. Space limitations prevent the authors from some of the more exacting details of mail marketing and, of course, successful campaigns do not happen by magic. They take careful planning, strategy, and execution. They also require a coordinated organizational and human effort to be successful. But direct mail marketing does offer a potentially new arena of marketing for most hospitals. The expertise, skill, knowledge, and technology are in place. All that is really needed is the commitment on the part of the hospital leadership. PMID- 10104551 TI - The new old market: trends in hospital services for the aged. AB - Hospital health care services for the rapidly aging population should continue to expand. Several recent trends include the following: The overall number and proportion of admissions for the aged have increased since 1967 and will probably continue to increase in the future; The overall percentage of older patients in smaller hospitals has dropped steadily since 1967, but smaller hospitals continue to have a higher percentage of older admissions than do larger hospitals; The aged have a different seasonal pattern of admission compared to younger persons, reaching a nadir in August and an apex between January and April. The average inpatient length of stay for the aged has been dropping steadily over the last twenty years, long before the recent cost containment emphasis; Community hospitals are expanding their operations into long-term care services, including skilled nursing home care, intermediate care, and psychiatric long-term care; Emphasis on early patient discharge has led many hospitals to concentrate on continuity of care between institutions and the community, including increased emphasis on discharge planning and the coordination of services; and Hospitals plan to continue to expand care for the aging and aged population. As the population of the nation ages, hospitals will increasingly address the needs of older persons and continue to plan actively and aggressively and market their services to the aged, not only for humanitarian reasons but also for survival in an increasingly competitive environment. In the future, hospitals seem likely to continue to acquire new and more costly technology to enhance their acute care delivery. At the same time, however, they will continue to provide an increasing array of health care services to older persons. They will convert acute care beds to long-term care use, construct and or purchase nursing homes, and expand into other areas of care for the aged. Thus, the authors predict that hospitals will indeed evolve beyond acute care and play a central function in the provision of the nation's long-term care system. PMID- 10104553 TI - Unraveling rural EMS problems. PMID- 10104554 TI - Push is on to reverse federal neglect of rural EMS. PMID- 10104555 TI - New law may define EMS for the 1990s. PMID- 10104556 TI - Health care reform: fundamental change or incremental steps? PMID- 10104557 TI - This is the way a hospital ends ... not with a bang but a void. PMID- 10104558 TI - New medical waste laws in effect in Michigan. PMID- 10104560 TI - Image, identity, education elevate auxilians to the 21st century. PMID- 10104559 TI - Change key to continuity on hospital boards? PMID- 10104561 TI - Involving the 'right' physicians. PMID- 10104562 TI - Los Angeles's trauma system alarm heard across the country. PMID- 10104563 TI - Insurance reform debates echo industry discord. PMID- 10104564 TI - Hospitals are loath to cite satisfactory level of profit. AB - The healthcare industry likes to talk about the need to earn a reasonable profit, but no one wants to nail down what constitutes a reasonable profit margin for a hospital, says Michael Millenson. PMID- 10104565 TI - Effort to accredit 'responsible' hospitals gains interest, critics. AB - An effort to "accredit" the most socially responsible hospitals is gathering interest and support from some institutions. But others say the practice may hurt hospitals that don't make the grade, and the standards may not take into account the cumulative good rendered by all institutions in a market. PMID- 10104566 TI - Adventist to restructure NEMA unit. PMID- 10104567 TI - VHAE shareholders approve sale of 50% interest in Partners. PMID- 10104568 TI - 'Closures didn't affect access'. PMID- 10104569 TI - Analysis of hospital indicators is upbeat. PMID- 10104571 TI - Demand for health jobs strong--report. PMID- 10104570 TI - JCAHO releases latest conditional list. PMID- 10104573 TI - Bill would aid trauma centers. PMID- 10104572 TI - Humana asks Ky. for HMO exemption. PMID- 10104575 TI - Empire Health restructures. PMID- 10104574 TI - Improving managed care's management. AB - While health maintenance organizations may offer the best way to manage costs, experts say that their own management leaves a lot of room for improvement. HMOs are beginning to win back control of their companies with incentives aimed at attracting and retaining the leadership they need to counter the industry's obstacles. PMID- 10104576 TI - How healthy is your hospital? Executives often have no idea. AB - Is your hospital in trouble? Would you know if it is? Many administrators don't see the danger signs for months before a financial crisis hits, said turnaround specialist David Hunter. He offers a quiz to test executives on their knowledge of the key factors in a hospital's health. PMID- 10104577 TI - Environment, cost concerns spur new interest in reusables. AB - Disposable linens have blanketed the hospital market since the 1970s, but reusable products are attracting renewed interest. Sparking the reassessment are elevated costs of medical-waste disposal, innovations in recycled linens and blossoming environmental concerns. PMID- 10104578 TI - Development deals can help finance growth. AB - A New York hospital has broken new ground in financing construction costs by selling the development rights above a new facility for a private condominium project. PMID- 10104579 TI - CompCare expects $50 million loss. PMID- 10104580 TI - OR managers face AIDS ethical dilemmas. PMID- 10104581 TI - Nurses cannot refuse to care for AIDS patients. PMID- 10104582 TI - JCAHO shifts its emphasis to QI--quality improvement. PMID- 10104583 TI - How do courts determine prudent action? PMID- 10104584 TI - QA monitoring reflects OR's uniqueness. PMID- 10104585 TI - Patient accounts managers must broaden their horizons beyond their specialty. AB - Healthcare professionals interested in advancing their careers and helping their institutions to survive need to develop an understanding of industry trends. Managers need to learn about the issues facing other departments if they are to play a role in solving problems. PMID- 10104586 TI - Bad debt, charity care indicators increase. PMID- 10104588 TI - The physician's experience: witnessing numinous reality. PMID- 10104587 TI - Quality assurance and quality of care: II. Monitoring treatment. AB - The absence of meaningful linkages between quality assurance programs and quality of care has alienated them from each other, especially in psychiatry, where standards of care and process and outcome of treatment are vaguely defined and vigorously debated. This paper describes several factors contributing to the gap between quality assurance and quality of care as well as a treatment-monitoring process that attempts to bridge the gap. The form and review process described are criteria-based and concurrent, and they use methodology that both assesses documentation and promotes an interactive clinical review. Preliminary data that demonstrate the clinical usefulness of the process and its impact on a treatment service are presented. PMID- 10104589 TI - Health care in the U.S.: the social issues. PMID- 10104590 TI - The nurse's experience: stories of serving. PMID- 10104591 TI - Health care in the U.S.: facts and choices. PMID- 10104592 TI - Accepting our responsibility. PMID- 10104594 TI - A voice for the voiceless: the church and the mentally ill. PMID- 10104593 TI - The vision of the possible: what churches can do. PMID- 10104595 TI - The tradition of the church in health and healing. PMID- 10104596 TI - One congregation's experience: an introduction. PMID- 10104597 TI - The sufferer's experience: a journey through illness. PMID- 10104598 TI - Quality assurance reporting to the governing board. PMID- 10104599 TI - Systems fight to gain MD loyalty. PMID- 10104601 TI - Hospitals sponsor self-help groups. PMID- 10104600 TI - Executive compensation: what trustees need to know. PMID- 10104602 TI - Tough choices are ahead for all hospital leaders. PMID- 10104603 TI - Trustee goes to the movies. PMID- 10104604 TI - Profile of hospital governance: a report from the nation's hospitals. AB - During the 1980s, hospital governing boards struggled to solve a host of new and difficult problems while attempting to meet the needs of their communities. As we enter the last decade of the 20th century, different challenges lie ahead. To meet these challenges, hospital boards must first understand their various responsibilities. The results of this survey will provide a starting point to understand how hospitals are currently dealing with issues such as governing board composition and organization, board/CEO relations, and governing board operations. (Future articles in Trustee will focus on individual aspects of the survey.) In so doing, readers may begin to unlock the key to increased effectiveness. PMID- 10104605 TI - Pepper Commission report. PMID- 10104606 TI - The local alternatives. Why head out of town when a good community hospital will do? PMID- 10104607 TI - Patients have rights, too. A person can be bedridden without having to take discomfort lying down. PMID- 10104608 TI - Deciphering your hospital bill. Mistakes and overcharges are common. Here's how to keep from getting burned. PMID- 10104609 TI - Portrait of a hospital. Boston's Massachusetts General. PMID- 10104610 TI - Not even members agree. PMID- 10104611 TI - Why did I do that, anyway? PMID- 10104612 TI - Recruiting radiography students. PMID- 10104614 TI - Management of energy services in the 1990s. PMID- 10104613 TI - Engineering services--a power of good in the hospital. PMID- 10104615 TI - Contractual relationship between Board and Minister. PMID- 10104616 TI - Psychogeriatrics: the Cineralla subspecialty is coming to the ball! PMID- 10104618 TI - Perspectives. Technology assessment's winding road. PMID- 10104617 TI - Listening to technicians. PMID- 10104619 TI - Perspectives. Fewer health footsoldiers for the next century? PMID- 10104620 TI - Mental health and economic security. PMID- 10104622 TI - Program announcement for scholarships for the Undergraduate Education of Professional Nurses Grant Program--HHS. PMID- 10104621 TI - Maternity and childbirth costs. PMID- 10104623 TI - Request for comments: technical assistance to rural hospitals--HRSA. Notice: request for comments. AB - The Health Resources and Services Administration (HRSA), Office of Rural Health Policy (ORHP), is interested in obtaining public comments and suggestions to assist the Office in planning a program of technical assistance to rural hospitals. The ORHP is anticipating that funds may become available in Fiscal Year 1991 for technical assistance to rural hospitals. The ORHP invites comments on the needs of rural hospitals for technical assistance and support. PMID- 10104624 TI - Tallying the tab. AB - Though the Rockefeller panel on health care declined to say how to pay for its proposals, its report will force the public to address the question. PMID- 10104625 TI - The blindman's buff game of privatisation. PMID- 10104626 TI - A matter of resource. PMID- 10104627 TI - The trouble with danger. PMID- 10104628 TI - Team spirit on trial. PMID- 10104629 TI - Products tailored to needs. PMID- 10104630 TI - Dawn of a third era. PMID- 10104631 TI - How to court a clinician. PMID- 10104633 TI - Sign for the times. PMID- 10104632 TI - Risk versus incentives. PMID- 10104634 TI - Quality street snarl-up. PMID- 10104635 TI - What EDI (electronic data interchange) means for healthcare. PMID- 10104636 TI - Preventing medical malpractice suits: ten suggestions. PMID- 10104637 TI - Court erodes constitutional supports for tax exemptions. PMID- 10104638 TI - Noblesse oblige. PMID- 10104639 TI - "Heart smart" campaigns. PMID- 10104641 TI - Under the gun. AB - This year Congress will consider proposals to significantly restrict the access of not-for-profit healthcare organizations to affordable capital and other federal benefits of their tax-exempt status. The federal benefits of tax-exempt status are (1) exemption from federal tax on net income, (2) eligibility for tax deductible charitable contributions, and (3) access to tax-exempt financing. Of these, the last is probably most important because hospitals' capital needs are substantial and almost always met through the issuance of tax-exempt bonds. In recent years, budget pressures have prompted many state and local governments to challenge the tax-exempt status of not-for-profit organizations. At the federal level, tax-exempt bonds have been under sustained attack for the past 10 years, and tax-exempt organizations have been under scrutiny for the past 4 years. In 1989 several bills were introduced in Congress that would limit some of the benefits of tax exemption. This year the signs are particularly ominous: Budget pressures are severe, no one seems willing to call for "new taxes," and tax exempt organizations are considered fair game. To preserve their tax-exempt status, not-for-profits must act now to convince congressional decision makers that they deserve their tax exemptions and need them to continue to provide community service. PMID- 10104640 TI - Universal access versus universal insurance. AB - Debate over the nature of the American healthcare system reemerged in 1989. Advocates of universal health insurance and "universal access" argued their positions in the New England Journal of Medicine, and a Harris poll indicated that 89 percent of Americans feel the United States needs to make a fundamental change in its healthcare system. An adequate assessment of these reform proposals requires a clear understanding of what we want from our healthcare system. In 1981 the U.S. bishops specified six principles for U.S. healthcare policy. The bishops asserted that U.S. policy should (1) assume that healthcare is a right, (2) promote pluralism of delivery systems, (3) promote good health in addition to treating disease, (4) give consumers a choice of providers, (5) make healthcare planning essential, and (6) include methods of controlling costs. The bishops' principles help clarify both proposals' strengths and weaknesses. PMID- 10104642 TI - Children should be seen and heard. Chronically ill children should have a voice in treatment decisions. AB - Traditionally, sick children have obeyed orders--the doctor's orders, their parents' orders. Father (mother, doctor, nurse) knows best. But indications are that in the future, chronically ill children will have some say in their own treatment decisions. And although few healthcare facilities today have any policies in place to ensure such participation, they may face increasing pressure to implement such policies. Both the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research and the American Academy of Pediatrics recommend that children actively participate in the consent-assent-dissent process for healthcare decisions. Children's participation need not be total or complete; it may involve only selected aspects. Participation will (1) increase their ownership of the decision and encourage them to obtain the necessary follow-up care, (2) increase their ability to make such decisions in the future, and (3) perhaps make healthcare less threatening and more attractive to them as future healthcare consumers. Providers could encourage a cautious, gradual increase in participation by chronically ill children and adolescents. It should start by involving them in concrete tasks (like setting dates and times) and lead to active negotiation with parents and healthcare workers regarding treatment. PMID- 10104643 TI - Stop the world, they want to get on. AB - As life expectancy for many chronically ill children increases, new efforts are needed to make society more aware of the comprehensive needs of these children and their families. Chronically ill children must strive to succeed in two different worlds: the healthcare environment and the community. For the most part, there is a little networking between the two. And that is the problem. To develop their full potential, children with chronic health problems must be able to attend school, form friendships, and fulfill their desire to learn without being impeded by some uncontrollable factor such as a health problem. When significant people such as teachers and peers are misinformed about a child's illness, they may misinterpret what they observe about him or her, which can be a serious barrier to progress. The collective efforts of healthcare professionals, teachers, community groups, families, and the chronically ill children themselves are needed to improve the community's understanding of chronic illness. Educators can benefit from networking with healthcare professionals, who, in turn, can become better informed about the day-to-day concerns of school personnel when a pupil has a special health problem. PMID- 10104644 TI - A person of character. PMID- 10104645 TI - A mission to manage. PMID- 10104646 TI - Almost home. AB - It took two years to transform the oncology unit at Mount Carmel Medical Center, Columbus, OH, from a cold, sterile-looking environment into a comfortable, homey area. Now bright quilts adorn the walls, carpeting softens the floors in hallways and "family areas," flowered curtains balloon at windows, and a kitchen is available so visitors can fix favorite foods for patients and pour themselves a cup of coffee. The family of the late Jane Barks Ross, a former cancer patient at the hospital, provided a good chunk of the money for the project, and the hospital auxiliary chipped in additional funds. A design firm was hired to consult with staff and patient and come up with a scheme that everyone liked hospital construction workers did most of the labor, aided by off-duty staff and auxiliary members while the patients themselves had front-row seats to watch the progress. PMID- 10104647 TI - The use of debt. AB - Stewards of Catholic healthcare organizations must proceed cautiously before embarking on new construction or renovation projects. Many important issues are involved in financing such projects, including business risk, financial philosophy, financial structure, and forms of debt. The proper foundation for any financing structure must begin with financial philosophy. Some healthcare facilities have traditionally used no external financing; others have employed significant levels of debt. To determine a proper level of debt for the project(s) being financed, it is important to look at business risk. If a modest decline in revenues (or a similar increase in costs) would threaten the project's viability, the business risk would be high; therefore prudence would dictate that the level of debt undertaken be relatively small. A separate analysis is required to determine the appropriate mix of floating-rate and fixed-rate long-term debt. As a rule of thumb, fixed-rate debt would typically form two thirds of the debt structure; floating-rate debt, no more than one third. For healthcare, debt can take two forms: tax exempt and taxable. Tax-exempt financing has many constraints, including use of proceeds by a tax-exempt entity, arbitrage rules, tax legislation, and financial disclosure laws. Taxable debt can be issued by private placement or on a publicly traded basis. PMID- 10104648 TI - Homework. Architecture students design environments for the elderly. PMID- 10104649 TI - Nailing down construction costs. Design-build approach may have some answers. AB - Design-build firms, long accustomed to getting the smaller projects in the healthcare construction industry, have reason to be optimistic that the plum jobs will no longer be out of reach. At a time when the healthcare industry is under intense pressure to cut costs, but the need for renovation and new construction is increasing, design-build is a construction approach that promises to save time and money and guarantees price up front. As an alternative to traditional design bid-build construction methods, the design-build approach offers single-source, full-service design and construction as a package deal. One entity is responsible for the project and resolving any problems that should occur. It eliminates the bidding process, which can take up to three or four months. By employing their own architects, engineers, and construction professionals, design-build firms can get all members of the project team involved at the outset. This not only helps the company establish a firm price early on, it facilitates total coordination of the project. PMID- 10104650 TI - Comprehensive waste regulation dumped. A limited demonstration project is all that remains. AB - When medical wastes started washing up along the Eastern Seaboard and the shores of the Great Lakes in 1988, healthcare providers became subject to close public scrutiny. Not only was the situation deplorable; the solution, they feared, would keep them entangled in red tape for years. Public outcry sent members of Congress scurrying to legislate medical waste regulation. But what many had predicted would be a comprehensive, nationwide regulation that tracked medical waste from cradle to grave turned out to be a demonstration project limited to Puerto Rico and four states in the Northeast. The Medical Waste Tracking Act of 1988 went into effect in June 1989. When it expires in June 1991, the Environmental Protection Agency (EPA) will report to Congress on the program's impact, presumably with an eye toward whether further legislation and continuing regulations are necessary. In the meantime, participating states must establish a system of tracking medical waste from its point of generation to its disposal by either incineration or burial in a landfill. Medical waste generators must separate it from other kinds of waste and place it in special labeled containers. They must also prepare a tracking form that accompanies the cargo and requires sign-off by generator, transporter, and disposal facility operator. The EPA has legal access to medical waste tracking forms and can inspect any site where medical wastes are located. Violators are subject to stiff civil and criminal penalties. PMID- 10104651 TI - Flattery will get you nowhere. Getting the bottom line out of employee recognition programs. AB - Most industries, including hospitals, understand that recognizing employees for doing a good job helps increase their productivity and job satisfaction. And that is no doubt why they do it. But is it ethical? Is it all right to give someone a deserving pat on the back if the pat on the back is also self-serving? The motivating spirit of the Catholic healthcare ministry is recognition of the dignity and worth of each human being, whether those persons are patients or healthcare employees. Accordingly, employee recognition at Catholic facilities is based on the employee's dignity as a person, and it must come from the manager's heart. Respect for each person's dignity is a virtue that cannot be faked. Proper recognition means the manager affirms and values the employee's job, performance, and person. To properly exhibit employee recognition, the manager must be mature, honest in the sense of exhibiting some of his or her own feelings and attitudes, and able to listen to others. Recognition may motivate employees to work harder to increase productivity, even though it is not meant to. On the other hand, if its purpose is to increase productivity, recognition could have negative effects. PMID- 10104652 TI - Special events marketing. PMID- 10104653 TI - After the quake. PMID- 10104654 TI - Late innings. PMID- 10104655 TI - Determinants of primary caregiver stress and burden: area of residence and the caregiving networks of frail elders. AB - This research examines the association among characteristics of the caregiving network, primary caregiver stress and burden, and area of residence. The purpose is two-fold: to determine whether the structure of the relationship between the caregiving network, and stress and burden is uniform across rural, small city, and urban samples; and, to assess whether stress and burden are explained by a similar set of variables within area of residence categories. The data are drawn from a matched sample of 1,388 impaired elders and their primary caregivers from the 1982 National Long-Term Care Survey and the National Survey of Informal Caregivers. In general, the analysis shows that several characteristics of the care-receiver and the primary caregiver have a differential effect on stress and burden across residential categories, and that, within rural, small city, and urban samples, the determinants of stress and burden are not homogeneous. When the frail elder is able to reciprocate by doing chores, babysitting, or providing some other type of assistance for the primary caregiver, however, both stress and burden are reduced in all three residential categories. Similarly, the increased provision of assistance with instrumental activities of daily living by the primary caregiver uniformly increases stress and burden. These findings suggest that interventions designed to alleviate primary caregiver stress and burden may be able to have some common components, but may also need to be tailored in some ways to specific residential environments. PMID- 10104656 TI - Quality of care may depend on your attitude. PMID- 10104658 TI - We help poor kids--and still get paid. PMID- 10104657 TI - This trial could change the way you handle AIDS patients. PMID- 10104659 TI - Insights from a demonstration: CRAHCA's (Center for Research in Ambulatory Health Care Administration) gerontology project. AB - The Center for Research in Ambulatory Health Care Administration received a grant from the W.K. Kellogg Foundation in 1987 to demonstrate gerontology program models in primary care settings. The demonstration involved four MGMA medical groups and author Anna Bergstrom shares some insight into the results of these programs from the last three years. PMID- 10104660 TI - Meeting the future needs of the elderly. AB - Tapping into the aging network in any community can be quite challenging. Now is the time for medical groups and staff to build new types of relationships--to be the innovator, collaborator and facilitator between your group and community agencies who serve the elderly. Health professionals have the ability to bridge these partnerships and practice arrangements. These systems can guarantee high quality community service care for this growing and thriving elderly population. PMID- 10104661 TI - 'Practice makes perfect'. AB - Several group practices around the country are offering innovative services to meet the needs of their older patients. The Zitter Group, in conjunction with MGMA/CRAHCA and Syntex Laboratories, conducted a nationwide contest to find the most outstanding of these programs and the winners are featured in this article. PMID- 10104662 TI - Surveying medical groups in an aging America. AB - The Zitter Group also used an educational grant from Syntex Laboratories to survey medical groups on how the aging of the population is affecting them and how they are responding. The results are featured in this article by Connie Mahoney, Ph.D., and Amy Carlesen. PMID- 10104663 TI - Risks and new technology. PMID- 10104664 TI - Reduced residents' hours bite Big Apple. PMID- 10104665 TI - Universal health care needs key to coalition. PMID- 10104666 TI - Jordan v Sinai: informal defense interviews with physicians now verboten. PMID- 10104667 TI - Sy Gottlieb's predictions are based on experience. PMID- 10104668 TI - A job description for hospital trustees. PMID- 10104669 TI - Executive contracts from the board's perspective. PMID- 10104670 TI - OBRA requirements spotlight resident/provider rights. PMID- 10104671 TI - Residents' level of happiness related to staff cohesiveness. PMID- 10104672 TI - Community council promotes awareness, involvement. PMID- 10104673 TI - Sales process and marketing require training, organization. PMID- 10104674 TI - Purchasing process evaluations improve budget bottom line. PMID- 10104675 TI - Facilities should consider medication delivery options. PMID- 10104676 TI - ProCare's nurse assistant certification program. PMID- 10104677 TI - Decade of the child. Hard decisions & critical choices. PMID- 10104678 TI - Taxing dilemmas. Is charity too profitable? PMID- 10104679 TI - The ACR Practice Accreditation Program for radiation oncology. AB - Quality assurance, an issue receiving great attention in medicine of late, has its origins in the consumerism of the mid 60's and in the budgetary problems which became more pronounced following the oil embargo of the 1970's. Consumerism, initially concerned with product safety, eventually extended to the patient/doctor relationship. Physicians became providers of healthcare, and as such were increasingly viewed as liable for the results of that care. A bad result implied bad care. The rate of malpractice claims began to increase, with a concomitant increase in malpractice insurance premiums. This upward pressure on medical costs came at a time of economic crisis, related in part to increasing oil costs, competition from foreign manufacturers, and rising national debt. It was inevitable, therefore, that those who pay for medical care (private insurers and the government) would look for ways to ensure that the care they were buying was both necessary and of good quality. PMID- 10104681 TI - Income trends in the hospital industry. PMID- 10104680 TI - The ABCs of billing. PMID- 10104682 TI - A world of difference. PMID- 10104683 TI - Dioxins made simple. PMID- 10104684 TI - OSHA's laboratory chemical hazards standard. PMID- 10104685 TI - "Do you want to die?" The crisis in emergency care is taking its toll on doctors, nurses--and patients. PMID- 10104686 TI - Sick system. PMID- 10104687 TI - Unit dose drug distribution in teaching hospitals: key characteristics and centralized versus decentralized approaches. AB - A comparative review of decentralized versus centralized unit dose drug distribution systems for teaching hospitals is discussed. A drug distribution system Task Force, established at the Toronto Western Division of The Toronto Hospital, identified key characteristics of a safe, accountable and efficient drug distribution system. Included were considerations of patient safety, cost effectiveness, efficient use of nursing time, security, clarification of professional role, hospital and professional standards of practice, and evaluation criteria. Interdisciplinary task force discussions and extensive literature review resulted in a recommendation for the implementation of a decentralized unit dose drug distribution system. It was recognized that physical plant and material handling systems must be considered for each individual facility before a decision to decentralize can be made. PMID- 10104688 TI - Accreditation of hospital pharmacy residency programs: experience with on-site surveys. PMID- 10104689 TI - Avianca flight 52: a view from the ED. PMID- 10104690 TI - Of anchovies and ambulances. PMID- 10104691 TI - ED: phone home. PMID- 10104692 TI - The crisis in rural prehospital emergency care. PMID- 10104693 TI - Hazardous-materials response. AB - The preceding text has provided some of the basics that you should know to safely operate at a hazardous-materials incident. Unlike other types of emergencies, the plethora of dangers that exist at hazmat incidents may cause the rescuer to delay patient care. The key here is safety first--your safety! I can't overemphasize the need to properly protect yourself at these situations. Remember, you can't help the patient if you become one too! With the significant rise, worldwide, in the number of hazardous-materials incidents over the last 10 years, it has become apparent that extensive and continued training is needed to protect the rescuer and ensure quality patient care. PMID- 10104694 TI - The caring connection. PMID- 10104695 TI - Signing an organ donor card: psychological factors. AB - Personality factors related to organ donor card signing were explored in a sample of 94 students. Nondonors scored higher on Templer's Death Anxiety Scale, Collett Lester Fear of Death of Self, Death of Others, and Dying of Self subscales, and a scale of physical anxiety. Donors scored higher on a Likert scale reflecting acceptance of dying and, not surprisingly, on self-efficacy to sign an organ donor card. When regrouped on the basis of whether they believed in donation, those nondonors who believed they should donate were intermediate in self efficacy between donors and those who had no interest in donating. This nondonor/believer group may be most likely to donate but may be restrained by the anxiety factors noted above. Further efforts should focus on clarifying these issues, so as to increase donation of greatly needed organs. PMID- 10104696 TI - Special report on liability and insurance. Recent decisions further define scope of "Tarasoff" duty. PMID- 10104697 TI - Whistleblowing and the security director: an update. AB - Whistleblowers often find the path of conscience leads to the unemployment line. But, once fired, many also wear a path to the courthouse seeking damages. Recent cases involving hospitals and other employers are defining the risks for both employees and hospitals when someone blows the whistle. This report will outline some of those cases, provide tips from experts, and review state and proposed federal legislation aimed at protecting the rights of whistleblowers. PMID- 10104698 TI - Scary selling. Are your staffers losing scales? PMID- 10104699 TI - Everything's coming up flowers. PMID- 10104700 TI - At St. Francis, flowers make the difference. PMID- 10104701 TI - Opting for concurrent construction ensures flexibility and speed. PMID- 10104702 TI - Staff training critical for fire management. PMID- 10104703 TI - AHA opposes EPA's incinerator-emission rules. PMID- 10104704 TI - Are you ready for health care's building boom? PMID- 10104705 TI - Contaminant control ups cooling-tower efficiency. PMID- 10104706 TI - '90s labor-force trends present tough challenges. PMID- 10104708 TI - Vision needed if training not to sink without trace. PMID- 10104707 TI - The NHS: a prime candidate for job-sharing? PMID- 10104709 TI - How training contracts improve service quality. PMID- 10104710 TI - Application of federal antitrust laws to hospital mergers: understanding the evolving rules. PMID- 10104711 TI - Antitrust issues in the health care field: an introduction. PMID- 10104712 TI - HCFA issues first round of revised lab regs. PMID- 10104713 TI - Filling the special needs of extended-care facilities. AB - The growth of the geriatric population is widening the market for lab services to nursing homes. Laboratories can contribute by tuning in to the requirements of this age group. PMID- 10104714 TI - How we developed a microbiology training manual. PMID- 10104715 TI - Remodeling the microbiology lab. PMID- 10104716 TI - Medical standard setting in the current malpractice environment: problems and possibilities. PMID- 10104717 TI - Laundry--love it or leave it. PMID- 10104718 TI - Hazardous waste disposal and the clinical laboratory. AB - Negligent, unregulated hazardous waste management has resulted in real and potential threats to public health and safety. The federal government has responded with laws and regulations aimed at the producers of hazardous waste, including clinical laboratories. Clinical laboratory managers must understand how the requirements apply to their facilities and how to comply with them, or risk violating the law. The Resources Conservation and Recovery Act (RCRA) imposes controls on hazardous waste management through the Code of Federal Regulations (CFR). The Environmental Protection Agency (EPA) and the Department of Transportation (DOT) regulate these activities through 40 CFR and 49 CFR, respectively. 49 CFR specifies the characteristics of hazardous waste and lists more than 400 toxic chemicals, including several commonly used in clinical laboratories. Laboratories must conduct chemical inventories to determine if they should obtain an EPA identification number as a hazardous waste generator. Most clinical laboratories can operate satellite accumulation points and accumulate, store, transport, and dispose of waste in accordance with EPA and DOT regulations. Regulations pertaining to infectious waste, sure to affect many clinical laboratories, are being developed now by the EPA. The tracking system mandated by the federal government can be supplemented by state and local authorities and poses a significant regulatory challenge to clinical laboratory managers. PMID- 10104719 TI - Financial indicators. PMID- 10104720 TI - An examination of total charges in the long-term health care industry. AB - A significant amount of work relating to long-term health care costs has appeared in the literature. Although shortcomings exist, there is at least some understanding of the relationships underlying costs. The subject of charges for long-term health care, however, has essentially been ignored in the literature to date. The purpose of this study was to gain an initial understanding of those factors underlying differences in charges per resident. The study used descriptive data from the 1977 National Nursing Home Survey and regression analysis to examine the relative effects of three sets of characteristics on charges per resident: characteristics of the facility, characteristics relating to the resident's medical needs, and characteristics relating to the socioeconomic status of the resident. PMID- 10104721 TI - Predictors of outcome in nursing homes. AB - To develop predictors of outcome, 22 admission characteristics of 221 consecutive discharges in two nursing homes were analyzed using automatic interaction detector analysis. Length of stay was significantly predicted by level of nursing care and feeding problems in one home, and by similar variables in the other home. Type of discharge was significantly predicted by receiving rehabilitation therapy, toileting problems, being on welfare, and feeding problems in one home, and by similar variables in the other. Results and uses of the findings are discussed in this article. PMID- 10104722 TI - Life satisfaction and death anxiety in elderly nursing home and public housing residents. AB - To compare life satisfaction and death anxiety in older adults, 30 elderly residents of a public housing apartment complex and 20 nursing home residents completed the Death Anxiety Scale, the Philadelphia Geriatric Center Morale Scale, and a structured interview. Nursing home residents more frequently reported that in five years they expected to be dead, whereas public housing residents more frequently reported that in five years they would be doing about the same thing or nothing. The two groups did not differ on their reported death anxiety or life satisfaction. However, across both groups, those reporting higher life satisfaction also reported lower death anxiety and a more positive attitude toward growing older. It appears that, for the elderly individuals in this study, place of residence was not related to their expression of life satisfaction or death anxiety. PMID- 10104723 TI - Ethical dilemmas in the health care trenches. PMID- 10104724 TI - Measuring institutional change: a yardstick for ethics committees. PMID- 10104725 TI - Rx for American health system: universal access? PMID- 10104726 TI - Effectiveness of care should be used as rationing standard. PMID- 10104727 TI - Passage of Proposition 111 critical to California. PMID- 10104728 TI - Volunteers: essential hospital component in the 90s. PMID- 10104729 TI - Developing a hospital facilities plan for survival in the 90s. PMID- 10104730 TI - An unbundled campus plan for the 21st century. PMID- 10104731 TI - Psychoneuroimmunology: humanizing the inhospitable hospital. PMID- 10104732 TI - Evolving ambulatory care regulatory criteria. PMID- 10104733 TI - Is there a 'right' to health care? PMID- 10104734 TI - Everything you always wanted to know about medical waste. PMID- 10104735 TI - Needlestick injuries. PMID- 10104736 TI - Waste incineration, Part I: Technology. AB - Based upon an overview of the technology of incineration and the nature of hospital waste, HHMM offers the following suggestions: Old retort or other excess air incinerators should be replaced regardless of age. Even if emissions control equipment and monitoring devices can be retrofitted, excess-air incinerators are no longer cost-effective in terms of capacity, fuel consumption, and heat recovery. Audit (or have a specialist audit) your waste stream thoroughly. Consult a qualified engineering company experienced in hospital installations to get a system specified as exactly as possible to your individual conditions and needs. Make sure that the capacity of your incinerator will meet projections for future use. Anticipate the cost of emissions control and monitoring devices whether your state currently requires them or not. Make sure that your incinerator installation is engineered to accept required equipment in the future. Develop a strong community relations program well in advance of committing to incinerator installation. Take a proactive position by inviting your neighbors in during the planning stages. Be sure the contract governing incinerator purchase and installation has a cancellation clause, preferably without penalties, in case community action or a change in state regulations makes installation and operation impractical. The technology is available to enable hospitals to burn waste effectively, efficiently, and safely. HHMM echoes the concerns of Frank Cross--that healthcare facilities, as well as regional incinerators and municipalities, show the same concern for environmental protection as for their bottom lines. When emissions are under control and heat is recovered, both the environment and the bottom line are healthier. PMID- 10104737 TI - Plutonium-powered pacemakers: hospitals are responsible. PMID- 10104738 TI - The Canadian occupational performance measure: an outcome measure for occupational therapy. AB - The Canadian Association of Occupational Therapists, in collaboration with Health and Welfare Canada have developed and published a conceptual model for occupational therapy, the Occupational Performance model. This paper describes the development of an outcome measure, The Canadian Occupational Performance Measure (COPM), which is designed to be used with these guidelines for client centred clinical practice. The COPM is an outcome measure designed for use by occupational therapists to assess client outcomes in the areas of self-care, productivity and leisure. Using a semi-structured interview, the COPM is a five step process which measures individual, client-identified problem areas in daily function. Two scores, for performance and satisfaction with performance are obtained. This paper describes the rationale and development of the COPM as well as information about its use for therapists. PMID- 10104739 TI - Application of the guidelines for client-centred practice to paediatric occupational therapy. AB - This paper outlines the process of incorporating the "Guidelines For the Client Centred Practice of Occupational Therapy" into the practice of occupational therapy in an out-patient rehabilitation facility serving young people with physical disabilities. Specifically, the areas of practice addressed are screening and assessment. The process started in 1987 with an identification of the need to find a holistic framework that meets the complex needs of clients with chronic physical disabilities. The conceptual model of occupational performance, as outlined in the Guidelines, provided such a framework. The process of incorporating the Guidelines into the screening and assessment practices of occupational therapists at Erinoak Serving Young People With Physical Disabilities is described, with examples of documents developed by the department. Suggestions are given to integrate the conceptual model of occupational performance into the practice of occupational therapists working with children and adolescents with physical disabilities. PMID- 10104740 TI - Operational review: beyond the numbers game. AB - The first response to operational review is, traditionally, an examination of productivity indicators and a rationale for their defense. This paper describes the creative approach chosen by one hospital setting with specific reference to the occupational therapy department. The focus was placed on outcome for the child and productivity measurement. Results of the review for the occupational therapy department were positive and established a precedent for parts of the presentation when the review continued throughout the hospital. Occupational therapy managers are encouraged to become more innovative in the effective management of their departments, continuing to develop and build leadership skills for the future. PMID- 10104741 TI - Personnel problems in nursing. A theory on grapevine communication. PMID- 10104743 TI - Save children: offer prenatal and postnatal parent training. PMID- 10104742 TI - Medical staff planning with a database. AB - Staff planning requires a comprehensive program. A robust impact analysis of physicians requires information not normally contained within hospital physician records. Planners should integrate information from state sources with their medical staff data files, and be alert for new sources of online information. PMID- 10104744 TI - Utilization review and the art of not practicing medicine on the telephone. PMID- 10104745 TI - These are the 'good old days' of utilization review. PMID- 10104746 TI - Understanding the economics of health policy. Interview by C. Burns Roehrig. PMID- 10104747 TI - A year of business as usual ... or a prelude to reform. PMID- 10104748 TI - Is utilization management changing patient care? PMID- 10104749 TI - Sharps container prices hold steady. PMID- 10104750 TI - Baxter to divest urologicals and possibly other weak lines. PMID- 10104751 TI - New federal regulations, pollution laws due soon. PMID- 10104752 TI - Pharmacy directors continue to control pharmaceutical ordering, don't want to change. PMID- 10104753 TI - Materials managers should be aware of proper storage requirements for hazardous waste. PMID- 10104754 TI - HMM price watch. PMID- 10104755 TI - Materials managers must remember that oral contracts can be valid, but difficult to enforce. PMID- 10104756 TI - Some reflections on US health care. AB - Although the white paper is not proposing an American style NHS, some of its key ideas are of American origin and based on American experience, and American hospitals are currently facing intense competition. So what is happening in the USA is very relevant to the likely future of the NHS. Hugh Ross went there last year and found that some things were not exactly what he had expected. PMID- 10104757 TI - Education and staff development strategy in support of resource management. AB - The white paper looks to a wide development of the Resource Management Initiative. If the initiative is to succeed it will call for much education and staff development. Bob Dearden describes how these should be methodically developed. PMID- 10104758 TI - NHS overseas enterprises: gateway to the British NHS. AB - For a good while the NHS has been providing consultancy and other services to overseas countries. Valerie Wark explains how this service has been systematised and developed. PMID- 10104759 TI - Authority members and standards of clinical care. AB - In the first part of her article, published in February, Charlotte Williamson argued that authority members need to interest themselves more in clinical care. In this concluding part she discusses the application of this locally in the new style DHAs. PMID- 10104760 TI - The bottom line and beyond: paying for NHS training in the 1990s. AB - Training will be increasingly important in the 1990s, but in a world of "flexible firms", internal markets and the hiving off of non-core activities it will be organised in new ways. John Edmonstone describes the likely changes, and advises on the marketing of training. PMID- 10104761 TI - Long-stay hospital closure. Managing the staff. AB - The gradual closure of a long-stay hospital is stressful for staff. Some may have doubts about the case for community care, and almost all are affected by uncertainty and by the provisional step-by-step changes as patients gradually move out. The maintenance of staff morale during the transition is therefore important and difficult. This article examines some of the stresses and misunderstandings, and suggests how they could be managed. PMID- 10104762 TI - User friendly services. AB - Consumerism is fashionable in the health service, but there is a danger that it will prove no more than window-dressing. Liz Winn and Allison Quick, who recently wrote a book on user-friendly services, addressed particularly to the managers of community health services, summarise their conclusions, pointing out the possibilities and pitfalls if consumerism is to be taken seriously. PMID- 10104763 TI - A needs assessment investigation of continuing medical education in risk management. AB - Training of physicians in risk management has become an important task for continuing medical education (CME) directors, particularly in states where risk management education is required for licensure. Physicians in Florida who completed an introductory program in risk management were surveyed to determine future topics for risk management education. Physicians identified desired topics using a five-point Likert-type scaling (5 = high priority; 1 = low priority) and rated 55 topics within 10 major subject areas. The means, standard deviations, and rank order of topics within the subject areas are reported. Multivariate analysis of variance (MANOVA) revealed no significant differences between surgeons and non-surgeons with respect to the subject areas. A significant difference, however, was shown, between academic physicians and non-academic (private practice) physicians; non-academic physicians gave significantly higher scores to six subject areas: malpractice, medical records, acts or omissions constituting negligence, negligence/malpractice actions, defenses, and risk management programs. The results suggest that it is not necessary to plan separate risk management education programs for physicians according to their specialty; one should note, however, the higher priorities given by non-academic physicians and consider these differences when planning advanced risk management programs. PMID- 10104764 TI - Medical practice acquisitions: practical guidelines for the physician. AB - This article provides physician purchasers and sellers of medical practices with practical guidelines for making the important legal and business decisions associated with such transactions. PMID- 10104765 TI - Problems of the National Practitioner Data Bank. AB - After a two-year delay, the National Practitioner Data Bank, authorized by the Health Care Quality Improvement Act of 1986, has yet to begin its mission to collect and disseminate information concerning adverse actions affecting physicians' hospital privileges, licensure, and malpractice claims experience. This article discusses some of the problems that are likely to arise in the operation of the Data Bank. PMID- 10104766 TI - Techniques for integrating functions of hospital administration and medical staff. AB - To be successful in today's competitive market, hospital/medical staff relations must evolve to the point where the two entities work together within the health care institution in a combined effort to help people achieve their life goals by minimizing the effects of illness and maximizing physical and mental health. This article sets forth simple, practical techniques for moving a health care institution toward this goal. PMID- 10104767 TI - The revised Uniform Anatomical Gift Act: an analysis. AB - The Uniform Anatomical Gift Act establishes the legal framework for organ and tissue donation procedures. This article examines the recently proposed revision of this uniform law, and how its adoption would affect the organ procurement process and the role of the medical community in this process. PMID- 10104768 TI - Establishing and maintaining good referral relationships. AB - Establishing and maintaining a good referral network is important to the success of both the specialist and the medical center where he or she practices. Consequently, as this article will discuss, specialists should be alert to the many factors that can affect their relationships with referring physicians and should be careful to avoid any actions that might threaten those relationships. PMID- 10104769 TI - Forced medical treatment in pregnancy: resolving the conflicting rights of mother and fetus. AB - Developments in medical technology continue to increase the potential for conflict between the rights of mother and fetus during pregnancy. Although a number of court cases have ordered medical treatment over the objections of pregnant patients, the law has yet to address definitively the difficult issues raised by this kind of forced intervention. PMID- 10104770 TI - Peer review: Patrick redux. PMID- 10104771 TI - Hospitalwide product-line management: where does the medical record department fit in? PMID- 10104772 TI - Case study: a new focus--removing barriers and building teamwork to better serve medical records customers. PMID- 10104773 TI - Innovations and research review: job satisfaction of hospital medical record department managers--a national survey. PMID- 10104774 TI - Innovations and research review: differences in roles between entry-level ARTs and RRAs. AB - The Council on Certification continues to update the procedures used for AMRA role-delineation studies. The survey instruments being developed for future role delineation studies will provide data that not only identify tasks performed at entry level by ARTs and RRAs, but also differentiate the two groups across all task areas. PMID- 10104776 TI - Who are the customers of medical record departments? PMID- 10104775 TI - Legal review: AIDS patient records--legal issues of access and disclosure. AB - All 50 states require AIDS cases to be reported to the department of health. Many jurisdictions require HIV and ARC reporting, as well. Many states have also enacted confidentiality provisions that prohibit health care providers from releasing HIV-related information without the patient's consent, although exceptions to the statutes authorize disclosure without consent to other health providers, spouses, and other persons under certain conditions set forth in the legislation. In addition, the patient may obtain access to his or her own records and may authorize release to third parties. Providers who violate the provisions are subject to liability. The patient usually has a private cause of action for damages and costs; in addition, the state may impose fines and jail terms for more egregious violations. Finally, courts may authorize disclosure of confidential HIV information in certain situations. In the absence of a statutory provision governing court-ordered disclosures, courts will balance the patient's privacy interest against the plaintiff's need to know and the public interest involved. Several states have enacted statutes that modify this traditional balancing approach, although it is unclear whether these statutes provide additional protection for health care providers and patients seeking to prevent disclosure of information. Health record practitioners should keep abreast of legislative and regulatory developments in their states that affect use and disclosure of AIDS patient records. Careful discussion with the health institutions' legal counsel of any situation not covered clearly by applicable statue or regulation is strongly recommended. PMID- 10104777 TI - Job satisfaction: JPT survey results. PMID- 10104778 TI - Guidelines for the practice of pharmacy. Ontario College of Pharmacists. AB - What do pharmacists need to know, and what should they be doing in their practice of pharmacy? These questions have not been adequately answered by the profession. In March 1990, the American Pharmaceutical Association House of Delegates votes on the right of pharmacists to exercise judgment in the implementation of standards of practice. Our colleagues in Canada have provided a valuable set of guidelines that are succinct and practical. They are useful as a starting point for anyone who has responsibility for creating position descriptions, writing guidelines for education and training programs, informing third-party reimbursement programs, or establishing regulatory standards. The outline format makes the guidelines easily adaptable, and persons interested are encouraged to use them freely. There will be those who will say that some of the points stated are more applicable for pharmacy technicians, and I would agree. In fact, another use for this document is to consider what parts are appropriate for pharmacy technicians, because more differentiation is needed between the work that pharmacists and technicians do. PMID- 10104779 TI - Technician involvement in a quality-assurance program. PMID- 10104780 TI - Perspectives. Metropolitan hospitals: an urban tug of war. PMID- 10104781 TI - Perspectives. Fetal tissue ban: politicizing science? PMID- 10104782 TI - Perspectives. Health insurance: prospects in the 1990s. PMID- 10104783 TI - Health care facilities HVAC. Design incremental unitary room air conditioners fan coils and room coil induction units. PMID- 10104785 TI - The Hospital Engineering Training Service (HETS). PMID- 10104784 TI - Recommended roles and responsibilities for chartered engineers, incorporated engineers and engineering technicians. PMID- 10104786 TI - Fatigue and resident performance. PMID- 10104787 TI - Specialization vs. fragmentation: views from a former Regent. PMID- 10104788 TI - Physicians and the challenge of rising health care costs. PMID- 10104789 TI - The harmful effects of the "bad doctor" myth. PMID- 10104790 TI - Why malpractice victims don't sue. AB - More than 27,000 people in New York hospitals were victims of negligence in 1984. Yet only one in eight has ever filed suit. A new study explains why. PMID- 10104791 TI - HMO review: will it test whether employers care about quality? PMID- 10104792 TI - PPO review: will it tell employers what they want to know? PMID- 10104793 TI - Strategies for managing prescription drug costs. PMID- 10104794 TI - Mental health benefits: breaking through the clouds. AB - One state after another is making sure you can't simply cut or drop mental health benefits. But some creative companies are turning a liability into an asset. PMID- 10104795 TI - Health insurance in Hawaii: paradise lost or found? PMID- 10104796 TI - HMOs' and PPOs' role in health benefits. PMID- 10104797 TI - Positive politics. AB - The term "playing politics" usually brings to mind undesirable qualities such as manipulation, power abuse and overt self-interest. Yet politics is a constant in daily life and indeed is very necessary in gaining support for both personal and corporate projects. This article discusses how, through communication and leadership, political skills can be used to realize common goals in an organization. PMID- 10104798 TI - Training and certification of homemaker-home health aides. Foundation for Hospice and Homecare and National Association for Home Care. AB - "The home care industry is where the nursing home industry was 20 years ago- growing rapidly and unregulated," reported The Washington Post in 1986, a consensus shared by legislators, regulators, consumers, and providers. In response, the Foundation for Hospice and Homecare initiated the national certification project, which seeks to establish a national standard for the basic preparation of homemaker-home health aides. PMID- 10104799 TI - Training in testing: a pragmatic approach to recruitment and retention of homemaker-home health aides. AB - In response to concerns regarding the negative effect that competency-evaluation testing might have on the attrition and recruitment of homemaker-home health aides, the home health industry of New Jersey offers an inservice education module--training supervisors to prepare homemaker-home health aides for testing. PMID- 10104800 TI - Cooperative Home Care Associates: a status report. AB - Cooperative Home Care Associates, a worker-owned home health care company in the South Bronx section of New York City, was founded with the vision that home care paraprofessionals should have permanent salaried positions, adequate pay and fringe benefits, opportunity for career advancement, and a sense of belonging. Five years and 170 jobs later, business is good--total sales reached approximately $2.5 million in 1989. PMID- 10104801 TI - Burke Rehabilitation Center. A homemaker-home health aide program for disadvantaged adults. AB - In response to an area shortage of homemaker-home health aides, the Burke Rehabilitation Center has instituted a training program for financially disadvantaged persons, teaching them work in a home setting, caring for the frail elderly, children, and/or mentally impaired individuals. Both clients and homemaker-home health aides have benefited from this innovative program. PMID- 10104802 TI - Building the home care triangle: clients and families, paraprofessionals and agencies. AB - The New York City Home Care Work Group, initiated a research and planning project designed to draw a profile of the home care system of New York City and formulate specific proposals to address system-wide home care service delivery issues. The resultant report focuses on ways to improve the quality of home care services and means of involving government toward that end. PMID- 10104803 TI - Making the relationship work. Management of a hospital-based home health agency and hospital for-profit home health aide service. AB - In 1984, Overlook Hospital added a for-profit home health agency to its already established hospital-based home health agency. While the rationale for the development of two distinct organizations was sound, there were special legal, financial, and quality assurance issues and problems to consider. PMID- 10104804 TI - At St. Francis, time's on their side. PMID- 10104805 TI - National health insurance: prospects and problems. AB - The prospect of National Health Insurance raises key emotions and questions concerning the impact of NHI on hospitals. The ongoing debate is a reminder of the strategic shift such a development would impose on hospital executives. Major interest groups now are on record supporting universal access, if not universal insurance. PMID- 10104806 TI - Nurse recruiting requires careful media selection. PMID- 10104807 TI - Profiles of physicians and national median fees. PMID- 10104808 TI - Nurse bonus program draws staff to hospitals. PMID- 10104809 TI - Industry strategies have appropriate home in hospitals. Interview by Donald E.L. Johnson. AB - Lindsey Bradley, CEO of Mother Frances Regional Medical Center, a 358-bed facility in Tyler, Texas, heads the first such medical institution ever named Texas Business of the Year, an honor bestowed by the Texas Association of Business. Mother Frances was recognized for the many changes introduced in his hospital, changes that include a heart institute and other strategies borrowed from industry such as implementation of service line management. In the following interview with Donald E.L. Johnson, he describes the management concept and innovations that have worked in his institution and their implications for other medical centers. PMID- 10104810 TI - Current practices for release of medical information. AB - Are practices governing release of confidential medical information changing? This article presents a case study of current release of medical information policies and procedures. PMID- 10104811 TI - Labor campaigns for national health care reform program. PMID- 10104812 TI - An insider's look at the Canadian health system. Interview by C. Burns Roehrig. PMID- 10104813 TI - Working with others: try a little respect. PMID- 10104814 TI - Can we soon make health care available for all? PMID- 10104815 TI - The national health insurance debate: in what direction are we headed? PMID- 10104816 TI - Women--the missing persons in the AIDS epidemic. Part II. AB - In the Winter 1989 issue, Anastos and Marte wrote about the neglect of women in defining and treating AIDS. Women in the AIDS epidemic, they wrote, are considered mainly as vectors of transmission to men or children, not as people who are themselves HIV-infected and victims of transmission. They are predominantly women of color who, by the dictates of poverty and racism, live in communities at high risk for HIV infection. They are subjected to demeaning attitudes, poor health care services, and tragically late diagnosis in many cases. In this article the authors examine the issues of reproductive rights and HIV testing in women hospitalized for childbirth. Wendy Chavkin continues the discussion on p. 19, focusing on the efforts of AIDS prevention programs to target women solely because of their reproductive function and on the lack of services available for women who are tested. PMID- 10104818 TI - Labor confronts the health care crisis. PMID- 10104817 TI - Preventing AIDS, targeting women. PMID- 10104819 TI - The empires strike back. Broken promises: Columbia-Presbyterian Medical Center. Ignoring the community's needs: St. Luke's-Roosevelt Hospital Center. AB - In the fall of 1985 in an issue titled "Fighting Back Against the Empires" (Vol. 16, No. 5), Health/PAC reported on the plans of four of New York City's academic medical center "empires" for major expansion. The focus of our coverage was the efforts of two of the communities served by these institutions to ensure that the plans were responsive to their needs. At the time, we were cautiously optimistic that these events were signs that "although the empires still dominate New York City's health care system, they no longer rule unchallenged." In the past six months, the plans of two of these institutions, Columbia-Presbyterian Medical Center and St. Luke's-Roosevelt Hospital Center, warrant another look at the success of the efforts to hold the major medical centers responsible for the welfare of the communities in which they are located. PMID- 10104820 TI - Some facts about smoking. National Association of Health Authorities. PMID- 10104821 TI - Just closing one chapter. PMID- 10104822 TI - Treatment of serious urinary tract infections at a university teaching hospital: a retrospective chart review. AB - A retrospective chart review of all adult patients treated empirically for urinary tract infections (including pyelonephritis) with parenteral antibiotics over a 3-month period was conducted at this university teaching hospital. A total of 92 patient charts were located and reviewed. All patients had a complicating condition. Blood cultures were obtained on 67% of the patients; 23% were positive. E coli was the primary infecting organism (56%). All organisms tested against ceftriaxone and amikacin were found to be sensitive. Only 38% of isolates were sensitive to ampicillin. Empiric ceftriaxone therapy was used in 70% of the cases. The average length of parenteral therapy was 3.8 days. Based on the results of this study, the following recommendations were made: blood cultures should be obtained in all patients; the use of ampicillin alone should be avoided due to the drug's poor activity against isolated urinary pathogens; and ceftriaxone should be used for empiric therapy in the majority of patients, including diabetics, due to the drug's excellent activity against isolated urinary pathogens. PMID- 10104823 TI - A survey of hospital policies on verbal orders. AB - The authors present the results of surveys of directors of nursing and directors of pharmacy on the types and extensiveness of the policies their institutions have implemented to control the use of verbal and telephone orders. One hundred hospitals were selected at random from 874 hospitals meeting the following criteria: 250 beds or larger, general medical surgical, short stay, and nongovernmental. The survey results demonstrated that a significant number of hospitals are attempting to regulate the use of verbal and telephone orders. However, only 35.5% of the hospitals surveyed have any policies that prohibit the use of verbal orders when the physician is physically present on the unit where the order is given, in non-emergency and non-bedside procedure situations. Relative to the above policy, directors of nursing state that this policy is followed 41.1% of the time and directors of pharmacy in the same institutions state that the policy is adhered to 11.1% of the time. In addition to the survey, the authors explain situations that may serve as a source of medication errors when using verbal or telephone orders. They also offer several precautions to take when the use of verbal and telephone orders is absolutely necessary. PMID- 10104824 TI - A microcomputer spreadsheet for aminoglycoside kinetics. AB - Development of an aminoglycoside monitoring program need not entail large capital expenditures for pharmacokinetic software. Microsoft's Excel spreadsheet was used to develop a single compartment, first-order kinetics template for individualized aminoglycoside dosing. The formulas employed may be adapted to virtually any other microcomputer spreadsheet package to provide accurate professional results. PMID- 10104825 TI - Expanding clinical pharmacy services in a VA hospital. AB - The pharmacy staff at the VA Medical Center, Biloxi, Mississippi, has increased direct patient care activities for the Medical Center's inpatients by converting 139 beds from a manual system of unit dose to a computerized unit dose distribution system. Expanded clinical programs were primarily developed, implemented, and operated by staff pharmacists. PMID- 10104826 TI - Drug interaction microcomputer software evaluation: the Medical Letter Drug Interactions Program. AB - The Medical Letter Drug Interactions Program was evaluated using general and specific criteria. The installation process, ease of learning, and use were rated excellent. The user documentation and technical support were good. The quality of the clinical documentation was excellent. The scope of coverage and overall clinical performance were good. The frequency of updates is fair. The primary advantages of the program are low costs and fast, reliable screening tool for drug interactions. PMID- 10104827 TI - Meeting JCAHO drug usage evaluation requirements in a small hospital. AB - Our hospital successfully implemented a drug review program which met JCAHO standards. This was accomplished by analyzing our current situation to identify opportunities for improvement and then developing a drug review plan consistent with JCAHO requirements. The establishment of a DUE pharmacist to coordinate the program and the cooperation of the medical staff has been crucial to the success of our program. PMID- 10104828 TI - Pharmacy disaster emergency: the Huntsville tornado. PMID- 10104829 TI - Eliminating the printed formulary: a cost-effective alternative. AB - This article discusses the use of an in-house computer system to replace a printed formulary listing, parenteral guidelines, notification of cytotoxic or hazardous drugs, and a listing of formulary equivalents. Advantages of the system include availability of current information for physicians and nurses and cost savings for the hospital. PMID- 10104830 TI - A simplistic approach to establishing drug usage/quality assurance programs. AB - Eighty-eight percent of the hospitals accredited by the Joint Commission on Accreditation of Health Care Organizations don't fully comply with JCAHO standards in the area of drug usage evaluation, reports JCAHO in Hospitals, August 5, 1989. Why are so many hospital pharmacies receiving contingencies from JCAHO for QA/DUE? Do we lack a clear understanding of the required features and terms, and/or are we confused on how to best implement a comprehensive program? JCAHO has a number of publications which describe not only newer QA/DUE terminology and requirements but also a nine step process to establish a comprehensive program. This article will describe and summarize both terminology and the nine step process. Integration of the nine step process into the drug distribution system allows the pharmacists to identify drug related problems on an ongoing basis. This process is not only efficient but also cost effective. The article will provide simple examples of QA/DUE programs which dovetail with existing drug distribution processes. Lastly, current JCAHO published QA/DUE scoring guidelines will be discussed. The establishment of structured ongoing QA/DUE programs can begin to collect data vital to documenting the impact of the pharmacist on patient care. PMID- 10104831 TI - AIDS drugs in research. PMID- 10104832 TI - Confronting drug abuse on the job. PMID- 10104834 TI - How to be a business athlete. Interview by Joe Flower. PMID- 10104833 TI - Making the best decisions. PMID- 10104836 TI - The 1989 Healthcare Forum/3M organizational innovator awards. PMID- 10104837 TI - Visionary healthcare leadership. PMID- 10104835 TI - Joint ventures in the next decade: four approaches. AB - Hospitals and physicians will either learn how to integrate their strategies and businesses, or they will end up presiding over the "boutiques" of healthcare. PMID- 10104838 TI - 'OWAs'--other weird arrangements--transform healthcare. PMID- 10104839 TI - Marginal missions & missionary margins. PMID- 10104840 TI - Millennium: old troubles for new. PMID- 10104841 TI - The shape of things to come. Part 1. PMID- 10104842 TI - Romancing the stone. PMID- 10104844 TI - The healing environment of the future. PMID- 10104843 TI - The role of the leader. Interview by Joe Flower. PMID- 10104845 TI - Patient-centered design. PMID- 10104846 TI - Grace under pressure ... the emerging leaders, 1990. PMID- 10104847 TI - A talk with Paul Teslow. Interview by Sally Berger. PMID- 10104848 TI - Six predictions for the nineties. PMID- 10104849 TI - Medical staff antitrust decisions examine defenses available to defendants. AB - The 1990 decisions reported on below concern defenses established by both legislation and judicial precedent. To the extent defenses preclude the need for a trial on the merits, the saving in time, effort and expense for the defendants can be considerable. PMID- 10104850 TI - Education of clinical engineers in the 1990s. AB - This paper presents definitions of the terms bioengineering, biomedical engineering and clinical engineering. These definitions lead to the conclusion that clinical engineers must be individuals with at least a four-year bachelor's degree in an engineering specialty who are also well versed in the design, modification and testing of medical instrumentation. Educational programs for clinical engineers in the 1990s must be based upon clear definitions of these professionals' roles. Clinical engineering education should include direct professional experience obtained through internship programs similar to the program described here. PMID- 10104851 TI - Materials management with a bar code reader. AB - A materials management system capable of inventory control, accounting and the automatic recording of supplies for a clinical department has been developed for the George Washington University Hospital Department of Anesthesia. This system combines a microprocessor-based computer for data storage and a hand-held bar code reader to record the bar code scan of each item in the inventory. A relational software program with easy-to-use menus and help keys was written. Bar code information stored for each item includes item number, quantity, date and time of issue. Accumulated bar code scans are loaded into the computer by use of a serial port and then used to update current inventory in the computer. Comparison between current inventory and reorder levels by the computer will initiate automatic printing of appropriate purchase orders. Reorder levels are adjusted regularly, by comparing previous year or month usage to current needs; items already on order, items on back order and delivery lag time are also taken into account. PMID- 10104852 TI - National Practitioner Data Bank: implications for hospital administrators and care review professionals. PMID- 10104853 TI - The QA program evaluation: a powerful punch. AB - Even the best quality assurance program requires periodic review in order to attain or regain maximum efficiency and effectiveness. The JCAHO standard for annual QA program evaluation adds impetus to this obligation. Riverside Methodist Hospitals' QA program evaluation is constructed in a three year cycle. Internal evaluation in year one and external expert evaluation in year three are balanced in year two with a combined internal/external program review. The year one internal evaluation discussed in the article outlines a framework for evaluation which includes positioning the evaluation for maximum influence, identifying key QA program components and designing meaningful, comprehensive evaluation inputs. The informed judgments of professionals, as well as traditional documentation review, provide powerful evaluative insights. Evaluation outputs include a program rating, an identification of program strengths and weaknesses, and targeted recommendations for QA program improvements. PMID- 10104854 TI - Linking nursing information with QA. PMID- 10104855 TI - Recognition program for excellence in quality management. PMID- 10104856 TI - NAQAP (National Association of Quality Assurance Professionals) introduces new task force: external review organizations. PMID- 10104857 TI - The Joint Commission is coming! Correct answers to 12 surveyor questions on ambulatory QA programs. PMID- 10104858 TI - Wet scrubber systems for incinerators. PMID- 10104859 TI - Coaching the new central service employee to success. AB - Many benefits can be reaped by the central service department that provides an effective coaching program for new employees. A smooth transition into the department will increase new employee satisfaction and, in the long term, should have a positive impact on employee retention. In addition, well-trained employees project a positive image of your department and increase department productivity. Experienced central service personnel possess extensive knowledge and skill and when they coach, they are excellent resources for new employees. An additional benefit is that coaches experience greater job satisfaction and feel like a valuable part of the team. By utilizing the coaching process, coaches can ensure that new employees become effectively oriented to central service and satisfied, productive members of your department. PMID- 10104860 TI - Acquiring high-tech equipment: when is leasing right for you? PMID- 10104862 TI - OR tables. ECRI. PMID- 10104861 TI - Surgical table rebuilding: a cost containment option. PMID- 10104863 TI - FilmFAX: a new teleradiology technology. PMID- 10104864 TI - Are you a value-added manager? PMID- 10104865 TI - Large equipment decontamination. PMID- 10104866 TI - Health care personnel: meeting a growing challenge. PMID- 10104867 TI - Putting organizational development principles into practice. AB - Organizational development requires us to look at the whole system, rather than to isolate the parts. Its precepts urge widespread participation in planning and implementing change. Turning the organization into a conscious learning system ensures ongoing adaptation to an unpredictable environment. The role of everyone with OD knowledge in health care is to apply the guiding principles we have discussed. It is also to raise awareness about the potential harm that may ensue from ignoring these principles. Rarely will an OD intervention provide a quick fix. Substantive changes always go through a cycle of "worse before better." But, the lasting benefit from integrating OD principles into health care education and management is that they provide the resiliency that people and organizations need to thrive in a time of change. PMID- 10104868 TI - Managing the education function. AB - The challenge of hospital-based education is to motivate change in the participant to benefit the organization as a whole, while increasing individual competence and positively affecting the quality of service. Enabling people to transfer learning into effective work behavior is the goal of hospital education staff. To ensure a successful future, the manager of the education function needs to be passionately committed to service of the organization. The manager must be able, be seen as able, and be unafraid to assume the evolving role. On the cover of Jim Lundy's book, Lead, Follow or Get Out of the Way, he addresses a memo to those who lead or aspire to lead. He recommends the following: Share your goals and aspirations. Let the implementers be involved in the planning. Achieve clear understanding of expected results. Evaluate progress periodically and fairly. Reinforce the importance of others. Coach your subordinates for growth. Emphasize and reemphasize teamwork. Search constantly for improvement in understanding, performance, and results! (Lundy, 1986) These leadership strategies will serve the manager of the education function well. Choose to lead, follow, or get out of the way! Marilyn Ferguson shared in her 1986 address to the ASHET annual conference, "We can fear the future . . . or by taking courage from each other and tapping our hidden resources, we can help create it" (Ferguson, 1986). PMID- 10104869 TI - Change begets change: emerging role of the human resources development practitioner. AB - This article has discussed three essential role shifts for the HRD practitioner: reactor to initiator, "pair-of-hands" to collaborator, and problem solving consultant to action learning facilitator. These shifts in role are required for the process of helping manage organizational change in our hospitals. Ongoing learning will be the essential ingredient to successfully manage change in health care organizations. This continual learning is not for clients alone, but is also required by HRD practitioners who want to be taken seriously as contributing to the achievement of their organization's future vision. While the effective HRD practitioner will need to continually experiment with new approaches, a starting point today is with the role changes described in this article. PMID- 10104871 TI - Who's winning the outpatient battle? PMID- 10104870 TI - The Oz theory of hospital economics. PMID- 10104872 TI - Charity care fits my practice just fine. PMID- 10104874 TI - Charter's losses raise debt concerns. PMID- 10104873 TI - Multi-unit providers survey. AB - Hospital systems sold or converted unprofitable facilities curbed their acquisitive appetites and honed their productivity and quality management in 1989, and the bottom line blossomed. Profits rose 10% for the systems reporting financial data in Modern Healthcare's 14th annual Multi-unit Providers Survey. PMID- 10104875 TI - Columbia Hospital Corp. completes merger. PMID- 10104876 TI - Healthcare Int'l sells hospital. PMID- 10104877 TI - St. Louis hospital to limit indigent births. PMID- 10104878 TI - Insurer's troubles causing concern among hospitals. PMID- 10104879 TI - Survey. Psychiatric hospitals' growth lags to second slowest pace since 1985. AB - An industrywide expansion that began five years ago appeared to slow as providers coped with tighter reimbursement and overbuilding by large hospital systems. PMID- 10104880 TI - Survey. Healthy growth continues in rehab fields, but patient demand still exceeds supply. AB - Beds in freestanding rehabilitation facilities operated by hospital systems increased more than 10%, but even that didn't reflect the true size of the market, which also grew in the outpatient, transitional and hospital-based segments. PMID- 10104881 TI - Survey. Long-term care chains retrench to stem losses. AB - Nursing home chains began closing beds or converting them to other uses, a reflection of continued problems in the industry. However, some companies prospered despite difficulties. PMID- 10104882 TI - Survey. Slowdown signals transition for retirement centers run by nursing homes, hospitals. AB - At least 70% of providers in the survey reported they added no units or reduced the number of units they operated in 1989. Providers are contemplating their target market, how projects are designed and what services to offer. PMID- 10104883 TI - Survey. Managed-care organizations on the rebound. AB - After two years in which two-thirds of health maintenance organizations lost money, 1989 showed renewed vigor. Seventy percent of the healthcare organizations operating managed-care systems said their HMOs were profitable. PMID- 10104884 TI - Survey. Systems find ambulatory care no longer a niche, but a chasm. AB - Systems are looking outside hospital walls for more of their total revenue, and a maturity shaped by experience is making executives wiser in the ways of the joint venture. The business possibilities continue to proliferate. PMID- 10104885 TI - Survey. Despite gains in home infusion therapy, home-care revenue remains flat. AB - Home infusion therapy growth doubled in 1989, but the revenue picture for providers of home-care services was a flat landscape. The durable medical equipment business showed little improvement. PMID- 10104886 TI - Survey. Surgery centers continue making inroads. AB - The number of surgery centers grew more than 25% in 1989, and these outposts now perform one of every six outpatient procedures. Ten years ago, hospital-based surgery suites handled 98% of the market. PMID- 10104887 TI - Auditors say HealthVest has dubious future. PMID- 10104888 TI - Bond insurance firm takes precautions. PMID- 10104889 TI - Pa. hospitals win one, lose one in tax-exemption action. PMID- 10104890 TI - Generics still a favorite Rx for savings. AB - Despite recent scandals at generic drug companies that raised questions about quality and supply, few hospitals have shunned the off-brand products altogether. With stepped-up scrutiny of the industry by the Food and Drug Administration and purchasing groups, hospitals continue to show confidence in generics as a prescription for savings. PMID- 10104891 TI - JCAHO ending managed-care accreditation. PMID- 10104892 TI - Employers paring health benefits--GAO. PMID- 10104893 TI - Avoid becoming generic: promote your brand of care. AB - Hospital executives who don't create a unique reason for choosing their facility may allow it to become a nondescript, generic hospital. Then it will have to offer low pricing to make it stand out instead of creating greater value in its particular "brand" of care, says Arthur Sturm. PMID- 10104894 TI - Southern Calif. providers launch campaign to test transfusion recipients for AIDS virus. AB - Southern California hospital and physician groups are urging all recipients of blood transfusions in the early 1980s to get an AIDS test so they can seek care before they become ill. The drive emphasizes recent studies confirming that drugs can prolong and improve the lives of people infected with the AIDS virus. PMID- 10104896 TI - Groups question value of nursing home guide. PMID- 10104895 TI - Computer's full capabilities often go untapped. AB - Most hospitals use less than a quarter of their computer system's abilities, but vendors aren't much help in getting their clients to use a system properly, concludes a survey of 620 hospitals conducted for Modern Healthcare. More risk sharing by vendors may help resolve the situation, the study suggests. PMID- 10104897 TI - UHC to implement EDI system. PMID- 10104898 TI - Rate hikes could be boon or bomb for HMOs. PMID- 10104899 TI - New auditing rules to better document charity-care costs. AB - New accounting guidelines for hospitals will make financial statements more meaningful, experts say, in large part because the rules will end the practice of combining uncollected debt and charity care on a single line. That could aid the fight to preserve tax exemptions. PMID- 10104900 TI - SW Pa. hospitals dispute quality data. PMID- 10104901 TI - Samaritan Health Services CEO quits. PMID- 10104903 TI - Healthcare industry PACs among top contributors to congressional candidates. PMID- 10104902 TI - Give Oregon the room it needs to wrestle with rationing issue. PMID- 10104904 TI - OSHA to issue worker protection rules next year. PMID- 10104905 TI - Food service ventures turn back to standard recipes. AB - From in-house operations to marriages with fast-food operators, the food service at many hospitals has become a source of nourishment for budgets instead of a drain. But hospitals no longer are pushing the entrepreneurial limits of food sales like they did a few years back, mainly because they're realizing the effect their not-for-profit presence has on taxpaying competitors in the community. PMID- 10104906 TI - Navy shoves off for cost-control waters. AB - The U.S. Navy is the latest branch of the armed services to launch managed care as part of its CHAMPUS strategy against a barrage of healthcare cost increases. PMID- 10104907 TI - AmHS forms largest multihospital system liability insurance company. AB - American Healthcare Systems has formed an excess liability insurance company for about 225 affiliated hospitals and more than 100 nursing homes. The alliance expects to protect members from wide swings in premiums, and to save money by cutting out the insurer middleman. PMID- 10104908 TI - Creditor skirmish outlives Gateway reorganization. PMID- 10104909 TI - Purchasers fuel Minn. HMO merger talks. PMID- 10104910 TI - Leadership plus re-education equals quality. AB - Santa Teresita Hospital stood in serious violation of 13 accreditation standards in 1987. To regain quality control, the California facility first changed leadership and information systems and then launched a push to re-educate physicians about the beefed-up quality assurance plan. It worked. PMID- 10104911 TI - Overnight polls assess damage instantly in a crisis. PMID- 10104912 TI - Quorum Health Group sets out to acquire hospitals. AB - Quorum Health Group, the former HCA Management Co., is setting its sights on acquiring hospitals in small to medium-sized towns. The strategy is to broaden the company's scope beyond full-service management, a business that has been leveling off. PMID- 10104913 TI - Speaking fees augment policymakers' incomes. PMID- 10104915 TI - HMO quality perceptions differ--survey. PMID- 10104914 TI - AHA, AMA earn higher profit in '89. PMID- 10104916 TI - Shareholders repeat threat to CompCare. PMID- 10104917 TI - Defaults force Drew Medical to close. PMID- 10104918 TI - AHA sets reform framework. PMID- 10104919 TI - Hospital charges rate low in value. PMID- 10104920 TI - VA hospitals rank low on JCAHO study. PMID- 10104921 TI - Charter to close 25 outpatient centers. PMID- 10104922 TI - Columbia Hospital Corp. agrees to acquire HEI: deal is worth $50 million. PMID- 10104923 TI - More chief financial officers are setting their sights on the executive's suite. AB - More hospital chief financial officers are aspiring to the chief executive's suite, and many say they are better prepared for it than ever. However, industry experts say a lack of operations and leadership experience, and opposition from hospital boards, will keep CFOs from reaching the top. While the number of CEOs with a financial background is slim, some CFOs have reached their goals. PMID- 10104924 TI - Competition's failure means it's time for collaboration. AB - Competition isn't working as a means of controlling healthcare costs. So it's time for hospitals to voluntarily collaborate before a regulation comes along to force cooperation on them, says Gerald McManis. PMID- 10104925 TI - UniHealth in fast lane after making merge. AB - Burbank, Calif.-based UniHealth America, the product of a 1988 merger of LHS Corp., Los Angeles, and Health West Foundation, Woodland Hills, Calif., has moved swiftly to cultivate its own identity and to become a healthcare force to be reckoned with in Southern California. PMID- 10104926 TI - Consumers should bear more of their health costs--expert. PMID- 10104927 TI - Hospital power struggle ends with physicians in, exec out. PMID- 10104929 TI - High court ruling gives hospitals weapon in fight against mergers. PMID- 10104928 TI - High prices may hinder widespread use of needles with new safety features. AB - Needlestick injuries are getting attention now that hospital liability for blood borne diseases is a hot topic. But safer needle devices and alternatives to needles have yet to catch on, held down by high price and uncertain demand. PMID- 10104930 TI - Provider network in Mich. town aims to foster access to care, decrease bad debt. AB - A new program in Lansing, Mich., aims to identify the working poor and provide greater access to healthcare, helping local hospitals reduce their bad debt in the process. PMID- 10104931 TI - How to maintain control over the work of accounts receivable service firms. AB - Healthcare organizations that enter agreements with accounts receivable consulting firms should insist on various contractual safeguards. These controls allow a hospital to reject any recommendation without incurring extra costs; approve the format of bills sent to potential payers and review copies of bills later produced; insist that consultants identify themselves to payers as hospital representatives, not employees; and protect their interests in other ways. PMID- 10104932 TI - Future holds electronic cooperation with insurers--or peril. PMID- 10104933 TI - Giving staff good reason to stay: multifacilities go proactive to combat turnover. PMID- 10104934 TI - Multifacilities move toward regional orientation. PMID- 10104935 TI - Market remains attractive for long term investment. PMID- 10104936 TI - Recertification attained through aggressive challenge. PMID- 10104937 TI - Use of staff developers increases accountability. PMID- 10104939 TI - Legislator 'adoption' program encourages grassroots action. PMID- 10104938 TI - Providing care in Indiana: an insider's viewpoint. PMID- 10104940 TI - Assessment and care planning increase autonomy of practice. PMID- 10104941 TI - Identify resident bathing needs before selecting new equipment. PMID- 10104942 TI - Temporary help agencies thrive in regulatory loophole. PMID- 10104943 TI - Early neonatal discharge and home care. PMID- 10104944 TI - Prescription mailing service for seniors. PMID- 10104945 TI - Practical application of a patient satisfaction survey. AB - Patient satisfaction surveys are a practical method for studying one aspect of quality of care in an HMO. This report details the use of a patient satisfaction survey for this purpose. The focus is on the instrument chosen and the type of analyses carried out. Despite the interest and potential usefulness of the data obtained, the organizational response to the study can be the rate-limiting factor for using the findings. In general, the method can be used for periodic monitoring and as a valid method for detecting or confirming suspected trouble spots in the system. To be successful, the data must be interpreted in the spirit of a shared commitment to quality care. PMID- 10104946 TI - Integrating care for chronic pain patients. AB - Problems in the treatment of the chronic pain patient in a staff model HMO often lead to ineffective and expensive care. The authors support a multimodal approach, which includes medical, psychosocial, and behavioral elements. This treatment is offered in an individualized, integrated, and episodic fashion, which is particularly relevant to the multiple and extended needs of the chronic pain patient. Two cases are presented to illustrate the approach. PMID- 10104947 TI - Making computerized quality assurance work! PMID- 10104948 TI - Helicopter utilization by the hour. A new strategy for service pricing. PMID- 10104949 TI - 1990 AAMS (Association of Air Medical Services) financial survey. Part I: Air transport charges. PMID- 10104950 TI - The effects of regeneration equipment on food quality. PMID- 10104951 TI - Cook/chill equipment review. PMID- 10104952 TI - Safe disposal of clinical waste: practical implications for the Health Service. PMID- 10104953 TI - Choosing your building services consulting engineer. PMID- 10104954 TI - The NHS and developers. PMID- 10104955 TI - The market in the NHS. PMID- 10104956 TI - The application of down-draught ventilation systems in the pathology laboratory and post mortem room. PMID- 10104957 TI - Memories of adolescent hospitalization: results from a 4-year follow-up study. AB - During the summer of 1985, the posthospitalization reactions of 85 adolescents hospitalized for an acute condition were examined. Results from this study have been previously reported (Denholm, 1989). Four years after hospital discharge, 22 original patients participated in a follow-up study on memories of hospitalization, significant learnings, and suggestions for changes in hospital environments. PMID- 10104958 TI - Family-centered care in the critical care setting: myth or reality? AB - Family-centered care (FCC) has been upheld as the standard for providing quality health care for children. However, some professionals question its applicability in the critical care setting. Despite the barriers to FCC, ACCH's eight essential elements of FCC can provide the basis for devising strategies for successfully implementing FCC in the critical care setting. PMID- 10104959 TI - Using temperament theory to individualize the psychosocial care of hospitalized children. AB - Temperament theory is offered as a framework for systematically individualizing the psychosocial care of hospitalized children. Empirical research on temperament is cited. An application of the theory is illustrated through a presentation of three case studies of children who have cystic fibrosis as their primary diagnosis. The discussion of the children demonstrates how their psychosocial responses to hospitalization were related to their temperaments. The case studies also show how the hospital environment was adapted to meet the individual child's needs and also how children impact on their caretakers. PMID- 10104960 TI - A comparison of two stress-reduction treatments for mothers of neonates hospitalized in a neonatal intensive care unit. AB - Thirty mothers of preterm infants requiring neonatal intensive care unit (NICU) hospitalization were assigned randomly to one of three groups to assess differences in treatment effectiveness of facilitating parental adaptation to the NICU stresses. Groups consisted of: (a) a treatment group receiving videotape training in active problem-focused coping strategies; (b) a treatment group receiving videotape training in emotion-focused strategies to help manage anxiety; and (c) a control group receiving promotional information about the hospital and the NICU. On pretreatment measures most of the mothers exhibited little distress, a finding unlike those for the majority of NICU studies. On posttreatment follow-up both the problem-focused and emotion-focused treatment groups were significantly less anxious than the controls and lower levels of depression were observed for the emotion-focused group. Findings suggest that the coping interventions examined were cost efficient and appear promising in facilitating mothers' coping with NICU stresses. PMID- 10104961 TI - Paralysis or anticipation: mastering change. AB - An obsolete hospital information system can make or break a hospital's bottom line. Unfortunately, too few MIS planners and administrators consider the long term implications of obsolescence, and find out too late that the costly implementation or enhancement cannot deliver on their promises. PMID- 10104962 TI - Life after facilities management. AB - Healthcare organizations stand to benefit greatly from facilities management. Nevertheless, there is a glaring lack of interest among organizations to consider this option. Healthcare consultant Charles Singer explores the potential advantages of bringing in a second party to handle part or all of a group's data processing operations. PMID- 10104963 TI - National chains: why the experts were wrong. AB - Contrary to healthcare experts' predictions that a few nationwide hospital chains would dominate the industry by the beginning of this decade, local clusters now prevail in the marketplace. PMID- 10104964 TI - Information and corporate strategy. AB - Hospitals are plagued by growing economic pressures, and are becoming prime targets for stepped-up governmental intervention. Today, hospitals must pay careful attention to payors' needs, and must focus on maintaining the highest standards on all fronts. Within this context, information systems will be invaluable tools to meet these challenges. PMID- 10104965 TI - Accounting for retiree medical liabilities--considerations for selecting financial assumptions. AB - The Financial Accounting Standards Board proposed statement on employer's accounting for postretirement benefits other than pensions closely parallels the Board's pension accounting rules. Mr. Amoroso explains the calculations and financial assumptions involved. PMID- 10104966 TI - Fiduciary liability coverage--getting it and keeping it on reasonable terms. PMID- 10104967 TI - The hospital of the future is here today. PMID- 10104968 TI - Food shoppers give at a healthy clip. AB - California's City of Hope Medical Center has increased its food industry donations by seven figures through the Coupons of Hope program. PMID- 10104970 TI - Boards in change--the Alaska experience. PMID- 10104969 TI - AARP as a consumer advocate. PMID- 10104971 TI - Boards in change: the Maryland experience. PMID- 10104972 TI - Special report on taxation. Is your property tax exemption subject to challenge? PMID- 10104973 TI - When some are more equal than others. PMID- 10104974 TI - Healthcare data briefing. Hysteria about listeria? PMID- 10104975 TI - In search of a personal touch. PMID- 10104976 TI - Missing a vital link. PMID- 10104977 TI - Patterns in practice. PMID- 10104978 TI - Privatisation on parade. PMID- 10104979 TI - The key to efficiency. PMID- 10104980 TI - Health for all and all for one. PMID- 10104981 TI - Who guards the money? PMID- 10104982 TI - Let's save the world. PMID- 10104983 TI - Building to fit the bill. PMID- 10104984 TI - Listen and learn. PMID- 10104985 TI - A change of direction for the walking wounded. PMID- 10104986 TI - How the market crashed. PMID- 10104987 TI - Resourceful services. PMID- 10104988 TI - A network keyed into Liverpool. PMID- 10104989 TI - Local need overrides budget constraints, CON delays for SNF. PMID- 10104990 TI - Costs soar under EPA's waste-tracking program. PMID- 10104991 TI - How to control infectious-waste disposal costs and liability exposure, too. PMID- 10104992 TI - EDI (electronic data interchange): key competitive edge for materials purchasing. PMID- 10104993 TI - ATSDR (Agency for Toxic Substances and Disease Registry): medical waste poses no threat to public. PMID- 10104994 TI - Fuel quality key to preventing generator damage. PMID- 10104995 TI - New construction to overtake renovation in '90s. PMID- 10104996 TI - Time for systemic change. PMID- 10104997 TI - Riding out the storm of environmental turbulence. PMID- 10104998 TI - The rights debate. AB - To date, no proposal for systemic healthcare reform directly addresses whether healthcare is a right for all Americans. In fact, some proposals have avoided the issue altogether. Typically, proponents of reform have been more comfortable approaching healthcare services as something society has a moral obligation to provide rather than something individuals have a right to. Such an approach is consistent with the liberal democratic tradition's understanding of rights, which stresses individual freedom and autonomy. According to the Catholic social teaching of the past century, however, the right to participate in society takes precedence over the right to be free of governmental intrusions. From the Catholic perspective, furthermore, lack of access to healthcare is tantamount to being denied full involvement in social life. This tradition has stressed repeatedly that each individual achieves dignity and fulfillment only by being actively involved in the social world. In debates over systemic healthcare reform, it is imperative that advocates of the Catholic perspective recognize the difference between the meaning of "rights" as it has developed in their tradition and the meaning that has emerged from the context of the liberal democratic tradition. Their challenge will be to give the debate's key term a meaning that better reflects the tradition of Catholic social teaching. PMID- 10104999 TI - CHA principles for healthcare reform. PMID- 10105000 TI - Telling it like it is. PMID- 10105002 TI - Help for the hopeless. PMID- 10105001 TI - Streetside support. AB - Five years ago a small group of employees (health professionals and others) from Saint Joseph's Hospital, Atlanta, volunteered to prepare a meal for the homeless at one of the city's shelters. The experience led to a group decision to volunteer time to provide basic healthcare to the homeless. This soon led to the hospital-based Mercy Mobile Health Project, which, with community involvement, eventually became the Atlanta Community Health Program for the Homeless. Although the Saint Joseph's Mercy Care Corporation sponsors the program, a number of public and private agencies and professional groups are involved. All strive to expand efforts to address the problems of the homeless, to break the cycle of homelessness, and to provide continuing healthcare services where necessary. The number of clinic sites has more than doubled, while patient encounters have quadrupled. PMID- 10105003 TI - Marketing to and through employees. PMID- 10105004 TI - License to care. PMID- 10105005 TI - Ambiguities and contradictions in the provision of sheltered housing for older people. AB - This paper examines the current model of sheltered housing and explores a central contradiction in that model: namely that if only those people who most need and appreciate the unique features of sheltered housing were allocated places in schemes, the existing model ultimately could not provide sufficient support. This central contradiction leads to a fundamental lack of clarity in the role of sheltered housing. This is reflected in the ambiguities apparent in allocation practices, where judgements are typically made not only in relation to the tenants' needs and demands but also in relation to the impact on schemes. Evidence is presented from a recent study of sheltered and amenity housing in Scotland, which exposes these issues and suggestions are made as to how the traditional model of sheltered housing can be made more flexible and more suited to those who need and value it most. PMID- 10105006 TI - Employers won't give up fee-for-service. PMID- 10105007 TI - Which PPOs will take the biggest bite out of fees? PMID- 10105008 TI - What tax reform has done to doctors. PMID- 10105009 TI - Five pitfalls of delegation for new supervisors. PMID- 10105010 TI - Resolving conflicting interests of medical staff and governing body in revising medical staff bylaws. AB - Medical staff bylaws set out the rights, duties, and responsibilities of medical staffs and their members, and define the relationship between medical staffs and hospitals and their governing bodies. Areas of conflict between medical staffs and governing bodies are commonly highlighted during the process of revising medical staff bylaws. This article identifies some of the areas of potential conflict and offers suggestions for their satisfactory resolution. PMID- 10105011 TI - Hospital-based physicians and possible problems under the IRS affiliated service group rules. AB - Recent publicity surrounding the possible application of Internal Revenue Code Section 414(m)(5) to hospital-based physicians, and the effect such application would have on employee benefit programs they sponsor, has created confusion and uncertainty for these physicians and their advisers. This article explains the affiliated service group rules and the contrasts between the rules as set forth in the Internal Revenue Code and the proposed regulations interpreting those rules. PMID- 10105012 TI - The use of a severity-adjusted patient data base to establish standards for quality and cost-efficient medical practice. AB - In this article, the author describes the Acuity Index Method, a system that can be used to document levels of clinical quality and cost efficiency among physicians. This documentation can be used by physicians and health care institutions to analyze and enhance the quality of medical care they render and to demonstrate how quality medical care can be more cost-effective than "discount" medicine, with the patient being the ultimate beneficiary. PMID- 10105013 TI - Harrell v. Total Health Care: the corporate responsibility doctrine applies to managed care providers. PMID- 10105014 TI - S.B. 1211--California's new peer review legislation. PMID- 10105015 TI - Safe harbors & fraud alerts--a serious case of government overkill. PMID- 10105017 TI - HHS in the 90s. PMID- 10105018 TI - Insurance products for small groups--popularity growing. PMID- 10105016 TI - Factors influencing enrollment in a physiotherapy degree-completion program in Atlantic Canada: a survey. AB - The purpose of this study was to identify factors that influence enrollment in Dalhousie University's BSc (PT) degree-completion program. A geographically stratified, random sample of 100 nondegree physiotherapists practising in Atlantic Canada was surveyed by mail. The questionnaire solicited information on demographic data, program awareness and attitudes towards degree-completion programs. The response rate was 63 percent. More than 65 percent of respondents were trained in Canada, were older than 30 years, and had at least one child. Ninety percent of respondents were aware of the Dalhousie program; seven were currently enrolled. Ninety-three percent of respondents were confident they could continue to practise without a degree and 70 percent were confident they could meet academic standards required to complete a degree. Respondents were least certain on whether employers valued experience over a degree. Family responsibilities, age over 50, and job security were deterrents to enrollment. Nondegree physiotherapists in Atlantic Canada may not choose to upgrade to a degree because of the regional manpower shortage and job security. A strong pool of degree-completion students was not identified. PMID- 10105019 TI - Buyers/suppliers round table. PMID- 10105021 TI - The revised essentials of accredited programs. Association of Surgical Technologists. PMID- 10105020 TI - It's time for a bipartisan budget and health policy--Rostenkowski, Rockefeller lead: who will follow? PMID- 10105022 TI - Serious play. AB - For the Cook-Fort Worth Children's Medical Center, David Schwarz offers a successful blend of comfort and delight. PMID- 10105023 TI - Perspectives. Orphan Drug Act stumps lawmakers. PMID- 10105024 TI - Perspectives. Push for new directions in quality assurance. PMID- 10105025 TI - Selling to the elderly consumer. PMID- 10105026 TI - 1990 interior design awards. PMID- 10105027 TI - Chains take on retirement housing. PMID- 10105028 TI - DONs face budget dilemmas. AB - The annual nursing department budgeting process, which is one of the director of nurses' greatest challenges, has just gotten tougher. DONS will be forced to calculate the additional costs of meeting new federal mandates. PMID- 10105029 TI - Cut nursing aide turnover. AB - Directors of nursing seeking a solution to the turnover rate among their nursing assistant staff may take a cue from St. Barnabas nursing home in Gibsonia, PA. PMID- 10105030 TI - Staffing liability and risk. PMID- 10105031 TI - Good potential for a careful buyer. PMID- 10105032 TI - Universal health insurance: lessons of the 1970s, prospects for the 1990s. AB - In the 1970s, proposals for universal health insurance were not successful. Health care providers, insurers, and others negotiating in the political process foresaw a better future without such legislation. Today, the growth of health insurance coverage has unmistakably reversed. Moral discomfort and self-interest shape the new politics of universal health insurance for the 1990s. Hospitals, physicians, insurers, employers, and tens of millions of individuals would benefit from a universal health insurance plan that was mindful of their concerns and interests. Proposals that require employers to provide insurance for full time employees and expand public programs to cover to cover other uninsured persons now have the greatest chances for enactment. As leaders, health services and health insurance executives should be in the vanguard of efforts to enact universal health insurance. PMID- 10105033 TI - The politics and economics of health care finance: prospects for change. PMID- 10105034 TI - Universal health insurance: current perspectives on an old theme. PMID- 10105035 TI - A departmental stress management plan. AB - To reduce stress, most people and organizations need to improve their skills in recognizing and coping with stressors. Department plans like the one described provide a good method of understanding and learning to cope with specific stressors. Researchers analyzed the effects of a stress management plan for registered nurses in an acute care hospital. This plan, called stress inoculation, began with education on stress and coping skills. The nurses were then exposed to the real-life stressors and expected to use the newly learned coping skills. Later, the nurses were asked to evaluate the effectiveness of the coping skills. The results of the study showed that the nurses' stress was reduced through stress management and that coping skills were the key ingredient. Education was needed to teach the coping skills, but by itself, education showed no benefit. If supervisors and employees remain committed to the departmental stress management plan throughout the six phases, the likelihood of reducing stress, improving morale, and increasing productivity is high. PMID- 10105036 TI - Building a high-performance team. AB - Health care managers and supervisors face a particularly tough challenge. Today more than ever they must balance the increased demand for productivity with their own desires to provide excellent care. Many health care workers seem to feel that these objectives are antithetical. Given the methods for promoting productivity and increased performance that have been inflicted upon them in the past, such a view is not surprising, but it does not have to be this way. Most, perhaps all, health care workers have an intuitive awareness of what they need to do to meet their customers' highest expectations, because they have all been customers themselves. They know that productivity, quality, and courtesy are components of high performance. The wise manager taps into this knowledge and experience on the part of his or her employees to develop a vision of high performance that generates excitement and commitment within the work group. PMID- 10105037 TI - Playing politics fair and square. AB - Political action, like leadership behavior, may or may not be beneficial to the success of organizations and their personnel. At one end of the scale, political behavior is selfish. Some outliers are even unethical or illegal. In the upper registers, politically astute behavior supplements professional competency. It is beneficial not only to the practitioner, but also to his or her subordinates, superiors, peers, and employer. Negative political behavior is self-serving, manipulative, and violates the spirit of honest communication. It produces resentment and destroys morale. Often what is perceived as politics is merely poor communication. The remedy for this is better use of formal and informal channels of information. Incompetent employees often rationalize their failures by using politics as a scapegoat. To encourage positive political strategies, employers should institute training programs. Such programs should promote teamwork and teach positive interpersonal skills. Seminars on ethical decision making must be supplemented by model behavior on the part of upper managers. PMID- 10105038 TI - Nonadherence by health care professionals: strategies for supervisors. PMID- 10105039 TI - Strategies for resolving conflict. AB - In thinking through conflict management, there can be no quick fix that is a lasting one. This is not a threat to the integrity of the administrator, but rather a challenge to his or her ability to carry learned principles of management through to a satisfactory conclusion. While communication is only one of the keys to the process, concrete managerial ability and confidence in subordinates will prove to be the method of choice. PMID- 10105040 TI - Effective and ineffective college clinical supervisors: looking back. AB - The composite of the effective supervisor is that of an individual who is a knowledgeable professional who puts priority on high-quality instruction and guidance and gives specific, constructive evaluations to supervisees. The effective supervisor is a consistent observer who is accessible, enthusiastic, encouraging, a good listener, and humanistic. This supervisor is knowledgeable about the clients for whom the students are providing services, interacts with them, and demonstrates techniques for students. The supervisor has high expectations of the supervisees, while giving the students responsibility for decisions and input into the therapeutic process. Additionally, the effective supervisor shows interest in and respect for supervisees and guides them toward additional resources for information. The composite of the ineffective supervisor is opposite that of the effective supervisor. This individual is neither knowledgeable nor professional. Quality of instruction and guidance are not priorities for this often self-centered individual. The ineffective supervisor does not observe the students, and what little feedback is given is perceived by the students as negative and detrimental to instruction. This individual does not care about the students or clients who receive services. PMID- 10105041 TI - Managing health care costs: strategies available to small businesses. AB - Although health care costs continue to rise at an alarming rate, small businesses can take steps to help moderate these costs. First, business firms must restructure benefits so that needless surgery is eliminated and inpatient hospital care is minimized. Next, small firms should investigate the feasibility of partial self-insurance options such as risk pooling and purchasing preferred premium plans. Finally, small firms should investigate the cost savings that can be realized through the use of alternative health care delivery systems such as HMOs and PPOs. Today, competition is reshaping the health care industry by creating more options and rewarding efficiency. The prospect of steadily rising prices and more choices makes it essential that small employers become prudent purchasers of employee health benefits. For American businesses, the issue is crucial. Unless firms can control health care costs, they will have to keep boosting the prices of their goods and services and thus become less competitive in the global marketplace. In that event, many workers will face a prospect even more grim than rising medical premiums: losing their jobs. PMID- 10105042 TI - A giant step toward improved supervisory effectiveness. PMID- 10105043 TI - A supervisor asks: "One-on-one communication issues". PMID- 10105044 TI - Managing organizational change: strategies for the female health care supervisor. AB - In responding to resistance to change in the current health care organization, the new female supervisor can learn to support her staff in encountering and accepting these changes. The strategies and skills discussed above are characteristic of a supervisory style that may naturally occur for women, but also can be incorporated into the leadership style of men in health care management today. Health care leaders of tomorrow must work from an androgynous framework in which the behavior patterns and responses of each gender are learned and used appropriately by both men and women. Sargent suggests that the best managers are androgynous and that this is the inevitable wave of the future. Whether man or woman, a supervisor should learn, accept, and use methods that are characteristic of both sexes to be successful in managing people. Women and men must learn from each other's strengths and share these diverse skills. Given that women now outnumber men in health care management positions and organizations are changing to a more nurturing environment, the androgynous supervisor will be the successful leader of the future. Finally, women in health care supervisory positions have the potential to bring change where it is badly needed. Women in these roles often have a system wide view of health care policy issues that recognizes less federal commitment to social programs. Many women in health care positions believe that the issues of children, women, the elderly, the poor, and the homeless need focused attention. The growing number of women in health care supervisory and leadership roles is an important factor in changing national health policy for the benefit of these groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10105045 TI - Performance appraisal: support services' secret weapon. PMID- 10105046 TI - Complexity and contradiction in hospital support services. PMID- 10105047 TI - The impact of a shrinking labor force on support services. PMID- 10105048 TI - The role of the patient care committee at the Mount Sinai Medical Center. PMID- 10105049 TI - Can consultants help build a better support services division? PMID- 10105050 TI - What to do when the consultant comes. PMID- 10105051 TI - Addressing employee needs in the 1990s. PMID- 10105052 TI - Managing change in hospital support services. PMID- 10105053 TI - Hospital alliances in a maturing marketplace. PMID- 10105054 TI - Hospital waste management: where we are. PMID- 10105055 TI - New dimensions in hospital architecture. PMID- 10105056 TI - Promoting a positive image in hospital support services through coordinated apparel. PMID- 10105057 TI - Nurses' new approach to helping patients. AB - The person who uses a supportive facilitating approach assists another to grow. Although this approach has been used historically by parents and in education, it is only recently that medical and nursing professionals have adopted it. This approach promotes mutual participation in decision making and a collaborative rather than an authoritarian approach by the helper. A facilitating approach maximizes independence and, in the end, helps others to help themselves. PMID- 10105058 TI - Standard treatment goals speed recovery and reduce costs. PMID- 10105059 TI - Coping with the shortage: a nursing utilization model. PMID- 10105060 TI - Smoking: a content analysis of smoking policies in North Carolina hospitals. PMID- 10105061 TI - Motivation of healthcare workers. PMID- 10105062 TI - Locating child care as an employee incentive. PMID- 10105063 TI - Another look at escort services. PMID- 10105064 TI - Human resources and quality assurance. PMID- 10105065 TI - AIDS update. AB - AIDS continues to be a major health threat. Yet, life style changes and use of preventive measures have proved effective in dramatically slowing the spread of HIV in at least one group. Society's challenge is to find ways to make these benefits available to others--IV drug users, minority populations, and a new group, college students--both for humane reasons and because society must protect itself from deadly communicable diseases. Hospitals must find ways to provide efficacious, episodic treatment for acute phases of the illness and to assist organizations providing alternative sources of care. Financing this care will remain problematic for all providers. Caring for PWAs while protecting staff remains a major ethical and legal challenge and one in which managers must play a significant role. PMID- 10105066 TI - Visitors. PMID- 10105067 TI - Ready for quality? How one hospital introduced the Deming method. PMID- 10105068 TI - Management power and information technology. PMID- 10105069 TI - A health records initiative. PMID- 10105070 TI - Competition and financial information in the health service. PMID- 10105071 TI - Can national pay scales be made more fair and flexible? AB - It is increasingly recognised that rigid national pay scales are unsatisfactory. On the other hand to allow authorities or trusts to pay according to how they judge the market seems perilous. Professor Tony Kennerley proposes a method which steers a middle course between two undesirable extremes. PMID- 10105072 TI - Towards a DHA purchasing role. AB - Health authorities have been thinking about their future role, when they will be mainly purchasers of health care for their population. John Watson discusses some of the issues as they are seen at Bristol and Weston. PMID- 10105073 TI - What is quality in health services? PMID- 10105074 TI - Equality, fraternity and liberty? AB - The provision of health care is as much a matter of social and political arrangements as of medical science, and thus varies greatly from country to country, reflecting the values of different societies. Janet Stevens looks at the values implicit in the French service, and contrasts them with those of the NHS. PMID- 10105075 TI - Clinical psychology and general managers. AB - Peter Wilcock and Rowena Rossiter begin by describing changing responsibilities of clinical psychologists over the last 20 years. They show how some roles they undertake, which may seem far removed from client contact, have developed from psychologically based client-centred work, and this still lies at the root of the profession. They illustrate the current and potential contribution to be made to the NHS and general managers by clinical psychologists. PMID- 10105076 TI - Comment: impact of Illinois teen's refusal of treatment. PMID- 10105077 TI - Implementing public competition in Swedish county councils: a case study. AB - Earlier presentations of the theoretical framework for public competition (Saltman and von Otter, 1987) and of the comparative advantage of public competition as against a mixed market model (Saltman and von Otter, 1989a) suggest the importance of concrete arrangements to introduce a public competition approach at the operating level. This paper explores the administrative infra structure required to implement public competition within the Swedish county council-based health care system. PMID- 10105079 TI - Patient-care charge audits assessed. PMID- 10105078 TI - Management practices and priorities for mental health system performance: evidence from England and West Germany. AB - Performance priorities for high quality care, multiprofessional team care and deinstitutionalization of patients among mental health services in England and West Germany were found to be significantly influenced by management practices fostering goal congruence, peer review and staff participation in decision making. PMID- 10105080 TI - GAO cites confusion, poor coordination in federal programs for rural hospitals. PMID- 10105081 TI - Up & comers succeed by motivating others. AB - Few clues in the early lives of Modern Healthcare's 1990 Up & Comers indicate that they were destined to become young leaders of the healthcare industry. A diverse group, they started out in strikingly different directions. Gary Shorb trained as an engineer and aspired to be an admiral in the Navy. Deborah Johnson studied law but had dreams of becoming a professional musician. Larry Hough started out as a certified public accountant. Somewhere along the line, they were attracted to the healthcare profession. Despite their differences, they have much in common. A psychological survey conducted for the magazine by Michael Leibman of Caliper Human Strategies indicates they are strong motivators who set the tone for their organizations by soliciting the views of their staffs and structuring the agenda. As a group, they are bright, shrewd and goal-oriented. They also fully understand their role. As David Jimenez, president of Hialeah (Fla.) Hospital, said, "Every day you've got to go out there and demonstrate that you're capable of holding down the job, that you deserve to be the leader." These 12 executives, all 40 or younger, were chosen from more than 50 candidates suggested by Modern Healthcare's editorial staff and readers. They represent many facets of the industry and come from every part of the country. As the healthcare industry continues to evolve, they are well positioned to play a leadership role in meeting the challenges of providing high-quality and cost-efficient patient care. PMID- 10105082 TI - JCAHO, HCFA surveys inconsistent--GAO. PMID- 10105083 TI - AHA to test efficiency measurement. PMID- 10105084 TI - Humana's exemption from Ky. CON process approved. PMID- 10105085 TI - Personality profile shows up & comers lead by example. PMID- 10105086 TI - U.S., Japanese firms team up on both sides of Pacific. AB - American providers are orienting themselves to the healthcare needs of the Japanese. Hospitals are launching networks to deal with the growing number of Japanese businessmen and travelers who need medical personnel in an emergency who are fluent in their language. And some firms are angling to help build retirement communities in Japan. PMID- 10105087 TI - Panel hears case against Durenberger. PMID- 10105088 TI - Conditional accreditation irks CEOs--except for one. AB - Administrators have been fuming at the Joint Commission on Accreditation of Healthcare Organizations over the publicity and mixed signals surrounding "conditional accreditation" of their facilities. One exec who took the news in stride was so uncharacteristic that he almost got on a commission promo video. PMID- 10105089 TI - Humana launches multimillion-dollar image campaign. PMID- 10105090 TI - Adjusting charges helped rescue trauma unit. AB - A California hospital's trauma center is in the black after bleeding red ink for years. The simple solution: tally up all costs and set charges high enough to bring in a break-even amount of revenue. PMID- 10105091 TI - DME dealer's suit dismissed. PMID- 10105092 TI - AIDS conference marked by protests. PMID- 10105093 TI - GAO pans closing arguments. PMID- 10105094 TI - 'Hospitals should do more to get tax exemptions'. PMID- 10105095 TI - Governors, public hospitals battle over funds' distribution. PMID- 10105096 TI - Purchasing groups vie for control and clout. AB - To gain a competitive edge, group purchasing organizations and alliances realigned themselves and jockeyed for position in the market. They also emphasized member compliance with purchase volume commitments to gain or maintain leverage with vendors. And they responded to demand for more service contract agreements in addition to the traditional discounted-goods contracts. PMID- 10105097 TI - 'Some revenue recovery firms aim to inflate bills'. PMID- 10105098 TI - An ounce of prevention. AB - Hospitals that see financial trouble coming should do a candid assessment of their resources and structure as the first step in preventing a slide toward an emergency turnaround situation. That's the advice of Michael Rindler and Anthony Chirchirillo. PMID- 10105099 TI - Survey of hospital CEOs shows fewer fear demise of their facilities. PMID- 10105100 TI - Data exchanges provide latest leads on cost savings. AB - Entrepreneurs are setting up data services and exchanges that arm hospitals and physicians with the little solutions that chip away at medical costs and overhead. PMID- 10105101 TI - Hospital gets heat for AIDS treatment. PMID- 10105102 TI - Fewer trustees compensated--study. PMID- 10105103 TI - 2 tenants stop payments to HealthVest. PMID- 10105104 TI - It's official: VHAE stock can change hands. PMID- 10105105 TI - Black hospitals struggle to survive. AB - There are only eight black hospitals left in the nation; last month there were nine. Their dwindling number reflects not only financial operating pressures, but a growing public indifference to their contributions. Even black physicians are opting for the better-funded non-black hospitals, executives say. Without major changes or mergers, observers warn that the remaining black facilities may not survive. PMID- 10105106 TI - Recovery centers gaining interest. AB - It wasn't long ago that California hospitals were brooding over the introduction of post-surgical recovery-care centers. But the centers' ability to treat patients at lower costs is enticing some hospitals to establish friendly ties. PMID- 10105107 TI - Questions abound as start-up nears for physician data bank. AB - The start-up of the National Practitioner Data Bank is only weeks away, but hospitals and physicians still are raising questions about the system's pros and cons. While most laud the data bank's original mission--to prevent practitioners from concealing a history of incompetence--many physicians claim the scope of the system has grown too big and fear abuse of the information. PMID- 10105108 TI - VA, critics differ on meaning of JCAHO's quality scores. PMID- 10105109 TI - Physician referral service touts quality, not quantity. PMID- 10105110 TI - VHA Development adds new investors, becomes Greystone Communities. PMID- 10105111 TI - HFMA's recruiting service offers members a chance to advance. PMID- 10105112 TI - Industry responses mixed on right-to-die ruling. PMID- 10105113 TI - Suit over Ohio hospital's ownership pits trustees against Adventist system. PMID- 10105114 TI - Charter investigation widens; new operations chief named. PMID- 10105115 TI - 'Deals by AMA's ex-chief were unknown to board'. PMID- 10105116 TI - AMA drops plans for registered care technologists. PMID- 10105117 TI - Gateway's Chapter 7 liquidation a victory for AMI over creditors. PMID- 10105119 TI - GAO, hospitals spar over tax exemptions. PMID- 10105118 TI - Protestors horn in on Sullivan's closing speech to AIDS conference. PMID- 10105120 TI - Growth in endoscopy raises OR management challenges. PMID- 10105122 TI - OSHA finds most hospitals using universal precautions. PMID- 10105121 TI - Step two: delineating the scope of care. PMID- 10105123 TI - Interim managers hired to fill vacant top OR positions. PMID- 10105124 TI - Focus groups can be used to improve quality in OR. PMID- 10105125 TI - The OR turnaround: identify problems, set the priorities. PMID- 10105126 TI - Quality assurance and quality of care: I. Finding the linkages. AB - Efforts to adapt the problem-oriented record to the complex biopsychosocial determinants of illness and therapeutics are especially difficult with the seriously and persistently ill patient who requires more than a minimal hospital stay and for whom standards of care have not been developed. By focusing on a treatment system's capacity to achieve its goals, this report demonstrates one method for linking quality assurance behaviors with quality of care and integrating the work of the hospital psychiatrist and multidisciplinary team into the medical record. The vehicle for implementing this method is a multidisciplinary treatment-planning form currently used in the charts of an extended-length-of-stay treatment service. Its evolution and rationale are described, and an example form follows this report. PMID- 10105127 TI - Perspectives. Debunking small group insurance myths. PMID- 10105128 TI - A quality assurance evaluation. Appropriate insertion and documentation of umbilical arterial and venous catheters by neonatal flight nurses. PMID- 10105129 TI - Maintaining the highest standards. Commission on Accreditation of Air Medical Services works toward bright future of air medical industry. PMID- 10105130 TI - The status of air medical quality assurance. AB - In February of 1989, the AAMS Quality Assurance (QA) Committee surveyed 177 flight programs regarding their QA activities. There was a 58% return rate, with the majority of the respondents being single hospital-based programs. Eighty-nine percent of those surveyed stated that they wanted assistance with their QA programs. The majority of the respondents (95%) review patient care issues, with most performing regular flight record review (88%) and monitoring of the timeliness of care delivered (85%), such as scene/response times. The information generated by the survey has been used by the AAMS QA Committee in planning QA seminars, and may also be helpful to individual air medical programs in designing their QA programs, as well as a tool for use in comparing themselves to other programs. Specific areas needing improvement are mentioned and AAMS is challenged to offer leadership and support in these efforts. PMID- 10105131 TI - Efficient management of the estate as a whole. PMID- 10105132 TI - Project management--a personal view. PMID- 10105133 TI - Fire safety in health care premises. PMID- 10105134 TI - Clinical incineration--a viewpoint. PMID- 10105135 TI - A review of current practices for fire alarm detection systems in UK NHS hospitals. PMID- 10105136 TI - Application and management of technology in the health care sector. PMID- 10105137 TI - Pneumatic refuse collection or automatic vacuum collection systems. PMID- 10105138 TI - Statement of organization, functions, and delegations of authority--HCFA. PMID- 10105139 TI - 1990 architectural design awards. PMID- 10105140 TI - A look ahead: the next 10 years. Interview by Jim Bowe. PMID- 10105141 TI - Growth slows, but continues. PMID- 10105142 TI - The downside of "unbundling". PMID- 10105143 TI - Retirement centers are good neighbors. PMID- 10105144 TI - Nursing home bashing. PMID- 10105145 TI - Client-server MUMPS takes on the future. AB - The early stages of MUMPS demonstrated the language's reliability and functionality, yet it was limited to operating on standalone mainframe and minicomputer architectures. Slowly, as technology progressed and client-server networks became a reality, the speed and performance of MUMPS has brought new dimensions to healthcare. PMID- 10105146 TI - Brigham and Women's Hospital plans large MUMPS-based PC network. AB - Though many people say it simply cannot be done, Brigham and Women's Hospital is successfully implementing a network of 4,000 MUMPS-based PCs. The system takes advantage of standard hardware and software, and requires no customization. Today, the network serves as a prototype of similar installations nationwide. PMID- 10105147 TI - Integrating with MUMPS: fast, flexible and affordable. Interview by Ellen Pollock. PMID- 10105148 TI - Is there hope for the homeless? PMID- 10105149 TI - Homeless on the home front. PMID- 10105150 TI - The forgotten victims. PMID- 10105151 TI - Keeping your cool in a time of fear. PMID- 10105152 TI - OSHA tackles infection control. PMID- 10105153 TI - Hepatitis B: available vaccine safe, but underused. PMID- 10105155 TI - AIDS and health-care workers: case studies. PMID- 10105154 TI - The risk of AIDS-virus exposure during aeromedical transport of trauma patients. PMID- 10105156 TI - On the role of the expert witness. PMID- 10105157 TI - The Prego case: more AIDS lawsuits to come? PMID- 10105158 TI - Freeze dried what? AB - What would you do if your record storage area was exposed to 1,500 gallons of water per minute for 30 minutes? This article chronicles such a disaster and its aftermath. PMID- 10105159 TI - Will the real QA please stand up? AB - What does Quality Assurance mean, what is the purpose of quality assurance, and how can quality best be assessed or assured? This article explores these puzzling issues. PMID- 10105160 TI - Practice forum--outpatient record analysis. PMID- 10105161 TI - Practice forum--"new" birth certificates. PMID- 10105162 TI - Steps to a better service. PMID- 10105163 TI - How we won the contract race. PMID- 10105164 TI - Coping with a tragedy. PMID- 10105165 TI - Legacy of decay. PMID- 10105166 TI - Computing. The real world. PMID- 10105167 TI - Dispel that old myth. PMID- 10105168 TI - Partners in need. PMID- 10105169 TI - Keep it integrated. PMID- 10105170 TI - How to win a support worker. PMID- 10105171 TI - HCFA ushers in new era of nursing home certification requirements. PMID- 10105172 TI - Alternative dispute resolution: saving health care time and money. PMID- 10105173 TI - Nonprofit hospital mergers: DOJ Rockford victory. PMID- 10105174 TI - NLRB wins hospital union rules suit. PMID- 10105175 TI - Hospital strikes: adequate notice mandatory. PMID- 10105176 TI - Court-ordered caesarean sections: round II. PMID- 10105177 TI - Medical malpractice reform: light at the end of the tunnel? PMID- 10105178 TI - Biopharmaceutical payment and coverage: are cost control policies too restrictive? Industrial Biotechnology Association. AB - The use of recombinant DNA technology and monoclonal antibody technology has led to a variety of new "biopharmaceuticals" that aid the body in fighting disease. We are already seeing improvements in patients' quality of life as a result of these new technologies. Often, we also see a lowering of health care costs due to preventing or shortening hospital stays and the reduction of the need for other health care expenditures. However, it is important to recognize that there is also the possibility of an increase in health care costs as the new drugs enable people to live longer, and thus possibly consume more health care services. In recent years, a rising concern has been voiced about the rapid increase in health care spending. Despite vital health and economic benefits made possible by new pharmaceuticals, spending on drugs is a relatively small portion of total health care expenditures. As consumers demand access to high-quality health care, the issue of reimbursement has become highly controversial. As we stated earlier, we recognize that HCFA and other third-party payers have a legitimate interest in attempting to control health care expenditures. However, we are aware that restrictive policies on drug coverage and payment could deprive patients of access to medically necessary therapies and, ultimately, reduce biopharmaceutical manufacturers' revenues to the point where future research is hampered or halted. PMID- 10105179 TI - The Metropolitan Toronto Regional Geriatric Program: an innovative method of health care delivery. AB - The co-ordination of hospital services in large metropolitan areas presents a formidable challenge. History, university relationships, geography and a tradition of independence and autonomy mitigate against co-operative regional ventures. A new program is evolving in Metropolitan Toronto which represents a significant change in the delivery of specialized geriatric services. The regional geriatric program has been established with direct funding from the Ontario Ministry of Health and contractual agreements with participating hospitals to provide specific geriatric services. It is a collaborative venture with the participating hospitals and the University of Toronto voluntarily participating in its management and policy direction. Although many issues have yet to be resolved regarding the relationship of the program to the Ministry, between the hospitals and with the community, this model may become prevalent in other areas of specialty services, such as trauma and oncology. PMID- 10105180 TI - Can in-home hospital care be implemented in Ontario? Implications for public policy. AB - Two models of in-home hospital care were considered as ways to overcome the current problems plaguing the Home Care Program in Ontario. The hospital organized home care is an extension of some hospital services into the community, similar to the Verdun Hospital-In-The-Home. The extramural hospital, introduced in New Brunswick, emphasizes the integration of services. These two models were compared to the Ontario Home Care Program to consider feasibility. Clearly defined mandates and the division of services need to be established in addition to an evaluation of cost, the use of services and the impact on health status. PMID- 10105181 TI - Economic and ethical consideration in the intensive care unit. AB - Intensive care units (ICUs) sustain life but, in certain cases, this resource becomes a means to prolong dying, with great physical, emotional and financial impact. The cost to care for patients in the ICU is at least three times more than general ward care; thus, ICUs have become one of the largest cost centres in the hospital. Economic pressures require us to be mindful of whom the ICU treats and for how long. Health professionals working in the ICU must critically appraise the ethical basis for their behaviour and actions. In so doing, many are likely to appeal to the patient's right to self-determination and the physician's reliance on the principles of beneficence and non-maleficence as the underpinnings of morality in medicine. One approach is to examine the issues and rights pertinent to an individual case using a circular model. Decisions are based on medical facts and prognosis, a patient's right to self-determination, a patient's best interests and external factors. Health personnel would be compelled to consider all of these issues. Within this framework, prevention or resolution of moral dilemma can take place within the clinical rather than the legal forum. PMID- 10105182 TI - Setting community health goals: one District Health Councils experience. AB - The Niagara District Health Council has embarked on a strategic planning exercise to develop health goals, objectives and preliminary targets for action. This process was approached in three phases: establishment of a Health Goals Task Force and adoption of the five goals developed by the Premier's Council on Health Strategy; planning and implementation of a Health Goals Consultation Day to involve community members in the identification and priority ranking of objectives; and development of measurable and realistic preliminary targets through consultations with expert groups and individuals. This process is a practical planning tool applicable across sectors and communities. PMID- 10105183 TI - Answers inside. PMID- 10105184 TI - Looking for leaders. PMID- 10105185 TI - A house divided. PMID- 10105186 TI - Rediscovering abandoned values. PMID- 10105187 TI - The thinking manager. PMID- 10105188 TI - Glove prices steady or falling. PMID- 10105189 TI - Materials managers struggle with infection and cost control issues when buying linens. PMID- 10105190 TI - HMM price watch. Purchasing managers' index inches over 50 to 50.2 in April, up from 48.8 last month. PMID- 10105191 TI - Hospitals must pay property taxes on leased equipment unless a contract states otherwise. AB - A not-for-profit hospital has decided to rent medical and office equipment instead of purchasing the items. Under the terms of the lease, the hospital is required to reimburse the supplier for any property taxes on the equipment covered by the lease. The lessor has billed the hospital for personal property taxes assessed by the county government. The hospital materials manager is concerned that the hospital isn't able to claim its usual tax exemption since it didn't purchase the equipment and can't claim to be the owner of it. In this dialogue, Dr. Decker discusses this problem and offers some possible solutions. PMID- 10105192 TI - Consumer evaluation of the quality of hospital services from an economics of information perspective. AB - Consumer evaluations of the quality of hospital services have become increasingly important as the patient and the patient's family have become more involved in hospital selection. The authors investigate the appropriateness of the search, experience, and credence typology of economics of information theory as a framework for analyzing how consumers judge the quality of specific hospital services. Advertising strategies are recommended for each category for hospitals seeking to create images of quality and excellence. PMID- 10105193 TI - Will the real health care marketer please stand up? PMID- 10105194 TI - Private physicians or walk-in clinics: do the patients differ? AB - The authors use a consumer-oriented framework to compare patients of private physicians with those of walk-in clinics in terms of factors that influence selection of health care providers. Data suggest few differences in the way the two types of providers are perceived by their patients. Instead, a fairly strong income effect suggests that segmentation strategies for health care delivery systems should be reevaluated. The results provide insights for applying strategic marketing concepts within health care delivery systems. PMID- 10105195 TI - The British health system: will it work for America? PMID- 10105196 TI - Using a patient survey for marketing a professional health care practice. AB - Small, private, professional health care practices are at a disadvantage when conducting market survey research because they cannot afford to employ or purchase the expensive specialized marketing skills of their larger competitors. The author describes a method that small private practices can use to conduct patient marketing surveys. Survey findings are reported and examples are provided of how the results influenced subsequent marketing decisions. Suggestions are offered to help ensure the success of similar studies in other practices. PMID- 10105197 TI - Creating patient satisfaction and loyalty. AB - Many hospitals are considering enhanced approaches to patient satisfaction measurement and guest relations--or service management. Some are building in house satisfaction management systems. Others are evaluating the growing number of systems commercially available for purchase. The authors review the successful design, testing, introduction, and nearly 5-year use of an in-house system. PMID- 10105198 TI - Establishing an effective referring physician network. AB - Physician referrals are the lifeline of many organizations--the difference between prosperity and ruin. However, the physician referral process is difficult to understand and manipulate. The authors outline what is known about the referral habits of physicians and their impact on the organization. The Watson Clinic's referring physician program illustrates the components of a successful referral-building strategy. PMID- 10105199 TI - Developing integrated referral channels for cardiology services. AB - The author describes development of a vertical integration model for building patient referrals and revenue through channel management. The University of Alabama Hospital and Medical Center developed a program in which a satellite clinic was established in cooperation with a rural hospital in Alabama. This type of channel management enabled the medical center and hospital to increase outpatient capacity without affecting on-campus clinics and provided needed increases in the volume of up-channel cardiac services for revenue expansion. PMID- 10105201 TI - Different opinions don't make bad medicine. PMID- 10105200 TI - Primary care referral management: a marketing strategy for hospitals. AB - With increasing competition among hospitals, primary care referral development and management programs offer an opportunity for hospitals to increase their admissions. Such programs require careful development, the commitment of the hospital staff to the strategy, an integration of hospital activities, and an understanding of medical practice management. PMID- 10105203 TI - What if the patients billed us? PMID- 10105202 TI - Why did these doctors lose their malpractice insurance? PMID- 10105204 TI - Automated immunoassay systems: a new frontier. PMID- 10105205 TI - Do automated instruments reduce job satisfaction? PMID- 10105206 TI - Moving up is not the only way. PMID- 10105207 TI - PACs work their influence on the Hill. PMID- 10105208 TI - Charter plans sale of 5 hospitals; deal could raise up to $100 million. PMID- 10105209 TI - Comprehensive Care shareholders aim to oust board. PMID- 10105210 TI - Tracing turnover to the source. AB - Jeffrey A. Alexander wins the 1990 Governance Fellowship Award for his proposal to determine the influence of governing board structure and composition on the rate of turnover for chief executive officers. PMID- 10105211 TI - FTC homing in on merger in Carmichael, Calif. PMID- 10105212 TI - Two Rockford hospitals appeal to Supreme Court. PMID- 10105213 TI - Vendors show staying power. PMID- 10105214 TI - Info systems head toward central decisionmaking. AB - Information system vendors are moving away from consolidation and merger, while more multihospital systems that buy from the vendors are moving toward centralized decisionmaking, says George Kennedy. PMID- 10105215 TI - Researchers urge AZT programs for hospital workers. AB - Administering zidovudine, also known as AZT, to healthcare workers immediately after they've been exposed to blood suspected of being infected with the AIDS virus is a realistic attempt to reduce their likelihood of becoming infected. That was the conclusion of one of some 2,500 presentations made at the recent international AIDS conference. PMID- 10105216 TI - Nurses win RCT battle, but war isn't over. AB - Organized nursing outflanked the American Medical Assn. on the issue of physician controlled bedside workers in hospitals, but other battles over nursing care will be fought in the arenas of home healthcare and long-term care. PMID- 10105217 TI - Study probes strengths of stockless inventory. AB - Preliminary results of a study on stockless inventory emphasize that potential savings aren't built into the distribution method. Rather, the groundwork done by hospitals before starting a stockless program may determine its success. PMID- 10105218 TI - N.Y. lawmakers OK healthcare fills. PMID- 10105219 TI - Specialty healthcare stocks come out on top. PMID- 10105220 TI - HCA to refinance psych unit debt. PMID- 10105221 TI - Quorum to tackle troubled hospitals. PMID- 10105222 TI - Use of trust funds questioned. PMID- 10105223 TI - Computer use for OR management continues to grow. PMID- 10105224 TI - Draping: what's necessary, what's proven. PMID- 10105225 TI - OR inventory management is challenging. PMID- 10105227 TI - Vendors of OR management systems. PMID- 10105226 TI - Begin to prepare for OSHA bloodborne disease regs. PMID- 10105228 TI - AHCA continues proactive approach to fire safety. PMID- 10105229 TI - Standardization of services needed to define role. PMID- 10105230 TI - Life sustaining treatment policy: put it in writing. PMID- 10105231 TI - Staff supervisory training investment pays off. PMID- 10105232 TI - Turning away customers and other horror stories. PMID- 10105233 TI - Let the puree revolution begin with creative, appetizing meals. PMID- 10105235 TI - Changes in resident profile present many opportunities. PMID- 10105234 TI - Laundry systems offer savings in housekeeping labor costs. PMID- 10105236 TI - Burnout in the boardroom: recognizing and preventing a growing problem. PMID- 10105237 TI - Four symptoms of a troubled board. PMID- 10105238 TI - The Maryland Quality Indicators Project: trustees take the lead. PMID- 10105239 TI - Prudent investments for hospitals. PMID- 10105240 TI - Hospital prenatal care programs. PMID- 10105241 TI - Prego AIDS case leaves few answers. PMID- 10105242 TI - Paying your dues may pay off in the end. PMID- 10105243 TI - Board-CEO communication. PMID- 10105244 TI - Capital payments and PPS: impact on hospital finance. PMID- 10105245 TI - What is the board's role in hospital safety management?. Interview by Karen Gardner. PMID- 10105246 TI - CEOs give JCAHO mixed reviews. PMID- 10105247 TI - Johns Hopkins breaks controversial new ground in drug testing. PMID- 10105248 TI - Community profile--key to successful MD recruitment. PMID- 10105249 TI - The NLRB bargaining rules: why employees turn to unions. PMID- 10105250 TI - What trustees can do to reduce CEO turnover. PMID- 10105252 TI - Future health care reforms? PMID- 10105251 TI - Medical staff: realigning the power. PMID- 10105253 TI - Financial survival of a small, rural hospital. Interview by Karen Gardner. PMID- 10105254 TI - Should every baby be saved? PMID- 10105255 TI - Tragedy in the fog. PMID- 10105256 TI - Amtrak '87: a recap. PMID- 10105257 TI - It always happens "somewhere else": Coldenham 1989. PMID- 10105258 TI - The Kearns air disaster: a retrospective. PMID- 10105259 TI - Physician compensation based on performance appraisal. AB - Physician compensation in a group practice setting has long been a subject of discussion and time investment, both on the part of managers and physicians. With a changing external environment, including Medicare fee freeze, capitation, and other forms of discounted, contractual medicine, former income distribution plans may not serve group practices well anymore. The ability of group practices to attract, retain, and develop physicians is at least partially dependent upon physician compensation structure. Taking into consideration marketplace characteristics for different specialties and offering equity in the compensation process are important features of any income distribution plan. This paper emphasizes a longstanding business tool, performance appraisal, which may be a key future determinant of physician compensation. The utilization of performance appraisal in establishing physician compensation is discussed and a sample performance appraisal instrument is included as a model. PMID- 10105260 TI - Scott and White Clinic. Scott and White Memorial Hospital. PMID- 10105261 TI - Intergroup of Arizona. PMID- 10105262 TI - The Watson Clinic. PMID- 10105263 TI - Medical underwriting. Staying ahead of the competition. PMID- 10105264 TI - The elderly, the sick, and health care facilities. PMID- 10105265 TI - The catastrophic fires of 1989. PMID- 10105266 TI - Special report on medical staff relationships. Recent developments in federal law regarding patient transfers. PMID- 10105267 TI - Better intervention techniques through education. AB - The author focuses on the officer orientation program at his hospital in discussing how to establish a good security program to reduce criminal activity. PMID- 10105268 TI - Customer service and the security professional. AB - The author explains why customer service and public relations are the key to a good security program. He provides guidelines for security officers based on the program at his Philadelphia hospital. PMID- 10105269 TI - Tips for personal computer security. PMID- 10105270 TI - Emergency decontamination--is your hospital prepared? PMID- 10105271 TI - Community right-to-know. AB - This article discusses Title III of SARA--the Emergency Planning and Community Right-to-Know Act of 1986--and its requirements for your health care facility. PMID- 10105272 TI - Adding value is a must for survivors and thrivers. PMID- 10105273 TI - Choosing your partners carefully: what healthcare executives should know about managed care. PMID- 10105274 TI - Avoiding litigation: watch your forms. PMID- 10105275 TI - The psychology of job satisfaction and the management of job dissatisfaction. PMID- 10105276 TI - Hospital leadership project tackles managing change. PMID- 10105277 TI - Views on rationing healthcare examined. PMID- 10105278 TI - Partnership series 1990: building a healthcare team. PMID- 10105279 TI - Consultants' corner: financial health of healthcare organizations. Interview by Vaughan Smith. PMID- 10105280 TI - Exploring hospital production relationships with flexible functional forms. AB - This paper estimates a multiproduct variable cost function using data on a sample of California hospitals. The results provide useful insights into the advantages and disadvantages of flexible functional forms for cost analysis. The translog function appears to provide reasonable estimates of marginal costs when evaluated at or near the approximation point of the function. The estimated function performs less satisfactorily, however, when evaluated outside this range. The paper's results do not provide strong evidence of either ray scale economies or of weak cost complementarities. There is some evidence, however, that the degree of scale economies may be underestimated. PMID- 10105281 TI - Uncertainty and the demand for medical care. AB - This paper provides an analysis of the effects of uncertainty on the demand for medical care using a simplified version of Grossman's human capital model of the demand for health. Two types of uncertainty are analysed: the uncertainty surrounding the incidence of illness and the uncertainty surrounding the effectiveness of medical care. In the first the consumer's basic level of health is assumed to be a random variable; in the second the effectiveness of medical care is assumed to be random. Comparative static results are reported indicating the effects on the demand for medical care of both increases in the means of these distributions and mean-preserving spreads of the distributions. PMID- 10105282 TI - A geographic index of physician practice costs. AB - This paper develops a geographic index of physician practice costs. A Laspeyres index is derived for each Metropolitan Statistical Area and for the non metropolitan portion of each state. Relative prices by area are obtained for four practice inputs: physicians' own time, employee wages, office rents, and malpractice insurance. Each input price proxy is weighted by the share of physician gross revenues spent on that input. The index is useful in explaining geographic variation in physician fees. It may be used in reforming the way Medicare pays physicians. PMID- 10105283 TI - Agencies bring a fresh perspective. PMID- 10105284 TI - Change the way you look. PMID- 10105285 TI - Here's mud in your pie. PMID- 10105286 TI - Putting your best foot forward. PMID- 10105287 TI - Displaying old glory. PMID- 10105288 TI - When sales affect the bottom line. PMID- 10105289 TI - Managing costs of hospital advertising. PMID- 10105290 TI - Overcoming buyers' fear. PMID- 10105291 TI - Shopping for health. PMID- 10105292 TI - Don't forget the church women! PMID- 10105293 TI - Recipes with value added. PMID- 10105294 TI - Lobbying for licensure. PMID- 10105295 TI - Specialized messages attract nurse specialists. PMID- 10105296 TI - Introducing high-tech equipment. PMID- 10105297 TI - Targeted marketing builds physician referrals. PMID- 10105298 TI - Promoting clinical services. PMID- 10105299 TI - Nurses & marketers work together. PMID- 10105301 TI - Medical malpractice and alternative dispute resolution. PMID- 10105300 TI - 12 good reasons to be a nurse. PMID- 10105302 TI - Beyond diagnostics. A commitment to saving lives. PMID- 10105303 TI - Survival management in a litigious environment. PMID- 10105304 TI - PET. Clinical positron emission tomography. PMID- 10105305 TI - Improving performance with creative leadership. PMID- 10105306 TI - Accounting methods in radiation oncology. Case level cost determination. PMID- 10105307 TI - Hospitals support economy. PMID- 10105308 TI - Reading warning signs could save your job. AB - This is the last of a two part series about how CEOs should learn to read the warning signs of trouble from the hospital board. Part one, printed in the June issue of AOHA Today, followed the case of a hospital administrator who was praised by board members just two weeks before he was fired. This administrator found out the hard way that he was the victim of an informal relationship between a top hospital manager and a powerful board member. His problem is only one of many that could cause termination, and the authors' goal is to alert CEOs before problems begin. Part one gave tips for incoming CEOs to follow; part two picks up here with many more points for new and seasoned CEOs alike. PMID- 10105309 TI - Patient fund rules get a stack of comments. PMID- 10105310 TI - Piecing together the fragments. PMID- 10105311 TI - Go beyond points A and B. The rewards of terrific transportation. PMID- 10105312 TI - Unified marketing packs more punch. PMID- 10105314 TI - A warming trend. Climate right for condo/co-op development. PMID- 10105313 TI - Drawing a bead on assisted living. PMID- 10105315 TI - Learning made fun. PMID- 10105316 TI - Activities for low-functioning residents. PMID- 10105317 TI - Hello, my name is .... PMID- 10105318 TI - Documentation and defense. PMID- 10105319 TI - End of occupancy decline in sight. PMID- 10105320 TI - Image is reality. PMID- 10105321 TI - The three scrutineers. PMID- 10105322 TI - Leaping the culture gap. PMID- 10105324 TI - Beat the hackers. PMID- 10105323 TI - Break the vicious circle. PMID- 10105325 TI - A right to choose. PMID- 10105326 TI - When in Rome. PMID- 10105327 TI - Free speech, not lip service. PMID- 10105328 TI - A question of ethics. PMID- 10105329 TI - Computing. A standard to look for. PMID- 10105330 TI - The impact of computerization on medication discrepancies in a centralized unit dose drug distribution system. AB - A missing dose audit was conducted to evaluate the impact of computerization of a centralized unit dose drug distribution system on the number and source of medication discrepancies. The methodology used was the same as that used for a previous audit done before computerization. The cardiology and coronary care nursing units participated in the 12 day study. The pharmacy auditor and the nurse compared the contents of each patient's medication bin to the nursing profile daily. All discrepancies were documented, investigated, and resolved. All missing dose phone calls were recorded and evaluated. The results were compared to the results of the previous audit. The results of this audit showed that after computerization there was a 17% reduction in medication discrepancies and a 41% decrease in the number of phone calls received for missing doses. The audit uncovered additional areas where further change may be beneficial. PMID- 10105331 TI - Procedures on handling mifepristone (RU 486) in France. AB - Mifepristone (Mifegyne 200 mg) is a newly approved drug in France for termination of early pregnancy. Consequently, doctors and pharmacists have to follow strict legal rules of prescription, administration, storage, and dispensing. French requirements are reviewed with particular regard to practical procedures of dispensing. PMID- 10105332 TI - An intravenous potassium policy with concurrent physician evaluation. AB - Hospitals have an ethical, as well as a legal, duty to provide safe care to patients. Responsibility for providing care involving medications is distributed to practitioners within the institution including physicians, nurses, and pharmacists. Each practitioner plays an essential role in the provision of safe intravenous potassium supplementation. A procedure is described which incorporates drug usage evaluation into a safe, simple, intravenous potassium policy. PMID- 10105333 TI - Development of a patient controlled analgesia program in a pediatric hospital. PMID- 10105334 TI - The health care system future implications. AB - This article deals with the future prospects of our country's health care system and is based upon a survey jointly conducted by the Policy Research Institute and Project HOPE. The original survey also examined individual life expectancy, the health system's positive contribution to our well-being. The costs and allocation of health resources, the system's problems, and the future trends and outlook were also examined. PMID- 10105335 TI - Twentieth century indicators of change in American medical practice for the 21st century. PMID- 10105337 TI - The ethics of the ethics committees. PMID- 10105336 TI - The promise of the beneficience model for medical ethics. PMID- 10105338 TI - A physician's duty to inform of newly developed therapy. PMID- 10105339 TI - Distinguishing wrongful from "rightful" life. PMID- 10105340 TI - Medical professional liability and the delivery of obstetrical care. PMID- 10105341 TI - Discrimination: the difference with AIDS. PMID- 10105342 TI - New Orleans hospital reaccredited. PMID- 10105343 TI - Suit plays up Humana link to official. PMID- 10105344 TI - Subcommittee recommends ProPAC expand its focus. PMID- 10105345 TI - 'Americans least satisfied with health system'. PMID- 10105346 TI - Switch sought to not-for-profit. PMID- 10105347 TI - Hospital board members bid for Denver-area AMI facilities. PMID- 10105348 TI - 'Government should ensure health access'. PMID- 10105349 TI - Hospitals battling states to keep tax status. PMID- 10105350 TI - Houston's Methodist Hospital given charity-care ultimatum. PMID- 10105351 TI - Modern facilities trying to fit into aging tax laws. PMID- 10105352 TI - Debate linking tax status to charity care gains interest. PMID- 10105353 TI - Ads defend hospital industry. PMID- 10105354 TI - Plan puts marketing in hands of hired gun. PMID- 10105355 TI - Healthcare bond volume sharply higher. PMID- 10105356 TI - Republic sues 5 over buyout profits. PMID- 10105357 TI - Study of polls shows public support for healthcare reform carries many ifs. PMID- 10105358 TI - Healthcare lobbying efforts turn to states. AB - With federal policy action frozen by a budget and re-election frenzy, more healthcare legislative battles are turning up in the state capitals. Three states in particular are experiencing stepped-up lobbying activity from hospitals. And three lobbying giants, the American Assn. of Retired Persons, the American Hospital Assn. and the American Medical Assn., are struggling to overcome their own challenges. PMID- 10105359 TI - Merger's effects on charges, access studied. PMID- 10105360 TI - Santa Cruz merger target of antitrust probe. PMID- 10105361 TI - '1 in 10 hospitals distressed'. PMID- 10105362 TI - AMA struggles to shepherd diverse flock. PMID- 10105363 TI - Labor proposes rules governing foreign nurses. PMID- 10105364 TI - Senate panel denounces Durenberger. PMID- 10105365 TI - AARP recovering from catastrophic defeat. PMID- 10105366 TI - Hospitals invest assets more conservatively than other industries--survey. PMID- 10105367 TI - Expert sees quality of care becoming important factor in hospital credit ratings. PMID- 10105368 TI - Firms seeking partnerships with hospitals to cut costs through direct contracting. PMID- 10105369 TI - Hospitals find quality management is a process, not a program. PMID- 10105370 TI - Hospitals reduce demand for workers by redesigning jobs. PMID- 10105371 TI - 'CEOs need to back up physicians who recommend withdrawing life support.'. PMID- 10105373 TI - Health policy analyst to discuss myths, realities of rationing proposals. PMID- 10105372 TI - Five chosen for Hall of Fame. PMID- 10105374 TI - Systematic approach eases Kaiser's promotion process. PMID- 10105375 TI - Formal training program helps smooth transition for new board chairman. PMID- 10105376 TI - Alternative hospital models offering rural facilities strategies for survival. PMID- 10105378 TI - Tax-exemption challenge: the Burlington, VT, case. PMID- 10105377 TI - Role of physiotherapy auxiliary personnel in Nova Scotia: a descriptive survey. AB - This study was designed to gather information and opinion on the impact and role of auxiliary personnel in physiotherapy, in Nova Scotia (NS). The physiotherapist/auxiliary ratio and present and future levels of education, supervision, and activities of auxiliary personnel were investigated. All NS physiotherapists registered with the Nova Scotia College of Physiotherapists (NSCP) were surveyed by mailed questionnaire; one follow-up was sent. Two questionnaires were developed. Potential levels of the terms assistant and technician were defined to facilitate interpretation of the opinion statements. Questionnaire A was mailed to all registered physiotherapists (n = 279, response rate 83%). Questionnaire B was mailed with Questionnaire A to directors and clinic owners (n = 73, 79% response rate). Results showed a physiotherapist/auxiliary personnel ratio (excluding clerical) of 3.75:1. The majority of personnel were trained in-house. There was a trend toward less frequent supervision with more extensively trained auxiliary personnel. More respondents considered that formally trained assistants would best serve the profession of physiotherapy in the future. To conclude, this study adds to the body of knowledge of the Canadian Physiotherapy Association and the NSCP. It should assist the NS Department of Health and Fitness in analyzing needs for training of auxiliary personnel in Physiotherapy, and provide data for future studies. PMID- 10105379 TI - Hospital painting party. PMID- 10105380 TI - Touching the lives of the dying. PMID- 10105381 TI - Preparing volunteers for hospice. PMID- 10105382 TI - Burnout vs. grieveout. PMID- 10105383 TI - Tax exemption and the auxiliary. PMID- 10105384 TI - Gift shops' tax-exempt status. PMID- 10105385 TI - The tax deductibility of donations. PMID- 10105386 TI - How has your HMO responded to AIDS? PMID- 10105387 TI - Direct medical costs of Class IV HIV care. AB - Over an 18-month period (January 1987 to June 1988), Group Health Cooperative (GHC) examined the direct medical costs and service utilization of enrollees with Class IV HIV conditions. Data is presented on inpatient stays, outpatient visits by specialty, and outpatient pharmacy, laboratory, home health, and purchased outside services. Results for enrollees with Class IV HIV disease are compared to those for a control sample of enrollees, age and sex matched with the HIV sample. The per member per month (PMPM) cost for the HIV sample was $1,761, approximately 33 times greater than the PMPM cost for the control sample. Group Health's annualized cost of $21,130 per case and diagnosis-to-death cost of $31,700 $42,300 per case are comparable to costs of Class IV care in other settings. Primary care costs were 11 times that of controls. Several specialty areas (e.g., infectious disease, pulmonary, oncology, and radiation therapy) were impacted to a greater extent. PMID- 10105388 TI - Clinical reminders in ambulatory care. AB - Computerized reminders are a tool to improve patient care, increase compliance, and reduce medical liability in ambulatory health care. Continuity of care is often hard to achieve given large patient loads, cost containment pressures, and regulatory requirements. Recall reminders prompt patients to make or keep appointments for health maintenance or screening exams. Physician reminders are issued to clinicians at or between visits when their patients have specific screening or diagnostic needs. Reminder systems based on clinical protocols have the added advantage of providing explicit instructions for workup or treatment of abnormal conditions. These reminder systems are especially useful to standardize care in offices with many providers. Implementation of reminder systems is aided by careful staff preparation and resource allocation. Ultimately, reminder systems enhance quality of care, increase patient satisfaction, and reduce costs through improved continuity of care and early detection of serious illness. PMID- 10105389 TI - An HMO neonatology service. Providing care to high-risk newborns. AB - Clinical and technological advances in the treatment of premature infants and other acutely ill newborns have resulted in widespread use of neonatal intensive care units (NICUs). Along with this trend is concern over the high cost of NICU services. This paper describes how an HMO established a neonatology service in order to participate more directly in the care of its member infants and control the escalating costs of NICU therapy. Two years of NICU utilization data are presented. It is concluded that establishing a neonatology service within a managed care system can improve the clinical care of member neonates and decrease NICU costs. PMID- 10105391 TI - Health management system streamlines hospitals. PMID- 10105390 TI - Reform school. PMID- 10105392 TI - RUS (Resource Utilization System)--management information for the health service. RUS Consortium. PMID- 10105393 TI - The open systems revolution. PMID- 10105394 TI - Patient information services helped by computerisation. PMID- 10105395 TI - From hospital to district management: Wellington's model of service management. PMID- 10105397 TI - Work processes in health care--keeping it simple. PMID- 10105396 TI - Affirming action for women. Interview by Lesley Patterson. PMID- 10105398 TI - CEOs should learn to spot warning signs. PMID- 10105399 TI - Who will make health care decisions for me when I can't? AB - Medical professionals are increasingly faced with ethical dilemmas of caring for older patients who are decisionally incapacitated. Most often they rely on family to serve as surrogate decision makers. Does that practice agree with the preferences of the elderly themselves? Examined are the exploratory and qualitative findings of a sample of men and women, age 65 to 91 (N = 71). Comparisons are made between those elderly who have families and those who do not have families regarding the use of and interest in advance directives and proxy appointments. The findings suggest that elderly persons with families prefer to rely on relatives to conduct substitute decision making informally, unencumbered by legally executed living wills or proxy documents. Those without families view friends and doctors as their surrogate resource and endorse the use of legal proxy appointments. Implications for the use of advance directives and further public policy are discussed. PMID- 10105400 TI - Health care professionals and family involvement in care-related decisions concerning older patients. AB - This article examines care-related decision making within the context of in-home family care. It also uses the Andersen-Newman model to identify the correlates of physician involvement and centrality in decision making and the impact that it has on family members' caregiving satisfaction. Analysis of data from 244 family caregivers shows that elders (40%) and nuclear kin (53%) are key decision makers, indicating that families prefer to control care-related decisions. However, physicians are part of the decision-making process for nearly one fourth of the families in this study. The patient's impairment and the caregiver's education correlate with physician involvement in decision making. Shared residence and caregiver's overall satisfaction with the caregiving process correlate with physician centrality on the network. Discussion centers on implications for physician interactions with caregiving families around decision making. Included are indications for improved communication in decision-making contexts. PMID- 10105401 TI - Changes in aged populations served by home health agencies. AB - This article examines changes in clients served by home health agencies, and how changes are related to recent health care trends and local market structure. Two types of explanatory factors are examined: organizational measures and market factors. A theoretical model of isomorphism is tested, considering the effects of privatization within the context of the growth of chains and multifacility systems. Findings show that (a) system members are more likely than nonmembers to show increases in clients of all ages; (b) for-profits that are not system members are more likely to have increases in total clientele and in clients age 65-74, whereas for-profits' changes in clientele age 85 or over depends on their system membership--increasing among nonmembers, decreasing among members; and (c) agencies in states with home health "certificate of need" (CON) are more likely to have increases in clients age 65-74 and 85 and over. The results for total clientele and those age 65-74 support an isomorphism hypothesis. PMID- 10105402 TI - Investigation of death clusters in a nursing home. AB - The number of elderly residing in, and dying in, nursing homes is steadily increasing. In 1985, an investigation by the California attorney general's office was undertaken concerning a cluster of deaths in a single rural nursing home. The purpose of this study was to provide information for the investigation. The objectives of the study were to determine if there were excess deaths in the nursing home, and if so, to describe the circumstances surrounding the deaths and the policy implications for the quality of care in nursing homes. All the medical records for patients who died in a single nursing home between January 1, 1983 and April 30, 1985 were examined by the research team. Medical care was compared to desirable standards of care. A majority of the deaths, 52.5%, had major discrepancies from standard care that may have contributed to the patient's death. There were also major discrepancies in the cause of death between the death certificate and evidence from examination of the medical records. The data substantiated an unusual occurrence of deaths in the nursing home at the end of 1983 and again in early 1985, but no single factor or person could be identified as the major cause of the deaths. Although this is an isolated study of one nursing home, it is likely that these problems are not unique and the evaluation approach may be useful in other settings. It is recommended that nursing home deaths be routinely monitored, and that an unusual number of deaths should trigger an extensive investigation. PMID- 10105404 TI - Setting goals. PMID- 10105403 TI - Profitability of outpatient operations. PMID- 10105405 TI - The rationing of health care services: the case of Alameda County, California. PMID- 10105406 TI - Improving hospital ethics committees: testing an educational model. AB - Overall, the project described in this paper appears to represent a considerable success in the field of postsecondary education, moving from the identification of a population with special educational needs to the implementation of a well received program in a two year period. The extensive curriculum developed for the project seems to have been appreciated by participants and, in the case of relatively new members, to have improved their readiness to participate in committee work. Even in the case of more experienced HEC members, participation may have had significant, if unmeasureable, benefits. As one experienced HEC member noted, "It was a very stimulating, challenging, exhausting week and one I would recommend to others." These sentiments were echoed by another experienced participant who indicated that, "In the brochure the seminar looked like it might turn out to be the 'same old thing,' but it turned out to be a challenge and a chance to go home and begin again at a 'higher level'." Beyond its immediate benefits to individual participants, the project has led to the completion of 21 participant papers on procedural and bioethical issues, and the founding of a new journal for HEC members in which they will be published (HEC Forum, Pergamon Press, Oxford and New York). For the project faculty, the challenge ahead will be not only to respond to participant concerns, but to adapt the curriculum for presentation "on site" at hospitals across the country. While the move from formal demonstration to full-scale implementation will allow new flexibility, care must be taken to ensure that any changes do not sacrifice the program's clearly documented strengths.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10105407 TI - Termination of life support: guidelines for the development of institutional policy. Bay Area Network of Ethics Committees. PMID- 10105408 TI - Should hospital ethics committees have a budget? PMID- 10105409 TI - Perspectives. Living will concept boosted by Cruzan ruling. PMID- 10105410 TI - Perspectives. A shot in the arm for vaccine advocates. PMID- 10105411 TI - Project LEAN: a national campaign to reduce dietary fat consumption. AB - The Henry J. Kaiser Family Foundation initiated a social marketing campaign in 1987, to reduce the nation's risk for heart disease and some cancers. Project LEAN (Low-Fat Eating for America Now) encourages reduction in dietary fat consumption to 30 percent of total calories, by 1998, through public service advertising, publicity, and point-of-purchase programs in restaurants, supermarkets, and school and worksite cafeterias. The campaign has joined efforts with the Partners for Better Health, a coalition of over thirty national health and consumer organizations that are working towards a common goal of improved health through nutrition. Project LEAN has provided funds to states and communities to initiate local campaigns and work with chefs, food professionals, and the food industry to change norms and customs in food preparation and manufacturing. The goal of the campaign is to accelerate the trend in fat reduction and to stimulate the greater availability of low-fat food choices in the marketplace. PMID- 10105412 TI - Relational database technology in healthcare--the way forward. AB - Recognition of the need to manage a complex healthcare environment more precisely has significantly expanded the demand for management information. Present government initiatives such as resource management and the White Papers proposals for the NHS have increased the demands on health authorities to provide more detailed reporting and accounting of resources. Effective information handling is thus becoming the key for a growing number of health authorities and hospitals, combined with easy access to up-to-date information for resource management and consistent, planned treatment programmes. PMID- 10105413 TI - Revolution in medical records tracking. AB - It is now over two years since the Aberdeen Royal Infirmary implemented its locally developed computerised Medical Records Tracking System. The benefits of the system, which has turned a well organised Central Records Library into a highly efficient production unit for the Aberdeen Hospitals handling some 3,000 medical record movements per day, can best be illustrated by knowing that there were only 10 missing medical records for the 70,000 attendances at outpatient clinics over the last 3 month period. PMID- 10105414 TI - The pharmacist shortage: a challenge to hospitals. PMID- 10105415 TI - Communication is key to employee retention. PMID- 10105416 TI - Center serves as comprehensive health careers resource. PMID- 10105417 TI - Maddy says cost of health care is most important issue. PMID- 10105418 TI - Wish Upon a Star. Special program brings hope to patients. PMID- 10105419 TI - Travel contract nurses: a creative approach to supplemental staffing. PMID- 10105420 TI - Recruitment solutions help ease health personnel shortages. PMID- 10105421 TI - Caught in the FASB (Financial Accounting Standards Board) crossfire. PMID- 10105422 TI - What's driving your pay? Compensation survey. PMID- 10105423 TI - Improve performance by appraisal. AB - An effective performance appraisal system will not only evaluate employees' ability and motivation, but also opportunity--those elements in the work system which contribute to performance. The authors explain how this approach works. PMID- 10105424 TI - Code of conduct as corporate culture. AB - The purpose of any code of conduct is to define the limits of acceptable behavior of the employees being managed. An effective code results from trade-offs among the key elements of notice, discretion, risk and tone, which reflect the culture of the organization. PMID- 10105425 TI - Fetal protection policies I: Reproductive hazards in the healthcare workplace. PMID- 10105427 TI - A call for radical surgery. PMID- 10105426 TI - Fetal protection policies II: legal analysis. PMID- 10105428 TI - A limited right to die. PMID- 10105429 TI - How to formulate a data analysis strategy. PMID- 10105430 TI - Employer drug testing programs. PMID- 10105431 TI - List of designated primary medical care health manpower shortage areas (HMSAs); list of withdrawals from primary medical care HMSA designation--PHS. Notice. AB - This notice provides two lists. The first is a list of all areas, population groups, or facilities designated as primary medical care health manpower shortage areas (HMSAs) as of December 31, 1989. Second is a list of previously-designated primary medical care HMSAs that have been found to no longer meet the HMSA criteria and are therefore being withdrawn from the HMSA list. HMSAs are designated or withdrawn by the Secretary of Health and Human Services (HHS) under the authority of section 332 of the Public Health Service Act. PMID- 10105432 TI - Unions. AB - Dealing with a union is not complicated. If you are a member of the union, take that membership seriously and exercise your rights and responsibilities. Know what your contract says and live by it. If you disagree with what you are told to do by your supervisor, do it and grieve later. If you are a manager, know your contract and always keep it handy for reference. When you are unsure of the answer, get help from your labour relations advisor. Treat discipline as a process for helping an employee to perform the way you want them to perform. If you were a good manager before you became unionized, you can probably just continue on as you were before and you won't have any serious problems. For both management and non-management employees, remember that both of you have a job to do. Those jobs should be compatible. When you get to know your union, you will learn that they really are. PMID- 10105433 TI - Computers in the medical laboratory: here to stay. PMID- 10105434 TI - Pay equity. PMID- 10105436 TI - A survey of Canadian occupational therapy private practice. AB - This descriptive study provides an overview of the business structure and function of occupational therapy private practitioners in Canada. Aspects covered include basic demographic information, practice issues defining operational aspects of the business, financial issues including initial investment and fee structures, and other miscellaneous business issues. Some implications for the national and provincial professional organizations arose from the results and are presented in the discussion. PMID- 10105435 TI - Construct validation of an acute care occupational therapy cerebral vascular accident assessment tool. AB - This study was the last in a series of six investigations of the construct validity of the St. Marys CVA evaluation, a clinician constructed test composed of items designed to evaluate sensory, perceptual, motor, and self care performance in cerebral vascular accident patients. Data for the present study were obtained from 250 new patients referred for occupational therapy services from 1983 to 1988. Factor analysis with varimax orthogonal rotation was performed on 22 items of the evaluation including perception, recovery stages, measures of grasp and pinch strength and other functional variables. Three factors emerged - Right Function, Recovery Stage, and Left Hand Strength. The results of the study, combined with results of previous research, indicate that this CVA Evaluation has reasonable construct validity as an occupational therapy assessment tool in an acute care setting. PMID- 10105437 TI - Choosing a home infusion provider. AB - As the demand for home IV therapy increases, home care agencies must be confident in the quality and standards of the home infusion company they rely on. Having basic criteria to look for when selecting a potential home infusion company can make the task less overwhelming. PMID- 10105438 TI - Foundation for establishing a home i.v. program. AB - The nature of the health care industry is changing as increasingly greater numbers of patients are treated in the home setting. When setting up its own home IV program, a home care agency must address three areas involving nursing care: licensure requirements, hiring criteria, and patient selection. PMID- 10105439 TI - Home care models for infusion therapy. AB - The anticipated growth in the home infusion therapy market in the coming years will have a significant impact on home health agencies. In deciding how to provide infusion therapy services to their patients, agencies must also consider the best way to arrange for pharmacy services. A number of methods are available, each with distinct advantages and disadvantages. PMID- 10105440 TI - Visiting nurse home pharmacy: a successful home pharmacy venture. AB - One of the most publicized opportunities in home care is the rapidly growing home infusion therapy market. By starting their own home pharmacy, the Visiting Nurse Association of Los Angeles, Inc., entered into the home infusion therapy business. PMID- 10105441 TI - Risk management in high-tech home care services. AB - Advances in technology and medical knowledge, combined with economic pressures, have allowed patients formerly cared for in a hospital setting to have access to comparable services at home. These advances, however, are accompanied by new risks and liabilities for the health care provider. PMID- 10105442 TI - Standards--if we don't set them who will? AB - Anticipating the coverage of home IV therapy, the Arizona Association for Home Care set out to prepare the "Home IV Infusion Standards." In doing so, they had to consider the widespread variation in agency needs and operations. The standards were adopted in 1989, although the committee's work continues. PMID- 10105443 TI - Models of board governance. PMID- 10105444 TI - The rural hospital: Rx for survival. PMID- 10105445 TI - Reviewing and revising P&P manuals. PMID- 10105446 TI - Rural sites benefit from link to urban center. AB - Six-year-old Thomas Carter never knew that his risk of permanent injury was worse because he lived in Morton, in rural West Texas. But when Thomas chose to play with matches and was accidentally burned over 40 percent of his body, statistically the chances were slim that he could be saved from death or permanent injury. PMID- 10105447 TI - Consolidated lab serves multihospital system. AB - By consolidating eight hospitals into five, centralizing and networking laboratory services, and creating a single-structure medical staff, HealthEast multihospital system in St. Paul, Minn., has captured 50 percent of the city's primary care admissions, increased lab volume by 6 percent and saved 15 percent in full-time equivalents. PMID- 10105448 TI - The complementary roles of regional and local secure provision for psychiatric patients. AB - This paper describes the number of admissions, the referring source and the length of stay in the Leeds Special Care Unit over a three-year period July 1984 1987. For two of those years, details are given of admissions to the Regional Secure Unit from the two districts served by the Special Care Unit and from the Yorkshire Region. Finally, the relative contribution of the local Regional Unit to the overall provision of services to disturbed patients is described and contrasted. PMID- 10105449 TI - Can the suicide rate be used as a performance indicator in mental illness? AB - This paper follows from an examination of death rates from suicide as a possible performance indicator in mental illness. The wide variations observed in the proportion of undetermined deaths to suicides in Yorkshire district health authorities, suggest that coroners differ in their legal definition of suicide. To counteract the problem of coroner bias it is suggested that deaths from suicide and self-inflicted injury, and deaths from injury undetermined, whether accidentally or purposely inflicted in the 15 and over age group be combined. The paper outlines the advantages of such a performance indicator and stresses that a 'poor' indicator value merely poses questions which lead to a search for reasons for the value and is not an explanation in itself. PMID- 10105450 TI - What do doctors do at ports? The doctor's role at ports of entry in the United Kingdom. PMID- 10105451 TI - Alcohol and health: do we know enough? AB - This North East of England survey aimed to evaluate the level of knowledge about alcohol of groups, which included doctors, nurses and the police, who have a role to play in promoting health education. A comparison was made with sectors of the general public, known to be at risk from alcohol-related diseases, particularly young people and those in middle management in industry and commerce. The survey found that a proportion of doctors are unaware of the safe limits of alcohol consumption, and more than a third of the nurses were unaware that these limits were lower for women. Although campaigns did not appear to be reaching middle aged, and other at-risk groups 16-18-year-olds were well informed. PMID- 10105452 TI - Maternal attitudes to antenatal care: changes over time. AB - A survey to assess the effect of changes introduced to antenatal care services provided by a Bristol teaching hospital was carried out immediately before and three years after the changes were implemented (1983 and 1986). Some 751 women resident in a neighbouring health district who gave birth during March and April 1983, were compared with 794 of their counterparts who gave birth during March and April 1986. Aspects studied included the number of antenatal hospital appointments (increased), the number of different doctors seen during the visits (unchanged), and time spent waiting to be seen at the hospital (decreased) significantly. More women had alpha-feto protein tests for spina bifida and ultrasound scans, but many less were anxious about having the test. PMID- 10105453 TI - Acute hospital medical care for the elderly: is there a valid performance indicator? AB - Many clinicians have doubts about the validity of using activity data to measure the efficiency of health services, since they take no account of outcome. In elderly patients presenting with acute illness, minimising the time spent in hospital or institutional care is a justifiable aim in itself. If allowance is made for deaths and readmissions, valid performance indicators might be derived from the distribution of the resulting 'Adjusted Length of Stay'. By surveying all medical patients aged 65 and over, admitted as emergencies to the hospitals of one large health district, this study investigated whether such an index (the Adjusted length of Stay) could be of practical value. The influence of the following characteristics on the patient's length of stay were assessed; age, social circumstances, premorbid disability and the nature of the presenting complaint. Patients admitted to general medical and health care of the elderly wards were compared and investigated, to determine whether their outcome was similar after adjusting for differences in these characteristics. Although there was some overlap, marked differences emerged in age distribution, nature of the presenting illness and prevalence of previous disability. These factors were all found to have a substantial effect on the time spent in hospital. The Adjusted Length of Stay Index could be calculated with little change to existing methods of data collection. It provides a fairer basis for overall evaluation of acute medical services for the elderly than current performance indicators. PMID- 10105454 TI - Medical women in the middle: family or career? Periods not working and part-time work amongst women doctors who qualified in 1974 and 1977. AB - This paper is based on work which has been in progress for the past 13 years. Longitudinal data are presented on doctors who graduated from United Kingdom schools in 1974 and 1977 who reported periods of unemployment of at least three months' duration each, or who have worked part-time. The results reveal how their patterns of non-employment and part-time work have changed over the years. As expected, women were more likely to have been unemployed or to have worked part time and these differences were strongly linked to marriage and child-bearing. Finally, some of the implications for the career prospects of women doctors are discussed. PMID- 10105455 TI - Specialisation in general surgery. AB - This survey was designed to determine the current status of specialisation within general surgery amongst newly appointed consultants in the United Kingdom, and to document the extent of specialist training on programmes of higher surgical training. It was carried out in 1988 under the auspices of the Association of Surgeons in Training, to determine whether consultants appointed in recent years had maintained, developed, or abandoned subspecialist practice. A separate survey of senior registrars in general surgery examined their attitudes to the apparent need to offer a special interest at the time of consultant appointment, and afterwards in practice. Although a majority of general surgical trainees and newly appointed consultants support specialist training as a part of higher surgical training programmes, this survey suggests that some programmes are not achieving this ideal. PMID- 10105456 TI - Issues in the evaluation of AIDS education programs. The case of California. AB - Health education is currently considered the most important factor in the prevention of HIV infection. Many AIDS education programs have started within the past several years, but few have undergone rigorous evaluation. This article presents findings from an outcome evaluation of the state of California AIDS Education and Prevention Program, the largest AIDS public education program in the country. The data suggest that the specific educational intervention programs suffered from many design defects which made it impossible to determine accurately the effectiveness of the programs. The programs did not use standard pre/post design, for example, or use standardized testing procedures. Moreover, only cognitive knowledge about AIDS transmission and prevention was stressed in the educational interventions and measures of effectiveness. The Education and Prevention Program must now move to promoting and measuring attitude and behavior change in addition to cognitive knowledge. The article concludes that AIDS education and prevention programs must place greater emphasis on conducting thorough evaluations, if the goals of attitude and behavior change are to be achieved. PMID- 10105457 TI - Process evaluation. Assessing re-invention of community-based interventions. AB - Although complete program evaluation includes assessment of the program implementation process as well as examination of impact and outcome variables, such process evaluation does not always occur. During field implementation programs may be changed, or re-invented, by those adopting the innovation. A case study of the Arthritis Self-Care Project, a rural community-based intervention study, demonstrates the importance of process evaluation in determining the actual independent variable. Instances of re-invention uncovered by the Arthritis Self-Care Project are explored, and suggestions are provided for dealing with the re-invention inevitable in field research. PMID- 10105458 TI - The Client Interaction Scale. A method for assessing community support programs for persons with chronic mental illness. AB - The Client Interaction Scale (CIS) is a brief assessment tool for measuring client integration into the client-to-client interactive milieu in Community Support Programs (CSPs) for persons with chronic mental illness. Using a sample of 95 clients from three different CSPs, the scale shows excellent inter-item reliability. A factor analysis indicates that it measures the clients' level of integration on unique affective and instrumental dimensions. The scale also discriminates among environments known to differ on their interactive qualities. Its application to the evaluation of CSPs and other program environments is discussed. PMID- 10105459 TI - The chef's secret. Phase in healthful items. PMID- 10105460 TI - Time for a team effort. PMID- 10105461 TI - Menu pricing: Part I. PMID- 10105462 TI - Striving for quality: the next chapters. PMID- 10105463 TI - Organ transplants offer limited opportunities. PMID- 10105464 TI - Service first puts hospital in touch. Interview by Donald E.L. Johnson. AB - Good Samaritan Hospital, an 82-bed institution in Cincinnati, Ohio, won the 1989 Award of Excellence of the International Customer Service Association (ICSA), a non-profit organization dedicated to developing customer service. In the following interview with Health Care Strategic Management's publisher, Donald E.L. Johnson, Roger W. Weseli, Good Samaritan's CEO discusses the guest relations and service first programs that have changed his institution and earned it recognition as the first hospital to win the ICSA non-manufacturing group award. PMID- 10105465 TI - Marketing audit reveals holes and opportunities. AB - The marketing department is an essential function of the hospital. But do you know if your marketing efforts are meeting your institution's objectives? An audit of the department is as essential as any other part of the marketing plan. The author tells you "how" and "why" you should seek the services of an auditor to examine your marketing function. PMID- 10105466 TI - Fix the process, not the problem. AB - In 1983, a paper company was on the verge of filing Chapter 11 for a subsidiary, a mill acquired two years earlier that was losing more than $1 million a month. One year later, the paper mill was just about breaking even. Today it is a highly profitable operation. What happened? Everyone at the mill became a problem solver. Both managers and mill workers learned to take the initiative not just for identifying problems but also for developing better ways to fix problems and improve products. The key to the mill's success: a multiyear learning process in which employees developed four progressively more sophisticated problem-solving loops: Fix-as-fail-solving problems after they occur. prevention-keeping problems from occurring. Root causes-discovering what is truly causing a problem. Anticipation-solving problems before they occur and finding innovative solutions to customers' problems. Drawing on the paper mill's experience, the authors illustrate the four loops and suggest ways managers can help this organizational learning process move ahead. Paradoxically, a key to becoming a faster, smoother running operation is to start slow and avoid the temptation to jump to root-cause problem solving before you truly understand what your problems are or have freed up the resources to go after them. PMID- 10105467 TI - The graffiti problem--an update. PMID- 10105468 TI - Back to basics: inventory control. PMID- 10105469 TI - JCAHO update: clinical indicators. PMID- 10105470 TI - The older worker: harvesting the experience. Interview by Barbara Feiner. PMID- 10105471 TI - In-hospital anaerobic susceptibility testing: an aid to formulary decision making. AB - In this study, the susceptibility of 116 recent anaerobic isolates, including the Bacteroides fragilis group (n = 22), Bacteroides spp (n = 65), gram-positive cocci (n = 13), Clostridium spp (n = 10), and Fusobacterium spp (n = 6) were tested by agar dilution against a variety of agents suggested for prophylaxis or therapy. These agents included ampicillin sodium and sulbactam sodium, cefotaxime, cefoxitin, ceftizoxime, clindamycin, imipenem-cilastatin, metronidazole, and ticarcillin and clavulanate potassium. All anaerobes demonstrated 100% susceptibility to imipenem-cilastatin, metronidazole, ampicillin sodium and sulbactam sodium, and ticarcillin and clavulate potassium. Varying degrees of susceptibility (ranging from 60% to 100%) of Bacteroides spp to the selected panel of antibiotics were seen. Fusobacterium spp and the gram positive cocci were inhibited by all agents tested. Clostridium spp was 90% susceptible to cefoxitin, 80% susceptible to clindamycin, and 100% susceptible to the other six agents. Due to the varying activity of these agents, local susceptibility patterns, antimicrobic spectrum, and cost effectiveness must be considered in the choice of agents used for empiric therapy. PMID- 10105472 TI - Creative agreements reduce debt load for hospital and its MOB (medical office building). PMID- 10105473 TI - Evaluating your facility's biomedical program. PMID- 10105474 TI - How to prevent abductions of infants from hospitals. PMID- 10105475 TI - Waste risks occupational, not environmental. PMID- 10105476 TI - Housekeepers: hospitals' goodwill ambassadors. PMID- 10105478 TI - Do hospital policies establish a standard of care? PMID- 10105477 TI - Mid-season chiller checkup ensures efficiency. PMID- 10105479 TI - Court recognizes fear of cancer as a compensable harm in negligence suit. PMID- 10105480 TI - Federal court grapples with Jehovah's Witness issue. PMID- 10105481 TI - Bed rental costs flat or down. Price survey. PMID- 10105482 TI - Hospitals must comply with flame-retardant standards. PMID- 10105483 TI - Hospitals can save by evaluating inventory systems using EOQ and Poisson distribution. PMID- 10105484 TI - Materials managers should be aware of the legal implications of JIT (just-in time) distribution systems. AB - As a part of a just-in-time, single-source procurement plan, a supplier agreed with the hospital that the supplier would hold at its warehouse the bulk of a large order for medical supplies. The hospital signed a contract for the entire amount of the order and, under the terms of the contract, title passed at once to the hospital. Each day the hospital was to advise the supplier by telephone of the quantities consumed. The supplier would deliver to the hospital daily the items needed. In this dialogue, Dr. Decker discusses the legal issues in such an arrangement, including a word of warning. PMID- 10105485 TI - Catchment area management: a new management process for military health care delivery. PMID- 10105486 TI - PRIMUS (Primary Medical Care for the Uniformed Services) clinics: their influence on CHAMPUS utilization in military health care catchment areas. PMID- 10105487 TI - The CHAMPUS reform initiative and fiscal intermediary managed care. AB - Initiatives to maximize the purchasing power of DOD's health care dollars are critical to DOD's ability to function within an increasingly constrained federal budget and to provide a quality medical benefit for military family members. The CHAMPUS Reform Initiative and Fiscal Intermediary Managed Care, two leading edge programs, hold great promise in meeting this challenge. PMID- 10105488 TI - Artificial intelligence in emergency department triage. PMID- 10105489 TI - Teleradiology: managing change through technology innovation. AB - This teleradiology initiative is one of many examples of innovative approaches being pursued and implemented throughout the U.S. Army Health Services Command. In recognition of wide-ranging innovative practices, which include the teleradiology project, the command was recognized in the 1989 Healthcare Forum/3M Organizational Innovator Awards program as the gold medal award winner in the government facilities category. The teleradiology project is representative of the command's commitment: constantly striving toward improvement in the delivery of health services. PMID- 10105490 TI - Market orienting military health care through a voucher system. AB - The proposed voucher system may increase access; encourage the payer, the patient, and the provider to share responsibility for health; focus the patient's attention on the costs of treatment; and still provide the basic benefits needed to promote wellness and treat the sick. Because this system promises to fulfill four of the key principles of a just national health care system proposed by the NLCHC, it offers the further advantage of serving as a demonstration project for one approach to a national health care system. It may be time to undertake such a demonstration. PMID- 10105491 TI - Physician productivity in ambulatory care: for-profit and military primary care health clinics. AB - In summary, by being aware of the characteristics of their physicians and patients, ambulatory care managers might be able to influence their physician productivity. Specifically, managers may wish to hire physicians who are board certified or foreign medical school graduates. Similarly, managers may seek to attract patients with acute, nonsevere, nonurgent conditions. Managers seeking to enhance physician productivity should consider these characteristics regardless of the reimbursement or proprietary nature of their ambulatory care organizations. PMID- 10105492 TI - Fetal protection policies: a method of safeguarding fetuses or a way of limiting women in the workplace? PMID- 10105493 TI - Mother's rights prevail: In re A.C. and the status of forced obstetrical intervention in the District of Columbia. PMID- 10105494 TI - If it isn't written down.... PMID- 10105495 TI - The key to choosing your quality coordinator. PMID- 10105496 TI - Implementing strategies for treating teen-agers. PMID- 10105497 TI - Emergency vehicle management: tuning in to the '90s. PMID- 10105498 TI - Dispatch life support: establishing standards that work. AB - The consistency of care brought about by the AHA standards created order from the chaos that previously existed in the areas of BLS, CPR, and ACLS. But significant difficulties arise when they are applied directly to pre-arrival instructions given by EMSs. PMID- 10105499 TI - Facing the obligation to provide AIDS training. PMID- 10105500 TI - Reflections on renovation in central service. PMID- 10105501 TI - Designing docks: 14 tips for productivity. PMID- 10105502 TI - Inventory management from a central service perspective. 1990 IAHCSMM (International Association of Healthcare Central Service Material Management) Past President's award. PMID- 10105503 TI - Improving express carrier cost and service performance. A case study. PMID- 10105504 TI - Retrofitting decontamination equipment. PMID- 10105505 TI - Sterilization containers. ECRI. PMID- 10105506 TI - Aerobiology and hospital design. PMID- 10105507 TI - Overindulgence and cost containment. PMID- 10105508 TI - Your management style: is it proactive or reactive? PMID- 10105509 TI - Separation of clean and dirty: design considerations. PMID- 10105510 TI - Intimate strangers: the role of the hospital chaplain in situations of sudden traumatic loss. AB - Discusses the role of the hospital chaplain in situations of sudden traumatic loss making extensive use of the metaphore of the Stranger. Explicates biblical, theological, historical, and psychological perspectives on the metaphore as it appears within the Judeo-Christian tradition and critically relates this to much current crisis literature. Notes how hospital traumas demonstrate to the chaplain how God's presence may be witnessed in the strange and in ways not always placid or traditional. PMID- 10105511 TI - Serving the needs of persons with chronic mental illness: a neglected ministry. AB - Argues that the present disarray in services for persons with chronic mental illness opens the door for the Church to provide important and needed ministries. Describes various misconceptions and prejudices and the services church people can provide to meet the challenge. PMID- 10105512 TI - Hospice legal services: spiritual and counseling dimensions. AB - Explicates the various components of hospice legal services and draws attention to their possible spiritual dimensions. Notes particularly pastoral care implications of the many legal matters associated with the hospice patient. PMID- 10105513 TI - Compact CPE: a full unit of clinical pastoral education in 27 days. AB - Details a four-week Basic Clinical Pastoral Education Unit. Gives a rationale for the abbreviated unit. Notes positive factors as well as limitations of such an educational experience and urges other CPE supervisors to try the compact approach. Critical responses follow the article. PMID- 10105514 TI - Adult protective services for abused aged in Texas: program and research implications. PMID- 10105515 TI - Training caregivers: the development of an elder abuse prevention program. AB - As far as the authors know, their project is the only systematic effort to apply a psychosocial model to the prevention of elder abuse. They plan to disseminate the results of their project in the near future. Assuming positive results, they hope to encourage other practitioners and administrators to make such training available to caregivers. PMID- 10105516 TI - Health care policy and the Reagan administration: the case of family planning. PMID- 10105517 TI - Project BRAVO (Bronx AIDS Volunteer Organization): an inner city AIDS volunteer program. PMID- 10105518 TI - Educating the volunteer: issues in long-term care facilities. PMID- 10105519 TI - Should you tell the patient when you mess up? PMID- 10105520 TI - When an HMO takes the rap for a non-member doctor. PMID- 10105521 TI - What makes a computer run properly? A tough sales contract. PMID- 10105522 TI - How long are your patients languishing in the ER? PMID- 10105523 TI - Is this the ultimate health-care fraud? PMID- 10105524 TI - Quality: 'Miles to go before we sleep'. PMID- 10105525 TI - From quality care to quick care: can we reverse the trend? PMID- 10105526 TI - Leadership development in health care: encouragement in the midst of change. PMID- 10105527 TI - The trustee's role in resolving shared concerns of the future. PMID- 10105528 TI - Symptoms of organizational burnout. PMID- 10105529 TI - Beverly posts solid earnings. PMID- 10105530 TI - Sullivan says he won't support Canadian-style national health system. PMID- 10105531 TI - Senate votes to denounce Durenberger. PMID- 10105532 TI - 'Overpriced billing services may break anti-kickback laws'. PMID- 10105533 TI - New tricks of the trade show. AB - The business of trade shows isn't what it used to be. Vendors are more selective about participating, hospitals don't have money to send as many representatives, and competing state, regional and national associations spread the market thin. Some shows are disappearing; others are surviving by targeting specific audiences, catering to vendors and hatching non-aggression pacts with would-be competitors. PMID- 10105534 TI - Developing effective culture vital to hospital strategy. PMID- 10105535 TI - New Okla. benefits plan OK. PMID- 10105536 TI - Agencies raise eyebrows at selling receivables. PMID- 10105537 TI - Baxter, Comdisco offer new services. PMID- 10105538 TI - Expecting excellence is key to receivable success in small and rural hospitals. AB - Although small and rural hospitals may have trouble hiring experienced billing and collection personnel, they can succeed in keeping down receivable levels and receivable days by adopting two principles for the business office: expect excellence and inspect for excellence. These principles include setting goals for business office staff as well as listening to and implementing their ideas for more effective operations. PMID- 10105539 TI - Pre-admission is key to successful collections. PMID- 10105540 TI - Upgrading a radiology information system. AB - Expanding or replacing an RIS can be an overwhelming responsibility for the radiology manager; Ms. Rowe's article helps to define the task. According to the author, one of the primary decisions is whether to remain with the present vendor or to evaluate a new system, and the advantages and disadvantages of both alternatives are presented. PMID- 10105541 TI - Structuring freestanding diagnostic imaging centers for profitability. AB - Many hospitals have or are contemplating establishing freestanding diagnostic imaging centers with members of their medical staff. Some earlier joint ventures between hospitals and their physicians have not met expectations or financial projections. This article describes guidelines for evaluating the operating performance of freestanding imaging centers and is based on the author's assessment of several freestanding centers; it is not intended to depict the results of any one study or operational review. The areas addressed during an operations review should include: management and organizational structure, technologist and support staffing, equipment utilization, non-salary costs, and outside contracts. PMID- 10105542 TI - Justifying capital equipment in the 1990s. AB - Because of the plethora of problems caused by health care reimbursement to imaging departments, new equipment purchases are often not looked upon favorably by hospital administrators. To successfully justify technology acquisition in this cost containment environment, Mr. Schwartz advocates a clearer focus on market niche and a concerted effort to successfully meet the needs of referring physicians, third party payors and patients. PMID- 10105543 TI - Liability issues for radiology managers. AB - This article on legal issues is structured in two parts--the first details the fictitious case of a routine pyelogram in which the patient had an allergic reaction to the contrast media. In the second section, Mr. Hollingsworth gives up to-date information on liability issues and precautionary measures for managers. PMID- 10105544 TI - Trends in radiology: Part II. AB - The major force driving radiology today is the need to contain costs and find new sources of revenue. How is the field of radiology reacting to these forces? The remaining data from the 1989 AHRA Trends Survey reported in this article includes results on competition, marketing, new programs, operations, staffing, and equipment purchase and maintenance. Comparisons from the 1985 and the 1987 Trends Surveys are also included. PMID- 10105545 TI - NIMBY (not-in-my-back-yard)--the lingering stigma of mental illness. PMID- 10105546 TI - Call-for-Health hotline a huge success. PMID- 10105547 TI - Delano's Business Health Services Program. PMID- 10105548 TI - The purchase wizards. PMID- 10105549 TI - Legislative pace slows as elections approach. PMID- 10105550 TI - Changing the rules on dying. PMID- 10105551 TI - Targeting treatment. AB - As the gathering crisis in health care--its quality, its distribution, and above all its cost--nears the top of the national agenda, hospitals are developing more sharply focused physical responses to a changing spectrum of social and economic forces. PMID- 10105552 TI - Building a caring community. Freeport Hospital Health Care Village. PMID- 10105554 TI - Making special care special. Lake Pavilion/Family Birth Center, Baptist Hospital of Miami. PMID- 10105553 TI - Acute care stacked on public uses. Marin General Hospital addition. PMID- 10105555 TI - Purchasing principles to reduce acquisition and inventory costs. AB - Knowing how, what, when, and where to negotiate are all part of the system that finally determines how much you pay for products and services. Knowing the primary and secondary objectives of materiel management is important in establishing purchasing and inventory policies and procedures. Negotiating all of the terms and conditions up front, before you finalize any deal, is important to minimize your acquisition, operating, disposal, and inventory costs and to maximize profit. Most purchasers and negotiators only bargain for part of the costs; then they have to bargain to try to control the rest of the costs or they are at the mercy of others. Prepare to negotiate for all the factors that will influence the final operating cost from the beginning to the end of the negotiation process. PMID- 10105556 TI - The buyer-supplier interface under just-in-time relationships. AB - In any contractural relationship, legally and ethically, all parties much benefit. Minor concessions to one party can be significant gains for the other. To establish the win/win environment, it is sometimes necessary to make reasonable concessions that preserve the overall objective of the JIT concept. It is good business sense to make those concessions that are inexpensive and guarantee greater control. The concessions discussed strengthen the buyer-seller relationship and aid in reaching the objectives of JIT. PMID- 10105558 TI - Quality: reality or myth. PMID- 10105557 TI - Just-in-time: maximizing its success potential. AB - The effective implementation and use of JIT manufacturing practices depends largely on the education, training, and commitment of all levels of management to a fundamental quality-first policy. Management must transfer and demonstrate that commitment to every level and extension of the manufacturing endeavor. As a company establishes and reaches toward that goal, the move to JIT manufacturing practices becomes rational and justifiable. Failing to establish and commit to a quality directive greatly diminishes the potential benefits of JIT. If all levels of manufacturing participate in the JIT planning, implementing, and maintenance procedure, the realization of positive change and improvement drives the process. Total participation makes the task of JIT implementation not only possible, but practical. Enhanced mutual respect for all concerned is a likely consequence, advancing the productive environment. PMID- 10105559 TI - Developing employee ownership of the quality improvement process. AB - Developing true employee ownership of quality improvement is a process in itself. It begins with sending clear signals to employees that management fully supports the process and is committed to making it successful. It is reinforced when managers provide for the progressive education of all employees to ensure that job requirements are known and are achievable. Employee ownership of quality improvement continues to develop with ongoing management action that makes it clear that doing things right the first time is a part of the organizational culture. Encouraging the use of prevention--including quality improvement responsibilities in job descriptions and performance appraisals; the use of problem identification systems; and employee involvement in corrective action teams, quality improvement teams, and the management of the process--sends the message to employees that employee ownership of the process is a way of life in the organization. When success of the quality improvement effort is related to and understood as the key to the organization's success, as well as that of individual employees, and when each employee personally accepts the importance of his or her own role in making quality happen, the organization is well on its way to achieving its quality improvement objectives. PMID- 10105560 TI - Use of the inventory turnover measurement. AB - Without visiting a company or investigating how it conducts its business and what efforts it uses to control its inventories, we have a technique to measure its effectiveness. This technique involves calculating the inventory turnover ratio (turns) and comparing it to turns achieved by similar companies. Once we have determined that there are apparent opportunities for inventory reduction, the next step is to analyze what can be done to effect that reduction. But that's the topic of another lesson. PMID- 10105561 TI - Inventory management in the just-in-time age. AB - JIT will change our conventional thinking concerning the management of inventories and streamline our methods for inventory control. Proper selection and implementation of these methods will yield substantial benefits by improving customer service, shortening delivery lead times, and significantly reducing inventory investment. It does not, however, eliminate the need for sound inventory planning. PMID- 10105562 TI - Equipment replacement policy: a survey. AB - Over the past ten years there has been a considerable increase in application of theoretically correct measurement methods in determining the economic life of equipment. Approximately 89% of the firms surveyed have equipment replacement policies. The discounted rate of return method is the most widely used in determining the service life of equipment; the MAPI formula is not widely used. Difficulties in applying a replacement policy can be classified into three groups: operational, organizational, and economic. The problems mentioned most often are operational. In organizational difficulties there is usually a lack of coordination between staff and line managers. Economic problems are generally the limited funds available for equipment replacement. Formal educational programs are lacking for the development of equipment replacement managers. For the firms having replacement policies, individuals with engineering degrees are preferred over those in other disciplines for the management of the equipment replacement policy. PMID- 10105563 TI - Just-in-time purchasing: a case study. AB - This article presents a case study on how Hutchinson Technology Incorporated (HTI) organized and implemented just-in-time (JIT) purchasing. PMID- 10105564 TI - Business ethics: the materiel/manufacturing perspective. AB - The discussion of purchasing practices and product integrity, which have ethical implications for materiel/manufacturing management, serves to illustrate how routine decisions can have larger implications for the firm as a whole. Management needs to take a proactive role in confronting ethical issues by (1) demonstrating a corporate commitment to sound ethics in business practices, (2) providing written policies where appropriate to provide a basis for sound ethical conducts, (3) educating various functional areas to understand their responsibility in seeming unrelated ethical problems, (4) delegating authority in ethical issues where such issues are considered in decision making, and (5) fostering interfunctional communication as a means in establishing corporatewide responsibility. The basic philosophical principles of JIT serve as a blueprint for recognizing and managing ethical responsibility. The unexpected by-products of a JIT implementation may be vendor/customer good will and an excellent reputation for the firm. PMID- 10105565 TI - A requiem for the EOQ (economic order quantity): an editorial. PMID- 10105566 TI - Developing a community's consciousness. PMID- 10105568 TI - Community connections. PMID- 10105567 TI - Providing for the poor: urban hospitals feel the strain. PMID- 10105569 TI - Court upholds law's immunities in peer review cases. PMID- 10105570 TI - Visionary mergers and acquisitions. PMID- 10105571 TI - To each his own. PMID- 10105573 TI - A call to revolution. AB - Americans will not succeed in containing healthcare costs until they make some radical changes in the way they think about life, death, and the pursuit of good health. This is the contention of Daniel Callahan, who, in his new book, What Kind of Life: The Limits of Medical Progress, calls for a revolution of sorts-a change in the nation's psychological and political foundations. In Callahan's brave new world, limits rather than aspirations, risks rather than benefits, and pitfalls rather than opportunities would be emphasized. Research projects with costly and likely limited social payoffs would be rare; Americans, accustomed to demanding the most advanced technology that medicine has to offer, would have to accept the inevitability of disease and death. Callahan presents an outline for establishing healthcare priorities and rationing services. He frames those priorities within a context of limits on extending longevity and pursuing individual cures. The outline is pyramidal. Fewer people generally would receive health services as they ascend the pyramid's six levels, and the cost per person would rise dramatically. In this milieu, children would have "some priority" over adults, particularly the elderly. PMID- 10105572 TI - Ethics committees' future role. PMID- 10105574 TI - Be prepared. Hospitals should develop methods to ensure emergency equipment is workable and available. PMID- 10105575 TI - A tax strategy for healthcare workers. Section 403(b) plans are an alternative to weakened IRAs. AB - After the Tax Reform Act of 1986 reduced the tax-deduction benefits of investing in IRAs, many healthcare employees went looking for alternative tax-shelter investments. Several options are available. One alternative for taxpayers employed by tax-exempt organizations is Section 403(b) tax-deferred annuities (TDAs). Although the Tax Reform Act left Section 403(b) TDAs largely intact, it established a comprehensive set of nondiscrimination rules for certain statutory fringe-benefit plans--including Section 403(b) plans. The new rules are designed to restrict situations that favor participation by highly paid employees to the exclusion of other employees. Perhaps one of the harshest adjustments the 1986 law mandated is the imposition of an additional 10 percent income tax on withdrawals an investor makes from Section 403(b) plans before reaching the age of 59 years and 6 months. This excise tax had already applied to early withdrawals from an IRA, but the new law extends the penalty tax to cover all qualified plans, including TDAs. PMID- 10105576 TI - Keeping health promotion in the pink. Documentation can show how programs contribute to hospital goals. AB - Health promotion encompasses a wide range of services, including health information, health education, wellness, and employee health programs--important efforts, but hardly life-or-death matters. So with increased pressure to put programs to an institutional "worth" test, few health promotion programs make the grade, not because they fail, but because their managers do not know how to document and demonstrate their contributions to hospital goals. The tools that can be used to track program impact range from simple hand-written record keeping on file cards to more complicated and computer-supported systems of data gathering and analysis. It is a mistake to assume that only computer-based systems can yield meaningful information. In the documentation process it may be necessary to start small, but it is necessary to start. Sound management decisions depend on practical evidence that a program is helping a hospital's operations. When one hospital implemented an employee assistance program, program managers set out to document how the program saved the hospital money, improved the work environment, and improved quality of care. At another hospital, the manager of the inpatient cardiac rehabilitation program enlisted the assistance of the medical records department to document to the hospital that patients not in the program had longer lengths of stay than program participants. PMID- 10105577 TI - A senior care program depends on networking. PMID- 10105578 TI - Medical staff QA participation. PMID- 10105579 TI - Quality services: a first step toward integrated QA. PMID- 10105580 TI - Evaluating a nursing QA program. PMID- 10105581 TI - From contingency to compliance: Santa Teresita's QA turnaround. PMID- 10105582 TI - A model drug usage evaluation program. AB - Following the ten step process discussed above should bring a program into compliance with the guidelines of JCAHO. However, each facility is unique and should design its own DUE program. Since quality assurance is a dynamic process, each facility must keep abreast of frequent changes. With sufficient time and resources devoted to DUE activities, DUE programs can produce beneficial findings and impact positively on the quality and appropriateness of patient care. PMID- 10105583 TI - HQA (Healthcare Quality Assurance) Educational Foundation update. PMID- 10105585 TI - Is your hospital in danger of closing? PMID- 10105584 TI - Credentialing in managed care: the new frontier. PMID- 10105586 TI - How fast will private insurers adopt RBRVS? PMID- 10105587 TI - How going bare is working in Florida. PMID- 10105588 TI - Can doctors keep their net worth moving ahead? PMID- 10105589 TI - Incorporating safety concerns into design and construction. AB - The nursing facility industry has provided a high level of fire safety according to statistics from the NFPA. To keep and improve this record, fire safety in the design and construction of nursing facilities must be a priority. Since the ground work of fire safety is laid in the design phase and finalized in the construction phase, such a priority will help lower initial and operating costs, improve the function of the facility, and provide a fire safe environment for residents and staff. PMID- 10105590 TI - Fine-tuning construction and design. PMID- 10105591 TI - Complying with hazardous waste management laws. PMID- 10105592 TI - Employee program promotes positive staff/family relations. PMID- 10105593 TI - Department management study yields unexpected results. PMID- 10105594 TI - Nutrition screening initiative focuses on malnourished elderly. PMID- 10105595 TI - Developing a "we care" image with the right furniture. PMID- 10105596 TI - The Protective Services for Adults Program in New York City. PMID- 10105597 TI - Issues in providing home care services to the protective services population. PMID- 10105598 TI - Training aides and family caregivers. PMID- 10105599 TI - State family leave laws and the legal questions they raise. AB - Some lawmakers proclaim that their vote for family leave laws is a vote for the American family. This author surveys these popular laws state by state and discovers disturbing legal questions in this new front of costs and obligations that is advancing on employers. PMID- 10105600 TI - Affirmative action after the Supreme Court's 1988-1989 term: what employers need to know. AB - Three recent Supreme Court decisions have aroused fears about the future of a key weapon against employment discrimination: the affirmative action plan. The author reviews these cases and pronounces affirmative action alive and well--but warns that thoughtful planning is required to ward off challenges by nonminority groups claiming adverse impact. PMID- 10105602 TI - How much to discount? PMID- 10105603 TI - How real is the nursing shortage? PMID- 10105601 TI - Indoor air quality: what managers can do. AB - A significant number of workers suffer a variety of physical symptoms and illnesses associated with poor indoor air quality. These authors furnish employers with a guide for providing clean air in the workplace--an objective the achievement of which will reduce employee absenteeism and medical insurance costs, while increasing productivity and morale. PMID- 10105604 TI - The ordinary-extraordinary distinction reconsidered: a moral context for the proper calculus of benefits and burdens. AB - The traditional distinction between ordinary, i.e., obligatory means to preserve life and extraordinary, non-obligatory means is an especially useful tool for HECs in today's secular pluralist health care system, because it gives factors that can override the prima facie good of preserving the patient's life. I first indicate the need for such a tool. I then demonstrate the present misunderstanding of the distinction and give its proper understanding. Finally, I show the applicability of the distinction for HEC deliberations about three important types of cases: the conscious, irreversibly but not terminally ill patient who requests cessation of curative treatment; the provision of artificial nutrition and hydration to permanently vegetative patients; and the allotment of intensive care and other scarce medical resources. PMID- 10105605 TI - The moral right to a surrogate decision: the Cruzan case. PMID- 10105606 TI - Ethics of caring and the institutional ethics committee. AB - Institutional ethics committees (IECs) in health care facilities now create moral policy, provide moral education, and consult with physicians and other health care workers. After sketching reasons for the development of IECs, this paper first examines the predominant moral standards it is often assumed IECs are now using, these standards being neo-Kantian principles of justice and utilitarian principles of the greatest good. Then, it is argued that a feminine ethics of care, as posited by Carol Gilligan and Nel Noddings, is an unacknowledged basis for IEC discussions and decisions. Further, it is suggested that feminine ethics of care can and should provide underlying theoretical tools and standards for IECs. PMID- 10105607 TI - The Ethics Advisory Group at Boston's Beth Israel Hospital. PMID- 10105608 TI - Hartford Hospital Ethics Committee: membership policy. PMID- 10105609 TI - Summary of California law regarding life support issues. PMID- 10105610 TI - Ethics consultation process and time for decisions. (St. Agnes Hospital--Fond du Lac, Wisconsin). PMID- 10105611 TI - North central states learn the value of cooperation. PMID- 10105612 TI - Mid-year report. PMID- 10105613 TI - The development of air medical services in Czechoslovakia. AB - The Czechoslovakian system of centralized dispatch of all emergency medical services prevents competition between ground ambulances and air medical services. Although this program is less than two years old, remarkable progress has pushed Czechoslovakia to the forefront of modern-day air medical transport. However, the future of Czechoslovakian air medical transport will require the acquisition of better-performing EMS helicopters and accessibility to medical equipment using Western technology. As with all current United States helicopter EMS systems, Czechoslovakia will face many of the financial considerations required in funding this extensive and elaborate project. PMID- 10105614 TI - International air medical transport. Part I: Methods and logistics. AB - International air medical transport requires reliable equipment, skilled personnel and precise planning. A report is presented of an experience with 29 international transports. Details concerning equipment, personnel and logistics are presented. Results and problem areas are discussed. This early experience demonstrates the capability for the repatriation of critically ill patients, and the evacuation of patients who require access to a level of care which may be unavailable outside the United States. PMID- 10105615 TI - Ohio AAMS (Association of Air Medical Services): another chapter in aviation history. PMID- 10105616 TI - Hospital transport systems general background. PMID- 10105617 TI - FEANI (European Federation of National Engineering Associations) and its register of professional engineers. PMID- 10105618 TI - Staff and patient communications--trends and technologies. PMID- 10105619 TI - Hospital lift refurbishment. PMID- 10105620 TI - A village of healing. PMID- 10105621 TI - Governors' Committee on AIDS to examine concerns of the surgical community. PMID- 10105623 TI - National registry collects data on expert witnesses. PMID- 10105622 TI - Surgical practice in hospitals: HIV and the surgical team. PMID- 10105624 TI - Medical professional liability and the delivery of obstetrical care. PMID- 10105625 TI - National practitioner data bank; user fee--HRSA. PMID- 10105626 TI - National Practitioner Data Bank; announcement of opening date--PHS. Notice of opening. AB - The Health Resources and Services Administration, Public Health Service, Department of Health and Human Services (DHSS), is announcing the opening date of the National Practitioner Data Bank (Data Bank), as authorized by the Health Care Quality Improvement Act of 1986 (the Act), title IV of Public Law 99-660 as amended (42 U.S.C. 11101 et seq.). PMID- 10105627 TI - Bye-bye, Canada; hi, Germany. PMID- 10105628 TI - HCFA to untwist the reg-writing pipeline. PMID- 10105629 TI - Housing hybrid competes for nursing home clients. PMID- 10105630 TI - Medication: greater use, closer scrutiny. PMID- 10105631 TI - Enter the computer age. ARA automates to benefit nurses. PMID- 10105632 TI - Teamwork squelches infection transmission. Interdepartmental systems produce best results. PMID- 10105633 TI - Untying the elderly. PMID- 10105634 TI - A diocese as owner. AB - For 76 years, the Sisters of St. Joseph of Toronto provided dedicated and skillful service in the Comox Valley. The Sisters witnessed to the three essential elements of nursing: compassionate care, efficient promotion of health and faithful commitment to the health care profession. The Sisters have left a wonderful heritage which the diocese is committed to maintain. PMID- 10105635 TI - Empower the people. AB - In July 1988, President Gerry Hiebert of Misericordia Hospital, Edmonton, created a Task Force to review the hospital's values, goals and structures to determine if the organization was providing adequate support to staff and to recommend directions for change. The Task Force's report emphasizes the real need for empowerment which is a key goal for every mission effectiveness program. PMID- 10105636 TI - A definition of human health. AB - One of the biggest problems facing health care professionals in Canada today is that they don't know what a healthy human looks like. One of the biggest problems facing Christian health care professionals in Canada today is that they do know what a healthy human looks like--but they are reluctant to tell anybody! PMID- 10105637 TI - Pastoral care and bereavement. AB - Ministering to the bereaved is a demanding task. Pastoral caregivers have to learn to forget about themselves, to enter into the center of others' concerns. They have to be willing to deny themselves, stop concentrating on their problems to create the space where God can work. Their faith and insight into life must form the core of their pastoral work. PMID- 10105638 TI - Software. It's worthless without the vendor's commitment to performance. AB - When a home health agency purchases software, it also buys a five-year relationship with the vendor for maintenance support and services. It is paramount for the home care agency to examine key attributes of the vendor, including its financial stability, market presence, profile of other clients, installation schedule, customer support services, and willingness to enhance products. PMID- 10105639 TI - Computers. The rocky road. AB - This article deals with one administrator's problems in automating a home health care agency. It points out many of the pitfalls to be avoided while also trying to be positive and show guidance. The steps to designing and implementing a computer system are explained using personal examples. PMID- 10105640 TI - A partnership in success. AB - Computers are an integral part of the administrative, financial, and clinical facets of long-term health care. Many home care agencies have automated their entire operations; others are considering acquisitions to automate one or more functions within their agency. Why automate? What functions can be automated? How can the process of vendor selection, implementation, and continuing support be assured a high success ratio? AIMS, Inc., a ten-year veteran in supplying software and support services to long-term health care facilities, and Group Health Cooperative of Puget Sound, an AIMS client, have joined together to discuss these questions. PMID- 10105641 TI - The clinical director's role in selecting a computer system. AB - The clinical director's people skills and understanding of agency staff, combined with a priority of optimum patient care, makes her participation in the selection of an agency's computer system invaluable. PMID- 10105642 TI - The good old days are now! AB - This article discusses the advantages of automating an agency and the criteria an administrator should consider before purchasing a computer system. Specific attention is given to nursing documentation software, as this area of home health care is of utmost importance. PMID- 10105643 TI - Automating a clinical management system. AB - Automating the clinical documentation of a home health care agency will prove crucial as the industry continues to grow and becomes increasingly complex. Kimberly Quality Care, a large, multi-office home care company, made a major commitment to the automation of its clinical management documents. PMID- 10105644 TI - Computer-based clinical charting and patient case management. AB - During the past several years, computer systems have become an essential office tool in the day-to-day operation of many businesses, from large corporations to small companies. Like other businesses, home health care agencies are using computer systems to automate various aspects of their operation. Many companies soon discover that their computer system is second in importance only to their telephones in terms of accomplishing daily tasks. PMID- 10105645 TI - Automating the medical record: changes and challenges. AB - As the home health care industry continues its rapid growth, agencies are being stressed to meet new challenges and respond to changes, while dealing with an ever-increasing paperwork burden. An automated medical record system would increase nursing productivity and make medical information standardized and retrievable, while allowing agencies to focus on the future. PMID- 10105646 TI - Saving time with a computer. AB - When the Health Care Financing Administration implemented the 485-486-487 series, home health agency staff and administrators were caught in a tremendous paperwork overflow. To combat the problem, one agency developed a tool that has resulted in the staff being able to spend less time filling out forms and moretime providing care. PMID- 10105647 TI - So you need more than a personal computer? AB - As home care agencies become more automated they may find they have outgrown their personal computers. Multi-user computer systems offer lower costs, branch office automation, hardware independence, and have room for future expansion. PMID- 10105648 TI - Workload measurement in long term care pharmacy. AB - This paper describes the implementation of the Canadian Hospital Pharmacy Workload Measurement System (CHPWMS) by the pharmacy department of a 475-bed long term care facility. The CHPWMS description of a computerized individual patient prescription service provided the basis for the implementation. Following an initial appraisal of similarities between chronic care pharmacy services and the services outlined by CHPWMS, a program was developed and evaluated with the assistance of a pharmacist consultant. During a four-month trial all measurable work was recorded in a process that separated reportable (CHPWMS-defined) activities from other work activities. Eighty percent of the department's workload was accountable as reportable units using standard times. Nonreportable workload was documented using actual times, and adapted standard times. Dispensing accounted for the largest proportion of workload (79%). Manufacturing was the most frequently performed nonreportable activity. Pharmacist workload supported the desired level of 50% nondispensing activities. The productivity index of available worked hours was 70%. The consistent pattern of the recording suggested staff commitment. The program has been used to justify and monitor staffing levels. PMID- 10105649 TI - Effectiveness of an antibiotic cost containment measure. AB - University Hospital, University of British Columbia (UBC) Site, a 600-bed teaching hospital in Vancouver, British Columbia, adopted several cost containment measures on August 2, 1988 in an attempt to limit the rise in antibiotic expenditures. One cost containment measure involved extending the dosing intervals of cefazolin, clindamycin and metronidazole by a pharmacy-based automatic dosing interval interchange. Cefazolin and clindamycin orders were changed to an every eight-hour dosing schedule, and metronidazole orders to an every 12-hour schedule. Data were retrospectively collected and tabulated from August 1987 to February 1988 (pre-implementation or PRE period) and August 1988 to February 1989 (post-implementation or POST period). During the POST period, the mean doses per course were significantly less for metronidazole. Estimated cost savings from the measure was $7,300 for the seven-month POST period. Annualized, the expected savings would be $12,600, which is 4.4% of 1988/1989 total antibiotic expenditures. This cost containment strategy achieved its goal of effective cost savings for University Hospital, UBC Site. Although a small reduction in total drug budget was seen, this study suggests that savings can be achieved through this cost containment measure. PMID- 10105650 TI - Improving pharmacy input in patient care through reorganization of clinical functions. PMID- 10105651 TI - American Express emphasizes service, training and R&D. Interview by Carolyn Dunbar. AB - Larry Ferguson, president of the Health Systems Group of American Express Information Services Company, tells Computers in Healthcare what has happened in the year since the company acquired enough "critical mass" through purchasing McDonnell Douglas Health Systems Company to become a major player in the healthcare computing industry. PMID- 10105652 TI - The battle of Gettysburg. AB - When a small, struggling, rural healthcare facility mustered the courage to purchase a state-of-the-art hospital information system, the results were dramatic. Today, receivables have risen significantly, and overall operating efficiency has measurably improved. PMID- 10105653 TI - Total quality management: healthcare's complex and timely choice. PMID- 10105654 TI - Counterpoint. There are additional lessons to be learned. PMID- 10105655 TI - One tier or two? Comprehensive change in our healthcare system. PMID- 10105656 TI - Managed care personalities. Physician adjustment to the staff model HMO. The role of personality & development assessment. AB - Managed health care in HMOs represents an innovation for which many physicians have not had preparation to assist adjustment. Successful adjustment in the HMO draws from organizational and individual variables; the former to promote enculteration, the latter to foster a "good fit." Individual factors include the physician's personality and stage of life. This article delineates roles of individual and organizational factors and develops the former with the use of psychological methods to assist the transitioning physician during the orientation period. PMID- 10105657 TI - Executive focus. Gundersen Clinic, Ltd. PMID- 10105658 TI - Executive focus. Cleveland Clinic Foundation. PMID- 10105659 TI - The United States Medical Licensing Examination (USMLE): background and structure of the examination. PMID- 10105660 TI - Back to basics: purchasing. PMID- 10105661 TI - Change management. PMID- 10105662 TI - Increasing cafeteria revenues. PMID- 10105663 TI - An exploration of the applicability of situational segmentation in the health care market: development of a situational taxonomy. AB - Competition in the health care market has intensified in recent years. Health care providers are increasingly adopting innovative marketing techniques to secure their positions in the marketplace. This paper examines an innovative marketing technique, situational segmentation, and assesses its applicability to the health care market. Situational segmentation has proven useful in many consumer goods markets but has received little attention in the context of health care marketing. A two-stage research process is used to develop a taxonomy of situational factors pertinent to health care choice. In stage one, focus group interviews are used to gather information which is instrumental to questionnaire development. In stage two, the responses of 151 subjects to a 51 item questionnaire are factor analyzed. The results demonstrate that situational segmentation is a viable strategy in the health care market. PMID- 10105664 TI - Small business leaders' viewpoints on health care insurance: a marketing and social perspective. AB - A mail survey, which generated 270 responses from Virginia small business CEOs, reveals that the vast majority (95%) offer their full-time employees the opportunity to enroll in a health care insurance plan through their employer. The typical premium for employee-only coverage is from $75-99, and in 52% of the firms, the employer pays the entire cost. Employer-sponsored coverage of part time employees is quite different, however, as the vast majority of the CEOs indicate a low percentage of these workers can enroll in a company health care plan, due to cost concerns. The CEOs feel hospitalization is the most important type of health care coverage to their employees as 93% rate it as being "very important" and 7% as "important." This rating is followed closely by the CEOs' perceived priority of coverage for lab and X-ray tests and for catastrophic costs, as 97% and 89%, respectively, feel these areas are "very important" or "important." In addition, over 80% of the CEOs rate three additional areas as having high importance, including prescription drugs, maternity care, and doctors visits and physicals. Overall, a generally high degree of satisfaction exists among the CEOs regarding their firm's health care insurance plan. However, while 90% feel "very satisfied" or "satisfied" regarding the coverage, and 82% feel similarly about the service, over 60% are "dissatisfied" or "very dissatisfied" regarding the cost. Regarding covering the health care costs of those who are uninsured, the CEOs feel an approximately equal role should be borne by four groups, namely the state and federal governments, employers of uninsured workers, and hospitals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10105665 TI - Segmenting blood donors by their perceptions and awareness about blood donation. AB - A battery of 26 items was used to assess blood donors' perceptions on donor eligibility, blood testing, and notification procedures. An analysis of these items from a mail survey of 392 California blood donors resulted in the identification of four clusters of differing perceptions regarding four aspects of the blood collection process. Three of the four segments identified exhibited moderate to strong degrees of skepticism regarding blood donation. Implications for the continued encouragement and maintenance of donor pools are discussed. PMID- 10105666 TI - The nature of physician's services: marketing implications. AB - A specific system for classifying services is applied to physicians' services in an attempt to better understand those services. Other services organizations are identified that are similar to these services along each of the dimensions suggested by the classification system. In addition, marketing insights and implications are offered for marketing physicians' services. PMID- 10105667 TI - The impact of health care provider market served on health care channel relationships. AB - A conceptual framework is provided in which manufacturer-wholesaler relationships are addressed in the context of the health care provider segment served by the wholesaler. A study of the medical supply channel demonstrates how the particular market served by the wholesaler shapes the manufacturer-wholesaler relationship along the behavioral dimensions of manifest conflict, coercion, satisfaction and openness of communications. The health care provider segment served was found to have a significant impact on these dimensions. The results of this research suggest that channel member strategies, policies and operating procedures must account for variations in input (supply) and output (market) environments. PMID- 10105668 TI - ICD-9-CM. International Classification of Diseases, 9th revision, Clinical Modification. 3d edition, volumes 1, 2 and 3. Official authorized addendum effective October 1, 1990--HCFA. PMID- 10105669 TI - Report to Congress on health personnel. PMID- 10105670 TI - 1990 membership update. PMID- 10105671 TI - Executive message--American Medical Record Association or component state medical record associations. PMID- 10105672 TI - The effect of performance standards on productivity among medical record department employees. AB - This is the first of two articles discussing the author's implementation of management techniques to measure and evaluate employee performance and job satisfaction in the medical record department she directed. PMID- 10105673 TI - Our professional definition sets the boundaries of our practice. What are they today? PMID- 10105674 TI - 1990 buyer's guide listing. PMID- 10105675 TI - Results from the 1989 study of computerized health information systems. PMID- 10105676 TI - Specialty societies step up guideline involvement. PMID- 10105677 TI - A case history: developing guidelines for cardiac pacemakers. PMID- 10105678 TI - Evaluating effectiveness in Washington. PMID- 10105679 TI - One hybrid approach toward long-term care. PMID- 10105680 TI - Ending separate and unequal health care. PMID- 10105681 TI - Is a rift in the medical community imminent? PMID- 10105682 TI - Practice parameters: the legal implications. PMID- 10105683 TI - If you don't see what you want--please ask. PMID- 10105684 TI - Only the fittest survive. PMID- 10105685 TI - Please speak your mind. PMID- 10105686 TI - Mind that child. PMID- 10105688 TI - Quiz something simple. PMID- 10105687 TI - Paradox on the market. PMID- 10105689 TI - When second class care is a death sentence. PMID- 10105690 TI - Great expectations. PMID- 10105691 TI - Building on a voice. PMID- 10105692 TI - Keeping an open mind. PMID- 10105693 TI - Audition for an audit. PMID- 10105695 TI - Hurdles on the path to medical audit. PMID- 10105694 TI - Looking to the heavens for waiting list aid. PMID- 10105696 TI - Tapping the market. PMID- 10105697 TI - New lamps for old. PMID- 10105698 TI - Standard bearers. PMID- 10105699 TI - Take it easy, friend. PMID- 10105700 TI - Service for the customer. PMID- 10105701 TI - Healthcare data briefing. Variations in immunisation. PMID- 10105702 TI - Laying down the law. PMID- 10105703 TI - When east meets west. PMID- 10105704 TI - Keep on moving. PMID- 10105705 TI - On a learning curve. PMID- 10105706 TI - Challenges of a P & T Committee in a community teaching hospital. AB - Lutheran General Hospital, a 650-bed, tertiary care and trauma center in Park Ridge, Illinois, has had a P & T Committee in place for 11 years. In this exclusive Hospital Formulary interview, David Cooke, MD, and Jackie Kessler, MS, the respective chairman and secretary of that committee, discuss the challenges their committee faces. Somewhat unique to a community hospital, this committee manages a relatively restricted formulary. They attribute their success to dedicated P & T Committee members and a committed pharmacy. Among the more difficult issues still to be resolved at Lutheran General are relationships between pharmaceutical companies and P & T members and the possible institution of a conflict-of-interest disclosure policy, as well as the never-ending battle of evaluating drug use in their institution. PMID- 10105707 TI - Distributive and clinical activity measurement using spreadsheet software. AB - Documentation of distributive and clinical activities is an important factor in maintaining and expanding pharmacy services. In order to illustrate the impact of pharmacists' efforts on risk management and the reduction of drug costs, the pharmacy must effectively monitor workload. This report describes a method to identify and estimate time required for both distributive and clinical functions. Tabulation of the distributive work units is automated through the hospital billing system. Clinical monitors are dependent on manual documentation by decentralized clinical pharmacists. The clinical coordinator and the pharmacy director review the documented clinical monitors to insure compliance and standardization. Productivity and workload calculations are performed automatically via the spreadsheet software once all the distributive and clinical units are entered. Identifying clinical functions and measuring the associated workload has aided in justifying new positions. Future considerations include calculating the impact of clinical services on revenues, expenses, and staffing. PMID- 10105708 TI - A system for monitoring and dispensing epoetin. AB - This article describes one hospital's system of providing epoetin therapy for patients with renal failure undergoing dialysis. Nurses complete a drug dosing worksheet which alerts pharmacists to the need for both epoetin and iron dextran doses. The patient's weight and hematocrit are included on the form as are initial dose calculations made by the nurse. Pharmacists use this information for patient monitoring and double checking dose calculations. Then individually packaged unit dose injectables are prepared by pharmacy for use by nurses. A drug use evaluation for epoetin assures that appropriate use criteria are fulfilled when epoetin is used. PMID- 10105709 TI - Error 441--naming drug products is serious business. PMID- 10105710 TI - Hospital diversification for survival. PMID- 10105711 TI - New forms to enhance medication ordering and processing. PMID- 10105712 TI - Why other nations' Rx won't work. PMID- 10105713 TI - Healthcare's international marketplace: how do you say 'quality' in...? PMID- 10105714 TI - Working abroad: dipping your toe in international waters. PMID- 10105715 TI - International perspectives on healthcare. PMID- 10105716 TI - Visiting healthcare executives: more than just guests. AB - It wasn't a tailgate party but a desire for a sense of real accomplishment that recently returned some healthcare executives to university campuses--for as little as one week or as long as six weeks per term. They made these encore appearances as visiting executives in health administration programs throughout the United States and Canada. Their goal: to restore the balance between theory and practice that once existed as the standard approach in the academic preparation of health administration students. PMID- 10105717 TI - Consultants' corner. International opportunities for U.S. healthcare providers. Interview by Vaughan Smith. PMID- 10105718 TI - Trends in health services management. AB - This paper describes how the NHS in the United Kingdom needs to continue to adapt and evolve in response to six major pressures, and how the corresponding challenge facing managers in the NHS is how to cope, adapt and tackle those pressures. The foundation was laid in 1984 with the introduction of general management from central government down to the sub-units of the nine District Health Authorities in Wales. This signalled a change in the service from one merely administered to one which was actively managed. The NHS manager must now concentrate on a number of fronts, notably planning, performance objectives, policy management, resource allocation and positive management of change. The Corporate Management Programme for Wales published in 1988 reinforces fundamental management principles and describes an agenda of management initiatives and objectives for the NHS in Wales over the next five years. The Programme has initiated the process of Corporate Planning. The future trend in health services management is interwoven with the programme of reform of the NHS introduced by the Government's White Paper 'Working for Patients' published in 1989. Initiatives introduced in Wales which will assist this programme of reform are described. PMID- 10105719 TI - Center consolidates its four power plants to improve efficiency. PMID- 10105720 TI - How to performance-test your medical gas system. PMID- 10105721 TI - Legal options for hospitals' asbestos lawsuits. PMID- 10105722 TI - Expectations, goals praise key to staff motivation. PMID- 10105723 TI - Load management cuts energy, equipment costs. PMID- 10105724 TI - LTC facilities to spend more on new construction. PMID- 10105725 TI - Liability risk of imprudent correspondence. PMID- 10105726 TI - The duty to disclose: upon whom does it fall? PMID- 10105727 TI - No liability for death of participant in fun run. PMID- 10105728 TI - How people power fuels a high-flying carrier. AB - America West Airlines, in operation for only seven years, has grown to become the country's eleventh largest carrier. The key to the organization's growth has been its ability to forge an unusually strong bond between management and employees. PMID- 10105729 TI - European and U.S. managers: breaking down the wall. AB - Here, the author describes some key differences between European and U.S. managers and provides a strategy for successful collaboration. These differences could prove crucial for U.S. companies seeking to take advantage of the newly emerging opportunities in Europe. PMID- 10105730 TI - Today's worker in tomorrow's workplace. PMID- 10105731 TI - Incentives: the missing link in strategic performance. PMID- 10105732 TI - Contracts reduce Baxter InterLink system by 6%. PMID- 10105733 TI - Linen & towel prices steady. PMID- 10105734 TI - FOB (free-on-board) terms can save hospital time and money. PMID- 10105735 TI - HMM price watch. Purchasing managers' index keeps on climbing, reaching 51.1 in June from 50.7 in May. PMID- 10105736 TI - Turning goods over to distributor: record keeping and possible product disparagement. AB - A distributor of medical supplies and devices is now representing a new manufacturer. He wants the buying hospital to also switch to this new manufacturer. The distributor has offered to replace existing stocks of items with those from the new manufacturer. The distributor would take the items from the hospital's existing stocks and use them as demos or otherwise dispose of them. The hospital materials manager is agreeable but wonders about legal complications. In this dialogue, Dr. Decker discusses the legal issues involved in this proposition of the distributor. PMID- 10105737 TI - The NHS at a time of radical change. AB - In his Presidential Address Michael Schofield discussed some of the issues facing the NHS--not the implementation of "Working for Patients", but such things as providing a customer service, and making the best use of staff. PMID- 10105738 TI - Community health councils. Their role after the NHS White Paper. AB - Christine Hogg and Fedelma Winkler review the major and varied changes being introduced in the management of community health councils by different regional health authorities in the wake of the NHS Bill. This piecemeal approach may lead to more variations in the standards of service that individual CHCs offer the public and they argue that there needs to be a coherent policy about the role of CHCs and evaluation and monitoring of their functions. PMID- 10105739 TI - One path to a comprehensive district psychiatric service. AB - Brighton, which never had its own large psychiatric hospital, now has a comprehensive community psychiatric service. Sarah Hood and Tony Whitehead describe the development of the service and argue that the closure of large hospitals need not and should not result in the neglect or exploitation of former patients. PMID- 10105740 TI - Resource management and management cultural change. PMID- 10105741 TI - Some consequences of market forces in US hospitals: lessons for the new look NHS. AB - "We write", say Ann Greer and Scott Greer, "with the thought that an idea should not travel unencumbered by the experience of its implementation". They survey the arguments for a market in health care, describe the impact of competitive health policies in the USA and conclude that none of the expected benefits of the market have materialised. PMID- 10105742 TI - A morning at the hospital. PMID- 10105743 TI - Training and developing health services administrators in Zimbabwe. AB - An article by Stephen Thornton in "Hospital and Health Services Review" in 1984 ended with a challenge to the unwary: "Could we as members of a highly developed profession in the United Kingdom assist our colleagues in Zimbabwe to acquire the necessary skills to become a thriving profession in a health care system so clearly modelled on our own?" Allan McNaught found himself in a situation where he was able to take up the challenge. This article outlines his experience in Zimbabwe, over 1987-1989, developing a local training programme for health services administrators. His work was undertaken as part of the World Bank funded "Family Health Project". His formal contract of employment was held by the British Overseas Development Administration, which contributed to most of the Project's "Management Strengthening Component". PMID- 10105744 TI - Joint planning. The day of reckoning draws high. AB - Joint planning: the very words seem to undermine the validity of the concept, so synonymous have they become with the bidding cycle for joint finance. Taken in a wider sense to encompass the development of all statutory and voluntary services to a priority client group, they conjure up the image of a most arduous and unmanageable task. Dylan Tomlinson and Andrew Nocon discuss the prospects for joint planning after "Caring for People". PMID- 10105745 TI - The Audit Commission and the NHS. PMID- 10105746 TI - Understanding the central-local relationship in health care: a new approach. AB - One of the basic assumptions of governmental health planning policy is that the government can effectively take final responsibility for the development of the health care system. Failure to reach policy goals is explained in terms of inadequate planning technology and instruments to control implementation. In this article an alternative explanation is offered, based on the theory of strategic organizational behavior. According to this theory, the government must be seen as but one actor in a complex interorganizational network. From this, a different perspective on effective health planning policy is developed. Policies will fail if they are not based on a valid analysis of the policy space of health care institutions and the interdependencies between government and health care organizations. This article starts with an outline of the nature of the central local relationship as seen from the perspective of strategic organizational behavior theory. Next, this theory is used to frame two cases in which Dutch health care institutions successfully pursued their own strategies that ran counter to the existing health planning policies. The article ends with a discussion of the implications of the theory of strategic organizational behavior for the development of effective central health care policies. This development starts with a thorough analysis of the policy space and interdependencies of all relevant actors in the health system, the government included. Following, policy makers can set the governmental goals and then have to start negotiations with health care institutions about mutual adaptation of their strategies and the governmental goals. The result is a negotiated health care order. PMID- 10105747 TI - 'Tipping the balance towards primary health care': managing change at the local level. AB - This article addresses the problem of managing change at the local level, by focusing on the experience of the research and action project 'Tipping the Balance Towards Primary Health Care'. The experience of this project and case studies in other countries is abstracted. It includes some characteristics of the actors and forces under which local services operate, pointing to some opportunities and constraints in managing change and development, as well as organizational relationships in the field of primary health care. In this article it is argued that the ongoing structural reform is a necessary prerequisite, but it is not the unique key, for solving local health services problems. If the mission of the health sector is to satisfy the real and the perceived needs of the population, skilled professionals, appropriate technology, and enough financial resources must be allocated to the local level. PMID- 10105748 TI - Changing relations between hospitals and primary health care: new challenges for hospital management. AB - Hospitals in the Netherlands are now operating in a rapidly changing environment. Most changes directly result from government's policy to achieve effective cost containment in health care. Some of them basically affect the existence and functioning of hospitals. These changing environmental conditions inspire hospitals to undertake innovative activities to protect or even strengthen their position. This will be illustrated below by a case in which a small acute hospital attempted to establish a close relationship with primary health care in order to protect its position. Our focus will be upon this innovative initiative and upon some management problems that must then be resolved. PMID- 10105749 TI - The importance of organizational culture on development activities in a primary health care organization. AB - The aim of this article is to examine, by means of an empirical study, the: a) relationship between formal and cultural structures; b) similarities and differences between professional subcultures (medical, nursing and managerial); and, c) the effects of the social assumptions of the work teams on development activities in one large primary health care organization. The results show that different professional groups have created quite different sets of social values, norms and assumptions, which have significant consequences, both for patients care and organizational performance. PMID- 10105750 TI - 'Managing the cracks': management development for health care interfaces. AB - The realm of public policy (including health policy) is, in many ways, more complex than that of decision-making within the corporate organisations found in the private sector. The range of stakeholders is generally wider; many of the ways of influencing action are more subtle and indirect; and, arrangements for representation, accountability and consultation are correspondingly more elaborate. A future of this complexity in healthcare systems is the presence of numerous organisational and managerial interfaces. The paper considers three key sectors and the interfaces between them: primary health care, hospital care, and community care. Proposals for reforming the British National Health Service and community care services are destined to multiply the interfaces to be managed since they are predicated upon a split between purchasing services and providing them. The intention is to encourage a plurality of providers who will compete for contracts. The paper argues that the challenge posed by interface management is probably greater than any other in healthcare management. The requisite skills for successful interface management are reviewed. The paper concludes that these network skills are in short supply and that those responsible for management development in the NHS must tackle this lacuna as a matter of some urgency. PMID- 10105751 TI - Management development initiatives for healthcare managers in the Irish context: a tale of pilgrim's progress. AB - The purpose of this paper is to identify some of the organizational relationships that exist in the Irish healthcare system and to describe a development programme for senior health service managers developed, and being delivered, in the context of these relationships. PMID- 10105752 TI - The booming EMS marketplace: inquire within. PMID- 10105753 TI - Women in EMS: moving up or moving out? PMID- 10105754 TI - Climbing the fire service EMS ladder. PMID- 10105756 TI - Employee ownership: the company we keep. PMID- 10105755 TI - Changing the complexion of EMS. PMID- 10105758 TI - 10 tips for building your EMS resume. PMID- 10105757 TI - Employee relocation: will they haul or U-Haul? PMID- 10105759 TI - OSHA mandates infection control for EMS and fire service. PMID- 10105760 TI - Screening costs in a hepatitis B vaccine program. AB - Current statistics from the Centers for Disease Control (CDC) reveal that approximately 39 percent of all fire/rescue personnel have been vaccinated against hepatitis B. Iti well-documented that hepatitis B viral infection presents the greatest occupational health risk to emergency personnel, yet program development and care-provider participation have been slow to evolve. PMID- 10105761 TI - Everybody still owns it: the peer-based chart audit, revisited. PMID- 10105762 TI - Destination policy lands in court. PMID- 10105763 TI - Volunteer advocates: differing role expectations of long-term care facility administrators and volunteers. AB - Volunteers and volunteer advocates are becoming important members of the long term care team. A much needed improvement in volunteer advocacy programs is the development of mutual consensus between volunteers and facility administrators. PMID- 10105764 TI - Physical design, social climate, and staff turnover in skilled nursing facilities. PMID- 10105765 TI - Creative arts over 60: creativity, imagination, accomplishment can continue throughout a lifetime. PMID- 10105766 TI - Job reduction: downsizing or rightsizing? AB - The author describes institutional staff restructuring, considering traditional downsizing and a more strategically planned restructuring, "rightsizing", which seeks to achieve operational and financial objectives with considerably less trauma. PMID- 10105767 TI - Downsizing of hospitals: avoiding liability. PMID- 10105768 TI - Material management's role in disaster planning. AB - This article discusses lessons learned about disaster preparedness when the authors' institution, the Medical University of South Carolina in Charleston, was buffeted by Hurricane Hugo. PMID- 10105770 TI - Pulse oximeters. ECRI. PMID- 10105771 TI - Eliminating resistance to change: the magic formula. PMID- 10105769 TI - Using a product profile for product evaluation and standardization. AB - This article discusses a form developed by the materiel management staff at Richmond General Hospital in Vancouver, British Columbia--the Product Profile--to aid their product standardization and evaluation efforts. PMID- 10105772 TI - "We are unique". PMID- 10105773 TI - Universal precautions: regaining the initiative. PMID- 10105774 TI - Guest relations...a lesson for all of us. PMID- 10105775 TI - Market segmentation for multiple option healthcare delivery systems--an application of cluster analysis. AB - Healthcare providers of multiple option plans may be confronted with special market segmentation problems. This study demonstrates how cluster analysis may be used for discovering distinct patterns of preference for multiple option plans. The availability of metric, as opposed to categorical or ordinal, data provides the ability to use sophisticated analysis techniques which may be superior to frequency distributions and cross-tabulations in revealing preference patterns. PMID- 10105776 TI - Is quality of health care a meaningful guide? AB - Health care consumers are beginning to learn that "what you don't know can hurt you." Though consumers consistently rank quality of care as an important attribute, "quality of care" does not appear to be particularly useful in decision making. The quality of health care is difficult to measure, communicate, and interpret. Yet if consumers are to make efficient choices including both value and cost in their decisions, quality information must be available to them. This paper outlines a scheme to conceptualize quality of care and suggests some ways to operationalize measures of quality that could provide empirically based indices of quality of care to facilitate health care consumer decision-making. PMID- 10105777 TI - Something's not working--but it's not marketing. AB - This paper addresses both the increased use of marketing by hospitals and frustrations which have more recently been felt with such programs. A series of seven factors are presented as suggested explanations of current dissatisfaction with the effectiveness of marketing efforts in the hospital of the late 1980s. PMID- 10105778 TI - The challenge of marketing home health care in the nineties. AB - This paper explores the recent growth and development of home health care services. Rising medical costs and technological and social changes have made home care a competitive alternative to hospitalization and other forms of institutionalization. Providers of home health care need to familiarize themselves with the demographic trends affecting their customer base. A strategic marketing orientation is suggested for future growth and profitability. PMID- 10105779 TI - Cognitive age: demographic and psychographic dimensions. AB - This empirical study, based on a random self-report mail survey, explored perceptions of age among mature Americans aged 60+. Respondents were members of a systematic probability sample located in the Mid Atlantic region. Two inner-age dimensions were considered: the first, Cognitive Age, is a measure of self perceived age and assesses a person's "actual" age-role self-concept; the second, entitled Youthfulness, is a new measure of youth scored by what percentage a respondent's Age-of-Birth is greater than his or her Cognitive Age (Chronological Age/Cognitive Age). The study first explored the relationships between the age variables, and then, through Multivariate Analyses of Variance (MANOVAs), the associations between four trait-sets (demographics, health, Quality of Life, and psychographic traits) and the two inner-age dimensions. PMID- 10105780 TI - Comparative analysis: subsegments of the elderly to younger adults. AB - The purpose of this paper is to shed some further insight into the elderly market. Based on the results reported in recent literature in marketing and healthcare, we broke down the elderly market into three subsegments: 55-64; 65 74; and over 74. Using a series of general and political lifestyle statements, a comparative analysis was carried out to determine if there were in fact differences between younger consumers and each of the subsegments of the elderly, as well as between each of the subsegments of the elderly. The principal technique used to carry out the analysis was MANOVA. The results indicate that there are significant differences between each of the age groups analyzed, and that more careful attention must be paid to gaining a better understanding of the elderly market. PMID- 10105781 TI - The decision process for selecting a retirement community. PMID- 10105782 TI - Change in the healthcare delivery system. PMID- 10105783 TI - Here come the "Gray Berets" to the rescue. PMID- 10105784 TI - Can you make your income-division formula work better? PMID- 10105785 TI - How to keep capitated plans from wrecking your formula. PMID- 10105786 TI - Slicing the income pie in multispecialty groups. PMID- 10105787 TI - Proposed flexible spending regulation: what direction should hospitals take? AB - A proposed regulation requires employees to make their annual flexible spending arrangement election before the beginning of the plan year. How will this affect the hospital? Will there be a potential for losses if, for example, an employee becomes seriously ill before he made full contribution to his plan? Hospitals need to be prepared with alternative benefit plans. PMID- 10105788 TI - Your pension: can you take it with you? PMID- 10105789 TI - Closed hospitals' legacies shine on. AB - Hospitals across the country, when realization sets in that they must eventually close, are setting up foundations that continue to serve the health needs of their communities in creative ways and leave a legacy for the closed facilities. PMID- 10105791 TI - A day in the life of a hospital--May 23, 1990. PMID- 10105790 TI - Doing the right thing. PMID- 10105792 TI - New benefits work for employees and hospitals. PMID- 10105793 TI - The prevention of organizational burnout. PMID- 10105794 TI - Employee benefits: a critical component to an effective recruitment strategy. PMID- 10105795 TI - Administrative law judge dismisses Ukiah complaint. PMID- 10105796 TI - House, Senate approve emergency AIDS funding. PMID- 10105797 TI - Congress revitalizes scholarship program. PMID- 10105798 TI - Telemedicine goes the distance. AB - Telemedicine is advancing rapidly, and with it the diagnostic and treatment possibilities. X-ray and MRI images, tissue specimens and medical record data are being transmitted between distant cities even now. For rural hospitals, this means having around-the-clock access to radiology expertise--without having to compensate a full-time radiologist. And for off-site clinics, it means fewer trips out to have an image interpreted. PMID- 10105799 TI - Justice Dept. conducting first probe of an existing not-for-profit system. PMID- 10105800 TI - Employee-involvement plan needs executive involvement. PMID- 10105801 TI - Baptist uses expansion, alliances to bypass Mayo Jacksonville beachhead. AB - What's a community hospital to do when the world-renowned Mayo Clinic comes to town? In Jacksonville, Fla., Baptist Medical Center is protecting its turf by strengthening its pediatrics partnerships with other healthcare organizations and by expanding its referral base. PMID- 10105802 TI - Study tallies demands for hospitals' data. PMID- 10105803 TI - Pa. system finds benefit in bankruptcy. AB - Two financially troubled hospitals in Philadelphia plan to defy the skeptics by pooling their assets to form a new not-for-profit corporation. PMID- 10105804 TI - Report fuels criticism of state boards. PMID- 10105805 TI - AMI, Maxicare talking settlement. PMID- 10105806 TI - New Orleans plans regional med center. PMID- 10105807 TI - HHS' Sullivan seeks tighter cost controls, less cost shifting in any reform package. PMID- 10105808 TI - Charter Medical to divest 12 properties. PMID- 10105809 TI - Debating the benefits of regulation. AB - Franklin Square Hospital Center, Baltimore, spent nearly $1 million in 1989 on certificate-of-need and incinerator requirements alone, said Charles Mross, above, the hospital's president. Modern Healthcare asked Franklin Square and two other hospitals to estimate last year's regulatory costs (p. 40), and a broader study of regulatory costs was commissioned for this report on government regulation's merits and its impact on hospital overhead. PMID- 10105810 TI - Study suggests two cardiac procedures increase risk of death after heart attack. PMID- 10105811 TI - Counting the cost of complying with regulations. PMID- 10105812 TI - HMOs, hospitals link up for the long term. AB - More managed-care companies are attempting to make their prepaid health plans more predictable and stable by signing long-term hospital contracts. The hospitals, in turn, are establishing a reliable source of revenue. PMID- 10105814 TI - Business group asks hospitals to set prices. PMID- 10105813 TI - Contract management firms gain ground. PMID- 10105815 TI - Nursing unions target all professionals. AB - State nursing groups, not content to wait out the legal tangles over new federal bargaining units, are seeking to organize all professionals instead of just nurses. The strategy seems to be picking up steam, said hospital labor expert G. Roger King, above. PMID- 10105816 TI - Rules aim to standardize recording of donations. PMID- 10105817 TI - 2 hospital ships, medical personnel head for Mideast. PMID- 10105818 TI - Report recounts rural AIDS woes. PMID- 10105819 TI - Dissident shareholders oust CompCare directors, replace chief executive. PMID- 10105820 TI - SEC conducting probe of Charter's 1988 buyout. PMID- 10105821 TI - Board takes on geographic status debate. PMID- 10105822 TI - Graduate programs get back to basics. AB - Healthcare graduate programs are tilting back toward practical instruction in management after two decades of emphasizing theory and academic research. Still, many hospital executives worry that the administration candidates coming out of school aren't equipped with the interpersonal skills needed to deal with physicians and employees. PMID- 10105823 TI - Osteopathic Hospital Assn. to vote on merger with AHA. PMID- 10105824 TI - Mobilizing of reserves could affect hospitals. PMID- 10105825 TI - Republic strategy calls for physicians to foot the bill for equipment they want. AB - Hospital-based physicians usually are in a position to make big profits while the host facility springs for the overhead costs of equipment. Republic Health Corp. is altering the status quo by making the physicians pay for their own equipment in return for long-term security. PMID- 10105826 TI - Liability at issue as firms target drug costs. PMID- 10105827 TI - Some hospitals seek to build up nursing ranks by financing housing projects. AB - Healthcare workers can't afford to live in many of the metropolitan and resort areas that need them. Hospitals are building their own subsidized housing to bring rental costs in line with worker salaries and develop a hiring edge over the competition. PMID- 10105828 TI - AHA's Bachofer, Woodrum submit resignations. PMID- 10105829 TI - JCAHO dispels some myths about its nursing standards. PMID- 10105830 TI - Endoscopes. Tough problems with their cleaning and reprocessing. PMID- 10105831 TI - An examination of three draping questions. AB - Rising costs and a new emphasis on outcomes are stimulating closer scrutiny of traditional OR practices such as draping. What is truly necessary? What is proven? What makes sense? This is the second of a two-part article on draping. In the July issue, we examined draping for clean-contaminated procedures, total body draping, and adherent drapes. In this issue, we tackle three more draping questions. PMID- 10105832 TI - Identifying indicators for aspects of care. AB - This is the fourth article on applying the ten-step model for monitoring and evaluation developed by the Joint Commission on Accreditation of Healthcare Organizations. PMID- 10105833 TI - When collecting on unpaid balances, phone calls can produce the right answers. AB - Healthcare organizations trying to resolve aged patient accounts often find more success in personal contact by telephone. The approach allows payers to respond directly and allows collection employees to work on problem solving. PMID- 10105834 TI - Applying a quality philosophy to days receivable. PMID- 10105835 TI - Customized menus keep 400 companies at top of market. PMID- 10105836 TI - Light motifs. More healthful foods accent 400 companies' menus and marketing efforts. PMID- 10105837 TI - Right-to-die damage actions: developments in the law. AB - This note traces the history of the "right-to-die" damage action. These are cases in which health care providers have been sued for providing unwanted life sustaining treatment. After briefly describing the development of basic right-to die law, the principle theories behind damage claims and the cases themselves are discussed, and the primary stumbling blocks are analyzed. PMID- 10105838 TI - AIDS knowledge and attitudes for October-December 1989. Provisional data from the National Health Interview Survey. PMID- 10105839 TI - Linking administrator & physician. Collaboration in capital equipment decisions. PMID- 10105840 TI - Networking for computer brain power. PMID- 10105841 TI - How women have changed EMS--and vice versa. PMID- 10105842 TI - Field documentation myths. PMID- 10105843 TI - Does your documentation reflect your care? PMID- 10105844 TI - Litigation: one system's experience. PMID- 10105845 TI - EMS leaders speak out on OSHA's proposed rule. PMID- 10105846 TI - Put the seal on safety. PMID- 10105847 TI - Gallup defines new opinion groups for market analysts. PMID- 10105848 TI - Pain centers need dollars, resources from hospitals. PMID- 10105849 TI - Rehabilitation: forecast for continued growth, ambulatory shift in the 1990s. PMID- 10105850 TI - Market scan: ten leading trends for rehabilitation in the 1990s. PMID- 10105851 TI - Hospital CEO's viewpoint for future of health care marketing. AB - In summary, the CEOs have a wide variety of views on what role the marketer will play and what needs the marketer will fill for the CEO. It is important for the marketer to clarify the expected roles as they interview for jobs. Once in the position, it is important to keep communications open with the CEO to know the marketer's expected role. PMID- 10105852 TI - Assessing business leaders' perspectives on health care issues. AB - The survey results reported here shed light on how CEOs perceive various health care issues in general, and factors and proposed solutions regarding uncompensated or indigent care, in specific. The problem of indigent care has reached such dimensions that various legislative remedies are being sought, such as the Indigent Health Care Trust Fund and mandated health insurance coverage. Although the uninsured are not being denied health care, the cost of such care is rising far above that which can continue to be absorbed by hospitals and other providers. Thus, something must be done, legislatively or otherwise. In sponsoring this survey the VHA sought to gather information that would guide and facilitate their response to the problem of financing the cost of indigent health care. The CEO responses: (1) indicate the need for an education program; (2) provide support for legislative proposals; and, (3) highlight areas which need further investigation. Business leaders need to be informed as to the true causes of increasingly high health care costs, with the increasing role of indigent health care cost clearly illustrated, as well as other key areas of concern such as technology, unnecessary medical procedures, and malpractice suits. Hospital associations could develop comparative fact sheets addressing perceptions, misconceptions, and the actual causes of increased health care costs. This informational advertising campaign could eventually be broadened to encompass some of the issues which need further consideration, such as hospital inefficiency and who should pay for indigent health care. The respondent's support for and responsiveness to tax incentives to encourage employers to provide more health care coverage, and CEO support for the Indigent Health Care Trust Fund, should be used to shape legislative proposals. The CEOs' perception of the importance of health care (being third in priority out of eight key current issues) should aid the VHA in their efforts to gain the needed legislative attention to the problems of health care cost. The recognition by the CEOs' of the need for hospital profitability and their desire for limited regulation should also provide support for VHA legislative proposals. Several areas which need further investigation and consideration include: hospital inefficiency, who should pay for indigent care, part-time employees without insurance, cost and availability of health insurance coverage, and equal access to quality care. The widely held belief that hospitals are inefficient needs to be addressed.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10105853 TI - The marketing implications of migration on hospital and physician supply and demand in the United States. AB - Physician and hospital service supply and demand issues lie at the forefront of healthcare policy today. Among the factors affecting state and local supply and demand is the often times overlooked impact that migration has had on interarea population size and composition. This paper discusses the role of migration in the restructuring of population in the context of health care needs. Significant in- or out-migration is shown to be strongly related to a discrepancy between physician and hospital supply and demand. The marketing implications of these imbalances are discussed. PMID- 10105854 TI - Survey of physician attitudes towards available business services. AB - Hospitals recognize that attracting and retaining physicians to their medical staff is the single most important means of increasing utilization. Further, the competitive environment makes it imperative for most hospitals to seriously compete for physicians' allegiance. Hospitals often have marketable business expertise and also share many of the same business problems as the physicians who are on their staff. That means that hospitals might be able to diversify their product line and strengthen their physician ties at the same time. This twofold benefit is very attractive. Business software and hardware vendors are also aware of this potential. They have come forward with packages in the data processing area to help physician and hospital computers share information. Sharing information via computer can potentially increase billing accuracy and efficiency, among other things, for the participating physicians. There have been reports of success in this area with hints that this service is attracting physicians and retaining them as medical staff members. That is exciting to hospitals looking for another way to build and maintain their medical staff.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10105855 TI - Effects of changes in micro- and macro-environmental factors on the supply of hospitals services. AB - The failures, marketing difficulties and financial hardships hospitals have experienced raises a question as to whether they have been responsive to the changes in the micro and macro-environmental factors. To determine how responsive hospitals have been to these changes, we investigate the impact of a number of selected factors on the supply of hospital services during 1972 through 1978. The findings indicate that despite the fact that the economy went through recessionary periods, and the demographic distribution exhibited both a shift and a change in the aging and birth rates of the nation, the changes in hospitals' responsiveness have been less than satisfactory. It appears that hospitals readily respond to the changes in the micro-environment than to the changes in macro-environment. Their response to the changes in the macro-environment. Their response to the changes in the macro-environment may be characterized as an effort to create a higher level of production whose goal is to create a still higher level of needs and wants. PMID- 10105856 TI - Marketing health services to elderly couples: aspects of marital role specialization in the decision process. AB - This paper examines the nature of mature market spousal role specialization for health services. The data show that spouses indicate similar role specialization and decision making when sampled independently. This information together with responses to qualitative variables help to develop suggestions for the marketing of health services to this segment. The data come from 57 couples over the age of 50. PMID- 10105857 TI - Health care services and pricing. AB - In a recent survey it was found that the use of optimum pricing would yield not only greater income for the health care provider, but also lower prices for consumers, resulting in greater participation on part of consumers. Consumer demand, however, could sometimes also pose some ethical problems for the health care provider. PMID- 10105859 TI - High-tech & close touch: medical librarianship for the new millennium. PMID- 10105858 TI - Health care innovations from the internal marketing perspective. AB - This paper presents an opportunity to apply the marketing concept internally to the diffusion and implementation of innovative services which can help organizations to achieve an advantageous external market position. An internal marketing communications model is discussed in this paper to identify factors and relationships influencing the internal diffusion and implementation of innovative services. Three case studies are presented to demonstrate the applicability of the model to a specific innovation in the health care industry. The notion of marketing innovative services from the inside out also is critical for other service firms. Further operational models are needed to present opportunities for marketing of innovative services. PMID- 10105860 TI - Throwing out the baby with the bathwater: reform in the system for compensating obstetric accidents. PMID- 10105861 TI - Performance appraisals: more than just a feedback tool. Legal documentation for employment decisions. AB - Unjust discharge suits filed on behalf of disgruntled employees are becoming frequent occurrences. The employment-at-will doctrine, which has protected an employer's right to discharge employees for any reason or no reason at all, is continually being challenged. This stream of litigation has caused organizations to take a new look at how employment decisions are made. The result has been a renewed interest in the performance appraisal process--a key method in providing feedback and documenting worker performance. Aside from providing organizations with legal documentation, effective performance appraisals provide organizations with several benefits. First, feedback fosters positive actions and eliminates inappropriate behaviors. Second, the supervisor-employee relationship is improved. Third, effective performance appraisals increase motivation, morale, and job satisfaction--ultimately resulting in increased productivity. PMID- 10105862 TI - Chemiluminescence: a new end-point for clinical assays. AB - A key decision for clinical laboratory managers in the 1990s will be the type of detection system to adopt for immunoassays and DNA hybridization assays. It seems certain that assays based on radioactivity will not be desirable because of concerns about safety, stability of reagents, and environmental issues. Chemiluminescence is a prominent contender as the detection system of choice for both immunoassays and DNA hybridization tests. This article examines the features of various chemiluminescent reactions available and discusses the current range of commercial chemiluminescent test kits and reagents. PMID- 10105863 TI - How to keep your best people for the '90s. AB - Getting good people to join us merely sets the stage for achievement. the real payoff depends on how we deal with them and how long they stay. From the CEO's perspective, the most important requirements for the '90s are: Know what you mean by performance in all jobs, in all functions, and at all levels. Hire accountable people. Know what it takes to hire and keep the best people and do it. Invest what it takes to fill at least 70% of your promotions with people from the inside; they will consistently perform better than outsiders. Weed out non performers promptly and as religiously as you seek outstanding new people. Have a human resource plan in place before you grow beyond your people's capability to deliver. Build a strong, active, useful board of directors to provide an objective perspective on your actions as CEO and on the development of the company. Do not try to clone yourself. Hire people who are better than you and keep them as long as you can. Listen to them; invest in them; and benefit from them, so that when you are ready for retirement, you can sit on their board of directors. PMID- 10105864 TI - The Hitachi 704. PMID- 10105865 TI - As we see it. Physician outreach programs. PMID- 10105866 TI - Putting anesthesia review in perspective [corrected]. PMID- 10105867 TI - Evaluating going concern: SAS (statement on auditing standards) #59. PMID- 10105868 TI - Trends in hospital governance. PMID- 10105869 TI - Vying for time. Work and family. AB - Time--there is never enough of it. There are never enough hours in the day to do everything at work and at home. Today's employees, forced to choose between work obligations and family responsibilities, often feel frazzled and guilty. Some employers recognize these conflicts and are finding ways to lighten the work/family load. They are offering a sophisticated combination of dependent-care options, flexible work hours and family-related benefits tailored to meet the needs of the employees within their specific industries. HRMagazine looks at leaders in six major industries--manufacturing, health, communications/technology, financial management, government and retail. No one can give employees that 25-hour day that everyone feels they need to juggle all their work and family obligations. But these industry leaders have provided a nurturing environment where employees can successfully balance those obligations. PMID- 10105870 TI - Low-cost recruiting for quality. AB - With a little creativity, some recruiters are turning previously overlooked applicant pools into sources of low-cost, quality hires. A look at one recruiter's program for creating a partnership with state job services. PMID- 10105871 TI - How to control overcharging by physicians. PMID- 10105872 TI - Focusing in on a vision plan. PMID- 10105873 TI - Assessing quality of care: three different approaches. PMID- 10105874 TI - Cookson's recipe for benefits savings. PMID- 10105875 TI - Baxter's successful cost cutting mix. PMID- 10105876 TI - Small employers and benefit mandates. PMID- 10105877 TI - What hasn't been said about Canada. PMID- 10105878 TI - Data watch. Corporate views on health care quality. PMID- 10105879 TI - Essential electrical systems play important role in nursing homes. AB - The National Electrical Code requires emergency power systems for nursing homes. A number of system options are available for specifying engineers. PMID- 10105880 TI - Case management--the latest buzzword: what it is, and what it isn't. AB - Case management is a term that has become increasingly popular, yet has many definitions. True case management is the coordination of resources to meet the needs of the client, and it is the responsibility of the health care provider to ensure that these needs are met. PMID- 10105881 TI - Community-based home care programs are not for everyone--yet. AB - New Jersey's Community Care Program for the Elderly and Disabled was developed to help prevent institutionalization of the participants by providing an array of community-based health services. Legal and ethical concerns in service delivery are presented by way of case studies. The intent is to provoke thoughtful analysis of the rights and responsibilities of both clients and providers. PMID- 10105882 TI - Gaining control in a changing environment. AB - The rapid evolution of home care has frequently produced chaotic and unmanageable situations for home care personnel. This article will assist clinical supervisors with daily operations as they teach their staff how to effectively gain control and stabilize the chaos--how to manage, rather than be managed by, home care. PMID- 10105883 TI - The challenge of the '90s: where to find new patients. AB - The consumer of today shops for health services in the same way as he or she shops for other consumer goods--by gathering information and making an educated decision based on cost, product, and performance. As the health care industry becomes more competitive, and customers become more savvy, providers may want to look closely at the advantages of direct mail marketing. PMID- 10105885 TI - Case management: blessing or curse? PMID- 10105884 TI - Voice mail: enabling nurses to focus on health care. AB - Agencies looking to alleviate the paperwork burden, as well as increase staff efficiency, should consider voice mail. This electronic message system makes communication with sometimes difficult-to-reach homecare workers easier and more efficient. PMID- 10105886 TI - PURs (private utilization review organizations) raise serious problems, questions. PMID- 10105887 TI - Small talk ... about UR. PMID- 10105888 TI - DPs (discharge planners) and NHACs (nursing home admissions coordinators): what they think about each other. PMID- 10105889 TI - Utilization review: friend or foe? PMID- 10105890 TI - DP/UR (discharge planning/utilization review): can they work together? PMID- 10105891 TI - Continuing care: linking admission to discharge. PMID- 10105892 TI - Infection control concerns in hospital housekeeping. PMID- 10105893 TI - Healthcare housekeeping management update: a constantly changing challenge. PMID- 10105894 TI - Computerized housekeeping plays vital role in admitting patients. PMID- 10105895 TI - Hospital smoking bans: how effective are they? PMID- 10105896 TI - A profile of the inactive nurse. One solution to the shortage? AB - The reasons why short-staffed hospitals should consider attracting inactive nurses back to practice are clear: they are an excellent potential source of staff, and there are nearly 400,000 of them. How to attract them back, however, is not as evident. A North Carolina health-education agency surveyed approximately 430 inactive nurses, asking them what made them leave and what would bring them back. PMID- 10105897 TI - A New York kind of survey. AB - Among the healthcare regulations enacted by New York State Health Commissioner Dr. David Axelrod is one requiring a comprehensive compulsory survey of each New York hospital by the state health department. A medical director offers his thoughts on the survey and describes its impact on his hospital. PMID- 10105899 TI - Courtesy in caring. The patient as customer. AB - If you were paying $500 a night for a hotel room,. would you be happy if you were told you would be sharing it with a stranger? While such a question cannot be literally asked about a hospital experience, metaphorically it can be--and is- asked every time a patient enters a hospital. The idea of patient-as-consumer is not longer just another trendy concept but an integral part of the way many hospitals do business, and it's the hospital manager's responsibility to ensure the customer's satisfaction. PMID- 10105898 TI - Relieving overcrowded emergency departments through ambulance diversion. AB - One city's solution to overcrowded emergency departments and a shortage of beds was the installation of an ambulance-diversion system, whereby ambulances carrying patients with relatively minor injuries were diverted, when necessary, from the city's busy emergency departments to less crowded ones in neighboring counties. PMID- 10105900 TI - The physician's role in an aging America: taking the team approach to eldercare. AB - With the advent of an aging patient population, the healthcare community is sharpening its focus on geriatric medicine and on how current resources will fare under the demands of an aging America. One approach to effective eldercare is that of a "team" of physician and nonphysician providers, cooperating to meet the multifaceted needs of the elderly patient. As the traditional primary care provider, the physician is a natural choice for the role of team leader. PMID- 10105901 TI - Hospitals and the Health Care Quality Improvement Act. PMID- 10105902 TI - Business and personal travel. PMID- 10105903 TI - The distribution of indigent care among hospitals: in search of the fair share. AB - Although the magnitude and consequences of indigent care are well known, the terms and methods used to define and assess such care are less clear--yet these measures are vital to any solution of the problem. Using data from 151 Tennessee hospitals, two economists analyze the problems, concepts, views, and trends of indigent care and its distribution among hospitals. PMID- 10105904 TI - In search of the "well-being" company--1989. AB - This article presents the findings of a survey of over 900 organizations concerning their offerings of physical fitness, health assessment, nutritional aids, and health education for their employees. The relationship of several organization demographics is discussed. PMID- 10105905 TI - Wellness: the marketing of health promotion in America's heartland hospitals. PMID- 10105906 TI - Surpluses and shortages in the study of wellness programs: an assessment of the field's development and call for academic research. PMID- 10105907 TI - Mutual support groups to reduce alcohol consumption by pregnant women: marketing implications. AB - This paper reports on a study of social support and alcohol consumption of 153 women during pregnancy. The majority of women changed their alcohol intake patterns during pregnancy because of concern for the health of the fetus. Most women decreased the amount and frequency of drinking and changed their beverage of choice. Social support was found to be significantly related to reduction in alcohol use during pregnancy. Social support came from relationships with specific individuals and groups of individuals. Health care providers may be able to extend the range of their work by designing specific prevention strategies targeted toward the development and implementation of mutual support groups for pregnant women. The marketing discipline has identified certain characteristics of the mutual benefit association, an organization which exists exclusively for the benefit of its members. The authors propose that the mutual support group, often used to promote health-related behaviors, is a special case of the mutual benefit association; further, that appropriate application of established marketing principles and practices will be effective in promulgating the mutual support group. The authors offer a marketing strategy for the mutual support of pregnant women, a strategy which should be effective in further reducing the alcohol intake of pregnant women. PMID- 10105908 TI - Market evolutions in health care and the emergence of employee wellness as a new product category. AB - Over the next decade employee wellness could grow to be the dominant specialty product in the health care industry. A number of market evolutions, both on the provider side (hospitals) and the receiver side (companies), have influenced this emergence of employee wellness as a substantial new product category. The product category is in the formative stages and in need of marketing contributions; this paper presents the origins of employee wellness as prerequisite information. PMID- 10105909 TI - Promoting wellness for older adults. PMID- 10105910 TI - Healthcare data briefing. Medical negligence. PMID- 10105911 TI - Personnel identities. PMID- 10105912 TI - Spreading the word. PMID- 10105913 TI - Visions of future benefits. PMID- 10105914 TI - Some good, some bad, most bewildering. PMID- 10105915 TI - Don't waste those skills. PMID- 10105916 TI - Keep up the small talk. PMID- 10105917 TI - Darling of the week. PMID- 10105918 TI - The trials of training. PMID- 10105919 TI - Staying full of energy. PMID- 10105920 TI - Sickness in the system. PMID- 10105921 TI - Staff crisis hit home. PMID- 10105922 TI - Better out than in? PMID- 10105923 TI - Tax exempt status for medical clinics: a complex, rewarding option. PMID- 10105925 TI - Health care providers' many hats create legal "identity crisis". PMID- 10105924 TI - Clinical laboratories regulations: HCFA proposes another important set. PMID- 10105926 TI - The clinical engineering profession: a new society. AB - The formation of the new American College of Clinical Engineering (ACCE) on February 17, 1990 is a significant event in the development of the profession of clinical engineering. The issues facing the new society are substantial. ACCE founding fathers debated for nearly a year before making the decision to launch the new organization. Their path has taken them from individual and organizational professional society memberships, through an Ad Hoc Task Force on Clinical Engineering, to the formation of a new organization with a stated mission--but, so far, with only a handful of members to fulfill it. A founding group of 12 charter members elected Yadin David, P.E., Ph.D., C.C.E., of Texas Children's Hospital (Houston) to the ACCE presidency. David and a panel of five ACCE founding members conducted an open forum--National Clinical Engineering Society: One Year Later--during the 25th annual Association for the Advancement of Medical Instrumentation (AAMI) meeting in Anaheim, California in May, 1990. This feature article summarizes the presentations and deliberations that occurred, and is a follow-up to the November 1989 feature article (Stern, 1989) and March 1990 publisher's editorial (Pacela, 1990) that appeared in this journal. PMID- 10105927 TI - 1990 survey of hospital salaries & job responsibilities for clinical engineers & biomedical technicians. AB - The Journal of Clinical Engineering has conducted its fifth survey of the salaries paid to Clinical Engineers and Biomedical Equipment Technicians in U.S. hospitals. This paper reports the salary and work responsibility data obtained from 1,453 professionals in relationship to: Certification; Region of the U.S.; Teaching Versus Nonteaching Facilities; Years of Experience; Education; Union Membership; and Gender. Data are included on Wage Increases and Job Responsibilities. All data are as of 12/31/89. The average BMET I has 3.3 years of experience and earns $19,394 +/- $4,144 (Std. Dev.). The average BMET II has 6.4 years of experience and earns $26,166 +/- $4,900. The average BMET III has 11.7 years of experience and earns $31,334 +/- $4,977. The average BMET Supervisor has 12.9 years of experience and earns $35,371 +/- $6,416. The average Clinical Engineer has 9.5 years of experience and earns $36,971 +/- $7,515. CE Supervisors are the highest paid in the field with an average 13.3 years of experience and an average salary of $46,265 +/- $11,115. Wages remain the highest on the West Coast and lowest in the Southeast. From 1988 to 1989, the wage ranges for all job types except BMET Is increased: BMET IIs, +1.9%; BMET IIIs, +3.0%; BMET Supervisors, +3.2%; CEs, +3.9%; and CE Supervisors, +1.8%. The highest quartile of CE Supervisors now earns between $52,000 and $95,000 per year. While certified individuals earn $521 to $4,953 more than noncertified, this is attributable in part to years of experience. PMID- 10105928 TI - Contamination of the medical air supply with oxygen: a clinical engineering incident investigation. AB - Two incidents of oxygen contamination in the hospital medical air supply occurred on consecutive weekends. This paper describes those incidents and the investigation that followed. The cause of the contamination was determined to be faulty check valves in some Bird air/oxygen blenders. The investigation of the incidents was hindered because the conventional blender test methods did not detect the problem. Only after monitoring the medical air and oxygen pressures and simulating the real conditions did the cause of the problem surface. PMID- 10105929 TI - The BMET (biomedical engineering technician) Internship Program at University Hospital Stony Brook, New York. AB - Biomedical engineering internships can influence the growth and technical competence of biomedical engineering technicians. Internships allow the biomedical engineering department that coordinates the internship program to grow and expand services and create trained, competent technicians. These new technicians become an employment resource for the coordinating biomedical engineering department and other BME departments. PMID- 10105930 TI - Multichannel bed temperature recorder as a monitor of pressure sores. AB - The objective of this study was the measurement of skin temperature of patients with decubitus ulcers during long-term illness. IC temperature sensors, arranged on the bed sheet, were used to monitor body movement without attaching sensors directly to the skin; the spatial distribution of temperature was measured. The results of these studies showed that decubitus ulcers were caused by reduced body movement; higher temperature distribution was observed in the area of decubitus ulcers than in normal areas. The difference in skin temperature between the decubitus ulcer areas and normal areas varied from 1.6 degrees C to 3.1 degrees C. The temperature in the decubitus ulcer area was found to be higher than the temperature of areas in which decubitus ulcers were either developing or healing. PMID- 10105931 TI - A dose of imaging. PMID- 10105932 TI - Electronic imaging finds niches. Four organizations experiment with four different uses. PMID- 10105933 TI - Calvary hospital turns to micrographics. PMID- 10105934 TI - Burbank Hospital eases into full document automation. PMID- 10105935 TI - Research libraries reassess document preservation technologies. How does electronic imaging stack up against micrographics? PMID- 10105936 TI - Evaluating rural nurses for preparation in implementing nutrition interventions. AB - With the increase in wellness programs, earlier hospital discharges, higher health care costs, and more home health care, rural nurses are required to generalize their practices and draw from a more extensive knowledge base. The purpose of this study was to examine nursing interventions, specifically nutrition education practices, based on nutrition knowledge that is used in health promotion. A stratified random sample of rural nurses from hospitals, nursing homes, and community health agencies in North Dakota was invited to participate in this study. Data were obtained via questionnaires. The questionnaire consisted of two parts: the first analyzing demographic data and the second analyzing nutrition knowledge. Nutrition information requests were received by 90.9 percent of the practicing registered nurses. The community/public health nurses had the highest nutrition knowledge scores while medical-surgical hospital nurses had the lowest nutrition knowledge scores. With nutrition information and education being a frequently sought intervention by the rural health client, it would seem that registered nurses should be highly prepared and knowledgeable to meet these clients' needs. PMID- 10105937 TI - AIDS knowledge and attitudes among adolescents in the rural southwest. AB - A survey of adolescents living in rural southwestern towns demonstrated their knowledge of the basic transmission routes of Acquired Immune Deficiency Syndrome (AIDS). Nevertheless, misconceptions and attitudes, which may interfere with adopting safe behaviors, persist. Significant differences in knowledge did exist between the ethnic groups surveyed. Further, American Indian and black adolescents were more likely to express attitudinal biases against people who have AIDS. We conclude that current media efforts have been successful in communicating basic information regarding transmission, but there may exist a need for ethnically specific programs that focus on the misconceptions and attitudes surrounding AIDS. PMID- 10105938 TI - Alternative models for the delivery of rural health care: a case study of a western frontier state. AB - This is a case study illustrating the wide variety of models for rural health care delivery found in a western "frontier" state. In response to a legislative mandate, the University of Nevada School of Medicine created the Office of Rural Health in 1977. Utilizing a cooperative, community development approach, this office served as a resource, as well as a catalyst, in the development and expansion of a variety of alternative practice models for health care delivery to small, underserved rural communities. These models included small, single, and multispecialty group practices; self-supporting and subsidized solo practices; contract physicians; midlevel practitioners; and National Health Service Corps personnel. The rural health care system that was created featured regional and consortial arrangements, urban and medical school outreach programs, and a "flying doctor" service. PMID- 10105939 TI - Community financed and operated health services: the case of the Ajo-Lukeville Health Service District. AB - The concept of a health service district, as a variation of the special tax district, is described and discussed. Tax districts have traditionally been used to support both capital construction (revenue bonds) and operational expenses of single-purpose governmental entities. The health service district, where authorized by state laws, may be used by local areas to subsidize the delivery of ambulatory health care. A particular case, the Ajo-Lukeville Health Service District in Arizona, illustrates what can be accomplished by this mechanism with the cooperation of local residents and outside agencies. Both the process of establishing such a district and the outcome of the Ajo-Lukeville experience is described. Reasons why health service districts may prove potentially attractive at this time are reviewed. Impediments to the development of more health service districts are also explored, including the lack of technical assistance, an inadequate awareness of the potential of health service districts, and the absence of a widespread orientation toward community financed and controlled health care. Movement in this direction should facilitate the development of additional health service districts. PMID- 10105940 TI - Rural hospitals under PPS: a five-year study. AB - This research examines the impact of prospective payment (PPS) on the financial performance of Kansas hospitals, which are predominantly rural. Financial ratios are presented and regressed on bed size and year. The data suggest that bed size has the strongest effect on financial viability. There are indications of a delayed effect of PPS on the rural, smallest hospitals (fewer than 25 beds), suggesting that non-operating sources of revenue (local property tax mill levies) are being used to subsidize them in the short term. Small hospitals appear to be delaying all capital and long-term costs to survive. The research suggests that the effect of PPS may be long term. PMID- 10105941 TI - Factors related to job satisfaction and autonomy as correlates of potential job retention for rural nurses. AB - This study of 167 nurses in 10 rural Georgia agencies examines the relationships among personal characteristics, factors of job satisfaction, autonomy, and job retention. The findings indicate that, contrary to expectations, personal characteristics (e.g., age, education, salary, marital status, and number of dependents) are not strong predictors of job retention in this sample. Some of the factors of job satisfaction do correlate negatively with indicators of impending job change, but the strongest relationships were those related to nursing autonomy. The study concludes that, of the variables studied, autonomy was the most effective predictor of job satisfaction and intention to remain in the current position. PMID- 10105942 TI - An exploratory study of the correlates of intent to quit among certified registered nurse anesthetists in North Dakota. AB - Certified registered nurse anesthetists (CRNAs) provide the majority of anesthesia services in rural hospitals. Some services provided by CRNAs are routine, while others are for emergency conditions. The effect of the current nurse shortage on the potential pool of nurse anesthetists becomes a critical concern when considering the nature of CRNA services in rural areas. This study investigated the potential factors that relate to the desire of CRNAs to continue practicing in rural hospitals of North Dakota. All CRNAs licensed in North Dakota (n = 125) were mailed survey questionnaires. Approximately five weeks later responses were received from 54 respondents for an overall return rate of 43 percent. Correlational analyses were used to examine responses of the subjects. A moderate degree of relationship was found among the work-related variables. The average interscale correlation, calculated using an r to z transformation, for the seven work-related variables was 0.47. Overall, pay and promotion satisfaction exhibited strong (r greater than 0.60) correlations with turnover intentions. Supervisory satisfaction was only moderately (r = -0.33) related to intention to quit. These results are discussed in terms of their implications for the management of CRNAs in rural hospitals. Revised salary schedules, clinical ladders for promotions, supervisory training, and the identification of potential performance constraints are suggested as areas in which rural hospitals should focus attention in an attempt to manage turnover in CRNAs. PMID- 10105943 TI - Patient receivables: an opportunity for success, an excuse for failure. AB - Hospitals are aggressively seeking innovative ways to enhance their overall performance through converting patient accounts receivables to cash. By developing well-defined credit and collection policies and procedures, they can increase recovered dollars in a shorter time frame while reducing the cost associated with this recovery. PMID- 10105944 TI - Nontraditional record completion methods bring financial payback. PMID- 10105945 TI - Medicine and the question of suffering. AB - Doctors are not health care providers, and medicine is not a commodity. To practice medicine well, the doctor must attend to each patient as a whole person and be faithful in giving care when cure is not possible. PMID- 10105946 TI - The ethics of using Nazi medical data: a Jewish perspective. AB - The notorious experiments on concentration camp prisoners conducted by Nazi scientists produced a body of data still referred to by researchers. The Jewish tradition offers resources for deciding on the morality of using this material. PMID- 10105947 TI - Personhood: current legal views. AB - Medical developments have given people unprecedented control over the beginning and end of life but have also altered traditional and legal concepts of personhood. Recent court decisions on prefetal life, fetuses, the infirm, and the dying reflect a struggle with the new ambiguity surrounding the definition of "person." PMID- 10105948 TI - Tapping human potential: an interview with Norman Cousins. AB - Active, responsible partnership between patient and physician creates the best environment for healing. The patient with a strong will to live--who summons spirit, faith, love, hope, purpose, determination, festivity--helps doctors get the best out of medical science. PMID- 10105949 TI - Moral principles shaping public policy on euthanasia. AB - People's fear of enduring a prolonged, costly dying while attached to life sustaining machines has prompted support for the legalization of active euthanasia. Four major principles--sanctity of life, prohibition against killing, autonomy, and the common good--have a bearing on the debate. PMID- 10105950 TI - The exclusion of theology from public policy: the case of euthanasia. AB - It is commonly assumed that ethical decisions made on theological grounds belong in the private sphere, but theological arguments have a distinct place in the public's ethical conversation. PMID- 10105951 TI - Access to care: how trustees can help. PMID- 10105952 TI - Do you need an audit committee? PMID- 10105953 TI - Total quality improvement: a hospital case study. PMID- 10105954 TI - Building medical staff alliances. PMID- 10105956 TI - Chilling effect on mergers? PMID- 10105955 TI - Combating the high cost of high-tech. PMID- 10105957 TI - Recognizing the value of nurses. PMID- 10105958 TI - Revisiting the three-legged stool. PMID- 10105959 TI - AHA seeks changes in PPS. PMID- 10105960 TI - Hospital associations, political advocacy, and trustees. Interview by Karen Sandrick. PMID- 10105962 TI - Health fraud rakes in big bucks. PMID- 10105961 TI - Transfer agreements help hospitals comply with anti-dumping laws. PMID- 10105963 TI - Health fraud and the elderly. PMID- 10105964 TI - Key point of National's policy for hospitals. PMID- 10105965 TI - New telephone system makes it easy. PMID- 10105966 TI - Pants are back in style! PMID- 10105967 TI - After first 100 days ... bright outlook for Auckland Board. PMID- 10105968 TI - PAXUS expands Australasian health sector capability. PMID- 10105969 TI - Affirmative action for Pacific Island people. PMID- 10105970 TI - Transport of meals between hospitals. Taranaki Area Health Board. PMID- 10105971 TI - Continuous batch washer appreciated by Taranaki laundry staff. PMID- 10105972 TI - Women on the move. PMID- 10105973 TI - National Party policy on hospitals "putting patients first". AB - National will make the reduction of hospital waiting lists a first priority ... inviting private hospitals to tender for public health work ... granting public hospitals greater autonomy ... and introducing a new funding policy which will lead to greater efficiency. As the full benefits of these moves begin to flow through the system we will then be in a position to lift our hospital system back to a front rank position in world health. Preparatory to this a New Technology Advisory Group will be appointed. We will also lower the barriers that have traditionally separated the public and private hospital systems; allowing work and funds to flow freely between the two, thus leading to greater productivity and a better health service for all New Zealanders. National not only wants to achieve "Health by the Year 2000", but to restore health care in New Zealand to a level where we will once again be the envy of the world. PMID- 10105974 TI - Sexual harassment issues in the workplace. PMID- 10105975 TI - Update: effective initiative. PMID- 10105976 TI - Quality equals success. PMID- 10105977 TI - Key to fund-raising: people only give to people. PMID- 10105978 TI - Metropolitan puts focus on the future. PMID- 10105979 TI - Organizational factors affecting growth and decline in adult day-care programs: a comparative study. AB - Data derived from a mailed questionnaire of adult day-care providers in Illinois and from the records of the Illinois Department on Aging for fiscal years 1984 and 1985 were analyzed to determine which factors affect growth or decline in the programs, measured in terms of number of clients served and units of service provided. Initial analysis revealed that all providers under contract with the state for less than 3 years were growing, and approximately one half of the older providers had similar changes. A separate regression analysis of the older adult day care providers indicated that growth tended to be positively associated with reports of good relationships with referral agents and resource support from umbrella organizations and the larger community, and negatively associated with longevity of the provider. These findings highlight the importance of supportive interorganizational relationships for program growth. PMID- 10105980 TI - Doctors' order. PMID- 10105981 TI - Imported ingenuity. PMID- 10105982 TI - A vision for excellence. AB - One hospital integrates employee relations, customer service and commitment to quality into one successful, award-winning program. Employees at AMI Palmetto General are motivated to constantly consider the hospital's goals and strive for excellence. PMID- 10105983 TI - Handling health-care costs in the '90s. AB - Managed-care programs with utilization reviews may be the best approach to cost cutting. But to really curb costs, providers, insurers, employers and employees must form partnerships to overcome the outrageous inflation in the U.S. health care system. PMID- 10105984 TI - The economics of high-technology medical imaging. AB - The field of high-technology medical imaging equipment and methods have recently received undue negative attention in the battle against sharply increasing health care costs. This article identifies numerous imaging methods and examines the field's vulnerable areas such as high capital equipment costs and subsequent high operating costs. Comparison is drawn between the cost of high-tech medical imaging and the total cost of health care. The multiple benefits of medical imaging to the practice of medicine in relation to its total cost are also discussed. Evidence is presented to support the view of Dr. D. MacEwan, former president of the Radiological Society of North America: "High-technology imaging devices do not have to increase the cost of health care and can actually save money if passed judiciously." This conclusion was reached from a 13-year study examining the health-care records of more than one million Manitobans. PMID- 10105985 TI - Physician assessment of pharmacists' interventions--a method of estimating cost avoidance and determining quality assurance. AB - The impact and quality of select pharmacists' interventions were assessed by four physicians with pharmacology experience. Each physician was sent 30 interventions and asked to indicate if the intervention by the pharmacist was of a positive nature and would prevent morbidity and/or mortality. They were also questioned regarding effect of the intervention on hospital stay. Each physician received 15 interventions which were, and 15 interventions which were not assessed by three other physicians. Of the 15 interventions assessed by all four physicians there was favourable agreement among the physicians with respect to the impact of the intervention with 86.7 percent (52 of 60) of the judgements indicating that the pharmacists' intervention had a positive effect on therapy. There was less agreement with regard to whether hospital stay would, and the extent to which it would, have been prolonged. Using consensus it was estimated that eight of 15 interventions would have prolonged stays approximately 3.7 days each. The use of physicians was helpful in assessing the impact of pharmacists' interventions. PMID- 10105986 TI - Parenteral packaging waste reduction. AB - The consumption of pharmaceutical products generates waste materials which can cause significant environmental impact when incinerated or landfilled. The purpose of this work is to stimulate discussion among hospital pharmacists and purchasing managers relating to the waste management aspects of their purchasing decisions. As a case study example, a number of commercially available "single use" parenterals are evaluated from a waste reduction perspective, for both the product container and for the packaging of these containers. Glass vials are non incinerable, and are currently non-recyclable due to the higher melting temperatures required for borosilicate glass. However, plastic vials are potentially both incinerable and recyclable. Packaging quantities are considerably lower for plastic vials on a unit container basis, and also vary to a measurable degree between different manufacturers for a given type of container material. From an environmental perspective, waste reduction potential should become an important criterion in the selection of pharmaceutical products for hospital use. PMID- 10105987 TI - The use of a mini-accreditation program to prepare for a CCHFA (Canadian Council on Health Facilities Accreditation) accreditation survey. PMID- 10105988 TI - Cellular communication. AB - Generally, cellular-telephone communications seem to be a valuable means for the public to communicate that an accident has occurred on highways in metropolitan areas. Response time is reduced and congestion quickly relieved. This system could be improved by making a provision in emergency call boxes for the separation of vehicle problems from true emergency calls to ensure the proper response priority. Cellular-telephone communications are a valuable adjunct to EMS radio communications for biotelemetry, when channels are overcrowded or communications are needed in a "dead" area. A system of dedicated hospital emergency-department lines and telephone numbers is needed. Cellular telephones shouldn't be used as a primary means of providing medical control. Advance planning should be undertaken to ensure immediate access to hospital emergency departments if cellular is used for secondary purposes. The amount of communication traffic at and surrounding a multi-casualty incident or disaster may overwhelm a local cell. Priority numbers providing immediate access and bumping of non-emergency calls for emergency responders are needed. All means of communication should be coordinated by an EMS communications MCI or disaster plan. PMID- 10105989 TI - Hawaii's medical coconut wireless network. PMID- 10105990 TI - Promises, promises: does EMD (emergency medical dispatch) really work? PMID- 10105991 TI - Microwave/satellite relays. AB - The intent of this article is to show examples of how microwave/satellite relays can be used in the design of public-safety communication systems. It's important to keep in mind that microwave/satellite relays are used to move information from one location to another. Information can be two-way-radio voice traffic, paging and data access. There are many other applications that can utilize microwave satellite relays, but they are beyond the scope of this article. Ultimately, microwave/satellite relays should be considered a resource that can greatly enhance both public-safety and EMS responsiveness. PMID- 10105992 TI - Advanced technology for mobile radio. PMID- 10105993 TI - A hospital without walls. AB - Pacific Presbyterian Medical Center has chalked up an impressive string of successes. What's ahead? A $20 million cancer center. PMID- 10105994 TI - Excuses! Excuses! Excuses! PMID- 10105995 TI - Charitable solicitation acts and fund raising: Part two. PMID- 10105996 TI - Current JCAHO emphasis. PMID- 10105997 TI - Healthcare data briefing. Women and cancer. PMID- 10105998 TI - Help yourself to health. PMID- 10105999 TI - Care out of control. PMID- 10106000 TI - Upfront on shutdown. PMID- 10106001 TI - Understanding complaints. PMID- 10106002 TI - Reflections on leadership in health care. Interview by Samuel Levy. PMID- 10106003 TI - Clinical ethics, mission, and vision: practical wisdom in health care. PMID- 10106004 TI - Product line management in hospitals: an exploratory study of managing change. AB - Hospitals often have looked to industry as a source of solutions to business problems. In recent years, they have begun to adopt a concept that has been used by manufacturers for more than 50 years--product line management (PLM). One characteristic of PLM is the designation of a product champion whose responsibility it is to promote the product both inside and outside the organization as well as to view for organizational resources to support the product. This article presents the findings of an exploratory study that indicates that although many hospitals are successfully utilizing PLM, a number of barriers to the implementation of this concept remain. PMID- 10106005 TI - Patient satisfaction surveys: an opportunity for total quality improvement. AB - To identify deficiencies in the design and administration of patient satisfaction surveys and their actual use in institutional quality assurance programs we analyzed the survey instruments and practices of five teaching hospitals, three community hospitals, and two health maintenance organizations. There is a considerable gap between the content of many patient satisfaction surveys and what prior research has indicated to be important determinants of patient satisfaction. Often insufficient attention is directed to patient satisfaction with technical competence, outcomes, continuity, or patient expectations, and nonsystematic approaches and weak methodologies similarly limit the value of many patient surveys and inhibit their use in total quality improvement efforts. PMID- 10106006 TI - Effect of an admission monitoring and scheduling system on productivity and employee satisfaction. AB - This article develops and evaluates an admission monitoring and scheduling system designed to reduce fluctuation of work load on nursing units. Effects of the system on work-load distribution, full-time equivalents, labor cost, and employees are assessed in a 235-bed hospital. The system provided more stable work loads and had a potential for improving productivity by about 3 percent, and reducing by about 40 percent the number of days nurses are asked to take off without pay during low-census periods. PMID- 10106007 TI - Report on baccalaureate career development. Prepared by the Joint Committee of the American College of Healthcare Executives and the Association of University Programs in Health Administration. PMID- 10106009 TI - Federal appellate court upholds HMO liability. PMID- 10106008 TI - Sexual harassment: third party issues. PMID- 10106010 TI - From little "q" to big "Q". Interview by Sarah Tackett. PMID- 10106012 TI - Total quality improvement. PMID- 10106011 TI - TQM (total quality management): the new frontier for quality and productivity improvement in health care. PMID- 10106013 TI - Some practical applications of Deming's 14 points. PMID- 10106014 TI - Using total quality management to improve patient relations programs. PMID- 10106015 TI - Does your organization's mission statement need updating? PMID- 10106016 TI - Quality is moving "upstairs". PMID- 10106017 TI - CEMENT: a statistical data base in occupational health. PMID- 10106018 TI - New Jersey's air ambulances grounded by hospitals. PMID- 10106019 TI - Tackling stress management from all sides. PMID- 10106020 TI - Rating stress in EMS: a responder survey. PMID- 10106022 TI - JEMS fifth annual buyers' guide. 1991 edition. PMID- 10106021 TI - Thorough assessments. Giving patients a fighting chance. PMID- 10106023 TI - Reflections of a hospital chaplain. AB - Jane Vieira wrote the Journal of Healthcare Chaplaincy enclosing an "open letter" reflecting on her own experience of ten years as a hospital chaplain. While this is in no way an "article," Chaplain Vieira's testimony to her love of chaplaincy was worth sharing. PMID- 10106024 TI - The valuation of pastoral care by hospital administrators: a survey of selected for-profit and non-profit institutions. AB - This paper reports on a study of 600 hospital administrators, half of which were in non-profit institutions and half of which were in hospitals owned or managed by the Hospital Corporation of America. The project was designed to identify what differences, if any, existed between surveyed administrators in both types of institutions in their valuation of pastoral care. No significant differences were found between the two groups of administrators in the valuation of pastoral care. All administrators were found to be concerned about the quality of patient care and to value aspects of care such as pastoral care which are personal and difficult to quantify. PMID- 10106025 TI - Integrating community clergy into the hospital health care team. AB - Presentation of one model of integrating community clergy into the health care team of an acute care general hospital including descriptions of the relevant history of the program and the ways community clergy are included in the planning and execution of the hospital care of parishioners from their own congregations. PMID- 10106026 TI - I am a hospital chaplain who happens to be a Jewish woman. AB - The author describes her experience through several quarters of Clinical Pastoral Education as a Jewish woman. She recounts the story of her own sense of urging toward chaplaincy as an expression of her spirituality, as well as much of the "mixed" nature of her journey among a predominantly Christian group. Included are stories of patient encounters as well as a record of her ongoing conversation with her surroundings. PMID- 10106027 TI - Oxygen might be a factor in the fire in OR at UCLA. PMID- 10106028 TI - OR nurses are joining efforts to stem medical waste stream. PMID- 10106029 TI - Some ET (endotracheal) tubes fail fire-resistance test. PMID- 10106030 TI - Offensive sexual conduct basis for harassment suit. PMID- 10106031 TI - Indicators are flags to possible problems. AB - This is the fifth article about applying the ten-step model for monitoring and evaluation developed by the Joint Commission on Accreditation of Healthcare Organizations. PMID- 10106032 TI - OR turnaround: looking at problem areas. AB - This is the fourth in a series on management strategies for "turning around an OR." The first three articles appeared in the January, April, and June issues of OR Manager. PMID- 10106033 TI - Are reusable fabrics making a comeback? PMID- 10106034 TI - OR nurses concerned about environment. PMID- 10106035 TI - Corporate volunteerism in the 1990s. PMID- 10106036 TI - Cuddling medically fragile infants. PMID- 10106037 TI - A hospital children's learning center. PMID- 10106039 TI - Corporate volunteer programs. PMID- 10106038 TI - HAVE (Hospital Awards for Volunteer Excellence) winners describe their programs. PMID- 10106040 TI - Working with corporate volunteers. PMID- 10106041 TI - The administration and you. AB - Respect and understanding must exist between the administration and volunteer and auxiliary organizations in a hospital so both groups can effectively perform their respective jobs. In the following article, E.E. (Gil) Gilbertson, president emeritus of St. Luke's Regional Medical Center, Boise, ID, explains how administrators and auxilians and volunteers can enhance their working relationships and, in the process, meet the hospital's goals. PMID- 10106042 TI - An auxiliary retreat: why? Why not? AB - Although the first auxiliary educational retreat was held in 1982 and articles have been written about retreats periodically since then, many auxiliaries still have not sponsored one. In the following article, Marge Lattman, member of the AHA's Committee on Volunteers, past-president of the Association of Florida Hospital Auxiliaries, and active member of the Venice (FL) Hospital Auxiliary, explains why an auxiliary educational retreat is valuable and highlights some of her experiences as a retreat presenter. PMID- 10106043 TI - LMs earn their pay. PMID- 10106044 TI - Physical aspects of quality assurance. The Committee on Quality Assurance in Radiation Oncology. PMID- 10106045 TI - Power, politics & people. PMID- 10106046 TI - The American College of Radiology Mammography Accreditation Program. PMID- 10106047 TI - Magnetic resonance imaging. PMID- 10106048 TI - MRI: a forecast for the future. PMID- 10106049 TI - The age of high think. PMID- 10106050 TI - Tennessee salary survey. PMID- 10106051 TI - The healthcare environment and its impact on radiologic education: a working model. PMID- 10106052 TI - Radiology & radiation therapy affected by hospitals' financial trends. PMID- 10106053 TI - Justification for capital equipment purchases. Radiology's challenge for the 90's. PMID- 10106054 TI - The basics: quality assurance in radiation oncology. PMID- 10106055 TI - Commitment: holding pharmacy accountable for technician certification. PMID- 10106056 TI - Technicians and the goal of excellence. PMID- 10106057 TI - Safety by design. Shock trauma center's helipad received special consideration during its planning and construction. PMID- 10106058 TI - On-site facilities. LIFE FORCE's decision to build. AB - The size and cost of an on-site maintenance and operations facility will vary greatly depending on the size and location of the structure. The decision to build such a facility must involve an effective feasibility study to evaluate the actual needs and requirements of the air medical program in association with the budgetary constraints of the sponsoring hospital. PMID- 10106059 TI - 1990 helipad survey. PMID- 10106060 TI - AAMS (Association of Air Medical Services) resource document for air medical quality assurance programs. PMID- 10106061 TI - International air medical transport. Part II: Results and discussion. AB - International air medical transport requires reliable equipment, skilled personnel and precise planning. A report is presented of an experience with 31 international transports. Details concerning equipment, personnel and logistics are presented. Results and problem areas are discussed. This early experience demonstrates the capability for the repatriation of critically ill patients, and the evacuation of patients who require access to a level of care which may be unavailable outside the United States. PMID- 10106062 TI - Ethylene oxide control technology. I: Occupational exposure. PMID- 10106063 TI - Strategies to contain health care costs. PMID- 10106064 TI - Solving the health data management puzzle. PMID- 10106065 TI - Managed care liabilities for employers. PMID- 10106066 TI - Data watch. The human resource manager's view. PMID- 10106067 TI - No home, no help. AB - What can be done about abuse children and the homeless mentally ill? Some experts propose putting them back in orphanages or mental hospitals. But institutionalization is an approach the nation had renounced about two decades ago. PMID- 10106068 TI - New leadership and vision are vital. PMID- 10106069 TI - Cheaper by the dozen: group purchasing gains momentum. PMID- 10106070 TI - Food service priorities a matter of perspective. Survey finds conflicting perceptions. PMID- 10106071 TI - Cook up an OBRA solution. meeting new dietary regs. PMID- 10106072 TI - Upgrading care and improving retention. Genesis offers aides, nurses special incentives. PMID- 10106073 TI - Down but not out. Reviving distressed retirement centers. PMID- 10106074 TI - Life Care, National Heritage part ways. Merger talks scrapped. PMID- 10106075 TI - Nip patient abuse in the bud. Aides tackle conflict resolution. PMID- 10106076 TI - Take control of the survey process. PMID- 10106077 TI - Caring for the care givers. PMID- 10106079 TI - Setting standards for risk management. PMID- 10106078 TI - Humanizing hospital care. PMID- 10106080 TI - Managed care/case management: what, why, and how to cope. PMID- 10106082 TI - Follow-up: AIDS and the black community. PMID- 10106081 TI - Small talk ... about managed care. PMID- 10106083 TI - Case management: everyone wins or everyone loses. PMID- 10106084 TI - Taking the pulse: managed care revisited. PMID- 10106085 TI - Unit-based staffing, team approach equals effective discharge planning. PMID- 10106086 TI - R&DP/research and discharge planning. PMID- 10106087 TI - Discharge planning for ventilator-dependent patients. PMID- 10106088 TI - Revisiting the garden: medicine and management in the 1990s. AB - The importance of effective hospital-physician relationships is acknowledged by all. Yet few empirically based guidelines exist for strengthening such relationships. Based on an in-depth examination of ten sites' experience, this article suggests a number of approaches and ideas for forming more effective hospital-physician relationships in the 1990s. Among the issues addressed include the nature of hospital-physician collaboration and competition, embracing risk, forging new forms of partnership, creating value for purchasers, and grooming younger physicians for leadership roles. PMID- 10106089 TI - Cloistered garden or public park? PMID- 10106090 TI - Is that broccoli growing in the rose garden? PMID- 10106091 TI - Medicine and management in the 1990s. PMID- 10106092 TI - Agency for Health Care Policy and Research (AHCPR). PMID- 10106093 TI - Making tracks at the University of Iowa Hospitals and Clinics: design and implementation of a bar coded medical records tracking system. PMID- 10106094 TI - The effect of performance standards on job satisfaction among medical record department employees. AB - This is the second of two articles discussing the implementation by the author of management techniques to measure and evaluate employee performance and job satisfaction in the medical record department of a 136-bed general hospital. PMID- 10106096 TI - The hassle factor: views around the country. PMID- 10106095 TI - The challenges to physician autonomy and advocacy. AB - The rapid changes occurring in the organization, delivery and financing of health care has come at the expense of the medical profession. Control of the health care system now appears to have shifted from providers to purchasers and payers. PMID- 10106097 TI - Challenging times for ABIM (American Board of Internal Medicine) and internal medicine. Interview by C. Burns Roehrig. PMID- 10106098 TI - Duty, honor and a crisis of values? PMID- 10106099 TI - Don't be caught by surprise over POLs (physician office laboratories). PMID- 10106100 TI - Spending time on saving energy. PMID- 10106101 TI - Trying to resolve an identity crisis. PMID- 10106102 TI - The standard bearers. PMID- 10106103 TI - Care is the key. PMID- 10106104 TI - In need of home comfort. PMID- 10106105 TI - From toy to tool. PMID- 10106106 TI - Enjoy your stay at our patient hotel. PMID- 10106107 TI - Positive base for change. PMID- 10106108 TI - How big can we grow? PMID- 10106109 TI - A many headed beast. PMID- 10106110 TI - Trust in your intuition. PMID- 10106111 TI - Companions for the road. PMID- 10106112 TI - Of production, quality, and pharmaceutical care. PMID- 10106113 TI - Megatrends a la pharmacy: potential and promise. AB - Society is experiencing major restructuring best articulated by John Naisbitt's Megatrends. This article contends that many changes in pharmacy practice are not incongruent with overall megatrends being experienced by our nation in general. Thus pharmacy practitioners and the profession must work diligently to ensure that both reflect social adjustments that lead to optimal results for patients. PMID- 10106114 TI - Merit raises expected to average 5.2% in '90. PMID- 10106115 TI - Program creates stream of entry-level workers. PMID- 10106116 TI - JCAHO defines 11 interim life-safety measures. PMID- 10106118 TI - Dispute-resolution alternatives save time, fees. PMID- 10106117 TI - ASHE (American Society for Hospital Engineering) helps to identify key issues for the 1990s. PMID- 10106119 TI - Study: managers' influence rises for furniture buys. PMID- 10106120 TI - A survey of physicians' uses/opinions regarding nutrition education resources. AB - Since physicians are one of the public's main sources of nutrition information, a study was conducted to investigate physicians' sources of nutrition knowledge, patient education resources, and opinions about potential nutrition services. A questionnaire was mailed to a random sample of family physicians. The response rate was 53% (n = 255). Fifty-three per cent of respondents ranked their personal knowledge and training as their most frequent source of nutrition information. The most widely reported sources of patient education resources were Health and Welfare Canada and industry. Physicians ranked resources from Health and Welfare Canada as highest for quality characteristics, and industry information as lowest. Pamphlets were ranked as the most/very useful patient service (70%), and physician reimbursement as the most useful physician service (59%). One-quarter of physicians asked for patient information on heart disease. The results of this study suggest physician reimbursement for nutrition education needs to be addressed by health insurance plans if physicians are to be expected to provide nutrition intervention. Further nutrition training for physicians should be conducted through medical education, continuing education and medical journals. PMID- 10106121 TI - Economic recession might keep plastic price rises low. PMID- 10106122 TI - Food prices to climb 5.5%-10%. PMID- 10106123 TI - 50% of hospital materials managers manage OR inventories; others will within two years. PMID- 10106124 TI - Cost containment plan saves $1 million. PMID- 10106125 TI - HMM price watch. Purchasing managers' index reverses 3-month climb, drops to 47.4 in July from 51.1 in June. PMID- 10106126 TI - Measuring up: GAO reviews charity care standards. PMID- 10106127 TI - Should money matter? PMID- 10106128 TI - CHA looks to the future. PMID- 10106129 TI - Overhauling overtime standards. The Fair Labor Standards Act should be updated. AB - The minimum wage provisions of the Fair Labor Standards Act (1938) have drawn considerable attention through the years. But the act's overtime provisions have created some major problems yet generated little debate. As it now stands, the act stipulates that employees be paid overtime for hours worked in excess of 40 during a workweek. Certain employers, like hospitals and residential care facilities, have the additional option of paying overtime on the basis of a 14 day period for hours worked in excess of eight hours a day or of 80 hours during a two-week period. Recent amendments to the act have made it increasingly unresponsive to changes in employers' and employees' needs. The act reduces the scheduling flexibility many employers, like hospitals, need. Allowing more exceptions to the act's current provisions would create more flexibility. A workable plan would be to permit organizations open for business seven days a week to calculate overtime on the basis of a straight 80-hour work period. Such a change would not preclude management and labor from negotiating overtime pay for hours worked in excess of 8, 10, 12, or more a day. PMID- 10106130 TI - Revitalizing the ministry. AB - The twentieth century's last decade presents religious institutes with a golden opportunity to confront the dilemmas surrounding sponsorship. Sponsors can develop a number of strategies to allay current anxieties and to transform potential crises into advantages. One is to revitalize the corporate mission by basing it on professed values rather than on existing structures. Institutes can also articulate their mission by building networks that encourage cooperation between those involved in traditional services and those in alternative services. Strengthening collaboration with the laity is also critical. Sponsorship forums are one way to promote mutual understanding and reflection. In addition, involving lay leaders in planning and decision making will broaden their understanding of issues that affect the healthcare institution. Finally, with the laity assuming a greater share of responsibility in Catholic healthcare, many institutes will have to develop strategies that allow them to "let go." The process will require inner transformation. Recognizing the institute's contribution to the development of the Catholic healthcare ministry can help members accept the need for change. Actively planning for the changes will also help members cope with them. PMID- 10106131 TI - Sponsorship in evolution. AB - Sponsorship appears to be evolving from an original model in which the sponsoring religious institute related to its facilities in a manner resembling a family business, to a model of sponsorship akin to a franchise, to a ministerial partnership. Factors leading to this evolution include tremendous changes within the religious institute itself, including decreases in the number of members and financial stability. Changes within healthcare itself--such as greater competition and declining revenues-have forced hospitals to diversify. One result of these developments has been a radical change in the "rules" of the game. Historically independent entities--hospitals, sponsors, physicians--now have to value interdependence and mutuality. In the family-run model the family (sponsor) had special privileges, as though they "owned" the business. When the number of family members dropped below that necessary to govern, administer, and staff the institute's facilities, they began to move away from the family model to the franchise model, which has more open communication, greater input to decision making by non-family members, and a shift in the family's attention from actual operations to oversight and accountability. Eventually, the franchise model began to give way to the ministerial partnership, characterized by mutuality. Both family and others have roles not only in carrying out the mission, but in actually shaping and forming it. PMID- 10106132 TI - Managing change. A step-by-step process helps sponsors implement change smoothly. AB - During the past six years the Catholic Health Association (CHA) has developed and modified a process to help leaders evaluate and implement merger, cosponsorship, and sponsorship transfer decisions. CHA's highest priority in these efforts has been to keep Catholic healthcare facilities under Catholic sponsorship, control, and management. Proposals to change sponsorship arrangements usually originate with sponsoring institutes, whereas local boards generally initiate merger proposals. In either case, it is critical that all interested parties--such as sponsors, boards, administrators, medical staff, employees, and the local Church- be involved in the decision-making process at some point. Once leaders have decided on a course of action, they should appoint a task force to implement the proposal. The board, administration, and medical staff will all have important roles to play in the implementation process. Another important step is to establish criteria for evaluating candidates for a proposed merger or sponsorship transfer. Leaders should ensure that people affected by the transaction have an opportunity to give input and to grieve their loss. After leaders have selected a candidate, they must negotiate the details of the agreement and take the necessary legal steps to complete the transaction. It is imperative that a facility secure outside legal counsel to help it through this stage. PMID- 10106133 TI - A clockwork nursing unit. Analyzing how nurses spend their time is the first step toward improving productivity. AB - Until recently, productivity analysis has been a relatively underdeveloped tool in nursing. As healthcare costs continue their upward spiral, however, managers have been pressured to measure and evaluate nursing productivity. The right combination of efficiency and effectiveness is the key to optimal productivity. Nursing can be efficient but highly ineffective and thus of little value to the patient; conversely, nursing can be effective and valuable, but grossly inefficient. To determine a nursing unit's level of productivity, managers can keep a daily record of the number of nursing hours per patient day. When the record indicates too many ineffective or inefficient days, an analysis of how nurses use their time can help solve the problem. The first step is such an analysis is to have management engineering or the nursing staff itself collect data on time spent per task. Once these data are collected, they can be analyzed by shift (for the entire hospital), by individual unit, by task category, etc. With this information in view, managers can ask key questions to help pinpoint areas where efficiency might be improved. PMID- 10106135 TI - The power of marketing. PMID- 10106134 TI - Is it ethical to advertise morals? PMID- 10106136 TI - Wisdom in a small package. PMID- 10106137 TI - Before and after Cruzan in Illinois: a State Supreme Court addresses the issue of withholding nutrition and hydration from an incompetent patient. PMID- 10106138 TI - A practical guide for hospital counsel in decisions to withhold or withdraw medical treatment. PMID- 10106139 TI - Stochastic modeling as an approach to policy analysis: application to elder abuse. PMID- 10106140 TI - Elder abuse services in the local area: adequacy and need. PMID- 10106141 TI - To report or not to report: physicians' response to elder abuse. PMID- 10106143 TI - The largest HMOs are growing even bigger. PMID- 10106142 TI - The cost of not listening to employees: the case of a union movement at Bradford Hospital. PMID- 10106144 TI - What to say when the patient says, "Let me die". PMID- 10106145 TI - The doctor shortage in rural areas may worsen. PMID- 10106146 TI - Is your malpractice coverage like the emperor's new clothes? PMID- 10106147 TI - Earnings make a huge breakthrough. PMID- 10106148 TI - Games insurers play with your reimbursements. PMID- 10106149 TI - What you'd make if you worked for an HMO. PMID- 10106150 TI - Are health-care services worth their cost? PMID- 10106151 TI - Take it from a D.C.: a lot of chiropractic is a sham. PMID- 10106152 TI - What experiences contribute to satisfaction with the hospital? PMID- 10106153 TI - 'Hotline' reveals bills leaving bad impression. PMID- 10106154 TI - Confronting the nursing shortage: be innovative. PMID- 10106156 TI - Dual responsibility: how much should remain at the board table? PMID- 10106155 TI - AIDS. Starting the second decade. PMID- 10106157 TI - The auxilian: a member of the team. PMID- 10106158 TI - Preparing potential board members. PMID- 10106159 TI - Public opinion, some international comparisons, and the future of the U. S. health care system. PMID- 10106160 TI - Hospital bills source of ire. PMID- 10106161 TI - Public attitudes about health care in Michigan. PMID- 10106163 TI - 48% say health costs are about right. PMID- 10106162 TI - Tornado disaster tests hospitals. PMID- 10106164 TI - AHA reform draft excludes hospital contributions. PMID- 10106165 TI - Utah's tax-exemption rules called too lenient. PMID- 10106166 TI - Reforms likely to promote savings through prevention. PMID- 10106167 TI - Hospitals stretch to meet needs of young and old. AB - The two extremes of the population spectrum tend to need healthcare services the most, and hospitals face a shortage of resources in their attempts to serve both the very young and very old. The elderly have a political voice and the security of Medicare, but hospitals still strain to cover their costs. Policy attention is now focusing on the plight of uninsured children, but it hasn't translated into significant funding. PMID- 10106168 TI - Purchasing groups scramble to enlist Adventist members. PMID- 10106169 TI - Framework for reform. AB - Ordinary people are starting to add their voices to the debate on the U.S. healthcare system. But the chorus is not yet loud enough to transcend a budget crisis, a savings and loan bailout, competing interests of other industries and a siege of self-interest within the healthcare industry. PMID- 10106170 TI - Foundation enlists hospitals in mission of prevention. PMID- 10106171 TI - Rural cooperative consolidates expertise. PMID- 10106172 TI - Appeals court upholds hospital's right to require employee AIDS testing. PMID- 10106173 TI - San Francisco clinics plan new payment policy. PMID- 10106174 TI - Fledgling IBM-Baxter joint venture confronts start-up struggles, formidable competition. AB - Spectrum Healthcare Solutions, the potentially powerful marriage of software operations at International Business Machines and Baxter Healthcare Corp., has held its own but hasn't jelled as quickly as observers had hoped. While the venture gears up, it faces stiff challenges from competitors. PMID- 10106175 TI - Negotiated fees climbing at slower rate. PMID- 10106176 TI - Reprieve ends; hospital margins slide in 1989 as costs climb, debt bill grows. AB - Hospital profitability dipped once again in 1989 after a one-year reprieve from a pattern of sinking margins that has developed since 1985, according to an annual study published by Deloitte & Touche and Health Care Investment Analysts. PMID- 10106177 TI - Call-up of reserves affecting hospitals. PMID- 10106178 TI - IRS goes easy on not-for-profit lobbies. PMID- 10106179 TI - Rockford merger rejection not best for patients--briefs. PMID- 10106181 TI - Last of 3 new UCLA medical facilities opens. PMID- 10106180 TI - Middle East crisis frustrates offerings. PMID- 10106182 TI - AHA reform plan slightly modified. PMID- 10106184 TI - Defensive medicine: is legal protection the only motive? AB - This article on defensive medicine is the fifth in a periodic series of articles about rising healthcare costs. Specifically, the series explores healthcare expenditures on items other than direct patient care. The intent of the series is to indicate areas of hospital operations that may need trimming, particularly if executives want purchasers and payers of care to know that hospitals are doing everything they can to minimize costs without sacrificing quality of care. Like regulatory costs, which were covered in the last article, defensive medicine is sometimes beyond the control of hospitals. The first report of the series appeared Jan. 15; subsequent articles appeared April 30, Aug. 6 and Aug. 20. PMID- 10106183 TI - Census throws rural interests for a loss. PMID- 10106185 TI - Opposition may jeopardize AOHA, AHA consolidation. PMID- 10106186 TI - Hospitals must close the gap between high price, low regard. AB - A recent survey on perceptions of value showed how poorly hospital services are regarded when compared with their cost. Arthur Sturm calls the survey disturbing, but even more disturbing is how lightly the healthcare industry seems to be taking the results. PMID- 10106187 TI - Group-practice model brings nursing unit's turnover to nil. PMID- 10106188 TI - Better contract management, right mix of services can cut equipment maintenance cost. AB - More hospitals are trying to save on in-house staff costs by contracting out for equipment maintenance. But some experts say the short-term gain in operating dollars may not be worth the long-term cost. Prospects for savings depend on how well the service contracts are managed. PMID- 10106190 TI - Severely mentally ill receive low-quality care, group says. PMID- 10106189 TI - Review firms under review. PMID- 10106191 TI - Boost fund-raising efforts, execs urged. PMID- 10106192 TI - NLRB supports review of rules by high court. PMID- 10106193 TI - U.S. execs find Romanian health system 'depraved'. PMID- 10106194 TI - Hospitals reassess home-care ventures. AB - Hospitals viewed home healthcare as a golden egg to add to their diversification strategy basket in the 1980s. So luring is the $16 billion home-care market that the number of participating hospitals has nearly tripled to 2,000 since 1983. PMID- 10106195 TI - CEOs' passion for building fuels growth of home care. PMID- 10106196 TI - Illinois testing severity adjustment system to compare hospital charges, utilization. PMID- 10106197 TI - Virginia legal battle highlights unrest between hospitals, physicians. AB - A bitter dispute over a proposed management-services contract has ended a decades old business alliance between Culpepper (Va.) Memorial Hospital and Virginia Radiology Associates. PMID- 10106198 TI - Maxicare campaign theme: 'All is well'. PMID- 10106199 TI - UCLA facility aims to alter exclusive image. PMID- 10106200 TI - Sandoz pressured to make drug accessible. PMID- 10106201 TI - IRS opinions outline criteria for judging HMO tax status. PMID- 10106202 TI - Experts outline managed-care strategies. AB - Hospitals and physicians are wasting time, energy and money trying to be insurance agents when they should be trying to figure out the best setting for treating patients, says a new book edited by Peter Boland, a Berkeley, Calif., healthcare consultant. PMID- 10106203 TI - Commission expected to recommend reform of N.J. hospital payment system. PMID- 10106204 TI - International aging policy group formed. PMID- 10106205 TI - Proposals to force drug discounts get boost. PMID- 10106206 TI - UB-82 forms offer wealth of information, misinformation. AB - UB-82s, those ubiquitous green forms hospitals rely on for proper reimbursement, also are being used as a research tool, a purpose for which they weren't designed. While the data have some valid applications, flaws such as inconsistent coding, distorted data and omitted information make their use unreliable for broad studies in such critical areas as quality of care and utilization. PMID- 10106207 TI - Backlash prompts AOHA to call off plan to join AHA. PMID- 10106208 TI - Groups vie for development contract. PMID- 10106209 TI - Study downplays effect of severity on some teaching hospitals' costs. PMID- 10106210 TI - Problems prompt second thoughts about Mass. universal health plan. AB - Support for Massachusetts' universal health insurance law has eroded since being signed into law 2 1/2 years ago. A budget crisis has made a political issue out of the law's cost, but providers now fear the cost estimates are vastly underestimated. And a network of interconnected compromises is in danger of coming apart. PMID- 10106211 TI - Extra savings cited in AmeriNet buying plan. PMID- 10106212 TI - Hospital sold on single-distributor system. PMID- 10106213 TI - Health PACs modest donors--study. PMID- 10106214 TI - Claims help can benefit consumers, providers. PMID- 10106215 TI - Automated systems can help dial up more claims dollars. AB - Overdue outpatient bills can pile up, but the relatively small amount of money per bill makes it hard to justify a staffer's time dialing numbers all day. For more and more hospitals, the solution is an automatic dialing system. PMID- 10106216 TI - AHA head gets vote of confidence. PMID- 10106217 TI - Extra funds sought for Texas border. PMID- 10106218 TI - Market/regulation changes prompt diversification interest. PMID- 10106219 TI - Making effective use of the pre-admission conference. PMID- 10106220 TI - The social worker as an effective PR representative. PMID- 10106221 TI - Increase staff morale by building an effective team. PMID- 10106222 TI - Specialized forms promote regulatory compliance. PMID- 10106223 TI - AHCA (American Health Care Association) urges providers: "Make best use of OBRA". PMID- 10106224 TI - A practical rationale for trustee education. AB - In addition to the need for effective trustee orientation, continuous development is important for all board members to help them focus on strategic goals and develop leadership skills. PMID- 10106225 TI - Community hospital affiliates. PMID- 10106226 TI - Using criteria for medical staff reappointment. PMID- 10106227 TI - Business demands cost reforms. PMID- 10106229 TI - Hospital and corporate boards: growing closer. PMID- 10106228 TI - Cultivating physician leaders. PMID- 10106230 TI - Successful community relations programs need trustees' help. PMID- 10106231 TI - Identifying drug use prenatally. PMID- 10106232 TI - The Planetree model: personalized patient care. AB - Initiated at a San Francisco hospital, the Planetree model hospital unit encourages patients and families to be active participants in their own care by challenging some of the traditions of hospitalization. PMID- 10106234 TI - First annual fixed-wing survey. PMID- 10106233 TI - Statewide helicopter utilization review: the Massachusetts experience. AB - Air medical services began in Massachusetts in 1982, and Utilization Review (UR) of both programs in the state began in 1985. The UR program consists of external review of all flights according to screening criteria established by an independent Helicopter Utilization Review Committee (HURC). Between 1982 and 1989, over 2,500 flights were reviewed, with under 2% deemed inappropriate by the committee. Results of this process have helped to improve referrals from specific prehospital and hospital care providers, identified specific patient groups of interest, such as those transported for transplants or because of hospital bed shortages in specific regions, and assisted with improved third party reimbursement. Utilization review has not yet assisted with identification of unmet need or inappropriate resource utilization by ground ambulances, and has not compared the outcome of equal levels of care provided by different transport modes. We conclude that a coordinated utilization review process can be of benefit to both patients and air medical services. PMID- 10106235 TI - Position paper on the appropriate use of emergency air medical services. Association of Air Medical Services. AB - Hospitals must document effective use of their resources every three years for the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) through a utilization review program. Air medical services remain a large expense for healthcare institutions, so the board of directors of the Association of Air Medical Services (AAMS) directed the Medical Advisory Committee to develop a document on the appropriate utilization of air medical services. The purpose of the paper was to suggest broad guidelines for the use of air medical services and to thereby help ensure the proper allocation of available resources. This project generated substantial interest among program directors and medical directors. Early drafts were sent out by regional representatives, and a large response resulted. Many revisions were made before the Medical Advisory Committee met to decide the details of the final draft. When completed in May 1990, the document was sent out to all program directors and medical directors for their approval. The response was overwhelmingly positive. In July 1990, the AAMS Board of Directors gave its unanimous approval for the document published here. PMID- 10106236 TI - Regional air medical safety committees. Will they fly? Ours did. PMID- 10106237 TI - Marketing from ground zero. PMID- 10106239 TI - Resources for optimal care of the injured patient: an update. Task Force of the Committee on Trauma, American College of Surgeons. PMID- 10106238 TI - Mountaintop disaster. PMID- 10106240 TI - Screening and breast cancer: a surgical perspective. PMID- 10106241 TI - Profile of the consulting-specifying engineer. PMID- 10106242 TI - Variable-frequency drives take hold in HVAC market. PMID- 10106243 TI - Case management: a primary nursing approach. AB - The Visiting Nurse Association of Albany, Inc., believes that the role of case manager can be readily assumed by the primary care nurse, whose comprehensive knowledge of patient and family ensures quality assurance through increased continuity of care. However, as federal and state regulations and the increased acuity level of patients have changed the scope of basic case management, the VNA has had to redefine agency case management expectations. PMID- 10106244 TI - Blue Cross Blue Shield. Individual case management: a win-win proposition. AB - Individual case management can help ease the emotional and financial costs of long-term illness by identifying high-risk patients early and can help them get the most from their health coverage by managing their benefits. PMID- 10106245 TI - HIV/AIDS home care: an HMO experience. AB - As HIV/AIDS becomes a chronic illness, understanding all the issues of long-term care and home-based services will be paramount for home care agencies. The Group Health Cooperative of Puget Sound has successfully developed a program specifically for HIV and AIDS case management. PMID- 10106246 TI - Fee-for-service case management. Visiting Nurse Services, Seattle, Washington. AB - Recognizing that one of the elderly population's primary needs is better access to information about aging and related services, the Visiting Nurse Services in Seattle developed two programs: ElderCare, which offers information about aging and caregiving; and Consultations in Aging, a private case management program. PMID- 10106247 TI - Physician case management. Reimbursement raises a controversy. AB - Home health agencies are finding themselves in a difficult position over the issue of reimbursement for physician care management. HHAs are generally aware that neither Medicare nor most other insurers will reimburse them for any payments they make to physicians for such activities, but some physicians may not be aware of the legal restrictions imposed on payments to them for certain case management activities. PMID- 10106248 TI - Administrative priorities: decisions and strategies that attract and retain quality staff. AB - This article represents the second part of a presentation delivered at the 1989 National Association for Home Care annual meeting. This segment addresses structural components necessary to attract and retain quality staff, and issues related to retention that are within administrative control. PMID- 10106249 TI - Survey focus: services for PWAs (persons with AIDS). PMID- 10106250 TI - Small talk ... about grants. PMID- 10106251 TI - A practitioner speaks out. PMID- 10106253 TI - R & DP (research and discharge planning). PMID- 10106252 TI - Counselor intervention enhances life, reduces costs. PMID- 10106254 TI - Campaigning for health care reform. PMID- 10106255 TI - The universal health care law in action. PMID- 10106256 TI - Patchwork not perestroika. The promise and problems of UNY*Care. PMID- 10106257 TI - Importing health care reform? Issues in transposing Canada's health care system to the United States. PMID- 10106258 TI - The debate is in the states. PMID- 10106259 TI - Organization and operation of P & T Committees in the state of Florida: a survey. AB - To determine the structure and function of P & T Committees in Florida, a survey was initiated. Questionnaires were mailed to all 289 hospitals in the state. Topics addressed included hospital demographics (type of service provided, institution ownership, hospital size), P & T Committee structure (size of the committee, membership breakdown by specialty, chairman specialty, number of meetings per year), formulary additions (personnel authorized to request drug additions, process for adding drugs to the formulary, monitoring new drug use), and formulary systems (prevalence of therapeutic interchange programs, methods of communicating formulary changes). Overall survey response rate was 71.5%. In general, P & T Committees in Florida appear to be functioning at a relatively high level. Since there is little current information about the composition and operation of P & T Committees in hospitals around the country, it is hoped that this survey will be useful to P & T Committees that wish to upgrade or expand their activities. PMID- 10106260 TI - Doing it yourself. PMID- 10106261 TI - Conflict of interest. Part 1: Ethical implications of the hospital-physician joint venture. PMID- 10106262 TI - The role of information systems in managing quality. PMID- 10106263 TI - Healthcare reform: strategic implications for hospitals. PMID- 10106264 TI - The shape of things to come: Part 3. Inspiring peak performance. AB - New "contingent" compensation programs tailored to the hospital work unit provide employees with incentive payments for outstanding performance that augment--or replace--the annual merit increase. PMID- 10106265 TI - Court examines radiologist's displacement after loss of exclusive contract. PMID- 10106266 TI - Meeting those who pay the health care bill: HealthTrust Chairman reaches out to business. PMID- 10106267 TI - Rationing care: Oregon law ushers in national debate. PMID- 10106268 TI - Connections at Rush-Presbyterian-St. Luke's Medical Center. PMID- 10106270 TI - Contractors on the grow. AB - These 15 foodservice management companies say there is plenty of market share to be won. Here's what they are doing to keep growth on the rise. PMID- 10106269 TI - Sullivan's role in health policy reform. PMID- 10106271 TI - Jobs '90. Attitude aptitude. AB - Is your job all it's cracked up to be? Take R&I's job$ quiz and compare your opinions about career and industry issues with those of your executive colleagues. PMID- 10106272 TI - The teaching of health statistics: meeting the needs of a changing practice. AB - The findings of the study did support the faculty's hypotheses. First, only 50% of the hospitals retain responsibility for the statistical function. This finding was, however, affected by the size of the hospital, with 100% of the hospitals of 400 beds or less retaining such responsibility. Second, the findings showed that only 12.5% of the hospitals had entirely manual statistical systems. However, 50% of the hospitals did compile some statistics manually, including the daily hospital census and discharge service statistics. Finally, in looking at the UT Memphis statistics curriculum and those of 14 other medical record administration programs in the Southeast, the hypothesis that curricula did not mirror this changing practice was confirmed. Although 100% of the programs surveyed had students memorize statistical formulas, only 36% had students working with computers in the statistics course. Of the 14 programs, only 6 specifically covered QA of statistical data in the statistics course, and 9 did not deal at all with how to assess the adequacy of policies and procedures for gathering statistical information. As a result of these findings, UT Memphis has modified its statistical course to increase the emphasis on computerization, QA, and assessment of statistical policies and procedures. These changes will better prepare the UT Memphis graduate for the statistical responsibilities that they will face in the workplace. PMID- 10106274 TI - Participation and persistence in a nontraditional allied health education program. AB - The results of this study suggest the following three practical applications. First, adult educators and program planners in medical record administration can use the results of achievement motivation studies in recruitment, counseling, and screening efforts in both medical record technology and nontraditional ART progression programs to determine which ART candidates possess a strong need to achieve. Once identified, these individuals may be the most successful in reducing or eliminating situational, institutional, dispositional, and informational barriers to participation and persistence. Second, to increase the number of ARTs participating in nontraditional medical record administration programs, educators need to institute counseling and support programs to encourage and assist ARTs in overcoming barriers to participation that were found in this study. Lastly, based on the finding that ARTs in this study were fairly internal in their control orientations as a group, educators will need to orient counseling and advising strategies and educational activities toward this control orientation. This can be done by providing independent learning projects, correspondence learning, and other individually oriented instructional methods. Further research is needed to determine whether findings are applicable to other medical record administration nontraditional program participants and nonparticipants and to a larger, random sample of active ARTs. A study examining the characteristics of this study in other health professions is needed to determine if professionals working in other allied health fields exhibit motivational characteristics and coping strategies similar to the ARTs in this study.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106273 TI - The effects of positive incentive programs on physician chart completion. AB - It seems evident that both concurrent review programs and positive incentive programs have been implemented by a number of facilities in which little, if any, monitoring has occurred. Only half of the hospitals performing concurrent analysis provided statistics concerning the percentage of daily discharges arriving in the medical record department complete. Only one fourth of the hospitals provided information concerning the number of incomplete and delinquent medical records before and after the implementation of concurrent review. These data underscore the need for medical record administrators to evaluate the effectiveness of various strategies used to improve completion of medical records. Likewise, only a few of the hospitals that have implemented an incentive program for chart completion were able to provide all of the requested statistics concerning their chart status prior to and following the implementation of their programs. The results of the study indicate that numerous innovative procedures have been implemented in hospitals, with varying degrees of impact on the number of incomplete and delinquent medical records. The use of positive incentive programs in conjunction with punitive action is effective in helping to reduce the number of incomplete medical records. PMID- 10106275 TI - Health: another gender gap. A crackdown on research bias against women should produce change. PMID- 10106277 TI - Rules may mandate accurate discount records by hospitals. PMID- 10106276 TI - Questions linger over Medicare malpractice rules. PMID- 10106278 TI - Keeping the record straight: guidelines for charting. Professional Liability Program, Farmers Insurance Group of Companies. PMID- 10106279 TI - Perspectives. Medicare rate hike challenges hospices. PMID- 10106280 TI - Medicare program; changes in payment policy for direct graduate medical education -HCFA. Correction of final rule. AB - This document corrects technical errors to the final rule published in the September 29, 1989 issue of the Federal Register [FR Doc. 89-23026], beginning on page 40286. PMID- 10106281 TI - Achieving competitive advantage through information management. AB - Healthcare organizations exist to deliver quality services at appropriate prices. The issue, of course, is how to define quality services and appropriate prices- or, in other words, how to compete. To ignore this question is to invite erosion of market share and deterioration of margins--the twin components of superior performance. PMID- 10106282 TI - Computers in Healthcare 1990 market directory update. PMID- 10106283 TI - EMS' 1990 EMT and paramedic training facilities. PMID- 10106284 TI - Successful strategies for hiring a chef. PMID- 10106285 TI - Catheterization lab fulfills need, creates outpatient care 'zone'. PMID- 10106286 TI - In-house construction: will it work for you? PMID- 10106287 TI - Marketing strategies for small-share players. PMID- 10106288 TI - Managing resources for world-class performance. PMID- 10106289 TI - Diabetes Management Center: a dream come true. PMID- 10106290 TI - Sharing the wealth. Catholic multi-institutional systems offer an array of services to nonmember facilities. PMID- 10106291 TI - The push for standardization. The origins of the Catholic Hospital Association, 1914-1920. PMID- 10106292 TI - Louder than words. A multi-institutional system sets ethical standards for corporate action. AB - After establishing its Resource Center for Ethical concerns, Wheaton Franciscan Services, Inc. (WFSI), Wheaton, IL, set out to develop corporate ethics standards. The standards were to manifest a vision that acknowledged the mutuality of relationships among providers and those they serve, and among local and global communities. To establish "ownership" of the standards, WFSI wanted to involve as many people as possible in the planning process. Center staff established a 25-member working task force with broad representation of disciplines and system institutions, then prepared a position paper to serve as a basis for the formulation of the standards. The paper examined current issues in corporate ethics, the theoretical basis of corporate ethics, the appropriateness of corporate ethics for Catholic-sponsored institutions, and the role ethics standards play in an institutional setting. Staff then prepared the first draft of corporate standards. At the first workshop in October 1988, task force members critiqued the draft and modified the proposed corporate standards. Staff sent the draft for critique to a total of 157 persons throughout the system and encouraged them to pass it around to get the advice of others. From the feedback, staff compiled a third draft, which was ultimately approved. WFSI's Corporate Ethics Standards addresses provision of services, relationship with employees, social responsibility, confidentiality, and conflict of interest. PMID- 10106293 TI - Cuts to the quick. How to soften the blow of layoffs. AB - No one relishes a layoff, but with the volatile changes in healthcare, financial imperatives may force many administrators into the unpleasant task of laying off trusted employees. When faced with the possibility of closing a hospital's doors, personnel reductions may be the only reasonable alternative. The actual process of laying off employees can be traumatic. At a time so highly charged with emotion, it is best to have a procedure to follow. Layoffs should affect employees in every pay grade and not single out any one group. Also, managers should take employees outside their department to give them the bad news. The plan should also include a list of those to be let go, criteria for the order of layoffs, and a list of teams to meet with affected employees. In addition, managers should ascertain the total cash entitlement for each employee to be let go and arrange for a complete paycheck on the last day, prepare to discuss other pay options that are available, gather all documents pertaining to the employee, and give the employee all the information in writing. PMID- 10106295 TI - Information resources. Look no further. Here's the source of all the EMS information you need. PMID- 10106294 TI - A system of values. Values committees help a system preserve its mission. AB - In response to the challenge of maintaining their Christian values in the face of increasing economic pressures, St. Joseph Health System in Orange, CA, has implemented its VISION program (Values Integration Systemwide in Ongoing Networking). The program consists of values implementation policies, self assessment, and regular systemwide reporting. The idea for evaluating values implementation took shape in 1987 at a representative task force meeting. After agreeing on a conceptual framework, the group recommended the formation of values committees to assess their organizations' status and develop action plans. The task force provided the first step by identifying nine areas for self-assessment. The committees met in January 1988 to examine their tasks and share ideas. They were encouraged to translate the values concepts into actual attitudes and behaviors that could be applied in their work. Later they gauged the relative stages of their entities' values implementation through surveys, assessments, and interaction. PMID- 10106296 TI - EMS in the United States--a survey of providers in the 200 most populous cities. PMID- 10106297 TI - Government intervenes in suit. PMID- 10106298 TI - Report upholds Medicare trust fund forecast. PMID- 10106299 TI - Supreme Court to decide states' right to sue. PMID- 10106300 TI - What it takes to "turn around" an OR suite. PMID- 10106301 TI - Medicaid spend down: now we can separate myth from reality. PMID- 10106302 TI - Understanding and utilizing Medicare ancillary services. PMID- 10106303 TI - HCFA's manual revision on community spouse protection. PMID- 10106305 TI - Predicting financial failure. PMID- 10106304 TI - The strategy checkup: how healthy is your strategic plan? PMID- 10106306 TI - Special report. HHS sends FY91 budget to Congress. PMID- 10106307 TI - Statistical process control: a quantitative approach to ensuring quality. PMID- 10106308 TI - Statement of organization, functions, and delegations of authority--HCFA. PMID- 10106309 TI - Medicare program; establishment of Medicare Economic Index effective April 1, 1990--HCFA. Notice. AB - This notice updates the Medicare Economic Index (MEI), which is used to calculate the prevailing charge levels that help to determine reasonable charges for certain physician services under the Medicare Supplementary Medical Insurance (Part B) program. For physician services furnished on or after April 1, 1990, and before January 1, 1991 the increase for primary care services will be 4.2 percent, and for other services it will be 2.0 percent. PMID- 10106310 TI - A new decade brings new challenges. PMID- 10106311 TI - Cost strategies for filing CONs. PMID- 10106312 TI - Post-SNF/ICF Medicaid rates. PMID- 10106313 TI - Physician payment reform. PMID- 10106314 TI - Physician payment "reform". OBRA '89 highlights. PMID- 10106315 TI - Improving hospital board effectiveness: an update. AB - This article defines governance as the making or not making of important decisions and the related distribution of legitimate power and authority to make them. A distinction is drawn between what governing boards do that is not restricted to governance, and governance that is not the exclusive function of governing boards. This article focuses on governing boards. Recommendations are made for improving the effectiveness of hospital governing boards. Discussed in detail are integrating clinician and administrative governance; supporting management in managing change; focusing and energizing the board on policymaking; and, specifying and evaluating the hospital's contribution to the health of a defined population at reasonable cost. The author surveys the current hospital environment and reconsiders and updates his 1985 recommendations on improving governance. Board effectiveness is reconceptualized, and those recommendations that have been made to improve board structure and function are reviewed. Governing boards are shown to work differently in multihospital systems, hospital alliances, and under restructuring. A research agenda to improve hospital board effectiveness is proposed. PMID- 10106316 TI - 1989 Herbert M. Platter luncheon address. The Federation: a personal perspective. PMID- 10106317 TI - Specialty PPOs--finding the niche opportunities. PMID- 10106318 TI - Alternative futures in health care. AB - Many trends will shape the future of medicine and health care architecture, including economics, social, environmental and political forces; however a glimpse into probable futures suggests that technology will play a dominant role in medicine, greatly affecting the types of health care facilities needed. PMID- 10106319 TI - Medicaid litigation: providers challenge state constraints. PMID- 10106320 TI - Redesigning facilities for people with AIDS. PMID- 10106321 TI - 'Tax cut could hurt hospital fund.'. PMID- 10106322 TI - New York, Massachusetts plan large Medicaid cuts. PMID- 10106323 TI - Speedy Medicare payments not likely soon. PMID- 10106324 TI - HCA, Humana may have to repay funds. PMID- 10106325 TI - Panel recommends 5% average Medicare payment raise. PMID- 10106326 TI - Bush budget pares $5.5 billion from Medicare. PMID- 10106328 TI - Panel debates rationing of care. PMID- 10106327 TI - Pa.'s Medicaid system illegal, judge rules. PMID- 10106329 TI - Veterans groups say budget hike not enough. PMID- 10106330 TI - Use Social Security surplus for hospitals, expert urges. PMID- 10106331 TI - Assistance programs offer relief for rural hospitals. PMID- 10106332 TI - Congress strengthens MSP (Medicare secondary payer) enforcement. PMID- 10106333 TI - Budgets and the patient accounts manager: putting receivables expertise to work. PMID- 10106334 TI - Good budgeting means cash forecasting. PMID- 10106335 TI - Reconceptualizing the nature and consequences of part-time work. AB - This article presents a theoretical framework for understanding the impact of part-time work on employees' attitudes and behaviors. A series of hypotheses also are presented to explain the varying consequences that different types of part time employment arrangements, work-context factors, and demographic variables have on the experiences of part-time workers. Future issues for theory development and research methodology are discussed as well. PMID- 10106336 TI - Psychotherapy in the HMO: clinical perspectives. AB - Tensions between expectations and possibilities in providing mental health services are more evident in closed systems like an HMO. These stresses have an impact on clinical providers of psychotherapy. Because further contact cannot substitute for lack of clinical success, special demand is placed on the clinician to achieve an alliance and then reach closure. The situation of the psychotherapist in the HMO is discussed. PMID- 10106337 TI - Proper respect. AB - There is no reason the expect that governmental and other efforts to regulate medical practice in the interest of cost containment will abate even though there is general skepticism that it will produce meaningful savings. In this situation, multispecialty group practices should continue to exploit the comparatively favorable climate that they now enjoy by insisting that their incentives and performances should replace outmoded models as benchmarks of efficiency and quality for the national agenda, especially as the sentiment for some sort of national health care system increases. PMID- 10106338 TI - A clinical laboratory environmental assessment and its implications for strategic planning: Part I. PMID- 10106339 TI - How to conduct quality meetings. AB - Meetings are commonplace in modern America with the average executive spending 17 hours a week in session. In addition to the working-hours meetings, nearly everyone participates in meetings of professional societies, civic associations, service clubs, and church groups. With meetings occurring so frequently one could expect them to be a source of satisfaction and accomplishment. However, this often is not the case. This article will help to improve the quality of your meetings, whether you are a leader or a participant. It is based on the premise that an effective meeting achieves its objective within a reasonable amount of time. The article is divided into four sections: planning meetings, conducting meetings, improving meetings, and a conclusion. PMID- 10106340 TI - Quality assurance, an administrative means to a managerial end: Part I. A historical overview. AB - Quality has become the hallmark of industrial excellence. Many diverse factors have heightened national concern about managing quality control throughout the health-care industry, including laboratory services. Industry-wide focus on quality control has created a need for an administrative program to evaluate its effectiveness. That program is medical quality assurance. Because of national and industry-wide concern, development of quality assurance theory has gained increasing importance in medical accreditation and management circles. Scrutiny of the application of quality assurance has become particularly prominent during accreditation inspections. Implementing quality assurance programs now demands more of already finite resources. The professional laboratory manager should understand how quality assurance has developed in the United States during the past 150 years. The well-informed manager should recognize why the health-care industry only recently began to develop its own expertise in quality assurance. It is also worthwhile to understand how heavily health care has relied on the lessons learned in the non-health-care sector. This three-part series will present information that will help in applying quality assurance more effectively as a management tool in the medical laboratory. This first part outlines the early industrial, socioeconomic, and medicolegal background of quality assurance. Terminology is defined with some distinction made between the terms management and administration. The second part will address current accreditation requirements. Special emphasis will be placed on the practical application of accreditation guidelines, providing a template for quality assurance methods in the medical laboratory. The third part will provide an overview of quality assurance as a total management tool with some suggestions for developing and implementing a quality assurance program. PMID- 10106341 TI - Strategic management: lessons for success. PMID- 10106343 TI - Strategic planning for information technology. Part III: Development criteria & considerations. PMID- 10106342 TI - Special report. Par or non-par: still a big decision despite physician payment reform. PMID- 10106344 TI - Medicare program: updated HMO qualification determinations--HCFA. Notice. AB - This notice sets forth the names, addresses, dates of qualification, and service areas or expanded service areas of entities determined to be Federally qualified health maintenance organizations during the period November 1988 through December 1989. PMID- 10106345 TI - HCFA clarifies Medicare SNF transition coverage. PMID- 10106346 TI - Priorities for a turnaround. PMID- 10106348 TI - Paid newsletters offer profit potential to medical centers. PMID- 10106347 TI - Designing effective health promotion and disease prevention programs. AB - Numerous researchers stress the importance of health promotion and disease prevention programs as a means of helping people to foster positive health and lifestyle habits. Typically, health promotion and disease prevention programs strive to educate the public about risks involved in health abuses and the impact of lifestyle upon health status. Research, however, also reveals that health promotion and disease programs are often poorly designed. In response to the problem, a course model for teaching future health professionals how to strategically plan health promotion and disease prevention programs is presented. PMID- 10106349 TI - Partners: group practices and hospitals. AB - Many hospital executives see the emergence of medical group practices as a threat to their autonomy. However, the degree of future success of hospitals and group practices may depend on their willingness and ability to develop common goals and strategies. PMID- 10106350 TI - Meeting managed mental health demands. AB - The market for managed mental health care is growing and payer dissatisfaction with existing arrangements is creating significant opportunities for providers who can obtain good therapeutic outcomes in the least restrictive/expensive way. This article describes what a hospital may offer to the market and the special considerations involved. PMID- 10106351 TI - Strategic planning for material services in a multihospital system. PMID- 10106352 TI - The Baptist Medical Centers' model: a general systems approach to managing material in a health care organization. PMID- 10106353 TI - Operations research and information technology for materiel management in the 1990s. PMID- 10106354 TI - Ionic versus nonionic contrast media: the cutting edge. PMID- 10106355 TI - Materiel management in the 1990s: a new paradigm. PMID- 10106356 TI - Viewpoints: evaluating the RBRVS impact. What are key health policy-makers saying?. Interview by Diana L. Madden. PMID- 10106357 TI - Evolution of a revolution. Highlights of ASIM's leadership to reform the physician payment system. PMID- 10106358 TI - A decade to remember: ASIM and RBRVS. PMID- 10106359 TI - Here at last: RBRVS and physician payment reform. PMID- 10106360 TI - RBRVS and physician payment reform: what it will mean for you. PMID- 10106361 TI - Service with a smile. PMID- 10106362 TI - The strategies and autonomy of university hospitals in competitive environments. AB - University-owned hospitals face increasingly threatening and unstable environments. This article examines the strategies that university-owned hospitals are using, and can use, to respond to their changing environments. Further, it examines factors that can hinder or promote the effective development of university-owned hospital strategies. PMID- 10106363 TI - Hospital-physician joint ventures: a strategic approach for both dimensions of success. AB - Joint ventures between hospitals and the physicians on their medical staffs have produced successes and failures. Each joint venture has two very different dimensions of success--financial and collaborative. The most successful ventures are able to accomplish both of these often conflicting goals. To enhance hospital executives' success in joint ventures with physicians, a strategic approach with a series of six steps and their corresponding models or maps is proposed. The steps in this strategic approach are: (1) identify key stakeholders and linkages among them; (2) surface stakeholder conflict using problem-oriented maps; (3) diagnose the venture on both dimensions of success; (4) classify the venture using both dimensions of success; (5) select a strategy to optimize the venture's current potential for success; and (6) select an approach to transform the venture with limited potential for success. PMID- 10106364 TI - The health care quality quagmire: some signposts. AB - Escalating price competition in health care has pushed providers and purchasers to scramble for outcome measures to use as indicators of minimum acceptable quality. This article suggests that health care managers assist purchasers in developing quality measures that include patient perceptions in addition to technical competence and also build a general philosophy that values quality. PMID- 10106365 TI - Annual pharmaceutical manufacturers' directory--1990. PMID- 10106366 TI - "Trade-off" between medical cost controls and quality of care? Maybe, maybe not! Part I. PMID- 10106367 TI - QA, RM and UM functions require coordinated information management. AB - The public demand for access to health care data in general has created a flurry of activity at the health care provider level. Specifically, data on quality plays a pivotal role in this competitive, litigious and cost-conscious environment. Currently, data (manual or computerized) on clinical and organizational performance is sparse, although health care institutions have traditionally had QA and related utilization review, risk management and peer review activities in place to fulfill requirements for licensing and accreditation. Where data exists in isolated pockets, little coordination or integration has occurred, thereby diminishing the potential value of the data as part of a comprehensive information system. Today, institutions are responding to the demands for QA, RM, UR data in many ways. Much progress has been made in establishing comprehensive QA programs utilizing centralized, coordinated data from multiple sources to demonstrate both clinical and organizational performance. These comprehensive programs have clearly defined the need for computerization with the ability to re-use existing information. Applying this technology, however, requires assessment and planning. Allowing department oriented, microcomputer-based application prevents sharing of resources and in many cases results in redundant and perhaps uncoordinated data capture. Decentralizing of the decision-making process leaves the ultimate selection of computerized QA and related applications to the individual user, whose focus is generally centered on his/her own priority. These systems are frequently incompatible with other existing systems. This approach will not support the institution's need to provide timely, accurate, complete information about the quality of service rendered nor information critical for internal management and planning.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106368 TI - Monitoring the care of the ventilator-dependent patient. PMID- 10106370 TI - 1989 top 10 trends revisited: batting average .800. PMID- 10106369 TI - The new medicine: Part I--"Medical megatrends" for the 1990s. PMID- 10106371 TI - The new medicine: Part II--Constructing an integrated health system (IHS). PMID- 10106372 TI - Restructuring the hospital-physician relationship. PMID- 10106373 TI - Select IS bibliography. PMID- 10106374 TI - The environment and future of health information systems. PMID- 10106375 TI - Expectations and outcome skills of a generalist health care administrator. AB - The question of the degree of technical versus managerial competence to be found in future graduates from health administration programs is not easily resolved. In the HIMSS 1988 survey of CIOs the attributes needed for success are listed in descending rank order as follows: leadership ability, vision/imagination, knowledge of hospital systems, business acumen, decisiveness, and technical competence. CIOs ranked technical competence as less important than other attributes associated with general management success. The expectations for attitudes, knowledge, and skills presented in this article support the greater importance of management abilities relative to pure technical competence. However, it is vital that an appropriate level of technical knowledge and skill be maintained to enable future alumni of health administration programs to function effectively as administrators. Depending on their role in a health care organization, greater or lesser technical knowledge may be needed. Those pursuing a career path toward CIO must, of necessity, have greater technical knowledge and skill. We have discussed necessary and expected attitudes, knowledge, and skills that will be needed by the generalist health administration graduate in the future. It will be important to develop and maintain an attitude that MIS is a strategic tool, that health care technology is a corporate asset, and that information is power. Graduates must recognize the necessity of maintaining and enhancing their knowledge and skills through continuing education. The knowledge base of MIS education should focus on determining information needs to support strategic goals, understanding of general systems theory, principles of systems analysis, design, implementation and maintenance, awareness and exposure to standard application software, and an awareness of external sources of data.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106376 TI - IS curriculum assessment and implementation strategies. PMID- 10106377 TI - A resource guide for faculty and practitioners. PMID- 10106378 TI - Reform of Medicare reimbursement for physician services. PMID- 10106379 TI - Implementing the Health Care Quality Improvement Act. PMID- 10106380 TI - An examination of the Omnibus Budget Reconciliation Act of 1989: the evolution of national health policy. PMID- 10106381 TI - How to make yourself a lightning rod for Medicare. PMID- 10106382 TI - Growing into laboratory quality assurance. PMID- 10106383 TI - Panel ordered to focus on Medicaid, uninsured. PMID- 10106385 TI - Patient outcomes emphasized in recommended PRO reforms. PMID- 10106384 TI - Hospitals reject AMA's overture to join forces over Medicare. PMID- 10106386 TI - Medication refusal: suggestions for intervention. AB - The civil rights and deinstitutionalization movements of the 1960s gave rise to legal and ethical challenges to the physician's authority to prescribe psychoactive medication to patients who refuse such medication. While no definitive legal ruling has been rendered in this area--and may never be rendered -a review of the important cases to date identifies consistent themes of patient competency, the possibility of physical threat, risks versus benefits, due process, and patient advocacy, all of which form the framework for intervening with patients who choose to refuse medication while preserving their right to do so. PMID- 10106387 TI - Inpatient treatment of alcoholism: a necessary part of the therapeutic armamentarium. AB - Recent reviews of alcoholism treatment have argued strongly against the efficacy of inpatient treatment for alcoholic patients. This paper briefly considers the findings those reviews were based on and highlights some of the flaws that have led to the conclusion that inpatient treatment for alcoholism is unsuccessful and unnecessary. This paper suggests that the negative reports about inpatient treatment are biased and argues for the effectiveness of inpatient treatment, especially for patients with severe alcohol dependence or extensive social, psychiatric, or medical comorbidity. PMID- 10106388 TI - Fraud and abuse. PMID- 10106389 TI - A new breeze. PMID- 10106390 TI - The MRI decision process. PMID- 10106391 TI - U.S. Air Force patient airlift. From balloons to high-speed jets. PMID- 10106392 TI - Privacy Act of 1974; systems of records--HCFA. Deletion of Privacy Act System of Records from HCFA Inventory. AB - On August 21, 1989, HCFA published a notice of a new Privacy Act system of records, "Drug Bill Processor Records on Medicare Prescription Drug Beneficiaries," HHS/HCFA/BPO No. 09-70-0528 (54 FR 34612). This was under the authority of section 1842(o)(4) of the Social Security Act as amended by the Medicare Catastrophic Coverage Act (MCCA) of 1988 (Pub. L 100-360). This system was established to enable HCFA to collect and maintain records on Medicare prescription drug benefits for Medicare beneficiaries. Because the MCCA was repealed by the Congress, we are hereby giving notice that we are deleting this system from our inventory as required by the Privacy Act and Office of Management and Budget guidelines. PMID- 10106393 TI - Fiscal year 1990 estimated national average monthly payments for extended care services under Part A of Title XVIII of the Social Security Act--HRSA Notice. AB - This notice announces the Fiscal Year (FY) 1990 estimated national average monthly payments for Medicare extended care services under part A of title XVIII of the Social Security Act. This information is provided for the purpose of determining the limitation on total payments to States under title XXIV of the Public Health Service (PHS) Act, section 2401(a), part A--Formula Grants to States for Home and Community Based Health Services, with respect to Acquired Immune Deficiency Syndrome (AIDS). PMID- 10106394 TI - Privacy Act of 1974; computer matching program--HCFA. Clarification--computer match between HCFA and the Internal Revenue Service (IRS)--notice published in the Federal Register on July 5, 1989. AB - Pursuant to the Computer Matching and Privacy Protection Act of 1988, Public Law 100-503, October 18, 1988, and the Office of Management and Budget (OMB) Guidelines on the Conduct of Matching Programs, the IRS published a notice in the Federal Register (54 FR 28149; July 5, 1989) announcing their intention to conduct a match with a number of Federal and State agencies including HCFA. These matches, in accordance with various provisions of section 6103 of the Internal Revenue Code (IRC) of 1986, provide these agencies with tax information from IRS records to assist them in administering the programs and activities as described. The match with HCFA is pursuant to IRC 6103(1)(7). The IRS is required, upon written request, to disclose current information from returns with respect to unearned income to any Federal, State, or local agency administering certain federally approved programs to provide, among other things, medical assistance. HCFA is publishing this notice to ensure that the public is aware that it is participating in this match to verify Medicaid eligibility. The HHS Data Integrity Board has approved an Agreement between HCFA and the IRS on February 8, 1990, as required by the Computer Matching and Privacy Protection Act of 1988. PMID- 10106395 TI - Hospital preparation: the children's story. AB - This paper reports on the self-identification of hospital preparation learning needs of rural children, both before and after their hospital experience. Children who were scheduled for a hospital admission were interviewed in their home settings 1 to 2 weeks before their hospital admissions. The interviews were replicated 1 week after discharge from the hospital. Changes in knowledge acquisition and learning needs from the pre-hospital to the post-hospital state were examined. The study identifies from the child's perspective the type of information and program delivery method most appropriate to meeting the psychosocial needs of children related to a planned hospital stay. PMID- 10106396 TI - Nurses' perceptions of parent and nurse roles in caring for hospitalized children. AB - Twenty-five nurses were interviewed and asked to describe their perceptions of parent and nurse roles in caring for hospitalized children. Data were analyzed using content analysis. Six types of roles were identified: providing nonmedical care; providing technical and medical care; being a gatekeeper; being an advocate; providing psychosocial care; and providing general care. It seemed that often the nurses' need for control influenced the psychoemotional care they provided for parents. PMID- 10106397 TI - Parents' and health professionals' perceptions concerning parental stress during a child's hospitalization. AB - This study compared mothers', fathers', nurses', and physicians' perceptions of parents' reactions to stressful stimuli when their children were hospitalized. Thirty-six mothers, 14 fathers, 27 nurses, and 23 physicians rated 36 stressful stimuli on an inventory the investigators developed. Analysis of Variance and subsequent multiple comparison tests disclosed numerous differences between parents and health care professionals and between mothers and fathers on the Parental Uncertainty, Annoyance, Child Discomfort, and Negative Emotional States Scales. Further analyses of ratings on individual items from the scales revealed the bases of the differences. Implications for health professionals and directions for further research are discussed. PMID- 10106398 TI - How to plan, organize, and conduct a board/staff retreat. PMID- 10106399 TI - Strategic planning for fundraising. PMID- 10106400 TI - Learning to serve the secondary market. PMID- 10106401 TI - In praise of hierarchy. AB - Hierarchy has not had its day. After 3,000 years as the preferred structure for large organizations, managerial hierarchy is still the most natural and effective organizational form that a big company can employ. Now, as in the past, the key to organizational success is individual accountability, and hierarchy preserves unambiguous accountability for getting work done. Unfortunately, hierarchy is widely misunderstood and abused. Pay grades are confused with real layers of responsibility, for example, and incompetent bosses abound. As a result, many experts now urge us to adopt group-oriented or "flat" structures. But groups are never held accountable as groups for what they do or fail to do, and groups don't have careers. The proper use of hierarchy derives from the nature of work. As organizational tasks range from simple to very complex, there are sharp jumps in the level of difficulty and responsibility. Surprisingly, people in hundreds of companies in dozens of countries agree on where these jumps take place. They are tied to an objective measure-the time span of the longest task or program assigned to each managerial role-and they occur at 3 months, 1 year, 2 years, 5 years, 10 years, and 20 years. As the time span increases, so does the level of experience, knowledge, and mental stamina required to do the work. This increasing level of mental capacity lets companies put people in jobs they can do, it allows managers to add value to the work of their subordinates, it creates hierarchical layers acceptable to everyone in the organization, and it allows employees to be evaluated by people they accept as organizational superiors. Best of all, understanding hierarchy allows organizations to set up hierarchies with no more than seven layers-often fewer-and to know what the structure is good for and how it ought to perform. PMID- 10106402 TI - Five ways to keep disputes out of court. AB - Even if you win, a lawsuit can be a disaster. Attorney fees eat up $20 billion a year in the United States alone, and that doesn't count the cost of diverting key personnel from productive work or of damaging profitable business relationships. But more and more managers are discovering that litigation can be avoided with inventive use of alternative dispute resolution, or ADR. All forms of ADR are designed to do two things: save time and money and soften the sharp edges of the adversarial system. In the majority of cases, disputants settle their differences quickly and to the satisfaction of both parties. In the best of cases, opponents resolve their disputes cooperatively and forge new ties. Arbitration, the oldest and most adversarial form of ADR, is now a compulsory prerequisite to litigation in about 20 states. Mediation, perhaps the most versatile and the least coercive, depends greatly on the skill and personality of the mediator. Other methods include the rent-a-judge program, summary jury trial, and minitrial, all of which simulate real litigation to one degree or another but with greater speed, more privacy, and less expense. (The last two have settled several bitter disputes in weeks-after years of litigation.) Variations and hybrids of ADR methods are limitless. In picking the ADR method best suited to your circumstances, factors to consider include: the extent to which both disputants are committed to ADR, the closeness of the business relationship between the two parties, the need for privacy, the urgency of reaching a settlement, the absolute and relative financial health of both parties, the importance of the principles involved, the complexity of the case, the size of the stakes, and the ability and willingness of company executives to get involved. PMID- 10106403 TI - Ad spending: maintaining market share. AB - Accuracy in manufacturers' advertising budgeting is hampered by reliance on the case rate system, which ties budgets to sales. A better measure is a brand's market share compared with its share of voice (the brand's share of the total value of the main media exposure in that product category). New brands are often "investing" in the market: speaking in a louder voice than their market shares would justify. Popular brands are often "profit taking"--keeping their voices low but enjoying a disproportionately large market share. The interrelationship between market share and share of voice, with either "investing" or "profit taking" the desired result, is not usually considered when determining ad budgets. But as advertisers realize how market share can respond to advertising pressure through switches in the share of voice, this method of market testing should gain in importance. PMID- 10106404 TI - Ad spending: growing market share. AB - If I yell louder but you yell even louder, the audience will hear you. So I shouldn't expect to be heard if I also start yelling louder, unless you become quieter. That, in essence, is the key to the relative share of voice effect in advertising. In most markets, consumer goods markets are in a state of equilibrium, where advertising expenditures are relatively stable and changes in market share are small. To gain ground in market share, a competitor has to launch a huge ad campaign for a sustained period that outspends the biggest rival by at least double. PMID- 10106405 TI - The value-adding CFO: an interview with Disney's Gary Wilson. Interview by Geraldine E. Willigan. AB - Financing a company is more complex than ever-and more important to its economic success. The demands on a CFO are tremendous. Optimizing capital costs requires an unprecedented level of technical sophistication. Yet the best CFOs today are not mere technicians. They are also strategists and innovators. Gary Wilson exemplifies the new CFO. In his 5 years as executive vice president and CFO of the Walt Disney Company and his 12 years at Marriott Corporation, he has shown how the finance function can add value-not just account for it. How does a CFO create value for shareholders? "Just like all the great marketing and operating executives," Wilson says, "by being creative." To Wilson, being creative means rethinking assumptions and finding clever ways to achieve financial and strategic goals. Some of Wilson's innovative deal making-like the off-balance-sheet financing he used at Marriott-is well known. At Marriott, he discovered the power of separating the ownership of an asset from its control. Marriott's strength was in operations, yet the company had a great deal of money tied up in real estate. Growth would require even more investment in real estate. Wilson's solution was to sell the hotels-in effect, removing them and the debt used to finance them from the balance sheet-and contract to operate them. In this interview, Wilson gives his view of the role of finance in today's corporation and explains the thinking behind some of the successful deals he has engineered-including Disney's Silver Screen movie-making partnerships and Euro Disneyland. PMID- 10106406 TI - Yes, but will it work? PMID- 10106407 TI - Order out of chaos. PMID- 10106408 TI - Defining and achieving an information system's benefits. PMID- 10106409 TI - The 'racer's edge' in hospital competition: strategic technology plan. PMID- 10106410 TI - Complex information systems options: how one CEO triumphed. PMID- 10106411 TI - Selecting an HIS vendor: avoiding some common traps. PMID- 10106412 TI - Using technology to save time and upgrade the decision-making process. PMID- 10106413 TI - Office automation brings new efficiencies to the CEO's desk. PMID- 10106414 TI - Educating healthcare leaders for the 21st century: evolution not revolution. AB - In April of 1988, the Accrediting Commission on Education for Health Services Administration began reviewing its criteria, policies, and procedures for accreditation. The goal was to update the criteria and revise the policies and procedures to reflect advances in knowledge and practice and to ensure that accreditation judgments are objective and consistent. Since input from those most affected by the new criteria--faculty and practitioners--is essential, the commission sought assistance from the field. Through this collaboration, it is ACEHSA's intention to continue to encourage the dynamic collaboration of the field of education and the field of practice in health services administration that's characteristic of ACEHSA's 20-year history. PMID- 10106415 TI - Congress heeds pleas from the hinterland. PMID- 10106416 TI - The leadership of Father Moulinier. The Catholic Hospital Association comes of age, 1921-1928. PMID- 10106417 TI - Ambulatory surgery facilities: definition and identification. PMID- 10106418 TI - Fraud, abuse and inurement: the growing impact on provider-physician relations. PMID- 10106419 TI - Expanded enforcement of the fraud and abuse laws. PMID- 10106420 TI - Who cares about trauma? PMID- 10106421 TI - Off-site storage--move it! AB - The planning and implementation of the onsite proposal required the devotion and creativity of many individuals, including administrative, clerical, and line workers, and has been accomplished through the completion of a series of objectives. While the plan took three years to be realized, cost containment efforts of this magnitude signify the important contribution a material management department can make in the healthcare industry. Departmental credibility and support from customers are the foundation for implementing such a plan in any medical center. Materiel management departments continue to incorporate creative and innovative programs into their daily operations, which contributes to the institution's bottom-line. This on-site project has brought The University of Michigan Hospitals one step closer to its ultimate cost containment goal of a total stockless purchasing/supply program. PMID- 10106422 TI - Technology assessment, Part 2. PMID- 10106423 TI - Recruitment and retention of rural physicians: issues for the 1990s. AB - This paper briefly describes a number of structural and economic changes in the profession of medicine and in the rural medical care delivery system that have occurred since about 1970. Changes in the national physician supply; in the training, work, and practice characteristics of physicians; in the demographic characteristics of physicians; in the medical resources available in rural communities; and in federal and state support for the provision of medical services are noted. Four conceptual models that underlie physician recruitment and retention programs for small towns and rural communities are described. These include affinity models, which attempt to recruit rural persons into training or foster interest in rural practice among trainees; economic incentive models, which address reimbursement or payment mechanisms to increase economic rewards for rural practice; practice characteristics models, which address technical, collegial, referral, and other structural barriers to rural practice; and indenture models, which recruit temporary providers in exchange for scholarship support, loan forgiveness, or licensure. Examples of applications of each model are provided and the effects of changes in the medical care system on the effectiveness of each model are assessed. Finally, it is argued that elements of an optimal model for the recruitment of physicians to rural practice include the promotion of medical careers among rural high school students, the provision of financial and cultural support for their training, the development of technical and collegial support systems, and the limited use of indenture mechanisms to meet the needs of the most impoverished or isolated rural settings. PMID- 10106425 TI - This doctor proved that PROs can be sued successfully. PMID- 10106424 TI - A rural hospital's impact on a community's economic health. AB - This research illustrates the importance of a hospital to the economic health of a community. A simulation model of a rural community in Oklahoma is used to demonstrate how the implementation of the DRG reimbursement policy has impacted a rural community, and to project how the closing of the hospital would impact the economy of the community. The results indicate that rural hospitals play a vital role in the economics of their communities. The closing of a rural hospital has a devastating impact on the community, while the DRG reimbursement policy has had a significant impact on the community. PMID- 10106426 TI - The bureaucrats killed our fine little hospital. PMID- 10106427 TI - Hospitals can tally the benefits of contract management services. PMID- 10106428 TI - AMA proposes national healthcare reform plan. PMID- 10106429 TI - Gov. rejects plan to expand access to care. PMID- 10106430 TI - Physician reforms to jostle hospitals. PMID- 10106432 TI - Deficit reduction proposal lauded as fair. PMID- 10106431 TI - Medicare plan unlikely to lead to jump in liver transplants. PMID- 10106433 TI - Bill would require states to raise Medicaid AIDS rates. PMID- 10106434 TI - Congress eyes budget options. PMID- 10106435 TI - Teaching-hospital funding cut gets cool response in Congress. PMID- 10106436 TI - In patient accounts management, five simple objectives still rule the day. AB - Although patient accounts management has become crowded with complications, a winning staff follows time-tested rules. All departmental goals branch out from one top priority: to decrease accounts receivable. PMID- 10106437 TI - Who cares? The evolution of the legal duty to provide emergency care. PMID- 10106438 TI - Hospital quality measurement: a story of failure and success. PMID- 10106439 TI - The patient flow management model: a process for quality assurance. PMID- 10106440 TI - America's scandalous health care. Here's how to fix it. PMID- 10106441 TI - The organization, delivery, utilization and financing of rehabilitation care for the elderly. AB - In order to meet the needs of a large elderly disabled population in the 1990s, the inevitable close linkage between the hospital and post-acute care providers will place increased demands and responsibilities upon the hospital management team and their hospital practicing physicians for patient care decisions along the continuum of care for the elderly. PMID- 10106442 TI - How to not get burned by consultants. AB - Benefit consultants run the gamut, from specialized independents to international corporations employing various types of benefits people. Find out how to choose a consultant that is compatible with your organization. PMID- 10106443 TI - Is there a future for retiree health benefits? AB - Faced with a shrinking active work force, and a growing retiree population, employers are rethinking who pays for what. Adding urgency to the issue are new regulations, expected to take effect in 1992, that will require company financial statements to reflect health benefits obligations to current and future retirees. PMID- 10106444 TI - Medicare program; criteria for Medicare coverage of adult liver transplants- HCFA. Proposed notice. AB - This notice proposes Medicare coverage of liver transplantations in adults under certain circumstances. We would provide coverage for adult liver transplants based on the results of an assessment conducted by the Office of Health Technology Assessment of the Public Health Service and our subsequent determination that liver transplants are a medically reasonable and necessary service when furnished to adult patients with certain conditions and when furnished by participating facilities that meet specific criteria, including patient selection criteria. PMID- 10106445 TI - Medicare program; Medicare as secondary payer and Medicare recovery against third parties--HCFA. Final rule; reinstatement of regulations. AB - This rule amends final regulations published on October 11, 1989, at 54 FR 41716 in order to replace changes that were intended to clarify policy, but have been interpreted by some readers as expressing substantive policy changes. With the exception of updated cross-references, we therefore are reissuing language that was in effect before the effective date of the October 11, 1989 final rule. PMID- 10106446 TI - A mathematical model of radiotherapy department dynamics. AB - Technical managers are increasingly called upon to plan for the future needs of radiotherapy departments. Such planning involves calculating budgetary and staffing requirements, as well as identifying equipment purchases. To anticipate these needs, a means to assess the department's patient capacity is necessary. This article proposes a mathematical model examining patient flow to assist with the expansion plans of radiotherapy departments. PMID- 10106447 TI - Making changes. Reforms needed today, longer-term solutions, and how to get there. PMID- 10106448 TI - An intolerable alternative. Gramm-Rudman-Hollings cuts & the threat to home care. PMID- 10106449 TI - Public policy and the American hospice movement. The tie that binds. PMID- 10106450 TI - Coming to grips with the paperwork burden. PMID- 10106451 TI - The national health care imperative. AB - In summary, the nation's health care system is in serious need of reform. It is expensive and woefully inefficient. Millions of people are excluded from coverage, while others receive limited or second-class care. For those millions who suffer serious chronic problems that require long-term care, there is virtually no help. There is no help for the family whose loved one suffers from Alzheimer's disease. There is no help for the family whose child is born with cerebral palsy or epilepsy. There is no help for the middle-aged father, disabled in an automobile accident. Providing good care to all Americans is not a matter of money. America currently spends some 13% of its gross national product on health care, and yet the health statistics of Americans are the worst in the industrialized world. What America needs is a comprehensive system of health care that includes both acute and long-term care. Congress must take action to restore health care as a basic constitutional right of all Americans. Coverage for long term care must be included within the context of any new national health care program. Funding for such a program should come from the most progressive tax that the Congress can fashion, which to this point is the federal income tax. Although there is an appropriate role for private insurance, it should function as a supplement to rather than as a substitute for a new national program. There are several other elements that are key to a national health care program: Home care must be the first line of any national long-term care program.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106453 TI - Special report on reimbursement. Strategies for appeals from PRO denials. PMID- 10106452 TI - Cost containment measures in hospital pharmacy: a bibliography. AB - The pharmacy literature was searched for cost containment articles. The articles were classified according to content and the Canadian studies were identified. In total, 170 publications were identified, of which 51 (30%) were Canadian. Overall, 28.2% dealt with hospital administrative measures, 20.0% with pharmacy operations management, 14.7% with pharmacy materiels management, and 37.1% with clinical pharmacy services. The area of most frequent focus for Canadian articles was clinical pharmacy (43.1%), followed by hospital administrative measures (35.3%). References were provided for all articles. PMID- 10106454 TI - Ride on a rollercoaster. PMID- 10106455 TI - Information--lifeblood of the NHS. PMID- 10106456 TI - The rural health care market: strategies for survival. PMID- 10106457 TI - Happy at the end: Medicare as secondary payer. PMID- 10106458 TI - Medicare funded depreciation: a plan for hospitals. PMID- 10106459 TI - Regulation and hospital strategic planning in Canada. AB - Constraints on resources push hospitals into strategic planning. Although this process is accelerating in the United States, Canadian hospitals need to approach planning according to the provincial structure. This study included a literature and policy review as well as interviews of key stakeholders. Decisions toward centralized planning versus hospital-initiated development were found to depend on the availability of planning and policy staff, and the views of the elected representatives. Implications for Canadian health care planners were offered. PMID- 10106460 TI - Hanging on to what you've got. AB - Professor Norman Metzger maintains that the way to cope with the demographic time bomb is not to seek ways of encouraging new staff but to retain the people you already have. PMID- 10106461 TI - Search for certainty. PMID- 10106462 TI - Marketing crucial to keep GPOs growing. PMID- 10106463 TI - Hospital personnel must support materials management sales representative policies. PMID- 10106464 TI - The managed care marketplace. PMID- 10106465 TI - Developing referral systems: a key to survival. AB - The authors discuss the advantages of developing a referral system. The importance of access and formalized relationships as components of an effective referral system are described. The authors also identify a series of issues that any health care organization should consider in establishing a referral system and a list of ways to evaluate its effectiveness. PMID- 10106466 TI - Setting ambulatory care nursing standards. AB - A review of current literature will show that nursing standards of care abound for the hospitalized patient, but that very little has been written in reference to ambulatory care nursing. Author Patricia Miller writes that nurses have an obligation to ensure that nursing care is safe and within accepted levels of quality and thus standards of care have been established within the profession to help meet these expected levels of nursing care. PMID- 10106467 TI - Fee schedule may sabotage Medicare HMO scheme. PMID- 10106468 TI - N.Y. protests mandated Medicaid rate hike for AIDS. PMID- 10106469 TI - Moving ahead with the challenge: making sense of OBRA. PMID- 10106470 TI - Toward rational physician compensation. PMID- 10106471 TI - One physician's view of payment reform. PMID- 10106472 TI - Capital payment: occupancy adjustment discussed. PMID- 10106473 TI - Health policy reform in the '90s. PMID- 10106474 TI - An interview with PPRC's Paul B. Ginsburg. Interview by John Herrmann. PMID- 10106475 TI - AST (Association of Surgical Technologists) strategic plan to the year 2000. PMID- 10106476 TI - COBRA (Consolidated Omnibus Budget Reconciliation Act of 1985). PMID- 10106477 TI - When small rural hospitals close. PMID- 10106478 TI - Emergence of the California health system. Roots of uniqueness, 1850-1915. PMID- 10106479 TI - Children's hospitals: policy and payment. PMID- 10106480 TI - Medicare, Medicaid and CLIA programs; revision of the laboratory regulations for the Medicare, Medicaid, and Clinical Laboratories Improvement Act of 1967 programs--HCFA. Final rule with comment period. AB - This rule revises regulations for laboratories regulated under the Medicare, Medicaid and Clinical Laboratories Improvement Act of 1967 (CLIA '67) programs. The revisions recodify the regulations for these programs into a new part 493 in order to simplify administration and unify the health and safety requirements for all programs as much as possible. We will now have a single set of regulations for the three programs, with an additional subpart for the licensure procedures unique to the CLIA program. We are revising the regulations to remove outdated, obsolete and redundant requirements, make provision for new technologies and place increased reliance on outcome measures of performance. We provide for new uniform proficiency testing standards. We have also added requirements for additional specialties, such as clinical cytogenetics. We also implement the now and self-implementing provisions of the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88). PMID- 10106481 TI - Medicare program; changes to maintenance of effort requirements (section 421 of the Medicare Catastrophic Coverage Act)--HCFA. Notice. AB - This notice announces the effect on employers of the repeal of section 421 (Maintenance of Effort Provision) of the Medicare Catastrophic Coverage Act of 1988 (MCCA). The enactment of Public Law 101-234 (Medicare Catastrophic Coverage Repeal Act of 1989) on December 13, 1989 repealed many of the provisions of MCCA and restored the Medicare benefit levels to those available prior to January 1, 1989. Consequently, employers are relieved of their Maintenance of Effort responsibilities effective January 1, 1990. PMID- 10106482 TI - Quarterly listing of program issuances and coverage determinations--HCFA. General notice. AB - This notice lists HCFA manual instructions, interpretative rules, statements of policy, and national coverage determinations that were published during July, August and September 1989 that relate to the Medicare program. Section 1871 (c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register every three months. We also are providing the contents of several revisions to the Medicare Coverage Issues Manual. On August 21, 1989 we published (42 FR 34555) the content of the Manual and indicated that we will publish quarterly any updates. Adding the Coverage Issues Manual changes to this listing allows us to fulfill this requirement in a manner that facilitates easy identification of coverage and other changes in our manuals. PMID- 10106483 TI - Building confidence through demographics. The proper analysis measures merit and strength. PMID- 10106484 TI - Repackaging for rehab entree. Financially rewarding services increase market share. PMID- 10106485 TI - Rehab requires interdisciplinary approach. Restorative nursing programs on the rise. PMID- 10106486 TI - New Medicare/Medicaid requirements. Emphasizing pressure sore prevention. PMID- 10106488 TI - Four essential principles of utilities master planning. PMID- 10106487 TI - Resource based relative value scale: a new challenge and opportunity for health care cost management. AB - Beginning in 1992, the use of resource based relative value scale (RBRVS) will greatly change the way physicians are reimbursed for services to Medicare patients. This new system will also have implications for trust funds and corporate providers of health care benefits. PMID- 10106489 TI - Avoiding the hidden costs of ineffective wayfinding. PMID- 10106490 TI - Committee, planning guide simplify relocations. PMID- 10106491 TI - Institutional strategic planning. The role of the materiel management department. AB - The author discusses the components of the strategic planning process, how the process is managed, and how the materiel management department can incorporate its goals and objectives into the overall organizational mission. PMID- 10106492 TI - Northwestern Memorial Hospital, Chicago, Illinois. AB - This article discusses the applications of a materiel management strategic plan in a major metropolitan hospital. PMID- 10106493 TI - Technology decisions: high prices, hard choices. PMID- 10106494 TI - Political handcuffs restrain VA reform. PMID- 10106495 TI - Hospitals win in disproportionate-share battle. PMID- 10106496 TI - Sen. Pryor's formulary plan attacked by drug industry; other groups are less hostile. PMID- 10106497 TI - Beth Israel rating underlines New York woes. PMID- 10106498 TI - Bonding employees after a merger. PMID- 10106499 TI - HMO contracting presents SNFs with benefits, opportunities. PMID- 10106500 TI - In one state Medicaid pays part--provider response is mixed. PMID- 10106501 TI - Strategic choices for hospitals. PMID- 10106502 TI - CEO selection: strategic leadership. PMID- 10106503 TI - Ten-step template. PMID- 10106504 TI - Quality assessment plan: division of radiation oncology. PMID- 10106505 TI - A review of five major community-based cardiovascular disease prevention programs. Part II: Intervention strategies, evaluation methods, and results. AB - Major community-based cardiovascular disease prevention programs have been conducted in North Karelia, Finland; the state of Minnesota; Pawtucket, Rhode Island; and in three communities and more recently in five cities near Stanford, California. The main hypothesis is that community intervention will reduce the prevalence of cardiovascular disease risk factors and consequently reduce cardiovascular disease incidence, morbidity, and mortality. Intervention strategies include community mobilization, social marketing, school-based health education, worksite health promotion, screening and referral of those at high risk, education of health professionals, direct education of adults, and modification of physical environments. Formative evaluation provides short-term feedback to program managers about immediate effects of intervention strategies. Outcome evaluation examines the effects of intervention on longitudinally sampled cohorts and compares cardiovascular risk status and morbidity and mortality in intervention and comparison communities. Results from North Karelia and the Stanford Three Community Study indicate that this model is efficacious and cost effective. The National Heart, Lung, and Blood Institute biomedical research spectrum envisions research in knowledge transfer and innovation diffusion as the last link in the causal chain whereby research affects the health of the population, but research in this area remains undeveloped compared to other aspects of cardiovascular disease prevention. This is Part II of a two part article; Part I appeared in Volume 4, Number 3. PMID- 10106507 TI - How consistent is MEDLINE indexing? A few reservations. PMID- 10106506 TI - Effective management of a hospital-based health promotion program: keys to success. PMID- 10106508 TI - Medicare program; physician involvement in physical therapy and speech pathology services--HCFA. Final rule. AB - This rule adopts as final without revision previously published provisions of an interim final rule regarding physician involvement in physical therapy and speech pathology services. PMID- 10106509 TI - Medicare program; withdrawal of coverage of extracranial-intracranial arterial bypass surgery for the treatment or prevention of stroke--HCFA. Proposed notice. AB - This notice announces the Medicare program's intent to withdraw Medicare coverage of extracranial-intracranial (EC-IC) arterial bypass surgery when used to treat or prevent ischemic cerebrovascular disease of the carotid or middle cerebral arteries. Available evidence does not show that this surgery is effective. PMID- 10106510 TI - Medicare program; monthly supplementary medical insurance premium beginning January 1, 1990--HCFA. Notice. AB - This notice announces the monthly premium rate, as changed by the Omnibus Budget Reconciliation Act of 1989 and the Medicare Catastrophic Coverage Repeal Act of 1989, for aged (age 65 or over) and disabled (under age 65) enrollees in the Medicare Supplementary Medical Insurance (SMI) program for calendar year 1990. The 1990 SMI premium will be $28.60. This notice also announces the repeal of the monthly catastrophic coverage premium for aged and disabled enrollees. PMID- 10106511 TI - Seeking the cure. AB - With Washington paralyzed by partisan politics, states are taking the lead in experimenting with ways to solve the nation's growing health care crisis. This is the second of two articles on responses to the growing health care crisis. A report on organized labor's efforts begins on p. 704. PMID- 10106512 TI - Working with an architect. PMID- 10106513 TI - The role of marketing in developing a hospital departmental business plan. PMID- 10106514 TI - Special report on reimbursement. What to do if the Inspector General subpoenas your records. PMID- 10106515 TI - From affirmative action to affirming diversity. AB - Affirmative action is based on a set of 30-year-old premises that badly need revising. White males are no longer dominant at every level of the corporation (statistically, they are merely the largest of many minorities), while decades of attack have noticeably weakened racial and gender prejudices. At the intake level, affirmative action quite effectively sets the stage for a workplace that is gender-, culture-, and color-blind. But minorities and women tend to stagnate, plateau, or quit when they fail to move up the corporate ladder, and everyone's dashed hopes lead to corporate frustration and a period of embarrassed silence, usually followed by a crisis-and more recruitment. Some companies have repeated this cycle three or four times. The problem is that our traditional image of assimilating differences-the American melting pot-is no longer valid. It's a seller's market for skills, and the people business has to attract are refusing to be melted down. So companies are faced with the task of managing unassimilated diversity and getting from it the same commitment, quality, and profit they once got from a homogeneous work force. To reach this goal, we need to work not merely toward culture- and color-blindness but also toward an openly multicultural workplace that taps the full potential of every employee without artificial programs, standards, or barriers. The author gives his own ten guidelines for learning to manage diversity by learning to understand and modify your company's culture, vision, assumptions, models, and systems. PMID- 10106516 TI - An insider's call for outside direction. AB - The large public corporation has been an unrivaled creator of wealth and jobs in our century. But public corporations depend on patient capital, and patient capital depends on boards of directors that are conscientious and responsible. Unfortunately, the prosperity and economic stability of the last 50 years have allowed boards to grow complacent, clubby, and passive. Now explosive developments in five areas have shaken the corporate world to its roots: information technology, flexible manufacturing, global markets, workplace democracy, and pension-fund capitalism. As a result, large corporations find themselves under attack from a hornet's nest of small, aggressive competitors, and at the same time, professional investors and the constant threat of takeover have forced corporations to focus on short-term results rather than on long-term investments. Although pension funds ought to behave like any other patient capital, the fact is we cannot count on institutional investors to buy stock for the long term and to hold a board's feet to the fire to protect their investments. One reason is legal. Securities laws hinder stockholders from working together to make their weight felt with boards of directors. So they tend to vote with their feet instead and sell the stock when unhappy with management. The author recommends a variety of measures to reinvigorate corporate boards, reduce their fear of fiduciary liability in the investment of pension-fund monies, and encourage pension-fund investors to take a more active role in the direction of the companies whose stock they own. PMID- 10106517 TI - Beyond products: services-based strategy. AB - Services technologies are changing the way companies in every industry- manufacturers and service providers alike--compete. Vertical integration, physical facilities, even a seemingly superior product can no longer assure a competitive edge. Instead, sustainable advantage is more and more likely to come from developing superior capabilities in a few core service skills--and out sourcing as much of the rest as possible. Within companies, technology is increasing the leverage of service activities: today, more value added comes from design innovations, product image, or other attributes that services create than from the production process. New technologies also let independent enterprises provide world-class services at lower costs than customers could achieve if they performed the activities themselves. These changes have far-reaching implications for how managers structure their organizations and define strategic focus. Companies like Apple, Honda, and Merck show that a less integrated but more focused organization is key to competitive success. They build their strategies around a few highly developed capabilities. And they outsource as many of the other activities in their value chain as possible. To help managers develop an activity-focused strategy, the authors offer a new way to approach competitive analyses, guidelines for determining which activities to outsource and which to retain, and an overview of the risks and rewards of strategic outsourcing. Throughout, they draw on the findings of their three-year study of the major impacts technology has had in the service sector. PMID- 10106518 TI - Contracts at Numberside. PMID- 10106519 TI - Tightropes and umbrellas. PMID- 10106520 TI - Older adults: a growing market for ambulatory care services. PMID- 10106521 TI - Managed care: update and future directions. PMID- 10106522 TI - Options in ambulatory care for the elderly. PMID- 10106523 TI - American hospitals in the British health care market. PMID- 10106525 TI - Rural health care: the future of the hospital. PMID- 10106524 TI - Clinical ethics and HIV-related illnesses: issues in treatment and health services research. PMID- 10106526 TI - Acute and long-term care linkages: a literature review. PMID- 10106527 TI - Bush's plan for Medicare PPO faces uphill climb. PMID- 10106528 TI - Government holds on to occupancy adjustment option. PMID- 10106530 TI - Organizations sue over Medicare rates for ASCs (ambulatory surgery centers). PMID- 10106529 TI - Future policies' impact on hospitals anyone's guess. PMID- 10106531 TI - The value of facility master plans. PMID- 10106532 TI - Medicaid: an uncertain future. PMID- 10106533 TI - Steering a center from start-up to success. PMID- 10106534 TI - Reimbursement prospects and strategies for the future. PMID- 10106535 TI - The development of a points system to compare the potential running costs of different development options for new hospitals. AB - The points system provides a simple method of assessing the design aspects of health care facilities which have a significant influence on their eventual operating costs. It is intended to assist planning teams working in the early stages of designing a health care facility. The system offers a systematic form of analysis which should be used in the preparation of development proposals as an aide-memoir, and as a method of comparing and evaluating alternative design solutions. It comprises seventeen worksheets which should be used by planning teams as a checklist of Design for Reduced Operating Costs factors. The system was developed by using the 'delphi' methodology and has been tested in a series of repeatability tests and field trials; and it is now being used for developments within the NHS. PMID- 10106536 TI - Nurse-managed foot care services. PMID- 10106537 TI - Developing an environmental assessment for effective clinical laboratory strategic planning: Part II. A five-step process. AB - The 1990s will pose a unique set of opportunities and challenges for clinical laboratories and the health-care field. Successful positioning of the clinical laboratory requires a well-thought-out strategic plan for the next 3 to 5 years and beyond. To develop an effective strategic plan, you must assess the environment in which your organization operates. This article, the second in a two-part series, focuses on the strategic planning process for the clinical laboratory and on environmental assessment. The first article (1) discussed CLMA's environmental assessment process and its findings. This article will present a step-by-step approach you can use to develop your own clinical laboratory environmental assessment. The future of the clinical laboratory and related industries provides the context within which clinical laboratories must position themselves to effectively meet their clients' needs. These two articles provide a starting point for developing a vision of the future for the clinical laboratory industry and for the individual clinical laboratory. PMID- 10106538 TI - Botsford--25 and still counting. PMID- 10106539 TI - Directory of air medical services. PMID- 10106540 TI - A review of five major community-based cardiovascular disease prevention programs. Part I: Rationale, design, and theoretical framework. AB - Major community-based cardiovascular disease prevention programs have been conducted in North Karelia, Finland; the state of Minnesota; Pawtucket, Rhode Island; and in three communities and more recently in five cities near Stanford, California. These primary prevention programs aim to reduce cardiovascular disease incidence by reducing risk factors in whole communities. These risk factors are smoking, high blood cholesterol, diet high in cholesterol and saturated fat, hypertension, sedentary lifestyle, and obesity. This strategy may be contrasted with secondary prevention programs directed at patients who already have symptomatic cardiovascular disease and "high risk" primary prevention programs directed at individuals found through screening to have one or more risk factors. The design of the five major programs is similar in that intervention communities are matched for purposes of evaluation with nearby comparison communities. Underlying these programs are theories of community health education, social learning, communication, social marketing, and community activation, as well as more traditional biomedical and public health disciplines. This is Part I of a two-part article. PMID- 10106541 TI - What can be done for troubled teens? PMID- 10106542 TI - Valuing diversity: ways to answer minority needs. PMID- 10106543 TI - Medicaid program; state plan requirements and other provisions relating to state third party liability programs--HCFA. Final rule. AB - This final rule implements certain Medicaid State plan requirements and other provisions relating to State third party liability (TPL) programs. Its provisions deal with: (1) The integration of a State's pursuit of third party claims with its Mechanized Claims Processing and Information Retrieval System; (2) exceptions to the cost avoidance method of claims payment in TPL situations; and (3) provider restrictions and penalties related to attempts at collection of cost sharing or portions of those amounts from Medicaid recipients when TPL has been established. These regulations implement portions of section 9503 of the Consolidated Omnibus Budget Reconciliation Act of 1985. PMID- 10106544 TI - Medicare program; carrier bonuses for increasing physicians' participation or payments--HCFA. Notice. AB - This notice describes the methodology we will use to award fiscal year 1989 incentive payments to carriers that successfully increase the number of participating physicians, i.e., physicians who agree to accept Medicare's reasonable charge for all Part B services that they provide to Medicare beneficiaries. It implements provisions of the Omnibus Budget Reconciliation Act of 1986 and the Omnibus Budget Reconciliation Act of 1987 which require us to publish a notice in the Federal Register describing our system for providing payment of a bonus to carriers based on their performance in increasing the number of participating physicians or the proportion of payment for participating physicians' services in their service areas. PMID- 10106545 TI - Medicare program; catastrophic outpatient drug benefit, home intravenous drug therapy benefit, and screening mammography services--withdrawal--HCFA. Withdrawal of proposed rules. AB - This notice announces the withdrawal of several proposed regulation documents that would have implemented certain provisions of the Medicare Catastrophic Coverage Act of 1988 by establishing new outpatient drug and home intravenous drug therapy benefits, expanding immunosuppressive drug coverage, and providing limited coverage for screening mammography services under Medicare part B. This notice implements section 201 of the Medicare Catastrophic Coverage Repeal Act of 1989 (Pub. L. 101-234, enacted December 13, 1989). PMID- 10106546 TI - Quarterly listing of program issuances--HCFA. General notice. AB - This notice lists HCFA manual instructions, regulations and other Federal Register notices, and statements of policy that were published during October, November and December 1989 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register every three months. PMID- 10106547 TI - Medicare program, fiscal year 1990; mid-year changes to the inpatient hospital prospective payment system--HCFA. Final rule with comment period. AB - This final rule with comment implements several provisions of the Omnibus Budget Reconciliation Act of 1989 that affect Medicare payment for inpatient hospitals and that, in general, take effect on April 1, 1990. This final rule also responds to comments received concerning the changes we made in 1989 in implementing provisions of the Medicare Catastrophic Coverage Act of 1988 concerning adjustments applicable to prospective payment hospitals and to the target amounts of hospitals and units excluded from the prospective payment system due to the elimination of the day limitation on covered inpatient hospital days. We are making additional changes in these provisions to take into account the Medicare Catastrophic Coverage Repeal Act of 1989, and changes in the law made by the Family Support Act of 1988, which clarified the criteria for adjusting target amounts and changed the date for implementing that provision. PMID- 10106548 TI - What goes around, comes around. New HCFA chief favors separate bureau. PMID- 10106549 TI - Preparing for surveyors. AB - The arrival of surveyors at a nursing home is an especially stressful time for the administrator, director of nursing and nursing staff. Compounding this stress is the Oct. 1 implementation of the new Medicare/Medicaid nursing home requirements, which pose a number of new challenges to providers. PMID- 10106550 TI - Quality: a systematic approach. AB - One approach to quality in healthcare is total hospital quality management. It helps hospital staff to focus on the common goal of delivering the best possible health care through a well-defined program. It requires a long-term commitment but it can yield financial benefits and reductions in the cost of mistakes. PMID- 10106551 TI - Special report on reimbursement. Appeal rights provide opportunity to limit PRO denials of payment. PMID- 10106552 TI - Handling Hurricane Hugo: disaster planning that works. PMID- 10106553 TI - Coding notes. CPT-HCPCS, ICD-9-CM. PMID- 10106554 TI - Over the great divide. PMID- 10106555 TI - Time for a change. PMID- 10106556 TI - AIDS and hospitals: the policy options. AB - This article examines several policy decisions faced by American hospitals as they respond to the current AIDS epidemic. The article reviews the basic moral responsibilities of the hospital, the health care needs of HIV-positive and AIDS patients, and the risk of acquiring HIV infection in the hospital setting. It examines the hospital's responsibility to care for AIDS and HIV-positive patients, AIDS infection-control practices, and hospital policy regarding HIV positive health care professionals. PMID- 10106557 TI - Improving financial performance: a study of 50 hospitals. AB - This article provides an analysis of key differences between a small sample of high-performing and low-performing hospitals where performance was defined as return on equity. Some of the more significant findings were: (1) high-performing hospitals achieve their superior performance through cost control rather than higher prices; (2) high-performing hospitals minimize their investment in plant assets and accounts receivable. They are also likely to have a newer plant than low-performing hospitals; (3) high-performing hospitals are not afraid to use debt in their capital structure, but they use significantly less debt than low performing hospitals; (4) high-performing hospitals have set aside greater reserves for future plant replacement, which helps them to keep their level of debt reasonable and generates significant amounts of investment income; and (5) high-performing hospitals have greater market share than low-performing hospitals. PMID- 10106558 TI - Restrictive reimbursement policies and uncompensated care in California hospitals, 1981-1986. AB - To examine the effect of restrictive state, federal, and private hospital reimbursement policies in California, we examined trends in uncompensated care and other deductions from hospital revenues from 1981 to 1986. During a period when the number of uninsured in California increased substantially, uncompensated care grew, but not as rapidly as other deductions from revenue, especially Medi Cal and private-sector contractual allowances. A trend toward redistribution of uncompensated care from public to private hospitals reversed. Voluntary teaching hospitals, whose Medi-Cal and private-sector contractual allowances grew rapidly, recently reported a decline in uncompensated care. As reimbursement pressures increase, private hospitals may resist pressures to provide uncompensated care, increasing the burden on public institutions and perhaps limiting the access of indigents to quality care. PMID- 10106559 TI - Application of severity measurement systems for hospital quality measurement. AB - As hospitals increasingly emphasize efforts to measure and improve quality of care, the related issue of severity measurement emerges as a topic of strong interest. Severity measures can support hospital quality management in at least two areas: selection of medical records for individual case review and monitoring of patterns of care including analysis of rates of adverse outcomes. Some systems currently available for measuring the severity of general medical and surgical admissions in acute care hospitals base severity scores on data available in computerized discharge abstracts, while others use detailed clinical data abstracted directly from patient medical records. One is based on both detailed medical record data and International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes. This article discusses issues important to the definition and measurement of patient severity and examines the strengths and limitations of specific systems and their potential contributions to quality management. PMID- 10106560 TI - Oklahoma shop makes all the right moves. PMID- 10106561 TI - Advance directives for the critically ill: the federal legislative initiative. PMID- 10106562 TI - Hospital CEO role study--1989 update. PMID- 10106563 TI - Guidelines for achieving recertification. PMID- 10106564 TI - Merging cultures: successful CEOs read warning signs. PMID- 10106565 TI - Corporate culture: healthcare's change master. PMID- 10106566 TI - The operation was a success, but the patient died. Integrating the organizational and professional aspects of the quality of patient care. PMID- 10106567 TI - Recent developments give hospitals opportunity to revive Medicare appeals and secure additional reimbursement. PMID- 10106568 TI - St. Francis Regional to install a computerized educational system to help C.S. personnel. PMID- 10106569 TI - Funding children's mental health services in an underfunded climate: collaborative efforts. AB - In New York State and elsewhere, the lack of outpatient services results in inappropriate psychiatric hospitalization of children. Funding for specialized mental health services for children is not federally or state-mandated and county levied dollars often are required to generate a state match. In New York State, counties relying exclusively on traditional sources of mental hygiene funding are unlikely to develop a variety of quality programs for children. This article discusses in detail how interagency collaboration developed in Dutchess County, New York resulted in procurement of funds that financed an array of children's outpatient mental health services to county residents. PMID- 10106570 TI - The Ventura Planning Model: a proposal for mental health reform. AB - The Ventura Planning Model is a proposal for public mental health reform. It addresses the decline in mental health funding. It offers a rationale for increased support--and funding--for public mental health services. The Planning Model grew out of the experience of implementing and operating the Ventura Children's Demonstration Project. The model has five characteristics, or planning steps: 1) multi-problem target population; 2) systems goals; 3) interagency coalitions; 4) services and standards; and 5) systems monitoring and evaluation. The Ventura Children's Demonstration Project implemented these planning steps, with an infusion of $1.54 million in funds from the state legislature. The project offset at least 66 percent of its cost by reducing other public agency costs and improved a variety of client-oriented outcomes. The success of the project in offsetting its costs has led the legislature to provide additional funds for three more California counties to implement the model for children and youth, and $4 million a year for four years for Ventura County to test the model for adults and seniors. Emphasizing cost offsets in addition to client-oriented outcomes provides a practical rationale for proposing increases in public mental health funds. This rationale also implies substantial changes in the operations of many public mental health agencies. PMID- 10106571 TI - Study of community-based services for children and adolescents who are severely emotionally disturbed. AB - This article presents the results of a descriptive study of community-based services for children and adolescents who are severely emotionally disturbed. The study was funded by the National Institute of Mental Health Child and Adolescent Service System Program (CASSP) and was designed to obtain state-of-the-art information about several promising and innovative treatment approaches emerging in the field--home-based services, crisis services, and therapeutic foster care. The methodology involved literature reviews, a survey to identify programs, detailed questionnaires to learn about identified programs, and site visits to a sample of programs in each category. Two of the service components explored in the study are described in this article. Home-based services include intensive counseling, support, and case management services provided on an outreach basis to troubled children and their families in their own home. Both crisis-oriented and longer-term home-based models are discussed. The crisis services described include a variety of innovative residential crisis services which have been highly successful as alternatives to more restrictive placements in crisis situations. The authors emphasize that these services should not be seen as panaceas but as essential components of a comprehensive, community-based system of care for emotionally disturbed youngsters and their families. PMID- 10106573 TI - Medicare weighs options to gain lower test prices. PMID- 10106574 TI - Implementation of the Health Care Quality Improvement Act and the future of peer review. AB - On October 17, 1989, after a long delay, final regulations under the Health Care Quality Improvement Act of 1986 were published. This article analyzes the requirements under the Act and the regulations and how their implementation will affect the future of peer review. PMID- 10106572 TI - Examining the research base for child mental health services and policy. AB - This article reviews the existing research base for child mental health services and policy. It emphasizes the importance of research that looks at the overall community-based system of care as the unit of analysis, and stresses the need to maintain a systems perspective, even when research is focused on components of the overall system. The review concludes that there is a need for a considerable increase in child mental health services research but also indicates that there has been a recent increase in research that has the potential of building a base to change policy. In particular, a need is identified for well-controlled studies that assess both clinical and cost outcomes and for studies that examine the mega issues of the organization and financing of systems of care. PMID- 10106575 TI - Techniques for defending health care fraud and abuse cases. AB - The successful defense of a health care fraud and abuse case requires the early initiation of an aggressive, pro-active approach. In this article, the author describes various techniques for establishing client relations, assessing the case, developing a favorable defense, and avoiding exclusionary sanctions. PMID- 10106576 TI - Update: the Ethics in Patient Referrals Act. PMID- 10106577 TI - Medicaid HMOs struggle for viability; federal plan aims to ease the burden. PMID- 10106578 TI - States balk at mandates that would expand Medicaid. PMID- 10106579 TI - Medical libraries, no longer mandated by Medicare, are losing out at budget time. AB - Hospitals once needed to maintain a medical library to qualify for government reimbursement programs, but the requirement was lifted at the same time that cost constraints from prospective pricing began to squeeze budgets. Now the library is a prime target in cutback campaigns. PMID- 10106580 TI - Current problems and future options for Medicare's home health system: an exploratory survey of home health agencies. PMID- 10106581 TI - New hospital 'antidumping' laws. PMID- 10106583 TI - Radiology business lines. PMID- 10106582 TI - The alignment of technology and structure through roles and networks. AB - This paper outlines a role-based approach for conceptualizing and investigating the contention in some previous research that technologies change organizational and occupational structures by transforming patterns of action and interaction. Building on Nadel's theory of social structure, the paper argues that the microsocial dynamics occasioned by new technologies reverberate up levels of analysis in an orderly manner. Specifically, a technology's material attributes are said to have an immediate impact on the nonrelational elements of one or more work roles. These changes, in turn, influence the role's relational elements, which eventually affect the structure of an organization's social networks. Consequently, roles and social networks are held to mediate a technology's structural effects. The theory is illustrated by ethnographic and sociometric data drawn from a comparative field study of the use of traditional and computerized imaging devices in two radiology departments. PMID- 10106584 TI - Changes in health service use and mortality among U.S. elderly in 1980-1986. AB - Concern has emerged about the impact on quality of care of recent changes in Medicare reimbursement for acute hospital episodes (i.e., the introduction of the Prospective Payment System based on the Diagnosis Related Groups Reimbursement methodology). One aspect of those concerns is that very sick patients would be prematurely discharged to nursing homes in which the high level of medical care required would not be available. This was recently studied in terms of changes between 1981 and 1985 in the location of deaths (e.g., hospital, institutional) reported on U.S. death certificates. We analyzed the death certificate data for a longer period of time (1980 to 1986) and stratified the analysis by both age and cause of death--which we felt were important determinants of location of death. We also examined data from the 1982 and 1984 National Long Term Care Surveys linked to data on Medicare service use. In those analyses we could explicitly identify chronically disabled and institutionalized populations and study death rates in different locations within those populations. Our analyses showed little evidence of increased mortality rates due to premature hospital discharge. There were, however, significant changes in the patterns of service use. More home health agency (HHA) and skilled nursing facility (SNF) services were consumed though the rates of death per episode in those venues declined. PMID- 10106585 TI - A pre-admissions program for a children's hospital. PMID- 10106586 TI - Medicare program; changes to the inpatient hospital prospective payment system and FY 1990 rates; correction and technical amendment--HCFA. Final rule; correction and technical amendment. AB - In the September 1, 1989 issue of the Federal Register (FR Doc. 89-20481), (54 FR 36453), we made revisions to the Medicare inpatient hospital prospective payment system and set forth the prospective payment rates for FY 1990. This notice corrects technical errors made in that document. In addition, we are making a conforming change to section 412.92(a)(2)(iii) to accurately reflect the less burdensome criteria for classification as a sole community hospital. This language conforms to the change we made in section 412.92(a)(3). We intended to change both sections at the same time, but mistakenly left out the changes to section 412.92(a)(2)(iii). PMID- 10106587 TI - Privacy Act of 1974; systems of records--HCFA. Notice of proposed new routine use for an existing system of records. AB - HCFA is proposing to add a new routine use to the "Medicare Physician Supplier Master File," HHS/HFCA/BPO, No. 09-70-0516, to permit the release of the Unique Physician Identification Number (UPIN) to entities that bill for services they performed upon order or referral from a physician. PMID- 10106588 TI - Selecting air handling units. AB - Proper selection of air handling unit components plays a critical role in occupant acceptance of a conditioned space. PMID- 10106589 TI - Controlling nuisance alarms. AB - Nuisance alarms can be greatly reduced in most fire detection systems by careful specification, proper installation and regular maintenance of detectors. PMID- 10106590 TI - Attaining HIS benefits. AB - In summary, healthcare decisionmakers should shorten the amount of time and reduce the resources spent on planning and selecting information systems. To this end, they should focus tightly on implementation-related issues. Hospitals should concentrate on describing expected system benefits and working toward realization through a carefully planned and managed implementation process. PMID- 10106592 TI - Quality Improvement Act: a bibliography (1987-present). PMID- 10106591 TI - Getting the most out of advertising and promotion. AB - Until recently, believing in the effectiveness of advertising and promotion was largely a matter of faith. Despite all the data collected by marketing departments, none measured what was really important: the incremental sales of a product over and above those that would happen without the advertising and promotion. Thanks to a qualitatively new kind of marketing data, that situation is changing. "Single source" data correlate information on actual consumer purchases (available from universal-product-code scanners used in supermarkets and drug-stores) with information on the corresponding television advertising those consumers receive or on the promotion events they see. This allows managers to measure the incremental impact of advertising and promotion and to improve marketing productivity. To take advantage of the new single-source data, however, managers have to throw out much of the conventional wisdom about advertising and promotion that has grown up over the years. They must learn how to evaluate marketing differently by continually examining the appropriate balance between advertising and promotion. They must also train their sales force to do a different and extremely important job: to demonstrate to retailers the consumer pull of the company's advertising and promotion programs, as well as the effect of these programs on retailer profitability. PMID- 10106593 TI - Hospital ownership and the care of uninsured and Medicaid patients: findings from the National Hospital Discharge Survey 1979-1984. AB - From 1980 to 1984 Americans with no health insurance increased from 13.9% to 17.1% of the non-elderly population. Non-elderly persons covered by Medicaid declined from 6.2% to 5.6%. Previous studies of the share of the burden of uncompensated care borne by various provider groups present opposing findings. The National Hospital Discharge survey data presented here demonstrate that for profit hospitals serve significantly lower percentages of uninsured discharges than secular or church-affiliated non-profit hospitals and public hospitals. The same pattern of differentials is observed with respect to Medicaid. On the whole the results of the survey tend to support the argument that private non-profit hospitals do indeed render greater public services in treating indigent patients than do for-profit hospitals. It must also be emphasized, however, that the results show all private hospitals falling somewhat short of the standard set by public hospitals in treating indigents. Thus, the continued shrinkage of the public hospital sector has serious policy implications. PMID- 10106595 TI - EMS enters the 21st century. JEMS software review. PMID- 10106594 TI - Annotated bibliography: legal and ethical aspects of AIDS. PMID- 10106596 TI - Implementing a multipurpose information management system: some lessons and a model. PMID- 10106597 TI - Policy networks and the implementation of community care policy for people with mental handicaps. AB - Although community care has been the professed policy of successive governments over three decades, according to the Prime Minister's own adviser, Sir Roy Griffiths, 'in few areas can the gap between political rhetoric and policy on the one hand or between policy and reality in the field on the other hand have been so great'. This paper examines the extent and causes of this 'implementation gap' in respect of services for people with mental handicaps--a consistent priority group for national policymakers. We examine centre-periphery relations in the health and personal social services in the light of Rhodes' power-dependence framework and his concepts of policy networks and policy communities. The NHS has been described as the archetypal professionalised policy network but we conclude that it is possible to account for implementation failures in community care only partly in terms of the dominance of the medical professions' values and interests and the deficiencies of accountability and control due to clinical autonomy. Such failures are due also to the inherently limited power of the centre. Sub-central units are not merely its meek agents. Moreover, the centre must explicitly structure local environments by itself providing a coherent framework of service and resource policies compatible with the national objectives it is seeking to achieve. PMID- 10106598 TI - No hiding place: on the discomforts of researching the contemporary policy process. AB - It has never been easy to conduct research into currently sensitive policy issues, but there is now accumulating evidence to indicate that various forms of resistance to scholarly investigation are on the increase. Such a climate handicaps all social policy research, but may have the greatest impact on ethnographic projects. Yet, it is argued, ethnography is increasingly widely recognised among academics as having a particularly valuable contribution to make to the study of the policy process. Unfortunately, many policy practitioners (and occasionally some academic colleagues) perceive ethnographic research as being of questionable validity and low helpfulness. This behaves policy-oriented ethnographers to demonstrate that they do indeed have procedures for assuring validity, even if their style of investigation is never likely to be popular with government. PMID- 10106599 TI - Coping with change in the NHS: a frontline district's response to AIDS. AB - The core of this paper is a case study of how a District Health Authority (Paddington and North Kensington, now Parkside DHA following a recent merger with Brent DHA) in Inner London responded to a major new health care issue of the 1980s--Aids, but the paper also seeks to locate this case study material within wider debates. What theories are there of organisational change which could be used to illuminate policy and service change in the health care sector? How, indeed, do we best study change in health care organisations? The paper is thus in three parts. In the first section we identify some streams of literature which act as a frame of reference defining our initial research question and discuss implications for methodology. The second section presents the case itself, while the last section discusses some emerging findings. PMID- 10106600 TI - Sales force development in health services organizations; a boundary spanning perspective. AB - Sales force development is of growing importance to HSOs in their increasingly competitive and heterogenous health care markets. There is always some danger that, under such circumstances, strategies new to HSOs will be adopted without sufficient attention to how they function and how they might best be integrated into the organization's overall mission. The sales force is becoming an important part of administration in the modern HSO. Ensuring that sales personnel effectively meet the needs of clients and of all relevant units of their HSO calls for attention to a number of concerns raised in organization-environment theory. Concepts from the literature on organizational boundaries and boundary spanning used here organize and illuminate major issues in sales force development. The approach taken is one which underscores the importance of these issues, illustrates some possible responses, and encourages HSO administrators to reflect on organizational implications of sales force development. The perspective offered provides a base for more detailed design considerations in planning and implementing a sales force. PMID- 10106601 TI - Demographics, strategic planning, and marketing: a low budget approach. AB - Health care organizations with constrained planning budgets can access data sources which will be of great assistance in strategic and market analysis. The data described in this article can be obtained for $250 or less. For segmenting the market even further, down to the International Classification of Disease (ICD)-9 Code Level, the National Center for Health Statistics of the Department of Health and Human Services publishes an annual data book which indicates the use rates for every ICD-9 Code. This extremely valuable data source is all less than $10. Managers can take inexpensive data from the Census and from HHS and proceed to determine major opportunities and challenges facing their institutions. The same data then serve as the basis for planning about how to meet those challenges or take advantage of those opportunities. Finally, the same data will allow product line management to proceed on the basis of quantitative goals that are established in terms of the actual facts of the local situation. The skills required to perform these analyses are not complex, but the task is time intense. PMID- 10106602 TI - ProPAC advises against cost-based pay. PMID- 10106603 TI - Rural hospitals still traveling a bumpy road. AB - Now that Congress has begun approving higher reimbursement for rural hospitals, have the facilities seen their fortunes change? Yes and no. Some payment gains have been offset by other payment cuts, and many long-time problems continue to linger. But rurals are finding fiscal strength in system affiliations and creative operating strategies. PMID- 10106604 TI - HCFA's new area wage index to create big payment swings. PMID- 10106605 TI - Pa. to halt Medicaid payments this week as fund runs dry. PMID- 10106606 TI - HMO payment increase proposal meets resistance. PMID- 10106608 TI - AHA offers advice on how to close hospitals. PMID- 10106607 TI - Anti-kickback liability broadened. PMID- 10106609 TI - 'Single-room maternity plan pleases nurses'. PMID- 10106610 TI - Definition of partial hospitalization. The National Association of Private Psychiatric Hospitals and the American Association for Partial Hospitalization. AB - The National Association of Private Psychiatric Hospitals (NAPPH) recently joined with the American Association for Partial Hospitalization (AAPH) to provide mental health professionals with a clear, industry-supported definition of psychiatric partial hospitalization, an option on the continuum of care used by clinicians to treat mental illnesses. In 1988, Congress approved a major benefit change for the Title XVIII Medicare program by including reimbursement for partial hospital programs that meet a strict definition and provide a series of treatment services. As defined by Congress, partial hospitalization means an outpatient program specifically designed for the diagnosis or active treatment of a serious mental disorder when there is a reasonable expectation for improvement or when it is necessary to maintain a patient's functional level and prevent relapse or full hospitalization. That definition and the service components are endorsed by NAPPH and AAPH, and they offer a model for other insurers or employers considering the addition of this highly specialized program to healthcare benefit plans. Partial hospital programs are usually furnished by a hospital as a distinct and organized intensive ambulatory treatment service of less than 24-hour daily care. Partial hospitalization is not a substitute for inpatient care. For some patients, the availability of partial hospitalization may shorten the length of stay of full hospitalization or serve as a transition from inpatient to outpatient care. It may allow some patients to avoid hospitalization. Placement in a partial hospital program is a clinical decision that can be made only by a physician thoroughly knowledgeable about the patient's illness, history, environment, and support system. PMID- 10106611 TI - Strategic planning for the financially distressed hospital. PMID- 10106612 TI - America's best hospitals. Exclusive survey. AB - To identify the nation's best hospitals, U.S. news surveyed in 12 specialties from aids to urology. The survey yielded 57 different hospitals, many of which appear on more than one of the 12 specialty lists. The following hospitals, all of which found their way onto at least four of the lists, represent the cream of America's medical institutions. PMID- 10106613 TI - Medicare cost shifting: you ain't seen nothin' yet. PMID- 10106614 TI - Repealing catastrophic coverage: truth and consequences. PMID- 10106615 TI - Who's making the big decisions? PMID- 10106616 TI - Medicare fee schedule in place. AB - The Omnibus Budget Reconciliation Act of 1989 (OBRA '89) eliminates Medicare's "reasonable charge" method of reimbursing physicians, replacing it with a fee schedule based on a relative value scale. The new payment system's major goals are to decrease Medicare's long-term spending growth rate for physician services and to divide Medicare physician payments more equitably. The two major components of the fee schedule are a relative value scale and a conversion factor. With adjustments to accommodate geographical variations in practice costs, Medicare will pay the lower of (1) a physician's actual charge for service or (2) the fee schedule amount. The nucleus of the fee schedule will be a resource-based relative value scale (RBRVS), which is intended to reflect the costs efficient physicians are expected to incur when providing a service. OBRA '89 directs the Health and Human Services (HHS) secretary to review the RBRVS at least once every five years. The conversion factor, which the HHS secretary may calculate separately for all physician specialties combined or for groups of specialties, will initially be based on 1991 aggregate Medicare spending. Thereafter a formula will be used to update the fee schedule each year. Another feature of OBRA '89 will be a cap on fees charged by physicians who do not participate in Medicare. Because a number of tasks remain to be completed before RBRVS can be implemented, OBRA '89 provisions may be delayed. There is even a remote possibility that the new payment system may not be implemented. PMID- 10106617 TI - Advocacy with impact. PMID- 10106618 TI - Stark reality. AB - On Feb. 9, 1989, amid considerable attention in the healthcare industry, Rep. Fortney H. ("Pete") Stark, D-CA, introduced in Congress the Ethics in Patient Referrals Act (H.R. 939). At the time, the so-called Stark bill would have effectively prohibited physicians from referring Medicare patients to any healthcare entity in which they had a financial interest, including hospitals, hospital departments, and physician-hospital joint ventures. The bill that emerged and was signed into law months later is but a shadow of its former self: The prohibition against physician referrals is directed only at certain clinical laboratories and certain relationships between physicians and the laboratories. Hospitals and physicians may be overly optimistic about the results of this most recent incursion into physician ownership. This was not the first government intrusion into physicians' financial affairs, and it is not likely to be the last. Congress will no doubt continue to focus attention on physicians and hospitals that seek revenues through joint investments in healthcare providers. In fact, Congress has already put referring physicians on notice, saying that if the Government Accounting Office finds evidence of inappropriate referrals, or increased Medicare costs, "it would be the intent of the relevant Committees to consider legislation banning referrals at the earliest possible date." PMID- 10106619 TI - Catastrophic's school of hard knocks. PMID- 10106620 TI - What to do before the Inspector General comes. PMID- 10106621 TI - Executive information systems require accurate data. PMID- 10106622 TI - Strategic adaptations to PPS by rural hospitals: implications for theory and research. AB - Medicare's Prospective Payment System (PPS) has introduced a new environment in which hospitals must either alter their strategies for delivering services or face closure. This is a challenge for rural hospitals that often lack the resources and supportive economic climate of their urban counterparts. Few guidelines are available to assist rural hospitals in responding organizationally to PPS-induced constraints. This article examines the plight of rural hospitals from the perspective of strategic adaptation. A conceptual framework is proposed for studying strategic adaptations to PPS by rural hospitals. The implications for developing a sound research methodology are also discussed. On the basis of this research agenda, it may be possible to clarify how rural hospitals should adapt to PPS (and similar) constraints now, and in the future. PMID- 10106623 TI - Will HCFA use RBRVS to cut everyone's fees? PMID- 10106624 TI - How much is careless coding costing you? PMID- 10106625 TI - Applying geriatric case management in your medical group practice. AB - One of the biggest questions medical groups will have to answer in relation to America's shifting demographics is how to deal with the diverse needs of the elderly effectively. Authors Candace Bruno and Cheryl Schraeder believe one alternative is a case management approach. Their article presents ways in which other medical groups are using case management to meet the needs of the elderly. PMID- 10106626 TI - Financing health care services for the elderly. AB - Medicare is constantly under scrutiny by the federal government, according to author Kathleen Konka. Medicare will play an increasingly important role as the population continues to shift and administrators will need to be alert as the government continues to change Medicare reimbursement. PMID- 10106627 TI - Danger in the safe harbors. Medicare fraud and abuse. PMID- 10106628 TI - Predicting hospital accounting costs. AB - Two alternative methods to Medicare Cost Reports that provide information about hospital costs more promptly but less accurately are investigated. Both employ utilization data from current-year bills. The first attaches costs to utilization data using cost-charge ratios from the previous year's cost report; the second uses charges from current year's bills. The first method is the more accurate of the two, but even using it, only 40% of hospitals had predicted costs within plus or minus 5% of actual costs. The feasibility and cost of obtaining cost reports from a small, fast-track sample of hospitals should be investigated. PMID- 10106629 TI - Privacy Act of 1974; report of new systems of records--HCFA. Notice of new system of records. AB - In accordance with the requirements of the Privacy Act of 1974, we are proposing to establish a new system of records, "HCFA Medicare Mortality Predictor Data File, "HHS/HCFA/ORD No. 09-70-0047. We have provided background information about the proposed system in the "Supplementary Information" section below. Although the Privacy Act requires only that the "routine uses" portion of the system be published for comment, HCFA invites comments on all portions of this notice. PMID- 10106630 TI - Medicare program; protocol for the reuse of dialysis bloodlines--HCFA. Final rule. AB - This final rule implements section 1881(f)(7) (B) and (C) of the Social Security Act, added by sections 9335(k) and 4036(c) of the Omnibus Budget Reconciliation Acts of 1986 and 1987. That legislation precludes end-stage renal disease (ESRD) facilities from reusing dialysis bloodlines after July 1, 1988 unless the Secretary has established a protocol for their reuse and the facility follows the protocol. These provisions constitute both a Medicare condition of coverage for ESRD facilities and a condition for payment for dialysis treatment involving reused bloodlines for those facilities which elect to reuse them. PMID- 10106631 TI - Criteria and standards for evaluating intermediary and carrier performance--HCFA. General notice with comment period. AB - This notice describes the criteria and standards to be used for evaluating the performance of fiscal intermediaries and carriers in the administration of the Medicare program beginning June 1, 1990. The results of these evaluations are considered whenever HCFA enters into, renews, or terminates an intermediary or carrier agreement or takes other contract actions; assigns or reassigns providers of services to an intermediary; or designates regional or national intermediaries. This notice is published in accordance with sections 1816(f) and 1842(b)(2) of the Social Security Act, which requires us to publish for public comment in the Federal Register those criteria and standards against which we evaluate intermediaries and carriers. PMID- 10106633 TI - EMS and mass gatherings. PMID- 10106632 TI - Quality assurance and certification program for an aminoglycoside monitoring service. AB - A Quality Assurance Program (QAP) should both evaluate and improve the quality of a service. In order to train newly employed pharmacists and ensure provision of a consistently high level of clinical service, a pharmacist training program for an Aminoglycoside Monitoring Service (AMS) and a QAP involving pharmacist certification was established. The certification program consists of a pretest, a reading/information package, an "on the job" training requirement and a posttest which pharmacists work through at their own speed. Certification requires completion of 45 hours of supervised AMS activity and a score of 90 percent on the posttest. Yearly recertification is required. As an integral part of the QAP, the clinical coordinator reviews the AMS monitoring forms monthly for specific performance standard indicators. Problems are identified and dealt with on an individual basis. The program is not mandatory, however, all pharmacists have elected to complete certification. Seven pharmacists and three pharmacy residents have participated in the certification program. All seven pharmacists and one resident received certification. A questionnaire completed by the pharmacists indicated that all felt certification was necessary and contributed to standardization and consistency of the AMS. PMID- 10106635 TI - Departmental image: what it is, why it matters, and how to achieve a desirable one. PMID- 10106634 TI - When terror strikes. PMID- 10106636 TI - Petal pushers. PMID- 10106637 TI - HCFA issues new regulations for clinical laboratories. PMID- 10106638 TI - How to pick the best PM (preventive-maintenance) software package. PMID- 10106639 TI - Use strategic planning to reshape your lab's future. AB - Following a carefully thought-through battle plan helps uncover and defuse the treacherous mines that dot the ground ahead. "Generals" of the laboratory are advised to take the long view. PMID- 10106640 TI - Cholesterol screening. Part IV. Benefits of cooperative efforts between the lab and a hospital wellness program. PMID- 10106641 TI - Vendor-proof your LIS (laboratory information systems) contract. PMID- 10106642 TI - Small firm adaptation: responses of physicians' organizations to regulatory and competitive uncertainty. AB - This study addressed the pattern of small organizations' adaptation responses to uncertainty in the regulatory and competitive sectors of their environment using data from physicians in solo practice. An existing general model of adaptation was modified to reflect small-firm work processes. The result is a four-cell model that distinguishes adaptive strategies in terms of their functional orientations and how firms pursue them--whether alone or in collaboration with other firms. Data analyses supported the propositions that adaptation in small firms is a multicomponent construct and that regulatory and competitive uncertainty differentially influence the adaptation process. Although individual relationships found among the sets of adaptation activities supported the contention that adaptation choices follow a hierarchical cost pattern, the overall fit of the model suggests modification of the theory in subsequent research efforts. PMID- 10106643 TI - Peers as key contributors to the socialization of newcomers. AB - How can clinical laboratory managers retain employees as the shortage of medical technologists grows? They can help to ensure that new employees become satisfied and productive by using peers as agents for socialization. According to results from both oral interviews and written questionnaires, peers bring newcomers "on board" by providing key information. Responses of 83 organizational newcomers indicate that peers have four qualities: accessibility; empathy; organizational experience; technological proficiency; that equip them to contribute significantly to the socialization of newcomers. Also, joining a newcomer with a peer helps the newcomer to acquire essential, work-related information. PMID- 10106644 TI - Are you entrepreneurial material? PMID- 10106645 TI - Quality assurance: the current challenge. AB - Occupational therapists are being challenged to measure and evaluate the care provided to their patients. This paper discusses the various stages of development of a quality assurance program within a large pediatric occupational therapy department. Several quality assurance activities undertaken are described, including the development of standards of clinical practice (based on the "Guidelines for the Client-Centred Practice of Occupational Therapy") and the development of assessment and documentation protocols. Outcome measurement in pediatric occupational therapy is addressed in relationship to the process measures which were developed in the department. The approaches to outcome measurement are outlined within the context of an audit attempting to evaluate the effectiveness of occupational therapy intervention based on five areas of evaluation. PMID- 10106646 TI - Developing guidelines for client-centred occupational therapy practice. AB - The Canadian Guidelines for the client-centred practice of occupational therapy are national, generic, consensus guidelines developed to address growing concerns inside and outside the profession for assuring the quality of health services. From 1979 to 1987, successive Task Forces, sponsored by the Department of National Health and Welfare and the Canadian Association of Occupational Therapists, developed three volumes of guidelines. A pivotal guideline in Volume I is a conceptual framework of occupational therapy's central concern: occupational performance within an individual's physical, cultural and social environment. Volume I also outlines stages in the process of client-centred occupational therapy practice, and specific assessment and program planning guidelines. Volume II covers issues, concepts and fundamental elements of intervention, as well as specific guidelines for intervention, discharge, follow up and evaluation. Volume III reviews issues in outcome measurement given occupational therapy's primary concern for occupational performance. The authors, members of the Task Forces, provide an overview of the development of and their hopes for the Guidelines. Uses and influences of the Guidelines have not been formally documented. However, projects are arising from the Guidelines and a new CAOT Client-Centred Practice Committee is proposing an updating process for the three volumes. PMID- 10106647 TI - Occupational performance measures: a review based on the guidelines for the client-centred practice of occupational therapy. AB - In 1987, Health and Welfare Canada and the Canadian Association of Occupational Therapists Task Force recommended that work go forward to develop an outcome measure for occupational therapy which reflects the Occupational Performance Model. The first step in this process was to review critically those outcome measures which assess occupational performance and that are currently available in the literature. This paper will present the review process, describe in more detail eight assessments that fulfilled many of the review criteria, discuss the limitations of these measures using the "Guidelines for the Client-centred Practice of Occupational Therapy as the framework, and make recommendations for the development of a new outcome measure for use in occupational therapy. PMID- 10106648 TI - Searching Medline. Finding needles in the medical haystack. PMID- 10106649 TI - Neurology offers range of opportunities for hospitals. PMID- 10106650 TI - Hospital portfolio analysis. AB - Portfolio analysis is a management technique that rationalizes the process of allocating funds to programs. Each program is screened based on financial performance and organizational relevance. A decision-making matrix prioritizes programs into an orderly form. When resources are scarce, as they were at Tampa General, portfolio analysis can be the key to keeping a strategic plan on course. PMID- 10106651 TI - Medical staff literature grows. AB - Every now and then it pays to review the more thoughtful literature to make sure that what you learned on the job or in school is still current. Here are some recent books that provide important insights you won't get from reading magazines and newsletters or attending medical staff planning meetings. PMID- 10106652 TI - Waiting for managing health services. Reflections on the workplace as a learning environment. PMID- 10106654 TI - Product-line management defined. AB - PLM will have a significant impact on an organization's mission, management philosophy, marketing plan, and most definitely, day-to-day operations. PLM offers an alternative to traditional management approaches for the medical record department and the health care industry as a whole. The medical record professional should understand PLM both as a hospital wide structure and as an internal structure used to maximize departmental productivity and use of resources. PMID- 10106653 TI - The evolution of quality assurance systems in health care--a personal retrospective. AB - This article is an account of the evolutionary development of quality assurance systems in the health care field. It is presented from the perspective of the author, who participated extensively in the development of these systems. PMID- 10106655 TI - Product-line administration: a framework for redefining medical record department services. AB - Product-line administration is a viable approach for managing medical records services in an environment that demands high quantity and quality service levels. Product-line administration directs medical record department team members to look outside of the department and seek input from the customers it is intended to serve. The feedback received may be alarming at first, as the current state of products usually reveals a true lack of customer input. As the planning, defining, managing, and marketing phases are implemented, the road will not be easy and rewards will be slow to come. Product-line administration does not provide quick fixes, but it does provide long-term problem resolution as products are refined and new products developed to meet customer needs and expectations. In addition to better meeting the needs of the department's external customers, the department's internal customers' needs and expectations will be addressed. The participative management approach will help nurture each team member's creativity. The team members will have the opportunity to reach their full potential while reaping the rewards and benefits of providing products and services that meet the needs and expectations of all department customers. The future of the health care industry promises more changes as the country moves toward some form of prospective payment in the ambulatory setting. Reactive management and the constant struggle to catch up can no longer be accepted as a management approach. It is imperative that the medical record department be viewed as a business with product lines composed of quality products. The planning, defining, managing, and marketing components of product-line administration afford responsiveness to the current situation and the development of quality products that will ensure that medical record departments are prepared for the future. PMID- 10106656 TI - Using the Deming quality improvement method to manage medical record department product lines. AB - The above application of the quality improvement cycle provides insight into the use of the Deming method to address one of several identified customer needs and expectations obtained during the managing phase of product-line administration. Implementation of the quality improvement method requires a major commitment from all team members. Process improvement requires a willingness to be detail oriented. Gathering of statistics--such as analysis turn-around time--and evaluation are critical. This objective view of processes requires accountability and a commitment to change. Improvements focus on long-term problem resolution, not the quick fixes that result from addressing symptoms of problems. True problem resolution occurs by solving the root causes of variations. Medical record departments must move from being outcome oriented to being process focused. It is no longer feasible to be constantly putting out fires in an environment that demands well-planned and well-designed products that meet customers' expectations. The long-term management of product lines requires a systematic method of planning, doing, checking, and acting. The Deming quality improvement method provides a framework for positive change that focuses on quality processes resulting in a quality product that meets consumers' needs. PMID- 10106658 TI - Perspectives. Medigap market melee: next round. PMID- 10106657 TI - Prescribing for unlabeled conditions: patient benefit or therapeutic roulette? AB - There is ample evidence that prescribed medications are employed for uses far broader than the approved label indications in the U.S. An enormous research agenda thus exists that should be addressed in the not-too-distant future. In fact, it seems essential that operation of the Medicare Catastrophic Drug Benefit program be designed with the best available knowledge in this area. Perhaps it might be appropriate for several universities, the U.S. Pharmacopeial Convention, and/or the FDA to establish a center to study this question. This model has been applied with clinical/surgical registries, with adverse reaction reporting, and with device failures. We need a rational, science-compatible, and uniform policy free of political and emotional arguments to address the issue of handling, monitoring, and regulating the use of drugs for unlabeled conditions. Comprehensive data should be provided for policy makers, regulators, payers, and clinicians in their evaluating the use of different drug products. Even a brief glance at any page from the National Disease and Therapeutic Index shows intended use that would cause most experts to react in disbelief. Further, there seem to be relatively few instances in which the use of a given pharmaceutical for an unlabeled indication would qualify as a drug of choice in the first place. The therapeutic and economic consequences of the use of legend drugs for unlabeled indications are difficult to document. We do know that a significant proportion of hospital admissions and days can be traced to the inappropriate use of pharmaceutical products but the net impact of our subject on institution cost has not been established.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106659 TI - Multi-company working as one. AB - The consolidation of HR information processing in multi-union environments can result in significant cost savings; efficiencies in decision making; and flexibility to make changes. PMID- 10106660 TI - New Medicare fee schedule includes payment for liability costs. PMID- 10106661 TI - Physician reimbursement update. PMID- 10106662 TI - Criteria and standards for evaluating intermediary and carrier performance--HCFA. Correction. PMID- 10106663 TI - What about the quality of care. AB - As the numbers of homemaker-home health aide services grow, it is clear that there is an urgent need to improve and maintain the quality of paraprofessional services. Because homemaker-home health aide services affect the public good, it is important that the federal government be involved in developing and enforcing quality assurance standards. The establishment of national standards must become a priority for the government as well as for national, state, and local associations. PMID- 10106664 TI - Hospital-based SNFs: a good bet for institutions? PMID- 10106666 TI - Legal issues--Update V. PMID- 10106665 TI - Medical staff planning. Too few beds? AB - Medical staff plans may provide an answer to capacity overload. Hospital strategic managers should consider reducing the size and mix of the medical staff to be more in line with the institution's strategic plan for clinical services. They must assess active medical staff membership in relation to the needs of the market area in developing future policies. PMID- 10106667 TI - The on-again, off-again campaigns for national health insurance. PMID- 10106668 TI - Lessons from the empires. PMID- 10106669 TI - Mission-based planning. PMID- 10106670 TI - Beyond the hospital's mission: the people speak. PMID- 10106671 TI - Tactics--the hot and sweaty work. PMID- 10106672 TI - Pitfalls in state-authorized treatment of minors. AB - Recently a federal court in Georgia ruled that several physicians and several state officials could be sued for state-authorized treatment of a minor over his father's objection. State authorization protects providers only if it is properly obtained and the authorizing official has the power to grant the authorization in the existing circumstances. PMID- 10106674 TI - Vision--health care leadership's challenge for the '90s. PMID- 10106673 TI - Turnover: strategies for staff retention. AB - This discussion has focused on a number of areas where organizations may find opportunities for more effectively managing employee retention. Given the multitude of causes and consequences, there is no one quick fix. Effective management of employee retention requires assessment of the entire human resources process, that is, recruitment, selection, job design, compensation, supervision, work conditions, etc. Regular and systematic diagnosis of turnover and implementation of multiple strategies and evaluation are needed (Mobley, 1982). PMID- 10106675 TI - A glance at the future: a Delphi study of trends affecting health care education. PMID- 10106676 TI - Basic recruiting tactics that work. PMID- 10106677 TI - CD Plus: MEDLINE on CD-ROM. AB - Developed by CD Plus (formerly Online Research Systems, Inc.), CD Plus MEDLINE is a welcome addition to the growing number of MEDLINE CD-ROM products. CD Plus MEDLINE offers monthly updates and coverage of the full MEDLINE database back to 1966. Some of its features include mapping to MeSH, explode capability, permuted term index, scope notes from the Annotated MeSH, and access to the tree structures. The system is designed for the novice as well as the professional searcher. The article takes a descriptive look at MEDLINE on CD Plus, its software, searching capabilities, limitations, special features, and system requirements. PMID- 10106678 TI - MEDLINE and PsycLIT on CD-ROM: a survey of users in an academic medical library. AB - A survey of users of PsycLIT and MEDLINE on CD-ROM was performed at an academic medical library. The questionnaire was designed to gather information about the user population, satisfaction of the users, the assistance needed to use the systems, and the type of searches being performed. The majority of users were graduate students in the schools of medicine, nursing, and pharmacy. In general, users were satisfied with the performance of the systems. Assistance from a librarian, printed documentation, or another patron was required by 85% of users, and they were generally satisfied with this assistance. Most searches were performed to obtain information on a subject. The results were remarkably similar for both databases. PMID- 10106679 TI - Building a clinical consulting program. PMID- 10106680 TI - PPS pushed for outpatient services. PMID- 10106681 TI - HME fee variations prompt restraint talk. PMID- 10106682 TI - Study questions special payment adjustment. PMID- 10106683 TI - Proposed rules broaden anti-kickback law. PMID- 10106684 TI - AHA wins round in lawsuit over insurance payments. PMID- 10106685 TI - N.Y. hospitals seek rate relief. PMID- 10106686 TI - Proposal to reduce peer review in HMOs elicits cheers, caution. PMID- 10106687 TI - Early postpartum discharge: implications for HMOs. AB - Early postpartum discharge, defined as discharge of the postpartum mother and newborn infant from the hospital 12-24 hours after delivery, has been shown to be a safe, well-accepted, economical alternative to the traditional hospital stay. Because of consumer pressure to treat pregnancy and birth as a healthy rather than an illness state, the current trend is toward decreased medical intervention and increased self-care for the postpartum mother and infant. Many HMOs have instituted such programs, and others may want to consider this consumer preference and implement early postpartum discharge programs to increase consumer satisfaction and, at the same time, decrease health care costs. This literature review summarizes various early discharge programs including preadmission criteria, early discharge criteria, procedures, complications, consumer satisfaction, staff training, and cost effectiveness. PMID- 10106688 TI - Rounding MAACs up to the next dollar: conflicting interpretations of legality befuddle physician offices nationwide. PMID- 10106689 TI - The payment predicament. Programs nationwide face poor reimbursement. PMID- 10106690 TI - The Department of Health Estates Directorate. PMID- 10106691 TI - Waiver of certain membership requirements for certain health maintenance organizations (HMOs), and state option for disenrollment restrictions for certain HMOs under Medicaid--HCFA. Final rule. AB - These regulations revise current Medicaid rules to bring them into conformity with statutory changes that (1) expanded the waiver authority of the Secretary to permit certain health maintenance organizations (HMOs) meeting specified requirements to exceed the composition of enrollment limit, (2) permitted certain organizations to contract on a risk basis, (3) permitted continuation of benefits to recipients enrolled in certain organizations after they have lost entitlement to Medicaid, and (4) granted States the option of restricting a Medicaid enrollee's right to disenroll from certain types of risk HMOs and other organizations. The statutory changes that are reflected in these regulations were enacted in section 2364 of the Deficit Reduction Act of 1984, as amended by section 9517 of the Consolidated Omnibus Budget Reconciliation Act of 1985 and section 4113 of the Omnibus Budget Reconciliation Act of 1987. We are also making a technical correction concerning HMO and PHP contracts. PMID- 10106692 TI - Medicare program; inpatient hospital deductible and coinsurance and skilled nursing facility coinsurance for 1990--HCFA. Notice. AB - This notice announces that the inpatient hospital deductible for calendar year 1990 under Medicare's hospital insurance program (part A) remains the same as announced on September 29, 1989 at 54 FR 40205. However, the repeal of the Medicare Catastrophic Coverage Act of 1988 by the Medicare Catastrophic Coverage Repeal Act of 1989 restored 1988 part A coverage and cost-sharing rules, including the benefit period provisions, coinsurance charges, and the three-day prior hospitalization requirement for skilled nursing facility (SNF) care. Because the Part A catastrophic benefits under the Medicare Catastrophic Coverage Act of 1988 were in effect in 1989, the Medicare Catastrophic Coverage Repeal Act of 1989 included several provisions that apply to beneficiaries who were inpatients of hospitals or SNFs both at the end of 1989 and the beginning of 1990. PMID- 10106693 TI - Directory of professional associations and societies. PMID- 10106694 TI - 1990 specifier's guide. PMID- 10106696 TI - The Medicare secondary payer crisis: why some third party administrators are being sued and what can be done about it. PMID- 10106695 TI - Storm warning: danger signs during software implementation. AB - Software can be implemented successfully, but it is a feat that takes careful planning to accomplish. A number of warning signs can help hospitals avoid potential disaster that may follow on the heels of systems implementation. PMID- 10106697 TI - Developments in the law. Medical technology and the law. PMID- 10106698 TI - On a business path. PMID- 10106699 TI - Reducing waste volumes: 3 obstacles to overcome. PMID- 10106700 TI - A grand design for quality. PMID- 10106701 TI - Development of a service organization. CHA (Catholic Hospital Association) from post-World War II through Vatican II. AB - Having weathered the Depression and war years, CHA in the late 1940s looked forward to a new era in Catholic healthcare. The third and fourth articles of Health Progress's six-part history of CHA described how Rev. Alphonse M. Schwitalla, SJ, led the association through one of the most difficult periods in U.S. history. This article follows CHA's development into a modern service organization under the leadership of Rev. John J. Flanagan, SJ. The series' final installment, which will appear in the July-August issue, describes how CHA has modernized its services and structure in the past two decades to help its members adjust to a turbulent environment. PMID- 10106702 TI - Systems that share. PMID- 10106703 TI - Testing the water. AB - For the past several decades mergers have been an attractive option for systems looking to diversify and for small hospitals trying to find a way to survive. Before entering into a merger agreement, each of the parties involved should carefully assess whether the move is in its best interests. Chief executive officers of small hospitals should determine whether a merger will improve their facility's ability to provide needed programs and services to their community. They should also evaluate their and their partner's current fiscal status to assess whether the timing is right for a merger. Another important consideration is whether or to what extent the new governance structure will provide each partner with appropriate representation. For healthcare systems looking to acquire a smaller hospital, two key concerns are whether the facility is in a favorable location to gain increased market penetration and whether resources are, or can be made, available to consummate the merger. Systems should also ask if the smaller hospital will at least be a break-even operation and if political opposition might undermine a merger attempt. Finally, although merger proposals are likely to disturb some members of the community they affect, a well-planned and credibly negotiated merger is usually in the region's best interests. PMID- 10106704 TI - Can HCFA force managed care on the elderly? PMID- 10106705 TI - Your new guide to fee schedules. PMID- 10106706 TI - Weighting performance made our merit raises fairer. PMID- 10106707 TI - A model QA program as a management tool. PMID- 10106708 TI - How we adapted a CE model for our clinical lab. PMID- 10106709 TI - Physician payment reform--implementing resource-based relative value scales. AB - In this article, the author summarizes recently enacted legislation that will result in a phaseout of the traditional usual and customary fee reimbursement system for physicians under Medicare, explains how a system of relative value scales will be implemented, and offers some suggestions for physicians concerned about their economic futures. PMID- 10106710 TI - Physician and provider obligations under the Medicare antidumping provision. AB - The Medicare antidumping provision enacted in 1986 and revised in 1989 has serious implications, not only for hospitals, but also for physicians who provide care for emergency patients. In this article, the author discusses the obligations of health care providers under that provision, some recent developments under the emerging case law, and the implications of these developments for physicians. PMID- 10106711 TI - Collateral sanctions for criminal convictions in the Medicare and Medicaid programs. AB - Under current federal and state laws, physicians convicted of Medicare and Medicaid program-related crimes face numerous possible sanctions that may be imposed in addition to the applicable criminal penalties. In this article, the author describes some of the collateral sanctions that physicians and their attorneys should be aware of in order to make informed decisions concerning the proper defense strategy in a criminal case. PMID- 10106712 TI - Board certification: an index to the specialty boards. AB - Here are answers to the most often-asked questions regarding how to take the Boards, including exam dates, general requirements, application deadlines, exam topics, pass/fail rates, fees, and where to call or write for further information on your chosen specialty. PMID- 10106713 TI - Medicare payment for capital. PMID- 10106714 TI - A national health policy? PMID- 10106716 TI - Catastrophic confusion. Clarifying the Medicare revisions. PMID- 10106715 TI - Speak English! PMID- 10106717 TI - Managerial indecisiveness: when the monkeys run the zoo. PMID- 10106718 TI - Intrapreneurial constituency management: a success profile for the 1990s. PMID- 10106719 TI - A comprehensive needs analysis equals training department credibility. PMID- 10106720 TI - Is COBRA poised to strike? A critical analysis of medical COBRA. PMID- 10106721 TI - High court protects Medicaid challenges. PMID- 10106723 TI - Medicare cutbacks impair 'safeguard' programs--GAO. PMID- 10106722 TI - Study figures losses from Medicare trims. PMID- 10106724 TI - Higher interest upheld. PMID- 10106725 TI - Humana joins call for extension of most catastrophic benefits. PMID- 10106726 TI - Payment fears spur purchases. PMID- 10106727 TI - Ohio Medicaid rates nixed on appeal. PMID- 10106728 TI - HHS computer program flags drug resellers. PMID- 10106729 TI - Panel maps PPS expansion, awaits word from summit. PMID- 10106730 TI - Perspectives. Court gives providers new hope. PMID- 10106731 TI - Medicaid program; medical eligibility quality control (MEQC) program requirements -HCFA. Correction. PMID- 10106732 TI - Implementing OBRA pushes legal limits. PMID- 10106733 TI - Prior hospitalization drives costs higher. PMID- 10106734 TI - The computerized medical record: an invitation to dialogue. AB - This article is a companion to "Computerized Medical Records--the Need for a Standard" which appeared in the March 1990 issue of JAMRA. The author has created a workable image of the future with these two articles. In this vision of the future, the control of information appears as one of the greatest medical advances of all history, and the stewards of medical data take an honored position in patient care and research. The author requests that readers be critical in their evaluation of these articles. Great expense and the health of millions will depend upon timely definition of the optimal medical record. Such a task deserves the attention of many minds. We sincerely hope that these articles will elicit lively dialogue. PMID- 10106735 TI - Recordkeeping systems: rehabilitation centers. PMID- 10106736 TI - Family coping: caring for the elderly in home care. AB - This paper focuses on the nature and significance of family caregiving problems when providing assistance to chronically ill or frail older adults. It includes theoretical frameworks that provide explanations of related research about family coping problems, a guide for assessment of family caregiving problems, and a summary of current findings relative to home care agency planning and health care policy. The Family Caregiver Assessment Guide for use in home care agencies is included in the appendix to the paper. PMID- 10106737 TI - Tailoring teaching to the elderly in home care. AB - This paper provides a brief overview of teaching and learning principles common to all adult learners and then discusses the latest research findings and their implications for adapting teaching materials and methods for the elderly. Sensory abilities, cognitive abilities, motor dexterity, developmental tasks, cohort influences, and the current situation in which the older person exists are included. Summary tables of key information are provided throughout the text for easy reference. Guides for assessment of the older adult, aids for evaluating educational materials, and a list of resources for teaching the older adult are provided in the appendix. PMID- 10106738 TI - Medication regimens and the home care client: a challenge for health care providers. AB - This paper synthesizes literature related to medication-taking behaviors of the elderly population and examines factors related to medication compliance problems. A review and critique of the literature focused on interventions and strategies for improving medication compliance is also presented. This analysis provides direction for developing assessment guides, intervention strategies, and educational materials which may be helpful for health providers in assisting patients and families to manage medication regimens. The paper also includes a comprehensive medication assessment guide and a resource list of educational materials for family care-givers and health providers. The last section of the paper describes the clinical testing study of the medication assessment guide. PMID- 10106739 TI - Medicare physician payments: shapes of things to come. PMID- 10106740 TI - Hill-Burton enforcement: slow but relentless. PMID- 10106741 TI - Physician recertification: should doctors be "weeded"? PMID- 10106742 TI - Physician payment reform: what's ahead for MDs? PMID- 10106743 TI - Medical manpower planning. AB - Since 1980, numerous articles have discussed impact analysis; in addition, the Ontario Hospital Association and the Ontario Medical Association are about to publish guidelines to assess the impact of additional physician manpower and instructions on various techniques to conduct such an analysis. However, little has been published on medical manpower planning at the hospital level, in spite of the fact that a medical manpower plan is at the core of a successful hospital strategic plan. This article presents a population-service-based model of a medical manpower plan and reviews its use at Peel Memorial Hospital. PMID- 10106744 TI - Corporate buying of health care plans: a framework for marketing theory and practice. AB - Much of the research in health care plan and provider selection has focused on the patient's selection process. The authors report on the increasing need to understand the corporation's decision process in selecting health care plans and providers. Managed care marketers need to understand this process in order to design and market such plans successfully. PMID- 10106745 TI - How to write a business plan for your laboratory. PMID- 10106746 TI - The search for Medicaid money. AB - A recent ruling from the Supreme Court has given hospitals more ammunition in their battle for Medicaid reimbursement. The ruling has bolstered pending lawsuits and has dealt hospitals a trump card in ongoing negotiations with states over Medicaid funds. But some hospitals haven't been waiting for a ruling; they're angling for federal matching funds to boost their Medicaid coffers. PMID- 10106747 TI - Nursing homes hope ruling fattens OBRA reimbursement. PMID- 10106748 TI - Pa. trims Medicaid budget $39 million. PMID- 10106749 TI - Identifying the important aspects of care. PMID- 10106750 TI - Rely on data, not politics, when redesigning schedule. PMID- 10106751 TI - Independent ownership. Managing the price of quality. PMID- 10106752 TI - Deciding to participate. PMID- 10106753 TI - Maximizing Medicare to achieve financial stability. PMID- 10106754 TI - Shared MD/hospital values. PMID- 10106755 TI - Effective fund-raising requires sound strategic planning. PMID- 10106756 TI - Strategic planning and debt policy. PMID- 10106757 TI - Criteria for new strategic options. PMID- 10106758 TI - Medicare program; update of ambulatory surgical center payment rates effective July 1, 1990--HCFA. Notice with comment period. AB - This notice implements section 1833(i)(2(A) of the Social Security Act, which requires that the payment rates for ambulatory surgical center services be reviewed and updated annually, and responds to public comments we received concerning the ambulatory surgical center payment rate update notice published on February 8, 1990 (55 FR 4577). PMID- 10106759 TI - Graduate medical education costs to be reaudited. New Medicare payment methodology. PMID- 10106760 TI - Physician payment reform. How the new Medicare fee schedule affects you. AB - Ernst & Young, an Associate Member of AGPA, has prepared an analysis of the Omnibus Budget Reconciliation Act of 1989 (OBRA 89), which contains more than 80 provisions, to explain the timetable and methodology for implementation of new Medicare fee schedules. W. Susan Dempsey, a senior manager with Ernst & Young, prepared the tables and charts for this article in the Group Practice Journal to highlight those provisions that will have the greatest impact on group practices. While all questions may not be answered in one summary of this complex law, hopefully the explanations and illustrations provided by the accounting-health care consulting firm will provide useful enlightenment. PMID- 10106761 TI - Health maintenance organizations in developing countries: what can we expect? AB - Health maintenance organizations (HMOs) are a relatively new and alternative means of providing health care, combining a risk-sharing (insurance) function with health service provision. Their potential for lowering costs has attracted great interest in the USA and elsewhere, and has raised questions regarding their applicability to other settings. Little attention, however, has been given to critically reviewing the experience with HMOs in other countries, particularly concerning their introduction to settings other than the USA. This paper first reviews the current experience of HMOs in low- and middle-income countries, including Argentina, Bolivia, Brazil, Colombia, Ecuador, Uruguay, Chile and Indonesia. Secondly, the paper reviews the USA experience with HMOs: prerequisites for the establishment of HMOs in the USA are identified and discussed, followed by a review of the performance of HMOs in terms of cost containment, integration of care and quality of care for the elderly and poor. The analysis concludes that difficulties may arise when implementing HMOs in developing countries, and that potential adverse effects on the overall health care delivery system may occur. These should be avoided by careful analyses of a nation's health care system. PMID- 10106762 TI - The man behind the security camera. PMID- 10106763 TI - Winning employee support for your crime prevention program. PMID- 10106764 TI - A model of foreseeability. AB - This article gives criteria for a complete analysis of crime foreseeability, which can be used to evaluate the adequacy of your premises security program. PMID- 10106765 TI - Preventing violence in hospitals. AB - The author discusses the areas of potential concern and why it is necessary to have a plan in place in advance. In this day and age, security must be prepared to handle violent situations in the hospital setting. PMID- 10106766 TI - A theoretical (but practical) model for managing hospital security programs. AB - The author describes a comprehensive security program planning model he developed and successfully tested in an inner-city hospital in Detroit, MI. PMID- 10106767 TI - Financial viability is more than just survival. PMID- 10106768 TI - Hospital turnarounds--thinking strategically. AB - Healthcare executives throughout the country are losing confidence that their organizations can remain viable without significant organizational change. Now is the time to review principal trends in this area--conversions and partnerships- and to assess how well particular arrangements seem to be working. PMID- 10106769 TI - The year's work in serials, 1989. PMID- 10106770 TI - Physician payment reform: an idea whose time has come. PMID- 10106771 TI - Innovation in medical care organizations: a synthetic review. PMID- 10106772 TI - An integrative overview of the quality dimension: marketing implications for the consumer-oriented health care organization. PMID- 10106773 TI - Rising above the tide of junk. PMID- 10106774 TI - Managing for high performance. PMID- 10106775 TI - Design & architecture in radiology. PMID- 10106776 TI - Johns Hopkins charged by panel. PMID- 10106778 TI - American Hospital Assn. keeps its eye on Medicare issues, year in and year out. PMID- 10106777 TI - House panel OKs tougher anti-dumping rules. PMID- 10106779 TI - Planning, evaluation are important first steps in construction decisions. PMID- 10106780 TI - Planning for successful fund-raising. PMID- 10106781 TI - Governor candidates give views on health care crisis. PMID- 10106782 TI - History of the California health system. First defeat of compulsory health insurance in California. PMID- 10106783 TI - Crafting secure retirements. PMID- 10106784 TI - Medicaid program; Medicaid eligibility quality control (MEQC) program requirements--HCFA. Final rule with comment period. AB - This rule revises the regulations governing the Medicaid eligibility quality control (MEQC) program to include more specific program requirements and to establish new timeframes for completing and reporting MEQC case findings to HCFA. The rule also establishes a performance-based threshold for States to meet before HCFA will consider good faith waiver requests of disallowance of Federal financial participation (FEP) in erroneous Medicaid payments and provides more definitive criteria for evaluating States' good faith efforts to meet the national standard error rate. In addition, the rule makes several technical changes and provides that a State may rebut its projected error rate only when it can present evidence that its projected error rate was based on erroneous data. These revisions will strengthen the basic MEQC program and provide flexibility and incentives to States to produce accurate Medicaid eligibility determinations. PMID- 10106785 TI - Medicare program; payment for physician outpatient maintenance dialysis services and other physician services for ESRD patients--HCFA. Final rule. AB - This final rule reinstates a modified version of the initial method of payment for physician dialysis services and clarifies and modifies some of the principles of the monthly capitation payment method. Under both the initial method and the monthly capitation payment method, we specify that, to be payable, physician services must meet certain requirements that distinguish services furnished to individual patients from services furnished to facilities that benefit the facilities' patients generally. The reinstatement of a modified version of the initial method is necessitated by a court order. PMID- 10106786 TI - Medicare program; physician liability on non-assigned claims--HCFA. Final rule. AB - This rule establishes in regulations the circumstances in which a nonparticipating physician who does not accept Medicare assignment of a claim is required to refund to the beneficiary any amounts collected for physician services determined to be not reasonable and necessary. Its purpose is to extend limitation of liability protection to beneficiaries with non-assigned claims when the physician knew or could reasonably have been expected to know that Medicare would deny payment for the services. Physician appeal rights are also specified. This rule conforms our regulations to section 9332(c) of the Omnibus Budget Reconciliation Act of 1986. PMID- 10106787 TI - Quarterly listing of program issuances--HCFA. General Notice. AB - This notice lists HCFA manual instructions, regulations and other Federal Register notices, and statements of policy that were published during January, February and March 1990 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register every three months. PMID- 10106788 TI - Rationing health care. AB - Will America be forced to cut medical care to its neediest citizens? Yes, some critics say, and it already is doing that. They say it's time to face reality. PMID- 10106789 TI - Manage or be managed: where do you stand? AB - Proficiency in administration is an essential component for all occupational therapists whether they are managing a caseload or directing the activities of a large department. However, more attention needs to be paid to preparing therapists for management roles by professional organizations in occupational therapy, at both provincial and national levels. Occupational therapy managers have a role to play as well. The issues are reviewed briefly and recommendations to improve the situation are made. PMID- 10106790 TI - I.v. therapy: the legislative and regulatory arena. AB - The inclusion of home IV drug therapy in the Medicare Catastrophic Coverage Act of 1988 brought IV therapy issues to the attention of regulators and providers. Although the legislation was revoked, the issues that were raised in its development must be addressed under the current programs and in any future home IV therapy legislation. PMID- 10106791 TI - A review of diabetes care initiatives in primary care settings. AB - This paper describes a variety of initiatives by general practitioners who assumed varying degrees of responsibility for diabetic patients. The initiatives differ in size, the way they were launched, the support given to general practitioners and the groups of people with diabetes. Evaluation of two projects demonstrate that general practitioners in selected practices, when compared to hospital colleagues, achieve as good or even better outcomes in terms of metabolic control and thoroughness of review. The outcomes of other initiatives are less encouraging, although the evidence is exteremely sparse and somewhat dated. A full quality assessment of all kinds of initiatives is urgently required. PMID- 10106792 TI - Verbal communication skills and patient satisfaction. A study of doctor-patient interviews. AB - This research attempted to quantify specific behaviors in the physician's initial interviewing style and relate them to patients' perception of satisfaction. Five physicians were tape recorded during their initial interviews with 52 adult patients. The patients were asked to complete the Medical Interview Satisfaction Scale, a 29-item instrument with a 7-point response scale. These interviews were transcribed, timed, coded, and analyzed with the use of the Computerized Language Analysis System. Selected variables of the language dimensions were entered as the predictor variables in a multiple regression, along with satisfaction scores as the dependent variables. Twenty-seven percent of the variance (p less than .01) in the satisfaction scores of initial interviews were explained by three aspects of a physician's language style: (a) use of silence or reaction time latency between speakers in an interview, (b) whether there was language reciprocity as determined through the reciprocal use of word-lists, and (c) the reflective use of interruptions within an interview. Considering the complexity of human communication, the fact that three variables were identified, which accounted for 27% of the variance in patients' satisfaction, is considered a substantial finding. PMID- 10106793 TI - Core competencies define medical centers of the future. PMID- 10106794 TI - How Medicare will distribute 1991 hospital payments. PMID- 10106795 TI - Matrix management: not a structure, a frame of mind. AB - In many of the world's leading corporations, strategic thinking has outdistanced organizational capability. As business challenges have grown more complex over the past 20 years, most companies have avoided the trap of one-dimensional strategic responses-stick to your knitting, stick to the big markets. But many of them have fallen into a second, structural trap and adopted elaborate organizational matrices that actually impair their ability to implement sophisticated strategies. Keeping a company light on its feet strategically while still coordinating its activities across divisions, functions, even continents, means eliminating parochialism, improving communications, and weaving the decision-making process into the company's social fabric. Altering formal structure from the top down is a poor way to achieve these goals. It is easier to work from the bottom up, focusing on the attitudes and behavior of individual managers. The companies that have made best use of this focus-among them NEC, Philips, and Unilever-employ three techniques to capture the capabilities and commitment of each manager: 1. They communicate a clear, consistent corporate vision. 2. They use training and career-path management to broaden individual perspectives and increase identification with corporate goals. 3. They co-opt individual energies and ambitions into the broader corporate-wide agenda. The goal is to build a matrix of corporate values and priorities in the minds of managers and let them make the judgments and negotiate the deals that make strategy pay off. PMID- 10106797 TI - Pinpointing troublespots via roof-problem analysis. National Roofing Contractors Association. PMID- 10106796 TI - The profitable art of service recovery. AB - In services, mistakes are a fact of life. No matter how hard companies try, they can't prevent the occasional late flight or missed delivery. But they can learn to recover from them. Consider how Club Med-Cancun turned a service nightmare into a memorable experience. When a flight to Cancun left New York six hours late, made two unexpected stops, ran out of food, and had a rough landing, the vacationers on board were certain their holiday was ruined. But the Club Med manager greeted the travelers with food and music and chauffeured them back to the resort. In the end, the vacationers had a better time than if the flight had gone like clockwork. Service recovery starts with identifying the problem. The Bank of Maine in Portland pays customers $1 for writing a letter about the service they received. American Express uses an "800" number to solicit customer complaints. Once they've identified a problem, service companies must act fast. When Smith & Hawken realized that it was taking months to resolve customers' problems by mail, the company decided to use the phone instead. Most important, service companies should encourage frontline employees to deviate from the rules when necessary. Some companies use role playing to help employees develop the creative thinking needed to deal with unusual situations. Sonesta Hotels uses a game in which teams win points for coming up with good solutions to realistic problems. Also, employees must have the authority and responsibility to act on their beliefs-to make phone calls, credit accounts, or send flowers.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106798 TI - Managing your competitor's strategy. PMID- 10106799 TI - Decision support systems help planners hit their targets. AB - DSS software integrates corporate information on past performance with what is currently happening. Planners at a variety of companies are using this information technology to make more accurate strategic decisions. PMID- 10106800 TI - Telecommunications opens new strategic vistas. PMID- 10106801 TI - Strategic planning: public health nutritionists strengthen their capacity to function in a changing environment. AB - In 1987, the public health nutritionists who work in Ontario's 42 health units and the Ministry of Health, initiated a province-wide strategic planning process. That same year, three major reports received by the Ontario Ministry of Health proposed new directions for health services. This article briefly describes the strategic planning process used by the nutritionists and presents the resulting "Strategic Plan for Nutrition in Public Health." It also reviews the three reports and illustrates how they support the priorities established by the nutritionists under four major themes: data needs and data collection; economic/environmental issues; program/service issues; and professional issues. The relevance and significance of the parallels among the reports and strategic plan are explored. PMID- 10106802 TI - Technology planning is key to purchasing of costly scanner. PMID- 10106803 TI - Strategic technology planning: selecting the niches of high-tech medicine in the 1990s. PMID- 10106804 TI - 1990 ambulance manufacturers directory. PMID- 10106805 TI - Elder abuse: an overview of social and medical indicators. PMID- 10106806 TI - Elder abuse by adult offspring: the relationship of actual vs. perceived dependency. PMID- 10106807 TI - Ten (tentative) truths about elder abuse. PMID- 10106809 TI - Pepper Commission urges expanded services. PMID- 10106808 TI - Medicaid lawsuit win a major step in health care funding dilemma. PMID- 10106810 TI - Legislation mandating living wills criticized. PMID- 10106811 TI - VA drops contract with drug maker. PMID- 10106812 TI - Major study finds no tie between mortality rates, quality of hospital care. PMID- 10106813 TI - New strategies--managing hospitals in the '90s. PMID- 10106814 TI - HCFA & CEOs in the hotseat--panel discussion. PMID- 10106815 TI - Proposed HCFA revisions to the hospital market basket. PMID- 10106816 TI - Round 2: more fraud and abuse regulations. PMID- 10106817 TI - Are the Medicare Hospital Trust Funds being misused? PMID- 10106818 TI - Material requirements planning: a better way to plan material. AB - MRP systems can benefit hospitals in their management of material. Systems provide the means to schedule surgical procedures, calculate material requirements, release orders, plan future capacity requirements, and release and track work orders. MRP can be a powerful tool if properly implemented. All it takes is individuals dedicated to maintaining the discipline and data integrity required to make MRP successful. PMID- 10106819 TI - Inventory auditing: a manufacturing perspective. AB - Despite the mystery that usually surrounds the annual audit program, its plan is easy to understand if you learn the basic concerns of the auditor. A five-step inventory audit plan usually consists of proving that the inventory exists, is completely represented, belongs to the firm, is properly valued, and is properly classified. To develop the inventory audit plan, an auditor must verify a firm's system of internal controls, in addition to verifying management's financial assertions by obtaining evidence about them. The time, cost, and frequency of the inventory audit with even the best plans may vary because of changing factors. PMID- 10106820 TI - Planning a storeroom operation: a case study. PMID- 10106821 TI - The modern association. Preserving a Catholic presence in the U. S. healthcare system. AB - A leader in U. S. Catholic healthcare since 1915, CHA has helped Catholic hospitals meet the challenges of the standardization movement, the Depression, and two world wars. The fifth Health Progress article on CHA's history (June 1990) described the association's postwar emergence as a service organization under the leadership of Rev. John J. Flanagan, SJ. This article, the last in the series, charts CHA's response to the revolutionary changes within Catholic healthcare brought about by the Second Vatican Council and the passage of Medicare. It recounts the struggles within the U.S. Catholic healthcare community to sustain its Catholic identity, as well as the community's increased presence as an advocate for a just healthcare system. In the spirit of the institutes of women religious who established the Catholic healthcare ministry in the United States, CHA enters the 1990s committed to advocating for universal access to healthcare and enhancing its members' ability to serve the poor and vulnerable. PMID- 10106822 TI - A realistic approach for gaining physician support of QA. PMID- 10106823 TI - PRO use of Medicare data. PMID- 10106824 TI - Supreme Court ruling supports right to fair Medicaid rates. AB - Virginia Hospital Association should send a clear message to both the states and HCFA that Medicaid providers are entitled, as a matter of right, to challenge their Medicaid rates in federal courts on both substantive and procedural grounds. Accordingly, it is legally incumbent upon the states and HCFA to make the plan amendment process meaningful in terms of state submissions and HCFA's review and approval. Only direct provider participation can ensure this result. PMID- 10106825 TI - Survival strategies for Community General. AB - A survival strategy for Community General in Harrisburg, PA, has saved the hospital $750,000. They have learned to do more with less--and to do it well. PMID- 10106826 TI - Perspectives. Medicare at 25. PMID- 10106827 TI - A concerted effort to boost Medicare reimbursement in North Carolina. AB - In summary, a group of hospital-based air medical services in North Carolina were able to work cooperatively to develop a one-day seminar for their Medicare intermediary. This utilized personnel from all of the participating hospitals in an educational framework designed to enhance understanding of the uniqueness of air medical services and their differences from ground transport services. The benefits of this effort are being seen on a regular basis through enhanced Medicare payment of claims. PMID- 10106828 TI - America's uninsured: Part I: A long history, an uncertain future. PMID- 10106829 TI - Status report on federal efforts to improve trauma care. PMID- 10106830 TI - Medicare program; Medicare coverage of hepatitis B vaccine for high and intermediate risk individuals, hemophilia clotting factors and certain x-ray services--HCFA. Correction of final rule. AB - This document corrects technical errors to the final rule regarding Medicare coverage for hepatitis B vaccine published in the June 4, 1990 issue of the Federal Register [FR Doc. 90-12845], 55 FR 22785. PMID- 10106831 TI - Difference of opinion over Boren decision. PMID- 10106832 TI - OBRA. Pulling the pieces together. PMID- 10106834 TI - Home care computer companies. Corporate profiles. PMID- 10106833 TI - The joys and perils of computerization. AB - The decision to computerize comes after an agency grows beyond its capacity to efficiently control the day-to-day business and/or gather data to plan for future needs. Once the decision to computerize is made, several questions must be answered, including, "What are the computer needs of the agency?" "What functions must it provide?" and "Which system will serve the agency?" PMID- 10106835 TI - Community hospital embraces high-tech training. AB - Training remains an elusive issue to healthcare institutions that are forced to commit massive dollars and resources to ongoing educational programs. A state-of the-art interactive videodisc system installed at a community hospital has delivered measurable return on investment in terms of resources, productivity and time. PMID- 10106836 TI - It could never happen here! AB - Any disaster represents a reactive situation. The key in disaster recovery is to limit this reactive period by quickly evaluating the damage and then implementing the contingency plan. All action should be known and planned. In this way, management can deal with the crisis, and operations can be restored efficiently and effectively. PMID- 10106837 TI - Is managed care manageable? AB - Managed care means a system of providing health care that includes: the selective association of providers in a community, the requirement that patients use these providers if they are to receive insurance coverage, and the active intervention by an outside agent in the doctor-patient relationship to control the health care delivery process. PMID- 10106838 TI - Minnesota's fifteen-year romance. Managed care: lessons learned and survival approaches for hospitals and physicians. AB - For the last 15 years, Minnesota has lived with managed care. The Minnesota story is important because it is a singularly unique example of the natural history of managed care in the United States, from the indemnity response to HMOs to PPOs to "open-ended" HMOs to comprehensive managed care. PMID- 10106839 TI - Strategic planning: health plan perspective. AB - The managed care industry is one of the most dynamic industries in the health care business. The development of new products, formation of alliances, changes in legislation and other types of changes are regular occurrences. This kind of dynamic environment makes it more important than ever to use strategic planning to guide management decisions. PMID- 10106840 TI - Finetuning HMO policy. PMID- 10106841 TI - Strategic planning: provider perspective. AB - The premise of this article is that there is both a process that can be tailored to specific situations and outcomes that can be formatted to guide any managed care business. However, if neither are put together under the guise of strategic management, the managed care business (as we know it) will become both "futile" and "fatal" for many. It is understood that the managed care perspective for the provider can be much different than for the buyer/payor. In fact, the process for planning these outcomes (strategic management) remains the same. What changes is the perspective! This article presents a framework for that perspective. PMID- 10106842 TI - Ambulatory quality assurance in the academic medical center. PMID- 10106843 TI - Rx: social reconnaissance. AB - The Kaiser Foundation's grassroots approach enables communities to set their own health priorities. The technique works--and it's become contagious. PMID- 10106844 TI - Megamarketing strategies for health care services. AB - Megamarketing, as coined by Kotler (1968), is a strategic way of thinking which takes an enlarged view of the skills and resources needed to enter and operate in obstructed or protected markets. The concept of megamarketing emphasizes the mastering and coordination of economic, psychological, political, and public relation skills and suggest that organizations can take a proactive stance in shaping macroenvironmental conditions. As health care delivery is characterized by a highly regulated environment, this marketing approach has definite applications for the health care marketer. PMID- 10106845 TI - Focus group positioning and analysis: a commentary on adjuncts for enhancing the design of health care research. AB - As health care competition increases, and as the penalties for making poor decisions become potentially more devastating, market research continues to play an increasingly important role in the decision-making process for hospitals. Concern over the appropriate use of market research and the costs related to it remains high. As such, efficiency in research design and clarity in research outcome are clearly the goals. This paper examines the focus group process and its adjunctive role in enhancing the overall design of health care market research. Specifically, the function and placement of focus groups within the research plan as well as several methods of creative focus group analysis are considered within the context of an effective research design. PMID- 10106846 TI - The end of health care marketing? PMID- 10106847 TI - Building an effective competitive intelligence system for health care service providers. AB - With the increasing competitiveness of the health care marketplace, the need for information by service providers has increased concomitantly. In response to this need, strategic and competitive intelligence systems have emerged as a vital source of information. This article establishes a basis for the development and operation of a competitive intelligence system. Initially, strategic and competitive intelligence systems are conceptualized, then followed by a discussion of the areas which are candidates for inclusion in the intelligence system. The remainder of the article focuses on system development and operation. Attention also is directed toward information utilization and integration. PMID- 10106849 TI - Medical record practice. PMID- 10106848 TI - The need for consumer behavior analysis in health care coverage decisions. AB - Demographic analysis has been the primary form of analysis connected with health care coverage decisions. This paper reviews past demographic research and shows the need to use behavioral analyses for health care coverage policy decisions. A behavioral model based research study is presented and a case is made for integrated study into why consumers make health care coverage decisions. PMID- 10106850 TI - Increases in volume: lessons from Medicare. AB - Earlier attempts by Medicare to freeze physician fees fell short in controlling rising expenditures. Why did this happen? Some point to the forces of the medical care market. Others look at the influence of physicians. PMID- 10106851 TI - Making sense of the volume equation: the physician's view. AB - It has been estimated that physician practice patterns influence more than 70 percent of all medical services. However, the growing demand for medical care does not fall solely at the physician's doorstep. PMID- 10106852 TI - Reducing the hassles, maintaining the gains. PMID- 10106853 TI - Making the RBRVS blueprint work. PMID- 10106854 TI - Taking over the helm at HCFA. Interview by Peter G. Tuteur. PMID- 10106855 TI - A complete solution. PMID- 10106856 TI - Lead and follow through. PMID- 10106857 TI - Dinghies for the flood. PMID- 10106858 TI - Prescription drug abuse and control--1990. PMID- 10106859 TI - Surveillance of AIDS and HIV infection: opportunities and challenges. AB - Surveillance for AIDS/HIV infection is essential for planning, implementing and evaluating AIDS control programs. Each of the different methods used, AIDS surveillance, surveillance for HIV infection and HIV seroprevalence, sero incidence studies in selected populations, have advantages and disadvantages. A combination of these methods is generally needed to accurately monitor the HIV epidemic, and the methods used will depend on the objectives of the surveillance system. Surveillance data need to be adequately analyzed and made available to the public, public health planners, health care professionals and politicians. Most importantly, surveillance data need to be used for preventive action. PMID- 10106860 TI - Technology assessment in health care--decision makers and health care providers: what they need to know. AB - The assessment of a new technology requires decision makers to gather information in many different fields. The questions addressed are technical, medical, ethical, legal and economic in nature. Learning from the experience of our own country and of others, we present here the sum of the information we deem necessary to decide on whether to adopt a new technology or not, and which strategy to choose for its implementation. PMID- 10106862 TI - Construction-budget control depends on communication. PMID- 10106861 TI - Use of Medicare data in international comparisons. AB - This paper provides a detailed description of the statistical systems of the U.S. Medicare program and discusses how these data bases can be used for health policy analyses and for international comparisons of health systems at the microeconomic level. First, the Medicare program in the context of the entire U.S. health care financing and delivery system is described. Second, the Medicare data collection process and the detailed data elements collected as part of the various Medicare administrative and research data bases are discussed in detail. Third, the use of these microdata for international comparisons of medical effectiveness, incentive effects of alternative reimbursement systems, technology assessment, service use by consumers, and industry impacts is suggested. International comparisons of health systems based on microdata are essential for understanding the underlying dynamics of health systems as well as for attributing performance to specific features or policies. PMID- 10106863 TI - Nine steps for developing a sound landscape budget. PMID- 10106865 TI - What happens after restructuring? PMID- 10106864 TI - Relationship marketing: positioning for the future. PMID- 10106866 TI - Central and local control in Nordic health care: the public organisation spectrum revised. AB - One of the distinguishing characteristics of national health care systems is the degree of public involvement in service provision, funding and policy making. In international comparisons the Nordic countries are usually seen as a uniform group. Yet, the countries do have important differences, and a descriptive model was sought to demonstrate these, and, at the same time, to differentiate the concept of public control. Using the central-local dichotomy, differences within the public framework were demonstrated between the countries, e.g. in methods of funding, financial regulation, formal planning instruments, and control of resource allocation. Financial control and planning were identified as two distinct components of public control. An analysis of the degree of centralisation along both dimensions separated the Nordic countries, which are otherwise homogenous as to public sector dominance. PMID- 10106868 TI - Compensation: how attitudes affect pay. PMID- 10106867 TI - Hospital strategy and regional planning in France. AB - Cost containment policy in health implies changes in hospital management and regional planning. There is a movement in France towards the strategic management of hospitals and towards a new way of planning. That calls for new models and the paper presents, as an example, regional arrangements of neonatal care. Hospital managers and local authorities set up a model and an information system to allow the best way possible for involving hospitals in the building of a regional scheme, leading to the negotiation of contracts. This experiment is conducted by the National School of Public Health with the aim of gaining experience in bringing together professionals and teachers, doing research and producing materials for management development. PMID- 10106869 TI - CAHEA-accredited EMS programs. Committee on Allied Health Education and Accreditation. PMID- 10106871 TI - Cooperation only answer for health care. PMID- 10106870 TI - Family care giving: what price love? AB - The role played by family care givers is critical to the well-being of their impaired elderly family members and to the well-being of society as a whole. Studies indicate that a key determinant of institutional placement is the breakdown of an older person's informal caregiving system. Given the demographics of our aging population and the medical advancements of recent years, the giving and receiving of care is an issue that will affect most individuals' daily lives during some part of the life cycle. The responsibilities for giving care will continue to fall more and more disproportionately upon elderly spouses who themselves may have health problems and upon daughters and daughters-in-law who often have work commitments outside the home and young children in the home. Giving care often results in financial, physical, social, and emotional problems and stresses. Current demographic trends such as marriage at a later age, the increasing number of divorces, fewer and later births, and the rising number of women in the work force will only serve to complicate the role conflicts and exacerbate the stresses of care giving on family members. In order for family care giving to continue--indeed, to raise it to a more productive and satisfactory level--a range of supportive fiscal, medical, and social services must be provided to families. National public policy must begin to address the needs of families by supporting options other than institutional care for the disabled elderly.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106872 TI - HCFA opposes call for blended wage index. PMID- 10106873 TI - CAHHS (California Assn. of Hospitals and Health Systems) sues state over reimbursement. PMID- 10106874 TI - Managed-care groups infuriated by PRO's data showing more quality woes at HMOs. PMID- 10106875 TI - Human resource managers should prepare for 'big one'. AB - The staffing shortages in hospitals today are nothing compared with what they'll be in the future unless significant long-range planning begins right now, says Don Arnwine. PMID- 10106876 TI - Delayed budget endangers Medicare payments--experts. PMID- 10106877 TI - Diagnostic ultrasound. A bright future. PMID- 10106878 TI - Keeping the PRO satisfied. Avoiding Medicare billing traps. PMID- 10106879 TI - Medicare program; uniform relative value guide for anesthesia services furnished by physicians--HCFA. Final rule. AB - We are establishing a relative value guide for use in all carrier localities in making payment for anesthesia services furnished by physicians under Medicare Part B. This final rule implements section 4048(b) of the Omnibus Budget Reconciliation Act of 1987. The relative value guide is designed to ensure that payments using the guide do not exceed the amount that would have been paid absent the guide. This final rule also implements section 6106 of the Omnibus Budget Reconciliation Act of 1989. Section 6106 revises the method under which time units are determined for anesthesia services furnished by anesthesiologists or certified nurse anesthetists on or after April 1, 1990. PMID- 10106880 TI - Medicare Program, fiscal year 1990; mid-year changes to the inpatient hospital prospective payment system--HCFA. Correction of final rule. AB - This document corrects technical errors to the final rule published in the April 20, 1990 issue of the Federal Register (FR Doc. 90-9208), beginning on page 15150. PMID- 10106881 TI - Hospitals plan for the aging of America. AB - In planning for the senior market, hospitals face several key issues: determining position in a competitive marketplace, maintaining cost-effectiveness in times of financial challenge, and providing quality treatment in often complex cases. The authors review the trends for the next decade. PMID- 10106882 TI - Cardiology needs good planning for the future. AB - In today's health care environment, hospitals have to develop strategies to maintain their market share, especially in cardiac services. The authors share generic strategies in cost leadership, product differentiation and technological leadership that can be adapted and implemented in cardiac centers. PMID- 10106883 TI - Planning indicators. Heart disease: Medicare discharges and deaths. PMID- 10106884 TI - Planning hospital boards for the future. Interview by Donald E. L. Johnson. AB - Lancaster General Hospital, a 553-bed institution in Lancaster County, Pennsylvania, was founded in 1893. Hospital services include trauma, cancer, and neo-natal centers and open-heart and neurosurgery specialties. In the following interview with Health Care Strategic Management's publisher, Donald E.L. Johnson, Paul G. Wedel, President and Chief Executive Officer discusses the future challenges confronting hospital foundation boards. Lancaster General's 18-member planning board which charts the course for the 28,000 employee and 550 medical staff institution serves as a familiar point of reference. PMID- 10106885 TI - An Rx for direct-to-consumer advertising of prescription drug products. PMID- 10106886 TI - The status of marketing in multi-hospital systems: a view from the top. PMID- 10106887 TI - Pricing of hospital services: issues and some propositions. AB - Pricing in relation to tangible products has been studied at great lengths by both economists and marketers. The pricing of services has received less attention. Only a few studies concerning pricing in the health care area have been conducted. A review of relevant pricing issues concerning services, and particularly health care, is presented. Several limitations of an existing pricing model for hospitals are discussed. Improvements are proposed. PMID- 10106888 TI - Marketing alternatives for hospitals to the nursing crisis. AB - The current nursing shortage problem as defined in this article, is the result of a supply and demand imbalance. The demand for nurses is growing at a faster rate than the supply. If strategies are not implemented to correct this imbalance the demand for nurses will continue to surpass the supply, negatively affecting access to and delivery of quality patient care. Factors contributing to the increased demand for nurses and the dwindling supply must be examined if solutions to the problem are to be found and implemented. Factors contributing to the growing demand for nurses include the decreasing use of ancillary personnel by hospitals in an effort to tighten their budgets; the impact of Medicare's prospective payment system on hospital lengths of stay; the increase in patient acuity with advances in medical technology; and alternative health care opportunities pulling nurses away from the hospital setting. The supply of RNs is shrinking in relation to demand because of low retention rates; declining nursing school enrollment; non-competitive wages; poor working conditions; alternative career opportunities for women; and the lack of power and support within the nursing profession. An active marketing approach that relies on this assessment of contributing factors has been formulated in an attempt to resolve the problem and meet the increasing demand. Recommendations have been made and ranked in the order of their priority and pros and cons established for each. The strategies developed have been divided into four basic marketing categories of product, price, place, and promotion. If the problem is to be resolved these strategies must be marketed to hospitals, their administrators, nurses, other allied health professionals, third party payors, educators, and the general public. The nursing profession itself must find the unity and strength within its own group of professionals to build political and economic powers to enhance their product. Nursing is at a crossroad. Much depends on how we cope with the current shortage and its related issues. Nurses have the opportunity to shape their future. Hopefully, with proactive strategies, the profession will transform from a passive role to an active, vital force of the health care environment. The authors believe that through our marketing approaches this can be accomplished. PMID- 10106889 TI - Quality assurance, an administrative means to a managerial end: Part II. The JCAHO ten-step process--selecting indicators of quality. AB - This is the second of a series of articles on medical laboratory quality assurance (QA). It provides a synopsis of the federal regulations and Joint Commission on Accreditation of Healthcare Organizations (JCAHO) standards that are driving health-care QA at the laboratory level. The article also reviews the role of the College of American Pathologists (CAP) in laboratory accreditation and QA. This article explains the JCAHO ten-step process in detail. The Joint Commission model can be extremely helpful in designing a QA program and is a very practical template for a QA plan. Understanding the ten-step model, as well as the path of work flow, is essential to selecting meaningful laboratory indicators. Current concepts of quality, quality control (QC), and QA in the health-care industry are still in the developmental stage. Consequently, semantic differences of opinion exist among many laboratorians in regard to QA nomenclature and methods. These ambiguities have been generated, partly, by an extremely rapid evolution of federal and JCAHO guidelines. A major "gray" area exists in defining quality, QC and QA, and methods of quality management. The author has adhered closely to the definitions and nomenclature of the JCAHO to resolve some of the ambiguity. The reader also can review definitions that are presented in detail in the first part of this series (1). The source of most of the following information is federal, JCAHO, and CAP documentation. Some of the information in this article reflects personal managerial experience offered in the hope that it will be of some practical assistance to the reader. PMID- 10106890 TI - Information technology and the clinical laboratory. Agenda for the '90s. AB - The innovative use of information technology will be an essential response to the intense pressures and challenges health-care institutions face entering the final decade of the 20th century. Those pressures will affect the clinical laboratory and will result in significant use of improved information technology. The implications for laboratory management are significant. Changes in work methods, human resource needs, knowledge of information technology, and even laboratory organization will refocus the manager's attention. Routine, day-to-day activities that consumed the manager's attention will be handled automatically; long-range strategic planning, quests for productivity, and quality improvements will become more important and demanding. This article reviews current and evolving innovations in information technology and projects their impact on the clinical laboratory. Hardware, software, and communications technologies are examined. The effects on the laboratory, its manager, and the hospital are discussed. PMID- 10106891 TI - Product management of outpatient services. Enhance your strategic position. PMID- 10106892 TI - Strategic planning for every manager. AB - All managers plan, but many managers of small organizations limit their planning activities to developing and guiding discrete projects. This decision stems from two erroneous assumptions: strategic planning is useful only in large organizations, and it is too complex for a small organization. As a result, these managers deprive their organizations of an essential tool for long-term survival and prosperity. Strategic planning helps any organization effectively use its scarce resources by relating every decision to the organization's mission. The process for doing this consists of a sequence of decisions that applies in all cases. However, the effort involved in reaching each of these decisions varies with the size and complexity of the organization. Consequently, leaders of small units need not forego using this essential managerial tool. In this article, each decision is described and illustrated with an example from a typical small enterprise. PMID- 10106893 TI - Quality of care and medical equipment management. PMID- 10106894 TI - Medicare, Medicaid and CLIA programs; revisions of the laboratory regulations for the Medicare, Medicaid, and Clinical Laboratories Improvement Act of 1967 programs; correction--HCFA. Final rule; correction notice. AB - This document makes some technical corrections to parts 405, 416, 483 and 493, as amended or added, as applicable, by our final rule on March 14, 1990, 55 FR 9538, which generally is effective September 10, 1990. In addition to correcting a number of typographical errors, we are correcting 42 CFR 405.2163, CONDITION: Minimal service requirements for a renal dialysis facility or renal dialysis center, to restore current text. PMID- 10106895 TI - Medicaid program; deadline for submitting moratorium state plan amendments--HCFA. Notice. AB - This notice announces the deadline for Medicaid State agencies to submit State plan amendments requesting moratorium protection under section 2373(c) of the Deficit Reduction Act of 1984, as amended by the Medicare and Medicaid Patient and Program Protection Act of 1987. Section 2373(c) initiated a moratorium period during which HCFA cannot take any compliance, disallowance, penalty or other regulatory action against a State agency whose State plan contains an income or resource methodology or standard for determining eligibility for medically needy and certain categorically needy groups that is less restrictive than the required standard or methodology. This notice provides formal notification to States that plan amendments requesting moratorium protection will not be accepted after the last day of the first full calendar quarter following publication of this notice in the Federal Register. PMID- 10106896 TI - Multivendor EMS (energy management systems) for nursing homes. AB - Energy management software allows a single, central interface for multivendor systems and provides for future expansion. PMID- 10106897 TI - Ways vending can work for you. PMID- 10106898 TI - Channel leadership in health care marketing: a natural role for hospitals. AB - Health care has entered an era of rapid change. Most observers agree that important long-term changes will fundamentally reshape health care as we know it. To that end, health care providers should consider the benefits of operating vertically integrated marketing system with hospitals as the channel leader. Whether an administered VMS (hospitals have the power to gain compliance) or a corporate VMS (hospitals own successive levels of care providers), integrated channel management holds the promise of cost containment and quality patient care for the future. However, a great deal of integrating work must be done before VMSs will become a practical solution. Research studies are needed on each of the issues just discussed. As marketers, it is time we make a transition from treating health care marketing as a disjointed entity and instead treat it as an industry where all marketing principles are considered including channel management. PMID- 10106899 TI - Questions of quality. PMID- 10106900 TI - Playing data games. PMID- 10106901 TI - Routing seniors into HMOs: Medicare is losing ground. PMID- 10106902 TI - Physician Medicare payment reform: can volume of services be controlled? PMID- 10106903 TI - Courts give green light to Medicaid rates lawsuits. PMID- 10106904 TI - Hospitals win Medicare secondary payor policy change. PMID- 10106906 TI - Keyworkers for elderly people in the community: case managers and care co ordinators. AB - In the United Kingdom a range of services for elderly people in the community has developed that is delivered by a variety of professionals and administered within different organisations. This has resulted in a problem of co-ordinating services to meet the individual needs of the most frail elderly people. In the United States 'case management' has been introduced as a way of improving the co ordination of care. Despite structural differences in the provision of health and social services between the United States and the United Kingdom, the concept of case management has influenced the design of a number of innovatory schemes in the United Kingdom, including the Gloucester Care for Elderly People at Home project (CEPH). These innovatory schemes have demonstrated the need for a 'keyworker' and clarified the tasks that are involved in taking responsibility for co-ordinating services to meet the needs of elderly people at risk of failing to cope at home. There is, however, a danger of proliferating the complexity of service provision by creating a new breed of professional; an alternative might be to alter the responsibilities, attitudes and team orientation of existing professional workers so as to include taking on the keyworker role for some of their clients. PMID- 10106905 TI - Clinical engineering & equipment policy for Sao Paulo State, Brazil. AB - A comprehensive equipment policy was established for the health system of Sao Paulo State, Brazil. Research, development and regulation issues were integrated with all phases of the equipment life cycle, including: planning, procurement, acceptance testing, commissioning, maintenance, repair, refitting, and decommissioning. This policy was implemented by a multidisciplinary group, which advised and coordinated planning and procurement, created a technology management and maintenance network composed of clinical engineering teams and reference centers, and worked closely with manufacturers, universities and research institutes to improve the quality and increase the variety of domestic medical products in order to substitute for imported devices. PMID- 10106907 TI - Planning for change: 1993. PMID- 10106908 TI - Planning for M & E (monitoring and evaluation). PMID- 10106909 TI - Medicare program; model fee schedule for physicians' services--HCFA. Notice with comment period. AB - This notice announces and invites comments on a model fee schedule for physicians' services that is required by section 6102 of the Omnibus Budget Reconciliation Act of 1989. The model fee schedule provides very preliminary estimates for some, but not all, services to illustrate the effects of the Medicare physician payment fee schedule that will begin to take effect in January 1992. In accordance with section 6102(f)(11), we are making the model fee schedule available to the public through publication of this notice. Any comments received from the public will be considered carefully, but not specifically addressed in a subsequent proposed rule. PMID- 10106910 TI - Medicare program; Geographical Classification Review Board; procedures and criteria--HCFA. Interim final rule with comment period. AB - This interim final rule with comment period implements provisions of the Omnibus Budget Reconciliation Act of 1989 establishing the Medicare Geographical Classification Review Board (MGCRB) and sets forth criteria for the MGCRB to use in issuing its decisions concerning the geographic reclassification of hospitals for purposes of payment under the prospective payment system. PMID- 10106911 TI - Medicaid program; eligibility of aliens for Medicaid--HCFA. Final rule. AB - This regulation revises current Medicaid rules applicable to aliens who meet eligibility requirements as categorically needy or medically needy. It establishes that aliens lawfully admitted for permanent residence or permanently residing in the United States under color of law may be eligible for all Medicaid services. It clarifies and identifies certain categories of persons permanently residing in the United States under color of law. It also identifies those aliens who may be eligible only for limited services as a result of recent legislation. These revisions conform our regulations to changes made by the Omnibus Budget Reconciliation Act of 1986 (Pub. L. 99-509), and the Immigration Reform and Control Act of 1986 (Pub. L. 99-603), and the Medicare Catastrophic Coverage Act of 1988 (Pub. L. 100-360). PMID- 10106912 TI - Nine surefire ways to get the big gift. PMID- 10106913 TI - Establishing a meaningful grants committee for your foundation. PMID- 10106914 TI - Building a GP platform. PMID- 10106915 TI - Putting audits on line. PMID- 10106916 TI - Physician unions: any doctor can join, but who can bargain collectively? AB - Employees in the health care industry, including physicians, have recently taken more interest in unions and collective bargaining. At the present time the health care industry is approximately 20 percent unionized. Labor leaders believe that existing conditions are fertile ground for significant union activity that has been on a recent upswing after a decline during the early 1980s. While current attention is being drawn to the shortage of and increased union organizational activities by nurses, physicians may not be far behind. It is conceivable that by the year 2000 the majority of physicians in the United States will work in full time salaried positions. In addition, the antitrust laws that currently restrain independent physicians from collective bargaining are being challenged and are likely to change as more physicians become salaried and begin to resemble other professional employee groups. The ruling determining that interns and residents are students rather than hospital employees is also certain to be challenged and changed, especially as pressures on the National Labor Relations Board (NLRB) are brought by house staff union organizations. After a 1987 ruling that the NLRB had been improperly interpreting the 1974 amendments to the Taft-Hartley Act, the NLRB was ordered to exercise its rule-making power in defining bargaining units for health care workers in acute care hospitals. Physicians would then be one of eight occupations defined as a separate health care bargaining unit. PMID- 10106917 TI - Achieving competitive advantage through strategic human resource management. AB - The framework presented here challenges health care executives to manage human resources strategically as an integral part of the strategic planning process. Health care executives should consciously formulate human resource strategies and practices that are linked to and reinforce the broader strategic posture of the organization. This article provides a framework for (1) determining and focusing on desired strategic outcomes, (2) identifying and implementing essential human resource management actions, and (3) maintaining or enhancing competitive advantage. The strategic approach to human resource management includes assessing the organization's environment and mission; formulating the organization's business strategy; assessing the human resources requirements based on the intended strategy; comparing the current inventory of human resources in terms of numbers, characteristics, and human resource management practices with respect to the strategic requirements of the organization and its services or product lines; formulating the human resource strategy based on the differences between the assessed requirements and the current inventory; and implementing the appropriate human resource practices to reinforce the strategy and attain competitive advantage. PMID- 10106918 TI - Design considerations for integrated hospital information systems. AB - This article describes the main characteristics of the integrated hospital information system (HIS) environment, discusses design objectives, and analyzes four design issues--system architecture, conceptual data base design, application portfolio, and plans for development and implementation. The main objective is to provide managers and system designers with a guiding blueprint for HIS design based on state-of-the-practice technological capabilities and current experience with integrated HIS. Clearly, the capabilities of present information technology provide more feasible ways to implement integrated HIS in a distributed environment. This approach answers hospital information needs by shifting some of the processing and data to the end-user level, yet allows management to retain control of the central portion of the data base while facilitating data sharing among various organizational units. PMID- 10106919 TI - Process and cultural impediments to health care innovation. AB - This article examines a failed attempt to institute wholistic health care, which promotes prevention and patient control of the medical process, at an existing community health clinic. Cultural (organizational, professional, and societal) and change-process-related sources of this failure are analyzed using a theory of organizational culture and a model of participative decision making as frameworks. PMID- 10106920 TI - Planning the move of patient activities at a large medical center. AB - The planning for the move of inpatients and outpatients to a new 845-bed, 1.5 million square foot facility that took place over a period of two and one-half years and encompassed the health care, safety, and social needs of both inpatients and outpatients and their families is described. The length of time given to the planning process allowed the hospital personnel to undertake planning the move along with their regular duties and without the need for additional staff, plus allowed for very detailed planning. The precise estimate of time requirements for the inpatient move resulted in the move being completed within two minutes of the projected 150-minute estimate. Moving patients from one health care facility to another can be accomplished safely and efficiently with the aid of a well-developed plan and sufficient practice of all needed functions. PMID- 10106921 TI - Developing a blueprint for quality. PMID- 10106922 TI - Clinical pastoral education for laity. AB - Medical science, with its high technology, has had a major impact on today's hospitalized patient. Not only has the length of stay been shortened dramatically but the level of illness is much more intense. Both of these factors have influenced the role pastoral care plays as a member of the health care team if patients and families are to receive holistic care. Carefully selected and trained laity can help meet the expanding pastoral care needs of hospitalized patients. This article describes a program designed exclusively for laity, which equips these volunteers through a clinical process similar to that of Clinical Pastoral Education (CPE). The authors contend that any program designed to prepare laity for pastoral care must include the clinical component. Their experience with 38 laity who have completed the program described in this article has led them to the conclusion that such a process inspires a dynamic growth in faith as laity claim their rightful authority in pastoral care. PMID- 10106923 TI - Radiology in the war zone. PMID- 10106924 TI - Accessing information in national computer databases. PMID- 10106925 TI - Hospitals and seniorcare: separating myth from fact. AB - Not every hospital should attempt to serve the senior market. For the right hospitals, it can be extremely rewarding, both professionally and financially. A hospital management team should be able to answer "yes" to most of the following questions if they want to proceed. Do 65+ persons exceed 12 to 15 percent of the population in your service area? A concentration of senior persons is required to provide a sufficient market for services. Are there organized groupings such as lifecare communities, adult communities, etc. within you service area? Marketing efforts can be targeted to these groups, including personal calls and special physician programs. Do you have physicians/groups that specialize in geriatric care? These groups provide the basis for quality care and will help promote the interest of other physicians in senior programs. Do you have strong cardiac, oncology, and orthopedic programs? These are the areas most often used by senior patients as they progress through their experiences with chronic illnesses. Do you have an aggressive and developing social work group? Social workers help locate patients in the service area, provide a basis for group activities, and outplace patients after a hospital stay. Is the volunteer group strong, populated with 50+ individuals and looking for more to do? Seniors are excellent emissaries in the community and they relate well to inpatient seniors who are often reluctant to interface with ill peers. Is your facility a low cost provider, i.e., can you break even or better on Medicare? Having a seniorcare program will obviously increase the Medicare numbers in the hospital census.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106926 TI - Pharmaceutical manufacturers listing: 1990 update. PMID- 10106927 TI - Perspectives. Saving infants' lives. PMID- 10106928 TI - Medicare, PPOs, and employers. PMID- 10106929 TI - Retiree health care: who will pay? PMID- 10106931 TI - Massachusetts Medicaid taps out. PMID- 10106930 TI - Medicaid program; MMIS system performance review revisions--HCFA. Final notice. AB - This notice revises the system performance review standards, procedures and methodologies previously published in the Federal Register on June 30, 1981 (46 FR 33653) that we have used to evaluate State Medicaid Management Information Systems. These revisions are intended to improve the economy, effectiveness and efficiency of the Medicaid program. PMID- 10106932 TI - National groups hard at work fighting for adequate Medicaid coverage. PMID- 10106933 TI - How to hire a winner. Preparation and planning are the key. PMID- 10106934 TI - Participative strategic planning. PMID- 10106935 TI - Avoiding the tar pit. PMID- 10106936 TI - High-tech home care: making it work. PMID- 10106937 TI - Recordkeeping systems--correctional facilities. PMID- 10106938 TI - The hassle factor: America's health care system strangling in red tape. American Society of Internal Medicine. PMID- 10106939 TI - Easing physician tension: HCFA's plan for communication. PMID- 10106940 TI - A legislative approach toward the hassle factor. PMID- 10106941 TI - Deficit reduction: a return to closed-door politics? PMID- 10106942 TI - Acceptance of pharmacists' suggestions by prescribers: a literature review. AB - Acceptance of pharmacists' suggestions by prescribers is a necessary component of the evaluation of clinical pharmacy services that is often overlooked. A literature search was performed to review the information on this topic. Acceptance was defined as a measure of a prescriber's compliance with a pharmacist's recommendation regarding drug therapy. In order for the pharmacist to impact upon the quality of patient care or drug costs, the prescriber must accept the suggestions. A total of 23 studies was found that addressed the topic. The average rate of acceptance was 85.5%. Factors affecting acceptance included time, communication, solicited versus unsolicited recommendations, type of prescriber, and type of pharmacist. Factors leading to non-acceptance included lack of physician awareness of pharmacokinetic parameters, quality of suggestions, prescribers' exercise of caution with respect to patient safety and well-being, and negative attitude toward clinical pharmacy. More research needs to be done in order to evaluate the importance of these factors. PMID- 10106943 TI - Hospital pharmacy computer systems. PMID- 10106944 TI - Planning French-language health services: a case illustration of Niagara region. AB - Niagara's health plan for the '90s includes a French-language service component and is a joint effort of the Niagara District Health Council (NDHC) and l'association canadienne francaise de l'Ontario (ACFO), whose mandate includes the promotion of francophone objectives and perspectives in Ontario. The planning process undertaken contains traditional "hard" elements of planning such as the collection of data, data analysis and recommendations. It also contains the "soft" elements, which are discussed by a review of the major tasks: designing the project structure; designing the research method; formulating a network of health and related social services; and building consensus toward the final plan of action. The results of the study produced 23 recommendations to address five key issue areas, which will ensure that plans become a reality with tangible results for Niagara's French-speaking community. PMID- 10106945 TI - Will cogeneration pay off for your health facility? PMID- 10106946 TI - Contracts pertinent for limiting impossibility as an excuse for supplier non performance. AB - A supplier has notified the hospital materials manager that a contract delivery date for medical supplies won't be met. When pressed for an explanation, the supplier says that it is impossible for performance to be made. This puzzles the materials manager, and he wonders if the supplier can avoid performance for such a reason. In this dialogue, Dr. Decker discusses the legal issues involved. PMID- 10106947 TI - Mental healthcare: expand with caution. There is more involved than financial incentives. AB - Increased needs, insurance coverage, and physical expansion are evidence of mental healthcare's growth. Greater societal acceptance, the demand for more local care with deinstitutionalization, and liberal reimbursement have expanded mental health services. However, reduced federal funding and competition demand specialization in such areas as geriatric services. Ambulatory services make mental healthcare more affordable and accessible. Providers must target populations who use such outpatient care and study local trends before planning these programs. Inpatient mental health services continue to expand, although at a slower rate. Thus organizations and professionals have begun selective contracting, and capitation reimbursement based on case management is developing. Providers considering expansion or initiation of mental health services confront competitive marketing and must recognize trends in outpatient, chronically ill patient, and after-care services. Strategic planning is essential to uncover opportunities and potential risks. Other issues to consider include the psychiatrist shortage, uncertain payment systems, and a possible reversal of growing mental health services and declining acute care needs. PMID- 10106948 TI - The call to collaboration. Pursuing and completing a merger requires planning and perseverance. AB - In 1987 Mercy Health Care System (MCHS) of Scranton, PA, and Mercy Health System (MHS) of Cincinnati took the first steps toward a merger. Leaders of the Scranton province, who had for some time been seeking to establish a relationship with another Mercy-sponsored health system, had approached MHS with the proposal. In late summer 1988 MHS began a thorough analysis of the facilities of the Pennsylvania system, assessing their mission, margin, and market strength; plant and property conditions; and human resources. At the same time the two provincial teams and CEOs from facilities in both systems, along with an outside consultant, began to negotiate the proposed merger's sponsorship and governance structure. Careful avoidance of "we-they" thinking was the hallmark of the entire negotiating process. Having agreed that they wanted a cosponsored system, the negotiating teams struggled to determine the degree of representation the Scranton province (five facilities) and the Cincinnati province (18 facilities) would have. The teams also had to iron out differences of opinion regarding the viability of one facility. Negotiators also worked out a decision-making procedure ensuring appropriate input from the Scranton member of the corporation. Help was sought to ensure that the merger agreement was in accordance with both canon and civil law. A sophisticated, step-by-step implementation process helped bring MHCS facilities on line as quickly as possible with minimal disruption. A series of celebrations commemorated the merger's completion. PMID- 10106949 TI - Breaking down complex problems: the use of decision analysis. PMID- 10106950 TI - 15 state Medicaid suits near--survey. PMID- 10106951 TI - Vets complain about VA system in Dallas. PMID- 10106952 TI - Children's advocates seeking political clout to equal that of the elderly. PMID- 10106953 TI - Long-term hospital chain's narrow niche offers rapid growth, cost-based payment. PMID- 10106954 TI - Medicare payments to drop in 33 areas, increase in 24. PMID- 10106955 TI - HCFA physician fee schedule to include 'behavioral offsets'. PMID- 10106956 TI - Nation's first hospital holds history, healing. PMID- 10106957 TI - Lawmakers rip administration on Medicaid. PMID- 10106958 TI - Medicare proposal draws fire. PMID- 10106959 TI - Experts see reforms speeding move to managed care. PMID- 10106960 TI - AHA boards to mull Medicaid standard. PMID- 10106962 TI - Plan would trim Medicare $5.9 billion. PMID- 10106961 TI - Mass. study finds insurance status affects access to care. PMID- 10106963 TI - AIDS patients' dependence on Medicaid grows--study. PMID- 10106964 TI - Study: reimbursement for risk management yields benefits. PMID- 10106965 TI - The significance of the Wilder case. PMID- 10106966 TI - Program listings with aircraft operators and types. PMID- 10106967 TI - America's uninsured: Part II: Some proposed solutions. PMID- 10106968 TI - College initiates projects relating to physician reimbursement. PMID- 10106969 TI - Statement of organization, functions, and delegations of authority--HCFA. PMID- 10106970 TI - The social/HMO. Case management in an integrated acute and long-term care system. AB - The Social/HMO is a national demonstration that has been in operation for five years at four private, nonprofit sites around the country. Key functions of Social/HMO case management include targeting the long-term care benefit/eligibility determination, service prescription that integrates post acute and long-term care, close monitoring of clients, and fiscal accountability for long-term care benefit budgets. PMID- 10106971 TI - The paradox of case management. AB - In attempting to contain costs, case management, as it is often conducted, negatively impacts the quality of patient care. In many instances this is because the clinical aspect of case management is performed by personnel lacking in clinical experience. Over the next few years federal and state legislators will be looking at the issue of case management and who provides it. Many groups will be putting in their bid. The home care community must be prepared to fight, support, or activate its own case management program. PMID- 10106972 TI - 1989 legislative session: year of transition. PMID- 10106973 TI - California dreaming. Universal health insurance in one state? PMID- 10106974 TI - Physician contracting. PMID- 10106975 TI - Getting ready for physician fee reform. PMID- 10106976 TI - Group advantage. How hospitals can capture the benefits of the large multi specialty group practice. PMID- 10106977 TI - The well-structured hospital-physician partnership. AB - Presbyterian Intercommunity Hospital began its journey along the right path toward successful diversification when it decided to modify, rather than destroy, the legal structure of InterHealth. PMID- 10106978 TI - Managing quality. Interview by Joe Flower. PMID- 10106979 TI - "Access" continues to haunt states. PMID- 10106980 TI - The race to universal health coverage. AB - Health is on center stage at the state level. In virtually every state, legislation has been enacted or is pending. The momentum being generated will create multi-dimensional health reforms. Regardless of loyalties to the traditional law-making process, initiatives are likely to spread throughout the nation when society or special interests reach the point that relief or protection becomes more important than process and political considerations. States may compete for federal funds, Medicare contracts and special grants to sustain their health plan. Whatever the case, it is incumbent upon hospitals to unite, form the strongest possible coalition and exert the leadership to achieve enactment of a health plan that meets the needs of their residents. Only through listening to our publics and exercising the best of our intellect and ingenuity can we make progress with improvement. PMID- 10106981 TI - 1990 state by state legislative survey. PMID- 10106982 TI - Strong motive for reform. PMID- 10106983 TI - Wilder decision: more heat than light? PMID- 10106984 TI - The CIO and IRM (information resources management) alliance: maneuvering for the competitive edge in hospital information management. AB - In 1986, Johns noted that "The hospital industry was caught unprepared for the external demands and information needs required in a case-mix reimbursement environment." Lack of a data-processing philosophy and inattention to external forces were cited as having hampered technology upgrade and integration of financial and clinical databases. The intervening years have witnessed a growth of information dissemination in the health care industry concerning information value and resource management. The frequency of appearance of articles on information management in the professional literature and the number of workshops and professional meetings addressing the topic attest to the current visibility of the information resource. Despite this flurry of interest, the industry has not developed its own models of information resources management nor validated its information evolution with accepted management information systems models. While interest in health care information resource management exists, understanding of the complex issues in this area has not developed as one would expect. While there are a myriad of reasons for this, a contributing factor is the lack of a research foundation for development and application of theory and models. Even though various graduate programs exist in medical informatics and biomedical computing, few concentrate on the study of health information resource management from an organizational perspective. Because of this, academic research in the area has been minimal. The scarcity of graduate-level programs has also meant that few individuals have been educated to deal with the challenges of managing the many disparate functional activities associated with health care information resource management. Due to a variety of internal and external forces, extreme demands were placed on the hospital information resource during the past decade.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10106985 TI - Managed care: quality management differentiates the product. AB - Comprehensive quality management is a goal that requires major corporate commitment to implement and maintain. The best results in a quality management program will be achieved when all components are tied together in a comprehensive program. To do that, a significant investment in personnel and equipment is required. As the benefits of having a program such as the one as described above become more widely known and accepted, more and more managed care insurers and providers will adopt these or similar standards. The question, "How do you know that patients are getting high-quality and sufficient care?" cannot be answered today by insurers who do not have such a program. PMID- 10106986 TI - Strategic information systems: can you support your decisions? AB - Information technology will continue to have a profound effect on decision analysis. Clinicians and technologists must continue to work together to achieve systems that enhance patient quality and managerial decision making. Users will continue to grow more sophisticated in using information systems for patient care and organizational analyses. Strategic information systems will not solve all problems that health care professionals may face. However, better decisions will result from improved availability of information. The acceptance, support, and imagination of power users will enhance and drive information system development and design. Strategic information systems will provide opportunities for data analysis enabling health care professionals to better support decisions. PMID- 10106987 TI - Legal review: informed consent--a shift from paternalism to self-determination? AB - This shift from a paternalistic standard for determining how much information should be disclosed to a person to a standard that values the self-determination of a person is consistent with the philosophical change in decision-making in a variety of areas of health care. Haber begins his article with a discussion of the psychiatry profession's proposed change in terminology from "patient" to "client." He argues that such a change would be more than semantic: It would serve the moral purpose of increasing such a person's autonomy. The right of patients to see their own medical records was formally recognized as part of the Patient's Bill of Rights in 1972 and has since been recognized by courts and incorporated into many state statutes. Likewise, the refusal of medical treatment has become a right more commonly recognized by the law throughout the 1970s and 1980s. For example, "living wills" are now a common vehicle for patients to express their views regarding the right to refuse treatment. Courts have recognized this right in cases of Jehovah's Witnesses refusing transfusions, the right to have life-sustaining procedures discontinued, and the restrictive involuntary commitment statutes that arose in the 1970s. Both the risks and benefits of medical treatments have increased with the forward march of technology. Patients have the right to choose to participate with their physicians in their own health care decision making; the trend toward the reasonable patient standard in medical malpractice suits that relied on negligent failure to obtain informed consent reflects a recognition of that right. PMID- 10106988 TI - Implementation of an optical disk system for medical record storage. AB - MARS was a joint developmental effort between Maine Medical Center and Advanced Healthcare Systems, Inc. It has taken nearly three years to get the system (hardware, software, and staff) to a point where it can now meet daily production requirements. This project was truly unique, so there was no opportunity to learn from the experiences of others. The optical disk system has been an attractive solution to some of the problems experienced at Maine Medical Center. The result was worth the effort in terms of both dollars and other less quantifiable benefits that have had a positive impact on patient care. PMID- 10106989 TI - Blood product monitoring using statistical aggregate data analysis. PMID- 10106990 TI - Guidelines for charting: documentation of medications and i.v.s. Prepared by the Professional Liability Program, Farmers Insurance Group of Companies. PMID- 10106991 TI - Controlling private utilization review: legislative vs voluntary approaches. PMID- 10106992 TI - Reducing the risk from ED phone-ins. PMID- 10106993 TI - Case consultation: the committee or the clinical consultant? PMID- 10106994 TI - Ethics committees and institutional fixes. PMID- 10106995 TI - Ethics committees in nursing homes: a qualitative research study. PMID- 10106997 TI - DNR documents. PMID- 10106996 TI - Heroics and healing. PMID- 10106998 TI - Front-row seat: dramatic (and mundane) moments mark doctor, patient victories & losses at Part B ALJ hearings. PMID- 10106999 TI - Approaching lab regulation sends medical practices scrambling. PMID- 10107000 TI - Letting and making death happen, withholding and withdrawing life-support: morally irrelevant distinctions. AB - The author argues that there is no morally relevant distinction between letting and making death happen, and between withholding and withdrawing life-support. There is a discussion of possible adverse consequences in believing that there are moral distinctions. And then he shows that acknowledging the absence of such a distinction does not necessarily imply any endorsement of active euthanasia. PMID- 10107001 TI - Letting and making death happen: is there really no difference? The problem of moral linkage. PMID- 10107003 TI - Perspectives. What women want in medical research. PMID- 10107002 TI - Limiting the role of the family in discontinuation of life sustaining treatment. AB - In matters of discontinuation of life-sustaining treatment, traditional role of the family to speak on behalf of the incompetent patient is questionable. We explore the reasons why physicians perceive patient autonomy to be transferrable to family members. Principle of patient autonomy may not suffice when futile treatment is demanded and may serve to erode the ethical integrity of medical profession. An enhanced role for bioethics committees is proposed when physicians propose to discontinue life-sustaining treatment against the wishes of the patient or their families. PMID- 10107004 TI - Perspectives. Joint ventures: mixing medicine and profits. PMID- 10107005 TI - Perspectives. Health care reform: Soviet style. PMID- 10107006 TI - Medicare takes center stage in budget deal. PMID- 10107007 TI - Perspectives. Coping with drug-exposed infants. PMID- 10107008 TI - House committees approve Medicare/Medicaid cuts. PMID- 10107009 TI - Cost reductions and conceptual benefits through early engineering planning for health care facilities. PMID- 10107010 TI - Hypothesis for recuperating, architecturally and functionally, obsolete hospital facilities with pavilions, enhancing and automatic services and connecting passageways. PMID- 10107011 TI - The medicine of dragons: inside the Taiwanese health system. PMID- 10107012 TI - How one California hospital stopped its health care benefits cost hemorrhage. PMID- 10107013 TI - Subacute care: an experiment in efficiency. PMID- 10107014 TI - Productivity: its achievement may be easy and inexpensive. PMID- 10107015 TI - The productivity challenge: a creative approach. PMID- 10107016 TI - Balancing patients' right to privacy and public's right to know. PMID- 10107018 TI - Isenberg says access and cost containment are big issues. PMID- 10107017 TI - Law sets limits on release of patient information. PMID- 10107019 TI - Major changes in 1990-91 Medicare hospital reimbursement coming. PMID- 10107020 TI - Domestic partner benefits changes. AB - As the definitions of spouse and the nuclear family change, health plans and insurance coverage may have to be restructured to include "significant others" as well as husbands, wives and offspring. But will expanded benefits lead to expanded costs? PMID- 10107021 TI - The nurse as health manager. PMID- 10107022 TI - Rationing by choice. PMID- 10107023 TI - The goal: a nurse in each nursing home. PMID- 10107024 TI - Quarterly listing of program issuances--HCFA. General notice. AB - This notice lists HCFA manual instructions, regulations and other Federal Register notices, and statements of policy that were published during April, May and June 1990 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register at least every three months. PMID- 10107025 TI - Statement of organization, function and delegations of authority--HCFA. PMID- 10107026 TI - Privacy Act of 1974; matching program--HCFA. Notice of a matching program--the Internal Revenue Service (IRS), the Social Security Administration (SSA), and HCFA--disclosure of IRS taxpayer identity and filing status information to be matched with SSA earned income information for Medicare beneficiaries and their spouses. AB - As required by Section 6202 of the Omnibus Budget Reconciliation Act of 1989 (OBRA 1989), Public Law 101-239, the Department of Health and Human Services is providing public notice that the IRS and the SSA will disclose certain information regarding the taxpayer identification and filing status and the earned income of Medicare beneficiaries and their spouses for HCFA's use in identifying Medicare secondary payer (MSP) situations. This will enable HCFA to seek recovery of identified mistaken payments that were the liability of another primary insurer or other type of payer. The matching report set forth below is in compliance with the Computer Matching and Privacy Protection Act of 1988 (Pub. L. No. 100-503). PMID- 10107027 TI - Criteria and standards for evaluating intermediary and carrier performance--HCFA. General notice with comment period. AB - This notice describes the criteria and standards to be used for evaluating the performance of fiscal intermediaries and carriers in the administration of the Medicare program beginning October 1, 1990. The results of these evaluations are considered whenever HCFA enters into, renews, or terminates an intermediary agreement or carrier contract or takes other contract actions; assigns or reassigns providers of services to an intermediary; or designates regional or national intermediaries. This notice is published in accordance with sections 1816(f) and 1842(b)(2) of the Social Security Act, which requires us to publish for public comment in the Federal Register those criteria and standards against which we evaluate intermediaries and carriers. PMID- 10107028 TI - Medicare program; changes to the inpatient hospital prospective payment system and fiscal year 1991 rates--HCFA. Correction. PMID- 10107029 TI - Current list of laboratories which meet minimum standards to engage in urine drug testing for federal agencies--HHS. Notice. AB - The Department of Health and Human Services notifies Federal agencies of the laboratories currently certified to meet standards of subpart C of Mandatory Guidelines for Federal Workplace Drug Testing Programs (53 FR 11986). A similar notice listing all currently certified laboratories will be published monthly, and updated to include laboratories which subsequently apply and complete the certification process. If any listed laboratory fails to maintain its certification, it will be omitted from updated lists until such time as it is restored to full certification under the Guidelines. PMID- 10107031 TI - Professionally trained activities personnel needed: unqualified staff overlook therapeutic intent. PMID- 10107030 TI - Patient, heal thyself. PMID- 10107032 TI - Veterans' LTC program is "flawed." VA plans to implement alternatives. PMID- 10107033 TI - Look before leaping into expansion. Build upon the community's strengths. PMID- 10107034 TI - OBRA's effect on nursing homes' social workers. PMID- 10107035 TI - There's no substitute for experience. PMID- 10107036 TI - A cottage industry. Boon or bane for retirement housing? PMID- 10107037 TI - California rejects OBRA. PMID- 10107038 TI - Just what the doctor ordered. Marketing to MDs improves referrals. PMID- 10107040 TI - Public relations payback. PMID- 10107039 TI - Climbing the nursing ladder. PMID- 10107041 TI - Going beyond the inner loop. Hospital-owned facilities explore marketing options. PMID- 10107042 TI - Computerization maximizes sales performance. Retirement centers pack more punch. PMID- 10107043 TI - Shift under way in standard of care criteria. PMID- 10107044 TI - Careful QA program key to decreasing medication errors. PMID- 10107045 TI - M.A.O. (Minneapolis Age and Opportunity Center). The home care agency of the future. AB - The Minneapolis Age and Opportunity Center, under the direction of Daphne Krause, offers and coordinates an impressive array of services for its homebound and disabled clients. With services ranging from legal assistance to home-delivered meals, from skilled nursing to home maintenance, MAO is quite possibly the "home care agency of the future." PMID- 10107046 TI - Evaluating expansion of traditional home care agencies. AB - In a changing health care environment, it is important for home care agencies to regularly review their mission and goals and evaluate the services offered in the community. The participation of the entire home care team is essential in this process. For American Nursing Care in Cincinnati, a strong focus on teambuilding and mission development has resulted in the successful expansion of services and branch offices. PMID- 10107047 TI - A VNA diversifies: VNA of Butler County, Inc. AB - In order to keep pace with changing community needs, today's visiting nurse associations must be willing to change structures and programs. The VNA of Butler County, Inc., has done just that. Presently it has under its umbrella corporation a retail home medical equipment company, a pharmacy, and a hospice; it is also a real estate partner in a local cancer center. PMID- 10107048 TI - How to establish a perinatal home care program. AB - Current clinical data indicates that despite advances in the obstetric and neonatal arenas, preterm birth and subsequent low birth weight infants continue to be born. Technology-based perinatal home care programs are the fastest growing segment of services available to high-risk pregnant women, recuperating post partum women, and newborns. It is anticipated that these services will alter forever the traditional measures of care for high-risk pregnant women and newborns. PMID- 10107049 TI - The eyes have it. Ophthalmic nursing--a vision of the future. AB - Home health providers have traditionally shied away from ophthalmic nursing because of reimbursement problems. However, as competition among home care agencies grows more intense, it is those agencies providing innovative services such as ophthalmologic nursing that will survive. PMID- 10107050 TI - Adult day care & home health: a community partnership. AB - The establishment of an adult day care center is one way for home care agencies to both expand their service offerings and ensure that clients get the care they need to remain at home. In setting up a center the agency must initially make decisions regarding where the center will be located, who will staff it, and how it will be funded. PMID- 10107051 TI - Coming home. Work, family and services in the 1990s and beyond. AB - The current trend of the 1990s appears to be one of increased work at home, home manufactured products, and home-delivered services. Corporations, both large and small, are struggling to address the changing needs of working-age women and men as they attempt to strike a balance between career and family. The home care community, already deeply dedicated to family-focused care and keeping families together, is in an excellent position to expand services to meet the growing demand. PMID- 10107052 TI - Pet therapy for the homebound elderly. AB - The Visiting Nurses Association-Community Services, Inc., responding to community interest and support, developed a pet therapy program for homebound clients. Early reports indicate that the program has improved the physiological as well as psychosocial wellbeing of participants. PMID- 10107053 TI - Containerized vegetable gardening for homebound patients. AB - The containerized vegetable gardening project for homebound patients is a joint project of the Alabama Cooperative Extension Service and Home Health Care Agency of North Alabama. Patients who could benefit by having a container vegetable garden are identified by home health nurses. Volunteers recruited by the Extension Service help set up the gardens and visit patients. Through this project patients receive fresh produce, as well as an increased sense of self worth. PMID- 10107054 TI - An art therapy group for bereaved youth in hospice care. AB - Through art, music, and drama children can creatively express the feelings of sadness and anger that occur when a family member dies. In so doing, they can often avoid later difficulties resulting from unresolved emotions. Hospices may want to develop an art therapy group to facilitate this process with clients and their families. PMID- 10107055 TI - Mobile X-ray services. AB - Responding to a need in their community, Halifax Home Care in Daytona Beach, Florida established a mobile x-ray service for clients with a limited ability to ambulate. PMID- 10107056 TI - VNA Independence Plus. Creating and building a home maintenance program in a home health agency. AB - In response to a strong demand for "house-related services" among the elderly, the Robert Wood Johnson Foundation established a Supportive Services Program for Older Persons. Not only does the program help the elderly maintain their homes, it provides an important link between its clients and home health agencies. PMID- 10107057 TI - A mobile clinic for the homeless and mentally ill: meeting the needs of a target population. AB - Six years ago, a home care nurse doing research for a school project discovered a population of elderly, mentally ill, and homeless people who were not receiving adequate health care. The nurse's efforts resulted in her home care agency's expanding its services to include a mobile clinic program. Today, the program employs five nurses who provide health assessment and group education to over 1,000 people. PMID- 10107058 TI - Developing & marketing childcare programs. AB - Over $ billion in work hours is lost annually in the United States due to family responsibilities. Employees cite adequate child care as their biggest career concern. American Nursing Care of Cincinnati, Ohio responded to this need--and business opportunity--by successfully expanding its existing child care program to include sick- and well-child care. PMID- 10107059 TI - Rosehedge: a home and skilled care facility for people with AIDS. AB - Community Home Health Care's mission is to distinguish itself as a provider of new and innovative services in response to needs within the Seattle community. Rosehedge House, a residential home for people with AIDS, is an excellent example of how this traditional home care agency worked with other community organizations to create a home for people who would otherwise not have access to home-based care. PMID- 10107060 TI - Confronting 2000 and beyond: tomorrow's healthcare information system. AB - The promising healthcare information systems of tomorrow will be founded on strategies and technology that is already available today. In this article, Tim K. Zinn examines the information systems of the future, as well as the developments that will make such systems a reality. PMID- 10107061 TI - Medical records in the information age: a sleeping giant stirs. PMID- 10107062 TI - Simplification of mortality case review. AB - With so many various parties vying for access to the medical record after patient dismissal, one of the least appreciated "competitors" is review of the record for quality care concerns, and more specifically, mortality record review. Through use of existing computerized data, a reporting system can easily be developed that will result in increased availability as well as a more timely and effective mortality case review process. The author details how St. Francis Regional Medical Center in Wichita, Ks., developed such a system. PMID- 10107063 TI - Computerized HIS as a tool in quality medicine. PMID- 10107064 TI - "Do or die in Bed-Stuy". PMID- 10107065 TI - Congratulations--it's a baby! PMID- 10107066 TI - Rescue and the EMS professional. PMID- 10107067 TI - Bioethical issues surrounding the transport of neonates. PMID- 10107068 TI - Sherman Hospital incinerates infectious waste. PMID- 10107069 TI - Riverside Community Hospital: a new standard for infectious waste management in Southern California. PMID- 10107070 TI - Heavy-duty reusable towel "works well". PMID- 10107071 TI - Sampling clinicians' activities using electronic pagers. AB - Pager-based activity sampling (PAS) is described as a cost-effective and unobtrusive method for sampling residents' activities in clinical settings. A sample program evaluation is presented using residents in an urban children's hospital resident-training program. The purposes of the program evaluation were: (a) to establish a behavioral baseline that would help clinical faculty understand how residents were using their time, and (b) to determine whether alterations in the way residents were assigned within the hospital resulted in desired changes to time spent. The primary rationale for changing resident assignment policies were: (a) to decrease the time residents were spending in transit between various locations within the hospital, and (b) to increase the time spent by residents in educational activities and in direct contact with patients and their families. This PAS application demonstrates that the technique can produce statistically supportable conclusions, at minimal cost, without unduly disrupting either the residents or their patients. PAS is compared with other time-sampling methods, its limitations are discussed, and suggestions for future applications are provided. PMID- 10107072 TI - Models for the supply of pharmacists. AB - The BHPr (formerly Bureau of Health Professions) Supply Model for pharmacists is presented and analyzed. Recommendations are made for improvement of the supply model. Included are considerations of additional variables and improvement of tables of separation rates to more accurately reflect working patterns of male and female pharmacists. The supply model shares many features of supply models for other health professions such as nursing and medicine. The variables suggested for improvement of supply determinations parallel supply measures of other health professions also. The adoption of suggestions for improvement of the pharmacy supply model to other health professions' supply models is suggested. PMID- 10107073 TI - Teaming with ideas. AB - Faced with an uncertain future and increasingly discerning customers, foodservice at Providence Medical Center has introduced an array of service innovations. PMID- 10107074 TI - Profiting from promotions. Basic guidelines can help operators introduce new products successfully. PMID- 10107076 TI - The labor experiment. AB - Foodservice professionals & down-and-outers are coming together in a daring, dynamic, government-funded training program at Cedars-Sinai Medical Center in L.A. that may become a model solution for the entry-level labor shortage. PMID- 10107075 TI - Pricing strategies: Part II. How to factor in food & other costs to arrive at a selling price for non-cafeteria items. PMID- 10107077 TI - Evaluating research in worksite health promotion. AB - Critical review of studies published in the area of worksite health promotion is an important skill for health promotion professionals. Most studies have some weaknesses which make it difficult to draw meaningful conclusions. Therefore, it is important to consider the research design of these studies. By accurately evaluating the conclusions of health promotion investigations, health promotion professionals will be able to make better recommendations for effective program development. PMID- 10107078 TI - Factors associated with, issues related to, and suggestions for increasing participation in workplace health promotion programs. AB - This review examines factors associated with, issues related to, and suggestions for increasing participation in workplace health promotion programs. The purpose is to help health professionals better understand why people participate and how program planners can effect participation. The lack of results and contradictory findings of some studies emphasize the complex nature of participation. Studies have shown that participants are likely to be young with high education and income. Preliminary studies have also shown a relationship between participation and some behavioral and psychosocial variables, although these studies have yet to be confirmed. The participation issues of self-selection and comprehensiveness are discussed. Suggestions for increasing participation are offered. PMID- 10107079 TI - The purpose of health fairs as perceived by university-based health educators. AB - The purpose of this study was to assess the attitudes of university-based health educators on the role of health fairs. Ninety-nine health educators from throughout the country completed a three-part survey requesting information regarding local health fairs, demographics of the respondent, and a series of Likert-type questions regarding the role and function of health fairs. Results indicate that one's level of training and level of involvement played a significant role in determining attitudes regarding the purpose of health fairs. Health educators with doctoral training, when compared to individuals with master's-level training, were less likely to approve of health fairs. PMID- 10107080 TI - Significance of the lifestyle system to employee health and assistance. AB - Data from a corporate-wide (N = 21, 325) health risk appraisal were analyzed for interrelationships between health variables. Findings supported the lifestyle system hypothesis. Employees generally had a consistent pattern of health practices influencing how overall physical health was reported. Implications are discussed regarding the incorporation of lifestyle system principles in employee health and assistance programs. PMID- 10107081 TI - Health economics: are we being realistic about its value? PMID- 10107082 TI - Zero defections: quality comes to services. AB - Companies that want to improve their service quality should take a cue from manufacturing and focus on their own kind of scrap heap: customers who won't come back. Because that scrap heap can be every bit as costly as broken parts and misfit components, service company managers should strive to reduce it. They should aim for "zero defections"--keeping every customer they can profitably serve. As companies reduce customer defection rates, amazing things happen to their financials. Although the magnitude of the change varies by company and industry, the pattern holds: profits rise sharply. Reducing the defection rate just 5% generates 85% more profits in one bank's branch system, 50% more in an insurance brokerage, and 30% more in an auto-service chain. And when MBNA America, a Delaware-based credit card company, cut its 10% defection rate in half, profits rose a whopping 125%. But defection rates are not just a measure of service quality; they are also a guide for achieving it. By listening to the reasons why customers defect, managers learn exactly where the company is falling short and where to direct their resources. Staples, the stationery supplies retailer, uses feedback from customers to pinpoint products that are priced too high. That way, the company avoids expensive broad-brush promotions that pitch everything to everyone. Like any important change, managing for zero defections requires training and reinforcement. Great-West Life Assurance Company pays a 50% premium to group health-insurance brokers that hit customer-retention targets, and MBNA America gives bonuses to departments that hit theirs. PMID- 10107083 TI - Information partnerships--shared data, shared scale. AB - How can one company gain access to another's resources or customers without merging ownership, management, or plotting a takeover? The answer is found in new information partnerships, enabling diverse companies to develop strategic coalitions through the sharing of data. The key to cooperation is a quantum improvement in the hardware and software supporting relational databases: new computer speeds, cheaper mass-storage devices, the proliferation of fiber-optic networks, and networking architectures. Information partnerships mean that companies can distribute the technological and financial exposure that comes with huge investments. For the customer's part, partnerships inevitably lead to greater simplification on the desktop and more common standards around which vendors have to compete. The most common types of partnership are: joint marketing partnerships, such as American Airline's award of frequent flyer miles to customers who use Citibank's credit card; intraindustry partnerships, such as the insurance value-added network service (which links insurance and casualty companies to independent agents); customer-supplier partnerships, such as Baxter Healthcare's electronic channel to hospitals for medical and other equipment; and IT vendor-driven partnerships, exemplified by ESAB (a European welding supplies and equipment company), whose expansion strategy was premised on a technology platform offered by an IT vendor. Partnerships that succeed have shared vision at the top, reciprocal skills in information technology, concrete plans for an early success, persistence in the development of usable information for all partners, coordination on business policy, and a new and imaginative business architecture. PMID- 10107084 TI - Values make the company. Interview by Robert Howard. PMID- 10107085 TI - An interview with: Steven Miller on restaurant employee theft. PMID- 10107086 TI - Crime at the top: detecting and preventing fraud, theft, and embezzlement. AB - Perhaps the most financially damaging scenario a hospital can face is when its chief executive officers (CEOs)--presidents and top financial directors--engage in fraud, theft, and embezzlement. Not only are these crimes often impossible to detect, they usually involve dollar amounts in the millions. So harmful is top level crime to the reputation of a hospital that, all too often, it remains covered up and goes unprosecuted. In this report, we will present several criminal cases and offer advice on practical steps you can take to ensure that such crimes do not occur at your hospital. We will also discuss proactive measures a security department can employ to become involved in investigating crime at the top. PMID- 10107087 TI - Developing a client-driven quality assurance program. AB - The four roles of quality assurance within a partial-hospital program are discussed, along with suggestions for integrating clients into the 10-step quality assurance model recommended by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). PMID- 10107088 TI - The three phases of time-limited day-hospital treatment. AB - The course of treatment in a time-limited day-hospital setting can be usefully understood in terms of three phases. Close examination of the treatment goals, difficulties, benefits, and tasks for both patients and staff for each phase provides a greater understanding of the curative process. These observations are based upon clinical work in a Veteran Administration Day Hospital and are reinforced with clinical examples from that work. Identification of these phases of treatment can be put to practical use. Knowing in which phase a patient is working helps staff members focus their thinking. Such an awareness can also help staff members cope with "burnout" over the frustrations that come with a particular phase. Information about these phases has been valuable to patients and their families in helping them understand the course of their treatment. PMID- 10107089 TI - Partial-hospital treatment of potentially violent patients, or who's afraid of Tatiana Tarasoff? AB - Partial hospitalization has taken on an increasingly important role in the treatment of violence-prone patients. In response to the 1976 Tarasoff decision in California and its progeny widening the scope in many jurisdictions of a therapist's duty to protect endangered third parties from the violent acts of such individuals, strategies relevant to the day hospital need to be formulated. Treaters can provide beneficial containment through the use of informed consent, the therapeutic contract, and reality-based work which involves the patient and significant others. Nevertheless, the partial-hospital team must not lose sight of the limits of such interventions and should consider inpatient care as a serious option. PMID- 10107090 TI - Integrating the halfway house with day-hospital treatment: three perspectives. AB - In this paper, three treaters from three different psychiatric hospitals delineate specific criteria for developing a mutually beneficial, interactive relationship between day hospitals and halfway houses. Ideas for setting up such a cooperative venture are based on the strengths of these three existing programs at the Menninger Clinic, Timberlawn Psychiatric Hospital, and Harding Hospital. Potential problem areas are discussed such as admission and discharge criteria, communication between separate program components, treatment responsibility, staff roles, and program goals and boundaries. PMID- 10107091 TI - Understanding partial hospitalization through organizational models. AB - This paper discusses three interrelated organizational models relevant to partial hospitalization. Such a management perspective can play an important role in the planning of effective mental health-care delivery structures. PMID- 10107092 TI - Internal Medicine chief residents suggest need to improve health care delivery and public policy education. Internal Medicine Center to Advance Research and Education. AB - The primary objective in medical training remains skill development in the delivery of medical care through the understanding of bedside data collection, natural history of disease, use of diagnostic tools and the influence of therapy- all applied to a specific patient. More recently, also considered important is training on the broader issues of health care delivery and public policy, especially since the environment of medicine is changing rapidly. With limited curricular time these issues must compete with the traditional and important clinical training. To evaluate how these subjects have been included in internal medicine training, the Resident Physicians Section (RPS) of the American Society of Internal Medicine (ASIM) sponsored a survey of United States internal medicine chief residents which was conducted by the Internal Medicine Center to Advance Research and Education (IMCARE). The objectives of the study were to 1) study the extent of training on health care delivery and public policy issues offered to residents by internal medicine residency programs; 2) assess training opportunities now available; and 3) determine areas of study not fulfilling perceived needs. The questionnaire contained 12 questions. Chief residents rated the 1) quality of their program in preparing residents on health care delivery, public policy issues and practice management; 2) level of instruction provided on 12 topics; and 3) degree of priority these same topics should have. Respondents were asked to identify 1) any other relevant areas their residency program covered particularly well; 2) the amount of time which should be devoted to these socioeconomic topics in each year of training; and 3) the most appealing formats for learning about these topics. Despite the rapidly growing influence of socioeconomic issues on medical practice, many chief residents perceive that important topics are not being addressed adequately. This study provides information on areas addressed well and topics that should receive greater attention. Recommendations are made for further studies and strategies to increase the emphasis on socioeconomic topics during medical education. PMID- 10107093 TI - De facto rationing: does it exist by design or through inconvenience? PMID- 10107094 TI - Developing medical practice guidelines: IMCARE's (Internal Medicine Center to Advance Research and Education) workshop. PMID- 10107095 TI - Developing a strategy for quality assessment. Interview by Janice C. Simmons. PMID- 10107096 TI - Can access survive Congress? PMID- 10107097 TI - Outcomes research: the art of making the right decision. PMID- 10107098 TI - The threat to physician office labs. PMID- 10107099 TI - Rationing: not "if" but "how"? PMID- 10107100 TI - Prioritization or rationing: what do we call spending fewer health care dollars? PMID- 10107101 TI - The Oregon Plan: rejecting invisible rationing. PMID- 10107102 TI - Skills mix to match costs. AB - The key to an integrated and cost effective staffing strategy is to match what is to be done to the skills needed to do it. Pat Oakley and Jo Coulstock explore the issues. PMID- 10107104 TI - Caring: at home or away? PMID- 10107103 TI - A growing demand. PMID- 10107105 TI - Costing up progress. PMID- 10107106 TI - Healthcare on trust. PMID- 10107107 TI - Surveying one grim future for the NHS. PMID- 10107108 TI - Making of an IT monster. PMID- 10107109 TI - Grasping the nettle. PMID- 10107110 TI - Looking for a way out. AB - In the second part of his overview of the deinstitutionalisation policy of the 1980s Bob Hudson examines the reasons for its apparent failure and looks at what needs to be done in the 1990s. PMID- 10107111 TI - Three is company. AB - 'Caring for people in Cornwall' is a project that involved GPs, the FHSA (Family Health Services Authority) and the HA (Health Authority) as three equal partners. Laurie McMahon explains how it evolved. PMID- 10107112 TI - Be well connected. PMID- 10107113 TI - Healthcare data briefing. Hospital death rates. PMID- 10107114 TI - Fair play ahead. AB - Capital charging will speed up and broaden the contracting out of health services -and increase the proportion of successful private bids, claims Andrew Moncreiff. PMID- 10107115 TI - Trusts versus suspicions. AB - The real battle for the ambulance service is just beginning--with patient services and staff jobs in the firing line. Julian Dobson contracts managers' rosy views of the future with the unions' bleaker outlook. PMID- 10107116 TI - Fixing up the fleet. PMID- 10107117 TI - Green light for new image. PMID- 10107118 TI - Changes in the air. PMID- 10107119 TI - Grasp the moment. PMID- 10107120 TI - Rewarding performance. AB - How will NHS pay be determined in the next 10 years? To find some answers, Edward Lewis looks at companies that introduced performance review for individuals and organisations. PMID- 10107121 TI - Means to a better end. PMID- 10107123 TI - When taking risks is a management duty. PMID- 10107122 TI - Forecasting change. AB - Planning the use of resources is central to the NHS reforms. In the first of a series on forecasting the impact of change on the health service Dr Roger Beech, Jayne Thompson and John Smyth examine the use of computer modelling. PMID- 10107124 TI - Learning from their mistakes? AB - Embracing competition American style could turn out to be an expensive mistake, says Donald Light. In the first of a series of five articles he explains how bad advice and underfunding could turn the American dream into a British nightmare. PMID- 10107125 TI - Education for all. PMID- 10107126 TI - Sorry to keep you waiting. PMID- 10107127 TI - Framework for care. PMID- 10107128 TI - An ideal model. AB - Responding to the challenges faced by community services, Medway HA has implemented a system to model the changes. Brian Clover explains, in the second article on planning models. PMID- 10107129 TI - Rafts on an open sea. PMID- 10107130 TI - Bending the rules. AB - It is naive to claim that competition leads to efficiency, warns Donald Light. In the second of five articles, he describes how sellers have manipulated the US healthcare market. PMID- 10107131 TI - A model of service. AB - General practice may become the focus for primary and community care, but strong community health services remain important. Pam Constantinides and Pat Gordon propose some scenarios for the 1990s. PMID- 10107132 TI - The rise and rise of private care. PMID- 10107133 TI - A system for survival. AB - The district planning model does not exist yet, but it should, to help health authorities cope with the responsibility of implementing the NHS reforms, argues Brian Clover in the third article on computer modeling. PMID- 10107134 TI - Hospital participation in politics: federal regulation of hospitals' legislative and political activities. PMID- 10107135 TI - Cruzan: right to die questions unanswered. PMID- 10107136 TI - Congressional focus on health care: Part I--Hospital finances. PMID- 10107137 TI - New restrictions on patient dumping: greater burdens for health care. PMID- 10107138 TI - The physician as customer: a strategic perspective. PMID- 10107139 TI - Privatisation in health care: concepts, motives and policies. AB - Over the last decade privatisation has been used frequently as a policy instrument to reduce the financial burden of the public sector. In most countries there is a mix of public and private interests in health care. Because of this, privatisation is an important issue in health care policy analysis. In this article we deal with different concepts and motives for privatisation in general. We will distinguish various types of privatisation and show how these can be applied to changes in health care policy. As far as the latter is concerned we will use Dutch experiences. In the analysis we emphasise especially the effects of privatisation in health care on the private non-profit organizations. PMID- 10107140 TI - Britain's new market model of general practice: do consumers know enough to make it work? AB - In 1989 the British Government announced radical plans, now in the process of implementation, for the reform of the National Health Service. The proposals for primary health care imply a market model, insofar as they assume that patients will be active consumers searching out those general practices which best meet their needs. This paper tests one key assumption of this strategy, i.e., that patients have the information required to make such choices. It does so by analysing the data generated by a survey of the health beliefs and practices of 4266 people. The results suggest that British consumers lack the knowledge needed to make market-style choices and that, more generally, policy makers applying the market model to health care should explicitly address the problem of how to create a better informed public. PMID- 10107141 TI - Parking study points out another serious problem: where's the front door? PMID- 10107142 TI - Fall inspections ensure cooling-tower efficiency. PMID- 10107144 TI - Radon in health facilities: how to evaluate the threat. PMID- 10107143 TI - Cooling-tower upgrades: an economical alternative to replacement. PMID- 10107145 TI - Evaluation, integration key to safety-program success. PMID- 10107146 TI - Time management: work smarter, not harder. PMID- 10107147 TI - EPA corrects HCl-emission rates for incinerators. PMID- 10107148 TI - Used equipment can be a bargain--sometimes. PMID- 10107149 TI - How to safely maintain asbestos-containing tile. PMID- 10107150 TI - Materials managers disagree on value of stockless plans. PMID- 10107151 TI - Block stockless and lose job. PMID- 10107152 TI - Patient utensil prices to fluctuate -5% to 10%. PMID- 10107153 TI - Registered pharmacists' clinical and inventory management background good fit for MM. PMID- 10107154 TI - Group purchasers face compliance dilemma. PMID- 10107155 TI - HMM pricing index. Drug indexes down .6% from first quarter. PMID- 10107156 TI - HMM price watch. Purchasing managers' index continues to drop, falling .8% to 47.0 in August from 47.7 in July. PMID- 10107157 TI - Contracting parties should clearly establish their intent to validate open-ended contracts. AB - A hospital materials manager reports that when he took over the job, he found several supply contracts with no price included in the terms. He wonders if these contracts are valid. In this dialogue, Dr. Decker discusses the issues raised by "open term" contracts. PMID- 10107158 TI - Business and health: ten leading corporate strategies to control health costs in the 1990s. PMID- 10107159 TI - Financial management. PMID- 10107160 TI - The drug bill. PMID- 10107161 TI - General management in Glasgow: the search for efficiency. AB - In 1986 Laurence Peterken, who had not previously worked in the health service, was appointed general manager of Greater Glasgow Health Board. He has had a great impact on Glasgow's health services. The trade unions accuse him of butchering the service, the doctors accuse him of acting like God and MPs accuse him of privatising the NHS. He sees things rather differently. PMID- 10107162 TI - Making sense of Chinese walls or how to sort the purchasers from the providers. AB - One of the odd consequences of the white paper is that until NHS Trusts become the norm, districts have to manage their units but as purchasers must keep their distance. Peter Catchpole, Steven Phoenix, David Ellis and Claire Holloway discuss the various ways in which this might be achieved, and describe the model chosen in Mid Downs HA. PMID- 10107163 TI - The campaign for real management. PMID- 10107164 TI - The NHSTA (National Health Service Training Authority): time to assert real authority. PMID- 10107165 TI - Out-patients and quality: the need for information. PMID- 10107166 TI - Decommissioning hospitals--a checklist. AB - Decommissioning a hospital is not an every day management task, but as the health service endeavours to make better use of its estate it is likely to face more managers. St Stephen's Hospital, Chelsea, was recently decommissioned to make way for a new teaching hospital, and Tim Battle and Lynne Clemence offer a checklist based on the experience. PMID- 10107167 TI - Utilization review. Keeping air medical services in the air. AB - Are air medical services taking patients for a ride? Establishing a utilization review process can help justify the necessity of services rendered to patients and assist in reimbursement. PMID- 10107168 TI - Interactive technology. EMS training goes online in Idaho. PMID- 10107169 TI - Take your pick. Choosing your co-workers. PMID- 10107170 TI - Employers spread the blame for rising health costs. PMID- 10107171 TI - Look who's going to get more ambulatory visits. PMID- 10107172 TI - Why the Oregon plan deserves your support. PMID- 10107173 TI - Nine babies died before this doctor was stopped. PMID- 10107174 TI - Where do your fees fit in? PMID- 10107175 TI - When a patient asks you to let her die. PMID- 10107176 TI - HMO employees--including doctors--must unionize. PMID- 10107177 TI - When peer review becomes a media event. PMID- 10107178 TI - How to capture slippery nursing-home charges. PMID- 10107179 TI - Can more doctors be lured into Medicaid? PMID- 10107180 TI - Past shapes present, future--a chronology. PMID- 10107181 TI - The future of group practice and MGMA (Medical Group Management Association). Interview by Dennis Barnhardt. PMID- 10107182 TI - Notes on the history of group practice: the tradition of the dispensary. AB - According to author Donald Madison, M.D., medical group practice is, "an original American phenomenon...its appearance coincided with specialization in medicine and much of the early growth was fed by the experiences of American physicians who served...during World War I." Madison answers the questions of how, where, when and why group practice developed as it did. PMID- 10107183 TI - Physician employment contracts--challenge of a new decade. AB - Part two of author C. Kay Freeman's three-part series, based on the MGMA Series of Strategic Agreements, takes a look at physician employment contracts and how they intertwine with the needs of the organization. PMID- 10107184 TI - The anatomy of buying power. AB - The Federal Risk Retention Act of 1986 was intended to enable commercial insurance purchasers to utilize new approaches to reduce insurance costs, according to authors Arthur Parry, Ph.D., and G. Michael Hutchens, FACMGA. This article traces the steps of a group of physicians in their efforts to restructure their insurance program. PMID- 10107185 TI - Audit and feedback as a cost-effective strategy. AB - Despite more than a decade of cost containment initiatives, medical care costs continue to rise at levels that concern both policy makers and third-party payers. Various explanations can be offered for this apparent lack of success. A crucial factor in the opinion of the authors, Robert Braham, M.D., and Hirsch Ruchlin, Ph.D., is the way in which cost containment is approached. Braham and Ruchlin describe how their organization successfully tackled this concern. PMID- 10107186 TI - Texas ambulatory-care center started. PMID- 10107187 TI - Voluntary review guidelines released. PMID- 10107188 TI - New proposal challenges tax-exempt status. PMID- 10107189 TI - Caring for people, not profits, brings success. AB - The path to success in healthcare institutions must become more centered on caring for people instead of caring about profits, says Kristine Peterson, a longtime consultant taking a sabbatical from the industry. PMID- 10107190 TI - Iowa hospital's expansion plans tap rural networks. AB - Iowa Methodist Medical Center, Des Moines, is expanding in size and reach by developing centers of excellence, tapping rural networks and forming alliances with primary-care physicians to increase referrals. PMID- 10107192 TI - Preliminary FTC ruling opposes acquisition. PMID- 10107191 TI - Budget negotiators work to avoid automatic cuts. PMID- 10107193 TI - R.I. hospital group acts as quality catalyst. PMID- 10107194 TI - Deal nets hospital a 'free' medical building. AB - A developer is about to break ground on a $6.2 million medical office building on land owned by a California hospital. The deal will result in a haven for referral physicians at no cost to the hospital, though it will forgo equity and some management control. PMID- 10107195 TI - AMA calls for resignation of HHS inspector general. PMID- 10107196 TI - Military call-up costly to CHAMPUS HMO. PMID- 10107197 TI - Ill. hospitals form holding company. PMID- 10107198 TI - Turmoil-plagued nursing home chain expects big loss. PMID- 10107199 TI - Revolt in Congress may doom budget agreement. PMID- 10107200 TI - Nursing homes seek funding assurances. PMID- 10107202 TI - Hospitals are easily complying with immigration law changes. AB - Complying with the Immigration Reform and Control Act of 1986 was predicted to be a major headache, but hospitals have found the law easy to follow and the fallout limited--if some basic steps aren't overlooked. PMID- 10107201 TI - Rural areas' AIDS care lacking. PMID- 10107203 TI - Humana to buy Chicago hospital, HMO. PMID- 10107204 TI - To centralize or not centralize. AB - Not-for-profit systems increasingly are turning to centralized management systems in an effort to reduce duplication of services at local hospitals and to save money. At the same time, some for-profit systems are abandoning their traditional centralized philosophies and are eliminating services provided by the corporate office, often as a result of having to shoulder heavy debt loads. PMID- 10107205 TI - The rise of risk management. AB - Risk managers are playing a more prominent role in hospitals. Regulatory mandates and quality and liability concerns are prompting an increase in their numbers and an elevation in their positions. Along with the rise in income and respect come changes in the qualifications expected of them. PMID- 10107206 TI - Calif. medical groups to merge. PMID- 10107207 TI - Study finds stockless inventory saves money, but many barriers keep it from gaining favor. AB - A major study commissioned by the Health Industry Distributors Assn. finds a lot of merit in the conversion of hospitals to stockless inventory. But it also finds a lot of resistance and barriers. PMID- 10107208 TI - Conn., R.I. subsidies lessen demand to justify tax status. AB - Two states, Connecticut and Rhode Island, have responded to the issue of tax exemptions for hospitals and colleges by declaring them benefits to the public and granting subsidies to the municipalities that carry the burden of providing services. PMID- 10107209 TI - Charter to centralize contracting. PMID- 10107210 TI - N.J. panel urges payment revamp. PMID- 10107211 TI - Humana buys land from chairman. PMID- 10107212 TI - Plan drafted to east Dallas' trauma load. PMID- 10107213 TI - New spending plan shifts more burden to providers. PMID- 10107214 TI - States fear budget crisis will cost them. PMID- 10107215 TI - Study strips Agent Orange link. PMID- 10107216 TI - Direct contracting: a recipe for savings. AB - Hospitals, anxious to maximize patient revenues, and purchasers, just as anxious to contain soaring healthcare costs, are getting together through direct contracting. But the arrangements aren't the answer for all providers. Such efforts are fruitless without adequate financial commitment, cooperation from the medical staff and a reputation for quality. However, if the key ingredients are there, the deals can be sweet indeed. PMID- 10107217 TI - Hospital groups squabble over budget plan. PMID- 10107218 TI - U.S. Supreme Court takes NLRB bargaining unit case. PMID- 10107219 TI - CEOs, chairmen split over CEO background. AB - A new survey shows that board chairmen and chief executive officers have different opinions about what type of background future hospital leaders should have. Most chairmen say CEOs should have specialized educational training, but CEOs and heads of graduate programs say leaders should have generalist backgrounds. PMID- 10107220 TI - Experts agree quality is measurable, but agreeing on measurement is another matter. AB - Putting quality initiatives into effect is going to be daunting, experts agreed at a conference sponsored by the Joint Commission on Accreditation of Healthcare Organizations. Among other things, standards will need to be enforced in a way that encourages true internal improvement in hospitals rather than a cover-up mentality aimed at out-foxing inspectors. PMID- 10107222 TI - FTC getting tough on false healthcare advertising. PMID- 10107221 TI - Emerging contract incentives can add to hospitals' savings. AB - Group purchasing organizations are trying to draw more volume out of their hospital members by offering additional price breaks if purchases meet performance targets, says John Henderson. The purchasing groups see the approach as a way to keep their promise to manufacturers of volume in return for discounts. PMID- 10107223 TI - Call-up won't be quite as costly to CHAMPUS managed-care plan. PMID- 10107224 TI - Study critical of insurers' overhead costs. PMID- 10107225 TI - Bond volume dips in 3rd quarter. PMID- 10107226 TI - AOHA agrees to restructuring. PMID- 10107227 TI - Vanderbilt stockless supplies bows out. PMID- 10107228 TI - Managers facing reserve call-ups; staffing shortages. PMID- 10107229 TI - Is the all-RN OR staff still a realistic goal? PMID- 10107230 TI - Indicators signal areas needing evaluation. AB - This is the sixth article about applying the ten-step model for monitoring and evaluation developed by the Joint Commission on Accreditation of Healthcare Organizations. PMID- 10107231 TI - Recovery care centers complement ASCs (ambulatory surgery centers). PMID- 10107232 TI - Situational leadership helps staff growth. PMID- 10107233 TI - Shared governance: does it apply to the OR? PMID- 10107234 TI - OR turnaround: focusing on problem areas. AB - This is the final article in a series on management strategies for "turning around" a problem OR. Previous articles appeared in the January, April, June, and September issues. PMID- 10107235 TI - AHCA pursues improvements in Medicare reimbursement limits. PMID- 10107236 TI - Caregiving enters a new era. AB - Twenty-five years after creation of the Medicare and Medicaid programs, the Omnibus Budget Reconciliation Act of 1987 (OBRA) takes effect--with promises of increased quality care for nursing facility residents. In addition to expressing enthusiasm about the potential impact of new nursing facility regulations, some individuals voice concern about the effect of implementation glitches on the future. PMID- 10107237 TI - The challenges of implementing OBRA. Industry leaders discuss hopes, concerns. PMID- 10107239 TI - Effective collection approach requires sensitivity. PMID- 10107238 TI - Increased importance placed on resident-centered design. PMID- 10107240 TI - Resolving ethical decisions with advance directives. PMID- 10107241 TI - Increase community support through coalition development. PMID- 10107242 TI - Infection control reduces work-related exposure to AIDS. PMID- 10107243 TI - Establishing procedures to implement drug therapy rules. PMID- 10107244 TI - Food and wine tasting fairs add spice to daily menus. PMID- 10107245 TI - Home care: the Ontario experience. PMID- 10107246 TI - Caring for the geriatric patient in Great Britain: an American social worker's perspective. PMID- 10107247 TI - Home care services for older people in New Zealand: current developments and future directions. PMID- 10107248 TI - Aspects of cooperative home care for the elderly in Bologna, Italy. PMID- 10107249 TI - Lobbying for a hospitable hospital coffee shop. PMID- 10107250 TI - Age-based rationing and technological development. PMID- 10107252 TI - Educating patients about living wills. PMID- 10107251 TI - Hospital repositioning: the leadership imperative. PMID- 10107253 TI - CFOs see physician relations as key to hospital survival. PMID- 10107254 TI - Joining service and quality strategies. PMID- 10107255 TI - AHA Chairman-elect designate: enhancing physician relations. Interview by Frank Sabatino. PMID- 10107256 TI - Hospital programs ease the transition to home. PMID- 10107257 TI - Cruzan and beyond. PMID- 10107258 TI - An investment in quality assurance today yields future dividends. PMID- 10107260 TI - Executive compensation. PMID- 10107259 TI - Purchasing is for the board. PMID- 10107261 TI - Trustees who make a difference to health care. AB - Profiles of trustees from each of the nine AHA geographic regions demonstrate the intense commitment that trustees have for their hospitals and communities. These trustees illustrate how creativity and enthusiasm make a difference to the success of hospitals. PMID- 10107262 TI - AIDS knowledge and attitudes for January-March 1990. Provisional data from the National Health Interview Survey. PMID- 10107263 TI - Screening for prostate cancer: is ultrasound the answer? AB - The high incidence and subsequent mortality from prostate cancer in progressively older US males is a serious health concern. Prognosis is related to extent of spread of the disease at the time of diagnosis and to pathologic grading of the tumor cells. The argument for early detection is somewhat clouded by a high incidence of latent prostate cancer related to increasing age, which may or may not progress to clinical disease. Recent applications of ultrasound technology have greatly improved our ability to image the prostate gland and raised the possibility of using ultrasound to screen for prostate cancer. The conclusions of this investigation are that ultrasound should not yet replace annual digital rectal examination as the primary screening tool, but ultrasound is a useful diagnostic adjunct. This recommendation may change with further application of the technology and as more information is gathered. PMID- 10107264 TI - An HMO psychopharmacology service. AB - A pilot HMO psychopharmacology service is described. The program utilized a consultant psychopharmacologist (14 hours per week on-site) and two master's degreed nurse-clinicians who spent four and eight hours per week treating psychopharmacology patients. The psychopharmacologist evaluated all patients, initiated drug therapy, and referred selected patients to the nurse-clinicians for follow-up. The latter functioned as independent clinicians, making treatment decisions and writing prescriptions (which were countersigned by the psychopharmacologist or other staff psychiatrists). Support services (e.g., emergency triage) were provided by the mental health department. At the end of one year, the service was managing a caseload of 184 patients, 64 of whom were being followed by the two nurse-clinicians). Patient acceptance was good, and the service was supported by other mental health and medical personnel, who viewed it in pragmatic terms of increasing access to care. Issues related to the implementation of such a service in HMO settings are discussed. PMID- 10107265 TI - Technology assessment. PMID- 10107266 TI - Are HMOs the answer? AB - Although many differ on how to stem rising health care costs, there is general agreement that the 11.5% of GNP currently being spent is too high. Furthermore, health care is outstripping other parts of the economy in growth. Combined with the current de facto system of shifting costs onto an already burdened corporate America, this growth has alarmed some observers. Health care analysts voiced their concern at a recent national conference, and cast a strong "yes" vote for HMOs as the single most plausible delivery system capable of meeting the nation's growing needs. PMID- 10107267 TI - Interview Gail R. Wilensky, Ph. D.. Interview by Anne Paxton. PMID- 10107268 TI - Conflict of interest: a key concept for ethical analysis. PMID- 10107269 TI - Organizational innovation and the laboratory information system. AB - There is an urgent need for more innovation in health care and in clinical laboratories. Innovation can be divided into five separate categories: core products, components of the core products, production processes, uses of products, and the organization of production. Organizational innovation is an important as technological advances in increasing the quality and efficiency of clinical laboratories. The use of a laboratory information system (LIS) can stimulate organizational innovation such as the assignment of computer-oriented tasks to personnel within individual clinical laboratories. The authors refer to such LIS support personnel as "hidden personnel" and suggest that such a shift of responsibility empowers laboratory professionals and makes them stakeholders in automated information processing. PMID- 10107270 TI - Principles for communicating with aging health-care consumers. AB - The health-care marketplace is aging by leaps and bounds and bringing with it new and different medical needs. As costs soar and public assistance programs dwindle in impact, health-care providers will need better marketing strategies to bring treatments to patients/consumers. This article looks at the research findings of behavioral scientists and offers guidelines for effective communication with aging audiences. Health-care providers can use these findings to design more effective advertising, promotional brochures, newsletters, and a host of other communication tools targeted at an older market. Health-care managers and other professionals should find the guidelines useful in their daily interactions with patients and colleagues. PMID- 10107271 TI - CLIA (Clinical Laboratory Improvement Amendments) '88: alternatives proposed by CLMA (Clinical Laboratory Management Association). PMID- 10107272 TI - The Roche MIRA. PMID- 10107273 TI - Staffing according to volume. PMID- 10107274 TI - Area health boards: exclusive or inclusive? PMID- 10107275 TI - Resource utilisation system. PMID- 10107276 TI - The Canterbury Area Health Board. Reaching out into the community. PMID- 10107278 TI - Breaking old barriers to quality, key to MCG (Mount Clemens General) future. PMID- 10107277 TI - Recruiting: DOs in demand. PMID- 10107279 TI - How important is functional status as a predictor of service use by older people? AB - In studies of older people, it is often assumed that biophysical, or functional, status is the primary determinant of formal service use. This article reports baseline data from a longitudinal study of a community-based, linked random sample of frail elders (n = 635) and their informal caregivers (n = 429) to investigate the relative contribution of social circumstances to the use of community-based formal services. Elder respondents were categorized into three groups defined by their primary source of care: (a) informal only, (b) mixed help with predominantly informal care, (c) mixed help with predominantly formal services. Of the respondents, 79% received most of their help from informal caregivers, whereas 21% relied on formal services for most of their assistance. A series of logistic regression models were developed to identify variables that discriminated between major sources of care. The social factor of living alone is the consistent predictor of reliance on formal services. Only for those elders living alone does the physical factor of level of frailty predict reliance on formal services. Elders who live with a caregiver, particularly a spouse, are likely not to use any formal services regardless of their level of frailty. Finally, elders reliant on formal services receive much less care overall. PMID- 10107280 TI - Health status, retirement plans, and retirement. The Kaiser Permanente retirement study. AB - The purpose of this study was to assess the stability of short-term plans to retire and to evaluate the role of self-reported health status in predicting both plans to retire and actual retirement from a sample of 1,165 older members of a prepayment, group practice model, health maintenance organization. The study sample was derived from a random sample of members 60 to 66 years of age. Mailed questionnaires were completed that obtained data on the following variables: self reported health status, work status, demographic variables, and plans to retire in the next year. Telephone interviews were conducted throughout the study period to determine dates of retirement from both those who planned to retire and those who had not. Results indicated that retirement plans were relatively stable for this population. Logistic regression analyses revealed that poorer health status was related to both retirement plans and actual retirement for women but not for men. PMID- 10107282 TI - Financial leverage: how much is enough? PMID- 10107281 TI - Age group differences in the use of breast cancer screening tests. The effects of health care utilization and socioeconomic variables. AB - The age-related decline in the use of breast cancer screening tests, specifically periodic mammography and physical breast examinations by a doctor, is especially problematic given that breast cancer risk increases with age. Survey data (N = 3,507) from the Awareness of Breast Cancer Project are used to compare the effects of socioeconomic variables and usual health care use variables on recent use of breast cancer screening tests in women 50 to 75 years of age on Long Island, New York. Having annual checkups and seeing an obstetrician/gynecologist for routine health care are the best predictors of recent mammography and breast physical exams for all women. Income level and education are not independent predictors of recent screening for women over 65. The implications of the effect of primary care practioners on periodic breast cancer screening in older women are discussed. PMID- 10107283 TI - Medical tests under closer scrutiny. PMID- 10107285 TI - Special report. Congress votes dozens of Part B changes for FY 91. PMID- 10107284 TI - Medical malpractice rates going down. PMID- 10107287 TI - Perspectives. Hitting the FDA ... again. PMID- 10107288 TI - Senate Bill hard on seniors, softer on providers. PMID- 10107286 TI - Respect for donor choice and the Uniform Anatomical Gift Act. PMID- 10107289 TI - Perspectives. Rural help on the way. PMID- 10107290 TI - Perspectives. Budget deal: where's the pain? PMID- 10107291 TI - Perspectives. Hospital unity: the impossible dream? PMID- 10107292 TI - The role of medical records in infection control. AB - The concept of "infection" has been well known to the medical world ever since an interest began to be taken in medicine. Infection has taken many hundreds of thousands of lives, and even today it is a very serious threat for human beings. Hospital, or nosocomial infections (NCI) are a major health problem in every medical institution in the world. In the light of the seriousness of the problem, this paper is to demonstrate how medical records can play an important role in effective alerting and infection control programmes before an outbreak turns into an epidemic. PMID- 10107293 TI - Guidelines for clinicians on medical records and notes. Royal College of Surgeons of England. AB - The 'Guidelines to Clinical Audit in Surgical Practice' issued in March 1989 by the Royal College of Surgeons of England comprised an outline of the underlying principles of clinical audit and the basic components of a surgical audit programme. PMID- 10107294 TI - Shaping up the bottom line. AB - Company-sponsored fitness programs help employees stay healthy and decrease employers' medical costs. Several case studies show the results of established programs in different industries. PMID- 10107295 TI - The National Practitioner Data Bank. What surgeons should know. AB - The National Practitioner Data Bank began operation on September 1, 1990, nearly a year after the final regulations for it were published in the October 17, 1989, Federal Register. One of two major provisions of the Health Care Quality Improvement Act (HCQIA) of 1986 (P.L. 99-660), the data bank is expected to have widespread implications for all surgeons and Fellows of the College. This article summarizes the effects it is anticipated the data bank will have on Fellowship and provides a general outline of the regulations that will affect surgeons. PMID- 10107296 TI - Medical professional liability issues capture congressional interest. PMID- 10107297 TI - Perspectives on the Canadian health care system. PMID- 10107298 TI - Medicare program; Part A. Premium for the uninsured aged for 1991--HCFA. Notice. AB - This notice announces the hospital insurance premium for the uninsured aged for calendar year 1991 under Medicare's hospital insurance program (Part A). The monthly Medicare Part A premium for the 12 months beginning January 1, 1991 for individuals who are not insured under the Social Security or Railroad Retirement Acts and do not otherwise meet the requirements for entitlement to Part A is $177. Section 1818(d) of the Social Security Act specifies the method to be used to determine this amount. PMID- 10107299 TI - Factors affecting a clinician's decision to provide fieldwork education to students. AB - Fieldwork represents an important component of the education of an occupational therapist. In this study thirteen occupational therapists in small Saskatchewan occupational therapy facilities were interviewed to determine the factors and the relationships among these factors that affected their involvement in the fieldwork process. The directors of the two large occupational therapy departments in Saskatchewan, together with eight Canadian university fieldwork coordinators were interviewed for comparison purposes. The findings of the study have shown that there were four major influences affecting Saskatchewan therapists' involvement in the fieldwork program of occupational therapy students. They were: workload; feelings of isolation; the parameters of a placement; and professionalism. This study is important because it has identified significant factors for university fieldwork coordinators to consider in their contact with therapists. It has also provided a model for other similar studies. PMID- 10107300 TI - Move to specialize gains momentum. Planning is key to success. PMID- 10107301 TI - Left in the lurch. Standardized data exchange hastens hospital transfers. PMID- 10107302 TI - Filling an information void. Foundation spreads the word about retirement housing. PMID- 10107303 TI - Strike out unionization. Simple steps prevent tough problems. PMID- 10107304 TI - Training emphasizes emotional needs. Red Cross, Beverly co-develop program for aides. PMID- 10107305 TI - Relief from overseas threatened. Feds favor use of U.S. nurses. PMID- 10107306 TI - Where the buck stops. PMID- 10107307 TI - Productivity enhancement: implications for medical group management. AB - Productivity enhancement is critical for every medical group practice. In today's environment, without productivity enhancement, many medical groups will not be able to survive. This paper examines what administrators must do to determine what aspects of their group's performance should be measured and monitored. PMID- 10107308 TI - Downsizing a branch clinic system. AB - Medical group practices often underestimate the cost and complexity of building a branch clinic network. This case study follows the Ramsey Clinic's experience in countering this problem. PMID- 10107309 TI - Pitfalls in the joint planning process between a group practice and a hospital. AB - Organizations contemplating or attempting joint strategic planning should be aware that it is difficult and that there is no right or wrong way to proceed. This case study follows the Ramsey Clinic in its effort to establish such a process. PMID- 10107310 TI - Marketing--putting it all together in a rural practice. AB - Marketing medical practices, whether in a metropolitan or rural area is a reality in today's competitive environment. This paper follows the development of a successful marketing plan for a rural medical group practice. PMID- 10107311 TI - Managing in the new paradigm. AB - The 1990s represent a profoundly exciting time to be in health care. The following paper asserts that it is time for physicians and management to relinquish old baggage, to dream about what is best, and help create a new medical culture. Guiding the choices about what is best for the future of health care are three broad issues: cost and value, patient satisfaction, and standards of care. PMID- 10107312 TI - Physical therapist's opposition to being employed by medical groups. AB - The movement by physical therapists to work independently of physicians is having an impact on the ability of group managers to recruit and retain physical therapists. This paper discusses the development of physical therapy as a profession and its evolution to the point of demanding independent status from physicians. PMID- 10107313 TI - Establishing a hospital fund raising foundation. PMID- 10107314 TI - External assessments report: an update on risk management. PMID- 10107315 TI - Changing expectations of hospital directors. PMID- 10107316 TI - An RRSP (registered retirement savings plan) for health care: the registered investment health plan. PMID- 10107318 TI - Leadership in caring for Medicare. PMID- 10107317 TI - Reflections on trusteeship. PMID- 10107319 TI - Health technology assessment in Canada. PMID- 10107320 TI - Termination practices of Canadian employers. PMID- 10107321 TI - Mail-order drug programs--where are we now? PMID- 10107322 TI - Optimizing the effectiveness of your case management program. PMID- 10107323 TI - The Immigration Law is important to your business. PMID- 10107324 TI - An assessment of dental care for the underserved. AB - Despite changes and improvements in the delivery of dental-care in the United States, almost half the population is "by current standards of dental practice, a medically underserved population." The impact of fluoridation has reduced the incidence and resultant prevalence of dental caries, and insurance and alternative payment systems have helped to improve access to dental care for many Americans, but a large underserved population has not reaped the full benefits of these positive developments. This paper analyzes some major inequities of dental care delivery in the United States and proposes some policy solutions. PMID- 10107325 TI - Multi-attribute analysis of benefit managers' preferences for smoking cessation programs. AB - This article reports the results of formative research on worksite benefit managers' preferences for smoking cessation programs. Procedures focused on application of a multi-attribute preference evaluation method known as conjoint analysis. Literature reviews, small-sample telephone interviews, and a focus group were used to guide selection of cessation program attributes for this analysis. Personnel benefit managers representing a variety of worksites (N = 103) across the U.S. were then randomly selected for participation in the study. Results suggested that cost per employee, program management options, success rates, and endorsements were associated with relatively higher utility values, as compared with attributes concerning program materials or content (e.g., emphasis on cessation preparation vs. maintenance techniques). Benefit manager response simulations indicated a low-cost program with flexible delivery options received the strongest overall response of the six types of programs tested. Results also suggested there were preference differences associated with the type of worksite. Implications of these results for future study are briefly discussed. PMID- 10107326 TI - Medicine goes Madison Avenue: the deadly deception. PMID- 10107327 TI - Graduate medical education: the accreditation process. PMID- 10107328 TI - ECFMG (Educational Commission for Foreign Medical Graduates) certification. PMID- 10107329 TI - The medical degree from foreign institutions. PMID- 10107330 TI - Industries with promise in 1991. PMID- 10107331 TI - Cardiac rehabilitation enhances hospital image. PMID- 10107332 TI - Hospital image based on quality, fact, perception. AB - Quality "in fact"--appropriate clinical outcomes--and quality in "perception"- consumer evaluation--are two important parts of the "image equation" for a hospital. But, how do administrators use either to promote their institutions? The authors explain how to use both to give your institution the competitive edge. PMID- 10107333 TI - Recession may force hospital planners to reassess strategies. PMID- 10107334 TI - Planning indicators. Coronary artery bypass grafts: Medicare discharges. PMID- 10107335 TI - Parker discusses vision. Interview by Donald E. L. Johnson. AB - What special challenges face a major multi-hospital network as it enters the 1990s, offering care to diverse communities? What problems will its CEO have to deal with in an era of cutbacks and change? Scott S. Parker, president and chief executive officer of Intermountain Health Care, Inc., (IHC), a not-for-profit health care delivery system of 24 hospitals in Utah, Idaho, and Wyoming, plus an array of other medical facilities and services, discusses the challenges and accomplishments with Donald E. L. Johnson, publisher of Health Care Strategic Management. In the following interview, he talks about strategies and opportunities among many other topics. PMID- 10107336 TI - Are standardized recipes outdated? PMID- 10107337 TI - If it looks and smells good--it should taste good. PMID- 10107338 TI - Pizza--big-time and little-time. PMID- 10107339 TI - Copyrights, trademarks, and patents in food and nutrition services. PMID- 10107340 TI - Central sterile supply productivity and time study analysis. AB - As a result of the productivity study in both areas, the following objectives can be attained: Ascertain the number of FTEs necessary for staffing requirements. Determine the efficiency level in daily production of trays and sets. Develop standards to measure the overall effectiveness in delivering service. Although this represents a quantitative analysis of the productivity within a CSS department, it is important not to forget the human element in the relationship between CSS and OR employees. PMID- 10107341 TI - Anatomy of an instrument tray from central sterile supply to the operating room. AB - One can understand the importance of quality control measures to ensure that instrument trays meet specific standards on a consistent basis. The essence of the role of the quality control supervisor of CSS is to support the surgical services provided in the OR. Since technology is constantly changing, it is paramount that the quality control supervisor keep abreast of new knowledge and improve services to meet the needs of the OR. PMID- 10107342 TI - The central sterile supply-operating room connection. PMID- 10107343 TI - Establishing a stock distribution system. PMID- 10107344 TI - The four Cs of a successful central sterile supply-operating room relationship. AB - Often, a director of materiel management's primary challenge is to transform a CSS-OR relationship that is plagued by criticism, cynicism, confrontation, and chaos into one that embodies communication, credibility, consideration, and consistency. The task, of course, is not accomplished overnight but rather through the development of strategic plans and periodic assessments to ensure that the four Cs become a reality. PMID- 10107345 TI - Creating change in a health care facility: the evolving role of the materiel manager. PMID- 10107346 TI - Capital equipment acquisition: coping with the present and planning for the future. PMID- 10107347 TI - Custom procedural trays. PMID- 10107348 TI - Materiel management in the operating room: a case study. AB - The hospital continues to be pleased with the progress of our material services program in all areas, but especially surgery. It took a few simple, basic methods, such as exchange carts and inventory control, mixed them with people who actually care about doing a good job, and the whole program moved forward dramatically. People, both in materiel services and surgery, have accomplished a tremendous amount in the past two years. They have made, and will continue to improve, an already excellent program. PMID- 10107349 TI - In-house versus off-site sterilization. AB - After a comprehensive review of in-house costs versus off-site sterilization costs, and considering financial and physical constraints, the decision was made to use the contracted service. Through the incorporation of the innovative concept of off-site sterilization. Flushing Hospital Medical Center was still able to provide a high standard of quality care as well as realize a significant cost savings. As hospitals face increasing demands to control costs, they may be forced to explore "uncharted waters" and give serious consideration to the use of outside services for a more efficient and effective CSS department. PMID- 10107350 TI - A disaster's effects on material management operations. AB - No one should ever have to encounter a disaster of the magnitude of Avianca flight 052, Hurricane Hugo, or the San Francisco earthquake of 1989. However, we all learn about the appropriate preparation and response that is necessary for managing a disaster effectively after these events. The importance of material management functions in providing the resources for the implementation of direct patient care is often neglected, and recognition is rarely given to these heroes in a disaster situation. PMID- 10107351 TI - A simple process for controlling operating room specialized inventory. AB - As with any new system, success would not exist without team efforts. Cooperation from the materiel service department played an important role in its success. Prompt purchase orders and a prompt delivery system are a must when PAR levels are kept at a minimum. The new manual inventory system became an efficient and effective alternative to controlling products within the surgery department at Tampa General Hospital. And now for automation! PMID- 10107352 TI - The central sterile supply employee motivation program. PMID- 10107353 TI - The essentials of sterilization and cross-contamination. PMID- 10107354 TI - Developing rapport between materiel management and surgery. AB - A materiel management system, developed into an efficient organization, seems to be the most practical solution to solve interrelations between two complex operational departments, the CPD and surgery, be it for supply acquisition, inventory, processing, or distribution. The goal is to develop the most intelligent and efficient method so that the materiel management facility renders the required service to the surgical department, which in turn, services patient needs at the lowest possible cost. PMID- 10107355 TI - Measuring cost savings in the operating room: a matter of FOCUS (follow-through, obsolescence, control, utilization, standardization). AB - In summary, changes came slowly at first in the OR. The biggest inventory reduction came about a year after the effort had begun. It would seem that tackling obsolescence, standardizing products, etc. would give an initial "big chunk" savings, with small amounts coming later as inventories are lowered. What we expected did not occur, due to the inherent nature of practices and what was customarily being used. For example, previously, some equipment purchases were paid for by purchasing product, which resulted in long-term commitments and high supply costs. The OR at times seemed more like a process of managing change, not just supplies. FOCUS is a daily process. How many times can you afford to overlook this process? How often are the mistakes of the past repeated? In review, we suggest this simple outline: Follow-through (review each case from start to finish), Obsolescence (schedule inventories every six months), Control (achieve inventory management by adjusting PAR levels to needs), Utilization (utilize product/equipment with your control), and Standardization (standardize products and measure results). PMID- 10107356 TI - ICD-9-CM coding and reporting official guidelines. American Hospital Association, American Medical Record Association, Health Care Financing Administration, National Center for Health Statistics. PMID- 10107357 TI - Current practices in discharge analysis and record assembly. AB - Are practitioners adopting the "less is best" philosophy for management of medical records? Making record abstracting less time consuming, and assembling charts to appear as they do on the patient units have been debated over recent years. This article reports on a survey of practitioners to see if newer methods are being adopted or if traditional practice prevails. PMID- 10107358 TI - The physician's role: respecting a patient's right to live or die. PMID- 10107359 TI - Understanding the tides of physician payment reform. Interview by C. Burns Roehrig. PMID- 10107360 TI - RBRVS and the internist's share of the pie. PMID- 10107361 TI - Cost containment vs. access: what has first priority? PMID- 10107362 TI - Untangling the hassle factor. PMID- 10107363 TI - MVPS (Medicare volume performance standards): the needed solution to growing volume? PMID- 10107364 TI - Let's replace the red tape with some humanism. PMID- 10107365 TI - A primer for patients and physicians: making the informed decision. PMID- 10107366 TI - Making individual decisions: states and courts enter the arena. PMID- 10107367 TI - Why the flagship may founder on its past. PMID- 10107368 TI - Labelling waste as inefficiency. AB - In the third of a five part series of articles, Donald Light goes in search of justification for the sweeping changes affecting the NHS and finds that the current reforms ignore some basic problems. PMID- 10107369 TI - United fronts. PMID- 10107370 TI - A safety net for mending. PMID- 10107371 TI - Reconciling demands. AB - How can hospitals keep a tight rein on their finances while satisfying changing demand? Kevin Richards explains how the hospital planning model helped Coventry HA. PMID- 10107372 TI - When the price is right. AB - Pricing services is one of the first and major tasks of hospitals taking on NHS trust status. James Birrell describes how the Royal Liverpool Children's Hospital is tackling the problem. PMID- 10107373 TI - Steps to a milestone. AB - Information systems need urgent upgrading if hospitals are to become successful providers of services after April 1991. Guy Palmer, Vic Peel and John Cruickshank advise how to prepare. PMID- 10107374 TI - How to be an informed buyer. PMID- 10107375 TI - Switching on to medical audits. PMID- 10107376 TI - Turning data into dialogue. AB - Health visitors often see resource management as threatening, so changing their attitude is no easy task. But one training scheme did just that, as Joyce Steen and Marie Thistleton explain. PMID- 10107377 TI - Biting hard on the research bit. AB - Underfunding can be a major source of waste argues Donald Light in the fourth of a five part series of articles as he identifies some systemic inefficiencies. PMID- 10107378 TI - Battle to stem the shortage tide. AB - Almost a quarter of the NHS budget is spent on nursing, but recruitment and morale have reached crisis point. In two new reports Virginia Beardshaw and Celia Davies propose some long term solutions. PMID- 10107379 TI - Working towards change. PMID- 10107380 TI - At the top of the bill. PMID- 10107381 TI - Going live on a realtime system. Interview by Neville Ash. AB - Newcastle health authority is set to tackle the financial uncertainties of the internal market with its new realtime financial system. Neville Ash asks Martin Herd how the HA decided which system to buy. PMID- 10107382 TI - The five critical areas for effective governance of not-for-profit hospitals. AB - The pressures on hospitals continue to mount. Voluntary boards increasingly are nervous, making management's tasks all the more difficult. We believe the environment demands a new approach to the process of not-for-profit institutional governance. The volunteer board model has worked very well, but it must be adapted to the changed environment. There must be a direct link between the function of institutional governance and the priorities identified through the strategic planning process. It is our observation that truly effective boards have the following areas clearly in focus within the board and between the board and management: (1) a common working definition of "governance"; (2) a clearly defined mission with specific goals and objectives; (3) a well-planned decision making process; (4) a board structure tailored to the priorities at hand; and (5) an information, reporting, and communication system that keeps the priorities clearly in focus. This article explores these factors and suggests ways to link the board's work directly to the strategic plan. PMID- 10107383 TI - A new era for health services research? AB - The suggestion that health services research is now on the threshold of a new era of importance is a commonplace theme in selected forums. Concern over escalating costs and quality assurance in the health care industry have inspired government, business, insurers, and health care organizations to search for answers in health services research. Those who expect a new era of assessment and accountability will be disappointed, however, if certain key conditions, such as financial resources, multidisciplinary cooperation, significant new training programs, and unified action on national and state public interest research agendas, are not satisfied. PMID- 10107384 TI - The design and implementation of hospital-based coordinated care programs. AB - This article contains the initial findings of an ongoing evaluation of a hospital based coordinated care demonstration. The goal of the demonstration is to investigate the appropriateness and feasibility of providing hospital-based case management services for extended periods to elderly individuals living in the community. The rationale for the demonstration is reviewed, and the structure of each participating hospital's coordinated care program is described. Data are presented on the characteristics of clients served by the programs during the first six months of the demonstration. The factors that influenced implementation and early operations of these programs are analyzed, and their implications for hospital managers are discussed. PMID- 10107386 TI - Coping with unbalanced information about decision-making influence for nurses. AB - The leaders of the nursing profession are trying to change nursing so that nurses will be better able to practice their profession the way it is taught in nursing schools--in a manner that will afford them the job satisfaction, power, and prestige that will attract more of the best people into nursing. Part of what is encouraging these changes is a literature that calls for increased decision making power for nurses, power that often takes the form of increased decentralized, participative, or autonomous decision making. A problem with this literature is that a sizable portion of it is unbalanced in its support of nurse influence and in its opposition to hospital bureaucracy. This article illustrates and discusses this imbalance and considers what hospital administrators might do to cope with its consequences. PMID- 10107385 TI - The performance of urban and public hospitals and NHCs (neighborhood health centers) under Medicaid capitation programs. AB - This article reports the results of a study that examined what happened to the utilization of Medicaid beneficiaries, eligible under Aid to Families with Dependent Children, who were mandatorily enrolled in several capitated alternatives in the Kansas City area. Their experience is contrasted with that of a comparison group selected from the St. Louis area. The types of plans analyzed include those sponsored by hospitals, neighborhood health centers, HMOs, and private physicians (IPAs). With the exception of emergency room use, all plans controlled utilization equally well. Results are explained in light of their management and policy implications. PMID- 10107387 TI - Hospital nursing technical efficiency: nurse extenders and enhanced productivity. AB - Nurse staffing patterns have come under increased scrutiny as hospital managers attempt to control costs without harming service quality or staff morale. This study presents production function results from a study of nurse output during the period 1985-88. The results suggest that productivity varies widely among hospitals as a function of staffing patterns, methods of organization, and the degree of reliance on nurse extender technicians. Nurse extenders can enhance the marginal value product of the most educated nurses as the RNs concentrate their workday around patient care activities. The results suggest that nurse extenders free RNs from the burden of nonnursing tasks. PMID- 10107388 TI - Using matrix organization to manage health care delivery organizations. AB - Matrix organization can provide health care organization managers enhanced information processing, faster response times, and more flexibility to cope with greater organization complexity and rapidly changing operating environments. A review of the literature informed by work experience reveals that the use of matrix organization creates hard-to-manage ambiguity and balances of power in addition to providing positive benefits for health care organization managers. Solutions to matrix operating problems generally rely on the use of superior information and decision support systems and extensive staff training to develop attitudes and behavior consistent with the more collegial matrix organization culture. Further improvement in understanding the suitability of matrix organization for managing health care delivery organizations will involve appreciating the impact of partial implementation of matrix organization, temporary versus permanent uses of matrix organization, and the impact of the ambiguity created by dual lines of authority upon the exercise of power and authority. PMID- 10107389 TI - The Planetree Model Hospital Project: an example of the patient as partner. AB - The Planetree Model Hospital Project at Pacific Presbyterian Medical Center in San Francisco uses a patient-centered philosophy to incorporate the patient as a partner in the care process. This article describes the Planetree unit and discusses two aspects of the program--training patients to be partners and increasing nurse satisfaction. Such programs have the potential for improving the health outcomes of patients and aiding hospitals by assuring quality of care with greater patient participation, by improving public relations, and by promoting staff satisfaction. PMID- 10107390 TI - Concerns of a pediatric hospital's P & T Committee: quality care emphasized over cost considerations. AB - One of the greatest challenges faced by the P & T Committee at Children's Hospital of Denver--a full-service, regional pediatric referral center--is the absence of pharmacologic and pharmacokinetic data for many drugs that are on the market for the treatment of adults but are unapproved for pediatric use. To acquire the needed information, Children's Hospital will rely on its P & T Committee to conduct numerous drug usage evaluations. In addition, the committee is undertaking a cooperative data-exchange venture with other children's hospitals across the U.S. and Canada. Although cost issues must be addressed at Children's Hospital, issues such as quality of care--and even how various formulations taste--are top priorities at this hospital. PMID- 10107391 TI - Drug usage evaluation of aminoglycoside-induced nephrotoxicity in a community hospital. AB - A DUE was conducted at this institution to determine the incidence of aminoglycoside-induced nephrotoxicity. The charts of all patients (113) who received an aminoglycoside during the first quarter of 1989 were reviewed. Information gathered included patient age, aminoglycoside used, loading and maintenance doses, serum peak and trough concentrations, changes in serum creatinine during aminoglycoside administration, and culture and sensitivity results. Physicians were inconsistent in prescribing loading doses, while all patients dosed by the pharmacy received an initial dose of 1.5 to 1.75 mg/kg of ideal body weight for gentamicin and tobramycin. Ninety percent of maintenance doses were calculated by the pharmacy. All patients had serum peak concentrations between 3 and 10 micrograms/ml, and only three patients had serum trough concentrations greater than 2 micrograms/ml. No patient demonstrated changes in serum creatinine suggestive of clinically apparent nephrotoxicity. This study suggests that with routine pharmacist intervention (via a pharmacist-managed dosing service), aminoglycosides can be prescribed with a low incidence of nephrotoxicity. PMID- 10107392 TI - Assuring safe use of parenteral dosage forms in hospitals. PMID- 10107393 TI - Protocols for pharmacists' intervention in a 160 bed hospital. AB - The structure of many hospital pharmacy departments has become decentralized in order to provide pharmacists and other health care professionals with access to patient records. This change in departmental structure decreases the manager's ability to supervise the clinical activities of staff pharmacists. A policy for pharmacist intervention was developed by the pharmacy department. The policy identifies actions to be taken in specific situations, thus serving to standardize care. PMID- 10107394 TI - Resources for pediatric drug information. AB - Finding information on the use of drugs fro infants and children is becoming easier with the publication of excellent resources for pediatric and neonatal drug information. Useful pediatric texts and journals are listed. Texts are graded A and B. Category A books would be useful to include in a basic pharmacy library; Category B books are more comprehensive but expensive, or texts that are not as highly recommended as those in Category A. Some of the resources listed include: (1) Pediatrics--Nelson Textbook of Pediatrics, Rudolph's Pediatrics, Current Pediatric Diagnosis and Treatment, Manual of Pediatric Therapeutics; (2) Dosage Guides--The Pediatric Drug Handbook, Harriet Lane Handbook, Problems in Pediatric Drug THerapy; (3) Intensive Care--Textbook of Pediatric Intensive Care; (4) Infectious Disease--Report of the Committee on Infectious Diseases, Pocketbook of Pediatric Antimicrobial Therapy; (5) Poisoning--Handbook of Poisoning, Medical Toxicology; (6) Parenteral Nutrition--Manual of Pediatric Parenteral Nutrition; (7) Pregnancy and Lactation--Drugs in Pregnancy and Lactation; (8) Compounding--Handbook on Extemporaneous Formulation; (9) IV Administration--Guidelines for Administration of Intravenous Medications to Pediatric Patients; (1) Neonatology--Schaffers Diseases of the Newborn, Neonatology, Basic Management, On-Call Problems, Diseases, Drugs, Drug Therapy in Infants; (11) Pediatric Journals--Pediatrics, Journal of Pediatrics, American Journal of Diseases of Children, Pediatric Infectious Disease Journal, Pediatric Alert, Clinics in Perinatology, Pediatric Clinics of North America, Pediatric Clinical Oncology Journal, and Pediatric Surgery. PMID- 10107395 TI - Pharmacy protocol for adjusting patient-controlled analgesia. AB - The use of patient-controlled analgesia (PCA) to manage pain post-operatively is becoming increasingly popular. The potential for pharmacist involvement is larger. Traditional areas of pharmacy involvement include PCA pump evaluation and selection, choice of narcotic-analgesic to be used, education of other health care professionals on PCA use, and development of PCA protocol guidelines. Monitoring post-operative pain and adjusting the PCA dosage are not traditional areas of pharmacist involvement. The purpose of this report is to describe a protocol which allows hospital pharmacists in an inpatient setting to adjust the PCA dose so that postoperative pain relief is maximized and sedation is minimized. PMID- 10107396 TI - The impact of the Health Care Quality Improvement Act on peer review. PMID- 10107397 TI - Manpower shortages in radiological technology and sonography. PMID- 10107398 TI - Health care facilities may ask staff about AIDS status. PMID- 10107399 TI - Proposed Medicare and Medicaid exclusion regulations loom. PMID- 10107400 TI - FTC challenge to nonprofit hospital mergers continues. PMID- 10107401 TI - Is physician refusal to deal with CRNAs (certified registered nurse anesthetists) an antitrust violation? PMID- 10107402 TI - Protecting hospitals from judicial narrowing of state peer review statutes. PMID- 10107403 TI - Continuity and change in preferred provider organizations. AB - This paper presents the results from a national survey of preferred provider organizations (PPOs) that was conducted in 1988. It is based on telephone interviews conducted by the authors with executives in over 170 PPOs in the United States. We compare the survey results with those obtained from similar surveys conducted in 1985 and 1986, allowing us to assess the extent to which PPOs have grown and changed. We found that PPOs have continued to grow at an extremely rapid rate. During the Summer and Fall of 1988, the time in which the survey took place, 37.6 million people were eligible to use PPO benefits, compared to the 16.5 million figure we obtained two years earlier. We did not find, however, that PPOs are moving in the direction of providing more innovative forms of health care cost containment. Most PPOs still rely on discounts from providers and utilization review to achieve savings. There is little trend towards using incentive reimbursement techniques and choosing preferred providers that have shown themselves to be cost-efficient. We conclude that in the coming years PPOs must demonstrate the ability to control rising health care costs. To accomplish this, they will need to put more pressure on providers to use resources more sparingly. Otherwise, they may lose their market share to other forms of managed care. PMID- 10107404 TI - Resource management in New Zealand hospitals: the RUS (resource utilization system) system--an illustration of its applications. AB - This study demonstrates a potential application in the planning and policy area of a resource management system (known as the Resource Utilisation System (RUS)) first introduced into New Zealand in 1987 and now becoming the definitive resource management tool in the New Zealand public hospital sector. A retrospective cohort of 193 individuals (mean age 60.2 years, 73% males) admitted to Dunedin Public hospital with their first acute myocardial infarction in 1978 was followed through for 10 years in order to describe their inpatient resource utilisation as well as their morbidity and mortality experience. The cumulative mortality for the group over 10 years was 57%. The potential years of life lost (PYLL) amounted to 1340 years, or 6.9 years per person. The overall inpatient resource utilisation amounted to $2,317,300 for the whole group, or $12,006 per person (1988 NZ dollars) over the 10 years follow-up. PMID- 10107405 TI - Awareness of an AIDS campaign directed at Norwegian adolescents. AB - Awareness of a condom campaign directed at Norwegian adolescents was studied in terms of individual characteristics and social processes. The material comprised a representative sample of 3000 Norwegians aged 17 through 19 years. The response rate was 60.9%. Data were collected by self-administered, anonymous, questionnaires. The campaign consisted of five different elements. The awareness of the elements varied between 50% and 9%. Forty-eight percent reported awareness of at least one element. Six background variables included in a multiple regression model explained only 6% of the variance in awareness of the campaign. In order to illustrate social processes leading to awareness of the campaign, a path model was constructed. Coitus experience, educational aspirations and sex seemed to influence awareness of the campaign through three different paths, in which IPC was included in each path as a intervening variable. Thus, through indirect processes, IPC was mediating the main effects of the three independent variables on awareness. IPC served as a mediating variable between personal characteristics and awareness of the campaign. The results from this study indicate that increasing the adolescents' ability to communicate about sexual topics, are important educational tasks for future prevention of HIV/AIDS. PMID- 10107406 TI - Hospital cost for patients with HIV infection in a university hospital in The Netherlands. AB - Precise data on the utilization of health care facilities by HIV infected patients are generally not available. Nor are there data on the related cost, effectiveness and efficiency of the treatment provided. This is due mainly to the lack of a suitable method for recording demographic, medical and financial data on individual patients in hospitals. For this reason we have been developing a system of data collection, which provides a detailed cost record of each patient. The application of this system for 52 patients with HIV infection treated in a university hospital over a two-year period showed that for a patient with AIDS the mean cost of inpatient and outpatient hospital services was $19,507 per person-year. For patients with HIV infections other than AIDS the mean costs ranged from $1,769 for CDC III patients to $2,064 for CDC II patients (expressed in 1987 US dollars). Continued operation of the registration system will make it possible to analyze the causal background of costs as well as the cost effectiveness of the treatment. PMID- 10107407 TI - The health situation of Turkish inhabitants of Rotterdam and Antwerp. AB - Both in Antwerp (Belgium) and in Rotterdam (The Netherlands) a health interview survey was held among Turkish and autochthonous (adult) citizens. In this article the data on the Turkish respondents in Antwerp and Rotterdam are compared. Turkish respondents in Antwerp, in general, give more positive answers to most questions that concern their own health, especially to those questions that concern the more 'subjective' indicators of health (a general rating of the own health and a questionnaire that consists of 'vague' physical complaints). Chronic diseases are reported slightly more often by Turkish women in Antwerp. Turkish people in Rotterdam visit a doctor far more frequently than the Turkish people in Antwerp. Some possible explanations for these differences are given. Because of the absence of 'hard' data these explanations are of a speculative nature, and can be seen as suggestions for further research. PMID- 10107408 TI - In-house team remodels medical records area--doing one half at a time. PMID- 10107409 TI - Controlling dryer make-up air key to energy saving. PMID- 10107410 TI - 10 steps for developing a telecommunications RFP. PMID- 10107411 TI - Should you computerize the space-management function? PMID- 10107412 TI - Leadership depends on how well you "sell" ideas. PMID- 10107413 TI - Grants cover energy-saving capital improvement. PMID- 10107414 TI - Central service pay range: $20,775 to $37,019. PMID- 10107415 TI - Diversion of emergency patient leads to large punitive damage award. PMID- 10107416 TI - "Raiding" provision upheld by court. PMID- 10107417 TI - Access to sensitive patient records explored. PMID- 10107418 TI - Exposing four myths of strategic planning. AB - Some assumptions of planners are no longer valid, and the tools they use to formulate strategy may need updating. The author investigates those assumptions and suggests a few techniques to supplement a planner's toolbox. PMID- 10107419 TI - Learning from HMOs. AB - Successful HMOs share essential characteristics that need to be incorporated more fully and more widely in the future. PMID- 10107420 TI - Home care past and future. AB - Uniquely American, care for patients at home offers an increasingly effective way to widen access and control costs. PMID- 10107421 TI - To save and to let go. AB - Recognizing what's right with the U.S. health-care system is as helpful in shaping reform as pointing out what's wrong. PMID- 10107422 TI - The people's will. AB - While Americans say they don't like the "system" itself, they give high marks to their own doctors, nurses and hospitals. PMID- 10107423 TI - Hospitals and vendors expect to see higher freight charges. PMID- 10107424 TI - Iv solution prices to rise 4%-8%. PMID- 10107425 TI - Group purchasing organizations target hospital CEOs to gain membership loyalty. PMID- 10107426 TI - Hospital with a well-planned, efficient laundry saves on linen purchases and tracks inventory. PMID- 10107427 TI - Hospital materials managers foresee price hikes of 1%-10% for disposable adult diapers. PMID- 10107428 TI - Consignment offers hospitals cost benefits. PMID- 10107429 TI - HMM pricing index. Med-surg prices up 0.8% in the second quarter. PMID- 10107430 TI - HMM price watch. Purchasing managers' index continues 3-month drop, falling 6% to 44.4 in September from 47.0. PMID- 10107431 TI - Hospital materials managers need to be aware of liability for equipment shipped to hospitals. AB - A contract for the purchase of hospital equipment provided for shipment free-on board destination. The equipment arrived via common carrier and was signed for at the unloading dock. When uncrated, concealed damage was discovered and the supplier was notified. The supplier offered to repair the equipment at its expense. The hospital would rather have a replacement unit. The hospital notified the supplier that the equipment was being returned at the supplier's expense. The supplier contended that this couldn't be done as title passed to the hospital upon shipment and that it had been accepted by the hospital when signed for at the unloading dock. In this dialogue, Dr. Decker discusses the legal issues raised in this query from a reader. PMID- 10107432 TI - Materials managers deem vendor consulting advice acceptable for some materials area. PMID- 10107433 TI - Hospital capital payment debate takes a new twist. PMID- 10107434 TI - CHA offers a shared data base. PMID- 10107435 TI - Tradition in transition. What it means to be a Catholic healthcare facility today. AB - Until recently we rarely questioned whether Catholic healthcare facilities would remain Catholic. New types of business ventures, however, have changed this. More important, the traditional elements that identified a facility as Catholic no longer seem enough to sustain the ministry. What are the distinct qualities that identify a healthcare facility as Catholic? Three elements are crucial to successfully defining any identity: distinctiveness, relatedness, and richness. To determine the meaning of Catholic identity, we must look at these elements from the perspective of the changes occurring in the Catholic Church and in healthcare in the United States. In light of this we can identify distinctive features that characterize U.S. Catholic healthcare. These components include understanding healthcare as a ministry, being guided by Church teachings, collaborating with others, participating in care for the world community and the poor, giving holistic care, promoting self-determination, and respecting and protecting human life while accepting suffering and death. Only in their totality, however, can these components set forth a vision rooted in our past that speaks to the realities of the present and calls us forward to a future where greater justice will reign. PMID- 10107436 TI - On-line, on time. A centralized laboratory information system speeds the results. AB - Catholic Medical Center of Brooklyn and Queens (CMC), Jamaica, NY, is a multihospital system that is concerned with providing a more cost-effective method of delivering healthcare in an urban environment. To reach this goal CMC centralized its laboratory services to save time, cut costs, and ultimately improve patient care. The centralized laboratory's manual delivery and tracking system put in place at first appeared to hinder the success of the centralized laboratory concept. Through a detailed planning and review process, CMC then implemented a multihospital laboratory information system to allow the centralized laboratory (1) to electronically access patient information from any on-line hospital and (2) to transmit test results back to the originating hospital. CMC believed the automated system would improve the quality of care, reduce the number of duplicated tests, eliminate late charges, and reduce the length of a patient's hospital stay. Since the implementation of the laboratory management system, its member hospitals agree that CMC has finally begun to realize the full benefits of its centralized laboratory services. PMID- 10107437 TI - After Cruzan. The U. S. Supreme Court's decision settles the case but raises new questions. AB - In its Cruzan v. Director, Missouri Department of Health, decision the U.S. Supreme Court addressed only states' authority in the refusal of medical treatment. But the case itself drew national attention to the issue, and physicians and healthcare facilities should expect to see living wills and durable powers of attorney increase as a result. Legal concerns will also arise as a result of misconceptions regarding the law. The Court was careful to qualify and limit its support of the Missouri Supreme Court's decision. As opposed to the latter's nearly outright denial of an individual's right to refuse medical treatment, the U.S. Supreme Court's majority opinion asserted that a competent person has a "constitutionally protected liberty interest in refusing unwanted medical treatment." And although the Court upheld Missouri's requirement that there be "clear and convincing evidence" of an incompetent patient's previously expressed wishes before treatment can be discontinued, it did not make such evidence mandatory for states with different law. Finally, in a separate concurring opinion Justice Sandra Day O'Connor asserted that a patient-designated proxy could be an acceptable "source of evidence" of a patient's intent. If the proxy does in fact have some constitutional status, this status should motivate state courts and legislatures to recognize the practice. PMID- 10107438 TI - The ethics of Cruzan. Families, not states, should make treatment termination decisions. AB - Although the U.S. Supreme Court justices frequently alluded to ethical concepts in delivering their opinions in the Cruzan decision, no clear or consistent ethical framework supported this jargon. The decision, in fact, resolves none of the ethical and professional questions that initially brought the case to the courts. The various arguments about whether and when it is ethical to terminate treatment are the first source of ethical confusion in questions about death and dying. Individuals arriving at the same conclusion can begin from significantly different ethical principles. An added complexity arises as a result of differences among medical professionals regarding what constitutes a fatal pathological condition. A resolution of these differences would clarify a number of ethical questions. The biggest problem with the Missouri Supreme Court's decision was that it gave absolute precedence to the state's interest in preserving life, excluding quality-of-life considerations and disregarding personal, familial, and professional values that should have affected the decision. In fact, since a medically well-informed family is in most cases in the best position to make a decision that would conform with a family member's wishes, applying the "clear and convincing" evidence standard in the Cruzan case shifts the burden of proof to the wrong party. Instead, the state should be obliged to give convincing evidence of why it has intervened in a decision for which the patient's family and physician should have authority. PMID- 10107439 TI - Helping people prepare. Catholic healthcare facilities can give patients advice on advance directives. AB - Although state courts have tended recently to allow surrogates to make healthcare treatment decisions for incompetent patients, the Missouri Supreme Court went against the trend by denying Nancy Cruzan's family the right to withdraw her artificial nutrition and hydration. The U.S. Supreme Court upheld the Missouri decision. At the same time, however, the Court's opinions strongly implied that it would uphold other state courts' decisions affirming the right of surrogates to make treatment decisions for incompetent patients. In his majority opinion, moreover, Chief Justice William Rehnquist upheld a competent person's liberty interest in refusing medical treatment, including artificial nutrition and hydration. Catholic healthcare facilities should be prepared to provide information to the many patients and long-term care residents seeking advice on advance directives as a result of the Court's ruling. Because living wills are proving to be less effective than many at first thought they would be, providers can best help individuals by giving them information on preparing proxy documents. PMID- 10107440 TI - Does your hospital have an admissions policy on living wills? PMID- 10107441 TI - Flexible telecommunications. An enhanced system can cut costs and generate revenues. AB - Hospitals can cut costs and even generate new revenues by updating their telecommunications systems. Hospitals with sophisticated systems can cut costs in a number of ways. They can bypass local telephone service, use common carrier services, integrate internal transmission systems, establish private networks, and avail themselves of other specialized, cost-reducing services. A sophisticated system can also enable a hospital to generate revenue by reselling excess long-distance and local service, becoming a common carrier, installing pay telephones, and providing other services. Facilities or systems choosing to develop a large, complex system must, however, address certain legal and managerial issues. Not-for-profit organizations must, for example, determine whether selling services will endanger their tax-exempt status. A number of other legal issues will also arise. In addition, facilities or systems planning a large telecommunications upgrade should assemble a knowledgeable, experienced telecommunications project team early. PMID- 10107442 TI - Genetic counseling in Catholic hospitals. Facilities must provide guidance to keep pace with new knowledge and techniques. AB - As advances in the knowledge of human genetics change the practice of medicine, Catholic healthcare facilities will, according to ethicists, be increasingly obliged to provide genetic counseling services to their patients. Facilities should ensure that counselors make genetic information available in a context in which no pressure, overt or subtle, is exerted to use that information in a way that may violate an individual's value system. Some hospitals may, for example, set up a separate genetic counseling department, which does not diagnose or treat genetic disorders but does facilitate access to these treatments when patients need them. Effective counseling requires accurate, current knowledge about tests and treatments, as well as about theological discussions and Church decisions on the subject. Counselors also need to be aware of some typical misconceptions people have about genetic disease. Catholic hospitals should also work with other Catholic organizations to influence legislation addressing human genetic issues, especially when such legislation addresses reproductive rights. PMID- 10107443 TI - COBRA takes another bite. PMID- 10107444 TI - Services for seniors. PMID- 10107445 TI - Banishing ghosts and fears. PMID- 10107446 TI - Promoting health in the next decade. PMID- 10107447 TI - A charter for success. PMID- 10107448 TI - Oregon Act to allocate resources more efficiently. The proposal would guarantee healthcare access to all. PMID- 10107450 TI - Transcending trauma: the growing focus on rehabilitation. PMID- 10107449 TI - The proposal will deny services to the poor. The Oregon Act is ethically flawed. PMID- 10107451 TI - Healing and hope. A multiservice healthcare provider gives elderly patients a chance to return to the mainstream. AB - Responding to a mission commitment to serve the elderly, Mercy Medical, Daphne, AL, has developed a multiservice rehabilitation program that includes inpatient and outpatient care, as well as residential and home health services. Mercy Medical staff assume that even elderly patients who have suffered a catastrophic injury or illness can return to mainstream life--if they can participate in an effective medical treatment program. The Mercy Medical philosophy is to encourage patients to take an active role in their treatment programs and to stress from the beginning that patients are expected to recover. The staff also encourages patients to take risks that might speed their recovery, and the staff itself is willing to experiment with more effective ways of increasing patients' functional ability. Like most rehabilitation programs, Mercy Medical uses an interdisciplinary approach, with a physician heading a staff team that includes nurses, social workers, pharmacists, and physical, occupational, and respiratory therapists. PMID- 10107452 TI - A growth opportunity. Catholic hospitals can improve their mission and margin by developing rehabilitation services. AB - Developing rehabilitation services should be an attractive diversification strategy for Catholic hospitals during the 1990s. Although the number of inpatient rehabilitation providers more than doubled during the 1980s, many markets remain underserved. Rehabilitation units can enable facilities to generate revenues and, at the same time, better serve the community. A number of other factors make creating rehabilitation programs a sound venture: Hospitals can choose from among a variety of product lines when deciding which services to include; reimbursement mechanisms are at present favorable to rehabilitation; businesses are making increasing use of these services; the segment of the population that most often requires rehabilitation services is growing; and many acute care hospitals have a ready-made source of rehabilitation referrals in their occupied beds. For Catholic healthcare facilities now offer teritary or subspecialty programs and have developed sophisticated ancillary services, they are well placed to add rehabilitation programs. PMID- 10107453 TI - Facts and figures. How Catholic rehabilitation services compare with others. PMID- 10107454 TI - Durable data. A rehabilitation center collects and distributes information for functional assessment and program evaluation. AB - As physical rehabilitation services have expanded nationwide, both payers and providers have increasingly felt the need for adequate outcome data. In 1988 organizers at Marianjoy Rehabilitation Center, Wheaton, IL, launched the Center for Rehabilitation Outcome Analysis-a service for rehabilitation facilities that want to develop in-house functional assessment and program evaluation systems. The center has focused on meeting three major needs of rehabilitation providers: outcome data analysis and reporting, education, and research. It uses the Patient Evaluation and Conference System for a variety of needs from planning programs to establishing functional outcome expectations. The center also educates participants on the use and meaning of outcome data. In addition, it has enlisted the help of the profession's behavioral scientists, evaluators, and statisticians to scrutinize and enhance program evaluation and measurement models. PMID- 10107455 TI - A continuum of rehabilitative care. A day hospital extends patients' lifeline to the medical center. AB - Alexian Brothers Medical Center in Elk Grove Village, IL, carries out its commitment to a continuum of care through the Alexian Brothers Rehabilitation Center and its Physical Rehabilitation Day Hospital. The day hospital treats patients who need rehabilitation but do not need around-the-clock hospitalization. The day hospital individualizes its intensive comprehensive, pulmonary, and arthritis programs. An important component of these outpatient programs is education and preventive techniques to reduce the need for repeat treatment. Only medically stable patients are transferred to the rehabilitation center, where an interdisciplinary team helps them achieve the maximum function possible within the limits imposed by their disabilities. The rehabilitation center sponsors a community support group for young adults who have sustained head injuries and a group for alumni of the center. Through its home healthcare program and its adult day care program, the medical center offers a variety of treatment delivery methods that enhance the center's continuum of care. PMID- 10107456 TI - Effective physician credentialing. Properly monitoring medical staffs can protect hospitals from liability. AB - Healthcare facilities today are finding themselves increasingly liable in malpractice suits if they have hired incompetent physicians or allowed them to remain on the medical staff. Thus appropriate processes for physician credentialing are important. The hospital medical staff has the authority to evaluate medical staff membership status and clinical privileges and to take disciplinary and corrective action. If the medical staff fails to do its job, however, the hospital governing board is responsible for making sure the credentialing process is carried out properly. The same rules apply to the reapplication process. The hospital must associate its credentialing process with its prevailing concern for high-quality patient care and document that ideal. Preservation of market share and elimination of competition must never enter into the credentialing process. Well-framed hospital bylaws will help provide protection from liability, if they are followed correctly. If a hospital deviates from its bylaws when processing an application or granting clinical privileges, it risks a lawsuit. Congress has passed the Health Care Quality Improvement Act of 1986-an act that not only protects patients from incompetent practitioners but also can help limit facility's risk of liability by requiring facilities and third-party payers to report any adverse actions taken against physicians. The National Practitioner Data Bank is an information clearing-house opened in September 1990 that hospitals must use to report and obtain professional information about physicians. PMID- 10107457 TI - Data bank has operational impact. Proper peer review can protect hospitals from antitrust and defamation suits. AB - The Health Care Quality Improvement Act of 1986 can help protect medical professionals and healthcare facilities from antitrust and defamation claims and other forms of litigation arising from the peer review process. Some hospitals may need to make major changes in their peer review activity as a result of the act. The healthcare entity, not the physicians involved in peer review, has the burden of complying with the provisions of the act. Failure to comply with the act can lead to loss of immunity from damages, fines, and potential exclusion from the Medicare program. The potential for liability has sparked a need for hospitals to reexamine and possibly reorganize medical staff and update procedures and related governing documents. Healthcare entities may consider changes such as implementing a director of medical affairs function, choosing medical staff for multiple-year terms, and centralizing physician review files. In the 1980s many hospitals created quality assurance and risk management programs. Risk managers need to share data with quality assurance personnel, who must in turn share the information with medical staff involved with credentialing, peer review, and medical affairs management. Legal counsel will need to be familiar with the legalities of the act, as well as the hospital's peer review procedures and operations. General legal counsel should oversee coordination of hospital proceedings and assist in educating staff on the legalities of peer review. PMID- 10107458 TI - Getting the word out. PMID- 10107459 TI - Sharing a good-bye. PMID- 10107460 TI - Electronic healthcare records: a discourse. PMID- 10107462 TI - The malpractice crisis in obstetrics. PMID- 10107463 TI - The Virginia story: "no-fault" malpractice insurance. PMID- 10107461 TI - Obstetrics: strategic centerpiece of "full service" hospitals in the 1990s. PMID- 10107464 TI - Warning! Payers and regulators are targeting obstetrics. PMID- 10107465 TI - Hospital image and the positioning of service centers: an application in market analysis and strategy development. AB - The research confirms the coexistence of different images for hospitals, service centers within the same hospitals, and service programs offered by each of the service centers. The images of individual service centers are found not to be tied to the image of the host facility. Further, service centers and host facilities have differential rankings on the same service decision attributes. Managerial recommendations are offered for "image differentiation" between a hospital and its care centers. PMID- 10107466 TI - Segmenting the antihistamine market: an investigation of consumer preferences. AB - The authors combine conjoint analysis and contingent valuation into a single model to estimate the value of product attributes for antihistamine drugs. One hundred forty-three allergic rhinitis suffers were examined. The results show evidence of validity in the data. Cluster analysis reveals five segments of patients with various patterns of preference for product attributes. PMID- 10107467 TI - Self-monitoring and relative perceived power as determinants of communication evaluation in a medical dyad. AB - Communication between a physician and patient is imperative for the successful delivery of health care services. Patient satisfaction with the communication process is part of the total health care service evaluation. Research has shown that patient satisfaction may make the difference between effective and ineffective health care. Consequently, health care marketers must understand the determinants of successful communication in order to meet patient health care needs most effectively. PMID- 10107468 TI - The effects of mortality cues on consumers' ratings of hospital attributes. AB - A 2 x 2 x 2 factorial study with two levels each of price, quality, and mortality data was undertaken to determine consumers' reactions to hospital advertisements that include mortality statistics. Both as a simple effect and in selected interaction effects, mortality statistics are found to be significant to hospital choice, measured in terms of intentions and attitudes. PMID- 10107469 TI - Variables affecting pharmacists' willingness to accept third-party prescription contracts: a conjoint analysis. AB - Pharmacists were asked to rate their willingness to accept 12 hypothetical third party prescription contracts offering different combinations of dispensing fees, average wholesale price levels for the ingredients, and payment lag times. Dispensing fee explained the most variance in the dependent variable of willingness to accept third-party contracts, followed by payment lag time and average wholesale price level. PMID- 10107470 TI - A comparison of retail dental center and traditional dental center patrons. AB - Retail dental centers have emerged as an alternative delivery system for dental care. Previous research examining retail dentistry has focused on patients of specific retail dental centers in limited geographic areas. The authors extend past efforts by comparing the perceptions and demographic and patronage characteristics of retail and traditional dental center patients in a nationwide survey. PMID- 10107471 TI - Hospital finance and marketing. AB - Objection is taken to descriptions of finance and marketing in health care institutions as being in conflict. The author explains the financial contributions of marketing in areas such as pricing and investment. He also notes the marketing concerns of finance that make these two disciplines inseparable in well-functioning, competitive organizations. PMID- 10107472 TI - Violating assumptions of statistical procedures: JHCM reporting guidelines. AB - JHCM authors have a responsibility to provide enough information for the reader to evaluate reported study conclusions and implications adequately, and to do so without overshadowing attention to statistical detail. Guidelines are presented for discussing the assumptions and requirements underlying the statistical procedures used, including what to report when there are violations. PMID- 10107473 TI - The growing threat of AIDS: how marketers must respond. AB - The authors attempt to expand the dialogue between the health care industry and the marketing discipline on perhaps the most crucial issue facing health care marketers today--AIDS. They offer a critique of a JHCM article by Ronald Paul Hill. Their intent is to prompt a reconsideration of the normative propositions Hill suggests for health care marketers in response to the AIDS crisis. PMID- 10107474 TI - Factors influencing physician choice of an outpatient surgery and testing facility. AB - Factors that influence physician choice to use the outpatient satellite facility of a major pediatric medical center are examined. Results are reported separately for surgeons' use of outpatient surgery suites and general pediatricians' referral to testing services. The findings support the importance physicians assign to high quality technical/medical support services when making decisions about choice of service provider. They also support the importance of patient preferences in choosing an outpatient satellite facility. PMID- 10107475 TI - Comment: American Stores and private antitrust actions against hospital mergers. PMID- 10107476 TI - AHA files amicus in Austin v. McNamara. PMID- 10107477 TI - The real world of malpractice tort reform. Part I. PMID- 10107478 TI - Survey of constitutional arguments in medical malpractice award limit cases. PMID- 10107480 TI - A critical appraisal of the Navajo health care system. AB - The purpose of this study is to assess the health needs of the Navajo Indians of North America, and the appropriateness of the health care services provided by the Navajo Health Care System with respect to these health needs. Our study is based on the analysis of the secondary socioeconomic and health related data collected and compiled in the Navajo area, and on the interviews conducted among health care professionals and administrators working in the Area. The 'Q index' was used for priority ranking of the most prevalent diseases. Appraisal is based on the holistic health concept components. Navajo Indians have not yet reached the health status of the general US population. In spite of the fact that the Indian Health Services has decreased the disparity between the Indians and the US population in general, especially regarding communicable diseases, other more complex health problems created by biculturalism and the on-going acculturation exceed the limits of the Navajo Health Care System which is basically oriented toward medical care. Alcoholism and alcohol abuse, inadequate nutrition and lack of geographic and socio-organizational accessibility are the main risk factors in the Area. This situation is further aggravated by economic problems and the high unemployment rate of the Navajo Indians. PMID- 10107479 TI - Organizational development and privatization: a Bolivian success story. AB - This article presents a case study of a US Agency for International Development sponsored privatization effort in Bolivia. This privatization effort differs from AID's more common approach in that rather than merely helping already existing organizations to expand, this project has created a new organization. More ambitious and encompassing, this approach is also preferable because it directly addresses one of the most serious bottlenecks to economic development, viz., organizational development. The article describes the evolution of PROSALUD, a private, non-profit network of 17 community-sponsored health centers. The article describes factors and characteristics which have either conditioned or have directly contributed to PROSALUD's success. First, PROSALUD's health care environment is analysed, starting with a broad brush profile of select characteristics and trends which exist throughout the health sector of Bolivia, then narrows the focus to the local health sector. The structure and operations of PROSALUD are then analysed, focusing on the organization's managerial practices and financing and the series of tradeoffs it has been forced to strike: in its pricing strategy, between striving for financial viability and maintaining access to care; between, on the one hand, responding to community needs and demands and improving coverage by opening more facilities, and, on the other hand, focusing managerial efforts and outreach on a more limited number of clinics and neighborhoods; between providing a socially desirable mix of services -in particular, continuing to provide a great deal of free preventive care--and focusing care on more lucrative curative services; between maintaining commitments to neighborhoods and communities and eliminating the less economically viable (especially rural) clinics. PMID- 10107481 TI - A mobile breast screening project in Scotland: lessons learned for national screening. AB - In 1986, a project was undertaken to determine the feasibility and cost of screening for breast cancer, using single oblique view mammography. Screening was offered to women aged between 40 and 65, on an open access basis, to those living in rural areas near Edinburgh. This article reports on: the logistical difficulties encountered; the costs of mobile screening; a comparison of costs when screening from a static centre; and, identifies factors found to influence attendance rates. The lessons learned from the project were incorporated into the planning of the mobile van operating in the South-East of Scotland Screening Programme, part of the National Breast Screening Programme; comparisons, where possible, have been included. PMID- 10107482 TI - New concepts in health care: some preliminary ideas. AB - Health care discussions in many countries tend to focus on cost containment without taking into account the problem of quality of care. The starting point for our ideas is the description of quality as the optimal relation between care demander and care provider. The difficulties in assessing quality of care are outlined. The question remains which health care model offers the best opportunities to have both high quality care and affordable costs. A proposal is made for a model in which the care demander and care provider, i.e. the client and physician, are natural allies. A special role is fulfilled by the family physician: a key role, as case manager, as gatekeeper. Special attention should be directed towards the financial consequences. It is proposed that small-scale experiments should be started to evaluate the model advanced in the text. PMID- 10107483 TI - Put the stress on recognition, appreciation and acceptance. PMID- 10107484 TI - Building self-esteem and personal enrichment in the workplace. PMID- 10107485 TI - Burnout: an organizational response. PMID- 10107486 TI - Strategic planning in long-term care organizations. AB - This article has endeavored to show that strategic planning is applicable to even the smallest, least complex organization. Strategic planning does not have to be, nor should it be, an extra burden foist on an already overworked staff. It can be an important, supportive element of the management process. Inclusion of strategic planning in an organization's routine management practice can help to perpetuate the organization. As one author (Infield 1989) recently noted, "In the current competitive health care environment, strategic planning capabilities may determine the survival of many long-term care programs and services." PMID- 10107487 TI - The gerontological nurse practitioner in the nursing home: 12 years later. AB - Comparing graduates of a GNP program 12 years ago with those graduating from a recent program revealed that GNPs are now staying in their roles. This is in spite of a number of barriers to practice over the years. GNPs also are continuing to work in nursing homes. At the University of Washington, we believed that training and hiring GNPs was one way to improve the care of patients in nursing homes. Our program was designed to meet that goal. That it has been achieved is evidenced by the low turnover and the GNPs' satisfaction in their roles. States should therefore encourage nursing homes to hire GNPs, as in Washington. As the clinical arm for the director of nursing service, and working together with the physician, the GNP can improve patient care as never before. PMID- 10107488 TI - Feeling good: humor in the facility. PMID- 10107489 TI - The relationship between work environment and burnout in nursing home employees. PMID- 10107490 TI - Special section: Impact of managed care on the private hospital. PMID- 10107491 TI - Myths and mystifications of managed care. AB - This paper reviews some of the major conceptual "myths" that have been propagated to support the cost containment activity referred to as "managed care." It discusses the facts and logic inherent in these myths and examines the implications such myths have for compromising the integrity of clinical care. PMID- 10107492 TI - Linking quality assurance and quality of care. AB - Since the introduction of the problem-oriented record into hospital work nearly 30 years ago, psychiatry has struggled to adapt it to the complex bio-psycho social determinants of illness and therapeutics. This struggle has been especially difficult with the seriously and persistently ill patient who requires more than a minimal hospital stay. Justification of the work with the longer-stay patient has now come under extreme pressure from utilization review, third-party payors and quality assurance, but hospital psychiatrists continue to have the same difficulties with documentation. Based on two years of chart review with clinical teams, principles of psychosocial rehabilitation and a dynamically oriented philosophy of inpatient treatment for the long-term patient, this presentation demonstrates one method for linking problems and goals with length of stay, quality assurance behaviors with quality of care, and integration of the multidisciplinary team into the entire process. PMID- 10107493 TI - Identifying clinical appropriateness in the catastrophic psychiatric case. AB - Catastrophic psychiatric illness has been commonly identified by demographic factors such as cost (greater than $10,000) and length of treatment (greater than 30 days). In order to determine which cases could have been better managed in order to prevent the high cost and long length of treatment, clinical identifiers were formulated by the authors. The authors examined reviews of cases identified by third-party payors and reviewed by psychiatrist reviewers. They found that the majority of the catastrophic cases were not truly clinically catastrophic but were catastrophic in terms of resource utilization. This was due to patient non compliance, poor treatment management and poor benefit management. The authors conclude that catastrophic costs and extended treatment could be prevented, in some cases, through the use of better practice patterns and case management. PMID- 10107494 TI - Synthesis of research on the costs of institutional and community-based care. AB - Cost studies in the long-term care field are reviewed, with emphasis on those relating to people with developmental disabilities. Studies frequently stressed the cost-effectiveness of community programs but often had significant methodological problems. Among the predominant findings in the literature were: 1) the generally lower average costs per client in community programs versus institutional programs; 2) unexplained wide cost ranges in similar community programs; and 3) significant cost shifts among federal, state, and local governments associated with deinstitutionalization initiatives. The implications of these findings for public officials and the advocacy community are discussed. PMID- 10107495 TI - An analysis of financial incentives in the performance contract of Montana. AB - In an effort to contain costs and provide appropriate services, a growing number of states are experimenting with the terms of their fiscal transfers to localities. This paper contains an analysis of the economic incentives present in one such effort, the performance contract of the state of Montana. This contract contains incentives which do not fully support the attainment of a number of possible social goals, but these incentives could be strengthened by some simple amendments to the existing structure. PMID- 10107496 TI - Community mental health: who is being served? What is being offered? AB - Policy changes in the 1980s have altered the financial status of community mental health centers. Directors have operated, in most cases, with fewer resources than in past decades. How have these reduced resources changed the service delivery system and the characteristics of clients being served? To address these questions, a research project including 69 mental health centers from 27 states was conducted in 1987. While most of the originally mandated community mental health services are still provided, consultation, education and prevention services have been cut back substantially or terminated. Revenue-producing programs and time efficient treatment methods are used more frequently. Despite a higher priority given to the chronic mentally ill, community mental health centers are not serving those without the ability to pay in the same numbers as they have in the past. Some thoughts regarding a modification of the community mental health model are offered. PMID- 10107497 TI - The seven elements of RFP evaluation: is an RFP a solution or an added problem? AB - Administrators often receive requests for proposals (RFP), alerting them of the availability of funding. Applying for such funded service programs may or may not be beneficial to the agency the administrator leads. This article suggests a series of seven evaluation procedures for use in determining the potential outcome of securing the proposed program. It is recommended that this evaluation process be considered before the administrator responds to an RFP. PMID- 10107498 TI - An estimate of the lifesaving benefit of child restraint use legislation. AB - This paper presents the first econometric estimate of the lifesaving benefit of automobile child restraint use legislation. In contrast to previous econometric analyses of traffic safety regulations, modified count data models are employed to account for the rarity of childhood fatalities. Results of the modeling suggest that legislation reduces childhood car-occupant fatalities by 39% for infants, and 30% among toddlers. A simple simulation indicates that such legislation is currently saving the lives of about 160 children per year in the United States. PMID- 10107500 TI - The production of health care services and changing hospital reimbursement. The role of hospital-medical staff relationships. AB - The production of health care services has the unique feature that physicians do not face explicit costs for hospital inputs. This paper develops models of the production process given alternative hospital and medical staff relationships, and analyzes the impact of the change in hospital reimbursement under Medicare from a cost-based system to the Prospective Payment System (PPS). A basic theoretical result finds that the switch to PPS forces physicians to alter their input mix, changing both physician and hospital income. The effects of the introduction of PPS on hospital inputs, physician income, and hours of work are empirically examined. PMID- 10107499 TI - Regulatory intensity and hospital cost growth. AB - This article parameterizes and examines the regulatory intensity of New York's all-payer rate setting system. The model, using hospital level data, compares the effects of specific features of rate-setting designed to promote cost containment. Two indicators measuring regulatory intensity were examined; the extent of hospital-specific disallowances, and how frequently the base year was adjusted (the degree of prospectivity). The results indicate that both the degree of prospectivity and the extent of disallowances importantly affect cost growth. Hospitals, when constrained, primarily achieved cost savings through reductions in non-medical personnel. PMID- 10107501 TI - Air pollution, cigarette smoking, and the production of respiratory health. AB - Previous studies of the determinants of respiratory health have treated both smoking and air pollution as being exogenous. Using an instrumental variables approach, we estimate a simple production technology in which smoking is treated as being endogenously determined. Doing so, we find, increases the predicted absolute effects of smoking on respiratory health; relative to air pollution, smoking becomes a more important determinant when it is treated as an endogenous variable. PMID- 10107503 TI - Variations in length of stay. A conditional likelihood approach. PMID- 10107502 TI - Effects of HMOs on the creation of competitive markets for hospital services. AB - Why do health maintenance organizations (HMOs) use particular hospitals, and do they concentrate patients in hospitals where they obtain low prices? We answered these questions with a study of six HMOs in four large metropolitan areas in 1986. A two-part model was estimated for the probability that a hospital would be used and the demand for general inpatient admissions at hospitals that were used. Four staff-network plans in our study do shop for hospital services on the basis of price more than was generally believed. However, two independent practice association (IPAs) plans use more hospitals in the community and do not concentrate patients effectively at hospitals that offer the lowest prices. PMID- 10107504 TI - Child abuse reporting requirements: liabilities and immunities for clergy. AB - Alerts clergy and pastoral counselors to the role of child abuse reporting requirements in their pastoral care and counseling ministries. Outlines the rationale for child abuse reporting statutes, noting particularly the "spiritual healing exception"; and explains how penalties can be imposed for those who fail to comply with statutes. PMID- 10107505 TI - Supplier-induced demand for pastoral care services in the general hospital: a natural experiment. AB - Assesses the effects the elimination of a pastoral care training program and a reduction in staff had on referral rates for pastoral care. Results showed a decrease in referrals initiated by pastoral care staff but an increase in pastoral care referrals initiated by medical staff and patients. Notes that when pastoral care staff were less available, the demand for their services became more apparent. PMID- 10107506 TI - The making of a dictionary: a case study in pastoral care and counseling literature. AB - Tells the story of how the newly published Dictionary of Pastoral Care and Counseling came to be--its origins, principles, and editorial adventures--as a case study toward understanding the contemporary field of pastoral care and counseling in America. PMID- 10107507 TI - Avoiding the traps in managed care contracts. AB - In deciding whether or not to enter into managed care arrangements, physicians must consider a number of important and problematic issues. In this article, the author describes the potential problems and discusses how they can be avoided through careful negotiation and analysis of the managed care contract. PMID- 10107508 TI - Strategies for appeals of PRO payment denials. AB - Review of care furnished to Medicare patients by peer review organizations often results in denials of payment for services found not to be "covered" by the Medicare program. Providers should be aware that they can appeal these denials of payment, and that, at least at present, there is a good chance that such denials can be reversed on appeal. PMID- 10107509 TI - Regulatory agency abuse: the need for protection of physicians' rights. AB - As a result of recently increased regulatory attention, the medical profession has become a heavily regulated "industry" and now must respond not only to the requirements of patients, but also to governmental agencies, insurance providers, and third-party payors. In this article, the author describes the ways in which agencies have abused their regulatory authority and what physicians should do to reverse this attack on their profession. PMID- 10107510 TI - Increasing the supply of organs for transplantation: the role of ethics and law. AB - In the face of constantly escalating shortages of organs and tissues, all options for increasing the supply of transplantable body parts must be explored. To make the current system more effective, donor cards and required request laws should be respected and enforced. Alternatives to the current system, such as incentives for donation and presumed consent laws, must also be carefully considered. Health care professionals, ethicists, and attorneys need to work together to address the issues posed by those medical advances--including the use of living partial organ donors and non-heartbeating cadaveric donors--that promise to increase the supply of transplantable organs and tissues necessary to save lives. PMID- 10107511 TI - Fair hearings for physicians denied participation in managed care plans. AB - As a result of the imminent application of the doctrine of corporate negligence to health maintenance organizations and other providers of managed care, those entities are likely to become much more active in the credentialing processes they undertake. Adversely affected physicians should be entitled to the same procedural protection currently afforded by hospitals, a "fair hearing" that at least provides a notice of charges and an opportunity to respond to the charges. PMID- 10107512 TI - Austin v. McNamara: immunity from suit under the Health Care Quality Improvement Act. PMID- 10107513 TI - Medicare billing for locum tenens prohibited. PMID- 10107514 TI - Don Quixote revises the medical staff bylaws. PMID- 10107515 TI - Privacy and confidentiality in clinical research. AB - The information contained in clinical research records is often highly sensitive and personal. This article describes some of the issues that can arise with respect to preserving the confidentiality of these records. PMID- 10107516 TI - An interview with Senator John Engler. Interview by George Adams. PMID- 10107517 TI - England's health care system studied by Michigan delegation. PMID- 10107518 TI - One person's health care perspective from both sides of the Atlantic. PMID- 10107519 TI - Jacque Sammet looks back on his 14 years with MHAIC (Michigan Hospital Association Insurance Company) PMID- 10107520 TI - Incentive for loss prevention: discounts for risky business. PMID- 10107521 TI - Legislators, governor: do your homework. PMID- 10107522 TI - A response from the office of Governor James Blanchard. PMID- 10107523 TI - Hospital benefits from senator on board. PMID- 10107524 TI - Lawmakers set to tackle budget plan differences. PMID- 10107525 TI - Four hospital groups announce various forms of merger deals. PMID- 10107526 TI - One-third of hospitals seek reclassification. PMID- 10107527 TI - Court leaves merger issue muddy. PMID- 10107528 TI - Experts question whether Medicare's trust fund should finance care for the poor. PMID- 10107529 TI - Hay/Modern Healthcare compensation survey. AB - Compensating increases for hospital senior managers this year show that more healthcare providers are investing in their management teams as a whole, rather than just in the top dog. While the average base salary for chief executive officers is still higher than for other top hospital executives, CEOs' average raises were surpassed by other managers' average increases, according to the 1990 Hay/Modern Healthcare Compensation Survey. PMID- 10107530 TI - Rand study says care hasn't worsened under PPS. PMID- 10107531 TI - Who'll pay Blues plan's bills? PMID- 10107532 TI - Hospitals, physicians need to be allies, not adversaries. AB - The only way to bring hospital costs under control without sacrificing quality is to end the adversarial relationship between administration and physician staff, says Philip Hoggard. It's time to integrate the two camps into a shared organizational model that allocates risks and rewards fairly. PMID- 10107533 TI - N.J. pediatric AIDS program starts. PMID- 10107534 TI - '91 Medicare rates have HMOs eyeing changes. AB - A skimpy payment upgrade for Medicare health maintenance organizations is prompting some HMOs to consider changes in their coverage of elderly enrollees. The consequences of the money crunch vary widely depending on where the HMOs are located. PMID- 10107535 TI - N.Y. expects to have automated record this decade. PMID- 10107536 TI - Lack of standards hampers hospitals' attempts to size up fund-raising efficiency. AB - Though hospitals are depending more on charitable donations, there's no standardized method of determining the overhead of fund-raising activities. That makes it difficult to establish when and whether fund raising is worth the cost. PMID- 10107537 TI - Schemes to boost Medicaid pay opposed. PMID- 10107538 TI - REIT, hospital firm discuss merger. PMID- 10107539 TI - Collection of overpayments delayed. PMID- 10107540 TI - Congress nears end of budget battle. PMID- 10107541 TI - Reform advocates worry that new taxes could drain potential funding sources. PMID- 10107543 TI - Providers leery of attributing liability relief to tort reform. PMID- 10107542 TI - Ballot initiatives could affect health funding. PMID- 10107544 TI - Wash. project aims to measure delivery of quality in obstetrics. PMID- 10107545 TI - Charter again replaces head of hospital group. PMID- 10107546 TI - Cutting costs is first step toward reform--Sullivan. PMID- 10107547 TI - High costs, risks cited in Blues plan's demise. PMID- 10107548 TI - Hospitals may be overlooking opportunities to make the most of their cash, experts say. PMID- 10107550 TI - Michigan hospitals to see jump in Medicaid rates as result of pact. PMID- 10107549 TI - Unusual partnership eyed for hospital. PMID- 10107551 TI - Authority makes facility's payment. PMID- 10107552 TI - Providers to bear brunt of budget cuts. PMID- 10107553 TI - Low equity level endangers Nu-Med listing. PMID- 10107554 TI - Design winners build success on simplicity and excellence. PMID- 10107555 TI - HHS appropriations include $220 million in AIDS relief. PMID- 10107557 TI - Midwest CEOs turning inward for solutions--study. PMID- 10107556 TI - New association's leaders selected--Health Industry Group Purchasing Assn. PMID- 10107558 TI - Montana rural hospital project gets OK. PMID- 10107559 TI - Ballot initiatives make hospitals winners, losers. PMID- 10107560 TI - Congressional election results may bode well for healthcare. PMID- 10107561 TI - Hospital's mobile PET scanner a first. PMID- 10107562 TI - Medicaid expansions dodge budget knife; funds will aid hospitals, children, elderly. AB - Although projected healthcare spending took a highly publicized cut overall in the fiscal 1991 budget, the level of some less publicized expansions in Medicaid spending for pregnant women and children was surprising even to their advocates. PMID- 10107563 TI - Hospitals are under pressure to justify cost shifting. AB - You hear it over and over like a recording: Cost shifting is essential to recover losses from Medicare, Medicaid and charity care. But the days of cost shifting as implicit and accepted social policy are over. Payers are looking at hospital profits and resisting the time-honored argument for higher charges. Coalitions of businesses are pooling data to challenge hospital hard-luck stories. Still want to blame prices on the usual demons? Be prepared to prove it. PMID- 10107564 TI - McCarthy's resignation prompts concerns about morale, succession, other top execs. PMID- 10107565 TI - There's a right way to do strategic planning. PMID- 10107566 TI - Nursing homes operating at a loss. PMID- 10107568 TI - USC hospital replacement facilities to cost $1.6 billion. PMID- 10107567 TI - Humana won't need CON for Michael Reese. PMID- 10107569 TI - Hospital teams find solutions, savings through quality management techniques. PMID- 10107570 TI - Clinical lab manager salaries rise rapidly. PMID- 10107571 TI - Finance authority's offer to make payment not expected to become common practice. AB - A state finance authority's recent decision to make a debt payment for a shuttered hospital isn't likely to start a trend industry experts say. PMID- 10107572 TI - Pittsburgh blood bank stripped of its tax exemption. PMID- 10107573 TI - Ill. hospitals sue over Medicaid rates. PMID- 10107574 TI - Beverly reins in divestiture plans. PMID- 10107575 TI - AMI agrees to sell Denver-area assets. PMID- 10107576 TI - JCAHO releases survey on hospital compliance. PMID- 10107577 TI - Pittsburgh officials offer tax deal. PMID- 10107578 TI - Red tape restricting revenues. PMID- 10107579 TI - Waging war for nurses. Hospitals could become casualties as salaries escalate. AB - There's a recruiting war going on, a pitched battle for nurses. The pitch includes lucrative sign-on and shift bonuses, which then must be matched by competing hospitals that need to keep their beds staffed. It's all leading to an explosive rise in nurse compensation, for bedside nurses and managers alike, according to the Hay-Modern Healthcare nurse compensation survey. PMID- 10107580 TI - General Motors drops six HMOs, brakes enrollment in 19 others in effort to cut costs. PMID- 10107581 TI - Healthcare costs top CEOs' concerns. PMID- 10107583 TI - Profits at for-profits dip below the rest. PMID- 10107582 TI - Nurses see healthy gains up and down the ladder. PMID- 10107584 TI - State groups clamored for McCarthy ouster; execs differ on the urgency of replacing her. PMID- 10107586 TI - AMA converts to product-line management scrutiny. PMID- 10107585 TI - Experts still deliberating effectiveness of N.Y. rules limiting residents' hours. AB - A New York state law limiting the schedules of interns and residents has resulted in 15 citations so far, a degree of compliance one hospital spokesman said is higher than anticipated. It's less discernible whether the curbs are having their intended effect of keeping house staff rested and supervised, and whether other states will take New York's lead. PMID- 10107587 TI - HUD agrees to guarantee public facility's building loan. AB - Boston City Hospital is the first publicly owned and operated facility to be granted a guaranteed loan from the U.S. Dept. of Housing and Urban Development. PMID- 10107588 TI - Execs form group to track labor issues. PMID- 10107589 TI - Physician income increases drop significantly--AMA. PMID- 10107590 TI - Fire dept makes recommendation for class I drapes. PMID- 10107591 TI - Study: stockless inventory can save money. Health Industry Distributors Association. PMID- 10107592 TI - Giving the employees a piece of the action. PMID- 10107593 TI - The pregnant employee in a hazardous workplace. PMID- 10107594 TI - QA: establishing thresholds for evaluation. AB - This is the seventh article about applying the ten-step model for monitoring and evaluation developed by the Joint Commission on Accreditation of Healthcare Organizations. PMID- 10107595 TI - Computer used to track the OR's instrument inventory. PMID- 10107596 TI - Tracking in-house accounts receivable can identify potential problems. AB - Developing a program to track in-house accounts receivables can help hospitals identify cases that may result in bad debt or charity care write-offs. A case management approach that includes analysis of patients' financial, social, and clinical information will allow hospitals to work ahead of problems rather than behind them. PMID- 10107597 TI - Flexible staffing approach can improve service quality, lift morale. PMID- 10107599 TI - Dealing with life with cancer. PMID- 10107598 TI - 50 fast facts to reduce cancer risk. PMID- 10107600 TI - Gain-sharing promotes cost-saving. PMID- 10107601 TI - Sensitive but not scary. PMID- 10107602 TI - Gifts sent in bright boxes to referrers. PMID- 10107603 TI - Day-care service for elderly. PMID- 10107604 TI - Low-budget birthday bash. PMID- 10107605 TI - Sleep center is eye-opening success. PMID- 10107606 TI - Goodwill van joins golf tour. PMID- 10107607 TI - Medicine & fitness work out in Illinois. PMID- 10107608 TI - So you think you can't afford TV. PMID- 10107609 TI - Caring for AIDS babies. PMID- 10107610 TI - Breaking through ad clutter. PMID- 10107611 TI - Generic ad boosts family practice physicians. PMID- 10107612 TI - Sparkles the spokesdog steals the show. PMID- 10107613 TI - New star rises in the Lone Star State. PMID- 10107615 TI - Calendar theme boosts blood donations. PMID- 10107614 TI - Membership has its privileges. PMID- 10107616 TI - Annual report seeds donations. PMID- 10107617 TI - Circle gets the square. PMID- 10107618 TI - Overcoming stereotypes leads to improved care delivery. PMID- 10107619 TI - Risk of Medicare/Medicaid exclusions pose real threat. PMID- 10107620 TI - Successfully packaging projects to attract financial lenders. PMID- 10107621 TI - Reach prospective residents through target advertising. PMID- 10107622 TI - Portable medical record program provides peace of mind. PMID- 10107623 TI - Hospital discharge planners welcome facility involvement. PMID- 10107624 TI - Support group helps residents establish positive outlook. PMID- 10107625 TI - Industry meets consumer needs with broader care continuum. PMID- 10107626 TI - Encouraging and recognizing employees builds winning team. PMID- 10107627 TI - Utilizing nurse call systems as data collection centers. PMID- 10107628 TI - Rehabilitation: facilities target service to a changing market. PMID- 10107629 TI - Medical malpractice cases not to file. PMID- 10107630 TI - Medical information, health sciences librarians, and professional liability. AB - As a gatekeeper to medical literature and a critical link in the delivery of information to physicians, the librarian's role raises the issue of the librarian's professional liability. The paper suggests several ways in which liability may attach to the librarian or the librarian's employers. Although the librarian's personal risk is negligible, the physician's exposure due to ineffective library work is substantial since the courts have held that a physician must keep abreast of progress in his field. Librarians can also become associated with professional liability actions as part of a case against a physician or hospital through the legal doctrine of vicarious liability. The paper concludes by suggesting several proactive steps for health sciences librarians to pursue to insulate themselves from professional liability and to insulate physicians and institutions from vicarious liability. PMID- 10107631 TI - Creative competitive advantage through information technology. Trustees should think of technology as an investment in the future. PMID- 10107632 TI - Why the board should require a risk-management program. PMID- 10107633 TI - Hospital/physician linkups. PMID- 10107634 TI - Trends in equipment acquisition. PMID- 10107635 TI - Board directs system turnaround. PMID- 10107636 TI - Access and affordability: forging a health care policy. PMID- 10107637 TI - Serving seniors--everyone benefits. PMID- 10107638 TI - Self-sacrifice garners McGaw prize. PMID- 10107639 TI - Technology acquisition: board/physician cooperation. Interview by Karen Gardner. PMID- 10107640 TI - Tax exemption and charity care--what can hospitals expect? PMID- 10107641 TI - AIDS care funding. PMID- 10107642 TI - Doubling up on degrees. PMID- 10107643 TI - Ethics of the heart & mind. PMID- 10107644 TI - Quality management: radiology's challenge. PMID- 10107645 TI - The mid-field MRI center: 1990's answer to the continuing crisis in healthcare costs. PMID- 10107646 TI - The plan to expand. PMID- 10107647 TI - RIS (radiology information systems) selection criteria: Part 2. PMID- 10107648 TI - Gaining ground in the war on cancer. PMID- 10107649 TI - Productivity measurement in radiation oncology. PMID- 10107650 TI - Don't say can't--say Gantt. PMID- 10107651 TI - Creative strategy development for hospitals. PMID- 10107652 TI - In search of buried talents. Part 1. PMID- 10107653 TI - Recommendations for physics staffing in diagnostic radiology. PMID- 10107654 TI - RIS (radiology information systems)--the basics. Part 1. PMID- 10107655 TI - Changing for the better. PMID- 10107656 TI - Monitoring mammographic performance. PMID- 10107657 TI - A step above ... marketing the cancer center. PMID- 10107658 TI - Are severance plans making plaintiffs' lawyers rich? PMID- 10107659 TI - Perspectives. New governors face uninsured. PMID- 10107660 TI - Perspectives. How healthy is American medical education? PMID- 10107661 TI - Future issues in children's health care: addressing psychosocial concerns. AB - A panel of experts, participating in a Delphi poll, identified significant issues facing psychosocial aspects of health care for children in the future. In three rounds of feedback and evaluation, ten top future issues were composited in rank order: chronic illness and complex health care needs; sociogenic problems; unequal access to health care; lack of financial resources for psychosocial services; increased focus on prevention; children without primary caregivers; complex ethical questions; family-centered care; training of health care professionals; and interdisciplinary integration. Implications of these issues are discussed. PMID- 10107662 TI - The role of the Canadian Institute of Child Health in promoting family-centered care. PMID- 10107663 TI - Perspectives on health care delivery systems for American Indian families. AB - The national effort to improve services to children with special health care needs presents unique challenges for the delivery of services to American Indian families. This study took place in New Mexico. American Indian families whose children have special needs and health care providers were interviewed. Their responses about obstacles to health care for their children and suggestions for improving services were examined. Generally, both groups identified similar obstacles, although important differences between groups were noted. The findings point to the need for understanding cultural barriers and the unique concerns of low income families living in rural areas. This has important implications for planning changes in the health care system for American Indian children with special needs. PMID- 10107664 TI - Play in health care settings: a challenge for the 1990s. AB - Play, particularly unstructured and nondirective, has been believed to lessen the negative impact of hospitalization through expression of feelings, reversal of roles, and control of materials, concepts, and actions. Over time, however, changes in perspectives on play, hospital policies and practices, and the nature of illnesses of children have combined to influence the context for this form of play. Challenges to child-focused play and possible implications are derived from past events. PMID- 10107665 TI - The changing role of families in health care. AB - In the last fifty years while there have been dramatic changes in the science and technology of pediatrics, there have also been major changes in the participation of families in child health care. Since its founding, ACCH has helped to shape these changes and will continue this leadership in addressing the challenges of the 1990's. PMID- 10107666 TI - A parent's perspective. The changing role of parent involvement in the health care system. PMID- 10107667 TI - Necessary but not sufficient components--training issues in child life. PMID- 10107668 TI - Negotiating the 90s--an FM roundtable. PMID- 10107669 TI - Bringing hospitality into foodservice. PMID- 10107670 TI - Preselling your boss. PMID- 10107671 TI - Giving foodservice its own space. Harris County Healthcare System is setting a trend with a freestanding production center. PMID- 10107672 TI - Managing strategic change. AB - Strategic business planning is a two-step process--(1) formulation and (2) implementation. While much effort has been placed on how to formulate strategies that are consistent with internal and external environmental pressures, the key lies in making strategies work. Management cannot stop with formulation but must concern itself equally with the implementation process. This means paying attention to the change process and its management. PMID- 10107673 TI - Life, death, and liability: duties of health care providers regarding withdrawal of treatment. AB - Many of the issues surrounding refusal and withdrawal of medical treatment are so new and complex that the U.S. society has not resolved the ethical or legal questions involved. Questions such as where life ends and death begins, how to determine the circumstances when withdrawal of treatment is appropriate, and who should make such decisions will have to be resolved before the law in this area can become settled. Naturally, society is a long way from resolving these issues, since they involve such fundamental social, moral, medical, and legal considerations. Nevertheless, a body of law has developed that increasingly recognizes the right of an individual to direct his or her own medical care. To that end, an individual's clearly expressed intention to discontinue medical treatment will generally be honored, even if death results from the withdrawal of that treatment. Legislatures and courts have also encouraged health care providers to abide by the wishes of their patients by giving immunity to health care providers who comply in good faith with the provisions of a living will. Courts have also been reluctant to impose liability on health care providers for withdrawal of treatment absent a living will if it were done in good faith (with the consent of family or guardian) and was in accordance with accepted medical practice. It would appear that as the law gives individuals increased control over the private matter of their own medical treatment, health care providers may face more civil suits for maintaining life support systems against the patient's (or family's) wishes. In any event, while society is in the process of catching up with medical technology, individuals can best protect their right to medical self-determination by expressing their wishes clearly in the form of a living will and durable power of attorney. Health care providers can best protect themselves by keeping abreast of medical and legal developments in connection with these issues and by communicating effectively with their patients as to their wishes regarding life-prolonging medical treatment. PMID- 10107674 TI - Building departmental influence in health care organizations. AB - This article has outlined several steps to follow in assessing and building department influence at the top management levels of health care organizations. Identifying and contributing to resolving the organization's key areas of uncertainty are strategies that have improved the influence of many departments in recent years. Individual strategies, such as developing one's expertise and sharing that expertise with other departments and top management (an example of the "involvement" technique), also are being used daily by effective department managers. Decentralized management, which entails the assignment of greater responsibilities to middle managers, is increasingly popular in health care organizations. This trend will no doubt facilitate the building of departmental influence in organizational decision making. However, the steps outlined in this article can be implemented whether or not top management endorses a decentralized management style. In a critical sense, departmental influence is too important to be left to top management. It is up to department managers to exert their influence for the good of their employees, the organization as a whole, and their own careers. PMID- 10107675 TI - Wellness: ten ways to make your workplace healthier. AB - These 10 suggestions to make the workplace healthier are just a few ideas to get a health promotion or wellness program started. Employees are a great resource for ideas and suggestions, and unless the health care supervisor asks, the needs of the worker may remain unfulfilled. If a health care facility decides to initiate such a program, it will find that everyone will win. The employees will feel cared about and will, in return, care more about their jobs and responsibilities. Health care team members should be promoting health, not only for patients, but for themselves and their employees as well. In 1974, then Governor of North Carolina Terry Sanford said: "We need to invent and present more alternative approaches to health care, principally in teaching people how to care better for themselves, and the more difficult challenge--convincing them that they should." Institutions can start with their own health care employees, by making it easier for them to take better care of themselves. PMID- 10107676 TI - Profile of nonverbal sensitivity: the PONS test as predictor of the outcome of patient-medical staff interaction. PMID- 10107677 TI - When performance appraisal happens: timing is everything. PMID- 10107678 TI - A decade of rural health research: looking back, thinking ahead. PMID- 10107679 TI - Rural America in the 1980s: a context for rural health research. PMID- 10107680 TI - Children and pregnant women. AB - A review of the literature of the 1980s reveals that women living in rural American are at risk for receiving inadequate prenatal and maternal care. Documented risk factors include poverty and concomitant lack of medical insurance, residence in the most restrictive Medicaid states, and loss of local services including the closure of obstetric units of rural hospitals and the decision by local physicians to discontinue obstetrics. A prominent factor in a physician's decision to stop providing maternity care is the escalating cost of medical liability insurance; however, other forces are also at work, including interference with personal and family activities, disruption of other aspects of professional life (e.g., office schedule), inadequate reimbursement, and an inability to keep up with advancing technology. A research agenda for the 1990s should be consistent with previous recommendations and must stimulate the development of new programs that will induce the maximum number of providers to again offer high quality perinatal care to rural women. Other items on the 1990s research agenda include: (1) the clarification of the impact of lost perinatal services in rural areas, (2) the effects of travel time and distance on perinatal outcomes and cost of care, (3) the effect of loss of obstetric services on other health care services for women and children, and (4) comparisons of regionalized versus centralized systems for the provision of perinatal services. PMID- 10107681 TI - The health status, health services utilization, and support networks of the rural elderly: a decade review. AB - Research from the 1980s on several dimensions of health and health care among the rural elderly is reviewed. Following a brief discussion of the demographic patterns and life conditions of the rural elderly, the current state of knowledge regarding health status, health services utilization, and the potential for informal and familial care of the elderly is examined. The review concentrates on studies that include comparisons between rural and urban populations and/or control for additional variables that are known to covary with residence. Such analyses permit the documentation of the effects of residential location on health indicators net of other factors. The review concludes that the rural elderly are relatively disadvantaged in terms of both health status and access to health care services, and have little if any advantage over the urban elderly in their access to informal sources of care. Following the review, an agenda for future research is identified. PMID- 10107682 TI - Occupational health and the rural worker: agriculture, mining, and logging. AB - More than 50 million Americans live in rural areas. These rural residents often work for small businesses or in the extraction industries (farming, mining, and logging). Because of the size of the businesses, the mandate of the Occupation Safety and Health Administration (OSHA) does not cover these workers and they are seldom afforded the same protection as urban workers. This review focuses on the special health problems facing farm workers, farmers, miners, and loggers. Farm workers are often ill and are affected by psychological illness, injuries, parasites, skin diseases, and the dangers of agrichemicals. Farm owners also face the hazards of stress and have very high rates of suicide. In addition, they are often injured on the job and suffer the highest rate of job related fatality of any work group. The complex farm environment presents a continuous threat to the lungs. This danger has worsened with the increased use of confinement buildings for poultry, hogs, and cattle. As farming has changed with increased mechanization, attendant medical problems have arisen. These "illnesses of innovation" are important. Mining and logging also are dangerous occupations with acute and chronic problems including respiratory illness, vascular problems, and malignancy. The decade of the 1990s must be one of increased attention to rural occupational health care and research. PMID- 10107683 TI - Alternative models for the delivery of rural health services. AB - A number of alternatives to the solo, fee-for-service physician model have been pursued in an attempt to alleviate some of the specific problems associated with the delivery of primary care in rural areas. This article reviews and critiques the literature published in the 1980s for four alternative models: organized group practices, community health centers, community-oriented primary care and managed care systems. The review examines the strengths and shortcomings of the existing literature, and identifies high-priority research areas for each model. These four alternative models were introduced and promoted during the 1970s with little in the way of research evidence to support them. The subsequent literature pertaining to their performance was primarily descriptive. Of the quantitative studies, many utilized 1970s data. Therefore, the effects of the many environmental changes in rural areas during the 1980s on the viability of these models is unknown. In addition, little, if anything, is known about the life cycle of these models. While longitudinal, cross-organizational studies present several logistic difficulties and require considerable resources for data collection, they hold the promise of extending the existing knowledge concerning alternative models beyond its present states. PMID- 10107684 TI - America's rural hospitals: a selective review of 1980s research. AB - We review 1980s research on American rural hospitals within the context of a decade of increasing restrictiveness in the reimbursement and operating environments. Areas addressed include rural hospital definitions, organizational and financial performance, and strategic management activities. The latter category consists of hospital closure, diversification and vertical integration, swing-bed conversion, sole community provider designation, horizontal integration and multihospital system affiliation, marketing, and patient retention. The review suggests several research needs, including: developing more meaningful definitions of rural hospitals, engaging in methodologically sound work on the effects of innovative programs and strategic management activities--including conversion of the facility itself--on rural hospital performance, and completing studies of the effects of rural hospital closure or conversion on the health of the communities served. PMID- 10107685 TI - Financing rural health and medical services. AB - The provision and utilization of health care services in rural areas are tied directly to the structure of financing. The model of rural health care shaped by federal policies over three decades was significantly altered by changes during the 1980s. With reactions of third-party payers to health care costs rising faster than inflation, the difficulty of accommodating access to care and cost efficiency in provision became evident. This review begins with the literature on patient services and capital financing of rural hospitals, then continues with the financing of clinics, community centers, and other supply forms. Research during the 1980s provides insight into the effects of various financing policies on the supply of services. The demand for health care in rural areas is characterized by less generous third-party coverage, leaving residents paying a larger share of their incomes for care than do urban residents. As a consequence, access to care is especially difficult for low-income and elderly people, heavily dependent upon government financing. Third-party payers have severely reduced cost shifting as a mechanism for taking care of the health care needs of a sizable share of the population, thereby placing providers in an uncomfortable position. Several potential and more formalized financing options for replacing cost shifting are discussed. Several important changes will take place with rural focused legislation enacted in the late 1980s. These are used to present a rural financing research agenda for the 1990s. PMID- 10107686 TI - Availability and accessibility of rural health care. AB - The 1980s saw a retrenchment of the ideology that government intervention could solve the problems of inadequate access to health services in rural areas. Increased emphasis was placed on an ideology that promoted deregulation and competitive market solutions. During the 1980s, the gap in the availability of physicians in metropolitan versus nonmetropolitan areas widened. Also during that time period, the gap between metropolitan and nonmetropolitan populations' utilization of physician services widened. In addition, many indicators of the health status of nonmetropolitan residents versus metropolitan residents worsened during the 1980s. As we enter the 1990s, concern about equitable access to needed health care services and for the vulnerability and fragility of rural health systems has resurfaced. A number of national policies and a research agenda to improve accessibility and availability of health services in rural areas are being considered. PMID- 10107687 TI - Mental health and rural America: a decade review. AB - This article reviews research findings in rural mental health services during the past 10 years. Specifically considered are the prevalence of mental disorder in rural areas and aspects of the organization of mental health services delivery. Gaps in knowledge are identified and a research agenda is proposed. PMID- 10107688 TI - Professional preparation for rural medicine. PMID- 10107689 TI - Education of nurses for rural practice. AB - There is an excitement about the potential for nursing to make a difference in meeting rural health needs in the 1990s. Work places are attempting to respond to salary compressions and offering more autonomy for nursing over its own practice. There is better communication among hospital administrators, physicians, and nurses. Schools of nursing are more responsive to the needs of nontraditional students, and the federal and state governments are working together to find solutions. Innovation and creativity are key ingredients in our approach to ensuring rural nurse providers for the future. PMID- 10107690 TI - Education for rural health services administration. PMID- 10107692 TI - VHA's robust year to result in $6 million cash disbursement. PMID- 10107691 TI - Studies question Medicaid eligibility expansions. PMID- 10107693 TI - 'Mergers don't cut access'. PMID- 10107694 TI - Change should aid peer review groups in disciplining physicians. PMID- 10107695 TI - Hospitals changing their buying habits. Overhauled technology-acquisition processes help equip facilities to make prudent purchases. AB - As hospitals face increasing pressure to rein in costs, equipment spending faces stiff competition for limited funds. When facilities replace aging or outdated equipment, they're often replacing the entire technology assessment process as well. One hospital facing a $4 million bill to equip a new building is revamping its purchasing process based on department "wish lists." And an Ohio system has formed a special division to speed assessment and implementation of new technologies and procedures. PMID- 10107696 TI - Beverly to appeal NLRB ruling. PMID- 10107697 TI - New info systems chiefs can use this as a primer. AB - You're newly in charge of information systems, or you've been in charge for a while but aren't comfortable yet with the complexity of technology and language. Owen Doyle has some tips to help you gain control and head in the right direction. PMID- 10107698 TI - JCAHO, HRET to team up on quality-research project. PMID- 10107699 TI - Reform plans would improve profits--study. PMID- 10107700 TI - HMO's selective pharmacy agreements trim spiraling costs but irk independents. AB - Selective contracts with large pharmacy retailers are viewed as essential to controlling managed-care drug costs. But independent pharmacists are fumming over being excluded and some are fighting back through the news media or the statehouse. PMID- 10107701 TI - Consignment provides alternative to stockless. AB - Purchasing for hospitals unable or not inclined to convert to stockless inventory, consignment can offer some of the same savings on inventory costs without imposing extra computer and tracking needs on materials management. PMID- 10107702 TI - Budget cuts expected to gouge N.Y. hospitals. PMID- 10107703 TI - Laventhol & Horwath partners negotiate for work. PMID- 10107704 TI - New Zealand's health care system--a model for failure? AB - Should the U.S. consider adopting a national health insurance plan, a la Canada? Caution: Look at what FAHS Review found is happening to New Zealand's U.K. system. PMID- 10107705 TI - Do the right thing. AB - In the July/August 1990 issue of FAHS Review, a feature article focused on the new strategies needed for managing hospitals in the '90s. Suffering from the combined punch of restricted utilization and reduced reimbursements, hospitals can't help but feel the financial crunch created by these predicaments. Strategies for economic survival have included trying to maximize revenues by either increasing volume or reducing unnecessary expenses. But increasing price through rate increases or cost-shifting has limited potential in today's medical market. Increasing volume via participation in managed care programs is a risky maneuver at best, based on the extent of the volume-discount trade-off. Limiting expenses traditionally has been accomplished by following sound business cost containment techniques, maximizing FTEs and productivity, improving staffing patterns at all levels of the organization, and eliminating non-profitable services. But there is one additional item that should be taken into consideration--the need to reduce expenses by improving efficiency in medical operations. PMID- 10107706 TI - Cleveland Health Quality Choice Project. AB - A Cleveland CEO spearheads Health Quality Project. Reliance Electric's John Morley, who chairs the project's leadership group, speaks for a concurrent national reform effort patterned after Cleveland's. PMID- 10107707 TI - The Cleveland initiative. PMID- 10107708 TI - The limits of outcomes research. PMID- 10107709 TI - The hospital response. PMID- 10107710 TI - Insurer view. PMID- 10107711 TI - The GE strategy. Every employee at GE has the same flexible, option-loaded health plan. PMID- 10107712 TI - National trends in health benefits cost containment strategies. PMID- 10107713 TI - Liability of medical reviewers. California changes its position (maybe). PMID- 10107714 TI - The Cruzan case: an update. PMID- 10107715 TI - Integrated information transforms William Beaumont Hospital. PMID- 10107716 TI - Health care for children: our future--our destiny. PMID- 10107717 TI - Too little and too late for GME programs. PMID- 10107718 TI - Ethics consultation and ethics committees. PMID- 10107720 TI - Solomon--the ultimate moral expert? AB - When faced with difficult moral decisions, many people would prefer to shift the burden of moral responsibility to a moral expert. I imagine what appears to be the perfect moral expert: a computer program called SOLOMON designed to fit in a computer on one's wrist. After noting some advantages of using SOLOMON, I claim that moral agents would find individualizing the program as difficult as making moral decisions in the past. A revised version of the ultimate moral expert is also considered: one hires the wisest, kindest person on earth--Solome--to accompany one as a moral guide. However, turning over our moral problems to an expert, even to the noble Solome, still falls short. For the process of coming to moral decisions is itself import. One's values and personality may change as a result of moral deliberation. PMID- 10107719 TI - Planning for hospital ethics committees: meeting the needs of the professional staff. AB - Hospital ethics committees (HECs) have historically been instituted "top-down", often ignoring the needs of the professionals and patients who might use their services. Seventy-four physicians and 123 nurses participated in a hospital-wide needs assessment designed to identify their perceptions of the functions of the HEC, determine which services and educational programs were most desired, and explore which forums were most preferred for discussion of ethical problems. Results indicated that utilization of the HEC focused around five areas of concern: withdrawing/withholding treatment, rationing and control of health care, children's rights, role of the patient and family in decisionmaking, and disagreements about treatment. Physicians and nurses differed widely in their attitudes. Perceptions about the appropriate functions of the HEC strongly influenced decisions regarding which HEC services to use. Needs assessment can play an important role in developing HEC goals and designing programs that meet the needs of professionals. PMID- 10107721 TI - Ethics for hospital ethics committees: an introduction. PMID- 10107722 TI - Letter of reply to Howard Liss, M.D.: on DNR orders. PMID- 10107723 TI - The North Dakota Institutional Ethics Committee Network. PMID- 10107724 TI - The Northwest Network of Ethics Committees: (Oregon/Washington). PMID- 10107725 TI - The National Committee for Bioethics for the College of Chaplains. PMID- 10107726 TI - Impact of a physical fitness program in a blue-collar workforce. AB - The purpose of this study was to examine the impact of participation in the Wellness--Paths to Health Physical Fitness Program on selected physiological and personal health variables including blood pressure, pulse, body weight, trunk flexibility, cardiovascular endurance, abdominal strength, percent body fat and a cumulative fitness score. The subjects (N = 129) of this study were divided into four levels of adherence to this exercise-based health program. Data analysis examined relationships between adherence levels and changes in the selected physiological and personal health variables across two measures. In addition, data from high-risk participants were analyzed. The results of the study found statistical significant changes in the selected variables between repeated assessment measures. In addition, statistically significant relationships were found between levels of adherence to the program and six of the dependent variables. PMID- 10107727 TI - Women as motivators in the use of safety belts. AB - A sample of rural and urban women was interviewed using a questionnaire based on Fishbein's and Ajzen's Theory of Reasoned Action. Two hundred women were asked about their intentions to use safety-belts and to encourage others to use safety belts. Both intent and nonintent women highly valued saving lives, feeling safer, and reducing the likelihood of injuries, but they differed markedly in their beliefs that using safety-belts would necessarily save life, enhance their feeling of safety, and reduce the likelihood of injuries. Intent and nonintent users differed least in their beliefs that safety-belts would reduce injuries. Women who intended to use their safety-belts felt their action would encourage others to use belts and believed that they should encourage others to use their safety-belts. These intent safety-belt users did not see a strong social support for encouraging others to use safety belts and therefore were unlikely to do so. Programs to promote safety-belt use would capture the generally supportive attitudes of women if they could assist women to develop skills and confidence to express effectively their existing predisposition for safety-belt use. PMID- 10107728 TI - Emerging from the golden chrysalis. PMID- 10107729 TI - Prescription for a system. AB - Health authorities' drug budgets are large and difficult to control. Alan Willson and colleagues outline the system requirements for audit, resource management and costing reports. PMID- 10107730 TI - Preferential insights. PMID- 10107731 TI - A case for the prosecution. PMID- 10107732 TI - Flexible friend. AB - Norwich health authority has introduced a fully integrated personnel and payroll system which offers greater flexibility for managers. Paul Thain highlights the benefits. PMID- 10107733 TI - Right to die dilemma: when parents don't agree. PMID- 10107734 TI - Biotech industry considers foreign competition measure. PMID- 10107735 TI - Right to die after Cruzan: Florida upholds living wills. PMID- 10107736 TI - Newspapers may obtain hospitals' JCAHO reports. PMID- 10107737 TI - Hill-Burton charity care not limited to funded site. PMID- 10107738 TI - Hospital crimes: expecting the unexpected. PMID- 10107739 TI - The real world of malpractice tort reform, Part II. PMID- 10107741 TI - Hospitals' latest "goodwill" gesture. PMID- 10107740 TI - Nursing standard of care in medical malpractice litigation: the role of the nurse expert witness. PMID- 10107742 TI - Will budget woes close more doors to the indigent? PMID- 10107743 TI - How I fight the preauthorization racket. PMID- 10107745 TI - The history of medicine--or why we need physician unions. PMID- 10107744 TI - Bias against a woman doctor can land you in court. PMID- 10107746 TI - Are you seeing your fair share of patients? PMID- 10107747 TI - Can old age be given a public meaning? AB - Anti-ageism has done much to eliminate bias and stereotyping, but it has given us no positive vision of what old age might be. A shared interpretation of the physical and social realities of the elderly can enhance the lives of aging people and provide the foundations for public policy. PMID- 10107749 TI - Religion: friend or foe of the aging? AB - Religion can be a guide in the quest of older adults for a fuller understanding of their lives and purposes as they cope with the diminishments brought about by aging. PMID- 10107748 TI - The case: a story found and lost. AB - This first case in our series presents an elderly patient's encounters with the medical system as chronicled in her medical records. PMID- 10107750 TI - On Germain Grisez: can Christian ethics give answers? AB - The natural law ethics of Catholic moral theologian and philosopher Germain Grisez is applied to seven common questions in medical ethics. PMID- 10107751 TI - Hospitals in the trenches. Turn back to PR basics. PMID- 10107752 TI - Your partners in health care. PMID- 10107753 TI - How the public eyes hospitals. PMID- 10107754 TI - Deal a winning hand. Media relations for hospital CEO's. PMID- 10107755 TI - More hospitals ban smoking--few fume. PMID- 10107757 TI - New media image for nursing. PMID- 10107756 TI - Congress views employee benefits. PMID- 10107758 TI - Hospitals get pressed. PMID- 10107759 TI - Education as a management tool. PMID- 10107760 TI - Apprising the board of provider competency. PMID- 10107761 TI - Communication through publication. PMID- 10107762 TI - Bring back those monthly meetings? PMID- 10107763 TI - Guidelines for charting: documentation of medications and i.v.'s--II. Professional Liability Program, Farmers Insurance Group of Companies. AB - This article is a continuation of a series that provides guidelines for documentation in the medical record. See QRC Advisor 6:3 (January) for general charting guidelines, 6:4 (February) for obstetrics charting, 6:6 (April) for perioperative charting, and 6:12 (December) for Documentation of Medications and i.v.'s--I. PMID- 10107764 TI - Pharmacy intervention and the anesthesia drug exchange drawer. AB - We implemented an ED drug system for anesthesia carts at no net cost. Cooperation by the departments of pharmacy and anesthesia permitted the establishment of services without additional funds for new personnel or equipment. The system offers a number of important advantages over individual-cart drug stocking. Benefits include reduced costs, improved patient safety, improved drug handling, and better communication between anesthesia and pharmacy personnel. We conclude that when a satellite pharmacy is not feasible, or as an interim measure, an ED system can provide substantial benefits over individual anesthesia carts. We further observed that anesthetists' drug-handling behaviors improved when carts were common and standardized. PMID- 10107765 TI - Advances in hospital pharmacy computing. AB - These brief descriptions of hospital pharmacy computer applications only scratch the surface of the many different areas in which they have the potential of being used. As the pharmacy profession becomes more knowledgeable in the application of computers, these systems will be used to the fullest degree. The computer is a very important tool for the pharmacy. A whole new vision of hospital pharmacy can be seen in which pharmacy personnel must master existing systems and instigate a wide variety of new programs in order to create more efficient and wide-ranging services. PMID- 10107766 TI - Tax fever infecting nonprofit hospitals. PMID- 10107767 TI - Bournemouth General Hospital--phase 1A. PMID- 10107768 TI - Asset management projects. PMID- 10107770 TI - Trade contractors' view of management contracting. PMID- 10107769 TI - The case for design and build in piped medical gases. AB - The proposal is not new or radical in that currently many small works are and historical have been carried out implicitly utilising this system. Furthermore, this idea is not suggesting that M&E consultants be omitted from the process only that their role be redefined in terms of approving/checking proposals/installations/commissioning etc. There is an appropriate form of contract already available through JCT '80 why not utilise it? As is being done with boilers, water treatment, lifts etc. etc. The recommendation would improve quality, reduce time and cost, directly apportion accountability and involve the knowledgeable professionals within the industry. PMID- 10107771 TI - The Westminster and Chelsea Hospital project. PMID- 10107772 TI - The implications of Project 2000 for nursing libraries. AB - Drawing on their experience as a demonstration district for Project 2000 the authors discuss the implications of the changes to nurse education for nursing libraries and the services which they provide. A survey of library usage patterns under the 'new' curriculum is also described. PMID- 10107773 TI - The Japan Medical Library Association--past, present and future. PMID- 10107774 TI - New American medical libraries: report of a study tour. AB - Descriptions highlighting the design and range of services of modern American libraries are given. Five medical school libraries and the National Library of Medicine are discussed. PMID- 10107775 TI - Using information technologies to bridge the international information gap. PMID- 10107776 TI - AIDS and surgical care: a challenge for the '90s. PMID- 10107777 TI - The vital role in medicine of commitment to the patient. PMID- 10107778 TI - Measuring hospitals by outcomes. PMID- 10107779 TI - How Pacific Telesis put health care costs on hold. PMID- 10107780 TI - COBRA: the aftermath of the 1989 Act. PMID- 10107782 TI - Keeping employees healthy. PMID- 10107781 TI - Health care: a crisis of consensus. PMID- 10107783 TI - Prevalence of vision benefits. PMID- 10107784 TI - Choosing a vision care provider. PMID- 10107785 TI - Vision care benefits boom. PMID- 10107786 TI - Statement of organization, functions and delegations of authority--HCFA. PMID- 10107787 TI - Reflections on ART certification. AB - Development of self-directed study skills and problem solving abilities is not nurtured in an environment in which every subject is specified and choices are few. The CSLT would do well to propose fewer requirements and to keep them process-related. It should have more faith in the universities and the candidates. A degree will develop the key skills to be life-long learners. The work environment and CE courses will help keep information current and relevant. The professional body, the CSLT, should produce an ART evaluation instrument that assesses both skills and knowledge at an appropriate level. Submission of a case study and an oral examination based on the case, if properly constituted, can fulfill this role. The Task Force On Future Trends and the ART Working Group are to be congratulated on developing a blueprint for future advanced certification. Their job has been enormous. They deserve our thanks for having the courage to propose major changes that, while not universally popular at the outset, should serve the membership well in the long term. As the new system evolves, it is important for all views to be heard. Members who have something to contribute, should speak up now. The ART process is still unfolding, and we may be able to influence its direction. PMID- 10107788 TI - Communication issues for the laboratory. PMID- 10107789 TI - Are you a candidate for "burn-out"? PMID- 10107790 TI - Code of Ethics. Canadian Association of Medical Radiation Technologists. PMID- 10107791 TI - Technologists and the law. PMID- 10107792 TI - The church's healing mission in the world. PMID- 10107793 TI - Faithful to a mission--Catholic Health Association of Canada. AB - To celebrate its 50th anniversary, the CHAC published a history which is now available. For the readers of the CHAC REVIEW, we offer the conclusion of this exciting book. PMID- 10107794 TI - An adult education optic on mission education. AB - Mission education peculiar to the Catholic health care facility has as its goal the development and deepening of the institution's culture. It seeks to create an increased awareness of the vision and values for which that institution stands. PMID- 10107795 TI - Paramedic of the Year. Beating the odds. PMID- 10107796 TI - Armed America: demands on the EMS system. PMID- 10107797 TI - Saving yourself: the first order of business. PMID- 10107798 TI - Domestic disputes. PMID- 10107799 TI - Dispatch concerns. PMID- 10107800 TI - Sociological issues. PMID- 10107801 TI - Joint oncology programs offer market opportunities. PMID- 10107802 TI - Strategic plan needs focus, structure to aid vision. AB - Having a strategic vision for a hospital is of no use unless it is supported by a focused plan and a management ready to make it work. But, there are generic factors that impede the success of strategic change, barriers that can be lessened, if not eliminated, with structure. In the following article, the author describes the ingredients necessary to turn strategic vision into practice. PMID- 10107803 TI - Direct contract tactic for health care marketplace. AB - Direct contracting offers an aggressive approach to health care cost containment in an era when employers, patients and providers must do more than just talk about saving dollars. Eliminating the "middleman" through customized insurance plans, direct contracts can combat rising costs. The author explains what hospitals must do to initiate a program. PMID- 10107804 TI - Stockless purchasing offers potential savings for hospitals. PMID- 10107805 TI - Planning indicators. 5-year data confirm shift to outpatient site of care. PMID- 10107806 TI - Challenge is redefinition. AB - What are the key strategic concerns of a major hospital network? How do the top executives of a group guide administrators of their individual hospitals so that corporate goals are met but autonomy is maintained? In the following interview, Charles N. Martin, Jr., president and chief operating officer of Health Trust Inc., a privately-held hospital formed in September 1987 through an employee stock ownership plan, discusses the particular problems of overseeing a network that includes 87 hospitals in 21 states. PMID- 10107807 TI - Sports medicine centers offer marginal profits. PMID- 10107808 TI - Humana tries important entry into Chicago market. AB - The proposed purchase of Chicago's Michael Reese Hospital and Medical Center by Humana Inc., is hailed as one of the first such takeovers driven by the value of an HMO plan rather than the value of the parent hospital. The author discusses the proposed $50 to $70 million Reese purchase and its impact on the market. PMID- 10107809 TI - Positioning must have new place in health arena. AB - Positioning is a marketing concept that has growing application in health care. Medical administrators must look at the traditional definition of the term--the placement rather than the modification of services--in marketing speciality services competitively. The author describes the forces impacting health care, prompting positioning of services. PMID- 10107810 TI - Positioning Institute of Cancer Control requires promotion. PMID- 10107811 TI - Networks strengthen ties, status of rural hospitals. AB - Rural hospitals are a integral part of the health care system in this country. But a lack of funds and a shrinking patient-base are leaving many of them without the resources to provide state-of-the-art care in their communities. In the following article, the authors discuss a network model that brings urban hospitals to the financial and service aid of rural facilities. PMID- 10107812 TI - Cancer accounts for 8% of Medicare hospitalizations. PMID- 10107813 TI - Trauma raises questions. AB - In an era of shrinking federal resources and a growing indigent patient population, how can a major hospital retain a successful trauma center that doesn't drain its financial base? Jeptha W. Dalston, Ph.D., president of Houston's Hermann Hospital, a 516-bed institution that revamped its trauma center, and, in the process, turned its bottom line from red to black, discusses the important issues hospital administrators must address before closing the door on emergency care. PMID- 10107814 TI - Special report on reimbursement. Recent federal case enjoins enforcement of Medicare secondary payer regulations. PMID- 10107815 TI - Certification programs in security: an update. AB - Does it pay to undertake the time, trouble, and expense to become a CPP? Or a CHPA? Or both? What other programs are available that can help you advance in the security field or get a better position? There have been a number of recent developments in the area of certification that hospital security directors should be aware of. In this report we'll review the major programs in detail, and give you the frank reactions to them of your colleagues who have become certified. PMID- 10107816 TI - Model fee schedule for physicians services. PMID- 10107817 TI - Manpower resource guide. AB - With a grant from FORE, a Manpower Resource Guide to investigate and explore the emerging roles and functions of medical record practitioners was developed. The preparation of the Guide and its contents are described in this article. PMID- 10107818 TI - Recognizing outstanding dictators. PMID- 10107819 TI - Disaster planning. PMID- 10107820 TI - AIDS/HIV infection. PMID- 10107821 TI - Metronidazole cost containment: a two-stage intervention. AB - A two-stage intervention was undertaken to extend the dosing interval of metronidazole--from the typically prescribed q6h or q8h regimen to a q12h dosing interval. Following an 2-week informational period, all prescriptions for parenteral metronidazole specifying a dosage interval of 8 hours or less were modified to 12-hour dosage intervals, unless overridden by the prescriber. Prescriptions for the 6-month periods prior to and following the intervention were reviewed to assess its impact on prescribing patterns and cost containment. The incidence of regimens involving 12-hour intervals increased from 5 to 95% following the intervention. A 2-year general hospital/drug utilization health record screen found no drug substitution effect, nor any change in postoperative infection rate or death among metronidazole recipients. Overall, the two-stage intervention was a well-accepted and effective means of cost containment, resulting in an estimated yearly cost savings of $28,000. PMID- 10107822 TI - In what ways does the pharmacy department actively participate in P & T Committee meetings? PMID- 10107823 TI - A mathematical model of retrieval system performance. AB - There have been a number of major evaluations of the performance of retrieval systems against large full text and surrogate (bibliographic) databases. These evaluations have concentrated on the experimental determination of the Precision Ratio, the fraction of retrieved items that are relevant to an information request, and the Recall Ratio, the fraction of the total number of relevant items that were actually retrieved. While these measures have met with general acceptance, they have also generated much controversy. The purpose of this article is to review the results of several of the largest evaluations and to propose a simple model for the performance of such systems that may help explain the relationship between these measures and user behavior. PMID- 10107825 TI - NYU Medical Center. One of twenty luxury suites by Charles P. Swerz Interior Design. PMID- 10107824 TI - Book availability as a performance measure of a library: an analysis of the effectiveness of a health sciences library. AB - User satisfaction as a measure of library effectiveness has been studied by using Kantor's branching technique. Cleveland Health Sciences Library, Cleveland, Ohio, was used as the center of this study. The study measured independently the user bibliographic information performance, collection development policy performance, acquisition policy performance, user catalog performance, circulation performance, library operation/functioning performance, and the user search performance. Each of these categories represented one or more of the factors of library performance that could account for the possibility of users' failure. The sample size consisted of 1000 requests for book titles. The book availability rates were 59.60% without the help of the librarian and 63.50% with the help of the librarian. The results indicate that a dynamic study of library policies at regular intervals by using the Kantor's method, which is easily reproducible, can maximize library resources for the most effective fulfillment of user demand. PMID- 10107826 TI - Birthing center. A hospitable hospital room by Loebl Schlossman and Hackl. PMID- 10107827 TI - Medical device networks. PMID- 10107828 TI - Developing hypermedia systems: avoiding hyperchaos. AB - Hypermedia systems allow storage of huge collections of information from a wide variety of sources and afford immediate and random access to the collections. While providing unprecedented possibilities for storing and disseminating information, hypermedia systems have the potential to confuse the developer and the user alike with a multitude of intricacies. When hypermedia are being used in the teaching/learning process, they can cause cognitive overload and disorientation, if not designed properly. One way to resolve these problems is to develop system and content flowcharts. Although developing system and content flowcharts seems to be time-consuming work, it saves time and energy over the long run. Furthermore, it promotes efficiency. PMID- 10107829 TI - Uncertainty based approach for symbolic classification of numeric variables in intensive care units. AB - In intensive care units (ICUs), certain parameters must be interpreted taking into account the intrinsic characteristics of each patient or the peculiarities of the clinical case under consideration. Similar temporal evolutions of some parameters in different patients could have different interpretations. Artificial intelligence techniques can aid in resolving this problem through the construction of expert systems (ES). These systems are capable of performing contextual evaluations of the parameters typically monitored in ICUs. This contextual evaluation is usually carried out using symbolic elements. Thus, the symbolic processing of numeric data is an important task to perform. In any event, the assignment of semantic labels to numeric values is always an uncertain and arbitrary process. This suggests the convenience of defining and implementing representation schemes capable of dealing with uncertain knowledge. This paper presents a model for the symbolic processing of numeric variables in which the uncertainty associated with the assignment of literals appears spontaneously. The categorical approach for the symbolic classification of numeric values is a particular case of the proposed model. PMID- 10107830 TI - A new paradigm for explaining and linking knowledge in diagnostic problem solving. AB - Medical expert systems frequently use causal models to capture knowledge and diagnostic-problem-solving expertise. A significant obstacle confronting these systems is providing informative explanations without prohibitive computational expense. The explanations should allow the user to understand the decisions of the expert system and obtain additional details when needed. A new method, called HyperExplain, has been devised to flexibly link explanations with conclusions generated by a causal reasoning system. This approach creates a patient specific explanatory (PSE) model for the medical expert system that provides decision support from a variety of perspectives. A key feature of this method is the ability to alter the focus of explanations depending upon the problem-solving context and patient manifestations. The method has been implemented in a program that provides diagnostic assistance to physicians in the domain of neurophysiology. PMID- 10107831 TI - Microcomputer-based coronary care unit central station. AB - A four-bed central station that can be connected to any commercial intensive-care bedside monitor was developed. The system is based on a personal computer (IBM-AT compatible) as a local unit and on a microcontroller Intel 8031 as a remote unit. Four ECG signals are low-pass filtered, multiplexed, sampled at 256-Hz per channel, 8-bit A/D converted, preprocessed, and converted to a serial format RS 232 by the remote unit. The real-time display of the signals is at the standard speed of 25 and 50 mm/sec. Heartrate, alarms, trend plots, and general patient data are shown on an Olivetti M280 and EGA 13'' color monitor as the local unit. The communication speed was set at 57.6 Kbaud full duplex. Additionally, to reach standard monitoring sweep rates using a 13'' screen with 640 x 350 pixels, an ECG data-compression algorithm was implemented in the remote unit. This unit can support up to eight input channels and can work with any personal computer, via RS-232, with the appropriate software. It also allows other signal preprocessing software that could be developed, such as QRS detection or ST segment quantification, to be loaded into its random access memory and to be run under PC command. The development of this system demonstrated the use of a widespread piece of commercial equipment, the PC, in a very specific application, CCU monitoring, assuring low-cost system implementation. This feature is particularly attractive in upgrading existing CCU units in less developed countries. PMID- 10107833 TI - Workforce 2000: management and motivation of health care's human resources. PMID- 10107832 TI - A real-time anesthesia record keeping system using video. AB - A real-time, Automated Anesthesia Record Keeping (AARK) system was constructed using commercially available video hardware. This system can acquire all of the information that is presented visually to an anesthesiologist directly from monitor screens. The information is recorded on VHS format tape. Use of such a system avoids the need for digital processing while capturing all waveforms, trends, data messages and numerics. Since the data are stored directly to tape, subsequent data analysis can be accomplished. This system can be used with virtually any medical monitor. PMID- 10107834 TI - Human resource management in the 1990s: what the experts predict. PMID- 10107835 TI - Undergraduate health administration education in the 1990s. AB - The current destabilizing period of the health care industry and higher education has major implications for undergraduate education, especially given its adolescent stage of development. Although undergraduate programs have progressed a great deal in gaining acceptance within the industry and the academy, it must not be assumed that curricula, programs, or a consortium of programs can rest on past accomplishments. This paper has attempted to describe the threats and opportunities facing undergraduate programs and to discuss some strategies for future development that might be explored collectively or individually. It is hoped that the above observations will provoke a healthy dialogue as well as a plan of action by undergraduate programs. Undergraduate health administration programs must respond to the future and make themselves relevant and necessary to the new challenges facing the field of both practice and higher education. PMID- 10107836 TI - Critical issues in the undergraduate health administration curriculum. PMID- 10107837 TI - The roles and relationships of graduate and undergraduate programs in health administration: a view from the University of Toronto. PMID- 10107838 TI - Approaches to assessing educational outcomes. PMID- 10107839 TI - The development of baccalaureate health administration education: an overview of AUPHA initiatives. PMID- 10107840 TI - Practitioner perceptions of the knowledge and skills required for successful practice in health administration. PMID- 10107841 TI - Full undergraduate membership criteria, adopted April 1989. Association of University Programs in Health Administration. PMID- 10107842 TI - Report on baccalaureate career development, December 1989. American College of Healthcare Executives and Association of University Programs in Health Administration. PMID- 10107843 TI - A practitioner's perspective of baccalaureate education in health administration. PMID- 10107844 TI - Undergraduate health administration education: a practitioner's viewpoint. PMID- 10107845 TI - Using hospital-specific costs to improve the fairness of prospective reimbursement. AB - Payment rates in Medicare's Prospective Payment System (PPS) are based on averages of historical hospital costs. Compared to reimbursing each hospital's own costs, pricing at the average of costs implies a massive redistribution of payments among hospitals. Because not all sources of hospital costs are accounted for in the PPS, some of this redistribution is 'unfair'. Information in hospital specific costs on unmeasured patient severity and input prices can be exploited to reduce payment inequities. However, fully hospital-specific rates are not optimal because costs also reflect treatment intensity and efficiency differences among hospitals. PMID- 10107846 TI - A simple objective method for determining a percent standard in mixed reimbursement systems. AB - In a mixed system for hospital rate setting, reimbursement is set at the weighted average of provider-specific and standard unit costs. With one or more explanatory variables, forward and reverse regression is used to motivate the simple but objective choice of one minus the squared correlation coefficient as the proportion standard. Special treatment is given to nuisance variables that help explain cost but not reasonable cost. Efron's bootstrap provides confidence intervals for the proportion standard. This regression approach is contrasted with the conventional use of the coefficient of variation, and with economic models for the optimal proportion. PMID- 10107847 TI - The dynamic relationship between low birthweight and induced abortion in New York City. An aggregate time-series analysis. AB - We use a vector autoregression to examine the dynamic relationship between the race-specific percentage of pregnancies terminated by induced abortion and the race-specific percentage of low-birthweight births in New York City. With monthly data beginning in 1972, we find that induced abortion explains low birthweight for blacks, but not for whites. There is no evidence of feedback from low birthweight to induced abortion. The findings suggest that unanticipated decreases in the percentage of pregnancies terminated by induced abortion would worsen birth outcomes among blacks in New York City. PMID- 10107848 TI - Equity and accuracy in medical malpractice insurance pricing. AB - This study examines alternative classification approaches for setting medical malpractice insurance premiums. Insurers generally form risk classification categories on factors other than the physician's own loss experience. Our analysis of such classification approaches indicates different but no more categories than now used. An actuarially-fair premium-setting scheme based on the frequency and severity of the individual physician's losses would substantially penalize adverse experience. Alternatively, premiums could be set for groups of physicians, such as hospital medical staffs. Our simulations suggest that even staffs at rather small hospitals may be large enough to be experience-rated. PMID- 10107849 TI - Consumer information and providers' reputations. An empirical test in the market for psychotherapy. AB - This paper estimates the price effects of provider-specific reputations measured as the percent of each provider's clients who are referred by 'informed community sources', such as other health professionals, school counselors, businesses, clergy, and attorneys. Using data on the prices of outpatient psychotherapy visits to private-practice social workers in Massachusetts, the results suggest that social workers with established reputations for high-quality care charge higher prices. In addition, the results suggest that intra- and inter professional competition can constrain the pricing decisions of psychotherapists, and that increasing consumer information increases the effectiveness of this competition. PMID- 10107850 TI - The economic determinants of specialty choice by medical residents. AB - This paper analyzes how economic factors (relative expected earnings, relative expected hours worked, and relative length of training period) affect the distribution of medical residents across specialties. The results show that the percent of residents in a given specialty changes more than proportionately when relative hours change (hours elasticities averaged between -1.2 and -2.0) and less than proportionately when relative earnings change (earnings elasticities averaged between 0.3 and 0.6). Residents appear to be quite unresponsive to changes in the length of training period. PMID- 10107851 TI - What proportion of hospital cost differences is justifiable? PMID- 10107853 TI - Suddenly, the future looks brighter for HMOs. PMID- 10107852 TI - How are we doing? A look at the compensation levels of Rhode Island volunteer administrators. PMID- 10107854 TI - How cost-cutting measures can backfire on patients. PMID- 10107855 TI - HCFA's new rules may shut down your office lab. PMID- 10107856 TI - Will this case ignite another malpractice explosion? PMID- 10107857 TI - Quit Medicare? It's easier said than done. PMID- 10107858 TI - Practice expenses take the leap of the decade. PMID- 10107859 TI - Enid Graham memorial lecture 1990. Idealism to burnout: bridging the gap. PMID- 10107861 TI - Today's support service managers: professionals or hired hands? PMID- 10107860 TI - An analysis of the epistemic orientation of first- and third-year students in a physiotherapy program. AB - Previous research has demonstrated that practitioners within the same profession share a common approach to knowledge acquisition and transmission. A search for the identification of this common approach to knowledge in physiotherapy was undertaken using the Epistemic Orientation Model. The research reported was premised on the assumption that students admitted to physiotherapy programs in Canada possess an epistemic orientation that is similar to the epistemological structure of the knowledge base considered important to the program. Using a standardized instrument known as the Knowledge Accessing Modes Inventory (KAMI) to measure epistemic orientation, data were collected from a sample (N = 59) of first- and third-year students registered in a physiotherapy program in a central Canadian university. The data indicated that a high degree of association exists between the epistemological structure subsumed in the knowledge base deemed essential to gain admission to the program and the dominant rational epistemic mode of the practitioners-to-be. Based on the results, the article examines the usefulness of the epistemic orientation concept on activities within the profession. Implications for professional development are noted and avenues for further research are suggested. PMID- 10107862 TI - Is this a rental laundry? Is this an NOG laundry? PMID- 10107863 TI - All systems "go" at this Canadian laundry. PMID- 10107864 TI - Evaluating the QM (quality management) program. PMID- 10107865 TI - Reducing the cost of short-term nursing vacancies. PMID- 10107866 TI - Abandoned planning costs. Are they capital-related? Do they affect your contractual allowances? PMID- 10107867 TI - Special report. "Doc--we shrunk the group". PMID- 10107869 TI - Perspectives. High stakes bidding on capital. PMID- 10107868 TI - Perspectives. Taking the public's health care pulse. PMID- 10107870 TI - Perspectives. 1990: a year in review. PMID- 10107871 TI - EMS pilots: selecting the very best. AB - This article has reviewed factors that should be taken into account when screening prospective pilots for EMS flight programs. While all may not apply directly to all programs, assessing the elements relevant to a particular program will enhance the quality of the selection process. Additionally, the orientation process can be shortened considerably when pilots who already have the necessary skills and experience are hired. This can prove more cost-effective, by shortening the time it takes for a pilot to meet the program's requirements. Safety is also impacted positively, as pilots with experience and skills in all elements are less likely to make potentially life-threatening mistakes through lack of knowledge. If pilots truly are the most critical factor in maintaining the safety of flight operations, it makes sense to choose the very best available. Hospital program managers should determine who is responsible for pilot selection, and take steps to ensure that the most qualified pilots are being recruited. Consideration of the factors mentioned here in the selection process will give managers a better shot at choosing the very best. PMID- 10107872 TI - Managing a flight crew. Interview by Howard M. Collett. PMID- 10107874 TI - Evaluation of an end-tidal carbon dioxide detector in the aeromedical setting. AB - Endotracheal intubation is a lifesaving technique performed by flight crews often under difficult circumstances. Inadvertent unrecognized esophageal intubation is reported to occur up to 8% of the time. Recently a new disposable device has been developed to assist in determining proper endotracheal tube placement. The FEF end-tidal carbon dioxide detector (Fenem Co.) was evaluated in this study. From June 1989 to January 1990, all patients intubated or transported with endotracheal tubes in place by LifeStar, helicopter Emergency Medical Service, had the FEF detector positioned on the endotracheal tube. Flight crews continuously monitored changes in the indicator of the FEF during transport. On arrival to the emergency department, tube position was verified with direct laryngoscopy by an emergency department physician or trauma surgeon. Thirty-five patients were entered into the study. Thirty-four were identified by direct laryngoscopy as having proper placement of the their endotracheal tube and one was found to be intubated in the esophagus. The FEF device properly identified the single esophageal intubation and accurately identified proper position of the endotracheal tube in thirty-two patients. Of the three patients in cardiopulmonary arrest, the FEF device was accurate in detecting tube position in each case. The overall sensitivity of the FEF detector in this aeromedical setting was 94%. Specificity was calculated as 100%. The overall positive predictive value of the FEF detector was 100%. We therefore conclude that indication of a tracheal intubation by the FEF detector is reliable after six breaths in the aeromedical setting and advocate its use as an adjunct for monitoring tube position while in flight. PMID- 10107873 TI - Predictors of flight nurse job satisfaction. AB - A mail survey was conducted to investigate occupational stress, depression, and job satisfaction among flight nurses. Multivariate multiple regression was used to predict job satisfaction and depression simultaneously. Age, gender, marital status, years employed in air medical transport, employment in a hospital-based program, employment in a program which made scene responses, and stress were the independent variables. The multivariate equation (lambda = 0.54, F14,684 = 17.55, p less than 0.0001) and the univariate equations predicting depression (F7,343 = 24.04, p less than 0.0001) and job satisfaction (F7,343 = 24.09, p less than 0.0001) were significant. Stress was a highly significant predictor of both depression (t = 12.48, df = 1, p less than 0.0001) and job satisfaction (t = 12.13, df = 1, p less than 0.0001). Older respondents were more likely to be satisfied with their jobs (t = 1.99, df = 1, p less than 0.05), and respondents who made scene responses were less likely to be satisfied (t = -2.41, df = 1, p less than 0.05). Identification of flight nurses experiencing high levels of stress and interventions to alleviate this stress, utilizing the experience of older flight nurses, and adequate preparation for scene responses may enhance job satisfaction and perhaps reduce attrition. PMID- 10107875 TI - Looking into LOX. The benefits and limitations of liquid oxygen systems for air medical helicopters. PMID- 10107876 TI - A helicopter cost analysis. PMID- 10107877 TI - Conference showcases newest aircraft and configurations. AAMS conference report. PMID- 10107878 TI - Services expand in a newly unified Germany. PMID- 10107879 TI - HCFA clarifies reimbursement for air medical services. PMID- 10107880 TI - Health care: trends and turmoil. PMID- 10107881 TI - Hospital Admitting Personnel Week. PMID- 10107882 TI - Kids can't wait while adults debate. PMID- 10107883 TI - Health care: similarities and differences, Canada and the United States. PMID- 10107884 TI - Utilization management: the most serious problem facing hospitals. PMID- 10107885 TI - Medicare beneficiary message. PMID- 10107887 TI - Standardization of insurance information. PMID- 10107886 TI - Standardization: the issue and the action plan. PMID- 10107888 TI - Innovation in the supply and installation of a liquid oxygen tank. PMID- 10107889 TI - The application of modern nurse call systems to flexible nursing. AB - This paper has shown how modern digital technology is being applied to nurse call systems and how integrated bed head services can be provided using the minimum number of cables and offering the maximum facilities within a very modest cost increase. PMID- 10107890 TI - Replacing Strowger PABX's. PMID- 10107892 TI - Nothing but the facts? The legal side of interviews. PMID- 10107891 TI - Questions, questions & more questions. PMID- 10107893 TI - Interview preparation. How to avoid surprises. PMID- 10107894 TI - The application. A sleeping giant. PMID- 10107896 TI - Back to the future with computer interviewing. PMID- 10107895 TI - After the interview, what's next? PMID- 10107897 TI - Resource directory. Pharmacy state licensing agencies and associations. American Pharmaceutical Association. PMID- 10107898 TI - Treatment for overcoming rejection. PMID- 10107899 TI - The journey to selection. Interview dynamics. PMID- 10107900 TI - The anatomy of an interview. PMID- 10107901 TI - What's ahead for 1991? PMID- 10107902 TI - What's ahead for retiree health? PMID- 10107903 TI - Claims administration: finding the right match. PMID- 10107904 TI - More employers deal directly with hospitals. PMID- 10107905 TI - Rewarding healthy behavior. PMID- 10107907 TI - Data watch. The future of health benefits. PMID- 10107906 TI - Court narrows landmark liability ruling. PMID- 10107908 TI - Contract medical care; non-federal hospital payment rates--DVA and HHS. Final regulations. AB - The Department of Health and Human Services (HHS) and the Department of Veterans Affairs (VA) have jointly amended VA's medical series of regulations to carry out provisions of Public Law 99-576, Veterans' Benefits Improvement and Health-Care Authorization Act of 1986. These regulations describe the payment methodology and amounts for non-Federal public and private hospital care provided at VA expense. Payment methodology and amounts will be determined by the Health Care Financing Administration (HCFA) PRICER. PMID- 10107909 TI - Privacy Act of 1974; computer matching program--HCFA. Notice of a matching program--HCFA's Health Insurance (HI) Master Record and information from four Railroad Retirement Board (RRB) systems of records. AB - The Department of Health and Human Services is providing public notice that the RRB agrees to disclose information concerning Medicare eligible railroad retirees to HCFA. The matching report set forth below is in compliance with the Computer Matching and Privacy Protection Act of 1988 (Pub. L. No. 100-503). PMID- 10107910 TI - Medicare program; changes to the inpatient hospital prospective payment system and FY 1991 rates; correction--HCFA. Final rule; correction. AB - In the September 4, 1990 issue of the Federal Register (FR Doc. 90-20677), (55 FR 35990), we made revisions to the Medicare inpatient hospital prospective payment system and set forth the prospective payment rates for FY 1991. This notice corrects errors made in that document. PMID- 10107911 TI - Medicare program; inpatient hospital deductible and hospital and skilled nursing facility coinsurance amounts for 1991--HCFA. Notice. AB - This notice announces the inpatient hospital deductible and the hospital and skilled nursing facility coinsurance amounts for services furnished in calendar year 1991 under Medicare's hospital insurance program (part A). The Medicare statute specifies the formulae to be used to determine these amounts. The inpatient hospital deductible will be $628. The daily coinsurance amounts will be: (a) $157 for the 61st through 90th days of hospitalization in a benefit period; (b) $314 for lifetime reserve days; and (c) $78.50 for the 21st through 100th days of extended care services in a skilled nursing facility in a benefit period. PMID- 10107912 TI - Medicare program; changes to the inpatient hospital prospective payment system and fiscal year 1991 rates--HCFA. Correction. PMID- 10107913 TI - State of organization, functions, and delegations of authority--HCFA. PMID- 10107914 TI - Federal financial participation in state assistance expenditures; federal matching shares for Aid to Families with Dependent Children, Medicaid, and aid to needy aged, blind, or disabled persons for October 1, 1991 through September 30, 1992--HHS. Notice. AB - The Federal Percentages and Federal Medical Assistance Percentages for Fiscal Year 1992 have been calculated pursuant to the Social Security Act (the Act). These percentages will be effective from October 1, 1991 through September 30, 1992. This notice announces the calculated "Federal percentages" and "Federal medical assistance percentages" that we will use in determining the amount of Federal matching in State welfare and medical expenditures. The table gives figures for each of the 50 States, the District of Columbia, Puerto Rico, the Virgin Islands, Guam, American Samoa, and the Northern Mariana Islands. Programs under title XIX of the Act exist in each jurisdiction; title IV-A programs in all jurisdictions except American Samoa and the Northern Mariana Islands; programs under titles I, X, and XIV operate only in Guam and the Virgin Islands; while a program under title XVI (AABD) operates only in Puerto Rico. The percentages in this notice apply to State expenditures for assistance payments and medical services (except family planning which is subject to a higher matching rate). The statute provides separately for Federal matching of administrative costs. Sections 1101(a)(8) and 1905(b) of the Act, as revised by section 9528 of Pub. L. 99-272, require the Secretary of Health and Human Services to publish these percentages each year. The Secretary is to figure the percentages, by formulas in sections 1101(a)(8), and 1905(b) of the Act, from the Department of Commerce's statistics of average income per person in each State and in the Nation as a whole. The percentages are within upper and lower limits given in those two sections of the Act.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10107915 TI - Medicare program; establishing procedures for transmitting information between Medicare carriers and Medicare supplemental insurers--HCFA. General notice. AB - This notice announces and describes the procedure for the automatic transfer of claims information from Medicare carriers to Medicare supplemental (Medigap) insurers when a beneficiary has assigned his or her right of payment to a participating physician or supplier. It delineates the roles of the Medicare carriers, Medigap insurers, State insurance departments, beneficiaries, physicians and suppliers, and HCFA. The procedure for the automatic transfer of claims is required by section 1842(h)(3)(B) of the Social Security Act, as added by section 4081(a) of the Omnibus Budget Reconciliation Act of 1987 and is intended to speed payment of Medicare supplemental insurance benefits to participating physicians and suppliers. PMID- 10107916 TI - Medicare hit is not all that painful. PMID- 10107917 TI - Opportunities for better health in the elderly through various forms of mass catering. AB - Mass catering systems can be used to provide food for the elderly in their own homes, in luncheon clubs, in residential homes and similar establishments and in hospitals. Food and service should be not only nutritionally correct, but also pleasing and acceptable. Eating contributes to psychological and social as well as physical health. Because of limited budgets, strict control of suppliers must be maintained with clear specifications of all items. Staff responsible for menu planning and food service must be adequately trained. Meals should be enjoyable as well as healthy. PMID- 10107918 TI - Effects of an intervention program and its components on NICU infants. AB - This study examined the effect of a parent training program and its two components on the development of 48 graduates of neonatal intensive care units. When the infants were 6 months of age, infants whose parents participated in either of the treatment groups that included the parent education class scored higher on the Bayley Mental Scale than the other groups of infants. All treatment group parents were rated by the babies' physicians as providing better nutrition for their infants. The developmental assessment component of the training program was not found to enhance infant mental development. Implications for intervention, program development, and research are presented. PMID- 10107919 TI - The psychosocial responses of school-age children to hospitalization. AB - This study examined the psychosocial responses of school-age children to hospitalization. The subjects were 50 children, between 8 and 12 years of age, who were unscheduled admissions. The children's usual pre-hospital behavior was compared to their behavior during the first week following hospitalization and one month after dismissal. Repeated measure analysis of variance was used to demonstrate that there was no change in the school-age children's behavior following hospitalization. A moderate relationship was found between the children's usual prehospital behavior and the number of previous hospitalizations. Family function was related only to the children's behavior one week after dimissal. the children's usual prehospital behavioral problems were related to their behavior at all three times. No relationship was found between the length of hospitalization or the number of previous hospitalizations and their post hospital behavior. PMID- 10107920 TI - Children's Day--a cooperative effort in planning a health fair. AB - Children and Hospitals Week has traditionally been a vehicle for educating the community and health care professionals about the psychosocial needs of hospitalized children. An effective way of reaching both populations is by hosting a children's health fair. This paper describes how the staff of a 531 bed community based hospital collaborated to implement such an event. PMID- 10107921 TI - Anencephalic infants as a source of organs: the need for caution. PMID- 10107922 TI - Clinical pharmacy workload measurement: pharmacokinetic and drug information services. AB - Clinical workload measurement statistics have not been completely documented or related to service characteristics. The Clinical Hospital Pharmacy Administrative Group of British Columbia measured the time required for provision of clinical pharmacokinetic and drug information services utilizing standard definitions of component activities. Pharmacists in 10 participating hospitals independently recorded the time required for the various components of these services. The data collected allows for an estimation of workload requirements by similar institutions and allows for comparison of the impact of differences in methods of organization of the services on workload measurement. PMID- 10107923 TI - Bulk compounding in Canadian hospitals--a survey. AB - A five-page English survey was mailed to 350 Canadian hospitals with 100+ beds to identify aspects of pharmacy bulk compounding services. The survey used open ended questions to determine demographic and background information of the hospitals surveyed, availability of bulk compounding services and associated personnel requirements, products and dosage forms compounded, and compliance with "CSHP Guidelines for Bulk Compounding of Products in Hospitals". A 47.4 percent response rate was achieved. Sixty-six percent of respondents provided bulk compounding services. Proportionately, teaching hospitals were more likely to compound (84.6%) than other types of hospitals. Hospitals with 400+ beds were more likely to compound (85.7%) than hospitals with less than 400 beds (55.7%). No pattern was determinable for personnel requirements necessary for bulk compounding services. Items compounded most frequently were topical (80%) or oral (79.1%) preparations. Dosage forms most likely to be compounded were solutions (81.8%), ointments (69.1%) and suspensions (68.2%). Cocaine solution was the most commonly prepared product (47.3%). Compliance with CSHP standards was generally good (50-90%). PMID- 10107924 TI - Cefoxitin use review. AB - Due to an increase in cefoxitin use at The Mississauga Hospital, a Drug Utilization Review (DUR) was conducted as part of the DUR program. The study was designed to determine the cefoxitin prescribing pattern, assess the appropriateness of use, calculate the cost associated with inappropriate use, and estimate future potential cost savings. Two evaluators (pharmacist and infectious disease specialist), reviewed cefoxitin use retrospectively during a four-month period for 82 patients who received a total of 100 courses of therapy. The appropriateness of cefoxitin use was assessed according to the predefined criteria that were developed and accepted by the hospital pharmacy, infectious disease and medical staff. Cefoxitin was prescribed more frequently by the department of surgery (45%) of the courses studied, while the medical and obstetric and gynecology services were responsible for the remainder of courses (24% and 31% respectively). Overall, 42% of the courses were deemed inappropriate and 11% were questionable, based on the choice of agent (62%) and the duration of treatment and prophylaxis (33%). The observed inappropriate use represented 22% of the amount spent on the total cefoxitin treatment of the 82 study patients. If cefoxitin had been prescribed appropriately, an estimated $11,873 could potentially have been saved annually by the hospital. Based on these results, recommendations for improving the quality and quantity of cefoxitin use were developed. Follow-up concurrent DUR's with pharmacist interventions were initiated and found to be cost-effective. PMID- 10107925 TI - The feasibility of using EMLA (eutectic mixture of local anaesthetics) cream in pediatric outpatient clinics. AB - EMLA is a eutectic mixture of local anaesthetics, lidocaine and prilocaine, effective in alleviating the pain of venous puncture in children. The lag time of 60 minutes, which is necessary to achieve effective anaesthesia after skin application, may be an important obstacle to the use of EMLA. In this study we recorded the routine practice of six pediatric outpatient clinics which may use EMLA. Our data show a large variability in the feasibility of using EMLA: In the Hematology-Oncology clinics 85% of the patients could benefit from EMLA without prolonging their hospital stay; in the Neurology clinic the mean waiting time is 60.2 +/- 45 minutes, and an additional 15 minutes would be required for only 26 percent of the patients. In four other clinics where the blood work is performed at the phlebotomy station, the waiting time before venous puncture ranges from five to 12 minutes and the use of EMLA would require major changes in the organization of the clinic, or a longer waiting time. In children suffering from chronic diseases, for whom painful medical procedures are a major cause of anxiety, the additional waiting time may be acceptable by both patients and their parents. PMID- 10107926 TI - Conversion from minibags to mini-infuser syringe pumps. PMID- 10107927 TI - Consultant pharmacists to assist with cost-containment and enhanced drug use management. PMID- 10107928 TI - HMO databases: fertile ground for epidemiological research. AB - The computerized databases maintained by health maintenance organizations (HMOs) are a rich new source for health research. The authors describe the process by which health-related research became sanctioned at Lovelace Medical Center in Albuquerque, N.M., and its affiliated HMO. They review research conducted with several other HMO databases and suggest numerous possibilities for studying the incidence, distribution and control of disease using the vast data collected in managed care database systems. PMID- 10107929 TI - From mini to mainframe: how one HMO made the leap. AB - As HMO enrollment climbs, managed care companies like Sacramento-based Foundation Health are turning to easily upgradable systems to give management and customers the information edge they need to thrive in the 1990s. PMID- 10107930 TI - Choosing practice management systems wisely. PMID- 10107931 TI - Using the LIS as a strategic tool. AB - A major shift in emphasis is now occurring in pathology informatics, the subdiscipline within pathology that focuses on automated information management. This shift involves a much greater emphasis on both the strategic value of the pathology database and high-level applications running on the laboratory information system (LIS). PMID- 10107932 TI - Hospital reaps benefits from PC-based LIS. AB - The activity that takes place in a hospital's laboratory can greatly impact the real and perceived quality of patient care. And, as one Ohio hospital found, a networked laboratory system can make the benefits that much greater. PMID- 10107933 TI - Proposed HCFA lab rules: the changing face for LIS. AB - The proposed Subpart P regulations are well-intended, but in many instances fail to take into account the capabilities of present state-of-the-art laboratory information systems and, in effect, may result in increased cost. This may preclude many laboratories from taking advantage of today's available technologies and systems. However, a number of the regulations are reasonable and non-aversive, and in fact reflect what is presently occurring in most well managed computerized laboratories. CIOs and MIS directors may be interested in the ASTM (American Society for Testing and Materials) 1990 Annual Book of ASTM Standards, which includes several useful standards pertaining to computerized laboratory systems. PMID- 10107935 TI - Parental and family leave laws: a review and analysis. PMID- 10107934 TI - Designing information systems to increase quality care. PMID- 10107936 TI - Benefits in a changing workforce. AB - Demographic, social and political trends have strong implications for benefit programs, Mr. Caulfield notes. He discusses their particular significance for health care benefits. PMID- 10107937 TI - Managing vision care benefits. PMID- 10107938 TI - A clarification of recent COBRA changes. PMID- 10107939 TI - 1990 N.E.H.A. (National Executive Housekeepers Association) salary survey. PMID- 10107940 TI - Neutral all-purpose cleaner. PMID- 10107941 TI - Sanitation and disinfection key to infection control. PMID- 10107942 TI - How the US responded to disaster in the Soviet Union. PMID- 10107943 TI - Increasing the supply of health personnel: what has been gained? PMID- 10107944 TI - The 1990s: core values, core change. PMID- 10107946 TI - And what else is new for health professionals? PMID- 10107945 TI - Health personnel: the challenges ahead. AB - The interrelations between the changing supplies of health professional personnel and the evolving health care system have been conspicuously underresearched and underevaluated. In part this reflects the relative independence of the two sectors--health education and training, and health services--in ambulatory and hospital settings. In part it reflects the strong guild arrangements that make it difficult for health care managers to exercise much initiative/discretion in developing new patterns of personnel utilization aimed at greater efficiency and economy. Considering the fact that personnel costs account for about 60 percent of all health care costs, this relative neglect of improved personnel utilization is that much more costly. This article sets out the major dimensions of the three critical personnel groups--physicians, nurses, and allied health workers--and reviews the forces affecting their numbers and utilization. Finally, it raises some issues related to the near- and middle-term changes that lie ahead. PMID- 10107947 TI - Development of an organizational strategic planning process for a hospital department. PMID- 10107948 TI - Having your personnel decisions supported by upper management. PMID- 10107949 TI - Intimidation and the nurse manager. PMID- 10107950 TI - How to generate power in meetings. PMID- 10107951 TI - A brief look at information about AIDS: are you up-to-date? PMID- 10107952 TI - Criteria for evaluating performance: an empirical study of nonprofit hospitals. PMID- 10107953 TI - Occupational health risks for hospital nurses: significant concerns for administrators. PMID- 10107954 TI - The changing face of people management: effects on the first-line supervisor. PMID- 10107955 TI - Special report on medical staff relationships. An update of cases under COBRA/OBRA patient transfer law. PMID- 10107956 TI - The power of product integrity. AB - In the dictionary, integrity means wholeness, completeness, soundness. In products, integrity is the source of sustainable competitive advantage. Products with integrity perform superbly, provide good value, and satisfy customers' expectations in every respect, including such intangibles as their look and feel. Consider this example from the auto industry. In 1987, Mazda put a racy four wheel steering system in a five-door family hatchback. Honda introduced a comparable system in the Prelude, a sporty, two-door coupe. Most of Honda's customers installed the new technology; Mazda's system sold poorly. Potential customers felt the fit--or misfit--between the car and the new component, and they responded accordingly. Companies that consistently develop products with integrity are coherent, integrated organizations. This internal integrity is visible at the level of strategy and structure, in management and organization, and in the skills, attitudes, and behavior of individual designers, engineers, and operators. Moreover, these companies are integrated externally: customers become part of the development organization. Integrity starts with a product concept that describes the new product from the potential customer's perspective- "pocket rocket" for a sporty, subcompact car, for example. Whether the final product has integrity will depend on two things: how well the concept satisfies potential customers' wants and needs and how completely the concept has been embodied in the product's details. In the most successful development organizations, "heavyweight" product managers are responsible for leading both tasks, as well as for guiding the creation of a strong product concept. PMID- 10107957 TI - Ways women lead. AB - Women managers are succeeding not by adopting the traditional command-and-control leadership style but by drawing on what is unique to their experience as women. According to a study the author conducted for the International Women's Forum, men and women in similar managerial jobs make the same amount of money and experience roughly the same degree of work-family conflict. But when they describe their leadership styles, vast differences arise. Men are much more likely than women to view leadership as a series of transactions with subordinates, and to use their position and control of resources to motivate their followers. Women, on the other hand, are far more likely than men to describe themselves as transforming subordinates' self-interest into concern for the whole organization and as using personal traits like charisma, work record, and interpersonal skills to motivate others. Women leaders practice what the author calls "interactive leadership"--trying to make every interaction with coworkers positive for all involved by encouraging participation, sharing power and information, making people feel important, and energizing them. In general, women have been expected to be supportive and cooperative, and they have not held long series of positions with formal authority. This may explain why women leaders today tend to be more interactive than men. But interactive leadership should not be linked directly to being female, since some men use that style and some women prefer the command-and-control style. Organizations that are open to leadership styles that play to individuals' strengths will increase their chances of surviving in a fast-changing environment. PMID- 10107958 TI - The case of the machinists' mutiny. AB - "You can't be serious!" Mike Trail, the president and fourth-generation owner of Trail Manufacturing, stared at five older men standing in his office. "I'm afraid we are, Mike." Sandy, the most senior of the five, was polite but firm. "We won't switch over to the new equipment." Trail Manufacturing was a small Midwestern company trying to define itself in a new world of competition. Working with engineering chief Marco Duncan, Mike Trail, its young CEO, developed a program to revolutionize the company's manufacturing capability by installing six computerized machining centers. The $4 million automation program was proceeding smoothly, or at least it seemed to be, until the sixth of eight production teams, whose members included the company's most respected machinist, refused to continue participating. Mike canvased his colleagues for suggestions. "We can't let any screw machines remain in operation," Marco insisted. "The problem wasn't just old machines. The problem was--and is--the whole company. We need a clean break with the past." Shop manager Darrell Montgomery didn't necessarily disagree, but he worried about alienating Sandy. "You know what Sandy means to this place," he said. "If it wasn't for him, we never would have survived the startup." Bob Block, the company's CFO, went a step further. He questioned Marco's all-or-nothing vision and counseled compromise. "With half the new cells up, the screw machines are running a lot fewer jobs," he noted. "But they still account for over half our sales and even more of our profits. Maybe these guys are right." Four experts on change examine the crisis at Trail Manufacturing and debate Mike Trail's next step. PMID- 10107959 TI - Managing hybrid marketing systems. AB - As competition increases and costs become critical, companies that once went to market only one way are adding new channels and using new methods - creating hybrid marketing systems. These hybrid marketing systems hold the promise of greater coverage and reduced costs. But they are also hard to manage; they inevitably raise questions of conflict and control: conflict because marketing units compete for customers; control because new indirect channels are less subject to management authority. Hard as they are to manage, however, hybrid marketing systems promise to become the dominant design, replacing the "purebred" channel strategy in all kinds of businesses. The trick to managing the hybrid is to analyze tasks and channels within and across a marketing system. A map - the hybrid grid - can help managers make sense of their hybrid system. What the chart reveals is that channels are not the basic building blocks of a marketing system; marketing tasks are. The hybrid grid forces managers to consider various combinations of channels and tasks that will optimize both cost and coverage. Managing conflict is also an important element of a successful hybrid system. Managers should first acknowledge the inevitability of conflict. Then they should move to bound it by creating guidelines that spell out which customers to serve through which methods. Finally, a marketing and sales productivity (MSP) system, consisting of a central marketing database, can act as the central nervous system of a hybrid marketing system, helping managers create customized channels and service for specific customer segments. PMID- 10107960 TI - Why change programs don't produce change. AB - Faced with changing markets and tougher competition, more and more companies realize that to compete effectively they must transform how they function. But while senior managers understand the necessity of change, they often misunderstand what it takes to bring it about. They assume that corporate renewal is the product of company-wide change programs and that in order to transform employee behavior, they must alter a company's formal structure and systems. Both these assumptions are wrong, say these authors. Using examples drawn from their four-year study of organizational change at six large corporations, they argue that change programs are, in fact, the greatest obstacle to successful revitalization and that formal structures and systems are the last thing a company should change, not the first. The most successful change efforts begin at the periphery of a corporation, in a single plant or division. Such efforts are led by general managers, not the CEO or corporate staff people. And these general managers concentrate not on changing formal structures and systems but on creating ad hoc organizational arrangements to solve concrete business problems. This focuses energy for change on the work itself, not on abstractions such as "participation" or "culture." Once general managers understand the importance of this grass-roots approach to change, they don't have to wait for senior management to start a process of corporate renewal. The authors describe a six step change process they call the "critical path." PMID- 10107961 TI - What working for a Japanese company taught me. AB - In the late 1970s, John E. Rehfeld read everything he could on Japanese business. Most of the discussions focused on interest rates, the education system, and the culture--all very interesting but not very useful. What did these things have to do with day-to-day management? Since then, by working for Japanese companies, he has discovered more than ten Japanese management techniques that have everything to do with running a business. As vice president and general manager of Toshiba's U.S. computer business for nine years and president of Seiko Instruments USA for two, he has seen firsthand how the Japanese manage, and he has applied those techniques in the United States. Using six-month budget cycles, quantifying intangibles, and looking back to see what you could have done better are among the seemingly insignificant practices that combine to have big impact. For example, the author first saw budgeting for 6 months instead of 12 as twice as much work. But he came to appreciate the benefits: managers work harder because they have two deadlines a year, and planning and control improve because managers can adjust their targets to changing conditions more quickly. The author had another change of heart when he was asked to specify how many PCs would sell as the result of a demo program, a task he first thought ridiculous. Though he still thinks such numbers are shaky, he values the discipline of the thought process. These and other techniques, he says, explain much of Japanese companies' success and are tools that managers anywhere can use. PMID- 10107962 TI - The myth of the missing manager. PMID- 10107963 TI - Excerpts from "The President and the Board of Directors." Originally published in March-April 1972. PMID- 10107964 TI - How I learned to let my workers lead. AB - In 1980, Ralph Stayer owned a successful, growing sausage company that had him badly worried. Commitment was poor, motivation was lousy, the gap between performance and potential was enormous. Over the next five years, Stayer turned the company upside down, but only by turning himself upside down first. For years he had insisted on his own control, made all decisions, delegated nothing. But when he tried to picture what the company would have to look like to sell the most expensive sausage and still enjoy the biggest market share, he saw an organization whose employees took responsibility for their own work. After several false starts, he finally began in earnest by making himself give up much of his own authority. Stayer turned quality control over to the workers on the production line. Workers also began answering letters of complaint from customers. Rejects went from 5% to 0.5%. Employees thrived on their new responsibility and asked for more. Gradually, people on the shop floor took over personnel functions as well, followed by scheduling, budgeting, and capital improvements. Managers came to function more as coaches than as bosses. Stayer--a little to his own dismay--began to find himself superfluous. In mid-1985, the company faced a watershed decision--whether or not to accept a massive new order that would make huge demands on every employee and strain the company's capacities. Stayer asked the employees to make the decision. They accepted the challenge, and productivity, profits, and quality all rose dramatically. By the late 1980s, Stayer had reached his goal of working himself out of a job. PMID- 10107965 TI - Excerpts from "Let's Get Back to the Competitive Market System." Originally published in November-December 1973. PMID- 10107966 TI - Infant kidnapping: an update. PMID- 10107967 TI - Menu planning to control costs. PMID- 10107968 TI - Employee recognition programs without food. PMID- 10107969 TI - The Planetree patient care model. PMID- 10107970 TI - Stress--what causes it? How can you reduce it? PMID- 10107971 TI - Strategies for managing the merger. Helping the staff adjust. AB - A strong reason why many mergers fail is the corporation's neglect of the human side of the venture; the resulting high turnover of personnel naturally takes its toll on the young conglomerate. While keeping everyone satisfied is obviously not easy (or even possible), there are concrete strategies for leading your staff through the transition. PMID- 10107972 TI - Changes in the healthcare profession: from denial to acceptance. AB - As the government and other factors seem to be increasingly gaining control over the healthcare industry, many hospital managers and staff feel as if they're increasingly losing control over their jobs and their futures. Indeed, some administrators and physicians are experiencing a kind of stress that may be seen as a grief for the way things once were. Using Elisabeth Kubler-Ross's stages of the grieving process, the author explains how such stress can be managed and some control regained. PMID- 10107973 TI - Putting the squeeze on emergency medicine. The many pressures on today's ED. AB - Whether it's indigent care, cost containment, transfer laws, financially wary HMOs, overcrowding, reimbursement, or emergency-department inefficiency, the factors "putting the squeeze" on emergency medicine seem to multiply with each new survey. These pressures, the authors feel, are not only weakening the provision of emergency care but also strengthening the argument for a national health plan. PMID- 10107974 TI - A materials-management quality assurance program. AB - Because the quality of a hospital depends on more than just the quality of its clinical departments, shouldn't the QA efforts required of clinical departments be duplicated throughout the institution? With the sensible insistence that quality should be a hospital-wide phenomenon, one materials manager explains how his hospital developed and implemented a materials QA plan. PMID- 10107975 TI - Staff suggestions on the nursing shortage. Nurses' recommendations on short- and long-term solutions. AB - The current nursing shortage has been with us in lesser forms for years, yet only now is attention being paid to possible solutions. To elucidate those solutions, the authors interviewed twenty-five New York City staff nurses, who eagerly gave their views on short- and long-term answers to the shortage, such as the use of temporary nurses and the need for autonomy and respect. PMID- 10107976 TI - The home environment. PMID- 10107977 TI - Hospitals and the False Claims Act Amendments of 1986. PMID- 10107978 TI - Assessing the requirements of hospital-sponsored child daycare. AB - Staff shortages have made many hospitals consider providing child daycare for employees. This article summarizes employee expectations and the market findings of an analysis conducted at Shands Hospital at the University of Florida. It evaluates the financial feasibility of a child daycare center and discusses factors that make child daycare a questionable business venture. It also looks at strategies for enhancing available child daycare without providing services directly. PMID- 10107979 TI - Walk-in-clinics versus private practitioners: determinant attributes of health care provider choice among the elderly. AB - This study investigated the perceptions of elderly individuals concerning their choice between two types of health care facilities: walk-in-clinics and private practitioners. A determinant attribute approach was employed using the perceptions of the elderly on twenty-six attributes and the importance of each of these attributes in choosing a health care facility. It was found that quality, sociopsychological, and economic attributes were determinant while convenience attributes were not determinant. Implications for health care providers are discussed. PMID- 10107980 TI - Health care coverage--resolving the uninsured employee dilemma: government mandates or incentives? PMID- 10107981 TI - University catalogues and HMO co-payments: simple lessons in economic rationing. AB - The rise of health maintenance organizations and its preferred provider kindred has encouraged an increased use of so-called reduced fee services. HMOs have historically marketed themselves as a cost-efficient, more holistic approach to providing for health care needs than do fee-based plans (insurance). But the typical pricing structure appears to have caused unanticipated and undesirable usage patterns to appear. Similar problems are shown to exist in non-medical environments. PMID- 10107982 TI - Determinants of health care satisfaction: a national study of HMO and fee-for service consumers. AB - This study examines the extent to which different health care attributes determine health care satisfaction. It employed two national cross-sectional samples, one of HMO members and the other of NON-HMO health care users. The comparative analysis revealed that the pattern of results for both samples were similar. The two most important attributes for both samples were health care costs and availability of specialists. Results suggest different marketing and related management strategies. PMID- 10107983 TI - Identification of significant information sources in a health care coverage decision. AB - Using partial correlation analysis, this research identified the significant information sources in a health care coverage decision. The findings were used to make communication suggestions for the marketing of open and closed panel prepaid health care coverage plans. PMID- 10107984 TI - Executive message ... education is the foundation upon which a profession is based. PMID- 10107985 TI - Analyzing the relationship with correspondence copying services. AB - Some healthcare managers think that medical record departments are not receiving the full benefits available to them from their correspondence copy service. What are they receiving and what should they be receiving? And, what are the copying service companies getting? What should they be getting? This article examines and redefines the relationship between copying services and medical record departments. PMID- 10107986 TI - Document image management systems: promise versus reality. AB - Do you dream of using a document image management system at your facility? This article balances the reasons why healthcare facilities are slow to invest in such technology against the benefits offered by electronic document image management systems. The author also provides a list of vendors. PMID- 10107987 TI - Professional development. PMID- 10107988 TI - Practice forum: the "fat chart" diet. PMID- 10107989 TI - When is it time? PMID- 10107990 TI - Taking charge: winning strategies for hospital CEOs in new positions. PMID- 10107991 TI - Attitudes and career experiences of male and female healthcare executives. AB - While the expression "battle between the sexes" may be a cliche, the question being asked in business and healthcare management circles focuses on who is rising to the top of the management hierarchy--the male or the female executive. Previous research has shown a smaller percentage of women than men make it to the senior levels of management in business. PMID- 10107992 TI - Transition from military to civilian healthcare. PMID- 10107993 TI - No violins, no apologies necessary: considering a career as a rural hospital executive. PMID- 10107994 TI - Postgraduate fellowships: are they fulfilling their career development promise? PMID- 10107995 TI - Executive performance: the demands of the 1990s. AB - Top executives will be required to have strong leadership skills, combined with solid communication and team-building skills, to move their organizations through a decade that will promise tight fiscal constraint, increasing involvement in the decision-making process from medical staff, trustees, government officials and facility personnel. The evaluation of the chief executive officer (CEO) will continue along traditional lines with the development of goals and objectives in defined areas of accountability. There will, however, be increased emphasis on the development of measurable standards, and the CEO's ability to lead the organization, motivate the organization's people resources and reallocate resources to meet the organization's mission and the health care needs of the community. PMID- 10107996 TI - Conceptual models of the professions and their implications for the professionalization of health administration. AB - The extent to which health administration can be considered a profession is examined in the context of the five major models of the professions in the literature (historical, trait, functional, economic and power). A synthesis of the various models into a proposed integrative model, or typology of occupations, is also presented. Control over entry and control over conduct are identified as the two major dimensions by which the professional status of various occupations is measured. Health administration is seen as a profession in this context, and the prospects for further professionalization are discussed. PMID- 10107997 TI - Quality utilization management: preliminary results to a Canadian approach. AB - VI-CARE (Victoria Integrated Care Alternative Review and Evaluation) was introduced in 1988 to improve utilization of hospital services while matching patient needs to their care. Objective criteria were used to review admissions: examination of occupancy, waiting lists, the MedisGroup patient severity index and surgical hours indicate the preliminary success of the program. Formal research is underway, but article two of the two-part series suggests targeted utilization be implemented in conjunction with quality assurance activities. PMID- 10107999 TI - Link your business plan to a performance plan. AB - Because the planning process is where change originates, planners are in a unique position to provide leadership. Here are some techniques that planners can use to drive the productivity improvement process. PMID- 10107998 TI - Ethics committees in Canadian hospitals: report of the 1989 survey. AB - A survey of English-language hospitals with more than 300 beds in Canada was conducted in 1989 to assess institutional ethics committees. A dramatic increase was found in the growth of such committees, compared with a similar survey taken in 1984. The growth and the activities of institutional ethics committees are discussed, noting the need for more attention for research on their effectiveness. PMID- 10108000 TI - Self-directed work teams yield long-term benefits. AB - A growing number of business experts advocate that workers should take on some management tasks. Many companies are already experimenting with self-managing work teams. Here's how one company was able to achieve record productivity gains through total employee involvement. PMID- 10108001 TI - Rationing healthcare: is it time? PMID- 10108002 TI - In case of emergency. PMID- 10108003 TI - Making room in the marketplace. PMID- 10108004 TI - Passing the torch. Medical staff retirement planning maintains continuity of care. AB - A medical staff retirement program can ensure long-term accessibility to care for the community and financial viability for the hospital. Thus hospitals should become actively involved in the physician retirement planning process. By so doing, they can preserve a patient base that may have taken years to develop and, once lost, may be difficult to recover. To establish a successful medical staff retirement plan, hospitals should: 1. Analyze medical staff demographics. 2. Set procedures for determining the practice's value. 3. Develop an approach for financing the sale. 4. Define the hospital's role as a financial intermediary in the sale. 5. Determine whether the hospital will share costs with the seller. 6. Establish a communication plan to introduce the retirement program to the medical staff. In the sale of a physician's practice, some of the hospital's options include purchasing the practice, helping the seller find an associate to purchase the practice, initiating a group at the hospital and merging the practices into the group, or simply providing the physician with moral support. PMID- 10108005 TI - Network integration. A new vision for Catholic healthcare systems in the 1990s. AB - The 1990s will be the decade of network integration for many of the nation's healthcare organizations. Catholic healthcare systems will have to refocus on local and regional healthcare delivery. To succeed in local and regional markets, the systems will have to offer various levels of care through numerous types of providers, share services among facilities, cooperate with secular organizations, and build stronger affiliations with local parishes. Managing this change (from offering fragmented healthcare services to offering integrated services) will be a major challenge facing organizations in the decade ahead. They must develop a clearly articulated vision to provide stability during this time of rapid change. To meet the challenges of the 1990s, Catholic healthcare systems will have to determine the types of functional sharing that will be beneficial at the local level, divest and transfer sponsorship of facilities that burden the system's mission, and expand the activities of the laity. PMID- 10108006 TI - Alternative agendas. System priorities for the 1990s will differ from those of the last decade. AB - The Sisters of Charity Health Care Systems (SCHCS) was established in 1979 in response to changes in the U.S. healthcare system and to new needs of sponsors and Catholic healthcare facilities. However, the agenda that SCHCS leaders (and leaders of other systems) set at that time must now give way to an agenda that will address the new challenges and responsibilities facing the Catholic healthcare ministry in the 1990s. In its first decade of existence, SCHCS established and fulfilled a number of goals: It strengthened governance relationships, helped systems and sponsors better identify with local communities, enabled facilities to steward resources more effectively, and facilitated members' understanding of mission and sponsorship values. In the 1990s, however, systems will have to create more opportunities for regional, collaborative, and networking relationships among member facilities and between members and non-members. To achieve this, they will have to reevaluate their structures, find ways to faciliatate collaboration, make resources available to institutions outside the system, and develop an overall philosophy that enhances both the fiscal and spiritual well-being of member facilities. PMID- 10108007 TI - Common ground. Affiliations help freestanding facilities strengthen their ministry. PMID- 10108008 TI - At the core. A system measures the level of employee commitment to its core values. AB - Corporate culture has been described as the shared values that drive employee satisfaction and enhance employee commitment to the organization. Therefore system leaders must know the strength of their corporate culture. Sisters of St. Francis Health Services, Inc. (SFHS), wanted to measure whether it had a strong corporate culture based on its stated values. Executives, managers, and physicians completed surveys that assessed employee job satisfaction, commitment to the organization, and perceived strength of the system's culture. The survey achieved a 68 percent response rate. SFHS learned that it had a strong culture based on tradition and that special and unique core corporate values define "systemness" throughout its different facilities. Although each facility serves significantly different functions, leaders throughout the system make everyday decisions using the same core corporate values. PMID- 10108009 TI - Selecting a labor information system. What to ask, what to avoid. AB - Payroll expenses may account for over half of all of a hospital's expenses. Manual time card processing requires an abundance of staff time and can often result in costly errors. To alleviate this problem, many healthcare facilities are implementing computerized labor information systems. To minimize the risk of selecting the wrong system, hospital administrators should ask the following questions before committing to any computerized labor information system: Is the software designed for hospital use and easily adaptable to each hospital's unique policies? How flexible is the software's reporting system? Does it include automatic scheduling that creates generic schedules? Does the system have the capability of securing time and attendance records and documenting the audit trail? Does the system include an accurate and reliable badge reader? What type of hardware is best for the particular hospital--microcomputer, minicomputer, or mainframe? Finally, to guarantee successful software installation, the vendor should have extensive experience and documentation in the system's implementation. PMID- 10108010 TI - Does the Data Bank inhibit peer review? PMID- 10108011 TI - You've got a friend. PMID- 10108013 TI - Reaching inside for innovative ideas. PMID- 10108012 TI - Holy Cross Health System. Recruiting an endangered species. PMID- 10108014 TI - A bridge in time. PMID- 10108015 TI - NAQAP position paper: The role of QI (quality improvement) in health care QA. National Association of Quality Assurance Professionals. PMID- 10108017 TI - Interfacing QA and safety. PMID- 10108016 TI - Nursing QA in the '90s: revisions in the JCAHO nursing services standards. PMID- 10108018 TI - Ochsner Clinic QI (quality improvement) project: day-of-admit surgery chart availability for the anesthesiologist. PMID- 10108019 TI - NAQAP (National Association of Quality Assurance Professionals) looks to the future. PMID- 10108020 TI - Top 10 health care law firms--ranked by number of attorneys spending more than 75% of their time on health law. PMID- 10108021 TI - The President's message to the House of Delegates. National Association of Quality Assurance Professionals. PMID- 10108022 TI - Community and migrant health centers: an overview. PMID- 10108023 TI - Community health centers at 25: a retrospective look at the first 10 years. PMID- 10108024 TI - The hospital-health center collaborative: a model for ambulatory care. AB - In summary, the staff and administration of the Muhlenberg-health center project feel it has thus far been successful in meeting its original goals of reducing duplication, ensuring access, controlling costs, and maintaining quality care. We believe that this model of cooperation benefits both organizations and provides the patients served with an ambulatory care program that is superior to either of its predecessors. PMID- 10108025 TI - A hospital-community health center joint venture in Utah. PMID- 10108026 TI - Prepayment in community health centers. PMID- 10108027 TI - Prepayment and CHCs in North Carolina. PMID- 10108028 TI - Financing of outpatient care: the case of community health centers. PMID- 10108029 TI - Using epidemiologic data in primary care planning. PMID- 10108031 TI - Health screening and wellness programs for corporate executives: a new niche service. PMID- 10108030 TI - The medical autopsy: death analysis and community health centers. PMID- 10108032 TI - Sounds of the future? Ultrasonography in the field. AB - During the past two decades, the development and maturation of ultrasonography as a diagnostic tool has revolutionized the practice of radiology, cardiology, obstetrics and surgery. In fact, few areas of medicine have not been affected by this technology. Unlike the still-frame images of standard X-rays and computerized axial tomography (CAT) scans, ultrasound technology displays an ongoing cross-sectional image of an anatomic area in "real time," which can then be stored and played back on videotape. This ability to quickly assess function, as well as anatomy, has become invaluable in the management of critically ill patients. PMID- 10108033 TI - Seize the moment. The EMS role in organ donation. AB - Often the first on scene, EMTs and paramedics can play a crucial role in facilitating organ donation. Find out how you can identify potential donors and, ultimately, make transplantation possible. PMID- 10108034 TI - When there's a living will, is there a way? PMID- 10108035 TI - Seminar on the quality of medical care in hospitals. Special lecture: Future medical care in hospitals and in-hospital education. PMID- 10108036 TI - Japan's ODA and the Department of International Cooperation, National Medical Center Hospital. PMID- 10108037 TI - A new exchange movement among medical students in Asian countries. PMID- 10108038 TI - Japan's hospital management crisis. PMID- 10108039 TI - A decision support model and analysis for hospital administrators when choosing future strategies of their hospitals. AB - How to allocate a hospital's finite resources to health care is an extremely important problem for hospital management. This paper shows what kind of business strategies a given hospital should consider, and present a model to support such decision making. From the model, a hospital can decide how much to emphasize different tasks in order to set a given direction for the future. We used nonlinear discriminant functions to derive a decision support model, based on findings from 831 hospital directors. This model provides a probabilistic basis for deciding how much a given hospital should emphasize any of a number of different strategies. PMID- 10108040 TI - Comprehensive computer system in the outpatient clinic. AB - A clinical computing system in a one-physician outpatient clinic is described. It consists of a computer-stored medical history at its center with associated blood examination equipment, a drug delivering machine and a cost calculation program. Two-month's experience has demonstrated its eligibility to clinical practice. PMID- 10108041 TI - An application of an optical disk filing system to the management of medical records. AB - An optical disk filing system is a promising new method to memorize the contents of medical records. However, due to problems of image quality, input speed and durability with the disk, this has not yet been put to practical use. In the present study the image quality of the laser disk system installed in our hospital were checked, and this system was thought to be useful to store discharge summary. We developed discharge summary management system by inputting into the optical disks the discharge summary written freely by doctors and the discharge abstract automatically formed by computer. PMID- 10108042 TI - Development of an automatic medical summary report system. AB - We developed a medical summary report system. In this system, each department can specify the predetermined conditions for issuing the summary report. The summary is made through a hierarchical database in the integrated hospital information system according to the predetermined conditions. The summary automatically issued after reception of the outpatient, or also issued by on-line summary report program with the patient number if requested by doctors. The report is sent to the proper consulting room from the reception desk using an air-shooter. The report contains the patient information such as a patient name, age, sex, birthday, a clinic name, a chart number, a patient number, diagnoses and examinations. The doctors can refer to the points of the clinical history of the patient in his own and other departments, and make a correct diagnoses and avoid the overlaps of the examinations and medications. This system has contributed to the quality-up of the patient care by availability of patient information even in other departments without the medical chart. PMID- 10108043 TI - A disposable patient identification card made of a paper. AB - This paper describes a patient identification system with a disposable paper card. In general, total costs of cards themselves, equipments and personnel are remarkable, not negligible for the hospital management. Therefore, a disposable identification cards made of a paper were issued to out-patients in our hospital. Many order forms were integrated into only one sheet. Patient identification data were printed on this sheet by a computer system when a patient came to the reception desk, and quickly transmitted to physicians. We could save the hospital costs and printing works by physicians, and also shorten the waiting time of patients at reception desks. PMID- 10108044 TI - Utilization of a computerized system at the pharmacy department of the University of Tokyo Hospital--impact of prescription order entry and computerized dispensing system. AB - (1) A medication order entry system, (2) a fully automatic tablet counting and packaging machine connected with a medication order entry system, and (3) a check system for one dose package developed and implemented in the University of Tokyo Hospital are described. The principal objectives of these systems are (1) to reduce medication errors and the clerical workload of staff, (2) to make more efficient use of staff, (3) to provide staff with sufficient drug information for patient drug therapy. We compared computerized systems (post-computerization) and traditional multi-dose dispensing systems (pre-computerization) by analyzing inquiry rate and dispensing time in the pharmacy for inpatients. Inquiry rate was 23.0% and 2.6% for pre-computerization and post-computerization, respectively. Total dispensing time per patient was 207 seconds and 147 seconds for pre computerization and post-computerization, respectively. Implementation of the computerized systems helped significantly in decreasing inquiry rate and time needed to complete the dispensing process when compared with a traditional dispensing system. Implementation of the computerized systems was very useful for physicians, pharmacists, and nurses in conducting drug therapy. PMID- 10108045 TI - Therapeutic results of stomach and colorectal cancers in farming villages and measures to be taken in the future. PMID- 10108046 TI - Of "Arzt, Tod und Madchen" and Prof. Ivo Saliger. PMID- 10108047 TI - National statistics on multiphasic health testing (human dock and AMHTS)- especially for the annual-course change during the last five years. AB - We have gathered national statistics on multiphasic health testing since 1984, and especially analyzed annual-course changes of the past five years. 1) Subjects for questionnaire survey: Despite an increasing number of hospitals with human dock and institutions with automated multiphasic health testing and services (AMHTS), the reply rate to the questionnaire survey has also increased with the number of subjects for the survey being 900,000 in 1988. 2) In the survey of national statistics under the internal organ distinction, the detection rate of cancer of the stomach was the highest, followed by the rates of cancers of the large intestine and lung, in that order. The rate of cancer of the stomach to all the detected cancers decreased by 11.1% during these five years, whereas that of cancer of the large intestine increased to represent 40% of the rate of the stomach. The rate of early stage cancer for all cancers was high, for example, approximately 70% for the stomach and 75% for the large intestine, proving that multiphasic health testing provides excellent accuracy. 3) In the total results collected under item distinction, we examined six items (obesity, glucose tolerance failure, hepatic defficiency, hypertension, hypertriglyceridemia and hypercholesterolemia) which appear frequently and become sources of adult disease. We concluded that especially, hepatic deficiency and hyperlipidemia had increased each year, indicating a deterioration of health and also that regional differences showed a decreasing tendency. 4) The present analysis of the national statistics has apparently provided effective information as data of a preventive counterplan against adult disease. PMID- 10108048 TI - Placements & salaries 1989 steady on. PMID- 10108049 TI - Can patients evaluate the quality of hospital care? AB - We have found that patients have distinct opinions about many components of hospital care, but that little recent work has identified those components important to today's patients in the United States. Investigators have constructed reproducible scales to obtain evaluations. Patient evaluations of the interpersonal features of hospital care are influenced by interventions that physicians or nurses identify as "higher" quality of care. We do not know if patient reports and ratings of specific aspects of care accurately reflect the effects of hospital care on health outcomes--the quality standard that public agencies and payers may consider the most important. However, patient evaluations of nursing care and medical care are independently related to patients' overall satisfaction, overall assessments of quality, and intentions to recommend and return to the same hospital. More studies are needed to clarify whether other components of hospital care also contribute to these ratings and intentions and, if so, how much. Nonresponse bias affects patient surveys, making patient ratings of care in each sample more favorable than the population mean; we do not know how this affects conclusions of surveys that compare hospitals or treatments. Few studies have compared how different methods affect the reproducibility and accuracy of patient reports and ratings. Practical issues may be the most important obstacles for users of patient ratings, particularly regarding whether potential users will be able to interpret results and accept them. Finally, no comprehensive instrument or survey method in the published literature has been tested enough to be recommended as a reproducible, accurate, and interpretable quality measure: a few do, however, appear worthy of further testing. PMID- 10108050 TI - Improved stakeholder management: the key revitalizing the HMO movement? AB - In summary, our purpose has been to propose and to demonstrate that the survival of HMOs (in whatever form) depends on the proper identification and management of key stakeholder strategies. It is believed that identification and assessment of key stakeholders holds much promise for improving both HMO management and the future performance of HMOs. PMID- 10108051 TI - Planning and teamwork: critical health delivery issues. PMID- 10108052 TI - Physicians unions, are they healthy? PMID- 10108053 TI - How do your physician's earnings compare to MGMA survey results? PMID- 10108055 TI - AMA discloses salaries of top execs. PMID- 10108054 TI - End the search for the ideal physician income distribution plan. PMID- 10108056 TI - AMA conspiracy case comes to an end. PMID- 10108057 TI - Deficit could squeeze healthcare programs. PMID- 10108058 TI - AHA's latest reform plan could lead to rationing. PMID- 10108059 TI - Utah providers offered tax rules they now criticize. PMID- 10108060 TI - Pointing the finger. Who's to blame for high healthcare costs? AB - Who's to blame for soaring healthcare costs? How can we gain control of the problem? Is it time for rationing? Who'll pay for universal access? These are some of the questions posed in a poll of consumers, employers, physicians and hospital executives conducted for Modern Healthcare. While the results showed the four groups had common concerns regarding the scope of the problem, consensus was in short supply when it came to solutions. PMID- 10108061 TI - Surviving bankruptcy. Choate-Symmes emerges with plans to thrive. AB - Choate-Symmes Hospitals was a trend-setter in 1981 when it was formed to take advantage of economies of scale. Now the system, which has emerged from bankruptcy reorganization, may again prove a leader for the growing number of financially strapped hospitals and systems that could be facing a bankruptcy filing. PMID- 10108062 TI - Texas sues Methodist over charity care. PMID- 10108063 TI - Turnover turmoil in the executive suite. AB - Hundreds of hospital CEOs and thousands of other healthcare managers change or lose their jobs each year. For many executives who've lost their positions because of mergers, restructuring or poor performance, unemployment can be one of the most difficult turnaround situations in their careers. PMID- 10108064 TI - Republic opts for ambulatory care to increase share of San Diego market. PMID- 10108065 TI - HRET (Hospital Research and Educational Trust) chief dons many hats as a leader in healthcare's continuing quality quest. PMID- 10108066 TI - Hospital strike incidence stayed level in '90. PMID- 10108067 TI - Laventhol clients sit tight. PMID- 10108068 TI - Operating margins remain flat. PMID- 10108069 TI - Tax levy gives hospital chance for survival. AB - In 1987, executives of Preston Memorial Hospital, Kingwood, W. Va., said the hospital risked closure in five years. But now the facility, bolstered by a special tax levy and community support, is being touted as an example of how a rural hospital can redefine itself to remain competitive in the marketplace. PMID- 10108071 TI - New image-storing system introduced. PMID- 10108070 TI - Baxter to sponsor special TV forum. PMID- 10108072 TI - Physicians outscore nurses in care survey. PMID- 10108073 TI - SMS shareholder urges a merger. PMID- 10108074 TI - McGaw, Block Medical sign pact. PMID- 10108075 TI - UniHealth contracts with ServiceMaster. PMID- 10108076 TI - Two Charter execs resign. PMID- 10108077 TI - New law will require providers to inform patients of living wills. PMID- 10108078 TI - Ambulatory care of the 1990s stretches the imagination. AB - Hospitals are responding to consumers' demand for outpatient care in big ways. Some of the more innovative projects include renovating abandoned retail malls, building "superclinics" and leasing space in malls for health stores. But some experts say that even though the ambitious ambulatory-care projects generate traffic, they don't necessarily translate into more patients and revenues for the sponsoring hospitals. PMID- 10108079 TI - FTC probe threatens Calif. merger. PMID- 10108080 TI - Graduate medical education needs some new approaches. AB - Administrators want a more explicit system of funding graduate medical education to match costs more fairly and promote the training of more family-practice physicians, Sally Berger says. PMID- 10108081 TI - Graduate medical education payments may not escape Medicare cuts next year. PMID- 10108082 TI - Hospitals seek savings by cross-training caregivers. AB - A program at a handful of hospitals is seeking to improve efficiency by cross training skilled employees and staffing hospital positions according to location within the hospital instead of by specialization. PMID- 10108083 TI - Health services foundation to offer students financial aid. PMID- 10108084 TI - One L.A. hospital's strategy: more Medicaid, AIDS cases. AB - A community hospital in Los Angeles has picked a path to survival that many hospitals would choose to avoid: taking on extra Medicaid and AIDS patients to fill unoccupied beds. PMID- 10108085 TI - Maxicare emerges from Chapter 11. PMID- 10108086 TI - AMA endorses AIDS test reporting. PMID- 10108087 TI - VHA resolves dispute with medical building vendor. PMID- 10108088 TI - Drug marketing practices criticized. PMID- 10108089 TI - 'Federal Medicaid funding should be revamped'. PMID- 10108090 TI - Sandoz reverses pricing policy. PMID- 10108091 TI - FTC steps up antitrust probe. PMID- 10108092 TI - Study says closure decreased access. PMID- 10108093 TI - Tight margins lead hospitals to cost accounting systems. AB - Hospital margins are getting tighter, and healthcare executives are realizing that they can't afford not to know whether payments for care are covering their costs. And they're realizing that without some type of cost accounting system, they probably don't have a true understanding of what their costs are. PMID- 10108094 TI - Trying to make sense of hospital charges. PMID- 10108095 TI - FTC accuses Fla. physicians. PMID- 10108096 TI - Three hospital systems on the rebound from financial and organizational woes. AB - Modern Healthcare last year profiled three hospital organizations in a story about systems that hadn't delivered promised benefits. Since then, HealthEast and Baptist Hospitals and Health Systems have become profitable, and St. Benedict's Health System has benefited from becoming part of a larger system. PMID- 10108097 TI - Henry Ford derives profits from diversity. AB - Henry Ford Health System has just one strategy: vertical integration. The Detroit system spent the 1980s collecting healthcare businesses to balance its full service delivery system, and now it's filling in the gaps and streamlining operations. PMID- 10108098 TI - Providers test clinical outcomes product. PMID- 10108100 TI - Study finds high profit margins at some U.S. teaching hospitals. PMID- 10108099 TI - Physician revenue up sharply. PMID- 10108101 TI - Study by state attorneys general finds at least 70 antitrust cases in healthcare since 1985. PMID- 10108102 TI - Teaching hospitals, universities part ways. AB - For financial and autonomy reasons, university teaching hospitals are splitting away from their sponsoring academic institutions. Sometimes the hospital wants more freedom to react to the healthcare market. But sometimes it's the university that wants to distance itself from the hospital and the accompanying charity load. PMID- 10108103 TI - Bush, HHS stymie plan to equalize Medicare rates in Nebraska, Okla. PMID- 10108104 TI - 22 states file suit against Sandoz. PMID- 10108105 TI - HCFA report rips practices at Humana HMOs in Florida. PMID- 10108106 TI - OMB offers ideas for $2.7 billion in Medicare savings for fiscal '92. PMID- 10108107 TI - Uncertainty clouds congressional forecast. PMID- 10108108 TI - Hospitals dispose of destructive waste habits. Recycling protects the environment, but facilities are finding it can pay off in numerous ways. AB - Across the country, hospitals are setting up recycling programs. While protecting the environment is their first concern, they've also found that recycling offers other benefits, such as lower landfill fees, reduced energy and supply costs, less cluttered work areas, better employee morale and improved community relations. PMID- 10108109 TI - Tentative settlement over inadequate Medicaid funds may keep suit out of trial. PMID- 10108110 TI - Disposable diapers get dumped. PMID- 10108111 TI - Tumult, triumphs and turning points. Year of cuts, gains and reform proposals sets the stage for '91. AB - It was a year of decisive wins and losses, a year that for many healthcare organizations signaled a turning point. The resignation of AHA President Carol McCarthy, a Supreme Court decision on Medicaid payments and myriad proposals for healthcare reform were among the events setting the stage for 1991. PMID- 10108112 TI - Study analyzes referral service formula. PMID- 10108113 TI - Protesters rise in Cruzan case. PMID- 10108114 TI - Utah releases final tax-exemption standards. PMID- 10108115 TI - More facilities face demand for deep discounts. AB - Efforts by employers to set up their own managed-care networks will impose the harsh reality of managed care on markets that have been spared the need to negotiate deep discounts in return for patients. PMID- 10108117 TI - St. Louis firms ask for hospitals' prices. PMID- 10108116 TI - In the bond insurance game, small hospitals often shut out. AB - Smaller hospitals have trouble getting their bond issues insured, even if their credit rating is investment grade. Bond insurance companies typically adhere to policies that prohibit insuring hospitals of fewer than 150 to 200 beds. PMID- 10108118 TI - Merger forms new psychiatric system. PMID- 10108119 TI - Work restructuring transforms support staff. PMID- 10108120 TI - Manager's bane: scheduling and utilization. PMID- 10108121 TI - Tips for better management of technology. PMID- 10108122 TI - Collecting and organizing OR data for QA. AB - This is the eighth article about applying the ten-step model for monitoring and evaluation developed by the Joint Commission on Accreditation of Healthcare Organizations. PMID- 10108123 TI - Laser or electrosurgery? No consensus yet. PMID- 10108124 TI - How to better handle patient complaints: seven simple rules of the road. PMID- 10108126 TI - Reconsidering national health insurance. PMID- 10108125 TI - Credit bureaus: the long arm of collections. AB - Credit bureau services often are ignored by healthcare providers as a resource for reducing bad debt. Reporting guarantors' credit information--especially bad debt--to credit bureaus can prevent debtors from obtaining new credit before an overdue hospital bill is paid, thereby reducing the number of past due accounts and increasing the hospital's cash flow. PMID- 10108127 TI - Job description: CST surgical assistant. PMID- 10108128 TI - Fund-raising: how and why. PMID- 10108129 TI - Strategic plan complements community development. PMID- 10108130 TI - Can quality research change the way physicians practice? PMID- 10108131 TI - Physicians in governance: is there life beyond the board? PMID- 10108132 TI - Anatomy of four hospital defaults. PMID- 10108133 TI - Experts optimistic about outpatient cancer care. American Hospital Association's Society for Ambulatory Care Professionals. PMID- 10108134 TI - Hospitals fear HCFA lab regulations. PMID- 10108135 TI - Who should mind the shop during an executive search? PMID- 10108136 TI - Medicare plan: more hospital cuts. PMID- 10108137 TI - CEO evaluation--fairness above all. Interview by Karen Gardner. AB - How effectively the hospital governing board communicates with and evaluates its CEO may have a direct impact on CEO turnover. Board chairman Richard Moses of Tuomey Hospital, Sumter, SC, describes the process for conducting a fair and meaningful evaluation. PMID- 10108138 TI - Sacrificing organization for mission. PMID- 10108139 TI - A new auxiliary assessment tool. PMID- 10108140 TI - Three junior programs that work. Student ambassadors, teen volunteer program, Youth Engaged in Service--YES! PMID- 10108141 TI - 20-year reunion of junior volunteers. PMID- 10108142 TI - Tornado in Plainfield, IL. PMID- 10108143 TI - A successful hospital tax levy. PMID- 10108144 TI - Perceptual and archival measures of Miles and Snow's strategic types: a comprehensive assessment of reliability and validity. AB - Despite the widespread research use of Miles and Snow's typology of strategic orientations, there have been no systematic attempts to assess the reliability and validity of its various measures. The present work provides such an assessment using data collected at two points from over 400 organizations in the hospital industry. We examined dimensions of the typology using both perceptual self-typing and archival data from multiple sources. The results generally support predictions across a variety of measures. Implications for further testing and research are discussed. PMID- 10108145 TI - Tracking the elusive MRI referral pattern. PMID- 10108146 TI - Courting the hidden organization. AB - While most hospitals and clinics are not run as tightly as military organizations, the formal healthcare system is usually organized along the same model. PMID- 10108147 TI - Blessings of a mixed marriage ... a creative approach to R.T. education. AB - Cooperative education programs produce confident students with realistic career goals, and employees who can immediately contribute to their department. PMID- 10108148 TI - Difficult questions. Treating the self-referred patient. PMID- 10108149 TI - The self-referred patient. A challenge to breast imaging practices. PMID- 10108150 TI - The purchase of specialized radiologic [corrected] software: evaluating the program. Part I. PMID- 10108151 TI - Who framed Roger PACS? PMID- 10108152 TI - Professionalism in radiation oncology. PMID- 10108154 TI - Stripping the myths of mergermania. PMID- 10108153 TI - Healthcare in rural America--the saga continues. PMID- 10108155 TI - How your hospital can avoid a union. PMID- 10108156 TI - Collective bargaining: a positive force in the workplace. PMID- 10108157 TI - Buying & selling--the vendors speak up. PMID- 10108158 TI - Supporting excellence. PMID- 10108159 TI - Perspectives. Physician payment reform: struggling to be born. PMID- 10108160 TI - The first flying ambulance. The beginnings of rapid transport of trauma patients. PMID- 10108161 TI - Southeast Mississippi Air Ambulance District. Twenty-one years of service and safety. PMID- 10108162 TI - 1991 job market. Less turnover, more hiring from within. PMID- 10108163 TI - Turning tragedy into triumph. Rocky Mountain Helicopters and LifeGuard Alaska transport injured boy from Russia. PMID- 10108164 TI - Retention strategies that survive a sale. AB - To keep key employees during rocky times, HR professionals strategically design high-powered compensation programs. PMID- 10108165 TI - New salary system supports changing culture. AB - Changing job classification, salary administration and benefits programs for the sake of change can create considerable problems in an organization. However, as the organizational culture changes, these HR systems need to adjust to help the process. Associate involvement requires considerable planning, time and effort, but the results often prove worthwhile. As the company moves into the future, this involvement process or something similar will help shape other human resource programs. PMID- 10108166 TI - EEO program deals management a good hand. AB - The U.S. General Accounting Office's EEO program provided managers with more than just legal information. Instead of focusing on how to avoid legal problems, the program gave managers tools and skills they could use to cultivate diversity and improve productivity. PMID- 10108167 TI - Do you drug test your employees? PMID- 10108168 TI - Staying afloat during restructuring storms. AB - By 1988 Jack Pfister could see the writing on the wall. His 80-year-old utility company, the Salt River Project (SRP), would no longer be sheltered from competition's chill wind. Its special status as a governmental entity was being challenged by emerging deregulation in the power industry. "Foreign" producers could now wheel their surplus power into his backyard at bargain rates. PMID- 10108169 TI - New lawsuits expand employer liability. PMID- 10108170 TI - Anthropologist uncovers real workplace attitudes. AB - Employee opinion surveys offer some clues about workplace problems. Unfortunately, they are difficult to interpret and viewed with skepticism by both management and employees. A new approach--an anthropologist studying corporate culture from an insider's perspective--offers some unique advantages. PMID- 10108171 TI - Channeling energy through committee membership. PMID- 10108172 TI - Teamwork: joining hands to meet organizational goals. PMID- 10108173 TI - One state's road to credentialing. The credentialing of respiratory care practitioners in the State of Maryland. PMID- 10108174 TI - Respiratory therapy state credentialing agencies. PMID- 10108176 TI - Unlocking the mystery of the pyramid--the organizational chart. PMID- 10108175 TI - A day in the life of Kathleen G. Jones, Director of Finance, Sharp Memorial Hospital, San Diego, CA. PMID- 10108177 TI - Acclimating to shift work--a survival kit. PMID- 10108178 TI - Easing new job jitters. Orientation and preceptors can help. PMID- 10108179 TI - Professional associations for nursing, physical and respiratory therapy. PMID- 10108180 TI - Experience talking: an opportunity for physical therapists to educate the consumer. Interview by M. J. Thomas. PMID- 10108181 TI - A day in the life of Margaret L. McClure, Executive Director of Nursing, New York University Medical Center. PMID- 10108182 TI - Professional development: choreographing your career. PMID- 10108183 TI - Double duty: meeting demands of work and school. PMID- 10108184 TI - Climbing the ladder to success: are clinical ladders your answer? PMID- 10108185 TI - Nursing specialty organizations and interest groups. PMID- 10108186 TI - A day in the life of Ginny Simmons, Director of Nursing Education, Community Hospital of Chula Vista, CA. PMID- 10108187 TI - Graduate education--selecting the right program for you. PMID- 10108188 TI - Practice guideline development ignites physician interest. PMID- 10108189 TI - New balance billing limits. PMID- 10108190 TI - Alternative forms of dispute resolution. PMID- 10108191 TI - Planning for hospice services. Clinical and personnel issues in providing interdisciplinary services for the terminally ill. AB - The development of hospice services requires consideration of the patient and family, respect for the strengths of different disciplines, a belief in holistic care, and attention to the needs of staff. PMID- 10108192 TI - Preparing homemaker-home health aides to care for hospice clients. AB - The physical and emotional demands placed on hospice homemaker-home health aides require that special care be taken in recruiting personnel and orienting them to the hospice concept. Pre-employment screening, education, and regular evaluations will assist in selecting and retaining quality hospice aides. PMID- 10108193 TI - Volunteer hospice programs. A valuable asset to the hospice community. AB - Communities that wish to offer full and comprehensive support to those facing death will benefit from having both medical and volunteer hospice programs. Volunteer hospices, which rely totally on community contributions of time and money, must be especially attentive to volunteer's needs for training, support, and recognition. PMID- 10108194 TI - Hospice. An essential and growing part of the continuum of care. AB - When hospice was first introduced to America more than 25 years ago, terminal illness was a forbidden subject. Today, there are more than 1,700 hospices in this country; the largest growth in recent years has occurred in home health agency- and hospital-based hospices. There will be an even greater reliance on hospice services in the near future as the baby boomers and their parents confront their mortality. PMID- 10108195 TI - Patients without a primary caregiver. A model for caring for persons with AIDS. AB - The hospice program of Hospital Home Health Care Agency of California provides hospice care to persons with AIDS in residential group homes in collaboration with other community-based organizations. As a model, it is applicable to other geographic areas and/or situations where the absence of a primary caregiver prevents access to hospice care. PMID- 10108196 TI - Recruiting and training volunteers to work with persons with AIDS. AB - Volunteers, an integral part of the hospice interdisciplinary team, provide valuable emotional and physical support for the patient and family. Special consideration should be given to the recruitment, training, and support of volunteers working with AIDS/HIV patients. PMID- 10108197 TI - Planning your way to fundraising success. AB - Successful fundraising can help a hospice bridge the budget gap, as well as generate publicity and positioning in the political health care arena. Special events are a popular way in which to solicit funds; however, they require significant advance planning and the involvement and support of staff, board, and volunteers. PMID- 10108198 TI - Quality assurance in hospice. PMID- 10108199 TI - Hospice management. Operational, reimbursement, and financial issues. AB - Of the estimated 1,700 hospices in the United States, approximately half are Medicare-certified. In 1990 alone over 200 hospices have become Medicare certified. Much of this recent growth can be attributed to both a need for hospice services and the 20% increase in hospice rates legislated by the Omnibus Budget Reconciliation Act of 1989. Medicare certification now presents an opportunity for financial success for hospices, non-participating hospices, and certified home health agencies. PMID- 10108200 TI - Nursing supply and retention. PMID- 10108201 TI - Should public hospitals conduct business? PMID- 10108203 TI - The high cost of malpractice. PMID- 10108202 TI - A framework for decision making. PMID- 10108204 TI - HL7, MEDIX and the pursuit of the unified standard. AB - The move toward open systems environments in healthcare computing has gained momentum in recent years. The authors, both deeply involved in the development of standard communication protocols for disparate systems, explain the status of current convergence efforts both here and abroad, with emphasis on HL7 and MEDIX. PMID- 10108205 TI - Architectural strategy: key issue of the 1990s. PMID- 10108206 TI - Networking: the era of the '90s. PMID- 10108207 TI - Facts and fax make for successful hospital/physician networks. AB - "With a phone, fax machine and a little planning you can pull off a worthwhile hospital/physician network," according to Ralph Wakerly, who has performed extensive research into what characteristics form successful HPNs that will increase revenue and add market share. PMID- 10108208 TI - HL7: are you ready for it? PMID- 10108209 TI - Information services need leadership to effect change. PMID- 10108210 TI - Toward enterprise-wide networking. PMID- 10108211 TI - The political boundaries of strategic decision support systems. AB - Decision support systems have begun to impact the healthcare strategic planning environment. What are the repercussions to the chief financial officer as these systems make further headway? PMID- 10108212 TI - Referral tracking system shows accurate bottom-line assessment. AB - Rose Medical Center in Denver, Colo., needed a way to track referrals from its many offsite care centers to determine their impact on revenue. Programmers at Rose developed a microbased system, eventually bought by SMS, that measures profitability against investment to become a true decision support tool for hospital executives. PMID- 10108213 TI - Designing DSS (decision support systems) and EIS (executive information systems) applications to fit executive user needs. AB - The effectiveness of executive information systems and decision support rests on the level of understanding, commitment and use that top management devotes to the system. The author describes new technologies that help promote executive commitment to DSS/EIS. PMID- 10108214 TI - Hello, MIS medical record (wherever you are). AB - A management information system record takes an imaginary orientation journey through El Camino Hospital in Mountain View, Calif., and meets a cast of seven hospital staffers who acquaint it with their own specific requirements. PMID- 10108215 TI - How one CEO needs "R&R" in everyday life. AB - At the HCA Center for Health Excellence in Houston, "R&R" stands for more than rest and relaxation--it also means recruitment and retention of physicians. PMID- 10108216 TI - Technology enters the hospital's executive suite. AB - Two major forces are driving the emergence of more powerful and comprehensive executive information systems: compression of the time horizon--CEO's cannot wait weeks or months for historical trends data--and EIS technological development that allows executives to tap into daily operations on all levels. PMID- 10108217 TI - EMS buyers guide. PMID- 10108218 TI - Department of Transportation (DOT) National Highway Traffic Safety Administration and the American Medical Association Commission on Emergency Medical Services air ambulance guidelines. AB - These guidelines were developed as national EMS voluntary standards to: 1) Establish standard nomenclature for levels of aeromedical crew members; 2) Define the training requirements for each level; 3) Define the medical control requirements for aeromedical crew members; 4) Describe the application of the standards; and 5) Describe the general content areas of the training of aeromedical crew members. The AMA Commission on EMS has reviewed the current draft of the proposed national EMS voluntary standards and decided to accept them for inclusion in this second edition of the Air Ambulance Guidelines with the expectation that the final version of the ASTM Committee F-30 standard will be essentially the same as the current draft standard. The guidelines are designed to acquaint practicing physicians, especially those practicing in rural and remote areas, with the following factors which affect the transportation of patients by air ambulance: 1) Risks to the patient flying at high altitudes; 2) Equipment, both general and specific, required to render anticipated care; 3) Qualifications of personnel aboard the air ambulance, and the level of care required in transit; 4) Care required for specific medical and surgical conditions during flight. PMID- 10108219 TI - EMS state and province survey. AB - This 1991 Emergency Medical Services State and Province Survey gives you the most complete collection of data we've ever provided. Listings include 50 states, the District of Columbia, the Virgin Islands, and 10 Canadian provinces. Our sincere thanks to the many people who responded to our request for information. PMID- 10108220 TI - EMS organizations. AB - Following is an updated listing of not-for-profit associations and organizations in emergency medical care and transportation. To qualify for inclusion, your organization must be pertinent to the field of EMS; be of sound reputation; and have a non-profit financial base. To be included in next year's listings, send relevant information to: Associations Editor, EMS, 7628 Densmore Ave., Van Nuys, CA 91406-2088. PMID- 10108221 TI - Code of ethics of the National Association of EMTs. PMID- 10108222 TI - The EMT Oath. PMID- 10108223 TI - 1990 AGPA salary survey. American Group Practice Association. AB - This report was prepared from data compiled in a study conducted by the AGPA in cooperation with the recruitment firms of James Russell, Inc. and Davis-Smith Medical, Inc. David O. Born, Ph.D., an independent research consultant and professor at the University of Minnesota Department of Health Ecology, was retained to direct the project and analyze the data. PMID- 10108225 TI - Highway trauma. PMID- 10108224 TI - Professional fee billing. AB - Good billing system management information is critical for maximizing income and providing the understanding health care providers need to make their practices profitable. PMID- 10108227 TI - When death is imminent. PMID- 10108226 TI - U.S. auto injuries. PMID- 10108228 TI - Your elderly patients. PMID- 10108229 TI - Just a matter of time. AB - As Midwestern foodservice directors & dietitians recently discovered when an earthquake alert was sounded in their area, it's never too early to review & update emergency plans. Herein is a compendium of tips that can be used by any foodservice professional working in an area at risk of disaster, whether it be earthquake, tornado, hurricane, blackout or flood. PMID- 10108230 TI - Self-serve equipment. Offering labor savings & flexibility, this equipment has many potential benefits. PMID- 10108231 TI - A primer for menu making. Producing your own menus can be valuable & cost effective. PMID- 10108232 TI - Profitable women's centers demand latest services. PMID- 10108233 TI - Good planning alleviates bad effects of stoppages. AB - Work stoppages can stifle, if not halt, the activity of a hospital, especially when they involve nurses. What lessons can be learned from a strike? How do administrators "reintegrate" striking professionals after a settlement? In the following article Elizabeth Rosenthal cites a study involving nurses to address those issues. PMID- 10108234 TI - Community input valuable asset for hospital board. AB - How can a hospital--looking at the future--learn what its community needs are and satisfy them? The answer lies in input from community resources beyond members of the hospital's board. Adrienne Nyman Miller offers guidelines for hospital administrators who want to incorporate those community leaders in their strategic planning process. PMID- 10108235 TI - Planners should play bigger roles in their hospitals. PMID- 10108236 TI - Planning indicators. Medicare-allowed fees for physicians' services: 1983-87. PMID- 10108238 TI - What you should know about living wills. American Society of Internal Medicine. PMID- 10108237 TI - Alliance strengthens care. AB - When hospital administrators want to fortify the care and programs they provide, what creative vehicles can they initiate? Orlando Regional Medical Center (ORMC), a 1,000-bed tertiary care center in Orlando, Fla., and the University of Texas M.D. Anderson Cancer Center, a 518-bed research facility in Houston, Texas, are establishing a joint alliance that will strengthen the oncology care in central Florida. John Hillenmeyer, chief operating officer and senior vice president of ORMC, describes the structure of the joint venture. PMID- 10108239 TI - Hidden costs of turnover. PMID- 10108240 TI - Medical house arrest. PMID- 10108241 TI - Management: a foreign concept. PMID- 10108242 TI - Ins and outcomes. PMID- 10108243 TI - An eye for the facts. PMID- 10108244 TI - Groundwork for audit. PMID- 10108245 TI - Making the most of audit workers. PMID- 10108246 TI - The right class of residential care. PMID- 10108247 TI - Checklist for April 1991. PMID- 10108248 TI - Value in real terms. PMID- 10108249 TI - Back to the future. AB - Planting a time capsule to mark the radical changes at Rainhill Hospital seemed a simple idea. Nobody had reckoned on the time and emotional energy involved, as John Bentley explains. PMID- 10108250 TI - A cost comparison of intravenous cimetidine delivery systems. AB - Five systems for preparing and three systems for administering intravenous medications, using forty doses for each system were evaluated on the basis of product acquisition, ancillary supply and personnel costs. Time and motion studies were conducted on solutions (System 1: minibag prepared with a vial of cimetidine; System 2: minibag prepared with a premixed syringe; System 3: ready to-use minibag; System 4: large volume cimetidine infusion; System 5: premixed syringe) prepared by pharmacy technicians and administered by nurses. The total cost for the large volume infusion system was 50% less than the other systems. Labor costs accounted for only a small portion of total cost and did not appear to influence the rank established by drug and supply costs. Based on the study results, using a large volume cimetidine infusion could result in a cost savings for both pharmacy and nursing departments and should be considered when pharmacy and nursing time is at a premium. PMID- 10108251 TI - Physician order form with lines that will not FAX. PMID- 10108252 TI - Antitrust liability of pharmacists involved with quality assurance programs. PMID- 10108253 TI - Lilly hospital pharmacy survey 1990. PMID- 10108254 TI - Technology assessment. AB - Decisions about which technologies to purchase, to upgrade, to maintain, or to watch for further development have taken on immense import. PMID- 10108255 TI - No consensus, no vision for the nineties. PMID- 10108256 TI - Is it worth it? PMID- 10108257 TI - Hospitals and prisons. An action plan for the liberation of our patients. AB - Each day about 24,000 people are imprisoned in America's penal institutions. The experience for those people is humiliating, disturbing, and degrading. I know. I used to put them there. When I resigned from the United States District Attorney's office in 1975 after serving for three years as a federal prosecutor (and later as a night court judge) and started my new role as a hospital executive, I thought I was leaving the process of imprisonment behind. In the winter of 1975-76, as I went about the task of learning how hospitals functioned, I visited the emergency room. I visited the admitting area. I visited the floors. I watched doctors, nurses, and X-ray technologists at work. Gradually, a disturbing thought came to me: Hospital patients are treated much like convicted felons. PMID- 10108258 TI - Restoring the human scale. Healthcare facilities will be designed as living spaces for families, not warehouses for sick people. PMID- 10108259 TI - Selecting and developing outstanding performers. The shape of things to come: Part 4. PMID- 10108260 TI - The quiet superstars. Part 1. AB - Dynamic, outward-looking, aggressive, with the ability to manage change and build shared values, these low-profile hospitals see limitless possibilities in each new challenge. PMID- 10108261 TI - Quality is not enough. PMID- 10108262 TI - Of tension, harmony & dilemma-busting. Interview by Joe Flower. AB - We in the West tend to look for consensus, and the Japanese are beating the hell out of us because they think in a different way. They look for what I like to call "harmonies of difference." PMID- 10108263 TI - Doing the right things right. Part 1. PMID- 10108265 TI - Psychiatry: facts and perceptions. PMID- 10108266 TI - Maternity-wing "face lift" becomes big renovation to recoup market share. PMID- 10108264 TI - Conflict of interest. Part 2. PMID- 10108267 TI - Quality-control programs reduce construction woes. PMID- 10108268 TI - Chain of command, policies, training key to waste plans. PMID- 10108269 TI - NFPA (National Fire Protection Association) mulls over sprinkler changes in safety code. PMID- 10108270 TI - How to fire up committees to achieve real results. PMID- 10108272 TI - Carpets catch: appearance vs. maintainability. PMID- 10108271 TI - How to select the best water-treatment supplier. PMID- 10108273 TI - Nutrition monitoring in the United States. PMID- 10108274 TI - Importance of a nutrition monitoring and surveillance system for research and practice in Canada. PMID- 10108275 TI - Design of nutrition monitoring and surveillance systems: questions to be answered. PMID- 10108276 TI - Nutrition education research in health promotion. PMID- 10108277 TI - Bringing a community development approach to nutrition education. PMID- 10108278 TI - Needle, syringe makers wage war. PMID- 10108279 TI - Purchasers expect protective supply volumes to stabilize. PMID- 10108280 TI - New York hospitals join Highland Hospital in regional incinerator construction project. PMID- 10108281 TI - HMM price watch. Purchasing managers' index continues to decline, falling 5% to 41.3 in November. PMID- 10108282 TI - Materials managers must know their rights on contracts requiring payment before delivery. PMID- 10108283 TI - Optical disk storage of medical records. PMID- 10108284 TI - The "barrier effectiveness" of personal protective clothing. PMID- 10108285 TI - Records retention: a practical approach. PMID- 10108286 TI - Office equipment: a hidden threat to hospital productivity. AB - While considered relatively unsophisticated by technological standards, office machines touch virtually every employee, and, perhaps due to their simplicity, affect hospital operations, efficiency and total costs in a similar manner as computers and telecommunications. Developing a plan for their use, maximizing their efficiency and managing them as powerful assets will produce a benefit well beyond the effort or cost expended. PMID- 10108287 TI - Resuscitation devices. PMID- 10108288 TI - Material management: is it a profession or not? PMID- 10108290 TI - On-site sterilizer/compactors: one solution to the infectious waste dilemma. PMID- 10108289 TI - Who should decide the rationing of health care? PMID- 10108291 TI - Staff interactions: communicating with co-workers. AB - The issue of staff attitudes toward their jobs has always been of vital importance, and the pressures of today's healthcare industry makes this issue even more critical. The role communication plays in developing positive attitudes towards one's workplace is immense. Both verbal and non-verbal communication can project an image of being cold, unfeeling, unprofessional and indifferent. These are not the messages anyone wants to receive! Humanistic verbal communications sends the messages that should be received by every staff person--messages of a warm, caring and concerned workplace for everyone. PMID- 10108292 TI - Storage considerations: a self-learning tool. PMID- 10108293 TI - How I became a "questionable" doctor. PMID- 10108294 TI - Let paraprofessionals boost your practice. PMID- 10108295 TI - Michigan Hospital Association. 1991 membership directory. PMID- 10108296 TI - Peak performer psychology for health care executives. PMID- 10108297 TI - Charter expects $210 million loss. PMID- 10108298 TI - N.J. charity fund evaporates; summit toiling to reinstate it. PMID- 10108299 TI - $413 million deal completes Beverly debt restructuring. PMID- 10108300 TI - Appeals court upholds verdict in Fla. DME case. PMID- 10108301 TI - Services cut at Texas hospital. PMID- 10108302 TI - Motives suspect in caesarean repeats--study. PMID- 10108303 TI - More firms limit mental health plan. PMID- 10108304 TI - AOHA's acting CEO gets the job. PMID- 10108306 TI - VHA signs 10-year contract with Anderson Consulting for on-line data bank. PMID- 10108305 TI - Conn. hospitals sue to gain 'reasonable' Medicaid rates. PMID- 10108307 TI - Proposed fee-schedule cut trips alarms. PMID- 10108308 TI - Nu-Med selling two hospitals. PMID- 10108309 TI - Get mammography message out. PMID- 10108310 TI - 1991 outlook: progress will require partnerships, improved productivity- roundtable discussion. AB - To address the myriad problems and challenges in the next year, the operative word will be partnership. That's according to members of Modern Healthcare's editorial advisory board in their discussion of the healthcare industry in 1991. The experts see the need for hospitals, physicians and the business community to team up to control costs, solve staffing woes and take initial steps toward healthcare reform. PMID- 10108312 TI - Second right-to-die case unfolds in Missouri. PMID- 10108311 TI - Hospital executives eye congressional shifts. PMID- 10108313 TI - Providers, vendors venture into the U.S.S.R. AB - As the Soviet Union begins to make medical care a higher national priority, American healthcare providers and vendors are entering the market in growing numbers. The business and clinical ventures--both for-profit and not-for-profit- include everything from alcoholism treatment and plastic surgery to facility design and professional education. PMID- 10108314 TI - Not-for-profits like the fit of former for-profits. AB - Not-for-profit hospitals and systems are expanding market share through purchases of for-profit facilities that have come up for sale. As for-profits scale back their growth or divest properties to finance leveraged buy-outs, not-for-profits are there to add key markets that may not have been accessible otherwise. PMID- 10108315 TI - 28 states face potential deficits. PMID- 10108316 TI - Data base would cover all hospitals in 35 states. PMID- 10108318 TI - 'Medicare HMOs should be nixed or reformed'. PMID- 10108317 TI - Sullivan opposes budget recommendations. PMID- 10108319 TI - Pentagon turns down Foundation expansion. PMID- 10108320 TI - Building strength on the home-front. Preserving radiology staff. PMID- 10108321 TI - Tracking talent in the management pool. PMID- 10108322 TI - The purchase of specialized radiologic software: estimation of investment. Part II. AB - For the most part, specialized radiologic software addresses narrow vertical markets that are not large enough to attract the larger software firms. This can work to the benefit of the user, for smaller companies tend to be more flexible and are better able to respond to the user's needs and to tailor their product to meet specific requirements. However, because the companies are small and often relatively young, some do not have the stability associated with larger, well established firms. As a result, it may be more risky to commit to one of their programs. Nevertheless, with appropriate cautions regarding the company and its product, with proper training of departmental personnel and with adequate safeguards to protect data, these programs can represent a secure and prudent investment. PMID- 10108323 TI - The costs of low dose rate remote afterloading compared to manual afterloading brachytherapy. AB - A relatively recent development in the United States in brachytherapy technology is the use of equipment to remotely afterload radioactive sources into the patient applicators. This technique competes with past practices where the source was placed by hand. With remote afterloading, the sources are automatically removed from the patient and placed into a lead safe whenever healthcare personnel enter the patient's room. The primary benefit of remote afterloading brachytherapy is to reduce the radiation exposure to the patient's visitors and healthcare providers. By comparing the operating and maintenance costs for remote afterloading brachytherapy (RAL) and manual afterloading (MAL) for patients receiving conventional low dose rate brachytherapy from interstitial and intracavitary implants, estimates of the prospective cost of this increased safety can be offered. PMID- 10108324 TI - Which hospital admissions are appropriate? AB - The Appropriateness Evaluation Protocol (AEP) is a criterion audit tool used extensively in the USA to assess the appropriateness of admission to hospitals. This study evaluated the utility of the AEP in an Australian teaching hospital, and recommends minor modifications to the criteria to improve the efficiency of the audit process. Six per cent of admissions in the sample were inappropriate according to the AEP criteria. These cases could have been managed in an alternate facility providing a lower level of care, or care provided on an outpatient or day-patient basis. The additional cost of the inappropriate admissions to an acute hospital is estimated at $A1750 per case. PMID- 10108325 TI - AIDS, ethics and hospitals. AB - The issue of AIDS has raised a number of concerns for the health professions and for hospital administrators. An outline of some of the fundamental facts about HIV infection and AIDS and of the human rights obligations is provided. A number of issues for both practitioners and patients are raised. Administrators and practitioners are asked to develop policies through a careful consideration of the facts and issues and to set in place safeguards that recognise the rights and needs of all concerned. PMID- 10108326 TI - Health care management by consensus--myth or reality? PMID- 10108327 TI - Developing power and political skills. AB - One characteristic of power is the ability to influence others; managers cannot be effective without it. Politics is the network of interactions by which power is acquired, transferred, and exercised; it is a fact of health-care life. Like the money in our economy, politics is the medium of exchange in an organization. Managers must be political beings to meet their objectives. This article helps you to assess your political behavior and describes specific methods to increase power and develop political skills. Using these techniques can result in getting what you want and having things done your way, resulting in better job performance and career advancement. PMID- 10108328 TI - Ethics, health care and the 1990s: Part I. PMID- 10108329 TI - Managerial decision-making in the laboratory. AB - Although managers make decisions daily, they do not always make them well. Because of the complexity of some decisions, a decision aid such as the multiattribute utility model is often helpful. This model can help a decision maker in problem structuring, including determining the criteria on which the alternatives should be judged, how important these criteria are in relation to each other, and how well the alternatives stack up against these criteria. Finally, the model brings all this information together so that the decision maker can make appropriate recommendations. By using a multiattribute utility model, this case study shows the applicability of the model to the decision of choosing among alternative hematologic instruments in a medical laboratory. The model, in any of its forms, is also useful for many other types of decisions. The model can be used either to help make a choice or to reinforce a choice made by other means and to help communicate the factors on which a choice was made. PMID- 10108330 TI - Making performance appraisals a positive experience. AB - Performance appraisals can be fearful and frustrating experiences for both supervisors and subordinates. Many of the negative attitudes are due to conflicting goals for performance appraisal or to employee uncertainty and fear about the process. By involving employees in developing performance appraisal instruments and being sure they understand the entire process, laboratory managers can reduce the apprehension. The confidence of supervisors can be increased by teaching them how to accurately evaluate performance and to provide feedback. With an investment of time and effort, laboratory managers can make their performance appraisal programs a positive experience for both supervisors and subordinates. PMID- 10108331 TI - Competitive bidding. PMID- 10108332 TI - Clinical laboratory robots: their impact on laboratory management. PMID- 10108333 TI - The Helena REP (Rapid ElectroPhoresis) system. PMID- 10108334 TI - In-service education. PMID- 10108335 TI - Continuous quality improvement. PMID- 10108336 TI - Assessing adequacy of return on investment. PMID- 10108337 TI - Doctors' orders. PMID- 10108338 TI - I treat all my patients aggressively. PMID- 10108339 TI - Perspectives. Life and death after Cruzan. PMID- 10108340 TI - Balancing conflicting values: Jehovah's Witnesses and blood. PMID- 10108341 TI - Technology trends in patient care. PMID- 10108342 TI - Searching for health care answers: a journey to three continents. PMID- 10108343 TI - Midlife career burnout: a hazard on the horizon. PMID- 10108344 TI - Payment reform: obstacle or opportunity? PMID- 10108345 TI - Grassroots support for life and death issues. PMID- 10108346 TI - The depression and the county health system fight in California. PMID- 10108347 TI - Prospects for universal health care look better in 1991. PMID- 10108348 TI - More bureaucracy isn't answer to health care coverage. PMID- 10108349 TI - Medicare program; hospice care amendments: Medicare--HCFA. Final rule with comment period. AB - These rules amend the hospice care provisions on physician certification of terminal illness-- To allow up to 8 days to obtain written certification of terminal illness, provided oral certification is obtained within 2 days after the initial period of care begins; and To modify the certification statement which, in its previous form, was shown to discourage physicians from certifying terminal illness and thereby discourage hospice participation in Medicare. These changes are necessary-- To conform HCFA rules to amendments made by section 6005(b) of the Omnibus Budget Reconciliation Act of 1989 (OBRA '89); and To carry out the recommendations of the General Accounting Office (GAO), aimed at encouraging greater participation of hospices in the Medicare program. These rules also simplify and clarify other hospice policies, remove outdated content, and correct cross-references. PMID- 10108350 TI - Indian Health Service; statement of organization, functions, and delegations of authority--PHS. PMID- 10108351 TI - Recovery for a floundering industry. Leadership is required more than ever. PMID- 10108352 TI - Nursing homes expected to use very little restraint. OBRA pushes for resident freedom. PMID- 10108353 TI - The search for optimum size. 1990 multi-facility operators survey. PMID- 10108354 TI - A milestone in caring for the elderly. Trendsetting CCRC opens $20 million nursing facility. PMID- 10108355 TI - OBRA '87 amendments cause setbacks. PMID- 10108356 TI - A united stand prevents falls. Team effort builds safety foundation. PMID- 10108357 TI - Nutrition in home care. AB - The well-nourished patient can better tolerate treatment, experiences fewer postoperative complications, and recovers more quickly from illness or injury. Although Americans realize the importance of good nutrition, malnutrition has been reported in 52-85% of long-term care patients. The Nutrition Screening Initiative has been launched to raise the consciousness level of both professionals and the public regarding nutrition and the value of nutritional screening. PMID- 10108358 TI - The home care team approach to dysphagia. AB - Chronic medical problems and multiple medications can contribute to dysphagia, compromising the patient's nutritional status. Early detection, followed by evaluations, treatment, and education can provide the patient with the best opportunity for a positive outcome. PMID- 10108359 TI - Nutrition services in home care. AB - As nutrition technology continues to advance, important nutrition issues for home care policymakers include determining the type and level of nutrition care needed to most effectively meet the patient's needs, determining who should provide nutrition services in the home, and reimbursement for nutrition services. PMID- 10108361 TI - Downsizing. PMID- 10108360 TI - Computerized diet analysis in home care. AB - The computer makes diet analysis a practical, efficient tool for evaluation of patient status and progress, and many optional programs and prices are now available. Seattle/King County Visiting Nurse Services contracts with a nearby university to provide the agency with an economical and accurate system. PMID- 10108362 TI - Nurses in resident evaluation. A qualitative study of the participants' perspectives. AB - This study complemented a large psychometric study using nurses to assess medical residents' humanistic behavior. It was designed to identify how nurses and residents defined humanistic qualities and behaviors and what factors affected their views of residents' performance and evaluation. The study also illustrates how qualitative methods were used to complement quantitative psychometric data and thereby yield a more complete assessment of the value of a new performance evaluation form. The results indicated that nurses' definitions of humanistic behavior often differed from residents', tending to reflect a broader perspective on the physician's role and responsibility in patient care. Nurses and residents disagreed about whether nurses were qualified to evaluate residents' humanistic behavior and about what nurses actually observed on the wards. Professional respect was an issue for both nurses and residents. The discussion section identifies some implications for resident training and nurse-resident relationships and supports the value of combining research strategies when evaluating complex human behavior. PMID- 10108363 TI - Special report on antitrust. State law: the emerging focus in the second century of antitrust law. PMID- 10108364 TI - Satisfaction guaranteed? PMID- 10108365 TI - Hot air in the small print. PMID- 10108366 TI - Artificial limbs: a real need. PMID- 10108367 TI - Beware the bad old days. PMID- 10108368 TI - Creating common purpose. PMID- 10108369 TI - Danger: AIDS at work. PMID- 10108370 TI - A commonsense model. PMID- 10108371 TI - What's in a name? PMID- 10108372 TI - Made to measure survey. PMID- 10108373 TI - Unpicking the monolith. PMID- 10108374 TI - Backing a united front. PMID- 10108375 TI - A facility for change. PMID- 10108376 TI - No going back. PMID- 10108377 TI - Taking IT (information technology) on trust. PMID- 10108378 TI - Ready and able. PMID- 10108379 TI - Nothing damning to be published. PMID- 10108380 TI - Healthy eating in Hull. PMID- 10108382 TI - Turning audit around. PMID- 10108383 TI - Breathing the oxygen of publicity. PMID- 10108381 TI - A view from the other side. PMID- 10108384 TI - Framework for change. PMID- 10108385 TI - Teaching by example. PMID- 10108386 TI - Communicating the vision. PMID- 10108387 TI - Visions communicated. PMID- 10108388 TI - Market-driven communication strategy. PMID- 10108389 TI - Planning for success in ambulatory care. PMID- 10108390 TI - The shape of things to come: Part 5. Getting peak performance in the knowledge based organization. AB - Previous articles in this series have examined several methods to enhance performance in healthcare organizations. We have described the flattened, fluid, outcome-oriented organizational structures that characterize successful healthcare enterprises. We have looked at the elements of organizational culture that distinguish successful hospitals. We have seen how cutting-edge institutions design compensation programs to spur and reward extraordinary results. And we have analyzed competency-based techniques for selecting and developing high performance people. This article addresses the key that will bring all of these together to gain a competitive advantage: knowing how to motivate employees to peak performance. PMID- 10108391 TI - The quiet superstars. Part 2. Catherine McAuley Health Center, Ann Arbor, Michigan; McNeal Hospital, Berwyn, Illinois; Lexington Medical Center, West Columbia, South Carolina. PMID- 10108392 TI - The art and craft of followership. Interview by Joe Flower. PMID- 10108393 TI - Empowering your people, Part 2. PMID- 10108395 TI - Hospital leadership: uncovering its real meaning. PMID- 10108394 TI - The ethics of advocacy & policy: honor among thieves? PMID- 10108397 TI - The board's role in strategic planning. PMID- 10108396 TI - The hospital governing board's quest for 'supermanager'. PMID- 10108398 TI - Innovative approaches in governance: a case study of the Greater Southeast Healthcare System. AB - Washington, D.C.'s Greater Southeast Healthcare System is like a spinning top- balanced by internal energy and driven by external forces. Those forces, the voices of the system's community, have provided Greater Southeast with direction and governance that have brought the system national recognition as well as an agenda for change. Even more important, they have resulted in services that have grown deep roots in the community. PMID- 10108399 TI - Hospital closings: fact and fiction. AB - The majority of hospitals that closed in 1988 appear to have closed because they could not compete with other alternatives. In short, there was not sufficient value to justify their continuation. PMID- 10108401 TI - Key legal issues in foreign contracts. PMID- 10108400 TI - Searching for a new job: some first-hand advice. PMID- 10108402 TI - A conflict of morals? PMID- 10108403 TI - Avoiding unplanned financial losses. PMID- 10108404 TI - Promoting healthy management in the NHS in the 1990s. PMID- 10108405 TI - Why women are "simply not good chaps" when it comes to a career in medicine. PMID- 10108406 TI - Can the NHS afford not to worry about alcohol at work? AB - The NHS has a special responsibility to set an example on alcohol awareness at work. How should managers set about setting this example. Ray Earwicker reports. PMID- 10108407 TI - Caring--is the price staff are paying too high? PMID- 10108408 TI - The hidden significance of the union notice board. PMID- 10108410 TI - The NHS management agenda for the 1990s. PMID- 10108409 TI - A very public civil servant. Interview by Alison Hyde. PMID- 10108411 TI - Moving targets. Discussing health-care issues would be easier if the target didn't move--if we all agreed on the meaning of "health". PMID- 10108412 TI - New yardsticks. Standard indicators of hospital activity have failed to keep pace with changes in hospitals and in the practice of medicine. PMID- 10108413 TI - Access to what? For whom? PMID- 10108414 TI - Coming forward. Hospitals should take the initiative to ensure that the public has the information it needs to make judgments about quality. PMID- 10108415 TI - Getting aggressive about quality. PMID- 10108416 TI - Benefitting communities. Helping hospitals measure their own performance is the key to a new Hospital Community Benefit Standards Program. PMID- 10108417 TI - Americans' views on healthcare and rationing. PMID- 10108418 TI - An academy of leaders. PMID- 10108419 TI - OBRA's open-book test is no breeze. PMID- 10108420 TI - Teaching tools. PMID- 10108421 TI - In search of the "win-win" RFP. PMID- 10108422 TI - Success or survival. Redeploying strategic assets to maximize their value. AB - As capital sources dry up, hospitals should consider restructuring their finances to maximize the value of current assets, to achieve greater cost efficiency, and to fund new businesses and services that will generate new revenues. Strategic asset redeployment consists of analyzing assets; plans for new business development, equipment, and real estate acquisitions; and the impact on the budget. Hospitals are leasing more frequently to finance new equipment and property, but they are also looking at existing equipment and property to determine whether refinancing through a sale/leaseback makes sense. Also, before a hospital decides to offer a costly new service, such as magnetic resonance imaging, an impartial analysis should first determine the market for and the financial feasibility of the service. Once a service is determined to be viable, the term of the financing should match the life span of the project. PMID- 10108423 TI - Counting community benefits. CHA survey reveals members' commitment to providing care for the poor and other community services. Catholic Health Association. AB - In its 1990 National Community Benefits Survey, the Catholic Health Association (CHA) found that in recent years Catholic hospitals increased the amount of uncompensated care they provided, despite growing fiscal constraints. CHA also found that, in the two years since it introduced the Social Accountability Budget, 60 percent of Catholic healthcare facilities have used either CHA's process or a similar structured approach to reinforce, measure, and plan their contributions to the community. Of the hospitals that responded to the survey, 91 percent provided nonbilled services targeted to low-income populations in 1989, more than 75 percent provided free or discounted services to other populations with special needs, and about 82 percent made free or discounted services available to the broader community. In addition, the majority of Catholic facilities can now more accurately report the dollar value of the uncompensated care they provide. In Illinois 31 of the state's 52 Catholic hospitals were able to quantify the value of the benefits they provide to the poor and the broader community. Moreover, facilities and systems throughout the nation are intensifying their efforts to plan and coordinate programs to meet community needs and the needs of the poor. PMID- 10108424 TI - Seeing to one's self. Those who care for persons with AIDS must also preserve their own well-being. AB - Those who care for persons with AIDS face a number of special issues. They must understand the complex clinical course of the disease, be ready to cope with its devastating effects on patients, know how to address social prejudices against persons with AIDS, and be prepared to deal with the stresses of providing care under difficult circumstances. To be effective, care givers must know how to take care of themselves. Having a philosophy of care is one key component of self-care because it gives care givers a clear sense of direction and helps them enjoy a greater sense of well-being and personal satisfaction. Creating a motivating environment, taking responsibility for the challenges and stresses of the job, building a supportive team, understanding the AIDS experience, and confronting the effects of grief are also important components in the self-care of the AIDS care giver. PMID- 10108425 TI - Compassion fatigue. Healthcare professionals are vulnerable as care giving becomes more stressful. PMID- 10108426 TI - Easing the burden of stress. A stress management program can help eldercare professionals cope. AB - Healthcare professionals in general, and those who care for the elderly in particular, must cope with a number of stressors in the working environment. Moreover, because care givers tend to put others' needs before their own, they often place an added burden of stress on themselves. Eldercare professionals must often forego the reward of finding a cure for their patients. In addition, the persons they care for can sometimes become overly dependent, depressed, unappreciative, self-centered, and demanding. The daily effort to deflect or diffuse this negative energy can take its toll on care givers, leading to coping deficiencies that themselves increase workplace tension and stress. Not only individuals, but entire departments can develop dysfunctional reactions to stress. To break this vicious cycle and improve workplace morale, facilities can implement stress management programs. As part of such a program, supervisors and managers identify stressors in the environment and suggest ways to alleviate or eliminate their effects. Once morale improves, coordinators should shift the program's focus to maintaining employee morale. PMID- 10108427 TI - A source of support. An ethics committee helps nurses do the right thing. AB - In 1984 Archbishop Bergan Mercy Hospital, Omaha, established a nursing bioethics committee to increase its professional nurses' knowledge of applied ethics. The committee's original objectives were to (1) help nurses assume the authority and responsibility to make ethical judgements, (2) influence the development of policies on healthcare standards, (3) serve as a resource to clinicians and managers responsible for delivering high-quality nursing care, (4) develop systemwide support for nurses' participation in ethical decision making, and (5) serve as a source from which nurses could be selected to the hospital's Human Values Committee. The bioethics committee established a formal mechanism to ensure that nurses receive support when they take the initiative in ethical decisions. The nurse and the committee member from his or her department organize a "community of concern" consisting of all persons necessary to address the essential ethical components of the issue at hand. PMID- 10108428 TI - Efficiency experts. Hospitals can improve performance by starting in the human resources department. AB - In our changing economic environment, efficient human resource (HR) management is especially crucial to hospitals. Has the emphasis on HR activities responded to this changing environment? We studied 165 hospitals to determine whether they are making good use of HR. The results of our study show that HR activities remain important during these turbulent times. The emphasis hospitals place on HR activities increased slightly between 1985 and 1986. Performance evaluation ranked the highest in emphasis; job redesign and analysis were also high ranking. These are important mechanisms for improving performance and productivity. Respondents also rated HR activities by importance. Several categories that ranked high in change in emphasis ranked low in importance, and vice versa. One reason for this discrepancy between emphasis and importance is that HR activities that directors consider important may have already received a great deal of emphasis, leaving no room for increase. Also, circumstances may dictate increased emphasis on an activity (e.g., layoffs) even though HR directors consider it unimportant. PMID- 10108429 TI - A commitment to values. A system integrates core values with leadership development. AB - The Values in Leadership program, a new leadership development program created by the Sisters of Charity Health Care Systems (SCHCS), is designed to empower effective leaders to live out personal values compatible with those of the organization. The program, designed for middle and senior managers, comprises seven educational modules- Living Our Values; Valuing Individual Differences; Leader as Servant; Leader as Visionary; Leader as Catalyst; Leader as Mentor; Formative Leadership; and Leader as Mentor; Motivational Coaching. Throughout the sessions, participants discuss the four roles of an effective leader-servant, visionary, catalyst, and mentor-which are grounded in SCHCS core values. Participants are also challenged to identify specific actions that can be integrated into their leadership styles. These actions, drawn from SCHCS leadership practices and core values, are reinforced when participants return to their jobs and write plans to incorporate these practices into their daily work. PMID- 10108430 TI - Reason for interest. PMID- 10108431 TI - Fatherly advice. PMID- 10108432 TI - A gift of hope. PMID- 10108433 TI - The future of public health. PMID- 10108434 TI - The "greening" of American hospitals. PMID- 10108435 TI - The public's health: how healthy will America be in the 1990s? PMID- 10108436 TI - Community care. PMID- 10108437 TI - Waiting lists reduced. PMID- 10108438 TI - Ambulance services. PMID- 10108439 TI - Six key issues in successful resource management extension. PMID- 10108440 TI - Self-governing hospitals in a publicly funded system. PMID- 10108441 TI - A spoonful of competence helps the medicine go down. AB - The Organisation Development Consultancy based in the training department of the North Western RHA has been involved recently in a variety of projects researching into management competencies. This article outlines the findings from a project undertaken at Tameside and Glossop HA. The aim of the research was to provide an information base on which to build an appropriate recruitment and selection strategy and training and development policy for the continued future development of the district. PMID- 10108442 TI - Organisation studies: time for change. AB - Young managers, argues David Thompson, need to understand organisations, but do not at present learn anything like as much as they could from organisation theory. He therefore proposes a revision of the IHSM syllabus in the subject. PMID- 10108443 TI - Using customer satisfaction surveys to improve service quality. PMID- 10108444 TI - Doctors, managers and audit. AB - Audit as a requisite part of clinical practice in this country is in its infancy. As with all new arrivals, it has already begun to test relationships- particularly those between clinicians and general managers. There is some uncertainty about how audit will grow and develop--how big will it get? Will it be obedient and loyal to clinicians? What will it achieve? PMID- 10108446 TI - A hospital manager's guide to handling medical negligence claims. PMID- 10108445 TI - Health planning: a vital role for district health authorities. AB - Next April the planning function of DHAs will change. However, planning will still be vitally important if they are to perform their purchasing role effectively. Douglas Scott discusses the implication of this and describes the approach to planning being developed in Leeds. PMID- 10108447 TI - A classification of health computer systems and how it could help in deciding investment requirements. AB - Investment in information technology by the NHS is reaching unprecedented levels. This is true throughout the service, from the highly publicized district information systems and hospital information support systems to the investment of GPs in microcomputers. To place all these system developments in context, Peter Cross considers the changes in the structure of health computing in the 1980s and sets out a methodology for assessing both the need for computer systems and their success. PMID- 10108448 TI - Organizational choices for hospital cooperative service organizations. PMID- 10108449 TI - Revisiting FireMed. Ambulance membership programs. AB - Launched in Oregon in 1986, FireMed programs are springing up in other states, offering unique benefits to fire departments and patients alike. Learn the keys to their success. PMID- 10108450 TI - Spotting hot trends in fire service EMS. AB - With fire prevention and public education reducing the need for fire-fighting capabilities, it makes sense for fire services to aggressively pursue patient care opportunities. Read about this and other hot trends likely to ignite change in fire service EMS. PMID- 10108451 TI - Getting a jump on automatic defibrillation. PMID- 10108453 TI - Seeing eye to eye. PMID- 10108452 TI - Caring for the elderly. A new generation of patients. AB - As the geriatric population grows, so must our knowledge of the physiological and psychological needs unique to the elderly. This article focuses on common scenarios involving geriatric patients, such as drug-related emergencies, thermoregulatory dysfunction and mental syndromes. PMID- 10108454 TI - Anxiety and creation in the clinical pastoral education context: a theology of pastoral formation. AB - Draws on the writings of Mircea Eliade, Paul Tillich, Soren Kierkegaard, and Henry Nelson Wieman to explicate a theology of pastoral formation as it may take form in the context of Clinical Pastoral Education. Proposes that an appreciation of the dynamics of grief is especially capable of connecting a theology of pastoral development to both the psychology of individual development and the sociology of cultural change. PMID- 10108455 TI - So great a cloud of witnesses: the use of family systems process in forming pastoral identity and facilitating pastoral functioning. AB - Describes the use of genograms in units of Clinical Pastoral Education. Provides the reader with a theoretical base for viewing experiences in CPE as manifestations of family of origin factors. Reflects on how such connections can enrich recognitions of the power of transference in relationships and thus provide the caregiver with greater insight into how he or she may express ministry and caregiving activities. PMID- 10108456 TI - Instruments used to measure change in students preparing for ministry: a summary of research on clinical pastoral education students. AB - Surveys studies in which psychometric tools were used in an attempt to measure change in students as a result of their participation in Clinical Pastoral Education. Gives special attention to the use of The Minnesota Multiphasic Personality Inventory, the Personality Orientation Inventory, Edwards Personal Preference Schedule, the Adjective Check List, the Osgood Semantic Differential, Cattells' Sixteen Personality Factor Test, Leary's System for Interpersonal Diagnosis, the Carkhuff Scale, and The Empathy Test. Notes positive as well as limiting factors of research in which psychometric instruments have been used. PMID- 10108457 TI - The patient could have died for all his HMO cared. PMID- 10108458 TI - How much power do physicians wield in group practices? PMID- 10108460 TI - Rush-Presbyterian, Chicago hospital discuss affiliation. PMID- 10108459 TI - This doctor turned in a colleague for Medicare fraud. PMID- 10108461 TI - Tighter lab regulations recommended by HHS. PMID- 10108462 TI - Chicago hospital agrees to stop elective abortions. PMID- 10108463 TI - AIDS removed from immigration restrictions. PMID- 10108464 TI - Firm told to lift cap on AIDS claims. PMID- 10108465 TI - Debt downgradings outnumber upgrades 3-1. PMID- 10108466 TI - White House scales back assault on medical education adjustment. PMID- 10108467 TI - Hospitals set to bounce back in '91. PMID- 10108468 TI - Florida providers in heated battle for cancer referrals. AB - Providers in Florida are building up their cancer-care arsenals with ambitious building projects and affiliations with brand-name institutions. While the intensity of the "oncology wars" in Florida is partly a result of the state's large elderly population, analysts believe the heated competition there is an indicator of what the rest of the nation may soon experience. PMID- 10108469 TI - Military health system mobilizes for war. PMID- 10108471 TI - More hospitals seek managed-care specialists. PMID- 10108470 TI - Healthcare in Chinatown: a mix of medicine, culture. AB - Located in San Francisco's densely populated Chinatown district is Chinese Hospital, a small, acute-care facility that has a long tradition in the community. The hospital's mission is to mix modern medical care with touches of the traditional Chinese culture, all the while dealing with the pressing economic problems facing most U.S. hospitals. PMID- 10108472 TI - Safety needle sales soar after price slash. PMID- 10108473 TI - Healthcare law firms find malpractice verdict 'chilling'. PMID- 10108474 TI - Putting your strategic plan into effect. AB - Everyone has huddled over it for months, and now it's a can't-miss strategy for your hospital. Or is it? To find out whether the facility is ready for it, do an "organizational diagnostic" as explained by Gerald McManis in Modern Healthcare's first Managing feature for administrators. PMID- 10108475 TI - Fourth-quarter bond volume rises 27.6%. AB - As capital markets showed signs of coping with the war threat in the Persian Gulf, tax-exempt bond volume for the fourth quarter of 1990 rose 27.6% from the previous three months. PMID- 10108476 TI - AMI reports $20.7 million first-quarter loss. PMID- 10108477 TI - Epic reports improved financial results. PMID- 10108478 TI - Nu-Med leases hospital to physician group. PMID- 10108479 TI - St. Louis hospital set to jettison Fla. affiliate. PMID- 10108480 TI - Findings on Hispanic health no surprise to border hospital. PMID- 10108481 TI - Boston facility adds local services. PMID- 10108482 TI - Residential care facilities offer broad continuum of care. PMID- 10108483 TI - Reaching target audience with complete marketing program. PMID- 10108484 TI - Recruitment program begins with community outreach. PMID- 10108485 TI - Medication evaluation system monitors psychotropic drug use. PMID- 10108486 TI - The role of patient-controlled analgesia in postoperative pain management. AB - Patient-controlled Analgesia (PCA) permits patients to treat their postoperative pain by activating a pump to deliver doses of intravenous narcotic. This technique was developed in response to the undertreatment of postoperative pain with conventional intramuscular therapy. PCA allows patients to balance pain control with sedation, and permits nurses to implement other aspects of patient care once pain is controlled. Concerns regarding PCA include mechanical errors, overdosage, and inadequate patient instruction. Careful patient screening and preoperative teaching are essential. While data regarding cost-effectiveness are limited, increasing use and patient satisfaction could make PCA the standard of care in the future. PMID- 10108487 TI - Subsidizing screening mammography through induced revenues and profits. AB - By segregating asymptomatic from symptomatic patients and realizing the significance of induced revenue and profits created by screening mammography, community hospitals and physicians can make this screening procedure affordable to women in their community. Induced revenue is the total gross revenue produced by subsequent exams due to equivocal results of the initial exam. Profits result from this induced revenue less insurance adjustments and costs incurred by the institution in performing subsequent exams. PMID- 10108488 TI - Show that you care. AB - Are you an Ebenezer Scrooge when it comes to reward and recognition for your staff? How many times last week did you phone a member of your staff, or better yet, visit in person to say that you appreciated something they did? When was the last time you wrote a note of thanks? Do you routinely recognize special efforts during staff meetings? When was the last time you awarded a certificate of appreciation to an employee for a job well done? Are employees working "behind the scenes" recognized? Do you have a system in place to recognize groups who work well as a team? If you answered "no" to most of these questions, don't fret. Establishing a reward and recognition program is relatively easy to do. And, it won't break the budget either. PMID- 10108489 TI - Hospital wars. AB - According to the author, marketing warfare precipitated by increased competition and recent public policy decisions is a distinct possibility in the health care environment. Since the military marketing metaphor has been useful in describing the current situation, Dr. Dempsey presents clear explanations of both attack and defense strategies with examples of organizations that have used them. PMID- 10108490 TI - Survey on job content and salary: Part II. AB - Part II of the results of the AHRA Statistical Resource Committee salary survey reviews radiology administrators' salaries and job content. Salary levels are analyzed in relation to a number of parameters, including procedure volume, budgets, full-time equivalent staff and others. In addition, survey results look at the effect of sex, educational level and facility setting on both salary and satisfaction level. PMID- 10108491 TI - A fault-based administrative alternative for resolving medical malpractice claims. PMID- 10108492 TI - National scientific registry of organ transplantation: data needs and uses. AB - There is a lot of work yet to be accomplished through the scientific registry, which will be made more efficient by the consolidation of information into patient-specific files rather than the existing "file by form" set-up. Additionally, users will be able to input data directly, eliminating the problem of the time delays between transplant and follow-up dates and the actual use of the forms. The registry data also will become more useful as the database grows. The data on long-term graft and patient survival will directly influence future policy decisions and transplant practices. The clinical outcomes of transplantation also will be influenced by donor management and organ preservation techniques, all of which can be addressed through the use of registry data. The ultimate goal is to make transplantation more reliable, more predictable, more widely available, and less expensive. The national, comprehensive database accomplishes that goal. PMID- 10108493 TI - Coordinating data management for multiple ongoing clinical trials and registries. AB - The Epidemiology Data Center at the University of Pittsburgh has developed a standard set of data management procedures, reports, and computing configurations for use on multicenter research projects. Based on budget restrictions and study design considerations, a project-specific data management system can be quickly constructed by utilizing appropriate components from the EDC tool kit: the PoP software system for the computerization of the database from paper forms to data entry screens; program shells for telecommunication and backup procedures; and procedural documents for providing the necessary training materials for centralized or decentralized processing environments. The EDC data flow specification provides quality control assurances from entry through statistical analysis. PMID- 10108494 TI - Transplant information management system: a center-oriented approach to transplant data management. AB - TIMY is the ideal management system for novice data-entry personnel as well as for the research staff, nurses, and physicians at our facility. Access to data through the use of menus and security systems makes TIMY a user-friendly database. It has excellent data export capabilities so that more complex data analysis can be performed using dedicated software such as SPSS/PC, BMDP, or SAS. This provides great flexibility as well as the power needed for the study of complex data sets. PMID- 10108495 TI - Insulin-dependent diabetes mellitus: applications of health records for understanding etiology. The Pittsburgh IDDM Registry Group. AB - The estimation of incidence (or risk) of disease depends on accurate and complete reporting of new cases and precise estimation of the population at risk. Therefore, incidence studies are often based on population-based incidence registries. A critical problem in diabetes research, however, has been the lack of adequate population-based data. For diseases that have a distinct and rapid onset, the best method of obtaining population-based data is to develop registries of community health information. These disease registries form an important tool for assessing the clinical course of diseases and can lead to an understanding of their etiology and pathogenesis. Moreover, by facilitating identification of cases, disease registries can serve as a population source for genetic and immunological testing, the results of which can be directly related to absolute risk. Evaluation of factors associated with a disease can suggest methods for reducing its incidence and even lead to its eradication. Such registries also permit the evaluation of existing or proposed health care measures. Registry information can rapidly be communicated to the local area health authorities to assist in altering patterns of care. Registries are therefore important for understanding the etiology and complications of chronic diseases as well as for evaluation of medical care in populations. For diabetes, and in particular, insulin-dependent diabetes, the development and comparison of registries in diverse populations worldwide may be more important than for other diseases. A major reason for developing them is that the disease is very costly both for patients and society.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10108496 TI - Anatomy of a statewide trauma registry. AB - The Pennsylvania Trauma Systems Foundation has existed for five years. A concept that in 1984 seemed like a futuristic dream has been accomplished. Standards for trauma center accreditation have been developed, and trauma centers are accredited in a fair, unbiased, and systematic manner. Pennsylvania's voluntary system could not have succeeded without the full support of the hospital, medical, and nursing communities. Trauma centers are not edifices alone; the commitment of the institutions and their personnel was phenomenal. Pennsylvania has the largest and most comprehensive trauma registry in terms of complete data compliance in the United States. Data collected have been used for quality assurance, the accreditation process, and trauma prevention and research. The commitment by medical record professionals to develop and maintain individual hospital trauma registries as well as the PTSF trauma registry has been enormous. The future of trauma system development in Pennsylvania lies in the data collection system and the research in trauma systems and trauma care that is generated from the database. PMID- 10108497 TI - The trauma registry: an administrative and clinical tool. AB - A commitment to the maintenance of a comprehensive trauma registry can provide numerous benefits, both administrative and clinical. Uses of the information collected can vary in nature and scope based on the needs of the facility and the requirements of external regulatory bodies. Ultimately, the choice of data applications rests with the facility collecting the information. As the facility grows and evolves, so can--and must--its registry. PMID- 10108498 TI - Evolution of a hospital-based trauma registry. PMID- 10108499 TI - The California tumor registry: a state-of-the-art model for a regionalized, automated, population-based registry. PMID- 10108500 TI - A statewide cancer registry: the Pennsylvania experience. AB - Pennsylvania has been successful in establishing a statewide cancer registry. The success of this registry results from the efforts of many different groups. The program has benefited from strong legislation making cancer a reportable disease and assigning the responsibility of reporting to hospitals. The PCR has implemented many initiatives to ensure that the cooperation of hospitals in operating the system is maintained, and that there is sufficient knowledge among hospital personnel to ensure complete casefinding. As the amount of statewide incidence data is increased over several years, the utility of these data for program planning and epidemiologic studies will increase greatly. The establishment and ongoing operation of the PCR ensure that cancer incidence data are available in providing answers to questions such as some of those asked following the accident at Three Mile Island. PMID- 10108501 TI - The relational clinical database: a possible solution to the star wars in registry systems. AB - In summary, having data from other service areas available in a relational clinical database could resolve many of the problems existing in today's registry systems. Uniting sophisticated information systems into a centralized database system could definitely be a corporate asset in managing the bottom line. PMID- 10108502 TI - Investment management for the long term. PMID- 10108503 TI - The advantages of networking for urban/rural hospitals. PMID- 10108504 TI - Planning for early MD retirement. PMID- 10108505 TI - Patient-centered care: can you afford not to have it? PMID- 10108506 TI - Geriatric care management saves money, improves care. PMID- 10108507 TI - Lawsuits can be rocky road to adequate Medicaid reimbursement. PMID- 10108508 TI - What is the business of hospitals? PMID- 10108509 TI - Executive outplacement services: what trustees need to know. PMID- 10108510 TI - Hospitals need informed trustees. PMID- 10108511 TI - Hospitals face conflicting environmental laws. PMID- 10108512 TI - Corporate restructuring prompts board self-evaluation. Interview by Jane Martinsons. AB - The Iowa Methodist Medical Center, Des Moines, today is not the same as the medical facility of the early 1980s. Since then, the hospital has been part of a major corporate restructuring. In the mid-1980s, a holding company was formed with the 710-bed medical center as its principal subsidiary. Other not-for-profit and for-profit subsidiaries also were established. An HMO was founded and then later sold. In the midst of this activity stood a large and cumbersome board of directors. So along with efforts to streamline the health system's services, efforts were made to streamline or downsize the hospital board. At the tail end of this busy process, the board thought it time to evaluate its effectiveness. Ralph Schlenker, vice chairman of Iowa Methodist's board of trustees, recently talked with Chicago-based free-lance writer Jane Martinsons about how and why the board sought self-assessment. Schlenker, who before his retirement was vice chairman of Iowa Power Inc., Des Moines, has been a trustee of Iowa Methodist Medical Center for 10 years and vice chairman of the board for the last two. PMID- 10108513 TI - Infectious diseases in the workplace: pointers for an ethical management policy. AB - Infectious diseases in the workplace can present difficult dilemmas for employers, who must balance the rights of infected employees against obligations to protect other employees from infection. Anti-discrimination legislation imposes additional obligations on employers to ensure that any steps taken in response to the risk of infectious disease do not amount to unlawful discrimination against employees who may be disease carriers. This paper analyses the operation of anti-discrimination in this context and points to ways in which employers can formulate an infectious diseases policy that is both ethically and legally defensible. PMID- 10108514 TI - The education of future senior health service managers. AB - Primarily due to economic forces, health services are being forced into a tight organisational framework of hospitals, clinics and services which need to be managed by educated professional managers. These managers need to be competent general and financial managers, competent planners, knowledgeable about health status, health issues, the Australian health care systems and knowledgeable about society, law and ethics. Assumptions that recruitment of people with such a formidable array of talents would be difficult are incorrect as judged by current experiences. Very talented and experienced candidates are being attracted to graduate education programs in health service management in many Australian universities. Accordingly the future management of Australian health services should be in good hands. PMID- 10108515 TI - Professional nursing education in the university context. AB - This paper examines the notion of the character of the nurse, how it was moulded with the development of modern professional nursing in the patriarchal society of the time and how it has changed in the context of the rise of modern medicine. Emphasis is given to the importance of ensuring the humanising development of the nursing student in the university context through an appropriate balance of theory and practice and access to study of the liberal arts. PMID- 10108516 TI - Technology marches on: considerations for the nursing profession. AB - The rapid development of health care technology particularly the so-called 'high tech' innovations is having a significant impact upon the Australian health care system. The technological changes are occurring in a climate of economic constraints and are having notable effects on clinical nursing practice. Implications for clinicians, academics and managers are outlined. PMID- 10108517 TI - Nursing and leadership: a personal view from outside the profession. AB - Following identification of some key concepts in leadership, the structure of the nursing profession is approached via class, gender, culture, practice, education and industrial features. While the need for micro-level leadership is identified, it is argued that major opportunities exist in restructuring nursing's educational bases and practice organisation, supported by mastery of industrial matters. Unification of the profession is necessary to achieve a higher profile and greater respect. PMID- 10108519 TI - UCDS (Uniform Clinical Data Set): a closer look at what's just around the corner at HCFA. PMID- 10108518 TI - Performance indicators--can you afford not to have them? Royal Children's Hospital--a structured approach. AB - The thought of performance assessment may send chills through even the most experienced hospital manager. It conjures up the worst facets of negativeness, failure, being 'watched', funding cuts and being 'on trial'. Yet the constructive use of performance indicators is undoubtedly an essential tool to all levels of management within a hospital. Performance indicators are as important to health agencies as they are to B.H.P. Stringent financial restraints, calls from 'shareholders' to demonstrate performance and to be more accountable are placing management under increasing scrutiny. Overseas work points to the use and abuse of indicators, and the difficulty in arriving at appropriate and meaningful performance indicators. A computer search of Australian literature reveals a dearth of papers on the subject of health service performance indicators. Perhaps the cultural norm of reticence towards formal performance appraisal is reflected by this dearth. Within individual agencies, however, performance indicators are being utilised in varying degrees. The Royal Children's Hospital, Melbourne, has compiled a structured set of performance indicators for two purposes--firstly, as a means of monitoring performance on a regular basis, and secondly, as a quality assurance tool. The hospital's chosen indicators cover not only throughput, but attempt to shed some light on efficiency and effectiveness. They are designed to highlight areas/trends which diverge from the 'norm', which act as warning signals to investigate further. Whilst some measures relate specifically to the activities and objectives of the Royal Children's Hospital, many are sufficiently general to the hospital field to be worth considering by any hospital interested in a more structured, formal review of its performance. It may also be possible to obtain many of the measures shown without necessarily having in place extensive/comprehensive computer information systems. Introduction of measures may therefore be undertaken progressively. PMID- 10108520 TI - Quality in the market-place: White Paper challenges. PMID- 10108521 TI - Medical audit and libraries--an opportunity for progress. AB - Working for patients has necessitated the use of medical audit as a quality assurance tool. This paper presents an overview of the form and content of audit, and examines the supporting role of the library. It notes the failure of many Regional Medical Audit Implementation Plans to recognize the value of library services, and proposes a strategy to enable librarians to play an active part in the process, and by doing so to increase awareness of library services and improve decision making. PMID- 10108522 TI - The effects of CD-ROM on library services. AB - This paper presents a wide-ranging overview of compact disc technology in the library environment. It raises important issues currently being debated in the literature and aims to question and stimulate thought on the nature and purpose of CD-ROM provision in health-care libraries. PMID- 10108523 TI - Getting together with compact disc: a regional MEDLINE CD-ROM initiative for libraries. AB - An initiative by the North West Thames Regional Information Technology Agency has resulted in the provision of some 30 CD-ROM drives and copies of the MEDLINE database in National Health Service libraries. The development of the scheme and its implementation are described and future developments outlined. PMID- 10108524 TI - Effect of CD-ROM in a Spanish medical library: a case study. PMID- 10108525 TI - The training implications of library automation: approaches to staff and end-user training in health libraries. PMID- 10108526 TI - Training end users on CD-ROM MEDLINE: a case study. PMID- 10108527 TI - Disclosure of AIDS-test results stirs mixed reactions. PMID- 10108529 TI - Patient self-determination becomes law of the land. PMID- 10108528 TI - Cruzan family's determination spurs patient self-determination. PMID- 10108530 TI - Medicare program; Medicare Economic Index update for 1991--HCFA. Notice. AB - This notice updates the Medicare Economic Index (MEI), which is used to calculate the prevailing charge levels that help to determine reasonable charges for certain physician services under the Medicare Supplementary Medical Insurance (part B) program. As mandated by section 4105 of Public Law 101-508, for physician services furnished on or after January 1, 1991, and before January 1, 1992, the increase for primary care services will be 2 percent. There will be no increase for all other physician services. PMID- 10108532 TI - Discharge procedures. George Washington University Medical Center, Washington, DC. PMID- 10108531 TI - The day the tornado hit. PMID- 10108534 TI - Disaster plan: an executive summary. George Washington University Medical Center, Washington, DC. PMID- 10108533 TI - Disaster workers: human beings. PMID- 10108535 TI - Disaster victim tracking system. George Washington University Medical Center, Washington, DC. PMID- 10108536 TI - Marketing. Strategies for creativity. PMID- 10108538 TI - Q Plan cuts costs & boosts nurses. PMID- 10108537 TI - Pre-empting quality improves margins. PMID- 10108539 TI - Healthcare access for Japanese business. PMID- 10108540 TI - Bar codes cut lab costs. PMID- 10108541 TI - Building a stronger donor list. PMID- 10108542 TI - Promoting EAPs ... a delicate balance. PMID- 10108543 TI - This is the place for nurses to work. PMID- 10108544 TI - Courting nurses: then and now. PMID- 10108545 TI - Getting board support. An obstacle to effective marketing: your hospital board. PMID- 10108546 TI - Getting board support. Suggestions: forge an alliance hospital-patient-board. PMID- 10108547 TI - Wearing a helmet can be fun. PMID- 10108548 TI - Don't be a street stain. PMID- 10108549 TI - A center without walls. PMID- 10108550 TI - Copycat art draws a lineup. PMID- 10108551 TI - All eyes on this health club. PMID- 10108552 TI - The 'just in case' first aid case. PMID- 10108553 TI - Send out the brigade! PMID- 10108554 TI - Anatomy lessons for pediatric referrals. PMID- 10108555 TI - Then & now: newsletter logos. PMID- 10108556 TI - Just one look: your newsletter's name & masthead. PMID- 10108557 TI - AHCA surveys top forty nursing facility chains. American Health Care Association. PMID- 10108558 TI - Moving away from restraints. PMID- 10108559 TI - Financial instability of states leaves providers uncertain. PMID- 10108560 TI - Nursing student practicums offer recruitment potential. PMID- 10108561 TI - Distinct parts lawsuit may restrict access to care. PMID- 10108562 TI - Psychogeriatric nurses help reduce stress in residents. PMID- 10108563 TI - Social workers individualize assessments, care plans. PMID- 10108564 TI - Medicaid drug bill mandates pharmaceutical discounts. PMID- 10108565 TI - Electronic security systems monitor resident activity. PMID- 10108567 TI - Class dismissed! PMID- 10108566 TI - Solutions to nurse shortage include 'role-appropriate' responsibilities. PMID- 10108568 TI - Medical staffs face new COBRA amendments. PMID- 10108569 TI - HCFA quality intervention plan does not fit training programs. PMID- 10108570 TI - Earnings or cash: what should be your focus? PMID- 10108571 TI - The costs of unhappy patients. PMID- 10108572 TI - What has caused the increase in outpatient benefit costs? PMID- 10108573 TI - Perspectives. Caring for the homeless: more than talk. PMID- 10108574 TI - Perspectives. Rural health at a cross roads. PMID- 10108575 TI - Developments in operating departments. PMID- 10108576 TI - The application of electro magnetic boiler water treatment. PMID- 10108577 TI - West Fife Hospital--phase 2. PMID- 10108578 TI - New integrated gas turbine CHP (combined heat and power) and incinerator plant. AB - Despite the complex nature of the project, the clients brief of a 14 month design and installation period was achieved within the approved budget of 2.5 million pounds. Early performance figures indicate that the scheme is on target to achieve the original payback of under four years. Queen Elizabeth Hospital: installation of integrated combined heat and power plant. Client: Central Birmingham Health Authority. Consulting Engineers/Project Managers: Yates, Edge and Partners. Architects: Temple Cox and Nichols. Structural Engineers: Peel and Fowler. Quantity Surveyor: West Midlands Regional Health Authority. PMID- 10108579 TI - Unconventional site energy strategy. PMID- 10108580 TI - Privacy Act of 1974; system of records--HCFA. Amendment of an existing system of records. AB - In accordance with the requirements of the Privacy Act of 1974, we are proposing to amend our system of records entitled, "Payments for Interns and Residents," HHS/HCFA/BPO No. 09-70-0524. The amendment will expand the information contained in the system to include the information on interns and residents required in 42 CFR 413.86 (Direct Graduate Medical Education Payments). We have provided information about this amendment in the "Supplementary Information" section below. PMID- 10108581 TI - Medical devices; patient examination and surgeons' gloves; adulteration--FDA. Final rule. AB - The Food and Drug Administration (FDA) is issuing a final rule to: (1) Define adulteration for patient examination and surgeons' gloves; and (2) establish the sample plans and test method the agency will use to determine if these gloves are adulterated as defined by the rule. With the prevalence of human immunodeficiency virus (HIV) infection and the risk of clinical transmission of other infections, the importance of the quality of an effective barrier to the transmission of infection in health care settings is crucial. The public health will benefit through improved quality control of these protective barriers. PMID- 10108582 TI - Advisory committees; establishment and termination--FDA. Final rule. AB - The Food and Drug Administration (FDA) is announcing the establishment by the Commissioner of Food and Drugs of the Medical Devices Advisory Committee and the termination of the existing devices panels. This document revises the agency's list of standing advisory committees to show these actions. PMID- 10108583 TI - Medicaid program; modification of certain requirements for health insuring organizations--HCFA. Final rule. AB - This final rule implements statutory changes which expressly made certain Health Insuring Organizations (HIOs) subject to Medicaid Health Maintenance Organization (HMO) rules. The statute implemented in this rule requires that an HIO which became operational on or after January 1, 1986, and arranges for comprehensive health services for Medicaid recipients on a risk basis be subject to HMO requirements. The statute also provides that exemptions from certain HMO rules are permitted for HIOs which began operation on or after January 1, 1986, if the HIOs are operating under a section 1915(b) waiver obtained prior to that date, or if an HIO is otherwise identified in the law. The exemptions continue as long as the waiver under section 1915(b) of the Social Security Act remains in effect. The statutory provisions implemented in this rule were enacted in section 9517(c) of the Consolidated Omnibus Budget Reconciliation Act of 1985, as amended by section 9435(e) of the Omnibus Budget Reconciliation Act of 1986, and section 1895(c)(4) of the Tax Reform Act of 1986. PMID- 10108584 TI - Medicare and Medicaid programs, freedom of information (FOI) guidelines--HCFA. Notice. AB - In accordance with the settlement agreement reached in the case of Home Health Line v. HCFA, District Court of District of Columbia, Civil Action (D.D.C., C.A.) No. 90-1006 LFO, HCFA is publishing in the Federal Register a notice describing and clarifying HCFA's guidelines concerning expedited processing of Freedom of Information (FOI) requests. PMID- 10108586 TI - Health Resources and Services Administration; nurse training; delegation of authority. PMID- 10108585 TI - Office of the Assistant Secretary for Health; delegation of authority. PMID- 10108587 TI - Medicare program; physician performance standard rates of increase for federal fiscal year 1991--HCFA. Notice. AB - This notice announces the Federal fiscal year (FY) 1991 physician performance standard rates of increase for expenditures and volume of physician services under the Medicare Supplementary Medical Insurance (part B) Program as required by section 1848(f)(2)(C) of the Social Security Act as added by section 4105(d) of the Omnibus Budget Reconciliation Act of 1990. The physician performance standard rates of increase for FY 1991 are the following: 7.3 percent for all physician services, 3.3 percent for surgical services, and 8.6 percent for nonsurgical services. PMID- 10108588 TI - Medicare program; Medicare coverage of screening mammography--HCFA. Interim final rule with comment. AB - This interim final rule implements section 4163 of the Omnibus Budget Reconciliation Act of 1990 (Pub. L. 101-508), which provides limited coverage for screening mammography services. It amends current Medicare regulations to set forth payment limitations and conditions for coverage of screening mammography. The conditions consist of quality standards to assure the safety and accuracy of screening mammography services performed by qualified physicians and other suppliers of these services. PMID- 10108589 TI - The health insurance crisis in America. PMID- 10108590 TI - Crisis in psychosocial occupational therapy: a closer look. AB - To date, there are no existing data concerning similarities and differences in occupational therapist shortages among the broad areas of clinical practice. Accordingly, this study sought to develop a profile of therapist shortages in Metropolitan Toronto within three broad foci of intervention, namely, physical dysfunction (PD), psychosocial dysfunction (PS), or a combination of both (C). Seventy-seven questionnaires were mailed to occupational therapy managers in Metropolitan Toronto. The 74% response rate from managers supervising a total of 516 therapists provided information which included numbers of existing positions (full- and part-time), numbers of vacancies and vacancy periods, as well as perceptions concerning reasons for vacancies and need for additional positions. Although no significant differences were found among vacancy rates in the three areas there was a perception that the greatest shortage was within the PS area of practice. Implications of these results are discussed in light of the perceived crisis in psychosocial therapy. Recommendations for future research are delineated. PMID- 10108591 TI - Smith Seckman Reid, Inc.: riding the health-care wave. AB - Nashville-based giant builds national reputation on its expertise in complex, integrated mechanical and electrical systems for health care facilities. PMID- 10108592 TI - Consulting engineering giants. PMID- 10108593 TI - Mission survey. PMID- 10108594 TI - Five families share their views of ethical decisionmaking in the NICU. AB - Five families' descriptions of their experiences with neonates in the intensive care nursery provides a glimpse into their perceptions of ethical problems and moral actions. Based on clinical experiences with families of high-risk neonates in the community health setting, a need for parents to share their reflections with a broader audience was identified. Definitions of conflict, identification of moral problems, and determination of right action showed similarities and differences among the families. Future study is suggested to validate these impressions for generalization to additional families. PMID- 10108595 TI - The premature infant home intervention program. AB - The Premature Infant Home Intervention Program, a collaborative effort of the Visiting Nurse Association of Cleveland and Rainbow Babies and Children's Hospital of Cleveland, is designed to provide family support and medical surveillance for high-risk premature infants, to ensure post-discharge wellbeing, and improve survival outcome during the first years of life. PMID- 10108596 TI - The HUG Center--caring for special children. AB - The HUG Center in Atlanta, Georgia is a home-like facility established to provide care for medically fragile children. Children receive the skilled care they require at the HUG Center, as well as daily therapy and the opportunity to interact with other children. Parents, actively involved in Center activities, receive both support and instruction in caring for their special child. PMID- 10108597 TI - Ashley House--faithful care for fragile children. AB - Ashley House offers an innovative approach to transitional care for medically fragile children, providing skilled nursing care in a homelike environment for children who might otherwise languish in hospitals or nursing homes. Most importantly, the Ashley House program provides comprehensive support for the family, including case management, training in home health care techniques, and grief counseling. The goal of the program is to facilitate a transition home for as many children as possible. PMID- 10108598 TI - Rural home care for medically fragile children. The importance of community involvement. PMID- 10108600 TI - AIDS predicted to be major cause of pediatric death in 1990s. PMID- 10108599 TI - The clinical utility of event recording. AB - In summary, event recording is a cost-effective means of obtaining objective evidence about a baby's cardiorespiratory patterns at home. It is particularly useful in joint decisionmaking at the time of discharge if parents (or clinicians) remain anxious about the status of a child. Event recording is also indicated in the followup of families where there are multiple or questionable reports of serious events at home. In such instances it may clarify whether symptoms are worthy of concern, and may play a role in problem resolution. Monitors are now available that continuously record events and compliance (for example, the E-link system produced by Corometrics Medical Systems, Inc., Wallingford, Connecticut). Such monitors will reduce parental anxiety, facilitate more prompt diagnosis and treatment of genuine disease states, and make possible the further exploration of relationships between parental anxiety and symptom reporting. Although there are technical trade-offs with such monitors (for example, shorter battery life) and higher personnel costs associated with the transcription of recordings, the total length of monitoring and the need for rehospitalization or evaluation of symptoms may be decreased, thus making such monitors cost effective. PMID- 10108601 TI - Home phototherapy. AB - Home phototherapy has both social and economic benefits: newborns diagnosed with neonatal bilirubin jaundice can leave the hospital with their mothers, and home treatment can realize a cost-savings of up to 50%. As pediatric home care expands, agencies may want to consider adding home phototherapy to their array of services. PMID- 10108602 TI - Hospitals move to multiple computer suppliers. AB - By the end of 1989, one of every three hospitals over 100 beds was using six or more software vendors, according to industry consultant Sheldon Dorenfest. This situation mandated that software and hardware solutions "talk to each other," and has made a difference in the healthcare market share of top hardware suppliers. PMID- 10108603 TI - Technology centers showcase networking possibilities. AB - Two technology centers for healthcare information systems are now in business- the Hospital of the Future for Andersen Consulting in Dallas and the Healthcare Information Technology Center for Coopers & Lybrand in Parsippany, N.J. Although they are very different in size, style and approach, both centers allow prospective buyers to "see" and "touch" new technologies that enable disparate systems to communicate and share information. PMID- 10108604 TI - PC development gives Baptist Medical Center mainframe power. AB - Sophisticated distributed applications are easier to develop and maintain when prototyped using personal computer (PC) technology. Baptist Medical System, the largest hospital system in Arkansas, is using PC technology to prototype and then develop mainframe-based applications that augment mission-critical, distributed systems. PMID- 10108605 TI - Hotter than a pepper sprout. AB - This year's federal budget contains a five-year deficit reduction plan that requires Medicare Part A and Part B be cut by $44.1 billion through fiscal 1995. One idea to help ease the transition would be to extend the prospective payment system to ever-growing outpatient charges under Part B through a system called Ambulatory Patient Groups. PMID- 10108606 TI - The strategic advantage: decision support through EIS (executive information systems). AB - Increasing pressures from a variety of sources are tightening the bottom line for hospital executives and managers. Decision support systems have to be developed to cope with a radically changing healthcare market. PMID- 10108607 TI - Information systems in strategic planning in healthcare. AB - CEOs are faced with a wide variety of complex issues that threaten the very survival of the provider. In the early 1980s, the management at Harrisburg Hospital recognized that a solution was needed to deal with evolving trends and issues. That effort resulted in expanding the hospital to become a diversified but integrated healthcare delivery system--the Capital Health System. PMID- 10108608 TI - Mentally disordered homeless offenders--diversion from custody. AB - The homeless mentally ill petty offender is a familiar sight in the Inner London Magistrates' courts and presents a considerable problem regarding appropriate placement. This paper describes a new psychiatric service which transfers the focus of assessment of such offenders from the prison to the magistrates' courts. The service commenced in February 1989 and centres on two Inner London magistrates' courts, Bow Street and Marlborough Street. It provides a psychiatric assessment of the homeless mentally ill petty offender at the earliest possible opportunity following arrest, with the intention of diverting them from custody. This paper discusses the advantages of this scheme compared with prison-based assessments, and describes its success in diverting defendants from custody without necessarily resorting to hospital admission. PMID- 10108609 TI - Monitoring of general practitioners' outpatient referral rates by Family Health Services Authorities: how practical? AB - The Government proposes that Family Health Services Authorities should monitor general practitioner referral rates, although the information available to them might be inadequate for the task. This study was undertaken to assess the difficulties Family Health Services Authorities could face when monitoring referrals using rates related to doctors' list size. This paper describes an investigation into this problem which analysed all outpatient referrals from one general practice from 1984 to 1988. Referral rates showed important variations between calendar quarter recording periods, and rates based on list size were inaccurate compared with those based on consultations. Proportions of obstetric, gynaecological and private referrals varied widely between the doctors. These findings suggest that monitoring of referral rates by Family Health Services Authorities will be relatively crude, and can only be improved by the full cooperation of general practitioners. PMID- 10108610 TI - Case management. AB - This paper discusses the advantages and disadvantages of case management systems for the co-ordination of care of people with long-term mental illness living in the community. Many of the principles are equally applicable to other client groups with long-term needs, eg elderly people or people with learning difficulties. Some of the historical background to the emergence of case management concepts is discussed, culminating in the recent White Paper on Community Care. The underlying concept of case management is examined, together with a number of fundamental questions concerning who should act as case managers, what kinds of training they will require, problems of inter- and intra agency co-operation, and the empirical evidence regarding its effectiveness. It is concluded that case management could be an important element in a comprehensive range of mental health services, but it is not a substitute for basic community provisions. PMID- 10108611 TI - Community ward rounds. AB - The shift to community care in psychiatry has resulted in more work with seriously ill patients outside hospital settings. Clinical experience suggests that traditional outpatient working practices cannot adequately meet the needs of such patients and recent research confirms this. This paper describes the development of a community round by a small suburban catchment area team. The introduction of the round avoided displacement of chronic patients by acute referrals and brought a multidisciplinary perspective to the management of all patients. A more pressing need was found for structuring the review process in the community than in the inpatient setting. Community rounds are recommended as a means of reducing professional isolation, absorbing stress and ensuring effective training and audit. Finally the primary aim of the community round is achieved by providing patients in the community with the same comprehensive treatment plan provided to inpatients. PMID- 10108612 TI - Case registers. AB - This article describes the important steps that need to be taken when introducing and operating a case register system. Emphasis is placed on the need for a system which is dynamic and pays as much attention to the organisation and communication with case managers, as to the collection of data about patients. PMID- 10108613 TI - Do social admissions exist?: a clinical study of emergency admissions into residential care in Birmingham. AB - A medical and social assessment was performed on 132 emergency admissions into Local Authority residential care. The main reasons for admission included withdrawal of an informal carer, disturbed behaviour and a physical disaster. Medical conditions were commonly found, and chronic brain failure was present in over half of all admissions. The incidence of severely disturbed behaviour was found in a small proportion of clients, with psychiatric disability predominating in just under half of those assessed. Both medical and social services were slow to respond to the need for appropriate placement, with fifty per cent of admissions occupying the emergency bed after four weeks. A medical assessment at the time of admission would have led to a more appropriate course of action, although in many cases this would have meant admission to hospital. PMID- 10108614 TI - The Gospel Oak Project: the use of health and social services by dependent elderly people in the community. AB - The Gospel Oak Project surveyed a community sample of elderly people. Prevalence rates of depression and dementia were determined. Cases were assessed in detail and subject to long-term follow-up. Demographic information and morbidity data identified details of health service, social service and informal service contact. This paper reports the findings of the first survey of this population completed in 1987. It examines the effect of the increase in the very elderly on the need for health and social services, including contact with general practitioners. Duplication of service contacts are explored and the dependent elderly people not in receipt of services are identified. Finally, the survey investigates the effect of informal care on the level of service contact. Results confirm that contact increases with age, especially multiple service contact, implying a need for an expansion in future services. Although most depressed residents do not usually complain of depression, they have increased contact with health services but are not treated with anti-depressant medication. Few dependent elderly people receive no services; conversely there is no evidence of service duplication. Finally, receipt of informal care affected attendance at a day centre but no other service provision. PMID- 10108615 TI - Assessing the need for hospice beds. AB - This paper considers means for determining the level of hospice provision that might be appropriate for particular populations. An analysis of the need for hospice beds is described, and the findings are assessed in relation to the subsequent experience of hospice utilisation. Finally, the implications for hospice provision are discussed. PMID- 10108616 TI - The complaints procedure. AB - Between October 1981, when the Health Services Complaints' Procedure was introduced, and June 1989, the Regional Medical Officer of the North West Thames Regional Health Authority received 171 complaints with a request for an independent professional review. This was granted in 75 cases, and this paper describes the procedure and the results of the analysis. PMID- 10108617 TI - Managing the million dollar contract. PMID- 10108618 TI - A consolidated approach to physician/hospital bonding--Ramsey Clinic style. AB - This article describes the results made by Ramsey Clinic during the second year following consolidation of the Clinic with a Hospital (St. Paul-Ramsey Medical Center); a medical education/research Foundation (Ramsey Foundation) into a public benefit corporation (Ramsey HealthCare, Inc.). Many issues inspired Ramsey Clinic to examine ways and means to stabilize its growth and development as a multi-specialty physician and dentist group practice in the highly competitive health care environment of Minneapolis-St. Paul, MN. Influencing the need to change were such elements as shrinking reimbursement for physicians from government and other third party payers; increasing malpractice and general liability premiums; as well as, escalating competition among area health care providers reflected by significant variations in charges for similar services and exclusivity agreements with HMO's and PPO's for select services. In the fall of 1987, Ramsey Clinic consummated its consolidation as a subsidiary member of Ramsey HealthCare, Inc., a public benefit corporation established by an Act of the Legislature of the State of Minnesota, 1986 Laws of Minnesota, Chapter 462. As a public benefit corporation, Ramsey HealthCare, Inc. was chartered to "engage in the provision and delivery of health care and related services." Ramsey Clinic serves as the physician organization for the corporation. An article appeared in the March/April 1989 issue of the Group Practice Journal titled "A Natural Partnership" which described the Ramsey approach and illustrated 1988 results following consolidation. Continued change has resulted in further integration of services among the subsidiaries with a focus on expense reduction, revenue enhancement and increased operating efficiencies. This article provides a longitudinal follow-up on operational amalgamations and 1989 results. PMID- 10108619 TI - Group practice management strategy and information technology: "the missing link". PMID- 10108620 TI - Winning the referral marathon. Turning your marketing strategy inside out. PMID- 10108621 TI - Blood-borne diseases. What you don't know can hurt you. Information for compliance with OSHA regulations. PMID- 10108622 TI - Promotions are a key to retention. PMID- 10108623 TI - Recovery centers Rx for excess beds in hospitals. PMID- 10108625 TI - New product lines planning priorities. PMID- 10108624 TI - Appropriate design takes input from all corners. AB - The design of a children's hospital requires more than just putting schematics on paper and opening the doors. It requires detailed planning to meet not only the needs of children, but their family members as well. In the following article, members of the medical and design team involved in a Minneapolis hospital outline the important factors. PMID- 10108626 TI - Planning high on agenda. Interview by Donald E. L. Johnson. PMID- 10108627 TI - Assuring that you have the right people. Step 1: Creating the job specifications. PMID- 10108628 TI - The changing American hospital: back to the future. PMID- 10108629 TI - The impact of a focus on quality. PMID- 10108630 TI - Hospitals and material management in the coming decade. AB - The 1990s will be a decade of increasing dramatic and traumatic change for hospitals. Reimbursement, technology, and consumers, either alone or in concert, will be the forces that will shape hospitals in the future. At the end of the 1990s we will have hospitals that offer technology to the critically ill, outpatient surgical services, and comforting care for those in the late years of life. Material management will be important to hospitals because expense control will be as important as ever. However, I believe the role of a material manager will diminish as the services provided change and as the role is folded into the responsibilities of those who manage one of the three critical business areas hospitals will be in. This new hybrid of today's manager will still apply all of the concepts to the distribution of supplies in a hospital as today's material managers do but will use them as only a part of their overall management responsibility. PMID- 10108631 TI - Case management: quality care today. AB - The literature demonstrates that the concept of case management offers quality, patient-centered care. Case management promotes the wise utilization of resources and has economic advantages. The benefits of case management are widespread. Everyone concerned with patient care is affected positively, including the patient, family, caregivers, and the facility itself. The benefits far outweigh the potential problems outlined in the literature, and these problems can be eliminated with proper education. The movement toward the use of case management makes good business sense. It will continue. PMID- 10108632 TI - Case management nursing: indications for material management. PMID- 10108633 TI - Material management in a changing environment: reactive or proactive? PMID- 10108634 TI - The new role of material managers in hospital strategic planning. AB - The future direction and challenges of hospital strategic planning require the knowledge and skills of material managers. The approach taken in participating in hospital planning efforts is not as important as the level of involvement. Understanding the strategic planning process at the hospital and knowing what information is critical to that process will improve the ability of the material manager to become an active participant and a valuable contributor to the strategic planning process. Cost management will continue to be the overriding concern of the health care industry in the 1990s. Hospitals will reorganize to control cost and improve productivity, while striving to maintain the quality of care. Material managers must align their departments with hospital strategic goals and assert their new roles in achieving those goals. PMID- 10108635 TI - Strategic planning for the material management function. AB - Strategic planning and strategic management are essential if a department intends to adapt and survive in the rapidly changing health care environment. Many hospitals require their individual departments to submit strategic plans and annual budgets. This is a sound management practice. In those institutions that do not require strategic plans, I would suggest that the departments take it upon themselves to go through this exercise. The benefits are tangible and long lasting. PMID- 10108636 TI - Indicator selection framework for material management. PMID- 10108637 TI - Managing quality in a service business. PMID- 10108638 TI - Electronic data interchange: a strategic approach. AB - The potential of EDI is virtually unlimited, but the success of any EDI initiative hinges on its ability to directly support strategies that achieve your institution's business objectives. At its most fundamental level, EDI technology automates current business practices, speeding up the exchange of business information. This application of EDI most often is found in a hospital's material management department. But EDI integrated internally within a hospital and externally with suppliers and vendors has the potential to go beyond simple automation and to transform processes. This is where the full value of EDI can be realized. No matter which level of EDI participation hospital management decides is appropriate to fulfill its business objectives and strategies, EDI will affect the entire institution's exchange of information with its internal and external audiences. The question management must answer is: Will the hospital's EDI strategy be offensive and managed, or defensive and reactive? Today's environment leaves no room for a "no-strategy" EDI option. The options are either to proactively shape EDI, or reactively play catch-up. EDI can work for you. Adequately developing an EDI game plan in support of your business objectives and calling on your suppliers and other trading partners to work with you will ensure EDI is an asset to your facility. PMID- 10108639 TI - Paperless purchasing, higher inventory turns, information management: the way of the future. PMID- 10108641 TI - Is materiel management the beast in the basement? PMID- 10108640 TI - Managing unofficial inventory: a piece of the materiel management foundation. AB - The implementation plan will remain the same: target an area of opportunity, measure and document the amount and value of the unofficial inventory, establish PAR levels, implement the use of hand-held terminals to assist in inventory control, and integrate inventory control with the implementation of new programs that will impact ordering, receiving, distribution, and invoicing. It is anticipated that the inventory in the main OR alone can be reduced by $1.5 million if we move forward with a stockless JIT system. This would reduce the days of inventory on hand from approximately 100 days to between 7 and 14 days. This could also mean a holding cost reduction of $150,000. The merit of reducing unofficial inventory is evident. Managing unofficial inventory is merely one piece of the successful materiel management foundation. The other foundation pieces include contract compliance and price negotiations, systematic methods of ordering products, and timely distribution of products to the end user. PHS cannot effectively move forward to a new, innovative materiel system for the future until we first measure, analyze, and document the present conditions. Once the foundation is laid by improving present business practices, then the framework of the structure can be designed and constructed. The goal is to implement a system that utilizes the full potential of people, equipment, logistics, and information so that our customers, the patient caretakers, do not have to worry about anything except the delivery of quality care.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10108642 TI - Gearing up for the 1990s. AB - It would be difficult to address personnel issues in this article, due to the complexities inherent in staffing requirement. However, the approach discussed here is to keep systems simple yet controlled, and to make information available to reduce orientation and training time. By having many of the systems discussed in place, materiel management should be able to react quickly to the hospital's changing needs. In addition, controlling qualitative assets and measuring performance is accomplished, allowing feedback to administration from both a performance and a potential standpoint. By ensuring that the present system is working as efficiently as it was designed, and by having key indicators in place to monitor that performance, the foundations will be in place to react to changing demands on space, inventory investment, and staffing. Having the proper tools to react to these pressures in a professional manner will be necessary to ensure that the logistical systems meet the requirements of the institution as it approaches the 21st century. PMID- 10108643 TI - Medical implant registry begins search for heart valve patients. PMID- 10108644 TI - Insights and updates on veterinary medical recordkeeping practice. AB - Practices in maintaining veterinary medical records have changed greatly during the past decade. Computerization is largely responsible for this trend. This article brings readers up to date on veterinary recordkeeping. PMID- 10108645 TI - The new medical record manager: getting off to a great start. PMID- 10108646 TI - Productivity in the medical record department: a bibliography. PMID- 10108647 TI - Design heals. Orlando Diaz-Azcuy brings a fresh perspective to issues of privacy and autonomy in an intensive care unit designed for change. PMID- 10108648 TI - Healing comfort. Daroff Design Inc. and GBQC create a caring place for the handicapped and ill at the Children's Seashore House. PMID- 10108649 TI - Healing revolution. A new medical/surgical unit is designed to encourage patients to participate in their own treatment. PMID- 10108651 TI - C. John Tupper, MD: Strengthening the AMA for service. Interview by C. Burns Roehrig. AB - The American Medical Association's current president, an ASIM pioneer, talks about his long road of service in the medical community and his vision of the future for the AMA and all physicians. PMID- 10108650 TI - States assume role to fill the 'health policy void'. AB - The president of the American Federation of State, County and Municipal Employees sees the states--not the federal government or employers--taking the lead in filling in gaps currently found in the American health care system. PMID- 10108652 TI - The enigmatic 101st Congress: great accomplishments ... huge disappointments. PMID- 10108653 TI - Patient care outcomes: more than just a simple formula. PMID- 10108654 TI - On being a physician: are you in or out? PMID- 10108655 TI - Risk management in practice: the 12 R's of malpractice prevention. PMID- 10108656 TI - The EKG controversy: an act of bad faith by Congress. PMID- 10108657 TI - A state legislator's perspective on health policy in the 1990s. AB - The majority leader of the New York State Assembly says state legislatures can play an important role in working with the public and the federal government in developing an effective health care system. PMID- 10108658 TI - The Nation's governors look toward reform. AB - Washington state's governor, who is chairman of the National Governors' Association, reviews the serious problems governors and their states face in making sure their residents have access to adequate health care. PMID- 10108659 TI - Development of guidelines for the preparation and administration of ribavirin. AB - Due to numerous inquiries from neonatal professional staff members regarding the potential teratogenic effects of ribavirin, the decision was made to establish institutional guidelines for its safe administration and preparation. The neonatal pharmacist was asked to prepare guidelines from available information in the literature and other institutions' practice standards. PMID- 10108661 TI - Use of a personal computer to monitor adverse drug reactions. AB - The Pharmacy department at Sewickley Valley Hospital, Sewickley, Pennsylvania, has developed an adverse drug reaction database using DBase III Plus software. The computer database allows instant, custom manipulation of large amounts of data, and aids in the analysis of adverse drug reaction reports for quality assurance purposes. PMID- 10108660 TI - Documentation of drug interchange in the medical record. AB - The hospital medical record has become increasingly exposed to retrospective audits by third party insurers, quality assessment studies, and billing inquiries. As a result, the demand for complete documentation in the record has steadily increased during the past few years. Institutional medical practices are subject to a variety of regulations and standards. Economic pressures are continually exerted on hospitals for cost reduction measures, which include patient drug costs. While hospitals have engaged in a variety of methods of drug interchange to reduce costs, documentation procedures for interchange are not specifically regulated. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) appears to be the only source for applicable regulations regarding medical record documentation. With respect to therapeutic drug interchange, few guidelines exist to "legalize" this common practice. A procedure to provide the physician's informed consent for therapeutic interchange is explained. This article will focus on drug interchange notification procedures for non-teaching community hospitals. Legalities, practicalities, and regulations for medical record documentation are addressed. In addition, suggestions for the documentation of drug interchange are proposed. PMID- 10108662 TI - Evaluation of drug interaction microcomputer software: comparative study. AB - Twelve drug interaction microcomputer software programs were evaluated and compared using general and specific criteria. This article summarizes and compares the features, ratings, advantages, and disadvantages of each program. Features of an ideal drug interaction program are noted. Recommended programs based on three price ranges are suggested. PMID- 10108663 TI - Physician payment reform. PMID- 10108664 TI - Annual pharmaceutical manufacturers directory--1991. PMID- 10108665 TI - Uncertain Medicare payment policy for graduate medical education costs. PMID- 10108666 TI - Fetal protection policies. PMID- 10108667 TI - OBRA '90: preview of nationalized health care? PMID- 10108668 TI - New health care laws: common sense initiatives. PMID- 10108669 TI - Immigration trends affecting health care employment. PMID- 10108670 TI - Organ donation, the legal framework. AB - Various factors influence the availability of post-mortem organs. The most important ones (systems to be applied for organ retrieval to be lawful, organizational and financial aspects, information of the public) are discussed. Because there will always remain some shortage of organs, the selection problem of recipients of an organ is also discussed. Its public acceptability and the possibility for scrutiny are pleaded for. Commercialization is rejected as being against the health interest of donor and recipient. A design for a European (legal) framework is given with a view to create optimal chances for a patient in need of an organ. Further cooperation in this field between the European Communities, the Council of Europe and the World Health Organization is recommended, which might result in the drawing up of a Convention on the subject matter. PMID- 10108671 TI - Criteria for selecting organ donors and recipients. AB - As there is a world-wide shortage of organs for transplantation, the selection of the patients is more defined by the availability of transplantable organs than by the medical condition of the potential recipient. This shortage of cadaveric organs is mainly responsible for the use of living donors. With HLA identical sibling donors the results are better than with cadaveric organs, but the ethical problems are usually underestimated. For the parent-to-child donation, the HLA compatibility is less than what could be achieved with well-matched cadaveric donors. The use of genetically unrelated donors is unacceptable from the ethical as well as from the medical point of view. The short- and long-term risk of donation has been insufficiently documented. The experience with the introduction of an opting-out legislation in Belgium in 1987 demonstrates that the shortage of cadaveric organs can be overcome. Harmonization of the legislation is, however, necessary so as to achieve comparable organ retrieval rates between countries participating in organ-exchange organisations. PMID- 10108672 TI - A second opinion--in defence of the living donor transplant. PMID- 10108673 TI - Organ donation: the role of hospitals. AB - Three models of cooperation between hospitals and transplant centres are: (1) performance of brain death diagnosis, organ removal and preservation at the peripheral hospital; (2) performance of brain death diagnosis at the peripheral hospital and transportation of the dead body under ICU modalities to the transplant centre; (3) transport of a potential organ donor to the transplant centre. The key issues for success in cooperation between peripheral hospitals and transplant centres are: positive attitudes of hospital representatives; motivation and acceptance of ICU staff, supported by the whole community; and availability of adequate facilities to perform organ recovery in practice. PMID- 10108674 TI - The diffusion of organ transplantation in Western Europe. AB - The moment of introduction of clinical organ transplantations varied in Western Europe from country to country. In retrospect, one can distinguish pioneering countries (most notably the U.K. and France), and countries that were early or late adopters of the new technologies. An early start did not necessarily lead to extensive diffusion of organ transplantations, as shown by the example of the U.K. In general, Western Europe is lagging behind the U.S.A. In diffusion of organ transplantation technologies. With few exceptions, the introduction and diffusion of organ transplantations in Western Europe have been largely autonomous developments, not regulated by government or third party payers and only slowed down by lack of organs, facilities or funds. The lack of organs has been reduced by the activities of organ procurement and exchange organisations, and perhaps by legislation promoting organ donation. Nevertheless, the growth of the number of patients waiting for an organ is in almost all countries outpacing the increase in availability of organs. PMID- 10108675 TI - Orthotopic liver transplantation in The Netherlands. The results and impact of a medical technology assessment. AB - In 1985 Dutch health care authorities and health insurance companies initiated a large-scale technology assessment (TA) of liver transplantation (LTx) in The Netherlands. The 10-year experience of the existing programme in the University Hospital Groningen was investigated. Topics included were patient flow, selection policies, survival, quality-of-life, costs, need, supply of donor organs and organisational aspects. Estimation of the consequences of a non-transplantation scenario allowed for the execution of a cost-effectiveness analysis. Results showed clear improvement by LTx of survival and quality-of-life, though to a lesser degree than expected. Costs of the first transplantation year amounted to Dfl 180,000 (approx US $90,000). The cost-effectiveness ratio ranged from Dfl 47,000 to Dfl 133,000 per life year gained. No overt imbalance between need and donor supply existed or was expected in the near future. The impact of this study is related to the informational value and to the contribution to the decision process. Even at its appearance in 1988, the final report provided health policy makers with new information. Health policy concerning LTx was considerably influenced, as a rule in agreement with the study conclusions. We conclude the Dutch case study to be an example of a useful and efficient TA. PMID- 10108676 TI - The policies of organ transplantation in Europe: issues and problems. AB - Transplantation has evolved from an experiment to a routinely performed procedure for a widening range of organs. Transplantation in Europe is dominated by the scarcity of organs from deceased donors leading to problems of selection criteria for recipients, of legal protection for donors and of the empowerment of agencies for allocative decisions. Although public involvement is very emotional, there has been a benign neglect in several European countries by policy makers, accepting implicitly organ transplantation leading to a variety of programs for diffusion, organization, and financing of transplantation. Non-transplanting hospitals play a key role in organ procurement and transplant centers are increasingly subject to quality assessment, whereby the issue of the relation between improved outcome at higher volumes comes to the forefront. International cooperation is critical for the development of effective transplant programs in Europe. PMID- 10108677 TI - Early, thorough planning critical for overcoming parking-structure snags. PMID- 10108678 TI - Air-conditioning shutdown is as critical as its start-up. PMID- 10108679 TI - Safety-compliance audits: 4 steps to ensure success. PMID- 10108680 TI - EPA delays its new rule on radiation monitoring. PMID- 10108682 TI - Despite slump, health construction still booms. PMID- 10108681 TI - Safety, liability dictate efficient snow removal. PMID- 10108683 TI - An enforcement problem. PMID- 10108684 TI - Cash-flow-poor hospitals like consignment. PMID- 10108685 TI - GPO's activity in medical waste management grows. PMID- 10108686 TI - Film prices up. PMID- 10108687 TI - Forsyth Memorial cuts disposal costs by 77%. PMID- 10108689 TI - HMM price watch. AB - Purchasing managers' index continues 4-month drop, falling 2% in October from 44.4. Producer price index hits 122.3 in October; medical care commodities index up to 166.8. PMID- 10108688 TI - Hospitals' tracking and recording costs for chargeable supplies may exceed revenues. PMID- 10108690 TI - Hospital materials managers need to be aware of actions that constitute legal acceptance. AB - A hospital invited bids for building materials for a hospital construction project. A supplier submitted a bid which asked the hospital to sign and return a trade association form contract. The hospital didn't return the form but used the supplier's bid as part of the general contract for the entire project and notified the supplier and the general contractor. Later, the supplier submitted a higher bid for the same material contending that the hospital hadn't accepted the first bid as they hadn't followed the instructions. The hospital materials manager feels that the bid was properly accepted. In this dialogue, Dr. Decker reviews the legal issues involved in the different ways of accepting an offer. PMID- 10108691 TI - Group purchasing organizations will play a role in stockless purchasing programs. PMID- 10108692 TI - Magnetic resonance imaging safety: caution urged as incident reports increase. AB - This article summarizes much of the current research on MR safety concerns and bioeffects as discussed during recent scientific meetings, as obtained through interviews with prominent medical, engineering, FDA and other MRI experts, and from investigative and scientific reports in the professional literature. PMID- 10108693 TI - Determining patient satisfaction in a Medicare health maintenance organization. PMID- 10108694 TI - The use of dedicated software to customize ambulatory care reporting. PMID- 10108695 TI - Risk management and physician characteristics in a preferred provider organization credentialing program. PMID- 10108696 TI - Electronic medical records in the ambulatory setting: the quality edge. AB - The electronic medical record in the ambulatory setting will be a force to be reckoned with during the 1990s. The increased quality of the medical record will lead to an increased quality of patient care at a fairly level cost (no long-term increase). With the new and increasing excitement about continuous improvement in health care, the electronic medical record can be a cornerstone of our quality assurance program and our quality improvement program. The electronic medical record needs to be taken seriously. PMID- 10108697 TI - Achieving black belt excellence in marketing health care. PMID- 10108698 TI - Employee wellness programs: a strategy for increasing participation. AB - Employee wellness programs can bring dramatic reductions in organizational health insurance premiums. However, employee participation in such programs is voluntary and averages only about 20% within sponsoring companies. Higher participation rates could be achieved by using a marketing approach. The authors illustrate a consumer-oriented marketing approach that examines the influences on employees' decisions to participate in employee wellness programs. PMID- 10108699 TI - The role of health care attributes and demographic characteristics in the determination of health care satisfaction. AB - The authors investigate the influence of demographic characteristics and health care attributes on overall health care satisfaction. They use a national cross section sample of HMO members and another of non-HMO members. Demographic characteristics are treated as antecedent to satisfaction with the health care attributes in the determination of overall health care satisfaction. The health care attributes are very similar in impact for both samples, suggesting HMOs should emphasize those attributes both to ensure reenrollment and to encourage new enrollment. Findings also show that satisfaction with several health care attributes varies along a few demographic dimensions, suggesting demographic bases along which the health care market can be segmented. PMID- 10108700 TI - Hospital advertising: does it influence consumers? AB - Though consumers generally favor hospital advertising, it has not emerged as a major factor in hospital choice research. A survey examined the effectiveness of hospital advertising and its strength as a factor in hospital choice. The majority of the respondents approved of hospital advertising and showed knowledge of hospital specialties. However, hospital choice was influenced primarily by physician recommendation and location, rather than advertising. PMID- 10108701 TI - Exploring perceptions of hospital operations by a modified SERVQUAL approach. AB - The authors employ a modified SERVQUAL approach to understanding the relationships among patients' perceptions of inpatient, outpatient, and emergency room services and their overall perceptions of service quality, satisfaction with their care, and willingness to recommend the hospital's services to others. Three models of these perceptions and related behavioral variables are developed. Dominating these models is a dimension labeled "patient confidence," which has a significant impact on nearly all measures of patient satisfaction. PMID- 10108702 TI - Influencing decision-making of referring physicians. AB - As marketing budgets for physician liaison departments increase, health care marketers are being held more accountable for their efforts by managers. Market researchers at The Cleveland Clinic Foundation (CCF) have developed a health care organizational information dissemination model that provides an understanding of how referring physicians choose a referral center for their patients. Interviews with 89 new referring physicians show patient influence and interpersonal media to be the two most influential channels of information. Financial analysis of referrals shows that a true physician referral generates significantly more revenue than a patient-influenced referral. CCF managers and marketers have used the data to understand better the effectiveness of their current programs targeted at physicians. PMID- 10108703 TI - Developing supplemental activities for primary health care maternity services. AB - Supplemental health care activities are described in the context of the augmented product. The potential benefits of supplemental services to recipients and provider are discussed. The author describes a study that was the basis for (re)developing a supplemental maternity service. The implementation of the results in terms of changes in the marketing mix of this supplemental program is discussed. The effects of the marketing mix changes on program participation are presented. PMID- 10108704 TI - A multifacet typology of patient satisfaction with a hospital stay. AB - The author views patient satisfaction after a hospital visit as a combination of several different and distinct evaluations. Patients are posited to form satisfaction judgments concurrently for each of the individual "objects" (e.g., physician, insurance provider) comprising the health care system. With patient data from four geographic areas, the author examines this multifacet view empirically and uses it to derive a typology of patient satisfaction. The study results suggest two broad groups of patients, the "satisfieds" and the "dissatisfieds." Finally, the author delineates the behavioral and demographic characteristics that discriminate between the two groups. Implications for health care researchers, practitioners, and public policy officials are presented. PMID- 10108705 TI - Diagnostic imaging centers: broadening their patient bases. PMID- 10108706 TI - Why I pulled the plug on a competent patient. PMID- 10108707 TI - Which third parties pay you the most. PMID- 10108708 TI - Doctors offer their prescriptions for ending the malpractice plague. PMID- 10108709 TI - Participate in Medicare? For '91, there's more incentive. PMID- 10108710 TI - What the new patient-dumping laws mean for you. PMID- 10108712 TI - Here's how rationing of care really works. PMID- 10108711 TI - How fast are patients abandoning doctors for midwives? PMID- 10108713 TI - Is this ruling really a boost for peer review immunity? PMID- 10108714 TI - Is Uncle Sam reneging on Medicare fees? PMID- 10108715 TI - The legal risks of doing peer review are overblown. PMID- 10108716 TI - Is this the beginning of a malpractice revolt? PMID- 10108717 TI - If I'm sick, don't send me to medicine's hallowed halls. PMID- 10108718 TI - How employers rate tactics for cutting health costs. PMID- 10108719 TI - After CON--Colorado's experience. PMID- 10108720 TI - The Engler victory: what will the impact on Michigan hospitals be? PMID- 10108721 TI - The rural health package: an idea whose time had come. PMID- 10108722 TI - We must plan for the future of hospital auxiliaries. PMID- 10108724 TI - Reform possibilities improve with new governor. PMID- 10108723 TI - Matrix organizations. Their significance to trustees. PMID- 10108725 TI - Michigan's CON regulations: a closer look. PMID- 10108726 TI - Columbia targets psych market. PMID- 10108727 TI - Health Trust reports profit for first time since spinoff. PMID- 10108728 TI - Allegheny, United Hospitals plan merger. PMID- 10108729 TI - American Express sues McDonnell Douglas. PMID- 10108730 TI - Calif. ordered to comply with law. PMID- 10108731 TI - Firm separates drug's price from monitoring system. PMID- 10108732 TI - Hospital-product suppliers mobilize. PMID- 10108733 TI - Charter trying to restructure its debt to stave off default. PMID- 10108734 TI - Nation's hospitals brace for casualties. PMID- 10108735 TI - Congress vows to keep up the fight for health reform. PMID- 10108736 TI - Paying doctors for hospital tasks. PMID- 10108738 TI - AHA crafts wish list for new leader. PMID- 10108737 TI - Board makeup plays role in CEO turnover. AB - Jeffrey A. Alexander explores the impact of board structure and composition on turnover of chief executive officers in this summary of his winning research project in the second Governance Fellowship award, sponsored by the Governance Institute and Modern Healthcare. PMID- 10108739 TI - AHA reform plan goes back for revisions. PMID- 10108740 TI - Bond insurers fault hospitals' shaky situation in California. AB - Some hospitals in earthquake-prone California may be sound financially, but their location on a major fault line can be enough to make bond insurance firms steer clear of the area. The insurers see the faults as constant threats to an institution's bond repayment ability. PMID- 10108741 TI - Mass. hospitals sue. PMID- 10108742 TI - Neb. hospitals sue. PMID- 10108743 TI - Court lifts order blocking transfer of comatose patient. PMID- 10108744 TI - Medicare HMOs lack quality safeguards--GAO. PMID- 10108745 TI - HCFA loses bid to recoup home dialysis payments. PMID- 10108746 TI - 10 W.Va. hospitals go to court. PMID- 10108747 TI - Home equipment industry to touch up image. PMID- 10108748 TI - Hospital faces civil rights complaint. PMID- 10108749 TI - Pa. facility still foundering despite reorganization. PMID- 10108750 TI - Repayment of long-term debt will let VHA expand. PMID- 10108751 TI - 15% of nation's hospitals have money ills--study. PMID- 10108752 TI - Baxter's net income increases 28% in fourth quarter. PMID- 10108753 TI - Drug makers skirting law, Sen. Pryor says. PMID- 10108754 TI - Infected N.Y. workers allowed to keep jobs. PMID- 10108755 TI - Pacific Standard gains board clout at National Heritage. PMID- 10108756 TI - Two executives resign from Hospital Research and Educational Trust. PMID- 10108757 TI - Capital reimbursement prospective payment plan carries 10-year phase-in. PMID- 10108758 TI - Texas joins parade of states suing over Medicaid. PMID- 10108759 TI - Learn from the fallen leaders: don't neglect your constituency. PMID- 10108761 TI - VA faces skepticism about ability to accommodate war casualties. PMID- 10108760 TI - Total quality management becomes big business. AB - Total quality management, a method other industries have used to improve quality and reduce costs, has become a lucrative business for consultants, healthcare organizations and even hospitals. However, the commercialization of the strategy actually may be adding substantially to hospitals' operating costs--the precise ailment that total quality management is supposed to cure. PMID- 10108762 TI - War highlights close relationship between Saudi, American providers. PMID- 10108763 TI - Concealing compensation from the IRS. AB - Tougher reporting requirements from the Internal Revenue Service are prompting some not-for-profit hospitals to seek ways to hide compensation arrangements from the public and the media. Critics believe those tactics could get hospitals in hot water with the law, especially now that the IRS has launched a new, aggressive auditing offensive. PMID- 10108764 TI - Many state hospital association presidents would resist efforts to establish price lists. AB - In Modern Healthcare's first monthly FAX poll of state hospital association presidents, more than half of the leaders surveyed said they would urge member hospitals to resist efforts by local business coalitions to establish guaranteed price lists for hospital services. The poll also addressed the degree of such efforts and the state of the relationships between the associations and business groups. PMID- 10108765 TI - Calif. agency urged to consolidate HMOs. PMID- 10108766 TI - Pittsburgh-area healthcare organizations form alliance. PMID- 10108767 TI - Probe delays acquisition--Sentara Health System, Humana. PMID- 10108768 TI - Capital ideas culminate in done deals. AB - Healthcare institutions got creative in raising capital to finance projects that wouldn't have gone ahead otherwise. In other instances, the funding was conventional but the project was unique. Projects were nominated by the healthcare financial community. PMID- 10108769 TI - CEO's proposal would end tax-exempt financing. PMID- 10108770 TI - Health administration grads' salaries rise 20%. PMID- 10108771 TI - Courts again block transfer of Missouri patient. PMID- 10108772 TI - Eight facilities placed on probation. PMID- 10108773 TI - JCAHO withdraws accreditation of Cook County Hospital. PMID- 10108774 TI - FASB proposal targets retiree health benefits. PMID- 10108775 TI - A guide for dealing with your POTW (publicly owned treatment work). How to make sure you get a fair deal. PMID- 10108776 TI - AIDS knowledge and attitudes for April-June 1990. Provisional data from the National Health Interview Survey. PMID- 10108777 TI - Evaluating the effectiveness of wellness programs: urban and rural hospital experience. PMID- 10108778 TI - Pressure for health reform is coming from constituents and budgets, state leaders say. PMID- 10108779 TI - Health insurance and medical care. Health of our nation's children, United States, 1988. PMID- 10108780 TI - Getting the best out of your consultant. AB - The past few years have seen a considerable increase in the use of external consultants within the National Health Service. Given the costs of using such personnel, it is vital that the employing organisation obtains the benefits from day one. PMID- 10108781 TI - Clinical records management--the future. AB - A move to Region from patient services management may sound like the death knell to many, but it has certainly given me the opportunity to look at records management in more strategic terms and to meet many colleagues in health records departments throughout this region. PMID- 10108782 TI - Thirty years on: 'Going' over four editions. PMID- 10108783 TI - Standards, guidelines and so on .... PMID- 10108784 TI - The psychology of reading: an essay in honour of Mona Going. PMID- 10108785 TI - The Sheila Moore award: twenty-five years on. PMID- 10108786 TI - Reminiscence therapy in a Scottish hospital. PMID- 10108787 TI - National Institutes of Health; statement of organization, functions and delegations of authority--PHS. PMID- 10108788 TI - Statement of organization, functions and delegation of authority--HHS. PMID- 10108789 TI - How to choose a pest control company. PMID- 10108790 TI - Be prepared for regulated medical waste disposal. PMID- 10108791 TI - PM Forum embraces controversy. AB - Taking risks in board education can pay big dividends in trustee commitment and loyalty. The idea is to let board members confront the issues, disagree and learn from each other. PMID- 10108792 TI - The nominating committee: effective tool for improving the board. AB - By using this process, individuals are recruited for board and committee service. It can also remove members who no longer meet the organization's needs. PMID- 10108793 TI - Spotlight on free beds. AB - What happens in today's hospitals when keeping the faith with donors clashes with fiscal politics? An enterprising assistant attorney general asked that question and turned up some disquieting answers. PMID- 10108794 TI - The new lobbying regulations: a federal definition of "fund raising". Part 2. PMID- 10108795 TI - Older adults examine health-care options. PMID- 10108796 TI - Special report on medical staff relationships. Some "do's and don'ts" for complying with COBRA/OBRA patient transfer restrictions: a positive approach. PMID- 10108797 TI - Teaching wound care in the home. AB - A survey of Medicare-certified agencies in Alaska, Idaho, Montana, Oregon, and Washington identified wound care and teaching wound care as being among the highest ranked clinical problems related to earlier hospital discharges that have resulted from Medicare Diagnostic Related Groupings (DRGs). Home care nurses are treating increasingly complex wounds and are required to teach complex wound care skills to clients and caregivers. This paper provides guidelines and resources to home care nurses for teaching wound care to their elderly clients and caregivers. The process of developing and implementing a teaching plan is described through the use of the community health nursing process. Following the presentation of the process content, a sample teaching wound care plan and sample teaching handouts are presented with a list of available teaching resources about wound care. PMID- 10108798 TI - Cost containment and home health agencies. PMID- 10108799 TI - A comparison of hospital and home assessment of parenting potential. AB - Factors influencing parenting were compared when assessments were done: (1) on the hospital postpartum ward and, (2) in the home. Thirteen factors thought to contribute to parenting potential and two items summing the risk for abuse/neglect were assessed. Items evaluating the mother's health and her ability to talk out problems provided more accurate assessment in the hospital; child focused items could be evaluated in either setting; the mother's isolation, and perception of herself were more accurately assessed in the home. Most mothers generated less concern at home. If postpartum assessment raises concerns for future parenting dysfunction, it is imperative to re-evaluate in the home and initiate appropriate referrals. PMID- 10108801 TI - Highly skilled, highly paid ancillary staff--key to health care in the 1990s. PMID- 10108800 TI - Public light and private dark: the privatization of home health services for the elderly in the U.S. AB - The privatization of health care has been a controversial topic that has consumed an increasing share of national attention in both the United Kingdom and the United States. In this paper we consider several definitions of privatization; outline two strategies of privatization--privatization by replacement and privatization by reduction or attrition; identify possible consequences of various policies of privatization for health and social services for the elderly; and offer some ideas about how trends toward privatization may be assessed, utilizing empirical data from research on the impact of medical cost containment and privatization on community-based services in the U.S. That the substance of government policy is moving toward privatization is without question; that these policies may have serious consequences for outcomes of social equity is still under debate. The trends suggested in our research have potentially negative consequences for marginal elderly clients in U.S. If the consequences of privatization can be linked to the denial of service to needy clients, privatization may, indeed, represent a dark alternative to the welfare state. PMID- 10108802 TI - Wanted: "bloody heroes" to lead the NHS troops. PMID- 10108803 TI - Self governing trusts urged to be brave and go public on their mission statements. PMID- 10108805 TI - Getting the right framework for NHS training. PMID- 10108804 TI - Career development for personnel staff. PMID- 10108807 TI - The argument for notional case loads in speech therapy. PMID- 10108806 TI - District heads--the "vulnerable children" of the NHS? PMID- 10108808 TI - Keeping the NHS reforms on the road. PMID- 10108809 TI - NHS joins battle to woo women back to work. PMID- 10108810 TI - Presumed insufficient. The importance of the prehospital care report. PMID- 10108811 TI - Cash for caliber. EMS and the pay-by-merit system. PMID- 10108812 TI - Like it or not, sex is here to stay. PMID- 10108813 TI - 1991 almanac. EMS in the United States: a survey of providers in the 200 most populous cities. PMID- 10108814 TI - 1991 almanac. Information resources. Associations & organizations. PMID- 10108815 TI - 1991 almanac. State EMS directors. PMID- 10108816 TI - Stimulating pharmaceutical innovation. PMID- 10108817 TI - A healthier approach to health care. Oregon seeks to extend coverage by prioritizing services on the basis of cost-effectiveness. PMID- 10108818 TI - Volunteerism and community building in continuing care retirement communities. AB - In summary, CCRCs are arenas in which four types of natural helping and volunteerism occur. The CCRC may, therefore, be a microcosm of a community system, serving multiple functions in a campus setting. Volunteer program coordinators can benefit from the experiences of others, and research into helping patterns and the process of community building may provide insight as new CCRCs develop. PMID- 10108819 TI - Gay Men's Health Crisis. PMID- 10108820 TI - 1991 forecast: the year of restructuring. AB - How is the foodservice industry faring under the clouds of three big uncertainties--oil prices, recession and war? All things considered, its doing quite well. This annual status report of commercial and institutional business shows fast food, catering, nursing homes and employee feeding with growth percentages on the good, left side of the decimal point. Our forecast includes business trends to watch, food trends to guide menu planning and pricing, and interior- and kitchen-design trends that can be a blueprint for a successful new year. PMID- 10108821 TI - Annual forecast. Hospitals. PMID- 10108822 TI - Annual forecast. Nursing homes. PMID- 10108823 TI - Institutional loyalty and job satisfaction among nurse aides in nursing homes. AB - The high rate of turnover among nurse aides employed in nursing homes has been associated with the low job status and the poor job benefits accorded workers. However, this is not always the case. Competitive benefit packages and limited labor market opportunities increase the likelihood that nurse aides in some nursing homes may stay on the job despite their dissatisfaction with it. The present study investigated "institutional loyalty," an attitudinal proxy for job turnover, among 219 nurse aides for its relationship to a number of job-related factors. Somewhat unexpectedly, the quality of the social environment of the nursing home was found to be as important as attitudes toward job benefits in accounting for institutional loyalty. PMID- 10108824 TI - Patterns of stability and change in health use among elderly people. Do service systems leave an imprint on behavior? AB - Stability and change in patterns of health service use over a 3-year period were determined for a sample of elderly people in an urban area who claimed one of five types of health service provider as a primary source of health care--a hospital, a private physician, a network model health maintenance organization (HMO), a hospital-based group practice program (G-HMO), or a preferred provider organization (PPO). Despite certain differences in use rates for individual services, the total volume of ambulatory service use was equivalent for all five groups as was the relative rank order of use of specific ambulatory services for four of the five groups. People who claimed a hospital as their primary care source had the most unique use patterns over a full range of health care services, characterized by extremely low rates of physician visits and the highest rates of visits to hospital outpatient clinics across three time periods. G-HMO members used health-related services more frequently than did all others. PPO members, at baseline, had lower rates of total and mean hospital days than other source group members except hospital users. People who changed principal source of care during the study period were most likely to report a hospital as their care source initially. Although there is much consistency in hospital and ambulatory use across groups, the persistence of certain use patterns for members of some groups suggests that health care systems can leave an imprint on the health service use of people for whom they provide regular care. PMID- 10108825 TI - Statewide mammography directory now available; women over age 35 encouraged to utilize service. PMID- 10108826 TI - Childcare: changing times prompt new role for hospitals. PMID- 10108827 TI - Cardiac care services expanding for Jerseyans. PMID- 10108829 TI - Hospital special events. From 'food tests' to steeplechases, big-draw happenings help with fund raising. PMID- 10108828 TI - Hospital statistics much in demand; T.H.I.S. service providing one-stop shopping. PMID- 10108830 TI - The secret weapon in the war for customers. AB - Organizations regularly utter platitudes about their commitment to service. Those winning the battles have quality service on the front line. PMID- 10108831 TI - Evaluating the HR function. AB - HR departments are evaluated more frequently in organizations that have created a human resource mission statement. PMID- 10108832 TI - Risk management in suspected acute appendicitis. AB - Acute appendicitis is a disease in which the essential elements for timely diagnosis are available. These elements are a careful history and thorough physical examination, the latter repeated as necessary until clinical judgment indicates that exploratory surgery should be performed or the patient safely discharged. The hospital that does not provide its staff with facilities to do so invites a potentially successful malpractice claim. In the absence of properly documented care, such a claim could include allegations of improper or inadequate evaluation of a person presenting for medical care, negligent medical care based on failure to properly use referral and consultant sources, and failure to provide adequate follow-up (including hospital admission). Such allegations would describe the foreseeable and significant consequences of the adverse event, be it premature discharge or negative exploration. Risk management includes education of hospital administration about the importance of an adequate observation period in this diagnosis, and education of the professional staff about the need for thorough documentation of the serial examinations when surgery is deferred. This article has presented fact, references, and opinion, which should help hospital risk managers to assess the documentation of appendicitis cases now being seen in their hospital, to plan educational interventions with the administration and professional staff, and to assist the hospital collections personnel if payers contest admissions that did not result in surgery. PMID- 10108833 TI - Management's responsibility for risk assessment. PMID- 10108834 TI - Previous visits to emergency departments by patients with chest discomfort. PMID- 10108835 TI - Are risk management and health care ethics compatible? PMID- 10108836 TI - Assessing quality of hospital risk management services. PMID- 10108837 TI - Office staff responsibilities in preventing surgery malpractice suits. AB - Improved communications, procedures, administration, and system routines in a medical office are everyone's responsibility. It is an area in the overall treatment of the medical malpractice disease in which the entire office staff plays a critical part. The reward is that everyone--the patient, the physician, and the staff--benefits. Office staff can make a vital contribution to achieving a pleasant, efficient office where very few mistakes occur and preventable errors are eliminated. PMID- 10108838 TI - Medicare program; legislative changes concerning payment to hospitals for federal fiscal year 1991--HCFA. Notice of legislative changes. AB - This notice describes changes to the Medicare prospective payment system for inpatient hospital services concerning the hospital wage index and the regional payment floor resulting from the provisions of the Continuing Resolution of October 1, 1990 (Pub. L. 101-403). Also described in this notice are those self implementing portions of sections 4001 (a) and (c), 4002 (e) and (f), 4007, 4151, and 4158 of the Omnibus Budget Reconciliation Act of 1990 (Pub. L. 101-508) that affect Federal fiscal year 1991 payments to prospective payment hospitals and hospitals and units excluded from the prospective payment system. The changes required by these sections affect the following: 15 percent capital payment reduction, use of the regional payment floor, offset for physician assistant services, market basket percentage increase, standardized amounts, hospital specific rates for sole community hospitals and Medicare-dependent small rural hospitals, target rate of increases for excluded hospitals and units, hospital wage index, payments for graduate medical education, and Part B payment reduction. PMID- 10108839 TI - Medicare program; mid-year FY 1991 changes to the inpatient hospital prospective payment system--HCFA. Final rule with comment period. AB - This final rule with comment period implements several provisions of section 4002 of the Omnibus Budget Reconciliation Act of 1990 (Pub. L. 101-508) that affect Medicare payment for inpatient hospital services and that take effect with discharges occurring on or after January 1, 1991. The provisions of section 4002 of Public Law 101-508 affect the following: The standardized amounts, the hospital wage index, rural counties whose hospitals are deemed urban, and hospitals that serve a disproportionate share of low income patients. PMID- 10108840 TI - Congress spells out detailed role for providers. Greater participation in right to die issues required. PMID- 10108841 TI - Battle over OBRA '87 costs may move to court. HCFA rejects AHCA Medicaid petition. PMID- 10108842 TI - Design principles bind diverse industry. Facing the facts about assisted living. PMID- 10108843 TI - Low occupancy hurts Indiana market. Overbuilding diminishes acquisition interest. PMID- 10108844 TI - Purchasing groups and local alliances helpful. How to obtain products and services within budget. PMID- 10108845 TI - Tumultuous outlook tempered by guarded optimism. PMID- 10108846 TI - Outcome analysis underlies rating system. VA may have answer to OBRA '86 mandate. PMID- 10108847 TI - Fairness battles fear. AIDS compels providers to examine their roles. PMID- 10108848 TI - Youth movement opens new markets. Retirement centers set sights on younger clientele. PMID- 10108849 TI - Grant helps wishes come true. Charitable organizations fund nursing improvements. PMID- 10108850 TI - Resident assessment: means justifies end. PMID- 10108851 TI - Aging mentally retarded: are we keeping up? PMID- 10108852 TI - New HCFA regs present a chance to shine. PMID- 10108853 TI - Information systems form large part of strategic plan. AB - Strategic planning is often a low priority for community hospitals because it is often too impractical. The difference for Ed McFall, chief information officer at Pitt County Memorial Hospital (PCMH) in Greenville, N.C., is that his hospital's and affiliated medical school's information systems plans work. PMID- 10108854 TI - A crisis of leadership in healthcare systems. PMID- 10108855 TI - Computers are stepping stones to improved imaging. AB - Never before has the radiology industry embraced the computer with such enthusiasm. Graphics supercomputers as well as UNIX- and RISC-based computing platforms are turning up in every digital imaging modality and especially in systems designed to enhance and transmit images, says author Greg Freiherr on assignment for Computers in Healthcare at the Radiological Society of North America conference in Chicago. PMID- 10108856 TI - Desktop supercomputers. Advance medical imaging. AB - Medical imaging tools that radiologists as well as a wide range of clinicians and healthcare professionals have come to depend upon are emerging into the next phase of functionality. The strides being made in supercomputing technologies- including reduction of size and price--are pushing medical imaging to a new level of accuracy and functionality. PMID- 10108857 TI - HIS technology trends. AB - In the hospital information systems of the year 2000, futuristic technology will play a major role in managing the data needs of providers. Although systems managers face formidable challenges, they can make effective use of these new technologies by coordinating the roles of systems, personnel and planning in their own facilities. PMID- 10108858 TI - Electronic billing: a cost-reduction opportunity. PMID- 10108859 TI - HL7: facilitating multiple approaches to systems integration. AB - System interfaces of the 1980s are being replaced by system integration of the 1990s. Standards such as Health Level 7 (HL7) are facilitating this integration process. The authors dispel several persistent misconceptions about the HL7 standard and illustrate two working approaches to HL7-based networking. PMID- 10108860 TI - Judicial review of NLRB rulemaking in the health care industry: implications for labor and management. AB - In 1987 the National Labor Relations Board set out to promulgate a rule to define the appropriate bargaining units for the health care industry, making the first use of its substantive rulemaking powers. This departure from the traditional process of adjudication of unit determination issues occurred because of thirteen years of NLRB frustration resulting from congressional admonition against proliferation of bargaining units and subsequent inconsistent judicial interpretation of that admonition. This article traces the factors that led to the decision to rulemake, discusses the development of the rule itself, and examines the rule's judicial experience to date. It presents empirical findings of hospital union election activity during the period from 1985 through 1987 that confirm the thesis that bargaining unit size is a significant variable in election outcomes. Finally, the authors assess the likely outcome of the impending Supreme Court decision on the rule, along with implications for labor and management. PMID- 10108861 TI - The rewards of room service. PMID- 10108862 TI - Reaping the benefits of construction. PMID- 10108863 TI - Garbage wars '91. Report from the front. AB - In this first of a three-part series examining the status of waste management strategies available to non-commercial foodservice operators, Food Management looks at the use and recycling of polystyrene in light of the McDonald's Corp.'s decision to replace polystyrene with paper and paper-based packaging. PMID- 10108864 TI - Application of quality concepts to the guard service industry. AB - The author analyzes a fundamental problem in the relationship between contract vendors and users. His premise is that the potential to achieve quality goods and services is when the employer-employee relationship is one of mutual respect and benefit. Therefore, the relationship between a user and vendor must be similarly based if quality is to result. Major changes are needed in the way vendors and users do business. PMID- 10108865 TI - When the shooting starts. AB - Why the need for an emergency response plan to deal with health care violence is greater than ever. The author discusses how to set up such a plan. PMID- 10108866 TI - Risk management and security services interaction--a must in today's health care environment. AB - The author shows why risk managers and security directors are natural partners in the effort of a hospital to reduce risks from such occurrences as baby kidnappings, serial killers, thefts, and rapes/sexual assaults. PMID- 10108867 TI - Creating a licensed police agency within a medical center. AB - The authors report how restructuring the department of public safety into a licensed campus police force has improved security and safety at a large Dallas hospital. PMID- 10108868 TI - The security survey: a prescription for enhancing security. PMID- 10108869 TI - Strategies for the successful socialization of security personnel. AB - By more effectively bringing officers 'into the fold'--or socializing them- security managers can reduce turnover, improve job performance, and increase productivity of their officers, says the author. PMID- 10108870 TI - On-the-job thievery: common schemes of the working man. PMID- 10108871 TI - Using computer bulletin boards in hospital pharmacy. AB - Computer bulletin boards (BBSs) are new tools that can be used by hospital pharmacists to communicate electronically with colleagues and obtain information easily and quickly. This article explains what pharmacy BBSs are, some uses for them, and lists some of these services that are available currently. It also gives step by step instructions for contacting a pharmacy BBS. PMID- 10108872 TI - Continuous quality assurance monitoring by staff pharmacists. AB - The article describes a system of continuous quality assurance monitoring which is accomplished by pharmacists at the medical center. This 856 bed Veterans Affairs facility is provided pharmacy services through a decentralized unit dose distribution system. Pharmacists are assigned to separate patient care areas and provide or coordinate all drug distribution functions and additionally provide clinically-oriented services including quality assurance intervention. Pharmacists are provided guidelines on selected medication therapy which warrant pharmacist monitoring to assure high quality of care. In addition to these guidelines, pharmacists are encouraged to intervene in other therapeutic areas where their expertise favorably impacts quality of patient care. A report of clinically significant intervention is prepared monthly and submitted to the Drug Use Evaluation Subcommittee for review. This report is distributed along with the Pharmacy and Therapeutic Committee minutes to all pharmacists, physicians, and supervisory nursing personnel. The system of continuous quality assurance monitoring encourages pharmacists to use their expertise in a manner which assures quality of medical care provided by the medical center. Documentation of pharmacist intervention meets many JCAHO requirements for quality assurance. PMID- 10108873 TI - Financial management--1990. PMID- 10108874 TI - Human resources management--1990. PMID- 10108875 TI - Out of the frying pan. PMID- 10108876 TI - Healthcare as quality trendsetter. PMID- 10108877 TI - The team approach to change. Quality case study. I. PMID- 10108878 TI - Measurement tools eliminate guesswork. Quality case study. II. PMID- 10108879 TI - Quality through customer service. Quality case study. III. PMID- 10108880 TI - Clinical quality improvement without fear. PMID- 10108881 TI - Teaching for quality. PMID- 10108882 TI - The shape of things to come: Part 2. Management culture & processes. PMID- 10108883 TI - The chasm between management and leadership. Interview by Joe Flower. PMID- 10108884 TI - In defense of healthcare management. PMID- 10108885 TI - Trends, physician productivity and computer links. PMID- 10108886 TI - Reaching people when they least expect it. PMID- 10108887 TI - Health care 1991: top ten trends for the health industry. PMID- 10108888 TI - The 1990 survey of the healthcare materiel management and central service professions. PMID- 10108889 TI - Strategic planning for training: how to manage the competence of your workforce. AB - Peak performance in today's challenging business environment requires systematic management of workforce competencies. The strategic planning approach to training offers a systematic method for defining the competency requirements of the workforce; devising plans, policies and strategies for developing these competencies; allocating resources; and implementing a performance-based training system. The strategic training plan is a vehicle for putting management in control of the competence of the workforce by gaining control of the training system. PMID- 10108890 TI - Will you find your next job or will it find you? PMID- 10108891 TI - Directory of education. AB - One of the most important tools to career building and personal satisfaction is education! The fields of central service and materiel management, like other professional fields, have an assortment of educational opportunities that you should take advantage of. Some are available through your professional associations (see the "Directory of Associations" for more information on those). Others are available through correspondence courses, on-site courses at local colleges and universities, and from seminar programs of associations, vendors and seminar groups. We've assembled a list of courses and seminars of interest to you and your colleagues. There may be others offered in your area, so contact your local institutions of higher learning to take advantage of what they have--or to develop a course with them! PMID- 10108892 TI - Directory of resources. AB - Have you found yourself becoming more and more exasperated by the large volume of information that crosses your desk? Some of it is useful, but more of it may be totally irrelevant to your work and life. How do you find what you really need? We've taken a lot of the guesswork out of your search for useful information by compiling this directory of resources that target your specific needs. You'll find everything from periodicals to online databases to get your information pipeline under control! PMID- 10108893 TI - Directory of associations. AB - Associations have proven to be valuable clearinghouses of information, centers for educational enrichment and switchboards for making connections between practitioners of a given profession. The healthcare central service and materiel management professions are represented by five associations: the American Society for Healthcare Central Service Personnel (ASHCSP), the International Association for Hospital Central Service Materiel Management (IAHCSMM), the American Society for Hospital Materials Management (ASHMM), the Health Care Material Management Society (HCMMS) and the National Association of Hospital Purchasing Materials Management (NAHPMM). Within these associations you will find groups of people who have interests and goals similar to yours. Pursue your interests together--join an association! PMID- 10108894 TI - Corporate profiles, mission statements, and key corporation and product line information. PMID- 10108895 TI - Surgical instrument management and training the CD-ROM way. PMID- 10108896 TI - Materiel management for pressure ulcer care: outlook for the 1990s. PMID- 10108897 TI - How effective are chemical and biological sterilization indicators? PMID- 10108898 TI - The supply module and your local area network. PMID- 10108899 TI - Product matrix: materiel management information systems. A look into the 90s: software catches up with hardware. AB - As always, you'll have to fight for the dollars to buy systems, competing with departments who produce revenue. Financial managers and hospital boards respond most favorably to a good return on investment (ROI) presentation. Join forces with your software vendor of choice and give your board the best ROI argument they'll hear this year. Keep two things in mind: 1) today's innovations, particularly in reducing inventory, interfacing and lower hardware costs will help you make your case and 2) make sure the system is growing consistent with the industry to ensure you won't be asking for a similar purchase three years from now. PMID- 10108900 TI - Continuous improvement in health care: an overview. PMID- 10108901 TI - Developing quality of care through information systems. PMID- 10108902 TI - AAMI (Association for the Advancement of Medical Instrumentation) completes recommended practice on decontamination. PMID- 10108903 TI - Special report: lab salaries make altruism still a vital component. AB - Pay is rising, but is it rising enough? MLO's biennial national survey investigates the whole pay package, from fringe benefits to retention efforts, and how readers feel about it all. PMID- 10108904 TI - You can learn a lot from your new employees. PMID- 10108905 TI - What every laboratorian should know about RSV (respiratory syncytial virus). PMID- 10108906 TI - Why and how to establish criteria-based performance standards. PMID- 10108907 TI - Introducing high school students to the clinical lab. PMID- 10108908 TI - Reliable instrument maintenance with a PC. PMID- 10108909 TI - How lab supervisors fared on the salary front. PMID- 10108910 TI - Finding public opinion data: a guide to sources. PMID- 10108912 TI - Measures of hospital market structure: a review of the alternatives and a proposed approach. AB - Efforts to evaluate the plethora of recent programs adopted by public and private payers to promote hospital price competition critically depend on the availability of measures of local market structure. To gauge the effects of these policies, researchers must be able to delineate hospital market areas and measure the intensity of competition within these markets. This article reviews alternative methods that have been used to define hospital market areas and measure market structure. We propose an empirical patient origin-based method for measuring hospital market structure. The results of sensitivity analyses using data on California hospitals demonstrate the robustness of our measures over a broad range of parameter values. PMID- 10108911 TI - A simulation model for evaluating a set of emergency vehicle base locations: development, validation, and usage. AB - This paper describes our experiences in developing a simulation model for evaluating a set of emergency response vehicle base locations. The project was undertaken jointly by the University of Arizona and the Tucson Fire Department. The issues of model development, data collection, model validation, and experimentation are discussed. The critical nature of the problem and the clients' lack of experience with mathematical models, made model validation the major step in gaining user acceptance. We show that looking solely at standard performance statistics such as the calls successfully serviced, may lead to the acceptance of an invalid model. We also show that the high level of detail used in many simulation models for evaluating base locations is unnecessary in the current case. An analysis evaluating two alternative sets of locations for the Tucson system is discussed. PMID- 10108913 TI - Foregoing life-sustaining treatment: what are the legal limits in an aging society? PMID- 10108914 TI - Safe harbor for health care cost containment. PMID- 10108915 TI - How does your plan provide case management? PMID- 10108916 TI - Case management for the elderly: benefits for the physician. PMID- 10108917 TI - The price of quality and the perplexities of care. PMID- 10108918 TI - Health risks and educational interests in an HMO. AB - A health survey was randomly administered to 1000 members of a 250,000 member HMO to help develop education programs and establish baseline risks and interests among HMO members. The sample was found to have lower than average risks related to smoking, average risks for weight, and above average risks related to exercise compared to state and national reference standards. The highest level of interest was reported for exercise, followed by stress reduction, weight loss, and smoking cessation. The older age groups were less likely to report an interest in attending fitness programs. The more educated respondents were less likely to attend weight control and stress programs. Based on these results, strategies for increasing involvement in educational programs to reduce health risks are discussed. PMID- 10108919 TI - Council formed to help hospitals provide best possible healthcare. PMID- 10108920 TI - Hospital staff cafeterias lead the way. PMID- 10108921 TI - What can we expect from our hospital system in the 1990s? PMID- 10108922 TI - Healthcare waste management: a new era of concern. PMID- 10108923 TI - Healthy communities--Otago. PMID- 10108924 TI - Applying the Ottawa Charter. PMID- 10108925 TI - Funder/provider options for health in New Zealand--some new thoughts. PMID- 10108926 TI - Cancer patients finding more options at NJ facilities. PMID- 10108927 TI - Shared governance, key to the nurse's new role. PMID- 10108928 TI - Hospital psychiatric services expand, adapt to changing times. PMID- 10108929 TI - Clay Sherman, Ed.D.. Interview by Ron Czajkowski. PMID- 10108930 TI - Perspectives. Bush budget: something new for '92. PMID- 10108931 TI - Use of airframe and avionics options reaches all-time high. PMID- 10108932 TI - Eighth annual aircrew survey. PMID- 10108933 TI - Hazardous materials in the air medical workplace. PMID- 10108934 TI - The need to train for IMC (instrument meteorological conditions). PMID- 10108935 TI - Roles of a helicopter emergency medical service in mass casualty incidents. AB - The Connecticut helicopter emergency medical service (HEMS) has responded to 12 mass casualty incidents (MCI) in two years. Eight were drills and four were actual events. An MCI response plan was instituted prior to the onset of the HEMS program. All MCIs were reviewed to determine actual victims, knowledge of MCI prior to lift-off, and roles of the HEMS. The actual roles were compared with the pre-established roles. The four actual MCIs (building explosion, hotel fire, bus rollover and plane crash) were reviewed. Sixty-seven victims were involved. Prenotification occurred in one MCI. The roles of the HEMS in each MCI were: triage (n = 4), medical treatment (n = 4), transport (n = 3), augmented response (n = 1), and air surveillance (n = 0). The roles of HEMS response to MCI should be well-defined prior to an event. Air medical benefits include response within a large geographic area, highest level of prehospital medical care, identification of trauma receiving hospitals, and facilitation of transport. PMID- 10108936 TI - Geripsychiatric medicine: new frontier in mental health. PMID- 10108937 TI - Partial hospitalization helps close insurance gap. PMID- 10108939 TI - Earthquake report calls for action by hospitals. PMID- 10108938 TI - Clinic offers treatment for sleep disorders. PMID- 10108940 TI - The managed care approach to mental health care costs. PMID- 10108941 TI - Swimming upstream in the mental health benefit debate. PMID- 10108942 TI - The HRIS and HR applications software. PMID- 10108943 TI - A delicate balance protects everyone's rights. AB - Clashes between employee and employer rights spill from the workplace out into the community at large. Drug testing, negligent hiring, sexual harassment and employment at will are issues that affect the individual, the company and the community at large. PMID- 10108944 TI - Safety leadership cuts costs. PMID- 10108945 TI - Money isn't everything. AB - Three elements are essential to an effective incentive strategy: various reinforcers, the employee's motivational needs and the organization's business goals. When these factors are integrated into a coherent incentive policy, employees can focus their attention on the company's business goals. PMID- 10108946 TI - Is your maternity policy ready for the '90s? AB - The increasing number of women in the work force has forced some companies to take a critical look at their maternity policies. Direct costs for these policies are hard to measure. But, demographic, social and legislative pressures may force companies that haven't addressed this issue to do so in the '90s. PMID- 10108947 TI - Corporate culture enhances profits. AB - Companies are beginning to recognize that simply having highly skilled workers who use the latest machines and equipment isn't enough to assure productivity and market share. What makes a difference? Transforming a corporate culture may well be the key to an organization's future. PMID- 10108948 TI - Upgrading management opportunities for women. PMID- 10108949 TI - Point: drug test all employees randomly. PMID- 10108950 TI - Counterpoint: test suspected users only. PMID- 10108951 TI - What's new in surgery for 1991? General thoracic surgery. PMID- 10108952 TI - What's new in surgery for 1991? Transplantation. PMID- 10108953 TI - State legislative roundup--1990. PMID- 10108954 TI - Health plan options: inquiring employees want to know. PMID- 10108955 TI - Employer strategies in managing prescription drug costs. PMID- 10108956 TI - Are rising mental health costs driving you crazy? PMID- 10108957 TI - Cost shifting overshadows employers' cost-containment efforts. PMID- 10108958 TI - Square D flexes its wellness muscle. PMID- 10108959 TI - Florida debates universal access. PMID- 10108960 TI - Mental health care: buyers take the lead. PMID- 10108961 TI - Managing mental health costs. PMID- 10108962 TI - Medicare program; payment to federally funded health facilities--HCFA. Technical amendments. AB - Final regulations published on October 11, 1989, at 54 FR 41736 redesignated 42 CFR 405.312 as 42 CFR 411.8 and, more specifically. redesignated section 405.312(f) as section 411.8(b)(6). In the redesignation of section 405.312(f) we- 1. Unintentionally omitted a word that characterized certain funds and facilities as "Federal"; and 2. Overlooked the need to reflect, in 42 CFR part 410, the rules for Medicare payments to Federally funded health centers. This document corrects those errors by amending sections 410.152 and 411.8. PMID- 10108963 TI - Statement of organization, functions and delegations of authority--HCFA. PMID- 10108964 TI - Softening resistance. AB - Though still wary of national health insurance, many businesses are entertaining a government role in health care reform, eyeing cost control methods such as tax penalties and uniform pricing. PMID- 10108965 TI - Be ready for the reckoning. PMID- 10108966 TI - Yes, but will it wash? PMID- 10108967 TI - Bridging the training gap. PMID- 10108968 TI - A survival strategy. PMID- 10108969 TI - Deming's quality principles: a health care application. AB - W. Edwards Deming is considered a guru of quality by many international manufacturers. His ideas revolutionized Japan's auto industry in the 1950s, but did not make a substantial impact in the United States until 1980. Increasingly, service organizations, from hotels to public utility companies, are experimenting with his principles. This article explains how a 165-bed community hospital- Brazosport Memorial Hospital in Lake Jackson, Texas--is putting Deming's ideas to work in health care. Deming's philosophy and principles are described as is the hospital's application and implementation of his ideas; preliminary results are encouraging. PMID- 10108970 TI - Liability for wrongful terminations: are hospitals at risk? AB - This article examines the extent to which the three principal exceptions to the common-law doctrine of employment-at-will--namely the public policy, implied contract, and good faith and fair dealing exceptions--have been recognized in hospital termination cases. State supreme court and appellate court cases are analyzed to illustrate the type of conduct that precipitated wrongful termination claims against hospitals during the 1980s, how the courts disposed of these claims, and the rationale underlying their decisions. Suggestions, based on these and related cases, for avoiding or at least minimizing liability for wrongfully terminating hospital employees, are presented. PMID- 10108971 TI - Renewal and change for health care executives. AB - Health care executives must consider renewal and change within their own lives if they are to breathe life into their own institutions. Yet numerous barriers to executive renewal exist, including time pressures, fatigue, cultural factors, and trustee attitudes. This essay discusses such barriers and suggests approaches that health care executives may consider for programming renewal into their careers. These include self-assessment for professional and personal goals, career or job change, process vs. outcome considerations, solitude, networking, lifelong education, surrounding oneself with change agents, business travel and sabbaticals, reading outside the field, physical exercise, mentoring, learning from failures, a sense of humor, spiritual reflection, and family and friends. Renewal is a continuous, lifelong process requiring constant learning. Individual executives would do well to develop a framework for renewal in their careers and organizations. PMID- 10108972 TI - Total quality management in health care. PMID- 10108973 TI - The right to refuse medical treatment. PMID- 10108974 TI - A perspective on local-level governance in multiunit systems. AB - The traditional functions of the hospital board are affected significantly when the institution is part of a multiunit system. The local board in multiunit systems often does not have the unrestricted ability to define its mission and goals and typically does not have total responsibility and authority for selecting, appointing, and evaluating the performance of the hospital's CEO. Some type of system-level involvement in shaping and/or approving the local institution's strategic plan and budget is common. Local boards generally have retained the principal role in the appointment and credentialing of medical staff members. In general, the continuing growth of multiunit systems has profound implications for the present and future role of local-level governance, but that role continues to have great importance and must be defined carefully. PMID- 10108975 TI - How top managers in health organizations set directions that guide decision making. AB - Cases describing strategic decisions made in health care organizations were analyzed to determine how top managers set directions that guide decision making. Four tactics were identified--issue, idea, objective, and reframing. Decision adoption rates, decision merit, and duration of the decision-making process were used to determine the effectiveness of each tactic. The effects that stem from using each tactic were qualified by factors describing urgency, importance, and differences between the tactics used by CEOs and middle managers (leverage). Tactics were found to have more influence on decision effectiveness than the intervening variables of urgency, importance, and leverage. Reframing was found to be the most effective tactic under all conditions but was the least frequently used by decision makers. Issue and idea tactics were the least effective, but idea tactics were used more often than any other tactic. Issue tactics were even less effective when applied to urgent and important decisions. Objectives were surprisingly effective in a crisis and for the more important decision. PMID- 10108976 TI - Intensive care units in the triage mode: an organizational perspective. AB - Decisions to admit and discharge patients to and from the intensive care unit (ICU) when beds are scarce should be made in accordance with the triage principle -that is, allocate resources on the basis of the ability to benefit from intensive care. However, uncertainty over resource capacity and patient prognosis limits the ability of decision makers to use this prioritization principle and results in ICUs containing inappropriately placed patients who are denying or delaying care to patients who could benefit more. Using Jay Galbraith's "information processing" model, ICU admission and discharge decision making is described. Organizational strategies to reduce uncertainty and improve decision making are discussed, including strengthening the management role of the ICU physician director and employing prognostic instruments (e.g., mortality prediction models) to share and process information. PMID- 10108977 TI - Protecting employees against hepatitis B. PMID- 10108978 TI - The not-for-profit hospital as a charitable trust: to whom does its value belong? PMID- 10108979 TI - How long can Indiana remain a malpractice paradise? PMID- 10108980 TI - Physicians' fees: fewer PPOs may go discount shopping. PMID- 10108981 TI - Why so many doctors-to-be are failing their national boards. PMID- 10108982 TI - Consultants don't always wear black hats. PMID- 10108983 TI - We absorbed 16 practices--and we're ready for more. PMID- 10108984 TI - Study shows leap in pay for 1st-year emergency doctors. PMID- 10108985 TI - Medicaid deficiencies cited by task force 20 years ago are same ones debated today. PMID- 10108986 TI - Arizona Adventist group sues AHS/West. PMID- 10108987 TI - Hospital alliance target of FTC antitrust probe after buying HCA facility. PMID- 10108988 TI - The many reasons why hospitals buy technology. AB - Hospitals spent almost $9 billion on capital equipment in 1989. Many factors enter in the decisionmaking on technology acquisition, some having more to do with hospital politics or competitive demands than with a facility's true clinical requirements. But administrators are learning lessons from past acquisition mistakes and are placing more of the burden on vendors and physicians to prove that new technology is a prudent purchase. PMID- 10108989 TI - Credit card companies push plastic as way to boost revenue collections. AB - Credit cards are finally catching on as a way to pay for medical services, stimulated in part by the increasing tendency among providers to demand payment now rather than bill patients later. PMID- 10108990 TI - Hospitals struggle to survive along U.S.-Mexican border. AB - Along the border with Mexico, hospitals fight a constant battle against disease and poverty that inundates their institutions with Mexican nationals and poor Americans who need care but can't pay for it. The strained providers see the border phenomenon as a national problem, but the U.S. government sees the situation as a local matter. PMID- 10108991 TI - Life Care Centers of America ends plans to buy National Heritage. PMID- 10108992 TI - Methodist Hospital states charity-care case. PMID- 10108993 TI - Faced with inaction in Washington, states forge ahead with plans to cover uninsured. AB - At least seven states have weighed universal access legislation this year, and more are expected to consider such measures in the fall. States are finding they can't wait for Washington to grapple with coverage for the uninsured. PMID- 10108994 TI - Mental health programs seek religious following. AB - A handful of mental health treatment programs are building therapy around prayer sessions and Bible study in an attempt to attract mainstream Christians who otherwise would be wary about seeking treatment. PMID- 10108995 TI - Workers more susceptible to unionizing--survey. PMID- 10108996 TI - System's strategy aims to raise credit rating. AB - Mercy Health Services is taking calculated steps to boost its credit rating in hopes that its house will be in A+ order the next time it wants to borrow from the capital markets. PMID- 10108998 TI - Top AHA exec sees bigger squeeze ahead as federal budget gap widens. PMID- 10108997 TI - Budget action to affect health. PMID- 10108999 TI - Chairman-elect, 7 new members appointed to board of trustees. PMID- 10109000 TI - Reform issues test conventional wisdom. PMID- 10109001 TI - Report on charity care flawed--CHA. PMID- 10109002 TI - Deals with Pa. taxing bodies listed. PMID- 10109003 TI - Cuts could force Michigan to suspend Medicaid program. PMID- 10109004 TI - N.Y., N.J. governors bite into Medicaid funds. PMID- 10109005 TI - Broward doctors spurn antitrust settlement. PMID- 10109006 TI - HCFA wants monthly data on Humana HMO. PMID- 10109007 TI - Methodist unloads duck lodge to avoid flap. PMID- 10109008 TI - Rural chain ends lease pact. PMID- 10109009 TI - 'Rising costs lead employers to managed care'. PMID- 10109010 TI - Drug industry sees 12% revenue hike in '91. PMID- 10109011 TI - Hospitals lose $13.2 billion on uncompensated care and Medicaid, AHA reports. PMID- 10109013 TI - Public hospitals to lobby for trust fund. PMID- 10109012 TI - State of the Union doesn't thrill reform advocates. PMID- 10109014 TI - Bypass surgery targeted for pricing test. PMID- 10109015 TI - HIMSS cites grievances, may depart AHA. PMID- 10109016 TI - You don't think healthcare industry could become a utility? Think again. PMID- 10109017 TI - Jewish hospitals yesterday and today. AB - How times have changed at America's Jewish hospitals. The facilities, some dating to before the Civil War, were built mainly to serve large populations of Jewish immigrants. Today, the patient population at large has changed considerably, as have the financial challenges these mainly inner-city facilities face. But executives say the hospitals' mission and ethic remain the same. PMID- 10109018 TI - Federal appeals court declares public hospitals aren't beyond the reach of antitrust laws. PMID- 10109019 TI - IRS says affiliated not-for-profits can share their for-profit services. PMID- 10109020 TI - Advisory group to hospitals: snap up physician practices. AB - To protect long-term profitability, hospitals should acquire primary-care and specialty physician practices, according to the Health Care Advisory Board. Such a move guarantees hospitals control over where patients are sent for expensive procedures as well as the expenses physician-employees incur to care for their patients, something that's nearly impossible to do with independent practitioners. PMID- 10109021 TI - Teaching hospital bids for attention. PMID- 10109022 TI - Hospital alliances are taking root in rural America. AB - Rural hospitals are finding that alliances can offer them the advantages of multihospital systems without the strings attached. Their numbers are increasing, and a new study says rural alliances are likely to flourish if given sufficient funding and support by hospital chief executive officers. But they also must overcome problems of high turnover rates among rural administrators and lean funding sources. PMID- 10109023 TI - Standard computer interface gets respect. PMID- 10109024 TI - Capital payment's architect gets cool reception. PMID- 10109025 TI - Government releases funds to avoid Medicare pay delays. PMID- 10109026 TI - ProPAC suggests cutting education adjustment. PMID- 10109027 TI - Catholic facilities increase free services; profit margins drop. PMID- 10109028 TI - Settlement ends Va. hospitals' legal dispute. PMID- 10109030 TI - Crash tests communications system. PMID- 10109029 TI - Anti-kickback evaluation outlined. PMID- 10109031 TI - Bell unit dials hospital market. PMID- 10109032 TI - PacifiCare forms HMO network. PMID- 10109033 TI - Healthcare Int'l merger detailed. PMID- 10109034 TI - Republic ends legal dispute with former officers. PMID- 10109035 TI - Northern Nev. hospitals under investigation. PMID- 10109036 TI - Executives ready to sacrifice for reform. PMID- 10109037 TI - 'Experts' miss the mark on medical equipment ruling. PMID- 10109038 TI - Caring beyond the bottom line. Daughters of Charity West's CEO chosen Young Executive of the Year. AB - As CEO at the Daughters of Charity National Health System West in California, Michael D. Connelly, 37, oversees operations of six hospitals, a job he's held for just a year. But his innovative management style predates his move west to a long career at a DCNHS hospital in Chicago where he is credited with "taking the bull by the horns" and spearheading a turnaround. Mr. Connelly's accomplishments have earned him this year's Young Executive of the Year award from the American College of Healthcare Executives. PMID- 10109039 TI - Malpractice reform could tax hospitals. PMID- 10109040 TI - Bush budget proposal irks health advocates. PMID- 10109041 TI - Unix becoming healthcare's standard operating system. AB - An unfamiliar buzzword is making its way into healthcare executives' vocabulary, as well as their computer systems. Unix is being touted by many industry observers as the most likely candidate to be a standard operating system for minicomputers, mainframes and computer networks. PMID- 10109042 TI - Child health initiative drains other programs. PMID- 10109043 TI - Insurance regulators recommend requiring larger cash reserves for open-ended plans. PMID- 10109044 TI - Outcomes research affecting devices. AB - Outcome measurement is having an increasing impact on the success of medical devices in the marketplace, according to a new report from the Health Industry Manufacturers Assn. The report is intended to help the manufacturers of medical equipment determine when outcomes research will be necessary in introducing new products. But it also offers a glimpse into future device marketing strategies. PMID- 10109045 TI - Ponder remains top financial adviser; Chapman & Cutler still top bond counsel. PMID- 10109046 TI - AHA reform plan estimated to cost $30 billion to $35 billion. PMID- 10109047 TI - HHS reports 76 hospitals closed in 1989. PMID- 10109048 TI - Hospitals turning to physician services to cope with call-up. PMID- 10109049 TI - Living wills: making life and death decisions. AB - Each day, health care providers and families across the United States struggle with decisions regarding life-sustaining treatments for patients in irreversible vegetative states. And each day, these decisionmakers must face the potential for lawsuits for agreeing or refusing to carry out directives that may have been the "wish" of the patient, but were never put in writing. PMID- 10109050 TI - Medicaid 'spend down' provision often avoided by wealthy. PMID- 10109051 TI - Pre-planning saves time when evacuation order comes. PMID- 10109052 TI - Advance directives linked to residents' rights mandate. PMID- 10109053 TI - Vaccine provides protection from hepatitis B virus. PMID- 10109054 TI - Dental care services enhance residents' quality of life. PMID- 10109055 TI - Interpretive guidelines to greatly reduce use of psychotropics. PMID- 10109056 TI - Limited nursing services give residents more care options. PMID- 10109057 TI - Keeping hospital accounts profitable. PMID- 10109058 TI - Lessening strains between parent and local boards. PMID- 10109059 TI - Medicaid: key to health care reform. PMID- 10109060 TI - Master-site planning: a trustee's guide to the process. PMID- 10109061 TI - JCAHO report assesses hospitals standards compliance. PMID- 10109062 TI - Fund raising in hard times. PMID- 10109063 TI - Study reveals nature of board-CEO relations. PMID- 10109064 TI - Industrial rehabilitation--a win/win outpatient program. PMID- 10109065 TI - System stresses balance. PMID- 10109066 TI - Going on a JCAHO survey. PMID- 10109067 TI - Community hospital builds new facility with an eye to the future. Interview by Karen Gardner. AB - Hunter Greenlaw, vice chairman of the board, Mary Washington Hospital, Fredericksburg, VA, discusses how the board and administration collaborated in a two-year planning process that will culminate in a new medical campus by mid 1994. PMID- 10109068 TI - Achieve efficiency and prove it! PMID- 10109070 TI - Balance sheet growth of the hospital industry. PMID- 10109069 TI - Calculating the marginal cost of excessive stays. PMID- 10109071 TI - Looking at the hospital through the kitchen window. PMID- 10109072 TI - Carol McCarthy. Interview by Carolyn Forcina. PMID- 10109073 TI - Air medical accident rates: a historical look back at causes. PMID- 10109074 TI - Safety in the '90s: strategies that helped make 1990 a banner year. PMID- 10109075 TI - Permanent internal pacemaker safety in air medical transport. AB - Helicopter and fixed-wing air medical transportation provides an important role in the management of critically-ill patients. As the use of cardiac pacemakers continues to grow, knowledge of their expanding capabilities and sophistication is important. The environments of our "airborne intensive care units" are subject to many sources of electromagnetic and vibrational interference. Although pacemaker shielding mechanisms have become quite elaborate, further studies are needed to define their reliability in modern aircraft. Further, the possible effects of electromagnetic and vibrational interference upon inflight reprogramming require further study. PMID- 10109077 TI - The evolution of biomedical technology. PMID- 10109076 TI - Flight nurse turnover: where they go, why, and what they do. PMID- 10109078 TI - 1990 program survey. PMID- 10109079 TI - Central scheduling: catalyst for change. PMID- 10109080 TI - Do it right, do the right thing--develop an outpatient centralized scheduling process. PMID- 10109081 TI - Computerized pre-certification: keeping pace with health care cost containment. PMID- 10109082 TI - EtO phone home: the future of sterilization in hospitals. PMID- 10109083 TI - Goodnight xylene? So far, substitutes have failed. PMID- 10109084 TI - OSHA enforces free hepatitis B vaccination requirement. PMID- 10109085 TI - Alliances--no substitute for core strategy. PMID- 10109086 TI - Old wine in new bottles: strategic alliances within the NCI. PMID- 10109087 TI - Strategic alliances in health care: the challenges of cooperation. AB - As many industries face uncertain and changing environments, strategic alliances are rapidly emerging as a vehicle for interorganizational cooperation. Similarly in health care, alliances represent a mechanism for organizations to seek collaborative solutions to common problems. Drawing on a general typology, alliances in health care are categorized as service, opportunistic, or stakeholder alliances. Existing health care alliances serve to illustrate and characterize the purpose, structure, and operation of each of the three types. Strategic alliances offer significant challenges in managing the inherently fragile relationships within these emerging organizational forms. These challenges center around issues of commitment (v. control) as the underlying managerial philosophy; expectations for alliance performance; managing relationships, communication, and operations; member participation in alliance programs and activities; and stability of alliances over time. Alliances require new ways of thinking about organizations. Sensitivity to their unique characteristics and understanding the factors that can lead to their success are essential to managing them effectively. PMID- 10109088 TI - Managing alliances. PMID- 10109089 TI - Are you an effective food service manager? PMID- 10109090 TI - Professionals, share positions! Hospitals, share professionals! PMID- 10109091 TI - Learning from the 80s: we'd better know what's going on in government. PMID- 10109092 TI - Want to market your services, increase productivity and sales at the same time? PMID- 10109093 TI - Conditions influencing the marketing efforts of hospitals. AB - This research assesses the degree to which environmental change, competitive conditions and position, hospital characteristics, and organizational performance influence the extensiveness of a hospital's marketing activities. Changes in occupancy, revenue, and patient mix did not predict the level of marketing activities. Instead, the perceptions of marketing decision makers about changing environmental conditions were found to predict these activities. PMID- 10109094 TI - Rural physicians' market share retention. AB - In sparsely populated rural communities, the need to retain market shares for local providers has become increasingly important. Using data from the ARCH (Affordable Rural Coalition for Health) demonstration project, this study demonstrates the importance of information and the image of services for the retention of local clientele in rural communities. The unaware tend to migrate for health care to referral centers where needed services can be assumed present. PMID- 10109095 TI - Proficiency in personal selling: prescription for physician marketing. AB - In a highly competitive and dynamic environment health care providers are turning to marketing techniques to compete. To date, the majority of marketing efforts in the health care industry have revolved around the use of promotional tools, mainly advertising, publicity and public relations. It is proposed here that personal selling is a neglected, but important, promotional tool for health care marketers, especially physicians. The analogy between physician and salesperson is drawn, various influence techniques commonly used in personal selling situations are discussed, and a methodology proposed for the systematic study of how physicians might adjust their use of such personal influence techniques to the situation so as to be more effective in terms of patient satisfaction and compliance. PMID- 10109096 TI - The dilemma of the rural hospital: the case of Pinal General Hospital. AB - While rural hospitals often provide high quality healthcare, the growth of healthcare specializations and the advent of specialized professionals has put them in a very weak competitive position in relation to nearby urban hospitals. This article discusses the position of just such a hospital: Pinal General Hospital in Florence, Arizona. PMID- 10109097 TI - Intentions to join HMOs: perceived relative performance versus satisfaction/dissatisfaction. AB - This study employed a national sample to investigate the determinants of consumers' intentions to join HMOs by considering different health care attributes. It employed two models, a performance model and a satisfaction model. The study found that the robustness of the performance model was substantially stronger in explaining intentions to join HMOs than the satisfaction model. More specific findings indicated that the health care attributes of cost and quality of care were important in both models, although to a far greater extent in the performance model, and that availability of physicians was also important in the performance model, albeit to a lesser degree. The study also examined demographic characteristics that may serve as a basis for segmenting the health care market. Of those considered, only two, age and urban/rural residence, were found to be significant. Age was considerably the more important of the two and younger respondents were far more interested in joining HMOs than their older counterparts. The pattern of results for the young subsample paralleled those found for the entire sample. PMID- 10109098 TI - Attributes and perceived benefits of women's health care services. AB - To protect against declining admission rates and revenues, many hospitals are introducing innovative services to attract patients and physicians to their facilities. Women's health programs have been developed and offered in many markets consistent with this need. This paper examines the actions that hospitals have taken to date, and compares them to the attributes that have been cited in the literature that are seen to influence patient choice. The paper provides a framework which can be used to more effectively define and target programs of this type. PMID- 10109099 TI - Consumers' perceptions and opinions of health care challenges--case study by the Virginia Hospital Association. PMID- 10109100 TI - Consumer driven strategies in the management of long term care services. AB - This paper discusses the concept of consumer oriented long term care management. It is argued that when long term care managers have a consumer orientation they are more responsive to the needs of their clients. This orientation puts the needs and preferences of clients at the forefront of planning and marketing decisions. PMID- 10109101 TI - How to market home health services. PMID- 10109102 TI - Demographic change and the supply of physicians, hospitals, and hospital beds: marketing implications. AB - Demographic conditions are a major component of the business environment in which health care marketers must compete. The following study assesses the impact of demographic factors on health care supply and finds that population size, population change, age structure, and income are important predictors of physician, hospital, and hospital bed supply. The results are discussed in the context of marketing implications. PMID- 10109103 TI - Identifying consumers favorable to hospital advertising. PMID- 10109104 TI - The change in importance of hospital purchase decision criteria as a result of prospective payment. AB - Changes in the importance of various hospital purchase decision criteria as a result of prospective payment were explored. The purchasing agents in the survey reported that product price and an administrator's request were more important with prospective payment while the familiarity of the sales representative declined in importance. PMID- 10109105 TI - When you go to war with Medicare, bring some heavy artillery. AB - Underpaid and uninformed by a bumbling carrier, a rural FP fought back with the help of her senator and congressman. PMID- 10109106 TI - The quiet drug revolution. AB - Routine approval of new products often requires a decade. But in a little-noticed change, people who are gravely ill can get breakthrough medicines much faster. PMID- 10109107 TI - Practicing in a fish bowl. AB - Intent on recovering "overpayments" to doctors, private insurers are turning to on-site practice audits. Here's a survival guide for these quasi-legal skirmishes. PMID- 10109108 TI - The feds take aim at bad doctors--and hit everyone in sight. AB - Their new databank on M.D.s' mistakes is so inclusive that, one way or another, it will hurt every practitioner, an attorney argues. PMID- 10109109 TI - What if your patient's insurance is bogus? AB - It's a possibility you'll have to consider from now on. Because of legal loopholes, dozens of outfits have started selling counterfeit coverage. PMID- 10109110 TI - Tips from doctors who've never been sued. AB - Some veteran M.D.s manage to elude malpractice claims year in and year out. The author surveyed 200 of them to find what they have in common. What makes patients sue? A separate study uncovers some surprising answers. PMID- 10109111 TI - The presidential effect: the public health response to media coverage about Ronald Reagan's colon cancer episode. AB - Little previous research has been done on the public health impact of mass media coverage of cancer episodes of public figures. This paper uses a variety of data sources to examine the impact of President Reagan's colon cancer episode of July, 1985. Records of phone calls to the Cancer Information Service of the National Cancer Institute are examined as a measure of public interest and concern about colorectal cancer; data on the use of two colorectal early detection tests- proctoscopy and fecal occult blood tests--are looked at as a measure of behavioral change; and data on the incidence of early and advanced colorectal cancer are used to estimate the potential public health impact of this behavioral change. We find that there was a sharp, albeit somewhat transitory, increase in public interest in colorectal cancer in the wake of President Reagan's colon cancer episode, with a corresponding increase in the use of early detection tests. The incidence data on early and advanced disease is indicative of a beneficial public health impact, but this can be confirmed only after additional data on mortality becomes available. PMID- 10109112 TI - Improving management practices: a case study of linen usage. AB - As part of an action research project, a thorough review was undertaken into the system for linen acquisition, distribution and usage in a large metropolitan hospital. As a result, new systems of management control were introduced, with considerable cost savings resulting. The project illustrated the importance to effective hospital management of the implementation of systematic review and redesign processes to incorporate measurement and accountability into management systems. PMID- 10109113 TI - Organisation change on the run: a simplified model for managers. AB - Frequently the organisation change literature is stronger on theory than it is on practical information for the line manager. This action research project which involved the computerisation of the supply system in a small public hospital provided an example of the type of change activities which face the practising manager. It also provided the opportunity for a comparison with organisation change literature which led to the development of a simple model of a change process which can provide guidance to the manager faced with implementing change. PMID- 10109114 TI - Action research, organisation change and management development. AB - The nature of action research and its role as a means of achieving organisation change and management development is described using the examples of action research published in this issue of the Australian Health Review. PMID- 10109115 TI - Implementing a systems approach to manage assets. AB - This article describes the implementation, on a trial basis, of an Asset Management System at two Victorian Public Hospitals. During the course of this activity, based on research and case history learnings, a Systems Commissioning Document was developed. This document facilitates system implementation, promotes standardised procedures and provides guidance which has general application in other Victorian Public Hospitals as well as in settings other than hospitals. PMID- 10109116 TI - Implementation of clinical budgeting in a public teaching hospital--first steps. AB - An action research project commenced the process of introducing a clinical budgeting system into the clinical areas in a large public teaching hospital. Focused interviews were used as the initial activity aimed at involving Heads in using the system. The process underlined a number of issues which need to be managed in this type of process and pointed to a number of factors which should be present to assist its introduction. PMID- 10109117 TI - Power in practice. AB - An action research project was undertaken which involved the implementation of a computerised system in a large public hospital. This paper describes the nature of the power dynamics present during the process. It was found that the potential for the use of power was particularly evident in an environment of organisational turbulence and that a variety of power bases and activities were present. The relevance of power and influence in the achievement of effective management action is discussed. PMID- 10109118 TI - Change in a public sector health setting: some factors contributing to success. AB - The differential impact of two action research projects involving the implementation of change in a public sector psychiatric health setting was examined. Particular factors which influenced the projects were the political and policy environment and the internal organisational culture. Implications for the management of change and for the policy implementation process are discussed. PMID- 10109119 TI - The NSW Ambulance Service healthy lifestyle program--a case study in the evaluation of a health promotion program. AB - A variety of approaches have been used to reduce Cardiovascular Disease (CVD) risk in the community, including programs based in the workplace. To date, it has been difficult to draw accurate conclusions on the effectiveness of worksite CVD risk reduction programs. Typically, such programs suffer from poor participation and high attrition rates and most lack physical and biochemical validation of self-reported lifestyle changes. The present paper describes an evaluation of four health promotion worksite interventions (screening, education, incentive and lifestyle change) conducted in the NSW Ambulance Service. The study achieved very high participation and low attrition rates. Self-reported changes in lifestyle were validated with physical and biochemical measures. The results suggest greater change in some risk factors for those individuals receiving the incentive and lifestyle change programs compared to screening alone or education. PMID- 10109121 TI - How health promotion services can make a public health impact. PMID- 10109120 TI - Evaluations of health promotion: combining realism with rigour. AB - Large-scale, publicly-funded programs to reduce the risk of cardiovascular disease, cancer, AIDS and other health problems are now common in Australia. There is a need to objectively evaluate the effects of these programs, but there should be realistic expectations of such evaluations. Decisions about the appropriateness of conducting evaluation studies in the field settings need to be made with an awareness of whether new methods are being tested or whether already tested procedures and principles are being used. The limitations on research and evaluation in field settings should also be acknowledged and the changes which are expected should be identified. Planners and administrators should have an explicit rationale for the goals, intervention methods and expected outcomes of health promotion programs. But they should be realistic about the limitations of program evaluations and avoid the traps of either attempting to adhere to inappropriately high standards of scientific rigour or of abandoning any attempts at evaluation. Some guidelines are suggested to assist planners and administrators make decisions about the extent and the appropriateness of conducting health-promotion evaluations. PMID- 10109122 TI - Health promotion--a focus for hospitals. AB - A hospital is in a unique position, both as a service provider and an employer, to provide a focus for disease prevention and health maintenance based on a greater understanding of the relationship between social and physical environment and lifestyle factors on health. Developing hospitals to become a resource for health instead of merely another link in the sick-care chain requires a substantial change in philosophy, management and practice. Reaching out into the community, establishing new and different relationships with consumers, and creating an environment conducive to healthy behaviour are only some of the changes necessary to reflect a health promotion focus. This paper discusses the experiences of establishing, developing and maintaining health promotion services at Flinders Medical Centre. PMID- 10109123 TI - Hospital-based group smoking cessation programs. AB - Since 1983, a standard eight-session group smoking cessation course (Fresh Start) has been disseminated throughout Victoria by the Anti-Cancer Council of Victoria with participation of various health agencies, including hospitals. During the five years since the Fresh Start program began, 94 groups were conducted under the auspices of hospitals and there were attended by 894 smokers (43% men, 57% women). Their mean age was 40.6 years. They had smoked for an average of 20 years. Their average precourse daily consumption of cigarettes was 27.7. One year after the course, 24% of the total initial enrollment reported themselves to be not currently smoking. The more course sessions participants attended, the more likely they were to succeed in quitting. PMID- 10109124 TI - Perspectives. The rebirth of the Blues. PMID- 10109125 TI - HCFA nursing home guide put on hold. OBRA changes require revisions. PMID- 10109126 TI - Medicaid budget crisis now in full bloom. Governors press for relief. PMID- 10109127 TI - The right delivery system delivers the right results. Protect quality, schedule and cost. PMID- 10109128 TI - Marketing to attract private-pay residents. The courtship of a vital resource. PMID- 10109129 TI - Rx homecare: prescription for greater reach. PMID- 10109130 TI - Overcoming limited access to financing. Persistent for-profits add acquisitions. PMID- 10109131 TI - Assisted Living Facilities Association of America. Assisted living in the spotlight. New association eyes expanded Medicaid funding. PMID- 10109132 TI - Facility-wide focus on resident care. PMID- 10109133 TI - Reducing med pass error rates. Consultant pharmacists lend a hand. PMID- 10109134 TI - Addressing resident incapacity under OBRA '87. PMID- 10109135 TI - Pharmacy. Presenting effective inservice programs. PMID- 10109136 TI - Caution and optimism define retirement housing market. New directions in a changing era. PMID- 10109137 TI - The alcoholic physician: a journey to recovery. PMID- 10109138 TI - The National Practitioner Data Bank: intrusion or innovation? PMID- 10109139 TI - William B. Walsh, MD: the guiding light of Project HOPE. Interview by C. Burns Roehrig. PMID- 10109140 TI - Congress and health care: what's in the wind? PMID- 10109141 TI - Let's give RBRVs a chance before 'bundling' physician services. PMID- 10109142 TI - A medical society's response to physician impairment. PMID- 10109143 TI - Achieving an effective committee through reorganization: the Ohio State University Hospital's experience. AB - The P & T Committee at Ohio State University (OSU) Hospitals, Columbus, is unique in that it accomplishes the bulk of its tasks through subcommittees. Four subcommittees are currently in place: a formulary subcommittee, a policy and surveillance subcommittee, an antibiotic subcommittee, and a therapeutic drug monitoring subcommittee. An advantage to this method of organization is that it allows for much more medical staff involvement in P & T Committee activities. Other unique aspects of this P & T Committee are that it is responsible for maintaining both an inpatient and outpatient formulary, and it provides decision making services for a specialty cancer hospital. Expansion of their drug usage evaluation program, further development of their therapeutic monitoring program, and improved communication with the medical staff are future goals of this P & T Committee. PMID- 10109145 TI - Renovation and addition turn hospital cafeteria into bigger profit center. PMID- 10109144 TI - Drug usage patterns in the ICU: profile of a major metropolitan hospital and comparison with other ICUs. AB - Drug use patterns observed in an intensive care unit (ICU) at a large tertiary teaching hospital (Brigham & Women's Hospital [BWH], Boston) were documented and compared with patterns reported from ICUs of hospitals at two other sites. Antibiotics, analgesics, and H2 antagonists were the most frequently prescribed classes of drugs. Despite the variability in ICU populations studied, similar patterns of drug use (drug classes and frequency of use) were seen at all three institutions. Pharmacy charges for ICU care at BWH were calculated with respect to total hospitalization charges and were found to account for 10% of total charges. Identifying drug use patterns in ICUs--an area of potentially high drug use, risk, and cost--provides valuable information for P & T Committees as well as for medical staff quality assurance and usage evaluation functions. PMID- 10109146 TI - 'Homework' is crucial to staying within your construction budgets. PMID- 10109147 TI - Written plans, drills key to bomb-threat response. PMID- 10109148 TI - OSHA lab-safety standard requires written plans. PMID- 10109149 TI - 'Zone mechanics' up PM productivity by 300%. PMID- 10109150 TI - Part-time staff key to covering full-time shortage. PMID- 10109151 TI - Low-level radioactive waste disposal: a potential nightmare for hospitals? PMID- 10109152 TI - Persian Gulf War not yet causing staffing problems for Michigan hospitals. PMID- 10109153 TI - Why trustees should become health care lobbyists. Interview by Maryanne Butt. PMID- 10109154 TI - The relationship between auxiliaries and departments of volunteer services--must it be stressful? PMID- 10109155 TI - The tactically proficient health care executive--Part one. PMID- 10109156 TI - Conquering the growing problem of medical waste. PMID- 10109158 TI - Lawsuit looms over HMOs' home-care responsibilities. PMID- 10109157 TI - Facilities seek review criteria. PMID- 10109159 TI - HMO review to switch to random samples. PMID- 10109160 TI - Emphasis on business over mission has put hospitals in a jam on tax status, experts say. PMID- 10109161 TI - Execs would 'regret' thwarting capital plan. PMID- 10109162 TI - Pa. files more challenges to tax exemptions. PMID- 10109163 TI - Healthcare's war capability a carryover from bygone era. PMID- 10109164 TI - Life after mandatory insurance: Hawaii providers tide a new wave. AB - While the nation looks to universal access laws as a solution to hospitals' rising costs of caring for the uninsured, laws covering all workers are standard operating procedure in Hawaii. The state's mandatory insurance law was meant to reduce hospitals' indigent-care losses, but losses have continued to mount at some facilities. Despite the overall benefits of the law, Hawaiian hospitals struggle just like their mainland counterparts to survive. PMID- 10109165 TI - AIDS-care programs struggle as grant funding runs out. AB - Four years ago, the Robert Wood Johnson Foundation provided $17.2 million in grants to AIDS providers in nine cities. Now each of those areas is operating programs that treat AIDS patients outside the acute-care setting. However, all of the grants will expire by the end of this year, sending the programs scrambling to line up new money to keep the projects alive. PMID- 10109166 TI - Inexpensive innovations can help bring physicians and referrals to your doorstep. PMID- 10109167 TI - Fla. panel urges co-op as part of access plan. AB - As part of a far-reaching blueprint for ensuring primary care for the uninsured in Florida, a state task force is urging the formation of a public-private "purchasing cooperative" in pursuit of affordable care for all residents. The panel also envisions a regulatory agency with wide-ranging powers to weed out duplication of services and spearhead insurance reforms. PMID- 10109168 TI - AHA takes cue, may ease grip on membership units. PMID- 10109169 TI - Hospital CEO turnover still high but decreasing. PMID- 10109170 TI - Bylaws dispute jeopardizes accreditation. PMID- 10109171 TI - Hospital chain's LBO reads like textbook case. AB - Health Management Associates' leveraged buyout was done during the swirling and headlong LBO mania of the 1980s, but this one was structured to keep the company from being crushed under the weight of its debt. That cool calculation is paying off in cool millions for management and institutional investors as a return to public ownership reaps stock-price dividends. PMID- 10109172 TI - Ga. physicians charged with price-fixing. PMID- 10109173 TI - AMI completes sale of two hospitals to new company. PMID- 10109174 TI - Universal sells three hospitals in Britain. PMID- 10109175 TI - HCA not expected to have trouble paying off loan. PMID- 10109176 TI - St. Louis hospitals sign affiliation agreement. PMID- 10109177 TI - Mass. hospitals attack cost study. PMID- 10109178 TI - N.J. hospital group sues state to release dormant $22 million for care of uninsured patients. PMID- 10109179 TI - Barstow seeks hospital buyer. PMID- 10109180 TI - Bolar agrees to guilty plea in generic drug probe. PMID- 10109182 TI - Wood, Lucksinger healthcare law practice breaking apart. PMID- 10109181 TI - Genentech suing SmithKline Beecham. PMID- 10109183 TI - Hospitals resist business bid to list St. Louis-area prices. PMID- 10109184 TI - Allegheny General loses property tax exemption. PMID- 10109185 TI - Oregon, hospitals settle Medicaid payment suit. PMID- 10109186 TI - AHA, NLRB argue vices and virtues of bargaining unit rules to high court. PMID- 10109187 TI - PPS plan for capital is built on fairness, not cost-cutting. PMID- 10109188 TI - Hospitals signaling distress. AB - As financial analysts list a growing number of hospitals in "distressed" condition, more executives are acknowledging the shaky status of their institutions and are seeking help. And assistance is in plentiful supply as specialized turnaround consultants multiply. But at many of these hospitals, being dubbed "distressed" is an inaccurate characterization--financial results and other criteria may not tell the whole story. PMID- 10109189 TI - Changes continue at top of AHA hierarchy. PMID- 10109190 TI - FTC scrutinizing Wis. merger. PMID- 10109191 TI - Consumers trail other groups in concern over healthcare cost, but interest is rising. AB - A recent survey cited healthcare costs as the nation's No. 1 problem as judged by physicians, hospital administrators and employers. But only a third of consumers felt the same way, and only 1 in 5 consumers said healthcare costs were their greatest personal concern. PMID- 10109192 TI - Creative proposal plays to a tough crowd. AB - Even avowed opponents of prospective payment for capital debt admit the plan unveiled by Administrator Gail Wilensky is creative and addresses the hospital industry's complaints. But there's skepticism about how the solutions will hold up in practice, and not many are willing to embrace it yet. PMID- 10109193 TI - Finance experts say rule is better than past tries, but they still have their doubts. PMID- 10109194 TI - AMI issues notes totaling $606 million. PMID- 10109195 TI - Foundation loans aid rurals' access to capital. AB - Hospital groups in two states are using $500,000 loans from the Robert Wood Johnson Foundation to help open the capital pipeline for rural facilities that often find it difficult or impossible to obtain financing. While a Nevada group is merging its funds with a state appropriation to establish a conventional loan fund, a Wisconsin co-op is leveraging its proceeds by setting up a loan guarantee pool. PMID- 10109196 TI - Hospitals the loser on Medicaid drug law--pharmacists. PMID- 10109197 TI - Ethical issues in health care institutions. Lesson one: Professional virtues. AB - In this first lesson of a five-part WMU/AHRA magazine course on ethics, Dr. Pritchard concentrates on the virtues or character traits that professionals should possess. "This is an important factor," the author suggests, "because abuse of power can easily result when individuals have specialized knowledge and expertise." Through the use of three case studies, Dr. Pritchard demonstrates that having virtuous professionals actually does affect the quality of health care provided. PMID- 10109198 TI - Relative value units: practical productivity measurement. AB - The relative value system of measuring productivity can be an effective measurement tool for radiology administrators if properly designed and implemented. Since the financial future of the health care industry continues to dominate both private and public agendas, qualitative measurements of health care delivery alone will not suffice. Even if the relative value system is not the ultimate panacea for evaluating productivity, it is at least one reasonable method of attempting to address the issue of quantitative measurement of radiology services. This article will introduce relative value units (RVUs) as a practical method of measuring productivity in the radiology department. PMID- 10109199 TI - Quality assurance in MRI. AB - "With the prospect of the federal government waiting in the wings to mandate and oversee quality assurance in radiology, managers should waste no time in establishing adequate quality assurance programs for MRI, the latest new technology," declare the authors. Determining standards for quality assurance is certainly a difficult task, considering all the stakeholders involved, say the authors. They focus on evaluating the appropriateness of the imaging test and insuring the accuracy of the diagnosis as the key elements to be monitored. PMID- 10109200 TI - Materiel management and radiology: building a teamwork relationship. AB - Mr. Burke and Mr. Cirino explain how a teamwork relationship between radiology and materiel management can serve both well--radiology can continually strive to provide high quality diagnostic data and superior patient care, while materiel management can provide a continuous flow of supplies and services, keep inventory investment low, and develop a competent supplier base. Effective communication is the necessary element that will allow each to achieve its respective goals. PMID- 10109201 TI - AHRA survey. Survey on job content and salary: Part III. AB - Part III of the AHRA Statistical Resource Committee salary survey compares the AHRA data with other studies. Comparisons are also provided between AHRA data from 1984 to 1990, highlighting trends in salary and education level, annual increases, and job satisfaction. PMID- 10109202 TI - How to make salary comparisons and negotiate a raise. AB - For the first time, the AHRA salary survey includes factors of job responsibility related to salary level. Ms. Nielsen explains how radiology managers can use this data to determine how their compensation compares with the marketplace. She also provides helpful tips on negotiating a raise. PMID- 10109203 TI - How to build the perfect technologist. Licensure of nuclear medicine technologists and sonographers. PMID- 10109204 TI - New delivery unit for National Women's Hospital. PMID- 10109205 TI - Hospital watch. PMID- 10109206 TI - Clinical waste--the hidden menace. PMID- 10109207 TI - Special recognition for Wellington's Total Energy Centre. PMID- 10109209 TI - Auckland Area Health Board feature. PMID- 10109208 TI - Job evaluation in the health sector. PMID- 10109210 TI - Point and counterpoint: should the ethics committee visit the patient? No: HEC members should not visit the patient. PMID- 10109211 TI - Point and counterpoint: should the ethics committee visit the patient? Yes: visiting the patient helps to fulfill obligations of fairness and to avoid paternalism. PMID- 10109212 TI - Strength enough: thoughts on age-based rationing and intergenerational equity in Britain. PMID- 10109213 TI - Decision making and the incompetent patient: a tale of two committees. PMID- 10109215 TI - Joint Commission's agenda includes change for medical records. PMID- 10109214 TI - The 'medicine is war' metaphor. PMID- 10109216 TI - Changing regulatory environment requires stronger risk management controls. AB - JCAHO standards and NPDB regulations heighten risk management concerns in hospitals. This article points out the similarities and differences between the two and suggests that the meeting ground to address the standards and regulations is in consolidated risk management efforts. PMID- 10109217 TI - White Paper: coding and classification systems--implications for the profession. PMID- 10109218 TI - The practitioner as recruiter. AB - The following article by Donna J. Wilde, MPA, RRA, is the first in a series of brief articles aimed at focusing members' attention on the vital importance of recruiting students to medical record programs. If our profession is to grow in numbers and in high level performers, we must begin attracting students to the challenging world of healthcare information management. Wilde discusses the topic from the educator's viewpoint. PMID- 10109219 TI - Facsimile (fax) technology. AB - Fax technology is the transmission of text and graphic data between two locations via telephone lines. The advantages of this technology include the speed with which a document can be sent anywhere in the world and the decreased cost versus traditional courier and Telex services. Several different types of machines exist, but standard operating parameters are set by the Consultative Committee for International Telephone and Telegraph (CCITT). There are four categories of machines, called Groups, which aid in classifying the various fax units. Group 3 machines are the most common comprising about 75% of the market. Standard features vary between and within groups, depending on the manufacturer and model. Features such as polling, document broadcasting, security levels, and computer linkage are discussed. The healthcare industry has been slow to adopt fax technology. Applications in hospital pharmacy are the main focus of attention of some hospital administrators and directors of pharmacy. A few studies have shown decreased medication order turnaround time after implementation of a fax-based pharmacy order system. However, problems such as order clarity and legibility, elevated nursing expectations and increased use of paper can decrease its usefulness. Overall, facsimile technology will find a place in the healthcare arena and may become an integral part of the modern pharmacy department. PMID- 10109220 TI - Pharmacists in the continuing fight against measles. PMID- 10109221 TI - Measuring the ability of clinical pharmacists to effect drug therapy changes in a family practice clinic using prognostic indicators. AB - This study was designed to analyze physicians' acceptance of pharmacists' drug therapy recommendations in a Family Practice Clinic. It also measured the relationship between specific prognostic indicators and pharmacists' recommendations regarding drug therapy in individual patients. Once the recommendations were implemented, outcome data were collected to assess the impact on patient care. Thirty-nine patients were seen by a pharmacist during 49 clinic visits. A total of 36 recommendations were made to change therapy. Recommendations to change therapy occurred most frequently when one indicator, medication regimen changed four or more times during the past year, was present. Recommendations were accepted by physicians in 32 or 89% of cases. Patient outcome improved in 95% (18 of 19) of cases and remained unchanged in 5% (1 of 19) of cases for which outcome data were available. PMID- 10109222 TI - Mental healthcare: access, excess, and fragmentation. PMID- 10109223 TI - Religion: wings or shackles? PMID- 10109224 TI - Thought police. Healthcare executives must carefully guard intellectual property developed in their facilities. AB - Healthcare executives should have a working knowledge of intellectual property law--the legal principle that, for a limited period, treats intangible ideas and concepts as if they were products or property. Not only should administrators be aware of how to protect their facilities' patents, trademarks, copyrights, and trade secrets, but they must also be sure that employees in their own facilities do not infringe on the intellectual property of others. A patent is granted when an inventor proposes a useful new process, machine, "article of manufacture," or composition of matter, including any new and useful improvement on existing items in these same categories. A trademark is a name, symbol, device, or combination thereof adopted and used by an institution to identify its goods or services and to distinguish them from its competitors' goods or services. Expressions of ideas and thoughts set forth in words, sentences, paragraphs, sketches, pictures, graphs, or any other means of conveying ideas or concepts commonly understood to be works of authorship--both published and unpublished--may be protected by a copyright. Trade secret law applies to those who might misappropriate information that has been given to them because of their special relationship with the holder of the trade secret (i.e., through employment, contract, or other fiduciary or trust relationship). PMID- 10109225 TI - Natural resources. Social workers are a community's link to charity care. PMID- 10109226 TI - Strengthening physician relationships. Improving service to medical practices helps hospitals meet patients' needs. AB - In 1983 Sacred Heart Hospital, Yankton, SD, launched a medical staff-based marketing plan. Initial research focused on discovering service-area referring physicians' perceptions and level of utilization of Sacred Heart and its medical staff. The plan's ultimate goal was to strengthen relationships with referring physicians and thus improve the hospital's ability to deliver high-quality healthcare to those in its service area. Physicians were asked to indicate how important certain attributes were in choosing a medical specialist and a referral hospital. Among the attributes they most often cited as "very important" in choice of a specialist were specialist's reputation, patient's previous satisfaction, communication with a referring physician, and patient's preference. For choosing a referral hospital the most frequently cited attributes were availability of latest technology and equipment, hospital's reputation, patient's previous satisfaction, and patient's preference. The study also gathered information on physicians' utilization of and satisfaction with a variety of Sacred Heart services. As a result of the study, the hospital implemented a seven part strategy to increase referring physicians' satisfaction with and utilization of the hospital and its medical staff. A follow-up study five years later revealed a 6.7 percent increase in the number of service-area physicians who referred patients to Sacred Heart and a 14.2 percent increase in the number of physicians who were "very satisfied" with the hospital's services. The consumer study revealed that high-quality professional services and highly personalized services were very important to patients. PMID- 10109227 TI - Rights and respect. Legal and ethical issues challenge today's mental healthcare professionals. AB - The special circumstances of patients in mental health facilities often make questions concerning patient autonomy, freedom of choice, and consent to treatment even more complex than they are in other contexts. Individual facilities need to identify the ethical issues they are likely to encounter and create policies that address them effectively. The advent of managed care has created unprecedented access problems for mental healthcare providers. In many cases patients must be proven dangerous to themselves or others before they can be admitted for emergency care; because it is difficult to prove this, many persons go without needed treatment. The high costs of care and prejudices against persons with mental illness also create ethical problems. The necessity of performing clinical evaluations raises important ethical issues as well. Care givers evaluating someone at the request of a school, employer, or court should be sensitive to the possible consequences of their evaluation. They should also restrict their diagnoses to their area of competency and inform clients of the purpose of the evaluation, its possible consequences, and the limits of its confidentiality. Mental health professionals must also respect patients' rights to informed consent and understand the issues of voluntary or involuntary admissions. In addition, care givers should be aware of the various issues created by the need to occasionally control patients' behavior. Finally, for mental healthcare facilities, it is essential to establish an ethics committee to address these issues. PMID- 10109228 TI - The reimbursement blues. A psychiatric hospital copes with decreasing reimbursement and declining admissions. AB - Beginning in 1989, Harbor View Mercy Hospital, a freestanding psychiatric facility in Fort Smith, AR, saw a flattening of growth in inpatient days and declines in discharges. In addition to decreasing admissions, it faces the problems of decreasing reimbursement, the need to provide more services with fewer resources, and greater government regulations. The greatest problem is inadequate reimbursement. Psychiatric hospitals fare worse than their acute care counterparts under both Medicaid and Medicare. To fulfill its mission to serve those in need, Harbor View has allocated 43 percent of its revenue budget this year to cover charity care, bad debt, etc. Ron Summerhill, the hospital's chief administrative officer, predicts a slowdown in the growth and profitability of psychiatric services in both the for-profit and not-for-profit sectors. But he is combating this trend by increasing use of managed care arrangements, diversifying, offering more outpatient services, and advocating for change in the reimbursement situation. PMID- 10109229 TI - Trends in mental healthcare. During the 1980s availability of services increased, lengths of stay decreased. PMID- 10109230 TI - Opening doors to the needy. An archdiocese coordinates a physician referral network. AB - The availability and accessibility of healthcare to those unable to pay is deteriorating rapidly. One place this is clearly apparent is in our nation's capital, where extremes of poverty and wealth abound. In an effort to improve access to healthcare for the poor, homeless, and medically indigent in the Washington, DC, area, the Washington Archdiocese Health Care Network (AHCN) was formed in 1984 under the leadership of Card. James A. Hickey. The AHCN is a coordinating agency that refers people in need to physicians, physical therapy and rehabilitation services, and dentists who have agreed to volunteer their services to this vulnerable population. The formation, operation, and continuation of the AHCN are performed by five members of one steering committee on behalf of the hundreds of volunteers who make it work daily. PMID- 10109231 TI - Increasing Medicaid clients' access to care. Church, state, and private providers collaborate. AB - Medicaid clients often have difficulty obtaining a physician referral and thus seek treatment for nonemergent conditions in hospital emergency rooms. A committee with representatives from Alexian Brothers Health System, Inc., Elk Grove Village, IL, and Catholic Charities of the Archdiocese of Chicago, Rolling Meadows, IL, has collaborated with six other organizations to put an end to this misuse of the healthcare system in Chicago's northwest suburbs. Catholic Charities Physician Referral Service came about as the result of research conducted by the committee which indicated that persons on public aid have limited resources available to secure primary healthcare. The committee also reviewed a United Way needs assessment and a survey of healthcare professionals and community leaders which substantiated that the community needed a referral service. In the past, Medicaid clients often had to make numerous futile telephone calls to locate physicians who would accept them. Through this service, however, Medicaid clients simply call Catholic Charities Physician Referral Service (which has information on participating physicians' specialty, location, and hospital affiliations) and then call the physician to whom they are referred. When physicians join the referral service, they specify the number of Medicaid patients they are willing to treat during the year. Catholic Charities will help the participating physicians secure payment from the Illinois Department of Public Aid for the health services they have provided. PMID- 10109232 TI - Care for life. PMID- 10109233 TI - Focus on physicians. PMID- 10109234 TI - Mercy Health Services--diversity in the workplace. PMID- 10109235 TI - Sisters of the Sorrowful Mother Ministry Corporation--seeds of innovation. PMID- 10109236 TI - An inside view of our healthcare system. PMID- 10109237 TI - Otolaryngology: the long, steady road to prosperity. PMID- 10109238 TI - Patients want doctors who'll talk to them. PMID- 10109239 TI - How to get rid of hired guns. PMID- 10109241 TI - Responding to Medicare physician payment reform. PMID- 10109240 TI - How to give a power of attorney and not regret it. PMID- 10109242 TI - The changing hospital-medical group relationship. PMID- 10109243 TI - The measurement of quality. PMID- 10109244 TI - Some observations on medical group leadership. PMID- 10109245 TI - Facing the prospect of changing jobs. AB - Everyone in the health care field faces, at some point in their career, the prospect of changing jobs, writes Brian McAlpin, FACMGA, The resulting feelings can range from fear to joy and McAlpin offers several useful tips on preparing for and completing the job search. PMID- 10109246 TI - It's your move now. AB - For whatever reason, on average, administrators move once every five years. Michael Taylor looks at some of the myths and realities involved in a job change including suggestions on how to make it work best for you. PMID- 10109247 TI - Failure at 50--alive at 55. AB - Author Dale Molesworth was fired from his job at the age of 50. In his article, Molesworth takes an honest (and sometimes biting) look at the emotions and consequences of such an event and how to get back on your feet afterwards. PMID- 10109248 TI - Outplacement--who needs it? AB - In this article, Sandra Naiman writes from the employer's point of view on why and how outplacement counseling should be provided to the terminated employee. She also describes what services should be provided and how to choose the right outplacement firm. PMID- 10109249 TI - Physician practice profiles--a valuable information system for HMOs. AB - Authors Warren Betty, M.D., et. al., describe how the Staten Island Medical Group computerized the data entry functions necessary for a workable physician audit and feedback program and how the program has been successful in some settings in bringing about lower utilization levels. PMID- 10109250 TI - Administrator employment contracts--a strategic step toward preventing administrator failure. AB - Part three of three in author C. Kay Freeman's series looks specifically at administrator employment contracts and the legalities involved. She covers such topics as communication, evaluations and contract language in offering practical tips on creating an administrator employment contract. PMID- 10109251 TI - Health care administrator: heal thy organizational self. AB - Many problems in today's group practice marketplace exist because organizations are confused about what constitutes the "business" side of health care in relationship to its philanthropic past. Eugene Dawson Jr., Ph.D., examines some of these problem conditions and offers suggestions on coping with the changing environment. PMID- 10109252 TI - Charter submits restructuring plan. PMID- 10109253 TI - Reasons for ambulatory care differ. PMID- 10109254 TI - Price-disclosure plan endorsed. PMID- 10109255 TI - Prudential unit to buy Johns Hopkins HMO. PMID- 10109256 TI - 2 large Minn. HMOs settle on a merger. PMID- 10109257 TI - HPI cancels 20 small-hospital contracts. PMID- 10109258 TI - N.Y. facilities must report community service. PMID- 10109259 TI - Coalition sets principles for reform plans. PMID- 10109260 TI - Florida physicians fight FTC's attempt to settle price-fix charges in cash. PMID- 10109261 TI - Hospital groups turning to advertorial campaigns to improve public image. AB - The hospital industry is taking an unusual approach to improving a public image tarnished by such issues as certificate-of-need battles and calls to justify not for-profit tax-exempt status. The advertorial campaigns seek to express the hospital industry's views on health issues and to educate the public about hospitals' community contributions. PMID- 10109262 TI - AFL-CIO stops short of endorsing single-payer system. PMID- 10109263 TI - IRS warns Texas not-for-profits. PMID- 10109264 TI - Low supply plus military need equals blood-product shortage. AB - The nation's hospitals are facing a critical shortage of albumin, a blood component, and the situation will worsen if a full-scale ground war in the Persian Gulf increases military demand for the product. PMID- 10109265 TI - Number of Medicaid lawsuits belies complexities involved in such filings. PMID- 10109266 TI - Medicaid cuts not expected. PMID- 10109267 TI - Tale of survival tails off. AB - When Reader's Digest wove the tale of a scrappy rural hospital in Montana that raised enough in donations to keep from going under, it looked like a happy ending. But the last chapter on Sweet Grass Community Hospital's fight to survive is still being written, and it's a cliffhanger. PMID- 10109268 TI - Long-awaited capital payment plan unveiled. PMID- 10109269 TI - Medicaid in cross fire of partisan Mich. fight. PMID- 10109270 TI - Mercy system joins AmHS purchasing program. PMID- 10109272 TI - Marketing pact could boost medical records. PMID- 10109271 TI - Oregon panel releases Medicaid ranking. PMID- 10109273 TI - Proposal would ease losses from call-up. PMID- 10109274 TI - Getting down to business. PMID- 10109275 TI - Scheduling strategies. AB - This article describes a scheduling technique used at the San Francisco Magnetic Resonance Center to fill its daily scan schedule from early to late. A full schedule guarantees the success of a site, and this method reduces the possibility of unfilled early-day appointments and ensures open later-day appointments for purposes of "same-day" scheduling. PMID- 10109276 TI - Changing organizational structures. PMID- 10109277 TI - Let's put "care" back into health care. AB - Organizations that clearly demonstrate they care about their people reap the benefits of a positive self-image, higher productivity and financial gains. Consider the effects that a demoralized, unappreciated staff have on productivity, recruitment and retention, public relations, marketing, customer satisfaction and the resulting financial repercussions. Can we afford not to care? PMID- 10109278 TI - Implementation of a multimodality program. AB - Economic changes in the health care system have presented a unique opportunity for radiographers and other imaging personnel. Hospital administrators are becoming aware of the advantages of employing multiskilled technologists. The single-skilled technologist must recognize the benefits of additional education and overcome the negative perceptions of the profession. A well-conceived educational program developed and managed by a continuing education department will provide not only the required didactic and clinical courses to ensure competency, but also recognized credentialing for each modality. PMID- 10109279 TI - Job content/salary survey: Part I. American Healthcare Radiology Administrators. AB - The Statistical Resource Committee surveyed 1,232 AHRA members in March 1990 to determine their current responsibilities and related salaries. Part I of this report reviews respondents' responsibilities, administrative relationships, job satisfaction, level of education and the level of institutional support for educational seminars. Part II, scheduled for reporting in the fall issue of Radiology Management, will review data extracted on radiology administrators' salaries and related responsibilities for procedure volume, budgets, departments, FTEs, institutional committees, and education programs. PMID- 10109280 TI - Correlates to radiology managers' job satisfaction. AB - The satisfaction derived from one's job has implications for both employee and organization. This study examined the effect of five facets of the job on the overall job satisfaction of radiology department managers. Results indicated that work (tasks) performed and supervision received significantly contributed to managers' perception of their overall job satisfaction. The implications of these findings are discussed as they relate to the employee and organization. PMID- 10109281 TI - Restraints: friend or foe? PMID- 10109282 TI - Restraint or martial arts: should nurses tie people down? PMID- 10109283 TI - Who's restraining whom? PMID- 10109284 TI - Liability from a lack of restraint. PMID- 10109285 TI - Crisis communications: enlightenment for a dark hour. PMID- 10109286 TI - Freedom from restraints: patient right or patient risk? PMID- 10109287 TI - Wronging rights. Righting wrongs. PMID- 10109288 TI - Early billing intervention makes sense. PMID- 10109289 TI - Equity financing of healthcare companies, 1989. PMID- 10109290 TI - Perspectives. Medical research: coping in a new era. PMID- 10109291 TI - Perspectives. Health care reform: it won't come easy. PMID- 10109292 TI - Medicare model fee schedule undergoes review--Part I. PMID- 10109293 TI - Surgical scholarships and fellowships available. PMID- 10109294 TI - What surgeons should know about peer review organizations and quality intervention plans. PMID- 10109295 TI - Exasperation on both sides of the stethoscope. PMID- 10109296 TI - Statement on laser surgery. American College of Surgeons. PMID- 10109297 TI - Medicare model fee schedule undergoes review--Part II. PMID- 10109298 TI - ACS 1990 federal activities in review. PMID- 10109299 TI - Program planning and costing: a blueprint for success. AB - Intense competition and rapid technological changes have pressured the home care industry to respond to the need for new program and service line development. There is no secret to assured success. However, systematic planning to include identification of the program's purpose and objectives, market assessment, analysis of the program alternatives, resource needs and availability, and the impact of the program on the home care agency's market niche and financial state are all essential to facilitate successful implementation. PMID- 10109300 TI - Hospital-based discharge planning: the beginning of home care for many. AB - Discharge planning can be viewed as the first step in home care for many individuals. This article examines the process through the discussion of the stages of discharge planning, and a study of discharge planning in an acute-care hospital. Several recommendations are made that would strengthen the role of home care providers in the process, who are encouraged to work for a more active role in discharge planning. PMID- 10109301 TI - Quality assurance in home care: a diversified organization's approach. AB - The rapid growth of home care brings with it greater risks and liabilities, making quality assurance increasingly more important. Home Health Services Foundation, Inc., a diverse, multi-corporate structure, developed an effective quality assurance program through communication and information sharing. PMID- 10109302 TI - Quality assurance guidelines for clinical practice in speech/language pathology. AB - The quality assurance guidelines for clinical practice in speech/language pathology are effective for assuring the provision of quality clinical services to patients, as well as increasing revenues for hospitals and home care agencies by decreasing or eliminating denials for speech/language pathology claims. The guidelines can be used to evaluate the service and performance of speech therapists employed either directly or by independent contract. PMID- 10109303 TI - Cardiovascular education programs in the home health arena. AB - Hospital-based cardiovascular education programs are not achieving the results hoped for by the medical and nursing profession. Patients are too ill and frightened at this level to learn. A study of a cardiovascular education program undertaken in a home care agency achieved encouraging results: patients learn much better at home. PMID- 10109304 TI - A time for caring: healing a sick society. PMID- 10109305 TI - The Independent Living Program: an alternative to institutionalization. AB - The Independent Living Program is a joint venture demonstration project in Ardmore, Pennsylvania. Partners are Community Health Affiliates, a one-hundred plus-year-old visiting nurse association and integrated home care agency, and neighboring Ardmore House, a 63-unit residential facility for a well-elderly population with extremely limited financial means. PMID- 10109306 TI - Sick-child care and the workplace: a program for working parents. AB - Day care provides an indispensable service in today's society of double-income families. When a child is too ill to attend day care, however, one parent must stay home. To fill this child care gap, Counseling Home Care Services, Inc., has developed a sick-child care program. PMID- 10109307 TI - The VNA of Chicago: providing new services for 100 years. AB - Started by socialites in 1889, the Visiting Nurse Association of Chicago has been providing quality care for over 100 years. From tuberculosis to polio to AIDS, the VNA has successfully responded to the changing needs of the city it serves by consistently providing progressive and innovative services. PMID- 10109308 TI - Reimbursement issues for the 1990s. AB - In order to survive and prosper in the 1990s home care administrators must be cognizant of several reimbursement issues, such as cost reporting, Medicare cost limits, and payment for hospice and physician services. PMID- 10109309 TI - Coming to terms with committees. PMID- 10109310 TI - Ten key concerns about risk management. PMID- 10109311 TI - Orientation: a progressive approach. PMID- 10109312 TI - Measuring up. PMID- 10109313 TI - A shock to the systems. PMID- 10109314 TI - Target: terrorism. PMID- 10109315 TI - The European response. PMID- 10109316 TI - Resuscitation gear. PMID- 10109317 TI - Fewer patients will curb pediatric orthopedic areas. PMID- 10109318 TI - Model provides structure for strategy development. AB - Hospitals are finding it more difficult to manage programs without experiencing a decline in profits. What guidelines and approaches can administrators utilize in their efforts to stem, if not reverse, declining revenues? In the following article, the author proposes a strategic model that focuses on individual programs. PMID- 10109319 TI - Ambulatory care to drive hospital services in 1990s. AB - Health care providers can expect a dramatic change in ambulatory care in the next decade. Driven by a variety of factors, including double digit growth in key outpatient areas, hospital administrators can expect a continuation of a trend that began in the 1980s. In the following article, the author details the changes that will focus on outpatient services. PMID- 10109320 TI - Planning necessary to win major awards for hospitals. PMID- 10109321 TI - Planning indicators. Trend continues: hospitals spend more, earn less. PMID- 10109322 TI - Award showcases programs. Interview by Donald E. L. Johnson. AB - Mount Zion Hospital and Medical Center, a 290-bed institution in San Francisco, Calif., displayed a commitment to a mission of "caring, grounded in learning, supported by acts of personal kindness" to win the 1990 American Hospital Association's Foster G. McGaw Prize for community service. In the following interview with Health Care Strategic Management's editor and publisher Donald E.L. Johnson, Martin H. Diamond, the hospital's CEO, explains how the institution earned recognition for its community-based programs to aid disenfranchised groups. PMID- 10109323 TI - Terminal illness? The mounting evidence of hazards from computer emissions. PMID- 10109324 TI - Oil and water? A united German health care system. PMID- 10109325 TI - Case management: a new solution for caring for people with AIDS? PMID- 10109326 TI - Breath taken: exposing the ongoing tragedy of asbestos. AB - Health/Pac has been covering the asbestos tragedy for nearly 20 years, but never has the personal devastation and meaning of the industry cover-up been brought home more compellingly than in Bill Ravanesi's photographic exhibit, "Breath Taken: The Landscape and Biography of Asbestos." The exhibit opened at the Boston University Art Gallery in spring 1989 and continues to tour the country under the auspices of the Center for Visual Arts in the Public Interest. Debbie Socolar walks Health/Pac readers through this brief glimpse of the exhibit and summarizes some of the many issues it touches on in portraying the ongoing occupational, environmental, and public health disaster of asbestos. PMID- 10109327 TI - Healthcare data briefing. The health costs of alcohol. PMID- 10109328 TI - Squaring a difficult circle. PMID- 10109329 TI - A look before you leap. PMID- 10109330 TI - Vigilance: the price of freedom. PMID- 10109331 TI - Differences in a scheme of change. PMID- 10109332 TI - Striking a bargain. PMID- 10109333 TI - A sickly shade of green. PMID- 10109334 TI - Conversions: remedy for financially troubled hospitals? PMID- 10109335 TI - Mistakes physicians make about bankruptcy. PMID- 10109336 TI - Early warning signs of hospital distress. PMID- 10109337 TI - Prescription drug marketing: bribing health care workers? PMID- 10109338 TI - Bankruptcy law issues for health care programs. PMID- 10109339 TI - Top management program: management development in New Zealand's health services. AB - This article describes New Zealand's program for developing managers in health services, called the National Management Development Program (NMDP), run by a newly established unit of the Department of Health. This is a set of programs for training various groups of individuals in health administration: those with no experience who wish to enter the field, those in a particular area of health, and those who are already managers in the health field. The Top Management Program, designed for professionals already heading health agencies, offers continuing education as a sustained approach to improving individual management ability. PMID- 10109340 TI - Public health and health administration: collaboration or competition? An Australian perspective. AB - The Review of Postgraduate Public Health Training in Australia 1988, commissioned by the Australian Public Health Association, identified as a major issue the degree of collaboration between independent postgraduate courses in health administration and courses in public health. This paper suggests that the two fields share the common goal of health service education, which they pursue by the respective pathways of effectiveness and efficiency. We argue that the identity and the complementarity of the disciplines are best served by a collaborative model and discuss ways to encourage and achieve this aim. PMID- 10109341 TI - Publication in research- or practice-oriented journals by health administration faculties. PMID- 10109342 TI - Strategic planning for graduate health administration education: a case study. PMID- 10109343 TI - Nonexempt uses of tax-exempt hospital bonds. PMID- 10109344 TI - Caring for AIDS patients in an existing nursing home. PMID- 10109345 TI - AIDS and the long-term care system: a nursing home survey. PMID- 10109346 TI - Hillhaven Ho Ho Hotline brings joy to all. PMID- 10109347 TI - A nursing home for AIDS patients: risks and responsibilities. PMID- 10109348 TI - Nursing home care for AIDS patients. PMID- 10109349 TI - Meeting the needs of AIDS patients. PMID- 10109350 TI - JIT (just-in-time): the latest acronym in hospital materiel management. PMID- 10109351 TI - Successful, documented studies favoring indefinite shelf life. PMID- 10109352 TI - Surgical lights. ECRI. PMID- 10109353 TI - When clinicians and vendors ally. PMID- 10109354 TI - Preparing activity reports. PMID- 10109355 TI - Predicting household consumption: spouse profiles as indicators of alcohol use. PMID- 10109356 TI - HMOs and the small business market. AB - In many urban areas with an abundance of health maintenance organizations (HMOs), small businesses are probably one of the few untapped markets. A 1986 survey by Arizona's prepaid Medicaid program, the Arizona Health Care Cost Containment System (AHCCCS), found that 43% of the state's small businesses of 25 or fewer employees do not offer health insurance to their employees. Insurers and HMOs have traditionally found small businesses undersirable for a multitude of reasons. They are considered to be higher utilizers of services, expensive to administer and subject to higher employee turnover. Little data have been available to substantiate the above premises. The Health Care Group, a program administered by AHCCCS and funded by the Robert Wood Johnson Foundation and Arizona's Flinn Foundation, was developed to address the problem of small businesses that do not have health insurance. This paper will consider the lessons learned by Health Care Group in marketing coverage to small groups. PMID- 10109357 TI - Selecting a primary care physician: results of a study. PMID- 10109358 TI - Consumer perspectives of direct marketing techniques and charitable contributions to healthcare institutions. AB - This study analyzes consumer sentiment toward the use of direct mail and telemarketing in the solicitation of donations for healthcare organizations. In addition, reasons for giving to healthcare organizations are examined. It was found that consumers have a more positive disposition toward the use of direct mail than in the use of the telephone. This study also provides an indication of healthcare's relative position to other charitable organizations. PMID- 10109359 TI - The challenge of the 90's--where to find new hospital patients. PMID- 10109360 TI - Determinant of hospital marketing effectiveness: the importance of conflict. AB - As hospitals and health organizations become more marketing oriented, and more interwoven into the environment, the more they face internal resistance. The careful handling of conflict not only helps the health care marketer to overcome hostility and antagonism, but also rewards the health care institution with the "productivity of confrontation." PMID- 10109361 TI - Comparing service quality expectations in hospitals and health care to other service businesses. PMID- 10109362 TI - A new role for hospitals: leading the channel of distribution for wellness products. PMID- 10109363 TI - Propensity of health administration faculty to publish in scholarly research journals. AB - Health administration faculty are interested in publishing activities in academic research journals. Perceived institutional quality and faculty professional advancement are strongly influenced by faculty's propensity to publish articles in scholarly journals. A five-year review of 10 of the health administration field's research-oriented journals showed that between 1983 and 1988 publication activity was heavily concentrated among four to seven institutions. These institutions also tended to publish in a greater breadth of journals selected by our criteria. PMID- 10109364 TI - Significant court decisions rendered in 1990. PMID- 10109365 TI - Medical liability reform: the time is now. PMID- 10109366 TI - When the surveyor knocks: friend or foe? PMID- 10109367 TI - Cutting your staff without cutting your throat. PMID- 10109368 TI - The tactically proficient health care executive--Part two. PMID- 10109369 TI - Is Michigan losing its edge in caregiving? Do other states have the answers? PMID- 10109370 TI - System's failure makes reform imperative. PMID- 10109371 TI - Entering the age of computers. PMID- 10109373 TI - Facilities must become players in tracking OBRA costs. PMID- 10109372 TI - Buyer's guide to software firms. PMID- 10109374 TI - Staff development directors may help ensure quality of care. PMID- 10109375 TI - 'Self determination' precedent established in Florida courts. PMID- 10109376 TI - 'Enrichment Program' returns residents to community. PMID- 10109377 TI - Medication delivery systems simplify drug dispensing. PMID- 10109378 TI - Need for advance directives focus of AARP campaign. PMID- 10109379 TI - Health promotion sparks community service initiatives. PMID- 10109380 TI - Economic credentialing: balancing quality with financial reality. PMID- 10109381 TI - Balancing the board-CEO relationship: the trustee's role. PMID- 10109382 TI - Strategic planning: a "how-to" guide. PMID- 10109383 TI - Promoting job skills in health care. PMID- 10109384 TI - Developing effective DNR policies. PMID- 10109385 TI - New law on advance directives. PMID- 10109386 TI - Women in the boardroom: auxilians define the word "volunteer.". PMID- 10109387 TI - HCFA Administrator Gail Wilensky discusses capital payment. Interview by Karen Gardner. PMID- 10109388 TI - Viewpoint: it's not too late for HCFA to reconsider capital payment plan. PMID- 10109389 TI - Reaffirming mission under threat of tax-exemption loss. PMID- 10109390 TI - Doing QI their way: Vermont's partnership in quality. PMID- 10109391 TI - What do indicators indicate? PMID- 10109392 TI - To data share or not to data share, that is the question. PMID- 10109393 TI - Dietetic service indicators. PMID- 10109394 TI - Nutrition and the average length of stay. PMID- 10109395 TI - Procedure-specific credentialing. Physician qualifications begin to factor into Medicare payment. PMID- 10109396 TI - Perspectives. UCDS: HCFA's ambitious automated review project. PMID- 10109397 TI - Perspectives. The battle over nursing home reform. PMID- 10109398 TI - Rural Hospital Center: eight years of service to rural hospitals. PMID- 10109399 TI - White elephants, rural hospitals and mission statements. PMID- 10109400 TI - Health personnel development strategies for rural hospitals. PMID- 10109401 TI - Essential Access Community Hospital program. PMID- 10109402 TI - Farm Bureau program assists rural hospitals. PMID- 10109403 TI - Bronzan says budget crisis may stall health care reforms. PMID- 10109404 TI - Feng shui explores relationship between design and health--ancient Chinese art of placement. PMID- 10109405 TI - Modular inpatient care unit eases critical bed shortage. PMID- 10109406 TI - Los Angeles County/USC Medical Center master plan. PMID- 10109407 TI - Recognizing interests of HIV-infected health care workers. PMID- 10109408 TI - A second look at rural hospitals and cost reimbursement. PMID- 10109409 TI - ProPAC investigates PPS system and rural hospitals. PMID- 10109410 TI - New technologies raise concerns about protecting patient confidentiality. PMID- 10109411 TI - Hospitals explore ways of educating patients about advanced directives. PMID- 10109413 TI - Nurses and Florida hospital hear patients and respond with ways to meet their needs. PMID- 10109412 TI - Hospital-based child care centers grow into adolescence; nearly 1,000 accept children across the U.S. PMID- 10109414 TI - Ethical code spells out responsibilities, sets conduct for patient reps. National Society of Patient Representation and Consumer Affairs. PMID- 10109415 TI - What's new in flex benefits? PMID- 10109416 TI - Outcomes management: buying value and cutting costs. PMID- 10109417 TI - Genetic testing: what will it mean for health insurance? PMID- 10109418 TI - EPO (exclusive provider organization): latest beast in the managed care menagerie. PMID- 10109419 TI - Cost shifting in New Jersey. PMID- 10109420 TI - Data watch. Flex plans on the rise. PMID- 10109421 TI - Medicare program; quarterly listing of program issuances and coverage decisions- HCFA. General notice. AB - This notice lists HCFA manual instructions, regulations and other Federal Register notices, and statements of policy that were published during July, August and September 1990 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register at least every three months. We also are providing the content of revisions to the Medicare Coverage Issues Manual published during this quarter. On August 21, 1989 (54 FR 34555), we published the content of the Manual and indicated that we will publish quarterly any updates. Adding the Medicare Coverage Issues Manual changes to this listing allows us to fulfill this requirement in a manner that facilitates identification of coverage and other changes in our manuals. PMID- 10109422 TI - Health Resources and Services Administration; statement of organizations, functions and delegations of authority--PHS. PMID- 10109423 TI - Privacy Act of 1974; system of records--HCFA. Notice of proposed new routine use for existing system of records. AB - One of the top priorities of HHS is to assure high quality and effective health care. HCFA is proposing to revise the system notice for the Medicare Bill File (Statistics). System No. 09-70-0005, by adding a new routine use for release of Medicare Hospital Mortality Information which is derived from data in the Medicare Provider Analysis and Review (MEDPAR) File, and other files available to HCFA. The purpose of this routine use is to allow individuals hospitals to participate in quality of care studies and activities by using data that they have previously supplied to HCFA. This new routine use will allow release to individual hospitals of patient-specific data including mortality predictors which have been statistically derived. PMID- 10109424 TI - Health Resources and Services Administration; statement of organization, functions and delegations of authority--PHS. PMID- 10109425 TI - Indian Health Service; medical reimbursement rates for calendar year 1991; inpatient and outpatient medical care--PHS. PMID- 10109426 TI - Changes to Medicare Secondary Payer (MSP) provisions--HCFA. Notice. AB - This notice describes how subsections 6202(b), (c), and (e) of the Omnibus Budget Reconciliation Act of 1989 (Pub. L. 101-239) affect the Medicare Program These subsections: Create uniform rules for computing Medicare secondary payments for all MSP situations; Exempt from the MSP provisions services performed for a religious order by members of the order who take a vow of poverty; Prohibit group health plans (GHPs) from "taking into account" that an individual is entitled to Medicare when Medicare is the secondary payer; Prohibit GHPs from differentiating, in the services they provide, between individuals with end-stage renal disease (ESRD) and other individuals covered by the plan; Require that GHPs of employers of 20 or more employees provide the same benefits under the same conditions to employees age 65 or older and employees' spouses age 65 or older as they provide to employees and spouses under age 65; Impose a 25 percent excise tax on contributions that employers and employee organizations make to nonconforming GHPs, i.e., plans that do not comply with the MSP provisions; Extend to all MSP situations the Federal Government's right to take legal action to collect double damages if a primary plan fails to comply with the Medicare secondary payment requirements of the law; Make the provisions for special enrollment periods for the disabled parallel to those in effect for the working aged. The statutory changes made by subsections 6202(b), (c), and (e) can be put into effect without first issuing regulations because it is clear on the face of the statute what the Congress intended.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10109427 TI - Communicating with our patients. PMID- 10109428 TI - Review of Coulter JR Interpretive Report and manual blood film assessment. AB - The Interpretive Reporting feature of the Coulter JR, particularly suspect messages, was examined to determine instrument comparison with manual differentials and blood film assessment. Reliability of the Coulter JR instrument in identifying abnormal specimens was proven in the true positive rating obtained in this study. This emphasized the need to further investigate those specimens which generate suspect flags and supports the decision in our laboratory to include the presence of suspect flags as one of the criteria for manual differential and blood film assessment. The significant false negative rating shown by our study demonstrates that patient specimens may be categorized as normal by the instrument, when in fact some abnormality may be detected by manual assessment. This discrepancy was primarily due to an increase in absolute numbers of band cells. Good correlation was demonstrated between the Coulter JR histogram differential and the manual differential, exclusive of absolute monocytes. The instrument adds an important dimension to morphology quality control through comparative analysis of technologist-instrument results. PMID- 10109429 TI - Technological change and the medical technologist: a stress survey of four biomedical laboratories in a large tertiary care hospital. AB - Medical technologists from four clinical laboratories in a large teaching hospital were surveyed for their perceptions of occupational stress or job dissatisfaction concomitant with the advent of major technological and procedural change. Overall the data support the interpretation of excessive stress and job dissatisfaction. More than one-third (37.7%) of the laboratory personnel experienced psychological symptoms of occupational stress; 46.4% had experienced physical symptoms of stress. There was a marked and significant increase in reports of adverse effects among the group of laboratory workers subjected to the most extensive technological changes. Main components of the stress difference related to work overload, feelings of uncertainty in the face of new technology, lack of direction from supervisors and lack of influence on management. Age, type of shift worked and years of employment were associated with physical and psychological manifestations of stress. Implications and recommendations for laboratory workers, hospital administrators and educators are discussed. PMID- 10109430 TI - WHMIS (Workplace Hazardous Materials Information System) II--The sequel. PMID- 10109431 TI - Lower drug prices may trigger increase in cost of services. PMID- 10109432 TI - Assisted living comes of age. New association pursues ambitious agenda. PMID- 10109433 TI - Colorado's incentive allowance entices out-of-state operators. PMID- 10109434 TI - Congregate care provider sizes up assisted living. PMID- 10109436 TI - The beginning of a beautiful relationship. How to recruit top talent. PMID- 10109435 TI - Balancing an assisted living budget. Attention to detail facilitates planning and operations. PMID- 10109437 TI - Facing change and making choices. PMID- 10109438 TI - Increase family involvement in care planning. PMID- 10109439 TI - Quality vs. cost: prolonging life for the elderly. PMID- 10109440 TI - Publishing a newsletter enhances visibility. PMID- 10109441 TI - Current statistics on AIDS. PMID- 10109442 TI - Getting comforted by communication in the '90s. AB - The benefits scene is full of troubling, confusing changes. Employees need effective, "comforting" communication to help them understand these changes, Ms. Rhodes observes. PMID- 10109443 TI - Ambulance trends for the '90s. AB - The changing profile of the EMS professional--with increased access to technology, better education and more experience--has dictated that ambulances, too, evolve along with the profession. How will ambulances change over the next decade? EMS recently asked some of the industry's leading manufacturers for their predictions. PMID- 10109444 TI - Rapid rescue: the Illinois tornado. PMID- 10109445 TI - Housekeepers suffer highest sharp-object injury rate. PMID- 10109446 TI - Ten steps to improve morale and reduce turnover. PMID- 10109447 TI - D.I.B.S.--drop in the bucket system. PMID- 10109448 TI - Plan now, plan well and then, pray it doesn't happen! PMID- 10109449 TI - Fire risk analysis: general conceptual framework for describing models. AB - A general conceptual framework has been developed as an aid to discussions of alternative approaches to fire risk analysis. The purpose is to show how each alternative seeks to address a few common concerns. Basic concepts and key elements--notably scenario structures, appropriate probability functions, and security and outcome measures--are defined and discussed, as are types of modeling approaches. A number of diverse examples are then presented using the framework to illustrate its value in making comparisons. PMID- 10109451 TI - Solving the labor problem & containing costs, Part I. PMID- 10109450 TI - Fuel loads in U.S. cities. AB - Sources of burnable material within U.S. cities are analyzed. Based on a detailed evaluation of construction practices, storage of burnable contents, building function and layout, and density of buildings in city districts, we derive urban fuel load densities in terms of land use type and geographic location. Residential building fuel loads vary regionally from 123 to 150 kg m-2; nonresidential building classes have loads from 39 to 273 kg m-2. The results indicate that average U.S. urban area fuel loads range from 14 to 21 kg m-2. PMID- 10109452 TI - Flaws & fallacies of performance evaluations. PMID- 10109453 TI - Self-management: your key to success as a supervisor. AB - To the supervisor, self-management is an essential part of management within the organization, and self-improvement, the process of changing one's self for the better, is an unending part of self-management. To enjoy long-term success in changing the way you approach the supervisory job, follow these guidelines: Do not try to accomplish too much too soon. Many of the best intentions have fallen by the wayside because someone tried to accomplish massive change in a few days or weeks. Recognize the power of habit and appreciate the difficulty of altering behavior that has long since become second nature to you. Rely on continual self reinforcement to maintain your progress in your newly chosen direction. Push yourself to the extent necessary and recognize that success in keeping yourself moving in constructive directions also confirms that you have the self-starting ability necessary for success in management. Self-management provides the soundest foundation for management itself. Common sense suggest that those who succeed in effectively managing others are those who have first learned how to effectively manage themselves. PMID- 10109454 TI - Building productive relationships with movers and shakers. AB - Movers and shakers often demonstrate capabilities that health care managers should recognize before attempting to build productive relationships with them. First, the charisma associated with outstanding leaders is reflected in superior communication skills and presence. Next, a broad experiential base coupled with penetrating analytical skills allows movers and shakers to earn exceptional authority and power. Third, movers and shakers are able to focus on strategic visions. Movers and shakers work through other team members to select and implement solutions that are consistent with organizational mission statements. Fourth, their entrepreneurial mindset enables them to take calculated risks and design creative solutions in response to formidable challenges. Finally, movers and shakers are not reticent to face facts and make tough decisions. Not all movers and shakers possess all of these characteristics equally. Nor are they all concerned about the same issues. As individuals, they bring differing interests and capabilities to health care organizations. Health care managers may strive to cultivate one or more of these characteristics themselves. Self-improvement begins with identifying personal deficiencies and systematically planning to overcome them. Until health care managers mature into movers and shakers, they can coopt the influence and power associated with movers and shakers. By establishing a trusting relationship and using borrowed power constructively, they can earn the respect and confidence of movers and shakers. A third approach promotes power transfer through a continuing viable relationship. Health care managers may need to use some combination of these methods. Additionally, they can consider tailoring various methods into a coordinated strategy. Health care managers have a variety of promising strategies available for building productive relationships with movers and shakers. Pursuit of these strategies may improve personal prospects and promote the achievement of organizational missions and objectives. PMID- 10109455 TI - The psychological impact of the head nurse manager in transition: organizational roles for minimizing stress. AB - The role of the head nurse continues to expand within the contemporary health care system, and the impact of that role will seriously affect the financial viability of health care organizations. Therefore, it is apparent that these organizations must reevaluate this role in relationship to its goals and objectives. They must also adopt strategies to select the appropriate individual for the particular job and provide sufficient training for successful management behaviors. The organization that expects its novice managers to hit the ground running must prepare these managers to clear the high hurdles, endure the marathons, and sprint to the finish line. PMID- 10109456 TI - Identifying and correcting the leniency factor in health care employee performance appraisals. PMID- 10109457 TI - How does an HMO decide whether to create its own home health care agency or contract out for services? PMID- 10109458 TI - Nurses' perceptions of temporary nursing service agencies. AB - Temporary staffing agencies have indeed carved out a role for themselves, and our free enterprise system lends itself to the perpetuation of the entrepreneurial spirit in all: nurses, agencies, and hospitals alike. It is wiser to learn to work with current structure realizing that supply and demand plays an important role in the survival and success of agencies. Although there are problems associated with temporary nursing staffing, they are surmountable. Orientation programs, performance monitoring, ensuring accountability of both nurse and agency are but a few that can enhance utilization and quality of service. PMID- 10109459 TI - Managerial work behavior and hierarchical level: implications for the managerial training of first-line supervisors. AB - Mintzberg proposed that managers at all levels enact ten roles. There is, however, a relative importance ascribed to the various roles given the manager's location in the hierarchy. Like Mintzberg's ideas on the utility of ten roles, we found that managers at all levels, to varying degrees, need the three skills proposed by Katz. We have argued that a variety of roles and skills describe what managers do. At the same time, the predominance of one role or skill over another may be influenced by the location of the manager in the hierarchy. The question is not whether roles would be enacted at different levels or whether skills will be required, but whether one role or skill or a set of roles and skills will be predominant for the first-line supervisor. The first-line supervisor's work requires that he or she be predominantly proficient in the areas of human and technical skills in order to fulfill supervisory responsibilities. Current empirical research supports this assertion; however, the continuing study of managerial roles and skills and other variables such as functional specialty will offer other opportunities for the study of first-line supervisors. For example, will the predominance of the roles and skills that we have discussed vary if the supervisor is a line or staff manager or if the supervisor works in a production or service related organization? Organizations adapt to change to meet the expectations of those within and outside the organization with something at stake. Organizations need managers to facilitate the realization of organizational goals, so organizations need to continuously train managers, targeting appropriate roles and skills given each manager's location in the hierarchy. The preceding pages should provide resource materials to individuals and organizations interested in evaluating and designing the training and development of first-line supervisors. This roles-and-skills information can be productively utilized to assist the organization with its management training, particularly of first-line supervisors. PMID- 10109460 TI - A supervisor asks: "Second-hand complaints.". PMID- 10109461 TI - Insurers will force look at quality for payments. PMID- 10109462 TI - Sales force can lead to dollars for OH (occupational health) services. AB - As hospitals enter the 1990s, one of the challenges they will face is finding additional sources of revenue. Occupational Health (OH) programs offer an opportunity for increased dollars--but only for hospitals willing to use sales tactics common to corporate America. In the following article, the author tells how an institution can sell OH services. PMID- 10109463 TI - CQI (continuous quality improvement) system puts process into improving hospital. AB - Hospital departments in the 1990s will be increasingly called on to run efficiently if institutions are to improve their bottom lines. But, how do administrators address problems that interfere with workflow and completing jobs? In the following article, the author introduces a quality process to identify and deal with those issues. PMID- 10109464 TI - Report on internal medicine finds internists discouraged. PMID- 10109465 TI - Planning indicators. Ten-year hospital trends reveal latest AHA findings. PMID- 10109466 TI - Baylor opens $20 million Landry Sports Medicine Research Center in Dallas. PMID- 10109467 TI - Florida outreach fits plan. Interview by Donald E. L. Johnson. PMID- 10109469 TI - The performance measurement manifesto. AB - The leading indicators of business performance cannot be found in financial data alone. Quality, customer satisfaction, innovation, market share--metrics like these often reflect a company's economic condition and growth prospects better than its reported earnings do. Depending on an accounting department to reveal a company's future will leave it hopelessly mired in the past. More and more managers are changing their company's performance measurement systems to track nonfinancial measures and reinforce new competitive strategies. Five activities are essential: developing an information architecture; putting the technology in place to support this architecture; aligning bonuses and other incentives with the new system; drawing on outside resources; and designing an internal process to ensure the other four activities occur. New technologies and more sophisticated databases have made the change to nonfinancial performance measurement systems possible and economically feasible. Industry and trade associations, consulting firms, and public accounting firms that already have well-developed methods for assessing market share and other performance metrics can add to the revolution's momentum--as well as profit from the business opportunities it presents. Every company will have its own key measures and distinctive process for implementing the change. But making it happen will always require careful preparation, perseverance, and the conviction of the CEO that it must be carried through. When one leading company can demonstrate the long-term advantage of its superior performance on quality or innovation or any other nonfinancial measure, it will change the rules for all its rivals forever. PMID- 10109468 TI - Championing change: an interview with Bell Atlantic's CEO Raymond Smith. Interview by Rosabeth Moss Kanter. PMID- 10109470 TI - The case of the team-spirit tailspin. AB - Richard Johnson, newly appointed president of Century Airlines, knew the company's survival depended on customer service, which in turn depended on motivated employees. So he created the Century Spirit program to build team spirit by encouraging employee participation, individual initiative, and open communication. Among the program's early successes was a newspaper started by a group of flight attendants. The Plane Truth published information about benefits and work conditions as well as feature stories and humorous articles. It quickly became popular not only with flight attendants but also with pilots, machinists, and baggage handlers. As time went on, though, the Plane Truth began to run articles critical of the company. When management cut back workers' hours, the newspaper questioned what sacrifices the executives were making. When technical services released figures showing long turnaround times, the paper questioned the machinists' work ethic. Worried that customers might see the newspaper, Richard Johnson wanted to cancel it. The president of the flight attendants union also wanted to see it go because it was stirring up trouble with the machinists. Joan Raffin, Century's human resources director, was asked to stop the publication. But she hesitated. She knew that employee morale was on the brink, but she didn't know whether the newspaper was venting workers' frustrations and reinforcing team spirit or stirring up old animosities and bringing the whole company down. Was it creating more tension than unity or vice versa? Experts on organizational change, motivation, and management analyze the situation and make recommendations for what Joan Raffin should do. PMID- 10109472 TI - The turnaround value of values. AB - John Thorbeck is an executive with a ten-year career history of successes--and a sense of repeated failure. Just out of business school, he was marketing director at the Aspen Skiing Company for three years and helped to reverse thirteen seasons of decline. At the Timberland shoe company in the mid-1980s, he led a marketing strategy that tripled sales. At the Bass shoe company, where he was CEO from 1987 to 1990, he took the company from big losses to big profits. Now he is president, CEO, and part owner of a third shoe company--Geo. E. Keith--that is surely the oldest, perhaps the smallest, and arguably the finest shoemaker in the United States. But the high points of Thorbeck's resume conceal a leadership education that led him only slowly to abandon confrontational management in favor of management by history, values, competence, and what he calls organizational coherence. In his first two marketing jobs, he fought wars with his opponents and won. Then at Bass, he tried to recapture the company's proud past. He revived company folklore and history, gave workers back their pride in workmanship, and used this rejuvenated company spirit to meet and win new markets. Yet he was trying to take Bass someplace its owners simply wouldn't let it go, and he left the company profitable but divided, the work force eager to go one way, owenership another. In each of his jobs, Thorbeck overlooked some vital part of the organizational community.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10109471 TI - Ways men and women lead. PMID- 10109473 TI - Marketing is everything. AB - Technology is creating customer choice, and choice is altering the marketplace. Gone are the days of the marketer as salesperson. Gone as well is marketing that tries to trick the customer into buying whatever the company makes. There is a new paradigm for marketing, a model that depends on the marketer's knowledge, experience, and ability to integrate the customer and the company. Six principles are at the heart of the new marketing. The first, "Marketing is everything and everything is marketing," suggests that marketing is like quality. It is not a function but an all-pervasive way of doing business. The second, "The goal of marketing is to own the market, not just to sell the product," is a remedy for companies that adopt a limiting "market-share mentality." When you own a market, you lead the market. The third principle says that "marketing evolves as technology evolves." Programmable technology means that companies can promise customers "any thing, any way, any time." Now marketing is evolving to deliver on that promise. The fourth principle, "Marketing moves from monologue to dialogue," argues that advertising is obsolete. Talking at customers is no longer useful. The new marketing requires a feedback loop--a dialogue between company and customer. The fifth principle says that "marketing a product is marketing a service is marketing a product." The line between the categories is fast eroding: the best manufacturing companies provide great service, the best service companies think of themselves as offering high-quality products. The sixth principle, "Technology markets technology," points out the inevitable marriage of marketing and technology and predicts the emergence of marketing workstations, a marketing counterpart to engineers' CAD/CAM systems. PMID- 10109474 TI - Even closer to the customer. PMID- 10109476 TI - Tips on conducting pre-employment criminal and honesty checks. PMID- 10109475 TI - Preventing wheelchair theft. AB - With the cost of replacing a wheelchair estimated at $500 to $700, hospitals are eager to make it more difficult for would-be thieves to steal this piece of essential equipment. In this report, we will describe the steps several hospitals are taking to prevent wheelchair theft and the devices available to make such theft more difficult. A wheelchair inventory control form is also included. PMID- 10109477 TI - Gang violence in hospitals: how four hospitals are handling it. PMID- 10109478 TI - An interview with: John R. Hall, Jr. on fires and the elderly. PMID- 10109480 TI - Negotiating your contract. PMID- 10109479 TI - Emergency room violence: an update. AB - Since our last special report on emergency room violence (see the report in our August 1989 issue) in which we warned of the growing threat of drug-induced behavior, the rate of drug-related emergency room visits continues to rise and has become a major cause of ER violence in many cities. As serious as this development is, there are a number of other causes of ER violence that continue to threaten the security of ER staff, patients, and visitors, as well as the hospital's ability to provide effective emergency medical care. In this update, we'll visit three hospital ERs that truly have been on the violence firing line. We'll speak to both security directors and ER directors. We'll learn how they are dealing with the daily (and nightly) challenges, the options that confront them, and the decisions they are making. PMID- 10109481 TI - JCAHO scoring guidelines. PMID- 10109482 TI - Cash handling procedures. PMID- 10109483 TI - Assuring that you have the right people. Step 2: The interview. PMID- 10109484 TI - Recruiting physicians for small and rural hospitals. Guidelines for attracting, screening, and hiring the best candidates. AB - The unique challenges of rural practice and the general shortage of rural M.D.s make physician recruitment in such areas a daunting prospect. However, as outlined here, an emphasis on the advantages of small-town practice and a thoughtful and organized recruiting strategy will increase the odds in everyone's favor. PMID- 10109485 TI - Trends in hospital deductions from revenue. Increases in uncompensated care and payment adjustments. AB - The 1980s produced tighter restrictions on Medicaid eligibility, greater reluctance among insurers to cover small groups, and increased price competition, resulting in a larger percentage of unreimbursed charges. Here the authors use financial data from a cross-section of California hospitals to explore the extent and variation of such deductions from revenue. PMID- 10109486 TI - The manager's right to fail. AB - Positioned as they are between administration and staff, hospital middle managers are especially vulnerable to risks, failures, and the emotions and stress that accompany them. "Failure," however, is a relative term, and turning failure into success chiefly entails a change in perspective and an acceptance of the manager's right to make mistakes. PMID- 10109487 TI - The dynamics of hospital leadership. Defining what it takes to survive. AB - Leadership is a combination of tangible and intangible qualities that is becoming extra-important to hospitals' survival. With an eye to the future of healthcare, the authors present an overview of the characteristics, styles, and challenges of the leader. In an upcoming issue, the authors will discuss organizational survival. PMID- 10109488 TI - Hospitals' ethical responsibilities. Assisting the impaired physician. PMID- 10109489 TI - Interruptions and crises. PMID- 10109490 TI - Female healthcare managers and the glass ceiling. The obstacles and opportunities for women in management. AB - Despite the large number of women in the healthcare field, healthcare management resembles other industries in its severe lack of women in upper-management positions and in the "glass ceiling" that contributes to this dearth. Although not enough has been specifically written on women healthcare managers, the author reviews what is available, along with some of the general management literature. PMID- 10109491 TI - Next stop 21st century: a look at the future as an extension of the past. AB - This comprehensive forecast of the 21st century reinforces the continuing importance of information and its management. Although focused toward association executives, readers should find much of the discussion of particular relevances. PMID- 10109492 TI - High stakes copying--the healthcare manager's guide to correspondence copying services. PMID- 10109493 TI - Clearing away cobwebs. PMID- 10109494 TI - Towards the vales of health. PMID- 10109495 TI - Making the IT (information technology) jigsaw fit. AB - Providers will need good information systems to survive in the internal market. In the first of the Journal's regular special features on computing (to appear in the last week of every month) we examine the strategic issues facing hospital managers investing in information technology, and look at two very different approaches to harnessing IT--one of which is a sophisticated hospital management package, the other a rough and ready early warning system. PMID- 10109496 TI - Taking to TIPPLES. PMID- 10109497 TI - Early warning system. PMID- 10109498 TI - Rough but ready. PMID- 10109499 TI - Paying for goods that were 'free'. PMID- 10109500 TI - Lessons in protocol. PMID- 10109501 TI - Healthcare data briefing. Unpaid care. PMID- 10109502 TI - The caring card--but is it 'smart' enough? PMID- 10109503 TI - Love nursing, hate the job. PMID- 10109504 TI - A way through the maze. PMID- 10109505 TI - Knowing your market. PMID- 10109506 TI - Leading from the front. PMID- 10109507 TI - Targeting the discontented. PMID- 10109508 TI - Planning the unpredictable. PMID- 10109510 TI - Estates. New designs, old values. PMID- 10109509 TI - Ring the changes softly. PMID- 10109511 TI - Estates. Cold reality, hot topic. PMID- 10109512 TI - Patient controlled analgesia: drug options, infusion schedules, and other considerations. AB - Patient controlled analgesia (PCA) has a number of advantages compared with traditional methods of pain management. Some of these advantages include superior pain relief, less sedation due to superior drug titration, increased psychological satisfaction due to patient control of pain management, individualized analgesic dosing, decreased staff time for patient care, and increased patient activity and mobility. Although a few cases of respiratory depression have been reported with the use of PCA, there is a relatively low risk of this complication in most patient populations. Appropriate candidates for PCA include terminally ill-cancer patients, postoperative patients, mentally clear and alert trauma patients, and patients who require massive doses of oral narcotics to control pain but are experiencing intolerable side effects. This article focuses on the principles involved in selecting the optimal analgesic and the therapeutic variables involved in using PCA. PMID- 10109513 TI - A trial of the use of bar code technology to restructure a drug distribution and administration system. AB - As we move into the 1990s, the challenges we face are many. Our ever-changing health care industry is giving managers, directors, and administrators much to ponder: how do we reduce costs and improve patient care? One promising area that may help answer this question in pharmacy services is bar code technology. This article offers helpful advice about the development of bar code and drug delivery systems and discusses the future applications of bar code technology in pharmacy practice, based on 3 years of hands-on experience at Florida Medical Center. PMID- 10109514 TI - Disease audits and drug usage evaluation: future performance evaluation tools for pharmaceutical care? PMID- 10109515 TI - Private involvement can prejudice tax-exempt financing. PMID- 10109516 TI - Health care providers can avoid negligent hiring claims. PMID- 10109517 TI - Protecting personal assets of health care providers. PMID- 10109518 TI - Physician manpower politics in Sweden. PMID- 10109519 TI - The political dynamics of physician manpower policy. The case of Spain. PMID- 10109520 TI - The political economy of medical underemployment in Mexico: corporatism, economic crisis and reform. PMID- 10109521 TI - Medical specialist manpower planning in The Netherlands. PMID- 10109522 TI - Medical manpower in Israel: political processes and constraints. PMID- 10109523 TI - The history and future of physician manpower development in the Federal Republic of Germany. PMID- 10109524 TI - The politics of the U.S. physician supply. PMID- 10109525 TI - Medical manpower planning: dynamics without direction. PMID- 10109526 TI - Towards a concept of bounded rationality. PMID- 10109527 TI - The political dynamics of physician manpower policy. Synthesis and prospects. PMID- 10109528 TI - The political dynamics of physician manpower policy. International Conference held 24-27 May 1988 at the King's Fund Centre in London, England. PMID- 10109529 TI - The debates on the numbers of physicians. PMID- 10109530 TI - The Canadian Hospital Executive Simulation System (CHESS). AB - The Canadian Hospital Executive Simulation System (CHESS) is a computer-based management decision-making game designed specifically for Canadian hospital managers. The paper begins with an introduction on the development of business and health services industry-specific simulation games. An overview of CHESS is provided, along with a description of its development and a discussion of its educational benefits. PMID- 10109531 TI - Patient counseling services: a multidisciplinary department. AB - Most contemporary urban hospitals in Canada provide social services, pastoral care and psychological services, usually in separate departments. The similarities in many of the services provided by these three professions has often been noted, along with the observation that organizational restructuring could support such collaboration. The Misericordia Hospital, Edmonton, has amalgamated social services, pastoral care, psychological services and the pastoral institute into the Department of Patient Counselling Services. Its main purpose is to allocate more resources to direct patient care and enhance interdisciplinary collaboration. PMID- 10109532 TI - Comprehensive auditing systems: potents, possibilities and promises in the health care sector. AB - This paper examines key issues of comprehensive audit systems in health care in Canada. The concept of comprehensive auditing preparedness is explored and a synopsis of the central challenges are presented. The need for sound accountability structures, strategic effectiveness targets and effectiveness control systems in health care facilities as solid management building blocks is underlined. PMID- 10109533 TI - Getting together: administrative and clinical teamwork creates a geriatric care program for the hospital. AB - Sunnybrook Medical Centre, Toronto, has designed a written, multidisciplinary program of care for elderly patients in acute care. The program includes specific community outreach activities that support the in-hospital program and addresses the challenges presented by an increasingly aged population. Some of its objectives are to develop a measurement for length of stay patterns, a reduction in the number of patients waiting for relocation to a long-term care institution (commonly and derogatorily referred to as "placement problems") and an increase in patient, family and staff satisfaction. A method for program evaluation is being designed. The program takes a three-level approach to care: (1) the non problematic elderly patient, (2) the more complex elderly patient and (3) the care of patients who have finished treatment for their acute illness but who require long-term care institutionalization. PMID- 10109534 TI - Utilization management: a literature review for Canadian health care administrators. AB - Utilization management (UM), the attempt to measure, understand and reduce inappropriate hospital use, has been in development for over 20 years. It is an outgrowth of two related phenomena: (1) the increasing responsibility of large institutional third party payers for health care costs and the increasing demand of those payers for accountability; and (2) in Canada, particularly, the debate surrounding the adequacy of hospital funding and the perceived inadequacy of cost control using global budgeting. Given the interest in UM, hospital administrators, provincial and federal associations representing hospitals, hospital employees and physicians would find a review of UM programs useful in terms of what is known about their effectiveness, and the specific initiatives in Canada. The authors underscore the critical need for formal evaluation of UM programs; to date there has been little systematic research into issues related to its implementation and impact. This issue is particularly pertinent because UM programs have not been widely implemented in Canada. PMID- 10109535 TI - Lighting for the aging eye. PMID- 10109536 TI - Training systems. You get what you plan for or not, as the case may be. PMID- 10109537 TI - Walking the tight rope of career planning--a vital skill. Interview by Alison Hyde. PMID- 10109538 TI - Zen and the art of management excellence. PMID- 10109539 TI - Why stress is a management issue. PMID- 10109540 TI - What makes good practice in the use of women returners? PMID- 10109541 TI - Why potholes and sprained ankles await health authorities handling of negligence claims. PMID- 10109542 TI - Looking forward to the future. Interview by Alison Hyde. PMID- 10109543 TI - Pay determination--how the Canadians do it. PMID- 10109544 TI - Generic drug prices may rise 8-10%. PMID- 10109545 TI - IMS updates HMM's med-surg indexes. PMID- 10109546 TI - HMM pricing index/price watch. PMID- 10109547 TI - Hospital materials managers should recognize and promote their roles in their institutions. AB - The hospital board has instructed the hospital administrator to make a study that will lead to a better organization of the lines of responsibility and authority within the hospital. The administrator has asked the materials manager to make recommendations as to where materials management should fit into the organizational structure of the hospital. In this dialogue, Dr. Decker speaks to the place of materials management in the internal organization of the hospital. PMID- 10109548 TI - Medicare: a strategy for quality assurance. AB - This paper has outlined a strategy proposed by an IOM study committee for a quality review and assurance program for Medicare. The committee intended that such a program respond to several major issues, including: the burdens of harm of poor quality of care (poor performance of clinicians in both technical and interpersonal ways, unnecessary and inappropriate services, and lack of needed and appropriate services); difficulties and incentives presented by the organization and financing of healthcare; the state of scientific knowledge; the problems of adversarial, punitive, and burdensome external QA activities and the need to foster successful internal, organization-based QA programs; the adequacy of quality review and assurance methods and tools; and the human and financial resources for quality assurance. In comparison with the existing federal peer review organization program, the IOM's proposed program is intended to focus far more directly on quality assurance, cover all major settings of care, emphasize both a wide range of patient outcomes and the process of care, and have a greatly expanded program evaluation component and greater public oversight and accountability. In laying out the details of such a program, the IOM committee advanced 10 recommendations to support its proposed program. Two of these call for the Secretary of DHHS to support and expand research and educational activities designed to improve the nation's knowledge base and capacity for quality assurance. Finally, the committee emphasized both the extraordinary challenges of quality assurance and the diversity of support for addressing those challenges, noting that patients, providers, and societal agents all have a responsibility in this regard. Building the nation's capacity through additional research and expanded educational efforts is a major cornerstone of the entire enterprise. PMID- 10109549 TI - QA vs. QI (quality improvement): the changing role of quality in health care. PMID- 10109550 TI - Reporting on QA activities at the time of reappointment. PMID- 10109551 TI - The quality assurance program at Affiliated Hospitals of Indiana, Inc. PMID- 10109552 TI - Risk management in a psychiatric hospital: Wichita Falls State Hospital. PMID- 10109553 TI - Total management, not total quality management. AB - Part I: "The Quality Problem is Real." Hospitals fail because of management. This failure is primarily a result of a lack of a total management (TM) approach. This leads to a crazy quilt of individual add-on programs and projects which struggle to survive in a management climate of constant crisis and reactivity. Worthy initiatives like total quality management (TQM) are at high risk in such organizations and run the risk of failure. Part II: "The Need for Total Management." In order for quality improvement efforts to succeed, there must first be a reorientation of the organization's management approach and culture. What is needed is organization development which reorients the hospital to TM. This New American Hospital creates the foundation for specific change tools such as TQM. PMID- 10109555 TI - Hospital-physician relationships in the 1990s. PMID- 10109554 TI - Quality assurance not equal to quality improvement. AB - The intent is not to be critical and the misconceptions are easy to understand. The verbiage related to QI and QA sound alike. Quality improvement is not an easy undertaking for any industry. Some industries have tried QI and failed, while others have tried with admirable successes (e.g., Ford, Florida Power and Light, Motorola). The undertaking of the successful programs has not been easy or painless. QI requires extensive education, change of management philosophy and re evaluation of our organizational structure. For QA professionals this transition will not be easy or painless . We must first accept that the terminology sounds similar but that the definitions are different. We must accept that our prior processes are far from perfect and can improve. As QA professionals, we must accept that the time is here to learn and to improve. We must begin by improving those processes which we own. This effort must coincide with identification of our customers and implementing systematic mechanisms for identifying their needs and expectations. Through energy expenditure and analysis of data over time, we can improve our processes and ultimately improve the output of our efforts. Only after we have learned QI processes, practiced them through daily application, and improved them can we begin to think about applications of QI to clinical process. After we expend the energy to learn about QI and apply it daily, we will be among the informed. QA professionals must prepare for and learn to value this change. Quality improvement and its technology represents a concept which may truly improve America's healthcare.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10109556 TI - Medical staff development strategies for the 1990s. AB - The next five years will be critical. A hospital can 'make its market' with bold initiatives with its physicians,s or lose market share and referrals to a more proactive competitor. Take an active posture in hospital-physician relations. Here are five promising approaches to developing a strong, committed relationship between a hospital and its key physicians. PMID- 10109557 TI - Health care in Finland. PMID- 10109558 TI - Providing quality care. PMID- 10109559 TI - Pioneering planning agreements. PMID- 10109560 TI - Pay flexibility and the NHS. PMID- 10109561 TI - The design of buildings. PMID- 10109562 TI - Evaluating health care services. PMID- 10109564 TI - Macau: a unique challenge in the management of health. PMID- 10109563 TI - Business planning: new wine in old bottles? PMID- 10109565 TI - Patient-focused hospital. PMID- 10109566 TI - Major building on a hospital site: enabling works. PMID- 10109567 TI - Lowell E. Bellin: writings and commentary. PMID- 10109568 TI - The politics of ambulatory care. PMID- 10109569 TI - Dr. Bellin's abiding message for health care managers. PMID- 10109570 TI - The association between community physician's attendance at a medical center's CME courses and their patient referrals to the medical center. AB - This study attempts to quantify an overall association between CME course attendance and referrals. Attendance at formal CME courses given by the University of Michigan Medical School and referrals to the University Hospitals were examined over a two-year period. Attendance and referrals were linked to physicians in Michigan identified through the Michigan Department of Licensing and Regulation and through the American Medical Association. For physicians who are office-based and likely to be in active practice (age less than 70), those who attended at least one of the University's CME courses referred more patients than those who did not attend one (means of 1.9 referrals per physician and 1.3 referrals per physician, p less than .001). The causal direction of the relationship is not clear, but probably operates in both directions. It is reasonable for medical center marketers to consider CME as an indirect method for marketing clinical services. It is also reasonable for CME directors to identify referring physicians as high-priority groups for marketing CME. Both marketing efforts may be significantly enhanced by linking data bases for referrals and for CME attendance. CME directors must also ensure that marketing efforts do not compromise the objectivity and integrity of the content of the institution's CME program. PMID- 10109571 TI - Exploring the effects of leadership behavior and task characteristics on burnout in a health care center. PMID- 10109572 TI - Ambivalence by public administrators towards contracting for health and human service delivery. PMID- 10109573 TI - Implementation planning for a neuro-behavioral unit in a public health hospital. PMID- 10109574 TI - Can you practice properly without a cellular phone? PMID- 10109576 TI - Why I want patients to write out their complaints. PMID- 10109575 TI - So you're selling out to a hospital. Caveat doctor! PMID- 10109577 TI - "We can't kill your mother". PMID- 10109578 TI - When PROs themselves are reviewed. PMID- 10109579 TI - You can't escape the living-will issue. PMID- 10109580 TI - Who'll win this high-stakes battle over privileges? PMID- 10109581 TI - Negotiating and analyzing managed care contracts. AB - Despite some uneven performance in the 1980s, health maintenance and preferred provider organizations are here to stay. Author Keith Korenchuk believes that negotiating satisfactory managed care contracts will become increasingly important in the next decade and he offers several suggestions to reach this goal. PMID- 10109582 TI - Multispecialty groups: will they survive prepaid managed care? PMID- 10109583 TI - Responding to managed care proposals. AB - To continue to use the term alternative delivery systems in relation to managed care is inappropriate, writes Darrell Schryver, D.P.A., since these systems are rapidly becoming the predominant method for delivering health care. Because such managed care programs are administered by individuals trained in business, it is imperative that medical practices adopt a similar business attitude to negotiate advantageously with these programs. PMID- 10109584 TI - Primary care providers: managing today's prepaid risk. AB - Participating in managed care systems involves the issues of enrollment, marketing, referral patterns and information systems among others. The most important aspect, writes David Kouba, is reimbursement. Kouba offers several ideas for successfully managing the associated risk. PMID- 10109585 TI - Meeting the challenge of managed care. AB - A proliferation of managed care organizations in the St. Louis area, each initiating its own operating policies and procedures, presented a serious management and operations problem for the St. Louis University School of Medicine. Author Cynthia Bodewes, et. al., describes the steps taken by her organization to successfully deal with this dilema. PMID- 10109586 TI - How to be your own consultant. Improving your operations and control. AB - For your group to attain peak performance, you as an administrator must focus on long-term operations rather than short-term demands, writes author Will Latham. Finding time to focus on the long-range operational improvements necessary for your group is tough, but the potential benefits in terms of cost savings and revenue enhancements make the effort worthwhile. PMID- 10109587 TI - Developing a physician compensation plan. AB - Southern Ohio Health Services Network was founded in 1976 as a non-profit corporation to address the lack of accessibility to primary care physicians in four rural southern Ohio counties. The majority of recruited physicians are obligated to fulfill service obligations as a result of NHSC scholarships. Author Stephen Wilhide, M.S.W., M.P.H., describes how the organization improved its physician retention rate through a carefully devised compensation program. PMID- 10109588 TI - Computerization: key to a successful QA program. PMID- 10109589 TI - The 'doer syndrome': major hazard for lab supervisors. PMID- 10109590 TI - Software choices for today. PMID- 10109591 TI - Self-scheduling can increase job satisfaction. PMID- 10109592 TI - Giving blood donation a stamp of approval. PMID- 10109593 TI - Putting on gloves in the fight against AIDS. PMID- 10109594 TI - Abnormal hematology patients: flagged and not forgotten. PMID- 10109595 TI - Creating Levey-Jennings charts on a PC. PMID- 10109596 TI - How employees survived a major lab merger. PMID- 10109597 TI - Marketing your lab's services more effectively. PMID- 10109598 TI - Overlooked aspects of employee orientation. PMID- 10109599 TI - Turnover rate for clinical lab managers. PMID- 10109600 TI - Organizing the functions of the lab management team. PMID- 10109601 TI - Which PC to buy now. PMID- 10109602 TI - The growing crackdown on laboratory fraud and abuse. PMID- 10109603 TI - When MTs mind the Paps: QA for send-out tests. PMID- 10109604 TI - Helping the plateaued employee reach a new level of confidence. PMID- 10109605 TI - A community cholesterol screen: five days, 8,656 tests. PMID- 10109606 TI - Walking the new-supervisor tightrope. AB - Hospitals have traditionally expected technologists to learn supervision on their own. Here's a mini-seminar to help brand-new supervisors maintain that delicate balance. PMID- 10109607 TI - Utility software programs to unclutter your PC. PMID- 10109608 TI - AIDS: the cost of universal precautions. PMID- 10109609 TI - Supreme Court declines to cap punitive awards. PMID- 10109610 TI - Phoenix system adopts drug tests for new workers. PMID- 10109611 TI - GE Medical, R Squared settle suits. PMID- 10109612 TI - Hospitals hit with higher drug costs. PMID- 10109613 TI - HME groups discuss merger. PMID- 10109614 TI - Mercy buyer group to be AmHS liaison. PMID- 10109615 TI - M.D. referrals clarified. PMID- 10109616 TI - Providers form coalition to fight proposed Medicare cuts. PMID- 10109617 TI - Exec-turned-patient gets overdose of managed care. PMID- 10109618 TI - Healthcare construction survives ailing economy. Architects, contractors see building demand for outpatient-care projects. AB - Capital for healthcare construction is tight and is likely to get tighter, but other forces in the industry are expected to foster moderate growth in building projects. While an ailing economy has afflicted commercial construction in other sectors, extensive renovation work associated with healthcare mergers and consolidations and a renewed emphasis on hospital-based, ambulatory-care facilities are trends that will continue to translate into new construction projects, according to MODERN HEALTHCARE's annual Construction & Architects survey. PMID- 10109619 TI - U.S. companies competing for health business in Kuwait. PMID- 10109620 TI - Congressman introduces single-payer insurance plan. PMID- 10109621 TI - 2 insurer groups pitch their plans for affordability. PMID- 10109622 TI - Proposed standard likely to spark increase in electronic payments. PMID- 10109623 TI - Larger players caught up in HMO shakeout. PMID- 10109624 TI - Billings, Mont., medical center tickled to be a leader in RIBSAVRS (residual interest bonds, select auction variable rate securities) financing. PMID- 10109625 TI - Beverly prepares to buy Vantage. PMID- 10109627 TI - Humana completes Michael Reese acquisition. PMID- 10109626 TI - Capitol Hill Hospital closes acute-care beds. PMID- 10109628 TI - CFO average pay rises 31% since '88, survey shows. PMID- 10109629 TI - Ill. budget plan pares payments. PMID- 10109630 TI - N.M. weighs tax on not-for-profits. PMID- 10109631 TI - Baxter signs three stockless contracts. PMID- 10109632 TI - Bill would let providers waive military copayments. PMID- 10109633 TI - Healthcare employers prone to test for drugs--study. PMID- 10109634 TI - 2 of 37 St. Louis hospitals submit prices. PMID- 10109636 TI - Number of hospital closings drops despite experts' dire warnings. PMID- 10109635 TI - Truce called in Calif. nursing home war. PMID- 10109637 TI - Healthcare already may be getting fair treatment. PMID- 10109638 TI - Painful lessons. AB - In light of government proposals to radically reduce reimbursement for graduate medical education and because of increasing pressures from payers, America's teaching hospitals are turning to innovative strategies to make up shortfalls and accomplish more with less. While some managers are talking layoffs and other cost cutting moves, hospital groups are vowing to lobby hard in defense of GME funding. PMID- 10109639 TI - Knowing where to start is key to itinerary when marketing services abroad. AB - You could have a market for your hospital's excess capacity in other countries, especially Central and South America, the Caribbean and Canada. The man in charge of Tampa General's successful international marketing program has advice on how to start one up. PMID- 10109641 TI - Groups get peek at AHA's reform plan. PMID- 10109640 TI - The two (quality) faces of HCHP (Harvard Community Health Plan). AB - When it comes to total quality management, Harvard Community Health Plan has two personalities. It's using the principles espoused by such TQM gurus as Joseph Juran to reduce costs and improve quality in its clinics and offices. But HCHP also is enhancing its image in the healthcare industry by teaching TQM principles to others for big bucks. PMID- 10109642 TI - California hospital systems use not-for-profit foundations in pursuit of physician practices. PMID- 10109643 TI - Specialty providers getting paid sooner. AB - A recent revision in Medicare payment policy is leading to more prompt payment for specialty providers, which are reimbursed differently than most acute-care hospitals under an incentive/penalty system. The providers often face a wait of 12 to 14 months for some money due, a practice they have complained about for years. The revisions are the result of a lawsuit against HHS. PMID- 10109644 TI - Bill ties tax exemption to explicit charity-care rules. PMID- 10109645 TI - Task force to study emergency care. PMID- 10109646 TI - VHA to return $75 million to hospitals. PMID- 10109647 TI - Hospitals vow to fight general assistance cuts. PMID- 10109648 TI - Ky. law boosts hospital tax, adds levy to other providers. PMID- 10109649 TI - HMO sues Wis. to raise surplus requirement. PMID- 10109650 TI - Tenn. bill targets 'most-favored-nation' clauses. PMID- 10109651 TI - Stockholder hires investment banker to shop SMS around. PMID- 10109653 TI - Inflation, budget cuts diluting physician pay reforms--PPRC. PMID- 10109652 TI - Group plans to sell bonds to buy AMI Denver assets. PMID- 10109654 TI - Capitol Hill waking up to children's needs. PMID- 10109655 TI - FTC challenges proposed hospital acquisition in Ga. PMID- 10109656 TI - Nursing home wins tax fight; hospitals hopeful. PMID- 10109658 TI - Charter rejects Community Psych's $1.1 billion offer. PMID- 10109657 TI - Towns breathe new life into closed hospitals. AB - Most of the time, when a hospital closes, it closes for good. But once in a while the community is shocked into realizing it has to support the local hospital and use it, or it won't be around when they want it. Modern Healthcare profiles some of these rebirths, some vigorous and others still struggling. PMID- 10109659 TI - Ruling could enable hospitals to recoup millions from HCFA. PMID- 10109660 TI - Accidents detract from laser's potential. AB - Breakthroughs in laser applications to surgery have sparked interest in laser technology. But as equipment proliferates, so does the potential for malfunctions and operator errors. Serious accidents happen when such a powerful force goes astray. PMID- 10109661 TI - Massachusetts gets aggressive with antitrust enforcement. AB - The federal government isn't the only focus of stepped-up healthcare antitrust investigation. The Massachusetts attorney general office has initiated a series of lawsuits against healthcare organizations in one of the most aggressive state efforts in the nation. PMID- 10109662 TI - State execs want laws to decrease antitrust danger. PMID- 10109663 TI - Credit unions a safe bet for hospitals. AB - Though Rhode Island has had its troubles recently, credit unions are still a financially sound and popular employee benefit, experts said. A credit union costs a healthcare institution virtually nothing to sponsor, and the cooperatives are in much better shape than savings and loans. PMID- 10109664 TI - Deloitte completes capital pay model. PMID- 10109665 TI - Humana reports 14% earnings jump for second quarter. PMID- 10109666 TI - Columbia completes financing. PMID- 10109667 TI - Rehab firm to sell, lease back Ariz. facility. PMID- 10109668 TI - Back Medicaid pay squabble resolved. PMID- 10109669 TI - Mass. lawmakers delay mandate for health insurance. PMID- 10109671 TI - Calif. hospitals cut water usage. PMID- 10109670 TI - Parents of uninsured kids usually work--study. PMID- 10109672 TI - HealthVest suit set for trial. PMID- 10109673 TI - 'Pharmacy head untapped source of key expertise'. PMID- 10109674 TI - CHA sets rationing limits. PMID- 10109675 TI - 'Calif. resident conditions better'. PMID- 10109676 TI - Wrongful termination charges cited most often in D&O claims. PMID- 10109677 TI - AHA unit wants more pointed reform plan. PMID- 10109678 TI - Mission and Marlboros don't mix: group. PMID- 10109680 TI - Health bills pass before Congress rests. PMID- 10109679 TI - Paying attention to emergency care. AB - Most hospital emergency departments focus on increasing patient volume and improving payer mix to boost revenues and turn money-losing departments into winners. But experts said many hospitals overlook three other important management areas that can boost revenues in their emergency departments. PMID- 10109681 TI - Hospital extends benefits to gay couples. PMID- 10109682 TI - Changes in patient dumping law offer hospitals pluses, minuses. PMID- 10109683 TI - Optical disk testing opens hospital's eyes. AB - After six months of testing, Beth Israel Medical Center in New York City is ready to say "yes" to optical disk storage of medical records. Eventually, the system is expected to help eliminate storage costs for 4 million pieces of paper per year, microfilming costs of $200,000 per year and labor costs for pulling and refiling 700 charts every day. PMID- 10109684 TI - Dental group on offensive in fight with FTC. PMID- 10109685 TI - Trust, commitment key to board/CEO relations. AB - Hospital chief executive officers who set long-term strategy and business goals, communicate openly and honestly with their boards and work in partnership with their medical staffs are meeting the key expectations of trustees. Within these parameters lies the formula for successful board/CEO relations, hospital board chairmen say. PMID- 10109686 TI - ESOPs get mixed results as financing tool. AB - For three hospital chains that have used the employee stock ownership plan as a financing technique, the success rate is 2-1. Some experts say Health Trust--The Hospital Co. and Epic Healthcare Group are poised for success because they've adopted the employee-ownership idea in everyday activities. Charter Medical Corp. has been criticized for not doing enough to involve employees. PMID- 10109687 TI - 'Bolster charity with Medicaid monies'. PMID- 10109688 TI - Mass. gov. continues push to scrap mandated coverage. PMID- 10109689 TI - Mich. Blues may owe Medicaid millions. PMID- 10109690 TI - Charter bondholders likely to discuss purchase offer. PMID- 10109691 TI - Hospital hopes to hike payments with spinoff. PMID- 10109692 TI - Class I surgical drape flammability designation is causing confusion. PMID- 10109693 TI - Turnover time is linked to variety of factors. PMID- 10109694 TI - Closing the loop essential to QA process. PMID- 10109695 TI - Traveling personnel help fill staffing gaps. PMID- 10109696 TI - Productive criticism can produce change. PMID- 10109697 TI - Central admissions improves patient flow. PMID- 10109698 TI - Providers voice concerns over upcoming UB-82 changes. PMID- 10109699 TI - Compare benefits before entering receivables financing. AB - Financing accounts receivables is becoming a popular strategy in the healthcare industry. Factoring and securitization are two financing methods available to hospitals. Patient accounts managers who understand the programs' structures, incentives, and costs will be able to achieve the maximum benefit for their hospitals when choosing one of these transactions. PMID- 10109700 TI - Securitization is wave of future for hospitals. PMID- 10109701 TI - HCFA implements screening mammography rules. PMID- 10109702 TI - An economic perspective on health politics and policy. AB - This article uses a self-interest model to explain health care legislation. Seemingly uncoordinated, contradictory, inefficient, and inequitable legislative outcome are shown to be the result of a rational process in which the participants, including legislators, act according to their calculation of costs and benefits. Those groups able to offer political support receive net benefits at the expense of those who are less politically powerful. This framework is used to examine different types of health legislation with the emphasis on explicit redistributive policies such as Medicare and Medicaid. PMID- 10109703 TI - Health policy revolution: the search for minimum supply price. AB - This article provides comments on Feldstein's article on "Health Policy Issues: An Economic Perspective." The predictive ability of Feldstein's analysis is extended. The importance of exogeneous shocks is discussed, specifically the role of technology in shaping health policy and the development of the health care industry. PMID- 10109704 TI - Understanding the flow of health policy in the United States: self-interest or ignorance? AB - Health policy decisions are made in an uneven manner, eluding attempts to explain developments with a coherent theory. Numerous explanations have been suggested to explain individual policy actions, but recently Feldstein has attempted a broader formulation. This Self-Interest Model of Health Policy, however, assumes full knowledge of a policy's benefits and costs. This is an unrealistic assumption, and the model is unable to explain important decisions that have been made in three areas: insurance for long-term care, universal access, and efficiency incentives. This article presents a broader, more powerful formulation of the Feldstein model, specifically incorporating public ignorance as a policy determinant. The vital role of education and health policy research is underscored. PMID- 10109705 TI - Future issues in health economics: one view from Washington. AB - These are comments about how policy issues at the federal level may create a demand for research in several areas of health economics. As background, there is a discussion of the current federal budget situation and the cost-containment pressures this puts on public health programs. The longer-term problem of financing of the Medicare trust fund is also discussed. Four areas where new research may affect future health policy are identified: the market for physician's services, medical technology, competition in health care, and the market for health insurance. PMID- 10109706 TI - American health politics, 1970 to the present: some comments. AB - This article reviews the attempts of the 1970s and 1980s to rationalize health care provision in the United States. It critically discusses the contorted debate between competition and regulation as a means of controlling health care costs. The second part of the article takes up Eli Ginzberg's contentions about American health care. We agree that the United States has not been able to control medical inflation because it lacks the necessary condition of concentrated finance. But we present evidence from public opinion polls in the 1970s and the 1980s that challenges Professor Ginzberg's contention that "there is no evidence that the American people want to change [their] system" of medical care. PMID- 10109707 TI - The health care cost "problem". AB - This serves as an introduction to this special issue devoted to a selection of papers chosen and revised from a conference on public policy entitled "Health Care Policy: Where Is the Revolution Headed?" sponsored by the Thomas Jefferson Program in Public Policy at the College of William and Mary, Williamsburg, VA, November 12-14, 1987. PMID- 10109708 TI - Health care policy: where is the revolution headed? Conference on public policy sponsored by the Thomas Jefferson Program in Public Policy at the College of William and Mary, Williamsburg, VA, November 12-14, 1987. PMID- 10109709 TI - Financing the correct rate of growth of medical technology. AB - This article suggests ways to preserve innovation while partially restraining the impressive growth rate in new medical technology. Health care will soon consume 12 percent of GNP. There is a wide range of opinions as to whether medical technology is a major or minor source of rising health care expenditures. Given our current fiscal problems, health care providers will be in direct competition with education and other domestic programs for a limited supply of R&D funds. More funding will have to come from the private sector. The challenge for prudent buyers of health care services is to control costs without eroding the biomedical capacity of the nation. PMID- 10109710 TI - The competitive solution and the health care problems of today. AB - Mark Pauly claims that a "competitive" health care system will solve the health care cost crisis. This article examines how well the competitive solution deals with the five central problems of the health care system: (1) almost universal lack of adequate health insurance for nursing homes and home care; (2) Medicaid's penurious approach to payment for health services for the poor; (3) the emergence of a dual health care system, especially for children; (4) the entrenched waste and inefficiency of the health care system; and (5) consumers' inability to judge the quality of health care. The competitive solution does not eliminate any of these problems--and may not even improve some of them. PMID- 10109711 TI - The branding of institutions. AB - Institutional operations capitalizing on national foodservice brands have seen sales increase as much as 40%, operators say. But what if operators choose to stay independent and develop their own brands? Our feature presents both business strategies and the concepts that are winning customers. PMID- 10109712 TI - Injury prevention vs. patient communications. PMID- 10109713 TI - Resource allocation, equity and public risk: dying one at a time vs dying all together. AB - This paper focuses on the evaluation, from an individual and societal perspective, of risk in terms of possible loss of life due to an exposure to two different types of events over a period of time. The two types are: risk of death from a catastrophic event (a sudden death of many people in a disaster at a yet unknown point in time) expected to occur during a planning period, or risk of death from another event (e.g. disease, road accident, etc) which claims fewer lives each year, but for which the expected total number of deaths over the planning period is equal to the expected number of deaths from the catastrophic event. Our analysis considers the extreme case in which these two types of events have the same probabilities of death every year and the same expected number of fatalities over the planning period. The individual's decision problem is described using a von-Neumann Morgenstern (vNM) utility function. The model suggests that the choice between these types of events depends on the value of the following variables: the probability of death over the planning period, the length of the planning period, the individual's time preference pattern, and the utility of being in different anxiety states. Stochastic extensions that may direct the public decision making process (involving aggregated preferences) are discussed. We also discuss issues of implementation. PMID- 10109714 TI - Evolving theories of malpractice liability for HMOs. PMID- 10109715 TI - AST (Association of Surgical Technologists) member survey: summary of results. PMID- 10109716 TI - If your doctor has AIDS. PMID- 10109717 TI - Meeting the challenge: a multidisciplinary clinical ladder program. PMID- 10109718 TI - The last third. R&D: the return on our investment. AB - "The challenge is to balance what is good for the individual against what is in society's best interests without providing disincentives for product development." This quotation from a 1988 JAMA article by Peter Jacobson and John Rosenquist exploring contrast media issues goes beyond the usual scope of concern and also crystallizes why the low osmolar contrast agent (LOCA) controversy is so typical of the dilemmas that healthcare and society as a whole will continue to confront. The first two-thirds of this quotation presents a challenge that has been the subject of the LOCA debate for some time now: how to weigh the benefit to the individual versus the cost to society. The last third of this challenge acknowledges the importance of research and development, which has been largely ignored although it represents a vital ingredient for future healthcare improvements. PMID- 10109719 TI - Reimbursement for nonionics. PMID- 10109720 TI - New Budget Reconciliation Act affects radiology. AB - The Omnibus Budget Reconciliation Act of 1990, which was signed into law by President Bush on November 5, 1990, contains numerous changes in Medicare law affecting reimbursement to physicians and hospitals for outpatient radiology services. The basic fee schedule and cost reimbursement principles established over the past several years are not affected. Instead, the Act adjusts the calculation of payment amounts under these principles so that payments for radiology services (as for most other services) will be ratcheted down in 1991. The changes affecting both hospitals and physicians are described below, along with the one expansion of Medicare radiology coverage--for screening mammography- included in the Act. PMID- 10109721 TI - Optimizing performance of the billing company. PMID- 10109722 TI - Billing tactics. Advantages of a professional billing service in radiation oncology. AB - An efficient billing system for your professional services must include the following items: 1. A significant amount of personal involvement by the physician in the origination of the patients' charges. 2. Friendly, courteous, and helpful personnel for patient interaction. 3. Timely and accurately posting of accounts. 4. An absolute separation of receipt of payments and account reconciliation. 5. A personal interest by the physician in the accounts receivable balance as well as monthly financial summaries of the ongoing business of your practice. 6. Knowledge of the patient's credit history and ability to pay for services. 7. Dedication to serving you in the most efficient cost-effective manner. 8. A method for remaining absolutely current on any changes occurring in the healthcare reimbursement sector. 9. Frequent meetings between the radiation oncologist and the service responsible for professional billing. 10. Timely review and management of all past due accounts making decisions toward collection or adjustment. 11. A method for tracking referral physician identification and disease categories which are now a part of Medicare billing requirements and should allow you to be able to graphically demonstrate trends in your practice referrals. PMID- 10109723 TI - Sources of inspiration. AB - Two recent projects by Jeffrey Hildner for a private nursing home in Princeton, New Jersey, reconcile the architect's interest in art and the client's emphasis on utility. PMID- 10109724 TI - Special report. Front-row seat: dramatic (and mundane) moments mark doctor, patient victories & losses at Part B ALJ (administrative law judge) hearings. PMID- 10109725 TI - Perspectives. ACT UP: playing the inside & the outside. PMID- 10109726 TI - Perspectives. Medicaid physician payment reform: the next horizon. PMID- 10109727 TI - Annual transport statistics. PMID- 10109728 TI - An administrator's perspective on managing safety. PMID- 10109729 TI - Operational quality assurance: a new concept defined. PMID- 10109731 TI - Directory of air medical services. PMID- 10109732 TI - Product & service guide. PMID- 10109730 TI - Association officers. PMID- 10109733 TI - International air medical services. PMID- 10109734 TI - The new pressure systems regulations (and how they affect the hospital engineer). PMID- 10109735 TI - Environmental Protection Act: waste provisions. Waste Management Division, Department of the Environment. AB - This paper is a guide to the waste management provisions in Part II of the Environmental Protection Act relating to England and Wales. It is not an exhaustive guide; many of the provisions dealing with waste collection and recycling are excluded. Nor should it be treated as definitive; it contains simplifications, and for further clarification the Act itself should be consulted. With reference to LAWDCs, the paper expresses the current view, which may be subject to modification. PMID- 10109736 TI - Waste disposal and the new legislation. Are you prepared? PMID- 10109737 TI - Supreme Court hears arguments on unions in hospitals; ruling could open doors to widespread unionization. PMID- 10109738 TI - Massive study of patients' concerns points to interpersonal needs. PMID- 10109739 TI - Medicare takes more punches in President's budget; opponents, hospital advocates vow slugfest. PMID- 10109740 TI - Robots beep while they work at Connecticut hospital, delivering meals and promises for the future. PMID- 10109741 TI - Making a difference for patients and hospitals begins with understanding customer service terms, strategies. PMID- 10109742 TI - Texas hospital serves up lunch for employees as long as the meal comes without beefs. PMID- 10109743 TI - Studies try to sidetrack abortion politics with focus on "pre-embryo". AB - The politics of abortion has completely halted NIH studies on in vitro fertilization and experiments involving transplants of human fetal tissue. The following articles describe some efforts on the part of medical organizations and religious thinkers to break this political barrier. PMID- 10109745 TI - Skills, roles, and responsibilities of ethics consultants suggested. PMID- 10109744 TI - Near-death experiences come under scrutiny. PMID- 10109746 TI - Courting the issues: decisions in Minnesota and Missouri. PMID- 10109747 TI - Kevorkian banned from using euthanasia device. PMID- 10109748 TI - Neo-no-fault proposals for medical malpractice claims. PMID- 10109749 TI - Laminar airflow systems: a 1991 update. PMID- 10109750 TI - PROs explore changes in current review process. PMID- 10109751 TI - College report analyzes recent Medicare data. AB - The growth in Medicare payments to physicians continues to be a major concern for federal policymakers. In order to gain a better understanding of the trends in Medicare spending for surgical services, the College obtained Medicare Part B claims data for the years 1986 through 1988, which were analyzed and published in a report that was issued in December 1990. The following article describes the federal activity that prompted the College to commission this report on Medicare Part B spending trends, and presents some of the significant results of the analysis. PMID- 10109752 TI - Utilization review: the art of polite interference. PMID- 10109754 TI - How to hire a benefits consultant. PMID- 10109753 TI - Comeback for the company doc? PMID- 10109755 TI - A health plan designed by employees and physicians. PMID- 10109756 TI - On the periphery: vision care in the 90s. PMID- 10109757 TI - Potential liability when a health plan fails. PMID- 10109758 TI - Enlarging access: Maryland and Ohio. PMID- 10109759 TI - Our moribund health insurance system. PMID- 10109760 TI - Data watch. Leaders look at health care. PMID- 10109761 TI - Annual update of the HHS poverty income guidelines--HHS. Notice. AB - This notice provides an update of the HHS poverty income guidelines to account for last (calendar) year's increase in prices as measured by the Consumer Price Index. PMID- 10109762 TI - Cooperation in identifying and providing information to assist states in pursuing third party health coverage--Family Support Administration, HHS. Final rule. AB - This final rule implements section 12304 of the Consolidated Budget Reconciliation Act (COBRA) of 1985 which requires each applicant or recipient to cooperate with the State in identifying and providing information to assist States in pursuing any third party who may be liable to pay for care and services available under State plans for medical assistance under title XIX, unless such individual has good cause for refusing to cooperate as determined by the State agency in accordance with standards prescribed by the Secretary. The regulations are applicable to the AFDC program in all jurisdictions. PMID- 10109763 TI - The neonatal intensive care experience. PMID- 10109764 TI - Decisions in the NICU: the moral authority of parents. PMID- 10109765 TI - Parameters for establishing family-centered neonatal intensive care services. AB - This article discusses the basis for providing family-centered services in neonatal intensive care. It is suggested that these services should be developed within the following parameters: adaptive fit, response to family identified needs, family empowerment and independence, and the recognition that families are complex dynamic systems. Physical and organizational changes necessary for the implementation of family-centered neonatal intensive care services are discussed. PMID- 10109766 TI - Critical elements of transition from NICU to home and follow-up. AB - The continued expansion of NICU's and the subsequent increase in the survival rate of infants and children with special health care needs warrants an examination of the variables that contribute to a successful transition from hospital to home. While best practices have been identified for both families and professionals, many of the 1150 NICU's across the country are not in a position to implement such practices, primarily because of fiscal and time constraints. This article presents an overview of a project designed to identify and facilitate critical elements of transition that can be implemented at minimum cost for all families transitioning from hospital to home care in Connecticut. The identified elements include: (a) the use of a parent to parent support network, (b) the use of a standard discharge summary form to enhance communication among family and care providers, (c) the use of a continuing care plan to facilitate the accessibility of community services, and (d), the identification of on-going training activities for both families and providers. PMID- 10109768 TI - Evaluating family-centered programs in neonatal intensive care. AB - With the passage of P.L. 99-457 in October of 1986, the field of early intervention has been faced with the challenge of broadening its scope (Silber, 1989). This legislation expanded early intervention from a child-centered service to a service offered to families within a variety of contexts; from a service for children with special needs to a service available to families as soon as risks are identified. New programs are being designed and developed with an interagency focus which serve not only children with developmental disabilities but also their families in health, education and social services (Cornwell and Thurman, 1990). Current legislation suggests that services should be available to families as soon as their children are identified as being at-risk (Smith, 1987). In response to the legislation, states are developing definitions of "at-risk" based on criteria other than the child's test scores. Therefore, in many cases, early intervention services are being offered to families while their at-risk infants are still hospitalized and receiving intensive care. Evaluation of these innovative and complex service delivery programs is being addressed as these services are developed. With the broadening of the scope of early intervention comes the need to rethink the traditional methods of evaluating these programs. This paper will address some of the issues involved in evaluating family-centered programs which are based in neonatal intensive care units (NICU). PMID- 10109767 TI - Evolving models of family-centered services in neonatal intensive care. AB - The article examines the evolution of models for providing family-centered services in neonatal intensive care settings. Child-focused, parent-infant interaction, and ecological models are presented and discussed. One specific ecological model, the family-centered care model, is examined in detail. While most current programs endorsed family-centered care (FCC) as a "best practice" for developmental intervention with infants, few were found that implemented these practices. Most utilized only limited components of FCC. Instead, programs operating in NICU settings had features directed toward child care, staff training, family support and transition to the community, rather than impacting the philosophy of care and/or service delivery system in the NICU. Suggestions for working toward FCC in NICU settings are given and barriers are discussed. PMID- 10109769 TI - The effect of newborn intensive care on parents' psychological well-being. PMID- 10109770 TI - Aging population gives hospitals potential focus. PMID- 10109771 TI - High quality health focus could cure ills of system. AB - Health care is moving closer and closer to a nationalized system. Traditionally, hospitals have depended on reimbursement rather than creating cost-effective delivery systems. In the following article, the author proposes a new delivery model that provides for quality and cost-containment by focusing on a well defined population and the workplace. PMID- 10109772 TI - Flow chart eases planning process for hospitals. AB - If planning is the key word for hospitals in the next decade, how do their administrators get through the tedious tasks associated with formulating strategy, making purchases or changing directions for individual units? In the following article, the author suggests a methodology to streamline the process and put it in the hands of department managers. PMID- 10109774 TI - National survey asks about health care reform. PMID- 10109773 TI - Communicate your hospital's quality by writing, speaking. PMID- 10109775 TI - Systems face challenges. Interview by Donald E.L. Johnson. AB - The regional hospital system has become a mainstay in the structuring of health care during the past decade. How will it fare in the next 10 years? In the following interview with Health Care Strategic Management's editor and publisher Donald E.L. Johnson, Fred L. Brown, president and chief executive officer of Christian Health System, the St. Louis, Mo.-based umbrella organization for nine hospitals, six nursing facilities, and one retirement community, predicts a bright future for the health care system. He also discusses the strategies that are unique to the success of such a system. PMID- 10109776 TI - The aging eye. PMID- 10109777 TI - Are budget cuts compromising quality? AB - Despite the lack of concrete evidence that Medicare cutbacks have diminished access and quality of care, an underlying feeling appears to be emerging that continued cuts could weaken the fabric of trust that binds physicians to their Medicare patients--and care may suffer as a result. PMID- 10109778 TI - Women make strides in American medicine. Interview by Janice C. Simmons. AB - The president of the American Medical Women's Association observes how the health care community needs to look at issues including maternity leave, day care and women in medical research. PMID- 10109779 TI - Who are the Congressional health policy players? PMID- 10109780 TI - A clear and present danger. PMID- 10109782 TI - State Senator Chet Brooks. Interview by Margaret Roberts. PMID- 10109781 TI - Measles: a border experience. PMID- 10109783 TI - Uncompensated care. Balancing on a thin fiscal line. AB - Uncompensated care affects every hospital in Texas--and threatens the very survival of some. As the volume of uninsured services grows, and the question of who will pay for those who cannot remains largely unanswered, hospital administrators are left to perform fiscal balancing acts. Health Texas visited with three hospitals that typify the serious problems uncompensated care poses for the health care industry. PMID- 10109784 TI - Innovations, local solutions arise from the shortage. PMID- 10109785 TI - MEDNET: vital communication links for rural hospitals. PMID- 10109786 TI - Paying out enough rope. PMID- 10109787 TI - Learning to live together. PMID- 10109788 TI - Please treat me nicely. PMID- 10109789 TI - To be partners in care? PMID- 10109790 TI - Power to the people. PMID- 10109791 TI - Caring for quality. PMID- 10109792 TI - Be smart for market. PMID- 10109793 TI - Shifting the focus of audit. PMID- 10109794 TI - Measure of care. PMID- 10109795 TI - Building round the ward. AB - This month's special feature is devoted to computers and nursing. We look at the possibilities and pitfalls in selecting a nursing management system, ask whether senior nurses are making the most of resource management and quality assurance programmes, and find promising results from an experiment with handheld computers by community nurses. PMID- 10109796 TI - Feather in a nurse's cap. PMID- 10109797 TI - Data bank made handy. PMID- 10109798 TI - Operation, formulary decision-making activities of a P & T Committee in a managed care setting. AB - Managing drug benefits in a Health Maintenance Organization (HMO) is perhaps best accomplished through a formulary, as demonstrated by Kaiser Permanente of Colorado. According to Dr. Jim Adams and Ms. Jackie Richardson, the Chairman and Secretary, respectively, of Kaiser Permanente's P & T Committee, since the advent of their formulary only a few years ago, the cost of drugs has been kept well under control, without jeopardizing the quality of care. Both physician and patient education are critical to the success of a formulary in a managed care system--both monumental tasks for Kaiser Permanente of Colorado considering that prescribers exceed 300 and the number of patients they treat approaches 250,000. What is clear in this exclusive Hospital Formulary interview is that HMOs--long recognized for their ability to control costs--can also provide quality health care for patients who use their facilities. PMID- 10109799 TI - Projected cost savings associated with cefmetazole: a new cephamycin for the hospitalized patient. AB - In this article, a cost-minimization model was used to make an economic comparison between cefmetazole and cefoxitin--two drugs with comparable in vitro spectra of activity, clinical efficacy, and safety profiles. Drug acquisition costs were estimated from published information and labor and material costs were calculated based on actual costs at Presbyterian Hospital of Dallas. Costs of the agents were calculated based on the dosage and administration schedules typically used in published clinical trials of cefmetazole and cefoxitin and on the typical dosing patterns of cefoxitin used at Presbyterian Hospital. Results of the cost analysis revealed that an annual savings of $36,015 to $59,143 could be realized at Presbyterian Hospital if cefmetazole were used in place of cefoxitin for surgical prophylaxis. Furthermore, use of cefmetazole in place of cefoxitin for wound treatment would yield annual savings of $33,242. PMID- 10109800 TI - Nursing in the nineties. PMID- 10109801 TI - EuroQol--a new facility for the measurement of health-related quality of life. AB - In the course of developing a standardised, non-disease-specific instrument for describing and valuing health states (based on the items in Table 1), the EuroQol Group (whose members are listed in the Appendix) conducted postal surveys in England, The Netherlands and Sweden which indicate a striking similarity in the relative valuations attached to 14 different health states. The data were collected using a visual analogue scale similar to a thermometer. The EuroQol instrument is intended to complement other quality-of-life measures and to facilitate the collection of a common data set for reference purposes. Others interested in participating in the extension of this work are invited to contact the EuroQol Group. PMID- 10109802 TI - GP budget holding in the United Kingdom: learning from American HMOs. AB - A key component of the 1989 British National Health Service White Paper, 'Working for Patients', is the so-called budget holding plan for general practitioners. This controversial proposal calls on GPs to manage their patients' budgets for consultant (specialist) services and hospital care. Most aspects of the scheme, now only contemplated in the U.K., have functioned for years in American health maintenance organisations (HMOs). The thesis of this article is that an analysis of the GP budget holding proposal, in light of the many years of experience with HMOs, will provide valuable insight into how the British innovation might (or might not) function. Moreover, we believe the U.S. HMO experience has a high degree of relevance for the design, implementation and management of budget holding practices in the NHS of the 1990s, as well as other similar proposals being considered across the European continent. PMID- 10109803 TI - Service management: New Zealand's model of resource management. AB - The health system in New Zealand, which in many respects is similar to that of the United Kingdom NHS, is currently undergoing massive change. In 1989 fourteen area health boards were formed, each board being accountable to the minister of health for achieving health goals and providing comprehensive health services for its defined population. This process has been assisted by the promulgation of a set of national health goals and a national health charter. Within area health boards the principle of general management is being implemented. Organisational structures are moving away from hospitals to services in a process which is being called service management which may be defined as the decentralisation of general management to the clinical workface. Similar in many respects to the resource management initiatives in the NHS it brings together medical, nursing and business management at the operational level with one person being accountable for the achievement of quality of care objectives within a budgetary framework. Budgetary restraints in excess of 10% have been achieved in the last 12 months partly through the service management process. Service management is seen to be a major paradigm shift in health services organisation and could be of international significance in its potential for achieving medical accountability for cost containment and quality assurance, and for coordinating care across agency and disciplinary boundaries. PMID- 10109804 TI - Hospital changes ED as the number and type of patients seen changes. PMID- 10109805 TI - CAD (computer-aided drawing) systems: which one will work the best for you? PMID- 10109806 TI - How to read and interpret material safety data sheets. PMID- 10109807 TI - JCAHO's PTSM (plant, technology and safety management) changes subtle--but important. PMID- 10109808 TI - T&P (temperature and pressure-relief) valve inspections up safety, limit liability. PMID- 10109809 TI - Study: field split over use of contract services. PMID- 10109810 TI - In-house group builds Muir's unique outdoor rehab-therapy garden. PMID- 10109811 TI - Timing is everything: scheduling a group-practice office product. PMID- 10109812 TI - Which waste-treatment option is best for you? PMID- 10109813 TI - PTSM (plant technology and safety-management) standards shed light on utility features. PMID- 10109814 TI - Up-front homework means cooling-tower success. PMID- 10109815 TI - GAO criticizes EPA's poor record on disinfectants. PMID- 10109816 TI - Disposable OR pack prices go up 5%. PMID- 10109817 TI - Hospitals skittish about war, some brace for shortages. PMID- 10109818 TI - Hospital materials managers expect the price of blood culture bottles to escalate 2% to 6%. PMID- 10109819 TI - Hospital materials managers need to know what consignment really offers purchasers. PMID- 10109820 TI - MM department at Rhode Island Hospital helps facility cut deficit with cost reductions. PMID- 10109821 TI - HMM price watch. PMID- 10109822 TI - Hospitals should include clauses in contracts when renting medical equipment to patients. AB - A piece of equipment was loaned by the hospital to a patient for home use. The equipment required an electrical connection for proper functioning. The use of the equipment placed an overload on the electrical circuit in the patient's home. A fire resulted. The home was extensively damaged, the patient suffered third degree burns, and the patient's cat was killed. In this dialogue, Dr. Decker discusses the legal issues involved. PMID- 10109823 TI - Price survey. Paper prices to escalate 2% to 5%. PMID- 10109824 TI - Mercy estimates 6% savings with AmHS buying affiliation. PMID- 10109825 TI - Solid, thorough bid process helps hospitals find best telecommunications systems values. PMID- 10109826 TI - Focus: recycling. Shore Memorial Hospital's purchasing criteria change to include recyclability. PMID- 10109828 TI - Hospitals need to examine and contract for demonstrating medical equipments' safe use. PMID- 10109827 TI - Hospitals examine stockless options despite resistance. PMID- 10109829 TI - Productivity, efficiency, & effectiveness in the management of healthcare technology: an incentive pay proposal. AB - Modern healthcare managers are looking for better ways to motivate their employees as well as document and evaluate employee performance. The term productivity is familiar to most healthcare managers. The term efficiency is less familiar. These terms are defined and their significance for use as unique and valuable indicators of effective employee performance is discussed. Similar criteria were applied to make a general comparison between biomedical technician performance in two different hospitals in Tegucigalpa, Honduras, in Central America. A performance-based incentive program using an Incentive Pay Index chart is proposed as a tool through which hospital or company managers can provide technicians or technologists with ongoing motivation to improve both their productivity and efficiency on the job. PMID- 10109830 TI - The Safe Medical Devices Act of 1990: are hospitals ready to deal with the FDA? AB - The Safe Medical Devices Act of 1990, long anticipated by regulatory affairs and compliance professionals in the medical device manufacturing industry, was signed by President George Bush on November 28, 1990. The law will significantly alter the structure of medical device regulatory mechanisms, and will expand the scope of the FDA's activities. The new medical device legislation sets requirements for hospitals as well as industry. PMID- 10109831 TI - Instrument to test patency of lacrimal drainage system. AB - The lacrimal drainage system drains fluid that exists normally on the surface of the eye into the nasal cavity. This paper describes a hand-held, personal computer-based instrument to quantitatively estimate the resistance to fluid flow through the lacrimal drainage system. This resistance measurement is proposed as a possible means to diagnose blockage of the system and to verify the degree of change in resistance after clinical treatment. The instrument system consists of a hand-held syringe attached to pressure and flow transducers. Resistance is calculated as the ratio of differential pressure to flow rate and is displayed in real time on a computer monitor. PMID- 10109832 TI - Medical engineering in Switzerland. AB - The clinical engineering or medical engineering departments in the hospitals in Switzerland are in a phase of rapid development. In particular, staffing, as well as official recognition by hospital management, needs improvement in many of the hospitals, as is also found in other countries. An overview is given of the current state of affairs in medical engineering in Switzerland, and of the amount of annual investment in medical equipment in the public hospitals. The activities of the Swiss Association of Hospital Engineers in this field are described. The main goals, responsibilities, and tasks of medical engineering departments are presented. The importance of the integration of the medical engineering operation in the management decision process is stressed. PMID- 10109833 TI - Service management: a New Zealand model for shifting the balance from hospital to community care. AB - New Zealand's health system has undergone a radical reform in recent years. A central feature of this reform is the area health board, a partly elected and partly appointed body responsible for all health services for its defined population. Within the area health board, the organizational structure which is based upon general management is moving away from institutional towards service or programme management. This is involving clinicians in the management process as service managers, within an accountability structure which cuts across the traditional hospital/community service boundaries. This is a major paradigm shift in health services management which could have major implications for a shift from hospital to community-based care and from secondary to primary health care. PMID- 10109834 TI - An assessment of rural hospital trustees' health care knowledge base. AB - Rural hospital trustees are usually volunteers who serve important roles in the governance of a hospital and, therefore, in defining health care policy in their communities. Because most trustees are not health professionals, their orientation to the hospital and continuing education about the hospital present a special challenge to administrators. One hundred and three trustees from 10 rural hospitals in western New York were surveyed to better understand their demographics, their knowledge base regarding the hospital, and their roles as trustees. Sixty-six percent of the respondents were male and the average age of the sample was 48 years. Trustees had served an average of six years and spent seven hours per month on hospital business. Eighty-three percent recalled receiving some orientation. Answers about average hospital census, length of stay, payor type, and hospital services were correct less than 50 percent of the time. Trustees were aware that recent quality assurance guidelines increased their liability and half believed it was their most important activity. We conclude that greater effort should be applied to the orientation and continuing education of hospital trustees. Given the significant time commitment already asked of trustees, this education should be woven into the hospital governance routine. PMID- 10109835 TI - Utilizing cooperative extension services to meet rural health needs. AB - Professionals concerned with rural health issues sometimes overlook the possibilities that the Cooperative Extension Services (CES) hold for addressing rural health problems. Joint venturing between health care and CES professionals can help address the growing rural health care concerns associated with cost containment strategies and the federal deficit, as well as the traditional problems associated with the scarcity of health care resources in rural areas. Cooperative extension, a 75-year-old national, community-based system can provide the structural and program delivery capacity to help shape health care delivery in rural areas through community organization and education. The structure and functions of the CES, brief examples of successful CES programs, and some helpful hints provide insights into the potential for successful cooperation and collaboration. This collaboration can represent a cost-effective strategy to address problems in the changing health care climate. PMID- 10109836 TI - Hospital-sponsored rural health clinics: an effective diversification alternative for rural hospitals. AB - Changes in rural health care are resulting in new challenges for the administrators of rural hospitals. The lack of available care, economic deterioration, and demographic changes in rural America are contributing factors to rural health care problems and are detrimental to the financial well-being of rural hospitals. Diversification is becoming commonplace in these hospitals as administrators seek strategies to gain financial viability for their facilities. The concept of hospital-sponsored rural health clinics is more than a decade old, yet there are fewer than 30 such clinics nationwide. Reasons for the underutilization of such clinics may include the lack of knowledge that such clinics exist as well as inadequate information describing the establishment, operation, and financial feasibility of the clinics. The hospital-sponsored rural health clinic "concept" will be introduced, including potential benefits of such clinics to both the hospital and the communities they serve, factors to be considered in developing such a system, and problems that may arise in this development. This article presents a case study of how one rural hospital incorporated such clinics into its long-range plans. PMID- 10109837 TI - The merger of rural primary care and home health services. AB - The merger of rural primary care and home health services offers the potential for increasing the administrative efficiency of health care, and thereby enhancing the quality of care and increasing access to services, particularly health promotion. However, the proposed benefits of any merger can only be realized if the merger process is successfully completed. An analysis of the factors that were important in a case study of successful and unsuccessful mergers of rural health centers and home health care agencies in northeastern Vermont is presented. Three components were found to be necessary to start the merger process: complementary needs, opportunity, and common philosophy. The involvement and support of key individuals was crucial to sustaining merger interest. Good communication throughout the process contributed substantially to the maintenance of both community and staff support. Others considering similar mergers should recognize that the process of consolidating organizations and satisfying regulations takes some time to complete. PMID- 10109838 TI - Prolonged travel time to neonatal intensive care unit does not affect content of parental visiting: a controlled prospective study. AB - Decreased local obstetric care appears to be increasing the rate of premature births to rural populations. With increased numbers of premature and complicated births in rural populations, understanding the impact of the Neonatal Intensive Care Unit (NICU) environment on the development of parent-child relationships becomes critical. NICU infants appear to be at increased risk for failure to thrive, child abuse, and neglect. Some reports suggest that the frequency of parental visits to the NICU can predict infants likely to be at risk. Because rural parents visiting infants hospitalized in urban centers are likely to visit less often, understanding this possible relationship is critical. In this controlled prospective study, three groups of parents were observed visiting their hospitalized infants: (1) those visiting "in house" while the mother was still hospitalized; (2) those whose visits required one hour or less in travel time; and (3) those whose visits required more than one hour in travel time. Results showed that travel time influenced the frequency of visits, with fewer visits from those living furthest from the NICU. However, those visiting from greater distances stayed with their infants longer so that there was no difference in the total visiting time over a two-week period. Direct observations of the visits by both mothers and fathers showed no differences in the content of parent-child interactions among groups. Thus, visit frequency alone must be viewed cautiously as a potential indicator of failure to bond with a hospitalized infant, especially in settings serving rural populations. PMID- 10109839 TI - Health services administration and technological change: the challenge of success -a symposium. PMID- 10109841 TI - Providing, producing, and paying for trauma care. PMID- 10109840 TI - Lifestyle choices and medical technology: allocating organ transplants. PMID- 10109842 TI - Interorganizational collaboration with health administration technology: the case of aeromedical services. PMID- 10109843 TI - Strategic management in hospitals. PMID- 10109844 TI - The case of Cal/OSHA: change strategy and constituent response. PMID- 10109845 TI - Intergenerational equity and interdependence: a public policy issue for the 1990s. PMID- 10109846 TI - Russian medicine. Perestroika is getting there. PMID- 10109847 TI - Hospitals may be feeling a pinch, but administrators aren't. PMID- 10109848 TI - Why I love my HMO. PMID- 10109849 TI - Malpractice experts who can tell if your patient lied. PMID- 10109850 TI - Let people with AIDS share in medical decisions. PMID- 10109851 TI - That's my hospital standing right behind me--cringing. PMID- 10109852 TI - Pressure grows on psychiatrists' earnings. PMID- 10109853 TI - Are third parties denying patients the surgery they need? PMID- 10109854 TI - 'Boosting Medicaid doctors' fees too costly'. PMID- 10109855 TI - Michigan slashes Medicaid budget 9.2%. PMID- 10109856 TI - Pa. plan seeks matching funds. PMID- 10109857 TI - $500,000 added to nurses unionizing efforts. PMID- 10109858 TI - Medical lab supervisory vacancies on the rise. PMID- 10109859 TI - Practitioner data bank's tap-on fee to triple. PMID- 10109861 TI - 'Overhaul N.Y. regulations'. PMID- 10109860 TI - Project to expand. PMID- 10109862 TI - HMO to finance trials of cancer treatment. PMID- 10109863 TI - Community Psych offering flat-rate services. PMID- 10109864 TI - Pittsburgh hospital sues partner in HMO venture. PMID- 10109865 TI - California accused of restraining too many nursing home patients. PMID- 10109866 TI - Reduction in fee schedule advised. PMID- 10109867 TI - Costly errors: an encounter with the federal inspectors. PMID- 10109869 TI - 'Merge Part A, Part B to save trust fund'. PMID- 10109868 TI - Watchdog gets touch on Medicare fraud. Inspector general has strong-armed nearly $10 million in hospital settlements. AB - The HHS investigative branch has wrested $10 million in settlements from 43 hospitals or hospital systems since the start of Medicare's prospective payment system in 1983. The federal government is hurling its resources at hospitals, which have found it more cost-effective to work out a discreet deal rather than fight allegations in court. Some charge that the inspector general's office is more interested in being punitive with providers than prudent with taxpayer's money. PMID- 10109870 TI - HMO sues to recover Medicare funds. PMID- 10109871 TI - Vying for control of CHAMPUS funds. AB - Advocating a "coordinated care" approach to healthcare for military retirees and their dependents, the Pentagon is hoping for a victory in its battle with civilian managed-care contractors for control of CHAMPUS funds. But coordinated care, which would give military hospital commanders the added responsibility of overseeing healthcare spending outside military facilities, has drawn fire from critics who say commanders lack the expertise to run such a program. PMID- 10109872 TI - Radiologic purchase patterns tracked. AB - A recent report of hospitals' radiology purchasing processes and buying plans for the future shows they're generally happy with the equipment they have and would replace it with the same brand. The report looks at what types diagnostic imaging equipment, who decides what to buy and what improvements hospitals would like to see in their imaging equipment. PMID- 10109873 TI - Cancer center jumps hoops to issue bonds. AB - If community hospital executives think they have a tough time trying to issue tax exempt debt these days, it could be worse. Case in point--the Fred Hutchinson Cancer Research Center in Seattle. The world-renowned center, which was seeking financing for replacement facilities, faced a tough sell after it found itself with a couple of strikes against it, namely a high reliance on federal grants and balking credit-rating agencies. But a long-awaited government exemption and letter-of-credit guarantees got the project going. PMID- 10109874 TI - Protestant health group launches restructuring in effort to sharpen identity, get back to issues. PMID- 10109875 TI - Nu-Med sales done. PMID- 10109876 TI - NME to close founding hospital. PMID- 10109877 TI - Offer for Charter extended. PMID- 10109878 TI - HealthVest takes asset write-down. PMID- 10109879 TI - Bonus plan won't risk exemption--IRS. PMID- 10109880 TI - FTC drops merger probe in Carmichael, Calif. PMID- 10109881 TI - AMI's parent loses $9.3 million in quarter. PMID- 10109882 TI - Recession pushes uncollectibles to new high. PMID- 10109883 TI - Primary-care program under review in N.Y. PMID- 10109884 TI - Hospitals' managed-care alliances investigated. PMID- 10109885 TI - VA accepts blame for 6 deaths at Chicago-area medical center. PMID- 10109886 TI - Income gain allows HMO to hold premium hike to 11%. PMID- 10109887 TI - Employers ending 100% payment, hiking out-of-pocket maximums. PMID- 10109888 TI - 'Inmates need AIDS education'. PMID- 10109889 TI - 'Business executives want health reform'. PMID- 10109890 TI - Budget committee rejects Bush's Medicare cuts. PMID- 10109891 TI - Nation's infant mortality rate drops 8.1%. PMID- 10109892 TI - Turf battle focuses on cataract guidelines. PMID- 10109893 TI - Analysis pegs capital winners, losers. PMID- 10109894 TI - It's time for not-for-profits to justify their tax subsidies. PMID- 10109895 TI - Humana banking on insurance. AB - In a push to regain Wall Street's affection, Humana is forging ahead with its insurance business. But some critics wonder if the growing emphasis on health plans is at the expense of the company's hospital division. Humana recently expanded its reach into Chicago, where it bought both a health plan and a hospital. In Florida, Humana's push to expand its insurance presence in a number of markets already is under way. PMID- 10109897 TI - Practitioner restrictions gain momentum. AB - One bill cleared a legislative house in Washington state. Guidelines advanced by the American Medical Assn. and American Dental Assn. have gotten widespread attention. The theme: Force healthcare practitioners infected with the AIDS virus to disclose their conditions and limit their practices. It's a development that threatens to disrupt patient care and lead hospitals into a legal trap, according to industry observers. PMID- 10109896 TI - Satellite networks dish up expanded programming as they vie for viewers. AB - Competition among hospital satellite networks could heat up this year as a new player enters the game and others add programming and make other changes to improve their product. Networks hope the savings their educational programs can offer, as well as lower costs for satellite receiving equipment, will have more hospitals tuning in and more revenues rolling in. PMID- 10109898 TI - Background checks on potential workers easing some hospitals' liability concerns. PMID- 10109899 TI - Bell companies ring for hospital business. PMID- 10109900 TI - Take reality check before physician search. PMID- 10109901 TI - Bond volume slips as refinancing slides. AB - Tax-exempt healthcare bond volume fell 4.3% in the first quarter of 1991 as hospitals put the brakes on refinancings. Most facilities already have refunded higher-interest-rate debt, and others must wait for current rates to drop further for refinancing to make economic sense. While refinancings subsided, there was a flurry of new issues as hospitals replenished their depleted capital coffers. PMID- 10109902 TI - War leaves gaps in OR staffing. PMID- 10109903 TI - Case example sums up series on ten steps. AB - This is the final article about applying the ten-step model for monitoring and evaluation developed by the Joint Commission on Accreditation of Healthcare Organizations. PMID- 10109904 TI - Medical devices act means more paperwork. PMID- 10109905 TI - Advice for managers of self-managed staff. PMID- 10109906 TI - Goal-setting in physical therapy practice. AB - Goal-setting is traditionally used by physical therapists; however, factors identified in the literature as increasing goal achievement are often not considered. The purpose of this paper is to describe the potential use of goal setting in improving and measuring effectiveness in physical therapy practice. Factors identified in the literature for effective goal-setting include setting specific and measurable goals, degree of goal difficulty, goal acceptance, and feedback. Active participation by the client in the goal-setting process is of primary importance. In order to maximize the use of goal-setting in physical therapy practice, reliable, valid, and sensitive clinical measures need to be identified and developed. There appears to be a potential for further use of goal setting in physical therapy practice both as a means of improving treatment effectiveness and as a method for measuring effectiveness of treatment programs. PMID- 10109907 TI - Improving our understanding of home care quality: what can we learn from industry and health care? PMID- 10109908 TI - Coping with risk in the community: is there a need to streetproof the community health care worker? PMID- 10109910 TI - The volunteer, auxilian stat sheet. PMID- 10109909 TI - The National Community Service Act of 1990. PMID- 10109911 TI - New management roles. PMID- 10109912 TI - Performance appraisal for volunteers. PMID- 10109914 TI - Organization directory. Radiology and radiation therapy resources. PMID- 10109913 TI - Gauging the heart of medical imaging. Probing the past, exploring the present, questioning the future. AB - In fifty years, will the radiologist be obsolete? If we listen closely, we can hear voices from the past whispering that same worry. We expect our fabulous machines to grow obsolete, but professions need not wither and fade if they evolve and innovate. Today, radiology can set foundations, begin to mold the future, and then await the show. For some of the main elements have not yet appeared or are not even being anticipated beyond the bend. As Arthur Clarke said, "the real future is not logically foreseeable." It lies a little past the impossible. PMID- 10109915 TI - Inspecting the sacred cow. PMID- 10109916 TI - Moving out. Technology transfer from hospitals to outpatient facilities. AB - The Temple Radiology Group opened on July 1, 1977 in the Temple Medical Center. The initial 10-room, full-service department has grown with new technology into approximately 25 rooms. The original four-room Temple surgery center has grown to 10 rooms. Additional support facilities that have evolved include: 1) a computer company; 2) physical therapy for orthopedic, neurological and cardiac patients; 3) a brain trauma center; 4) a collection agency; and most recently, 5) a 100-bed medical hotel. PMID- 10109917 TI - Expanding applications of a QA database. PMID- 10109918 TI - PRO amendments adopted in OBRA '90. PMID- 10109919 TI - Accreditation for UR firms. PMID- 10109920 TI - Accrediting medical groups. PMID- 10109921 TI - Monthly drug inspections. Save money, protect patients and practitioners. PMID- 10109922 TI - Assuring quality of care: nursing home resident councils. AB - Increasing concern over the quality of care in nursing homes has prompted the National Institute of Medicine to recommend that residents have regular input into nursing home administration, primarily through the development of resident councils. Yet little is known of the effectiveness of resident councils. The literature is divided in its assessment of the potential of the institutionalized to represent themselves. Rather than suggesting either that resident councils are impotent or that they are a cure-all, these data, which examine the activities and effectiveness of existing resident councils, suggest that resident councils are successful in accomplishing some but not all of their objectives, that their success is maximized when professional organizers are available to help residents overcome the many barriers they face, and that there are many institutional factors that resident councils are seldom in any position to control. PMID- 10109923 TI - Foundation support for aging in the 1990s: the emerging picture. AB - This survey of grantmakers and experts in the field of aging gives a picture of where grantmakers say their funds will be targeted in the first half of the 1990s and where experts believe these funds should go. A review of the similarities between grantmakers and experts indicates that community-based support services geared toward traditional populations are a priority among both groups. The most dramatic difference is in how best to package these services. We discuss implications of the findings. PMID- 10109924 TI - The regulation of home health care quality. AB - This descriptive study examined state regulatory activities for home health agencies in California and Missouri. In California, the state survey agency was increasingly unable to meet its annual survey requirements. Missouri's survey agency was able to remain current with its survey activities. Neither state used enforcement actions to any great extent for those facilities with problems to any great during the 1983 to 1988 period. Regulatory activities for home health agencies were not given a high priority in either state, and many barriers to the effective regulation of agencies were identified. This study suggests that additional research should be directed toward the study of state regulation and its relationship to quality of home health care. PMID- 10109925 TI - Maintaining tax-exempt status. PMID- 10109926 TI - Should you expand or reduce your board? PMID- 10109928 TI - Statistics on the 1989 failed hospitals. PMID- 10109927 TI - Hospital syndication with physicians. PMID- 10109929 TI - Perspectives. Movement on the malpractice front. PMID- 10109930 TI - The essential incineration of clinical waste. PMID- 10109931 TI - Unconventional site energy strategy. PMID- 10109932 TI - Incinerators--avoiding the pitfalls. PMID- 10109933 TI - Risk management in outpatient cardiac catheterization clinics. PMID- 10109934 TI - Adverse events, negligence in hospitalized patients: results from the Harvard Medical Practice Study. AB - In summary, we reviewed a random sample of 30,000 medical records from New York State in 1984, analyzing them for the presence of adverse events and substandard care. We believe that our findings indicate that there are certain risk factors, many definable, for the occurrence of adverse events and negligence. PMID- 10109935 TI - Legislative update ... the right-to-die issue. PMID- 10109936 TI - Small-town attitudes can be big-city problems. PMID- 10109937 TI - The assumptions are changing. AB - The gavel was pounding, there was a cacophony of sound throughout the room, the union representatives were standing and asking to be recognized by the chair. The administrator of the state agency that purchases health care for employees of the state had just announced a proposed benefits cut for all employees and teachers. Unfortunately, the State of Washington is not alone in running into a financial wall. For the first time in our history, rising health care costs are significantly affecting the state's ability to educate our children, preserve our environment and pay our employees. From a base of $640 million, the projections of what the state's health benefits costs would be were for a $293 million increase, to $932 million over the next two years. That's a 46 percent increase. Something had to give, and health benefits was that "something." PMID- 10109938 TI - Strategies for lowering health care costs. PMID- 10109940 TI - Medical Personnel Pool: the staffing director's reserves. Interview by Jennifer L. Smith. PMID- 10109939 TI - America's most wanted. AB - Too few nurses, X-ray techs, lab technicians, ER specialists, trauma nurses, rural physicians.... The recent military call-up illuminated the problem that had been skirted for years. PMID- 10109941 TI - Making the job better. PMID- 10109942 TI - Keeping a rural model alive. Interview by Jennifer L. Smith. PMID- 10109943 TI - Private sector approach to health care reform. Interview by Thomas G. Goodwin. AB - The Healthcare Leadership Council (HLC) was formed in 1990 by 50 CEOs of hospitals, hospital systems, pharmaceutical companies, medical device manufacturers, Insurers and medical professionals. HLC is a coalition to develop the necessary consensus to realistically influence health care reforms. HLC urges that the "U.S. public policy goal should be to seek the best mechanism for balancing quality, access and affordability." As for access for the poor, the HLC would standardize eligibility for Medicaid at the federal poverty level, establishing a minimum basic benefit and payment plan with funding to come from specific taxes. For the employed uncovered, HLC would extend the exemption from state mandates to small employers; enact appropriate market reforms and provide income-related subsidies for those near the poverty line and for small employers; encourage employer-provided coverage for all employees on a voluntary basis.... HLC also backs state subsidized uninsurable risk pools for people whose conditions would make premiums too expensive. As for affordability of health care, HLC says consumers should become involved in cost-effective health care plans, appropriate employee cost sharing, lifestyle incentives/penalties, etc. Also, legislation should be overridden that inhibits innovation, creativity (state-mandated benefits, restrictions on selective contracting, CON requirements...), and medical malpractice tort reform measures also should be enacted. What follows is an in-depth interview with HLC Chairman G. Robert O'Brien, president of CIGNA Employee Benefits Companies. PMID- 10109944 TI - Medicare's proposed capital prospective payment regulation. PMID- 10109945 TI - The Leadership Council: a catalyst for reform. PMID- 10109946 TI - Capital equipment procurement analysis. PMID- 10109947 TI - Effects of a war. PMID- 10109948 TI - Child support enforcement program; extension of services to Medicaid recipients and to former AFDC recipients--Office of Child Support Enforcement, HHS. Final rule. AB - These final rules implement sections 9141 and 9142 of Public Law 100-203, the Omnibus Budget Reconciliation Act of 1987, which amended title IV-D of the Social Security Act (the Act). Section 9141, effective December 22, 1987, amended section 457(c) of the Act to require State child support enforcement (IV-D) agencies to provide appropriate notice and to continue to provide IV-D services to persons no longer eligible for Aid to Families with Dependent Children (AFDC) under title IV-A of the Act. The IV-D agency must continue to provide services and pay any amount of support collected to the family on the same basis and under the same conditions as pertain to other non-AFDC families, except that no application, other request to continue services or any application fee for services may be required. Section 9142, effective July 1, 1988, amended section 454 of the Act to require State IV-D agencies to provide IV-D services to families who receive Medicaid and have assigned to the State, under section 1912 of the Act, their rights to medical support and to payment of medical care from any third party, and to provide for distribution by the State of medical support collections under section 1912 of the Act. PMID- 10109949 TI - Medicare program; establishment of the advisory committee on Medicare-Physician Relationships; establishment--HCFA. PMID- 10109950 TI - Cessation of services to terminated Utes--Indian Health Service. Notice. AB - The IHS is correcting a regional policy of providing services to descendants of terminated Utes. The regional practice of deeming descendants of terminated Utes eligible for IHS services has been determined to be contrary to the purpose of the Ute Termination Act 25 U.S.C. 677, as we interpret that Act, and therefore, descendants of such terminated Utes are outside the scope of authorized IHS services. PMID- 10109951 TI - Medicare and Medicaid programs; OBRA '87 conforming amendments--HCFA. Final rule with comment period. AB - These regulations amend certain sections of Medicare and Medicaid rules to reflect 15 self-executing provisions of the Omnibus Budget Reconciliation Act of 1987 (OBRA '87) and changes made by sections 102, 103, and 211(b) of the Medicare Catastrophic Coverage Act of 1988 (MCCA), section 608(d)(3)(G) of the Family Support Act of 1988 (Pub. L. 100-485), and sections 6113 and 6301 of the Omnibus Budget Reconciliation Act of 1989 (OBRA '89). They also clarify related rules. The amendments are needed to make HCFA rules consistent with current provisions of law and to ensure that users of the regulations are not confused by outdated provisions or unclear language. This document also makes technical amendments, primarily to correct internal cross-references, make nomenclature changes, and revise an outdated definition. PMID- 10109952 TI - Beyond the total quality management mystique. PMID- 10109953 TI - Illusion vs. reality. TQM (total quality management) beyond the yellow brick road. PMID- 10109954 TI - Making total quality management work. Successful CEOs read the warning signs. PMID- 10109955 TI - The six faces of quality. What total quality management really is. PMID- 10109956 TI - The National Practitioner Data Bank: a catalyst for review of the credentialing process. PMID- 10109957 TI - Healthy people. PMID- 10109959 TI - What should be the role of the consultant in a healthcare organization's quality improvement process? PMID- 10109958 TI - Assessing your career needs. PMID- 10109960 TI - Leaders' perspectives on healthcare reform. PMID- 10109961 TI - A full-time ministry. PMID- 10109962 TI - Board must lead in overseeing quality. PMID- 10109963 TI - New risk management issues in patient dumping cases. PMID- 10109964 TI - Program builds employee support of system's mission. PMID- 10109965 TI - Protecting patient self-determination. New legislation requires healthcare providers to inform patients of rights regarding advance directives. PMID- 10109966 TI - Confronting conflict. A nursing home staff comes to grips with an elderly patient's decision to refuse nutrition. AB - For the most part, cases involving young or middle-aged persons such as Nancy Cruzan and Paul Brophy have shaped the legal and ethical landscape regarding the obligation to provide nutrition and hydration to nutritionally compromised patients. But the issue of care givers' responsibility in this area also arises frequently in the long-term care setting. One of the most difficult situations to address is what to do when an elderly patient begins to refuse adequate nutrition. Staff at Apartment Community of Our Lady of the Snows, Belleville, IL, had to wrestle with this question when Jane, a 90-year-old resident, decided her life had become too unbearable to continue. She refused to eat and demanded that nutrition not be forced on her. As they considered her situation, staff had to ask whether they clearly understood Jane's position, what actions would be in her best interest, what their professional obligations were, what they could do if her decision conflicted with professional or institutional values, and whether Church teaching shed any light on the issue. Unable to devise an alternative course of action acceptable to Jane, staff eventually acquiesced to Jane's request. Although they realized the difficulty of knowing with certainty what the right course of action is in such a case, they found support for their decision in Church teaching and in legal rulings on conflicts between the state's interest in preserving life and a patient's right to privacy. PMID- 10109967 TI - Risk management or political micromanagement? AB - A major healthcare issue of the 1990s is whether providers will create effective risk management programs to cope with government reform mandates or whether an increasingly costly and complex regulatory structure will force them to make changes. Compliance with the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) standards on patient care will become increasingly important to healthcare risk management in the 1990s. The JCAHO standards create a benchmark from which government entities set their present standards and assemble agendas for the future. Another healthcare risk management factor is compliance with the National Practitioner Data Bank. The data bank is intended to protect healthcare consumers from providers who have demonstrated a tendency to commit malpractice. However, the data bank could cause problems for healthcare providers: Inaccurate or misleading data could unfairly haunt them. Healthcare risk managers should be familiar with the prohibitions on patient dumping found in the Consolidated Omnibus Budget Reconciliation Act of 1985. The amendments of the Omnibus Budget Reconciliation Act of 1989 (OBRA '89) do not create strict liability, nor do they impose traditional tort standards that could guide courts in cases that will inevitably result from new rules, creating a "litigation time bomb." And OBRA '90 significantly revises the law. Other risk management issues include the manner in which facilities handle and dispose of medical waste and the manner in which they resolve disputes. PMID- 10109968 TI - Social justice in a time of crisis. Catholic tradition offers creative ideas for solving the problems of healthcare costs and access. AB - In this moment of crisis, Catholic healthcare leaders must seek root causes and thorough solutions to the pressures of rising costs and the grave question of access to healthcare. The first question is whether the system can be fixed or if a more radical approach is needed. To reach a solution, government, business, hospitals, and physicians must sit down at a common table to debate the issue. In 1981 the bishops outlined a series of values or principles that should characterize the U.S. healthcare system, including treating the whole person and providing access for all. These values have characterized Catholic healthcare facilities in the past decades and should not be lost in the present crisis and in the decisions being made for the future. Today, Catholic healthcare leaders have a broadened understanding of Catholic identity and the need to continually probe what that means. They realize Catholic identity is more than a few moral codes; it is a broader concern about the way in which healing takes place. Another gain is the development of lay vocations, but these are often restricted and should be more fully developed. In conjunction with this concept, we need to see hospitals as belonging to the whole Church in terms of its mission and thus the responsibility of the entire body of believers. Finally, a new image is needed concerning how care is provided. We need to bring prevention and care closer together, preventing duplication of major services and making certain basic services available to all. PMID- 10109969 TI - Preparing stewards for tomorrow. A healthcare system's intern program provides mentors for potential trustees. AB - Mentors can provide support essential to a person's advancement and growth in a new business or position. Because of the complex and rapidly changing nature of healthcare, mentors can be particularly valuable to persons interested in becoming healthcare facility trustees. Since 1987, the Sisters of Mercy Health System (SMHS), St. Louis, has implemented a comprehensive intern program for potential trustees. Each intern is assigned to a board and a board member mentor at an SMHS facility. The program lasts for two years and includes a didactic component, independent study, clinical experience, regularly scheduled meetings, and issuance of a certificate on completion. Thus far, the interns have been sisters from education, healthcare, social service, or other ministries. They must show abilities crucial for successful trustees (such as listening skills), an appreciation of and strong support for the ministry, and a willingness to commit the time and energy to the program. Mentors chosen for the program also must devote time to orientation and meetings and must assist interns in integrating mission and values into board activities. In addition, mentors help interns identify the focus of present structures and resources and their appropriateness and discuss the trustee's role and responsibilities and dynamics for quality decision making. PMID- 10109970 TI - Turnaround time. A financially troubled Philadelphia hospital goes out of the red and into the black. AB - A large Medicare population, a higher than average length of stay, an aging medical staff, and difficulty in retaining professional staff were a few of the indications that Nazareth Hospital, Philadelphia, was headed for financial difficulties. Unfortunately, Nazareth leaders overlooked these warnings because the hospital was concentrating on a major construction project. In 1989 the hospital lost approximately $5 million from operations, resulting in debt covenant violations on a $33 million bond issue. Nazareth then adopted a revitalization program with the following basic components: Establishing extensive cost-cutting measures to help reverse the financial deficits Retaining outside consultants to serve as management advocates and to keep the repositioning effort moving forward Enhancing long-range strategic planning to lay firm groundwork for the hospital's future As a result of these efforts, Nazareth went from a fiscal year 1989 operating loss to a 1990 year-end break even position. Nazareth leaders attribute this success to the total commitment by the involved constituencies: board, managers, medical staff, and employees. PMID- 10109971 TI - In touch: keeping physicians' lines open. PMID- 10109972 TI - Timely arguments. PMID- 10109973 TI - The nameless child. PMID- 10109974 TI - Readership poll on Oregon plan. Respondents support the initiative. PMID- 10109975 TI - Standards for medical information. PMID- 10109976 TI - Computerizing the emergency services--a discourse. PMID- 10109977 TI - Increasing access to long-term care through Medicaid anti-discrimination laws. PMID- 10109978 TI - Development of JCAHO confidentiality guidelines. PMID- 10109979 TI - Managing waste at Methodist Hospital of Indiana, Indianapolis. PMID- 10109980 TI - Employee-driven waste management. PMID- 10109981 TI - Waste management to save you money--at last! PMID- 10109982 TI - National health insurance and the role of material management. PMID- 10109983 TI - What to do when the auditor comes. PMID- 10109984 TI - Electrosurgical units. ECRI. PMID- 10109985 TI - The emperor has new clothes, again. PMID- 10109986 TI - Making continuous quality improvement a reality: systems skills. PMID- 10109987 TI - Waste disposal: a quiz. PMID- 10109988 TI - Optimal payment systems for health services. AB - Demand-side cost sharing and the supply-side reimbursement system provide two separate instruments that can be used to influence the quantity of health services consumed. For risk-averse consumers, optimal payment systems--pairs of insurance and reimbursement plans--are characterized by conflict rather than consensus between patient and provider about the quantity of treatment. A model of conflict resolution based on bargaining theory is used to represent the outcome when the payment system creates divergences between desired demand and desired supply. Using that model, we describe the optimal combination of insurance and reimbursement systems that maximize consumer welfare. PMID- 10109989 TI - A model of capitation. AB - This paper presents a theoretical model of capitation contracts. The consumer's ex ante choice of medical plan is derived under flexible assumptions about provider-patient decision-making. The optimal medical plan is shown to combine full insurance with a provider payment system that is a mixture of capitation and partial reimbursement of provider costs. This solution strongly parallels the 'mixed payment' system derived by Ellis and McGuire (1986, 1990) in the context of prospective payment, though the optimal medical plan derived below may in fact be preferred to that solution in a world with endogenous admissions. PMID- 10109990 TI - The sixth stool guaiac test: $47 million that never was. AB - In a 1975 paper, Neuhauser and Lewicki analysed a colorectal cancer screening policy approved by the American Cancer Society. Their analysis yielded an incremental cost per case detected in excess of $47 million. This vivid demonstration of the impact of marginal analysis is frequently cited by health economists and is often used for pedagogic purposes. The analysis is incorrect because of two fundamental errors. We have reanalysed the protocol in two stages. After correction for these errors, the $47 million disappears, the marginal cost is quite modest and the policy appears to be defensible on economic grounds. PMID- 10109991 TI - Monitoring physicians. A bargaining model of medical group practice. AB - This paper challenges the proposition that large physician-owned groups will be inefficient because of failures to control opportunism. A bargaining model implies that even large partnerships will make efficient resource and monitoring decisions. In addition, opportunism has much the same payoff for employees and partners. The data show that most large medical practice organizations are physician owned. Empirical analyses of nine forms of monitoring by large groups generally show no clear link between monitoring and ownership. There is one exception. Physician-owned firms tend to base compensation on productivity, which may help explain the continued dominance of professional partnerships. PMID- 10109992 TI - Supplier inducement. Its effect on dental services in Norway. AB - In many western countries, supply of dental services exceeds demand, mainly because of the marked reduction in the prevalence of dental diseases during the last 10-15 years. An important issue is whether dentists can counteract this fall in demand by stimulating increased demand and/or utilization for their services. Some evidence that this may be the case was found in the present study, in Norway. The results indicate that demand and utilization for dental services are influenced by supplier inducement. PMID- 10109993 TI - The long debate on the sixth guaiac test: time to move on to new grounds. PMID- 10109995 TI - Performance plan: a nursing management strategy to improve care delivery. PMID- 10109994 TI - Computerized testing in a continuing education program. PMID- 10109996 TI - Customizing a customer relations program. PMID- 10109997 TI - Implementing your plans: a model and case study application. PMID- 10109998 TI - Meeting the challenges of a changing workforce. PMID- 10109999 TI - Keeping the union at bay: a guide to employee satisfaction. PMID- 10110000 TI - Evaluations help maintain efficiency, stability. PMID- 10110001 TI - Boren litigation may provide increase in Medicaid rates. PMID- 10110002 TI - "Self help" support groups can promote resident autonomy. PMID- 10110003 TI - Pharmacists should play role in physician prescribing policy. PMID- 10110004 TI - Range of care services meets needs of diverse population. PMID- 10110005 TI - Dining programs serve more than nutritional needs. PMID- 10110006 TI - Ombudsmen help to ensure quality resident services. PMID- 10110007 TI - Regulating physician investment and referral behavior in the competitive health care marketplace of the '90s--an argument for decentralization. AB - Congress regulates the investment and referral practices of physicians through the federal Anti-Fraud and Abuse statute. The Anti-Fraud and Abuse statute, however, limits the ability of physicians to adapt their investment and referral practices to an increasingly competitive health care industry. In order to restrict fraudulent practices without restricting competition, the authority to regulate physician investment and referral practices should be returned to the states, who can recognize and exempt beneficial competitive practices from the reach of the applicable state statutes. PMID- 10110008 TI - Organizationwide quality improvement in health care. AB - Organizationwide quality improvement has offered many organizations in many different industries a new approach to work and leadership. The lessons learned can be applied to the health care setting. QA professionals can play an important role in this change by leading through example--first in their own departments and the work they currently perform and then throughout the entire organization. PMID- 10110009 TI - Quality improvement techniques. PMID- 10110010 TI - Gaining customer knowledge: obtaining and using customer judgments for hospitalwide quality improvement. AB - Customer knowledge is an essential feature of hospitalwide quality improvement. All systems and processes have customers. The aim is to use customer knowledge and voice of the customer measurement to plan, design, improve, and monitor these systems and processes continuously. In this way, the hospital stands the best chance of meeting customers' needs and, hopefully, delivering services that are so outstanding that customers will be surprised and delighted. There are many methods, both soft and hard, that can be used to increase customer knowledge. One useful strategy is to use a family of quality measures that reflect the voice of the customer. These measures can generate practical and powerful customer knowledge information that is essential to performing strategic planning, deploying quality policy, designing new services, finding targets for improvements, and monitoring those continuous improvements based on customers' judgments. PMID- 10110011 TI - Continuous quality improvement and its implications for accreditation standards. PMID- 10110012 TI - Building the future on quality improvement. PMID- 10110013 TI - Total quality management: an implementation strategy for excellence in the medical record department. AB - Trustees do not seem to agree on how quality accountability will be accomplished, but they are starting to agree that procedures to establish quality accountability are necessary. They also agree that leadership from the board level, coupled with a firm resolve to monitor quality, will ensure that hospitals provide high-quality care and services to their most important and influential customers: patients. The manufacturing industry has provided the health care industry with the benefit of its experiences with continuous quality improvement, including the pitfalls. It is both exciting and challenging to learn the philosophies of total quality management and build a customized strategy for excellence, especially in medical record departments. As a customer of numerous processes throughout the health care organization and a supplier of products and services as well, the MRD represents a common thread throughout the organization, often linking people and departments together. A medical record professional who is working in a health care organization whose executives believe in TQM can expect great things in the decade ahead. PMID- 10110014 TI - Quality improvement versus quality assurance? AB - These suggestions for applications of QI philosophies and considerations for structural integration of QA and QI are not intended to convey that organizationwide adoption of QI merely involves use of QI tools and techniques, or that instilling QI philosophy in an organization is easily accomplished. Achieving continuous quality improvement on an organizationwide basis requires long-term, senior-level commitment, extensive training, adoption of the philosophies at all management levels, and behavioral and cultural change within the organization. The adoption of QI methods and philosophies in health care organizations does not preclude the use of or eliminate the need for QA approaches. Quality improvement and quality assurance are complementary endeavors for attaining continual improvement in health care quality. Improvement of the quality of care provided is and always has been the fundamental goal of health care quality assurance. Attainment of that goal can be advanced through building on the strengths of traditional quality assurance efforts and adopting philosophies and methods of quality improvement as the core forces of total quality management programs. PMID- 10110015 TI - Assuring quality by continuously improving quality: new directions for health record professionals. AB - Quality improvement is catching fire in the health care community, but there is much work to be done, much to learn, and much to teach. All health care professionals must remember that there are no short cuts to improving quality. American managers are so steeped in a quick-fix mentality that they resist the systematic infrastructure rebuilding described above. They scurry about fighting the same fires over and over, thinking they are doing their jobs. The truth remains that if results are to be improved, not just manipulated, then the processes that produce those results must be improved. For this to occur managers must be given the process improvement technology that separates the world class companies from those who are still wondering what hit them during the 1970s. PMID- 10110016 TI - Legal review: access to adoption records--recent developments in case and statutory law. AB - Recent state court decisions on access to adoption records manifest judicial lack of sympathy toward disclosure of confidential adoption information and a reluctance to abandon earlier precedents. The courts have long frowned upon any action that would potentially discourage or impede the adoption process or that would potentially hurt any of the parties involved. The state legislatures, in response to intense lobbying by adoption groups, have tempered the rigid standards of earlier laws, allowing for the creation of adoption registry services in 21 states and for independent searches for biological parents to solicit their consent in 9 states. Still, only 3 states give an absolute right of inspection, while 18 require a court order before access to records will be allowed. Medical records practitioners should determine the rules applicable to the medical records of adoptees in their states. In the absence of specific court or statutory authority permitting the release of such records or of the consent of the natural parents, practitioners should refuse access to these records. PMID- 10110017 TI - Adaptive change in corporate control practices. AB - Multidivisional organizations are not concerned with what structure to adopt but with how they should exercise control within the divisional form to achieve economic efficiencies. Using an information-processing framework, I examined control arrangements between the headquarters and operating divisions of such organizations and how managers adapted control practices to accommodate increasing environmental uncertainty. Also considered were the moderating effects of contextual attributes on such adaptive behavior. Analyses of panel data from 97 multihospital systems suggested that organizations generally practice selective decentralization under conditions of increasing uncertainty but that organizational age, dispersion, and initial control arrangements significantly moderate the direction and magnitude of such changes. PMID- 10110018 TI - Effects of compensation strategy on job pay decisions. AB - Previous research has revealed but not explained the occurrence of wide variations in pay for the same job, even within a single local labor market. We investigated how compensation managers from a wide variety of organizations combined information about current job pay rates, market rates, and job evaluation points to arrive at new pay rates. In addition, we examined the role of organizational pay leadership position and external or internal orientation in decisions about job pay, controlling for differences in organizational demographic characteristics. Results suggest that pay strategies affect assigned pay levels, with managers from market-leading and internally oriented firms assigning higher pay. In addition, pay strategies appear to influence the relative weights attached to market survey versus job evaluation information. Organizational demographics also affected assigned pay levels, but to a lesser extent than pay strategies. PMID- 10110019 TI - The radiology/cardiology interplay. PMID- 10110020 TI - Technologist staffing at the National Naval Medical Center. PMID- 10110021 TI - A perspective of the resource based relative value scale. AB - The authors address three issues associated with the implementation of the model proposed by Hsiao, et al. First, the mathematical model used and its underlying assumption, in particular as it relates to "time," is questioned. Second, the authors argue that measured rather than perceived (surveyed) data should be used whenever possible. This is particularly true for "time." Third, the authors raise the possibility that adjustments can and should be made based on the type and average complexity of examinations performed at different facilities. The potential implications of RBRVS reimbursement schemes on the practice of diagnostic radiology are significant and, once implement, they will be difficult to alter. PMID- 10110022 TI - Patient outreach: the key role of mammographic technologies in mammogram compliance. PMID- 10110023 TI - Digital storage of images. PMID- 10110024 TI - Profit maximization in referral-based practices. PMID- 10110025 TI - Perspectives. Opening the borders to Hispanic health. PMID- 10110026 TI - Community-based care: an alternative to institutionalization. AB - By focusing on the deinstitutionalization of the physically, mentally, and developmentally impaired, the public's attention is too frequently diverted away from the greater need for the development of community-based services. PMID- 10110027 TI - Development of a mental health home care program. AB - Serving the mental health patient at home requires the coordination and teamwork of a psychiatrist, a mental health nurse, and family members, as well as an extensive planning process. PMID- 10110028 TI - Visiting Nurse Service of New York: bringing the mental health clinic to the home. AB - The Community Mental Health Services Division of VNS Home Care, New York has evolved from a single mobil crisis program a wide array of services for children, adults, and elderly persons, addressing both acute and chronic psychiatric problems. PMID- 10110029 TI - Visiting Nurse Service of New York: the Mobile Crisis Service. PMID- 10110030 TI - Visiting Nurse Service of New York: providing in-home psychiatric assessment and treatment to HIV clients. AB - As HIV patients' lives are extended and more is learned about the disease, neurological and psychiatric disorders are seen with increasing frequency. The Visiting Nurse Service of New York recently expanded its AIDS project to include psychological services to HIV clients at home. PMID- 10110031 TI - Current statistics on AIDS. PMID- 10110032 TI - Visiting Nurse Service of New York: the home-based crisis intervention program. PMID- 10110033 TI - A model for integrating research into home care. PMID- 10110034 TI - Deinstitutionalization and mental health. AB - Better understanding of the problems related to deinstitutionalization is essential for all those involved with community care. Finding ways to address the issues raised by deinstitutionalization is the key to using all community resources-including home care-in building a better system of mental health care. PMID- 10110035 TI - The decision makers. Interview by Glen Hopper. PMID- 10110036 TI - More effective hospital foundations. PMID- 10110037 TI - Hospital boards: developing a vision. PMID- 10110038 TI - Standards for governance: mission, planning and goals. PMID- 10110039 TI - Developing effective labour relations skills: understanding the grievance process. AB - The grievance process provides a formal mechanism for dealing with worker management disputes arising from the application of negotiated collective agreements. This paper examines the literature describing the direct and indirect functions of the grievance process, grievance procedure language, and arbitration. Some of the unique features of labour relations and the grievance process in the public sector are also reviewed. Pharmacy Managers are encouraged to improve their personnel management skills by developing a greater understanding of the grievance process. A number of recommendations are provided to assist the Pharmacy Manager in the handling of grievances. PMID- 10110040 TI - Quality assurance program for a nuclear pharmacy. AB - The development of a quality assurance program for a nuclear pharmacy service is described. The program was established to complement and test the extensive quality control procedures in the nuclear pharmacy. Based on current nuclear pharmacy standards of practice and government regulations, audits were developed and tested for a 12-month period. Results of these audits were closely analyzed for their relevance and impact on the service. These results showed that the standards for the established quality control program were being met. It was concluded that the quality assurance program was a useful and practical tool. PMID- 10110041 TI - A peer review quality assurance program in drug information. AB - The development and implementation of a peer review quality assurance program for a drug information service is described. Eight drug information centres across Canada initially agreed to participate as peer reviewers. Critera were developed to select drug information requests that would qualify for the program. Peer review responses were compared to the centre's response by a panel of four drug information pharmacists. Thirteen of 14 requests sent to peer reviewers were returned and there was agreement between the conclusions and recommendations provided in the responses by our drug information centre and the peer review pharmacist in 11 cases. Peer reviewer pharmacists tended to prepare more in depth responses. This represents the first report of a peer review quality assurance program for a drug information service. PMID- 10110042 TI - Prescriber identification program. PMID- 10110043 TI - AIDS women, boarder babies: complex discharge problems. PMID- 10110044 TI - New Congress health priority: women's and children's issues. PMID- 10110045 TI - Psychiatric problems cause complex discharges. PMID- 10110046 TI - Complex discharges: emerging and emergent concerns. PMID- 10110047 TI - Coming to terms with OBRA. AB - The Omnibus Budget Reconcilitation Act of 1987 contains sweeping changes in nursing home regulations aimed at improving residents' quality of life. However, implementing these rules in today's economy has operators of even well-managed nursing homes worried. Here's why. PMID- 10110048 TI - Securing your assets. PMID- 10110049 TI - Solving the labor problem & containing costs, Part II. Broadbanding & empowering employees will help shape foodservice in the '90s. PMID- 10110050 TI - Rhode Island's patient-friendly computer system. This hospital's foodservice developed a computer program with staff and patients in mind. PMID- 10110051 TI - Special report on patient care. New OBRA 1990 requirements regarding advance directives. AB - The provisions of OBRA 1990 regarding advance directives reflect a heightened awareness in Congress of the need to recognize individual rights and preferences in the provision of health care. In the wake of recent decisions such as Cruzan v. Director, Missouri Department of Health, 110 S. Ct. 2841 (1990) (see Newsletter, Vol. 5, No. 9, September 1990, at 12), holding that state law governs the right of a surrogate to order the discontinuation of medical treatment for an incompetent patient, it is likely to remain true for the foreseeable future that differing state laws on the subject of advance directives will create confusion for some patients, particularly those unaware of the laws of their state, those living near the border between two states, and those traveling between states for medical treatment. For such patients, the provisions of OBRA 1990 may help to ensure that state laws governing advance health care decisions are explained at the time of treatment. PMID- 10110052 TI - Supporting a facility's mission through record system design. AB - This article describes a project in which the author was involved while employed as an assistant professor in the Health Information Administration Program at the University of Wisconsin-Milwaukee (UMW). PMID- 10110053 TI - AMRA's volunteer structure. PMID- 10110055 TI - Ambulatory care. PMID- 10110054 TI - Humor and stress: the workplace connection. PMID- 10110056 TI - The good news from Washington for internists. PMID- 10110057 TI - From the beneficiary's point of view. PMID- 10110058 TI - Do we have the courage to hammer out a solution to the access problem? PMID- 10110059 TI - What you should know about ... organ donation. American Society of Internal Medicine. PMID- 10110060 TI - Better safe than sorry. PMID- 10110061 TI - Cue for queue cutting. PMID- 10110062 TI - A wand for Cinderella. PMID- 10110063 TI - Home truths of community care. PMID- 10110065 TI - Transport. A fleeting problem? PMID- 10110064 TI - Transport. For fast acting relief. PMID- 10110066 TI - When the future is in futures. PMID- 10110067 TI - Derby Design Inc. PMID- 10110068 TI - Listen to the people. PMID- 10110069 TI - A question of teamwork. PMID- 10110070 TI - Management training. Knowledge by degrees. PMID- 10110071 TI - Management training. Me and my shadow. PMID- 10110072 TI - The introduction and evaluation of magnetic resonance imaging in Australia. AB - The introduction of magnetic resonance imaging (MRI) into Australia was linked to a formal assessment of the technology in public hospitals associated with restrictions on government funding. The assessment produced comprehensive data on the usage, cost and efficacy of MRI in the hospital setting. This paper summarises the major results of the assessment and considers issues related to the methodology used and the impact on the policy process. PMID- 10110073 TI - Minding our Ps and Qs? Financial incentives for efficient hospital behaviour. AB - In this paper, the empirical evidence addressing the particular issue of how hospitals may be reimbursed is reviewed. Most forthcoming is the indeterminate effect of prospective payment systems using diagnosis-related groups as a means of controlling costs. Such systems, by controlling only the price of hospital care, remain vulnerable to compensatory increase in patient throughput, cost shifting and patient-shifting despite hospital cost per case being reduced. Health maintenance organisations have been shown to reduce hospital costs, but their effects on patients selection and patient outcome are unclear. Selective contracting in California (similar to the U.K. Government's proposed internal market) has also been shown to reduce costs by affecting both the price and quantity of hospital care. But these effects have occurred only in areas with high concentrations of hospitals. Global and clinical budgeting (which control price times quantity) seem to offer the most potential for cost reduction whilst maintaining patient outcome. By monitoring both cost and outcome within clinical budgets it should be possible to reduce wasteful variations in health care and so establish more efficient hospital practice. PMID- 10110074 TI - A surplus of physicians in Israel: any lessons for the United States and other industrialized countries? AB - In Israel, there is a consensus that there is a surplus of physicians. An examination of the Israeli situation may suggest some responses that will be taken by policy makers and physicians in the United States and other industrialized countries as the supply of physicians continues to increase. Specifically, we examine the impact of rising physician supply on the geographic distribution of physicians in Israel, the length of the training period for residency programs, the interaction between physicians and other professionals, and the level of physician incomes compared to other Israeli workers. PMID- 10110075 TI - The COBRA anti-dumping law: new requirements and unresolved issues: Part 1. PMID- 10110076 TI - Choosing a hospital: analysis of consumer tradeoffs. AB - In today's competitive health care industry, hospital administrators and marketers must determine how important various product/service attributes are to potential consumers and how those attributes influence consumer choice decisions. The authors outline an approach (the analytic hierarchy process) that can be used to assess or predict health care choice decisions by consumers. The analytic hierarchy process is a method for analyzing consumer choice behavior whereby a hierarchical structure is used to determine the relative preferences of consumers for health care alternatives. Marketing strategies based on the study findings are suggested. PMID- 10110077 TI - A broadened view of ethics and health care marketing. PMID- 10110078 TI - How marketing oriented are hospitals in a declining market? AB - The role of marketing in a health care facility has been a focus of discussion during the past decade. Varied opinions have been expressed about the purpose and contribution of marketing within the health care industry. The authors empirically investigate (1) the extent of marketing orientation in hospitals, (2) the degree of marketing orientation as it relates to hospital characteristics, and (3) the relationship of marketing orientation to hospital performance. PMID- 10110079 TI - Considering the competition in strategy development: an extension of importance performance analysis. AB - The author extends importance-performance analysis by including competitors' performance. He demonstrates its value by applying it to a national sample of HMO members. Findings indicate that inappropriate strategies may result if a competition dimension is not included in the analysis. PMID- 10110080 TI - Cancer information: women's source and content preferences. AB - The authors examine the preferences of women who have undergone mammography for specific cancer-related information content from four information sources: doctors, friends/family, organizations, and media. Statistical analyses reveal significant interactions between content and sources and significant main effects for sources and for content. These findings raise important issues for health related marketing campaigns. PMID- 10110081 TI - The marketing decade: a desktop view. AB - The authors challenge health care marketers to put into perspective the brief history and development of the health care marketing function and process. They advocate closing the gap between strategy development, operations management, and strategy implementation, and suggest that "strategic management" may be the way to organize for marketing. Marketers' roles and readiness for strategic management are discussed. PMID- 10110082 TI - Strategic market planning in hospitals: is it done? Does it work? AB - A nationwide survey of strategic market planning within hospitals was conducted. The level of strategic market planning activity performed by hospitals is reported. Level of planning maturity also is determined. Levels of activity and maturity are related to satisfaction with strategic market planning. Results and implications are presented. PMID- 10110083 TI - Overnight assessment of marketing crises. AB - The Cleveland Clinic Foundation received significant negative publicity in 1987 when a surgical resident was reported to have AIDS. The resulting pressures from senior managers for immediate market information stimulated development of an overnight market research capability through prenegotiated contracts with market research suppliers so that studies could be implemented on short notice. Contracts have been signed with three market research companies and the overnight market research methods have twice been used successfully with only minor modifications. PMID- 10110084 TI - The importance of internal marketing: the case of geriatric services. AB - Hospitals seeking to become more aggressive often are tempted to introduce programs prematurely. Using the example of a geriatric services program at a large hospital, the authors illustrate the dangers of neglecting internal marketing and offer recommendations for ensuring internal coordination prior to introduction of a product externally. PMID- 10110085 TI - Residency after 40 is about 40 times tougher. PMID- 10110086 TI - Employers might lose a popular cost-cutter. PMID- 10110087 TI - Tracking your inpatients will get easier. PMID- 10110088 TI - An industry that's booming in spite of itself. PMID- 10110089 TI - Who'll be liable when a patient is injured? PMID- 10110090 TI - "They really should call it managed doctors". PMID- 10110091 TI - Will insurers pay for high-tech care? PMID- 10110092 TI - Effective committees: a contradiction in terms? AB - Because of the nature of committees, evaluating their effectiveness is highly subjective. The ultimate test is whether the group is able to arrive at good solutions and decisions which can be implemented. Author Robert Travis, M.B.A., looks at three actual committees, offering reasons for the success or failure of each, and then gives several pointers on creating effective committees. PMID- 10110093 TI - What is ahead for medicine in the 1990s? AB - Authors Judith Berger and Michael Kurtz write that many external factors are threatening the quality of health care in the 1990s. The authors look at health care developments, future trends and what it all means to group practice and health care in general. PMID- 10110094 TI - National health insurance and its impact on group practice. Part one. AB - In the last decade, medical group practices have readily adapted to the prospective payment system and managed care environment. In this article, Thomas Weil, Ph.D., speculates on the possibility and impact of equal access and universal coverage, i.e., national health insurance. PMID- 10110095 TI - The Deming method for problem solving in group practice. AB - Health care providers are entering a new age of delivery, write authors David Cooke, C.P.A., M.B.A., and Kathleen Iannacchino, RN. Gone are the days when health care was measured only by scientific and caring standards. Today, patients, payers and industry members are shopping for quality health care at the best price. Cooke and Iannacchino describe how the Keene Clinic, Keene, N.H., used the Deming approach to quality improvement in the area of health care. PMID- 10110096 TI - HealthLine--marketing and public education wrapped up in one. AB - A service which can promote both marketing and public education is especially useful in these highly competitive times, writes Bridget Larsen Wright, M.P.H., et al. HealthLine, an information service for the general public, was developed to promote these areas, and Wright explains how a Southern California clinic implemented the service, and provides some preliminary results. PMID- 10110097 TI - The health periodicals database: full-text access to consumer and technical health information. AB - The HEALTH PERIODICALS DATABASE, produced by the Information Access Company, is a unique online file which provides full-text access to both general interest health-related literature and key technical resources in the medical field. Available on DIALOG and CompuServe, the database is described as a useful tool for information on the health, fitness, and nutrition industries. Special features of the database are reviewed and comparisons are made with resources of similar scope. PMID- 10110098 TI - The effect of CD-ROM MEDLINE on online end-user and mediated searching: a follow up study. AB - Indiana University School of Medicine Library (IUSML) has traditionally been a high volume searching institution. The dramatic effect of CD-ROM on online end user searching and the negligible effect on mediated searching was reported in an earlier study. This follow-up study reveals that the proportion of mediated searching has been drastically reduced from 94% in 1986/87 to 39% as of November 1989. Mediated searches are declining in absolute numbers as well. End-user searching, by contrast, has increased by 54% percent over the previous year. A related trend is the increased use of CD-ROM by the librarian as an alternative to mediated online searching. These trends are expected to continue as IUSML expands its CD-ROM operation to include other databases. As mediated searching declines, the librarian's role will increasingly include end-user training. PMID- 10110099 TI - CD-ROM MEDLINE training: a survey of medical school libraries. AB - Most medical school libraries are attempting to provide some form of training for the CD-ROM MEDLINE user, according to this survey conducted in 1989. User guides and vendor-produced tutorials are helpful but are not usually a major aspect of the training. The training sessions vary considerably in length as well as number of attendees, with individualized training being the most widespread. Few facilities offer advanced classes. A core list of training topics has been identified. Evaluation of the training has been done in only a small percentage of the libraries. PMID- 10110100 TI - Teaching reprint file management: a hands-on approach. AB - The development of user-friendly search systems has enabled physicians to perform their own MEDLINE searches These physicians are recognizing a need to learn how to organize their growing reprint collections. Librarians at the University of Michigan, Alfred Taubman Medical Library have developed a unique course that presents a variety of techniques to meet the needs of a wide audience. For some users, such as students or house officers who have limited funds or lack support devices, a variety of manual methods are presented. Advantages and disadvantages of using manual versus computerized systems are discussed. Following the illustration of the manual methods, users are introduced to a simple computerized method using a utility type database management package, PC-FILE. Hands-on training under the direction of librarians allows students to develop and use a practice database while having experts available to answer questions. Users are encouraged to take a copy of PC-FILE (shareware) with them to experiment with before committing themselves to a more expensive database management software package. Before the class ends, those interested in a more sophisticated package with specialized report formats and downloading/uploading capabilities are given a brief demonstration of PRO-CITE. Evaluations have shown that there is interest in all three methods. PMID- 10110101 TI - HIFF: health instruments file database. PMID- 10110102 TI - Public access microcomputers. Part II: Operational planning. PMID- 10110103 TI - Physician payment reform--putting the fee schedule together. AB - In 1989, Congress enacted sweeping legislation to require that Medicare pay physicians under a single fee schedule beginning in January 1992. Although the law was detailed in specifying the structure of the fee schedule, it left many difficult policy and operational issues to be resolved. This article discusses how the agency charged with implementing the new law will address those issues and describes some of the key steps that will be taken to put the fee schedule together. PMID- 10110104 TI - Avoiding traps and pitfalls in National Practitioner Data Bank compliance. AB - Quirks in the National Practitioner Data Bank regulations and operations may catch medical staffs and hospitals unawares, creating potential traps and pitfalls that could result in exposure to lawsuits and federal sanctions. In this article, the author outlines several areas of possible difficulty and offers tips to help medical staffs avoid problems in these areas. PMID- 10110105 TI - Economic credentialing--why it must be stopped. AB - In this article, the author describes how hospitals are using economic factors in the credentialing process, points out the flaws in this practice, and discusses some of the relevant case law. The author concludes by explaining why economic credentialing should be discontinued and urges physicians to reject it. PMID- 10110106 TI - Potential liability in utilization review: the risk grows. AB - The use of cost containment measures in utilization review is a continuing topic of concern to physicians and payors. Focusing on a recent California case that dealt with this issue, this article discusses the potential liability of physicians and payors when such measures are used. PMID- 10110107 TI - The constitutional right to be free from double jeopardy: a new bastion against multiple punishments. AB - When physicians are charged with criminal conduct related to the practice of medicine, the matter is almost always referred to the state licensing board for discipline. If the conduct complained of is related to the Medicare or Medicaid programs, the physician may also be subjected to civil monetary penalties. As a result, physicians are often faced with multiple punishments for a single offense. In this article, the author discusses how a recent United State Supreme Court decision may provide immunity to physicians from multiple punishment. PMID- 10110109 TI - Highlights of 1990 Tax Act. PMID- 10110108 TI - Health care litigation: a common theory of noneconomic damages compensation. AB - In this article and the preceding article, the sixth and seventh in a series on health care litigation, the topic of noneconomic damages in medical malpractice cases is discussed. The preceding article addressed the law regarding noneconomic damages for emotional distress to third parties. This article describes a number of recent attempts to expand other categories of noneconomic damages, shows how this expansion can result in tort law problems, and suggests a possible solution. PMID- 10110110 TI - National Practitioner Data Banks's impact on medical groups. PMID- 10110111 TI - What every trustee should know about self-evaluation. PMID- 10110112 TI - Auxilians are the mortar of health care. PMID- 10110113 TI - Meetings are the battlegrounds of business. PMID- 10110114 TI - Michigan's hospitals in the 1980s. PMID- 10110115 TI - New Medicaid cuts threaten hospital stability. PMID- 10110116 TI - IRS warns against schemes to reduce income tax liability. PMID- 10110117 TI - Rate reductions could affect patient outcomes, study says. PMID- 10110118 TI - Senator rips condition of care at VA hospitals. PMID- 10110119 TI - Restructured McGaw racking up IV contracts. PMID- 10110120 TI - Failed insurer's annuities in doubt. PMID- 10110121 TI - Dukakis proposes universal health plan. PMID- 10110122 TI - GAO head endorses reform resembling national health plan. PMID- 10110123 TI - Hospital reps fear plan would create rate-setting groups. PMID- 10110124 TI - VA budget gets boost from Gulf war. PMID- 10110125 TI - Executives need to be aware of turns of fast-approaching new Medicare capital rules. PMID- 10110126 TI - Problems persist with organ donations. AB - A growing gap between the number of patients awaiting a transplant and the number of organs donated is forcing federal officials to try to improve the system of organ sharing among hospitals. Some professionals say tampering with the system could worsen the organ shortage. Others argue that a broader system of sharing would benefit everyone. PMID- 10110127 TI - Executive compensation committee plays key role in board's stewardship. AB - Board members charged with a facility's stewardship should include executives among the key assets involved, and the way to assure executive compensation committee, says Jos. Michael Galvin. PMID- 10110128 TI - Study estimates broad effects of capital rules. PMID- 10110129 TI - Bond insurer giving more issuers a chance. AB - Bond insurances firms generally provide credit enhancement only to A-rated hospitals. But a new player in the tax-exempt healthcare bond field is insuring a select number of hospitals with BBB ratings, saving those facilities millions of dollars in interest payments. PMID- 10110131 TI - Justice Dept. drops probe of Calif. system. PMID- 10110130 TI - FTC asks court to block Ga. hospital acquisition. PMID- 10110132 TI - AHM reports $15.6 million loss. PMID- 10110133 TI - HealthTrust's earnings rebound in 2nd quarter. PMID- 10110134 TI - 'Half of hospitals' ventilator costs aren't recovered'. PMID- 10110135 TI - An emergency department perspective: Part II. Process review. AB - Webster defines process as a "series of actions or operations conducting to an end." Each of the many processes that may be involved with providing a service or procedure comprises many smaller steps. It is the monitoring of those steps that we call a process review. The process review for quality management begins when a patient perceives the need to receive emergency care. It embodies the technical and interpersonal aspects of the patients, and the staff's interpersonal relationships. PMID- 10110136 TI - Coverage, technology assessment, and the courts. AB - Coverage decisions by third-party payers are relying more and more heavily on the conclusions of technology assessment programs about the safety and effectiveness of technologies applied in specific clinical situations. Assessment programs vary markedly in the sophistication and rigor of their methodology. Payers differ as to how such assessment information is integrated into their decision-making processes. Finally, coverage decisions about a specific technology can vary widely across the country. PMID- 10110137 TI - Management of conflict in organizations. AB - Effective communication is the fundamental principle for managing organizations. Building effective communication should begin with improvements at the lowest level, one-to-one. Conflict in an organization is an indication of the most basic communication failure. Failure to talk with someone. Failure to notify someone of something before it becomes public. Failure to involve someone in a problem solving process. PMID- 10110138 TI - Common sense leadership. AB - Common sense has to do with problem solving. In the complexities of everyday human life, we are faced time and again with the need to solve problems. In fact, every situation we face, at least at the first exposure, requires some form of problem solving. When we want food, we have to solve a series of problems from acquisition to preparation to serving and eating. When we deal with organizational needs, problem solving is the daily fare. PMID- 10110139 TI - Credentialing, the most important function for success. AB - After years of attempting to control costs by changing providers' behavior and practice patterns, it has become apparent that the solution lies in the study and cooperation of practitioners. Computers, reports, analysis, and payment reforms have discovered the truth: Many physicians and hospitals have always provided high-quality care efficiently. Costs will be controlled when these providers dominate the health care delivery system. PMID- 10110140 TI - Controlling group medical costs. AB - Benefit costs can be managed effectively, but they are not just the human resource or benefit manager's responsibility. It requires a team approach, with top management involvement and commitment. Cost management is an ongoing process, quite different from cost fixing, which is just a short-term bandage. This article deals with group medical and life plans. Subsequent articles will discuss long-term disability, retirement plans, and other benefit programs. PMID- 10110141 TI - Balancing the board-CEO relationship: the CEO's role. PMID- 10110142 TI - More cuts in outpatient payment. PMID- 10110143 TI - Physician leaders give management a report card. PMID- 10110144 TI - Geriatric psychiatric units: caring for patients nobody wants. PMID- 10110145 TI - RNs on the board: a leg to stand on. PMID- 10110146 TI - Bylaws dictate governance model. PMID- 10110147 TI - Trustees: agents of community need. PMID- 10110148 TI - Employing foreign nurses. PMID- 10110149 TI - Foundations take the reins in fund raising. Interview by Karen Gardner. PMID- 10110150 TI - Institutional decision making: what role for nurses? PMID- 10110151 TI - Medicaid program; eligibility groups, coverage, and conditions of eligibility; legislative changes under OBRA '87, COBRA, and TEFRA--HCFA. Final rule. AB - This rule amends the Medicaid regulations to incorporate or revise the following mandatory and optional eligibility groups of individuals for Medicaid coverage: (1) Pregnant women; (2) qualified children under a specified age; (3) children in adoptions and foster care; (4) certain disabled widows and widowers; and (5) certain disabled children being cared for at home. The rule also adds a condition of eligibility relating to third party liability for medical assistance expenditures. The amendments conform the regulations to certain statutory provisions of the Omnibus Budget Reconciliation Act of 1987, the Consolidated Omnibus Budget Reconciliation Act of 1985, and the Tax Equity and Fiscal Responsibility Act of 1982. PMID- 10110152 TI - Dispelling the common myths of systems procurement. PMID- 10110154 TI - Carousel or straight traylines? PMID- 10110153 TI - Organizing a hospital disaster response: an 11-point plan. PMID- 10110155 TI - Planning the leadership transition. AB - According to the author, a successful leadership change should not be left to chance. Such a transition must be planned and carefully managed. PMID- 10110156 TI - The true costs of nursing care. A simple approach provides more accurate accounting of nursing services. AB - Since the prospective payment system mandated that they define and control costs more efficiently, healthcare organizations have separated nursing care from fixed overhead and reevaluated cost-containment restraints. Nursing objectives and daily data collection help to assign patients to one of four classes, from routine to continuous care. Providers can use these four classifications to monitor nursing productivity and allocate labor, employing such set variables as hours per patient day, indirect care, constant time, productive and nonproductive time, and profit margin. The result of this system is variable billing that more accurately reflects the true cost of nursing care. This proposed system of more open cost accounting makes patients and families more knowledgeable consumers. Administrators reviewing such cost breakdowns can evaluate nursing and other departments more effectively and market specific services more competitively. The system shows that nursing can be a profit, not a cost, center, which increases nurses' commitment and satisfaction. Organizations should encourage nurse managers to incorporate business into their traditional role. Cost accounting within nursing makes identified costs more manageable and increases efficiency throughout the organization. PMID- 10110157 TI - Rule delay leaves foreign nurses in limbo. PMID- 10110158 TI - Government eases up on foreign nurses. PMID- 10110159 TI - New pathology lab designed for convenience. PMID- 10110160 TI - Border hospital's guard garb ripped. PMID- 10110161 TI - Little-noticed law should bring hospitals good cheer. AB - A little-noticed provision in the new federal budget law aims to sign up significant numbers of pregnant women and children for Medicaid, using simplified application forms that can be filled out and evaluated right in the hospital. Healthcare providers should be cheering about this development, says Jerome Brazda. PMID- 10110162 TI - The ties that bind: AHA and trustees. PMID- 10110163 TI - QBPA (quality based performance analysis): a quality management resource for sustaining competitive advantage. PMID- 10110164 TI - How to start your own TQM (total quality management) program. Part one. PMID- 10110165 TI - Medicare program; mid-year FY 1991 changes to the inpatient hospital prospective payment system; correction--HCFA. Final rule with comment period; correction. AB - In the January 7, 1991 issue of the Federal Register (FR Doc. 90-30619), (56 FR 568), we implemented several provisions of section 4002 of the Omnibus Budget Reconciliation Act of 1990 (Pub. L. 101-508) that affected Medicare payment under the inpatient hospital prospective payment system for discharges occurring on or after January 1, 1991. This notice corrects errors made in that document. PMID- 10110166 TI - Medicaid program; modification of certain requirements for health insuring organizations--HCFA. Correction notice. AB - This notice corrects 42 CFR 434.20, Basic rules, to restore current text which was inadvertently deleted in the final rule, to make a conforming redesignation change, and to correct technical errors. PMID- 10110167 TI - Indian Health Service; method for evaluating and establishing reimbursement rates for health care services authorized under the Indian Health Service contract health service regulations--Portland area--PHS. General notice. AB - Indian Health Service (IHS) issues this General Notice to inform the public that IHS will conduct a pilot project in the Portland Area, IHS, to determine whether an alternative method of evaluating and establishing reimbursement rates for contract health services (CHS) will result in greater participation by health care providers and lower costs to IHS. The pilot project is limited to the Portland Area, and does not affect the present methods of evaluating and establishing reimbursements rates and awarding contracts for health care services in other IHS Areas. In addition, the pilot project does not change the current IHS payment policy requirement that health care services be procured at rates which do not exceed prevailing Medicare rates. PMID- 10110168 TI - Cookbook medicine. AB - A new federal health agency to establish guidelines for the practice of medicine started out with high hopes that it can help lower the nation's health care bill. But big savings seem unlikely. PMID- 10110169 TI - Buffering effects of four social support types on burnout among social workers. PMID- 10110170 TI - Assessing the effect of vendorship on fee setting for social workers: an empirical test. PMID- 10110171 TI - The relationship between social support and burnout: clarification and simplification. PMID- 10110172 TI - Global work force 2000: the new world labor market. AB - Just as there are global markets for products, technology, and capital, managers must now think of one for labor. Over the next 15 years, human capital, once the most stationary factor in production, will cross national borders with greater and greater ease. Driving the globalization of labor is a growing imbalance between the world's labor supply and demand. While the developed world accounts for most of the world's gross domestic product, its share of the world work force is shrinking. Meanwhile, in the developing countries, the work force is quickly expanding as many young people approach working age and as women join the paid work force in great numbers. The quality of that work force is also rising as developing countries like Brazil and China generate growing proportions of the world's college graduates. Developing nations that combine their young, educated workers with investor-friendly policies could leapfrog into new industries. South Korea, Taiwan, Poland, and Hungary are particularly well positioned for such growth. And industrialized countries that keep barriers to immigration low will be able to tap world labor resources to sustain their economic growth. The United States and some European nations have the best chance of encouraging immigration, while Japan will have trouble overcoming its cultural and language barriers. PMID- 10110173 TI - The case of the downsizing decision. AB - New CEO Charles Rampart's decision to make deep across-the-board cuts at Universal Products Company, Ltd. presents division manager Andrew Jordan with a thorny problem. Plagued by slow growth, a declining stock price, and an increasingly skeptical investment community, UPC needs to control costs and control them fast. But Jordan's division is the most profitable in the company, and the 11% cut proposed by Rampart could destroy already shaky morale and seriously threaten the division's ability to compete. "There comes a time in every manager's career when he has to fight a bad decision made by his boss," argues Sam Godwyn, Jordan's vice president for marketing and sales. "To cut across the board is to take a blunt axe to the company when a surgeon's scalpel is called for." He suggests it is better to line up support for an alternative plan that links cuts to a long-term strategy and that differentiates between successful and unsuccessful divisions. "It would be a terrible mistake for us to focus only on the narrow needs of the division when the future of the whole company is at stake," counters Mary Wyatt, Jordan's vice president for finance. Yes, the downsizing will hurt the division in the short term, but the real issue is getting behind the new CEO. Supporting the downsizing decision is a necessary investment in this future credibility and effectiveness--whatever the short-term costs. Four commentators debate Jordan's dilemma and how he should resolve it. PMID- 10110174 TI - Demand better results--and get them. AB - This HBR classic, first published in 1974, asks and answers one of management's most important questions: Why do so few organizations reach their productivity potential? The answer: because most senior executives fail to establish expectations of performance improvement in ways that get results. They fail because making heavy demands involves taking risks and threatens those who have the demands imposed on them. It's safer to ask for less. To avoid facing the reality of underachievement, managers may rationalize that their subordinates are doing the best they can or that better performance requires more authority or greater resources. They may put their faith in incentive plans that don't need their personal intervention. They may actually set high goals but let subordinates escape accountability for results. To get out of these doldrums, executives have to be willing to invest time and energy; responsibility can be delegated only so far. The key to the recovery strategy is to set a specific, modest, measurable goal pertaining to an important problem in the organization. If this goal is met, management uses the success as a springboard for more ambitious demands, each one carefully supported by plans, controls, and persistence directed from the top. Resistance can be expected from many levels. But as the organization registers genuine achievement, consciousness-raising in the form of recognition transforms expectations into positive factors. The fact is, most people like to work in a results-oriented environment. In a retrospective commentary, the author writes that while companies today are more impressed with the need for performance improvement, the ability to establish high expectations is still the most universally underdeveloped managerial skill. PMID- 10110176 TI - A motivation system with no budgetary implications. PMID- 10110175 TI - Defining quality care. PMID- 10110177 TI - Once reorganization--then downsizing--now rightsizing. PMID- 10110178 TI - Assuring that you have the right people. Step 3: Questions and answers. PMID- 10110179 TI - Strategies for merger success. PMID- 10110180 TI - New marketing mix stresses service. AB - The seven Ps of service management include some nontraditional ingredients to help formulate marketing strategy. Two examples illustrate how competitive advantage can be won or lost based on applying or ignoring the seven Ps. PMID- 10110181 TI - How to develop an information technology strategy. PMID- 10110182 TI - Techniques for making people more productive. PMID- 10110183 TI - Why CEOs have difficulty implementing their strategies. PMID- 10110185 TI - Trucking along with Grateful Med. PMID- 10110184 TI - Ambulatory care: the second "core business" of hospitals in the 1990s. PMID- 10110186 TI - Kaisen. EMS as theater of the streets. Part two. AB - Passing an EMT or paramedic course is a considerable achievement, as you have had to acquire a huge and fascinating volume of medical knowledge. But, did the program teach you acting skills? Acting? Whoever said that EMS professionals need to know anything about acting? We submit that you do; prehospital workers can gain many unanticipated benefits by using various acting skills and tactics in the field. One such benefit is the avoidance of the "complacency trap," or the boredom that can develop if you adopt the viewpoint that one crisis is much like another. But, more importantly, you will be more effective at delivering prehospital care, and you'll have a lot more fun on the job. PMID- 10110187 TI - The future of FEMA (Federal Emergency Management Agency). PMID- 10110188 TI - Does EMS get burned by the Fireman's Rule? PMID- 10110189 TI - Scouting medical advances in Operation Desert Storm. PMID- 10110190 TI - Please don't drag the bag. PMID- 10110191 TI - Pulling your weight in EMS politics. PMID- 10110192 TI - EMS and the IRS: clarifying a taxing relationship. PMID- 10110193 TI - Getting online with the times. Medical literature searches. PMID- 10110194 TI - Increasing the board's involvement in strategy. AB - For a long time, boards of directors have been considered weak, incapable of contributing to the financial success of their companies. This article proposes a way to revitalize boards by involving them in mapping corporate strategic directions. Building on recent changes in boardroom practices, it outlines eight conditions for an effective strategic contribution by boards and specifies areas of potential for an effective strategic contribution by boards and specifies areas of potential interest to directors. Taken together, these suggestions are expected to ensure continuous and disciplined contribution by boards to strategy and, ultimately, to effective corporate performance. PMID- 10110195 TI - Levi's corporate AIDS programme. AB - AIDS is a contemporary phenomena that has been extensively covered by the media but its impact on the employers of the sufferers is only now being measured and assessed. This article describes the personnel policies that have been developed by one particular organization to deal with the problem. Educational and training programmes have been initiated and management given clear directives to ensure that high morale and productivity are maintained during potentially adverse situations. PMID- 10110196 TI - Volunteers in the U.S.: who donates the time? PMID- 10110197 TI - Trends in employer-provided health care benefits. PMID- 10110198 TI - Employer-sponsored prescription drug benefits. AB - In summary, between 1979 and 1989, prescription drug costs increased by 151 percent, the rate of growth second only to the costs of hospital room and board. While expenditures on prescription drugs in the United States account for only 3 percent of all medical expenses, there is great interest in prescription drug coverage. PMID- 10110199 TI - Alternate-site testing: mixed feelings about the inevitable. PMID- 10110200 TI - Evolving issues related to bedside glucose testing. PMID- 10110201 TI - Developing a laboratory chemical hygiene plan. AB - OSHA hath decreed that every lab must have a CHP in place by Jan. 31. Although interpreting the standard can be confusing and frustrating at times, you'll find most of the information is at hand. PMID- 10110202 TI - A quick, simple protocol for evaluating clinical chemistry methods. PMID- 10110203 TI - Find the right LIS ... with EASE. PMID- 10110204 TI - How the states rank nationally in health. PMID- 10110205 TI - Handling criticism: Part I. Giving constructive criticism with aplomb. PMID- 10110206 TI - The varied and useful role of the pathologists' assistant. PMID- 10110207 TI - Dynamics of the lab-vendor relationship. PMID- 10110208 TI - An MT student on the Navajo reservation. PMID- 10110209 TI - Computer graphs clarify linear regression modules. PMID- 10110210 TI - Programming spreadsheet graphics on a PC. PMID- 10110211 TI - Dispensing and the technician: Part I. PMID- 10110212 TI - Issues in contemporary drug delivery. Part IV. Insulin therapy. AB - Continuous insulin infusions are a valuable way of managing highly selected patients, although patients and healthcare practitioners must be aware of the limits and the increased risks involved with this type of technology. Maximum benefit from the CSII technology is achieved when the patient is part of a complete healthcare team accessible on a daily basis to respond to the changing nature of the underlying diabetes. Intranasal and pulmonary delivery of insulin, in contrast, represent a minor technology that will potentially add convenience to some diabetic management plans and possibly provide a new treatment approach for noninsulin-dependent diabetic patients. PMID- 10110213 TI - Liability and new drug studies. Informed consent and clinical trials at the National Institutes of Health. AB - The liability risk in carrying out clinical trials can be severely affected if the informed consent process is poorly carried out. A poorly informed patient could prematurely drop out of a costly study. Worse yet, if the patient discovers that information is withheld, the patient could sue the sponsor, physician investigator, or IRB and hold them liable, though this is unlikely for investigational drug studies. These costs can be avoided by making sure the clinical trial is properly carried out according to strict federal regulations. It is also critical that clinicians keep the research participant informed on an ongoing basis. The chain of command is vital: The monitor informs the sponsor, the sponsor in turn informs the investigator, and the investigator in turn informs the patient of any new treatment information that may affect his willingness to stay in the trial. Finally, wherever the clinical trial is conducted, it should conform with the ethical principles outlined in the Declaration of Helsinki or with the latest regulations of that country--whichever guidelines provide the greater protection for the patient. PMID- 10110214 TI - Dispensing and the technician: Part II. PMID- 10110215 TI - Auxiliary label use by pharmacists in South Carolina. AB - This study shows the variability in auxiliary labeling recommendations among reference sources as well as the variability in auxiliary label selection by pharmacists. Pharmacists' responses matched the Pharmex, USP DI, and Facts and Comparisons recommendations 6.1, 2.4, and 0.9 percent of the time, respectively. Pharmacists' use of auxiliary labels was correlated to professional setting, computer software, and years of pharmacy practice, but the interaction of these variables was not determined by our study. Finally, pharmacists are not satisfied with current auxiliary reference sources, including computer software programs. PMID- 10110216 TI - Perspectives. Searching for small market reforms. PMID- 10110217 TI - Perspectives. A victory for hospital unions. PMID- 10110218 TI - Medicare deemed status gets sparse support. PMID- 10110219 TI - Developing tomorrow's elder-care facilities. PMID- 10110220 TI - Keep wanderers inside without locking the doors. PMID- 10110221 TI - Fishing for financing. Where to turn to land a loan. PMID- 10110223 TI - Honing hiring skills. The 40 best interview questions to ask. PMID- 10110222 TI - Restraint removal. Old habits die hard. PMID- 10110224 TI - Stake a claim for safety. Program highlights risk reduction. PMID- 10110225 TI - Successful restraint reduction techniques. PMID- 10110226 TI - Making a clean sweep during surveys. Inside advice on how to shine during inspections. PMID- 10110227 TI - Nursing plays integral role on ethics committees. PMID- 10110228 TI - Complexities of cottage residential services. PMID- 10110229 TI - Material management: the customer service advantage. PMID- 10110230 TI - Quantifying materiel management. PMID- 10110231 TI - Just-in-time and stockless programs for hospitals: fad or trend? AB - The JIT and stockless approach to provider-supplier relationships has proven to be a win-win proposition for the partners that have implemented it in many manufacturing industries and health care organizations as well. This strategy will fundamentally impact the entire cost structure within the hospital supply distribution chain. rewards have proven attainable and more comprehensive than had been hoped in the health care applications. The sweeping changes the health care industry experienced during the 1980s are leading creative materiel managers to seize the initiative to improve the current operating costs of their hospitals. They do not want to be left behind "holding the inventory." PMID- 10110232 TI - Implementing total quality management programs in health care organizations. PMID- 10110233 TI - 2001: a health care odyssey. PMID- 10110234 TI - A systematic approach to optimization of inventory management functions. PMID- 10110235 TI - Creating a first-class patient transportation department: a 10-point plan. PMID- 10110236 TI - Successful implementation of a PAR-level supply distribution system: it's everybody's business. PMID- 10110237 TI - Partners in quality: managing your suppliers. AB - Just expecting more from your supplier is not what partnership is about. We have had the experience where the quality improvement and partnership banner has been waved but the tone and spirit of the meeting did not encourage or support a joint quality improvement effort. Benefits will not be achieved until the wall truly begins to come apart and the relationship is built on mutual respect and trust. Data collection and open answers to questions often reveal embarrassing errors and obvious needs for improvements. As stated before, blame and finger-pointing must be replaced with a mutual commitment to asking and answering the question, "How can we improve?" As Dr. W. Edwards Deming has stated, "End the practice of awarding business on the basis of price tag. Instead, minimize total cost. Move toward a single supplier for any one item on a long-term relationship of loyalty and trust." The structured approach of a quality improvement process and the application of quality methods and techniques has proven useful in removing emotion and helping the team focus on the process rather than the people and the issues involved. Quality improvement methods are focused on achieving both customer and supplier goals--customer satisfaction, employee satisfaction, and operational efficiency and effectiveness. Our experience with Partners in Quality as well as our experience with the quality leadership process supports a recent quote in the Harvard Business Review: "Quality is not just a slogan...(it is) the most profitable way to run a business." PMID- 10110238 TI - Back to the patient: a matter of attitude and service. PMID- 10110239 TI - Getting organized for the 1990s: change is good. PMID- 10110240 TI - Beyond customer-supplier partnerships: a vision of the future. PMID- 10110241 TI - Partnering in the 1990s. PMID- 10110242 TI - Materiel management in the 1990s: the decade for leadership. PMID- 10110243 TI - Strategic imperatives for managing materiel into the next century. AB - The next century of opportunity is less than a decade away. Materiel management must involve itself in the strategic changes occurring within the health care industry and its respective institutions. Those materiel managers who are aggressively ensuring that their operations are supported by a well-developed and well-orchestrated operational infrastructure are now well positioned to address the future challenges of this decade. Unfortunately, many other materiel managers are focusing their attention and efforts solely on the management of materiel for which they currently have control. Materiel managers must develop an acute awareness of the support needs of their respective organizations. Those who are not apprehensive about venturing from the traditional materiel management world will be exposed to incredible educational opportunities and will receive responsibilities of unparalleled organizational importance. PMID- 10110244 TI - The use of a decision analysis model in multidisciplinary decision making. AB - This paper describes a conceptual decision analysis model for use in multidisciplinary decision making. Decision analysis was used to structure a decision process that ensured the best choice through consensus building among hospital decision makers. The four basic steps of the decision analysis model included: (1) identifying and establishing boundaries of the decision problem; (2) structuring the decision problem; (3) characterizing information needed to fill in the structure; and (4) choosing a preferred course of action. The selection of the best intermittent intravenous drug delivery system for Presbyterian Hospital illustrates the application of the conceptual model. This type of decision analysis model becomes a useful consensus building and communication device for the administrative pharmacist who is involved in multidisciplinary decision-making processes. PMID- 10110245 TI - Development of the Joint Commission's indicators for monitoring the medication use system. AB - The Joint Commission on Accreditation of Healthcare Organizations, as part of the Agenda for Change, has directed extensive efforts toward the development and testing of patient care indicators. The medication use indicators are designed to target processes and outcomes of the drug use system as defined by five major components: 1) selection and prescribing, 2) preparation and dispensing, 3) administration, 4) monitoring and 5) systems management/control. The indicators focus on several aspects of the drug use process including: serum drug level monitoring, medication errors, adverse drug reactions, patient teaching, pharmacist interventions and the appropriateness of prescribing. The testing of indicators is currently underway at test-site hospitals and includes 2 major phases: Alpha and Beta. Alpha-testing is designed to assess the face validity and collectability of the indicators, while Beta-testing will evaluate data collection and analysis as well as the reliability of the indicators. These indicators are intended to serve as measures of aspects of patient care that can be used to guide and monitor the quality and appropriateness of health care delivery and to facilitate continuous improvement in care. PMID- 10110246 TI - Survey of pharmacy computer vendors--sources of clinical databases. AB - Ninety-nine pharmacy computer vendors were surveyed to determine the sources of their clinical data bases for drug-drug interactions, drug-food/nutrient interactions and IV compatibilities. Sixty-five percent of the vendors cited two drug-drug interaction software programs most frequently. These are Drug Therapy Screening System from Medi-span and RxTriage from First Data Bank. First Data Bank is also the most frequently cited source for the drug-food interactions and IV compatibility databases. PMID- 10110247 TI - Drug usage evaluation: focusing in on topic selection and indicator development. PMID- 10110248 TI - Exhausting alternatives. There are disadvantages to relying on the states, but many feel forced to take aggressive steps to cover the uninsured. PMID- 10110249 TI - Constructive debate in a real world. Debate of new health policies should compare each proposal with existing systems as well as with a theoretical ideal. PMID- 10110250 TI - The state-federal seesaw. PMID- 10110251 TI - California gazing. Proposals being made in the most populous state could give a preview of what the future holds for national health policy. PMID- 10110252 TI - Managing in Maryland. Maryland's all-payer rate-control system enjoys the support of providers, payers and legislators as well as the public. PMID- 10110253 TI - A thousand flowers. To solve our national health-care dilemma, we're going to have to experiment with many approaches at the state level. PMID- 10110254 TI - Technology assessment, transfer, and management: the implications to the professional development of clinical engineering. AB - Technology, as applied in healthcare, is an encompassing term for products, equipment, procedures and services allied in some way with healthcare. This paper discusses technology as the word applies to healthcare. Areas of activity under the umbrella of technology--technology transfer, technology assessment and technology management--will be defined and discussed from the standpoint of their interaction with clinical engineering. The clinical engineering profession has approached participation in each of these activities in a nonsystematic manner, resulting in limited impact and a limited role. To go beyond its present role, the profession must study the processes of technology assessment, transfer, and management to understand their components, critical paths, strengths and weaknesses. This research should be undertaken by a joint group of clinical engineers representing practitioners and academia. Existing key players or professions should be identified, the role clinical engineers wish to pursue as a professional group and the skills required to assure competency should be declared, and appropriate resources for acquiring knowledge and experience identified. PMID- 10110255 TI - Focus on: Boston City Hospital Department of Clinical Engineering. AB - This paper describes the Clinical Engineering Department at the Boston City Hospital, Boston, Massachusetts. Boston City Hospital is the largest component of the City of Boston's Department of Health and Hospitals. The Clinical Engineering Department maintains in excess of 2,700 devices located at Boston City Hospital, Long Island Hospital, Mattapan Chronic Disease Hospital, and three neighborhood health centers that operate under the License of the Department of Health and Hospitals. The Clinical Engineering Department is responsible for the management, repair, testing, calibration, modification, and installation of medical equipment at each of the facilities. The department is also active in the training of clinical and professional staff members, and participates in anesthesia and laser research. PMID- 10110256 TI - Clinical engineering in Brazil: current status. AB - It is estimated that 20-40% of all existing healthcare equipment in Brazil is not working because of a lack of service, parts, or supplies, or because it has not been installed. Traditionally, equipment goes completely unattended until a complete failure occurs. Then, it sits idle, paralyzing those services provided by it, until its owner gathers enough money to afford the extravagant repairs provided by manufacturers and their representatives, with little continuing assurance of quality and efficacy. During the last 10 years, a few medical institutions have started to establish their own clinical engineering (CE) teams. Besides providing significant savings, these pioneers are contributing to the improvement of the process of managing the introduction of technology into healthcare. Now, about 10% of all hospitals with more than 150 beds have their own CE departments. Three years ago, the Brazilian Association of Hospital Engineering and Maintenance was created to promote the recognition of CE as a new profession. The main difficulties that inhibit the faster and wider adoption of the self-reliant approach are analyzed and some possible solutions are discussed. PMID- 10110258 TI - '17% of hospitals financially distressed'. PMID- 10110259 TI - Charter to lease one hospital, stop providing care at another. PMID- 10110257 TI - Laboratory and hospital testing of new infrared tympanic thermometers. AB - A patented approach to infrared thermometry based on the use of a standard pyrosensor has resulted in the development of two new infrared tympanic thermometers, one for professional use, the other for home use. Both were tested to evaluate accuracy in the laboratory and to evaluate equivalence to standards, correlation to standards, and precision in human subjects. Accuracy was found to be well within ASTM standards on both models. Mean ear temperatures were 0.2 degrees C below oral and 0.7 degrees C below bladder temperature. Correlations between ear and oral and ear and bladder temperatures were r = .77 to .84. Repeatability in the same ear was very high at r = .95 (left) and .97 (right). Reproducibility between left and right ear ranged from r = .89 to .92. PMID- 10110260 TI - Baxter investigation widens. PMID- 10110261 TI - Group says government is lax in enforcing patient-dumping law. PMID- 10110263 TI - Nevada hospitals sue state over Medicaid payments. PMID- 10110262 TI - IRS official backs legislation on tax-exemption standards. PMID- 10110264 TI - VA chief says quality-review system failed. PMID- 10110265 TI - Funds to find black organ donors promised. PMID- 10110266 TI - Hospitals eyeing physicians' practice patterns. Economic credentialing is being tested to reduce expenses and improve quality. AB - In an effort to reduce expenses and improve the quality of medical care, some hospitals are turning to economic credentialing. They believe utilization review and peer pressure can alter physicians' inefficient practice patterns without threatening their clinical privileges. But executives of a two-hospital system employing credentialing say the threat of losing clinical privileges is the best way to remind physicians to comply with hospital standards. PMID- 10110267 TI - System pioneers credentialing. PMID- 10110268 TI - IRS allows unusual not-for-profit affiliation. AB - The Internal Revenue Service has approved an unusual transaction that allows a small not-for-profit hospital with a declining patient census to affiliate with a larger hospital, sell part of itself to staff physicians, maintain its tax-exempt status and stay afloat. While the IRS declined to name the hospitals involved, MODERN HEALTHCARE has discovered their identities and tracks their unconventional path toward affiliation. PMID- 10110270 TI - Reform a federal task, execs and doctors say. PMID- 10110269 TI - State hospital association presidents report proposals to expand health access. AB - Nearly half of 24 state hospital association presidents report that proposals have been introduced in their states this year that are aimed at expanding access to healthcare services for the uninsured, underinsured or uninsurable. Four other executives say such legislation already has passed in their states this year, according to Modern Healthcare's monthly Fax poll of state hospital association executives. PMID- 10110271 TI - Reform needed soon, Sullivan told. PMID- 10110272 TI - Kids offered special care through PALS (pediatric advanced life support). PMID- 10110273 TI - ProPAC endorses Medicare capital payment plan with reservations. PMID- 10110274 TI - Request puts claims over timely appeals. PMID- 10110275 TI - Calif. hospital wins tax challenge. PMID- 10110276 TI - Foundation goes for the big picture. PMID- 10110277 TI - Hospitals storing more donated cash. PMID- 10110278 TI - Suggested means for improving organ donation raises ethical concerns. PMID- 10110279 TI - Care of the dying. New actions taken in Missouri, Georgia, and New Jersey. PMID- 10110280 TI - Rising tide of euthanasia support turns to ripples of caution. PMID- 10110281 TI - New data emerges on attitudes toward advance directives. PMID- 10110282 TI - Medicare program; withdrawal of coverage of extracranial-intracranial arterial bypass surgery for the treatment or prevention of stroke--HCFA. Final notice. AB - This notice announces the withdrawal of Medicare coverage of extracranial intracranial (EC-IC) arterial bypass surgery when used to treat or prevent ischemic cerebrovascular disease of the carotid or middle cerebral arteries. Available evidence does not show that this surgery is effective. PMID- 10110283 TI - Medicare program; monthly actuarial rates and monthly supplementary medical insurance premium rates beginning January 1, 1991--HCFA. Notice. AB - As required by section 1839 of the Social Security Act, this notice announces the monthly actuarial rates for aged (age 65 or over) and disabled (under age 65) enrollees in the Medicare Supplementary Medical Insurance (SMI) program for calendar year 1991. It also announces the monthly SMI premium rate to be paid by all enrollees during calendar year 1991. The monthly actuarial rates for 1991 are $62.60 for aged enrollees and $56.00 for disabled enrollees. The monthly SMI premium rate for 1991 is $29.90. PMID- 10110284 TI - Compensation for harm from charitable activity. PMID- 10110285 TI - Pediatric oncology patients no future profit center. PMID- 10110286 TI - New Act makes directives part of hospital policy. AB - Changes in the legal system are hitting hospitals from every vantage point- including the hospital's role with patients in dealing with advance directives, documents that instruct physicians on the removal of life-sustaining equipment. In the following article, the author addresses the legal basis of a new federal law as a mandate for hospitals. PMID- 10110288 TI - Multi-unit providers will focus on benefits rather than size. PMID- 10110287 TI - Hospital pension money deserves proper strategy. AB - The financial viability of the hospital's pension plan depends, in large part, upon the ability of its managers to invest and supervise the money. Mismanagement of funds can lead to diminished available funds and have devastating effects on the hospital's reserves. The following article looks at combatting fund mismanagement by hiring a professional financial manager. PMID- 10110289 TI - Planning indicators. Government deemed responsible for health care change. PMID- 10110290 TI - AHA initiates new advertising guidelines. PMID- 10110291 TI - Capital rule to put reins on hospital spending. AB - In an effort to get an even tighter hold on rising medical costs, the Health Care Financing Administration has proposed a new Capital Rule for reimbursement of capital expenses under Medicare. It would replace the existing cost-base system with a prospective payment structure. But how are hospitals adjusting to the proposed rule which will go into effect Oct. 1, 1991? The following article examines the preliminary reactions of administrators across the country. PMID- 10110292 TI - Fort Sanders expands options. Interview by Donald E.L. Johnson. AB - Is developing a multi-hospital alliance the route for most hospitals facing the challenges of the 1990s? Officials of Fort Sanders Alliance, a 1,100-bed metropolitan multi-hospital system in Knoxville, Tenn., services residents in that city as well as neighboring Sevierville and Loudon, Tenn. How has the Alliance worked and what is its purpose? In the following interview with Health Care Strategic Management's publisher, Donald E. L. Johnson, president of Fort Sanders Alliance, Alan C. Guy, discusses the venture. PMID- 10110293 TI - Medicare coverage of screening mammography: guidelines for suppliers. PMID- 10110294 TI - Children of alcoholics: policy initiatives. PMID- 10110296 TI - Liturgical ministry to the sick: an overview. AB - Samples the rites and liturgies available to contemporary caregivers and notes particularly the current liturgical renewal having many implications for the hospital chaplain and pastoral counselor. PMID- 10110295 TI - Reciprocal dealing arrangements: health antitrust theory of the 1990s? PMID- 10110298 TI - Patients may not be entirely to blame for their lifestyles. PMID- 10110297 TI - The malpractice data bank is turning into a Frankenstein. PMID- 10110299 TI - Dear Dad: will this jury find me guilty of malpractice? PMID- 10110300 TI - The best experts of all help run our practice. PMID- 10110301 TI - Should this whistle-blower have lost his privileges? PMID- 10110302 TI - When--and when not--to protect patient privacy. PMID- 10110303 TI - Humana to waive fees in Ala. PMID- 10110304 TI - Oregon estimates rationing will save 22%. PMID- 10110305 TI - AmeriNet starts new distribution unit. PMID- 10110307 TI - States go easy on freestanding facilities--GAO. PMID- 10110306 TI - SunHealth unveils new planning initiative. PMID- 10110309 TI - N.J. medical society calls for universal AIDS testing. PMID- 10110308 TI - Chicago facility suspends residents after lawsuit. PMID- 10110310 TI - 2 companies work on turnarounds. PMID- 10110311 TI - Hospital industry prepares to fight capital proposal. PMID- 10110312 TI - Rewriting medical doctrine in the fight to save GI lives. PMID- 10110313 TI - Staff cross-training caught in cross fire. AB - Saying the healthcare industry no longer can afford turf battles over which professionals will perform which patient-care duties--such as a recent skirmish in California concerning the role of perfusionists--a growing number of hospital executives are moving away from specialized staff and are cross-training workers in multiple skills. Advocates say it will relieve persistent labor shortages and save money, but foes say cross-training will only harm quality and increase costs. PMID- 10110314 TI - Unless vendors differentiate, market could shrink--analyst. AB - Unless vendors become better at differentiating their systems from one another's and at proving that they benefit their clients, the total market for hospital information systems will remain static and could shrink during the next several years, a new analysis says. A recent survey of vendors shows them cutting their prices in 1990 to generate sales. To increase their sales, vendors have to get on the bandwagon of reducing healthcare costs, the analysis says. PMID- 10110315 TI - Defense Dept.'s cost-cutting could forge new civilian links. AB - Defense Dept. belt-tightening could provide new opportunities for managed-care joint ventures between military and civilian providers. A new, three-year program would empower military hospital commanders to establish provider networks and negotiate discounts with civilian providers. But civilian providers must be prepared to endure sometimes protracted negotiations when seeking new business with the military, civilian and military representatives said. PMID- 10110316 TI - HCFA report names 161 'high-mortality' hospitals. PMID- 10110317 TI - HMO enrollment rises nearly 5% to 36.5 million in 1990--GHAA. PMID- 10110318 TI - Experts second-guess AHA's strategy to block NLRB rules. PMID- 10110319 TI - PPS architect criticizes Medicare's capital plan. PMID- 10110320 TI - Physician files $29 million lawsuit against Columbia. PMID- 10110321 TI - Users to report device-related deaths to FDA. PMID- 10110322 TI - Stockless inventory: study says it saves money, but ... will it work in the OR suite? PMID- 10110323 TI - Trends in OR education. Steps for evaluating care and taking action. AB - This is the eighth article about applying the ten-step model for monitoring and evaluation developed by the Joint Commission on Accreditation of Healthcare Organizations. PMID- 10110324 TI - Technology basis of our ethical dilemmas. PMID- 10110325 TI - Staffing formulas determine correct levels. AB - In this time of nursing shortages and cost containment, OR managers must determine the correct staffing for their hospital. They cannot afford to be overstaffed, nor can they risk being understaffed. This article will describe two staffing formulas and discuss RN-to-technologist ratios and personnel assigned per room. PMID- 10110326 TI - Maintaining patient accounts records is important. PMID- 10110327 TI - Outstanding receivables: one effect of Desert Storm. PMID- 10110328 TI - How to plan today for tomorrow's potential disasters. AB - Hurricanes, earthquakes, and tornadoes are not the only disasters that can disrupt a patient accounts department's operations. Localized fires, power outages, vandalism, and hardware or software failure can pose even greater threats to operations. To minimize downtime and resume normal operations, disaster preparedness strategies should be part of a department's daily procedures. PMID- 10110329 TI - The changing faces of foodservice. AB - Asian and Hispanic immigrants will continue to flow into the United States through the '90s. The cultural diversity they bring can infuse an operation with energy. But language and cultural barriers will continue to challenge all levels and segments of foodservice. Our feature shows how operators can avoid misunderstandings with immigrant employees and patrons. PMID- 10110330 TI - The changing face of death: computers, consciousness, and Nancy Cruzan. PMID- 10110331 TI - Where to get the goods. A roundup of garment/flatgood manufacturers/distributors. PMID- 10110332 TI - Mercy Family Plaza, San Francisco, California. Mission of Mercy. A Catholic order in San Francisco spearheaded the conversion of a former hospital's outbuildings into affordable housing. PMID- 10110334 TI - Compensation and the computer. PMID- 10110333 TI - Perspectives. The U.S. contraceptive gap. PMID- 10110335 TI - Four ways to build cooperative recruitment alliances. AB - Cooperative recruitment programs or recruitment by networking can improve the quality and cost of hiring. Four strategies involve alliances with employee leasing firms, community-based organizations, educational institutions and competitors. PMID- 10110336 TI - Employers protected by at-will statements. AB - Requiring job candidates to sign at-will statements before they're hired will not protect all employers from wrongful discharge claims. This protections process, however, can reduce the number of risks brought on by employee termination. PMID- 10110337 TI - Employee conduct outside the workplace. PMID- 10110338 TI - Seven reasons to examine workplace ethics. PMID- 10110339 TI - New law protects older workers. PMID- 10110340 TI - Physician office managers hold keys to business; Baltimore hospital attempts to unlock doors to patients. PMID- 10110341 TI - Centers offer a whiff of relief for patients with smell and taste problems. PMID- 10110342 TI - Reducing high infant care costs begins with free prenatal care at Pennsylvania hospitals. PMID- 10110343 TI - Establishing ownership of the hospital bill in admissions: a key to protecting your facility's fiscal integrity. AB - You have a plan and you have educated and documented that the patient is cognizant of his/her responsibility. Reality often dictates that problems surface after discharge. How can we prevent the patient from placing the bill on a shelf and forgetting it? As a part of your hospital's bottomline, you have a responsibility to ensure that its fiscal integrity is protected. Afterall, your hospital is also a business as well as a healing institution. Taking the lead in getting the right information at the admission or precertification stage is a vital element in the collection loop. Second, realize that not all, but a majority of patients, are beginning to investigate their benefits and coverage limitations. They may be doing so without a total understanding of insurance terminology or the difference in how much of the hospital/physician charges are paid or what percent rests with them. Last, in Pennsylvania at least, the state requires active participation by hospitals in healthcare cost containment by requiring submission rate and medical outcome information. Why not take this opportunity as an admitting professional to try some of the strategies mentioned. Informing the patient of their insurance benefits and providing an estimate of the bill will increase your department's contribution, and educate the patient about "consumerism". Consumerism is developing within the healthcare industry.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10110344 TI - Dispelling myths about patient information systems. PMID- 10110345 TI - Improving your facility's fiscal integrity: an HMO perspective. PMID- 10110346 TI - Vassar Brothers Hospital--on the move! PMID- 10110347 TI - Limiting exposure to uncompensated care. PMID- 10110348 TI - Medicaid; eligibility of aliens for Medicaid--HCFA. Technical amendments. AB - This document makes technical corrections to final regulations regarding eligibility of aliens for Medicaid published on September 7, 1990, at 55 FR 36813. PMID- 10110349 TI - Medicaid program; eligibility groups, coverage, and conditions of eligibility; legislative changes under OBRA '87, COBRA, and TEFRA--HCFA. Final rule; correction notice. AB - This notice corrects 42 CFR 440.210, Required services for the categorically needy, and 42 CFR 440.220, Required services for the medically needy, to restore current text which was inadvertently deleted in the final rule and to make conforming redesignation changes. PMID- 10110350 TI - Nose-thumbing Rx. PMID- 10110351 TI - Unrisky business. AB - Both the health insurance industry and its critics agree that reforms are needed to guarantee medical coverage for small businesses and their employees. The question is, how sweeping will the changes be? PMID- 10110352 TI - I.S.R.R.T. breast screening recommendations. International Society of Radiographers and Radiological Technicians. PMID- 10110353 TI - The knowledge and attitudes of radiologic technologists and allied health students regarding AIDS and AIDS patients. AB - Two questionnaires on AIDS knowledge and attitudes were administered to allied health and radiologic technology students, and a group of radiologic technologists. Generally negative attitudes and poor knowledge prevailed. No correlation could be found between knowledge scores and attitudes. Implications for entry-level and continuing education are also discussed. PMID- 10110354 TI - Occupational doses to medical radiation technologists in Manitoba (1978-1988). AB - In Canada, occupational exposure to medical technologists accounts for about 8 per cent of all occupational exposure. In this paper, occupational doses to Manitoban radiation technologists (RTs) in diagnostic radiology, nuclear medicine and radiotherapy are presented for the period 1978-1988. Particular attention is paid to the distribution of dose among this population. The importance of age and sex demographics on radiation detriment is also estimated. PMID- 10110355 TI - Code of ethics. Canadian Association of Medical Radiation Technologists. PMID- 10110356 TI - 1991 interior design awards. PMID- 10110357 TI - Fit and trim: CCRC wellness centers pay big dividends. PMID- 10110358 TI - Put a lid on costs: systematic budget analysis eliminates excess spending. PMID- 10110359 TI - Life and death decisions: program encourages dialogue on terminally ill. PMID- 10110360 TI - Putting on the Ritz: upscale facility attracts upper echelon. PMID- 10110361 TI - Foreign nurse saga continues. PMID- 10110362 TI - Corrective action counseling. PMID- 10110363 TI - Reaping greater returns from budgets. PMID- 10110364 TI - In search of excellence: the personnel issue of the future. PMID- 10110365 TI - Designing a clinical career ladder for the home care nurse. AB - Acknowledging and rewarding home care nurses for the achievement of a higher level of practice should be of benefit to the agency, the professional, and the patient. An agency deciding to design a clinical career ladder for nurses should identify the long-range goals of the program. This agency chose to have as the focus of its program the retention of those nurses who exhibited advanced practice in the delivery of home health nursing. These higher-level positions allow professionals to receive validation from the agency and their peers, and move into a salary range comparable to a management career ladder. It is the belief of the agency that nurses should be encouraged to achieve and should be recognized and rewarded for higher levels of home care nursing practice. The benefits to the individual, the profession, and the agency can only lead to the ultimate goal of delivery of the highest quality of care to the patient and family. PMID- 10110366 TI - The clinical nurse specialist: a valuable resource in home care. PMID- 10110367 TI - An incentive plan for nurses: linking bonuses to both care and documentation. AB - Productivity and quality are not mutually exclusive as many nurses believe. Management's responsibility to its staff is to provide systems that will allow for safe and realistic productivity expectations while not compromising quality care. Incentives add to the program, but they are the last step in a series of changes that must be jointly agreed on before nurses can be financially rewarded. This program, which combines salary plus incentive for those nurses wishing to participate, is the end result of much effort, cooperation, and negotiation between nursing staff and management. PMID- 10110368 TI - Implementing a pay-per-visit program while ensuring quality care. AB - Creative staffing alternatives that meet quality assurance standards and respond to current market trends is a challenge for today's home care provider. Tri Hospital Home Health Program of Passaic, New Jersey, produced almost 4,000 additional visits in 1989 with a pay-per-visit program, which proved to be very cost effective, despite a DRG reimbursement system. PMID- 10110369 TI - Rewarding overproductivity: an incentive or disincentive for staff? AB - A rapidly growing home care agency implemented a productivity system designed to reward its staff for "overproductive" visits rather than rely on temporary staff. While the system was positively received, it actually became more of a disincentive than a motivator. PMID- 10110370 TI - The home care nursing shortage. PMID- 10110371 TI - The financial burden of Medicare documentation in home care. AB - The Health Care Financing Administration 485/486 forms constitute the greatest paperwork burden for most agencies. This article suggests a method for analysis of the amount of resources consumed in the 485/486 process and estimates labor costs incurred to produce these documents. PMID- 10110372 TI - Take good care of yourself. AB - Caring for the terminally ill can have a cumulative effect on the caregiver, who may begin to view life as a succession of endless sufferings, as well as feel guilty for his or her own good health. Taking the time to care for oneself is not only necessary to maintain good mental and physical health, it is an essential part of the care extended to others. PMID- 10110373 TI - An ethnographic study of job satisfaction among home care workers. PMID- 10110374 TI - Patient care systems. Point-of-care revolution. AB - Interest in bedside information systems continues steadily, and purchasers now view point-of-care systems as a "when" and not an "if" acquisition, according to a comparison of three Computers in Healthcare surveys on this technology. Yet, cost justification and return on investment still wave cautionary flags that keep growth in this market fairly slow. Support from nursing executives will become a key success factor. PMID- 10110375 TI - Patient care systems: do they meet the needs of nursing? AB - A consulting firm has interviewed nursing executives at 24 hospitals throughout the country assessing nursing automation needs and comparing two of the top 10 patient care systems vendors on a wide range of variables. Nursing involvement in system selection is vital. PMID- 10110376 TI - VA develops integrated text and image data system. AB - A standard PC workstation allows physicians to review a patient's entire record- both text and images--with a new integrated HIS now installed at the Department of Veterans Affairs Medical Center in Washington, D.C. The system uses high resolution video cameras and the latest in fiberoptic technology. PMID- 10110377 TI - RBRVS--a new software system? PMID- 10110378 TI - Is computer proficiency a necessity? PMID- 10110379 TI - Making your way through the product jungle. PMID- 10110380 TI - Back to the future. PMID- 10110381 TI - The evolutionary war. Open forum. PMID- 10110382 TI - Hazmat training. AB - Federal laws and regulations require hazardous-materials-response training for EMS personnel and other emergency responders. The requirements, however, aren't entirely clear about the amount of time and topics to be covered for EMS training. EMTs and paramedics should either be trained to the highest level at which they are likely to perform, or their performance levels should be restricted to the highest level to which they have been trained. PMID- 10110383 TI - Paramedic run. The road to maturity. PMID- 10110384 TI - Categorical imperatives. PMID- 10110385 TI - Hazardous materials training. PMID- 10110387 TI - Color me? PMID- 10110386 TI - Telephones and computers sanitized and plastic restored. PMID- 10110388 TI - A Yankee approach to energy use. PMID- 10110389 TI - Special report on antitrust. Criminal antitrust enforcement--when, who, and why? AB - Government civil antitrust enforcement and private antitrust litigation are not always easy to avoid, because even innocent actions can be alleged to have been improperly motivated or to adversely affect competition. On the other hand, criminal antitrust violations can be readily avoided by following a set of basic, simple, and easy to remember rules: 1. Providers should not agree with competing or potentially competing providers on any terms of price, quantity, or quality of service; 2. Providers should not agree with competing or potentially competing providers as to which patients (or payors) will be served, what kinds of services will be offered, or where to locate offices or facilities; and 3. Providers should not agree with competing or potentially competing providers to refuse to offer services to payors or other alternative delivery systems. There are circumstances in which exceptions to these general rules are appropriate, such as when an agreement among providers is necessary in order to participate in a legitimate alternative delivery system, preferred provider organization, or individual practice association. However, these exceptions are narrow and technical. The best advice is the following warning to providers by Charles F. Rule, former U.S. Assistant Attorney General for antitrust: "You should never act as if an exception applies until after you have consulted an experienced antitrust lawyer or until you have obtained adequate assurance that competent counsel has structured the system to eliminate antitrust problems." PMID- 10110390 TI - Holding on to what you've got. AB - Hiring's the easy part--retaining nurses is the real challenge. Restructuring the traditional hierarchy gives nurses a stake in their careers and pays off for the hospital. PMID- 10110391 TI - Search firms provide a needed service. PMID- 10110392 TI - Sovereign immunity and tort claims. PMID- 10110393 TI - Budget denotes more of the same for health care. PMID- 10110394 TI - Picking a philosophy. PMID- 10110395 TI - Wringing the changes. PMID- 10110396 TI - Which way to haven? PMID- 10110397 TI - Too many bits and pieces. PMID- 10110399 TI - Health and homelessness. PMID- 10110398 TI - Pick it up with the shopping. PMID- 10110400 TI - Tell them I'm in a meeting. PMID- 10110401 TI - Weaving a caring network. PMID- 10110402 TI - Finance: controlled big bang. PMID- 10110403 TI - Finance. How to play safe. PMID- 10110404 TI - The hospital as a social institution, new-fashioned for the 1990s. Parker B. Francis management lecture. PMID- 10110406 TI - Improving subjective decision making in health care administration. AB - Managing a health care institution typically requires the consideration of many nonquantifiable factors, such as community relations, quality of service, and employee morale. As a result, subjective judgments are an inevitable, and often major, part of decision making in health care financial management. A large body of scientific research has shown that people's subjective, or intuitive, judgments tend to be biased and inaccurate. This article reviews the major types of errors typically found in four phases of decision making: defining the problem, estimating the effects of different alternatives, choosing an alternative, and evaluating the outcomes as the basis for subsequent action. In addition to alerting health care administrators to these potential judgment errors, several methods to improve subjective decision making are explained. PMID- 10110405 TI - The power of health care value-adding partnerships: meeting competition through cooperation. AB - Given the hypercompetitive health care industry, proposing cooperation as a means to survive and prosper appears radical. This article develops a case for the formation of a health care value-adding partnership as a viable, if not preferred, alternative to the integrated health care system owned and controlled by a single entity. The conceptual and the practical aspects of obtaining voluntary cooperation are addressed, and examples of successful value-adding partnerships are presented. PMID- 10110407 TI - Scenarios: a planning tool for health care organizations. AB - An organization's strategic planners require an understanding of future developments in the environment in which their decisions will be made. However, there is increasing recognition that there is no single predetermined "future." Therefore, the use of alternative future scenarios can be helpful. Scenario construction is a technique for combining possible environmental developments in a systematic way to help managers assess the potential consequences of alternative decisions. This article discusses the scenario technique and shows, as an example, its application to one organization in the health care field. PMID- 10110408 TI - The use of cash flow to analyze financial distress in California hospitals. AB - Previous studies of financial distress have utilized operating margins to measure this outcome. This study examines financial distress from the standpoint of cash flow, which is defined as net income plus depreciation adjusted for accruals. Defining financially distressed hospitals as ones with negative cash flows, the findings of the study show that these hospitals possess a lower occupancy rate, exhibit a slower collection of receivables, and have higher amounts of debt. However, the findings show that it is harder to predict financial distress defined in terms of cash flow than in profitability. PMID- 10110409 TI - A determination of institutional and patient factors affecting uncompensated hospital care. AB - For this study, a sample of 985 patients classified as "charity" and "bad debt" cases in 1986 were identified from 28 Indiana hospitals. In a multiple regression model, insurance coverage, total hospital charge, pregnancy-related diagnoses, marital status, employment status, discharge status, urban location, and total hospital revenue were significant factors in predicting unpaid hospital bills, when controlling other demographic characteristics. Sixty percent had some form of insurance and were responsible for 40 percent of the uncompensated amount, justifying the need to examine the adequacy of patient insurance coverage. However, providing insurance coverage will not entirely eliminate the problem of uncompensated care; hospitals also need to increase collection efforts for all unpaid bills. PMID- 10110410 TI - At-will employment doctrine--are patient care employers vulnerable? AB - This article analyzes the importance of changes in the at-will rule of employment law to hospital and other health care employers. A survey of wrongful termination cases brought against health care defendants is presented, and recommendations as to employment procedures are made. PMID- 10110411 TI - Clinical engineering in today's hospital: perspectives of the administrator and the clinical engineer. AB - In 1987-88, the first of two surveys conducted questioned the administrator's viewpoint on choice of reporting authority for plant operations and clinical engineering departments as well as the job satisfaction and prestige associated with these responsibilities. The second tested the response of clinical engineers on similar issues as well as the effect of certain organizational factors on their degree of functional involvement in the equipment-management process. In the first survey, two-thirds of the administrators chose a structure that, as shown in the second survey, leads to a higher degree of involvement and satisfaction for clinical engineers. Other organizational factors that have an effect are: the type of hospital (teaching and nonteaching), the presence of qualified university-degree engineers, and ensuring that the clinical engineering role within the health care institution is recognized and supported. Teaching hospitals are found to provide a better climate than nonteaching ones for the support of the research and education activities. Clinical engineering departments, whose role has been recognized and supported by their institution, are more substantially involved in all aspects of the equipment-management process than those who are still seeking this recognition. Finally, departments where university-degree engineers have been hired again show more involvement and commitment to the quality and efficiency of their operation. PMID- 10110413 TI - IHSM (Institute of Health Services Management) membership. PMID- 10110412 TI - Computer questions. PMID- 10110414 TI - April 1st. PMID- 10110415 TI - Study and research...a Centre for Health Policy and Research. PMID- 10110416 TI - Oiling the wheels. PMID- 10110417 TI - Measuring the costs of hospital in-patient care in the NHS. AB - John Ashford and Gordon Cumming argue that statistical costing has many advantages over cost accounting in the present state of the NHS and is capable of filling an important gap in the information currently available to clinicians and managers. They apply specialty costing to eight specialties in acute hospitals in England. PMID- 10110418 TI - Hospital closure: maintaining staff morale. AB - Closing a large psychiatric hospital is a complex exercise, and one of the main tasks for management is to maintain staff numbers and staff morale during the run down period, and to help staff find new and rewarding roles in the community based service. Alistair Bailey and Martin Barkley explain how this was tackled at Netherne Hospital. PMID- 10110419 TI - Records oriented work statistics: theory & practice. AB - The concept of applying units of work to quantify workloads within hospitals is already an accepted form of work analysis and in paramedical areas is totally unremarkable. However, within medical records departments the concept and use of work units does not appear to have materialised as a widespread phenomenon. Roger Cheesman and Karen Harrison-Taylor describe how such a system was devised and successfully implemented at Tawam Hospital, Abu Dhabi. PMID- 10110420 TI - Valuing and rewarding employees in the changed health service. AB - Last November, at the IHSM conference on human resources, Vicky Wright spoke on valuing and rewarding people. Here, with David Patterson and Helen Murlis, she amplifies her argument. In a changing service pay policy must change, but change is not without risk and will not in itself revolutionise human resource management. PMID- 10110421 TI - Future organisation of therapy service. AB - Therapists are considering the best organisation for their services and how to draw up contracts. This article is based on consultancy research into these subjects with physiotherapists, occupational therapists, speech therapists, psychologists, chiropodists, and dietitians. John Ovretveit presents models and a series of steps to help therapists and general managers clarify the options for the future and decide which form of organisation to work towards. PMID- 10110422 TI - Quality in the NHS: real or illusionary change. PMID- 10110423 TI - Private hospitals and medical ethics. AB - The majority of hospitals in the United Kingdom are public authority hospitals administered according to the National Health Service Act 1977. However, there exist throughout the country a variety of independent hospitals run either as charities or for commercial gain. Elizabeth Macdonald examines the private hospitals' duty of care and the ethical basis from which it stems. She suggests mechanisms to monitor and support ethical standards in private hospitals. PMID- 10110424 TI - Management training for senior registrars. PMID- 10110425 TI - Radiology: an opportunity waiting to happen. AB - This article discusses the opportunity for cost savings in radiology for the materiel manager who builds a partnership with a strong potential ally in the department--the radiology administrator. PMID- 10110427 TI - Service maintenance contract for equipment. PMID- 10110426 TI - Capital equipment management planning and control. PMID- 10110428 TI - Managing patient equipment as an asset. AB - As materiel managers review asset management of patient equipment, it is important to remember that tracking the use, not the inventory of the equipment, could increase revenue and operating profits. Tracking utilization, making effective acquisition decisions with regard to purchasing, leasing or renting, and considering the life cycle and support necessary for products will optimize the management of capital assets, and produce real savings. PMID- 10110429 TI - Bed scales. ECRI. PMID- 10110430 TI - Asset disposal: follow company policies or follow the law? AB - Several ethical issues can arise in disposing of assets. The proper management of these issues involves awareness of the applicable laws and development of policies and enforcement that respect those laws. Several examples of appropriate policy, following classical management principles, served to document the points under discussion. PMID- 10110431 TI - Disaster preparedness. AB - A natural disaster can be a frightening experience, where events are out of our control. Safety in such an emergency cannot be taken lightly. It is important to remember that safety is everyone's responsibility; plan ahead and know what you are to do! Review and rehearse emergency plans, know your work area and be prepared. Above all, stay calm. Your survival may depend on it! PMID- 10110432 TI - Mammography screening services: market segments and messages. AB - Mammography has become a vital tool for the early detection of breast cancer. Although many organizations and health care facilities are working to educate and motivate women to take advantage of the life saving opportunity that is offered through screening mammography, only twenty percent of women who should be screened actually have the procedure performed. In order to reach women who have not been screened, it is important to learn which factors most strongly motivate those women who do choose to have a mammogram. Depth interviews with 18 women attending a mobile mammography unit were conducted to explore the decision making process of women obtaining mammography screening services and to develop a profile of prevalent emotions, attitudes, and feelings associated with receiving breast cancer screening services. Analysis of the interview transcripts revealed several important themes to which health care professionals can direct marketing and health promotion strategies. PMID- 10110433 TI - A comparison of health care offerings as perceived by employers. AB - This empirical study examines the health care coverage climate of 130 large and medium sized companies in New England. Human resource managers and/or benefits managers were asked to compare the plans that they currently offer their employees on a number of points. The primary focus was in the area of cost and cost containment. An attempt is made to identify the cost containment trends that are now a very high priority among employers. PMID- 10110434 TI - Reference price: a tool for pricing new healthcare services. AB - The convergent validity and scale reliability of three measures of Reference Price (R-Price) were assessed for a "new" healthcare service using an adult sample. The Pearson correlation, Cronbach's alpha and Factor analysis results indicate that the multiple scale R-Price measure exhibits both reliability and convergent validity. As a result, the R-price scale could be used as an additional input for estimating demand of a healthcare service at a given price. The paper also draws some managerial implications for healthcare professionals. PMID- 10110435 TI - Methodological issues in aging research. PMID- 10110436 TI - Designing healthcare transportation for the elderly: an empirical study. AB - The growing elderly market in the United States has spawned a number of studies examining different aspects of the elderly market such as their expenditure patterns, healthcare needs, attitudinal types, etc. One of the least studied areas in this field is the transportation of the elderly to their primary health care facilities. This study was undertaken to assess the likelihood of adoption by the elderly of two proposed transportation alternatives by a hospital in a major metropolitan area: a shuttle service and an escort service. The receptivity to the proposed new service was hypothesized to differ across age subsegments among the elderly. Five-hundred and fifty-three elderly, selected at random, were studied in telephone interviews. The results show that the escort service was received more favorably than the shuttle service and the 75+ age group was the most receptive to the two services. The 71-75 age group appeared to be the least receptive to the proposed services. PMID- 10110437 TI - An empirical investigation of two competing models of patient satisfaction. AB - This paper empirically examines two competing models of patient satisfaction. Specifically, a five factor SERVQUAL model proposed by Parasuraman et al. (1988) and a tripartite model posited by Smith, Bloom, and Davis (1986) are examined. The two models are tested via factor analysis based on data collected from a field survey of hospital patients. The results of this study indicate that the five dimensional SERVQUAL model is not supported by data. On the other hand, there is general support for the tripartite model. Implications of our results for health care practitioners and researchers are discussed. Future directions for research are also outlined. PMID- 10110438 TI - The decision process for retirement center development: is market research being used effectively? AB - This paper examines the role of market research in the decision process used to invest in continuing care retirement centers (CCRCs). Given changing demographics and the availability of financing, there has been a rapid increase in the number of CCRCs that are being developed. However, a large number of these centers have either failed or are experiencing financial difficulty. Some industry participants have blamed poor or inadequate market research as a factor contributing to the failure of many centers to meet expectations. This paper discusses how the process used to invest in centers and how the motivations of the different actors in the investment decision can influence the role and use of market research. Recommendations are suggested for how industry investors can better understand and use market research in the decision to invest in a retirement center. PMID- 10110439 TI - Developing a successful senior care program: a research based approach. AB - Shifting environmental pressures have moved healthcare organizations to look to new products and services as a means of survival. One new product offering that has developed in many hospitals is the senior care program. Unfortunately, many of the senior care programs developed across the nation have not been successful. The authors have described a senior care program that is research based and physician centered. The benefits of which include physician loyalty to the hospital, a managed referral network and the ability to measure the impact of the senior care program on the bottom line. PMID- 10110440 TI - Assessment of demand for a healthcare system membership plan: an intent translation approach. PMID- 10110441 TI - The impact of source credibility characteristics on physicians' satisfaction with pharmaceutical salespeople. AB - Pharmaceutical salespeople are important sources of information for physicians about new and existing drugs. This study examines the relative impact of various source characteristics (i.e., expertise, trustworthiness and attractiveness) on physicians' satisfaction with the salesperson as an information source. The results suggest that although perceived expertise and trustworthiness are significant predictors of satisfaction, attractiveness is not. Implications are offered. PMID- 10110442 TI - Consumer self treatment with over the counter medication: emerging attitudes in a professional arena. PMID- 10110443 TI - Importance/performance analysis: a tool for service quality control by clinical laboratories. AB - A study of customer satisfaction with clinical laboratory service is used as the basis for identifying potential improvements in service and more effectively targeting marketing activities to enhance customer satisfaction. Data on customer satisfaction are used to determine the aspects of service most critical to customers, how well the organization is doing in delivery of service, and how consistent service delivery is. Importance-performance analysis is used to highlight areas for future resource reallocation and strategic emphasis. Suggestions include the establishment of performance guidelines for customer contact personnel, the enhancement of timely delivery of reports via electronic transmission (computer and fax), and the development of standardized graphics for request and report forms to facilitate identification of appropriate request forms and guide clients to key items of information on reports. PMID- 10110444 TI - Healthcare: considerations for changing practice. AB - Changes are rampant in the healthcare industry. Some are economically driven while others occur because of revisions in the national health policy, mandates of third party payors to alter reimbursement policies, and efforts of consumers to influence health professional's practices. As a result, healthcare institutions must monitor the quality and the cost effectiveness of their product. Yet, implementing a Quality Assurance (QA) program necessitates numerous changes on the part of all who work within an institution. A healthcare organization's leaders must have the ability to respond rapidly to the domino effects of change. For some institutions, this may mean modifying a long-standing infrastructure, purchasing new biotechnology, reorganizing staffing patterns, or revising management practices. Hence, it is important for health care providers to understand the change process. Likewise, health professionals should be aware of, and anticipate the potential responses to change. Because humans are motivated by different forces, there is need for a repertoire of strategies to address these individual needs. Ultimately, these efforts can facilitate the implementation of change. Overview of the Content: In this submission I will define common terms associated with change theory. This is followed by an overview of Lewin's and Rogers' theories of change. Subsequently, the models are applied to a household innovation (microwave oven). Finally, strategies to implement changes, specifically QA activities, are provided for the reader's consideration. The information herein is useful for management, education, as well as hypothesis development relative to research on change in healthcare. PMID- 10110445 TI - Automated system marketplace 1991. Redefining system frontiers. PMID- 10110446 TI - The most popular databases. PMID- 10110447 TI - How firm size and industry affect employee benefits. AB - Smaller establishments and service-producing industries typically provide fewer benefits than larger establishments and goods-producing industries, but the extent of benefit coverage varies widely within industrial and establishment-size groupings. PMID- 10110448 TI - Is your staff wise in waste management? AB - All laboratorians must learn their labs' protocols for hazardous waste disposal, including emergency plans and comprehensive procedures for storage, packing, and hauling. PMID- 10110449 TI - New directions in federal regulations on hazardous waste. PMID- 10110450 TI - The medical waste outcry: a personal update. PMID- 10110451 TI - Hazardous material officer: opportunity for laboratorians. PMID- 10110452 TI - Handling criticism: Part II. Receiving criticism with confidence. AB - Allow yourself to learn from criticism directed at you. Even if it is invalid, respond diplomatically. Conclusion of a series on personal and personnel judgments in the lab. PMID- 10110453 TI - Preparing the small lab for a first state inspection. PMID- 10110454 TI - Taking the 'byte' out of method evaluation number crunching. PMID- 10110455 TI - Full-text and bibliographic database searching in the health sciences: an exploratory study comparing CCML and MEDLINE. AB - An exploratory study to investigate perceived differences between searching full text databases and bibliographic databases was undertaken. BRS's full-text database, Comprehensive Core Medical Library (CCML), and BRS's current MEDLINE file (MESH) were compared. Identical literature search topics were run in the two databases and the results evaluated regarding currency of search results, success in answering specific questions, uniqueness of information retrieved, and relevancy of retrieval. Additionally, connect time and costs were noted to aid in determining the feasibility of offering full-text database searching as a service for which the authors' institution would charge. PMID- 10110456 TI - Risk management information for HIV infection. AB - This article discusses HIV infection in terms of the risk manager's information needs in the health care environment. The malpractice problem, increasing workman's compensation suits, the greater role of the ombudsman, implementation of the National Practitioner Data Bank, and the Joint Commission on Accreditation of Health Care Organizations' (JCAHO) emphasis on clinical excellence are conditions which have given greater importance to the risk manager's position. Included in this article are hedges to retrieve various components of risk management and a select bibliography from AIDSLINE. PMID- 10110457 TI - Chicago-area HMO to drop Medicare risk coverage. PMID- 10110458 TI - HCFA can use 'sampling' to calculate IOUs--court. PMID- 10110459 TI - Groups want HCFA to guarantee minimum capital payments. PMID- 10110460 TI - Mass., N.Y. push managed care. PMID- 10110461 TI - 'Coordinate quality efforts'. PMID- 10110462 TI - HCFA airs alternatives to graduate medical education financing. PMID- 10110463 TI - AMI assembling refinancing package. PMID- 10110464 TI - Appellate ruling stymies attempt to get hospital deal done in Ga. PMID- 10110465 TI - Invitation to hospitals: join the push for a single-payer, waste-avoiding health system. PMID- 10110466 TI - Practitioners are filling in for scarce physicians. AB - Facing a dearth of physicians, rural America is turning to mid-level practitioners. The changing rural healthcare system is relying more on primary care and outpatient services, and mid-level practitioners are viewed as the most economical providers of such care. States, swayed by arguments that rural access to care is decreasing, are loosening licensing restrictions so "mid-levels" can treat where few physicians want to work. PMID- 10110467 TI - Team to assess damage, provide care in Kuwait. PMID- 10110468 TI - Adventist Health System: after the break-up. AB - The demise of the Adventist Health System a year ago marked the end of an eight year experiment. Part of its problems stemmed from disagreement between regional group presidents and AHS executives over consolidated financing and poor diversification decisions that cost the Adventists more than $100 million between 1984 and 1989. But what ultimately sank the system was a rift among Adventist regional group presidents, hospital executives and church leaders over authority and control. PMID- 10110469 TI - Providers give rationing substantial support. AB - Rationing healthcare services to help control soaring medical costs gets more support from providers than from consumers or employers, a recent survey of consumers, business executives and healthcare professionals shows. When asked whether healthcare should be rationed, 57% of the hospital chief executive officers and 46% of the physicians said "yes". But only 29% of the employers and 16% of the consumers agreed. PMID- 10110470 TI - CAC-Ramsay finds formula for growth, profit in South Florida. AB - CAC-Ramsay, a unit of Coral Gables, Fla.-based Ramsay-HMO, seems to have found a formula for growth and profit, specializing in serving the Hispanic populations of southern Florida. Thanks to above-average federal reimbursement rates, the HMO can offer Medicare enrollees a multitude of free perks and healthcare services through its clinic-based network. The company also is pursuing opportunities through commercial contracts and Medicaid plans. PMID- 10110471 TI - System for reporting medication errors proposed. PMID- 10110472 TI - UniHealth joint venture links hospitals, physicians. PMID- 10110474 TI - 'Computerize all patient records by 2001'. PMID- 10110473 TI - IRS' proposed rule changes for reimbursement bonds may complicate financings. PMID- 10110475 TI - Bill exempts rurals from antitrust laws. PMID- 10110476 TI - Educating nurses ranks high with hospital CEOs--survey. PMID- 10110477 TI - JCAHO gets better grades from chief execs. PMID- 10110478 TI - SEIU accelerates organizing drives in wake of ruling on bargaining units. PMID- 10110479 TI - UB-82 updated, UB-92 begun. PMID- 10110480 TI - Five steps help administer successful contracts. AB - Healthcare trends and statistics indicate the growing number of managed care contracts will continue. For patient accounts managers, this means more challenges in managing and administering different kinds of contracts. Communication, management, and feedback will become essential tools for ensuring successful administration of managed care contracts. PMID- 10110481 TI - Coping with managed care in the business office. PMID- 10110482 TI - Mastering DOL (Department of Labor) paperwork eases recruitment of foreign nurses. PMID- 10110484 TI - Residential care providers must define proper care services. PMID- 10110483 TI - Survey results may be valuable facility risk assessment tool. PMID- 10110485 TI - Housekeeping services are vital link to infection control. PMID- 10110486 TI - Nursing home medicine--a gloomy profession? AB - By controlling life-style and environmental hazards and seeking appropriate medical care, many people can enjoy a healthy, independent old age; various psychological schema provide models for such "successful" aging. But we must turn to the humanities for a vision of aging that sees meaning in lives characterized by incontinence, immobility, and confusion. PMID- 10110487 TI - All things in relation to God. An interview with James M. Gustafson. PMID- 10110488 TI - Private and non-profit firms need D&O coverage, too. PMID- 10110489 TI - Antitrust treatment of hospital mergers. PMID- 10110490 TI - Capital payment proposal: a riverboat gamble. PMID- 10110491 TI - Taking risks to redefine the strategic plan. PMID- 10110492 TI - Boards lead capital campaign. PMID- 10110493 TI - New approaches in quality: CQI (continuous quality improvement). PMID- 10110494 TI - Women are key health care market. PMID- 10110495 TI - Will consumer concerns about hospitals cloud legislators' views? PMID- 10110496 TI - Board-CEO compensation concerns. PMID- 10110497 TI - Medical winter of our discontent. Physicians and hospitals must create an integrated health care system. PMID- 10110498 TI - The care and feeding of a CEO. PMID- 10110499 TI - CEO turnover: study findings help boards solve the puzzle. PMID- 10110500 TI - When physicians join the governance team. PMID- 10110501 TI - Coordinating human services delivery. PMID- 10110502 TI - Trans-organizational management: the new frontier for social work administrators. AB - This paper has presented a basic thesis: we cannot rely on institutional rearrangement as our primary vehicle of systemic change. By doing so, we would be repeating the mistakes of the 1960s by instituting changes that will not result in fundamental and log term improvements to societal human services systems. Change can only flow from recognition that there are two types of management that must co-exist: institutional and trans-organizational. In public and nonprofit social work agencies, the former is almost the sole focus of administrative knowledge and skills. Slowly, all the human services (Jaeger, Kaluzny & Magruder Habib, 1987) are beginning to concentrate on trans-organizational systemic arrangements. Increasingly, social work administrators are acquiring knowledge++ and ability in trans-organizational management. It is a prerequisite for the fundamental systemic changes required by the new demographics of the next decade and the next century. PMID- 10110503 TI - Current perspectives on inter-organizational relationships. PMID- 10110504 TI - Negotiating: a tool for inter-organizational coordination. PMID- 10110505 TI - Case management: planning and coordinating strategies. AB - In summary, planning a case management system involves moving through sequenced stages; namely, (1) a developmental stage; (2) a phase-in stage; and (3) an operational stage. During the developmental stage, before processes have been formalized, attention is given to the political realities, the formation of a representative planning group, formulating goals and objectives, obtaining administrative support, information gathering, assessment of needs, resource procurement, program structure and design, selection of a case management model, participatory decision making, determining organizational fit, and beginning networking. During the phase-in or early implementation state, the formal stage of system introduction, attention is given to the establishment of interorganizational relationships, contracting for services, job descriptions, work assignments, training, problem solving, and conflict resolution. During the operational or full implementation stage, a period when the system should become more stabilized, attention needs to be given to managing movement of the client through the system, the flow of information, program updating, quality assurance, recordkeeping, resource management, evaluating, and system refurbishing. In practice, these stages will interact and overlap. Closure, if the system is to remain viable and open to change, should never occur. PMID- 10110506 TI - Factors affecting agency capacity for inter-organizational coordination. PMID- 10110507 TI - Inter-agency collaboration: some working principles. PMID- 10110508 TI - American Laundry Digest distributors directory. PMID- 10110509 TI - Granting advantages to the disadvantaged. PMID- 10110510 TI - Learning and earning: new ways to master health administration. PMID- 10110511 TI - A white man's land. PMID- 10110512 TI - Hospitals defend lawsuits on quality of care. PMID- 10110513 TI - Managing medical waste. A road map for health care institutions. PMID- 10110514 TI - Catch'em and keep'em. Reel solutions to lure employees. PMID- 10110516 TI - TQM (total quality management) is not a quick fix. PMID- 10110515 TI - How to start your own TQM (total quality management) program. PMID- 10110517 TI - Small hospital thinks big. PMID- 10110518 TI - Producing more with fewer people. PMID- 10110519 TI - Impact of quality on hospital demand. PMID- 10110520 TI - Rate-making and physician-owned insurance companies. PMID- 10110521 TI - HIV testing of health care workers. The need for additional data. PMID- 10110522 TI - ACS participates in PPRC payment reform activities. PMID- 10110523 TI - Trauma: responsibility, resources, and responsiveness. PMID- 10110524 TI - From the trenches: strategies that work. PMID- 10110525 TI - Healthy babies for healthy companies. PMID- 10110526 TI - Cracking the big case. PMID- 10110527 TI - Sending 'care' packages to the workplace. PMID- 10110528 TI - Managed care bites benefit! PMID- 10110529 TI - Data watch. Dependent care and related benefits. PMID- 10110530 TI - A wellness program financed by employees. PMID- 10110531 TI - Health insurance for small businesses. PMID- 10110532 TI - Is your self-funded health plan safe? PMID- 10110533 TI - America's health care potential. PMID- 10110534 TI - Toward a capital hospital. PMID- 10110535 TI - Medicare program; schedule of limits for skilled nursing facility inpatient routine service costs--HCFA. Final notice with comment period. AB - This final notice with comment period sets forth an updated schedule of limits on skilled nursing facility inpatient routine service costs for which payment may be made under the Medicare program. PMID- 10110536 TI - National Practitioner Data Bank for Adverse Information on Physicians and Other Health Care Practitioners--PHS. Final regulations. AB - This final rule amends the existing regulations governing the National Practitioner Data Bank for Adverse Information on Physicians and Other Health Care Practitioners (the Data Bank), codified at 45 CFR part 60, authorizing the reporting and release of information concerning: (1) Payments made for the benefit of physicians, dentists, and other health care practitioners as a result of medical malpractice actions or claims; and (2) certain adverse actions taken regarding the licenses and clinical privileges of physicians and dentists. This final rule revises section 60.12 to change the process for collecting user fees from eligible individuals and entities requesting disclosure of information from the Data Bank. PMID- 10110537 TI - National Practitioner Data Bank change in user fee--HRSA. PMID- 10110538 TI - The International Classification of Diseases: the structure and content of the Tenth Revision. AB - The Tenth Revision of the International Classification of Diseases is due to be published this year, and introduced from 1993. The aim of the classification is to facilitate comparisons between countries at the same point in time and within, and between, countries over time. The provision of comparable statistics is essential for facilitating policy decisions relating to health promotion and disease prevention, and for the collection of epidemiological data for research purposes. This article describes the major changes and important features in this revision, and compares them to the Ninth Revision of the International Classification of Diseases. PMID- 10110539 TI - Worcester Development Project: where do patients go when hospitals close? AB - The philosophy of Community Care has resulted in the closure of several mental hospitals in this country. The ethos of the Worcester Development Project saw the closure of St Wulstan's and Powick Hospitals, and their replacement by a community-based service. This paper briefly describes the outcome of a three-year retrospective study completed in 1988 following the closure of both hospitals. The findings provide a comparison of the two hospitals, including details of the destination of all the patients. It is suggested that the term 'hospital replacement' might be preferable to 'hospital closure.' PMID- 10110541 TI - Trends in guardianship usage following the Mental Health Act 1983. AB - The Mental Health Act 1983 substantially modified Guardianship, a previously little used facility for the compulsory care of mentally ill and mentally handicapped people in the community. This paper describes the results of a survey of information based on the annual returns from Local Authorities to the Department of Health and Social Security, and examines the impact of the new legislation upon the use of Guardianship in psychiatric practice. Although the number of Guardianship Orders in force remains relatively small compared to hospital admissions, recent trends indicate a significant increase in its application to people with a mental illness, and a decline in its use for people with a mental handicap. Despite the overall increase in use, the Regional differences of cases in England remain essentially unchanged and reflect the differing attitudes and policies of Local Authorities towards Guardianship Orders. PMID- 10110540 TI - Worcester Development Project: the closure and replacement of a mental hospital. AB - The Worcester Development Project began in 1968 when the Department of Health and Social Security brought together the Worcester and Kidderminster Hospital Management Committee and the County Council in a co-ordinated joint planning venture. Powick Hospital was chosen as the location for testing the hypothesis that closing a mental hospital and replacing it with general hospital psychiatric units, supported by a variety of community facilities, would provide a more economical and better service. This paper describes the outcome of this unique opportunity to study the problems involved in closing a mental hospital and its replacement with other facilities. PMID- 10110542 TI - Community care for adolescents with developmental retardation: problems and proposals. AB - The quality of community care provision for adolescents with developmental retardation was examined in a health district with a well-developed community service. This paper describes a representative sample of such adolescents living at home, and is based on data from a wider study of the dependency needs of this group. Although many professionals and agencies were involved with each family during the six months prior to the study, their input was poorly co-ordinated and did not focus on the group's special needs. Psychiatric disorder in the adolescent, and relationship difficulties with the primary carer, were the least well catered for, and these results support previous research findings. The paper concludes with proposals for improving the services in the context of current legislation. PMID- 10110543 TI - The cost of acute asthma--how much is preventable? AB - Asthma is known to be widely under-treated, and unnecessary morbidity from the disease is common. This paper reports a prospective survey of hospital admissions for acute asthma and assesses the efficacy of pre-admission therapy in terms of preventing hospital admission. District and national costs were estimated for hospital admission of patients with acute asthma and, although the direct cost to the patients was not measured, a calculation was made of the number of working days lost annually. The results of this survey show the need for improved education of both doctors and patients, and in particular for improved clinical management. The findings also suggest that the cost to the patient, including those costs incurred by hospital admission, are potentially preventable. PMID- 10110544 TI - The burden of chronic illness in local authority residential homes for the elderly. AB - A survey of all Part III residential homes in the Central and Southern area of Liverpool Health District examined the diagnoses and medication of 331 residents. A heavy burden of chronic illness was observed with cardio-vascular, psychiatric and orthopaedic problems being the most prevalent. Of the top 10 diagnoses, accounting for over half of all conditions, all disease instances required monitoring of their response to treatment. At least two thirds of these diseases were likely to progress, and the usual treatment of three quarters of the sample was associated with possible side-effects. This heavy burden of chronic illness in Part III residential homes implies a major need for both anticipatory and event-related medical care. These needs are unlikely to be met, given that the subtle, but significant, deterioration in the health of residents has been shown to go undetected. PMID- 10110545 TI - Time spent in hospital by children: trends in the Oxford Record Linkage Study area. AB - Routine statistics of hospital care are conventionally based on episodes of care. Thus, whilst statistics on lengths of stay per episode of hospital care are readily available, information is not routinely collected on the total time spent in hospital by individuals who experience several episodes of care. This paper presents data from the Oxford Record Linkage Study which was used to calculate the total length of time spent in hospital by children in each year from 1975-84. The findings of this study provide reassurance that, despite the increase in admission rates in childhood during this period, the total length of time children spend in hospital has generally declined. PMID- 10110546 TI - Selected characteristics of nurses and physicians who have living wills. AB - The purpose of this report is to determine what characteristics are most closely associated with nurses and physicians who favor a living will. A statistical analysis called classification and regression trees (CART) was used on the data set from a previous study. The five predictor variables that were analyzed were chosen following incorporation of a univariate screening process in which variables were chosen by their association with the likelihood of signing a living will. In addition, variables that did not have complete data sets were not considered in the analysis. The CART procedure was then used to determine which of these five variables were considered significant predictors. Three variables were selected: religion, length of experience with the terminally ill, and nature of the relationship (professional or personal) with the terminally ill. The two nonsignificant and therefore rejected variables were education/occupation and current region of residence. Within the predictor variable religion, CART selected the grouping of values (agnostic/atheist and Christian/non-Christian) as the best predictor of nurses and physicians likely to sign a living will. The second best predictor variable identified was length of experience in providing care to at least one patient, family member, or friend who was terminally ill. The nature of the relationship (professional or personal) with the terminally ill was the next strongest predictor variable of signing a living will. No previous studies of the living will have used such multivariate techniques as CART analysis to predict the likelihood of a health care provider signing a living will. PMID- 10110547 TI - Wrongful death statutes and expert testimony. AB - This article addresses issues arising within the evolving practice of the use of expert witnesses in wrongful death cases. It begins with a sketch of the currently extant variety of wrongful death statutes. Next, it characterizes the types of expert witness testimony that have been standardly recognized in such cases. It then outlines and critically assesses an attempt by an economist to enter testimony seemingly beyond legitimate bounds. Finally, it raises and addresses a range of issues related to damage awards in wrongful death cases and the legitimacy and limitations of expert witness testimony. PMID- 10110548 TI - United we cope: support groups for the dying and bereaved. AB - Historically, self-help groups have been the backbone of Western culture. They are found in every facet of society from the women's health movement to the urban poor. They are prominent in professional as well as nonprofessional settings, meeting the needs and desires of people in every walk of life. This article examines the development of the self-help movement with particular emphasis on the psychological, educational, and motivational functions performed. Particular attention is focused on the significant resources that self-help support groups provide for the bereaved and those coping with life-threatening illness. PMID- 10110549 TI - Euthanasia. PMID- 10110551 TI - Menu affects more than food cost. PMID- 10110550 TI - Special report. Electronic article surveillance systems in health care--an update. AB - Patients who wander from hospitals and nursing homes are a challenge to personnel in charge of their protection. Patients with Alzheimer's disease, head injuries, Parkinson's disease or other forms of dementia are likely wanderers. In our special report on Electronic Technology and the Wandering Patient (February 1986 issue,) we reported that several hundred nursing homes and a few hospitals had turned to Electronic Article Surveillance (EAS) systems that detect wanderers. Since then, the same type of technology has been extended to protect newborns from being kidnapped from hospital maternity wards as well as protect hospital property from being removed. In this report we will describe many of the leading EAS systems in use in the health care environment. We'll also present firsthand reports by users on their experience with this technology. PMID- 10110552 TI - Are you a manager or a leader? PMID- 10110553 TI - Assuring that you have the right people. Step 4: Avoiding the pitfalls. PMID- 10110554 TI - Production and usage records: a basis for planning and controlling costs. PMID- 10110555 TI - Safe in their hands? The health marketplace comes to Britain. PMID- 10110556 TI - National alert: gridlock in the emergency department. PMID- 10110557 TI - Not in cities only: Georgia's health care crisis. PMID- 10110558 TI - Who's playing monopoly? PMID- 10110559 TI - Putting a foot right. PMID- 10110560 TI - Freedom for living. PMID- 10110561 TI - Sour sweetener on the menu. PMID- 10110562 TI - Towards moral rearmament. PMID- 10110563 TI - Computing. A base for national data. PMID- 10110564 TI - Hospitals object to changes in capital payment policy. PMID- 10110565 TI - Desperately seeking nurses: recruitment and retention strategies. PMID- 10110566 TI - Chaplains check in with outpatients. PMID- 10110567 TI - A remarkable beginning. Rerum Novarum laid the foundation for church teachings on social justice. PMID- 10110568 TI - The theater of labor relations. Confessions of a CEO. PMID- 10110569 TI - Practicing what you preach. To achieve social justice, church-related institutions must respect workers' right to unionize. PMID- 10110570 TI - The social teachings of the Church. PMID- 10110571 TI - Do you know where you are? A look into one hospital's emergency department. PMID- 10110572 TI - Traumatic trends. Emergency departments abound as the number of trauma centers spirals downward. PMID- 10110573 TI - An endangered resource. Hospital emergency departments are threatened by closures and a reduction in services. AB - Many factors threaten the hospital emergency department. Socioeconomic and healthcare trends are forcing facilities to eliminate some services. Society's failure to deal with these issues portend disaster for high-quality care and for timely access to emergency care. Hospital administrators must collaborate with emergency department managers and plan strategies to ensure the survival of this valuable resource. Hospital emergency departments will have to redefine the scope of services they provide to meet specific consumer needs. The number of older Americans is increasing rapidly. Emergency departments must understand and cater to their unique needs. Some emergency department staffs are collaborating with competitors to share resources and reduce overlapping services. The emergency department has an impact on the facility's bottom line. The emergency department can positively affect this by ensuring accurate billing, analyzing fee schedules, and requesting payment at the time service is provided. Other survival issues include developing strategies to retain staff, develop management, negotiate managed care, and reassess the department's design. PMID- 10110574 TI - Key issues in mergers and acquisitions. Healthcare organizations must approach collaborations with caution. AB - Most collaborations between healthcare providers are based on a desire to better serve their communities, develop critical mass, eliminate duplicative services, create economies of scale, and enhance survivability. Unfortunately, collaborations may not always produce the benefits desired. Thus careful planning and execution are critical to first determine whether the transaction makes sense and, if it does, to develop strategies that maximize the expected benefits. Whether the participating entities are secular, religious, public, or private, I recommend they consider the following 11 key issues when evaluating or pursuing a merger or acquisition: (1) understand the transaction's magnitude, (2) assess the alternatives, (3) select potential partners carefully, (4) determine and examine threshold issues early, (5) focus on the right issues, (6) agree on a valuation approach, (7) recognize the importance of governance, (8) develop an acceptable structure, and use a memorandum of understanding, (9) establish and adhere to a communications policy, (10) perform due diligence, and (11) recognize the significance of activities after the transaction. PMID- 10110575 TI - Connecting healthcare providers. An effective computer network can create durable relationships. AB - Physician networks are computerized systems that link primary care physicians and specialists to one another and to hospitals and other providers. The networks have four key components: communication, practice management, practice marketing, and diagnostic testing capabilities. Advantages of physician networks for hospitals include increased physician loyalty and increased market share through additional admissions and outpatient registrations. From physicians' perspective, networks can help them expand their patient bases and increase revenue, provide additional services for existing patients, automate their offices, and improve their administrative efficiency. Networks also affect the way physicians practice medicine. Changes in practice patterns improve patient care, speed test results, and improve physicians' relationships with each other and their patients. They also save time for physicians and their staff. In deciding whether to develop a network, executives must examine the architectural framework and components they need, their commitment to physician relations, how reliant they are on primary care referrals, the competitive environment, the resources they are willing to commit, legal issues, and the physicians' role in planning. PMID- 10110577 TI - Taking care of business. PMID- 10110576 TI - Rooting out organizational conflict. PMID- 10110579 TI - Wheaton Franciscan Services. A point of light in Milwaukee. PMID- 10110580 TI - Mercy Health System. Spirit of mercy. PMID- 10110578 TI - Measuring mission effectiveness. PMID- 10110581 TI - Loosening the ribbon of restraint. PMID- 10110582 TI - The HMO industry: evolution in population demographics and market structures. PMID- 10110583 TI - Health care strategy research, 1985-1990: a critical review. PMID- 10110584 TI - Lasers expand boundaries of noninvasive treatment. PMID- 10110585 TI - OR newsletter bridges communication gap. PMID- 10110586 TI - Consultants directory. AB - This is a listing of consultants in perioperative nursing and related areas. The information has been provided by the consultants listed. PMID- 10110588 TI - Key strategies help to tame turnover time. PMID- 10110587 TI - Your serious players are worth cultivating. Interview by Susan Klann. PMID- 10110589 TI - Job sharing can be a win-win situation. PMID- 10110590 TI - Advice for users on compliance with Devices Act. PMID- 10110591 TI - Grantees begin work to strengthen nursing. PMID- 10110592 TI - Lasers' future role in general surgery and orthopedics. PMID- 10110593 TI - Interactive planning is guiding concept for nursing grantees. PMID- 10110594 TI - Eyewear policies are a major safety issue. PMID- 10110595 TI - Retention factors for physiotherapists in an underserviced area: an experience in northern Ontario. AB - The purposes of this study were to establish baseline information about the extent of physiotherapy (PT) retention problems in Northern Ontario, and to identify potentially significant factors for retention. Potential correlates of retention were grouped into four domains: personal, professional experience, occupational and environmental factors. The questionnaire was sent to all PTs registered to practise in Northern Ontario; a response rate of 82 per cent was achieved. Multiple regression techniques were used to identify significant variables (p. less than 05) directly associated with intention to leave Northern Ontario. Path analysis was also completed to identify factors with indirect relationships to the outcome measure. The most significant factor was the perceived opportunity for career development, results have implications for health care administrators and planners in their development of strategic plans to increase employee retention. PMID- 10110596 TI - Can you be replaced by a computer? PMID- 10110597 TI - Physiotherapy and research: future visions. PMID- 10110598 TI - Tomorrow's stars shine today: staging a health care conference for student volunteers. PMID- 10110599 TI - Area health education centers: research issues in the 1980s; an agenda for the 1990s. PMID- 10110600 TI - A curtain up on wellness. A U.S. delegation learns about methods of alternative healing in the subtropical resorts of the USSR. PMID- 10110601 TI - Job aids for volunteers: tools to help them successfully complete their jobs. AB - Developing a system for implementing a job aid program within your organization may go a long way to enhancing volunteer job satisfaction and increasing productivity. Job aids have problem to be valuable tools at all four stages in the volunteer management process. They can be useful in recruiting and orienting the volunteer about what the job entails. They serve as tools to help the volunteer perform the job at an acceptable level. And finally, they serve as an excellent way to evaluate the volunteer's performance. PMID- 10110602 TI - A new era in federal health care financing policies. PMID- 10110603 TI - Perspectives. HCFA takes heat on lab regulations. PMID- 10110604 TI - Perspectives. Hospitals prepare to swallow capital reform. PMID- 10110605 TI - Perspectives. VA under fire for quality of care. PMID- 10110606 TI - Perspectives. Supreme Court ruling opens Pandora's Box. PMID- 10110607 TI - The cost of hospital regulations and the need for regulatory performance standards. PMID- 10110608 TI - Postretirement benefits. PMID- 10110609 TI - Recession. What's ahead for hospitals?. Interview by John Herrmann and Jennifer L. Smith. PMID- 10110610 TI - Health care tops everyone's agenda. PMID- 10110611 TI - Michigan hospitals tug at the grass roots. Interview by Thomas G. Goodwin. PMID- 10110612 TI - New issues in brain research. PMID- 10110613 TI - Cleveland's health initiative: Part two. PMID- 10110614 TI - The capital issue: high-stakes lobbying. PMID- 10110615 TI - 1991 directory of for-profit segment: stability as strength. PMID- 10110616 TI - Upcoming Supreme Court decisions crucial for hospitals. PMID- 10110617 TI - Premier's Physician Services. PMID- 10110618 TI - Supplier grants and goodwill. PMID- 10110619 TI - Making managed care work for you. PMID- 10110620 TI - Fairness and dangers in contracting. PMID- 10110621 TI - Medicare's proposed capital payment system--will it work? PMID- 10110622 TI - A capital plan. PMID- 10110623 TI - Financing capital under Medicare--an evaluation. AB - Here's a "middle-of-the-road" evaluation of HCFA's capital reimbursement proposal from a physician and president of a leading Washington, D.C., consulting group, former policy adviser to the Secretary of HHS and the man who chaired the task force that developed and implemented PPS. PMID- 10110624 TI - A capital plan. AB - A panel of experts responded to the Health Care Financing Administration's proposed capital reimbursement regulations at the recent Annual Conference of the Federation of American Health Systems in Orlando, Florida. What follows are edited versions of some of the panelists--but not all--concerning the issue and HCFA's position. PMID- 10110625 TI - Outsourcing. PMID- 10110626 TI - Coping with health care costs. PMID- 10110627 TI - Unlocking third-party maintenance of high-tech equipment. PMID- 10110628 TI - Will partisan politics cloud reform? PMID- 10110629 TI - The quest for quality and productivity in health services. AB - The leaders of health care organizations across the country are facing significant pressures to improve the quality of their services while reducing the rate of cost increases within the industry. Total Quality Management (TQM) has been credited, by many leaders in the manufacturing industry, as an effective tool to manage their organizations. This article presents key concepts of TQM as discussed by quality experts, namely, Deming, Juran, and Crosby. It discusses 12 key concepts that have formed the foundation of TQM implementation at Henry Ford Health System. The process of implementation is presented in detail, and the role of TQM in clinical applications is discussed. Success factors and visible actions by senior management designed to reinforce the implementation of TQM in any organization are presented. PMID- 10110630 TI - TQM and clinical medicine. PMID- 10110631 TI - Blazing the trail of quality: the HFHS quality management process. PMID- 10110632 TI - A CEO's perspective of TQM. PMID- 10110633 TI - Humor: a research and practice tool for nurse scholar-supervisors, practitioners, and educators. AB - The nurse scholar, whether a supervisor, an educator, or a practitioner, has a lifetime of research opportunities as well as personal experiences related to the human need for humor. We need to develop the means to assess the individual's and group's response to humor. Nurse scholars, particularly the nurse supervisor, can make a significant contribution in the search to harness some of the energy we use in laughing and direct it toward helping us heal our human conditions. PMID- 10110634 TI - Team up for safety. PMID- 10110635 TI - The plight of Michigan's rural hospitals: a survey of chief financial officers. PMID- 10110636 TI - Smoking in the workplace: rights of smokers and nonsmokers. PMID- 10110637 TI - Control, narcissism, and management style. PMID- 10110638 TI - The human resource role in addressing the nursing shortage. AB - A new initiative on the part of hospital management is needed to involve itself and the HRD more actively in addressing the nursing shortage. Hospital management can provide organizational support, the HRD the needed leadership, and financial managers the measuring tools to adopt a retention posture or balanced solution approach. Ultimately, hospital management wants to know how increased expenditures on human resources, and specifically nurses, affect the bottom line. However, two points need to be mentioned. First, not all steps taken by the HRD will require a dollar investment (for example, improved communication), but they will need the attention and support of hospital management. Secondly, if hospital management is waiting for an exact, accounting-supported cost-benefit analysis that justifies additional expenditures on nurses, then the effort will probably never be made. It is difficult to show a cause-and-effect relationship between discretionary expenditures (such as research and development, advertising, employee training programs) and the bottom line. PMID- 10110639 TI - What supervisors want to know about decentralization. AB - Many organizations in various industries have tended to move away from strict centralization, yet some centralization is still vital to top management. With 19 of the 22 executives interviewed favoring or implementing some form of decentralization, it is probable that traditionally centralized organizations will follow the trend and begin to decentralize their organizational structures. The incentives and advantages of decentralization are too attractive to ignore. Decentralization provides responsibility, clear objectives, accountability for results, and more efficient and effective decision making. However, one must remember that decentralization can be overextended and that centralization is still viable in certain functions. Finding the correct balance between control and autonomy is a key to decentralization. Too much control and too much autonomy are the primary reasons for decentralization failures. In today's changing, competitive environment, structures must be continuously redefined, with the goal of finding an optimal balance between centralization and decentralization. Organizations are cautioned not to seek out and install a single philosopher-king to impose unified direction, but to unify leadership goals, participation, style, and control to develop improved methods of making all responsible leaders of one mind about the organization's needs and goals. PMID- 10110640 TI - Putting your human resource department to work for you. AB - As a staff function, human resources is organized as a service activity. Service activities render no patient care; they do not advance the work of the organization. However, they support the performance of the organization's work and in a practical sense become necessary. For example, if a pure service, such as building maintenance, did not exist, the facility's physical plant would gradually self-destruct. Similarly, without human resources to see to the maintenance of the work force, the overall suitability and capability of that work force will steadily erode. Recognize human resources for what it is--an essential service function required to help the organization run as efficiently as possible. Learn what the HR department does, and especially learn why the department does what it does. Provide input to the human resource department. Forge a continuing working relationship with the HR department, making it clear that you expect service from this essential service department. Challenge the HR department to do more, to do better, and to continually improve service--and put the human resource department to work for you and your employees. PMID- 10110641 TI - Orientation and training of nurse managers: a case study. PMID- 10110642 TI - Dangerous liaisons or wedded bliss? PMID- 10110643 TI - An anti red-tape man allowed too much rope? PMID- 10110644 TI - A good day's practice. PMID- 10110645 TI - Let the trained take the strain. PMID- 10110646 TI - Double discrimination. PMID- 10110648 TI - Healthcare data briefing. Equal opportunities for women in medicine. PMID- 10110647 TI - More means less. PMID- 10110649 TI - An income in the valleys. PMID- 10110650 TI - Swings and roundabouts. PMID- 10110651 TI - Health promotion in practice. PMID- 10110652 TI - Computing. On the cutting edge. PMID- 10110653 TI - Computing. Clerical army demobbed. PMID- 10110654 TI - Compact for contracts. PMID- 10110655 TI - Innocent victims of caring capitalism. PMID- 10110656 TI - Making the most of a reversal of misfortune. PMID- 10110657 TI - Giving them what they want. PMID- 10110658 TI - Pioneering placements. PMID- 10110659 TI - Evaluation and selection of patient-controlled analgesia infusion pumps. AB - Seven PCA infusion pumps from seven manufacturers were evaluated. The condition for acceptable use of most of the units is that they not be used at low volumes that could result in overinfusion from the stored volume when an occlusion is cleared. All pumps met most accuracy, electrical safety, and performance criteria. Purchasing decisions should also take into consideration the cost of disposables, application, and medication security. PMID- 10110660 TI - Evaluation of a facsimile (fax) transfer system for medication order delivery. AB - Delivery of medication orders for initial processing is often slowed by distance between the nursing unit and the pharmacy. Messengers and pneumatic tubes are not always available or reliable. Facsimile (fax) machines are able to transmit photocopies of medication orders in seconds. An initial evaluation of available fax machines led to selection of three models for a trial installation. Criteria for fax evaluation included medication order turnaround time (TAT), percentage of orders requiring more than 2 hours to be received by the nursing unit, and number of orders recopied by nursing personnel for pharmacy use. An initial review identified the time required for order processing using a reliable pneumatic tube system to deliver orders to the central pharmacy. The number of orders recopied by nurses into the chart to provide working copies of misplaced or lost orders for pharmacy was also recorded. The fax system was installed and the initial data collection process was repeated. Statistics focused on the total time required to transmit an order to pharmacy and provide the initial dose to the nursing unit. Analysis of the mean (+/- SD) showed an initial TAT of 1.59 (+/- 1.30) hours (n = 92). TAT after initiation of fax transmission was 1.36 (+/- 1.15) hours, P = 0.20 (n = 104). This improvement is greater than it appears because 1.10 hours of both of these times are fixed times involving pharmacy order processing. The percentage of orders that required more than two hours to provide medication to the nursing unit was reduced from 29% (27/92) to 18% (19/104) P less than 0.05. The average number of nursing recopies into the chart was reduced. PMID- 10110662 TI - Citation analysis of selected clinical pharmacology journals. AB - Perceptions of pharmacy and medical journal quality vary widely. One objective measure of the quality of a scientific journal is the impact factor that can be defined as "a measure of the frequency with which the 'average article' in a journal has been cited in a particular year." The purpose of this study was to evaluate the clinical pharmacology journals available through the Science Citation Index and determine those that have the greatest impact. From these data, it appears that the premier primary literature journal in clinical pharmacology is Clinical Pharmacology and Therapeutics while the premier review journal has been Clinical Pharmacokinetics. Possible explanations for impact factor fluctuations over time are also discussed. PMID- 10110661 TI - Evaluating albumin usage in an urban acute care hospital. AB - At Cabrini Medical Center, a 499-bed acute care hospital in New York City, a concurrent review of 25% albumin usage was performed. A nationwide shortage, and a 40% increase in usage over the same time period the previous year, provided the justification for the study. Twenty-five percent albumin usage was monitored for a 2-month period. Patient characteristics, as well as information including type of medical service, number of units of albumin administered, dose, total serum protein, serum albumin, and patient outcome were recorded. A study population of 54 patients was identified. Of the 770 units of 25% albumin administered, 668 (87%) were deemed inappropriate, with the medical service responsible for 614 units, and the surgical service 54 units. This represented 92% and 8% of inappropriate use, respectively. Overall, 86% of albumin usage was by the medical service. This is in sharp contrast to the results obtained by previous investigators. PMID- 10110663 TI - Investigational drug protocols--hidden costs. PMID- 10110664 TI - Medication errors--1991. PMID- 10110665 TI - Hospital Medicare problems fuel national reform calls. PMID- 10110666 TI - Data collection and sharing by federal agencies: implications and guidance. PMID- 10110667 TI - Hanlester Laboratories decision: important test of antikickback statute. PMID- 10110669 TI - Outsourcing revisited. New ways to develop your information asset. PMID- 10110668 TI - Managing the management of information systems. What healthcare executives need to know. PMID- 10110670 TI - Medical technology in a competitive market: is regional planning a solution? PMID- 10110672 TI - How much is that CEO in the window? PMID- 10110671 TI - Technology management in the '90s. PMID- 10110673 TI - Technology assessment and procurement. Interview by Vaughan Smith. PMID- 10110675 TI - Hospital replicates its 50-year-old boardroom in new office building. PMID- 10110674 TI - Enhancing minority opportunities in healthcare management. PMID- 10110676 TI - Federal regulation of waste still uncertain as tracking pilot ends. PMID- 10110677 TI - How to choose furnishings for administrative spaces. PMID- 10110678 TI - JCAHO survey reports: where to turn for help. PMID- 10110679 TI - Timely maintenance improves a roof's longevity. PMID- 10110680 TI - How to compare the costs of contract laundries. PMID- 10110681 TI - How to protect yourself from vendor bankruptcy. PMID- 10110682 TI - Uncertainty and unpredictability in application of peer review privileges statutes. PMID- 10110683 TI - Comment: DNR orders--judicial authorization or statutory mandate? PMID- 10110684 TI - The re-creation of life rituals in long-term care facilities. PMID- 10110685 TI - Family members' perceptions: how they view care of Alzheimer's patients in a nursing home. PMID- 10110686 TI - Effectiveness of technical assistance in the development of psychiatric rehabilitation programs. AB - Most mental health programs need technical assistance to develop effective psychiatric rehabilitation programs. This article discusses how psychiatric rehabilitation was introduced into three community mental health programs and describes the elements of a psychiatric rehabilitation program and the phases of a technical assistance process. A case study illustrates how technical assistance consultants can be trained to develop psychiatric rehabilitation programs. Barriers and facilitators to the technical assistance are discussed in the context of several other technical assistance studies. PMID- 10110687 TI - Data and decisions: can mental health management be knowledge-based? AB - Three major factors suggest a healthy future for data-based decision making within mental health authorities: (1) the improved knowledge base related to the treatment and management of serious mental illness, (2) advances in data processing technology and (3) conceptual advances in management information system design, most notably the National Institute of Mental Health (NIMH) Mental Health Statistics Improvement Package. This paper briefly outlines these three factors and goes on to examine information needed by state mental health authorities (SMHAs) to enhance decision making. The client-level data necessary for data-based policy decisions, while still scarce, are increasingly available and are increasingly finding homes within SMHA management information systems. As SMHAs improve their information systems to accommodate such data, they face substantial implementation challenges and substantial payoffs in terms of increased knowledge for decision making. PMID- 10110688 TI - Early HIV detection: a community mental health role. AB - This paper documents the changing need for early detection of human immunodeficiency virus (HIV) infection and proposes a role for community mental health centers (CMHCs). Ignorance of HIV infection status can result in greater risk of medical complications and denies the individual the opportunity to take the steps necessary to prolong life and prevent further transmission of the virus. Individuals who know they are infected can obtain good medical care, avoid infection, avoid becoming pregnant, behave responsibly and plan their lives appropriately. Advances in specific therapeutics now make it important for infected individuals to know their HIV status well before becoming overly ill. The social history, sexual history, drug use history, and physical and mental status of each client will provide important clues regarding infection status. Reluctance to refer for testing because of concerns about level of stress, liability and confidentiality should be tempered by a policy of referring for testing whenever any indication of infection arises. PMID- 10110689 TI - Prediction of use of psychiatric services: application of the CART (classification and regression trees) algorithm. AB - A computerized recursive partitioning program called Classification and Regression Trees (CART) was used to identify potential high users of services among low-income psychiatric outpatients. Sociodemographic variables, clinical variables (e.g., psychiatric diagnosis and type of presenting complaint), source of referral and the most recent psychiatric treatment setting used were studied. Discharge from inpatient psychiatric treatment right before admission to outpatient psychiatric treatment was found to be the most consistent, the most powerful and the only necessary predictor of high use of outpatient psychiatric services. PMID- 10110690 TI - A method for employee participation in the policy development process. AB - A method for policy development is described that permits employee participation at all levels within a mental health agency. This method is adaptable to a variety of organizational structures and does not require major administrative changes. It does require a commitment to participatory management and the belief that employees should be involved in the organizational change process. A step-by step procedure is related, and guidelines for developing draft policies are offered. PMID- 10110691 TI - Reliability of an observational system used to monitor behavior in a mental health residential treatment unit. AB - This article discusses the importance of carefully monitoring and documenting patient behavior in mental health inpatient programs. A structured behavioral observation system is presented along with data evaluating its reliability. This Unit Coverage system is shown to have acceptable reliability, as reflected in an obtained interobserver agreement of 86.2%, corrected for chance. PMID- 10110692 TI - Toward a smoke-free policy in mental health facilities. PMID- 10110693 TI - Consumers' satisfaction with health care delivery: issues of measurement, issues of research design. AB - The measurement and tracking of patient satisfaction is an area of increasing importance today. Because of this importance, researchers have begun to more closely examine conceptual, operational and research design issues implicated in this measurement. In this context, this paper focuses on selected research design issues. Three key issues are discussed; namely, appropriate measures, item phrasing and data collection approaches. Issues, problem areas and suggested recommendations are provided. We hope our discussion will help future researchers achieve better and more meaningful measurement of patient satisfaction. PMID- 10110694 TI - Using internal communication as a marketing strategy: gaining physician commitment. AB - In the ambulatory care industry, increased competition and promotional costs are pressuring managers to design more creative and effective marketing strategies. One largely overlooked strategy is careful monitoring of the daily communication between physicians and ambulatory care staff providing physician services. Satisfying physician communication needs is the key to increasing physician commitment and referrals. This article outlines the steps necessary to first monitor, then improve the quality of all communication provided to physicians by ambulatory care personnel. PMID- 10110695 TI - Overcoming the promotional bias in health care marketing: a human relations approach. AB - In recent years the health care industry in general and ambulatory care in specific has been in a state of intense competition. In an attempt to survive and prosper, many health related organizations have turned to marketing as a means of developing viable strategies. Unfortunately, all too often the marketing function is equated with advertising and promotion: a small subsection of what a total marketing effort should be. In this paper, means of overcoming this limitation will be discussed using a human relations approach. PMID- 10110696 TI - Industrial rehabilitation comes of age. AB - Yes, industrial rehabilitation has come of age. The "trendiness" and "glitz" associated with such programs are now gone (or, at least, on the wane). These programs are now being subjected to the same scrutiny as other business ventures, no longer seen as the "cash cows" that single-handedly can end the financial woes of an organization. Along with this maturity has come an accreditation system with accepted standards of practice, care and methodological style; a data base reporting on the range and limits of program capability; and the realization by the insurance community that industrial rehabilitation can be effective and that these programs are reasonable assessment and intervention alternatives for selected patients. We have also noted that as these programs grow past their adolescence it will be important to pay close attention to basic questions of cost, value, and worth. While most programs have not been totally "institutionalized" into the health care provision system, their honeymoon phase has reached a positive conclusion. It's now time to look very closely at where we are today, remember where we have come from, and look to the future with a realistic and clear view. PMID- 10110697 TI - Ready, aim, fire: assessing the occupational health market. PMID- 10110698 TI - Rehabilitating the injured worker: opportunities and pitfalls. PMID- 10110700 TI - Internal marketing. PMID- 10110699 TI - Reaching out to industry: establishing a successful off-site clinic. PMID- 10110701 TI - The emergency medicine contracting market. PMID- 10110702 TI - Providing high quality occupational medical services. AB - As people become more aware that their work and the environment can adversely affect their health, greater attention will focus on the role of occupational health in preventing and evaluating certain medical concerns. This wider awareness will further the demand for quality occupational medical services. Clearly, an opportunity exists for the business and health care communities to work in concert to prevent occupational and environmental health problems. Marketing efforts that can support occupational medical services range from seminars and newsletters to unique approaches of health care delivery. Examples of the latter include "fast-track" treatment of work related injuries that bypass customary delays in most emergency departments. In this manner, client organizations benefit from the special treatment, which encourages the use of the occupational health program. Conferences geared to the business community, where topics such as back injuries, drug testing or medical surveillance are presented, can enhance the credibility of the services. Moreover, since the role of occupational medicine, especially with respect to small businesses, is poorly understood, these meetings can help establish the capabilities of the program. Efforts that promote the institution itself can also be beneficial, especially regarding highly specialized equipment and services, including magnetic resonance imaging, physical therapy equipment and research efforts of its staff. As the issues evolve, occupational health professionals will need to adapt and keep abreast of the changes. Both health care providers and business should be aware of the specialized area of knowledge associated with occupational health professionals, especially the specialty of occupational medicine. Similarly, the business community is advised to take a critical review of any provision of health services to its employees. Attention to the type of staff at a medical facility as well as their training and protocols will help insure that appropriate and quality services are being provided. PMID- 10110703 TI - Recipe for lower health costs: a dash of this, a drop of that. PMID- 10110704 TI - Primary care is medicine's dinosaur. PMID- 10110706 TI - Revitalize your practice with an office renovation. PMID- 10110705 TI - Could your group's health insurance leave you bare? PMID- 10110708 TI - Trends in managed care contracting. AB - This article describes trends in managed care contracting and offers physicians practical guidance for evaluating managed care plans and negotiating and dealing with problems in managed care contracts. PMID- 10110707 TI - Medical staff membership criteria: a credentialing minefield. AB - In today's increasingly competitive medical practice environment, legal challenges to credentialing decisions abound. To minimize the risk of liability, hospitals and their medical staffs must be especially careful when adopting and applying the criteria for medical staff membership. PMID- 10110709 TI - Patient allegations of sexual abuse--surviving a lawsuit. AB - In this article, the author examines patient allegations of sexual abuse by physicians, focusing on the legal theories for such suits and possible defenses, together with the complications of professional liability insurance coverage. In addition, practical suggestions for physicians charged with sexual misconduct are offered. PMID- 10110710 TI - Health care litigation: achieving fairness and reasonableness in punitive damages awards. AB - This article, the eighth in a series on health care litigation, discusses whether due process considerations require that the common-law procedures for awarding punitive damages be modified and whether juries have undue discretion in awarding punitive damages. The authors analyze an important recent United States Supreme Court punitive damages case and examine the changes states may need to make in their punitive damages assessment procedures to conform with the Supreme Court's holding. PMID- 10110711 TI - Providers with HIV/AIDS--a new dilemma. AB - Recently, a great deal of attention has been focused on health care providers who have or may have the human immunodeficiency virus or, as it is known in its later stages, acquired immune deficiency syndrome. This article explores some of the duties physicians have, or soon may have, to their patients and employers in the areas of testing, disclosure, and practice restraints. PMID- 10110712 TI - Use of statistical sampling and extrapolation in overpayment audits of physicians. AB - The successful defense of claims for physician overpayments by insurers requires the health care attorney to be familiar with the statistical sampling procedures employed during these types of audits. In this article, the author describes when audits are initiated, the factors that are taken into account in determining if statistical sampling is appropriate, how the statistical sampling study is conducted, and what defenses the health care attorney can assert when confronted with the results of a statistical sampling audit. PMID- 10110713 TI - Impact of OBRA 1990 on physicians. PMID- 10110714 TI - California's new physician discipline law: a prototype for the future? PMID- 10110715 TI - California's approach to the Health Care Quality Improvement Act. PMID- 10110716 TI - John Wayne Cancer Clinic affiliating with new hospital. PMID- 10110717 TI - Inpatient bias keeps ambulatory growth modest; rehabilitation, sports medicine increase their pace. PMID- 10110718 TI - Acquisitions add up to home-care revenue growth. PMID- 10110719 TI - Nursing homes file suit. PMID- 10110720 TI - VA construction budget proposed. PMID- 10110721 TI - Organ donations up in 1990. PMID- 10110722 TI - Group lists disciplinary actions. PMID- 10110723 TI - Daughters offers to rebuild Charity. PMID- 10110724 TI - Hospital groups press for minimum payment guarantee in capital rule. PMID- 10110725 TI - Rural facility's predicament: Medicare capital revamp could force it to close. PMID- 10110726 TI - Those pliable occupancy rates. PMID- 10110728 TI - FTC to file against Fla. physicians. PMID- 10110727 TI - Earnings escalate at hospital systems. PMID- 10110729 TI - Hospitals in Houston to cut beds, staff. PMID- 10110730 TI - Hospitals lukewarm to Bush's liability proposal. PMID- 10110731 TI - Pressure from payers continues to slow growth of psychiatric hospitals; chains report decline. PMID- 10110732 TI - Nursing home industry holds its ground. PMID- 10110733 TI - HCA net income holds steady. PMID- 10110734 TI - NME opens medical center at USC campus. PMID- 10110736 TI - Capital crunch restrains CCRC development. PMID- 10110735 TI - Charter reports net loss for second quarter. PMID- 10110737 TI - Managed-care plans with provider financial backing report growth; about half see profit. PMID- 10110738 TI - Red Cross beginning two-year overhaul of blood collection, testing procedures. PMID- 10110739 TI - FHP may acquire Bridgeway Plan for Health. PMID- 10110740 TI - Mich. court ruling allows transfer to Medicaid fund. PMID- 10110741 TI - New Jersey Senate OKs reform package; hospitals to fight financing plan. PMID- 10110742 TI - Pa. omits inpatient Medicaid funds. PMID- 10110743 TI - Lawmakers vow to expand efforts to keep elderly out of homes. PMID- 10110744 TI - San Francisco hospitals cleared to merge as FTC drops antitrust probe. PMID- 10110745 TI - New rules governing long-distance service in effect. PMID- 10110746 TI - Oregon rationing plan should go to federal review board--group. PMID- 10110747 TI - Danger: hospital in distress. PMID- 10110748 TI - Nursing supervisors continue to lead climb up the ladder. AB - Modern Healthcare's third annual survey shows that raises for nursing supervisors continued to outpace raises for staff positions last year. However, those raises varied by region, presumably reflecting regional differences in the severity of the recession and local personnel shortages. The survey also showed that many hospitals have added salary levels, called clinical ladders, to compensate experienced bedside nurses. PMID- 10110749 TI - Rural hospital executives won't oppose new capital plan, but changes sought. PMID- 10110750 TI - Helpers let nurses spend more time nursing--study. PMID- 10110751 TI - Insurance, business leaders fault state-mandated benefits. AB - As healthcare costs continue to soar, the cost of providing medical insurance is becoming unaffordable for many businesses, contributing to the growing number of uninsured. Business and insurance leaders say part of the blame rests with the growing number of state-mandated benefits, which they say should be rolled back. PMID- 10110752 TI - Execs' antidotes to union activity. AB - State hospital association executives overwhelmingly support the development of educational programs on employment issues as the best strategy to counter increased union activity following the implementation of the National Labor Relations Board's hospital bargaining-unit rules, according to Modern Healthcare's fifth monthly Fax poll of state hospital association presidents. PMID- 10110753 TI - Healthcare stocks expected to remain strong. AB - While healthcare stocks are likely to remain at the top of Wall Street's list of favorites, healthcare analysts and money managers say they don't expect to see the same quality of healthcare companies issuing stock the rest of the year. They say that in the coming months, more companies of lesser quality will sell stock at inflated prices, compared with their earnings. PMID- 10110754 TI - AHM to sell Miss. hospital. PMID- 10110756 TI - Case-by-case review clause suggested for capital rule. PMID- 10110755 TI - RehabCare files for public offering. PMID- 10110757 TI - Hospitals, government resolve dispute over copying records. PMID- 10110758 TI - AHA releases reform plan. PMID- 10110759 TI - Bill would implement Pepper Commission recommendations. PMID- 10110760 TI - HCFA considering modifications to proposed capital payment rule. PMID- 10110761 TI - Proposed physician fee schedule rules released. PMID- 10110762 TI - HCFA orders states to cover Clozaril costs; watchdog group urges warning on drug. PMID- 10110763 TI - Judge allows organ harvesting without family's OK. PMID- 10110764 TI - Pa. nursing homes prepared for payment halt. PMID- 10110765 TI - Medlantic to revamp board in move to soothe physicians. PMID- 10110766 TI - Psych length of stay keeps falling--survey. PMID- 10110767 TI - 'Personal responsibility key to improving black males' health'. PMID- 10110768 TI - Bill would give physicians tax breaks for practicing in underserved areas. PMID- 10110769 TI - Pay spiral leads nowhere. PMID- 10110770 TI - Red tape, antiquated laws keep computerized records on shaky legal ground. AB - Computerizing medical records in an effort to improve quality of care and cut costs may sound like a terrific idea. And the technology for doing so is becoming more affordable for a growing number of hospitals. But a patchwork of nebulous and antiquated state laws makes automated recordkeeping technically illegal in 12 states and legally ambiguous in many more. Some experts are calling on the federal government to provide a comprehensive solution. PMID- 10110771 TI - High court broadens antitrust risks. PMID- 10110772 TI - Teaching hospitals learning benefits of image advertising. PMID- 10110773 TI - 'Turnkey' favored over home-grown. PMID- 10110774 TI - Keane to offer Unix-based system. PMID- 10110775 TI - Ore. bills aim to protect exemptions. AB - At the request of the Oregon Assn. of Hospitals, state lawmakers have introduced several bills aiming to thwart or limit challenges to tax exemptions for the state's not-for-profit organizations. Tax-relief initiatives are expected to start squeezing local governments' revenues, making not-for-profits an increasingly attractive target for taxation. Hospital officials are seeking statutes that explicitly outline the obligations of their tax exemptions. PMID- 10110776 TI - Kusserow forges ahead on anti-kickback plans. PMID- 10110777 TI - Pa. hospital settles Medicaid fraud charges. PMID- 10110779 TI - AIDS groups urge Bush to take leadership role, boost funding. PMID- 10110778 TI - Recovery of interest expenses frustrated. PMID- 10110780 TI - Judge dismisses 2 suits by patients of infected Johns Hopkins surgeon. PMID- 10110781 TI - An ethic for all of us. PMID- 10110782 TI - Policing pollution. PMID- 10110783 TI - Friends of the earth. PMID- 10110784 TI - Factory, family, jungle and theater. Interview by Joe Flower. PMID- 10110785 TI - Everyday values. PMID- 10110786 TI - The day after...NHI. PMID- 10110787 TI - Changing the way we work. A second look at Mount Sinai Medical Center's extraordinary patient care improvement program. PMID- 10110788 TI - Best of both worlds. PMID- 10110789 TI - On quality. Between the predictable and the possible. PMID- 10110790 TI - The quiet superstars. Part 3. Memorial Hospital and Medical Center, Midland, Texas and Multicare Health System, Tacoma, Washington. PMID- 10110791 TI - Keeping track of medical records. PMID- 10110792 TI - Integrating child health services in Wellington. PMID- 10110793 TI - Hutt Hospital goes smokefree. PMID- 10110795 TI - Wellington Area Health Board--overview. PMID- 10110794 TI - Wellington could lead the way with "Wellbank". PMID- 10110796 TI - 'Information systems vital'. PMID- 10110797 TI - HBNZ (Health Boards New Zealand) group study tour. Preliminary report. PMID- 10110798 TI - Telecommunications in health. PMID- 10110799 TI - Reorganizing has been a big challenge for Otago Board. PMID- 10110801 TI - Dunedin Hospital's new oncology centre. PMID- 10110800 TI - The new Queen Mary Maternity Centre. PMID- 10110802 TI - Central Otago health services. PMID- 10110803 TI - Rectangularization of the survival curve: implications of an ill-posed question. AB - There has been considerable interest in the question of whether the human survival curve is becoming more rectangular as life expectancy in developed countries increases. However, despite the intuitive appeal of the rectangularization concept it has not been translated into a formally stated hypothesis about the shape of the human survival curve. This article examines how the hypothesis of rectangularization can be formally stated and the implications of that formalization for research on health and functional changes at later ages. PMID- 10110805 TI - Perspectives. Minority medical schools: rough sailing ahead. PMID- 10110804 TI - Implications of health status in analysis of risk in older persons. AB - This article explores the hypothesis that health status in old age acts as a summary measure of health exposures over time and, as such, plays a central role as a determinant of survival and morbidity trajectories in old age. Evidence is presented for the utility of health status as a modifier of risk in other areas of gerontologic research, and an example of modification pertinent to the cholesterol-heart disease controversy in old age is presented. The potential of differential health status in old age to affect both risk factors and risk estimates in epidemiologic analyses may be an important principle as epidemiologists continue to development research to preserve and augment the quality of life in old age. PMID- 10110806 TI - Perspectives. AHA rolls out welcome mat for new chief. PMID- 10110807 TI - 1991 program survey. PMID- 10110808 TI - Instrument flight for HEMS (helicopter emergency medical services). PMID- 10110809 TI - Biomedical technology: using it during patient transport. AB - The purpose of this article has been to discuss and present some of the current biomedical technology available for patient transport. Recommendations were offered concerning the evaluation of these products, so that they can be effectively used in the air medical environment. There is one step yet that needs to be taken. This step involves identifying the most appropriate application of this technology to the care of the patient. As asked at the beginning of this article, how many pumps and monitors are needed for safe and high-quality patient transport? The answer to that question is not within the scope of this article, but pieces to the answer are. Through research, those of us who provide care during transport should be able to answer this question and develop guidelines for the use of biomedical technology when caring for the patient during air medical transport. PMID- 10110810 TI - How you spend your pennies ... factors affecting the efficiency of human waste disposal systems (re-usable and disposable) and their cost. AB - Both re-usable and disposable systems have their merits and problems. The disposable system, being fully integrated, appears to be steadily gaining market share compared with the re-usable system. Since its introduction, the success of the re-usable system has been limited by the use of pans not designed for automatic processing. Where the 'perfection' pan has been superseded by 'open' shaped receptacles and those used in commode chairs, cleaning effectiveness can be improved by a factor of 10. For this and other reasons, nursing involvement in the re-usable system can be high while the 'perfection' pan is in use. A work study exercise to compare nursing involvement in re-usable and disposable systems is under way. When selecting a human waste disposal system for any site, it is vital that all disciplines discuss and decide objectives. The equipment usage, space, site conditions, availability and quality of supplies (eg water, electricity), the costs of maintenance, nursing time and other expenditure must be considered. The disposable system is capable of high process rates (more than double that of the fastest re-usable system). Its capital cost is currently about 1,000 pounds less than an average re-usable system, but in the busiest wards, revenue costs may be higher. In such wards the space for disposable receptacle storage can be as much as five to ten times machine volume. The design of macerators is generally simpler (having less components) than washer disinfectors. Monitoring and maintenance involvement are likewise expected to be lower, particularly in hospitals with modern drainage systems.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10110811 TI - Does engineering as a profession exist in Europe? PMID- 10110812 TI - The Nuffield Hospitals Group. PMID- 10110814 TI - Measures enabling existing incinerators to continue in use. PMID- 10110813 TI - The Hospital Building Notes--a user's view. PMID- 10110815 TI - Ozone depletion by CFC refrigerants. The refrigeration and air-conditioning industries response. PMID- 10110816 TI - Nurse retention program bolsters patient care goals. PMID- 10110817 TI - Professional nurturing for nurses in the rural setting. PMID- 10110818 TI - Enhancing the nursing 'image' to bolster recruitment efforts. PMID- 10110819 TI - Special advisory committee studies nurse shortage. PMID- 10110820 TI - Changing nurse middle manager role. PMID- 10110821 TI - Mercy turnaround offers lessons in financial management. PMID- 10110822 TI - Economist doubts Canadian health care systems will work in U.S. PMID- 10110823 TI - Protecting hospitals against insurer insolvencies. PMID- 10110824 TI - New Children's Hospital at Stanford to open in June. PMID- 10110825 TI - Seymour views access, infant mortality as key issues. PMID- 10110827 TI - Retention, support strategies help combat nurse shortage. PMID- 10110826 TI - Successful strategies for promoting hospital nurse retention. PMID- 10110829 TI - Architectural design award winner. New long-term care facility--less than 100 beds. Oak Park Care Center, Sheldon, IA. PMID- 10110828 TI - The fast track: federal agencies and the political demand for AIDS drugs. PMID- 10110830 TI - Architectural design award winner. New long-term care facility--more than 100 beds. River Garden Hebrew Home, Jacksonville, FL. PMID- 10110831 TI - Architectural design award winner. Long-term care facility renovation/rehabilitation. Hover Village, Longmont, CO. PMID- 10110832 TI - Architectural design award winner. New retirement center--150 units or less. Sunrise of Fairfax, Fairfax, VA. PMID- 10110833 TI - Architectural design award winner. New retirement center--more than 150 units. Brookridge, Winston-Salem, NC. PMID- 10110834 TI - The beginning of a new era. Interview by Jim Bowe. PMID- 10110835 TI - Management contracts step to forefront. 1991 retirement housing survey. PMID- 10110836 TI - A breath of fresh air. Options for the ventilator-dependent. PMID- 10110837 TI - Stir up participation in food service. Residents don aprons at Jersey facility. PMID- 10110838 TI - Crisis fuels need for nurse staffing waivers. Response to shortage varies from state to state. PMID- 10110839 TI - Today's employee may be tomorrow's lawsuit. PMID- 10110840 TI - Music therapy: sharing the sounds of life. PMID- 10110841 TI - Private pensions: will the money be there when you retire? AB - There is clear evidence that Social Security, even when taken together with the benefits of a private pension plan, may not be adequate income for America's future retirees. Employees must begin planning and implementing long-term savings strategies now to make up the difference. PMID- 10110842 TI - Elder abuse: America's hidden crisis. PMID- 10110843 TI - The older American: a willing and able employee. AB - Current and projected labor shortages are forcing employers to take a second look at hiring older Americans. A recent survey shows that workers over age 50 compare favorably with their younger counterparts. PMID- 10110844 TI - Public programs for the elderly ... can we afford them? AB - Is America draining its resources and short-changing the future of younger generations by funding programs for the elderly? A closer look explodes some of the myths surrounding this country's Social Security system. PMID- 10110845 TI - Coordinating housing and services for the elderly. AB - Though recent housing legislation represents something less than a major commitment to a housing-based strategy for maintaining the independence of frail older people, the cumulative effect is to increase greatly the possibilities for experimentation, especially at the state and local level. Consumer groups and service providers should be alerted to the possibilities to demonstrate creatively the important role that housing programs which are integrated with provision of services can play in serving frail and disabled people. An array of possibilities--from home repairs to service-enriched vouchers to congregate services--is now possible for those states and localities prepared to make the commitments to serving people with special needs. Through creative program implementation, we should expect to see housing coordinated with services play an appropriate and significant role in filling the gaps in the continuum of care for older adults. PMID- 10110846 TI - Aging in place. Providing mental health services for the elderly. AB - The elderly are at great risk of experiencing mental illness, and of not receiving necessary treatment. In Washington State, it was discovered that many of the elderly residing in public housing units suffered from mental illness and were too afraid to seek outside assistance or treatment. The Community Connections program was designed to provide onsite, cost-effective case management and stabilization services to these individuals. PMID- 10110847 TI - Health care needs of minority elderly. PMID- 10110848 TI - Eldercare. The challenge of the '90s. AB - The demands of caring for an aging parent can be great, especially when combined with career and other family responsibilities. As the population ages, however, eldercare will become increasingly more commonplace. PMID- 10110849 TI - Nutrition and the elderly. AB - Due to a variety of psychological, sociological, and economic factors, older persons are more likely to suffer the consequences of malnutrition. Home care providers are in a unique position to both observe and prevent the onset of nutritional problems. PMID- 10110850 TI - Seniors caring for seniors. Expanding eldercare services. AB - The Visiting Nurse Associations of America is spearheading a national demonstration project to create partnerships between nonprofit, community-based visiting nurse associations and the Senior Companion Program in an attempt to expand the scope of person-to-person volunteer programs and long-term care services. PMID- 10110851 TI - The patient's right of self-determination. AB - Recent legislation requires Medicare and Medicaid providers to assure the patient's right of self-determined care. This legislation necessitates that health care providers understand their state laws and standards affecting the patient's right to issue advance directives on health care, to refuse or accept treatment, and to make decisions concerning the receipt of health care services. PMID- 10110852 TI - Standards for governance. Board organization. PMID- 10110853 TI - The decision makers. Interview by Glen Hopper. PMID- 10110854 TI - Board meetings: open or closed? PMID- 10110855 TI - When reporters call. PMID- 10110856 TI - Evaluating quality assurance. PMID- 10110857 TI - Lifting the veil of secrecy. PMID- 10110858 TI - Advancing advance directives. Provider obligations and options: the Patient Self Determination Act. PMID- 10110859 TI - Advance directives and self-determination. PMID- 10110860 TI - Advance directives resources. PMID- 10110861 TI - Oregon Plan: access or rationing? PMID- 10110862 TI - Talking to patients about advance directives: if not now, when? PMID- 10110864 TI - Floor care system leads turnaround for nursing home. PMID- 10110863 TI - The Patient Self-Determination Act: one hospital's compliance program. PMID- 10110865 TI - Clean Air Act. PMID- 10110866 TI - A staffing standard proposal for patient and non-patient areas in hospitals. Philadelphia Chapter of the National Executive Housekeepers Association. AB - The Philadelphia Chapter of N.E.H.A. submits the following proposal for publication. We feel very strongly about the need to formalize some staffing standards for hospitals and all related healthcare facilities. The incentive comes from the current trend in administrative philosophies to "do more with less." The less means less for the support departments whose contribution is viewed most times as less worthy because we do not directly generate revenue. Oddly enough, the revenue generators cannot make money without the non-revenue generators. PMID- 10110867 TI - Odor neutralizer uses natural ingredients. PMID- 10110868 TI - New thoughts on contract management. PMID- 10110870 TI - Decade will foster new building. PMID- 10110869 TI - Diabetes offers niche--but for few hospitals. PMID- 10110871 TI - System nets economic plusses. AB - How will multi-hospital systems facilitate medical care in the future? How do administrators of such systems integrate the important components and personnel to achieve well-coordinated care for individual patients? In the following article, E. Wynn Presson, president and CEO of Health Midwest, a regional health care system involving 10 counties around metropolitan Kansas City, Kan., discusses the process of building and maintaining a regional care system of 40 health care entities including 11 hospitals and 2,350 licensed acute care beds. PMID- 10110872 TI - Special report on health care delivery systems. Hospitals should consider taking an active role in initiating the formation of medical groups for managed care contracting. AB - Hospital promotion of physician organizations as described in this article is a relatively new phenomenon. Approaches that have worked at one institution and time might not be appropriate elsewhere, and in any case will be unlikely to work every time. Nevertheless, the rapid pace of change in the health care industry demands a fresh look at existing modes of operation. Hospitals in immediate need of incremental revenue cannot afford to sit idly by, hoping their physicians will organize themselves sufficiently to bring additional payor contracts and patients to the institution. Taking an active role in helping physicians to develop contracting organizations that also benefit the hospital may well be worth the time and expense involved. PMID- 10110873 TI - Medicare-covered skilled nursing facility services, 1967-88. AB - The skilled nursing facility benefit under Medicare has been difficult to administer because its intent has been subject to misinterpretation. This article describes the series of legislative and administrative actions taken to align the benefit's use with its intent. Data are presented to show the changes in utilization and program expenditures in response to the actions taken. The 1988 clarifications to the level-of-care requirements seem to have resulted in an increased level of use of skilled nursing facility services. PMID- 10110874 TI - Health care indicators. PMID- 10110876 TI - Review effect on cost reports: impact smaller than anticipated. AB - Hospitals seeking Medicare payment are required to submit Medicare Cost Reports to their respective fiscal intermediaries, who in turn are required to desk review and sometimes audit the reports. The reviewed or audited report is considered more reliable than the originally submitted report and provides the basis for final Medicare payment. This study quantifies the impact of the review process, finding that, for the most part, the effect is quite small, usually less than 1 percent. Passthrough costs, however, were the exception to this rule. Capital and education passthrough costs, on a per discharge basis, were reduced about 6 percent. PMID- 10110875 TI - A public health model of Medicaid emergency room use. AB - This study builds a public health model of Medicaid emergency room use for 57 upstate counties in New York from 1985 to 1987. The principle explanatory variables are primary care use (based in physicians' offices, freestanding clinics, and hospital outpatient departments), the concentration of poverty, and geographic and hospital availability. These factors influence the emergency room use of all Medicaid aid categories apart from the Supplemental Security Income recipients. Inherent in these findings are a number of policy implications that are explored in this article. PMID- 10110877 TI - Financial aspects of adult day care: national survey results. AB - Using data from a national survey of adult day care centers, it was found that a typical center had revenues of approximately $140,000 and expenses that were slightly higher. Most of the revenue was from Federal sources, with Medicaid being the largest single source. The median cost per participant day was $29.50, over one-half of which was attributable to labor expenses. To the extent that adult day care programs can better utilize their capacity, considerable savings could be made in cost per participant day. PMID- 10110878 TI - Analysis of nursing home capital reimbursement systems. AB - An increasing number of States are using a fair-rental approach for reimbursement of nursing home capital costs. In this study, two variants of the fair-rental capital-reimbursement approach are compared with the traditional cost-based approach in terms of after-tax cash flow to the investor, cost to the State, and rate of return to investor. Simulation models were developed to examine the effects of each capital-reimbursement approach both at specific points in time and over various periods of time. Results indicate that although long-term costs were similar for the three systems, both fair-rental approaches may be superior to the traditional cost-based approach in promoting and controlling industry stability and, at the same time, in providing an adequate return to investors. PMID- 10110880 TI - Process and outcome measurement in Alberta's Coordinated Home Care Program. AB - A previous article in Home Health Care Services Quarterly described early work in the development of a Home Care Quality Assurance Program in Alberta, Canada. In this paper, the continued efforts of the Home Care Standards Committee in developing a client focussed outcome measurement tool is presented. PMID- 10110879 TI - Reform of health care in Germany. AB - For the past 45 years Germany has had two health care systems: one in the former Federal Republic of Germany and one in the former German Democratic Republic. The system in the Federal Republic was undergoing some important reforms when German reunification took place in October 1990. Now the system in eastern Germany is undergoing a major transformation to bring it more into line with that in western Germany. PMID- 10110881 TI - Foster care for older adults: issues and evaluations. AB - "Adult foster care" is a label that has been applied to very diverse programs. Although adult foster care appears to be a potentially important element in the continuum of care for older adults, its assumptions and characteristic features have not been clearly explicated. In this paper, common assumptions underlying adult foster care are suggested, representative adult foster care programs are examined, and persisting issues discussed. The results suggest that, as yet, there is no consensus among practitioners as to what are reasonable goals for adult foster care, who should participate in such programs, and what constitutes evidence of program success. Until these issues are resolved, adult foster care is likely to remain an underutilized form of long term care for older adults. PMID- 10110882 TI - Future preparation of home health nurse executives. AB - The responsibilities of home care nurse executives were investigated. A 51 item survey developed by an expert panel was completed by 54 home care nurse executives in Pennsylvania and New Jersey. Respondents evaluated the importance and time spent on each activity. A second expert panel identified where each activity is usually taught in an interdisciplinary curriculum. Based on the survey results, recommendations for graduate education for home care nurse executives were developed, emphasizing course content in the areas of law and policy, financial management, marketing, quality assurance, and organizational behavior. PMID- 10110883 TI - Home health nursing care: a comparison of not-for-profit and for-profit agencies. AB - The recent rapid growth in the numbers of for-profit and not-for-profit agencies delivering home health care raises questions about whether these agencies are serving different patient populations. Not-for-profit agencies were found to serve more indigent and medicaid patients than for-profits. Nurses from both kinds of agencies participated in this study and their patient case management activities are reported and compared for differences in their practice. PMID- 10110884 TI - A study of patients receiving no billed nursing care. AB - Although home health care traditionally is conceptualized as nursing care, in today's environment care at home may be delivered by a myriad of professional and nonprofessional practitioners. In fact, many patients who receive home care do not receive billed nursing visits. We studied a group of patients (n = 200) who received no billed nursing care, but rather received billed care from therapists, social workers and home health aides. This cohort of patients differed from patients who received billed nursing care in several ways: they were more frequently referred to home care from the community, their prognoses on admission to home care were significantly better, and their outcomes from home care services were considerably more favorable. Clearly patients not receiving billed nursing care have service and resource needs different from those of the population receiving billed nursing care. Therefore, new perspectives must be used when considering how to assess, deliver and perhaps pay for the requirements of these patients. PMID- 10110885 TI - Adverse drug reaction monitoring in Mississippi home health care agencies. AB - A statewide survey of home health care agency directors in Mississippi was conducted to determine the extent of Adverse Drug Reaction (ADR) monitoring and reporting by health care professionals. A 24-item questionnaire was sent to agency directors eliciting responses on agency characteristics, rate of occurrence of ADRs, and attitudes toward responsibility for monitoring ADRs. A total of 77 questionnaires were returned yielding a response rate of 48%. The average program enrolled 104 patients with 3.5 ADRs reported by health care professionals per year (range 0-65). Agency directors reported that physicians, nurses, pharmacists, and members of the pharmacy and therapeutics committee should monitor ADRs. Results indicated a need for all health-care professional involved in home health care to increase their ADR monitoring and reporting activities. PMID- 10110886 TI - The future of community-based services for the old-old: technological and ethical challenges. PMID- 10110887 TI - Home care worker resignations: a study of the major contributing factors. AB - Home care has become a major component in health care delivery. Increasingly demands are being placed on the base of the hierarchical personnel pyramid, the home care worker. These workers have a high turnover rate. This study examines the major reasons that contributed to a home care worker's decision to leave the job, and identifies where she/he went. The hypothesis tested was that factors other than salary influence a home care worker's decision to resign. The findings have implications for practice, education, research, and public policy. PMID- 10110888 TI - Physicians' views of home health. AB - The Mississippi State Department of Health surveyed 1412 physicians, response rate being 51.1%. Most had practiced in Mississippi over 10 years. Over 93% were aware of home health in their area. Open-ended responses revealed: (a) A need for better communication and on-going public information/relations concerning referral and available services, (b) Physicians' wish to manage their cases, (c) Complaints about burdensome paperwork and lack of compensation for time/liability, (d) Declines in some areas due to the number of competing agencies, and (e) The suggestion that nurses be assigned to specific physicians, clinics, and hospitals for referral generation. PMID- 10110889 TI - Community health nursing--expectations and performance in the working context. PMID- 10110890 TI - Redefining health care through outcomes management. Interview by Janice C. Simmons. PMID- 10110891 TI - The German health system: inside and outside. PMID- 10110892 TI - Can we learn health care lessons from Germany? AB - While Americans are unlikely to import a foreign health care financing system lock, stock and barrel, the country could learn from Germany's checks and balances that maintain fairness, economy and professional freedom, says this well known congressional adviser. PMID- 10110893 TI - Making it happen. Tuning up your team. PMID- 10110894 TI - But not for me. PMID- 10110895 TI - Building high-performance management teams. The shape of things to come: Part 6. PMID- 10110896 TI - The language of teamwork. Using a graphic language to create a mental framework that can be shared, understood, and remembered by all team members. PMID- 10110897 TI - From crisis to culture change. Downsizing, restructuring, or other large-scale change requires management of the emotional process involved in redefining beliefs, structures, and practices. PMID- 10110898 TI - Medicine and management--so much for "science". AB - The French think. The Americans do. The British sit on their duffs. but it all turns out the same. What does this mean to business and management? Lots. PMID- 10110899 TI - A talk with The Healthcare Forum's incoming chair. Interview by Sally Berger. PMID- 10110900 TI - Being effective. A conversation with Peter Drucker. Part 1. Interview by Joe Flower. PMID- 10110901 TI - The "hospital" of the future. PMID- 10110902 TI - Tools for staying ahead in the Nineties. Part 1. AB - The times require new management tools that focus, inspire, empower, and liberate organizations. Here are two dozen tools (12 here, 12 more in the next issue) that can help every healthcare executive deal with the turbulence ahead. PMID- 10110903 TI - Burkett Building. A health care facility for special services by Quantrell Mullins & Associates. PMID- 10110904 TI - Happiness heals. Ronda Reckseit designs pediatric medical offices that ease young patients' (and parents') apprehensions. PMID- 10110905 TI - Integrating senior care. PMID- 10110906 TI - A vision of collaboration. PMID- 10110907 TI - Revolution, not reform: a comprehensive proposal for healthcare. AB - The current problems with healthcare in the United States--lack of access and ever-rising costs--are largely due to a societal crisis, rather than a healthcare crisis. However, the majority of suggestions for corrective action deal with only a limited aspect of the healthcare system focusing on costs and ignoring the root causes. The problems with healthcare are multifactorial and include entrepreneurism; excessive technology; an emphasis on specialists; and the broader issues of poverty, abuse, violence, homelessness, and other social ills. Among the proposals for healthcare reform are the free-market model, improved management, implicit rationing, explicit rationing, and system reform. I advocate a final approach: accepting limits and the appropriateness of setting priorities in a healthcare system. This is feasible only with fundamental changes that include major attitudinal modifications in society, in the healthcare profession, in business, and in government. My proposal integrates but modifies concepts presented by Daniel Callahan in What Kind of Life? Four basic levels of care would be delivered in the community setting by personnel of varying levels of training. It is unclear on what moral grounds commitment of additional resources to the highest level of care--"highly advanced technological medical therapy"- can be justified at present. Central to acceptance of this idea is an attitude of sharing based not on self-interest but on caring. It involves action rooted in a community-based concern rather than traditional family, intergroup, or intergenerational reciprocity. PMID- 10110908 TI - A charism of collaboration. PMID- 10110909 TI - Risks and responsibilities. To make collaboration work, sponsorship modes must stress influence rather than control. AB - Although much has been written in recent years on the virtues of collaboration, the reality often does not match the rhetoric. Many sponsors have been caught in a "schizophrenia of spirit," in which their actions do not accord with the values they profess. One reason for this contradiction is that the institutional Church has given sponsors a control model with which to operate. According to such a model, sponsors set the mission, appoint boards, control assets, approve dissolutions, approve bylaws, appoint the chief executive officer, and approve the auditor. Maintaining this much control makes it difficult for sponsors to initiate effective collaborative ventures. On the contrary, effective collaboration requires a willingness to cooperate and use influence, rather than to exert control. An influence model also calls on sponsors to trust others and believe in their commitment to achieving a greater good. For many reasons, religious community leaders find an influence model difficult to implement. However, as resources become more scarce and as the numbers of poor continue to rise, sponsors will be increasingly called on to find creative ways to work with others. In such an environment, they must be willing to take the risks necessary to fulfill the healing ministry of Jesus. PMID- 10110910 TI - Combating infant mortality. A hospital collaborates with other groups to offer prenatal care in a rural area. AB - Prenatal care services are often lacking in poor rural areas. Consequently, rates of infant mortality and negative birth outcomes are relatively high. To address these problems, since 1987 St. Elizabeth Hospital Medical Center (SEHMC), Youngstown, OH, has successfully operated an innovative rural-based prenatal care clinic for indigent women. The Leetonia Clinic serves residents of Leetonia, OH, and about 20 surrounding communities. It offers on-site medical care using SEHMC obstetrics and gynecology residents and volunteer nurses. The local Catholic Charities organization funds a professional social worker. A prolife advocacy group and a women's self-help group offer volunteer counseling and referral services. They also manage paperwork at the clinic. The local Catholic church provides space in one of its school buildings to house the clinic. SEHMC also provides patient education and outreach. Over the past 4 years the clinic has served about 165 patients annually. About half are on welfare, and the rest are primarily self-paying. Studies are under way to assess the program's effect on infant mortality and morbidity. PMID- 10110911 TI - Partnerships for the future. A new vision for the Catholic healthcare ministry. AB - Collaboration among healthcare providers will help them more effectively meet the needs of their communities in the 1990s. San Francisco-based Catholic Healthcare West (CHW), formed in 1986, strives to provide high-quality healthcare by collaborating with Catholic and non-Catholic providers. CHW leaders believe that Catholic providers make ideal partners; however, they have found that Catholic healthcare providers often must look outside the Catholic healthcare ministry to find these partnership opportunities in order to remain viable and effectively carry out their mission. Besides system-to-system or hospital-to-hospital linkages, collaboration is also achievable with other types of healthcare providers, such as physicians. In collaborations between Catholic and non Catholic healthcare providers, Catholic providers must strive to maintain their Catholic identity. When evaluating potential partners, they must consider issues such as corporate culture, organizational compatibility, and sponsor influence. CHW leaders believe that for any merger or affiliation to be successful, it must clearly produce market and financial advantages for the new partnership and offer the community a significant improvement in quality of care and services. PMID- 10110912 TI - The board's role in meaningful collaboration. After negotiations are completed, a new round of work begins. AB - For collaborations that in some way modify involved organizations' assets and organizational or governance issues, negotiations are the responsibility of the congregation and not the healthcare system. Congregational leaders should, however, actively involve the system chief executive officer in the process and should also seek the advice of the system board. The board can be particularly helpful in offering financial, legal, and managerial advice to negotiators. Once an agreement is reached, however, the board must consider whether to approve it. And from this point forward, its involvement in the details of the collaboration will be more active. Because board members must evaluate a proposed collaboration from the perspective of the organization they serve, they may not always take the same view of it as did the congregational leaders. Moreover, what congregational leaders believe to be in the best interests of Catholic healthcare may not be consistent with the legitimate self-interest of some of the many constituencies affected by a collaboration. After negotiators have reached an agreement and the board has approved it, the board must make the necessary financial and organizational changes necessary to achieve the transition to a new corporate entity. In doing so, its goal will be to promote standardization without destroying the member institutions' rich traditions. PMID- 10110913 TI - Good neighbors. A collaborative effort develops housing for the low-income elderly on Chicago's southeast side. AB - On Chicago's southeast side, the Claretian missionaries--in collaboration with the Oblates of Mary Immaculate, members of the local community, and local business interests--will soon open Villa Guadalupe, a housing project for low income seniors. Recent developments have combined to make the creation of low income housing for the elderly more compelling than ever from a mission perspective and more feasible from a structuring and financing perspective. Since 1925, the Claretians have served a predominantly Hispanic population in south Chicago. The neighborhood suffered economic devastation in the 1960s with the collapse of the local steel industry. A 1985 needs assessment determined that nearly one in five elderly residents in the area lives at or near the poverty level. As a result of the assessment, the Claretians decided to develop the Villa Guadalupe project. For assistance in managing and financing the project, the Claretians drew on the resources and expertise of the Oblates of Mary Immaculate, who have a history of ministering to the elderly. The project also had to overcome legal obstacles to securing property tax exemption from the state of Illinois. The project cleared another hurdle when it secured financing by issuing tax-exempt bonds secured by a letter of credit issued by a commercial bank. In addition, interest in monies from an endowment fund will make up the difference between funds Villa Guadalupe will receive through rents and the income that is required to support the project. PMID- 10110914 TI - A haven for the spirit. A well-designed chapel can improve nursing home residents' spiritual and psychological health. AB - Where a strong conviction exists about the value of public worship for nursing home residents, leaders will make efforts to meet their religious needs. Although it is expensive, a spacious chapel can be one of the most important additions a long-term care facility can make. In July 1983 the board of directors at the Merkle-Knipprath Nursing Home, Clifton, IL, decided to build a spacious chapel for its residents. The building committee began planning by developing a list of what features the chapel would need to adequately serve the residents. Once it had established the needs, the committee began to consider what kind of design would fulfill them. The chapel was completed in 1985. Members decided that a somewhat circular building would work best. Pews are arranged in a semicircle around the alter, with an aisle on both ends of each pew for easy access. For practical reasons, seat cushions have vinyl covers and the floor is linoleum. Automatic doors open onto the chapel from the corridor. The chapel also has a quiet room with glass panels facing the altar. The room, with a front door leading into the chapel and a back door leading to the corridor connecting the chapel and the nursing home proper, can be used for the Sacrament of Reconciliation. To enhance the spiritual atmosphere, the committee commissioned an artist to design stained-glass windows, which extend from the floor to the lower part of the chapel's vaulted ceiling. An organ also adds a significant dimension to religious services. PMID- 10110915 TI - Home is where the heart is. Ministering to homebound patients opens new doors for pastoral care givers. AB - Today many patients must convalesce or die at home. Thus home healthcare is a growing service. Many home health agencies are finding that caring for patients' spiritual needs can be just as important to their well-being as caring for their physical needs. Four years ago Humboldt Home Health Services (HHHS), Eureka, CA, launched a pastoral care program in response to a growing patient need. HHHS now offers pastoral care free to all its patients. Each certified pastoral care counselor on the staff visits three to five patients each day. They encourage patients to tell their stories, describe adjustments they have had to make to their illnesses, and explore how they are coping emotionally and spiritually with their situations. PMID- 10110916 TI - The climate of opinion. PMID- 10110917 TI - Beyond traditional marketing. PMID- 10110918 TI - Carondelet Health Care Corporation. Being accountable. PMID- 10110919 TI - Health and mercy in Peru. Eastern Mercy Health System. PMID- 10110920 TI - Sharing a sacred moment. PMID- 10110921 TI - The implementation of image management systems in today's hospital: real world solutions to real world problems. PMID- 10110922 TI - The implementation and advantages of product-line management in cancer programs. AB - During the next decade, hospitals will continue to experience changes in case mix, technology, and reimbursement. The incidence of cancer will increase, and cancer patients are projected to become a larger portion of the overall treatment population served by hospitals. Because the term "cancer" refers to a complex group of diseases treated by many specialties, it is imperative that hospital administrators familiarize themselves with this product-line and address the clinical, financial, and programmatic issues inherent in this large, difficult-to manage patient population. In contrast to traditional departmental organizations where a number of services, such as nursing and respiratory therapy, are used independently to treat a specific patient, product-line management examines the appropriateness and utilization of all services used to treat a specific group of patients. This organizational approach to cancer treatment has been successful in improving the quality of care, promoting physician bonding, increasing market share, and maximizing resource utilization. This special report focuses on the implementation and advantages of product-line management in cancer care, and will discuss the organizational issues, the process of developing a product-line, and major problems. PMID- 10110923 TI - MRI: update on technology diffusion and acquisition. AB - Over the past three years, magnetic resonance imaging (MRI) has become accepted as a valuable diagnostic tool, and its applications continue to expand. During this time, the number of units installed in the United States doubled. By 1990 about 2,000 MRI units were in place in the United States and nearly 20 percent of the MRI-installed base was mobile, according to a research study conducted by the Hadley Hart Group (Chicago) and Drew Consultants, Inc. (Concord, MA). With the introduction of the prospective payment system, many hospitals were hesitant to spend limited capital on new technology, such as MRI. At the same time, freestanding diagnostic imaging centers were on the rise. Some hospitals and entrepreneurs who foresaw the potential of MRI in health care pioneered its use in the clinical setting. Hospitals began to examine new partnership arrangements and alternative forms of financing, so that they too could offer MRI services. By the end of 1988, the majority of hospitals offering MRI services did not own their own unit and about 40 percent of the hospitals offering MRI services were in a mobile configuration according to the Hadley Hart Group. While the technology has been diffused into 100-bed hospitals via mobile service vendors in some parts of the country, many medium-sized and large hospitals also have entered the MRI services market in this fashion. In the larger hospitals, the patient demand or need for the service often would justify acquisition of MRI, but the expense of the technology, and in many areas restrictive state health planning policies, modified purchase of MRI systems by hospitals. Mobile service vendors offered hospitals a way to startup MRI services in a limited fashion without a major capital expenditure and its associated risk. As hospitals gain experience with mobile MRI and achieve or exceed their early utilization projections, administrators are reevaluating the need to expand services to a full-time fixed site. Early fixed-site MRI providers have been constantly upgrading their MRI capability while planning on adding more units. The technology itself has continued to improve, primarily through the implementation of new software that permits new techniques such as MR angiography (MRA) to be performed. Units are available in a wide price range, price usually reflecting both the field strength (0.5 tesla units cost less) as well as the additional capabilities beyond routine imaging (MRA, spectroscopy).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10110924 TI - Regionalization of laboratory care: a viable option for the 21st century. AB - The conversion of the hospital laboratory to a cost center under pressure of prospective payment and fixed reimbursement is increasingly forcing hospitals to consider alternative modes for delivery of laboratory care. Changes in the health care environment, amended statutes and regulations, and, particularly, dramatic developments in laboratory equipment, methodologies, and data processing technology make it advisable and feasible to contemplate the creation of regional laboratory consortia. A fundamental step in this direction is the "commercialization" of the hospital laboratory through a change in focus from being an in-house support program to becoming a regional resource. By the same token, the hospital laboratory can become an effective competitor of independent laboratories and be reconverted to a profit center. Creation of hospital laboratory consortia in a splintered, competitive environment requires a committed entrepreneurial effort and convincing evidence of potential benefits. The sequence of steps needed to achieve regional laboratory integration include concerting the goals and objectives of the interested parties, creating an appropriate committee structure, conducting a feasibility assessment, identifying alternative organizational and operational options, selecting a favorite option viewed by all parties as a win/win proposition, developing a business plan, and determining an implementation action plan. The major disadvantages of regionalization of laboratories are employee displacement, potential leveling of quality standards, and reduced hospital control. The major advantages include elimination of duplicate capital, personnel, and service costs, improved efficiency through test batching, reduced unit costs, increased technical capability through staff, instrument, and systems sharing, disengagement from hospital-imposed limitations, strengthened ability to penetrate the marketplace, freeing of hospital space for more direct patient care activities, and achieving a means for bonding physicians to the institutions. PMID- 10110925 TI - Integrated information and image management systems for the 90s. AB - The rising number of implementations of PACS (Picture Archiving and Communications Systems) subsystems, specialized information systems (radiology, laboratory, pharmacy, and other ancillary departments), and increased interest in the role of optical storage systems hospitalwide, creates an environment that demands the integration of each of these systems if the hospital is to operate at maximum profitability levels. This has been recognized by several groups who have proposed standards for communication between vendors and systems, and their efforts, combined with the support of the hospitals, will hopefully allow the promise of a fully electronic hospital to become a reality. While the concept of a totally integrated fully electronic hospital has been with us for over a decade, only recently have medical vendors attempted to evolve from a conceptual phase to one of workable, cost-effective systems. Few will debate the fact that the fully integrated information and image management system is still several years away, yet many hospitals have recognized the importance of planning for use of the component technology available today. This planning stage is critical and, combined with the phased implementation of the existing technologies, it can provide significant advantages in the overall acceptance of this future technology. This paper addresses the role of the standards organizations in making this integration a reality, how conceptually a fully integrated information and image management system will work, new technologies and their potential uses in the hospital, and both the advantages the technology can bring in solving existing problems and hurdles that still need to be overcome. PMID- 10110926 TI - Buying and selling used medical equipment. AB - The used medical equipment market represents an opportunity for all hospitals to generate additional revenue and reduce capital costs. Every hospital should become acquainted with this marketplace and determine how it can participate to its financial advantage. PMID- 10110927 TI - MRI utilization model: results of a validation study. AB - In 1989, the American Hospital Association (AHA) conducted a survey to assess the predictive accuracy of the second generation Magnetic Resonance Imaging (MRI) Utilization Model. Of the 172 hospitals that had purchased the AHA model in 1987, 101 (59%) responded to the survey. Half of those responding were not offering MRI services yet, 10% had decided not to offer MRI services or were undecided, and 15% were operating services for less than four months. Our results are based on a sample of 21 hospitals. The major findings of this study are: 1. The "Current Year DRG Projection" is a good predictor of early utilization of MRI. 2. The "ICD 9-CM Projection" and the "1990 DRG Projection" are indicators of full utilization of MRI or steady state. Hospitals that have more experience with the technology and an educated referral base of physicians are achieving these projections. The "ICD-9-CM Projection" could be considered a more conservative projection of full utilization and the "1990 DRG Projection" a more aggressive full utilization projection. 3. Computed tomography (CT) usage has not changed much at the current stage of MRI utilization. Applications for use of CT have expanded. 4. An emerging area for MRI is the study of the extremities. The average volume of MRI studies of the extremities performed by hospitals in our sample was about 11% of the total MRI scan volume, but the range extended from a low of 1% to a high of 20%. PMID- 10110928 TI - Understanding COBRA's twists and turns. PMID- 10110929 TI - Bite the bullet. A case for body armor. PMID- 10110930 TI - Approach with caution. Surviving on the street. AB - When responding to a potentially violent scene, many EMS providers may be tempted to throw caution to the wind and neglect their own well-being for that of the patient. This article stresses the importance of personal safety and street survival training techniques. PMID- 10110931 TI - Little habits that could save you. PMID- 10110932 TI - EMS in the nation's capitol: a system in transition. AB - With the dubious distinction of having the highest per-capita call volume in the country, Washington D.C. EMS was long criticized for its lengthy response times. This article focuses on the system's three-year transition period, culminating in its adoption of a cross-trained, dual-role system. PMID- 10110933 TI - After the violation. Treating rape victims. AB - Rape is a devastating, violent crime that can occur to women and men of all ages, races and socioeconomic classes. For the prehospital provider, managing a sexual assault victim requires special skills and knowledge to sensitively handle the patient's physical, mental and emotional symptoms and preserve evidence for trial. PMID- 10110934 TI - EMS under siege: a tale of four cities. AB - This article depicts the escalating violence throughout the United States and the increased danger of working on the front lines of medicine. Find out what four U.S. cities are presently doing to combat such dangers. PMID- 10110935 TI - Child restraints: putting safety in the driver's seat. PMID- 10110936 TI - Building mutual trust and respect within the chaplain/physician relationship. AB - Trust and respect between physician and chaplain is built over a period of time, through deliberate effort. It is something that may be present from the start, but will be tested in conflict. On the physician's side a respect for religion in medicine must be developed. On the chaplain's side there must be a ministry to the physician. A complementarity between religion and medicine in which both spiritual and physical needs are met, fosters mutual trust and respect which enable doctor and chaplain to have their own needs met when faced with their own loneliness, sense of failure, ethical dilemmas, and the loss of income and/or authority in medicine. PMID- 10110937 TI - Developing chaplain/physician relationships in obstetrics. AB - Effective and comprehensive pastoral care within the obstetrical hospital unit depends on a close working relationship with the entire health care team. This article describes the intentionality, time and energy required to develop these relationships and openness to pastoral ministry. A brief history of obstetrics and pastoral care within this hospital is discussed. Building relationships with obstetricians requires involvement in clinical situations with patients/families, response to ethical issues, and contribution to their continuing medical education. Lastly, the article describes some advantages of a woman chaplain in obstetrics. PMID- 10110938 TI - Strengthening chaplain-physician relationships in long-term care settings. AB - Older, disabled adults are often cared for in long-term settings. Chaplains possess an important role with these older adults and in these settings. This article describes several ways in which chaplains can strengthen relationships with physicians through improved communication. PMID- 10110939 TI - Understanding physicians: an educational history and brief practice profile. AB - Physicians experience years of scientific training and practice with emphasis on objectivity, personal sacrifice in favor of career, struggle to survive demands/pressures, and the need to save life. These themes differ significantly from those experienced by chaplains. Chaplains can strengthen their relationships with physicians when they appreciate this thematic difference. This article describes the process of medical education, including residency, and points out selected contradictions within which medical practice must work. PMID- 10110940 TI - The chaplain/pastoral counselor as a behavioral medicine consultant in cardiac rehabilitation: a team approach. AB - Pastoral Behavioral Medicine Consultants can make a valuable contribution to the modern hospital particularly if physicians and other health care professionals are joined in offering creative and effective programs for healing. This article discusses several programs in which the traditional hospital chaplain's role is extended to that of a pastoral/behavioral medicine consultant (PBMC). The examples are meant to stimulate the reader's interest, ideas and intuition about innovative ways that the modern PBMC can not only survive but flourish in chaplain/pastoral counseling ministries. PMID- 10110941 TI - Help make your patient's insurer pay up. PMID- 10110942 TI - What worries people most about health care. PMID- 10110943 TI - Uncle Sam plays new games with medical statistics. PMID- 10110944 TI - Why we all should have living wills. PMID- 10110945 TI - Changes in hospital staffing patterns. PMID- 10110947 TI - Consensus, conflict, and the Engler agenda. PMID- 10110946 TI - Finding success in urban health care. PMID- 10110948 TI - Durable power of attorney: what's involved? PMID- 10110949 TI - Wait! What's not trash--it's recyclable! PMID- 10110950 TI - New fire code expands design potential. PMID- 10110951 TI - Getting the most from your marketing dollars. PMID- 10110952 TI - Nipping board problems in the bud. PMID- 10110953 TI - Recruitment--a crucial issue for auxiliaries. PMID- 10110954 TI - What to do between job searches. PMID- 10110955 TI - The geography of urban health care. PMID- 10110956 TI - Average price per nursing home bed fell in 1990--report. PMID- 10110957 TI - Hahnemann set to affiliate with Philadelphia facility. PMID- 10110958 TI - Sentara's acquisition of Va. facility expected within three months now that probe is over. PMID- 10110959 TI - VHAE shareholder suit hits hurdle. PMID- 10110960 TI - JCAHO lifts hospital's accreditation after visit. PMID- 10110961 TI - 'Jackhammer' could crush cost of treating kidney stones. PMID- 10110962 TI - Humana can't curb departing docs--judge. PMID- 10110963 TI - 2 bids eclipse Health Net's conversion price. PMID- 10110964 TI - VA not postponing construction projects intentionally--GAO. PMID- 10110965 TI - Hospitals predict big losses from physician fee schedule. PMID- 10110966 TI - How to replace a health system. PMID- 10110967 TI - Hay/Modern Healthcare compensation survey. AB - Healthcare chief executives' base salaries overtook those of their industrial counterparts, but they still lagged when comparing total pay, according to this year's Hay/Modern Healthcare Compensation Survey. Even in total compensation, however, healthcare execs were narrowing the gap. The survey also found disparities in pay levels reflected regional factors such as the competitive environment and high cost of living. PMID- 10110968 TI - Senate Democrats unveil healthcare reform package. PMID- 10110969 TI - New device gives mobility to monitoring equipment. AB - A new type of patient monitor can turn any bed into a monitored bed without special wiring. The Escort-Link wireless bedside monitor uses radio frequencies instead of cables to transmit information to a central viewing station. The monitor is now being used in emergency departments, step-down units and operating rooms in about 30 hospitals. If wireless networks prove practical, radio transmissions may become increasingly common in hospitals. PMID- 10110970 TI - Canadian-style changes in U.S. system could save enough to cover uninsured--GAO official. PMID- 10110971 TI - HMOs show new signs of consolidation. AB - As a record number of Americans join managed-care plans, the industry is showing signs of another round of consolidation. Enrollment in HMOs climbed 5% last year to 36.5 million, but the number of prepaid plans has dropped significantly since 1988. Experts forecast the continued expansion of managed healthcare, but they also expect continued shrinkage in the number of plans as healthier HMOs grow through acquisition of smaller, struggling competitors. PMID- 10110972 TI - Hospitals hand over gift shop operation. AB - Many hospitals are re-examining their gift shop operations and concluding that outside experts can do it better. Although only an estimated 30 hospital gift shops are operated by management services companies, interest in outside companies is growing as executives recognize that hospital gift shops can be extremely lucrative, and that hospital gift shop volunteers are an endangered species. PMID- 10110973 TI - AHA loses money in '90. PMID- 10110974 TI - 'Hospitals overpaid for IME (indirect medical education) costs'. PMID- 10110976 TI - Two new suitors come knocking at Health Net. PMID- 10110975 TI - Fla. PRO pleads guilty to filing false claim. PMID- 10110977 TI - Baxter scraps plans to build intravenous fluid plant in Syria. PMID- 10110978 TI - Recuperating at home preferred. PMID- 10110979 TI - 'Bare-bones' insurance policies don't offer enough, study says. PMID- 10110980 TI - New Orleans managed-care contract awarded. PMID- 10110981 TI - AMA to consider easing HIV-testing consent procedures. PMID- 10110982 TI - Los Angeles hospital opens largest outpatient AIDS clinic. PMID- 10110983 TI - Conn. facilities in joint venture to build rehabilitation hospital. PMID- 10110984 TI - Dreary forecast for PPS margins. PMID- 10110985 TI - Dems hope plan moves reform from back burner and turns up the heat. PMID- 10110986 TI - Credentialing is a fact of life. PMID- 10110987 TI - FTC probe centers on Phoenix hospital, physicians. PMID- 10110988 TI - Ways and Means sets hearings on hospitals' tax exemptions. PMID- 10110990 TI - AMA to lobby for fee schedule changes. PMID- 10110989 TI - Hospitals put teeth into efforts to collect bad debt. AB - The growth of bad debt and accounts receivable is prompting hospitals across the county to adopt more stringent collection policies. Some hospitals that have gotten tough are finding that these programs can significantly increase cash flow. But experts warn that such measures invite public criticism. Many hospital administrators, however, are finding they have no choice except to go after patients who have the means to pay. PMID- 10110991 TI - Will waste tracking become law of the land? AB - With the federal government's two-year waste-tracking demonstration set to end this month, hospitals are watching and waiting as Congress considers the need for replacement legislation that would make such a program the law of the land. Many executives say a national waste-tracking law would only duplicate state regulations and would place a disproportionate burden on hospitals. Whatever the flaws, experts were quick to cite pros to counter the cons. PMID- 10110993 TI - NLRB rules take effect after barriers lifted. PMID- 10110992 TI - Coalition urges Democrats to focus on achievable reform. PMID- 10110995 TI - Hospital subsidiary turns employee assistance, managed-care plans into referrals, revenues. PMID- 10110994 TI - 'Outsourcing' will continue to gain clients. AB - It's an arrangement that puts the day-to-day operation of your information systems software in the hands of an outside manager at an outside computer system. The attraction of "outsourcing" is the money saved by not paying for hardware or in-house computer technicians. And it frees your top computer people for software improvement. But it's not for everyone. Owen Doyle lists the advantages and disadvantages. PMID- 10110996 TI - Programs rein in mental healthcare costs. PMID- 10110997 TI - Ariz. hospital operating first nursing HMO. PMID- 10110998 TI - Patient-accounts managers' roles expand, but few recruiting, training programs exist. AB - Patient-accounts managers oversee collection of 90% of hospitals' gross revenues, yet experts say the healthcare industry isn't doing enough to educate, recruit and retain these professionals. The expanding roles of these managers--often known as business office managers--are fueling calls for more education to help them advance in their field and higher pay to interest more people in the position. PMID- 10110999 TI - AHM moves closer to goal of swapping debt for equity. PMID- 10111000 TI - Investor group to acquire Safecare Health Services. PMID- 10111001 TI - Spectrum changes name, moves headquarters to Fla. PMID- 10111002 TI - SMS adopts 'poison pill' plan to ward off takeover attempts. PMID- 10111003 TI - Conn. hospitals scale down proposal for new facility. PMID- 10111004 TI - HealthTrust to buy back securities held by HCA. PMID- 10111005 TI - Newspaper sues Vt. hospital alleging violation of First Amendment rights. PMID- 10111006 TI - AMI parent plans sales of 16.2 million shares. PMID- 10111007 TI - Operating margins rose slightly in '90. PMID- 10111008 TI - 'More money needed for drug research'. PMID- 10111009 TI - Commission on VA remap moves ahead. PMID- 10111010 TI - Get prepared for outpatient prospective payment system. PMID- 10111011 TI - Honoraria keep flowing in Congress. PMID- 10111013 TI - Patients, not physicians, are hospitals' customers. PMID- 10111012 TI - HIV-infected emergency patients require more time, effort--study. PMID- 10111014 TI - Cost reports providing distorted picture--ProPAC. PMID- 10111015 TI - Many seniors fail to claim benefit. PMID- 10111017 TI - Hospitals pursue cooperation. PMID- 10111016 TI - New purchasing company works for free if it doesn't produce savings for hospitals. AB - A new company is so sure it can save hospitals money over their previous purchasing contracts that it's willing to bank on it. If it doesn't save its clients cash, it doesn't get paid. Purchasing Support Services says it can produce savings of 5% to 35% for hospitals, and four hospitals already have taken the 2 1/2-year-old company up on its offer. PMID- 10111019 TI - Bond financing technique saves hospital $8.7 million. PMID- 10111018 TI - State groups oppose routine AIDS testing. AB - Most state hospital association executives oppose routine testing of hospital workers and patients for AIDS, according to Modern Healthcare's sixth monthly Fax poll of state hospital association presidents. Of the 17 executives who responded to the survey, 13 said their associations oppose routine AIDS testing of hospital workers and 12 oppose routine testing of patients. PMID- 10111020 TI - Firms help hospitals retrieve overpayments. AB - The money hospitals are losing in overpayments to vendors probably won't make or break an organization, but the dollars can start to add up. Managers can turn to companies specializing in retrieving such revenues. One firm said its audits find an average of $90,000 in overpayments at the typical hospital, with the facility and the firm splitting any money actually collected. PMID- 10111021 TI - GAO rips VA over 'large quantities' of stolen drugs. PMID- 10111022 TI - NLRB lists job classifications under new bargaining units. PMID- 10111023 TI - Cultural marketing. Centro de Impotencia targets Hispanic males. PMID- 10111024 TI - Physician relations. Brown-bag service for the doctor's office. PMID- 10111025 TI - Direct mail/direct response. Clinic to consumer. PMID- 10111026 TI - Women's center program. A word to the WomanWise. PMID- 10111027 TI - Marketing maternity services. Expecting wee care. PMID- 10111028 TI - Women's center opening. Tea for two hundred. PMID- 10111029 TI - Women's services. 'Be smart' theme attracts women. PMID- 10111030 TI - Women's center program. Targeting midlife women. PMID- 10111031 TI - Physician marketing. Setting up an infertility practice. PMID- 10111032 TI - Community relations. Walking away with good health. PMID- 10111033 TI - Community relations. Seniors get on their feet. PMID- 10111034 TI - Mall resource center. Library paves gateway to good health. PMID- 10111035 TI - Community relations. Advertorials make a community connection. PMID- 10111036 TI - Patient services literature. User-friendly map to services. PMID- 10111037 TI - Diabetes clinic. Ads pay off to 'hidden' diabetics. PMID- 10111038 TI - Nutrition services. The ABCs of good nutrition. PMID- 10111039 TI - Adolescent mental health. Giving help to troubled teens. PMID- 10111040 TI - Surgical suite opening. The operation was a success! PMID- 10111041 TI - Smoke-free facility. Smoke-free newsletter. PMID- 10111042 TI - Teleservice health line. Early caller with zero budget. PMID- 10111043 TI - Annual reports. Spirit of the patient shows progress. PMID- 10111044 TI - Preventing bed falls requires risk evaluation, adjustments. PMID- 10111045 TI - Accurate cost reports can help improve reimbursement levels. PMID- 10111046 TI - Nurses play primary role in facility infection control. PMID- 10111047 TI - Food service operations respond to quality of life mandate. PMID- 10111048 TI - Respite care programs support needs of elderly, caregivers. PMID- 10111049 TI - Congress gears up for debate over health care reform. PMID- 10111050 TI - Ethical issues in health care institutions. Lesson 2: Ethical considerations in group decision making and groupthink. AB - In this second lesson of a five-part WMU/AHRA magazine course on ethics, Dr. Alie tackles an interesting concept--group-think. According to the author, this tendency occurs when cohesive groups lose their ability to critically evaluate alternatives in problem solving. Since groups such as committees or task forces frequently resolve issues and make policy in health care organizations, warning signs of this phenomenon are detailed as well as suggestions to help avoid the problem. PMID- 10111051 TI - Power: a changing commodity. AB - "Rapid and tumultuous change in health care as well as business has precipitated a power shift," declares Mr. Hage in this candid discussion of a quality that is both abstract and concrete. Centralized power is no longer the order of the day; in fact, the new stance supports pushing power down into organizations where it can be better used by those closer to the action. The author maintains that effective participants in this new model will learn to share power and respect knowledge as the only tool that wields it. PMID- 10111052 TI - A consensus model for group purchasing. AB - Sisters of Providence, a multi-hospital system in Seattle, Washington, uses a group consensus model in assessing the acquisition and implementation of major capital items. In technology acquisitions for diagnostic imaging, six clinical and administrative perspectives are brought to bear on the objectives. Mr. Dickson outlines the steps in this consensus model. PMID- 10111053 TI - Immigration law and its effect on radiographer recruitment. AB - Due to the shortage of radiographers in the United States, the author examines the feasibility of recruitment from other countries. Information on visas, current quotas and classification of immigrants is presented in this well researched article, as well as roadblocks that managers who pursue this alternative may encounter. PMID- 10111054 TI - Work unit compensation. AB - The author describes an innovative "work unit compensation" system that acts as an adjunct to existing personnel payment structures. The process, developed as a win-win alternative for both employees and their institution, includes a reward system for the entire department and insures a team atmosphere. The Community Medical Center in Toms River, New Jersey developed the plan which sets the four basic goals: to be fair, economical, lasting and transferable (FELT). The plan has proven to be a useful tool in retention and recruitment of qualified personnel. PMID- 10111055 TI - Manpower shortage: observations of N.Y. state licensure and registration data. AB - In a random sample (n=411) of New York state radiologic and radiotherapy license and registration forms, univariate descriptive analysis showed women outnumbered men 2:1. Nearly seven of ten were born before 1961, most were licensed between ages 19 and 26, nearly nine of ten lived in New York state (one in five in New York City) and 7% lived in neighboring border states. Approximately 51% of sampled licensed technologists worked in hospital practice settings, 33% worked elsewhere and nearly 15% were not practicing. Hospitals experienced a net loss of 24 technologists (5.8%) between 1983 to 1988. Technologists born between 1951 and 1960 represented approximately 56% of hospital technologists, yet represented 37.5% of licensees. Females represented nearly 60% of hospital technologists, 68% of technologists in other settings and 77% of technologists not practicing. 92% had general licenses, 5% had therapy licenses, and 1% had both licenses. Approximately 47% of general license technologists were in hospital settings. A bimodal licensure duration histogram revealed two subpopulations--one with a mean of two to three years, and one with a mean of ten to 12 years. Licensure frequency, since 1973, was characterized by three cyclical peaks, each cycle with a four- to five-year period. New York and other states must look at nontraditional trainee recruitment pools; develop workforce planning strategies that factor in facilities, personnel and technology; and develop an effective workforce data base. PMID- 10111056 TI - A lethal 'health gap'. Blacks start self-help efforts to fight old enemies. PMID- 10111057 TI - Managing cultural diversity. PMID- 10111058 TI - If the hat fits. PMID- 10111059 TI - A Chinese volunteer program. PMID- 10111060 TI - Gift shop group purchasing. PMID- 10111061 TI - Entering the hospital boardroom. PMID- 10111062 TI - Exploring the subject of leadership. PMID- 10111063 TI - Team effort. The nuclear medicine decision making process. PMID- 10111064 TI - Play the hand you are dealt: a technique for administrative success. PMID- 10111065 TI - MRI service evaluation. Part II: Technological advances. PMID- 10111066 TI - Financial risk-sharing in radiology. Application to outpatient imaging. PMID- 10111067 TI - Hearkening to the mammographic technologist. PMID- 10111068 TI - The economic equation. AB - Any hospital's success is dependent on the medical staff, administration, and governing body's attention to quality, availability, and affordability of needed services. A cooperative working relationship helps address tough issues. Physicians have been reluctant to incorporate practice efficiency into guidelines or into performance appraisals; however, not doing so places the hospital at risk and thus jeopardizes a community asset. The cost of care, limited financial resources, and the threat to future generations' access to care may drive the process. If evaluation of economic performance is to be successful, its application and limitations must be understood and embraced by medical staffs and governing bodies to ensure that fair and realistic criteria are developed that promote and preserve quality medical care for hospital patients today and in the future. PMID- 10111069 TI - Criteria bank. PMID- 10111070 TI - Hazardous materials and waste management--a check-up. PMID- 10111071 TI - Productivity improvement is a must. PMID- 10111072 TI - Critical factors to successful capital campaigns. PMID- 10111073 TI - How much are you really paying for fuel? PMID- 10111074 TI - Money, membership programs, and patient care. PMID- 10111075 TI - 1991 transport charge survey. PMID- 10111076 TI - Financial reimbursement: the challenge of the 90s. PMID- 10111077 TI - Managing the diverse work force. PMID- 10111078 TI - Ways to make diversity programs work. Interview by Bill Leonard. PMID- 10111079 TI - Ten steps for communicating flex benefits. AB - Many companies are exploring flexible-benefits plans as a way to cut costs and still provide good benefits for their employees. Here are 10 steps for effectively communicating a flex plan. PMID- 10111081 TI - Computer databases built for HR. PMID- 10111080 TI - Effectively measuring the costs of EAPs. PMID- 10111082 TI - A '90s model for performance management. PMID- 10111083 TI - New rules for waivers by older workers. PMID- 10111084 TI - Waste minimization in healthcare facilities. PMID- 10111085 TI - Update: ribavirin exposure. PMID- 10111086 TI - Update: needlestick injuries. PMID- 10111087 TI - Two model proposals for consulting services. PMID- 10111088 TI - Follow-up: waste minimization. PMID- 10111089 TI - OSHA issues citation for laser safety. PMID- 10111090 TI - Update: pentamidine. PMID- 10111091 TI - The Clean Air Act Amendments: a preview. PMID- 10111092 TI - Update: formaldehyde. PMID- 10111093 TI - The OSHA hazard communication standard: new compliance instructions. PMID- 10111094 TI - Pentamidine: employee protection. PMID- 10111095 TI - Plumbing problems. PMID- 10111097 TI - Incentives for using health cards can help market hospitals. PMID- 10111096 TI - Self-insurance can be profitable for hospitals and cost-saving for employers. PMID- 10111098 TI - Health information centers keep hospitals in touch with public for outpatient services. PMID- 10111099 TI - No smoking policies gain acceptance but risk alienating smoking patients. PMID- 10111101 TI - Humor makes patients happier and healthier, hospitals find. PMID- 10111100 TI - Information security policies protect patients and hospitals. PMID- 10111102 TI - Ambulatory care is blossoming market for hospitals that plan well. PMID- 10111103 TI - Hospital guest houses cut costs for patients and hospitals. PMID- 10111104 TI - Well-planned pain clinics can meet mushrooming demand from patients. PMID- 10111106 TI - Hospital sleep disorder programs open doors to sleepy patients. PMID- 10111105 TI - Einstein program reduces paperwork for elderly patients. PMID- 10111107 TI - Hospital weight loss programs popular with patients. PMID- 10111108 TI - Patient care technicians ease shortage and free nurses for other duties. PMID- 10111109 TI - Adapting to culture of patients important to hospital treatment. PMID- 10111111 TI - Patient rights often overlooked in hospital AIDS testing. PMID- 10111110 TI - HDTV used for long distance consultation. PMID- 10111112 TI - Sensor pads help breast self-exam while providing hospital marketing. PMID- 10111113 TI - IBM introduces clinical workstation, upping ante in computerized patient care. PMID- 10111114 TI - Physician referral network for hospitals can widen the net for new patients. PMID- 10111115 TI - How Humana stays profitable and still satisfies patients. PMID- 10111116 TI - Dallas hospital hopes outreach program can provide prevention to neglected patients. PMID- 10111118 TI - Employee incentives improve patient relations, cut waste at Forsyth Memorial Hospital. PMID- 10111117 TI - Hospitals try novel approaches to AIDS treatment. PMID- 10111119 TI - Hospital of the future explores new information technology. PMID- 10111120 TI - Health fairs offer hospitals visibility, community service. PMID- 10111121 TI - Mediquik program reduces patient waits in Joplin Hospital emergency room. PMID- 10111123 TI - Columbia Presbyterian volunteers comfort ICU visitors, ease burden on medical staff. PMID- 10111122 TI - Shriners Hospital offer medical advice broadcast over store audio systems. PMID- 10111124 TI - Patient satisfaction and service take growing roles in hospitals. PMID- 10111125 TI - Computer assessments ease patient anxiety about answering sensitive questions. PMID- 10111126 TI - Riverside Methodist incentives improve staff performance. PMID- 10111128 TI - Residency manpower trends. PMID- 10111127 TI - Treating HIV-infected children: the surgeon's role. PMID- 10111129 TI - The PPRC: a 1991 update. PMID- 10111130 TI - 1990 ACOG survey. Professional liability and the delivery of obstetrical care. PMID- 10111131 TI - Physicians, heal thyselves! PMID- 10111132 TI - Innocent victims. PMID- 10111133 TI - Strategies for evaluating cost containment approaches. PMID- 10111134 TI - Fraud squads target suspect claims. PMID- 10111135 TI - Looking for Mr. Good Care. PMID- 10111136 TI - Golden oldies: striking a balance in retiree health care. PMID- 10111137 TI - Wellness incentives: how well do they work? PMID- 10111138 TI - Making a case for case management. AB - In summary, medical case management promises great advantages to plan sponsors, providers, employees, and dependents if run well. Improved operations, communications and reporting involving all parties are still needed to make medical case management achieve its potential. PMID- 10111139 TI - On the road to reform. PMID- 10111140 TI - Triage for the poor in Oregon. PMID- 10111141 TI - A ruling on doctors with AIDS. Is full disclosure really necessary? PMID- 10111142 TI - Physician, wheel thyself. PMID- 10111143 TI - Payment method for health care services under the Supplemental Health Care Program for Active Duty Members of the Uniformed Services; adoption of CHAMPUS procedures--DoD. Final rule. AB - This final rule partially implements 10 U.S.C. 1074(c), as amended by section 729 of the National Defense Authorization Act for Fiscal Years 1990 and 1991, Public Law 101-189. The recent amendment authorizes the Department of Defense to establish for the active duty supplemental care program payment rules similar to those used under the Civilian Health and Medical Program of the Uniformed Services (CHAMPUS). The supplemental care program is the program which provides for the payment to civilian (non federal-governmental) health care providers for care provided to active duty members of the uniformed services. This final rule would adopt CHAMPUS payment amounts for the supplemental care program. PMID- 10111144 TI - Prescriptions; requirements clarification--Drug Enforcement Administration (DEA). Final rule. AB - This final rule amends 21 CFR 1306.05 and 1306.13 to clarify the requirements of prescriptions for controlled substances, and to extend the partial filling of Schedule II prescriptions to patients in hospice or home-care that have a medical diagnosis documenting a terminal illness. The proposal regarding the use of medication order sheets for filling prescriptions for patients in Long Term Care Facilities under the provisions of 21 CFR 1306.11 is not adopted at this time and will be the subject of a separate proposed Federal Register announcement which will allow a period for additional comments. PMID- 10111145 TI - Payment method for health care services under the Supplemental Health Care Program for Active Duty Members of the Uniformed Services; adoption of CHAMPUS procedures--DoD. Final rule amendment. AB - On May 24, 1991 (56 FR 23800), the Department of Defense published a final rule on "Payment Method for Health Care Services Under the Supplemental Health Care Program for Active Duty Members of the Uniformed Services" concerning discharges occurring on or after June 24, 1991. Through an administrative error the effective date for the regulation should have been June 24, 1991, instead of May 24, 1991. This document is published to suspend the regulation. PMID- 10111146 TI - Statement of organization, functions, and delegations of authority; Office of Coordinated Care Policy and Planning and the Office of Prepaid Health Care Operations and Oversight--HCFA. PMID- 10111147 TI - Statement of organizations, functions, and delegations of authority; Office of Prepaid Health Care Operations and Oversight divisions--HCFA. PMID- 10111148 TI - Medicare program; schedule of limits on home health agency costs per visit for cost reporting periods beginning on or after July 1, 1989--HCFA. Final notice. AB - This final notice sets forth a revised schedule of limits on home health agency costs that may be paid under the Medicare program. This revised schedule of limits applies to cost reporting periods beginning on or after July 1, 1989 and before July 1, 1991. As required by section 6222 of the Omnibus Budget Reconciliation Act of 1989 (Pub. L. 101-239), the revised schedule of limits incorporates the hospital wage index in effect for cost reporting periods beginning prior to July 1, 1989. PMID- 10111149 TI - Special conditions: modified Boeing Model 767-200 and -300 series airplanes; installation of a medical oxygen system utilizing liquid oxygen--Federal Aviation Administration. Final special conditions; request for comments. AB - These special conditions are issued to E-Systems for design of Civil Reserve Air Fleet aeromedical evacuation ship set kits used to modify Boeing Model 767-200 and -300 series airplanes. Removal of existing passenger seats and installation of the kit will result in these airplanes being equipped with an aeromedical evacuation interior that can accommodate up to 111 litter patients and their attendants. The aeromedical evacuation ship set kit includes an additional oxygen system, utilizing liquid oxygen for storage, that provides medical oxygen for the litter patients. The applicable regulations do not contain adequate or appropriate safety standards for the design and installation of liquid oxygen systems. These special conditions contain the additional safety standards which the Administrator considers necessary to ensure that the design and installation of the liquid oxygen system is such that a level of safety equal to that intended by the applicable regulations is provided. PMID- 10111150 TI - Administrative practices and procedures; promulgation of regulations for the efficient enforcement of law--FDA. Final rule. AB - The Food and Drug Administration (FDA) is amending its regulation governing notice-and-comment (informal) rulemaking by removing from the regulation the requirement that the agency issue interpretative rules and rules of agency practice and procedure by informal rulemaking. As amended, the regulation provides that informal rulemaking procedures by followed to the extent required by the Administrative Procedure Act. PMID- 10111151 TI - The Safe Medical Devices Act of 1990--FDA. Notice. AB - The Food and Drug Administration (FDA) is announcing the passage of the Safe Medical Devices Act of 1990 and FDA's initial plans for implementing its requirements. The intent of this notice is to provide a summary of the new legislation and to inform the public of FDA's plans for its implementation. PMID- 10111152 TI - Medicare program; criteria for Medicare coverage of adult liver transplants- HCFA. Final notice. AB - This notice provides for Medicare coverage of liver transplantations in adults under certain circumstances. We are providing coverage for adult liver transplants based on our determination that liver transplants are medically reasonable and necessary services if furnished to adult patients with certain conditions and if furnished by participating facilities that meet specific criteria, including patient selection criteria. PMID- 10111153 TI - Grants to states for construction or acquisition of state home facilities--VA. Final regulations. AB - The Department of Veterans Affairs (VA) is amending its medical care regulations, Grants to States for Construction or Acquisition of State Home Facilities (38 CFR part 17), to implement section 206 of the Veterans' Benefits and Services Act of 1988 enacted on May 20, 1988. This section changes from July 1 to August 15, the date on which VA will determine the priority of applications for construction or acquisition grants for State Extended Care Facilities for purposes of the priority list. Section 206 also provides the Secretary authority to conditionally approve an application and obligate funds for a grant is the Secretary determines that the State can meet all remaining Federal requirements within 90 days. At the same time, VA is updating the States home grant standards and veteran population of the various States set forth in these regulations. These revisions will assist the States in meeting deadlines for the priority list and subsequent grant awards. PMID- 10111154 TI - Indian Health Service; statement of organization, functions and delegations of authority--PHS. PMID- 10111155 TI - Medicare program; schedule of limits for skilled nursing facility inpatient routine service costs--HCFA. Correction. PMID- 10111157 TI - A brave new world for doctors. PMID- 10111156 TI - Radical surgeons. AB - Congress's recognized leaders on health issues face competition from newcomers who are fed up with the failings of the medical system. They are proposing changes ranging from applying federal benefits guidelines to copying Canada's national health plan. PMID- 10111158 TI - Code of ethics. Canadian Association of Medical Radiation Technologists. PMID- 10111159 TI - X-ray records and the law. PMID- 10111160 TI - Tech-tips/techni-trucs. PMID- 10111161 TI - The effectiveness of a family asthma program for children and parents. AB - An evaluation of a Family Asthma Program revealed significant gains in relevant knowledge and management skills for parents, but not 4- to 12-year-old children with asthma. There were no significant differences between program group families and two other groups of families with asthmatic children at post-test time in regard to various characteristics of family stress and coping. Suggestions for the improvement of Family Asthma Programs are discussed. PMID- 10111162 TI - Use of children's artwork to evaluate the effectiveness of a hospital preparation program. AB - Approximately 1.5 million children are hospitalized on an emergency basis per year and are not able to be fully prepared for the event due to the emergency (Azarnoff & Woody, 1981). For this reason many pre-crisis hospital preparation programs are being instituted by hospitals and pediatric nurses. This pilot study investigated the use of children's artwork to evaluate the effectiveness of a hospital preparation program. The 6 to 10 year old children attending summer school at a day care center participated in a hospital preparation program. The purpose of the program was to decrease children's anxieties and fears in the event of an emergency hospitalization. PMID- 10111163 TI - Local coalitions for coordinating services to children dependent on technology and their families. AB - The emerging population of children who are technology dependent has made a significant impact on the health care service system in the last decade. The unique characteristics and numerous unmet needs of this group of children engender grassroots planning to improve the responsiveness and coordination of the service system. A description of three local planning initiatives is presented within the framework of a collaborative statewide planning effort surrounding the needs of children who are technology dependent and their families. PMID- 10111164 TI - Transfusion-related AIDS litigation: permitting limited discovery from blood donors in single donor cases. PMID- 10111166 TI - Let your computer do the walking. AB - A personal computer and a modem can be an extremely powerful pair and, used properly, can represent fantastic savings in time and money. Too often, they are underutilized because managers and clinicians do not know how to approach the type of online researching that computers are beautifully designed to perform- the kind of research that can make a daily significant difference. PMID- 10111165 TI - Quality assurance: a shift in focus. AB - Computers in Healthcare Associate Editor William A. Schmitt writes that quality assurance (QA) systems and philosophy has shifted from a punitive approach to focus instead on its more positive aspects. Schmitt also discovers that through the pressures of outside forces, QA may be one of the most important issues of the decade because the survival of many healthcare institutions may depend on it. PMID- 10111167 TI - Physicians play key role in information systems planning. AB - Healthcare executives struggle with schemes to encourage their institution's affiliated physicians to "buy" into the information systems master plan. By involving physicians initially as members of an MIS Executive Committee, one tertiary-care medical center in Pennsylvania promoted not only "buy-in," but stimulated physician curiosity, active use and even demands about future directions of IS at the medical center. PMID- 10111168 TI - CIOs must look beyond the IS horizon. AB - Executives in healthcare have traditionally had a difficult time communicating with their information managers, believing that they themselves must be technically oriented to understand their own IS system. The author argues that it is the chief information officers who must deepen their knowledge of the industry they have decided to pursue. This in turn will help them become more valuable members of the top executive team as it formulates strategic plans. PMID- 10111169 TI - Network link helps an "old doc" learn new tricks. AB - The author recounts his experience using the Colorado Medical Information Network, an online system linking physicians with hospitals, pharmacies, labs and HMOs. Through the system--without any previous computer experience--the author has greatly enhanced his practice management capability. PMID- 10111170 TI - HIS: shouldn't they make hospitals more effective, efficient providers of care? AB - Computer systems ought to make hospitals run more smoothly, but the ideal sometimes doesn't jibe with the reality. One hospital CEO reminds the industry that form should follow function. PMID- 10111171 TI - Practical issues in administering welfare benefit programs for two career families. PMID- 10111172 TI - Managing benefits and compensation in lean times. PMID- 10111173 TI - Plan design innovations to control health care costs. AB - Southern California Edison has achieved measurable success in health care cost management. Dr. Sokolov observes that the essence of SCE's problem-solving approach can be transferred to almost any organization. PMID- 10111174 TI - State high risk insurance pools: their operating experience and policy implications. PMID- 10111175 TI - Accepting the inevitable. PMID- 10111176 TI - The next EMS frontier. PMID- 10111177 TI - Ranger 36 to the rescue. PMID- 10111178 TI - Risky business. PMID- 10111180 TI - Meeting approval. AB - Each of the five conference centers featured here displays the best its parent organization has to offer. Take a tour through Herman Miller, Inc.'s Marigold Lodge; UCLA Conference Center/Bruin Woods Family Resort, S.C. Johnson & Son, Inc.'s The Council House; Aetna Institute for Corporate Education; & Eastwood (Medical Center) Conference Center & discover conference dining's multifaceted mission. PMID- 10111179 TI - Built-in communications. PMID- 10111181 TI - Improving your tray line operation. PMID- 10111182 TI - Operating in a difficult labor market. PMID- 10111183 TI - The art of employee relations. PMID- 10111184 TI - Garbage wars '91. Report from the front. Part three. AB - This final installment in Food Management's three-part series on solid waste management highlights the effective strategies independent foodservice operators and contract companies are employing to promote recycling and waste reduction and to educate customers and employees about responsible waste management. PMID- 10111185 TI - No wonder patients are confused. PMID- 10111186 TI - The story behind quality improvement. PMID- 10111187 TI - The fund-raising environmental audit. PMID- 10111188 TI - Something new in hospital development. PMID- 10111189 TI - Direct mail can be fun. PMID- 10111190 TI - Writing and development--Part III. Write about real people, not cigar-store Indians. PMID- 10111191 TI - Now quality means service too. AB - In the latest phase of the quality campaign, managers are discovering that the point is not only to satisfy but also to delight the customer. Just ask IBM or Federal Express. PMID- 10111192 TI - The dying patient: a comparative study of nurse caregiver characteristics. AB - The nurse's interaction with the dying patient is thought to be influenced by death anxiety, attitudes toward death, and perceptions of control. Differences relative to these three variables between nurses who work on a continuous basis with the dying and those who rarely encounter a dying patient were examined. Using 3 paper and pencil questionnaires, data were collected from 105 nurses (32 palliative care nurses, 44 psychiatric nurses, 29 orthopedic nurses). Significant differences were found between the palliative care nurses and nonpalliative care nurses on attitudes toward death and on 3 of the 4 subscales that assessed death anxiety. Suggestions for future research include a systematic examination of the relationship of attitudes and feelings about death to patient care. PMID- 10111193 TI - The hospice movement in Poland. PMID- 10111194 TI - Advance directives and assisted suicide. PMID- 10111195 TI - Progress reported in hospital employee drug testing programs. PMID- 10111196 TI - Special report. Arming security officers: an update. PMID- 10111197 TI - Forecast or tally? PMID- 10111198 TI - Budgets: do they control or constrict? PMID- 10111199 TI - Labor shortage does not eliminate customer service demands. PMID- 10111200 TI - Increasing productivity at all levels. PMID- 10111201 TI - Legislative currents ... Department of Health and Human Services' regulatory agenda. PMID- 10111202 TI - Practice bulletin: guidelines for faxing patient health information. PMID- 10111203 TI - Recruitment: an issue for all health record professionals. AB - This article is meant to stimulate discussion of our education program recruitment and delivery systems, and to suggest an orientation toward the adult student and away from the traditional younger student, whose population is shrinking. PMID- 10111204 TI - Federal medical record librarians are no more. PMID- 10111205 TI - Utilization management: a bibliography (1989-1991). PMID- 10111206 TI - Guy's--first casualty of a capital blitz? PMID- 10111207 TI - A family matter? PMID- 10111208 TI - Singing in tune. PMID- 10111209 TI - Clarifying the law on mental responsibility. PMID- 10111210 TI - A security blanket for the health service? PMID- 10111211 TI - Care for ethnic elders. PMID- 10111212 TI - Debunking the plans bunkum. PMID- 10111213 TI - Nursing precious resources. PMID- 10111214 TI - Healthcare data briefing: state of the estate. PMID- 10111215 TI - Advocating accessible healthcare for all people. PMID- 10111216 TI - How we geared up for the Gulf. PMID- 10111217 TI - Out in the wide world. PMID- 10111218 TI - Estates. Identifying the problem. PMID- 10111220 TI - Playing the wild card of preferential treatment. PMID- 10111219 TI - Estates. It's quicker by tube. PMID- 10111221 TI - Sharpening up the strategy. PMID- 10111222 TI - Myths of competition. PMID- 10111223 TI - Infectious enthusiasm. PMID- 10111224 TI - Computing. Proceeding with care. PMID- 10111225 TI - Computing. Sharing the caring. PMID- 10111226 TI - Computing. An IT community toolkit. PMID- 10111227 TI - U.S. initiatives and approaches for outcomes and effectiveness research. AB - This paper provides an overview of the new Federal initiative underway to promote research in outcomes and effectiveness of services provided in the U.S. It discusses the factors that stimulated the U.S. government ot undertake this initiative and summarizes past research and current efforts to advance knowledge about utilization and outcomes of care. A focal point of this initiative is to take advantage of information in large, administrative data bases to monitor the use, costs and outcomes of medical services. As part of this initiative, the Federal Government for the first time assembled detailed data, by geographic area and by demographic groups, on the hospitalization, mortality and rehospitalization experience of the entire Medicare population. The paper describes this project and illustrates uses of these data. PMID- 10111228 TI - Annotated bibliography: Psychosocial aspects of AIDS on the professional caregiver. PMID- 10111229 TI - Court rules release ineffective on public policy grounds. PMID- 10111230 TI - Courts reach different results interpreting peer review privilege statutes. PMID- 10111231 TI - Failure to check chart leads to liability. PMID- 10111232 TI - Insurance policy interpretation favorable to the insured. PMID- 10111233 TI - Hospital found in breach of physician contract. PMID- 10111234 TI - Chart changes prompt disciplinary action. PMID- 10111235 TI - No liability for hospital in informed consent case. PMID- 10111236 TI - Court rules hospital board erred in performing appellate review. PMID- 10111237 TI - Learning the ten step QA process for use in pastoral care departments. Part I. PMID- 10111238 TI - The nursing process: watching it happen at Woodland Memorial Hospital. PMID- 10111239 TI - Using practice guidelines and standards in QA and RM programs. PMID- 10111240 TI - Making an integrated QA and infection control program work. PMID- 10111241 TI - A combined QA/RM program for the obstetrics department. PMID- 10111242 TI - How does QIP (quality improvement process) work with the JCAHO monitoring and evaluation process? AB - In summary, the Joint Commission is in the process of adopting the concept of continuous quality improvement as the basis of operation, both internally and externally. This will translate into a mandatory shift by hospitals from using traditional Joint Commission guidelines to the incorporation of the QIP model of continuous quality improvement. Proof of this direction is found in the Joint Commission's Beta Testing program. PMID- 10111243 TI - Urology and kidney care: centers of excellence for the "age wave". PMID- 10111244 TI - Factors associated with medical malpractice: results from a pilot study. PMID- 10111245 TI - A legislative initiative: the Ryan White Comprehensive AIDS Resources Emergency Act of 1990. PMID- 10111246 TI - Nursing's mission: spiritual dimensions of health care. PMID- 10111248 TI - Empty pockets: application of the fireman's rule to emergency medical technicians. PMID- 10111247 TI - The role of families as surrogate decisionmakers after Cruzan v. Director, Missouri Department of Health. PMID- 10111249 TI - Threats to Secret Service protectees: guidelines on the mental health services provider's duty to report. AB - This article presents a set of proposed guidelines for mental health care providers faced with the not uncommon problem of having a patient under treatment who makes statements that can be interpreted as threatening the life of the President of the United States or another protectee of the Secret Service. What is the provider's duty in this situation? When should such a "threat" be reported? What should be reported? And to whom? The questions are difficult ones that confront both the dictates of the federal presidential threat statute and the general duty-to-warn law of the state where the provider resides and practices. Professional ethics and common sense must, of course, also figure in the calculus of the proper course of action. This article begins with a brief history of the Secret Service, its formal responsibilities, as well as its evolving contacts with the mental health community, driven by the Service's own recognition of the need for mental health expertise in evaluating the intentions and capacities of those who issue presidential threats. Next, this article presents the guidelines themselves, followed by commentary that sets out their legal, ethical, and pragmatic underpinnings. PMID- 10111250 TI - Economic analysis in health care antitrust. AB - The Federal Trade Commission (FTC or Commission) has been very active in enforcing antitrust laws in the health care field for the past two decades. The staff has investigated a wide variety of cases covering a broad range of restrictions on competition. These cases can be divided into three basic types of cases in health care: (1) mergers and acquisitions, (2) horizontal restraints cases or agreements among competitors, and (3) input market monopolization cases, such as hospital privileges cases. The Commission relies on both legal and economic analysis in all of these cases. As Chairman Steiger of the Federal Trade Commission has stated, antitrust policy has been "increasingly reshaped by analysis based on economic theory." This article attempts to explain the economic analysis used in antitrust enforcement as applied to the first two of the three types of health care cases. Section I presents the basic economic framework that is used to assess the competitive implications of health care mergers and acquisitions. Section II describes the analysis applied to other agreements among competitors in the health care field and briefly explains how this analysis differs in other health care cases. PMID- 10111251 TI - The patient's right to decline medical treatment: the New York view. AB - This article, which I am pleased to dedicate to my friend, Professor Josephine Y. King, deals with the evolving caselaw in the State of New York concerning a patient's right to decline medical treatment. New York, like many other states, has been struggling with cases involving this troublesome area of the law. The New York State Court of Appeals consistently expressed the belief that these cases are best resolved by the Legislature and that the court's role should be limited to deciding only the cases which come before it. As a result of the court's persistence in this regard, the New York State Legislature has recently enacted certain statutes which have gone far toward resolving the myriad of problems presented by these cases. It has enacted laws which allow a patient to provide that he or she is not to be resuscitated and has allowed an individual to execute a form of proxy which permits a surrogate to make these decisions in the event the patient is incompetent to do so. PMID- 10111252 TI - Fighting AIDS in adolescents. PMID- 10111253 TI - Safety precautions for laser surgery. AB - This article discusses the dangers of laser surgery and how to best guard against them by using the appropriate products and protective gear and by setting up a laser safety committee to continuously address laser safety problems. PMID- 10111254 TI - Assuring compliance with OSHA's hazard communication standard. AB - The author briefly reviews OSHA's Hazard Communication Standard and discusses how material management can help a facility meet its requirements, particularly through the use of labeling and making material safety data sheets available to workers. PMID- 10111255 TI - A joint effort in cost containment at the University of Massachusetts Medical Center. AB - The author discusses how nursing management of a critical care unit at the University of Massachusetts Medical Center worked with material management to reduce inventory and storage space. He also discusses how nursing attitudes toward cost containment need to be developed before they go to work at a healthcare facility. PMID- 10111256 TI - Laminar airflow hoods. ECRI. PMID- 10111257 TI - Making continuous quality improvement a reality: customer service skills. PMID- 10111258 TI - How many observations are required for evaluation and quality assurance? PMID- 10111259 TI - Personnel/department hygiene in CS. PMID- 10111260 TI - Hospital services as a tool in physician marketing. AB - The marketing of hospitals to physicians is of importance because of the latter's hypothesized primacy in health care buying decisions. The notion of marketing to physicians was investigated in terms of types of services offered by hospitals. The results indicated that successfully performing hospitals are more likely to offer high technology services for diagnostic and therapeutic tasks. Further, there was no significant difference between successfully and unsuccessfully performing hospitals in the provision of services marketed to the community. It was concluded that offering these high technology services may be an effective way of marketing hospitals to physicians. PMID- 10111261 TI - Communication strategies for hospital positioning. PMID- 10111262 TI - A developmental model of the total quality management process for hospital products--Part one. PMID- 10111263 TI - Assessing the management style of future managers. PMID- 10111264 TI - Hospital choice criteria: an empirical evaluation of active hospital clients. AB - Because of increasing competition, hospital administrators need to understand the criteria consumers use when making the choice of hospital services. This empirical study found the physical plant of the hospital in addition to the hospital staff play prominent roles in consumer selection of a hospital. A hospitals' overall reputation in addition to any previous contact with the hospital also have a major impact on hospital choice. PMID- 10111265 TI - Organizational issues for the teaching hospital. PMID- 10111266 TI - Small rural hospitals: an example of market segmentation analysis. AB - In recent years, market segmentation analysis has shown increased popularity among health care marketers, although marketers tend to focus upon hospitals as sellers. The present analysis suggests that there is merit to viewing hospitals as a market of consumers. Employing a random sample of 741 small rural hospitals, the present investigation sought to determine, through the use of segmentation analysis, the variables associated with hospital success (occupancy). The results of a discriminant analysis yielded a model which classifies hospitals with a high degree of predictive accuracy. Successful hospitals have more beds and employees, and are generally larger and have more resources. However, there was no significant relationship between organizational success and number of services offered by the institution. PMID- 10111267 TI - Health care advertising: comparing the attitudes of hospital administrators and consumers. AB - A survey of health care institution administrators and consumers finds that the former give significantly more positive approval to their advertising than their consumers do. In fact, the latter perceive medical advertising to be rather unprofessional. Among the administrators, more positive attitudes toward their advertising is projected by those who have used advertising in the past and by female administrators. PMID- 10111268 TI - The effect of hospital competition on marketing strategies. PMID- 10111269 TI - A policy analysis of hospital waiting lists. AB - The Canadian system of publicly provided health care has been praised for its cost containment attributes. Conventional cost measures do not identify costs associated with rationing access to medical facilities. This paper explores the economic relevance of hospital waiting lists and offers estimates of the economic costs of waiting for different hospital procedures in Canada. The estimated costs are relatively low as a share of overall economic activity but appear quite comparable to losses associated with labour strikes and lockouts. PMID- 10111270 TI - Leading a high-commitment high-performance organization. AB - This article conducts a thorough review of the extensive literature on executive leadership. It provides a definition for the concept of superior executive leadership and then presents a model explaining the key roles and attributes required to perform effectively in top management ranks. The article then discusses the implications of this model for senior executives and describes how it can be used to assess the quality of executive performance. PMID- 10111271 TI - Strategic planning for the board. AB - Although the planning operation is regarded by some observers as unrealistic in conditions of rapid change and increasing competition, the discipline of strategic thinking and the need for strategic leadership continue to be of vital importance. The author examines the purpose of the Board of Directors and its role in the management of strategy. PMID- 10111272 TI - Cut your legal costs down to size. PMID- 10111273 TI - Let patients pay you with plastic? PMID- 10111274 TI - Will more Blue plans break down? PMID- 10111276 TI - No death knell for universal health insurance yet. PMID- 10111275 TI - Where doctors and bureaucrats found common ground. PMID- 10111277 TI - One small step would be one big stride in ER care. PMID- 10111278 TI - A doctor with AIDS is barred from the OR. PMID- 10111279 TI - Help a patient's survivors understand his death. PMID- 10111280 TI - Managed care, too, shall pass--the sooner the better. PMID- 10111281 TI - Making the choice. A close look at the joint venture option. Part I. AB - The rapidly changing, highly challenging present and future marketplace facing group practices raises many questions for administrators. One answer to this new marketplace is to form an alliance with a financial partner who can provide capital and management expertise. Author Keith Korenchuk, J.D., M.P.H., describes the concept of acquiring such a partner and how to handle the process. PMID- 10111282 TI - Facing the prospect of national health insurance and its impact on group practice. Part two. PMID- 10111283 TI - The interaction of facility design with management goals. AB - While medical groups have different goals based on their mission, size and market, they all seek to propagate and maintain a financially sound enterprise. Author William Lindeman, AIA, writes that a primary factor in achieving this goal is excellent facility design. While facility design is no guarantee for success, exceptionally poor design can make success all but impossible. PMID- 10111284 TI - Dealing with reimbursement difficulties in today's payment environment. AB - Medical groups nationally are struggling with reimbursement levels, writes author Suzanne Anderson. Groups effectively dealing with the problem realize the solution is not restricted to the billing office but rather begins prior to providing service and lasts until well after payment is collected. PMID- 10111285 TI - Patient, revenue and cost analyses for medical practices. AB - Authors Robert Stevens and Thomas Chatham write that revenue and cost analysis can be performed by medical groups from historical data they maintain. Such analysis provides the administrator with a data base for developing realistic objectives and identifying areas which should be more fully developed or even eliminated. PMID- 10111286 TI - Good medicine, good business: developing a breast diagnostic center. PMID- 10111287 TI - Health maintenance organizations: plan offerings and enrollments. PMID- 10111288 TI - How to establish business office incentive programs. AB - Incentive programs to help increase collections or reduce days in receivables are becoming popular among healthcare business offices. A successful incentive program addresses major issues during the planning stage and includes realistic incentive goals, simple measurement tools, meaningful incentive payments, and proper monitoring of results. PMID- 10111289 TI - Achieving results through incentive bonus programs. PMID- 10111290 TI - Numeric titles in vogue as EDI standards developed. PMID- 10111291 TI - Suggestions for success in patient financial services. AB - There are no secrets of success in the healthcare industry, but several key elements can help patient financial services professionals succeed in their careers. Determination, a commitment to the profession, the proper attitude, and a plan of action can help healthcare professionals achieve lasting and meaningful success. PMID- 10111292 TI - Three elements aid successful careers. PMID- 10111293 TI - State motivations differ on tax-exempt challenges. PMID- 10111294 TI - Plan carefully when selecting a patient accounting system. AB - For hospitals that have experienced it, choosing and implementing a new patient accounting system can be a grueling and tedious task--a once-in-a-lifetime undertaking. But with careful planning and some notable precautions, a hospital can ensure that the system selected is the system desired. PMID- 10111295 TI - Quality assurance: a vital aspect of the clinician's role. AB - Medical professionals are ethically obligated to document the quality of the care they provide for patients. Society's demands and patients' expectations make quality assurance an issue of concern to all health care providers. The Joint Commission on Accreditation of Healthcare Organizations has formulated a detailed process for monitoring clinical activities and evaluating quality. This report reviews the rationale for and recommended approach to monitoring and evaluating quality assurance. PMID- 10111296 TI - Institutional giants' cost cutting guide. AB - Look to this year's Institutional Giants, the country's largest schools, colleges, contract feeders, independent hospitals and hospital chains, and military food-service operations, for money-saving ideas. Their suggestions could fit into any foodservice operation. PMID- 10111297 TI - The clean restaurant. II: Employee hygiene. AB - Poor personal hygiene causes more than 90% of the sanitation problems in the foodservice industry. Government statistics show improper hand washing alone accounts for more than 25% of all foodborne illnesses. In Part II of R&I's sanitation series, experts describe in detail proper procedures for reducing cross-contamination in the workplace and suggest ways to deal with a new problem- style vs. safety, including what apparel, jewelry, cosmetics and hair styles can and cannot be worn on the job. PMID- 10111298 TI - 1991 Silver Plate winners. This year's nine IFMA award winners talk pride, politics and the future of the foodservice profession. AB - What challenges lie ahead for the food-service industry? All nine candidates for the International Foodservice Manufacturers Association's 1991 Gold Plate share their views on building staff unity, improving government relations and other critical issues. PMID- 10111299 TI - The sane approach to mental health care. PMID- 10111300 TI - Spreading the word about risk management. PMID- 10111301 TI - A framework for marketing image management. AB - Managers know that the customer's impression of an organization is important. And sometimes companies attempt to determine just what that impression is. They conduct ad hoc surveys and focus groups. But too often the data is insubstantial, or difficult to analyze, or even inaccurate. Barich and Kotler introduce the concept of "marketing image" and describe a system of image management: designing a study, collecting data, analyzing image problems, modifying the image, and tracking responses to that image. They argue that only a systematic approach will yield useful and accurate information that a company can translate into action. PMID- 10111302 TI - Predictions bullish for industry's future. AB - What's around the corner and down the road for the textile rental industry? Four CEOs--Richard Farmer, William Leonard, Richard Senior, and James Stefoff--give their views on future industry profitability, evolutionary trends and specialization, healthcare market stability, and survival tactics. PMID- 10111303 TI - A Medicare strategy for quality. PMID- 10111304 TI - Business office innovations improve hospital cash flow. PMID- 10111305 TI - Building teamwork by recognizing corporate cultures in the hospital. PMID- 10111306 TI - Risk management for the board. PMID- 10111307 TI - Decisions near the end of life. PMID- 10111309 TI - Trustees take hospitals' message to Congress. PMID- 10111308 TI - Health care reform: trustees can be part of the solution. PMID- 10111310 TI - Technology acquisition: system works toward planned approach, collaborative models. Interview by Karen Gardner. PMID- 10111311 TI - Top ten health trends. AB - With advances in medicine, science and technology coming fast and furious, today's bold ideas could easily be tomorrow's standard operating procedures. To keep you abreast of developments in medicine, fitness and nutrition, U.S. News has identified the 10 most important health trends for the coming year. From gene therapy to patients' rights, here's a look at what's ahead. PMID- 10111312 TI - Turbulence at the top: a new perspective on governance structure changes and strategic change. AB - Organizational theorists have traditionally focused attention on the relationship between chief executive officer (CEO) succession and strategic change. This study extends that perspective and explores the effects of changes in an organization's management, ownership, and board of directors on the process of strategic change. The results of this research suggest that changes in ownership and board have significant independent and interactive effects on strategic change. PMID- 10111313 TI - Antecedents and outcomes of decision speed in different environmental contexts. AB - This study refined and extended some findings of previous research on decision making speed. Decision speed was associated with simultaneous consideration of many alternatives, regardless of context. In contrast, the relationship between board experience and decision speed was context-specific. Similarly, decision speed was associated with higher performance only in high-velocity environments. PMID- 10111315 TI - In and out of the rabbit hole with Alice: assessing the consequences of efficiency prescriptions. PMID- 10111314 TI - AIDS knowledge and attitudes for July-September 1990. Provisional data from the National Health Interview Survey. PMID- 10111317 TI - Work, work, work. Rewiring, rebuilding equipment and some long needed maintenance brought this laundry up to speed. Part I. PMID- 10111316 TI - Cost: efficiency, austerity, and economics. PMID- 10111318 TI - Managing stress and anxiety in clinical laboratories. Guidelines for psychologically informed interventions. AB - Pressures to improve the cost effectiveness of the health-care delivery industry promise to make life stressful for those who work within the industry during the 1990s. Employees who work in stressful conditions eventually feel anxious about themselves, their performance, how they are being treated, and others. Employees cope with these anxieties by using psychological defenses that have a major impact on interpersonal relations and work performance. This article shows how stress and anxiety diminish employee effectiveness and illustrates the connection between managing employee defensiveness and performance. Intervention guidelines are provided to help clinical laboratory managers develop insightful, informed, and effective interventions when performance problems occur. PMID- 10111319 TI - Accident-prone norms: implications for clinical laboratories. A methods for examining groups norms and interaction networks. AB - Employee accidents are a costly problem for clinical laboratories. Consequently, investigation and prevention of accidents are integral parts of the clinical laboratory manager's job. There are a wide variety of traditional modes of accident research; however, they usually do not include investigations of work group norms and interaction networks. Group norms that contradict formal safety norms can arise in clinical laboratory work groups. These accident-prone norms often result in problematic procedures and activities. Examples of these accident prone norms include: failure to use safety equipment, failure to follow safety procedures, alcohol or drug use on the job, failure to pass on information about equipment problems, and failure to report job-related accidents. These norms are frequently transmitted through interaction networks. Sociometric techniques can provide insights about the networks and can be used to develop solutions to accident-prone norms. PMID- 10111320 TI - Practicing participative management in the clinical laboratory. Foster a productive and satisfying staff. AB - Employee participation and involvement are at the leading edge of management thinking today. Not only behaviorally oriented managers, but managers of all styles include personnel in decision-making. The purpose of this article is to communicate to clinical laboratory managers some recent developments in people management. Several suggestions for team building and the desired outcome of worker participation are included. Although employee participation has been a major issue in management for 10 years, many business schools still emphasize only the traditional quantitative subjects of accounting, finance, statistics, and systems engineering. Obviously, these subjects are important, but modern managers must learn qualitative or behavioral material as well. Students are affected by the lack of a notable behavioral emphasis. Unfortunately, some students think that learning in the behavioral domain is unimportant. Too often, these students encounter problems later in their careers with employees and can only wish for greater knowledge. PMID- 10111321 TI - Using high tech in employee selection. AB - To combat the growing labor shortage of the 1990s, recruiters must find ways to become more selective in their hiring practices. Using computers to ask applicants pre-interview questions allows interviewers to focus on critical areas during the interview. Selecting the right candidate improves company productivity and retention, thereby reducing hiring needs. Furthermore, the computer can track thousands of applicant responses and thus form an accurate data base for companies to develop the "successful" employee. Applicants appreciate the attention interviewers give them, and interviewers have the necessary information they need to conduct a relevant interview. More informed hiring decisions are made, resulting in reduced turnover and increased productivity. PMID- 10111322 TI - Technicon H-2 hematology system. PMID- 10111323 TI - Proposed CLIA '88 sanctions. PMID- 10111324 TI - Supplementing staff with technical assistants. PMID- 10111325 TI - CLMA position statement. Laboratory managerial functions and duties. PMID- 10111326 TI - Title III services: variation in use within a state. AB - Using data from Connecticut's management information system for Title III funds, we found, first, that such services are reaching at least one person in every town and thus modestly fulfilling a gateway function; about 9% of Connecticut's elderly use Title III services, with 20% of the oldest old obtaining such services. Nutrition services are reaching the most elderly, both numerically and geographically; among the oldest old (85+), home care service use was most widespread. Indices of use were not statistically related to specific characteristics of the towns' populations (i.e., percentage of elderly, poor, or minority elderly), but small cities and rural towns had the highest use levels. Presence of nutrition sites within the town and service through two of the five area agencies on aging (AAAs) were also correlated with high service use, controlling for the rural-urban continuum. Those two AAAs received the highest per capita amount of Title III funds, based on the state's targeting formulas. PMID- 10111327 TI - On the nesting of snowbirds: a question about seasonal and permanent migrants. AB - This essay asserts that seasonal and permanent migration may be connected, although there is no direct evidence for this relationship in the current research literature. We draw circumstantial and incomplete evidence for this proposition from findings of a recent survey of Canadian snowbirds in Florida and a parallel study of Canadian-Americans using the 1980 census public use sample migrant file. Other researchers are encouraged to settle the issue by including appropriate items in surveys of snowbirds that would determine whether or not some of the permanent migrants from the same origin serve as an unofficial reception committee for winter visitors, providing for them a socially receptive place to "nest" for the season. PMID- 10111328 TI - Daily illness characteristics and health care decisions of older people. AB - Although investigations of health care decision making typically deal with patterns of health service use, increasing attention has focused on lay- and self care actions in response to illness symptoms. This study examined the health care actions of a community sample of 142 older adults, who recorded illness symptoms and corresponding health care actions in daily health diaries for a 14-day period. Self-treatment and no-action decisions were found to be the most frequent response to illness symptoms. Professional-care decisions were associated with greater health care need, such as multiple symptoms and increased pain. Lay-care decisions were significantly related to symptoms of shorter duration. Women were also more likely than men to self-treat their illness symptoms. Results suggest that older people deal with a greater number of recurrent chronic symptoms than previously thought and that they make most treatment decisions without consulting their doctors or other health care providers. This investigation underscores the importance of a prospective diary methodology for studying the daily complexities of chronic illness experiences and for validating and conducting useful interventions. PMID- 10111329 TI - What do discharge planners plan? Implications for older Medicare patients. AB - This research examines the discharge-planning process, specifically assessing the extent to which components critical to effective discharge planning are implemented in acute-care settings. We surveyed 16 discharge planners in rural and metropolitan hospitals. The analysis examined the degree to which discharge planning programs incorporate client-centered planning activities, collect information about the client's care deficits, use community services to support the client on discharge, and the extent of interdepartment involvement in discharge planning. Results indicated that the majority of planners were client centered in their planning; however, a complete assessment of the client's resources and care deficits did not occur on admission. We discuss implications for discharge planning. PMID- 10111330 TI - Japan's coming crisis: problems for the honorable elders. AB - The rapid aging of the Japanese and United States populations represents a major challenge in terms of health care and the quality of life. This article provides a cross-cultural analysis of the status of the elderly in these two countries. Japan currently has almost 13 million people over the age of 65. This number will more than double in the next two decades, making Japan one of the oldest countries in the world. This change offers an opportunity to view the approaches, solutions, and dimensions associated with current and proposed directions for the elderly in the United States, who now number 32 million and will increase to 35 million by the year 2000. PMID- 10111331 TI - Perspectives. Fee schedule threatens payment reform. PMID- 10111332 TI - HMO's and physician practice groups: will you still love me tomorrow? PMID- 10111333 TI - Managed care: PPO's, HMO's, PPC's ... H.E.L.P.! PMID- 10111334 TI - Time study and volume analysis combine to measure workload and assess staffing patterns. PMID- 10111335 TI - Managed care: a way of life. PMID- 10111336 TI - When one body can save another. PMID- 10111337 TI - Matchmaker, find me a match. PMID- 10111338 TI - Special report. Integrating managed care. Data watch: when subtraction is a plus. PMID- 10111339 TI - Special report. Integrating managed care. PMID- 10111340 TI - Lost: another health benefit. When you retire, your blanket plan may be buried wherever the boss's promises go to die. PMID- 10111341 TI - Medicaid Program; eligibility groups, coverage, and conditions of eligibility; legislative changes under OBRA '87, COBRA, and TEFRA--HCFA. Final rule; correction notice. AB - This notice corrects 42 CFR 440.210, Required services for the categorically needy, 42 CFR 440.220, Required services for the medically needy, and 42 CFR 440.250, Limits on comparability of services, to restore current text which was inadvertently deleted in the final rule and to make conforming redesignation changes. This notice rescinds a correction notice published on March 14, 1991, in which certain corrections pertaining to sections 440.220 and 440.250 were inadvertently omitted. PMID- 10111342 TI - Federal old-age, survivors and disability insurance (1950- ); determining disability and blindness; extension of expiration date for cardiovascular system listing--Social Security Administration. Final rule. AB - We are extending the expiration date of the cardiovascular system listing found in appendix 1 of part 404, subpart P, from June 6, 1991, to June 6, 1992. We have made no revisions in the medical criteria in the cardiovascular listings; they remain the same as they now appear in the Code of Federal Regulations. We are presently considering revisions to update the medical criteria contained in part A and part B of the listing, and any revised criteria will be published as a proposed rule when we have completed our review. Insofar as Medicare eligibility is based on entitlement to disability insurance benefits under title II of the Act, this proposed regulation affects the Medicare program. To the extent that Medicaid eligibility is based on title XVI eligibility, this proposed regulation affects the Medicaid program. PMID- 10111343 TI - Agency for Health Care Policy and Research; establishment--HHS. PMID- 10111344 TI - Statement of organization, functions and delegations of authority--HCFA. PMID- 10111345 TI - Standards for protection against radiation--Nuclear Regulatory Commission. Final rule. AB - The Nuclear Regulatory Commission (NRC) is revising its standards for protection against ionizing radiation. This action is necessary to incorporate updated scientific information and to reflect changes in the basic philosophy of radiation protection. The revision conforms the Commission's regulations to the Presidential Radiation Protection Guidance to Federal Agencies for Occupational Exposure and to recommendations of national and international radiation protection organizations. PMID- 10111346 TI - Patient accounting systems: buying substantial, but declining. AB - Hospitals are not replacing their patient accounting systems in the volume they once did during 1987 and 1988, and the greatest decline in patient accounting software purchases has occurred among large hospitals, according to analysts at Sheldon Dorenfest & Associates, a Chicago-based consulting firm. Despite the maturity of the patient accounting software marketplace, those software vendors who can develop products that recognize the changing hospital environment will emerge over the next five years. PMID- 10111347 TI - Hospital receivables management: the hidden receivable. AB - When patient claims are delayed in their availability to Patient Accounting for billing, these delays can add to an organization's outstanding receivables. By controlling the inter-system processes more carefully, the financial department can target windows of opportunity to reduce the hospital's overall receivables. PMID- 10111348 TI - Automating time and attendance saves time and money. AB - Soaring patient care costs coupled with a shrinking work force demand that today's hospitals find new ways to increase the effectiveness of labor management. The Hospital of Saint Raphael, in New Haven, Conn., has replaced its outdated, manual time and attendance systems with an automated solution--and they have saved $150,000 annually in the bargain. PMID- 10111349 TI - Speeding the receivables pipeline: a new approach. AB - The decade of the '80s saw a dramatic nationwide increase in healthcare receivables. External factors including a tougher regulatory environment and tighter internal budgets augmented this rise. Hospitals that have been successful at managing their receivables have done so through a variety of both operational and system improvements including Receivables Performance Management and a performance accountability reporting system (PARS). PMID- 10111350 TI - Financial forecasts in healthcare. AB - Economic forecasts can be a vital tool for management to predict future outcomes and respond to them accordingly. They can also spell trouble for managers who don't know how to properly utilize them. The financial manager must therefore use every tool available when using financial forecasts during the planning process and the author describes the steps necessary in order to make sound judgments. PMID- 10111351 TI - Healthcare partnerships for the 21st century. AB - Traditional business models employed over the last 30 years began breaking down during the '80s and are completely disintegrating during this decade. Traditional organizational models have led to underutilization, waste and unnecessary excess. For healthcare institutions to survive and thrive, a new management model must be implemented by employing business partnerships and alliances to optimize information, systems, products and resources. PMID- 10111352 TI - Fast track evaluation methodology. AB - Evaluating hospital information systems has taken a variety of forms since the initial development and use of automation. The process itself has moved from a hardware-based orientation controlled by data processing professionals to systems solutions and a user-driven process overseen by management. At Harbor Hospital Center in Baltimore, a fast track methodology has been introduced to shorten system evaluation time to meet the rapid changes that constantly affect the healthcare industry. PMID- 10111353 TI - Operational restructuring key to "patient-focused" hospital. PMID- 10111354 TI - Moving from "small qa" to "large qa". An outcomes framework for improving quality management. AB - In this article we describe an "outcomes framework" for planning and analyzing quality management systems in relation to their ultimate purpose, enhancing the wide range of health care benefits. "Small qa" includes those methods that focus on structure or process and induce improvement of outcomes. These methods are essential but, predictably, often involve minimal improvement of health care. "LARGE QA" is defined as those methods that focus on unacceptable outcomes and deduce processes and structures to be changed to enhance outcomes. These methods focus on either "problems" or "opportunities" that predict substantial improvement in health care benefits. We briefly describe and analyze this outcomes framework for quality management in terms of its conceptual factors and its current and future emphasis. We then describe several major national program developments and resources that will facilitate moving the balance of quality management effort from small qa to LARGE QA. PMID- 10111355 TI - Medical treatment effectiveness research. A view from inside the Agency for Health Care Policy and Research. AB - The Medical Treatment Effectiveness Program (MEDTEP) is an intradepartmental federal program of the Department of Health and Human Services, for which the Agency for Health Care Policy and Research (AHCPR) has lead responsibility. This article presents a staff perspective on the conceptual framework for the MEDTEP research agenda and on the opportunity to address empirically the relationships between particular health care services and patient outcomes. It reviews programmatic priorities and identifies active MEDTEP research projects, with descriptions of 11 patient outcomes research team projects. Finally, it addresses the need to produce useful research findings in the short term and the implications of a dual concern for the quality and cost of health care. PMID- 10111356 TI - Physician recertification and outcomes assessment. AB - Physician recertification poses a unique challenge to member boards of the American Board of Medical Specialties (ABMS) charged with the responsibility of credentialing physicians. The key issue that emerges in recertification programs is how to evaluate performance in practice. Although some test of knowledge may be appropriate, an evaluation of clinical performance has become essential in recertification programs. To meet this challenge, ABMS boards have adopted methods to evaluate performance in practice. However, regardless of the methods chosen, criteria are needed to serve as standards. This article considers the application of outcomes assessment in the definition of standards for recertification. When direct outcome assessment may not be possible, outcome validated process measures may provide a suitable alternative. PMID- 10111357 TI - Clinical outcomes management and disease staging. AB - Clinical outcomes management includes multiple approaches for evaluating and improving the quality and cost effectiveness of medical care. The usefulness of outcomes assessments depends, in part, on how well the clinical issues have been specified and whether the analyses are sensitive to the diverse clinical characteristics of the patients receiving the medical care in question. Measures of severity of illness and, in particular, Disease Staging, have an important role in outcomes assessment by classifying diseases along dimensions that have prognostic significance. This article reviews current applications of Disease Staging for outcomes assessment and management. PMID- 10111358 TI - Changes in rates of unscheduled hospital readmissions and changes in efficiency following the introduction of the Medicare prospective payment system. An analysis using risk-adjusted data. AB - The purpose of this study was to analyze changes in rates of unscheduled readmissions and changes in technical efficiency following the introduction of the Medicare Prospective Payment System (PPS). We developed the Risk-Adjusted Readmissions Index (RARI), which allowed us to make comparisons in rates of unanticipated readmissions across hospitals and over time. Data envelopment analysis (DEA), a linear programming technique, was used to measure changes in technical efficiency by comparing the inputs used and the outputs produced across a cohort of hospitals, while adjusting for changes over time in case mix and case complexity. Rates of unscheduled readmissions and efficiency scores were computed for a sample of 245 hospitals for each year. Although both readmission rates and efficiency scores increased for most hospitals, there was no evidence that those hospitals that experienced the greatest increases in efficiency had the largest increases in their rates of unscheduled readmissions. PMID- 10111359 TI - A cure for what ails medical care. AB - Call it the American disease. The symptoms: unchecked health care spending and too many uninsured. The remedy: introducing more marketplace logic into the system. PMID- 10111360 TI - Yes, companies can cut health costs. AB - Most corporate medical bills are still rising at a feverish pace. But a growing number of employers are fighting back with a potent remedy: managed-care networks. PMID- 10111361 TI - Taking on public enemy no. 1. AB - America's CEOs aren't ready to nationalize health care--yet. Their cure: Get employees to pay more of the bill and persuade Washington to limit doctors' liability. PMID- 10111362 TI - Serving two masters: conflicts in practice. AB - Accustomed to putting patients' needs first, internists now face daily pressure to contain health care costs. With a view from the trenches, a practicing internist and former ASIM president enumerates the dilemmas physicians confront in trying to serve patients and payers. PMID- 10111364 TI - Seeking solutions to the health care access problem. Interview by Janice C. Simmons. AB - Rep. Johnson (R-Conn.), a five-term congresswoman and co-chairman of the House Republican Task Force on Health Policy, talks about concerns in Congress today over access to care, medical malpractice and effectiveness research. PMID- 10111363 TI - Cost containment and the physician's ethical obligations. AB - The chairman of the American Medical Association's Council on Ethical and Judicial Affairs evaluates the ethical relationship between physicians and payers, and cautions that physicians must use great restraint and diligence to maintain professionalism in an environment of cost constraints. PMID- 10111365 TI - Bad bills and mistaken policies: the case for legislative reform. PMID- 10111366 TI - Concurrent care denials: clouding the horizon. PMID- 10111367 TI - How to reduce carrier payment denials. PMID- 10111369 TI - Why Canada's health system wouldn't work in the U.S. PMID- 10111368 TI - Leave the posturing to the politicians. PMID- 10111370 TI - Professional ethics vs. cost containment: the inevitable clash. AB - Observing that the Hippocratic Oath is on a collision course with the cost containment movement, a prominent medical ethicist asks whether a physician ethically can refuse to treat patients with inadequate insurance coverage and if different levels of care are permissible. PMID- 10111371 TI - Formulary issues at a pediatric hospital: experience at Children's National Medical Center. AB - At Children's National Medical Center in Washington, DC, patients treated range from premature babies to 21-year-olds. Therefore, a broad base of drug therapy is practiced. University affiliated, the facility serves as the pediatric department for George Washington University School of Medicine. This hospital is seen as an innovator in specialized areas, such as neonatology, pediatric trauma, oncology, and organ and bone marrow transplantation. P & T Committee participation and communication are excellent, allowing members to focus sharply on therapeutic issues. One of their successful strategies has been the institution of a rather extensive subcommittee structure, which has facilitated intense but timely formulary review and strengthened drug policy. In this exclusive Hospital Formulary interview, Dr. George Cohen and Mr. Stephen Allen, Chairman and Secretary of the P & T Committee, respectively, share their experiences, providing insight for other P & T Committee members in hospitals serving both children and adults nationwide. PMID- 10111373 TI - Environmental affairs: now on the strategic agenda. AB - No company or industry can afford to be ill equipped to meet the mounting environmental challenges. Here is what some companies are doing. PMID- 10111374 TI - Identifying the employee of the future. AB - Hewlett-Packard evaluated its future marketing needs and compared it to the capabilities of current employees. This case study is an example of how other companies can ensure they have the best people to meet their strategic goals. PMID- 10111372 TI - U.S. intelligence system: model for corporate chiefs? AB - A fully dedicated intelligence support function for senior management is no longer a luxury but a necessity. Companies can enhance their intelligence capabilities by using the government model as a rough blueprint to structure such a program. PMID- 10111375 TI - Control the risks of high-stakes litigation. AB - A litigation crisis can be not only a costly jolt to a company's financial health but a disruptive force to company personnel and markets. Here is a blueprint for formulating a contingency plan for dealing with such a crisis. PMID- 10111377 TI - A strategic approach to employee motivation. PMID- 10111376 TI - Strategic repositioning through the customer connection. PMID- 10111378 TI - How to stay at the forefront of technological innovations. PMID- 10111380 TI - The pain and pleasures of flexible pay. PMID- 10111379 TI - Leaders and how they manage. PMID- 10111381 TI - Job evaluation--East Anglia style. PMID- 10111382 TI - The pros and cons of devolution--why it takes two to tango. PMID- 10111383 TI - Pay strategy--Pompey style. PMID- 10111384 TI - Soap operas and black holes. Why the NHS needs to get to grips with new skills. PMID- 10111385 TI - How benefits can be used to keep staff happy--and in post. PMID- 10111387 TI - Europe's top women--what skills are needed in the next decade? PMID- 10111386 TI - Why trade unionism is not quite dead in the NHS. PMID- 10111388 TI - A practicum in clinical nutrition as the internship component of an integrated masters/internship program. AB - In September 1990, Chedoke McMaster Hospitals (CMH) admitted two students to the Practicum in Clinical Nutrition. This program was developed at CMH in affiliation with the graduate programs in nutrition offered at McMaster University and the University of Guelph. This is the first program in Canada to integrate a graduate nutrition degree at the Master's level with a clinical nutrition training program. The purpose of this paper is to describe the need, goals, educational philosophy, developmental process and anticipated benefits of this practicum. PMID- 10111389 TI - A conceptual framework for dietetics. AB - The model for the practice of dietetics recently adopted by the CDA board of directors clarifies how the different facets of dietetics are interrelated and part of a common definition of dietetics. It is our hope that this discussion will help us to move beyond the question of identity we often feel in our profession and will stimulate debate and the development and testing of alternate models; this should further clarify the essence of dietetic practice and enable us to continue to improve our unique and common contribution towards the provision of quality nutritional care to the population. PMID- 10111390 TI - Prediction of graduate dietetic internship appointments in Canada. AB - A statistical model of dietetic intern selection was developed from a profile of selection criteria that was obtained in a 1988 survey of Canadian graduate dietetic internship directors. The model was composed of four clusters of variables that resulted from the most frequently used selection criteria: academic performance, work experience, communication skills, and extracurricular activities. Data from a convenience sample of 39 dietetic intern applicants were analyzed, using principal components analysis and discriminant analysis, to test the model's power to predict success in obtaining an internship appointment. In descending order, the criteria with the greatest predictive powers were: academic performance; extracurricular activities; and supervisory, teaching, or instructing types of work experience. The model accounted for 41% of the differences between those who were successful and those who were not successful in obtaining internship appointments in 1989 and correctly classified 30 of 39 subjects. These results provide baseline data on the predictive power of some criteria used for selecting dietetic interns. These findings suggest the need for a replication study with a randomized national sample to crossvalidate the results obtained in this exploratory research. PMID- 10111391 TI - Testing for neutral-to-ground connections in new construction. AB - A study was performed to seek out inadvertent connections between neutral and ground in the power distribution system of a newly constructed hospital, prior to occupancy. Such connections are not only violations of code but could cause medical device problems. Ground wires are not intended to carry load currents except during faults. When currents do flow in grounds, medical device chassis voltages are elevated and some devices may respond unpredictably. Suitable acceptance testing is not commonly done. In this study, a simple test method was developed that helped reveal and correct many neutral-ground misconnections. The authors advocate incorporating such a test into building construction contract specifications. PMID- 10111392 TI - Testing of central nervous system shunt devices. AB - This paper presents the results of a study performed by the U.S. Food & Drug Administration (FDA) under the Conformance Assessment to Voluntary Standards program. The ASTM voluntary standard F647-85 (American Society for Testing and Materials: Standard Practice for Evaluating and Specifying Implantable Shunt Assemblies for Neurological Applications) was evaluated as to the adequacy of its test methods and the reasonableness of its application to currently marketed shunt devices. The objective of this study was to assess the impact of ASTM: F647 85 on the safety and effectiveness of shunt devices and thereby assist the FDA in setting priorities for its mandatory standards development activities. By searching the FDA's postmarketing surveillance database and by testing seventeen shunt devices and three catheters from six manufacturers, it was determined that these devices conform with most of the ASTM standard requirements. However, no single device conformed to all of the requirements of the standard. Suggestions for improving the voluntary standard's impact on the safety of shunt devices are presented. PMID- 10111393 TI - The emergence of a new medical & biological engineering infrastructure. PMID- 10111394 TI - 1991 survey of hospital salaries & job responsibilities for clinical engineers & biomedical technicians. AB - The Journal of Clinical Engineering has conducted its sixth survey of the salaries paid to Clinical Engineers and Biomedical Equipment Technicians in U.S. hospitals. This paper reports the salary and work responsibility data obtained from 1,316 professionals in relationship to: Certification; Region of the U.S.; Teaching Versus Nonteaching Facilities; Years of Experience; Education; Union Membership; and Gender. Data are included on Wage Increases and Job Responsibilities. Data are as of 12/31/90 and are compared to 12/31/89. The average BMET I has 2.2 years of experience and earns $22,043 +/- $4,212 (Std. Dev.). The average BMET II has 6.5 years of experience and earns $27,627 +/- $5,466. The average BMET III has 11.6 years of experience and earns $33,843 +/- $6,099. The average BMET Supervisor has 13.5 years of experience and earns $38,159 +/- $7,701. The average Clinical Engineer has 8.5 years of experience and earns $39,127 +/- $7,884. CE Supervisors are the highest paid in the field with an average 13.9 years of experience and an average salary of $51,050 +/- $12,465. Wages are the highest on the West Coast. This year, the lowest wages were in the Southwest. From 1989 to 1990, the wage ranges for all job types increased substantially: BMET Is, +13.4%; BMET IIs, +5.3%; BMET IIIs, +8.0%; BMET Supervisors, +7.9%; CEs, +5.7%; CE Supervisors, +10.4%; and Supervisor, Other, +6.0%. The highest quartile of CE Supervisors now earns between $56,700 and $100,000 per year. While certified individuals earn $158 to $5,702 more than noncertified, this is attributable, in part, to additional years of experience. PMID- 10111395 TI - Centers of excellence: future trends for key inpatient service lines. PMID- 10111396 TI - Service line forecasting: predicting the growth (or decline) of a hospital's inpatient services. PMID- 10111397 TI - Health care and the homeless: a marketing-oriented approach. AB - Recent research suggests that the homeless in the United States are a large and diverse population. Studies have identified their wide range of health care needs, which currently are poorly serviced by health care professionals. The author proposes an improved process for the delivery of health care to the homeless. The marketing concept--defining needs and working to develop solutions- is applied to this critical problem to benefit homeless persons as well as health care providers. PMID- 10111398 TI - Marketing budgeting in nonprofit hospitals. AB - The authors summarize the results of an investigation of the marketing budgeting practices of nonprofit hospitals. They examine various dimensions of budgeting behavior, including (1) the prevalence of budgeting methods that are widely used in the marketing of consumer and industrial goods, (2) the relationship between budgeting practices and the budgeting process, and (3) the relationship between budgeting practices and hospital strategy and performance. The authors also discuss implications for marketing executives and directions for future research. PMID- 10111399 TI - Creating customer-oriented employees: the case in home health care. AB - Little empirical research has examined the organizational factors that influence the extent to which health care providers engage in customer-oriented behaviors. The authors examine the influence of role ambiguity, role conflict, and job satisfaction on the customer-oriented behaviors of home health care representatives. Managerial implications based on the study findings are discussed. PMID- 10111400 TI - Radio station acceptance of AIDS-related advertising messages. AB - Survey responses were received from the managers of 630 radio stations, who reported which type of AIDS-related commercials or public service announcements they are willing to accept for broadcast. The authors examine whether the public interest can outweigh fear of offending audience segments and discuss ways health education planners can increase acceptance of AIDS-related commercials. For planning a public health campaign, both the number and types of stations that will accept various public health messages are important if the messages are to reach high risk demographic groups. PMID- 10111401 TI - The impact of situational factors on health care preferences: exploring the prospect of situationally based segmentation. AB - Health care marketing research has examined the relationship between health care utilization and (1) client demographic characteristics and (2) service characteristics. The impact of situational factors on health care utilization has received limited attention. The authors find that the influence of situational factors in the health care market is substantial and suggest some preliminary situational segmentation strategies. PMID- 10111402 TI - No tree can grow to the sky: an interview with the Honorable Richard D. Lamm. Interview by Michael B. Guthrie. PMID- 10111403 TI - Effective internal marketing: the challenge of the 1990s. AB - Results of a recent public opinion study suggest that health care provider organizations are not taking advantage of several important public relations and internal marketing channels to educate the public through their employees. As increasing pressures on health care providers from other segments of the health care industry result in reduced revenues, lower margins, and downsizing, health care marketers and public relations managers should reassess their internal marketing efforts. PMID- 10111404 TI - The role of marketing research in securing a certificate of need for a new renal transplant facility. AB - The authors describe how a negative Certificate of Need decision on the establishment of a new renal transplantation center was reversed by the reintroduction of arguments based on primary data. Specifically, a research project was undertaken to survey attitudes of past and potential patients toward using the new facility. In addition to overturning the negative decision, the data gathered were of significant value to hospital and transplantation facility administrators. PMID- 10111405 TI - Humanizing patient care. A new medical paradigm. AB - Is the body of man merely a machine, with disease representing the breakdown of that machine, or should we adopt a more holistic view that reflects the integral relationship of mind, body and the environment? PMID- 10111406 TI - Assuring quality from the ground up. AB - Does your EMS system rely primarily on run-sheet reviews and medical-protocol compliance to ensure systemwide quality assurance? If so, other aspects of your service may be neglected. Provider-based quality assurance stresses employee instituted assessment and improvement of all aspects of a system's operation. PMID- 10111407 TI - The sound and fury at MIEMSS (Maryland Institute of EMS Systems). PMID- 10111408 TI - Worker displacement still common in the late 1980's. PMID- 10111410 TI - QuickDOC: an interlibrary loan department in a microcomputer. AB - Interlibrary loan (ILL) is a critical service in most libraries and one that may consume much staff time. QuickDOC, a software program written by a medical librarian, has been designed to expedite and organize the process of requesting loans, keeping records, and preparing reports on ILL activity. The software communicates with DOCLINE, the automated ILL and referral system of the National Library of Medicine (NLM), and simplifies the management of all borrowing and lending, regardless of how requests are transmitted. QuickDOC's creator is very responsive to suggestions from users and continues to enhance the capabilities of this excellent software package. PMID- 10111409 TI - Development and implementation of a microcomputer-based multi-user MEDLINE system. AB - The Health Sciences Libraries Consortium, a group of health sciences libraries based in Philadelphia, PA, has implemented a MEDLINE database retrieval system based on the CD Plus PlusNet2 system. The system provides access to the entire MEDLINE database file through three centralized servers and four distributed servers, and is accessible over the HSLC wide-area network linking all of its members. This article describes the implementation process, from selection of the system to future development. PMID- 10111411 TI - Issues in information malpractice. AB - In today's information explosion environment, the health sciences librarian is increasingly placed in the role of interpreting, translating, and evaluating information for clientele. With this emerging role and the burgeoning of fee for service programs, the question of information malpractice liability becomes an increasingly important issue. This paper explores the basis for legal actions against librarians and offers some precautionary measures to help protect against such legal action. PMID- 10111412 TI - Decision points in the integrative research review process: a flow-chart approach. AB - With the ever increasing volume of research information appearing in the literature, research syntheses are becoming more popular among researchers in various disciplines. This phenomenon demands application of rigorous and systematic review methodologies. Using Cooper's five-stage process for conducting an integrative research review, the authors have constructed a flow chart for health sciences librarians and others using this approach to identify decision points in this process. The accompanying narrative details the information that must be considered and analyzed. Included in the flow chart and text is an elaboration of meta-analysis and an integrative review to accommodate both quantitative and qualitative research results. A case is made for a collaborative relationship between the researcher and the librarian. PMID- 10111413 TI - IRIS: Integrated Risk Information System database. PMID- 10111414 TI - Hospitals settle charges of filing false claims. PMID- 10111415 TI - Settlement ends dispute over exec's charges he was tricked into leaving post. PMID- 10111416 TI - AHA study shows Medicaid winners, losers. PMID- 10111417 TI - Ore. lawmakers expected to vote on funding for rationing plan. PMID- 10111418 TI - Hospital converts to Catholic rule. PMID- 10111419 TI - Private investor group to buy Denver-area HMO. PMID- 10111420 TI - Major glitches postpone installation of new claims processing systems at Medicare intermediaries. PMID- 10111421 TI - Breadth of children's health problems reported. PMID- 10111422 TI - Ind. hospitals call off merger following probe. PMID- 10111423 TI - AMA votes to fight fee schedule. PMID- 10111424 TI - Healthcare's future holds a shared destiny, not a single-payer system. PMID- 10111425 TI - Foundations get behind the wheel of health reform. AB - Frustrated with the lack of government leadership on healthcare reform issues, private foundations are refocusing their grantmaking strategies to tackle some of the broader issues in healthcare today. Foundations are targeting issues that reflect their individual priorities, but their goals appear to be the same: to enhance access, improve quality and reduce costs. PMID- 10111426 TI - Hospitals find probation by JCAHO not as bad as they had imagined. AB - When the Joint Commission on Accreditation of Healthcare Organizations began conditionally accrediting hospitals two years ago, hospitals projected dire consequences. But interviews with hospitals that have been put on probation for quality problems by the JCAHO show that all regained full accreditation and few suffered any significant financial hardships. PMID- 10111427 TI - Cardiac administration taking off at hospitals. AB - The growth of cardiac services, advances in diagnosis and treatment technology, and the high revenues derived from cardiology services have created an administrative vacuum in hospitals. About 5,500 cardiac administrators are now filling that role, but demand for such administrators likely will rise as advanced cardiac services become available at more hospitals. PMID- 10111428 TI - Hospital developing powerful record system. AB - In what probably sounds like an unusual arrangement, a Texas hospital is hooking up with a nuclear weapons lab as it develops an electronic medical records system. The hospital is tapping the lab's supercomputer to make its Macintosh based system powerful as well as user-friendly. The facility hopes the result is a patient record that's as useful as traditional paper charts and also can be used for research purposes. PMID- 10111429 TI - Stark blasts AMA for opposing physician payment reform plan. PMID- 10111430 TI - Ad campaign announces San Francisco merger. PMID- 10111431 TI - Facilities now must tell all to lenders to get lines of credit, short-term loans. PMID- 10111432 TI - Pa. admission rates vary. PMID- 10111433 TI - AMI posts quarter's profit. PMID- 10111434 TI - Groups criticize plan to care for VA dependents. PMID- 10111435 TI - M.D. Anderson begins expansion. PMID- 10111436 TI - Deere hires Mayo to help plan, operate primary-care facility. PMID- 10111437 TI - Healthcare Affiliated delays Fusion's roll-out. PMID- 10111438 TI - HBO streamlining operations of two subsidiaries; 130 jobs cut. PMID- 10111439 TI - Moody's changes evenly split in first half of '91. PMID- 10111440 TI - Researchers say systems should use better yardstick to measure performance. PMID- 10111441 TI - Incentives hike Mass. costs--study. PMID- 10111442 TI - SunHealth aims to set 'benchmarks' for managers. PMID- 10111443 TI - Practice guides, managed care save big--AHA. PMID- 10111444 TI - Raise physician fees for Medicaid--PPRC. PMID- 10111445 TI - VHA Enterprises to sell assets, cease operations. PMID- 10111446 TI - Calif. HME dealer under FTC antitrust investigation. PMID- 10111447 TI - Whether to blow the whistle requires careful consideration. PMID- 10111448 TI - CONspiracies to crush competition. Hospitals using CON laws to thwart rival's projects. AB - In their eagerness to protect their market share and check advances by rivals, hospitals are trying to use state certificate-of-need laws to their advantage. Some hospitals are clinging to CON laws, which require state approval of new construction and renovation, because they protect them from competitors who threaten their market. A look into CON wars in five states uncovers some competitive tactics. PMID- 10111449 TI - Ruling leaves decisions about medical care in hands of family. PMID- 10111450 TI - HMOs form networks to serve firms with offices in more than one region. AB - Health maintenance organizations are establishing administrative links nationwide in response to concerns from the business community about cost and quality. At least six HMO groups have formed to service companies with offices in more than one part of the country. Industry experts point out that hospitals on good business terms with successful HMOs in their areas stand to benefit through increased volume and prestige. PMID- 10111451 TI - Income guarantee is hospitals' lure of choice. AB - Income guarantees are hospitals' lure of choice when trying to reel in physicians to their facilities. More than 90% of hospitals responding to a recent survey offer the income guarantees, which recruiters say physicians have grown to expect. Some 74% of the hospitals require physicians to repay the loan but will forgive the loan if the physician agrees to take on administrative or clinical duties at the hospital. PMID- 10111452 TI - Mathis chosen as AHA's new chairman-elect. PMID- 10111453 TI - Samaritan Health Services dissolving physician joint venture in Phoenix. PMID- 10111454 TI - Short sellers betting chain's stock will drop. PMID- 10111455 TI - Some bond deals may be overpriced--study. AB - A new study suggests hospitals often pay too high a price when they seek help from investment banks to arrange for the sale of bonds on a negotiated basis. The study says the premium amounts to an average of 75 basis points more in interest over the life of the bonds in such deals. But investment firms say the study's comparisons are flawed, and that costs often reflect deals structured specifically for a given facility. PMID- 10111456 TI - Hospitals feel pain of states' budget cutting. PMID- 10111457 TI - Mass. governor seeks reimbursement overhaul. PMID- 10111458 TI - Louisiana approves new governance of Charity. PMID- 10111459 TI - Pittsburgh hospital settles tax dispute. PMID- 10111460 TI - Do surgical prep sets need to be sterile? PMID- 10111461 TI - Outpatient clinic abuses spur call for new legislation. PMID- 10111462 TI - Training nursing assistants for the OR. PMID- 10111463 TI - Mobile OR brings surgery to the patient. PMID- 10111464 TI - Self-managed teams in a day surgery unit. PMID- 10111465 TI - A case of bad blood. Transfusion risks are low, but here's how to make them even lower. PMID- 10111466 TI - The evolution of an art therapy position. PMID- 10111467 TI - Shaking hands. Building partnerships in healthcare. PMID- 10111468 TI - The community of hospital and freestanding imaging centers. PMID- 10111469 TI - Cost containment in healthcare delivery. AB - Progressive increases in medical care costs can not continue. Resistance from those who pay the costs--businesses, the government, and individual consumers--is increasing. The cries for greater government insurance and control are becoming louder. Healthcare organizations trying to cut costs often simply reduce staff across-the-board instead of developing ways to reduce the costs related to individual functions performed. More attention must be given to reducing costs by improving processes. Here, healthcare and radiology specifically can take some lessons from the business world. PMID- 10111470 TI - Strengthening the keystone. The individual's response to worksite stress. PMID- 10111471 TI - Digital radiography with phosphor plates. PMID- 10111472 TI - On the road. Planning and operating a mobile mammography program. PMID- 10111473 TI - Why reinvent the wheel? The tumor registry as a radiation oncology quality assurance data base for hospitals. AB - The Tumor Registry wheel has a sound, tested, basic design and could serve the dual purpose of a Radiation Oncology QADB. Many of the issues raised by Williamson regarding a QADB have already been addressed and tested by the Tumor Registry and commercially available Tumor Registry software. Registry personnel are trained in this type of data collection, coding and reporting. You may already have a Tumor Registry that has the capacity to provide this service to your department with the addition of only minimal efforts. If your Tumor Registry only collects minimal data now, it is probably because it has only minimal support and use. If you choose to utilize the Tumor Registry for your Radiation Oncology QADB, your department can provide additional support in many ways in return for the services provided to you. Maximum support can be given by assuming full responsibility and locating the registry in the Radiation Oncology cost center. As mentioned earlier, many Radiation Oncologists have recognized the variety of benefits derived from this situation. Other forms of assistance might include financial support for the upgrading of computer hardware and software required to facilitate these new needs, or by providing additional secretarial personnel, possibly on a part-time basis. Support voiced to the administration from the Radiation Oncologist for the need and use of the Tumor Registry can be helpful in getting approval for upgrading tumor registry equipment or obtaining adequate personnel. Developing a symbiotic relationship between these two departments can strengthen the entire Cancer Program as well as each of the individual departments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10111474 TI - The new pyramid: laying the groundwork with motivational power. AB - To successfully implement a comprehensive, progressive management system, a manager must incorporate daily administrative or executive principles and duties with an array of motivational tactics. Various motivational strategies have been discussed since the generation of industrial psychological research, which is generally conceded to have had its genesis with Abraham Maslow. Maslow's simple premise regarding man's needs for self-esteem, security and affiliation is at the root of many theories and practicums in vogue today. PMID- 10111475 TI - The practical value of computer literacy. PMID- 10111476 TI - Federal activities related to health and economic outcomes. PMID- 10111477 TI - Team effort: the nuclear medicine decision making process. Part II. AB - This two part article examines the nuclear medicine purchase of Baptist Memorial Hospital in Memphis, the largest private hospital in the nation. Part I (May 1991) focused on what their needs were. This concluding installment looks at the committee mechanism itself and the reasoning that went behind their decisions. PMID- 10111478 TI - Quantitating quality: a medical physics management model. PMID- 10111479 TI - What QA is and isn't. What TQM is and isn't. PMID- 10111480 TI - Education and TQM. PMID- 10111481 TI - Strategic planning for bioethics committees and networks. PMID- 10111482 TI - Hospital staff perceptions of the ethics committee and the Bioethics Institute: a multi-disciplinary approach (Northridge Hospital Medical Center, California). PMID- 10111483 TI - Hospital ethics committees revisited: a pediatric neurosurgical perspective. PMID- 10111484 TI - Point and counterpoint. Should HECs provide advice counter to the law when they believe it inappropriate? PMID- 10111485 TI - Epidemiological use of NHS activity data. AB - The primary purpose of the medical record is to support clinical care of patients by keeping an accurate record of their condition and of treatment given or planned; its second role is as a source of information for management; but its uses do not end there. Both the medical record itself, and information derived from it at one or more removes, are important tools in medical research, audit and evaluation of services. This paper describes the use of routine NHS activity data in general, and the medical record in particular, in epidemiology. As the author works at the Institute of Child Health, most of the examples cited involve children. PMID- 10111486 TI - Periodic evaluation of medical record organisational needs. AB - There is a need periodically to evaluate each and every department in the hospital, to assess and take appropriate action on time, to provide the best possible service to patients and to meet the set goals of the hospital. The medical records department cannot be an exception to this. In fact, medical records is one of the most important service departments in the hospital and one which plays a very crucial role in rendering efficient patient care. As such it is imperative regularly to evaluate the medical record organisational needs, including the work performed by the Department and its staff. In Riyadh, a quarterly report in the following prescribed proforma has to be submitted to the following: Medical Records Committee; Quality Assurance Committee; Hospital Administrator; Government; by specified dates. PMID- 10111487 TI - Quality approach to records and information management in the South Western Region. AB - A few months before the introduction of "Working for Patients" the South Western Regional Health Authority published a document called 'Better Patient Care' which outlined the need to focus the plethora of unco-ordinated national directives on such matters as medical audit, internal markets and resource management into a coherent practical approach to the provision of patient care in the Region. The advent of the White Paper was therefore not such a cultural shock to us. 'Better Patient Care' recognised that a major requirement for practical success was good information which should provide timely, concise, accurate and well presented information about the quality and utilisation of resources. It also acknowledged that a major consideration in defining information requirements was that they should be extracted from the data collected for operational needs and from operational systems. The need for relevant training for all staff engaged in the records and information fields was also emphasised. PMID- 10111488 TI - The compendium of standards for health records and the National Vocational Qualification. PMID- 10111489 TI - Capital charging to the rescue. PMID- 10111490 TI - The art of public speaking. PMID- 10111491 TI - Novel use of building controls keeps power up and pollution down at hospital energy centre. Trend Control Systems Ltd. PMID- 10111492 TI - New lamps for old. PMID- 10111493 TI - Environmental Protection Act 1990--Part I. PMID- 10111494 TI - Relocation buyer's guide. Suppliers and services in employee relocation. PMID- 10111495 TI - Designing management reports. PMID- 10111496 TI - Teamwork boosts quality at Wallace. AB - When the Wallace Co. ran into the oil-industry slump of the mid '80s, the company shifted gears to focus on long-term quality improvement. The increased emphasis on training and customer service won them the Baldrige Award in 1990. PMID- 10111497 TI - Performance measures that work. AB - Measuring white-collar productivity is difficult in any setting but the complex operations of hospitals--where work load can vary hour to hour--are now being measured for peak efficiency. By developing standards and working with formulas and computer models, HR professionals are measuring productivity and predicting staffing needs. PMID- 10111498 TI - Paying for team results. AB - When employees work in teams, the whole organization benefits with better results and increased profits. But what benefits do employees get as a result of teamwork? How can their attention be properly focused on the kinds of results the organization needs? And, how should they be rewarded for producing the desired results? Let's explore the options. PMID- 10111499 TI - Merger management HR's way. PMID- 10111500 TI - Set the stage for employee involvement. PMID- 10111501 TI - Writing a winning position statement. PMID- 10111502 TI - HRIS buyer's guide. Supplies and services in human resource information systems. PMID- 10111503 TI - Advance directives. Head of steam builds for implementing PSDA (Patient Self Determination Act). AB - As the December 1 deadline for implementing the Patient Self-Determination Act (PSDA) nears, a variety of organizations are gearing up to offer programs and suggested policies to meet the act's requirements. The following articles summarize some uncertainties or problems areas related to interpretation of the act, some resources to draw on, and some concerns over areas not covered by the act. PMID- 10111504 TI - Popularity of ethics committees seen in nonhospital ventures. AB - Ethics committees, as a means of focusing discussion and reviewing options regarding ethical problems, is catching on. National consumer organizations are endorsing them, provider groups are acknowledging them, communities are exploring their use in noninstitutional settings, and institutions continue to search for the appropriate committee framework that works for them, as the following articles show. PMID- 10111505 TI - Marissa and Alyssa--new names in transplantation frontiers. AB - As the national media focused attention on teenager Anissa Ayala who received a transplant of marrow cells "donated" by her baby sister, Marissa, who was conceived for the purpose of providing the marrow, a less publicized unsuccessful transplant procedure performed on Alyssa Plum a month earlier probably poses a greater challenge to ethical analysis. The following articles describe both stories. PMID- 10111506 TI - Courts continue to plod through Wanglie and Busalacchi cases. AB - Midwest courts still continue to carry the brunt of the ethics caseload of interest to the nation as a whole, and by the slow pace they seem to be taking in moving the cases along, one wonders whether the load is a burden. The following articles update three ongoing cases, and then look at one study that tries to find out just how heavy the ethics caseload is for the lower courts. PMID- 10111507 TI - State legislatures become beehives of right-to-die statutes. AB - Since the U.S. Supreme Court ruling on Cruzan, state legislatures have passed an unprecedented amount of new advance directives legislation or changes in their existing living will laws. Forty states now have laws on advance directives. Some of the more recent actions, as well as one state's public initiative, are summarized in the following articles. PMID- 10111508 TI - Gagging the clinics. PMID- 10111509 TI - AIDS moves in many ways. PMID- 10111510 TI - Audit requirements for institutions of higher education and other nonprofit organizations--Department of Commerce. Interim final rule with request for comments. AB - The Department of Commerce is implementing Office of Management and Budget (OMB) guidance provided in Circular A-133, "Audits of Institutions of Higher Education and Other Nonprofit Organizations." As a result of this interim final rule, institutions of higher education and other nonprofit organizations that receive Federal assistance are required to periodically perform audits and submit the audit reports to the Federal government. This interim final rule establishes uniform audit requirements applicable to these organizations and defines the Department's responsibilities for implementing and monitoring these requirements. PMID- 10111511 TI - National emission standards for hazardous air pollutants--EPA. Final rule. AB - Today EPA is staying the effectiveness of subpart I of 40 CFR part 61, the National Emission Standards for Hazardous Air Pollutants for Radionuclide Emissions (54 FR 51654, December 15, 1989) as applied to facilities licensed by the Nuclear Regulatory Commission or an Agreement State ("NRC-licensed facilities"), other than nuclear power reactors, until November 15, 1992. The purpose or this rule is to afford EPA the time required to make an initial determination pursuant to section 112(d)(9) of the 1990 Clean Air Amendments before subpart I becomes effective for such facilities. EPA intends to propose a rule pursuant to section 112(d)(9) to rescind subpart I for nuclear power reactors, and to take final action no later than June 30, 1991, concerning a separate proposal to stay the effectiveness of subpart I for nuclear power reactors during the pendency of the rulemaking on recission. This rule staying subpart I for NRC-licensed facilities other than nuclear power reactors, and the Agency's final action on its proposal to stay subpart I for nuclear power reactors, will completely supplant all stays previously entered for such facilities during the Agency's reconsideration of subpart I under Clean Air Act section 307(d)(7)(B). PMID- 10111512 TI - Medicare program; criteria and standards for evaluating common working file hosts -HCFA. General notice with comment period. AB - This notice describes the criteria and standards to be used for evaluating the performance of Common Working File (CWF) hosts in the administration of the Medicare program, for the current evaluation period beginning June 1, 1991. The results of these evaluations will be considered whenever the Health Care Financing Administration enters into, renews/extends, or terminates a Medicare carrier contract which provides for the performance of CWF host services. Since these services are currently performed by Medicare carriers, this notice is published in accordance with section 1842(b)(2) of the Social Security Act which requires us to publish for public comment those criteria and standards against which we evaluate Medicare carriers. PMID- 10111513 TI - Medicare Program; OBRA '87 conforming amendments; correction--HCFA. Final rule; correction. AB - Federal Register document No. 91-4415, beginning on page 8832 of the issue of Friday March 1, 1991, conformed numerous sections of the HCFA regulations with self-executing provisions of the Omnibus Budget Reconciliation Act of 1987. A one page revision, dealing with the application of the Medicare blood deductible, was unintentionally omitted from column 2 of page 8852, where only the heading "P. Part 489" appears. Also omitted was a conforming change needed in section 482.12(c)(1)(iv) to reflect the amendment made by section 9336(a) of the Omnibus Budget Reconciliation Act of 1986 (Pub. L. 99-509). Section 9336(a) removed the provision that limited Medicare coverage of optometrist services to aphakia. This means that any optometrist services permitted by State medical practice laws are now covered. This notice corrects the omissions by publishing the amendment to part 489, which was discussed in section "D" of the preamble in the first column of page 8834, and including the revision of section 482.12(e)(1)(iv). The notice also makes numerous other minor corrections. PMID- 10111514 TI - Position paper on the role of occupational therapy in paediatrics. Canadian Association of Occupational Therapists. PMID- 10111515 TI - The participation of mental health consumers in health care issues. PMID- 10111516 TI - A vision for occupational therapy: tradition meets the future. AB - Advancing technology and world events will have an impact on the practice of occupational therapy. Computers, communication technology, and environmental concerns are all examples of issues that must be considered as major determinants in future practice decisions related to all groups. Incorporating these areas into the traditions of occupational therapy will result in a vital profession that cannot be replaced. However, these advances and events must not sway occupational therapists from their area of expertise. Technology will never be mastered if the profession continues to stray into areas of practice that do not form the core of occupational therapy. PMID- 10111517 TI - Managing paperwork: problem solving for job satisfaction. PMID- 10111518 TI - The split placement model for fieldwork placements. AB - There continues to be a shortage of placements in Canada for fieldwork education. It is crucial for occupational therapists to explore and implement a variety of supervision alternatives to maximize the utilization of fieldwork sites. This paper describes a model of split clinical placements, one in which students divide their time between two therapists who work in either different areas of clinical practice or in the same area of clinical practice. The supervision strategies that are most effective with this model are discussed as well as the advantages and disadvantages of this approach. PMID- 10111519 TI - Residency education: is it part of the future for your medical group? AB - This paper focuses on the changes affecting residency training programs (graduate medical education). It presents a brief historical perspective on the financing of residency training, explores alternatives that training programs are experimenting with, and proposes a model for experimentation. The impact of these changes on group practice are assessed and recommendations made to assist medical groups in preparing for the future. PMID- 10111520 TI - The relationship between management practices and financing of family practice residency training programs. AB - This paper summarizes almost ten years of investigation in the area of financing of Family Practice Residency Training Programs. The author has been a co principal investigator in this effort with responsibility for administration of two national surveys to study financing of the programs. PMID- 10111521 TI - Indicators of mental hospital bed use. AB - This study explored the use of survivorship curves as a type of indicator of lengths of hospital stay. Using data from the psychiatric services of a single Region, an attempt was made to determine the existence of a performance indicator with the advantages of fixed cohort analysis. By comparison with the proposed Department of Health indicators, this approach offers advantages in that it is less distorted by the presence in a District of large numbers of long-stay beds. However, although the findings show that patients are discharged more slowly from Districts with a large mental hospital and that a greater proportion of patients are still resident one year after admission, it is important to stress that measures of bed use of this type alone are not an indication of the quality of psychiatric services provided. PMID- 10111522 TI - Out-of-hours duties in public health medicine: a survey of doctors in the Yorkshire Region. AB - A survey of doctors involved in out-of-hours public health medicine was conducted in the Yorkshire Region. Although the majority were satisfied with their present arrangements and had received some formal training for such duties, the study revealed potential areas for improvement. A review of current responsibilities and education is indicated. PMID- 10111523 TI - Trauma care since 1988. PMID- 10111524 TI - All day drinking--its impact on an accident and emergency department. AB - In order to assess the impact of changes in the Licensing Laws in England, a prospective study was undertaken of patients attending the Accident and Emergency Department of the Newcastle General Hospital. Patients were breathalysed in October 1986, before the liberalisation of the Licensing Laws in England and Wales and again in October 1988, after this change. A blood alcohol level of greater than 50 mg/100 ml was detected in 13% of all attenders in 1986 and 14% in 1988. A comparison of the two years revealed no significant change in the number of patients who had ingested alcohol prior to attendance, although there was a trend towards increased frequency of alcohol ingestion in nighttime attenders. PMID- 10111525 TI - Variations in the provision of extended-trained ambulance personnel within the Welsh ambulance services. AB - This paper describes the distribution of extended-trained ambulance personnel within the nine Welsh Ambulance Services. While over a quarter of all emergency ambulance crews possess some extended skills, there is a wide variation in their distribution and protocols of treatment. Increasing numbers of ambulance personnel will receive such training in the future, leading to improved standards of pre-hospital care. To justify the use of such skills in terms of clinical outcome and expenditure, the ambulance services must provide accurate data to allow subsequent audit of pre-hospital clinical practice. It is therefore essential that the medical profession becomes aware of these developments and participates in advising, assessing and training extended-trained ambulance personnel. PMID- 10111526 TI - Epidemiology of deliberate self-poisoning: trends in hospital attendances. AB - A number of reports have suggested that the incidence of deliberate self-harm has been declining since the late 1970s. Most of these findings have emerged from studies of hospital inpatients, but a large proportion of patients are sent home directly from Accident and Emergency Departments. This study, based in the Nottingham Accident and Emergency Department, looked at attendances for deliberate self-poisoning over four separate years in the period between 1981 and 1988. The findings show a slight reduction over time in the number of attendances and overall rates, with age-specific rates holding steady for the younger age group (15-34 years), but diminishing as age increases. It is argued that age specific trends, based on inpatient statistics, could be distorted by Accident and Emergency discharges. It is recommended that future epidemiological studies of deliberate self-harm include patients who progress no further than the Accident and Emergency Department. PMID- 10111527 TI - Deliberate self-poisoning: the need for a new approach. AB - New community-based preventive initiatives are required if a reduction in deliberate self-poisoning is to be achieved. Local epidemiological data can be used in a health education approach, directed at professionals who have the most contact with potential cases of deliberate self-poisoning and also to those people falling within identified high-risk groups. Such initiatives require defined outcome measures and a number are proposed. The implications for data collection on deliberate self-poisoning are discussed. PMID- 10111528 TI - What are our patients taking? Do simple instructions help us to find out? AB - In 1989, a survey was undertaken in Nottingham to see whether patients could be encouraged by an oral, or written and oral instruction, to bring all their medication with them to the medical clinic. The medication brought was then compared with the prescription in the hospital case notes. Patients attending a medical clinic were randomly allocated into three groups; the 'oral' group was asked to bring their medication to their next appointment; the 'written' group had this request emphasised in writing; and the 'controls' were given no instruction. Although there was statistically no significant difference between the oral and written group, they both brought more medications than the controls. The survey found discrepancies between the medication taken and that recorded in the case notes of 20% of patients. These findings suggest that an oral instruction reinforced by a written reminder produces greater patient co operation and provides the means for validating prescribed medication. PMID- 10111529 TI - Distinction awards: analysis by type of award, specialty and percentage distribution at 31 December 1989--England and Wales. PMID- 10111530 TI - Medical and dental staffing prospects in the NHS in England and Wales 1989. Medical Manpower and Education Division, Department of Health. AB - The Medical Manpower and Education Division of the Department of Health publishes information in this Journal each year on the current state of medical and dental manpower in England and Wales, to assist medical and dental students and newly qualified doctors and dentists in their career choices. Additional information can be obtained from the national and regional census tables which are usually published by the Department of Health each Autumn. These are circulated widely to all health authorities, postgraduate deans and clinical tutors. Information based on census data is useful, but is always for the previous year. It should be used to consider trends in medical manpower prospects. PMID- 10111532 TI - To profit or not to profit. PMID- 10111531 TI - Telephone etiquette for the development office. PMID- 10111533 TI - Writing and development--Part IV. Soaking up the passion. PMID- 10111534 TI - On hiring a consultant. PMID- 10111535 TI - Responding to donor signals. PMID- 10111536 TI - Electric cadavers, 'metiphor,' and other medical software marvels. AB - "Grateful Med," "Fluids," "Metiphor," virtual reality, and electric cadavers are just some of the programs and buzzwords in the futuristic world of medical software affecting many areas of health care. PMID- 10111537 TI - Pioneers of the new balance. PMID- 10111538 TI - Bone marrow transplant offers limited potential. PMID- 10111539 TI - Matrix sorts hospital issues for urgent or long-term plan. AB - The strategic planning process requires many tools in determining and acting on the issues that will influence a hospital's future. To efficiently and effectively launch a strategic plan, administrators must begin by prioritizing problems and opportunities so that they are proactive rather than reactive. In the following article, the author suggests a matrix system that will aid in that effort. PMID- 10111540 TI - Teleservices center puts a new twist on an old concept. AB - Telemarketing has been used for decades to increase revenues for companies in every industry. But how can a Teleservices Center (TSC), the next generation of the telemarketing scheme, fit into a hospital's strategy for growth? The author suggests the importance of this technique to increase referrals and the number of physicians bonded to the institution. PMID- 10111541 TI - Thorough planning critical to total quality management. PMID- 10111542 TI - Planning indicators. Survey shows lack of understanding of benefits. PMID- 10111543 TI - Systems require visionaries. Interview by Donald E. L. Johnson. AB - If metropolitan and regional multihospital systems are to be an integral part of the future of health care, what will separate the successful systems from the unsuccessful ones? How do administrators bring hospital medical staff members together in a cohesive, cooperative team? In the following interview with Health Care Strategic Management publisher, Donald E. L. Johnson, Don L. Arnwine, former hospital chief operating officer and current president of Arnwine Associates, discusses the elements of a successful multihospital system. Arnwine Associates is an Irving, Texas-based consulting firm. PMID- 10111544 TI - An interview with: Richard S. Kuhlman on what to do when you are sued. PMID- 10111545 TI - Protecting your hospital's drug inventory--in and out of the pharmacy. PMID- 10111546 TI - Canada's universal-comprehensive healthcare system. AB - The Canadian healthcare system consists of provincial- and territorial-based health insurance plans that provide universal-comprehensive coverage for medically necessary hospital and physician services, the public funding of healthcare with no financial-access barriers, and the private delivery of care. A profile of the Canadian system and its expenditures fosters some noteworthy comparisons between Canadian and U.S. healthcare. PMID- 10111547 TI - Healthcare for a new Germany: the West and East German health systems and their unification process. AB - One of the new Germany's many challenges will be merging a socialist, centralized healthcare system with a decentralized network much like our own. Both Germanys' health services have clear pluses and minuses, and while preserving the best of each may not be completely possible, it is not as remote a goal as one might think. With a summary of the pre-unification East and West health systems, the authors map out Germany's healthcare options. PMID- 10111548 TI - Changes and challenges in China. Is the "open policy" closing doors in Chinese hospitals? AB - Since 1978, China's economic reforms and her pursuit of modern technology have significantly opened the scope of her hospital services and financing. While the decentralization and higher incomes have given Chinese hospitals new freedoms, they have also raised the specter of new limitations on access to healthcare. The authors review these changes and consider what the future holds for the Chinese hospital system. PMID- 10111549 TI - A search for new approaches: learning from the international community. PMID- 10111550 TI - Time control: stress. PMID- 10111551 TI - Electronic signatures: one hospital's approach. PMID- 10111552 TI - Voice-recognition technology: key to the computer-based patient record. PMID- 10111553 TI - Selecting and implementing a computerized severity of illness system. AB - Identifying all the variables may be a formidable task. However, doing so ensures accuracy in selecting and implementing an appropriate product. A task checklist is an essential tool in making comparisons so that the vendor you select is suited to your needs. Any methodology can be chosen, but it is important to think of an SOI system as a tool and not the answer to solving quality assurance problems. PMID- 10111554 TI - The Uniform Clinical Data Set (UCDS). AB - UCDS is an expert system designed to make PRO review more consistent from State to State and to provide for the collection of clinical data which can be used to monitor the Medicare Program in a more uniform way. It will become the basis of PRO monitoring of Medicare inpatient hospital care in the near future. PMID- 10111555 TI - One flag, many worlds. Health issues at the border. AB - The U.S.-Mexican border divides two countries with widely differing priorities and expectations--and inseparable health, environmental, economic and cultural concerns. One half of this 2,000-mile border is in Texas. HealthTexas looks at border health, as typified by communities at either end of the state. Later this year, HealthTexas will examine how Texas hospitals market to Mexico. PMID- 10111556 TI - Energy conservation opportunities for hospitals. PMID- 10111557 TI - Utility audits. PMID- 10111558 TI - Chicken pox exposure form simplifies follow-up. PMID- 10111559 TI - The constitutionality of damage limitations. PMID- 10111560 TI - Accustomation course now required for foreign nurse graduates. PMID- 10111561 TI - Staffing management software has a variety of applications. PMID- 10111562 TI - Reporting dangerous and unsafe medical devices. PMID- 10111563 TI - Pointing the way: corporate ethics in health care. PMID- 10111564 TI - Recruiting today's franchise players--OB/GYNs. PMID- 10111565 TI - Texas hospitals under universal access. PMID- 10111566 TI - Temporary foreign nurses. PMID- 10111567 TI - Roll-call after roll-out. PMID- 10111568 TI - Tilting at those rubber windmills. PMID- 10111569 TI - Both a will and a way. PMID- 10111570 TI - Evaluation of drug-food/nutrient interactions microcomputer software programs. AB - Eight drug-food/nutrient interaction microcomputer software programs were evaluated and compared using specific criteria defined for these programs. This article summarizes and compares the features, ratings, advantages, and disadvantages of each program. There are no excellent drug-food/nutrient interactions programs. Three programs performed equally well and should be considered. These are Medicom Micro, Drug Therapy Screening System and RxTriage. PMID- 10111571 TI - Twenty-four-hour controlled substance documentation system: the optimal way to monitor use in the nursing units. AB - Accountability for the use of controlled substances in the nursing units is a top priority for nursing and pharmacy administration in any health-care institution. After several discrepancies were found in inventory at the John F. Kennedy Memorial Hospital in Indio, California, the pharmacy department revised the controlled substance handling system in the hospital and implemented a 24-hour controlled substance recording system. The system provided greater accountability and allowed follow-up on any discrepancy within the next shift. The system has been highly successful. There had been six discrepancies in 12 months before implementing the system. There has been no incident of discrepancy in the last 31 months. The authors conclude that 24-hour controlled substance documentation system is very effective in providing greater accountability and control over controlled substance use in the nursing units. PMID- 10111573 TI - Legal issues--1991. PMID- 10111572 TI - The rural hospital crisis. PMID- 10111574 TI - Drug formularies--1991. PMID- 10111575 TI - An investigation of the optimization of search logic for the MEDLINE database. AB - One of the key variables in the optimization of the retrieval process is the logic imposed on a set of query terms. If the query is small, a combinatorial algorithm can be employed to identify search expressions having an optimal logical form. An experiment is described in which this was done for queries expressed against MEDLINE, for a variety of criterion variables. The method employed is useful not only for assisting in identifying optimal logical forms, as demonstrated, but also as an experimental control device to assist investigations into the effects of varying the set, and number, of search terms. The experiment also suggests several novel properties of effective searching against MEDLINE, for example that searching with four MeSH terms is likely to be more successful than searching with a lesser number of terms, provided search logic is optimal. The latter result is, surprisingly, true for both Precision and Recall, i.e., a tradeoff between the maximally attainable values of these variables fails to hold when the number of search terms varies in this range. PMID- 10111576 TI - The Medline/full-text research project. AB - This project was designed to test the relative efficacy of index terms and full text for the retrieval of documents in those MEDLINE journals for which full-text searching was also available. The full-text files used were MEDIS from Mead Data Central and CCML from BRS Information Technologies. One hundred clinical medical topics were searched in these two files as well as the MEDLINE file to accumulate the necessary data. It was found that full-text identified significantly more relevant articles than did the indexed file, MEDLINE. The full-text searches, however, lacked the precision of searches done in the indexed file. Most relevant items missed in the full-text files, but identified in MEDLINE, were missed because the searcher failed to account for some aspect of natural language, used a logical or positional operator that was too restrictive, or included a concept which was implied, but not expressed in the natural language. Very few of the unique relevant full-text citations would have been retrieved by title or abstract alone. Finally, as of July, 1990 the more current issue of a journal was just as likely to appear in MEDLINE as in one of the full-text files. PMID- 10111577 TI - Organ transplants: deciding who lives, who dies and who pays. PMID- 10111578 TI - Nursing homes demand more Medicaid cash. PMID- 10111579 TI - Agency for Health Care Policy and Research: the new player in health care. PMID- 10111580 TI - New accounting rules will have immediate impact on health care industry. PMID- 10111582 TI - Grid-based design and 'team approach' boost chart-room efficiency. PMID- 10111581 TI - Hospital information systems contracts: navigating through the forest. PMID- 10111583 TI - Seeing the big picture: seven basic principles of fire risk management. PMID- 10111584 TI - Wayfinding in health care: 6 common myths. PMID- 10111585 TI - PTSM standards mean written utility-failure plans. Part 2. PMID- 10111586 TI - Cloth diapers benefit bottoms and bottom lines. PMID- 10111587 TI - Cleaning and caring: what the future holds for us. PMID- 10111588 TI - Eight-step audits help ensure smart utility buys. PMID- 10111589 TI - Hospital sees its child care facility as "fringe benefit for the 1990s". PMID- 10111590 TI - 4 basic approaches key to health-facility design. PMID- 10111591 TI - Post-occupancy audits: expectations vs. reality. PMID- 10111592 TI - Telecom manuals set policies, help train staff. PMID- 10111593 TI - How to set up a facility wide recycling program. PMID- 10111594 TI - Tracking patient-supply charges: yea or nay? PMID- 10111595 TI - Managers' perceptions of customers' satisfactions with their hospital cafeteria services. AB - It is important that hospital cafeterias deliver products that create customer satisfaction so that financial objectives are met. An exploratory descriptive survey of 12 selected hospital cafeterias used a self-administered questionnaire to determine how satisfied customers were with services provided. It also asked cafeteria managers to give their perceptions of their customers' relative satisfaction/dissatisfaction with the service. Principal components analysis, followed by varimax rotation, identified four underlying constructs of the 15 pre selected foodservice characteristics used to measure relative satisfaction. A multiple regression model, controlling for country, hospital size and customer demographics, in which the dependent variable was overall rating, found that the independent variables, the underlying rating constructs--food and service--made a much greater impact on overall rating than environment and accessibility. Most cafeteria managers' predictions about their customers' satisfaction were within two standard deviations of their customers' mean scores of satisfaction. While the managers' close association with their service may have accounted for this, it does not necessarily follow that they have the power to implement policy and product improvements. PMID- 10111596 TI - Hospitals look for alternatives to capital equipment buying. PMID- 10111597 TI - Price survey. Urological catheter prices up 5%-9%. PMID- 10111598 TI - Hospital purchasers expect declining overlay demand to hold price hikes to a minimum. PMID- 10111599 TI - Georgia hospital gearing up to offer sterile/laundry/incineration services to others. PMID- 10111600 TI - HMM pricing index/price watch. PMID- 10111601 TI - GPOs and their product evaluation committees should be aware of their legal liabilities. AB - A materials manager for a large group purchasing organization is a member of a committee involved in the decision as to which products and equipment are purchased for and used by the hospitals belonging to the GPO. These decisions are based upon requests from the member hospitals and proposals submitted to the GPO by suppliers. After review by the committee, a decision to buy is made. In this dialogue, Dr. Decker discusses the issues of legal liability assumed by the GPO, the committee and its individual members in making these decisions on which to buy. PMID- 10111602 TI - Estate management. PMID- 10111603 TI - Appreciating managers in the NHS. AB - The redefined roles within the NHS, and the changed organisational structures required to meet the challenges of the purchaser/provider environment, are bringing an unprecedented state of flux between organisations and their staff. New roles and altered responsibilities, more fluid organisational structures, all increase the risk of individuals being placed in inappropriate positions. Each one of these mismatches, argue Michael Church and Derek Houghton, represents a misuse of our most valuable resource--people, and is a cost or waste for the organisation. PMID- 10111604 TI - A difficult choice. AB - In their new role as purchasers health authorities will have to make difficult decisions about priorities. This, argues Brian Salter, is inevitably a political process and DHAs should not persuade themselves that there are objective approaches which avoid political pressures. PMID- 10111605 TI - Monitoring waiting times in out-patient departments. PMID- 10111606 TI - Can we get doctors to use computers? AB - David Young argues that although doctors are interested and willing to use computers, in general they do not use them in health care. It is a complex matter, but an important reason is that the system designers have ignored the clinical environment and the motivation of doctors. In particular the conventional approach to data input is inappropriate, and he suggests a better way. PMID- 10111607 TI - Recruitment in the 1990s--the case of radiographers. AB - During the 1990s it will be increasingly difficult to recruit from school leavers enough radiographers and other professions allied to medicine. Various strategies have been suggested for meeting the difficulty. Rosemary Klem examines these from an economic perspective and looks at the implications for managers. PMID- 10111608 TI - Specifications for hospital medical audit. PMID- 10111609 TI - Rules of engagement: key factors in the successful management of interagency projects. AB - In recent years the implementation of community care policies in relation to the mentally ill has led to increasing collaboration between the caring agencies. Unfortunately early experience has shown that joint projects employing multidisciplinary mental health teams are difficult and time consuming to manage. Phillip Vaughan comments on some of the difficulties encountered by such teams and offers suggestions for their remedy. PMID- 10111610 TI - TEACH--Information Management and Technology (IMT): training for health service managers and professionals. PMID- 10111611 TI - Management options for pathology laboratories. PMID- 10111612 TI - Commissioning new buildings: equipment. AB - Any new building will, with occasional exceptions, require new furnishings and equipment. In principle the organisation of this is straightforward. In practice it is a complicated exercise, full of snags. Phillip Simons discusses some of the problems. PMID- 10111613 TI - Out-patient services. PMID- 10111614 TI - Efficiency audits. PMID- 10111615 TI - Recent changes in the California health care delivery system, Part I. PMID- 10111616 TI - Selective contracting revisited: California's legacy. PMID- 10111617 TI - California's uninsured: the problem and proposed solutions. PMID- 10111618 TI - Ambulatory care in the public sector: perinatal care in Los Angeles County. AB - In planning its response to the increasing demand for perinatal services and the increasing rate of infant mortality and low-birthweight infants the Los Angeles County Department of Health Services faces a formidable set of tasks. Initiatives already in place are attempting to deal with some of the most pressing problems. However, increased services must be made available to enable the increasing number of women to access the system of care, and further outreach is necessary to encourage more women to begin prenatal care early in pregnancy. The county needs to increase the availability of perinatal care services, and these services must respond to the cultural and socioeconomic needs of pregnant women. Financial barriers to care must be eased, and the process of qualifying for Medi-Cal must be simplified. Additional private providers need to be brought into the system, and alternative care providers--such as birthing centers and delivery by midwives -should be expanded for low-risk pregnancies. The DHS has been forced to respond to staggering increases in demands for perinatal care services, and the population pressures and the widening socioeconomic gaps are unlikely to decrease in the near future. These same forces also require the DHS to respond to the increased demand for other health services. The DHS is being required to develop and maintain a complex program of health services without adequate financial resources. The solution to the perinatal care crisis in Los Angeles County and other localities with high rates of poverty cannot be found solely within local governments. It is unrealistic to expect that local taxation can support an increase of this magnitude in the need for care, and increased state and federal support is essential. Other nations, spending far less for health care, produce significantly better results: how much longer will it take this nation to recognize its responsibilities to its most vulnerable citizens? PMID- 10111619 TI - The Medicaid program in California: lessons from dentistry. PMID- 10111620 TI - Medical malpractice in California: recent trends and future prospects. AB - For many years, California court decisions and legislation have often presaged national trends. The expected debate over medical malpractice should be no exception. Thus, the court decisions on third party liability and the outcome of the MICRA negotiations are important both for California and as a harbinger of future national trends. PMID- 10111621 TI - Managing quality in corporate ambulatory health care centers: the Southern California Edison story. PMID- 10111622 TI - Southern California Edison's corporate-sponsored geriatric clinic. PMID- 10111623 TI - Corporate health care in the 1990s: a Southern California Edison profile. PMID- 10111624 TI - The growth of multispecialty medical groups 1982-1989. PMID- 10111625 TI - The Baxter Foundation Prize address. Looking back to go forward: history as health services research. PMID- 10111626 TI - An evening and weekend part-time hospital administrative residency program. PMID- 10111627 TI - Characteristics, functions, and skills of AIDS agency administrators: curriculum implications. PMID- 10111628 TI - The president's report: leadership in the 90s. PMID- 10111629 TI - Quality appraisal and cost finding. PMID- 10111630 TI - The practitioner-teacher model revisited. AB - Much of the recent literature on the future of health administration education notes the importance of strengthening linkages with practitioners by incorporating them into more formal roles within programs. This article describes the Rush University Department of Health Systems Management's process of implementing the practitioner-teacher model. The results of a faculty time commitment study support the conclusion that practitioners can play a key role in the development and administration of a graduate health care management program while maintaining their operational responsibilities. The implications of operating a fully integrated practitioner-teacher model and those aspects transferable to other graduate education settings are discussed. PMID- 10111631 TI - The National Practitioner Data Bank: a step toward more effective peer review. PMID- 10111632 TI - Antitrust risks of durable medical equipment arrangements. PMID- 10111633 TI - Automation at Ottawa General Hospital, Ottawa, Ontario. PMID- 10111634 TI - Automated transport comes of age. PMID- 10111635 TI - Case carts: myths and realities. PMID- 10111636 TI - A goals and appraisal program you can use. PMID- 10111637 TI - Surgical case carts. ECRI. PMID- 10111638 TI - Cart cleaning. PMID- 10111639 TI - Gems and flaws in the Japanese health care system. PMID- 10111640 TI - Problems of protocol practice in Japan. AB - With progress in medical knowledge and in the technology of medical care, the contents of medical practice have become increasingly complicated year by year. The protocol practice (clinical algorithms or scheduled care) has been experimentally employed as one of medical-practice systems aimed at providing better medical care and maintaining its high standards. In the protocol practice the criteria for decision-making, which are clinically employed, are precisely made up in advance so that practice will be performed systematically. The WHO has recommended this protocol practice as a medical-care system appropriate for realizing clinical experiments. In recent years a number of clinical studies have been born from the protocol practice and, thus, it has been considered to be a formula for conducting clinical experiments tolerant of scientific criticism. The protocol practice, however, since it is difficult to conduct smoothly, has not yet been settled. This study aims at considering what we should do to make the protocol practice system settled through the observation of pitfalls in the course of its application. PMID- 10111641 TI - A total hospital information system at Kagoshima University Hospital. AB - At Kagoshima University Hospital, we have been developing the total hospital information system named THINK (total hospital information system of Kagoshima University), using a large-size computer system. In this system, the entry of data is done only once at the point of origin. The mutual use of data is done by various subsystems, and the user interface is uniformity. As a result of the speed, accuracy, and flexibility of the system's software, we have achieved efficient medical services and hospital management by a unified database; furthermore, we have improved medical care to patients and we can use this database for supporting not only medical education but also clinical research. PMID- 10111642 TI - Changes in Japan's blood banking projects as viewed from infections. PMID- 10111643 TI - Computerized nursing system in hospital information system. AB - We have developed a computerized nursing system including a nursing information system, a nursing administration system and a nursing support system. This on line nursing system is linked to the total hospital information system. This paper describes the purpose and concept of the system development. The nursing system can be utilized in the individualized planning, delivery and evaluation of patient care. PMID- 10111644 TI - Total materials flow control system: intra-hospital transport service control system. PMID- 10111645 TI - Global health policy and health care system: "Innovative challenge by health system integration". PMID- 10111646 TI - Outlines of the Asahi General Hospital. PMID- 10111647 TI - Death rate as an index for medical audit methodology of hospitals. PMID- 10111648 TI - Administrative system at the Asahi General Hospital. PMID- 10111649 TI - Formal strategy in public hospitals. AB - This paper suggests that the difficulties associated with the application of formal strategic planning in public professional service organizations may have been underestimated in much of the literature. A survey of written strategic plans produced by Canadian hospitals showed that these plans were often heavily oriented towards expansion, ambiguous and rather loosely integrated, leading to questions concerning their realism and utility as a basis for strategic decisions. This phenomenon seems symptomatic of the complex (and often highly political) decision making environment faced by hospital administrators (and by managers of other professional service organizations such as universities and social service agencies). It is concluded that the benefits of formal planning may be different and less tangible for these organizations than for private business. PMID- 10111650 TI - Will you know what to do if your office catches fire? PMID- 10111651 TI - What happened after a blameless doctor got this note. PMID- 10111652 TI - Utilization review works--most of the time. PMID- 10111653 TI - What no collection agency can ever do for you. PMID- 10111654 TI - Strengthening the weak links in lab services. PMID- 10111655 TI - Short course updates physicians' microbiology skills. PMID- 10111656 TI - Satisfaction surveys improved our employee retention. PMID- 10111657 TI - At last, a guide to cost accounting in the lab. PMID- 10111658 TI - Dealing with laboratory crises before they happen. PMID- 10111659 TI - How internships eased our phlebotomist shortage. PMID- 10111660 TI - Assessing linearity the easy way. AB - Laboratories can comply with new Federal regulations for linearity verification by applying simple calculations and graphs to materials that are readily at hand. PMID- 10111662 TI - My useful niche as send-out technologist. PMID- 10111661 TI - We built a career ladder for our clerical staff to climb. PMID- 10111663 TI - Risk taking: a supervisory imperative. PMID- 10111664 TI - Lookup tables to speed data entry and reduce errors. PMID- 10111665 TI - Ethics and the clinical laboratory. Part I: How ethical dilemmas induce stress. PMID- 10111666 TI - A community blood center user group. PMID- 10111667 TI - Recycling xylene saves money and the environment. PMID- 10111668 TI - Promotional health screening as a marketing tool. PMID- 10111669 TI - From QA to TQM. AB - In the decade from 1950 to 1960, two quality-related processes--medical audit and total quality management--were being developed, one directly in the health care field and the other in the manufacturing sector. These processes remained isolated from each other until the mid-1980s. Each would have a separate but major effect on the health care industry. PMID- 10111670 TI - Developing an in-house physician advisor program. AB - The rapid rise in health care costs during the 1980s has led to a growing demand for utilization management companies, supported by teams of physician advisors. The increasing involvement of physician advisors in day-to-day case review has also led to a growing necessity for their being hired on an in-house basis. This article attempts to show a basic process for developing a functional and efficient in-house physician advisor program. PMID- 10111671 TI - Membership of institutional ethics committees. AB - There are no absolutes in regard to the composition of the institutional ethics committee. The basic principle of membership appears to be that it should be diverse in composition, large enough to provide a broad spectrum of perspectives, and yet small enough to function as a learning, dialoging, service panel. The average size appears to be 15 members, but the range is from 6 to 30. PMID- 10111672 TI - Federal court assumes ERISA claims jurisdiction. AB - In a recent appellate court decision, a practitioner was granted the right to challenge a claims denial under provisions of the Employee Retirement Income Security Act of 1974. This article reviews the reasoning of the court in allowing the practitioner standing in the court under ERISA and reviews the language of the insurance contract that led the court to affirm denial of payment to the practitioner. "Health Law" is a regular feature of Physician Executive contributed by Epstein Becker & Green. Mark E. Lutes of the law firm's Washington, D.C, offices serves as editor for the column. PMID- 10111673 TI - Meta-analysis: apples and oranges, or fruitless. AB - Meta-analysis is an impressive tool for systematic synthesis of health care management and policy research findings. Used wisely, it can impose an appealing order on the chaos of a large body of evidence. Occasionally, it can even contribute to resolution of a clinical controversy. However, the technique is currently in a state of evolution. Until it is further refined and standardized, its consumers must be mindful of its limitations and use meta-analytic reviews with care. PMID- 10111674 TI - Fiscal health of hospitals in a decade of Medicare. AB - The accompanying article is testimony that was presented by Dr. Long before the Subcommittee on Health of the Committee on Ways and Means of the U.S. House of Representatives on February 27, 1991. The testimony was presented in conjunction with the subcommittee's hearing on Hospital Payment under Medicare in conjunction with receiving ProPAC's Seventh Annual Report to Congress. PMID- 10111675 TI - Capital budgeting in hospital management using the analytic hierarchy process. AB - In recent years, the health care industry has been experiencing change to a degree unprecedented since the inception of the Medicare program. With traditional in-hospital care on the decline, hospitals are being forced to compete for business. They must identify within their own systems feasible alternatives for dealing with these changes and then determine which ones will best accomplish the goals of the organization. This paper offers a procedure that utilizes the analytic hierarchy process--a multicriteria decision-making tool that helps arrange the possible alternatives in hierarchical order given the priorities of relevant decision makers. An application of the method to a mid sized hospital is presented. Although the procedure is structured, it is flexible enough to be updated for the realities of any health care institution. PMID- 10111676 TI - A new approach to optimal selection of services in health care organizations. AB - A new reimbursement policy adopted by Medicare in 1983 caused financial difficulties for many hospitals and health care organizations. Several organizations responded to these difficulties by developing systems to carefully measure their costs of providing services. The purpose of such systems was to provide relevant information about the profitability of hospital services. This paper presents a new method of making hospital service selection decisions: it is based on an optimization model that avoids arbitrary cost allocations as a basis for computing the costs of offering a given service. The new method provides more reliable information about which services are profitable or unprofitable, and it provides an accurate measure of the degree to which a service is profitable or unprofitable. The new method also provides useful information about the sensitivity of the optimal decision to changes in costs and revenues. Specialized algorithms for the optimization model lead to very efficient implementation of the method, even for the largest health care organizations. PMID- 10111677 TI - A disaggregation model of a flexible nurse scheduling support system. AB - A nurse scheduling support system is developed in which the demand profile and nurses' preferences are input to an expert-like capability designed to formulate linear and/or goal programming representations of the problem. Solutions of the alternative optimization models of this decision support system are then evaluated. An assignment model for disaggregating the optimum work patterns of individual nurses based on their desires and compatibilities is discussed in detail. A brief overview of one of the scheduling models and its extension is also presented along with discussion of the various uses of the assignment model. PMID- 10111678 TI - Clinical ladders. PMID- 10111679 TI - Be prepared: conduct your own OSHA inspection. PMID- 10111681 TI - Can outcomes data affect end-of-life decisions? PMID- 10111680 TI - Toward a community-based health care system. PMID- 10111682 TI - Hospital attorneys fear COBRA link to malpractice cases. PMID- 10111683 TI - Supporting MD recruitment. PMID- 10111684 TI - How CEOs can use trustees' business skills. PMID- 10111685 TI - The hidden costs of health care. PMID- 10111686 TI - Trustees and service volunteers: the case for closer ties. PMID- 10111687 TI - Medical staff privileges: key to safeguarding quality. PMID- 10111688 TI - The AHA mobilizes constituents for health care reform. PMID- 10111689 TI - Child care arrangements: health of our nation's children, United States, 1988. PMID- 10111690 TI - Office visits by adolescents. PMID- 10111691 TI - AIDS-related knowledge and behavior among women 15-44 years of age: United States, 1988. PMID- 10111693 TI - . . . and more work. The second part of the resurgence of the Sierra Laundry in Reno. PMID- 10111692 TI - Children's exposure to environmental cigarette smoke before and after birth. Health of our nation's children, United States, 1988. PMID- 10111694 TI - Hold on to the old job when looking for a new one. PMID- 10111695 TI - Inservice education: a commitment to excellence. AB - An inservice education program was initiated in the Clinical Hematology laboratory at McMaster University Medical Centre, a division of Chedoke-McMaster Hospitals, in September 1987. Clinical Hematology staff work in the Hematology, Coagulation or Transfusion Medicine departments. Approximately 30 staff members, one of whom serves as an educational co-ordinator, are participants in the program. Goals for the program were set during the first year. Both formative and summative evaluation procedures are used to monitor achievement of these goals. Formative evaluation consists of audience reaction forms which are completed by participants at each session. This enables the co-ordinator to change the program during the year. Summative evaluation is a comprehensive look at the program. Questionnaires are used to solicit the participants' response to the program, and an interview is used to obtain feedback from the chief technologists. An evaluation report was generated at the end of each year of the program. Program design, goal structure and evaluation procedures are outlined. Partial results from three years of evaluation are also presented. PMID- 10111696 TI - Computer literacy and CSLT requirements. PMID- 10111697 TI - Medical devices alert. Subject: Transmission of blood-borne pathogens via spring loaded lancet devices. PMID- 10111698 TI - Consignment purchasing from industry to health care. PMID- 10111699 TI - Objective comparisons of consignment, just-in-time, and stockless. PMID- 10111700 TI - Implementing consignment: a material manager's viewpoint. PMID- 10111701 TI - Consignment and OR scheduling: how CPTs improve operating room efficiency. PMID- 10111702 TI - The impact of linen consignment and computerized linen management on laundry operations: a retrospective look. PMID- 10111703 TI - Materiel management and computerization: implementing software for inventory control. PMID- 10111704 TI - Consignment: a life cycle approach. PMID- 10111705 TI - Maximizing service from group purchasing organizations: earning compliance from members and vendors. PMID- 10111706 TI - Keeping up with health care trends: how consignment works in a modern day surgery center. PMID- 10111707 TI - Managing the unofficial inventory. PMID- 10111708 TI - Looking back at Danbury Hospital: a multiproduct program continues to produce dramatic savings for a hospital on 85 percent consignment. PMID- 10111709 TI - Consignment: present and future. PMID- 10111710 TI - Misconceptions about consignment: a material manager's guide to better understanding and redirecting staff concerns--a general overview. PMID- 10111711 TI - A survey of materiel management education in health care institutions. PMID- 10111712 TI - The high road in hospital materiel management. PMID- 10111713 TI - A do-it-yourself guide to assembling skilled nursing facilities. AB - No one in Texas hospital doubts the need for more skilled nursing care facilities. patients are leaving sooner and sicker, creating discharge-planning logjams. Few nursing facilities offer the subacute care these patients need--and in the current climate their operators can be increasingly selective about whom they choose to admit. These factors, coupled with lowered rates of hospital occupancy and yawning Medicare reimbursement gaps, are all reasons that furnishing skilled nursing care is an increasingly attractive option for Texas hospital administrators. For hospitals considering furnishing various long-term subacute care options, A. Ray Pentecost III, DrPH, offers a nuts-and-bolts guide. Pentecost, who is both a licensed architect and nursing home administrator, is director of the Health Environments Institute in The College of Architecture at the University of Houston, and is also president of Gerontological Health Consultants Inc. of Katy, Texas. PMID- 10111714 TI - New regulations for clinical labs bring confusion, consequences. PMID- 10111715 TI - The right to die. PMID- 10111716 TI - McMurphy project reaches out to tomorrow's nurses. PMID- 10111717 TI - Efficient MEDLINE searching of the radiologic literature. AB - The Radiology Information Service at the Bowman Gray School of Medicine of Wake Forest University performs a wide range of functions from physician continuing education to a photocopy service, including approximately 450 demand literature searches annually. The complexity of the field of radiology, the rapid advances in hardware and techniques, and the variety of interests on the part of radiologists and basic scientists requesting searches make online literature retrieval a challenge for even the expert radiology librarian. This paper presents up-to-date searching terminology, suggested search formulations, and bibliographic sources which have proved valuable in the functioning of the Radiology Information Service. PMID- 10111718 TI - Toxic chemical release inventory information. AB - As part of a U.S. government effort to inform the public about toxic or hazardous chemicals released into the environment, the National Library of Medicine (NLM) and the Environmental Protection Agency (EPA) are jointly producing the TRI (Toxic Chemical Release Inventory) databanks which consist of two separate files, TRI87 and TRI88. Both files reside on NLM's TOX-NET system. The files contain geographic information about reporting facilities and land, air, and water release data for approximately 300 listed chemicals. PMID- 10111719 TI - The creation and maintenance of a hospital archives. AB - The libraries of the Capital Health System and York Hospital have been given the responsibility for collecting and maintaining the archival materials of their respective institutions. After an initial evaluation of donated items, each library researched methods of archival conservation, adapting them to their individual needs. Included in this article is an overview of these methods with many examples from the authors' experiences. Also included is an annotated bibliography of materials of value to anyone setting up a hospital archives. PMID- 10111720 TI - MEDLINE end-user survey: the University of Florida experience. AB - The University of Florida Health Science Center Library (UF-HSCL) surveyed MEDLINE end-user activities of the faculty from the six colleges which the UF HSCL serves. A questionnaire was developed and sent to all faculty members. The Basic SAS program was used to analyze the collected data. This survey was intended to identify the users, the reasons for faculty members not being end users, the purpose for searching MEDLINE, the information retrieval methods, the level of end-user satisfaction, and the librarian's role in information retrieval activities. Many findings from this survey were in agreement with those of the 1988 study by the National Library of Medicine. PMID- 10111721 TI - Air taxi certificate: issues to consider. PMID- 10111723 TI - Current Medicare coverage and payment rules. PMID- 10111722 TI - Choosing an aircraft operator. PMID- 10111724 TI - Monitoring your air operator's vital signs. PMID- 10111725 TI - The development of a medication reminder card for elderly persons. AB - This paper describes the development and testing of a medication reminder card specifically designed for elderly persons on complex drug regimens. The need for such a system was confirmed by a survey of approximately 100 Canadian hospital pharmacy departments where no system provided at discharge by respondents met with our criteria for the "ideal" card. The new medication reminder card was tested in 29 ambulatory and 16 institutionalized elderly persons. Over 75 percent of patients continued to use the card two weeks post enrollment and a majority of ambulatory elderly were still using the card at six weeks. In addition to organizing medications and providing a reminder for patients to take drugs, the card facilitated communication with the pharmacist (a mean of 20 minutes) and with other health care professionals. Patients found the card easy to read and the system easy to understand. Despite time constraints, eight of nine participating community pharmacists indicated they would continue to use the system for select patients. A major obstacle to the use of the card was patient reluctance, for a variety of reasons. Although the card will require further modification in design, it provides a useful alternative as a compliance aid for ambulatory and hospitalized patients on chronic, complex drug regimens. PMID- 10111726 TI - A targeted review of vancomycin use. AB - In recent years vancomycin usage at the Ottawa Civic Hospital has been steadily increasing. In an effort to determine the reason for this resurgence, and whether or not it is justified, a prospective assessment of vancomycin utilization was performed. All new orders for vancomycin received in the pharmacy in a two-month period were evaluated against predetermined criteria for appropriate use, which were developed in conjunction with Infectious Diseases and Cardiac Surgery. Of the 55 orders evaluated during the study period, 32 (58.2%) were considered inappropriate, translating to a cost of approximately $5,500.00 for the seven week period. Use of vancomycin in penicillin-allergic patients without a confirmed history of IgE-mediated reaction, was responsible for the majority of vancomycin prescribed unnecessarily (-66%). As a result of the review's findings, the following actions were taken by the Pharmacy and Therapeutics Committee: (1) vancomycin was restricted to specific indications; (2) vancomycin will be prospectively monitored by the Pharmacy Department; (3) physician education on approved indications and dosing of vancomycin; and (4) development of guidelines for assessment and prescribing in penicillin-allergic patients. PMID- 10111727 TI - Implementation and evaluation of a therapeutic drug level requisition. PMID- 10111728 TI - How FDA safeguards the blood supply. AB - AIDS focused public concern on the safety of the blood supply. New donor screening methods and testing, as well as FDA monitoring and inspection of blood banks, make the blood products in this country safer than ever. PMID- 10111730 TI - The Ontario Mental Health Act: a review of court decisions on involuntary committal. PMID- 10111731 TI - From the patient's bed. There are scientific as well as ethical reasons for increased involvement by patients in decisions about their own care. PMID- 10111732 TI - Finding common ground. Guidelines must incorporate new knowledge of outcomes and accommodate values and preferences of individual patients. PMID- 10111733 TI - The road to guidelines. PMID- 10111734 TI - The best hope. While Congress may see its best hope in standards of care, employers and providers would do well to take the initiative. PMID- 10111735 TI - Appropriate and necessary. AB - In summary, we seem to be on our way to increasing our knowledge about what works and what does not. This information is desperately needed to help develop standards by which quality and appropriateness will be measured. However, enough information is currently available to allow hospitals and their medical staffs to develop standards, guidelines and parameters today in an effort to improve performance. The information produced from the application of the guidelines to actual practice can in turn be used to guide new effectiveness research into what works or does not. For instance, procedures that are frequently performed for equivocal reasons could become the focus of the effectiveness-research agenda. Meanwhile, methods research in both the effectiveness and appropriateness areas will continue so that more valid techniques in both of these areas can be developed. If cooperation between the people who generate new knowledge, the people who develop standards and the people who use the standards to improve institutional performance can be achieved, then we can improve the health of the American people at a price we will be willing to pay. PMID- 10111736 TI - A study pre and post unit dose conversion in a pediatric hospital. AB - Two pediatric medical wards were studied pre and post unit dose conversion using some of the methods described by Schnell et al. The proportion of nurses' time spent on medication related activities decreased from 23.7% pre to 21.6% post unit dose conversion. Nurses' attitudes to the roles of pharmacists and nurses did not change overall and there were significant improvements in their perceptions of the drug distribution system. Observed medication incident rates decreased from 10.3% to 2.9% when wrong time errors were excluded. Medication room audits showed less opportunity for error post-conversion. Work sampling of pharmacists' activities showed no significant change in the amount of time spent on distribution activities. Medication costs decreased by 4% under unit dose drug distribution. PMID- 10111737 TI - Curb economic credentialing. PMID- 10111739 TI - Relationships between knowledge and belief variables and health maintenance behaviors in a Danish population over 45 years of age. AB - The growing body of evidence regarding the importance of self-care behavior for the maintenance of health and functional capacity has stimulated research interest in identifying the factors and processes that influence health-related behavior. This article examines relationships between health knowledge and belief variables and two types of health maintenance behavior: (a) routine habits that affect health and (b) deliberately undertaken health-protective behavior. The findings suggest that generalized health beliefs may have limited influence on behavior. Health locus of control beliefs may be related to behavioral change, but were not related to either current tobacco and alcohol consumption or to conscious health maintenance behaviors. It is concluded that more attention needs to be directed toward cultural influences on health beliefs and behavior. PMID- 10111738 TI - Age-by-race differences in the health and functioning of elderly persons. AB - A review of health data identified four major trends in the elderly population: (a) a younger Black group that was more morbid than an older Black group, (b) an alternating pattern of Black morbid and robust age groups, (c) a Black disadvantage in health and functioning that was greater in race comparisons involving the Black morbid and less in comparisons involving the Black robust age groups, and (d) a Black health detriment that seemed to narrow at age 85. The trends suggest that age and health are more strongly related in the White elderly than in the Black elderly population. The trends also are compatible with the more rapid growth of Blacks aged 85 and over than any other group of the elderly, adverse mortality selection processes, and the racial mortality crossover. Issues for new research that will explain these four trends are discussed. PMID- 10111740 TI - Perspectives. Medicaid donations: scam or savior? PMID- 10111742 TI - Resource directory: occupational therapy state licensing agencies and associations. PMID- 10111741 TI - The resume: your passport in the job search. PMID- 10111743 TI - Collegiality: meeting the professional healthcare team--occupational therapy. PMID- 10111744 TI - Experience talking: clinical avenues for practice in occupational therapy. Interview by M.J. Thomas. PMID- 10111745 TI - Embracing the challenge of change. PMID- 10111746 TI - An interview with Congresswoman Pat Schroeder. PMID- 10111748 TI - Specialty practice in nursing: choices and opportunities. PMID- 10111747 TI - Nurse certification: the key to your professional future. PMID- 10111749 TI - Ready for the NCLEX? Plan with care. PMID- 10111750 TI - Resource directory: nursing. PMID- 10111751 TI - Healthcare's future: rising costs and concerns. PMID- 10111752 TI - New marketing opportunities for plastic card programs. PMID- 10111753 TI - New technology and service in the admitting/healthcare environment. PMID- 10111754 TI - Career apparel--a problem solver. PMID- 10111755 TI - Electronic mail: enhancing communications in a 24-hour hospital admitting department. PMID- 10111756 TI - Bridging the gaps in the surgical journey. PMID- 10111757 TI - Battlefields in health care reform. PMID- 10111758 TI - Training staff: a critical skill for today's access manager. PMID- 10111759 TI - Psychosocial factors as predictors of length of stay of Medicare patients under the prospective payment system. AB - The Prospective Payment System methodology is designed to predict inpatient hospital resource utilization. The system sets standards based on medical diagnosis (Diagnosis Related Groups), but it ignores psychosocial characteristics which often determine discharge options and therefore, directly affect a patient's length of stay. A study is described which examined the psychosocial characteristics of 234 elderly hospitalized patients in relation to length of stay and route of admission (elective or emergency room). Such data can be very useful to discharge planners in identifying high social risk patients, as well as to health planners attempting to modify the DRG methodology to incorporate psychosocial factors. PMID- 10111760 TI - The use of computerized need projection methodologies to implement health planning policies. AB - The Maryland Health Resources Planning Commission has developed a substantial proportion of its planning effort since 1982 to the development of need projection methodologies that fulfill the policy direction established in the State Health Plan. Because each service for which need is projected has a unique set of problems, policy direction leads to service-specific approaches to forecasting need. Each methodology takes into consideration appropriate minimum sizes and distribution of services, appropriate rates of growth, and appropriate reallocation of use from overserved to underserved areas. Examples from acute medical/surgical, acute psychiatric, comprehensive rehabilitation, and institutional longterm care services are given. PMID- 10111761 TI - AIDS and FDA drug-approval policy: an evolving controversy. AB - AIDS treatment policy has become controversial in recent years as the Gay AIDS Movement has challenged FDA drug-testing and approval policies. Based on the Social Movements Model (Frierson, 1985) this movement has reached the stage of establishing a compelling trend of public pressure and is moving toward the stage of the enactment of policy change. Gays have demanded a number of changes in clinical trials and other FDA rules such as the creation of community-based trials, changes in the clinical protocols, and the increased availability of experimental drugs. The FDA has made a number of changes in response but many of the most controversial demands of the Gay community and their medical allies remain open to debate. The implications and conclusions for the possible outcomes of this controversy are considered. PMID- 10111762 TI - Perceived control, knowledge and fear of AIDS among college students: an exploratory study. AB - It is reasoned that fear of AIDS can be an inhibiting factor for students' adopting protective health behavior against acquiring AIDS. The study examined (a) how knowledgeable students are about AIDS and being in control of their life situation and (b) the relationship between knowledge of AIDS, perceived control and other selected factors on students' fear of AIDS. Using a sample of N = 597, drawn from two east coast universities, it was seen that, although some misconceptions still persist, students were both knowledgeable and fearful about AIDS. Foreign students reported more fear of AIDS. Having less knowledge as to how AIDS is acquired and a perceived lack of control were two dominant factors shown to be statistically (P less than .05) related to a fear of AIDS. Some policy implications are discussed. PMID- 10111763 TI - An evaluation of a therapeutic health program for the black elderly. AB - This paper evaluates the effectiveness of a therapeutic health program which was offered in 1988 to the black elderly living in subsidized high-rise apartments in Nashville. The pre-program data (of 1987) indicated distinct differences in that the elderly living in the high-rises had significantly more medical problems, higher levels of depression, and smaller social support networks than those living in their own single dwelling homes. The therapeutic program included various modules such as cognitive and grief therapy, reminiscence therapy, social skills and remotivation therapy. Analyses of pre-post measures of selected variables showed that the program was effective in improving the health status of the participants. As compared to a non-treatment control group, the elderly in the experimental group showed significant improvements in depression, social network, and a sense of control over their lives. A discussion of these findings is provided. PMID- 10111764 TI - Certificate of need and nursing home bed capacity in states. AB - Rapid expenditure increases raise concern with nursing home utilization, of which bed stock is an important determinant. This focuses attention on state policies to limit bed stock, particularly certificate-of-need (CON). This paper reports a cross-sectional/time-series analysis of 1981-1984 changes in state nursing home beds per aged population as functions of CON factors and of other state policy and market factors. Nursing home CON appears to constrain expansion of bed stock, older CON programs having stronger effects. Bed stock changes are positively related to dollar amounts of state CON approvals per aged population--interpreted to reflect the stringency of state CON programs. PMID- 10111765 TI - Fire and the aging of America. AB - Older adults stand out as one of the largest groups in the United States at risk of dying in a fire. What can we do to change this unhappy statistic? PMID- 10111766 TI - The doctors take on Bush. PMID- 10111767 TI - The Canadian model of occupational performance: its relevance to community practice. PMID- 10111768 TI - The community work project: an occupational therapy programme. AB - The Community Work Project is a work adjustment programme, part of a range of prevocational services offered in the occupational therapy department of the Royal Ottawa Hospital, in Ottawa, Ontario. The special feature of this work adjustment programme is the use of an integrated work environment. Compared to institutionally-based programmes, this work adjustment programme consists of clients undergoing treatment alongside regular competitive employees in a real work setting. Another important feature of this programme is its open length of stay. The Community Work Project is described, with information on programme need, components, referral process and goals/objectives. Data on sex, age, diagnosis, attendance rates, lengths of stay, graduation placements and client satisfaction are also given. The Community Work Project demonstrates how the use of a productive activity in a real work setting assists individuals with psychiatric disabilities to progress in their vocational rehabilitation process. Implications for the vocational rehabilitation of this population are discussed. PMID- 10111769 TI - Access to Medicaid home care. PMID- 10111770 TI - The Medicaid hospice benefit: growing slowly but surely. AB - Since its introduction on the Senate floor more than six years ago, the Medicaid hospice benefit has been adopted by 32 states. Legislation is currently pending that would make the benefit mandatory, but without strong support, the Medicaid hospice benefit is threatened in this climate of budget cutbacks. PMID- 10111771 TI - Medicaid reimbursement rates. AB - Inadequate rates of payment have resulted in a decline of Medicaid-covered home care services. Although solutions to the payment rate problems exist, patients and providers may have to resort to litigation to enforce their rights under federal law. PMID- 10111772 TI - Rationing care in Oregon. AB - As a means of curtailing rising health care costs under Medicaid, Oregon has developed a priority list of some 700 medical conditions. The list will serve as the basis for determining what Medicaid services low-income people in Oregon receive. The plan is being heralded by some as a significant step toward universal access to health care, while others see it as unfairly depriving many of needed services. PMID- 10111773 TI - Medicaid fraud in New York State. AB - New York has taken a hard line on Medicaid fraud. Since its inception in 1975, the stat's Medicaid Fraud Control Unit has recovered more than $116 million in overpayments, fines, and restitution. PMID- 10111774 TI - Hospital governance: a framework for self-appraisal. PMID- 10111775 TI - The role of the trustee yesterday, today and tomorrow. PMID- 10111776 TI - Hospitals: a time for transformation. PMID- 10111777 TI - Trustee interview: Jochen (Joe) Struck. Interview by Glen Hopper. PMID- 10111778 TI - From bed care to health care. PMID- 10111779 TI - The decision makers. Interview by Glen Hopper. PMID- 10111780 TI - Standards for governance: direction, delegation and resourcing. PMID- 10111781 TI - The integrated hospital database in an open architecture environment. AB - Although open architecture has a number of advantages, it establishes a need to integrate information currently residing on numerous separate systems. There is no easy solution to retrieve all the data from a single application. An integrated hospital database can serve as a repository for key data from all the various systems. PMID- 10111782 TI - You may be a target for business reengineering. AB - Over the past 20 years, the complexity of hospital evolution has resulted in executive and mid-level management losing touch with the details of the operation. Business reengineering involves restructuring the business to conform to the most efficient operation model for delivering the service or product. PMID- 10111783 TI - Samaritan Health Services profits from executive information system. AB - With nine hospitals, 14 clinics, several managed-care plans, a multispeciality physician clinic, a large home health division--and the largest non-military air transport service in the U.S.--Samaritan Health Services in Maricopa County, Ariz., had a need for some major decision support. Their new EIS has passed the acid test--two new top executives began using it after less than an hour of orientation and continue to use it to shape the large organization's strategic direction. PMID- 10111784 TI - Implementing an executive information system. AB - Too often information systems have not provided the information executives need, in the necessary time frame and at the level of usability that they require. Executive information systems, which are designed to quickly cull through critical information and present it in a highly usable format, are appropriately positioned to fill this growing need. PMID- 10111785 TI - EIS (executive information system): unlocking the computer's strategic potential. PMID- 10111786 TI - Milford Hospital: a model recycling program. PMID- 10111787 TI - Corrections officers and acquired immune deficiency syndrome: balancing professional distance and personal involvement. AB - In this article the dynamic between professional distance and personal involvement is examined. Interviews were performed with New York City Correction Department officers who work with acquired immune deficiency syndrome (AIDS) patients on prison hospital wards to determine how they relate to inmates, to inmates who are dying, and to inmates who are dying of AIDS-related illnesses. The article focuses on the degree to which identification with inmates occurs and, as a consequence, how much grief is generated by their deaths. Grief is mediated by: (a) the social organization of prison work; (b) the social construction of AIDS; (c) magic and mythology related to AIDS; (d) corrections officers' occupational ideology; (e) social values; and (f) American attitudes toward death. PMID- 10111788 TI - Department of law and ethics. Quality of life. PMID- 10111789 TI - Improving the span of healthy life. PMID- 10111790 TI - A question of judgement. AB - Ministerial accountability was one of the founding principles of the NHS, but the shift to the internal market raises legal questions. David Hughes asks whether the duty to provide comprehensive healthcare can now be enforced in the courts. PMID- 10111791 TI - Following in the right footsteps. AB - An initiative which targets resources towards chiropody patients with the greatest needs has been taking place in Nottinghamshire during the past three years. Ian Morton and Peter Pratt describe its progress and outline its new goals. PMID- 10111792 TI - The high cost of turnover. PMID- 10111793 TI - Justification and evaluation of an aminoglycoside pharmacokinetic dosing service. AB - This article reviews the administrative and clinical processes and alternatives involved in justifying and implementing an aminoglycoside pharmacokinetic dosing service in a 500-bed community hospital. The methods used to document the initial problem areas and gain medical staff and administrative approval to propose alternative solutions are described. The financial and quality considerations used to justify a new clinical service to hospital administration are reviewed and the procedures employed to implement the new service are presented. Finally, the methods used to document performance of the new service are discussed. PMID- 10111794 TI - An evaluative study of unclaimed prescriptions. AB - Effects of implementation of an integrated hospital computer system have greatly increased the outpatient prescription non-compliance rate. The provider's electronic order entry initiates the prescription process resulting in receipt of the prescription order in the pharmacy without the intervention of the patient. A demographic study by clinic of origin and type of medications contributing to the increase in compliance failure is presented. Within a defined range of dates, the number of unclaimed prescriptions for each clinic is reported per total of unclaimed prescriptions for that period. Then, the number of unclaimed prescriptions per clinic is evaluated in light of the total number of prescriptions generated by that clinic. Finally, types of medications in the unclaimed prescriptions are broken down into American Hospital Formulary Service drug categories for data on the most commonly unclaimed type of medications. Conclusions are made on the correlation between compliance failure, clinic type and drug category. PMID- 10111795 TI - Physicians' perceptions of the effect of a pharmacokinetic service on their ability to independently function. AB - One hundred and thirty-nine physicians previously provided aminoglycoside dosage recommendations by a pharmacist were surveyed to determine the effect of this service on their perceived ability to independently calculate a dosing regimen. None of the forty-one responding physicians believed that pharmacist recommendations diminished their ability to independently calculate an aminoglycoside dose. In fact, nearly all of the physicians believed their ability to determine the dose was improved as a result of this service. PMID- 10111796 TI - Evidence and response to the impact of the Medicaid Drug Rebate Program (OBRA) on hospital pharmacy: a progress report from central Ohio. AB - Preliminary results of a survey conducted by the American Society of Hospital Pharmacists (ASHP) indicated that hospital drug prices increased since the implementation of rebate agreements between Medicaid and drug manufacturers. The question of how hospital pharmacy directors are planning to respond to the cost shifting that may occur in the recent future is raised in this article. Open ended questions posed to Central Ohio Hospital directors assessed their expectations, experience, and proposed strategies in response to the rebate program. The respondents expect increases in drug prices, reductions in discounts for volume purchases, rebate programs, and contract purchases. Increases in the use of special dating on invoice, bundling of contract purchases, shorter time period for guaranteed prices, and shorter dating on invoices are also expected. Using stricter hospital formularies and capitalizing on the negotiating strength of purchasing groups, was the common strategy considered by hospital pharmacies. PMID- 10111797 TI - Immunizations for international travel: Part I. PMID- 10111798 TI - Pressures on Medicaid mount. PMID- 10111799 TI - Shaping the tomorrow we desire. PMID- 10111800 TI - CHA 2000 recommendations: a guide to the future. Catholic Health Association. AB - The following is an excerpt of the CHA 2000 Task Force Final Report and Recommendations, approved by the Catholic Health Association (CHA) Board of Trustees at its April meeting. The recommendations for the future of CHA were presented to the CHA membership at the annual business meeting at the Joint Assembly of the Catholic Health Associations of Canada and the United States, June 10 in Montreal. PMID- 10111801 TI - Choosing an advance directive. Healthcare providers should scrutinize available forms before selecting one. PMID- 10111802 TI - Advance directives for healthcare decisions--a Christian perspective. AB - For various reasons, many people wish to execute an advance directive for healthcare. Like other important life decisions, choices about healthcare should be consistent with the person's religious faith and values. To help people prepare an advance directive that is both accurate and reflective of Christian teaching and values, we have written the following document. Copies of An Advance Directive for Future Health Care Decisions: A Christian Perspective may be obtained in booklet form from Center for Health Care Ethics, 1402 S. Grand Blvd., St. Louis, MO 63104. PMID- 10111803 TI - Preserving the mission. Sponsors and lay leaders must collaborate to maintain the Church's presence in healthcare. AB - As the number of women and men religious involved in healthcare decreases, the Church faces the task of sustaining and expanding its institutional presence in the healthcare world. Both the Gospels and Church teaching support the claim that the Church should be involved in social institutions such as healthcare. Documents such as the Second Vatican Council's Pastoral Constitution on the Church in the Modern World stress the Church's concern with the impact of God's kingdom on all dimensions of human life. Pope Paul VI's Evangelization in the Modern World clearly affirms that the Gospel cannot be complete until it is interrelated with social life. Jesus' ministries of teaching and humble service are also paradigmatic for Catholic healthcare. To preserve and extend its institutional presence, Catholic healthcare will have to meet a number of challenges in the coming years. Catholic healthcare facilities must be prepared to relinquish their autonomy and work with others, providers will have to become attuned to what is distinctively Catholic about their facilities, and the Church must commit itself to preparing lay leaders for the Catholic healthcare ministry. PMID- 10111804 TI - A trust relationship. A medical advisory board builds physician commitment to a healthcare facility. AB - Today physicians and hospitals are in competition. To ensure consistent physician input and a forum for two-way communication, St. Edward Mercy Medical Center, Fort Smith, AR, has established a medical staff board. The medical staff board was organized so physicians could formally address managers' concerns without duplicating work done by other medical staff committees (e.g., executive committee, medical staff sections, hospital committees). Membership on the 24 member board was limited to the active staff. A two-year term was established, allowing for two consecutive terms to ensure continuity. The chief of staff and chief executive officer (CEO) are ex-officio members. Some of the issues of interest to physicians include how well informed operating room personnel were on current technology and procedures, how effective the emergency department could be, having been designed almost 20 years ago, and how volume purchasing affects physician familiarity with certain products. St. Edward's medical staff board has the potential to enhance the physician-hospital relationship and to serve as an effective tool in building commitment to the medical center. PMID- 10111805 TI - A change from the top. One system self-manages its reorganization project. AB - Changes in healthcare arising from economic, legislative, social, and medical pressures will place greater demands on senior managers' future decision making. To maintain its position as a healthcare leader during these volatile times, the Sisters of Charity of the Incarnate Word Health Care System (SCH), Houston, embarked on a self-managed reorganization project in January 1989. The system's senior management team (SMT) established guiding principles that served as the basis for its goals and objectives. A mission statement helped keep the team focused on its goals. A revised SCH Strategic Direction served as the foundation for change. After analyzing the corporate office organizational chart in light of the new strategic direction, the SMT began a reorganization process. This involved the redefinition of many roles, elimination of some positions, and relocation of some functions. Staff attended workshops to adjust to the reorganization. At the workshops employees were given the opportunity to ask questions and participate in the organization's reshaping. The new collaborative management style has been in place two years. As staff develop more supportive cross-functional teams and specialized committees, they are able to tap deeper into their extensive creative resources and collaborate on a vision for SCH. PMID- 10111806 TI - Measuring service line competitive position. A systematic methodology for hospitals. AB - To mount a broad effort aimed at improving their competitive position for some service or group of services, hospitals have begun to pursue product line management techniques. A few hospitals have even reorganized completely under the product line framework. The benefits include focusing accountability for operations and results, facilitating coordination between departments and functions, stimulating market segmentation, and promoting rigorous examination of new and existing programs. As part of its strategic planning process, a suburban Baltimore hospital developed a product line management methodology with six basic steps: (1) define the service lines (which they did by grouping all existing diagnosis-related groups into 35 service lines), (2) determine the contribution of each service line to total inpatient volume, (3) determine trends in service line volumes (by comparing data over time), (4) derive a useful comparison group (competing hospitals or groups of hospitals with comparable size, scope of services, payer mix, and financial status), (5) review multiple time frames, and (6) summarize the long- and short-term performance of the hospital's service lines to focus further analysis. This type of systematic and disciplined analysis can become part of a permanent strategic intelligence program. When hospitals have such a program in place, their market research, planning, budgeting, and operations will be tied together in a true management decision support system. PMID- 10111807 TI - The action approach. Integrating a community's needs into the corporate planning process. AB - With the city of Detroit in turmoil, Mercy Hospitals and Health Services of Detroit (MHHSD) is trying to assimilate the community's unmet needs into the corporate planning process. Through the Community Assessment of Human Needs process, MHHSD identified the needs of the poor in three of Michigan's most impoverished areas. On the basis of these findings, MHHSD collaborated with the Poverty and Social Reform Institute to form the East Side Initiative, a community planning effort to address the community's unmet needs. An advisory group was established to oversee the East Side Initiative's planning process. The East Side Initiative participants met as one group and in smaller groups to focus on specific needs in the areas of healthcare, crime prevention, substance abuse, education, housing, economic development, and family (social) supports. The proposed action plans of each small group have received approval. In the second phase of the East Side Initiative participants will attempt to obtain the necessary resources to implement the groups' proposed actions. PMID- 10111808 TI - The new FASB (Federal Accounting Standards Board) requirements: time to prepare. PMID- 10111809 TI - Melding mission and marketing. PMID- 10111810 TI - What is the real issue in economic credentialing? PMID- 10111811 TI - Hands-on healers. SSM Health Care System. PMID- 10111812 TI - Holy Cross Health System. Mission outreach fund. PMID- 10111814 TI - Don't get squeezed by a managed-care contract. PMID- 10111813 TI - Mercy National Purchasing, Inc. High quality and savings. PMID- 10111815 TI - HIV tests of doctors won't shield patients from AIDS. PMID- 10111816 TI - Medicare fee climate: lousy now, worse later? PMID- 10111817 TI - Expected impact of RBRVS on physician relationships. AB - Physician payment reform will undoubtedly have a significant impact not only on physician income, but also on the environment in which physicians practice. In this article, the author examines the effect implementation of a resource-based relative value scale is likely to have on physicians' relationships with other physicians, with hospitals and managed care companies, and with their patients. PMID- 10111818 TI - Defining the proper attribution of responsibility for quality of care. AB - The term "medical care" is frequently used when either "health care" or "patient care" would be more accurate. This inaccurate use of terminology not only fosters the impression that physicians have sole responsibility for the entire health care system, but also hinders efforts to place properly the actual responsibility for the quality of care. This article proposes three precise definitions, based on the unique features that distinguish health care, patient care, and medical care, which emphasize the characteristics of each domain. Proper use of these definitions can prevent the confusion of one area of care with another, and should ultimately result in the quality of each area becoming better defined, and thereby better controlled. PMID- 10111819 TI - Physician economic efficiency--a new factor in credentialing. AB - "Economic credentialing"--the use of economic indicators in evaluating physicians for the purposes of staff appointment and reappointment--is a controversial new development in the ongoing struggle to control hospital costs while maintaining quality patient care. This article describes the concept of economic credentialing, discusses some of the legal considerations raised by the use of economic criteria in the credentialing process, and presents the findings of a recent study of the utilization of economic credentialing in hospitals today. PMID- 10111820 TI - Safeguarding the confidentiality of medical and mental health records. AB - In this article, the authors detail the nature of the right to confidentiality of medical and mental health records, the privileges against disclosure, how those privileges are lost, and the health care provider's liability for improper disclosure. The article also provides a "nuts and bolts" approach to safeguarding medical records against compelled disclosure and the legal foundation for resisting production of medical and mental health records. PMID- 10111821 TI - Program exclusions and civil money penalties: the administrative process. AB - The authority vested in the Secretary of Health and Human Services and the Office of Inspector General to combat fraud and abuse in the Medicare and state health care programs has continuously expanded during the past decade, and the government's experience in fighting fraud and abuse over the years has resulted in, and been augmented by, refined statutory and regulatory enforcement authority, culminating in the 1987 enactment of the Medicare and Medicaid Patient and Program Protection Act. This article addresses some of the expanded bases for exclusion and imposition of civil money penalties that were authorized by the 1987 legislation and set out in recently proposed regulations. PMID- 10111822 TI - Reporting requirements under "Stark". PMID- 10111823 TI - The corporate practice of medicine doctrine revisited. PMID- 10111824 TI - Health Dimensions facilities merge. PMID- 10111825 TI - HCA appeals IRS claims that it owes $150 million in taxes. PMID- 10111826 TI - State raps facility's infection control. PMID- 10111827 TI - 12 indicted in Calif. insurance fraud case. PMID- 10111828 TI - Recession prompts benefits changes. PMID- 10111829 TI - Intensive-care units studies. PMID- 10111830 TI - Lower career aspirations keep women back--study. PMID- 10111831 TI - Baxter has done nothing illegal. PMID- 10111832 TI - Medicare managed-care proposal faces skepticism it can cut costs, lure consumers. AB - The Bush administration is attempting to nail down specifies of its latest managed-care proposal for the Medicare program. HCFA Administrator Gail Wilensky predicted that the so-called point-of-service HMOs, which offer comprehensive services but allow individuals to move freely in and out of the plan, would be the "dominant form of managed care" in the future. But skeptics question the plan's ability to curb healthcare costs and attract consumer interest. PMID- 10111833 TI - Going online with outsiders. AB - Whether it's hiring expertise to straighten out a problem-plagued computer system, using a firm to smooth the transition to a new system, or saying goodbye to the mainframe altogether, a growing number of hospitals are handing over the management of all or part of their data processing operations to outsiders. "Outsourcing" can offer a variety of advantages, including helping control costs, making more effective use of capital and relieving staffing shortages. PMID- 10111834 TI - Wash. expected to pay higher Medicaid rates. PMID- 10111835 TI - Electrode system could save 'millions'. PMID- 10111836 TI - New laser printer emerges. PMID- 10111837 TI - Plans' execs mixed on impact of fee schedule. AB - With Medicare's physician fee schedule set to begin phasing in this January, executives at healthcare plans and medical groups are mixed on the impact of the plan. Because the schedule will lower fees for specialists and raise payments to primary-care providers, many healthcare managers are concerned about cost shifting. Others expect the schedule to have a minimal effect on fees because many prepaid plans already have resource-based payment methodologies. PMID- 10111838 TI - Bond volume rises 19.3%. AB - Tax-exempt healthcare bond volume climbed 19.3% in the first six months of 1991 compared with the same period last year. Hospitals sold 227 separate issues worth a total of $6.5 billion during the period, compared with 195 issues worth $5.4 billion in 1990. The increase was accelerated in part by anticipation of an Internal Revenue Service rule change expected to take effect in September. The change in "reimbursement bond" guidelines could restrict some hospital financings. PMID- 10111839 TI - HCFA to investigate FHP's marketing to seniors. PMID- 10111840 TI - NME earnings up for quarter, year. PMID- 10111841 TI - VA to use quality checklist. PMID- 10111842 TI - Pumping up profits. Hospitals lean toward fitness centers to fatten bottom lines. PMID- 10111843 TI - Reducing infant intensive care suggested for Medicaid savings. PMID- 10111844 TI - Interview with new AHA chief shows he values collaboration over competition. Interview by Clark Bell and Lynn Wagner. PMID- 10111845 TI - Expert outlines treatment for management maladies. PMID- 10111846 TI - Realizing new revenues with ideas, innovations. PMID- 10111847 TI - Hospitals, physicians forge new relationships. PMID- 10111848 TI - Helping hospitals manage a process called change. PMID- 10111849 TI - 10 'role shifts' for a more dynamic leadership role. PMID- 10111850 TI - Clear mission needed before strategic plan. PMID- 10111851 TI - N.J. hospital annuities frozen following insurer's takeover. PMID- 10111852 TI - Evolving technology may shift facility design. PMID- 10111853 TI - Capital borrowings may require proof of quality. PMID- 10111854 TI - Experts review effects of ruling on kickbacks. PMID- 10111855 TI - Reorganize military health system--report. PMID- 10111856 TI - AMI gets B2 rating on offering. PMID- 10111857 TI - Distressed facilities increase to 18% of total in quarter. PMID- 10111858 TI - Healthcare Int'l, HealthVest merger likely to be delayed. PMID- 10111859 TI - Calif. hospital first to feel effects of new NLRB rules. PMID- 10111860 TI - Nevada hospitals, state settle suit. PMID- 10111861 TI - States rebut AHA's gloomy Medicaid-payment rundown. PMID- 10111862 TI - 'Hospitals need to involve doctors in leadership'. PMID- 10111863 TI - Health Net execs' boosted offer criticized as too low. PMID- 10111864 TI - Distributor suing hospital over contract. PMID- 10111866 TI - Hospital-owned home medical equipment firms in California targeted in fraud, antitrust probes. PMID- 10111865 TI - Two hospital administrators, two hospitals settle charges of submitting false claims. PMID- 10111867 TI - AHM earnings jump 1,058%. PMID- 10111868 TI - VHA returns $31.2 million in net income to member hospitals. PMID- 10111869 TI - Samaritan Senior Services to sell seven facilities for $16.75 million. PMID- 10111870 TI - Bill seeks closer tracking of waste sent through mail. PMID- 10111871 TI - ICF International plans to sell Health and Sciences Network. PMID- 10111872 TI - Proposal would curtail Medicaid matching funds. PMID- 10111873 TI - Death of a hospital requires proper mourning period. PMID- 10111874 TI - Business-led efforts to control costs. AB - Business-led initiatives to compare medical quality and prices are becoming commonplace as employers seek ways to cap medical expenses. But employers are meeting with varying degrees of cooperation from hospitals. The tale of two cities' efforts to pry open the secrets of controlling costs provides a vivid contrast in the way purchasers have tried to solve the cost-containment puzzle. PMID- 10111875 TI - Government releases final 'safe harbor' regulations. PMID- 10111876 TI - Healthcare groups request meeting with government. PMID- 10111877 TI - Panel blasts Medicare physician fee schedule. PMID- 10111878 TI - Hospital's tax battle stretches definition of exempt property. AB - A dispute between a Chicago hospital and the Illinois Dept. of Revenue may have extended the limits of what's considered non-taxable property. The hospital began buying abandoned buildings and vacant lots surrounding its campus to improve the blighted area's aesthetics, but disagreement over the property's role in the hospital's charitable mission, and thus its tax status, landed the dispute in court. PMID- 10111879 TI - PPO buyout opens growth opportunities. PMID- 10111880 TI - Stockless inventory proves less dramatic but more applicable than many expected. PMID- 10111881 TI - Beating the odds against merger failures. AB - Inking a merger or acquisition agreement is only one hurdle in a healthcare industry that's increasingly bent on consolidation. Breaking the news to the work force and community can make or break the deal. Edward A. Kazemek outlines what should be done to keep emotional reaction from dooming negotiators' best efforts before the ink dries on the documents. PMID- 10111882 TI - Hospital closure leaves bondholders unfazed. PMID- 10111883 TI - Drug maker blasts consumer group's report. PMID- 10111884 TI - Demand from HMOs raising primary-care salaries. PMID- 10111885 TI - Pa. payment delays draw suit, HCFA warning. PMID- 10111886 TI - HBO to sell maintenance unit. PMID- 10111888 TI - Final accounting rules behind schedule. PMID- 10111887 TI - UR accreditation panel open for business. PMID- 10111889 TI - Medical-waste laws infuse disposal industry. PMID- 10111890 TI - Medicaid expansions' future shaky. PMID- 10111891 TI - Key Democrats want a floor for capital payments. PMID- 10111892 TI - Steelman panel's proposals surface. PMID- 10111893 TI - Physicians, not patients, are hospitals' true customers. PMID- 10111894 TI - Release of final 'safe harbor' rules sparks concern. AB - The release of the government's list of business arrangements that won't be vulnerable to investigation and prosecution under Medicare and Medicaid anti kickback statutes has sparked concern at hospitals and healthcare-related organizations nationwide. The rules, which are more stringent than expected, may indicate that some existing hospital-physician joint ventures need to be restructured to avoid federal scrutiny. PMID- 10111895 TI - Teaming up to improve quality of patient care. AB - A philosophy of care that involves family members or friends in patients' medical treatment is beginning to catch on at hospitals. Advocates say cooperative care increases quality and reduces costs because family members perform myriad tasks. Patients are involved in decisions about their own treatment and even have access to their medical records. But some question whether patients are ready to take on that much control. PMID- 10111896 TI - Ruling upholds FTC's authority over non-profits. PMID- 10111897 TI - Conn. orders quality audit at 2 Cigna units. PMID- 10111898 TI - Know ramifications of taking vendor to court. PMID- 10111899 TI - Hospitals can boost profits by going according to plan. AB - Hospitals that conduct strategic planning and implement comprehensive business plans are more profitable and efficient than hospitals without written plans, a new study shows. It also found that most successful hospitals included strategies to measure and improve quality and customer services in their business plans. Of the administrators that didn't conduct strategic planning, most said they hoped to begin in the next year. PMID- 10111900 TI - N.Y. hospitals coax medical students into primary care with educational event. PMID- 10111902 TI - Fla. study examines utilization, cost, access issues. PMID- 10111901 TI - Insurance industry troubles put pension, annuity plans at risk; experts urge checkup. AB - Because of recent troubles in the insurance industry, most notably the state seizure of Newark, N.J.-based Mutual Benefit Life Insurance Co., it's a good time for hospitals and associations that sponsor pension and annuity plans to check up on the financial health of their investments, experts say. The rapid rise in "non performing" mortgages held by insurance companies is among the maladies putting plans at risk. PMID- 10111903 TI - Moody's reviews Ohio hospitals. PMID- 10111904 TI - AMI's parent sells 17.3% of its debt in Epic. PMID- 10111905 TI - Nu-Med's earnings improve. PMID- 10111906 TI - Republic forms joint venture in San Diego. PMID- 10111907 TI - AHA president outlines goals in first address. PMID- 10111908 TI - AHA revises position on reclassification. PMID- 10111909 TI - Quality assurance and medical information processing. AB - Quality assurance of medical care is a process designed to improve quality of health care delivery by eliminating deficiencies. Since every quality assurance process starts with the assessment of quality and the recognition of deficiencies, quality assurance is in the first place a problem of information: if one does not know the inadequacy of the own care, one has no idea that it should be improved. Therefore, appropriate quality indicators differentiating between good and bad medical care and functioning information systems with or without computers are basic prerequisites for the assurance of quality. Additionally, external comparisons of the hospital's own data with the data of other hospitals stimulate the efforts of quality assurance committees. Computer based hospital information systems may be valuable tools to support quality assurance processes. However, further research and development of quality monitoring systems, practicable medical and economical quality indicators, and decision supporting techniques will be necessary to meet all requests of the quality assurance professionals. PMID- 10111910 TI - A review of nursing manpower issues. AB - This paper, presented by the E.C. Hospital Committee's Sub-Committee on Economics and Planning, reviews what is regarded by many as a crisis in hospital nurse manpower in the 1990's. Indeed, there are signs that the problem of recruiting sufficient qualified staff had already arrived in some places in the latter part of the 1980's. So what is the nature and extent of the problem? Information has been gathered about population, as it affects demands on health care and as a source of potential health service employees. The current position of nurse staffing has been investigated and is discussed together with indications from member states of ways of tackling the problem to safeguard the quality of patient care to which the member states are committed. PMID- 10111911 TI - Bundling--new products, new markets, low risk. AB - It has long been a marketing axiom that customers buy bundles of satisfaction, not products. It follows, then, that they'll respond to certain combinations of products and services--air conditioners with free installation, combinations of software packages, or season tickets with parking privileges. The difficulty is in devising the bundles that both appeal to consumers and give cost or demand enhancing benefits to the producer. Eppen, Hanson, and Martin argue that the best approach is to treat bundles not as marketing gimmicks but as new products. They offer seven guidelines for creating competitive bundles and a framework for implementing them. PMID- 10111912 TI - Practice guidelines--why not? PMID- 10111913 TI - Will clinicians accept practice guidelines? PMID- 10111914 TI - A survey of systems for after-hours care. AB - As part of medical care contracts and in response to patient needs for access, HMOs offer a full system of medical care, with 24-hour-per-day, 365-day-per-year coverage for emergencies. As economic units, HMOs strive to efficiently use staff, facilities and financial resources to provide these services. With high quality a goal for all medical services, the HMO needs to shape its emergency care coverage system to satisfy patient needs. Competitive forces and facility availability will play an important role in shaping the design of emergency and after-hours care in each medical community. This article will focus on patient needs, provider considerations, and HMO plan concerns for emergency and after hours care. PMID- 10111915 TI - After hours care in HMOs. PMID- 10111916 TI - The emergency and after-hours care system at Group Health Cooperative. AB - The Group Health Cooperative (GHC) emergency and after-hours care system has defined several roles that are unique in our community. The consulting nurse service provides a valued tie between patients and the many services available at GHC. The consulting nurses also encourage self care and autonomy. The GHC operated emergency departments function to maximize the efficiency of primary care physicians and specialists while providing high quality care and a professionally rewarding emergency medicine practice. PMID- 10111917 TI - Clinical triage at Harvard Community Health Plan. AB - Triage is the sorting of patients according to clinical urgency. The night-time triage program at the Health Centers Division of the Harvard Community Health Plan (HCHP) directs and coordinates all patient care. A thorough knowledge of the clinical and administrative program of HCHP as well as informed understanding of the external environment is necessary to accomplish this responsibility. As part of the orientation and training program for the night triage staff, a set of written clinical protocols for serious medical emergencies has been developed. Examples of clinical situations are provided in this article. PMID- 10111918 TI - After-hours telephone triage. Recruitment, training and retention of personnel. AB - Harvard Community Health Plan's nighttime telephone triage program, currently known as Telecommunications, has evolved through several stages, corresponding to HCHP membership growth, technological enhancements, and changes in the medicolegal environment. Recruiting, training, and retaining staff for nighttime telephone triage are discussed. PMID- 10111919 TI - Cost implications of an after-hours triage service. AB - The costs of an after-hours triage service and potential savings for a medium sized (90,000 member) division of an HMO are presented. Other benefits are also described, including access to member medical records and coverage information, direct-linked telephone conferencing, and more personalized and continuous care. PMID- 10111920 TI - Emergency service program at Health Insurance Plan of Greater New York. PMID- 10111921 TI - Medical documentation and the ED record: the key components. PMID- 10111922 TI - Educating patients about advanced directives. PMID- 10111923 TI - Special report. Proposed Medicare fee schedule reveals rescaled RVUs, new $26 conversion factor. PMID- 10111924 TI - Bond ratings plunge in corporate America. PMID- 10111925 TI - CIO: end of the line? PMID- 10111926 TI - Perspectives. Dumping doctor decision raises anxiety. PMID- 10111927 TI - TQM speeds patient trays. PMID- 10111928 TI - Food service manages cultural diversity. PMID- 10111929 TI - Federal funds help boost literacy in New Mexico. PMID- 10111930 TI - Santa Monica Medical Center to offer literacy class. PMID- 10111931 TI - The power to be human. PMID- 10111932 TI - Long-term marketing drives new recruiting program. PMID- 10111933 TI - History of the California health care system. An explosion in hospital and health association growth. PMID- 10111934 TI - Hospitals turn to in-house training to "grow" own personnel. PMID- 10111935 TI - TQM takes hold at Sutter Health. PMID- 10111936 TI - Emanuel Medical Center offers insights on TQM. PMID- 10111937 TI - What's ahead for outpatient reimbursement. PMID- 10111938 TI - Trends in psychiatric outpatient services. PMID- 10111939 TI - Health care reform: the issue is trust. PMID- 10111940 TI - Baylor tackles sports medicine in a big way. PMID- 10111942 TI - U.S. Supreme Court decision to generate more union activity. PMID- 10111941 TI - Raising the standard. PMID- 10111943 TI - Looking for Mr. Goodexec. PMID- 10111944 TI - The Texas Healthcare Exchange. PMID- 10111945 TI - Rehab managers prepare to meet the challenge of the 90s. AB - In this article, Health Systems REVIEW reports on the changes taking place in the lively rehabilitation hospital industry. Although exempt from the Medicare prospective payment system, rehabilitation hospitals are feeling the payment pinch experienced by their acute-care and psychiatric brethren in the delivery of government-paid services, as well as increased pressures from private payers. PMID- 10111946 TI - Medicare program; Medicare Geographic Classification Review Board--procedures and criteria--HCFA. Final rule with comment period. AB - This final rule with comment period responds to public comments on the September 6, 1990 interim final rule with comment period that established the Medicare Geographic Classification Review Board (MGCRB) and sets forth the criteria for the MGCRB to use in issuing its decisions concerning the geographic reclassification of hospitals for purposes of payment under the prospective payment system. In addition, this final rule with comment period implements provisions of the Omnibus Budget Reconciliation Act of 1990 concerning the MGCRB. PMID- 10111948 TI - High-wire health care act. PMID- 10111947 TI - Medicare program; payment for hospice care--HCFA. Final rule with comment period. AB - This final rule with comment period provides for new methodology to update the hospice daily payment rates and for an updated annual payment cap amount for hospice care under the Medicare program. The new methodology for calculating the daily hospice payment rate increase is set forth in section 1814(i) of the Social Security Act as amended by sections 6005 (a) and (c) of the Omnibus Budget Reconciliation Act of 1989. PMID- 10111949 TI - Malpractice morass. AB - Political maneuvering, not a medical crisis, has moved the malpractice issue to the fore on Capitol Hill. But it isn't likely to go anywhere until health care reform does. PMID- 10111950 TI - Correcting performance-rating errors in oral examinations. AB - Although oral examinations are widely used for making decisions regarding an individual's level of competence, they are frequently of limited reliability. A significant part of the error in oral performance ratings is due to the tendency for some evaluators to be lenient and others to be stringent in their assignment of ratings. This article describes and evaluates a simple method to identify and correct for errors of leniency and stringency. The method, which is based on a regression model recommended by Wilson (1988), extends and simplifies the procedures recommended by Cason and Cason (1984, 1985). The method provides an estimate of each individual's performance that has been corrected for errors of leniency and stringency. In addition, it produces for each rater an index of leniency or stringency and several other statistics useful in evaluating the properties of rating data. The regression method is applied to performance ratings from three separate administrations of an oral examination in a medical specialty. The results indicate modest but significant levels of leniency and stringency error; correcting for such errors would change the pass/fail decisions for about 6% of the examinees. Limitations of the procedure, as well as the need for additional research, are discussed. PMID- 10111951 TI - Response to a legal challenge. Five steps to defensible credentialing examinations. AB - In 1975 the National Board for Respiratory Therapy (currently the National Board for Respiratory Care) was named as a defendant in a class action suit field on behalf of three individuals seeking relief for alleged violations of Title VII of the Civil Rights Act of 1964, as well as the Sherman Antitrust Act. Although a pretrial settlement was reached, the conduct of this case demonstrates the potential vulnerability of credentialing examinations to complaints regarding discrimination and the necessity for credentialing organizations to be socially responsible for the potential use of test results by employers. The board has since instituted a systematic five-step research and development process that is used for all of its examinations to ensure and document that they are fair, valid, and defensible. This article recounts the salient aspects of the class action suit, discusses implications and current applicable technical standards and legal guidelines, and describes the components of the "Five Step Examination Development Process." PMID- 10111952 TI - Successful business planning for new programs in health care organizations. AB - Health care organizations implement business strategies through programs and services, and success depends on careful program design and execution. A conscientious design requires thorough efforts in organizing the planning process, conducting the decision analysis, and obtaining approval for a program. Weak methods and processes in the management of these efforts can result in faulty assumptions and costly errors in the development of new health care ventures, thus preventing the achievement of financial and operating goals. This article reviews the stages of business planning, and the points at which success may be impaired. PMID- 10111953 TI - Using fourth-generation evaluation in nursing. AB - Evaluation is disciplined inquiry undertaken to determine the value, including merit and worth, of some entity: a curriculum program, a clinical intervention, an academic course, a care plan. An evaluation is conducted to improve or refine the thing being evaluated (evaluand) or to assess its impact and effectiveness. Evaluation in nursing has been designed using various positivistic and post positivistic models in the first three "generations" in the evolution of evaluation practice. This article describes a new model of nursing evaluation more consistent with a nursing paradigm than with a traditional, scientific, medical paradigm. Responsive nursing evaluation informs and empowers all those involved in its outcomes (the stakeholders) when framed within the research stance called naturalistic or constructivist inquiry. The fourth-generation evaluation approach of Guba and Lincoln (1989) is consistent with a nursing paradigm and a constructivist approach. Fourth-generation evaluation is presented with specific application to nursing evaluation. PMID- 10111954 TI - Study of the effectiveness of a health-risk reduction program. AB - A program titled Contemporary Concerns about Food and Health (CCFH) was developed by the Florida Cooperative Extension Service after research in five counties showed 30%-74% of 2,308 middle-aged citizens to have three or more characteristics that placed them at above-average risk for developing diseases such as cardiovascular disease, adult-onset diabetes, and cirrhosis. CCFH addressed the effects of dietary and other practices that contribute to such lifestyle-related diseases. This article describes the test of the effectiveness of this program in increasing participant knowledge about the causes and preventions of health risk and in motivating them to make healthful risk-reducing changes in their lifestyles. A comparison, four-group, quasi-experimental design was used to study the program in five counties. The four groups included (a) those who participated only in CCFH lessons; (b) lesson participants who had also completed a computerized healthrisk profile; (c) a random sample of persons who completed only the health profile; and (d) a control group randomly selected to match both groups of lesson participants closely in age, sex, race, and county of residence. Results showed that lesson participants knew the answers to a significantly greater number of knowledge items than did the comparison groups, and they reported making more, and more important, changes in their lifestyles for reducing their risks of developing health problems. PMID- 10111955 TI - Quality improvement process--Part II. Step-by-step QIP reviews will result in major savings for your foodservice department. PMID- 10111956 TI - How to build a winning team. PMID- 10111957 TI - Merging for efficiency. PMID- 10111958 TI - America's hottest HMO. PMID- 10111959 TI - Special report on medical staff relationships. Handling "impaired" health care professionals. AB - Applying the doctrine of corporate negligence, courts will, in appropriate circumstances, deem hospitals and other institutional health care providers responsible for the quality of patient care in their institutions and for the consequences of negligent physician performance that could have been discovered and prevented. See, e.g., Darling v. Charleston Community Memorial Hosp., 33 Ill. 2d 326 (1965), cert, denied, 383 U.S. 946 (1966); Johnson v. Misericordia Community Hosp., 99 Wis. 2d 709 (1981); Elam v. College Park Hosp., 132 Cal. App. 3d 332 (1982). In such a climate, and with Data Bank reporting now a reality, neither institutional providers nor health care professionals on their medical staffs can afford to ignore problems of practitioner impairment. Recognizing this reality, some state laws now mandate an organized approach--such as the establishment of an impaired practitioners committee--to problems of professional impairment. However, whether state-mandated or not, providers must have policies and procedures in place to insure not only that impaired professionals are referred to available treatment programs, but that they fully participate in and complete such programs, and achieve rehabilitation, before they return to practice at the institution. The earlier detection and treatment are initiated, preferably before peer review action becomes necessary, the better for patients, institutions, and practitioners themselves. PMID- 10111960 TI - The Independent Health Facilities Act: a first for North America. PMID- 10111961 TI - The value of clinical judgment in competency assessments. PMID- 10111962 TI - Mental competency to make medical decisions. PMID- 10111963 TI - The marketing planning process: a strategic model (Part three) PMID- 10111964 TI - Effectively marketing prepaid medical care with decision support systems. AB - The paper reports a decision support system (DSS) that enables health plan administrators to quickly and easily: (1) manage relevant medical care market (consumer preference and competitors' program) information and (2) convert the information into appropriate medical care delivery and/or payment policies. As the paper demonstrates, the DSS enables providers to design cost efficient and market effective medical care programs. The DSS provides knowledge about subscriber preferences, customer desires, and the program offerings of the competition. It then helps administrators structure a medical care plan in a way that best meets consumer needs in view of the competition. This market effective plan has the potential to generate substantial amounts of additional revenue for the program. Since the system's data base consists mainly of the provider's records, routine transactions, and other readily available documents, the DSS can be implemented at a nominal incremental cost. The paper also evaluates the impact of the information system on the general financial performance of existing dental and mental health plans. In addition, the paper examines how the system can help contain the cost of providing medical care while providing better services to more potential beneficiaries than current approaches. PMID- 10111965 TI - A survey of customers and non-customers of chiropractic services: an empirical observation. PMID- 10111966 TI - AIDS prevention and college students: male and female responses to "fear provoking" messages. AB - This study was designed to examine the effects of fear appeals in AIDS prevention messages and to determine whether or not males and females differ in their response to these appeals. MANOVA results from a sample of 179 junior and senior business students at a mid-Atlantic urban university indicate that significant differences in message effects were associated with type of appeal, gender of the respondent, and the interaction between appeal and gender. PMID- 10111967 TI - Catalysts for OTC drug communication strategies: perceptions of information source characteristics by the elderly. AB - The elderly are the prime users of all medication and especially self-medication using Over-the-Counter (OTC) drugs. This group also has the greatest risk from misuse or interaction of multiple medications. To minimize the risk, information about OTC consumption must be provided to the elderly. This research reports on the importance of various information sources to light and heavy users of OTC medications among the elderly and an evaluation of those information sources with respect to perceived expertise, credibility, understandability and relevance. Communication strategies are suggested for reaching this at-risk group. PMID- 10111968 TI - Ethical ideology and product confidence: future pharmacists' attitudes toward generic drug substitution. AB - The impact of generic drugs on the prescription drug market has received widespread attention in the health care and marketing disciplines. Most research to date has focused solely on market factors' effect on pharmacists' attitudes toward generic drug substitution, and little attention has been given to individual factors. The present study extends previous research using Multiple Discriminant Analysis to ascertain the importance of ethical ideology and product confidence on pharmacists' attitudes toward future generic drug substitution across a salient set of market factors. The findings suggest that these individual factors are important in profiling pharmacists' disposition toward making a generic substitution in the future. PMID- 10111969 TI - An examination of physician use of and attitudes toward closed formulary drug programs. AB - Efforts to control the rising costs of drug budgets has centered primarily on the use of "closed formularies"--systems in which a set of drug products are pre approved for dispensing to those eligible for expense coverage. Controversy, however, has surrounded these systems with respect to their effectiveness in controlling costs and their impacts on the quality of care for recipients. This study examined California physician attitudes towards the California Medicaid program's use of a closed formulary and treatment authorizations which must be obtained in order to dispense drugs not on the Medi-Cal pre-approved list. A survey of physicians focused on the extent to which they sought to use non formulary medications, their experience with formulary products that were not their drugs of choice, and the extent to which the overall system impacted their practices. Results of the survey indicated that the closed formularly discouraged physicians from dispensing drugs of choice. Furthermore, physicians often experienced adverse or sub-therapeutic results with formulary medications that they would not have expected had they dispensed their preferred medications. PMID- 10111970 TI - The effect of price on the consumers' perception of physicians. AB - This attitudinal study indicates that consumers do not perceive a price-quality association for physician services. However, existing patients of physicians, if satisfied, are willing to pay more for their physician's services. Thus, physicians looking to attract new patients may find a high price strategy to be no more ineffective than a parity pricing strategy. But physicians with existing 'satisfied' patients may be able to increase their professional fees without having a major attrition of patients or suffering a loss in patient satisfaction. PMID- 10111971 TI - Information acquisition and behavioral change: a social marketing application. AB - Previous literature provides insight into the importance of beliefs and other intrapersonal variables for health-related information acquisition and behavioral change. The results of an empirical investigation evidence the unique strength of the role of core health beliefs for each of the multi-level measures. Directions for the development of effective marketing strategy are discussed. PMID- 10111972 TI - Adding a competitive dimension to importance-performance analysis: an application to traditional health care systems. AB - This study introduced an extension of importance-performance analysis by further including the performance of competitors. It demonstrated its value by applying it to a national sample of fee-for-service health care users. This study found that inappropriate strategies may result from importance-performance analysis that excludes a dimension of competition. In particular, the two attributes, availability of both physicians and emergency services, were found to be "high" on importance and "good" on fee-for-service performance. From the basic classic importance-performance approach, a relatively passive strategy would be recommended for each of these attributes. When also considering competition, however, a more appropriate, vigorous strategy of head-to-head competition clearly emerges. PMID- 10111973 TI - Perceptual attitudes of a charitable organization: an investigative approach. AB - United Way of America is known nationwide for its services as a coordinator of local fund raising activities designed to meet the needs of the local community. Each United Way has many local agencies that depend upon the fund raising efforts of the organization for a significant amount of their budget. The United Way of Horry County (UWHC) operates in this manner, and over the years they have raised a significant amount of funds to support local service agencies. The UWHC is now attempting to examine possible changes by embarking upon a study designed to measure among the public the degree of awareness of United Way and the services which they provide. A sample survey was conducted and data were collected via telephone solicitation from individuals selected randomly throughout the market area of Horry County. The study identified the four most important services as: emergency assistance such as housing, fire, flood, etc., senior citizens, health care services, and drug and alcohol abuse. Furthermore, the study indicated that services which need to be added to this list include AIDS research, aid for homeless, mentally ill, and elderly. PMID- 10111974 TI - The do-it-yourself health care consumer: preliminary identification and marketing implications. AB - Although the presence of do-it-yourself (DIY) segments in some service-markets have long been taken for granted (e.g., home improvement and auto repair), the recent emergence of DIY segments in law, health, and other service-markets has been surprising to many observers. This paper examines the DIY segment in the health service market. The emergence of a DIY segment may be misconstrued by some service-marketers as being synonymous with lost clientele. This paper (1) explains some of the marketing implications of a DIY health services segment and (2) provides a brief profile of the DIY health services consumer. The paper concludes that the DIY segment represents new opportunity rather than lost clientele to service-marketers. PMID- 10111975 TI - Historical notes on partial hospitalization. AB - The author addresses the historical antecedents of three important aspects of partial hospitalization: (1) therapeutic use of the milieu, (2) decentralization of hospital-based care, and (3) a pluralistic view of the human organism. In the process, a tour d'horizon of Western psychiatry from the period of Phillipe Pinel to that of Adolf Meyer is provided. Such an excursion into history permits a greater appreciation of the partial hospital setting and the relevance of history in the evolution of psychiatric thinking. PMID- 10111976 TI - Recruitment and retention of psychiatrists in day-treatment centers: a national survey. AB - In 1988 a questionnaire was sent to all institutional members of the American Association for Partial Hospitalization to gather information concerning their program and staffing characteristics as well as information concerning the recruitment of staff psychiatrists for these programs. A total of 388 questionnaires was mailed out, yielding 209 responses representing 230 programs. This paper presents the survey findings as well as their implications for day hospital programs. PMID- 10111977 TI - Outcome in children's day treatment: relationship to preadmission variables. AB - Outcome in children's day treatment has been studied infrequently. There is little information available to suggest which types of children may or may not benefit from day treatment services. In an earlier study, Gabel et al. (1988) found that preadmission factors related to parental/family dysfunction (i.e., suspected child abuse/maltreatment and parental substance abuse) and preadmission factors related to child dysfunction (i.e., suicidality and severe aggressive/destructive behavior) correlated with poor outcome in day treatment by the criterion of a recommended out-of-home placement on discharge. Of these factors, severe aggressive/destructive behavior was most important in predicting outcome. In this study, discharges from two additional centers were reviewed to determine if these findings could be generalized. There is support for the earlier results when the three centers' discharges are considered as a whole but not when the two new centers' discharges are considered separately. Reasons for these findings are discussed. Further study of these preadmission variables, especially severe aggressive/destructive behavior, as possible predictors of poor outcome in children's day treatment, seems warranted. PMID- 10111978 TI - Outcome after partial-hospital treatment of severely disturbed adolescents. AB - Results of a follow-up study of 50 adolescents treated in a day-hospital program are reported. The program admits seriously disturbed adolescents, over two-thirds with a personality diagnosis. Patients are treated in the day hospital for an average of 3 to 9 months. Outcome results are two-thirds adaptive outcome and one third poor outcome as measured on a level of function scale in the areas of peer and social functioning, occupational functioning, and family relationships. Variables that were significantly related to outcome were significant relationships to peers and staff at discharge, diagnosis, learning disabilities, age at admission, family substance abuse, and type of discharge. These findings are explained in the context of the treatment philosophy. PMID- 10111979 TI - State statute reference concerning partial hospitalization, 1988. AB - A survey process was begun in 1983 collecting and examining state statutes governing Partial Hospitalization programs. Data were collected from 37 states and the Country of Canada, which were then analyzed into the categories of definition, goals, target population, length of stay, frequency of patient participation, duration of a program day, program services, staffing, and documentation and quality assurance. The results revealed a great diversity of the operationalization of the treatment modality of partial hospitalization through state statutes. There is a clear need for increased levels of clarity and uniformity of this treatment mode. PMID- 10111980 TI - Predictors of long-term outcome for veterans participating in a day-hospital program. AB - While recent studies have investigated the relationship between patient characteristics and immediate treatment outcome in day-hospital treatment, none have investigated the relationship between these variables and long-term outcome. the present study attempts to expand upon previous research by including long term follow-up variables based on posttreatment psychiatric hospitalization. A total of 96% of the admissions to a DVAMC Day Hospital Program in 1985 was reviewed retrospectively and for a 4-year follow-up. As with previous studies, the only consistent predictor of both immediate and long-term treatment outcome in day-hospital treatment was the number of pretreatment psychiatric hospitalizations. Immediate treatment and long-term treatment outcomes were also significantly associated, but variables which predicted the former did not necessarily predict the latter. PMID- 10111982 TI - Deliver the message. PMID- 10111981 TI - MRSA (methicillin-resistant Staphylococcus aureus) guidelines have positive financial impact. PMID- 10111983 TI - Protecting confidentiality in the fax age. PMID- 10111984 TI - Hospital promotes a healthy environment. TMC EarthCare. PMID- 10111985 TI - Rural hospital rises to the occasion. PMID- 10111986 TI - The Healthy Children Program: a network of solutions. PMID- 10111987 TI - The rights of pregnant patients: Carder case brings bold policy initiatives. PMID- 10111988 TI - Medicare Part B forum shopping: legitimate enhancement or abusive practice? PMID- 10111989 TI - Health insurance industry shouldn't be exempt from antitrust laws. PMID- 10111990 TI - Success versus survival: are they the same? PMID- 10111991 TI - Hospital collaboration. PMID- 10111992 TI - Can inner-city hospitals survive? PMID- 10111993 TI - Fundraising. PMID- 10111994 TI - Hospital CEO turnover. Phase II: A longitudinal study comparing leavers and stayers (1979-90). PMID- 10111995 TI - Retreats: getting your money's worth. AB - Though well-done retreats can be sound investments, those investments can be substantial. Direct expenses alone can range from $200 for an in-town luncheon to $450,000 for a week-long event. PMID- 10111996 TI - Information technology is not enough. PMID- 10111997 TI - Balancing doing well and doing good. PMID- 10111999 TI - Reshaping healthcare: setting the pace. PMID- 10111998 TI - Advocacy and the healthcare executive. PMID- 10112000 TI - Survival: proactive roles in a changing environment. PMID- 10112001 TI - 1996 forecast: physician, hospital relationships. PMID- 10112002 TI - Creative financing to meet multiple missions. PMID- 10112003 TI - Identifying technology's revenue potential. PMID- 10112004 TI - Resume rules for healthcare executives. PMID- 10112005 TI - Managing the paper blizzard. PMID- 10112006 TI - Impaired healthcare executives. American College of Healthcare Executives ethical policy statement. PMID- 10112007 TI - New lounge is key part of hospital's long-range physician-bonding plan. PMID- 10112008 TI - Capitalizing on the EPA's shift in favor of "in-place" asbestos management. PMID- 10112009 TI - What does the future hold for EtO-gas sterilization? PMID- 10112010 TI - System-failure reports meet JCAHO, Q/A needs. PMID- 10112011 TI - Cogeneration: will it work at your health facility? PMID- 10112012 TI - Communication key to coping with NLRB ruling. PMID- 10112014 TI - Special issue. Strategic alignment of health care organizations: management case studies. PMID- 10112013 TI - Engineers hold sway over building-control buys. PMID- 10112015 TI - Competition, integration, and diversification: seven hospitals of Growthville, U.S.A. AB - Summing up across the three phases of this case, the pattern of evolution was (1) emergence of a market orientation by hospitals as the industry moved away from regulation; (2) steady expansion of what the hospitals considered to be their business, to include nonacute hospital and medical services as well as insurance, with vertical integration and concentric diversification serving as the vehicles for accomplishing this expansion; (3) remarkable change with respect to who was competing with whom, stemming from restructuring of hospital relationships away from open competition among many toward domination by a few; (4) a shift in the market from one of consumer choices among physicians and hospitals toward one of competitive choice among health plans; and (5) the emergence of negotiated pricing within the context of the new oligopoly, stemming from the heightened and organized power of corporate purchasers. Finally, we return to a concept presented in the introduction to this case: strategic alignment. The case has described the substantial realignment of our study hospitals to their new and changing environment. And it has highlighted their managers' use of boundary scanning, competitor analysis, and strategy to achieve this realignment. James Thompson's word for this process is "co-alignment," referring to "the most critical managerial function, and the skill closest to creativity." This case has illustrated this management skill, defined as "the discernment of hitherto unnoticed relationships in the complex environment, calculating their cause effect relationships, and translating them into appropriate programs of action". This is both a summary of the performances of our case study managers and a powerful prescription for those who might face similar circumstances and challenges. PMID- 10112016 TI - Analyzing the financial performance of hospital-based managed care programs: the case of Humana. PMID- 10112017 TI - Capitated Medicaid and St. Joseph's Hospital. AB - This case study presents the initial reactions of St. Joseph's Hospital and Medical Center, a large nonprofit hospital in Phoenix, Arizona, to the creation of a competitively bid, prepaid, managed care Medicaid program in 1982. It also presents the events in the first year of the Medicaid experiment and the subsequent reactions of the hospital. It illustrates the diverse set of issues that a hospital faces when it moves toward greater vertical integration in health care. PMID- 10112018 TI - Managing health insurance risk under capitation. PMID- 10112019 TI - The integration of health care as a model for the future. AB - Ten years ago, health care was characterized as a three-legged stool, each leg representing hospitals, physicians and insurance, respectively. That view is no longer correct, according to Albert Barnett, M.D., who foresees a new, integrated system and what it means for the future of health care. PMID- 10112020 TI - The foundation of group practices' future: vertically integrated health care systems. AB - Darrell Schryver writes that hospitals and physicians need to establish unified goals and objectives to meet society's changing needs. A vertically integrated health care delivery system, which Schryver describes in detail, is one way to achieve this unification. PMID- 10112021 TI - Medical groups and hospitals. Win/win collaboration using technology. AB - The linkage of hospitals and medical groups in an on-line computer network results in benefits for many groups including patients, medical practices, hospitals and third party payors. Joy McGee-Cory, M.B.A., and Leigh Hantho, M.B.A., describe these benefits and also offer a successful case study. PMID- 10112022 TI - Leadership, making a difference in the 1990s. PMID- 10112023 TI - Health care delivery in the 1990s--putting the pieces together. AB - Robert Bohlmann, FACMGA, well-known for his "Ear to the Ground" column in MGM Update takes an in-depth look at the restructuring taking place in America's health care system. He looks at this restructuring by examining why change is taking place; characteristics of the ultimate health care system; current status of the health care industry; and challenges to maximize the ultimate system. PMID- 10112024 TI - Physician/hospital relationship building. PMID- 10112025 TI - That delicate balance: physician services within a multihospital system. AB - Group practices and multihospital systems now are beginning to reap the benefits of centralized expertise, management and economies of scale, write Donald Lovasz and Nancy Roberts. These benefits, they warn, must be balanced with the entreprenurial spirit of physicians and hospital administrators and able to respond to local and current situations. PMID- 10112026 TI - From 12 solo practices to a hospital-based LMSG (large multispecialty group) in 100 easy steps. AB - In this final article, authors John Benvenuto, M.D., M.B.A., M.P.H., Michael Stark, D.O., and Richard Radoccia, M.B.S., M.P.H., describe how the visions of hospitals and physicians have remained virtually the same for the past century. What has changed is the business of health care and this change has impacted two areas they describe in detail--income and control. PMID- 10112027 TI - Collaborative production and resource allocation: the consequences of prospective payment for hospital care. AB - This article presents a model of the intensity of care provided by hospitals and physicians and how such intensity was affected by the change to prospective payment by Medicare. Prospective payment introduced an incentive for hospitals to shorten average length of stay, but in order to keep the patient recovery level constant, intensity of inpatient care was forced to increase. Physicians reacted to hospital changes by increasing their own intensity of care provided to inpatients. Implications of the model for admissions and physician office time are also explored. Empirical results indicate that for the period 1983-1987, spanning the introduction of PPS, both hospital and physician intensity of care per inpatient rose significantly. PMID- 10112028 TI - Walk-in refrigerators are key to proper cold storage. AB - Often overlooked as an important kitchen design element, properly sized refrigeration and freezing equipment is an important contributor to a kitchen's functionality. In many operations, particularly large-volume units, walk-in refrigerators are the anchors of a good cold-storage system. A walk through three different foodservice operations--a college, a hotel and a hospital--finds walk ins at work. PMID- 10112029 TI - Wanting everything done while others do without: an irony in American health care. PMID- 10112030 TI - The case: Denny's story. PMID- 10112031 TI - Insurance reform: Congress to proceed cautiously. PMID- 10112032 TI - Adversaries must ally to combat high health care costs. PMID- 10112034 TI - Standards for clinical information processing. PMID- 10112033 TI - Standards for the electronic transfer of clinical data: progress and promises. AB - Data exchange standards have two components: the message format or syntax and the dictionary of codes (semantics). For many applications, message standards already have been developed. For a few kinds of clinical entities, such as drugs, these code systems (e.g., the National Drug Code) are virtually complete, but a few gaps must be filled and an agreement must be reached about the level of granularity needed. The available codes for clinical descriptors are inadequate but the National Library of Medicine's Universal Medical Language (UML) project will do much to redress this deficiency. Codes for clinical variables such as blood pressure and blood glucose which have methods, units, normal ranges, and physiologic correlates are very inadequate. CPT4 provides some of the needed codes but has huge gaps. An early effort to extend CPT4 is included in ASTM 1238. Work being done by ASTM E31.12 and the Euclides project will offer robust codes for clinical laboratory measurements. If we want to pool data from different institutions for clinical and policy research, universal codes for observations are prerequisite. And agreement of an international coding system for observation bearing variables should be a major agenda item for standards groups in the next year. Our goal has been to standardize the communication of clinical data between clinical systems, not the systems themselves or their internal operation. In fact, standardizing the internals of clinical application could be counterproductive at the present. It would deflect energy from, and delay the spread of, CDI standards. Moreover, it gives undue attention to computer systems, rather than the data they contain. The data are the most expensive part of any data system. They are the raison d'etre for such systems. Computer systems come and go. The data last forever. Yet we have been mesmerized by the computer system while ignoring its contents. As a result, most computer-stored clinical data must live like the tragic boy in the bubble. They cannot "live" outside of the computer system in which they were born. So, we find at every hospital the bizarre rituals of humans reading computer-generated reports so they can type this information in another computer. Electronic (e.g., stored clinical) data should not depend upon the internals of a particular program, language, or machine for its interpretation. The clinical data entered into one computer system should be directly available to any other computer system that now receives them through manual transcription. Data interchange standards give life to our data--independent of the source system. PMID- 10112035 TI - The role of ASTM (American Society for Testing and Materials) in computer information standards for medicine. AB - The computer is a valuable tool for processing information and knowledge in medicine. Its ability to store, correlate, display, and transfer vast amounts of information rapidly and economically has already greatly impacted medicine. As the standards needed to connect the diverse parts of the current systems are put into place, future capabilities will be even more significant and encompassing. With these standards will come the ability to readily draw diverse information together for appropriate display, analysis, and interpretation. Good standards are essential for the continuation of the computer revolution in medicine. PMID- 10112036 TI - Standards for automated patient records. AB - The work in standards development is essential to the rapid development of automated patient records. The standards set forth the common pathways needed to support and strengthen parallel efforts in automation throughout medicine. Automation fosters a changing paradigm in patient records. Automated records will not only provide more timely, accessible patient information, but will provide opportunities to link practitioners to knowledge systems, thereby supporting the diagnostic process and quality indicators that generate clinical interventions and reminders. A dynamic, complete patient record consistently maintained across diverse care sites will continue to be an essential component in patient care. Standards for the information content, vocabulary, and linkage between systems will provide the foundations for patient care information systems. Because the individual patient record uniquely represents the patient, these systems will advocate more completely for individual patients and support practitioners' decision making on their behalf. As expressed by Waters and Murphy, "We can describe a patient in many ways, according to many needs, according to many characteristics, yet in so doing we will inevitably compile a set of information inseparable from a particular individual." That concept is unchanging. Technology supported by accepted standards ensures that patients can be served through effective, timely, complete information. In serving the patient, the health care system can be served. In an article in Decisions in Decision Economics Dr. Paul Lang explained that Successful management, that is, the acquisition, collation, organization, storage and retrieval of patient-related information, is not only essential to an acceptable future for the health care-system, but is also critical to surviving the crisis of the present.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10112037 TI - IEEE (Institute of Electrical and Electronic Engineers) P1157 Medical Data Interchange (MEDIX): application of open systems to health care communications. AB - IT offers the potential for controlling the rising costs of health care while continuing to improve the quality of health care delivery. Health care communications standards are a necessary condition to accelerating the diffusion of IT in health care. The IEEE P1157 standards, which are international in scope, are being developed by a process of open participation under the auspices of the IEEE EMBS to meet strict conformance to the ISO/OSI standards. The IEEE P1157 standards are being coordinated with related health care information systems and will make an important contribution in this area. The initial focus of the IEEE P1157 committee will provide a needed subset of the eventual standard in 1991. The long-term focus on the patient record will provide the groundwork for extension of the effort to cover communications in all of health care. Development of these standards is based upon voluntary effort. All health care professionals with an interest in this area are urged to participate actively in the process. PMID- 10112038 TI - Health Level 7: an application standard for electronic medical data exchange. AB - The development of the HL7 is proceeding along two lines. Much effort is being spent on solving the ambiguities of version 2.1 and in extending the standard to areas that are not yet well defined. For example, at a recent working group meeting new messages were defined for dealing with pharmacy records, specifically those relating to IVs. As the number of vendors implementing the standard and as the number of organizations using the standard increase, the standard will continue to be refined and expanded along current formats. As often as possible, these efforts will be "backwards compatible" and may be implemented by vendor choice as the need arises. These changes will be distributed as chapter updates to the current release. A parallel effort is underway that will add formality to the development of the standard. These efforts incorporate a number of case tools, including data modeling. The biggest advantage of this approach will be to reduce significantly the ambiguity in data element definitions. Completeness and correctness of data relations will be enhanced as well. New approaches to documentation, including an object-oriented specification of the data model, will increase understandability. There are still a number of domain-specific areas in which the standard needs to be defined and examples generated to show how the standard applies. Forms of data transfer other than text must be accommodated. HL7 again will take advantage of existing work in these areas, such as the work of American College of Radiology/National Equipment Manufacturers Association (ACR/NEMA) in standards relating to image transfer. HL7 will continue to move toward OSI-compatibility.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10112039 TI - The Institute of Medicine's patient record study and its implications for record administrators. PMID- 10112040 TI - Innovations and research review: insights on hospital medical record managers using personality analysis. AB - In general, the hypotheses presented at the onset of the study were supported by the results reported here. Over 75 percent of the medical record managers surveyed were from facilities of less than 300 beds. Findings are consistent with characteristics of supervisors in small-to medium-sized departments. The most unique finding relates to the overrepresentation of NP managers in the larger facilities. The NP manager has a global, innovative perspective but also may have trouble coming to closure on projects and decisions. This managerial type will quite easily find other intuitive managers. Other perceiving managers will be found much less frequently and the perceiver must be prepared to have this perspective viewed as unique by other managers who are predominantly Js. Further research is needed to provide detailed explanations for this portion of the results. The majority of this group were classified in the SJ temperament grouping. More sensors were found among ARTs, in smaller facilities, and in the hospital medical record department manager population as a whole when compared to other managers. These findings provide insights that must be recognized and evaluated by the profession as it looks to the future and focuses on long-term goals. This research focuses on hospital medical record managers, only one of many groups that make up the medical record profession. Additional studies are needed to verify results and to evaluate individuals in other hospital medical record positions and in other settings, as well as other allied health managers. This research does, however, provide the basis for future comparisons. PMID- 10112041 TI - Forum: continuous quality improvement in health care. PMID- 10112042 TI - Plugging the medigap. New health plans should cut costs. PMID- 10112043 TI - Positive discipline. PMID- 10112044 TI - Moving patient care technology into the future. PMID- 10112045 TI - Teach them to work harder: thoughts about improving peak performance. PMID- 10112046 TI - MRI anxiety reduction. PMID- 10112047 TI - Patient feedback. PMID- 10112048 TI - Medicine, society, and the hour of technology. Where are we? Where are we going? PMID- 10112049 TI - Management of SNF beds in a group model HMO. AB - The appropriate use of alternatives to the acute care hospital is an essential component of the HMO's ability to manage utilization. The Skilled Nursing Facility (SNF) can be a particularly useful and flexible alternative. The present article describes how Fallon Community Health Plan, a 130,000-member group model HMO that includes a 16,000-member Medicare risk contract known as Senior Plan, integrates SNFs into its overall delivery of patient care. The article discusses the types of patients admitted, reasons for admission, types of services provided, and outcomes. The article also discusses the continuing evolution of the HMO's use of the SNF in patient care management. PMID- 10112051 TI - Selected bibliography on HECs. PMID- 10112052 TI - Fundamental rights: comments on Medical Discrimination Against Children With Disabilities, a report of the U.S. Commission on Civil Rights, Washington, D.C.; 1989. PMID- 10112050 TI - A geriatric nurse practitioner/physician team in a long-term care setting. AB - A large Massachusetts group practice and affiliated HMO studied the effects of a geriatric nurse practitioner/physician team on quality and cost of health care delivery in a long-term care setting. A geriatric nurse practitioner (GNP) was recruited to work with one physician in three nursing homes. The GNP/MD team made joint routine visits; the GNP provided primary care, including episodic visits as needed. After one year, a retrospective chart review was conducted comparing the periods before and after the implementation of the GNP/MD team. There was a 26% reduction in hospital admissions, and a decrease in the total number of hospital days after the GNP/MD team was implemented. Patients, nursing staff, and physicians all expressed satisfaction with the program. This study suggests that significant cost savings and increased quality of care can result from the implementation of a GNP/MD team in a long-term care facility. PMID- 10112053 TI - Do not resuscitate policies of New Jersey hospitals. AB - The do not resuscitate (DNR) policies of 100 New Jersey hospitals were investigated using a questionnaire to evaluate hospital characteristics, DNR documentation, decisionmaking, consent, satisfaction with present policies, and revision plans. Among responding hospitals, 78% indicated they had a policy, with -61% being established between 1984 and 1987. Twenty-two percent of hospitals with a DNR policy accepted oral orders, 39% accepted telephone orders, and 36% required written consent from a competent patient. Forty-nine percent of hospitals with a policy accepted qualified orders such as, "do not intubate." Sixty-two percent of responding hospitals were satisfied with their current policy. For 22 hospitals without a policy, 80% indicated dissatisfaction with their current practice. When hospitals with a DNR policy were compared to those without a policy, government supported hospitals were less likely to have a DNR policy than non-governmental hospitals (P = .04). Hospitals without a policy were more likely to perform "slow codes" than those with a policy (P = .007). A two year follow-up survey found seven hospitals without DNR policies. PMID- 10112054 TI - Point and counterpoint: should an institution's risk manager/lawyer serve as HEC members? PMID- 10112055 TI - Murder or mercy? The debate over active euthanasia has only just begun. PMID- 10112056 TI - Special report. Proposed Medicare fee schedule reveals rescaled RVUs, new $26 conversion factor. PMID- 10112057 TI - Building business through partnerships. AB - In a request-driven environment, human resources can be pressured to "do a program," which solves the immediate problem. Such procedures result in a reactive mode of operation, which may not address the more global needs of the organization. PMID- 10112059 TI - Automate the entire employment function. PMID- 10112058 TI - Domestic-partner benefits. PMID- 10112060 TI - The high potential woman. PMID- 10112061 TI - Private companies offer long-term incentives. PMID- 10112062 TI - Piecing together the diversity puzzle. PMID- 10112063 TI - Renewed push under way in New York to mandate patient advocate position in hospitals. PMID- 10112064 TI - Concerns about patients' rights and rising costs lead hospitals to form medical ethics network. PMID- 10112065 TI - Rural Oregon hospital builds new way of care giving, spreading patient-oriented 'revolution'. PMID- 10112066 TI - Spotting reading problems among patients can help ensure they receive proper care. PMID- 10112067 TI - Patient rep role expands at Atlanta hospital using quality improvement principles. PMID- 10112068 TI - Staff and management learn communications can be key in stimulating morale and improving patient care. PMID- 10112069 TI - Discounts for patients drum up business for hospitals and companies. PMID- 10112070 TI - Seniors scan computer in search of personalized benefits. PMID- 10112071 TI - Hospital finds clues to care by measuring patient outcomes according to specific ailments. PMID- 10112072 TI - Innovative ways to improve working conditions for nurses also contain benefits for patients. PMID- 10112073 TI - Advances in food service technology speed meals and cut costs while spelling out convenience for patients. PMID- 10112074 TI - Two Michigan hospitals seek women patients in different ways; offer distinct services. PMID- 10112075 TI - Hospital affirms rights of pregnant patients in landmark case; new policy could be model for other hospitals. PMID- 10112076 TI - New ruling draws Cruzan case to a close but leaves heated ethical debate. PMID- 10112078 TI - Patient reps reach new heights and predict even more changes ahead for the profession. PMID- 10112077 TI - Scanner speeds processing of patient satisfaction data and shoots information back to various departments. PMID- 10112079 TI - Montana to experiment bringing hospitals to remote areas and serving patients often cut off from local care. PMID- 10112080 TI - Patients get a free ride from hospitals intent on driving out their transportation woes. PMID- 10112081 TI - Medical staff credentialing and privileging determinations: the emerging role of the risk manager. PMID- 10112082 TI - Risk management crisis control: inpatient suicide. PMID- 10112084 TI - Tough choices: handling illegal questions. PMID- 10112083 TI - Managing loss adjustment expenses: strategies for health care risk managers. AB - Like most businesses, adjusting companies are not charitable organizations. They are entitled to a reasonable profit, which the risk manager should not begrudge. As a buyer of adjusting services, a risk manager with an inordinate obsession with slashing adjusting bills can destroy the goal of high-quality service. It is best for risk managers to pick and choose the areas for cutting adjusting expenses. To an extent, health care risk managers should view payment of high quality adjusting services as an investment, with the payback being money saved by fighting fraudulent, exaggerated, and questionable claims. PMID- 10112085 TI - The NABPLEX (National Pharmacy Licensure Exam): increasing your odds. PMID- 10112086 TI - Resource directory--pharmacy. Licensing requirements. PMID- 10112087 TI - Blueprint for an interview. PMID- 10112088 TI - Strategic planning. How to play the game. PMID- 10112089 TI - No secrets, no surprises: understanding the NBRC (National Board for Respiratory Care) credentialing exams. PMID- 10112090 TI - Positive projections: a dynamic future for respiratory care. PMID- 10112091 TI - Resource directory--State licensing and credentialing boards for nursing and respiratory care. PMID- 10112092 TI - Corporate culture: modern day rites & rituals. PMID- 10112093 TI - Major changes mark the 1991 Life Safety Code. PMID- 10112094 TI - Regulating contents and furnishings. AB - The criteria in the 1991 edition of the Life Safety Code are a first attempt to address the fire hazards associated with upholstered furniture and mattresses. Recognizing that the criteria do not represent a complete hazard analysis, it is anticipated that the subcommittee will continue its efforts and will evaluate the appropriateness of additional criteria. The NFPA Standards Council also has appointed a Technical Committee on Contents and Furnishings, which will meet in August 1991. This committee will have primary responsibility for developing fire hazard calculation procedures and documents that other committees can use to control the fire hazards of contents and furnishings. PMID- 10112095 TI - Looking backward: 2001-1991. The history of the Health Care Financing and Reform Act of 1998. PMID- 10112096 TI - Change of hearts. AB - Some very caring companies are now directly contracting with centers of excellence, which specialize in organ transplants and other cutting-edge procedures. PMID- 10112097 TI - Risky business: HMOs and managed care. AB - Are HMOs doing all they can do to control health care costs? Or are they enjoying the best of both worlds; that is, healthy subscribers and "equal dollars"? PMID- 10112098 TI - Physician, cut thy costs. AB - Everybody knows that health care costs are out of control--everybody, that is, except physicians. But now even the providers are getting the economy message and considering taking part in the cost cutting battle. PMID- 10112099 TI - Putting guidelines into practice. AB - Establishing standards of practice--and making certain practitioners operate within their bounds--are two of the most recent challenges to appear on the managed care scene. PMID- 10112100 TI - Ford has another idea. AB - Issuing databased report cards to hospitals on what they do right or wrong has saved Ford Motor Company money and improved hospital performance. PMID- 10112101 TI - Employers and managed care. PMID- 10112102 TI - Managed care from above. PMID- 10112103 TI - Should U.S. health care go global? PMID- 10112104 TI - Testing EAPs for coordination. AB - Though not yet a widespread practice, a few employers have tried their hand at integrating their EAPs and managed mental health programs. PMID- 10112105 TI - Workers and managers of the world, unite! AB - With their relationship less and less adversarial in nature, labor and management are putting aside historical differences for a worthy cause. They're now combining their brain power to come up with a workable solution to the nation's health care woes. PMID- 10112106 TI - Laboring to manage care. AB - What happened at AT&T is an example of the possibilities when labor and management cooperate. Both sides contributed their input, and the result was a health care plan that was acceptable to everyone involved. PMID- 10112107 TI - Unions rev up health reform engines. AB - Union leaders have some difficult choices to make. There are a number of proposals for the reform of health care and unions must decide which position they will support. PMID- 10112109 TI - Constraints on modifying health benefits. PMID- 10112108 TI - Union engineers a better health care system. AB - The Operating Engineers installed a managed care program that focuses on reducing costs by putting controls on key areas like patient length-of-stay and physician unbundling. But it also attempts to maximize quality of care. PMID- 10112110 TI - Data watch. Unions and health care. PMID- 10112111 TI - Medicare program; changes concerning interest rates charged on overpayments and underpayments--HCFA. Final rule. AB - We are revising the Medicare regulations to provide for the assessment of the higher of the private consumer rate or the current value of funds rate of interest on overpayments and underpayments to health care providers and suppliers. This change is being made to protect the Government's interest, as provided by the rules of the Secretary of the Treasury applicable to charges for late payments. We are also making clarifying changes in the regulations. PMID- 10112112 TI - Notice to Medicare providers--HCFA. PMID- 10112113 TI - Twenty years later: where has MUMPS gone and how did it get there? AB - The past chairman of the MUMPS Users' Group and the MUMPS Development Committee, Richard Walters, traces the development of MUMPS from its inception through its subsequent fragmentation and eventual standardization. He also suggests what the future will look like for MUMPS-based technologies. PMID- 10112114 TI - Western State Hospital: implementing a MUMPS-based PC network. AB - Western State Hospital, a state-administered 1,200-bed mental health institution near Tacoma, Wash., confronted the challenge of automating its large campus through the application of the Healthcare Integrated Information System (HIIS). It is the first adaptation of the Veterans Administration's Decentralized Hospital Computer Program software in a mental health institution of this size, and the first DHCP application to be installed on a PC client/server network in a large U.S. hospital. PMID- 10112115 TI - An open, modular, distributed and redundant computer system for hospitals. AB - Based on his experience at the University of Wurzburg in Germany, Dr. Schuller shows how a successful MUMPS-based hospital information system can be developed, including goals and requirements, networking, software hierarchies, programming in MUMPS, medical applications, data security/privacy and international standards. PMID- 10112116 TI - The service threshold. AB - New technologies are developed and refined every day, but the healthcare industry need not wait until they arrive to offer quality patient service. Moreover, a change in the service mindset of the Information Systems department can help an organization prepare to implement new technological advances that will directly improve quality of care. PMID- 10112117 TI - Opening new potential for MUMPS. AB - In an interview with Computers in Healthcare, Terry Ragon, founder and president of InterSystems Corporation, says that as MUMPS-based technologies become further refined in the next few years, they will serve as platforms for additional technologies such as RDBMS and application generators. He also looks at the directions for the expanding international MUMPS community. PMID- 10112118 TI - Sweepstakes--a benefit for whom? PMID- 10112119 TI - Special report on labor and employment. Supreme Court upholds NLRB bargaining units rule. AB - Providers should expect the number of union organizing campaigns to rise quickly in the wake of the Supreme Court's decision in AHA v. NLRB. Despite this increased activity, providers that offer good working conditions and maintain open lines of communication between employees and management, and that understand their legal rights in connection with such situations, will be much more likely to be effective in responding to union organizing activities. PMID- 10112120 TI - Maximizing sales through menu analysis. PMID- 10112121 TI - Knowing your employees: beyond demographics. PMID- 10112122 TI - Waiting for a better alternative. PMID- 10112123 TI - Over the road to health gain. PMID- 10112124 TI - Who should do the housework? PMID- 10112125 TI - Figuring out the future. PMID- 10112126 TI - Healthcare data briefing. Medical practice variations. PMID- 10112127 TI - Medication errors: new form aids in discovery, analysis, and prevention. AB - At St. John's Hospital, Springfield, Illinois, the Medication/Clinical Variance Subcommittee investigated medication/IV incident reporting. The subcommittee reviewed various problems and recommended changes in their report form. PMID- 10112128 TI - Learning the ten step QA process for use in pastoral care departments. Part II. AB - In the March/April issue of the Journal of Quality Assurance, Vol. 13, No. 2, pp. 10-15, the authors presented the first half of a ten step model used to teach the QA process to pastoral care directors and chaplains. Workshop members participated in a series of simulated exercises for a fictitious acute care facility, "St. Good Hart Health Center." This article continues with steps six through ten, including the definition and explanation of each step, St. Good Hart's story line, directions and illustrations, and the key QA issues that emerged from the process. PMID- 10112129 TI - Monitoring and evaluation: the management of blood borne pathogens. PMID- 10112130 TI - Environmental rounds: implementation of a continuous clinical safety improvement program. AB - The environmental rounds survey process at the UCLA NPI & H has been effective in providing clinicians and administrators with continuous data regarding clinical safety. This formal hospital-wide process is complemented by informal environmental rounds made periodically by clinical nurse managers and unit managers. Through these efforts, clinical safety is maintained by eradicating actual and potential patient/staff safety hazards. PMID- 10112131 TI - Immunity for peer review under the Health Care Quality Improvement Act of 1986. PMID- 10112132 TI - Healthcare Quality Educational Foundation update. PMID- 10112133 TI - Quality in ambulatory care: the two minute demonstration. AB - When asked to produce convincing evidence of quality, 281 ambulatory healthcare professionals suggested 98 different components of an ambulatory program. Obviously no overwhelming majority exists, nor is there a clear focus on what constitutes quality in the ambulatory setting. This demonstrates and highlights both the diversity of ambulatory care and the difficulty of defining quality in the ambulatory environment. We all feel that we know what quality is and that we provide quality care in our organizations. Quality is high priority, yet when asked for the most important demonstrator of quality, ambulatory care professionals gave 98 different answers. Based upon the Pareto diagram's top five categories as shown in Figure One, we can put together a composite definition. This composite would present the combined judgment of nearly 80% of the 281 seminar attendees. Quality ambulatory health care--meets the expectations (pleases) the patients, is enhanced and demonstrated by an effective quality assurance program, is the achievement of desired outcomes for patients, is dependent upon the excellence of the provider staff, and is enabled by an accurate, timely, and complete medical record system. The message for those of us in ambulatory care is that the process of working toward the definition of quality may be just as important as the actual definition of quality. A consensus on a definition of quality in the ambulatory setting is unlikely as there is too much diversity. It is important that each of our ambulatory centers should set out to determine its own definition of quality. The process itself is useful because it will help us to focus on the dimensions of quality. (ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10112134 TI - Standardization of patient care documentation in hospital, Part II. PMID- 10112135 TI - Volunteers are people, too! PMID- 10112136 TI - Reflections on aging. Communicating with elderly patients. AB - Like it or not, many of our attitudes about aging are based on our personal experiences with elderly people. Yet providers need to replace myths and stereotypes with an understanding of the cultural and socioeconomic factors at play when communicating with this burgeoning patient population. PMID- 10112137 TI - Linking the elderly to community services. AB - Sometimes, the only contact elderly patients have with outside medical services is through the EMS network. Find out how one city uses prehospital providers to link these patients with community services tailored to their needs. PMID- 10112138 TI - Bystander intervention. Help or hindrance? AB - Rubbernecks, lookie-loos, gawkers: Are they the bane of your existence, or can they be used to your advantage at the scene? And what makes them tick? PMID- 10112139 TI - Emergency in the clouds. AB - With more than 1,000 medical emergencies occurring each year on domestic flights, the chances of being called upon to assist one of these victims is soaring. What resources are available to healthcare providers 35,000 feet in the air? PMID- 10112140 TI - One size doesn't fit all. Choosing pediatric equipment: Part I. AB - Recent studies suggest that half the battle in treating pediatric patients is having access to the proper equipment. This article, the first in a two-part series, describes the factors to consider in selecting pediatric equipment for the prehospital setting. PMID- 10112141 TI - Defining a sense of duty. PMID- 10112142 TI - Emergency preparedness: the best defense for major disasters. AB - This article discusses how Silver Cross Hospital in Joliet, Illinois developed its disaster plan and how that plan was successfully tested when a tornado plowed through its service area, causing mass casualties who required both inpatient and outpatient care. PMID- 10112143 TI - Continuous quality improvement: implementation made easier for materiel management. AB - The author describes the step-by-step implementation of continuous quality improvement, based on the Hospital Corporation of America's model for CQI, to correct a persistent problem in CS. PMID- 10112144 TI - Charging for CS supplies by bundling low-cost items. AB - The authors describe how their hospital developed a new method to charge for CS supplies--by bundling low-cost items as an average daily patient charge added into the room rate--with the hope of increasing productivity, cutting down on expenses and maintaining reasonable revenues. PMID- 10112145 TI - Blood warmers. ECRI. PMID- 10112146 TI - Making continuous quality improvement a reality: people skills. PMID- 10112147 TI - Tracking the use of reusables. PMID- 10112148 TI - Equity and the distribution of UK National Health Service resources. AB - This paper examines the extent to which the British NHS allocates health care according to need. The results, based on 1985 data, show that within morbidity groups the poor receive, on average, more health care than the rich. This does not necessarily indicate pro-poor inequity. There is some evidence of a positive relationship between income and health within any morbidity category. The results contradict those of an earlier study which found bias favouring the middle classes. It is argued that the methodology adopted in the present study is more appropriate for the examination of allocation according to need. PMID- 10112149 TI - The effects of excise taxes and regulations on cigarette smoking. AB - We estimate a generalized linear model to examine adult and teenage cigarette demand. Out analysis focuses on the extent to which excise taxes and regulations restricting smoking in public places affect cigarette consumption. The adult results indicate that the price elasticity of demand is unstable over time, ranging from 0.06 in 1970 to -0.23 in 1985. These estimates are lower than most found in previous studies. The teenage price elasticity does not differ statistically from the estimates for adults. Additionally, regulations restricting smoking in public places have a significant effect on both adult and teenage cigarette demand. PMID- 10112150 TI - Alcohol advertising bans and alcohol abuse: an international perspective. AB - This paper examines the effect of banning broadcast advertising of alcoholic beverages. The data used in this study are a pooled time series from 17 countries for the period 1970 to 1983. The empirical results show that countries with bans on spirits advertising have about 16% lower alcohol consumption than countries with no bans and that countries with bans on beer and wine advertising have about 11% lower alcohol consumption than countries with bans only on spirits advertising. PMID- 10112151 TI - An econometric investigation of low birth weight in the United States. AB - Gravelle (1984) describes the pitfalls that can arise in the specification of empirical models of mortality rates. This paper concentrates on the low birth rates in the United States, a major correlate of the infant mortality rate and a continuing source of concern for health policymakers, and attempts to provide a methodological framework that addresses the issues raised by Gravelle. PMID- 10112152 TI - On nursing home quality: a review and analysis. PMID- 10112153 TI - Spatial competition and cooperation in local hospital markets. PMID- 10112154 TI - Mission statements: selling corporate values to employees. AB - This article investigates the reasons for the increasing use of the Company Mission Statement. Using information from a survey of U.K. companies in 1989 it looks at the types of statements issued by companies, their content, usage, and value to managers. Of particular interest is whether the mission is primarily used for the motivation of staff, or for external image building. Related issues are the value of the mission drafting process in bringing managers together to agree common objectives and the use of a hierarchy of statements to reconcile internal and external stakeholders' interests. The conclusion is that the Mission, which includes a statement of company values, is an important tool for managers to assert their leadership within the organization. PMID- 10112155 TI - Washington turns up antitrust heat on doctors. PMID- 10112156 TI - How managed-care contracts can drag down your income. PMID- 10112158 TI - The impact of the HELP computer system on the LDS Hospital paper medical record. AB - This study sought to answer the question: What percentage of an LDS Hospital patient's chart is contained in the HELP system? Using the number of pages in the record as the criteria, the answer is about 26 percent overall, but between 35 percent and 40 percent for patients in nursing divisions where computerized nurse charting is used. Although this fraction is likely to rise in the near future, the critical factor driving computerization is the desire for data usable in computerized decision making rather than the need to computerize the entire chart per se. The medical record at LDS Hospital will probably be a hybrid of computerized and paper data for some time to come. PMID- 10112157 TI - Off-day scheduling with hierarchical worker categories. AB - A work force includes workers of m types. The worker categories are ordered, with type-1 workers the most highly qualified, type-2 the next, and so on. If the need arises, a type-k worker is able to substitute for a worker of any type j greater than k (k = 1, ..., m - 1). For 7-day-a-week operation, daily requirements are for at least Dk workers of type-k or better, of which at least dk must be precisely type-k. Formulas are given to find the smallest number and most economical mix of workers, assuming that each worker must have 2 off-days per week and a given fraction of weekends off. Algorithms are presented which generate a feasible schedule, and provide work stretches between 2 and 5 days, and consecutive weekdays off when on duty for 2 weekends in a row, without additional staff. PMID- 10112159 TI - Implementing a clinical information system. AB - The design of CIS utilizing the hospital's network allows for the flexibility of providing clinicians with on-line access to additional valuable patient information. The acceptance of CIS and the continuing demand for access to CIS are excellent indicators that development of this system was well worth the efforts of the individuals and teams involved in the planning, design, and implementation of CIS. Although it cannot replace the traditional paper medical record, CIS certainly is being recognized as a timely and reliable resource for the communication of patient information in the Ohio State University's numerous patient treatment facilities. PMID- 10112160 TI - Case study: development of a forms-design guidebook. AB - Implementation of the approval and official format of medical record forms procedure along with the use of the forms-design guidebook will result in a forms management program that will be efficient and effective. This program is sufficiently detailed to provide forms that are consistent and useful. The procedure will provide the necessary documentation for forms control and will facilitate an approval process that is standardized and faster than before. An overview of the steps taken to complete this project are listed in the box entitled "Steps for Revision of Forms-Control Process." The control of medical record forms will provide documents that are useful and accurate for purposes of communication and planning of quality patient care and will meet the requirements of licensing and accrediting agencies. Also, the concentration on the consideration of cost throughout this project will reduce costs by improved efficiency in the paperwork system and by reducing both the production and the usage costs of forms. PMID- 10112161 TI - Euthanasia in The Netherlands: medical record documentation requirements. PMID- 10112162 TI - Medical record review for clinical pertinence. AB - This clinical pertinence review process described was in effect for seven months, after which the author terminated affiliation with the hospital. Despite resistance by many physicians, this monthly review process focused the medical staff's attention on good documentation practices. To the author's knowledge, the plan is still in use. PMID- 10112163 TI - Sources of stress and coping mechanisms of medical record students. PMID- 10112164 TI - Legal review: The Patient Self-Determination Act--"Miranda" rights in health care. AB - The Patient Self-Determination Act should help patients make their own health care decisions without the intervention of the courts. Health care providers will acquire a large responsibility for helping to educate the public concerning the availability and use of advance directives. It is hoped that the additional investment providers will make in administering the provisions of the Act will bear dividends in better informed patients and in loss of time and suffering avoided when health care decisions are required for incapacitated patients. PMID- 10112165 TI - Hospitals sizing up impact of Medicare physician fee schedule. PMID- 10112166 TI - Medical credentialing and the impact of the data bank. PMID- 10112167 TI - Hospitals deficient in filing tax form for community benefit. PMID- 10112168 TI - A guide for rural health care. PMID- 10112169 TI - New AHA president sets association's course. Interview by Mary Grayson. PMID- 10112170 TI - Effective board communication. PMID- 10112171 TI - Medical office buildings--a marketing strategy. PMID- 10112172 TI - The board's job in QA depends on the information it receives. PMID- 10112173 TI - Board confronts community opposition to hospital merger. Interview by Karen Gardner. PMID- 10112174 TI - Hospitals fit for healing. PMID- 10112175 TI - National Ambulatory Medical Care Survey: 1989 summary. PMID- 10112176 TI - AIDS knowledge and attitudes for October-December 1990. Provisional data from the National Health Interview Survey. PMID- 10112177 TI - Perspectives. Immigration law opens golden doors--for some. PMID- 10112178 TI - Perspectives. New safe harbors shelter few joint ventures. PMID- 10112179 TI - Perspectives. Twenty years of Maryland rate regulation. PMID- 10112180 TI - Medical malpractice: an empirical examination of the litigation process. AB - New data on medical malpractice claims against a single hospital in which a direct measure of the quality of medical care is available are used to investigate the roles of the negligence rule and incomplete information in the dispute settlement process in medical malpractice. We find that the quality of medical care (negligence) is an extremely important determinant of defendants' medical malpractice liability. More generally, we find that the data are consistent with a model in which plaintiffs are poorly informed ex ante about whether there has been negligence, file suit to gather information, and either drop the case if they find that negligence was unlikely or settle for a positive payoff if they find that negligence was likely. We also find that the cases are resolved earlier in the litigation process when the parties are more certain, one way or the other, about the likelihood of negligence. PMID- 10112181 TI - Uncertain litigation and liability insurance. AB - Legal penalties and liability insurance seem to have counteracting effects on the incentives of a potential injurer to take due care. However, if legal penalties are set efficiently and implemented perfectly, unrestricted access to insurance can be optimal. In contract, if the standards of guilt assessment are uncertain, the size of the legal penalties may act as a spur to litigation. Therefore, the penalties required to maintain incentives when access to insurance is unlimited may provoke too much litigation, and as a consequence, the costs of ensuring due care may decline when insurance is restricted by mandate. PMID- 10112182 TI - OSHA proposes revised asbestos regulations. PMID- 10112183 TI - Is the hospital incinerator a thing of the past? PMID- 10112184 TI - Wellness centers offer out-reach program for hospital marketing. PMID- 10112185 TI - Travelers clinics offer vaccines and advice on how to avoid foreign illnesses. PMID- 10112186 TI - Mammograms are a growing market for hospitals willing to innovate. PMID- 10112187 TI - Well-informed employees can be hospital's best advertisement. PMID- 10112188 TI - Patient satisfaction surveys often are inadequate measures. PMID- 10112189 TI - First hospital attempt to randomly test physicians for drugs runs into delays. PMID- 10112190 TI - Volunteers help to make patient stays more pleasant at Florida hospital. PMID- 10112191 TI - Assertive behavior reduces tensions among hospital workers and teaches staff to better deal with patients. PMID- 10112192 TI - Patients draw extra attention in hospital's nurse restructuring model. PMID- 10112193 TI - Program reduces hospital stays and maintains patient satisfaction; creator earns cash prize and fellowships. PMID- 10112194 TI - Teams and pairs limit number of people patients must deal with. PMID- 10112196 TI - Hospitals focus on right-to-die issue after high court affirms Missouri law. PMID- 10112195 TI - Training shows care givers way to handle aggressive patients. PMID- 10112197 TI - Patients like discharge process explained in advance. PMID- 10112198 TI - Illinois hospital trims weight loss program as Congress probes industry. PMID- 10112199 TI - Designing services for homeless women. AB - The complexity of homelessness suggests that the development of policy and service strategies requires careful analysis of the unique features of identifiable groups within the homeless population. To begin this process, the characteristics and needs of homeless women are specified and their routes to homelessness delineated. Responses to homeless women, with the exception of battered women, have focused primarily on the provision of emergency services. Future policy and services must focus on the adequacy and accessibility of these emergency services as well as the need for transitional and long term housing and social services. The multidimensional nature of homelessness and the heterogeneity of homeless women require a wide range of alternatives that can be tailored to each woman's unique needs for service. PMID- 10112201 TI - Determinants of health services utilization among the black and white elderly. AB - Andersen's (1968) behavioral model was used to assess whether factors predictive of health services utilization are the same or different for elderly blacks and whites. We hypothesized that because the black elderly have fewer resources, lower psychological well-being, and are in worse health, situational and attitudinal factors suggested by the model have different effects for blacks and whites. Using three measures of utilization--physician contact, hospital contact, and nights hospitalized--our findings show some support for differential effects, particularly in the case of physician contact. Neither resource factors such as health insurance nor psychological well-being were predictive of utilization within the black population. We conclude with some suggestions for future research. PMID- 10112202 TI - The relationship between alcohol and marijuana use and competence in adolescence. PMID- 10112200 TI - Adolescent fathers: an approach for intervention. AB - Many myths exist concerning the needs and problems confronting adolescent fathers. Research on adolescent pregnancy has proliferated in the last decade. We now have a substantial body of empirically-based findings in this area. Unfortunately, few substantive findings are available on adolescent fathers, yet the magnitude of this problem has reached epidemic proportion. This article will provide an overview of current research on adolescent fathers and their needs and offer suggestions for appropriate intervention. PMID- 10112203 TI - Report on surgical manpower. A look at past and present trends. PMID- 10112204 TI - Professional dissonance: balancing personal imperfection and professional genius. PMID- 10112205 TI - PPRC submits report on Medicare payments for assistants at surgery. PMID- 10112206 TI - Getting involved at the local level. PMID- 10112207 TI - Laser safety in health care facilities. An overview. PMID- 10112209 TI - Federal interest in medical liability reform intensifies. PMID- 10112208 TI - Are there too many surgical societies and annual meetings? PMID- 10112210 TI - ACS general surgeons participate in payment reform activities. AB - As reported in the Bulletin at various times over the past several years, the American College of Surgeons has frequently been called upon by federal agencies and commissions to provide clinical information and advice on issues that are associated with implementation of the Medicare physician payment system reforms mandated by the Omnibus Budget Reconciliation Act of 1989 (OBRA '89). In doing so, the College has often relied on the expertise of Fellows who are deeply committed both to the practice of general surgery and to the College. The purpose of this article is to provide a review of the College's participation in activities related to implementation of the Medicare reforms, as viewed by some of the general surgeons who shared in those efforts. PMID- 10112211 TI - Walking out on the boys. Interview by Elizabeth L'Hommedieu. PMID- 10112212 TI - Shape up--or else! PMID- 10112213 TI - Doctors and AIDS. AB - Just a year ago most authorities considered the chances of patients contracting AIDS from doctors and other healthcare workers a virtual impossibility. But last week a Florida woman who got AIDS from her dentist lay near death, and two Minneapolis physicians admitted they had treated hundreds of patients since being diagnosed with the virus. Although doctors are at far greater risk than patients, the Minneapolis cases renewed the debate over the right of sides to know each other's HIV status. PMID- 10112214 TI - Federal policy for the protection of human subjects. Final rule. AB - This document sets forth a common Federal Policy for the Protection of Human Subjects (Model Policy) accepted by the Office of Science and Technology Policy and promulgated in regulation by each of the listed Departments and Agencies. A Proposed Federal Policy for the Protection of Human Subjects published November 10, 1988 (53 FR 45661) has been revised in response to public comments. The Policy as revised is now set forth as a common final rule. For related documents, see other sections of this Federal Register part. PMID- 10112215 TI - Protection of human subjects; informed consent; standards for institutional review boards for clinical investigations--FDA. Final rule. AB - The Food and Drug Administration (FDA) is amending its regulations on institutional review boards (IRB's) and on informed consent to conform them to the "Federal Policy for the Protection of Human Research Subjects" (Federal Policy) published elsewhere in this issue of the Federal Register. Existing FDA regulations governing the protection of human subjects share a common core with the Federal Policy and implement the fundamental principles embodied in that policy. PMID- 10112216 TI - Adjustment of status; certain H-1 nonimmigrant nurses--INS. Interim rule with request for comments. AB - This interim rule implements section 162(f) of the Immigration Act of 1990 (IMMACT 90), Public Law 101-649, November 29, 1990. The interim rule establishes procedures for the adjustment of status to that of lawful permanent resident for certain alien nurses, their spouses and children. PMID- 10112218 TI - Civil money penalties for failure to report on medical malpractice payments and for breaching the confidentiality of information--HHS. Final rule. AB - This final rule establishes civil money penalties (CMPs) pursuant to title IV of Public Law 99-660, the Health Care Quality Improvement Act of 1986 (HCQIA), as amended by section 402(a) of Public Law 100-177. Section 421(c) of HCQIA establishes a CMP against any entity that fails to report information that is required to be reported on medical malpractice payments. Section 427(b) of HCQIA establishes a CMP against any person that breaches the confidentiality of information which is reported or furnished pursuant to HCQIA and which the Secretary has established the National Practitioner Data Bank to collect and disseminate. PMID- 10112217 TI - Civilian Health and Medical Program of the Uniform Services (CHAMPUS); annual fiscal year deductible for outpatient services or supplies--DoD. Final rule. AB - This amendment incorporates the applicable provisions of recent statutes relevant to the deductible amounts for outpatient care. Public laws 101-510 and 101-511 provide that effective April 1, 1991, the deductible amounts for medical care or services will increase from fifty dollars ($50.00) to one hundred and fifty dollars ($150.00) for an individual and from one hundred dollars ($100.00) to three hundred dollars ($300.00) for a family to include all CHAMPUS beneficiaries except dependents of active duty sponsors in pay grades E-4 or below. However, the Persian Gulf Conflict Supplemental Authorization and Personnel Benefit Act of 1991, Public Law 102-25, stipulates that, in the case of dependents of a member of the Uniformed Services who served or serves on active duty in the Persian Gulf theater of operations in connection with Operation Desert Storm, the provisions of Public Laws 101-510 and 101-511, shall not become effective until October 1, 1991. This latter category is defined in the rule as those dependents whose sponsors, are, or were, entitled to Special pay for Hostile Fire/Imminent Danger authorized by section 310 of title 37, United States Code, for service in the Persian Gulf Area. PMID- 10112219 TI - Statement of organization, functions, and delegations of authority--HCFA. PMID- 10112220 TI - National Library of Medicine programs--PHS. Final rule. AB - These regulations govern the programs of the National Library of Medicine (NLM). The regulations permit the Regional Medical Libraries to recover part or all of the costs of providing photocopies of biomedical materials; improve readability of the regulations; and update references to statutory authorities and uniform administrative requirements. PMID- 10112221 TI - Medicaid program; correction and reduction plans for intermediate care facilities for the mentally retarded--HCFA. Final rule. AB - This final rule amends the portions of the Medicaid regulations under which an intermediate care facility for the mentally retarded (ICF/MR) with substantial deficiencies that did not pose an immediate jeopardy to the health and safety of clients could continue participation in the Medicaid program. These regulations gave State Medicaid agencies the option of submitting written plans to either correct deficiencies or permanently reduce the number of beds in the certified portion of the facility. This rule removes all requirements for submitting, approving, and monitoring correction plans for ICFs/MR. The requirements for submitting and approving correction plans are being removed because the time limit for submission of these plans has passed. The provisions for monitoring correction plans are being removed because there are no remaining facilities for which these provisions apply. This final rule also removes requirements for submitting and approving reduction plans for ICFs/MR because the time limit for submitting these plans has passed. It retains and updates the requirements for monitoring and compliance that apply to those ICFs/MR for which reduction plans were approved by January 1, 1990. PMID- 10112222 TI - Medicare program; quarterly listing of program issuances and coverage decisions- HCFA. General notice. AB - This notice lists HCFA manual instructions, substantive and interpretative regulations and other Federal Register notices, and statements of policy that were published during January, February, and March 1991 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register at least every three months. We are also providing the content of the revision to the Medicare Coverage Issues Manual published during this quarter. On August 21, 1989 (54 FR 34555), we published the content of the Manual and indicated that we will publish quarterly any updates. Adding the Medicare Coverage Issues Manual changes to this listing allows us to fulfill this requirement in a manner that facilities identification of coverage and other changes in our manuals. PMID- 10112223 TI - Medicare program; Medicare secondary payer data match--HCFA. Notice. AB - This notice provides employers with information about the Medicare Secondary Payer (MSP) Data Match Program that involves HCFA, the Internal Revenue Service, and the Social Security Administration. The Data Match was provided for by Section 6202 of the Omnibus Budget Reconciliation Act of 1989. Under this provision, employers who receive data match questionnaires from HCFA for those employees who are Medicare beneficiaries or the spouse of a Medicare beneficiary must report certain health plan coverage information. The information will be used to determine whether Medicare payments for these beneficiaries should be or should have been primary or secondary to any payment that should be or should have been made by an employer group health plan (GHP). PMID- 10112224 TI - The dirty dozen marketing mistakes of the 1980s. PMID- 10112225 TI - A reimbursement quandary. Rate equalization, property payments batter Minnesota. PMID- 10112226 TI - Every facility has its price. PMID- 10112227 TI - Responsibility from top to bottom shapes QA. PMID- 10112228 TI - Regular check-ups keep residents rolling. Vans and buses need TLC, too. PMID- 10112229 TI - Employee training and motivation. Experts share insights on improving quality. PMID- 10112230 TI - Draw a crowd. Special marketing activities raise facility visibility. PMID- 10112231 TI - Activities revolve around volunteers. Enlisting extra help makes outings far easier. PMID- 10112232 TI - The 24-hour report: more than meets the eye. PMID- 10112233 TI - The interpretive guidelines: rote, reason or regulation? PMID- 10112234 TI - Who's on first? Panel discussion. AB - Are nurses suited for the prehospital-care setting, and are EMTs/paramedics equipped to function in the ED? Leading EMS authorities offer their perspectives. PMID- 10112235 TI - Compensation controversies. AB - Are EMTs and paramedics paid fairly? The author believes EMS providers have a long way to go before salary parity is achieved. PMID- 10112236 TI - A prescription for growth. AB - Can paramedicine be a career? Is career advancement possible? The author offers a strategy for enhancing professionalism and attaining credibility. PMID- 10112237 TI - Switching gears. PMID- 10112238 TI - The age of awareness. PMID- 10112239 TI - Street scene. Part 1: The hot zone. PMID- 10112241 TI - Of "grunts" and "groids". PMID- 10112240 TI - Coming of age. PMID- 10112242 TI - Geriatric emergencies. PMID- 10112243 TI - The other side of the story. PMID- 10112244 TI - Street scene. Part 2: The hot zone. PMID- 10112245 TI - Swede talk. PMID- 10112246 TI - Where the real money is in planned giving. AB - In planned giving, 80 percent of the money comes from bequests and 20 percent from life income agreements. But fund raisers still spend most of their time pursuing the 20 percent. PMID- 10112247 TI - Characteristics of the successful fund-raising executive. PMID- 10112248 TI - Allocating health resources ethically: new roles for administrators and clinicians. AB - Rationing of health care is an inevitable correlate of living in a world of finite resources. It is morally necessary. The Hippocratic ethic commits clinicians to do whatever will benefit the patient and therefore must be abandoned in a world of moral rationing. After looking at some unacceptable preliminary strategies, two patient-centered adjustments in the Hippocratic ethic, adopting a more objective standard of patient benefit and adding a principle of patient autonomy, are defended. Still, however, cutting the fat out of the system will not be sufficient. A true social ethic of resource allocation will be necessary. A social contract approach supports a principle of equity as a necessary supplement to utility and cost-benefit analysis. It does not follow, however, that clinicians must take on these social ethical decisions. Clinicians should be exempt from normal social ethics so they are free to pursue the objective welfare of patients (provided they consent to such benefit). Administrators are in no better position to allocate scarce resources. What is needed is input from patients to (a) set categorical limits on their own care, (b) articulate principles for fine-tuning the allocation decisions, and (c) supervise professional agents who will make specific gatekeeping decisions for allocating a pool of resources legitimately thought to belong to the patient population. Neither administrators nor clinicians will be responsible for rationing decisions. In 1989 we spent $604.1 billion on health (U.S. Department of Health and Human Services 1990). That is almost $2 billion a day. Sometimes the benefits are dramatic: the pneumonia cured, the heart transplanted, the children spared from infectious diseases with immunizations that cost only pennies. Even so, the American health care system leaves much to be desired. Many other countries have higher life expectancy at birth. Infant mortality in the United States is far higher than countries like Japan and Sweden (United Nations Children's Fund 1990). If we look at the distribution of health status in the United States, the problems look even worse. Today, depending on the study, about 13 to 15 percent of the population has no health insurance at all (U.S. Bureau of the Census 1989; Short, Monheit, and Beauregard 1989). Another 13 percent is woefully underinsured (Farley 1985). Social variables such as income, education, and race reveal dramatically different health status (Short, Monheit, and Beauregard 1989; Farley 1985). To respond to these needs, rationing will be essential.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10112249 TI - Ethical decision making requires collaboration between administrators and clinicians. PMID- 10112250 TI - Setting policy: the need for full participation. PMID- 10112251 TI - Ethical roles can exist only in an ethical system. PMID- 10112252 TI - Survival through productivity improvement. AB - There are dozens of additional case studies as well as success stories. The number of ways in which the information can be presented is limited only by the creativity of the user. In order of importance, the three principles remain 1. Convert all data to ratios. 2. Study emerging trends in the way the ratio changes over time. 3. Compare changes over time as well as static ratios to an outside source. To begin this program one needs to see what information is available at a particular hospital. If no other acceptable statistic is available use adjusted patient days. It is important that a productivity tracking system not be delayed until a system for statistical reporting is developed. It is also important to keep the system simple. Productivity monitoring is difficult because it requires a new perspective. We are used to using historical data and unique characteristics of a hospital in the budget process. Productivity gains require a detached perspective. Often only an outsider can identify some examples of overstaffing. The process is difficult, but it is not complicated. Productivity experts tell us we can produce a service faster, cheaper, or better, but not all three. Health care quality control ensures a better service. A standard cost accounting system for the health care industry may provide a less expensive service through better cost control. Productivity--the ratio of work output to resource input (health care costs)--can be increased. To make productivity improvement work the users must take the view of the entire institution rather than that of a department. Productivity measuring is necessary to ensure the survival of hospitals. This process could have saved many of the hospitals that were forced to close, and it could improve the financial health of many hospitals today. PMID- 10112253 TI - Organ donation and transplantation: an ethical analysis. AB - The experience of developing and implementing an organ procurement program for a health care agency is most rewarding. Being so deeply involved in the program development forces one to look at the ethical issues head on in an attempt to deal with them personally. Rather than just study the ethical issues at hand, participation in a program allows one to examine the issues in practice. It is likely that medical technology will continue to advance in scope. Health care professionals must keep abreast of the rapid changes that are occurring and confront the ethical issues involved. Only by confronting these issues can health care professionals begin to realistically resolve concerns and provide support for advances that will ultimately allow for growth in practice. PMID- 10112254 TI - Good guys finish last: understanding organizational politics. PMID- 10112255 TI - The impact of computer usage on the perceptions of hospital secretaries. AB - This study explored the perceptions of hospital unit secretaries regarding computer usage. Specifically, six attitudinal variables: performance, resistance, interpersonal relations, satisfaction, challenge, and work overload were examined. The study had two major findings: (1) hospital unit secretaries have positive perceptions of job performance, satisfaction, and challenge as a result of using the PHAMIS computer system and (2) hospital unit secretaries do not feel resistant to the system, overloaded with work, or inclined to increase their interpersonal interaction with coworkers. These two findings might appear contradictory on the surface, but in fact are consistent with overall positive perceptions about the PHAMIS system. The study also considered the impact of two independent variables--age and number of years at work--on the responses of subjects. The analysis indicated that together these two variables explained some variations in the values of at least two of the dependent variables--resistance and challenge. The authors therefore concluded that the installation of the hospital computer system has established a favorable working environment for those whose work is affected by it. The dramatic expansion of computer systems in nonprofit institutions as well as in profit-oriented institutions has made people more familiar with computer technology. This trend can account for the overall positive perception of the unit secretaries toward the new computer system. Moreover, training programs and the support of top management for the system may also have enhanced the positive attitude of the users. PMID- 10112256 TI - The appraisal interview: constructive dialogue in action. AB - The rater's role in performance appraisal is pivotal. Providing consistent feedback and winning the trust of the employee by honest and open verbal exchange are deciding factors in the overall success of the appraisal program. The manager must be trained to perform evaluations skillfully and with a commitment to the employee and to the organization. In addition, the appraiser must recognize that actively attempting to improve appraisal skills is a key responsibility of a good manager. PMID- 10112257 TI - Implementation of a patient classification system: using current resources to achieve organizational goals. AB - DeGroot describes five key activities and attitudes needed to successfully implement a PCS: commitment, coordination, education, involvement, and communication. As a result of careful planning by the nurse executive, these factors were present at PGH. This nursing organization's response to change was believed to be typical of most small community hospitals. The description of strategies used to facilitate a smooth transition to a computerized PCS, however, demonstrates one method of managing change. This organizational culture, similar to many nursing cultures, was once committed to preserving the status quo and is now committed to adaptation. As hospitals strive for economic survival, the nurse executive continues to have a pivotal role in developing proactive strategies to promote effective and efficient patient care delivery systems. Selecting and implementing a PCS is one strategy to achieve that goal. PMID- 10112258 TI - Preparing for networking information systems in health care organizations. AB - Because the health care administrator faces unprecedented demands concerning information, well-designed and carefully selected information systems have become a critical factor in the viability and survival of health care institutions. Local area network systems are having a significant impact in this regard. Among their advantages are flexibility, dependability, low cost, and modularity. Health care facilities, have found networking to be a simple, cost-effective solution to collecting, processing, and distributing large volumes of data. The keys to a successful implementation recommended in this article should assist health care professionals once they have made the hard decision to use a local area network to process their day-to-day transactions. PMID- 10112259 TI - Bringing performance appraisal's most common problems into the open. PMID- 10112260 TI - A supervisor asks: "Going in their own directions". PMID- 10112261 TI - A review of successful hospital suicides and their aftermaths. AB - Suicide is common in hospitals, particularly psychiatric units and mental hospitals. But psychiatric patients aren't the only ones who commit suicide. Many hospitals have seen suicides in renal failure units, for instance, says one hospital security director. Suicides also occur in emergency rooms, parking decks, cancer wards, and virtually any other general service area. When they happen, suicides can spur lawsuits exposing hospitals to substantial damage awards. This special report will analyze reports of suicides at hospitals nationwide to look at patterns of the occurrences. It will focus on how some institutions have handled suicide problems. It will describe in detail two representative lawsuits and their outcome. PMID- 10112262 TI - Special report. Getting ready for JCAHO's no-smoking standards: what problems can be expected and how to meet them. PMID- 10112263 TI - 1-2-3 forecasting. PMID- 10112264 TI - Negotiating your package--severance or compensation. PMID- 10112265 TI - What are your patients reading? PMID- 10112266 TI - Managing the kitchenless, cookless, stockless, employeeless operation. PMID- 10112267 TI - English, Spanish, native language, or service? PMID- 10112268 TI - The registrar's registry: an automated tumor registry system. PMID- 10112269 TI - Health information students' perceptions of their chosen profession. PMID- 10112270 TI - Each one reach one: a recruitment program by the Georgia Medical Record Association. PMID- 10112271 TI - It was the worst of times, it was the best of times. PMID- 10112272 TI - Managing for success update. PMID- 10112273 TI - Utilization management: a bibliography (1989-1991). PMID- 10112274 TI - Understanding the current law and the gray areas of fraud and abuse. AB - New regulations at the federal level, especially the Medicare/Medicaid anti kickback law, could have chilling effects on physician business arrangements. What should physicians be aware of in order not to risk charges of fraud or abuse? PMID- 10112275 TI - Can the AMA weather the latest internal and external upheavals?. Interview by C. Burns Roehrig. PMID- 10112277 TI - Let's mount a right-to-die movement. PMID- 10112276 TI - Placing blame ... or finding solutions? PMID- 10112278 TI - Putting guidelines into practice. PMID- 10112280 TI - Assuring access to health care for all. PMID- 10112279 TI - Truth, justice and American medicine: what way are we headed? PMID- 10112281 TI - Fighting Medicare and Medicaid fraud and abuse. AB - The Department of Health and Human Services' inspector general has become more aggressive in recent years in ferreting out cases of fraud and abuse against the Medicare and Medicaid programs. Where will this "watchdog" focus future efforts? PMID- 10112282 TI - The physician's view: stop fraud and abuse by not paying for it. AB - Fraud and abuse in the health care field is no greater than in other areas of life, but it still occurs. One way to stop abuse of the system is for insurers to stop paying for seemingly fraudulent bills and by informing patients. PMID- 10112283 TI - Preparing the next generation: is internal medicine in trouble? AB - Without some immediate changes in graduate medical education programs, general internal medicine could be on the road to disappearing during the next decade, according to this internist and educator. PMID- 10112284 TI - Taking health issues to the forefront in the 102nd Congress. AB - Rep. Waxman (D-Calif.), head of the House Subcommittee on Health and the Environment and one of its more visible congressmen on health issues, comments on pressing problems currently facing the 102nd Congress. PMID- 10112285 TI - The Medicare fee schedule: fairness to physicians ... and Congress. PMID- 10112286 TI - Let's work together to safeguard the original promise of physician payment reform. PMID- 10112288 TI - Shopping for Medigap insurance. PMID- 10112287 TI - Taking aim at the real target: the 'conversion factor'. PMID- 10112289 TI - Internal medicine: a troubled but still great specialty. AB - Lifestyle issues, difficult patients, the hassle factor, the gatekeeper role and income may be cited by internists as some of the problems they face today. The solutions may not always be easy, but there are ways to make the speciality more rewarding. PMID- 10112291 TI - Counting the cost of toppling 'top-ups'. PMID- 10112290 TI - Radical blueprint or a grey area. PMID- 10112292 TI - First welfare state at the end of the road. PMID- 10112293 TI - A wild card in the pack? PMID- 10112294 TI - Bridging the gap. PMID- 10112295 TI - Right approach, wrong method. PMID- 10112296 TI - Issues in the selection of local anesthetics. AB - Several factors influence the safety with which neural blockade is performed, and something as simple as proper packaging can make a significant difference. For example, bulk packaging, individual boxes, and labels all should be color coded for easy identification and to alert the prescriber of ingredients requiring particular caution. One must also take care not to confuse single-use with multiple-use products, if the latter cannot be eliminated from formulary. Furthermore, substitutions must be made properly, particularly to avoid complications associated with products that contain preservatives. PMID- 10112297 TI - The relation between quantity and quality with coronary artery bypass graft (CABG) surgery. AB - Many technical procedures may be done with better quality at higher volumes. In this paper, we examine the experience with coronary artery bypass graft (CABG) surgery. Immediate death rates (death during the hospital admission) with CABG vary widely, from lows of 1 percent or so to highs approaching 15 percent and perhaps higher. Research from the United States demonstrates clearly that there is a volume effect. Centres and surgeons with higher volumes have lower immediate mortality. The volume effect persists even at relatively high levels, that is, above 650 procedures a year for a hospital and above 116 procedures a year for a physician. This fact strongly supports regulation to centralize CABG facilities. In The Netherlands and Sweden, CABG is so regulated. No other European countries have strong regulation to centralize CABG provisions. Outcomes could be improved by such regulation. PMID- 10112298 TI - Health services reform in Poland: issues in recent developments. AB - After ten years of debate and discussion, the political situation within Poland finally allows the possibility to implement basic reforms in the health care system. Parallel development of the political and technical aspects of the reform has now lead to a final proposal for fundamental reforms in health system responsibility, financing and management. This article describes the current conceptual developments and the political and social context for these final reform proposals at the time of their submission to the government. The primary changes suggested are aimed at increasing the awareness of local, regional and national administrations, health care professionals and the general public that health care has a cost, and that resources must be used carefully if they are to cover health needs. In addition, 'health care' as a term must be extended to include factors and activities besides direct medical services. Such factors as air and water quality, diet, smoking and alcohol consumptions are examples of matters which will also be included in the focus of health system planners. A key element of the organisational reforms is decentralisation of responsibility for health care planning and administration within the framework of nationally set standards and priorities. Based on local decisions, the current basic organisation unit of health care delivery, the ZOZ or integrated health care units, will be redefined and either decomposed into their component services or receive newly defined responsibilities more adapted to the local realities of available manpower and medical facilities. In addition, the development of a private health care sector complementing and even competing with the public services sector will be actively encouraged. PMID- 10112299 TI - EuroQol: health-related quality of life measurement. Valuations of health states by the general public in Norway. AB - The EuroQol instrument consists of a self administered questionnaire where subjects are asked to value health states on a visual analogue scale. The instrument is playing a role of linking cross-national data in the field of health status measurement. An experiment in Norway with an alternative lay out added little to the feasibility of the instrument. On the other hand, reducing the number of states to be valued did increase the response rate significantly. Valuations in a random sample of Norwegian subjects were quite similar to valuations made by subjects in England, Holland and Sweden. EuroQol valuations may have to undergo a radical transformation before being used as utility weights for life years, but the similarity in valuations across countries is a promising finding in itself. To the extent that these similarities are validated in later studies, authorities in any one of these four countries wishing to use health status indices in medical decision making, may in the future allow themselves to draw on results obtained in any of the other three countries. Particularly for a small country like Norway there is an obvious advantage in this. PMID- 10112300 TI - EuroQol: health-related quality of life measurement. Results of the Swedish questionnaire exercise. AB - The EuroQol Group, which currently comprises 7 centres in 5 countries, has been testing the feasibility of jointly developing a standardised non-disease-specific instrument for describing and valuing health-related quality of life. The instrument employs a visual analogue scale of the 'thermometer' type to allow respondents to rank a number of health states. As part of the Swedish IHE's contribution to the EuroQol Group's work, questionnaires were sent to 1000 people randomly selected to provide a representative sample of the Swedish population aged 16-84 years. 349 persons responded and 208 provided sufficient information for detailed analysis. From these 208 it proved possible to derive health status information in a quantitative form. The most interesting result was that the health state valuations from this survey indicated a striking similarity with those of EuroQol studies in Frome (England) and Bergen op Zoom (The Netherlands). The lessons learned from undertaking the survey are briefly discussed. The Swedish IHE is encouraged by the exercise to continue to play its part in the continuing developments of the EuroQol methodology. PMID- 10112301 TI - Territorial justice and RAWP (Resource Allocation Working Party). AB - This study evaluates the success of the RAWP reallocation of health care resources at the regional level in England between 1975 and 1985. This is achieved by studying the degree of territorial justice-the spatial relationship between needs and resources--in these two years. It is discovered that there was greater territorial justice in 1985 than in 1975, which suggests that the RAWP reallocation had at least partially achieved its objective. PMID- 10112302 TI - Policy and implementation of user fees in Jamaican public hospitals. AB - User fees and other forms of copayment for health care are becoming of increasing interest to policymakers in developing countries. As indigenous populations continue to expand in response to current and historically high fertility, and government resources become constrained due to macroeconomic circumstances, publicly provided health care is being squeezed financially. Most developing countries have committed their governments to either providing for all health care or at least ensuring that all citizens have access to health care regardless of ability to pay. This has translated in most contexts into blanket coverage for the entire population financed and generally provided by the government. Recent periods of slow growth, high debt burdens and restricted spending on high recurrent cost sectors, such as health care under International Monetary Fund and other donor agreements have reduced many developing countries' budgets and often the real value of health expenditures. The costs of inputs (personnel, drugs and consumables), however, have not declined and quality or quantity have been necessarily reduced. At the same time, options for financial relief outside the tax system have become of increasing interest to financially constrained governments. User charges are straightforward, easily understood and can in theory be profitable in the short term. From a fairness perspective, they also charge those who actually use the health system. Their major drawback for policymakers is the potential for undermining equity in the health system. PMID- 10112303 TI - Restructuring to create a climate for clinical excellence for nursing. AB - A fundamental responsibility and urgent requirement of health care leaders is to create and develop organizational structures and environments that support nurses and nurses' work--whose ultimate goal is to support the analytical, interpersonal and technical skills that combine with knowledge to produce wise and thoughtful caring. The ways in which structure can facilitate and enhance care delivery often are not clearly understood. This article describes a strategic reorientation and reorganization of the Department of Nursing of the Sir Mortimer B. Davis Jewish General Hospital in Montreal, designed to meet the needs of patients, nurses and the hospital more effectively. PMID- 10112304 TI - Role statement: one hospital's experience. AB - This article is a case study of a strategic planning process used by one Edmonton teaching hospital to develop a five-year planning document or role statement. In contrast to hospital role statements that are typically composed in the organization by senior personnel, input was sought from other health care providers, affiliated organizations and community groups. The role statement has since been endorsed by the provincial government and is the primary reference document for future funding strategies. General conclusions and observations are offered regarding role statements and their development. PMID- 10112305 TI - Planning for shared services: lessons from experiences of the Princess Margaret Hospital. AB - The plan to rebuild The Princess Margaret Hospital (PMH) on University Avenue in Toronto has provided several opportunities for institutions in the area to share programs and services. The PMH planning process has raised questions about the factors that influence the development of shared services plans, and the organizational and management challenges posed by such plans. This experience suggests 13 principles to develop effective shared services. PMID- 10112306 TI - Merger and medical staff: an approach to integration. AB - One of the most important aspects of a hospital merger is the impact on the medical staff. At University Hospital in British Columbia, which was established when two large general teaching hospitals merged, the comprehensive process to reorganize the medical staff structure was designed to account for this impact. Preliminary indications are that the process used was effective in creating a positive atmosphere and that the fundamental arrangements that resulted are conductive to future development. Although a formal evaluation of the overall integration of the medical staff at University Hospital is some time off, general evaluative criteria are proposed for future application. PMID- 10112307 TI - A blueprint for green marketing. AB - Companies have rushed to market environmentally acceptable products. But according to the author, many have ignored the planning considerations that should have preceded the development and promotion of these "green" products. PMID- 10112308 TI - The return of high performance to the U.S. workplace. PMID- 10112309 TI - Orchestrating the planning process. AB - Strategic planning at Lord Corporation is developed by line and staff managers. As a result, those responsible for implementation "own the plan," while the CEO directs the formulation of the strategy. PMID- 10112310 TI - Evaluating marketing assets in mergers and acquisitions. AB - Marketing factors often explain why mergers and acquisitions subsequently succeed or fail. Here are guidelines for appraising the value of marketing assets of companies that are M&A candidates. PMID- 10112311 TI - Cephalosporin prices rising in wake of Pryor bill. PMID- 10112312 TI - Hospitals see steady purchasing of specialty protective wear against blood aerosols. PMID- 10112313 TI - Count on spending $35,000 per LDR (labor delivery-recovery) unit for monitors and equipment. PMID- 10112314 TI - Hospitals cautious with sharps containers. PMID- 10112315 TI - Breaking down the communication barrier. AB - Dr. Hawkins addresses the problem of how QA managers can best persuade physicians of the importance of QA programs. Since communication is the basis of educating clinicians, the author analyzes the diametrically opposite perspectives of QA managers and physicians even as they pursue the common goal of quality healthcare. While doctors are primarily loyal to patients and peers with an immediate care focus, process-oriented QA managers emphasize the institution and its longer-term goals. To overcome physician resistance to change, Dr. Hawkins offers an adult learner model that stresses understanding the medical staff's viewpoint, negotiation and respect. Physicians are enthusiastic about QA when it helps solve "the endemic daily system problems." The author concludes by recommending that QA managers join physicians on their clinical rounds to bridge the gap between their different approaches. PMID- 10112316 TI - Improving the quality of inter-hospital transfers. AB - This study is unique in that it involved the efforts of several professional groups at eight medical centers to solve a common quality assurance problem. The study used a systematic approach to evaluate and improve the quality of care provided to veterans transferred from one facility to another. The initial survey of personnel identified perceived problems with the transfer process. Both the concurrent and the retrospective focused reviews substantiated these problems. As a result of the study, an inter-hospital transfer form was developed and implemented at eight VA medical centers with plans to expand its use to other facilities. An important benefit of the inter-hospital transfer form is the ability to use it to continuously monitor and improve the quality of inter hospital transfers. The study was conducted by Medical District No. 1 MEDIPRO. The Medical District Initiated Peer Review Organization is a physician directed system of quality assurance within the Department of Veterans Affairs. In each geographic District, VA medical centers provide physician representatives to a medical peer review board. The MEDIPRO board, with staff support, identifies potential quality issues, designs studies, establishes standards and thresholds, and analyzes and reports study results to the medical centers. The goal of MEDIPRO is to assure and continuously improve the quality of medical care provided in VA medical centers. PMID- 10112317 TI - Patient flow management. PMID- 10112318 TI - The utilization management policy/procedure manual made easy. PMID- 10112319 TI - The coordinating council: creating an integrated QA professional community. PMID- 10112320 TI - Hospital quality intervention strategies. PMID- 10112321 TI - Why become certified? PMID- 10112322 TI - Standardization of patient care documentation, Part I. PMID- 10112323 TI - New retirement communities target the "70-something" market. PMID- 10112324 TI - Running "hot" and the case of Sharron Rose. PMID- 10112325 TI - On scene, off duty. PMID- 10112326 TI - One size doesn't fit all. Choosing pediatric equipment: Part II. AB - This is the second in a two-part series designed to instruct EMS providers as to the benefits of procuring specially sized equipment for pediatric patients. This installment builds on the variables unique to this patient population and recommends specific types of pediatric equipment. PMID- 10112327 TI - Discipline with due process. AB - What steps must an EMS employer take when an employee requires disciplinary action? Determining what constitutes appropriate corrective action while affording due process to the employee can be especially challenging for EMS agencies. PMID- 10112328 TI - COBRA snakes its way around the system. AB - Many unresolved issues and conflicting interpretations have evolved since the enactment of COBRA six years ago. Although two recent amendments are noteworthy, perhaps the most significant COBRA development to date was spurred on by a little known internal memo issued by the Department of Health and Human Services. PMID- 10112329 TI - Destination dilemmas. Government ups the ante. AB - Never a simple matter, determining where to transport a patient has become increasingly difficult for EMS providers. Not only must traditional factors such as vehicle and facility availability be considered, but the increasing involvement of state and federal governments and national organizations has further clouded the decision-making process. PMID- 10112330 TI - 1991 ambulance manufacturers directory. AB - In order to fit form to function, ambulance design should be a democratic process that involves the participation of all providers within a service. Our annual updated list of ambulance manufacturers can provide the tools to ensure that custom-built rigs meet specific functional needs. PMID- 10112331 TI - Withholding resuscitation. The medical, legal and ethical concerns. AB - EMS training and system protocols have not kept pace with the changing perceptions of society and the medical community regarding patients' rights to die with dignity. Providers, therefore, often seem left to their own devices when deciding whether to initiate resuscitative measures. PMID- 10112332 TI - Client typology based on functioning level assessments: utility for service planning and monitoring. AB - Cluster analysis was used to develop a six-group typology based on level of functioning data from 2,447 clients with serious mental illness served by the Michigan public mental health system. The groups are described in terms of level of functioning in 16 domains, global functioning, diagnosis, demographic characteristics and services used. A group of older, poor functioning clients with high health needs was identified. A second group of highly dysfunctional clients with few health needs was also found. Two groups of young adult "chronic" clients were found: one with extensive substance abuse problems and one with moderate substance abuse problems and extreme levels of suicidal and aggressive behavior. Two groups of relatively good functioning clients were also identified: one with some problems in many areas and a second with functional problems in a number of life areas and pronounced symptoms of depression and demoralization. The results point to the utility of cluster analysis as a mechanism to organize and identify patterns within the rich array of information provided by multidimensional level of functioning assessments. The uses of empirically derived client types in planning and monitoring mental health services are discussed. PMID- 10112334 TI - The community competence scale as a measure of functional daily living skills. AB - Competence assessment is of growing interest to administrators and clinicians who work with deinstitutionalized psychiatric and geriatric populations. A new instrument, the Community Competence Scale (CCS), is a multiscale structured interview administered in a similar manner to the Wechsler Intelligence Scales. The CCS requires the subject to answer questions and perform tasks which are proximal corollaries of daily living skills. The psychometric properties of the CCS are reviewed. Results of studies involving administration of the CCS to deinstitutionalized psychiatri patients and geriatric patients are presented. The available data suggest that the CCS has considerable value as a preplacement screening instrument for determination of residential settings for chronic psychiatric patients. Since the original CCS requires between 60 and 90 minutes for administration, several recent studies have focused upon development of a short form. The results of this research effort are described. In sum, the CCS appears to demonstrate considerable value as a tool to aid decision making about community placement, social skills training and clinical competence determinations. PMID- 10112333 TI - The utility of level of functioning to characterize community residential settings. AB - An assessment of client functioning was utilized to characterize differences among community residential placement facilities, with the aim of understanding the relationships among settings. Clients recommended for placement in one of nine settings differed significantly on seven scales measuring community living skills, self-care skills, sociability, nuisance behaviors, violence, irritability and nursing needs. Results indicate that community residential settings, although characterized as forming a continuum, may be better conceptualized as an array of settings, where clients may differ in some but not all functional abilities. Facilities may also serve different functions for clients of different ages, either because of expectations concerning older clients or due to different patterns of functioning. Illustrations of the implications that can be drawn for purposes of policy-making and service planning are provided. PMID- 10112335 TI - A Canadian model for developing mental health services in rural communities through linkages with urban centers. AB - The development of mental health care services in rural areas has been a constant challenge in most countries of significant geographical size. By use of a case study from Canada, the development of a relationship between rural and urban mental health services was described. Issues including referral patterns, service accessibility, professional recruitment and the development of service in rural regions were studied. It is advanced that mental health administrators, policy makers, clinical service coordinators and educators will find that this approach to the development of mental health services in rural areas has some utility in Canada and in other countries. PMID- 10112336 TI - Bringing the abusive employee back. AB - In many health care settings, some dispute resolution process exists which limits the discretion of the employer to simply terminate an employee suspected of inappropriate or abusive behavior. On occasion, the working of such disciplinary processes results in an employee, who is viewed by management as having broken a fundamental trust, being returned to the workplace. In managing the return of these individuals, provider agencies must develop strategies to reduce the likelihood of any future client injury and to increase the chances of returning the employee to a productive functioning level. We surveyed employees returned to work after an abusive incident along with their supervisors to determine what specific supports each group saw as necessary for a successful return. As a result, an individualized, structured program was developed to deal with such returns and piloted. The authors' results indicate that the program might serve as one possible model for wider use. PMID- 10112337 TI - Focus group: implications for program evaluation of mental health services. AB - The focus group is a qualitative research method that involves group interaction based on a selected topic. It generally involves eight to 12 individuals who discuss a particular topic under the direction of a moderator who promotes interaction and guides the discussion on the topic of interest. This paper presents theoretical perspectives and a review of focus group methodology applied in related disciplines. A research project, which applied the focus group methodology, is described to illustrate important principles in utilizing this qualitative research technique. Information related to preparation for focus group sessions, structure, setting, participants, principles related to conducting the session and analysis are presented. The relevance of this methodology for research and practice in mental health also is discussed. PMID- 10112338 TI - Mental health crisis in California. AB - Over the last 30 years, California dejure (legislated) mental health policy has been based on deinstitutionalization and outpatient care through community mental health systems. But by the end of the 1970s, there was a growing concern over whether deinstitutionalization had successfully occurred, whether community mental health systems had failed and whether mental health systems had ever been adequately funded. In a national study released in 1990, California was named one of four states where mental health delivery has regressed in the past two years. A review of current California mental health policies indicates dejure and defacto policies are not the same. Most mental health dollars are going to state hospitals and community acute inpatient facilities. Budgets for community mental health have been steadily eroded, and the current mental health system is in crisis. Implementation of mental health policy is dependent on intergovernmental financing, and each level of government tries to avoid costs. Definitions of which clients are to be served remain unclear while pressures for more social control mount. Mental health remains segregated from physical health policy making and continues to operate at a political disadvantage in general fund budget battles. PMID- 10112339 TI - A summary measure of client level of functioning: progress and challenges for use within mental health agencies. AB - A summary measure of clients' level of functioning could assist mental health agencies to better document and evaluate their services. Currently, numerous state mental health authorities collect a level of functioning measure within a management information system on virtually all clients served with state resources. The uses of these data include describing the clientele, defining a priority population for services, preparing performance indicators and measuring contract obligations. However, clearer delineation of the construct of functioning, further exploration of the psychometric properties of the instruments and stricter procedures to ensure the accuracy of data would result in data that are more useful for both management and research. PMID- 10112340 TI - Uses of an empirically derived client typology based on level of functioning: twelve years of the CCAR. AB - The Colorado Client Assessment Record (CCAR) is a problem checklist and level of functioning rating instrument used to describe admission to a public mental health system. A brief, non-technical summary of recent research and administrative applications involving this instrument is presented. A stable factor structure, generalizable to several diverse client populations, is reported. Scaling procedures for measuring these procedures and a client typology based on this scaling are described. The client typology is differentially related to the types of services received and the costs of treatment episodes. The typology is also used to understand differences in case mixes and lengths of stay at two state hospitals. PMID- 10112341 TI - The value of hospital chaplains: patient perspectives. AB - Reports the results of a questionnaire mailed to insurance claimants (N = 2480) recently discharged from a hospital. Analyzes the results and concludes from the data that patients place high value on pastoral services. Suggests that both hospital administrators and chaplains make sure that adequate attention be given to serving patient families, long-stay and repeated admission patients, and to the patients' demonstrated need for frequent visits, particularly in these times of rapid changes in condensing hospital stays. PMID- 10112342 TI - "Teach us to pray": pastoral care of the new nursing home resident. AB - Discusses the many traumatic factors associated with leaving and entering a nursing home. Points to the significance of personal prayer in making such transitions, and offers specific guidelines for pastoral caregivers as they seek to meet the special needs of nursing home residents. PMID- 10112343 TI - Where's the line between primary and specialty care? PMID- 10112344 TI - Bias in medical education? Take my word for it! PMID- 10112345 TI - What I learned from 14 years as a Medicare cop. PMID- 10112346 TI - View from the top: what makes Vernice Davis Anthony tick?. Interview by George Adams. PMID- 10112347 TI - Legislators move on medical liability. PMID- 10112348 TI - How to be an effective board chairman. PMID- 10112349 TI - Hospitals and auxiliaries--a common thread. PMID- 10112350 TI - Board retreats: benefits or boondoggles? PMID- 10112351 TI - The future of final care. PMID- 10112352 TI - Pa. increases Medicaid payments, cuts funding for cost-containment council. PMID- 10112353 TI - Proposal would limit Medicaid provider tax, donation schemes. PMID- 10112354 TI - Check helps her exit site of killings. PMID- 10112355 TI - Rockefeller won't seek presidential nomination. PMID- 10112357 TI - Twin cities firms team up to offer multi option plan. PMID- 10112356 TI - 'State restrictions would reduce plans' efficiencies'. PMID- 10112358 TI - HCFA draft regulation 'bundles' charges for non-physician services. PMID- 10112359 TI - Justice Dept. abandons criminal antitrust probe of Boston allergists. PMID- 10112360 TI - Justice Dept. investigating Salt Lake City pediatricians. PMID- 10112361 TI - Epic mortgages 27 of its hospitals to refinance debt, gain cash flow. PMID- 10112362 TI - 5 selected for Health Care Hall of Fame. PMID- 10112363 TI - AHM noteholders agree to debt-for-swap. PMID- 10112364 TI - Republic debtor agrees to deal. PMID- 10112365 TI - SunHealth contracts for quality management. PMID- 10112367 TI - N.J. law targets deadbeat patients. PMID- 10112366 TI - Integrated Health Services finds profitable niche in geriatric medical care. PMID- 10112368 TI - Tenn. hospital downgraded after suspension of rating. PMID- 10112369 TI - 6 New Orleans-area hospitals to take part in study. PMID- 10112370 TI - Calif. hospitals fare worst in reclassification. PMID- 10112371 TI - Patients sue Philadelphia hospitals over cost of copying medical records. PMID- 10112372 TI - 'Physician ownership boosts Fla. costs, use'. PMID- 10112373 TI - Guidelines for partial hospitalization released. PMID- 10112374 TI - Bay State HMO's board takes over. PMID- 10112375 TI - Chicago hospital may close soon. PMID- 10112376 TI - Nurses' empathy for AIDS patients shown to drop over time. PMID- 10112377 TI - AMI completes refinancing, settles suit. PMID- 10112378 TI - Lawmaker wants Humana price lists following report of high markups. PMID- 10112379 TI - AHA tries to hold industry together as reclassification pits rurals vs. urbans. PMID- 10112380 TI - FTC reinstates antitrust complaint against Ukiah, Calif., hospital. PMID- 10112381 TI - Two Minneapolis systems explore merger. PMID- 10112382 TI - Hospitals could end up loser in Medicaid-donation game. PMID- 10112383 TI - Contract management firms continue their growing years. AB - Hospitals continue to welcome contract management firms into their facilities, as evidenced by another year of healthy growth in 1990. The 75 companies responding to Modern Healthcare's annual survey reported a 13.7% gain last year in the number of contracts. Clinical sectors spearheaded the growth, with emergency department management now the overall leader. PMID- 10112384 TI - Draft of final capital rules shows hospitals win some concessions. PMID- 10112385 TI - Teaching hospitals challenge GME adjustment. PMID- 10112386 TI - Launching a performance-based pay plan. AB - Performance-based compensation is increasingly replacing the annual bonus as hospitals seek ways to motivate their management. Two Ernst & Young authorities outline how to establish the incentive approach and put the performance measures in place. In the process, the performance goals should communicate what's important to the organization. PMID- 10112387 TI - VA contracts give unfair advantage to Picker--study. AB - Service contracts for computed tomography scanners in Dept. of Veterans Affairs hospitals have given an unfair advantage to Picker International, according to a study by the VA's inspector general's office. The report is the latest round in a controversy that has pitted Picker against at least two independent service organizations and enmeshed it in a $1.65 billion lawsuit. PMID- 10112388 TI - Foundation, Calif. providers offering small-group product. PMID- 10112390 TI - New facility built around peach of a plan. PMID- 10112389 TI - Soviet nurses help alleviate Baltimore hospital's shortage. AB - A pilot program is boosting a Baltimore hospital's nursing rolls while providing on-the-job training to immigrant Soviet nurses. For the short term, the Soviets fill important non-professional positions in the hospital's nursing department while working toward gaining their nursing credentials so they can become eligible to be hired by the hospital, easing its long-term nursing shortage. PMID- 10112391 TI - Charter showing signs of turnaround. PMID- 10112392 TI - HealthVest's restructuring could force primary tenant into Ch. 11. PMID- 10112393 TI - Home Intensive Care finds new takers for offering. PMID- 10112394 TI - Ruling could obligate hospitals to millions more in indigent care. PMID- 10112395 TI - Proposal for TQM study wins award. PMID- 10112396 TI - Governors given hope of less fed red tape in health reform. PMID- 10112397 TI - Nurses begin Romanian mission. PMID- 10112398 TI - Deadline extended for meeting new FCC rules. PMID- 10112399 TI - Payment from Aetna puts VHAE in the black. PMID- 10112400 TI - Final tax and donation rules for Medicaid resemble draft proposal. PMID- 10112401 TI - Women's hospitals redefine strategy. AB - As more general acute-care hospitals add obstetrical services, women's hospitals are being forced to re-examine the services they offer. Some are choosing to diversify, join a system or affiliate with a general acute-care facility. Others maintain that their facilities offer unique services unavailable at general hospitals and intend to remain independent. PMID- 10112402 TI - Employers look to hospitals to help control costs. AB - The high cost of health insurance for employees is forcing employers to take a second look at ways to control their rising costs, and they are looking for help from hospitals, according to a national study conducted by National Research Corp. In addition, four out of 10 employers surveyed said they believe more taxes should be shifted to hospitals and healthcare services. PMID- 10112403 TI - U.S. ventures unscathed by coup try. PMID- 10112404 TI - Growth in self-insurance puts squeeze on Minnesota risk pool. AB - HMOs and other health plans in many states are diversifying into self-insurance to protect market share, but in Minnesota such a shift is leading to a growing deficit in the state-sponsored risk pool for uninsurable residents. That's because health plans must pay an assessment based on revenues to help fund the state's plan, but the burgeoning self-insured plans aren't required to ante up. PMID- 10112405 TI - IRS cites private inurement in sale of Florida hospital. AB - The Internal Revenue Service has ruled that the sale of a Florida not-for-profit hospital to a for-profit corporation formed by the facility's board of directors violated federal law concerning "private inurement," thus the not-for-profit corporation's tax exemption should be revoked. The ruling would make the not-for profit organization liable for taxes dating back to 1983. PMID- 10112406 TI - Written investment policies offer protections. PMID- 10112407 TI - Grand jury investigating La. hospital's top executives. PMID- 10112408 TI - VA refuses further probing of Picker contracts. PMID- 10112409 TI - Ohio hooks up claims system. PMID- 10112410 TI - Reclassification board loses rural member. PMID- 10112412 TI - Management firm's sale called off. PMID- 10112411 TI - Charter reaches tentative agreement on debt deal. PMID- 10112413 TI - Survey: what OR managers are earning. PMID- 10112414 TI - ASCs accepting older, higher risk patients. PMID- 10112415 TI - A model in Montana: ensuring access to care. AB - Montana's medical assistance facility (MAF) demonstration project may provide a model for other states facing problems in maintaining access to primary health care in sparsely populated areas. Under the state's guidelines, MAFs provide treatment to ill or injured persons before transporting them to hospitals and inpatient care for persons needing it for no longer than 96 hours. PMID- 10112416 TI - Hospitals' problems--and solutions--vary by region. PMID- 10112417 TI - An emergency department perspective--Part III, Outcomes. AB - The outcome of care has traditionally been defined as a "change in the patient's current and future health status that can be attributed to antecedent health care." However, this definition provides a "unidimensional view of quality." It fails to take into account the customer's attributes and the many small steps or process variances that can contribute to an unexpected outcome. This failure can be especially pronounced in the emergency department. PMID- 10112419 TI - Life or death: whose choice? PMID- 10112418 TI - Fraud and abuse: the payer's perspective. AB - As the health care sector consumes an ever-increasing portion of our nation's gross national product (GNP)), forecast to represent 15 percent of the GNP by the year 2000, increasingly intensive efforts are being used to control the growth rate of these costs. Medicare fraud alone is estimated to represent $2 billion yearly. Abusive billing of private health insurers represents a far larger amount. This article discusses the concept of fraudulent and abusive physician billing practices. PMID- 10112420 TI - The treatment of paraprofessional workers in the home. PMID- 10112421 TI - Abuse and neglect of the frail elderly. PMID- 10112422 TI - The double message of regulation: institutional and governmental concerns versus individual autonomy. PMID- 10112423 TI - The right to die. It's alive and well. PMID- 10112424 TI - Working out pays off. PMID- 10112425 TI - On track. Employees play own game. PMID- 10112426 TI - Solving A/R management. PMID- 10112427 TI - Support groups answer health needs. PMID- 10112428 TI - Targeted marketing. The teleservices hub. PMID- 10112429 TI - Tough times--tough decisions. PMID- 10112430 TI - The many forms of fitness. PMID- 10112431 TI - American Laundry Digest Buyer's Guide. Manufacturers directory. AB - The following is the annual American Laundry Digest Buyer's Guide which is being circulated to all segments of the laundry industry. The Guide contains a list of manufacturers who responded to our questionnaire. This is followed by a list of product categories and the various manufacturers who make these products. You may contact these companies directly or by using the reader service card in this issue. PMID- 10112432 TI - Through joint ventures, special programs, rehab companies rack up another robust year. PMID- 10112433 TI - Gulf Coast Hospital attracts patients with its atypical style. PMID- 10112434 TI - Osteopathic hospitals need to stick together to influence GME law. PMID- 10112435 TI - Designing an appropriate AIDS policy. PMID- 10112436 TI - Pharmacy technician competency. A comparative evaluation of formally trained and on-the-job-trained pharmacy technicians in Minnesota. Part I. PMID- 10112437 TI - Improving job satisfaction and enlarging the role of technicians. AB - The process used in preparing this administrative report provided the means of documenting departmental support of technician task expansion, cost benefits, increased availability of professional time, and the need for a dynamic department. Some of the benefits to St. Luke's Regional Medical Center and its Pharmacy Department were an increase in technician job satisfaction, improved quality of patient care attributable to the increased scope of pharmacy service, and up to 8554 hours per year of professional time available for more clinically oriented responsibilities. If technician turnover were decreased by half, technician pricing errors eliminated, and technicians assumed the identified technical tasks, potential monetary benefits could be as much as +116,900 per year. The departmental cost of implementing these recommendations would be an additional 4.16 technician FTEs, and the professional time for training, supervising, and coordinating technicians and functions. These recommendations were well received by pharmacy administration, and the committee was asked to develop a list of priorities and an implementation plan for administrative approval. PMID- 10112438 TI - Should a pregnant flight nurse be allowed to fly? AB - The question posed at the start of this article, "Should a pregnant flight nurse be allowed to fly?" must be answered with qualifications. A flight nurse should not necessarily stop flying at the beginning of her pregnancy. The known and unknown risks specific to a particular program should be identified. The risk posed for maternal-fetal oxygen can be combated by using supplemental oxygen for the flight nurse who reaches cabin altitudes greater than 8,000 feet, although no documented adverse fetal effects have been reported at higher altitudes. A pregnancy policy that allows the flight nurse to leave active flight status when necessary, for whatever reason, and to return after maternity leave is optimal. An air medical program can always benefit from a temporary "ground nurse" who takes an intense look at quality assurance, community outreach, or flight nursing research. PMID- 10112439 TI - The development of a clinical ladder for an air medical service. AB - The clinical ladder at STAT illustrates the service's commitment to clinical excellence and high-level patient care. It also shows that management values the professional efforts of the flight professionals, and are prepared to reward exceptional performance. A clinical ladder program benefits the individual, the patient, the institution, and the air medical field. PMID- 10112440 TI - Mid-year report ... growth of twin-engine helicopters as a percentage of the market. PMID- 10112441 TI - A Canadian emergency medical helipad service. PMID- 10112442 TI - Hospitals marketing. PMID- 10112443 TI - Recycling--the demand of the moment. PMID- 10112444 TI - Staffing and productivity assessment of the engineering department. PMID- 10112445 TI - Downloading from MEDLINE: a comparison of personal database software. AB - The compatibility of downloaded MEDLINE references with software packages designed for maintenance of personal bibliographic databases is considered. The nine packages reviewed enable one to import batches of records downloaded from one or more presentations of the MEDLINE database, online or CD-ROM; and enable the user to re-format records into the various styles required by journal editors. Some basic features of the packages are tabulated, and details of record importing facilities are described. Details of suppliers and prices are given. PMID- 10112446 TI - Promoting library resources in Age Concern day centres. AB - In this report, an experiment to test the effectiveness of library resources with frail elderly people is described. Four day centres run by Age Concern Leicester were selected: two which cater for mentally frail clients, one for physically frail but mentally active people, and one for those with a mental handicap. A series of group sessions using library resources was run by the librarian in each centre, and the results observed. Frail elderly people were found to be a potentially enthusiastic group of library users, with a special need for assistance in gaining access to resources. Guidelines for librarians planning similar sessions to promote their stock are presented. PMID- 10112447 TI - Heavy metals in incinerators. PMID- 10112448 TI - MSDSs (Material Safety Data Sheets): practical problems. PMID- 10112449 TI - Canada and the U.S. differ on ribavirin risk. PMID- 10112450 TI - Fetal protection update: the Supreme Court decision. PMID- 10112451 TI - Reach out and cure someone. AB - A new 900 number offers medical advice by phone, but can it replace a family physician's personal touch? PMID- 10112452 TI - UR only as good as what you save. PMID- 10112453 TI - Time to feed the FASB (Federal Accounting Standards Board). PMID- 10112454 TI - Practice audits made perfect. PMID- 10112455 TI - Case management: solving the 70/10 equation. PMID- 10112456 TI - Managed care law west of the Pecos. PMID- 10112457 TI - Overutilization and M.D. self-referrals. AB - In sum, as government and industry look for new methods of curbing expanding health care costs, it seems inevitable that all parties will continue to look to the effect of self-referral to determine whether the practice fuels the rise in health care costs. PMID- 10112458 TI - Managed care: the final option. PMID- 10112460 TI - Bundling outpatient costs. PMID- 10112459 TI - Data watch. Rising retiree costs. PMID- 10112461 TI - Indian Health Service; statement of organization, functions, and delegations of authority--PHS. AB - Part H, chapter HG (Indian Health Service) of the Statement of Organization, Functions, and Delegations of Authority of the Department of Health and Human Services, Public Health Service (PHS), chapter HG, Indian Health Service (IHS), 52 FR 47053-67, December 11, 1987, as most recently amended at 56 FR 22015-16, May 13, 1991, is amended to reflect the establishment of an organizational substructure for the Bemidji Area Office to more accurately reflect current activities in the Area Office. PMID- 10112462 TI - Healthward ho! PMID- 10112463 TI - Creative financing. AB - By taxing or seeking donations from health care providers, states have increased federal matching to pay medicaid costs. The Bush Administration views the practice as a scam. PMID- 10112464 TI - The politics of a renovation. Interview by Paul King and Donna Boss. AB - Recently, Shands Hospital at the University of Florida in Gainesville completed a $14-million foodservice renovation, one element in an 11-year-long, $100-million hospital-wide expansion project. Having successfully finished the work in her department, Food & Nutrition Services Director Ruby Puckett offers advice to her colleagues about how to stay in control of the renovation process from beginning through to the end. PMID- 10112466 TI - Improving operational efficiencies--Part I. PMID- 10112467 TI - Something old, something new. PMID- 10112465 TI - The days ahead. AB - How are government controls affecting healthcare foodservices?Are growing elderly & outpatient populations changing foodservices' missions. What are the hottest trends? As members of the American Society for Hospital Food Service Administrators prepared for their annual meeting in Orlando, FM queried 11 Southeastern directors to learn their most pressing concerns & how they are positioning their departments for the future. PMID- 10112468 TI - Ethics and the quality of care. PMID- 10112469 TI - The patient-focused hospital. PMID- 10112470 TI - New approaches to caregiving. PMID- 10112471 TI - Are you ready for structural change? PMID- 10112472 TI - The shape of things to come, Part 7. The people side of patient care redesign. PMID- 10112473 TI - Ten steps for restructuring patient care. PMID- 10112474 TI - A conversation with Peter Drucker, Part 2. It's late in the day. Some thoughts on the future of healthcare. Interview by Joe Flower. PMID- 10112475 TI - More tools for the nineties, Part 2. AB - The times require new management tools that focus, inspire, empower, and liberate organizations. The May/June issue offered a dozen tools to help you to stay ahead in this turbulent decade. Here are a dozen more. PMID- 10112477 TI - The COBRA anti-dumping law: new requirements and unresolved issues: Part 2. PMID- 10112476 TI - Stories from the front lines. AB - When expert nurses are freed to practice nursing in the way they know is good, with others who care about positive patient outcomes, in a supportive environment, they will want to stay in that work setting and that setting will attract others of like mind. How to begin? With storytelling. PMID- 10112478 TI - Management development for primary health care: a framework for analysis. AB - Strengthening management has been widely promoted as a critical component of any strategy concerned with improving the implementation of primary health care (PHC). Management development programmes are, however, subject to conflicting demands and differing expectations. The situation is confounded by the wide diversity of strategies subsumed under the heading of management development, and the confusing nature of much of the terminology currently in use. This article presents a simple conceptual framework that can guide analysis and help programme planners review the options, opportunities and limitations of management development programmes. The framework presented examines management development from three different perspectives: the approach adopted; the outcomes expected; and the process of expansion, extension and adaptation. Our analysis of management development strategies allows us to reach some conclusions in areas where there is a degree of consensus. In countries where there is a mismatch between the strategies of PHC and the organizational structures through which they are to be implemented, management development has a role to play in effecting change. Its potential to do so is limited by powerful social, political, economic and organizational forces. Therefore, the capacity to critically analyse the context in which change is planned, emerges as a key element in programme design. We argue that there is no one best approach to management development, and the design of strategies will be contingent on a variety of factors. We do, however, reaffirm the view that where organizational structures and conditions do not support the implementation of PHC strategies, intervention through training alone is almost certain to be inadequate. To be effective, a more comprehensive programme will be required. Finally, the article points to a number of unresolved issues in areas where there is either controversy, lack of clarity or limited experience. PMID- 10112479 TI - Organisational issues and effectiveness of the health sector in the Republic of Slovenia, Yugoslavia. AB - The republic of Slovenia is one of the six republics of the Socialist federal republic of Yugoslavia. The article deals with the health situation over the period from 1975 to 1988. Illness and hospitalisation data are shown in Slovenia for the year 1988, and the movement of common illnesses shown over the period 1980-1988. The health infrastructure is presented for the year 1986, and the stock of cadres of health worker i.e. doctors, dentists, pharmacists, nurses, is shown in tabular and graphic form, together with changes in the composition of that stock over the last fifteen years. These data are then used to develop trends, and a commentary on progress made. Finally, the level of financing of health care is shown, and movements in the share of the social product (GNP) from 1975 to the present time. Over that period, the share has remained constant, though significant fluctuations have taken place from year to year. PMID- 10112480 TI - Managing the unmanageable: public hospital systems. AB - There are significant challenges to those who work in large public health care delivery systems: political imperatives; resource constraints; sometimes rigid personnel systems; and, the reality that everything occurs in a public forum. The fact that many nations are reviewing and, in some instances, restructuring their national health care systems, has added to the complexity and feeling of continual turbulence experienced by their managers. State run systems like that in the United Kingdom are introducing market forces to increase effectiveness and value for money; while market systems, like that in the United States, are increasing regulatory interventions to achieve the kind of cost control available to countries with large public systems which operate with global budgets. Public hospitals in the United States offer examples of public institutions operating in a highly competitive market environment. A decade of management changes undertaken to enhance the efficiency and effectiveness of the New York City Health and Hospitals Corporation (HHC), the largest public hospital system in the United States, is presented as a case study of public health services and public management in a market environment. PMID- 10112481 TI - Health for all Nigerians: some revolutionary management dimensions. AB - Health For All by the Year 2000, usually referred to as HFA/2000, is a goal that has been accepted by most nations of the world. PHC is the strategy designed to achieve this laudable goal. In Nigeria, there is no doubt that remarkable strides have been made to achieve the goal of HFA/2000 in recent years. However, in order to fully realise this goal, some further revolutionary management steps are needed. This article first examines the progress on HFA made so far in Nigeria; and then, discusses some management initiatives that need to be taken or accelerated to be able to reach that desirable destination. PMID- 10112482 TI - To ease their stay: the "Welcome a New Resident" volunteer program. AB - To ease the transition for new residents from the community to the nursing home, the Department of Volunteer Services at The Jewish Home and Hospital for Aged (JHHA) Manhattan Division created a "Welcome a New Resident" Program. An interdisciplinary group of Department Heads and Administration saw the need and, with their considerable advice, the program took shape. Since May 1989 specially trained volunteers have had eight to ten weekly sessions with residents in their first months following admission. The volunteers answer residents' questions and assist them in finding their way around a very large facility, learning how to accomplish simple tasks for themselves and, most important, to become part of their new community by participating in activities and meeting other residents. PMID- 10112483 TI - Preventing burnout: taking the stress out of the job. AB - The purpose of this article and of the workshop on this subject presented at the 1989 International Conference on Volunteer Administration is to inform Directors of Volunteers of a new approach to burnout prevention which can directly impact occurrences among themselves and their co-workers. We in volunteer administration are not immune; our burnout rates average 3 1/2 years. This situation, left unchecked, poses a threat to the long term effectiveness of our organizations. PMID- 10112484 TI - Volunteer protection legislation. PMID- 10112485 TI - An untapped volunteer resource: people with HIV disease, ARC, or AIDS. PMID- 10112486 TI - National survey. Personal computers in the clinical laboratory. Part I. Available in most labs, fully utilized by few. AB - Most U.S. clinical labs now have personal computers, an exclusive MLO survey reveals, yet use them primarily for routine paperwork. Exciting possibilities remain largely untapped. PMID- 10112487 TI - National survey. Personal computers in the clinical laboratory. Part II. Fighting resistance, many use PCs in wise and creative ways. PMID- 10112488 TI - Ethics and the clinical laboratory. Part II. What has happened to patient confidentiality? PMID- 10112489 TI - Integrating an LIS into a PIN (patient information network). AB - Cooperation from many hospital departments enabled the lab at a large medical center to coordinate an institution-wide system. Now available: A total view of patient data. PMID- 10112490 TI - S&P upgrades AMI debt ratings. PMID- 10112491 TI - 2 providers form behavioral health venture. PMID- 10112492 TI - Detroit hospital files for Ch. 11 protection. PMID- 10112493 TI - Radiologists' suit says fee was illegal kickback. PMID- 10112494 TI - Ruling blocks HCFA from denying payment for lenses. PMID- 10112495 TI - Physician fee schedule gets $7 billion boost. PMID- 10112496 TI - Disproportionate share likely next battleground. PMID- 10112497 TI - Capital payment rate lower than expected. PMID- 10112498 TI - Some urban hospitals to get PPS jolt. PMID- 10112499 TI - Board structure at not-for-profits is stifling. PMID- 10112500 TI - Hospital, system boards adjust to changing roles. AB - A growing number of multihospital systems are flexing their centralized power over individual hospital boards in an attempt to realize the competitive edge that systems were supposed to provide. As a result, governance at the hospital level is becoming more and more advisory. Obviously, trustees in a lot of locales aren't coming quietly into the new relationship. But experts say healthcare's financial climate makes such change just a matter of time. PMID- 10112501 TI - HealthTrust plans to recapitalize. PMID- 10112502 TI - VHA, Aetna to pay $16.4 million to settle suit. PMID- 10112503 TI - Campaign employs star power to combat nursing shortage. AB - A marketing campaign aimed at encouraging high school students to consider nursing as a career taps the popularity of a television star to help combat the nursing shortage. Army nurse Colleen McMurphy from the television series "China Beach," portrayed by actress Dana Delany, is the centerpiece of a campaign that was initiated by the Texas Hospital Assn. and distributed free to the nation's 17,000 high schools last winter. PMID- 10112504 TI - HCFA proposal takes zip out of EFTs (electronic fund transfers). AB - HCFA recently proposed reimbursing providers through electronic fund transfer, a low-cost, fast, efficient means of deposit and payment now commonplace throughout the country. EFTs promise hospitals benefits such as clerical savings through computerization, but regulations proposed by HCFA would inhibit the increased efficiency and cash flow such transactions also can offer. PMID- 10112505 TI - Letters of credit getting more expensive. AB - Hospital executives who haven't been in the market recently for a new or renewed letter of credit will find it a more expensive way to back their variable-rate debt. Annual fees are surging, for reasons ranging from an international banking agreement that goes into effect next year to more conservative fee structures being instituted because of bad loans made by some banks in the past decade. PMID- 10112506 TI - Employees ante up more. PMID- 10112507 TI - Soviets turn to private insurance. PMID- 10112508 TI - Firm lands contract for traveling nurses. PMID- 10112509 TI - S&P now rating underlying credit of enhanced issues. PMID- 10112510 TI - Menu changes balance low costs and high nutrition. Health-care foodservice grapples with scratch vs. preprepared foods. PMID- 10112511 TI - 400: Part II. Rankings: top 400 by segment. PMID- 10112512 TI - Characteristics of persons with and without health care coverage: United States, 1989. PMID- 10112513 TI - Accidents don't have to happen. PMID- 10112514 TI - Special report. Investment safe harbors: new challenges for MD joint ventures. PMID- 10112515 TI - Dying made legal: new challenge for advance directives. PMID- 10112516 TI - Judgments of futility: what should ethics committees be thinking about? PMID- 10112517 TI - Ethics review committees [in biomedical research] in the Nordic countries: history, organization, and assignments. PMID- 10112518 TI - Ethics committees in Germany. PMID- 10112519 TI - U.S. ethics committees: perceived versus actual roles. PMID- 10112521 TI - Perspectives. The rules of the game in health care lobbying. PMID- 10112520 TI - Alexandria [Virginia] Hospital bioethics committee: history and purpose. PMID- 10112522 TI - The interaction between forms of insurance contract and types of technical change in medical care. AB - A simple three-parameter description of medical technology is introduced to investigate the relationships between technical change, welfare, and type of insurance contract. The value of a particular change in technology depends on the existing form of contract. The marginal equilibrium expected utility to consumers of different types of technical change hinges on the manner in which the insurance arrangement is designed to mitigate moral hazard. These results open the way for a positive model of the effects of insurance arrangements on the types of technology that are adopted and the effects of technical changes on the prevalent forms of insurance contract. PMID- 10112523 TI - Minister announces that NHS must take a lead in effecting environmental change. PMID- 10112524 TI - The management of energy consumption and savings for the period 1985/86 to 1989/90. PMID- 10112525 TI - Environmental Protection Act 1990, Part I. Local authority air pollution control system. Department of the Environment. PMID- 10112526 TI - Special report. HHS issues final safe harbors: but underwater mines await hospital-MD ventures. PMID- 10112527 TI - VA medical centers deliver quality care. PMID- 10112528 TI - Alabama Office of Rural Health Care. PMID- 10112529 TI - Advance directives ... is the law clear? AB - Until recently, few people had even heard of living wills. Thanks to a young woman named Nancy Cruzan, that is no longer the case. PMID- 10112530 TI - Healthy beginnings: making a difference. AB - Infant mortality--one of the greatest healthcare problems plaguing Alabama today. Desperate measures have been implemented, with only marginal success. But now, there is a new program on the block. PMID- 10112531 TI - The saving of an Alabama hospital. PMID- 10112532 TI - What's good for the team: making management agreements work. AB - Joint hospital agreements, consultation or vendor contracts can be the ideal game plan for hospitals trying to lower costs or improve efficiency. Still, such arrangements must be handled skillfully by the coaching staff to avoid jeopardizing team morale. PMID- 10112533 TI - Wanted: the Medicaid-eligible. AB - The benefits are available, yet there is still a high number of people who qualify for medicaid who are not enrolled. Why? That is what hospitals and several state programs would like to know, and they are making an effort to find out. PMID- 10112534 TI - Focus: Governor Guy Hunt. PMID- 10112535 TI - The managed care-hospital relationship. Part 2 of 2. AB - When asked what they look for in a participating hospital, the managed care companies all had the same initial response: quality. But they also indicated that providers combining quality care with cost-containment measures are looked upon most favorably. PMID- 10112536 TI - Costs, quality important issues for new AlaHA chairman. PMID- 10112537 TI - Reform long overdue: panel seeks to end purchasing nightmare. AB - During the purchase and installation process for new healthcare information systems, the inept, self-serving and sometimes short-sighted behavior of healthcare institutions, consultants and vendors surfaces time after time. The Center for Healthcare Information Management (CHIM) Business Conduct Committee has been engaged in frank discussions of the purchasing boondoggle. A panel of committee members and others now call for reform and point to better-educated buyers as the most effective and practical solution. PMID- 10112538 TI - Physicians who use the system help hospitals gain advantage. AB - The chief consumers of patient information--physicians--are often the last to actually use systems that are designed to provide that information quickly. The reasons for this are deeply entrenched, but if physicians are properly incentivized and adequately trained, they can leap this hurdle. Competitive advantage to hospitals is an immediate benefit, as well. PMID- 10112539 TI - Workstations speed care delivery to critically ill. AB - A busy intensive-care unit in the Veterans Affairs Medical Center in Palo Alto, Calif., has begun to put the power of workstation technology to good use in caring for the facility's sickest patients. Adam Seiver, M.D., chief of general surgery, told Computers in Healthcare that the system tracks patient information far more accurately than the manual methods used previously. Before the system, a patient's ICU records were filed away after each 48-hour period. Now a complete history of the patient's ICU stay is accessible at the beside through the duration of the episode. PMID- 10112540 TI - The hand-held, voice-controlled terminal: medical information interface of the future. AB - In its push to cross the barrier of fixed-site, fixed-format information displays, Texas Instruments is busy working on prototypes of a small device that healthcare knowledge workers can carry with them onsite or offsite to enter orders, display test results, view images, listen to audio comments and record other patient data. TI won't specify a delivery date, and they say it's still several years away. Vision must precede form. PMID- 10112541 TI - Winning design. 3 projects recognized in First Annual Health Care Environment Awards. PMID- 10112542 TI - Contract 1990 annual directory. PMID- 10112543 TI - Experts cautiously optimistic about future of healthcare system. PMID- 10112545 TI - To buy or not to buy a Medicare supplement? PMID- 10112544 TI - Health care rationing. AB - The following two-part article sets the scene for an ongoing dialogue in future Updates on rationing and its impact on our health care delivery system and on society at large. Part one establishes the framework for future discussions, while Part two zeros in on the efforts of one state to confront the issue head on. PMID- 10112546 TI - Living wills take center stage in Congress. PMID- 10112547 TI - Don't forget the children. PMID- 10112548 TI - Health care executives look at rationing. AB - In summary, executives want change. They want it done openly and they reaffirm their guiding principle of underwriting effective health care services. They are more circumspect on more specific methods, such as basing decisions on minorities' needs or the results of a public opinion poll. They do agree, however, that developing a plan to reduce the root causes of poor health would work to begin change. PMID- 10112549 TI - Home care: facts/figures. PMID- 10112550 TI - Rural EMS communications. PMID- 10112551 TI - Humanistic dispatch. PMID- 10112552 TI - When hooves appear. PMID- 10112553 TI - It can happen to you. PMID- 10112554 TI - 1991 consultants guide. PMID- 10112555 TI - Balancing act. PMID- 10112556 TI - Infant kidnapping prompts security changes at three RI hospitals. PMID- 10112557 TI - Northern issues loom large for health team. PMID- 10112558 TI - Wheels within wheels: the debate grinds on. PMID- 10112559 TI - Organising a bloodless coup. PMID- 10112560 TI - Where Darwin meets Beveridge. PMID- 10112561 TI - Computing and medical audit. Grasping the nettle. PMID- 10112562 TI - Computing. When no tech is best. PMID- 10112563 TI - Computing. Cracking the codes. PMID- 10112564 TI - Here comes the era of the volunteer. PMID- 10112565 TI - In poverty and in health. PMID- 10112566 TI - Taking extra care. PMID- 10112567 TI - How to keep fit--and survive. PMID- 10112568 TI - A policy for care--or for chaos? PMID- 10112569 TI - When fear rules freedom of speech. PMID- 10112570 TI - Promoting gain to end pain. PMID- 10112571 TI - Citizens' rights v voting wrongs. PMID- 10112572 TI - Assessing financial outcomes of not-for-profit community hospitals. AB - Health care executives and health professionals often compare financial outcomes among not-for-profit community hospitals, such as operating margins and excess of revenue over expenses. Some performance measures used in these comparisons tend to be uniform yardsticks across community hospitals; other measures may vary significantly by legal, organizational, and reporting-practice differences among hospitals. A unique database of certified financial statements now permits an examination of these reporting-practice differences in the context of a three year study of financial outcomes for 1,297 hospitals. Six panels are used in the study for partitioning hospitals in response to differences in reporting practices. Revenue over expenses expressed to net patient revenue and to total unrestricted assets are partially explained by 15 factors. The relative outcomes for these measures within a panel are combined with two common yardsticks of financial condition so the 1,297 hospitals can be classified into five status categories: (1) 121 hospitals in a crisis status, (2) 203 hospitals in a warning status, (3) 511 hospitals with average results, (4) 312 hospitals with excellent performance, and (5) 150 hospitals with outstanding performance. PMID- 10112573 TI - Ambulatory care centers: are they a competitive advantage? AB - A common assumption found in literature about hospital-sponsored ambulatory care centers is that they increase inpatient admissions and market share. However, little empirical evidence exists to substantiate these assumptions, and it is reasonable to question their accuracy given the nonemergency, routine nature of many of the visits to ambulatory care centers. This study of hospitals in four Massachusetts markets in which at least one hospital sponsored an ambulatory care center questions whether inpatient admissions and market share are affected. The findings indicate that at least in these four markets, ambulatory care centers do not have the desired effects, relative either to past performance or to competing hospitals. PMID- 10112574 TI - The continuing care retirement community executive: a manager for all seasons. AB - The continuing care retirement community industry is a growing source of residential and health care services for the elderly population. It is also a relatively new and expanding career path for both health care and hospitality managers. Using in-depth interviews with executives in a sample of 26 communities, this study provides one of the most complete portraits to date of the nature of managing these communities. The findings indicate that these organizations are complex and multifaceted, demanding versatile skills and abilities. Most critical are those skills that enable a manager to interact effectively with residents and staff to build and maintain a hospitable, accommodating community environment. As competition in the industry intensifies, community viability may become synonymous with customer satisfaction. Management training and development will need to be highly attentive to the distinctive features of these intriguing organizations. PMID- 10112575 TI - Hospital audit committees: a comparative analysis of structural and functional characteristics. AB - In an effort to counteract rising costs and financial problems, many hospitals have adopted certain management practices that are followed by commercial corporations. In particular, the boards of directors for many hospitals have created audit committees to enhance organizational governance in the areas of internal control, accounting, auditing, and financial reporting. The formative stages in which most hospital audit committees currently exist creates a need for shared information. Such information can serve as a potential source of guidance for the further development of existing hospital audit committees, as well as for boards that are near the point of establishing an audit committee for the first time. The purpose of this study is to present an analysis of the structure, responsibilities, and activities of hospital audit committees. Data for the analysis was obtained through a questionnaire survey of 400 hospitals. The analysis of structural and functional differences affords a basis for suggesting several specific ways in which hospitals can improve their organizational governance through a more effective audit committee. PMID- 10112576 TI - Utilization and management of multiskilled health practitioners in U.S. hospitals. AB - This article examines the utilization and management of multiskilled health practitioners by U.S. hospitals. Results indicate such utilization is greatest for small hospitals as well as for other not-for-profit and government nonfederal hospitals. Flexibility, efficiency, and cost containment are the major reasons for utilizing such personnel. Secondary skills added to most multiskilled workers were of a parallel or lower level. Managerial issues and implications in utilizing multiskilled workers including training, compensation, evaluation, supervision, and competency assessment are also discussed. PMID- 10112577 TI - Cash budgeting: an underutilized resource management tool in not-for-profit health care entities. AB - Cash budgeting is generally considered to be an important part of resource management in all businesses. However, respondents to a survey of not-for-profit health care entities revealed that some 40 percent of the participants do not currently prepare cash budgets. Where budgeting occurred, the cash forecasts covered various time frames, and distribution of the document was inconsistent. Most budgets presented cash receipts and disbursements according to operating, investing, and financing activities--a format consistent with the year-end cash flow statement. By routinely preparing monthly cash budgets, the not-for-profit health care entity can project cash inflow/outflow or position with anticipated cash insufficiencies and surpluses. The budget should be compared each month to actual results to evaluate performance. The magnitude and timing of cash flows is much too critical to be left to chance. PMID- 10112578 TI - Nursing recruitment: do health care managers gear strategies to the appropriate audience? AB - Senior management at Guthrie Healthcare System, a regional referral center located in rural Pennsylvania, discovered several fascinating findings in its nursing recruitment research. Anticipating the consequences of the nursing shortage and seeking to avoid the entrapments of lucrative short-term recruitment enticements, Guthrie directed its recruitment efforts toward developing a supply of new nursing resources. Through the development of a career opportunity program that underwrites baccalaureate nursing education for qualified individuals, Guthrie management uncovered a vast supply of interested, potential nursing student candidates. Intrigued by the possibility of developing this market in the face of a dire nursing shortage, Guthrie Healthcare System management conducted an investigation to analyze the characteristics of these prospective nursing students. The findings of the study identify a large existing pool of qualified potential applicants. Most important, these individuals possess a true interest in nursing. This investigation suggests that removal of financial barriers to a nursing education uncovers a large market of nursing student candidates. Thus a reexamination of recruitment strategies is required to refocus efforts toward reaching this identified market. PMID- 10112579 TI - Patient and family perceptions of hospital chaplains. AB - While most hospitals provide chaplaincy services for patients, families, and staff, these services are seldom studied and their contribution is poorly understood. A questionnaire created by the College of Chaplains of the American Protestant Health Association was mailed by an insurance company to patients recently dismissed from the hospital, requesting evaluation of three non-medical services (social services, chaplaincy, and patient representatives) and how well the spiritual needs for support/counseling, prayer, and sacraments were met. Responses revealed that, in comparison to the other two non-medical services, patients receive more visits from chaplains, evaluate these visits as more important (p less than 0.000), and report that these visits meet their expectations more highly (p less than 0.000). Regression analyses demonstrate that when the chaplain meets the patient's need for support/counseling, the respondent is more likely to select the hospital again (p = 0.04) and recommend it to others (p = 0.05). Similarly, when chaplains meet the family's need for support/counseling, the respondent is likely to choose the hospital again. Since chaplains clearly make an important contribution to patients, their families, and the hospital, administrators should review the adequacy of their chaplaincy services in the light of these data. PMID- 10112580 TI - The nontraditional use of commercial advertising in prescriber education. AB - The availability of prescribing guidelines for antibiotics stimulated audits of antibiotic use in Melbourne hospitals. Following such audits, an advertising campaign to change prescribing was conducted at The Royal Melbourne Hospital. The success of this pilot study prompted a wider campaign to examine the power of marketing techniques in influencing prescribing. The Therapeutics Committee of the Victorian Medical Postgraduate Foundation (VMPF-TC) was established to administer this project and to undertake promotional activities. The Victorian Drug Usage Advisory Committee, which was established to advise the Minister for Health on matters relating to drug usage in public hospitals, recommended that posters be used in hospitals to promote rational and cost-effective drug therapy. The VMPF-TC was asked to prepare posters for sale to hospitals on the basis that economies of scale could make it financially viable. Oral rather than parenteral administration of antibiotics was chosen as the theme for the first poster. PMID- 10112582 TI - A statewide survey of pharmacokinetic service provision in Georgia. AB - A survey of pharmacokinetic service (PKS) provision and characteristics of the service was conducted in Georgia's 223 hospitals. The survey's questionnaire, returned by 133 (59.6%) institutions, showed that 23.3% currently had a PKS and that 47% of those without a PKS had plans to establish one in the future. Services were primarily provided by pharmacists (93%) who were certified to provide the consultations in only 40% of the institutions and the PKS was run through either the pharmacy (93%) or pathology laboratory. All services used calculators and/or computers with a variety of software programs to assist in pharmacokinetic evaluations. Patients were charged for the service in 38% of the institutions. PMID- 10112581 TI - The use of norfloxacin in a university hospital. AB - Because of increasing norfloxacin use and the development of resistant organisms, an evaluation was undertaken in a University Hospital to assess the appropriateness of norfloxacin for the treatment of urinary tract infections and to calculate the potential cost savings associated with more cost-effective antibiotic therapy. Medical records of 64 patients receiving norfloxacin for a 31 day period were concurrently reviewed. Of these, 58 patients were treated for urinary tract infections and four patients received urinary tract infection prophylaxis. Fourteen patients were prescribed solely empiric therapy whereas an additional 44 patients received definitive treatment confirmed by culture results. Based on the predetermined criteria, norfloxacin use for the definitive treatment of urinary tract infections was deemed to be appropriate in 34 of the 44 patients. Three additional courses of therapy were also judged to be appropriate due to documented signs and symptoms associated with urinary tract infections, despite cultures with less than 10(5) colony forming units per mL urine. Reasons for inappropriate use in the remaining seven patients included isolation of fewer bacteria than required by the criteria in asymptomatic patients (3 cases), isolation of organisms not sensitive to norfloxacin (1 case) and lack of dosage adjustment for renal insufficiency (3 cases). Nineteen of 32 evaluable inpatients (59%) received norfloxacin when a less expensive, equally effective agent was available. Although savings from more cost-effective therapy of urinary tract infections are minimal, due to the potential emergence of resistant organisms, norfloxacin should be reserved for infections not amenable to treatment with other oral antibiotics. PMID- 10112583 TI - Immunizations for international travel, Part II. PMID- 10112584 TI - Effects of cost sharing in health insurance on disability days. AB - We assess how cost sharing for medical services affects restricted activity days (RADs) and work loss disability days (WLDs), using data from a controlled experiment. We grouped the experimental insurance plans into four categories, one providing free care and the other three requiring varying amounts of cost sharing. RADs per person per year decreased by one to two days with greater cost sharing, with the strongest effects among those of average or poor health status, especially the non-poor. Unlike RADs, WLDs showed no systematic differences by plan. PMID- 10112585 TI - The costs of treating hypertension--an analysis of different cut-off points. AB - In this article the effects of different cut-off points for hypertension treatment are analysed, with respect to treatment costs. A theoretical blood pressure distribution is used to calculate the potential annual cost of treating all persons in Sweden above certain cut-off points for drug treatment. A lowering of the cut-off point from 105 mm Hg to 100 mm Hg diastolic blood pressure could potentially lead to an increase in annual costs of approximately 80m pounds. Further lowering from 100 to 95 mm Hg in turn could increase annual costs by about 110m pounds. The potential annual cost of treating all persons (roughly 1.6 million) with a diastolic blood pressure of greater than or equal to 95 mm Hg with drugs is calculated as being roughly 40 pounds per inhabitant in Sweden. The Swedish cut-off point for treatment (95 mm Hg) can be expected to lead to roughly 50 per cent higher treatment costs than the British cut-off point (100 mm Hg). PMID- 10112586 TI - Quantitative measures of medical activities in relation to diagnosis in primary health care. AB - In a study that covers three years, the extent of medical activities was analyzed in relation to the sex, age and treatment diagnoses of patients visiting district physicians at three health centres in a Swedish primary care district. All visits were registered with the aid of a specially designed encounter form. The most frequent medical activities were: drug prescriptions, follow-up measures and clinical chemical investigations. Diabetes, other metabolic diseases, malignant tumours and cardiovascular disease were the diagnosis groups associated with the most activities, while traumas, middle ear infections and check-up visits were associated with the least. In the case of both men and women, the number of activities per visit increased in proportion to age. The present study indicates that quantitative measures of medical activities, combined with diagnoses or other patient characteristics as sex and age, can be employed in clearly quantifying the content of consultations in primary health care. PMID- 10112587 TI - Urban health in The Netherlands: health situation, health facilities and public health policy. PMID- 10112588 TI - Medical center turns an old warehouse into a new financial center. PMID- 10112589 TI - The ultimate bottom line: 1990 salary hikes outpace inflation and net margins. PMID- 10112590 TI - Construction management: what is it? Who uses it? PMID- 10112591 TI - Effective training key part of PTSM compliance. PMID- 10112592 TI - How to conduct a cogeneration feasibility study. PMID- 10112594 TI - Patrol carts help meet patient-transport needs. PMID- 10112593 TI - Carpet or sheet vinyl? Form helps you to decide. PMID- 10112595 TI - Price survey. Supply keeps glove prices down. PMID- 10112596 TI - Univ. of Minnesota slashes $2 million from inventory. PMID- 10112597 TI - HMM price watch. PMID- 10112598 TI - Purchase contract is performed and title passes at least when goods are delivered. AB - The hospital received a quotation from a supplier offering to provide an item of biomedical equipment at a stated price. The hospital issued a purchase order providing delivery instructions. The equipment was delivered to the hospital, properly received, and put into service. A month later the supplier's representative came to the hospital and asked that the materials manager sign a sales order report covering the equipment. The supplier's representative explained that the equipment was from demonstrator stock and the only way it could be replaced was for the hospital to sign this form. When the materials manager refused to sign, the supplier's representative threatened to remove the equipment contending that title hadn't passed to the hospital. Later the materials manager did sign the sales order report, all the while contending that the representative had no legal right to remove the equipment. In this dialogue, Dr. Decker considers the legal issues involved in this transaction. PMID- 10112599 TI - Hospital mergers: much-needed consolidation may not happen. PMID- 10112600 TI - New and expanded causes of action in employment law. PMID- 10112601 TI - Cutting the costs of aging. PMID- 10112602 TI - Health care for the uninsured. PMID- 10112603 TI - Are you overlooking your "invisible" patients? PMID- 10112604 TI - Doctors struggle to stay ahead of inflation. PMID- 10112605 TI - A killer course in what med school never taught me. PMID- 10112606 TI - You can't satisfy every patient. So why try? PMID- 10112607 TI - A malpractice insurer threw this doctor to the wolves. PMID- 10112608 TI - I'll take the Ivory Tower over a community hospital any day. PMID- 10112609 TI - Is George Bush the white knight of malpractice reform? PMID- 10112610 TI - You can't beat my marketing plan--or its price tag. PMID- 10112611 TI - Michigan's changing demographics--what they mean to health care. PMID- 10112612 TI - A Brit's view of Michigan health care. PMID- 10112613 TI - The Canadian system as seen by a Canadian. PMID- 10112614 TI - The changing face of Michigan's smaller and rural hospitals. PMID- 10112615 TI - Striking a balance at DSS (Department of Social Services). Interview by Peter Pratt. PMID- 10112616 TI - Excellence is not a goal: its a way of thinking. PMID- 10112617 TI - Health care reform--what does the U.S. need? PMID- 10112618 TI - Michigan's vantage point on reform. PMID- 10112619 TI - Fla. medical group raps report on referrals to doc-owned sites. PMID- 10112620 TI - Judge to hear whether PPS is unfair to rurals. PMID- 10112621 TI - Groups near 'deemed status'. PMID- 10112622 TI - 'HCFA should oust more hospitals'. PMID- 10112623 TI - Salt Lake City hospitals, physicians subpoenaed in federal antitrust probe. PMID- 10112624 TI - VHA, Aetna formally end relationship earlier than expected. PMID- 10112625 TI - State associations lash out at AHA's bid to limit impact of hospital reclassifications. PMID- 10112626 TI - AMA program aims to bolster self-policing of rules on referrals. PMID- 10112627 TI - Only four lose AMA membership. PMID- 10112628 TI - ANSI enters standardization effort. PMID- 10112629 TI - HBO to develop patient-care software. PMID- 10112630 TI - Survey ranks women's choices for pediatric units. PMID- 10112631 TI - Kusserow gives kickback warning. PMID- 10112632 TI - 'Limiting Medigap benefits could improve coverage'. PMID- 10112634 TI - Health Care Hall of Fame. AB - Five honorees join the other 20 healthcare leaders that have been inducted into the Health Care Hall of Fame since 1988. Those chosen this year are Robert M. Cunningham Jr., a journalist; Margaret Daugherty Lewis, a founder of home healthcare; Gerhard Hartman, an educator; William A. Hillenbrand, a businessman; and Harold W. Hinderer, a financial adviser. PMID- 10112633 TI - Hospital alliances must stop strong-arming their suppliers. PMID- 10112635 TI - Fla. facility's rating falls, default possible. PMID- 10112636 TI - HealthTrust restructuring ends ESOP contributions. PMID- 10112637 TI - 'Managed care not a national solution'. PMID- 10112638 TI - PacifiCare plans merger. PMID- 10112639 TI - Nation's first hospital preserves tradition of healing. PMID- 10112640 TI - Focus pay incentives on long-term results. AB - The need to tie executive compensation to results rather than just effort or longevity has spawned the shift to performance-based objectives and the rewards for attaining them. Two consultants say that's not enough: Healthcare organizations must further induce results-oriented behavior by erasing the short term focus that still permeates performance. PMID- 10112641 TI - Drug dispensing system unlocks savings. PMID- 10112642 TI - Satisfaction with group purchasing tracked. PMID- 10112643 TI - Affiliation proposal adds twist to Calif. consolidations. PMID- 10112644 TI - Health futures await approvals, full roster. AB - Regulatory hurdles and difficulty recruiting insurance company participants have delayed the Chicago Board of Trade's hot new health insurance futures and options contract. The new product, which is being touted as a risk-management tool for hospitals, was scheduled to begin trading Oct. 1. Now the launch date has been postponed until mid-1992 because the final product isn't ready. PMID- 10112645 TI - Hospital Fund adds long-term investments. PMID- 10112647 TI - Who should take care of the OR's video equipment? PMID- 10112646 TI - Computer in every room a growing trend. PMID- 10112648 TI - Federal project may affect surgery volume. PMID- 10112650 TI - Building a sound risk management program. PMID- 10112649 TI - Orientation is a fast-track to productivity. PMID- 10112651 TI - Managing performance: feedback and action. PMID- 10112652 TI - Cutting absenteeism with a leave-time bank. PMID- 10112653 TI - Quality improvement programs can boost a hospital's image, bottom line. AB - To ensure customer satisfaction, hospitals must maintain the quality of services provided. This is especially true in a patient accounts department, which can have the greatest effect on a patient's perception of a hospital. A quality improvement program can identify problem areas and offer solutions meant to increase customer satisfaction and a hospital's bottom line. PMID- 10112654 TI - Correcting the practice styles of errant physicians. AB - In spite of their reluctance, physicians cannot continue to avoid judgments on the practice styles of their professional colleagues. Both tort law and an increasingly aggressive buyer and consumer community demand attention to problem physicians. Physician executives can play a leadership role in helping physicians understand their role in the peer review process. PMID- 10112655 TI - Resolving and avoiding conflict with the professional staff. AB - The professional staff perspective radically diverges from that of management. Whereas the professional staff sees the hospital in terms of its providing quality health care to each individual patient, hospital executives see the hospital in terms of its financial and systemwide performance. Unless these divergent perspectives are effectively integrated to solve problems and formulate hospital policies, chronic conflict between hospital management and the professional staff is inevitable. PMID- 10112656 TI - Effectiveness, accountability, and efficiency. AB - Management of health care is compromised by its singular reliance on billing information--i.e., a claims trail tells little of what providers think. It relates to neither prevention of disease nor reduction of unnecessary health care costs. Billing information is not the substrate to be used in the pursuit of appropriateness, effectiveness, and value. To improve medical management of health care, a protected, but accessible clinical database is needed. PMID- 10112657 TI - Physician bonding techniques surveyed. AB - Success in the health care marketplace depends largely on satisfaction of the needs of patients and their physicians. To assess the success of specific physician bonding techniques and compare them to results obtained in an institution-specific study, the author surveyed hospital-based members of the College in late 1990. The outcome of the latter survey is summarized in this article. PMID- 10112658 TI - Enhancing efficiency: step by step. AB - The debate over which mechanism for health care delivery will provide the widest, most efficient access has reached a crescendo. While the debate on the macro level accelerates, many significant approaches continue to be discussed and implemented on a micro level. Among these activities are imminent release of the final rule on "Criteria and Procedures for Making Medical Services Coverage Decisions that Relate to Health Care Technology--Medicare," implementation of the Safe Medical Devices Act of 1990 by the FDA, and a proposal that payers establish a cooperative national technology assessment program. PMID- 10112659 TI - National health insurance--to be or not to be. AB - It has been pointed out by advocates of change in the U.S. health care delivery system that, with the exception of the Republic of South Africa, the United States is the only industrialized nation without a system of national health care. Rising costs and an increasing percentage of Americans without insurance and with limited access to health care services has heightened interest in the development of a mechanism for payment for health care services in this country. PMID- 10112660 TI - Wellspring gives control to the patient. PMID- 10112661 TI - HMO competes with cost-cutting and coyotes. PMID- 10112662 TI - Around the world and at home. PMID- 10112663 TI - Touch cards trace breast lumps. PMID- 10112664 TI - One-minute spots teach and earn. PMID- 10112665 TI - Building a small town partnership. PMID- 10112666 TI - Make a run for referrals. PMID- 10112667 TI - Skiers & parents respond to giveaways. PMID- 10112668 TI - Travel nurses boost careers & fill jobs. PMID- 10112670 TI - Cancer center beats the odds. PMID- 10112669 TI - Easy to swallow story capsule. PMID- 10112671 TI - Best place to have a baby. PMID- 10112672 TI - Lasers pierce gallbladder market. PMID- 10112673 TI - Free arthritis forum attracts seniors. PMID- 10112674 TI - The beat goes on. PMID- 10112675 TI - Asthma workbook airs first for adults. PMID- 10112676 TI - Focus on vision screening. PMID- 10112677 TI - Formal counterparts of informal caregivers: paraprofessional home care workers who live with their clients. PMID- 10112678 TI - The informal caregivers of the confused elderly and the concept of partnership: a New Zealand report. PMID- 10112679 TI - Consumer-oriented quality assurance in home care. PMID- 10112680 TI - Ethical issues in health care institutions. Lesson three: Hospital ethics committees. AB - The hospital ethics committee serves as the topic for this third lesson of a five part WMU/AHRA magazine course on ethics. Proliferating during the last ten years and fostered by the Karen Ann Quinlan case, hospital ethics committees today function in three areas: education, development of guidelines and policies, and individual case consultation. Using specific examples in the discussion of each function, the authors give a detailed picture of the valuable contribution these committees make to the institutions they serve. PMID- 10112681 TI - Practical considerations in evaluating a radiology information management system for your environment. PMID- 10112682 TI - A transcription incentive program for diagnostic imaging. AB - Unhappy with a five-day report turnaround time in 1989, managers of Rhode Island Hospital's diagnostic imaging department began to investigate transcription incentive programs and created a model for the organization based on the research. The authors provide implementation details in this article and report that after 15 months, the organization is experiencing increased productivity, decreased costs, motivated staff and improved report turnaround! PMID- 10112683 TI - New trends in portable x-ray batteries and technology. AB - "Technological improvements in lead-acid battery design have caused them to rival the performance of wet cell NiCd batteries," declares Mr. Hasse. Since there is substantial maintenance involved with wet cell NiCds, a changeover to a different battery type could be a cost saving move. This informative article brings the reader up-to-date on all the recent lead-acid entries in the market, along with the advantages and disadvantages of each. PMID- 10112684 TI - 1991 staffing concerns survey. PMID- 10112685 TI - Ethical issues in health care institutions. Lesson Four: Allocation of medical resources. AB - Health care rationing is the subject of the fourth lesson in a five-part WMU/AHRA magazine course on ethics. Since not every citizen in our country is guaranteed the right to basic health care, there exists a rationing system in which health care is allocated on the basis of ability to pay and need, asserts Dr. Hartline. Ethical problems abound within this system. This article addresses the issues and proposes possible remedies. PMID- 10112686 TI - The physician cartel--potential hospital federal antitrust liability in class based denial of staff privileges to clinical psychologists. PMID- 10112687 TI - Leadership in action. PMID- 10112688 TI - How states cook the books. Step 1: Inflate medical fees. Step 2: Make Uncle Sam pay for them. PMID- 10112689 TI - Disclosing information and treating patients as customers. A review of selected issues. AB - Although many insist that full disclosure of health care information is essential, it may be insufficient to help patients make health care decisions. As the patient's agent, the physician should translate medical information for the patient. Providing information on the quality of care may also be a problem. In view of the lack of consensus among experts about measures of quality, widespread disclosure of quality data should occur only when the data are better validated. In the HMO setting, patients may also face complex choices about insurance coverage that are beyond their comprehension. The HMO is challenged to determine the degree to which individuals must be treated as patients rather than as consumers. PMID- 10112690 TI - Strategies for avoiding episiotomies. AB - Changing trends in obstetrics have case serious doubt on the value of episiotomy. It may often be far more harmful than beneficial. This viewpoint is discussed and various methods for avoiding episiotomy in many situations are presented. PMID- 10112691 TI - When patients complain. A special challenge--point and counterpoint. PMID- 10112692 TI - The time has come. HMOs and the uninsured. PMID- 10112693 TI - Decisions without information. The intellectual crisis in medicine. PMID- 10112695 TI - Children's hospitals. PMID- 10112694 TI - Perspectives. Geographic reclassification triggers dissension. PMID- 10112696 TI - The art of healing. PMID- 10112697 TI - Urban vigor. St. Luke's Medical Tower, Houston, Texas. PMID- 10112698 TI - Modern vision. Shiley Eye Center, University of California, San Diego. PMID- 10112699 TI - Homeward bound. Shenandoah Regional Campus, Manassas, Virginia. PMID- 10112700 TI - Campus cure. 200 UCLA Medical Plaza, University of California, Los Angeles. PMID- 10112702 TI - Working with consultants. How to select building-systems experts to achieve state of-the-art design. PMID- 10112701 TI - Advice from healthcare experts. Top practitioners offer insights into designing for the ever-changing medical market. PMID- 10112703 TI - Getting the most for your software dollars. PMID- 10112704 TI - Expanding the talent search. 19 ways to recruit top talent. PMID- 10112705 TI - Rescuing workers in violent families. PMID- 10112706 TI - Customized skills assessments. Assessment software can help HR track employee performance. PMID- 10112707 TI - Black families of Boston and their local courts. PMID- 10112708 TI - The church's task: advocacy for new institutions and additional professionals. PMID- 10112709 TI - The Metropolitan Council for Educational Opportunity. PMID- 10112710 TI - Looking ahead: problems and solutions. PMID- 10112711 TI - The two Americas, the two Bostons: a response. PMID- 10112712 TI - A new definition of black Boston. PMID- 10112713 TI - Poverty and family considerations. PMID- 10112714 TI - Family and economic considerations. PMID- 10112715 TI - Changing family roles. PMID- 10112716 TI - Low birth weight and infant mortality. PMID- 10112717 TI - The family life of older black adults: stressors and resources. PMID- 10112718 TI - Contemporary Boston black community and family characteristics. Introduction. PMID- 10112719 TI - Teen-age pregnancy. PMID- 10112720 TI - Violence. PMID- 10112721 TI - The Boston economic community: its impact on black families. Introduction. PMID- 10112722 TI - The Boston economic community's impact on black families. PMID- 10112723 TI - Development and displacement in the black community. PMID- 10112724 TI - Children's survival. PMID- 10112725 TI - A bumpy road to Medicare payment reform. AB - The publication of proposed rules for the Medicare physician fee schedule has triggered intense controversy, especially over the level of the conversion factor. Under the Health Care Financing Administration's interpretation of the provision requiring "budget neutrality," fee levels would be at least 16 percent lower than they would have been under the current payment method. That reduction stems from projections of physician behavior in response to changes in fees and the interaction of an asymmetric transition with the budget neutrality requirement. Other interpretations would better reflect the intent of Congress and would make better policy. The relative value scale still is far from final, but the version just published shows a greater shift in payment toward evaluation and management services than the initial phase of the study by Hsiao and colleagues. PMID- 10112726 TI - Treat the causes, not the symptoms of the health care cost problem. AB - The design of the American health care system is guaranteed to create an inflationary spiral. A third party payment system combined with cost-based reimbursement of hospitals, fee-for-service payments to physicians, tax deductible health insurance premiums, and a litigious society that also demands more services have created a growing sense of urgency that something must be done to control costs. Medicare's experience with prospective pricing and use of coordinated care has helped change the incentives that lead to higher costs. Greater use of such approaches shows promise but proposals to impose rigid expenditure caps could create what is tantamount to a pressure cooker unless the underlying incentives are changed. PMID- 10112727 TI - Winners & losers: how medical malpractice disputes are resolved. AB - Conventional wisdom regarding medical practice disputes is not supported by facts, and proposals to limit the size of awards or the size of attorneys' fees do not appear likely to curb the incidence of lawsuits. A 1989-90 survey of 187 Florida families who had filed suits against physicians shows that patients are more likely to sue to exact retribution and to "find out what happened." Those who sued often cited poor communication by physicians and hospital emergency room personnel. A prior relationship with a doctor or hospital didn't protect the provider from a suit. In four-fifths of the cases studied, total economic loss exceeded payment. In settlements before trial, the gap was even larger. Limits on awards would merely exacerbate that shortfall. PMID- 10112728 TI - Presidential politics: health care & the Holy Grail. AB - Since Harry Truman called for national health insurance in 1948, presidential candidates have tried with little success to engage the nation in a discussion of health policy. With the single exception of John Kennedy in 1960, candidates of both major parties have failed to raise health care to the "first tier" of campaign debate. As the U.S. prepares for the 1992 election, Democrats hope to break that cycle. While polls show greater interest among voters, indications are a serious national debate is not likely until 1996. PMID- 10112729 TI - Alternatives for expanding health insurance coverage. AB - In March 1990, nearly 14 percent of the U.S. population was without health insurance. This article examines five approaches to increase coverage: tax credits for the purchase of private insurance; changes in the regulation of the private insurance market; additional requirements on employers to provide employment-based insurance; expansion of Medicaid to selected groups; and a universal public health insurance program. Coverage would be most improved under a universal public insurance plan, and least improved by regulatory changes in the private insurance market. Significant but incomplete increases in coverage could be achieved through either new employer mandates or expansion of Medicaid. A tax credit could increase coverage appreciably only if it was substantial relative to the cost of insurance, and even then most of the credits would go to those who would have purchased insurance anyway. PMID- 10112730 TI - How in the world is WHO doing? AB - The World Health Organization has chalked up some impressive victories in its 43 years but is nowhere near reaching its ambitious goal of "Health for All by the Year 2000." Uphill battles against some intractable health conundrums and shrinking financial resources face the Geneva, Switzerland-based organization, threatening its stated goal of guaranteeing universal health care within the decade. PMID- 10112731 TI - The rise and fall of New Jersey's uncompensated care fund. AB - Since 1982, acute care hospitals in New Jersey have been reimbursed on a diagnosis-related group (DRG) basis along with a provision for 100 percent reimbursement of uncompensated care (bad debts and charity care). Initially, that system was based on a hospital-specific surcharge. Eventually, that was replaced with a uniform charge for all hospitals, including reimbursement by Medicare. But the growth in the number of uninsured, an inequitable financing system, increases in bad debts, and the elimination of Medicare payments led to the program's demise. An extended legislative stalemate has resulted in a pair of temporary extensions--aided by an infusion of federal Medicaid dollars--but the state still must find a permanent solution. PMID- 10112732 TI - Causation: pitting doctors against lawyers. PMID- 10112733 TI - DataLine--U.S. health labor force. PMID- 10112734 TI - Burning of hazardous waste in boilers and industrial furnaces--EPA. Final rule: corrections; technical amendments. AB - On February 21, 1991, the Environmental Protection Agency (EPA) published a final rule to regulate air emissions from the burning of hazardous waste in boilers and industrial furnaces (56 FR 7134). Today's notice corrects typographical and editorial errors that appeared in the regulatory text, including corrections to appendices II and III, and adds two appendices, appendix IX and appendix X, to part 266. Appendices IX and X were not ready at the time of publication; therefore, a note was placed in the appropriate location in the rule to inform readers that these appendices were to be published at a later date. Copies of these appendices were, however, made available to the public through the RCRA Docket maintained at EPA and through the National Technical Information Service (NTIS). PMID- 10112735 TI - Medicare program; home health agencies: conditions of participation--HCFA. Final rule. AB - This final rule responds to the major comments we received on an interim final rule that was published on August 14, 1989 (54 FR 33354). That interim final rule added requirements to the current conditions of participation for home health agencies (HHAs). Specifically, the rule specified requirements for protecting and promoting patient rights; training and competency evaluation of home health aides; notifying State entities responsible for the licensing or certification of HHAs of changes in ownership of the agency or management of the agency; including an individual's plan of care as part of the individual's clinical records; and operating and furnishing services in compliance with applicable Federal, State, and local laws and regulations and with accepted professional standards and principles that apply to professionals furnishing home health services. Most of the provisions of the rule implemented section 930 of the Omnibus Reconciliation Act of 1980 (Pub. L. 96-499), section 4021 of the Omnibus Budget Reconciliation Act of 1987 (Pub. L. 100-203), and section 411(d) of the Medicare Catastrophic Coverage Act of 1988 (Pub. L. 100-360). This final rule implements changes, based on our review and consideration of the public comments, concerning patient notification of changes in payment liability, requirements for evaluators and instructors of home health aides, in-service training, and supervisory visits, and clarifies other home health issues. PMID- 10112736 TI - Comprehensive, coordinated care for persons with AIDS. AB - As persons with AIDS are increasingly referred to home care, there is a need for home care agencies to offer comprehensive care to meet the special needs of this population. Over the past six years, the Visiting Nurse Association of Los Angeles has developed a program involving the coordination of services and staff of their affiliated corporations. PMID- 10112737 TI - Nutritional support in HIV disease. AB - As the management of HIV disease enters the realm of life-long treatment, rather than treatment for a terminal disease, nutrition becomes an important part of the treatment plan. Studies have shown a clear relationship between good nutritional status and the longevity of the AIDS patient. PMID- 10112738 TI - Insuring comfort for homemaker-home health aides: delivering services to the AIDS population. AB - New York City's Partners in Care, a subsidiary of the Visiting Nurse Service of New York, has implemented several innovative programs involving education, training, and followup support for their homemaker-home health aides providing care to patients with HIV or AIDS. These programs have proved essential to the development of a successful community care program for persons with AIDS. PMID- 10112739 TI - Ten years of living with AIDS. AB - Everyone who has been involved in AIDS work over the past decade has lost a loved one to the disease. The crisis, unfortunately, is far from over; the loss of life will continue for many years. This tenth anniversary provides an opportunity both for reflection and for garnering strength for the tasks that lie ahead. PMID- 10112740 TI - Making terminal care decisions. AB - The practical aspects of where a patient wants to die and under what conditions are as influential in determining a patient's comfort with dying as is his or her spiritual approach to death. PMID- 10112741 TI - Loss, grief & growth associated with AIDS. AB - On the surface, one may assume that the attitudes surrounding death from AIDS are the same as those associated with any other terminal illness. However, the unique medical and social aspects of the disease make the grief process different in many ways. Health care workers caring for PWAs and their families and friends should be aware of these differences. PMID- 10112742 TI - Survey of Canadian oncology pharmacy services--the emergence of a specialty. AB - The provision of pharmacy services to oncology is a substantial component of hospital pharmacy practice at several Canadian hospitals. To determine the scope of such pharmacy services a survey was developed and distributed to 103 hospital pharmacies and 11 ambulatory oncology pharmacies in 1988. There were 72 responses (65%), although only 96 centres were known to offer oncology services (adjusted response = 72 of 96 = 75%). Surveys were distributed and returned in reasonable proportion across the country. Inpatient and outpatient services were reported separately, for size of service offered, and categories of work in which staff were employed. Twenty-four of fifty-seven centres report large inpatient pharmacist services, and 21 of 57 had large inpatient technician services. The ratio of pharmacists to technicians appeared to be about equal, but technicians were less likely than pharmacists to be permanently assigned (one-third vs. one half permanently assigned). About one-half of both large and small services indicate a desire for increased time for both pharmacists and technicians. Outpatient services were reported by fewer respondents, and the job assignments in this setting were mostly permanent. Manpower usage in both settings is primarily dedicated to drug preparation and distribution, although two-thirds of centres report small clinical services (most centres desired increased clinical services). Future planning topics ranked improved clinical services and standardization of practice highest. A 91% majority agree that there should be standards for pharmacy practice in oncology pharmacists in Canada. Many factors, including insufficient clinical services, impede specialty development and recognition, but are priority areas for future development. PMID- 10112743 TI - Medication use during neonatal and pediatric critical care transport. AB - The Pediatric Critical Care Unit (PCCU) at the Children's Hospital of Western Ontario provides a transport service and team (critical care physician, critical care nurse, respiratory therapist) which transports critically ill newborns, infants, and children. The purpose of this study was to identify the medications used during transport and to determine age-related differences. Results of a prospective study of all drugs administered by the transport team to 174 patients during their stabilization and transport from November 1, 1987 through October 31, 1988 are presented. One hundred and twenty-one (69.5%) patients received at least one medication. The most frequently administered medications were antibiotics (38.5% of patients), followed by morphine (27.0%), anticonvulsants (23.6%), neuromuscular blockers (14.4%), respiratory drugs (11.5%), inotropes (10.9%), and sedatives (7.5%). Miscellaneous medications were administered to 48.8% of patients. The use of different classes of drugs varied with age; anticonvulsants were most frequently administered to children, sedatives and respiratory medications to infants, and antibiotics and miscellaneous medications to newborns. The wide range of medications used may reflect the diversity of diseases causing critical illness which reinforces that transport teams must have access to and knowledge of a variety of medications. The formulary of medications taken by the critical care transport team is included. PMID- 10112744 TI - Drug detailing in the hospital: background for policy development. PMID- 10112746 TI - Implementing a nutrition services payment system. PMID- 10112747 TI - Improving operational efficiencies--Part II. Appropriate equipment selection can cut costs while enhancing production versatility. PMID- 10112745 TI - Tax revolt causes long-term care crisis. PMID- 10112748 TI - Rochester Methodist finds the right blend. PMID- 10112749 TI - Special report on taxation. Prepare for impending legislation that could threaten your tax-exempt status! AB - With impending federal action, and the likelihood of "copycat" legislation at the state and local levels if a federal statue is adopted, nonprofit hospitals need to ensure that they will be in compliance if a mandatory charity care bill were to become law. Such facilities should take the initiative now, by clearly articulating their charity care policies and by describing their other undercompensated or uncompensated activities that are maintained in order to benefit their communities. They should also ensure that all of their activities that could be counted as charity care or community benefit are fully documented and quantified. Financial consultants and counsel may be helpful in this process. Exempt facilities also should, of course, closely monitor the progress of the bills discussed above. Most importantly, they should continue to test their charity care and community benefit statistics on a regular basis to determine if their facilities meet the thresholds specified in the bills as they proceed through Congress. PMID- 10112750 TI - Crime in hospitals 1988, 1989--the latest IAHSS (International Association for Healthcare Security & Safety) surveys. AB - Here are the results of the annual IAHSS surveys on crime in hospitals for 1988 and 1989. The results are compared with data from previous surveys. Detailed charts illustrating 1989 results are also presented. PMID- 10112751 TI - Stretching the security dollar. PMID- 10112752 TI - Risk management and hospital security: not a good idea. PMID- 10112753 TI - The role of safety and security directors in asbestos abatement programs for hospitals. AB - Asbestos removal in any building can pose a health risk to both workers and occupants of the building. This is especially true in hospitals. What precautions should the hospital safety and security directors take to minimize health risks? This article discusses ways to develop and implement an asbestos abatement program for hospitals that is both safe and effective. PMID- 10112754 TI - Hazardous materials and hospitals--a potentially deadly mixture. PMID- 10112755 TI - Diagnosing crime trends. AB - Reporting is the key to the successful curbing of crime. Without good reporting, there can be no compilation of statistics for analysis and subsequent action. This article examines a crime-tracking program at a group of 14 hospitals in northern California. PMID- 10112756 TI - Hospital security: is the patient at risk? AB - This article focuses on the safety and security of the hospital patient, especially the role of the caregiver, as an important element in today's hospital environment. The author believes that not only the nursing unit but the entire hospital employee staff must be utilized to provide a reasonably safe and secure environment for not only the patient, but the staff and visitors as well. PMID- 10112757 TI - Hospital emergency room security--the next decade. PMID- 10112758 TI - A case history of a baby kidnapping. PMID- 10112759 TI - K-9 teams in a California hospital. AB - The author discusses the acquisition of K-9 teams by his hospital. The need for the program, its results, and the role of the team in the hospital are explored. PMID- 10112760 TI - Service-oriented security: saying "how may I help you" and really meaning it. PMID- 10112761 TI - A systems approach to understanding problems and solutions in the healthcare security field. AB - This article describes an applied 'systems approach' for understanding hospital security needs problems and solutions. It is a companion to 'A Theoretical (but Practical) Model for Managing Hospital Security Programs' by the author, which appeared in Volume 6, Number 2 of this journal. PMID- 10112762 TI - Funding security officer training: a creative approach. AB - Forces to cancel the first basic security officers training program in Maine in 1989, the author relates how the Pine Tree Chapter members were able to obtain state vocational education funds to finance two highly successful classes. PMID- 10112763 TI - Hospital security and safety--aloha style. AB - Visitors to Hawaii need not be fazed by concerns that they will be unable to communicate during a medical crisis. Trained IAHSS security officers representing all races and ethnic groups provide friendly, helpful service. The Hawaii Chapter of IAHSS coordinates activities of mutual concern among the nine major medical centers on Oahu and Maui. Hospital security does play an integral role in the activities of the Honolulu Police Department's Council of Police and Private Security (COPPS). PMID- 10112764 TI - The British are coming. AB - In this article, the author discusses the visit of six British constables to his hospital, and gives some lessons in healthcare security to be learned from the British. PMID- 10112765 TI - A comparison of Medicaid and non-Medicaid obstetrical care in California. AB - The use of prenatal care and rates of low birth weight were examined among four groups of women who delivered in California in October 1983. Medicaid paid for the deliveries of two groups, and two groups were not so covered. The analyses suggest that longer Medicaid enrollment improved the use of prenatal care. The association between prenatal care and birth weight was less clear. For women under Medicaid, measures of infant and maternal morbidity, hospital characteristics, and Medicaid eligibility were all statistically related to charges, payments, and length of stay for the delivery hospitalization. PMID- 10112766 TI - Health care indicators. AB - Contained in this regular feature of the journal is a section on each of the following four topics: community hospital statistics; employment, hours, and earnings in the private health sector; prices; and national economic indicators. These statistics are valuable in their own right for understanding the relationship between the health care sector and the overall economy. In addition, they provide indicators of the direction and magnitude of health care costs prior to the availability of more comprehensive data. PMID- 10112767 TI - Loss of Medicaid and access to health services. AB - In this article, the authors assessed the effects of the loss of Medicaid eligibility on access to health services by the medically indigent population in two California counties. An historically derived baseline of health services received by each county's medically indigent adults under Medicaid was compared with the volume of services provided by the county to the same population after they lost Medicaid eligibility. The baseline figures were used as an "expected" volume of services which can be compared with the actual, or "observed," volume of services. The analysis found fewer hospital discharges than expected in Los Angeles and much fewer outpatient visits than expected in Orange County, suggesting that these groups experienced substantial reductions in access related to loss of Medicaid eligibility. PMID- 10112768 TI - Measuring geographic variations in hospitals' capital costs. AB - The Health Care Financing Administration (HCFA) has proposed incorporating hospital capital payments into the Medicare prospective payment system. HCFA's proposal includes an adjustment to capital payments for geographic differences in capital costs, derived from the prospective payment system area hospital wage index. Alternatively, the geographic adjustment could be based on an area construction cost index. Geographic construction cost indexes calculated from the cost per square foot of finished structures or from construction labor and materials input prices are evaluated in this article. PMID- 10112769 TI - Medigap preferred provider organizations: issues, implications, and early experience. AB - The Health Care Financing Administration is sponsoring the Medicare Physician Preferred Provider Organization (PPO) Demonstration to assess the feasibility and desirability of including a PPO option under Medicare. Two sites are currently operational. At one site, Blue Cross and Blue Shield of Arizona is offering a PPO linked with a medigap insurance plan. This "medigap PPO" and its initial experience are described, and a preliminary assessment of the viability and effectiveness of medigap PPOs nationally is provided. Impediments to the development and effectiveness of medigap PPOs are identified and possible government actions discussed. PMID- 10112771 TI - Contracts of a clinical kind. PMID- 10112772 TI - Making a clear case for care. PMID- 10112770 TI - Access to hospital care for California and Michigan Medicaid recipients. AB - This article is a comparison of the characteristics of hospitals serving the general population and Medicaid recipients in California and Michigan, using data from Medicaid uniform claims files and the American Hospital Association Annual Survey for 1984. A greater concentration of discharges in a small number of "high Medicaid volume" urban and rural hospitals in each State was observed for Medicaid recipients compared with the general population. In addition, discharge data suggest that Supplemental Security Income crossovers (individuals covered by both Medicaid and Medicare) and other recipients (mostly children not enrolled in the Aid to Families with Dependent Children program) receive inpatient care in different hospitals from the general population as well as from other Medicaid eligibility groups. Medicaid cost-containment policies and differential access to hospital care are discussed. PMID- 10112773 TI - Job satisfaction? PMID- 10112774 TI - Measure for measure. PMID- 10112775 TI - A process for implementation of the strategic plan: from strategic planning toward strategic management. AB - Although the principles and process for developing a strategic plan are well established, little information exists on how organizations can implement these plans. The authors developed a framework and methodology for The Ontario Cancer Institute/Princess Margaret Hospital that connects the implementation of the strategic plan with resource allocation and the budget; thus, the budget is a quantified expression of the strategic plan. To accomplish this, a specific cycle of events leading to the development of a corporate calendar was undertaken, which results in the establishment of the annual budget. PMID- 10112776 TI - Estimating replacement costs for hospital equipment. AB - This paper presents a methodology for predicting future replacement costs of hospital capital equipment. The methodology is applied to the equipment inventory of a large Canadian teaching hospital. The authors used forecasted Producer Price Indexes for several equipment categories, and applied them to the estimated equipment replacement needs. The Canadian Management Information System schedule and the American Hospital Association schedule were used to determine the estimates, which varied considerably between the two schedules. However, the test case demonstrated that such estimates can help hospitals to document capital funding needs in relation to available funds. PMID- 10112777 TI - Managing for change: a departmental quality improvement program (QIP). AB - The development and implementation of an integrated Quality Improvement Program (QIP) for the Department of Surgery at The Hospital for Sick Children was approached as a problem-solving process by which departmental managers could bring about change so that actual results would align more closely with desired outcomes. A planned and systematic process was developed, through which managers are able to reach decisions about when and where to make useful changes that result in improved quality of care and services provided. Three useful techniques were employed: team-building, continuing education and quality circles. PMID- 10112778 TI - Use of severity to evaluate appropriateness of admissions and length of stay. AB - We undertook a case study for a Canadian teaching hospital to see if use of a severity of illness system could facilitate management of utilization practice in the hospital. The two issues selected were low severity emergency room admissions and length of stay on medical services. Use of a severity system allows for comparisons within case mix groups and also should control for large differences in severity within CMGs. The results of the study were consistent with the prior expectation of the hospital with respect to the relative efficiency of the physicians under study. PMID- 10112779 TI - "Zero-based health planning" and "hospitals without beds": two thought experiments for health care planners. PMID- 10112780 TI - Salutatorian's address 1991. Canadian College of Health Service Executives. PMID- 10112781 TI - Great expectations. What do EMS volunteers want from management? AB - When people volunteer their time and services to an organization or cause, they expect and deserve compensation of some kind in return. Find out what motivates volunteers and how to meet their needs. PMID- 10112782 TI - The rural route to success. Comparing EMS in three Alabama counties. AB - Why do volunteer EMS systems in otherwise healthy economic communities fail, while other communities, with low per-capita incomes, enjoy thriving volunteer services? This article studies three volunteer systems in rural Alabama to determine the keys to success. PMID- 10112784 TI - The changing portrait of today's volunteer. PMID- 10112783 TI - Money talks, nobody walks. Financial incentives for volunteers. PMID- 10112785 TI - The signs of silence. Communicating with deaf and hearing-impaired patients. AB - Nearly 7 percent of the U.S. population is deaf or hearing-impaired. Yet few EMS providers know how to identify or communicate with these special-need patients. Find out how to bridge the gap to deal effectively with this patient population. PMID- 10112786 TI - Paramedic licensure. New wave or washout? AB - The debate between paramedic licensure and certification is a complex one, with myriad pros and cons on each side. How would licensure change your role as an EMS provider? And what would the impact be on your salary? This article addresses these questions and more. PMID- 10112787 TI - The perils of reciprocity. PMID- 10112788 TI - The economics of EMS employment. PMID- 10112789 TI - Continuing education. Who needs it? PMID- 10112790 TI - A practical approach to paramedic precepting. AB - Field-training programs allow paramedic students to train in the field with other EMS providers before they are thrust out on their own. However, paramedic trainers--better known as preceptors--are not given the same luxury of time and training to perform their jobs effectively. This article serves as a guide to ensure that the needs of the intern, preceptor and EMS agency are all well served. PMID- 10112792 TI - CAHEA (Committee on Allied Health Education and Accreditation). Accredited EMS programs. PMID- 10112791 TI - The graying of EMS. AB - Prehospital providers may be aging along with the rest of the population, but there is strength and value in silver--as well as spunk, wisdom and experience. In this article, the current status of older EMS providers is revealed through the personal accounts of 12 senior responders who consider their work a labor of love. PMID- 10112793 TI - Preparing for the worst. The challenge facing NDMS (National Disaster Medical System). AB - Although mass-casualty disasters in the United States have been rare, as populations grow, so does the prospect of a full-scale emergency occurring in our midst. Federal agencies have been at work for nearly a decade developing the National Disaster Medical System to care for the victims of such disasters. PMID- 10112794 TI - Disaster response in paradise. PMID- 10112795 TI - Events precipitating psychiatric hospitalization of children. AB - The precipitating events that preceded the admission of 50 children to an inpatient psychiatric program were studies and defined. These events, while varying in their particulars, could be grouped into three broad conceptual categories: 1) emotionally related events; 2) severe-conduct events; and 3) school-related events. The emotionally related events were the most numerous: suicide threats or attempts preceded the admission of 22% of the sample. The study findings are discussed in terms of their developmental, treatment, and preventive significance and are compared with the findings obtained from a previous study with adolescent patients. PMID- 10112796 TI - Inpatient treatment for depressed children and adolescents: preliminary evaluations. AB - Reported are the results of two uncontrolled outcome studies that evaluate the effectiveness of inpatient psychiatric treatment of children and adolescents suffering from clinical depression. Study 1 employed a sample of 7 children and measured outcome with the Depression Self-rating Scale (DSRS), the Hopelessness Scale for Children (HSC), and the Global Asssessment of Functioning (GAF) scale, which were administered to each child upon admission and again at discharge. Inpatient treatment involved multiple interventions, including individual psychotherapy, medication, milieu therapy and token economy, and other procedures. At discharge, statistically significant improvements were found on the patients' GAF and HSC scores, but not on their DSRS scores. Study 2 used a sample of 15 adolescents, also admitted for clinical depression. Administered at each patient's admission and discharge, the Beck Depression Inventory (BDI), Generalized Contentment Scale (GCS), and Index of Self-esteem (ISE) were used to measure outcome. The multi-modal treatment program offered to the sample in Study 2 was similar to that offered the sample in Study 1. At discharge all three outcome measures reflected statistically significant improvements in the patients studies; therefore, these results provide addmtional support for the inpatient treatment of depressed children and adolescents. PMID- 10112797 TI - Nursing turnover in a psychiatric hospital. AB - Demands for quality nursing care in both psychiatric and general hospitals are increasing as the nation experiences a shortage of registered nurses (RNs). The average national turnover rate in the healthcare industry is almost 23%, and nurses account for 50% of that percentage (1). Because a stable, competent nursing staff is essential to meet the mandates of physicians and patients for quality inpatient care, the failure of a hospital to provide high-quality nursing in today's competitive healthcare climate may cause physicians and patients to go elsewhere. The nursing shortage and high nursing turnover rates have had a negative effect on both general and psychiatric hospitals. The focus of the study described in this article was on a specific psychiatric hospital, and the objective was to determine how hospital management might respond to the current nursing personnel challenges. An action research model was used to determine what employment factors were viewed by nursing personnel as most valuable and how satisfied the nurses were with these factors in their workplace. The results are reviewed. PMID- 10112798 TI - The effect of inpatient psychiatric hospitalization on weight gain in children and adolescents. AB - Measures of weight were obtained both at admission and at discharge for children and adolescents receiving inpatient services at a private psychiatric hospital. The sample included 20 males and 20 females from each of three units: child psychiatric, adolescent psychiatric, and adolescent substance abuse. The difference between the actual weight change of the subjects and the weight change predicted from growth charts was obtained. Overall, subjects gained a significant amount of weight. The actual mean increase in weight was roughly 3.5 times greater than the predicted increase, and there were no significant differences in weight gain between males and females among patients from each of the three units. Potential explanations for this increase in weight are explored, and the implications are discussed. PMID- 10112799 TI - Nutritional practices, knowledge, and attitudes of psychiatric healthcare professionals: unexpected results. AB - This study investigated inter-relationships among nutrition knowledge, habits, and attitudes of psychiatric healthcare providers. Data of nutritional intake was compared with that of the general population of the state of South Carolina, obtained from a previous public health study. Nutritional habits were determined from both a 24-hour recall and a separate three-day recall of dietary intake. Nutrition knowledge and attitudes were determined by validated questionnaires. The knowledge questionnaire consisted of 50 multiple-choice questions. Attitudes were determined using a semantic differential instrument consisting of phrases of descriptive bipolar adjectives. Dietary intake was analyzed using the Food Processor software and compared with the RDAs and with the intake of the general population. Nutrition knowledge was measured by the number of correct responses. Nutrition attitudes were assigned numerical scores and measured by a Likert scale. Only 3 of the subjects met 70% of indicator nutrients (iron, calcium, vitamin B6, and vitamin C). No significant relationships were established among attitudes, habits, and knowledge. Sixty-three percent of subjects perceived themselves as role models to patients, yet 90% of them practiced poor nutrition habits as compared with 97% of the general population. The higher the education level, the more likely that subjects felt nutrition is important for health. A comprehensive nutrition education program is essential for health care providers to promote successful nutrition education for the patients they serve. PMID- 10112800 TI - Impact of a natural disaster on a psychiatric inpatient population: clinical observations. AB - Natural disasters do not always lead to post-traumatic stress disorders (PTSD) for their victims, although stress-related symptoms are commonly reported as results of such disasters. The impact of a natural disaster on the treatment of a hospitalized psychiatric population has never been systematically evaluated. In the fall of 1986, severe river flooding caused evacuation of a 160-bed psychiatric facility. One hundred and twenty-one hospitalized patients were taken to nearby hospital facilities, and many were separated from their primary therapists, fellow patients or both. A mail survey two months post-evacuation assessed stress-related symptoms, the patients' opinions of the impact of the flood on their treatment and functioning, and the patients' views of the evacuation procedures. Patients also responded to questions about their cognitive and affective reactions during each phase of the disaster. Clear evidence of PTSD was not found with this population; however, the findings underscore the importance of keeping patients with familiar staff and peers when possible. Differences between this study and previous disaster studies are noted, and suggestions for coping with natural disasters in inpatient or residential psychiatric facilities are offered. PMID- 10112801 TI - Liability without fault and the AIDS plague compel a new approach to cases of transfusion-transmitted disease. PMID- 10112802 TI - Health care in the '90s: a human resources revolution. PMID- 10112803 TI - Lessons from a first-time borrower. PMID- 10112804 TI - Is traditional quality assurance on its way out? PMID- 10112805 TI - Toward integrated care: new medical staff organizations. PMID- 10112806 TI - Are hospitals prepared for more growth in ambulatory care? PMID- 10112808 TI - Avoiding trustee conflict of interest. PMID- 10112807 TI - Quality and costs: do you hear the next shoe dropping? PMID- 10112809 TI - Leadership volunteers are responsible to their communities. PMID- 10112810 TI - Teaching hospitals: maintaining balance. Interview by Karen Gardner. PMID- 10112811 TI - Medicaid financing bolsters argument for health care reform. PMID- 10112813 TI - Communication can ease normal merger tensions. PMID- 10112812 TI - Preventing malpractice: the board's role in risk management. PMID- 10112814 TI - Computer streamlines DVS (director of volunteer service) management, motivates volunteers. PMID- 10112815 TI - HAVE (Hospital Awards for Volunteer Excellence) winners describe programs. PMID- 10112816 TI - Meet AHA's new president. Interview by Mary Grayson. PMID- 10112818 TI - Kellogg's view of volunteerism. PMID- 10112817 TI - Auxiliary and DVS (director of volunteer services) issues in mergers. PMID- 10112819 TI - Improving the merger climate. PMID- 10112820 TI - Give a Little--Get a Lot: a citywide volunteer recruitment campaign. PMID- 10112821 TI - TMC (Tucson Medical Center) boosts volume with fewer people. AB - Is it possible to just about double your volume and reduce your number of FTEs at the same time? See how it was done at this Arizona laundry. PMID- 10112822 TI - Communication is the key to a manager's success. PMID- 10112823 TI - Different answers from different managers. AB - How well is your laundry operating? Columnist Carl Shusterman believes you should keep in close touch with your contemporaries and compare your facility to others in your area. PMID- 10112824 TI - Health industry prepares to embrace EDI. PMID- 10112825 TI - Increasing an X-ray department's operating efficiency. PMID- 10112827 TI - Guidelines for the pharmacist on the role of the pharmacy technician. Ontario College of Pharmacists. PMID- 10112826 TI - Technician education and training programs. 1991 update. PMID- 10112828 TI - Perspectives. Dentistry wrestles with change. PMID- 10112829 TI - Perspectives. Into the fray: states take the lead on health reform. PMID- 10112830 TI - Implementing quality improvement for air medical services. PMID- 10112831 TI - Air medical tracheal intubation: establishing a threshold for this QA indicator. AB - Endotracheal intubation is a critical skill necessary in a number of situations encountered by air medical personnel. The purpose of this study was to establish a threshold for the quality assurance indicator of successful tracheal intubation in a physician-staffed air medical system. The records of all patients transported by a physician-staffed air medical system over a 36-month period were reviewed. One hundred and forty-three patients had endotracheal intubation attempted. Blind nasotracheal intubation attempts were successful in 71% of those in whom it was attempted, while the overall intubation success rate was 92%. Based on this study and the existing literature, a threshold of 90% is recommended for the quality assurance indicator of successful tracheal intubation in physician-staffed air medical systems. PMID- 10112832 TI - Airbags and the rescue professional. PMID- 10112833 TI - Quality assurance in the Connecticut Helicopter Emergency Medical Service. AB - Quality Assurance (QA) is a vital aspect of the Connecticut Helicopter Emergency Medical Service (HEMS). The program has three components: 1. scene flight audit, 2. random chart audit, and 3. biweekly patient care QA conferences. The scene flight audit identifies patients who, in retrospect, may not have required helicopter transportation. These patients are identified by the following criteria: trauma score greater than 12 and injury severity score less than 16, emergency department deaths, discharged within 24 hours, medical patients. Patient care QA involves review of all flights. A random chart audit is a method of peer review of the written flight record for completeness. The scene flight audit was from 6/85 to 12/87, with 17/107 (16%) in group one, 0/137 (0%) in group two, 5/29 (17%) in group three, and 8/54 (15%) in group four not justified. There were four audit review periods, each with a feedback mechanism to share results with providers. Each audit resulted in a decrease in the number of non-justified flights. There were 57 patient care QA conferences with 231 cases presented. Technical errors and policy issues decreased over time. Random review of five charts/month were reported quarterly. Omitted elements of standard documentation decreased over time. QA can be accomplished in HEMS. Monitored areas should include appropriateness of flights, proper documentation, and patient care review. A QA program improves appropriateness of flights, medical record keeping, and care given. PMID- 10112834 TI - Let the patient maintain. AB - This paper concerns itself with storage and retrieval systems. These are problems which concern us all and sometimes seem to be insoluble. When you add the cost of staff and the difficulty of recruiting good people to do this essential work, the problems get worse. PMID- 10112835 TI - A place for microfilm in medical records. AB - Since man started keeping records, his problem has always been that the numbers grow, seemingly unchecked. In some industrial and commercial situations it is reasonable to throw out old records once they have reached a certain age-even income tax and VAT records do not have to be retained for more than seven years. PMID- 10112836 TI - The archives project at York Health Authority. PMID- 10112838 TI - Don't wait for a rainy day: backup your data base. PMID- 10112837 TI - Information requirements post-review and medical records. PMID- 10112839 TI - Better benefits emerge from tax-wise choices. PMID- 10112840 TI - Effective ways to hire contingent personnel. PMID- 10112841 TI - Increase finances through progressive management. PMID- 10112842 TI - Succession plans designed to manage change. PMID- 10112843 TI - The "basics" of in-house skills training. PMID- 10112844 TI - Where do I start? PMID- 10112845 TI - The layoff legacy. PMID- 10112846 TI - Corporate scale down, what comes next? PMID- 10112847 TI - What's wrong with Workforce 2000? PMID- 10112848 TI - High-tech recruiting at low cost. PMID- 10112849 TI - Smooth steps to transition meetings. AB - New teams go through a maturation process that can, but often does not, lead to productivity. A properly conducted transition meeting can speed the process and ensure its success. PMID- 10112850 TI - The sexlessness of harassment. PMID- 10112851 TI - EPA boiler regulations affect hospital heating plants. PMID- 10112852 TI - OSHA inspection procedures and fine schedules. PMID- 10112853 TI - Resource directory. Licensing/credentialing requirements in respiratory therapy. AB - Most call it licensing. Others say credentialing or certification. Whatever the terminology, you will have to meet certain requirements to practice your healthcare discipline in any given state. Because these qualifications differ throughout the nation, you should gather this information from the state in which you wish to practice as soon as possible. To help you become familiar with these qualifications, we have compiled a state-by-state summary of practice requirements. We start with respiratory therapy and will continue with occupational therapy, pharmacy, nursing and physical therapy in later issues. For more complete information, contact appropriate state licensing/credentialing agencies. Their phone numbers and addresses will be featured in HT&T's upcoming Resource Directories. PMID- 10112854 TI - A day in the life of Bill Colwell. PMID- 10112855 TI - Future promises, challenges and opportunities. PMID- 10112856 TI - Using the past to see your future. PMID- 10112858 TI - Resource directory--occupational therapy. Licensing requirements and state licensing agencies. PMID- 10112857 TI - The what, when, why and how of the National Certification Exam. PMID- 10112859 TI - Time to leave the capsule ... if you dare. AB - Outpatient prescription drugs now make up one of the fastest growing components of America's health care bill. Managed care can help cut it. PMID- 10112860 TI - Stressed to kill. AB - Many employees are suffering burnout due to work and family-related stress. What are the effects of stress in the workplace? And what can employers do to check the effects of this unseen, but dangerous, enemy? PMID- 10112861 TI - Electronic claims: still buyer beware? AB - Information obtained from electronic claims systems can help employers make good decisions. But with all the different packages out there, how will employers know which ones are best for them? PMID- 10112863 TI - The medical-industrial complex. PMID- 10112862 TI - Getting to know about AIDS. AB - Through an extensive AIDS education program, Sun Life Insurance prepared its employees for the possibility of AIDS cases within the company. Its focus was on disseminating accurate information, keeping employees up to date, and dealing with AIDS victims compassionately. PMID- 10112864 TI - Old, sick and far away. How to find care for your elderly parents when you can't do the job yourself. PMID- 10112865 TI - Last rights. In sickness and in health, more people are taking life's biggest decision away from doctors and into their own hands. AB - When dying is all that awaits them, more and more people are choosing certain death now rather than uncertain life on medical support systems. But the decision seldom comes easy, as a Newsweek reporter discovers during three weeks with the doctors, nurses, patients and families in an intensive-care ward. A best-selling guide to suicide fires debate over when it is right to let life go--and who should make that choice when the patient no longer can. PMID- 10112866 TI - Choosing death. PMID- 10112867 TI - Quality management program and misadministrations--Nuclear Regulatory Commission. Final rule. AB - The Nuclear Regulatory Commission (NRC) is amending regulations governing therapeutic administrations of byproduct material and certain uses of radioactive sodium iodide to require implementation of a quality management program to provide high confidence that the byproduct material or radiation from byproduct material will be administered as directed by an authorized user physician. The Commission believes this performance-based amendment will result in enhanced patient safety in a cost-effective manner while allowing the flexibility necessary to minimize intrusion into medical judgments. This amendment also modifies the notification, reporting, and recordkeeping requirements related to the quality management program and misadministrations. PMID- 10112868 TI - Medicare and State health care programs: fraud and abuse; OIG anti-kickback provisions--HHS. Final rule. AB - This final rule implements section 14 of Public Law 100-93, the Medicare and Medicaid Patient and Program Protection Act of 1987, by specifying various payment practices which, although potentially capable of inducing referrals of business under Medicare or a State health care program, will be protected from criminal prosecution or civil sanctions under the anti-kickback provisions of the statute. PMID- 10112869 TI - Nursing student loan program--PHS. Final regulation. AB - This rule amends existing regulations governing the Nursing Student Loan (NSL) program to require schools to: (1) Invest their NSL funds and return earnings from the investments to the NSL funds; (2) identify and return to the Department excess cash from the NSL funds; and (3) determine the collectibility of defaulted loans and, for loans determined to be uncollectible, either obtain approval to write off the loans or reimburse the fund for the amount that remains uncollected on the loans. However, schools are not required to obtain write-off approval or reimburse the fund for loans that became uncollectible prior to January 1, 1983. The Department expects that these revisions will enhance its enforcement capabilities for improving the cash management practices of schools participating in the NSL program. PMID- 10112870 TI - Establishment of criteria for determining priorities among designated health professional shortage areas--HRA. Notice. AB - In accordance with the requirement of section 333A(c) of the Public Health Service Act, as amended by Public Law 101-597 (the National Health Service Corps Revitalization Amendments of 1990), this Notice establishes the criteria which the Secretary will use to make determinations under section 333A(a)(1)(A) of the health professional shortage areas (HPSAs) with the greatest shortages, using the exclusive factors specified in section 333A(b). PMID- 10112871 TI - Retention of laboratory records. PMID- 10112872 TI - The laboratory workload measurement system revisited--the MIS group. PMID- 10112873 TI - Task force on RT examinations. Summary of the feedback. AB - There was a large volume of feedback and comment on the discussion paper on the future format of RT examinations. Published in the Canadian Journal of Medical Technology, volume 52, #4, 1990. A total of 63 individual submissions was received, of which 12 addressed cytotechnology only and three addressed RT subject examinations. Because many of the responses came from groups, such as faculty liaison committees or instructor groups, some 300 didactic and clinical teaching personnel were involved in the feedback. Submissions were received from 21 of the 31 RT general programs and from six of the nine cytotechnology programs. The responses can therefore be taken as representing a good cross section of opinion among training program personnel. The feedback was studied recommendation by recommendation, to determine the levels of agreement and disagreement and to summarize the questions, comments and concerns. PMID- 10112874 TI - ART certification--an overview. AB - The committees involved in developing the new ART process have received many comments from various groups and individuals in the country. There has been little, if any, response from employers, whose comments would be appreciated to determine if those who attempt the new ART will better meet their expectations. It was felt that the technologist with the new ART designation will be a more rounded technologist. PMID- 10112875 TI - Safe blood. A technologist's history of the Canadian Red Cross Blood Transfusion Service. PMID- 10112877 TI - Code of Ethics. Canadian Association of Medical Radiation Technologists. PMID- 10112876 TI - The significance of policies relating to clinical laboratory specimens. PMID- 10112878 TI - Using touch to enable patient care in radiography. AB - This article explores the use of touch in patient care in radiology departments. Touch can work positively in many ways, however, radiologic technology articles have failed to explore its possibilities. This article reviews literature from other fields and describes how some authors view how touch can improve patient care. PMID- 10112879 TI - Discipline of technologists. PMID- 10112880 TI - Laughter: the best medicine. AB - Introducing the joy of play and laughter into high-stress, high-demand work environments can increase creativity, productivity and motivation, as well as improve communication and boost morale, say several experts on humor in the workplace. PMID- 10112881 TI - Advice on excelling during surveys. Responsive facilities perform like well-oiled machines. PMID- 10112882 TI - Cultural diversity. Aligning tomorrow's work force. PMID- 10112883 TI - Regulations plus respect equal good business. Consultant pharmacists upbeat about the future. PMID- 10112884 TI - Aiming at not-for-profits. Congress looks for justification of tax exemptions. PMID- 10112885 TI - Stamping out MARSA. War against infection escalates. PMID- 10112886 TI - Plugging into computerized assessment. Mandatory MDS (minimum data set) automation on the way. PMID- 10112887 TI - Neglect and abuse prevention. PMID- 10112888 TI - Consultants play key role in infection control. PMID- 10112889 TI - Preparation of parents for the ICU experience: what are we missing? AB - This study examined the stress experienced by parents of children hospitalized in an intensive care unit (ICU) and explored the degree to which parents are prepared for specific aspects of the ICU environment. Twenty-two mothers and 6 fathers of 22 children hospitalized in a pediatric ICU were interviewed using the Parental Stressor Scale: Pediatric Intensive Care Unit, the Parent Preparation questionnaire designed for this study, and a personal-situational questionnaire. A majority of parents (82%) responded that they had been prepared in some manner and considered the preparation adequate. The dimensions of the ICU that were perceived by parents as most stressful were the child's behavior and the child's emotional response, and parental role alterations. The dimensions of the ICU environment that parents were least likely to have been prepared for or receive help with were these same dimensions. When parents were prepared for or helped with aspects of the ICU, they perceived the adequacy of that help as high. The results of this study suggested that an important focus in parental education and support should be on the parent-child relationship, the most stressful aspect of a child's ICU admission for parents. PMID- 10112890 TI - Nurse supportive acts for mother-preterm infant pairs. AB - Nurse Supportive Acts were measured during the conduct of a nursing intervention designed to facilitate mother-preterm infant acquaintance in the hospital and at home. The most frequently performed supportive acts included "active listening," "sounding board," "information exchange," and "validation." Use of these communication skills allows the health care provider to give care which is flexible and sensitive for mothers and their preterm infants. PMID- 10112891 TI - Examining emotional distress during pediatric hospitalization for school-aged children. AB - Emotional distress was examined in 80 school-aged children during pediatric hospitalization. Using multiple regression analyses, children's depressive and anxious symptoms were positively related to duration of physical symptoms and parental distress. Depressive symptoms were negatively related to age and the perceived social support available from the family. Unexpectedly, the frequency of medical procedures and previous hospitalization experiences were not associated with depressive or anxious symptoms. Because many of the children in this study had experienced enduring symptoms and frequent previous hospitalizations, it was hypothesized that they may have habituated and adjusted to many of the experiences of hospitalization and thus were not adversely affected by such experiences. PMID- 10112892 TI - Focus group interview with parents of children with medically complex needs: an intimate look at their perceptions and feelings. AB - The purpose of this paper was to identify the needs of parents of children with medically complex needs from their own perception. In order to provide in-depth information, the focus group interview technique was used. Several strong recurrent themes were identified. The most persistent need was for a general organization or framework with which the care providers could operate. Along these same lines, the fragmentation of training, needs and services was consistently stated. A general lack of information in terms of home care and how to plan for the future was identified. Support groups were universally lauded for the invaluable services provided to the care parents. PMID- 10112893 TI - Pediatric family home visitors: effectiveness in problem solving. AB - A number of studies have shown the value of using home health visitors in intervention outreach programs for low-income families. This study was designed to examine the relationship between home visitors' and nurses' training/home visiting experience and their decision-making ability as determined by the Defining Issues Test (DIT). The subjects were 36 home visitors, 13 visiting nurses, and 28 controls. A difference was found between the home visitors' and nurses' training/experience levels and group scores on the DIT, F(3, 75) = 3.13, p = 0.03. The nurses were better able to make decisions based on issues of fairness and justice than were the home visitors or the controls. The findings suggest the advisability of providing educational opportunities for home visitors to improve decision-making skills. PMID- 10112894 TI - A call to action in behalf of children and families. PMID- 10112895 TI - A survey of pharmacy-coordinated investigational drug services. AB - Over the past few years, pharmacy involvement in investigational drug studies has grown. In 1986, Kingston General Hospital conducted a nation-wide survey assessing the extent of pharmacy involvement in clinical drug trials. The aims of the present survey were to show how Investigational Drug Services (IDS) have changed in recent years, to determine areas that need improvement, and to characterize methods of reimbursement for IDS. A total of 148 Canadian hospitals (300 or more beds) were mailed a detailed IDS questionnaire. A response rate of 68% was achieved. Survey results were grouped in the following categories: increase in clinical trials involvement, IDS staffing levels, sponsorship of trials, major areas of clinical drug research, areas of IDS needing improvement, and reimbursement issues. The results of this survey indicate that since 1986 pharmacy departments are becoming more involved in the coordination of clinical drug trials. Perceived areas for improvement in IDS were strikingly uniform between institutions, despite a large variation in the extent of existing services. Reimbursement procedures are not consistent and several methods are used to obtain pharmacy funding. Recommendations are offered for assistance in the development or expansion of pharmacy-coordinated IDS in Canadian hospitals. PMID- 10112896 TI - The Canadian Oncology Pharmacy Research Network. AB - Research in hospital pharmacy has been increasingly highlighted in recent years, with special attention focused by the Research Committee of the Canadian Society of Hospital Pharmacists (CSHP). In a first attempt to organize potential oncology pharmacist researchers, an invitation to join a research network was distributed to hospital pharmacists across Canada in late 1988. Data sheets, including personal demographic data, practice and research information, members' perceived roles in future research projects, experience and training, interest in multi centre research projects, and specific areas of research involvement were used to create a roster of pharmacist researchers. Sixty-nine pharmacists submitted their names to the roster. Details on each respondent were then transferred to a standardized data spreadsheet which was distributed back to each network member. Members then had a listing of potential researcher colleagues to aid in their development or participation in multi-centre studies. Data provided by the respondents were analyzed to characterize the nature of this network. Twenty of 60 members reported qualifications beyond BSc and 11 members hold advanced degrees. There was a wide variation of time available for research activities. A weekly commitment of three to ten hours (reported by 25/48) is a reasonable amount of time for successful research involvement. Previous training and experience are also positive factors: 25/69 had postgraduate training, 25/68 had previous experience conducting a research project and 34/67 had collaborated on a study project. There were two cohorts of potential researchers in oncology pharmacy--those who are prepared to run a project, and those who wish to contribute to projects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10112897 TI - Medication profiles in an outpatient cancer facility. PMID- 10112898 TI - Directors of pharmacy--your performance is being appraised. PMID- 10112899 TI - Quality management: fad or future? AB - The number-one job of healthcare chief executive officer is to be the standard bearer for quality healthcare delivery, says the top man of the Chicago-based Lutheran General Health Care System, an extensive multicorporate health organization. As long as the CEO remains vigilant and personally responsible for quality at his or her institution, quality management cannot become just a passing fad. PMID- 10112900 TI - Information systems support for healthcare quality: a comprehensive framework. AB - Although management concepts for delivering quality products and services have been employed extensively in other industries, their inroads into healthcare have been comparatively slight. In the first of a two-part series, healthcare information systems consultant Peter Spitzer, M.D., sets forth a framework for defining high-quality healthcare delivery, and he tells how information systems can be put to work to achieve this goal. PMID- 10112901 TI - Quality assessment: from paper shuffle to paperless review. AB - Even though much of the quality-assurance process had been automated at Kettering Medical Center (KMC) in Dayton, Ohio, reviewers still had to key in data from paper records each day. An extensive paper trail continued until Kettering took the leap to total paperless review using eight laptop computers with internal modems. PMID- 10112902 TI - QA systems must balance functionality with data security. AB - Confidentiality of patient records has been a critical focus of automated clinical systems since their inception. The added dimension of quality assurance studies, however, greatly broadens the area of confidentiality and liability, heightening security concerns for quality-assurance professionals. PMID- 10112903 TI - Laboratory consolidation, coalescence and coalition. AB - Forces are now in place that may dismantle the laboratory industry as we know it today and create a new different and "blended" medical lab industry. Information systems technology will play a key role in this reshaping process. PMID- 10112904 TI - The LIS: the overlooked tool for TQM. PMID- 10112905 TI - Regulatory change impact upon hospital laboratory operations. AB - Dealing with the constantly changing regulatory landscape has become a routine aspect of the work of any hospital administrator or clinician in the past several years--and the laboratorian is no exception. Recently, however, two aspects of regulatory change have particular potential to require attention from the laboratory manager. They are the Resource-Based Relative Value Scale (RBRVS) Fee Schedule for Medicare Physician Payment and the Proposed Prospective Payment System for Inpatient Hospital Capital-Related Costs. PMID- 10112906 TI - A foot in the door. Interview by Carolyn Dunbar. PMID- 10112907 TI - Break the infection chain. Controlling infection potential prior to disposal of liquid infectious waste. PMID- 10112908 TI - Housekeepers "host" patients. PMID- 10112909 TI - Selecting a computerized housekeeping management software system. PMID- 10112910 TI - Computerized system simplifies cleaning chemical management. PMID- 10112911 TI - Basic skill development and the housekeeper. An experiment in workplace literacy. PMID- 10112912 TI - Slim profits, moral issue characterize AIDS care. PMID- 10112913 TI - Vertical integration increases opportunities for patient flow. AB - New sources of patients will become more and more important in the next decade as hospitals continue to feel the squeeze of a competitive marketplace. Vertical integration, a distribution tool used in other industries, will be a significant tool for health care administrators. In the following article, the authors explain the vertical integration model that shows promise for other institutions. PMID- 10112914 TI - Transitional planning calls for new thinking, approach. AB - The true challenge for hospital administrators in the future will be to rethink and retool the structure of their institutions. What must they do to accommodate the hospital in a rapidly changing health care field? The author suggests a transitional planning model that will be more than an interim step. It will be the final step in a long line of planning processes. PMID- 10112916 TI - Indicators confirms trend: hospitals slipping fiscally. PMID- 10112915 TI - Hospitals should track alternative care providers. PMID- 10112917 TI - Consultants calm hospital waters. Interview by Donald E.L. Johnson. AB - What do hospital administrators do when their institutions are in financial or other crisis? When is it appropriate to call in a specialist to right the situation? In the following interview with Health Care Strategic Management publisher, Donald E. L. Johnson, David L. Woodrum, president of The Woodrum Group, a Chicago-based health consulting firm, discusses the "turnarounds" and "revitalizations" of hospitals. In doing so, Woodrum draws on his past experience as executive vice president and chief operating officer of the American Hospital Association as well as chief officer for several hospitals. PMID- 10112918 TI - The boundaries of business: commentaries from the experts. AB - The World Leadership Survey, which began a worldwide dialogue on a set of important issues facing managers in the 1990s, continues with commentaries from four recognized experts, each of whom addresses the survey results from a different perspective. Kenichi Ohmae, chairman of McKinsey and Company in Tokyo, addresses "The Perils of Protectionism." Ohmae argues that the old definitions of national boundaries and corporate interests reflect obsolete economic theories. The real test of national well-being, Ohmae suggests, should be the economic welfare of a nation's citizens. Sylvia Ann Hewlett, economist and former director of the Economic Policy Council in New York, analyzes the survey in terms of "The Human Resource Deficit." According to Hewlett, four principles should guide corporate strategies in the 1990s: human resource development should move up the scale of corporate priorities; a family-friendly workplace will attract and keep talented workers; companies will take limited direct responsibility for training and education; the private sector will promote public investment in social issues. James E. Austin, the Richard P. Chapman Professor of Business at the Harvard Business School, writes about "The Developing-Country Difference." In developing countries, Austin observes, managers display attitudes and follow practices that diverge from those in developed nations. In particular, the role of government, investments in education and technology, and environmental concerns set these nations apart. Michel Crozier, president of the Centre de Sociologie des Organisations in Paris, writes about "The Changing Organization." In the 1990s, Crozier argues, managers need to break from old management theories and practice, questioning hierarchy, control, distance, access to information-the whole managerial system. PMID- 10112919 TI - A new compact for owners and directors. The Working Group on Corporate Governance. AB - The virtual demise of hostile takeovers and leveraged buyouts has not cooled the tensions over corporate governance. In congressional hearings, at annual meetings, and in proxy contests splashed across the business pages, senior executives and powerful shareholders continue to confront each other. The basic issues remain remarkably consistent. When do investors' legitimate needs for returns translate into destructive pressures on long-term corporate prosperity? What kinds of accountability do top managers owe shareholders in terms of strategic consultation and disclosure? What is the precise role of the board of directors as a management monitor and shareholder representative? More than a year ago, a working group of distinguished lawyers representing large public companies and leading institutional investors began a series of meetings to cut through the rancor. Their goal was to reach common ground on a set of principles that reconciles the tensions between owners and managers. Recently, the group agreed on a statement that all eight members endorsed. The statement, "A New Charter for Owners and Managers," deserves wide readership, scrutiny, and commentary. HBR is pleased the working group chose it as the exclusive forum to release its statement. PMID- 10112920 TI - What does it mean to be green? AB - Today a company is not considered environmentalist unless it moves beyond mere compliance with government regulations to behavior its competitors, and even customers, do not expect. How should it set its agenda? Author Art Kleiner proposes that, to be green, a company must ask three questions: What products should we bring to market? How much disclosure of pollution information should we support? And how can we reduce waste at its source? These questions can't be answered, Kleiner says, unless managers insist on sustainable growth. In this sense, a big investment in environmentalism is like a big one in R&D--both presuppose patient capital and managerial maturity. What are green products? Kleiner cautions against giving in to misinformed public opinion--as McDonald's did in giving up its styrene "clamshells," which were more recyclable than the composite papers it switched to. Rather, companies should rely on literature that analyzes the product life cycle. As for public disclosure, the benefits may be unexpected. Federal legislation requiring companies to report the emission of potentially hazardous waste to a central data bank has not made environmentalists attack them. Rather, it has forced companies to learn what chemicals they inadvertently produce and how much--knowledge that helps them improve production processes. Sharing it helps ecological researchers study the combined effects of plant emissions. As for pollution prevention, Kleiner notes the analogy to quality and observes that it is better to design harmful waste products out of the system than catch them at the end of the line.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10112921 TI - The making of a French manager. AB - France's recent successes make it more important than ever to understand what makes its managers tick. This year, France surpassed Japan and the U.K. in acquisitions of U.S. companies. And many French companies are world leaders, including Michelin and L'Oreal. According to the authors, who have studied the French model of management development, the system stands as a coherent whole. Its clear logic and rules provide unambiguous signals that shape managerial action. Thus French industry has a focus and sense of purpose that the rest of the world should not underestimate as a key to strong economic performance. In France, management is a "state of mind" rather than an interpersonally demanding exercise. It is managers' cleverness, not skills, that distinguishes them. And these managers are not simply born. They are molded through an elaborate education and induction into the managerial elite. Alumni of the grandes ecoles dominate the upper echelons. These elite colleges have grueling entrance exams resembling Japan's "examination hell." Graduates automatically enter the tight knit cadre circle--the managerial elite who enjoy the same social prestige as doctors or lawyers. French managers prefer to put things in writing, even informal interactions. They excel in quantitative expression, at ease with putting figures to proposals. Hierarchy in French companies is often literal--the head of L'Air Liquide works on the top floor, while the typing pool is in the basement.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10112922 TI - Corporate imagination and expeditionary marketing. AB - In the 1980s, competitive success came mostly from achieving cost and quality advantages over rivals in existing markets. In the 1990s, it will come from building and dominating fundamentally new markets. Core competencies are one prerequisite for creating new markets. Corporate imagination and expeditionary marketing are the keys that unlock them. McKinsey Award winners Gary Hamel and C.K. Prahalad argue that corporate imagination quickens when companies escape the tyranny of their served markets. (Motorola, for example, sees itself as a leader in wireless communications, not just as a maker of beepers and mobile phones). Think about needs and functionalities instead of marketing's more conventional customer-product grid. Overturn traditional price/performance assumptions. (Fidelity Investments unlocked a vast new market by packaging sophisticated investment vehicles for middle-income investors.) And lead customers rather than simply follow them. Creating new markets is a risky business, however--a lot like shooting arrows into the mist. Imaginative companies minimize the risk not by being fast followers but through the process the authors call expeditionary marketing: low-cost, fast-paced market incursions designed to bring the target quickly into view. Toshiba introduced laptop computers to the market at such a blistering pace that it could explore every conceivable niche--and afford an occasional failure without compromising its credibility with customers. To stimulate corporate imagination, top management needs to redefine failure and develop new time- and risk-adjusted yardsticks for managerial performance. Managers must be encouraged to stretch their company's opportunity horizon well beyond the boundaries of its current businesses. PMID- 10112923 TI - The fallacy of the overhead quick fix. AB - Facing pressure from a few large, low-cost competitors, Thornton, an old-guard specialty-equipment manufacturer, fought back by eliminating overhead. Over two years, it outsourced components and consolidated operations. But instead of cutting overhead, it added more and became still more uncompetitive. Thornton is not alone in either its predicament or its failed reaction. Many large manufacturing companies are finding themselves at a cost disadvantage in markets they have dominated for years. One reason is excessive overhead structures, the result of an unchecked buildup of indirect employees needed to control rising organizational complexity. Another reason is the emergence of the "robust" competitor, comparable in size and product scope but able to produce at a lower unit overhead cost. Data collected from more than 100 manufacturing plants worldwide illustrate the differences between overhead cost structures of bureaucratic, niche, and robust companies. The gulf between these groups highlights the need for action by bureaucratic companies, and, in some cases, by niche companies. But high-overhead companies are doomed if they cut overhead out of the system either by outsourcing or downsizing. If they expect to retain their size and also become more cost competitive, they must rethink their manufacturing systems. Well-designed and well-controlled processes mean higher product quality, faster cycle time, improved flexibility, and lower overhead costs. Sustainable overhead reduction means a commitment to continuous improvement. This includes segmenting, mapping, and measuring existing processes and then working to improve them.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10112924 TI - AMRA's new executive director: a visionary leader. PMID- 10112925 TI - Understanding computers or some of the things you always wanted to know about computers ... but were afraid to ask. AB - Criteria for computer systems evaluation are changing. No longer can we rely on an evaluation based solely on what the combination of hardware and software does for the user (functional criteria). Significant improvements in software productivity have occurred in recent years as a result of the availability of tools such as relational database management systems and fourth-generation languages. Meanwhile new technologies such as image processing and graphical user interfaces, e.g. MS-Windows and X Window, are coming onstream. Most of these technologies and capabilities require substantially more computing resources than traditional character-based systems. Fortunately, the open systems revolution is creating a more competitive marketplace and computer price/performance ratios are soaring, making the additional computing resources readily available at reasonable prices. But the opportunities of the future will not be for everyone. They will exist only for those medical record practitioners who recognize that a shift away from purely functional evaluation is necessary. Those that make the shift successfully will not become computer technicians, but they will understand the few technical criteria that are truly essential in systems evaluation. They will, in short, apply the 80/20 principle successfully to make future system selections. Medical record professionals must take steps to upgrade their computer system knowledge in order to accommodate the needs of technical criteria evaluation. For the active practitioner this means taking the time to learn from the many sources available in print, educational programs, and knowledgeable persons. Students should seek out courses that will give them a balanced view of the computer sciences, without being overloaded with specifics. AMRA should look for ways to augment the computer sciences requirements in the student's curriculum. Development of study tracks that concentrate on combining standard curricula with computer science would both create a new breed of practitioner and expand the horizons of the profession. The medical record profession must actively work to keep pace with the ever-changing information management environment in order to maintain its position of healthcare information management leadership. PMID- 10112926 TI - Information management: a shifting paradigm for medical records professionals? PMID- 10112927 TI - Spotlight on Catherine J. Reres, RN, CPQA, ART. Interview by Ann Buckland. PMID- 10112928 TI - 1991 buyer's guide listing. PMID- 10112929 TI - Quality management/severity of illness. PMID- 10112930 TI - AMRA Alliances and Information Processing Standards. Report from the ASTM Committee E31.12 Medical Informatics. PMID- 10112931 TI - American Medical Record Association Position Statement. Protecting patient information after a closure. PMID- 10112932 TI - Teamwork in tandem with technology. PMID- 10112933 TI - Performance indicators: pointer dogs in disguise--a commentary. AB - This article discusses the feasibility of integrating specific quality indicator dimensions and proposes a method through which indicators may prove useful to hospitals in search of quality. PMID- 10112934 TI - Electronic signatures: a brief overview. PMID- 10112935 TI - Medical records in healthcare for the homeless. AB - How do medical records in healthcare settings for the homeless compare with other healthcare records? This article offers us insights about homeless patients' records from a medical record practitioner who volunteers her expertise at Christ House in Washington, DC. PMID- 10112936 TI - A vision for future patient records. AB - This article discusses The Computer-based Patient Record: An Essential Technology for Healthcare, the eagerly awaited report from the Institute of Medicine. The report presents the conclusions and recommendations of the multidisciplinary committee convened to explore how patient records could be improved, a project supported in part by AMRA. PMID- 10112938 TI - Medical record briefing. PMID- 10112937 TI - Advance directives. PMID- 10112939 TI - Seating directory. A complete alphabetical listing of 326 manufacturers and distributors of contract seating and the type of products available to the specifiers. PMID- 10112940 TI - Toward a national health policy. PMID- 10112941 TI - The 10-step QA model made easy. PMID- 10112942 TI - OBRA mandates greater patient participation in health care. PMID- 10112943 TI - Beware of striking wrong chord with copyright law. PMID- 10112944 TI - Foreign nurse recruitment. PMID- 10112945 TI - The changing role of the trustee. AB - Trustees in large hospitals often wrestle with tough choices. But in a sign of changing times, their counterparts at a county hospital with 35 beds, 60 employees and a medical staff of four are becoming equally knowledgeable about a range of complex issues. Throughout the state, trustees face the same basic problems--those created by government involvement in the provision of health care, and those resulting from unlimited demand for limited resources. PMID- 10112946 TI - Sorting out medical waste. AB - Medical waste is part of the larger issue of solid waste disposal facing America today. Its management often elicits deep fears and concerns among the public. The reality is that medical waste poses few health risks and many hospitals may be using more caution than actually necessary to protect the public. For a variety of reasons, however, waste disposal is presenting hospital managers with an unprecedented challenge. PMID- 10112947 TI - Antitrust Act applies to hospitals. PMID- 10112948 TI - Financing options loom for capital equipment. PMID- 10112949 TI - Food prices on the way up due to weather extremes. PMID- 10112950 TI - Materials managers question how Uniform Commercial Code treats faxed purchase orders. AB - A hospital materials manager is considering eliminating routine purchase orders for most items of medical supply. This is due to the increased use of the telephone and of electronic devices such as fax, transceivers and computer hookups. Written purchase orders would continue to be mailed to suppliers for capital equipment and other major expenditures. The materials manager is wondering how this time-saving practice might be affected by purchase law under the Uniform Commercial Code (UCC). In this dialogue, Dr. Decker responds to this reader's inquiry. PMID- 10112951 TI - Hospitals purchase abators to heed regulations. PMID- 10112952 TI - Defend or dismantle? Proposals for modifying Medicaid. PMID- 10112953 TI - The thinking hospital. PMID- 10112954 TI - Nursing home restraints: the legal issues. PMID- 10112955 TI - In search of a purpose. PMID- 10112956 TI - Body, mind, and soul. The parish nurse offers physical, emotional, and spiritual care. AB - Many hospitals see the parish nurse program as a way to bring their mission to the community and collaborate with area parishes. Because people are finding it increasingly difficult to access our nation's complex healthcare system, the parish nurse program is becoming more popular with hospitals, parishes, and the communities they serve. The parish nurse is a resource person--a health educator, a personal health counselor, a volunteer coordinator and support group organizer, a community liaison, and a role model for the relationship between one's faith and health. Parish nurses do not provide invasive treatments. Parish nurse programs that have been most successful have been developed through the hospital's pastoral care department in conjunction with the nursing department. The hospital establishes a steering committee to guide the program's formation. Daily, the faculty, a group made up of a physician and representatives from nursing and from pastoral care, supervise and monitor the parish nurse program. PMID- 10112957 TI - Hospice growth. PMID- 10112958 TI - The spirituality of dying. Pastoral care's holistic approach is crucial in hospice. AB - Attention to the spiritual dimension of a person is essential in a holistic approach to hospice care. Although other hospice team members may be involved in matters of faith with patients, chaplains are the primary professionals concerned with the transcendent nature of life and the integrative role that spirituality plays in care for the dying. Understanding spirituality in a person's living and dying requires an understanding of religion and theology. Religion is meant to connect us to a caring community and to give us a place on which to stand--a tradition. Theology is a search for meaning. Spirituality is "the life principle that pervades a person's entire being ... and generates a capacity for transcendent values." The body cannot be touched without the spirit's being affected, and vice versa. Efforts to help patients toward wholeness necessitate helping them accept freely their whole lives. The chaplain is not limited to nor bound by religious language. The needs of the patient should determine the use of prayer or God-talk. Listening is one of the greatest spiritual gifts a chaplain can give a suffering patient. Being a companion is often all the chaplain can do. Pastoral care personnel are also sensitive to the needs of the hospice staff. The chaplain does not so much fulfill a role as represent a perspective based on concern and solicitude for the whole person, the whole family unit, the whole staff. PMID- 10112959 TI - A just alternative. Church tribunals may be the best forum for settling wrongful discharge disputes. AB - The threat of a wrongful discharge lawsuit should be a concern for every employer. However, Church employers can minimize their risk if they follow Church teaching in their employment practices and policies and if they use the Church tribunal system to settle employer-employee disputes. As it originally developed in common law, the "employment-at-will" concept stipulated that an employer could discharge an employee at any time, for any reason, or for no reason at all. Most states have adopted this common law concept, although courts and legislatures have created a number of exceptions to it. Despite these exceptions, employment at-will has proven to be a powerful tool in the hands of employers. However, employees of Church institutions who feel they have been discharged wrongfully can turn to Church tribunals, which are governed by canon law. A Church tribunal can do virtually anything a civil court can do, with the exception of ordering someone to jail. Moreover, because the standards of justice and equity applied by Church tribunals are stricter than those applied by American courts, employees of Catholic institutions in the United States may make increasing use of them in the future. Disputes that come before a Church tribunal will be settled by either arbitration or mediation. Arbitration is a kind of informal litigation. Mediation, however, is preferable because it forces the parties involved to examine themselves, their motives, and their effects on each other and the Church as a whole. PMID- 10112960 TI - Surviving in rural America. Providers must adapt to the changing healthcare environment. AB - As the rural healthcare environment changes, the abilities to assess the situation quickly and to implement decisions under conditions of uncertainty are crucial success factors. Rural healthcare providers and rural communities must examine certain assumptions underlying the delivery of healthcare services in rural areas, including the following: The rural renaissance of the 1970s will return. Rural communities need and want hospitals. Local physicians are the backbone of rural healthcare delivery. Transportation is a major barrier to healthcare service delivery. Competition in the delivery of healthcare services is appropriate for rural areas. The questionable validity of these assumptions implies that the current infrastructures for delivering rural healthcare services may no longer be appropriate. To adapt to changes, providers must (1) ensure changes fit with local conditions, (2) consider regionalization, (3) integrate all human services, not just health services, into a cooperative arrangement, (4) consider alternative configurations for providing physician services, and (5) place greater emphasis on transportation and telecommunication systems as means for ensuring timely access. PMID- 10112961 TI - Turn around or pull the plug? Lessons in hospital diversification. AB - Diversification has reached a crossroad. Ventures that are profitable or break even are likely to continue as such. For those which are not, management can divest through sale or liquidation or choose the "turnaround" route, which entails carefully and objectively appraising each diversification activity or entity. The initial step in a turnaround is to review the original strategic diversification objectives to determine if they remain valid. Next is a strategic overview and appraisal of the system's diversification activities. Specific, measurable objectives and action plans are necessary to guide the turnaround process. But even with the best turnaround plan, managers must anticipate the possibility of failure by establishing a "pull-the-plug" threshold. This is the point at which a venture's operating losses exceed the value of profits. Experience with successful turnarounds shows that corporate managers must consider the following steps: (1) the specialized skills and experience of the diversification activities' managers, (2) market-based volume and revenue projections, (3) downsizing space allocations, sharing space, or adding new services, (4) ways to keep from drowning in overhead, (5) appropriate organizational controls, (6) ways to improve patient access, (7) employee incentives, (8) use of equity capital, (9) effective management information systems, and (10) "sticking to the knitting." PMID- 10112962 TI - Fund-raising: creativity pays off. PMID- 10112963 TI - Establishing a spiritual resource center. PMID- 10112964 TI - Physicians get HAPPI. Daughters of Charity National Health System. PMID- 10112965 TI - Bon Secours Health System. Commitment to quality. PMID- 10112966 TI - A special kind of care. PMID- 10112967 TI - Social accountability budget: progress report. PMID- 10112968 TI - Preparing for increased union organizing. A commitment to deal justly with employees is the best response to the new bargaining unit rules. AB - The U.S. Supreme Court recently upheld a National Labor Relations Board regulation giving unions of healthcare workers the right to organize as many as eight different kinds of hospital bargaining units. With the Court's decision, hospital administrators must prepare for increased union organizing by maintaining policies that evidence the institution's commitment to social justice in the workplace. Hospital administrators can reduce the potential for labor management conflict by stressing the institution's commitment to social justice and establishing programs to educate managers and other employees about Catholic teaching on social justice. Facility administrators should also establish a written philosophy statement outlining the institution's position on unionization, institute labor relations training, survey employees' opinions of management and their work environment, conduct audits of managers' perceptions of the organization's effectiveness, and periodically review the state of labor relations in the organization. PMID- 10112969 TI - Nurses and the new NLRB rules. Implications for healthcare management. AB - The inclusion of nurses as an allowable bargaining unit is one of the most significant aspects of the U.S. Supreme Court's decision to uphold the National Labor Relations Board's new collective bargaining unit rules. For a number of reasons, the decision makes it more likely that nurses at a given hospital will vote to form a union. Union nurses receive, on average, 6 percent higher salaries than do their nonunion counterparts. In addition, being able to organize into a smaller unit gives nurses a much stronger bargaining position. Finally, because of the new collective bargaining unit rules, labor leaders now find hospitals an attractive place to attempt to establish unions. In responding to the possibility that nurses might unionize, hospital managers should acknowledge that nurses often have legitimate grievances concerning pay and working conditions. They should also be aware that changes in the healthcare system during the 1980s often led managers and administrators to neglect focusing on nurses' satisfaction in favor of an emphasis on the bottom line. In the future, if managers can offer nurses the same rewards a union organizer offers and at the same time establish a cooperative, employee-oriented hospital atmosphere, nurses will benefit from the Supreme Court Ruling, whether or not they ultimately join a union. PMID- 10112970 TI - Hub-and-spokes regionalization. The teaching hospital should be the hub of its healthcare market. AB - To remain viable, teaching hospitals must be horizontally and vertically integrated, multilevel healthcare delivery systems. Such integration is needed for a teaching hospital to remain the hub of its urban or rural regional healthcare market and to generate sufficient fiscal resources to support its medical education programs, research activities, quality of care, and innovative technology. Teaching hospital trustees, physicians, and managers must evaluate an increasing number of alternatives to improve quality of patient care, maximize educational and research opportunities, and increase revenues. These options include merging with community hospitals and improving relationships between community physicians and teaching hospitals and their full-time clinical faculty. To ensure long-term viability, teaching hospitals may need to use an approach that concurrently employs a hub-and-spokes arrangement, a horizontal and vertical diversification, and a multilevel healthcare delivery system configuration. PMID- 10112971 TI - Ethical problems in healthcare rationing. Testimony to the Senate Special Committee on Aging. PMID- 10112972 TI - Trends in volunteerism. A new way of managing volunteers furthers providers' goals. AB - Today's volunteers come from many walks of life--professionals, children, people with disabilities, and skilled tradespeople. Each has a special skill to offer in the spirit of volunteerism. To take advantage of the increasing number of volunteers, hospitals must begin to form more meaningful alliances with their communities. Healthcare volunteerism creates opportunities for renewed linkages between the community and the hospital. Hospitals should also look even closer to home--their own neighborhoods. Often staff fail to see their neighbors' failing conditions as services for the disadvantaged have declined. This creates ill will. But some hospitals are avoiding this by recruiting volunteers to help improve the lives of their yards, fixing up their houses, and fulfilling other needs. Another area where volunteers can be beneficial to the hospital is in political activism. Healthcare leaders, however, must discuss political issues with volunteers, and not keep them in the dark on issues of importance. Many volunteers are active politically and can give healthcare a voice in crucial matters. PMID- 10112973 TI - The future is now. Long-range planning helps a hospital adapt to changes in volunteer utilization. AB - To get an idea of how volunteers were currently being used in the hospital industry, in 1987 the director of volunteer services at St. Joseph Hospital, Flint, MI, began an informal survey of what individuals thought and felt on the subject. He also reviewed the hospital literature on volunteers. The research revealed that many hospitals had fewer inpatients and a more rapid patient turnover than they had had before, that competition for patients and volunteers was intensifying, that paid staff were busier, and that department heads who used volunteers were satisfied with them and wanted more of them. To improve its use of volunteers, the department initiated formal discussions among volunteer group leaders to identify major areas of concern. Once these areas had been identified a Task Force Leadership Group worked to establish goals for addressing these areas of concern. Six volunteer committees were then formed, each with the task of generating recommendations regarding how volunteer services could be improved. The committees eventually generated more than 130 recommendations. The volunteer services director and a consultant consolidated, reclassified, and rewrote these, ultimately submitting 79 proposals for approval. A number of these recommendations have already been implemented, and the volunteer services department will implement more of them in the future. PMID- 10112974 TI - Catholic identity, Catholic integrity. A shared faith allows religious and laity to live out their commitments in one another's company. AB - This article is adapted from an address to participants in the Catholic Identity Project, Fordham University, New York City, in April 1991. The project engaged leaders in a process to enable institutional ministries in higher education, health, and social services to maintain their Catholic identity. Proceedings and commentary of the symposium that was part of the project's second phase will be available in spring 1992 from Msgr. Charles J. Fahey, Third Age Center, Fordham University. PMID- 10112975 TI - A winning proposition. Michigan communities benefit from positive hospital collaborations. PMID- 10112976 TI - A regional strategy. Networking gives rural residents access to high-quality healthcare. AB - In 1978 the Board of Trustees at St. Edward Mercy Medical Center, Fort Smith, AR, adopted a policy that the center would increase its bed size only to meet community needs or to offer needed services. The policy choice was the first step in the development of a regional network that now serves five rural communities. Although there was some resistance to the move at first, when management formalized some of its basic assumptions and values, it became clear that establishing a regional network was right for St. Edward. It would provide economic benefits to the communities in which facilities were acquired or constructed; it would give rural residents better access to primary healthcare; and it would provide the Religious Sisters of Mercy an opportunity to extend their ministry. Networking has also allowed the facilities involved to develop economies of scale and to avoid costly duplication of certain basic services. In addition, primary care physicians in rural communities served by the network have been an important source of referrals to specialists who utilize St. Edward. PMID- 10112977 TI - Focus on education. PMID- 10112978 TI - Building ties that bind. PMID- 10112979 TI - Ancilla Systems. Decision support system. PMID- 10112981 TI - Worth a thousand words. PMID- 10112980 TI - Catholic Medical Center of Brooklyn and Queens. System plans to meet needs of elderly. PMID- 10112982 TI - Benchmark matrix and guide: Part I. Headquarters Air Force Logistics Command, Wright-Patterson Air Force Base, OH. AB - The President's Award for Quality and Productivity Improvement is the highest recognition of improvements in quality and productivity in the federal government and is equivalent to the Malcolm Baldrige Award. It is awarded to agencies, or major components of agencies, that have implemented total quality management (TQM) in an exemplary manner resulting in high quality products and services, and effective use of taxpayers' dollars. On May 23, 1991, Headquarters Air Force Logistics Command at Wright-Patterson Air Force Base was notified that it had won this prestigious award. This first article of a three-part series was authored by a special working group within Headquarters Air Force Logistics Command that was tasked with developing a benchmarking system to measure progress in implementing total quality management (TQM). The tasking was in support of the near-term vision initiative to develop a guideline pamphlet for measurement. This benchmark matrix should be used periodically to identify those categories that need additional emphasis, but it should be seen as a self-assessment tool only. The intent was to provide a method of measuring behaviorally oriented activity that can be documented or observed. Real process improvement can begin only when a process cna be understood and measured. Benchmarking is a viable means to do this and should be used in combination with other TQM methodology. PMID- 10112983 TI - Flow charting for quality improvement. AB - This article analyzes the merits of flow charts in their relatively new application to healthcare quality management. Specific examples are given that show how a step-by-step diagram can clarify policies and procedures. Patrice Spath explains "imagineering," a technique for problem identification that compares the steps that a process actually follows with a flow chart of what steps the process should follow. In the discrepancies between the two, problems are revealed. Warnings are given that each detail in a flow chart must pertain to its actual subject and that pictorial symbols should be simple and clear. The author lists some software packages that allow flexibility and speed in flow charting. As a tool for discovering redundancies and inefficiencies, the flow chart is a valuable method for refining quality systems. PMID- 10112984 TI - From quality assurance to quality improvement: the Joint Commission and the new quality paradigm. AB - Frank Appel, NAQAP's representative on the Joint Commission's QI Task Force, describes the ongoing Agenda for Change as progressively defining a new vision of effectiveness in healthcare organizations. This vision, first articulated in 1989 in the Principles of Organization and Management Effectiveness in Healthcare Organizations, is based on the fundamental concepts of total quality management (TQM), the new paradigm in healthcare. The first direct outcome of these principles is a new set of leadership standards that will appear in the 1992 Accreditation Manual for Hospitals (AMH). The Joint Commission is using the mechanism of standards' revision to lead healthcare organizations into a transition to continuous quality improvement (CQI). The 1992 AMH contains a revision of the current QA standards in the direction of quality assessment and improvement standards. The transition to CQI standards will be complete by 1994, when the data-driven process of CQI will also be incorporated into information management. Major CQI revisions also will occur in other parts of the management. Major CQI revisions also will occur in other parts of the AMH. "Second generation" clinical indicators presently under development reflect the process and cross-functional orientation of CQI. TQM is seen by the Joint Commission as the next step in a logical progression in QI methods, while CQI offers answers to the weaknesses of current QA programs. Mr. Appel concludes with an outline of these weaknesses, and a strong message of encouragement to the quality professional to meet the challenge of leadership during this transition. PMID- 10112985 TI - The quality council: a catalyst for improvement. AB - Before quality improvement can occur, an environment must be created that demonstrates a decisive commitment to change. In this article, Sarah Tackett presents the concept of the "quality council," a structure that fosters employee participation and clearly defines the leadership roles needed to evaluate and implement improved processes. The quality council should be the first organizational step toward quality improvement because it will set the tone, establish policy, and create institutional readiness for the changes to come. Chaired by the organization's CEO, the council should consist of senior management and clinical department heads, administrators, and a quality advisor. Larger institutions may need several coordinated quality teams to focus on various areas. The author's lucid analysis of the process that the quality council should follow begins with the development of shared values that all employees can endorse. The next step is to select appropriate projects that have high interest and will result in an improved process, not just a new system or a predetermined solution to a problem. Ms. Tackett stresses the importance of picking the best possible team members, shifting workloads to allow a full focus on quality, and providing extra training in QI strategies to teams where needed. Finally, quality innovations should be recognized and shared throughout the institution. PMID- 10112986 TI - Quality management through statistics. AB - One of the responsibilities of a quality assurance professional is to assess patient care data in an effort to meet "outcome" requirements as established by the institution, the patient, the patient's family, the Joint Commission, the Health Care Financing Administration, the state PRO, and other regulatory agencies. A major goal of effective quality management is to assure that patients treated in a similar diagnostic category achieve similar outcomes. To accomplish this, the QA manager must gain and maintain control over patient care processes. To obtain this control, the conditions of patient care processes must be measured. Over one hundred years ago, the English scientist Lord Kelvin said, "When you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is...unsatisfactory." This article will describe some of the statistical quality control techniques that will assist in measuring the performance of specific patient care processes and outcomes and expressing them in numbers. A review of the numbers will show whether a particular patient care process is running smoothly or needs further investigation or adjustments. Using statistical quality control techniques will enable the QA manager to predict how well patient care processes and outcomes will run in the future. The simple statistical techniques discussed in this article can be used to measure the performance of patient care processes and outcomes both before and after corrective actions have been taken. They apply both to attempts to bring a specific process or outcome into "control" or to break through to a new, improved level of quality performance. PMID- 10112987 TI - Strategies to prevent failure of the new paradigm. AB - Despite the hopes, hard work, and research of many in healthcare, the long-term success of the new paradigm of continuous quality improvement (CQI) is far from assured. The authors suggest that the premature demise of CQI in healthcare is a possibility unless certain trends and forces are addressed and altered. Six challenges to the long-term viability of CQI are discussed in this article along with practical strategies to protect the integrity and vitality of the movement. PMID- 10112988 TI - The human side of quality: service oriented employees. AB - Motivating employees to care about the quality of the services they provide is an essential ingredient in quality improvement. In this article the author presents eight methods that employers can use to translate expectations into actions. Becoming aware of what today's employees want is the first step; money and job security are not as important as respect, challenging work that shows results, and managers who listen. Since customer relations mirror management's attitudes toward employees, caring about staff is basic in a quality service organization. Education and training of workers are also crucial, as are communication of expectations and providing prompt feedback. Employees also need reward and recognition. Hiring the right people is another necessity for quality service. Finally, managers must be leaders who can articulate values and the organization's vision in order to enlist employees in the cause of quality service. PMID- 10112989 TI - Quality improvement: one-third of the quality equation. AB - In the search for the answer of how best to assure quality healthcare, the latest entry is quality improvement (QI). Quality improvement, however, is neither new nor the panacea for all of our quality concerns. Although it is a significant step along the way toward improving the management of our healthcare organizations, QI is not the total equation. Rather, QI adds to the equation an element that was absent in how we traditionally thought about and performed quality assurance (QA). This article reviews the components of quality management, compares QA with QI, and provides guidance in integrating QI with current QA practices. PMID- 10112990 TI - Building knowledge for quality improvement in healthcare: an introductory glossary. AB - At the heart of organization-wide quality improvement in healthcare is the need to build knowledge for improvement that complements the subject matter knowledge of healthcare. Dr. W. Edwards Deming, the quality improvement pioneer, has suggested that "profound knowledge," or knowledge required for improvement, consists of four basic dimensions: Knowledge of the organization as a system. At its heart this knowledge is an understanding of the methods of production, the methods of improvement, and the aim of the entire enterprise. This concept was first presented by Deming at Mount Hakone, Japan, in 1950. In his book Out of the Crisis (1986), Deming illustrates the organization as a system. Knowledge of variation. This understanding comes from the awareness that a system of causes is at work producing any result. These sources of the variation, which can be observed in any process, are what must be acted upon to improve the results of the process. Studying the variation in a process can provide clues to the most economical actions that managers can take for improvement. It involves knowledge of the difference between common and special cause variation. Knowledge of psychology. The focus is on an awareness of the power of intrinsic motivation, a sense of self-worth and pride in what is done in the workplace. Theory of knowledge. How is new knowledge built? What is the purpose of knowledge? What is the nature of knowledge? Unless these issues are clear, it will not be easy to build useful knowledge. Deming has provided further insight into this framework in a recent unpublished essay and is currently working to further expand these concepts in additional publications in preparation. This framework helps build the knowledge necessary for the improvement of healthcare. As you work to build that knowledge, however, you will confront a wide variety of terms and a language that may in some ways be unfamiliar. In recognition of that, an introductory glossary is offered for your use and reference. With time, it can, should, and will be replaced by an expanded lexicon. Other sources that interested readers may wish to consult include the references listed at the end of the glossary. PMID- 10112991 TI - The Los Angeles County trauma system: a status report. PMID- 10112992 TI - Reducing unnecessary care: different approaches to the "big ticket" and the "little ticket" items. PMID- 10112993 TI - Commentary on the state of the art in quality assessment and assurance. PMID- 10112994 TI - Ambulatory care--1990: a view from the trenches. AB - In summary then, many of the changes that have accompanied the massive shift to outpatient care in the past decade have been good. However, change itself is not inherently good, and the effect of change upon the individual physician is extremely important. In my opinion, the increasing hassle, overregulation, and second guessing that have accompanied recent changes have had a significant negative effect upon physicians. The signs of this happening are clear. This in turn does not bode well for patients and the quality of medical care that will be available to them in the future. I would submit that the focus of any scrutiny of the benefits of changes in our medical care delivery system should be the practicing physician. The impact of such changes upon physicians and their ability to carry out their mission of patient care will provide our best guide for the course that we choose for our future. PMID- 10112995 TI - Addressing the uninsured: the Hawaii experience. PMID- 10112996 TI - The California Major Risk Medical Insurance Program. PMID- 10112997 TI - A force field evaluation tool for telephone service in ambulatory health care. AB - The tool presented here is useful in analyzing the constraints and capabilities of a health care telephone service. It also provides a systematic method for assessing systems problems. As part of our analysis, we recommended that the manager implement the following steps. First, the manager determines whether the driving force on the unit is continuity of care by an individual provider or consistency of response. This focus directly affects how the unit's telephone service can be best organized (i.e., decentralized or centralized) and clarifies the factors most needed for success. For example, to function effectively and efficiently, a centralized phone service needs strong provider-endorsed protocols. Second, the manager should carefully examine neutral constraint factors to determine methods to transform these constraints into capabilities, such as planning for extra staff or office hours (or both) during influenza season. Planning for extra hours or staff depends largely on whether budget and resource planning is done in advance and whether value is placed on customer access and satisfaction during peak demand periods. The manager must next determine whether the service delivery format (centralized or decentralized) is consistent with the force field analysis findings. If the findings are not consistent, can the analysis present a compelling argument for using the opposite approach? Finally, the manager must create a plan of action for minimizing the constraints revealed and maximizing existing capabilities to achieve the overall goal of excellent phone service. The process of analysis and creating a plan of action is an excellent opportunity to involve staff, providers, and administrators in efforts to achieve better health care telephone service for all customers. PMID- 10112998 TI - Productivity: a context for excellence. AB - Inductively created measures of the sort described above enable the ambulatory care manager to make a crucial decision: Are the outcomes worth the cost involved? As Collins (1988, p. 235) notes, "Our nursing product is quality care based on principles and standards of practice... and substantiated and enhanced through quantifying our practice." By using nursing resources wisely, we can "moderate the march on the market...for caring and access of what we are here for" (Cunningham, 1983, p. 90). In relaying her feelings during treatment for a malignant breast tumor, Kaufman (1989) supports the contention that caring and access are essential parts of a therapeutic regime. Curtin (1987, p. 7) warns that "You cannot provide health care by taking the care out of it." This project allowed nurses to create their own measurement system that identified and quantified the professional nursing tasks involved in each workload indicator. Nonprofessional activities were also identified, quantified, and delegated to appropriate levels of staff, thus increasing the control of the nurses over their own practice environment. In the words of Curtin (1987, p. 7), "Losers count time to make heads roll. Winners use their heads to make time count. This country cannot afford to place its health in the hands of losers." PMID- 10112999 TI - Dollars and (non)sense. PMID- 10113000 TI - Health insurance litigation. PMID- 10113001 TI - Self-insurance under ERISA, is it a license to discriminate? PMID- 10113002 TI - The quality of United Hospital, Grand Forks, North Dakota. AB - Comprehensive quality improvement is the name of this hospital's program! Good practice and helpful innovation keeps this hospital on the list of the most progressive in total quality management. PMID- 10113003 TI - Patients and healthcare workers with AIDS--the debate continues. AB - News stories may speculate about the threat caused by healthcare workers with AIDS or by patients with AIDS, this author, however, deals with the real issues that should be debated. PMID- 10113004 TI - Medical care for AIDS: cost planning. AB - The author discusses various improvements made in the treatment of persons with AIDS, and how the advancements will affect decisions made by materiel managers. PMID- 10113005 TI - The supply module: recouping lost revenue. AB - The authors describe how computerization helped to improve materiel management in the OR, including inventory control and purchasing, and how they acutally enabled them to recoup lost revenue. PMID- 10113006 TI - Electric critical care beds. ECRI. PMID- 10113007 TI - AIDS and public policy: can epidemiologists influence legislation? PMID- 10113008 TI - Universal precautions. PMID- 10113009 TI - Cost of innovation in the pharmaceutical industry. AB - The research and development costs of 93 randomly selected new chemical entities (NCEs) were obtained from a survey of 12 U.S.-owned pharmaceutical firms. These data were used to estimate the pre-tax average cost of new drug development. The costs of abandoned NCEs were linked to the costs of NCEs that obtained marketing approval. For base case parameter values, the estimated out-of-pocket cost per approved NCE is $114 million (1987 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a 9% discount rate yielded an average cost estimate of $231 million (1987 dollars). PMID- 10113010 TI - Canadian medical malpractice liability: an empirical analysis of recent trends. AB - The determinants of the frequency of Canadian malpractice claims, the proportion of claims that result in payment, and the severity of these claims are examined. Inter-specialty variation in the frequency of malpractice claims is almost entirely related to the differential performance of major surgery. Various legal doctrines concerning both compensation and liability appear responsible for approximately half of the upward trend in the propensity to initiate malpractice litigation. We believe that the remaining explanations for growth in claims frequency are changes in social attitudes toward risk-bearing, increasing social distance between patients and physicians, and innovations in medical technology. PMID- 10113011 TI - The costs of compliance with the 1962 FDA amendments. PMID- 10113012 TI - A national policy for health care technology assessment. PMID- 10113013 TI - Capital expenditure decisions and the role of the not-for-profit hospital: an application of a social goods model. PMID- 10113014 TI - The differential effects of a change in reimbursement on public and private university hospitals. AB - The primary purpose of the government's prospective payment system was to decrease the rate of federal spending for Medicare patients by paying fixed prices for services and by transferring the financial risk for the care provided to the hospital. While PPS certainly has affected all hospitals, this article has attempted to identify some of the expected and unexpected consequences of the change in reimbursement on publicly and privately owned university hospitals. Of importance is the discussion that has analyzed the specific effects of PPS on the components of the UHs' missions. The implementation of PPS may exaggerate the effects of the payment change on both types of UHs. The provision of broadly based primary and specialty care services may be in question as institutions find themselves potentially unable to deliver these services on a price-competitive yet profitable basis. The costs associated with educational, research, and community service programs can no longer be subsidized by excess patient care revenues as payers streamline payments to reflect only the costs of clinical care. Thus, university hospitals may be forced to reexamine their missions and change their operating plans to reflect the current fiscal environment. If taken to an extreme, it is likely that the local society may be negatively affected by these actions. Clinical and community services that increase access, assure continuity of care, or provide needed but costly (public) health services may be eliminated or reduced in scope in an effort to contain costs. Even those services that are cost beneficial from a societal perspective may be eliminated without some form of subsidy or direct payment as institutions are forced to reallocate their limited funds from these types of public health services to support nonprofitable, but critical clinical or academic programs. The potential impact on access, continuity of care, and morbidity and mortality will not be known for many years. Although it is not known how these changes will eventually affect university hospitals, two outcomes seem clear. University hospitals with different governance and management structures may not change their missions and means for achieving institutional goals as much as might have been expected. The interdependence of the university hospitals' goals and the role they play in their local communities may force them to begin to explore new ways to achieve their missions. Public-private sector cooperation is suggested as one approach to use in response to the demands of payers and patients while the institution remains true to its historical mission.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10113015 TI - Can we ever halt America's litigation epidemic? PMID- 10113016 TI - What nuisance suits do to us is criminal. PMID- 10113017 TI - Just how far have women doctors come? PMID- 10113018 TI - For women doctors, the road is still bumpy. PMID- 10113019 TI - Could you recover from the ultimate financial disaster? PMID- 10113020 TI - AIDS information from the National Library of Medicine. AB - As part of a U.S government effort to combat AIDS, the National Library of Medicine (NLM) is expanding its information services in this area. In response to the Health Omnibus Program Extension Act of 1988, NLM has expanded its AIDS Bibliography, enhanced its DIRLINE file with AIDS-related organizations, and developed three new online MEDLARS (Medical Literature Retrieval and Analysis System) databases: AIDSLINE, AIDSTRIALS, and AIDSDRUGS. NLM's AIDS-related programs and services are discussed. PMID- 10113022 TI - The Health Devices Alerts database. PMID- 10113021 TI - Use of NEXIS in a medical research library. AB - The NEXIS online system is used a great deal in business and law libraries, but has been virtually overlooked by medical librarians due to their perception of the system as expensive and difficult to search. The changing health care environment has placed new demands on medical searchers for just the type of legal, business, governmental, and news information found in the full-text files in NEXIS. Through the recent introduction of News Plus software, NEXIS can be searched as never before by those unaccustomed to full-text search techniques. Besides simplifying the search process, the new software has cost-saving features since search building and file selection are accomplished offline, and several activities may be done simultaneously. NEXIS via News Plus should be seriously considered as an addition to the repertoire of online systems accessed by medical librarians. PMID- 10113023 TI - HMO reimbursement to rise 6%. PMID- 10113025 TI - Humana's one-county exemption to Ky.'s CON law struck down. PMID- 10113024 TI - Criminal investigation of Caremark shows feds won't ignore home-care industry. PMID- 10113026 TI - Malpractice insurer's rate increase hits 15%. PMID- 10113027 TI - Ukiah hospital sues FTC. PMID- 10113028 TI - Don't yank welcome mat for foreign docs, Congress told. PMID- 10113029 TI - Merger talks fail; Fla. hospital's bond rating falls into C range. PMID- 10113030 TI - Union to sue again to put Denver hospital under state control. PMID- 10113031 TI - Mergers sap Twin Cities competition--study. PMID- 10113032 TI - 'Competitors most likely to squeal on kickback violators'. PMID- 10113033 TI - Ill. hospitals pinched for donation cash. PMID- 10113035 TI - Hospitals eroding public trust. PMID- 10113034 TI - Medicaid-donation rule assailed. PMID- 10113036 TI - Providers team up to reach corporate clients. AB - Chicago's Rush-Presbyterian-St. Luke's Medical Center is one of a growing number of providers realizing that teaming up with local business and professional groups to "co-market" their services can be a winning strategy. The hospital is promoting its downtown Corporate Health Center in an effort to better serve business clients and expand its patient base through relationships such as direct contracting. PMID- 10113037 TI - HealthTrust enters Utah tax fray. AB - Over the course of the Utah property-tax dispute, not-for-profit hospitals have battled a typically unseen enemy--for-profit hospitals. While not-for-profits long have suspected the state's for-profit facilities of feeding unflattering information about them to tax assessors, the media and the public, recent property-tax hearings have unmasked at least one nemesis of Utah's not-for profits: HealthTrust--The Hospital Co. PMID- 10113038 TI - Court upholds tough definition of false claim. PMID- 10113039 TI - Proposed rule change might sweeten HMOs for employers, speed spread of managed care. PMID- 10113041 TI - Operating profit at three-year high--study. PMID- 10113040 TI - N.Y. hospital moves in on opportunity. AB - A financially struggling hospital in New York's Harlem section is turning financial distress into an opportunity for economic recovery with the help of private grants, state rate relief and an innovative capital financing program. North General Hospital will move into a new, $65 million facility in December- five months ahead of schedule and $9 million under budget. PMID- 10113043 TI - ProPAC to test pegging area wage indexes to nearest competitors'. PMID- 10113042 TI - Hospitals plan to boost equipment expenditures, limit building projects. PMID- 10113044 TI - Nurse sets up project to recycle OR waste. PMID- 10113045 TI - EPA will consider waste-tracking recommendations. PMID- 10113046 TI - Should DNR orders be suspended in OR? PMID- 10113047 TI - Planning is key to performance management. Part I. PMID- 10113048 TI - Controlling external factors affecting accounts receivable. AB - External factors such as complex billing arrangements, decreasing healthcare benefits, and increasing numbers of uninsured workers contribute to a hospital's outstanding accounts receivable. Instituting measures for getting payment in full and as soon as possible can help control for outside influences and reduce outstanding receivables. PMID- 10113049 TI - Medical support for athletic events. AB - With the continued growth of individual and team sports competition, there has been an increasing demand for qualified medical coverage at athletic events. Clinicians who provide medical coverage at athletic events must be prepared to handle a variety of injuries and other emergencies. This report reviews the clinician's medical responsibilities in athletic coverage, and lists the supplies and equipment that should be included in a field kit for this use. PMID- 10113050 TI - America's best hospitals. PMID- 10113052 TI - The revolution in psychiatric care. PMID- 10113051 TI - Hands-on healers. PMID- 10113053 TI - The best hospitals, from AIDS to urology. PMID- 10113054 TI - 1991 best hospitals. A guide to the best. AB - The 45 hospitals identified as the giants in their specialties are profiled below. Beyond size and daily room rates, you'll find special features from kosher menus to schooling for young patients. The ratio of nurses to beds is one measure of how much TLC you can expect. (Because the ratio reflects full-time employment, the number of nurses per bed on any 8-hour shift will be about one third of that indicated.) Phone numbers are provided so you can follow up with your own questions. PMID- 10113055 TI - Don Arnwine. AB - Mr Don Arnwine is the principal of Irving, Texas-based Arnwine Associates. He formerly headed Voluntary Hospitals of America. Mr Arnwine considers below the question of the dangerously widening gap between care consumers and caregivers in the United States. PMID- 10113056 TI - Acute care, profits and marketing. PMID- 10113057 TI - Hospital co-operation between eastern and western Europe--the dawn of a new era. PMID- 10113058 TI - Should managers recruit managers? PMID- 10113059 TI - Tunnel washing from the user's viewpoint. AB - It's become a matter of fact. Whenever a launderer is considering some sort of production upgrade, the tunnel washer is one of the options that is investigated. Everyone is aware of the basic concept of tunnel washing, but all of the units that are marketed in the U.S. have some engineering differences that make them unique. To decide which unit is best for your laundry, it is necessary to do some extensive research. This means talking to manufacturers, knowledgeable chemical suppliers, and other launderers who have already taken the plunge. During the past few years, the DIGEST has asked manufacturers to comment on various aspects of tunnel washing. This year, however, we have decided to get the inside story from operators who have installed these units in their plants. We also have some input from chemical suppliers who are experienced in developing formulas for tunnels. PMID- 10113060 TI - Management challenges in the 90's. PMID- 10113061 TI - Outpatient prospective payment. AB - In September of this year, the Health Care Financing Administration (HCFA) will present Congress with its recommendations for developing a prospective payment system for all Medicare outpatient services. Whichever plan is ultimately adopted, this system of payment will greatly impact the structure and management of outpatient services and, in particular, reimbursement for radiology services and use of technologies. While a system is perhaps at least two years away from full-scale implementation, providers are already witnessing diminishing reimbursement as a result of incremental payment changes since the early 1980's. With the across-the-board cuts of six percent for all hospital outpatient services, authorized for the first time last year by Congress, some providers are experiencing an escalation of payment short-falls. Further, if current experience with implementation of the inpatient prospective payment system is replicated in the outpatient arena, payments will not only be less but they will be dramatically different for various providers. Since implementation of DRGs, Medicare has achieved savings of $18 billion for inpatient care. While some hospitals have reported their best years financially, others are consolidating or closing. A prospective payment system for outpatients will also have such "winners and losers," but as a single policy initiative it will probably have a greater impact than both DRGs and the resource-based relative value scale (RBRVS) combined. Because fixed payments for inpatients have proliferated the push to outpatient care, a DRG-like system for outpatients will result in capping payments for the entire continuum of services provided in hospitals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10113062 TI - Bucking the system. Or: the tomato deal that saved taxpayers thousands. PMID- 10113063 TI - Magnetic resonance imaging. A national survey. PMID- 10113064 TI - The management of change: an antidote to administrative obsolescence. PMID- 10113065 TI - Cancer screening of the medically underserved. PMID- 10113066 TI - Assessing hospital radiology productivity. PMID- 10113067 TI - Reporting child abuse. AB - This article reviews some representative state statutes in special reference to the responsibilities of the radiographer, in the hope to give radiographers and those in charge of departments of radiology a means to determine their liabilities according to their own state laws and institutional guidelines. It is not intended to serve as specific legal advice, but rather as a guide to radiographers and department managers. PMID- 10113068 TI - The Internet. PMID- 10113069 TI - Technical costs and reimbursement. An AFROC (Association of Freestanding Radiation Oncology Centers) survey. AB - Based upon this survey, the technical cost per RVU is $16.87 in freestanding radiation oncology centers. A 47% increase in technical reimbursement is needed in order to cover technical radiation oncology costs. Because technical costs are continuing to escalate, the gap between cost and reimbursement will widen unless modifications in the system are made. The data from this survey does not justify the implementation of an energy modifier for reimbursement purposes (although there was limited data from single unit, high energy facilities). Total costs increase with increasing beam energy; however, total services or RVUs are inversely proportional to beam energy and the resultant technical cost per RVU does not increase with treatment beam energy. In this survey, 13 of 80 centers (16%) had the capability to treat with a photon beam energy greater than 11 MV. PMID- 10113070 TI - Special report. Integrating managed care. Managed care is more than cost containment. PMID- 10113071 TI - Government mulls joining suit against provider. PMID- 10113073 TI - Costing out nursing: combining PCSs (patient classification systems), DRGs, and standards of care. AB - Perhaps the greatest challenge hospitals face today is simultaneously providing high-quality care and containing costs. To meet this challenge, nursing services must master the ability to accurately project staffing that guarantees high quality care within justifiable cost limits. Nursing is an important cost center in hospitals; therefore, it is necessary to extract nursing care costs from room and board costs. By establishing a PCS and a set of standards of care for each DRG category, nurse administrators can control nursing staff ratios while ensuring quality care, therefore, effectively and efficiently using their nursing resources. This study suggests that direct nursing care can be delivered to meet the patient care needs within the DRG trim points and that by delivering care according to a set of standards, nursing care costs can be determined for a specific group of patients. These findings assist the nurse administrator in establishing control measures and setting resource allocation priorities. PMID- 10113074 TI - Healthcare spending expected to rise 10%. PMID- 10113072 TI - Physicians, financial managers join forces to control costs. AB - A case-mix management system relies on the skills of physicians, nurses, and financial managers to devise cost effective treatment plans and product line initiatives. By merging financial and clinical data, one hospital used the approach to identify practice patterns that were inflating expenses. Its case-mix management program--which consists of presenting economic studies of certain cases, profiling physician practice patterns, and budgeting by product lines--is designed to conserve resources while ensuring quality care. PMID- 10113075 TI - 1980s prove uncertainty of instant cures. PMID- 10113076 TI - Charting a course for the 1990s. PMID- 10113077 TI - Rehabilitation programs offer cost-effective resident care. PMID- 10113079 TI - Perspectives. Physician payment reform: the ultimate solution? PMID- 10113078 TI - Interview with Alice Rivlin of the Brookings Institution. PMID- 10113080 TI - Supreme Court to examine withdrawal of nutrition and hydration. PMID- 10113081 TI - Medicare's new reductions and regulations: MIS challenges. PMID- 10113082 TI - The metamorphosis of an industry. PMID- 10113083 TI - The economics of health care in the 1990s--a stalemate. PMID- 10113085 TI - Nursing: changing and growing. PMID- 10113084 TI - Seniors of America: a health care crisis. PMID- 10113086 TI - Taking care of the children. Some Texas hospitals are getting involved in child care--and reaping the benefit of more satisfied employees. PMID- 10113087 TI - Corporate negligence doctrine expanded in recent Nevada ruling. AB - In summary, Texas courts generally do not hold hospitals liable for negligent acts of non-employee physicians under the theory of corporate liability. Hospitals should take care to maintain fair and efficient procedures for granting and reviewing physician staff privileges. Hospitals clearly have a duty to maintain competent staff members and should withhold staff privileges if a physician is incompetent. Unfortunately, some plaintiffs' attorneys attempt to equate incompetence with a particular, and often singular, act. No Texas court has upheld this claim, and none should. A bad result, a negligent act or a medical accident does not, by itself, constitute incompetence. PMID- 10113088 TI - Mentally handicapped workers find a place in health care. PMID- 10113089 TI - PCB-transformer reclassification is key to savings. PMID- 10113090 TI - Collective bargaining in 1989: old problems, new issues. AB - Some problems which plagued negotiators throughout the decade continue into the next, and are joined by additional issues such as rising cost of health insurance, family care, and health and safety concerns. PMID- 10113091 TI - Collective bargaining in 1990: health care cost a common issue. PMID- 10113092 TI - Between life and death lies dignity. PMID- 10113093 TI - Physician payment panel debates threat of rationing due to spending controls. PMID- 10113094 TI - How to do an ROI (return on investment). AB - More and more hospitals are looking to automation through the use of medical information systems to support the achievement of increased profitability for the hospital. Those hospitals who are serious about the acquisition of such systems use return on investment (ROI) analysis as a tool to determine the projected level of profitability improvement offered by planned information systems. The potential level of savings varies widely among the many systems available on the market today. Those systems that have the greater depth of applications and most importantly are designed for direct usage by hospital professionals such as doctors and nurses yield the highest level of savings and profitability. The analysis and examples discussed in this article are based on the use of such a comprehensive medical information system. PMID- 10113095 TI - Could health care swallow us all? PMID- 10113096 TI - 1990 software buyers guide. A listing of software providers servicing the long term care industry. PMID- 10113097 TI - Bed conversions gain momentum. PMID- 10113098 TI - Filling the void left by catastrophic's repeal. PMID- 10113099 TI - Hospital and physician joint venture IPAs threaten HMOs. PMID- 10113100 TI - The long term care record. AB - Since residents of long term care facilities may stay for an extended duration, the maintenance of the long term care medical record may provide a unique challenge for the medical record practitioner. Such challenges may include the analysis and storage of voluminous medical records, thinning active records, and working with other facilities to ensure that the proper information is received and sent in order to provide effective continuity of care. Other areas where the long term care medical record practitioner may assist the facility include quality assurance and the teaching or orientation of all disciplines. PMID- 10113101 TI - Optical disk imaging--tomorrow's technology today for medical records. AB - This article provides a comprehensive overview of optical disk technology, an information management system that is just over the horizon for most medical record practitioners. PMID- 10113102 TI - Software reference guide: encoding, DRG assignment, and refined DRGs--Part II. PMID- 10113103 TI - Work out your DRGs. PMID- 10113104 TI - First train your staff. PMID- 10113105 TI - Evaluation of ticarcillin/clavulanate potassium in the treatment of obstetric and gynecologic infections. AB - The number of cesarean sections and hysterectomies performed in the United States continues to increase. Infections that occur subsequent to these procedures are usually polymicrobial in nature and treatment is often initially empiric and consists of the use of antimicrobial(s) that provide broad coverage. Combining clavulanate potassium with ticarcillin disodium (Timentin) significantly extended ticarcillin's spectrum of activity to include coverage of many beta-lactamase producing strains of bacteria--coverage of which is a growing problem in the treatment of serious infections. Clinical studies have shown that ticarcillin/clavulanate potassium is as safe and effective as clindamycin plus gentamicin or other single agent drugs used in the treatment of obstetric/gynecologic infections. The cost-saving potential of this combination agent as compared with clindamycin plus gentamicin as well as with cefoxitin is illustrated in a study conducted by this author and discussed in this article. PMID- 10113106 TI - Quantifying system benefits an elusive task. PMID- 10113107 TI - Hospitals forming geriatric specialties. PMID- 10113108 TI - The promise and potential of case-mix payment systems. PMID- 10113110 TI - Overview of current law relating to the confidentiality of health care information. "What have we learned from past experience?". PMID- 10113109 TI - The long-term hospital treatment of the young chronic patient: follow-up findings. AB - A follow-up of sixty young-adult psychiatric patients hospitalized at least six months revealed that, at one to three years post-discharge, 83 percent were living in the community. Nearly two-thirds of the 60 patients were actively involved in aftercare treatment. A method of categorizing outcome based on overall level of functioning revealed that good outcomes occurred even among patients whose prognoses, based on treatment history and diagnosis, might be considered guarded. Findings are discussed in relation to the need for information on the efficacy of long-term psychiatric inpatient treatment and the identification of patients who might benefit from this form of care. PMID- 10113111 TI - Access to information by patients. AB - Patient records should be accessible to patients and/or parents or guardians. Hospitals should not be included in broad access to information legislation. Patient access should be included in the Public Hospital Act and in the Mental Health Act. Consistent, clear standards for the release/access of information must be established. Patients should have the right to correct records or include their disagreement. The Public Hospitals Act and the Mental Health Act should be consistent. PMID- 10113112 TI - The privacy provisions of the Freedom of Information and Privacy Act. PMID- 10113113 TI - Patient confidentiality and access to medical records: a physician's perspective. PMID- 10113114 TI - Access to health care information: legal imperative or moral responsibility? PMID- 10113115 TI - Confidentiality and quality assurance. PMID- 10113116 TI - Computerization of health care information. PMID- 10113117 TI - Data for all. PMID- 10113118 TI - Opposition thwarting Pepper Commission. PMID- 10113119 TI - A national perspective on UR (utilization review). AB - Quality of care is the responsibility of each and every attending physician. There are many definitions of quality, none of which encompasses the universe of medical practice. Care that is neither medically necessary nor appropriate can never be considered good, no matter who renders it or how good the outcome. It is upon these premises that utilization review firms focus. PMID- 10113120 TI - Medicare catastrophic coverage: a postmortem. AB - As we move beyond the 1980s, it is worth reflecting on the rise and fall of the Medicare Catastrophic Coverage Act of 1988 (P.L. 100-360). Hailed by nearly everyone at its passage as both sensible and needed, it died less than two years later without ever becoming viable. Attacked vigorously by the elderly whom it was designed to serve, the measure finally succumbed to political pressure and passed from the scene, except for some items relating to Medicaid, on the first day of this year. This article examines the Act and the circumstances that led to its demise. PMID- 10113121 TI - Nurses' strikes: a profession maturing. AB - Very few metropolitan areas have experienced nurses' strikes. Even fewer have contended with a second potential strike and aveted it. The Twin Cities experienced a nurses' strike in 1984. In May 1989, a similar strike was threatened. An agreement was reached less than 48 hours before the strike vote. This article analyzes the changes that occurred between the two strikes. PMID- 10113122 TI - Managing in a merger and acquisition era. AB - Medical group administrators are quickly learning what big business has known for years-mergers and acquisitions represent a new and powerful option. If this option is to be employed successfully, however, group management has to understand the terms and be prepared well before merger or acquisition talk begins. PMID- 10113123 TI - Court decisions hold implications for managed care plans--Part one. AB - The managed care industry--and HMOs in particular--is now facing the realities of a maturing business. Maturity has brought a competitive tension to the HMO/managed care field, one consequence of which is increased litigation, not only among HMOs but also between HMOs and their suppliers, customers, and indemnity insurers. Entanglement in the legal system is an outgrowth of efforts to gain or preserve a competitive edge, reduce costs, and attract customers. This article highlights selected legal developments from the past two years that reflect the causes and effects of this environment. Additional cases will be discussed in the March-April 1990 issue of the journal. PMID- 10113124 TI - Payment for drug therapy. AB - This regular column of Physician Executive deals with the issues surrounding expanding technology in the delivery of health care services. Although technology is most commonly viewed in terms of equipment and procedures, the growing cost and complexity of drug therapy has made even this technology the target of assessment. The following report details the positions taken by the buyers of health care services on payment for drug therapy. PMID- 10113125 TI - Advantages of local UR (utilization review). AB - Physicians recognize that there is a certain amount of waste and inefficiency in the current health care delivery system. They also realize that everyone stands to gain if the areas of waste can be identified and eliminated. Statistics consistently reveal that a small percentage of providers and patients are responsible for a very large percentage of inappropriate care. A properly structured utilization review program is a reasonable way to rid the delivery system of this waste. PMID- 10113126 TI - Be nice to your kids. For long-term care, don't ask what your country can do for you--just yet. PMID- 10113127 TI - The bumpy road to long-term care reform. PMID- 10113129 TI - High-tech home care: what's in it for hospitals? PMID- 10113128 TI - Cost-effectiveness of therapeutic drug monitoring. AB - Cost effectiveness analysis (CEA) has been applied to a wide range of health care procedures including TDM. The need for CEA of TDM has resulted from economic pressures for cost justification exerted by hospital administrators, government and, in the United States, by third party health insurers. The lack of well designed studies has made it difficult to prove (or disprove) the credibility of TDM on an economic basis. When conducting a cost analysis evaluation of TDM, all costs and benefits must be identified, and to determine the program's viability, a study-specific analytical model is required. Ideally, the study should be controlled, comparative, prospective and have patient outcome as an assessed endpoint. Therapeutic drug monitoring has been shown to be cost-effective when SDCs are used with a sound pharmacokinetic basis, when the drugs monitored show a strong correlation between serum concentration and therapeutic outcome, and when the program has been well accepted by the professional personnel within the institution. PMID- 10113130 TI - Medicare: what went wrong? PMID- 10113131 TI - Texas leads nation in 1989 hospital closures. PMID- 10113132 TI - Texas hospitals will lose $317 million on Medicare in 1990. PMID- 10113133 TI - Small hospital makes big push to protect Medicare. PMID- 10113134 TI - DataPulse focuses on hospital financial picture. PMID- 10113135 TI - Dying with dignity. PMID- 10113136 TI - Right place, right time. PMID- 10113137 TI - Who will provide long-term care for AIDS patients? PMID- 10113138 TI - Prompt reimbursement sought for minimum wage increase. PMID- 10113139 TI - A talk with Mark Jerstad of the Good Samaritan Society. PMID- 10113140 TI - America's silent rationing. PMID- 10113141 TI - The national effort to achieve physician payment reform. An interview with Congressman Stark. Interview by Linn Meyer. PMID- 10113142 TI - A bright light in a troubled market. Case-mix improves outlook in Texas. PMID- 10113143 TI - Preparing for long-term care needs. PMID- 10113144 TI - Board chairman Edward Mattix on long-term care. Interview by Karen Gardner. PMID- 10113145 TI - Caring for the elderly chronically ill: a foundation's perspective. PMID- 10113146 TI - Public policy perspectives. PMID- 10113147 TI - Independent hospital foundations and other historical oddities. PMID- 10113148 TI - Selling and buying planned gifts. PMID- 10113149 TI - The Q-tip (qualified terminable interest property) trust. PMID- 10113150 TI - Golf tournaments--surveying the line. PMID- 10113151 TI - Ethics and consequences. PMID- 10113152 TI - Philanthropy and the nonprofit hospital. PMID- 10113153 TI - Creating an image for fund-raising success. PMID- 10113154 TI - Beyond the donor wall. PMID- 10113155 TI - Counsel and the capital campaign. PMID- 10113156 TI - Hospital corporatization and development officer turnover. PMID- 10113157 TI - Leadership--NAHD style. PMID- 10113158 TI - Effective leadership. PMID- 10113159 TI - Successful fund raising. PMID- 10113160 TI - Long-term care bioethics committees: a cooperative model. PMID- 10113162 TI - Recommending a new role. Pepper Commission brings new perspective. PMID- 10113161 TI - Lender interest in LTC analyzed. PMID- 10113163 TI - Evaluating plan design options. PMID- 10113164 TI - Medication administration via feeding tube. AB - Increasing numbers of tube fed patients in nursing homes, together with tighter surveyor scrutiny of resident outcomes are two key reasons why providers should review their policies and procedures for administering medications via the feeding tube. PMID- 10113165 TI - How hospital medical record departments can benefit from retrospective DRG review. AB - DRGs and PPS have had a major, negative effect upon hospital reimbursement. Hospitals now focus upon methods for improving and increasing reimbursement from third-party payers. More payers are using DRG-based reimbursement methods. DRG payment review offers a viable solution to the problems brought by stringent payment plans and has potential benefits for the MRD as well. MRD directors should investigate DRG payment review alternatives and from such efforts, attempt to maximize the benefits to the hospital and their own departments. Success with DRG payment review identifies the MRD as an objective, results-oriented revenue generator and, thereby, can improve performance throughout the hospital and among the medical staff. PMID- 10113166 TI - Hospitals & physicians. The new relationship. AB - Gone are the days when the hospital with the best physicians' lounge got the best doctors in town. Today's competition is far more sophisticated, and you might argue, more critical for hospitals' survival. Physicians evaluate not only the hospital itself, but its management, services, equipment, competitive position, financial incentives and even the town itself before making a decision where to practice. From the hospital's point of view, making the right impression on the right physician can be a life-or-death matter. Nearly 80 percent of all hospitals in the United States are actively recruiting physicians. And you can bet that 100 percent are trying to retain the physicians they already have. Especially difficult for rural hospitals are recent statistics showing that fewer than 10 percent of doctors who grew up in small towns return home to practice. How can you compete against these odds, especially if your hospital, city or town might have a few drawbacks? Those most successful in recruiting and retaining physicians share the same attitude--ask not what a physician can do for your hospital but rather what your hospital (and particularly your community) can do for a physician. PMID- 10113167 TI - Flow revisited. An old hospital learns some new tricks. AB - An old hospital learns some new tricks. A year ago, Denton's Flow Memorial Hospital was dark and nearly empty, the victim of increased competition and inadequate reimbursement. Today, the hospital is once again open and providing health care services. But things are very different this time around. PMID- 10113168 TI - Hospitals can't rely on protection from tort claims. PMID- 10113169 TI - Successful hospitals rely on effective people management. PMID- 10113170 TI - Hospital lecture series offers alternative to health fairs. PMID- 10113172 TI - Cost effectiveness of three child mental health assessment methods: computer assisted assessment is effective and inexpensive. AB - In order to survive severe funding reductions, community mental health centers (CMHCs) have implemented a number of systems-level interventions that attempt to minimize the impact of budget cuts on treatment effectiveness. The present study focused on ways to maintain the effectiveness of clinical assessment while lowering the assessment cost. The present study evaluated the relative cost effectiveness of three methods for collecting information and developing clinical assessment reports on children at a CMHC: (a) a traditional narrative clinical assessment report; (b) a form-style clinical assessment; and (c) a computer assisted clinical assessment. The results revealed that the computer-assisted assessments was at least as effective as the two alternative assessment methods and only 20 percent to 45 percent as costly. The effect of using the computer assisted assessments was reported to be favorable by therapists. While computer technology can be used to cut service delivery costs, the use of computers in CMHCs has generally been limited to administrative tasks, and clinical applications have been ignored. PMID- 10113173 TI - Developing a long term care facility program for AIDS patients. PMID- 10113171 TI - A natural evolution. PMID- 10113174 TI - AIDS and the long term care continuum. PMID- 10113175 TI - Expenditures for unintentional injuries among the elderly. AB - This article presents national estimates of the probability of having an unintentional injury, the types of medical care associated with unintentional injuries, and the costs of unintentional injuries that occurred in calendar year 1977 for persons aged 65 and older. Data come from the 1977 National Medical Care Expenditure Survey (NMCES) and the 1977 National Nursing Home Survey (NNHS). Among persons aged 65 and older, we found differences in the probability of having an unintentional injury by age, sex, and living arrangement, which suggests that unintentional injuries are not "accidental," or random, events. Our estimates indicate that total medical care expenditures for unintentional injuries for the elderly population in 1977 may have been over $2 billion. Using simple adjustments, we also estimated that the amount expended on injury-related medical care in 1984 might have been as high as $5 billion. Given the large amount of monetary, and presumably nonmonetary, costs associated with unintentional injuries, programs designed to reduce such injuries may well pay off in a cost-benefit or cost-effectiveness framework. PMID- 10113176 TI - Is there a cure for America's medical inflation? PMID- 10113178 TI - Health-cost report predicts future shock. PMID- 10113177 TI - The equity and efficiency principle in the financing system of the NHS in Portugal. AB - The public financing systems of primary health care services and hospital services in Portugal have traditionally been separated. In the United Kingdom where a similar separation exists, inefficient transfers of services take place from the hospital services to the primary care services. In this article a new way of financing of the NHS is proposed which will try to combine the efficiency principle existing in the financing of hospital services with an equity principle reflected in a ceiling on target expenditure for each district. PMID- 10113179 TI - Judge rules Michigan's Medicaid system is invalid. PMID- 10113180 TI - Conn.-based HMO gains accord. PMID- 10113181 TI - Pensions, savings, health expenditures, long-term care, and retirement grant announcement--HHS. PMID- 10113182 TI - Data security. PMID- 10113183 TI - Practitioner's data bank: will it improve health care? PMID- 10113185 TI - THA (Texas Hospital Association) data products provide wide range of information. PMID- 10113184 TI - Be creative in seeking support for surveillance. PMID- 10113186 TI - Living with NHI. AB - Our current healthcare delivery system is failing, and a number of health policy leaders have proposed some version of a national health insurance (NHI) program to reform it. Lawmakers, the nation's business community, unions, and the uninsured and underinsured are all pursuing ways to reduce the nation's healthcare expenditures. Most proposed NHI plans would be federally sponsored and state administered and funded by a combination of employer contributions and general revenues. If the government were the sole entity collecting premiums and making payments, the arrangement would reduce the nation's healthcare costs by an estimated 10 percent. NHI would eventually assign hospitals a "global budget," rather than reimburse them for specific services rendered. Although NHI as a whole will mean a loss of revenue for most hospitals, it may actually strengthen efficient and effective geographically linked healthcare systems (and thus could be an advantage to many healthcare systems). NHI would also allow hospitals to shift focus from the bottom line to patient care. Although NHI would mean less revenue for physicians, it would mean greater access to healthcare for members of communities. PMID- 10113187 TI - Competition and rural primary care programs. AB - Rural primary care programs were established in areas where there was thought to be no competition for patients. However, evidence from site visits and surveys of a national sample of subsidized programs revealed a pattern of competitive responses by the clinics. In this study of 193 rural primary care programs, mail and telephone surveys produced uniform data on the organization, operation, finances, and utilization of a representative sample of clinics. The programs were found to compete in terms of: (1) price, (2) service mix, (3) staff availability, (4) structural accessibility, (5) outreach, and (6) targeting a segment of the market. The competitive strategies employed by the clinics had consequences that affected their productivity and financial stability. The strategies were related to the perceived missions of the programs, and depended heavily upon the degree of isolation of the program and the targeting of the services. The competitive strategy chosen by a particular program could not be predicted based on service area population and apparent competitors in the service area. The goals and objectives of the programs had more to do with their competitive responses than with market characteristics. Moreover, the chosen strategies may not meet the demands of those markets. PMID- 10113188 TI - Trends tell story of Michigan hospitals. PMID- 10113189 TI - Financing long term care: factor in access, quality, cost. PMID- 10113190 TI - A look at long term care ethics: dilemmas and decisions. PMID- 10113191 TI - Ethical considerations will dominate 90s' policy debate. PMID- 10113192 TI - The image of hospitals. PMID- 10113193 TI - Physician payment reform seeks equity, predictability. PMID- 10113194 TI - Community support key to public hospital's survival. PMID- 10113195 TI - TQM (total quality management): a glimpse at the future of quality control. PMID- 10113196 TI - Cancer: #1 center of excellence for the 21st century. PMID- 10113197 TI - CCRC statutes: the oversight of long-term care service delivery. AB - A 1987 national survey revealed 27 states with continuing care or life care legislation. State oversight staff in 22 states responded to questions concerning characteristics of the regulated continuing care retirement community (CCRC) industry, the regulation of health and human service delivery within CCRCs, and interdepartmental working relationships between oversight agencies and other state units. Discussion focuses on the regulation of long-term care service provision in the CCRC industry. PMID- 10113198 TI - Propositions 111 and 108 on June ballot would benefit hospitals. PMID- 10113199 TI - The Physician Payment Review Commission: a 1990 update. AB - Major changes have been effected in Medicare Part B payment policy during the past year. Many of the objectives of both the PPRC and the ACS have been attained, and implementation of the reform measures will take place over the next five years. Much work remains to be done to polish the technical factors that are necessary for implementation, but current progress is on schedule. The single major difference of opinion between the PPRC and the ACS is related to the provision for a separate MVPS for surgical procedures. Clearly, better data are required before this issue can be resolved, and continued cooperation will be necessary to satisfy the congressional mandate for separate surgical and nonsurgical MVPSs. Payment for Medicaid services frequently is woefully inadequate, and the PPRC feels a strong obligation to make appropriate recommendations to Congress in order to correct these inequities. Finally, the PPRC and the ACS are on record as strongly opposing the administration's budget proposals for 1991 and instead as having supported congressional counterproposals that would result in much less severe reductions in Part B outlays. PMID- 10113200 TI - The Pepper Commission Report. A new age for long-term home care. AB - In its historic report, The Pepper Commission has clearly and courageously defined a new direction for American health care. Because of the Commission's recommendations for vastly increased coverage of long-term care needs, the demand for homemaker-home health aide services and the personnel to deliver those services will grow at an explosive rate. The home care community must be prepared to meet these demands. PMID- 10113201 TI - Internal marketing: outstanding service starts here. PMID- 10113202 TI - Forced fetal protection creates legal, moral dilemmas. PMID- 10113204 TI - What hospitals can learn from successful LBOs (leveraged buyouts). PMID- 10113203 TI - Trustees bear greater responsibility for physician relations. PMID- 10113205 TI - U.S. Representative Michael Andrews. Interview by Melinda Muse. PMID- 10113206 TI - Putting people before logic. PMID- 10113207 TI - Realising your potential. PMID- 10113208 TI - DRGs being adopted by other insurers. PMID- 10113209 TI - Certificate program fills void for consultant pharmacists. PMID- 10113210 TI - The Pepper Commission Report and the response. AB - The recommendations of the "Pepper Commission" [the Bipartisan Commission on Comprehensive Health Care] on health care policy reform (see box on page 20) would cost an estimated $66 billion to implement. As a result, many in Congress already have declared the Pepper report to be politically nonviable. Nevertheless, Commission Chairman John D. Rockefeller IV intends to pursue legislative activity on the report. Recently, Rockefeller said that the Commission's majority recommendations likely will be offered in Congress as one large bill--with the option to break out some of its features for individual consideration. For example, Rockefeller said he will try this year to enact the Commission's recommendations to improve health care coverage for pregnant women and children--as well as suggestions for reform in the health insurance industry. The West Virginia senator said he believes these two proposals will cost about $3.5 billion in new federal funds. The basics of the plan, and the political obstacles facing its enactment, were discussed by several members of the Pepper Commission during the press conference at which the recommendations were unveiled. FAHS Review covered that press conference, and below we reprint excerpts from a tape transcription of the remarks of several Commission members. PMID- 10113211 TI - Wake up call on mandatory insurance. PMID- 10113212 TI - Sailing on a sea of change. LTC insurance plays uncharted waters. PMID- 10113213 TI - Universal health insurance: an end or a means? PMID- 10113214 TI - The law of consent. PMID- 10113215 TI - The funding of hospitals: hospitals as businesses. PMID- 10113216 TI - Does Canadian law prepare you for death? PMID- 10113217 TI - Detention of accused persons found not guilty by reason of insanity: diversion or preventive treatment. PMID- 10113218 TI - Health care logistics: back to the future. PMID- 10113219 TI - What's wrong with the retirement industry? PMID- 10113220 TI - Pepper Commission misses policy opportunity. PMID- 10113221 TI - Legislative currents--summary of proposed changes. PMID- 10113222 TI - Matter of life or death. PMID- 10113223 TI - Overhauling Medicare. PMID- 10113224 TI - Outlook 2000. The major trends. AB - The American economy is expected to grow by 30 percent between 1988 and 2000, while the labor force will increase by 16 percent. This summary of trends for the economy, the labor force, industries, and occupations also looks at some implications of the projections. For example, continued growth opens the way to a more equitable labor market in the future, but only if workers have the education and training needed by employers. PMID- 10113225 TI - The 1990-91 job outlook in brief. AB - To learn how employment in 250 occupations is expected to change between 1988 and 2000, all you have to do is look at this article. PMID- 10113226 TI - Willingness to pay for publicly-provided goods. A possible measure of benefit? AB - The results presented in this paper arise from a U.K.-based study aimed at determining peoples' willingness to pay for two publicly-provided goods, namely continuing-care for elderly people in either hospital or National Health Service (NHS) nursing homes. Seventy-one per cent of respondents provided evaluations which could contribute to the analysis which showed that the group which preferred NHS nursing-home care could potentially compensate the group which preferred hospital care and still remain better off, thus rendering NHS nursing home care the efficient option to undertake. No variable could be found which discriminated between those who could place a value on both types of care and those who could not. The willingness-to-pay methodology is very experimental in this context and should be investigated thoroughly before its widespread adoption in the evaluation of health care techniques. PMID- 10113227 TI - Comparing the cost-effectiveness of drug regimens in the treatment of duodenal ulcers. AB - This paper compares cost-effectiveness of drug regimens based on omeprazole, ranitidine and sucralfate in the treatment of duodenal ulcers. Measures used were expected total costs and expected healthy days in a six month period after starting treatment. Both measures were calculated by decision tree analysis using healing and relapse probabilities estimated by logit regressions from results of earlier RCTs. Omeprazole and sucralfate regimens tied in the direct C/E comparison and were clearly superior to ranitidine regimens. Yet problems with patient compliance and faster relief from pain/symptoms with omeprazole may contribute to breaking the tie to omeprazole's advantage. PMID- 10113228 TI - Community-based long-term care for the elderly: evaluation practice reconsidered. PMID- 10113230 TI - Severity-of-illness systems. An overview for medical directors--Part two. AB - In Part One of this article in the March-April 1990 issue of Physician Executive, the authors explored severity-of-illness systems that relied on administrative data for their formulation. In the second part of the article, the authors deal with systems that use clinical and/or physiologic data as their basis. PMID- 10113229 TI - A comparative study of severity indexes. AB - Health care cost statistics have always been suspect because of a lack of uniformity among patients. "Our patients are sicker" is the standard retort of those providers whose costs are higher. No doubt this is true in some cases, but it is unlikely in other cases. Consequently, there is a need to standardize cost statistics to reflect just how ill patients are. What is required is severity adjustment or severity indexing. PMID- 10113231 TI - Bioethics, medicine, and the moral ground. AB - "Bioethics" and "biomedical ethics" are new expressions, conveying new ideas and new concerns. They entered the language in the 1960s. "Ethics," of course, is an ancient word meaning the study of applied moral philosophy. Bioethics is an interdisciplinary field of study that considers ethical issues in wellness and illness. Some would strongly argue that it even embraces our entire natural ecology. It certainly concerns the profession of medicine. Bioethics, like ethics itself, seeks to know and understand "goodness." PMID- 10113232 TI - Outpatient care from the payer's perspective. AB - Beginning with this issue of Physician Executive, members of the Society on Insurance of the American College of Physician Executives will provide an ongoing column for readers on the unique point of view of the health care insurer. The column starts with an offering by the Chairman of the Society on the physician executive's role in resolving the anomalies of the health care payment system. PMID- 10113233 TI - The role of cost-effectiveness analysis in health care decision-making. AB - Over the past 15 years, there has been a dramatic increase in the number and diversity of cost-effectiveness analyses (CEA) of medical technologies and an exponential growth in the number of published CEA studies in health care professional journals. At the same time, both the methodologies applied and the subject matter of CEA have expanded. Contributing to this growth has been increased government and private sector concern over managing the cost of health care and limiting third-party payer coverage to those medical techniques and procedures that are clinically effective and resource efficient. PMID- 10113234 TI - But 'twas a famous victory. AB - The Omnibus Budget Reconciliation Act of 1989 sets forth the basic parameters for physician payment reform. The program requires the Health Care Financing Administration to (1) set (regulate) all physicians' fees for services delivered under Part B of Medicare commencing January 1, 1992, with a four-year phase-in period, (2) limit the dollar amounts of balance billing by tying those amounts to the regulated rates, and (3) establish "Volume Performance Standard Rates of Increase" (previously known as "Expenditure Targets") as a mechanism for attempting to regulate the quantities of services delivered. PMID- 10113235 TI - '90s may be decade for physician payment reform. AB - The '80s in health care were characterized by reform of Medicare payment for hospital services. The '90s are likely to be characterized by reforms in the manner in which physicians are paid for services to Medicare beneficiaries. In this article, the authors examine the steps that are already under way or proposed for reforms in the payment for physician services under Medicare. PMID- 10113236 TI - Computing. Summing up DRGs. PMID- 10113237 TI - Hospitals not in a hurry to plug in computers by the bedside. AB - Despite years of talk about the coming day when there will be a computer at every bedside, terminals are still an uncommon sight in hospital rooms. While hospitals that have installed bedside systems rave about the quality-of-care improvements and time savings they've reaped, most administrators have opted to wait. For many hospitals, the systems currently available just don't fit their clinical needs or their budget limitations. PMID- 10113238 TI - Americans oppose cutting back Medicare to reduce deficit--poll. PMID- 10113239 TI - Hospital effectiveness, organisational culture, and benefit-cost. PMID- 10113240 TI - Cost-benefit and cost-effectiveness analysis for health promotion programs. AB - Health promotion programs have been hailed as having great potential to help solve the problem of rapidly increasing health care costs. In order to assess whether health promotion programs are "worth it," some kind of cost-benefit or cost-effectiveness analysis must be included as part of program evaluation. This article provides a basic introduction to the concepts of cost-benefit and cost effectiveness analysis, compares them, and presents a simple procedure for performing a basic cost-effectiveness analysis. The potential for health promotion programs to impact on the rising costs of medical care is discussed. PMID- 10113241 TI - Corporate execs can make a difference. PMID- 10113242 TI - Nutritional support in hospitals in the United Kingdom: national survey 1988. AB - The increasing sophistication of enteral and total parenteral nutritional support techniques has resulted in improvements in the clinical practice of such support in recent years. This survey was designed to establish current clinical practice in the management of nutritionally-compromised hospital patients in 206 districts in the United Kingdom. However, despite recent developments in these techniques, the response revealed a wide variation in the practice of clinical nutritional support. The results also indicate that in each district there should be a group of people, with an interest in clinical nutrition, to monitor and advise on nutritional support. It is suggested that, a national multidisciplinary group should be formed, similar to the American and European Societies of Parenteral and Enteral Nutrition. The group would promote the appropriate use of, and research into, nutritional support specifically for the nutritionally compromised patient in the United Kingdom. PMID- 10113243 TI - Tracking turns 19-month tide to hospital bottom. AB - When Saline Community Hospital, an 82-bed hospital in Saline Mich., saw its losses due to lower Medicare reimbursements mount, despite a review system already in place, administrators installed two intervention tools. The author discusses how an interactive software program and a plan to target "losing" DRGs can turn losses for any hospital. PMID- 10113244 TI - Formulary decision making in a specialty hospital: effective management of potent and costly drug therapies. AB - Substantial progress has been made in the treatment of cancer in the past few decades. Complex drug therapy regimens, supportive-care therapies, and therapeutic complications--namely, infection--have made clinical management challenging, however. In this exclusive Hospital Formulary interview, Michael Keating, MD, and William Dana, PharmD, Chairman and Secretary, respectively, of the University of Texas M.D. Anderson Cancer Center's P & T Committee, discuss successful methods of maintaining an effective formulary in a cancer center. Although efficacy and toxicity of therapy remain the primary considerations when evaluating drugs, with a formulary weighted with cancer chemotherapeutic agents, antibiotics, and other supportive intravenous formulations, cost is also critical. These health professionals describe how they balance the issues associated with rational, yet cost-effective drug therapy. PMID- 10113245 TI - Impact of a pharmacist education program on nonformulary drug use. AB - The effect of an educational program for pharmacists that included instructions for handling nonformulary drug requests and determining suitable formulary alternatives for frequently prescribed nonformulary drug requests was measured. Results indicate a significant increase in the number of appropriate nonformulary drug dispensings when the postintervention phase was compared with the preintervention phase. Other values, including the financial impact per nonformulary drug request, did not differ significantly between the two phases. Since all nonformulary drug requests require pharmacist time, a more cost effective nonformulary drug policy might focus the pharmacist's efforts on nonformulary drug products that are more costly than their formulary alternatives. PMID- 10113246 TI - Improving drug usage evaluation with microcomputer database software. AB - The use of microcomputer database software can help overcome many of the potential weaknesses of criteria-based drug usage evaluation (DUE) through the collection and assessment of drug use statistics on a broad basis. By allowing for more systematic and comprehensive data analyses, database software can target the selection of the most appropriate DUE topics; improve the accuracy, efficiency, and acceptance of DUE reports; and enhance the overall therapeutic- and cost-effectiveness of drug use in the institutional setting. The development of antibiotic use statistics in the area of surgical prophylaxis is presented as an example, with recommendations for similar applications in other therapeutic areas. PMID- 10113247 TI - Materials managers must lay the foundation for a new facility's supply distribution system. PMID- 10113248 TI - Rotec Theory: planning tool to position hospitals on the technology curve. AB - The mission statement of a prominent California hospital has been revised as part of a strategic planning process less than two years before the hospital began experiencing substantial financial difficulties. When the "red numbers" began to appear, management was quick to blame changing demographic patterns and the competitive environment. Those were not the only problems. A major contributing factor that management failed to recognize was a delay in how quickly the hospital moved to adopt high technology or new medical procedures. In a few short years, it had changed from being the first community hospital to implement state of-the-art programs to one that was slow to introduce technology. In retrospect, the hospital's mission statement did not address the role of technology and therefore it could not detect the movement away from one of its critical success factors. The Rotec Theory was developed to assist this hospital to understand the economics of technology on its current and planned operations. PMID- 10113249 TI - A specialty-based ambulatory workload classification system. PMID- 10113250 TI - A comparison of ambulatory classification systems: a preliminary report. PMID- 10113251 TI - Severity-of-illness systems. An overview for medical directors--Part one. AB - To a baseball fan, the weight of a player's bat is not very important, and the grace with which it is swung has only slightly more appeal. Both these factors matter far less than how often and with what results the bat meets the ball. Similarly, in today's competitive health care environment, the medical director has to focus on results. Not only external demands from constituencies such as insurers, payers, consumers, and regulators, but also internal pressures for sound management decisions require accurate information about the outcomes of care. In this two-part article, the authors examine the contributions that severity-of-illness systems can make to outcomes monitoring. PMID- 10113252 TI - System measures ambulatory care quality. AB - As physician executives, what we need in ambulatory quality assurance is a very carefully thought out system that will enable us to monitor quality in such a way that we will also be able to measure it. Only if we have the capability to measure quality can we begin to manage it. PMID- 10113253 TI - Who lost the health care revolution? AB - Just a year ago, in the March-April 1989 issue of Harvard Business Review, Professor Regina E. Herzlinger of the Harvard Business School took a long look at the U.S. health care system and declared the much touted revolution in the health care delivery system a failure. This article is a summary of the arguments that Professor Herzlinger marshaled for her treatise. In the following two articles, members of the College assess those arguments in terms of the medical management profession and in terms of the organizations, a hospital and a managed care company, for which they work. Finally, Professor Herzlinger returns to the subject with a response to these physician executives. PMID- 10113254 TI - Resource exchange theory: a problem-solving tool. AB - In the creation and operation of work environments, problem solving can be more effective with some theories or models than with others. In this article, the author describes a theory that he has found to be especially useful for his management responsibilities. The Resource Exchange Theory, he says, engenders a unique view of power that is useful in managing a reward system, negotiating, managing conflict, and empowering people. PMID- 10113255 TI - Do these guys know why they're applauding? AB - Contained in Title IV, Section 6102, of the Omnibus Budget Reconciliation Act of 1989 are more than 21 pages of legislative language designed to require the Health Care Financing Administration (HCFA) to set all physicians' fees for services delivered under Part B of Medicare commencing January 1, 1992, and phased in over the following four years. In addition, balance billing dollar limits keyed to the regulated rates are set forth, as are "Volume Performance Rates of Increase," a reincarnation of a vehicle previously known as "Expenditure Targets." PMID- 10113256 TI - Success will require a conscience. PMID- 10113257 TI - One community hospital--2000 AD. AB - The hospital with which the author has been associated for more 40 years is undergoing the most dramatic changes in its century of existence. These changes have been added to a catalog of past changes and speak to changes that are yet to come. The author describes the process by which this community hospital, and by inference others, has reached its present status and suggests what it may look like in the future. PMID- 10113258 TI - Sammons departure portends organizational changes. AB - The American Medical Association enters the '90s at a peak of its power and influence. Its recovery from the institutional doldrums of the mid-1970s is now complete. The surprise resignation of Executive Vice President James Sammons, MD, following the Interim Meeting of the AMA House of Delegates could position the AMA for further changes and for an increasingly influential voice in health care policy making. The College Delegate and Alternate Delegate to the AMA House report on the December 1989 meeting. PMID- 10113259 TI - Court decisions hold implications for managed care plans--Part two. AB - This article highlights selected legal developments from the past two years that reflect the causes and effects of the competitive environment in which the managed care industry finds itself. Additional cases were discussed in the January-February 1990 issue of the journal. "Health Law" is a regular feature of Physician Executive contributed by Epstein Becker & Green. Douglas Hastings, Esq., a partner in the law firm's Washington, D.C., offices, serves as column editor. PMID- 10113260 TI - Health care technology. Evolution toward revolution. AB - The assessment process has a significant effect on the development and diffusion of any new technology. An assessment during the infancy of a new technology may have to be updated as more experience and data accumulate and change the analysis of the technology's safety and effectiveness. An outdated assessment can result in inappropriate utilization either by hindering diffusion of a valuable technology or by promoting utilization of an inappropriate technology. Those who conduct technology assessments must recognize that technologies have life cycles of their own. PMID- 10113261 TI - The revolution revisited. PMID- 10113262 TI - Balancing needs to build effective continuum of care. PMID- 10113263 TI - 1990 Provider LTC buyers guide to products & services. American Healthcare Association. PMID- 10113264 TI - Perspectives. Medicaid at 25: rising expectations. PMID- 10113265 TI - Perspectives. Keeping an eye on the pie. PMID- 10113266 TI - Know scope of practice parameters. PMID- 10113267 TI - Geographic variations in Medicare utilization of short-stay hospital services, 1981-88. AB - The change in Federal fiscal year 1984 from cost-based reimbursement to prospective payment at a fixed price for a known and defined product--the hospital stay--represents a fundamental change in the role of the Medicare program within the health care delivery system. In this article, national and selected geographic trends in Medicare short-stay hospital inpatient discharges since 1981 are presented, and they show the impact of the implementation of the prospective payment system. PMID- 10113268 TI - Health care indicators. Community hospital statistics; employment, hours, and earnings in the private sector; health care prices; and national economic indicators. PMID- 10113269 TI - Reports to Congress: Medicare physician payment. AB - This single volume presents three congressionally mandated reports that provide detailed evaluations of technical and administrative issues associated with implementing proposed physician payment systems under Medicare. The reports were released to Congress on October 18, 1989. It is expected that Congress will use these reports to address the issues identified herein. PMID- 10113270 TI - Alternative geographic configurations for Medicare payments to health maintenance organizations. AB - Under prevailing legislation, Medicare payments to health maintenance organizations (HMOs) are based upon projected fee-for-service reimbursement levels for enrollees' county of residence. These rates have been criticized in light of substantial variations in rates among neighboring counties and large fluctuations in rates over time. In this study, the use of nine alternative configurations and the county itself were evaluated on the basis of payment-area homogeneity, payment rate stability, and policy criteria, including the fiscal impacts of reconfiguration on HMOs. The results revealed rather modest differences among most alternative configurations and do not lend strong support for payment area reconfiguration at this time. PMID- 10113271 TI - Alternatives for using multivariate regression to adjust prospective payment rates. AB - Multivariate regression analysis has been used in structuring three of the adjustments to Medicare's prospective payment rates. Because the indirect teaching adjustment, the disproportionate-share adjustment, and the adjustment for large cities are responsible for distributing approximately $3 billion in payments each year, the specification of regression models for these adjustments is of critical importance. In this article, the application of regression for adjusting Medicare's prospective rates is discussed, and the implications that differing specifications could have for these adjustments are demonstrated. PMID- 10113272 TI - Impact of the Maine Medicaid waiver for the mentally retarded. AB - To evaluate the impact of Maine's Medicaid waiver for the mentally retarded, baseline and 1-year followup data were obtained for 191 waiver clients and a comparison population of 115 persons excluded from the program because of enrollment limits. Program effectiveness was evaluated through measures of changes in clients' personal and community living skills. Medicaid and other data were used to establish individual and aggregate costs. It was found that the waiver program is a cost-effective alternative to intermediate care placements but that client screening is necessary to limit the enrollment of clients not at risk of institutional placement. PMID- 10113273 TI - Assessing cost effects of nursing-home-based geriatric nurse practitioners. AB - Employment of geriatric nurse practitioners (GNPs) is one strategy to improve nursing home care. The effects of GNPs on costs and profitability of nursing homes and on costs of patient medical service use outside the nursing home are examined. Employment of GNPs does not adversely affect nursing home costs or significantly affect profits. There is some evidence of cost savings in medical service use for newly admitted patients but no evidence of savings for continuing residents. GNPs reduce the use of hospital services for both groups, and the reduction is statistically significant for newly admitted patients. PMID- 10113274 TI - Institutional alternatives to the rural hospital. AB - An important aspect of the ongoing debate on rural health policy is how to deliver inpatient care in sparsely populated rural areas. One alternative is to create a new classification of rural inpatient facility that would deliver more limited services than available in a rural hospital, have more flexibility in staffing requirements, and possibly be reimbursed differently. The support of the Health Care Financing Administration for the concept of a limited service rural hospital is critical, since such a facility would not be financially viable without Medicare payment. Several organizational and public policy issues that merit consideration in the design and implementation of institutional alternatives to rural hospitals are discussed, including licensure and certification, scope of services, personnel, quality assurance, and payment. PMID- 10113275 TI - Swing-bed services under the Medicare program, 1984-87. AB - Under Medicare, swing beds are beds that can be used by small rural hospitals to furnish both acute and post-acute care. The swing-bed program was instituted under the provisions of the Omnibus Reconciliation Act of 1980 (Public Law 96 499). Under Medicare, post-acute care in the hospital would be covered as services equivalent to skilled nursing facility level of care. Data show that the program has had a rapid rate of growth. By 1987, swing beds accounted for 9.7 percent of the admissions to skilled nursing facility services, 6.0 percent of the covered days of care, and 6.2 percent of the reimbursements. Over one-half of the swing-bed services are furnished in the North Central States. PMID- 10113276 TI - Coding notes--coding addendum effective October 1, 1990. PMID- 10113277 TI - Insuring health in today's health care environment. Interview by Janice C. Simmons. PMID- 10113278 TI - Understanding volume: a Medicare primer. AB - Volume, rather than real fee increases, has been the driving force behind increasing physicians' costs throughout the 1970s and the 1980s, these researchers from the Health Care Financing Administration say. But where has it been growing? PMID- 10113280 TI - Bridge marketing: the continued evolution of hospital marketing. PMID- 10113279 TI - Niche marketing. Is it the future for selling health services? PMID- 10113281 TI - Changes in immigration law affect health care employers. PMID- 10113282 TI - Conserve medical staff resources with combined committee. PMID- 10113283 TI - Guest relations: the invisible survival strategy. PMID- 10113284 TI - The special demands of marketing specialized programs. PMID- 10113285 TI - Withdrawal of nutrition and hydration from an incompetent patient: legal developments leading to Cruzan. PMID- 10113286 TI - The constitutional dimensions of the right to refuse medically assisted nutrition and hydration: an analysis of Cruzan. PMID- 10113287 TI - Take an accounting of the good that we do. PMID- 10113288 TI - How family spending has changed in the U.S. AB - Since the Monthly Labor Review began, the proportion of family expenditures allocated for food has dropped by half, the incidence of homeownership has doubled, and spending for transportation, medical care, and recreation has increased significantly. PMID- 10113289 TI - Family-related benefits in the workplace. AB - The emergence and subsequent expansion of employer-provided benefits since 1915 have been fueled in part by the changing needs of employees and their families. PMID- 10113290 TI - The effect of prospective payment under DRGs on the market value of hospitals. AB - This article investigates the effect of a change in Medicare payment regulations on for-profit hospital market values. A theoretical argument on the effects of this regulatory event is presented in which hospital managers are concerned about firm wealth but also value prestige, provider perceptions of quality, and perhaps other prerequisites. In this case, DRGs will induce hospitals to seek higher wealth because they increase the opportunity cost of nonpecuniary benefits. The issue is pursued empirically by estimating the market response to DRG legislation using seemingly unrelated regressions. PMID- 10113291 TI - A microscope on nursing-home plans. PMID- 10113292 TI - Perspectives. Health care reform: state's-eye view. PMID- 10113293 TI - Case management organizational models & administrative methods. AB - Case management is one of the more popular buzzwords in the health care marketplace today. It is also commonly misunderstood. Virtually all providers have some experience with case management activities, either as direct providers of service, or as health care providers who interact with other agencies that practice case management on behalf of clients. This article will define some of the leading organizational models of case management programs and explain the implications of their alternative practice philosophies. This discussion is followed by an outline of the essential core elements of any case management program. Agencies can compare their own case management methods to widely recognized standards that characterize successful strategies used by different organizations throughout the United States. PMID- 10113294 TI - Developing a quality assurance program in case management service settings. AB - Increasingly good quality case management is a necessary part of assuring appropriate and timely access to home care and other community-based services. This article focuses on how to develop a program to monitor the quality of case management services. It includes discussion of an approach for thinking about quality assurance, identifies objectives that are appropriate for quality assurance in case management settings, and provides suggestions for developing quality assurance activities in case management settings. PMID- 10113295 TI - Case management and the payor: where are we and where do we go from here? AB - Over the past 20 years, increasing numbers of states have sought to control the costs of their home care programs by establishing case management systems. These payor-directed case management systems duplicate the activities of the caregiver agency and have proven to be quite costly. It is generally assumed that case management will continue to be an essential component of public home care programs, including any future federal long-term care program. However, there is reason to believe that cost considerations and other factors will lead to a much reduced payor case management role. PMID- 10113296 TI - Safety before cost. PMID- 10113297 TI - Medicare program; changes to the inpatient hospital prospective payment system and fiscal year 1991 rates--HCFA. Final rule. AB - We are revising the Medicare inpatient hospital prospective payment system to implement necessary changes arising from legislation and our continuing experience with the system. In addition, in the Addendum to this final rule, we are describing changes in the amounts and factors necessary to determine prospective payment rates for Medicare inpatient hospital services. In general, these changes are applicable to discharges occurring on or after October 1, 1990. We also set forth rate-of-increase limits for hospitals and hospital units excluded from the prospective payment system. This final rule also responds to comments received concerning changes to hospital payments made in an April 20, 1990 final rule with comment. These changes include mid-year changes to the inpatient hospital prospective payment system that implemented provisions of the Omnibus Budget Reconciliation Act of 1989; and adjustments applicable to prospective payment hospitals and to the target amounts of hospitals and units excluded from the prospective payment system due to the elimination of the day limitation on covered inpatient hospital days made by the Medicare Catastrophic Coverage Act of 1988 and later repealed by provisions in the Medicare Catastrophic Repeal Act of 1989. The April 20, 1990 final rule with comment also incorporated changes to these provisions made by the Family Support Act of 1988, which clarified the criteria for adjusting the target amounts and implementation date. In addition, this final rule clarifies the documentation requirements necessary to support the cost allocation of teaching physicians and the allowability of costs for rotating residents in determining payment for the direct costs of an approved graduate medical education program. This clarification is being made as a result of a September 29, 1989 final rule that made changes in Medicare policy concerning payment for the direct graduate medical education costs of providers associated with approved residency programs in medicine, osteopathy, dentistry, and podiatry. PMID- 10113298 TI - Can we afford new-parent meal programs? PMID- 10113299 TI - Texas Hospital Association 1990/1991 leadership guide. PMID- 10113300 TI - Consent to the release of privileged communications between physician and patient. AB - Physician-patient communications are considered confidential, ensuring a relationship built on trust. Assuring patients of that protection can eliminate many of their concerns about unauthorized disclosures. PMID- 10113301 TI - Achieving the impossible dream: no nursing shortage. PMID- 10113303 TI - A glimpse at the hospital of the future. AB - Bedside computer terminals and "smart cards" are among the innovations in information technology that will help hospitals manage costs and quality. PMID- 10113302 TI - Quality requirements: starting small can yield big results. PMID- 10113304 TI - The health care worker shortage: the gap widens. AB - This time last year, HealthTexas reported on the continuing shortage of nurse professionals and the growing problem finding workers in other areas such as physical and respiratory therapy, pharmacy and radiology. An American Hospital Association survey underscored the growing disparity between demand and supply in these areas. Twelve months later, not much has changed. Hospitals continue to look for ways to find and keep workers and increase the overall pool of qualified personnel. Efforts continue to bring the problem to the attention of lawmakers, policy makers, education and business. PMID- 10113305 TI - Growing pains for hospices. PMID- 10113306 TI - New HCFA chief shares LTC outlook. Interview by Ronald M. Schwartz. PMID- 10113307 TI - Right-to-die options and recommendations. Advice on overcoming legal impasse. PMID- 10113308 TI - Special report on patient care. Supreme Court upholds state court decision in Cruzan. PMID- 10113309 TI - Diagnostic coding quality and its impact on healthcare reimbursement: research prospectives. AB - This article reviews research on the sources of coding errors and summarizes the findings. It presents a research model and justification for experimental research to measure the factors affecting the sources of coding error and the potential impact these factors have on coding quality and subsequent reimbursement levels. PMID- 10113311 TI - Fund raising in the multi-institutional environment. PMID- 10113310 TI - Overview of provincial home care programs in Canada. AB - Across Canada, the phenomenal success of home care has led to rapid growth, demand outstripping resources and fragmentation of services. These problems and many others are facing home care managers today. Four controversial issues are discussed and comments are made on how they may be (or should be) resolved: (a) what groups should home care serve? (b) what should the link be between home care and the other components of the health system? (c) co-ordination of the array of services for the elderly population and (d) control of home care. PMID- 10113312 TI - Is it fund-raising or development? PMID- 10113313 TI - The donor sophisticate. PMID- 10113314 TI - Motivate, educate, activate. PMID- 10113315 TI - Ask ... and it shall be. PMID- 10113316 TI - AMT (alternative minimum tax)--pain or problem? PMID- 10113317 TI - Professionalism and ethics in a new decade. PMID- 10113318 TI - From the fading "tax shelter" fad to the ethics of disclosure. PMID- 10113319 TI - Why the controversy? PMID- 10113320 TI - Does your planned giving program need a sprinkler? PMID- 10113321 TI - The home loan program. PMID- 10113322 TI - Getting one on one with planned giving prospects. PMID- 10113323 TI - NAHD (National Association for Hospital Development)--an expanded mission. PMID- 10113324 TI - The da Vinci complex--don't major in minor things. PMID- 10113325 TI - Charity care and tax exemption. The government's challenge to non-profit hospitals. PMID- 10113326 TI - The brave new world of health systems fund raising. PMID- 10113327 TI - Insurance projects criticized. PMID- 10113328 TI - Preparing to be a long term care provider ... contemporary professional development. PMID- 10113329 TI - Faculty Fellowship Program brings classroom to facility. PMID- 10113330 TI - Area Agencies on Aging: the community care connection. AB - This article reviews the conceptual difficulties in using the existing Medicare and Medicaid systems to provide community-based long-term care to older persons, discusses the role of the Older American's Act and Area Agencies on Aging in the effective provision of community-based long-term care, and presents several basic principles for long-term care legislation. PMID- 10113331 TI - Private-pay case management. Let the seller beware. AB - Selling case management to adult children and older persons as a discrete service is neither as simple nor as lucrative as many people believe. This article addresses some issues related to private-pay case management: What is case management? What agencies and organizations provide this service? What opportunities exist for a home care agency to become involved? Is there really a need for case management? PMID- 10113332 TI - The Supreme Court speaks on treatment refusal: the Cruzan case. PMID- 10113333 TI - Poll shows mood to spend on health. PMID- 10113334 TI - Myths & realities. Why most of what everybody knows about long-term care is wrong. PMID- 10113336 TI - Private/public financing scheme stalemated. Waxman opposes Medicaid/ insurance consolidation. PMID- 10113335 TI - Trends in the health service industry. PMID- 10113337 TI - Nutrition and the elderly. AB - Living alone, enduring deteriorating health, and losing sensory abilities can make it difficult for elderly people to get all the nutrients they need. Some experts offer advice on making mealtime more appealing--and nutritious--for seniors. PMID- 10113338 TI - The double jeopardy of sales promotions. AB - The maturing of most consumer markets in the United States has put great pressure on manufacturers in their search for growth. They have concentrated on building sales and expanding share proportions in the stagnant markets with devices like niche products, product extensions, mergers, and international ventures. They have shifted emphasis to sales promotions at the expense of advertising. But promotions, when you come right down to it, mean price reductions. Trade promotions are almost always rebates, and consumer promotions are usually temporary price reductions or coupons. The cost in reduced profit, demonstrated mathematically through calculations of price elasticity, is severe. Besides, when the promotion is over, the manufacturer has not moved forward an inch in shoring up the brand franchise. Promotions bring volatile demand, whereas the producer seeks stable demand. By sustaining a brand image and building customer loyalty, on the other hand, theme advertising can stabilize demand. Moreover, this type of advertising is less likely than promotion is to invite destructive competitive retaliation. Calculation of the advertising elasticity of a brand indicates that sometimes even modest sales increases can produce healthy profit improvement. In a well-planned marketing campaign, there is often good reason to include trade or consumer promotion--to counter a leading competitor's moves, for example. But there is no point in carrying out wild swings at rivals in a struggle for market share. Mathematical techniques can aid the efficiency of marketing planning and put on a more rational basis the decision on where to put the dollars. PMID- 10113339 TI - Rural hospitals: still on the critical list. AB - "Survive 'til '95." This rural hospital battle cry may prove to be prophetic. The next five years will determine how health care is delivered in the United States. Time is critical for rural hospitals, and their responses to changes ahead will determine their future. PMID- 10113340 TI - Rural hospitals are adapting for survival. PMID- 10113341 TI - Finding funds for HIV treatment programs. PMID- 10113342 TI - Recycling program saves trees, reduces solid waste costs. PMID- 10113343 TI - When AIDS comes home. AB - Without loosening its grip on urban centers, AIDS is becoming more common in small-town and rural Texas. As a result, all hospitals face serious implications. PMID- 10113344 TI - A health care worker's story. PMID- 10113345 TI - Time's up! PMID- 10113346 TI - Containing pharmacy costs requires careful review, cooperation. PMID- 10113347 TI - The value of market research. PMID- 10113348 TI - Modern trends in surveillance techniques. PMID- 10113349 TI - Network gives children top priority. AB - The South Texas Regional Pediatric Network--an arrangement between San Antonio's Children's Hospital and 21 other hospitals--trims critical patient transfer time. For seriously ill infants and children throughout South and West Texas, it's a lifesaver. PMID- 10113350 TI - Health care technology in Australia and New Zealand: contrasts and cooperation. AB - Australia and New Zealand are neighbouring countries with similarities due to their settlement by Europeans, but with major differences in their economies, populations, geography and political systems. These differences have led to contrasting approaches to the introduction and control of health care technologies. New Zealand has historically had greater success in limiting the use of health technologies which have often been adopted more widely and rapidly in Australia. Recent initiatives in health technology assessment have involved participation by both countries, giving the potential for a joint approach to policy formulation on use of some medical devices and procedures. PMID- 10113351 TI - Appropriateness of acute medical care for the elderly: an analysis of the literature. AB - Over the past 30 years, an explosion in health care expenditures has occurred. Prior to 1960, health care accounted for 4.4% of the U.S. Gross National Product; today it is 11%. Before rational solutions to controlling this rise can be proposed, we must determine whether the care that we are currently paying for is appropriate to the needs of the elderly. This paper analyzes the literature regarding appropriateness of acute care provided to the elderly. We identified 17 articles that explicitly cited appropriate or inappropriate care (including under , over- and misuse) provided in hospital and ambulatory settings and for procedures, and 19 articles that presented data on the appropriateness of medication use in the elderly. Virtually every study included in this review found at least double-digit levels of inappropriate care. Perhaps as much as one fifth to one-quarter of acute hospital services or procedures were felt to be used for equivocal or inappropriate reasons, and two-fifths to one-half of the medications studied were overused in outpatients. The few studies that examined underuse or misuse of services also documented the existence of these phenomena. This was especially true for the ambulatory care of chronic physical and mental conditions and concerned the use of low-cost technologies (visits, preventive services, some medications). Thus, we conclude that there appears to be a substantial problem in the matching of acute services to the needs of elderly patients. This mismatch occurs both in terms of overuse and underuse, at least for areas where research has been conducted. PMID- 10113353 TI - U.S. health care: the high price tag doesn't bring satisfaction. PMID- 10113352 TI - Assessing the economic burden of injuries due to accidents: methodological problems illustrated with some examples from the literature. AB - This paper provides a survey of methodological problems encountered in an assessment of the economic consequences of accidents in The Netherlands. A sound epidemiological basis for such calculations appears to be lacking due to inadequate data-registration systems. We also discuss some studies of the economic costs of injuries due to accidents for other countries, which have used either a prevalence or an incidence-based approach. It is highlighted that they may be helpful in indicating the relative economic burden posed on society but that they cannot guide priority setting in health care resource allocation. Economic evaluation studies using incidence-based scenario comparisons may be more promising in that respect. PMID- 10113354 TI - Pepper proposal includes funding options. PMID- 10113355 TI - Clinical practice guidelines: promise or illusion? AB - The uncertainties about appropriateness and rates of use are unfolding against the backdrop of rising costs and an explosion in new biomedical and technological information. Achieving consensus in this environment is increasingly difficult as payers demand proof of effectiveness, consumers want access to the newest technology, and physicians struggle to assimilate new information. The net result is a drive toward practice standards or guidelines. PMID- 10113356 TI - Status quo won't work. AB - The division between those who provide health care services and those who pay for them may be widening. Costs continue to rise, quality remains ill-defined, and there don't seem to be any easy answers to the dilemma. Joseph W. Duva, Director of the New York Region Health/Welfare Benefits Consulting Practice of Ernst and Young, believes the answer has been found. While Director of Employee Benefits at Allied Signal Corp., he was instrumental in the formulation of a total managed health care plan for employees. He recently founded the Managed Health Care Association to share the experience at Allied Signal with others and to provide a business forum for exploration of the managed care concept. Duva's views on managed care as a cost containment strategy were the subject of an interview conducted by Physician Executive at the National Conference of Physician Executives in San Antonio in May. PMID- 10113357 TI - Managed care is data management. AB - As managed care evolves, it has become apparent that greater control of both the patient and the provider side of the process is necessary. Specifically, improvements are necessary in monitoring the appropriateness of service, accessibility, authorship and authorization of referrals and claims, patient advocacy, and assimilation of data. PMID- 10113358 TI - Quality improvement act gets first antitrust test. AB - In an opinion issued on February 20, 1990, the Federal District Court for the Central District of California summarily dismissed the claim of Dr. George M. Austin that Santa Barbara Cottage Hospital and five individual physicians conspired to suspend his hospital privileges in violation of Section 1 of the Sherman Act. The decision was based on the court's determination that the actions of the hospital and defendant physicians were immune from federal antitrust liability under the Health Care Quality Improvement Act of 1986. The case is the first test of the Act in connection with a staff privileges claim under the antitrust laws and is the first affirmance of the immunity protections of the Act. PMID- 10113359 TI - A model for reducing the cost of care in VA medical centers that offer adult day health care. AB - One approach to providing cost-effective adult day health care (ADHC) services is to guide both the inputs to ADHC services and the provision of other services so that substitution for institutional services can realistically take place. This approach has been used in a randomized clinical trial to evaluate the medical efficacy and cost of ADHC in the Department of Veterans Affairs (DVA). This article describes the strategies that were used to improve the cost effectiveness of ADHC during the evaluation. Cost and use estimates were developed based on the best data available from the DVA and previous research on the cost for patients' use of ADHC, nursing home, hospital, and ambulatory care. A cost workshop was attended by the ADHC managers to develop plans for controlling costs. Plans were identified that increase the likelihood that ADHC can be shown to be less costly than customary care. PMID- 10113360 TI - Muriel Driver Memorial Lecture. Occupational therapy--our time has come. PMID- 10113361 TI - 1991 products & services directory. PMID- 10113362 TI - System identifies problems of hospital department. AB - Identifying and quantifying problems within and outside a hospital business unit is essential if quality improvement is to be successful. In the following article, the author describes how to establish a system in which those problems can be identified and dealt with by the managers and staff of any business unit in the hospital. PMID- 10113363 TI - Hospitals as businesses: a government perspective. PMID- 10113364 TI - A multidisciplinary public hospital? PMID- 10113365 TI - Quality assurance for health clinics in the community. PMID- 10113366 TI - Can quality medical care be assured outside hospitals? PMID- 10113367 TI - Government and health care policy. PMID- 10113368 TI - Hospital governance. PMID- 10113369 TI - Managed care. PMID- 10113370 TI - Reviewing managed care plans: tips from a pro. PMID- 10113371 TI - Brown bag lunch series helps reach out to public. PMID- 10113373 TI - Aging physician population makes succession plans a must. PMID- 10113372 TI - Pediatric nosocomial infections differ in scope, incidence. PMID- 10113374 TI - Hospital advocacy network relies on grassroots politics. PMID- 10113375 TI - New law governs hospital districts' ability to use sales tax. PMID- 10113376 TI - Energy audits yield big savings for small hospitals. PMID- 10113377 TI - Healthcare data briefing. Spending for a change. National Association of Health Authorities and Trusts. PMID- 10113378 TI - Legal risk-management programs in nursing homes: who has them and do they work? AB - Legal risk-management systems are designed to identify, prevent, or mitigate the negative effects of situations that potentially expose a health care facility and its staff to avoidable legal and financial liability. This article reports findings on the current status of risk-management systems in nursing homes. The relative costs and benefits of such programs are also discussed. PMID- 10113379 TI - Computer assisted neonatal parenteral nutrition order formatting. AB - Neonatal parenteral nutrition solutions are a vital part of the treatment regimen for premature infants. Protocols that dictate the formulation of these expensive intravenous solutions must assure absolute safety for the neonate. The procedure for the initiation, calculation, and compounding of parenteral nutrition solutions involves both physician and pharmacist. Simplified physician ordering forms with printed guidelines for solution ingredients assists in error free ingredient prescribing. Pharmacist calculation programs formulating neonatal parenteral nutritions need to be accurate and easy to use. Documentation of ingredients outside of normal ranges insures patient protection from human error. With the assistance of a tailor made computer program, a procedure has been developed to provide accurate pharmaceutical calculations while documenting unusual ingredient dosages. PMID- 10113380 TI - Health and the allocation of public expenditures. AB - In a cross-country study we use a multiple regression in order to estimate the contribution of several factors to life expectancy. We find schooling as the main variable. Medicine also has a significant contribution. Calorie supply has a positive contribution only in the less developed countries. PMID- 10113381 TI - The changing pattern of medical activity in a major Belgian university hospital. AB - To evaluate the changes in the pattern of clinical activity in a 1900-bed Belgian teaching hospital in the period 1979-1987, we extracted data from the historical files of the hospital's central invoicing system. The total charge for a day of hospitalization, care and treatment increased by 83%. In this total per diem charge the share of hospital charges in the strict sense declined from 60 to 53%; the shares of charges for services and for pharmaceuticals rose, respectively, from 29 to 32, and from 10 to 15%. Within charges for services the share for diagnostic services declined by 22%; the share for surgery rose by 16%, and that for miscellaneous other services by 89%. For diagnostic services the decline was particularly clear for laboratory medicine (-32%) and for conventional imaging services (-22%), while cardiac and endoscopic investigations show a prominent expansion (+78 and +83%, respectively). In surgery the growth is quite homogeneous with the charges for urology, ophthalmology and orthopedics as the most important growers. In a group of miscellaneous, not diagnostic nor surgical services, which grows faster than all other groups, there is a marked shift from rather simple to technologically more advanced services. The increase in the pharmacy's bill results from increases in charge for both drugs (+49%) and materials (+95%). We conclude that the observed changes in charges reflect an intensification of care and an impact of technological innovation on clinical practice, including a phenomenon of substitution of old technologies for newer ones. PMID- 10113382 TI - A non-conforming view. AB - The U.S. health-care system must be meeting societal goals; otherwise we wouldn't be pumping so much money into it. PMID- 10113383 TI - Estimating vaccine costs for EPI (Expanded Programme on Immunization) cost effectiveness analysis. PMID- 10113384 TI - Right-to-die ruling begs the question: who will decide? AB - The Supreme Court's first right-to-die ruling, in the Missouri case of Nancy Cruzan, upheld a standard requiring "clear and convincing" evidence of an incompetent patient's wishes before removing life support. But the ruling is anything but clear to providers. The vague ruling has left open to interpretation who can decide when to pull the plug, and under what circumstances. PMID- 10113385 TI - Benefits of stereotactic aspiration cytology. PMID- 10113386 TI - The contrast media controversy: implications of a landmark safety study. PMID- 10113387 TI - Perspectives. Battling health care reform in New Jersey. PMID- 10113388 TI - Health care costs: the other point of view. AB - Health care delivery in America is not efficient. Hospitals are not efficient and many are still wasteful. Some of the most blatant wastes in hospitals are staffing patterns that developed during the years of cost reports. Spending patterns become the norm, rather than excess, when they continue unabated for years. There are many reasons for cost increases in health care and specifically in hospitals. However, it is difficult to make these reasons add up to the total cost increase. No one has the answers; observation can only be made of what has been occurring and what continues to occur. Whatever the reason for the increase in health care costs, the consumer will bear the burden because of the circular flow of income and expenditures between the business sector and the household sector. Increased health care costs are passed on to the consumer in the form of increased expenditures for household goods and services or taxes. Ford Motor Company President Mr. Peterson says that $1,500 of every new automobile represents employee health care costs. The American consumer created the demand for health care services, and only the consumer can control the demand. One solution would be to let the consumer bear health care costs directly and remove the inefficiencies created by third party insurance carriers. This hypothesizes that the health care consumer is the most efficient shopper for health care services, and that third party insurance carriers are an important source of inefficiency in the health care delivery system. Many other solutions have been proposed by the government and by the insurance and health care industries, but most have only increased the cost of health care. Perhaps some day the health care industry will learn how to control the dynamics of this four-party purchasing decision. Until then, costs will continue to grow dramatically, and the executives of the industries who compete in the two-party purchasing system will wonder why the process is so complicated. PMID- 10113389 TI - Curb spending, use single payer--study. PMID- 10113390 TI - Rurals using new techniques to finance long-term care. AB - As the population of rural America ages, rural hospitals are seeing opportunities for new revenue in long-term care. To meet those needs, they are turning to tax exempt revenue bonds, something they rarely used in the past, and private venture capital, an entirely new wrinkle. PMID- 10113391 TI - An unexplored vista. Ambulatory care's furious growth seriously outpaces internal management controls. PMID- 10113392 TI - Guess what's alive again--DRGs for doctors. PMID- 10113393 TI - Old and thin. AB - Viewing an elderly patient's refusal of food from the perspective of the jain tradition of sallekhana (voluntary starvation) permits the author to reconcile her need to "do something" with her belief in the principle of patient autonomy. PMID- 10113394 TI - Dealing with labor shortages in long-term care: a marketing problem. AB - A recent analysis of data from the Bureau of Labor statistics raise serious implications for the long-term care industry. The human resource problems faced by managers in long-term care will escalate into a fullblown crisis by the end of this century. This will result from a decrease in the number of young workers available to work in unskilled and semiskilled occupations. The effect of this shortage will be exaggerated by an expansion of other sectors of the service industry. Long-term care facilities will be forced to compete with the fast food and retail industry as well as other sectors of the health industry for scarce workers. This article briefly examines the causes, consequences of this problem and suggests several strategies to mitigate the effect of the coming labor shortage. PMID- 10113395 TI - National health expenditures, 1988. Office of National Cost Estimates. AB - Every year, analysts in the Health Care Financing Administration present figures on what our Nation spends for health. As the result of a comprehensive re examination of the definitions, concepts, methods, and data sources used to prepare those figures, this year's report contains new estimates of national health expenditures for calendar years 1960 through 1988. Significant changes have been made to estimates of spending for professional services and to estimates of what consumers pay out of pocket for health care. In the first article, trends in use of and expenditure for various types of goods and services are discussed, as well as trends in the sources of funds used to finance health care. In a companion article, the benchmark process is described in more detail, as are the data sources and methods used to prepare annual estimates of health expenditures. PMID- 10113396 TI - Comparing case-mix systems for nursing home payment. AB - Case-mix systems for nursing homes use resident characteristics to predict the relative use of resources. Seven systems are compared in structure, accuracy in explaining resource use, group homogeneity, and ability to identify residents receiving heavy care. Resource utilization groups, version II (RUG-II), was almost uniformly the best system, although management minutes and the Minnesota case-mix system were also highly effective. Relative weights for case-mix groups were sensitive to cost differences and should be recomputed for new applications. Multiple criteria should be used in choosing a case-mix system, including consideration of inherent incentives and how residents' characteristics are defined. PMID- 10113397 TI - Illness-episode approach: costs and benefits of medigap insurance. AB - Over two-thirds of Medicare beneficiaries have private supplementary coverage, but few know enough about Medicare, their own supplements, or available alternatives to make intelligent comparisons and informed purchasing decisions. The illness-episode approach, a new way to provide insurance information to Medicare beneficiaries, calculates out-of-pocket costs likely to be faced by beneficiaries experiencing 13 illnesses, under Medicare alone and under different medigap policies. Applying the approach to six policies marketed in Los Angeles in 1986 revealed that plans varied widely in their ability to reduce financial vulnerability; many still leave the elderly with substantial out-of-pocket costs. PMID- 10113398 TI - Volume and intensity of Medicare physicians' services: an overview. AB - From 1978 to 1987, Medicare spending for physicians' services increased at annual compound rates of 16 percent, far exceeding increases expected based on inflation and increases in beneficiaries. As a result, Medicare spending for Part B physicians' services has attracted considerable attention. This article contains an overview of expenditure trends for Part B physicians' services, a summary of recent research findings on issues related to volume and intensity of physicians' services, and a discussion of options for controlling volume and intensity. The possible impact of the recently enacted relative-value-based free schedule on volume and intensity of services is discussed briefly. PMID- 10113399 TI - Hospital outpatient services under Medicare, 1987. AB - Presented in this article are data related to hospital outpatient services provided for aged and disabled Medicare beneficiaries during calendar year 1987. Trend data are also presented for selected calendar years 1974-87. Hospital outpatient covered charges and Medicare program payments (in total and per enrollee) are the statistics employed to measure the use of hospital outpatient services. The data contained in this article should provide information to help identify trends and patterns of care for monitoring the Medicare hospital outpatient services. PMID- 10113400 TI - Health expenditures in major industrialized countries, 1960-87. AB - In this article, levels and changes in health care expenditures for Canada, France, the Federal Republic of Germany, Italy, Japan, the United Kingdom, and the United States are analyzed. First, the levels and changes in the share of gross domestic product (GDP) devoted to health are reviewed in terms of the health-to-GDP ratio, nominal health expenditure and GDP growth, and changes in population and prices. Second, absolute levels of health spending denominated in U.S. dollars are compared over time. Finally, some concluding observations are made. PMID- 10113401 TI - Health care indicators. AB - Contained in this regular feature of the journal is a section on each of the following four topics: community hospital statistics; employment, hours, and earnings in the private health sector; health care prices; and national economic indicators. PMID- 10113402 TI - Revisions to the National Health Accounts and methodology. PMID- 10113403 TI - Findings from the Medicaid Competition Demonstrations: a guide for states. AB - The Medicaid Competition Demonstrations were initiated in 1983-84 in six States (California, Florida, Minnesota, Missouri, New Jersey, and New York). State experiences in implementing the demonstrations are presented in this article. Although problems of enrolling Medicaid recipients in prepaid plans or with primary care case managers under these demonstrations proved challenging to States, lessons were learned in three key areas: program design and administration, health plan and provider relations, and beneficiary acceptance. Therefore, States considering similar programs in the future could benefit from these findings. PMID- 10113404 TI - A reassessment of hospital product and productivity changes over time. AB - Were the changes found in the first year of the prospective payment system (PPS) one-time changes that attenuated as hospitals gained familiarity with the system? The results of this research show that, over time, discharges to home (self-care) continued to decrease, discharges to home health agencies continued to increase, but transfers and discharges to skilled nursing facilities or intermediate care facilities accounted for an increasing share of total discharges. After a dramatic decrease in the first year, the use of laboratory tests, diagnostic tests, and X-rays returned, over time, almost to pre-PPS levels. PMID- 10113405 TI - Setting capitations for Medicaid: a case study. AB - This article examines the methodology New York State used to set capitation rates for a Medicaid health maintenance organization. By examining the methods used and the assumptions made in a particular case, some general lessons are drawn about the ratesetting process. Greater reliance on statewide data to assure fair and statistically stable estimates is needed. Although the article focuses on one State and its ratesetting for one particular plan (Health Care Plus), the issues raised have general interest for other plans and for other States concerned with the setting of capitation rates for Medicaid enrollees in prepaid plans. PMID- 10113406 TI - Cost and volume trends in health care facility construction. AB - In 1987, the Health Care Financing Administration proposed adding capital cost reimbursement to the prospective payment system. A data base was developed from which an index was calculated to adjust for geographic variation in construction cost. Findings from the data base, along with a description of trends in health care facility construction from 1970 through 1986, are presented. Spending (in constant 1986 dollars) and volume of health care facility construction declined from 1970 to 1986. Construction cost per square foot increased until 1983, followed by a decline to pre-1980 levels after the 1983 implementation of the prospective payment system. PMID- 10113407 TI - Dependency and interdependency: the incomes of informal carers and the impact of social security. AB - Consideration of the income and social security needs of informal carers has remained conspicuously absent from discussions about 'community care'. Similarly, carers have been more or less invisible in the development of social security policies. This paper reports on a study of the financial circumstances of a sample of working age carers, who were living with and providing substantial amounts of help and support to a disabled person in the same household. The study highlights first, the substantial work-related costs incurred by carers with full time employment; and second the financial dependency of carers without full time earnings, on their spouse, sibling or on the person being cared for. The implications of these findings are discussed in the light of recent developments in social security policies. PMID- 10113408 TI - The effect of utilization review on hospital use and expenditures: a review of the literature and an update on recent findings. PMID- 10113410 TI - 100% nonionics: everything added up. PMID- 10113409 TI - Getting physicians involved in clinic resource allocation. PMID- 10113411 TI - Arthrography: is it a viable imaging modality? PMID- 10113412 TI - Nonionic agents: okay, they're safer--now what? PMID- 10113413 TI - Nonionic agents: okay, they're safer--but how much safer and at what cost to society? PMID- 10113414 TI - Hospital physician organizations. Models for success. AB - Physician group and hospital organizational arrangements can provide benefits such as improved capital formation, marketing clout, economies of scale, and increased profitability. PMID- 10113415 TI - Tool for the trade. PMID- 10113416 TI - An econometric model of an episode of mental health care for patients with mild conditions: implications for caregiver substitution. AB - This article presents a model of the number of hours of mental health care, the concurrent improvement in the patient's condition, the probability the patient will receive medications, and the reasons for treatment termination. The variables related to these aspects of mental health care are analyzed separately for patients of psychiatrists, psychologists, and social workers. Estimates of the average length of treatment, the average price and income elasticities, and the average cost of treatment are obtained from the model. The major conclusions from this study are that psychiatrists do not have a benefit-cost advantage in the treatment of relatively mild conditions, and that consumer responsiveness to variations in price appear to be largely confined to the decision to seek treatment. These and other findings provide a basis for making tentative recommendations about personnel substitution and reimbursement policies in mental health. PMID- 10113417 TI - NHT (nursing home type)--what does it mean? PMID- 10113418 TI - The refined diagnosis related groups system: an early look at its potential for Australia. AB - The DRG patient classification system is widely used in Australia, and its use is likely to increase. However, it has some weakness, including the failure to adequately take account of variations in resource use among patients in the same classes. A new version, called the Refined DRG (or RDRG) system became available in January 1989. Inter alia, it makes better use of data on secondary diagnoses; and defines three or four levels of resource use intensity for all major types of conditions, rather than just two levels for fewer types of conditions. The new system is briefly described. Some preliminary results of its use on Australian data are presented, which suggest that it does have advantages in terms of increased homogeneity of resource use in classes. If the RDRG system is to replace the DRG system as the international standard, there are some important implications for Australia. In particular, it would seem to be advisable for health agencies to plan for its imlementation on a national basis. PMID- 10113419 TI - The role of government in health care. PMID- 10113420 TI - Health care in the United States: whose responsibility? PMID- 10113421 TI - Congress takes modest action on Pepper Panel report. Home- and community-based services expanded. PMID- 10113422 TI - Push for combining LTC insurance/Medicaid fails. Proposals may resurface next year. PMID- 10113423 TI - Steps to cost-effective inservice training. PMID- 10113424 TI - Avoid the routine nursing care compliance gap. PMID- 10113425 TI - Successful interaction with physicians. PMID- 10113426 TI - Medicaid loopholes hurt everyone. Providers can take steps to counter abuses. PMID- 10113427 TI - State and federal reimbursement for home nutrition support. AB - Dietitians offer valuable services to home care agencies and their clients. In order to begin or continue providing such services agencies must be assured of adequate coverage. Since dietary and nutrition services are not covered, as such, under Medicare, agencies should consult with fiscal intermediaries, carriers, and home care accountants on billing and cost-allocation methods. PMID- 10113428 TI - Home parenteral nutrition for the patient with bowel syndrome and ostomy. AB - For patients who have lost all function of their gastrointestinal tract, home parenteral nutrition represents not just enormous costsavings over inpatient parenteral nutrition, it also allows patients to resume many of the routines of their daily life, at home. PMID- 10113429 TI - Healthcare data briefing. Healthcare: European comparisons. PMID- 10113430 TI - Tectonic forces driving healthcare reform debate. PMID- 10113431 TI - Health spending eludes recession. PMID- 10113432 TI - Managed-care projects strive for affordable long-term care. AB - Four small managed-care pilot projects are showing that long-term care can be provided affordably to senior citizens. Proponents say the prepaid health plans may provide a blueprint for the future role of hospitals in delivering and financing long-term care. PMID- 10113433 TI - Why such a hurry? AB - Over the past decade or so, federal health policy has chased health care costs that grew out of control largely because of federal intervention in the form of the Medicare/Medicaid programs. Having implemented a prospective pricing system for institutional providers, the government has followed up with a resource-based relative value system for physicians. The prognosis for this new effort may be no better than that for past attacks on health care costs, and the outcome could be substantially worse. PMID- 10113434 TI - Integration of quality assessment and physician incentives. AB - The ultimate challenge in dealing with any type of risk incentive system is to be able to integrate the quality of care and the cost of care into an equitable system and to monitor the system and detect either barriers to care or the withholding of appropriate services. We believe it is possible to do this and have based our incentive model upon this premise. At U.S. Healthcare, we have been successful in developing some measures of quality in the ambulatory setting and have tied the measurements to our payment mechanism. PMID- 10113435 TI - Measuring the quality of ambulatory care. AB - The challenge of the 1990s is measuring the quality of medical care. The author has developed a comprehensive matrix to measure the quality of medical care in an ambulatory setting. This matrix was designed with both patient-consumer and physician input. While the matrix has not been field-tested, it should be able to identify areas of weakness and strength and guide corrective actions. The author is now seeking funding for the testing that will be needed to make the matrix operational. PMID- 10113436 TI - Economic feasibility of a primary care practice. AB - To make informed career decisions, the new physician must acquire basic skills in medical management and health care economics and learn how to evaluate the potential survival and growth of a primary care practice. The authors have developed a model designed to aid physicians in determining the economic feasibility of establishing a practice in a specific community or joining an established practice. PMID- 10113437 TI - Medicare's physician payment reform. AB - The Omnibus Budget Reconciliation Act (OBRA) of 1989 continues the recent tradition of including far-reaching legislation in what ostensibly is a budget act. The Physician Payment Reform section of OBRA '89 amends Part B of Title XVIII of the Social Security Act by the addition of Section 1848. This article reviews the major substance of the amendment and analyzes the economic effects of the new section on the stakeholders (payers, providers, and consumers). PMID- 10113438 TI - Prospective payment system subject of Texas pilot test. PMID- 10113439 TI - State health care issues drive national policy agenda. PMID- 10113440 TI - A lesson in legal theft. AB - Yes, Mr. Hage admits the cost for health care is high--it's now 11% of the GNP. However, "society reaps real and tangible benefits from its availability," defends the author. This article questions a government which on the one hand denies appropriate care to many of those who need it most through health care cutbacks while on the other hand accepts a $500 billion bill for the S&L bailout. PMID- 10113441 TI - Non-salary retention incentives for social workers in public mental health. AB - While workers' reasons for leaving jobs are myriad, little is known of what might induce workers to remain in jobs. The literature reports that money, alone, is not sufficiently persuasive as an incentive. This study of social workers in the public mental health system in Colorado reveals the incentive value of a set of non-salary retention measures. The findings of the study show that measures which furthered professional enrichment, contribution to the profession, and the exercise of professional autonomy are rated most highly. Cross-tabulations with some demographic variables reveal significant findings. Recommendations for implementing the findings are presented. PMID- 10113442 TI - Diagnosis related groups, refined diagnosis related groups and pediatric modified diagnosis related groups in specialist children's hospitals. AB - The value of Diagnosis Related Groups, Refinement Diagnosis Related Groups and Pediatric Modified Diagnosis Related Groups in measuring the output of specialist children's hospitals was evaluated by the examination of discharge data for 1987 88 from three major Australian children's hospitals and four district hospitals. The study included all patients aged 0-18 years but excluded those with specific neonatal diagnoses. Findings indicated that Refinement Diagnosis Related Groups seem to give a better measure of the output of specialist children's hospitals than Version 5 Diagnosis Related Groups in that they explained a higher proportion of variation of length of stay. Pediatric Modified Diagnosis Related Groups developed in the United States of America for specialist children's hospitals overall did not seem to have major advantages over Refinement Diagnosis Related Groups but there were some specific Pediatric Groups that appeared beneficial. Further modification of the Refinement Diagnosis Related Groups could allow these advantages to be incorporated. Overall it seems preferable for there to be a similar system measuring output of both children's hospitals and general hospitals and this could be achieved by some minor changes to the Refinement Diagnosis Related Groups. PMID- 10113443 TI - Costs, technology, and insurance in the health care sector. PMID- 10113444 TI - Residential care communities integrate residents' needs. PMID- 10113445 TI - Cogeneration and its application in hospitals. PMID- 10113446 TI - Labor market trends for new college graduates. PMID- 10113447 TI - Beyond your paycheck: an employee benefits primer. AB - Most jobs are worth much more than their salaries. Paid vacations, sick leave, pensions, health insurance, and other benefits can add almost $3 to every $10 you earn in salary. PMID- 10113448 TI - Emerging careers. PMID- 10113449 TI - Ranking occupational earnings. PMID- 10113450 TI - Cultural changes challenge doctors. PMID- 10113451 TI - Containing health costs in the Americas. AB - In recent years, a series of policy measures affecting both demand and supply components of health care have been adopted in different Latin American and Caribbean countries, as well as in Canada and the United States. In applying these measures various objectives have been pursued, among them: to mobilize additional resources to increase operating budgets; to reduce unnecessary utilization of health services and consumption of pharmaceuticals; to control increasing production costs; and to contain the escalation of health care expenditures. In terms of demand management, some countries have established cost recovery programmes in an attempt to offset declining revenues. These measures have the potential to generate additional operating income in public facilities, particularly if charges are levied on hospital care. However, only scant information is available on the effects of user charges on demand, utilization, or unit costs. In terms of supply management, corrective measures have concentrated on limiting the quantity and the relative prices of different inputs and outputs. Hiring freezes, salary caps, limitations on new construction and equipment, use of drug lists, bulk procurement of medicines and vaccines, and budget ceilings are among the measures utilized to control production costs in the health sector. To moderate health care expenditures, various approaches have been followed to subject providers to 'financial discipline'. Among them, new reimbursement modalities such as prospective payment systems offer an array of incentives to modify medical practice. Cost-containment efforts have also spawned innovations in the organization and delivery of health services. Group plans have been established on the basis of prepaid premiums to provide directly much or all health care needs of affiliates and their families. The issue of intrasectorial co-ordination, particularly between ministries of health and social security institutions, has much relevance for cost containment. In various countries, large-scale reorganization processes have been undertaken to eliminate costly duplications of resources, personnel, and services that resulted from the multiplicity of providers in the public subsector. Given the pluralistic character of the region's health systems, an important challenge for policy makers is to find ways to redefine the role of state intervention in health from the simple provision of services to one that involves the 'management' of health care in the entire sector. PMID- 10113453 TI - The mentally incompetent patient: a perspective from the Competency Clinic. PMID- 10113452 TI - Ingredients for comprehensive consent to health care legislation. PMID- 10113454 TI - The unsafe workplace. PMID- 10113455 TI - The unsafe workplace: a hospital's perspective. PMID- 10113456 TI - Trends and patterns in place of death for Medicare enrollees. AB - Two changes in the Medicare program in 1983 may have affected where aged persons die--the change from retrospective hospital reimbursement to the prospective payment system and passage of the Medicare hospice benefit. Patterns and trends in where people die--hospitals, other institutions such as nursing homes, decedents' homes, and other places--for persons 65 years of age or over from 1980 through 1986 are examined. The proportion of deaths in hospitals declined somewhat after implementation of prospective payment. The hospice benefit may have caused the shift among cancer patients away from hospital deaths toward deaths at home. PMID- 10113457 TI - Medicare end stage renal disease population, 1982-87. AB - A synopsis is given between the relationship of the number of end stage renal disease (ESRD) patients to the total Medicare population and their associated expenditures. The aging trend within the ESRD population is examined in terms of enrollment statistics and incidence (new cases) counts. Also, longitudinal trends in expenditures, program enrollment, and incidence of ESRD are included. Findings indicate that the ESRD population is growing at a faster rate than Medicare in general. Further, within ESRD, the beneficiary population is aging. PMID- 10113458 TI - Omnibus Budget Reconciliation Act of 1989, Public Law 101-239. AB - On December 19, 1989, the President signed into law House Resolution 3299 as Public Law 101-239. Title VI of that law applies to Medicare, Medicaid, maternal and child health, and other health provisions; Title VIII contains human resource and income security provisions; and Title X contains miscellaneous and technical Social Security Act amendments. Following is a summary of the provisions that pertain to Medicaid. PMID- 10113459 TI - Payment to health maintenance organizations and the geographic factor. AB - The adjusted average per capita cost (AAPCC) payment system for Medicare risk based plans uses a county level geographic adjustment factor to account for differences in beneficiary costs across areas. The implications of abandoning the county unit as the basis of the geographic area are examined and the merging of counties to match the geographic definition used in the prospective payment system are considered. Year-to-year variation in a county AAPCC is inversely associated with county population size and, based on year-to-year AAPCC variation, 86 percent of all counties are too small to be used for the geographic adjustment. PMID- 10113460 TI - Quality of ambulatory care for the elderly: formulating evaluation criteria. AB - Efforts to assess the quality of ambulatory care services provided to Medicare beneficiaries cannot meaningfully proceed unless a concerted effort is made to develop criteria and standards for ambulatory care quality assessment that reflect the specific characteristics and needs of the elderly. In this article, we describe some of those characteristics and needs--such as physical and mental impairments and multiple coexisting conditions--and we show how they affect the care provided to the elderly and, therefore, the proper assessment of that care. We also outline an approach for the orderly development of the requisite criteria and standards. PMID- 10113461 TI - Procedure codes: potential modifiers of diagnosis-related groups. AB - Proposals to make complexity-of-illness adjustments to the diagnosis-related group system have relied on secondary diagnosis codes and additional clinical information obtained from the hospital record. Another potential mechanism for modifying diagnosis-related groups involves the use of non-operating room procedure codes. The use of these codes has the advantage of reliably identifying costly subgroups of patients and thus the potential to provide for fairer compensation to hospitals caring for the sickest patients. There are a number of disadvantages, however, and therefore the criteria with which to evaluate procedures as potential modifiers are suggested. PMID- 10113462 TI - Functionally and medically defined subgroups of nursing home populations. AB - The functional and health characteristics of nursing home residents in New York State using a multivariate classification procedure are examined in this article. This analysis suggested that these characteristics could be explained in terms of six dimensions. The association of these six dimensions with two existing sets of nursing home case-mix groups was analyzed in order to determine how groups based only on the health and functional characteristics of residents related to groups based primarily on measures of current service use. A number of resident characteristics were not described well by case-mix measures based only on service use, suggesting the need to modify such groups using additional sources of input. PMID- 10113463 TI - Medicaid prospective payment: case-mix increase. AB - South Carolina Medicaid implemented prospective payment by diagnosis-related group (DRG) for inpatient care. The rate of complications among newborns and deliveries doubled immediately. The case-mix index for newborns increased 66.6 percent, which increased the total Medicaid hospital expenditure 5.5 percent. Outlier payments increased total expenditure further. DRG distribution change among newborns has a large impact on spending because newborn complication DRGs have high weights. States adopting a DRG-based payment system for Medicaid should anticipate a greater increase in case mix than Medicare experienced. PMID- 10113464 TI - Structure and performance of health maintenance organizations: a review. AB - During the past decade, the number of and enrollment in health maintenance organizations (HMOs) have grown dramatically. In 1980, 236 HMOs served 9 million members. By 1989, there were 591 HMOs with over 34 million enrollees. New HMOs are very different in organizational structure and arrangements than the HMOs that were operating in the 1970s, and the health care markets they serve also have changed substantially with the increasing supply of physicians and declining hospital admissions. Consequently, the accepted research findings on HMO performance in the 1970s may have only limited usefulness in understanding the role of HMOs and their effect on today's market for health services. This is of particular concern as the Health Care Financing Administration considers the further expansion of managed care options available to Medicare and Medicaid beneficiaries. In this article, the author reviews evidence on the relationship between HMO organizational arrangements and performance, and the trends within the HMO industry toward new organizational structures. The implications for Medicare and Medicaid risk contracting are also examined. PMID- 10113465 TI - Health maintenance organization environments in the 1980s and beyond. AB - Throughout the past decade, health maintenance organizations (HMOs) were buffeted by dramatic regulatory and competitive changes. In this article, literature of the 1980s is reviewed to update our knowledge on the HMO industry and to suggest future research. The influence of intensified competition on these organizations and the determinants of market entry, expansion, and exit are examined. These organizations are now beginning to require copayments and deductibles and to offer point-of-service choice, while indemnity plans are developing sophisticated utilization management techniques. Given these significant structural changes, past distinctions among HMO, preferred provider organization and fee-for-service medicine must be replaced with a distinction between degree of provider choice and level of benefits. PMID- 10113466 TI - Financial performance in the social health maintenance organization, 1985-88. AB - Since early 1985, four social health maintenance organizations have delivered integrated health and long-term care services to Medicare beneficiaries under congressionally mandated waivers that included shared public-program risk for losses. Three of four sites had substantial losses in the first 3 years, primarily because of slow enrollment and resultant high marketing and administrative costs. After assuming full risk, two of the three showed surpluses in 1988. Service and management costs for expanded long-term care were similar across sites and were affordable within the framework of Medicare and Medicaid reimbursement and private premiums. PMID- 10113467 TI - The patient population of a major chain of investor-owned ambulatory care walk-in centers. AB - In sum, people go to a walk-in office for quick, convenient service, and overall they are happy with their experience. Although we cannot generalize from this case study of one chain of walk-in centers to walk-ins nationally, results from other studies of walk-in patient populations are approximately similar to ours. PMID- 10113468 TI - Interpreting the new Medicaid agreement. PMID- 10113469 TI - Health care for the elderly. What can we learn from Great Britain? PMID- 10113470 TI - Reports detail healthcare's robust performance. PMID- 10113471 TI - DRG study shows disparity among hospitals. PMID- 10113473 TI - Changing physicians' habits. PMID- 10113472 TI - Health industry waiting for final rules revamping Medicare coverage policy. PMID- 10113476 TI - Growth draws regulatory attention. Emerging long-term care insurance trends. PMID- 10113475 TI - Hospital Association calls for end to confusing patient billing system; recommends other regulatory changes. PMID- 10113474 TI - The provision of home health care services through health maintenance organizations: conflicting roles for HMOs. PMID- 10113477 TI - The Canadian and U.S. health care systems: profiles and policies. AB - Comparisons are made in this article between the Canadian and U.S. health care insurance and delivery systems. Canada has universal, comprehensive, and publicly funded health insurance for medically necessary hospital and physician services. The United States does not. Aggregate health care expenditures for both countries are examined as are those for the hospital and physician services sectors. Policy differences between both systems, including system models, health insurance financing, resource commitment and control, and service limits, are presented. Observations are made regarding two elements of the Canadian model--prospective physician sector and prospective hospital global budgeting--and whether they are transplantable to the United States. PMID- 10113478 TI - A cost-containment agenda for academic health centers. AB - Many people, particularly the business leaders and legislators who must find ways to pay most of the nation's health care bill, consider current and projected rates of health expenditure growth a serious problem. Effective solutions to this intractable problem have thus far eluded policymakers. The problem has complex and intertwined roots; its amelioration will require action by many players in the health sector. Academic health centers (AHCs), as the breeding ground for so much of the technological and organizational base of medical care and as the training ground for so many of the professionals in the health sector, bear some of the responsibility for the rate of health expenditure growth. Thus, they have a clear responsibility to help develop an effective response to this vexatious challenge. Three specific recommendations for steps the leaders of AHCs can take to assist in slowing the rate of growth in health care expenditures form the basis for this article. PMID- 10113479 TI - Low wages, poor benefits tied to nurse assistant turnover. PMID- 10113480 TI - More states may let patients say no to artificial life support. PMID- 10113481 TI - Hospital-based long-term care beds on the rise. PMID- 10113482 TI - 1991 software buyers guide. A listing of software providers servicing the long term care industry. PMID- 10113483 TI - How one Michigan hospital turned a losing situation under DRGs into a winning one. PMID- 10113484 TI - Mass. hospital expenditures above average. PMID- 10113485 TI - APGs coming. PMID- 10113486 TI - Perspectives. Long term care looks for long term gains. PMID- 10113487 TI - Medicaid home and community-based waivers for acquired immunodeficiency syndrome patients. AB - Acquired immunodeficiency syndrome (AIDS), an increasingly significant health problem, presents a special challenge to Medicaid programs. Analyzed in this article is one particular approach to providing services for Medicaid-eligible AIDS patients: the Medicaid home and community-based (section 2176) waiver program, authorized by the 1981 Omnibus Budget Reconciliation Act and amended in 1985 to include persons with AIDS. The authors conclude that the AIDS-specific waiver is an attractive program for the States, but that changes in program administration and in how cost effectiveness is determined would likely facilitate broader acceptance by the States. PMID- 10113488 TI - Medicaid mysteries: transitional benefits, Medicaid coverage, and welfare exits. AB - The links between Medicaid and welfare exits are examined using longitudinal Medicaid program data. Few people who leave welfare get any sort of ongoing or transitional Medicaid protection. Moreover, it appears that many who are eligible for transitional benefits are not getting them. Finally, people with high expected medical costs appear to be less likely to leave welfare. The loss of Medicaid associated with leaving welfare probably does have an important deterrent effect on welfare exists. PMID- 10113489 TI - Medicaid-financed residential care for persons with mental retardation. AB - Two sources of Medicaid support for persons with mental retardation and related conditions (MR/RC) are examined, the intermediate care facility for the mentally retarded (ICF/MR) program and the home and community-based services (HCBS) waiver. Results indicate that Medicaid support through the ICF/MR program has shown little recent growth in terms of number of persons served, although expenditures continue to increase. Medicaid's HCBS waiver is being used increasingly by States to support residential placement because of its greater flexibility and more individualized approach relative to ICF/MR care. Use of Medicaid to finance care for persons with MR/RC varies considerably across States. PMID- 10113490 TI - Trends in Medicaid payments and utilization, 1975-89. AB - Trends in Medicaid payments and utilization from 1975 through 1989 are examined in this article. Medicaid payments grew significantly over the period 1975-89, but the rate of growth was uneven. Total payments grew rapidly from 1975 through 1981, but the rate of growth slowed considerably from 1982 through 1988. Recent data suggests that there may be a new discontinuity in the series; payments increased sharply in 1989. Sectors that account for growth in the costs of the program are identified by examining who are served and what types of services they receive. The dynamics of change in Medicaid payments within sectors also are explored by examining changes in the number of people receiving services and the average payment per recipient. PMID- 10113491 TI - State initiatives for the medically uninsured. AB - Recently, Medicaid has changed in terms of both perception and reality. After a period of decline in entitlement, that trend has been reversed through both Federal mandates and an increasing role for Medicaid in dealing with the uninsured. As States and the Federal Government seek structural solutions, further eligibility expansions may be necessary, such as public subsidies of private insurance of using Medicaid as a reinsurance mechanism. Currently, there is considerable State activity in identifying such solutions. These activities have given us some ideas about what is necessary to expand coverage to more of the population. Continued demonstrations and better definitions of the respective roles of the private and public sectors are needed. PMID- 10113493 TI - Addendum: a brief summary of the Medicaid program. PMID- 10113492 TI - Medicaid, the uninsured, and national health spending: federal policy implications. AB - Implications are discussed for Federal policy of "gap-filling" initiatives at the State and Federal level to deal with the problem of the uninsured. Measures currently under active consideration that involve expansions of Medicaid and employment-related insurance are considered in the light of recent studies of the uninsured and recent simulations of their cost and coverage impacts. The limited impact of these gap-filling measures on additional national health spending, in contrast to program costs and Federal outlays, is emphasized. Placing greater emphasis on this broader societal perspective could assist Federal policymakers in developing an acceptable strategy for covering the uninsured. PMID- 10113494 TI - Perspectives on the Medicaid program. PMID- 10113495 TI - Deciphering Medicaid data: issues and needs. AB - The wide range of data bases that can be used for Medicaid analyses and research are reviewed in this article. The Health Care Financing Administration, State Medicaid agencies, and other groups have developed useful data bases and made them available to the public. Efforts could be made to obtain better quality national data, including annual reports on State participation, expenditures and program characteristics, and person-based data bases about medicaid clients and services. State-level analyses and research could be enhanced and disseminated more widely. More complex data collection and analysis efforts are an inevitable tradeoff for the flexibility of the Federal-State structure of Medicaid. PMID- 10113497 TI - Medicaid: challenges and opportunities. PMID- 10113496 TI - Accessibility and effectiveness of care under Medicaid. AB - We suggest a framework for assessing the accessibility, appropriateness, and outcomes of care to Medicaid recipients and review studies in these areas. Evidence is limited, and variation among States and the paucity of national data pose further problems. There is evidence that Medicaid recipients receive less medically necessary care (e.g., prenatal care) than the insured, but evidence on the quality of their care is limited. Differences in payment rates between Medicaid and private insurance appear to explain only part of the variance. Studies have demonstrated major direct effects of diminished access on health status. Evaluation of program changes should focus on health outcomes rather than counts of services rendered. PMID- 10113498 TI - Ambulatory practice variation in Maryland: implications for Medicaid cost management. AB - Simulation modeling with data from the Maryland Medicaid Management Information System has provided an opportunity to examine policy options and assess their likely impact on savings before program decisions were made. Analysis of a large sample of the Maryland Aid to Families with Dependent Children (AFDC) Medicaid subpopulation confirms that a significant difference in utilization and cost to Medicaid exists between usual sources of care for AFDC clients even after controlling for patient demographics and case-mix differences. Findings indicate that savings from reduced use of hospital outpatient departments may offset increases of as much as 40-50 percent in physician fees under certain assumptions. PMID- 10113499 TI - Medicaid and third-party liability: using information to achieve program goals. AB - With Medicaid programs in most States coming under ever-increasing fiscal pressures, the issue of third-party liability is receiving more attention and scrutiny. A relatively small investment in determining health insurance coverage can yield significant savings. In New York State's program, counties are compared and ranked to give a view of how well they are succeeding in identifying eligibles with third-party coverage. In addition, health insurance premiums are analyzed to determine if policies are cost effective. Other jurisdictions may benefit from this approach to program evaluation and enhancement. PMID- 10113500 TI - Improving state Medicaid programs for pregnant women and children. AB - Beginning in 1986, States have made the reduction of infant mortality a major policy priority. As progress on important maternal and infant health indicators has slowed and/or worsened. States have taken advantage of numerous Federal Medicaid options to implement innovative strategies to enhance low-income women's access to prenatal care and to improve the content of that care. Acting initially to expand Medicaid eligibility up to and above the Federal poverty level, States have moved to further improve programs by streamlining eligibility systems, enhancing outreach initiatives, attempting to recruit obstetrical providers into participating in Medicaid, and adding enriched nonmedical prenatal benefits to their State plans. Although policymakers must await formal evaluation results, State reforms appear encouraging. PMID- 10113501 TI - Preventive health care for Medicaid children. AB - In this article, we measure the extent to which California Medicaid children in 1981 received preventive care services through either the regular or the Early and Periodic Screening, Diagnosis, and Treatment component of Medicaid. On average, 62 percent of children up to 15 years of age who were continuously enrolled for that year had no preventive care visits, with the percentage increasing with age. Forty-five percent of children under 5 had no preventive visits paid by Medicaid. Children outside of urban areas received fewer preventive care visits than did urban children. PMID- 10113502 TI - Medicaid: a view from the front lines. PMID- 10113503 TI - Economic consequences for Medicaid of human immunodeficiency virus infection. AB - Medicaid is currently a major source of financing for health care for those with acquired immunodeficiency syndrome (AIDS) and to a lesser extent, for those with other manifestations of human immunodeficiency virus (HIV) infection. It is likely to become even more important in the future. This article focuses on the structure of Medicaid in the context of the HIV epidemic, covering epidemiological issues, eligibility, service coverage and use, and reimbursement. A simple methodology for estimating HIV-related Medicaid costs under alternative assumptions about the future is also explained. PMID- 10113504 TI - New Zealand health care: from ossification to action. PMID- 10113505 TI - Euthanasia and long-term care: values of the long-term care professional. AB - Nursing home administrators and other long-term care professionals appear positively predisposed toward respecting the autonomy of residents in decisions involving euthanasia and assisted-suicide. PMID- 10113506 TI - Stockless/just-in-time: the next step in inventory management. PMID- 10113507 TI - Is stockless/JIT right for your organization? It wasn't for ours. AB - The authors, investigating the feasibility of a stockless/JIT inventory management system in their hospital, developed a cost analysis model comparing the new system to their current system. This article presents this cost model and their conclusions for their institution. PMID- 10113508 TI - An emergency department perspective--Part one. AB - High patient volumes requiring rapid turn around times, critical decision making processes, and a necessity for establishing an accurate working diagnosis are a few of the many challenges in hospital emergency departments. Quality management, rather than quality assurance, most accurately describes how activities in the emergency department should be monitored to meet these challenges. Already an important factor in manufacturing and service industries across the United States, quality management will become the essential driving force in the health care industry. To survive in the '90s, the emergency department must include in its goals the development of plans and processes that meet the challenge of the ED environment and that focus on customer satisfaction. PMID- 10113509 TI - Helping physicians manage challenging patient encounters--Part I. AB - In today's rapidly changing and challenging health care environment, where physicians have limited time with patients who have become more knowledgeable and demanding, the relationship between physician and patient has extra stresses placed on it. Medical malpractice litigation has increased as the physician patient relationship has become more complex because of those stresses. In this article, some of the problems and effects of poor physician-patient interaction are explored, and a program designed to develop existing physician skills for successfully interacting with challenging patient encounters is described. In the January-February 1991 issue of Physician Executive, the author will describe the method of implementing the program in an organization. PMID- 10113510 TI - A new look at restrictive covenants. AB - While the restrictive covenant issue most often arises in medical group practice with the announcement of a physician's departure, addressing this issue in the planning phase of a group's operation will produce dividends for years to come. It allows preventive planning on these issues to be made in a less emotional context. PMID- 10113511 TI - A tale of two systems: a personal account of a successful consolidation. AB - "It was the best of times, it was the worst of times." This isn't a "tale of two cities." It's a tale of two Catholic health care systems in one city. For nearly a century, we were vigorous competitors. We were forced to consolidate our operations in 1987 as a result of the consolidation of our national Health Care sponsors. This is a detailed account of how that consolidation was achieved. PMID- 10113512 TI - 'Frail Elderly' bill to provide home, community care options. PMID- 10113513 TI - New Medicaid bureau get high marks. Better grasp of issues improves efficiency. PMID- 10113515 TI - Making a comeback. Integrating rehab into daily routines restores independence. PMID- 10113514 TI - Extra profit from enterals often overlooked. PMID- 10113516 TI - Aging issues for the year 2000. AB - Life expectancy has increased notably in the 20th century, bringing with it certain aging-related consequences. As America's population ages in the 1990s, long-term care issues--home care, eldercare, and personnel shortages--will dominate the public's attention. PMID- 10113517 TI - Home equity conversion and seniors: prolonging the American dream. AB - Many older Americans on fixed incomes struggle daily to meet ever-increasing living expenses. Ironically, the same inflation that has forced many senior citizens to tighten their economic belts has also increased the value of their property--a resource that can be tapped through home equity conversion. PMID- 10113518 TI - Reimbursement and financial issues influencing governmental agencies. PMID- 10113519 TI - Major elements of medical cost management--1990 and beyond. AB - This author sees hopeful signs that medical costs may be somewhat "manageable." He describes promising approaches to controlling costs, including a Pennsylvania system that has had some positive results. PMID- 10113520 TI - The return map: tracking product teams. AB - With a new product, time is now more valuable than money. The costs of conceiving and designing a product are less important to its ultimate success than timeliness to market. One of the most important ways to speed up product development is through interfunctional teamwork. The "Return Map," developed at Hewlett-Packard, provides a way for people from different functions to triangulate on the product development process as a whole. It graphically represents the contributions of all team members to the moment when a project breaks even. It forces the team to estimate and re-estimate the time it will take to perform critical tasks, so that products can get out fast. It subjects the team to the only discipline that works, namely, self-discipline. The map is, in effect, a graph representing time and money, where the time line is divided into three phases: investigation, development, and manufacturing and sales. Meanwhile, costs are plotted against time--as are revenues when they are realized after manufacturing release. Within these points of reference, four novel metrics emerge: Break-Even-Time, Time-to-Market, Break-Even-After-Release, and the Return Factor. All metrics are estimated at the beginning of a project to determine its feasibility, then they are tracked carefully while the project evolves to determine its success. Missed forecasts are inevitable, but managers who punish employees for missing their marks will only encourage them to estimate conservatively, thus building slack into a system meant to eliminate slack. Estimates are a team responsibility, and deviations provide valuable information that spurs continuous investigation and improvement. PMID- 10113521 TI - Characteristics of multiple admissions. PMID- 10113522 TI - Critical match points. PMID- 10113523 TI - Home intravenous therapy bibliography for pharmacists (1970-1989). AB - A comprehensive bibliography on home intravenous therapy is presented for use in developing a home health care pharmacy practice. Over 500 references representing 26 topics relevant to home care are included. Advantages of the bibliography over current on-line computer programs are discussed as are the limitations of this type of resource. PMID- 10113524 TI - Home health care--1991. PMID- 10113525 TI - Intravascular contrast media. PMID- 10113526 TI - The political dynamics of physician manpower policy. The case of Britain. PMID- 10113528 TI - The advent of hepatitis C testing. PMID- 10113529 TI - New hearing ordered in request to move brain-injured woman. PMID- 10113527 TI - Privatizing health care: caveat emptor. AB - Many Western European countries are moving toward privatization of their health care systems. The United States' health care system, since it is almost entirely privatized, is therefore worthy of study. Doing so raises several questions. How is privatization being managed in the US? How could its management be improved? What management lessons must be kept in mind if it is to be used effectively? What potential pitfalls should European countries consider as they move toward greater privatization? With operating costs, European countries must avoid the mistakes that have led to dramatic increases in annual health care costs in the US, simultaneous with reductions in access and quality. Doing so requires designing systems that promote hospital behavior consistent with a country's health objectives. With capital costs, an approach must be designed that allows policy-makers to work closely with both managers and physicians in order to make strategically sound choices about access and quality. Such an approach will require physicians to incorporate their clinical judgments into community standards of care, and to adopt a regional (rather than an institutional or personal) perspective in the determination of any incremental capital expenditures. By making regulation proactive and strategic, rather than punitive, health policymakers in Western Europe can achieve the best privatization has to offer without feeling the sting of its unintended consequences. In so doing they can help to move their health systems toward achieving the multiple and illusive goals of access, quality and reasonable cost. PMID- 10113531 TI - Medicaid spending rises in New Mexico. PMID- 10113530 TI - Hearings turn attention to long-term-care issues. PMID- 10113532 TI - Financing health care: out of whose pocket? AB - Health expenditures have grown steadily in the United States, but though United States spending is the highest in the world, it may not be as far out of line as is often assumed. However, although the economy is capable of absorbing an increasing amount of health care without reducing other consumption, financing mechanisms are breaking down. That part of Medicare financed through payroll taxes will be insolvent by the year 2003; the rest of Medicare and all of Medicaid adds to a growing budget deficit. And, the free market fails to provide rational long-term financing of long-term care. PMID- 10113533 TI - US health care policy in 1990: looking back, looking ahead. AB - Health policy in the United States is best understood as a policy of incrementalism with major interventions occurring only in response to crisis, as in the case of the Medicare legislation that profoundly altered our historic financing of health care. The characteristically minor, unplanned, adjustments that are made often have major unanticipated consequences, and these serve to explain the radical transformation of the nation's health system in the half century since World War II. The main elements in this change--the evolution of employment-tied private insurance for the majority of the population, the predominance of specialism and superspecialism in medical practice, the expansion of the voluntary hospital system with capital liberally raised through tax-exempt bond issues, advancing technology and medical capability are reviewed. The major persistent policy issues--uncontrolled expenditures and the increasing numbers of uninsured--will ultimately precipitate change, perhaps by the end of the decade, very likely a minimum benefit, universal federal-state insurance system, supplemented by the private market--hardly radical systemic reform. PMID- 10113534 TI - Technology as culprit and benefactor. AB - Technologies can be viewed as a mixed blessing: rising health care costs versus improved diagnosis, treatment, and health status. This article briefly discusses the influence of key factors on the demand for technology and its utilization. These factors include rising health expenditures, changes in populations, and the development of cost containment strategies. Resulting shifts in incentives and utilization are examined. Because of the difficult and complex issues associated with the increasing use of medical technologies, hard choices will need to be made about quality of life, technology assessment, and the allocation of health resources to the terminally ill. PMID- 10113535 TI - Financing health care. AB - This article reviews the causes of growth in health care costs and concludes that only changes in the rate of growth in intensity of care are likely to be effective. It proposes a model of consumer choice (with advice) among health plans, and competition among plans on the basis of the rate at which new technology is introduced, as a solution to the problem of picking the appropriate rate. It argues that the existence of the uninsured is evidence of government failure. PMID- 10113536 TI - The problem of attaining an efficient capital stock. AB - Serious problems exist with the nature of health care financing in the United States. This article summarizes problems caused by the high cost of serving an aging population, the lack of incentives in insurance plans for preventive care, and the growing number of uninsured people in the population. The article then focuses on efforts to bring about greater efficiency by changing the contractual relations between the principal--either the payor or the patient--and the agent- the provider. These new contracts attempt to place a greater share of the financial burden on the provider. Evidence of the success of these new contracts is mixed. The major point of the article is that real efficiencies will not be reached unless these incentive mechanisms together with competitive market forces relieve the excess capacity in the health care industry. PMID- 10113537 TI - Health care expenditures for the elderly: a current and future dilemma. AB - Financing health care for the elderly is becoming a familiar topic in the popular press. Considering that those aged 65 yr and older constitute 12% of the population and consume about 30% of all health care expenditures, health care financing for the elderly makes a timely and interesting topic. In this paper the financing issue is addressed. With the elderly, on average, becoming more affluent, the issue of self-financing must be explored. This of course does not mean the elimination of Medicare but possibly development of a different/alternative approach. As part of our analysis, the potential political pressure from the younger generation is considered. PMID- 10113538 TI - Screening strategies to inhibit the spread of AIDS. AB - In this paper we explore the costs and benefits of screening programs for the human immunodeficiency virus (HIV). Because of the low prevalence rate of the virus among the general population, the cost per detected case of a program to screen the population at large is very high. We show how this cost changes with the prevalence rate, and how screening high risk groups reduces the cost per detected case. Screening has little point, however, unless there are follow-up activities to reduce the continued spread of the virus. To this end, we present a modeling framework for determination of optimal policy alternatives after screening. PMID- 10113539 TI - A new estimate of the welfare loss of excess health insurance. PMID- 10113540 TI - Living benefit options: another way to finance long term care. PMID- 10113541 TI - Entry level jobs: defining them and counting them. PMID- 10113542 TI - Medicare future: increasing pressure for radical reform. AB - Despite efforts to trim the Medicare budget, some predict that the program will consume nearly one-eighth of the federal budget by 1995. Keeping this in mind, the federal government may pursue other avenues of reform--some perhaps radical- to restrain Medicare cost growth. PMID- 10113543 TI - Targeting Medicare in the Federal budget: an annual event? AB - When it came time to reduce the 1991 federal budget, it was not surprising that the budget cutters set their sights on Medicare to reduce the deficit. But why does Medicare appear to be such a major target at budget time, and when are "cuts" really cuts? PMID- 10113544 TI - Promoting healthy behaviour: the importance of economic analysis in policy formulation for AIDS prevention. AB - Considerable attention has been paid in the literature to modification of high risk behaviours as a means to control the spread of the Human Immunodeficiency Virus. The success of such policies will depend crucially on the underlying causal mechanisms of these high-risk behaviours. To date the application of economics to the problem of AIDS has tended to focus on estimating the economic burden of the condition and the resource consequences of clinical strategies for care. Yet as a behavioural science economics should provide a useful input into the policy process aimed at behaviour modification. In this paper we extend the application of economic analysis to the determinants of individual behaviour to identify (i) the implications of current policies for the incidence of high-risk behaviour and (ii) the wider determinants of behaviour warranting greater attention in the policy-making process. PMID- 10113545 TI - Switching drugs from prescription-only to over-the-counter availability: economic benefits in the United Kingdom. AB - Recent years have seen suggestions that legislation restricting certain drugs to prescription-only availability should be relaxed. This paper estimates the economic benefits of such changes, with specific reference to two drugs recently switched in the United Kingdom: Ioperamide and 1% topical hydrocortisone. The findings suggest that making these products available from the pharmacy without a prescription has resulted in substantial benefits by reducing costs to consumers and saving general practitioners' time. In view of these benefits, the disadvantages of such changes should be evaluated. PMID- 10113546 TI - Costs and benefits of early detection of prostatic cancer. AB - During recent years prostatic cancer has emerged as an increasing health problem in many countries. However, there is reason to believe it can be cured if detected at an early stage while still confined to the prostate. An effective screening programme could thus alter the natural history of the disease and reduce the overall mortality. But the benefit of such a programme is still under debate. A pilot programme using rectal-digital examination to investigate organisational, social and economical aspects was carried out. This information was then used to estimate the consequences of routine prostatic screening in the Swedish health service with aid of a decision analysis model. The study shows that prostatic cancer screening by rectal-digital examination can be organized as an integral part of primary health care, with high acceptance by the public. The total economic burden of screening on the health care sector will be high. The total expected health care cost in Sweden for all diagnosed prostatic cancers during the next 2 years, without screening, was estimated to be 53 million USD (in 1989 prices). 1048 patients were expected to be offered some potentially curative therapy. With rectal-digital examination the total cost during the next 2 years would be 131 million USD and 6522 patients would be given treatment. Alternatively, with transurethral ultrasound examination, the total cost would be 174 million USD and 10275 patients would receive potentially curative therapy. The ultimate health benefits of potentially curative treatment remain uncertain. Until we have scientific evidence of the cost-effectiveness of this method the model presented for analysing the consequences of different strategies could well prove helpful in policymaking for this complex problem. PMID- 10113547 TI - An income-weighted international average for comparative analysis of health expenditures. AB - Data from 17 countries across 28 years are used to estimate an international health expenditure function based on real per capita GNP. Actual and expected spending levels are compared for 24 countries. Between 1960 and 1987, it has been rare for health expenditure in any country to be more than +/- 20 per cent from the projected value. The norm is for spending to rise at 1.5 times the growth rate of GDP. Two countries appear to display significant anomalies. Spending in the United Kingdom is consistently 15-25 per cent below normal for all years, and Danish expenditure has declined from 7 to 6 per cent of GDP since 1975. PMID- 10113548 TI - Health sector planning led by management of recurrent expenditure: an agenda for action-research. AB - Health services in developing countries face a crisis of recurrent costs. Far from being able to fund primary health care (PHC) developments, governments now have difficulty in keeping existing health services in operation. This article proposes an approach to the problem based on the proactive planning and management of recurrent health expenditure. The system addresses existing services as well as future plans and allows explicit trade-offs to be made in resource allocation. This may be termed 'recurrent-expenditureled planning'. The article describes a diagnostic health sector review, which incorporates a recurrent expenditure profile in four planes: by type of provider, source of finance, level of care and recipient population group. A fifth dimension of time trends for certain expenditure categories can be added. The steps of a strategic planning cycle for health services resources are then described, which allows health service strategies to be tested for broad economic feasibility. It also results in the establishment of resource targets that can act as benchmarks against which actual levels of funding can be compared. The targets help to maintain sectoral priorities in resource allocation even in times of economic constraint and to channel funds preferentially to localities and facilities in greatest need. The system calls for innovations in the methods of health planning and financial management in the health sector. Implementation will require health systems action-research at the country level. The essential purpose is to promote PHC policy-led resource allocation and use. No amount of planning can substitute for political action to realize 'health for all', but this system provides technical support to the political forces in favour of distributive PHC policies. PMID- 10113550 TI - Take radical approach to cost control, report urges. PMID- 10113549 TI - Management implications of DRGs in hospitals. PMID- 10113551 TI - A time-ordered, systems approach to quality assurance in long-term care. AB - This article clarifies concepts and theories used in quality assurance and their applications and offers a time-ordered conceptual framework for quality assurance standards and indicators, emphasizing the necessity for balance among them. Processes of monitoring and feedback are discussed as major components of quality assurance systems. This time-ordered, systems approach to quality assurance was applied to home care services in Ohio. This theoretical perspective is related to current public policy aimed at nursing home reform. PMID- 10113553 TI - Quality assurance in long-term care. PMID- 10113552 TI - Assessing the impacts of community-based health care policies and programs for older adults. AB - This article presents a framework for evaluating long-term care policies and programs to determine how well community-based programs benefit the older adult population. Equity, accessibility, quality, and efficiency are identified as core criteria for implementing and evaluating long-term care policy. Special problems with conducting process and/or outcome evaluation of community-based programs are noted, and findings of evaluation research on community-based health care programs are reviewed. Most previous research indicates that community-based health programs for older adults are not a substitute for institutional care and do not reduce either informal caregiving or ambulatory medical services. The article concludes with policy implications. PMID- 10113554 TI - Nursing home quality: a framework for analysis. AB - Previous efforts to evaluate nursing home quality have been hampered by the lack of a conceptual model that specifies the major components and specifically associates measurable indicators with quality. An extensive literature review reveals many fragmented pieces of information, but no framework in which to fit the pieces together. The model presented here identifies four major dimensions of nursing home quality: (a) staff intervention, (b) physical environment, (c) nutrition/food service, and (d) community relations. These dimensions go beyond traditional "quality of care" by including quality-of-life considerations as well. The dimensions are each further divided into two subdimensions. I propose that measurable indicators for each of these eight subdimensions can be combined to make an effective and comprehensive quality measure. PMID- 10113555 TI - Medicaid's effect on the elderly: how reimbursement policy affects priorities in the nursing home. AB - This article examines the social impact of Medicaid policy on the elderly in long term care and identifies a previously unrecognized problem produced by Medicaid in New York State. Recent fieldwork in proprietary nursing homes in New York City shows that this state's Medicaid system results in a selection hierarchy on admissions and within nursing homes not only in terms of sponsor of payment but also in value, based on residents' functional level. Specifically, New York State Medicaid's Resource Utilization Groups (RUGs II) system is responsible for a new and startling phenomenon in long-term health care of the elderly: the creation of "minihospitals" in lieu of traditional skilled nursing facilities. This problem indicates the complex ways in which reimbursement policy drives priorities in nursing homes and creates unintended negative outcomes. In light of this consideration, various policy alternatives to Medicaid that would improve the plight of the elderly in long-term care are suggested and evaluated. PMID- 10113556 TI - The quality of home and community-based services. AB - The quality of long-term home health services is particularly difficult to study because of (a) the multidimensionality and chronicity of patients' needs, (b) the complexity of and the number of social and health-related services provided, (c) the isolation of care in individual homes, and (d) the lack of norms and standards on which to base judgments. A study was undertaken of the quality of care received by two client groups receiving home- and community-based services, in which some of these difficulties were addressed. An expert committee of home health practitioners wrote criteria for process and outcomes of care based on local norms of practice. Applying these criteria to the care received by the study groups, the committee found a high degree of quality of care. Specific problems identified in the care were a lack of appropriate case management and poor chart documentation. In most cases, if good care was received, the client experienced good outcomes. PMID- 10113557 TI - Possible implications of the Environmental Protection Act for clinical (hospital) waste incineration--the in-house options available. PMID- 10113558 TI - Ensuring care for infants and children who require technological support at home. PMID- 10113559 TI - National health expenditures, 1989. AB - Spending for health care in the United States grew to $604.1 billion in 1989, an increase of 11.1 percent from the 1988 level. Growth in national health expenditures has been edging upward since 1986, when the annual growth in the health care bill was 7.7 percent. Health care spending continues to command a larger and larger proportion of the resources of the Nation: In 1989, 11.6 percent of the Nation's output, as measured by the gross national product, was consumed by health care, up from 11.2 percent in 1988. PMID- 10113560 TI - Giving physicians incentives to contain costs under Medicaid. AB - In this article, the risk arrangements in Medicaid programs that put physicians at risk are summarized. These programs--partial capitation and health insuring organizations--pay physicians a capitation amount to cover some or all physician services. Physicians also receive part of the savings from reduced hospitalization. Most of these programs have successfully lowered Medicaid costs. They could serve as models for other Medicaid programs, State-level programs to cover people ineligible for Medicaid, and programs abroad, such as in the United Kingdom. PMID- 10113561 TI - Use of Medicare-covered home health agency services, 1988. AB - From 1974 through 1983, Medicare-covered home health visits and expenditures increased at double digit rates (18.4 and 29.0 percent annually, respectively). During the period from 1984 through 1987, intensified bill review by fiscal intermediaries and increased denial rates led to a decline in the number of home health visits. New reimbursement policies led to a markedly reduced rate of increase in the payments for home health services. By 1988, the use of and expenditures for home health services resumed rising. In this article, the trends in home health service use and expenditures are presented and the changes in legislation and policies that affected them are discussed. PMID- 10113562 TI - The burden of health care costs: business, households, and governments. AB - In this article, the authors recast health care costs into payer categories of business, households, and Federal and State-and-local governments which are more useful for policy analysis. The burden that these costs place upon the financial resources of each payer are examined for 1989 and for trends over time. For businesses, their share of health care costs continues to creep upward compared with other payers and relative to their own resources, despite many changes they are making in the provision of employer-sponsored health insurance to their employees. PMID- 10113563 TI - Health care indicators. AB - Contained in this regular feature of the journal is a section on each of the following five topics: community hospital statistics; employment, hours, and earnings in the private health sector; health care prices; hospital skill mix changes: 1980s; and national economic indicators. PMID- 10113564 TI - Changes in Medicare skilled nursing facility benefit admissions. AB - In this article, the changes in Medicare skilled nursing facility (SNF) benefit admissions from 1983 through 1985 are examined and factors that influence changes in access since the implementation of Medicare's prospective payment system are analyzed. During this period, use of the SNF benefit increased nationally by 21 percent. Multivariate analysis is used to determine factors associated with changes in admissions. Changes in SNF benefit admissions were found to be negatively associated with changes in area hospitals' lengths of stay and changes in hospitals' discharges. Medicaid reimbursement policies were also shown to affect changes in utilization. PMID- 10113565 TI - Medicaid payment rates for nursing homes, 1979-86. AB - The issue of the cost containment effects of payment systems on per diem payments by Medicaid to nursing homes is addressed. Estimates of real payment rates as a function of broadly defined payment system classifications and economic and demographic variables using State-level data are presented. Little support for the notion that prospective payment systems substantially restrain payment rates for intermediate care facilities is found, but some model specifications indicate possible cost savings associated with prospective payment systems for skilled nursing facilities. Significant methodological concerns that need to be addressed in future research on the cost containment effects of payment systems are also discussed. PMID- 10113566 TI - Hospital back-up days: impact on joint Medicare and Medicaid beneficiaries. AB - In this article the question of whether nursing home market characteristics affect the ability of hospitals to discharge patients to nursing homes is examined. Also examined is the question of whether joint Medicare and Medicaid beneficiaries have a more difficult time being placed than do other patients. The principal conclusions are first, that the nursing home bed supply and the type of Medicaid payment system affect the ability of hospitals to discharge patients to nursing homes. Joint Medicare and Medicaid beneficiaries have a more difficult time being placed in nursing homes in States with fewer beds and more restrictive Medicaid payment policies, and joint beneficiaries do not appear to have longer stays in hospitals. Rather, they have a greater likelihood of being discharged to home. PMID- 10113567 TI - Medicare risk contracting: determinants of market entry. AB - The Tax Equity and Fiscal Responsibility Act (TEFRA) of 1982 made it more attractive for health maintenance organizations (HMOs) and other competitive medical plans to enter into risk contracts with Medicare. Since the start of the TEFRA program in April 1985, more than 160 HMOs have had risk contracts with Medicare under the program. An investigation of factors associated with TEFRA risk-market entry at the end of 1986 revealed that high adjusted average per capita cost payment levels, prior Medicare cost-contract experience, and prior Federal qualification were the most important factors distinguishing market entrants from nonentrants. PMID- 10113568 TI - Comparison of alternative weight recalibration methods for diagnosis-related groups. AB - In this article, alternative methodologies for recalibration of the diagnosis related group (DRG) weights are examined. Based on 1984 data, cost and charge based weights are less congruent than those calculated with 1981 data. Previous studies using 1981 data demonstrated that cost- and charge-based weights were not very different. Charge weights result in higher payments to surgical DRGs and lower payments to medical DRGs, relative to cost weights. At the provider level, charge weights result in higher payments to large urban hospitals and teaching hospitals, relative to cost weights. PMID- 10113569 TI - How much change in the case mix index is DRG creep? AB - We re-abstracted a nationally representative sample of 7,887 Medicare charts to determine how much of the change in Medicare's Case Mix Index between 1986 and 1987 was true change in the complexity of cases and how much was upcoding or 'DRG creep'. About two-thirds of the change is true. Most of the remaining third is attributable to a general change in the completeness of coding; some is attributable to changes in the Grouper program. Thus, most of the additional $1 billion paid to hospitals because of the Case Mix Index change appears justified by the additional complexity of patients hospitalized. PMID- 10113570 TI - Measuring real case mix change under Medicare's prospective payment system. PMID- 10113571 TI - The nurse is chief investigator in care planning process. PMID- 10113572 TI - Knowing when to pull the plug. Several key factors reveal when it's time to terminate a program. PMID- 10113573 TI - Executive message ... accuracy of diagnostic coding for Medicare patients under the prospective payment system (PPS). PMID- 10113574 TI - Economic evaluation in health care: is there a role for cost-benefit analysis? AB - This paper is devoted to the contingent valuation (CV) method and its possible area of application in health economics. With the CV method willingness to pay or willingness to accept is measured with survey methods. The CV method has been developed in environmental economics and is now the most commonly used method of measuring environmental benefits. The method has, however, seldom been used in economic evaluations of health care. The development of economic evaluation in the health care area is reviewed, and the existing methods (the human capital approach, cost-effectiveness analysis and cost-utility analysis) are compared with cost-benefit analysis using the CV method. It is shown that existing methods have several weak points, this makes the CV method an appealing alternative and/or complement to existing methods. From the empirical applications of the CV method in economic evaluations of health care it is evident that it is possible to achieve acceptable response rates. The methodological problems encountered when measuring willingness to pay with survey methods are shown to be similar to the problems encountered when measuring utility and quality of life in cost utility analysis. Further studies with the CV method are necessary to further explore questions concerning the reliability and validity of the method. PMID- 10113576 TI - Proposals promote long-term-care insurance. PMID- 10113575 TI - Budget deficits threaten to shut out Medicaid benefits. AB - Revenue shortfalls are prompting state officials to seek creative ways to keep their Medicaid programs afloat. Some tactics include voluntary provider contributions and provider taxes to increase federal matching funds and paring back on the number and kind of benefits that states offer. Hospital groups, meanwhile, are starting their own grass-roots campaigns to shield Medicaid from crippling budget cuts. PMID- 10113577 TI - New directions in health-care financing: their impact on EMS. PMID- 10113578 TI - The high cost of customization: compounding drugs. AB - Physicians wishing to make a special compound for an inpatient for the first time, should contact the pharmacy well in advance of its need. Physicians should consider that the cost of compounding is very expensive. Furthermore, it is often less accurate in its dose than manufactured products. This is particularly important to remember with regards to mg/kg dosing. Provided certain conditions are met, the pharmacy will specially compound a product for an inpatient, if it has the ability to do so. Currently, the pharmacy cannot compound or dispense products for outpatients, or provide special compounding services to the BUSM, labs, departments, or clinics. If there are any questions about what can or cannot be done in the way of special formulations, contact the Pharmacy. PMID- 10113580 TI - Technology faces HCFA cost test. PMID- 10113579 TI - Healthcare spending up sharply. PMID- 10113581 TI - Withholding nutrition and hydration: some old and new questions. AB - Discusses the question, Are a patient's best interests ever served by the removal of artificial nutrition and hydration supports? Poses ethical and theological questions generated by the case of Nancy Cruzan and offers an outline of necessary conditions which ought to be present to make the withholding of artificially induced nutrition and hydration morally licit. PMID- 10113582 TI - Health care: shifting the blame as well as the cost. PMID- 10113583 TI - Let's expose medicine's real price-gougers. PMID- 10113585 TI - Growing beyond game playing: LTC insurance enters adolescence. PMID- 10113584 TI - Observation beds--is it the missing link? PMID- 10113586 TI - Reducing med pass risks. PMID- 10113587 TI - The funding debate revisited: who's for the mixed economy? PMID- 10113588 TI - Does reconciling charges still make sense? PMID- 10113589 TI - Marketing and health care implications of hospitals adapting to DRG reimbursement for Medicare clients. AB - The mounting financial pressures placed on acute care facilities have resulted in many closings and mergers. They have impacted patient services and other traditional areas of hospital concern. The adoption in 1983 of the Prospective Payment System of reimbursement for Medicare clients has forced increased scrutiny by hospitals of length of stay. This study reviewed the pattern of length of stay (LOS) of all 553 Medicare clients referred for assistance with discharge planning through utilization of home care coordination in a midwestern, 150-bed, acute care hospital in 1989. This descriptive, retrospective study anonymously compiled basic demographic data of all such clients in addition to DRG, LOS, and time of initiation of discharge planning activities by the Home Care Coordinator (HCC). One finding of the correlational statistical analyses showed that as the number of days from the clients' admission to HCC contact increased overall LOS increased. Strong implications exist regarding nursing involvement with discharge planning. Identifying needs and making prompt referrals by members of the health care team can provide positive outcomes for clients and the hospital. Impact on the image and reputation of the hospital from early intervention for discharge planning caused by DRG reimbursement clearly pose marketing problems. This paper identifies areas in which appropriate market opportunities may be discovered and addressed as the hospital makes necessary adaptations to DRG reimbursement. PMID- 10113590 TI - An exploration into elderly consumers' responses to direct marketing appeals of health care. PMID- 10113591 TI - Quality assurance: the team approach. AB - Measuring quality has become an integral part of nursing facility operations. This cover story examines the components of a successful quality assurance program and how facilities across the country have implemented programs that meet the needs of facility residents and staff. PMID- 10113592 TI - Art appreciation courses can become "museum without walls.". PMID- 10113593 TI - 1991 corporate profiles. PMID- 10113594 TI - Review of physician documentation--identifying a better sample. PMID- 10113595 TI - Restructuring medicine: mega-groups, super clinics and "medical groups without walls". PMID- 10113596 TI - The initial impact of the Medicare prospective payment system on U.S. health care: a review of the literature. PMID- 10113597 TI - The right system at the right time. PMID- 10113598 TI - A formula for funding. PMID- 10113599 TI - People who need care and the people who care for them: personal views of a geriatrician. PMID- 10113600 TI - Our army of doctors is waging war on health costs. PMID- 10113601 TI - Information sharing in the managed care setting. AB - In this article, the author describes how physicians in independent practice associations can benefit from the use of information exchanges and illustrates by describing a method for balancing costs and quality in the managed care setting that was developed via an information exchange. PMID- 10113602 TI - Summit to spin off unit in IPO. PMID- 10113603 TI - Home-care companies' offerings take off. AB - Some home infusion therapy companies have been the beneficiaries of cash infusions thanks to the bullish reception of public offerings this year. The lucrative industry, reimbursed primarily by private payers and one of the fastest growing in healthcare, has long been a favorite on Wall Street. The companies plan to use proceeds from the successful offerings to pay off debt and finance expansion. PMID- 10113604 TI - Voluntary spending target proposal gets mixed reviews. PMID- 10113605 TI - Maintaining standards at reduced costs. PMID- 10113606 TI - Home care: the cornerstone of long-term care for elderly Americans. AB - The only solution to America's devastating long-term care problem among the nation's elderly is the enactment of a federally funded program under which disabled and chronically ill individuals--regardless of their ability to pay--are eligible for a broad range of home-based services. PMID- 10113607 TI - Regulation of private long-term care insurance. AB - There has been a significant improvement in the quality of private long-term care insurance policies in the past five years. As the market continues to mature, national standards need to be assessed and strengthened to protect the consumer. PMID- 10113608 TI - Long-term care offers opportunity for revenue. AB - Hospital administrators already know that diversification will be a key to success in the future. Applying that philosophy to long-term care of the elderly is just one way to capture a growing consumer market. In the following article, the author addresses three potential variations for delivering such care by the hospital to this group. PMID- 10113609 TI - Planning indicators. Next decade to focus on long-term care, outpatient services. PMID- 10113610 TI - Measuring hospital input price increases: the rebased hospital market basket. AB - The input prices indexes used in part to set payment rates for Medicare inpatient hospital services in both prospective payment system (PPS) and PPS-excluded hospitals were rebased from 1982 to 1987 beginning with payments for fiscal year 1991. In this article, the issues and evidence used to determine the composition of the revised hospital input price indexes are discussed. One issue is the need for a separate market basket for PPS-excluded hospitals. Also, the payment implications of using hospital-industry versus economywide measures of wage rates as price proxies for the growth in hospital wage rates are addressed. PMID- 10113611 TI - Medicare expenditures for physician and supplier services, 1970-88. AB - The trend data in this article focus on Medicare expenditures and allowed charges for physician and supplier services rendered during the period from 1970 through 1988. A brief overview is presented on the provisions of the new Medicare physician payment system mandated by Congress and scheduled to be phased in starting January 1, 1992. The data provide one of the baselines that could be used for measuring and evaluating the impact of the new Medicare payment system for physician services. PMID- 10113612 TI - Social health maintenance organizations' service use and costs, 1985-89. AB - Presented in this article are aggregate utilization and financial data from the four social health maintenance organization (S/HMO) demonstrations that were collected and analyzed as a part of the national evaluation of the S/HMO demonstration project conducted for the Health Care Financing Administration. The S/HMOs, in offering a $6,500 to $12,000 chronic care benefit in addition to the basic HMO benefit package, had higher start up costs and financial losses over the first 5 years than expected, and controlling costs continues to be a challenge to the sites and their sponsors. PMID- 10113613 TI - Patterns of outpatient prescription drug use among Pennsylvania elderly. AB - The Pennsylvania Pharmaceutical Assistance Contract for the Elderly (PACE) provides outpatient prescription drug coverage for nearly one-half million State residents 65 years of age or over with income under $15,000 per year. A description of the PACE program is provided herein, along with data and multivariate results relating to the demographic characteristics of PACE beneficiaries, duration of enrollments, drug utilization and expenditure rates, average prices for covered prescriptions, and drug expense distributions. PMID- 10113614 TI - Health care cost containment in the Federal Republic of Germany. AB - Since 1977, cost containment has been an integral part of health policy in the Federal Republic of Germany. The common goal of the cost-containment acts was to bring the growth of health care expenditures in line with growth of wages and salaries of sickness fund members. The Health Care Reform Act of 1989 is the most recent manifestation of this policy. The main features of the numerous cost containment acts are described in this article, and the effects of cost containment on supply and demand are analyzed. PMID- 10113616 TI - Trade-offs for German physicians: a look at income and supply. AB - Most health policy experts agree that Germany has proved successful at restraining health care expenditures, but what price do physicians pay for this efficiency? A policy analyst for the American Medical Association examines some of the drawbacks physicians are encountering. PMID- 10113615 TI - The German health care system: a close-up view. PMID- 10113617 TI - Wishful thinking and the clamor over administrative 'waste'. PMID- 10113618 TI - Healthcare spending continues to increase. PMID- 10113619 TI - Facilities slow to join Medicaid HMOs. AB - Hospitals generally have been slow to get involved in public-sector managed-care programs, even though proponents say the programs increase provider reimbursement and improve access to care, but hospitals' fear of managed care and a lack of cooperation between physicians and hospitals on the programs may doom a nationwide hospital-sponsored managed-care approach. PMID- 10113620 TI - Creating a national health care policy. PMID- 10113621 TI - Optical technology demonstrates benefits. AB - This article explores four applications of optical technology in the healthcare industry. The author has approached several end users of existing optical technology-based systems to learn their reasons for choosing these systems and what benefits they have realized. PMID- 10113622 TI - A dictated and transcribed medical record can be cost effective. PMID- 10113623 TI - Refined DRGs: trials in Europe. AB - DRGs have recently been revised to account for severity of illness through a more refined use of additional diagnoses (comorbidities and complications). Under the refined model, patients are differentiated with respect to classes of additional diagnoses that are disease and procedure specific. The Refined DRGs were evaluated with data from selected Barcelona hospitals and the findings compared to those obtained with Norwegian and English hospital discharge information. In terms of predictive performance, the Refined DRGs represent only a very small improvement over the second revision DRGs for the study's sample of European data. This lack of significant improvement is likely attributed to misclassification of the European discharges due to limited reporting of additional diagnoses. It is recommended that European countries use the Refined DRGs as a descriptive framework for reporting utilization statistics in order to encourage more complete reporting of comorbidities and complications. PMID- 10113624 TI - Hospital comparisons using a Euro Health Data Base for resource management and strategic planning. AB - A European approach for resource management and strategic planning has been implemented in the HOSCOM project of AIM by defining information standards needed across countries, as well as a methodology to measure resources and costs at the institutional and interinstitutional level. A Euro Health Data Base (EHDB) has been obtained in order to test data availability and comparability as well as to validate models through macrocomparisons using case-mix (DRG's, refined grouping, disease staging) and microcomparisons based on three diseases (cardiac valve replacement, diabetes mellitus and hip fracture). The EHDB's presently based on 274 164 medical record summaries sampled from 7 countries allowed us to build prototypes (using Clipper, Prolog and SQL) in order to export uniform aggregates in the different countries, with standard software tools for statistical comparisons. It showed the present feasibility of using case-mix based on the European Minimum Basic Data Set (MBDS) and the difficulty of obtaining uniform data on resources and costs other than length of stay across countries. Medical data confidentiality was assured but not yet population-based representativity. Given the present state of the EHDB, problems have been clearly identified in order to be solved by international research and development projects in the near future. PMID- 10113626 TI - Special issue: International comparability of DRGs. PMID- 10113625 TI - The development of cost information by DRG--experience in a Barcelona hospital. AB - The determination of hospital patient costing adjusted by case-mix is one of the possible applications arising from the emergence of patient classification systems, such as Diagnosis Related Groups (DRGs). Most of the experiences up until now have given priority to the determination of the total costs by DRG, making it difficult to establish comparisons between hospitals. In this article, results of an experience in Barcelona with a direct patient costing model are presented, with these later being grouped into DRGs. Descriptive information is given together with statistical analysis of the intra-DRG variability and the relationship between costs and the length of stay. Patient costing systems represent a useful instrument for hospital management as they allow analyzing variation and its reasons at DRG level. It is in fact the primary level of information required in order to develop management control in hospitals. PMID- 10113627 TI - Advanced home health care. AB - Home health care in the United States is growing rapidly, as reflected in numbers of persons treated and national expenditures for care. Recent growth in this sector reflects the emergence of 'high-tech' care, such as intravenous infusion therapy, total parenteral nutrition and home dialysis. This focus on device-based therapy detracts from a larger issue, the efficient production of medical care subject to acceptable levels of cost and quality. The structure of payment and quality assurance mechanisms will shape the emergence of advanced home health care in the 1990's and beyond. PMID- 10113628 TI - The Medicare Catastrophic Coverage Act of 1988: issues of equity in a policy reversal. PMID- 10113629 TI - Industry concerns on uniformity echoed by others. PMID- 10113630 TI - Methodological issues in efficiency-focused program evaluation: the case of mental health. PMID- 10113631 TI - Swing-beds: the Arizona experience. AB - Swing-beds are acute-care hospital beds temporarily used for long-term care. A demonstration program was developed to evaluate the effectiveness of using swing beds as catalysts for the expansion of rural hospitals into community health centers to respond better to the needs of older persons in their respective communities. We examined the background and implementation issues of the swing bed demonstration program in six rural Arizona hospitals. PMID- 10113632 TI - Special report. Integrating managed care. When managed care is a system. AB - In a comprehensive managed care system, all participants benefit from the improved quality and cost efficiency. When payers, beneficiaries, and providers communicate, share data, and participate in decision making, the result is more appropriate and more cost-efficient care. The following articles take a look at how each player in the health care system benefits from a comprehensive approach to health care. Payers (employers) benefit by being able to track the cost effectiveness of their health care through integrated data systems. Beneficiaries (employees and dependents) benefit by becoming more involved in the decisions being made by providers and third party payers about their care through patient education and advocacy programs. And health care providers benefit by gaining an increased leadership role in directing the management of their patients' care through practice guidelines. These guidelines will help doctors make decisions that lead to high quality care as well as build a foundation for standardized review criteria throughout the industry. PMID- 10113633 TI - Centralized maintenance responsibilities: a case study. AB - This paper reviews a total equipment management program that has been documented since 1983. One department was given responsibility for all maintenance activities needed for the hospital's electronic equipment, including many items that were, at the time, not maintained by most biomedical engineering departments. The department combined customer satisfaction and cost-effectiveness into a single goal and produced excellent results. Costs decreased, customers were satisfied, and effectiveness increased. The program has saved over $1,000/bed/year for the last seven years, and total documented savings are over $5,000,000. The cost/unit was almost 30% below the average values for many other biomedical engineering departments. PMID- 10113634 TI - Study ranks costs by city. PMID- 10113635 TI - Long-term-care insurance abuses prompt new calls for regulation. PMID- 10113636 TI - MRI service evaluation. Part 1: Measuring performance. PMID- 10113637 TI - The name of the new game. PMID- 10113638 TI - The role of permanent magnet MRI in healthcare delivery. PMID- 10113639 TI - Perspectives. Medicaid under the microscope. PMID- 10113640 TI - Healthcare in Japan: its professionals, institutions, and financing. AB - Like the United States, Japan's healthcare system is a conglomerate of government, employer, and individual financing--but that's about as far as the similarity goes. Universal access to basic healthcare has been achieved in Japan through comprehensive employer/employee plans and government subsidies. However, the United States should not be too hasty in emulating Japan, for culture plays a definite role in healthcare on both sides of the Pacific. PMID- 10113642 TI - International healthcare expenditures: spending totals and public satisfaction among the OECD nations. AB - As an introduction to this Hospital Topics theme issue on international healthcare systems, our guest editor and one of our authors present aggregate health expenditures and public-satisfaction data from member nations of the Organization for Economic Cooperation and Development. Although healthcare funding is not the explicit focus of this issue, it underlies most of the points raised, and however the health systems examined here may vary in structure or impact, financing remains a shared challenge and one of our best base lines for comparison. PMID- 10113643 TI - Build new or build anew? How to evaluate renovation against new construction. PMID- 10113641 TI - The U.S. healthcare system after NHI: financial ramifications for providers and personnel. AB - Although much attention has been paid to the general structure and possible implementation of a U.S. national health-insurance program, there remains the brass-tacks question of how such a plan would specifically affect today's providers and payers. Here the author outlines some of NHI's financial and organizational implications for patients, facilities, and staff. PMID- 10113644 TI - The Southern California HMO marketplace: growth, innovation, and integration. AB - The 1980s have been a period of rapid growth in the Southern California HMO industry. Much of this growth is related to the emergence of network-model HMOs and, more recently, IPA-model HMOs, as a major competitive force that provides an alternative to the massive and rapidly growing Kaiser plans. The growth of the industry has been made possible by and, at the same time, has facilitated the development and growth of multispecialty medical groups and hospital-based IPAs throughout Southern California. This development has brought the HMO industry and the practice of prepaid medicine into the mainstream of health care and had led to the extensive involvement of community hospitals and independent physicians and physician groups in prepaid medicine. The coming decade will be marked by further growth and by continued integration of physician practices, hospitals, and HMOs into more efficient, high quality, vertically integrated systems of health care. PMID- 10113646 TI - Using referral labs efficiently. Part I: The make-or-buy decision. AB - In this three-part series, the author supports extensive send-outs in a myriad of situations. This month: how to determine whether it would be wise to do that new assay in-house. PMID- 10113645 TI - Health expenditure growth in Japan and the United States. AB - This paper compares the effects of governmental policy changes on health care expenditures in Japan with similar effects in the United States. Our results indicate that Japanese economic expansion and inflation before 1982 generated higher health expenditure growth rates than those in the United States. But after a policy change in 1982, Japanese health expenditure growth dropped from 15 to 5.5 percent annually while expenditure growth in the United States remained high despite Medicare's Prospective Payment System (PPS). PMID- 10113647 TI - What is quality, and how is it measured? AB - There is currently no universally accepted definition of "quality of care." This article describes two aspects of measurement that contribute to an assessment of quality--the perception of quality of care held by patients and comparisons of clinical care to established standards. Ongoing monitors that lead to this assessment of quality in a large HMO are described in detail. They include patient satisfaction surveys, quality of care evaluations, comparative medical expense reports, cost-effectiveness studies, and a unique physician incentive bonus plan. PMID- 10113648 TI - Quality assurance in an IPA setting. AB - The experience at CIGNA Healthplans shows that a quality assurance program can be instituted in an IPA-model HMO at low cost and with the addition of little new staff. Existing resources can be effectively restructured to implement a functional program of a traditional type that is easily understood by employer groups, members, and providers. It can serve as a transitional process until the HMO is large enough to put a total quality management program in place. PMID- 10113649 TI - Developing a method of assessing quality of care in nursing homes, using key indicators and population norms. AB - This article illustrates how population norms on key indicators of quality can be used to assess quality of care in nursing homes. Five key indicators of quality were chosen from a Patient Care and Services Survey carried out by the Rhode Island State Department of Health: prevalence of contractures, in-house-acquired decubiti, use of restraints, lack of participation in an activities program, and nasogastric tube feeds. The population prevalence of these indicators was adjusted according to the case mix and size of each nursing home. A measure of quality suggested was the difference between the case-mix-adjusted prevalence and the prevalence observed by state surveyors. It was concluded that although the system is still in the exploratory stages, it has the potential to supplement the clinical judgment of nursing home surveyors with a more objective method of assessing compliance with quality of care standards. PMID- 10113650 TI - One remedy for the nation's worst problem: a plan for healthcare reform. PMID- 10113651 TI - State home and community-based services for the aged under Medicaid. AB - Expansion of home and community-based services for the elderly has been a focus of attention for some time by policymakers, advocates for development of a more comprehensive long-term care system, and consumers alike. However, the development of a comprehensive alternative long-term care system has been slow to evolve. Increased public financing for home and community-based services has been even more limited, thus inhibiting expansion of these services. PMID- 10113652 TI - Pennsylvania's Medicaid crisis. PMID- 10113653 TI - Acute and long-term care begin to work together. PMID- 10113654 TI - Fla. physicians offer settlement. PMID- 10113655 TI - Rostenkowski pushes his own healthcare reform bill. PMID- 10113656 TI - Past predictions take shape. PMID- 10113657 TI - Why healthcare executives should support a national cost containment plan. PMID- 10113658 TI - Physician/hospital bonding. PMID- 10113659 TI - The 1990-91 recession: impact on health care. AB - The Persian Gulf war is over. The U.S. economy is experiencing some signs of relief from the recession. However, it's too soon for health care executives to forget these events. Their effects on health care will be felt for some time to come. PMID- 10113660 TI - Long term care insurance's future. PMID- 10113661 TI - QALYs and the equity-efficiency trade-off. AB - As the volume of research on quality-adjusted life years (QALYs) has increased, concern has begun to be expressed about the equity aspects of resource allocation decisions based on the results of this research. This paper suggests that a common theme running through the criticisms of the QALY approach is a concern about inequality. It also suggests that the method for incorporating distributional concerns which is currently being pursued by advocates of the QALY approach will only ever capture concerns other than a concern about inequality. The paper suggests a method for incorporating both sets of concerns into resource allocation decisions. PMID- 10113662 TI - Assessing Medicare's prospective payment system for hospitals. AB - The Medicare prospective payment system for hospitals was created to slow the growth of government spending on health care. This analysis has shown that the program has accomplished its cost-containment objective in the first five years of its existence. The average length of hospital stay has dropped sharply under PPS, reducing hospital costs. These reduced costs combined with payments based on higher pre-PPS historic costs have given hospitals high profits in the early years of PPS. One of the expected but unwanted outcomes, more admissions, has never occurred. The unexpected rop in admissions under PPS has been responsible for government savings on Medicare inpatient care. Although Medicare outpatient hospital and physician expenditures have grown at fast rates during PPS, there is no evidence in aggregate date that they have grown any faster because of inpatient care shifting to avoid PPS payment controls. The Medicare PPS savings have extended to all U.S. hospital spending, which has grown at much slower rates since the implementation of PPS. There have also been negative outcomes from PPS, and some questions posed about PPS remain unanswered. The inflation in "DRG creep" or upcoding that was predicted for PPS did occur. The government has since washed much of this code inflation out of the permanent payment base, but this phenomenon may not be a self-limiting problem, as was widely hoped. To date there is no convincing evidence of poorer quality of care under PPS, but most of the available evidence is based on mortality studies, which have limited use in measuring changes in quality of care. While PPS has helped to slow the growth in Medicare and national hospital spending, it has not had an appreciable effect on the rate of growth in the nation's total health spending. Although it was unintended, PPS has been providing a natural experiment on the issue of whether increased cost sharing dampens demand for health care services. By slowing the growth rate of inpatient hospital spending, PPS has increased the share of Medicare spending under SMI, where beneficiaries have higher coinsurance. The short-run beneficiary response appears to be an increase in demand for Medi-gap health insurance rather than a dampening of demand for services. To this point it appears that Medicare's PPS has been successful in containing the growth in hospital costs while avoiding, or managing, unwanted consequences. (ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10113663 TI - The share of Medicaid for nursing home care. AB - Over one-third of Medicaid dollars go to nursing homes, a share that is decreasing but that varies widely among the states. This paper examines demand, supply, and policy factors explaining interstate variation over time in the nursing home share of state Medicaid dollars. Nursing home bed stock shows strong effects; Medicaid expenditures for acute hospital and for ICF-MR care are important; and various demand factors also explain nursing home share. In this model, residual nursing home share of Medicaid declines over time, which is interpreted to reflect omitted state policy factors explaining state ability to constrain Medicaid nursing home utilization and expenditures. PMID- 10113664 TI - A proposed cost effectiveness method for use in policy formulation in human service organizations. AB - This article builds on a previous publication and presents additional information on how cost effectiveness analysis may be used by policy and decision-makers in human service organizations (HSO's). It presents a brief history of the use of cost effectiveness analysis to demonstrate its efficacy in assisting policy makers in a variety of fields. It then comparatively describes two of the best known cost effective methods--cost benefit analysis (CBA) and cost effective analysis (CEA), and argues that the latter is the more appropriate method to be used to effect policy decisions in HSO's. The discussion centres around refining the limitations of the CEA method and proposes a simple model for use in this regard. Recommendations and implications are directed toward managers, administrators and decision-makers of HSO's. Finally, the article is attempting to fill a distinct void in the literature in this field and also suggests the use of more meaningful policy formulation and analyses methods in HSO's. PMID- 10113665 TI - Meal equivalents: the food service productivity measure. PMID- 10113666 TI - Healthcare data briefing. The nation's health. PMID- 10113667 TI - Publicly financed competition in health care: legislative issues. AB - The concept of publicly financed competition serves as a possible strategy for controlling expenditures and improving the efficiency of the health care system in Ontario. Potential cost savings, although rough estimates, for a 10-year period range from $1.0 billion to $1.6 billion, depending upon the model structure. This paper investigates the assumptions and structure of a publicly financed competition proposal and addresses legislative issues concerning the feasibility and desirability of such a system. PMID- 10113668 TI - The strategist's role in shortening product development. PMID- 10113669 TI - Cooperative incinerator may cause problems if not-for-profit venture. AB - Eight hospitals within a 40-mile radius are building a regional incinerator which will be designed to meet the needs of the hospitals in complying with state and federal regulations for handling wastes, including those deemed to be hazardous. A question arises as to whether this incinerator can be operated as a not-for profit cooperative. In this dialogue, Dr. Decker discusses the legal issues involved. PMID- 10113671 TI - Long-term care: top ten trends for the 1990s. PMID- 10113670 TI - A multidisciplinary QA program for enteral nutrition in high-risk patients. AB - An increase in elderly patients and severity of illness rates means greater use of nasogastric feeding tubes for both high-risk acutely ill and chronically ill patients. When the QA screening process at Booth Memorial Medical Center revealed a certain percentage of complications with small bore, weight-tipped feeding tubes inserted through the nares, a multidisciplinary peer review committee (MPRC) was formed to review the enteral nutrition program. After a literature review to determine possible complications, the MPRC identified lung perforations due to tube misplacement, tube feeding aspiration into the lungs leading to possible aspiration pneumonia, and an internal tip separation from the tube product failure. Unconscious incubated patients on ventilators were shown as at high risk for feeding tube misplacement in an initial MPRC patient study. A second study evaluated several different feeding tube products in the medical, respiratory and surgical ICU. The MPRC established a credentialing process for physician assistants, interns and residents in feeding tube placement. The MPRC proceedings were presented to the hospital-wide QA committee for review, endorsement and recommendations on all policy and procedure changes. The conclusions were that a more concerted effort must be made to improve medical management and encourage ongoing education in the administration of enteral feedings to high-risk patients. PMID- 10113673 TI - Rostenkowski introduces healthcare reform package. PMID- 10113672 TI - Tax-deduction bill gets key backing. PMID- 10113674 TI - Summit delays long-term-care unit spinoff. PMID- 10113675 TI - Investigational: what's in a name. AB - The term "investigational" has become the fulcrum upon which coverage decisions turn. All third-party payers, including the federal government, use varying definitions of the term for the purpose of excluding treatments from coverage for payment. Unfortunately, no consistent definition of the term is available to payers to guide them in their coverage decisions. PMID- 10113676 TI - The three R's of long term health care for the elderly: regulation, rationing, and railroading. Panel discussion. PMID- 10113678 TI - Realizing information technology benefits. AB - The Regional Medical Center at Memphis--the oldest hospital in Tennessee- acknowledged that information technology is a critical key to the pursuit of medical and managerial excellence. By outsourcing much of the center's computing and telecommunications needs, the MED's CEO, Lucy Shaw, feels she has maximized information technology benefits to her institution with maximum cost control. PMID- 10113677 TI - Hospital role delineation: the technology and the politics. AB - Regulated health systems are under increasing pressure to improve the efficiency of their hospital provision. One approach is to have more coordinated hospital provision through hospital role delineation. This short communication proposes the use of Diagnosis Related Groups as part of the role delineation process. However, the role delineation process is not solely a technical one: it requires a blend of technical and political decisions. Political aspects of the role delineation process are also reviewed. PMID- 10113679 TI - Cellular solutions. PMID- 10113680 TI - Special report. When they want to cut your security budget: some options to consider. AB - The financial woes of the health care industry may dictate further budget cuts in all departments, including security. A strategy to avoid further cuts or to minimize them is essential. In this special report, we will look at how security directors can try to prevent budget cutbacks before they occur. We will also examine the need for planning--what every security director should do to prepare for budget cuts--and various ways to trim the budget without leaving the hospital unprotected. PMID- 10113681 TI - NAHAT spring survey brings inflated hopes. PMID- 10113682 TI - Health economics and resource management: a model for hospital efficiency. AB - As health care spending continues to climb, government and industry, as the two major purchasers of health care services, are intensifying their scrutiny over health care delivery in an attempt to reduce their health care burden. The first round of utilization controls and reimbursement restrictions focused on necessity of admission and efficiency of care, causing a profound effect on hospital-based services. Declining occupancy rates, reduced inpatient reimbursements, and mounting contractual losses have pushed many hospitals to the point of financial disaster. The second round of controls has expanded into the outpatient sector and will begin to focus on both appropriateness of treatment and outcome of care, affecting both hospital and physician-related services. In an environment of increasing external pressures for appropriateness, justification and outcome of medical services, and potential financial risk imposed by reimbursement cutoffs or penalties for unnecessary care, hospitals and physicians are under increasing pressure to improve their efficiency as health care providers. The resource management model is presented as an example of how hospitals and physicians can monitor health care services and improve their performance in the delivery of more cost-efficient, high-quality medical care. The importance of hospital physician education, communication, and interaction is stressed as a means of attaining internal control over a system plagued by resource-limited external constraints. PMID- 10113683 TI - Substitutability of a process innovation in medical diagnosis: some empirical results. AB - The health sectors in many countries have been increasing in relative size, and medical innovations have been identified by some as a factor contributing to the rise in health expenditures. This paper begins by reviewing the various approaches that economists have employed to determine the connection, if any, between rising health expenditures and new medical technologies. It is then argued that another way to approach the issue is to determine if innovations have substituted for previously existing technologies. Thus this method cannot be applied to product innovations: it is restricted to process innovations. This procedure is applied to the innovation of fibre optic colonoscopy, a procedure for diagnosing diseases/conditions in the lower gastrointestinal tract. The data relate to private medical practice in Australia which operates on a fee-for service basis. The empirical results indicate no evidence of substitution of the 'new' for the 'old' technology. Thus, there is some reason to believe that this innovation will have contributed to rising health expenditures for diagnosis of the lower gastrointestinal tract. The paper concludes by considering policy options that could address the issue. PMID- 10113684 TI - Recent trends in expenditures on physicians' services in Canada. AB - Analysis of Canada's restraints on the growth in volume of physicians' services can help shape the framework and direction of policy development in other countries. This paper analyzes trends in recent expenditures on physicians' services in Canada from 1982 to 1987. Growth in payments to physicians who were paid fee-for-service is broken down into three component parts in Canada nationwide and in four provinces: Ontario, Quebec, Nova Scotia and British Columbia. The three component parts are: (1) growth in the number of services billed; (2) physician service prices; and (3) the mixture of high- and low-priced services billed. Expenditure increases are disaggregated according to some major categories of medical services, both per physician and per capita. Increases in growth in physician payments were explained mainly by increases in prices, while some evidence of an increase in higher priced services per physician was found. The varying payment restraint policies across Canadian provinces were manifested in different patterns with respect to components of payment change. Higher rates of payment and volume growth were found for diagnostic/therapeutic and office medical services than for surgeries, although a few contrary patterns across provinces occurred. Interprovincial utilization growth, both per physician and per capita, was variable. This suggests that Canada's regionally administered system is neither uniform nor monolithic. PMID- 10113686 TI - Disposables or reusables? Try 4-step analysis. PMID- 10113687 TI - Hospitals compare mattresses, consider beds vs. overlays. PMID- 10113685 TI - Chiropody and the QALY: a case study in assigning categories of disability and distress to patients. AB - Quality adjusted life years (QALYs) are claimed to be a universal means of measuring output from health care interventions. However, existing QALY research has been carried out mainly in 'high-tech', life extending areas of health care. This paper presents an application of QALY measurement to a 'low-tech' life quality enhancing area of health care, chiropody. Information on changes in quality of life following chiropody interventions was elicited from both practitioners and patients. We found the apparently low benefit, but low cost service of chiropody to be a potentially cost-effective use of NHS resources. Methodological issues are also addressed relating to the assignment of patients to health states, and whether practitioners' or patients' assessments of changes in quality of life should be used. PMID- 10113688 TI - Do the answers to U.S. health care problems lie within Canada? PMID- 10113689 TI - Health data facts. Canada. MHCI Health Policy Analysis. PMID- 10113690 TI - The eternal triangle: cost, access, and quality. AB - No matter who is in charge of health policy, no matter what his or her ideological bent, no matter whether the economy is in boom or bust, three concerns stubbornly dominate the discussion: the cost of care, access to care, and the quality of care. The main variation among them is that normally each in turn receives the most attention from policy makers, payers, and the public, over time. PMID- 10113691 TI - Nurses as case managers. PMID- 10113692 TI - Connecticut's public/private partnership: an innovative approach for financing long term care. PMID- 10113693 TI - In-house CT program development. AB - "Accomplishing in-house CT maintenance can be a lengthy process," warns the author speaking from his own experience at the Department of Veterans Affairs Medical Center, Philadelphia, Pennsylvania. However, Mr. Brown insists that the payoff can be substantial in terms of significant cost savings and decreased downtime. His step-by-step advice and documentation are structured to help managers interested in investigating this option. PMID- 10113694 TI - Home care for HIV disease: a community-based model. AB - In an effort to better meet the needs of the largest populations of HIV-infected individuals in the country, California instituted a state-funded home care pilot project that provides cost-effective care in a comforting and familiar setting. PMID- 10113695 TI - Home infusion therapy options for patients with AIDS. AB - With the advent of new catheter technologies and techniques, IV therapy options for the AIDS patient are increasing. To meet the needs of individual patients and achieve the best results with home infusion therapy, both the practitioner and the patient should be well informed about the range of available catheters. PMID- 10113696 TI - Community-based LTC Act introduced in Washington State. PMID- 10113697 TI - Time-bound terminology: short-term, long-term, and indeterminate. PMID- 10113698 TI - Reactive-proactive: a loss control perspective for healthcare. AB - The author shows why the concept of a good, proactive loss control and prevention program is the proper and cost-effective choice for healthcare facilities. He discusses why security practices based on a police image and police response are inappropriate in view of the proliferation of lawsuits for malpractice and negligence. PMID- 10113699 TI - Medicare short-stay hospital services by diagnosis-related groups. AB - The 1983 amendments to the Social Security Act (Public Law 98-21) provided for a prospective payment system (PPS), effective October 1, 1983, for most short-stay hospitals certified to provide inpatient services to Medicare beneficiaries. A brief description of the assignment process for diagnosis-related groups (DRGs) is presented, because assigning a DRG code to a short-stay hospital discharge record is tantamount to the Medicare prospective payment to the hospital, subject to certain statutory adjustments. Shifts in the distribution of the discharges and average length of stay among the DRGs since 1983 reflect the adaptation of hospitals to the incentives embedded in PPS and the ongoing refinements in the methods of assigning DRGs to discharges from short-stay hospitals. Interpretation of the shifts is based on a consideration of the significant refinements in the medical coding system, the technological and scientific advances in the practice of medicine, the effect of shifting patient treatment to alternative sites, policy or legislative changes affecting Medicare coverage, and the annual recalibration of the DRG weights. PMID- 10113700 TI - Savings estimate for a Medicare insured group. AB - Estimates of the savings potential of a managed-care program for a Medicare retiree population in Michigan under a hypothetical Medicare insured group (MIG) are presented in this article. In return for receiving an experience-rated capitation payment, a MIG would administer all Medicare and employer complementary benefits for its enrollees. A study of the financial and operational feasibility of implementing a MIG for retirees of a national corporation involving an analysis of 1986 claims data finds that selected managed care initiatives implemented by a MIG would generate an annual savings of 3.8 percent of total (Medicare plus complementary) expenditures. Although savings are less than the 5 percent to be retained by Medicare, this finding illustrates the potential for savings from managed-care initiatives to Medicare generally and to MIGs elsewhere, where savings may be greater if constraints are less restrictive. PMID- 10113701 TI - An evaluation of diagnosis-related group severity and complexity refinement. AB - In 1988, an ambitious and extensive project was undertaken in New Jersey to evaluate severity class adjustment of the all-payer prospective payment system. Another project objective was to evaluate alternative strategies for refining diagnosis-related groups (DRGs). The evaluation presented here includes a comparison of DRG refinement using Computerized Severity Index classes and Yale University complexity classes. Statistical methods and payment simulations are used to assess the impact of DRG refinement and consequent revenue changes. When a high volume subset of DRGs is refined, simulated payment shifts between hospitals on the order of 5 percent of total hospital costs are indicated by this analysis. PMID- 10113702 TI - The 1991 national executive poll on health care costs and benefits. AB - This year's National Executive Poll graphically reveals employers' opinions, and current trends regarding topics such as cost containment, retiree benefits, and wellness programs. Analysis also compares 1991 data to last year's. PMID- 10113703 TI - The highs and lows of PPOs. AB - Anywhere from 38 to 65 million people obtained health care from PPOs in 1990. These numbers are on the upswing, and so seems to be employers' satisfaction with this managed care option. PMID- 10113704 TI - Don't overlook the decision influencer. Sandwich generation carries plenty of clout. PMID- 10113705 TI - "What's the right thing to do?" Canada asked, U.S. should answer. PMID- 10113706 TI - Medical ethics in the 1990s. Emphasis on death-and-dying issues will continue but social concerns will command increased attention. AB - During the 1990s medical ethics will undergo changes. Individual clinical issues, especially those related to death and dying, will continue to create conflict and preoccupy hospital staffs. But professional ethicists will focus on social concerns more frequently than they have in the past. Following are some of the most crucial ethical issues and directions they are likely to take in this decade: Clinical practice and the law will move toward less demanding standards of proof regarding the withdrawal of treatment from patients who are no longer competent. Public policy will set more lenient standards for judging whether a person would refuse artificial nutrition and hydration if he or she were able. Unless sensible people strengthen the distinction between active and passive euthanasia, more physicians and legislatures will move toward physician-assisted suicide. Those proposing a higher-brain definition of death, as opposed to whole brain definitions, will gain ground with the general public, but not with legislators. New transplantation technologies will increase medical options but create more problems with paying for the procedures. As techniques are perfected, ethical questions will focus more on financing than on the source of transplantable material. AIDS treatment priorities will clash with other medical demands (e.g., treatment for breast cancer), and concerns about protecting both providers and patients from contracting AIDS will move policy toward routine testing. Progress in public argument will be made on the abortion issue. Members of ethics committees will have to be trained to address financing issues. Some medical schools and residency programs will add courses on the concept of character and on character development to their ethics programs.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10113707 TI - U.S. healthcare reform: lessons from other countries. PMID- 10113708 TI - Proposition 99: raising the cigarette tax and paying for health care in California. PMID- 10113709 TI - On the measurement of horizontal inequity in the delivery of health care. AB - This paper offers a critical appraisal of the various methods used to date to investigate inequity in the delivery of health care. It concludes that none of the methods used to date is particularly well equipped to provide unbiassed estimates of the extent of inequity. It also concludes that Le Grand's (1978) approach is likely to point towards inequity favouring the rich even when none exists. The paper offers an alternative approach, which builds on the approaches to date but seeks to overcome their deficiencies. PMID- 10113710 TI - Participation and screening programmes for colorectal cancer: more would be better? AB - In clinical terms, a screening compliance rate of 100% may be deemed optimal in that the number of abnormalities detected is thereby maximized. This paper explores optimum compliance rates from the cost-effectiveness point of view by modelling the individual's decision to participate in the screening programme. Using data derived from contemporary colorectal screening trials, it assesses the compliance and cost effects of utilizing differing methods of screening invitation, and explores the incremental cost and benefits associated with compliance enhancement techniques. Given the estimated costs and benefits, attempts to attain higher levels of compliance would appear justifiable. PMID- 10113711 TI - Conversion factor instability in international comparisons of health care expenditure. AB - Parkin, McGuire and Yule (1987) (hereafter PMY) report that a regression of per capita health care expenditure on per capita income using different conversion factors (exchange rates, GDP PPPs, health PPPs) gave rise to different results. In this note we apply updated data to the same empirical relationship. In contrast to PMY, we find no noticeable conversion factor instability in that relationship either with respect to the health care income elasticity or with the magnitude of multiple correlation coefficient. PMID- 10113712 TI - The distribution of health care revisited: a commentary on Wagstaff, van Doorslaer and Paci, and O'Donnell and Propper. PMID- 10113713 TI - The relationship between the cost and quality of hospital care: a review of the literature. PMID- 10113714 TI - Cash in on the cost-containment push in health care. PMID- 10113715 TI - Implementing total quality management (TQM) in health-care laboratories. AB - Health-care organizations are beginning to apply the principles of total quality management (TQM). Implementing TQM in a health-care laboratory requires incorporating quality improvement (QI) and quality planning (QP) with quality laboratory practices (QLP), quality control (QC), and quality assurance (QA) to provide a complete quality management system. QI and QP can be initiated by developing a strategic plan as a pilot QI project. QI project teams are then introduced to accomplish the highest priority goals. This implementation approach improves strategic planning by using group problem-solving tools and techniques, such as process flow charts, brainstorming, nominal group, fishbone diagrams, consensus decision making, and Pareto analysis. The approach also improves the success of project teams by providing a clear management agenda and a commitment to project-by-project QI. PMID- 10113716 TI - Laboratory cost and utilization containment. AB - The authors analyzed laboratory costs and utilization in 3,771 cases of Medicare inpatients admitted to a New England academic medical center ("the Hospital") from October 1, 1989 to September 30, 1990. The data were derived from the Hospital's Decision Resource System comprehensive data base. The authors established a historical reference point for laboratory costs as a percentage of total inpatient costs using 1981-82 Medicare claims data and cost report information. Inpatient laboratory costs were estimated at 9.5% of total inpatient costs for pre-Diagnostic Related Groups (DRGs) Medicare discharges. Using this reference point and adjusting for the Hospital's 1990 case mix, the "expected" laboratory cost was 9.3% of total cost. In fact, the cost averaged 11.5% (i.e., 24% above the expected cost level), and costs represented an even greater percentage of DRG reimbursement at 12.9%. If we regard the reimbursement as a total cost target (to eliminate losses from Medicare), then that 12.9% is 39% above the "expected" laboratory proportion of 9.3%. The Hospital lost an average of $1,091 on each DRG inpatient. The laboratory contributed 29% to this loss per case. Compared to other large hospitals, the Hospital was slightly (3%) above the mean direct cost per on-site test and significantly (58%) above the mean number of inpatient tests per inpatient day compared to large teaching hospitals. The findings suggest that careful laboratory cost analyses will become increasingly important as the proportion of patients reimbursed in a fixed manner grows. The future may hold a prospective zero-based laboratory budgeting process based on predictable patterns of DRG admissions or other fixed-reimbursement admission and laboratory utilization patterns. PMID- 10113717 TI - If two heads are better than one, why do I have bruises on my forehead? Managing the group process. AB - Managers are using groups more frequently for solving complex organizational problems because of numerous organizational and environmental factors. Yet, many managers see group decision-making meetings as more of a problem than a solution. This article discusses situations where groups should and should not be used and recommends specific skills a leader can use to improve the effectiveness of group decision making. Emphasis is placed on managing the group process to achieve a satisfactory outcome. An exercise to test the validity of the suggestions is provided. PMID- 10113718 TI - Understanding and appreciating association management tasks and responsibilities. The CLMA experience. PMID- 10113719 TI - NOVA STAT profile instruments. PMID- 10113720 TI - Scanning tunneling microscopy and atomic force microscopy. PMID- 10113721 TI - Preparing for unionization efforts. PMID- 10113722 TI - Eliminate employer-based health insurance. PMID- 10113723 TI - No surprises! Mastering the art of the survey--Part 1: Preparation. PMID- 10113724 TI - Seven tips for successful appeals. PMID- 10113725 TI - Living with others as an alternative to nursing home use. AB - The authors studied a synthetic sample combining information on nonmarried women from surveys of community-resident elderly and nursing home residents to identify factors affecting the probability of observing individuals in one of three situations: living alone, living with others, and residing in a nursing home. Increasing income increased slightly the probability of living alone and had a positive effect on the probability of residing in a nursing home for most income levels within the sample range. As expected, disability and increasing age were very important in distinguishing those in the nursing home from those residing in the community, and also increased the probability of living with others, other things remaining constant. Whites were slightly more likely to live alone and less likely to reside in a nursing home, other things remaining constant. Residing in a warmer climate decreased the probability of being a nursing home resident. The analysis indicates that factors distinguishing nursing home residents from community residents are also at least somewhat useful in distinguishing those who live alone from those who live with others, supporting the inclusion of shared community living arrangements with the nursing home as part of a continuum of supportive living arrangements. PMID- 10113727 TI - Selling receivables to raise cash. PMID- 10113726 TI - A longitudinal study of the causal relationship between social networks and health of the poor frail elderly. AB - Research over the past two decades has documented a positive relationship between social support and health. The causal interpretation of these associations has, however, been unclear. This study aims at filling the gap in our understanding of this causal link with respect to the frail poor elderly. The main questions addressed are, Does lack of social ties affect the elderly's health? or are unhealthy people less likely to establish and maintain social ties? We employed a time-series panel design to overcome problems of causal explanations and examine social networks and health in a sample of 3,559 poor frail elderly, participants of the California Multipurpose Senior Services Project. The results indicate that social networks have a positive effect on health (though only in the short run). However, neither the subjective nor the objective health measures have a significant effect on social networks. Implications for intervention are discussed. PMID- 10113728 TI - New York's revised survey process aims at improved results. PMID- 10113730 TI - ANA head outlines role of nurses in quality assurance. PMID- 10113729 TI - Ohio hospital tries new approach to cost/quality goals. PMID- 10113731 TI - Outcome study foresees greater patient input. PMID- 10113732 TI - How an emergency department can build effective QA. PMID- 10113733 TI - Radiology programs seen as improving quality of service. PMID- 10113734 TI - Family physicians offer program to upgrade care. PMID- 10113735 TI - AHA head pledges active support to hospitals' QA role. PMID- 10113736 TI - ACOG increases its participation in QA activities. PMID- 10113738 TI - HCFA mortality studies. PMID- 10113737 TI - Quality of care stressed in peer review guidelines. PMID- 10113739 TI - New data bank on adverse actions to open next month. PMID- 10113740 TI - Discharge planning can prevent later patient problems. PMID- 10113741 TI - Practice parameters called key to effective QA programs. PMID- 10113742 TI - Can quality be preserved when generics are used? PMID- 10113743 TI - Rural fax network enhances flow of patient data. PMID- 10113744 TI - Maryland project seeks hospital performance data. PMID- 10113745 TI - Public Health Service to get new health care policy unit. PMID- 10113746 TI - Assessing quality of ambulatory care. PMID- 10113747 TI - Washington group fosters use of health care data. PMID- 10113748 TI - Minnesota hospital cuts delays in treating heart cases. PMID- 10113749 TI - Blues increase emphasis on monitoring QA. PMID- 10113750 TI - Newspaper defines role in publishing performance data. PMID- 10113751 TI - Preventive services closely linked to quality concerns. PMID- 10113752 TI - PRO program to focus efforts on two objectives. PMID- 10113753 TI - IOM study urges a major shift in QA strategy. PMID- 10113754 TI - Colorado group develops aid for documentation. AB - The Colorado Peer Review Organization (PRO), the Colorado Foundation for Medical Care, has implemented the PROMPTER concept in an effort to assist physicians in charting information essential to PRO review. The examples that follow are adapted from those widely distributed in Colorado by the PRO and sent to all PRO medical directors. PMID- 10113755 TI - APA aims for broad role in quality area. PMID- 10113756 TI - Medicare changes require closer MD/patient ties. PMID- 10113757 TI - Loss prevention in the office. PMID- 10113758 TI - Perspectives. Medicaid case management: a rare bright spot. PMID- 10113759 TI - Perspectives. Fences loom for free-ranging drug prices. PMID- 10113760 TI - Safety management vs. picking leaves. AB - A safety program will generally have as its base a comprehensive written document made available for everyone in the organization. The document should indicate a positive commitment to safety by management. It should not be a "how to" guide, but rather a broad outline to establish responsibilities, goals, and methods. The safety manager is appointed in writing and answers to the highest level of management. As opposed to a "doer," the safety manager acts as a director and administrator of the safety program. This is accomplished through the advisory capacity of the safety program for solicited and unsolicited problems. The focus of the safety manager is on the system and how it contributes to safety problems, rather than individual problems. Management has the ultimate responsibility for safety. Their efforts should reflect a proactive attitude to correct problems in the system. In order to identify areas of interest, technically competent input from the safety manager should be required. The support of the safety program by top management determines the success of the program. Without a clear and firm commitment by the organization, safety will receive no more than lip service from the employees. The benefits of a proactive approach will be realized in the organization's ability to manage safety issues, rather than reacting to them. PMID- 10113761 TI - Managing EMS pilots: between a rock and a hard place. PMID- 10113762 TI - Update: The Commission on Accreditation of Air Medical Services. PMID- 10113763 TI - Night vision goggles may be in your future. PMID- 10113764 TI - A clinical nurse specialty could benefit your program. PMID- 10113765 TI - Personnel implications for health records staff. PMID- 10113766 TI - Records management--retention and patient access--a clinician's view. PMID- 10113767 TI - Medical audit--the measurement of quality and its implications for the medical record. PMID- 10113768 TI - A guide to the Access to Health Records Act 1990. PMID- 10113769 TI - Implementing paperless medical records. PMID- 10113770 TI - "There's a gap in my clinic.". PMID- 10113771 TI - Selective provider contracting: a viable program. AB - The contracting program more than fulfilled the expectations of its legislative sponsors. Substantial savings were achieved with little, if any, reduction in inpatient access for the recipients. PMID- 10113772 TI - Medi-Cal selective contracting creates inequities, limits access. AB - SPCP rate reductions, intended to encourage cost-effectiveness and efficiency, simply slash desperately needed funds. The reduced rates paid to Los Angeles county hospitals caused an estimated $130 million loss of Medi-Cal funds in the first four years of the contracting program alone. PMID- 10113773 TI - Medi-Cal challenge: strengthening the safety net. PMID- 10113774 TI - On the horizon: Medi-Cal managed care. PMID- 10113775 TI - Hospital makes tough decision to terminate Medi-Cal contract. PMID- 10113776 TI - "Disproportionate-share" hospitals receive extra funding. PMID- 10113777 TI - Selective contracting program too high a price to pay for cost savings. AB - An economist finds that compromised negotiation postures, payment disparities and potentially escalated government buying power may be too high a price to pay for cost reductions achieved through a "competitive" system. PMID- 10113778 TI - How to negotiate a Medi-Cal inpatient contract. PMID- 10113779 TI - How to prepare data for Medi-Cal negotiation. PMID- 10113780 TI - Consider impact before terminating Medi-Cal contract. PMID- 10113781 TI - The post Medi-Cal blues. PMID- 10113782 TI - No harmful emissions from microwaving waste. PMID- 10113783 TI - Plasma pyrolysis for clean medical waste treatment. AB - At Kaiser Permanente in San Diego, plasma pyrolysis will be used instead of incineration to treat hospital waste without creating corrosive gases, PVCs or groundwater-contaminating ash. Here's why plasma pyrolysis offers so much promise for waste treatment and why hospitals should follow this project closely. PMID- 10113784 TI - New law requires hazardous waste source-reduction plans. AB - For the first time, the state of California requires waste generators to be able to show official plans and reports for the source-reduction of hazardous waste. PMID- 10113786 TI - Comparative health systems: the future of national health care systems and economic analysis. PMID- 10113785 TI - Second defeat of compulsory health insurance. PMID- 10113787 TI - Comparative health systems. The United Kingdom. PMID- 10113788 TI - Comparative health systems. Canada. PMID- 10113789 TI - Comparative health systems. Japan. PMID- 10113790 TI - Comparative health systems. France. PMID- 10113791 TI - Comparative health systems. Sweden. PMID- 10113792 TI - Comparative health systems. Italy. PMID- 10113793 TI - Health care systems in ten industrial countries. PMID- 10113794 TI - Comparative health systems. The Netherlands. PMID- 10113795 TI - Comparative health systems. The United States. PMID- 10113797 TI - Ethylene oxide control technology II: Environmental protection. PMID- 10113796 TI - Comparative health systems. Switzerland. PMID- 10113798 TI - Update: whither medical waste? PMID- 10113799 TI - Addendum: chromium in incinerator ash. PMID- 10113800 TI - Knowing your customers opens opportunities for hospitals to target consumers. PMID- 10113801 TI - Hospitals, patients question right to know when practitioner acquires AIDS. PMID- 10113802 TI - AHA predicts disruptions in care after nation's highest court affirms nurses' right to sole unions. PMID- 10113803 TI - Reducing patient stays and improving satisfaction take one giant step. PMID- 10113804 TI - Patients can 'reach out and touch' workers, extending thanks at Kentucky hospital. PMID- 10113805 TI - Developing an ethical model for risk management. PMID- 10113806 TI - The effect of DRGs on termination-of-treatment issues. PMID- 10113807 TI - Ethics and the insurance broker. PMID- 10113808 TI - When the family wants 'everything' done: avoiding risk through informed consent. PMID- 10113809 TI - Terminating medical treatment: what risk managers need to know. PMID- 10113810 TI - ASHRM code of ethics. American Society for Healthcare Risk Management. PMID- 10113811 TI - The impact of technological advance on risk management. PMID- 10113812 TI - Demographics and health spending. PMID- 10113813 TI - State budget problems affect health care legislation. PMID- 10113814 TI - State legislative survey. PMID- 10113815 TI - Meeting the peer review challenge. PMID- 10113816 TI - Facilities planning under the new HCFA capital regs. PMID- 10113817 TI - A fix at the University of Texas Medical Branch. AB - PROBLEM: A well established teaching hospital geographically isolated is having difficulty getting physicians to refer patients to its island location. SOLUTION: 1) Purchase an electronic network connecting the hospital with physicians within about a 100-mile radius of the hospital; 2) choose a network that offers physicians insurance and demographic information, test results from various hospital departments. The network also will offer physicians the ability to complete pre-admission paperwork for a patient on the system, as well as obtain discharge summaries. Physicians also will be able to use the teaching hospital's medical library in their offices or in their homes. PMID- 10113818 TI - Nation's governors adopt broad reform strategy. PMID- 10113819 TI - The ideal of shared decision making between physicians and patients. PMID- 10113820 TI - The Human Genome Project and bioethics. PMID- 10113821 TI - Basic resources in bioethics. PMID- 10113822 TI - Japan's dilemma with the definition of death. AB - Japan is unusual among industrialized countries in its reluctance to use brain criteria to determine death and harvest transplant organs. This results from public distrust of the medical profession due to an earlier incident, and from concern that technological interventions will threaten religious and cultural traditions surrounding death and dying. Public acceptance is growing, however, as medical professional groups and universities develop brain criteria, and as pressure from patients who could benefit from a transplant, as well as from foreign countries, increases. PMID- 10113823 TI - Development of an institutional policy on artificial hydration and nutrition. AB - The issues involved in deciding whether to use artificial methods of delivering hydration and nutrition are often very difficult for patients, families, and health care providers. Once private and personal matters, these decisions now frequently involve the judicial system. Five years ago, Hospice of Washington recognized the need for a written policy and wrote the one published here. Its goal is to respect individual preferences and family concerns while addressing the nutrition and hydration needs of dying patients. The policy sets parameters on the issue, provides basic information, and encourages crafting the most fitting resolution to each situation. PMID- 10113824 TI - Judaism, justice, and access to health care. AB - This paper develops the traditional Jewish understanding of justice (tzedakah) and support for the needy, especially as related to the provision of medical care. After an examination of justice in the Hebrew Bible, the values and institutions of tzedakah in Rabbinic Judaism are explored, with a focus on legal codes and enforceable obligations. A standard of societal responsibility to provide for the basic needs of all, with a special obligation to save lives, emerges. A Jewish view of justice in access to health care is developed on the basis of this general standard, as well as explicit discussion in legal sources. Society is responsible for the securing of access to all health care needed by any individual. Elucidation of this standard of need and corresponding societal obligations, and the significance of the Jewish model for the contemporary United States, are considered. PMID- 10113825 TI - The Patient Self-Determination Act. PMID- 10113826 TI - Teaching ethics in the health care setting. Part I: Survey of the literature. PMID- 10113827 TI - The medical record. AB - In summary, the medical record not only helps a physician care for a patient, but may in the future also offer an indelible defense if the record is kept carefully and meticulously. 'In the courtroom, medical records are witnesses whose memory never dies.' PMID- 10113828 TI - Oregon moves closer to rationing care. PMID- 10113829 TI - College responds to HCFA's proposed Medicare fee schedule. PMID- 10113831 TI - Uncle Sam wants you to talk about community health. PMID- 10113830 TI - Why do blacks die young? AB - The gap in life expectancy between the races in America remains wide. The search for causes runs from poverty and prejudice to life-style. PMID- 10113832 TI - Coalitions strive for quality. PMID- 10113833 TI - Detroit wants coalitions in the driver's seat. PMID- 10113834 TI - Coalitions and spiraling health care costs. PMID- 10113835 TI - Guidelines for health care coalitions. PMID- 10113836 TI - Data watch. Coalitions across the country. PMID- 10113837 TI - Coalitions: the convergence continues. PMID- 10113838 TI - Performance standards for ionizing radiation emitting products: diagnostic x-ray systems and their major components; computed tomography equipment; removal of a requirement; citizen petition--FDA. Final rule. AB - The Food and Drug Administration (FDA) is issuing a final rule to remove a requirement in the performance standard for diagnostic X-ray systems and their major components regarding computed tomography (CT) equipment. PMID- 10113839 TI - Administration for Children and Families; general reorganization; statement of organization, functions and delegations of authority--HHS. PMID- 10113840 TI - Delegations of authority and organization; Ryan White Comprehensive AIDS Resources Emergency Act of 1990--FDA. Final rule. AB - The Food and Drug Administration (FDA) is amending the regulations for delegations of authority by adding a new authority delegated by the Assistant Secretary for Health to the Commissioner of Food and Drugs. The authority being added is under title XXVI of the Public Health Service Act, section 2672, Provisions Relating to Blood Banks, as amended. PMID- 10113841 TI - Medicare and Social Security: fraud and abuse; civil money penalties for misuse of certain terms, symbols and emblems--HHS. Final rule. AB - This final rule implements section 428(a) of Public Law 100-360 which authorizes the imposition of civil money penalties for the use--in advertising, solicitations or other communications--of certain words, letters, symbols or emblems associated with the Department of Health and Human Services' Social Security and Medicare programs in a manner that the user knows, or should know, would convey a false impression that (1) the communicated item was approved, endorsed or authorized by the Department or its programs, or (2) the responsible person or organization has some connection with, or authorization from, the Department or these programs. This rulemaking is designed to assist in protecting citizens from misrepresentations concerning the services offered and programs administered by the Social Security Administration and the Health Care Financing Administration. PMID- 10113842 TI - Federal Employees Health Benefits Program: medically underserved areas for 1992- Office of Personnel Management. Notice of medically underserved areas for 1992. AB - The Office of Personnel Management has completed its annual determination of the States that qualify as Medically Underserved Areas under the Federal Employees Health Benefits (FEHB) Program for calendar year 1992. This determination is necessary to comply with a provision of FEHB law that mandates special consideration for enrollees of certain FEHB plans who receive covered health services in States with critical shortages of primary care physicians. Accordingly, for calendar year 1992, OPM has determined that the following States are Medically Underserved Areas under the FEHB Program: Alabama, Idaho, Louisiana, Mississippi, New Mexico, North Dakota, South Dakota, West Virginia, and Wyoming. This list is the same as that for 1991, with the exception of the addition of Alabama. PMID- 10113843 TI - Medicare program; changes to the inpatient hospital prospective payment system and fiscal year 1992 rates--HCFA. Final rule. AB - We are revising the Medicare inpatient hospital prospective payment system to implement necessary changes arising from legislation and our continuing experience with the system. In addition, in the addendum to this final rule, we are describing changes in the amounts and factors necessary to determine prospective payment rates for Medicare inpatient hospital services. We are also setting forth the new target rate percentages for determining rate-of-increase limits for hospitals and hospital units excluded from the prospective payment system. This final rule also responds to the comments we received concerning changes to hospital payments made in a January 7, 1991 final rule with comment. These changes include midyear changes to the inpatient hospital prospective payment system that implemented several provisions of section 4002 of the Omnibus Budget Reconciliation Act of 1990. In addition, this final rule responds to comments received concerning changes in the procedures and criteria of the Medicare Geographic Classification Review Board (MGCRB) that were set forth in a June 4, 1991 final rule with comment period. PMID- 10113844 TI - Prospective payment system for inpatient hospital capital-related costs--HCFA. Final rule. AB - We are revising the Medicare payment methodology for hospital inpatient capital related costs for hospitals paid under the prospective payment system. As required by section 1886(g) of the Social Security Act, we are replacing the reasonable cost-based payment methodology with a prospective payment methodology for hospital inpatient capital-related costs. Under this prospective payment methodology, a predetermined amount per discharge will be made for Medicare inpatient capital-related costs. PMID- 10113845 TI - Medicare program; coverage of erythropoietin (EPO) used by competent home dialysis patients--HCFA. Interim final rule with comment period. AB - This final rule-- Provides for Medicare coverage of EPO used by ESRD beneficiaries who dialyze at home and are competent to use the drug without medical or other supervision; and Establishes criteria for selection of patients that can be considered "competent" and for monitoring of the patients who are selected. This rule is necessary to implement section 4201(d)(1) of the Omnibus Budget Reconciliation Act of 1990 (OBRA '90). The purpose is to facilitate use of EPO at home, while ensuring that such use of the drug is safe and effective. PMID- 10113846 TI - Medicare program; Peer Review Organizations: revised scopes of work for Delaware, Missouri, Montana, Nebraska, New Jersey, Nevada, Oklahoma, Rhode Island, South Carolina, Washington, and Wyoming--HCFA. Final notice. AB - This notice describes requirements for the review activities of Utilization and Quality Control Peer Review Organizations (PROs) for the next contract cycle in the States listed above. Section 1153(h)(1) of the Social Security Act requires us to publish any new policy or procedure adopted by the Secretary that affects substantially the performance of PRO contract obligations at least 30 days before the date the policy or procedure is to be used. Specifically, this notice describes significant changes in the way in which cases will be selected for review and also describes continuing requirements. This notice also implements provisions of the Omnibus Budget Reconciliation Act of 1990 and announces the future direction of the PRO program. PMID- 10113847 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); reimbursement of individual health providers--Department of Defense. Final rule. AB - This final rule implements the provisions of the Defense Appropriations Act for Fiscal Year 1991, Public Law 101-511, section 8012, which limits increases in maximum allowable payments to physicians and other individual health care providers and authorizes reductions in such amounts for overpriced procedures. PMID- 10113848 TI - Medicaid program; State share of financial participation--HCFA. Interim final rule with comment. AB - Under certain circumstances, States are currently permitted to use voluntary contributions (donated funds) from providers and all revenues from State-imposed taxes, as the State share of the costs of the Medicaid program. There is now widespread use of State donations or other voluntary provider payment programs that unfairly affect the Federal share of Federal Financial Participation (FFP). This practice circumvents the States' statutory obligation to expend funds for medical assistance. Therefore, effective January 1, 1992, this interim final rule requires that the amount of funds donated from Medicaid providers be offset from Medicaid expenditures incurred on or after this date before calculating the amount of FFP in Medicaid expenditures. It also interprets section 4701(b)(2) of the Omnibus Budget Reconciliation Act of 1990, which added section 1903(i)(10) to the Social Security Act. Section 1903(i)(10), precludes Federal Financial Participation (FFP) in State payments to hospitals, nursing facilities, and intermediate care facilities for the mentally retarded for facility expenditures that are attributable to provider-specific State taxes. PMID- 10113849 TI - Medicare program; review of information collection and recordkeeping requirements for providers of outpatient physical therapy and/or speech pathology services- HCFA. Final rule. AB - This final rule changes several regulations to reduce information collection and recordkeeping requirements. The requirements, which were identified by the Office of Management and Budget, are contained primarily in the Medicare conditions of participation for providers of outpatient physical therapy and outpatient speech pathology services, and the Medicare conditions for coverage of the services of physical therapists in independent practice. The purpose of this rule is to remove or make modification of those information collection and recordkeeping requirements and to explain the basis for retaining others. PMID- 10113851 TI - Don't look to states for a cure. PMID- 10113850 TI - Medicare program; explanation of enrollee rights and other provisions applicable to health maintenance organizations and competitive medical plans--HCFA. Final rule. AB - This rule revises current Medicare requirements relating to health maintenance organizations and competitive medical plans. It eliminates the requirement that an organization enroll two new Medicare beneficiaries for each present Medicare enrollee converted from a cost to a risk contract (the "two-for-one" rule), expands the amount and type of information which an organization must provide to enrollees, and requires annual notice of enrollees' rights under the plan. This rule also authorizes HCFA to terminate a contract with an organization for noncompliance with the composition of enrollment standard requiring that no more than 50 percent of an organization's membership be comprised of Medicare or Medicaid enrollees (hereinafter referred to as the "50/50 rule") and authorizes sanctions when an organization fails to comply with the 50/50 rule or the terms of any waiver or exception to that rule. These provisions conform our regulations with changes made by the Omnibus Budget Reconciliation Acts of 1986, 1987 and 1989. PMID- 10113852 TI - Governors talk turkey on health care. PMID- 10113853 TI - Profit from buying existing retirement communities. Eight rules to success. PMID- 10113854 TI - Medicaid taxes, donations pit feds against states. PMID- 10113855 TI - Not-for-profits feel the squeeze. PMID- 10113856 TI - Stability and low acquisition prices prevail. PMID- 10113857 TI - Issues & answers. Food service gains entree into care planning. PMID- 10113858 TI - Housekeeping departments come clean. CLTC survey finds problems, solutions. PMID- 10113859 TI - At-home spouses don't have to feel isolated. Facilities restore togetherness. PMID- 10113860 TI - There until the end. Hospice services build census, enhance image. PMID- 10113861 TI - Motivations, expectations, realizations. Questionnaire assesses CCRC (continuing care retirement communities) residents' experiences. PMID- 10113862 TI - Pack more punch. Developing high impact collateral materials. PMID- 10113863 TI - Bridging the gap. Joint ventures overcome financing/development chasm. PMID- 10113864 TI - The right chemistry. Measuring and assuring resident satisfaction. PMID- 10113865 TI - Ins and outs of discrimination. Fair Housing Act triggers sweeping changes. PMID- 10113866 TI - Climbing the management ladder. How to ease the transition from nurse to manager. PMID- 10113867 TI - Weighing nutritional status. Push under way for routine screening. PMID- 10113868 TI - The effects of AIDS & HIV research. AB - Scientific and clinical research in AIDS has not only contributed to an understanding of the disease itself, but also expanded our understanding of issues that span the length and breadth of the medical and biological sciences. PMID- 10113869 TI - AIDS legislation. AB - Significant and varied legislation relating to the AIDS crisis has been passed, and much remains pending for further debate. These measures, in various stages of the legislative process, affect PWAs and those who come into contact with the health care system. PMID- 10113870 TI - AIDS and public hospitals. AB - Public hospitals have assumed a disproportionate and growing share of AIDS care in the US, causing financial distress and disruption of services to patients with and without AIDS. PMID- 10113871 TI - Home and community care for children with AIDS. PMID- 10113872 TI - AIDS: an overview. PMID- 10113873 TI - Some concerns in providing home care for i.v. drug users. AB - Home care providers working with IV drug-abusing clients with HIV must deal not only with the physical and psychological effects of the disease but also with those that frequently accompany drug abuse. Clients may exhibit manipulative, violent behavior; continued use of street drugs may also interfere with their prescription drug therapy. To help assure the most effective treatment possible, caregivers must be aware of the symptoms and possible effects of clients' behavior. PMID- 10113874 TI - Bargaining units in acute care hospitals: the Supreme Court upholds NLRB rulemaking. PMID- 10113875 TI - Don't become a statistic. AB - Trained to help others, EMS personnel often fail to take care of themselves. Are you neglecting your personal needs? PMID- 10113876 TI - Shaping up. AB - EMS administrators across the country are turning couch potatoes into lean, mean rescuing machines. Is your squad physically fit? PMID- 10113877 TI - Solid waste management: a paradigm imperative. PMID- 10113878 TI - An investigation of maternal morbidity with identification of life-threatening 'near miss' episodes. AB - This study was designed to investigate the pattern of obstetric morbidity and to determine the frequency of serious life-threatening episodes as a basis for clinical audit. The records of over 2,000 maternities from a National Health Service Consultant Unit during a six-month period were analysed. Morbidity was noted in almost a quarter of the cases, and life-threatening episodes, termed 'near miss' morbidity, were identified. As the maternal death rate has fallen in this country, maternal morbidity has come to represent a more useful indicator of obstetric care than mortality. The results of this study identify the need for an agreed set of definitions for 'near miss' morbidity, and suggest that not only should it be included for discussion in unit perinatal meetings, but that Regional obstetric morbidity enquiries would provide valuable denominator data on morbidity. PMID- 10113879 TI - Newark Information Sharing Project: lessons for Medical Audit Advisory Groups. AB - This article describes one method of professional performance review which relies heavily on confidentiality and comparability. For the Newark Information Sharing Project, an association of five practices collected data for two years on registrations, workload, prevention, referrals, prescribing, and disease prevalence. After central collation, the averages and ranges were returned to the individual practices with their position confidentially indicated. Unlike previous reports of inter-practice comparisons, this project involved no research funds or special assistance. The time and financial costs are quantified. This model is suitable for adoption by Medical Audit Advisory Groups. PMID- 10113880 TI - Clinical standards to assist audit in medical rehabilitation. AB - The professional need for audit has been acknowledged and the discipline of rehabilitation medicine is now included in training programmes in general medicine and surgery. In rehabilitation medicine the data which would allow medical audit to take place have not always been recorded in routine clinical practice. However, the measurements required are not difficult, and have been validated by extensive research in academic units. This paper describes a series of simple, reliable measures and tests which can be used as baseline measures of progress in patients following rehabilitation programmes. It is essential that rehabilitation specialists are familiar with, and use, these basic tools, so that the usefulness of different treatments can be assessed, and their value accurately audited. PMID- 10113881 TI - Needs assessment needs assessment.... AB - Needs assessment is now a high priority, but it is conceptually muddled and technically difficult. In the past a variety of academic disciplines addressing different aspects of health care have produced a range of definitions on 'need' applicable to their own setting. In the context of the National Health Service Review, 'need' may best be defined as the ability to benefit from 'health care', which depends both on morbidity and on the effectiveness of care. An analysis of its relationship with 'demand', which is the health care that people ask for, and 'supply', which is provided, exposes the limitations of current information sources, and confirms that the formal assessment of needs will inevitably be a lengthy task. Despite these difficulties there is much that can and should be done incrementally to influence contracts between providers and purchasers towards meeting health care needs. PMID- 10113882 TI - The evolution of a Regional Cancer Organisation: the Yorkshire model. PMID- 10113883 TI - Four-year retrospective survey of fire incidents in a psychiatric hospital. AB - This paper describes a four-year retrospective survey of fire incidents in a psychiatric hospital. The results suggest that there were sufficient similarities between a fire incident and a violent incident for the former to be included in a hospital register of violent incidents. The authors recommend that fire incidents should be studied prospectively, and that hospital fire officers should be an integral part of the multidisciplinary team auditing such incidents. PMID- 10113884 TI - The impact of the observation ward on acute admissions at Guy's Hospital. AB - This paper describes an evaluation of the short-stay ward at Guy's Hospital Accident and Emergency Department. It includes an audit of the operational policy, the care provided to patients, and the impact of the short-stay ward on hospital admissions. The results indicate that by concentrating patients in a short-stay ward, the quality of care is improved, delays are reduced, and the pressure on inpatient beds is relieved. PMID- 10113885 TI - Who should review the walking wounded? Reattendance at accident and emergency departments. AB - There has been great variation between District Health Authorities in the proportion of attenders at Accident and Emergency Departments who reattend for further care. Eight Accident and Emergency Departments were studied during 1987 to ascertain the extent to which this reflects different medical policies. Information extracted from a random sample of 4,682 first attendances found that the sample reattendance rates lay closer together than the reported ones, with only a three-fold, rather than a six-fold variation between departments. Important causes of the exaggerated variation in the reported rates were different ways of organising follow-up clinics, and differences in hospital and departmental practices of aggregating and reporting statistics on activities in these clinics. The variation between departments in their booked reattendance rates could not be explained by differences in case-mix or treatment practices. The results of this study suggest that differences in medical and organisational policies produce different reattendance rates. However, it is not known which of the different management policies on reattendance are the most cost-effective. PMID- 10113886 TI - Speech therapy and elderly people: a study of therapists' attitudes. AB - This paper describes a survey of the attitudes of speech therapists towards working with elderly people. The findings are compared to those of similar studies of medical students and physiotherapists. A positive orientation towards the elderly was found to relate to the time spent working with older people, but not to the time since qualifying. The results indicate a marked increase in the amount of teaching and clinical experience received by speech therapy undergraduates, and demonstrates that training might not be influencing therapists' attitudes to the elderly. The implications of these findings on the services for the elderly are discussed. PMID- 10113887 TI - Methods of determining the cost of health care in the Department of Veterans Affairs medical centers and other non-priced settings. AB - Cost is increasingly important in the evaluation of health care. Though charges are often used as a proxy for cost, some health care systems such as the Veterans Administration do little or no billing. This article describes, presents examples of, and evaluates four options for determining the cost of care within the Department of Veterans Affairs: measuring input costs, the Department's cost accounting system, the reimbursement system, and use of charges from a surrogate health care facility. Each approach is evaluated for accuracy, ability to compare the costs of different treatments, and effort required to estimate cost. PMID- 10113889 TI - The 10-cornered hat approach to fund-raising strategy. PMID- 10113888 TI - Validity and reliability of psychosocial factors related to breast cancer screening. AB - This research explored the construct validity of hypothesized survey items and data reduction procedures for selected psychosocial constructs which are frequently used in breast cancer screening research. Factor analysis was used to validate relationships between survey items and hypothesized constructs suggested by several theories of behavior change. These constructs included perceived barriers and benefits of breast cancer screening compliance behavior. Reliability analyses were then used to evaluate the consistency of the resultant scales applied across three data sets, resulting from surveys conducted by two different methods (telephone and in-person interview) over three time periods. These analyses found reliability coefficients ranging from .53 to .69. PMID- 10113890 TI - A hospital employee giving program. PMID- 10113891 TI - A collision of timetables. PMID- 10113892 TI - The International Medical Scholars Program (IMSP). Objectives and philosophy. PMID- 10113893 TI - The International Medical Scholars Program (IMSP). Selection of applicants and development of educational experiences. PMID- 10113894 TI - Some things the state medical board can not do. PMID- 10113895 TI - The impaired physician: a legal view. PMID- 10113896 TI - Medical boards and the physician with impaired sexual behavior. PMID- 10113897 TI - Market offers few slots for hospital burn centers. PMID- 10113898 TI - Real estate investments demand strategic planning, objectives. AB - Real estate may present a great opportunity for institutions to positively affect their bottom lines. But it takes planning and foresight to achieve a solid real estate plan. In the following article, the author describes the process necessary to develop a program that goes beyond converting empty buildings into nursing homes. The process goes from identifying strategic objectives to examining financial alternatives and preparing an implementation plan. PMID- 10113899 TI - Administrators should help restore the image of physicians. AB - Physicians are being knocked from the proverbial pedestal by every conceivable player involved in health care: the consumer, the federal government, the payer. How can hospitals, specifically administrators, aid in revamping the image? In the following article, the author proposes several steps to help physicians recover their image--and perhaps build loyalty to the institution in the process. PMID- 10113900 TI - Health care proposals call for mere tinkering to overhaul. AB - What approaches are available to the health care industry in repairing its own inequities and providing care for millions of Americans? Which one of three umbrella proposals provides the best route for change? Or is there a best route? The following summary of Blue Cross and Blue Shield's Environmental Analysis 1991 examines the major proposals on the drawing board: centralized reform, regulated pluralism and incremental change. PMID- 10113901 TI - CEO holds keen observer role. Interview by Donald E.L. Johnson. AB - What tactics does the successful head of a hospital system use to keep that system in check? How does that chief interact with his or her board in running the individual institutions? In the following interview with Health Care Strategic Management's Donald E. L. Johnson, David A. Reed, president and chief executive officer of the St. Joseph Health System, a system with seven acute care hospitals in California and Texas, affiliations with additional institutions and numerous other HMO and insurance ventures, discusses developing rapport with key players as well as creating a strategic plan. PMID- 10113902 TI - Sleep centers' outlay can reap rewards. PMID- 10113903 TI - Changing physician behavior is tool to reduce health care costs. AB - Hospital administrators in the next decade will be looking at every avenue to reduce health care costs at the suggestion of the payers and patients. What is the role of physicians in such an effort? In the following article, the authors discuss the pros and cons of influencing physician practice patterns to cut excesses and improve quality of care. They summarize the "influencing strategies" and explain why some of them will create opposition among practitioners. PMID- 10113904 TI - CEO-MD ties focus for future. AB - Now more than ever, hospitals and physicians must work closely if both are to succeed in the future. This is just one conclusion, if not the most important one, of a recently released study by the American College of Healthcare Executives and Arthur Andersen and Co., reviewed in this issue. PMID- 10113905 TI - Hospitals need strategies for collaboration, competition. PMID- 10113906 TI - Planning indicators. Premiums soar, employers' rates up for coverage. PMID- 10113907 TI - Hospital agenda to prioritize. Interview by Donald E. Johnson.. AB - How does a teaching hospital balance the needs of patient care with its educational mission? What changes in focus must the CEO make to accommodate reductions in federal funding while maintaining academic excellence? In the following interview with Health Care Strategic Management's Donald E. L. Johnson, John D. Forsyth, executive director of the University of Michigan Hospitals, discusses the challenges facing his institution. The interview focuses on many topics including setting priorities, funding researchers and countering any "anti science" perceptions. PMID- 10113908 TI - How networks reshape organizations--for results. AB - Recently a new term-networks-has entered the vocabulary of corporate renewal. Yet there remains much confusion over just what networks are and how they operate. Ram Charan, a leading international consultant, has spent four years observing and participating in the creation of networks at ten companies in North America and Europe. These companies--which include Conrail, Dun & Bradstreet Europe, Du Pont, and Royal Bank of Canada-are clear about why they are creating networks, what networks are, and how they operate. A network is recognized group of managers (seldom more than 100, often fewer than 25) assembled by the CEO. Membership criteria are simple but subtle: What select group of managers, by virtue of its business skills, personal motivations and drive, and control of resources is uniquely positioned to shape and deliver on the strategy? Networks begin to matter when they change behavior-the frequency, intensity, and honesty of the dialogue among managers on priority tasks. The process of building a network starts at the top. Senior managers work as change agents to build a new "social architecture." Once the network is in place, they play three additional roles: 1. Define with clarity the business outputs they expect of the network and the time frame in which they expect it to deliver. 2. Guarantee the visibility and free flow of information to all members of the network who need it. 3. Develop new criteria for performance evaluation that emphasize horizontal collaboration and leadership. PMID- 10113909 TI - Service comes first: an interview with USAA's Robert F. McDermott. Interview by Thomas Teal. PMID- 10113910 TI - The case of the unhealthy hospital. AB - On a cold March morning, Bruce Reid, Blake Memorial Hospital's new CEO, visited the Lorris housing project clinic, one of six off-site clinics operated by Blake Memorial. He was not encouraged by what he saw: peeling paint, leaking pipes, and cramped conditions. When he asked Renee Dawson, the clinic's primary care physician, how she endured the conditions, she just stared at him. "What are my options?" she asked. That was a good question. Blake Memorial was in poor financial health, due to rising costs and stagnating revenue. The hospital's quality of care was also a major problem. In addition, the clinics were losing over $250,000 a year. As Reid worked on Blake Memorial's 1992 budget, he saw he would have to cut some services in order to fund others. One of the services he was considering cutting was the clinic program. But there were a number of conflicting forces that Reid had to consider. On the political front, the recently appointed commissioner of health services said she would challenge Blake Memorial's tax-exempt status if Reid dismantled the clinics. Within the hospital were two warring factions. One wanted more high-tech services for the hospital and favored closing the clinics. "Instead of clinics, we should have a shuttle bus from the housing projects to the hospital," one doctor suggested. The other faction wanted to expand the clinics. "Wherever the service is most needed, that is where the hospital should be," argued the clinics' director. Reid must decide what to cut and what to keep. But to do so, he must first settle on Blake Memorial's long-term mission.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10113911 TI - Knee-deep and rising: America's recycling crisis. AB - Every year, Americans generate 180 million tons of solid waste, 70% of which goes into landfills. Since 1979, the United States has exhausted more than two-thirds of its landfills; another one-fifth will close over the next five years. Solving the problem will require a new understanding between industry and government--an understanding that combines industry competence and government authority. But the two sides are mired in an unfortunate combination of good intentions and failed systems. A classic example that epitomizes the problem is the recycling of plastics. Two stories capture the sense of chaos that pervades the recycling of plastics. The first is a comedy of errors played out in Minneapolis, Minnesota, where the city council passed a measure that would have banned all plastic packaging from the city. In this case, the government acted without the competence of industry. The second story involves McDonald's decision to abandon its polystyrene packaging and switch to plastic-coated paper. In this case, a single business's approach to recycling proved fruitless because of the lack of government authority. According to the authors, five principles provide the underpinnings to a new solid-waste management infrastructure: business and government are partners; the infrastructure is a system and must operate in balance; economics and politics must act as partners; all levels of government have roles to play; and generating less trash and recycling more depends on a workable system. Setting up the system will require an infrastructure that balances supply and demand, an advisory committee to manage the infrastructure, and a management system that uses incentives and disincentives to balance the system. PMID- 10113912 TI - Is American business working for the poor? AB - At first glance, poverty seems to have little to do with business. When most people--managers included--think about poverty, they assume that people are poor because they are isolated from the mainstream economy, not productive participants in it. But according to Harvard University professors Mary Jo Bane and David Ellwood, this is a misleading image of the true face of poverty in the United States today. Most poor adults--and a full 90% of poor children--live in families where work is the norm, not the exception. Poor people often work or want to work. But at the low-wage end of the American economy, having a job is no guarantee of avoiding poverty. Poverty is a business issue, then, because the American poor are part of the American work force. And this poses a problem for managers. In a more competitive and fast-changing economic environment, the performance of companies increasingly depends on the capabilities of their employees. In response to this human-resource challenge, more and more managers are embracing the language of "empowerment". And yet how can low-wage employees believe empowerment when their experience of work is, quite literally, impoverishment? It is unlikely that American companies can create the work force of the future with the poverty policies of the past. Fortunately, there are some simple policy mechanisms that can assist the working poor without putting an undue burden on business. Enacting them, however, requires managers to see poverty policy as one part of a national human-resource strategy that links the strategic concerns of companies to a broad social agenda. PMID- 10113913 TI - The service-driven service company. AB - For more than 40 years, service companies like McDonald's prospered with organizations designed according to the principles of traditional mass-production manufacturing. Today that model is obsolete. It inevitably degrades the quality of service a company can provide by setting in motion a cycle of failure that produces dissatisfied customers, unhappy employees, high turnover among both--and so lower profits and lower productivity overall. The cycle starts with human resource policies that minimize the contributions frontline workers can make: jobs are designed to be idiot-proof. Technology is used largely for monitoring and control. Pay is poor. Training is minimal. Performance expectations are abysmally low. Today companies like Taco Bell, Dayton Hudson, and ServiceMaster are reversing the cycle of failure by putting workers with customer contact first and designing the business system around them. As a result, they are developing a model that replaces the logic of industrialization with a new service-driven logic. This logic: Values investments in people as much as investments in technology--and sometimes more. Uses technology to support the efforts of workers on the front lines, not just to monitor or replace them. Makes recruitment and training crucial for everyone. Links compensation to performance for employees at every level. To justify these investments, the new logic draws on innovative data such as the incremental profits of loyal customers and the total costs of lost employees. Its benefits are becoming clear in higher profits and higher pay- results that competitors bound to the old industrial model will not be able to match. PMID- 10113914 TI - Services under siege--the restructuring imperative. AB - Recent job losses in the U.S. service sector do not reflect a temporary recession. Those jobs are gone, the result of a massive restructuring of the sector that is just getting under way. The explanation for the restructuring is quite simple. Until recently, services have been shielded by regulation and confronted by few foreign competitors. They have allowed their white-collar payrolls to become bloated, their investment in information technology to outstrip the paybacks, and their productivity to stagnate. Now competition is heating up and exposing these inefficiencies. Just as intense competition forced the restructuring of Smokestack America in the 1980s, deregulation and foreign direct investment are shaking out service companies that cannot confront their shortcomings. The need for sweeping change in the service sector may come as a great shock to Americans who saw services as the means to continued economic prosperity. But there is a painful irony at work: job creation, the very thing proponents use to demonstrate the U.S. service sector's strength, is in fact a symptom of the sector's chronic neglect of economic efficiency. It is precisely that neglect that makes the service sector vulnerable as the race for market share intensifies and new players shift the terms of competition. Services must respond to the new competitive environment, but not by indiscriminate cost cutting. Instead, they should balance financial discipline with a comprehensive and immediate reexamination of strategy. PMID- 10113915 TI - The boundaries of business: commentaries from the experts. PMID- 10113916 TI - Samuel P. Martin on CEOs and security's role. PMID- 10113917 TI - Special report. When emergency backup power fails: what seven hospitals learned. PMID- 10113918 TI - Could your hospital win a Baldridge Award for quality improvement? PMID- 10113919 TI - Experts tell how you can create customer loyalty. PMID- 10113920 TI - How to calculate customer participation. PMID- 10113921 TI - You can boost revenue through employee sales training. PMID- 10113922 TI - American Medical Record Association position statement. Mandatory reporting of external causes of injuries and poisonings. PMID- 10113923 TI - American Medical Record Association position statement. The computer-based record: an essential technology for healthcare. PMID- 10113924 TI - More about recruitment--pick me! AB - In the search for the elusive perfect job, one critical activity you should not neglect is reading. Read solid books and articles about what is new and happening in the medical record/health information management environment. But also through reading and research, pursue insights into the ever-changing healthcare environment so that healthcare administrators can be impressed with your up-to the-minute knowledge and awareness of issues. Do not neglect to bone up on career planning and recruitment. How-to's about the career chase can be most helpful. We hope that our review of the recruitment picture from the candidate's point of view will help you reach your job placement goals. A career advancement can be an energizing and invigorating experience. If you win and get what you want, as soon as you can, be sure to document how you did it and the errors or pitfalls you experienced. The next time you enter the job candidate pool, you can profit by your experiences. Do not forget to thank those who helped you in your endeavors. You will be glad later that you did because those receiving your thanks will remember you favorably. PMID- 10113925 TI - Medical documentation and record management in Germany. AB - In the mid-1960s, the author was assigned the responsibility of modifying American medical record concepts, policies, procedures, and technology for a new university medical center in Berlin. Her basic design is now the law of the land in Germany. Here she describes health record information practices in Germany. PMID- 10113926 TI - The search for quality: an examination of current healthcare efforts. PMID- 10113927 TI - A survey of opinions concerning recruitment for the profession among the members of the Virginia Medical Record Association. AB - A MRA has employed Market Strategies, Inc. (MSI), to undertake a nationwide corporate communications study and campaign. This article discusses a project MSI carried out for the Virginia Medical Record Association. PMID- 10113928 TI - Counterpoint. Membership update continued. PMID- 10113929 TI - Recruiting and interviewing. PMID- 10113930 TI - Medicare, physicians and due process. AB - The physician's expectation of payment under the Medicare program is not a property right that the Constitution will protect. However, changes in certain aspects of the law do bode well for further scrutiny of carrier behavior. PMID- 10113931 TI - Nancy E. Gary, MD: providing HCFA with a new perspective on the 'hassle factor':. Interview by Janice C. Simmons. AB - As senior medical adviser to Health Care Financing Administration head, Gail Wilensky, Dr. Gary provides the agency with a physician's view on issues and has become a liaison with the medical community--with an open ear to the regulatory hassles that beset practicing physicians. PMID- 10113932 TI - Physician payment reform: back on track? PMID- 10113933 TI - Will guidelines save us? PMID- 10113934 TI - I can't get no (physician) satisfaction. PMID- 10113935 TI - Public speaking: a fate worse than death? PMID- 10113936 TI - Don't leave the politics of health care solely to the politicians. PMID- 10113937 TI - What is an internist? American Society of Internal Medicine. PMID- 10113938 TI - Rights, responsibilities and the power to negotiate. AB - Physicians sometimes may be overstepping their bounds, sometimes forgetting who has the right. Much of what physicians do today is actually a negotiation or balancing of power as government deals with segments of its society, says ASIM's President-Elect. PMID- 10113940 TI - Implementing guidelines: insurers take varied approaches. PMID- 10113939 TI - Physicians and their rights: a conversation with AMA's Kirk B. Johnson, JD. Interview by C. Brown Roehrig. AB - The American Medical Association's general counsel says physicians are in a Catch 22 situation: Although physicians do have certain rights, when the government is paying for services, it has a right to ensure they are necessary and are of reasonable quality. PMID- 10113941 TI - The medical community and evolving strategies for parameter implementation. PMID- 10113942 TI - J. Jarrett Clinton, MD: guiding the Agency behind guidelines development. Interview by Janice C. Simmons. PMID- 10113943 TI - The hassle factor one year later: many changes, but many miles to go. PMID- 10113944 TI - The tort system's influence on the cost of health care. PMID- 10113945 TI - Don't kill the messenger: a lesson for physicians. PMID- 10113946 TI - Implementation of practice guidelines: the next frontier. PMID- 10113947 TI - Removing the warehouse from cost-conscious hospitals. PMID- 10113948 TI - Moving "just-in-time" toward a stockless system. PMID- 10113949 TI - UR: a hospital's perspective. PMID- 10113950 TI - New law curbs UR companies. PMID- 10113951 TI - The use or misuse of tangible property. PMID- 10113952 TI - Texas nurses help Romanian colleagues. PMID- 10113953 TI - A paradigm shift. PMID- 10113954 TI - Small hospitals save big by trimming utility bills. PMID- 10113955 TI - Management consulting. Marketplace--horses for courses. PMID- 10113956 TI - Management consulting. Big v small--size isn't everything. PMID- 10113957 TI - Management consulting. Project management--passing on the skills. PMID- 10113958 TI - Management consulting. Overview. Helping--at a price. PMID- 10113959 TI - Management consulting. First steps--before you start... . PMID- 10113960 TI - The repossession of maternity ward M3. PMID- 10113961 TI - Passed with flying colours. PMID- 10113962 TI - The case for legal tendering. PMID- 10113964 TI - Health revolution brings the system down. PMID- 10113963 TI - Chaos has no victors. PMID- 10113965 TI - When two halves make total sense. PMID- 10113966 TI - Heads you win. PMID- 10113967 TI - A good measure for Eurohealth? PMID- 10113968 TI - Case for auditing audit. PMID- 10113969 TI - Health Advisory Service at the crossroads. PMID- 10113970 TI - On the road and heading towards Quality Street. PMID- 10113971 TI - Waste not, want not. PMID- 10113972 TI - Equity and efficiency. PMID- 10113973 TI - How to make a future champion. AB - Conflict between GP fundholders and health authorities could blow the health reforms apart--but co-operation could help improve the nation's health, argue Chris Ham and Chris Heginbotham. PMID- 10113974 TI - Stormy days ahead. PMID- 10113975 TI - Unable to manage. PMID- 10113976 TI - Computing--disasters, security and patient confidentiality. Security red alert. PMID- 10113977 TI - Computing. Guardians or gizmos. AB - Carefully planned security management strategies are as important as the latest gadgets for ensuring patient details stay confidential, says Barry Barber, while Bill Goodwin examines the case for a risk analysis and management package. PMID- 10113978 TI - Computing. Keeping it in the family. AB - There is no legal obligation on health authorities to ensure the confidentiality of patients' data. Simon Jenkins argues that this helps neither Joe Bloggs nor John Major. PMID- 10113979 TI - Standing up for equality and justice. PMID- 10113980 TI - Playing the waiting game. AB - A project aimed at improving an outpatient department unearthed bad organisation and communication and poor environment. Penelope Dash describes how managers and clinicians worked together to tackle these problems and discovered that dramatic improvements could be made within existing resources. PMID- 10113981 TI - Towards user power. AB - In the first of two articles, Vivien Lindow says managers of mental health services should consult their users by facilitating some form of patients' group. PMID- 10113982 TI - Best for Britain? AB - Work in Oregon to develop a system for explicit rationing of healthcare has attracted worldwide attention. But, say Morton Warner and colleagues, it isn't a model the UK should follow. PMID- 10113983 TI - Lessons in class. AB - In the second of two articles, Jenny Griffiths and colleagues look at the evolution of health promotion in Oxford region over five years in the light of The Health of the Nation. PMID- 10113984 TI - A healthy start? PMID- 10113986 TI - Pain of going public. PMID- 10113985 TI - Experts, lies and stereotypes. AB - In the second of two articles in involving mental health users in service development, Vivien Lindow discusses the Catch-22 of stigma and representativeness. PMID- 10113987 TI - Computing--the art of buying a system. Craft and graft. PMID- 10113988 TI - Computing. Informed decisions. AB - A key factor in providing a total integrated healthcare system is clear collaboration with suppliers, says Tony Scott, while Jon Melling looks at systems procurement in the US. PMID- 10113989 TI - Computing. Good tools, good workers. AB - The integrated approach to computing at Milton Keynes General Hospital has meant that staff feel a real sense of ownership and control which in turn benefits staff and patients, says Barbara Millar. PMID- 10113990 TI - What makes a magnet? PMID- 10113992 TI - Rating the estate. PMID- 10113991 TI - Divided opinions. PMID- 10113993 TI - Quality time. PMID- 10113994 TI - A quality status symbol. PMID- 10113995 TI - The challenge lies in pulling together. PMID- 10113996 TI - Unnatural selection. PMID- 10113997 TI - On target for health. PMID- 10113998 TI - Managing the estate. "Third resource" for the future? PMID- 10113999 TI - Managing the estate. How to get back on the board. PMID- 10114000 TI - Managing the estate. Signpost to success. PMID- 10114001 TI - Managing the estate. Striking the right balance. PMID- 10114002 TI - Defeated by the system. PMID- 10114003 TI - How a longstanding P & T Committee identifies and meets current therapeutic challenges. AB - The P & T Committee at the University of Michigan, Ann Arbor, has run smoothly for some time. Nevertheless, it is not immune to today's fiscal and drug therapy challenges. In this exclusive Hospital Formulary interview, Dr. Jeoffrey Stross, chairman; Dr. Richard deLeon, secretary; and Dr. Burgunda Volger, a key University Hospital P & T Committee member, candidly describe their committee's philosophy and the mechanics by which it functions. This committee uses restriction to modify inappropriate prescribing, but it also carries out educational activities. As newer, more expensive, therapies become available, the responsibility to ensure efficacious, safe, economical therapy becomes increasingly complex. The following discussion highlights some of their strategies for success. PMID- 10114004 TI - Drug usage evaluation: H2-receptor antagonist use in 30 hospitals. AB - In this 30-hospital survey, data on usage, adverse drug reaction (ADR) rates, and drug interactions (DI) of the H2-receptor antagonists (H2RA) cimetidine, ranitidine, and famotidine were analyzed. Approximately 8% (1,768 patients) admitted to participating hospitals received an H2RA (range: 0.5 to 30%). Patients admitted to a critical care area were significantly (p less than 0.025) more likely to receive ranitidine, were more likely (p less than 0.005) to receive more than one H2RA, and were more likely (p less than 0.0005) to receive an H2RA for "stress ulcer" or a "history of peptic ulcer disease". Doses of the H2RAs were appropriate in less than 50% of cases. Sixty ADRs and 29 DIs were reported. There was no significant difference (p greater than 0.70) between cimetidine and ranitidine with regard to the number of ADRs reported; however, cimetidine was associated with a significantly greater (p less than 0.0005) number of reported DIs. The results of this utilization review indicate that H2RAs are frequently prescribed drugs in hospitalized patients. All ADRs and DIs were reported in patients in critical care areas, suggesting that these patients are "at risk" of developing side effects to H2RAs. PMID- 10114005 TI - How involved is hospital administration in your P & T Committee? PMID- 10114006 TI - HA-1A monoclonal antibody (centoxin) guidelines. Ad hoc Austin City-Wide Formulary Committee for Review of HA-1A. PMID- 10114007 TI - A quick reference chart for pediatric therapeutic drug monitoring. AB - Several factors, including dose administered, sample time, and method of administration, can affect serum drug concentration determinations. These factors can vary widely, especially in the pediatric population, leading to attainment of serum concentrations that are uninterpretable. A quick reference chart was developed to assist pharmacists, nurses, and residents to optimize the number of appropriately-obtained serum drug concentrations. PMID- 10114008 TI - Documentation of pharmacist interventions in a decentralized unit dose system. AB - The purpose of this study was to justify the increased costs of providing decentralized pharmacy service by defining therapeutic interventions as they relate to improved patient care and by documenting cost savings generated by decentralized pharmacist interventions. Data were collected on a daily basis from information provided by the decentralized pharmacists using a daily worksheet. The various interventions were then categorized as cost-saving interventions and therapeutic interventions. Decentralized pharmacist interventions do provide important therapeutic interventions as well as cost-effective interventions. The total cost-saving interventions in 1989 was $126,509 and this included the automatic drug conversions. The pharmacists also provided 2506 therapeutic interventions. PMID- 10114009 TI - Use of paper clips in organizing unit dose fills. AB - A system is described that improves the quality of medication cart filling, increases the speed and quality of medication cart checking, and decreases omissions or incorrect dosage errors in medication administration. In a system where scheduled medications and PRN medications are kept in separate drawers, all of the patients' oral medications are attached by a paper clip to a long (2" x 10") card. The medications are organized so that each dose is separated, even when two tablets equal one dose. A medication given three times a day will have three consecutive but separate paper-clipped doses to the card. Nursing and pharmacy staff have an improved ability to check for compliance of medication administration at the end of each shift. PMID- 10114010 TI - Get it in writing: documenting immunizations. PMID- 10114011 TI - Cost-effective implementation of clinical pharmacy services in an ambulatory care clinic. AB - Implementation of clinical pharmacy services in the current economic environment of the health care system requires cost justification of the service in addition to quality patient care services. Herein described is the evaluation of the cost effectiveness of a clinical pharmacy service implemented in an ambulatory care clinic of a regional Veterans Administration Medical Center. This evaluation assessed the ability of a clinical pharmacist to decrease the prescribing of nonsteroidal anti-inflammatory drugs (NSAIDs) by clinic physicians. Through analysis of prescription data prospectively collected for a period of 18 months, average cost of NSAIDs both before and after initiation of a clinical pharmacy presence was evaluated. A comparison was made between Evaluation Clinic providers (EC) and all other ambulatory care providers (OAC). The decrease in the average cost/prescription of NSAIDs for EC and OAC was 23.4% and 5.2% (P less than 0.005), respectively. This decrease was associated with a net annual savings in drug costs of $38,776. This single intervention cost-justified a clinical pharmacist's position. PMID- 10114012 TI - Time limit on multidose vials after initial entry. PMID- 10114013 TI - Biotechnology--1991. PMID- 10114014 TI - Pharmacy design--1989. PMID- 10114015 TI - A database model for medical consultation. AB - The database model presented in this article is suitable for applications in which queries may require noncrisp references to certain attributes. The data item (attribute) values may be crisp or fuzzy. For instance, such adjectives as "high" or "normal" may be attribute values for the attribute "blood pressure." A disease or a condition can be described by a number of symptoms which may be crisp alphanumeric values or fuzzy terms such as "high" or "normal." A query into this database can retrieve diseases which have "similar" symptoms. The similarity or "indistinguishability" is a measure defined by the database user on the relations that describe a family of diseases. This database system in conjunction with a rule base can provide the framework for a medical consultation system. PMID- 10114016 TI - Computer human interaction for image information systems. AB - Increasingly images are being incorporated into computer-information systems, allowing faster and more reliable access to legal documents, fingerprints, medical images, and so on. But designing viable computer-human interactions (CHI) for image-information systems can be particularly difficult. This article presents an overall approach to developing viable image CHI involving user metaphors for comprehending image data, and methods for locating, accessing, and displaying computer images. Since medical-image applications involve almost all image display problems, a medical-image radiology-workstation application is used as a driving example to present critical image CHI issues. PMID- 10114018 TI - What happens because of how we choose: the case of children. PMID- 10114017 TI - How do healthcare teams measure up? PMID- 10114020 TI - Partnering strategies and tactics. PMID- 10114019 TI - Partnering--the ultimate alliance. PMID- 10114021 TI - Five pitfalls of managing in a recession. PMID- 10114022 TI - Come the revolution. A conversation with Noel M. Tichy. Interview by Joe Flower. PMID- 10114023 TI - The way it was. Excerpts from Fifty Years: an anthology by ten contributors who helped shape the history of California hospitals. PMID- 10114024 TI - The new marketing. PMID- 10114025 TI - Pioneering quality in the intermountain West. PMID- 10114027 TI - Breast cancer activism: the birth of a movement. PMID- 10114026 TI - Physician payment reform. PMID- 10114028 TI - Hospital mergers and acquisitions: satisfying the constituencies. PMID- 10114030 TI - An interview with the College's Chairman, Paul Ellison. Interview by Walter Wachel. PMID- 10114029 TI - Peer review: current law and policy problems. PMID- 10114031 TI - Break down walls with business integration. PMID- 10114032 TI - A question of governance: who's leading whom? PMID- 10114033 TI - Remaking the medical staff. PMID- 10114034 TI - Meeting hospital community benefit standards. PMID- 10114035 TI - Team building: back to basic values. PMID- 10114036 TI - Conversations: a trustee, physician, and CEO respond. Interview by S. Spence Meighan and Walter Wachel; comment. PMID- 10114037 TI - What is the likely impact of the safe-harbor regulations on hospital-physician partnerships and how should boards proceed in view of these changes? PMID- 10114038 TI - CA hospital 'recycles' a 10-year-old building as urgent care center. PMID- 10114039 TI - Use of housekeeping and laundry contract services to increase--but slowly. PMID- 10114040 TI - Is it time to upgrade your parking garage's lighting? PMID- 10114041 TI - EPA outlines status of PCB-transformer rules. PMID- 10114042 TI - Manual standardizes project documents. PMID- 10114043 TI - Uniforms, surveys 'market' departmental image. PMID- 10114045 TI - Lighting retrofit reaps 18-month payback. PMID- 10114044 TI - Vendor quality key to keeping repair costs low. PMID- 10114046 TI - Questions arising in implementing federal patient self-determination requirements. PMID- 10114047 TI - Refusals to authorize treatment held not to bar necessary care. PMID- 10114048 TI - Integrated monitoring can detect critical events and improve alarm accuracy. AB - A computer-based, integrated monitor system was designed and utilized to collect and interactively manage physiologic data (13 variables and 3 waveforms) from six routinely used operating room monitors. Various approaches were developed to reduce false alarms, classify waveforms, and recognize events. False alarms: false alarms in ECG heart rate detection were reduced from 37.3% to 2.6% (p=0.005) of total alarms using multi-variable analysis and rate-of-change limits. Waveform classification: using artificial neural networks (AN), CO2 waveforms were classified into (a) spontaneous, (b) mechanical, and (c) mechanical/with spontaneous breathing attempts. The system properly classified 47 of 71 spontaneous, 65 of 67 mechanical, and 37 of 44 mechanical breaths/with spontaneous breathing attempts. Another ANN was used for detection of elevated and depressed ST segments in the ECG signal. All ST segment elevations and depressions of 0.1 mV were correctly identified. Event recognition: an algorithm developed to identify endotracheal intubation correctly recognized 13 of 17 intubations. This resulted in a 42% reduction in low end-tidal-CO2 false alarms. PMID- 10114049 TI - The role of clinical engineering in the redesign of existing hospital patient monitoring systems. AB - Clinical engineering can have a key role in the redesign of existing hospital patient monitoring systems. This paper presents a systematic approach to the process of reinstrumenting highly specialized cardiovascular operating suites. A detailed definition of system requirements is presented for both basic and specialized instrument sets. Configuration flexibility was given the utmost attention. The method presented here suggests that system requirements should reflect information gathered from direct interviews of both the clinical and support personnel. Consideration is given to all applicable codes, standards, and practices. Special attention must also be focused on proper and efficient interfacing of the components of the new system to all components of the existing system. The project described here was conducted within and supported by the University of Alabama Hospital of the University of Alabama at Birmingham. PMID- 10114050 TI - Internally developed medical equipment management system: a viable alternative. AB - A medical equipment management computer system, internally developed by Rhode Island Hospital, is presented. Hospital biomedical engineering departments must contend with ever-increasing regulatory requirements for patient-care equipment. Computerization is a viable solution to meeting the documentation standards dictated by healthcare governing bodies. Rhode Island Hospital's system consists of a Macintosh computer, Panorama database software, and Psion LZ64 Organiser handheld computer. Files were set up on equipment data, JCAHO-required historical documentation, service, inspections, part codes and locations, and vendor contact information. Technician inspection data recording time was reduced by approximately 30%. PMID- 10114051 TI - The medical information bus: overview of the medical device data language. AB - The Medical Information Bus (MIB) reference model defines a new, object-oriented Medical Device Data Language (MDDL), under development by the Institute of Electrical and Electronic Engineers Society (IEEE) P1073 MIB Standard Committee. The MDDL treats medical devices, host computers, humans and device parameters as objects, and provides a flexible and extensible language for describing and passing messages between objects. This paper describes the MDDL semantic reference model and presents an overview of the MDDL structure, within the framework of the International Standards Organization (ISO) System Management Overview (SMO) model. A simple example of how the MDDL can be used to construct a device event report is also described. PMID- 10114052 TI - The training and use of an artificial neural network to monitor use of medication in treatment of complex patients. AB - An artificial-neural-network-based drug interaction warning system was developed for use with a computerized real-time entry medical records system. The goal of the study was to provide physicians and nurses with timely warnings of potential drug interactions as therapies were prescribed. In a dialysis unit, physicians and clinical pharmacists defined rules of proper drug therapy, then trained a neural network with those rules. When the network was used to review the therapies of this patient population, a number of inconsistencies were discovered, and medication orders were changed on several patients. Real-time implementation of this monitoring system could provide messages to assure that drug therapy is consistent and proper, according to rules created by the providers of healthcare, thus preventing occasional mistakes in drug therapy. PMID- 10114053 TI - Evolution of the medical record format during two years' use of an open-format microcomputer charting system. AB - In 1988, the authors implemented a microcomputer charting system (SmartChart) within a busy dialysis unit and an outpatient dialysis practice, to be used as the primary recording instrument for physicians and nurses. The program defined the organization of the medical record as three types of titles: problems, therapies, and numerics. Each title had a variety of associated data, such as comments, dosages, values and normals. Predefined care plans were created, and keyboard entry was in a completely open format. Over the next two years, the overall format of this medical record proved to be highly effective, and strict problem orientation allowed both nurses and physicians to use the same problem list. A more specific organization of the title lists in the medical record was needed, however. Separate symbols were placed in front of: problem titles related to prior therapies; problems recorded during current therapies; History and Physical (H&P) data; Plans/Orders; and inactive problems. PRN therapies, those therapies related to patient treatments, vital signs, and numeric data recorded during treatments were identified. The basic format of the medical record that evolved has proven suitable for outpatient, inpatient, and specialized treatment centers. PMID- 10114054 TI - The new governance: five most critical trustee functions in the 1990s. PMID- 10114055 TI - IHSM Presidential address: The challenge of change. PMID- 10114056 TI - Agents for change: a resource for management. AB - The Internal Change Consultant Development Programme is designed to equip senior NHS managers in Scotland with the appropriate skills, knowledge and attitudes to enable them to support organisational initiatives in pursuit of the new agenda for the Scottish NHS. John Edmonstone and Maggie Havergal describe the programme and attempt to assess its success to date. PMID- 10114057 TI - General management in the NHS: comparisons and contrasts between Scotland and England. AB - The NHS takes rather different forms in England and Scotland, and comparisons can be instructive. David Hunter and Peter Williamson look at the way general management was evolved in the two countries. If so far it has not flourished in Scotland that may be because it was the adoption of arrangements designed for England, but it may also reflect differences between the two countries. PMID- 10114058 TI - Purchasing with vision. AB - Although the new NHS has brought new tasks and opportunities to providers, the really new role, and the critical one, is that of purchasers. Bob Dearden outlines the six inter-related functions which purchasers need to get right. PMID- 10114059 TI - Changing for quality. AB - How can we improve the quality of life for elderly people in continuing care? Paul King describes a project on a geriatric continuing care ward. PMID- 10114060 TI - The tale of a consortium. AB - Most articles about health service management report successes, but accounts of failure can be no less instructive. Paul Walker describes the failure of a consortium to develop a computer system for the administration of A&E departments and draws some general lessons. PMID- 10114061 TI - An agenda for care programming and care management. AB - Lack of central clarity within the implementation guidance (HC(90)23/LASSL (90)11) and differing time scales for implementation have led to a lack of consideration of the relationship between the care programming approach (CPA) and care management (CM). Instead, says Steve Onyett, there appears to be a short sighted scrabble to achieve the requirements of the care programming circular at the expense of rational longer-term planning. This article has two aims: to argued that there is no sensible long-term basis for differentiating the CPA and CM, and to set out a longer-term agenda for their development. PMID- 10114062 TI - Costing quality. PMID- 10114064 TI - When the patient is a suspect. The EMS role in emergency searches. PMID- 10114063 TI - Special supplement. Health care financing in Latin America and the Caribbean. PMID- 10114065 TI - JEMS Sixth Annual Buyers' Guide. 1992 edition. PMID- 10114066 TI - Pick a pack of pocket scorecards. PMID- 10114067 TI - Of science and salesmen. Deciphering product research and evaluation. AB - Do EMS-product manufacturers follow a code of honor when developing their products? And is the research that supports these products an honest, scientific substantiation of their worth? This article explores the science and "pseudo science" behind EMS-product manufacturing and discusses the pursuit of profit vs. the need for valid data to support EMS-product choices. PMID- 10114068 TI - StarCare. Guidelines for customer sense. PMID- 10114069 TI - Comparing CPR during ambulance transport. Manual vs. mechanical methods. AB - Performing CPR during transport is easier said than done and may, in fact, pose significant danger to prehospital providers. Factors such as road conditions, speed and vehicle type, as well as specific CPR methods, are compared in this comprehensive study. PMID- 10114070 TI - Contract processing and sterilization. AB - Contract processing and sterilization has a number of advantages to offer hospitals. In order for a hospital to realize those advantages it must be able to accurately assess its needs and the effect the service will have on its bottom line. There is a good future for contract processing and sterilization services. Hospitals that have taken this approach do not return to in-house instrument sterilization. The "what happens if the truck breaks down" and "will surgeons accept standard trays" questions are finding answers in effective management of this important contract service. PMID- 10114071 TI - Service agreements: an integral tool for ensuring customer satisfaction. AB - This article describes the use of a unique quality tool at the Cleveland Clinic Foundation--service agreements between material management and its customers. PMID- 10114072 TI - Pharmacy and materiel management: a profitable alliance. AB - According to the author, materiel management can be a catalyst to a mutually beneficial relationship between their department and the pharmacy, particularly in wholesaler selection, buying group decisions and inventory control--if they use the right approach. PMID- 10114073 TI - Optimizing the service of contracted hospital laundries. AB - Linen processing is a significant but essential expense to hospitals. To minimize this expense, it may benefit may hospitals to consider processing laundry by either an outside commercial vendor or cooperative association. A comprehensive bid package is the cornerstone to such a relationship and will help ensure acceptable and cost-beneficial quality service to the hospital. PMID- 10114075 TI - Washer/sterilizers. ECRI. PMID- 10114074 TI - Washer/decontaminators. ECRI. PMID- 10114076 TI - Making continuous quality improvement a reality: innovation skills. AB - Creativity and innovation, according to Grudin, "lie near the heart of humanity." If CQI is to be the force that will transform healthcare organizations into more systems-conscious and customer-driven endeavors, creativity and innovation must be encouraged and practiced. Given that they have a responsibility to introduce new products and services to their organization, materiel management professionals are particularly well-suited to practice and encourage creativity and innovation. PMID- 10114077 TI - Contract management of material management: ethical issues. PMID- 10114078 TI - Infection control consortia. PMID- 10114079 TI - Understanding decontamination. PMID- 10114080 TI - Religious perspectives of doctors, nurses, patients, and families. AB - Reports the results of a survey examining religious denomination, belief in a higher power, church attendance, and religious coping among physicians (N = 130), nurses (N = 39), patients (N = 77), and families (N = 60). Differences are noted and discussed. Notes that while a large proportion of patients and families found religion to be the most important factor enabling them to cope, only a small percentage of physicians felt that way. Observes that the results of this and other studies may indicate a gap in religious orientation between health care providers and patients and that such a gap could hinder the recognition of and proper care for spiritual needs in the hospital setting. PMID- 10114081 TI - Pastoral care planning: a process-oriented approach for mental health ministry. AB - Proposes a systematic and systemic pastoral diagnosis model based on the formulations of James W. Fowler, Stephen S. Ivy, and Wayne E. Oates. Illustrates the application of the model via a care-planning case study. PMID- 10114082 TI - The medical captivity of religion and health. AB - Uses actual hospital-based experiences to draw attention to and illustrate how modern chaplaincy may fall into forms of paternalism and iatrogenesis. Notes particularly how high tech iatrogenesis and high touch chaplaincy may interact in counterproductive ways. Opines that the church once again needs a revisioning of health which is based on theological notions of the church as sustaining community and as a school for empowerment. PMID- 10114083 TI - Evaluation of the hospital chaplain's pastoral care: Catholic and Protestant differences. AB - Reports the results of a questionnaire survey of Roman Catholic and Protestant insurance claimants (N = 445) who were asked to evaluate their hospital stays in terms of pastoral care, social services, and patient representatives. Discusses the results--including a ranking of the levels at which spiritual needs were met- and offers guiding questions for future research. PMID- 10114084 TI - Cultivating physician relations to enhance rural hospital utilization. AB - Rural hospitals are searching for new strategies to enhance utilization in view of constraints introduced by prospective payment and other environmental pressures. Developing physician relations is an approach that is reportedly leading to better hospital-physician collaboration and subsequently to improved utilization. This paper examines rural hospital-physician relations and the association with utilization. The findings suggest that rural hospitals emphasize quality care as well as diagnostic and treatment equipment procurement as methods for building relationships with physicians. These strategies are correlated with efforts to build a larger medical staff. Higher rural hospital utilization, in terms of occupancy, discharges and patient days provided, is associated with a larger medical staff. The results suggest that rural hospitals' attempts to cultivate physician relations have the potential for making significant differences in utilization outcomes. However, the linkages between utilization and physician relations are complex and require further research. PMID- 10114085 TI - Health care in Canada: lessons for the United States. AB - This paper considers various aspects of the Canadian health care system and the implications for the improved delivery of rural health care in the United States. The major aspects examined are access to care, rural hospitals, and rural physicians. A search of the pertinent literature revealed a large amount of information concerning rural physicians in Canada, but less that dealt directly with rural hospitals and access to health care in rural areas. Universal access is the cornerstone of the Canadian health care system, which is operated by each province under certain mandates of the federal government, with both providing funding for the system. The diffusion of medical technology has been slower in Canada than in the United States, which is perceived by some as a major success of the system. Little distinction is made between rural and urban hospitals in Canada, with all hospitals funded by annual global budgets from the province, rather than by direct payment for each service provided. Funding for capital items must be requested separately. This method of reimbursement allows better planning in meeting the needs of each community. Physicians in Canada are mostly private practitioners who are reimbursed by fee for service. As in the United States, there has been difficulty in attracting physicians to rural areas. However, all but one province have incentive programs to encourage physicians to practice in underserved rural areas, with some having disincentives for those locating in overserved areas. Overall, the Canadian health care system has chosen to control costs by focusing on the provider rather than the consumer and appears to be more successful in providing access to health care in rural areas of the country. PMID- 10114086 TI - A multivariate assessment of the effects of residence on infant mortality. AB - This research examines the relationship between residence and infant mortality. The purpose of the study was to identify the effects of maternal residence on infant mortality, using a multivariate model which included both individual and county-level variables known to be associated with suboptimal birth outcome. Data on all births in Florida during 1987 were drawn from birth and infant death certificates. In addition, information concerning county sociodemographic structure and medical resources were gathered and linked to the individual records. After examining the distributions of selected risk variables across a five-category measure of residence (from most urban to most rural), a logit model was estimated to predict the odds of an infant death associated with maternal residence. At the bivariate level, rural residents were found to have increased odds of an infant death compared to residents of all other residence categories. Second, a logit model was estimated that controlled for the influence of important maternal, infant, and county risk characteristics. The results of this second, more fully specified model indicate that residence did not have an independent direct effect on infant mortality when the influence of the other risk factors was controlled. We conclude that although residence does not influence infant mortality directly, it does influence mortality indirectly through its association with key risk factors. In particular, because population characteristics and medical resources are differentially distributed across rural and urban areas, residence remains an important factor to be considered when predicting health outcomes. The implications of these findings for policy-makers and health planners, as well as for health services researchers, are also discussed. PMID- 10114087 TI - Barriers to the retention of registered and licensed practical nurses in small rural hospitals. AB - The availability of nursing resources is one of the most critical issues facing health care organizations in the country. The study investigated the potential factors that relate to the desire of registered nurses (RNs) and licensed practical nurses (LPNs) to continue practicing in rural hospitals of North Dakota. All RNs and LPNs who worked in North Dakota hospitals with fewer than 100 beds (490 hospitals) were mailed survey questionnaires. Approximately eight weeks later, responses were received from 291 respondents for an overall return rate of 59 percent. Correlational analyses were used to examine the subjects' responses. A moderate relationship was found among the work-related variables. Overall job satisfaction and performance constraints were the only variables to make significant contributions to the prediction of turnover intention for both RNs and LPNs. Overall job satisfaction accounted for the largest percentage of the variance (R2 = 0.42 and R2 = 0.44) for RNs and LPNs, respectively. Satisfaction with promotion was the only work-related variable to make a significant contribution to the prediction of turnover intention for RNs (R2 = 0.23). Performance constraints, role ambiguity, and shift worked were the only work related variables contributing to the prediction of turnover for LPNs. These results are discussed in terms of their implications for the management of RNs and LPNs in rural hospitals. Clinical ladders for promotions, the identification of potential performance constraints, and supervisory training are suggested as target areas in which rural hospitals might focus attention for managing turnover in RNs and LPNs. PMID- 10114088 TI - Perspectives on psychological burnout, IV: Testing the phase model, Part 2. PMID- 10114089 TI - Shelving levels of burnout for individuals in organizations: a note on the stability of phases. PMID- 10114090 TI - Burnout and job satisfaction among public hospital administrators: preliminary findings. PMID- 10114091 TI - A test of the relationship between self-efficacy and burnout. PMID- 10114092 TI - Creating a sense of mission. AB - Mission is still a relatively neglected area of management, and there is no clear agreement on what it encompasses. The Ashridge Strategic Management Centre conducted a 2-year research project designed to fill this gap. The research found that if mission is more clearly defined it can be managed better, and developed a model of mission that includes four elements--purpose, strategy, behaviour standards and values. The project identified companies where, in addition to strong links between these elements, employees also showed an emotional commitment to their company which Campbell has called a 'sense of mission'. This commitment was deepest when there was a match between the employee's values and the company's values. PMID- 10114093 TI - Joint-ventures as strategic choice--a literature review. AB - The concept of 'strategic options' has become firmly established in recent years- this regards choices such as 'organic growth', acquisition, merger, and so on. This paper explores one such route forward, the option of joint-ventures. The examination is undertaken within a framework that considers market structures and the pressures for change. Initial sections introduce a form of analysis based upon the work of Michael Porter. This is used to suggest how and why joint ventures and other alliances are attractive. Later discussion considers some of the practical considerations when setting-up a joint-venture. PMID- 10114094 TI - Brief case: mission, vision and strategic intent. PMID- 10114095 TI - Removing the obstacles to effective strategic planning. AB - The purpose of this article is to explore the reasons for the decline in the importance and practice of strategic planning across American industry. The article identifies numerous bureaucratic obstacles to effective planning, and suggests how these obstacles can most effectively be eliminated by attacking their root causes. The article points out the risks to the planning process that are created by attempts to eliminate these obstacles. But, it concludes that unless these obstacles are removed and the promised financial returns from strategic business planning realized, the decline of long-term strategic business planning will continue. PMID- 10114096 TI - Strategic staircases: planning the capabilities required for success. AB - Creating an adequate supply of the requisite skills and competitive capabilities is a fundamental objective of strategy. Managing this process in an effective and systematic manner is difficult. Employing the strategic staircase is a proven way of overcoming this difficulty. The framework enables managers to break the strategic agenda into bit-sized pieces, it guides the selection of priorities and provides a powerful device for communicating strategy throughout the organization, thereby bridging the gap between strategy and action. PMID- 10114098 TI - What your colleagues are charging. PMID- 10114097 TI - Using computer software to improve group decision-making. AB - This article provides a review of some of the work done in the area of knowledge based systems for strategic planning. Since 1985, with the founding of the Center for Knowledge-based Systems for Business Management, the project has focused on developing knowledge-based systems (KBS) based on these models. In addition, the project also involves developing a variety of computer and non-computer methods and techniques for assisting both technical and non-technical managers and individuals to do decision modelling and KBS development. This paper presents a summary of one segment of the project: a description of integrative groupware useful in strategic planning. The work described here is part of an ongoing research project. As part of this project, for example, over 200 non-technical and technical business managers, most of them working full-time during the project, developed over 160 KBS prototype systems in conjunction with MBA course in strategic planning and management decision making. Based on replies to a survey of this test group, 28 per cent of the survey respondents reported their KBS were used at work, 21 per cent reportedly received promotions, pay rises or new jobs based on their KBS development work, and 12 per cent reported their work led to participation in other KBS development projects at work. All but two of the survey respondents reported that their work on the KBS development project led to a substantial increase in their job knowledge or performance. PMID- 10114099 TI - Myths that make you a malpractice lightning rod. PMID- 10114100 TI - Where euthanasia may become a legal medical service. PMID- 10114101 TI - Why your buy-sell agreement is a time bomb. PMID- 10114102 TI - Hospitals wield a heavy club against high-cost doctors. PMID- 10114103 TI - The feds are looking harder at your medical investments. PMID- 10114104 TI - Managing change in troublous times. PMID- 10114105 TI - Pitfalls to avoid in bringing a new analyzer on line. PMID- 10114106 TI - Measuring performance and promotability of middle managers. PMID- 10114107 TI - Covering the bases with a new QA program. PMID- 10114108 TI - Ethics and the clinical laboratory. Part III. Laboratory quality and economic necessity: values in collision. PMID- 10114109 TI - Managing the transition to a certified toxicology lab. PMID- 10114110 TI - Simplify humdrum PC tasks with batch files. PMID- 10114111 TI - Adapting to the National Practitioner Data Bank: perspectives for physicians. AB - Now that the National Practitioner Data Bank is fully operational, the reporting requirements and the potential public availability of information contained therein have generated legitimate concern among physicians. This article discusses some of the legal and practical implications of compliance with the requirements and explores possible options for physicians seeking to minimize the risk of triggering the reporting requirements. PMID- 10114112 TI - Physician employment contracts. AB - This article describes some of the issues relevant to the different kinds of contracts that are likely to be offered to physicians entering private practice upon completion of residency programs or in the early years of practice and discusses how such issues can be resolved in the course of negotiating those contracts. PMID- 10114113 TI - Avoiding antitrust liability for denial of access to resources: some safe harbors. AB - Antitrust issues frequently arise in connection with claims that providers were denied access to institutions, such as hospitals and payors, and their resources. This article sets forth some "safe harbors," circumstances under which liability is unlikely, that may often avoid antitrust liability in denial of access cases. PMID- 10114114 TI - "Do not resuscitate" orders: the New York statutory model--Part I. AB - This two-part article examines the statutory framework in New York State for the issuance of DNR orders. Part I addresses the procedure for issuance of a DNR order, including determination of capacity to consent to issuance, the effect of consent to a DNR order by an adult patient or a surrogate, issuance of a DNR order for an adult who lacks capacity and for whom no surrogate is available, and consent to DNR on behalf of a minor. Part II, which will appear in the next issue of this journal, will address revocation of consent to, and cancellation of, DNR orders, the dispute mediation system, the role of the courts, and the effects of a DNR order. [Note: As this article was going to press, the New York State Legislature passed a statute (1991 N.Y. Laws Ch. 370) that amends New York Public Health Law Article 29-B, discussed herein. As a result of these amendments, some of the provisions discussed in Part I have been modified. A summary of these modifications will appear in Part II.] PMID- 10114115 TI - Health care litigation: assuring consistency and proportionality in punitive damages awards. AB - This article, the ninth in a series on health care litigation, explains possible reforms that could be implemented to prevent juries from awarding unreasonable and unfair amounts of punitive damages. One way to minimize this problem would be to establish a system that promotes consistency in punitive damages awards. Another reform would involve instituting mechanisms to ensure proportionality in punitive damages awards. This article explores the steps involved in establishing a new system, and the benefit to defendants if the punitive damages system is reformed. PMID- 10114116 TI - The formation of medical groups for managed care contracting. AB - The formation of organized medical groups for managed care contracting is becoming increasingly common in this new era of cost containment. In this article, the author suggests that hospitals should consider taking an active role in the formation of medical groups and highlights some of the important considerations that should be taken into account in order for medical group formation to be successful. PMID- 10114117 TI - Resisting disclosure of mental health records during Medicaid investigations and audits. AB - In a previous article, the author discussed the legal foundation for resisting the disclosure of medical and mental health records, the nature of the right to confidentiality of medical and mental health records, the privileges against disclosure, how those privileges are lost, and the health care provider's liability for improper disclosure. In this article, the author offers a "nuts and bolts" approach to resisting the disclosure of mental health records for counsel representing health care practitioners and institutions involved in Medicaid audits and investigations. PMID- 10114118 TI - New Medicare requirements regarding patient advance written directives for medical treatment. PMID- 10114119 TI - Hospital-physician joint ventures: beware of hospitals bearing gifts. PMID- 10114120 TI - Revamp increases nurses' job satisfaction. PMID- 10114121 TI - Public hospital's CEO takes new job, leaves feud behind. PMID- 10114122 TI - Pressured by physicians, hospital fires CEO. PMID- 10114123 TI - House says no to cash for D.C. hospital. PMID- 10114124 TI - VA, Defense paying more for drugs--GAO. PMID- 10114125 TI - Oregon plan hit as costlier than advertised. PMID- 10114127 TI - Move now to communicate your mission to the public. PMID- 10114126 TI - HHS adopts tough kickback definition. PMID- 10114128 TI - Benefits plans focus on flexibility. Hospitals increase choices for employees as emphasis moves from recruitment to retention. AB - As hospitals turn their attention from employee recruitment to employee retention, flexible benefits plans are becoming increasingly popular as a means of meeting workers' preference for choice when it comes to issues such as healthcare coverage, insurance and vacation days. At the same time, such programs can help hospitals hold down their long-term costs. PMID- 10114129 TI - Mass. panel seeks end to rate regulation. PMID- 10114130 TI - PIA suit charges kickbacks, fraudulent bills. PMID- 10114131 TI - Here's what to ask when hiring search firm. AB - Knowing what to look for when you search for a search firm can avert some of the aggravation of monitoring its performance and getting your money's worth. Jordan Hadelman offers some considerations you should weigh before reaching an agreement. PMID- 10114132 TI - Effect of parental leave laws debatable. AB - A federal parental leave law will cause few problems for hospitals because many offer similar benefits voluntarily. But supporters of a federal parental leave law, including the American Nurses' Assn., have used "horror stories" involving female hospital employees to show lawmakers why parental leave should be mandated. PMID- 10114133 TI - Hospital fund-raisers changing their focus. AB - As skepticism mounts over hospital spending practices and competition heats up for donor dollars, hospitals are sharpening their fund-raising message. They're getting away from lists of what they need, emphasizing instead the results and benefits the donations will produce for the community. PMID- 10114134 TI - New York prosecutes nursing home for 'dumping'. PMID- 10114136 TI - CareNetwork reorganizes in quest to expand. PMID- 10114135 TI - Second study shows uptick in hospital margins. PMID- 10114137 TI - Physicians balk at Humana's proposed pay plans in San Antonio. PMID- 10114138 TI - AMA seeking congressional allied in latest assault on physician payment regulations. PMID- 10114139 TI - W. Va. hospitals oppose AHA reclassification stand. PMID- 10114140 TI - Cuomo plan would have N.Y. pay for all Medicaid costs. PMID- 10114141 TI - Report: prescription costs soar, Congress should act. PMID- 10114142 TI - Commission urges all-out assault on AIDS. PMID- 10114143 TI - HIV-infected surgeon's patients notified. PMID- 10114144 TI - AHA rips IG draft advisory on physician arrangements. PMID- 10114145 TI - 4 hospitals settle Medicare/Medicaid charges. PMID- 10114146 TI - VNAA kicks off for-profit ventures. PMID- 10114147 TI - HHS picks states for 'eaches, peaches'. PMID- 10114148 TI - HHS head seeks summit to cut health paperwork. PMID- 10114149 TI - Iowa judge denies nursing home firm's exemption. PMID- 10114150 TI - Administrators play key role in curing alcoholic staffers. PMID- 10114151 TI - Managing diversity. AB - One look at projections for the U.S. work force through the year 2000 shows why healthcare administrators will be facing some new challenges. With the majority of new workers belonging to minority groups, "managing diversity" has become the newest catch phrase as executives work to reduce tensions resulting from race, gender or culture-based differences among workers, while also learning to understand and value those differences. PMID- 10114152 TI - $80 million complex planned in Austin, Texas. PMID- 10114153 TI - Lawsuits claim overcharging by Fla. hospitals. PMID- 10114154 TI - Chemical could let MRIs do what PETs can. PMID- 10114155 TI - Research project to test collaboration. AB - Seven Denver-area hospitals have agreed to consider collaborating on cardiac-care services as part of a research project that could serve as a model for planning high-technology medical services. The hospitals and a private research organization have pledged $320,000 to fund development of a prototype program. But not all hospitals are sold on cooperation, and some have raised antitrust concerns. PMID- 10114156 TI - System cuts costs by providing its own credit enhancement. AB - While many hospitals are facing increasing costs when obtaining letters of credit from commercial banks, one hospital system has found a way around those expenses. In a recent $35 million borrowing through variable-rate bonds, St. Joseph Health System in Orange, Calif., used its own strong cash flow and liquid investments as the underlying credit enhancement on the bond issue. PMID- 10114157 TI - AmHS unveils new pooled financing tool. PMID- 10114158 TI - 'Facilities not ready for all violence'. PMID- 10114159 TI - Attacks raise security concerns. PMID- 10114160 TI - Consultants to weigh Twin Cities mergers. PMID- 10114161 TI - FTC investigates merger in St. Augustine, Fla. PMID- 10114162 TI - Lincoln National Corp. plans to sell off HMO, group health operations. PMID- 10114163 TI - United HealthCare to buy HMO in Columbus, Ohio. PMID- 10114164 TI - Business coalitions hatch network in Fla. PMID- 10114165 TI - Quorum leases hospital, offers new services. PMID- 10114166 TI - RehabCare, Beverly form joint venture. PMID- 10114167 TI - HCFA's fraud and abuse oversight criticized. PMID- 10114168 TI - ProPAC recommendations seek to restrict disproportionate-share hospital designation. PMID- 10114170 TI - Patient-focused approach demonstrates advantages. PMID- 10114169 TI - N.Y. insurance head monitors Blues after denying rate hike. PMID- 10114171 TI - Mo. facility defends proposed limits. PMID- 10114172 TI - IPA dissolves to settle charges of price-fixing. PMID- 10114173 TI - Dems want rewrite of Medicaid limits. PMID- 10114174 TI - 1990 health tab--$666.2 billion. PMID- 10114175 TI - Committee hears AIDS patients' pleas against mandatory testing. PMID- 10114176 TI - We'd manage to care more if industry changed its name. PMID- 10114177 TI - Medicare eligibility at age 60 would relieve many burdens. PMID- 10114178 TI - Study rates U.S. hospitals vs. other nations, industries. AB - American hospitals generally are further along with their total quality management programs than their Canadian counterparts but lag behind companies in other U.S. industries, according to a comprehensive international study that examined four industries--healthcare, automotive, banking and computer--in four countries--the United States, Canada, Germany and Japan. PMID- 10114179 TI - HIAA targets states for its pitch on small-group health reform. PMID- 10114180 TI - Insurer reps rap Democrats' plan. PMID- 10114181 TI - Presidential candidates seize health as an issue. PMID- 10114182 TI - Excellence in risk management. AB - Salt Lake City-based Intermountain Health Care's risk-management program, which espouses early intervention, prevention and the maximum use of in-house resources to control costs and liability, has won the first award for excellence in healthcare risk management, given by Modern Healthcare and the MMI Cos. York (Pa.) Hospital was given special recognition for its project to reduce intravenous medication errors. PMID- 10114183 TI - Franchisees boost growth of Hispanic PPO. AB - What began as a local marketing effort by two Chicago hospitals to reach the city's fast-growing Hispanic population has turned into a national program with franchises in San Diego and San Antonio, Texas. Formed in 1989, Hispanocare, a preferred provider organization catering to Hispanics, began attracting attention in other cities with large Hispanic populations, prompting the Chicago hospitals to begin a marketing push. PMID- 10114184 TI - Amex offers 3 options to users of discontinued hospital system. PMID- 10114185 TI - AmHS' pooled financing plan has other alliances looking on with interest. AB - The potential for big savings through a tax-exempt pooled financing program developed by American Healthcare Systems has other alliances looking on with interest. Such a vehicle can offer savings by consolidating a system's multistate borrowings under one financing authority. While the program's lead banker declined to name the alliances showing interest, SunHealth Corp. is in the early stages of assembling its own program. PMID- 10114186 TI - Hospital of Tomorrowland. PMID- 10114187 TI - Status-seekers elbow each other on the ladder of accreditation success. PMID- 10114188 TI - Well-rounded technique. PMID- 10114190 TI - VA to draft CT contract guidelines. PMID- 10114191 TI - AHM to swap stock for debt. PMID- 10114189 TI - Latest tax-exemption rulings set off new disputes in Utah. PMID- 10114192 TI - Community Psych earnings drop 98% in third quarter. PMID- 10114193 TI - Legislation would lessen fee reductions. PMID- 10114194 TI - HealthTrust boosts tender offer by $6.8 million. PMID- 10114195 TI - Mass. panel issues rules to keep the payments flowing. PMID- 10114196 TI - 3 more Utah hospitals keep tax exemptions. PMID- 10114197 TI - Don't do GAO survey, 2 hospital groups urge. PMID- 10114198 TI - States storm Hill, but gain little ground on Medicaid. PMID- 10114199 TI - Deal for Healthcare Int'l and HealthVest fizzles. PMID- 10114200 TI - Fraud charge hits NME stock, management. PMID- 10114201 TI - Consolidation strategy focuses on community, not corporation. PMID- 10114202 TI - Dealing with the authorities. AB - Tax-exempt bond financings, inherently complex transactions, can become even more complicated, cumbersome and costly as hospitals come to terms with restrictive policies imposed by some state financing authorities. Executives also find they sometimes get caught in authorities' political machinations that may have little to do with the business of the municipal bond markets. PMID- 10114203 TI - White House, Dems at odds over progress toward reform. PMID- 10114204 TI - Employers balk at provider-backed efforts to limit reach of utilization-review firms. AB - Businesses are beginning to take more of an interest in the way some states are regulating utilization review firms. Employers complain that provider-backed laws are restricting the use of utilization review, a key tool in containing healthcare costs. PMID- 10114205 TI - Researcher seeks uniform mattress ratings. AB - Are special mattresses and pads truly effective in reducing the problems associated with pressure scores? A California-based group says there's no effective way to tell whether the products are living up to their claims, and the group's head is seeking an improvement in the measures used to assess those products. PMID- 10114206 TI - Bond volume jumps 90% in third quarter. AB - Tax-exempt healthcare bond volume soared 89.6% in the third quarter to $5.9 billion as hospitals took advantage of lower interest rates and anticipated a change in Internal Revenue Service rules regulating "reimbursement bonds." A total of 174 bond issues were sold during July, August and September, 82% of them were sold to finance construction and renovation projects. PMID- 10114207 TI - AHA to add payment details to its plan. PMID- 10114208 TI - Blues proposal taps managed care as solution. PMID- 10114209 TI - Owens & Minor to buy Plains-area supplier. PMID- 10114211 TI - Alliant Health purchases HELP system. PMID- 10114210 TI - Stark, consumer group fight HMO conversion. PMID- 10114212 TI - L.A. the priciest for health benefits. PMID- 10114213 TI - No further PPS adjustments needed--ProPAC. PMID- 10114214 TI - Republic recapitalization complete. PMID- 10114215 TI - Humana's chairman defends pricing. PMID- 10114216 TI - NME fights Texas allegations with ads, exec pay changes. PMID- 10114217 TI - Amex designs Saint system to work on Unix computers. PMID- 10114218 TI - Hancock to test drug program. PMID- 10114219 TI - U.S. will have national health plan by 1996--GHAA president. PMID- 10114220 TI - Nine HMOs tell HCFA they plan to drop from risk contract program. PMID- 10114221 TI - Medicaid restriction clarifications to define disproportionate share. PMID- 10114222 TI - AHA hopes reassessment of reclassification issues heals wounds in the process. PMID- 10114223 TI - Blanks on medical records may give payers denial ammo. AB - Incomplete and inaccurate patient records have always left hospitals vulnerable to losing malpractice suits. But increasingly, good records mean hospitals are more likely to collect on bills that are scrutinized by utilization review firms, Medicare peer review organizations and other such bill examiners. That places a higher premium than ever on paying meticulous attention to a patient's medical record. PMID- 10114224 TI - Bill would give small businesses insurance lever. PMID- 10114225 TI - Bondholder pact will take Charter 'public' again. PMID- 10114226 TI - Medicaid penalties: crackdown or shakedown? AB - Hospitals that file inaccurate Medicaid claims may be the dupes in a new federal initiative to finance expansion of the government's civil enforcement efforts, a Modern Healthcare reveals. A look at eight settlements by hospitals in Pennsylvania over false claims shows growing collaboration between the state, HHS' office of the inspector general and the U.S. Justice Dept. Modern Healthcare found that the amount of the Pennsylvania settlements, some $500,000, was identical to the amount given back to the Justice Dept. to further boost their policing efforts. Attorneys believe such collaborative efforts are likely to spread nationwide. PMID- 10114227 TI - Panel urges changes in provider education. PMID- 10114228 TI - Study: more facilities use annual incentives. PMID- 10114229 TI - Feds slow to part with paybacks for losses. AB - In the early '80s, the federal government was happy when hospitals were sold for a profit because, under Medicare's rules, it received a share of the profits. Under those same rules, the government also is required to share in losses resulting from the sale of a hospital. But as more financially troubled facilities are forced to sell at a loss, it appears the feds aren't too happy about making those payments. PMID- 10114230 TI - AMA, FTC end 16-year physician-advertising fight. PMID- 10114231 TI - Ban all physician-owned referral ventures--Stark. PMID- 10114232 TI - QI finds lasting solutions to tough problems. PMID- 10114233 TI - Doing it with data: QI's statistical tools. PMID- 10114234 TI - QI and QA: JCAHO explains the difference. PMID- 10114235 TI - Everyone's involved in CQI effort at HCA. PMID- 10114236 TI - OR 'super unit' makes use of QI in improving service. PMID- 10114237 TI - Integrated model for perioperative nursing. PMID- 10114238 TI - Inadequate performance requires action. PMID- 10114239 TI - In times of budget strain, look to basic staffing concepts. AB - As healthcare providers tighten budgets, financial managers are seeking creative ways to run their patient accounting departments with fewer personnel. Implementing basic concepts that use limited assets--such as management and staff -can help a patient accounts manager do more with less. PMID- 10114240 TI - How a departmental downsizing plan can succeed. PMID- 10114241 TI - Health care in Europe. PMID- 10114242 TI - The role of the university in health policy development. PMID- 10114243 TI - Health care in Belgium: looking toward 1992. PMID- 10114244 TI - Health and hospital care in Denmark. PMID- 10114245 TI - Proposed changes in the UK health-care system. PMID- 10114246 TI - A report of the main aspects and problems of the Greek National Health System. PMID- 10114247 TI - Hospital care in Italy. PMID- 10114248 TI - Hospital services in Ireland and how they have evolved. PMID- 10114249 TI - The place of hospitals in the Dutch health-care system. Facts, trends and problems. PMID- 10114250 TI - Aspects of the health-care system in Portugal. PMID- 10114251 TI - Physiotherapy behind bars: a challenge in rehabilitation. AB - Prison inmates, like the population at large, are entitled to physiotherapy care. However, the lack of information in the literature suggests physiotherapy in prisons is not commonplace. Where it does occur, the physiotherapist is often confronted by unfamiliar and unpleasant circumstances as there are significant differences between community or hospital based practices and a prison practice. The purpose of this communication is to describe, from the author's perspective, the various factors that make a prison practice difficult. Problems relating to jail security and attitudes are discussed. Health and behavioural problems unique to prison inmates are explored and methods of dealing with them examined. The physiotherapist's role in prison health care is addressed and, finally, some ideas for increasing the profile of physiotherapy in prisons are presented. PMID- 10114252 TI - Quality care is key to survey success. PMID- 10114253 TI - Planning new jobs can reduce turnover of new employees. PMID- 10114254 TI - High quality appraisal reports require facility cooperation. PMID- 10114255 TI - Survey presents opportunity for building legal defense. PMID- 10114256 TI - Coordinating RAPs is vital in planning resident care. PMID- 10114257 TI - Creative movement promotes health, self-expression. PMID- 10114258 TI - Facility design meets needs for independence, integration. PMID- 10114259 TI - Effective laundry operation boosts quality, efficiency. PMID- 10114260 TI - Maryland's well-mannered nursing home. PMID- 10114261 TI - What sells? 1991 Menu Census. AB - The boneless chicken fillet, seasoned fries and broccoli pictured on our cover are an operator's dream: According to the operators surveyed for R&I's Menu Census, these items not only sell well enough to be on the menu--they're top good sellers. In this issue's Menu Census exclusive, "What Sells," we examine the major menu categories and identify, for both commercial and institutional operations, which menu items qualify for good-seller status. Compare your menu to our list of what sells--how do your offerings stack up? Bonus: Sidebars show most menued items and top-scoring rookie entries. PMID- 10114262 TI - A cost containment malpractice defense: implications for the standard of care and for indigent patients. PMID- 10114263 TI - Compensating healthcare management. PMID- 10114264 TI - Cantina cooking. PMID- 10114265 TI - Negotiating the system ... the invisible social worker. PMID- 10114266 TI - Heart and soul: employees want more than money. PMID- 10114267 TI - Fix it or close it. PMID- 10114268 TI - Walking the ERISA (Employment Retirement Income Security Act) tightrope. PMID- 10114269 TI - Controlling costs. PMID- 10114270 TI - Automated employee benefits. PMID- 10114271 TI - Back to the bedside. PMID- 10114272 TI - Cafeteria plans flex muscle. PMID- 10114273 TI - A new threat to nonprofits. PMID- 10114274 TI - What proposals for national health insurance ignore. PMID- 10114275 TI - TRSA's (Textile Rental Association of America) strategic analysis of the industry for 1992. AB - Growth exceeding Gross National Product (GNP), strong competition, ongoing consolidation, and improving profitability--trends that have characterized the textile rental industry throughout the 1980s--continued in 1990. And despite a recession in the latter part of the year, the trends appear to be indicative of the decade ahead. The compelling question for the industry and the country is whether or not the recession is over, also unclear is the rate of recovery that can be anticipated. Economic assumptions, developed jointly by the Council of Economic Advisers, the U.S. Treasury, and Office of Management and Budget, show a resumption of economic growth in the latter half of 1991 with the pace accelerating into 1992. Real GNP growth is predicted to become about three percent annually by 1995-96, and to be accompanied by gradual declines in inflation and interest rates. This annual strategic analysis by TRSA officers and staff offers insights into industry trends as well as the issues affecting customers and the market place. PMID- 10114276 TI - Strategic analysis of the industry for 1992. Action plans: marketing. PMID- 10114277 TI - Strategic analysis of the industry for 1992. Action plans: purchasing. PMID- 10114278 TI - Strategic analysis of the industry for 1992. Action plans: production. PMID- 10114279 TI - Strategic capital planning: system looks toward the future. PMID- 10114281 TI - Preventing board conflict over mission versus margin. PMID- 10114280 TI - Back to basics: dismantling elaborate corporate structures. PMID- 10114282 TI - Cost containment through control of services: lessons from Oregon. PMID- 10114283 TI - Changing MD behavior through continuous quality improvement. PMID- 10114284 TI - MD recruitment in rural hospitals requires special trustee support. PMID- 10114285 TI - Easing passages: a hospital's policy on life-sustaining treatment. PMID- 10114286 TI - Changes in outpatient payments could cost a bundle. PMID- 10114287 TI - Annual compensation survey: incentive plans on the upswing. PMID- 10114288 TI - How to fight killer health costs. PMID- 10114289 TI - Real health-care fixes. PMID- 10114290 TI - Decision making style and leadership patterns in nonprofit human service organizations. AB - The authors report on the adaptation of twelve nonprofit human service organizations. This analysis is part of a research project that entailed a comprehensive study of both the fiscal patterns and policy patterns of nonprofit organizations. Through the use of interviews in an exploratory descriptive design, several major patterns were identified concerning organizational adaptation. Three categories of events effected the adaptation of these organizations: executive staff turnover, program/service structure change and financial issues. The three industrial subsectors studied demonstrated unique patterns in these events. A reactive decision making style was the overwhelming choice of these organizations. Leadership was a phenomenon shared by CEOs and Boards of Directors. Resource dependency theory offers some explanation for the change that occurs in this cluster of organizations. PMID- 10114291 TI - A service tracking and referral form to monitor the receipt of services in a case management program. AB - Too often, systematic recording procedures are not developed which describe and assess the delivery of social work--and, more specifically, case management- services. The authors report on the Service Tracking and Referral Form developed by California's Adolescent Family Life Evaluation Project to document the receipt of services by pregnant adolescent clients as a result of case management intervention. The rationale and process underlying the development and use of the project's Service Tracking and Referral Form are discussed. Data are presented to illustrate the kinds of information which can be generated from the form. Finally, the authors discuss the form's utility and the possible uses of these types of data for case management, supervisory, administrative, and evaluative purposes. PMID- 10114292 TI - Eight myths on motivating social services workers: theory-based perspectives. AB - A combination of factors has made formal motivational and reward systems rare in human service organizations generally and virtually non-existent in social service agencies. The author reviews eight of these myths by reference to eight motivational theories which refute them: need theory, expectancy theory, feedback theory, equity theory, reinforcement theory, cognitive evaluation theory, goal setting theory, and social influence theory. Although most of these theories have been developed and applied in the private sector, relevant research has also been conducted in social service agencies. The author concludes with a summary of guidelines suggested by the eight theories for motivating human service workers. PMID- 10114293 TI - A "consumer-friendly" model of implementation. AB - Policy analysts and citizen groups have long struggled with the complexities of the implementation process. The model presented here empowers students, community organizers, and consumers with theoretically sound and practically useful procedures for assessing the extent to which social agencies are implementing any particular policy or piece of legislation. It also identifies key implementation processes for citizens to target in their agency change efforts. Specific research results are presented to illustrate the practical utility of the model. PMID- 10114294 TI - Organizational affiliation and effectiveness: the case of rape crisis centers. AB - Many rape crisis centers (RCCs) that were founded as autonomous organizations have affiliated with other organizations. The relationship of affiliation type and effectiveness is examined in a sample of 25 RCCs in Florida. Effectiveness is defined in terms of range of services for rape victims and involvement in rape prevention (social change) activities. The data show that 23 RCCs are affiliated with six types of organizations and two are free-standing. Each affiliation type has advantages and disadvantages but, overall, free-standing RCCs appear to be most effective and RCCs affiliated with community mental health centers, least effective. Of the seven types, free-standing agencies are most involved in rape prevention activities aimed at social change. PMID- 10114295 TI - Clinical and financial aspects of shared/part-time practice. AB - Shared and part-time medical practices are popular with both the medical group and the clinicians who fill these positions at Group Health Cooperative. The medical group benefits from the flexibility provided by part-time practitioners. Part-time clinicians have the opportunity to devote time to their families or second careers. There are, however, additional costs and administrative problems associated with shared and part-time practices. PMID- 10114297 TI - Opportunities, challenges, and accountability for HMOs. PMID- 10114296 TI - Screening program for colorectal cancer: participation and follow up. AB - The benefit of screening for colorectal cancer with the fecal occult blood test (FOBT) remains controversial. In 1985, an annual FOBT screening program for colorectal cancer was begun at Harvard Community Health Plan (HCHP). We subsequently reviewed 409 randomly selected medical records of members over age 50 to determine whether screening had been performed, how members with positive test results were evaluated by their physicians, and what gastrointestinal lesions were found as a result of positive screening tests. One hundred and ninety seven of 409 members (48%) were screened at least once during the two-year study period. One hundred and eight of 180 members (60%) who had one periodic health review (PHR) and 72 of 88 members (82%) who had two or more PHRs during the study period were screened at least once. Sixteen of 197 members who were screened at least once (8%) had positive tests. Eleven of the 16 members with positive tests were adequately evaluated by their physicians. Four had colorectal polyps and five had some other benign gastrointestinal lesion. The conclusion drawn is that FOBT screening for colorectal cancer is practical in the HMO setting. Members who have periodic health reviews are more likely to participate in screening. Physicians and members must be better educated to ensure adequate evaluation of positive tests. PMID- 10114298 TI - Practice guidelines: promise or threat? PMID- 10114299 TI - The myth of micro-data. PMID- 10114300 TI - Tribal warfare in organizations: turning turf battles into teamwork in hospitals. AB - Professional groups within the health-care setting exhibit many of the same characteristics found in intact cultures or tribes anywhere in the world. They also exhibit the same tendencies to defend their own group from attack or threat from the outside. Each group of health-care professionals has its own view of reality and is likely to take the stance that the other professionals in their facility are not only different--but wrong. This sets the stage for conflict and turf battles among groups. The tribal characteristics often displayed by professional groups can be divided into five categories: language or dialect differences, value differences, training differences, thinking differences, and rules or norms for behavior. Bridging these gaps requires a clear understanding of the differences themselves and a basic respect for the fact that each group is right in most cases--from its own professional point of view. The goal is to link the tribes together through collaborative negotiations to produce the best combination of right answers for the organization as a whole. PMID- 10114301 TI - Quality service management in health-care organizations. AB - This article discusses the importance of high-quality service delivery in health care organizations and provides recommendations for managers who seek to develop service-oriented organizational cultures. Additionally, reasons why health-care organizations should be responsive to consumer needs are identified. These include humanistic, economic, efficiency, and marketing reasons. Suggestions for managers on how to improve services in their departments are also provided. PMID- 10114302 TI - Ethics and the organizational human resources strategy: Part II. PMID- 10114303 TI - Laboratory roll-in. PMID- 10114304 TI - The Kodak Ektachem 500. PMID- 10114305 TI - Recruiting and retaining phlebotomists. AB - The phlebotomy team is receiving greater recognition than ever before for its contribution to the service image of the laboratory. Laboratory managers must recognize that phlebotomists are the laboratory's goodwill ambassadors. Because phlebotomists work on the front line, their technical skills and professional demeanor are prime factors in getting physician referrals and attracting patients to the facility. To recruit and retain a skilled professional phlebotomy team, laboratory managers must assess their operations and determine the skills, personal attributes, and education needed to perform the phlebotomy duties. To keep your best employees, try to continually upgrade your training, continuing education, and career advancement opportunities. To learn what makes a successful phlebotomy team, CLMR surveyed several CLMA members to find out how they are recruiting and developing their phlebotomists. Our special thanks go to all our respondents for sharing their expertise and experiences with us. PMID- 10114306 TI - Quality, ethics and accountability will be main criteria for the 1990s: Waiora Waikato. PMID- 10114307 TI - Facing the future role of information technology. PMID- 10114308 TI - Radical surgery prescribed for NZ's health system. PMID- 10114309 TI - "Your health and the public health"--threat or promise to our health. PMID- 10114310 TI - Charity care for tax exemption. PMID- 10114311 TI - Perspectives. An apathetic fight against AIDS. PMID- 10114312 TI - Perspectives. Antitrust looming larger for health care institutions. PMID- 10114313 TI - Perspectives. Administrative costs: is there gold in them bills? PMID- 10114314 TI - Perspectives. Free clinics: hippie holdover or wave of the future? PMID- 10114315 TI - Perspectives. Dispute resolution sidesteps court clashes. PMID- 10114316 TI - Courts continue to wrestle with the Wanglie and the Lawrance cases. AB - The deaths of Helga Wanglie in Minneapolis and Sue Ann Lawrance in Indiana have not affected the intensity of debate over nor the pursuit of resolutions to the issues their cases have raised. The following is an update of where these cases stand, in addition to a summary of a new New York law that extends the DNR concept to persons at home and in the community. PMID- 10114317 TI - Grand jury and publications add fuel to heated debate over suicide. AB - Three physicians, each with a different view on how to approach and accomplish physician-assisted suicide, are in the news as a result of a grand jury hearing and the publication of two new books on the subject. PMID- 10114318 TI - Should basic care get priority? Doubts about rationing the Oregon way. AB - Recognition of the need to ration care has focused attention on the concept of "basic care." It is often thought that care that is "basic" is also morally prior. This article questions that premise in light of the usual definitions of "basic." Specifically, it argues that Oregon's rationing scheme, which defines "basic" in terms of cost-effective care, fails to pay sufficient attention to important ethical principles such as justice. PMID- 10114319 TI - Toward an expanded vision of clinical ethics education: from the individual to the institution. AB - This paper advances a new paradigm in clinical ethics education that not only emphasizes development of individual clinicians' skills, but also focuses on the institutional context within which health care professionals work. This approach has been applied to the goal of improving the care provided to critically and terminally ill adults. The model has been adopted by about thirty hospitals and nursing homes; additional institutions will soon join the program, entitled Decisions Near the End of Life. Here, we describe the history and rationale for this approach, its goals, pedagogical assumptions, and design. PMID- 10114320 TI - Bioethics at the National Institutes of Health. AB - The National Institutes of Health is the largest biomedical research institution in the world. It has become one of the world's most highly respected research centers in part because of its efforts over the years to provide the research community with leadership in both the ethical and scientific parameters of research involving humans. As its 113th birthday approaches at the turn of the century, its great legacy is providing an environment to stimulate and nourish the diversity and creativity of ideas, and thereby enable science to progress. This research must continue to be guided and tempered by consistent and critical federally-supported ethical analyses. PMID- 10114321 TI - Teaching ethics in the health care setting. Part II: Sample syllabus. PMID- 10114322 TI - Health and the homeless teenager: evidence from the national health care for the homeless program. PMID- 10114323 TI - An invisible health and social policy issue: homeless/runaway youth. AB - Among the most 'invisible' people of this society are homeless and runaway youth. They present a major public health issue for society. Health problems, physical and mental, acute and chronic, are commonly found in studies of such youth. Many of their problems are exacerbated by and related to social policies of our society both in genesis and severity. PMID- 10114324 TI - Homeless youth: statement of problem and suggested policies. AB - There are an estimated 100,000 to 300,000 adolescents living on the streets with no supervision, nurturance or regular assistance from a parent or responsible adult. These young people are not "Huck Finns" seeking adventure but have been forced into this lifestyle and frame of mind. The reasons range from family dysfunctions such as abuse, sexual exploitation, neglect, and abandonment to inaction at the "system" level with regard to the overburdened child protective system, inadequate minimum wage, and lack of affordable housing opportunities. The consequences of this national problem are devastating and must be responded to. PMID- 10114325 TI - HMO viability and the economically disadvantaged. AB - This study uses data from the 1984 Kaiser Foundation national health care survey to assess the viability of HMOs for the economically disadvantaged in light of important health care attributes. To achieve this, the paper examines their satisfaction with different health care attributes and their preferences for alternative health care systems with respect to these same attributes. These data are used to assess overall health care system preference. This study found that the economically disadvantaged population was largely indifferent between an HMO or traditional fee-for-service health care system. This finding supported the prospect that the economically disadvantaged and Medicaid beneficiaries were somewhat amenable to HMO coverage. A fairly strong preference for fee-for-service health care system was found with respect to the quality of care attribute. This suggests that the economically disadvantaged will view HMOs as the health care system of choice depending on their ability to provide quality care. In light of these findings, several policies are recommended. PMID- 10114326 TI - Behavioral medicine: an emerging field of social work practice. AB - The burgeoning field of behavioral medicine is reviewed in terms of its relevance and implications for social work practice. This article reviews the behavioral medicine paradigm and its applications relevant to social work practice in health care settings. Specific applications of social learning theory to the treatment of cardiac disorders, chronic pain, headaches, obesity, and smoking are reviewed. The manuscript concludes with a review of practice issues. PMID- 10114327 TI - Multi-institutional service system development for high risk infants. AB - This article describes the development of a county-wide multi-institutional follow-up system for a high risk population of children and their families and proposes guidelines for health service system building. The target population for this program known as the Alliance for Infants and based in Allegheny County, Pennsylvania, was the very low birthweight infant and their families. Passage of legislation, P.L. 99-457, Education of the Handicapped Act Amendments of 1986, included provisions for Handicapped and At Risk Infants and Toddlers Program, which provided funds to states to develop and implement early intervention services such as the program described in this article. PMID- 10114328 TI - Access to insurance and length of psychiatric stay among adolescents and young adults discharged from general hospitals. AB - This study examines the characteristics of over 100,000 young people hospitalized in short-term, general hospitals throughout the United States between 1986 and 1988 for psychiatric and substance abuse diagnoses. Adolescent patients (ages 13 17) are compared with young adults (ages 18-22) in terms of demographic characteristics, diagnosis, source of payment, and length of stay. The study focuses on the relationship between the patients' access to private insurance and length of stay. PMID- 10114329 TI - The MT library of commonly used references. PMID- 10114331 TI - How I became my own transcriptionist. PMID- 10114330 TI - Certification exam results. PMID- 10114332 TI - Home-based medical transcription. PMID- 10114333 TI - AHA (American Hospital Association) 1989 survey on human resources--executive summary. PMID- 10114334 TI - Can you keep a secret? PMID- 10114335 TI - The Q-P zone. Arguments against a national productivity standard. PMID- 10114336 TI - So you want to be in business.... PMID- 10114337 TI - Important changes impact certification examination. Report from the May 1991 meeting of the Certification Council. PMID- 10114338 TI - U.S. employers: the new pioneers of health care cost containment. AB - The federal government traditionally has served as the principal agent for change in the financing and delivery of health care within our nation. Increasingly, however, private corporations are becoming frontrunners in efforts to reduce health care costs. PMID- 10114339 TI - Women in surgery: a study of first-year medical students. PMID- 10114340 TI - The physician-patient relationship: ten precepts. PMID- 10114341 TI - What surgeons should know about ... the Unique Physician Identification Number. PMID- 10114342 TI - Special report. Strategies for assessing HMOs. What Honeywell wants from HMOs. PMID- 10114343 TI - Special report. Strategies for assessing HMOs. An HMO primer. AB - Not all HMOs are alike. This handy reference spells out the four basic models and their advantages and disadvantages. PMID- 10114344 TI - Special report. Strategies for assessing HMOs. How to check out an HMO. PMID- 10114345 TI - Special report. Strategies for assessing HMOs. Data watch. An HMO industry profile. PMID- 10114346 TI - Special report. Strategies for assessing HMOs. Are "choice plans" too good to be true? AB - Insurers and HMOs have created a new product to meet employers' demands for cost controls and employees' desire for a wider choice of providers. But will the system work? PMID- 10114347 TI - Special report. Strategies for assessing HMOs. PMID- 10114349 TI - Data watch: a report card for managed care. PMID- 10114348 TI - Special report. Strategies for assessing HMOs. What every employer needs to know about HMOs. PMID- 10114350 TI - Are you paying other companies' health care bills? PMID- 10114351 TI - Data management: winning the numbers game. PMID- 10114352 TI - Does U.S. health care need a dose of Canadian medicine? PMID- 10114353 TI - Point of service: communication is the key to success. PMID- 10114354 TI - Taking the long-term view. PMID- 10114355 TI - Hershey's newest nonfat product: wellness. PMID- 10114356 TI - Employers fighting the battle of the bulge. PMID- 10114357 TI - Measuring employee satisfaction. PMID- 10114358 TI - And donor makes three. AB - A growing number of infertile women are being implanted with embryos conceived from their husband's sperm and eggs donated by other women. Though some clinics report a success rate of one in three, such adopt-an-embryo procedures pose legal, ethical and emotional problems. PMID- 10114359 TI - State of emergency. Hospitals are seeking radical solutions to ease walk-in patient overload. PMID- 10114360 TI - Indian Health Service; statement of organization, functions, and delegations of authority--PHS. PMID- 10114361 TI - Medicare program; data, standards and methodology used to establish budgets for fiscal intermediaries and carriers--HCFA. Final notice. AB - This notice announces that we are adopting as final without revision previously published proposed data, standards and methodology to establish fiscal intermediary and carrier budgets for the fiscal year beginning October 1, 1990. PMID- 10114362 TI - Food and Drug Administration; statement of organizations, functions, and delegations of authority. PMID- 10114363 TI - Medical devices; reclassification and codification of absorbable poly(glycolide/L lactide) surgical suture--FDA. Final rule. AB - The Food and Drug Administration (FDA) is announcing the reclassification and codification of the absorbable poly(glycolide/L-lactide) surgical suture (PGL suture). FDA issued an order in the form of a letter to the manufacturer reclassifying the PGL suture from class III into class II. PMID- 10114364 TI - Performance-oriented packaging standards; revisions to transitional provisions- Department of Transportation. Final rule; partial response to petitions for reconsideration and revisions. AB - This amendment makes revisions to a final rule published in the Federal Register under Docket Nos. HM-181, HM-181A, HM-181B, HM-181C, HM-181D and HM-204 (55 FR 52402, December 21, 1990). That final rule comprehensively revised the Hazardous Materials Regulations (HMR; 49 CFR parts 171-180) with respect to hazard communication, classification and packaging requirements. The changes were based on the United Nations Recommendations on the Transport of Dangerous Goods (UN Recommendations) and RSPA's own initiative. The revisions contained in this document are in response to petitions for reconsideration addressing the transitional provisions contained in the final rule. This amendment also extends the effective date for certain quantities of infectious substances and incorporates all rulemaking actions issued under Docket HM-142A (56 FR 197, January 3, 1991, and 56 FR 7312, February 22, 1991) into Docket HM-181. RSPA will respond to other petitions for reconsideration in a forthcoming corrections document. The revision of the transition period will allow adequate time for persons subject to the HMR to evaluate domestic products for changes in classification, descriptions on shipping papers, product marking, labeling and vehicle placarding, to conduct package testing, and to provide sufficient time for the retraining of shipper, carrier, enforcement, and emergency response personnel in the new requirements. PMID- 10114365 TI - Statement of organization, functions, and delegations of authority--HCFA. PMID- 10114366 TI - Medicare program; criteria and standards for evaluating intermediary and carrier performance--HCFA. General notice with comment period. AB - This notice describes the criteria and standards to be used for evaluating the performance of fiscal intermediaries and carriers in the administration of the Medicare program beginning October 1, 1991. The results of these evaluations are considered whenever HCFA enters into, renews, or terminates an intermediary agreement or carrier contract or takes other contract actions (e.g., assigning or reassigning providers of services to an intermediary; or designating regional or national intermediaries, etc.). This notice is published in accordance with sections 1816(f) and 1842(b)(2) of the Social Security Act, which require us to publish for public comment in the Federal Register whose criteria and standards against which we evaluate intermediaries and carriers. PMID- 10114367 TI - Medicare program; conditional designation of States in which Medicare SELECT insurance policies may be issued--HCFA. General notice with comment period. AB - This notice announces the Secretary's conditional determination of the 15 States in which Medicare supplemental insurance policies (commonly referred to as "Medigap" policies) may be issued as Medicare SELECT policies. The Omnibus Budget Reconciliation Act of 1990 (OBRA '90), Public Law 101-508, amended section 1882 of the Social Security Act to provide for the simplification and standardization of Medicare supplemental insurance policies and to authorize the approval of Medicare SELECT policies in fifteen States, as determined by the Secretary, for a three-year period. Under State-approved Medicare SELECT policies, insurers may restrict full Medicare supplemental insurance benefits to items and services provided by a network of physicians and providers under contract with the insurer. This notice implements section 4358(c) of OBRA '90, which provides for the designation of the 15 States in which Medicare SELECT policies may be approved for issuance during the period January 1, 1992 through December 31, 1994. PMID- 10114368 TI - Advisory committees; OTC Drugs Advisory Committee; establishment--FDA. Final rule. AB - The Food and Drug Administration (FDA) is announcing the establishment by the Commissioner of Food and Drugs of the OTC Drugs Advisory Committee in FDA's Center for Drug Evaluation and Research. Elsewhere in this issue of the Federal Register, FDA is publishing a notice requesting nominations for membership on this committee. This document adds to the agency's list of standing advisory committees. PMID- 10114369 TI - Medicare program; grace period and termination for nonpayment of Supplementary Medical Insurance (Part B) premiums for insured and uninsured persons--HCFA. Final rule. AB - This final rule changes the termination date for Supplementary Medical Insurance (SMI) (Part B) enrollees who fail to pay their Medicare Part B premiums. Presently, there is a 90 day grace period for the enrollee during which he or she may pay all overdue premiums and continue Part B coverage uninterrupted. The grace period begins at different times depending on whether the individual is or is not eligible for monthly social security, railroad retirement or civil service retirement benefits. This final rule establishes a uniform timeframe for determining the 90 day grace period which precedes the termination of SMI enrollees who fail to pay their Medicare Part B premiums. PMID- 10114370 TI - Medicare and Medicaid; requirements for long term care facilities--HCFA. Final rule. AB - These final regulations revise and consolidate the requirements that facilities furnishing long term care are required to meet to participate in either or both the Medicare and Medicaid programs. They revise our February 2, 1989 (54 FR 5316) final regulations to reflect our response to comments submitted by the public and to conform them to statutory provisions that were not in effect when we issued the prior rule, and to include various minor and technical changes in the requirements made by the Omnibus Budget. PMID- 10114371 TI - Medicare and Medicaid programs; nurse aide training and competency evaluation programs--HCFA. Final rule. AB - This rule amends the Medicare and Medicaid regulations pertaining to facilities to incorporate Federal requirements that States have training and competency evaluation by Medicare participating skilled nursing facilities and Medicaid participating nursing facilities and also have a nurse aide registry. The purpose of these provisions is to ensure that nurse aides have the education, practical knowledge, and skills needed to care for residents of facilities participating in the Medicare and Medicaid programs. These requirements implement, in part, sections 4201(a) and 4211(a) of the Omnibus Budget Reconciliation Act of 1987, section 6901(b) of the Omnibus Budget Reconciliation Act of 1989, and sections 4008 and 4801 of the Omnibus Budget Reconciliation Act of 1990. PMID- 10114372 TI - Infectious substances (etiologic agents); revisions to transitional provisions- Department of Transportation. Final rule; partial response to petition for reconsideration. AB - This amendment extends the transition provisions in 49 CFR 171.14 concerning the regulations for the transportation of infectious substances (etiologic agents), which were published under Docket No. HM-142A (56 FR 197, January 3, 1991, and which was incorporated into Docket HM-181 in a final rule published September 18, 1991 (56 FR 47158). The September 18, 1991, final rule extended the effective date for certain quantities of infectious substances, partially in response to a petition for reconsideration. This further revision to the transition provisions in section 171.14 is necessary because RSPA anticipates issuing a further response to the petition for reconsideration in a forthcoming corrections document. This amendment also makes a minor technical correction to section 171.14(b)(4)(ii). PMID- 10114373 TI - Fees for certifying insulin drugs--FDA. Interim rule; opportunity for public comment. AB - The Food and Drug Administration (FDA) is issuing interim regulations to revise the fee schedule for insulin certification services. Under the revision, FDA will charge a fixed fee for each master lot or batch submitted for certification. The changes in fee schedule reflect a change in agency testing policy for certification and release of batches of insulin. The changes in fees will allow FDA to continue to maintain an adequate insulin certification program as required by the Federal Food, Drug, and Cosmetic Act (the act). The fees are intended to recover the full costs of operation of FDA's insulin certification program, including the unfunded liability of the Civil Service Retirement Fund and appropriate overhead costs of the Public Health Service and Department of Health and Human Services. PMID- 10114374 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); reimbursement of individual health providers--Department of Defense. Final rule. AB - The Department of Defense is publishing this document to correct errors in the final rule on reimbursement of individual health providers contained in section 199.14(g). In addition to typographical and proofreading errors, the final rule failed to specify that changes to 1991 payment levels apply to the lesser of prevailing charges or the fiscal year 1988 prevailing charge levels adjusted by the Medicare Economic Index. The Fiscal Year 1991 Defense Appropriations Act prohibited payments "in excess of amounts allowed in fiscal year 1990 for similar services." Such amounts are, by definition, the lesser of prevailing charges, MEI limited 1988 prevailing charge levels, or actual charges. PMID- 10114375 TI - Medicare program; continuous use of durable medical equipment--HCFA. Interim final rule with comment period. AB - We are setting forth in this interim final rule with comment period the Secretary's determination, required under section 1834(a)(7)(A) of the Social Security Act, of the meaning of the term "continuous" as that term is used in defining a period of continuous use for which we make payments for durable medical equipment. PMID- 10114376 TI - Medicare program; home health agencies: conditions of participation--HHS. Correction of final rule. AB - This document corrects technical errors that appeared in the final rule published in the Federal Register on July 18, 1991 [56 FR 32967] entitled "Medicare Program; Home Health Agencies: Conditions of Participation." PMID- 10114377 TI - Medical and dental reimbursement rates for fiscal year 1992--Department of Defense. PMID- 10114378 TI - Educated guesswork. AB - Just about everyone applauds the use of cost estimates for federal programs as a way to curb the federal government's tendency to spend in the face of rising budget deficits. But a nagging question arises: Just how good are these cost estimates? PMID- 10114379 TI - Risk for HIV infection among health care workers. Nine questions physicians often ask. AB - Consideration is given to the risk from needlestick injury and other accidental exposure to blood and bodily fluids infected with HIV. Recommendations are made for postexposure prophylaxis with zidovudine: how soon to start administering the drug, optimal dosages, and subsequent monitoring of the person who has been exposed. Also discussed is the possibility of additional risks incurred by pregnant health care workers. PMID- 10114380 TI - Authority: changing attitudes. AB - George Langill, MHA, executive director of the Royal Ottawa Health Care Group, spoke at the 1990 CHAC Administrators' Seminar in Toronto. Langill addressed the issue of sponsorship and passing on mission values to future lay leaders from the point of view of a lay administrator. PMID- 10114382 TI - Values communication. PMID- 10114381 TI - Mission education: what has worked for us. PMID- 10114383 TI - Ageing well. PMID- 10114385 TI - Designing a road map for success: through common values and mission. AB - Employees must know the goals of an organization if they are to be expected to work toward their accomplishment. Concerned Care, Inc., found that through the identification of its values and the development of a mission statement, it was able to design a road map for its employees to follow, which led to success for the company. PMID- 10114384 TI - Building staff commitment: the role of caring values. AB - When an organization and its staff share the same goals and values, the staff know what the organization stands for, and staff performance and behavior supports those values. PMID- 10114386 TI - The value team approach: integrating personal and organizational values. PMID- 10114387 TI - Perceptions of caring: do patients and nurses agree? AB - A recent study of home care nurses and their patients showed that perceptions of nurse caring behaviors often vary among the two groups. Understanding these differences can help agencies allocate resources and nurses offer more appropriate care. PMID- 10114388 TI - Quality assurance: achieving compliance with home care regulations. PMID- 10114389 TI - The power of caring: management by values. AB - The record success that the home care industry is currently enjoying comes with its own set of problems--increased competition, personnel shortages, quality assurance worries, and increased regulation. The best insurance for success that an agency has is a solid set of values based on the quintessential value of caring. Those who harness its power will own the future. PMID- 10114390 TI - Utilizing outcomes in home care. PMID- 10114391 TI - Exceptional services, exceptional caring. AB - Responding professionally and compassionately to the health care needs of clients has always been the number-one priority of home care agencies. Recently, however, agencies have become aware of the significant implications that customer service has on the financial future of their organizations. PMID- 10114392 TI - Entrepreneurial human service: can business & caring coexist? AB - As big business enters the home care industry, agencies will have to depend on salesmanship for their survival. This means developing marketing skills and viewing the client as customer. PMID- 10114393 TI - ABEL Health Management Services, Inc.: caring is big business. AB - Providing the best home care services possible is Edward Abel's mission. This philosophy, rather than concern with the bottom line, has been instrumental in building a successful business. PMID- 10114394 TI - Health care: the fundamental rights of all Americans. PMID- 10114395 TI - Legal implications of withholding and withdrawing medical treatment. AB - It is important that home care providers be aware of recent developments in the law and public policy regarding terminal care decisions, as well as develop guidelines that both avoid legal and regulatory difficulties and ensure that the client is treated with dignity. PMID- 10114396 TI - New provider responsibilities under the Patient Self-Determination Act: living wills, durable powers of attorney, and the law. AB - Home care and hospice providers participating in Medicare or Medicaid are subject to the new obligations created by the Patient Self-Determination Act, and therefore must be familiar with their states' laws on patients' rights to direct medical care. PMID- 10114397 TI - Home care agency provider rights in the survey and certification process. PMID- 10114398 TI - Coping with investigators and investigations. AB - Most businesses in highly regulated industries like health care are likely to face an investigation at some point. By knowing ahead of time how to properly respond to investigators' requests and by exercising caution during the investigation, health care agencies can minimize the potential damage. PMID- 10114399 TI - The Medicare safe harbor rules and their effect on home care. AB - The Office of Inspector General has issued regulations that provide categories or standards for permissible relationships (safe harbors) which might otherwise be suspect under the kickback law. To take advantage of safe harbor protection, however, it is necessary to comply with all of its terms. PMID- 10114400 TI - Legal issues in home care. AB - While home care agency staff are overseeing the care of their clients, agency administrators must be conscious of the wellbeing of the agency itself. Many of the legal issues concerning any business venture apply equally to home care. At the same time, there are many legal concerns unique to health and home health care. To survive and flourish in the 1990s, administrators must be cognizant of both business and health law requirements. PMID- 10114401 TI - Independent contractors, overtime wages, and negligent hiring. Assessing an agency's risks. AB - Independent contractors, the payment of overtime wages, and negligent hiring practices present legal risks to home care agencies. Conducting an internal review now could save having to defend an agency on a government audit later. PMID- 10114402 TI - Common mistakes in personnel policies. AB - Personnel policies are the basic documents defining and managing an agency's relationship with its employees and its compliance with legal requirements. Unless properly prepared, an agency's personnel policies can create costly pitfalls for the agency as well as contribute to poor employee relations. PMID- 10114403 TI - Owner's compensation. PMID- 10114404 TI - Related parties? But I hardly know the guy. AB - When Medicare's auditors determine that a provider is "related" to a supplier of services, to the landlord of the provider's premises, or to the seller of provider assets, costs allowable under the Medicare program are usually limited to actual costs incurred by the related party rather than the higher charges or fees the provider paid. This article will discuss the criteria used by the Medicare program to determine related parties and the available exceptions and special application situations that impact on that determination. PMID- 10114405 TI - Coping with Medicare overpayments and other cash-flow problems: bankruptcy and nonbankruptcy alternatives. AB - Over the last several years, many home care agencies have encountered serious financial difficulties as a result of, among other reasons, Medicare's attempts to recover alleged overpayments. Depending on the cause of the financial difficulties, a provider, in consultation with accountants and attorneys, may decide to restructure its business through either a nonbankruptcy workout or a Chapter 11 bankruptcy filing. PMID- 10114406 TI - Average weekly earnings of full-time health care workers in private hospitals, 1989. PMID- 10114408 TI - Visualizing the mission. PMID- 10114407 TI - Managing quality: the role of the hospital board. PMID- 10114410 TI - Improving accreditation. PMID- 10114409 TI - The search for the right CEO. PMID- 10114411 TI - Standards for governance: governing within the law. PMID- 10114412 TI - Trustee interview: Robert E. Radford. Interview by Tracy Knudson. PMID- 10114413 TI - The problem with quality. PMID- 10114414 TI - The CEO of the 1990's: manager or leader? PMID- 10114416 TI - The economic wisdom of regulating pharmaceutical "freebies". PMID- 10114415 TI - Retroactivity and administrative rulemaking. PMID- 10114417 TI - The financial status of the Social Security and Medicare programs (1990). AB - To summarize the major points I have covered: The Social Security and Medicare trust funds are carefully held and monitored by three five member boards of trustees, and each board has two members who represent the public's interest. The combined Social Security trust funds are well financed for many years into the future; however, there is reason to monitor the financing for the disability insurance trust fund; and actions will in all likelihood ultimately be required to assure the long-term financial integrity of the combined OASDI programs over the next 75 years. The Medicare trust funds are adequately financed for the short term; however, the HI program faces serious mid- and long-range financing problems that must be addressed. As a result, there is a strong need for Congress to take remedial action to improve the financing and provide an adequate contingency reserve for the program. PMID- 10114418 TI - Family feud. As EMS providers, we are often the ones who are called in to pick up the pieces when a family dispute goes awry. PMID- 10114420 TI - Notification news. Many EMS providers remain unaware of a law that ensures they're notified of possible exposure to infectious diseases. PMID- 10114421 TI - Flying docs. PMID- 10114422 TI - Keeping morale high--even in difficult times. PMID- 10114419 TI - Lessons from the Gulf. PMID- 10114423 TI - The craft of artful buying. Dietitians' expertise can provide valuable input for carefully planned purchasing programs. PMID- 10114424 TI - When you can't employ a chef. PMID- 10114425 TI - Minor changes, major improvement. Patients at one L.A. hospital are satisfied with small but significant food production changes. PMID- 10114426 TI - Managing outcomes: the perspective of the players. AB - Outcomes management is most deeply rooted in clinical issues that interrelate concerns about quality with cost effectiveness of care. This is ground-breaking activity from many perspectives. Researchers must work more closely with clinicians and decision makers than ever before. Hospital executives must contend with many new external data demands and determine how to operationalize outcomes management programs within their institutions. There are new roles for clinician executives who act as change agents within health care organizations, while data on outcomes of care can lead to increased bargaining power among purchasers of services. In this article we discuss the major implications this new focus on managing outcomes is having on researchers, hospital executives, clinicians, and the purchasers of health care services. PMID- 10114427 TI - Perspectives on the outcomes movement. PMID- 10114428 TI - Successful outcomes management. PMID- 10114429 TI - Keys to successful outcomes management implementation. PMID- 10114430 TI - America's fastest risers. AB - Swift exploiters of change, the 100 companies that make up this new Fortune list attest to an entrepreneurial spirit undiminished by the weak U.S. economy. They owe their success largely to two often-touted but seldom followed managerial practices: putting the customer first and moving with relentless speed and adaptability. Old-line giants had better learn from them--or watch out. PMID- 10114431 TI - Is health insurance in Greece in need of reform? AB - This paper aims to assess the relationship between insurance contributions and health benefits in Greece by using information from sickness funds' accounts. The paper argues that the fragmentation of social health insurance, and the particular ways in which sickness funds' financial services are organized, are a major source of inequity and are grossly inefficient. The survival of these systems in the 1990s cannot be explained except on grounds of inertia and corporate resistance. PMID- 10114432 TI - Treatment and the Mental Health Act: a review board perspective. PMID- 10114433 TI - The Ontario Mental Health Act: a review of District Court "competence" decisions. PMID- 10114434 TI - Exit procedures of forensic psychiatric hospitals in The Netherlands: current problems and future prospects. AB - In this paper, I have outlined both the legal framework and the organizational structure of the Dutch system of hospital order treatment. I have also dealt with a number of developments, such as the changing composition of the patient population and the disappointing results achieved with sexually violent patients. In addition, I have described a number of developments in the field of exit procedures: the lack of interim rehabilitation facilities, the need for constant supervision of some patients after completion of their hospital order, and the critical attitude of the courts towards recommendations for the extension of hospital orders. Finally, I have issued a plea for comparative international research of a descriptive nature aimed at improving the quality of forensic psychiatric care worldwide. PMID- 10114435 TI - Legal access to patient health records/protection of quality assurance activities. PMID- 10114436 TI - JCAHO standards changes for 1992. PMID- 10114437 TI - Is there a place for the entrepreneur in health care? PMID- 10114438 TI - Having fun being a manager. PMID- 10114439 TI - Spotlight on rehabilitation. AB - Purchasing equipment for a comprehensive rehabilitation program is "patient driven." That means that the equipment needed will be inextricably intertwined with evaluation and restoration of patient function, both medically and psychologically. In addition to being concerned about the traditional managerial functions, that is equipment costs, usefulness, and maintenance, institutional liability, finance, and reimbursement guidelines, Materiel and Purchasing Directors must be knowledgeable about patient safety, rehabilitation QA, and the general impact of QA on direct patient care. As such, Materiel and Purchasing Directors become integral members of the therapeutic interdisciplinary patient care team. PMID- 10114440 TI - Computerization of intraocular lens consignment. AB - Consignments can save a tremendous amount of time and reduce ordering costs when they are managed effectively. To special order the over 5,000 lenses used by BPEI in a year would require a much greater expenditure of time and dollars. Although consignment is a widely used method for maintaining inventories of IOLs, many problems such as obsolescence, shortages, and billing discrepancies can occur if close attention is not given to them. Based on the volume and variety of lenses used in a particular organization, computerization of consignments may be of great value. PMID- 10114441 TI - Marketing specialty hospitals in the 1990s: making patients the best marketing spokespeople. AB - These are a few of the ways that a health care provider can influence the patient's perception of the treatment received. That impression is a lasting one. A positive referral can be a strong marketing tool that generates revenue and goodwill. If an institution provides quality health care services in a comfortable environment, then patients can easily be encouraged to tell their families and friends about their experiences in the institution. PMID- 10114442 TI - Managing materiel in a multidivisional corporation. AB - By using centralized purchasing and prime vendor contracts, the Allied Services material management department has been able to handle very effectively the purchasing needs of this multidivisional health care complex. Through active enforcement of Allied Service's materiel management policies and procedures, the department continues to be able to acquire the products and services that are necessary to keep the many programs running. Most importantly, these products and services continue to be acquired while the three significant attributes of materiel management--quality, availability, and service--are maintained. PMID- 10114443 TI - Children's hospitals: specialty hospitals that treat children specially. AB - Any reader who has children will agree that they make special patients, whether at home or in the hospital. These patients have unique requirements for love and compassionate care, and children's hospitals deliver on their promises. The well run children's hospitals researched for this article have converted their material management operational challenges to opportunities. They have built thoughtful material management strategic plans, reorganized their support services to provide customer service to end users, and they have centered their materiel management efforts around service and quality improvement. PMID- 10114444 TI - A mutually beneficial supply partnership at Columbia Hospital for Women Medical Center. AB - Columbia Hospital's variation of the JIT system to support its repetitive-type surgical procedures performed by the L&D and OR departments has proven to be the right system for this specialty care hospital to ensure that the right product at the right price is available at the right place and time. This system established by the cooperative efforts of the three partners involved (the hospital, manufacturer, and distributor) has been a win-win system for all. The manufacturer and distributor receive a profitable return for their products and services, and the hospital receives reimbursement for the products it utilizes to provide quality care to its ultimate customer, the patient. Columbia's supply flow system, as described herein, is a creative example of the many variations of the stockless or JIT supply systems being established in the world of hospital materiel management today. PMID- 10114445 TI - Specialty products: the next challenge for alliances. AB - As group purchasing matures, alliances and GPOs will need to expand their contract portfolio to include specialty products. As groups and manufacturers negotiate successful specialty products agreements and hospitals actively support those contracts, the industry as a whole stands to benefit. If alliance and manufacturers do not attempt to negotiate specialty products agreements that bring value to both parties, hospitals will miss out on savings, and suppliers will lose market share opportunities. PMID- 10114446 TI - Patient equipment management: integrating a flexible alternative to purchase or lease. AB - As hospital CSS and OR departments work together to manage patient equipment, alternatives to purchase are available that can provide them with needed flexibility and responsiveness. A rental equipment provider that can meet the standards demanded for quality health care can become a valuable asset when developing and refining a hospitalwide equipment management program. But in order to receive the level of quality and service they should expect, hospitals must continually communicate their changing needs while holding their providers accountable to established standards. PMID- 10114447 TI - Procurement aspects in a government specialty hospital. AB - In summary, the various aspects involved in the procurement and supply management process of this institute have been outlined. The decisions that are made in the procurement process may vary; however, the goal to provide the users with the item at the time of need never varies in any environment. PMID- 10114448 TI - A three-way corporate partnership for specialty hospitals. AB - Ultimately, the burden of escalating health care costs will be shared by all. A coalition of hospitals, suppliers, and group purchasing organizations possesses the power to communicate with each other as well as to ensure viability in the 21st century. Creative contracting will hopefully become the wave of the future in the health care industry. PMID- 10114449 TI - Basin sets: recycling is best. PMID- 10114450 TI - Child Health Corporation of America: a different perspective on materiel management. AB - Today, based on current programs and services, CHCA is recognized as one of the leading specialty hospital alliances in the country. This is made possible by the excellent support and commitment of its shareholder hospitals. As CHCA looks toward the future, it is anticipated that it will expand its horizons with additional programs and member hospitals. PMID- 10114451 TI - Procurement for a comprehensive cancer center. AB - The director of materials management services at M.D. Anderson is a position of endless opportunities, as well as continual challenges. The procurement process provides the opportunity to be an integral part of a team that has made a significant difference to many of the patients in the areas of cancer prevention, education, detection, diagnosis, treatment, cure, and rehabilitation. All involved in health care purchasing derive a personal fulfillment not available to purchasers in other industries. At MDA, however, this goes even one step further, as our department supports a team in the battle against cancer--a battle that affects nearly every household in America today. MDA can state that more than half of all patients treated are considered cured, and that is certainly a great team with which to be associated. But even more exciting are the years to come, as materiel management services supports the M.D. Anderson mission of eliminating cancer and allied diseases as significant health problems throughout the world. PMID- 10114452 TI - Free-standing surgery centers; the wave of the future. AB - To summarize, it should be realized that acceptance of surgicenters has happened. Surgery centers expect heightened awareness of their services as patients, in conjunction with their own physicians, make decisions based on cost, service, and convenience of the care provided. As copayments and deductibles increase, consumers have become better educated, taking a more active role in selecting their health care providers. This activity has given rise to joint ventures between physicians and hospitals offering new ambulatory care packages previously based in hospitals alone. The net effect will divide the health care industry into two markets, one that will manage high-intensity surgical procedures and one that will promote outpatient surgical procedures. PMID- 10114453 TI - A healthy choice. PMID- 10114454 TI - American Association for Partial Hospitalization Child and Adolescent Special Interest Group: standards for child and adolescent partial hospitalization programs. AB - This article describes standards and guidelines for the treatment of children and/or adolescents in partial hospitalization programs. Developed through the Child and Adolescent Special Interest Group of the American Association of Partial Hospitalization, they are intended to aid in the establishment of quality treatment programs. PMID- 10114455 TI - Overnight hospitalization of acutely ill day hospital patients. AB - As the trend toward community-based treatment of the seriously mentally ill has continued, partial hospital programs have admitted an increasing number of highly symptomatic individuals. As a result, patient crises occur more often in these programs, and staff have had to develop novel crisis intervention strategies that do not rely on standard hospital care. One such strategy involves the use of "overnight hospitalization" or a "backup bed" to provide temporary safety and clinical management with the goal of returning the patient to the partial hospital within 24 hr. Given the lack of data on this intervention the present study was designed to provide further information about the implementation and effectiveness of this clinical strategy. The authors outline the rationale and procedures for a backup bed system and provide data on outcome that is drawn from an examination of backup bed utilization in a public-sector mental-health setting over a 1-year period. Clinical implications of the findings for future use of overnight hospitalization with partial hospital patients are reviewed. PMID- 10114456 TI - American Association for Partial Hospitalization standards and guidelines for partial hospitalization. AB - This article reflects the first major revision in the standards for adult partial hospitalization which were developed by the American Association for Partial Hospitalization and initially published in Volume 1, Number 1 of this journal. They are intended to guide the development of quality treatment programs. PMID- 10114457 TI - A group psychotherapy model for acute treatment settings. AB - Traditional models of group psychotherapy have become less applicable in inpatient and partial hospital programs as the lengths of stay in these programs have decreased. Shorter lengths of stay are associated with rapid changes in group membership and high levels of symptoms among group members. The clinical objectives and clinical techniques suggested by traditional group models are simply less relevant under these conditions. In this paper the authors outline a model of group psychotherapy designed to meet the needs of acutely ill patients and accommodate to the demands of the short-term acute-care setting. Drawing on previous research that has identified the therapeutic factors that operate in these groups, the authors offer specific recommendations regarding group structure, therapist role, and clinical technique. PMID- 10114458 TI - Child and family outreach services as an adjunct to child and adolescent mental health treatment. AB - Child and Family Outreach Services have been an important adjunct to urban community child and adolescent mental health treatment. The Child and Family Outreach Services Program was developed as an extension of a child and adolescent outpatient and child partial hospitalization program to provide a comprehensive continuum of treatment. The Child and Family Outreach Program generalizes and links traditional therapeutic services to the patient's and family's environment through in-home, in-school, and community intervention. The latter treatment model enables the mental health service provider comprehensively to treat and effect positive change with high-risk patients and their families. Outreach service involvement has increased treatment compliance and reduced out-of-home placements. PMID- 10114459 TI - Medication group in a day hospital. AB - Many psychiatric outpatients need maintenance psychotropic medication, but noncompliance remains a major problem. One-half of psychiatric outpatients do not take their medications as prescribed. Medication compliance can be increased by proper and timely education regarding the psychiatric illness and the need for medication. A medication group in a day hospital setting is described which encourages the patient to take an active role in ensuring his best possible health. The goals of this group are to increase compliance by increasing understanding of psychiatric illness, actions and side effects of medications, how to cope with side effects, and how to avoid drug interactions. Fears and myths regarding use of medication are dealt with. Ongoing and repetitive discussions regarding medication use have been found to be useful and increase compliance. PMID- 10114460 TI - The challenge of patient power. AB - How can the rights of psychiatric patients best be safeguarded--and how far should those rights go? In the first of two articles, David Glasman reports on the Dutch experience. PMID- 10114461 TI - Strategy of a military kind. AB - The way in which two military hospitals in Saudi Arabia prepared to receive Gulf war casualties offers important lessons for NHS hospitals, says John Lane. PMID- 10114462 TI - Heart of the matter. AB - Nearly half of all deaths in Wales are from cardiovascular disease. Christopher Riley and colleagues set out how health planners aim to change all that with protocols for health gain. PMID- 10114463 TI - It's better by day. AB - Day surgery has had a slow record f growth in the UK, despite the benefits it offers. Robert Chapman explains the advantages of planning a dedicated unit. PMID- 10114464 TI - In sickness and in health. AB - Public health problems are predominantly of a chronic disease nature and can only be tackled through a more integrated approach by professional groups, says Walter Holland. PMID- 10114465 TI - Weaving the web of knowledge. PMID- 10114466 TI - To test or not to test? PMID- 10114467 TI - Personnel and training. Turbulent waters. PMID- 10114468 TI - Personnel and training. On a careful diet. PMID- 10114469 TI - Personnel and training. New lamps for old. PMID- 10114470 TI - Guy's the limit in a grim scenario. PMID- 10114471 TI - Channel islanders face a policy decision. PMID- 10114472 TI - Making a monkey out of us. PMID- 10114473 TI - The three faces of medical audit. PMID- 10114474 TI - In defense of formulae. PMID- 10114475 TI - Up against a barrier. PMID- 10114476 TI - Computing. Medical records are no joke. PMID- 10114477 TI - Computing. Images for the future. PMID- 10114478 TI - Computing. Finding answers close to home. PMID- 10114479 TI - Out of the darkness. AB - New DoH guidelines make informed, willing consent a vital issue in children's services. Priscilla Alderson points out the benefits in terms of quality care and shows how managers can help patients and professionals to overcome obstacles. PMID- 10114480 TI - Paying dearly for charity. PMID- 10114481 TI - Total quality. PMID- 10114483 TI - Is Britain likely to follow the Oregon trail? PMID- 10114482 TI - A service whose number is up. PMID- 10114484 TI - Is death the best fundraiser? PMID- 10114485 TI - Green power. AB - The NHS has a unique environmental role in the UK and managers need to be eco conscious. Simon Hodgkinson and Erica Ison provide a checklist for environmental audit. PMID- 10114486 TI - Joe Stalin and the NHS revolution. PMID- 10114488 TI - Discretion assured. PMID- 10114487 TI - Half the aggro. AB - A project at a London hospital is helping to iron out friction between the A&E department and local GPs, write Judith Green and colleagues. PMID- 10114489 TI - A perspective on universal health insurance. PMID- 10114490 TI - Using utilization review information to improve hospital efficiency. AB - Hospitals are currently under great pressure to improve the efficiency of internal operations without sacrificing quality of care. In the rush to do this, they often overlook an extremely useful source of information that already exists -data routinely collected as part of the utilization review (UR) process. This article describes a system using UR data for management purposes that was developed in a large urban teaching hospital. The components described are: (1) data collected systematically by trained reviewers applying the Appropriateness Evaluation Protocol; (2) software for data collection using inexpensive, highly portable computers; and (3) formats for reporting UR findings to hospital administrators and physicians. Information derived from UR in the study hospital is discussed, as well as factors to be considered in adapting some or all of the system's components in other hospitals. PMID- 10114491 TI - Factors influencing physician choice. AB - This study investigates the importance individuals place on each of 19 criteria in their choice of a physician. Through personal interviews 205 adults in Eastern Kentucky were asked to rate the importance of choice criteria on a scale from very important to very unimportant and to rank the five most and least important of these. Comparisons of mean ratings for men and women show that women have a tendency to rate criteria as more important than men, particularly those variables related to the physician's interpersonal manner. PMID- 10114492 TI - Responses to AIDS: large urban and small rural hospitals. AB - This study examines the assumptions that large urban hospitals will differ strikingly from small rural hospitals in their experience with AIDS patients, the staff-related problems caused by AIDS patients, and the administrative actions undertaken by the hospital in response. Results from a national stratified random sample of U.S. hospitals showed that by mid-1989 nearly all large urban hospitals had admitted AIDS patients, while only one-quarter of small rural hospitals had done so. Yet, over three-quarters of small rural hospitals have already adopted administrative policies about HIV testing of patients, and the contents of such policies differ little from those adopted by large urban hospitals. Despite similarity in official administrative responses, attitudinal differences exist. Staff fears of contagion and attitudes about isolation of HIV-positive patients are more evident in small rural hospitals; yet, recruitment difficulties triggered by staff concerns are greater in large urban hospitals. PMID- 10114493 TI - Protect the health of your health care worker. AB - This article reviews the many health and safety risks that confront health care workers every day and lists the various regulations that administrators need to understand and implement to provide for the well-being of hospital employees. In an age of growing public awareness of health and safety issues and an increase in litigation covering such issues, this article demonstrates how crucial it is for administrators to take the offensive to ensure that their hospitals are in full compliance with all health and safety regulations. This article describes possible health hazards in various hospital departments, cites appropriate restrictions and guidelines, both governmental and JCAHO, and offers suggestions for remediation. PMID- 10114494 TI - Productivity-enhancing work innovations: remedies for what ails hospitals? AB - Prospective pricing, the proliferation of alternative delivery systems, and the demands of third party payers and corporate employers for the containment of health care costs have engendered the keen interest of hospital executives seeking strategies for improving labor productivity. Despite this interest, the relevant literature suggests that few work innovations designed to enhance labor productivity have been implemented in hospitals. This article describes generic versions of four such work innovations--quality circles, union-management committees, autonomous work groups, and gainsharing--and discusses relevant research indicating the types of benefits gained from each and the reasons why some have failed. Each innovation's potential for success in hospitals is evaluated, and suggestions for increasing the effectiveness of each in hospitals is offered. PMID- 10114495 TI - Implementing computer information systems for hospital-based case management. AB - Like all health care services, case management is a process that relies on information. Based on the experiences in implementing computer information systems in six hospital-based case management programs, several financial, technical, and management issues are reviewed. These issues, which are also relevant for other specialized hospital-based programs, include information priorities, user acceptance, quantifying data, data entry methods, data security, and systems integration. The lessons learned regarding these issues are discussed, and categories of software alternatives are presented. PMID- 10114496 TI - A systemic health care quality service program. AB - This article describes a systemic quality service program implemented in a community hospital as an initial component of a total quality approach. The program interventions are based on consumer research and principles that have been effective in producing organizational change and enhancing worker performance. The description of the program is organized around six change and performance-enhancement principles: (1) establishing the importance of the performance, (2) specifying the expected performance, (3) ensuring the ability to carry out the performance, (4) accurately measuring the performance, (5) providing consequences, and (6) addressing systemic blocks to effective performance. Evaluative data are presented, indicating enhanced performance in the critical areas of documented resolutions to problems and reduced response time to problems. PMID- 10114497 TI - Hospital turf battles: the manager's role. PMID- 10114498 TI - Significance of transactional and transformational leadership theory on the hospital manager. PMID- 10114499 TI - Guidelines for a faculty practice fellowship program. Prepared by the Joint Committee of the American College of Healthcare Executives and the Association of University Programs in Health Administration. PMID- 10114500 TI - Concurrent antibiotic use evaluation in a community hospital. PMID- 10114501 TI - Genetic predictive testing and private insurances. AB - Genetic information is a potential tool for selection of job applicants and of candidates for insurance. Social implications of genetic information may represent a threshold for the access to health care facilities. Some of the issues related to the use of predictive genetic information by private life and health insurance companies are discussed. They include the potential threat for the privacy of the individual and his relatives, the pressure to undergo genetic testing and the social consequences of the use of genetic information by private insurance companies. The justified financial interests of insurance companies and the interests of the individual to have his privacy protected and to be able to partake in social attainments have to be brought into balance. A ban on genetic testing in connection with access to insurances and a limitation to the use of existing genetic information have been suggested by the Dutch Health Council. This approach to the problem should be adopted throughout the European Communities, so that medical progress does not turn out to be against the interests of the consumer. PMID- 10114502 TI - Health policies and Health For All strategies in the Nordic countries. AB - In the 1980s all five Nordic countries expressed, at the highest political level, their commitment to WHO's program Health for All (HFA) by the Year 2000. This program aims at improving the prerequisites for a healthier and longer life by changing lifestyles, decreasing environmental hazards and by shifting the emphasis in health care from specialized services towards primary health care. Following their policy statements all the Nordic countries formulated national HFA strategies during the latter half of the 1980s. This paper looks at the background and the formulation and implementation of these strategies, covering the period up until the end of the 1980s. The implementation of national strategies seems to be a slow and difficult process. The monitoring of progress toward accepted healthy policy goals is not easy, because measurable objectives or targets are mostly missing. PMID- 10114503 TI - Evaluation from population registry data of health care expenditure during the 6 months after cancer diagnosis. AB - It is currently estimated in France, that the cost of cancer has risen to $3.8 billion, with an annual growth of 5-10%. This represents approximately 6% of all health expenditure. The data from the Registry of Tumors in the Doubs region have enabled us to make an evaluation of health expenditure, reimbursed by the French Securite Sociale (S.S.), and its distribution in relation to different activities (diagnosis, type of treatment, follow-up, transport), according to cancer site. In 1984, the average cost per patient within the first 6 months of the illness was evaluated at $4,000. The results show major differences for the cancer sites, care facilities and budget items. Diagnosis assessment represents 27% of all expenditure, surgery 37%, radiotherapy, chemotherapy and transport, 11% each. All kinds of expenses are fully reimbursed by the French S.S. and transportation, which at the beginning used to avoid hospitalization, is now used as a comfort system and represents a high cost to the S.S. The different costs for the same illness between private, general public and university hospitals do not reflect a difference in care, but rather different systems of calculating and functioning. Till now there has not been any logical evaluation of care in the French health system. PMID- 10114504 TI - Total quality in acute care hospitals: guidelines for hospital managers. AB - Quality improvement can not focus exclusively on peer review and the scientific evaluation of medical care processes. These essential elements have to be complemented with a focus on individual patient needs and preferences. Only then will hospitals create the competitive advantage needed to survive in an increasingly market-driven hospital industry. Hospital managers can identify these patients' needs by 'living the patient experience' and should then set the hospital's quality objectives according to its target patients and their needs. Excellent quality program design, however, is not sufficient. Successful implementation of a quality improvement program further requires fundamental changes in pivotal jobholders' behavior and mindset and in the supporting organizational design elements. PMID- 10114505 TI - Guidelines to shape clinical practice. The role of medical societies: the Dutch experience in comparison with recent developments in the American approach. AB - In the last few years there has been a growing interest in the development of guidelines for care. The most important aim of these guidelines is to improve the quality of care by changing the daily practice of physicians in the desired direction. Therefore besides the scientific basis of guidelines, emphasis should be placed on the implementation of guidelines. Experience in the Netherlands, where medical societies contribute significantly to the procedure of consensus guidelines development, are described in comparison with new ideas in the U.S.A. regarding criteria setting. Involvement of physician organisations to the development procedure is a necessary requirement for guidelines to shape clinical practice. Furthermore, some interventions used in The Netherlands for improving implementation of guidelines in daily practice are mentioned. PMID- 10114506 TI - Policy relevance of a survey on smoking and drinking behaviour among Dutch school children. AB - Data from the first measurement of a cohort study among secondary schoolchildren allowed us to investigate policy correlates to smoking and drinking behaviour to some extent. Regular smoking is related to anti-smoking campaigns among boys and regular drinking is related to alcohol education at primary school. Regular drinking is also related to economic availability (free availability of alcohol and pocket money). The findings on economic availability and health education are directly policy relevant. PMID- 10114507 TI - Hospital creates a more efficient and accessible outpatient check-in area. PMID- 10114508 TI - Safe Medical Devices Act: what you need to know now to comply with the new law. PMID- 10114509 TI - Keeping interior-design costs low via three R's. PMID- 10114511 TI - Sound maintenance prevents costly boiler repair. PMID- 10114510 TI - Generator logs: ensuring JCAHO compliance. PMID- 10114512 TI - Top facility managers select nurse-call systems. PMID- 10114513 TI - Energy-storage system chills electricity costs. PMID- 10114514 TI - Courts review responsibilities in teaching hospital context. PMID- 10114516 TI - Turbo marketing through time compression. AB - A host of advantages will flow to companies that learn to make and deliver goods and services faster than their competitors. However, four key questions must be answered to determine if a turbo marketing approach is suitable for your company. PMID- 10114515 TI - Moving beyond lean and mean. AB - Traditional downsizing strategies often ignore the fact that corporate resources are inefficiently deployed. Here is a six-step approach to realigning, eliminating, and reallocating resources to improve overall operations. PMID- 10114517 TI - Avoid the breakdowns between planning and implementation. AB - There are eight areas in a business plan where energy is often wasted. Here's how to spot the gaps that prevent plans from being put into action. PMID- 10114518 TI - Why customer focus strategies often fail. AB - The author details nine pitfalls that sabotage efforts to execute a quality improvement strategy and insists that management must take a more active role in promoting the importance of customer-focused quality. PMID- 10114519 TI - A strategy for service--Disney style. AB - The organization's customer service philosophy was established over 35 years ago by its founder. Today, every aspect of the resorts and theme parks is geared to serve--and satisfy--its "guests." PMID- 10114520 TI - The right way to downsize. AB - Downsizing has seriously eroded the loyalty of U.S. workers. The author, who calls for a new kind of corporate culture, describes how two firms have balanced the needs of employers and employees. PMID- 10114521 TI - Senior management must champion business intelligence programs. PMID- 10114522 TI - The benefits of strategic naming. PMID- 10114523 TI - A Baby Bell reexamines itself. AB - U S WEST, one of the seven Regional Bell Operating Companies spun off from AT&T in January 1984, reevaluated all aspects of its business from top to bottom- including its corporate culture. PMID- 10114524 TI - 3M ruling calls hospital, GPO contracts into question. PMID- 10114525 TI - Linen and towel prices slip as market softens. PMID- 10114526 TI - Hospitals on yellow alert over allergic reactions to latex gloves. PMID- 10114527 TI - Disposables, convenience kits are costing hospitals an unnecessary fortune. PMID- 10114528 TI - Hospital buyers mull over high-frequency ventilators. PMID- 10114529 TI - Pharmacists have more responsibilities, liabilities than hospital materials managers. Part 1. AB - A hospital materials manager is also a registered pharmacist. In dealing with other materials managers at state and group meetings, he reports that a question often arises as to what professional responsibilities and liabilities a pharmacist has in addition to those of materials manager. In this dialogue, Dr. Decker reviews the professional responsibilities and liabilities of a pharmacist. In a subsequent article, the issue will be narrowed to the hospital pharmacist. This is Part 1 of a two-part series on pharmacist responsibility and liability. PMID- 10114530 TI - Confronting the "rights" issue in health policy. PMID- 10114532 TI - Collaboration as a source of strength. Specific criteria guide potential collaborative relationships. AB - Leaders at SSM Health Care System (SSMHCS), St. Louis, believe collaboration can ensure that existing Catholic healthcare ministries continue to serve and to provide a full continuum of care. They see collaboration as both a source of strength and an expression of their Catholicism. To facilitate collaboration, SSMHCS leaders have developed six relationship models in which two types of collaborative arrangements are possible--informal and formal. Informal cooperative relationships may include consultation and participation by non SSMHCS entities in established SSMHCS activities. Formal collaborative relationships include joint ventures at the operating entity level and in contract management, joint ventures at the governance-management level, and total affiliation (merger-acquisition). To ensure that SSMHCS leaders adequately evaluate healthcare providers with whom they may collaborate, in 1987 the system established criteria for collaboration. The criteria are based on specific mission, planning, financial, and operations principles. SSMHCS weights the mission criteria more heavily than other criteria because of the emphasis on mission in all its ministries. PMID- 10114531 TI - From ethical dilemma to hospital policy. The withholding or withdrawing of artificially provided nutrition and hydration. AB - In 1990 St. Joseph's Hospital and Medical Center, Paterson, NJ, established a committee to create an institutional policy to facilitate the decision-making process when patients or their legally authorized surrogates request the withholding or withdrawing of artificially provided nutrition and hydration. Before drafting a policy, the committee agreed on the philosophical, ethical, and medical assumptions that would be the foundation for the policy. The group adopted nine policy assumptions and provided guidelines that address concerns common to all healthcare facilities. No policy that addresses the issue of when to withhold or withdraw life-sustaining treatment will be perfect, nor will it resolve all the complexities of such a decision. However, an imperfect policy is preferable to the absence of a policy, which can lead to an abuse of patients' rights and contribute to arbitrariness in medical decision making. PMID- 10114533 TI - Trimming energy costs. A well-conceived conservation program can provide significant savings for hospitals. AB - Healthcare facilities can realize significant savings on their energy costs if they adopt an effective energy management program. For hospitals beginning such a program, an energy audit is a good first step. Auditors observe and evaluate all energy-using systems and study factors that affect energy use. They then write a report containing on-site observations, an analysis of at least one year's energy bills, and recommendations for low-cost and no-cost energy-reducing measures and capital projects, including new installations and retrofits. Lighting is one area where costs can be cut significantly. During the past few years a revolution in lighting technology has provided many choices for new installation and retrofit. Many utility companies have established rebate programs for certain relamping projects. In addition, integrated heating, ventilating, and air-conditioning systems can present hospitals opportunities to improve patient comfort and energy efficiency. Maintaining and upgrading system boilers and chillers and installing equipment designed to adapt efficiently to changing seasonal needs can generate significant energy savings. Improved energy distribution and control systems should also be a part of a hospital's energy management program. PMID- 10114534 TI - Nurturing mission. A case study of a hospital's cultural growth. AB - Recognizing the need to enhance his hospital's fulfillment of its mission as a religious organization, the chief executive officer of Lutheran Hospital of Indiana, Inc., Fort Wayne, initiated a process to change the institution's corporate culture to reflect the mission. After assessing hospital managers' perceptions of the hospital's mission, a planning committee drafted a mission statement. The statement was condensed into an easily remembered motto, "Reach out and reflect God's love!" to guide employees' actions. The hospital expanded its position descriptions to include the facility's expectations for employee behavior that is consistent with the mission. An orientation program for new employees emphasizes incorporating the mission concepts of courtesy and compassion into all activities. To establish the mission firmly as part of the corporate culture, the hospital established three recognition programs and redesigned its pay plan to recognize performance that reflects the hospital's mission. Redecorating the drab facility has improved employees' attitudes toward their work environment. Five years into the change process, the hospital now has clear direction for strategic decisions, a more cooperative atmosphere, and increased admissions. The process continues, and assessment of the mission establishment process will lead to the initiation of continuous quality improvement concepts. PMID- 10114535 TI - Corridors of care. A proposal for increasing inner-city residents' access to healthcare. PMID- 10114536 TI - A case for giving. Stressing its mission to care helps an inner-city hospital attract charitable donations. AB - In the current economic environment, voluntary not-for-profit hospitals must rely increasingly on private philanthropy. At St. Vincent's Hospital and Medical Center, New York City, leaders in the Division of Development and Public Affairs have found that emphasizing the commitment to mission in all the hospital's fund raising, public-relations, and marketing efforts is an effective way to attract philanthropic support. For more than a century, St. Vincent's has been actively engaged in efforts to raise funds to support its philanthropic projects. However, since the creation of a formal development office in the 1940s, organized fund raising efforts have flourished. And the inclusion of the hospital's development, public relations, and marketing departments in the same division in the 1980s further enhanced its philanthropic projects. The coordination of these departments' efforts has made it possible for St. Vincent's to highlight its commitment to mission in all of its communications, from letters soliciting funds from potential donors to paid advertisements in the New York Times. And the response to these coordinated efforts has been a significant increase in charitable donations. PMID- 10114537 TI - Diocesan support in philanthropy. Inner-city hospitals should work with bishops and parishes in fund-raising. PMID- 10114538 TI - Financial trends for urban Catholic hospitals. AB - To identify some of the reasons for the declining financial health of hospitals in large urban areas, staff from the Catholic Health Association's Department of Research and Information gathered data on such factors as average total profit margins, Medicare PPS margins, payer mix, and deductions from revenue between 1982 and 1989. In addition, the study tracked such indicators as occupancy, admissions, average payment period, and days in accounts receivable. Location and local community context were also studied. Based on the data, the study classified 28 of the 125 Catholic hospitals in large urban areas as "consistently sound," another 27 as "adversely affected," and 14 as "losing ground." The study compared these groups to one another, as well as to a group of nine Catholic hospitals from large urban areas that had closed by 1988. The study revealed that, despite differences in financial performance, consistently sound and adversely affected hospitals exhibited a number of similarities. Over the period covered, for example, the two groups had similar occupancy and received similar percentages of gross patient revenue from Medicare patients, third-party payers, and self-paying patients. Adversely affected hospitals contributed a significantly greater proportion of their resources to care for the poor. Consistently sound hospitals, on the other hand, had significantly fewer families below the poverty line, lower unemployment, and fewer nonwhite residents in their local communities. PMID- 10114539 TI - CHA's inner-city project. PMID- 10114540 TI - A continuum-of-care focus for hospitals. PMID- 10114541 TI - Building hospital-physician partnerships. PMID- 10114542 TI - Franciscan Health System. Hope for the homeless children. PMID- 10114543 TI - Humility of Mary Health Care System. Training sister trustees. PMID- 10114544 TI - Disgrace at St. Somewhere. PMID- 10114546 TI - Planetree's "healing revolution": the way it should be. PMID- 10114545 TI - Hospitals of the future: architecture and design for the year 2000. PMID- 10114547 TI - Beyond blueprints: integrated health systems for the 21st century. PMID- 10114548 TI - Health administration in Australia. PMID- 10114549 TI - Health administration in Australia--an overview. PMID- 10114550 TI - Education for management in the new public health. AB - The new public health movement has developed over the last decade and is emerging as an alternative to traditional concepts in Europe, Canada, and Australia, but not in the U.S.A. Fundamental principles, evolved mainly by the World Health Organization under the banner of the "Health for All by the Year 2000" Strategy, include community participation in health policy development and implementation of programs, emphases on primary health care and health promotion, and inter sectoral cooperation involving agencies whose influence impinges on health. Little attention has been given to organizational and management activities. Decentralized organization of public health activities appears to be an absolute requirement, along with firm political commitment to new public health concepts. Typically, however, health authorities have tended to develop separate bureaus for new public health activities rather than integrate the latter with traditional administrative structures. It is evident that a new style of management is needed with emphases on flexibility and interactional skills. Formal attempts to incorporate new public health principles in graduate educational programs are currently underway in Europe, where all nations are committed to the concepts. The European M.P.H., which includes an as-yet undefined component of management education, will have a core curriculum based on the new public health. Although there has been considerable activity in Australia, uncertainty remains over the viability of the new movement due to the creation of separate bureaus operating parallel to traditional health departments and their reliance mainly on a single source of funding from the federal government. PMID- 10114551 TI - Accreditation, evaluation, and review in Australian programs: the end of the beginning? AB - The approaches to accreditation, evaluation and review, particularly in health services management education, in the U.S.A. and England are contrasted briefly. The Australian approaches, in first a binary system and then a unified national system, are described. Differences between the proposals in the Federal Policy Statement on higher education and actual practice in the establishment of accreditation as an external process with developmental objectives are analyzed. The introductory approach in developing a methodology for program self-review is outlined, as is the extensive but largely informal system of evaluation. PMID- 10114552 TI - The development of a degree for health service managers for the 1990s. AB - The changing needs for Australian health service managers and health professionals involved in management were identified, and the postgraduate course for health service managers, the Master of Health Administration, was extensively revised to accommodate these changes. The process of the review is outlined briefly, and the factors which were considered are highlighted. The results of the review and a description for the revised course are presented. Some future changes are anticipated. PMID- 10114554 TI - Applying learning principles to the development of health services managers. AB - An Australian health services management program which leads to an M.H.A. for experienced managers was designed with a strong basis in principles of adult learning and management development. The program emphasizes management competencies, self-managed learning methodologies, team learning, learning contract processes, work-based projects, and choice for participants to undertake learning activities most relevant to their evolving careers. PMID- 10114553 TI - The New Zealand experience: integrating management development into a rapidly changing health system. AB - New Zealand has seen sweeping changes in recent years in its economic and social policies. Central to these has been the concept of better management in all phases of government activity with an emphasis upon performance, outcomes, and efficiency in achieving economic and social goals. There has been a massive reform of the health sector with restructuring of the Department of Health, devolution of most health delivery responsibilities to fourteen geographically defined area health boards, and the implementation of the principle of general management throughout the system. National health goals have been formulated to be implemented largely through area health boards. These developments have had important effects on educational programs in health services management, public health, and health policy. Collaboration through a New Zealand network of providers has been developed and a rapid growth in those seeking education and training programs has occurred. Education and training inputs are seen to be a major factor in the successful implementation of the major transformational change in New Zealand health systems. PMID- 10114555 TI - Educational implications of developments in the care and management of elderly people in Australia. AB - A current feature of Western nations is the attention governments are giving to the interests and needs of their aged populations. This is mainly due to the aging of these societies, but also acknowledges that to be effective, policies often need to address specific groups. This paper considers the aging of the population within Australia, the related development of government policy on care services and the educational implications for the caring professions. Particular mention is made of the role of postgraduate multidisciplinary courses in gerontology and brief descriptions are given of the three such programs currently available in Australia. PMID- 10114556 TI - Safe harbors for toy boats: an analysis and commentary. PMID- 10114557 TI - Surrogate decision-making legislation: the next frontier in life-sustaining treatment policy. PMID- 10114558 TI - Professionalism and progressivism: administration in the 90's. PMID- 10114560 TI - Medicaid reimbursement in a time of state budgetary crises. PMID- 10114559 TI - Implementing an automated care planning system. PMID- 10114561 TI - Predicting the future: can Medicare/Medicaid survive? PMID- 10114562 TI - Can we maintain a viable Medicaid program? PMID- 10114563 TI - Long term care under national health insurance. PMID- 10114564 TI - Effective risk management in long-term care. PMID- 10114565 TI - Organizational self-study: a case history. PMID- 10114566 TI - Preferences of elderly music listeners residing in nursing homes for art music, traditional jazz, popular music of today, and country music. AB - The purpose of this study was to investigate seniors' comparative music preference for four generic styles including art music, country music, popular music of today, and traditional jazz. The study also attempted to identify certain variables that have an effect on preference. Sixty-three subjects with a mean age of 82.5 from four nursing homes in the South Central Michigan area participated in the study. An interview and musical preference test were administered to the subjects individually. The listening test consisted of 16 music selections, four from each style. The seniors judged how much they liked the selections on a scale from 1 to 5, with 5 indicating greatest preference. Results indicated that country music style was preferred the most, followed by traditional jazz, art music, and lastly popular music. Variables that were found to affect preference were education level, community size in which the seniors grew up, and music training outside the school setting. PMID- 10114567 TI - 'Profit' variability in for-profit and not-for-profit hospitals. AB - This paper proposes two tests of the hypothesis that not-for-profit hospitals (NFPs) behave differently than for-profit hospitals. The profit variability test states that the profits of an NFP will be less variable over time than profits of a for-profit hospital if the NFP maximizes utility subject to a profit constraint. The second test examines whether NFP profits respond less to change in exogenous factors, such as Medicare reimbursement rates, than profits of for profit hospitals. Both tests, performed on panel data from 1983 to 1988, support the hypothesis that NFPs behave differently than for-profit hospitals. PMID- 10114568 TI - Cost function analysis of Medicare policy: are reimbursement limits for rural home health agencies sufficient? AB - This paper estimates a hybrid total cost function to determine to what extent an urban/rural differential exists in home health agency expenditures in Wisconsin in 1987-1988. We find that costs are over $16 higher per visit in urban Milwaukee than in rural and small MSA counties, providing no evidence that Medicare reimbursement limits should be raised to reflect 'ruralness'. However, the cost of providing skilled nursing care exceeds both urban and rural reimbursement limits. Because rural agencies depend more on Medicare clients and provide disproportionately more skilled nursing visits, this might represent the source of any financial difficulty. PMID- 10114569 TI - Equity considerations in utility-based measures of health outcomes in economic appraisals: an adjustment algorithm. AB - In this paper we consider whether methods currently used to measure utility of health outcomes are consistent with the equity criteria adopted by researchers. We show that unless the chosen equity criterion is incorporated in the design of the measurement instrument, the derived health state utilities are inconsistent with the equity criterion (except under special circumstances). Adjustment algorithms are derived, based on the axioms of von Neumann-Morgenstern utility theory, which take account of difference equity criteria currently adopted in the literature. The proposed approach is based on simple lottery questions of the type already used widely in empirical studies. PMID- 10114570 TI - Note. Evaluating exclusionary interventions. AB - In evaluation research, some interventions are designed to affect both the subjects that receive the intervention and those that do not. Preferred provider organizations (PPOs) are an example, because if they are successful, PPOs will direct patients away from non-preferred providers towards preferred providers. When the intervention affects all subjects, the excluded group cannot serve as a control group if one wishes to estimate the experience of subjects in the absence of the intervention. That estimate must come from subjects completely unaffected by the treatment. PMID- 10114571 TI - Must adverse selection cause premium spirals? PMID- 10114572 TI - The competitive effects of horizontal mergers in the hospital industry: a closer look. AB - Woolley (1989) attempted to analyze the competitive impact of horizontal hospital mergers using the 'event study' method. Woolley characterized his results as consistent with traditional 'oligopoly' theories of market behavior. We scrutinize in detail a large number of his events, however, and find that most either generated concentration increases too small to plausibly produce market power, or could not have conferred monopoly returns on firms improperly characterized as rivals. Accordingly, any observed abnormal returns are likely attributable to some other cause; we suggest some alternative interpretations of his results. Our paper highlights the need for care in the selection of events and the identification of rivals when applying the event study method to the analysis of mergers. PMID- 10114573 TI - The competitive effects of horizontal mergers in the hospital industry: an even closer look. PMID- 10114574 TI - Write procedures that work. PMID- 10114575 TI - Study shows hospital libraries save lives. PMID- 10114576 TI - Practice agreements. Set them up right and head off trouble. PMID- 10114577 TI - To my hospital's computer, I'm just a big spender. PMID- 10114578 TI - Have you met these health-care pirates yet? PMID- 10114579 TI - Practice costs are back under control. PMID- 10114580 TI - RBRVS: a new strain on doctor-hospital relations. PMID- 10114581 TI - Will new CPT codes complicate billing and cut your fees, too? PMID- 10114583 TI - The smartest phone call you'll ever make. PMID- 10114582 TI - How to defend your hospital privileges. PMID- 10114584 TI - The simplest, best cure for our health-care crisis. AB - Could national health insurance (NHI) cap the explosive rise in medical costs and at the same time give everyone access to health care? More and more people believe so, and for the first time in 20 years NHI proposals are being taken seriously in Washington. But the author contends NHI proponents have misread the causes for America's health-care crisis, and have been misled in their search for a solution by the example of the Canadian health system. All we really need she says, is a home-grown reform that's surprisingly simple and remarkably inexpensive. PMID- 10114585 TI - Why "safe harbors" leave doctors in danger. PMID- 10114586 TI - It's unfair--and unwise--to shun Medicaid patients. PMID- 10114587 TI - When my patients went bust, I followed right along. PMID- 10114588 TI - How I reach patients who can't reach me. PMID- 10114589 TI - RBRVS impact on academic practice. PMID- 10114590 TI - Academic group practice: facing its greatest challenge ever. AB - Academic practices are facing serious financial challenges, particularly in regard to declining margins. By responding appropriately, writes Kenneth Wilczek, academic practices can benefit from the future--and that benefit may be significant. PMID- 10114591 TI - Motivating employees: an incentive program. AB - Motivating employees is a challenging and critical task for all managers--no matter what the field. Robert Barczewski, M.B.A., and Linda Michelson describe how a successful incentive program at the Washington University School of Medicine was developed. PMID- 10114592 TI - Developing a merit compensation plan in an academic setting. AB - UACCMF believes it has created an effective tool to quantify departmental goals and objectives and the faculty's performance in attaining those attributes. Formulating the plan and marketing it to the faculty was time consuming. On several occasions, UACCMF contemplated scrapping the plan but persevered because staff believed it was supported by sound theory. By changing certain details, it won faculty acceptance. Any large change makes people resistant because it involves uncertainties, especially when compensation is affected. Naturally, people view the plan first from their own perspective (How will this affect my pay?) and only later from the department's perspective. Now that a blueprint of department values is established, faculty members have concrete goals on which to focus and some direct control over their salaries. PMID- 10114593 TI - Training surgery residents in group practice management. AB - As health care delivery continues to grow in complexity and uncertainty, academic practitioners must integrate clinical disciplines with research, financial management, marketing, law and many other areas. Jill Ridky, Ph.D., and Tom Bennett, M.B.A., D.Div., M.S.W., write about survey results on the current use and need for practice management training in residency programs. PMID- 10114594 TI - Becoming chart smart the academic way. AB - Instead of relying on another "quick fix" approach to medical record problems, write Eileen Chiama, M.S., Robert Morisse, M.A., M.P.H., and Barbara Nawrocki, M.P.H., the University of Connecticut School of Medicine took an academic approach--using a detail-oriented, two-year process led by committee. PMID- 10114595 TI - The academic administrator's role in ... the sudden death of a resident physician. AB - In an academic administrator's role, writes Kathy Roberts, one's day-to-day responsibilities involve the management of a wide variety of administrative matters; however, no amount of training totally prepares one for the sudden death of a resident physician and the consequences thereof. Roberts describes just such an incident and how her organization dealt with it. PMID- 10114596 TI - Measuring productivity in the academic setting. AB - As medical schools rely more heavily on clinical revenues for their viability, successful practices will be those that can emulate private practice operations. James Reuschel and Donald Earle offer guidance on measuring productivity in the academic setting. PMID- 10114597 TI - Forming PHOs for direct contracting. PMID- 10114598 TI - Facing the prospect of national health insurance and its impact on group practice. AB - Thomas Weil, Ph.D., in the March/April and May/June MGM Journals speculated on the probability and effects of a national health insurance system. The MGM Journal invited response from several MGMA members and their commentaries appear here. PMID- 10114599 TI - The cyclincal nature of health insurance. PMID- 10114600 TI - Total financial management. AB - Total financial management is a program designed by author Robert Katz, M.S., C.P.A., which says that by managing from the top down, the physician/administrator team can regain control of the practice and its major financial centers. His article describes the two-phased approach to total financial management. PMID- 10114601 TI - Electronic spreadsheet vs. manual payroll. AB - Medical groups with direct employees must employ someone or contract with a company to compute payroll, writes Michael Kiley, Ph.D., M.P.H. However, many medical groups, including small ones, own a personal or minicomputer to handle accounts receivable. Kiley explains, in detail, how this same computer and a spreadsheet program also can be used to perform payroll functions. PMID- 10114602 TI - Appealing Medicare payment denials. PMID- 10114604 TI - Building a sense of teamwork within the organization. Getting along with your practice partners. AB - Experiencing teamwork is positive, energizing and motivating, writes Joan Wagner Zinober, Ph.D., M.B.A., in the third article of her series on the management and leadership of people. What is not so well known, however, is the impact of destructive professional relationships on the bottom line. Zinober offers guidelines on how to promote positive working relationships among practice partners. PMID- 10114603 TI - An insider's view of overpayment audits. PMID- 10114605 TI - Giving credit its due in the group practice setting. How credit cards can improve cash flow. AB - The health care industry is moving toward more patient service, and one aspect of service often overlooked is billing, writes Marcia Pear. Some practice managers believe credit cards aren't cost effective. In reality, they can actually accelerate cash flow and allow patients to resolve financial obligations sooner. PMID- 10114607 TI - Certification of laboratorians: an update. AB - More than a dozen national organizations certify clinical laboratory professionals. As regulations and job descriptions evolve, the debate over certification requirements continues. PMID- 10114606 TI - To collect or not to collect. The internal woe of the physician's office. AB - Physicians are obliged to provide health care services regardless of race, creed, color or the ability to pay, write Carol Miller and Harry Wolpoff, Esq. Yet, a medical group is a traditional business which requires cash payments to continue operations. Miller and Wolpoff discuss such issues as physician sensitivity to collections, patient responsibilities and staff training in creating an effective collection program for medical groups. PMID- 10114608 TI - The making of a new certification exam. PMID- 10114609 TI - Designing an in-house phlebotomy training program. PMID- 10114610 TI - A temporary supervisor reports from the front lines. PMID- 10114611 TI - Turning around the behavior of uncooperative employees. PMID- 10114612 TI - Structuring your RFI and RFP for an objective LIS evaluation. PMID- 10114613 TI - JCAHO takes new approach to quality. AB - The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has recently released its 1992 Accreditation Manual for Hospitals. A shorter, more concise version of its 1991 counterpart, the 1992 version marks the beginning of a multi-year transition to standards that emphasize the application of continuous quality improvement principles and concepts. In an effort to clarify some of the changes, Michigan Hospitals asked JCAHO officials to provide answers to some of the most commonly asked questions about the new standards. Following are their responses. PMID- 10114614 TI - An explanation of the Medicaid Voluntary Contribution Program. AB - The Engler Medicaid Voluntary Contribution Program provides a vehicle to address the current economic pressures on the state and hospitals, while committing all parties to work on reform of the current system. PMID- 10114615 TI - Access to health care emerges as a public issue. PMID- 10114616 TI - Are Michigan hospitals complying with the Required Request Law? Transplant and Health Policy Center. PMID- 10114617 TI - Values, cohesiveness, and volunteers: icons for our future. AB - Newly installed MHA Chairman Edward B. McRee, president of Ingham Medical Center in Lansing, addressed MHA members and guests during the association's 1991 Annual Corporate Membership Meeting on Mackinac Island this summer, saying the key to success for the association, and for the health care industry in general, lies in our cohesiveness. Following is the text of his remarks to the group. PMID- 10114618 TI - On trusteeship. From the statehouse to the boardroom. Interview by Ralph D. Ward. PMID- 10114619 TI - Auxilians contribute to the quest for quality. PMID- 10114620 TI - The value of your resume. PMID- 10114622 TI - Vision project: health care 2000. PMID- 10114621 TI - Transforming health care organizations through total quality management. PMID- 10114623 TI - Baxter, Olympic Committee forge donation deal. PMID- 10114624 TI - Picker blasts allegations that its service business undercut its competitors. PMID- 10114625 TI - Violence takes fiscal toll on D.C. hospitals. PMID- 10114626 TI - FHP Int'l revamps pay system following probe. PMID- 10114627 TI - Pa. Medicaid officials deny crackdown seeks revenge. PMID- 10114628 TI - 'Family matters in rural recruiting'. PMID- 10114629 TI - Studies analyze group practice pay. PMID- 10114630 TI - Malpractice moves up on health-reform list. PMID- 10114631 TI - House panel votes to delay Medicaid limits. PMID- 10114632 TI - Healthcare ventures won't fly without the right management. PMID- 10114633 TI - Form, function and flexibility by design. AB - From a children's residential psychiatric unit in California to a medical campus in Japan, this year's winners in MODERN HEALTHCARE'S sixth annual design awards competition showed great innovation and skill in blending the projects into surrounding communities, cultures or existing structures. PMID- 10114634 TI - Bids for geographic reclassification top 1,300 for fiscal 1993. PMID- 10114635 TI - Hospital staffs suffer losses from Calif. fire. PMID- 10114636 TI - Nursing students learn about computer-age care. AB - Part of the problem in computerizing the patient-care process is that caregivers are used to doing things the old-fashioned way, which they may have learned years ago when they got their professional training. One nursing program is including a course on the use of computers in healthcare. PMID- 10114637 TI - Consumers to help write W. Va. 'no frills' plan. AB - West Virginia law gives the state insurance commissioner authority to write a "no frills" insurance plan available to all residents through commercial insurers. The commissioner is enlisting the help of small businesses, the primary purchasers, to identify what benefits they want and how much they can afford to pay. PMID- 10114638 TI - Columbia, Medical Care Int'l team up to build Texas hospital. PMID- 10114639 TI - HHS investigating Alabama hospital. PMID- 10114640 TI - Healthcare International considering Chapter 11. PMID- 10114641 TI - Health Management, Vencor planning stock offerings. PMID- 10114642 TI - Court ruling unleashes 47 union petitions. PMID- 10114643 TI - San Diego hospital hopes for 'mercy' on fine for illegal patient transfer. PMID- 10114644 TI - Other payers should reimburse VA--panel. PMID- 10114646 TI - Drugmaker boycott may be expanded. PMID- 10114645 TI - Study: quality process aids integration. PMID- 10114647 TI - FTC set to vote on Fla. acquisition. PMID- 10114648 TI - HealthTrust posts fiscal year profit. PMID- 10114649 TI - Sale of investment helps AMI to profit. PMID- 10114650 TI - MGMA members back plan to open D.C. office. PMID- 10114651 TI - Dems agree on reform 'principles'. PMID- 10114652 TI - Rostenkowski reform legislation criticized. PMID- 10114653 TI - Study finds unnecessary stays. PMID- 10114654 TI - SMS, officers are hit with SEC charges. PMID- 10114656 TI - HCFA testing electronic claims standards. PMID- 10114655 TI - Tracking costs understated--study. PMID- 10114657 TI - Swing-bed option takes hold. PMID- 10114658 TI - Radical surgery needed to stop spread of healthcare spending. PMID- 10114659 TI - Safe harbor rules create infusion confusion. Physician ties may put business in a bind. AB - Home infusion has been one of healthcare's healthiest businesses, but providers are concerned about the future in light of new "safe harbor" guidelines and recent crackdowns by the HHS inspector general's office. Despite that uncertainty, the industry continues to prosper: Revenues have risen at an estimated 25% annual rate, thanks to home infusion's ability to get patients out of hospitals quicker. PMID- 10114660 TI - Informing through 'advertorials'. PMID- 10114661 TI - Prepping for Patient Self-Determination Act. AB - Dec. 1 is the effective date of the Patient Self-Determination Act of 1990, which requires all healthcare institutions to provide information to patients on living wills, durable powers of attorney and other "advance directives" governing the extent to which life-sustaining treatment should be administered. Healthcare attorney Michael R. Callahan capsulizes the law's requirements and tells how to meet the deadline. PMID- 10114662 TI - Thorough trial period cut changeover travails. AB - If you want a little advice on how to change information systems without experiencing an unwelcome increase in accounts receivable, a Waterloo, Iowa, hospital has some to offer. And it's pretty simple--take the time to train your staff and eradicate the system's bugs. By insisting on two extra months time before taking the system "live," the hospital avoided common problems and saw only a minuscule increase in accounts receivable. PMID- 10114663 TI - Kusserow unloads on physician-fee stipulations. PMID- 10114664 TI - System's pension-plan consolidation pays off. AB - A couple of years after Daughters of Charity National Health System merged its 54 pension plans into one fund, the payback is proving the arduous process was worthwhile. An in-house study shows the 36-hospital system's consolidated fund is saving almost $2 million per year in administrative expenses, including reduced insurance premiums and managers fees. Experts see a growing trend of consolidation. PMID- 10114665 TI - Ex-board members, others named in $10 million suit. PMID- 10114666 TI - Fla. PRO layoffs spark fears of pay slowdown. PMID- 10114667 TI - Illinois nursing home payment system ruled invalid. PMID- 10114668 TI - Nashville public facility, teaching hospital to merge. PMID- 10114669 TI - Humana unscathed by inquiries--analysts. PMID- 10114670 TI - 2 suburban L.A. hospitals talking merger. PMID- 10114671 TI - HCFA grants rare plea to extend pact. PMID- 10114672 TI - Pa. appeals rate ruling to Supreme Court. PMID- 10114673 TI - Mass. hospitals rip rankings. PMID- 10114674 TI - Ala. becomes first to challenge new Medicaid donation rules. PMID- 10114675 TI - Hospital in Augusta, Ga., settles antitrust complaint with FTC. PMID- 10114676 TI - 6 AMI execs axed as O'Leary reshapes top management. PMID- 10114677 TI - Ill. cost-containment council cancels pact. PMID- 10114679 TI - 15% spending growth projected. PMID- 10114678 TI - New SunHealth contracts offer savings. PMID- 10114680 TI - DEC (Digital Equipment Corp.) to transfer responsibility for DECrad to IDX. PMID- 10114681 TI - The big get bigger--TMC buys land. PMID- 10114682 TI - IPA sues Deere HMO over use of fee schedule. PMID- 10114683 TI - Healthcare puts its stamp on Pa. Senate upset, other votes. PMID- 10114684 TI - White House initiatives target HME fraud. PMID- 10114685 TI - Outcry over Final Exit ignores medical root of the problem. PMID- 10114686 TI - Groups see more use of pacts, target alternate sites. 1991 group purchasing survey. AB - Purchasing groups and alliance purchasing programs accounted for $11.1 billion in goods and services bought by hospitals last year, according to MODERN HEALTHCARE's 1991 group purchasing survey. Trends included the folding of additional hospital departments into central purchasing and increased targeting of alternate-site markets. The responses also documented significant growth and realignment in the industry. PMID- 10114687 TI - Single-payer system would save states $30 billion--study. PMID- 10114688 TI - Final physician fee regulations expected to include 6.5% offset. PMID- 10114689 TI - L.A. acute-care facility switches to niches. AB - A little-known hospital in Los Angeles surrounded by larger facilities with well recognized names is leaving the general acute-care business in hopes of making a name for itself through niche services. The new focus at 91-bed Westside Hospital will be a dedicated AIDS-care facility along with centers of excellence in outpatient plastic surgery, industrial medicine and family medicine. PMID- 10114690 TI - Despite slowing rate growth, HMO execs upbeat about '92. PMID- 10114691 TI - 'Prepackaged' bankruptcy wraps up process quickly. AB - Charter Medical Corp. has joined a small group of companies that have turned to prepackaged bankruptcy plans to quickly and efficiently restructure debt. By reaching agreements with creditors before going to court, distressed companies can shorten the time it takes to emerge from bankruptcy and greatly reduce expensive professional fees. PMID- 10114692 TI - Community Health has pacts to manage four not-for-profits. PMID- 10114693 TI - HCI, HealthVest control shifts. PMID- 10114694 TI - Number of distressed hospitals steady--report. PMID- 10114695 TI - CPC stock hits new low as shareholders consider suits. PMID- 10114697 TI - La. governor pick puts health gains on the line. PMID- 10114696 TI - Denver zoning law aims to end battles over expansion plans. PMID- 10114698 TI - VHA gives Baxter a corner on private-label distribution. PMID- 10114699 TI - Charter gears up for outcomes data. PMID- 10114700 TI - NME scraps swap plan, will buy stock. PMID- 10114701 TI - Hospital groups pool their clout in support of delay on Medicaid-donation rule. PMID- 10114702 TI - New Jersey providers may be first to test prospective payment for outpatient care. PMID- 10114703 TI - 'Bedside ICU computers aid direct care'. PMID- 10114704 TI - Appeals of discrimination ruling expected. PMID- 10114705 TI - More hearings planned in Humana inquiry. PMID- 10114706 TI - Texas probes Humana HMOs after complaints over quality. PMID- 10114707 TI - Public hospitals sue HCFA over Medicaid tax/donation rule; states bargain with feds. PMID- 10114708 TI - Expose attacks health policy behind the consequences. AB - A new book by Walt Bogdanich, special writer for the Wall Street Journal, aims to flag down passing consumers and show them some of the wreckage caused by healthcare institutions in the real world of healthcare competition, prospective payment, cost containment and personnel shortages. His message to the public in The Great White Lie: How America's Hospitals Betray our Trust and Endanger our Lives is that all hospitals and physicians aren't the same and that the public must demand access to medical performance records. Modern healthcare asked him what his message is to healthcare executives and policymakers, who take the brunt of his criticism. PMID- 10114709 TI - Keeping history alive. Archivists at nation's oldest hospitals face shortages of money, space in their work to preserve the past. AB - As hospitals reach milestones for longevity, their interest heightens in gathering historical mementoes and telling the public about their past achievements. However, for some of the nation's oldest hospitals, a shortage of money and space are substantial barriers they face in trying to preserve and promote their beginnings and legacy. PMID- 10114710 TI - Physicians' blitz unlikely to sack fee rule. PMID- 10114711 TI - Increase in surveys, survey fees helps triple JCAHO's earnings. PMID- 10114712 TI - IRS, courts enter battle between nurse services. AB - Are nurses who are represented by nurse registries actually independent contractors or are they employees of the registries? The answer determines whether the nurse or the registry is responsible for paying or withholding employment related taxes. The answer also decides which side gets a competitive price advantage. PMID- 10114713 TI - Employers making use of price, quality data. AB - In efforts they hope will reduce costs, healthcare purchasers are becoming more active in helping beneficiaries choose providers. Such efforts include increased use of widely available price and quality data. Quaker Oats, for example, publishes hospital price guides, while Navistar International and Hershey Foods are developing their own provider networks. PMID- 10114714 TI - Members of payment panels back spending limits. PMID- 10114715 TI - GE tax-exempt lease plan saves time, money. AB - A new tax-exempt lease financing program in Massachusetts is expected to save the state's hospitals time and money when they acquire medical equipment from GE Medical Systems. GE is looking to expand the program to other states, and it could serve as a model for other equipment manufacturers. PMID- 10114716 TI - Berkshire system head on temporary leave. PMID- 10114717 TI - The physicians practice profile: a piece of the quality puzzle. AB - In responding to a New York State law and regulations that essentially mandated high quality and required hospitals to implement a system of physician practice profiles, Genesee Memorial Hospital involved the medical staff at all stages and made heavy use of computers for the ultimate system. The result is a profile system with the backing of physicians and with easy access to maximum amounts of information. Still, the author asserts, such profiles are at best an imperfect response to issues of quality. PMID- 10114719 TI - HHS Inspector General publishes final safe harbor regulations. AB - The Department of Health and Human Services Office of Inspector General has finally published the long-awaited Medicare/Medicaid final safe harbor regulations. The regulations, implementing the Medicare and Medicaid Patient and Program Protection Act of 1987, protect from criminal and civil sanctions certain payment practices that could otherwise be proscribed under the Medicare/Medicaid antikickback statute. Unfortunately, the final safe harbors appear not to reach many common business arrangements among health care providers currently in place. PMID- 10114718 TI - Physicians can ease nursing shortage. AB - In spite of a small increase in nursing school enrollments for the first time in five years, the demand for nursing services will continue to outstrip the supply during this decade. The solutions to this dilemma are obvious: More efficient use of the current supply of nurses and increased numbers of people entering the nursing profession. This article addresses the second solution, exploring the influence of physicians on career choices in nursing and describing a model doctor/nurse relationship that brings nurses pride and job satisfaction. PMID- 10114720 TI - Patient dynamics, staff burnout, and consultation-liaison psychiatry. AB - This paper discusses the valuable role of the consultation-liaison psychiatrist in reducing hospital staff burnout, particularly in working with difficult patients admitted to nonpsychiatric services. Direct patient consultation is a reimbursable service. However, staff-oriented consultation, while not reimbursed by most third-party payers, can be an invaluable means of improving staff-patient relations, reducing liability risk, and alleviating staff stress. The consultation-liaison psychiatrist can be an important element in a hospitalwide, ongoing, comprehensive program to reduce burnout and thereby optimize staff retention and staff effectiveness. PMID- 10114722 TI - Health policy guided by five questions. AB - As the U.S. Congress pursues a course for the restructuring of the U.S. health care system, it will have to carefully evaluate potential solutions in terms of their effect on cost and access. This article explores five questions, the answers to which will have to guide any health care policy changes at the federal level. PMID- 10114721 TI - Of orphans and balloons. AB - Technologies with significant implications for expenditures continue to reach the health care system. These technologies range from orphan drugs/biologicals used to treat rare diseases to balloons used to treat the common occurrence of benign prostatic hyperplasia (BPH) in aging men. Because payment for these technologies can represent a serious financial drain on third-party payers, utilization has to be carefully evaluated, monitored, and controlled. PMID- 10114723 TI - Annual report sends teams in circles. PMID- 10114724 TI - Quick entry earns this military market. PMID- 10114725 TI - The environment: a grass roots idea. PMID- 10114727 TI - A business coalition formed in-hospital. PMID- 10114726 TI - EAP pays off for good employees. PMID- 10114728 TI - Telephone link to latchkey kids. PMID- 10114729 TI - Waldo, you're my hero! Kids club presents cross-sell opportunities. PMID- 10114730 TI - 'Must-do' theme attracts women. PMID- 10114731 TI - Happy birthday under budget. PMID- 10114732 TI - Pain vein runs through ads. PMID- 10114733 TI - Pain is hard, but referral is easy. PMID- 10114734 TI - Trees grow in Florida beach. PMID- 10114735 TI - Tough ads set up prostate exams. PMID- 10114736 TI - Mammography promotion introduces new facility. PMID- 10114737 TI - High tech stories with human touch. PMID- 10114738 TI - Narrowcasting good health. PMID- 10114739 TI - Cartoons cross hiring lines. PMID- 10114740 TI - Teams make the decisions. PMID- 10114741 TI - Rhyming royalty grant in-house wishes. PMID- 10114742 TI - Hospital liability for defamation of character during the peer review process: sticks and stones may break my bones, but words may cost me my job. PMID- 10114743 TI - Opportunities abound for specialty consultants. AB - SH profiles Fowler Healthcare Affiliates, Inc., an Atlanta-based consulting firm which has developed a unique niche in specialty services consulting. Frances J. Fowler, president, and Harriet S. Gill, managing partner, explore why specialty services diversity presents growth opportunities for hospitals today, especially in the South. They also present guidelines for selecting consultants and ensuring the best results from them. PMID- 10114744 TI - Egleston's whiz kids: keeping up with classmates through bedside computers. PMID- 10114745 TI - 55Plus: off to a great start. PMID- 10114746 TI - Consulting in the 90's--boardroom to bedside. AB - Much like the healthcare industry, the consulting industry is in a period of great change. The traditional services that once were the mainstay of consulting are giving way to broader, more strategic services. New consulting firms are emerging; others are consolidating. The best firms are those that are growing and changing along with the clients they service in order to meet the variety of needs in today's complex, competitive environment. PMID- 10114747 TI - The less decade. AB - Although outsourcing is a relatively new buzzword, it actually amounts to contract management, a solution hospitals have used for years to manage operations areas such as dietary, housekeeping and maintenance. Many hospitals have found outsourcing a cost-effective way to meet their information system needs. Northeast Georgia Medical Center in Gainesville, Ga. is one example. Ten HealthQuest employees, including programmer Jerry Porter, work at NGMC under the medical center's facilities management agreement. PMID- 10114748 TI - Humana Hospital-Medical City Dallas introduces first PET-scanner in North Texas region. PMID- 10114749 TI - How to get the most from outside consultants: the CEO's perspective. PMID- 10114750 TI - Childcare--an issue hospitals can't afford to ignore. PMID- 10114751 TI - Nurse educators key on computers. PMID- 10114752 TI - RN re-entry course--it's a winner. PMID- 10114753 TI - Evolution of the 90's nurse. PMID- 10114754 TI - Big or small, room for all. AB - In today's world of high demand, nurses have more of an opportunity than ever to get just what they want. Nurses find rewards in what they do no matter where they work. SH profiles nurses from two Texas hospitals. PMID- 10114755 TI - HANDS (Healthcare Application Network Delivery System) shakes up imaging. PMID- 10114756 TI - Then and now: one nurse's view. AB - Nursing is a profession rich in history and tradition. Old fashioned virtues of caring and service are only a part of the role of the 90's nurse. One nurse from The Children's Hospital of Alabama describes the evolution of the new decade nurse who has emerged with high-tech skills, is corporate-minded and research oriented. PMID- 10114757 TI - C-R-N-A (certified registered nurse anesthetist): a healthcare hot spot. PMID- 10114758 TI - Flying high in Louisiana. PMID- 10114759 TI - EAP: gatekeeper for employee problems. PMID- 10114760 TI - Nurse execs showcase skills. PMID- 10114762 TI - Risk management: an overview. AB - It is not known what the future holds for the health care industry in the way of risk. It is pretty clear that the environment is dynamic with daily, if not hourly, changes. Risk managers must be willing to meet the challenge to improve quality of care, meet the needs and expectations of patients and payors, and reduce the potential for loss. PMID- 10114761 TI - Taking care of business: community hospital focuses on area employers. PMID- 10114763 TI - Trends in utilization management: legal implications for health records administration. AB - Utilization management will continue, under whatever label or within whatever framework, to demand the attention of records administrators. Since all quality and utilization review is ultimately based on the data in the medical record, the role of health record administrators is central to this activity. As programs and requirements continue to evolve, successful health care providers will draw on educated records professionals to assist in successful management strategies. PMID- 10114764 TI - The role of medical staff credentialing in a risk management program. AB - Because the courts have recognized that only the hospital and medical staff are capable of enforcing standards of professional performance, the hospital, board of directors, and medical staff must develop systems for determining who shall be allowed to practice and what procedures he or she will be allowed to perform. Practitioners do not enjoy an absolute right to practice merely because of licensure. Credentialing criteria reasonably related to considerations of patient care and hospital operations will almost certainly withstand judicial scrutiny. PMID- 10114765 TI - Risk management: role of the medical record department. AB - Good record-keeping practices contribute to the high quality of the medical record. Is the medical staff actually aware of the multiple uses of the medical record today as opposed to only a few years ago? This is all in keeping with multiple requirements for accreditation, state licensing requirements, hospital medical staff rules and regulations, and a more aggressive consumer. Physicians and attorneys alike depend on the documentation in the medical record to support their case. An independent detailed recollection of the case by caregivers without use of the medical record would be extremely difficult. Nothing can take the place of an accurate account of the patient's care in the medical record. Defense in the absence of supporting documentation would be very weak, if not lost. It is clear that inadequate or incomplete medical records expose the physician and the hospital to risk. Hospital rules and regulations should be strictly enforced to enhance patient care and to avoid potential legal action. If documentation problems are identified, utilize the medical staff committees for recommendations and action. Medical records are an integral part of patient care responsibility and should be treated as such. The medical record is a legal document that is the most reliable record of care rendered to the patient. In legal settings, the record will be scrutinized by expert witnesses for the plaintiff and the defense. What the records do not contain may be as important as what they do contain when there is an allegation that the patient's condition warranted intervention or action that was not taken. PMID- 10114766 TI - Risks associated with clinical databases. AB - Providers will succeed who are evaluating themselves, and who are continuously striving to examine who they are and where they are going. Conscientious providers know that countless other agencies have them under the microscope and that they have to work to stay ahead in assessing their actions through their clinical database. "Medical care value purchasing" is what every employer and payor is looking for, and providers need to find ways to illustrate cost in relation to quality. The basics of data security and protection should be in place in order to concentrate on the bigger picture. The knowledge of the risk associated with individual hospital databases as well as the risk associated with comparative databases is critical. The hospital-level clinical database is the hub of the wheel. If the risk there can be minimized, the data headed for various investigative sites will have less inherent risk. When it is really recognized and accepted that all financial decisions are made based upon the clinical data generated at the site of care, then data integrity will become a strategic advantage for the industry. Clinical database goals will, over time, cause minimization of risk at all levels. As this occurs, variation in treatment will be explained artfully. PMID- 10114767 TI - Legal review: coping with celebrity patients. AB - These policies and procedures accomplish two objectives. The most important objective is the protection of patient confidentiality. A secondary objective is to establish the hospital's reputation as an institution that cares about its patients and a place where celebrity patients can feel their confidentiality is secure. Failure to meet these objectives may expose the hospital to liability for breach of its patients' confidentiality and will certainly erode the hospital's reputation in its community. PMID- 10114768 TI - Innovations and research review: the impact of the HELP computer system on the LDS Hospital paper medical record. AB - This study sought to answer the question: What percentage of an LDS Hospital patient's chart is contained in the HELP system? Using the number of pages in the record as the criteria, the answer is about 26 percent overall, but between 35 percent and 40 percent for patients in nursing divisions where computerized nurse charting is used. Although this fraction is likely to rise in the near future, the critical factor driving computerization is the desire for data usable in computerized decision making rather than the need to computerize the entire chart per se. The medical record at LDS Hospital will probably be a hybrid of computerized and paper data for some time to come. PMID- 10114769 TI - High-tech health care: how much can we afford? PMID- 10114770 TI - States battle new Medicaid funding regulations. PMID- 10114771 TI - Identifying capital needs consistent with hospital mission. PMID- 10114772 TI - When internal candidates want to be CEO: guidelines for the board. PMID- 10114773 TI - MDs seek management positions. PMID- 10114774 TI - Trustees and health care priorities. PMID- 10114776 TI - High-tech medical equipment--acquisition is just the beginning. PMID- 10114775 TI - Working with a search consultant. PMID- 10114777 TI - Home care: the wave of the future? PMID- 10114778 TI - Safe harbors make for rough sailing. PMID- 10114779 TI - Strategic planning: using a matrix to help set priorities. PMID- 10114780 TI - Exposure to alcoholism in the family: United States, 1988. AB - About 43 percent of U.S. adults--76 million people--have been exposed to alcoholism in the family: they grew up with or married an alcoholic or a problem drinker or had a blood relative who was ever an alcoholic or problem drinker. Exposure was higher among women (46.2 percent) than among men (38.9 percent) and declined with age. Exposure to alcoholism in the family was strongly related to marital status, independent of age: 55.5 percent of separated or divorced adults had been exposed to alcoholism in some family member, compared with 43.5 percent of married, 38.5 percent of never married, and 35.5 percent of widowed persons. Nearly 38 percent of separated or divorced women had been married to an alcoholic, but only about 12 percent of currently married women were married to an alcoholic. These findings are highlights of an analysis of the 1988 National Health Interview Survey on Alcohol that is presented in this report. PMID- 10114781 TI - A foot in the door: art therapy in the nursing home. AB - Inclusion of art therapy in the residential nursing home and a day-care facility had positive effects on the elderly. Socialization, self-esteem, and memory retrieval were enhanced by the art experience. In addition, the staff and administrators of both the nursing home and day-care facility found art therapy to be valuable and arranged to continue the program. The funding agent for the pilot project was particularly interested in supporting a program that included an educational component, and the university recognized this program as an excellent training opportunity. The five art therapy interns gained experience in working with a population that will need increased professional services in the future, and the successful addition of part-time art therapists at the two pilot agencies will assure a continuation of intern training sites for art therapy students interested in gerontology. By developing sites for art therapy interns, we have opened the door to a method which will not only train professionals to work with older adults but will also offer job sharing between nursing homes. It has been suggested by the administrator of the nursing home in the program that we investigate the possibility of one art therapist serving two or three nursing homes on a part-time/full-time employment basis. Programs would then be affordable at most sites, and thus more people would be able to benefit from art therapy. PMID- 10114782 TI - Ethical concerns in geriatric cancer care. PMID- 10114783 TI - Motivation in the radiology department. PMID- 10114784 TI - Safe harbors and physician investment interests. PMID- 10114785 TI - Rebundling of outpatient services. PMID- 10114786 TI - The direct hit. Targeting your patients via the mail. PMID- 10114787 TI - Computer links: probing the RIS-HIS interface. PMID- 10114788 TI - Cost management. Contracted radiation therapy services. PMID- 10114789 TI - Strong medicine. Milstein Hospital Building, Columbia Presbyterian Medical Center, New York City. PMID- 10114790 TI - Risk management and related staff responsibilities in small rural hospitals in Vermont. PMID- 10114791 TI - State lawmakers weight ethical underpinnings of health care reform. PMID- 10114792 TI - ANA and VA organize ethics centers. PMID- 10114793 TI - Defining "ethical" and avoiding "dilemmas". PMID- 10114795 TI - At PSDA (Patient Self-Determination Act) deadline, hospitals rush to establish policies. PMID- 10114794 TI - Economic realities of health care spur ethical considerations. PMID- 10114796 TI - New Illinois and Ohio laws differ in spirit. PMID- 10114797 TI - The psychological trauma of a medical malpractice suit: a practical guide. PMID- 10114798 TI - "To think and act as a unit.". PMID- 10114799 TI - Special report. Buyer's guide to managed care. The new look of utilization management. AB - Today's utilization management involves many diverse programs for managing health care. The key for employers is to determine what their UM needs are, choose programs that fulfill them, and forget the rest. PMID- 10114800 TI - Special report. Buyer's guide to managed care. Going network? Look for quality and cost efficiency. AB - Provider networks come in all shapes and sizes. But companies interested in getting quality care at a reasonable cost will make sure candidates live up to certain criteria. PMID- 10114801 TI - Special report. Buyer's guide to managed care. Managing mental health controls costs. PMID- 10114802 TI - Special report. Buyer's guide to managed care. Planning your health care strategy. PMID- 10114803 TI - Special report. Buyer's guide to managed care. Data watch. Wellness, HMOs, and cost control. PMID- 10114804 TI - Medicare physician payment reform. An introduction to the new fee system and its implications for hospitals. AB - Set to go into effect on October 1, the new Medicare physician-reimbursement system attempts to bring Medicare payments ever closer in line with physicians' actual costs. Among other things, the new fee schedule should eventually reduce the disparity between specialty and family-practice physicians' reimbursements and encourage more med students to enter primary care. Hospitals should be aware, however, that some things--like conflict between their and physicians' financial incentives--will not change. PMID- 10114805 TI - The hospital library is crucial to quality healthcare. AB - In a 1988 report, an advisory committee of the Medical Library Association (MLA) wrote that "no one would argue against information as the foundation for efficient cost-effective business or against access to knowledge as a prerequisite for developing new knowledge." Yet the increasing number of threats to the hospital library--largely from within the industry--suggest that many hospitals do not value information in the same way their counterparts in other businesses do. In the first of two articles in this issue on hospital library and information services, the executive director of the MLA uses the MLA's experience and a variety of research findings to restate the case for the hospital library's vital role in quality care. PMID- 10114806 TI - The liability of the hospital librarian. Why you need a professional medical librarian. AB - Would you hire a cashier instead of a qualified accountant to manage your hospital's financial department? Certainly not--the stakes are too high. The same test holds for your hospital library: Besides running the risk of possible liability and embarrassment for your hospital, hiring an untrained person to manage your library would not serve the best interests of your medical staff and- most importantly--your patients. PMID- 10114808 TI - The dynamics of hospital survival: leading your organization through change. AB - In the Winter 1991 Hospital Topics, Professors Biggerstaff and Syre described the dynamics of hospital leadership. Here they do the same for hospital survival in the 1990s, detailing administrators' diverse efforts to usher their hospitals through change. PMID- 10114807 TI - Preventing falls in hospitals. The roles of patient age and diagnostic status in predicting falls. AB - Patient falls are some of the most frequent accidents in hospitals, and they can lead to significant personal and financial costs for both patients and facilities. This study examines the relationship between two patients characteristics and patient falls at a large general hospital and a small psychiatric facility in Tennessee; its findings should be useful for hospital risk management. PMID- 10114809 TI - Factors influencing nurses' job decisions. A survey of applicants. AB - One of the creative ways in which hospital administrations are addressing the nursing shortage is their use of traditional market-research techniques to pinpoint and attract potential staff. Here the authors used a market tool called "laddering," in which nursing applicants ranked job-decision factors from most to least influential. The authors' survey revealed not only the priorities of nurses in general but also those of subgroups such as graduate RNs and older, more experienced nurses. PMID- 10114810 TI - Quality improvement and quality assurance compared. PMID- 10114811 TI - Time control: rest periods. PMID- 10114812 TI - The courts and healthcare reform. How our judiciary might shape a more equitable system. PMID- 10114813 TI - Prison hospitals in the dock. PMID- 10114814 TI - Measured steps to outcomes. PMID- 10114815 TI - Stretched to the limit. AB - Everyone agrees that junior doctors work excessively long hours. The difficulty has been finding a solution to the problem within staffing limits. Penelope Dash and Angela Jones set out two ways to stretch the human resources available to make best use of them. PMID- 10114816 TI - Strength in numbers. AB - How can care management be truly responsive to people with serious mental disorders? In the second of two articles, Charles Patmore and Tim Weaver look at the key benefits of a team approach. PMID- 10114817 TI - Data briefing. Women in the NHS. National Association of Health Authorities and Trusts. PMID- 10114818 TI - Midlands and East Anglia: ECRs (extra-contractual referrals) hold new surprises around every corner. PMID- 10114819 TI - P & T Committee rises to challenges of the changing healthcare environment. AB - The ever-increasing importance of the P & T Committee is well illustrated in this exclusive interview with members of a committee from a leading academic, private practice, health-science center--Rush-Presbyterian-St. Luke's Medical Center. The participants detail the progress achieved in P & T Committee policy making, particularly in recent years. Unprecedented change in the healthcare environment has demanded a more aggressive P & T Committee, and theirs has responded appropriately. Because the medical staff at Rush constitute a unique blend of academicians and private practitioners, the mechanics of their decision making tends to be consensus-related, while the implementation of those decisions is education-oriented. Other P & T Committees can learn from their political and professional strategies in the management of drug therapy. PMID- 10114820 TI - Interviewing and counseling patients about immunizations. PMID- 10114821 TI - Pharmacy: a profession of issues and opportunities. PMID- 10114822 TI - Pharmacy drug error awareness program. AB - Medication errors are a major concern in hospital pharmacy practice. The prevention of medication errors involves mainly the departments of pharmacy and nursing. Though there are many safeguards used to prevent medication errors, they still occur, posing potential harm to patients. To decrease the chance for medication errors to occur pharmacists must take the responsibility to expand their knowledge and teach others about frequent errors. In an effort to decrease medication errors during 1990 at Fresno Community Hospital and Medical Center, Fresno, California, the pharmacy department evaluated the errors made during the calendar year 1989. This evaluation provided information concerning the most frequently occurring medication errors. This information was used to initiate a drug error awareness program (DEAP). PMID- 10114823 TI - The project shift: a form of participative management and staffing. AB - North Colorado Medical Center is a 326 bed primary and tertiary care medical center serving northeastern Colorado and southwestern Nebraska. The pharmacy department provides 24-hour-a-day clinical and distributive services to both inpatients and outpatients with a staff of 1 clinical pharmacy coordinator, 10 pharmacists (excluding pharmacy manager), and 11 technicians. Rather than rely on one assistant manager, the pharmacy manager involves all interested staff pharmacists in various administrative, clinical, and distributive projects. These project (P) shifts are scheduled 8-hour shifts with minimal or no drug distribution duties. This staffing system and form of participative management has been used since 1983 and has been successful in achieving three objectives: it provides assistance to the manager in achieving certain departmental objectives; it provides job variety and professional growth/satisfaction for staff pharmacists; and it provides flexible and readily available source of pharmacists to meet personal leave days (vacation, illness, time off) needs. PMID- 10114824 TI - Use of generic screening criteria for clinical interventions that link prescribing to credentialing. AB - Current JCAHO standards require hospitals to link the use of drugs to prescriber credentialling. The pharmacy service at the Veterans Affairs Medical Center, Iowa City, Iowa, has developed a prescriber-specific program that documents clinical interventions and links that information to physician credentialling through the Pharmacist Intervention Report and associated quality assurance (QA) program. A severity index level was also developed to rate the significance of the interventions. The Pharmacist Intervention Report is used by all medical departments in their respective QA programs. PMID- 10114825 TI - Personal computers and hospital pharmacists. PMID- 10114826 TI - Operating room satellite pharmacies: demographics, services and implementation. AB - OR (operating room) satellite pharmacies are still a relatively new addition to the system of pharmacy-coordinated drug distribution. For the last ten years, however, hospitals creating OR satellite pharmacies have found that they provide improved service, reduced inventory, better narcotic control and more efficient drug delivery. Hospital Pharmacy and the OR Satellite Pharmacy Bulletin published a questionnaire to obtain information about OR satellite pharmacies from those actively involved in their planning, implementation, and operation. The questionnaire covered three major areas: demographics, functions and services. This article summarizes the results. PMID- 10114828 TI - Health center's design mixes community feel with individual decor. PMID- 10114827 TI - Evaluation of IV compatibility microcomputer software programs. AB - Four microcomputer software programs that contain IV compatibility information were evaluated using specific criteria for these programs. This article compares scope of coverage, quality of clinical documentation, frequency updates, and clinical performance for these programs. There are no excellent IV compatibility programs. Of the programs tested, Micromedex performed the best. Therapeutic Software is not considered a comprehensive IV compatibility program. IV-Check PC and Medicom Micro performed equally well. PMID- 10114829 TI - Most indoor air quality problems can be solved via trained in-house staff. PMID- 10114830 TI - A design/build approach for not-for-profit facilities. PMID- 10114831 TI - Prepare chillers, cooling towers now for summer. PMID- 10114832 TI - Study: key managers buy wall coverings, paint. PMID- 10114833 TI - Snow-melting system puts the skids on liability. PMID- 10114834 TI - Reimbursement disputes involving experimental medical treatment. PMID- 10114835 TI - Comment: employer mandated health insurance: a solution for the working uninsured? PMID- 10114836 TI - PRO photocopying settlement approved by District Court. PMID- 10114837 TI - Hospital medical staff privilege issues: "brother's keeper" revisited. PMID- 10114838 TI - CHC saves ER overhead with Community Care Clinic. PMID- 10114839 TI - QI in radiology. PMID- 10114840 TI - QA in the resident clinic. PMID- 10114841 TI - Appropriateness of lab services reviewed. PMID- 10114842 TI - Quality improvement--cooperation or conflict. PMID- 10114843 TI - Hospitals can apply practice parameters. PMID- 10114844 TI - Findings of state boards available in FSMB data bank. PMID- 10114845 TI - Medical staff support vital to good QA program. PMID- 10114846 TI - How to avoid the common pitfalls of validation surveys. PMID- 10114847 TI - Potassium administration. Problems identified. PMID- 10114848 TI - Greater emphasis on infection control urged. PMID- 10114849 TI - Self-analysis is active process. PMID- 10114850 TI - Teaching hospital finds continuous QI works. PMID- 10114851 TI - How to document anesthesia care. American Society of Anesthesiologists. PMID- 10114852 TI - Pressure sores: evaluating quality of care. PMID- 10114853 TI - Integrated quality management program reaps benefits. PMID- 10114854 TI - Quality advancement and practice parameters. PMID- 10114855 TI - Use of outcomes to judge clinical competence. American Society of Anesthesiologists. PMID- 10114856 TI - IOM issues report on practice guidelines. PMID- 10114857 TI - HCFA modifies mortality data. PMID- 10114858 TI - Practice parameters tied to state laws. PMID- 10114859 TI - Is private sector UR cutting too close to the bone? PMID- 10114860 TI - Competency and credentialing in practice parameters. PMID- 10114861 TI - Practice parameters may ease liability climate. PMID- 10114862 TI - Quality of care: objectives and strategies. American Hospital Association, American Medical Association, Blue Cross and Blue Shield Association, Health Insurance Association of America. PMID- 10114863 TI - Joint Commission revises 1992 quality standards. PMID- 10114864 TI - 1992 Joint Commission AMH: standards on quality assessment and improvement. PMID- 10114865 TI - State health care cost containment and quality of care legislation. Board of Trustees, American Medical Association. PMID- 10114866 TI - The use of control charts in quality assurance. PMID- 10114867 TI - Promoting ambulatory care quality. PMID- 10114868 TI - HCFA's Uniform Clinical Data Set. Board of Trustees, American Medical Association. PMID- 10114869 TI - The importance of hospital peer review. Board of Trustees, American Medical Association. PMID- 10114870 TI - Assessing non-clinical outcomes. PMID- 10114871 TI - Practice parameters: cesarean birth. Minnesota Clinical Comparison and Assessment Project. PMID- 10114872 TI - Perspectives. Can abstinence make Americans live longer? PMID- 10114873 TI - Perspectives. Advance directives get a cautious welcome. PMID- 10114874 TI - Determinants of total family charges for health care: United States, 1980. AB - This report addresses a question of importance for policymakers: "What are the determinants of the total charges for health care that U.S. families face?" Policymakers' concerns about this question have two main grounds. First, U.S. health care costs are large and growing rapidly. They now exceed 11 percent of the gross national product, and the answer to the question can shed some light on their troubling growth. Second, total family charges for health care reflect the quantity of health care received by families, and it is important to know whether the determinants of total charges are principally the need for health care, or involve other factors less related to need. In this report, the determinants of total charges and their importance are identified principally through multiple regression analysis. Total charges are defined as the full amount charged for all types of health care for all family members regardless of whether these amounts are paid out of pocket, paid by insurance (or public health care coverage programs), or go unpaid. The data used are from the family data files of the 1980 National Medical Care Utilization and Expenditure Survey (NMCUES). This report presents data on the approximately 5,000 multiple-person families interviewed in this year-long longitudinal survey. The report provides a separate analysis for each of three socioeconomic family populations that have consistently been of interest to policymakers. These are (1) older families (defined for this report as all U.S. multiple-person families with a member 65 years of age or over); (2) younger, lower income families (all U.S. multiple-person families below 200 percent of the poverty level in 1980 and with all members under 65 years of age); and (3) younger, better off families (all U.S. multiple-person families at 200 percent of the poverty level or higher in 1980 and with all members under 65). Multiple regression analysis was used to investigate the effect on total family charges of family demographic and sociocultural characteristics, family illnesses, special health events (such as births, deaths, and hospitalizations of family members), general family health status, family income, family health insurance characteristics, and family geographic and urbanization characteristics. Regressions were run separately for each of the three socio economic family populations, with total family charges as the dependent variable and approximately 45 variables measuring these family characteristics as independent variables. Because of the large number of independent variables involved, a multiple-step regression process (described in appendix I) was used.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10114875 TI - Health care in Northern Ireland. Conference address. PMID- 10114876 TI - The concept of facilities management. PMID- 10114877 TI - A new hospital wing in Buenos Aires. PMID- 10114878 TI - Clinics provide care to those who can't pay. PMID- 10114879 TI - The benefits of doing business electronically. AB - Hospitals know the benefits of automating billing. Now they can take advantage of automating payments and remittance information from Medicare, Medicaid and major commercial payors. By January 1992, the Health Care Finance Administration (HCFA) and major commercial payors including Aetna, Travelers, Metropolitan Life and others are expected to adopt a new electronic data transfer standard which will allow hospitals to reap the quality, cost reduction and even goodwill benefits of automation--if they are willing to make their patient accounting needs known. PMID- 10114880 TI - New Zealand health care system provides care for all. PMID- 10114881 TI - The new equilibrium. AB - This is the eighth and final article based on his recently completed Harvard University Ph.D. dissertation, "The Struggle for Control of California's Health Care Marketplace." PMID- 10114882 TI - The financial impact of HMOs on hospitals. PMID- 10114883 TI - CFOs spend with caution. PMID- 10114884 TI - Secrets of achieving a better bottom line. PMID- 10114885 TI - Fraud and abuse safe harbors. PMID- 10114887 TI - Single payer or big brother? PMID- 10114886 TI - Managed care in the hospitals. Interview by John Herrmann. PMID- 10114888 TI - Little Rock fights back. PMID- 10114889 TI - Why do independent hospitals lose union elections? PMID- 10114890 TI - New uses for computer-aided facility management. PMID- 10114891 TI - Health education: fulfilling a mission. PMID- 10114892 TI - State agendas: universal plans, Medicaid, insurance. PMID- 10114893 TI - National health reform: putting the pieces together. PMID- 10114894 TI - Is managed care working? Part 1 of 2. PMID- 10114895 TI - Alabama's hospital legacy. Interview by Rosemary Blackmon. AB - Jackson, Carraway, and Flowers--three men who truly personify medicine in the state of Alabama. ALAHA public relations director Rosemary Blackmon recently spoke with each of them about the past and future of healthcare. PMID- 10114896 TI - When your doctor has AIDS. PMID- 10114897 TI - List of designated primary medical care health professional shortage areas (HPSAs); list of withdrawals from primary medical care HPSA designation--PHS. Notice. AB - This notice provides two lists. The first is a list of all areas, population groups, or facilities designated as primary medical care health professional shortage areas (HPSAs) as of June 30, 1991. Second is a list of previously designated primary medical care HPSAs that have been found to no longer meet the HPSA criteria and are therefore being withdrawn from the HPSA list. HPSAs are designated or withdrawn by the Secretary of Health and Human Services (HHS) under the authority of section 332 of the Public Health Service Act. PMID- 10114898 TI - Home medical equipment: playing a growing role in the nation's health care system. AB - Technological advances and an increased demand for home care have led to home medical equipment's growing role in this nation's health care system. PMID- 10114899 TI - A financial survey of home medical equipment dealers. AB - The Health Industry Distributors Association's ninth annual survey of home medical equipment dealers allows firms to compare their performance to industry averages, enabling managers to identify those specific aspects of company performance that demand their attention. PMID- 10114900 TI - The home medical equipment industry's expense structure. AB - A substantial portion of the costs associated with home medical equipment services are locally driven. Therefore, if access to care is to be ensured, it is critical that reimbursement sources consider local and regional differences. PMID- 10114901 TI - Waste and abuse in Medicare reimbursement for durable medical equipment and supplies. AB - A Senate Budget Committee investigation of Medicare's durable medical equipment and supply program has revealed expenditure of millions of dollars on inflated and unnecessary claims. The committee has made legislative recommendations and is continuing to review billing practices. PMID- 10114902 TI - Preserving program integrity: HCFA's program to prevent and detect Medicare fraud and abuse. AB - The Health Care Financing Administration's program integrity goal is to control and prevent fraud and abuse through monitoring, enforcement, and deterrence. Toward that end, HCFA is working with the Office of Inspector General to improve review procedures and reduce opportunities for fraud and abuse. PMID- 10114903 TI - Beneficiary complaints, provider numbers and carrier shopping: Medicare contractor operations. AB - The number of Medicare claims processed annually will double in the next 10 years, making it imperative that contractors review claims accurately and ensure that payments are made only for medically necessary, high-quality care. Effective identification and prosecution of fraud and abuse in the Medicare program will depend on a cooperative effort between Medicare contractors, the Health Care Financing Administration, and the Office of Inspector General. PMID- 10114904 TI - The home medical equipment industry: a home care perspective. AB - The home medical equipment industry, under fire from the media and consumer affairs organizations, is aligning itself with the home care industry in an attempt to change its image. Until the medical equipment industry is able to take care of some problems, however, the home care industry should be wary of such an alliance. PMID- 10114905 TI - Ethical home medical equipment business practices. AB - National uniform standards as a condition for receipt of a Medicare provider number would help rid the home medical equipment industry of those unethical and unscrupulous suppliers who have tarnished the industry's reputation. PMID- 10114906 TI - Joint Commission on Accreditation of Healthcare Organizations: standards and accreditation for durable medical equipment providers. AB - The accreditation survey for home medical equipment suppliers, as performed by the Joint Commission on Accreditation of Healthcare Organizations, emphasizes the process of care delivery, which includes equipment management and patient/caregiver instruction. Companies preparing for a survey are advised to perform a self-assessment to determine areas in need of review and improvement. PMID- 10114907 TI - Community Health Accreditation Program, Inc.: standards for home medical equipment providers. AB - The Community Health Accreditation Program, Inc., is an important resource for home medical equipment providers committed to quality and patient satisfaction. PMID- 10114908 TI - A survey of home respiratory equipment suppliers' practices. AB - Durable medical equipment suppliers in five states were surveyed to obtain information about the services they provide to clients using ventilators and/or oxygen concentrators at home. Results revealed a wide variety of services, practices, and personnel backgrounds, as well as a need for enhanced communication between suppliers, care providers, manufacturers, patients, and the Food and Drug Administration. PMID- 10114909 TI - Silent partners in home care. AB - Continuity of care requires both cooperation and coordination of all services involved in providing equipment or services to patients in their homes. Each service provider, be it the equipment supplier or the home care nurse, must know the capabilities and services provided by their silent partners. PMID- 10114910 TI - Home medical equipment for hospice patients. AB - Hospice patients are often quite different from more "typical" home care patients, in terms of both physical condition and emotional sensitivity. As a result, needs for home medical equipment may vary. Both the home care agency and the HME supplier should be aware of these different needs in order to best serve the hospice patient and his or her family. PMID- 10114911 TI - The development of pediatric standards of care for home medical equipment suppliers. AB - Standards of care for home medical equipment suppliers serve as both an educational tool and a quality assurance mechanism, promoting the development of a successful home care program. A committee of home medical equipment suppliers was convened to develop such standards appropriate to a pediatric home care population. PMID- 10114912 TI - Bundling in Vermont. AB - In response to the needs of high-tech children, Vermont's Medicaid program designed a controversial system whereby the durable medical equipment company is the main service provider. Some say the program has been successful; others say it unnecessarily complicates provision of care. PMID- 10114913 TI - An equal protection analysis of United States reproductive health policy: gender, race, age, and class. PMID- 10114915 TI - Congruence between nursing education and nursing service: a common conceptual/theoretic framework for nursing units. AB - The results of the incorporation of a conceptual/theoretic framework in this nursing service setting have been an improvement in the service to consumers of nursing, an effective restructuring of the environment of the health care agency advantageous for the client and for nursing staff, and the differentiation of practice roles according to education, experiences, and client needs. It has fostered understanding, acceptance, and support of the contribution of theory development and nursing research to nursing and health care. It brought together nurse leaders in education and service to the benefit of both and with maximum benefit to the consumer of nursing services. The specification of the philosophy, outcome behaviors, and conceptual/theoretic frameworks has allowed nurses to have control over nursing. It has incorporated nurses in setting the pace for the future of nursing practice, promoted the development of peer activity and review, and demonstrated how nursing can make a difference. The benefit for the nurse includes increased job satisfaction, enhanced professional and personal development, increased self-esteem, and the realization that the service of nursing is a valued and valuable service to consumers. Promotion of the image of the nurse was another outcome, as was the realization that nurse educators and nurse supervisors share common goals. The timeframe may be different in that educators see a finished product years ahead while nurse supervisors see client outcomes on a daily basis. The gap between these two efforts is bridged by the use of common conceptual/theoretic frameworks for the design and administration of both the nursing education and nursing service units.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10114914 TI - Give tech a try. AB - More than simply increasing speed and efficiency, technology can help achieve program goals. But staff need to keep an open mind. PMID- 10114916 TI - Intuition and the nurse manager. AB - In spite of the present move in health care into the computer age, there is increasing awareness that intuition is an important nursing management technique and that it is linked to success as a manager. Intuition is most effectively implemented by the self-confident manager with experience and expertise as a manager. Nevertheless, a novice manager who values and seeks intuition will find it a technique that will assist in the development of excellence as a manager. Managers who perceive themselves as having limited skills in intuition and yet are sensitive to the need for intuition can compensate for this deficiency by close association with a coworker who can provide intuitive perceptions and evaluations. For example, a head nurse who is primarily analytical may discuss assignment of nurses with an assistant who is highly intuitive. Managers who are able to compensate for intuitive deficiencies by surrounding themselves with competent and trusted subordinates who have intuitive qualities may be able to effectively use both analytic and nonanalytic managerial techniques. PMID- 10114917 TI - Middle managers: gatekeepers for turnover. AB - Certainly, none of these ideas will solve the turnover problem. Middle managers should recognize that some turnover is inevitable, some is positive, and turnover can be measured in a variety of ways. Also, being the gatekeeper means that people should be encouraged to leave a unit or an organization when it is in the best interest of the individual or the organization. Being the gatekeeper for turnover is an important role and one that will likely take on even more significance in the future. It is essential that the middle manager prepare in advance to deal with the inevitable conflict associated with the role and thus avoid becoming a turnover statistic. PMID- 10114918 TI - The grieving process in cultural change. AB - A real sense of loss is experienced by many middle managers as hospitals change their cultures and evolve toward participatory management. To work through the loss involved, managers need time and resources to grieve for the old as they learn the new. Although the grieving process is relatively straightforward, difficulty arises because the need to talk and grieve for the old occurs precisely when all attention and effort focuses on the new. Administrative groups may feel threatened by middle management's expression of grief. Unwillingness to acknowledge and support that grief may provoke greater anger and resistance, increasing the problems associated with change. In the long run, time spent grieving for the old will make the transition to the new that much smoother. Organizations will see a positive return from time spent in the grieving process. Inability to let go of the old is often at the root of the uneasiness, resistance, and lack of visible commitment to the new. Why should we not spend the required time appreciating and then letting go of the old even as we teach the new? As we progress to the learning organization, to a staff empowered to resolve problems and seize opportunities, let it be known that expressions of the staff's humanity will be tolerated. Mistakes will be much more acceptable than lack of effort for fear of error. In working together, better patient care can be attained along with personal and organizational strength. Recognizing Annette's, or any manager's or staff member's, loss and allowing the grief necessary to resolve that loss will benefit all.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10114919 TI - Developing a quality-of-care system in hospitals. PMID- 10114920 TI - A psychoeducational model of management consultation. PMID- 10114921 TI - Quality circles: the nurse executive as mentor. AB - Changes within and around the health care environment are forcing health care executives to reexamine their managerial and leadership styles to confront the resulting turbulence. The nurse executive is charged with the profound responsibility of directing the delivery of nursing care throughout the organization. Care delivered today must be of high quality. Declining financial resources as well as personnel shortages cause the executive to be an effective innovator in meeting the increasing demands. Quality circles offer the nurse executive an avenue of recourse. Circles have been effectively implemented in the health care setting, as has been consistently documented over time. By way of a participative management approach, quality circles may lead to increased employee morale and productivity, cost savings, and decreased employee turnover rates, as well as realization of socialization and self-actualization needs. A most effective approach to their introduction would be implementation at the first line manager level. This promotes an acceptance of the concept at the management level as well as a training course for managers to implement the process at the unit level. The nurse executive facilitates the process at the first-line manager level. This facilitation will cause a positive outcome to diffuse throughout the entire organization. Quality circles offer the nurse executive the opportunity to challenge the existing environmental turmoil and effect a positive and lasting change. PMID- 10114923 TI - In search of objective measurement in performance appraisal. PMID- 10114922 TI - Applying ethics to health care: the role of continuing education. AB - The study of ethics will not provide health care professionals with specific answers to specific ethical dilemmas they as individuals may face. it will not provide specific rules of conduct. The ability to examine ethical dilemmas sets forth practical wisdom that provides guidance when making decisions. The study of ethics helps to define problems and establishes basic principles to be used in solving these problems. It can help health care professionals identify appropriate goals and give them direction in achieving those goals. Health care supervisors have an obligation to provide the educational opportunity that will enable professionals to emerge with a perspective that allows them to take an ethical stand and to support that position with sound, rational thinking. In fulfilling this obligation, individuals working within health care facilities can significantly contribute to their profession and to society. PMID- 10114924 TI - A supervisor asks: "delegation's downside". PMID- 10114925 TI - The way to win in cross-border alliances. AB - Global competition has paved the way to new corporate combinations--and opened up new pitfalls along the way. In "The Way to Win in Cross-Border Alliances," Joel Bleeke and David Ernst offer the unconventional lessons of their study of 49 cross-border alliances. For example, alliances between a weak and a strong company usually don't work; but fifty-fifty ownership of joint ventures actually improves decision making. PMID- 10114926 TI - Advice and dissent: rating the corporate governance compact. AB - The July-August 1991 HBR presented "A New Compact for Owners and Directors," a set of principles for reconciling differences between owners and managers. In "Advice and Dissent: Rating the Corporate Governance Compact," a panel of three experts evaluates the Compact--and takes issue with its fundamental recommendation. Clifton R. Wharton, Jr., chairman and CEO of TIAA-CREF, describes how his organization brings delinquent managers and directors to task. Harvard Business School professor Jay W. Lorsch explains why strengthening the role of outside directors will develop more effective corporate control. And Lord Hanson, chairman of Hanson PLC, reaffirms the importance of maintaining a unitary board of directors and maximizing shareholder value. PMID- 10114927 TI - A case of AIDS. AB - "A case of AIDS" by Richard S. Tedlow and Michele S. Marram explores the issues involved in managing an HIV-infected employee over time. When an opening on his team occurs, should Greg hire Joe despite his HIV infection? How should Greg handle the issue of confidentiality? And when Joe asks for a promotion, how should Greg manage the issue of Joe's long-term career? Three experts discuss each stage of the case as it unfolds. PMID- 10114928 TI - Does privatization serve the public interest? AB - "Does Privatization Serve the Public Interest?" ask John B. Goodman and Gary W. Loveman. Supporters of privatization claim that it will bring more efficiency and better quality. Critics, however, argue that other values--the broader public interest--must be accounted for. The authors draw a valuable lesson from the debate over corporate takeovers: the form of ownership is less important than the establishment of managerial accountability. PMID- 10114929 TI - The new productivity challenge. AB - "The single greatest challenge facing managers in the developed countries of the world is to raise the productivity of knowledge and service workers," writes Peter F. Drucker in "The New Productivity Challenge." Productivity, says Drucker, ultimately defeated Karl Marx; it gave common laborers the chance to earn the wages of skilled workers. Now five distinct steps will raise the productivity of knowledge and service workers--and not only stimulate new economic growth but also defuse rising social tensions. PMID- 10114930 TI - How the Baldrige Award really works. AB - "How the Baldrige Award Really Works" by David A. Garvin draws on a series of in depth discussions with Baldrige Award judges and senior examiners to give the first clear account of the real purpose and operation of the prestigious--and contentious--award. Accompanying the article is "An Open Letter on TQM," a call from James D. Robinson III, Harold A. Poling, John F. Akers, Robert W. Galvin, Edwin L. Artzt, and Paul A. Allaire for closer cooperation between business and universities to promote quality. PMID- 10114931 TI - Projections of national health expenditures through the year 2000. AB - In this article, the authors present a scenario for health expenditures during the 1990s. Assuming that current laws and practices remain unchanged, the Nation will spend $1.6 trillion for health care in the year 2000, an amount equal to 16.4 percent of that year's gross national product. Medicare and Medicaid will foot an increasing share of the Nation's health bill, rising to more than one third of the total. The factors accounting for growth in national health spending are described as well as the effects of those factors on spending by type of service and by source of funds. PMID- 10114932 TI - Recent revisions to and recommendations for national health expenditures accounting. AB - The Health Care Financing Administration (HCFA) has importantly revised the methodology for estimating annual national health expenditures. Among other changes, the revisions estimated out-of-pocket spending directly, disaggregated expenditures to a greater degree, and reduced undercounting and double counting. Estimates of total spending and out-of-pocket spending changed. This article summarizes a meeting of a technical advisory panel, convened by HCFA, that reviewed the modifications adopted and made recommendations for future revisions. PMID- 10114933 TI - Health care indicators. PMID- 10114934 TI - National health expenditures, 1990. AB - During 1990, health expenditures as a share of gross national product rose to 12.2 percent, up from 11.6 percent in 1989. This dramatic increase is the second largest increase in the past three decades. The national health expenditure estimates presented in this article document rapidly rising health care costs and provide a context for understanding the health care financing crisis facing the Nation today. The 1990 national health expenditures incorporate the most recently available data. They differ from historical estimates presented in the preceding article. The length of time and complicated process of producing projections required use of 1989 national health expenditures--data available prior to the completion of the 1990 estimates presented here. PMID- 10114935 TI - Medicaid payment policies for nursing home care: a national survey. AB - This research gives a comprehensive overview of the nursing home payment methodologies used by each State Medicaid program. To present this comprehensive overview, 1988 data were collected by survey from 49 States and the District of Columbia. The literature was reviewed and integrated into the study to provide a theoretical framework to analyze the collected data. The data are organized and presented as follows: payment levels, payment methods, payment of capital-related costs, and incentives in nursing home payment. We conclude with a discussion of the impact these different methodologies have on program cost containment, quality, and recipient access. PMID- 10114936 TI - Modeling the costs of case management in long-term care. AB - A conceptual approach to developing models for analyzing cost is applied to case management in long-term care. This conceptual approach uses four dimensions to classify case management programs. The application results in identifying five case management cost models. Empirical measures of case management costs and a set of determinants of the within-model variation in these costs are suggested for each model. This article discusses several policy relevant hypotheses that could be addressed by the empirical implementation of these cost models. PMID- 10114937 TI - Concordance between planned and approved visits during initial home care. AB - Based on little prior information and a brief interview, the Medicare home health agency intake case manager must estimate the types and amounts of services a new client will require during the first 60 days of home care. We systematically examined the concordance between types and amounts of planned services with those actually approved and reimbursed during the first 60 days of care for a sample of 2,431 clients during 1986. Overall, the mean number of planned visits during the first 60 days was 24.76, and the mean number of approved visits was 15.95. Approved visits as a percent of planned visits averaged 64.4. PMID- 10114938 TI - Comparison of Medicaid nursing home payment systems. AB - This article summarizes the main findings of a study comparing three generic Medicaid nursing home payment systems: case-mix, facility-specific, and class rate. The major comparative analyses examined patient-level case mix and quality, facility-level costs, Medicaid payment rates, and profitability. The study also analyzed case-mix payment systems in greater detail, emphasizing the earlier systems. The results suggest advantages and disadvantages for all system types and highlight important considerations for policyplanners, particularly in States considering case-mix systems. The article concludes with a discussion of issues important to further research on nursing home payment. PMID- 10114939 TI - The role of search firms in the changing world of health care employment. PMID- 10114940 TI - Health care fraud and abuse: tales from the dark side. PMID- 10114941 TI - National Cancer Act: progress by inches. PMID- 10114942 TI - The FDA's restrictions against prescription drug advertising: more hindrance than help. PMID- 10114943 TI - "Hanlester Laboratories": HHS joint venture standards remain unclear. PMID- 10114944 TI - Medicare Part B forum shopping: impact of proposed reforms. PMID- 10114945 TI - Safe harbor regulations: the more things change, the more they stay the same. PMID- 10114946 TI - Examining the CEO's first year on the job: coping with change. Interview by Walter Wachel. PMID- 10114947 TI - Today's healthcare environment: new career trends and opportunities. PMID- 10114948 TI - The reference check: what you need to know. PMID- 10114949 TI - Career stability in unstable times: managing the unmanageable. PMID- 10114950 TI - It's time to consider long-term incentive compensation. PMID- 10114951 TI - Putting balance back into the executive equation. PMID- 10114952 TI - Career planning in uncertain times. PMID- 10114953 TI - Physician and hospital relationships. PMID- 10114954 TI - Higher asset return through cost control. PMID- 10114955 TI - Changing business needs and remuneration strategies. PMID- 10114956 TI - A case of a financial approach to manpower planning in the NHS. PMID- 10114957 TI - Making more time for your family. A stress guru's answer to NHS overload. Interview by Joanna Lyall. PMID- 10114958 TI - Entry to nursing: a highly unionised area of employment. PMID- 10114959 TI - Looking after middle management in Family Health Services Authorities. PMID- 10114960 TI - To merge or not to merge? PMID- 10114961 TI - Health of the Nation. PMID- 10114963 TI - The policy practice interface in Wales. AB - The National Health Service in Wales, through the work of the Welsh Health Planning Forum (WHPF), has developed a new and exciting way of planning and managing its services. This encourages consumers to exert influence from the individual right through to the national level. Furthermore, managers are required to seek out and involve people, and to take advice from consumer-led groups. In this paper, Jeremy Felvus and colleagues describe briefly this new way of working and give practical examples of its impact on strategy development at all levels. PMID- 10114962 TI - "I've got a job to do!" A study of the Clubhouse Model. AB - Clubhouses are designed to provide work, educational and social opportunities for people with long-term mental health difficulties. Based on their experience in the USA, where the clubhouse model was pioneered, Sue Hutt and Pam Buttrey have written a report, summarised here, which puts forward some good reasons for establishing clubhouses throughout the UK. Their research was assisted by a grant from the Institute's Health Services Management Development Trust. PMID- 10114964 TI - Purchasing for people. AB - Newcastle Health Authority is taking a consumer-led approach to its purchasing activity. Here Ingrid Barker argues that user participation is vital to the success of the purchasing role and the achievement of relevant contracts for services. Newcastle's own progress in establishing consumer groups to inform purchasers is described and some indications are given of future directions. PMID- 10114965 TI - Quality assurance in outpatient departments. AB - Outpatients departments are prime targets for quality assurance. They are probably the most visible department of a general hospital in terms of patient throughput and, clearly, the service quality standards projected to patients will significantly influence their perceptions of the hospital as a whole. Angela Hopper describes a research project funded by the Institute's Health Services Management Development Trust. PMID- 10114966 TI - A quality checklist for children's facilities. AB - Despite advances in the care of children in hospital, environmental aspects are often overlooked. The principles set out in this article by James Rainbird suggest a basis for quality in the environment for children. PMID- 10114967 TI - Who needs architects? AB - It is essential to put the NHS estate high on the list of priorities, according to architect, Haydn Bennett. In this article he explains why and provides a few pointers for obtaining the best value for money from the estate. PMID- 10114968 TI - Are waiting lists becoming "the tail that wags the dog"? AB - Waiting lists are not just to do with money and until politicians and administrators in the DoH understand this, the 'waiting list problem' will plague each and every administration, according to ADB Chant. PMID- 10114969 TI - Do hospital risk management programs make a difference?: relationships between risk management program activities and hospital malpractice claims experience. PMID- 10114970 TI - The defensive effect of medical practice policies in malpractice litigation. PMID- 10114971 TI - Rethinking responsibility for patient injury: accelerated-compensation events, a malpractice and quality reform ripe for a test. PMID- 10114972 TI - S. 1232--a late entry in the race for malpractice reform. PMID- 10114973 TI - Legal responses to patient injury: a future agenda for research and reform. PMID- 10114974 TI - Medical malpractice risk management early warning systems. PMID- 10114975 TI - Risk factors for hospital malpractice exposure: implications for managers and insurers. PMID- 10114976 TI - Merit rating for physicians' malpractice premiums: only a modest deterrent. PMID- 10114977 TI - Practice guidelines as legal standards governing physician liability. PMID- 10114978 TI - Medical malpractice: lessons for reform. PMID- 10114979 TI - Cost and compensation of injuries in medical malpractice. PMID- 10114980 TI - Indiana's malpractice system: no-fault by accident? PMID- 10114981 TI - Mediation and medical malpractice: problems with definition and implementation. PMID- 10114982 TI - The medical malpractice crisis: a comparative empirical perspective. PMID- 10114984 TI - Juries and justice: are malpractice and other personal injuries created equal? PMID- 10114983 TI - Resolving malpractice disputes: imaging the jury's shadow. PMID- 10114985 TI - How high-earning doctors get that way. PMID- 10114986 TI - Just how confidential is your malpractice data-bank file? PMID- 10114987 TI - More Munchausens are out there than you think. PMID- 10114988 TI - Three Michigan hospitals recognized for community contributions. PMID- 10114989 TI - The shifting role of hospital auxilians and volunteers. PMID- 10114990 TI - Qual-Med bid forces United HealthCare to ante up more for HMO. PMID- 10114991 TI - CHAMPUS managed-care plan extended, expanded. PMID- 10114992 TI - House panel finds 30 VA hospitals deficient. PMID- 10114993 TI - VA preps plan to open hospitals to non-vets. PMID- 10114994 TI - Red Cross reorganizes to ensure blood safety. PMID- 10114995 TI - Hospital executives anxious over ramifications of final physician fee rules. AB - The final Medicare physician fee schedule regulations represent the biggest change to the Medicare system since it was enacted 26 years ago. The new rules, which will dramatically change the way physicians are paid, have hospitals scrambling to comprehend their effects while looking for ways to keep delicate relations with their medical staffs from deteriorating. PMID- 10114996 TI - Congress draws closer to delaying enforcement of Medicaid restrictions. PMID- 10114997 TI - Pack that golden parachute. PMID- 10114998 TI - Packaged hospitals get second chance in the Third World. AB - They're products of the Cold War that fortunately were never needed. Prepackaged disaster hospitals, civilian M.A.S.H. units containing everything needed to create a 200-bed hospital except an exterior structure, have been packed away in crates since the '50s and '60s. But the hospitals-in-a-box are being shipped to less-developed countries where even the 30-year-old equipment often is a big improvement over what's currently available. PMID- 10114999 TI - Chain seeks to open AIDS nursing facility. PMID- 10115000 TI - Assessment process helps hospitals determine what's wrong and what's to be done about it. AB - When costs overwhelm revenues in a particular service or program, it's time to stop and get a handle on what's gone wrong. Maybe the program idea is still good but needs a course correction or two. Maybe it was a bad idea all along, or it's become a loser because of new market forces. Getting at the problem requires a systematic approach, according to Sally Berger and Sandra Wisener of Ernst and Young. PMID- 10115001 TI - Treating chest pains brings big financial gains. Specialized emergency units saving lives while building market share in lucrative cardiac care. AB - Chest pain emergency departments can provide big benefits for both hospitals and their customers. They offer facilities for persons experiencing chest pains to come to the hospital to monitor their condition. And they give hospitals opportunities for additional revenue and potential admissions. PMID- 10115002 TI - Antitrust guide to merge missions of FTC, Justice. PMID- 10115003 TI - Hospitals that are purchasing second-hand rose. PMID- 10115005 TI - GOP takes heed, talks up reform. PMID- 10115004 TI - Top-performing hospitals come in all states and sizes. PMID- 10115006 TI - NME's stock skids on estimate of lower profit. PMID- 10115008 TI - VHAE posts profit, but not from operations. PMID- 10115007 TI - Chicago facility files to block its sale. PMID- 10115009 TI - Deregulation takes center stage in Mass. PMID- 10115010 TI - N.Y. agency to issue stringent regulations for treatment facilities. PMID- 10115011 TI - N.Y.C. hospital to end affiliation with HHC facility. PMID- 10115012 TI - AHA tries again, but discussion plan may fan fire. PMID- 10115013 TI - Calif. movement seeking physician-assisted suicide. PMID- 10115014 TI - Florida obstetrician settles charges of leading boycott. PMID- 10115015 TI - Hillhaven undertakes restructuring. PMID- 10115016 TI - IRS to joint ventures: the party's over. PMID- 10115017 TI - Hospitals to carry on fight over Medicaid restrictions. AB - While the compromise over Medicaid tax and donation programs was an improvement over the original rules proposed in September, hospital executives are voicing their displeasure with some of its provisions. The battle now moves from Capitol Hill to state legislatures, where questionable tax/donation schemes will have to be reworked to conform to the new law. Hospital officials in some states have vowed to carry on the crusade. PMID- 10115018 TI - Reform panel remains divided. PMID- 10115019 TI - A better building's benefits. PMID- 10115020 TI - Cost containment: carrot or the stick? AB - All sides in the debate over healthcare reform seem to agree that it's an idea whose time has come. The consensus appears to be that the first generation of cost curbs failed to do the job. But when will the nation see real cost containment? And what form will it take? Proposals run the gamut from free-market approaches to greater governmental intervention. PMID- 10115021 TI - New X-ray film/screen system promises higher resolution. PMID- 10115022 TI - Shortage of imaging technicians eases in East, worsens in Midwest; supply ebbs. PMID- 10115023 TI - HMOs choosing IPA partners with care. AB - As managed care continues to grow, medical groups are being forced to offer a greater range of services and improve their use of resources to stay in business. As a result, they're affiliating or merging with other groups and HMOs to boost revenues and trim expenses. While such relationships tend to be symbiotic, they also can be risky for HMOs, which continue to practice care in choosing their partners. PMID- 10115024 TI - Pension plans drift toward diversification. AB - Following New Jersey's seizure of Mutual Benefit Life Insurance Co. last summer, hospital associations have begun revamping their pension offerings, in some cases steering away from venerable, fixed-income insurance products and into diversified plans such as stock funds, which may offer better returns. But insurer-based plans remain a favorite as many programs stay on the conservative course. PMID- 10115025 TI - Cleveland, K.C. groups end longstanding arrangements. PMID- 10115026 TI - Magnetic source imaging advances. PMID- 10115027 TI - Orlando Regional Medical Center gives away four trips--total cost: less than $500. PMID- 10115028 TI - Pretreatment standards: categorical regulations on the horizon. AB - As Congress writes aggressive wastewater laws and EPA tightens its regulatory grip, the question of whether to fight or compromise becomes even more pressing for the textile rental industry. As Congress moves forward on the reauthorization of the Clean Water Act, EPA's authority to issue pretreatment standards could be greatly strengthened. Categorical pretreatment standards would set national limits on the concentrations of various pollutants that are being discharged to publicly owned treatment works (POTWs). As EPA lays out its recommendations to Congress, perhaps it's time for the textile rental industry to reevaluate its position on categorical standards. PMID- 10115029 TI - Wastewater treatment methods from A to Z. AB - With local wastewater disposal regulations varying from nonexistent to nightmarish, operators must choose the method of treatment that best suits their needs. Various types of wastewater pretreatment equipment and processes are currently used in rental and commercial laundries. Here's information on systems ranging from simple settling pits and screens to sophisticated membrane filtration systems. PMID- 10115030 TI - AIDS: how management should respond. PMID- 10115031 TI - Retiree medical plan design: determining the philosophy, communicating the need. AB - Much has been written, both in benefit-related journals and in the general press, about the recent statement, FAS 106, issued by the Financial Accounting Standards Board (FASB). This statement requires most employers to begin accounting for retiree health care benefit costs for active employees as well as current retirees, creating a significant negative financial impact. Most of the attention has been focused on getting the numbers that will tell the extent of the impact resulting from FAS 106. The next step has been to review retiree medical coverage to see how the affected companies can change it to reduce their liability. Although the urge is strong to adopt a quick-fix solution, employers can greatly benefit by reviewing their benefit philosophies and making plan decisions that make sense for them. This article discusses key questions that can help focus the issue on company philosophies and lays out a framework for determining suitable plan designs that can also help companies manage the retiree medical liability. PMID- 10115032 TI - The status of employee health care benefits: a management dilemma. PMID- 10115033 TI - Characteristics of nursing homes that affect resident outcomes. AB - Although there has been increased interest in using outcomes as measures of quality, few studies have shown a link between structure or process and outcomes. In this analysis, based on approximately 2,500 residents in 80 nursing homes in Rhode Island, multivariate models estimate which aspects of care are associated with resident outcomes after controlling for resident characteristics. Outcomes, measured over a 6-month period included death, functional decline, and functional improvement. Results suggest that higher staff levels and lower RN turnover were related to functional improvement. Facilities with high catheter use, low rates of skin care, and low participation in organized activities were associated with negative outcomes. Facilities with few private-pay residents were also associated with negative outcomes. Receipt of a serious federal citation was associated with improved outcomes. For-profit facilities appeared to be more efficient in use of resources. PMID- 10115034 TI - Mental illness and psychotropic medication use in the nursing home. AB - The authors examined mental illness and psychotropic medications use among nursing home residents. Data were drawn from the Texas Long-Term Care Reimbursement Project, a 1986 study of nearly 2,000 residents in 49 nursing homes. The study measured the use of antipsychotics and other psychotropic medications, physical health conditions, mental illness diagnoses, behavior, and nursing and other direct-care time for sampled residents. The findings indicated that 45% of the sample was receiving an antipsychotic or other psychotropic medication. Although psychotropics were prescribed more extensively for those with a psychiatric diagnosis, nearly one half of persons without a psychiatric diagnosis were receiving psychotropic medications at the time of the survey. Moreover, psychotropics were quite prevalent among those with unstable medical conditions and/or severe activities of daily living impairment. Neither a mental illness diagnosis, evidence of a behavioral problem, nor use of psychotropics was significantly correlated with the amount of nursing or other direct-care time received by residents. The findings raise concerns about the widespread prescribing of these medications, especially among residents who have no supporting psychiatric diagnosis and/or who have physical health conditions making them vulnerable to adverse drug effects. PMID- 10115036 TI - Electronic media claims: savings cited by users. PMID- 10115035 TI - Variation in long-term care service use by aged blacks. Data from the Supplement on Aging. AB - Data from the Supplement on Aging to the 1984 National Health Interview Survey were used to identify patterns of long-term care (LTC) service use among older Blacks. A subset of the SOA, including all 1,217 Blacks aged 55 and over, was the focus of the research. About 37% of all older Blacks in the sample reported difficulty in carrying out at least one activity of daily living (ADL) or instrumental activity of daily living (IADL); 27% reported receiving help with at least one of the ADLs or IADLs. Older Blacks were not significant users of community-based LTC services, with 11.9% reporting using a senior center, the highest percentage of use among a list of 10 community and social services. Five LTC factors were identified: ADL Help, Community Services, Home Health Services, Home Management Services, and Personal Services. Multiple regression analyses identify need factors as most dominant in explaining variation in LTC service use by older Blacks. PMID- 10115037 TI - Perspectives. Transplants: limited resources, unlimited need. PMID- 10115038 TI - Perspectives. Technology assessment: a stronger federal role? PMID- 10115039 TI - What it takes to succeed at the top. PMID- 10115040 TI - Do you have the right stuff? PMID- 10115041 TI - What does the CEO want? CEOs reveal what they expect from their HR executives. PMID- 10115042 TI - Right-sizing reshapes staffing strategies. PMID- 10115043 TI - No job is safe from discrimination. PMID- 10115044 TI - The forgotten figure in cost containment. PMID- 10115045 TI - The RCRA (Resource Conservation and Recovery Act) Amendments bill. PMID- 10115046 TI - Health risks from low blood-lead levels. PMID- 10115047 TI - Occupational health, safety, and environmental compliance plan for physician offices. PMID- 10115048 TI - The problem of mercury--again. PMID- 10115049 TI - A natural experiment in the organization of entry-level labor markets: regional markets for new physicians and surgeons in the United Kingdom. AB - The histories of seven regional markets for new physicians and surgeons in the United Kingdom are considered. Like the American market, these markets have experienced failures that led to the adoption of centralized market mechanisms. Because different regions employ different centralized mechanisms, these markets provide a test of the hypothesis that the success of the American market is related to the fact that it produces matches which are stable in the sense that no two agents mutually prefer to be matched to one another than to their assigned partners. Even in the more complex U.K. markets, this kind of stability plays an important role. Centralized markets that produced unstable matches in environments in which agents could act upon instabilities fared no better than the decentralized markets they replaced. PMID- 10115050 TI - Experimental treatment: who pays? PMID- 10115051 TI - Don't blame medical technology. PMID- 10115052 TI - Data watch. Reform: looking forward and back. PMID- 10115053 TI - Who pays for new technology? AB - New medical technology presents an interesting dilemma. While it can offer improvements in patient care, it is often quite expensive. Thus, many health care payers may not be as willing to cover care involving new technologies. PMID- 10115054 TI - Self-funded benefits plans enjoy freedom and flexibility. AB - Freedom from state mandates and premium taxes have long persuaded companies to self-fund their benefits plans. Then they discover an additional benefit to self funding--flexibility. PMID- 10115055 TI - Many roads lead to health system reform. PMID- 10115056 TI - Militant medicine. AB - The Defense Department has health care costs in its bombsights. There may be strategic lessons here for employers. PMID- 10115057 TI - Is there a doctor in the house? AB - Unless employees can readily access your physician network, even the best physicians won't do them much good. Here is a state-of-the-art system for measuring access to care. PMID- 10115058 TI - High turnover anxiety. PMID- 10115059 TI - Delegations of authority and organization; Center for Devices and Radiological Health--FDA. Final rule. AB - The Commissioner of Food and Drugs is redelegating authorities to certain officials of the Food and Drug Administration's (FDA's) Center for Devices and Radiological Health (CDRH) to temporarily suspend premarket approval applications and to recall devices in the event those devices would cause serious adverse consequences to health or death. These authorities were given to the FDA by the Safe Medical Devices Act of 1990. PMID- 10115060 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS)- Department of Defense. Notice of revised rates. AB - This notice provides the updated adjusted standardized amounts, DRG relative weights, outlier thresholds, and beneficiary cost-share per diem rates to be used for FY 1992 under the CHAMPUS DRG-based payment system. It also describes the non regulatory changes made to the CHAMPUS DRG-based payment system in order to conform to changes made to the Medicare Prospective Payment System (PPS). PMID- 10115061 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); Fiscal year 1992 update--Department of Defense. Notice of updated mental health per diem rates. AB - This notice provides for the updating of hospital-specific per diem rates for high volume providers and regional per diem rates for low volume providers; the updated cap per diem for high volume providers; and the beneficiary per diem cost share amount for low volume providers to be used for FY 1992 under the CHAMPUS Mental Health Per Diem Payment System. PMID- 10115062 TI - A licensing story. PMID- 10115063 TI - Certifying foreign-trained technologists: should the CSLT change? AB - The certification of foreign-trained technologists is a very sensitive issue, and the CSLT must proceed with caution in making changes to the system. The policy cannot afford to be too lenient, lest in this litigation-conscious climate an incident were to occur that could undermine the credibility of the certification process. On the other hand, it must not be protectionist and discriminatory. If the labour market does become undersupplied with medical technologists, employers in non-regulated provinces may choose to replace their ranks with non-CSLT certified employees. If this were to happen to a significant degree, employers might come to rely less and less on the CSLT's stamp of approval. In either case, the value of the CSLT, and the RT itself, is at risk. PMID- 10115065 TI - WORXWELL Towel--new and improved. PMID- 10115064 TI - The 1991 CCHFA (Canadian Council on Health Facilities Accreditation) standards and risk management. PMID- 10115066 TI - 1991 non-profit software package directory. PMID- 10115067 TI - There is a better way to pick software. PMID- 10115068 TI - There is a place for the non-profit community in the regulatory process. PMID- 10115069 TI - The second time around: reaching for the right package. AB - There are several key questions to ask when replacing a software package. Taking the time to get the answers will save a lot of time, money and grief. PMID- 10115070 TI - Who's in charge here? You or your computer?! AB - To pinpoint problems, look at hardware, software, support training and the user. The problem may reside in any one, or several, of these areas. PMID- 10115071 TI - Helping employees in need. PMID- 10115072 TI - Leadership and the effective executive. PMID- 10115073 TI - Product update: infant monitoring systems. PMID- 10115074 TI - Special report. The new hospital labor picture: More unions? More strikes? More problems for security directors? AB - A recent U.S. Supreme Court decision upholding National Labor Relations Board (NLRB) rules for hospital bargaining units appears to be fueling union efforts to organize hospitals nationwide. As unions gain more footholds in hospitals, the prospects for strikes and labor unrest increase. This expected surge in organizing may place hospital security departments in critical situations, whether they're the specific target of unions or not. This report reviews the implications of the new bargaining unit rules as they affect hospital security operations. PMID- 10115075 TI - Intergenerational continuity and reciprocity through the use of community-based services: theory and practice. AB - This paper aims to expand the current debate on intergenerational issues by examining the interactions of the generations and their sentiments as represented in recent community program studies, participant-observation reports, and autobiographical work. The error in intergenerational inequity thinking is asserted to be in its belief that a generation that otherwise would have had to support its parents would be in favor of cutting social security benefits. Two, if researchers and policy makers take into account only economic exchange, they will never be able to predict usage or plan appropriate programs. Three, the state has a stake in supporting informal caregivers. Finally, real equity lies in normative social exchange. PMID- 10115076 TI - Home health care post-PPS: some California data. AB - California home health data for the years 1982 through 1987 are analyzed to explore the effects of the implementation of the Prospective Payment System in 1983 and the increase in denial rate for Medicare reimbursed home care in late 1985. After 1983 the following declined: average number of patients per agency, average number of visits per patient, number of freestanding agencies and percentage of reimbursement from Medicare. After 1985 there were declines in the number of patients served, total number of visits, average number of visits per aged client, and number of agencies (proprietary and non-profit) submitting annual reports. PMID- 10115077 TI - Controlling hospital readmission of elderly persons living at home: a risk factor analysis. AB - A large proportion of hospital stays stem from rapid readmission of elderly patients. These patients represent high cost users of inpatient care. Intervention in the hospital admission-readmission cycle may serve the interests of patients and payors alike. Data collected through comprehensive geriatric assessment can be useful in identifying those patients at high risk of readmission and who might benefit from more intensive in-hospital or post hospital attention. However, risk factors for readmission are largely unknown. We conducted a prospective study of elderly patients admitted to a metropolitan teaching hospital medical service and assessed by a geriatric team, to increase our knowledge of the factors associated with hospital readmissions. The most powerful predictor of hospital readmission within 6 months proved to be prior hospitalization. Attempts to reduce rehospitalizations in elderly patients must focus on those with prior recent hospitalizations. PMID- 10115078 TI - Cancer symptom management in the elderly. AB - Clear and concise written guidelines must designate accountability for coordination of the persons involved. As might be assumed by the preceding discussion, the process takes considerable time and effort. The development of clear guidelines is a long term venture and usually does not occur quickly. In some cases a nearby agency may have developed a useful protocol that when shared with area providers, is quickly accepted. However, one to two years is not uncommon to developing a complex plan of care or protocol which can be used effectively and is specific to the conditions in a particular setting. Written guides, when developed correctly, should save all providers' time, and ensure better client care. Clear directions regarding the care to be provided and well established lines of communication can save health care providers time and increase the likelihood of better health outcomes for the client. The coordination of planning within the home care agency, and across professional, agency and geographic boundaries is a prerequisite for successful cancer symptom management. The central aim in planning is to enhance the family's ability to manage independently and to facilitate continuity of care in the use of health care services. For the client to have the greatest potential for symptom amelioration, the home care agency must assume a major role in the coordination of care providers in the delivery of care. PMID- 10115079 TI - Aggressive physician recruiting: why and how. PMID- 10115080 TI - Can "barebones" insurance replace state health mandates? PMID- 10115081 TI - States can prohibit Medicare balance billing. PMID- 10115082 TI - FTC authority over nonprofit hospital mergers confirmed. PMID- 10115083 TI - The NLRB hospital union rules are here: is your hospital ready? PMID- 10115084 TI - Health care data base marketing: a key strategy for the '90s. PMID- 10115085 TI - Management education. A major challenge for the NHS. PMID- 10115086 TI - Creating corporate loyalty in the NHS. PMID- 10115087 TI - Not drowning but swimming with the tide. PMID- 10115088 TI - Union membership. Not just professional versus union minded. PMID- 10115089 TI - Selection processes in the NHS--random or scientific? PMID- 10115090 TI - Top managers--the NHS must grow its own! PMID- 10115092 TI - Visions, values and impediments. PMID- 10115091 TI - A perception gap. AB - This article presents preliminary findings on research by the Public Agenda Foundation, a nonprofit, nonpartisan research organization. When complete, this research will provide one basis for a major public-television special on health policy being produced by WGBH-TV in Boston under a grant from Baxter International Inc. and for accompanying educational materials being produced by Public Agenda for a nationwide program of community and town meetings. The findings discussed here are based on focus groups conducted in nine cities across the country between January and June 1991. We have also reviewed existing survey data and interviewed a number of experts and decision-makers in the health-care field. While findings from focus groups should be considered preliminary until they can be confirmed through surveys, our observations here reflect the views of a cross section of Americans from around the country. PMID- 10115093 TI - The media and health policy. PMID- 10115094 TI - Does the system fit? AB - A new poll shows an American social ethic similar to other people's. So why is our health-care system so different? PMID- 10115095 TI - Insurers under fire. PMID- 10115096 TI - Safe Harbor may mean rough waters for hospital contracts. PMID- 10115097 TI - I.V. solution prices to jump 7%. PMID- 10115098 TI - Stockless programs sputter after initial boom. PMID- 10115099 TI - Proper planning makes capital equipment purchasing easier and more efficient. PMID- 10115100 TI - Former materials manager tackles operating room inventory at Desert Springs Hospital. PMID- 10115101 TI - Powders added to body fluids facilitate waste handling. PMID- 10115102 TI - Hospitals, pharmacists share equivalent responsibilities and liabilities for actions. Part 2. AB - An earlier article outlined in a general way the professional responsibilities and the legal liabilities of a pharmacist. In this dialogue, Dr. Decker applies these general concepts to the hospital pharmacist and summarizes the liability of the hospital for the activities of those in the hospital pharmacy. PMID- 10115103 TI - A method of teaching negotiating skill. AB - Can physicians and managers both enjoy successful contracts? Is it necessary for one party to win and the other party to lose? If both parties could win, or at at least have a perception that they won, perhaps the unpleasant nature of contracting and negotiation could be mitigated. Can inexperienced negotiators learn negotiating skills? The focus of this study is to attempt to answer formally the above questions. An experiment was conducted to investigate the effects of analytical information on the quality and efficiency of individual decisions during negotiations. The experiment required M.H.A. and medical students to agree in a medical services contract between a health maintenance organization and a group of physicians. A computer-based bargaining choice model was developed to elicit each subject's preferences and value trade-offs. Selected subjects used the analytical information when preparing for the contract negotiation. Significantly higher levels in quality of individual negotiator decisions and efficiency were observed when analytical information was used prior to negotiating. Also, significantly higher levels of joint quality and success in negotiation were observed in subjects using analytical information. The results provide strong support for developing models of individual negotiator choice behavior for use in actual health care negotiation and the education of health care administrators and physicians. PMID- 10115104 TI - Time management and leadership styles: an empirical study of long-term health care administrators. AB - Is there a relationship between the type of leadership style employed by long term health care administrators and the effective use and management of time? This paper describes a 1989 study of 188 administrators of skilled nursing facilities and intermediate care facilities in Connecticut. Two self-rating instruments were employed: the Executive Time Management Inventory (Hartley, Kramer, et al.) and the LEAD-Self instrument (Hersey and Blanchard). Four hypotheses were tested at the .05 level of significance to examine relationships among time management, leadership style, size of facility, administrator experience, and cost factors. Statistical procedures included Pearson Product Moment correlations, analysis of variance, t-tests, and partial correlations. Results of the study included (1) time management effectiveness increased as administrators gained more experience; (2) no significant relationship existed between type of leadership style and time management effectiveness; (3) women administrators perceived themselves as significantly more effective time managers than men did; (4) most health care administrators employed the same primary leadership style: "selling," which is defined as high relationship/high task; and (5) institutional size was not related to the time management effectiveness of the administrator. The findings have implications for pre-service and in-service training and for future studies in health administration education. PMID- 10115105 TI - Health analytics: a new product line for health administration education programs. PMID- 10115106 TI - Up in the air over British Columbia. PMID- 10115107 TI - Your response to air-medical transport. Results of the JEMS November 1989 survey. PMID- 10115108 TI - When hope is lost ... dealing with the suicidal patient. AB - In a time when at least five out of every 100 calls for 9-1-1 assistance are suicide-related, EMS providers need to know how to answer these cries for help. In addition to tending to the patient's physical needs, providers must offer psychological support despite any personal feelings to the contrary. PMID- 10115110 TI - Get what you want through the fine art of negotiation. PMID- 10115109 TI - CAAMS (Commission on Accreditation of Air Medical Services). Developing a voluntary air-medical accreditation process. PMID- 10115111 TI - Commonly asked questions about hepatitis B vaccination. PMID- 10115112 TI - Q-probes: a tool for enhancing your lab's QA. PMID- 10115113 TI - On the move with Children's Hospital. PMID- 10115115 TI - Pulling the plug on an LIS project that failed. PMID- 10115114 TI - A hard look at performance reviews. PMID- 10115116 TI - What do Michigan RNs want? AB - Which is more important to your RNs--professional status or pay? The information in this article will help you attract and retain your share of highly skilled RNs in today's competitive market. PMID- 10115117 TI - The cost of a "bad hire:" how search firms can help. AB - What's the key to competitive advantage and total quality management? O'Connor believes it's hiring top-quality people that are a "good fit" with your organization, and he tells how a search firm can help you do just that. PMID- 10115118 TI - Strategies for recruiting clinical and technical professionals. PMID- 10115119 TI - Cardiac ultrasound: is outsourcing for you? PMID- 10115120 TI - Health data facts. Employment in health services. PMID- 10115121 TI - Health care in the USSR: one woman's story. PMID- 10115122 TI - Will schools be able to meet our personnel needs? AB - Demand for skilled health care workers is outstripping supply, and the situation promises to get worse before it gets better. What can hospitals and educators do? PMID- 10115123 TI - Are Michigan hospitals facing a shortage of trained personnel? AB - The 1990 MHA Health Personnel Shortage Survey requested information on 31 personnel positions to determine the extent of personnel shortages, the sources of replacement personnel, the positions for which it is most difficult to recruit applicants, and the positions for which it is most difficult to retain personnel. In addition, hospitals were asked about the impact of personnel shortages on hospital services, the strategies they had implemented to alleviate the problems caused by shortages, and their commitment to, and involvement in, training and educational programs to increase the availability of health care personnel in Michigan. A total of 77 Michigan hospitals and health care institutions responded to the survey. Analyses were performed on a sample of 69 community hospitals distributed similarly, with respect to hospital bed size category and geographic location, to the state total of 176 Michigan community hospitals. For more information, or for a copy of the complete 1990 MHA Health Personnel Shortage Survey report, contact the MHCI Health Policy Analysis Department. PMID- 10115124 TI - Factors associated with differential utilization of professional care among elderly people: residents of old people's homes compared to elderly people living at home. AB - To investigate factors that explain differential utilization of professional care among elderly people a study was performed in Maastricht, the Netherlands. For that purpose 657 interviews with elderly people were held. In this article a comparison is made between elderly people living at home, with or without professional home care, and residents of old people's homes. Besides the functional status, as measured by limitations in household activities and activities of daily living, the composition of the household of the elderly person is recognized as a major discriminating factor between the three groups. The role of depressive complaints in care utilization is less prominent than expected from an earlier study. A bivariate analysis clearly showed the frequency of mental problems and the poorly developed social network among elderly persons using professional care. Implications for caregiving and policy planning are discussed. PMID- 10115125 TI - The art of multidimensional management. How successful executives think. PMID- 10115126 TI - A performance appraisal system that means something. An easy way to document and communicate daily performance. PMID- 10115127 TI - Interactive static image analysis: a major enhancement to histopathology and cytology. AB - Recent developments in computerized data processing and digital video technology have made it possible to perform cytology and histopathology in quantitative as well as qualitative terms. The most common method for studying the DNA content of tumors in clinical laboratories is flow cytometry. The development of image analysis (IA) to study DNA content by Feulgen staining and microspectrophotometry actually preceded the development of flow cytometry, but the complexity of the method was so great that it never received widespread usage. In recent years computerized interactive static IA on microscope-based instruments has been developed. These instruments involve microscopy, a television camera and monitor, and a computer to analyze the data. They can be put together from separate components or are available as complete instrument packages from commercial companies. In addition to the study of DNA content, software is also available to perform quantitative immunoperoxidase determination and morphometry. These commercial instruments emphasize user-friendly software. Companies such as CAS (Cell Analysis Systems, Elmhurst, Illinois) provide operator training and annual user meetings. There is a growing interest among laboratories in bringing this technology into their institutions. This review will deal with the following aspects of IA: what it can do, how it works, what skills and training are required for an operator to use it, financial considerations, and how image cytometry compares to flow cytometry. PMID- 10115128 TI - Creating and implementing a chemical hygiene plan. AB - January 31, 1991 was the deadline for laboratories to have developed and implemented their chemical hygiene plans (CHPs). OSHA may fine laboratories that do no comply--up to $2,500 per day. Managers have a responsibility to their employees to ensure a safe working environment, and the CHP is a useful tool for reducing risks and for informing employees about possible health hazards. Preparing a CHP does not have to be an arduous task--especially if you work from a model plan. This month's As We See It should help you refine (or develop) your CHP. PMID- 10115129 TI - The OSHA hazardous chemical occupational exposure standard for laboratories. AB - OSHA's chemical occupational exposure standard for laboratories is an outgrowth of the previously issued Hazard Communication Standard. The standard relieves laboratories from complying with general industry standards but does require compliance with specific laboratory guidelines. The heart of the standard is the creation of a Chemical Hygiene Plan (CHP). The CHP addresses major issues such as safety equipment and procedures, work practices, training, the designation of a chemical hygiene officer, and the provision of medical consultation and examination for affected employees. This new standard, in full effect as of January 31, 1991, presents yet another regulatory challenge to laboratory managers but also ensures a safer environment for laboratory workers. PMID- 10115130 TI - Creating a quality culture in your organization. AB - Service quality is the great differentiator of the 1990s. It means understanding and consistently meeting customer requirements. A lack of complaints is a poor indicator of customer satisfaction. Reliability is the most important factor affecting your customers' perception of quality. This article outlines a do-it yourself process for creating and enhancing a quality culture in a clinical laboratory. This process requires understanding the nature and importance of quality; adopting quality goals and performance measurements; asking for customer input; rewarding satisfactory performance; creating self-managed teams that aim for continuous improvement; and encouraging unrelenting service directed at delighting customers. In a competitive marketplace, quality is the great differentiator that pays impressive dividends. PMID- 10115131 TI - Resolving the eight key issues in network management strategic planning. AB - No strategic plan for information systems or networks will be adequate without careful consideration of the pace, content, and direction of network management systems. Here are the eight key issues in strategic planning for network management and how to resolve them. PMID- 10115132 TI - How to keep a migration project on course. AB - A migration project can be a nightmare for even the most capable CIO. But, with careful planning, the outcome of the project can be the realization of the company's dream for the future. PMID- 10115133 TI - Insurers discover expert systems. AB - The insurance industry is suffering from a dearth of expert underwriters, but by capturing available expertise in knowledge-based systems, many insurers have reaped measurable benefits. PMID- 10115134 TI - Electronic mail and privacy: setting your company's policy. AB - In setting a privacy policy, a company must consider not only its interest and the interests of its employees, but also the interests of third parties, including suppliers, customers, law enforcement agencies, and others who may have a legal right to or interest in accessing company records, including electronic mail. PMID- 10115135 TI - Pennsylvania's HCCCC (Health Care Cost Containment Council): cost/quality watchdog or paper tiger? PMID- 10115136 TI - A survey of New Jersey hospital ethics committees. AB - A mail survey in 1988 of all 108 hospitals in New Jersey, and telephone follow-up in 1990, investigated the extent and structure of ethics committees with attention to the distinctions between prognosis, infant care review committees (ICRC) and general ethics committees (HECs). It disclosed that as of August, 1990, 74 hospitals had prognosis committees, 16 had ICRCs, and 64 had HECs. All types of committees tend to cluster in teaching hospitals and in hospitals with 200-500 beds. HECs average 13 members which include 4-5 physicians, 2-3 nurses, administrators and clergy (1-2 each), and fewer than one each for any other single profession. The primary purpose of HECS is to develop hospital ethics policy (96%), followed by educating hospital staff (80%), and providing counsel and support to physicians (67%). Case review with recommendation is provided by 54% of the HECs and 21% are involved in confirmation of prognosis. PMID- 10115137 TI - Pastoral care representation on the hospital ethics committee. AB - A recommendation for pastoral care representation on hospital ethics committees (HEC) is commonplace in the literature, but the rationale for this recommendation (and the actual practice) often is assumed or unarticulated. The authors propose a holistic anthropology which acknowledges the bodily, psychological, and spiritual aspects of all persons as a starting point for discussing the reasons for pastoral care representation. The spiritual aspect of the human person is described together with the role of the clinical chaplain on the HEC. The qualifications, skills, and training required for the HEC representative are also provided. PMID- 10115138 TI - Medical ethics committees in Hungary. AB - Hungarian medical ethics committees were established at the end of the 1950s. They came into being on the Communist Party's initiative. They could hardly be called "interdisciplinary" since their membership was made up of high-ranking physicians and a few head nurses. Their main task was to counter the practice of "tipping." Medical ethics and "tipping" were practically synonymous. These committees did not confront or try to resolve ethical problems concerning such issues as patient rights, informed consent, refusal of treatment, human experimentation, abortion, etc. These committees - whether it is believable or not - belonged to the Physicians Health Workers Trade Union. They were under the guidance and supervision of this social organization. The public was excluded from their meetings, and the committees' duty was to follow the health laws which were supposed to have given excellent ethical guidance. Even in a textbook on medical ethics used at one of the medical universities, written by a psychiatrist, the health laws were presented and explained back and forth. Of the 88 pages only 23 dealt with morals in general and the Hippocratic tradition. The Hungarian National Health Service as well as its medical ethics committees are similar in many respects to the Soviet and Eastern European countries' health care system and ethics committees. Since radical changes have taken place in these so-called "former" communist countries, it can only be hoped that these committees will eventually develop into groups who will deal directly with the moral questions or medicine and health care. PMID- 10115139 TI - Ethics consultation: the Hospital for Sick Children initiative [Toronto, Ontario]. PMID- 10115140 TI - Guidelines for bioethics consultations at the Hospital for Sick Children [Toronto, Ontario]. PMID- 10115141 TI - Should HECs assess whether 'clear and convincing evidence' standards have been met before recommending the discontinuation of life support, including nutrition and fluids? Point and counterpoint. PMID- 10115142 TI - Avoiding unnecessary peer review. PMID- 10115143 TI - Continuous quality improvement in healthcare. Quality Assurance Section, American Medical Record Association. PMID- 10115145 TI - Perspectives. 1991: a year of rising expectations. PMID- 10115144 TI - Michigan's voluntary health data base. PMID- 10115146 TI - An evaluation of potential prognostic indicators in cardiac patients. AB - Cardiovascular disease results in more deaths and higher medical costs than any other medical problem. Cardiac patients may be transported to centers for specialized care. We evaluated historical, current event, and physiologic items (n = 32) for ability to predict use of specialized care and hospital costs. For 199 patients studied, seven items were prognostic. A model classifying patients by presence of predictors was developed. For the group without predictors and the group with multiple predictors, sensitivity and specificity were respectively very good. For 125 (63%) of the patients in middle categories, the model was not sufficiently sensitive to be prognostic. A scoring system for all cardiac patients could not be developed. Patients requiring only diagnostics were responsible for financial deficits, as were all Medicare patient groups. Patients staying longer than seven days, or having surgery, or both, were responsible for the largest deficits (if on Medicare) and the highest profits (if not on Medicare). Advance validation of the need to transport is difficult, with far reaching medical and financial implications. PMID- 10115147 TI - ASRS (Aviation Safety Reporting System): an underused resource. PMID- 10115148 TI - Emergency egress scenarios. PMID- 10115149 TI - Pediatric, neonatal, and maternal patient care addendum to the AAMS/NFNA resource document for air medical quality assurance programs. AAMS Quality Assurance/Standards Committee and NFNA Special Interest Group. PMID- 10115150 TI - 1991 program listings with aircraft operators and types. PMID- 10115151 TI - Air medical response to the 1990 Will County, Illinois, tornado. AB - At least 29 people were killed and over 300 injured on August 28, 1990, when a powerful tornado cut a path of destruction through the outskirts of Chicago. The tornado's destructive force began a mammoth rescue effort from over 50 emergency medical service agencies, 80 ambulances, 1,000 rescue personnel, and Chicago's two air medical helicopters. The EMS effort was supplemented by an equally large response from police, fire, heavy rescue, K-9, and other emergency teams across north and central Illinois. Medical mass casualty incident procedures were activated and coordinated through the Will-Grundy Emergency Medical Services System, located at Silver Cross Hospital in Joliet. The towns of Crest Hill, Plainfield, and Joliet were the hardest hit, with more than $200 million in damages. The tornado strained not only the ground-based EMS and rescue systems, but taxed the resources of the city's air medical programs as well. This paper reviews the response by critical care air medical transport teams to this natural disaster. PMID- 10115152 TI - CFCs: the way ahead for refrigerants and sterilisation mixtures. PMID- 10115153 TI - Design and construct--a healthy way to build? PMID- 10115154 TI - Developments in medical imaging. PMID- 10115155 TI - Fax poll results. PMID- 10115156 TI - Data watch. A glimpse into the future. PMID- 10115157 TI - The little coalition that could. PMID- 10115158 TI - An ounce of prevention. PMID- 10115159 TI - What's ahead for managed care? PMID- 10115160 TI - Is it time to back chiropractic? PMID- 10115161 TI - New role for nurses: tending to the bottom line. PMID- 10115162 TI - Seeing benefits in vision care. PMID- 10115163 TI - On sale now: hospital services. PMID- 10115164 TI - How healthy is your sick leave program? PMID- 10115165 TI - Prepaid health care: obsolete provisions--HCFA. Final rule. AB - This rule amends the regulations on prepaid health care to remove outdated content, convert undesignated center headings to designated subpart headings, and redesignate specified sections. These changes are necessary to--Make the section numbers of the redesignated sections available for rules needed to implement recent changes in law and policy; Preclude confusion as to the rules that are currently in effect; and Facilitate reference to different portions of part 417, through the use of the subpart titles. PMID- 10115166 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); mental health services--Department of Defense. Final rule. AB - This final rule implements changes required by the National Defense Authorization Act for Fiscal Year 1992 and the Department of Defense Appropriations Act for Fiscal Year 1991, as amended by the Persian Gulf Conflict Supplemental Authorization and Personnel Benefits Act of 1991, concerning mental health services under CHAMPUS. The Acts change the existing day limits and waiver criteria for acute inpatient psychiatric care, introduce new day limits for residential treatment center care, and protect against economic interests in referrals to inpatient facilities by health care professionals. PMID- 10115167 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); mental health services--Department of Defense. Final rule. AB - This final rule establishes a mandatory preadmission authorization program for mental health services under CHAMPUS. Such a program is needed to promote quality assurance and contain rapidly increasingly costs in inpatient psychiatric care under CHAMPUS. By maintaining most of the procedures of the current voluntary preadmission authorization program, the final rule minimizes inconveniences for providers. PMID- 10115168 TI - Radiation therapy--past and future. AB - Not long ago, cancer was generally looked on as a lethal disease. In the last decades, recovery chances for various forms of cancer have increased spectacularly. And research is still going on. Various new therapeutical techniques have been implemented recently or will be in the near future. In my paper, I will first briefly mention some achievements of the past 25 years. Then I will discuss some methods that have been developed recently, or that are still in an experimental stage. I will also concentrate on aspects that are of interest to the radiographer, and that may influence daily routine and workload. PMID- 10115169 TI - Radiation therapy advanced certification. 1991 survey results. PMID- 10115170 TI - Sexual harassment in the workplace. PMID- 10115171 TI - Synergistic growth and economies of scale. Hospitals and nursing homes eye housing. PMID- 10115172 TI - Easing the task of employee performance evaluation. PMID- 10115173 TI - Health hazard. How to minimize medical waste liability. PMID- 10115174 TI - Success through fine dining. Survey sinks its teeth into food service. PMID- 10115175 TI - Why nurses leave. Texas project seeks solutions to widespread problem. PMID- 10115176 TI - An end to anonymity. Who's buying LTC insurance and why. PMID- 10115177 TI - Buyer beware. Due diligence in acquisitions averts disaster. PMID- 10115178 TI - The sky's the limit. "Blue-sky" marketing program stresses intangibles. PMID- 10115179 TI - Locking into restraint removal. Effects on residents, staff, costs examined. PMID- 10115180 TI - On the same side of the fence. Beverly, insurer ink managed care agreement. PMID- 10115181 TI - Preserving skin integrity. Pressure ulcer guidelines stress an ounce of prevention. AB - Clinical guidelines aimed at anticipating, preventing and treating pressure ulcers are due to be released soon. These guidelines are expected to offer practical advice on solving a pervasive problem. PMID- 10115182 TI - Ergonomics reduce costly back injuries. Assistive devices play key role. PMID- 10115183 TI - Life and death decisions. PMID- 10115184 TI - PET offers high-tech tool--but with high price tag. PMID- 10115185 TI - Early input from all sources drives cost down for project. AB - Declining financial resources will force administrators of hospitals entering construction or other facility acquisition projects to think creatively in putting together such projects. In the following article, the authors show how "partnering," a concept that unites all parties involved in a hospital acquisition project early so that decisions can be made in the most cost efficient way, worked in constructing a mid-Michigan physician office. PMID- 10115186 TI - Planning to plan: the process of success for the future. AB - Taking the confusion out of the planning process is a challenge for hospital administrators who, in the 1990s, will be called on to reevaluate strategies for both the institution and individual clinical areas. Identifying a planning process that fits the hospital and its management style is as important as producing the plan itself. In the following article, the author discusses the factors and players that must be considered in the planning process. PMID- 10115187 TI - Public anger makes health care reforms more likely. PMID- 10115188 TI - Planning indicators. Compound factors drive health care costs up. PMID- 10115189 TI - Network improves rural care. Interview by Donald E. Johnson. AB - Rural institutions may face one of the biggest challenges in providing up-to-date care that keeps patients in the local facility, rather than sending them to regional centers. In the following interview with Health Care Strategic Management publisher, Donald E.L. Johnson, Lloyd V. Smith, president of St. Luke's Hospitals MeritCare, a Fargo, N.D.-based health care network, reveals an educational outreach model for cardiac care that can be emulated by other institutions. PMID- 10115190 TI - Special report on reimbursement. Final Medicare fraud and abuse safe harbors are published. AB - There has been great concern in the health care industry that business arrangements that do not comply with the Safe Harbors will automatically be deemed illegal. HHS has confirmed that this is not so; the commentary to the Regulations expressly states that "The failure of a particular business arrangement to comply with these provisions does not determine whether or not the arrangement violates the statute because...this regulation does not make conduct illegal. Any conduct that could be construed to be illegal after the promulgation of this rule would have been illegal at any time since the current law was enacted in 1977....This regulation is intended to provide a formula for avoiding risk in the future." 56 Fed. Reg. at 35955. In the final analysis, the majority of transactions will fall outside the Safe Harbors and thus will continue to be judged by the standards established by the Medicare antifraud statute enacted 14 years ago. Under these standards, as HHS states, "the degree of the risk [in any particular transaction] depends on an evaluation of the many factors which are part of the decision-making process regarding case selection for investigation and prosecution." Id. at 35954. Providers that are mindful of these criteria should therefore still be able to accomplish, with relative safety, transactions that do not qualify for Safe Harbor protection. PMID- 10115191 TI - Medicaid wrap-up. AB - The 72nd Legislature restored Medicaid cuts, expanded coverage for infants and pregnant women. While no dramatic changes are right around the corner, Texas is poised for a major re-examination of the Medicaid program. PMID- 10115192 TI - High school helps medical hopefuls. PMID- 10115193 TI - Hospital-physician relations. Beyond courtship to the ties that bind. AB - Years ago, perhaps when relationships were simpler and possibly more enduring, physicians had one request of hospitals, namely, "Give us a good workshop in which to practice." With increased diversification and competition in the health care environment, their demands have become more complex, even as hospitals have become more eager to please. Hospitals and physicians know they need each other, but the hospital usually plays the role of the suitor. It is a role that can involve wasteful investments in time, energy and money if the courtship isn't inspired by real knowledge of what physicians actually want from the relationship. PMID- 10115194 TI - Physicians uneasy as RBRVS approaches. PMID- 10115195 TI - Investing in continuing education can reap rewards. PMID- 10115196 TI - Enticing nurses back to hospitals. PMID- 10115198 TI - A question of academic credibility. PMID- 10115197 TI - 10 steps to increased health care productivity. PMID- 10115199 TI - Bubbles of learning. PMID- 10115200 TI - Winning at the primaries. PMID- 10115201 TI - From little acorns. Welsh Office NHS Directorate. PMID- 10115202 TI - Not a quick fix. The Euroqol Group. PMID- 10115203 TI - Data briefing. The whole truth? PMID- 10115204 TI - Income generation. Material world. PMID- 10115205 TI - Connecticut court takes a keen look at consent issues. PMID- 10115206 TI - CHA seeks input on systemic reform proposal. PMID- 10115207 TI - Health insurance: a growing middle-class issue. PMID- 10115208 TI - Where is tomorrow? Implications and opportunities. PMID- 10115209 TI - A full-time commitment to care. PMID- 10115210 TI - Autonomy's responsibility. A gloss on the Wanglie affair. AB - In 1990, 87-year-old Helga Wanglie suffered cardiac arrest while being treated for lung disease at a chronic care facility. When she failed to regain consciousness after being resuscitated, a physician suggested the possibility of discontinuing treatment. At this point, her family requested that she be transferred to a hospital for evaluation. After a variety of procedures failed to improve her condition, the attending physician told the family he was no longer willing to prescribe the respirator because it could not serve her personal medical interests and that her unconscious state precluded the possibility of her appreciating life. However, the family insisted that the hospital provide Ms. Wanglie care, and she remained in treatment until she died 13 months later. The dispute between the hospital and the Wanglie family brings into focus the fundamental premises of the doctor-patient-family relationship. The rules for these relationships-described by such terms as "rights," "responsibilities," and "informed consent"--have both private and public dimensions. Mr. Wanglie had a clear right to be fully informed of all medically reasonable treatments and a right to choose or refuse any therapy the physician prescribed. He did not, however, have a right to demand any treatment he wanted. PMID- 10115212 TI - Narrow harbors. Few joint ventures will find haven in the investment-interest safe harbor. AB - Investors and potential investors had hoped for meaningful guidance from the safe harbor regulations on appropriate structures for healthcare joint ventures. Unfortunately, the narrowly drawn final investment-interest safe harbor offers relatively little meaningful guidance or protection for the vast majority of such ventures. The Illegal Remuneration Statute (also known as the fraud and abuse statute) was first enacted in 1972 to prohibit members of the healthcare community from exchanging patient referrals for any kind of remuneration. In 1987 Congress instructed the secretary of Health and Human Services to create "safe harbors" for legitimate payment practices that, although they may violate the statute's strict prohibition, will be protected from prosecution. The investment interest safe harbor has garnered the most attention. It provides two safe harbors, one for investments in large entities and one for investments in small entities. Both safe harbors contain onerous threshold requirements and other restrictions that diminish the usefulness of the safe harbor for all but a very few ventures. In addition, the Office of the Inspector General has created other obstacles to forming and preserving "safe" healthcare business ventures, including a refusal to "grandfather" or create a "safe harbor restructuring period" for existing business arrangements. Because most existing or planned joint ventures do not qualify for the investment-interest safe harbor, investors are forced to make their business decisions on the basis of the same factors used before publication of the safe harbor regulations. Such analysis will continue to focus on factors that demonstrate organizations' intent in making payments to investors as a return on investments. PMID- 10115211 TI - American culture and euthanasia. The changing definition of a "good death". AB - Divisions run deep in contemporary America over the issue of assisted suicide or mercy killing. The active, directly intended, and freely chosen self-destruction that was once unspeakable has become speakable. A recent best-seller providing "how-to" information on suicide; Initiative 119 in Washington State, which would allow "aid-in-dying"; and other publications and polls indicate that the proponents of mercy killing may have won over American culture, or at least established a dominant foothold. One of the chief criticisms of policies that permit mercy killing and assisted suicide is that they inevitably encourage suicide among those who are neither terminally ill nor suffering from physical pain. American culture is extreme in its desire to eliminate suffering. In a culture that can no longer depend on religious insights into human suffering, all kinds of preemptive strikes against suffering seem inevitable. The success of proponents of euthanasia is an indirect indictment of a healthcare system that fails to provide good palliative care and support. In our curative and rescue oriented healthcare system, management of pain is not a priority. And our society also undervalues caring in its most basic sense. It is not so much death as the absence of caring and the denial of reality that may be the enemy. The desire to control pain has always been valid, but not the desire to press control so far as to directly cause death itself. Death by lethal injection is best understood as a tyranny of technological control.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115213 TI - Strength in numbers. Hospitals that encourage group practice development may have a strategic advantage in the 1990s. AB - Group practices have become increasingly popular among physicians in recent years. And as competition increases and operating margins become perilously thin, hospitals with significant group practice participation among medical staff appear to be in an enviable position. Before deciding to promote group practices, however, hospital managers should be become familiar with their advantages and disadvantages and determine whether a market exists for group practice development at their facility. The advantages for hospitals include more effective recruiting and a more stable patient base. Among the disadvantages are the fact that groups give physicians a stronger power base from which to request concessions from the hospital and that a preponderance of group-affiliated physicians on staff may discourage referrals from nongroup physicians. A number of considerations are involved in preparing for and coordinating group practice development. In the planning stages open communication with physicians is critical. Physician leaders and a cross section of active staff should participate. Planners should discourage formation of "groups without walls," in which hospitals manage group practices of physicians who remain at different sites. A hospital may, however, choose group-like arrangements (e.g., limited partnerships) without necessarily promoting group practice. Hospitals may also help a group purchase a facility of its own or even create the facility and allow the group to build equity in it. PMID- 10115214 TI - Easing the strain. The physician and the long-term care facility should work together to improve patient care. AB - Numerous regulations, inadequate reimbursement, and poor communication can strain the physician--long-term care facility relationship. Three major roles define the physician's responsibilities in the nursing home: care giver, communicator, and complier. Although the physician's roles in the nursing home may be similar to those in an office practice, they can be complicated by a number of factors. Many professionals, such as the nutritionist, social worker, and pharmacist, care for the nursing home resident. The physician thus loses some control over the patient's care. Communication barriers, such as the nursing home's misinterpretation of federal regulations, can frustrate both the physician and the facility's medical staff. This can lead to suboptimal patient care. Nursing homes must ensure that they keep physicians who treat residents abreast of facility regulations and federal and state guidelines. Although a physician may want to continue providing care to a patient who has entered a long-term care facility, he or she may find it necessary to transfer care to the medical director or house physician. Often the time and distance a physician must travel prohibit the physician from giving patients the high-quality care to which they are entitled. PMID- 10115215 TI - A focus on common needs. CHA's physician-facility project looks at future directions in healthcare. AB - Physicians and administrators of healthcare facilities lack integrated planning and decision-making processes, trust and confidence in each other, and a professional sense of satisfaction. A focus on common needs and interests is necessary to get the relationship on the desired track in the future. In 1989 the board of directors of the Catholic Health Association (CHA) created a special study group to review and develop recommendations on the relationships between physicians and healthcare organizations. The study group has addressed issues causing stress in these relationships, future changes in healthcare delivery that could affect these relationships, support CHA might provide, and ways to promote emphasis of these relationships and related issues among CHA members. The study group decided that collaborative planning and decision making will be the keys to getting to the desired future. This integration must go beyond shared planning activities and involve some degree of shared economic risk. The study group's final report, to be disseminated in spring of 1992, will identify key issues that significantly affect the physician-facility relationship, include resource materials to assist local organizations in assessing that relationship, and recommend ways to change the relationship through education. PMID- 10115216 TI - Putting the poor first. A system's assessment project identifies community needs. AB - To enhance its mission of promoting compassionate and high-quality holistic healthcare to all people, especially the poor and underserved, Franciscan Health System (FHS), Aston, PA, launched the Service Area Needs Assessment (SANA) project in 1990. The project focused on population segments who live in the most economically deprived ZIP codes within member hospitals' service areas. SANA coordinators surveyed FHS hospitals about their programs and services for the poor and underserved and documented the programs' scope, value, and benefit to the community. When hospital personnel learned the results of the survey, they felt encouraged to interact with one another and learn more about their facilities' contributions to care for the poor and underserved in their communities. SANA coordinators and team members then interviewed community agency representatives, physicians, other service providers, and community residents. The agencies and healthcare providers identified several unmet needs that residents verified. However, the interviews revealed a gap between what providers think the problems of the poor are and what these individuals themselves believe their problems to be. As a result of these interviews, several hospitals have established programs to meet the identified needs. Of the 33 initiatives proposed, 16 represent new activities, 10 represent expansion of existing activities, and 7 represent collaboration with other organizations on new and existing programs. FHS believes the SANA project is just the beginning of a renewed commitment to caring for the poor and underserved. PMID- 10115217 TI - Creative fund-raising for nursing homes. An additional revenue source in tough economic times. AB - Nursing home administrators and sponsors should look to fund-raising as a way to increase their facilities' revenues. The board should first appoint a development coordinator and a special board to be responsible for the fund-raising program. The nursing home can reach potential contributors by regularly sending printed material to specially selected persons from its mailing list. The staff must know the procedures to follow when someone wants to make a donation (e.g., to whom the check should be made payable). To generate interest and to motivate contributors, the fund-raising board should identify specific needs for which the contributions will be solicited. A computer program can help keep track of to whom acknowledgements must be sent. Options for a fund-raising program include memorial and honor gifts, gifts in kind, grants and special gifts, special events, deferred gifts, educational programs, and membership clubs. PMID- 10115218 TI - Making IT work. PMID- 10115219 TI - Strategic management of human resources. PMID- 10115220 TI - Sisters of Charity of Leavenworth Health Services Corporation. Clinics for the uninsured. PMID- 10115221 TI - Catholic Healthcare West. Investing in community strength. PMID- 10115222 TI - Mercy Health Services. Joining forces for community service. PMID- 10115223 TI - Sometimes it's no accident. PMID- 10115224 TI - Unscheduled admissions within 84 hours of an outpatient visit: a measure of ambulatory care quality? AB - The occurrence screen, unscheduled medical or surgical admission within 84 hours of an outpatient visit, was found not to be useful in assessing quality of care or in suggesting actions to improve quality. A main finding of this study was the rather high percentage (69%) of episodes in which the reason for unscheduled admission was an exacerbation of a problem that could not be anticipated at the time of the outpatient visit. The quality of care at most institutions is likely to be high enough that alternative approaches to assessing and improving quality are recommended. PMID- 10115226 TI - Physician recruitment and retention in community health centers. AB - The common denominator for the problems of recruitment and retention of physicians is the lack of finances. There is considerable overlap between the etiology of and possible solutions to the two problems. Funding may not be available to address the financial situation immediately, so other avenues have to be explored. It is possible for both these issues to be addressed by a single model involving the development of a centralized recruiting agency. CHCs would be promoted and marketed more efficiently, and physicians would be selected who are more likely to consider community medicine a long-term career choice. PMID- 10115225 TI - Toward internal medicine day care: estimating need and cost savings. PMID- 10115227 TI - Predicting post-hospital discharge health care costs. AB - Patients in this study represented an important group for health services research; their postdischarge costs were high, resulted from readmissions (especially for nonelective reasons), and were incurred by a minority of patients. Moreover, intensive interventions delivered by ambulatory care providers has the potential to reduce overall costs if patients at highest risk for readmission could be identified prospectively (Smith et al., 1988; Weinberger et al., 1988). We developed a model to predict post-hospital discharge costs in these patients using strategies to maximize their predictive capability. Although the model appeared to account for more variance in costs than currently available models in the derivation set, its performance in the validation set, albeit statistically significant, was disappointing. Because we considered a broad array of predictors, expanding the number of patient-oriented variables may not be fruitful. Instead, future research may need to consider more homogenous subgroups of patients in whom specific laboratory tests would have clinical significance; variance in providers' behaviors; and studies in health maintenance organizations, where control over resource utilization may make costs more predictable. Finally, empirically derived models must be tested in an independent sample. Without validating predictive models, the models' ability to predict health care costs may be overestimated. PMID- 10115229 TI - Joint costs in health care: application to blood component production. PMID- 10115228 TI - Emphasizing screening activities in a community health center: a case study of a breast cancer screening project. PMID- 10115230 TI - Ambulatory care and the law: the murky waters of employment physicals. PMID- 10115231 TI - Changes in knowledge and attitudes following implementation of a structured ambulatory quality assurance system. PMID- 10115232 TI - Ambulatory care in nursing homes: an emerging problem. PMID- 10115233 TI - Antitrust challenges by allied health care professionals involving hospital staff privileges. PMID- 10115234 TI - Emergency rooms: the triage metaphor error. PMID- 10115235 TI - Patient Self-Determination Act requirements. PMID- 10115236 TI - Analyzing learner problems. PMID- 10115237 TI - The role of staff development during a staff reduction: one hospital's experience. PMID- 10115238 TI - Good training is good communication. PMID- 10115239 TI - Building a professional reading program for the health care educator. PMID- 10115240 TI - Organizational/office politics training: a managerial necessity. AB - The ability of managers to succeed in health care organizations depends in part on their "political" skills. Memorial Hospital of South Bend, a 526-bed tertiary care facility, supports the professional development of its managers and secretarial staff by offering an in-service program to (1) sensitize participants to the need for political skills, (2) suggest techniques to succeed politically, and (3) emphasize the importance of ethical political actions. The in-service is upbeat and concrete and focuses on solving real problems of participants. This article has described an in-service program that was taught to over 250 managers and secretarial staff from 1985 to 1989. PMID- 10115241 TI - Competencies necessary to conduct patient and self-care education in the medical setting. AB - The education of patients has recently taken on increasing importance in the medical community due to the following factors: The escalation in the costs associated with health care The competition for patients The realization that it is wiser to prevent illness and disease than to treat them once they occur The recognition that patients need to access the health care system less frequently if they know how to provide self-care This article presents the rationale for patient and self-care education. It also describes the settings in which patient and self-care education occur, with particular emphasis on private practice medical care. Specific guidelines for the selection of patient educators are also recommended. Finally, implications of the adoption of these recommendations are explored. PMID- 10115242 TI - It doesn't pay to get too cozy with a hospital. PMID- 10115243 TI - Earnings in primary care: which doctors do best. PMID- 10115244 TI - Minnesota providers announce deal. PMID- 10115245 TI - Post-surgical recovery-care center operators in California might seek acute-care licenses. PMID- 10115246 TI - Cuomo's deficit-reduction plan for N.Y. cuts a swath through provider payment. PMID- 10115247 TI - Hospital payment deregulation clears Massachusetts' House. PMID- 10115248 TI - Report: research a must to find customers' needs. PMID- 10115249 TI - Md. raises rates to cover bad debts. PMID- 10115250 TI - FTC investigating whether lithotripsy deal in Memphis adds up to monopoly. PMID- 10115251 TI - Medicaid-tax wrangling goes down to the wire. PMID- 10115252 TI - Wash. settlement to boost payments 10%. PMID- 10115253 TI - Legislators use bills to put long-term care in public eye. PMID- 10115254 TI - Dr. Sullivan, we don't need another panel on computers. PMID- 10115255 TI - Too many cooks batter technology assessment. AB - The bustling activity and interest in technology assessment obscures two growing problems. More than 70 groups, sporting a variety of agendas, are involved in assessing new devices, drugs and procedures; variations in the information they seek or the methods they use sometimes produce findings that conflict or can't be compared. PMID- 10115256 TI - Patient care gets most of AIDS budgets. PMID- 10115257 TI - Shock therapy: Texas inspects psych facilities. PMID- 10115258 TI - 45 hospitals don't get reclassification buffer. PMID- 10115259 TI - Report views imaging equipment trends. PMID- 10115260 TI - Hospitals signing onto data bases to help set sights as they target potential patients. AB - Hospitals are beginning to improve the focus of their marketing efforts by using information they already have--from billing records, physician referrals and patient visits to urgent-care centers. Such data bases help spot potential repeat customers. Tactical marketing has been practiced in other industries for years, but it's relatively new to healthcare. PMID- 10115261 TI - Software upgrade can end with hard landing. AB - A hospital's plan to switch over to the latest version of software for its information systems often can result in a nasty surprise--the facility's hardware isn't up to the task, and the solution will cost a bundle, often hundreds of thousands of dollars. Providing your vendor with thorough and precise data can help avoid such pitfalls. PMID- 10115262 TI - Program allows Ill. providers to cash in Medicaid receivables. AB - The Illinois Health Facilities Authority soon will start a $100 million commercial paper program that will use a pool of Medicaid receivables from hospitals and nursing homes to back the issue. The plan is designed to provide money to improve cash flow at facilities facing long delays in reimbursement for Medicaid patients. PMID- 10115263 TI - Century Healthcare selling facility, restructuring loans. PMID- 10115264 TI - Exec turnover hinders United Medicorp turnaround. PMID- 10115265 TI - Foundation Health to manage Medicaid care in Mass. PMID- 10115266 TI - AHA policy paper pushes community-care networks. PMID- 10115267 TI - Comprehensive plan offered for R.I. seniors. PMID- 10115269 TI - Healthcare costs eat 12% of family income--report. PMID- 10115268 TI - AmHS proposal sets short-term, long-term goals. PMID- 10115270 TI - Rochester, N.Y., experiment makes $4.2 million payback to the federal government. PMID- 10115271 TI - AMA OKs patient testing without specific consent. PMID- 10115272 TI - Six systems drop QMMP sponsorship. PMID- 10115273 TI - PhyCor plans stock offering to raise $28 million for group practice acquisitions. PMID- 10115274 TI - OMB seeks $4 billion in Medicare restraints. PMID- 10115275 TI - Medicare margins fall to -3.4% in fiscal '90. PMID- 10115276 TI - Dems aim reform pitch at public. PMID- 10115277 TI - IRS on firm ground in asking if projects merit tax exemption. PMID- 10115278 TI - The hospitals' enemies are out there--or are they? PMID- 10115279 TI - Troubled times for psych hospitals. AB - Horror stories of patient abuse and unscrupulous practices at some psychiatric hospitals have made the public skittish and prompted a growing number of governmental inquiries. One observer says the industry is in "free fall" while others say it's just a normal bust following the boom of the 1980s. Regardless, the negative publicity and other trends are reshaping the psych-care industry. PMID- 10115280 TI - Congressional panel wants FTC antitrust probe documents. PMID- 10115282 TI - Mulling PACS? start small. PMID- 10115281 TI - Mixed views on wound product. AB - Wound-care management has developed into a $2 billion market, and some hospitals are turning to Procuren, a product that uses a patient's own blood platelets to stimulate healing. However, some physicians are skeptical that it's the wonder drug that it's portrayed to be. PMID- 10115283 TI - Radiology system uses Unix. PMID- 10115284 TI - AMA toughens guidelines on physician self-referrals. PMID- 10115285 TI - 2 Southern Calif. facilities mull affiliation. PMID- 10115286 TI - AHA downplays effects of IRS venture ruling. PMID- 10115287 TI - Finance authorities fighting pooled program. PMID- 10115288 TI - Albert Einstein buoyed by debt upgrade. AB - Albert Einstein Medical Center is going against the trend, gaining a debt upgrade from Moody's Investors Service. The rise to an A rating from Baa1 was accomplished by only two facilities in all of 1990, and only 14 institutions overall enjoyed rating upgrades, Moody reported. PMID- 10115289 TI - HealthTrust raises $560 million in initial public offering of stock. PMID- 10115290 TI - IG to audit Humana facility in Texas to study pricing. PMID- 10115291 TI - $5.4 million settlement reached in lawsuits against HealthVest, Healthcare International. PMID- 10115292 TI - Charter reports $130 million loss for year. PMID- 10115293 TI - Conflicting reports on HealthPASS. PMID- 10115294 TI - Blues taking part in testing of new breast cancer treatment. PMID- 10115295 TI - VHA sues insurers that refuse to pay $8.4 million settlement. PMID- 10115296 TI - Judge's ruling a good signal for Calif. nursing homes. PMID- 10115297 TI - PRO's pink slip leaves bills 'up in the air'. PMID- 10115298 TI - Despite protests, IHA to continue selling physician, patient data. PMID- 10115299 TI - N.Y. ordered to release physicians' mortality rates. PMID- 10115300 TI - Bush team sketches health reforms for State address. PMID- 10115301 TI - HCA announces plans to go public again. PMID- 10115302 TI - 2 groups want probe of JCAHO. PMID- 10115303 TI - A public hospital fights back. PMID- 10115304 TI - Profitable public hospitals. AB - Public hospitals, the "safety net" for the poor and uninsured, are typically overwhelmed and under-reimbursed, but some have managed to stay out of the red. What's their secret? An analysis conducted for Modern Healthcare shows what profitable public hospitals have in common, and some of the steps administrators are taking to offset the burden of indigent care. PMID- 10115305 TI - Steelman advisory panel can't reach a consensus on health system reform. PMID- 10115306 TI - Uninsured, Medicaid rolls show big jump. PMID- 10115307 TI - Has battle for business carried a cost? AB - A diversity of opinion surrounds that question. National Research Corp. found a range of answers among hospital CEOs, consumers, employers and physicians. Most hospital administrators believe competition's helped; most employers aren't so sure. But as for costs, administrators believe competition has accelerated expenses, not slowed them down. PMID- 10115308 TI - The year in review. AB - In the waning days of 1991, it's time to pause and reflect about the stories that had a big impact on the healthcare industry this past year. Modern Healthcare's staff was polled on the top 10 stories of the year; the results and a recap of those events help put this tumultuous year in perspective. PMID- 10115309 TI - Fairview buys second half of Minneapolis medical center. PMID- 10115310 TI - Humana's earnings flat in first quarter. PMID- 10115311 TI - 'States lag in regulating self referrals.'. AB - Physician ownership, which is getting plenty of attention from federal regulators and lawmakers, remains a largely unregulated activity at the state level, according to a study obtained exclusively by Modern Healthcare. Even in states with statutes dealing with such issues, the language of the laws often is vague and enforcement is lacking. But some states have enacted tough legislation, and more are likely to follow. PMID- 10115312 TI - Are small groups riskier? Study seeks answers. PMID- 10115313 TI - Approval of age-based Medigap premiums a victory for western Pennsylvania Blues. PMID- 10115314 TI - Texas Children's divides off--and conquers. PMID- 10115315 TI - NME restructuring: PIA, Rehab titles out. PMID- 10115316 TI - Sued Fla. hospitals seek to keep prices secret. PMID- 10115317 TI - Cleveland Clinic's disclosure stance irks investors. PMID- 10115318 TI - Conn. hospitals now required to pay into charity-care fund. PMID- 10115319 TI - Hospital catering: for profit or not for profit? AB - When hospitals today hold budget meetings, the typical foodservice operation contributes more than the coffee and doughnuts. Many have found new dollars as well as positive public relations by offering catering programs. Southwest General Hospital, Cleveland, is one example. PMID- 10115320 TI - Feminism and bioethics: an overview. AB - Despite differences in style, tone, and emphasis, the various schools of feminist thought share a primary concern with the stories and lives of women. This concern gives them distinctive perspectives on medical practice and the field of bioethics. PMID- 10115321 TI - Providers offer prescription for Medicaid drug-pricing law. PMID- 10115322 TI - CEO firings: warning signs of unhappy boards. PMID- 10115323 TI - Investing limited capital funds. PMID- 10115324 TI - Nurses seek expanded role in quality improvement process. PMID- 10115325 TI - Getting the right people involved in medical staff planning. PMID- 10115326 TI - Risk management--the next step after D&O insurance. PMID- 10115327 TI - Trustees who make a difference to health care. PMID- 10115328 TI - Picking a medical plan. PMID- 10115329 TI - Large washer roundup. A look at the selection of washers or washer-extractors rated at 100 lbs. or more that are currently on the market. PMID- 10115330 TI - Bed management in today's health care environment. PMID- 10115331 TI - Draw the line in the sand: the billable admission standard. PMID- 10115332 TI - Impact of new technologies in healthcare. PMID- 10115333 TI - Launching an ethics committee. Issues & answers. PMID- 10115334 TI - If QA does not equal QI: will QAPs become obsolete? PMID- 10115335 TI - No surprises! Mastering the art of the survey--Part 2: Presentation, posture, and post-survival. PMID- 10115337 TI - Reducing your investment in accounts receivable. PMID- 10115336 TI - Constructing a new agenda. PMID- 10115338 TI - Causes of health insurance increases. PMID- 10115339 TI - 1990 giving to hospitals. PMID- 10115340 TI - RBRVS effects. PMID- 10115341 TI - King Khalid University Hospital Drug and Poison Information Service. A descriptive report and comparison with the University of Minnesota Drug Information Center. AB - During the first four years of its existence, the Drug and Poison Information Service at King Khalid University Hospital established itself as an integral part of the clinical pharmacy program and was appreciated by the medical staff. In terms of references and request categories it was similar to the UMDIS. Differences result from dissimilar formularies and a large number of physician inquiries, as opposed to the large number of consumer inquiries received at the UMDIS. PMID- 10115342 TI - Pharmacy technician competency. Part II: Study design, hypotheses, and results. PMID- 10115343 TI - Impact of a clinical pharmacist on antibiotic prescribing. A multicenter trial. AB - Within the past two decades, hospital pharmacists have become increasingly involved in providing consultation to physicians for drug management. Antibiotic use has become a complex and rapidly expanding discipline, complicated by the introduction of multiple new antimicrobial agents, each with unique features, and the pressures of prospective payment schemes. This study demonstrated that a team including a pharmacist had a positive impact on medical residents' utilization of antibiotics. PMID- 10115344 TI - Referrals from outside sources. PMID- 10115345 TI - Managed care: forging external partnerships. PMID- 10115346 TI - The Ohio Hospital Association: its history and mission in the management of healthcare receivables. PMID- 10115347 TI - Government and employee cost containment initiatives a provider squeeze play! PMID- 10115348 TI - Could you tell me the name of a good doctor? PMID- 10115349 TI - Admitting Nurses Association--its growth and importance. PMID- 10115350 TI - The hospital/nursing home connection. PMID- 10115351 TI - Physicians' offices: partners in healthcare. PMID- 10115352 TI - Maximizing the performance of your real estate assets. PMID- 10115353 TI - The patient focus in quality care. PMID- 10115354 TI - Medicine behind the Iron Curtain. PMID- 10115355 TI - The expert witness in malpractice suits. AB - This survey of 1,097 Fellows resulted in usable data from 336 surgeons, of whom 129 had claims (n = 212) against them from January 1, 1984, through December 31, 1989. Risk by specialty varied greatly, but population of practice area seemed unimportant. Plaintiff expert witnesses could be identified by 28 surgeons; four of these were from medical school faculties. Defense expert witnesses were identified by 37 surgeons, 18 of whom were from university faculties. We were unable to identify any repeat "itinerant" plaintiffs' expert witnesses from this five-year period in Tennessee. It seems obvious that surgeons, even those who have been sued, pay little attention to even the identification of opposing expert witnesses. PMID- 10115356 TI - Coding for evaluation and management services. PMID- 10115357 TI - Abnormal occurrences for second quarter CY 1991; dissemination of information- Nuclear Regulatory Commission. PMID- 10115358 TI - Cost of hospital and medical care and treatment furnished by the United States; certain rates regarding recovery from tortiously liable third persons--Office of Management and Budget. PMID- 10115359 TI - Medicare program; swing-bed program changes--HCFA. Final rule. AB - This final rule responds to comments we received on an interim final rule relating to hospital swing beds that was published on September 7, 1989 (54 FR 37270). The interim rule expanded the swing-bed program to encompass rural hospitals with 50 to 99 beds. It established requirements that approved swing-bed hospitals with more than 49 beds must meet. This rule establishes the interim rules as final regulations with changes. These changes are based on our review and consideration of the public comments. PMID- 10115360 TI - Labor condition applications and requirements for employers using aliens on H-1B visas in specialty occupations--Department of Labor. Interinal final rule; request for comments. AB - The Employment and Training Administration (ETA) and the Employment Standards Administration (ESA) of the Department of Labor (DOL or Department) are promulgating regulations governing the filing and enforcement of labor condition applications filed by employers seeking to use aliens in specialty occupations on H-1B visas. Under the Immigration and Nationality Act (INA), as amended by the Immigration Act of 1990 (Act), an employer seeking to employ an alien in a specialty occupation on an H-1B visa is required to file a labor condition application with, and receive the approval of, DOL before the Immigration and Naturalization Service (INS) may approve an H-1B visa petition. The labor condition application process will be administered by ETA; complaints and investigations regarding labor condition applications will be the responsibility of ESA. PMID- 10115362 TI - Statement of organization, functions, and delegations of authority--HCFA. PMID- 10115361 TI - Participation in the National Practitioner Data Bank--Department of Veterans Affairs. Final rule. AB - This rule sets forth the policy of the Department of Veterans Affairs (VA) for participation in the National Practitioner Data Bank (Data Bank). VA will request information from the Data Bank concerning physicians, dentists and other health care practitioners who provide or seek to provide health care services at VA facilities and will also report information to the Data Bank regarding malpractice payments and adverse clinical privileges actions. The intended effect of this policy is to participate in the Data Bank for the purpose of promoting better health care at VA and non-VA health care facilities. PMID- 10115364 TI - Office for Civil Rights; statement of organization, functions and delegations of authority--HHS. PMID- 10115363 TI - Medicaid program; State share of financial participation--HCFA. Interim final rule with comment. AB - On September 12, 1991, we published in the Federal Register an interim final rule with comment entitled "Medicaid Program; State Share of Financial Participation" (56 FR 46380). It dealt with the use of State taxes and provider donations as the State share of the costs of the Medicaid program. Because of misunderstanding created by certain portions of that rule, we are publishing this interim final rule to withdraw and cancel it and to set forth a clearer interim final rule on donations and taxes. PMID- 10115365 TI - Indian Health Service; statement of organization, functions, and delegations of authority--PHS. PMID- 10115366 TI - What is death with dignity? PMID- 10115367 TI - Catholic health ministry into the '90s. PMID- 10115369 TI - Living will and durable power of attorney. PMID- 10115368 TI - Evaluation: risky yet necessary. PMID- 10115371 TI - Project Re-Connect wins 1991 Eleanor Clark Award. PMID- 10115370 TI - Discharge planning: a bidisciplinary model. PMID- 10115372 TI - Financing Medicaid: new problems. PMID- 10115373 TI - Discharge planning: shared-governance model. PMID- 10115374 TI - Catastrophic illness: challenges and opportunities. PMID- 10115375 TI - Defibrillation training. PMID- 10115377 TI - The infection connection. Help wanted. PMID- 10115376 TI - Rural ALS? PMID- 10115378 TI - Consultants' plans marry the best of two existing hospitals. AB - Planning for a new hospital facility takes more than the approval of the board and guidance from the CEO. In the world of high technology, such designing requires the services of outside architects and planners. In the following article, the principals involved in the Delnor-Community Hospital project discuss how two facilities came together under one concept--and roof! PMID- 10115379 TI - Hybrid approach offers option for long term older adult care. AB - Hospitals in the future will be called on increasingly to administer to the medical needs of an aging population. But what are alternative forms of care beyond nursing homes and what must hospitals do to position themselves with those alternatives? In the following article, the author discusses the advantages of a "hybrid approach" to caring for older patients. PMID- 10115380 TI - TQM is key to improving services, but it's not for every hospital. AB - Total Quality Management (TQM) is a term that has been known to the manufacturing industry for years. Now the concept is finding its way into the vocabulary of the hospital industry as well. How can TQM positively affect systems in a health care institution? What can administrators expect from it? In the following article, the vice president of medical affairs at a Milwaukee hospital discusses the pros and cons of TQM. PMID- 10115381 TI - Marketing to managed care groups challenges hospitals. PMID- 10115382 TI - Planning indicators. Construction cost vary by location, formula. PMID- 10115383 TI - New facility builds on experience. AB - Combining two older hospitals into one centralized facility requires consummate planning on the part of administrators, architects and outside consultants. When Delnor-Community Hospital in Geneva, Ill., opened the doors to its $38 million facility in August, it was the culmination of at least five years of planning. In the following interview with Health Care Strategic Management's Donald E.L. Johnson, Craig Livermore, Delnor's president and CEO, discusses the construction and planning needs of this new 118-bed institution. PMID- 10115384 TI - Special report on reimbursement. The safe harbor for small investment interests: where do joint ventures go from here? AB - There is no specific federal self-referral legislation presently proposed or in effect that statutorily prohibits providers from referring Medicare or other patients to entities in which the referrers have an investment interest, except for existing "Stark" legislation, which applies only to clinical laboratory services, effective January 1, 1992. (See Newsletter, Vol. 6, No. 1, January 1991, at 3.) Thus, health care joint ventures are not per se illegal. The publication of the Safe Harbor Regulations does nothing to change this fundamental fact, and it should not cause providers to abandon existing joint ventures, or planned ones, in a "knee-jerk" fashion, without careful analysis. Of course, there is no guarantee that expanded "Stark" legislation, or some other new self-referral legislation, will not be enacted in the future to prohibit providers from referring patients to entities in which they have an investment interest. Because of this uncertainty, all health care joint ventures should contain "unwinding" provisions to govern the rights and obligations of investors in the event that the venture is required to, or the participants voluntarily elect to, dissolve. Any new venture being contemplated should plan for dissolution, and existing ventures should undertake an internal review of their charter documents to assess whether the rights and duties of all participants upon dissolution are properly spelled out. If not, amendments should be made now, while all participants are on good terms. A failure to agree in advance upon such important issues is an invitation to discord, and possibly even litigation. PMID- 10115385 TI - Hospitals seen as growing targets of sexual harassment complaints. PMID- 10115386 TI - Special report. Integrated access control systems in hospitals: an update. AB - Voice-activated doors. Magnetic card access systems. Covert video cameras. CCTV with motion detectors. When it comes to integrated access control, there are plenty of devices available. But do they work well in hospitals? Are they worth the money? In this report, we'll review how the new technology is being used at a number of facilities, and present some tips from security directors experienced in such use on problems to anticipate and avoid. PMID- 10115387 TI - Plan ahead for time off. PMID- 10115388 TI - Plan for employees remaining after downsizing. PMID- 10115389 TI - Home is where the hospital is. PMID- 10115390 TI - Tragic legacy of the wards in isolation. PMID- 10115391 TI - Who's going to foot the bill? PMID- 10115392 TI - Next move for Hungary. AB - After 40 years of communism, Hungary is a tired nation. But now an enormous task faces its government; bringing its antiquated healthcare system into line with those of western Europe. Annabelle May reports from a conference in Budapest. PMID- 10115393 TI - Masters of change. PMID- 10115394 TI - All singing, all dancing. AB - There is widespread dissatisfaction with IPR among private sector managers as well as in the NHS, and organisations need to develop a more holistic approach, say Michael Pounsford and Deborah Rowland. PMID- 10115395 TI - Open to suggestions. AB - A survey of patients' attitudes to GP opening hours produced strong evidence for extending surgery times for patients' convenience and to meet specific health needs, say Chris Atkinson and Marjorie Gardner. PMID- 10115396 TI - Forecasting and analysis. Can you believe the oracle? PMID- 10115397 TI - Off the shelf. PMID- 10115398 TI - Scale models. PMID- 10115399 TI - Down and out in the West Midlands. AB - The privatisation of Qa Business Services caught the spirit of the Thatcherite times. Eighteen months later it is in the hands of the receivers. Gren Manuel tells the tale of its decline and fall. PMID- 10115400 TI - How children could be seen and still heard. PMID- 10115401 TI - Trusts in the ballot box. AB - The general election campaign will arouse yet more furious debate between Labour and the Conservatives over whether or not the NHS is being privatised. Joe Jacob examines the statutes to show that both sides are likely to be right--and wrong. PMID- 10115402 TI - 'Sometimes it makes you frightened to go to hospital ... they treat you like dirt'. AB - This attitude to mainstream healthcare is typical of homeless people, who prefer services located within their own landscape. Peter Shiner and Say Leddington describe a survey which let homeless people tell their own story. PMID- 10115403 TI - Street plans. AB - Research shows that homeless people have greater health needs than other groups, and service planners must take account of this as they allocate resources, writes Mary Ann Sheuer. PMID- 10115404 TI - Thumbs down for Oregon rations. AB - Although three out of four people want the NHS to continue providing a comprehensive service, they are evenly divided about paying more for it. Peter Davies reports on the Journal's seventh annual opinion poll findings. PMID- 10115405 TI - Hidden bounty for the NHS. PMID- 10115407 TI - To market to market.... AB - There are clear parallels between the problems of industrial firms in eastern Europe and those faced by NHS managers in meeting the challenge posed by the internal market. Stuart Cumella looks at the ever-changing rules of the game. PMID- 10115406 TI - Happy ever after? AB - Health authorities are responding to the NHS reforms with a variety of approaches to joint purchasing, some in collaboration with FHSAs. Chris Ham and Chris Heginbotham explore the future of these relationships. PMID- 10115408 TI - The singers, not the song. PMID- 10115409 TI - Let them eat soap. Radical Statistics Health Group. PMID- 10115410 TI - Money well spent. PMID- 10115411 TI - Developing a drug usage evaluation program. AB - One of the goals of the University of Illinois Hospital and Clinic's Pharmacy and Therapeutic Agent Review Program is to monitor and evaluate prescribing practices for drugs used in their facilities and to comply with Joint Commission standards with regard to conducting drug usage evaluations (DUE). Presented below is an overview of each step taken in the DUE process at the University of Illinois. The process described here can be adopted by other institutions that wish to improve their own DUE program. PMID- 10115412 TI - Impact of a revised pediatric parenteral nutrition order form. AB - At the University of Maryland Medical System, a utilization review was conducted to evaluate the usefulness and effectiveness of a revised order form for pediatric parenteral nutrition. The results of this review are presented below. PMID- 10115413 TI - Patient care redesign is badly needed. PMID- 10115415 TI - Work, work, work! PMID- 10115416 TI - Keeping the flame alive. Seven steps to remedy burnout. PMID- 10115414 TI - Rationing healthcare: crisis and courage. PMID- 10115417 TI - Scenes from St. Francis. PMID- 10115418 TI - Don't wait for the crisis. Finding the paradigm in the pattern. Interview by Joe Flower. AB - Joel Barker has been talking about the future for a long time past. His message: Change happens. Change happens as paradigms shift--the way we picture the universe shifts, and life is different. Relationships and values change their meaning. And because they mean something different, we change them. Barker's question is: How do you manage this change? How do you get ahead of it, and not lag behind it? How do you become its partner and not its victim? These are challenging questions, and hundreds of corporations have invited Barker to come ask them. His client list ranges over much of the Fortune 500--from IBM and DuPont to Honeywell, Boeing, and Gulf Oil--and it includes such healthcare clients as Merck, Upjohn, the Mayo clinics, and the Sisters of Charity. Barker has worked with these questions for the past 17 years, first as director of the pioneering Future Studies Department of the Science Museum of Minnesota, then as president of Infinity Limited, Inc. He has put his answers into a video, "Discovering the Future," and two books, the 1985 Discovering the Future: The Business of Paradigms, and the new Future Edge: The Paradigm Principles Guide for the '90s. We spent a recent morning talking with him about what a paradigm is, and what happens when a paradigm shifts. PMID- 10115419 TI - Strategic thinking and the road to relevance. PMID- 10115420 TI - Managing resource use. PMID- 10115421 TI - Patient satisfaction pilot reveals gains and limits. PMID- 10115422 TI - Principles for funding on a case mix basis: construction of case weights (RIWs). AB - The construct of Resource Intensity Weights (RIWs) contains implicit financial incentives if they are used for hospital funding purposes. This paper compares the RIW (funding) credit to the expected average per diem cost for each of the new subcategories (typicals, deaths, transfers, signouts and outliers) of Case Mix Groups (CMGs). RIW construction, and inherent incentives for a hospital to reduce costs or length of stay (LOS), differ significantly for each subcategory. At some point or points in a patient's LOS, when RIW credit equals case cost, RIWs are incentive neutral. However, it can also be demonstrated that RIW credit is not generally congruent with average costs on each day of a patient's stay. Financial incentives (both positive and negative) arise when RIW credit and costs differ. Only by being fully aware of these differences can hospitals determine how to respond to the introduction of case mix funding to maintain financial viability. Funding agencies, too, need to appreciate the sometimes subtle policy implications that come with the adoption of RIWs for funding purposes. PMID- 10115423 TI - Ontario's hospital transitional funding initiative: an overview and assessment. AB - In 1989, the hospital transitional funding initiative, which incorporates case mix measurement into the hospital funding process, was started in Ontario. This initiative is the beginning of a new, more objective basis for determining hospital funding. In its initial stages, incremental growth and interhospital equity adjustments are made to the global budgets. In this paper, we describe the launching of this initiative and the funding formulas that emerged from its first phase. The issue of incentive effects is then discussed and, as this is an evolving or "transitional" undertaking, we comment on several economic issues arising as a result of this new venture. PMID- 10115424 TI - Innovative revenue generation. AB - Innovative revenue generation by Canadian hospitals is drawing increasing attention. After a critical examination of the literature, we classified these into six areas: clinical/diagnostic insured services, clinical/diagnostic non insured services, hotel services, retail services, administrative services and financial activities. We concluded that many Canadian hospitals are engaging in innovative revenue generation activities, the success of such activities has been mixed, there are many factors to consider when selecting revenue generation activities, many aspects of innovative revenue generation involve sophisticated business and risk management skills not traditionally required in hospital management, and implementation of many such activities requires support from the hospital board, hospital staff and medical staff. PMID- 10115425 TI - Guidelines for strategic information planning. AB - Developing a strategic information plan is an essential step for companies that want to realize the advantages of today's information technology. This article discusses ways to avoid the pitfalls that frequently occur during stages of information planning. PMID- 10115427 TI - A strategy for executive staffing. PMID- 10115426 TI - The power of partnerships. AB - Increased competition, especially from foreign competitors, and the rising cost of technology have forced companies to seek out strategic alliances. A growing number of firms have learned to reap the benefits--while avoiding the pitfalls- of partnering. PMID- 10115428 TI - Sharps container prices hold firm due to competition. PMID- 10115429 TI - Pacemaker fraud compels hospital vendor scrutiny. PMID- 10115430 TI - Munroe Regional to standardize pacemakers. PMID- 10115431 TI - "Battle of the Forms": a materials management paper chase with legal consequences. AB - One of the problem areas most often discussed by hospital materials managers at seminars and study sessions is what is commonly known as "The Battle of the Forms." This situation arises from the exchange of purchase and sale documents between hospitals and suppliers. In this dialogue, Dr. Decker reviews the problem and offers some suggestions for dealing with it. PMID- 10115432 TI - Advancing your career in clinical engineering or biomedical technology. AB - Career advancement options available to the aspiring biomedical technician, clinical engineer or supervisor are described. "Paths" to professional development include: obtaining additional education, getting certified, joining professional associations, finding a mentor, on-the-job training and improving working style. Suggestions are offered on how to start this process in one's own career. PMID- 10115433 TI - The BMET (biomedical equipment technician) career: academic curricula, hospital needs, & employee perceptions. AB - Research conducted over a two-year (1988-1989) period compared the concepts of job performance of Biomedical Equipment Technicians (BMETs) with the job descriptions and academic requirements of healthcare organizations and the current academic curricula used to teach biomedical equipment technology. This study indicated that, while the BMETs and healthcare organizations held similar views of job performance requirements, there was disparity concerning the BMET's academic requirements as viewed by healthcare organizations when compared to the BMET's perception of academic preparedness. There was an even greater disparity between those perceptions and requirements when compared to the academic programs currently in place. PMID- 10115434 TI - Careers "Fact Sheets" for clinical engineering & biomedical technology. AB - Three Careers "Fact Sheets" include information on CE and BMET job titles, job descriptions, and certification. These materials are intended to aid in furthering professional recognition for Clinical Engineers and BMETs, and may be useful in communicating with Administration or Human Resources departments. PMID- 10115436 TI - Directory of local & regional biomedical organizations. PMID- 10115435 TI - Career tools: resume writing and the job interview. AB - A resume is one of the fundamental tools for career advancement, and it is successful when it results in a job interview. This article discusses job search preparation, the most effective resume styles, and how to use the job interview to convince an employer that you should be hired. Effective communication skills are stressed throughout the job search process. PMID- 10115437 TI - Pediatrics 2000: top 10 trends for children's health services in the 1990s. PMID- 10115438 TI - 1991 survey of the healthcare materiel management and central service professions. PMID- 10115439 TI - The essential materiel manager. AB - Pressures to control supply costs in hospitals will continue to escalate. As materiel managers we must become increasingly involved in analyzing and controlling these costs. This increased involvement will require significantly more cost and usage information, especially for non-stock items. It will also require skills to manipulate this information after it is obtained, and to perform meaningful analysis relating to the hospital's financial statements. Materiel managers must respond to these demands now. Training in hospital accounting, financial analysis and automation can be obtained from almost any community college. Additionally, most hospital CFOs will readily discuss these issues and can provide insight into the factors important in their respective institutions. By focusing on those factors which truly affect overall supply cost and inventory values, the materiel manager can assume one of the most significant management roles within the hospital. This role may include promotion into hospital administration or may simply include the expansion of the materiel manager's responsibilities. In either case, managers who assume responsibility for overall supply costs and who exhibit the skills needed to provide real answers will have carved themselves an essential niche in their institutions. PMID- 10115440 TI - Workforce literacy: do we have a choice? AB - Rapidly occurring demographic change and the demand for higher and higher skills in the workforce present a challenge for business and education. The investment the workplace makes in basic education for its employees will not only increase skills, but positively affect attitudes toward the employer, stimulate a desire for education and promotion and raise self-esteem. The rich mix of racial, ethnic and global experiences represented in today's workforce is a great potential advantage. We must face the question of best developing this potential for the future. Investment in personnel is not only worth-while--there is no other choice. We must not lose the opportunity. PMID- 10115441 TI - Modern central service management. PMID- 10115442 TI - Directory of education. AB - One of the most important tools to career building and personal satisfaction is education. And there are a wide variety of ways for you to get it. Some are available through your professional associations (see the "Directory of Associations" for more information on those), others are available through correspondence courses, on-site courses at local colleges, and from seminar programs of associations, vendors and seminar groups and still others are available in audiovisual formats. We've assembled a list of educational offerings that should be of interest to you and your colleagues. There may be others offered in your area, so contact your local institutions of higher learning to take advantage of what they have--or to develop a course with them! PMID- 10115443 TI - Directory of resources. PMID- 10115444 TI - Directory of federal offices. AB - This Directory of Federal Offices is an aid in your endeavors to obtain information from the federal government. It will hopefully eliminate some routing from one wrong department to another. Don't surrender if you don't succeed on the first try; the federal government spends billions of dollars on healthcare research and produces volumes of extremely valuable information. You simply need the secret to getting through the federal maze, and the information is yours. This directory lists major departments and offices, followed by their specific areas of expertise. It should help get you going in the right direction. PMID- 10115445 TI - Directory of associations. AB - Associations have proven to be valuable clearinghouses of information, centers for educational enrichment and switchboards for making connections between practitioners of a given profession. The healthcare central service and material management professions are represented by four associations: the American Society for Healthcare Central Service Personnel (ASHCSP), the International Association of Healthcare Central Service Materiel Management (IAHCSMM), the American Society for Hospital Materials Management (ASHMM), and the Health Care Material Management Society (HCMMS). Within these associations you will find groups of people who have interests and goals similar to yours. Pursue your interests together--join an association! PMID- 10115446 TI - 1991 corporate profiles. AB - We feel a very important part of the career development of any healthcare supply manager is knowing the companies you do business with. The following Corporate Profiles, which contain information about the mission, structure, background and products of leading companies in the healthcare field, are an excellent way to achieve this knowledge. PMID- 10115447 TI - Physician payment reform: how will medical specialties fare under the new Medicare fee schedule? AB - In 1989, the federal government legislated a major overhaul of the Medicare payment system for physician services, to be implemented beginning in January 1992. Under the new plan, payments will be set according to a national fee schedule based primarily on a "resource-based relative value scale." This article summarizes the development of the new payment system and explores the likely impact of its implementation on medical and surgical specialties. PMID- 10115448 TI - "Do not resuscitate" orders: the New York statutory model--Part II. AB - This is the second part of a two-part article examining the statutory framework in New York State for the issuance of DNR orders. Part I addressed the procedure for issuance of a DNR order. Part II discusses recent changes in the DNR legislation, including nonhospital DNR orders, and describes the statutory procedure for cancellation of a DNR order, the dispute mediation system, the role of the courts, the interrelationship of the DNR statute with statutory health care proxies, the effects of a DNR order, and open questions and conflicts under under DNR statute. PMID- 10115449 TI - Strategies for eliminating unfairness in peer review. AB - Physicians often find themselves the victims of uninformed peer review practices whereby hospital boards make decisions regarding medical staff privileges without adequately evaluating the charges and without affording physicians the appropriate due process protections. In addition to damaging a physician's reputation, such unfair review practices can lead to liability exposure and expensive and prolonged litigation. This article describes how medical staff physicians and hospital board members can avoid these problems by taking an active and informed role in the peer review process. PMID- 10115450 TI - Evaluating antitrust risk in joint provider negotiations with payors. AB - Health care providers who combine to jointly negotiate contracts with third party payors risk violating the antitrust laws and incurring liability. This article describes the types of scrutiny to which joint activities are subject and outlines a number of factors that should be considered in analyzing the degree of antitrust risk involved in any joint provider arrangement. PMID- 10115451 TI - Advance directives and health care proxies: recent developments in the law. AB - The last few years have brought rapid developments in the law regarding advance directives--both statutory and case law. This article provides an overview of these changes, including the recent amendments to the Medicare and Medicaid laws requiring hospitals and other institutional health care providers to inform adult patients and educate staff and the community about the availability and use of advance directives and the New York and Massachusetts statutes providing for the appointment of health care agents by proxy. PMID- 10115452 TI - Legislative and regulatory analysis. Final Safe Harbor regulations. PMID- 10115453 TI - The Medicare and Medicaid anti-kickback law: charting your safe harbors. AB - The Medicare and Medicaid fraud and abuse provisions create many potential pitfalls for physicians; navigating around these problem areas can be tricky. This article discusses recently published federal regulations providing "safe harbors" from the anti-kickback provisions of Medicare and Medicaid law, with particular emphasis on the more common relationships between physicians and hospitals. Those safe harbors that are most and least useful to the physician are highlighted, and advice is offered for evaluating the relative risks involved where no safe harbor is available or fully applicable. PMID- 10115454 TI - Hospital attempts to control physician practices must be resisted. PMID- 10115455 TI - Thoracoscopy may change the face of thoracic surgery. PMID- 10115456 TI - Making performance appraisals positive. PMID- 10115457 TI - Protocol for employees' exposure to patient's blood. PMID- 10115458 TI - Why use double-barrier sterile packaging? PMID- 10115459 TI - PPS Year 9 final rule published. PMID- 10115460 TI - Precautions minimize payment risks with foreign patients. AB - International patients offer another source of revenue for hospitals and a potential source of headaches for hospitals' patient accounts departments. Having a plan in place when dealing with foreign customers can help hospitals reduce risk and ensure complete payment. PMID- 10115462 TI - Medicare capital rules published. PMID- 10115461 TI - Courtesy can help diffuse patient complaints. PMID- 10115463 TI - Can psychiatric hospitals survive managed care? PMID- 10115464 TI - The impact of cost containment on psychiatric practice: implications and options. PMID- 10115465 TI - Directions in contracting for psychiatric services managed care firms. AB - An "irresistible force" has surely emerged in American healthcare; its name is Managed Care. It's a force embarked on an economic holy war, fired by the passions and anxieties of a competitive market economy that now seems uncommitted to spending more on health services. Its army is made up of an ununited confederation of utilization review organizations, health maintenance organizations (HMOs), preferred provider organizations (PPOs), exclusive provider organizations (EPOs), and a number of other entities that have been enlisted to restrain++ the medical-industrial complex. In their march across America, they have frequently assailed the shibboleths and established structures of treatment systems, especially psychiatry and often fought with one another. While some are mercenary forces, others appear as peoples' armies, committed to preserving and strengthening the healthcare system they are transforming. As it encounters the inhabitants of this domain, Managed Care becomes both their master and their slave. As with any occupying force, it must win their hearts and minds over to the new way of doing things. The winning-over process is not going well now. Many patients and providers are angry at the inefficiencies, unproven effectiveness, administrative burdens, affronts to traditions, and threats to quality sometimes posed by Managed Care. This collective unrest has resulted in both a mounting resistance to the problems emanating from managed care changes in the healthcare system and a call to check its unrestrained incursions into professional practice through regulation. The growing tension between what seems an irresistible force and an immovable object can be viewed as part of the natural evolution of all change, particularly in a free market or in a society with requisite checks and balances.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115466 TI - Rationale for a hospital-based managed mental healthcare service. AB - Managed mental health companies are gaining tremendous power in the delivery of behavioral health services. Contracts can literally shift market share from one facility to another in a matter of weeks. For most inpatient providers, managed mental health bodies ill in the forms of fewer admissions, shorter lengths of stay, and lower service fees. The first section of this article explains some of the factors driving the growth of managed mental health care. The second cites the benefits of developing a hospital-based managed mental health service. PMID- 10115467 TI - Impact of benefit limits and managed care on discharge plans and outcome: a research design and preliminary results. PMID- 10115468 TI - Hospitals take charge: survival tactics for the 90s. PMID- 10115470 TI - Promotions. Marketing--light-hearted promos. PMID- 10115469 TI - The impact of cost containment: quality and morale. PMID- 10115471 TI - Nutrition. Trends. Disappearing 'light lines'. PMID- 10115473 TI - Dietitians. Careers. The revolution continues. AB - Freelance consulting and specialty diversification are vital today as the demand for dietetic services increases. In fact, the common bond between the members of your profession that we've profiled here is that none of them is tied down to one segment or one company. The dietitians described in our third annual compendium have risen to the challenge and met the needs of a changing society and a changing profession. PMID- 10115472 TI - Purchasing. Business strategies. Purchasing groups find savings in numbers. PMID- 10115474 TI - Industry overview. Dietitians speak out. AB - As their profession changes, dietitians are constantly breaking stereotypes. Gone are the days when all dietitians wore lab coats and worked in hospitals. Expanding knowledge, increased community support and new technology all present dietitians with more and more career opportunities. Here's what some of your peers had to say about the expanding world of dietetics. PMID- 10115476 TI - A competitive analysis of most favored nations clauses in contracts between health care providers and insurers. AB - A most favored nations (MFN) clause is a contractual agreement between a buyer and a seller stating that the price paid by the buyer will be at least as low as the price paid by other buyers who purchase the same commodities from the seller. During the past decade the anticompetitive impact of MFN clauses in the health care industry has been challenged under federal antitrust laws. The cases have considered MFN clauses included in contracts between large third-party payers, specifically Blue Cross and Blue Shield (BCBS) plans, and providers of health care. The clauses prohibit providers from selling their medical services to BCBS's competitors at a price lower than the price at which they sell to BCBS. The cases have challenged these clauses on the grounds that they limit selective discounting to the competitors thereby making it difficult for the competitors to attract subscribers from dominant BCBS plans by lowering premiums. In this Article, Professor Celnicker asserts that MFN clauses have significant anticompetitive potential. The Article examines the competitive consequences of MFN clauses used in the health care industry. The Article's analysis draws heavily from the economic criticisms of the Robinson-Patman Act, which prohibits a seller from discriminating in price between customers in certain circumstances. The Article concludes that in certain circumstances, MFN clauses discourage discounting, facilitate oligopolistic pricing, and deter entry or expansion by more efficient distribution systems. PMID- 10115475 TI - Packing. Disposable packaging: an institutional wrap-up. PMID- 10115477 TI - How to identify and analyse hospital acquired infections. AB - In order to get for the first time, well founded and representative data on the actual level of the infection rate in acute hospitals, in 1988, the German Hospital Federation (DKG) asked Infratest-Public Health Research, Munich, to conduct a research project on the "identification and analysis of hospital acquired infections." The survey revealed that the infection rate in acute hospitals ranged between 5.7 and 6.3%. Below are the results of the final report. PMID- 10115478 TI - Future prospects for long term care providers. PMID- 10115479 TI - Changes in the Hungarian health system. AB - Dr. Peter Lepes fascinating article presents a comprehensive picture of the Hungarian health care system presently undergoing fundamental reforms in the wake of might political changes sweeping over Hungary, and looks for the roots of its shortcomings and deficiencies by analysing the methods prevailing under the socialist regime. He examines the innovative health policies of the Reform Secretariat. PMID- 10115480 TI - The seasons of a CEO's tenure. AB - This article proposes a model of the dynamics of the CEO's tenure in office. The central argument is that there are discernible phases, or seasons, within an executive's tenure in a position, and that these seasons give rise to distinct patterns of executive attention, behavior, and, ultimately, organizational performance. The five delineated seasons are (a) response to mandate, (b) experimentation, (c) selection of an enduring theme, (d) convergence, and (e) dysfunction. The theoretical and practical implications of the model are discussed. PMID- 10115482 TI - AIDS knowledge and attitudes of Hispanic Americans: United States, 1990. Provisional data from the National Health Interview Survey. PMID- 10115483 TI - Restraint-free on a shoestring. How to get a program up and running. PMID- 10115481 TI - The effects of regulatory tools on organizational populations. AB - One of the main activities of regulation is the control of market development by influencing the number of firms in an industry, their entry into an industry, and their exit from an industry. Population ecology is used as a framework for explaining both the direct and indirect effects of regulatory activity on entry, exit, and market structure. This framework is then used to derive specific propositions about regulatory effects on entry, exit, and market structure in the health maintenance organization industry. PMID- 10115484 TI - Positioning assisted living for the 1990s. PMID- 10115485 TI - Litigation presses for reimbursement relief. PMID- 10115486 TI - Role of the volunteer. PMID- 10115488 TI - Welcomed with open arms. AIDS patients find refuge in special facilities. PMID- 10115489 TI - Cleaning up the laundry. Facilities iron out cost wrinkles. PMID- 10115487 TI - Nursing homes rally on Wall Street. Initial public offerings rebound. PMID- 10115490 TI - Safety is job one. Oversight is key to proper program. PMID- 10115491 TI - More bang for the buck. Manor Care fine tunes supply system. PMID- 10115492 TI - Taking the hassle out of continuing education. Beverly, NLN forge alliance. PMID- 10115493 TI - Computer fun: not just kid's stuff. High-tech activities are a big hit. PMID- 10115494 TI - When ombudsmen knock at the door. PMID- 10115495 TI - Medication use and falls. PMID- 10115497 TI - Multihospital integration issues: it doesn't get much harder than this. AB - Multihealthcare organizations face unique challenges when it comes to providing information services for all of their entities. They must consider corporate philosophy, geography, computing configurations and whether their I/S approach capitalizes on centralized economies of scale or regional flexibility and control. Multisystem experts George Kennedy and Stan Jaworksi of The Kennedy Group, Redwood City, Calif., describe system integration trends in multihealthcare organizations and provide an overview of the implications for information systems executives. PMID- 10115496 TI - 1992 products & services directory. PMID- 10115498 TI - Keeping a balanced perspective on open systems. PMID- 10115499 TI - In pursuit of a single healthcare computing standard. PMID- 10115500 TI - Information architecture: bridging the islands. PMID- 10115501 TI - What comes first: the workplan or the special request? AB - How does your MIS Department handle ad hoc requests for I/S projects? CIH Advisory Board member Fran Turisco tells how her MIS Department at the Lahey Clinic deals with this problem and solicits ideas from CIH readers via our "FAX IT BACK" response form. PMID- 10115502 TI - Management by information: a new imperative. PMID- 10115503 TI - Reengineering the hospital: making change work for you. AB - Two of the industry's prominent management experts and authors explain that the Information Systems Department can take a leading role in reengineering the management infrastructure of a healthcare organization. Change is no longer the enemy of management if the infrastructure is set up to accommodate and promote change from within. PMID- 10115504 TI - Today, I closed my kitchen. AB - Cedars-Sinai Medical Center has recently switched to a kitchenless patient foodservice program. In addition to cutting 15 FTEs & contributing to nearly $500,000 in annual savings, foodservice has also released $1.5 million worth of real estate for revenue-generating activities. PMID- 10115505 TI - A kitchenless future. PMID- 10115506 TI - Vending--taking the next step. PMID- 10115507 TI - A team approach. PMID- 10115508 TI - Job rotation: a key to labor success. PMID- 10115509 TI - "We are not in a growth industry." Foodservice's outlook for 1992 should mirror the economy--sluggish. PMID- 10115510 TI - The battle over benefits. AB - Squeezed in a tight economy, companies are looking for savings where once they didn't dare: in health insurance and pension costs. Employees get panicky at the thought. PMID- 10115511 TI - Learning to compete. Rural hospitals find ways. PMID- 10115512 TI - Making a difference. The physician liaison. AB - Physician liaison profile ... Who are they and what role do they play in the physician hospital relationship? The Virginia hospital featured found even the smallest changes and improvements can make a big difference. PMID- 10115513 TI - Fighting burnout in CCU. PMID- 10115514 TI - Redefining physician bonding. PMID- 10115515 TI - Building the team. AB - The physician liaison proves to be a vital link. A Florida hospital has moved beyond "bonding," doing things 'for' and 'to' physicians. Communicating common goals makes it clear--the physician and hospital are in it together. PMID- 10115516 TI - Tax-exempt. An endangered species? PMID- 10115517 TI - Recruiting within the bounds. Understanding the law. PMID- 10115518 TI - Reaching out. Pros and cons of special events. PMID- 10115519 TI - On the road again. Marketing success. PMID- 10115520 TI - Just say no. Staff passes test. PMID- 10115521 TI - Readying for a healthcare revolution. Outpatient care: a textile rental service opportunity. AB - Textile rental companies are poised on the edge of a boom in the healthcare marketplace. The detonator is outpatient care. Between 1984 and 1990, outpatient visits increased from almost 233 million to more than 310 million, or about 33 percent. The shift from traditional hospital care to outpatient or ambulatory service is creating a new market opportunity for textile rental services. Innovative medical services are cropping up in suburban malls and neighborhoods, and demand is high for high-quality linen supply or contract laundry services. PMID- 10115522 TI - The other healthcare market. Doctors' offices and medical clinics are a profitable and growing market niche for some operators. AB - The healthcare market doesn't just mean hospitals anymore. For some textile rental operators, doctors' offices and medical clinics are a profitable and growing niche. On the positive side, this market offers growth, low abuse, good prices, and light soil. But operators also must weigh the cons--scattered deliveries, low volume, small stops, and medical waste management. Is the "other" healthcare market for you? PMID- 10115523 TI - Are your employees protected from blood-borne pathogens? OSHA standards charge textile rental companies with responsibility for worker safety. AB - Congress is putting pressure on OSHA to finalize its Universal Precaution standards by December. When the standards go into effect, textile rental companies that serve medical, dental, and outpatient care facilities--including private physician and dentist offices--must take steps to protect employees from blood-borne pathogens. Soiled linens, towels, gowns, and other items from any customer in risk categories link a textile rental facility and/or commercial laundry with the OSHA regulations. Read and heed this information. PMID- 10115524 TI - On the track of medical waste. Will a national medical waste policy wash up on the beach? AB - There's no question that medical waste pushes the nation's panic button. It took only two summers (1987 and 1988) of needles and syringes washing ashore to generate a groundswell of public anxiety that caused Congress to pass the Medical Waste Tracking Act of 1988. The act was the federal government's first attempt at cradle to grave waste management through a two-year pilot program involving four states and Puerto Rico. Now that the act and the pilot program have expired, Congress must evaluate their impact and decide whether to pursue a national medical waste policy. Such a policy likely would address the work practices of occupational groups, such as laundry workers, who frequently have contact with medical waste. PMID- 10115525 TI - Pennsylvania challenges hospital tax exemptions. AB - When a charitable hospital begins competing with businesses that normally are "for profit," such as laundries, the hospital stands a substantial chance of losing its state and county tax-exempt status. Nevertheless, healthcare organizations across the country routinely undertake commercial projects and amass profits without challenge. Here are two case histories that prove citizen involvement can spell the deathknell for unfair competition. PMID- 10115526 TI - A right-to-die reminder. A new law requires hospitals to read you your medical rights. PMID- 10115527 TI - The octopus orientation theory. AB - Starting a new position is an exciting opportunity that can and should be a positive experience. Listed below are some general concepts that may be applied to help the transition. 1. Volunteer to serve on committees. Don't isolate yourself. Consider being cochair of the United Way or of a fund drive. 2. Keep promises. If you commit to something, do it! No matter how trivial or minor the request, it is important to your credibility that you follow through. If asked when you can accomplish a certain task, evaluate the request and add in a safety margin. Report back to the employee and tell them of your timetable, then deliver it earlier than you promised. Exceed their expectations. 3. Set goals and share them with your staff. Stay focused on these goals, keeping the employees' concentration on the objectives. Peter Druker was on target when he wrote: "Concentration is the key to results, no other principle of effectiveness is violated as constantly today as the basic principle of concentration." 4. Distribute "justice to all." It is critical to your success that you always apply fairness, consistency, or whatever term you associate with equality. Don't establish double standards; making exceptions only leads you down a dark path with no end in sight. 5. "Don't fix it unless it's broken." It is like pulling that tiny thread on your new sweater: once pulled, you immediately realize that you have caused an even bigger problem--one that you can't repair.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115528 TI - Building upon assumptions. An Office of Technology Assessment report examines breast cancer screening for women over 65. PMID- 10115529 TI - Breast imaging. Accompanying patients through the labyrinth of claims. PMID- 10115530 TI - Deployment of outpatient technologies. The hospital-based versus freestanding dilemma. PMID- 10115531 TI - Image data compression for PACS. PMID- 10115532 TI - Who's minding the shop? Executive boards and public accountability. PMID- 10115533 TI - To centralize or compete is not the issue at hand. AB - AR's November 1990 issue featured "Stripping the Myths of Merger-mania," by Frederick Thayer, Professor Emeritus, University of Pittsburgh's Graduate School of Public and International Affairs. The article is a provocative effort toward educating healthcare professionals, whose academic backgrounds have been rooted mainly to clinical and technological concerns, regarding the fundamental causes that have led to the current economic environment inside which we struggle to plot strategies to provide patient services on a more equitable basis for the majority of people. In this year's January issue, Herbert Bernstein, Professor of Economics at Drexel University's College of Business and Administration in Philadelphia responded to Thayer's experienced pondering of the why's, how's, and cumulative effect of corporate activity (mergers) on the ongoing well-being of the physical entity resulting from such stripping and learning. The March 1991 issue of AR gave vent to Thayer's subsequent rebuttal. Here, again, are thoughts from Bernstein and Thayer, offered with the intention of exposing AR readers to a perspective of the world a bit removed from acquisition or application of technology, but directly connected to the larger issues that "world leaders" and national policy makers are struggling to cope with. Underlying the thoughts of both Bernstein and Thayer is a desire to do their part to stimulate front line healthcare workers, physicians, and executive-level management to understand the forces at play in the ever-changing face of our economic structure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115534 TI - Utilization of a linear accelerator. PMID- 10115535 TI - Dissecting a waiting list. AB - This study examines a list of 1,283 patients waiting for general and orthopaedic surgery in an outer London borough. In general surgery varicose vein and hernia surgery accounted for 60% of those waiting more than one year. Of those who had waited more than a year on the orthopaedic list 25% were waiting for knee replacement surgery. The average length of time spent waiting was 10 months, with some people waiting over 5 years. The impact of the numbers waiting a long time on aggregate waiting time was highlighted by weighting the numbers waiting by the months spent waiting. Analysis of urgency codes indicates that although there was a statistically significant relationship between urgency and the length of waiting time there were some anomalies. There was considerable inter-consultant variation in list size, waiting times and the case mix. Analysis of the flows onto the list and work done in one month showed that it would take a considerable time to clear some lists at present rates of activity. Disaggregated information such as this which explores the flows of patients on to and off of the lists is essential for the management of waiting lists and will become increasingly important as waiting lists become a feature of--'contracts'--service agreements, in the reformed NHS. PMID- 10115536 TI - Power in the National Health Service: a case study of a unit considering NHS Trust status. AB - There are a number of theoretical frameworks which aim to provide a language for understanding and discussing the nature of power and influence in organisational decision making. One of the most recent and comprehensive frameworks is that developed by Mintzberg. Following a resume of the most pertinent sections of Mintzberg's framework, this paper uses it to investigate the power relationships in an NHS Mental Health Unit (MHU) considering NHS Trust status. This investigation reveals some important conclusions about the nature of power in the NHS but also explores some of the limitations of the framework as a descriptive and predictive tool. PMID- 10115537 TI - Service patterns in local hospital markets: complementarity or medical arms race? AB - In this paper we investigate how the availability of selected services in individual hospitals is influenced by the number of neighbors who are potential or actual competitors. Hospitals offer a wide range of services, and some services may display a complementary pattern while others may contribute to a competitive medical arms race. We will examine the types of services that show these opposite patterns to analyze the dynamics that have characterized local hospital service decisions. PMID- 10115538 TI - The use of the FHSA (family health services authority) registration index for a health needs survey. AB - The FHSA patient registration index was used as a sampling frame for a population questionnaire survey. The main survey of 3,359 was preceded by a pilot study of 250. Ethical issues such as anonymity and release of data were addressed in order to obtain the approval of the ethical committee and LMC. The acceptability to GPs and the public of using FHSA Registration data was tested. The validity of the survey was indicated by the proportion of wrong addresses, the response rate and the representativeness of the sample and responders. Appropriate software is needed for selecting a random sample and producing address labels. PMID- 10115539 TI - Hospital closures: what is the story? AB - This paper examines the data and research findings on hospital closures in order to understand better the phenomenon and to evaluate the seriousness of its impact. It presents a description of the patterns and trends and, from this, attempts to identify the factors which contribute to closings and the effects on the community, the physicians, and other hospitals. In examining the research findings, a number of managerial and research propositions are identified. PMID- 10115540 TI - Monopolistic competition and the health care sector. AB - The model of monopolistic competition is appropriate for describing the behavior of the health care sector in the United States. Uncertainty about quality of medical and related services promotes product differentiation especially when consumers do not bear the full costs of care. New technologies can be used to signal quality even when their clinical usefulness is unproven. Recent cost containment measures may reduce employment of ineffective technologies but may also inhibit the adaptation of genuinely useful developments. PMID- 10115541 TI - Linkworkers in antenatal care: facilitators of equal opportunities in health provision or salves for the management conscience? AB - A number of reports have highlighted non-English speaking Asian women as being at risk from limited health care provision (eg Whitehead, 1987). Of particular relevance to the present survey is their low uptake of antenatal care which may contribute to the above-average perinatal mortality rates for this group. In an attempt to ameliorate this problem, a Linkworker service was introduced in a number of multi-racial health districts. The survey reported here was an attempt to establish the efficacy of this service. From an initial sample of 30 health districts, 20 replies were obtained which provided some valuable insights on the current status of the Linkworker provision. In summary, the responses indicated that there is a worrying mis-match between client need and service planning, largely because relevant information about supply and demand is not collated. The net result is that many of the at-risk group are still denied the full and appropriate services of the Linkworker. It is concluded that if Linkworker provision is seen as a valuable commodity in enhancing equal opportunities in health care, then the service needs to be systematised. If it is perceived to be of little demonstrable value, then it should be scrapped. In either case, some clear policy decisions are required. PMID- 10115542 TI - Structural and political models of analysis of the introduction of an innovation in organizations: the case of the change in the method of payment of physicians in long-term care hospitals. AB - This article presents the results of a study on the introduction of sessional fees remuneration for physicians working in Quebec long-term care hospitals. More generally, this research was concerned with the determinants of the capacity of an organization to implement an innovation. Both a political and a structural model of analysis were empirically probed. We found strong support for the political model and moderate support for the structural model. This article contributes to the understanding of the relative contribution of structural and political determinants in the implementation of changes in organizations. PMID- 10115544 TI - Perspectives. Health care goes to school. PMID- 10115543 TI - Improvement of therapeutic drug monitoring. PMID- 10115546 TI - Perspectives. Limited victory in the war on cancer. PMID- 10115545 TI - Perspectives. Assisted suicide: the debate of the 90s. PMID- 10115547 TI - Can runaway health-care costs be stopped? PMID- 10115550 TI - Assessing employee dependent-care needs. PMID- 10115549 TI - Pay goes up as HR jobs broaden. PMID- 10115548 TI - Ten facts about point-of-service plans. PMID- 10115551 TI - Employee benefits buyer's guide. PMID- 10115553 TI - Update: OSHA proposes revised formaldehyde standard. PMID- 10115552 TI - HRIS benefits software buyer's guide. PMID- 10115554 TI - Medical transcription as communication. PMID- 10115555 TI - Update on certification examination changes. The history and rationale behind recent changes in AAMT certification exam policies. PMID- 10115556 TI - The myth of medical transcription. PMID- 10115558 TI - A new face for an old nemesis. PMID- 10115559 TI - Revision of fee schedules; 100% fee recovery; clarification of size standards- Nuclear Regulatory Commission. Final rule. AB - The Nuclear Regulatory Commission (NRC) is amending its regulations concerning the payment of annual fees to clarify the provisions that identify the size standards used to determine whether an NRC licensee would qualify as a "small entity" under the Regulatory Flexibility Act for the purpose of paying a reduced annual fee. This clarification is necessary because the size standards presented in the regulations did not clearly indicate the complete range of size standards adopted by the NRC. PMID- 10115557 TI - Condition: critical. AB - Millions of Americans have no medical coverage, and costs are out of control. Here are 10 ways to fix what ails us. PMID- 10115560 TI - Order for transitional class III devices; submission of safety and effectiveness information under section 520(1)(5)(A) of the Federal Food, Drug, and Cosmetic Act--FDA. Notice. AB - The Food and Drug Administration (FDA) is issuing an order requiring manufacturers of transitional class III devices to submit to FDA a summary of, and a citation to, any information known or otherwise available to the manufacturers respecting the devices, including adverse safety or effectiveness information which has not been submitted under section 519 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360i). This is the first step in the process of determining the appropriate classification of transitional devices under the Safe Medical Devices Act of 1990. PMID- 10115561 TI - Medicare program; inpatient hospital deductible and hospital and skilled nursing facility coinsurance amounts for 1992--HCFA. Notice. AB - This notice announces the inpatient hospital deductible and the hospital and skilled nursing facility coinsurance amounts for services furnished in calendar year 1992 under Medicare's hospital insurance program (Medicare Part A). The Medicare statute specifies the formulae to be used to determine these amounts. The inpatient hospital deductible will be $652. The daily coinsurance amounts will be: (a) $163 for the 61st through 90th days of hospitalization in a benefit period; (b) $326 for lifetime reserve days; and (c) $81.50 for the 21st through 100th days of extended care services in a skilled nursing facility in a benefit period. PMID- 10115562 TI - Medicare program; monthly actuarial rates and monthly supplementary medical insurance premium rates beginning January 1, 1992--HCFA. Notice. AB - As required by section 1839 of the Social Security Act, this notice announces the monthly actuarial rates for aged (age 65 or over) and disabled (under age 65) enrollees in the Medicare Supplementary Medical Insurance (SMI) program for calendar year 1992. It also announces the monthly SMI premium rate to be paid by all enrollees during calendar year 1992. The monthly actuarial rates for 1992 are $60.80 for aged enrollees and $80.80 for disabled enrollees. The monthly SMI premium rate for 1992 is $31.80. PMID- 10115564 TI - Employment-based immigrants--Immigration and Naturalization Service. Final rule. AB - This final rule implements section 121 of the Immigration Act of 1990, Public Law 101-649, November 29, 1990 (IMMACT), by providing petitioning procedures for employment-based immigrants under sections 203(b) (1) through (5) of the Immigration and Nationality Act (Act). It will also implement new immigrant classifications and requirements established by Public Law 101-649, and clarify, for the general public and businesses, requirements for classification and admission for these new immigrant classifications. This rule is necessary to help American businesses hire highly skilled, specially trained personnel to fill increasingly sophisticated jobs for which domestic personnel cannot be found. PMID- 10115563 TI - Medicare program; Part A premium for 1992 for the uninsured aged and for certain disabled individuals who have exhausted other entitlement--HCFA. Notice. AB - This notice announces the hospital insurance premium for calendar year 1992 under Medicare's hospital insurance program (Part A) for the uninsured aged and for certain disabled individuals who have exhausted other entitlement. The monthly Medicare Part A premium for the 12 months beginning January 1, 1992 for individuals who are not insured under the Social Security or Railroad Retirement Acts and do not otherwise meet the requirements for entitlement to Medicare Part A is $192. Section 1818(d) of the Social Security Act specifies the method to be used to determine this amount. PMID- 10115565 TI - Medicare program; standard claim forms for Part B claims completed and submitted by physicians, suppliers and other persons--HCFA. General notice with comment period. AB - This notice announces that effective April 1, 1992, Medicare carriers will no longer accept nonstandard claims. These are claims accompanied by attachments, in lieu of the biller entering required information in designated blocks of prescribed claims forms. This change is intended to eliminate costly and inefficient claims processing practices for Medicare carriers. PMID- 10115566 TI - Temporary alien workers seeking classification under the Immigration and Nationality Act--Immigration and Naturalization Service. Final rule. AB - This final rule implements provisions of the Immigration Act of 1990 (IMMACT). Public Law No. 101-649, November 29, 1990, and the Armed Forces Immigration Adjustment Act of 1991. Public Law No. 102-110, October 1, 1991, as they relate to temporary alien workers seeking nonimmigrant classification and admission to the United States under sections 101(a)(15) (H), (L), (O), and (P) of the Immigration and Nationality Act (Act), 8 U.S.C. 1101. This rule also contains technical amendments which reflect the Service's operating experience under the H and L classifications. This rule will conform Service policy to the intent of Congress as it relates to these classifications, implement new nonimmigrant classifications and requirements established by Public Law 101-649 and Public Law No. 102-110, and clarify for businesses and the general public requirements for classification, admission, and maintenance of status. PMID- 10115567 TI - Middle-class Medicaid. AB - Medicaid was designed to help the nation's poor. But with help from government and smart lawyers, relatively well-to-do Americans are finding new ways to have the program pick up their nursing-home bills. PMID- 10115569 TI - Therapeutic use of storytelling for older children who are critically ill. AB - Like play, a story can be functional and therapeutic in the care of children dealing with chronic illnesses such as cancer, even when patients' courses prove terminal. Examples include both oral telling and reading of stories, picturebooks, novels and accounts of natural phenomena, as well as children;s recounting of desires and fantasies. The field of therapeutic stories offers unlimited opportunities for both practitioner and parent to learn better ways to support children's own inner processes of imagination and motivation, to strengthen and to provide comfort. PMID- 10115568 TI - Analyzing drawings of children who are physically ill and hospitalized, using the ipsative method. AB - Children use drawings and pictorial representations as a way of expressing their feelings about themselves and their world. The ipsative method for analyzing drawings is an excellent way for a child health professional to assess and monitor a child's emotional and developmental progress during a physical illness or hospitalization. Case examples illustrate the ipsative method. Specific guidelines for the clinical use of children's drawings are given. PMID- 10115570 TI - The use of stuffed, body-outline dolls with hospitalized children and adolescents. AB - The process of creating and personalizing a blank, stuffed, body-outline doll can provide children with a pleasurable, expressive activity that can be used by staff to facilitate effective coping. Observation of this process can provide staff with important assessment information. The dolls' permeability and flexibility make them ideal for use in preparation interactions and for promoting postprocedural health care play. The degree to which it is possible to individualized the dolls appears to enhance their value to the patients who create them. Examples of ways health care professionals can most effectively utilize the dolls are detailed. PMID- 10115571 TI - Medical play and preparation: questions and issues. AB - Medical play and preparation have become increasingly visible components of psychosocial programming for children in health care settings. Each strategy varies to the extent to which adults structure and direct, which may influence children's responses and posthospital adjustment. Medical play and preparation represent different philosophies and theories on children's learning, adaptation, and development. The ever-changing medical environment may currently favor adult directed experiences over those that are spontaneous or child initiated, with potentially differing impacts on children. Issues are raised regarding the potential impact as well as that of programs with various combinations of adult- versus child-structured experiences. PMID- 10115572 TI - Self-understanding and reaching out to sick children and their families: an ongoing professional challenge. AB - Health care professionals face a series of taxing, emotionally wrenching, painful experiences as they begin to care for frightened, ill children and their families. Loss, grief, overidentification with patients, and overwhelming anxiety are among their "occupational hazards." Open, frank discussion of intense feelings and reactions and mutual support are essential elements in helping caregivers to cope in ways that do not result in withdrawal from children and families. By developing strategies that reach out to patients and their families, professionals enhance their own personal professional gratification and self esteem. The insights of parents are used extensively both to illustrate concepts and to emphasize the critical role parents can play as "resources" for professionals and "partners in care." PMID- 10115573 TI - Emotions in pediatric emergencies: what we know, what we can do. AB - Emotional reactions are an important, but often ignored, aspect of the pediatric emergency medical encounter. The importance of the family's definition of emergency is discussed along with literature on reaction to trauma, developmental issues, and needs in the emergency encounter. Specific actions are discussed in four categories: (a) recognizing and legitimizing emotions, (b) assessing emotional aspects, (c) responding to emotional needs, and (d) following up with all involved. PMID- 10115574 TI - Promoting infant development during neonatal hospitalization: critiquing the state of the science. AB - Contemporary neonatal intensive care units treat infants with very different medical conditions from those of a decade ago. Approaches to ensuring optimal outcome following high-risk birth must reflect the changing conditions and needs of these infants. This paper will review the cause and nature of change in infant status and attempt to reconcile the increasing demand for supporting stages of neuromaturation and social-emotional development during hospitalization with our current limited understanding of how fragile infants process and respond to interventions. Special cautions will be directed to well-meaning caregivers who may unwittingly jeopardize infant health and development by implementing new clinical models without empirical support. Opportunities for integrating psychosocial and medical care of these infants will also be highlighted. PMID- 10115575 TI - Computer-assisted compounding of neonatal/pediatric parenteral nutrition solutions. AB - A computer software package was developed to perform the calculations involved in compounding neonatal/pediatric parenteral nutrition (PN) solutions. A 16-bit micro-computer was used to develop and evaluate the software. The program requires a minimum of user input and is menu-driven. It performs the calculations, prints appropriate labels, a preparation card and a summary of the nutritional content of the solution. Error check routines and a check for calcium phosphate compatibility are imbedded in the program. The effect of the package on PN compounding was evaluated using a computer model. The evaluation indicated the computer-assisted system was more efficient than a manual system and the possibility of computational error was reduced. The increase in efficiency with the computer-assisted system was between 12-15% compared to a manual system. Computer modeling appeared to be a useful tool in both evaluating the software package and determining the effect it would have on work flow. PMID- 10115576 TI - Timeliness of receipt of manufacturers' new product information. AB - In February 1988, the Pharmaceutical Manufacturers Association of Canada (PMAC) published a Code of Marketing Practices which recommends that PMAC members provide essential product information to drug information centres a minimum of two weeks prior to the marketing of new prescription drugs. A one-year study was undertaken by our Drug Information (DI) Centre to assess the compliance of PMAC companies with this guideline. Product information was mailed to our DI Centre two weeks or more prior to marketing for only 3/28 (10.7%) new prescription drugs and for none of 27 (0%) new prescription drug dosage forms or strengths. No product information was received for 10/28 (35.7%) new prescription drugs and 21/27 (77.8%) new prescription drug dosage forms or strengths. In several situations, new drugs appeared in journal advertisements or were being detailed to physicians prior to receipt of new product information. Manufacturers are encouraged to review their procedures for disseminating new product information to ensure that DI centres are notified of new product introductions at least two weeks in advance of detailing or marketing. PMID- 10115577 TI - Quality assurance of data collection in an aminoglycoside dosing service. AB - An aminoglycoside dosing service (ADS) has been in existence at the Hospital since 1984. As part of an overall Quality Assurance (QA) plan for the service, an audit was conducted to ensure that all necessary data were available to allow for proper interpretation of the serum aminoglycoside levels. The initial audit revealed complete documentation of required data in 75% of PRE-dose levels and 63% of POST-dose levels drawn. Several problems were identified: staff were not aware of procedures on how to complete the serum antibiotic level requisition forms; inaccurate assumptions of infusion times were made by pharmacists; and discrepancies were found to exist in the Hospital's Laboratory Manual and Pharmacy Intravenous Medication Manual. Corrective action was initiated through: education on proper documentation on the serum antibiotic level requisition forms through the hospital-wide distributed Pharmacy Bulletin; revision of the Hospital's Laboratory Manual and Pharmacy Intravenous Medication Manual; communication with head nurses to emphasize the need for documentation of infusion times; and active follow-up with nurses on missing information by the clinical pharmacist. A re-audit was initiated following implementation of the corrective actions. Complete documentation of required data increased to 93% with PRE-dose levels and 84% with POST-dose levels. This improvement was statistically significant (p less than 0.001). PMID- 10115578 TI - An analysis of pharmacist interventions. AB - In a 620-bed acute care teaching hospital, the hospital pharmacists are therapeutic specialists and have become integrated members of the health care team working on the nursing units. To determine the extent of cost avoidance and savings achieved by pharmacist monitoring of drug prescribing and administration, a six month study was undertaken in one of five pharmacy satellites. The pharmacists documented each clinical intervention on form designed for this investigation. Cost reductions or cost avoidance accrued due to the pharmacists' clinical interventions, such as monitoring overuse of drugs, unnecessarily prolonged hospitalization, correction of medication errors, and reassessment of prescriptions. This study suggests that pharmacists clinical expertise in drug use can benefit patients, physicians, nurses, and the hospital administrators who are confronted with ever increasing costs. PMID- 10115579 TI - A pilot study of process and outcome assessment in antibiotic therapy. AB - A quality assurance survey of cefazolin therapy was conducted by pharmacists using process-related and outcome-related assessments. The purpose of this survey was to study the possibility of having pharmacists review and categorize the appropriateness and success of antibiotic therapy. During a three week period, 168 orders for cefazolin were identified and 67 prophylactic and medical therapies were selected and submitted for possible pharmacist review. Thirty seven therapies were reviewed by staff pharmacists who scored each therapy for the acceptability of risk of adverse drug effect, the cost-effectiveness, and the overall appropriateness. An evaluation form was used, but explicit utilization criteria were not provided. The average scores (+/- SD) on a 10 centimeter visual analog scale were 9.1 (+/- 0.71), 8.7 (+/- 1.21), and 8.8. +/- 0.79) respectively. Twenty-six (70%) of these therapies were monitored to resolution, and 24 (65%) were successful in achieving the therapeutic goal. No adverse effects were noted. The average estimated times to complete the initial review and follow-up review were 10.1 (+/- 5.60) and 3.5 (+/- 2.29) minutes respectively, less than the 19.5 minutes estimated using the Canadian Hospital Pharmacy Workload Measurement System. This survey demonstrated that pharmacists can provide both process-related and outcome-related QA data. PMID- 10115580 TI - The Independent Health Facilities Act. AB - The Independent Health Facilities Act represents an attempt by the Ontario Government to control the unplanned proliferation of health clinics in the community offering specialized services often seen as competing with public hospitals, and to provide mechanisms to ensure that standards and quality care are maintained in these clinics. Although the Act was originally aimed at about 25 ambulatory surgi-centers performing such procedures as cataract surgery and abortions, amendments have broadened the Act's scope to include most clinics offering such diagnostic services as x-ray and ultra sound. The legislation was opposed by some medical specialties and proved very controversial. Other provinces have looked to this legislation as a means of controlling health care costs by reducing reliance on hospitals for certain kinds of procedures and by moving from fee for service to various alternative funding mechanisms for those procedures provided by out-of-community clinics as approved and licensed in a place and manner decided upon by government. The papers in this issue of the journal reflect a conference sponsored by the Canadian Institute of Law and Medicine to examine this legislation one year after it came into force. The comments of government, physicians, lawyers and others most directly affected by this new statute are set out in a selected number of presentations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115581 TI - The Independent Health Facilities Act: why is it necessary? PMID- 10115582 TI - The role of district health councils in the Independent Health Facilities Act. PMID- 10115583 TI - Quality assurance and the Independent Health Facilities Act. PMID- 10115584 TI - Key factors in the audit of independent health facilities: a prescription for a healthy outcome. PMID- 10115585 TI - The Independent Health Facilities Act: cost versus quality. PMID- 10115586 TI - Legal aspects of the sale of an independent health facility. PMID- 10115587 TI - The business of obtaining a licence for an independent health facility. PMID- 10115588 TI - Blue skies, sunny days. AB - The storm clouds and bad news surrounding rural hospitals sometimes block out the other side of the story. In this issue, HealthTexas looks at three rural health care providers--Medina Community Hospital, Starr County Memorial Hospital, and Moore County Hospital District--that are doing far more than just hanging on; they are succeeding. What they share is important and instructive: a strong commitment to their communities, a whatever-it-takes-to-get-the-job-done attitude, and a creative approach to defining the role of rural health care providers. PMID- 10115589 TI - Guest: send new HCFA rules back to fix-it shop. AB - John A. guest, president and CEO of the Bexar County Hospital District in San Antonio and THA's chairman, delivered a message Sept. 30 in Washington on behalf of Texas hospitals regarding HCFA regulations to restrict federal matching funds for state Medicaid programs. The following is excepted from his testimony before the House Subcommittee on Health and the Environment. PMID- 10115590 TI - Recruiting new physicians could be courting IRS problems. PMID- 10115591 TI - What's all the fuss about red-bag trash? PMID- 10115592 TI - Pennsylvania voters prove healthcare is an important issue. PMID- 10115593 TI - Entering the debate. PMID- 10115594 TI - The excesses of individualism. For meaningful healthcare reform, the United States needs a renewed sense of community. AB - In the United States at the end of the twentieth century, the balance of values tilts too far toward the individual and away from the community. What is needed is a renewed sense of community that enhances the lives of individuals as it serves the common good. The first step toward creating a new balance is a critique of the present imbalance, which is shaped by excessive forms of individualism that affect every aspect of our healthcare delivery system. Technological individualism occurs when the value of technology is measured only by its service to the individual. The results are a technological imperative, unreasonable expectations on the part of the community, distorted judgement on the statistical likelihoods of individual outcomes, fragmentation of care, and a reliance on rescue medicine. A psychosocial individualism has misshapen our attitudes about ourselves and our communities, bringing with it a deepening sense of alienation. The results in U.S. healthcare include commercialization, exclusion of the poor, a litigious provider-patient relationship, declining respect for life, and a sense of community that excludes other generations and nations. Libertarian individualism has created political isolation and prevents the evolution of democratic decision making and real partnerships in healthcare. The results are an unpooling of insurance risk, an interpretation of freedom that is inimical to family and community ties, hostility to government, a view of healthcare as a commodity, and deprofessionalization of the medical professions. Healthcare reform must seek to change what medical technology does for us, repair the psychosocial harms healthcare individualism has produced, and promote citizen participation in the healthcare system in new and important ways. PMID- 10115595 TI - The vision of jubilee. A starting point for healthcare reform in the United States. PMID- 10115596 TI - Medicare physician fees overhauled. The RBRVS fee system and its implications for hospitals. AB - Medicare has begun to implement a new payment system for physician services; the system's cornerstone is a resource-based relative value scale (RBRVS) that divides physician services into three components--physician work, practice expense, and malpractice insurance--and calculates a relative value for each component. The relative values for the components are adjusted for geographic differences between regional and national resource costs. Then a conversion factor transforms a relative value into a payment amount. The full RBRVS fee will be paid beginning January 1, 1992, if the fee does not differ by more than 15 percent from the service's adjusted historical payment basis. If the difference generally exceeds 15 percent, the RBRVS fee will be phased in over four years. The Medicare RBRVS fee schedule applies to both office- and hospital-based physicians. Several special provisions apply to physicians ordinarily defined as hospital based--radiologists, anesthesiologists, and pathologists. Other provisions of the fee schedule address site-of-service differentials, electrocardiograms, nonphysician practitioners, new physicians or practitioners, and Health Professional Shortage Areas. Administrators need timely strategies to manage successfully in the new environment and to sidestep lost or delayed reimbursement. RBRVS has financial and operational implications in terms of physician compensation, outpatient hospital reimbursement, new CPT codes, and new outpatient billing procedures. PMID- 10115597 TI - Revise or preserve? A flurry of views on revision of tax-exemption standards. AB - Many groups would be affected if Congress changes the tax laws governing not-for profit hospitals. The community benefit standard now in place focuses on nondiscriminatory treatment of patients whose care is paid for by public programs such as Medicaid. It also fosters universal access to emergency care regardless of ability to pay. In 1990, however, a U.S. General Accounting Office (GAO) report suggested that if Congress believes tax-exempt hospitals should provide more charity care, it should consider revising the criteria for exemption. This created a flurry of responses from the groups that would be affected. In response to the GAO's report, Rep. Edward R. Roybal, D-CA, introduced H.R. 790, and Rep. Brian J. Donnelly, D-MA, introduced H.R. 1374, bills linking tax exemption to charity care. The Roybal bill requires not-for-profit hospitals to have an open door policy for Medicare and Medicaid patients and to provide services to a reasonable number of these patients. The Donnelly bill would in essence codify the IRS's interpretation of the community benefit standard and add to it a charity care requirement. The administration reported it was opposed to a change from the current community benefit standard to an express charity care standard. Nevertheless, it would not oppose a more limited change that codifies the current position. Not-for-profit hospitals have opposed any changes, arguing that the existing community benefit standard is sufficient and that the decision of how to benefit the community should be made by an individual hospital and its community. PMID- 10115598 TI - Community benefit prevails. Are radical changes in hospital tax-exemption laws necessary? AB - Voluntary, not-for-profit hospitals are in danger of losing their tax-exempt status as policymakers lean toward stricter charity care requirements that would penalize hospitals which failed to provide at least a predetermined level of charity care. Proposed legislation abandons community benefit and advocates a relief-of-poverty standard. The relief-of-poverty standard advances the notion that hospitals are not providing enough charity care to merit their tax exemption. However, the voluntary hospitals' share of uncompensated care costs (as a percentage of total costs) increased from 70 percent in 1981 to 75 percent in 1989. The relief-of-poverty standard is inferior to the community benefit standard because it does not take into account that the character of community benefit varies among hospitals and communities. However, community benefit must be better defined. Some current activities--individual hospital reassessments, collective hospital reassessments, voluntary development of criteria, and statutory standards--will be instructive in efforts to arrive at a definition of community benefit that is appropriate for the specific community. Leaders in voluntary, not-for-profit hospitals need to develop positive and equitable criteria for hospital tax exemption. These hospitals' accountability is in question, but it is their integrity that is at stake. PMID- 10115599 TI - Taxation as metaphor. The hospital and public responsibility. AB - In the debate over the tax status of voluntary hospitals, most hospital executives and trustees do not seem to comprehend--or want to comprehend--the underlying issues. First, the terror of being associated with a tax hike has led many politicians to seek other "revenue enhancements" that are more ingenious than they are honest. On the other hand, many of these governments have legitimate financial problems and are seeking new sources of revenue. A second, related issue is uncertainty over what should be done about the uninsured and Medicaid populations. In the absence of an acceptable solution, we will continue to provide direct public support to public hospitals and indirect public support to private providers--including charitable tax exemptions. The third underlying issue is hospitals' curiously narrow view of their private-sector status. Most of the functions hospitals provide are not only publicly funded; they are, in fact, public functions. Finally, hospitals believe they are inherently moral organizations because they provide an inherently moral service. But hospitals grew to their present role in society almost by accident; their services are neither unique nor ethically superior. It is in how hospitals provide care that their morality can be measured, not in the fact that they provide some kind of care to somebody. An honest appraisal of these issues will help each hospital answer the basic question: As an ethical and moral matter, should this organization be paying taxes? But is this fight really about taxes? I believe society and government are using taxation as a metaphor for trust in hospitals. PMID- 10115600 TI - New arrangements, new scrutiny. The IRS reconsiders hospital-physician relationships at tax-exempt facilities. AB - The pressure to maintain adequate operating margins has forced many not-for profit hospitals to adopt more overtly competitive behavior than they have in the past. However, in struggling to remain economically viable, these facilities should carefully avoid actions that would threaten their tax-exempt status. Not for-profit facilities should be particularly careful that their arrangements with physicians, which often appear designed to increase referrals, do not violate the criteria according to which the Internal Revenue Code extends tax exemption to charitable organizations. Section 501(c)(3) of the code exempts organizations "no part of the net earnings of which inures to the benefit of any private shareholder or individual." According to this provision, "insiders" (i.e., those with a personal interest in or opportunity to influence organization activities from the inside) are entitled to no more than reasonable payment for their goods or services. The Internal Revenue Service (IRS) takes the position that, as employees or individuals having a close professional working relationship with a hospital, physicians are insiders. Thus a hospital that pays physicians what the IRS judges to be more than fair market value for services (or charges physicians less than fair market value for office rental) may find its exemption in jeopardy. If not-for-profit hospitals want to maintain their tax-exempt status, they must be certain the arrangements they enter into with physicians truly further their exempt purpose: to promote the health of the community. PMID- 10115601 TI - Reporting charity care. Hospitals must prepare to comply with new AICPA accounting rules. AB - To comply with new accounting rules issued by the American Institute of Certified Public Accountants (AICPA), hospitals will have to change the way they report charity care in the financial statements they prepare for fiscal years ending mid July 1991 and later. In the past, those hospitals which did report charity care information usually lumped it with bad debts under a caption such as "uncompensated services" or disclosed a specific amount of charity care to comply with Hill-Burton or other governmental programs. From now on, however, providers' financial statements must distinguish bad debt from charity care, not report gross patient revenues in the income statement, not imply that charity services generate revenue or receivables, make specific disclosures about the level of charity care provided, and report bad debts as an expense, rather than as a deduction from revenue. Distinguishing bad debts from charity care will be difficult. The AICPA defines bad debts as actual or expected uncollectibles resulting from an extension of credit, and charity care as services for which the provider does not expect payment. The AICPA believes that facilities which establish a definitive management policy on charity care should be able to distinguish between the two. To collect the data necessary to meet the AICPA requirements, hospitals need to establish a method to catalog the charity services they provide. Facilities should also ensure that patients and staff are familiar with their charity care policies. PMID- 10115602 TI - Bringing home mental healthcare. In-home peer counseling benefits the elderly. AB - Elderly persons who live alone often feel isolated and depressed, especially when they live in remote rural areas. Humboldt County, CA, is known for its rugged mountain terrain and as much as 39 inches of precipitation each winter. This can lead many homebound elderly to feel isolated. So in 1987 Humboldt Home Health Services, Eureka, CA, together with other county agencies, established a free, in home peer counseling program for area residents over age 60. After attending a free, five-day peer counseling session, representatives from HHHS and other county agencies discussed which agency would be responsible for certain peer counseling program tasks and began the counselor recruitment process. In June 1989, 12 volunteers attended the first training session. Once they complete their training, the volunteer peer counselors commit to working at least eight hours a week for one year. The eight hours are taken up by counseling sessions, travel time, meetings with supervisors, group discussion, and record keeping. Peer counselors have been trained to listen and respond to calls for help. Unlike professional counselors, however, they do not diagnose and treat complex pathological problems. On the other hand, because they have smaller caseloads than professional counselors, peer counselors are able to spend more time with their clients. PMID- 10115603 TI - A postmortem on Initiative 119. PMID- 10115604 TI - Euthanasia and assisted suicide: elements of Church teaching. PMID- 10115605 TI - Preserving our tradition of community service. PMID- 10115606 TI - In touch with visitors. PMID- 10115607 TI - Franciscan Health System of Cincinnati. Housing for the poor. PMID- 10115608 TI - Sisters of Providence Corporations. The defeat of Washington's Initiative 119. PMID- 10115609 TI - Wheaton Franciscan Services. Collaboration means long-term continuum of care. PMID- 10115610 TI - A tale of two rivers. PMID- 10115611 TI - The developing world and biomedical equipment. PMID- 10115612 TI - Accreditation and clinical engineering. PMID- 10115613 TI - Quality assurance in biomedical or clinical engineering. AB - Biomedical department directors must begin serious consideration of quality assurance (QA) implementation if they are to satisfy JCAHO directives. This consideration need not be approached with fear or anxiety. The purpose of this paper is to focus attention on the need and purpose of quality assurance in the biomedical or clinical engineering discipline while demonstrating the ease with which QA may be integrated into an existing biomedical environment. Because every biomedical program is unique, the approach described here can serve as a basic guide for tailoring essential components into a working quality assurance system. PMID- 10115614 TI - A defective unidirectional dome valve was not discovered during normal testing. AB - An incompetent unidirectional dome valve, that is, a valve which allows a significant amount of retrograde gas flow, was inadvertently discovered on an anesthesia machine that had been in daily clinical service for five years. The defective valve was not previously discovered during daily pre-use machine checkout or quarterly preventive maintenance. A review of the literature revealed that valve incompetence is prevalent and has caused patient morbidity; published daily pre-use checkout and preventive maintenance procedures do not test for valve incompetence. A simple procedure is proposed that positively tests unidirectional dome valves for both obstruction and incompetence. PMID- 10115615 TI - The Wentworth Center for Clinical Engineering: a collaborative and interactive venture. AB - A program has been developed in Boston to bring together hospital and industrial biomedical engineers, BMETs, CEs, nurses, physicians, the Massachusetts Medical Devices Society, academic engineering technologists, and students. This program is headquartered at the Center for Clinical Engineering at the Wentworth Institute of Technology, and is designed to serve and support the interests of the participants for educational, professional, networking and interdisciplinary activities. Because of the availability of engineering technology programs at Wentworth, and the willingness of local professionals to participate, a comprehensive and unique program has been developed to train BMETs and CEs. This program emphasizes hands-on electronic technology, biomedical lectures and laboratories, management lectures and in-hospital preceptorships under the supervision of BMETs, CEs, biomedical directors and nurses. PMID- 10115616 TI - Prosthetic valve selection for a pulsatile LVAD. AB - During the final development of a unique Magnetically Actuated Left Ventricle Assist Device (MALVAD), three of the most widely used clinical prosthetic valves were evaluated to determine their suitability for the stringent requirements for LVAD use, in both the inflow and outflow positions. The three valves (St. Jude Medical-SJM; Medtronic Hall-MH; Bjork-Shiley Convex-Concave-BSCC), with lumen size of 25 mm, were tested in the same appropriate mock loop to the following set of hydraulic parameters: 1) after-load systemic pressure = constant 100 mmHg; 2) preload pressure ranged from 3 mm to 18 mmHg; 3) beat rate ranged from 60 bpm to 80 bpm. Pump actuator power was held constant, correspondent with specific bpm rate, for all valves tested. Results from a series of 10 bench tests per valve showed that the SJM was significantly better, on a statistical basis, than both the MH and BSCC valves, at fill pressures of 5 mmHg. At 10-mm fill pressure, however, the statistical flow rates for both the SJM and the MH valves were significantly superior to the BSCC valve, so that the BSCC valve was classified as a marginal candidate for LVAD use. The SJM and MH valves had bench test flow rate values whose numerical difference was too small to serve conclusively as an arbitrary basis for valve choice. Because of this, the two valves were further evaluated in terms of two widely recognized, mandatory LVAD valve design criteria: (1) comparative mechanical ruggedness, and (2) relative ease and simplicity of LVAD design inclusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115617 TI - Portable anesthesia transport system. AB - Medical procedures that require general anesthesia outside of the traditional operating room setting have become commonplace. This paper describes a portable inhalational anesthesia machine developed for use in these outlying areas within the hospital. The device combines the basic components of vaporizer, oxygen analyzer, oxygen flow-meter, disposable carbon dioxide absorber and oxygen flush valve into a small package that may be carried with one hand. The unit may be used as a tabletop anesthesia machine or may be attached to a patient transport bed by means of a dedicated stand. PMID- 10115618 TI - Benchmark matrix and guide: Part II. AB - In the last issue of the Journal of Quality Assurance (September/October 1991, Volume 13, Number 5, pp. 14-19), the benchmark matrix developed by Headquarters Air Force Logistics Command was published. Five horizontal levels on the matrix delineate progress in TQM: business as usual, initiation, implementation, expansion, and integration. The six vertical categories that are critical to the success of TQM are leadership, structure, training, recognition, process improvement, and customer focus. In this issue, "Benchmark Matrix and Guide: Part II" will show specifically how to apply the categories of leadership, structure, and training to the benchmark matrix progress levels. At the intersection of each category and level, specific behavior objectives are listed with supporting behaviors and guidelines. Some categories will have objectives that are relatively easy to accomplish, allowing quick progress from one level to the next. Other categories will take considerable time and effort to complete. In the next issue, Part III of this series will focus on recognition, process improvement, and customer focus. PMID- 10115619 TI - Planning for quality. AB - By being aware of one another's needs and roles in the process--even when situations changed--the system remained clear and supported change. We learned that when we see each other as customers and fully understand our customers' needs, our processes then acquire the adaptability they need to truly individualize patient care. The project team has continued to meet sporadically over the past year to improve the care processes for these patients. Elements of both the process and patient outcomes are being monitored as well. We feel that the application of CQI concepts and methods aided us in planning for quality. The encouragement this experience brought prompted us to become even more committed to full implementation of TQM. We now have a two-year training program underway to involve every employee and physician. Project teams are working on other processes such as preoperative teaching and vendor selection. We are beginning to appreciate the fundamental change that occurs when we plan for quality. PMID- 10115620 TI - The integration of a QA/RM program in a rural healthcare obstetrical service. AB - Obstetrical services in a rural healthcare setting have special problems because the number of deliveries per month is below 100, with some facilities averaging fewer than 10 to 15 births per month. Medical resources may include obstetricians, pediatricians, or family practitioners, but not necessarily all three. Because it is not cost-effective to staff an obstetrical unit 24 hours a day when a low census is the norm, staffing patterns may be atypical and creative. The development of an effective credentialing system for both nursing and medical staffs is the first component of a QA/RM plan. Nursing staff play a vital role in modifying potential risk. When nurses do not routinely provide care on a unit, an efficient quality assurance plan is vital. Components of the plan must include staffing patterns and ratios, policies and procedures, and documentation. QA indicators should address both volume and outcome-oriented clinical indicators. Medical follow-up when indicated should also be part of the plan. Ongoing communication among team members and utilization of outside resources can assist in promoting an effective program. Although obstetrics is an area where the potential for risk exposure remains great, it is possible to create an efficient, practical risk management system. PMID- 10115621 TI - Selecting a healthcare consultant, Part I: How to get started. AB - Janet L. Scheuerman and Vaughan A. Smith outline the factors that determine why and when consulting services are appropriate, presenting an overview of the initial steps in consultant selection. The expertise of a consultant is often needed for specialized problems, problems needing immediate assessment, drastic rescue situations, difficulties that defy standard solutions, and changes in the regulatory and competitive environment. Many organizational and planning issues also require outside consulting expertise. Institutions use consultants for specialized information, an independent perspective, as catalysts for change, and for cost-effective service and education. The consulting process consists of five phases; Part I provides a careful analysis of crucial preliminary selection activities. An organizational commitment to the process must be made, and needs, key issues, and expectations defined before selecting a committee and identifying potential consulting sources. Part II will appear in the next issue of the JQA. PMID- 10115622 TI - Qualidex: a measure of quality. PMID- 10115623 TI - CPQA forum ... the Quality Assurance Certification Board (QACB). PMID- 10115624 TI - The President's message to the House of Delegates. National Association of Quality Assurance Professionals. PMID- 10115625 TI - The quality revolution in health care: five trends for the 1990s. PMID- 10115626 TI - Pennsylvania's Health Care Cost Containment Council. PMID- 10115627 TI - The future of TQM/CQI: five trends for the 1990s. PMID- 10115628 TI - Does COBRA work? The problem of patient dumping and possible solutions. PMID- 10115629 TI - Making COBRA work: the role of the federal courts. PMID- 10115630 TI - Nurses failing licensing exam get unemployment compensation. PMID- 10115631 TI - Options for state health policy: alternative benefit designs. PMID- 10115632 TI - Private-public partnerships to expand health care access. PMID- 10115633 TI - Public data and private doctors: Maine tackles treatment variations. PMID- 10115634 TI - Strategies for controlling health care costs. National Governors' Association. AB - Putting a lid on health costs is a job that states can and must tackle. There are many options available and many states are already testing them. But success in this arena will require strong leadership and cooperation among key state officials. PMID- 10115635 TI - The South accepts the challenge. PMID- 10115636 TI - Forget CEA (cost effectiveness analysis). Use DEA (data envelopment analysis)! PMID- 10115637 TI - An empirical analysis of hospital union election outcomes: implications for management. PMID- 10115638 TI - Mental health services for native Hawaiians: the need for culturally relevant services. PMID- 10115639 TI - DEA (data envelopment analysis) or dubious efficiency assessment. PMID- 10115640 TI - EFPF (economic frontier production function): DEA (data envelopment analysis) preview. PMID- 10115641 TI - Productivity analysis: DEA (data envelopment analysis) with fixed inputs. PMID- 10115642 TI - Measuring efficiency in acute care hospitals: an application of data envelopment analysis. AB - In this article, the authors attempted to demonstrate how DEA can be useful to hospital administrators and health care planners. They used actual data collected by the American Hospital Association through its Monitrend Data Service. Since these were national data, they are presented here for illustrative purposes only. The efficiency with which a hospital operates may well depend upon the local or regional labor market, the competition among health care providers in that market, and the demographics of the service area. The choice of variables was dictated by reasonableness and availability of data. Given the routine collection of case mix data by DRG since 1984, the use of a different set of output variables for any future studies would be quite appropriate. Additionally, if DEA were to be used, a consensus concerning relevant controllable and non controllable input variables would need to be achieved. There are more technical caveats of which the reader should be aware. 1) The efficiency scores are all relative and are based on the performance of the other hospitals being compared; nothing can be said about the absolute efficiency of a given hospital. However, the relative ratings are conservative in that the approach "bends over backwards" to give the individual hospital the benefit of the doubt in terms of the relative importance of the various outputs and inputs utilized. The approach maintains equity in that any weights chosen for a given hospital must be feasible for all of the other hospitals. 2. The ratings assume a causal impact of the inputs on the outputs. In addition, it is possible that inclusion of additional inputs and outputs could modify the relative scores and/or help explain the differences. However, based on the factors available, any unit rated inefficient is inferior in a very real and demonstrable sense. 3. DEA is based on the generalized notion of convexity which assumes that the performance arrived at by taking any linear weighted combination of other hospitals' inputs and outputs represents a feasible and achievable technology. The general frontier surface is approximated by piecewise-linear segments with the result that observed differences in efficiency cannot be explained away as differences in economies of scale. 4. The inefficiency score and the resource conservation potentials are based on a unit's so-called contraction path, i.e., all of the controllable inputs are required to be reduced by the same factor.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10115643 TI - Mass. hospitals to be paid under competitive system. PMID- 10115644 TI - One group of Charter debtholders OKs plan. PMID- 10115645 TI - Fla. deal gets FTC's attention, but it approves transaction. PMID- 10115646 TI - IG to investigate VA bidding practices. PMID- 10115648 TI - New York's HHC names investment banking team. PMID- 10115647 TI - HCFA probe finds FHP methods acceptable. PMID- 10115649 TI - 50 hospitals in venture with new benefits firm. PMID- 10115650 TI - HealthSouth, Continental announce plan to merge. PMID- 10115651 TI - 2 Pittsburgh hospitals settle tax dispute with county. PMID- 10115652 TI - Outcry shrinks size of malpractice award. PMID- 10115653 TI - Results of reform polls vary by viewpoint. PMID- 10115654 TI - Tax-exempt bond volume rises 32% to $16.4 billion in '91. PMID- 10115655 TI - U.S. health spending soars 11%. PMID- 10115656 TI - Investing in survival in the inner city. PMID- 10115657 TI - 1992 healthcare business outlook. AB - Whether it's with apprehension or expectation, most of us are wondering what the new year will hold. With that question in mind, Modern Healthcare staff writers and healthcare industry leaders offer their short- and long-range forecasts for all sectors and on a variety of all-encompassing issues. Some key questions: Will presidential politics pressure healthcare reform efforts? How will investor-owned companies fare under another year of regulatory scrutiny? What awaits hospitals and physicians under the new fee schedule and other Medicare rule changes? PMID- 10115658 TI - Merger permutations muddle the picture in Minnesota. AB - Merger mania again is sweeping the volatile Minneapolis-St. Paul healthcare market. Three of the four systems there are pondering a combination. Additionally, a major suburban hospital recently merged with a large group practice there. The machinations are caused in part by the systems' desires to counteract threats from managed-care organizations. PMID- 10115659 TI - JCAHO's 'Agenda for Change' to place new demands on systems. AB - The Joint Commission on Accreditation of Healthcare Organizations hasn't told hospitals enough about the new demands that its "Agenda for Change" will place on hospitals' information systems. Hospitals will have to be able to abstract medical records electronically and analyze their data to fully benefit from the program, executives at one test site say. PMID- 10115660 TI - Hospital fund raising becomes joint venture. PMID- 10115661 TI - Jobs. How do you rate? AB - Only 47% of respondents to R&I's 23rd annual Job$ Survey reported satisfaction with their last raise--that's down 10% from last year. Leading reasons for the drop: According to survey verbatims, belt-tightening companies froze salaries and delayed promotions, but increased responsibilities. To get at the prevailing attitudes of foodservice professionals about their jobs, our special report employs demographic profiles and personal interviews. PMID- 10115662 TI - Beefing up operations in service firms. AB - Many articles exhort service firm managers to empower workers and first-line supervisors, exploit technology, focus on the customer, and, above all, provide outstanding service. This article proposes a framework to help you evaluate your company's competitive standing in each of these areas. It discusses four types of companies on a continuum, from the company that is simply "available for service" to the firm that delivers world class service. The authors focus on operations, the function that controls the service encounter, and apply the manufacturing strategy paradigm to services as a means of implementing change. PMID- 10115663 TI - Coping with success: new challenges for nonprofit marketing. AB - In the tight, competitive economic climate of the 1990s, nonprofits are as concerned with marketing as are for-profit organizations. But nonprofit marketing is undoubtedly more complicated than conventional business marketing. Nonprofits have multiple, nonfinancial objectives; they can't rely on a risk cushion; they cater to multiple publics, including customers who are often not the ones who pay; they can collaborate as well as compete with competitors; and they garner more public attention, both positive and negative, than the average business. In this paper, Gallagher and Weinberg review the difficulties associated with introducing marketing into nonprofits and highlight the new challenges facing nonprofits that have successfully adopted a marketing orientation. PMID- 10115664 TI - Bundling patented drugs and medical services: an antitrust analysis. PMID- 10115665 TI - Hidden costs of employee leasing. PMID- 10115666 TI - Out of the shadows. PMID- 10115667 TI - Bringing cancer care home. AB - Community hospitals in the South are seeing new and more cancer patients. Hospitals aggressively seeking new and faster methods to treat patients in their home towns bring benefits to both. PMID- 10115668 TI - JIT. Just in time. Materials management for the 90s. PMID- 10115669 TI - Delivering patient care. 90s style. PMID- 10115670 TI - An environmental eye to the future. PMID- 10115671 TI - 1990 surgical technologist job analysis. AB - The job analysis provides information about job tasks currently performed by surgical technologists that will be used to update the certifying examination outline. Looking beyond this essential need, it also provides a wealth of information about the people in the job. It ensures that surgical technologists have a clear picture of their important role in the larger field of health care. This knowledge will enable them to chart a course for the future. PMID- 10115672 TI - Preparing for a challenge to your hospital's tax-exempt status. PMID- 10115673 TI - Pay for performance: compensating senior executives. PMID- 10115675 TI - Hospital collaboration: tough but rewarding for the 1990s. PMID- 10115674 TI - Wellness programs pay off for hospitals and their employees. PMID- 10115676 TI - The times they are a-changing. PMID- 10115677 TI - A new era of cooperation among hospitals. PMID- 10115678 TI - Community advocates keep the hospital on course. PMID- 10115679 TI - Problems of uncompensated care deepen: ProPAC report. PMID- 10115680 TI - The hospital's role in the use of physician practice parameters. PMID- 10115681 TI - The graying of Japan. PMID- 10115682 TI - How to swallow prescription prices. PMID- 10115683 TI - Organizational performance and adaptation: effects of environment and performance on changes in board composition. AB - This study examined performance as a moderator of organizational adaptation to environmental change. Change in the composition of boards of directors was examined as a dependent variable reflecting organizational attempts to deal with changing external contingencies. We tested specific hypotheses in an analysis of 290 California hospitals over a seven-year period. Results indicate that hospitals change the composition of their boards to adapt to changing environmental contingencies but that the hospitals' performance moderates the rate of their response, with poorer performers being more willing to initiate changes in board composition than strong performers. PMID- 10115684 TI - Information processing and problem solving: the migration of problems through formal positions and networks of ties. AB - A study of the flow of information about organizational problems was conducted. We found that managers often avoided passing problems to formally designated problem solvers and used personal ties to forward information to problem solvers. The strength of ties between individuals had a weak effect on passing problems across professional boundaries. PMID- 10115685 TI - AIDS knowledge and attitudes of black Americans: United States, 1990. Provisional data from the National Health Interview Survey. PMID- 10115686 TI - Designing pathways to excellence. PMID- 10115687 TI - The 1-2-3s of tracking medical staff monitors. PMID- 10115689 TI - The dilemma: human organ transplants. PMID- 10115688 TI - A success story. PMID- 10115691 TI - Category "A" operations for twin-engine helicopters. PMID- 10115690 TI - Introduction of pulse oximetry in the air medical setting. AB - The importance of adequate oxygenation in critically ill patients is widely recognized. Pulse oximetry (PO) is a non-invasive, rapid technique of arterial hemoglobin oxygen saturation (SaO2) measurement. This report is a review of our experience using the PO during air medical transport. A chart review was conducted on patients who used air medical transport between October 1988 and March 1989. Types of patients included trauma and ICU patients who were transported from either accident scenes or outlying hospitals. SaO2 and vital sign (VS) measurements were obtained pre and postflight, and inflight interventions were documented. Four groups of patients were identified: Group 1: PO used, inflight intervention employed; Group II: PO used, no inflight intervention employed; Group III: no PO used, inflight intervention employed; Group IV: no PO used, no inflight intervention employed. A dependent, paired-t test was used to compare pre and postflight SaO2 and VS measurements. The mean difference between pre and postflight measurements of SaO2, systolic blood pressure, and pulse rate were calculated within each group. Then, an ANOVA with post-hoc Newman-Keuls Test compared the means between the four groups. Of the 137 patients reviewed, 82 used PO and 55 patients did not due to technical or anatomic problems. Of the 82 patients who used PO, 19 received an inflight intervention.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115692 TI - Evolution of flight nursing and the National Flight Nurses Association. PMID- 10115693 TI - The air medical crew: is a flight physician necessary? AB - The configuration of the air medical crew has been debated since the inception of hospital-based programs in the 1970s. Today, the majority of programs use non physician crew members with a nurse/paramedic mix as the most common team. The medical literature contains little scientific basis to support or reject the use of physicians as crew members. The key to an effective air medical team, despite the configuration, is adequate training and ongoing flight experience. Unless future studies define the role of physicians on the medical team, the air medical crew configuration will be determined by each flight program based on their perception of individual needs and available resources. PMID- 10115694 TI - Physician, cut thy costs. PMID- 10115695 TI - A dumping ground for granny. PMID- 10115696 TI - Federal financial participation in state assistance expenditures--HHS. Notice. AB - The Federal Percentages and Federal Medical Assistance Percentages for Fiscal Year 1993 have been calculated pursuant to the Social Security Act (the Act). These percentages will be effective from October 1, 1992, through September 30, 1993. This notice announces the calculated "Federal percentages" and "Federal medical assistance percentages" that we will use in determining the amount of Federal matching in State welfare and medical expenditures for programs under titles I, IV-A, IV-E, IV-F, X, XIV, XVI (AABD) and XIX. The table gives figures for each of the 50 States, the District of Columbia, Puerto Rico, the Virgin Islands, Guam, American Samoa, and the Northern Mariana Islands. The percentages in this notice apply to State expenditures for assistance payments and medical services (except family planning which is subject to a higher matching rate). The statute provides separately for Federal matching of administrative costs. Sections 1101(a)(8) and 1905(b) of the Act, as revised by section 9528 of Public Law 99-272, require the Secretary of Health and Human Services to publish these percentages each year. The Secretary is to figure the percentages, by formulas described in sections 1101(a)(8) and 1905(b) of the Act, using the Department of Commerce's statistics of average income per person in each State and in the Nation as a whole. The percentages are with upper and lower limits given in those two sections of the Act. The statute specifies the percentages to be applied to Puerto Rico, the Virgin Islands, Guam, American Samoa, and the Northern Mariana Islands.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115697 TI - Assignment of agency component for review of premarket applications--FDA. Final rule. AB - The Food and Drug Administration (FDA) is promulgating a new regulation to describe how the agency will determine which component within FDA will have primary jurisdiction for the premarket review and regulation of: (1) A combination drug, device, or biologic product or (2) any drug, device, or biologic product where the center with primary jurisdiction is unclear or in dispute. This rule describes how to identify the agency's assigned review component which will, in most cases, eliminate the need for a sponsor to obtain approval from more than one FDA component for a combination product. PMID- 10115698 TI - Delegations of authority and organization; Office of the Commissioner--FDA. Final rule. AB - The Food and Drug Administration (FDA) is amending the regulations for delegations of authority to redelegate the Commissioner's authority to designate primary jurisdiction over the premarket review and regulation of combination products under section 503(g)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353(g)(1)) a provision of the Safe Medical Devices Act of 1990 to the ombudsman as the product jurisdiction officer, Office of the Commissioner. Under a regulation published elsewhere in this issue of the Federal Register, the FDA ombudsman is the designated product jurisdiction officer. PMID- 10115699 TI - Delegations of authority and organization; Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Drug Evaluation and Research--FDA. Final rule. AB - The Food and Drug Administration (FDA) is amending the regulations for delegations of authority relating to premarket approval of products that are or contain a biologic, a device, or a drug. The amendment grants directors, deputy directors, and certain other supervisory personnel in the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), and the Center for Drug Evaluation and Research (CDER) reciprocal premarket approval authority to approve such products. PMID- 10115700 TI - Medicare program; quarterly listing of program issuances and coverage decisions- HCFA. General notice. AB - This notice lists HCFA manual instructions, substantive and interpretative regulations and other Federal Register notices, and statements of policy that were published during April, May, and June 1991 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register at least every three months. We also are providing the content of the revisions of the Medicare Coverage Issues Manual published during this quarter. On August 21, 1989 (54 FR 34555), we published the content of the Manual and indicated that we will publish quarterly any updates. Adding the Medicare Coverage Issues Manual changes to this listing allows us to fulfill this requirement in a manner that facilitates identification of coverage and other changes in our manuals. PMID- 10115701 TI - Medicare program: changes to the inpatient hospital prospective payment system and fiscal year 1992 rates; correction--HCFA. Final rule; correction. AB - In the August 30, 1991, issue of the Federal Register (FR Doc. 91-20778), (56 FR 43196), we revised the Medicare inpatient hospital prospective payment system and the amounts and factors necessary to determine prospective payment rates for Medicare inpatient hospital services. These changes are applicable to discharges occurring on or after October 1, 1991. This notice corrects errors made in that document. PMID- 10115702 TI - Physician fee schedule update for calendar year 1992 and physician performance standard rates of increase for federal fiscal year 1992--HCFA. Notice. AB - This notice announces the calendar year 1992 update to the Medicare physician fee schedule and the Federal fiscal year 1992 performance standard rates of increase for expenditures and volume of physician services under the Medicare Supplementary Medical Insurance (Part B) program as required by sections 1848 (d) and (f) respectively of the Social Security Act. The fee schedule update for calendar year 1992 is 1.9 percent. The physician performance standard rates of increase for Federal fiscal year 1992 are 10.0 percent for all physician services, 6.5 percent for surgical services, and 11.2 percent for nonsurgical services. PMID- 10115703 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); drug benefits; appropriate level of care provisions--Department of Defense. Final rule. AB - This final rule amends the DoD Regulation 6010.8-R (32 CFR part 199) by: (1) Establishing the absolute requirement for approval by the Food and Drug Administration (FDA) of all prescription drugs and medicines (drugs grandfathered by the Federal Food, Drug and Cosmetic Act of 1938 may be covered under CHAMPUS as if FDA approved); (2) clarifying that medical care related to the use of Group C drugs (approved and distributed by the National Cancer Institute) and Treatment Investigational New Drugs (INDs) will not automatically be considered as experimental when the patient's medical condition warrants the use of these drugs; and (3) reclarifying a CHAMPUS provision that allows benefits in an acute facility above the appropriate level of care. The above changes are reasonable and necessary for effective and uniform administration of CHAMPUS. PMID- 10115704 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); medical documentation--Department of Defense. Final rule. AB - This final rule amends DoD 6010.8-R (32 CFR part 199) which implements the Civilian Health and Medical Program of the Uniformed Services. The final rule clarifies and strengthens medical documentation requirements under the CHAMPUS. This will assist in the maintenance of an adequate level of quality care and help ensure that payment is made only for services rendered. PMID- 10115705 TI - Medical devices; medical device, user facility, distributor, and manufacturer reporting, certification, and registration--FDA. Tentative final rule. AB - The Food and Drug Administration (FDA) is issuing a tentative final rule to require that device user facilities and distributors, including importers, submit reports to FDA and to the manufacturers, of deaths, serious illnesses and serious injuries related to medical devices. FDA is authorized to issue regulations implementing reporting requirements for user facilities and distributors by certain provisions of the Safe Medical Devices Act of 1990 (the SMDA). This tentative final rule also amends existing reporting requirements for manufacturers to conform them with the proposed reporting requirements for user facilities and distributors, and requires distributors and manufacturers to report certain malfunctions that may cause a death, serious illness or serious injury. The tentative final rule also requires foreign manufacturers to be subject to the same reporting requirements as domestic manufacturers. FDA is designating this document a tentative final rule, although under the Administrative Procedure Act it is a proposed rule. Because of the statutory deadlines discussed below, this "tentative final rule" alerts the public not only to the agency's interest in receiving comments, but also to the need for device user facilities, distributors, and other affected persons to begin preparing for compliance. PMID- 10115706 TI - Multiculturalism and occupational therapy: sharing the challenge. PMID- 10115707 TI - Retention strategy: a clinical ladder for occupational therapists. AB - This article explores the issue of retention of occupational therapists and its impact on the facility, client, department and the profession. It also describes the use of a clinical ladder as a retention tool and presents the experience of one clinical facility in developing a clinical ladder. The literature, in association with the experience of the aforementioned clinical facility in the development of a clinical ladder in an occupational therapy department, does not provide conclusive evidence of the efficacy of a clinical ladder as a retention tool. However, it does lend enough support for the concept to encourage its further use in occupational therapy departments. There is a need to be creative in the design of retention methodologies which will decrease turn over and attrition from the profession in order to provide a stable pool of personnel to agencies that employ occupational therapists. PMID- 10115709 TI - Facing the future. AB - What lies ahead for Texas society and hospitals? By the year 2000, you'll see more ethnic diversity, more elderly needing specialized care, more Texans living in cities--and fewer skilled workers. PMID- 10115710 TI - Cafeteria plans give employees more for less. PMID- 10115708 TI - Reactions of beginning counselors to situations involving death and dying. AB - It has commonly been assumed by thanatologists that client problems centering on death and dying are particularly demanding and difficult for the mental health professional. The present study tested this assumption by asking 81 beginning counselors to rate their degree of comfort with 15 counseling scenarios, 5 of which involved death or loss (e.g., terminal illness, suicide, AIDS, grief) and 10 of which concerned other focal issues (e.g., rape, marital problems). As predicted, counselors rated situations involving death and dying as substantially more uncomfortable than other presenting problems. However, counselors' levels of experience and personal death threat were unrelated to their response to death situations, leaving the cause of their discomfort with such situations unexplained. PMID- 10115711 TI - Outlook: 1990-2005. PMID- 10115712 TI - Outlook: 1990-2005. Industry output and job growth continues slow into next century. PMID- 10115713 TI - Outlook: 1990-2005. Occupational employment projections. PMID- 10115714 TI - Designing a performance appraisal tool. Part 5. PMID- 10115715 TI - Regaining control of accounts receivable. AB - Reducing a high level of outstanding accounts receivable may mean revising some or all business office operations. The first step on the road to accounts receivable recovery is conducting an audit or evaluation of department procedures. After the audit, it is important to involve staff members in setting goals to ensure a successful recovery program. PMID- 10115716 TI - Coverage denied. PMID- 10115717 TI - Consistency in healthcare research priorities. PMID- 10115718 TI - Strategy formation for clinical programs. PMID- 10115719 TI - Reducing conflict in performance appraisal. PMID- 10115720 TI - The how and why of a marketing budget. PMID- 10115721 TI - Bridging the film-digital gap. PMID- 10115722 TI - FSC's face tightening noose. PMID- 10115723 TI - The future of clinical PET. PMID- 10115724 TI - AIDS update 1991. PMID- 10115725 TI - Whither, or wither nuclear medicine? AB - In summary it appears that the future of the use of radionuclide procedures will show a continual increase in demand, utilization and growth of Nuclear Medicine as a discipline. The future of nuclear medicine physicians is less clear. Can they continue as a Renaissance model, interpreting all studies on all organs with equal expertise, or will they gradually be absorbed into organ or organ imaging sections to become a specialist on all imaging techniques on that organ? Is it true that the high technological advances that have been incorporated into Nuclear Medicine may be difficult to integrate into another discipline. For example, PET imaging is very much a part of Nuclear Medicine now and its expected growth in the future, along with the accompanying cyclotron and radiochemistry complexities, may prove to be a very large bite for any other discipline to follow. This integration, if it occurs, will not be overnight. Few radiologists practicing today in non-nuclear medicine areas would feel comfortable assuming the responsibilities of radionuclide studies, based on their three to six month stint in Nuclear Medicine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10115726 TI - Breast cancer risk analysis. PMID- 10115727 TI - Targeting long-term care for the frail elderly: models from the Social/HMO demonstration. AB - This study examined the effect of differing eligibility rules for receipt of long term care services in the four sites of the Social/HMO National Demonstration Program. Data from the first year of Social/HMO enrollment were used to model the probability of receiving a comprehensive assessment of need for long-term care benefits. Sites using state criteria for Medicaid reimbursement of a nursing home stay were more likely to give assessments to elders with functional impairment problems, whereas those using broader eligibility criteria gave assessments to enrollees with a wider range of characteristics. The results indicate that decisions about eligibility for care have important access and cost implications for consumers, payers, and providers. PMID- 10115728 TI - Nutrition service availability: an interaction potential model. AB - Availability, defined as a measure of the supply of services relative to the needs in the community, is critical to older people, particularly the socially isolated and frail elderly who are less mobile than most of the population. This research proposes an interaction potential model to examine variation in availability of services by considering the capacity and location of service providers and demand for these services. The model does not constrain older people to meet their demand within their towns' borders. Several measures of availability are calculated for nutrition services in an area agency on aging region of Connecticut, using different beta values to represent varying levels of mobility for the total older population; considerable variation exists, depending on mobility assumptions. Availability measures can be used as independent variables in analyses of variation in actual use of services; a strong correlation exists between use and availability in Connecticut. PMID- 10115729 TI - The impact of supervised exercise on the psychological well-being and health status of older veterans. AB - This study examined the impact of supervised exercise on the health status (measured by the Sickness Impact Profile [SIP]) and well-being (measured by the Psychological General Well-Being Index [PGWB]) of a sample of 43 elderly veterans. The intervention consisted of 90 minutes of exercise, 3 days per week at 70% of maximal capacity. Twenty-three (53%) participants completed a 1-year follow-up. The mean PGWB score increased significantly from 83.0 +/- 15.8 to 89.4 +/- 8.9 (p = .01). Cardiovascular fitness (measured by treadmill performance) increased significantly (p = .004). Baseline SIP scores were low (little dysfunction) and changed little. The study suggests that small but significant improvements in well-being accompany physiological benefits that the elderly experience with exercise. PMID- 10115730 TI - Quality assurance standards. PMID- 10115732 TI - Standards of practice for medical records consultants. Medical Record Association of Australia. PMID- 10115731 TI - Manilla case folders. A case for quality and design. PMID- 10115733 TI - Resource management and medical records. PMID- 10115734 TI - Business planning for medical records services. PMID- 10115735 TI - Cannock Community Hospital. Measuring up. AB - Cannock Community Hospital was to set a daunting challenge to cost control. William C. Inman and Partners describe the quantity surveyor's role as contender. PMID- 10115736 TI - Cannock Community Hospital. PMID- 10115737 TI - Cannock Community Hospital. PMID- 10115738 TI - Community Hospital Cannock--engineering services outline. PMID- 10115739 TI - Pathology laboratories and post mortem rooms: management and control--health and safety aspects. PMID- 10115740 TI - Crime trends and preventive strategies. PMID- 10115741 TI - Environmental control of glutaraldehyde. PMID- 10115742 TI - Nickel-cadmium or lead-acid? The role of standby batteries in hospital maintenance. PMID- 10115743 TI - Approaches to higher productivity in health care system. AB - The prosperity of organisations is recognised as being dependent on their comparative productivity. Productivity expresses a relationship between outputs from a system and the inputs which go into this creation. Hospital activities have to be assessed. Results have to be evaluated. The medical and paramedical staff have to quantify procedure and assess them qualitatively in order to improve the standards of care. Assessment techniques already introduced in many hospitals have succeeded in reducing the number of antibiotics (and their cost) and the amount of blood used in certain operations and also cutting the wait for operations. As long as there is unused capability in the individual or the productive system, increases in productivity can be achieved without decline in quality. If one focuses on quality while holding speed constant, quality should improve, waste should be eliminated, and productivity should increase. This can happen as long as the individual, or group of individuals, is willing to exert effort and has the capacity to achieve the quality--productivity levels desired. It is the operations manager's task to provide the facilities, tools and desired (motivation) to do so. PMID- 10115744 TI - Performance indicators as a step towards evaluation of hospital services. PMID- 10115745 TI - Need, planning and establishment of eye bank. PMID- 10115746 TI - Organizing a central sterile supply department in a hospital. PMID- 10115747 TI - Organisation and administration of mobile intensive care units or mobile advanced life support unit. PMID- 10115748 TI - Nuclear medicine department. A plan for integration and isolation. PMID- 10115749 TI - Average length of stay: a managerial tool for raising hospital productivity substantially. PMID- 10115750 TI - Care of persons with HIV infection in India--practical strategies. PMID- 10115751 TI - Role of natural justice in hospital. PMID- 10115752 TI - Cost evaluation study of radiodiagnosis department in a teaching institution. PMID- 10115753 TI - Role of neurologist in education for primary health care. PMID- 10115754 TI - Maximum handling capacity: a new concept & approach in hospital services management. PMID- 10115755 TI - Managerial issues and perspective towards meeting the hospital requirement and challenges by 2000 AD. PMID- 10115756 TI - Hospital standards for the care of HIV infected persons. AB - The perception of HIV induced illness is changing. The emphasis in treating AIDS patients should be compassionate, low technology, cost-effective care. Patient care in the community should be encouraged and facilitated as much as possible, to allow them to live as normal a life as possible. It is not only the physical effects of disease that disable patients, daily life in its many dimensions may also be affected by the impact of AIDS. Though incurable, HIV induced disease is treatable leading to an overall improvement in the patients quality of life and survival, provided there is a will, love and compassion. PMID- 10115757 TI - Role of microbiology laboratory in surveillance and control of nosocomial infections. PMID- 10115758 TI - Study on quality assessment of neonatal tetanus cases admitted in the Infectious Diseases Hospital, Dhaka. AB - This study was conducted at the Infectious Disease Hospital, Mohakhali, Dhaka through an interview schedule and check list. The study population comprised of attendants of 64 neonatal tetanus cases. It has been observed that majority of neonatal tetanus patients came from low socio-economic condition. The follow-up records of 45% admitted cases did not include complete salient features. Treatment was not reviewed in majority of cases within 6-12 hours. Progress reports of serious cases were not maintained properly in about 50% cases. Case fatality rate was very high (64.46%) and recovery rate was only 12.4%. Standard criteria and norms should be developed as to measure the performance in terms of quality assurance of neonatal tetanus cases to justify the cost effectiveness. PMID- 10115759 TI - Implementing a patient care system in a large hospital--a case study. PMID- 10115760 TI - Good man management--only way to achieve health for all by 2000 A.D. PMID- 10115761 TI - Emergence of corporate hospitals. PMID- 10115763 TI - Special report. Employers' guide to dental benefits. Data watch: the cost of a dental plan. PMID- 10115764 TI - Special report. Employers' guide to dental benefits. PMID- 10115762 TI - Role of service departments in control of hospital infection. PMID- 10115765 TI - Medicare program; reporting requirements for financial relationships between physicians and health care entities that furnish selected items and services- HCFA. Interim final rule with comment period. AB - This interim final rule sets forth reporting requirements under the Medicare program for the submission by certain health care entities of information about their financial relationships with physicians. It implements section 1877(f) of the Social Security Act, which includes the requirements that entities furnishing Medicare covered clinical laboratory services must provide HCFA with information concerning their ownership arrangements. It also provides notice of HCFA's decision to waive the requirements of section 1877(f) with respect to certain entities that do not furnish clinical laboratory services. PMID- 10115766 TI - Medicaid program; state share of financial participation--HCFA. Withdrawal of interim final rule with comment. AB - On September 12, 1991, we published in the Federal Register an interim final rule with comment entitled "Medicaid Program; State Share of Financial Participation" (56 FR 46380). It dealt with the use of State taxes and provider donations as the State share of the costs of the Medicaid program. On October 31, 1991, we published a clarifying interim final rule with comment (56 FR 56132), which withdrew and cancelled the September 12, 1991, interim final rule. After further consideration, the Secretary has also decided to withdraw the October 31, 1991 interim final rule. PMID- 10115767 TI - Medicare program; schedule of limits on home health agency costs per visit for cost reporting periods beginning on or after July 1, 1991--HCFA. Notice with comment period. AB - This notice sets forth a revised schedule of limits on home health agency costs that may be paid under the Medicare program. This revised schedule of limits applies to cost reporting periods beginning on or after July 1, 1991. As required by section 4207(d) of the Omnibus Budget Reconciliation Act of 1990 (Pub. L. 101 508), this revised schedule of limits incorporates a blended hospital wage index. PMID- 10115769 TI - Computers in Healthcare market directory. PMID- 10115768 TI - Maternal and child assistance programs; model application form--HHS, Department of Agriculture. Notice. AB - This notice publishes a model application form that States have the option of using in full, in part, with modification or not at all. It would be used by pregnant women or by children under 6 years of age to apply for benefits simultaneously under several congressionally specified "maternal and child assistance programs": (1) The Medicaid program under title XIX of the Social Security Act; (2) the Health Care for the Homeless grant program under section 340 of the Public Health Service Act; (3) the Maternal and Child Health (MCH) Services block grand program under title V of the Social Security Act; (4) the Migrant and Community Health Centers programs under sections 329 and 330 of the Public Health Service Act; (5) the Head Start program under the Head Start Act; and (6) the Special Supplemental Food Program for Women, Infants and Children (WIC) under section 17 of the Child Nutrition Act of 1966. This notice is published in accordance with section 6506(a) of the Omnibus Budget Reconciliation Act of 1989 (OBRA '89) (Pub. L. 101-239), which requires the Secretary of Health and Human Services, in consultation with the Secretary of Agriculture, to develop a model application form for the specified maternal and child assistance programs for publication in the Federal Register. This model application form represents a first effort to develop a joint model application form covering the programs mandated by Congress. If modifications are necessary due to changes in program requirements, or States or other user experience, they will be pursued. PMID- 10115770 TI - Industry leaders assess information technology's contributions to healthcare. AB - "What is the most significant contribution that information technology will make to improve the management and delivery of quality patient care in the next few years?" Computers in Healthcare has put this question to 27 of our industry's top executive leaders. Their opinions, based on long experience in the healthcare computing marketplace, reflect their very specialized and knowledgeable "take" on this issue. Within these pages, you will read how they have challenged themselves as well as everyone involved in healthcare computing to truly deliver on the capabilities that information technology has promised to bring quality healthcare delivery. PMID- 10115771 TI - Voice recognition: the key to hospital dominance. AB - Although still three to five years away, digitized voice recognition and input may hold the key to a comprehensive electronic patient clinical record and ultimately permit hospitals to retain their position as the depository of patient clinical data, according to healthcare futurist Tim Zinn. PMID- 10115772 TI - A unique approach persuades physicians. Interview by Carolyn Dunbar and Michael L. Laughlin. AB - By combining a unique 'sales' approach with a system truly designed to meet users' needs, a Denver physician and medical affairs vice president is convincing healthcare providers that computers are not the way of the future, but of today. During an on-site visit with Computers in Healthcare Editor Carolyn Dunbar and Michael L. Laughlin, industry editor, Patrick Roney, M.D., explained how Denver's Swedish Medical Center is plunging into the Computer Age. PMID- 10115773 TI - The fox, the chicken and the beagle. AB - Despite the track record of some less-than-objective consultants, the president of Elan Systems contends that good procurement advice can be had. The key, he says, is selecting firms that adhere to the code of ethics mandated under accreditation by the American Association of Healthcare Consultants. PMID- 10115774 TI - Information systems purchasing: reform overdue. AB - Drastic reforms in the way hospitals select and buy information systems are required if institutions are to effectively deal with the deluge of available technology, says the CEO of Superior Consultants. He offers guidelines for implementation of reforms and some tough questions purchasers must ask themselves during the procurement process. PMID- 10115775 TI - Smoothing the transition to contract management. PMID- 10115776 TI - The rewards of delegation. PMID- 10115777 TI - Special report on licensure, accreditation and CON. JCAHO adopts shorter, more concise standards for 1992. AB - The 1992 AMH is a key step in what will be major ongoing changes in the JCAHO's approach to accreditation. After January 1992, hospital administrators and medical staff leadership should expect that JCAHO surveyors will be looking for indications of a diligent effort to interpret and apply the continuous quality improvement requirements. Meeting the new and revised standards will require rapid implementation of the continuous quality improvement approach. The JCAHO has provided two resources to assist hospitals in this process. The first is a description of the continuous quality improvement process, in both the Introduction and in the Quality Assessment and Improvement chapter of the 1992 AMH. Also, the JCAHO has published a booklet entitled "Transitions from Quality Assurance to Continuous Quality Improvement," which is available from the JCAHO Customer Service Department. It is important that hospital administrators and medical staff leadership review the 1992 AMH promptly and make any changes necessary to comply with the new standards. Despite the fact that JCAHO has been criticized in recent years, accreditation remains important to the viability of the vast majority of hospitals, primarily because of its importance to licensing agencies and third party payors. As accreditation standards become more comparable to the Medicare Conditions of Participation, hospital accreditation will become even more closely linked to a facility's ability to receive or maintain Medicare provider status. PMID- 10115778 TI - Helping your employees cope with stress. PMID- 10115779 TI - Updating sexual harassment policies. PMID- 10115780 TI - Self-serve or be served. PMID- 10115781 TI - Goals to guide the interactions of the mental health and justice systems. AB - Interactions occur routinely between the mental health and justice systems, yet they are hindered by misunderstandings and misconceptions regarding their proper course. In addition, a number of outside forces shape these interactions and complicate efforts to improve them. In order to more clearly delineate and facilitate these interactions, 50 professionals concerned with these interactions were assembled as part of a symposium on the interactions of the justice and mental health systems. One of the primary tasks was to identify goals to direct these interactions. This article describes and categorizes the goals that were generated. PMID- 10115782 TI - Pretrial evaluations for criminal courts: contemporary models of service delivery. AB - Pretrial forensic evaluations are provided for the criminal courts throughout the United States. A variety of models of service delivery exists, and these models vary in ways that are important to the organization and finding of state mental health services. The first part of this paper describes several models of service delivery, which vary primarily in terms of centrality (central state institution vs. community service provider) and the use of inpatient vs. outpatient procedures. The second part compares these models on a number of important measures, including cost and efficiency. The final section of the paper indicates the importance of specialized forensic training and describes important components of such training. PMID- 10115783 TI - A model for the provision of jail mental health services: an integrative, community-based approach. AB - Although a considerable amount of attention has been paid to the development and implementation of mental health services in prisons, relatively little work has focused on the provision of such services to jails. Jails generally serve two purposes: (1) they hold inmates awaiting arraignment or trial and (2) they serve as short-term correctional facilities for individuals who have been assigned relatively short sentences (no longer than one or two years). Because inmnates in the first category usually remain in jail for a short period of time, it is particularly challenging to provide them mental health services. This article describes an innovative program that has recently been developed for assessing the mental health needs of inmates awaiting arraignment or trial, and providing them with mental health services. PMID- 10115784 TI - The designated forensic professional program: a state government-university partnership to improve forensic mental health services. AB - As the law/mental health field has expanded and matured in the last 20 years, the sophistication required by mental health professionals in order to respond appropriately to legal questions has grown significantly. Courts and legislatures define a growing number of legal competencies. Judges and attorneys are more familiar with mental health law than they were 10 or 20 years ago. PMID- 10115785 TI - Designing conditional release systems for insanity acquittees. AB - Monitored treatment in the community, also known as conditional release, has been described as the most important advance in the treatment of insanity acquittees in the last decade. Despite the importance of the development of conditional release, however, there has been relatively little written about relevant issues and planning principles important in designing and implementing conditional release systems. The present paper discusses important considerations relevant to conditional release that are associated with key decision points within systems for persons found not guilty by reason of insanity (NGRI). Four planning principles, generalizable to all NGRI systems, are then presented in a way that integrates the previous discussion. It is concluded that conditional release plays a crucial role in the treatment of insanity acquittees and that mental health administrators may either proactively modify their systems, in a way that balances public safety with individual rights and treatment needs, or wait for the modification mandate to be forced upon them in the wake of a highly publicized, heinous offense. PMID- 10115786 TI - Administrative issues in the follow-up treatment of insanity acquittees. AB - This paper discusses issues in the community-based management of forensic patients. Community acceptance and safety demand a careful system of follow-up treatment for insanity acquittees. Many studies have examined the recidivism of this population, but few have dealt with administrative strategies to manage their care as outpatients. In this paper, we discuss our experiences in developing systems for follow-up care of insanity acquittees in the state of Maryland. Central to this work is the balancing of clinical, judicial and community concerns. The decision for outpatient care or movement of the patient to a non-forensic (regional) hospital is a significant turning point in the forensic patient's care. One of the major challenges faced by forensic mental health services is to develop consistency of practice throughout a state. A centralized system is easier to manage, but costly. A system embedded in community mental health centers is less duplicative, but requires major and ongoing educational support. A private practice model is flexible, but administratively challenging. The authors believe Maryland possesses well developed approaches for the evaluation, treatment and conditional release of insanity acquittees. The state continues to study and redesign its systems toward increased effectiveness and efficiency. PMID- 10115787 TI - Total quality management strategies in mental health systems. AB - This paper introduces the concept of total quality management (TQM) to top managers of mental health systems. While TQM is a philosophy of management at the cutting edge of U.S. business, it has only recently entered the vocabulary of health care managers. To our knowledge, TQM has yet to be systematically applied to the state mental health service delivery system. After introducing some key concepts and techniques, we develop two extensive examples of how TQM can be integrated into the already existing management structure of the psychiatric hospital. PMID- 10115788 TI - Benefit flexibility, cost shifting and mandated mental health coverage. AB - This paper presents a policy analysis of options for making a state's mandated mental health benefit more flexible while maintaining insurance premiums at a constant level. The analysis illustrates the difficult choices facing legislatures that attempt to balance improved coverage for mental health care with concerns about rising health care costs. A sophisticated simulation model is used to assess the costs of four alternative insurance benefit design options. PMID- 10115789 TI - How mental health providers see managed care. AB - This paper reports findings from two focus groups on managed care conducted in a large U.S. city in 1989. Questions addressed included how managed care had affected mental health practice, specific experiences with managed care, the mechanisms of managed care, and how managed care could be improved. The practitioners complained of multiple problems, but clearly distinguished between "good" and "bad" firms. Firms seen as more positive struck a balance between quality care and cost containment, built ongoing relationships with providers, and negotiated with providers, rather than prescribing a treatment plan. The authors conclude that some of the poor reception by providers of managed care may have been created unnecessarily by firms which have not attended to these factors, and that attention to such factors might lead to a more ready acceptance of managed care. PMID- 10115790 TI - Racial and gender myths as key factors in pastoral supervision. AB - Explores the various dynamics activated when a black male supervisor and a white female supervisee are part of a Clinical Pastoral Education team. Uses the notion of racial and gender myths as a way to understand such a relationship. Claims that it is exceedingly important to train culture and gender conscious supervisors and that such training can lead to significant racial and gender learnings having implications beyond the CPE context. PMID- 10115791 TI - Pastoral counseling and the informed relationship. AB - Discusses the legal, ethical, and therapeutic advantages of the informed relationship. Guidelines for obtaining informed consent and a sample consent document are suggested. PMID- 10115792 TI - 1992 Sourcebook. PMID- 10115794 TI - Columbia buys--and sells--same facility in one day. PMID- 10115793 TI - Getting to no: a study of settlement negotiations and the selection of cases for trial. PMID- 10115795 TI - Despite psychiatric division woes, NME's 2nd quarter income rises 7%. PMID- 10115796 TI - Merger of rehab firms to create cash-rich giant. PMID- 10115797 TI - Evangelical buys 50% of Parkside Health Management. PMID- 10115798 TI - Revoking HMOs' tax exemptions illegal--senator. PMID- 10115799 TI - Humana division in Texas drops plan to change physician pay. PMID- 10115800 TI - Court upholds loss of hospital's exemption. PMID- 10115801 TI - Wave of mergers, affiliations starts year for hospitals. PMID- 10115802 TI - Groups attack suggestion that RBRVS may limit seniors' access to physicians. PMID- 10115803 TI - Biotech drugs: high costs becoming hard to swallow. AB - Three years ago, when the biotech clot-buster Activase was introduced, its $2,200 per-dose price tag sent shock waves through hospital budget circles. Those waves could seem like mere ripples as new genetically engineered pharmaceuticals hit the market. While the drugs perform unprecedented feats, they also carry unprecedented feats, they also carry unprecedented prices, posing new challenges for executives. PMID- 10115804 TI - HMOs' savings have 'spillover effect'--studies. AB - Researchers are gathering evidence that as health maintenance organizations increase market share, they act as a brake on a community's rising medical costs. In other words, competitive pressures from HMOs have a 'spillover effect' on the free-for-service sector, according to the author of one study. Meanwhile, a study of hospitals in California attributed more than $1 billion in savings in one year to the influence of HMOs on the market. PMID- 10115805 TI - Economics slow to decide oximeter sensor debate. AB - Reusing pulse oximeter sensors is more economical for hospitals, but making the switch from disposables won't be easy. Personnel are used to the convenience of one-use sensors, and there's been some concern about the possibility that blood borne diseases could be transmitted. But economics may win out--one industry executive says hospitals could save $100 million annually by going with reusables. PMID- 10115807 TI - Blood shortages put some surgeries on hold. PMID- 10115806 TI - Healthcare bond volume jumped 32% in 1991. AB - HCFA's new capital payment regulations had little effect on municipal healthcare borrowing in 1991, analysts said, based on year-end results that showed some 575 separate healthcare bond issues were sold for a total of $16.4 billion. That's a hefty 32% increase from the previous year when 445 issues were sold for a total of $12.4 billion. PMID- 10115808 TI - Panel to investigate nursing home financing schemes. PMID- 10115809 TI - Decline in Calif. rating results in downgradings of 76 hospitals' bonds. PMID- 10115810 TI - Healthcare job growth to stay on fast track. PMID- 10115811 TI - White House paints costly picture of 'pay or play'. PMID- 10115812 TI - Donation plans reap reduction in hospital rates. PMID- 10115813 TI - TakeCare seeks fast-track growth, bids to buy 22 Lincoln National plans. PMID- 10115814 TI - Discount 'fade' perils hospitals. PMID- 10115815 TI - Utah university hospital pulls out of heart transplant cooperative. PMID- 10115816 TI - Calif. hospital sells own Medigap plan. PMID- 10115817 TI - Moody's downgrades debt of troubled Nu-Med. PMID- 10115818 TI - New Year's Eve closure makes it 11 for Texas in 1991. PMID- 10115819 TI - Top credit ratings required a better performance in '91. PMID- 10115820 TI - Bankruptcy looms for hospital defendant. PMID- 10115821 TI - Dance card filled in: Health One, LifeSpan. PMID- 10115822 TI - HCFA begins project to evaluate cost-based rates for ventilator units. PMID- 10115823 TI - GOP begins to bash reform proposals. PMID- 10115824 TI - Satisfied consumers still want changes. PMID- 10115825 TI - Don't let payment issue diminish importance of home i.v. therapy. PMID- 10115826 TI - Appearance of conflicts of interest can damage, too. PMID- 10115827 TI - Trustees' values can aid TQM success--study. Governance Fellowship award. PMID- 10115828 TI - Financial incentives in wellness plans aimed at reducing insurance costs by helping workers shed unhealthy habits. AB - Employers are using financial incentives in hopes of boosting worker participation in wellness programs and in turn trimming their healthcare costs. For example, one company offers a free health risk appraisal that analyzes workers' habits regarding diet, smoking and exercise. The company then offers rewards for changing harmful habits. PMID- 10115829 TI - Dems script a preview of election-year health push. PMID- 10115830 TI - Pooled loan program that's backed by Maine gives hospitals access to credit, lower rates. AB - Several states are watching how a new pooled loan program works in Maine. It links credit enhancements backed by the state to the pooled borrowings, raising their ratings and lowering borrowing costs for participating hospitals. The program also will help improve access to capital for the state's 40 acute-care hospitals. PMID- 10115831 TI - HCFA seeks payback from N.J. hospitals. PMID- 10115832 TI - High court rejects appeal of Pennsylvania ruling. PMID- 10115833 TI - NME won't divulge probe's findings. PMID- 10115834 TI - Ethical issues in health care institutions. Lesson five: Research ethics. AB - Well-constructed research protocols provide the mechanism to examine new clinical practices and new approaches to the provision of health care services which can be evaluated in a systematic manner. In order to be consistent with the underlying ethical duties of health care providers, the principle of respect for persons requires fully informed consent of those subjects who can act autonomously. If the subjects have diminished autonomy, special precautions must be taken to protect their interests and welfare if they are to take part in research projects which may be of benefit to them. Research, if it is to be consistent with duties of beneficence, must be directed toward the best interests of the subject. Careful attention must be paid to the assessment of potential benefits and risks, so that the balance of benefit to risk is a favorable one. Considerations of fairness prevent us from inequitably distributing the benefits and risks, thus subjecting the most disadvantaged groups in society to further disadvantage. The requirement for prospective review of research protocols by an IRB is important in protecting the rights, health and welfare of people who take part in research. PMID- 10115835 TI - Sorting out the three Rs: RVU, RVS and RBRVS. AB - This article relates the use of relative value units from its historical function of measuring productivity to how it has influenced the structure of national fee schedules. A comparative perspective is presented of the two fee schedules establishing professional rates of reimbursement from Medicare for radiology (RVS), and for all physicians (RBRVS). PMID- 10115836 TI - Issues in patient consent. AB - Patient consent is an issue relevant to a variety of disciplines--law, ethics and communication. This paper will discuss consent in general, as well as how it specifically related to radiology departments and the roles of technologists and radiologists. PMID- 10115837 TI - Approaching clinical advancement in radiology. PMID- 10115839 TI - Takeout foods profit hospital's image. PMID- 10115838 TI - Bone densitometry: establishing an osteoporosis diagnostic center. PMID- 10115840 TI - The new trend in life cycle benefits. PMID- 10115841 TI - A perspective on health care and the employer. PMID- 10115842 TI - Investigation and discovery. PMID- 10115843 TI - Deposition of hospital professionals. PMID- 10115844 TI - Trial preparation. PMID- 10115845 TI - The trial. PMID- 10115846 TI - The appeal. PMID- 10115847 TI - Preparing a nurse for litigation. PMID- 10115848 TI - Overview--the trial. PMID- 10115849 TI - Beginning the lawsuit. PMID- 10115850 TI - The once and future role of health education in HMOs. PMID- 10115851 TI - Successful implementation of a guideline program for the rational use of lipid lowering drugs. AB - Following the National Cholesterol Educational Program's (NCEP) 1988 screening and treatment recommendations, an educational and behavior-change program at Group Health Cooperative of Puget Sound (GHC) was developed to guide the use of lipid-lowering drugs within the larger context of cardiac risk reduction. The program has been successful in advancing a rational program to enhance care and manage costs of the use of lipid-lowering agents at GHC. Cost savings have been significant over the past two years. The educational design of the program includes training and ongoing education of a core group of "lipid gurus," who educate colleagues in area medical centers in a rational approach to hyperlipidemia. Patient education and patient participation in decision-making was emphasized. Program evaluation has demonstrated that physicians and patients are satisfied with the program, and inappropriate drug expenditures have been prevented. Key elements of the program include a critical review of outcome studies in the medical literature, use of information systems, algorithms and written materials organized into a well-designed, ongoing educational program, and development of a core group of physicians and pharmacists to administer the program at the clinic level. PMID- 10115852 TI - How does your HMO evaluate health education materials?. Interview by Susan Yox. PMID- 10115853 TI - The best of health education materials. AB - The editors of HMO PRACTICE are pleased to present the Best of Health Education Materials. We asked The HMO Group member plans to submit their best health education materials in three categories: Cancer/Heart Disease; Prevention/Health Maintenance/Nutrition; and Pregnancy/Infant Care. Peer reviewers from plans across the country judged the entries. The selections are model health education materials. They are scientifically up-to-date, their target audience and purpose are clear, the reading level is appropriate for the audience, and their format enhances their message. The editors would like to thank everyone who submitted materials. All entries were of high caliber, and choosing the winners was difficult. PMID- 10115854 TI - HMO innovations. Video-enhanced medical advice; senior zoo walkers; Group Health Resource Line; enhancing health education programs through desktop publishing; home health beat; innovative school health partnership. AB - The editors of HMO PRACTICE asked clinicians and health educators in HMOs across the country to submit reports on their unique, successful patient education programs. The following HMO Innovations testify to the wide range of new technologies, enterprising partnerships, and creative ideas that are shaping health education in HMOs today. PMID- 10115855 TI - Design features of new children's hospital. PMID- 10115856 TI - More diversity in service delivery can be expected, says Minister. PMID- 10115857 TI - A new world-class hospital for Auckland children. PMID- 10115858 TI - Perspectives. President Bush's election year budget. PMID- 10115859 TI - Brain death, religious freedom, and public policy: New Jersey's landmark legislative initiative. AB - "Whole brain death" (neurological death) is well-established as a legal standard of death across the country. Recently, New Jersey became the first state to enact a statute recognizing a personal religious exemption (a conscience clause) protecting the rights of those who object to neurological death. The Act also mandates adoption through the regulatory process of uniform and up-to-date clinical criteria for determining neurological death. PMID- 10115860 TI - Justice and the market for health insurance. AB - After reviewing some of the insurance-related obstacles to access to health care, some ethical criteria for evaluating proposals aimed at reforming the health insurance marketplace to achieve universal access are developed. The additional reforms needed to eliminate many of the deficiencies in the current health insurance marketplace are discussed. It is suggested that without such substantial reforms some of the other goals such as expanded consumer choice and overall societal health care cost savings may not be effectively promoted. PMID- 10115861 TI - The National Commission on AIDS. AB - A decade after the first cases were recognized in the United States, AIDS continues to vex policymakers and fascinate the public. It has been said that AIDS acts as a prism, refracting a spectrum of controversial topics. For bioethicists, these topics include: equity in the allocation of resources for treatment and research; forgoing life-sustaining care and proxy decision making; informed consent in the context of HIV testing and screening; the ethical duties of health care workers to provide care for persons with HIV disease; and competing obligations of health care professionals to patients and to third parties who may be put at risk. PMID- 10115862 TI - A lesson in compassion. PMID- 10115863 TI - Medical care reimbursement rates for FY 92--VA. Notice. AB - In accordance with provisions of OMB Circular A-11 section 13.5(a), revised reimbursement rates have been established by the Department of Veterans Affairs for inpatient and outpatient medical care furnished to beneficiaries of other Federal agencies during FY 1992. These rates will be charged for such medical care provided at health care facilities under the direct jurisdiction of the Secretary on and after December 1, 1991. PMID- 10115864 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); corrections to the CHAMPUS diagnosis related group (DRG) payment system rates and weights--Department of Defense. Corrections to notice of revised rates. AB - This document corrects errors that appeared in the notice of revised rates which was published on October 30, 1991, (56 FR 55895) and which revised the rates and weights to be used in the CHAMPUS DRG-based payment system effective for admissions occurring on or after October 1, 1991. PMID- 10115865 TI - Occupational exposure to bloodborne pathogens--OSHA. Final rule. AB - The Occupational Safety and Health Administration hereby promulgates a standard under section 6(b) of the Occupational Safety and Health Act of 1970 (the Act), 29 U.S.C. 655 to eliminate or minimize occupational exposure to Hepatitis B Virus (HBV), Human Immunodeficiency Virus (HIV) and other bloodborne pathogens. Based on a review of the information in the rulemaking record, OSHA has made a determination that employees face a significant health risk as the result of occupational exposure to blood and other potentially infectious materials because they may contain bloodborne pathogens, including hepatitis B virus which causes Hepatitis B, a serious liver disease, and human immunodeficiency virus, which causes Acquired Immunodeficiency Syndrome (AIDS). The Agency further concludes that this exposure can be minimized or eliminated using a combination of engineering and work practice controls, personal protective clothing and equipment, training, medical surveillance, Hepatitis B vaccination, signs and labels, and other provisions. PMID- 10115866 TI - The growth industry. AB - As health care consumes an increasing share of the economic pie, critics say the nation's competitive position is at risk. But social and moral arguments for health reforms may prove more compelling. PMID- 10115867 TI - "Publicly supported" charity or private foundation? PMID- 10115868 TI - Rebirth in Tarrytown. PMID- 10115869 TI - So long, sunny side up. Preventing food-borne illness in nursing homes. PMID- 10115870 TI - ICU roundtable. Beyond state-of-the-art: health care professionals discuss the 1990 Interiors Initiative. PMID- 10115872 TI - Healthy service. AB - The Hillier Group crafts a model customer service center for U.S. Healthcare that meets the agenda of the '90s. PMID- 10115871 TI - Tendering care. AB - The Northlake Cancer Treatment Center places high-tech medicine in a soothing environment. PMID- 10115873 TI - Why Guy's chickens might never hatch. PMID- 10115874 TI - Quack doctors of the NHS? AB - Management consultants have been called 'charlatans' who only tell you what you already know. But this pessimistic view obscures several inherent paradoxes which managers should be aware of when they use outside experts. Ardha Best and Brian Bloomfield examine the role of consultants in the field of information technology. PMID- 10115875 TI - The right key. PMID- 10115876 TI - Funny money. AB - The introduction of capital charges has created many anomalies. Neil Canwell says a considerable amount of clarification is needed to give managers a framework for effective healthcare planning. PMID- 10115877 TI - Growing with health. PMID- 10115878 TI - Entrepreneurial systems. Do it yourself for profit and pleasure. AB - You don't have to have a degree in computing or a 1 m pounds budget to create a system that improves efficiency or saves money. Gren Manuel introduces a special report which celebrates the small-scale initiatives devised and implemented by health staff armed only with a personal computer. PMID- 10115879 TI - Time lords. PMID- 10115880 TI - Warning bells start to ring. PMID- 10115881 TI - A nightmare in the making? PMID- 10115882 TI - In search of times past. PMID- 10115883 TI - Ghost in the machine. AB - Management insistence that nursing must be reduced to measurable tasks is undermining the intuitive and creative essence of the profession and removing it from its wider context, says Elizabeth Hart. PMID- 10115884 TI - Management style. PMID- 10115885 TI - M25 syndrome. PMID- 10115886 TI - New kids on the block? PMID- 10115887 TI - Whistling down the wind. PMID- 10115888 TI - 'A rotten place to end your days'. PMID- 10115889 TI - A grim tale of neglect and mismanagement. PMID- 10115890 TI - Tightrope management. PMID- 10115891 TI - Practice makes perfect. AB - A GP practice was able to identify and help patients on long hospital waiting lists--and update its records--for less than 5,000 pounds. Gerald Bulger explains how they did it. PMID- 10115892 TI - Better audit, better health. PMID- 10115893 TI - Over the rainbow. AB - What is required to renew purposeful and socially relevant leadership in Britain? In the fifth and final article of his 'Travelling Light' series, David Towell draws on the experience gained during his travels to consider how we can all contribute PMID- 10115894 TI - IT training. Through the training maze. AB - With information technology affecting every area of the health service, increasing numbers of staff are looking for training to help them keep up. John Hepworth offers some guidelines for choosing the right course. PMID- 10115895 TI - IT training. A classroom at your fingertips. AB - Computer-based training is still in its infancy in the NHS. Yet it could offer a cost-effective solution to the challenges posed by new technology, argues Andrew Fraser. PMID- 10115896 TI - Payment of hospital cardiac services. AB - This report describes how acute-care community hospitals in the United States get paid for services when their patients either are entitled to Medicare or Medicaid benefits or subscribe to a Blue Cross or Blue Shield plan, a commercial insurance plan, a health maintenance organization, a preferred provider organization, or some other third-party payment mechanism. The focus of this report is on cardiac services, which are the most common type of inpatient services provided by acute care community hospitals. Over the past three decades, extraordinary advances in medical and surgical technologies as well as healthier life-styles have cut the annual death rate for coronary heart disease in half. Despite this progress, cardiovascular disease remains the number one cause of hospitalization. On average nationwide, diseases and disorders of the circulatory system are the primary reason for 17 percent of all patient admissions, and among the nation's 35 million Medicare beneficiaries they are the primary reason for 25 percent of all admissions. In the United States heart disease is the leading cause of death and a major cause of morbidity. Its diagnosis and treatment are often complex and costly, often requiring multiple hospitalizations and years of medical management. To focus management attention and resources on the immense cardiology marketplace, many hospitals have hired individuals with strong clinical backgrounds to manage their cardiology programs. These "front-line" managers play a key role in coordinating a hospital's services for patients with cardiovascular disease. Increasingly, these managers are being asked to become active participants in the reimbursement process. This report was designed to meet their needs. Because this report describes common reimbursement principles and practices applicable to all areas of hospital management and because it provides a "tool kit" of analytical, planning, and forecasting techniques, it could also be useful to hospital marketing, planning, finance, and accounting personnel. In addition, the rich reservoir of data contained in the appendixes to this report may be of interest to hospital chief executive officers, cardiologists, and cardiovascular surgeons. In addition to the introduction and summary sections, this report contains five main sections. Sequentially, these deal with: the ways hospitals get paid for what they do; ICD-9 coding DRGs, PPS, and Medicare claims administration; ways to analyze how well your hospital is doing; planning and forecasting; the new Resource-Based Relative Value Scale.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10115897 TI - Physicians' attitudes and behaviors toward home health care services. AB - The authors investigate physicians' attitudes, information-seeking behaviors, and behavioral intentions toward home health care programs. Survey results show that physicians favor the concept, but knowledge and awareness levels about available programs vary with the physicians' specialties. Evidence also is reported on specific problems encountered, sources of information used to make home care referrals, and physicians' perceptions of the impact of home care programs on their practice. Finally, policy implications are drawn for marketers of home health care programs. PMID- 10115898 TI - The silent customers: measuring customer satisfaction in nursing homes. AB - Nursing home administrators concerned with customer satisfaction and quality of care need a tool to assess and monitor ongoing satisfaction of nursing home residents and family members. The authors report a preliminary effort to develop such a survey using focus groups. PMID- 10115899 TI - Using decision support systems to market prepaid medical plans. AB - A decision support system (DSS) is described that enables executives quickly and easily to (1) manage relevant marketing information and (2) convert the information into market-effective health plans. Because the system primarily uses available records and routine transactions, it can be implemented cost efficiently. PMID- 10115900 TI - Developing a scale to measure hospital sales orientation. AB - The authors examine the sales orientation of the hospital and how it relates to the implementation of sales management policies. By polling sales managers and marketing directors at 136 hospitals nationwide, they develop scales to measure hospital sales orientation and sales management policies, and explore the relationship between them. PMID- 10115901 TI - Improving quality through patient-provider communication. AB - Though three hospitals and their patient populations were similar, one hospital was rated significantly higher on quality by its patients than were the other hospitals. Patients at that hospital felt significantly more confident that their hospital performed reliably and that they would have successful medical outcomes than did patients at the other hospitals. Analysis of patient responses shows that communicativeness (information giving and taking) and understanding (interest shown in patient's personal concerns) of medical personnel were significantly different across the three hospitals. Results underscore the importance of educating medical consumers about their medical needs and of understanding and responding to their psychosocial needs. PMID- 10115902 TI - What is quality and how much does it really matter? AB - Perhaps no single word has appeared more often in health care literature during the last 12 months than "quality." Designing and marketing high quality health care services is likely to be a strategic issue through the 1990s. The purpose of this commentary is to describe why the adoption of a three-component definition of quality may be useful for designing strategies for continual quality improvements, as well as to suggest the principal ways quality should be assessed. Answers to the question, "How much does quality really matter?" are examined. The commentary is based on the keynote address presented at the 1991 Health Care Consumer Buying Guides Conference in Cleveland, Ohio, sponsored by the Academy for Health Services Marketing. PMID- 10115903 TI - Does greater usage of a health plan reduce satisfaction? AB - As health care providers assess the future of managed care, the satisfaction of individual purchasers becomes an important issue. Do they become disenchanted after heavier use of managed care plans--and if so, does that contrast with purchasers of indemnity plans? The authors explore such issues. PMID- 10115904 TI - The right combination: volunteers as health advocates for homebound elders. PMID- 10115905 TI - Achieving the customer-oriented laboratory. AB - How should a lab be run? By attending to the unique needs of various clients: patients, physicians, and other internal and external users of its services. PMID- 10115906 TI - The deficient supervisor: a special breed of performance problem. PMID- 10115907 TI - How to earn perfect scores from your JCAHO surveyor. PMID- 10115908 TI - A spreadsheet system for managing workload data. PMID- 10115909 TI - Health facilities take $1 billion hit in N.Y. budget. PMID- 10115910 TI - Wilder submits tax-heavy revamp. PMID- 10115911 TI - More facilities distressed in fourth quarter. PMID- 10115912 TI - New service to offer hospital performance data. PMID- 10115913 TI - Baxter to open center for AIDS cell therapy. PMID- 10115914 TI - Private insurers following in Medicare's footsteps with RBRVS-type fee schedules. PMID- 10115915 TI - Humana to buy chunk of Chicago HMO market. PMID- 10115916 TI - Change sought, not trade-offs. PMID- 10115917 TI - Decision time for rationing. AB - As Oregon state officials await a decision from HCFA on whether it will issue a waiver of Medicaid rules needed to implement a healthcare rationing proposal, the debate rages on. The state hopes for a decision by early February so the program can be up and running by July, but there are still many issues to be addressed before the plan's start-up. PMID- 10115918 TI - A week of good news, bad news for Baxter. PMID- 10115919 TI - Some inside information on recruiting physicians. AB - More than one-quarter of all hospitals, group practices and managed-care organizations have developed physician recruitment functions, up from only 3% four years ago. However, their effectiveness varies. Most can improve the effectiveness of their efforts by avoiding some common pitfalls that befall most recruiting efforts. PMID- 10115920 TI - HHS inspector general, three hospitals settle charges. PMID- 10115921 TI - Closing costs bill mars start of year for Ind. hospitals. PMID- 10115922 TI - Clinton unveils plan for simplified all-payer system. PMID- 10115923 TI - Senate committee approves Democratic proposal. PMID- 10115924 TI - 'Broadened Medicare rate use would hurt hospitals'. PMID- 10115925 TI - Court reverses IRS on HMO exemptions. PMID- 10115926 TI - Political action committee sets contribution record. PMID- 10115927 TI - AHA's campaign against Medicare outpatient plan finds friendly reception from a key congressman. PMID- 10115928 TI - Hospitals cool to PPO for N.C. workers. PMID- 10115929 TI - Minnesota probing 4 providers in Duluth for antitrust violations. PMID- 10115930 TI - Calif. hospital wins 2 rounds in expansion fight. PMID- 10115931 TI - IRS sets rules on reimbursement bonds. PMID- 10115932 TI - Moody's cuts 3 ratings in N.C. PMID- 10115933 TI - 2 bills could prove taxing for Neb. hospitals. PMID- 10115934 TI - Organizations team up to offer low-cost HIV test. PMID- 10115935 TI - AHA seeks more federal funds for reclassification. PMID- 10115936 TI - The costs of hospital mergers. AB - Most hospital mergers are sold to the community as a way to reduce service and staffing duplications, consolidate clinical programs, achieve economies of scale and increase profits to add services. But two new studies on hospitals that merge in small markets indicate such mergers don't always deliver on promised savings because of the costs of new construction and expansion into high-technology services. PMID- 10115937 TI - Bush reforms criticized as too vague, too subdued. PMID- 10115938 TI - Advertising down, but marketing spending climbs; survey says focus is on targeting, not overviews. AB - Hard economic times forced hospitals nationwide to cut their advertising budgets in 1991. But marketing expenditures hit an all-time high, as hospitals shifted the emphasis to high-technology marketing efforts that employ computer data bases and market research to seek and find potential business. PMID- 10115939 TI - Ferranti talks to potential buyers after Chapter 11 bankruptcy filing. AB - More than 500 nursing facilities and 26 hospitals that rely on the financial software of Ferranti Healthcare Systems Corp. are wondering what will happen now that the company filed for protection from creditors under the Federal Bankruptcy Act. Ferranti executives say they're talking to several potential buyers. PMID- 10115940 TI - Investors' service steps in to fill void in hospital data disclosure. AB - A new investors' information service hopes to open some new doors--those belonging to hospital chief financial officers. The service aims to provide up-to date financial data on hospitals that have tapped the tax-exempt credit market, information that many facilities are choosing not to provide. Many investors trading in already-issued bonds say they often are forced to rely on outdated information in their decisionmaking. PMID- 10115941 TI - Indemnity insurance costs up 13%. PMID- 10115942 TI - Medicare spared usual cuts--for now. PMID- 10115943 TI - AHA plan to limit costs getting mixed reviews. PMID- 10115944 TI - Working with people who have cancer: guidelines for physical therapists. AB - Physical therapists are frequently called upon to aid in the physical rehabilitation of cancer patients. They also share responsibility for the psychosocial aspects of care with other members of the treatment team. The objective of this paper is to provide guidelines to assist physical therapists in providing psychosocial support to cancer patients referred for therapy around the time of diagnosis or during the initial treatment period. Normal and pathological responses of patients faced with the diagnosis and treatment of cancer, including shock, fear, anger, anxiety and depression, are noted. Special attention is given to the importance of common defense mechanisms--denial, regression, rationalization and projection--and the difficulties faced by caregivers in dealing with these defenses. Principles of psychosocial intervention appropriate for use by physical therapists are presented. Two general types are suggested: the first concerns the patient's responses and feelings about the disease and the second involves educating the patient about how to most effectively deal with the disease. Physical therapists have an obligation to provide more than physical restorative services for cancer patients; they should be able to offer psychosocial support in an effort to enhance successful rehabilitation and reintegration to normal living patterns. PMID- 10115945 TI - A system of scheduled days off. AB - This article describes a system of Scheduled Days Off (SDO) that was implemented on a trial basis for one year by the Physiotherapy Section of Foothills Provincial General Hospital in Calgary, Alberta. Development of the SDO system was an attempt by the Physiotherapy Section to improve the quality of working life without a negative impact on productivity or quality of care. Each full-time physiotherapist extended work hours by 15 minutes per day and received an SDO following 30 working days. A productivity analysis of weighted units per paid hour and patient attendances per paid hour demonstrated an increase in productivity following implementation of the system. Work time used for personal appointments, sick time and staff satisfaction were evaluated and showed positive changes during the trial period. PMID- 10115946 TI - Investment revenue goes straight to the bottom line. A case study. PMID- 10115947 TI - Is marketing money hitting the target? PMID- 10115948 TI - Requirements for effective incentive programs. PMID- 10115949 TI - Medical staff peer review. PMID- 10115950 TI - Hospital quality management survey. PMID- 10115951 TI - The Cleveland Health Quality Choice Program. PMID- 10115952 TI - 1992 air medical profession forecast. PMID- 10115953 TI - 1992 job market. PMID- 10115954 TI - The philosophy and realities of autorotations. PMID- 10115955 TI - Prehospital cricothyrotomy in air medical transport: outcome. AB - In an attempt to determine outcome, this study reviewed the records of air medical patients undergoing prehospital cricothyrotomy (CRIC) from 1987 through 1989. The study included initial airway management, Trauma Score (TS) before and after CRIC and on arrival to the hospital, outcome, and initiator of airway- either emergency medical services (EMS) or LifeFlight air medical crew (LF). There were 68 CRIC in 3285 completed missions (2%). Patients averaged 31.4 years old with 46 males and 22 females. In rural environments, 60/68 patients were injured, with 65/68 injuries by blunt mechanisms. CRIC was performed by EMS in 24/68 patients and by LF in 44/68 patients. TS before CRIC, after CRIC, and on arrival to the hospital was not significantly different, averaging 5.8, 5.8, and 5.2. There were three complications of CRIC: two bleeds and one failure to insert. Five CRIC were changed to another airway at the receiving facility. Twenty-one out of 68 patients survived to discharge. There were no statistically significant differences in complications or overall mortality between LF and EMS CRIC. Prehospital CRIC appeared safe and complications were infrequent. The CRIC, once placed, remained the airway of choice in most patients. The eventual outcome in this population suggested serious injury with the majority of patients (69%) dying. PMID- 10115956 TI - The union pitch has changed. PMID- 10115957 TI - Spent solvents. PMID- 10115958 TI - Same crisis, different day: an update on rural physician recruitment. AB - The May/June 1990 issue of Healthcare Alabama touched briefly on the need for physicians in rural areas of Alabama. As we revisit the subject, many months have passed, but the problem has not. PMID- 10115959 TI - Recruiting to the rural hospital. PMID- 10115960 TI - Hospice: the ultimate care. PMID- 10115961 TI - Taking the risk out of hospital risk management. AB - New Federal regulations, Joint Commission standards and a modest increase in litigation against hospitals are focusing new attention on the risk management role. Many hospitals are paying scant attention to the field. But can they afford to ignore it? PMID- 10115962 TI - Money madness. Are private psychiatric hospitals resorting to kidnapping in their quest for paying patients? AB - In their zeal for lucrative insurance reimbursement, some private psychiatric hospitals seem to have gone over the edge themselves. A number of these institutions, critics charge, use outright coercion to commit and retain patients. Now some formerly abducted "recruits" are fighting back with lawsuits. PMID- 10115963 TI - Medicaid program; model Medicaid application form--HCFA. Notice. AB - This notice publishes a model Medicaid application form that States have the option of using in full, in part, with modification or not at all. It would be used for noninstitutionalized individuals applying for benefits under title XIX of the Social Security Act who are not receiving cash assistance under the Aid to Families with Dependent Children (AFDC) program, Part A of title IV of the Social Security Act. This notice is published in accordance with section 6506(b) of the Omnibus Budget Reconciliation Act of 1989 (Pub. L. 101-239), which requires the Secretary to develop a model Medicaid application form for publication in the Federal Register. PMID- 10115964 TI - An in-depth investigation into a food poisoning outbreak. AB - On and shortly after the 6th May 1990, 16 people were affected by food poisoning in an old peoples' residential home, of whom two died. The vehicle of infection was identified as a baked Alaska contaminated by Salmonella enteritidis phage type (PT) 8 and, at an early stage of the investigation, the source was attributed to a single infected egg. A separate investigation by the author, however, revealed that the baked Alaska meringue had been dispensed from an inadequately cleaned piping bag which had been recovered from the kitchen a month after the outbreak. A pure, profuse culture of S. enteritidis PT8 was isolated from it. At least one secondary case may have been attributable to food made with this bag. Ministry of Agriculture Investigations of the flocks suspected of producing the eggs used for the baked Alaska demonstrated an absence of S. enteritidis. On this basis, the author considered a more likely cause of the outbreak to be the piping bag, contaminated from source or sources unknown within the kitchen. Furthermore, the possibility of human carrier transmission cannot be wholly ruled out. The incident underlines the dangers of jumping to conclusions at the outset of food poisoning investigations and emphasises that hypotheses formulated on sources of contamination must be properly tested, the absence of which, in this instance, led the investigators to unwarranted conclusions as to the cause of the outbreak. PMID- 10115965 TI - Outlook: 1990-2005. PMID- 10115966 TI - New institute shoots for the moon. AB - The Institute of Medicine's (IOM) exhaustive study on the computerized patient record is finally complete. One of the study's first recommendations is to establish an institute for the computer-based patient record to get the ball rolling. Computers in Healthcare Editor Carolyn Dunbar asks a key leader of the IOM study, Richard Dick, Ph.D., why the ball is now rolling and picking up speed rapidly toward a true electronic medical record. PMID- 10115967 TI - An eye single to the patient. Interview by Carolyn Dunbar. AB - Ralph Korpman has been thumping his "patient-centered computing" drum for some time now, and evidently somebody out there is listening--if a recent $60 million, 11-hospital contract with New York City Health and Hospital Corporation, plus three installation contracts totaling an additional $10 million, are any indication. Korpman maintains that healthcare information systems should be designed around the true unit of information: the patient. PMID- 10115968 TI - Information systems support for healthcare quality: Part II. AB - In the second and final part of his series of quality management, healthcare information systems consultant Peter Spitzer, M.D., describes how I/S can support quality healthcare services by improving the care-delivery process and by providing the data needed for quality support, monitoring and management. PMID- 10115970 TI - Information integration: the future of HIS. AB - In moving toward integrated solutions, the healthcare industry attempts to deal with the daunting amount of data required daily by healthcare knowledge workers. Frank Cavanaugh, partner and national director of the Healthcare Information Systems practice of Coopers & Lybrand, Chicago, says integration will happen incrementally. He explores several workable approaches in this first of a two part study on information integration strategies for healthcare. PMID- 10115969 TI - Integrating patient-focused information systems in an open-architecture environment. AB - The healthcare industry is beginning to realize that its services and information systems need to be customer-centered. The author contends that not only is the patient a primary customer of the healthcare provider, but the patient's physician, employer and insurerer are also "customers" who need patient-related information. These interrelationships demand integration. PMID- 10115971 TI - Adverse selection: case study of one company's experience. PMID- 10115972 TI - Super Bowl safety. PMID- 10115973 TI - When colors kill. AB - Although street gangs currently aren't present in every community across America, mounting evidence and the prophecies of many gang members have demonstrated that the number of gangs and gang membership are rising at alarming rates. Current trends in our society lead us to believe that gangs are here to stay, until there's an effective social system that will replace the gang "family," an employment structure that will allow potential gang members to "get off the streets" and a criminal-justice system that will prosecute gang-related crimes severely. If we are to safely continue to serve the public in our chosen professions, we must be able to recognize and understand the inherent dangers to which we're exposed. We must continue to expand our perceptions and learn what these dangers are to survive in the safest manner possible. Careful, constant attention to our surroundings can go a long way toward ensuring our personal safety. PMID- 10115974 TI - Rural dilemmas. AB - Problems unique to rural EMS tend to be overlooked and often remain unresolved. What will it take to remedy the situation? PMID- 10115975 TI - Waiting, waiting, waiting. AB - "Much of war is uncertainty over whether your skills are adequate to perform your mission. My mission was patient care." PMID- 10115976 TI - Workplace fire safety. PMID- 10115977 TI - Preparing for the '90s. AB - How to integrate resource development, strategic planning, marketing and public relations in the modern healthcare setting. PMID- 10115978 TI - User charges for health care: a review of recent experience. AB - This paper reviews recent experiences with increases in user charges and their effect on the utilization of health care. Evidence from several countries of differences in utilization between rich and poor is presented, and recent accounts of sharp, and often sustained, drops in utilization following fee increases, are presented and discussed. Fee income, appropriately used, represents a small but significant additional resource for health care. Recent national experiences appear to have concentrated on achieving cost recovery objectives, rather than on improving service quality and health outcomes. Appraisal of financing changes must be linked to probable health outcomes. Successful large-scale experience in linking these two is in short supply. PMID- 10115979 TI - Special report. Patients in possession of illegal drugs: what can you do about it? AB - Illicit drug use affects every area of the hospital/health care setting and presents thorny legal dilemmas for security directors and risk managers when patients are found using and/or attempting to sell controlled substances. Should you handle it privately or should you call in the police? Do local law enforcement and prosecutors really want to be bothered with every $25 worth of cocaine seized from a patient? If you inform the police and arrests are made, could your hospital develop a reputation as a drug-infested combat zone? If you handle it privately, are you at risk for litigation because of invasion of privacy or an illegal search? On the other hand, if drugs are reported and you do nothing, are you liable for a negligence lawsuit? Clearly, there is a need for proactive planning and policy development prior to being confronted with patient drug possession. In this report, hospital security directors discuss how they handle this situation at their facilities and how they formulate policies and procedures. We'll also offer advice from legal experts on patient privacy issues and interacting with local law enforcement. PMID- 10115980 TI - Contagious urban decay and the collapse of public health. PMID- 10115981 TI - Young adults in the 1980s. Why mortality rates are rising. PMID- 10115982 TI - The 'slave health deficit'. Racism and health outcomes. PMID- 10115983 TI - Barriers to care. The case of breast cancer. PMID- 10115984 TI - Resisting the quick fix. Screening is not enough. PMID- 10115985 TI - Shredding the safety net. The dismantling of public programs. PMID- 10115986 TI - The financing of long term care in Ireland. AB - Major changes are proposed for the financing and regulation of the nursing home sector in Ireland. For the first time the payment of public subvention is to be related explicitly to the means and dependency of old people. More detailed proposals have, however, yet to be worked out. This paper reviews the proposed developments and makes concrete recommendations with respect to the means testing of income and assets. The issue of consumer sovereignty is also considered. Finally, the necessity for a co-ordinated and integrated policy with respect to the financing, regulation and organisation of public and private care is stressed, particularly as a means of improving the quality of service provision. PMID- 10115987 TI - Competing hospitals: assessing the impact of self-governing status in the United Kingdom. AB - The proposals contained in the White Paper 'Working for Patients' have been described as an attempt to introduce competition into a non-competitive situation. Together with the introduction of practice budgets for family practitioners, the granting of self-governing status to NHS hospitals is the principal mechanism by which this aim will be achieved. Very little is known about the effects of competition on the delivery of health care. Evidence from the United Kingdom is non-existent and from the United States of America is inadequate and contradictory. Yet, despite the inconclusive nature of this evidence, the U.K. Government is implementing the most radical reforms of the NHS since its inception without any systematic attempt to monitor the extent to which the reforms achieve the desired ends. In the absence of any systematic evaluation the responsibility for monitoring the effects of self-governing status will fall to the managers and public health specialists in the purchasing authorities. A variety of methods are described which would enable the reforms to be evaluated without holding back their implementation. No radical reform of the NHS can be expected to have an unambiguously beneficial impact on the delivery of health care. If the U.K. Government is genuine in its desire to improve health services, it should be prepared to subject its proposals to the sort of evaluation described in this paper. PMID- 10115989 TI - The year after Kobuleti: what difference does it make? AB - Following and pursuant to a conference held in Kobuleti, Soviet Georgia in April, 1990, a paper describing proposed principles for legislation establishing a health insurance system for the U.S.S.R. and Union Republics was published. It proposed supplementing the existing publicly financed medical care system with a system of regionally based 'health insurance' funds, as well as formally recognized direct payments to health care providers. While creating the opportunity for insurance funds which were to be regionally based, the system was to be centrally directed. Since the publication of that paper, the reforms it envisions have progressed more slowly than expected. This is due to at least three factors. First, the general state of the Soviet economy, coupled with a strengthening of the movement toward greater autonomy for the Soviet Republics and an accompanying reluctance on the part of the Republics to contribute to the Union budget, has resulted in a greater reduction of that budget (and a greater budget deficit) than anticipated. Second, due in part to perverse financial incentives, the capacity of the Soviet health care system to increase production, even if the financial resources were available, is limited, and has deteriorated during the past year. Third, the patience of health care workers with their working conditions is wearing thin, resulting in less willingness on their part to cooperate with anything less than total and fundamental reform than has been the case in the past. At this point, it appears that any reform of Soviet health care will emphasize autonomy at the levels of the Republics, and a diminution of central power and control. There is a growing feeling that anything short of a significant improvement in the general Soviet economy linked with total reform of health care financing and delivery will fail to reverse the deterioration of the Soviet health care system. PMID- 10115988 TI - Prevalence of HIV infection and cost of medical follow-up for asymptomatic seropositive patients followed in general practice in France. AB - To estimate the number of HIV patients followed by general practitioners and the average cost of their medical care, a questionnaire was mailed to 500 general practitioners of the French Communicable Diseases Network (1% sample, representative of French general practitioners). They were asked the number of HIV seropositive patients detected in 1987, the number of HIV positive asymptomatic patients regularly followed, the number of consultations and the type of biological and clinical examinations prescribed. The response rate was 78%. During the past year 29% of practitioners were caring for one or more infected patients. The mean number of HIV seropositive patients known per general practitioner was 1.37 corresponding to an estimated 69,000 +/- 3000 cases, (mean +/- S.D.) for France. The mean number of HIV seropositive patients diagnosed in 1987 was 0.60 per general practitioner (30,000 +/- 2000 cases) and the mean number of HIV seropositive patients followed regularly was 0.89 per general practitioner (45,000 +/- 2500 cases). Two-thirds of HIV seropositive patients were regular patients of general practitioners. The mean number of visits per patient was 3.6 per year. Biological examinations regularly prescribed were blood count, CD4/CD8 ratio, lymphocyte counts, thrombocyte counts, HBs antigen detection and HIV antigen detection. Average costs were 523 +/- 18 FF for the first visit and 446 +/- 36 FF for subsequent examinations. In total, the average cost of general practitioner visits per patient per year have been estimated at 2,288 +/- 251 FF (380 +/- 42 US$). PMID- 10115990 TI - Trends in diagnosis over a 10-year period in a Swedish primary care district. AB - In a study that covers ten years, the panorama of diagnosis was studied at three health centres in a Swedish primary care district with the aid of an encounter form. Frequencies for the different diagnosis groups varied considerably. In the case of malignant tumours, diseases of the thyroid, other endocrine diseases, symptoms and check-up visits there were more than 3-fold differences in diagnosis frequencies between various years. The results for individual years, therefore, were not representative of diagnosis distribution in the long-term perspective. Both systematic changes and temporary fluctuations occurred during the period. There was no evident lowest common denominator for the six diagnosis groups that increased (benign tumours, diseases of the thyroid and symptoms) or decreased (urinary tract infections, other urogenital diseases and back complaints). Although frequencies for individual diagnosis groups varied sharply from year to year, the diagnosis panorama in its entirety did, however, not change decisively. Permanent district physicians took charge mainly of the chronically ill, while other doctors were more involved with acute illness. It can be concluded that with such a varied diagnosis panorama in primary care it is difficult, based on temporary statistics from individual health centres, to draw general conclusions about the composition of patients. Thus, reliable figures on diagnosis should probably be founded on continuous registration at each clinic rather than on data collected periodically from especially selected reference centres. PMID- 10115991 TI - Meta-analysis. AB - Meta-analysis corresponds to all systematic methods which use statistical techniques for combining results from several independent studies. The aim is to get a consistent estimation of the global effect of a procedure on a specified outcome. The technique allows us to increase the power of statistical testing, and to get information which cannot be drawn from one individual study. Two approaches are possible, and often combined: the qualitative approach consists of weighing various studies according to their methodological quality; the quantitative approach consists of pooling the results of different studies, in order to generate results with a higher statistical power. A meta-analysis is a long and rigorous process, which follows several steps: statement of objectives; definition of articles inclusion and exclusion criteria; literature search; collection of data and evaluation of the quality of each study; tests for homogeneity; pooling; sensitivity analyses; presentation of results; and conclusions. Meta-analysis has several advantages: it estimates the size of an effect; it improves the generalizability; it compels to rigor; it lessens the part of subjectivity. When meta-analysis is cautiously and properly done, it brings new useful information, and helps physicians and health policy makers in answering to a specific question. PMID- 10115992 TI - Home service costs: the Swedish experience. AB - This article will show that the annual cost of service and care for a receiver of home service in Sweden ranges from SEK 5,000 to SEK 435,000 according to individual disability. In our sample, the average annual cost amounts to slightly less than SEK 100,000. Furthermore, the cost of service and care for pensioners of good mental health is about SEK 50,000 higher than for the group of mentally disabled (everything else being the same). Not quite unexpectedly, the annual cost of service and care decreases when assistance from relatives increases. Without help from relatives, the annual cost increases by approximately SEK 16,000 per individual. The average annual cost is higher for home service receivers who live at home and have an alarm telephone than for those who have not got an alarm telephone (everything else being the same). Alarm telephone systems which require staff for supervision and home visits account for half of the recorded difference in cost. Both living in one's own home with handicap adjustment and living in a service flat mean a lower cost of service and care than living in one's own home without handicap adjustment (everything else being the same). For persons who are in great need of daily help, living at home implies a cost that is slightly more than 20 per cent higher than the cost for living in a service flat. PMID- 10115993 TI - Health care expenditure in Sweden--an international comparison. AB - This paper analyses health care expenditure in Sweden and compares this with the corresponding expenditure in OECD countries. The definition and measurement problems of health care expenditure are discussed, new figures for the development of health care expenditure are presented and different measures of health care expenditure are provided. We found that health care expenditure has increased by about 20% in constant prices for Sweden between 1980 and 1988, but that health care expenditure as a share of the GDP has dropped during the same period in current prices. Health care expenditure disaggregated on different age groups show for Sweden that in the age group 15-64 years, health care expenditure has not increased in constant prices between 1976 and 1985, but in the oldest age group, health care expenditure has increased considerable during this period. Health care expenditure in Sweden is as high as would be expected, taking into account the degree of economic development and the growth of expenditure during the 80s, and has followed that in comparable OECD countries. However, the relative price is lower, which means that the input of real resources are greater than in other countries. PMID- 10115994 TI - Structure, process, effectiveness and efficiency of the check and review system in Japan's health insurance. AB - Keeping medical costs at an adequate and affordable level cannot be realized by the efforts of medical facilities alone, nor by the revision of fee schedules and price schedules of drugs in Japan's health insurance systems. Rationalization and improvement in the efficiency of all of the systems, including the various insurance organizations and the organizations for review and payment, are imperative. This paper first examines the system of review and payment for insurance claims under Japan's health insurance systems with emphasis on three main points, namely (1) qualification checks, (2) check and review of insurance claims and (3) computerization of the screening process. Relevant issues facing the check and review system are then discussed. PMID- 10115995 TI - Health care expenditure and mortality from amenable conditions in the European Community. AB - This paper addresses the question whether within the European Community a higher national level of health care expenditure is associated with a larger degree of success in eliminating mortality from preventable and curable conditions. An aggregate measure of mortality from 12 amenable conditions was derived, incorporating an adjustment for the level of socio-economic development. In 1980 84, between country variation in this measure was almost 2-fold and showed surprising patterns. Rates are relatively low in Greece, The Netherlands and Denmark, and relatively high in Portugal, Italy and Germany. There was no association at all between this measure and the level of health care expenditure. These disturbing findings, which suggest substantial variation in the cost effectiveness of different health service systems, warrant further investigation. PMID- 10115996 TI - Managed care in the United States: promises, evidence to date and future directions. AB - In the United States, health maintenance organizations (HMOs) and preferred provider organizations (PPOs) have proliferated during the past decade. To a great extent, their growth has been based on the perceived promise of these organizations to reduce health care costs without compromising quality of care and introduce a level of competition into the health care market that would result in a more efficient and effective health care system. This paper examines the promise of managed care as delivered through HMOs and PPOs, the evidence to date on the extent to which their promise has been met, and recent developments in the organization of managed care systems. PMID- 10115997 TI - WI hospital overcomes neighbors' opposition to its parking structure. PMID- 10115998 TI - Experts, statistics agree: health care construction will remain strong in '92. PMID- 10115999 TI - Good energy management: 8 factors ensure success. AB - In June 1984, the Chicago-based American Hospital Association convened a national forum on energy management in health facilities. The conference generated a report titled "Cost Containment through Energy Management: a Guide for Executive Action". Recently, the AHA's Institutional Practices Committee updated the contents of and reaffirmed the message of that management advisory. The following article was adapted from the revised version of the original report. PMID- 10116000 TI - NFPA issues interpretation on sharps containers. PMID- 10116001 TI - Productivity: what is it? How do you measure it? PMID- 10116002 TI - Housekeeper hourly pay range: $5.30 to $10.74. PMID- 10116003 TI - Monitrend II offers third-quarter '91 laundry data. PMID- 10116004 TI - HCQIA's grant of immunity: panacea or Pandora's box. PMID- 10116005 TI - Surgeon, but not hospital, liable for surgery on the wrong hand. PMID- 10116006 TI - Improved customer service: measuring the payoff. AB - Will enhanced levels of service automatically lead to greater sales and profits? Here's how two companies measure the payback from improved service. PMID- 10116007 TI - Overcome the barriers to superior customer service. AB - Numerous barriers inhibit companies from implementing an effective customer service strategy. Here are some practical steps that managers have taken to overcome those barriers. PMID- 10116008 TI - Executive development as a business strategy. PMID- 10116009 TI - The generic strategy trap. AB - Management experts claim that for a company to thrive, it must concentrate on a single generic strategy--on one thing it does better than its rivals. But specialization also has its disadvantages. The author suggests that a broader, mixed approach may be preferable. PMID- 10116010 TI - A customer's definition of quality. AB - What's the best way to get "close to the customer"? One company has developed a customer feedback system to drive product design, sales, service, and support functions in order to ensure better customer responsiveness. PMID- 10116011 TI - Customer focus helps utility see the light. AB - Florida Power & Light knew it had to transform the way it operated to remain competitive. The key was to understand changing customer needs and build those needs into its planning process. PMID- 10116012 TI - The impact of the Healthiest Babies Possible Program on maternal diet and pregnancy outcome in underweight and overweight clients. AB - The Healthiest Babies Possible Program (HBP) is a prenatal intervention program for the City of Toronto and is designed to reduce the incidence of low birth weight babies. This study was undertaken to assess the impact of the HBP on dietary change and birth outcome for underweight and overweight expectant mothers. Dietary change was measured by the use of food scores applied to 24-hour dietary recalls throughout the pregnancy. Three recalls collected during the early stage of the program were selected to represent early interventions; three of the results collected during the latter stage of the program represent the late stage of intervention. Birth outcome was determined by weight gain and infant birth weight. For both groups, food scores improved throughout the early intervention period and the improvements were sustained through the remainder of the program. During pregnancy the underweight women gained more weight than the overweight women but delivered infants with lower birth weights. PMID- 10116013 TI - Medical waste becomes monster in cost-cutting fight. PMID- 10116014 TI - GPOs, alliances re-examine waste treatment options. PMID- 10116015 TI - Film prices rise. PMID- 10116016 TI - Hospitals have several methods available to treat and dispose of medical wastes. PMID- 10116017 TI - Medical Center Hospital gears up for waste handling program that recycles pre-op trash. PMID- 10116018 TI - When not-for-profit hospitals provide services, supplies outside the hospital. AB - Inquiries have been received about situations where not-for-profit hospitals provide services and/or supplies outside the hospital. Specific questions have been raised about hospice, home health care, nursing homes and ambulance services. In this dialogue, Dr. Decker examines the issues involved in such situations and makes some recommendations. PMID- 10116019 TI - Issues to consider before investing in bedside terminal systems. PMID- 10116020 TI - Paying for the past. Affirmative action, yes. And hands off the standards! PMID- 10116021 TI - Safety and health compliance for hazmat. The "HAZWOPER" (Worker Protection Standards for Hazardous Waste Operations and Emergency Response) standard. AB - With as many as 1.8 million workers at risk for hazardous-materials exposure, OSHA and the EPA have recently published rules regulating hazmat safety operations. This article summarizes these rules, commonly referred to as HAZWOPER, and addresses their impact on EMS agencies and employees. PMID- 10116022 TI - Burning the EMS candle. EMS shifts and worker fatigue. AB - Has coffee become your best friend? Do you sleep only in your dreams? Is your bed merely an illusion? If so, you are not alone; sleep deprivation is a fact of life for many EMS personnel. Though widely accepted, isn't it time that we question the effects of those long days and nights? PMID- 10116023 TI - EMS offshore. A new horizon for paramedics. AB - The difficulty in getting medical aid to offshore drilling platforms can be a source of life-threatening delays. Recently, some companies have charted new waters by actually stationing EMS crews on their rigs. PMID- 10116024 TI - 1991 EMS salary survey. AB - Does money make the EMS world go around? This fourth annual survey looks at nationwide compensation levels according to 13 different career positions in EMS. PMID- 10116025 TI - Determining adequacy of physicians and nurses for rural populations: background and strategy. PMID- 10116027 TI - The use of health service areas for measuring provider availability. AB - Measurement of the availability of health care providers in a geographic area is a useful component in assessing access to health care. One of the problems associated with the county provider-to-population ratio as a measure of availability is that patients frequently travel outside their counties of residence for health care, especially those residing in nonmetropolitan counties. Thus, in measuring the number of providers per capita, it is important that the geographic unit of analysis be a health service area. We have defined health care service areas for the coterminous United States, based on 1988 Medicare data on travel patterns between counties for routine hospital care. We used hierarchical cluster analysis to group counties into 802 service areas. More than one half of the service areas include only nonmetropolitan counties. The service areas vary substantially in the availability of health care resources as measured by physicians and hospital beds per 100,000 population. For almost all of the service areas, the majority of hospital stays by area residents occur within the service area. In contrast, for 39 percent of counties, the majority of hospital stays by county residents occur outside the county. Thus, the service areas are a more appropriate geographic unit than the county for measuring the availability of health care. PMID- 10116026 TI - Estimating rural health professional requirements: an assessment of current methodologies. PMID- 10116028 TI - Rural populations and rural physicians: estimates of critical mass ratios, by specialty. AB - As physicians and other providers of health care services see their traditional markets erode, an increasingly important element of any provider location decision is the determination of a population base or "critical mass" that can professionally and financially support a given set of health care services. While the size of a local population is not the sole determinant of success, ultimately an adequate population base to support a given spectrum of services must be defined, and providers increasingly need tools for evaluating opportunities in the new economic market. This is especially true in rural areas. An earlier supply and demand model for estimating the critical mass of population needed to support a physician in any one of 25 specialties and subspecialties in urban and suburban areas is adapted to the rural market. The assumptions inherent in the earlier model are examined and the issue of "critical mass" is examined from a rural health care perspective in this paper. PMID- 10116029 TI - HMOs and managed care: implications for rural physician manpower planning. AB - American health care is changing dramatically. Health maintenance organizations (HMOs) and other managed care plans are central to this change. Today, the majority of Americans living in metropolitan areas receive their care from these types of plans. The goal of this article is two-fold. First, it will discuss the potential implications of HMOs and managed care for physician needs and supply in rural regions. Second, it will derive insight into alternative approaches for meeting rural health manpower needs by analyzing HMO staffing patterns. As HMOs and other managed care plans expand, rural physicians, their practices, and their patients will almost certainly be affected. As described in this paper, most of these effects are likely to be positive. The staffing patterns used by HMOs provide an interesting point of comparison for those responsible for rural health manpower planning and resource development. HMOs appear to meet the needs of their enrollees with significantly fewer providers than are available nationally or suggested by the federal standards. Moreover, HMOs make greater use of nonphysician providers such as nurse practitioners and physician assistants. PMID- 10116030 TI - Issues surrounding the distribution and utilization of nurse nonphysician providers in rural America. AB - The cost and quality of health care is an ever-increasing concern. Responsible people are looking for logical solutions. One solution is the increased involvement of nurse practitioners and certified nurse midwives in the delivery of health care services to patients. This paper reviews the supply, education, and responsibilities of nurse practitioners and certified nurse midwives, government studies of the need for nonphysician providers, the cost-effectiveness of health care delivered by nurse practitioners and certified nurse midwives, and impediments to practice. PMID- 10116031 TI - Future trends in nursing practice and technology. AB - Rural hospitals will be affected by changes in nursing anticipated in the future. Welcome changes will be the maturity and life experiences new graduates will bring to the work setting, knowledge of computers, and a broadening database. New graduates will also know various methods of care delivery, including case management, and will be able to select the delivery system that best meets the needs of the patients and institution. They will be more autonomous and possess leadership and management skills. With their knowledge of community as well as institutional nursing, they will be able to draw upon the skills of both groups to bring the two areas of nursing into continuity of care for patients. A difficulty ahead for rural hospitals is recruitment of new graduates, the majority of whom will have established families and lives elsewhere. And the practice of developing their own employees for higher levels of nursing will be compounded by the doubling of time necessary to complete nursing programs in the future. PMID- 10116032 TI - The 1990s and beyond: determining the need for community health and primary care nurses for rural populations. AB - Increased numbers of primary care and advanced practice nurses with unique generalist skills will be required to meet the accelerating physiologic and sociocultural health care needs of rural populations. Several factors have been identified that will influence the demands and position of community-based nurses in rural practice settings during the next decade. A back-to-basics type of health care offered out of a growing elderly population; technological breakthroughs that make it possible for more chronically ill patients to live at home; serious substance abuse and other adolescent problems; AIDS; and high infant morbidity and mortality statistics are only some of the concerns that will demand nursing intervention. These changes speak to the need for improved nursing coordination, stronger collegial relationships, and better communication between physicians and nurses. Health care is moving in new directions to offer more efficient and technologically sophisticated care. These changes enhance the need for clinically expert educators who teach and jointly practice in programs with a rural focus. Telecommunications, and heightened computer literacy, will play a major role both in nursing education and clinical practice. The goals of kindergarten through 12th grade health promotion and disease prevention strategies in school health will be the norm and will require better prepared, and positions for, school nurses. More midwives and public health nurses will be needed to care for the growing population of sexually active adolescents who are in need of family planning and prenatal care. Underinsured and indigent populations will continue to fall within the purview of midlevel practitioners, as will providing anesthesia services in small rural hospitals. The transition of some rural hospitals into expanded primary care units (e.g., EACHs and RPCHs), and new models of case management will greatly influence nursing demands. This paper will further identify critical areas of advanced practice nursing within community settings, including new relationships with other health care providers, and will introduce strategies upon which rural health policy recommendations for the 1990s can be addressed. PMID- 10116033 TI - Geographic distribution of physician manpower: the GMENAC (Graduate Medical Education National Advisory Committee) legacy. AB - The Graduate Medical Education National Advisory Committee (GMENAC) projected the need for and supply of physicians and other providers, recommended time and access standards for health care services, and developed guidelines for the geographic distribution of physicians. Since this study, analysts have given scant attention to national problems of physician geographic distribution. The issue deserves additional scrutiny in light of the current continuing problems of underservice in rural areas. The emergence of geographic information systems offers a unique opportunity to acquire data on provider distribution and provide a framework for developing and testing redistribution policy. PMID- 10116034 TI - Current approaches to shortage area designation. AB - This paper reviews the various indicators and criteria that are in use to identify rural and urban areas with shortages of primary care physicians, dentists, psychiatrists, or nurses; areas with medically underserved populations; high migrant impact areas; and areas of greatest need/shortage, leading to lists of designated shortage or underserved areas eligible for various federal and state programs; and to lists of areas with priority for resource placement. Presenting these shortage and underservice criteria at a workshop dealing with adequacy was not meant to suggest an equivalency between the concepts of "shortage," "underservice," and "adequacy," but the shortage and underservice criteria can be thought of as a floor on the definition of adequacy, and may contain elements of that definition. Refinements or revisions to the various criteria could probably better identify the needs in rural areas, or the kind of staffing mix needed in various types of areas, or improve priority setting among designated areas; but the existing criteria remain a good first screen to identify those areas with health services-related needs that require further attention. PMID- 10116035 TI - Determination of nurse adequacy in rural areas. AB - The examination of the adequacy of nursing resources requires an analysis of a variety of factors. Because registered nurses primarily provide their services as employees of organized health care delivery structures, the number, size and type of these structures in an area are key to the nursing resources required and the nurse supply. PMID- 10116036 TI - Interorganizational theory and research: implications for health care management, policy, and research. PMID- 10116037 TI - ORs facing pressure for higher utilization. PMID- 10116038 TI - Ratios are useful for tracking performance. PMID- 10116039 TI - Surgical techs perform scrub-related tasks. PMID- 10116040 TI - Hospitals are catering to working mothers. PMID- 10116041 TI - Criteria for monitoring IV sedation patients. PMID- 10116042 TI - Team players replace turf protectors in OR. PMID- 10116043 TI - Managing performance with peer appraisal. PMID- 10116045 TI - Managers need to plan now for implementing UB92. PMID- 10116044 TI - Methods for solving nonlinear equations used in evaluating emergency vehicle busy probabilities. AB - In this paper we present two iterative methods for solving a model to evaluate busy probabilities for Emergency Medical Service (EMS) vehicles. The model considers location dependent service times and is an alternative to the mean service calibration method; a procedure, used with the Hypercube Model, to accommodate travel times and location-dependent service times. We use monotonicity arguments to prove that one iterative method always converges to a solution. A large computational experiment suggests that both methods work satisfactorily in EMS systems with low ambulance busy probabilities and the method that always converges to a solution performs significantly better in EMS systems with high busy probabilities. PMID- 10116046 TI - Respite service delivery: learning from current programs. PMID- 10116047 TI - Long term care and alternative site therapy project. AB - This paper is an evaluation of a geriatric assessment unit in an acute general hospital in a rural region of Australia: short term impact on patient's health, functional status, and use of medicines. PMID- 10116048 TI - The academic medical center and community health care for the elderly. PMID- 10116049 TI - The homeless elderly. PMID- 10116050 TI - Spontaneous ignition fires: is your plant susceptible? AB - Spontaneous ignition fires pose an unpredictable threat that textile rental operators may overlook in their safety planning. The possibility that a fire can start spontaneously in clean linen or towels may seem remote, but fire experts say the phenomenon is quite real. The lethal combination is hot, damp, oxygenated, and cotton--conditions that are present in laundries every day. Yet, fires can be prevented if companies educate their employees, adhere to dryer manufacturers' recommendations, and exercise safety vigilance. PMID- 10116051 TI - The burden of technology. AB - How do you think medical imaging technology has advanced patientcare, caused rising costs, or driven the "high-touch" out of healthcare? The question above, posed in a recent survey of administrative Radiology Journal's readers, elicited many thoughtful, often challenging responses. Whether respondents agreed with the question's slant or not, their reactions bespeak some very determined and caring people. They are committed to serving their patients and their facilities, no matter what obstacles will arise. Confronting and discussing such issues can only be a good exercise. Listening to each other's viewpoints can offer comfort or possibly provide insights to a broader vision. In the end, it helps to identify and affirm one's own values and encourages their incarnation into our daily tasks and relationships. While the "big" questions continue to be tossed around by Professional Thinkers in ethics classes and courtrooms--meanwhile, our readers are dedicated to actually living their values and reaching out to those in need. PMID- 10116052 TI - Buyers' guide supplement [corrected]. PMID- 10116053 TI - Excluded babies. PMID- 10116054 TI - Do advance directives have more rights than patients? PMID- 10116055 TI - Successful wellness programs. PMID- 10116056 TI - The edge of life. Advance directive protocols and the Patient Self-Determination Act. PMID- 10116057 TI - Meeting patients' legal needs: the void. PMID- 10116058 TI - Errors as a way of life. Part V. Who is responsible? PMID- 10116059 TI - Use of clinical pharmacists to prevent medication errors in children. PMID- 10116060 TI - Pharmacy technician competency. Part III: Statistical analysis of study results. PMID- 10116061 TI - Perspectives. More money, more money, more money. PMID- 10116062 TI - Perspectives. The good, the bad, the incomplete: Medicare's fee schedule. PMID- 10116063 TI - Perspectives. The sizzle without the steak: Bush's health care plan. PMID- 10116064 TI - Perspectives. Drug utilization review: apocalypse when? PMID- 10116065 TI - Device user regulations, not user friendly. AB - The FDA invited input from healthcare organizations on the Safe Medical Devices Act of 1990, but they ended up receiving more questions than comments. PMID- 10116066 TI - Battling with the media can be deadly. PMID- 10116067 TI - Reduction because of hospitalization--VA. Final rule. AB - The Department of Veterans Affairs (VA) has amended its adjudication regulations on reductions of pensions of certain veterans receiving institutional care. These amendments are based on recently enacted legislation and further consideration of previous legislation. The intended effect of these amendments is to minimize pension reductions when VA provides institutional care. PMID- 10116068 TI - Medicaid program: Medicaid eligibility quality control program--HCFA. Response to comments on final rule. AB - This document responds to public comments received by the Department on a final rule issued on May 31, 1990, relating to the Department's decision not to publish regulations on the basis of the results of congressionally mandated studies of the quality control systems for the Aid to Families with Dependent Children (AFDC) program and the Medicaid program. The purpose of the studies, which were required by the Consolidated Omnibus Budget Reconciliation Act of 1985, was to examine how best to operate quality control systems in order to obtain information which would allow program managers to improve the quality of administration and provide reasonable data on which to base withholding Federal matching payments for excessive levels of erroneous State payments. PMID- 10116069 TI - Medicare program; payment for customized wheelchairs--HCFA. Interim final rule with comment period. AB - Section 4152(c)(4)(B) of the Omnibus Budget Reconciliation Act of 1990 (Pub. L. 101-508) amended section 1834(a)(4) of the Social Security Act to provide that a wheelchair furnished on or after January 1, 1992 is treated as a customized item for payment purposes under part B of Medicare if it meets the definition provided in that paragraph, unless the Secretary develops specific criteria before January 1, 1992, in which case the Secretary's criteria go into effect. This interim final rule with comment period sets forth the Secretary's criteria that a wheelchair must meet to be considered a customized item. PMID- 10116070 TI - Blood Donor Locator Service--Social Security Administration. Final rules. AB - We are issuing these final regulations to govern the Blood Donor Locator Service, which we will establish and conduct, as required by section 8008 of the Technical and Miscellaneous Revenue Act of 1988 (Pub. L. 100-647). Under these regulations, we will furnish to participating States at their request the last known personal mailing address (residence or post office box) of blood donors whose blood donation shows that they are or may be infected with the human immunodeficiency virus (HIV) which causes acquired immune deficiency syndrome, if the State or an authorized blood donation facility has been unable to locate the donors. If our records or those of the Internal Revenue Service (IRS) contain an adequate personal mailing address for the donor, we will provide it to the State so that the State or the blood donation facility can inform the donor that he or she may need medical care and treatment. PMID- 10116071 TI - Infant formula record and record retention requirements--FDA. Final rule. AB - The Food and Drug Administration (FDA) is amending its infant formula regulations with respect to records, and retention of records, that relate to various subjects, including, but not limited to, microbiological and nutrient testing, manufacturers' audits, and consumer complaints. This action is in response to the 1986 infant formula amendments to the Federal Food, Drug, and Cosmetic Act (the act). The amended regulations will help ensure a safe, wholesale, and sanitary sole source of nutrition for infants. PMID- 10116072 TI - Hazardous waste management system; identification and listing of hazardous waste- EPA. Final rule and response to comments. AB - On May 19, 1980, as part of its regulations implementing section 3001 of the Resource Conservation and Recovery Act (RCRA). EPA promulgated a series of criteria for listing wastes as hazardous. On July 19, 1991, the Agency proposed to conform the language of the regulation to reflect the Agency's intent and consistent interpretation of that regulation. Today's rule finalizes the proposed rule. PMID- 10116073 TI - Pregnancy disability and child care leave: what does Title VII require? PMID- 10116074 TI - 1992 Buyer's Guide. PMID- 10116075 TI - Department of Transportation (DOT) training guidelines. PMID- 10116076 TI - Code of Ethics of the National Association of EMTs. PMID- 10116078 TI - Directory of EMS organizations. PMID- 10116077 TI - 1992 Emergency Medical Services state and province survey. PMID- 10116079 TI - The rewards of mentoring. PMID- 10116080 TI - Making the most of merchandising. PMID- 10116081 TI - Standing up to the big squeeze. AB - Consumer confidence is at its lowest ebb since 1980. Economic growth is at a standstill & unemployment & inflation are both rising. Here's a front-line report from more than three dozen operators who are fending off the recession's dual pressures of slow sales & rising costs. They are using discount pricing, partnering with vendors, setting pay for performance standards & a variety of other recession-beating practices. PMID- 10116082 TI - Inpatient orthopedics offers profitable entre. PMID- 10116083 TI - In-house recruiters: new role needs clear direction to benefit. AB - Physician recruiters are fast becoming part of the hospital's personnel arsenal. But how do administrators use these positions within the confines of their institution and when do they hire outside consultants to do the work or at least, supervise it? In the following article, the author discusses how to effectively formulate and utilize such a position in the hospital. PMID- 10116084 TI - Teamwork approach to strategy keeps CEOs in tune with players. AB - Hospital administrators will learn quickly--or by trial and error--what approach works best for developing and implementing a strategic program or plan in their institutions. But a participatory process that utilizes key physicians, board members and managers throughout will go a long way in streamlining the decision making process. The authors describe the steps of such an approach. PMID- 10116086 TI - Planning indicators. Health dollars hold high spot in order of expenditures. PMID- 10116085 TI - Cedar Rapids may become a model for collaboration. PMID- 10116087 TI - Creating health delivery systems. Interview by Donald E. Johnson. AB - Coalitions between health care providers and employers that enable hospitals to focus on the important issues of the community will go a long way in controlling costs as well as answering questions of industry. In the following interview with Health Care Strategic Management's Donald E.L. Johnson, Samuel T. Wallace, president of St. Luke's Hospital, Cedar Rapids, Iowa, a 520-bed institution that serves as a center for cancer, neonatal and heart services, describes a coalition concept that can help control costs while addressing the specific health care problems of local employees. PMID- 10116088 TI - Economic humidity control: an alternative to reheat. AB - Heat pipe technology will have a significant impact on the power consumption of many manufacturing industries, the installation costs of new or replacement air conditioning systems, and on electric utility peak demands. PMID- 10116089 TI - Efficient approach to health care industry material resource management: an empirical research. AB - The feasibility of JIT implementation in the health care industry was examined through in-depth case studies and survey research. Specifically, this research examined two different groups in the health care industry: health care institutions that have introduced JIT philosophy into their operations and those that have not. Based on this classification, the research reveals the different impacts that the introduction of JIT philosophy has had on the health care industry's inventory management, service quality, and competitiveness. According to the research result, the introduction of the JIT philosophy in the health care industry's material management system improved that system and reduced implementation problems even though the differences between the JH and the NJH were not high. However, this research found that great potentials exist for the successful implementation of JIT philosophy for material management even though most of the JIT in the health care industry is still in its early stages. Moreover, with the maturing of the stockless material management system, differences between the JH and the NJH groups will be even more significant. PMID- 10116090 TI - Developing a quality improvement program in materiel management. AB - Materiel management frequently considers itself a service organization but infrequently considers the service provided as contributing to quality patient care. Quality patient care can only be delivered if every department is delivering quality service. Materiel management's ultimate customer is the patient waiting for the supply that is to be delivered by central stores or the prosthetic device to be obtained through purchasing. Quality service is the key to success, and materiel management must be proactive and deliver quality services. PMID- 10116091 TI - Managing a manual system. PMID- 10116092 TI - The management service company's expectation of the customer. AB - The one constant factor in health care today is change. Choose your management support company carefully, expect high quality results, and communicate both positive and negative feedback immediately. This formula will give you excellent results as well as a long-term productive partnership in which cost, risk, and the end objectives can be balanced for maximum benefit. PMID- 10116093 TI - The departmental capital plan. AB - The capital budget process can be a long and time-consuming process. However, if the proper amount of effort is expended, a positive result can be achieved. This can lead to departmental and personal pride, not to mention efficiencies for the department and the hospital. With the proper capital additions in place, the hospital can go about its true business of delivering quality medical care. PMID- 10116094 TI - After the merger: now what? AB - The advantages of undertaking a linkage strategy are compelling; as more hospitals consider such, the material manager should be poised to capitalize upon strategic advantages afforded by such an occurrence and implement them. The very actions undertaken by this vital position within the organization could very easily determine the degree of success realized by a linkage strategy. PMID- 10116095 TI - Soliciting and evaluating quality-based bids. AB - This example clearly indicates that the further application of this methodology within the hospital industry is both useful and beneficial: useful as an aid in selecting the best product, and beneficial to the hospital and consumers because, in many cases, it may serve to lower the costs associated with the procurement of these products. Although the methodology itself is quite simple to use, the impact of this methodology can be far reaching. This experience also further supports the need for the adaptation of techniques within the hospital industry from other fields and from other industries. PMID- 10116096 TI - The 1990s: prescription for success. AB - MCH materiel management has successfully utilized an information system to achieve the objectives of the past decade, and it is now well into accomplishing the objectives of the 1990s. Those objectives revolved around revenue enhancement, which will occur through further integration of the information system throughout the institution. Currently the information system links accounts payable, general ledger, budgeting, and, to a lesser degree, nursing and the ancillaries. However, the plan is to enhance its integration to all departments in order to control and track not only official inventory but all patient chargeable items. This system will be able to ensure that all patient chargeable items are infact billed. One should consider, for example, the revenue effect in the surgery department, considering the dollar volume of noninventory purchases. Thus it becomes apparent that for materiel management in the 1990s there are many opportunities and challenges. Management must be able to utilize the resources available to find success and excel toward achievement of future goals. PMID- 10116097 TI - A healthy bottom line and quality patient care: can they coexist? AB - In summary, it is the writer's opinion that a healthy bottom line and quality patient care can coexist. With today's economic pressures and with more and tighter controls and regulations being imposed by the government and regulatory agencies, providers (especially hospitals) need to be cost efficient and cost effective. Will the cost-containment measures necessary to maintain a healthy bottom line reduce the quality of patient care? They needn't. In point, such measures might actually increase the quality of care by avoiding wasteful clinical practices. Quality patient care comprises three basic elements: value, service, and compassion. To omit any one of these ingredients is to remove the quality from patient care. Should this happen, no cost-containment measure will be enough to sustain a hospital. Financial accountability is essential; quality care is imperative. Blended together thoroughly, they are the recipe to survival- for the hospital and for the patient. PMID- 10116098 TI - Cost cutting for hospitals: a heuristic approach. AB - This article has suggested a model that can provide some consistency and order as hospital managers attempt to find reliable yet palatable means of cutting their institutions' costs. Like any model, it is only as sensitive as the manner in which it is applied; it is a guide rather than a substitute for clear thinking by management. Used in context, however, the model encourages clear thinking when hospital managers might otherwise be tempted to dispose of facts that do not conform to their own theories or, alternatively, find isolated budget solutions that are simple and neat but suboptimal. In the final analysis, thinking clearly is the ultimate model when the order comes to cut costs. PMID- 10116099 TI - Restructuring materiel management functions: a method for prioritizing changes and reducing costs. AB - The success of any manager depends highly on the ability to seize on opportunities that will achieve the organization's goals. Hospitals are currently searching for ways to reduce costs while maintaining or enhancing the quality of services. Quality services are increasingly being defined as those that are most responsive to customer needs. It is important, as hospital management restructures materiel systems or methods of operation for reduced costs, to focus on the user departments as the customers. The consolidation of materiel management activity should not be seen as a loss of control at the user department level. Instead it can be seen as a new way of providing service with higher quality. User departments should see concrete benefits on a weekly basis, including reduced time spent on materiel management functions; increased planning of purchasing, inventory, and distribution functions; and assistance in meeting restricted supply budgets. PMID- 10116100 TI - Play to heal. Children's Medical Center of Dallas. PMID- 10116101 TI - PPRC and the outcome of physician payment reform. AB - Medicine was right to support the new payment system because it will correct geographic inequities and channel more money toward primary care services, writes a member of the Physician Payment Review Commission who serves on the American Medical Association Board of Trustees. PMID- 10116102 TI - How the new fee schedule measures up. PMID- 10116103 TI - The payment reform lesson: political action can pay off. PMID- 10116104 TI - Medicare's new payment system. PMID- 10116105 TI - Has reform taken us where we wanted to go? AB - ASIM's executive vice president assesses the history of physician payment reform and the implications for internists. Although the new fee schedule may not be perfect, the RBRVS is right on target--it reduces the disparities between payments for cognitive and procedural services. PMID- 10116106 TI - TB transmission in hospitals. PMID- 10116107 TI - The effect of head nurse behaviors on nurse job satisfaction and performance. AB - Many nursing executives ponder the repeated problems at the unit level and occasionally surmise that effective supervision at that level holds the key to quality patient care. These pragmatic concerns, while commonplace, have yet to be explored empirically. The relationship of head nurse direction and support on subordinate job satisfaction and performance is not clearly understood. This study examines these relationships in the context of three moderating factors- role clarity, job anxiety, and unit size. Additionally, head nurse support is examined as a moderator of relationships between head nurse direction and subordinate satisfaction and job performance. Using a sample of 103 registered nurses in a medium-capacity metropolitan general hospital, the results show some significant correlations between head nurse behavior and job satisfaction and performance, and in moderating the effects of job anxiety, unit size, and support. The study highlights the need for replication in other settings. Additionally, other variables relevant to job satisfaction and performance such as life stressors (death or illness in the family) require investigation. The findings of this study reveal implications for management at the unit level and the importance of understanding subordinate behaviors in the context of head nurse support and direction. PMID- 10116108 TI - Contract management and institutional cost control. AB - The ability of contract management to control hospital cost is explored. Trends in cost-related performance factors for 61 contract-managed hospitals, three years pre- and three years postcontract, omitting the contract year, are examined. The study also considers factors derived from contract features and hospital characteristics that have been missing from past studies and more than doubles the data base of previously reported studies. To focus on current policy needs, cost-containment issues are emphasized. Analysis of these data suggests that contract management contained costs in the small isolated hospitals that have historically purchased these services during a period when cost containment was not rewarded by reimbursement policy. PMID- 10116109 TI - The public's perception of quality hospitals II: Implications for patient surveys. AB - Because there is growing consensus that monitoring quality care should be based, at least in part, on patients' perceptions (Davies and Ware 1988), this article expands earlier findings on how the public perceives the quality of hospitals and hospital care (Boscarino 1988b). In this study, the public's overall quality ratings of 155 short-term medical and surgical hospitals are analyzed by the type, size, staff ratio, mortality rate, case mix, and location. The hospitals in the study represented a national cross-section of institutions, with the results based on 20,000 adults surveyed in 40 U.S. market areas. Initial analysis shows that the public rates nonrural, larger, tertiary care, teaching, higher-patient census, better-staffed, and lower-mortality facilities higher in overall quality. Hospitals that are located in the Midwest or West, have higher average employee salaries, and that are more costly are also perceived to be of a higher quality. A multiple regression analysis reveals that combined these variables account for 50 percent of the public's quality perception, with the most important being tertiary care level, patient-census level, average employee salary, and teaching status (all positively related to higher quality). Using these variables in a discriminant function analysis, hospitals with high-perceived quality can be correctly identified 80 percent of the time. It is suggested that these findings have major significance for monitoring the quality of care, based on patients' perceptions. A practical model for doing this, one that minimizes patient biases and incorporates medical outcomes, is described in detail. PMID- 10116110 TI - Problem areas faced by hospital administrators. PMID- 10116111 TI - Pieces of the puzzle: steps toward affordable health care. AB - This essay proposes a multiple-part solution to the health care affordability crisis. Solution elements include: changing the most commonly held health insurance product to a plan with high-deductible design, and reinstituting community-based health planning. It is proposed that the federal tax code be used to create incentives to change the most commonly held benefit. Further, it is suggested that "capital licenses" be provided to support health planning. PMID- 10116112 TI - A universal access plan: a step toward national health insurance? AB - There is increasing interest by the public and by many providers in the enactment of a universal access plan for the more than 60 million Americans who are now without health insurance benefits at some time during each year. After discussing the heterogeneous characteristics of those such a plan would cover, the reasons that some key players are now supporters of a minimal benefit plan, and the funding options for such a proposal, it is concluded that there is growing support for a universal access plan to be enacted soon. The almost insurmountable issues of such a plan involve the determination of eligibility and the specific benefits to be provided, the cost and administration of the new coverage, and the predictable increase in the nation's expenditure for health care services. This article concludes with the opinion that the passage of a universal access plan is a necessary and incremental step that will provide additional time for the discussion of whether and, if so, when the United States will be prepared to implement the final steps toward a more single-payer, centrally controlled health care delivery system. PMID- 10116113 TI - Competitive strategy for successful hospital management. AB - This study examined financial and operating data for approximately 1,000 U.S. hospitals categorized by Medicare as "large urban" to determine critical relationships between business strategy and financial performance. Cost control was found to be the most important factor influencing financial performance. Other factors of importance included market share, diversification, and financing policy. PMID- 10116114 TI - Aligning business and information technology domains: strategic planning in hospitals. AB - This article develops a framework for strategic information technology (IT) management in hospitals, termed the Strategic Alignment Model. This model is defined in terms of four domains--business strategy, IT strategy, organizational infrastructure, and IT infrastructure--each with its constituent components. The concept of strategic alignment is developed using two fundamental dimensions- strategic fit and integration. Different perspectives that hospitals use for aligning the various domains are discussed, and a prescriptive model of strategic IT planning is proposed. PMID- 10116115 TI - Taxation of nonprofit hospitals: a cost impact model. AB - At a time when taxing authorities at all levels of government are reexamining present exemptions, nonprofit charitable hospitals may become concerned about potential new tax liabilities. The Tax Impact Model described here can predict the dollar amount of new taxes, the probable amount of shortfall in major payers' reimbursement for these expenses, and the resulting net financial impact. This model incorporates a set of issues that should be considered and factors for which data or assumptions are needed. It can be applied to hospitals singly or in groups. Here, the model's application to a single hospital shows that payer mix and pretax financial strength are important determinants of the impact of taxation. These findings also suggest that hospitals with a large disproportion of Medicare and Medicaid patients, and those with small revenue margins, are least able to absorb new tax expenses. PMID- 10116116 TI - Comparison of the efficacy, safety, and therapeutic usage of HA-1A and E5 in the treatment of gram-negative sepsis. AB - Clinical trials have shown that the murine monoclonal antibody E5 and the human hybrid monoclonal antibody HA-1A increase survival of patients with gram-negative sepsis. However, significant reduction in mortality associated with E5's use was limited to patients who had not progressed to refractory shock. Patients treated with E5 compared to placebo receivers were also significantly more likely to experience resolution of organ failures. Significant reductions in morbidity and mortality associated with HA-1A's use were limited to patients with gram-negative bacteremia, and occurred even in patients with shock. Treatment with HA-1A also had a significant positive effect on resolution of the major complications of sepsis (shock, disseminated intravascular coagulation, acute renal failure, acute hepatic failure, or adult respiratory distress syndrome) in patients with documented gram-negative bacteremia. Both products appear to be safe, with generally mild, transient, and clinically insignificant adverse effects reported. PMID- 10116117 TI - Pediatric emergency information sheet using a microcomputer. AB - Calculating the appropriate dosage of a drug and the right equipment size during an emergency situation can be a time-consuming, frustrating, and error-prone process, considering the shortage of time during a resuscitation. A microcomputer program was developed to aid in the care of pediatric patients in emergency or 'code' situations. This is accomplished by use of a printout of a patient specific chart for most needed critical care drugs and equipment used during an emergency. This program is written in "C" language and is menu-driven. PMID- 10116119 TI - Annual pharmaceutical manufacturers directory--1992. PMID- 10116118 TI - A comparison of the accuracy of unit dose cart fill with the Baxter ATC-212 computerized system and manual filling. AB - Pharmacy Service of the Department of Veteran Affairs Medical Center in Lincoln, Nebraska recently implemented a computerized Baxter ATC-212 Unit Dose System. During implementation of this system, pharmacy technicians completed an accuracy comparison with manual filling. The Baxter ATC-212 System was 99.98% accurate and manual filling was 92.62% accurate. The accuracy of the combination of manually and ATC-212 filled drawers was 98.77%. The technicians had a median error rate of three errors per day with an average 352 doses filled per day. PMID- 10116120 TI - Implementation and analysis of a non-floor stock controlled substance unit dose system in a pediatric hospital. AB - The purpose of this study was to evaluate the implementation of a modified unit dose dispensing system for schedule II controlled substances. Each dose is signed out of stock for the intended patient. Changes in the system required revision of dispensing records and procedures in pharmacy and nursing. After implementation the error rate for controlled substances was reduced to a level equivalent to non controlled substances. A workload study was conducted in the pharmacy and on two general medical-surgical units. Small increases in workload occurred. Although this system is a modified unit dose system it does provide some of the safety features found in unit dose systems. Patient care benefits may decrease hospital liability in high-risk patients to offset cost factors. PMID- 10116121 TI - America's growing diversity: melting pot or rainbow? PMID- 10116122 TI - The shape of things to come, Part 8. The new workforce. PMID- 10116123 TI - Benefiting from workforce diversity. PMID- 10116124 TI - Lessons from UPS. PMID- 10116125 TI - Making the invisible visible. PMID- 10116126 TI - Measuring how your organization really works. PMID- 10116127 TI - Making a community agenda. PMID- 10116128 TI - Managing diversity--resources. AB - The Healthcare Forum Journal has compiled the following compendium of resources to serve as an aid to hospitals and other healthcare organizations in managing diversity optimally. This listing is not exhaustive. If you know of additional resources to help hospitals in managing diversity, please let us know by writing to: Editor, Healthcare Forum Journal, 830 Market Street, San Francisco, CA 94102. We'll report further resources and programs in upcoming issues. PMID- 10116129 TI - The practical zealot. Interview by Joe Flower. AB - In 1987, Ellen Gaucher took an unusual trip. As senior associate director of the University of Michigan's sprawling 11,000-employee Medical Center, she was invited to a conference about a movement that was rapidly growing in the word of business--total quality. The occasion was the organizational conference of the National Demonstration Project on Quality Improvement in Health Care, led by the Harvard Community Health Plan in Boston. Gaucher was skeptical at first. Total quality seemed a great way to make better cars, light bulbs, and aluminum siding, but would it work in a service industry? More to the point, would it work in an industry as complex, as critical, as pressured, as high-tech, as human, and as intellectual as healthcare? But by the second day, she says, "I was sold that this was what we had needed for a long time." She hurried back to Michigan like a missionary trekking into cannibal country. Today, not only is the University Medical Center deep in a total quality conversion experience, so is the University itself, through its president, James J. Duderstadt. He was exposed to the idea through Gaucher: In his ex-officio position as chairman of the Medical Center's board, he had experienced her vivid and enthusiastic educational efforts. Gaucher has related her intense experiences with TQ at conferences, in articles, in the 1990 book, Transforming Healthcare Organizations (winner of the Hamilton Award given by the American College of Healthcare Executives for the best book of the year) as well as the forthcoming Total Quality in Healthcare (both co-authored with Richard Coffey). (ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10116130 TI - Borrowing the Disney magic. PMID- 10116131 TI - Physician self-referrals and joint ventures: should they be banned? PMID- 10116132 TI - Malpractice liability: can arbitration replace litigation? PMID- 10116133 TI - Computerizing medical records: legal and administrative changes necessary. PMID- 10116135 TI - Lumber warehouse on a flood plain becomes centralized data center. PMID- 10116134 TI - Hospital capital costs: the new Medicare reimbursement system. PMID- 10116136 TI - New rules, public outcry spur increase in regional waste-treatment options. PMID- 10116137 TI - Deadlines loom for FCC's rule on telephone access. PMID- 10116138 TI - Two-page FDA form eases device-act compliance. PMID- 10116139 TI - Solving 7 common carpet troubles in health care. PMID- 10116140 TI - Monitrend offers third-quarter '91 security data. PMID- 10116141 TI - Remanufactured equipment 'as good as new'. PMID- 10116142 TI - Management competences--do they help? PMID- 10116143 TI - Alternative futures for the training function. PMID- 10116144 TI - Setting up a pay and benefits information unit. PMID- 10116145 TI - The Lincolnshire Joint Emergency Services Initiative for staff at risk following critical incidents. AB - This article is based on a paper presented by Roderick J. Orner at the Annual Conference of the National Association for Health Service Personnel Officers, Bristol, 20-21 September 1991. The scheme won the Prize for Innovation in HRM at the National Healthcare Awards for Excellence in Human Resource Management 1991. PMID- 10116146 TI - The development of manpower and business planning skills among line managers. PMID- 10116147 TI - Nurses in the National Health Service. Reflections on recent industrial unrest. PMID- 10116148 TI - Care for the elderly must be tailored to their needs. PMID- 10116149 TI - The NUPE (National Union of Public Employees) presence among nurses. PMID- 10116150 TI - What do you know? AB - Available data don't tell us enough about costs, trends or utilization patterns to guide efforts at reform of the system. PMID- 10116151 TI - Misleading notions. Social, political and economic myths prevent us from learning from other countries' experiences in financing health care. PMID- 10116152 TI - Where does all that money go? PMID- 10116153 TI - Incompatible goals. Experience with the Medicaid program offers lessons about the economics and politics of public-sector health insurance. PMID- 10116154 TI - Tracking the dollars. PMID- 10116155 TI - The unrefined art of documentation. PMID- 10116156 TI - New act compels EMS to define new roles. PMID- 10116157 TI - Post-traumatic stress disorder. When the rescuer becomes the victim. AB - Many people associate PTSD with veterans of the Vietnam War. But emergency responders are also vulnerable to this condition when trauma takes its psychological toll. PMID- 10116158 TI - A province-by-province look at Canadian EMS. AB - Recent elections in the United States have put politicians on notice that people are voting their dissatisfaction with this country's lack of a national health care plan. Suddenly, Congress is flooded with health-care financing legislation, and presidential candidates are hustling to propose plans in their platforms. As we consider various health-care solutions, what can we learn from Canada's experience? PMID- 10116159 TI - Debating quality assurance vs. quality improvement. PMID- 10116160 TI - 1992 Almanac. EMS in the United States: a survey of providers in the 200 most populous cities. PMID- 10116161 TI - 1992 Almanac. State EMS directors. PMID- 10116162 TI - 1992 Almanac. Information resources. PMID- 10116163 TI - Total hospital inventory control. PMID- 10116164 TI - Computers and materiel management workflow. PMID- 10116165 TI - EtO sterilization: a taxing question. PMID- 10116167 TI - Computer information systems, bedside. ECRI. PMID- 10116166 TI - Labor relations: an update. AB - Preventive labor relations training for managers and supervisors is vital today. Management must take the necessary steps to prepare its leadership to face the reality of hospitals being a prime organization target in the 1990s. The U.S. Supreme Court ruling will undoubtedly result in increased union activity as was experienced following the enactment of the 1974 healthcare amendments. Because of the rapid changes taking place within the healthcare industry and these new bargaining unit rules, hospitals will be targeted by unions. Management must be prepared in order to remain union free. Employee opinion surveys and preventive labor relations training for managers and supervisors are positive steps to be considered for a union-free workplace. PMID- 10116168 TI - "At-will" termination and the right to keep a job. PMID- 10116169 TI - Maintaining health in office environments. PMID- 10116170 TI - Does Germany hold the key to U.S. health-care reform? PMID- 10116171 TI - German medicine--through a doctor's eyes. PMID- 10116172 TI - The fee schedule will be only one of your worries. PMID- 10116173 TI - HMOs have turned hospital doors into stone walls. PMID- 10116174 TI - That was me--the doctor in the unemployment line. PMID- 10116175 TI - Only you can prevent employee burnout. PMID- 10116176 TI - Everybody wants to play doctor. PMID- 10116177 TI - Did a hospital's "old boy" network maroon this doctor? PMID- 10116178 TI - How much is a life worth? PMID- 10116179 TI - Design a charge slip that gets you paid every time. PMID- 10116180 TI - Health-care reform: what does Hawaii have to teach? PMID- 10116181 TI - Families face a doubled burden in health costs. PMID- 10116182 TI - It's time to close the health-and-racket clubs. PMID- 10116183 TI - How doctors fare in the most populous states. PMID- 10116185 TI - That's me, the medical-book author. You can be one, too. PMID- 10116184 TI - Don't let visitors sabotage your patient's recovery. PMID- 10116186 TI - Would my battle with the bureaucrats never end? PMID- 10116187 TI - Henry Ford Hospital--a multi-phase learning experience. PMID- 10116188 TI - Pushing ahead for CON reform. PMID- 10116189 TI - How can you keep your psychiatric patients safe? AB - Psychiatric facilities must not only help support beneficial activities and therapies, they also must ensure the safety of staff and patients. A specialist in medical and psychiatric facility design offers his advice on hidden hazards, interior doors, vestibules, windows, and other elements of design. PMID- 10116190 TI - Are you violating antitrust laws? AB - A hospital enters into an exclusive contract for staffing of its emergency room. Physicians band together into a managed care organization. Another hospital enters into an exclusive contract for anesthesiology services. Yet another agrees to refer patients exclusively to a vendor of durable medical equipment. These and similar arrangements, increasingly common in the health care industry, have one thing in common: They have been challenged repeatedly as antitrust violations. The providers have won some of these lawsuits and lost others. Short of avoiding all exclusive contracts, how can you avoid such a lawsuit, or at least improve your chance of winning it? This article outlines the antitrust principles that apply to exclusive contracts and joint ventures between health care providers. Its purpose is to alert you to situations that may implicate the antitrust laws. Because antitrust law is complex and turns on the specific facts of each situation, you should consult with your legal counsel whenever antitrust questions arise. PMID- 10116192 TI - David Gubow--legislator by day, trustee by night. Interview by Ralph D. Ward. PMID- 10116191 TI - How to plan and market for your clinical areas. PMID- 10116193 TI - Auxilians pitch in on hospital building projects. PMID- 10116194 TI - Yellow lights for health care executives. PMID- 10116195 TI - Tackling those problem renovations. PMID- 10116196 TI - Management switch pits landlord against Healthcare International. PMID- 10116197 TI - Two psychiatric firms consider shift in bed use after reporting dismal financial performances. PMID- 10116198 TI - FBI targeting healthcare. PMID- 10116199 TI - 22 antitrust probes under way--Justice Dept. PMID- 10116200 TI - Hospital managers, x-ray firm execs face charges after federal probe. PMID- 10116201 TI - Boston allergists settle federal price-fixing case. PMID- 10116202 TI - Hearing to weigh antitrust laws. PMID- 10116203 TI - Amex to offer piece of info subsidiary to public. PMID- 10116204 TI - Hospital in Venice, Fla., pays $3.3 million antitrust settlement. PMID- 10116205 TI - Keane acts quickly, signs letter to buy business, software of troubled Ferranti. PMID- 10116206 TI - Gift annuities marketed as source of interest income. PMID- 10116207 TI - HCFA gives N.J. hospitals time to pay up. PMID- 10116208 TI - Missouri governor wants to put CON decisions in different hands. PMID- 10116209 TI - Legislation advancing in California would outlaw self-referrals. PMID- 10116210 TI - Bush healthcare reform plan gets a mixed reaction. PMID- 10116211 TI - Time to prepare for final trip, not prolong the inevitable. PMID- 10116212 TI - Battle of Dem health plans takes to the air. PMID- 10116213 TI - PRO fund cut seen with alarm. PMID- 10116214 TI - Computer system RFPs: long form vs. short form. AB - Requests for proposal, the thousand-page tomes hospitals write when shopping for a new computer system, evoke an array of emotions. Some hate them, saying they're too long, too expensive to answer and leave too many false impressions. Others like them, saying RFPs are valuable, especially as an organizational tool. Some hospitals say they have the answer--a more focused approach. PMID- 10116215 TI - The aftermath of the Carilion merger. AB - What's up since the controversial Carilion merger in Roanoke, Va., was consummated in July 1990? Prices, costs and construction for starters. A competitor is up, too, up in arms that is. During its long battle with the Justice Dept. over antitrust questions, Carilion argued that the proposed merger could provide significant economic efficiencies. But the system's main competitor contends that just hasn't been the case. PMID- 10116216 TI - Hospital-sponsored health plans battle the big guys. AB - Hospitals are developing their own healthcare networks and managed-care plans to take on the industry's giants. And, against seemingly long odds, they're finding some success as they see increases in the medical services performed at their facilities and capture bigger pieces of market share. Executives say the local plans have a cost advantage, enabling them to develop more competitive packages. PMID- 10116217 TI - Transmission of images next in line for hospitals? AB - Two bills being considered by Congress would allow the telephone industry to modernize the nation's telecommunications infrastructure, which would upgrade transmission services exponentially. One of the early benefits could be derived by community hospitals, which would be able to obtain affordable transmission of radiology images in the blink of an eye. PMID- 10116218 TI - HCFA issues rules on OBRA reforms. PMID- 10116219 TI - Hospitals must get specific on bad debt, charity care. PMID- 10116220 TI - Court rules N.Y. must pay the Medicare deductibles, coinsurance for poor patients. PMID- 10116221 TI - CHA reform proposal favors single-payer system. PMID- 10116222 TI - Charter pares 1st quarter loss. PMID- 10116223 TI - Hialeah (Fla.) Hospital given 'D' rating. PMID- 10116224 TI - Summit updates IPO registration. PMID- 10116225 TI - Baxter also named in Hermann suit. PMID- 10116226 TI - Two Seattle not-for-profits plan to merge in six months. PMID- 10116227 TI - 4 more indictments in film scam. PMID- 10116228 TI - AHA seeks donations for care package to former Soviet states. PMID- 10116229 TI - Iowa physicians face price-fixing investigation. PMID- 10116230 TI - IRS rules on management fees. PMID- 10116231 TI - Second panel seeks records from FTC. PMID- 10116232 TI - Ask-A-Nurse's company plans initial offer of stock. PMID- 10116233 TI - Beverly ends second consecutive profitable year with strong quarter. PMID- 10116234 TI - Samaritan Foundation decides not to sell seven long-term-care facilities to REIT. PMID- 10116235 TI - Bedside terminal system transmits information using radio frequencies. PMID- 10116236 TI - Diversion of medical education funding opposed. PMID- 10116237 TI - Fight ads with ads on health issues. PMID- 10116238 TI - Experts see dangers in rules implementing Safe Medical Devices Act. AB - Final rules for the Safe Medical Devices Act of 1990 have yet to be published, but hospitals now must comply with an interim version of the law. The rules, designed to ensure that equipment is safe and effective, are proving to be controversial: Some say they're too vague and will be too burdensome for providers, while others say complications should be minimal. PMID- 10116239 TI - Critics lay into Bush reform package. PMID- 10116240 TI - Va. provider tax voted down but not out; mayor of D.C. hatching a levy of her own. PMID- 10116241 TI - Pay incentives for the long haul. AB - While only a small percentage of the nation's acute-care hospitals use long-range compensation programs to reward executives for their performance, more are turning to the idea. Facilities see it as a way to achieve a variety of objectives--some financial, some not--while improving their ability to retain key executives. PMID- 10116242 TI - Indemnity plans rate higher in worker satisfaction. AB - Despite a cost disadvantage, employees enrolled in group indemnity plans are happier with their medical care than are their colleagues who are enrollees of health maintenance organizations, a new survey shows. However, as purchasers continue to confront annual double-digit increases in indemnity costs, the shift toward managed care is expected to continue. PMID- 10116243 TI - Inspector general issues final 'exclusion' rules. PMID- 10116244 TI - Woes of Charter's ESOP show vulnerability of plan's funds. AB - While many economic experts tout employee stock ownership plans as a way to increase workers' ownership of their company, ESOPs do involve risk. Employees at Charter Medical Corp. may be the losers there, as their retirement plan--valued at as much as $634 million at one time--may be worth about $16 million after the company emerges from restructuring. PMID- 10116245 TI - Law firm seeks group action on alleged outlier shortfalls. PMID- 10116246 TI - Republic to purchase Safecare. PMID- 10116247 TI - Fla. Blues seek deal to serve as PRO for '92. PMID- 10116248 TI - Missouri Blues to drop role as intermediary. PMID- 10116249 TI - N.J. hospitals fight to survive as state may force closures. PMID- 10116250 TI - Training feeds fighting spirit. PMID- 10116251 TI - The risk manager's guide to trying times. PMID- 10116252 TI - Keyless data capture: emerging technologies in health information processing. AB - As middle managers, medical record practitioners will be involved in justification of auto ID technology to upper management. To prepare a good justification, one must have a thorough knowledge of the technology and its advantages and disadvantages. One must also be familiar with the payback period and the installation process. This article has attempted to introduce the reader to some emerging technologies in health care, and answer some of the questions that are key to justifying their acquisition. By most estimates, these technologies are finding their way into health care, however slowly, and hold much promise for improvement in productivity and accuracy in data collection. PMID- 10116253 TI - Bar codes in health information management: status, standards, and selections. AB - The demands placed on medical record professionals can be overwhelming. However, these challenges present the opportunities to develop the new, exciting role of health information manager. The technologies and potential benefits are there. It is up to the medical record professional to make use of the opportunity. PMID- 10116254 TI - Bar code tracking system enhances record- and film-handling productivity. AB - The bar coding system has proven to be highly successful. Use of the bar code label has already been added to the dictation system in medical record and medical imaging services departments for entry of patient identification of each dictated report. Other system enhancements under consideration include tracking ancillary department reports as they are forwarded to the medical record department for storage in the permanent patient record and tracking individual volumes of a patient's medical record. PMID- 10116255 TI - Looking back: evaluating the use of bar coding in medical record processing. AB - It is great to be able to say, if we had it to do over again, we would still do it.... But hindsight tells us we could have done some things better. We should have sinned bravely, and forged ahead with chart tracking in the main file room. The truth is, our inexperience with the technology made us overly cautious. We were, however, absolutely correct about the use of bar coding. Swift collection of accurate data is a treasure to be sought, bar coding is insurance of that treasure. PMID- 10116256 TI - Image-based document management systems for medical records. AB - Using image scanning as a document capture mechanism at time of treatment or on day of discharge automates the medical record to achieve the larger objectives of simultaneous concurrent access to an electronic chart. This form of keyless document capture, although appearing labor intensive, is justified for improving business management and quality of care. Coupled with optical character recognition or barcode recognition for keyless data capture, medical information may be more easily made available for clinical research. Not merely a microfilm alternative, a medical record management system accelerates chart completion. Labor reduction is realized by eliminating filing and retrieval of active charts, loose sheet handling, photocopying, chart assembly, and chart location control. By reducing the reasons for chart completion delays, accelerated billing of Medicare accounts will occur, resulting in a reduction in receivables. Image based document management systems accomplish the three things required of a senior manager in health care: (1) solve problems, (2) save money, and (3) make money. PMID- 10116257 TI - Generating medical documentation through voice input: the emergency room. AB - We look in one to three years to continuous speech recognition without sacrificing large vocabulary recognition or speaker independence. At that point we will lose some of the risk management value of structured reporting. But if the experience of emergency medicine is any indicator, it is clear that ASR is here to stay, and will increasingly become the gateway to the hospital information systems of the 90s. PMID- 10116258 TI - Voice recognition for the radiology market. AB - Voice recognition is an exciting technology that is only starting to catch on in radiology. By reducing training time from days to several minutes, today's voice recognition systems are more practical than their predecessors. Voice recognition systems will improve the productivity of radiologists, allowing them to spend less time dictating their findings and more time concentrating on their specialty. Ultimately, the major benefit is increased patient care. As more and more hospitals become automated, voice recognition systems are a natural fit in this process. Radiology departments will be able to have integrated systems that will allow everything from initial patient entry, procedure status and tracking, and report dictation with voice recognition, to electronic report signature, report archiving, and patient billing. PMID- 10116259 TI - Patient cards: storage and input for medical data. AB - The literature concerning the diffusion of innovations reveals that it is not surprising that a promising technology is confronting obstacles in its development and implementation. Alternative technologies also often appear that address the same or similar problems. Better information enables physicians to provide medical care that is less expensive and less error prone. The prescription of medications is reduced in number and cost when the prescribing physician knows the current and previous medications of the patient. The ordering of clinical tests is reduced in number and cost, and the ordering of timely retesting is more likely when physicians have before them information about previous testing of their patient. The challenge is in how the portability of the patient card and its ability to be self-contained can enhance medical practice. PMID- 10116260 TI - Research review: investigation of keyless data capture technology in medical record academic curricula. PMID- 10116261 TI - New missions statement creates unity for health care system. PMID- 10116262 TI - Collaboration and community service. PMID- 10116264 TI - Easing medical staff friction. PMID- 10116263 TI - Using a finance committee agenda. PMID- 10116265 TI - Hiring in-house counsel in hospitals. PMID- 10116266 TI - System recruits corporate directors. PMID- 10116267 TI - Trustees' dual role of representation. PMID- 10116268 TI - Building for ambulatory care: Children's Hospital grows with the times. Interview by Karen Gardner. AB - The Children's Hospital of Philadelphia, a 294-bed regional referral center, was the first dedicated children's hospital established in the United States in 1855. Although 39 percent of its beds are designated for intensive care, in 1985 the hospital's board recognized the necessity of expanding its ambulatory care capacity. Much of the credit for implementation of this vision goes to Roger Colley--a trustee recruited in 1983 for his business acumen. At the time he joined the board, Colley had been president of Betz Laboratories Inc., Philadelphia. In 1988, Colley started his own company--Envirogen--a company dedicated to finding new, innovative and lower-cost technologies for treating toxic and hazardous industrial waste. He is president and CEO of Envirogen, Lawrenceville, NJ. Colley was one of the original members of the hospital's long range planning committee and served as chairman of the board's building and grounds committee during construction (from 1987-89) of the six-story Richard D. Wood Ambulatory Care Center. He recently spoke with Trustee editor Karen Gardner about the process of building this new facility, which opened in September 1989. PMID- 10116269 TI - Trustee recruitment: the first step in governance continuity. PMID- 10116270 TI - Helping nations in need: hospitals donate surplus medical supplies. PMID- 10116271 TI - The shame of emergency care for kids. PMID- 10116272 TI - Perspectives. The Indian Health Service: a flawed diamond. PMID- 10116273 TI - Setting fair pay policy. PMID- 10116274 TI - Seven basic quality tools. PMID- 10116275 TI - Seven ways to reduce harassment claims. PMID- 10116276 TI - Indoor air quality regulation: still blowin' in the wind? PMID- 10116277 TI - Update limonene: the EPA report. PMID- 10116278 TI - Getting the lead out: radiology aprons. PMID- 10116279 TI - Minimizing risk through incident investigation and intervention. PMID- 10116280 TI - An improved emergency department X-ray follow-up system. PMID- 10116281 TI - Health risk appraisals as a risk management tool. PMID- 10116282 TI - Educating the RN: the risk manager's role. PMID- 10116283 TI - Effective peer review at Brooke Army Medical Center. PMID- 10116284 TI - Utilization review and risk management: a quality liaison. PMID- 10116285 TI - ACHE study finds no immediate relief from health care crisis. PMID- 10116286 TI - Special report: the value of pharmaceuticals. Better drugs will reduce total health care costs. AB - On the basis of expected advances in biomedical technology, in the next quarter century dramatic increases will occur in the number of lives saved. Additionally, the number of patients with disabling diseases will drop considerably. PMID- 10116287 TI - Special report: the value of pharmaceuticals. Misused or unused prescriptions may cost your health plan plenty. AB - Medication noncompliance is seriously affecting patient well-being, health care costs, and the national economy. The health consequences of noncompliance include prolonged illness, uncontrolled chronic disease, hospitalization, disability, and death. PMID- 10116288 TI - Special report: the value of pharmaceuticals. Data watch. Managed care and prescription drugs. PMID- 10116289 TI - Data watch. The cost shifting burden. PMID- 10116290 TI - Health care blunders: is your company liable? AB - Not too long ago, the idea of a company being held liable if an employee was harmed by its health plan would have been scoffed at. But today, employer dollar payouts in such cases can run into the millions. PMID- 10116291 TI - The pros and cons of point-of-service plans. AB - A relatively new addition to the growing list of managed care options, POS plans contain some of the cost control elements of HMOs. Yet they also allow enrollees some of the freedom of choice associated with PPOs. PMID- 10116292 TI - Everyone pays when small businesses are left out in the cold. AB - When small companies can't get, or afford, health insurance, large companies must foot some of the bill. Reform will help both. PMID- 10116293 TI - Employees pay more, get more. AB - One benefit plan shares costs with employees by increasing deductibles. But the plan also allows employees to share in the savings it creates. PMID- 10116294 TI - Jackson Hole Group offers health care reform plan. AB - One way to end the health care crisis is to provide health insurance for everyone. The Jackson Hole Group has developed a reform plan that would have the private sector do just that. PMID- 10116295 TI - Outpatient UR: chasing a moving target. PMID- 10116296 TI - Contract health care services; reimbursement and Medicare allowable rates--Bureau of Prisons, Dept. of Justice. Notice. AB - The Bureau of Prisons is issuing this Statement of Policy to inform the public that when it becomes necessary to supplement the direct delivery system of health care the Bureau provides to persons committed to its custody, the Bureau ordinarily will contract to purchase health services only with those hospitals, physicians and other health care providers which agree to accept, as payment in full, reimbursement at rates no higher than the prevailing Medicare allowable rates (including deductibles and co-payments). This encompasses those rates established by the Health Care Financing Administration as "sole community providers" or "regional referral centers". The Bureau will phase this policy into the administration of its contract health services program. PMID- 10116297 TI - Caring for each other: a parish approach. PMID- 10116298 TI - It couldn't happen here ... or could it? PMID- 10116299 TI - The forgotten ministry: health and the local church. PMID- 10116300 TI - Determining and controlling costs. PMID- 10116301 TI - A national contributory elder care exchange program. AB - The state of the United States health care provision system is discussed; special attention is given to issues of eldercare. A new contributory health care concept is described which would reduce need for health care, and would supply labor to care for the fast-growing elderly population for the present and the future. The role of industry in provision of health care today and in this plan are discussed. Potential obstacles are suggested. Further research and areas of exploration are discussed for development of this concept. PMID- 10116302 TI - Integrating housing and long-term care services for the elderly: a social marketing approach. AB - Subsidized senior high-rise apartments have tended to neglect the needs of an increasingly aged and frail resident population. Research demonstrates that this population has greater unmet needs than elderly who reside in traditional community housing. This paper makes the case for a vertically integrated marketing approach to serving the elderly. Such an approach would combine housing and community based long-term care services into a single system of care. Enriched senior high-rise apartments are a viable alternative for elders who need assistance in order to maintain an independent lifestyle. PMID- 10116303 TI - Marketing a community mental health center. PMID- 10116304 TI - The chiropractic market segment: a viable market opportunity for M.D.'s? AB - Physicians have traditionally paid closer attention to the competition from other medical practitioners, but have ignored competition arising from "alternative therapies" such as hypnosis, acupuncture, or chiropractic. The purpose of this article is to survey the market segment served by one such unconventional practitioner, i.e., chiropractors, with the intention of determining its likelihood as a viable market to be pursued by M.D.'s. PMID- 10116305 TI - A health hierarchy of effects model: a synthesis of advertising and health hierarchy conceptualizations. AB - Work by both advertising and health researchers has independently yielded hierarchy of effects models which can be used to predict campaign success. Unfortunately, however, previous work has been criticized as "common sense" approaches which are more "assumed" than "proven." This analysis argues that much of the problem is due to the lack of precision often associated with over simplified "uni-dimensional" models. Instead, this perspective synthesized a "two dimensional" health hierarchy of effects model and outlines a pragmatic strategy for campaign measurement. PMID- 10116306 TI - Understanding and assessing service quality in health maintenance organizations. AB - Health maintenance organizations (HMO's) have been one of the major innovations in providing healthcare. However, as the HMO enjoyed success as an alternative delivery system, competition among individual HMO's intensified. As a result, the 1990's will require continued attention to the effective delivery of quality services to clients. Providers of healthcare services must work toward establishing a strong competitive position in the marketplace which means that they will have to understand how their customers perceive value in the services rendered. The authors examine exchange relationships that occur in the HMO and offer an approach for analyzing the dimensions of service quality demanded by the HMO's constituents. Practical ways to enhance service quality are discussed. PMID- 10116307 TI - Medical doctors and consumers view medical advertising. AB - This study finds that more and more medical doctors are advertising their services and changing their opinions of that advertising., Overall, consumers still have a more positive attitude toward doctor advertising than do the doctors. Within the medical ranks, specialized dentists reflect a more positive attitude toward the advertising of their services than other practicing doctors. PMID- 10116308 TI - The public's image of doctors, dentists, and pharmacists. AB - The basic purpose of this study was to evaluate the public's image of three health professions. Q questionnaire was administered by telephone to a random sample of 150 residents of a southern metropolitan area. Respondents were asked to evaluate seven professions on (1) social standing (prestige), (2) honest and ethical standards, (3) importance to society and nation, and (4) interesting and challenging occupation. Overall findings indicate that doctors rated significantly higher than dentists, and pharmacists in all areas except honest and ethical standards. The three groups were rated equally on this factor. Cross tabulations of respondents by income, age, education, and sex revealed that there were no significant differences in the ratings of these groups on the basis of socio-economic characteristics of respondents except for pharmacists. Male respondents rated pharmacists significantly lower than female respondents. PMID- 10116309 TI - Home intravenous therapy: Part II--Resource guide. AB - Part II of the paper is a resource guide which lists resources that agencies may use to develop a home intravenous therapy program. In the first section, national organizations and journals and books concerned with intravenous therapy are listed as well as journal articles, guidelines and guidebooks and client and provider educational materials. National and regional product and service representatives of intravenous therapy related companies are also listed. In the second section, addresses for the State Boards of Nursing are given for Alaska, Idaho, Montana, Oregon and Washington. Each state section includes a list of those agencies who indicated in the 1988 survey that they would be willing to share materials. In addition, product and service vendors of intravenous therapy supplies and equipment are listed for the State of Washington. PMID- 10116310 TI - In-home physician visits and large medical groups. AB - In-home care has grown rapidly in the past decade and has become increasingly complex. Accompanying these changes has been a resurgence of what was once thought to be an endangered if not extinct species, the physician house call. This paper is concerned with the involvement in the provision of physician home visits by large medical groups, and with how this involvement is related to the characteristics of the medical group. In December 1989, telephone interviews were conducted with 174 large medical groups (those with more than 50 physician members), representing a response rate of 73 percent of the universe of (239) groups found to fit study criteria. Of responding groups, 52 percent indicated that they provided physician home visits. Groups in states with higher proportions of population aged 85 years and over and groups that report accepting physician house calls are more likely to provide house calls. It is concluded that the provision of house calls by large medical groups is likely to increase with the greater complexity of in-home care, the shift of acute care into the home, and the rapid growth of the very old population. PMID- 10116311 TI - Results of the assessment of Kentucky's Medicaid home- and community-based services waiver. AB - In states where a Home- and Community-based Services Waiver is operating under the Medicaid program, HCFA requires an independent assessment of the program. This paper reports on two assessments of the costs and use of services under Kentucky's HCBS waiver: one comparing waiver clients to a matched control group of regular Medicaid home health clients, and the other comparing elderly female waiver clients to a matched control group from nursing homes. Analyses of costs and use of home health services, hospital care, physician services, nursing home admission, and other services showed little difference between waiver clients and control groups. Waiver clients used more home health, but used other services at the same rate. Their costs were lower overall. PMID- 10116312 TI - Home care the American way: an historical analysis. AB - An historical inquiry, this study examines a 100 year tradition of home-based nursing care in the United States. Whether considering turn of the century origins or contemporary re-emergence, the continuities in organization and delivery of home-based care are apparent and striking. Most remarkable in the American saga of home-based care are our dependence on local definition of perceived need and appropriate response; the amount of individual ingenuity required to obtain care from an often confusing assortment of competitive, duplicative and fragmented home care services; and our reliance on public sentiment and devotion to individual freedom rather than more "rational" planning methods. PMID- 10116313 TI - Home intravenous therapy: Part I--Issues. AB - Concerns related to providing home intravenous therapy were among the top ten clinical problems identified by Northwest Medicare-certified home care agencies in a 1986 survey. This paper addresses issues related to home intravenous therapy and provides lists of resources for the development of home intravenous therapy programs. Part I of the paper covers concerns related to intravenous therapy as expressed by home care agencies in the Northwest and synthesized the literature about home intravenous therapies. Survey results are presented, followed by a discussion of client and caregiver concerns. These include: discharge planning, client admission criteria and client and caregiver education. Standards, staffing, and staff education issues are discussed followed by sections on economics, marketing regulations and legal and ethical concerns. Finally, there is a discussion of issues related to specific types of intravenous therapies: parenteral nutrition, antibiotic therapy; chemotherapy; blood and blood component therapy and other less frequently used types of intravenous therapies. Each therapy is discussed with regard to complications, client and caregiver instruction and financial considerations. Part II of the paper is a resource guide which lists resources that agencies may use to develop a home intravenous therapy program. In the first section, national organizations and journals and books concerned with intravenous therapy are listed as well as journal articles, guidelines and guidebooks and client and provider educational materials. National and regional product and service representatives of intravenous therapy related companies are also listed. In the second section, addresses for the State Boards of Nursing are given for Alaska, Idaho, Montana, Oregon and Washington. Each state section includes a list of those agencies who indicated in the 1988 survey that they would be willing to share materials. In addition, product and service vendors of intravenous therapy supplies and equipment are listed for the State of Washington. PMID- 10116314 TI - Health care 1992: top 10 trends for the health field. PMID- 10116315 TI - Personal selling in health care organizations: a status report. AB - The authors report the state of the art of personal selling in health care organizations in the United States. The research was conducted through the use of a previously validated sales orientation index, administered to various types of health care organizations. The findings indicate that personal selling is far from being a fully integrated promotional tool in the health care industry. Differences in the sales orientation of health care organizations are found to be related to environmental and organizational factors. PMID- 10116316 TI - Modeling the effect of hospital charges and quality on choice. AB - The authors apply a conditional choice model to simulate the results of patient and physician choices of hospitals for a specific surgical procedure in response to improvements in quality or changes in charges. The model includes all zip code areas and relevant hospitals in a large metropolitan area and estimates the impact on admissions at each hospital. It can be used to estimate both the impact of decisions by a given hospital and the potential responses of competitors, as well as the effects of selective contracting with hospitals by certain payors. PMID- 10116317 TI - Determination of fees by professionals: an exploratory investigation of dentists. AB - Previous research has attempted to infer dentists' pricing practices from aggregate data, such as those derived from insurance claims. In a disaggregated analysis based on a mail survey of 327 dentists in private practice, the authors find the most important influence on dental fees to be cost, followed by fees charged by other dentists and perceptions of patient sensitivity to prices. The relative importance of the various influences on dentists' fees is related to several practice characteristics, including location and gross income. PMID- 10116318 TI - Marketing the concept of becoming a potential organ donor. AB - Medical technology now enables thousands of people with terminal organ diseases to return to productive lives. Thousands more, however, will die because suitable donor organs are not currently available. Despite an early call for marketing approach to the problem of recruiting potential organ donors, little progress has been made to date. The author reviews the current literature on organ donation, discusses previous organ donation research conducted by a team he led, and makes suggestions for marketing the concept of becoming a potential organ donor. PMID- 10116319 TI - Investor-owned ambulatory care walk-in centers: how have primary care physicians responded? AB - Investor-owned walk-in centers are a recent innovation in ambulatory care. The authors surveyed private practice primary care physicians about their marketing strategies before and after the advent of a local walk-in center. Respondents were more likely to report that they accepted walk-ins and that they advertised in the latter than in the former time period. Findings are discussed in the framework of previous predictions about the impact of walk-in centers on the delivery of care in traditional primary care practice settings. PMID- 10116320 TI - Market research guides an RN recruitment/retention campaign. AB - A 600-bed metropolitan hospital reduced agency nurse fees by $2.5 million a year by using market research to determine and produce the most effective advertising messages and media for its nurse recruitment/retention marketing effort. PMID- 10116321 TI - Excellence in mental health service delivery: state-university collaboration in Maine. PMID- 10116322 TI - A program for excellence in human services. PMID- 10116323 TI - Can the job satisfaction of hospital employees be enhanced? Findings from an empirical study. PMID- 10116324 TI - Protestors rip NME's access limits to new hospital in low-income area. PMID- 10116325 TI - 2 Chicago hospitals weighing affiliation. PMID- 10116326 TI - Sutter halts pursuit of managed-care pacts through alliance; investigation dropped. PMID- 10116327 TI - 17% of Mich. mammography units substandard. PMID- 10116328 TI - Our environment: a healthcare commitment. Symposium sponsored by Inova Health Systems, Arlington, Va., March 8-10, 1992. AB - Healthcare providers are under increasing pressure to protect the environment. That's added extra cost and effort to operations. However, many hospitals are finding that it pays to be environmentally conscious. A seminar on this topic, sponsored by Inova Health Systems, is planned for early March, and a special section of articles on topics to be covered is intended to give executives an overview of the field. PMID- 10116329 TI - Healthcare one of top concerns of N.H. voters. PMID- 10116330 TI - Healthcare PACs' fund raising, spending were modest in 1991. PMID- 10116331 TI - Partisan pasting begins: Democrats heap criticism on Bush health plan. PMID- 10116333 TI - SunHealth phasing out management business. PMID- 10116332 TI - AHM mulls conversion of 4 Calif. hospitals to not-for-profit status. PMID- 10116335 TI - Forces dig in on reform strategies, boosting likelihood of a stalemate. PMID- 10116334 TI - Muncie, Inc., nurses sue two firms over 'defective' gowns. PMID- 10116336 TI - VHA Enterprises asks shareholders to approve its liquidation plan. PMID- 10116337 TI - On-line service targets equipment buyers, sellers. PMID- 10116338 TI - Humana lays off 75 in San Antonio area. PMID- 10116339 TI - HCA closes Texas psychiatric facility. PMID- 10116340 TI - Suit filed over management pact fight. PMID- 10116341 TI - Hospital employs TQM principles to rework its evaluation system. AB - One Kansas hospital has taken the traditional employee evaluation process--with all its performance criteria, point systems and rankings--and turned it on its head. The new system employs total quality management principles and promotes personal development, education and teamwork. And everyone gets the same raise. PMID- 10116342 TI - Hospitals seeking to improve investment return should pick manager whose style matches need. PMID- 10116344 TI - Beth Israel pact not seen as model. PMID- 10116343 TI - Head-injury providers ripped. PMID- 10116345 TI - Wis. outcry may prompt return of rate limits. PMID- 10116346 TI - VHA plans standards to measure if hospitals merit tax-exempt status. PMID- 10116347 TI - NME combines 3 management divisions to aid marketing, serve its clients better. PMID- 10116348 TI - Sloan-Kettering the latest to try branching out. PMID- 10116349 TI - Nursing centers gain popularity. PMID- 10116350 TI - Home providers tap hot equities market. PMID- 10116351 TI - Pryor bill to enter fray over drug costs. PMID- 10116352 TI - Funds to help 10 states collect health data. PMID- 10116353 TI - Hospitals not tapping computer data--survey. PMID- 10116354 TI - Vet groups' attack overruns VA facility plan. PMID- 10116355 TI - Nursing facilities' evolution needs decisive regulatory, financial, management acts. PMID- 10116356 TI - 'Buyers' demands for quality to aid reform of system'. PMID- 10116357 TI - To market, to market. Physician groups seek tax-exempt financing to compete with hospitals. AB - Physician groups are rapidly appreciating the benefits of financing growth into new areas, as they try to take advantage of the shift of care to outpatient settings and attempt to make up for the money they're losing through Medicare pay changes. PMID- 10116358 TI - Trade mart, meeting facility seeks to advance Birmingham. PMID- 10116359 TI - Indiana crafts selective Medicaid tax plan. PMID- 10116360 TI - National Blues plan settles with W.Va. hospitals. PMID- 10116361 TI - Hospital, Hispanic TV station put health series on the air. AB - A Florida hospital has teamed up with a Hispanic television station to produce a weekly Spanish-language health information show. It's aimed at older Hispanic women who have been in the United States less than 20 years. They're the ones who frequently make the healthcare decisions in the family. PMID- 10116362 TI - 'Long-term records may cut lab tests, aid treatment decisions.'. PMID- 10116363 TI - Recovery strategies help faltering hospital pull back from brink of bankruptcy. AB - Delaware Valley Medical Center was slipping fast, heading toward bankruptcy or closure. But thanks to a corrective business plan established a year ago, the Langhorne, Pa., osteopathic facility has turned profitable a year ahead of schedule. Physician recruitment, new services and a flexible hospital board have played key roles. PMID- 10116364 TI - Lobbyists assail some of panel's stringent cost-containment ideas. PMID- 10116365 TI - Ask the doctor: answers may surprise you. AB - In summary, physicians tend to base their final decision not only on the combination and culmination of all of the information that they gain about the location and the practice opportunity, but it seems that the final decision is mainly based on a trust factor. This trust factor lies in the belief that comments the administrator may have made while walking the halls with the candidate were true. Many physicians comment that they decide to go to one location over the other when both are equally as impressive in terms of quality of life and quality of practice style, because they trusted and had a higher comfort level and established a rapport more quickly with one administration or medical staff over another. PMID- 10116366 TI - Beyond crisis: the chaplain's changing role. PMID- 10116367 TI - Watching practice patterns change. PMID- 10116368 TI - Teaching and community hospitals: differences are their greatest strengths. PMID- 10116369 TI - Running the high tech race. PMID- 10116370 TI - Recruiting with southern charm. PMID- 10116371 TI - Information technology: the key to surviving the 90s. PMID- 10116372 TI - Buyer beware: how to negotiate your IS contract. PMID- 10116373 TI - Linking southern hospitals to the world. AB - Hospitals have been frustrated with the low return on their substantial IS investment. The greatest benefits arise from connecting the hospital to the commercial world. PMID- 10116374 TI - Health-care gridlock. PMID- 10116375 TI - Small business pulls the strings. PMID- 10116376 TI - 4 former execs of top surgery chain start their own. PMID- 10116377 TI - A comprehensive career ladder for the clinical laboratory. AB - Retention and promotion of current staff are highly desirable goals for today's clinical laboratory because recruitment and replacement are costly. In the face of balancing these costs with competition for technologists and limited upward mobility within the laboratory, a comprehensive career ladder that expands employee job horizons and gives depth to their jobs is a powerful tool for staff retention and, at the same time, increases the organization's productivity and recruitment potential. PMID- 10116378 TI - Total quality and the management of laboratories. AB - Total Quality Management (TQM) is a continuous quality improvement process that evaluates processes from a customer satisfaction point-of-view. The aim is continuous process improvement. TQM is a paradigm shift for most health-care organizations and will require changes in hospital conditions. TQM uses old tools -such as check sheets, run charts, and flow charts--in new ways. Laboratories are particularly suited to TQM because laboratorians are already familiar with these tools. However, laboratorians must learn to apply these tools to new areas. This may be perceived as threatening by some. This article will describe how TQM uses old tools in new ways, barriers to implementing TQM, and how to overcome these barriers. PMID- 10116379 TI - Quality assurance, an administrative means to a managerial end: Part III. AB - This is the third of a series of articles on medical laboratory quality management. Part I concentrated on the historical background and regulatory basis of quality surveillance. Part II addressed surveillance guidelines of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and the College of American Pathologists (CAP), emphasizing quality assurance (QA) and the ten step process. Part III focuses on the JCAHO Agenda for Change and the transition to continuous quality improvement (CQI). A strategic plan for health care in the U.S., the Agenda is revolutionizing quality management of operative laboratory functions and organizational behavior. Understanding this JCAHO plan is essential for a successful transition from QA to CQI. PMID- 10116380 TI - TQM: passion and process. PMID- 10116381 TI - Committing to CQI. PMID- 10116382 TI - Assessing the legality of performance appraisals. AB - Performance appraisals have recently become the focus of legal scrutiny. Because the appraisal process may lead to salary adjustments, promotions, opportunities for development, discipline, or even termination, issues such as fairness and discrimination are raised. This paper discusses specific constitutional and statutory laws that prohibit discrimination in performance appraisals. In addition, specific rulings from select court cases illuminate key legal defense factors in performance appraisal. Questions are posed to help identify weaknesses in a laboratory's performance appraisal system. PMID- 10116383 TI - Automation in immunoassays--an overview. PMID- 10116384 TI - Communicating more effectively. AB - Communicating is something people take for granted. But some organizations have still not learned that information should not be a closely guarded commodity, but something to be shared freely. To be productive, employees must know the organization's goals and constraints. Managers must develop an early warning system so little problems do not grow into big ones. They must be able to assess their employees' morale and prevent personality problems from getting out of hand. In this issue, we asked some top communicators for their tips on promoting better information exchange. PMID- 10116385 TI - The continuing search for solutions: maximizing human resources. PMID- 10116386 TI - CLMA comments on the amendment to Title VII of the Public Health Service Act. PMID- 10116387 TI - CLMA comments on VA exemption from CLIA '88. PMID- 10116388 TI - Improving cardiology through consensus-building exercises. PMID- 10116389 TI - Capturing patients' perceptions. PMID- 10116390 TI - Source, nature and symptomology of indoor air pollutants. PMID- 10116391 TI - Efficient energy use in hospitals--trend and emerging technologies. PMID- 10116392 TI - Females' use of alcoholic beverages: a study in context. AB - The literature on female uses of alcoholic beverages is sparse. This paper advocates studying consumption contextually, and by using secondary data, presents initial findings which support the utility of the approach. PMID- 10116393 TI - The economic returns from investments in physical and mental health: a case study of migrant farmworkers in rural New York. AB - Spiraling costs of medical care services and limited federal and state resources necessitate discriminating and cost-effective strategies for financing health care to indigent populations. Thus, while the selection among intervention strategies is aided by information on both the cost and benefits of program alternatives, data on the latter aspect is more difficult to obtain. Human capital research provides a mechanism for assessing one of the multifarious aspects of the benefits of medical services. Research suggests that labor market earnings opportunities are affected by health status. The present study explores this relationship for migrant farmworkers in a vegetable production county (Orange County) in upstate New York. Multivariate analysis indicated that mental well-being was an important predictor of earnings for migrant farmworkers. Directions for public health policy intervention strategies are also discussed. PMID- 10116394 TI - Special issues in prenatal care outreach. AB - Approaches to prenatal care outreach taken by public providers vary widely. To date, few have evolved from systematic, data-based casefinding strategies. The following case study describes the findings of a research project concerned with both care seeking and care getting behaviors of low income women and the relationship between those behaviors and birthweight outcomes. Analysis of project data reveals that the greater the delay between seeking and getting care, the greater the likelihood of low birthweight. Application of this research data has yielded information useful to outreach planning, staff development and program evaluation procedures. PMID- 10116395 TI - Programming, budgeting, and control in the North Carolina "Willie M." program: a case of public sector accountability. AB - In eight years of program operation, the State of North Carolina has spent upwards of $200 million on its Willie M. program. In doing so, the state has developed a model program of services for severely emotionally disturbed children. This paper describes the program legacy wrought by the Willie M. class action suit against the State of North Carolina. The response of the state is reported in terms of the programming, budgeting, and control challenges generated by North Carolina's voluntary settlement of the suit. PMID- 10116396 TI - Multivariate analysis of family risk factors in predicting appointment attendance in a pediatric otology and communication clinic. AB - Parents of pediatric patients attending regional otologic medical clinics were given a questionnaire to document family risk factors predictive of poor appointment attendance, and to determine barriers which caused non-attendance of medical appointments. Family risk factors which affected clinic attendance were studied using univariate and multivariate analyses. Univariate analyses revealed all factors except patients' sex and family size to be correlated with attendance. However, multivariate analysis revealed that parental age (p less than 0.0153), ownership of car (p less than 0.0012), parental education (p less than 0.0048), and age of patient (p less than 0.0023) were major predictors of clinic attendance. Although ownership of a car was a major independent factor, it was highly correlated with parental age and parental education and only shown to be significant in the subset of patients not having access to public transportation. The identified parental factors which affect pediatric health care delivery underscores the importance of family centered case management in promoting the health care of children and casts doubt on the effectiveness of interventions which are solely centered on the patient or are designed to mitigate only one of these factors. PMID- 10116397 TI - Health care. Cutting through the gobbledygook. PMID- 10116398 TI - Criteria for designation of mental health professional shortage areas--PHS. Final rule. AB - This final rule amends the existing regulations governing the criteria for designation of health manpower shortage areas, or HMSAs (now health professional shortage areas, or HPSAs; name changed by Public Law 101-597, the National Health Service Corps Revitalization Amendments of 1990) under section 332 of the Public Health Service Act. Specifically, this amendment revises the existing criteria for designation of HMSAs having shortages of psychiatric manpower, transforming them into criteria for designation of HPSAs having shortages of mental health professionals, to take into account not only psychiatrists but also mental health service providers other than psychiatrists. The intended effect of this amendment is to more accurately assess the supply of mental health service providers when making shortage area determinations. This notice also summarizes the comments received by the Department on the Notice of Proposed Rulemaking published on August 8, 1989, which set forth the proposed methodology for making this and other changes to the HMSA criteria. It also formally changes "HMSA" to "HPSA" throughout the regulation, to conform with Public Law 101-597. PMID- 10116399 TI - Medicare Program; quarterly listing of program issuances and coverage decisions- HCFA. General notice. AB - This notice lists HCFA manual instructions, substantive and interpretative regulations and other Federal Register notices, and statements of policy that were published during July, August, and September 1991 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register at least every three months. Wefd also are providing the content of the revisions to the Medicare Coverage Issues Manual published during this quarter. On August 21, 1989 (54 FR 34555), we published the content of the Manual and indicated that we will publish quarterly any updates. Adding the Medicare Coverage Issues Manual changes to this listing allows us to fulfill this requirement in a manner that facilitates identification of coverage and other changes in our manuals. PMID- 10116400 TI - Federal Employees Health Benefits program: direct payment of FEHB premiums for annuitants--OPM. Final rule. AB - The Office of Personnel Management (OPM) is adopting its previously issued interim regulation that implements section 1 of Public Law 101-303. This section of law allows all annuitants to make direct payment of premiums for their Federal Employees Health Benefits (FEHB) coverage when their annuity is too low to cover the insurance premiums. Previously, only annuitants in the Federal Employees Retirement System (FERS) were allowed to make direct payment of their FEHB premiums. PMID- 10116401 TI - Medicare program; prospective payment system for inpatient hospital capital related costs; correction--HCFA. Final rule; correction. AB - In the August 30, 1991 issue of the Federal Register (FR Doc. 91-20779) (56 FR 43358), we revised the Medicare payment methodology for inpatient hospital capital-related costs for hospitals paid under the prospective payment system. We replaced the reasonable cost-based payment methodology with a prospective payment methodology for capital-related costs. This notice corrects errors made in that document. PMID- 10116402 TI - Advance directives: development, opposition, and criticism. AB - Since the PSDA became law on December 1, all Medicare and Medicaid health care providers are required to develop policies and procedures to comply with the law. The principles of autonomy and distributive justice are basic to the Act, and the social worker's vital role will continue to develop as the law is implemented. PMID- 10116403 TI - Must guardians honor advance directives? AB - A question asked at a recent advance directives seminar brought divided opinions from the attorneys present, resulting in a lively discussion of whether a court appointed guardian must honor a patient's advance directive. The question is presented in this article with the first of several legal opinions to be published. As background, the Update presents the following discussion of advance directives by Suzanne Mitchell, assistant professor, Loyola University Law School Institute for Health Law. PMID- 10116404 TI - PSDA (Patient Self-Determination Act): related state legislation. PMID- 10116405 TI - An interview with: Anthony N. Potter, Jr. on implementing improved hospital safety and security programs. PMID- 10116406 TI - Special report. New products that improve officer performance, safety. AB - The need for products that improve performance of security officers is counterbalanced these days by budgetary constraints. While this may limit major investments in security systems and personnel, less costly improvements or innovations might be worth considering. In this report, we will discuss four advances that may be valuable not only in hospital security, but in other industries as well. One of them, a smoke filter, was originally developed for the hotel industry. Another, a drug detection device, may replace the use of undercover agents or drug-sniffing' dogs in certain circumstances. The third new product is an economical patrol vehicle for parking facilities which might replace more costly vehicles such as golf carts or cars. The fourth product, a roving CCTV camera, is actually being tested at a Midwest medical center and may allow you to monitor areas of parking garages with cameras instead of officers on patrol. PMID- 10116407 TI - CIO. Roles and relationships. Interview by Walter Wachel. AB - Today's chief information officer has a dual role. As a technical expert, the CIO must stay atop rapid changes and strategically plan, implement, and build an organization's technological backbone to support better patient-care delivery, quality, and cost-containment efforts. As an executive, the CIO must possess the management know-how to lead organizational change and work processes. PMID- 10116408 TI - Negotiating a system purchase: 8 principles for protecting your institution's interests. PMID- 10116409 TI - Strategic communications. PMID- 10116410 TI - Critical decisions, critical plans: purchasing hospital information systems. PMID- 10116411 TI - Managing for technology to improve service. AB - What challenges today's healthcare executive is deciding what new technologies to purchase and exactly when to do so. Scan the marketplace for them--both in the healthcare field and in industry. PMID- 10116412 TI - Understanding your ethical responsibilities. PMID- 10116413 TI - Strategies to improve care and control costs. PMID- 10116414 TI - Interior Design 1992 Buyers Guide issue. AB - The Interior Design Magazine Buyers Guide is compiled with you, the designer, in mind. So it's packed with the most comprehensive collection of sources available anyplace--arranged for fast, easy access. First, the Keyword Index presents all the Buyers Guide product categories alphabetically (see the first tab divider). Refer to the page number indicated in the Product Index (second tab divider) to view various manufacturers of products under each category heading. Addresses, phone and fax numbers, regional and international showroom/representatives are located in the A-Z Index (third tab divider) in alphabetical order. Consult the table of contents for trade associations, lighting consultants, marts, and other useful sections. PMID- 10116415 TI - Managed care outlook: "alternative delivery systems" become dominant health plans. PMID- 10116416 TI - Nonprofit equity: a behavioral model and its policy implications. AB - This article assumes that nonprofit decisionmakers have an incentive to earn and accumulate surpluses, and it suggests six reasons for this being the case. Based on the assumption that both the program outputs and the equity of a nonprofit yield satisfaction to its decisionmakers, a behavioral model is developed. This is used to derive a demand function for equity, which is then applied to a national sample of 6168 charitable nonprofits drawn by the Internal Revenue Service for the 1985 taxable year. The results substantiate the hypothesis that nonprofit decisionmakers consciously plan to increase their organization's equity. Currently, evidence of continued equity buildup is not sufficient to call into question a nonprofit's exempt status, because federal tax laws assume that surplus accumulations will ultimately be used in support of program mission. However, equity accumulation can become excessive. We present several criteria to define excessive equity accumulation and discuss why large equity accumulations may not be in the best interest of society. PMID- 10116417 TI - Preauthorized payments system rescues the "self-pay" portion of patient accounts from "no-pay" status. AB - Delinquencies on the self-pay portion of patient accounts are rising alarmingly. Creative medical practice personnel are seeking new methods to solve this problem. Preauthorized payments, more common among insurers, are proving to be one solution. PMID- 10116418 TI - Lessons for providers from a purchaser's perspective. AB - On Jan. 1, 1991, the John Hancock National Transplant Program (JHNTP) became operational, matching kidney, heart, liver, and bone marrow transplant patients from a potential pool comprising more than two million covered lives, with organ transplant programs at 14 institutions across the country. Conceptualizing the program and selecting and contracting with the transplant centers took more than 18 months. This article shares some of the insights from that process that are pertinent to providers of transplant services and to others considering entering this or other forms of specialized contracting. PMID- 10116419 TI - Bringing calm to the storm. PMID- 10116420 TI - A combat support hospital in the Gulf War. AB - The war in the Persian Gulf was an incredible undertaking from almost any viewpoint. The distances involved, the political alliances forged, the numbers of men and women participating, and the amount of equipment moved have not been seen since the Second World War. The medical effort to ensure that all combatants received appropriate health care was equally massive. PMID- 10116421 TI - The hospital of the year 2000: three scenarios. AB - Based on a presentation at the 27th Annual Duke Forum on Health and Hospital Affairs conducted in 1991 in Durham, N.C., this article is a discussion of the forces with a stake in national health policy, a discussion of three ways those forces might come together, and a description of those three scenarios and the issues each would raise. PMID- 10116422 TI - Eliminating smoking from the workplace. AB - Employers are more readily realizing that a nonsmoking policy in the workplace is a more effective way to run their businesses. They are recognizing costs such as productivity losses, increased health and life insurance costs, employer liability for diseases jointly linked to smoking and occupational exposures, absenteeism, passive smoking-induced health care costs among nonsmokers, workers' compensation, and fire losses. Concomitantly, employees are supporting policies that limit smoking to achieve a clean air environment. Former Surgeon General Koop's goal of "a smokefree society by the year 2000" is being recognized by more and more segments of society. PMID- 10116423 TI - ABMT (autologous bone marrow transplantation): a microcosm of the U.S. health care system. AB - The continuing controversy over appropriate utilization of high-dose chemotherapy (HCDT)-autologous bone marrow transplantation (ABMT) in the treatment of cancer epitomizes the debate in this country over increasing expenditures for the application of health care technology. The debate includes all imaginable constituencies--patients, physicians, hospitals, payers, employers, lawyers, economists, and the media. The issue is fascinating, as it continually presents new twists and turns. Additionally, the way in which the HCDT-ABMT controversy is resolved (or not resolved) will presage the manner in which similar issues are addressed in the 1990s. PMID- 10116424 TI - Hiding your criteria will never work. AB - In this era of managed care, the message has been that the health care industry has provided inappropriate or inefficient care, causing the ruination of medicine and ultimately of the U.S. economy. Published research data on small area analysis have demonstrated marked differences in utilization rates for the same surgical procedure in various locations. Researchers and others have logically surmised that criteria used by providers in recommending these procedures have also varied from location to location. Correction, therefore, will require attention to the establishment of logical and defensible criteria. PMID- 10116425 TI - Data bank reporting requirements pose vexing issues. AB - Even though the National Practitioner Data Bank is now more than a year old, health care organizations continue to struggle with its reporting requirements. In some instances, it is possible to achieve the quality goals of the data bank without triggering a report and unnecessarily damaging a practitioner's reputation. This article details some of the cautions that need to be observed. PMID- 10116426 TI - Implementing a quality assessment program. AB - It is difficult to imagine a more stressed organization than today's hospital. If the scope of change is not a sufficient challenge, the rate of the change is staggering, especially in quality assessment. Now we are poised for continuous quality improvement, whereby outcomes identified by quality assessment become the focus for system and process review and modification. It is imperative that a good quality assessment program be in place before implementing and integrating a continuous quality improvement process. The purpose of this article is to show how a quality assessment system can be implemented in a community hospital, regardless of size or scope of services. Key to the process is making all staff members part of the system's development and operation. PMID- 10116427 TI - Jewish Hospital plays their cards right. PMID- 10116428 TI - PR crisis: the HIV positive doctor. PMID- 10116429 TI - Campaign creative produces born winner. PMID- 10116430 TI - Physician training spreads people skills. PMID- 10116431 TI - Birthday bash doesn't break bank. PMID- 10116432 TI - Guest relations: TOPS (truly outstanding patient service) in programs. PMID- 10116433 TI - Testimonials boost rehab center's image. PMID- 10116435 TI - "Everybody Wins" when staff trims costs. PMID- 10116434 TI - Soft sell hits the mark. PMID- 10116436 TI - Nobody ever tells me anything. Employee fairs use fun to encourage internal communication. PMID- 10116437 TI - PREFERS (Patient Preference Evaluation and Recording System) gives patients treatment options. PMID- 10116438 TI - Be gentle about death ... and leave the balcony open. AB - This meditation on advance directives shows how such documents are part of a larger social movement. People are now reclaiming the right to direct their own dying, a process that requires the active support of the community around them. PMID- 10116439 TI - Wholly responsible for a part, or partly responsible for a whole? The concept of spiritual care in nursing. AB - Spiritual care is an inseparable part of patient care--not the exclusive province of chaplains, religious nurses, or would-be psychoanalysts. Its essence is the capacity to enter the world of others and respond to them with feeling, and every nurse should feel confident about giving such care. PMID- 10116440 TI - Locating emergency medical services in small town and rural settings. AB - Locating emergency medical services in small town and rural settings presents subtle, but significant differences to those in metropolitan areas. The lack of service mix and unit choice, the measurement of response time in minutes rather than seconds, and the limits of the planning environment are discussed. Using time-distance comparisons and location-allocation techniques within a microcomputing environment, some aspects of planning emergency medical services are illustrated within the context of the Kingston (Ontario) Regional Ambulance Service. PMID- 10116441 TI - High-tech equipment--present and future options for rental operators. AB - U.S. and European laundry equipment manufacturers are striving to gain efficiencies with high technology. They are well aware that operators want to use resources--including energy, water, labor, and merchandise--better. Also, meaningful information about plant operations is becoming a top priority. Many high-tech options are available now and others are in the works to carry this industry into the next century. PMID- 10116442 TI - Wastewater treatment systems. AB - Textile rental operators face tough wastewater cleanup challenges in many communities nationwide. Depending on the local POTW regulations and the textile rental company's customer base, wastewater pretreatment isn't always necessary. However, many plants must pretreat or risk being put out of business. In this article, eight manufacturers of wastewater treatment equipment explain their systems to help industry operators comply with POTW limits. PMID- 10116443 TI - Office visits to pediatric specialists, 1989. PMID- 10116444 TI - Critical-incident response: heading the wounds of traumatic events. PMID- 10116445 TI - Employee surveys: what employers are doing and what works. PMID- 10116446 TI - Depression among caregivers of impaired elders. AB - Studies have reported that rates of depression among caregivers are higher than in the general population. However, these studies have been limited primarily to caregivers of cognitively impaired elders. Using the Center for Epidemiological Studies Depression (CES-D) Scale, this study investigated depression among caregivers for physically impaired elders. The authors found that one third of these caregivers reported depressive symptoms, a lower rate than for caregivers of cognitively impaired elders but still twice the rate for the general population. The data show that depressive symptoms are related primarily to health status but also to aspects of the caregiving situation, including both the negative impact of that care as well as the relationship of the caregiver to the frail elder. Depressive symptoms are not mediated by formal or informal support. PMID- 10116447 TI - The Patient Self-Determination Act (PSDA) and the incapacitated patient: policy suggestions for healthcare ethics committees. PMID- 10116448 TI - Assisted suicide and the ethics of self-preservation. PMID- 10116450 TI - UNESCO and the HEC movement. PMID- 10116449 TI - An ethics committee's recommendations on testing patients for HIV antibodies when health care workers suffer exposure to blood-borne pathogens. PMID- 10116451 TI - Hospital ethics committees in Quebec: an overview. AB - In June 1989, La Direction de la Sante physique (ministere de la Sante et des Services sociaux) (MSSS) undertook a major research project focusing on ethics committees in Quebec, in cooperation with Laval University's Groupe de recherche en Ethique Medicale (GREM). Initially, three major objectives were set out: to prepare a faithful overview of ethics committees in Quebec; to inform all those involved of the available resources, and to collect the data required to eventually carry out in-depth research on ethics committees. A number of government documents refer to the existence of ethics committees, whether to request their cooperation or to entrust mandates to them; moreover, the Law Reform Commission of Canada recently published a document that proposed establishing a Canadian Advisory Council on Biomedical Ethics. The MSSS, therefore, had to study the situation in Quebec with regard to ethics committees in order to be in a position to clarify its position in future discussions. This overview is the outcome of the first stage of this research project. Essentially, it represents the first of three main sections of a single document. It [1] presents general data on ethics committees, [2] contains a description of each committee by socio-sanitary region and type of committee, and in section three it deals with the principal resources available in bioethics in Quebec, Canada, and throughout the world. PMID- 10116452 TI - Hospital ethics committees in Portugal. PMID- 10116453 TI - Point and counterpoint. Are ethics committees of an enduring nature? PMID- 10116454 TI - Point and counterpoint. A response to White and Gottlieb. PMID- 10116455 TI - Advance directives pamphlet. University Hospital, Little Rock, Arkansas. PMID- 10116456 TI - Perspectives. Trying to rein in Medicare cost increases. PMID- 10116458 TI - Hospitals set 1992 public policy agenda. California Association of Hospitals and Health Systems. AB - On behalf of patients and hospitals who care for them, CAHHS developed this year's public policy agenda in cooperation with the Hospital Council of Northern and Central California, the Hospital Council of San Diego and Imperial Counties, and the Hospital Council of Southern California. CAHHS and the Hospital Councils work with the hospital constituency groups to maximize the effectiveness of hospitals and present a unified front on major issues. As advocates for patients and hospitals, CAHHS places the highest value on life, the treatment of patients with dignity, and equitable access to quality care. PMID- 10116457 TI - State of the state's health care. AB - California leaders tell us what's right and what's wrong with our health care system. While consensus on health care reform is far from being reached, all agree that universal access, cost control and preventive services must be part of any health reform plan. PMID- 10116459 TI - Point-counter/point. Solving California's health care crisis. PMID- 10116460 TI - Looking for the ethical basis in health care reform plans. PMID- 10116461 TI - Kevorkian indicted on murder charges in Michigan. PMID- 10116462 TI - New Jersey ethics committees: a tale of two surveys. PMID- 10116463 TI - Studies of health care policies show allocation inequities. AB - A study released January 22 by the Employee Benefits Research Institute (EBRI), Washington, DC, shows that nearly 17 percent of the U.S. population under the age of 65 were without private or public insurance coverage in 1990. Jill Foley, an EBRI research analyst and author of the study, said the rise in the number of uninsured Americans--35.7 million in 1990 compared to 34.4 million in 1989--can be attributed, in part, to a decline in the number of workers who receive health coverage through their employers. These results lend substance to assumptions expressed by politicians and policymakers who are now addressing reforms in health care and economic spheres. The effects of public policies on allocation of resources are discussed in the following articles. PMID- 10116464 TI - Surveys indicate physician reluctance to treat AIDS patients. AB - From the viewpoint of the American Medical Association's Council on Ethical and Judicial Affairs, a physician may not ethically refuse to treat a patient solely because the patient is infected with human immunodeficiency virus. Nonetheless, reports of recent surveys indicate that a sizable number of physicians are, in fact, refusing to care for HIV-infected patients. PMID- 10116465 TI - Questions of limits arise over advance directives. AB - The Patient Self-Determination Act (PSDA) is off and running with very little in the way of complaints from hospitals to date. Word obtained from a few hospitals contacted by Hospital Ethics indicates that, as expected, patients are responsive to rather than frightened by conversations initiated by health care personnel regarding advance directives. Some time will pass before the impact of the PSDA will really be known, in particular, whether more patients will have actually signed advance directives, and whether they will have been followed in the event they are called up for clinical decision making. In the professional literature, however, the place of advance directives--their form and function--in the hospital setting is receiving careful scrutiny, and discussions of when and why advance directives might or should be limited are eliciting suggestions of how the process might be improved. Summaries of these discussions follow. PMID- 10116466 TI - On their own: a profile of the individually insured. AB - More than 13.6 million Americans under the age of 65 own a health insurance policy that they purchased directly from an insurance company or agent. Buyers tend to come from a "Golden Girls" cohort-- white, widowed or divorced, age 55 64, and working for a small company. High premiums have helped to reduce the number of individual policyholders. Insurers incur high administrative costs, have low loss ratios, and have suffered financial losses. As a result, the market is serving neither buyer nor seller well. One solution would establish competitive bidding at the state level limiting the franchise to sell individual insurance to three-to-five carriers; require bidders to include cost controls; and reduce agent commissions and other marketing costs by having states take an active role in informing the public. PMID- 10116467 TI - Choosing from the health care reform menu. AB - Rising costs and diminished insurance coverage have reduced support for the U.S. health care system among all stakeholders. Proposals for reform have arrayed policymakers along discrete lines, with some favoring incremental reform, others endorsing an expanded role for employers, and still others pushing for a radical conversion to a publicly-financed, publicly-administered program. Each carries enough negatives to make it difficult, if not impossible, to achieve. Rather than waiting for a consensus on one or the other, the U.S. can adopt a strategy that would extend insurance coverage without fueling inflation. All Americans would be guaranteed coverage via a mandate on employers, an expanded public program, and creation of powerful quasi-governmental financial agents who would negotiate and set prices paid to providers. PMID- 10116468 TI - Dominos that wouldn't fall: understanding the failure of competitive reform. AB - Ten years ago, there was widespread optimism that market competition would succeed in controlling health cost inflation and restructuring the health care industry in socially desirable ways. Today, many view competitive reform as a failed strategy. Costs remain uncontrolled and both government and private payers are turning to regulation and monopsony power. Formidable and longstanding barriers to price competition in the markets for health insurance and health care services were underestimated. Efforts to promote competitive reform were halfhearted and partially offset by a growth of regulation. What lessons can be learned from the competitive experiment and how will health policy evolve in the future? PMID- 10116469 TI - DataLine. More! AB - U.S. health care spending continues to rise, making up 12.2 percent of the gross national product in 1990. In that year, Americans spent $1.8 billion a day on health care services; $76 million in every hour; and $1.3 million every minute. PMID- 10116470 TI - Medicaid voluntary donations & provider specific taxes: a sirens' song. AB - Faced with a rising Medicaid budget, increased demands for eligibility expansions from the federal government, and a declining economy, many states have turned to the use of voluntary contributions and mandatory taxes paid by health care providers to raise money for Medicaid and reap federal matching payments. On September 12, the Health Care Financing Administration proposed eliminating many, if not all, of these financing plans. Such action would throw states into chaos as governors and legislators search for needed funds in the middle of their fiscal years. The federal government created the demand for such financing approaches and cannot simply shut the money valve and assume the problems will go away. With debate already begun on broad reform of the health care system, the regulations should be withdrawn so that an overhaul of Medicaid can be considered. PMID- 10116471 TI - Champions of science or blacklisting bureaucrats? AB - Unconvinced that science could police itself against research misconduct, the federal government in 1989 created an Office of Scientific Integrity (OSI) within the National Institutes of Health. Since then, OSI has launched high-profile investigations into big-name scientists using a method that researchers say violates their due process of law and destroys reputations. Changes are in the offing, but are they enough to protect the integrity of government-funded research and scientists' right to due process? PMID- 10116472 TI - Why cash flow analysis cannot accurately measure hospitals' financial health. PMID- 10116473 TI - Anti-dumping law creates difficult standard. PMID- 10116474 TI - Nights at the roundtable: forum combines style & substance. PMID- 10116475 TI - Learning from the Aloha State. AB - Since 1974, Hawaii has required its employers to provide health insurance to all employees working at least 20 hours a week. More recently, the state created a new program to cover the "gap group" of 50,000 uninsured residents, along with a new program to create a "seamless system of health care" for all Aloha State residents. And Hawaii has managed to insure nearly all of its citizens while keeping the annual price of health insurance at nearly half of that paid in many mainland states ($1,300 per person and $4,000 per family). At the same time, life expectancy is the highest in the nation and infant mortality is among the lowest. In seeking to reform a dysfunctional national insurance system, policymakers should learn from the Hawaiian experience, which shows that small business can live with an employer mandate, universal coverage can cut costs by encouraging early preventive care, and a dominant payer can reduce administrative expenses. PMID- 10116476 TI - Interview with Michael S. Dukakis. Interview by Richard Sorian. AB - In early 1991, former Massachusetts Gov. Michael Dukakis spent three months at the University of Hawaii School of Public Health studying the state's unique system of health insurance. Recently he talked with JAHP Editor in Chief Richard Sorian about the lessons he learned from looking at Hawaii's "universal health coverage" and why the experience was different in his home state. PMID- 10116477 TI - Wofford-Thornburgh: a turning point for health reform. AB - The November 5 special election in Pennsylvania pitting appointed Senator Harris Wofford against former U.S. Attorney General Richard Thornburgh was a turning point in the national debate over health reform. Under the glare of media spotlights, Wofford mounted a come-from-behind victory over the heavily favored Thornburgh by trumpeting "national health insurance." Since Wofford's victory, President Bush has rethought his previous indifference to health reform and promised to announce a comprehensive plan in January, more than a year ahead of schedule. PMID- 10116478 TI - The 1991 Pennsylvania Senate race and national health insurance. AB - Voter interest in reform of the American health care system played a central role in the November 5 come-from-behind reelection victory of Democratic Senator Harris Wofford of Pennsylvania over Republican candidate Richard Thornburgh. In a post-election poll of 1,000 Pennsylvania voters, over 50 percent identified "national health insurance" as one of two issues that mattered most in deciding how to vote. And 21 percent of voters said the issue was the "single most important factor" in their voting decision. The results of the Pennsylvania Senate race suggest that universal health care has arrived as a mainstream political issue and that political candidates who fail to address the issue do so at their peril. PMID- 10116479 TI - A second look at the Pennsylvania special election. AB - Rather than a referendum on national health insurance, the November 5 victory of Harris Wofford over Richard Thornburgh was a reflection of voters' discontentment with incumbent politicians and the status quo. A poll of 600 voters found growing personal anxiety about the national economy; 57 percent of those polled said their vote was intended to "send a message" to President Bush on the economy. Only 14 percent said they voted to "adopt a national health insurance plan." But there is a general and understandable voter concern about the worsening health care situation. PMID- 10116480 TI - Physicians' responses to their changing environment. AB - The loss of physician autonomy, the changing shape of physicians' practices, and efforts to control the cost of health care have left American physicians increasingly dissatisfied with the U.S. health care system. A survey of 300 office and hospital-based physicians shows 59 percent favor reform of the U.S. system; only 31 percent favor retaining the current system. Doctors face increased competition for patients (the supply of physicians has increased three times faster than the population), reduced autonomy because of intervention by government and other third party payers, pressure from patients to provide unnecessary care including expensive new technology, and increased cost containment. Yet a majority of physicians believe the causes of rising health care costs are patient demand for services and the current medical malpractice system. A minority (23 percent) blame hospitals and physicians for rising costs. PMID- 10116481 TI - The Patient Self-Determination Act: new responsibilities for health care providers. AB - On December 1, 1991, most health care provider organizations became subject to the portions of The Omnibus Budget Reconciliation Act of 1990 informally known as the Patient Self-Determination Act (PSDA). This law does not create new substantive rights but instead requires providers to inform patients of their existing rights under state law to make health care decisions and to execute "advance directives," such as durable powers of attorney for health care and living wills. The PSDA could end up as just one more federal bureaucratic intrusion into health care that increases its cost while enhancing neither its effectiveness nor its humanism. A better outcome is possible only if providers treat it as an opportunity to work with their staff (including attending physicians) to enhance the quality of patient decisionmaking and planning for future illness, so that the real discussions needed to create useful advance directives can go on among patients, their family members, and the health care professionals who care for them. PMID- 10116483 TI - Appropriate care and the market for physician services. AB - Rising health care costs have led policymakers to look at ways to assure the appropriateness of care. But attempts to control spending on physician services by either reducing price or limiting utilization may be ineffective due to backward bending supply. In seeking further limits on physician spending, policymakers will have to consider this possibility. PMID- 10116484 TI - Experimental or conventional? Ask a judge. PMID- 10116482 TI - Bound and gagged: America's family planning network. AB - During the past decade, the number of family planning clinics receiving support from the federal government has fallen from 5,000 to 4,000 despite a growing demand for their services among poor women and teenagers. At the same time, family planning providers have been under regulatory attack, forced to fend off a "squeal rule" aimed at teenagers and to stop a "gag rule" preventing abortion referral. With the climate in Washington unlikely to change, family planners should consider integrating other services into their network or press to include family planning in other care networks. A new national commission could help break the logjam on federal legislation. PMID- 10116485 TI - Kaiser Foundation: positioned for change. Interview by Cathy Tokarski. PMID- 10116486 TI - Pharmacokinetic consultation service workload measurement study. AB - A study was conducted to collect work measurement data for pharmacokinetic drug consultation services. A stopwatch was used to measure the time required to perform pharmacokinetic consultations in the Ottawa General Hospital, a 530-bed tertiary care teaching hospital. Ten pharmacists provided 166 drug consults primarily for phenytoin, aminoglycosides, digoxin, and theophylline. The time required to obtain drug level measurements averaged 1.10 minutes. Consults required an average of 8.28 (SD = 4.72) minutes. Initial consults took 10.35 (SD = 5.07) minutes, while repeat consults took 6.62 (SD = 3.67) minutes. The difference was significant (t = 5.48, df = 164, P less than 0.001). No significant differences were found among consults for different drugs nor between primary and secondary patient coverage areas. There was a significant difference in the time required to perform a consult among pharmacists. Consult times were considerably less than those reported by the Canadian Hospital Pharmacy Workload Measurement Study. PMID- 10116487 TI - Impact of a pharmacist on the educational value of pharmaceutical industry film showings. AB - A controlled trial was performed to assess the impact of drug information provided by a pharmacist on the educational value to physicians of pharmaceutical manufacturers' film showings. The trial consisted of two teams of physicians who attended pharmaceutical manufacturers' films and who afterward answered multiple choice questions on the drug being promoted. In one group, the liaison pharmacist, who had no knowledge of the content of the questionnaire, presented information on the drug being featured prior to the film showing while the control group did not have a pharmacist presentation. Out of a perfect score of five, there was a higher test score in the group of physicians who attended the pharmacist presentation/film showing (n = 75) than in the group which only attended the film (n = 65) (3.3 +/- 1.1 versus 2.8 +/- 1.2, respectively (p = 0.017)). While there was no difference in the scores obtained by the clerks, interns and residents (3.2 +/- 1.1, 3.3 +/- 0.9, 3.4 +/- 1.2 respectively) when a pharmacist was present, in his or her absence the scores for clerks, interns and residents were 2.5 +/- 1.3, 2.8 +/- 1.0, 3.6 +/- 1.2 respectively with residents scoring higher than clerks (p = 0.047). A pharmacist can enhance the educational value of a pharmaceutical manufacturer's film showing. PMID- 10116488 TI - Leading the change process. Interview by Michael L. Laughlin and Carolyn Dunbar. AB - 'Change or cease to exist.' In interviews with Computers in Healthcare six industry leaders agree that increasing market pressures will force many organizations to drastically modify the way they do business. Those that don't will eventually fail. PMID- 10116489 TI - Healthcare I/S executives look toward the next decade. AB - A survey of I/S executives conducted specifically for Computers in Healthcare reveals that the perception of the institutional mindset as leader, follower or average hospital makes a great deal of difference both in approach to I/S issues and in their relative priority. PMID- 10116490 TI - Patient-centered care delivery and the role of information systems. AB - Ways of working with patients as well as ways of managing information technology are now changing as all facets of service delivery move closer to the bedside. The industry can look forward to new reengineering strategies and implementations. PMID- 10116491 TI - Discharge planning: philosophy, procedures, and tasks. PMID- 10116492 TI - Quicker and sicker: real or imagined? AB - In spite of continued public statements regarding the premature discharge of patients from America's hospitals, the study presented here indicates that Vanderbilt Medical Center patients do not have this problem. It is projected that similar results would be found in hospitals across the country. PMID- 10116493 TI - Discharge planning: before the fact. PMID- 10116494 TI - The ER social worker: cost-effective, crisis-oriented discharge planning--and more. AB - The emergency room social worker exemplifies, in a crisis-oriented context, the ability of social workers to make a difference, in real terms, in situations of patient and family need--physical, environmental, and emotional. Our hospital has come to see the opportunity for community care and support, coupled nicely with the ability to decrease burdensome and costly social admissions and lessen time patients spend waiting in the ER. Patients and their families are well served in our ER. Much clinical social work is done because the workers are there, available, caring, and able to help. ER social workers have also served as clinical supervisors for graduate social work students in field placements. The ER social worker serves as a valued extension in our discharge planning. We recommend this role for your consideration. PMID- 10116495 TI - Drug usage evaluation of warfarin sodium: the need for improved patient education. AB - Due to documented problems encountered during therapy, the potential for drug drug interactions, and possible readmissions due to therapy complications, the Ohio State University Department of Pharmacy decided to conduct a drug usage evaluation (DUE) of warfarin sodium. The results of their DUE are presented below. PMID- 10116496 TI - Pharmacy-nursing facsimile systems: set-up considerations and operational issues. AB - The use of facsimile (fax) machines for the electronic transmission of physician's orders from nursing areas to a hospital pharmacy has become increasingly popular. Although the uses and benefits of fax machines are straightforward in this practice setting, namely a significant decrease in order processing turn around time, the problems that may develop are often not described in the literature. This article describes some of the set-up concerns, operational problems, forms considerations, staff training, paper costs, equipment needs, transmission volume, and equipment maintenance involved with fax systems. PMID- 10116497 TI - Emergency department medication and drug interaction evaluation. AB - The emergency department evaluation had two primary objectives: 1) to determine the accuracy of the oral medication history given at arrival at the emergency department and 2) to determine how often the emergency department physician may prescribe medications which when taken with current medications, may cause a potential drug interaction. Data were collected from 228 emergency department visits of clinic patients 65 years old and older. The average number of medications reported by the patients' medication history was 3.0 +/- 2.3 (range 0 13). The number of medications the patient "forgot" was 1.3 +/- 1.8 (range 0-9). A complete medication history was given by 50.4% of patients. There was an upward trend that correlated with an increased chance for an incomplete medication history as the total number of current medications increased. The rate of a potentially significant drug interaction between a newly prescribed medication in the emergency department and current medications was 3.4% for patients receiving a new medication. PMID- 10116498 TI - Controlling the cost of prescription drugs. PMID- 10116499 TI - Is competition compatible with Gospel values? PMID- 10116500 TI - Preparing for ambulatory patient groups. PMID- 10116501 TI - Preserving Catholic identity in mergers--an ethical and Canon Law perspective. AB - A merger or joint venture between a Catholic healthcare facility and a non Catholic healthcare facility that provides procedures the Catholic Church believes to violate moral principles raises a number of issues to be considered by diocesan bishops. The 1983 Code of Canon Law provides bishops with guidelines to help establish the Catholicity of a Catholic hospital that has affiliated with a non-Catholic hospital. The diocesan bishop exercises his authority through a threefold ministry of teaching, sanctifying, and governing. These ministries stand as a reminder of his decision-making authority in matters that affect the spiritual state and growth of those entrusted to his care. Catholic identity, as it is presented in the Code of Canon Law, can be determined through the presence of a relationship between an institution and ecclesiastical authorities, the legal establishment of the entity, and a degree of control that the Church exercises over the institution. When evaluating a possible merger of joint venture between a Catholic hospital and a non-Catholic hospital that is performing procedures not in accord with Catholic Church teaching, the diocesan bishop must consider what limits must be observed. The good effects of the affiliation must be intended and direct, and the harmful effects must be perceived as unintended and indirect. The difficulties in determining and protecting the identity of Catholic hospitals in possible mergers or joint ventures should not prevent facilities from considering alternative forms of corporate structures. The Code of Canon Law and the Church's ethical teachings provide guidelines to ensure these possibilities. PMID- 10116502 TI - Values and vision--CHA's plan for healthcare reform is based on two unique perspectives. AB - The Catholic Health Association (CHA) Leadership Task Force on National Health Policy Reform has offered a proposal that, if enacted by Congress, would result in profound changes in the way providers deliver healthcare in the United States. The proposal would result in fewer acute healthcare facilities, challenge some acute care facilities to provide additional services and require each Catholic healthcare provider to collaborate with Catholic providers and others. Two features distinguish CHA's plan from the many other healthcare proposals that have been offered. First, CHA's plan is rooted in six tenets of Catholic healthcare. Second, the plan primarily focuses on client-centered delivery reform rather than on financing issues as other proposals have done. The task force believed it first had to create a vision of what the nation's future healthcare delivery system should look like. The task force decided that providers must do a better job of meeting clients' healthcare needs. To be a credible leader in the healthcare reform debate, the task force believes that CHA must offer a plan that primarily focuses on the needs of people and, second, controls costs effectively. PMID- 10116503 TI - A starting point for delivery reform. Catholic healthcare providers can receive guidance from "A Time to Be Old, a Time to Flourish". AB - The ideal healthcare delivery system is client focused and ensures that the individual and the family receive the appropriate mix of services to meet their needs. Healthcare delivery should be presented as a coordinated continuum of care. Key integrating elements are essential to provide healthcare services on a day-by-day basis as a continuum of care. Integrating elements that form the bridge between clients and services include planning, care management, a management information system, financing, and an appropriate administrative structure. Many Catholic healthcare providers are expanding by acquiring a variety of services. However, many of these acquisitions are in response to today's competitive environment, whereas a true continuum of care must focus on the client's range of functional needs. Catholic providers must keep in mind that not all services they provide will be profitable. Although Catholic healthcare providers will be pressured to focus on fiscal strength and market position, they must put the client's holistic needs first. By doing so, they can help create a client-centered healthcare system in their communities. PMID- 10116505 TI - Safeguarding creation. PMID- 10116504 TI - Cultivating quality. CQI helps a system's members provide efficient, effective care to their clients. AB - In 1990 the SSM Health Care System (SSMHCS), St. Louis, introduced its employees to continuous quality improvement (CQI), a new management paradigm focusing on process, customers, and statistical thinking. For nearly a year before the introduction of CQI, a system implementation team studied CQI and its impact on businesses and healthcare providers. Team members were struck by the close correlation between the system's own mission and CQI principles. When it had completed its study, the team began to develop strategies for implementing CQI. System leaders committed themselves to ensuring that CQI would address both clinical and managerial processes, encouraging managers and medical staff to support CQI, establishing a structure at each entity to support involvement in the process, fostering a high level of awareness in CQI, recognizing employees who make significant contributions to the effort, offering education programs, and communicating successes and encouraging their replication. Before any facility appointed a quality improvement team and began to apply CQI principles, its administrative council (leadership team) was required to work through a series of readiness screens. The implementation process has involved redefining the manager's role as one of empowering employees, cultivating and securing physician involvement, and educating employees and physicians about processes. In the early phases of implementation, the major barriers the system has faced have involved time-the time required of administrators and managers to teach CQI courses and the time it takes teams to work through the SSMHCS CQI model and adapt the system to CQI implementation. PMID- 10116506 TI - The stairway to recovery. An emerging worldview uncovers God's wisdom in nature. AB - What is lacking for the renewal of the earth is not so much ethical consensus as political will. The myth of "man" as the self-sufficient and autonomous master of "inanimate" nature has been ingrained for centuries, and it will take a powerful force to dislodge it. However, we are in a unique period of convergence--a time when we might be transformed by the truth if we only seek it. This new spiritual awakening represents a conscious commitment to a common cause that lies beyond individual self-interest. The commitment has been kindled by a perception that we are creatures intimately connected with the rest of creation and to the power that has called us into being. And it is a commitment carried out in action through a disciplined way of life. If we want to heal the earth, we have to get better ourselves, because it is the way we think and live and act that is harming the earth. We have much to learn from participants in Alcoholics Anonymous, who have learned the secret of proclaiming the good news by doing it, one step at a time, by living it, day by day. The first step is acknowledgment that, as a society--indeed, as the human race-we are at the bottom and cannot get back up. Once we admit we have hit the bottom, there is hope for the environment because we have taken the first step to recovery. PMID- 10116507 TI - A new era. Healing the injuries we have inflicted on our planet. AB - The health of the earth is essential for the well-being of every living creature on the planet; however, our plundering industrial economy has disrupted the earth's biosystems. Such neglect can no longer be accepted. Medicine is in the same situation as the entire range of human activities: All must find a way to exist in harmony with the natural world. We have been so caught up in our scientific capacity to alter the natural world that we have ignored its most basic structure. We must, therefore, enter a new era-the "Ecozoic" era, a period when humans would live on the earth in a mutually enhancing manner. This transition will require changes at a most profound level in human activity. Three principles form the basis for the Ecozoic era: Humans must recognize the universe as a communion of subjects, not a collection of objects. The earth is primary; humans are derivative. The planet will never again function as it has in the past. To enter the Ecozoic era, humans need sciences that create a new way of understanding the natural world as possessing its own unique spontaneities. Especially needed are biological sciences that have a "feel for the organism." This move from anthropology to "earthology" and cosmology is a comprehensive challenge to all our professions. PMID- 10116508 TI - A movement gains momentum. Catholic providers throughout the United States are launching programs to preserve the environment. PMID- 10116509 TI - The medical waste audit. A framework for hospitals to appraise options and financial implications. AB - The generation, handling, and disposal of medical wastes involve virtually every department in the hospital. To enhance coordination, managers must comprehensively describe the total system and specify the roles of key functions and individuals. Hospitals produce about 77 percent of the approximately 500,000 tons of regulated medical waste produced annually in the United States. The amount produced by different hospitals varies, primarily because of differences in "waste-management practices." The Environmental Protection Agency is trying to develop a greater understanding of the types of medical wastes that are infectious, methods of transmission, and the likelihood of transmission in the handling and disposal of waste within the hospital environment. To ensure that medical waste is being handled and treated in the most cost-effective manner and with the least health risk to employees and the community, hospital administrators must undertake a comprehensive appraisal of the activities associated with the generation, handling, and disposal processes. A "medical waste audit" requires the following steps: Generation profile to identify origination points, categories or types of waste, and associated generation rates. Inventory of handling practices, including existing regulations, procedures and protocols, training programs, definitions regarding waste segregation, and documentation. Review of current disposal practices and existing and developing alternatives. Cost analysis PMID- 10116510 TI - Spiritual care of the person with AIDS. Literature and art can touch closed hearts. AB - Spiritual ministers, challenged to find meaningful ways to heal the hearts of persons with AIDS, are turning to some untraditional sources for help. Poetry, art, and stories are among the creative instruments for healing that pastoral ministers are bringing to the bedsides of the terminally ill. The story is the primary tool of spiritual care. Spiritual ministers working with persons with AIDS and their families should elicit and listen to their stories, which serve multiple purposes. Telling the stories is therapeutic for the person with AIDS. For the minister, the stories identify areas that need reconciliation, as well as those which call for celebration. Finally, when the time is right, the minister can tell another story, one that offers consolation and hope to the afflicted. Ritual is another tool of spiritual care. Just as the concrete image symbolizes the spiritual reality, so, too, does ritual facilitate or help celebrate spiritual healing. The Bible is a rich source of ideas for creative ritual. Other effective tools are art, drama, poetry, guided meditations, and dreams. In the hands of sensitive care givers, they are instruments of spiritual healing. PMID- 10116511 TI - Making a difference in the community. PMID- 10116512 TI - Catholic Health Corporation. Collaboration from the bottom up. PMID- 10116513 TI - Cathedral Healthcare System. Public relations for physicians. PMID- 10116514 TI - Sisters of Mercy of the Americas. A tool for transformation. PMID- 10116516 TI - The Patient's Charter. PMID- 10116515 TI - Mr. God Bless. PMID- 10116517 TI - 2nd and 3rd wave trusts. PMID- 10116518 TI - Unified commissioning of primary and community health care. The first year. AB - Barking and Havering FHSA covers a population which exhibits symptoms of urban deprivation and which has been the victim of erosion in the quantity and quality of community and primary care services. Geoffrey Shepherd and Sharon Haffenden describe a unified commissioning project with the local health authority with the aim of improving services. PMID- 10116519 TI - The development of neighbourhood forums in North Staffordshire. AB - The development of neighbourhood forums in North Staffordshire is the result of a simple belief that, to deliver cost-effective services of quality, care needs to be provided through a partnership with those who live and work in that neighbourhood. Glenn Warren outlines the role and function of forums. PMID- 10116520 TI - Driving forward. AB - A new management structure, new equipment and technology are changing the culture of the London Ambulance Service and enabling it to meet the challenges of the 90s. David Lloyd describes how. PMID- 10116521 TI - Human resource development: the hidden resource. PMID- 10116522 TI - A successful transplant. AB - The urgent need for management training has led to adaptation of the IHSM/OU's Managing Health Services course to suit the Ugandan culture. Jane Shaw describes its successful 'transplant'. PMID- 10116523 TI - Management of suppliers. AB - A proper balance of power is essential between purchasers and suppliers of goods and services to the NHS. Rory Graham gives some advice to those taking on responsibilities as buyers. PMID- 10116524 TI - Care profiles: a key to clarity in community care. PMID- 10116525 TI - All change in Romania? PMID- 10116526 TI - We "de-capitated" our practice. PMID- 10116527 TI - Emergency physicians: they're racking up big gains. PMID- 10116528 TI - There's a surefire way for doctors to cut health costs. PMID- 10116529 TI - Why some malpractice threats never die. PMID- 10116530 TI - Did doctors really win this fight with Medicare? PMID- 10116531 TI - Columbia earnings jump; stock sale considered. PMID- 10116532 TI - Healthcare International issues reorganization plan. PMID- 10116533 TI - HCA's initial public offering receiving warm reception from analysts, investors. PMID- 10116534 TI - Houston psychiatric hospital converting to rehab facility. PMID- 10116535 TI - Shuttered Dallas hospital reopens; competing facility files lawsuit. PMID- 10116536 TI - Calif. hospitals weigh tie; others await FTC decision. PMID- 10116537 TI - Hospital fields story of courageous teen. PMID- 10116538 TI - Video firms channeling new services to hospitals. PMID- 10116539 TI - Insurance reforms tacked onto tax bill. PMID- 10116540 TI - Minnesota hospital facing antitrust test. PMID- 10116541 TI - Groups question value of insurance reform. PMID- 10116542 TI - Ties with environmentalists dilute resistance to waste plan. PMID- 10116543 TI - Systems geared up for coming reforms. AB - With some version of reform almost a sure thing somewhere down the road, healthcare systems appear to be well-positioned. Some experts believe various forces--including provider support for regional networks, the bundling of outpatient services, payers seeking capitated contracts and the growing clout of integrated organizations--will come together this decade to put systems at the center of a restructured delivery system. PMID- 10116544 TI - Hospitals earned $7 billion in '90. PMID- 10116545 TI - Study ranking Iowa hospitals draws fire. PMID- 10116546 TI - Hospital campaign against drug price increases is making a dent. AB - A Michigan hospital is seeing results from its 5-month-old effort to reject drug price increases that exceed the medical consumer price index and ban representatives of companies whose prices it considers excessive. So far, three vendors have rolled back prices or guaranteed long-term price protection, three others have said they would consider negotiating and four have declined to make any concessions. PMID- 10116547 TI - High utilization rate offsets efficiencies in pilot military mental healthcare program. AB - Higher than expected utilization has resulted in millions of dollars in unexpected costs in a pilot project designed to fill gaps in mental health services for children of Army families. While the plan has succeeded in paring costs per patient, the overall price tag has called into question the ability of the military to design and operate a managed-care delivery system economically. PMID- 10116549 TI - Davidson pitches reform plan to panel. PMID- 10116548 TI - Venture capitalists home in on healthcare. AB - Gamblers known as venture capitalists, who once piled their chips on electronics and computer software, are now turning to fast-growing medical companies for a return. And they're not just playing hunches with biotechnology or other glitzy start-ups. Recent investments include rehabilitation, hospital management and emergency department ventures in addition to medical device development. PMID- 10116550 TI - 2 healthcare search firms merge. PMID- 10116551 TI - Mass. seeks capital, free care link. PMID- 10116552 TI - Calif. 'economic credentialing' pact set. PMID- 10116553 TI - Computers aid in meeting new OSHA rules. PMID- 10116554 TI - New certification exams for first assistants. PMID- 10116555 TI - Peer review promotes professional growth. PMID- 10116556 TI - Program to train OR laser nurse specialists. PMID- 10116557 TI - Whack on the side of head spurs creativity. PMID- 10116558 TI - Advance directives give patients a new voice. PMID- 10116559 TI - Empowered teams build participative system. PMID- 10116560 TI - What happens to hospital boards during financial crisis? PMID- 10116561 TI - How to build partnerships with physician trustees. PMID- 10116563 TI - Executive search: avoid the trap of stereotypical thinking. PMID- 10116562 TI - Home care PPS demonstration project edges forward. PMID- 10116564 TI - Effective board leadership. PMID- 10116565 TI - Avoiding conflict of interest can eliminate potential board problems. PMID- 10116566 TI - The shape of things to come: restructuring hospitals for the '90s. Interview by Karen Gardner. AB - John D. Leech, chairman of the health care practice in the law firm of Calfee, Halter & Griswold, Cleveland, OH, has been a hospital trustee for more than 20 years. From 1970-87, he served as president and chairman of the board of Hillcrest Hospital, Mayfield Heights, OH, and for the last four years he has been a trustee of Health Hill Hospital for Children, Cleveland, where he is currently secretary of the board. In addition to his professional and hospital responsibilities, Leech has been a trustee mentor for the American Hospital Association for a number of years; in this capacity, he has helped more than 30 hospital and system boards understand their governance role and function more effectively. From his legal practice as well as his contact with boards all over the country, Leech has developed a keen understanding of how hospitals are adapting to the changing health care environment and what role boards must play in the evolutionary process. He recently talked with Trustee editor Karen Gardner about hospital restructurings and the issues confronting governing boards. PMID- 10116568 TI - Health care reform: opportunities for political and community advocacy. PMID- 10116567 TI - Presidential leadership essential for health care reform. PMID- 10116570 TI - Outcomes management: the impetus and impact. PMID- 10116569 TI - Cost/benefits of high-tech medicine--forum. PMID- 10116571 TI - Prospective payment for outpatient services. PMID- 10116572 TI - Collaboration--the new AHA theme. PMID- 10116573 TI - The emerging revolution in health care marketing. PMID- 10116574 TI - The Patient Self-Determination Act: it's in effect. PMID- 10116575 TI - New year finds health care still top issue in statehouses. PMID- 10116576 TI - More financial burdens for hospitals. PMID- 10116577 TI - The health consequences of economic recessions. AB - Unemployment has been demonstrated to be a stressful life event with severe health consequences. This paper reviews the literature on the relationship between unemployment and health. Specific risks and the mechanisms that lead to adverse outcomes are identified. Suggested social work interventions to reduce health risks during economic downturns are discussed. PMID- 10116578 TI - Public knowledge, attitudes, and behavior toward Kansas mandatory seatbelt use: implications for public health policy. AB - State law and policies established by legislative bodies represent an important machinery for amplifying the effects of behavior change efforts in individuals and groups. This study shows the inter-relationships of public health policy, behavior, attitude, knowledge of the general public and how their outcomes can affect health and safety, policy formulation, enactment, implementation, policy evaluation and its revision or repeal. Observational and interview surveys of the driving public were conducted over an eighteen month period (1987-1989) in Kansas. Results showed major differences in the public's knowledge, attitudes, and behavior toward the new mandatory seatbelt law across different geographic locations of metropolitan, urban and suburban areas. The new law had the support of more than half of those interviewed. The public's knowledge and attitude on the seatbelt use and law were far from being ideal. Much work is needed to convince about 27% of the driving public who declared they never use their seatbelts and would ignore any law/policy that would force them to comply. PMID- 10116579 TI - "Working for Patients": the National Health Service in the 1990s. AB - The National Health Service in England is on the verge of sweeping changes that would apply free-market methods to the state-financed health care system. The government proposal, WORKING FOR PATIENTS, would bring about the most far reaching changes in the NHS since it was founded following World War II. This paper examines a number of important issues and questions raised by the White Paper on the NHS. One cannot understand the proposed changes in the NHS in abstraction from the broader context of the basic principles upon which the NHS was originally established: universalism, equality, accessibility, and continuity of care. The so-called reforms contained in the White Paper potentially threaten an internationally unique national health care system. PMID- 10116580 TI - The mandation of insurance coverage for in vitro fertilization. AB - For many infertile couples, in vitro fertilization represents a last hope; yet few couples can afford this expensive procedure, which health insurers do not routinely cover. To force health insurers to pay for in vitro fertilization, infertile couples have successfully lobbied in six state legislatures for "mandation" legislation, which will force insurers to pay for the procedure. This paper discusses the legislative battlefield for in vitro fertilization mandation and the long-term implications of such victories. PMID- 10116581 TI - Educating allied health professionals to provide care for cancer patients and their families. AB - From 1985 to 1988, a state-wide program of cancer education was offered to community-based allied health professionals (AHPs) at five different program sites in Pennsylvania. During this three-year period, 512 social workers, clergy, dieticians, physical therapists and others received training to increase their knowledge about cancer and counseling, improve their supportive attitude regarding cancer patients and families, and decrease stress related to their work with this population. Overall, the Program was successful in reaching AHPs working with cancer clients who had little formal training in the cancer field. At the beginning of training, it was observed that AHPs with initially higher levels of education and more years of work experience with cancer patients had higher levels of counseling knowledge. Those who were women, worked in hospitals, or had worked with cancer patients longer exhibited higher levels of cancer knowledge. Participants who were women and who had more education had reported lower levels of job stress. Among those AHPs who completed the training courses, cancer knowledge increased by 14 percent. In addition, knowledge related to counseling cancer patients and their families improved by 11 percentage points. Perceived job stress among the AHPs also declined by 10 percent. Finally, participant supportive attitude concerning cancer clients improved. PMID- 10116582 TI - Pennsylvania's medically uninsured population: findings from a statewide survey. AB - Pennsylvania is currently considering legislative options to expand coverage and improve access to medical care for state residents who lack health insurance. Relevant data are presented from a telephone survey of 10,809 Pennsylvania households. Almost nine percent (8.5%) of the state's population lacks health insurance, representing over one million people. Those most likely to be uninsured are children and young adults, non-whites and the poor. A substantial number of poor people are not covered by the state's Medicaid program. The uninsured report poorer health status, more obstacled to receiving care and greater use of hospital services for primary care. PMID- 10116583 TI - Long term care needs and personal care services under Medicaid: a survey of administrators. AB - Home and community based care services constitute a public initiative in the development of a long term care service network. One such home based initiative is the personal care service program of Medicaid. The authors conducted a national survey of administrators of this program. They received a response from 16 administrators of such programs in 1987-1988. The responses raise significant issues regarding training, access to and equity of services, quality of services, administrative oversight and the coordination of home-based care in a network of available services. Based on administrator responses, the authors draw several conclusions. PMID- 10116584 TI - Storytelling as a therapeutic technique in a group for school-aged oncology patients. AB - Storytelling in a support group may be a useful technique for helping children with chronic illness resolve psychological conflicts related to their illness. This paper will describe the author's experiences with two open-ended groups for children with cancer. Significant stories that demonstrate the technique and its usefulness will be discussed. Implications of such a technique will be given. The technique is adaptable to many settings and with many different diagnoses. PMID- 10116585 TI - The availability of psychosocial interventions to children with cancer and their families. AB - Awareness of the need for and efficacy of psychosocial services for pediatric oncology patients and their families has increased greatly in the last decade. However, it is currently unknown to what extent these services are available. Therefore, a national survey of pediatric oncologists was conducted to determine the availability of the following services: psychological/psychiatric and social work consultation, support groups for patients and family members, nonpharmacological pain and anxiety management, and nonpharmacological treatment of anticipatory emesis. Results suggest that most centers offer social work consultation and support groups to parents. Fewer support groups are offered to patients and even fewer nonpharmacological services to assist patients in coping with anticipatory nausea and pain are offered. Results are discussed in terms of the pattern of service delivery and cost-effectiveness. PMID- 10116586 TI - A day in the life of a rural community health nurse. Tales from the trenches. AB - The rural nurse is a community nurse--an integral part of her neighbors' lives, with too few hours in the day to meet their specialized needs. PMID- 10116587 TI - Crisis intervention: managing the at-risk situation. Tales from the trenches. AB - The rural home care nurse provides more than health care, often being forced to meet clients' social needs. PMID- 10116588 TI - The vital link: the frontier home care nurse. Tales from the trenches. AB - A remote, impoverished, and aging population depends on the creativity and persistence of local home health care providers. PMID- 10116589 TI - Overcoming obstacles: the special needs of the rural client. Tales from the trenches. AB - Home care in a rural area is time-consuming, expensive, and sometimes dangerous. Only committed, resourceful caregivers need apply. PMID- 10116590 TI - Health beliefs and practices of rural elders. AB - Understanding the rural elderly is essential to developing effective programs to prevent disease and promote health. PMID- 10116591 TI - Bringing gerontic education to rural nurses. AB - An innovative continuing education program provides current gerontic information to geographically isolated nurses who care for the rural elderly. PMID- 10116592 TI - Staffing a pediatric home care agency. PMID- 10116593 TI - Delivering home care in rural areas: results of a nationwide survey. AB - The special problems that home care providers face in delivering health care in rural and frontier areas, including poor accessibility, increased travel times, and staffing shortages, make providing quality and efficient service a challenge. PMID- 10116594 TI - OSHA mandates AIDS protection. AB - The Occupational Safety and Health Administration's recently published final rules, designed to protect health care workers from infection by bloodborne pathogens, will prevent 200 deaths and 9,200 bloodborne infections a year. PMID- 10116595 TI - A time for reengineering. AB - Industry consultant Rich Helppie claims that information systems changes throughout the last decade brought about a change in systems, and little else. Healthcare organizations during the 1990s must reengineer their operations--with the benefit of I/S technology--to stay competitive ... to stay in the game at all. PMID- 10116596 TI - It's time to recognize the I/S needs of marketing. AB - Although the industry has begun to embrace the role of marketing in healthcare, this recognition has not been matched by a commensurate commitment of capital resources, including expenditures for information systems that help healthcare managers to market "smart". PMID- 10116597 TI - Wake up to managing customer relationships. AB - A survey of 50,000 American households on their habits in purchasing healthcare services shows that healthcare marketers need to "wake up" to managing their customer base more effectively before they miss critical opportunities to capture and retain business. PMID- 10116598 TI - A whole greater than the sum of its parts. AB - By marrying the strategic functions of the planning, marketing and information services departments at the senior administrative level, leaders at Children's Hospital in Columbus are able to build a more accurate and useful picture of their market, and they can better coordinate their approaches to it. PMID- 10116599 TI - Marketing trends call for database management. PMID- 10116600 TI - The '90s paradigm shift for electronic claims. AB - In the development of any new industry, certain events signal a paradigm shift. Those affected by the "new way" finally seem to grasp that change is inevitable. The paradigm shift has begun for electronic claims submission. PMID- 10116601 TI - Electronic claims are smart way to trim costs, share outcomes. AB - Health and Human Services wants to trim the administrative fat from the country's $666 billion healthcare bill. The Hartford Foundation is letting bids for a system that allows individual communities to share healthcare data for a variety of purposes. Both efforts draw significantly on electronic media claims. PMID- 10116602 TI - Standards bring the vision closer to reality. AB - A large multi-entity health system in the Midwest now processes more than 150,000 electronic claims each year. With industry-wide standards for EMC formats and edits, Franciscan Health System looks to significantly increase that number with a commensurate increase in billing efficiency. PMID- 10116603 TI - Planned giving: wealth is not a prerequisite. AB - Concentrate on consistent donors and volunteers. Look for older individuals and pay special attention to those who have no direct heirs. PMID- 10116604 TI - U.S. Savings Bonds: the planned-gift forgotten asset. AB - As older Americans take a close look at their assets, promote their interest in unlocking the wealth accumulation in their U.S. Saving Bond holdings. Use careful planning and advice when promoting this gift strategy. PMID- 10116605 TI - Planned gifts on a shoestring budget. AB - How can a small non-profit educate donors about planned giving and market the benefits? A simple program of seminars and newsletters may be the answer. PMID- 10116606 TI - A planned-giving officer's checklist. PMID- 10116607 TI - Anatomy of a merger. PMID- 10116608 TI - Shifting the paradigm for health care leadership. PMID- 10116609 TI - Health care leadership in the public interest. AB - Successful institutional leaders articulate a sense of organizational purpose and mission, and establish and maintain an organizational culture that fits with that purpose, while anticipating and responding to external and internal dynamics that will affect the organization's capacity to meet its role. In health care, the organizational purpose is necessarily directed to the broader community, and the dynamics that must be anticipated include not only technological and economic change, but also changes in public attitudes and expectations. In order for the institution to thrive over time, it must both be near the front of the curve of those changes while protecting and preserving excellence in its core activities. The key to effective leadership in health care organizations is effective two-way communication with internal constituencies, with the organization's communities, and with the broader public policy process. Health care leaders must take a more active role in responding to their communities' health needs and in shaping public policy toward health care. PMID- 10116610 TI - Do we expect too much from our leaders? PMID- 10116611 TI - Health care leaders--it is time to step forward. PMID- 10116612 TI - Toward a renewed leadership Gestalt. PMID- 10116613 TI - Hospitals choose reusable over disposable sensors. PMID- 10116614 TI - Needle, syringe prices fall. PMID- 10116615 TI - Set up a needlestick reporting and tracking program to see if safety devices are needed. PMID- 10116616 TI - Consignment grows in O.R., stalls in med/surg. PMID- 10116617 TI - How the laws govern advertising and promotional allowances given by suppliers. AB - A hospital materials manager reports that a supplier has offered his hospital some advertising and promotional allowances. He wonders what laws govern these allowances and how the courts have interpreted them. In this dialogue, Dr. Decker develops the law relating to advertising and promotional allowances given by manufacturers and suppliers. PMID- 10116618 TI - Stockless program momentum slows in 1991. PMID- 10116619 TI - Generic drug prices still falling. PMID- 10116620 TI - Hospital Price Index to track revenues. PMID- 10116621 TI - A supplier's firm offer not revocable within time allotted, according to federal code. AB - A hospital materials manager writes that he is having a problem with a supplier trying to renege on an offer to sell that the supplier had stated would be held open for 60 days. In this dialogue, Dr. Decker reviews the concept known as the firm offer and offers some suggestions for gaining the most from it. PMID- 10116622 TI - Hospital systems use off-site warehouses for internal stockless inventory programs. PMID- 10116623 TI - Hospital management: integrating the dual hierarchy? AB - Traditionally, hospitals are seen as dual hierarchies: in addition to the formal administrative pyramid, the professional medical system forms a second line of authority. Equally traditional, this poses substantial problems for hospital management. The present study reported in this article took place as part of a larger research project on Industrial Democracy in Europe (IDE-2), aimed at studying changes in industrial relations and internal relations in metal and insurance companies. In the Netherlands, this project was enlarged to include hospitals. A number of significant changes have taken place in the past decade in Dutch general hospitals. As a reaction to environmental changes, e.g. in legislation, planning and financing, organizational structures have shown interesting developments. Examples are an increased hospital size due to mergers, the emergence of mid-level management, divisionalization (inpatient vs outpatient wards), and integration of medical specialists in the organization. As a result, several changes in power positions have occurred, mainly at the strategic decision level: middle and top management have gained while the medical profession has lost some influence. The Works Council has established its position, and made a significant gain in influence on strategic decision making. PMID- 10116624 TI - Can a community development model be used for health programmes in an industrialized country? AB - Injury resulting from accident is a serious public health problem in Sweden, as it is in the rest of the world. Theoretically, almost all incidents can be prevented. However, in practice, injury-prevention is a complex problem. A community-level intervention programme for prevention of accidents was developed in the municipality of Sollentuna, Stockholm County. The primary strategy has been to involve the community through representatives as well as through local organizations and groups. Project organization has been built up in cooperation with the municipal primary health-care department, local authorities, voluntary organizations and citizen agencies. A common opinion is that it is the actual process in a community programme which is important, that alters the type of involvement from a 'top-down' to a 'bottom-up' approach. Can a local community take over responsibility for running such a programme which has been initiated by an external authority or organization? We think that, at least for Swedish circumstances, the community development approach is far too optimistic in its expectation that community members should and can stay actively involved in programme decisions. Based on our experience, it does not seem possible to maintain a broad self-sustained programme solely with input from community members. PMID- 10116625 TI - Cost of treatment of congenital dislocation of the hip. AB - Early treatment for congenital dislocation of the hip is usually simple and inexpensive. However, if the disease is not detected by 6 months of age, treatment is often complicated and expensive. We evaluated the potential cost saving of screening, by examining the costs in 36 late cases born in 1980 and found an average cost of pounds 6,674 per case for treatment to this date. This amount could justifiably be spent on each case detected in an effective screening programme. PMID- 10116626 TI - The validity of a visual analogue scale in determining social utility weights for health states. AB - Asking people to place health states on a visual analogue scale is a commonly used technique for establishing social utility weights for life years. Recently, the technique has been adopted for setting priorities in the Oregon Medicaid Program in the US; as well as by the Euroqol Group in their development of an instrument meant to serve as a tool for linking cross-national valuations of health states. However, it is unclear what people mean when they value health states on a visual analogue scale. In a series of empirical studies, subjects expressed little depth of intention in relation to the valuations beyond the act of ranking states. Comparisons of the valuations, with valuations elicited by means of the equivalence of numbers technique, indicated that intervals between states on the visual analogue scale must be weighted more the closer they are to the bottom of the scale. This is the same as saying that visual analogue scale values should not be used directly as utility weights for life years. A transformation of the values is needed, and a power function may be suitable for this purpose. PMID- 10116627 TI - Innovation as hospital culture: a trial and demonstration facility in an acute care hospital ward. AB - This short communication describes the establishment of a trial and demonstration facility for new products, technologies, methods and procedures in an acute-care hospital ward at Concord Hospital in Sydney, Australia. The importance of innovation for all businesses, including hospitals, is discussed; and, why a project like the Model Ward can promote innovation as part of the corporate culture. The Model Ward development, implementation and its benefits are reported on and discussed. PMID- 10116628 TI - Hospital CEOs' priorities and perceptions regarding industry issues and the Virginia Hospital Association's activities. AB - Based on a survey of Virginia hospital CEOs, it was revealed that four industry issues are causing a high degree of concern, namely Medicare/Medicaid reimbursement policies, personnel shortages, indigent care, and increased operating expenses. Each of these issues will be discussed regarding the VHA's activities to devise possible solutions. Regarding Medicare, the VHA has worked closely with the American Hospital Association in their federal advocacy efforts encouraging members to write, call, and visit their Congressional representatives to persuade them to pass legislation increasing the Medicare budget. Regarding Medicaid, which is administered by each state and in Virginia involves a 50/50 sharing of the funding between the federal and state governments, the VHA has challenged what it believes to be an illegal hospital reimbursement system through the federal judicial system. While the process is continuing, the VHA is encouraged by the U.S. Supreme Court's decision (July 1990) affirming hospitals' and all other health care providers' right, to pursue via the judicial process their allegation that a state is violating federal law by setting inadequate and inequitable Medicaid reimbursement rates to hospitals. In order to address the personnel shortages issue, the VHA has actively addressed recruitment and retention challenges by establishing a Health Manpower Resource Center and hiring a full-time director. This office targets high school students, second-career adults, and current health care professionals through communication and education programs. The area of indigent care represents one of the VHA's most notable achievements to date. This entails the recent Virginia legislation creating the Indigent Care Trust Fund. This fund's initial amount is some $15 million and represents an approximate 60/40 contribution ratio involving both the State of Virginia and hospitals in Virginia. A formula has been developed for each hospital in Virginia to assess how sensitive they are to indigent care patients, which includes patients who are either in households whose annual income is below the federal poverty level and/or patients who do not have health care insurance. Those Virginia hospitals who are less sensitive to indigent care will contribute to this fund, while those who have more exposure to indigent care patients will be reimbursed from it. Legislation will be proposed to the state legislature to broaden the contributory base to the Indigent Care Trust Fund by requiring employers who do not currently offer health care insurance to their employees to also contribute to the fund. Reimbursements from the fund to Virginia hospitals are scheduled to begin in FY 1991.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10116629 TI - Marketing ambulatory services to the elderly: the special role of the physician. AB - Elderly health care consumers are different. Understanding these differences is the key to the development of successful marketing strategies. This paper examines the area of dental services, preventive health care, physician services and mental health services. It explores how elderly health care consumers respond differently than their younger counterparts. Finally the special role of the primary physician in marketing to the elderly is examined. PMID- 10116630 TI - Wellness and prevention programs as internal marketing programs for hospitals: the current status. AB - Employee wellness programs are demonstrating promise in helping abate America's health care cost crisis. It also would appear natural for hospitals to play a leadership role in the important development of this new product category in health care marketing. By offering Health Care Programs to employees, hospitals could develop and improve several offerings. This study investigates the nature of the problem and extent of employee wellness leadership provided by hospitals as compared to 900 other companies and organizations representative of American industry. Hospitals may provide the appearance of leadership through volume of services offered but may falter in the reasoning behind such services and financial commitments for further development. PMID- 10116631 TI - Why are many plastic surgeons reluctant to acknowledge and accept the use of marketing in their practices? PMID- 10116632 TI - The role of cost in hospital pricing decisions. PMID- 10116633 TI - Case mix management: rationale, implementation, and administration. PMID- 10116634 TI - PPS implementation effects on efficiency and cost control in the hospital industry. AB - Empirical evidence is provided concerning the impact of Public Law 98-21 on the operation of United States hospitals. The Box-Jenkins autoregressive integrated moving average model was used to analyze the impact of the law on efficiency and cost containment practices over a 24-year time period. Four cost containment variables and three efficiency variables were studied. Public Law 98-21 was the intervention and 1984 was the intervention year in which to evaluate impact assessment. Children's hospitals were used as a control group. Results of the research indicated no impact on cost containment practices and a significant impact on efficiency of hospital operations. PMID- 10116635 TI - Questions of ethics and performance arise for medical marketers in the 1990s. PMID- 10116636 TI - Atmospherics, the marketing concept, and a marketing tool for hospitals. AB - Researchers have demonstrated that the conscious use of atmospheric structuring can induce marketer-desired behaviors in service consumers. This may be particularly relevant to marketers of hospital care since consumer judgments often depend upon peripheral rather than core evidences of quality and satisfaction. Under these circumstances, health care marketers have an obligation to explore the phenomenon of atmospherics and its practical implications in the health care marketing mix. PMID- 10116637 TI - Marketing parallax in health care industry: an empirical study of hospitals. AB - It is about two decades since the marketing scholars identified the need and relevance of marketing in health care organizations. The health care industry itself has been undergoing significant changes brought on by deregulation, declining demand, intraorganizational competition and growth of HMO's and PPO's. Yet, the industry has not fully implemented the marketing concept. For many health care organizations, marketing seems still to mean advertising and public relations as evidenced by an empirical study. PMID- 10116638 TI - Is the hospital patient market receptive to incentives? Results of an attitude survey. AB - A survey was taken of attitudes towards offering five specific services, free of charge, as incentives to encourage patients to choose a hospital different from their current preference. 48.5% of those interviewed indicated incentives would influence their choice. Twenty-three percent would use incentives even when their physician recommends another hospital. PMID- 10116639 TI - A model of service quality perceptions and health care consumer behavior. AB - Analysis of covariance structures (LISREL) was used to examine the influence of consumer held perceptions of service quality on consumer satisfaction and intentions to return. Results indicate that service quality is a significant predictor of consumer satisfaction which, in turn, predicts intention to return. Health care marketing implications are discussed. PMID- 10116640 TI - Top managers view organizational politics. PMID- 10116641 TI - Quality improvement: a race with no finish. AB - Quality improvement has been used in other industries for its ability to help achieve objectives in price sensitive markets and against tough competition, according to authors Kevin Sullivan and Ellen Meier, RN, M.B.A. Quality improvement also has strategic implications for every group practice concerned about maintaining profit margins, satisfying patients and payers and lifting the morale of its employees. PMID- 10116642 TI - Deming, quality and the small medical group administrator. AB - As administrators, writes Douglas Noll, we can coordinate and implement quality measures affecting our practices and which impact the patient's total medical experience. Unfortunately, many smaller groups cannot hire an outside consultant or single employee whose sole purpose would be to monitor quality. Noll offers several simple practices that administrators can use to improve the quality of service in their groups. PMID- 10116643 TI - A short course in the methods of quality assurance. AB - When medical groups decide to implement quality assurance (QA) programs, they often appoint committees to oversee the process. Donald Ervin, M.D., explains and defines the important terms and concepts for committee members and administrators who have never been involved in a QA program. PMID- 10116644 TI - Are open-ended or point-of-service plans right for you? AB - Open-ended and point-of-service plans are relatively new methods of financing and delivering health care, writes Joseph Mack, M.P.A. He describes both plans in detail, along with the operational aspects of a medical group's involvement in such arrangements. PMID- 10116645 TI - Program helps residents make practice selection. AB - At the University of Massachusetts Medical Center, a curriculum for family practice residents has been developed to educate them about the aspects of various types of health care delivery systems. Christine Micklitsch, M.B.A., describes how the school accomplishes this curriculum through a process called "swings." PMID- 10116647 TI - Are you getting the most from your HMO enrollees? AB - Competition among health maintenance organizations (HMOs) continues to grow and their chief marketing focus is what they can offer and deliver to consumers. But, writes R. Scott MacStravic, Ph.D., there is another side to the coin that is equally important: what might consumers offer and deliver to the HMO as loyal, supportive enrollees? PMID- 10116646 TI - Making practice retirement acquisition work for you. AB - Author Richard Holdren writes that medical practice acquisition can have a dramatic impact on hospital and group practice revenue in a "zero-sum game," where both parties are competing for a shrinking patient and dollar base. Holdren describes how such a program is built on the concepts of support management and "grow your own." PMID- 10116649 TI - The Charter Medical Corporation clinical information system: a preliminary report. AB - Charter Medical Corporation's computerized Clinical Information System is described. The computerized system helps clinicians formulate and document individualized patient treatment plans along the continuum of care and to improve internal medical record keeping. The system can also help improve the efficient collecting, storing, retrieving, and reporting of clinical information, both for internal use and for external utilization review and case management. In the future, the system will be linked to Charter's continuous quality improvement efforts and to its new Clinical Outcome Monitoring System. PMID- 10116648 TI - Information systems management under pressure. AB - Changes in clinical management and reimbursement approaches have placed new pressures on psychiatric hospitals to have immediate access to critical information. Information systems management is in the difficult position of responding--while under this pressure--to a host of requests for computer applications that may be at cross purposes with each other. Pine Rest Christian Hospital, a full-continuum, 146-bed, not-for-profit psychiatric facility in Grand Rapids, Michigan, has been preparing tactics to deal with information systems management under pressure. This paper describes the consequent information systems management approaches and some of the critical computer applications Pine Rest has installed. PMID- 10116650 TI - National data standards for mental health management and performance indicators. AB - National developments suggest that the Mental Health Statistics Improvement Program (MHSIP) offers a suitable philosophical framework as well as standards for a minimum core of mental health data for the total field. With an emphasis on agency-level development and use of data systems, MHSIP could further management objectives in both the public and private sectors. Performance indicators derived from the MHSIP content could be the vehicle for the transformation of automated reams of data into a meaningful and useful consolidated management tool, a tool that would also further quality of care. This article briefly describes the background and content of the MHSIP and the type of performance indicators that can be derived from it and used by management. PMID- 10116651 TI - Information systems for private psychiatric hospitals: selection and management. AB - Private psychiatric hospitals are acquiring information systems to provide timely and accurate data for improved patient care and financial operations. Serious commitment of staff time, effort, and financial resources is required during the selection and management of the system to achieve full benefits from this technology. Active participation by senior management and the end-user community in the planning and acquisition process will lay the foundation for a successful system implementation. PMID- 10116652 TI - Survey documents national auxiliary, volunteer impact. PMID- 10116654 TI - Tips on handling complaints. PMID- 10116653 TI - Gift shops: a financial report. PMID- 10116655 TI - Promoting health care reform. PMID- 10116656 TI - Hospital hospitality houses: coping with a growing lodging issue. PMID- 10116657 TI - For families of ill children, home is often a Ronald McDonald House. PMID- 10116658 TI - Health professional education: time for a change. PMID- 10116659 TI - Long way to go to achieve a uniform European health system. PMID- 10116660 TI - The role of medical technology in the hospital. PMID- 10116661 TI - Re-utilisation and recycling of waste in hospitals. PMID- 10116662 TI - Innovation in the delivery of primary care. PMID- 10116663 TI - Steriliser refurbishment--a superior option. PMID- 10116664 TI - Perspectives. Academic health centers: responding to change. PMID- 10116665 TI - Perspectives. Academic & government: love on the rocks? PMID- 10116666 TI - The bloodborne pathogens standard: the final rule finally arrives. PMID- 10116667 TI - The Sporicidin recall. AB - Sporicidin products have been recalled by a joint action of the Food and Drug Administration (FDA), the Environmental Protection Agency (EPA), and the Federal Trade Commission (FTC). HHMM emphasizes that other glutaraldehyde-based cold sterilant products are still acceptable for use. An FDA spokesperson could not offer a reason why Sporicidin products failed the Association of Official Analytical Chemists test protocol for sterilants (see HHMM July 1990; 3[10]:1). The official press release issued by FDA is reprinted below in its entirety. PMID- 10116668 TI - Many hats, experiences and rewards for ER patient rep; presence quells tensions, helps families. PMID- 10116669 TI - Rural hospitals reach out to learn why customers pass them by. PMID- 10116670 TI - Competition to entertain patients no laughing matter. PMID- 10116671 TI - Hospital day care attracts parents, patients; who runs centers? Hospitals or contractors. PMID- 10116672 TI - In-home care of mildly ill children: risk management issues. PMID- 10116673 TI - Contingency planning for health care information systems. PMID- 10116674 TI - Adverse drug reaction surveillance and risk management. AB - ADR programs are most successful when developed from a multidisciplinary approach. Physicians and other health care workers should be encouraged to report and evaluate ADRs to potentially decrease risks involved in an ADR case. Management of ADRs should include prompt feedback of individual patient and grouped data for educational and risk management purposes. Risk managers should play a significant role in all aspects of an ADR surveillance program. PMID- 10116675 TI - Effective interviewing techniques. PMID- 10116676 TI - Captive insurance companies in health care. AB - A health care system or individual hospital should consider establishing a captive insurance company if any one of the following situations exist: The organization's professional liability program is arranged with a self-insured retention of $500,000 or more, or consideration is being given to such an arrangement. A trust fund has been established for a self-insured exposure- professional liability, workers' compensation, or employee benefits. A portion of the organization's professional liability excess insurance program is arranged with an insurer that uses a fronting insurer. The organization currently sponsors, or is considering sponsoring, a physicians' liability insurance program for medical staff members. If any of those situations exist, a comprehensive feasibility study should be undertaken, preferably by an independent, objective organization that does not have a financial interest in the outcome of the study. PMID- 10116677 TI - NFPA Journal Buyers' Guide 1992. Fire protection & fire service reference directory. PMID- 10116678 TI - Customizing productivity standards. PMID- 10116679 TI - Certification examination results. Discussion and statistics from AAMT's 1990 radiology certification exam. PMID- 10116680 TI - The new Medicare fee schedule: estimating the impact by specialty and state. PMID- 10116681 TI - The new Medicare fee schedule--Part II. PMID- 10116682 TI - Band-aids to patch up health care. AB - The President and his Democratic rivals unfurl plans for curing the crisis. But all of them have drawbacks, and none is likely to be adopted in the fury of an election year. PMID- 10116683 TI - When health plans fail. PMID- 10116684 TI - Health care programs: fraud and abuse; amendments to OIG exclusion and CMP authorities resulting from Public Law 100-93--HHS. Final rule. AB - This final rule implements the OIG sanction and civil money penalty provisions established through section 2 and other conforming amendments in the Medicare and Medicaid Patient and Program Protection Act of 1987, along with certain additional provisions contained in the Consolidated Omnibus Budget Reconciliation Act of 1985, the Omnibus Budget Reconciliation Act (OBRA) of 1987, the Medicare Catastrophic Coverage Act of 1988, OBRA of 1989, and OBRA of 1990. Specifically, these regulations are designed to protect program beneficiaries from unfit health care practitioners, and otherwise to improve the anti-fraud provisions of the Department's health care programs under titles V, XVIII, XIX and XX of the Social Security Act. PMID- 10116685 TI - Indian Health Service; medical reimbursement rates for calendar year 1992 inpatient and outpatient medical care--PHS. PMID- 10116686 TI - Specialization in home care: a cardiopulmonary model. AB - The Visiting Nurse Service of Rochester and Monroe County, Inc. has developed an innovative method of clinical practice to meet the needs of patients after acute episodes of heart or lung disease. The cardiopulmonary program has a multidisciplinary approach, focusing on disease management through physical assessment, symptom management, diagnostic testing, and rehabilitation via progressive activity tolerance. The program has been successful in either preventing or increasing the length of time between hospital admissions, and has increased the agency's referral base, improved staff job satisfaction, and reduced turnover. PMID- 10116687 TI - Internship programs for high-tech, high-touch home care. AB - An innovative internship program developed by Creighton University's School of Nursing assists professional nurses with the knowledge and skills needed to care for high-tech clients in the hospital or home. PMID- 10116688 TI - The clinical nurse specialist: a bridge to community resources. AB - Access to early intervention and continual health care services through the use of multicultural professional interventions and follow-up programs after discharge can mean the difference between life and death for the high-risk infant. PMID- 10116689 TI - Multidisciplinary documentation for home care. AB - Documentation serves as a primary measure of clinical practice and reimbursement eligibility and as a tool of professional accountability and quality assurance. This article presents a multidisciplinary documentation system designed to accommodate these multiple dimensions of quality home care. PMID- 10116690 TI - Discharge planning: whose responsibility is it? AB - A survey of twenty hospitals in southwestern Virginia revealed that a lack of a discharge planning process was the most frequently reported reason for failure in the discharge system. All health professionals who come in contact with clients during hospitalization are responsible for preparing them and their families for discharge--only then can true continuity of care occur. PMID- 10116691 TI - Patient satisfaction and quality care. AB - As the home care industry becomes increasingly more competitive, providing high quality and cost-effective care can be a challenge. Using patient satisfaction surveys as tools to enhance services and ensure quality of care can give the home care agency of the 1990s a competitive advantage. PMID- 10116692 TI - Community-based mental health services for the elderly: nursing meets the need. AB - Special needs exist for older persons who have acute and chronic mental illness and disability; however, individual and societal barriers can prevent these services from reaching those in often desperate need. Intervention and expertise delivered to the urban elderly primarily in the home by psychiatric-mental health clinical nurse specialists is a viable option in primary prevention and crisis intervention. PMID- 10116693 TI - The near-death experience and caregivers: helping and being helped. PMID- 10116694 TI - America's tough new job market. AB - Look for plenty of opportunity but less security. More people will work in small companies and at home. Those who get the good jobs will be skilled, adaptable, and able to keep learning. PMID- 10116696 TI - Determining and controlling production and service costs. PMID- 10116695 TI - Special report on liability and insurance. An update on assignment of patient benefits under ERISA. AB - While the holdings in Davidowitz and Arkansas Blue Cross & Blue Shield arose in different contexts, they both reflect the courts' increasing willingness to consider the importance of cost containment in the health insurance arena, even though patient accessibility to health care may be restricted as a result. If the holding in Davidowitz is not successfully appealed, providers may need legislative relief in order to retain their ability to take valid assignments of patient claims for payment from ERISA plans. It is uncertain whether such legislation can be sought at the state level or must instead come from Congress due to ERISA preemption of state legislation. Clearly, the district court decision on remand in Arkansas Blue Cross & Blue Shield will be closely watched for any light it may shed on this question. On a pragmatic note, providers who have not entered into "participation" agreements with insurers or other private payors may now have a greater incentive to do so, and "nonparticipating" providers who continue to obtain assignments from patients in order to collect directly from insurers or other private payors should determine on a case-by-case basis whether the source of the patient's benefits is a group health plan--which is likely to fall under ERISA and may contain nonassignment provisions--or some other form of coverage. For an additional perspective on insurers' responses to copayment waivers, see Newsletter, Vol. 6, No. 10, October 1991, at 7. PMID- 10116697 TI - Helping your employees write effectively. PMID- 10116698 TI - Managing the employee who has stopped growing. PMID- 10116699 TI - What administrators need to know about clinical engineers. Understanding the equipment manager's responsibilities and concerns. AB - Despite the proliferance of computer systems in hospitals, many administrators- both new and experienced--have only a passing knowledge of technology management and managers. To make both the administrators' and the clinical engineers' jobs less difficult and more effective, the authors offer a profile of the "typical" clinical engineer. In the process, they underscore how health-care-administration programs need to increase students' exposure to and training in technology management. PMID- 10116700 TI - The employee who complains. Understanding and responding to staff complaints. AB - A manager's mood sets the tone for the work environment and should be a positive role model. When employees complain, the manager should listen and make careful note not only of the content of what is expressed but also of the feelings behind the message. In short, the manager should address the dynamics behind the complaint in order to be able to appropriately receive, investigate, and respond to complaints. It is the wise manager who accepts that complaints are an inevitable part of the managerial role and who works to develop expertise in ways of handling this human reaction. PMID- 10116701 TI - What do you pay your volunteers? The benefits and bases of a hospital volunteer program. AB - All volunteers need something in return for their services, whether it's recognition, experience, or personal satisfaction. Successful volunteer programs identify and meet these expectations. Although this requires the same kind of commitment and energy administrators give their paid staff, the results--bottom line and otherwise--are well worth the effort. PMID- 10116702 TI - Making the move from clinician to manager. Do you have what it takes? AB - From the outside, management doesn't look like so difficult a job: schedule a few employees, attend a few meetings. From the inside, however, it's a different story, especially when it is the "inside" of the manager that determines managerial success. Although the author addresses clinicians who are interested in management, she has words of wisdom for all future and current managers. PMID- 10116703 TI - Nurses counseling patients about smoking cessation--why, when, and how. AB - In patient health education, nurses are a natural choice for on-the-spot counsellors and teachers. Yet many nurses feel uncomfortable about broaching subjects such as smoking cessation with their patients or the patients' families. The authors argue that it is time for nursing programs and hospitals to prepare and encourage nurses to take the initiative in smoking-cessation counseling. PMID- 10116704 TI - The basics of radiation protection for hospital workers: considerations and procedures. AB - Radiology is probably one of the most widely misunderstood technologies in healthcare. The health risks of x-ray exposure are not as great as many think, nor are x-rays the only source of radiation. The author dispels some of the mysteries with a definition of radiation, an explanation of its sources and standards, and some basic tips on protection. PMID- 10116706 TI - Delegation. PMID- 10116705 TI - After Cruzan, hospitals and the right to die. The implications for AMDs. PMID- 10116707 TI - The hospital administrator as public figure, Part 1. Responding to grass-roots healthcare reform. PMID- 10116708 TI - Internists grapple with how they should respond to requests for aid in dying. PMID- 10116709 TI - A modern argument against legalizing active euthanasia. AB - A Seattle nephrologist cautions against making euthanasia a public policy, citing contemporary concerns over the ethical, legal, medical and societal questions that the issue raises. PMID- 10116710 TI - In support of Initiative 119. AB - A Seattle internist analyzes why voters in Washington rejected a proposal that would have made their state the first place in the world to legalize active euthanasia. Though initiative 119 failed, similar proposals may find greater acceptance from patients who desire a dignified death. PMID- 10116711 TI - Dick Davidson: bringing the AHA into an era of cooperation. Interview by C. Burns Reohrig. PMID- 10116712 TI - The access debate: whither the center? PMID- 10116713 TI - It's time for nursing home reform. PMID- 10116714 TI - Reforming our health care system. American Society of Internal Medicine. PMID- 10116715 TI - Let's get rational about suicide. AB - Recent events have focused national attention on the appropriate role for physicians in relieving the suffering of the terminally ill. Is suicide ever rational? Should physicians participate? An attorney-nurse turned ethicist examines well-known cases and helps frame the debate. PMID- 10116716 TI - DUE of ciprofloxacin in the treatment of urinary tract infections in hospitalized patients. AB - In this retrospective study of 30 patients with urinary tract infections, a drug usage evaluation indicated that 60% of the patient population sampled were appropriately switched to ciprofloxacin from IV antimicrobial agents; inappropriate use was identified in 40%. The drug's safety profile indicates that patients can be safely removed from IV antimicrobial therapy and continue treatment on ciprofloxacin, a measure which reduces treatment costs. These costs also can be lowered when inappropriate ciprofloxacin use is ruled out in patients with organisms sensitive to less costly oral antimicrobials. Identifying which patients should be removed from parenteral therapy maximizes the economic benefit of ciprofloxacin therapy and optimizes the impact of pharmacy intervention on patient care. PMID- 10116717 TI - What process does your P&T Committee use to obtain staff physicians' input regarding formulary decisions? PMID- 10116718 TI - What is the most difficult DUE your P&T Committee has ever conducted? How did you overcome its obstacles? PMID- 10116719 TI - Developing control charts to review and monitor medication errors. AB - There is a need to monitor reported medication errors in a hospital setting. Because the quantity of errors vary due to external reporting, quantifying the data is extremely difficult. Typically, these errors are reviewed using classification systems that often have wide variations in the numbers per class per month. The authors recommend the use of control charts to review historical data and to monitor future data. The procedure they have adopted is a modification of schemes using absolute (i.e., positive) values of successive differences to estimate the standard deviation when only single incidence values are available in time rather than sample averages, and when many successive differences may be zero. PMID- 10116720 TI - Patient care contributions of clinical pharmacists in four ambulatory care clinics. AB - This study investigates both cost-avoidance and improvement in the quality of care and patient outcome attributed to pharmacist intervention in four ambulatory care clinics. Four clinical pharmacists reported 199 interventions made in the pharmacotherapeutic management of 87 ambulatory clinic patients in 1 month. The majority of interventions were based on acceptable professional practices as ranked by peer reviewers. Positive impact of the interventions on patient outcome based on objective and subjective data was documented in 49% of the interventions. Forty-two percent of the interventions improved the process of care with no measurable impact on patient outcome. Cost avoidance was calculated according to interventions made at different steps of the drug use process. Net cost avoidance figures projected to 1 year amounted to $221,056. PMID- 10116721 TI - Impact of a pharmacist/physician cooperative target drug monitoring program on prophylactic antibiotic prescribing in obstetrics and gynecology. AB - The pharmacist's role in promoting rational, cost-effective use of drugs has been described in the literature. In a target drug monitoring program (TDMP), a single agent or group of agents becomes targeted for review. Antibiotics have been the primary focus of TDMP because of their therapeutic impact and cost considerations. The objectives of this project were to assess the prophylactic antibiotic prescribing habits of OB/GYN physicians and to evaluate the impact of a pharmacist/physician cooperative TDMP on prophylactic antibiotic prescribing and cost. The study was conducted in three phases: 1) a retrospective chart review of 150 patients, 2) an in-service education session, and 3) a concurrent chart review of 107 patients. Patient selection, timing of preoperative dose, and use of single dose prophylaxis were according to criteria in greater than 90% of patients both before and after the in-service training. Compliance with recommended regimens increased from 45 to 73% after the in-service training. A cost savings was not realized because the physicians wished to use a regimen with anti-anaerobic coverage (i.e., cefotetan) rather than a less expensive agent. However, the cost of selection of resistant organisms must be considered when discouraging the use of multiple broad spectrum agents. Active involvement of the medical staff in a pharmacy-based TDMP produces a cooperative atmosphere in which to educate clinicians and promote rational prescribing habits. PMID- 10116722 TI - Computer assisted neonatal parenteral nutrition solution protocols. AB - Hospital pharmacies compound neonatal parenteral nutrition solutions for administration to premature infants until enteral feedings are tolerated. The majority of these solutions pose no problem for the hospital pharmacist to prepare. Occasionally, premature infants are prescribed low volume solutions that challenge the pharmacist to ensure the proper mixing and dilution of ingredients. Formulation and dilution protocols have been developed to guide the pharmacist in determining the safest procedure for compounding neonatal parenteral nutrition solutions. Staff members of Charlton Memorial Hospital pharmacy have developed a computer assisted calculation program that aids the pharmacist in following these protocols. Formulation changes suggested by the computer program should be verified by the pharmacist. Computerized documentation of formulation changes aid communication between the pharmacist and the physician. Infant safety is the primary goal of these formulation changes. PMID- 10116723 TI - An analysis tool to investigate theft or tampering of controlled substances. AB - The authors describe a quantitative analysis method to investigate narcotic theft or tampering on a nursing unit. It provides procedure to follow after any suspected tampering or outright theft of controlled substances. Several methods to review all current controlled substance activity for a given nursing unit and their possible relations to the loss are described. In addition several working documents are described to aid in the analysis of the loss. PMID- 10116724 TI - Hospital pharmacy technicians function in Desert Storm enemy prisoner of war camps. AB - The 300th United States Army Reserve Field Hospital from Ashley, Pennsylvania was activated in November 1990 and deployed to Saudi Arabia in January 1991 in support of Operation Desert Shield/Storm. The mission of the hospital was to treat enemy prisoners of war (EPWs) located at the 401st and 403rd Prisoner of War Camps. This article describes the role of the hospital pharmacy technicians performing their duties in the prison camp medical tent. Pharmacy technicians were added to the prison camp medical staff, which consisted of medics, physicians, and nurses to assume the challenging task of both ordering and prepackaging the large quantities of pharmaceuticals required to treat the enormous numbers of EPWs. PMID- 10116725 TI - Modular facility grafts speed with lower costs in customized skin clinic. PMID- 10116726 TI - New 1995 CFC deadline puts the heat on chiller owners, manufacturers. PMID- 10116727 TI - CAFM: how 6 key factors can determine its success. PMID- 10116728 TI - AHA objects to key parts of device regulations. AB - In the Nov. 26, 1991, issue of the Federal Register, the U.S. Food and Drug Administration (FDA) published its tentative final rule to implement the reporting requirements for the Safe Medical Devices Act (SMDA) of 1990. In the months before and after the rule's publication, the Chicago-based American Hospital Association studied the rule and offered guidance to its members and to the FDA on the act's reporting requirements. The rule's public-comment period ended March 27; here's a condensed version of what the AHA told the FDA. PMID- 10116729 TI - Planning, maintenance key to a roof's longevity. PMID- 10116730 TI - Atrium plants: proper care brings the outdoors in. PMID- 10116731 TI - Monitrend II offers third-quarter '91 utilities data. PMID- 10116732 TI - Hold everything! Custom cabinets control clutter. PMID- 10116733 TI - Testing the political waters of healthcare reform. PMID- 10116734 TI - Selecting the cream of the crop (Part II). PMID- 10116735 TI - Progress in Romania. PMID- 10116736 TI - Bringing rationality to information transfer. PMID- 10116737 TI - Protecting workers from pathogens. Employers must act now to comply with OSHA's new standard on bloodborne pathogens. AB - A new standard set forth by the Occupational Safety and Health Administration (OSHA) requires healthcare employers to implement sweeping new controls in areas such as record keeping, engineering, hazard prevention, and work practice. Through the bloodborne pathogen standard, which went into effect on March 6, OSHA acknowledges that healthcare workers face significant health risks as a result of occupational exposure to blood and other infectious materials. Although most prudent healthcare providers already adhere to the Centers for Disease Control's universal precautions, the OSHA regulations include several additional mandatory measures that are more specific and stringent. The additional measures include the development of an exposure control plan, procedures for responding to an employee's exposure to bloodborne pathogens, the implementation of certain engineering and work practice controls to eliminate or minimize on-the-job exposure risks, and the provision of personal protective equipment and information and training programs. OSHA estimates that the greatest cost component of implementing procedures to bring a facility into compliance is attributable to the purchase of personal protective equipment. Although the costs of compliance are substantial, OSHA has estimated that these costs represent less than 1 percent of the healthcare industry's annual revenues. Violation of the bloodborne pathogen standard may result in penalties of up to $70,000, depending on the severity of the infraction. Criminal penalties are also possible for willful violations that result in worker death. PMID- 10116738 TI - Capitalism ex cathedra. Sources of hope in tough economic times. AB - Pope John Paul II's encyclical Centesimus Annus--written in honor of the centennial anniversary of Rerum Novarum, the first papal social encyclical- examines the present world socioeconomic situation in light of traditional Catholic social teaching. The pope warns the West not to be too quick to celebrate the demise of communism as a victory for capitalism. Capitalism has some good points, the pope acknowledges, but by themselves, market mechanisms do not ensure the just distribution of food and other goods that fulfill essential human needs. When capitalism relies on market forces alone, it creates a culture of consumerism that promotes selfishness and greed. Capitalism has been in flux for decades. After World War II, developed Western societies began moving toward "Keynesian capitalism," which subjects the mechanisms of the free market to public control. After Keynesian capitalism's apparent failure in the United States in the 1970s came the "monetarist" theory and a return to an earlier, liberal form of capitalism in which society relies on market mechanisms alone to revitalize the economy and regulate the production and distribution of goods. The monetarist policies of the 1980s turned out to be part of a global plan to reorganize the economy around the giant multinational corporations. This forced individual countries to compete for capital investment and led to unemployment and neglect of low-income people. Structural adjustment policies have been adopted by governments all over the world, in poor countries as well as developed. All are moving toward the form of capitalism that is repudiated by Catholic social teaching in general and Centesimus Annus in particular. PMID- 10116739 TI - The personal challenge of advocacy. AB - Advocacy is the embracing of a cause or issue, a conversion to a mission that makes a very real claim on the advocate. It is the activity of altering structures, of changing the status quo. Like prophetic ministry, the task of advocacy is to nurture, nourish, and evoke consciousness of different ways of considering and doing things, to champion new models of organization. Effective advocacy entails three distinct steps: envisioning an alternative, challenging the status quo, and energizing persons and communities. It is characterized by the emergence of an alternative community concerned with different issues and different ways of doing things. It also involves the integration of advocacy into our daily lives and a penetration of the numbness of life. How will we know when we are truly serving as advocates of the Church's healing ministry? We will have an inkling that we are on the right track when we move from charity to justice. PMID- 10116740 TI - System-directed grassroots advocacy. AB - In 1990 leaders at the Catholic Health Corporation (CHC), Omaha, decided that the system should take an active role in advocacy efforts on health policy issues. CHC determined that developing a grassroots network would be the most effective way to pursue advocacy initiatives. The system also decided that it should concentrate solely on national health policy issues with potential impact on CHC facilities. Planners determined that the first step in creating a network would be to specify a contact person at each of the system facilities. They also decided that it would be more effective to encourage local community members to contact their elected officials on health policy issues than for the system to engage directly in advocacy efforts. The system itself would monitor and assess changes and developments in national healthcare policy and initiate advocacy efforts. Finally, a steering committee of facility chief executive officers (CEOs) would act as a liaison between system affiliates and the corporate office. CHC corporate staff now establish a public policy agenda that identifies initiatives the system will focus on each year. The system sets performance goals for CEOs and encourages them to participate in strategic planning for public policy initiatives. PMID- 10116741 TI - A matter of integrity. AB - Catholic healthcare providers today can live out their vision and values only if they become public policy advocates. They must learn how to shape effective public policy to help heal the ailing U.S. healthcare system. Although from a political perspective they might feel ill-equipped to advocate in the public policy arena, Catholic healthcare providers are richly endowed from the perspective of their tradition of social teaching. They must uphold the common good as a primary criterion in healthcare reform. Two important issues provide an extraordinary opportunity and challenge for Catholic healthcare leaders to demonstrate their commitment to the common good: euthanasia and healthcare reform. PMID- 10116742 TI - For the good of the child. AB - Legislative activities of the past 10 years have led many hospitals to develop grassroots advocacy programs that focus on specific issues. At Cardinal Glennon Children's Hospital, St. Louis, advocacy efforts involve employees, physicians, board members, and others. Situated near the Missouri-Illinois border, Cardinal Glennon serves patients from both states and deals with the legislatures and government agencies of each. Cardinal Glennon has formed alliances with children's hospitals in Missouri and in Illinois to lobby for fair funding from both states' Medicaid programs. Cardinal Glennon has formed a public policy committee that evaluates issues, sets priorities, and identifies trends. Hospital staff work with legislators from both states, inviting them for a first-hand look at children's needs. The hospital has also formed the Letter-Writing Advocacy Committee. Committee members write their representatives, stating their viewpoint on specific issues. Cardinal Glennon sponsors the Southern Illinois Perinatal Program. The hospital is also home to Missouri's regional poison control center, which in 1991 saved the state of Missouri $400,000 in Medicaid funds and saved private insurance carriers approximately $2.2 million. Cardinal Glennon's advocacy efforts extend beyond specific hospital programs, however, Hospital representatives often testify to legislative committees on more universal issues such as child abuse, lead poisoning, primary care needs, and trauma care. PMID- 10116743 TI - A threatened privilege. AB - Because their tax-exempt status was at stake, Wisconsin hospitals joined together in 1990 to study and develop a system to better measure and quantify their provision of needed community services. The goal of a task force made up of members of the Catholic Health Association of Wisconsin (CHA-W) and the Wisconsin Hospital Association (WHA) was to develop a proactive response to potential legislative and municipal initiatives that could challenge the tax-exempt status of not-for-profit hospitals. The CHA-W/WHA Task Force on Social Accountability decided to generate data to demonstrate hospitals' tax-exempt worthiness and to show that hospitals pay for many of the direct municipal services they receive. The task force surveyed Wisconsin hospitals on the services they provide to their communities, the municipal service fees they pay, and whether any of their services compete with local businesses. The survey results showed that Wisconsin hospitals do provide needed community services. However, the hospitals do not always adequately communicate to their communities the extent of these benefits. The survey results also showed that Wisconsin hospitals pay most service fees that are quantifiable and measurable. In 1991 the task force adopted a statement of policy which emphasizes that hospitals must clearly demonstrate that they have assessed the health-care needs of their communities, implemented programs to respond to those needs, and maintained their mission to serve. PMID- 10116744 TI - Humor's healing potential. AB - In the past three decades the medical world has begun to take more serious notice of the healing power of humor and the positive emotions associated with it. Humor and laughter are currently being employed by psychotherapists and other care givers as tools to promote and maintain health, as well as intervention and rehabilitation tools for a host of maladies and illnesses related to stress and life-style. Although this empirical medical approach is relatively new, the study of humor has revealed a complex psychological phenomenon. Senses of humor have been categorized in types associated with personality. Humor has many styles and can be found in almost any situation, on any occasion. Theories of humor include the superiority theory, the incongruity theory, the release/relief theory, and the divinity theory. Laughter has many clinical benefits, promoting beneficial physiological changes and an overall sense of well-being. Humor even has long term effects that strengthen the effectiveness of the immune system. In healthcare, humor therapy can help relieve stress associated with disease and illness. It serves as a diversionary tactic, a therapeutic tool for disorders such as depression, and a coping mechanism. It also is a natural healing component for care givers trying to cope with the stress and personal demands of their occupations. PMID- 10116745 TI - The limits on self-destruction. PMID- 10116746 TI - An inside view of rehabilitation. PMID- 10116747 TI - Breaking the chain of poverty. PMID- 10116748 TI - Sisters of Charity Healthcare Systems Inc.--Protecting assets by auditing services. PMID- 10116749 TI - A smile for Jenny. PMID- 10116750 TI - Hospital positioning: a strategic tool for the 1990s. AB - The authors extend the process of market positioning in the health care sector by focusing on the simultaneous utilization of traditional research methods and emerging new computer-based adaptive perceptual mapping technologies and techniques. PMID- 10116751 TI - Positive perspectives, concerned perspectives, and action suggestions for long term health care marketing success. PMID- 10116752 TI - Health care service decision influences: an exploratory investigation of search and nonsearch criteria for professionals and patients. AB - Despite numerous studies examining buying behavior, research on types of evaluative criteria for vendor selection involving consumers and health care professionals (functioning as market "intermediaries") has been lacking. Building on previous conceptualizations reported in marketing and health care literature, the author examines the relative influence of search and nonsearch evaluative criteria in the decision making of both patients and hospital-based health care providers. Decisions involving post-acute service vendors are analyzed to determine the relative impact of each attribute set in the selection of respiratory therapy services by patients and health care professionals. Data are presented that point to significant differences in decision-making styles between patients and health professionals, as well as among health care providers in different organizational, institutional, and professional roles. Key marketing implications are discussed. PMID- 10116753 TI - Retail versus private dental practices: do the patients differ? AB - Using a consumer-oriented framework, the authors contrast private dental patrons and retail dental patrons in terms of demographic characteristics, choice criteria, and patronage behavior in selecting a dental care provider. Assessments are made of these consumers' attitudes and perceptions toward various dental practice attributes or characteristics. Differences are found across several attributes, but dimensions of quality service, reputation, and competence are not distinguishing characteristics between the two dental patron groups. These results provide some insights and interesting debate about the image and general marketing practice of private dentists and retail dental facilities. PMID- 10116754 TI - Evaluating health care quality: the moderating role of outcomes. AB - An integrative model of health care quality is presented. "Health care quality" is defined as provider conformance to patient requirements at three benefit levels: core, intangible, and tangible. The model is operationalized and tested in a clinical setting, a large center for fertility studies with more than 5000 patients. Health care "process variables" such as physician and patient interactions were not as important in patients' evaluations of health care quality when successful outcomes occurred (pregnancy). However, when patients experienced unsuccessful outcomes (no pregnancy), health care "process variables" were important and had a significant influence on patient perceptions of health care quality. Hence, service outcomes can significantly affect the measurement and interpretation of health care quality. Implications for health care management and research are discussed. PMID- 10116755 TI - Measuring product meaning for prescribed medication using a means-end chain model. AB - On the basis of a means-end chain model, the product attribute and consequence levels of consumers' product meaning for prescribed medication were measured for a sample of 550 consumers. Using exploratory factor analysis on a 30-item scale, the authors identified five product attribute dimensions and three consequence dimensions. The means-end chain model can help marketers of health care learn more about how consumers categorize product meanings, which in turn can be used in the development of marketing strategies. PMID- 10116756 TI - The value of physician advertising in the yellow pages: does the doctor know best? AB - The authors examine differences between physicians and consumers in their ratings of physician advertising in the yellow pages. Four versions of a hypothetical yellow pages ad were tested that differed in the amount and type of information included. The results provide some interesting insights into the value of the yellow pages as an advertising medium. PMID- 10116758 TI - Resource guide. PMID- 10116757 TI - Designing health promotion programs by watching the market. AB - More health care providers and payors are beginning to see health promotion programs as a significant tool for attracting patients, reducing costs, or both. To help design programs that take into account the values and lifestyles of the target group, naturalistic observation can be useful. The authors illustrate the approach in a study of pipeline workers that provided input for the design of nutrition and smoking cessation programs. PMID- 10116759 TI - Have we really come a long way? Women in EMS survey results. PMID- 10116760 TI - Is talk cheap? Communication skills for the EMS professional. PMID- 10116761 TI - Hiring top-notch employees. PMID- 10116762 TI - Carrots to kudos. Motivating EMS providers. PMID- 10116763 TI - HCFA final capital rules in review. PMID- 10116764 TI - Maintenance insurance programs for capital equipment. PMID- 10116765 TI - Planning and implementing systems integration for materiel management and accounting. PMID- 10116766 TI - OSHA's final rule on occupational exposure to bloodborne pathogens. AB - This report is intended as a brief review of some of the key points of the new OSHA rule. It should not be used in place of the complete rule, and you should contact your legal advisor with any questions about interpretations of the rule. Because circumstances of occupational exposure vary among employers, it is advisable that employers be thoroughly acquainted with all requirements of the rule. The preamble to the rule, starting on page 64004 of the December 6, 1991 Federal Register, may provide helpful background information for understanding specific provisions of the rule. PMID- 10116767 TI - Washer-sterilizers vs. indexed washer-decontaminators: a cost comparison. AB - Washer-sterilizers are the most common type of automated decontamination equipment in hospitals today, but from a cost standpoint, installing an indexed washer-decontaminator makes more sense for hospitals with active decontamination areas. An indexed washer-decontaminator is a highly productive and efficient machine that results in streamlined workflow in decontamination. Even in hospitals that own washer-sterilizers, the economics can be so compelling that they might want to consider replacing them with indexed washer-decontaminators. PMID- 10116768 TI - Cardiac ultrasonic scanners. ECRI. PMID- 10116769 TI - The future for healthcare capital investments. AB - Hospitals have entered into a new era of capital planning. A number of factors will influence hospital buying behavior now that the Medicare capital regulations are being implemented. As purchasing responsibility for additional departments is continually folded into hospitals' central purchasing function there will be increased opportunities for group contracts. As resources shrink and demand for services increases, GPOs will be relied upon for their expertise and financial finesse. The emphasis will be on boosting the use of group contracts among existing members, rather then seeking additional members in a shrinking hospital market. Through effective purchasing, it is generally recognized that a hospital can recover and keep, at best, 5-10 percent of the cost of all purchased goods and services. Group purchasing organizations need to develop better strategies of cooperation with vendors, distributors and hospitals to help providers control capital costs. In this challenging environment, GPOs will aggressively target markets other than acute care as the source of their future growth, just as healthcare facilities are branching out. To accommodate changing needs, the strongest GPOs will continue their evolution into structures more like alliances, offering an array of other cooperative and support programs beyond the purchase of goods and services. PMID- 10116770 TI - Continuous quality improvement: myths, doubts, realities. PMID- 10116771 TI - Proper use of heat sealers. PMID- 10116772 TI - Family medicine education and rural health: a response to present and future needs. AB - The importance of family medicine in providing rural health services has been established for quite some time. The need to train physicians who select the specialty of family medicine is critical at a time when medical student interest in the primary care specialties appears to be diminishing. Renewed efforts by educational institutions and incentives at the state and federal levels will be necessary to assist in the alleviation of shortages of rural physicians. The educational program at the University of Minnesota, Duluth, School of Medicine has achieved a great deal of success in training rural family physicians. A coordinated program effort, featuring the efforts of more than 200 family physicians during the past 15 years, has led to 52.5 percent of all graduates selecting family practice and more than 41 percent choosing practice sites with a population fewer than 20,000. Elements of the program at Duluth could serve as a model for other schools desiring to increase the number of students entering family medicine and rural practice. PMID- 10116773 TI - The economic impact of hospitals in rural communities. AB - This article presents how to assess the economic impact of a hospital on a rural community. The economic impact is identified by assessing the direct, induced, and indirect impacts that result because of the presence of a hospital in a rural community. The methodology utilizes survey data and estimation procedures for four rural hospitals. The economic impact estimates are based on microdata. Income multipliers are estimated for each of the rural communities. The research demonstrates that rural hospitals do make significant economic contributions to the communities they serve. Community leaders can use the model presented to evaluate the economic impact of their local hospital. PMID- 10116774 TI - Hospital choice of Medicare beneficiaries in a rural market: why not the closest? AB - As part of a larger study of hospital choice, the travel patterns of more than 12,000 Medicare beneficiaries residing in three overlapping rural areas were examined. During 1986 these Medicare beneficiaries were admitted to one of 53 hospitals in an area that encompassed parts of Minnesota, North Dakota, and South Dakota. Information on ZIP code of residence, closest hospital, and hospital of admission were used to analyze hospital choices of the Medicare rural elderly residing in this area. To summarize their travel patterns, the admitting hospital was categorized based on whether it was urban or rural, its size and whether or not it was the closest facility. Findings indicated that 60 percent of these rural Medicare beneficiaries used hospital services at their closest rural hospital, regardless of its size. However, 79 percent of those whose closest hospital was larger than 75 beds used it, while only 54 percent of those whose closest rural hospital was fewer than 75 beds obtained services there. Overall, 30 percent of those residing in this rural market area went to an urban hospital. These patterns appeared to reflect an evaluation by the physician and/or individual of the relative attractiveness of the local hospital versus alternatives available, as well as the individual's characteristics. Travel patterns varied by the beneficiary's age as well as his or her relative complexity of illness, as measured by a Disease Staging methodology. Findings have implications for the provision and financing of hospital services in rural areas. PMID- 10116775 TI - Poverty, primary care and age-specific mortality. AB - An important area of concern among rural health researchers and policy analysts is the social and ecological correlates of mortality levels. This research is concerned with the empirical relationship between the prevalence of poverty and the mortality experience of different age groups within the population. Poverty is viewed as a characteristic of the social organization of local areas and operationalized by employing several indicators, including a measure of rurality. The empirical results indicate that the magnitude of the association between the prevalence of poverty and mortality varies among different age groups. The impact of rurality, while being consistently positive, is shown to be statistically nonsignificant. The research also shows that the availability of primary care is associated with lower mortality. PMID- 10116776 TI - Rural Youth Disability Prevention Project Survey: results from 169 Iowa farm families. AB - Agriculture is now the most hazardous occupation in the United States and it is the only one in which children not only comprise a significant part of the work force, but also live and play at the work site. Annually, 23,500 pediatric agricultural injuries are reported, with nearly 300 fatalities (Rivara, 1985). The Rural Youth Disability Prevention Project was designed to use innovative, community-oriented methods to address the unique problems of child safety in agriculture. Toward this end, a survey instrument was designed to gather data both to assist in program development and to serve as a pretest for the subsequent evaluation. Analysis of these data indicated several issues to target for intervention efforts. One is lack of supervision--more than 40 percent of children who operate equipment do so unsupervised. Approximately 30 percent of children more than 3 years old play alone in work areas, and 80 percent of these children play near machinery in operation. Another issue is operation of farm machinery by very young children--respondents' children began operating equipment at an average age of 12 years. Coupling this with the finding that the parents believe their children are not capable of operating equipment until age 15 exemplifies the most important issue, the disparity between parents' levels of safety knowledge and safety behavior. Using the survey data to increase local involvement, efforts are being directed toward facilitating an ongoing, community sponsored intervention program to empower farm families to effect their own solutions. PMID- 10116777 TI - Technology-driven referrals, a fundamental problem for small rural hospitals. PMID- 10116778 TI - Volunteers as customers: a service quality perspective. AB - Not-for-profit service firms depend upon volunteer employees for the success of their programs. This article offers a change in perspective--volunteer as customer instead of employee--to stimulate insights and provide recommendations about attracting and retaining volunteers. The volunteer is viewed as a customer, the service purchased is the volunteer experience, paid for in the currency of donated time and energy, and the not-for-profit service firm is seen as being in the business of designing, managing, communicating, and delivering a quality volunteer experience. PMID- 10116780 TI - HMOs drove me out of Minnesota. PMID- 10116779 TI - Volunteerism by students at risk. AB - This program has made it possible for students to experience some important firsts: the first report card they are proud to share, the first award they receive at an honors assembly. Students have gained a new awareness of the elderly: "I never used to look up to them," one student said. "Now I really understand that they are history. I will have more respect for the elderly, because I will want respect when I am older." PMID- 10116781 TI - When, or whether, to retire. PMID- 10116782 TI - The key to lower health costs: a doctor's educated guess. PMID- 10116783 TI - What determines your new Medicare fees. PMID- 10116784 TI - Groups want you--and they're ready to pay the price. PMID- 10116785 TI - Are ERs and convenience clinics fleecing your patients? PMID- 10116787 TI - What to do when your PRO comes calling. PMID- 10116786 TI - What it will take to save rural practice. PMID- 10116788 TI - Keeping a lid on supply costs. PMID- 10116789 TI - What an HMO really is. PMID- 10116790 TI - Medical staff privileges and the antitrust laws: a view from the Federal Trade Commission. AB - This article describes the types of medical staff credentialing and peer review activities that invite the scrutiny of the Federal Trade Commission. To avoid antitrust problems, medical staffs and their members are advised to offer recommendations based on specific quality-of-care concerns. Antitrust problems will arise, however, if the medical staff or its members engage in collective activities that involve threats or coercion directed at the hospital's governing board or that are calculated solely to exclude an entire class of potential competitors. PMID- 10116791 TI - The Anti-Kickback Statute and hospital-physician financial arrangements. AB - Hospital-physician financial arrangements often involve transactions that could be construed by the government as illegal remuneration under the federal "anti kickback" statute. This article discusses some of the questionable types of relationships that arise and explores the government's reaction to these arrangements as manifested by a recent Office of Inspector General management advisory report and proposed and final safe harbor regulations. PMID- 10116792 TI - The need for tail coverage in medical malpractice insurance. AB - In today's litigious society, it is more important than ever that physicians purchase "tail" coverage--that is, insurance for claims asserted after the period covered by their basic insurance arising from occurrences during the insured period. This article describes the tail of a medical malpractice insurance policy, the need for and purpose of tail coverage, the methods of pricing such coverage, and the problems associated with the tail coverage provisions of medical professional liability insurance. PMID- 10116793 TI - The COBRA Patient Anti-Dumping Law: Part I--Requirements under the statute. AB - Under the federal patient anti-dumping statute, physicians are required to treat a hospital's emergency patients, including women in labor, and must comply with detailed statutory provisions that govern when it is appropriate to transfer a patient to another facility. A thorough understanding of this law is necessary to minimize the risk of liability to the physician and the hospital. This article, the first of two parts, discusses the requirements under the statute. Part II, which will appear in a future issue, will discuss court interpretations of the statute and its impact on medical malpractice claims. PMID- 10116794 TI - OIG Management Advisory Report: financial arrangements between hospitals and hospital-based physicians. PMID- 10116795 TI - Medical staff privileges and the antitrust laws: does the Intracorporate Conspiracy Doctrine apply? AB - The occasional imposition of antitrust liability on medical staff members for actions involving peer review is not a sufficient reason to abandon medical staff participation in the peer review process. This article reviews some of the case law in which the applicability of the intracorporate conspiracy doctrine to medical staff peer review activity has been decided and explains why appropriate medical staff involvement in such activity does not raise the risk of antitrust liability. PMID- 10116796 TI - Moody's boosts HCA's rating after debt reductions. PMID- 10116797 TI - Tenn. Blues drop Erlanger as PPO provider. PMID- 10116798 TI - Firm awarded damages from Picker. PMID- 10116799 TI - Carilion denies capital spending broke promises. PMID- 10116800 TI - 3 physician-owned labs, officers found guilty in Medicare kickback case. PMID- 10116801 TI - Bill seeking to cut drugmaker tax breaks defeated in Senate. PMID- 10116802 TI - Fla. hospitals drop merger to collaborate. PMID- 10116803 TI - Oncologists, firm fight over Fla. referral law. PMID- 10116804 TI - Non-emergency visits rise at suburban Kansas City facilities. PMID- 10116805 TI - Quorum signs letter of intent to acquire Dothan, Ala., facility. PMID- 10116806 TI - Pa. group's plan to provide cash if Medicaid falters. PMID- 10116807 TI - JCAHO mulls response to falsified records. PMID- 10116808 TI - Practice guidelines face broad-based test. PMID- 10116809 TI - St. Louis facilities affiliate. PMID- 10116810 TI - Managed care. Taking the direct approach. AB - Cost-conscious companies are turning to direct contracts with hospitals in efforts to reduce their medical bills, but they won't hesitate to sever the relationships if workers become dissatisfied with the quality or service. A national survey of some 250 Fortune 1,000 companies conducted for Modern Healthcare offers insights into what companies are looking for and what they're getting through such arrangements. PMID- 10116811 TI - Managed care. Purchasers seek relief from drug price hikes. AB - Public and private groups are seeking a consensus on replacement legislation for a federal law that requires drug manufacturers to give rebates to state Medicaid programs based on the "best price" available in the market. Critics of the law, including the Dept. of Veterans Affairs and other high-volume purchasers, claim the law is drying up their discounts and driving up prices overall. PMID- 10116812 TI - Questions to mull on managed-care pacts. AB - While managed care may sound like old hat to seasoned hospital trustees, consultants recommend proceeding with caution when negotiating managed-care contracts. The problem is that many hospitals proceed on basis of price alone without knowing the actual costs of servicing such agreements. Two executives from Ernst & Young offer some questions to ask during the negotiations. PMID- 10116813 TI - Black hospitals' fortunes, ranks still declining. AB - A 1990 story in Modern Healthcare identified only eight traditional black hospitals, a group that once numbered more than 200. Now, only a couple of those appear to be in reasonably good health. The facilities' heavy dependence on increasingly unreliable Medicaid as a payer is making it harder for them to survive, executives at those hospitals say. PMID- 10116814 TI - Stark seeks consensus by drafting reform plan. PMID- 10116815 TI - Healthcare service stocks hit rough waters even as broader market measures sail along. PMID- 10116816 TI - Cleveland Clinic to honor requests for financials. PMID- 10116817 TI - Coalition to set timetable for publishing hospital ratings. PMID- 10116818 TI - La.-owned hospitals gripped by political battle for control. PMID- 10116819 TI - VHAE shareholders approve liquidation. PMID- 10116820 TI - 2 hospitals in Northeast file for bankruptcy. PMID- 10116821 TI - HCIA acquires information service properties. PMID- 10116823 TI - CHAMPUS reform shift draws ire. PMID- 10116822 TI - Two physicians countersuing Desert Hospital. PMID- 10116824 TI - Picker to appeal $2 million judgment. PMID- 10116825 TI - N.Y. hospitals begin steps to counter TB. PMID- 10116826 TI - Missouri Supreme Court to rule on challenge to malpractice law. PMID- 10116827 TI - IG office report contends hospitals owe $200 million for Medicare overpayments. PMID- 10116828 TI - Congress seeks regulation of board-and-care industry. PMID- 10116829 TI - 'TQM' delivers as promised. PMID- 10116830 TI - Fla. physician referral ban approved. PMID- 10116831 TI - Maine bill would offer antitrust exemptions. PMID- 10116832 TI - Some groups weigh anger over AHA reform proposal. PMID- 10116833 TI - Virginia hospitals latest to face battles over tax exemptions. AB - Virginia has become the latest arena for efforts by local governments to tax the property or revenues of not-for-profit hospitals, which historically have enjoyed exemptions from such assessments. While one Virginia system already is paying a tax, another has made a donation to its municipal government to avoid being taxed. Several bills pending in the Legislature also could be taxing. PMID- 10116834 TI - Hospital borrows from position of strength. AB - Children's Hospital of Philadelphia is nearly debt-free and able to finance much of its own replacement and equipment needs. But rather than avoid debt obligations, it's taking on more than $200 million in new borrowing that capitalizes on the hospital's flush financial profile. Its strong balance sheet and credit ratings will keep capital infusion costs low. PMID- 10116835 TI - HealthTrust planning to sell 10-year notes. PMID- 10116836 TI - Humana per-share earnings dip for quarter. PMID- 10116837 TI - Nu-Med reports a string of new financial woes. PMID- 10116838 TI - Antitrust charge pared from radiologists' high-profile suit. PMID- 10116839 TI - Potential bidders learn details of 'coordinated care'. PMID- 10116840 TI - 2 Minneapolis HMOs, clinic eye affiliation. PMID- 10116841 TI - Extend rural adjustment--Pryor. PMID- 10116842 TI - Lawmakers seek reversal of EKG rule. PMID- 10116843 TI - AMI posts profit, completes moves in management, stock. PMID- 10116844 TI - Military overstates bed count for wartime casualties--GAO. PMID- 10116845 TI - CHA set to fight $150,000 limit on exec salaries. PMID- 10116847 TI - S&P upgrades ratings for HCA bonds. PMID- 10116846 TI - Ratings cut on 8 Pa. hospitals. PMID- 10116848 TI - NME earnings take on psychiatric hospital woes. PMID- 10116849 TI - Practitioner data bank reports, 'matches' up significantly--HHS. PMID- 10116850 TI - Making their voices clearly heard. Investor-owned facilities are working hard to share their opinions on healthcare reform. AB - For-profit facilities are reaching out into their communities in efforts to share their views on healthcare reform and forge stronger ties with local business groups and governments. Because healthcare reform is drawing more interest than ever, their executives believe it's crucial to voice concerns about any legislative action that may affect their facilities' bottom line. PMID- 10116851 TI - Texas to study rehab abuses. PMID- 10116852 TI - Public hospitals learning to live with shrinking subsidies. AB - Dwindling revenue sharing money and the recession's downward pressure on tax receipts are forcing state and local governments to take a scalpel, or in some cases an ax, to their direct subsidies to hospitals. One Louisiana hospital saw its entire subsidy eliminated because state officials said the facility had become self sufficient and didn't need the assistance, which exceeded $15 million last year. PMID- 10116854 TI - More states 'go private' to provide services. AB - Faced with mounting budget deficits, more states are taking a look at privatization--the closing or downsizing of state-operated psychiatric, rehabilitation and acute-care facilities--as a way of trimming outlays. Officials believe those services often can be provided more cost-effectively in the private sector, a solution that's preferable to reducing services or raising taxes. PMID- 10116853 TI - Here's some good medicine to supplement hospitals' efforts to stimulate pharmacies. AB - Hospitals started retail pharmacies with visions of revenues that would offset prospective payment shortages, but they soon found out that some key assumptions about profitability were off key. There are ways to tune the pharmacy operation, however, so it reaches out to its market and comes through for the hospital. Charles W. Murray explains some problems and solutions. PMID- 10116855 TI - HealthVest, IRS join to push bankruptcy plan on Healthcare Int'l. PMID- 10116856 TI - AHCA plan would expand federal coverage. PMID- 10116857 TI - Lawmakers call for long-term-care policy. PMID- 10116858 TI - Coming of age with technology. PMID- 10116859 TI - Provider software buyer's guide. AB - To help long term care providers find new ways to improve quality of care and efficiency, Provider magazine presents its second annual listing of software firms marketing computer programs for all areas of nursing facility operations. On the following six pages, nearly 80 software firms display their wares, with programs such as minimum data set and care planning, dietary, accounting and financials, physician orders, and inventory software. The guide also charts support available to users, compatible hardware, integration ability, as well as telephone numbers and company contacts, and easy-to-use reader service numbers. PMID- 10116860 TI - LPN certification programs offer one solution to nurse crunch. PMID- 10116861 TI - Providers must determine impact of broad-based provider taxes. PMID- 10116862 TI - Complying with safe harbor rules decreases risks for providers. PMID- 10116863 TI - Proper med pass techniques ensure resident safety. PMID- 10116864 TI - Support group helps spouses cope with unique losses. PMID- 10116865 TI - Quality care requires timely drug therapy assessments. PMID- 10116866 TI - Provider software showcase. PMID- 10116867 TI - Nutrition screening initiative promotes better dietary care. PMID- 10116868 TI - Delivery room resuscitation of the high-risk infant: a conflict of rights. PMID- 10116869 TI - How doctors decide who shall live, who shall die. PMID- 10116870 TI - Health care fraud. PMID- 10116871 TI - In the presence of animals. Health professionals no longer scoff at the therapeutic effects of pets. PMID- 10116872 TI - Personnel shortage. Supply and demand of healthcare professionals in Kentucky. PMID- 10116873 TI - Food for thought. Linking theory with practice. PMID- 10116874 TI - The National Practitioner Data Bank: new benefits and burdens. PMID- 10116875 TI - Hospitals ante up for nurses. PMID- 10116876 TI - Changing behavior: physicians/hospitals and the new payment reform. AB - Physician payment reform will have an unexpected but far reaching effect on practice patterns and on hospital/physician relationships. Just how much of an effect and strategies for hospital management are subjects the author put to key industry leaders. PMID- 10116877 TI - Practice parameters--hospitals and physicians working together. AB - The sheer numbers and complexity of physician practice parameters have thrown a spotlight on the critical role of this hospital-physician partnership. Hospitals share the responsibility for choosing the appropriate guidelines, knowing where to locate them and providing the technology and thoroughly trained support professionals to implement them. PMID- 10116878 TI - Hospital/physician joint ventures--alternatives for the future. PMID- 10116879 TI - Some Democrats question national health insurance. PMID- 10116880 TI - Joint ventures: still unclear waters. PMID- 10116881 TI - Financial implications of TQM. PMID- 10116882 TI - Management forum--employee empowerment programs. PMID- 10116883 TI - Psychiatric specialty hospitals: six tactics for surviving managed care. PMID- 10116884 TI - Help is available for compliance to OSHA AIDS protection rule. PMID- 10116885 TI - Cutting down a paper mountain: a case study. AB - Here is a classic case study of how bar coding and computerization allowed an 800 bed facility to solve the enormous problem caused by a labor-intensive, paper based patient account management system. As a plus, going to computers saved the hospital five full-time positions. PMID- 10116886 TI - Budgets, access still top legislative agendas. PMID- 10116887 TI - Medicare physician payment reform: how will it affect hospitals? PMID- 10116888 TI - Alternative dispute resolution--the new horizon. PMID- 10116889 TI - The great snake debate continues. PMID- 10116890 TI - "I will give no deadly drug." Why doctors must not kill. AB - Is the profession of medicine ethically neutral? If so, whence shall we derive the moral norms or principles to govern its practices? If not, how are the norms of professional conduct related to the rest of what makes medicine a profession? PMID- 10116891 TI - The Chief Medical Officer's address to the first national conference for Consultants in Communicable Disease Control--June 1991. PMID- 10116892 TI - Model of care for the hospital treatment of individuals with HIV infection. AB - This study was undertaken and completed in 1988, in an attempt to determine the reasons for admission to hospital, and the optimum care required for patients with Human Immunodeficiency Virus related illnesses. Approximately half of the total medical admissions stayed for less than a week, and patients admitted for terminal care and social care occupied a relatively small proportion of the beds. The single largest group of admissions were those for inpatient management of AIDS-related pneumonias. The results of this study provide a greater understanding of the resources currently required for such care, and suggest initiatives for meeting future needs. PMID- 10116893 TI - Community HIV/AIDS teams. AB - This paper describes a consecutive series of 103 patients with HIV and AIDS related illnesses who were referred to, and remained in, the care of two community teams. The characteristics of the patients are outlined and the early experiences of the teams are described. The findings of this study should assist doctors and nurses caring for patients with HIV and AIDS related illnesses in the community, and provide valuable data for service planners. PMID- 10116894 TI - How preventable are spinal cord injuries? AB - In order to determine how many spinal cord injuries are preventable in this country, and how effective a prevention campaign is likely to be, the causes of injury were analysed in 250 consecutive patients admitted to The Duke of Cornwall Spinal Treatment Centre in Salisbury. The results show that many spinal cord injuries are preventable, and the findings support the theory that a programme of prevention similar to that in Australia is urgently required. PMID- 10116895 TI - The measurement of referrals for practice audit. AB - The Royal College of General Practitioners and the Office of Population Censuses and Surveys have collaborated in three national studies of morbidity in general practice at approximately ten-year intervals. This paper presents data derived from the second survey conducted in 1970/71. A comparison of practice referral rates based on different measures is reported, and consideration given to the consequences of the choice of measure on how practices may be perceived. The findings of this study emphasise the need for caution in the interpretation of practice referral data while providing encouragement for general practitioners to engage in open peer review of their practice activities. PMID- 10116896 TI - Prevention of heart disease in general practice: the use of a risk score. AB - Between 1987 and 1988 seven general practices took part in a pilot study of a predictive risk score for ischaemic heart disease in men aged 40-59 years. The aim was to assess the feasibility and usefulness of this score as part of a coronary prevention programme. The score was generally well received by practice nurses and general practitioners, and found to be helpful as a method of focusing preventive activity. Most chose to reveal the score to the patient, although there was some concern that this could lead to false reassurance being perceived by those with a low score but remediable risk factors. Practitioners were able to use the score as a method for identifying a priority group for intervention, and it is concluded that the risk score is a useful component of health checks. PMID- 10116897 TI - Infectious disease notification--a neglected legal requirement. AB - The Acheson Report expressed concern about doctors' knowledge of the infectious disease notification system. This study was undertaken in order to quantify doctors' knowledge of the system, and guide action to improve its efficiency. A survey of 176 hospital doctors in one large Health District showed that, although 82% knew of the legal obligation to notify, 70% did not know where to obtain a notification form, and 40% did not know whom to notify. Over a third of those surveyed did not know that food poisoning and tuberculosis are notifiable diseases. Proposed changes in the law relating to infectious disease control will not compensate for such lack of knowledge. Consultants in Communicable Disease Control should take the lead in improving this vital information system. PMID- 10116898 TI - An audit of the clinical use of magnetic resonance imaging of the head and spine. AB - An audit was undertaken of the use of magnetic resonance imaging for clinical problems of the head and spine. Using a form of simulation, two consultant clinicians were asked to assess a sequential series of 200 patients referred for magnetic resonance. The clinicians considered that 200 magnetic resonance studies could replace about 330 other imaging and neurophysiology investigations; the cost of the alternative tests approximated the cost of magnetic resonance. However, there was considerable variation between cases in the costs of investigations potentially replaced by the procedure under audit, and this variation suggests ways in which magnetic resonance might be used more cost effectively in the future. PMID- 10116899 TI - Homeless women in London: the hostel perspective. AB - This is a service-related study of the prevalence of mental illness in 43 women referred to a visiting psychiatrist at a hostel for single homeless women in south-east London. Over 80% of those referred were mentally ill, and 21% of the total were diagnosed as suffering from schizophrenia. Despite the dedication and versatility of the care staff, the hostel was ill-equipped to meet the needs of the chronic mentally ill. The adequacy of community care provision is further brought into doubt. PMID- 10116900 TI - Drawing new researchers hard for small hospitals. PMID- 10116901 TI - Universal access to health care would alter hospital planning. AB - What would be the impact on hospitals of a federally mandated plan for universal access to health care? The author suggests that it could lead to fundamental changes in planning, marketing, patient mix and reimbursement patterns, especially considering that the uninsured population is larger in size, and less homogenous, than those receiving Medicare or Medicaid benefits. PMID- 10116902 TI - Physician relations: an evolving service not meeting its potential. AB - The relatively new concept of physician relations can help hospitals work with their medical staff as colleagues rather than competitors. Every hospital has someone performing at least some physician relation tasks, but too often that person is at the level of an administrative assistant. Only a few hospitals have full-blown physician relations departments with full responsibility for medical staff relations, quality assurance, credentialing and medical liability. PMID- 10116903 TI - Take an MDC look at your hospital's product lines. PMID- 10116904 TI - Planning indicators. Medicare and Medicaid spending (by type of expenditure). Health Care Financing Administration. PMID- 10116905 TI - Changing the image. AB - A quality environment is an important feature in health care provision. Good design need not cost a fortune--the winner of this Health Services Management competition will have up to 10,000 pounds-worth of design and project management expertise for free! PMID- 10116906 TI - Asking the people: an exercise in quality. PMID- 10116907 TI - CHCs: independent but working in partnership. PMID- 10116908 TI - Developing a workforce model. AB - Over the past two years Wales has been developing a demand-driven workforce model. Originally requested by mental health services to help plan the consequences of running down major institutions while attempting to change patterns of care, the model has matured into one which has potentially wider applications. David Reed outlines its development. PMID- 10116909 TI - Working together in a new policy concept. AB - Gerald Wistow suggests that joint working of all kinds has been an area of major disappointment and failure in the recent history of community care. Compared with the expectations of the mid-seventies, when current collaboration arrangements were put in place, achievements have been modest. PMID- 10116910 TI - Organisational symbolism--a community care consumer's dilemma. PMID- 10116911 TI - A central health authority view of clinical cost information systems. PMID- 10116912 TI - The need for clinical cost information systems: the hospitals' perspective. PMID- 10116913 TI - Clinical resource management: the information needs of regional health authorities. PMID- 10116914 TI - Hospital accounting and information systems: a critical assessment. AB - Public sector organisations seem to be caught up in the global wave of 'neo Thatcherism'. As such, they are being held 'accountable' today by their respective government finance departments for the costs and benefits of the services they provide to the general public. As the public purse tightens, hospitals (and related health service units) more and more compete with other public sector organisations (old-age pensions and services, post-secondary education, day-care centres, port authorities, unemployment insurance, parks and recreation, elite sport programs, aboriginal peoples aid and development, and so on) for a diminishing piece of what seems a smaller and smaller pie. In this 'fight-for-funding', hospitals seem particularly vulnerable. Sky-rocketing costs, public resentment of doctors' high income and a deliberate restriction and limiting of medical school places, among other things, contribute to general public antagonism. The message for hospitals is that cost-effective accountability will loom large when hospitals come begging at the public trough. Even left-wing politicians today seem to be heeding the words of free-market economists like Freedman of Chicago. 'Privatisation' is the constant threat for those deemed inefficient. As a consequence, hospital administrators around the world, caught up in this trend, seem to be stampeding to 'boot-up' some kind of new accounting information system. For example, at my own university hospital (Queen's University, Kingston, Canada), the hospital administrators are in the process of introducing a version of the Johns Hopkins Hospital (Baltimore, Maryland) case-mix-loading cost-accumulation system. In other parts of the world they are known by other fancy names such as 'patient-costing', 'diagnosis-related groups' (or DRGs). Trendy accounting systems seem to be the order of the day, a sort of panacea for the current plague of problems hospitals face. As the new systems become operational, however, traditional management accounting issues will likely surface. Particular departments, wards and surgeons will be fingered by the system for excessive costs, inefficiency, and under-utilisation of equipment. When this happens, the medical professionals will begin to pay attention to these systems. They will discover that the accounting decisions (which cast them in an unfavourable light) are subjective, arbitrary, and problematic. The old debates, such as incremental versus full-costing, transfer pricing and cost of capital, will be played out again; but now on the turf of hospitals. As the debates drag on, it seems likely that in the interim the new accounting systems could do more harm than help. The rest of the paper attempts to explain why. PMID- 10116915 TI - Physicians and effective resource management. PMID- 10116916 TI - The health professional-patient relationship and clinical resource management. PMID- 10116917 TI - A model for product line management in health care. AB - 'Product line management' is receiving much interest and attention in the health care industry. Success with the concept is highly varied, however, largely because it is neither well understood nor even clearly defined. Many managers and academicians believe the concept holds great promise for health care organisations. Others argue it is but a passing fad. This paper seeks to provide a framework to clarify and assist in conceptualising product line management and its various dimensions. This will provide a foundation for future research and for application of the concept in practice. The paper is based on both research of the relevant literature and data collected formally from four hospitals and multi-institutional systems at various stages of developing, implementing and managing product lines, in addition to anecdotal data obtained through teaching and consulting. PMID- 10116918 TI - Clinical management structure: the Royal Prince Alfred experience. PMID- 10116919 TI - Changing the management structure at the Royal Children's Hospital. PMID- 10116920 TI - Competition versus planning in health care: implications for corporate and individual incentives, efficiency & control. AB - This paper is about the management of change; and, most especially, about the changing tides of thinking that health planning and, more latterly, competition could bring about desired change in the health industry towards cost containment, efficiency and control. Looking back over the decade of the 1980s, it was characterised, for many countries, as a real questioning of the role of the public sector in people's life, and--in terms of public/private provision--a re examination of what is public and should be. Coupled with this inquiry was a growing belief that comprehensive health planning was too lofty a goal, and that however elegant in theory, its delivery in practice fell far short of its ideals. Attention has therefore focused on the workings of competitive markets, and the extent to which objectives of cost containment and economic efficiency can be better addressed through competition and internal markets. In reality, the mixed economy is the only policy option available to developed countries today. Public and private monopolies are frowned upon, and the search is on for intermediate possibilities that capture some of the advantages of markets without their disadvantages, and arrangements that motivate consumer choice and simultaneously yield efficiency in the production and distribution of health care. By way of illustration, this paper looks at a number of innovations taking place to address these issues; and, in the context of the UK, at the most recent government proposals in respect of self-governing trusts and GP budget holders, as illustrations of the move towards the internal market, or to managed competition. Not surprisingly, the two areas that feature large on the agenda are hospital (and community) information systems; and, the motivations, rewards and penalties of the provider institutions that deliver services, and the consumers and purchasers who will "buy" them. Whether the mould can and should be broken is left tantalisingly open in the concluding remarks, save that at the very least, it does require both political will and medical compliance. PMID- 10116921 TI - Beyond management by objectives: the implementation of a goal-directed performance management system in an Australian teaching hospital. AB - This paper describes management by objectives (MBO) as an approach by which organisations can be managed, with particular reference to health care institutions. An evaluation of MBO is presented and the disadvantages of MBO are discussed. A more comprehensive performance management system than MBO is advocated. The experience of St Vincent's Hospital, Sydney, in designing and implementing a goal-directed performance management program which builds on MBO methodology, is described. This experience provides guidelines by which senior managers may successfully implement goal-directed performance management programs in health care institutions in order to enhance organisational effectiveness and the goal-oriented behaviour of managers. PMID- 10116922 TI - Non-inpatient costing study. AB - Flinders Medical Centre, a University teaching hospital located in the south of Adelaide, spends approximately 27% of its annual budget in the treatment of ambulatory patients. In an attempt to gain a better appreciation of the profile of resource use by this group of patients, the hospital undertook a detailed cost survey. This study has made it possible to identify the cost impact of ambulatory attendances on each of the service areas of the hospital and compare variation in cost within and between specialist clinics. PMID- 10116923 TI - Ethics and the allocation of health resources to the elderly. AB - This paper examines some of the ethical issues confronting the allocation of scarce health resources in the context of an ageing society with increasing levels of chronic disease. The allocation of resources at both the micro and macro level is explored, utilising the ethical principles of patient-centred beneficence, autonomy, full beneficence and justice. The implications of the dominance of science and technology within health care are analysed along with the paternalistic and individualistic nature of traditional medical ethics. The possible variations in value systems between patients and health professionals are examined and a greater emphasis on patient autonomy is advocated. Such a change, it is argued, may well result in an actual decrease in demand for expensive high technology treatment. PMID- 10116924 TI - Hospital restructuring--the implications for allied health professions. AB - Allied health professionals are not immune to the forces affecting the health care system at the macro-policy and political level. Policy implementation at the organisational level can have serious consequences for health professions which are not effectively scanning the broader health care agenda and developing systematic strategic responses. This paper will explore the changing work environment for allied health professions as a result of current trends in organisational restructuring. Five models of hospital organisation will be presented and examined in terms of their potential impacts on the allied health professions. PMID- 10116925 TI - A shared vision--bridging the theory-practice gap. AB - The recruitment and retention of nurses continues to be an issue which the nursing profession must address. This paper will argue that the resolution of this problem lies in greater collaboration between the higher education and health care sectors. Collaborative strategies should focus on two major aspects. First of all, strategies to bridge the theory-practice gap are important for the retention of new graduates. Secondly, support for first-line nurse managers is needed since these managers are significant in the assimilation of new graduates into the workforce. PMID- 10116926 TI - Career progress: design or destiny. AB - One hundred executive members of the Australian College of Health Service Executives were randomly surveyed about which factors they perceived as promoting or constraining their career progress and to what extent. Seventy five responded. Most highly ranked promoting factors were determination to succeed, length and variety of job experience, and the holding of tertiary qualifications in health administration. Constraining factors were largely dismissed as challenges, not great impediments. Age variations amongst respondents did not substantially influence their views. Some results of the survey were presented at the 16th National Congress of the ACHSE, Adelaide, 21-23 June, 1990. PMID- 10116927 TI - Autopsies in an area health service: a quality assurance review. AB - The Hunter Area Health Service Quality Liaison Group reviewed autopsy practice in the Hunter Area, focussing upon clinical and resource utilisation effectiveness. Findings are discussed. Conclusions support views expressed in recent literature on the subject. The conclusion is reached that despite increase in consumption of limited resources, autopsies remain an integral component of quality care and should increase in number. Some recommendations are proffered to maximise utility and cost effectiveness in the future. PMID- 10116928 TI - Where do health service managers really come from? PMID- 10116929 TI - A survey of senior managers' participation in performance review programs in NSW public hospitals. AB - A performance review program is a management tool for enhancing the performance of employees. Such systems have been widely adopted by both private and public organisations during the last decade. Management writers strongly advocate the involvement of senior managers in performance review programs. In order to investigate the extent to which senior managers within public hospitals in New South Wales are presently involved in such programs, a survey was conducted. The aims of the survey were: to determine the number of senior hospital managers currently participating in a performance review program; to investigate the methodologies being used within hospitals to evaluate the performance of senior managers; to examine the reasons why hospitals with a formal performance review program in place had implemented that system; and to ascertain the reasons why some hospitals had failed to establish a formal performance review system for senior managers. The most frequently used methodology employed was based on the management-by-objectives model. The findings indicate that further education of those who influence the management of hospitals regarding the benefits of involving senior executives in performance review programs is necessary. PMID- 10116930 TI - Results of CLMA's survey of laboratory information systems. PMID- 10116931 TI - A model for selecting a clinical laboratory information system. A four-phase process. AB - Laboratory information systems (LISs) have become an essential part of an efficient and effective laboratory. In the past, selecting an LIS was a relatively simple procedure because there were only a few candidates to select from. Now, however, selecting an LIS from the myriad available has become a time consuming and complex process. This article presents a multi-attribute utility (MAU) method for selecting an LIS. This MAU method has four phases: identifying LIS vendors and disseminating requests for proposals (RFPs), analyzing RFP responses and selecting the top three vendors, validating responses of the top three vendors, and selecting a primary vendor and preparing a formal recommendation. By following this four-phase process, laboratories will simplify the complex LIS selection process and increase their chances of selecting the best LIS for their needs. PMID- 10116932 TI - Negotiating a laboratory information system contract. AB - The key to successfully negotiating a laboratory information system (LIS) contract is consensus. Before sitting down at the negotiating table, the LIS selection team must reach consensus on a variety of issues--ranging from financial concerns to political considerations. Once a vendor is selected, consensus must be reached regarding the laboratory's needs and the vendor's capabilities. This article discusses the entire LIS negotiating process--from selecting a vendor to writing the final contract. By looking beyond costs and working out problems in advance, the laboratory will have a better chance of negotiating a successful LIS contract. PMID- 10116933 TI - Taking the risk out of laboratory information systems. AB - Laboratory information systems (LISs) help laboratories deal effectively with regulations, technological change, economic pressures, and increased competition. Because they are such an essential part of the laboratory, it makes sense to do everything you can to reduce the risks associated with LISs. This article examines six areas of risk that could affect the successful acquisition and implementation of an LIS--vendor corporate failure, system failure, additional costs, delays in implementation, obsolescence, and noncompliance with regulations -and offers suggestions to help laboratory managers avoid these risk areas. PMID- 10116934 TI - Regulation of clinical laboratory information systems after the 1990 amendments to the Food and Drug Act. AB - Clinical laboratories are among the most sophisticated software users in the modern hospital. The 1990 Medical Device Amendments to the Food and Drug Act caused a significant change in the legal regulation of medical software. The Act replaces the earlier emphasis on premarket approvals with postmarket surveillance. Hospitals and other institutional users are now required to report to the Food and Drug Administration (FDA) product defects that cause injuries or death. The Act also provides for civil penalties. The combination of these factors may lead to enhanced FDA supervision of medical software, particularly with unregistered producers. Clinical laboratories must understand both the regulatory system and their own responsibilities under the Act. PMID- 10116935 TI - The laboratory information system as a medical device: inspection and accreditation issues. AB - Laboratory information systems (LISs) allow laboratories to produce more reliable results than can be provided with manual systems--as long as attention has been given to system testing, monitoring, maintenance, and repair of the LIS. Regulatory and voluntary accrediting agencies have recently begun reminding us of what we should have been doing all along--ensuring that our computerized systems are operating properly. Initial regulatory efforts caused some misunderstandings and confusion, but a more balanced approach is now being taken. The safety and reliability of software can be improved, at reasonable cost, by paying attention to standards for requirements definition, initial testing, monitoring, change control, and overall documentation. We must continue using and improving our automated systems, rather than abandoning automation in favor of error-prone manual systems. PMID- 10116936 TI - Laboratory information system test environment: validate upgrades, prevent disasters, and assist training. AB - A laboratory information system (LIS) test environment allows the laboratory to run and test programs without affecting the current production environment. This is essential for successfully introducing system enhancements and upgrades because it allows the LIS manager to uncover software errors before introducing them into the actual LIS system. A test environment is also a useful tool for training employees. In addition, a test environment enables laboratories to validate software before use in the live environment, which will probably be required by the Food and Drug Administration and the Health Care Financing Administration inspectors now that LISs are considered medical devices. This article examines the benefits, uses, and limitations of an LIS test environment; discusses the computer resources required; and explores the process of installing and validating a software release. PMID- 10116937 TI - Bar codes and the clinical laboratory: adaptation perspectives. AB - This paper provides an overview of the functional capabilities of bar-code technology within the laboratory environment and assesses the problems and solutions encountered during its introduction in our laboratory. An idea of the potential costs and personnel savings is offered, demonstrating that we have saved an entire full-time equivalent (FTE) medical technologist in clinical chemistry with an associated improvement in the accuracy of patient identification and a marked improvement in turnaround time for both chemistry and hematology routine procedures. We have estimated the savings of two FTE medical technologists while improving service and accuracy. Hardware costs should be recovered in 2 years. PMID- 10116938 TI - The deployment of information technology in clinical laboratories and its impact on professional roles. AB - New information technology is deployed in hospital clinical laboratories to increase both the quality and efficiency of laboratory operations. Although total laboratory expenses may rise as a result of technology deployment, the average cost per test may decline. S-curves can be used to illustrate the effects of new information technology--such as a laboratory information system (LIS)--on the useful output and use of resources in laboratories. Major changes are now occurring as a result of the deployment of information technology, most notably in the area of automated information management. The role of laboratory professionals must be modified in response to this new information environment. The generation of information within clinical laboratories should be considered as the beginning--not the end--of the responsibility of laboratory professionals. PMID- 10116939 TI - What's right and what's wrong with laboratory information system requests for proposals. AB - Using a formal request for proposal (RFP) has been widely promoted as an essential phase of laboratory information system (LIS) selection and acquisition. Recently, stories of system or project failure--despite adherence to the RFP procedure--have increased. Case reports suggest that the RFP itself may sometimes hinder, rather than facilitate, the system selection process. As with any tool, the RFP has strengths and weaknesses, either of which may predominate depending on how the tool is used. Laboratories should be aware of alternatives to the formal RFP and should view the RFP as part of an integrated process of system evaluation and selection. PMID- 10116940 TI - Information technology, health care, and the future: what are the implications for the clinical laboratory? AB - As new information systems are offered for the clinical laboratory, advanced applications and improvements in computer hardware continue to dominate marketing presentations and fascinate the decision maker. However, the most important issue for all of our clinical information systems is not the speed of the hardware, the reliability of the systems software, or the ability of applications to carry out routine tasks in some novel or elegant manner. Rather, it is "coping"--the ability of a system to manage new issues that arise as information requirements change over time and to manage all the unexpected events that occur in the course of regular work but that do not follow the usual sequence of procedures. The need for new processing conventions to cope with unexpected situations without creating new problems is not unique to health care. The need is present wherever the real world intrudes directly and significantly into critical operations. Moreover, the pressure to adjust to changing external circumstances continues to grow as the rate of change in our information-based society increases. The lack of general coping procedures, although long ignored, has become such a pervasive handicap that marked improvements in this type of flexibility will be introduced over this decade. New software designs that deal with coping issues are already beginning to appear and to bear fruit. When purchasing any new laboratory computer system today, software that demonstrates an effective coping flexibility should be given more weight than fascinating innovations in hardware or software that are the favorites of vendor marketers. It is now possible to test for such flexibility on a site-specific basis. PMID- 10116941 TI - Developing a strategy for improving quality. PMID- 10116942 TI - Observational data on time use and behavior problems in the nursing home. AB - A 3-month observational study of 24 agitated and severely cognitively impaired nursing home residents was conducted to document the typical ways in which residents spend their time and how time use relates to the manifestation of agitated behaviors. We found that these residents were involved in no activity during 63% of the observations. In addition, residents spent little time in structured activities (e.g., music therapy) or social activities (e.g., receiving visitors). Yet data analysis revealed that residents manifested a greater number of agitated behaviors when they were unoccupied and fewer agitated behaviors when involved in structured or social activities. We discuss implications for caregivers. PMID- 10116944 TI - Survey of health promotion in Pennsylvania nursing homes. AB - Health promotion programs for residents represent a discretionary organizational response to increased demand for service differentiation within the nursing home setting. More than half (57%) of facilities in a systematic sample of Pennsylvania nursing homes reported offering one or more health promotion programs. This article describes the variety of topical categories of programs. Guided by two alternative explanations of medical technology adoption--the key professional model versus the institutional/environmental model--an explanation is offered about why some facilities offer such programs and others do not. PMID- 10116943 TI - Research and the politics of decision making: planning services for elders. AB - Identification of the appropriate measures for determining levels of impairment and disability has emerged as a major challenge for the network on aging. Recommendations from the Pepper Commission as well as recent court decisions will increase pressures on state and area agencies to identify levels of impairment of activities of daily living (ADLs) as a trigger for eligibility for services and as a component of intrastate funding formulas. The use of different descriptors from the Supplement on Aging to the 1984 National Health Interview Survey as a basis for projecting future demand/need for services is discussed. Each scenario presents a different political/decision-making challenge for the network and for individual planners. Planners are encouraged to provide multiple models for decision making to assist the network in making service delivery decisions. PMID- 10116945 TI - Discontinuation of a psychogeriatric program for nursing home residents: psychotropic medication changes and behavioral reactions. AB - Changes in medications and behavior were recorded for residents of three nursing homes where a psychogeriatric rehabilitative program was either absent, maintained, or discontinued. Residents without the program received the greatest number of psychotropics. Discontinuation of the program was associated with two problems: (a) fewer reductions in medications and (b) more behavioral difficulties among clients with medication increases. The nursing home with continuous services was the only one where all types of medication changes were followed by an overall decrease in behavior problems or no problems at all. PMID- 10116946 TI - Residential attitudes and knowledge, use, and future use of home support agencies. AB - Critical review of the health and social service use literature reveals a need to elaborate on the dynamics of factors identified in the behavioral models applied to this field. In particular, research has tended to omit direct measures of attitudes and awareness of social services, including their interrelationships. This study examines determinants of knowledge, use, and future use of local home support agencies among a sample of community-dwelling elderly over the age of 74 living in Kitchener-Waterloo, Ontario. Measures of domestic self-reliance, independent living and perceptions of futurity are incorporated into the analysis. Logistic regression is used to test the models. The results show that attitudes regarding domestic self-reliance and independent living influence use of home support agencies largely through their impact on service awareness. Interestingly, these relationships are opposite to those hypothesized. Education is also found to be a predictor of knowledge of home support, and living arrangement, health status measures, and knowledge arise as important predictors of use and future use. The findings are discussed in terms of their implications for the underlying behavioral models, and for service providers and policymakers. PMID- 10116947 TI - Energy centres. PMID- 10116948 TI - Loss of Crown Immunity and the Environmental Protection Act 1990. PMID- 10116949 TI - Town and country planning and the health service. PMID- 10116950 TI - Case study:-calender covers in a hospital laundry. Energy Efficiency Office, Department of Energy. AB - Whipps Cross Hospital laundry is typical of many laundries, both in the commercial sector and NHS, in that it uses old calenders which are substantially less efficient than more modern machines. Although calendering is a relatively efficient method of moisture removal, the quantity of flatwork processed by this laundry means that the calendering section uses a significant proportion of the total laundry energy consumption. In common with many other laundries, the four calenders were producing a great deal of airborne lint which required expensive cleaning at regular intervals, and made the working environment uncomfortable, reducing the performance and morale of the operators. In an effort to improve this situation, covers were fitted to all the calenders in early 1989. These were claimed to improve energy efficiency by reducing the heat losses from the calender's upper surfaces and to improve the local atmosphere by reducing the quantity of lint and moist air escaping into the laundry. This case study examines the savings (both energy savings and others) achieved by the installation of the covers, and assesses any drawbacks which may have become apparent after extended use. PMID- 10116951 TI - Retiree health care costs: a workable plan. AB - Thirty-three million retired Americans have taken for granted the warm security that health care would be provided throughout their retirement--by Medicare, by their employers, certainly by someone, because it must be an inalienable right. As the financial aspects of retiree health care are examined, however, it is important to keep in mind who will pay for it and how much we are willing to spend. This raises three important questions: Are we ready to spend that much? Is that sum enough to produce the system we want? Will we get our money's worth or just start another round of health care inflation? This article suggests two programs, one for addressing this staggering problem and another to deal with the financing of retiree health care. PMID- 10116952 TI - Employer strategies to combat health care plan fraud. AB - Each year health care fraud drains millions of dollars from employer-sponsored health plans. Historically, employers have taken a rather tolerant view of fraud. As the pressure to manage health plan costs increases, however, many employers are beginning to see the detection and prosecution of fraud as an appropriate part of a cost management program. Fraud in medical insurance covers a wide range of activities in terms of cost and sophistication--from misrepresenting information on a claim, to billing for services never rendered, to falsifying the existence of an entire medical organization. To complicate matters, fraudulent activities can emanate from many, many sources. Perpetrators can include employees, dependents or associates of employees, providers and employees of providers--virtually anyone able to make a claim against a plan. This article addresses actions that employers can take to reduce losses from fraud. The first section suggests policy statements and administrative procedures and guidelines that can be used to discourage employee fraud. Section two addresses the most prevalent form of fraud--provider fraud. To combat provider fraud, employers should set corporate guidelines and should enlist the assistance of employees in identifying fraudulent provider activities. Section three suggests ways to improve fraud detection through the claims payment system--often the first line of defense against fraud. Finally, section four discusses the possibility of civil and criminal remedies and reviews the legal theories under which an increasing number of fraud cases have been prosecuted. PMID- 10116953 TI - Managing health care quality can lower costs and generate access. PMID- 10116954 TI - Improving access to cost effective health care: barriers to managed care. PMID- 10116955 TI - Health insurance and outcomes: comprehensive assessment of health system outputs. AB - Outcomes analysis in health care has historically meant the examination of clinical results of inpatient hospitalization. In response to climbing health care and health insurance costs, the organization of health care providers, the location of service delivery and reimbursement mechanisms have changed. As the health care industry changes, so too must the definition of outcomes. This article presents a conceptual framework for the analysis of health outcomes as health industry outputs, with an emphasis on the ways in which such outputs are being assessed and improved. PMID- 10116956 TI - Designing a guideline-based utilization management program. AB - Many public and private organizations are developing and publishing clinical guidelines to assist health care providers and patients in making appropriate medical decisions. Unless clinical guidelines are part of a well-designed managed care program, they have little effect on physician practice styles. This article explores integral components of an effective guideline-based utilization management program. Initial evaluation of this program suggests that, as part of a well-designed utilization management program, clinical guidelines can inform patients and physicians, and create appropriate incentives for effective health care delivery. PMID- 10116957 TI - Design of legal audits for utilization management. AB - Liability for managed care risks, the enactment of detailed state regulation of utilization management and the process requirements of accreditation agencies and managed care customers all create the need for new approaches to legal auditing. Concepts from industrial quality management theory can be used to define process elements that serve the legal adequacy of the utilization management process. The information systems that record information gathered and judgments made by reviewers and generate basic notices of certification can be designed so as to produce data relevant to compliance and liability management. These key process elements then can be analyzed statistically to develop plans for preventive counseling. PMID- 10116958 TI - Can managed care reduce employers' retiree medical liability? AB - The Financial Accounting Standards Board (FASB) has forced U.S. companies to look squarely at their current retiree health obligations and their future commitments. Accounting Statement No. 106 (FAS 106) requires employers to accrue liabilities for retiree health benefits during employees' active service, rather than record the costs as benefits are paid. Employers are scrambling to find ways to reduce the statement's effect on corporate balance sheets. While managed health care has been increasingly employed to control benefit costs in active employee health plans, it has not been as popular in retiree plans. This article reviews important demographic and health trends in the retiree population and summarizes employers' early responses to FAS 106. It explores why managed health care has thus far played a limited role in reducing employers' postretirement medical liability, and offers insight into how that role could be increased in the future. PMID- 10116959 TI - Special issue on managed care. PMID- 10116960 TI - Health care challenges and opportunities in the 1990s. AB - The 1990s offer both substantial challenges and opportunities for those involved in the delivery of health care. Increasing costs must be managed to ensure that the health of both Americans and America's economy are maintained. Managed care offers the brightest hope for effectively controlling costs while increasing the quality of care. PMID- 10116961 TI - Onsite concurrent review: impacts on utilization, medical complications and expense. AB - An evaluation of onsite concurrent review over and above the effects of Aetna's precertification program demonstrated reduced utilization and expenses, especially for ancillary services, and no adverse effects on rates of medical complications. PMID- 10116962 TI - L.A. County plans its disaster response. AB - The Los Angeles County Fire Department is one of many agencies making great strides in the development of urban search and rescue programs. Much of the department's USAR training, equipment, and strategies have been tested on real incidents. Each incident presents new challenges and teaches new lessons. Before the establishment of the three-tiered USAR system, those personnel nearest an incident handled it. Many never saw a similar incident again. The lessons they learned were often lost because there was no system to collect their experiences, retrieve the information, and make it available to other emergency responders in the form of training programs. A major advantage of tiered response is the system's ability to ensure rapid response by trained, experienced, and well equipped personnel. Rather than repeating mistakes and forgetting successful rescue methods, the system allows the retrieval of the experiences of personnel and their use in the development of training materials. Urban search and rescue specialists have the ability to build on earlier experiences to raise the overall level of skills. The net result is more effective training, increased efficiency, and enhanced safety for rescuers and victims. The field of urban search and rescue is still in its infancy. Many new and innovative strategies, techniques, and tools are on the horizon. In recent years, there has been growing interest in this specialty across the nation. We expect this trend to continue as breakthroughs occur. More than ever, it is important for all concerned agencies to share information and to work together to improve our ability to save lives. PMID- 10116963 TI - Hazard communication/right-to-know for health care facilities. AB - This manual is intended to provide useful information on the various new and pending health and safety regulations that affect hospitals. The governing bodies promulgating these regulations are the Occupational Safety and Health Administration (OSHA), the Environmental Protection Agency (EPA), and state and local governments. The majority of this document is dedicated to the OSHA Hazard Communication Standard (or federal Employee Right-to-Know Law) and the EPA Superfund Amendment Reauthorization Act (SARA) Title III Regulations (or federal Community Right-to-Know Law). PMID- 10116964 TI - Self-assessment by nonprofit boards. AB - Can nonprofit boards conduct accurate and trustworthy evaluations of their own performance? Factors that limit trustee self-assessments include problems with available instruments as well as with trustees' critical abilities. Drawing upon previous research that identified six dimensions of board competencies, the author developed and field-tested a new instrument for use in board self assessments. Information on the reliability and validity of this approach is presented, and implications are drawn for board efforts to monitor and appraise their performance. PMID- 10116965 TI - Why nonprofit nursing homes pay higher nurses' salaries. AB - It is generally agreed that nonprofit nursing homes pay higher wages to their employees, hire more staff per patient, and are thus more costly than for-profit nursing homes. We attempt to show that higher costs in nonprofit nursing homes are related to higher quality of care in these homes. Using the 1985 National Nursing Home Survey, we show that nurses in nonprofit nursing homes have different characteristics than nurses in for-profit homes and that these differences in characteristics account for the differences in wages, a finding consistent with our hypothesis concerning quality differences between types of homes. PMID- 10116966 TI - Incentive-based management for nonprofit organizations. AB - Nonprofit organizations should consider using incentive-based management programs so long as such programs are studied thoughtfully, implemented carefully, and closely tied to other important management practices. The article describes the experiences of one nonprofit organization, Citizens' Scholarship Foundation of America (CSFA), in successfully conducting a staff incentive program during the past several years. The author also reports briefly on the results of a recent survey among CSFA staff involved in the incentive plan, outlining the benefits of such a program in helping the organization to reach its objectives. Finally, the author addresses potential pitfalls to avoid in implementing an effective staff incentive program. PMID- 10116967 TI - Data bases in health care. PMID- 10116968 TI - Annual update of the HHS poverty guidelines--HHS. Notice. AB - This notice provides an update of the HHS poverty guidelines to account for last (calendar) year's increase in prices as measured by the Consumer Price Index. PMID- 10116969 TI - Nurses want I/S selection power, but do they have it? AB - A survey of nurse executives shows that the ability to track medications and prepare patient-care plans are the two most important features for a nursing system. Nursing staffs are fairly resistant to new system installations, and a surprising number of nurse executives say they are not involved in the system selection process. PMID- 10116970 TI - Healthcare industry to benefit from 'Baby Bell' court ruling. AB - Courts have cleared the way for regional Bell operating companies to sell electronic information. Although critics are fearful of the Baby Bells' power, others say the decision will open a myriad of possibilities that could have far reaching effects on the healthcare industry. PMID- 10116971 TI - Minimize paperwork, maximize patient care. AB - A nursing system at McKennan Hospital in Sioux Falls, S.D., allows nurses to eliminate traditional care plans. The nursing intervention becomes the basic unit of work that drives all other documentation. PMID- 10116972 TI - Healthcare's survival in the information age. AB - Strategic planning, CEO leadership, user consensus and close collaboration with software vendors are keys to creating an effective information system, say two top executives at Henry Ford Health System. PMID- 10116973 TI - The NLRB's first rulemaking: an exercise in pragmatism. PMID- 10116974 TI - Problem solving: where to get the help you need. PMID- 10116975 TI - Getting into--& staying in--the media loop. PMID- 10116976 TI - Consent to medical treatment: the use of consent forms. PMID- 10116977 TI - "Where there is a will, there may be a better way": legislating advance directives. PMID- 10116978 TI - Maintaining standards and quality assurance for independent health facilities: the role of the College of Physicians and Surgeons. PMID- 10116980 TI - RAP DEE (Recognition, Alert, Preparedness, Design, Education, and Enforcement)- responding to disruptive/violent behavior in the emergency department. AB - Recognition, Alert, Preparedness, Design, Education, and Enforcement (RAP DEE) are the keys to assisting staff and hospital security in reducing the risk to themselves or others when disruptive/violent incidents occur in the Emergency Department. PMID- 10116979 TI - Safety in health care facilities. AB - Safety plays an important role in the daily operation of any health care facility. Effective safety management not only assures employees that they have a safe working environment, but also allows patients to enjoy an atmosphere that is free from unnecessary risks and hazards. Having an effective safety program that addresses pertinent safety issues within the facility, as well as within the community will give the administration confidence that the facility is delivering the highest quality of patient care. PMID- 10116981 TI - Illicit drugs in hospitals. AB - This article addresses some of the issues involved in developing a policy/procedure for handling patients who are found in possession of illicit drugs--i.e., cocaine, crack, marijuana. PMID- 10116982 TI - Development and management of a hospital security training program. AB - The author describes how to develop and implement a cost-effective security training program by defining the hospital's specific training requirements and maximizing the use of available training resources. He also reviews various professional and regulatory requirements, and the standard of care applicable to the training of hospital security personnel. PMID- 10116983 TI - The perception gap. PMID- 10116984 TI - Violence in the workplace: establishing the nexus between security practices and premises liability. AB - This article discusses the increase in violence in the workplace. As risk factors increase, a greater duty to protect exists. The best approach, according to the author, is to develop a proactive stance where crime displacement control methods are attempted. PMID- 10116985 TI - Nurses at LA County hospitals settle prolonged 'security' dispute. PMID- 10116986 TI - Special report. Increased violence in hospitals: what can be done about it. AB - Incidents of violent behavior and physical assaults are dramatically increasing throughout the country, often ending up in the health care setting and necessitating enhanced security in hospitals and mental health facilities. In the wake of violence, many security and safety directors are now employing extreme measures from attack dogs to metal detectors to bulletproof glass. This special report details recent violent episodes occurring in health care facilities, examines areas of vulnerability in these institutions, and offers advice on proactive and reactive security measures that are being employed by many security directors. PMID- 10116987 TI - A question of balance. AB - Too few hospitals have clear policies to help patients to spend their money, and patients are often given too little choice. Health authorities and hospitals are in urgent need of better guidance, writes Ginny Jenkins. PMID- 10116988 TI - Who does what? PMID- 10116989 TI - Role call. PMID- 10116990 TI - Court in the slips. AB - Judges are only now coming to terms with the implications of resource allocation for medical negligence cases. But, warns John Tingle, managers should keep a close eye on how the law develops case by case. PMID- 10116991 TI - Midwife crisis? AB - While most pressure groups have been asking for more for their part of the health service, AIMS has been demanding less for the last 30 years. In the first of two articles on maternity services, Beverley Lawrence Beech and Jean Robinson explain why obstetricians should take a backseat role to midwives. PMID- 10116992 TI - Patient voices. AB - Patients and nurses at a psychiatric hospital were asked which aspects of care they rated most highly. The results showed that the two groups had very different perceptions. Tonmoy Sharma and colleagues report their findings and the implications. PMID- 10116993 TI - Breaking into prisons. PMID- 10116994 TI - Wise buys. PMID- 10116995 TI - Rush to arms. PMID- 10116996 TI - Power to the people. PMID- 10116998 TI - North Western region--between the margins. PMID- 10116997 TI - Hard labour. AB - Midwives have an ethically superior and more consumer-oriented code of conduct than doctors, argue Beverley Lawrence Beech and Jean Robinson, who claim women are safer in midwives' hands. PMID- 10116999 TI - Estates information. Zero plus one equals zero. AB - Provider units have greater incentives than ever to run the estate efficiently, but they need sound information to do so. We explore: why the new capital charging system broke down, and whether it can get back on the rails; how the ubiquitous works information management system (WIMS) has responded to the challenge of the reforms; how space utilization reviews can contribute to business planning. PMID- 10117000 TI - Coming of age. PMID- 10117001 TI - A review of issues in hospital technology acquisition. AB - The past decade has seen the restriction of reimbursement and increasing pressures for cost-containment mandate vast improvements in technology assessment. Because no single source of evaluative data exists, individual hospitals must develop their own assessment programs. Medical, monetary, legal and supplier issues must all be considered in response to any request for the acquisition of technology. This can be accomplished through a coordinated effort by a diverse grouping of the medical and technical talent found in any hospital. This paper reviews the important issues described in the literature and offers background and guidance for assessment concerns, in an attempt to assist the individual hospital in becoming a successful technology evaluator. PMID- 10117002 TI - A medical equipment replacement model. AB - A simple mathematical model has been developed to identify and prioritize medical equipment in need of replacement. The model contains a total of ten attributes addressing four primary replacement issues: equipment service and support; equipment function; cost benefits; and clinical efficacy. Sensitivity to incomplete or subjective data is significantly reduced through the use of a "yes no" (0,1) scoring scheme. Decision-making validity does not appear to be compromised with such a technique. When tested on a sample of 146 medical devices in five different categories, the model recommended that two devices be replaced within the existing fiscal year and eight in the following year, and that fifteen devices be placed in an advisory category. The model's recommendations appear to be compatible with existing subjective criteria. PMID- 10117003 TI - Evolving practices of medical equipment. Management following FDA inspections. AB - This paper outlines one hospital's response to the changing needs for: quality of care; risk management; cost control; and regulatory agency requirements. All recall, update, and product safety alerts are now routed to the office of The Director of Materials Management. The director notifies the appropriate department manager, who must reply in writing. The Clinical Engineering Department maintains a historical data file for medical equipment, which includes service costs information. New purchasing forms and terms have been developed for use in purchasing equipment and service. Maintenance of accurate historical data for medical devices begins at purchase, and continues to installation and through ongoing service. This requires the cooperation of the manufacturer, the service vendor, and the clinical department using the device. Because technology management can improve the quality of care and reduce risk, it is worth doing and can also reduce costs. PMID- 10117004 TI - Failure modes and effects analysis in clinical engineering. AB - Failure modes and effects analysis (FMEA) is a proactive quality assurance procedure that has been commonly used to address potential design flaws and product misuses during the design stage of a product's life. FMEA is becoming commonplace among manufacturing companies but is relatively unknown outside of manufacturing circles. One potential new application of FMEA is by medical device end-users who could address design or functional concerns specific to their situation. The continued increase in the amount and complexity of medical instrumentation necessitates an aggressive stance towards safety in each hospital, such as is recommended in this paper. PMID- 10117005 TI - A risk-related preventive maintenance system. AB - Recent changes in attitudes concerning medical equipment maintenance place more responsibility for planning appropriate levels of maintenance on the clinical engineer and biomedical equipment technician. A system is described in which maintenance decisions are based on the effects of equipment failure on quality of patient care and potential for injury to patients and staff. It is hoped that development of an acceptable classification scheme will simplify maintenance decisions. Such a system will provide levels of maintenance appropriate to the equipment function in patient care. PMID- 10117006 TI - An algorithm for drug waste reduction using pharmacokinetic principles. AB - When delivering several intravenous drug doses from a single bag, it is generally necessary to throw away any drug that remains in the bag, if the amount is insufficient to deliver the next dose. An algorithm has been developed to allow all of the drug in a bag to be used. Based on standard pharmacokinetic equations, the algorithm calculates the time when the remainder should be given, so that a desired peak serum drug concentration is achieved on the next dose. The algorithm requires as inputs the time limit on the bag, the dosing interval and the size of the dose. This algorithm applies only to drugs that obey single compartment, first-order linear kinetics (e.g. aminoglycosides), but is easily modified for other situations. In conjunction with computer-assisted infusion, use of the algorithm may potentially reduce the cost of aminoglycoside administration by reducing clinical drug waste. PMID- 10117007 TI - Survey process receives favorable reviews. PMID- 10117008 TI - Safety comes first at South Community Hospital. PMID- 10117009 TI - Agenda for Change fosters CQI concepts. PMID- 10117010 TI - Monitoring & evaluation standards for laboratories revised for 1992. PMID- 10117011 TI - Physician response to fee changes with multiple payers. AB - This paper develops a general model of physician behavior with demand inducement encompassing the two benchmark cases of profit maximization and target-income behavior. It is shown that when income effects are absent, physicians maximize profits, and when income effects are very strong, physicians seek a target income. The model is used to derive own and cross-price expressions for the response of physicians to fee changes in the realistic context of more than one payer under the alternative behavior assumptions of profit maximization and target income behavior. The implications for public and private fee policy, and empirical research on physician response to fees, are discussed. PMID- 10117012 TI - The doctor as double agent: information asymmetry, health insurance, and medical care. AB - In a model incorporating uncertainty and state-dependent utility of health services, as well as information asymmetry between patients/buyers and physicians/sellers, two types of equilibria are compared: (1) when consumers have conventional third-party insurance and doctors are paid on the basis of fee-for service; and (2) when insurance is through an HMO which provides health services through its own doctors. Conditions are found under which contractual or legal incentives can overcome the information asymmetry problem and bring about an efficient allocation of resources to health services provision. PMID- 10117013 TI - Adverse selection, moral hazard, and wealth effects in the Medigap insurance market. AB - Using data from a longitudinal study of the recently retired we attempt to separate the moral hazard effect of Medicare supplementary (Medigap) insurance on health care expenditures from the adverse selection effect of poor health on Medigap coverage. We find evidence of adverse selection, but its magnitude is unlikely to create serious efficiency problems. Taking adverse selection into account reduces the estimate of the moral hazard effect. In addition, we find a strong positive wealth effect on the demand for supplementary insurance. PMID- 10117015 TI - Utilisation as a measure of equity: weighing heat? PMID- 10117014 TI - Willingness to pay for antihypertensive therapy--results of a Swedish pilot study. AB - In this methodological study the results of a Swedish pilot study about willingness to pay for antihypertensive therapy are presented. The aim of the study was to test the feasibility of the contingent valuation (CV) method in this area. Open-ended and discrete CV questions were compared in a mail questionnaire. The open-ended CV question did not work well. The answers to the discrete question, analysed by logistic regression analysis, indicated a willingness to pay in the range SEK 2500-5000 per year for antihypertensive therapy. Further studies should be undertaken to explore the reliability and the validity of the CV method. PMID- 10117016 TI - Executive office activity: what is going on in executive offices? PMID- 10117017 TI - Executive office activity: striking a new balance in the system context. PMID- 10117018 TI - Executive office activity: striking a new balance in the academic medical center. PMID- 10117019 TI - Executive office activity: the new balance in the community hospital. PMID- 10117020 TI - Board room activity: what is going on in board rooms? PMID- 10117021 TI - Board room activity: a Western view. PMID- 10117022 TI - Board room activity: a Midwestern view. PMID- 10117023 TI - Board room activity: a Southern view. PMID- 10117024 TI - Board room activity: a New England view. PMID- 10117025 TI - Physician activity: what is going on in the doctors' lounge? PMID- 10117026 TI - Executive office activity: the implications of mergers for the new balance. PMID- 10117027 TI - Physician activity: a large group view. PMID- 10117028 TI - Morale builders. PMID- 10117029 TI - New approaches to managing health services. AB - The Swedish health care system is at the crossroads. During the next decade, decentralizing responsibility and authority in the county councils will be the most urgent task. But whatever changes may take place, the basic health policy that everyone in Sweden, regardless of economic status, is to have access to good health on equal terms will remain unaffected. PMID- 10117030 TI - Ethics and hospital law. PMID- 10117031 TI - The manpower shortage. It's everybody's problem. PMID- 10117032 TI - A guide to PACS-RIS/HIS communication. PMID- 10117033 TI - Providing services at a value. PMID- 10117035 TI - The hazards of outcome measures. PMID- 10117034 TI - Quality assurance: beneath the surface. PMID- 10117036 TI - Healthcare from another side. PMID- 10117037 TI - Medical imaging and radiation oncology resources. 1992 organization directory. PMID- 10117038 TI - When is it time to buy? Part II. PMID- 10117039 TI - Indispensable partners. Providers and managed care contractors. PMID- 10117040 TI - Readiness of hospitals to adopt quality improvement concepts. PMID- 10117041 TI - Quality management information: basic concepts. Hospital Research and Educational Trust. PMID- 10117042 TI - Improving patient care: experiment in planned change. PMID- 10117043 TI - Oral and maxillofacial surgery: guide for practice, monitoring and evaluation. American Association of Oral and Maxillofacial Surgeons. PMID- 10117044 TI - The supply of charity services by nonprofit hospitals: motives and market structure. AB - This article studies provision of charity care by private, nonprofit hospitals. We demonstrate that in the absence of large positive income effects on charity care supply, convex preferences for the nonprofit hospital imply crowding out by other private or government hospitals. Extending our model to include impure altruism (rivalry) provides a possible explanation for the previously reported empirical result that both crowding out and income effects on indigent care supply are often weak or insignificant. Empirical analysis of data for hospitals in Maryland provides evidence of rivalry on the supply of charity care. PMID- 10117045 TI - Medical records in litigation: the Dalkon Shield story. AB - The Dalkon Shield was manufactured by A.H. Robins Inc. in the early and mid seventies, before it was withdrawn from sale because of the influx of lawsuits against the manufacturers. The case has become the largest tort case in history, with approximately 200,000 claimants worldwide and will not be wound up for years to come. Slater and Gordon is an Australian firm of solicitors with offices in three states. They have the largest Dalkon Shield practice in the world and represent almost 3,000 claimants. One of their most difficult tasks in preparing the cases is the gathering of medical evidence to substantiate claimants' assertions. This entails collecting relevant medical records from across the country and around the world going back almost twenty years for almost 2,000 women. The project has magnified the importance of accurate and complete documentation, kept intact and made accessible. The influence of medical record administrators is highlighted. PMID- 10117046 TI - From the Fifties to the Eighties. PMID- 10117047 TI - International Federation of Health Records Organisations: past, present and future. PMID- 10117048 TI - The future of hospital/physician relations. PMID- 10117049 TI - Compensation challenges: unprecedented pressures on hospitals will change compensation practices in the 1990s. PMID- 10117050 TI - CAHHS and CMA develop joint statement. AB - Patients are the top priority of physicians and hospitals. Access to cost effective, medically necessary quality care in the most appropriate setting is the overriding consideration. Economic realities are a new dimension which must be managed within the context of quality care. Collaboration and cooperation between hospitals and medical staffs are essential. Through timely, meaningful communication, hospitals and medical staffs can meet the needs of patients and serve the best interests of the public. CMA and CAHHS are committed to supporting this collaborative relationship through leadership in public policy and promotion of responsible positions. CAHHS and CMA will offer a joint program to assist hospitals and medical staffs resolve conflicts. PMID- 10117051 TI - Point/counterpoint. Should economics influence credentialing? PMID- 10117052 TI - Management by agreement: contracting for library services in South West Thames. AB - On 1 April 1991, the financial base of the NHS underwent its most dramatic change since its inception in 1948. All NHS services are now based on contracts and this has major implications for library services. This change was perceived by the South West Thames Regional Library Service as presenting a unique opportunity and the paper outlines the background to the thinking and the strategy adopted to meet the challenges. Sources of library funding and precise spending details were identified by means of a survey and contracts agreed covering all NHS staff in each of the 13 districts. The contracts are operating as 'shadow contracts' for 1991-92 allowing a valuable period of evaluation and monitoring before any money actually changes hands. The survey form for collecting library budgetary information and the service agreement are included as Appendices to the article. PMID- 10117053 TI - Publishing, libraries and new technologies in Europe--today and tomorrow. AB - This paper addresses the challenges facing medical and health-care librarians from a European perspective. Drawing on his extensive knowledge of European affairs, the author emphasizes the historical roots of European cultural exchange and co-operation in the biomedical area. The impact of the new technologies and the unique opportunities offered by the CEC Plan of Action for promoting co operation in Europe are discussed. In conclusion, the threat to our cultural heritage posed by acid paper is outlined and European librarians are urged to develop collective initiatives to meet the challenges facing us all. PMID- 10117054 TI - Using new electronic information products to fund others. AB - Small medical libraries can, with a planned approach, respond positively to extra user demands generated by new information products, such as CD-ROM databases, by taking the initiative to raise, through fee-based services, income which can be used to fund other products. PMID- 10117055 TI - Volunteer clinic brings gift of health to Shenandoah Valley. PMID- 10117056 TI - Statement on certificates of special or added qualifications. American College of Surgeons. PMID- 10117057 TI - Let's improve our image. PMID- 10117058 TI - Data watch. Complying with FAS No. 106. PMID- 10117059 TI - What to demand of your managed care network. AB - Employers can get more for their money by tying managed care plans' fees to specific performance standards. Consultants share strategies for controlling costs and for judging the financial performance of an HMO. PMID- 10117060 TI - Using Medicare to ease the FAS No. 106 burden. AB - By letting Medicare pay the first part of retirees' health care, employers can achieve significant savings. There are several ways of integrating with Medicare; some are more beneficial than others. PMID- 10117061 TI - Do you need a managed mental health program? AB - Effective plan design and employee assistance programs can help employers manage the costs of mental health care. Employers have redesigned their mental health programs to save money, without sacrificing quality of care. PMID- 10117062 TI - Eldercare: more than company kindness. AB - Employees caring for aging family members could be costing your company money. Eldercare benefits could be the solution. Relatively inexpensive programs can make a difference in how employees see their company. PMID- 10117063 TI - Imaginative new alliance promises significant savings. PMID- 10117064 TI - Other people's money. The truth? Charities aren't all that thrifty. PMID- 10117065 TI - Medicare program; Medicare and laboratory certification program; enforcement procedures for laboratories--HCFA. Final rule. AB - These regulations set forth the rules for sanctions that HCFA may impose on laboratories that are found not to meet Federal requirements. These include the principal sanctions of suspending, limiting, or revoking the laboratory's certificate issued under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), and cancelling the laboratory's approval to receive Medicare payment for its services, and the alternative sanctions that may be imposed instead of or before the principal sanctions. These amendments are necessary to conform HCFA regulations to changes made in the law by the Omnibus Budget Reconciliation Act of 1987 (OBRA '87) and the 1988 amendments to section 353 of the Public Health Service Act (PHS Act). The latter are commonly referred to as "CLIA 88". The purpose of the amendments is to ensure that functioning laboratories are capable of providing accurate and reliable test results and that the health of individuals served by the laboratory and that of the general public is not adversely affected by laboratory operations and by testing procedures that do not meet the standards set forth in other subparts of part 493 of the HCFA regulations. PMID- 10117066 TI - A sick system. AB - After nearly two decades of skyrocketing costs, widespread gaps in insurance coverage and overwhelming public sentiment in favor of reform, health care has finally taken hold as a political issue. The Bush Administration, key Capitol Hill lawmakers and most of the major Democratic presidential candidates have advanced plans to break Washington's gridlock on overhauling the system. Here's a road map of the competing routes to reform and the hazards that are likely to be encountered along the way. PMID- 10117067 TI - Staking out turf. AB - The prospect of Congress taking a scalpel to health care has sent a shudder through the industry--and kicked K Street into overdrive. Though almost everyone agrees that there won't be a major overhaul this year, the jockeying for position is under way. PMID- 10117068 TI - Adaptive reuse: opportunities and pitfalls. Conversion dreams may turn to nightmares. PMID- 10117069 TI - Comparing long-term care insurance policies. PMID- 10117070 TI - Retirement housing. New growth opportunity. Hospitals expand their continuum of care. PMID- 10117071 TI - Going to bat for beneficiaries. Advocacy groups pursue denied Medicare claims. PMID- 10117072 TI - A declaration of autonomy. Training modules put spirit into OBRA law. PMID- 10117073 TI - Rounding up bad debts. Four steps help providers collect what's due. PMID- 10117074 TI - Mixing the good with the bad. Abuse registry irregularities threaten aides' rights. PMID- 10117075 TI - Computerized medical records: maintaining accuracy and privacy. PMID- 10117076 TI - The state of the incontinence product industry: an issue for residents, staff, families and the planet. PMID- 10117077 TI - The need for a strong cure. PMID- 10117078 TI - The triad of crises in health care. PMID- 10117079 TI - The poorest Americans: addressing children's health needs. PMID- 10117080 TI - Universal access to quality care. American Association of Retired Persons. PMID- 10117081 TI - The need for US health reform for uninsured & chronically ill Americans. AB - This special section brings together for CARING readers and National Association for Home Care (NAHC) members and friends critical views and information surrounding the nation's foremost issue. The following testimony by NAHC President Val J. Halamandaris, presented February 1992 before the House Select Committee on Aging, introduces CARING's examination of the need for US health reform, including provisions for long-term care. PMID- 10117082 TI - Electing a health care system. The presidential candidates state their positions on long-term care and home care. PMID- 10117083 TI - Developing a quality assurance system for home care. PMID- 10117084 TI - Chronic intensive home care: accessing non-governmental payment sources. AB - Advances have occurred recently within the private insurance industry and health maintenance organizations that create new opportunities for payment of high-tech home care to chronically ill patients. PMID- 10117085 TI - Attitudes and knowledge: middle-age and older Americans on home care. AB - Even though most middle-age and older Americans want to provide care for their frail and disabled relatives at home, many are ill-informed about home care in general or about the specific services available to make home care possible. PMID- 10117086 TI - Expanding options in the long-term care of our elderly. PMID- 10117087 TI - Pennsylvania's experience: Area Agencies on Aging and home health agencies. AB - A positive working relationship between the case manager and home care nurse is essential to the provision of quality care and the efficient use of resources. PMID- 10117089 TI - The evolution of strategy. PMID- 10117088 TI - USHealth: a proposal for reform. PMID- 10117090 TI - Case ten. Should two competing neighboring hospitals consolidate their emergency services? AB - Two hospitals sit together on a medical campus located in a large metropolitan area. The larger (746 beds) of the hospitals, St. Catherine's, was established in 1887 by a Catholic congregation of religious women. The other hospital (527 beds), Martindale, was established by a group of Lutheran pastors in 1916. The missions of the two hospitals are very similar. The hospitals are strategically located in the center of a metropolitan area. The marketplace is one which has been characterized as fiercely competitive, with 40 percent of the market enrolled in prepaid plans. The demand for hospital services continues to decline each year. There is significant over capacity in the metropolitan area, with an average occupancy around 50 percent. The hospitals have had a varied history of both cooperation and competition. In 1975, a joint venture organization was established to jointly share expensive technology and develop new shared programs. After a brief study of the declining volumes and profitability in both hospital emergency rooms and identifying that both were perceived as substandard by the public and by the physicians, the question became--"should two competing, neighboring hospitals consolidate their emergency services?" The case reports a problem commonly experienced by hospitals today--when to compete, when to collaborate and how to balance the two in pursuit of organizational competence and advantage. PMID- 10117091 TI - Case eleven. Children's hospitals' response to national coalitions: the creation of their own cooperative. AB - Over the past several years, national coalitions and multi-hospital systems have been expanding and increasing in popularity. These organizations have offered the member hospitals services and resources to enhance the competitive position of the member hospitals. As these coalitions have grown, they have approached children's hospitals but, in most cases, to be an affiliate of one of the general acute care hospitals. The services of these coalitions are designed to enhance the general acute care centers and have not been refined to address the needs of children's specialty centers. As children's hospitals around the country assessed how they should work with these national coalitions, they were faced with several challenges. These coalitions did pose a potential competitive threat to the children's hospitals. But, at the same time, the coalitions did not offer services to the children's hospitals that would justify membership and the large outlay in dues. Faced with this dilemma, a group of children's hospitals came together to develop a formal national coalition for children's hospitals. This case provides an excellent example of and the opportunity to explore the implementation of a collaborative strategy designed to create competitive advantage for each of the collaborators. PMID- 10117092 TI - Case twelve. Positioning a small rural hospital to respond to the requirements of a recently enacted state-wide medically indigent assistance act. AB - The case hospital was required to strategically respond to significant environmental challenges brought into play by the legislative enactment of a new Medically Indigent Assistance Act (MIAA). Publicity surrounding the debate leading up to the passage of the new law by the state legislature placed the hospital under unprecedented scrutiny by local taxpayers, healthcare recipients, elected officials, advocates for the poor and other local providers of healthcare services. This case reports the implementation of a highly desired strategy on the part of the hospital and the necessary roles of multiple stakeholders in the realization of hospital strategy. The case also illustrates the spill-over effects of stakeholder relationships developed in pursuit of particular strategy on the organization's ability to pursue future strategy. PMID- 10117093 TI - Case one. Evolution of a strategic plan: an organizational perspective. AB - The practice of strategic planning, both in business and healthcare, greatly expanded during the 1970's. Many process models were proposed and applied to determine environmental threats and opportunities, to identify achievable goals and to predetermine achievable courses of action. Developing and maintaining a strategic planning process is described as a requirement for healthcare organizations. This case report is a study of the successful evolution of a planning process which the author presents as a model for other institutions. The case describes the development of a formal process for strategy formulation, based on economic definitions of strategy, under what Ansoff would consider ideal conditions. It is unique in that it ties the process to product line management implementation. PMID- 10117094 TI - Case two. Development of a strategic plan and the planning process at a medical center. AB - In 1983, the medical center had no strategic planning process and no individual or department with an identified responsibility for planning to meet the needs of the organization and its service community. There were limited resources to apply to this endeavor and a prevailing attitude among current leadership that any planning done should be focused solely on facilities development. While the process pursued in this case is similar to that in Case One, unlike Case One, conditions within the organization are less than ideal for the implementation of any process, formal or informal, for the formulation of strategy. Read alone, the case is instructive. Considered in combination with Case One, it provides grist for a good discussion of the differences between organizations which have the capacity to be strategically managed and those which have learning to do. PMID- 10117095 TI - Case three. Developing a strategic plan through the use of task forces. AB - Although Carolina Community found itself continuing to grow and expand at a time when most facilities in the area were suffering from census declines, it was obvious that continuation of such growth would require more sophisticated strategic planning. At the time of the study, Carolina Community was growing in all areas. Inpatient census as well as outpatient utilization were taxing the resources of the organization. The strategic location of the facility and the support of a committed medical staff provided the institution with a competitive advantage over the other area facilities in the past. In the span of three months, two major competing institutions made strategically significant organizational changes. Both institutions hired new administrators known for their aggressiveness and organizational abilities. It became obvious very quickly that the playing field would soon be changing. No longer would Carolina Community's administration be able to move aggressively to protect and expand its markets without fear of competition. Carolina Community is a hospital with a long standing tradition of formal strategic planning forced by a rapid "heating up" of the environment to respond much more quickly than it has had to in the past and much more quickly than it is currently able. The case report describes a change in strategy formulation process which was designed to speed up response time and to modify the organization along Ansoff's eight characteristics to a more environmentally appropriate configuration. PMID- 10117096 TI - Case four. Synergistic strategy development. AB - Mercy Medical Center is a 467 bed, not-for-profit teaching hospital affiliated with a multispecialty group practice and health maintenance organization through contractual arrangements. Historically, strategy development was not helping the hospital remain viable while accomplishing its mission. Strategic planning was fragmented, not focused toward concern for balance of the overall product line, total growth of the organization or the best use of resources. The hospital did not involve the affiliated group practice or HMO in its planning. This last case in Chapter One describes the pursuit of synergy through strategy formulation. The case provides a good example of what Kanter describes as a post-entrepreneurial organization, striving for advantage through collaboration and linkage with "PALs." PMID- 10117097 TI - Case five. Development of criteria for hospital acquisition. AB - The problem explored in this case is the pursuit of horizontal and vertical growth by a multi-institutional system through hospital acquisition. Emphasis is on the selection of appropriate means to identify candidates for acquisition. Since the system did not have extensive experience in formal evaluation of acquisition candidates, it was necessary for system management to develop criteria for acquisition and a process by which to evaluate the criteria. The case is a good example of a thoroughly considered growth orientation. PMID- 10117098 TI - Case six. Introducing product line management in a multi-institutional healthcare organization. AB - This case reports a major shift in growth orientation pursued by a multi institutional system--systemwide product line management. Competitive response to one environmental disruption led to the initiation of a year-long study to re evaluate the corporation's mission, goals, strategies, growth and action orientations and organizational structure in light of the dramatic changes occurring in healthcare delivery. Of particular interest in this case is the connectedness between growth and action orientations, organizational culture, management style and organizational structure. PMID- 10117099 TI - Case seven. Managing mature operations in a competitive environment. AB - In this case, a medical center learns how to evaluate each of its services along a Product Life Cycle curve. Each stage of the cycle has characteristics that suggest appropriate strategic growth and action orientations. When services were plotted along the Product Life Cycle curve, many of the services were found to be mature or making the transition from growth to maturity. At the time of the case, Memorial Medical Center's competitors were entering many of its traditional markets creating a strong competition for market share. Greater competitive emphasis on performance and price reduced profits in the medical center's mature services. The case reports the medical center's approach to modifying its action orientation in light of a better understanding of organizational competence. PMID- 10117100 TI - Case eight. The acquisition of a community hospital by a religiously sponsored healthcare system. AB - St. Martin's for many years enjoyed a friendly and supportive relationship with a small community hospital nearby even though it was the leading provider of healthcare in the other's market place. In the highly competitive environment reported in the case, it was clear that the smaller hospital would have to move aggressively to increase its market share, consider closure or merge with one of the larger competing hospitals. St. Martin's administration knew that it needed to decide whether to attempt to align itself with Community in some fashion or to compete aggressively enough with Community to so dilute Community's market that it could no longer function. One of these actions was required to avoid serious erosion of St. Martin's own patient base. The decision was made to pursue acquisition. This case presents the successful implementation of a carefully crafted and realized strategy. It provides the opportunity to consider multiple "what ifs" in terms of the alternative strategies not chosen. PMID- 10117101 TI - Case nine. Two hospitals struggling to survive in a small rural community. AB - St. Luke's Hospital was the only hospital in town until 26 years before the time of the case. In the late 1950s St. Luke's Hospital was overcrowded and in dire need of renovation and expansion. Plans were devised and the hospital applied for Hill-Burton money to expand. At the same time, a group of local citizens decided to also apply for Hill-Burton money to build another hospital, County Memorial, in the community. The Hill-Burton money was divided and both received money. Both facilities opened within months of each other. For about 10 to 12 years, both hospitals prospered. At the time of the case, competition has heated up between the two facilities. Attempts at collaboration fail; the story is one of wasted resources and community pain because of the lack of ability of two competitors to put aside differences for mutual benefit. The case ends with there being only one hospital in town. Read alone, the case is instructive in terms of the difficulties created when organizations value survival in a known form above all else. Read and considered in concert with Case Eight, it encourages contemplation of the pros and cons of head-on competition versus collaboration. PMID- 10117102 TI - Killings in Killeen. PMID- 10117104 TI - Have ambulance, will travel. PMID- 10117103 TI - The final word. OSHA's final ruling offers firm deadlines for infection control. AB - Departments that have put off program development while waiting for the final ruling to be published have a lot of work to do. Many departments have been cited and fined by OSHA in the past year for failure to begin infection-control programs or provide hepatitis-B vaccines to personnel. Under the new budget, OSHA was granted permission to up its fine structure sevenfold--thus, a small fine is $7,000, and the highest fine for a single violation is $70,000. Fines can have a greater impact on a department's budget than implementation of the program over time. A key point to remember is that a strong infection-control program will reduce exposure follow-up costs and worker-compensation claims. Infection control is a win-win situation. PMID- 10117105 TI - Psychiatric transfers. Some EMTs treat psychiatric patients with hostility or indifference. PMID- 10117106 TI - EMS ethics. PMID- 10117107 TI - The education of health care professionals in the year 2000 and beyond: Part 1: The consumer's view. AB - In summary, consumers desire health care professionals with interpersonal communication skills; with ability to interpret nonverbal communication or body language beyond gross facial gestures; and with effective questioning techniques for taking family histories quickly and accurately yet uncovering some client feelings and life-style difficulties in the process. Consumers want health care professionals who know how to mobilize clients' personal healing resources through greater understanding of how the immune system functions and who know how to deliver difficult diagnoses to clients in a positive, challenging manner and involve the clients in the course of their own body's healing. They desire significantly more information and guidelines about nutrition, weight management, and the complex biochemical interactions associated with food, medication, and the combination of the two. Consumers want health care professionals with greater understanding of sleep and its effect on health and of biofeedback, hypnosis, exercise, meditation, relaxation, and support groups as disease-fighting tools. The genetic components of illness and wellness and how clients cope with some of the built-in genetic weaknesses must receive greater attention. The influence of the environment and pollutants on human health must be addressed. How to maintain health among an aging population, and utilizing norm data that is age specific, gender specific, and developmentally and socioculturally specific is essential to address. An emphasis shift is necessary towards healing and wellness. When we do all this, we still have to make it cost effective. What a challenge! How then can health care professionals be where the consumer wants them to be? How can professionals be responsive to their own human needs as well as those of the consumer? How can the faculty preparing health care professionals incorporate the dimensions outlined by futurists and by consumers by the year 2000? The answer lies in the curriculum solution to be developed in Part II of this presentation. The curriculum solution will explicate a human need theory/process-oriented approach to professional education and practice, assuring the consumer of a person-/family-/community-centered approach to health care and engendering for the carer a healthy, valued self and improved services. Trust your heart ... Never deny it a hearing. It is the kind of house oracle that often foretells the most important. PMID- 10117108 TI - Management preparedness criteria: a study of nursing home administrators. AB - The observations from this study seem to suggest that there are some correlations between education, experience, age, and sex on the level of preparedness in the practice domains identified. Specifically, this study finds that years of experience have a significant negative correlation with the practice domains of physical plant/building management, fiscal reimbursement, financial management, and overall preparedness in both Oklahoma and Connecticut respondents. Experience level further correlates negatively with all other practice domains (except licensing standards) in Oklahoma respondents. Education level, on the other hand, did not correlate with any practice domain (except licensing standards among Oklahoma respondents). Age correlated positively with financial management activities but only with Oklahoma respondents, while sex correlated positively with physical plant/building management (Oklahoma and Connecticut) and with financial management in Connecticut only. Sex, however, had a negative correlation with basic nursing activities among Connecticut respondents. This study suggests that the nursing home administrators from Connecticut in our study felt that they were more prepared in the practice domains identified as compared to those responding from Oklahoma. This can be attributed to the fact that Connecticut respondents had almost a 13 percent higher average of experience years. This was also demonstrated in the correlation table. Other factors such as sex, age at onset of administrator career, and educational level had no or very limited effect on the practice domains identified in the study (p greater than 0.05). This holds true for both Oklahoma and Connecticut respondents. Therefore, the hypothesis stating that education has a direct effect on job performance and preparedness of nursing home administrators does not hold true with this study. It is the years of experience that has a direct effect on performance and preparedness of nursing home administrators. PMID- 10117109 TI - Performance review interviews: planning for the future. AB - The planning phase of PRs is more important than the appraisal phase. At least 75 percent of the PR should be devoted to a discussion of future performance and career development. During the planning phase, the effective leader functions as an advisor, supporter, and facilitator. The formulation of goals and action plans is critical to this phase, and must be a cooperative effort with the employee having the major share of the input. PMID- 10117110 TI - How an expert corporate fitness program might be designed. AB - In this paper, the ideas and concepts of expert systems were combined with the principles of fitness to demonstrate how an expert system could be designed to prescribe exercise routines for corporate employees. Since the examples and the rules of fitness used herein were just a small fraction of what could be used in building such a system, it would be possible to spend years developing a huge system that employs thousands of rules. However, as the supply of skilled labor continues to fall short of corporations' needs, more effort will be brought to bear on maintaining fitness in the work force. Such expert systems may be a reality in the not-too-distant future. PMID- 10117111 TI - Continuous quality improvement in nursing service. AB - The 1991 Joint Commission standards specify continuous quality improvement in nursing services as a required characteristic. Chief nursing executives are in key positions to spearhead the quality movement in health care services. The 14 points of Deming's philosophy are highly relevant to health care organizations, specifically to nursing services. Each concept within the philosophy has broad applicability, and an organization with a firm commitment to neverending improvement will find it useful. Of primary importance is the recognition that short-run profits that sacrifice quality in patient care do not last. If a health care organization is to survive in a competitive environment, it is essential that a quality philosophy not just be espoused but practiced as well. PMID- 10117112 TI - Is productivity coming into its own--again? PMID- 10117113 TI - A supervisor asks: "From absentee management to visibility". PMID- 10117114 TI - Containing U.S. health care costs: what bullet to bite? AB - In this article, the authors provide an overview of the problem of health care cost containment. Both the growth of health care spending and its underlying causes are discussed. Further, the authors define cost containment, provide a framework for describing cost-containment strategies, and describe the major cost containment strategies. Finally, the role of research in choosing such a strategy for the United States is examined. PMID- 10117115 TI - Assessment of the effectiveness of supply-side cost-containment measures. AB - This article assesses the arguments and evidence concerning the likely effectiveness of four supply-side cost-containment measures. The health planning efforts of the 1970s, particularly certificate-of-need regulations, had very limited success in containing costs. The new and related tools of technology assessment and practice guidelines hold some promise for refining benefit packages, but they are inadequate for micromanaging complex medical practices. Payment policies, such as hospital ratesetting, have enjoyed some success in limiting hospital cost growth but are less effective at controlling total costs. None of these measures alone is likely to address fully the fundamental issues of equity and efficiency in health care resource allocation that underlie the problem of rising costs. PMID- 10117116 TI - Containing health costs in a consumer-based model. AB - The assumption that consumer choice cannot be used to achieve cost control in health care is invalid. It does not do so today because the tax treatment of health care leads to perverse consumer incentives that encourage cost escalation. By reforming the tax treatment of insurance and out-of-pocket medical costs, it is possible to design an efficient and universal system in which consumer choice is a powerful restraint on cost. PMID- 10117117 TI - Managed care: practice, pitfalls, and potential. AB - The results of coordinating and changing patterns of health care using managed care activities and organizations are reviewed in this article. Although utilization review and high-cost case management programs reduce the use of expensive services, incentives for providers of care, placing them at risk, are important for managing the intensity of health care. Managed care appears capable of reducing health care costs substantially. However, this increased efficiency has not translated to lower insurance premiums or modulated total health care expenditures because either purchasers are not aware or are not concerned about securing care at the least cost. To correct these deficiencies and deliver the potential of managed care, the author suggests the need to separate insurance into its three components parts (financing, risk spreading, and program management) and developed policies for each. PMID- 10117118 TI - All-payer ratesetting: down but not out. AB - In the United States, when the cost-containment paradigm shifted from regulation to competition, all-payer hospital ratesetting went out of favor. After reviewing the published literature and supplementing the existing literature with more current information, the author concludes that all-payer ratesetting is able to meet its multiple objectives of cost containment, reduction of the amount of cost shifting, improvement of access to the uninsured, and increased productivity. At the same time, all-payer ratesetting has not stifled the diffusion of competitive health care systems or new technology, and any impact on length of stay, admissions, and quality of care is small, if it exists at all. PMID- 10117119 TI - Prospective payment for Medicare hospital capital: implications of the research. AB - The special characteristics of capital have an important effect on the cross section variation in hospitals' capital costs. Variables reflecting capital age and financing differences perform as expected and add substantial explanatory power to capital cost models. However, even with the inclusion of these variables, the capital-cost models perform poorly compared with total-cost models. The empirical findings of this article support using the total-cost models to develop a common set of adjustment factors for capital and operating payment amounts in the Medicare prospective payment system. PMID- 10117121 TI - Successful strategies. Meeting the needs of children in adversity. PMID- 10117120 TI - Utilization management as a cost-containment strategy. AB - Utilization management (UM) is now an integral part of most public and private health plans. Hospital review, until recently the primary focus of UM, is associated with a reduction in bed days and rate of hospital cost increases. These reductions appear to have had limited impact on aggregate health care costs because of increases in unmanaged services. In the future, with electronic connectivity between payers and providers and the use of clinical guidelines and computer-based decision-support systems, the need for prospective case-level reviews will be reduced. With these changes, UM programs are likely to become more acceptable to providers and patients. PMID- 10117122 TI - In her own voice. Too little, too late: a child with AIDS. PMID- 10117123 TI - City views. Local governments, communities, and public health care. PMID- 10117124 TI - The ethics of empires. PMID- 10117125 TI - Seeking systemness. PMID- 10117127 TI - Building a prototype for the Nineties. PMID- 10117126 TI - Fulfilling the potential. As integrated systems, we must demonstrate our relevance--and we must do it quickly. PMID- 10117128 TI - Guidelines for managing integration. PMID- 10117129 TI - The future of integrated healthcare systems. Case study: UniHealth America, Inc. PMID- 10117130 TI - The future of integrated healthcare systems. Case study: Presbyterian Healthcare Services. PMID- 10117131 TI - Beating the box. PMID- 10117132 TI - New tools, new thinking. Interview by Joe Flower. PMID- 10117133 TI - 21st Century innovators. Interview by Joe Flower. AB - Last spring, The Healthcare Forum and 3M together announced the 21st Century Innovator Awards. They hoped to spotlight examples of the most forward-thinking organizations in American healthcare--organizations that could demonstrate readiness for the next century through the process of rebuilding their systems and structures. THF and 3M were looking for models for success with: (1) an organizational vision for the future, (2) an integrated planning process which reflected that vision, and (3) a measurable future benefit to the communities they served. The call elicited responses from more than 40 organizations across the country. THF and 3M were overwhelmed by both their range and quality. Choosing was difficult. But last September two winners were unveiled at the THF 3M Visionary Leadership conference in Hilton Head, South Carolina. Memorial Hospital and Health System of South Bend, Indiana, took the large, urban, regional, and national award for its progress in the long, tough process of revisioning itself according to a strategic concept CEO Phil Newbold calls "Quality Through People." The small, rural, and suburban prize went to Yavapai Regional Medical Center in Prescott, Arizona, where CEO Pat Linton is attempting to shape a "Total Healing Environment." We asked Joe Flower to visit both sites and send back an eyewitness report on what makes these two progressive organizations models for healthcare in the '90s and beyond. PMID- 10117134 TI - Two views on HDCT-ABMT breast cancer treatment controversy. Too experimental for insurers--or just too expensive? PMID- 10117135 TI - Curing our sickly health care system: is a single-payer government plan the answer? PMID- 10117136 TI - Ethics committees in Canadian hospitals: report of the 1990 pilot study. AB - The second phase of a Canada-wide study of ethics committees in English-language hospitals in Canada involved site visits to five selected hospitals to assess the effectiveness of the ethics committee. In this article the findings of this pilot study are reported, including the perspectives of physicians, nurses and hospital administrators on the ethics committee of the various hospitals. The results of the study, albeit limited by being a pilot study, raise a series of questions for hospital administrators, medical administrators and nursing administrators. PMID- 10117137 TI - Management training: how Canadian health care organizations compare. AB - Management training has been receiving increasing attention over the past decade. The present study reports on a survey of 1,000 randomly selected Canadian organizations having at least 500 employees. Analysis of returns from 56 health care organizations and 169 other Canadian organizations yielded many notable findings. Only 36 percent of health care and 37 percent of other organizations report formal policies and procedures for management training. Fortunately, many health care organizations are evolving toward a more articulated and comprehensive approach to management training; however, the constraint of limited funds for training is frequently cited. Overall, both health care and other Canadian organizations recognize the importance of management training for achieving organizational goals and they are striving to improve such training. PMID- 10117138 TI - A review process for a hospital at home. AB - The field of home health care is the focus of much attention as alternatives to institutionalization are sought. As a result, many types of organizations are now providing home care, health or otherwise, without the guidance of national standards similar to those found in accreditation models for care in an institutional setting. So that stakeholders in New Brunswick can be assured of the quality of the service it provides, the Extra-Mural Hospital has embarked upon the development of a review process which will, to some extent, follow established accreditation models. PMID- 10117139 TI - Hospital rightsizing: in line with long-term strategies and economic realities. AB - After two years of difficult financial times, the Kitchener-Waterloo Hospital was faced with another upcoming year of tight fiscal constraint. In February 1991, the hospital implemented a program review process to align its services with the hospital's long-term strategy and economic realities. The authors present a thorough review of the literature pertaining to downsizing decisions. From a practical perspective they demonstrate a downsizing process, its implications and lessons to be learned so that a "rightsizing" exercise can be implemented to minimize the effects of the program and staff reductions while focusing on the positive long-term benefits of strategic planning. Although downsizing is a difficult process, the Kitchener-Waterloo Hospital was able to develop and implement a plan that minimized the impact on the hospital services and its staff. A reduction in expenses of over $2 million was achieved without having to lay off any permanent hospital staff. This was achieved by streamlining programs, reducing management supervisory positions and eliminating 50 full-time equivalent positions through attrition. Ultimately, the hospital's board, senior management, medical staff and employees felt that a rightsizing decision had been made, one which minimized the negative impact of restructuring on service delivery, hospital employees and the community served. PMID- 10117140 TI - Taking strategy to the bottom line. AB - Many companies try to connect strategy with the financial plans that actually guide managers' actions, but only a few have devised good linkages. In this case study, the authors describe the steps taken by one organization to integrate strategic and financial planning. PMID- 10117141 TI - Designing a customer retention plan. AB - What is your company's customer retention rate? How many customers are price defectors? Have you identified barriers that prevent customers from switching to a competitor? In this article, the author outlines a game plan to increase customer retention. PMID- 10117142 TI - The pitfalls of niche marketing. AB - Corporate marketers have jumped on the micromarketing bandwagon, but many have discovered that the path to profits contains a number of potholes. This article details three companies' niche marketing mistakes; the author suggests how to avoid them. PMID- 10117143 TI - Creating a global health care company. AB - Global pharmaceutical mergers have spread the huge costs of research and enabled companies to sell their products in countries where they previously lacked a presence. Here's how the Beecham-SmithKline Beckman marriage was developed to propel the organization into a position as a worldwide player in the drug industry. PMID- 10117144 TI - Marketing to the Hispanic-American community. PMID- 10117145 TI - How should the US encourage innovation? PMID- 10117146 TI - Effective external communications in downsizing. PMID- 10117147 TI - Changing our health care system. PMID- 10117148 TI - Planning and controlling health capital: attaining an appropriate balance between regulation and competition. PMID- 10117149 TI - The process of choice of health care plan and provider: development of an integrated analytic framework. PMID- 10117150 TI - Antecedents of optimal decision making for client care in health services delivery organizations. PMID- 10117151 TI - Alternatives to hospital care under employee benefit plans. PMID- 10117152 TI - Bounds on a trauma outcome function via optimization. AB - One measure of the effectiveness of institutional trauma and burn management based on collected patient data involves the computation of a standard normal Z statistic. A potential weakness of the measure arises from incomplete patient data. In this paper, we apply methods of fractional programming and global optimization to efficiently calculate bounds on the computed effectiveness of an institution. The measure of effectiveness (i.e., the trauma outcome function) is briefly described, the optimization problems associated with its upper and lower bounds are defined and characterized, and appropriate solution procedures are developed. We solve an example problem to illustrate the method. PMID- 10117153 TI - New EKG interpretation rules implemented Jan. 1. PMID- 10117154 TI - Creative solutions improve hospital receivables. AB - The critical role of accounts receivables in the day-to-day operation of a hospital is irrefutable. Thus, the more one can "stay on top of things," the better the receivables department will run. Better equipment, persistence in process fine-tuning, and targeting quick payers serve to bolster and improve the state of accounts receivables. PMID- 10117155 TI - OSHA's bloodborne pathogens rule an opportunity/threat. AB - If you supply healthcare linen, OSHA's new ruling comes with a price tag, but it may be a marketing boon as well. The costs of compliance are high--about $1.19 million annually. One of the most costly and important parts of the ruling is the required employer-paid hepatitis B vaccination of employees. But behind the costs, there's good news for the textile rental industry. The opportunity to serve small medical facilities and nursing homes as well as hospitals with reusable healthcare garments could create a revenue source estimated to be at least $177 million a year. PMID- 10117157 TI - Perspectives. Tax credits: a paradise with snakes. PMID- 10117156 TI - Heal thyself. Hospital lighting. PMID- 10117158 TI - Perspectives. Medicaid managed care: is it time? PMID- 10117159 TI - Perspectives. Medical education: the slow pace of reform. PMID- 10117160 TI - Transporting the family and other concerned parties aboard air medical aircraft. AB - Patients flown on air medical aircraft are separated from family and other concerned parties, often for several hours and many miles. This paper studies the usefulness and safety of offering transport to these passengers on air medical aircraft. A nine-item questionnaire was mailed to 95 program directors. Only those air medical operations flying aircraft with the capability of carrying additional personnel were targeted. These aircraft included all fixed-wing craft; the helicopters included Bell 222, MBB BK 117, Sikorsky S-76, and Aerospatiale SA 365 Dauphin. Seventy responses were received. From these responses it was concluded that more than half of all helicopter programs can carry a patient's family, but do so only 5% of the time. All fixed-wing programs can carry family of patients and do so from 35% to 95% of the time. Various benefits and disadvantages were discovered, analyzed, and discussed. PMID- 10117161 TI - 1991 air medical helicopter accident rates. PMID- 10117162 TI - Enhancement of a critical care transport service. AB - The MICU has provided a much needed mode of transportation for the critically ill or injured patient in the Metro LIFE FLIGHT service area. Even though our primary focus is helicopter transport, the MICU has proved to be a valuable "backup" to our helicopter service. The MICU has paved the way to provide a more comprehensive service to the critically ill or injured patient in Northeastern Ohio, regardless of weather or lack of landing zones. PMID- 10117163 TI - Comparative evaluation of three end-tidal CO2 monitors used during air medical transport. AB - The purpose of this investigation on ETCO2 monitoring was to determine if the monitors would function effectively in the aircraft. When compared in a cumulative manner, little difference between the three monitors was noted. The ETCO2 monitor appears to function in the fixed-wing aircraft when transporting critically ill, mechanically ventilated patients. Although this study does not address the accuracy of the ETCO2 monitor during changes in altitude, a base-line reading can be established during flight. Light weight, small size and extended battery life appear to be the criteria most lacking in these three capnographs reviewed in this study. This study demonstrates the compatibility of three capnographs with the aircraft environment. Manufacturers will hopefully continue to develop ETCO2 monitors to meet the space and weight needs of flight personnel in the difficult conditions of the air medical environment. PMID- 10117164 TI - Blood donation centers: new partners in health care access management. PMID- 10117165 TI - Improving data collection. PMID- 10117166 TI - Merging admitting and registration departments in a multi-campus hospital. PMID- 10117167 TI - Seasonal population surges. PMID- 10117168 TI - Strategic planning in admissions? PMID- 10117169 TI - Coping with FASB Statement No. 106--"Accounting for Post-retirement Benefits other than Pensions". AB - The Financial Accounting Standards Board has recently adopted Statement No. 106 providing accounting rules for nonpension postretirement benefits. This change presents a complex series of design, funding and tax issues that will forever change the way employers view the offering of postretirement benefits. Careful analysis of these issues within the specific context of each employer's human resources and financial strategy will be needed to select the proper course of action for dealing with this new accounting statement. PMID- 10117170 TI - A selection model for employees confronted with health insurance alternatives. AB - Too often, employers offer their employees a menu of health insurance alternatives with little guidance other than a description of plan benefits and costs. A multiattribute health insurance choice model can provide employees with needed guidance. PMID- 10117171 TI - Flexible benefits and managed care: making it work. AB - The concept of integrating flexible benefits and managed care may seem contradictory. Flexible benefits seek to maximize choice, while managed care attempts to restrict choice. Can these two disciplines be intertwined without delivering conflicting messages to employees? The answer is definitely yes. By following some basic ground rules in design, flexible benefits and managed care can be combined effectively in a way that is attractive to both employers and employees. This article presents some general guidelines for designing a successful "managed flex" program and raises other issues as well, including financial, administrative and communication concerns. PMID- 10117172 TI - An analysis of capitation rates for prescription medication benefits from an insurance perspective. AB - The use of capitation payment systems to control costs for prescription medication benefits appears to be increasing. In such a system, risk is transferred to a pharmacist or group of pharmacists. The author examines the nature of that risk, factors that must be considered in setting capitation rates and ways to control risk in a capitation system. An insurance pricing model is used to calculate risk-adjusted capitation rates using observed and hypothetical data, and implications for pharmacists and insurers are discussed. PMID- 10117173 TI - Why small businesses don't have health insurance: results of a Florida survey. AB - While most of the insured population has health insurance under an employer sponsored group plan, the majority of the working uninsured are employed by small firms. Increasing the number of small firms that provide health insurance plans to their employees is important for decreasing the number of uninsured. This article summarizes the results of a survey designed to study characteristics of the firms that do not have health insurance, the obstacles to their getting insurance, and small business owners' interest in having a group health plan. PMID- 10117174 TI - Decision time for retiree medical accounting. AB - An employer's initial response to the new accounting rules for employer-sponsored retiree medical plans can irreversibly shape the retiree medical costs and liabilities that will emerge over the next several decades. PMID- 10117175 TI - What health care cost crisis? AB - Managed care has inherent limitations that, perhaps out of desperation for some degree of control of health care costs, we tend to disregard. A better understanding of the "crisis" and a host of new strategies become apparent when we separately consider the health care elements and cost elements of the crisis. Managed care is essentially palliative in that it eases symptoms without curing conditions. While this is not a call for the abandonment of managed care, it is a warning that our efforts will prove futile if we do not also address other fundamental elements of impaired health. PMID- 10117176 TI - Prospective screening of diagnostic testing: a valuable tool. AB - The elimination of unneeded services is a key to reducing medical costs and enhancing quality of care. Diagnostic tests have been a target of efforts to reduce costs primarily because they are discretionary and often appear to be unnecessary. Believing that the concept of prior review for many diagnostic tests is a good one, this pilot study sought to evaluate prospectively the propriety of diagnostic tests ordered during the first half of 1989 on individuals insured through a major insurance carrier. A physician review found that 21% of the tests were deemed inappropriate, leading to the conclusion that prospective review can be an effective means of screening inappropriately ordered tests. PMID- 10117177 TI - Universal basic benefits preempt mandated benefits. AB - Many states seek to expand health care access to uninsured people. As part of their efforts, states must define a basic level of health services to which all residents would have access. Presumably, this level of services would be leaner than that now covered by most health care policies. As it is, private insurers are already mandated by all states to include certain benefits, which differ widely from state to state. However, simple fairness argues that once a state defines a basic level of health services, that level should function as a floor for everyone and replace the previously mandated benefits (which, nonetheless, may be a useful guide in defining a basic level of health services). PMID- 10117178 TI - Combining health education, risk-rated insurance and employee rebates into an integrated health care cost management strategy. AB - Health education, risk rating and employee rebates can be combined into a comprehensive health promotion program within a benefits plan, reflecting health promotion in its truest sense. PMID- 10117179 TI - Benefits sought by the employed care giver. AB - More than 600 full-time employed care givers of older family members reported the impact of care giving on their work performance. While a large proportion reported a minimal negative impact on work performance, this impact was positively correlated with the extent of their care giving burden. When asked what employers could do to help, employees most often requested flexibility. PMID- 10117180 TI - Privacy Act of 1974; report of new system--HCFA. Notice of new system of records. AB - In accordance with the requirements of the Privacy Act of 1974 we are proposing to establish a new system of records, "The Medicare/Medicaid Multi-State Case-Mix and Quality Data Base for Nursing Home Residents," HHS/HCFA/ORD, No. 09-70-0050. We have provided background information about the proposed system in the "Supplementary Information" section below. Although the Privacy Act requires only that the "routine use" portion of the system be published for comment, HCFA invites comments on all portions of this notice. See "Dates" section for comment period. PMID- 10117181 TI - Attitudes of registered nurses toward euthanasia. AB - We sought to identify variables that contribute to euthanasia attitude and behavior, including demographics, death fears, experience with death, attitudes toward patient autonomy, and level of moral development. Subjects were 137 registered nurses from the southeastern United States representing 13 clinical nursing areas. Principal components analysis identified four factors that together explained 62.9% of total variance. These factors were belief in afterlife, nursing experience, liberal or conservative political view, and personal values. Variables identified through factor analysis were entered into regression analyses. These analyses showed that increased religious belief, years of nursing experience, and propensity to view death as an end of existence predicted opposition to euthanasia. Predictors for euthanasia support included a liberal political view, more experience with dying patients, and the belief that patients should have a personal responsibility for their own health-care decisions. PMID- 10117183 TI - International Work Group on Death, Dying, and Bereavement. A statement of assumptions and principles concerning education about death, dying, and bereavement. International Work Group on Death, Dying, and Bereavement. PMID- 10117182 TI - Bereaved older adults who seek early professional help. AB - The purpose of this exploratory study was to determine the characteristics of older bereaved spouses who sought early professional help related to their grief. Among a sample of 339 bereaved older adults, aged 50 years or older, 39 (11.5%) reported that they had obtained some form of professional help. The most commonly reported source of help sought was from clergy followed by that provided by the health-care system and community groups. Those who sought help reported higher depression, lower coping ability, and poorer perceived health as well as slightly lower self-esteem and instrumental and resource-identification skills. With a few exceptions, the particular source of help sought was not statistically related to many of the indicators examined. PMID- 10117184 TI - Setting standards: certification efforts and considerations in the field of death and dying. PMID- 10117185 TI - Top down, bottom up. PMID- 10117186 TI - Raw deal. PMID- 10117187 TI - Past imperfect, future tense. PMID- 10117188 TI - Training--have your cake and eat it. AB - Training programmes which take staff away from the workplace for long periods are unpopular with managers. In this special report we look at developments in on-the job training: how open learning has become the main growth area in staff development; why national vocational qualifications aren't yet living up to the ideal; how Cornwall providers have replaced 'sitting beside Nellie' with more effective IT training. PMID- 10117189 TI - Fishing for fundholders. PMID- 10117190 TI - Riding the dinosaur. PMID- 10117191 TI - An option to keep open. PMID- 10117192 TI - On the right tracks. PMID- 10117193 TI - Data briefing--family planning. National Association of Health Authorities and Trusts. PMID- 10117194 TI - Oxford--the scramble for status. PMID- 10117195 TI - A jigsaw for the people. PMID- 10117196 TI - Can't pay, won't pay, don't care. PMID- 10117197 TI - What would Bevan say? PMID- 10117198 TI - Inequality street. PMID- 10117199 TI - Time out. PMID- 10117200 TI - Dolce vita. PMID- 10117201 TI - Hard cash. PMID- 10117202 TI - Management information systems--green light for better info. AB - An EIS gathers financial and non-financial data from a variety of sources, both internal and external to an organisation, and presents them accessibly and understandably. It should facilitate the presentation of data so that it is timely and relevant to senior managers' needs. Generally, there are three categories of EIS: Front-end tools, which enhance the presentation of output from existing systems. For example, they can take the output from a general ledger system and enhance its appearance but do not change the content. Internal consolidation tools, which take data from a number of internal sources (such as the general ledger), store it in a central database, and present it to users. This is often done in report book format to which all EIS style functions may be applied. Integrators of information, which integrate data from internal and external sources. Much of the data is non-financial and a major emphasis is on the users' ability to communicate with each other. The key functions that may be included within an EIS are: Drill down. The facility to explore increasingly detailed levels of data. Trends and variances against pre-set targets, such as financial budgets. Graphics and tabular reporting. Data integrity checking. Analysis of the data, modelling and the production of forecasts using time series analysis techniques. Exception reporting through the use of some form of alert. Incorporation of text into the output. PMID- 10117203 TI - Jam tomorrow? PMID- 10117204 TI - Here we go again. PMID- 10117206 TI - Northern RHA--Geordies dying for a change. PMID- 10117205 TI - Background information. PMID- 10117207 TI - Out of the bunker. PMID- 10117208 TI - First division united. PMID- 10117209 TI - Communication breakdown. PMID- 10117211 TI - Hospital security--target practice. PMID- 10117210 TI - Make or break. PMID- 10117212 TI - Data briefing--capital costs. National Association of Health Authorities and Trusts. PMID- 10117213 TI - Do healthcare executives really know their physicians? Let's talk. PMID- 10117214 TI - Hospital-physician alliances: building an integrated medical delivery system. PMID- 10117215 TI - Charging forward: hospital-physician relations in managed care. AB - Creating a successful PHO is a delicate process that requires a great deal of finesse, experience, and collaboration. PMID- 10117216 TI - Physician/hospital trends for the 1990s raise some red flags. Successful CEOs read warning signs. PMID- 10117217 TI - Access to healthcare. AB - There are strategic questions about national healthcare that need to be asked. They represent the moral center of the enterprise that is healthcare delivery and they have an impact on healthcare executives. PMID- 10117218 TI - Medicaid perspective. PMID- 10117219 TI - Extinguishing healthcare burnout. AB - Caregivers are particularly prone to burnout because they are constantly exposed to life and death issues. They are often unable to separate their job from their personal life. PMID- 10117220 TI - Charting a course to efficiency. PMID- 10117222 TI - People care. Are we missing something? PMID- 10117221 TI - Do statistics really prove anything? An EMS consumer's guide to understanding research literature. PMID- 10117223 TI - Texas trauma. How much, and who pays? PMID- 10117224 TI - Tools for decision making on capital expenditures. AB - The above methods are useful to determine a project's worth. They can provide senior management with information that will be helpful when analyzing potential capital investments. Managers should make it their job to help administrators select the best investment projects. PMID- 10117225 TI - Quality evaluation for purchasing. PMID- 10117226 TI - A system approach to patient-safe rigid and flexible endoscopes: a microbiologist's point of view. AB - Many scientists have written at length on the myth of surgical sterility, and tried to shift focus from definitions of sterility and disinfection driven by artificial microbiological models to the really meaningful consideration of the patient-safe condition of medical equipment and/or products. J. C. Kelsey said it very well: "Although sterility is in theory an absolute term, in practice it may only be regarded as at best relative and at worst misleading. It is a philosophical concept that can never be unequivocally demonstrated in a real world. Experience has shown that it is virtually impossible, even if it is honest, to change the definition of a term that has been in use for many years; we may need a new term to indicate 'the state of having been sufficiently freed from microorganisms to be deemed safe for some special purpose by some competent body.' The abandonment of the term 'sterility' and the acceptance of some other term would remove confusion and enable the important matter of providing microbiologically safe medical products to be more rationally and realistically considered." The most practical way to produce a patient-safe endoscope is through a careful consideration of the whole processing system as discussed in this article, not by focusing strictly on the differences between high-level disinfectants and sterilants. A sterilant used within a poorly designed processing system could actually result in an unsafe, even microbiologically dangerous, endoscope. On the other hand, high-level disinfectants used within a well-designed and quality-controlled process can and do produce safe, even sterile, endoscopes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10117227 TI - Evaluating your group purchasing. PMID- 10117228 TI - EtO monitors. ECRI. PMID- 10117230 TI - Microbiology for central supply workers. PMID- 10117229 TI - Ethical issues and GPOs: how far have we advanced? PMID- 10117231 TI - Measuring the spiritual needs of hospital patients and their families. AB - Uses four psychometric instruments in an attempt to measure the spiritual needs of general hospital patients, family members, and persons from the community. Infers that the data suggest that family members tend to be more involved in a search for meaning than are patients and community persons. Discusses implications of the results for pastoral caregivers. PMID- 10117232 TI - Special issue: Issues in the structure, financing, and viability of rural hospitals. PMID- 10117233 TI - The WAMI Rural Hospital Project. Part 1: Historical and theoretical underpinnings. AB - This set of six manuscripts describes the content and impact of the WAMI Rural Hospital Project (RHP), a research and development effort supported by the W.K. Kellogg Foundation, designed to improve the delivery of health services in six rural communities in the Pacific Northwest and Alaska. The major objective of the RHP--an activity which spanned a four-year period from 1985 through 1988--was to assist the project communities in improving the financial stability and quality of care of their local health care systems. Special attention was directed at helping the communities determine and implement an appropriate scope of health services, improve management and governance of the local health care enterprise, recruit and retain additional health personnel, and increase the extent to which community residents used local health services. In this first section we discuss the historical antecedents and conceptual underpinnings of the RHP and describe the five principal phases of the project. These include: (1) selection of communities for participation in the RHP, (2) comprehensive analysis of the health care system in each community, (3) community health services planning, including the development of comprehensive strategic plans, (4) implementation of techniques to improve local health services, and (5) project dissemination and evaluation. A pre-test, post-test model was employed to assess qualitative and quantitative changes in a variety of key measures of health system performance, including organization and management, scope of services, fiscal viability of the rural hospital, and utilization and patient satisfaction with health services in each community. The results of this evaluation constitute the balance of this report. PMID- 10117234 TI - The WAMI Rural Hospital Project. Part 2: Changes in the availability and utilization of health services. AB - A major goal of the Rural Hospital Project (RHP) was to assist communities in defining an optimal scope of hospital and community health services. It was hypothesized that a rational basis for service planning would result in an expansion of locally provided health services, increased local hospital and physician market share, improved hospital workload performance, and higher levels of consumer satisfaction with community-based services. However, given the recent decline in performance of many small rural hospitals in general and in RHP hospitals in particular, at a minimum, stabilization of these troubled facilities could be considered a successful outcome. Data were collected from the six rural communities participating in the RHP both before and after the intervention (1985 and 1989) to assess changes in community scope of health services and utilization patterns. Comparative data were also compiled from peer group hospitals when available. Results generally demonstrated stabilization or expansion in: (1) the range of community and hospital services, (2) the availability of community physicians and visiting specialties, and (3) physician and hospital market share. While findings were mixed for patient days, average daily census, and number of births, substantial increases were documented for the number of surgical procedures, emergency room visits, and x-rays over the study period. RHP hospitals generally outperformed peer group hospitals on market share measures. PMID- 10117235 TI - The WAMI Rural Hospital Project. Part 3: Building health care leadership in rural communities. AB - The WAMI Rural Hospital Project (RHP) intervention combined aspects of community development, strategic planning and organizational development to address the leadership issues in six Northwest rural hospitals. Hospitals and physicians, other community health care providers and local townspeople were involved in this intervention, which was accomplished in three phases. In the first phase, extensive information about organizational effectiveness was collected at each site. Phase two consisted of 30 hours of education for the physician, board, and hospital administrator community representatives covering management, hospital board governance, and scope of service planning. In the third phase, each community worked with a facilitator to complete a strategic plan and to resolve conflicts addressed in the management analyses. The results of the evaluation demonstrated that the greatest change noted among RHP hospitals was improvement in the effectiveness of their governing boards. All boards adopted some or all of the project's model governance plan and had successfully completed considerable portions of their strategic plans by 1989. Teamwork among the management triad (hospital, board, and medical staff) was also substantially improved. Other improvements included the development of marketing plans for the three hospitals that did not initially have them and more effective use of outside consultants. The project had less impact on improving the functioning of the medical chief of staff, although this was not a primary target of the intervention. There was also relatively less community interest in joining regional health care associations. The authors conclude that an intervention program tailored to address specific community needs and clearly identified leadership deficiencies can have a positive effect on rural health care systems. PMID- 10117236 TI - The WAMI Rural Hospital Project. Part 4: Improving the financial health of rural hospitals. AB - Sound financial management has been identified as a critical component of effective hospital administration. Inadequate financial practices are a leading factor in the failure of hospitals. As part of the Rural Hospital Project (RHP), which operated in six rural Northwest communities from 1985 to 1988, detailed and extensive analyses of financial practices were conducted to identify strengths and weaknesses of the hospitals' financial management. In addition, 15 hours of formal education covering a variety of financial topics were presented to project participants. Results of the evaluation demonstrated that the greatest degree of change occurred in the financial management leadership capacity of the hospitals. All five hospitals, which either had no chief financial officer initially or subsequently experienced a turnover in the position, recruited individuals with strong qualifications. Vacancies in the administrator position in three of the four hospitals were filled by individuals with stronger financial management qualifications than their predecessors. Hospital board finance committees were formed in three of the four communities which previously did not have them. The biggest changes in financial practices occurred in the budgeting processes, which by 1989 better reflected the goals and strategies of the hospital's strategic plans. The financial performance of the six hospitals varied considerably over the study period. As a group, the RHP hospitals continued to require substantial nonoperating subsidies to remain solvent, despite improved financial practices. Despite the methodological limitations of this evaluation, we conclude that the intervention improved the capacity of the hospital administrations' financial leadership, as well as that of the governing boards, and led to substantial improvement in selected financial practices at all sites. Rural hospitals continue to operate in a hostile and precarious financial environment that limits their ability to sustain themselves on the basis of operating revenue alone. PMID- 10117237 TI - The WAMI Rural Hospital Project. Part 5: Community perception of local health care services. AB - Rural health care facilities commonly employ community health care surveys as marketing research instruments to assess consumer utilization of and satisfaction with local services. However, there is little information on the use of survey findings as a way to design interventions to enhance consumer satisfaction and hospital viability. A community survey was administered in six Northwest rural communities as part of the Rural Hospital Project (RHP) to identify weaknesses in local health care services, guide remedial activities, act as a catalyst for change, and assess changes in community perceptions following project interventions. Descriptive findings revealed problems typically observed in small rural communities, including relatively low hospital and physician market share, outmigration for certain types of health care not available locally, and dissatisfaction with some aspects of hospital and physician services. Satisfaction with various aspects of care tended to be lower among males, the uninsured, and younger respondents. Comparisons of survey responses before (1985) and after (1989) the RHP generally demonstrated stability in hospital and physician market share, with project hospitals performing well in 1989 in comparison to other rural hospitals of similar size. The percentage of respondents who rated overall quality of local hospital and physician care positively generally increased or remained stable over the study period. Substantial decreases in satisfaction levels were found for access to care. Importantly, gains were made in those areas and services which received particular emphasis in the project. PMID- 10117238 TI - The WAMI Rural Hospital Project. Part 6: Overview and conclusions. AB - The Rural Hospital Project (RHP) appeared to make a meaningful difference in the six Northwest rural communities that participated in this integrated community development and strategic planning effort. Although the methodological approach used in the evaluation precludes us from attributing observed changes in outcomes solely to the project interventions themselves, several elements of the process appear to be useful in stabilizing or expanding local health care systems. These include: (1) the involvement of outside organizations in fostering community change, (2) a high degree of community commitment and investment in all stages of the process, (3) comprehensive identification of problems in the health care system by outside consultants, (4) the use of periodic meetings of communities confronting similar issues, (5) identification and development of local leadership, (6) enhancing teamwork among local health care providers, and (7) the development of conflict-resolution mechanisms within health care organizations. Future attempts to use this strategy to strengthen rural health care systems can be enhanced by broadening the range of participation in health services planning, enlisting involvement of medical staff throughout the strategic planning cycle, addressing the issue of physician recruitment, and clarifying responsibility for implementation of community plans. Rural communities will predictably need to identify and resolve a set of core issues. To the extent that external organizations such as medical schools can strengthen the ability of rural health professionals and community leaders to identify and address these issues, the quality and viability of rural health care systems will be enhanced. PMID- 10117239 TI - The structure and characteristics of rural hospital consortia. AB - Rural hospital consortia are relatively new organizations that have been developed to help improve the viability of participating hospitals. This paper describes the characteristics of rural hospital consortia in the United States and develops and tests a measurement model of their underlying structure. The measurement model, which characterized consortia structure in terms of degree of member commitment, degree of complexity, scale of operations, and degree of formalization, provided a good fit to the sample data. Most consortia appear to have followed a relatively conservative course that involved the development of programs that had limited sensitivity and financial risk for individual hospitals. This suggests that rural hospital consortia may not become a model for major structural change in the rural health care system. Future research should examine the evolution of rural hospital consortia from an organizational life cycle perspective. PMID- 10117240 TI - Establishing a rural hospital cooperative: a case study. AB - Rural hospitals have traditionally been the providers of health services in rural areas. In recent years, however, rural hospitals have come under increasing economic and regulatory stress. Rural hospital cooperatives represent a new level of shared management that addresses mutual problems using a horizontal organizational model. In 1987, the Western New York Rural Health Care Cooperative was established by building on fragments of associations that had existed previously. Triggered by an opportunity for grant funding, a major regional cooperative evolved which has demonstrated effective responses to a variety of problems inherent in providing rural health care. Particularly successful programs have such features as a quality assurance plan that uses cooperative wide peer review, nursing and allied health education, physician recruitment, and the active involvement of a university medical school. This paper is a case study of the development and success of the Western New York Rural Health Care Cooperative. PMID- 10117241 TI - Has Medicare been a 'bad deal' for rural hospitals? AB - Understanding the links between Medicare involvement and financial performance in rural hospitals is important for evaluating reimbursement policy under Medicare's prospective payment system (PPS). While simple comparisons between urban and rural hospitals suggest that the latter have lower PPS profit margins on average, there is little multivariate evidence on how Medicare involvement affects financial performance in rural hospitals and whether this relationship differs between rural and urban hospitals. Existing multivariate evidence suggests that Medicare involvement improves PPS profits in both rural and urban hospitals after controlling for other hospital- and market-specific factors. By contrast, the present analysis considers the relationship between Medicare involvement and broader measures of profitability than PPS profits. This provides insight into whether Medicare reimbursement is adequate relative to other forms of third-party payment. The results indicate that Medicare involvement has a markedly different effect on the profitability of rural versus urban hospitals. Greater Medicare involvement is associated with lower patient care profitability in rural hospitals but has a strong positive and significant effect on both patient care and overall (i.e., patient and nonpatient) profitability in urban ones. Medicare involvement is not significantly related to overall profitability in rural hospitals, however, suggesting that these hospitals may be able to mitigate patient care revenue shortfalls from greater Medicare involvement by increasing their nonpatient care revenue sources. PMID- 10117242 TI - Implementing EACHs (essential access community hospitals) and RPCHs (rural primary care hospitals) on a statewide basis: a preliminary analysis. AB - Declining hospital utilization has created excess hospital capacity in rural areas, has depressed occupancy rates, and threatens the financial viability of rural hospitals. Access to hospital care could be reduced and rural economies damaged if rural hospitals close. The federal Essential Access Community Hospital (EACH) demonstration program is an attempt to address these issues by establishing regional hospital networks. A preliminary analysis of the impact of state-wide implementation of the EACH program in Iowa suggests that about 60% of rural hospital beds and about 28% of all hospital beds would be eliminated. The EACH program could well prove difficult to implement because of the need to select hospitals for reduced services. PMID- 10117243 TI - Ed Hodges on hospital governance and health care. Interview by Cheri Hicok. PMID- 10117245 TI - MAHA: a new structure for a new era. PMID- 10117244 TI - Negotiating guidelines for leaders. PMID- 10117247 TI - Calif. medical group, four hospitals to form regional healthcare network. PMID- 10117246 TI - Michigan's hospitals: a decade in review. PMID- 10117248 TI - HealthTrust earnings up 70% in first quarter since going public. PMID- 10117249 TI - Psych/rehab chain moves into subacute care. PMID- 10117250 TI - Community Psychiatric collects $4.7 million in Canadian settlement. PMID- 10117251 TI - Budget pact eases blow for N.Y. hospitals. PMID- 10117252 TI - U of I degree has health info focus. PMID- 10117253 TI - OSHA lacks hospital experience, some fear. PMID- 10117254 TI - FTC, Justice Dept. set merger rules. PMID- 10117255 TI - Executive pay pacts pinch profitability at Republic Health. PMID- 10117256 TI - More Medicare millions set to change hands in reclassification. PMID- 10117257 TI - Draft plan designed to replace Medicaid. PMID- 10117258 TI - Va. hospital terminates Quorum contract. PMID- 10117259 TI - Film image of healthcare exec calls for corrective campaign. PMID- 10117260 TI - Ultrasound evolution. AB - Ultrasound, one of the least-expensive diagnostic imaging techniques, also is the fastest-growing in hospitals' arsenal of technology. New advances and new applications are making it the tool of choice for a wider scope of initial screenings, but the expanded utilization and increased availability at locations away from hospitals are setting up turf battles among specialists and among various sites. PMID- 10117261 TI - IRS issues new audit guidelines covering not-for-profits. PMID- 10117262 TI - Data base tracking systems can measure actual effectiveness of marketing efforts. AB - More hospitals are using information they already have in their data bases to do a better job of marketing services to patients who will have an interest in them. It can be as simple as matching patients' needs to available programs. Making better use of this information is especially helpful to hospitals that are trying to gain an edge in competitive markets, experts and facility executives say. PMID- 10117263 TI - IBM wants to take 'byte' out of bedside market. AB - Whether it's through hardware or software, International Business Machines Corp. is intent on becoming a player in the potentially lucrative bedside computing market. IBM and its software partner, Baxter Healthcare Corp., are hedging their bets to ensure one or both companies will be in the running as a supplier when hospitals decide to employ computers at patients' beds. PMID- 10117264 TI - Hospital chains return to the junkyard. AB - The combination of low interest rates and healthy financial prospects at hospital chains have polished the tarnished image of junk bonds, making the high-yield, high-risk instruments an option for raising capital once again. Epic Healthcare Group and Columbia Hospital Corp. already have sold junk bond issues, and a sale by Health Trust--The Hospital Co. is expected in the next few weeks. PMID- 10117265 TI - JCAHO expands board by 4, to seek nurse representative. PMID- 10117266 TI - 8 senators oppose overhaul of PRO system. PMID- 10117267 TI - Agreement to send medical residents from Chicago to Denver for rotations. PMID- 10117268 TI - Blues see managed care as key in reform. PMID- 10117269 TI - Wofford offers legislation for public health system. PMID- 10117270 TI - Miss. Blues plan to be Missouri's fiscal agent. PMID- 10117271 TI - Dem leaders propose plan for long-term-care coverage. PMID- 10117272 TI - Two physician groups proposing their own healthcare reform plans. PMID- 10117273 TI - Florida hospital misses payment; bond rating downgraded to 'D'. PMID- 10117274 TI - VHA releases its own list of standards to help members show value to community. PMID- 10117276 TI - New merger guidelines identify acceptable types of efficiencies. PMID- 10117275 TI - Two public hospitals probed in New York City. PMID- 10117278 TI - Device manufacturers fear FDA product tracking rules to be a heavy financial burden. PMID- 10117277 TI - N.C. hospital caught in cross fire between ER management firms. PMID- 10117279 TI - Mich. inspectors say mammography unit failure rate's lower than first reported. PMID- 10117280 TI - Senate panel gets tough on balance billing. PMID- 10117281 TI - Report says New Medico facing charges of poor quality care, deceptive practices. PMID- 10117282 TI - Minn. providers settle antitrust charges. PMID- 10117283 TI - Group of House Democrats reveals managed-care-based reform plan. PMID- 10117284 TI - Government report says it's OK for hospitals' home-care agencies to get higher Medicare payments. PMID- 10117285 TI - Voters can't distinguish differences between parties' health reform plans. PMID- 10117286 TI - 900 Mass. residents lose low-cost health insurance coverage. PMID- 10117287 TI - More hospitals drop practice of sending birth announcements. PMID- 10117288 TI - Healthcare International amends plans. PMID- 10117289 TI - Merger guidelines improved, but significant pitfalls remain. PMID- 10117290 TI - If you can't stem the tide, try diverting a trickle. AB - More hospitals are turning to strategies like fast-tracking, which redirects patients with minor illnesses to less intensive sources of care. Still, there's an art to applying triage techniques effectively and relieving the pressure on overburdened emergency departments, which are seeing patient loads steadily rise. PMID- 10117291 TI - Moving day. AB - The horror stories--legends or true--about hospitals moving from one facility to another can strike fear in an administrator's heart. As with a residential move, planning is necessary--but for healthcare facilities, the planning must anticipate the tiniest detail. And finally, practice will make the perfect move. PMID- 10117292 TI - Federal healthcare data collection is incomplete and inadequate--report. AB - A new report criticizes federal efforts to collect data on the use of healthcare services, calling them fragmented, duplicative and inadequate for policymakers' needs. The report says a proposed overhaul of the National Center for Health Statistics doesn't go far enough and offers recommendations to steer the project toward more effective results. PMID- 10117293 TI - Latest study a boost for 'managed competition'. PMID- 10117294 TI - Bond volume soars 84% in first quarter. AB - Fueled by low interest rates and an increase in long-term capital projects, tax exempt healthcare bond volume skyrocketed 84% in the first three months of 1992. Not-for-profit hospitals sold 126 separate bond issues for a total of $4.05 billion in the first quarter, up from 94 issues worth $2.2 billion in the same period last year. PMID- 10117295 TI - AHA stays with 'play-or-pay' despite concern of affiliates, fading support from others. PMID- 10117296 TI - AHA totals the losses from all-payer Medicare rates. PMID- 10117297 TI - Restoring dignity. PMID- 10117298 TI - Nurses must take lead in health care reform. AB - The following is excerpted from a speech delivered by Sheila Burke, RN, chief of staff to Sen. Robert Dole (R-KS), to long term care nurses at the American Health Care Association/American Nurses Association Long Term Care Nurses Forum in Orlando, Fla. PMID- 10117299 TI - Management of specialty units: a must for today's DON. PMID- 10117300 TI - Successful QA program requires interdisciplinary approach. PMID- 10117301 TI - Case-mix payment rates reflect resident needs. PMID- 10117302 TI - Facilities must comply with new nurse assistant regulations. PMID- 10117303 TI - Children brighten facilities in business/education partnerships. PMID- 10117304 TI - Providers take systematic approach to discontinue medications. PMID- 10117305 TI - Interim care program helps residents return home. PMID- 10117306 TI - Health care: the double-edged sword of the 1992 elections. PMID- 10117307 TI - Starting up stress thallium cardiac imaging services. AB - This paper presents an evaluation of alternative methods for a hospital to establish stress thallium cardiac imaging services at a group of physicians' office. Volume-cost-profit analysis, break-even analysis and capital budgeting techniques were used to determine the most feasible method from a financial perspective without sacrificing quality of services. The main focus of this evaluation centers upon three alternative methods of procuring an imaging camera: (1) purchasing a new camera, (2) purchasing used equipment, or (3) leasing a new camera. Budgeted income statements were constructed using relevant revenue and cost information for each alternative. The payback period, net present value and the internal rate of return for each method of procuring a camera was computed. In addition, the break-even point was also determined for each alternative. After the analysis was completed, it was concluded that the method of choice, without sacrificing quality of service delivery, was that of purchasing a used camera. PMID- 10117308 TI - Integrated software packages and the radiology administrator. AB - An integrated software package offers word processing, database, spreadsheet, and communications in one common format that has enough power and flexibility to handle most radiology management computer needs. The ease of use, shorter learning time and the exchange of information between the modules are ideal for the radiology administrator's level of informational needs and time availability. PMID- 10117309 TI - Purchase considerations for a radiology information system. AB - Since choosing a radiology information system can be a trying endeavor, this "nuts and bolts" article offers some practical advice. The authors first emphasize that a strong partnership between the institution and vendor must exist for successful implementation to happen. Ms. Rowe and Ms. Parrish then proceed to outline the commitment, tasks and training necessary to ensure that your organization undertakes this project with favorable results! PMID- 10117310 TI - AHRA survey. Trends in radiology: Part I. AB - Trends in department workload, procedure volume, equipment purchase and other areas are reported in this first part of the AHRA's "Trends in Radiology" Survey. The authors also provide comparisons of data from this survey with studies done in 1985, 1987 and 1989. PMID- 10117311 TI - TQM approach may help solve physician practice problems. PMID- 10117312 TI - Choosing a maternity care system. PMID- 10117313 TI - Comprehensive vs. incremental reform: the debate intensifies. PMID- 10117314 TI - Hospital liability: a compelling case for comprehensive D&O insurance. PMID- 10117315 TI - Seven keys to financial survival. PMID- 10117316 TI - Selecting excellent advisers. PMID- 10117317 TI - Board structure/restructure. PMID- 10117318 TI - Continuous quality improvement: learning from the innovators. PMID- 10117319 TI - Congress links health care costs and antitrust law. PMID- 10117320 TI - Patient satisfaction: where does it fit in the quality picture? PMID- 10117321 TI - Managing information systems: an ethical framework and information needs matrix. AB - This paper urged administrators in human services to attend to values and ethics in the design and implementation of automated information systems. Toward this end, it presented an ethical framework reasserting the primacy of clients as citizens and encouraging the development of client-driven information systems. Finally, the paper presented the rationale for and two examples of an Information Needs Matrix to assist administrators in their deliberations about allocating discretionary resources among functional units within organizations. PMID- 10117322 TI - Methods to establish priorities for health care. AB - There is no right way to rank health care projects or patients requiring treatment. Different people or interests, either explicitly or implicitly, adopt different criteria: medical, economic, ethical, or political. This paper discusses the nature of these criteria and presents some strategies for improving our processes for setting priorities for health care expenditure. PMID- 10117323 TI - What makes an effective manager?--health care and general management perceptions. AB - This paper explores the perceptions of Australian health service managers (and health service management students) regarding the qualities of effective managers, comparing and contrasting these views with those of Australian general managers (and general management students). The study forms part of a wider international project aimed at exploring the role of national culture in managerial behaviour and effectiveness. Overall, the skills dimension was perceived to be more important in terms of managerial effectiveness, particularly amongst health service managers, compared to the other main dimensions of knowledge and learning, beliefs and values and personality characteristics. Decision-making and planning and evaluation were considered to be the most important amongst the range of skills listed, followed by negotiation and conflict resolution. Health service managers rated pertinent technical knowledge more highly than any other aspect in the knowledge and learning dimension, indicating the importance of specialist education for health service managers. Some implications of these and other findings are discussed. PMID- 10117324 TI - AIDS and confidentiality. AB - As the AIDS epidemic within Australia grows, a concerted effort should be made to preserve confidentiality of medical records for patients who are HIV positive. A significant number of the AIDS patients in Victoria are treated at Fairfield Hospital. Infected individuals need to retain control over disclosure of their HIV infection status to ensure that any adverse consequences such as discrimination are minimised. Stringent confidentiality procedures should be established and enforced by every Australian Health Care Institution. PMID- 10117325 TI - Imaging nursing--reflecting and projecting. AB - This paper sets out to consider reflected and projected images of nurses. When looking at the reflected images, those images that we see of ourselves, it attempts to consider the image of the role of the nurse, the image of the nursing workforce, and the image of nursing education. In projected images, it looks at nursing projected as a career, and the image of the nurse in law. The key theme running through the article is the privilege of intimacy which nursing provides. PMID- 10117326 TI - Quality assurance for all--a management viewpoint. PMID- 10117327 TI - Dear Minister, please save me from case-mix funding. An open letter to the Minister for Community Services and Health. PMID- 10117328 TI - Beijing Institute of Hospital Management. PMID- 10117329 TI - Don't be afraid of the bogeyman! Rejoinder to Johannes Stoelwinder. PMID- 10117330 TI - Case payment in Australian hospitals: any skeletons in the cupboard? AB - This paper examines two major concerns with the proposal to introduce case payment for Australian hospitals. The first relates to the potential negative impact on government budgetary outlays of an open-ended payment system based on output and the second to inherent incentives that may jeopardise quality of care. A number of options for capping payments are presented and the impact of the U.S. Medicare prospective payment system on quality described. PMID- 10117331 TI - Approaches to public funding of Australia's health care. AB - Three approaches to funding health services: historical funding, population based funding and output based funding, are characterised. Having dismissed the first and most common of these, some of the merits and pitfalls of the two remaining approaches to funding health services are briefly examined and it is argued that although they may appear to be based upon separate and competing principles, the one seeking to maximise equity and the other efficiency, a reconciliation is possible by applying both, but at different levels. PMID- 10117332 TI - Case payment: a New South Wales perspective. AB - This paper addresses the role of casemix systems within the NSW public health system. In NSW, Areas and Regions are funded according to a casemix modified population-based funding formula (Resource Allocation Formula). The RAF is compared with case payment as a means of funding hospitals. It is argued that because of the current shortcomings in casemix funding, including output orientation, inapplicability to ambulatory and non-acute inpatients, and limited scope for global expenditure control, case payment should not be introduced as the mechanism for funding hospitals. However, it is recognised that there is scope to combine population-based funding at area/region level, with case payment to individual agencies. PMID- 10117333 TI - Case based funding--how or when. AB - Casemix is on the move, and as with all new crazes, there are instances of the sensible running in parallel with the outrageous. There is certainly a danger that a desire to satisfy everyone's interests will lead to complex and convoluted systems with as little credibility as the current arrangements. The essential elements of case based funding systems are available and can be used to introduce more equity and common sense into health funding. The only thing missing is a clear commitment to use the available tools and limit opportunities to manipulate the system through political means. PMID- 10117334 TI - Casemix based funding for private hospitals or there are still a number of options so can we please slow down. AB - Australian private hospitals should ask themselves and answer four questions in relation to case mix based payment before they reach a firm decision of the merits of such funding. Firstly, does Australia in general and the private sector in particular need case mix based funding? Secondly, if we are to have case mix based funding, does it have to be based on DRGs and, in particular, the system in use in the United States--the Medicare prospective payment system? Thirdly, will the U.S. system be forced upon us? Fourthly, will sufficient time be allowed for development and phasing in of a new system? This paper addresses all these questions and argues that the case mix based system currently in use and being further developed within the private hospital sector may be a better proposition for long term private sector funding because of its relative simplicity and low administrative costs. The paper also urges less haste in the development and implementation of any radical change. PMID- 10117335 TI - The organisational change implications of casemix-based hospital management. AB - The 1970s and 80s have witnessed increasing concern about the efficiency and effectiveness of hospitals as core units of the health care system. In recent times, the solutions offered for improving hospitals have centred on the promotion of a more output and finance-driven approach to hospital-based service provision, strengthening managerial authority and more recently, incorporating clinicians into the day-to-day management of hospitals. The purpose of this paper is to examine the background to these developments, how they are being made manifest within hospitals and to foreshadow their implications for the work of clinician-managers. PMID- 10117336 TI - The practical application of DRG and casemix information in planning and funding models. AB - There is concern in some quarters about the practical application of casemix information and Diagnosis Related Groups (DRGs). Hospital executive and financial management staff have generally played an observation role as debate about technical issues continue. Notwithstanding, there are already many practical applications of DRGs in strategic service planning, and more recently, in drawing a closer and quantifiable relationship between casemix and costs. These techniques have been developed and applied in a wide variety of situations, from small rural, to larger tertiary referral hospitals. Ongoing use and refinement of these methods has led to the conceptual development of a financial and service planning tool, which has the potential to have wide practical application in the very short term. A positive approach to such a model will allow philosophical and technical debates to continue in the interim, without impeding the further development and application of useful casemix information, particularly at the hospital management level. PMID- 10117337 TI - Choosing a DRG grouper for Australia: issues and options. AB - Issues surrounding the selection in late 1990 of the New York grouper as the basis for the first Australian Diagnosis Related Group (DRG) version are discussed. The methods and results are reported for a large scale empirical study to identify the effects, based on Australian data of using different groupers developed in the United States (U.S.). The various applications of the DRG system for funding, hospital management, quality assurance and utilisation review pose different requirements for the selection of a grouper. The impact of the various options on these applications is explored along with possible future developments. This paper is an abbreviated version of an interim project report presented to the Consensus Conference held in Canberra in November, 1990. More recent results have been added here. PMID- 10117338 TI - Where are DRGs going? AB - The diagnosis related groups (DRG) classification of acute inpatient episodes was developed in the United States to meet the perceived needs of the U.S. hospital sector. Thus far, it has been used in Australia without significant modification. In this paper, we assess the DRG system in terms of basic principles of classification design and suggest some possible revisions which might be considered if there were reason to contemplate major changes for Australia. We conclude by making some suggestions on the process of managing the development of DRGs in Australia. PMID- 10117339 TI - Estimates of costs by DRG in Sydney teaching hospitals: an application of the Yale cost model. AB - The results are reported of a first round of costing by DRG in seven major teaching hospital sites in Sydney using the Yale cost model. These results, when compared between the hospitals and with values of relative costs by DRG from the United States, indicate that the cost modelling procedure has produced credible and potentially useful estimates of casemix costs. The rationale and underlying theory of cost modelling is explained, and the need for further work to improve the method of allocating costs to DRGs, and to improve the cost centre definitions currently used by the hospitals, is emphasised. PMID- 10117340 TI - Ambulatory casemix in Australia: APGs or AVGs? AB - Measurement of the ambulatory casemix of Australian hospitals is important as the next step beyond DRGs in better management of total hospital output. This paper describes and analyses two classification systems, Ambulatory Patient Groups (APGs) and Ambulatory Visit Groups (AVGs), designed by the Yale casemix development group for use in the United States. Despite their common origins, these two systems incorporate different principles of classification and of product line management in their structures. The paper evaluates the applicability of these systems in the Australian policy context and suggests modifications which might be necessary to better suit them for use in Australia. PMID- 10117341 TI - The problem of neonatal diagnosis related groups. AB - There is, as yet, no satisfactory set of Diagnosis Related Groups to measure the casemix and consumption of hospital resources in the care of newborn infants. To obtain further information, infants less than 28 days when admitted to the Royal Children's Hospital and Royal Women's Hospital, Melbourne were analysed. Both Refined Diagnosis Related Groups and Pediatric Modified Diagnosis Groups were used. Neonatal groups of the Pediatric Modified system included all infants aged less than 28 days on admission, whereas Refined Diagnosis Related Groups includes only those newborn infants who have diagnoses specific to the newborn period. Refined Diagnosis Related Groups and their higher order contained 1,237 discharges. Standard deviation and coefficient of variation and length of stay in these RDRG were high. However, if the patients in these RDRGs were further grouped according to PMDRGs, there appeared to be more homogeneous missing. The R2 values were four times higher. It is recommended that a satisfactory form of neonatal DRGs is to regroup patients in neonatal RDRGs through a PMDRG grouper. PMID- 10117342 TI - Proposed JCAHO standards changes bring welcomed consistency. PMID- 10117343 TI - Marketing quality. PMID- 10117344 TI - Managing risk in partnership with legal counsel. PMID- 10117345 TI - Spotlight on physicians shines path for Virginia hospitals. PMID- 10117346 TI - Survey finds patient reps average $30,000 annually. PMID- 10117347 TI - High tech for kids at children's hospitals. PMID- 10117348 TI - Hospital-run respite center relieves caregivers. PMID- 10117349 TI - Powder power improves spirits of women cancer patients. PMID- 10117350 TI - Should a school honor a student's DNR order? AB - Physicians first present the case of a sixteen-year-old cardiac patient who has refused a heart transplant and cardiac resuscitation. Her family and physicians accept the decision. The family has asked the school system to honor her do not resuscitate order if she goes into cardiac arrest in school The school system has refused to do so. Following the case presentation, a lawyer, a physician/ethicist, and an educator consider the important issues raised by this ongoing case. PMID- 10117351 TI - Multiple listing for organ transplantation: autonomy unbounded. AB - Recently, debate about the distribution of scarce organs for transplantation has focused on whether patients should have the right to place themselves on waiting lists at several transplant centers, thereby gaining an advantage over other potential recipients. This article explores the social and ethical issues raised by multiple listing, contrasting policies adopted at the national level with those implemented in New York State. It concludes by examining the implications of the debate for broader questions about entitlement and access to health care. PMID- 10117352 TI - Interpersonal issues in the Wanglie case. AB - The case of Helga Wanglie involved a conflict between the medical team, which concluded that a respirator was providing no medical benefit to the 87-year-old woman and should therefore be discontinued, and Ms. Wanglie's family who did not want the respirator removed. Most published commentary on the case has analyzed the medical team's conclusion. In contrast, this article examines the impact of the conflict on the conduct of the clinical case, and on the relationships among the various parties involved. PMID- 10117353 TI - The Institute of Medicine. PMID- 10117355 TI - A little clinic on the side. Should doctors profit from their referrals? PMID- 10117354 TI - Active euthanasia and assisted suicide. PMID- 10117356 TI - Medical devices; medical device, user facility, distributor, and manufacturer reporting, certification, and registration; correction--FDA. Tentative final rule; correction. AB - The Food and Drug Administration (FDA) is correcting a tentative final rule that appeared in the Federal Register of November 26, 1991 (56 FR 60024). The tentative final rule was published with some editorial errors. In the preamble under the "Paperwork Reduction Act" heading, the last two lines in the table "Estimated Annual Burden for Reporting" should have been in the table "Annual Burden for Recordkeeping". As a result, the total figures in both tables were incorrect. This document corrects the errors in these two tables. PMID- 10117357 TI - Health Resources and Services Administration; statement of organization, functions and delegations of authority--PHS. PMID- 10117358 TI - An evaluation of pharmacy assessment for geriatric patients. AB - Evaluation of a pharmacy assessment for geriatric patients on a geriatric assessment and rehabilitation unit is described. The assessment has been developed to identify functional, comprehension and therapeutic problems affecting an elderly patient's ability to self-medicate. The pharmacy assessment identified more obstacles to self-medication than the nursing and medical assessments. The detection of obstacles was particularly apparent in the areas of medication knowledge deficit, complicated medication regimes and the inability to follow directions. The pharmacist made more recommendations than the other health professionals for improving the safety and efficacy of drug therapy and medication compliance (p less than .01). Recommendations included simplification of medication regimes, requesting drug levels or specific lab tests, and the use of compliance aids. Seventy-seven percent of the recommendations made by the pharmacist were acted upon by the physician or nurse. Results of the study demonstrate the pharmacy assessment was the most significant predictor of self medication success. PMID- 10117359 TI - Observations and effects of educational consults on allopurinol prescribing. AB - Allopurinol has been used in the management of hyperuricemic states for several years. Despite its efficacy for these indications, recent concerns have been raised regarding the unnecessary morbidity and mortality occasionally associated with its inappropriate use. In an effort to assess the utilization of allopurinol, a concurrent drug utilization review was undertaken. Fifty patients who were prescribed allopurinol were entered into the study and underwent health record review and patient interview, to determine appropriateness of therapy and the need for educational intervention. A number of inconsistencies with regard to established guidelines were identified. As well, 11 of 50 patients (22%) required intervention because of either lack of indication or excessive dose. Fifty-five percent of the educational interventions, performed by the pharmacist, were accepted as written. The current utilization of allopurinol at our facility differs substantially from guidelines developed for optimal utilization of allopurinol. Further, a pharmacy based intervention program can improve prescribing practices of allopurinol. PMID- 10117360 TI - Pharmacists' activities in monitoring zidovudine therapy in an AIDS clinic. PMID- 10117361 TI - Carpet spot remover. PMID- 10117362 TI - Color in the workplace is here to stay. PMID- 10117363 TI - Children's mental health: current findings and research directions. PMID- 10117364 TI - What works for whom: the design and evaluation of children's mental health services. PMID- 10117365 TI - Special report on reimbursement. Medicare program abandons 1986 malpractice rule. AB - Hospitals with claims "properly pending" before fiscal intermediaries or in the courts need do nothing in order to obtain corrected reimbursement for fiscal years so pending. However, to speed processing of corrected reimbursements for fiscal years pending in appeals before the PRRB, hospitals should request that the Board determine its jurisdiction and remand to the fiscal intermediary for payment as soon as possible. It will be helpful to include with any such request a copy of the notice of program reimbursement and the original appeal letter for each fiscal year under appeal. Despite the fact that HCFA Ruling 91-1 effectively concedes that HCFA has applied an invalid regulation to all fiscal years since May 1, 1986, HCFA counsel have stated that HCFA will not permit reopening of closed cost reports to correct the inappropriate apportionment of malpractice insurance costs. Nevertheless, hospitals that do not presently have a claim or appeal pending have several options. Under the Provider Reimbursement Manual, HIM 15, sections 2930-2931, fiscal intermediaries are required to reopen cost reports filed within the three-year reopening period to correct errors. Accordingly, should a fiscal intermediary deny a provider's reopening request, the provider should seriously consider taking an appeal to the PRRB. The PRRB's jurisdiction to review fiscal intermediary denials of requests to reopen cost reports was affirmed by the United States Court of Appeals for the Ninth Circuit, see State of Oregon v. Bowen, 854 F.2d 346 (9th Cir. 1988), a decision that is controlling in California, Oregon, Washington, Nevada, Arizona, Montana, Idaho, Hawaii, Alaska, Guam, and the Northern Mariana Islands.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10117366 TI - Women as a business imperative. AB - In 1989, Felice N. Schwartz's HBR article "Management Women and the New Facts of Life" generated a huge debate over the rules established by corporations in their handling of women executives. Now in "Women as a Business Imperative," Schwartz follows up with practical insights about the costs companies incur in passing over qualified businesswomen. In the form of a memo to a fictional CEO, Schwartz describes how the atmosphere within most companies is corrosive to women and must change. Preconceptions harbored by male senior managers about women are so deeply ingrained that many men are not even aware of them. Yet senior managers must help women advance. Those companies that accept their responsibility to make radical change--both in women's treatment and in family support--can improve their bottom lines enormously. Treating women as a business imperative is the equivalent of creating a unique R&D product for which there is great demand. Most companies ignore child care and other family concerns. Many companies hire women to ensure mere adequacy and avoid litigation. Women's ambitions and energies are stifled by such businesses at the same time that women have demonstrated their competence and potential in the best business schools. High turnover results. However, the restraints that now hold women back can be loosened easily. CEOs and other senior managers must support their female employees by (1) acknowledging the fundamental difference between women and men--the biological fact of maternity; (2) allowing flexibility for women and men who need it; (3) providing training that takes advantage of women's leadership potential; and (4) eliminating the corrosive atmosphere and the barriers that exist for women in the workplace. PMID- 10117367 TI - The case of the hidden harassment. AB - The past year has seen a growing public awareness of sexual harassment in the workplace. The question of what constitutes sexual harassment and how to recognize it has been debated in the news, the courts, and Congress. This HBR case study is less concerned with defining it than with examining what a manager should do about it. When Filmore Trust manager Jerry Tarkwell found out one of his employees was being sexually harassed on the job, he thought he knew exactly what to do. Following company policy, he immediately notified the bank's equal employment office. Then he called Jill McNair, the employee being harassed. Her response dumbfounded him. "You had no right to call EEO before talking to me," McNair said angrily. Do you have any idea what could happen to me and to my career if people find out about this?" Tarkwell didn't understand; McNair wasn't to blame. He believed the only person who should be worried was the harasser. Tarkwell tried to spell out the procedure for her. "All you have to do is write a letter and ..." McNair cut him off. "If this gets investigated by EEO, everyone in the building could be questioned. I'll probably get transferred, and then I won't have a chance at promotion. And who'd want to work with me? Every man in the company would be afraid I'd report him if he so much as opened a door for me."(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10117368 TI - The vision trap. AB - At Mentor Graphics Corporation, Gerry Langeler was the executive responsible for vision, and vision, he discovered, has the power to weaken a strong company. Mentor helped to invent design-automation electronics in the early 1980s, and by the end of the decade, it dominated the industry. In its early days, fighting to survive, Mentor's motto was Build Something People Will Buy. Then when clear competition emerged in the form of Daisy Systems, a startup that initially outsold Mentor, the watchword became Beat Daisy. Both "visions" were pragmatic and immediate. They gave Mentor a sense of purpose as it developed its products and gathered momentum. Once Daisy was beaten, however, company vision began to self-inflate. As Mentor grew more and more successful, Langeler formulated vision statements that were more and more ambitious, grand, and inspirational. The company traded its gritty determination to survive for a dream of future glory. The once explicit call for effective action became a fervid cry for abstract perfection. The first step was Six Boxes, a transitional vision that combined goals for success in six business areas with grandiose plans to compete with IBM at the level of billion-dollar revenues. From there, vision stepped up to the 10X Imperative, a quality-improvement program that focused on arbitrary goals and measures that were, in fact, beyond the company's control. The last escalation came when Mentor Graphics decided to Change the Way the World Designs. The company had stopped making product and was making poetry. Finally, in 1991, after six years of increasing self-infatuation, Mentor hit a wall of decreasing indicators. Langeler, who had long since begun to doubt the value of abstract visions, reinstated Build Something People Will Buy. And Mentor was back to basics, a sense of purpose back to its workplace. PMID- 10117369 TI - Competing on capabilities: the new rules of corporate strategy. AB - In the 1980s, companies discovered time as a new source of competitive advantage. In the 1990s, they will discover that time is only one piece of a more far reaching transformation in the logic of competition. Using examples from Wal-Mart and other highly successful companies, Stalk, Evans, and Shulman of the Boston Consulting Group provide managers with a guide to the new world of "capabilities based competition." In today's dynamic business environment, strategy too must become dynamic. Competition is a "war of movement" in which success depends on anticipation of market trends and quick response to changing customer needs. In such an environment, the essence of strategy is not the structure of a company's products and markets but the dynamics of its behavior. To succeed, a company must weave its key business processes into hard-to-imitate strategic capabilities that distinguish it from its competitors in the eyes of customers. A capability is a set of business processes strategically understood--for example, Wal-Mart's expertise in inventory replenishment, Honda's skill at dealer management, or Banc One's ability to "out-local the national banks and out-national the local banks." Such capabilities are collective and cross-functional--a small part of many people's jobs, not a large part of a few. Finally, competing on capabilities requires strategic investments in support systems that span traditional SBUs and functions and go far beyond what traditional cost-benefit metrics can justify. A CEO's success in building and managing a company's capabilities will be the chief test of management skill in the 1990s. The prize: companies that combine scale and flexibility to outperform the competition. PMID- 10117370 TI - Creating project plans to focus product development. AB - The long-term competitiveness of most manufacturers depends on their product development capabilities. Yet few companies approach the development process systematically or strategically. They end up with an unruly collection of projects that do not match long-term business objectives and that consume far more development resources than are available. Instead of working on important projects, development engineers spend their time fighting fires. Their productivity sinks, and products are invariably late to market. To attack development malaise and reinvigorate the process, companies should put together an "aggregate project plan." The plan helps managers restructure the development process so they no longer think in terms of individual projects but in terms of the "set" of projects. It is the set, not individual projects, that shapes the creation of a successful product line. The aggregate project plan also helps managers allocate resources, sequence projects, and build critical development capabilities. A central element of the aggregate project plan is the project map. The map categorizes projects into five types: breakthrough, platform, derivative, research and development, and partnerships. Each project type has its own unique characteristics and requires a different amount of development time. Companies should have projects in all categories to ensure a robust development process. PMID- 10117371 TI - Beyond takeovers: politics comes to corporate control. AB - In the 1990s, politics will replace takeovers as the defining tool for corporate governance challenges, and a marketplace of ideas will replace the frenzied activity that once dominated the financial marketplace in the 1980s. In the transaction-driven market of the past, corporate raiders used junk bonds and other financial tools to take control of their targets. In the new marketplace of ideas, debate will replace debt as active shareholders press specific operating policies for their target corporations in a new politicized market for corporate control. John Pound, associate professor of public policy at the John F. Kennedy School of Government at Harvard, reports that investors are already using shadow management committees, independent director slates, and outside experts to influence management policy. Pound cites Carl Icahn's battle for control of USX as an example of the emerging trend. What began as a hostile takeover ended with a negotiated solution in which many constituencies ultimately played a role in the restructuring of the company. This political approach to governance gives management a chance to embrace a bargain that is in its long-term interest. By promoting politically based tactics, managers can generate political capital with their major investors. Managers in companies as diverse as Avon and Lockheed now meet regularly with investors, seeking their input on both financial and strategic decisions. In the new politicized market for corporate control, striking a bargain with long-term investors is ultimately in the best interest of the corporation. PMID- 10117373 TI - The focus of TQM. PMID- 10117372 TI - Building corporate character. Interview by Nan Stone. AB - Stride Rite is a good company by any definition: Keds, Sperry Top-Siders, and Stride Rite children's shoes are consumer favorites for their fit, quality, and comfort. Wall Street analysts praise the company's outstanding financial performance. Innovative programs such as the first corporate child-care center and public service scholarships support Stride Rite's reputation as one of the most responsible employers and corporate citizens in the United States. Behind Stride Rite's good performance are the building blocks of corporate character: a legacy of quality and service and a leader committed to keeping that legacy lively. When Stride Rite shipped its first children's shoes in 1919, they came with the company's commitment "to produce an honest quality product in an honest way and deliver it as promised." For Arnold Hiatt, that commitment has been the driving force behind the company's evolution from manufacturing into marketing and product development as well as the guiding principle in its relations with consumers, dealers, suppliers, and employees. But Stride Rite's corporate character is also a reflection of Hiatt himself. In his early 20s, Hiatt fled a management training program "designed to make carnivores" out of its new employees and bought Blue Star Shoes, a small manufacturing company that had gone into Chapter 11. Through experience and "stumbling around," he built Blue Star's sales to $5 million-and got a practical education in management, markets, and human nature that has proved equally useful in running Stride Rite. PMID- 10117374 TI - Correcting performance problems. PMID- 10117375 TI - Purchasing practices in a hospital environment: an ethical analysis. AB - The critical state of the hospital industry, as previously described, generates a difficult decision environment for the materiel manager and those in the purchasing function. The unique life- and death circumstances of hospitals impose a further onus on those who manage them. In the name of saving lives, they can find a convenient excuse to disregard all moral principles, forgetting the Socratic dictum "it is not enough that one lives, but that one lives well." Without the moral "right stuff," they can easily give in to the seductions of momentary gains and glory through ethical short-cuts. There is wisdom and consolation in the words that "nice guys may appear to finish last, but usually they're running in a different race." Studies have established a direct relationship between corporate excellence and ethical values. The reality of competition in the hospital industry dictates that the integration of ethics into the life of the organization should happen by design and not by accident. This is what is meant by strategy. If hospitals would strive for excellence to survive and grow, they should have a strategy with a mission statement that also embodies its moral values and moral agenda. Such an approach does not guarantee that an organization will become immune to moral contamination, but it does provide an antidote. PMID- 10117376 TI - The Joint Commission and quality patient outcomes: role of materiel management. AB - Again, employee orientation and ongoing education are crucial. The orientation should include not only cover protection of the employee but protection and management of supplies as they reach the consumer. The consultative role of the infection control person is also valuable, especially with regard to sterilizers and to sterilization and equipment management. Employees also need to understand the principles of effective sterilization, disinfection, and basic sanitation. There also need to be documented maintenance and surveillance of sterilization equipment. PMID- 10117377 TI - Claim substantiation in the health care industry. PMID- 10117378 TI - Maximizing purchase decision factors other than price. AB - Assessing and acquiring technology does not have to be chaotic, driven solely by price, clinical preference, and emotion. With the tools available, it can be distilled to a process of organized common sense, which results in maximum flexibility for the user and allows materiel managers to procure the best, most cost-effective equipment for the hospital. PMID- 10117379 TI - Searching the literature: more resources to make the purchase decision. AB - Searching the literature is easier than ever with the advent of CD-ROM. Cost effective and simple to use, this technology is being used for clinical patient management as well as health care administration. For the materiel manager, literature searches can provide additional information, and access to research and other data to assist in making objective, informed, defensible purchasing decisions. PMID- 10117381 TI - Nursing input into the purchase decision reveals costs not included in the price tag. AB - Working collaboratively with the institution's nurses not only will provide a more comprehensive view of products being considered for purchase but will also uncover the costs of bringing in a product that are not specified on the price tag. PMID- 10117380 TI - Making the purchase decision: factors other than price. AB - Taking price out of the limelight and concentrating on customer relations, mutual respect, and build-in/buy-in; involving the user; developing communication and evaluation processes; and being process oriented to attain the results needed require commitment on the part of administration and materiel management. There must be a commitment of time to develop the process, commitment of resources to work through the process, and a commitment of support to enhance the process. With those three parameters in place, price will no longer be the only factor in the purchasing decision. PMID- 10117382 TI - The Abbey-Shepherd device education model. PMID- 10117383 TI - Standards in health care materiel management. PMID- 10117384 TI - Career satisfaction on the decline among older physicians. PMID- 10117385 TI - Future perfect. AB - Shrunken and frail as winter birds, a tiny man and woman negotiate the short walkway and stairs to the geriatric day hospital at UTMB, Galveston. The man has one hand on his cane, the other his wife's arm--whether for gallantry or his own support is not clear. Nor is it immediately clear, once inside, that they've entered a hospital rather than a senior citizens center. Created to fill the multiple needs of a specific population, the day hospital is a modest experiment that may harbinger the future for health care delivery. PMID- 10117387 TI - With lives at stake, solutions to the trauma crisis. PMID- 10117386 TI - Matters hospitals must report pursuant to state law. PMID- 10117388 TI - Long term care: the case of the elderly. AB - Health care for the elderly in industrialized countries has been characterized by a variety of persistent myths, nurtured by an amazing blindness for facts, and pertaining to their number, the related morbidity, the models of care, the unbearable costs and the financial situation of the elderly. Today a more optimistic perspective about the elderly is emerging emphasizing an older person with a remarkable physical and mental fitness and living in satisfying housing and income conditions. There is a less alarming prognosis about the increase of the elderly population and the share of elderly in the increase of health care budgets seems to be incremental. A wide spectrum of models of care has unfolded over Europe and the plausible explanations for the differences relate to the North-South gradient, the cultural patterns, the history of the health care system and the level of economic development. Europe is focusing on community care: in northern Europe to substitute for institutional care and in southern Europe as a response to changing family patterns. There is a danger of overshooting with policies for the aged, but more than special attention is to be given to the vulnerable risk groups which are the octogenarians, suffering from dementia and poor in housing assets. PMID- 10117389 TI - The epidemiological future. AB - Forecasting the epidemiological future of industrialized countries for about thirty or maybe fifty years has been attempted. This will be determined by the future condition of relevant factors of the physical-biological, socio-economic and cultural environment of the population in question and by the socio demographic structures of the population itself. It is highly probable that substantial development in prevention and curing of diseases, and in a few cases even breakthroughs will occur in the next three decades or so. Also public awareness with respect to health promotion can be expected to rise substantially in the future. Under these circumstances health conscious behaviour and sophisticated medical technology will have a much more serious impact on the health of the population in the future than at present. The aging of the population will become faster as fertility is expected to remain constant at very low levels and mortality will become the major cause of aging. Consequently general mortality will eventually increase, yet infant mortality will further decrease and will be as low as 6.0 per thousand live births by the 2020's. Lifespan prolongation by selective dietary restrictions would become a feasible human option. If some chronic degenerative diseases will be eliminated or will be put at least under control then life expectancy at birth can be as high as 84.3 years. However, it has been suggested that delaying the progression of chronic diseases is more realistic than eliminating them. Consequently the prevalence of chronic disease in the population will increase, along with the associated costs of treatment and care. Yet another school of thinking forecasts the 'compression of morbidity'. It is an open question whether inequalities in health will increase or decrease. AIDS infection will spread dramatically, but mainly in the third world and prevention strategies will use general information, education and counselling in order to increase public awareness with respect to the chances of avoiding infection. PMID- 10117390 TI - Cross-cultural adaptation of health measures. European Group for Health Management and Quality of Life Assessment. AB - There is increasing interest throughout Europe in measuring health needs in the general population and in the 'quality of life' of patients. This has led to a demand for questionnaires capable of measuring health status in a reliable and valid manner. Most existing measures have, however, been standardised only in the U.S.A. and, to a lesser extent, in the U.K. The issue of translation and retesting of questionnaires prepared in the English language for use in other countries has received surprisingly little attention. This paper describes some of the technical, linguistic and conceptual issues raised by translation and the processes involved in producing acceptable country-specific versions of the Nottingham Health Profile according to a systematic method. PMID- 10117391 TI - Health care reform in the Russian Federation. AB - This paper discusses the reasons for and the aims of a new model of health care under consideration in the Russian Federation. The concepts on which the reform is based and the mechanisms to transit from the existing centrally planned and financed health services into more decentralized services, funded in a competitive environment from multiple sources including health insurance, are discussed. The related draft legislation is complemented with viewpoints and opinions of the author. PMID- 10117392 TI - Cost-effectiveness analysis of hypertension treatment--a review of methodological issues. AB - There is a lack of methodological conformity in cost-effectiveness analyses of hypertension treatment. They differ with respect to assumptions about the effectiveness of treatment, the outcome measure chosen, the cost-concept, the discounting of effects and the duration of therapy. The aim of this paper is to review these issues and estimate the importance of different assumptions for the cost per life-year gained. To analyse these assumptions a computer simulation model was constructed based on the Framingham logistic risk equations and Swedish cost data. It is shown that the cost per life-year gained is highly sensitive towards many of these assumptions. It is also shown that the average cost effectiveness ratios calculated in previous studies and the relevant marginal cost-effectiveness ratios can differ by several hundred per cent. The results of cost-effectiveness analyses in the hypertension field have to be interpreted with caution. Due to the lack of standardized methodology, the comparability between studies is limited. There is also a need to complement cost-effectiveness analysis in this area with other approaches, for example based on WTP. PMID- 10117393 TI - Praise, praise and more praise. Designing a creative environment in a health care setting. AB - In the first of two articles, Janet DiClaudio describes how the implementation of creative problem-solving techniques has helped to improve communications and job satisfaction with the Medical Records Department of a large general hospital. PMID- 10117394 TI - Nurse turnover costs. PMID- 10117395 TI - Ever enterprising: the NHS Training Directorate. PMID- 10117396 TI - Occupational stress in the ambulance service. PMID- 10117397 TI - President Bush joins the healthcare reform debate. PMID- 10117398 TI - Not-for-profit hospitals underuse short-term financing strategies. PMID- 10117399 TI - Patient-focused delivery promises to reshape hospitals. PMID- 10117400 TI - Telling our story. Catholics can cultivate genuine hope by emphasizing the human dimension in culture and politics. AB - In the West the experience of modernity frequently leads people to ask whether they are running things or things are running them. The answer lies in the connection between modernity and religious tradition. Are there useful and constructive and effective ways of thinking about the task of our living as though what Jesus taught and did makes sense, makes sense in a modern world that thinks and acts as if it has or will soon have all answers? Perhaps everything will turn out all right, but such optimism should not be confused with hope. As Vaclav Havel explains, hope "is not the conviction that something will turn out well, but the certainty that something makes sense, regardless of how it turns out." To cultivate a perspective from which things can make sense, Catholics need to find a way to tell their story so that it has relevance in the modern world. In particular, Catholics must find stories that will account for the shift that had been building in our culture over centuries but that the Church only fully acknowledged during the papacy of John XXIII. To some extent, the stories will have to offer a counterstatement to the unintended negative effects of certain facets of the modern agenda. The stories will have to address the overemphasis on individuality that has resulted from the democratization of politics and culture, the uncritical belief that change is always for the better, and the modern world's power to overwhelm our ability to think critically about it. Finally, the stories will have to return a human dimension to economic and cultural life. PMID- 10117401 TI - Toward a just healthcare system. AB - The U.S. healthcare delivery system is a patchwork nonsystem full of inequities, whose symptoms include the prolongation of the dying process, a lack of preventive care, and patient dumping. What can be done to make this nation's healthcare delivery system more just? The U.S. healthcare system should be modeled on the same underlying assumptions and justice-related values as the U.S. education system, a system based on need. Americans would find such a model psychologically acceptable because they are familiar with it, even though it is not perfect. Because they have the facilities and resources at their disposal, care givers must experience solidarity with all those who need care. The unity and solidarity of all creation is an explicitly Christian theme and is an appropriate value to emphasize with regard to compassionate healthcare. To establish a fairer healthcare delivery system, providers must consider their own Christian responsibilities and those of the Church, as well as the civic responsibilities of the government. If Catholic healthcare professionals do their part to change the status quo, Americans will be able to enjoy a fair system of healthcare delivery based on need, not on ability to pay. PMID- 10117402 TI - Rural healthcare needs and solutions. AB - Many rural communities are finding it necessary to create innovative ways to make healthcare more accessible to their residents. Successful rural healthcare delivery systems require the resources of an institution willing to serve the rural healthcare market, a community wanting to improve its healthcare, and dedicated practitioners. Physicians must be willing to see Medicaid and charity care patients. If physicians in the community are too busy or unwilling to accept indigent patients, the community may need more physicians. When the community recruits additional physicians, leaders must clarify that all physicians have a responsibility to serve indigent patients. As a result, a community-wide healthcare planning process is essential. Because residents might not always be aware that they should receive certain routine healthcare services or how to access those services, the community must establish strategies to reduce this knowledge gap. Urban healthcare centers can help by bringing health screening services to the rural community and by providing health education programs. Providers can close another part of the knowledge gap by helping patients fill out the insurance forms required to receive payment and by helping them find and apply for indigent patient coverage. To help solve the physician shortage problem in rural areas, communities can work with urban healthcare providers to purchase or start new practices in rural areas and then supplement the practices with additional primary care physicians or other healthcare practitioners. PMID- 10117403 TI - Hospitals on the frontier. AB - The concept of a limited service rural hospital recently gained nationwide attention when Montana introduced the medical assistance facility (MAF) model, which allows a hospital to have a license under less stringent rules (rather than close completely). The MAF is a down-scaled, limited-service rural hospital that makes extensive use of midlevel practitioners and has flexible staffing requirements. MAFs restrict admission to patients with low-intensity, acute illnesses who typically require short-term hospitalization. Montana currently has four MAFs certified as Medicare and Medicaid providers under the terms of a waiver agreement with the Health Care Financing Administration (HCFA). MAFs are located in four "frontier" communities--counties or regions with fewer than six residents per square mile. A 96-hour cap on inpatient stay effectively guarantees that the MAF's scope of services will be circumscribed. However, the array of services that meet the definition of low intensity and short term is potentially broad. The flexibility--and thus the real strength--of the MAF model is in the licensure rules, which relax some of the requirements that the small rural hospital has difficulty meeting (such as those regarding staffing). The demonstration project is now entering its final two years. So far, it has gained widespread interest and support. The central question is whether HCFA will extend the waiver after 1993. Another possibility is the reclassification of MAFs to rural primary care hospitals, which do not require waiver coverage to receive Medicare and Medicaid reimbursement. PMID- 10117404 TI - Rural hospitals' viability and strategic responses. AB - In 1989 the Catholic Health Association, in conjunction with the University of Iowa Center for Health Services Research, surveyed chief executive officers (CEOs) of rural hospitals regarding their hospital's viability and strategic behaviors and orientations. An extensive questionnaire was sent to the CEOs of all Catholic, all other religious not-for-profit, and all investor-owned rural hospitals, as well as to a 50 percent random sample of government and other not for-profit rural hospitals. CEOs on average perceived that their hospital's viability relative to that of other rural hospitals was higher in 1989 than it had been in 1987. Ninety-four percent of hospitals whose CEOs perceived an increase in viability had been medium- or low-viability hospitals two years earlier. Thus, despite reports of deteriorating conditions for rural hospitals, rural hospital CEOs appeared to be relatively optimistic regarding their institution's viability. Changes in strategic direction accompanied these perceived increases in viability. The predominant strategic orientation adopted by rural hospitals in 1987 was that of the defender, but many hospitals that used this approach switched to the analyzer orientation by 1989. Significant shifts also occurred toward the reactor orientation from the analyzer and defender orientations. A greater percentage of hospitals with a perceived increase in viability between 1987 and 1989 altered their organizational role. The most common change for these hospitals was from limited care to basic care. PMID- 10117405 TI - The changing face of rural Catholic hospitals. AB - Socioeconomic trends and developments within the U.S. healthcare system have challenged rural hospitals' ability to maintain adequate operating margins and offer needed services. However, some hospitals have fared better in this negative environment than have others. To clarify factors that distinguish the most viable rural Catholic hospitals from the least viable, our study identified a group of 30 "consistently sound" hospitals and 30 "adversely affected" hospitals based on profit margins and six other financial measures. As a group, rural hospitals suffered from declining inpatient utilization, increasing levels of indigency, and adverse reimbursement. However, the consistently sound hospitals' margins increased to 11 percent form 1985 to 1989, whereas margins at adversely affected hospitals fell nearly 8 percentage points during the same period. Adversely affected hospitals were less likely to belong to a system and had significantly fewer average staffed beds than did the consistently sound facilities. Their communities had significantly lower per capita income, and they devoted a greater percentage of their resources to care for the poor. Adversely affected hospitals also reduced the scope of available services more drastically than did consistently sound hospitals during the period under study. PMID- 10117406 TI - Nurturing the nurturers. AB - The nurse-retention problem plagues hospitals nationwide, but nowhere is the crisis more evident than in rural areas, where, if nothing is done, more hospitals likely will join the growing numbers that have simply closed. Researchers designed a study to identify effective strategies for managers and administrators to pursue in retaining nurses in rural hospitals. They asked nurses to rate 43 strategies according to the degree of influence each would have on the decision to remain on the job. "Winning" strategies fit into four major categories: (1) self- and professional development, (2) monetary needs, including benefits, (3) internal management, and (4) staffing and scheduling. Among the study's suggestions are these: Managers should increase opportunities for upward mobility to alleviate some of the nurses' frustrations at feeling trapped in one position. If a higher educational level is a prerequisite for upward mobility, hospital managers should simplify the process of obtaining that education. Rural nurses clearly do not believe they are being compensated enough for their efforts. Hospitals must respond accordingly if they intend to maintain an adequate nursing staff. Nurses want to know that when conflicts or disruptions arise, they will have a simple, direct means of resolution. Hospitals should manage conflict through communication and training and support at all primary care levels. Because nurses provide the majority of client care, they must have a more active, participative role in staffing and scheduling policies. PMID- 10117407 TI - How to strengthen ties with the Church community. PMID- 10117408 TI - Outcome data and ethics: getting doctors to pay attention. PMID- 10117409 TI - Bethany House. A long-term shelter offers abused women a chance for a new life. PMID- 10117410 TI - Easing the loneliness of death. PMID- 10117411 TI - National health care reform: three scenarios for the U.S. health system. PMID- 10117412 TI - Approaching the infant and child in the prehospital arena. PMID- 10117413 TI - Fraud alert targets ambulance services. PMID- 10117414 TI - OSHA gets tough on protecting providers. PMID- 10117415 TI - EMS in a new world order. Visiting the Commonwealth of Independent States. PMID- 10117416 TI - Mechanism of injury. Making a vital assessment tool work. PMID- 10117417 TI - Let's rock and roll. PMID- 10117418 TI - Responding to the child within. Child abuse and the EMS provider. PMID- 10117419 TI - Music therapy practices in gerontology. AB - A national survey was conducted using a representative sample of music therapists who work with older adults. The goals of the survey were: (a) to provide a profile of music therapists working with geriatric clients with respect to professional credentialing, regional membership, age, gender, educational background, salary, and reimbursement practices; (b) to provide a description of assessment practices used by music therapists with geriatric clients; (c) to provide clarification relative to how music therapy practices with elderly clients fit into various settings in which the therapist may be employed; and (d) to identify the types of goals and objectives that are most frequently specified for this population. An 87% response rate yielded 176 usable questionnaires (72% of original sample). Frequency analyses of dichotic and multiple choice responses were conducted and reported as percentages of respondents. Free response items, which were provided as opportunities for clarification and explanation, were presented as a simple frequency count. Comparative analyses between salaried and contractual respondents, and respondents in the eight NAMT regions were not conducted due to unequal sample sizes. PMID- 10117420 TI - Point of service HMO products. PMID- 10117421 TI - Health care reform under the 'Buy Right' strategy. AB - According to Walter McClure, Ph.D., the problem of high cost health insurance is not an insurance problem. It is, he says, a medical care system problem. In his in-depth article he presents his strategy of "Buy Right" as a solution to health care reform. PMID- 10117422 TI - Reviving America's failing health care system. AB - America is now at an important crossroad regarding its health care system, writes H. Wilson Graves, M.A., M.P.A., explaining that Americans increasingly see this system as a "paradox of excess and deprivation." Graves believes increased competition is the only viable alternative to revive our ailing health care system. PMID- 10117423 TI - The manager's checklist: how to keep your group legally up-to-date. AB - Most groups depend on their administrators to lead them through the maze of legal rules, regulations and arrangements that businesses in health care must now confront, writes Keith Korenchuk, J.D., M.P.H. He, therefore, presents an indispensable checklist to aid administrators in systematically keeping their group legally up-to-date. PMID- 10117424 TI - The philosophy behind setting your group's fees. AB - According to author Gregory Burgess, fee adjustments are an invitable part of practice management; therefore, increasing the odds that a payment will be allowed when increased is a necessity. His article explains how to use insurance reimbursement data to do just that. PMID- 10117425 TI - Physician services: income projection (PSIP) under Medicare reform. AB - By now, every administrator in America is well aware of the resource-based relative value scale (RBRVS) now being used for physician reimbursement. Unfortunately, many administrators are unable to predict its effects on their organization. It was for this reason, writes Mary Jo Hartwell, that the Center for Research in Ambulatory Health Care Administration developed software in 1990 to help physicians and administrators determine the potential impact of RBRVS on their group. PMID- 10117426 TI - Survey information vital to quality management in group practice. PMID- 10117427 TI - HCFA, IRS, FBI intensify fraud and abuse investigations. PMID- 10117428 TI - Readers' strategies for quality improvement. Part I. Making the grade on the long road to QI. PMID- 10117429 TI - Readers' strategies for quality improvement. Part II. How straight is the road to QI? AB - With miles to go, laboratorians are striving to negotiate the curves. Roadblocks include paperwork, lack of communication with physicians, and (of course) time and money constraints. PMID- 10117430 TI - A laboratorian calls for unionization. PMID- 10117431 TI - How to tell when it's time to replace your laboratory computer. PMID- 10117432 TI - Job-sharing: an innovative approach for administration. AB - A job-sharing arrangement for the Assistant Directors of Physiotherapy at the Royal Jubilee Hospital proved to be an innovative and successful experience demonstrating the feasibility of job-sharing at administrative levels in rehabilitation. Physiotherapy is traditionally a female dominated profession. By the time therapists are most highly skilled and clinically experienced, they have arrived at prime marriage and child-bearing years. Many valuable members are lost to the profession each year as therapists leave the work force to take care of their families, continue their education and participate in recreational activities. Alternative employment opportunities are needed to retain and return therapists to the work force. Convenience of work time is often important. Financial expectations may become a secondary consideration. A search of the literature revealed that while job-sharing has much to recommend it, it is not yet generally accepted in most health professional situations. A few anecdotal references described job-sharing in nursing. An industry-wide literature search revealed few references to the application of job-sharing at administrative levels. PMID- 10117433 TI - Water, water everywhere, but not a drop to wash in. AB - Could you continue operating under mandatory water restrictions? During a drought, textile rental operations can expect mandatory water cuts of 10% to 20% or more. If you're already running a tight ship and not wasting water, you may think you have no choice but to reduce the poundage of fabric processed. Not so. Here are some simple procedures to help you conserve water every day. PMID- 10117434 TI - Reusables win a battle over disposables. AB - The time is right to market the environmental benefits of reusable textiles. Take it from Stan Wiener, director of sales for Unitex Textile Rental Services, Mount Vernon, N.Y. Wearing one of his company's reusable cloth examination gowns, Wiener made a sales call to a leading New York health services center. Persuaded by the environmental friendliness of reusables, the health center made the switch from paper gowns and has realized a 5,000-lb. reduction in disposable trash. PMID- 10117436 TI - No sale on medical reform. PMID- 10117435 TI - OSHA gets into dirty laundry. AB - Second of a three-part series on the new bloodborne pathogens rule, this article covers exposure control plans, personal protective equipment for laundry workers, and compliance monitoring. In short, the rule mandates more record keeping for employers and less exposure for employees. By May 5, every laundry with employees who could "reasonably anticipate" coming into contact with blood-soiled linen and needles or sharps must establish a written exposure control plan. Turn to page 60 for information to help you get into compliance. PMID- 10117437 TI - Decision-making participation patterns: the role of organizational context. AB - Patterns of employees' participation in a number of specific decisions were studied in 101 Oregon nursing homes. The inquiry concerned whether such patterns vary according to the contextual properties of facility size, skill level, and profit-making orientation. Although interaction effects varied, main-effect results were strong. PMID- 10117438 TI - Which comes first--the paycheck or the career? PMID- 10117439 TI - Urban healthcare in crisis. PMID- 10117440 TI - Atherectomy tools for arterial treatment. AB - When considering limb salvage in patients with failed bypass or angioplasty, the threshold for cost effective use of atherectomy devices is important. Rotational ablation, in these cases, has offered a significant contribution to patient care. Decreased hospital stay, morbidity and mortality, plus improved quality of life are all factors in the calculation. Interventional radiologists, vascular surgeons and interventional cardiologists aim to maintain function, not to perfectly restore original anatomy. In this respect, percutaneous rotational ablation has a role as a useful device when indicated. Indications should include consideration of the pattern of disease and underlying pathology as much as the site and selection of the lesion. The Rotablator may be the device of choice in many coronary cases and it is an important device in planning peripheral revascularization procedures. It provides an option for patients and physicians who wish to achieve minimal invasion with the best possible results. PMID- 10117441 TI - A national PET utilization forecast. PMID- 10117442 TI - The team approach. PMID- 10117443 TI - Radiology reporting--a concatenation. PMID- 10117444 TI - Reducing repeat films through a total quality management approach. PMID- 10117445 TI - Department directors stand on common ground. PMID- 10117446 TI - Buyers' Guide supplement. AB - The following supplement is to accompany the Buyers' Guide appearing in the December, 1991 issue of Administrative Radiology. Several companies contacted us after publication date, stating they wished they had been included or that information that was included was inaccurate or out-of-date. Please take note of these corrections and additions to December's guide. PMID- 10117447 TI - Patient power: a commentary. PMID- 10117448 TI - Problems of hospital management in China. PMID- 10117449 TI - The Beijing Health Administrative Staff Training Centre. PMID- 10117450 TI - Consultation and capital works: a recipe for implementing change. AB - When the Royal Children's Hospital launched into a $50 million building/refurbishment program in 1987/88, there was a clear recognition of the need to establish appropriate consultation mechanisms with unions and employees. Little documentation existed on major capital works consultation models. As Monash Medical Centre and Western Hospital were involved in major projects, discussions took place between the three hospitals and the Health Department Victoria, which resulted in a model (based largely on Monash's existing arrangements), capable of being applied across the hospital field. This model was subsequently ratified by the Victorian Trades Hall Council on behalf of the unions, and implemented (with minor differences in each case) at the three hospitals. The purpose of this paper is to document this consultation model. Highlighted is the importance of tight project management, regular communication, and substantial involvement by staff affected in the area(s) under development in 'user groups'. As the model has been agreed by the Trades Hall Council for use in Victorian public hospitals, it is hoped that this paper may provide a useful basis for other hospitals contemplating major capital works. PMID- 10117451 TI - A participative approach to organisation restructuring: a case study from the Silver Chain Nursing Association (Inc). AB - This case study examines the review of the corporate structure of the Silver Chain Nursing Association. The design and conduct of the review process and the issues are discussed in the context of recent research and the published experiences of other organisations undergoing similar changes. The review was pro active in that the restructuring was carried out in anticipation of changes in the external environment (eg: increased service demand and decreased funding) and issues in the internal environment (eg: decreased flexibility of labour and a dilution of the service ethos). The significant feature of the review design was allowing employees to have an opportunity to define the issues requiring change; generate and evaluate opportunities for improvement; and recommend a new organisation structure. It is concluded that in a properly designed and managed process and provided with adequate information, employees are quite capable of making objective and well informed contributions about how their organisations can best operate. Participation appears to have facilitated better quality decisions and timely, acceptable implementation plans. PMID- 10117452 TI - A model of continuous quality improvement for health service organisations. AB - Continuous Quality Improvement (or Total Quality Management) is an approach to management originally used in manufacturing and now being applied in the health services. This article describes a model of Continuous Quality Improvement which has been used in NSW public and private hospitals. The model consists of Ten Key Elements. The first driving force of this model is 'defining quality in terms of customer expectations' of quality. The second driving force emphasises that 'quality improvement is a leadership issue'. Leaders are required to: coordinate staff participation in work process analysis; train staff in the customer service orientation; lead effective meetings and negotiate with both internal and external service partners. Increased staff motivation, quality improvement and reduction in running costs are seen to be the benefits of CQI for health service organisations. PMID- 10117453 TI - The New South Wales Resource Allocation Formula: a method for equitable health funding. AB - The Resource Allocation Formula has been developed to guide the allocation of health resources in NSW. The aim of the formula is to achieve a more geographically equitable distribution of resources compared to the concentration of facilities which resulted from the historical method of allocating on the basis of past expenditure. A key innovation in the formula is the separation of funding for tertiary referral services using Diagnosis Related Groups. Tertiary services are funded separately and assessed on the present and projected statewide activity levels. By contrast, primary and secondary health services are to be funded on the basis of adjusted population relativities. The formula, which has been approved for use in NSW sets notional target shares for each Area and Region ten years hence. Implementation of these shares is to be achieved through a progressive redistribution of funds. PMID- 10117454 TI - Assessing staff morale through a staff opinion survey. AB - This paper reports the results of a staff opinion survey conducted at a 309-bed Victorian public hospital. The reasons for the survey were to measure staff morale and attitudes across all the departments of the hospital. Staff members were able to participate in the survey, by completing a questionnaire which was distributed to all staff. The overall results indicate that staff members of Frankston Hospital consider they operate in a healthy working environment. Staff from some departments within the hospital responded to several questions in a manner that required further investigation. These have since been actively discussed and decisions taken to overcome them. PMID- 10117455 TI - Mental health, HIV and AIDS: a review of the literature. AB - HIV/AIDS is one of the major issues to be faced by the mental health care sector over the next decade. Many mentally ill people already have or will become infected with HIV due to a range of factors including lack of information and poor risk prevention skills. Others without a previous history of mental illness will develop mental health problems because of the effects of HIV on the CNS. Most people with HIV/AIDS will also experience severe depression and anxiety related to their infection while others will develop AIDS related dementia. HIV/AIDS related training is necessary for mental health professionals so that people with HIV/AIDS are given high quality non-discriminatory care. The need for further research in the area of HIV/AIDS and mental health is also discussed. PMID- 10117456 TI - Performance appraisal for medical staff. AB - Traditionally, selection and appraisal of young doctors has been subjective and based on impressions gained by senior colleagues. This paper outlines the features of the performance appraisal (PA) system used for junior medical staff in one West Australian teaching hospital and evaluates it against published standards of modern human resource management. It is found that this PA system in common with many such systems used around Australia falls far short of the ideal in terms of its benefits to the doctor being evaluated, the supervisors and the employing hospital. Furthermore, lack of objective assessment against set criteria could lead to difficulties in the hospital defending itself against allegations of discrimination or unfairness. Hospital managers responsible for junior medical staffing should consider as a matter of urgency the adequacy and appropriateness of their PA systems. PMID- 10117457 TI - Performance indicators--their place in health care evaluation. AB - OBJECTIVE: To report on some of the more important performance indicators used at St Vincent's Private Hospital, Sydney. METHOD: Clinical data collected using DRG technology is reviewed by the Clinical Review Committee and its subcommittees. Administrative data and consumer satisfaction sampling by questionnaire are used to provide other performance indices. Performance indicators are reviewed on a quarterly basis to assess quality of care. The importance of definitions and subset analysis is emphasised and the cost effectiveness of using DRG technology to retrieve data is presented. CONCLUSION: Performance indicators are a cost effective, sensitive tool to assist in the evaluation of the quality of health care. PMID- 10117459 TI - Perspectives. Chest pain centers providing relief. PMID- 10117458 TI - Preparing for a hospital merger challenge: a practical approach. PMID- 10117460 TI - Perspectives. Liability lawsuits: casting a wider net. PMID- 10117461 TI - Perspectives. Slow progress against infant mortality. PMID- 10117462 TI - The emerging healthcare environmental manager. AB - The following speech was delivered in November 1991 by Dr. Lerner at the New England American Society for Healthcare Environmental Services [ASHES] regional conference. It concerns issues vital to the management of environmental and occupational health and safety in healthcare facilities and should be read by hazardous materials managers and hospital CEOs alike. PMID- 10117463 TI - The final bloodborne pathogens standard: risk assessment and cost estimates. PMID- 10117464 TI - Allocating joint costs. PMID- 10117465 TI - Just-in-time inventory. PMID- 10117466 TI - Statement of organization, functions, and delegations of authority; freedom of choice waivers--HCFA. PMID- 10117467 TI - Pharmacy's lifeline to the North. PMID- 10117468 TI - Ministering to people in crisis. PMID- 10117469 TI - A call to heal. PMID- 10117470 TI - Coors Wellness Center--helping the bottom line. PMID- 10117471 TI - Multiple HMO/indemnity plan supplement design: a managed care strategy for employers with high HMO enrollment. AB - This article outlines a health care benefits strategy that combines features of the multiple HMO choice approach and the point-of-service approach. Although this plan design may not be appropriate for all employers, it may provide the greatest long-term cost savings for employers with high HMO enrollment, according to the author. PMID- 10117472 TI - Are financial incentives for wellness fair? AB - Employers have shown considerable enthusiasm for programs that use financial incentives to stimulate health-related changes in employee behavior and lifestyle. This article raises fairness issues in relation to these programs. PMID- 10117473 TI - NFPA 1581. Here's a rundown of the NFPA's standards for infection control. AB - NFPA 1581 is an important adjunct for those developing or updating their infection-control programs. This document, along with the OSHA regulations, will help you format your program. NFPA 1581 offers firm, clear specifics for fire departments. To obtain a copy, write to the National Fire Protection Association, P.O. Box 9101, Quincy, MA 02269-9101. PMID- 10117474 TI - No way out. A small town copes with its first major disaster. PMID- 10117475 TI - Thriving here in Allentown. Regionalized poison care is an accepted standard in these Pennsylvania counties. PMID- 10117476 TI - Splendid spaces. AB - Welcome to FM's third gallery exhibit of visually impressive & beautifully functional noncommercial foodservice design projects. The five new & renovated facilities on display are among the most interesting recent designs formulated to solve operational problems such as congested flow, restricted space and poor lighting. Wander through the gallery & observe how careful planning & architectural ingenuity have been arranged to create striking compositions of splendid space. PMID- 10117477 TI - Building better vendor relations. PMID- 10117478 TI - St. Anthony's rises to the challenge. PMID- 10117479 TI - On the road to TQM. PMID- 10117480 TI - Medical gas mix-up implicated in patient death. PMID- 10117481 TI - Pursuing cancer research despite limited funds. PMID- 10117482 TI - Building a research program. Interview by Donald E.L. Johnson. AB - Faced with shrinking funds for medical research, hospitals have had to evaluate the role of research and reexamine how research programs are funded and structured. In the following interview with Health Care Strategic Management's Donald E.L. Johnson, Jan R. Jennings, president of Millard Fillmore Hospitals in Buffalo, N.Y., discusses how critical a research program is to a teaching hospital. The major benefits are improving the quality of care and creating a more dynamic and stimulating environment. But there are pitfalls, as well. Clinical research must be run with strict financial discipline and monitored from ethical and legal standpoints. PMID- 10117483 TI - Health care reform: how hospitals, physicians should prepare. AB - As the momentum behind health care reform continues to build, hospitals should take specific steps to prepare for each likely scenario. The authors speculate about what form health care reform will take, discuss the strategic implications of each scenario and suggest steps hospitals should take, including an analysis of hospital/physician integration, marketing, services and efficiency. PMID- 10117484 TI - Check great data on pharmacy departments. PMID- 10117485 TI - Planning indicators. HMOs more profitable in 1990 than 1989. PMID- 10117486 TI - Dan M. Bowers on access control systems and industry trends. AB - The Bowers Report, Randallstown, MD, has announced the publication of the fifth edition of Access Control and Personal Identification Systems: Buyer's Guide and State-of-the-Art Report. The report provides information on access control techniques, devices, systems, and equipment--including card access, proximity readers, physical attributes, and computer security systems. In this interview, Dan M. Bowers, consulting engineer, discusses the latest trends in the access control industry and gives some advice to those thinking of purchasing an access control system. PMID- 10117487 TI - Special report: controlling aggression in hospitals--what security officers must know to avoid physical attacks. AB - Threats to the safety of security officers by persons they encounter in confrontational or potentially confrontational situations are an ever-present danger. This potential for physical violence can take place in the lobby, cafeteria, halls, elevators, or the parking lot of any corporate entity, not just hospitals. In hospitals, however, this danger is compounded by psychiatric patients and other hospital patients under stress. Hospital security personnel are often called to defuse potentially violent patient situations. Further compounding this risk of violence are increases in cutbacks in hospital personnel. Therefore, programs that teach hospital staff members how to control aggression will become increasingly important. Among the organizations have made a reputation for training security professionals and others in preventing and dealing with violence are R.E.B. Security Training, Inc., Avon, CT, and Wickersty & Associates, Inc., Bladensburg, MD. R.E.B. offers a two-day course in nonverbal communication that is taken by police officers and security directors. According to Ronald W. Ouellette, president, the course has also been attended by nurses, doctors, ambulance drivers, and psychologists. Wickersty & Associates has been conducting "Controlling Aggression" workshops in health care facilities for the past 12 years. According to Dr. Allan Wickersty, more and more hospitals are hiring consultants to teach staff members how to deal with aggressive behavior. But hospital violence remains an underreported problem. "One thing I have noticed is that the type of hospital experiencing violence is changing.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10117488 TI - Analyzing and reporting costs. PMID- 10117489 TI - You control your destiny. PMID- 10117490 TI - Eight tips for reducing labor costs. PMID- 10117491 TI - Closures and mergers of VNA home care agencies: a model for the study of causal factors. AB - Recent closures and mergers of visiting nurses associations (VNAs) raise some potentially serious questions regarding access to home care for the elderly Medicare and Medicaid populations. While VNAs comprise less than 10 percent of the nation's certified home health agencies, they provide approximately 31 percent of all medicare home care (HCFA, 1989). In March of 1986 there were 524 visiting nurses associations nationally whereas today there remain only 495 (HCFA, 1990). A model identifying potential causes of VNA mortality is presented along with some preliminary results. VNA mortality is defined and measured by the date that Medicare certification is terminated as a result of VNA closure or merger. PMID- 10117492 TI - Service consumption patterns over time among adult day care program participants. AB - A study of 59 adult day care (ADC) programs funded by area agencies on aging in Pennsylvania provides data which profiles the classic package of ADC services utilized by elder participants and traces the relationship between formal service consumption and the helping behaviors of family caregivers. Elder clients rejected 1 or more services offered by ADC staff 59% of the time. Consumption of homemaking, transportation, and counseling services escalated over time although total formal services used remained minimal. Family helpers performed both a greater range and intensity of support functions as compared to ADC programs (p less than .001). Program strategies and future research directions are suggested. PMID- 10117493 TI - Legal and ethical issues in family caregiving and the role of public policy. PMID- 10117495 TI - Rural home health care workers' attitudes toward the elderly: a replication study. AB - We collected data from 548 rural home health care workers in Southern Illinois in 1990 to replicate a study conducted in 1988 designed to identify and assess the attitudes of those workers toward the elderly and their elderly clients. Subjects were asked to respond to a fifteen item, self-report questionnaire. Reliability of the scale was estimated at .79, using Cronbach's alpha. Readability was estimated at the sixth-grade reading level as measured by the SMOG Readability Formula. Chi-square statistics were used to determine whether there were any differences between the 1988 and 1990 data sets, with a significance level of .003, using the Bonferroni correction procedures. Results were similar for both the 1988 and 1990 data sets. For example, whereas 31.8% of the 1988 respondents agreed with the statement: "most of my clients are pretty much the same," 30.5% of the 1990 respondents agreed. The findings from this study indicate that attitudes toward the elderly among this population of home health care workers have remained relatively consistent over this two year period. PMID- 10117494 TI - Transitions of older adults to home care. AB - To discover the process of admission and transition of older adults to home care following hospital discharge, or during periods of illness, ethnographic methodology was used to explore the experience of 65 participants in the "culture" of home care: patients, families, nurses, home care staff, and discharge planners. Two themes resulting from ethnographic analysis are presented: identification of patients and needs, and transfer of information. Support from family and friends was an essential addition to referral by discharge planners, physicians, and casefinding in facilitating transition to home care. Accurate, timely patient information was found to expedite home nursing assessment and insure continuity of care. PMID- 10117497 TI - Forward march. PMID- 10117496 TI - Determinants of hospice utilization among terminally ill geriatric patients. AB - Terminally ill geriatric patients have been found to prefer the type of care provided by home health hospices to the life-sustaining technologies received in hospitals. Nevertheless, disproportionately few dying elderly patients enroll in available hospice programs despite their preferences for, and Medicare's coverage of, hospice services. This study examines several critical factors expected to facilitate or inhibit the utilization of home-based hospice services. Seventy-six critically ill aged patients, their physicians and primary caregivers (e.g., family members) were interviewed about their attitudes and actions regarding the treatment of dying patients. The results indicate that patients who acknowledge their terminal health status, whose physicians disclose the terminal prognosis to them and do not fear malpractice, whose primary caregivers know about hospice and believe the patient would be receptive to enrollment in such a program, have a relatively high probability of home health hospice utilization. PMID- 10117498 TI - Ignorance and apathy. PMID- 10117499 TI - Spirit of trust. PMID- 10117500 TI - Healthcare in Europe: Sweden. Money, money, money. PMID- 10117501 TI - Hard and fast. PMID- 10117502 TI - Think big, act small. PMID- 10117503 TI - Gang mentality. PMID- 10117505 TI - Party lines--election focus. PMID- 10117504 TI - Spoil for choice. PMID- 10117506 TI - In-house group infuses comfort while bringing dialysis area up to code. PMID- 10117507 TI - Armed security officers in health care settings: deterrents or detriments? PMID- 10117508 TI - Retrofitting ballasts may pose PCB-disposal woes. PMID- 10117509 TI - Hard times, soft market for office equipment, furniture. PMID- 10117510 TI - OSHA to develop second lead-exposure standard. PMID- 10117511 TI - How to shut down your steam boiler for summer. PMID- 10117512 TI - How to set up an office-paper recycling program. PMID- 10117513 TI - Monitrend II offers third-quarter operations data. PMID- 10117514 TI - Need for persuasion. PMID- 10117515 TI - What's the question? AB - Current reform proposals won't get the political or popular support needed for adoption. A different approach is needed. PMID- 10117516 TI - More rights, less justice. AB - Reforms based on a "right" to health care divert attention and resources from more effective ways of improving health. PMID- 10117517 TI - Looking for leadership. AB - Despite campaign rhetoric, large reforms are unlikely without political leadership, cooperation and public consensus. PMID- 10117518 TI - Consumers vs. other interests. AB - We have to choose to protect the interests of the insurance and health-care industries or the interests of everyone else. PMID- 10117519 TI - Keeping score. PMID- 10117520 TI - Medicare HMOs: America's seniors are the next major market for managed care. PMID- 10117521 TI - Hospital governance: problems and prospects for health services research. PMID- 10117522 TI - What do we really know about the impact of boards on nonprofit hospital performance? PMID- 10117523 TI - Health insurance in the health administration curriculum. AB - Managers and policymakers knowledgeable in the delivery and financing of health care are needed in the health care industry, and health administration programs can meet this need by expanding course offerings which consider the role and operations of insurers. This paper surveys the major topics in the field of health insurance and presents a course overview for an introduction to the field of health insurance for health administration students. PMID- 10117524 TI - Assessing the continuing education needs of long-term care administrators in Ontario: results of a survey. AB - This article reports the results of a 1989 survey of the professional characteristics and educational needs of 429 managers and supervisors in long term care institutions and community-based service agencies in greater metropolitan Toronto. The data identify important gaps in the professional training of these administrators: while two-thirds report attainment of postsecondary education credentials, the remaining third, including a quarter of senior managers, have no formal college or university training. Moreover, of those with postsecondary credentials, only a minority are trained in health or human services and administration--skills and knowledge areas key to establishing and managing a client-centered continuum of long-term care. The data also demonstrate that there is widespread support in principle and practice among current administrators in the Toronto region for programs of education which address the particular challenges of long-term care administration, and that specific credentials in the field are seen as a future requirement for promotion to management positions. Preferred modes of education program delivery are short, intensive seminars and night classes. PMID- 10117525 TI - Health administration education for the learning organization: shifting the educational paradigm. PMID- 10117526 TI - The Baxter Foundation Prize address. Health services research and cost of care. PMID- 10117528 TI - Charge! FDA recommendations for maintaining defibrillator readiness. PMID- 10117527 TI - The Andrew Pattullo Lecture. Education and the health professions for the next generation. PMID- 10117529 TI - Clot busters. The future of EMS thrombolytics. AB - The importance of early identification and treatment of patients experiencing an AMI is clearly beneficial. Studies have shown that the time from pain onset to hospital administration of thrombolytic therapy can be reduced simply by early identification of patient eligibility by paramedics and notification of the receiving hospitals--as well as more efficient patient management after arrival at the ED. The limitations of thrombolytic therapy also may be related, in part, to patient denial of symptoms and reluctance to seek emergency assistance. To widen the net of patients who can receive thrombolytic therapy, extensive research has been and is being conducted to integrate the prehospital phase into the treatment window. The practicality of upgrading all EMS systems to provide thrombolytic therapy depends on many factors. EMS directors must accept the responsibility for the prehospital care delivered. Although the diagnostic accuracy is high and complications are relatively low when compared to the risk, the current legal environment in the United States may limit the willingness of some directors to promote a prehospital thrombolytic program. Additionally, the low yield of patients may not justify the significant capital outlay required to adequately train personnel and outfit ambulances with required telemetry systems. At a minimum, however, EMS programs can improve their ability to rapidly identify those patients who may be eligible for thrombolytic therapy. PMID- 10117530 TI - AED (automated external defibrillators). A physician's responsibility. PMID- 10117531 TI - What you must know to crack the new codes. PMID- 10117532 TI - What makes you vulnerable in an informed-consent suit? PMID- 10117533 TI - HMOs try to measure (and reward) "doctor quality". PMID- 10117534 TI - Let's stop terrorizing doctors-in-training. PMID- 10117535 TI - What happens when an NP competes with doctors? PMID- 10117536 TI - Time for a fresh look at hospital bonds. PMID- 10117537 TI - How "advance directives" can ease your burden. PMID- 10117538 TI - Britain's doctors and patients near a turning point. PMID- 10117540 TI - Our cost-containment efforts are doomed to fail. PMID- 10117539 TI - Want these people running our whole health system? PMID- 10117541 TI - Will private insurers start paying like Medicare? PMID- 10117542 TI - Get your office ready for Uncle Sam's new rules. PMID- 10117543 TI - How megaclinics are building competitive clout. PMID- 10117544 TI - Group's survey blasts Texas not-for-profits. PMID- 10117545 TI - HME dealer files second suit against Fla. hospital. PMID- 10117546 TI - Michigan-based health data firm is latest acquisition by HCIA. PMID- 10117547 TI - Abbott terms hospital products market 'soft'. PMID- 10117548 TI - Radiation Care to diversify into diagnostics as heat builds over physician ownership strategy. PMID- 10117549 TI - Bronx-area hospital plans AIDS center for children, families. PMID- 10117550 TI - Oregon says rationing plan will carry smaller price tag. PMID- 10117552 TI - Dems to Bush: got a better idea? Send us a bill. PMID- 10117551 TI - Ohio, Wis. bills would give hospitals antitrust immunity. PMID- 10117553 TI - GAO wades into power struggle over military managed-care plan. PMID- 10117555 TI - N.Y.C. facility fails JCAHO survey. PMID- 10117554 TI - Long-term care begins to emerge as an issue in health reform debate. AB - With the recent introduction of long-awaited legislation based on recommendations from the Pepper Commission, long-term-care reform may finally be getting more notice on Capitol Hill. But with the White House and the presidential candidates showing little interest and with attention fixated on acute-care reform, those in the long-term-care arena see little chance for any changes soon. PMID- 10117556 TI - Republic's out of the ordinary with pick of OrNda as new name for company. PMID- 10117557 TI - State legislators calling for more, less in pursuit of universal access to care. AB - In what may be partly the result of election-year politics, state legislators are following somewhat schizophrenic paths in pursuit of universal access to healthcare. While more states are expected to allow "bare bones" health coverage, thus lowering premiums and making insurance more affordable, lawmakers also continue adding to the mandated benefits many say boost costs and increase the uninsured. PMID- 10117558 TI - Nursing shortage! Nursing shortage? It seems to depend on who's talking. AB - What's the condition of the nursing shortage in America? Is it over? Is it still worsening? Was the problem exaggerated in the first place? Definitive answers don't come easily. Depending on whose statistics you use or the interpretation of the information, the answers can be quite different, as an examination of American Hospital Assn. and American Nurses Assn. data shows. PMID- 10117559 TI - For bondholders, limited access to executives often raises red flag. AB - When a hospital's bondholders hear that their facility is struggling financially, they want information. When a facility's chief executive officer doesn't let them talk to decisionmakers, such as board members and the medical staff chief, they feel like they're being denied information. This can come back to haunt the hospital that has to sell more debt in the future. PMID- 10117561 TI - N.J. governor's insurance proposal gets great rating from Blues, thumbs down from others. PMID- 10117560 TI - HCFA to review denial of Calif. plea to change pay plan for state homes. PMID- 10117562 TI - Colorado considers establishing its own health plan for needy. PMID- 10117563 TI - FDA withholds approval of anti-infection drug; manufacturer's stock price plunges. PMID- 10117564 TI - NME tells plan to take $250 million charge. PMID- 10117565 TI - Fla. system seeks antitrust probe. PMID- 10117566 TI - Humana's enrollment slips in Tampa, San Antonio. PMID- 10117567 TI - Justice Dept. to aid Fla. 'whistleblower' case. PMID- 10117568 TI - Ruling on Medicare lithotripsy rate will send HCFA back to start. PMID- 10117569 TI - S&P downgrades beat upgrades 3-to-1. PMID- 10117571 TI - Ohio Blues plan to appeal jury verdict to award W.Va. hospitals $22.4 million. PMID- 10117570 TI - Calif. jury clears Blues on UR call. PMID- 10117572 TI - 'Location, management key to PPS results'. PMID- 10117573 TI - Not-for-profits get until Sept. 1 to shed questionable ventures. PMID- 10117574 TI - Centacor stock dips again after articles on Centoxin. PMID- 10117575 TI - Survey casts shadow on long-term-care plans. PMID- 10117576 TI - Minn. hospitals likely to fight proposed tax. PMID- 10117577 TI - HCA boosts earnings, reduces debt in first quarter since going public. PMID- 10117578 TI - Keeping an eye on Kaiser the giant. AB - The Kaiser name is everywhere in California, and because of its size, competing hospitals tend to keep close track of what the company is doing. Through mergers and affiliations, more facilities are building the marketing and financial muscle needed to do battle with the giant. Meanwhile, as Kaiser has expanded outside the West Coast, struggles have accompanied the successes. PMID- 10117579 TI - IRS guidelines foster self-examination. PMID- 10117580 TI - Consumer group charges insurers wasted $16.7 billion on administrative expenses. PMID- 10117581 TI - Iowa hospitals' charges, lengths of stay are lower than national averages. PMID- 10117582 TI - Capital transition period needs strong start. AB - The blending of hospitals' capital payments from Medicare with reimbursement for treatment won't be completed until the year 2002. But good recordkeeping will be critical for how hospitals will fare during the 10-year transition period, states Ronald Sutter. In fact, hospitals are already entering an important time frame in the transition process. PMID- 10117583 TI - Latex gloves fingered in allergic reactions. AB - As more hospital workers don disposable latex examination gloves, reports of serious reactions and at least 16 deaths from latex allergies are being noted. Symptoms of latex allergy range from mild eczema to hives, welts and anaphylaxis. A rise in such incidents is of great concern for hospitals, which are expected to spend more than $500 million on latex examination gloves this year. PMID- 10117584 TI - HHS judge lowers boom on hospital that curbed HIV-positive pharmacist. PMID- 10117585 TI - Twin Cities merger clears federal hurdle. PMID- 10117586 TI - Credit firm sees steady rise in speculative-grade ratings. PMID- 10117587 TI - Derwinski's VA facility-sharing idea revived on Capitol Hill. PMID- 10117588 TI - VA hires outside firm to review its medical care systemwide. PMID- 10117589 TI - Charter settles ESOP suit for $82 million, advancing another step toward debt restructuring. PMID- 10117590 TI - Legacy Health System retooling to integrate its staff, services. PMID- 10117591 TI - Voluntary guidelines released to aid auditing of hospital bills. PMID- 10117593 TI - Disaster plan aids L.A. hospital in riot. PMID- 10117592 TI - HealthTrust boosts debt offering. PMID- 10117594 TI - Vacancy rates drop for most allied health professions. PMID- 10117595 TI - Columbia Hosp Corp. plans to buy Basic American in deal valued at $300 million. PMID- 10117596 TI - Insurers' trade group offers its own numbers to fend off administrative cost charges. PMID- 10117597 TI - Community kept in the dark will rise up against a merger. PMID- 10117598 TI - A rough ride during rural test drive. AB - A federal model to create alternative rural hospitals is stalled because of confusion and distrust. The model, frequently referred to as "each/peach," was funded to the tune of $9.8 million as an effort to ensure that a full range of care is available in rural areas. But questions and doubts swirl around the program, and some hospitals are declining to spend their grant money or are returning funds to HHS. PMID- 10117599 TI - Handful of states continuing to build their own models for alternative rural hospitals. PMID- 10117600 TI - Rochester health plan studied as a model for national reform. AB - Rochester, N.Y., which has experienced success in controlling healthcare costs while providing widespread access to care, is being studied as a possible model for national healthcare reform. Because of efficiencies in its system, employers there have been able to save hundreds of millions of dollars in recent years. But some say the city has benefited from special circumstances that may not last much longer. PMID- 10117601 TI - Healthcare fraud, abuse tab may hit $100 billion. PMID- 10117602 TI - Hospitals' profits highest since mid-1980s. PMID- 10117603 TI - Three hospitals lost JCAHO accreditation. PMID- 10117604 TI - Milwaukee network would be a first. PMID- 10117605 TI - Owing patients an explanation. AB - Some hospitals are trying to improve relationships with patients by making their bills easier to understand or providing material that helps patients make sense of those pages of charges. These hospitals are trying to make a patient's last contact with a facility a more pleasant one, to deflect arguments over bills and accelerate payments. PMID- 10117607 TI - Small-group reform targeted. PMID- 10117606 TI - Public ownership helps boost HMOs' profits. AB - Health maintenance organizations have found that the route to faster growth and better profitability may be turning into a for-profit business and issuing stock. For the past five years, such organizations have generally outperformed their older, not-for-profit counterparts that rely on debt to fuel growth. Since 1988, HMOs have completed 48 stock and debt offerings, raising $3.6 billion. PMID- 10117608 TI - Vermont providers face mandatory spending caps. PMID- 10117609 TI - Stark bill would require electronic claims process. PMID- 10117610 TI - Baxter initiatives aim to give growing non-hospital business more liberty to go its own way. PMID- 10117611 TI - Planned merger in Minneapolis will form state's largest HMO. PMID- 10117612 TI - HCFA narrows scope of data base project. PMID- 10117613 TI - Samaritan Foundation revives deal to sell five nursing homes to REIT. PMID- 10117614 TI - Fraud alert targets incentives to physicians. PMID- 10117615 TI - View mixed on new foray by Baxter. PMID- 10117616 TI - Group criticizes change in format for reporting actions against docs. PMID- 10117617 TI - Skeptics cool to peer-review revamp. PMID- 10117618 TI - Moody's returns to Mich., downgrades 5. PMID- 10117619 TI - Report totals up Mass. hospitals' impact. PMID- 10117620 TI - L.A. hospitals work to recover from violence. PMID- 10117621 TI - S.D. hospital escalates market battle by publicizing rivals' prices. PMID- 10117622 TI - NME launches three-phase systemwide recycling program. PMID- 10117623 TI - Bush sends small-group reform proposal. PMID- 10117624 TI - Employers unsettled on reform direction. PMID- 10117625 TI - Panel urges consolidation of surveys faced by hospitals. PMID- 10117626 TI - Safe ventures with doctors take money out of equation. PMID- 10117627 TI - The trials, tribulations of being a guinea pig. AB - Turning your hospital into a laboratory for developing new computer products is "not something for the foolish or faint-hearted," warned one information systems manager. Joint-development agreements can be risky business and cause many headaches for all parties, but the payback for hospitals can be a big price break or even a major competitive edge. PMID- 10117629 TI - Humana's Tampa plans address quality issues. PMID- 10117628 TI - Two rehabilitation giants call off planned merger. PMID- 10117630 TI - Dialysis providers cope with dwindling payments. AB - For-profit providers of outpatient dialysis services are reporting growing profitability, opening more centers and treating more patients. That's in spite of shrinking Medicare reimbursement levels. The industry segment hasn't been as good to hospitals, which find themselves in a struggle to maintain their dialysis programs in the very same environment. PMID- 10117632 TI - Epic moves into management with its first contract in Texas. PMID- 10117631 TI - Columbia, acquisition candidate both post strong quarter profits. PMID- 10117633 TI - Officials weigh taking Houston hospital district private. PMID- 10117634 TI - HMO to base hospital pay on quality. PMID- 10117635 TI - Hospital pharmacies watch prescriptions as debate rages over 'off-label' drug use. AB - Hospital pharmacies are closely monitoring physicians' prescribing practices in an effort to restrain drug expenditures by ensuring that drugs are used appropriately. But controversy continues over whether the increasingly common practice of using drugs for non-FDA-approved applications is appropriate and whether those uses should be allowed and covered by health insurers. PMID- 10117636 TI - Hospitals forgetting to query customers in quality process. PMID- 10117637 TI - Relaxed capital PPS rules are expected. AB - Hospital chief financial officers frustrated over some of the rules implementing last year's Medicare capital payment regulations may get some relief soon. HCFA's annual PPS regulations, expected to be released as early as later this month, will include a softening--or at least clarification--of some of the capital rules CFOs consider too harsh or onerous, one top HCFA official said. PMID- 10117639 TI - Service quality initiative improves hospital services. PMID- 10117638 TI - Fraud and abuse concerns prompt N.J. system to sell MedQuist stake. PMID- 10117640 TI - Collaborative practice eases OR problems. PMID- 10117641 TI - Niche marketing. Case history IV: When Japanese autoworkers need a Detroit hospital. PMID- 10117642 TI - Have speakers, will travel. Hospital system's staff gives nearly 150 free talks a year. PMID- 10117643 TI - Drawing on the talents of youth. Children's artwork livens campaigns and saves design dollars. AB - The spontaneous honesty and creativity of children's art can give a marketing or advertising campaign a fresh look. Often it can even save precious budget dollars. PR directors who have enlisted the fertile minds of children will tell you though that care must be taken to ensure that the youngsters' art conveys the right message and tone. Here are examples of how two very different healthcare facilities used kids' art successfully. PMID- 10117644 TI - An inquiring clinic wants to know: what do referring physicians need? PMID- 10117645 TI - Using TV to teach a mental health lesson. Popular 'State of Mind' series increases admissions. PMID- 10117646 TI - Niche marketing. Case history I: Understanding why Native Alaskans crave moose nose. PMID- 10117647 TI - Hospital sends itself back to school. Health curriculum builds bridge to schoolchildren. PMID- 10117648 TI - Capital campaigns/Part I. Capital campaigning with the red, white and blue. PMID- 10117649 TI - Community blitz fends off competition. PMID- 10117650 TI - This medical library is not for doctors only. PMID- 10117652 TI - Greetings from Toledo: Wish you were practicing medicine here. PMID- 10117651 TI - Niche marketing. Case history II: A Chicago clinic becomes African-American community's new neighbor. PMID- 10117653 TI - Niche marketing. Case history III: One hospital, two cultures in Hispanic Miami. PMID- 10117654 TI - Caring for the medically frail patient at home: a commentary. PMID- 10117655 TI - Behavior patterns and orientation among applicants to Medicaid-reimbursed long term care services. PMID- 10117656 TI - The evolving status of adult day care: evidence from Missouri. PMID- 10117657 TI - Non-traditional volunteer management in the 1990s. PMID- 10117658 TI - Health care and illiteracy: a patient care and employment problem. PMID- 10117659 TI - Recruiting retirees as volunteers. National Retiree Volunteer Center. PMID- 10117660 TI - Four steps to increased service. PMID- 10117661 TI - Health care reform and the AHA. PMID- 10117662 TI - Keys to managing older volunteers. PMID- 10117663 TI - Responsibility & governance in changing times. PMID- 10117664 TI - Building successful clinical programs. PMID- 10117665 TI - Implementing cardiac catheterization services: a case study. PMID- 10117666 TI - Assessing exam quality. PMID- 10117667 TI - Planning for the radiographer of the future. PMID- 10117668 TI - 1992 CPT coding changes. PMID- 10117669 TI - Department directors provide the steps to heavenly imaging. PMID- 10117670 TI - A question of survival? PMID- 10117671 TI - Do your patients really "hear" what you are saying? PMID- 10117672 TI - Evaluation of simulator accuracy with treatment planning CT scans. PMID- 10117673 TI - Defining core health services: many important issues must be resolved. PMID- 10117674 TI - Taranaki Board well placed to meet future challenges. PMID- 10117676 TI - The ethics and politics of health care delivery: where to now? PMID- 10117675 TI - Management options for elderly ill patients who present in the weekend. AB - An informal impression that there was a shortage of facilities for elderly patients who presented, with a routine illness, to a weekend duty doctor was studied by interviewing duty doctors and providers. The duty doctors stated that the major problems were the deficit in support from friends, relatives and neighbours and the lack of remuneration for the duty doctors. The doctors said that the main supports, paradoxically were friends, relatives and neighbours, and the acute medical ward. The recommended facilities included an urgent district nurse and a short-stay, assessment unit. Among providers only the medical ward and the private laboratories were willingly offering more than a minimal service. PMID- 10117677 TI - Marketing for health service organisations. PMID- 10117678 TI - Managing change and resolving conflict for efficient implementation of TQM. PMID- 10117679 TI - Applying QM tools to disaster management. PMID- 10117680 TI - Air medical communications centers. PMID- 10117681 TI - Professional air medical mechanics. PMID- 10117682 TI - Directory of air medical services. PMID- 10117683 TI - Association officers. PMID- 10117684 TI - The use of neuromuscular blocking agents by air medical services. AB - Neuromuscular blocking agents (NMBs) are frequently used to facilitate intubations in the hospital. The 1987 membership of the Association of Air Medical Services (AAMS) was surveyed to determine the frequency of NMB use by flight programs both before and after definitive airway control. Out of 141 programs, 101 returned completed survey forms. Of those responding, 39 of 101 used NMBs before intubation, and 67 programs used NMBs after intubation. The use of NMBs in the base hospital by emergency physicians was a significant predictor of the use by the air medical service. No other factors studied, including flight volume, percentage of trauma-related flights, percentage of flights to an accident scene, or the specialty of the service's medical director, predicted use of the agents after intubation. The presence of a physician on the flight crew was associated with the use of succinylcholine prior to definitive airway control. Reported complications included three deaths attributed to use of NMBs in the preceding two years. We conclude that NMBs are commonly used following intubation, and that NMBs are used before intubation by some flight programs, especially those that have physician crew members. PMID- 10117685 TI - Database brings in patients, bonds hospital with docs. PMID- 10117686 TI - TEAM (Together Everyone Achieves Miracles) players strive for good worker communications. PMID- 10117687 TI - Syndicated marketers aim programs at local hospitals. PMID- 10117688 TI - Unusual volunteers sniff out fun in hospital's halls. PMID- 10117689 TI - Hospital survival--the role of medical staffs and the public. PMID- 10117690 TI - Hospital data collection--the shape of things to come. PMID- 10117691 TI - Position statement on HCFA's Uniform Clinical Data Set (UCDS). American Health Information Management Association. AB - The Uniform Clinical Data Set (UCDS) is a computerized data collection and case finding system that has been developed by the Health Care Financing Administration (HCFA). It is a new mechanism for the screening by peer review organizations (PROs) of inpatient cases for utilization and quality of care problems. The intent is to replace the traditional PRO review process with a collection of a standard set of data about each hospitalization, subject that data to an expert system, and provide to the physician reviewer a case summary that reflects the specific areas which are being questioned and highlights the issues that need to be addressed. The goal is to select cases for review in each state by the identical standards, thus eliminating the differences in PRO review results attributable to individual judgment. HCFA plans to use the abstracted clinical data to evaluate patterns of care and outcomes. However, the UCDS system may have impact beyond the Medicare program. UCDS may become a template for the collection and analysis of data by hospitals and third-party payers for quality and effectiveness review of all patients. PMID- 10117692 TI - Healthcare computing standards: making sense out of the alphabet soup. PMID- 10117693 TI - Of professional interest: Medical Information Bureau. PMID- 10117694 TI - Health record completion guidelines. American Health Information Management Association. AB - It is a pleasure to introduce this important project report to the American Health Information Management Association (AHIMA) membership. Analyzing records for omissions, notifying physicians of needed information, counting delinquent records, and pursuing late documentation are some of the biggest chores in today's health information management departments. And they are chores that take time away from other priorities--managing, analyzing, and presenting health data, planning and implementing computerization, assessing and meeting customer needs. The heart of this statement is simple: it points out that there are other options to the traditional, detailed, record-by-record analysis. And those options may give us the results we need--timely and complete health records--while freeing up valuable staff time for other priorities. Take a serious look at the statement. If you are eager to make a change in your department's practices in records analysis and completion, it will back you up. If you are comparing the value of your department's records completion work to its benefit, this statement will give you ideas for change. And if you don't think you'd ever challenge tradition, this statement will give you food for thought. An added value to this statement is the fact that the ideas in it, and the very statement itself, are the product of our own profession. We are fortunate that leading-edge practitioners gave their expertise to the entire profession. The members of the strategy group for this project are listed above, we thank them for their wisdom. PMID- 10117695 TI - Implementation of reduced record completion procedures: practical insights. AB - Reduced record completion procedures represent a major departure from current practice to many health information management professionals. We share some insights from six practitioners. PMID- 10117696 TI - The role of health information managers in hospital financial management. AB - One area of internal analysis that has attracted increasing attention from healthcare managers is product line management. The coded data produced by the health information management professional is integrated with financial data to provide decision makers with valuable information about service quality and profitability. PMID- 10117697 TI - Gallup survey results. American Medical Record Association. PMID- 10117698 TI - Healthcare's quality orientation: implementation of total quality management at Sutter Health. AB - A hospital's commitment to quality has tremendous impact on all levels of the organization. In this article, the phases of total quality management implementation at Sutter General Hospital are presented. The theme of quality improvement through effective team work has reached to all departments including the medical record department. PMID- 10117699 TI - What is a "commitment to quality"? AB - Healthcare leaders are measuring one another's dedication to total quality management in order to recognize outstanding achievements. This article describes the application process and judging criteria used in the Healthcare Forum/Witt Associates' Commitment to Quality Award. PMID- 10117700 TI - Total quality management: a new challenge for quality assurance professionals. AB - What will be the role of the traditional quality assurance professional in healthcare's total quality management process? The author portrays what the hospital quality department might look like in the future and suggests how the quality assurance professional can prepare for this transition. PMID- 10117701 TI - The system analysis as a tool for medical record department improvements. AB - Selecting opportunities for process improvements in the health information management department can be achieved through a formal system analysis. This article covers the step-by-step examination of one department's quality improvement efforts. PMID- 10117702 TI - Side by side. PMID- 10117703 TI - Glossary of total quality management terms. PMID- 10117704 TI - Position statement on continuous quality improvement in healthcare. Quality Assurance Section. American Health Information Management Association. PMID- 10117705 TI - Search and find ... a PC database. AB - In this article on microcomputer databases, we will start off with a brief review of some common database terminology, specify some selection criteria, identify some common types of databases, and discuss some of the pros and cons of each. Two terms in usage with the classification of database software, flat-file versus a relational database, will also be explained. Then, I will share my personal use of each type of database, focusing in on an on-line Rolodex-type product to illustrate a canned, flat-file personal contacts database and a dedicated, programmable software program which can be used for unlimited relational database development. PMID- 10117706 TI - AHIMA questionnaire on computer knowledge and skills, and health information systems. PMID- 10117707 TI - The College's role in support of trauma care systems. PMID- 10117708 TI - Introducing the American Tort Reform Association. PMID- 10117709 TI - What can we do about cancer? PMID- 10117710 TI - Trauma manpower in the decade of aftershock. PMID- 10117711 TI - Medicare and Medicaid programs; advance directives--HCFA. Interim final rule with comment period. AB - This interim final rule amends the Medicare and Medicaid regulations governing provider agreements and contracts to establish requirements for States, hospitals, nursing facilities, skilled nursing facilities, providers of home health care or personal care services, hospice programs and prepaid health plans concerning advance directives. An advance directive is a written instruction, such as a living will or durable power of attorney for health care, recognized under State law, relating to the provision of health care when an individual's condition makes him or her unable to express his or her wishes. The intent of these provisions is to enhance an individual's control over medical treatment decisions. This rule implements sections 4206 and 4751 of the Omnibus Budget Reconciliation Act of 1990 (OBRA '90), Public Law 101-508. PMID- 10117712 TI - Supervision of home health paraprofessionals. A quality of care issue. AB - A new tool has been developed to assist community health nurses in the supervision of care provided by home care aides, the providers of personal care and the extension of skilled services. PMID- 10117713 TI - Home care aide evaluation. Assuring competency & quality. AB - Supervision and evaluation of the direct care provider can be a costly and time consuming activity. A comprehensive process to coordinate the various aspects of the home care aide evaluation is a creative solution for the efficient use of supervisory and staff time, paperwork reduction, and cost containment. PMID- 10117714 TI - Achieving a multicultural service orientation. Adaptive models in service delivery and race and culture training. AB - Human beings cannot be tossed together under the assumption that well-intentioned care will create a harmonious union. A multicultural service orientation does not eliminate all problems, but it does help reduce the likelihood of racial and cultural conflict between caregiver and client. PMID- 10117715 TI - A survey of home care aides. A personal and professional profile. AB - How can home health agency managers recruit and retain home care aides effectively? This study reveals the factors that influence aides' work choices, valuable information in battling worker shortage and costly turnover. PMID- 10117716 TI - Home care workers. A national profile. AB - This study presents the first nationally representative estimates of the characteristics of home care aides compared with nursing aides and hospital aides. For nearly every characteristic examined, substantial differences among the three types of aides exist. Understanding the distinct characteristics and needs of the home care aide is the first step toward increasing job satisfaction and reducing para-professional turnover. PMID- 10117717 TI - National uniformity for paraprofessional title, qualifications and supervision. Homemaker-Home Aide Association of America. AB - The core services around which a long-term care strategy should be forged are those cost-effective services that are performed by home care aides. It is essential that the duties and qualifications of these paraprofessionals be nationally defined and that credible standards be set; otherwise, the home care field will not be in a position to participate in policy discussions on a national long-term care system. Following is a draft position statement, which was developed by the Homemaker-Home Aide Association of America (HHHAAA) to begin discussions on home care paraprofessionals' title, function, and qualifications. This paper was endorsed in principle by the National Association for Home Care's (NAHC) Board of Directors in January 1992; HHHAAA is in the process of soliciting comments from interested parties and expects the statement to evolve based on continuing discussions. In late March, for example, the Advisory Board made additional changes and clarifications that may be incorporated in the future. Special thanks go to Ken Wessel of the Visiting Homemaker Service of Passaic County in Patterson, New Jersey, and an HHHAAA Advisory Board member, for his significant contribution to the development of this paper. PMID- 10117719 TI - Special homemakers for special needs. AB - The special health and personal problems that can accompany aging demand a special kind of home care worker. Two Boston agencies combined resources to bring the community's "difficult-to-serve" elders the experience, patience, and persistence they needed. PMID- 10117718 TI - The independent provider in home care. In search of a reasonable resolution. AB - The debate surrounding IP care has persisted for two decades--and intensifies as the demands for quality, accessible home care and client self-directed care grow. Policymakers must make every effort to thoroughly examine the issues related to IP care--from ambiguous employment status to competent care delivery--if a reasonable resolution is to be achieved. PMID- 10117720 TI - Is home care a dangerous occupation? Visiting Nurses Association, Dayton, OH. AB - The personal safety of field staff should be a concern to all home health agencies. The VNA of Dayton addressed the issue by creating a committee that focused on staff training, policy development, and equipment purchase. PMID- 10117721 TI - Infection control education for home care aides. AB - The very personal patient care provided by home care aides necessitates that they come into contact with patients' body fluids and secretions--a very real, although not always visible, source of infection and communicable disease. Therefore, educating HCAs about infection control and principles of universal precautions will maximize employee safety and improve quality patient care. PMID- 10117722 TI - The cost of turnover in a home care agency. AB - An agency experiencing an over-50% turnover rate of home care aides in one year took a hard look at what this meant in financial terms. PMID- 10117723 TI - Home care education for physicians. AB - Home care is on the rise, but physicians' involvement in home care has decreased. A vital part of the remedy is educating physicians in the principles and practice of home care. PMID- 10117724 TI - Communication between nurses and physicians in home care. AB - The increasing acuity of illness among home care patients and complexity of the in-home service network have created a greater need for frequent communication between the various members of the interdisciplinary home care team. This will likely become an increasingly important quality-of-care issue as home care continues to expand and to incorporate advances in technology. PMID- 10117725 TI - A new structured database for clinical information. AB - Assessing a patient's functional status and psychosocial conditions is accomplished more easily and with greater accuracy in the home. But how can physicians organize a database to convey information about specific clinical problems? PMID- 10117726 TI - Policy issues for physicians involved in home care. AB - The demand for home care services of all varieties will continue to grow in the next two decades, as will the need for well-informed physicians as members of the home health care team. It is hoped that an enlightened society will continue to develop reimbursement and regulatory structures that will foster a larger role for physicians in home care. PMID- 10117727 TI - A new home care role for physicians. Mechanical ventilation outside the hospital. AB - The increasing opportunities for oxygen-dependent and ventilator-assisted infants and children to receive long-term care in the home creates a new, vital role for physicians. Understanding and fulfilling this role requires determining which patients are suitable for home care; exploring the clinical, organizational, and management issues that home care introduces; and carefully strategizing discharge planning and followup medical care. PMID- 10117728 TI - Home blood anticoagulant monitoring--a physician alliance result. AB - Developing relationships with physicians can yield more than just a better relationship; it can directly impact an agency's ability to expand into new service areas. The alliance between the Visiting Nurse Association of Central Massachusetts and Dr. Jack Ansell led to the creation of the agency's highly successful home blood anticoagulant monitoring, a service that the growing number of cardiac patients in the United States will demand. PMID- 10117729 TI - Marketing home i.v. antibiotic therapy to physicians. AB - Home intravenous antibiotic therapy (HIVAT) is a safe, efficient, and cost-saving alternative to hospitalization--and the program of choice among patients and their families. Before the full spectrum of benefits can be realized, home infusion companies face the challenge of educating primary care physicians in HIVAT patient selection, antibiotic considerations, and the home care provider team approach. PMID- 10117730 TI - Home health care classification. AB - This article is the second in a series on the Home Health Care Classification research study conducted at Georgetown University School of Nursing (see the March 1992 CARING). The purpose of the study was to develop a method to assess and classify home health Medicare patients in order to predict their need for nursing and other home care services, including their outcomes of care. To accomplish this goal, data on actual resource use that could be objectively measured were used to predict resource requirements. A third article will provide more detail on the descriptive findings, statistical analyses, and the Preliminary Classification System. PMID- 10117731 TI - Art therapy with bereaved children. AB - The death of a loved one in childhood can create serious immediate difficulties and long-term psychological and somatic symptoms in adult life. This case portrayal illustrates how the group art therapy offered by a rural Michigan hospice helps children express and resolve their grief issues. PMID- 10117732 TI - Medical and dental staffing prospects in the NHS in England and Wales 1990. Medical Manpower and Education Division, Department of Health. AB - Information is presented in this paper to help those involved in medical and dental career planning. Further data are available from Regional tables, published annually by the Department of Health, and circulated to health authorities, postgraduate deans and clinical tutors. All of the information is retrospective, however, and can only be used to assess trends in prospects. PMID- 10117733 TI - Echocardiography or cardiac catheterisation--a comparison of risks, benefits and costs. AB - There are two techniques, echocardiography and cardiac catheterisation, that can be used to evaluate patients with valvular heart disease. This paper describes a comparison of these techniques, in terms of safety, side-effects, quality of imaging and cost. The authors conclude that there are good clinical and economical reasons why echocardiography should be used for evaluating patients with valvular heart disease. PMID- 10117734 TI - Facilities for the management of patients with lipid disorders in the United Kingdom: results of the British Hyperlipidaemia Association Survey. AB - A national survey was undertaken by the British Hyperlipidaemia Association to obtain data on the current clinical practice for the investigation and management of patients with hyperlipidaemia. An additional objective of the survey was to establish a United Kingdom register of lipid clinics. The results show a considerable variation in the availability of lipid clinics, and medical practitioners involved in these clinics came from a variety of specialty backgrounds. Some clinics had clearly defined policies with regard to acceptance of referrals. However, deficiencies in clinical services were identified including the lack of dietetic and laboratory support. PMID- 10117735 TI - Is the waiting list a safe place for outpatients awaiting coronary bypass surgery? AB - This study was undertaken to identify the safety of outpatients awaiting coronary bypass surgery. An audit of the outcome of 92 such outpatients at one Regional centre was undertaken by a retrospective review of medical records. Outcome measures were: time on the waiting list, anti-ischaemic medications, readmission for unstable angina, myocardial infarction and death. Almost half of the patients underwent surgery within three months, and three-quarters waited less than six months. No outpatient death occurred. However, 4 of the 7 adverse events occurred within this period. Despite advanced disease, the safety of outpatients awaiting coronary surgery within such a short time frame appeared to be acceptable, the only adverse events being non-fatal and occurring unpredictably. PMID- 10117736 TI - Management of myocardial infarction in the elderly: admission and outcome on a coronary care unit. AB - A data base of 1,511 patients admitted to a single Coronary Care Unit was analysed to examine the potential impact of thrombolytic therapy in elderly patients with myocardial infarction. Age was confirmed as a highly significant prognostic factor, and cost utility analysis showed that the cost of thrombolytic therapy with streptokinase in the elderly was lower per quality adjusted life year than in younger patients. However, median delay time of admission from onset of symptoms was significantly greater in this age-group, suggesting a need for a greater awareness of the benefits of thrombolytic therapy in elderly people. PMID- 10117737 TI - A survey of survivors of acute stroke discharged from hospital to private nursing homes in Nottingham. AB - Increasing numbers of disabled elderly stroke survivors are being discharged from hospital to Private Nursing Homes. However, there is little data available on which specific guidelines for the care of stroke patients in these homes can be based. A survey was undertaken therefore, to review patients on their discharge from hospital to Private Nursing Homes, and to assess the severity of their disability and handicap before and after entering the home. Nearly all patients were severely disabled on discharge from hospital, and the Barthel Activities of Daily Living scores of the survivors showed no significant change after four months. High levels of emotional distress and loneliness were identified by the Nottingham Health Profile, with little change after four months of nursing home care. The National Health Service has a continuing responsibility for the welfare of such vulnerable elderly people. The findings of this survey indicate that the emphasis of their care should be on the management of severe physical disability, exploitation of opportunities for further rehabilitation, alleviation of emotional distress and loneliness and, where appropriate, the provision of humane terminal care. PMID- 10117738 TI - Improving long-term outcome after stroke--the views of patients and carers. AB - Stroke is a major cause of long-term disability, often with devastating consequences for individuals and their families. Suggestions for alleviating these problems have come from professionals, but patients and carers have not specifically been asked their views on how to improve outcome. The results show that most care and support came from informal sources, formal services were poorly targeted and a third of carers were under considerable strain. Recommendations are made for improving services and support for patients and their carers. PMID- 10117739 TI - Dermatology outpatients in the West Midlands: their nature and management. AB - There is a lack of routinely available information about dermatology outpatient consultations which form the majority of the clinical work of this specialty. This survey was undertaken to prepare for clinical audit and assist in planning future developments of the service. Data were recorded from 2,940 outpatient consultations held during one week by 20 consultant dermatologists and their staff in the West Midlands Health Region in November 1988. The results show that collection and analysis of Regionwide data for a small specialty is feasible, and have indicated future areas of study for clinical audit. PMID- 10117740 TI - Recent trends in the use of domiciliary oxygen in England and Wales. AB - The volume of oxygen supplied to patients at home increased four-fold in the period 1982-89, largely due to the availability of oxygen concentrators on prescription since 1985. By 1989, health service expenditure on domiciliary oxygen reached 18 pounds million. Most users of long-term oxygen therapy suffer from chronic obstructive pulmonary disease, and many patients, eligible in terms of Department of Health and Social Security guidelines to receive long-term oxygen treatment, do not do so. However, the majority of those who receive oxygen, do so in amounts and for periods of the day which are below the levels known to prolong life or improve psychosocial functioning. A consensus of clinical opinion about the use of long-term oxygen therapy is needed. Without it, the use of this expensive service cannot be meaningfully audited. PMID- 10117741 TI - Enhancement of validity through qualitative approaches. Incorporating the patient's perspective. AB - Validity of research in a medical environment is enhanced through incorporating the patient's perspective by using qualitative approaches. Our efforts to improve the validity of measures led us to examine the research process more broadly through mechanisms of patient participation: a protocol adviser, a participant advisory panel, and focus groups. In our research program of biopsychosocial HIV studies in the military population, feedback from patient participants provided the research staff with information important for refining standard measures, improving the research process, and interpreting the quantitative data analyses. PMID- 10117742 TI - The impact of increasing intensity of health promotion intervention on risk reduction. AB - The HealthWise Stepped Intervention Study (1988-1990) at Pacific Gas and Electric was conducted to evaluate how a health promotion program affects behavior change and whether increasing levels of preventive interventions improve health status. The basic intervention components consisted of health risk assessment and health newsletter (Levels 1, 2, 3, and 4). Additional interventions were health resource center and self-care books (Levels 2, 3, and 4), behavioral change workshops and Division Healthwise team (Levels 3 and 4), and case management and environmental policy (Level 4). The study employed a quasi-experimental design with nonequivalent control groups. The overall risk status has significantly improved at all four intervention levels. The comparison across the four intervention levels found that Level 4, combining environmental policy with "high risk" targeting, showed the most impressive performance. Participants in Level 4 consistently showed significantly greater improvement in life-style factors, and their overall risk status also showed the greatest improvement. PMID- 10117743 TI - Toward the development of integrative risk-adjusted measures of quality using large clinical data bases. The case of anesthesia services. AB - This article describes a process to risk-adjust multiple outcomes of care and aggregate them into integrative measures of quality. A methodology is outlined for anesthesia services which is designed to use the new data base that is being constructed by the American Association for Nurse Anesthetists. Most of the methods should apply to other health professions as well, if outcomes of care and risk factors can be identified. The basic approach is to choose either exemplary or adverse outcomes of care which are under the control of the provider and to standardize these outcomes to take into consideration multiple risk factors. PMID- 10117744 TI - Planning an evaluation and estimating its cost. AB - Scientific evaluations can provide funders and program administrators with useful input concerning where to allocate scarce service dollars. But evaluation itself is legitimately the subject of cost concerns. What will it cost to get the various potential benefits of a scientific evaluation? What are the evaluation options of a given program, given its budget and the size and expertise of its staff? Where can a program administrator go for consulting help? This article provides a helpful framework for answering these important questions. First, it describes two types of evaluations which vary in both the questions they can answer and in their consequent cost. Second, it delineates and briefly describes the technical elements or steps required by each evaluation type. Third, it describes the nature and potential variability of costs associated with each technical step. Finally, it steers the reader to available sources of expert information and help. PMID- 10117745 TI - Kidnappings, hostage taking, drive-by shootings prompt added security. PMID- 10117746 TI - Steven R. Brown on investigating kickbacks. AB - (Steven R. Brown is the corporate security manager of the Southwest region for ARCO Oil and Gas. He primarily investigates and oversees investigations involving kickback and conflict of interest cases. He has travelled extensively to lecture on the topic. His 25 years of law enforcement experience includes serving as an instructor for the National Academy of the Federal Bureau of Investigation. While Brown speaks frankly about kickback problems in a large oil company, the nature of this kind of employee/vendor theft and the techniques for uncovering it apply equally to any sizable company or institution, public or private. PMID- 10117747 TI - Special report. CCTV (closed-circuit television) systems: why more hospitals are investing in them. AB - Advances in video technology and an increased variety in the use of closed circuit television systems have health care security directors buying CCTVs in record numbers. Three of four health care security decision-makers purchased CCTVs last year, according to Security magazine. System manufacturers say that in addition to cameras that are smaller, more lightweight, and more durable has come the increased use of color and infrared lighting. In this report, we'll review some of these advances and their applications. PMID- 10117748 TI - Who does well in a day treatment program? Following patients through 6 months of treatment. AB - Two rating scales were administered to 44 consecutive admissions to a day treatment program. The anticipated length of stay was 6 months. Better patient outcome was expected where the clinician's Global Assessment Scale (GAS) correlated with the patient's Self Assessment Scale (SAS). Data did not support the congruence of clinician and patient ratings. However, low GAS scores at the point of initial assessment seemed to "predict" early dropout. A follow-up inquiry showed that those who completed the program were in higher-functioning placements than those who dropped out early. Hence, those who benefited most were those who completed the program. Also observed was the fact that males had significantly higher SAS scores. How this contributed to length of stay is discussed. PMID- 10117749 TI - Patient satisfaction with a psychiatric day treatment program. AB - Patient perceptions can contribute significantly to partial hospitalization program evaluation. A retrospective study of patients' satisfaction ratings and comments concerning a day treatment program using a discharge questionnaire yielded high degrees of satisfaction. This may reflect a priori selection biases toward patients who formed a working alliance within the program. Comparison with a group of patients admitted to the program who did not complete a discharge questionnaire failed to differentiate the two groups on the basis of demographic or clinical characteristics. Attendance by males admitted to the program who completed a questionnaire was significantly (p less than .01) more frequent than by males who did not complete the questionnaire. Consistency in individual component ratings with overall satisfaction with the program suggests nonspecific benefits, with group psychotherapy evoking polarized perceptions. The latter observation suggests the need for careful matching of patients with specific treatment modalities employed in a day treatment setting. Suggestions are made regarding the administration and construction of a patient satisfaction questionnaire as well as for the application of this measure in enhancing program efficacy. PMID- 10117750 TI - Integration of cognitive and behavioral treatment strategies in a group family oriented partial hospitalization program for adolescents, children, and their families. AB - This article describes a partial hospitalization program for seriously emotionally disturbed children and adolescents in a public mental health setting. The article focuses on the integration of cognitive and behavioral treatment strategies in a group and family therapy based program. The literature on recent advances in the application of cognitive techniques in treating child and adolescent behavior problems is briefly reviewed. Specific cognitive and behavioral interventions that have proven useful with typical behavior problems in a partial hospitalization setting are outlined. PMID- 10117751 TI - Becoming a smoke-free day hospital. AB - The Connecticut Mental Health Center Day Hospital instituted a no-smoking policy at the time of relocation to a new building. The attitudes of staff and patients were surveyed before and after the move. Despite the concern and anxiety shown in anticipation of the change in policy, the patients were not affected in a significantly adverse manner. The importance of providing a safe environment for patients and staff includes measures to prevent the inhalation of cigarette smoke. This paper supports the implementation of smoke-free policies in psychiatric settings. PMID- 10117752 TI - The building blocks of a quality day treatment program: the needs assessment. AB - This paper is the first in a series of papers which discuss the many necessary ingredients that combine to produce a quality day treatment program. The theme of this article is the assessment of market needs. Included are (1) an introduction to the concepts of needs, (2) a discussion of the movement from need to change in society, (3) an examination of the process of quantifying needs, and (4) a brief description of several different types of needs assessments. The conclusion provides a description of each salient point and indicates its use in day treatment program development. PMID- 10117753 TI - Managed care's paradoxical effect. AB - This paper addresses the efforts made by the managed care industry to cut costs in the spending of the health-care dollar. It focuses on what appears to be disproportionate attention being paid to the dollar at the expense of appropriate patient care. It examines the effects of cuts in the mental health-care dollar as this relates to shorter lengths of stay in more expensive settings and not effectively utilizing a continuum of care. It also shows how managed care has impacted medical liability and the legal implications thereof. PMID- 10117754 TI - A model for a rurally based day hospital treatment program for sex offenders. AB - Services to perpetrators of child sexual abuse have been located primarily in larger urban centers. There has been a relative lack of services to family violence offenders, in general, and sex offenders, in particular, in rural Canada. This paper presents a model for sex offender treatment which has emerged out of a collaboration between federal and provincial justice agencies and a day hospital based in a rural mental health center. A preliminary group process evaluation is also included. PMID- 10117755 TI - Coping with the stress of change. AB - A psychiatrist offers internists thoughtful advice for appraising the changes that confront them and coping with the stress those changes bring. Physicians do well to follow the advice they give their own patients. PMID- 10117756 TI - Practice management challenges of the '90s. The Health Care Group. AB - How internists turn challenges into opportunities--and capitalize on those opportunities--will determine which practices thrive and which ones merely survive in the '90s. A leading health care consultant provides practical suggestions for modernizing your office and running your practice smoothly. PMID- 10117757 TI - CLIA: a win? A hassle? Or both? PMID- 10117758 TI - We have much to learn from other countries. PMID- 10117759 TI - The Stark ban: integrity has no price. PMID- 10117760 TI - Medicare: a rude awakening for the new internist. PMID- 10117761 TI - The work of internists: the key to reform. PMID- 10117762 TI - The future invades the medical profession. AB - The 1990s is a watershed decade for medicine--bringing Medicare reform, new limits on investments, regulation of office labs and possibly comprehensive reform in our health care system. The head of the American Medical Association calls on physicians to muster the courage and cooperation to preserve what is good and fix what is lacking. PMID- 10117764 TI - The U.S.-Mexico border: environmental squalor threatens public health. AB - Contaminated with raw sewage, the Rio Grande Valley has become a breeding ground for diseases normally associated with Third World countries. Poverty-stricken border communities cannot cope with the filth along our southern border, according to an El Paso public health official and leader in the Texas Medical Association. PMID- 10117763 TI - Radon and lung cancer: controlling a ubiquitous pollutant. AB - An epidemiologist and pulmonologist describes the research that links radon to lung cancer. Although radon poses a risk in many parts of the country, internists can assure their patients that a few, simple precautions can reduce the threat in their homes. PMID- 10117766 TI - Telephone care by your doctor. American Society of Internal Medicine. PMID- 10117765 TI - Effective lobbying and ASIM's alternative to 'all-payer' proposals. PMID- 10117767 TI - Environmental initiatives for physicians. AB - Physicians have a professional and moral responsibility to speak out about the environment's effect on health--particularly those hazards, such as smoking, that can be prevented, writes the U.S. surgeon general. PMID- 10117768 TI - P & T Committee response to evolving technologies: preparing for the launch of high-tech, high-cost products. Roundtable discussion. AB - P & T Committees are entering an exciting era in which the introduction of biotechnology-derived pharmaceuticals is providing life-saving opportunities for conditions for which there was little or no hope for a cure. The P & T Committee at Thomas Jefferson University Hospital has anticipated the challenge that these novel therapeutics present, and has already positioned itself for the pending approval of the first therapeutic human monoclonal antibody. Nebacumab (HA-1A, formerly known as Centoxin; by Centocor) will be used for the treatment of gram negative sepsis. Although this antiendotoxin has a good side effect profile, its use also carries a high price tag. This will raise several difficult ethical issues once the product is introduced. In this exclusive Hospital Formulary roundtable, members of Thomas Jefferson's P & T Committee and Technology Assessment Subcommittee provide their insights for responsibly managing a high tech, high-cost product such as nebacumab. PMID- 10117769 TI - Multi-purpose evaluation of H2-antagonist usage. AB - At Cabrini Medical Center, drug usage evaluation (DUE) and monthly purchasing data analysis were used to determine the indications for which H2 antagonists were being used, the appropriateness of parenteral therapy, the use of extended dosing intervals, and the cost effectiveness of cimetidine (Tagamet). The study was also used to review a decision of the P & T Committee to maintain cimetidine and remove ranitidine from the hospital formulary. PMID- 10117770 TI - Patient controlled analgesia--a pharmacy based service. AB - Patient controlled analgesia (PCA) is a proven method of administering analgesics via programmable infusion devices to relieve postoperative pain and pain associated with terminal illnesses. In mid-1989, a pain management service was started in the authors' hospital by the anesthesiology service. Since pharmacists had been previously involved in PCA postoperative pain management, it was decided they would continue in that capacity with the pain management service. Responsibility for procuring, storing, and programming the pumps, as well as drug preparation and patient instruction remains an integral part of the daily operation of our pharmacy. Physician orders written by the anesthesiologists for PCA therapy are processed in the pharmacy computer. The drugs are prepared, and pumps are programmed and primed by the central intravenous (IV) admixture service. The pumps with the drugs and accessory administration set and supplies are sent to satellites where staff pharmacists aid the nurses in starting the pumps and training the patients in their correct use. All subsequent programming including dose changes, rate changes, boluses, bag changes, and problem resolution are the responsibility of the staff pharmacists. Pharmacists are periodically certified in programming skills as part of the department's quality assurance program. In 1990, over 1800 patients received the benefits of this innovative service. PMID- 10117772 TI - Drug interaction microcomputer software evaluation: drug interaction facts on disk. AB - Drug Interaction Facts on Disk (DIF) was evaluated using general and specific criteria. The installation process, ease of learning and use, the user documentation, and the technical support were rated excellent. The scope of coverage, the quality of the clinical documentation, and overall clinical performance were also excellent. The frequency of updates is good. The program's clinical performance was compared to RxTriage and Drug Therapy Screening System using five recently reported drug interactions. The ability to screen for selected drug-food/nutrient interactions was also evaluated. Drug Interaction Facts is rated to be one of the better bargains in drug interaction software programs. PMID- 10117771 TI - Movement of the i.v. room to the postanesthesia care area: an alternative to an operating room satellite pharmacy. AB - The Jewish Hospital of St. Louis decided to combine the need for an operating room (OR) satellite pharmacy with the need to upgrade the existing intravenous (IV) room. This decision resulted in the movement of the move not only provided an upgraded IV room but its location allowed for direct access to the OR suites. The IV room can now provide the additional services of an OR satellite pharmacy. Cost savings estimates for a dedicated OR satellite pharmacy did not provide the hospital administration with the financial justification for the project. Only by combining the pharmacy's personnel and physical resources did the proposal become inviting enough for the hospital administration to support. The steps in the creation of the combined IV room/OR satellite pharmacy are presented. PMID- 10117773 TI - A cost effective approach to treatment of infection: "switch therapy". PMID- 10117774 TI - Building an image automatically--Madigan Army Hospital, Fort Lewis, Washington. PMID- 10117775 TI - Strategic facilities planning from the top down. AB - An institution's strategic plan can serve as a blueprint on which to build department goals. The authors discuss how they developed a master facilities plan that was closely coordinated with their institution's strategic plan. PMID- 10117776 TI - Safe harbor regulations for GPOs. AB - At one time, GPOs were placed under the umbrella of those who receive "kickbacks". Now, they have regulations that specifically exempt them from legal repercussions when accepting fees for recommending to its member hospitals that they do business with particular healthcare vendors. In short, for a GPO to legally accept fees from vendors, the GPO needs a written agreement with each hospital that permits the GPO to accept fees and it must report in writing to the hospitals at least annually the amount of the fees collected from each vendor. PMID- 10117777 TI - Cost cutting using radio frequency inventory control. AB - Bar coding should be a staple in every hospital by now--but it's not. The author tells how bar coding and the use of radio frequency transmission of inventory data direct to their mainframe computer has saved them time and money. PMID- 10117778 TI - Prefabricated headwall systems and service columns. ECRI. PMID- 10117779 TI - The cost of poor quality. PMID- 10117780 TI - Moving reusable supplies. PMID- 10117781 TI - Journals indexed by the AHA Resource Center for Hospital Literature Index and HEALTH database. AB - The American Hospital Association (AHA) Resource Center indexes journals for the Health Planning and Administration (HEALTH) database and Hospital Literature Index (HLI). These journals, designated special list health journals, are selected to provide access to a wide and balanced coverage of hospital and health care administration and health policy literature. This article provides background information on HEALTH and HLI and describes special list health journals in detail (including historical information, information sources, and broad subject divisions). It also discusses AHA policies relating to journal and article selection and current subject distribution of special list health journals. PMID- 10117782 TI - Cost recovery and usage tracking of CD-ROM databases with menuing software. AB - CD-ROM database products are in widespread use and offer potential cost savings over online products. Many libraries would find a cost-benefit analysis useful. Libraries often do not have sufficient funding simply to underwrite all costs related to CD-ROM workstations. Inexpensive menuing software permits usage tracking for data analysis and cost recovery of CD-ROM subscription, start-up, and operating costs. This article will explore the approach taken at the Fox Chase Cancer Center in Philadelphia to recover CD-ROM related expenses through user fees. PMID- 10117783 TI - Using EPIC to search the OCLC Online Union Catalog in a health sciences library. AB - EPIC is a service that provides keyword or subject access to the OCLC Online Union Catalog (OLUC). This capability increases the success rate for title location as well as the potential uses of the OLUC. The features of the EPIC system, application of these features to the OLUC, and specific uses in health sciences libraries are described in this article. PMID- 10117784 TI - OLIO+: an osteopathic medicine database. AB - OLIO+ is a bibliographic database designed to meet the information needs of the osteopathic medical community. Produced by the American Osteopathic Association (AOA), OLIO+ is devoted exclusively to the osteopathic literature. The database is available only by subscription through AOA and may be accessed from any data terminal with modem or IBM-compatible personal computer with telecommunications software that can emulate VT100 or VT220. Apple access is also available, but some assistance from OLIO+ support staff may be necessary to modify the Apple keyboard. PMID- 10117785 TI - Teaching end users the CD Plus MEDLINE menu mode in thirty minutes. AB - Guidance through the CD Plus menu mode is warranted and has proved worthwhile. The Stowe Library's Information Services Department offers instruction once per week; the session usually lasts thirty minutes but may run longer if the attendees are particularly astute or enthusiastic. Individuals or classes may also request instruction at times that are better suited to their schedules. Librarians who search CD Plus on a daily basis will undoubtedly become facile with the direct searching mode. New end users will probably enjoy more success by using the menu mode. The menu mode does not provide documentation; therefore, a modified text of this article including the illustrations might be considered an adequate print manual for the menus. However, many of the system capabilities cannot be used unless they are taught by an experienced operator. Such a basic but necessary introduction requires approximately one-half hour. The pace will be brisk, and time for extraneous experimentation is unlikely. A successful instruction session is a result of preparation rather than improvisation. If the specific interests of the clientele in attendance are known in advance, a reworking of the examples would be appropriate. Although no formal evaluation of this instruction technique has been made, most attendees express an appreciation and understanding of the system's capabilities by the end of the session. Tangible feedback comes from seeing an end user who had participated in instruction return to the workstation on an ongoing basis to search the database successfully. PMID- 10117787 TI - Does managed care save money? PMID- 10117786 TI - Michigan Medicaid managed care expanding. PMID- 10117788 TI - At last, health care is a major public concern. PMID- 10117789 TI - Butterworth Hospital campaigns for voters. PMID- 10117790 TI - Hospitals and community benefit: doing well and doing good. PMID- 10117791 TI - Let's take a grassroots approach to health care cost reform. PMID- 10117792 TI - Optimizing board/CEO relationships. PMID- 10117793 TI - Is managed care our last hope for cost control? PMID- 10117794 TI - The future of electronic billing. AB - A comprehensive patient accounting system is vital to achieving timely reimbursement. Industry-wide standardization of intermediary requirements can further aid the process. PMID- 10117795 TI - 'Celebration of Quality' reaches out to policymakers. PMID- 10117796 TI - Caring for people with AIDS. PMID- 10117797 TI - Program ensures proper disposal of infectious waste items. PMID- 10117798 TI - Proper billing of therapy costs maximizes reimbursement. PMID- 10117799 TI - Caring for people with AIDS requires knowledge of law. PMID- 10117800 TI - Preventing job burnout enhances nurse assistant satisfaction. PMID- 10117801 TI - Providers balance food choices with dietary restrictions. PMID- 10117802 TI - Pharmacists help reduce spread of infections. PMID- 10117803 TI - Developing special care units requires planning, expertise. PMID- 10117804 TI - 1992 corporate profiles. AB - As the long term care industry seeks out new products, new solutions, and new ways of providing quality care, it is important for long term care providers to know more about the companies they do business with. The following Corporate Profiles showcase information about leading companies in the long term health care industry. Some of the areas highlighted include: *Mission of Company*History*Product Lines*Support Services. We hope you will find this information useful when making purchasing decisions, and we're confident you'll keep this issue of Provider as a handy reference guide. PMID- 10117805 TI - The challenge of partial hospitalization in the 1990s. AB - Psychiatric partial hospitalization has existed in the shadows of both traditional inpatient hospitalization and outpatient therapies. Despite documented effectiveness, the modality has only recently received increased attention and growth, both driven by concerns about the costs of mental healthcare. This paper reviews historical factors affecting the use of this treatment setting, outcome research in the field, and anticipated future growth trends. PMID- 10117806 TI - Treatment-effectiveness research in child and adolescent partial hospitalization. AB - Partial-hospitalization services for children and adolescents continue to be an underutilized component of the mental health delivery system. With little treatment-effectiveness research available, there is limited incentive for shifts in reimbursement policies or for traditional referral sources to alter referral patterns. This paper provides an overview of published effectiveness research, a discussion of methodological difficulties, and an example of ongoing research for critique. Clearly, research in child and adolescent partial hospitalization must begin to address the lack of available effectiveness data. Partial hospitalization advocates must compare both various program models and treatment of specific populations. In addition, studies comparing outcome of partial hospitalization programs with outcome from other treatment modes are essential. The entire continuum of care must be subjected to rigorous and scientific study. The next decade will no doubt bring a large number of treatment-effectiveness studies, now lacking, for comprehensive analysis of options and outcomes. PMID- 10117807 TI - Treatment of the borderline patient in partial hospitalization. AB - Current reimbursement trends are forcing a search for less expensive alternatives to hospitalization for the mentally ill. Much of the literature on the treatment of patients with severe borderline personality disorders has focused on inpatient treatment, often on the pros and cons of long-term versus short-term programs. Little has been written about the treatment of patients with borderline disorders in partial hospitalization programs. This paper emphasizes the usefulness of such a setting and describes its staffing, program components, and approaches for intensive reconstructive treatment. Special emphasis is placed on admission and discharge boundaries, careful coordination of treatment, and crisis management. PMID- 10117808 TI - Specialized partial hospitalization for older adults: a clinical description of an intermediate-term program. AB - The field of geriatric mental health is confronted with the dilemma of a sharp rise in the elderly segment of the population and a concomitant shortage of age appropriate psychiatric intervention services. There is tremendous need for specialized hospital-based intervention for older adults with mental health problems. A creative and rapid response is imperative and should be based on a continuum of geropsychiatric services that includes acute inpatient, partial hospitalization, and outpatient services. Because Medicare reimbursement for partial hospitalization is restricted to hospital-based programs, private psychiatric hospitals are uniquely positioned to assume a dominant role in the geriatric mental health service delivery system. This article details one hospital's specialized, intermediate-term partial-hospital program for older adults. Partial hospitalization is demonstrated to be an essential component of comprehensive geropsychiatric services that can overcome problems of cost effectiveness, accessibility, and acceptability to consumers--all factors that presently restrict the development and use of such programs. Based on empirical findings, clinical adaptations to assessment and treatment procedures specific to older adults are presented. PMID- 10117809 TI - If partial-hospital programs come of age: some caveats. AB - The potential role of partial-hospital programs in solving both clinical and fiscal problems is acknowledged. The development of one partial-hospital program in the context of an inpatient-oriented hospital is reviewed in some detail. Lessons learned are identified, and anticipatory strategies are noted to facilitate the development of new programs should the funding become available. PMID- 10117810 TI - Understanding Canadian health care. PMID- 10117811 TI - Measuring the risk manager's performance. PMID- 10117812 TI - A new age for flexible benefits. PMID- 10117813 TI - Searching for proper judicial recognition of hospital ethics committees in decisions to forego medical treatment. PMID- 10117814 TI - The AHA's national health reform strategy: an overview. PMID- 10117815 TI - Hospitals make local reform efforts. PMID- 10117816 TI - MD-hospital collaboration revisited. PMID- 10117817 TI - The governing board: a moral force. PMID- 10117818 TI - Medical waste: the continuing saga. PMID- 10117819 TI - Involving MDs in a CEO search. PMID- 10117820 TI - The new cooperation: boards generate community partnerships. PMID- 10117821 TI - The obligation of trusteeship. PMID- 10117822 TI - Providers see danger in broadening use of Medicare rates. PMID- 10117823 TI - Setting policy on environmental issues. Interview by Karen Gardner. AB - Perhaps more than any other type of institution, hospitals are expected to be good neighbors, which involves respect for the community and respect for the environment. Louis Rasmussen, board chairman of Carondolet Health Corp., Kansas City, MO (the parent company for Saint Joseph Health Center, a 300-bed acute care hospital in Kansas City), and a retired executive of Kansas City Power and Light Co., sees the board's role in setting responsible environmental policy for the hospital as pivotal. In 1991, Rasmussen served on the American Hospital Association's Ad Hoc Committee on Recycling. Currently, he is a member of the AHA's Congress of Hospital Trustees. Participation in these activities, as well as his professional background in both engineering and law, gives him a broad view of both environmental issues and governance. Recently, Rasmussen spoke with Trustee editor Karen Gardner about the environmental issues confronting hospitals today and the board's role in dealing with those issues. PMID- 10117824 TI - Hospital-physician arrangements: the new IRS position. PMID- 10117825 TI - Image processing: can it answer your medical records needs? PMID- 10117826 TI - NYUMC (New York University Medical Center) image fusion saves lives. PMID- 10117827 TI - Overruled: objections to optical disk archiving. AB - In summary, while the Federal Rules of Evidence neglect to specifically address the admission of optical disk evidence, the Rules do recognize the reliability and admissibility of records maintained with modern computer storage techniques. In certain cases, information stored on optical disk will constitute original information; in others, the information will constitute an admissible duplicate. Regardless of the classification, the optical disk evidence should be admissible if the party offering the evidence can establish that the optical disk storage and retrieval process accurately reproduces the original document. The admission of medical records stored on optical disk will be challenged. The technology involved in optical disk storage, however, makes optical disk information more reliable than magnetic disk information. As a result, optical disk evidence currently should survive challenges more readily than magnetic disk evidence. PMID- 10117828 TI - 28 hospitals accept imaging's promise. PMID- 10117829 TI - Luxury or necessity? Document image processing. PMID- 10117830 TI - Optical disks: why one facility just said no. PMID- 10117831 TI - Nursing systems: the next generation. PMID- 10117832 TI - Bed tracking--new technology to benefit admitting first. PMID- 10117833 TI - Volunteers: a national treasure. PMID- 10117834 TI - Your board of directors. A closer look at the opportunities and structure of NAHAM's board. PMID- 10117835 TI - Don't use the 'D' word. PMID- 10117836 TI - Developing a utilization improvement program. PMID- 10117837 TI - Managing accounts receivable: sharing the responsibility. AB - Charleston Area Medical Center shows how the business office and medical records department can work together to improve accounts receivables. PMID- 10117838 TI - Creating a win-win situation in a competitive environment. AB - Acute care hospitals and rehabilitation facilities can work together and benefit each other. PMID- 10117839 TI - TQM at Corning. AB - Houghton has been with Corning for 30 years, up through the ranks. Now, as chairman and CEO, his individual leadership stamp is TQM. It's a major turn around story with Total Quality at its center. PMID- 10117840 TI - TQM at HCA. AB - HCA is a pioneer in the continuing quality movement. Its chairman/CEO/president tells why, and the specifics of the company's own brand of TQM. PMID- 10117841 TI - The JCAHO applauds TQM. AB - Beginning with his own Joint Commission, Dennis O'Leary got behind TQM and would love to see every hospital in America embrace its principles. PMID- 10117842 TI - TQM in hospitals. PMID- 10117843 TI - Healing more than the body. AB - Louisville has become the Mecca for new and classical theater, growing far beyond mere regionalism, with continual support from Humana. PMID- 10117844 TI - Canadian nurses head South. AB - What's going on with the Canadian Health System? Many nursing graduates are moving to the U.S. Example: one hospital in Texas is now operating with a 25 percent Canadian nursing staff. PMID- 10117845 TI - Outpatient payment--the view from HCFA. PMID- 10117846 TI - Developing outpatient care. AB - Hospitals know about the explosive growth of outpatient care. But no manager knows exactly what's ahead. "Flexible Planning" is a way to allow hospitals to quickly respond to rapid changes. PMID- 10117847 TI - Alternatives to Medicaid provider taxes. PMID- 10117848 TI - Merging MIS functions. PMID- 10117849 TI - Plain talk on health reform. PMID- 10117850 TI - Temporary alien workers seeking H-1B classification under the Immigration and Nationality Act--Immigration and Naturalization Service. Interim rule with requests for comments. AB - This interim rule implements certain provisions of the Miscellaneous and Technical Immigration and Naturalization Amendments of 1991, Public Law 102-232, December 12, 1991, as it relates to aliens seeking nonimmigrant classification and admission to the United States under section 101(a)(15)(H) of the Immigration and Nationality Act (Act). Public Law 102-232 altered, among other things, the procedures for petitioning for H-1B nonimmigrants and established new eligibility criteria for foreign physicians seeking employment in the medical profession in the United States. This rule contains the new procedures required by the legislation and makes Service policy consistent with the intent of Congress. This rule sets forth the new filing procedures and eligibility standards and clarifies for businesses and the general public the requirements for classification and admission. PMID- 10117851 TI - Executive information systems: winning the numbers game. AB - Boosting business by putting information to work--that's the premise behind executive information systems. Here's what an EIS can do for organizations, and some systems currently offered. PMID- 10117852 TI - 'Continuous adaptation' method aligns I/S with corporate goals. AB - Flexibility allows hospitals to meet their goals head on, grapple with problems and find solutions as a team. Claire Benjamin and Annette Valenta propose a managerial method that links the corporate strategic plan with experts who can best implement and use tomorrow's information tools. PMID- 10117853 TI - Healthcare pioneers lead the way. AB - Using the Pioneer space program as a metaphor for the spirit of adventure, the vision and the innovation embodied by all Computers in Healthcare Pioneers, CIH names four new Pioneers for 1992. These new Pioneers as well as our 13 current Pioneers will be honored at the Seventh Annual Computers in Healthcare Conference and Exposition May 27 and 28 in San Diego. PMID- 10117854 TI - Health information management: better care through quality data. AB - Authors Cassidy, Dowell and Bloomrosen set high goals for health information management professionals as they transform their profession. Their guidelines provide a chart and compass for those striding into the future. PMID- 10117855 TI - Ethics: a decision-making process. PMID- 10117857 TI - Ethics committees: impact on discharge? PMID- 10117856 TI - Ethics and complex discharges. PMID- 10117858 TI - The Civil False Claims Act: an important weapon in the war on health care fraud. PMID- 10117859 TI - The new OSHA regulations on occupational exposure to bloodborne pathogens. PMID- 10117860 TI - Patients mutiny against Orphan Drug Act. PMID- 10117861 TI - Hospital-physician joint ventures: new, menacing IRS stance. AB - To summarize, legitimate joint ventures between hospitals and members of their medical staffs to improve and increase the health care services and facilities available to the community are still possible without jeopardizing exemption. However, in joint ventures, and ultimately, in most other hospital-physician relationships, any time financial benefits are to be conferred upon physicians by the exempt hospital in which they practice, the hospital must be able to justify those benefits on the basis of benefits flowing directly to the community, and not indirectly through the increased referrals and admissions that the hospital expects to obtain. PMID- 10117862 TI - Responding to requests for references requires balancing moral, social and legal duties. PMID- 10117863 TI - Corporate practice doctrine remains a factor. PMID- 10117864 TI - Surgical pack prices inch up. PMID- 10117865 TI - X-ray film scam hits East Coast; 17 plead guilty. PMID- 10117866 TI - Hospitals eliminating heparin from I.V. catheter flushes save money, reduce patient side effects. PMID- 10117867 TI - Materials management must play key role in equipment planning, purchasing, maintenance. PMID- 10117868 TI - Henry Ford moves on drug reps; others debate tactic. PMID- 10117869 TI - Hospitals may be bound by terms added in supplier's acceptance of an offer. AB - A hospital materials manager reports that a supplier is attempting to hold the hospital to new terms that the supplier added in the acceptance of an offer to buy. The offer to buy was made in the hospital's purchase order. In this dialogue, Dr. Decker develops the law relating to such a transaction. PMID- 10117870 TI - Special fraud alert. Hospital incentives to physicians. Office of Inspector General. PMID- 10117871 TI - The strengths and scope of managed health care today. PMID- 10117872 TI - The risk of nursing home admission in three communities. AB - Beginning in 1982, the 3-year incidence of nursing home admission was determined for community-dwelling residents aged 65 and over in East Boston, Massachusetts (4%); New Haven, Connecticut (9%); and Iowa and Washington Counties, Iowa (12%). A common methodology was used to collect baseline risk factor and follow-up data on nursing home admissions among persons in each community as part of the National Institute on Aging's Established Populations for Epidemiologic Studies of the Elderly. A multivariate logistic regression model of baseline risk factors that included the participant's age, race, sex, history of prior admission, ADL limitations, cognitive function, living arrangements, and level of income predicted 80% of the users in each community. PMID- 10117873 TI - Stability of informal long-term care. AB - Driven by projections of increasing needs for long-term care coupled with changing social trends, fear of family abandonment of caregiving has persisted. Data from two longitudinal studies confirm that informal caregivers are not withdrawing their help. Not only were family and friends the first source of assistance, but they also continued to be the primary source of care over 10 years. Further, although the majority of elders retained the same primary caregiver, if there was a change, it was typically to a new informal caregiver in the next generation. Very few elders who remained in the community ceased receiving informal care or turned from informal care to formal services. PMID- 10117874 TI - Language acculturation and screening practices of elderly Hispanic women. The role of exposure to health-related information from the media. AB - The present study examined the hypothesis that language acculturation of Hispanics in the United States increases their exposure to media-based health information which, in turn, increases medical screening practices and knowledge of cancer symptoms. We interviewed 598 elderly Hispanic women (55-92 years of age) residing in Los Angeles. Language acculturation was measured with items on understanding of English and language preference for interpersonal communication, reading materials, television, and radio. Recency of screening (physician breast exam, Pap smear, routine physical exam, mammogram) and exposure to media-based health information were assessed with Likert-type scales; knowledge of symptoms of breast, cervical, colorectal, and oral cancers was assessed through open-ended questions. The results of multiple regression analyses provide support for the hypothesis. First, language acculturation predicted media exposure after controlling for demographic variables. Second, media exposure predicted screening and symptom knowledge after controlling for language acculturation and the demographic factors. The findings suggest that cancer prevention programs should use Spanish-language media to reach a wider Hispanic audience, especially those who are monolingual. PMID- 10117875 TI - Satisfaction with medical care among elderly people in fee-for-service care and an HMO. AB - This study investigates satisfaction with care among elderly Medicare beneficiaries enrolled in a health maintenance organization (HMO) and beneficiaries in fee-for-service (FFS) care in the same geographic area. Satisfaction with two dimensions of care, access/quality and costs, are examined, to investigate differences in enrollee/FFS evaluation of these dimensions of care as well as predictors of satisfaction with care. In addition, satisfaction among healthy and chronically ill elderly people in these two care settings is explored. Results indicate higher satisfaction with access/quality of care among those in FFS and higher satisfaction with costs among HMO enrollees. These relationships hold controlling for other variables and among the chronically ill elderly. Sources of variation in satisfaction are somewhat different among the HMO and FFS elderly. Satisfaction with paperwork and ease of getting to care, however, influences satisfaction with other aspects of care in both populations. PMID- 10117877 TI - Improved practice profiles called key to better care. PMID- 10117876 TI - Assessing the influence of adult day care on client satisfaction. AB - Using data collected from 74 adult day care centers, this study measured various program characteristics from four different categories of respondents--clients, caregivers, staff members, and administrators. The perceptions of these respondents were examined for their associations with each other and with client satisfaction. Three program characteristics, as perceived by clients, were significantly associated with client satisfaction (staff caring, general morale, and interior environment). The caregivers', staff members' and administrators' perceptions were not significantly associated with client satisfaction. In addition, most of these program component ratings were not significantly associated among clients, caregivers, staff members, and administrators. PMID- 10117878 TI - How indicator data can be used to monitor QA levels. PMID- 10117879 TI - Increased emphasis on outcomes needed in geriatric field. PMID- 10117880 TI - Input from many groups critical to good cancer care. PMID- 10117881 TI - How should problems with quality be controlled? American Medical Association. PMID- 10117882 TI - University's statewide network links rural doctors. PMID- 10117883 TI - Cooper integrates to avoid catastrophe. PMID- 10117884 TI - At-the-scene data capture. Automating initial patient care requires integration of diverse, existing technologies. PMID- 10117885 TI - Integrating medical records systems improves care. PMID- 10117886 TI - '92 LIS review. 6th annual state-of-the-lab. AB - The annual survey of laboratory information systems conducted by Healthcare Informatics and Dennis Winsten & Associates Inc., is intended to provide the prospective purchaser of an LIS a "quick look" at many of the important characteristics of vendors and their products. The survey also may be used by industry watchers to evaluate the ebb and flow of vendor fortunes and the strength of the LIS marketplace. PMID- 10117887 TI - A mini-history of laboratory information systems. PMID- 10117888 TI - Bar codes magnify efficiencies at Millard Fillmore. PMID- 10117890 TI - System users enjoy unusual price/performance ratio--Hummingbird LIS. PMID- 10117889 TI - Can you justify the cost of installing PACS? PMID- 10117891 TI - New purpose built mental illness unit at North Manchester General Hospital. PMID- 10117892 TI - Waste burning boiler. PMID- 10117893 TI - Hospital engineers and the law. PMID- 10117894 TI - Steam raising solar array. PMID- 10117895 TI - Advanced building controls to help new high-tech hospital maintain highest standards of care. PMID- 10117896 TI - A commercial approach to clinical waste incineration. PMID- 10117897 TI - Hospital waste disposal: issues, options and opportunities. PMID- 10117898 TI - Designing for AIDS. As the epidemic grows, architects develop new types of healing environments. PMID- 10117899 TI - The Critikon ProtectIV catheter issue. AB - Most healthcare professionals have already read about the union grievance over the Critikon ProtectIV catheter filed at San Francisco General Hospital. The union's position was that the catheter which is designed to prevent needlesticks during insertion and removal, should be used in all applications at the hospital, rather than only in those that seemed to present greater risk of injury or infection. HHMM believes that engineering controls--specifically safety needles- should be fundamental to a good exposure control plan for bloodborne pathogens. If the primary pathway of exposure is the needlestick and the point of the control plan is to reduce needlesticks, then it is hard to refute the logic that safety devices are the best approach. The following material consists of the statement made by Dr. Peter Lurie to the grievance committee at San Francisco++ General and a letter from Dr. Janine Jagger presenting initial data on the effectiveness of the ProtectIV catheter in reducing injuries. Both are reprinted with permission. HHMM offers these documents for the information they contain, as well as for the guidance they offer in how to begin evaluating safety needle devices. PMID- 10117900 TI - Using the OSHA Employment Classification Scheme. PMID- 10117901 TI - Prospects for national health care in the United States. AB - This paper provides an overview of both the current health care crisis in the United States and various reform proposals (some based on Canadian and British models) being considered at the federal and state levels. The proposals discussed fall into three categories--multiple payer national health insurance programs, one payer national health insurance programs, and a national health service program. The authors review four important criteria (cost, quality, access, and equity) that must be considered in evaluating the proposals for reform. Information is provided to assist health care professionals in understanding the various national health care proposals, applying evaluative criteria to these proposals, and advocating for needed changes. PMID- 10117903 TI - AIDS prevention: myths, misinformation and health policy perceptions. AB - This research assesses the degree and type of prevailing misinformation about AIDS transmission, as well as the relationship between misinformation, prior information exposure, and perceptions of health policy issues related to AIDS. It also identifies pockets of misinformation to provide a basis for targeting health policy and AIDS education campaigns. PMID- 10117902 TI - Physician and consumer attitudes and behaviors regarding self-help health support groups as an adjunct to traditional medical care. AB - This study assessed the creditability of self-help health support groups as an adjunct to traditional medical care among a sampling of physicians (N = 120) and group members (N = 73) located in the Dallas/Ft. Worth Metropolitan area. Findings suggest a general lack of awareness of local groups among physicians, referral to only a few select groups, as well as little communication between health care professionals and their patients. Physicians in group practice, surgical specialties, and having never referred patients to support groups responded less favorably. Several benefits were reported by the group members, although for a majority their patient-physician relationship remained relatively unchanged. PMID- 10117904 TI - A model research design to determine whether public programs providing health care for the poor and uninsured are successful. AB - The Mississippi State Department of Health has developed an empirically-proven two stage methodology of evaluation appropriate for agencies serving individuals that are poor and/or uninsured that utilizes qualitative data drawn from surveys and interviews to formulate a plan of action to collect relevant objective data. Findings are reported as being either supported, non-supported, or fallacious, and are accompanied by recommendations for intervention when appropriate. After comments on these have been assembled and disseminated, the program is required to submit a plan of action addressing all recommendations in the report. PMID- 10117905 TI - Self concept of pregnant teenagers. AB - This study is an exploratory research effort to investigate whether an association exists between self concept and teen pregnancy or repetitive teen pregnancy. The study was conducted at a special school for pregnant girls using the Tennessee Self Concept Scale instrument with 148 available sample. The pregnant girls in this study had a lower self concept in general than the norm group and specifically in moral, family and social dimensions. Among these subjects, black girls had a higher self concept in all areas than white girls. There was no statistically significant difference on their scores between the first and repetitive pregnant girls. The self concept measure as a correlate of pregnancy may be selectively utilized for possible identification of the most vulnerable group or cases among teenage girls. A long-term approach to teenage pregnancy would be to improve their self concept through various support services. Significant others in the teenagers' lives may help improve in moral ethical, family and social area with special concerted efforts. PMID- 10117906 TI - Health care firesafety: a prognosis for the '90s. AB - A look at the problems, standards, and fire record involving health care firesafety helps us predict future directions that it may take. PMID- 10117907 TI - President Bush's comprehensive health reform program. AB - To deal with the shortcomings of the current U.S. health care system, President Bush has proposed a comprehensive reform package that would offer tax credits and deductions to low- and middle-income Americans to purchase private insurance, reform small market insurance to ensure availability and portability of insurance, allow creation of Health Insurance Networks to allow small businesses and nonprofit organizations to pool their purchasing power, reduce administrative costs, and control the growth of government health programs. Combined, the proposals would build on the strengths of the present private/public system and preserve consumer choice and free market discipline. PMID- 10117908 TI - States must act to reform medical education. AB - U.S. medical education has remained largely unchanged for the past 40 years despite dissatisfaction with the training physicians receive. Efforts to reform medical education should focus on state medical boards, which control physician licensing, rather than on the faculties of medical schools and hospital residencies. PMID- 10117909 TI - America speaks. Was anyone listening? AB - Town meetings are a uniquely American political device intended to allow citizens to have a voice in the course of the local or even national policymaking process. On January 14, 1992, Democratic members of the U.S. House of Representatives conducted 140 such meetings to discuss health care reform. While the discussions ranged from the ridiculous to the sublime, Americans made it clear that they are fed up with a current system that they believe costs too much and provides too little. But a key question remains: Who, if anyone, was listening? House Democrats appear determined to avoid specifics and to pin President Bush with an "anti-health" label. The strategy is a risky one; a riled up populace could well turn against those who convinced them to be concerned in the first place. PMID- 10117910 TI - Does A.I.D. still spell relief? AB - The U.S. Agency for International Development has helped foreign governments lower infant mortality rates and extend life expectancy through a combination of disease prevention and medical treatment. But problems at home include allegations of fraud and abuse at the agency's highest levels. A.I.D.'s efforts abroad are complicated by the government's restrictive anti-abortion policy. PMID- 10117911 TI - Mass retreat: the demise of Massachusetts hospital rate regulation. AB - Massachusetts recently deregulated its 16-year-old hospital rate regulation system, after earlier voting in favor of a delay of its "play-or-pay" universal health care mandate. This retreat holds important lessons for the rest of the nation. Specific flaws in the design of the system weakened regulation's effectiveness and undermined its political support. The failure to control costs led to the postponement of universal access. Massachusetts' experience illustrates that neither competition nor regulation--as currently practiced--are adequate to meet the access and cost control challenges facing the nation. PMID- 10117912 TI - Competing to death: California's high-risk system. AB - Competition in California has cost lives and money. Shifting care out of hospitals reduced hospital spending relative to other states, but overall health spending per capita rose to the second highest in the nation in 1990. High spending coexists with low rates of coverage--the state ranks seventh in percentage of people lacking insurance. Hospitals have closed emergency rooms and other unprofitable services while marketing duplicative and often unnecessary services to the well-insured. With real free markets unattainable in health care, California's competitive rhetoric has rationalized growing inequalities and higher costs. The market's invisible hand has picked Californians' pockets and endangered both rich and poor. PMID- 10117913 TI - The empowered transcriptionist: a valued member of the health records team. PMID- 10117914 TI - Cost estimates and uncertainty: the expected value technique. PMID- 10117915 TI - Administrators of volunteer services: their needs for training and research. AB - Despite the importance of volunteer administrators to nonprofit and many government organizations, little systematic research has been focused on these officials. Using a large national survey of volunteer practitioners conducted in 1989-1990, this article examines empirically several hypotheses concerning organizational support to meet administrator needs for continuing education. Using the survey responses, the article also elaborates the subjects recommended by the administrators for treatment in a basic seminar in volunteer management, in an advanced seminar, and in further research. PMID- 10117916 TI - Effective boards: how executive directors define and develop them. AB - There is growing recognition in the nonprofit field that the executive director has a key role in determining whether the board of directors will function effectively. To aid executives in this vital role, two recent studies defined a "good board" from the point of view of two samples of executive directors of community agencies, then sought factors related to board performance as measured by this definition. In interviews, executives whose boards scored higher than their peers on this performance measurement related how they work with their boards in such areas as recruitment of new members, financial management, fundraising, and leadership development. PMID- 10117917 TI - Toward an understanding of the international nonprofit sector: the Johns Hopkins Comparative Nonprofit Sector Project. PMID- 10117918 TI - Healing by wire. PMID- 10117919 TI - Special report. Controlling headache costs. PMID- 10117920 TI - Data watch. Health plan costs continue to rise. PMID- 10117921 TI - Employers are experimenting with managed competition. PMID- 10117922 TI - Should employers make physicians account for costs? PMID- 10117923 TI - Health care costs: the shift goes on. PMID- 10117924 TI - A conversation with C. Everett Koop, M.D. PMID- 10117925 TI - Wellness promotes healthier employees. PMID- 10117926 TI - Reform group calls for universal access. PMID- 10117927 TI - Data watch. Tackling claims administration expenses. PMID- 10117928 TI - Growing home health care market is a boon for employers. PMID- 10117929 TI - The retiree health care question: to prefund or not to prefund? AB - Some experts say it's possible to control FAS No. 106 expense and liability by prefunding. Others say prefunding is an impractical solution for most companies. PMID- 10117930 TI - When companies must play God on a budget. AB - For companies that must decide whether to pay for experimental treatment not covered by the benefits plan, money is not the only determinant. Ethical questions come into play. PMID- 10117931 TI - A case study: lessons from a two-year-old point of service plan. AB - Marriott has saved $5 million by instituting a POS plan that allowed employees greater choice and contained health care cost increases. PMID- 10117933 TI - Progressive AIDS workplace policies offer many benefits. PMID- 10117932 TI - Uncle Sam tries to spread the managed care word. Interview by Joyce Frieden. PMID- 10117934 TI - Employers are demanding more from their claims administrators. AB - Companies that have negotiated performance-based contracts with their TPAs expect to save anywhere from 3% to 10% of their paid claims expenses. PMID- 10117936 TI - Ozarks employers make big strides. PMID- 10117935 TI - More employers self-insure their medical plans, survey finds. PMID- 10117937 TI - Is the federal health plan worth imitating? PMID- 10117938 TI - Let's care for employees--together. PMID- 10117939 TI - Medicare program; quarterly listing of program issuances and coverage decisions- HCFA. General notice. AB - This notice lists HCFA manual instructions, substantive and interpretative regulations and other Federal Register notices, and statements of policy that were published during October, November, and December 1991 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register at least every three months. We also are providing the content of the revisions to the Medicare Coverage Issues Manual published during this quarter. On August 21, 1989 (54 FR 34555), we published the content of the Manual and indicated that we will publish quarterly any updates. Adding the Medicare Coverage Issues Manual changes to this listing allows us to fulfill this requirement in a manner that facilitates identification of coverage and other changes in our manuals. PMID- 10117940 TI - Indian Health Service; statement of organization, functions, and delegations of authority--PHS. PMID- 10117941 TI - Health care programs: fraud and abuse; amendments to OIG exclusion and CMP authorities resulting from Public Law 100-93--HHS. Final rule; correction. AB - This document corrects technical errors that appeared in the final rule, published on January 29, 1992, that is designed to implement section 2 of Public Law 100-93, the Medicare and Medicaid Patient and Program Protection Act of 1987, along with other conforming amendments. PMID- 10117942 TI - Medicare program; offset of Medicare payments to individuals to collect past-due obligations arising from breach of scholarship and loan contracts--HCFA. Final rule. AB - This final rule sets forth the procedures to be followed for collection of past due amounts owed by individuals who breached contracts under certain scholarship and loan programs. The programs that would be affected are the National Health Service Corps Scholarship, the Physician Shortage Area Scholarship, and the Health Education Assistance Loan. These procedures would apply to those individuals who breached contracts under the scholarship and loan programs and who-- Accept Medicare assignment for services; Are employed by or affiliated with a provider, Health Maintenance Organization, or Competitive Medical Plan that receives Medicare payment for services; or Are members of a group practice that receives Medicare payment for services. This regulation implements section 1892 of the Social Security Act, as added by section 4052 of the Omnibus Budget Reconciliation Act of 1987. PMID- 10117943 TI - Advertising to seniors--keep it simple. PMID- 10117944 TI - Pinpointing the cost of caring for AIDS patients. PMID- 10117945 TI - Expanding their kingdoms. Annual survey finds chains in growth mode. PMID- 10117946 TI - Order of excellence. Invigorating innovations. Mary Conrad Center. AB - Contemporary Long Term Care's Order of Excellence is an annual tribute to the leading nursing homes and retirement communities in the nation. This program salutes the elite in long-term care. It singles out those providers that embody the leadership, vision and integrity that's so crucial to excelling in resident services, business management and facility design. The four recipients of this year's honors are the inaugural inductees. They will be joined every year by new members who also will be inducted into the Order of Excellence. Contemporary Long Term Care gratefully acknowledges the efforts of our editorial advisory board in selecting this year's inductees and thanks the corporate sponsors for their generous support of this program. PMID- 10117947 TI - Order of excellence. Research enriches care. MJHHA at Douglas Gardens. PMID- 10117949 TI - Order of excellence. Skillful management. The Renaissance. PMID- 10117950 TI - Nurses' far-reaching influence in CCRCs. Multi-faceted involvement is vital. PMID- 10117948 TI - Order of excellence. Impeccable service. Villa Campana. PMID- 10117952 TI - Therapeutic corridors and much more. Architectural interventions can enhance care. PMID- 10117951 TI - New medical devices reporting requirements. PMID- 10117953 TI - Overcoming labor shortages. A problem that can be managed. PMID- 10117954 TI - Budget deficits trigger shift to private payers. Payment cuts to be phased in. PMID- 10117955 TI - How to quell families' fears. PMID- 10117956 TI - Uncle Sam's liquidation sale. S&L bailout forces feds to auction facilities. PMID- 10117957 TI - What price peace of mind? Firms offer guidance for distant families. PMID- 10117958 TI - Physician reimbursement takes a turn for the better. New Medicare fees for nursing home visits unveiled. PMID- 10117959 TI - Breaking the ice. Simple steps help new residents feel welcomed. PMID- 10117960 TI - LTC software showcase 1992. PMID- 10117961 TI - Discovering how to do more with less. Incidental rehab improves functioning. PMID- 10117962 TI - The second time around. Recruiting inactive nurses. PMID- 10117963 TI - Children's prehospitalization conceptions of illness, cognitive development, and personal adjustment. AB - Although some empirical attention has focused on the predictors of children's reactions to surgery and hospitalization, few studies have examined the correlates of various dimensions of prehospital adjustment, even though there is some evidence that prehospital adjustment may be the best predictor of posthospital adjustment. This study included the investigation of several cognitive-related variables in association with the psychosocial adjustment of children 4 to 12 years of age who were scheduled for tonsillectomies and adenoidectomies at a Children's Hospital. Subjects were administered measures of illness conceptualizations, cognitive development, and adjustment a few days before hospitalization and surgery. The results indicated that illness concepts correlated highly with verbal receptive skills, conservation abilities, and age. Also, more sophisticated conceptualizations of illness, conservation skills, and age were associated with better prehospital adjustment, most noteably in the areas of lower levels of separation anxiety, anxiety about sleep, and apathy/withdrawal. PMID- 10117964 TI - Parents of children with chronic health impairments: a new approach to advocacy training. AB - Consumer advisory coalitions recognize the effectiveness of parents as advocates in obtaining services for their children with special health care needs. As a result, advocacy training programs for parents of children with developmental disabilities have become popular. Parents of children with chronic health conditions, who are not traditionally served through special education, find that they have concerns and needs not addressed by these advocacy training programs. This paper describes a unique program that targets these parents. A distinctive feature of this program is its focus on helping parents develop competency in utilizing communications skills to deal effectively with education and medical systems. PMID- 10117965 TI - Teacher, parent, and child evaluative ratings of a school reintegration intervention for children with newly diagnosed cancer. AB - The disruption of school participation and accompanying social experiences because of cancer and its treatment has been related to major problems in adaptation to the disease. For the child with cancer, continuation of his/her social and academic activities provides an important opportunity to normalize as much as possible a very difficult experience. The present study reports on the children's, parents', and teachers' subjective evaluations of the benefits of a comprehensive school reintegration intervention. Forty-nine children, newly diagnosed with cancer, received comprehensive school reintegration consisting of supportive counseling, educational presentations, systematic liaison between the hospital and the school, and periodic follow-ups. Children parents, and teachers were asked to rate their perceptions of the utility and value of the intervention approach. Overall subjective evaluations were very positive, providing support for the social validity of the school reintegration approach for children with newly diagnosed cancer. PMID- 10117966 TI - Psychosocial development of children with hemangiomas: home, school, health care collaboration. AB - Hemangiomas are among the most common neoplasms of childhood and often found on the face, head, and neck. In a society that places great importance on physical appearance, sustaining a hemangioma can significantly influence the psychosocial development of children. The purpose of this article is to briefly discuss the etiology of hemangiomas and provide practical suggestions for educators, health care professionals, and parents to foster the psychosocial development of children with a hemangioma. PMID- 10117967 TI - Parents' views of health care providers: an exploration of the components of a positive working relationship. AB - In spite of the growing recognition of the influence of interactions with health care providers on how patients and family members respond to illness, more research providing data-based conceptualizations of these interactions is needed. This paper contributes to the growing body of research on the nature of relationships between health care providers and consumers. Drawing on data from interviews with 102 parents (51 couples) of children with chronic illness, the authors explore provider behaviors that promote and sustain a positive working relationship with family members. PMID- 10117968 TI - Bankruptcy and risk allocation. PMID- 10117969 TI - Death, privacy, and the free exercise of religion. PMID- 10117970 TI - Intravenous admixture workload in a critical care pharmacy satellite. PMID- 10117971 TI - Computer experience in a drug information centre: taking the byte! PMID- 10117972 TI - Major drug information centres in Canada (February 1992). PMID- 10117973 TI - Infection correction. PMID- 10117974 TI - It's a bird! It's a plane! It's supermedic! PMID- 10117975 TI - Could this happen to you? AB - Some EMTs risk losing their lives by failing to protect themselves when responding to hazmat incidents. PMID- 10117976 TI - Mixed emotions. EMTs and paramedics are often ambivalent about treating the homeless. PMID- 10117977 TI - Reap the benefits of easy carpet care. PMID- 10117978 TI - The short-term effects of a fire safety education program for the elderly. AB - The high risk of fire death and injury among elderly people is well documented. To be effective, fire safety education must reach older adults in the settings in which they reside: nursing homes and other long-term care institutions, board and care homes, and independent living facilities including the person's own home. Training must also be targeted at the people who are responsible for fire safety. In the case of the nursing home or board and care home, the responsible people are the staff and owners. In the case of the majority of older adults who live independently in their homes, it is either the individual or family members. These programs must also be comprehensive. A fire safety education curriculum was developed by a group of experts in a variety of related fields including fire safety, gerontology, health care industry, developmental disabilities, research, and instructional design. Older adults were included in each planning session. Based on that curriculum, workshops and workshop materials were developed for each of the three target populations: staff of health care facilities, staff and owners of board and care homes, and elderly people living independently in their homes. Materials included both print and audiovisuals. A pilot test of each workshop was conducted to test the short-term effects of the programs. Results indicated significant gains in knowledge for all groups and a significant improvement in positive attitudes toward fire safety for most participants. Measures of effects of the programs on intentions to change fire safety practices indicated a potential for change. Results also showed that the measured traits, knowledge of fire safety and attitudes toward fire safety, were relatively stable. PMID- 10117979 TI - Southern hospitality. AB - Self Memorial Hospital's hostesses are the embodiment of a patient-oriented service philosophy instituted by Bob Borland when he created the $5-million-a year Hospitality Services department. PMID- 10117980 TI - The hidden costs of computerization. PMID- 10117981 TI - Lessons from the recycling veterans. PMID- 10117982 TI - Experience the possibilities. PMID- 10117983 TI - Choosing and using an ad agency. PMID- 10117984 TI - Fund-raising gala: a glittering success. AB - Calgary District Hospital Group used the opening of a shopping/entertainment center as a fund raiser. The event made everyone a winner. PMID- 10117985 TI - Burning fields vs. tending orchards: over-reliance on marketing techniques. AB - Marketing techniques are tools. They should not make us lose our focus--people give to people because they are inspired to do so. PMID- 10117986 TI - How to take care of aging parents. PMID- 10117987 TI - The search for the organization of tomorrow. PMID- 10117988 TI - The validation of interviews for estimating morbidity. AB - Health interview surveys have been widely used to measure morbidity in developing countries, particularly for infectious diseases. Structured questionnaires using algorithms which derive sign/symptom-based diagnoses seem to be the most reliable but there have been few studies to validate them. The purpose of validation is to evaluate the sensitivity and specificity of brief algorithms (combinations of signs/symptoms) which can then be used for the rapid assessment of community health problems. Validation requires a comparison with an external standard such as physician or serological diagnoses. There are several potential pitfalls in assessing validity, such as selection bias, differences in populations and the pattern of diseases in study populations compared to the community. Validation studies conducted in the community may overcome bias caused by case selection. Health centre derived estimates can be adjusted and applied to the community with caution. Further study is needed to validate algorithms for important diseases in different cultural settings. Community-based studies need to be conducted, and the utility of derived algorithms for tracking disease frequency explored further. PMID- 10117989 TI - How two competing hospitals collaborated on a surgicenter. PMID- 10117990 TI - Making alliances work. Interview by Donald E. Johnson. AB - As hospitals face ever increasing competition and the need for deep cost cutting, participation in alliances and multihospital systems can make all the difference in assuring a hospital's survival, says Allen M. Hicks, president of the MidWest Medical Center in Indianapolis. Hicks was instrumental in building Voluntary Hospitals of America and other multihospital systems, but now he works in the for profit hospital sector with Republic Health Care Corporation. In this interview with Health Care Strategic Management's Donald E. L. Johnson, he shares his views on the role that alliances should play today. PMID- 10117991 TI - HB/SNFs feasible, despite looming prospective payments. AB - Hospital-based skilled nursing facilities provide hospitals with favourable reimbursement levels because patient care is reimbursed according to costs rather than under a prospective payment system. The promise of case-mix Medicare reimbursements has not dampened the growth in the number of HB/SNFs. PMID- 10117992 TI - Effective medical staff planning stems from community needs. AB - Too often, hospitals rely on regional and national data in determining their medical staffing levels. In the planning process, they should include a careful analysis of local community demographics and health care needs as well as input from their current physicians. PMID- 10117993 TI - Starting with results. AB - As results are used to measure hospital performance, administrators must learn to recognize the interrelation of various outcomes measurements and balance their priorities. But most managers and marketers prefer being held accountable for measurable effort rather than for measurable results. PMID- 10117994 TI - CEO compensation storm requires telling it like it is. PMID- 10117995 TI - Market forecast indicators. Number of inpatients discharged from short-stay hospitals, by category of first-listed diagnosis, sex and age: U.S. 1990. PMID- 10117996 TI - Market forecast indicators. Avg. LOS for inpatients discharged from short-stay hospitals, by category of first-listed diagnosis, sex, and age: U.S. 1990. PMID- 10117997 TI - Planning indicators. Private sector pays less for health care. PMID- 10117998 TI - The new boundaries of the "boundaryless" company. AB - In an economy founded on innovation and change, one of the premier challenges of management is to design more flexible organizations. For many executives, a single metaphor has come to embody this managerial challenge and to capture the kind of organization they want to create: the "corporation without boundaries." According to Larry Hirschhorn and Thomas Gilmore of the Wharton Center for Applied Research, managers are right to break down the boundaries that make organizations rigid and unresponsive. But they are wrong if they think that doing so eliminates the need for boundaries altogether. Once the traditional boundaries of hierarchy, function, and geography disappear, a new set of boundaries becomes important. These new boundaries are more psychological than organizational. They aren't drawn on a company's organizational chart but in the minds of its managers and employees. And instead of being reflected in a company's structure, they must be "enacted" over and over again in a manager's relationships with bosses, subordinates, and peers. In this article, Hirschhorn and Gilmore provide a guide to the boundaries that matter in the "boundaryless" company. They explain how these new boundaries are essential for both managers and employees in coping with the demands of flexible work. They describe the typical mistakes that managers make in their boundary relationships. And they show how executives can become effective boundary managers by paying attention to a source of data they have often overlooked in the past: their own gut feelings about work and the people with whom they do it. PMID- 10117999 TI - Trial-by-fire transformation: an interview with Globe Metallurgical's Arden C. Sims. Interview by Bruce Rayner. AB - Globe Metallurgical Inc., a $115 million supplier of specialty metals, is best known as the first small company to win the Baldrige Award in 1988. But there is much more to this gutsy little company than total quality. During the 1980s, Globe transformed itself from a rust-belt has-been on the verge of bankruptcy into a high-technology, high-quality industry leader. Along the way, the company went private in a management-led leveraged buyout, embraced flexible work teams, adopted a high-value-added, niche marketing strategy, and took its business global. Leading the way in Globe's reinvention was Chief Executive Arden C. Sims, the slow-talking son of a West Virginian coal miner. When he joined the company in 1984, Sims had no experience in the new managerial techniques. He was a product of the old school of management: cut costs and trim operations to regain competitiveness. But he soon discovered that old-style management was not enough to battle offshore competitors, an unproductive work force, rising costs, and outdated production technology. He was forced to go looking for new ideas and practices. In a succession of learning experiences, Sims attended a seminar on total quality in 1985, paving the way for the company's quality program; he discovered the power of flexible work teams when management was forced to run the furnaces during a year-long strike; he organized an LBO, allowing him to change the work order even more dramatically; and he took the company global and into highly profitable niche markets by severing a long-standing relationship with Globe's sales and marketing representative. As a result of these and other changes, Globe leads the specialty metals industry in virtually all performance measures. PMID- 10118000 TI - The myth of Japan's low-cost capital. AB - The low rate at which U.S. companies are investing in manufacturing and the resulting decline in America's competitive position has been a topic of grave concern for more than a decade. During that time, critics have offered many excuses for this shortsighted investment behavior. Yet one excuse has steadily gained adherents and is becoming something of an article of faith--that is, that capital in the United States is more expensive than in other countries, particularly Japan. It is both a popular and appealing argument. Yet authors W. Carl Kester and Timothy A. Luehrman, professors at the Harvard Business School, warn that this argument is not only false but also dangerous. They assert that the empirical evidence does not support the claim that the U.S. manufacturing sector has persistently faced significantly higher average capital costs than the Japanese manufacturing sector. The authors argue that differences in capital costs have been isolated and temporary, not broad and persistent. To prove their point, Kester and Luehrman critically dissect both the common wisdom and the academic studies on the topic. They conclude that in the new global economy, all companies--Japanese, American, European, and others--must compete for the same capital. Some will succeed in obtaining it on temporarily favorable terms, not because they are Japanese but because they are efficiently organized and governed. But as long as an alleged international cost-of-capital gap is their excuse, U.S. managers run the risk of retaliating counterproductively against U.S. trading partners or doing nothing at all inside corporations. In short, managers should stop complaining about how much capital costs and worry more about how to manage it after it's been raised. PMID- 10118001 TI - The case of the high-risk safety product. AB - After several days of meetings, J.F. Winchester, president of MDC Industries, felt no closer to a decision. MDC, a manufacturer of wall and ceiling panels, was considering whether to exercise an option to buy a new and safer wallboard technology. The product was being touted as revolutionary, but, Winchester wondered, could MDC afford to carry the flag? According to its inventor, Robert Goerner, Smoke-Safe would be a vast improvement over standard safety-rated wallboard. With almost the same flame-retardant properties, Smoke-Safe had the advantage of giving off almost no fumes or smoke in fire tests. And, Winchester knew, most fire-related deaths are from smoke, not flames. Indeed, the numbers were grimly persuasive: 82% of fire-related injuries involving standard panels were caused by smoke inhalation. What's more, Smoke-Safe would cost about the same to manufacture as MDC's current wallboard. But MDC had several other good options for spending the $5 million Goerner was asking; building plastics was only one of its profit centers. And the prospect of launching a campaign to change building codes in order to market Smoke-Safe, which could spark a fight with competitors, was daunting. Since its current wallboard gave MDC only 18% of the wallboard market, many industry insiders speculated whether MDC had the market clout to influence major cities to revise their codes. Six experts in marketing, law, and ethics advise MDC Industries on how it can balance ethical and business imperatives in making its decision. PMID- 10118002 TI - Who should set CEO pay? The press? Congress? Shareholders? AB - Populist fervor in an election year has transformed executive compensation from a business issue into a political one. Critics, led by Graef Crystal, author of In Search of Excess: The Overcompensation of American Executives, charge that CEOs are ripping off shareholders with their outrageous salaries while running U.S. corporations into the ground. Politicians claim overpaid CEOs are the root cause of the U.S. competitiveness problem. Add a recessionary business climate to the fact that some CEOs earn 130 times more than their lowest paid employees, and you have the makings of a populist rebellion. In a bid to appease voters, Congress is considering several bills that would limit the deductibility of "excessive executive salaries," the SEC has opened the issue to shareholder comment, and the Financial Accounting Standards Board is looking at new accounting standards for granting stock options to executives as part of company compensation schemes. Andrew R. Brownstein and Morris J. Panner say it's time to put the debate back where it belongs--in a business context. The real question is not are executives paid too much, but are shareholders getting their money's worth. Most U.S. corporations use stock compensation to link company long-term performance to executive salaries. And because of the staggering market performance of U.S. corporations in the 1980s, an overwhelming majority of CEOs are actually paid in line with their performance. Rather than cut executive pay, Brownstein and Panner suggest that corporations extend incentive-based compensation plans to all employees, thus narrowing the salary gap and establishing pay for performance at every level of the organization. PMID- 10118003 TI - The purpose at the heart of management. AB - To succeed, startup enterprises need both passion and good management. But entrepreneurs can be famous for their visionary ardor and still be lousy managers. Traditionally, the key to long-term growth is getting the company founder to step aside so professional management can take over. Sometimes, however, this means abandoning a company's greatest asset in order to improve its procedures. A better solution is for the entrepreneur to learn to manage. Kye Anderson had motivation to spare. When she was 13, her 47-year-old father suffered recurrent shortness of breath followed by a massive heart attack. For her, the result was a single-minded career in medical technology and the development of innovative systems for diagnosing heart-and-lung disease. She had the zeal and determination it took to sell her ideas to investors and doctors, found a company, and grow it. But then, on the grounds that she lacked the financial and managerial expertise to carry her business from exuberant adolescence to profitable maturity, she stepped aside. A year and a half later, Anderson came back. She picked new board members who could act as entrepreneurial mentors. She reasserted certain original core values such as the importance of R&D and the emphasis on the patient as the ultimate customer. She discarded business lines that had strayed too far afield, and she learned how and what to delegate. Most important of all, Anderson realized that a leader's greatest obligation is to preach, and she began to spend much of her time communicating with her own employees about the purpose, mission, values, and strategy that could carry the company into a billion-dollar primary-care market. PMID- 10118004 TI - Corporate redemption and the seven deadly sins. AB - Competitive purgatory is the sorry state of too many formerly proud U.S. corporations. They are languishing from the devastating effects of seven familiar sins: inconsistent product quality; slow response to the marketplace; lack of innovative, competitive products; uncompetitive cost structure; inadequate employee involvement; unresponsive customer service; and inefficient resource allocation. To make matters worse, the maladies are mostly management-induced, and the remedies most managers are employing-shifting strategy, reallocating resources, focusing on operations--are proving ineffective. The cures don't address the cause of the disease: negative, risk-averse, bureaucratic work environments that flourished in decades of easy growth but today are undermining competitive performance. What's needed is a total reinvention of the soft side of the organization to produce a work environment that stresses speed, Spartanism, innovation, and marketplace focus. First, top managers must decide what their company stands for and convince their employees of this uniqueness. Second, they must set standards that drive their business to worldclass levels and be tough about enforcing and raising them. Third, they must push constantly to ensure that enough innovations take place to change the company's future significantly. Three other factors are crucial: the right talent, an effective reward system, and CEOs who can drive the desired changes personally. Creating a dynamic work environment is not easy: it takes perseverance, flexibility, and commitment. But these efforts will pay off: how people tackle problems, work together, and think about their jobs are the activities that make a company great. PMID- 10118005 TI - CFOs and strategists: forging a common framework. AB - Companies have become increasingly polarized into two divergent camps: those who consider shareholder value the key to managing the company and those who put their faith in gaining competitive advantage. Indeed, that age-old debate between investing for the long term and showing outstanding short-term results is back - only this time the camps are flying banners with the new buzzwords of corporate America: competitive advantage and shareholder value. In this article, Alfred Rappaport attempts to settle the debate once and for all, arguing forcefully that establishing competitive advantage and creating shareholder value both stem from a common economic framework. In fact, long-term productivity is the hinge from which both sustainable competitive advantage and consistent results for the shareholder hang. But many managers refuse to accept this theory and cling to the mistaken belief that the market does not actually value the long-term productivity of their company but judges it only by its short-term performance. They then jump to a second mistaken conclusion: assuming they must depart from the shareholder-value model to improve their competitive position. Rappaport attacks these mistaken beliefs, showing that the stock market does value the long term productivity of a company and that it is not necessary to depart from the shareholder-value model to improve a company's competitive position. Maximum returns for current shareholders will materialize only when managers maximize long-term shareholder value and deliver interim results that attest credibly to sustainable competitive advantage. PMID- 10118006 TI - New OSHA bloodborne pathogen regulations: promising start or too little, too late? PMID- 10118007 TI - Boren Amendment no shield against Medicaid payment delays. PMID- 10118008 TI - Physician payment reform: implications for the health care system. PMID- 10118009 TI - Sailing without safe harbors: physician recruitment and the law of fraud and abuse. PMID- 10118010 TI - Financing a national health insurance. AB - Financing national health insurance is a topic that has been discussed for a long time in the United States. It is also of relevance for less developed countries, in particular in the Far East where some countries have just introduced or are on the brink of introducing national health insurance. Furthermore, there is an urgent need to consult those former socialist countries wishing to introduce a national health insurance system. The paper deals with basic principles of health insurance and specific elements of a (compulsory) social health insurance in detail. PMID- 10118011 TI - Forecasting the impact of demographic change: the case of the British National Health Service. AB - By projecting trends over the period 1971-85 in discharge rates and lengths of stay in acute and geriatric National Health Service hospitals in England, it is estimated that by 1995 the discharge rate will have risen by 13% and average lengths of stay will have fallen by 26%. Combining these projections with current population projections for England, it is estimated that 13% fewer beds will be in daily use. These changes are shown to vary widely across specialties. The projections reveal that demographic change per se is a less important source of change than are changing activity rates. The 'trend' projections suggest that purchasers and providers within internal markets will have to take account of very different degrees of pressure between specialties. They can provide information which is essential for negotiations about local needs and local contracts. PMID- 10118012 TI - Setting priorities in prevention. AB - In the last few years prevention has again become the focus of attention because of various international developments such as the WHO strategy for Health for All by the year 2000. When resources are scarce, it is all the more important to set priorities. This applies to prevention as well as to curative care. In this paper, we describe a method for comparing prevention programmes with one another, using efficiency as the final parameter. To determine efficiency it is necessary to collect facts about a number of aspects of the health problems to be prevented: size of the health problem, degree of preventability, monetary and other costs involved and the probability that the prevention programme will cause changes in the overall pattern of morbidity and/or mortality. These aspects are discussed and some examples given. PMID- 10118013 TI - Achieving universal health insurance in Korea: a model for other developing countries? AB - As developing countries explore alternative methods to provide universal health insurance coverage, one potential model is South Korea. In twelve years (from 1977 to 1989), Korea was able to achieve universal health insurance coverage first by mandating employer based health insurance coverage for medium and large firms and then by establishing regional health insurance systems for small firms, farmers and the self-employed. A government medical aid insurance program was instituted for low income citizens. The specifics of the plan and some of the issues encountered in implementing the plan may be of interest to developing countries who want to achieve universal health insurance while maintaining a significant role for the private sector. PMID- 10118014 TI - Competition in health care delivery of the U.S.: panacea or poison? A critical view. AB - The U.S. are experiencing growth rates in health care cost, which in Europe have been reduced effectively in most states. The new strategy to reduce the cost increases relies heavily on price competition among providers. It is argued that while reducing cost among the paying patients, the constraints on the system will negatively effect the care delivery for the indigent population who are unable to pay for their health care services, revealing that savings are made on the back of the needy. As the U.S. health care system does not include care for those unable to pay for the services price competitive approaches will not be able to solve deficits of the American health care delivery system but rather lead to an increasing number of people who are in need of services, unless a national program to cover every American's basic health needs will be implemented. PMID- 10118015 TI - Economic evaluation of lipid lowering--a feasibility test of the contingent valuation approach. AB - A large number of cost-effectiveness analyses of treatment of high cholesterol levels have been published the last few years. Due to the inherent problems of cost-effectiveness analysis of prevention and the specific problems in the case of lipid lowering, it is important to test alternative approaches. This study reports the results of a pilot study of three benefit measures based on individual preferences. Willingness to pay (WTP), willingness to give up leisure time (WTGT) and maximum acceptable risk (MAR) for lowering cholesterol levels to normal were investigated among persons with hypercholesterolaemia in a postal survey. The respondents were on average prepared to pay about SEK 450 per month, to give up about 7 hours of leisure time per week or to take an immediate mortality risk of about 1.4% to get normal lipid levels. The WTP and WTGT questions seemed to be about equally acceptable, whereas the MAR question performed less well with respect to acceptability. It is concluded that especially WTP deserves further attention, due to its inherent advantages, since it performed at least as well as the other measures. PMID- 10118016 TI - Health related quality of life measurement--Euro style. AB - Several teams are attempting to produce generic health related quality of life measures: none, probably, as ambitious as the EuroQol group who are 'developing a standardised non-disease-specific instrument....with the capacity to generate cross-national comparisons' (EuroQol Group, EuroQol--a new facility for the measurement of health related quality of life, Health Policy, 16 (1990) 199-208). Unfortunately the instrument is flawed both conceptually and in its construction; it is unsurprising, therefore, that the response rates they obtain are so abysmal. Apart from these design faults, the main problem is the quite legitimate refusal of most normal people (respondents) to rate death on the same scale as health states. PMID- 10118017 TI - Monitrend II offers 4th-quarter '91 laundry data. PMID- 10118018 TI - Nine-story building gets the shaft--for two new staff elevators, that is. PMID- 10118019 TI - How to store and handle flammable, combustible liquids used in hospitals. PMID- 10118021 TI - ASHE (American Society for Hospital Engineering) celebrates member achievements. PMID- 10118020 TI - Chlorine, heat: popular ways to beat Legionella. PMID- 10118022 TI - JCAHO lists top causes of safety contingencies. PMID- 10118023 TI - Placement key to insect light trap effectiveness. PMID- 10118024 TI - Flooring options: carpet now a major contender. PMID- 10118025 TI - AIDS Resource Center. San Francisco's free counseling/testing facility inexpensively and sensitively designed by FACE. PMID- 10118027 TI - St. Dominic's. Thompson Design Associates of Reno, Nevada, heals the interior of this Manteca, California, acute care facility. PMID- 10118026 TI - Tuttleman Center. Stained glass murals help ease patient concerns in this hospital by KPA Design Group. PMID- 10118028 TI - N.Y. Hospital. Tony Mallen's sensitive design for the AIDS Care Center. PMID- 10118029 TI - Health care design. The growing health care field presents designers with new opportunities and new demands. PMID- 10118030 TI - Dawn of a new era for EKG interpretation. PMID- 10118031 TI - Potential liability of hospitals on corporate liability theory extended by Ohio decisions. PMID- 10118032 TI - AIDS: the management challenge for the 21st century. PMID- 10118033 TI - Long-term care for people with HIV/AIDS: challenges and opportunities. PMID- 10118034 TI - AIDS: the challenge for long-term care administrators. PMID- 10118035 TI - Economic issues in defining stable funding levels for HIV/AIDS research. PMID- 10118036 TI - AIDS in the 1990s. PMID- 10118037 TI - The management implications of HIV/AIDS: education for health executives. PMID- 10118038 TI - The response of health services management education to the AIDS crisis. PMID- 10118039 TI - The health services manager and the AIDS crisis. PMID- 10118040 TI - Building an AIDS/HIV research agenda for health management. PMID- 10118041 TI - HIV-related knowledge, attitudes, and stress among health care providers: a literature review and research agenda. AB - The role of health services administrators in assuring high quality care for HIV positive individuals and a physically safe, psychologically comfortable work environment for providers is an important one. Administrators need sound information on which to base policy and operational decisions about treatment of infected individuals. While the current literature provides some information in this regard, significant limitations and gaps remain. We have reviewed this literature and suggested a number of research issues that are relevant to administrative decision making. As the epidemic grows and changes in geographic diffusion and patient populations affected, empirical information to inform decision making will become even more critical. In addition, this information and the methods developed for data collection and interpretation in this area may be applicable to providers caring for a broader range of chronic conditions. PMID- 10118042 TI - Innovative strategies in AIDS education: the key to continued success. PMID- 10118043 TI - The Mock AIDS Task Force as an undergraduate health administration teaching device. PMID- 10118044 TI - A strategic approach to AIDS for rural communities. PMID- 10118045 TI - Patterns of illness behavior among rural elderly: preliminary results of a health diary study. AB - This paper summarizes the responses of rural elderly people to a variety of symptoms experienced during a three-week period. Responses to symptoms included causal attributions, consultation patterns, and intervention strategies. Data recorded in diaries during a three-week period highlight the importance of lay care in the illnesses of older people. Most symptoms were managed by older respondents themselves. When symptoms were discussed with someone else, the consultant was most likely a family member or friend rather than a health care professional. Only one third of the respondents contacted any formal provider about any of their symptoms. The majority of respondents combined medical and nonmedical explanations in interpreting their symptoms. The most frequent response to a symptom was doing nothing. The next two most commonly reported interventions were over-the-counter medications and activity limitation. Analyses revealed few differences among residential categories in patterns of illness behavior. Rural-urban differences often disappeared when controlling for demographic and socioeconomic background which covary with residence. PMID- 10118046 TI - A comparison of financial performance, organizational characteristics and management strategy among rural and urban nursing facilities. AB - Despite efforts to deinstitutionalize long-term care, it is estimated that 43 percent of the elderly will use a nursing facility at some point. Whether sufficient nursing facility services will be available to rural elderly is debatable due to cutbacks in governmental expenditures and recent financial losses among nursing facilities. This paper explores the challenges confronting rural nursing facilities in maintaining their viability and strategies that might be considered to improve their longevity. A comparative analysis of 18 urban and 34 rural nursing facilities in New Mexico is used in identifying promising strategic adaptations available to rural facilities. Among other considerations, rural facilities should strive to enhance revenue streams, implement strict cost control measures, emphasize broader promotional tactics, and diversify services commensurate with the constraints of the communities and populations served. PMID- 10118047 TI - Self-care and illness response behaviors in a frontier area. AB - Self-care and illness response to a recent medical event were examined based on a mailed questionnaire to a random sample of 416 adults in a frontier area in north central Idaho. A total of 494 questionnaires were returned (45% response rate), and 78 were eliminated. Self-care behaviors were classified as: (1) waiting to see what would happen, (2) purchasing or taking a nonprescription medication, (3) taking a prescription medication that was on hand, (4) taking both a prescription and a nonprescription medication, (5) contacting a physician, and (6) going to a hospital. These six variables were classified into three intervention constructs of no intervention (waiting), informal intervention (self-medicating), and formal intervention (contacting a health care professional). Fifty-six percent of the respondents reported self-medicating behaviors. Correlation analysis indicated that initial self-care and illness response behaviors in this frontier area were generally appropriate. Three multiple discriminant models were tested to differentiate those people who waited, self-medicated, and contacted formal providers from those who did not. A significant model could not discriminate between those who waited and those who did not. Models for self-medicating and contacting formal providers correctly classified cases 60 to 70 percent of the time. The analyses indicate that self-medicating was more likely to be reported by younger individuals, by those who lived further from the hospital, who perceived their health status to be better, who reported less satisfaction with community health care services, and that the self-medicating was appropriate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10118048 TI - Job retention of medical clerical Job Training Partnership Act trainees in rural health care settings. AB - According to the Bureau of Labor Statistics (cf. Crispell, 1990), the medical clerical field is one of the faster growing areas of employment. This paper reports on long-term employment of trainees involved in nontraditional medical clerical programs. These programs were funded by the Job Training Partnership Act (JTPA) and filled both the needs of the local rural health care facilities and the employment needs of unskilled youths and adults. These nontraditional students of low socioeconomic background and poor work history were successfully mainstreamed into university courses and consequently obtained productive employment. A follow-up study was conducted of 64 individuals who completed three different, one-year JTPA programs. The study investigated the following questions: Was the trainee currently employed? If so, was employment related to the training program, and were the quarterly salaries higher than minimum wage and previous salaries? How many different jobs were reported since training? Did the individual retain employment in a rural setting? The JTPA programs at Southern Illinois University included some innovative yet practical components that resulted in very high program completion rates, high initial placement, and a continuing pattern of long-term employment. These components included: emphasis on training for the most needed positions/jobs that matched university capabilities; the pursuit of higher starting salaries; informing participants of support services; training in job hunting and work readiness; using some individualized, competency-based instruction; establishing internship arrangements with prospective employers; and careful matching of the trainee to initial placement site with consideration of personality as well as skills. PMID- 10118049 TI - Containing health care costs in the United States. PMID- 10118050 TI - Health services for an aging society. PMID- 10118052 TI - Vertical integration in hospitals: a framework for analysis. PMID- 10118051 TI - Projected responses to changes in physician RBRVS reimbursement: induced-demand theory versus contingency theory. PMID- 10118053 TI - Public opinion about AIDS policies. The role of misinformation and attitudes toward homosexuals. AB - In an effort to better understand the cognitive and attitudinal factors underlying public opinion on AIDS-related issues, this article proposes and empirically tests a model of the relationships between (1) knowledge of HIV transmission, specifically the misinformation that AIDS can be transmitted easily through casual contact with HIV-infected persons; (2) attitudes toward homosexuals, the most prominent of the social groups presently affected by the AIDS crisis; and (3) support for restrictive public policies aimed at HIV infected persons. Data from two nationally representative surveys conducted in December of 1985 (N = 2,308) and in July of 1987 (N = 2,095) provide evidence that misinformation about AIDS transmission and negative attitudes toward homosexuals are strong predictors of support for stringent restrictions of persons with AIDS. The findings also suggest that several background factors, in particular, education and political liberalism, may also play decisive roles in influencing levels of support for restricting those infected with the AIDS virus. PMID- 10118054 TI - High-tech touches make service shine. PMID- 10118055 TI - Institutional giants face the waste issue. PMID- 10118056 TI - The relational structure of human services planning: an input-output analysis. AB - The relationship between human needs and human services can be quantified in terms of service standards and service units. A service standard is defined as the adopted norm for the minimum number of service units per person. The relationship between need, service (or care) and service standard is similar to the relationship between demand, supply and price in economics. Of particular interest in planning is the case where service units are given in terms of service providers per person. In a population where each person is considered to be a receiver of n categories of service and a provider of one category of service, the relationship between needs and services can further be presented in a service standard matrix. Examination of such a matrix shows that it fulfills a function analogous to the input-output matrix in economics. The principal eigen vector of the ser-vice standard matrix expresses ratios of activity levels for a human service system in an equilibrium. Another, related equilibrium is identified for a human service system in which there are providers as well as nonproviders. Application of the two equilibria identifies optimum planning conditions for the provision of human services when service standards and population are known. PMID- 10118057 TI - Management of nursing homes using data envelopment analysis. AB - Data envelopment analysis (DEA) is used to evaluate the relative technical efficiency and assist in the management of a chain of nursing homes. As with any DEA model, variables chosen are particularly important. The study looks at two possibly critical issues. The first is the appropriateness of models that include only financial and economic measures to evaluate administrators when quality care is an expected output. The second issue is the appropriateness of using noncontrollable variables, in this case operating income, to evaluate administrators. We show how efficiency scores differ when quality variables and/or operating income are included. We also demonstrate the usefulness of DEA information to both the home administrator and chain managers for improving operating efficiency. PMID- 10118058 TI - 1992 health guide. The top 10 health trends. PMID- 10118059 TI - American Laundry Digest distributors directory. AB - A state by state listing of companies that distribute laundry equipment (E), supplies (S), or other goods and services (O). PMID- 10118060 TI - Readers discuss "Managers recruiting managers" column. AB - Readers discuss "Managers Recruiting Managers" column. Our columnist Carl Shusterman expressed his views on finding your own successor, now see what some of our readers have to say about the subject. PMID- 10118061 TI - HIMSS (Healthcare Information and Management Systems Society) brings attention to the latest healthcare technology. PMID- 10118062 TI - Perspectives. Tight fiscal times force cooperation. PMID- 10118063 TI - Perspectives. Hawaii: universal care in paradise. PMID- 10118064 TI - Perspectives. Structured settlements: everybody wins. PMID- 10118065 TI - Perspectives. Family planning remains mired in politics. PMID- 10118066 TI - 40th Welch memorial lecture. Quality assurance: a personal commitment--a professional responsibility. PMID- 10118067 TI - The role of the technologist and consent to treatment. PMID- 10118068 TI - Skill acquisition during fieldwork placements in occupational therapy. AB - A critical shortage of occupational therapy fieldwork placements has led therapists to pose the question: how many hours of fieldwork are actually required in order for a student to acquire the breadth and depth of clinical competence required for entry level practice? In this study, student scores on the Performance Evaluation of Occupational Therapy Students, gathered over a four year period, were utilized to address this question. The level of competence expected of a new graduate on the CAOT Occupational Profile (Bridle, 1981) was used as the criterion against which student scores were judged. Statistical analyses were performed to determine the level of acquisition of occupational therapy skills and techniques, by item and by groups of items; to identify "core" and "specialty" items; and to determine whether 1200 hours of field work is the optimal choice for students to be able to demonstrate clinical competence in the field. Results indicate that, while most students attain many of the skills and techniques pertinent to occupational therapy, competence is reached only on those core skills which are frequently encountered and which have actually been experienced by the student across a number of placements. Recommendations include a re-examination by the profession of the expectations which have been set for an entry-level graduate. PMID- 10118069 TI - Clinical reasoning: an administrator's view. PMID- 10118070 TI - The manpower shortage in occupational therapy: implications for Ontario. AB - A consistently increasing imbalance between the supply of and demand for occupational therapists has led to a critical manpower shortage in occupational therapy. Based on a review of various government reports and related literature, this paper provides an overview of the extent of this manpower problem, identifies factors affecting retention and attrition of occupational therapists and discusses strategies to improve retention and reduce attrition. To address the supply-demand imbalance, recommendations in relation to education, employment, immigration and service delivery for the occupational therapy profession in Ontario are proposed. PMID- 10118071 TI - Strings attached. PMID- 10118072 TI - Thursday's children. PMID- 10118073 TI - My year of living dangerously. PMID- 10118074 TI - Under pressure. PMID- 10118075 TI - Credit where it's due. PMID- 10118076 TI - Counting the costs of legal claims. PMID- 10118077 TI - Crown duels. PMID- 10118078 TI - Good housekeeping. PMID- 10118079 TI - Love me tender. PMID- 10118080 TI - Casing the joint. PMID- 10118081 TI - Marking time. PMID- 10118082 TI - Children of the revolution. PMID- 10118084 TI - Data briefing. Family doctor service. National Association of Health Authorities and Trusts. PMID- 10118083 TI - All in a day's work. PMID- 10118085 TI - Managing risk: a priority in the health service. PMID- 10118086 TI - Ripe for change? PMID- 10118087 TI - A better pill to swallow. PMID- 10118088 TI - Right on cue. PMID- 10118089 TI - Mutual accord. PMID- 10118090 TI - Who needs fundholding? PMID- 10118091 TI - Personal touch. PMID- 10118092 TI - Smoke signals. PMID- 10118093 TI - Across the great divide. PMID- 10118094 TI - Against all odds. PMID- 10118095 TI - Quality improvement means better productivity. PMID- 10118096 TI - Productive work environments: how healthcare executives can stimulate productivity--an eight-step model. PMID- 10118097 TI - Patient-focused care. A macro approach to productivity and quality improvement. PMID- 10118098 TI - Ethical duties to employees. AB - Ethical standards of practice do not just happen automatically. They require explicit attention, articulation, education, practice, reinforcement, and rewards. PMID- 10118099 TI - Healthcare reform: the strategies. AB - Literally dozens of comprehensive national healthcare reform bills are pending in Congress. In capsule, here are the main plans under discussion. PMID- 10118100 TI - Taking charge of your performance review. AB - Make your efforts visible. Humility may be a virtue, but too much can obscure the very real contributions you make to your organization. PMID- 10118101 TI - Ethical policy statement--Responsibility to employees. American College of Healthcare Executives. PMID- 10118102 TI - Military and civilian healthcare--the facts. AB - There is much that military can bring to the civilian healthcare sector. They are often on the cutting edge of TQM, leadership training, and technology implementation issues. PMID- 10118103 TI - A demographic profile of Canadian public health nutritionists. AB - The purpose of this study was to obtain a comprehensive demographic profile of public health nutritionists employed in provincial and municipal/regional departments of health in Canada in 1988. One hundred and fifty three (78%) of all eligible Canadian public health nutritionists responded to a mailed questionnaire. Almost all (98%) respondents were female, with a mean age of 35.8 +/- 7.2 years. Most nutritionists (83%) worked full time, and had been employed in public health for a mean of six years and nine months. Seventy percent of respondents had worked in another profession(s) or other area(s) of nutrition prior to entering public health. Although 65% were members of the management team or represented by a nutritionist on the management team, 25% of nutritionists were not regarded as members of senior management in their health agency. While the majority of nutritionists in Ontario (84%) had completed a graduate degree, this was the case for the minority of respondents from British Columbia (35%), the Prairies (32%), Quebec (33%), and Atlantic Canada (27%). PMID- 10118104 TI - How an ethics panel can--and can't--help you. PMID- 10118105 TI - I've got to practice geriatrics in secret. PMID- 10118106 TI - Overlooking a source of help at your hospital? PMID- 10118107 TI - Will your Medicare claims stand up? AB - In the first two installments of our series, we gave you the details of reimbursement under the new Medicare fee schedule, and showed how to code evaluation-and-management services with the revised CPT system.* This issue, we'll tell what to expect from Medicare carriers as they teach and enforce the new payment rules. PMID- 10118108 TI - Psychiatrists keep me from helping my patients. PMID- 10118109 TI - How the phone lines can speed up your claims. PMID- 10118110 TI - Big houses can bring big trouble for doctors. PMID- 10118111 TI - Physician group offering to buy Nu-Med hospital, office building. PMID- 10118112 TI - Multi-unit providers ambulatory care survey 1992. Ambulatory facilities continue rise. PMID- 10118113 TI - Multi-unit providers home care survey 1992. All home care segments report gains. PMID- 10118114 TI - Case Western, hospital formalize affiliation. PMID- 10118115 TI - Variety of lures still used to land new docs--survey. PMID- 10118116 TI - Merger, sales on tap in Fargo, N.D. PMID- 10118117 TI - Fund to help hospitals pay bill for uncompensated care. PMID- 10118118 TI - 'Coordinated care' losing support on Hill. PMID- 10118119 TI - JCAHO gets tough on document falsification. PMID- 10118120 TI - REIT to trim holdings of head-injury care provider New Medico. PMID- 10118121 TI - Only 4 Blues indemnity plans are financially healthy--firm. PMID- 10118122 TI - U.K. revamp could be boon for U.S. suppliers. PMID- 10118123 TI - Insurance reform bills taking hits in House. PMID- 10118124 TI - High TB rate among hospital's docs may signal trouble for other facilities. PMID- 10118125 TI - Multi-unit providers hospital chains survey 1992. Hospital systems post fourth year of earnings gains. PMID- 10118126 TI - Tenn. reworks tax to square with new federal regulations. PMID- 10118127 TI - Vermont governor signs sweeping healthcare reform legislation. PMID- 10118128 TI - Drug firms exploit tax break--GAO. PMID- 10118129 TI - Multi-unit providers psychiatric hospitals survey 1992. Psych providers being buffeted by payer pressures, stricter scrutiny. PMID- 10118130 TI - Multi-unit providers rehabilitation hospitals survey 1992. Despite controversy, growth hasn't slowed in rehab segment. PMID- 10118131 TI - Disappointing results don't slow Ramsay plans. PMID- 10118132 TI - NME to close first facility in its reorganization. PMID- 10118133 TI - Multi-unit providers nursing home chains survey 1992. Long-term-care chains show slight growth. PMID- 10118134 TI - Multi-unit providers retirement centers survey 1992. Opportunities await in retiree communities. PMID- 10118135 TI - Healthcare Int'l to relinquish Dallas facility. PMID- 10118136 TI - Colorado hospitals post higher profits, Medicare shortfalls. PMID- 10118137 TI - Profits, spending up in Illinois--report. PMID- 10118138 TI - Ambulance service suing Mass. hospital. PMID- 10118139 TI - Fired CEO files $21 million suit against hospital, 3 physicians. PMID- 10118140 TI - NME cuts 2 psych hospitals, shrinks operations. PMID- 10118141 TI - AHA board unanimously OKs 'play-or-pay' reform proposal. PMID- 10118142 TI - Catholic Health Assn. cites reform-plan misconceptions. PMID- 10118143 TI - States in the eye of reform. AB - As the debate on a national healthcare reform strategy rages on, state lawmakers, hospital associations and other interest groups are taking action to address the thorny issues of access and financing. Florida, Minnesota and Vermont have enacted universal-access plans this year, and others are considering various market-based reforms. PMID- 10118144 TI - Revamped osteopathic hospital group flourishing. AB - Once on the brink of extinction, a restructured, relocated American Osteopathic Hospital Assn. is "well on the way to achieving its new mission," one observer says. The rebirth follows a near merger with the American Hospital Assn. in August 1990. Under new leadership, the group is growing, making money and expanding its advocacy of osteopathic medicine. PMID- 10118145 TI - Balanced-budget amendment has healthcare forces up in arms. PMID- 10118146 TI - Hospitals can avoid costly, frustrating searches for physicians by focusing on three key factors. AB - Finding a physician to fill a staff position can be a long, involved process that doesn't always end successfully. Hospitals can increase their chances of success by making sure the current medical staff fully supports the idea of a recruitment effort, having realistic candidate criteria and providing a competitive compensation package, says Daniel Ingram. PMID- 10118147 TI - Hospital forges ahead with its own bar code plan. PMID- 10118148 TI - Firms help companies carve savings from drug spending. PMID- 10118149 TI - REITs scramble to divest troubled tenants. AB - The decision by Health and Rehabilitation Properties Trust to trim its investments in rehabilitation provider New Medico Associates is another example of how real estate investment trusts are coping with shaky tenants. While most REITs are diversified and considered less at risk of losing investors' confidence, some have been penalized for holding troubled psych and rehab facilities. PMID- 10118150 TI - Hawaiian privatization nixed. PMID- 10118152 TI - Ore. hospitals neutral on tobacco tax hike. PMID- 10118151 TI - Mo. high court upholds malpractice law. PMID- 10118153 TI - Prof's plan sets up regional boards as hub of health reform. PMID- 10118154 TI - Fla. physician appeals ruling on antitrust claim. PMID- 10118156 TI - Columbia mulls acquisitions of hospitals, clinics in Houston. PMID- 10118155 TI - Coalition sets agenda for action in House. PMID- 10118157 TI - New York hospital to be site for 34-bed Planetree care unit. PMID- 10118158 TI - Greenery demands loan repayment. PMID- 10118159 TI - Probe prompts warning about rehab stocks. PMID- 10118160 TI - Ruling undermines hospital surcharge. PMID- 10118161 TI - 2 Calif. hospitals state case to Justice. PMID- 10118162 TI - PPRC proposes two tiers of physician payment. PMID- 10118163 TI - Plan for reform: whatever form it takes, some effects are sure bet. PMID- 10118164 TI - Hospital pays fine for teen's detention. PMID- 10118165 TI - Report outlines deep cuts under balanced budget. PMID- 10118166 TI - Hospitals struggle with the changing of the guard. AB - Not many chief executive officers want to think about the need to plan for the time when they're gone; even fewer do it. Even so, succession planning traditionally has been one of the CEO's main responsibilities to ensure the organization's long-term viability. However, some experts predict that only 10% of healthcare organizations have written down their succession plans. PMID- 10118168 TI - Minn. attorney general studies merger closer. PMID- 10118167 TI - Multi-unit providers HMOs/PPOs survey 1992. Provider-based plans improve performance. AB - Provider-based managed-care ventures that weathered the financial storms of the mid-1980s have accomplished their main goal--acquiring more patients without incurring staggering financial losses. Gains in enrollment have been solid, and improvements on the bottom line have been remarkable, especially in the not-for profit sector, according to this year's Modern Healthcare survey of HMOs and PPOs. PMID- 10118169 TI - Reclassification criteria change proposed. PMID- 10118170 TI - Despite questions of readiness, Defense Dept. to march ahead with hospital automation plan. PMID- 10118171 TI - CHC seeing fruits of efforts to improve communications. AB - Since its formation in 1980, the Catholic Health Corp. occasionally has grappled with conflict between central authority and individual hospital autonomy, often a result of fundamental communication problems. In response, the management company has begun a systemwide program aimed at simplifying the complex governance process and smoothing relationships between boards. PMID- 10118172 TI - Dems' reform plan lacks major access strategy. PMID- 10118173 TI - Program to take in-depth look at reform debate. PMID- 10118174 TI - Prices of healthcare stocks languishing; companies seek ways to interest investors. AB - The healthcare industry, which only six months ago was the darling of Wall Street, has fallen out of favor with investors. With prices generally down since the beginning of the year, some analysts are now referring to the sector as "health scare" stocks. As hospital companies feel the pressure to show big earnings gains, many are pursuing acquisitions, which are especially attractive in light of low interest rates. PMID- 10118175 TI - Institute to study tech's impact. PMID- 10118176 TI - Midwest sees drop in rate of climb. PMID- 10118177 TI - N.C. system files suit over state PPO plan. PMID- 10118178 TI - Panel OKs bills to boost access to VA. PMID- 10118179 TI - OR construction challenges for managers. AB - An OR building project is one of the biggest challenges a manager faces. With the dramatic changes in surgery, more managers will have that opportunity. Hospitals are adding on, renovating, and reconfiguring to serve a shifting market. What are the trends for health facilities? How do you gear up for a project? What should you know about the design process? And how do you survive construction--and moving day? In a series of articles in the next several months, veteran managers, planners, architects, and other experts will provide advice you can use so your new OR will be a safe, efficient environment for your patients, staff, and physicians. PMID- 10118180 TI - New facilities for outpatient services are patient oriented. PMID- 10118181 TI - CQI program decreases OR cancellations. PMID- 10118182 TI - Self-managed teams cross specialty lines. AB - OR Manager has been following efforts by Massachusetts General Hospital to restructure its OR nursing staff. Previous articles appeared in December 1990 and June 1991. PMID- 10118183 TI - Shift to OP surgery key issue in redesign. PMID- 10118184 TI - Violence in the healthcare setting. PMID- 10118185 TI - Falling between the cracks. AB - The cost of healthcare is crippling businesses in much the same way it's hurting families. Business and health provider parties must join forces. PMID- 10118186 TI - Enhancing interdepartmental relations. AB - In summary, it is important that the hospital manager have a positive attitude; recognize that not all projects will gain approval and that competition with others for scarce resources is a reality. A well throughout plan, anticipating questions, objections, and including affected departments, is a necessary first step to enhancing the manager's image. Being a polished orator is not essential, but being organized is. Most important, a progressive, "can-do" attitude is always respected by others. PMID- 10118187 TI - Controlling personal liability of the pension trustee. PMID- 10118188 TI - The Safe Medical Devices Act. AB - According to some estimates, one in every four consumer dollars is spent on products regulated by the FDA. You need to know about this Act's new mandatory reporting requirements. PMID- 10118189 TI - Coffee and doughnuts ... plus a whole lot more. PMID- 10118190 TI - Patients delight in chef's specials. PMID- 10118192 TI - Nicotine intervention for hospitalized smokers. PMID- 10118191 TI - It's all in the family. PMID- 10118193 TI - Sickness meets wellness. PMID- 10118194 TI - The safe harbors. PMID- 10118195 TI - Impact of a multidisciplinary, collaborative approach to implement and enforce an automatic stop order policy. AB - Although an automatic stop order (ASO) policy is mandated by the Joint Commission on Accreditation of Healthcare Organizations, the policy remains unenforced or exists only "on paper" in some hospitals. Strict enforcement of an ASO can lead to improvement of patient care by requiring physicians and other healthcare professionals to periodically review a patient's drug regimen. Following the approval of an ASO policy by our facility's pharmacy and therapeutics (P&T) committee, an audit of 160 orders of controlled substances revealed that 75 orders (47 percent) were continued for more than one dose without a physician's renewal order. This problem was then brought to the attention of the P&T committee where a decision was made to resolve the situation using a multidisciplinary, collaborative approach. With the help of all of the healthcare professionals involved in this issue, as well as our computer network, a system for strict enforcement of the ASO policy was subsequently implemented and has proven to be successful. PMID- 10118196 TI - Pharmacy technician competency. Part IV: Attitudes. PMID- 10118197 TI - Impact of pharmaceutical sales representatives on physician antibiotic prescribing. AB - This study revealed a significant impact on physician prescribing practices by PSRs, based on the results of evaluations of each agent's average number of new prescriptions per month, number of grams dispensed per month, and dollar values of those prescriptions. Comparisons of these data to regional, national, and world trends revealed no correlation. PMID- 10118198 TI - Feminist directions in medical ethics. AB - I explore some new directions - suggested by feminism - for medical ethics and for philosophical ethics generally. Moral philosophers need to confront two issues. The first is deciding which moral issues merit attention. Questions which incorporate the perspectives of women need to be posed - e.g., about the unequal treatment of women in health care, about the roles of physician and nurse, and about relationship issues other than power struggles. "Crisis issues" currently dominate medical ethics, to the neglect of what I call "housekeeping issues." The second issue is how philosophical moral debates are conducted, especially how ulterior motives influence our beliefs and arguments. Both what we select - and neglect - to study as well as the "games" we play may be sending a message as loud as the words we do speak on ethics. PMID- 10118199 TI - Ethical considerations in a surgical residency. PMID- 10118200 TI - Research and hospital ethics committees in Switzerland. AB - This paper presents the situation concerning research and hospital ethics committees (HEC) in Switzerland. In fact, HECs are almost nonexistent. All the so called "Ethics Committees" deal with the review of research projects. As there is no legislation governing research on human subjects, the Swiss Academy of Medical Sciences (SAMS) has issued guidelines concerning research on human subjects and, more recently, guidelines concerning Research Ethics Committees (REC). There is a wide disparity in the composition and the functioning of these committees, however. Half of them belong to university hospitals. Six of them review two thirds of all reviewed protocols. Many RECs function more as educational bodies to enhance the quality of submitted protocols than as committees having the task to control and prohibit particular research projects. PMID- 10118201 TI - Hospital ethics committees: problems in evaluation. AB - Hospital ethics committees continue to proliferate, despite the fact that their impact upon practice has not been rigorously evaluated. This paper investigates the reasons why the often recommended evaluation has not yet occurred. One reason cited is that three different roles - education, policy formulation, and case review - need to be assessed. The principal reason why the most novel of the roles, case review, has not been evaluated is because of unresolved dispute over the goals of review. PMID- 10118202 TI - A call for a HEC network in the military health care system. PMID- 10118203 TI - Selected bibliography on HECs. PMID- 10118204 TI - Perspectives. ERISA sets roadblock for state health reform. PMID- 10118205 TI - Is it time to upgrade your weather system? PMID- 10118206 TI - Pilot training simulators. PMID- 10118207 TI - Public relations and the pilot. PMID- 10118208 TI - Professionals belong! PMID- 10118209 TI - Annual transport statistics. PMID- 10118210 TI - Airway management and air medical transport. AB - A 5-year retrospective review of airway management by flight nurses was conducted to evaluate airway care and to determine the frequency of surgical cricothyrotomy. Intubation was attempted in 51% of patients, with a success rate of 80%. Oral intubations were attempted in the remaining patients and in those patients in whom initial attempts at nasal intubation failed, with a success rate of 81%. The success rate for intubations was 72% in 1985, 95 % in 1986, 92% in 1987, 97% in 1988, and 76% in 1989. Overall, 87% of patients were successfully intubated and surgical cricothyrotomy was required in only one patient. A greater success rate was achieved when intubations were performed before takeoff than during flight. PMID- 10118211 TI - COSHH (Control of Substances Hazardous to Health) in the NHS--beyond awareness: the practical assessment of risk. AB - This paper describes one approach to practical COSHH assessment developed for the (Scottish) Health Service. For completeness, the COSHH Regulations and corresponding Approved Code of Practice are reviewed from the point of view of undertaking a practical assessment of risk in hospitals. An assessment pro-forma developed for a Scottish Health Board is outlined. A hospital COSHH case study is briefly described. The training of health service COSHH assessors is considered. Finally, the need for a management approach to health and safety based on development and implementation of a suitable safety management system is proposed. PMID- 10118212 TI - Cogeneration. Austin Hospital leads the way. PMID- 10118213 TI - Report on impact of interstitial space on renovations of GICU (general intensive care unit). PMID- 10118214 TI - COSHH (Control of Substances Hazardous to Health)--the priorities for the NHS. AB - Managing COSHH is like managing anything else: define the issues; evaluate the priorities; select management options; implement them and monitor the outcome. In COSHH terms this means inventories, assessments, control measures and auditing. But much of the identification and assessment work should be centralised--after all, the hazards and risks arising from Glutaraldehyde usage or painting with eggshell paints is virtually identical not just across a hospital, but across a District and Region. That is why the Hospital Helpline was established, and has been such a success--a core of COSHH assessments made available to all, so that efforts can be focused on what COSHH is about, after all they are the Control not the Assessment Regulations. PMID- 10118215 TI - Health surveillance under COSHH (Control of Substances Hazardous to Health). PMID- 10118216 TI - Beating the odds. AB - The five core causes of health claims can be reduced if organizations focus on the "at-risk" employees who compose 10 percent of the workforce. PMID- 10118217 TI - Achieving benefit program objectives. PMID- 10118218 TI - The Medical Waste Tracking Act's impact on the hospitals within the demonstration program. AB - Despite indisputable evidence that it is not harmful, the medical waste issue just will not die. Congress is considering new, even tougher medical waste regulations; more and more states are enacting their own rules; hospitals are running out of reasonable options. In this issue, HHMM publishes the VHA medical waste cost study. CHEM feels that the survey is important because it demonstrates in hard numbers how medical waste regulation has increased the cost of healthcare. Hospitals should make sure that their state and local associations are aware of the VHA study--and they should pass it on to their congressional representatives and senators. If lawmakers will not be persuaded by technical reports, perhaps they will pay attention to cold cash. PMID- 10118219 TI - Taking California health insurance into the 21st Century. AB - California's system of financing and delivering health care is coming apart at the seams. High costs and large numbers of uninsured leave too many of the state's residents vulnerable to illness and exorbitant health care bills. A plan to reform the system must include: universal access, cost containment, equitable financing, a choice of systems, a unified plan, shared risk, and a greater emphasis on disease prevention. PMID- 10118220 TI - Community care networks: cornerstone of health care reform. AB - Calls to reform the American health care delivery system include proposals to expand access to insurance and to impose expenditure controls. That approach is flawed and could only lead to an increase in costs. To truly reform the system, the U.S. must fundamentally alter its health care delivery system. One proposal is to create community care networks to coordinate the care of patients. Such a system could operate under a capitated payment system that is publicly accountable. PMID- 10118221 TI - Stepping up to bat: states take the lead on health policy. AB - Long considered a training camp for Congress, state government has come into its own and now is leading the way on health reform. A transfer of some authority from Washington has helped to energize governors, legislators, and regulators. In an ironic sense, recession pressures have led to some innovative policymaking. Key leaders at the state level hope their efforts will help to break the national stalemate over health reform. PMID- 10118222 TI - New Hampshire, health care, and the 1992 election. AB - A poll of New Hampshire voters who participated in the February 17 presidential primary shows that the recession and overall concern for the economy was the most important factor in determining the outcome of the election. Health care and national health insurance ranked second, significantly outranking concerns over all other issues. When presented with the leading policy options for health care reform, the majority of voters favored a plan that would guarantee universal coverage by law--either a "play or pay" plan or an all-government plan. However, even though a majority of voters favored universal coverage, they also preferred plans that would make insurance available through private insurers rather than through an all-government plan. PMID- 10118223 TI - The art of the deal: health policy making on the fly. AB - In September 1991 the Health Care Financing Administration touched off a two month scramble by issuing regulations sharply curtailing states' use of voluntary donations and provider taxes to raise money for Medicaid. Days and nights of intrigue and dealmaking followed. Finally, on the day before Thanksgiving, Congress, the Administration, and the nation's governors agreed to a deal that may resolve the matter. During the course of those talks, all sides honed their negotiating skills and, in the process, uncovered basic flaws in the U.S. health care system. PMID- 10118224 TI - An American in London: the revolution in British medical care. AB - The failings of the creaky British National Health Service have helped spur the growth of a healthy private insurance business but the country still lacks the sort of competitive, consumer-oriented business culture that is prominent in the U.S. The problems of the NHS beg for more American-style innovation, including such modernization as managed care, utilization review, and ambulatory care. Changes made in recent years will ease the path to such improvements. PMID- 10118225 TI - Health care spending controls: a menu of approaches. AB - Health care costs are a driving force in the current health reform debate. Efforts to constrain costs include aggregate fiscal constraints, as well as changes in a combination of price and/or volume within the system to reduce total spending. PMID- 10118226 TI - Rewriting the definition of charity hospitals. PMID- 10118227 TI - Doctor Dean's prescription for health care reform. AB - One of the nation's smallest states is taking big steps to ensure universal access to health care for all of its citizens. Vermont will create a purchasing pool of public employees, individuals, and businesses who will enroll in a consolidated community-rated insurance plan. A new dispute resolution system will try to remove malpractice suits from the courtroom. Vermont's efforts are needed to show that states can and should develop universal systems of care, so that when a national system is produced states will be the only logical choice to run it. PMID- 10118228 TI - Under fire: insurers' leader absorbs the blows. PMID- 10118229 TI - Health law. The fuss over computer-based records. PMID- 10118230 TI - Contracting with photocopy services. PMID- 10118231 TI - Joint Commission activities. PMID- 10118232 TI - An ethical dilemma: coding medical records for reimbursement. AB - Coding accuracy is difficult enough with inconsistent and incomplete medical records adding to the challenge. But since the HCFA implementation of DRGs in 1983 to determine Medicare payments, coding has taken on an ethical dimension. In this article Leslie Ann Fox discusses the causes underlying this dilemma and proposes some solutions. PMID- 10118233 TI - Computer assisted coding quality management. AB - The increasing importance of accurately coded data cannot be overlooked. Although shortages of staff, time, and feelings of inadequate expertise exist, these barriers can be overcome by using computers as a basis for a focused review system that is incorporated into the daily coding routine. PMID- 10118234 TI - Developing a quality management program for coded data. AB - Improving the process of coding data is one important way health information professionals can fulfill their mission of "Quality Healthcare through Quality Information." This article describes principles of continuous quality improvement applied to the coding process. PMID- 10118235 TI - Continuous quality improvement of coded data: a data quality study for Category 650. AB - The AHIMA Council on Coding and Classification conducted a study on the use of category code 650, "delivery in a completely normal case." The findings are presented here as a sample of a data quality study. PMID- 10118236 TI - Functions of the Coordination and Maintenance Committee and modifying the ICD-9 CM, Volumes 1 and 2. AB - Balancing the multiple uses of ICD-9-CM with its central purpose as a statistical classification system is the function of the Coordination and Maintenance Committee. This article describes the process to modify diagnosis and procedure codes and how AHIMA members can contribute to improving ICD-9-CM. PMID- 10118237 TI - HIM Technology Committee. PMID- 10118238 TI - Highlight on coding. PMID- 10118239 TI - AHIMA position statement. Issue: Names of information-related departments. PMID- 10118241 TI - Oasis comes to the FORE: health information management model on display. PMID- 10118240 TI - AHIMA position statement. Issue: Patient access to personal health information. PMID- 10118242 TI - Advance directives. PMID- 10118243 TI - Advance directives--medical record aspects of the Patient Self-Determination Act. AB - The next several years should bring forth a great deal of both law and lore on the implementation of the PSDA. Health information managers should be close to all of these developments and, state by state, in a position to contribute to the accomplishment of the public policy goals reflected in the enactment of the PSDA. PMID- 10118244 TI - 1992 Accreditation Manual for Hospitals adds patient rights chapter. PMID- 10118245 TI - Coding notes: cardiac devices. PMID- 10118246 TI - Clinical notes: cardiac catheterization. PMID- 10118247 TI - Medical record access laws. PMID- 10118248 TI - Information technologies. Optical image storage and retrieval. PMID- 10118249 TI - Information technologies. Telephone access to dictated reports. PMID- 10118250 TI - Leadership logic. PMID- 10118251 TI - Information technologies. Physician-hospital networks. AB - Patient care efficiencies and quality of care improvements require progressive efforts to integrate the patient information systems and allow for on-demand accessibility to authorized information users. The dilemma facing the designers and managers of these systems is that each step toward improving accessibility seems to introduce another potential information leakage point. We are reminded once again that information is a very difficult resource to control because it is possible to steal it without removing it physically from its storage place. The essence of information security in physician links is captured by establishing mechanisms for identifying system users, limiting user authority, assuring the privacy of transmitted data, and monitoring system use and users. PMID- 10118252 TI - Alternative staffing services. Off-site coding. PMID- 10118253 TI - Alternative staffing services. Correspondence copiers. PMID- 10118254 TI - Alternative staffing services. Contract transcription. AB - Contract medical transcription services can be of great assistance in meeting the demands for transcription, without jeopardizing patient, physician, or institutional confidentiality. You simply must require the contract service to provide at least the same degree of protection and preservation of confidentiality that you should require inhouse. To achieve this you must make these requirements explicit, comprehensive, comprehensible, believable, and enforceable. Discuss the requirements with prospective contractors. Review them at least annually with existing contractors and when contracts are due for renewal. Be sure to specify the consequence of breaching confidentiality, and if there are breaches, enforce the terms of the contract. Consult your institution's legal counsel both in developing the contract and in enforcing its provisions. Take into consideration your department's and institution's policies, AHIMA's statement on confidentiality, as well as local, state, and federal laws. Above all, never lose sight of the patient. Ultimately, it is not patient information that you are obligated to protect. It is the patient. PMID- 10118256 TI - Patient champions: CHIA (California Health Information Association) confidentiality strategy. PMID- 10118255 TI - Socially responsible programs. Healthcare recycling plans. PMID- 10118257 TI - Gene mapping: is fortune or misfortune to be found? AB - An attempt to map the entire human genetic code, collectively referred to as the human genome, raises expectations of medical advances as well as moral dilemmas. PMID- 10118258 TI - Healthcare costs: America can't afford to be sick. AB - The pricetag on the nation's healthcare can stagger the imagination. But reform efforts have backfired, adding even more complexity to an already complex system. PMID- 10118259 TI - The computer-based patient record: risks, security, and the HIM role. PMID- 10118260 TI - The hardware components of a computer system. AB - The two goals of this article are to give you a very brief overview of the evolution of computing and an introduction to the elements of a computer. The birth of the modern computer can be traced to John von Neumann. The model he proposed consisted of four major parts: the control unit, the arithmetic unit, the memory, and the input/output unit. His concept for a "stored program" computer provided the foundation for five decades of computer designs. PMID- 10118261 TI - The concern for accurate, quality registry data. AB - The effective use of registries is critical to modern healthcare information management. But you've got to be careful in applying the data. PMID- 10118262 TI - Managed mental health care. PMID- 10118263 TI - Employers and providers in Iowa join to improve health care. PMID- 10118264 TI - A partnership takes a gamble to measure quality. AB - An alliance of employers and providers will be tested this summer when employers will be faced with the choice of keeping--or severing--relationships with certain hospitals. PMID- 10118265 TI - Hospital chain teams up with suppliers for quality improvement. PMID- 10118266 TI - Prenatal teamwork fosters an employer/employee partnership. PMID- 10118267 TI - Interactive video promotes patient-doctor partnership. PMID- 10118268 TI - An interview with Senator Durenberger. PMID- 10118270 TI - How a joint audit can improve point-of-service plans. AB - Marriott and Sears combined forces--and funds--to audit their managed care networks in California. PMID- 10118269 TI - Long term care insurance: the Rx for a graying America. AB - Connecticut's 10-year experiment adds a new wrinkle to LTC policies. More employers may add the benefit. PMID- 10118271 TI - Garamendi health reform plan relies on public-private partnership. PMID- 10118272 TI - New partnerships are key to reform. PMID- 10118273 TI - Software for hard issues. Who will live? Who will die? A computer votes. PMID- 10118274 TI - Federal Employees Health Benefits Program: limitation on inpatient hospital charges and FEHB program payments--OPM. Interim regulation with request for comments. AB - The Office of Personnel Management (OPM) is issuing an interim regulation that implements section 7002(f) of the Omnibus Budget Reconciliation Act of 1990 (5 U.S.C. 8904(b)). The law sets a limit on the charges and Federal Employees Health Benefits (FEHB) Program benefit payments for certain inpatient hospital services received by a retired enrolled individual. This regulation defines a retired enrolled individual and sets forth the circumstances under which the limit on charges and FEHB Program benefit payments takes effect. PMID- 10118275 TI - Occupational exposure to bloodborne pathogens; approval of information collection requirements--OSHA. Final rule; approval of information collection requirements. AB - On December 6, 1991, OSHA published a final standard governing occupational exposure to bloodborne pathogens (56 FR 64004). The standard is designed to eliminate or minimize occupational exposure to Hepatitis B Virus (HBV), Human Immunodeficiency Virus (HIV) and other bloodborne pathogens. At that time OSHA submitted the information collection requirements to the Office of Management and Budget (OMB) for review under section 3504(h) of the Paperwork Reduction Act (PRA) of 1980. Public reporting burden for this collection of information was estimated to average five minutes per employer response to an OSHA compliance officer's request for access to the employer's records. OMB reviewed the collection of information requirements for occupational exposure to bloodborne pathogens in accordance with the PRA, 44 U.S.C. 3501 et seq., and 5 CFR part 1320. OMB approved all information requirements contained in 29 CFR 1910.1030 under OMB clearance number 1218-0180. The OMB clearance expires on February 28, 1995. This document will also amend the December 6, 1991 rule to properly display the OMB control number. PMID- 10118277 TI - Abnormal occurrences for fourth quarter CY 1991; dissemination of information- NRC. PMID- 10118276 TI - Availability of clinical practice guidelines on Acute Pain Management: Operative or Medical Procedures and Trauma and Urinary Incontinence in Adults--AHCPR. PMID- 10118278 TI - Marketing is a science--not an art. Sophisticated strategies for tough times. PMID- 10118279 TI - Instituting employee drug abuse testing. PMID- 10118280 TI - The search for capital intensifies. Tighter credit criteria constricts new deals. PMID- 10118281 TI - Five reasons why Medicare makes sense. Part A participation is on the rise. PMID- 10118282 TI - How to shine during inspections. Don't leave aides in the dark about surveys. PMID- 10118283 TI - Long-term care administration and liability issues. PMID- 10118284 TI - Launching an agency ethics committee. AB - Home care agencies and family members are confronted on a daily basis with ethical issues that have a strong impact on methods of operation and care. Where can they turn for guidance when these ethical dilemmas occur? An ethics advisory committee has proven an effective and powerful answer in a VNA setting. PMID- 10118285 TI - Case studies in reconciling ethical differences. AB - Life-sustaining and end-of-life issues have a significant impact on both hospice and home care providers. Reaching consensus is difficult when families and caregivers hold differing opinions and emotions. Exemplary case consultations can serve as guides to reconciliations that promote mercy, prevent misery, and integrate morality. PMID- 10118286 TI - The friendship of hospice. AB - How can hospice caregivers provide better care? By cultivating the virtue of friendship as it relates to the ethical principle of "justice" in care. Friendship then becomes a paradigm for hospice care as caregivers--the new friends to the patient and family--enter another person's life during its final stage. PMID- 10118287 TI - The client's right to self-determination. AB - Home care providers must integrate clients' best interests with their right to self-govern their plan of care. This balancing act poses myriad ethical dilemmas for caregivers. PMID- 10118288 TI - Developing an organizational ethos. AB - A code of ethics and an ethics committee are tools that can improve the quality of the ethical judgment calls that home care agencies and their hands-on providers face daily. PMID- 10118289 TI - We can't abandon the elderly client. AB - An interdisciplinary team approach, supported by the ethics committee, is essential to managing effectively the difficult-to-service client living in an urban setting. At New York's Calvary Hospital's Certified Home Health Agency, this process has distributed decisionmaking and planning of care throughout all levels of personnel, improved staff morale, and brought desperately needed home care services to patients society has abandoned. PMID- 10118290 TI - Effective communication: basic to discharge planning. PMID- 10118291 TI - Two studies focus on interpreter services. PMID- 10118292 TI - The executive discharge planning review board. PMID- 10118293 TI - Disagreements in discharge planning. PMID- 10118294 TI - AIDS placement: turning the tide. PMID- 10118295 TI - Effective communication: a nondeficit approach. PMID- 10118296 TI - Interpreter services. A mandate to meet the challenge. PMID- 10118297 TI - Environmental Services internal quality assurance program. PMID- 10118298 TI - Non-acid bathroom cleaner kills HIV-1. PMID- 10118299 TI - Disaster planning keeps facility ready for any emergency. PMID- 10118300 TI - Do you spell sharps ouch? PMID- 10118301 TI - Finding a niche in the vast field of health care. PMID- 10118302 TI - Rationing: the unspoken issue. PMID- 10118303 TI - Three for the money. PMID- 10118304 TI - Planning to reach your full potential. AB - Abington Memorial Hospital puts great store in imagination and creativity in designing its fund-raising programs. The results speak for themselves. PMID- 10118305 TI - Why donors give. PMID- 10118306 TI - How to handle donor complaints. AB - Responding to donor complaints takes great care. But know who's complaining and keep things in perspective. PMID- 10118307 TI - Understanding strong donors. PMID- 10118308 TI - The CEO's secret of managing time. PMID- 10118309 TI - Community hospitals set sights on clinical research. PMID- 10118310 TI - Variety of factors to determine potential nursing home market. AB - As the nation ages, how will hospitals and other providers determine how to care for a growing patient population--those requiring nursing home beds? In the following article, the authors discuss nursing home demand projection methodologies that could be useful for administrators who want to pursue this patient population as a market area. The plausible solution, they note, is a composite approach that focuses on historical trends and both clinical and referral sources. PMID- 10118311 TI - Consumers link size, quality in rating U.S. hospitals: study. AB - The competitive environment in the health care industry nationwide is forcing hospitals to constantly reexamine their place in their immediate market. How do potential patients view them? How do perceptions change with the size and location of the institution? Do consumers link quality with such factors as census mix? In the following article, the author discusses the results of a survey that examines those trends. PMID- 10118312 TI - Develop long-range plan for clinical research. PMID- 10118313 TI - Consolidation benefits community. Interview by Donald E.L. Johnson. AB - Multi-unit hospital systems remain one of the important players in health care during the 1990s. But, what model works best for bringing superior care to a community or region? In the following interview with Health Care Strategic Management's Donald E.L. Johnson, Donald C. Wegmiller, President/CEO of Health One, a health care corporation offering services in 12 outlying communities in five states, as well as metropolitan Minneapolis-St. Paul, defines his vision for such a system and the community benefits that hospitals should be providing and measuring. PMID- 10118314 TI - Adult hospice day care. AB - This article describes the concept of adult hospice day care, argues that programs of adult hospice day care can be an important adjunct to home care and inpatient care, and provides a concrete illustration of ways in which a typical program of adult hospice day care might be implemented. PMID- 10118315 TI - Would patient care be better served if there were greater government regulation of physicians' financial arrangements? Yes: physician 'self-dealing' requires reform. PMID- 10118316 TI - Would patient care be better served if there were greater government regulation of physicians' financial arrangements? No: a rational view of joint ventures. PMID- 10118317 TI - Physician ownership after the Stark Bill and the Safe Harbors. PMID- 10118318 TI - At the helm in a time of reform. Interview by C. Burns Roehrig. PMID- 10118319 TI - Physicians and change: what to expect in 1992. PMID- 10118320 TI - Changes in Medicare for 1992. American Society of Internal Medicine. PMID- 10118321 TI - Physician 'self-referral': what do the studies really show? PMID- 10118322 TI - Not with a bang but a whimper: health reform in 1992. PMID- 10118323 TI - Grassroots advocacy makes a difference: delivering the message. PMID- 10118324 TI - New OSHA standards put legal force behind universal precautions. PMID- 10118325 TI - Hospital-physician joint ventures: updated for the '90s. PMID- 10118326 TI - Between the lines. AB - Germany's successful healthcare system avoids the problems of rationing, access and patient choice which afflict both state and market-dominated systems. But problems of accountability, cost, and equity need to be tackled--the purchaser/provider split has been a recipe for expensive care, argues Michael Moran. PMID- 10118327 TI - Power sharing. PMID- 10118328 TI - Free flow associated with electronic infusion devices: an underestimated danger. AB - Accidental, uncontrolled free flow after removal of administration sets from electronic infusion devices (EIDs) has only occasionally been reported. Recent evidence indicates that this problem is far more widespread and serious than previously understood. Well-documented cases of accidental death and serious injury have now come to light and are a particular cause for concern. Many of the EIDs commonly used in hospitals incorporate sets that offer no protection if someone removes the set from the device without first closing the set's flow control clamp. Because the problem has infrequently been reported and the risk is not well appreciated, only minimal warnings are issued about the problem by manufacturers. Standard intravenous tubing sets and other nonprotected EID sets are less expensive than protected sets and some hospitals have acquired EIDs that use unprotected sets without an adequate understanding of the risks of free flow (i.e., fluid overload and drug toxicity). Therefore critically ill patients receiving certain types of intravenous fluids or critical care drugs may be at great risk of injury when an overinfusion occurs. This article provides a better understanding of the extent of the problem and offers suggestions for minimizing or eliminating the problem. PMID- 10118330 TI - Hospitals fear increase in unionization activities. PMID- 10118329 TI - Evaluation of patient counseling microcomputer software programs. AB - Five patient counseling drug information programs are evaluated using specific criteria definitions. This article compares the features and ratings of each program. The scope of drug coverage is found to be good to excellent. Most of the programs fared poorly in the timeliness of the database. Updates to the programs range from quarterly to undefined schedule. The ease of readability of all the programs is excellent. The inclusion of key components of information is determined to be good to excellent. The overall patient performance ratings are excellent for each of the programs. The programs are all competitively priced. All of the programs evaluated are easy to use. The only distinguishing feature among the programs is the format of the printed output. PMID- 10118331 TI - Restraining sales reps bedevils materials managers. PMID- 10118332 TI - Paper prices fall nearly 2%. PMID- 10118333 TI - Hospitals refute price hikes by setting caps. PMID- 10118334 TI - Hospitals looking at alternative treatment methods to dispose of infectious medical waste. PMID- 10118335 TI - Primary supplier relationships for all inventory items can reduce a hospital's operating costs. PMID- 10118336 TI - Hospital materials managers must understand HHS's safe harbor regulations. Part 1. AB - Much has been written and said in the past year about what is being called the Safe Harbor Regulations of the Department of Health and Human Services. It is vital that hospital materials managers be attentive to these regulations and to the statutes from which they arose. In this dialogue, Dr. Decker reviews the background of the regulations and lists principal parts which relate to the hospital materials manager. Also covered are some of the provisions of the regulations which are of lesser concern to the hospital materials manager. In subsequent articles, provisions of the regulations which are of greatest concern to hospital materials managers will be dealt with in some detail, and several cases which preceded the regulations will be briefed. This is Part 1 of a three part series. PMID- 10118337 TI - Confusion and controversy on the road to healthcare reform. PMID- 10118338 TI - The changing economics of physician-hospital relationships. PMID- 10118339 TI - Volunteers for community health. An Ohio hospital sponsors parish nursing programs for area churches and synagogues. AB - Since 1989, St. Elizabeth Hospital Medical Center, Youngstown, OH, has been conducting a hospital-based, multidenominational volunteer parish nurse program, which now extends to 11 Roman Catholic, Lutheran, Presbyterian, Methodist, Jewish, and Greek Orthodox congregations. Seventeen volunteer nurses are involved, responding to needs within their congregations by providing a variety of healthcare and educational services while revitalizing the Church's healing ministry. Volunteers selected are competent, experienced registered nurses who can relate to and communicate with people of all ages, accurately assess health related problems, and make appropriate nursing decisions. Parish nurses focus on preventive care, health maintenance, and personal responsibility for maintaining a healthy life-style. Volunteer nurses determine their own schedule, contributing as much time as they can. Each volunteer nurse is responsible for developing a record-keeping system, documenting his or her parish activities, and submitting a quarterly report of volunteer hours and activities to the hospital. Hospital supports include the initial two-day orientation; monthly meetings at the hospital for information sharing, education, and mutual support; and nursing continuing education programs In addition, an advisory committee provides program support and education. St. Elizabeth Hospital Medical Center is exploring several methods of enhancing its health ministry outreach to congregations in dire need of such services. PMID- 10118340 TI - A sense of community. Senior living communities must allow for mission, mutuality, and myth. AB - Most persons move to senior living communities because they want to regain the sense of "community" lost when they left their families, neighborhoods, and community networks. By focusing on mission, mutuality, and myth, the organization can offer residents this feeling of belonging. The mission statement must become the heart of the organization. It should represent both resident and staff expectations and goals. Community also develops around mutuality, a life sustaining and growth-promoting matrix of care, comprising resident-staff care, staff-resident care, resident-resident care, and staff-staff care. Myth, the third component of community, is a way of making sense of what is often a senseless world and enhancing people's feeling of community. To facilitate coping with the stresses of aging, senior living community staff must sustain and promote myths, especially religious myths, images, and symbols. St. Leonard Center, Dayton, OH, is a senior living community that has incorporated these three components into its organization to make it a community in the true sense. PMID- 10118341 TI - Prevailing issues in long-term care. CEOs see urgent need for adequate funding and better communications among Catholic organizations. AB - The ongoing crisis in long-term care has forced administrators and chief executive officers (CEOs) to reassess their position within the U.S. healthcare system and define their response to the challenges they face. This article identifies the issues that Catholic long-term care CEOs find most pressing based on two recent opinion surveys conducted by the Catholic Health Association (CHA). In the area of management and governance, the subject of a 1990 CHA survey, respondents rated as their top concern the inadequacy of funds to treat chronically ill elderly persons. Other important issues included threats to the tax-exempt status of healthcare providers, availability of healthcare for the poor, and scarcity of nursing staff. Respondents to a 1991 survey that focused on collaboration within the Catholic healthcare ministry cited the lack of a forum for communications as the greatest hindrance to collaborative enterprises. A lack of available time to pursue and develop collaborative projects and the absence of compelling reasons to collaborate with other Catholic organizations were also identified as important issues. Overall, the consensus among long-term care CEOs was strong on the importance of certain management and governance issues and on the need for Catholic organizations to work together more closely. PMID- 10118342 TI - Care management: quelling the confusion. Case managers help clients access resources appropriate to their needs. AB - The vast number of available healthcare services can be confusing to those seeking care. Care managers can resolve these issues by helping the vulnerable and their families find and receive appropriate services. Care management is not limited to the elderly: Others with special needs also benefit from care management. Care managers integrate and coordinate services, providing a continuum between the client and the providers of acute, long-term, home-based, and community-based care. The care management model that most organizations adopt at first is the brokering model. In this model care managers identify the appropriate service package from resources in the community. In the service management model, the care manager authorizes the services provided within specified financial limits. The funding source influences what services he or she can recommend. Another model is managed care. The carrier of a high-risk group of clients or a group of enrollees in a certain healthcare program prospectively pays the organization providing care management. In the acute care setting, providers find the transition to care management challenging because they have been oriented to short, episodic care. These providers must adopt new protocols to be able to work with providers and programs within their own organization or at other organizations. In community-based care, care managers' goal is to help the client and family access appropriate services so the client can function independently within his or her home. Community-based referrals are from family members or agencies and infrequently follow an acute care hospitalization. PMID- 10118343 TI - HMOS' continuum of care. How HMOs target their services to meet the needs of the elderly. AB - As healthcare organizations begin to expand their services to serve the elderly, they can learn from the experience of managed care providers. Kaiser Permanente in San Diego, a health maintenance organization (HMO) integrates healthcare providers with more traditional hospital services such as discharge planning and placement coordination, as well as social services, care management, and rehabilitation. Having all these services in the same office facilitates good patient care and planning. When a patient goes into hospice, home care, or a skilled nursing facility, one of four physicians takes on sole responsibility for his or her treatment and continuity of care. Group Health Cooperative of Puget Sound, Seattle, is a consumer-governed HMO. Group Health makes decisions based on data about enrollees plus input from medical staff and senior groups. It emphasizes putting the right services with the right consumer using subgroupings based on functional status: healthy, moderately frail, and frail. Seniors Plus, a social HMO in Minneapolis, integrates acute and long-term care. Providers determine who needs functional assessment and care management by looking first at the diagnosis, then the severity of impairment and comorbidity, other medical problems such as depression and falling that indicate a need, and finally limitations in function and ability to perform activities of daily living. PMID- 10118345 TI - Computerization facilitates reporting of community benefits. PMID- 10118344 TI - Seniors programs help preserve dignity and quality of life. PMID- 10118346 TI - The three stages of leadership development. PMID- 10118347 TI - St. Joseph Health System. Center for Healthcare Ethics launches computer bulletin board. PMID- 10118348 TI - Humility of Mary Health Care System. DOCS Link speeds physicians' information retrieval. PMID- 10118349 TI - A witness of the human spirit. PMID- 10118351 TI - A handheld microcomputer system for control of a jet ventilator. AB - High-frequency jet ventilation is a relatively new mode of patient ventilation that has seen application in critically ill patients with respiratory failure. Because of the radically different nature of this modality of ventilation, clinicians often are unsure which ventilator parameter settings are appropriate. The authors describe in this paper a handheld microcomputer system to assist in the control of jet ventilators. PMID- 10118350 TI - Technology management: a perspective on system support, procurement, and replacement planning. AB - The escalating costs associated with medical technology present a host of challenges for the hospital clinical engineering department. As service and support costs comprise ever larger portions of a system's life cycle cost, innovative management of service provider mix and mechanisms can provide substantial savings in operating expenses. In addition to full-service contracts, the use of demand service and independents has become commonplace. Medical equipment maintenance insurance programs provide yet another service alternative, combining the flexibility of demand service with the safety of a capped budget. These programs have gained acceptance among hospitals as their providers have become more focused on the healthcare market and its many needs. In view of the long-term cost impact surrounding technology procurement, the authors recommend that hospitals refine system evaluation methodologies and develop more comprehensive techniques directed at capital equipment replacement planning. One replacement planning approach, based on an estimation of system value changes, is described and illustrated using data collected through client consultations. Although the validity of this method has not been demonstrated, it represents a simplified approach to life cycle cost analysis and is intended to provide a standard method by which system replacement planning may be quantified. As a departure from system devaluation based solely on depreciation, this method estimates prospective system values derived from anticipated operations and maintenance costs, projected revenue, and the availability of new technology. PMID- 10118352 TI - Low-cost, high reliability voice control unit (VCU). AB - A dedicated microcomputer system has been developed to provide voice control over a wide variety of motorized devices. Employing a 8051 microprocessor with 16 kilobytes of ROM and 16 kilobytes of non-volatile RAM, the system potentially realizes an OEM cost of under $100. Other features include: a simplified user interface, a failsafe stop and voice programmable capabilities. This system has the potential to bring voice control into the marketplace in a wide variety of applications. Currently, the system has been adapted to surgical microscopes and is used in controlling several types of hospital beds. PMID- 10118354 TI - The changing private practice environment: how to analyze opportunities. AB - The search by physicians for opportunities to improve the short-term performance and long-term value of their practices has resulted in the creation of a range of affiliation and group practice structures and changed the traditional private practice profile. The resulting ability to structure an environment that is optimal for each practitioner or group of practitioners can enhance the delivery of medical care and serve to attract an array of individuals to private practice. In order for this evolution to be successful, however, the entities must be developed with thoughtful and detailed analysis and should be flexible enough to adapt to the continually changing environment. PMID- 10118353 TI - Use of an electrocardiograph to record the skin-resistance response with a new type of electrode. AB - A new method is described for recording the emotion-induced decrease in skin resistance area, which is known as the skin-resistance response (SRR). The method employs a simple current source and a new type of tetrapolar electrode in which the SRR is measured with the non-current-carrying electrodes. The signal produced can be recorded with a standard electrocardiograph. Typical SRRs from two subjects are presented. PMID- 10118355 TI - The billing process: improving efficiency and effectiveness. AB - Physician practices as well as hospital and other health care institutions must work diligently to maintain viability given the economic severity of today's health care arena. Operational reviews, system reviews, and periodic internal audits all contribute to helping a practice be as efficient and effective as possible. Practices must make a conscious and continual effort to work toward meeting their established objectives. Versatile and flexible computerized systems seem to be a frequently chosen alternative for practices of all sizes to maximize reimbursement and streamlining the operational aspects of the practice. If the decision is made to purchase a computer system, it will require a team of energetic, enthusiastic people committed throughout the scope of the project. System conversion and implementation may take from two weeks to six months depending on vendor, practice size, and specialty. Ample training, conversion, and installation assistance must be arranged with the vendor. Dedication, hard work, and long hours are crucial to ensure success. The system's return on investment can be realized, yielding financial controls and operational stability. The end result is to make the practice more efficient, giving the physician more time to concentrate on the optimal mission--patient care. PMID- 10118356 TI - Marketing plans for physicians' practices. AB - There are certainly many strategies and techniques for physicians to employ within their marketing plan. It does prove worthwhile to draw on external and expert sources to supplement the plan. A practice can successfully navigate the market development and implementation process itself, utilizing its own personnel. It is important to realize the commitment required of the planning process and to manage the process successfully as an ongoing activity, with constant evaluation, change, and reevaluation. Marketing is a way for a practice to demonstrate to the consumer its distinctive competence and benefit, as a means to create value, and to add in a positive manner to the overall patient experience. PMID- 10118357 TI - Building information linkages between the physician and the hospital. AB - The economics and complexity of health care will continue to require better and faster methods of information access. As a multipurpose resource, physician networks can offer a host of benefits to institutions, caregivers, and patients. Early entrants into this technological arena can expect some degree of competitive advantage by attracting physicians who want sophisticated support systems and by expediting referrals for specialized care. Whether or not this proves to be of long-term merit, the need for administrative and patient care information systems will likely increase in the future. In this respect, innovation is purely a point in time. PMID- 10118358 TI - When medical practices change hands: the elements of successful practice transactions. PMID- 10118359 TI - Valuation guidelines for the acquisition or sale of a medical practice. PMID- 10118360 TI - Legal reality for physicians. AB - The practice of medicine as we have known it is rapidly becoming a "dinosaur" giving way to more complex business and legal relationships among physicians. Quality medical care, however, does not have to become obsolete. As physicians begin to collaborate with each other to survive and thrive in an increasingly competitive environment, their collective influence over payors and other guardians of the cost of health care should focus on ensuring the preservation of quality medical care. By minimizing the adverse consequences of administrative burdens on individual practices, physicians should be able to maximize their practice efficiency and earning potential while preserving their goal of providing quality medical care. PMID- 10118361 TI - Measuring quality of care in physicians' offices. AB - Quality ultimately is not solely the province of the physician. The chain of responsibility to prevent and treat disease is complex. It involves not only physicians and patients but also the payors of health care who are demanding more involvement in health care decision making. Payors want understandable information upon which to base their decisions. They are acquiring the means and the resolve to direct their patients to those who will effectively report such information and away from those who will not. Accordingly, physicians should be able to explain their quality assurance methods and be willing to demonstrate and document quality of care in their offices. PMID- 10118363 TI - The reality of quality management. PMID- 10118362 TI - Compensating and providing incentives for academic physicians: balancing earning, clinical, research, teaching, and administrative responsibilities. AB - Providing a comprehensive compensation and incentive plan for a group of faculty members in a department with multiple goals provides a challenge that few administrators may take. Many academic departments have given up on implementing a comprehensive compensation and incentive plan since department goals generate competing uses of a faculty member's time. Whatever the plan design your department adopts, you can be sure that it will generate controversy. The JPN department has attempted to reward and encourage faculty members to pursue scholarly activities balanced with clinical activities. As a result, this strategy has only considered physicians who can generate both clinical income and research funding. Thus far, the JPN department faculty have embraced the plan. Long-term effects are not known as this is the first year of the plan. The measure of a successful total compensation program is one that develops a sense of entrepreneurship among its members to develop new clinical programs, to pursue new research collaborations, and to devise innovative methods of training. The program described in this article is not intended to serve as the ideal model for all departments, even in academic institutions, but rather to provide a strategy that may have applicability to many other departments where the goals induce inherent conflict for faculty members attempting to decide where to place their time commitments. In addition, this strategy does not work well on an individual basis for young, beginning faculty members but does work well in the collective- to promote the goals of the department. Be prepared, however, to modify your plan after a trial period of perhaps two years. You must allow time to monitor the effects of your compensation plan and its impact on the goals and direction of the department. PMID- 10118364 TI - Implemented improvement system (IIS) tool for CQI. PMID- 10118365 TI - An update and review: the Joint Commission and continuous quality improvement. PMID- 10118366 TI - CS work simplification: computerizing with a restrained budget. PMID- 10118367 TI - Laser safety eyewear. ECRI. PMID- 10118368 TI - Continuous quality improvement: coaching. PMID- 10118369 TI - Handling dropped packaged items. PMID- 10118370 TI - Creating a workplace learning climate: obtaining administrative commitment. PMID- 10118371 TI - Implementing a community health education program in an acute care hospital. PMID- 10118372 TI - Staff nurses' perception of responsibility to provide patient education in hospital setting. PMID- 10118373 TI - Workplace literacy education: writing skills. AB - Remedial programs must be flexible and planned to meet the needs of the participants. Using both work and creative writing exercises provides a balance and relieves boredom. Educators need to be alert to the varying education and skill level of employees. For example, many management development program planners assume a certain level of literacy and English fluency among the managerial group. As a result, some supervisors may avoid programs or not learn the material because of difficulty in comprehending the material. The basic thread of our program was the integration of humor and content. Few classes ended without laughter. This laughter was not at the expense of an individual's self esteem. We laughed at humorous examples of unclear writing and mistakes unintentionally made by the instructors. We laughed at some of their own humorous writing. One of the participants wrote a particularly amusing and entertaining story of a disastrous camping trip. Other times members delighted in catching mistakes in hospital communications. It was obvious that they were reading with more alertness. An unexpected result of the program was the increased rapport between the involved supervisors, their managers, our department, and our local community resources. The program opened channels that have led to an on-site GED program and closer ties with the county literacy efforts. Managers in plant services have increased their involvement and support for employees seeking to improve their education. The TMC educational reimbursement system has been made more available for all. PMID- 10118374 TI - Managerial ethics training: critical for managerial success. AB - A manager's ability to make ethical decisions can determine if morale within a department or organization is high or low. It can also have a significant impact on employees' decision to organize. This article describes an in-service program on ethical decision making that has been successfully taught to management at a medium-sized Midwestern hospital. A program outline is suggested, possible reactions of managers are described, and results of positive and negative ethical decision making are examined. PMID- 10118375 TI - A time-series perspective on effectiveness of a health teaching program on chronic obstructive pulmonary disease. AB - The purpose of this research was to study the long-term effects of attendance at "Help Yourself to Better Breathing" classes on knowledge attainment, coping strategies, and anxiety, depression, and hostility in individuals with chronic obstructive pulmonary disease. Data were gathered immediately and six months following completion of the program. The results were then compared to those obtained before program attendance. The data showed a significant difference between the pretest, immediate post-test, and the six-month knowledge scores. Coping scores remained the same, which may indicate that not enough emphasis is placed on the development of these skills. There was a significant lowering of the depression scores at the six-month post-testing, and anxiety and hostility scores were lower, but not significantly so. In addition, some participants after the classes were completed chose to enroll in the Better Breathers Program support group and in a pulmonary rehabilitation program. Overall, this study indicates that beneficial effects are evidenced six months following attendance at "Help Yourself to Better Breathing" classes. PMID- 10118377 TI - Achieving total quality through intelligence. AB - American firms want 'total quality'. The time and money spent by U.S. companies attempting to qualify for the coveted Baldrige Award exemplifies corporate America's desire to achieve new quality standards. Corporate intelligence and 'total quality' are inextricably linked. In this article, the authors demonstrate how shared and properly-used information can be a powerful tool for elevating quality standards, and how corporate intelligence programmes can provide the information links vital for success in attaining the highest standards of quality. PMID- 10118376 TI - Using strategic planning to drive strategic change. AB - This article describes a case history of strategic planning, learning and change within a major division of Dowty plc. At Dowty CASE, a telecommunications company, the management team used strategic planning as a structured learning process to generate strategic change. There are many lessons which academics and practitioners alike can learn from this case of strategic planning and change in action. PMID- 10118378 TI - Brief case: managing inputs. AB - Jane Carmichael's views on Managing Inputs provide a further interesting contribution on a topic, strategic control, that we have covered on several occasions in this column. Carmichael's approach is to dig back behind the results being achieved to the 'inputs' on which they depend. But, while this may unearth causes of performance that can often be missed by a bottom-line orientation, results must ultimately remain vital; a business that is on track with all its input measures, but is missing its output goal is still in trouble. We continue to be interested in hearing from readers with views on strategic control processes, particularly those who have found productive ways of setting input and output targets. PMID- 10118379 TI - Managing strategic change--strategy, culture and action. AB - One of the major problems facing senior executives is that of effecting significant strategic change in their organizations. This paper develops a number of explanatory frameworks which address the links between the development of strategy in organizations, dimensions of corporate culture and managerial action. In considering such linkages, and by illustrating them with examples from work undertaken in companies, the paper also seeks to advance our understanding of the problems and means of managing strategic change. PMID- 10118380 TI - Achieving world class performance step by step. AB - Bridgestone of Japan acquired Firestone, a United States corporation, in early 1988. This article describes the integration process of the two organizations' cultures. There are many lessons in the approach that should apply to a variety of organizations. The Strategic Improvement Process, a rather highly structured approach, harnesses the strengths of both the Japanese and American organizations and starts the manufacturing and technical departments on the road to excellence. PMID- 10118381 TI - Creating customer value by streamlining business processes. AB - Much of the strategic preoccupation of senior managers in the 1990s is focusing on the creation of customer value. Companies are seeking competitive advantage by streamlining the three processes through which they interact with their customers: product creation, order handling and service assurance. 'Micro strategy' is a term which has been coined for the trade-offs and decisions on where and how to streamline these three processes. The article discusses micro strategies applied by successful companies. PMID- 10118382 TI - Strategic vision or strategic con?: Rhetoric or reality? AB - Major companies devote considerable effort to communicating corporate visions and missions. Yet three recent surveys suggest that much of this effort has been counter-productive. A gap has emerged between rhetoric and reality. Arenas of confrontation have arisen between directors and managers, head offices and business units, holding companies and their subsidiaries, and between specialists and generalists. A widespread desire for corporate transformation is not matched by understanding of how to bring it about. The lack of top management commitment and of communication skills are major barriers to change. More competent directors and more effective boards are needed. The article suggests key roles for the chairman and the chief executive. It examines how best to share a compelling vision, and identifies a requirement for new attitudes and approaches to communication. PMID- 10118384 TI - Grant will help start nursing data base. PMID- 10118383 TI - Rank Xerox--management revolution. AB - For 20 years Rank Xerox dominated the photocopier market until the Japanese entered the market in the late 1970s. Rank Xerox responded to the competitive challenge by instituting competitive benchmarking, and subsequently the Leadership Through Quality Strategy. The author describes the changes in the management philosophy and the organizational structure which enabled Rank Xerox to win back market share from the Japanese. Rank Xerox is now market led with sharp customer focus. It is strongly business led and has a team working culture to support it. PMID- 10118385 TI - Turf tussle goes to White House. PMID- 10118386 TI - Charter bondholders vote to accept restructure plan. PMID- 10118387 TI - Rule calls for smaller increase in 'federal rate' for capital expenses. PMID- 10118388 TI - Philadelphia hospital's C-rated debt may go lower. PMID- 10118389 TI - Top executive resigns amid New York City hospital's bid to regain accreditation. PMID- 10118390 TI - Alliance for Quality chooses 2 hospitals for first projects. PMID- 10118391 TI - More facilities on the drawing board--survey. PMID- 10118392 TI - Medical campus planned for rural Montana. PMID- 10118393 TI - Reports of overcharges, suit over Nev. health plan weighing Humana down. PMID- 10118394 TI - AHA is preparing report on hospitals and antitrust laws. PMID- 10118395 TI - Growth prompts HealthSouth restructuring. PMID- 10118396 TI - NME settlement with Texas valued at $8 million. PMID- 10118397 TI - Geography influences new Medicare pay rules. PMID- 10118398 TI - Half of infusion pumps could cause mishaps. PMID- 10118399 TI - Hospital executives' pay beginning to raise eyebrows. AB - The average base salary for hospital chief executive officers rose 9.7% this year to $150,800, according to a survey conducted by Hay Management Consultants and Modern Healthcare. That's down from the 10.9% increase last year, but is still considered high. As hospital executives' pay continues to rise, board members, community leaders and the local press are beginning to ask whether hospitals are getting their money's worth. PMID- 10118400 TI - Hospitals don't brush off the many benefits of art. AB - Art in a healthcare facility is more than decoration. The right kind of art can speed patients' recovery and enhance a facility's identity. However, in light of the myriad problems facing administrators today, art may be a low priority. To bridge the gap between wanting art and getting art, healthcare providers are turning to experts to help choose art and to benefactors to help finance its purchase. PMID- 10118401 TI - Allegheny to pay city $10 million in tax settlement. PMID- 10118402 TI - IG's query finds hospitals bill Medicare for inappropriate costs. PMID- 10118403 TI - Plans fear tug-of-war as result of new Medicare fee schedule. PMID- 10118404 TI - Boston building boom--is it an arms race? AB - A massive healthcare construction boom is under way in downtown Boston, prompting some observers to declare it a "medical arms race." Others, however, say the new projects are critical to some hospitals' ability to remain competitive. Whatever the case may be, there's big money involved--some $1.3 billion in projects that already have been started or soon will be. PMID- 10118405 TI - Cost-containment proposal fails to win nod from Ways and Means. PMID- 10118406 TI - The Nixon years: failed national health reform from both parties. AB - In the November 1991 elections, popular support for national health reform (NHR) enabled Harry Wofford to become a U.S. Senator from Pennsylvania. Since then a bevy of congressional proposals to reform America's health care system have emerged, with even national health insurance, or a single payer system, becoming a prominent contender for the first time in 20 years. National health reform is now a regular feature on the evening news. However, this is not the first time that NHR has attracted national attention. As pointed out in the first article in this series (Physician Executive, March-April 1992, page 23), there have been numerous efforts to enact NHR in the U.S. Each has failed because of strident opposition by interest groups, lack of active presidential interest in the specific legislation, and the absence of strong popular interest. PMID- 10118407 TI - A new perspective on quality. AB - The U.S. health care sector consumes nearly 13 percent of our nation's gross national product, $800 billion annually. Our nation allocates the highest amount per capita to health care in the world. Yet many measures of health care outcomes from these expenditures are inferior to other developed nations. The American health care system costs too much, excludes too many, fails too often, contains much excessive and inappropriate care, and knows too little about the effectiveness of the things it does. The purpose of this article is to discuss current payers' perspectives on the potential for quality improvement in the U.S. health care system. PMID- 10118409 TI - The limits of medical quality assurance systems. AB - Quality Assurance (QA) via the process of review systems is a retrospective look at what was. It is a picture of the past. Any such system is bound to have limitations, because the past cannot be changed. In QA, the ultimate aim should be to educate physicians as to where they made mistakes so that they can learn how to prevent them in the future. The distribution of what mistakes can be avoided, so that all physicians can learn from others' mistakes, takes the whole team closer to the aim of real QA--preventing mistakes. The first part of this article looks at QA in general terms; the second part looks at inherent biases that should be removed so that the team reaches the goal of bona fide quality. PMID- 10118408 TI - HIV testing of health care workers. AB - Until recently, nothing much beyond education and the dispensing of condoms was being done to control the spread of AIDS. We have not yet taken sufficient measures to prevent the spread of this disease. Instead, we insist on protecting the privacy of the HIV-positive individual. However, we ignore the right to privacy by mandating testing for syphilis, which is not nearly as serious a disease as AIDS. Now, mandatory testing of health care workers is being proposed more frequently. PMID- 10118410 TI - Physician perspectives on the structure and function of group practice HMOs. AB - This article explores physicians' perspectives regarding how their HMOs function and their satisfaction with and loyalty to HMOs. Three HMOs were studied: a mature (28-year-old) staff model, a 16-year-old staff model, and a 13-year-old group model with both HMO and fee-for-service patients. While these HMOs were found to vary somewhat in terms of emphasis on patient care versus costs, methods used to control costs and degrees of centralization of decision making, they all received high overall satisfaction and loyalty scores. The staff model HMO with a more decentralized decision making structure received the highest satisfaction/loyalty score from its physicians. The degree to which physicians perceive the HMO to be effective and supportive and the use of educational programs and peer review to influence resource use were also found to be significantly related to physician satisfaction and loyalty. PMID- 10118411 TI - A process for objective review of physician performance. AB - How do you objectively evaluate physicians at reappointment. How do you establish a common ground for the evaluation process that still acknowledges acceptable differences in performance? Perhaps one physician has some difficulty with documentation and attendance at meetings, but has no quality problems clinically. Another physician may have good documentation and meeting attendance, but has some quality problems. Another physician has a behavior pattern that is disruptive, a few documentation problems, but excellent quality. Yet another physician is a marginal practitioner with major problems in several areas, including quality. Reappointment of these physicians might be extremely difficult, especially if the credentials committee is recently appointed and not familiar with the details of the performance data. PMID- 10118413 TI - Organs for sale? Propriety, property, and the price of progress. PMID- 10118412 TI - Application of TQM principles to the utilization management process. AB - Application of the philosophy and principles of TQM and CQI to utilization management within an institution necessitates an in-depth review of the systems and processes of the flow of inpatients throughout their stay. This encompasses a total systems perspective, beginning with the admitting process and going through the discharge process. TQM and CQI philosophies identify that the most significant and costly inefficiencies are due to faulty systems and processes, not individuals. Applying this management strategy to a health care institution requires a detailed review and analysis of processes by which service is delivered and requires evaluation of the outcomes of patient care and patient satisfaction. PMID- 10118414 TI - Assessment and utilization of patient strengths in acute care treatment planning. AB - Strength-focused assessment and treatment planning are presented as a partner to diagnostic evaluation of symptoms, syndromes, and clinical history. It is not advocated as a replacement, but as an extension of what we now do. However, we must not underestimate the new attitude inherent in the search for barely visible coping moments and coping momentum. It's a new attitude more than a new technique for both the patient and the practitioner. PMID- 10118415 TI - Starting an in-hospital support group for employee victims of violence in the psychiatric hospital. AB - Violence perpetrated on the staff in our psychiatric hospitals is increasing. We believe an in-hospital support group for employee victims of violence is an effective and economical means of helping our staff, our patients, and the hospital in general. We believe that it is crucial to provide education about and to foster sensitization to issues of violence and that our staff must work together within the facility and with outside agencies, such as those in the legal system. We are just starting our support group at the Carter Center, and this paper discusses various practical points encountered thus far and some of the theoretical issues surrounding our beginning. We believe ours is an important prototype of staff support groups, which are vitally needed. I hope to publish a follow-up report on our group and the progress it has made. PMID- 10118416 TI - A question of survival. An interview with Reed Tuckson. PMID- 10118418 TI - OSHA targets AIDS in the workplace. PMID- 10118417 TI - A medicine of strangers or a medicine of intimates. The two legacies of Karen Ann Quinlan. PMID- 10118419 TI - Training and compliance high on OSHA's list. AB - This is the third in a series of three articles on OSHA's new ruling on bloodborne pathogens. It covers engineering and work practice controls, employee training, record keeping, and signs and labels. PMID- 10118420 TI - Patient self-determination: sharing the power. PMID- 10118421 TI - Hawaii--health care lessons for the nation debated. PMID- 10118422 TI - Why Maryland's clinical indicator project is building steam. PMID- 10118423 TI - Understanding antitrust law and its affect on hospital collaboration. PMID- 10118424 TI - Meeting physicians' needs helps to build stronger hospital ties. PMID- 10118425 TI - Rural hospital-state collaboration. PMID- 10118426 TI - Why are we having a retreat? PMID- 10118427 TI - Beyond the three-legged stool: board/CEO relations--Part one. PMID- 10118428 TI - Board development gets straight A's: a rural hospital example. Interview by Karen Gardner. AB - Copley Hospital, Morrisville, VT, is living proof that "good things come in small packages." The governing board of this 50-bed rural hospital has not let size stifle its imagination and eagerness to learn. Trustee Mary Paul Hankinson of Hyde Park, VT, has been instrumental in instituting board development activities at the hospital since she began her board tenure in 1979. Hankinson, who has taken a leave from full-time college development work to raise a family, devotes more time to Copley and her governance responsibilities than most salaried employees. As a member of the board's education and evaluation committee and the American Hospital Association's Congress of Hospital Trustees, Hankinson is alert to the educational needs and concerns of her colleagues. She recently spoke with Trustee editor Karen Gardner about the Copley board's sophisticated process for trustee orientation, self-evaluation, and continuing education. PMID- 10118429 TI - Are health care entitlement caps the wave of the future? PMID- 10118430 TI - Community care networks and AHA's reform strategy. PMID- 10118431 TI - Developing a pet visitation program. PMID- 10118432 TI - How to quantify volunteer input. PMID- 10118433 TI - Employees provide free housing. PMID- 10118434 TI - A statewide organ donation effort. PMID- 10118435 TI - Volunteer pastoral care programs: options and training issues. PMID- 10118436 TI - Meeting the elderly's spiritual needs. PMID- 10118437 TI - Office visits for diabetes mellitus: United States, 1989. PMID- 10118438 TI - Kindly light. HealthPark Medical Center, Lee County, Florida. PMID- 10118440 TI - Primary care and reform of health systems: a framework for the analysis of Latin American experiences. AB - The article first proposes a framework within which to assess the potential of health sector reforms in Latin America for primary health care (PHC). Two dimensions are recognized: the scope of the reforms, content, and the means of participation that are put into play. This framework is then complemented through a critique of the often-sought but little-analyzed PHC reform strategies of decentralization and health sector integration. The analytical framework is next directed to the financing of health services, a chief aspect of any reform aiming toward PHC. Two facets of health service finance are first distinguished: its formal aspect as a means for economic subsistence and growth, and its substantive aspect as a means to promote the rational use of services and thus improvement of health. Once finance is understood in this microeconomic perspective, the focus shifts to the analysis of health care reforms at the macro, health policy level. The article concludes by positing that PHC is in essence a new health care paradigm, oriented by the values of universality, redistribution, integration, plurality, quality, and efficiency. PMID- 10118439 TI - Undergraduate medical education towards health for all: progress, pitfalls, perspectives. AB - I discuss aspects of undergraduate medical education related to primary health care and analyse innovative programmes, with emphasis on problem-based methods and community-based education. Assessing the impact of these programmes shows problem-based learning is an interesting didactic exercise but not a necessary or sufficient condition for the adequacy of programmes to the Health for All (HFA) policy. Community-based education is pressed by several obstacles inside and outside educational institutions that put at risk its effectiveness as a real agent of change. Amongst these obstacles are political difficulties in building linkages amongst teaching institutions, services, and community; logistical problems in facilitating faculty and student work in the community; reactions from faculties; poor research opportunities in primary health care; pressures for more socially, professionally, and economically rewarding careers; biases in training the present generation of teachers; attempts to fulfill the social, behavioral, epidemiological, and preventive knowledge requirements for medical education by adding to an already overloaded information base; and shortage of relevant and significant sources of information for the medical students. Building corporations representing 'innovative' programmes, on one side, and 'conservative', 'traditional' ones, on the other, is not helpful and probably false. Each programme should be assessed in its strength and weaknesses in the light of political decisions committed to change in unequal, poor-quality health systems. PMID- 10118441 TI - Health care markets as interorganizational fields: a conceptual perspective. AB - This paper examines the interorganizational (IO) field approach to the study of local health care markets. An IO field conceptualization focuses attention on organizational behavior and interorganizational relations among providers and purchasers and other health care organizations relevant to the field. This perspective is suitable for guiding evaluations of the multiple effects of pro competition or regulative interventions on health care markets. PMID- 10118442 TI - Community participation and involvement: theoretical and empirical issues. AB - In 1978, the World Health Organization (WHO) and the United Nations International Children's Emergency Fund (UNICEF), in their Alma Ata Declaration, declared a war against ill health and lack of access to and use of health services by advocating a joint effort among countries to bring health for all for the year 2000. Although such wars have been waged many times before, this time the declaration had a slightly different message, one paying respect to the people who are the target of that declaration. The message was to help people achieve their health potential within their abilities, values, and technologies by helping them help themselves. Other significant parts to this message included dealing with the use of local technology, the involvement of intersectorial cooperation, and the view of health as integral to development (WHO, 1978). PMID- 10118445 TI - Assigning tasks effectively using a model. AB - The clinical laboratory is a fast-paced environment where accuracy and efficiency are crucial. A major responsibility of the clinical manager is to assign tasks clearly to ensure that a quality job is done right the first time. Have you ever heard a manager say "This isn't what I asked for?" When this happens, it is usually the fault of the manager. Managers often make incorrect assumptions and do not take 100% of the responsibility for ensuring that assigned tasks are understood. To assign tasks effectively, managers must state exactly what they want, how they want it done, and when they want it. And, in addition to stating the desired end results, managers must verify that the directions were correctly understood; this is done by asking for feedback through questioning and paraphrasing. The five-step model described in this article will help you to assign tasks that get the job done right the first time. PMID- 10118444 TI - Work morale assessment and development for the clinical laboratory manager. AB - Work morale has been a longstanding issue for managers in general, but it is assuming critical proportions for clinical laboratory managers today. Four key variables that determine work morale have been isolated: the job itself, the work group, management practices, and economic rewards. Regular assessment and development of these key morale variables via time-tested, effective, and easy-to use techniques will help clinical laboratory managers to attract and retain competent personnel, to enhance the prospects of organizational profitability, to sustain high-quality patient care, and to earn the respect and loyalty of other health-care employees. This article discusses the components of the four key areas of morale and offers "prescriptions" to improve morale in these important areas. A survey to assess morale is also provided. PMID- 10118443 TI - Corporate structure and administrators' job stress: the case of nursing homes. AB - This paper examined the relationship between the job-related stress of nursing home administrators and the structure of their work setting. Multivariate analysis of covariance (MANCOVA) was used to test the hypothesis that nursing home administrators who are employed in multi-unit, corporate-owned facilities experience more job-related stress than do administrators employed in independent, free-standing organizations. The results indicated that, when controlling for other potential stressors, administrators in corporate-owned nursing homes reported more general job stress and greater role ambiguity than their counterparts in single-unit, autonomous organizations. Recommendations for management strategies and for future studies in this area are discussed. PMID- 10118446 TI - Empowered employees--a good personnel investment. AB - Health care has entered a new competitive era in the 1990s, and, combined with the other pressures association with health care, clinical laboratory managers are facing the challenge of having to do more with less. This "pressure-cooker" environment requires clinical laboratory managers to find new ways to motivate their teams to perform at peak levels at all times; the key to doing this is empowerment. By empowering employees, managers create a nurturing environment in which their staffs can learn, grow, improve, and function effectively. This type of environment is created when managers are honestly concerned about their employees and exhibit a true "partner" attitude. This article describes five specific actions that clinical laboratory managers can take to empower their employees to work together to do better jobs. These actions include sharing expectations; providing new employees with helpers, guides, and buddies; giving feedback; involving employees in decision making; and paying attention to customer service and what other laboratories are doing. These actions will help clinical laboratory managers empower their employees to face the difficult challenges of the 1990s. PMID- 10118447 TI - Telepathology: practicing pathology in two places at once. AB - Technical advances in telecommunications and image processing make it possible to transmit high-quality images great distances. Diagnostic pathology--which relies on the accurate representation of cytologic detail, tinctorial properties of cells, and morphological patterns for analysis and interpretation--stands to benefit from these advances. Telepathology permits surgical pathology services to be extended to remote or relatively inaccessible areas, authoritative opinions to be issued by recognized experts on specific cases, and external review of histologic diagnosis for purposes of quality control. Although telepathology systems are simple in concept and operation, their use in the day-to-day practice of pathology is still evolving. PMID- 10118448 TI - Helena Laboratories ColumnMate. PMID- 10118449 TI - Turnaround time. AB - Advances in instrumentation have enabled laboratories to deliver results much more quickly. But as equipment has advanced so have expectations on turnaround time (TAT), driving up costs in the process. Laboratories must balance the needs of their clients against the need to cover their costs. In this issue, we asked our respondents: How do you address the issue of turnaround time? PMID- 10118450 TI - Oregon's healthcare reform proposal: right approach, faulty implementation. PMID- 10118451 TI - Business group backs QA role in cost controls. PMID- 10118452 TI - How outcome data can be used to evaluate care. Guidelines for physician mortality review. AB - Outcome data, such as hospital-specific mortality data, are indirect indicators of the quality of care. For example, in using hospital-specific mortality data as indicators of the quality of care, it is essential to determine if the deaths might have been prevented had better care been provided. To determine if deaths were potentially preventable, the process of the care provided must be reviewed. The Guidelines for Physician Mortality Review outlines a systematic, step-by-step process for physicians to use in reviewing the process of care to determine if the deaths might have been prevented. PMID- 10118453 TI - Understanding Medicare's regulatory process. PMID- 10118454 TI - Annual aircrew survey. PMID- 10118455 TI - Mechanical ventilation during air medical transport: techniques and devices. AB - The use of transport ventilators during air medical transport is influenced by the patient's needs, the experience of the transport crew, and the type of aircraft used. It is important to note that no single transport ventilator is suitable for all situations. Both environmental and operational attributes need to be considered when making a purchase. Hidden among these is the cost. When all of these considerations are balanced, the transport ventilator can be both practical and beneficial for patient care. PMID- 10118457 TI - Interest rate on overdue debts--HHS. PMID- 10118456 TI - Biological technical amendment--FDA. Final rule; technical amendment. AB - The Food and Drug Administration (FDA) is amending the biologics regulations to make a minor, technical amendment. The pressure stated at which a sustained sterilization temperature is attained is incorrect. This document corrects that error. PMID- 10118458 TI - Investigational new drug, antibiotic, and biological product applications; clinical hold and termination--FDA. Final rule. AB - The Food and Drug Administration (FDA) is issuing a final regulation that provides additional grounds for placing an investigation on "clinical hold" and for terminating an investigational new drug application (IND). Under this rule, FDA may require sponsors to cease distributing an experimental drug in an open, nonconcurrently controlled investigation if any of several specified conditions exist. This final rule is part of the Public Health Service's(PHS's) efforts to make promising drugs widely available to people with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV)-related disease who lack satisfactory alternative therapies, while simultaneously ensuring that the adequate and well-controlled clinical trials essential to establishing a new drug's safety and effectiveness are expeditiously conducted. PMID- 10118459 TI - Expanded availability of investigational new drugs through a parallel track mechanism for people with AIDS and other HIV-related disease--PHS. Notice final policy statement. AB - The Public Health Service (PHS) is announcing a final policy to make promising investigational drugs for AIDS and other HIV-related diseases more widely available under "parallel track" protocols while the controlled clinical trials essential to establish the safety and effectiveness of new drugs are carried out. The "parallel track" initiative establishes an administrative system designed to expand the availability of promising investigational agents and to make these agents more widely available to people with AIDS and other HIV-related diseases who have no therapeutic alternatives and who cannot participate in the controlled clinical trials. PMID- 10118460 TI - Limited revision of fee schedules--NRC. Final rule. AB - The Nuclear Regulatory Commission (NRC) is amending its regulations to make two limited changes to its assessment of license and annual fees. The final rule assesses license fees, which are based on the full-cost method, quarterly instead of semiannually and establishes a lower tier small entity annual fee for those licensees that are small entities with relatively low annual gross receipts or supporting populations. These final amendments are intended to improve NRC financial management and further mitigate the impact of the annual fee on small licensees with relatively low annual gross receipts or supporting populations. PMID- 10118461 TI - Delegations of authority and organization; issuance of written notices--FDA. Final rule. AB - The Food and Drug Administration (FDA) is amending the regulations for delegations of authority relating to the issuance of written notices concerning failure to file patent information and to comply with requirements pertaining to current good manufacturing practices and labeling for new drugs, new animal drugs, and feeds bearing or containing new animal drugs from the Commissioner of Food and Drugs to certain FDA officials. This action is being taken to make the process of issuing written notices more efficient. PMID- 10118462 TI - Conditioning the prospect. The new science of seniors marketing. PMID- 10118463 TI - A market vastly improved. Transition to case-mix underway. PMID- 10118464 TI - Reaching out to hospitals and physicians. PMID- 10118465 TI - Dancing without the elephants. How local managed care and national insurer contracts match up. PMID- 10118466 TI - 1992 interior design awards. PMID- 10118467 TI - Patching LTC insurance standards together. State-to-state regulatory variances limit marketing. PMID- 10118468 TI - Out on the town. Aides lead community outings. PMID- 10118469 TI - Breathing life into ventilator patients. Weaning requires high-tech skills. PMID- 10118470 TI - HHS exclusion for program-related abuses. PMID- 10118471 TI - Learning how to influence prescribing behavior. PMID- 10118474 TI - Menu plan impacts temperature retention. PMID- 10118473 TI - Are you listening? PMID- 10118472 TI - IRS General Counsel Memorandum threatens some hospital-physician joint ventures. AB - To defend against the heightened scrutiny of hospital-physician relations expected from the IRS, hospital management should closely examine any activities now conducted with physicians to determine whether each activity, as organized and operated, furthers the hospital's charitable mission of promoting the health of its community, rather than merely enhancing the financial health of the institution itself. Any arrangements that do not appear to satisfy the principles enunciated in GCM 39862 should be examined to see if they should be restructured or dissolved. In structuring new transactions and examining existing arrangements, the following principles should be kept in mind: 1. Transactions should not be premised upon increased utilization or physician referrals. Enhancing or protecting market share, even for the purpose of preserving an institution's presence in the community, will likely no longer be accepted as a justification for pursuing joint venture arrangements. In justifying such ventures, management must distinguish between benefit to the community and benefit to the institution. 2. Transactions whereby existing services or equipment are "spun off" to a hospital-physician joint venture run a serious risk of enhanced IRS scrutiny. 3. Transactions creating or providing new facilities or services should be more favorably perceived, particularly where participants other than the hospital take an active role in managing the venture. Where the hospital is the sole general partner and merely manages what it would have managed had there been no physician investors, the question of why physicians are involved will likely be of greater concern than it has been in the past.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10118475 TI - Presentation makes the difference. PMID- 10118476 TI - A versatile, low-cost marketing tool. PMID- 10118477 TI - Paradise lost: a 21st century fable. PMID- 10118478 TI - The reshaping of healthcare. Part 1. PMID- 10118481 TI - Bridging the leadership gap in healthcare. Healthcare Forum Leadership Center. PMID- 10118480 TI - Bridging your own leadership gap. PMID- 10118479 TI - Five futures. PMID- 10118482 TI - Lighting the way. Part 1. PMID- 10118483 TI - A talk with The Healthcare Forum's incoming chair, Rod Wolford. PMID- 10118484 TI - The patient-focused hospital. PMID- 10118486 TI - Emerging leaders 1992. Six agents of healthy change. AB - This election year, 1992, is a crucial year for the healthcare industry. Leaders and leadership are on many voters' minds, as are healthcare issues and reform. Politicians from the president on down suddenly are paying attention to the broad healthcare landscape--and many don't like what they see. There seems to be a growing belief that changes in healthcare delivery and health insurance must be imposed from the outside--perhaps by governmental fiat. But this year's Emerging Leaders--six very different individuals involved in various aspects of healthcare delivery--are doing their parts to reform and refocus the industry from the inside. They are leading by example, acting as agents of healthy change in their own institutions and surrounding communities. Sponsors Korn/Ferry International and The Healthcare Forum each year seek "decisive young leaders who have already made a mark" to honor as Emerging Leaders. In the 1992 honorees Charlotte Collins, Scott Goodspeed, Diane Iorfida, Michael Langberg, MD, Lynn Olman, and Denise Williams--four women and just two men, in itself an interesting sign of change in the industry--they have found that and more. Korn/Ferry International and The Healthcare Forum are proud to present them as the 1992 Emerging Leaders. PMID- 10118485 TI - The leaner, healthier company. Interview by Joe Flower. PMID- 10118487 TI - Competitive strategies in the NHS. AB - The NHS has, of necessity since implementation of the NHS and Community Care Act 1990, strengthened its skills in business, marketing and other functions borrowed from industry and commerce. One area where, however, the NHS is currently weak is in competitive intelligence. Hazel Coad and Barbara Kennedy explain what this strategically important function is and how it can help financial viability. PMID- 10118488 TI - Total quality management in the NHS. AB - In 1989, the Department of Health embarked upon a programme to encourage the introduction of a managed approach to quality in the NHS. In 1990 it extended this programme to include 23 sites ranging from departments within units to total districts. The criteria for inclusion in the programme were loose, but all successful pilots marched under the banner of total quality management (TQM), a clearly defined concept with a well-documented history. Tessa Brooks summarises TQM and considers its place in the NHS. PMID- 10118489 TI - What are trusts allowed to do? AB - NHS trusts may not be a feature of the health services for ever, but current legislation will be applicable for some time to come. Legal aspects of trust status are described in two features. In the first, Anita Morrish identifies what trusts are legally empowered to do and those areas where their powers, if they exist, are less clearly defined. PMID- 10118490 TI - GPs and contracting for secondary health care. AB - Publication of the NHS White Paper Working for Patients and subsequent legislation has introduced the requirement for district health authorities to assess the health and health care needs of their resident populations. Sam Ramaiah and colleagues describe their experience in South Tees of working with GPs to fulfil this objective. PMID- 10118491 TI - Managers and medical audit. AB - A study of the role of the manager in medical audit showed that few people had a clear idea of the manager's role; indeed there was little recognition that managers might have a significant role. The picture today, however, is changing. Deborah Harman and Geraldine Martin, who carried out the study, describe progress. PMID- 10118492 TI - Management. AB - For Frank Collins, General Manager of Kettering's acute and midwifery unit, the day begins with a look at the list of 'long waiters'. Will the internal strategy enable this to be reduced to zero by 31 March? What are the other issues facing the manager of this 640-bed unit in the East Midlands? PMID- 10118493 TI - A comparison of the effects of hard rock and easy listening on the frequency of observed inappropriate behaviors: control of environmental antecedents in a large public area. AB - Observation of clients at a state mental health hospital by direct care staff indicated that they appeared to act in more inappropriate ways when "hard rock" or "rap" music was played in an open courtyard than when "easy listening" or "country" music was played. A study was conducted to compare the inappropriate behavior of clients when hard rock and rap music were played (21 days), followed by easy listening and country and western music (21 days). This comparison was followed by a reversal phase in which hard rock and rap music were again played (18 days). The behaviors of the clients were observed and recorded via a controlled methodology. The results demonstrated that more inappropriate behavior was observed under conditions in which hard rock and rap music were played than when easy listening and country western music were played. The implications of these findings are discussed. PMID- 10118494 TI - CQI must involve all staff--including physicians. PMID- 10118495 TI - New method to transmit fire-alarm signals recently approved. AB - A new method to transmit fire-alarm signals, effective immediately, has been approved by the Joint Commission. The method, which can be used in all health care organizations with buildings classified as health care occupancies, is explained in the following paragraphs. PMID- 10118496 TI - Hospital evaluates orientation and education program prior to survey. PMID- 10118497 TI - AIDS, public policy, and the health administrator. PMID- 10118498 TI - Perspectives on unionization in hospitals. PMID- 10118499 TI - Impact of DRGs on home health care: the need for collaboration in research approaches. PMID- 10118500 TI - Cost containment, access, and American health financing: getting beyond the shell game. PMID- 10118501 TI - Performance in quasi-firms: an example from the Community Clinical Oncology Program. AB - In this analysis, the authors examined the effects of different sets of process, structure, and environmental variables on the performance of the CCOP as a quasi firm. Specifically, they distinguished between internal organizational processes, structural, and size characteristics of the CCOP and the organizational environment created by prior NCI program experience and the relationship within the quasi-firm. The analysis revealed that these sets of organizational and environmental characteristics have differential effects on treatment accrual. The strongest predictors are those associated with the quasi-firm relationship between the CCOP and its chosen research bases. Any definitive policy implications for the design of organizational network relationships--especially the CCOPs--will require further analysis. Particular attention needs to be given to the longitudinal nature of the relationships and the ability of these organizational and environmental factors to affect other aspects of performance. Several points have been made within this initial assessment. First, the structural character of the CCOP and its relationship to its organizational environment are important factors affecting accrual performance. The subtleties of this multivariate model are not as important as simply demonstrating that the various internal and external characteristics of these organizations as quasi firms simultaneously affect their ability to accrue patients to clinical trials. Secondly, the importance of research base relations, and particularly the significant role of nurses, needs to be emphasized. While CCOPs were originally designed as a network of physicians and hospitals, it appears that an infrastructure of professionally active nurses working within a larger organizational environment is critical to success--at least as defined by accrual to treatment protocols. Finally, the failure of prior experience with other NCI community programs to affect CCOP accrual performance suggests that such experience does not assure "organizational learning" that may enhance performance. This suggests that CCOPs can be designated de novo to maximize performance without necessarily having to undergo a developmental or experiential phase involving community cancer programs to be effective. However, the authors suspect that another method of characterizing experience may produce different results. Further analyses of these data will test these results against other measures of CCOP performance. Specifically, attention will be given to whether this same set of characteristics is predictive of accrual to cancer control research protocols. Similarly, these same organizational characteristics may or may not be associated with other dimensions of CCOP performance such as changes in physician practice patterns and/or levels of institutionalization of the CCOP within its local community.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10118502 TI - Anticipating change: a description of the environment of the Department of Veterans Affairs health care system. PMID- 10118503 TI - Consumer cost conscious behavior, utilization, and health care expenditures among an elderly population. PMID- 10118504 TI - Complying with the new OSHA regs. Part I. Teaching your staff about biosafety. PMID- 10118505 TI - Enhance laboratory workflow to save steps and money. AB - Beware: Small savings in the lab may be expensive for the hospital. Examine the flow of laboratory operations in the context of the entire facility. PMID- 10118506 TI - Surviving and flourishing in tough times. AB - "Test volume low, costs high" was the projection for 1991. The authors' large medical center took steps to compensate. PMID- 10118507 TI - Quality of care calls for joy and compassion. PMID- 10118509 TI - Billing audit guidelines receive final approval. PMID- 10118508 TI - AIDS precautions in the '90s: prudence or paranoia? PMID- 10118510 TI - Understanding Medicare disproportionate share. PMID- 10118511 TI - LTC financing: is it time for change? AB - This month, Provider asks leaders in health care policy to address health care reform and the value of grassroots lobbying efforts. Following are interviews with national congressional leaders, administration officials, and ACHA and other industry leadership on these issues. PMID- 10118512 TI - Federal efforts focus on incremental change. PMID- 10118513 TI - Winning in Washington through grassroots lobbying. PMID- 10118514 TI - Pre-emergency storm procedures help facilities avoid damages. PMID- 10118515 TI - Checkup evaluates health of retirement plans. PMID- 10118516 TI - Hiring foreign nurses requires preparation, documentation. PMID- 10118517 TI - Documentation guidelines protect against lawsuits. PMID- 10118518 TI - Age-appropriate activities help residents reach goals. PMID- 10118519 TI - Retirement centers benefit from short-term programs. PMID- 10118520 TI - Coming of age: home care in the 1990s. PMID- 10118521 TI - Developing home-based mental health services for Maine's older adults. PMID- 10118522 TI - How much insurance is enough? What to look for in a long term care insurance policy. AB - LTC insurance is a valuable financial tool to help pay for pending LTC. However, LTC insurance is not for everyone. For those who could benefit from a policy, questions arise as to how much to buy and what consumer options to purchase in a policy. Insurance is most appropriate for couples with assets of $110,000 or more, excluding their house, car, and personal belongings. Single persons with a need to protect assets should have at least $40,000 in assets. These individuals have smaller need for LTC insurance to protect assets for their children. How much insurance to buy depends on the cost of LTC and the financial resources of the person. Premiums for LTC insurance are level. A company cannot raise the premiums for an individual, but may request an increase for a class of people. With the potential that premiums may increase and that buying power of income may decline, the policy should be affordable both at time of purchase and in future. Policies pay a specified benefit amount for a specified benefit period. In deciding how much insurance to buy, it is advisable to buy a higher benefit amount for a shorter benefit period. This provides the greatest likelihood of receiving the policy's maximum benefit. The deductible amount should be between 20 and 100 days. In selecting a policy, the most important criterion is the company itself.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10118523 TI - Long term care for the elderly: major developments of the last ten years. PMID- 10118524 TI - Guarantees come to professional service firms. AB - Can lawyers, doctors, investment bankers, accountants, and consultants guarantee their work? Your money back if not absolutely delighted? Some professional service firms are doing exactly that, and they believe they are gaining not only satisfied customers but higher market share and improved service quality. The authors discuss the benefits and risks of unconditional and more limited guarantees. Firms that address this issue proactively now, they argue, will be less likely to rush into poorly considered guarantees later. PMID- 10118525 TI - Implementing service guarantees--the Delta Dental Plan story. PMID- 10118526 TI - The empowerment of service workers: what, why, how, and when. AB - In recent years, businesses have rushed to adopt an empowerment approach to service delivery in which employees face customers "free of rulebooks," encouraged to do whatever is necessary to satisfy them. But that approach may not be right for everyone. Bowen and Lawler look at the benefits and costs of empowering employees, the range of management practices that empower employees to varying degrees, and key business characteristics that affect the choice of approaches. Managers need to make sure that there is a good fit between their organizational needs and their approach to frontline employees. PMID- 10118527 TI - Intraoperative autotransfusion: an old idea comes of age. PMID- 10118528 TI - Healthcare and the new union movement. PMID- 10118529 TI - Universal healthcare coverage, Canadian style. PMID- 10118531 TI - The coder's dilemma. Expediency vs. accuracy. PMID- 10118530 TI - An administrative pitfall. Rewarding negative behavior. PMID- 10118532 TI - Who knows more? PMID- 10118533 TI - Physician self-referral. An ethical dilemma. PMID- 10118534 TI - The HMO physician. PMID- 10118535 TI - The pediatrician in the HMO. PMID- 10118536 TI - The family practitioner in the HMO. PMID- 10118537 TI - The specialist in the HMO. PMID- 10118538 TI - Making the change. Fee-for-service to HMO. Interview by Lee Jacobs. PMID- 10118539 TI - Recruiting physicians. Making the right choices. AB - Problems result when prepaid groups do not recruit physicians who fit well within the organization. Both the physician and the organization bring very specific needs to the recruitment process, and in the course of fulfilling these needs they may not fully evaluate each other. This article describes a comprehensive evaluation process that includes the role of the physician and the organization as well as tips for successful interviews. PMID- 10118540 TI - The HMO physician as team player. AB - For HMOs to function most effectively, physicians and support staff need to work together as teams. Successful teamwork requires a high degree of communication and coordination, attributes that are often lacking unless the HMO has decentralized authority and nurtures effective teamwork. This article describes barriers that impede teamwork, and focuses on specific steps that can be taken to enhance the team environment in a prepaid group practice. PMID- 10118541 TI - Perspectives. Public health attacks violence. PMID- 10118542 TI - Instrument decontamination in the medical office. PMID- 10118543 TI - Medicine, money, and mathematics. PMID- 10118544 TI - OSHA regulation of blood-borne pathogens. PMID- 10118545 TI - Academic programs evolve in their view of health care information management. PMID- 10118546 TI - Educational models for producing more management engineers. AB - Academic programs that attract and train health systems management professionals need the help of the profession working through our technical societies. We need to seek ways to interest IE and other faculty in these programs. Interactions between health care institutions and academic programs can be an important way for students to discover the wealth of opportunities that exist in health systems management. PMID- 10118547 TI - Education and training are critical to meeting the need for professionals. PMID- 10118548 TI - Increasing the number of academic paths to health care careers. PMID- 10118549 TI - Goal-setting starts with solid market positioning. Keeping up with the state of the art. PMID- 10118550 TI - The grass is always bluer. Switch to case mix well received. PMID- 10118551 TI - Nursing salary comparisons. What is the average wage for long-term care nurses? PMID- 10118552 TI - What's ahead for LTC? Financing reforms, OBRA enforcement emphasized. PMID- 10118553 TI - Building the continuum of care. Home care agencies add the final touch. PMID- 10118554 TI - The comeback trail. Aggressive intervention optimizes independence. PMID- 10118555 TI - Thinking big. Maryland CCRC serves 1,300 residents. PMID- 10118556 TI - Resident assessment pinpoints staffing needs. MDS (minimum data set) aids proper manpower allocation. PMID- 10118557 TI - As time runs out. Communication, compassion needed for the terminally ill. PMID- 10118558 TI - Prospective payment. An idea whose time has come. AB - The home care industry has experience with Medicaid per-visit rates and hospice daily and hourly rates capped by an overall patient limit. But no extensive home care prospective rates have been developed. Is this gap an opening for the industry to provide some valuable input? PMID- 10118559 TI - Valuing health care businesses. AB - Home care agencies have unique factors that contribute to their value--factors that are not always apparent. Do prospective buyers or owners who wish to sell know how to arrive at that value and approach the market? PMID- 10118560 TI - Improving your agency's financial health. PMID- 10118561 TI - How to perform an agency break-even analysis. AB - Financial solutions are fine in theory, but when it comes to applying them to one's own business, the formulas somehow become murky and muddled. This case study demonstrates how to determine the volume an agency needs to maintain to break even and to make a profit. PMID- 10118562 TI - Prospective payment still only a concept, but.... AB - The Medicare home health PPS demonstrations are now being conducted, after a lengthy and checkered past. They are leading toward a payment method that should avoid many of the former reimbursement problems. PMID- 10118563 TI - Tax-exempt status and the provision of charity care. Increasing congressional scrutiny. AB - Tax-exempt status has received considerable attention recently, primarily within the hospital industry. Examination of this issue also is valuable to the home care sector of the health care delivery system. Given the current economic environment, nonprofit organizations are being challenged to justify their tax exempt status on the local, state, and federal levels. Instances of revocation of real estate tax exemption are becoming increasingly common in the nursing home sector; can the effect on home care be far behind? PMID- 10118564 TI - Increasing federal funding for home care. AB - Only seven states and the District of Columbia have not instituted waiver programs under Medicaid to lower state spending on health care. But with changes in legislation, perhaps it is time to look again at possible savings under a waiver. Washington, DC could provide an example for others to follow with this or other federal funding programs. PMID- 10118565 TI - Medicaid EPSDT (Early and Periodic Screening, Diagnosis, and Testing) changes help home care. AB - The changes to the Early and Periodic Screening, Diagnosis and Testing program legislated in April 1990 have been described as the most significant improvement to Medicaid since its inception--yet states are being very quiet about these changes. Why aren't they trumpeting what may be hope for expanding needed home care services? PMID- 10118566 TI - Why nonprofits? Hospitals and the future of American health care. AB - The future of the nonprofit hospital depends on its relationship to the for profit and governmental sectors of our economy. A decade ago, the primary challenge came from the growing investor-owned hospital companies. Nonprofit hospitals' responses--both competitive and imitative--led to new challenges from government regarding tax-exempt status. The reasons underlying this challenge include the growing commercialism of health care, the nation's failure to deal directly with the problem of the uninsured, and the lack of a coherent theory of tax exemption. Although hospitals are likely to retain exemptions from federal taxation, challenges to local tax exemptions are likely to continue. Strategies that hospitals pursue for competitive purposes may undercut their legitimacy as tax-exempt institutions, but several groups are working to address the issue. PMID- 10118567 TI - A wake-up call for nonprofit hospitals in America. PMID- 10118568 TI - Hospital accountability: perceptions and costs. PMID- 10118569 TI - The mission is the motivation. PMID- 10118570 TI - Improving hospital billing and receivables management: principles for profitability. AB - For many hospitals, billing and receivables management are inefficient and costly. Economic recession, increasing costs for patient and provider alike, and cost-containment strategies will only compound difficulties. The author describes the foundations of an automated billing system that would save hospitals time, error, and, most importantly, money. PMID- 10118571 TI - A review of hospital-based women's health services: programs, customers, and facilities. AB - Because creative and innovative programming has become critical to hospital success, there has been a U.S. boom in hospital-based women's services during the past seven to eight years. As outlined here, many facilities are developing, marketing, and housing a variety of women's healthcare programs. PMID- 10118572 TI - Balancing urban high-tech with rural high-touch healthcare. A rural hospital's award-winning effort to retain patients referred to urban facilities. AB - How do you keep patients down on the farm after they've seen high-tech? In other words, how do rural hospitals encourage patients who have been referred to urban tertiary facilities to return home for their other healthcare needs? One rural hospital instituted the Care Connection, a program that not only helped the hospital retain clients but assisted referred patients with the often overwhelming logistics of using a large tertiary center. PMID- 10118573 TI - Using case-mix information in strategic hospital marketing. Deriving market research from patient data. AB - Hospital survival requires adaptation, adaptation requires understanding, and understanding requires information. These are the basic equations behind hospital strategic marketing, and one of the answers may lie in hospitals' own patient data systems. Marketers' and administrators' enlightened application of case-mix information could become one more hospital survival tool. PMID- 10118574 TI - Patients' knowledge of their caregivers' names. A teaching-hospital study. AB - In busy hospitals--particularly teaching hospitals--ensuring that patients know the names of those attending them is a task often given low priority. Yet such knowledge is a crucial element in establishing the high-priority patient-provider relationship, and certainly one within hospitals' control. In a university teaching hospital, the authors tested patients' knowledge of names before and after the use of an information sheet listing their particular caregivers. PMID- 10118575 TI - Productive relationships with mover-and-shakers. Recognizing the agents of influence in your hospital. AB - Hospital administrators need every available asset these days, and one potential resource is the people in every organization who seem to naturally attract and lead others. The authors tell how to, first, recognize such persons and, second, establish a constructive relationship with them. PMID- 10118576 TI - Hospital CEO turnover, 1987-1988: national, divisional, and class turnover rates. AB - This is the authors' third study of CEO turnover rates, the second to appear in Hospital Topics, and the most comprehensive study done so far. What is especially interesting for U.S. hospitals is that the 1987-1988 rate was the third successive year to decline--not yet a trend, but encouraging nonetheless. PMID- 10118577 TI - Administrators and patients: using the personal touch. AB - Although rarely discussed in management training, taking the time for a handshake or gentle touch on a patient's arm can yield multiple benefits for the administrator. The patient's confidence in the facility is increased, and the administrator is reminded that the patient is the true bottom line of the hospital. Moreover, both are reassured that, at the other end of the chain of service, there is another human being. PMID- 10118579 TI - Getting and staying organized. PMID- 10118578 TI - The continuing evolution of the medical staff organization: from MSO to PSO. AB - Regardless of the speed of the evolution from a MSO to a PSO, it is inevitable. During the course of this evolution, hospital management must be certain that individual clinicians and the PSO as a whole perform technical services that are integrated into the hospital's overall effort to achieve its goals. Although nonclinician managers cannot deliver clinical services or independently judge quality, they can obtain the expert advice and technical assistance needed to understand individual and aggregate PSO practice. Doing so allows managers to not only meet their ethical and legal responsibilities but also implement continuous quality improvement in the hospital, an activity of critical importance in the 1990s. PMID- 10118581 TI - Measuring outcomes at the IOM. Interview by C. Burns Roehrig. PMID- 10118580 TI - The hospital administrator as public figure, Part 2. Cultivating guidelines for decision making. PMID- 10118582 TI - Physician payment reform: what's next? PMID- 10118583 TI - Late night musings on practice guidelines. PMID- 10118584 TI - Outcomes measurement in hospitals: can the system change the organization? AB - The U.S. health care industry is in crisis--a crisis of accountability. Many believe that improved information, especially outcomes information, is at least part of the solution. If this assessment is accurate, outcomes measurement could offer a powerful opportunity to help mold our dysfunctional health care machinery into an effective infrastructure. This article explores whether implementing an outcomes measurement system in a hospital compels this kind of change. It examines the experiences of 31 hospitals that implemented a market-leading outcomes measurement system. Despite its potential, MedisGroups did not compel important improvements in hospitals' quality of care or their internal practices. Hospitals found it particularly difficult to maintain momentum throughout implementation and to structure the system as a supporting tool, rather than a driving influence, in their pursuit of operating improvements. PMID- 10118585 TI - Hospital CEOs view their careers: implications for selection, training, and placement. AB - A recent survey of hospital CEOs revealed that they seem content with their careers but apprehensive about the future, due particularly to their projections regarding contextual issues in the industry. Hospital CEOs believe that the industry will experience increased financial pressures and regulations and, as a result, anticipate the need to develop new skills. Their views on several career related topics are compared, and the implications for selecting, training, and placing CEOs are discussed. PMID- 10118586 TI - Collection performance: an empirical analysis of not-for-profit community hospitals. AB - Many not-for-profit community hospitals had major shifts in their annual collection performance between 1986 and 1988. The collection performance is measured by excess collection time; this is computed as the difference between the actual average collection time for a hospital and the median for one of the six panels to which the hospital is assigned based on ownership, control code, and financial reporting practices. The sample for this study has 1,246 not-for profit hospitals comprising over 50 percent of total revenue and expenses of all community hospitals (about 5,500). More than 16 percent of these hospitals had annual changes of ten-plus days in each of the years. Excess collection time within the six panels was examined by state, payer mix (Medicare, Medicaid, and Blue Cross), membership in the Council of Teaching Hospitals, medical school affiliation, case-mix index for Medicare, contractual allowance rate, debt service coverage, return on assets, new investments, age of property, and urban location. Major findings were that collection patterns are different among some states. The proportions of Medicare, Medicaid, and Blue Cross are negatively associated with excess collection time in three of the panels. Contractual allowance is positively related, and return on assets is negatively associated with excess collection time in two of the panels. The other factors had virtually no effect on the collection performance. PMID- 10118587 TI - Customer information and the quality improvement process: developing a customer information system. AB - As growing numbers of health care organizations institute quality improvement programs, the demand within these organizations for reliable information about customers increases. By establishing a customer information system (CIS)--a model for collecting, archiving, and accessing customer information--health care organizations can eliminate the duplication of research, ensure that customer information is properly collected and interpreted, and provide decision makers access to better, more reliable customer information. Customer-supplier relationships are defined, guidelines for determining information needs are provided, and ways to set up and manage a CIS are suggested. PMID- 10118588 TI - The hospital-physician computer communications network: an alternative application. AB - For more than five years hospitals have been developing computer communications networks as a physician bonding strategy because of their success in promoting hospital admissions and additional referrals to the sponsoring hospitals' specialists. An alternative, nonproprietary network may also be worthy of consideration because of the services and benefits it delivers to the total health care delivery system and to society as a whole--in addition to the advantages it offers the sponsoring hospital. An example of such a network is offered as an illustration. PMID- 10118589 TI - Hospital specialization and cost efficiency: benefits of trimming product lines. AB - Trends in hospital specialization are studied using multiple regression analysis for the period 1983-1990. The observed 26.9 percent rise in specialization was associated with a 6.9 percent decline in unit cost per admission. Specialization is also associated with improved quality of care. Specialization has been highest in competitive West Coast markets and lowest in the rate-regulated states (New York and Massachusetts). Hospitals have less incentive to contain costs by decreasing the array of services offered in stringent rate-setting states. The term "underspecialization" is advanced to capture the inability of some hospitals to selectively prune out product lines in order to specialize. Such hospitals spread resources so thin that many good departments suffer. Unit cost per case (DRG-adjusted) is higher in the less specialized hospitals. PMID- 10118590 TI - Strategic alliances between physicians and hospitals in multihospital systems. AB - Regional consolidation is one of the most frequently prescribed remedies for the ills facing hospitals today. Overcapacity, net revenue erosion, poor financial positioning, and high costs are some of the factors driving consolidation. One of the greatest challenges for multihospital systems is to align the interests among physicians practicing at the member hospitals and the system's corporate strategy (Hospitals 1990). This article offers a framework for analyzing these problems based on the economics of agency relationships and applies the framework to two case studies of strategic alliances between hospitals and physicians in a multihospital system. Both are examples of the physician-multihospital organization. PMID- 10118591 TI - Large employers and their coalitions: exploring a hospital constituency. AB - Hospitals may increasingly find large employers banding together in coalitions. Based on focus group data, insights from one coalition and a sample of its members are offered as an aid in understanding the circumstances under which such coalitions and their members resemble other "industrial buyers" and the circumstances under which they represent an adversarial constituency for hospital administrators. These data suggest that the cost of care and the trend of cost increases dominate the thinking of benefits managers; that these managers believe many corporations will work with fewer, more carefully selected providers in the future, and that therefore employee choices will be further restricted; and that the relationship between large employers or employer coalitions and hospitals depends on the employer's role and the provider's marketing orientation. PMID- 10118592 TI - Recruiting physicians: avoiding the legal minefield. AB - This article identifies and discusses the legal problems and pitfalls associated with the implementation of a physician recruitment program. Careful structuring is necessary to strike a balance meeting the requirements of both the Internal Revenue Code and the Medicare fraud and abuse provisions. The various tax considerations that may affect physician recruitment are comprehensively analyzed. Similar analysis is made of the Medicare fraud and abuse statute. Also included is a list of items that must be taken into consideration when embarking on a physician recruitment program. PMID- 10118593 TI - Assessment of clinical service contracts between hospital pharmacies and colleges of pharmacy. AB - The purpose of this study is to assess the advantages and disadvantages of various annual financial clinical contract options between the Atlanta metropolitan area hospital and the Mercer University Southern School of Pharmacy (Atlanta, GA). Forty-five surveys with 17 statements in a Likert scale format were mailed to all directors, clinical staff of each hospital (adjunct faculty), and full-time clinical faculty to validate the perceived advantages and disadvantages of financial contracts between their hospital and the School of Pharmacy. The survey questionnaire was returned by 84% of the participants. Survey results indicate that the School of Pharmacy and area hospital pharmacies appear to have benefited from this marriage of common interests in clinical program development with 79% agreeing that the overall benefits of the educational affiliation and contract out-weighed the disadvantages. PMID- 10118594 TI - Developing safe and effective preprinted physician's order forms. AB - Having good preprinted order forms is no accident. A system must be in place to ensure this. Common problems found in preprinted order forms are discussed. PMID- 10118595 TI - Medication pass observation, a new survey technique. AB - The United States Department of Health and Human Services, Health Care Financing Administration now requires that surveyors of pharmaceutical services in hospitals include a medication pass observation in the survey process. This observation affords the surveyor the opportunity to follow medications through the complete system, that is, from the time that the medication is prescribed by the physician to the time that it is administered to the patient. This enables the surveyor to determine if the quality of care provided to the patient meets the intent of the federal and state regulations. The article describes the surveyor's technique for performing the medication pass observation which has become an integral part of the survey process. PMID- 10118597 TI - Focusing on the preventability of adverse drug reactions. PMID- 10118596 TI - Strategic planning for biotechnology products. PMID- 10118598 TI - A management primer on labor relations. PMID- 10118599 TI - The state of the unions in the clinical laboratory. Part I. A disenchanted profession asks: are unions the answer? AB - Apprehension and lack of knowledge characterize laboratorians' impressions of unionization. While some remain adamantly opposed, others reluctantly say unions might cure current ills. PMID- 10118601 TI - Bravely entering the new world of flow cytometry. AB - Deciding whether this sophisticated testing method is feasible for your laboratory requires extensive research. If the answer is yes, implementation demands planning, dedication, and hard work. PMID- 10118600 TI - The state of unions in the clinical laboratory. Part II. Impassioned stares at a crystal ball. AB - Will unions become more prevalent in the lab? In fact, should they? Readers offer predictions, assessments, and a multitude of strong opinions. PMID- 10118602 TI - A cost-of-quality model for a hospital laboratory. PMID- 10118603 TI - Information management truths in small bytes. PMID- 10118605 TI - New York union negotiates raise, job security in three-year pact. PMID- 10118604 TI - Charity care: are hospitals giving their fair share? AB - How much are hospitals spending on charity care? Overall, they spend far less of their money--about 1% to 2% of annual revenues--on true charity-care cases than the industry would like everyone to believe. The debate over charity care has been muddied by inconsistent definitions of charity care, conflicting requirements from government agencies and misleading data from hospitals. PMID- 10118606 TI - Credit-card firm's payment record probed. PMID- 10118607 TI - Groups go to bat for Pa. cost/quality data council. PMID- 10118609 TI - N.C. system wins fight to participate in PPO. PMID- 10118608 TI - Hospital CEOs give good marks to JCAHO. PMID- 10118610 TI - AMA changes tune, sings praises of HMOs. PMID- 10118612 TI - Market war rises to higher level in Sioux Falls as McKennan woos largest group practice. PMID- 10118611 TI - Group acquisitions to put 2 hospitals in role of employing staffs. PMID- 10118613 TI - AIDS claims only a fraction of total--study. PMID- 10118614 TI - Defined-benefit plans still top hospital choice. PMID- 10118615 TI - GOP optimistic about its health reform plan. PMID- 10118616 TI - Hospital closings drop for third straight year. PMID- 10118617 TI - Facilities do their darndest to keep mum on charity care. PMID- 10118618 TI - Mortality data show some improvement. PMID- 10118619 TI - Consolidations in Minnesota help bring about the demise of state's health coalition. AB - Recent consolidations by healthcare purchasers and providers in the Minneapolis area have contributed to the demise of the Minnesota Coalition on Health, the 12 year-old consortium of provider, business and consumer groups that was a pioneer in educating healthcare consumers about cost-control strategies. Observers said much of the responsibility for analyzing healthcare services, costs and outcomes is now moving to the marketplace. PMID- 10118620 TI - Some bond authorities fight disclosure rules. AB - While the group that represents tax-exempt bond authorities would like to see that investors receive more financial information from hospitals, some of its members are fighting proposed disclosure guidelines because they're fearful the rules would swamp their staffs with added paperwork and other administrative burdens and, in some cases, even threaten their very existence. PMID- 10118621 TI - NME, FTC settle charges of false advertising. PMID- 10118622 TI - Judge's ruling lets hospital use 'economic credentialing'. PMID- 10118623 TI - Calif. bill to go easier on physician-owned ventures. PMID- 10118624 TI - Providers challenge Florida's ban on referrals to facilities they own. PMID- 10118625 TI - Former Center for Nursing VP hits AHA with $6 million slander suit. PMID- 10118626 TI - Elderly lobby assaults balanced-budget bid. PMID- 10118627 TI - Bill would require computerized records by '96. PMID- 10118629 TI - Showdown near over hospital in rural Texas town. PMID- 10118628 TI - Defense Dept. plans to proceed with new information system. PMID- 10118630 TI - Catholic hospitals, AHA to cooperate on reform. PMID- 10118631 TI - Leading House Democrats push cost-control plan. PMID- 10118632 TI - Patient dumping occurring, say 13% of CEOs. PMID- 10118633 TI - Court's ruling on N.J. uncompensated care plan could derail other states' plans. PMID- 10118634 TI - Former nurses at Tenn. facility file suit, request $35 million. PMID- 10118635 TI - Hearing on Medicare overcharges delayed; Humana report issued. PMID- 10118636 TI - Humana's net earnings drop during third quarter. PMID- 10118637 TI - Consolidation hits home market for high-risk pregnant women. PMID- 10118638 TI - Critical Care America, Medical Care Int'l to merge. PMID- 10118639 TI - $15.7 million, 100-bed facility to open in New Jersey. PMID- 10118640 TI - Geriatrician shortage expected to worsen. PMID- 10118642 TI - Proposal to streamline states' waiver process. PMID- 10118643 TI - Innovative nursing facility scheduled to open in Seattle. PMID- 10118641 TI - Eliminating inefficiencies could save hospitals $60 billion--study. PMID- 10118644 TI - Advice to grads: use service, not salary, to measure success. PMID- 10118645 TI - Hospital borrowers finding it tougher to scale the wall on Wall Street. AB - More hospitals, many located in rural areas or battling tough competition, are getting the cold shoulder from tax-exempt bond investors, even though the facilities desperately need capital to advance their operations. Meanwhile, well to-do systems and hospitals continue to reap the benefits of getting low-cost capital from the municipal bond market. PMID- 10118646 TI - Ga. planning agency to decide which of 4 rivals will build facility. PMID- 10118647 TI - New name can sharpen a hospital's image--or diffuse checkered past. AB - Hospitals change their names for a variety of reasons. Some seek a new identity that conveys a wider range of services; others need a new moniker as a result of a merger; still others hope a change can help the facility erase past problems. Whatever the case may be, a hospital's decision to change its name has evolved from a mere technical formality to a competitive, and often costly, marketing strategy. PMID- 10118648 TI - $15 billion needed in next 10 years to rebuild aging facilities--NAPH. PMID- 10118649 TI - Consumers see mortality data as useful tool. AB - Consumers have become more sophisticated in making healthcare buying decisions, and a growing percentage now realize they've gained a new tool for judging the quality of hospitals--the mortality data that are disseminated by HCFA. While physicians and administrators don't see that information as valuable, more consumers say they plan to use it. PMID- 10118650 TI - Congregations opening facilities to the public. AB - Roman Catholic congregations are seeking innovative, cost-effective ways to address the growing long-term-care retirement needs of their sisters. The Sisters of St. Joseph of Carondelet in St. Louis have adopted one popular strategy- opening the congregation's retirement and nursing facilities to the private paying public, which will allow the group to lower its retirement costs and offer a broader range of services. PMID- 10118651 TI - Physician pay increases smaller, but they're still outpacing inflation. PMID- 10118652 TI - Aggressive plan cuts cost of equipment maintenance. PMID- 10118653 TI - Children's Miracle Network continues raising money, public's consciousness. PMID- 10118655 TI - AMA seeks antitrust law change to allow negotiated physician fees. PMID- 10118654 TI - After-tax profit nearly triples for AMA. PMID- 10118656 TI - 25 hospitals bought mislabeled, used pacemakers from salesman. PMID- 10118657 TI - Oregon Medicaid officials voice frustration after HCFA misses deadline on waiver decision. PMID- 10118658 TI - Kansas plan singles out hospital. PMID- 10118659 TI - Md. plan wants to set up public company. PMID- 10118660 TI - Daughters of Charity hit with token judgment for breach of pact. PMID- 10118661 TI - Mass. facility to pay $12 million in settlement on Medicaid charge. PMID- 10118662 TI - Greenery fights Healthcare Int'l reorganization. PMID- 10118663 TI - Docs give AHA reform plan thumbs down. PMID- 10118664 TI - Entitlement programs to be open to attack in future battles over deficit reduction. PMID- 10118665 TI - In search of outcomes. AB - Psychiatric hospitals, stung by reports of alleged abuses, are furiously trying to work their way out of an industry slump by embracing outcomes research. For them, such research may be a way to justify the value and effectiveness of their services with increasingly demanding payer groups. Although outcomes research is fairly common in medical/surgical hospitals, its existence is new to mental health. PMID- 10118666 TI - Clinton gives some details of his healthcare platform. PMID- 10118667 TI - Self-referral issue targeted on two fronts. PMID- 10118668 TI - Data to help JCAHO pinpoint problem areas. AB - One change under the JCAHO's "Agenda for Change" will involve the commission's relationship with the healthcare organizations themselves. Hospitals can expect more visits and more contact of all kinds. More importantly, the JCAHO will use clinical data and responses to questionnaires to track potential trouble spots. When the survey team comes around, it'll be able to zero in. PMID- 10118669 TI - Rochester, N.Y., consortium ends outcomes data experiment. PMID- 10118670 TI - When the exec search firm comes calling, here's what to expect and how to prepare. AB - Because executive search firms are playing an increasingly important role in helping organizations develop their management teams, it's more important than ever for aspiring managers to position themselves for success if they become involved in a search firm's quest for candidates. Search firm executive Dorothy Billingsly explains the process and offers advice. PMID- 10118671 TI - Tax exemptions for Pa. hospitals could hinge on high court's ruling. AB - Not-for-profit organizations in Pennsylvania, especially hospitals, are awaiting a decision by the state's high court concerning a nursing home's property tax exemption. Unless the Supreme Court agrees to hear the case and then reverses the lower-court ruling, state hospital officials fear it could become virtually impossible for any organization to obtain a property tax exemption. PMID- 10118672 TI - HCFA decision a boost for electronic claims. PMID- 10118673 TI - 2 hospitals dispute Medicare cost audits. PMID- 10118674 TI - Calif. hospital pays feds $50,000 to settle kickback charges. PMID- 10118675 TI - Minn. becomes 1st state to fight not-for-profit hospital merger. PMID- 10118676 TI - Donations to healthcare organizations fall 2.3%. PMID- 10118677 TI - Healthcare groups extend helping hand overseas. PMID- 10118678 TI - Pain guideline stresses patient involvement. PMID- 10118679 TI - Early decisions crucial to successful building project. OR manager is key player in design of new OR suite. PMID- 10118680 TI - Informed consent: patient can set limits. PMID- 10118681 TI - Half of hospitals score low on surgical case reviews. PMID- 10118682 TI - A model to get you started in a CQI program. PMID- 10118684 TI - 1992 software buyers guide. A listing of software providers servicing the long term care industry. PMID- 10118683 TI - Construction & architects survey. Providers may see lower building bills. AB - Stagnation in the construction industry could spell increased competition and lower prices for healthcare projects in the next few years. Architects forecast that the number of projects will remain steady despite the soft economy, with continued emphasis on ambulatory-care facilities and critical-care areas. These are among the findings of Modern Healthcare's annual survey of healthcare design and construction. PMID- 10118685 TI - Families, providers often differ on tube feedings, researchers find. PMID- 10118687 TI - Interpersonal skills most influential in patient satisfaction. PMID- 10118686 TI - Patient Determination Act may actually invite lawsuits, attorney. PMID- 10118688 TI - Frontier hospitals pursue computer record as national effort moves on. PMID- 10118689 TI - Parking headaches cured for visitors, patients at California hospital. PMID- 10118690 TI - Humana moves to fee-per-use equipment financing deals. PMID- 10118691 TI - Foley catheter prices edge up. PMID- 10118692 TI - Hospitals ill-informed of GPO contract details, unaware of actual savings, executives say. PMID- 10118693 TI - Efficient shipping & receiving areas trim dross from materials management operating budget. PMID- 10118694 TI - Medicare reimbursement rules slow equipment buying. PMID- 10118695 TI - How warranties, discounts, GPO activities are governed by Safe Harbor regulations. Part 2. AB - An earlier article dealt with the general background of the Safe Harbor regulations issued by the Department of Health and Human Services in July 1991. That article also briefly outlined several parts of the regulations which are of lesser interest to hospital materials managers. In this dialogue, Dr. Decker develops those parts of the regulations that are of primary concern of hospital materials managers. A subsequent article will brief several court cases that were decided before the regulations were finally promulgated and will offer some conclusions and recommendations. This is Part 2 of a three-part series. PMID- 10118696 TI - Developing strategic thinking in senior management. AB - Chief Executive Officers have recently stated that their greatest staffing challenge for the 1990s is the development of strategic leadership in their senior management. In order to do this, it is necessary to identify the substance of strategic thinking, and the capabilities that must be mastered. Writers on strategy have identified six major elements of strategic thinking and these have been organized to reveal the tasks, questions, decisions, and skills that senior executives must acquire in order to lead their organizations strategically. Finally, the article identifies training programme elements which are used by Directors of Manpower Development to develop strategic leadership ability. PMID- 10118697 TI - Strategic control at the CEO level. AB - This study of 108 corporations is intended to identify and validate those strategic control factors that contribute directly to the success of strategic decisions made at the level of the CEO which are subsequently implemented throughout the organization. In direct response to a comprehensive questionnaire, 61 CEOs rated nine strategic control factors. Only the ratings of CEOs were accepted and processed in this study. Their ratings revealed areas of obvious strength and correctable weakness in their perceptions of strategic control within their respective organizations. These ratings tended to validate a conceptual process model of strategic control. PMID- 10118698 TI - Organizational assessment: concept, method and application. AB - The concept of organizational assessment of health institutions is explored in terms of why it is becoming increasingly popular, alternative approaches, and its potential as a tool for quality assurance or program evaluation. There is an outline of an approach to developing standardized performance criteria and a design for carrying out an assessment through a self-assessment method. Illustrations of the application of the model are included. PMID- 10118699 TI - The evaluation of NIMROD, a community-based service for people with mental handicap: revenue costs. AB - The cost implications of moving from a system of services for people with mental handicaps centred on large institutions to a network of community-based services are not precisely known. The provision of the NIMROD service in a part of Cardiff, with its aim not only to meet the residential needs of adults comprehensively by providing a number of houses in the community but also to develop a support service to people living in their family home, gave an opportunity to investigate and report the revenue costs of a number of service elements with respect to a defined total population. The residential costs of intensively staffed houses in 1986-87, varying in size from two to six places, were found to range between pounds 16,473 and pounds 23,319 per person per year. With the addition of community support costs, such as the provision of day services, the total costs of care per resident averaged pounds 21,708; range, pounds 18,883-pounds 26,009. These compared to the total costs in a minimally staffed house of pounds 9,678 per resident. The costs of community support services for people living in their family homes averaged pounds 5,614 inclusive of DSS benefits, of which pounds 1,743 was accounted for by the NIMROD domiciliary support service, office base and administrative overheads. The residential costs reported were compared to other cost data in the literature. The study supports previous conclusions that there is little evidence of diseconomy attached to small scale per se but that the way staffing levels and therefore staff costs are determined is critical. No evidence was found in this study to link greater cost to better quality. PMID- 10118700 TI - Relative performance evaluation of non-profit hospitals. AB - In this paper, we use the relative performance evaluation model of Gibbons and Murphy (1990) to examine the relationship between management compensation and the absolute and relative financial performance of 223 non-profit hospitals in Ontario, Canada for the year 1985-86. We find support for the hypothesis of a positive relationship between absolute hospital performance and management compensation and a negative relationship between relative hospital performance and management compensation. Management compensation is also influenced by the size, teaching status, and religious affiliation of the hospital. PMID- 10118701 TI - Changing cultures--determining domains in the NHS. AB - This article explores changes in the National Health Service (NHS) as an organisation, in the context of the emerging managerial culture. This new culture is also seeking to influence the other forms of organisational culture which have co-existed until now in the NHS; its success in doing so is limited by the lack of a shared value system within the new management culture. The issue is explored with reference to domain theory as suggested by Kouze and Mico (1979), and subsequently amended by others, to fit the developments occurring in the NHS. Consideration is given to the following issues with reference to the three domains of politics, management and professions. Can we establish: the continued existence of each domain; the changing location of groups between each domain; the interrelationship between the domains: the location of issues within or between the domains. The theory is then located within the broader discipline of organizational behaviour to provide a revised model for thinking about and acting upon the cultural change in the new NHS; the organizational learning now required is shown to require the following activities by each domain; identification, interpretation and communication. PMID- 10118702 TI - Bed size and system influence on financial structure: a time-series and cross sectional analysis of California hospitals. AB - Using California hospitals, this study examines both on a cross-sectional and time-series basis the influence bed size and system affiliation have on financial structure. Specifically, the study classifies these hospitals into eight bed size and system categories ranging from less than 100 bed, free-standing hospitals to over 400 bed, system-affiliated hospitals. Somewhat unexpectedly, the results did show that the total debt ratio for smaller, free-standing hospitals did not differ statistically from larger free-standing and system hospitals. However, smaller system-affiliated hospitals did have higher total and long-term debt ratios than larger, system-affiliated and free-standing hospitals. PMID- 10118703 TI - Factors affecting the supply of private hospital beds in the UK: private insurance, NHS pay beds, or NHS waiting list? AB - This study attempts to isolate the determinants of private hospital growth in the United Kingdom. Thirty-six variables, representing private medicine, the socio economic environment, the political and government conditions, and the health care systems characteristics were selected for analysis. Multiple regression analysis shows that the number of independent hospital beds in the UK can be explained almost entirely by the number of persons with private health insurance, the number of NHS pay beds, and the overall bed level. Further analysis reveals that the number of persons with private health insurance can be explained to a large extent by the length of the NHS waiting list. PMID- 10118705 TI - Involving physicians in hospital disaster planning. PMID- 10118704 TI - HCFA's close encounter with CQI. PMID- 10118706 TI - Perspectives. Containing costs by fighting fraud. PMID- 10118707 TI - Perspectives. Is health reform the answer to the deficit? PMID- 10118708 TI - Do you computer take this television ...? AB - Just as computerized information systems are revolutionizing the way hospitals distribute patient information around the healthcare system, interactive video technology now is revolutionizing the way television sets are used in patient rooms. The TV set is becoming a source of hospital and patient information, and helps provide patient education. PMID- 10118709 TI - Expanding enabling technologies into clinical settings. PMID- 10118710 TI - Contracting for a new computer system: the short course. PMID- 10118711 TI - Time & attendance. PMID- 10118712 TI - Pharmacy information systems: controlling costs, improving care. PMID- 10118713 TI - Outside help cures Clarkson's inside IS problem. PMID- 10118714 TI - '92 bedside systems report. PMID- 10118715 TI - Using computer systems for improved scheduling. PMID- 10118716 TI - Who needs bedside terminals? PMID- 10118717 TI - AHA study defines bedside terminal issues. PMID- 10118718 TI - Examining your insurance carrier. PMID- 10118719 TI - Selecting super service people. PMID- 10118720 TI - Securing your HRIS in a microcomputer environment. PMID- 10118721 TI - Models for skill-based pay plans. PMID- 10118722 TI - Financial realities of AIDS in the workplace. PMID- 10118723 TI - Self-insurance checkup. PMID- 10118724 TI - A case study of state managed care regulation: utilization review laws. PMID- 10118725 TI - Regulating managed care firms: the Connecticut plan. AB - Virtually every state in the country, as well as the federal government, is either considering or has recently considered legislation to regulate utilization review/managed care companies. Despite the magnitude of this issue, few legislative bodies have expended the resources to study the form that regulation should take. Recently, Connecticut, which has seen considerable growth in utilization review within managed care programs that insure Connecticut residents, funded such a study. This article, authored by two of the study's participants, reviews the issues and explains the study's recommendations. PMID- 10118726 TI - Comprehensive managed care evaluation. AB - To optimize the benefits of managed care delivery systems, employers must identify and reward those systems that are most efficient and effective. At the same time, their deeper involvement in system design and management exposes employers to greater potential liability. Employers thus need to better evaluate their managed care programs in order to enhance the benefits and minimize the risks. PMID- 10118727 TI - The relationship between wellness participation and health care benefit utilization. AB - To examine the relationship between participation in a wellness program and the amount of absenteeism and medical claims, seven years of retrospective absenteeism and medical claims records were collected for 207 employees (pre- and postwellness intervention) and entered into a database. A proportional stratified random sample of workers by wellness participation was selected. While there was no significant change in the amount of sick leave taken over time, a log transformation revealed a significant increase in the dollar amount of medical claims over time, particularly for the middle-aged group of employees. This confirms that wellness intervention slowed the rate of increasing claims among middle-aged participants after just three years of wellness intervention. PMID- 10118728 TI - Provider responses to utilization review. PMID- 10118729 TI - Affiliated societies of the Alabama Hospital Association. Number 2 in a series. PMID- 10118730 TI - Healthcare philanthropy: finding success through community support. PMID- 10118731 TI - The newest AIDS measures: what they mean to hospitals. AB - AIDS and other infectious diseases are on the rise - and so are measures to prevent them from being transmitted from patients to providers and vice versa. But are all of the efforts a matter of good policy, or simply overkill? PMID- 10118732 TI - Transcription by the pound. PMID- 10118733 TI - Quality assurance: key to cost containment in medical transcription. AB - Do you think it's too costly to institute a quality assurance program in your transcription department or service? In today's medical world, you can't afford not to. PMID- 10118734 TI - American Health Information Management Association. Position statement. Issue: advance directives. PMID- 10118735 TI - Health law: medical record implications of the Safe Medical Devices Act of 1990. AB - Health information management professionals have involuntarily been placed by Congress and the FDA not only in the important position of being able to assist their employers in complying with the SMDA, but also at the cutting edge in the development of new and more pervasive techniques of healthcare regulation. The implementation of the SMDA in the near term and over the next 48 months promises to have substantial implications for those charged with responsibility for medical record information. PMID- 10118736 TI - Joint Commission activities: changes to the 1992 Accreditation Manual for Hospitals "Medical Record Services" chapter. PMID- 10118737 TI - Coding notes: HCPCS (HCFA Common Procedure Coding System): what's it all about? PMID- 10118738 TI - Overview of trauma registries. AB - Registry data related to patient volume, flow, severity, resource use, and reimbursement sources provides valuable information to administrative staff for program management and strategic planning activities. PMID- 10118739 TI - The implementation of a trauma registry in an acute care hospital. PMID- 10118740 TI - Cardiac registries--their place in healthcare. AB - The largest benefit of having a cardiac registry is quality. Everyone from patients, payers, physicians, and the public wants to know your quality...many hospitals are unprepared to answer these questions. PMID- 10118741 TI - UNOS: United Network of Organ Sharing "the link between organ donors and organ recipients". PMID- 10118742 TI - Cancer registries are not just "black holes". AB - The most exciting development regarding access to national cancer data is the recent creation of the National Cancer Database. PMID- 10118743 TI - Birth registry. AB - Birth registries are among the most common type of registry found in hospitals. Brigham and Women's Hospital has a high number of births annually. The following represents a brief overview of the status of this type of registry in healthcare today. PMID- 10118744 TI - International Federation of Health Records Organizations (IFHRO)--past, present, and future. PMID- 10118745 TI - Data representations. PMID- 10118746 TI - Self-assessment for continuing education. Council on Certification of the American Health Information Management Association. PMID- 10118747 TI - Health law: medical records and the law--the special incident report. PMID- 10118748 TI - Guest alliance: uses of state-level hospital discharge databases. AB - The applications of state-level hospital discharge data are increasing. SDOs, however, face several substantial challenges if they are truly to be perceived as a legitimate tool for managing the healthcare system. These challenges include obtaining a commitment at the state and national levels, and in the public and private sectors, to the following principles: promotion of the long-term stability of SDOs; expansion of state databases beyond hospitals into ambulatory and long term care settings; and provision of necessary financial, technical, and educational assistance so that SDOs can meet their legislative mandates. Stakeholders should be educated about the value of state-level data. SDOs should expand their dissemination efforts as a way of reinforcing the importance of placing data in the public domain. NAHDO is working with SDOs and other data collectors and users to improve uniformity, standardization, access, and use of health data. PMID- 10118749 TI - California seeks to balance public information role with patient confidentiality risk. PMID- 10118750 TI - Hospital use of billing data for quality improvement. PMID- 10118751 TI - The Uniform Clinical Data Set: an update. PMID- 10118752 TI - Designing your medical record career path: successfully integrating work and family responsibilities. PMID- 10118753 TI - Coding education: a partnership between a hospital and an academic program. PMID- 10118754 TI - The Physician Network System. PMID- 10118755 TI - Software: using the hardware. AB - This concludes our overview of system software. We have not included all parts of that software and have only briefly described the parts we did include. However, we hope that you now have an appreciation of the many, many things going on "underneath the surface" when you click a mouse button or type a command on your computer. PMID- 10118756 TI - The computer-based patient record--secondary records and "what should you be doing?". PMID- 10118757 TI - Oregon's plan for health care rationing. PMID- 10118758 TI - Creative approaches to management. PMID- 10118759 TI - Learning values in adulthood. AB - In this article I have used Beck's six basic principles of values learning in adulthood as a framework for examining mission education within one health care institution. Utilizing these principles in this way has some distinct advantages. Beck's principles: provide a useful list of reference points from which to examine the area of educational processes for mission, philosophy and values within health care settings; help to further test the meaning and application of adult education principles, theories and practices as they apply to values education. They also suggest some further areas for exploration and study. These principles have provided a frame of reference to explain the rationale for mission education and adult values education and one mission educator's sensitivity to the issues and concerns of so many interest groups. PMID- 10118760 TI - Health care: a ministry of the Church. PMID- 10118761 TI - The CIO's key role in healthcare strategic planning. AB - Chief information officers are not longer technicians overseeing the computer room. They're full-fledged members of the healthcare team. What that means, however, is that the CIO must be both willing and able to participate in planning and building the infrastructure that will underpin healthcare delivery in the future. PMID- 10118762 TI - CEOs--listen up! AB - Chief information officers across the country are hopping mad. They're getting first-string pay but being cut from the game when it comes to strategic planning. Comments and figures culled from a recent Computers in Healthcare survey demonstrate that CIOs must become members of the executive decision making team. PMID- 10118763 TI - The role CIOs must play in multihospital strategic planning. Interview by Maida Reavis. AB - An interview with Jean A. Balgrosky, R.R.A., M.P.H., vice president of Information Resources at Holy Cross Health System Corporation reveals that hospital strategic planning must be accomplished around a framework of information systems. Costs and quality, says Balgrosky, demand it. PMID- 10118764 TI - Information industry leaders share visions of future. Interview by Carolyn Dunbar and Michael L. Laughlin. AB - Computers in Healthcare editors Carolyn Dunbar and Michael L. Laughlin spoke to nearly a hundred exhibitors during the 1992 Healthcare Information and Management Systems Society last February in Tampa, Fla. The themes of these conversations invariably turned to patient-focused systems, standards, integration and, of course, controlling healthcare costs. Many HIMSS participants offered valuable insights, and unfortunately space does not permit us to run every interview. In the following interviews, however, three industry leaders share visions of where their companies--and the industry--are headed. PMID- 10118765 TI - Planning to keep your job. AB - Keeping your job and moving up the ladder require a strategy that not only sets goals for the institution's information systems, but also keeps your boss happy. Being seen as "doing what is right" for the hospital, meeting expectations and maintaining credibility are vital to staying off the "hit list." PMID- 10118766 TI - Aiming high: the challenging path to the CIO's position. AB - Climbing the ladder of success takes a rare combination of background, education and technical skill. But there's more, according to this executive search expert. I/S professionals must "talk the talk" of senior-level hospital executives, and live and breathe hospitals, if they are to reach the pinnacle of success in their field--the CIO position. PMID- 10118767 TI - Traumatized kids, traumatized rescuers? PMID- 10118768 TI - Young guns. AB - Violence-related penetrating trauma in pediatric patients was a rarity years ago, but EMS providers are seeing a rapidly increasing incidence of gunshot wounds. PMID- 10118769 TI - Pediatric etiquette. PMID- 10118770 TI - License to kill? Advance directives make the provision of medical care more complex. PMID- 10118771 TI - Industrial-strength EMS. Take proper precautions when responding to an industrial site. PMID- 10118772 TI - All's fair. A unique EMS fair helps children learn what to do in an emergency. PMID- 10118773 TI - High-tech hazmat. An Ohio hospital launches a self-contained hazmat center. PMID- 10118774 TI - OSHA compliance. PMID- 10118775 TI - C-store profits in your future? PMID- 10118776 TI - Partnering with industry organizations. PMID- 10118777 TI - Preparing your operation for the HACCP (Hazard Analysis of Critical Control Point) process. PMID- 10118778 TI - Massachusetts General's 'patient-flexible' system. AB - Mass General uses a chilled tray line to ensure that all menu items remain cold until it is time for entrees, vegetables and starches to be heated for patient service. This process prevents bacteria from growing during tray assembly, when foods are out in the open air. PMID- 10118779 TI - Nonprofit corporations. PMID- 10118780 TI - Hospital tracks safety and security problems; wins JCAHO commendation. PMID- 10118781 TI - An interview with: David Sine on trends in hospital safety/quality management. AB - David M. Sine, president of David M. Sine & Associates, Inc., Austin, TX, is a safety and quality management consultant specializing in pre-accreditation auditing of health care facilities. Prior to becoming an independent consultant in 1980, he was a senior staff engineer for the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and has worked as a consultant to the American Hospital Association. He has lectured throughout the country and published numerous trade articles on safety and quality management issues. Here, he discusses recent trends and developments in hospital safety and quality management, and offers advice on measures to take in preparation for a Joint Commission accreditation survey. PMID- 10118782 TI - Growing violence by animal rights activists: what you should be aware of. AB - Recent publicized violent attacks by animal rights activists in hospital and university research facilities and the upcoming decision by Congress on whether to pass laws that would make attacks on animal research facilities a federal crime have again focused attention on the movement and elements in it that seem to be taking on tactics of political terrorists. This report provides details about the movement, presents some lessons to be learned from the recent attack on a Michigan State University facility, and gives tips on making your facility and researchers less vulnerable. We'll also update you on some disquieting news from abroad. PMID- 10118783 TI - 1992 IALD (International Association of Lighting Designers) awards. PMID- 10118784 TI - Invisible women. Lesbians and health care. PMID- 10118785 TI - German unification and European integration. AB - In the Winter 1990 issue of the Bulletin, Health/PAC published a report by Dr. Deppe and Dr. Winfred Beck comparing the health care systems of the two Germanies. In this article, Dr. Deppe extends that analysis to compare these systems with those of other Western European countries and to examine the lessons the absorption of Germany's socialist system into its capitalist neighbor may have for the integration of the European Community. Readers will note that what we commonly refer to as a health care system and its insurance and institutions is here termed a "sickness" system--a description used by European progressives to indicate that the health care system emphasizes care for people when they are sick rather than preventive care that would help them stay healthy. PMID- 10118786 TI - Access to what? Health care for whom? PMID- 10118787 TI - Occupational and environmental health. Bush declares open season on OSHA. PMID- 10118788 TI - Campaigning for health. Real debate on health care reform. PMID- 10118789 TI - Excluding more, covering less. The health insurance industry in the U.S. PMID- 10118790 TI - Health management qualifications. Pot luck. PMID- 10118791 TI - Health management qualifications. The importance of talking shop. PMID- 10118792 TI - Health management qualifications. Mastering management. PMID- 10118794 TI - Health management qualifications. Management degrees. PMID- 10118793 TI - Contract culture. PMID- 10118795 TI - Health management qualifications. Joint ventures. PMID- 10118796 TI - Just trust us. PMID- 10118797 TI - Shared cares. PMID- 10118798 TI - Depression and suicide. National Association of Health Authorities and Trusts. PMID- 10118799 TI - Soured dream. PMID- 10118800 TI - Judgement day. PMID- 10118801 TI - Getting the best from salary surveys. PMID- 10118802 TI - Evaluation of a staff stress management service. PMID- 10118803 TI - Teaching staff to let elderly people live a little. PMID- 10118804 TI - Early thoughts on a reward system for health care assistants. PMID- 10118805 TI - Why child care is still an issue for the NHS. PMID- 10118806 TI - Motors or medicine--does it matter? PMID- 10118807 TI - Healthy work for all 2000? PMID- 10118808 TI - Taking local management responsibility for NHS pay. PMID- 10118809 TI - Warrington: a star in the world of caring for staff. PMID- 10118810 TI - Integrated health systems: putting together the building blocks of community care networks. PMID- 10118811 TI - Stephen Shortell on integrated health systems: what will it take for the 1990s? PMID- 10118812 TI - UniHealth America takes on America's biggest market--Southern California. PMID- 10118813 TI - A stitch in time. Rethinking refresher courses. PMID- 10118814 TI - Help ... I've fallen and I can't get up. AB - "Help ... I've Fallen and I Can't Get Up!" This line, from the Life Alert television commercial, has become one of today's most famous TV slogans. In fact, mention personal medical-alert systems to most people and they are likely to respond with these words. But often, EMS providers will add some choice words of their own about the problems they have encountered with such systems. PMID- 10118815 TI - The FCC may be listening. An update on EMS communications. PMID- 10118816 TI - "Hello ... I'm a doctor". AB - You may find yourself between the proverbial rock and a hard place when you receive directions from a physician that are in direct conflict with your system's protocols. PMID- 10118817 TI - What's new in '92. Technological updates from the EMS Today exposition. PMID- 10118818 TI - 2020 trauma. A view of things to come. PMID- 10118819 TI - Is EMS communications still all talk? PMID- 10118820 TI - Logging onto EMS computer bulletin boards. PMID- 10118821 TI - Patient preference prevails. PMID- 10118822 TI - Whose fault is it doctors aren't "special" anymore? PMID- 10118823 TI - Insurance clerks are the real gatekeepers. PMID- 10118824 TI - Some real estate investments are still healthy. PMID- 10118825 TI - What's ahead in payment reform and practice controls?. Interview by Carol Stevens. PMID- 10118826 TI - PROs make us waste time and money. PMID- 10118827 TI - Business gets tougher than ever on doctors. PMID- 10118828 TI - Speed up the flow of third-party payments. PMID- 10118829 TI - Patient education: do it right, and everyone wins. PMID- 10118830 TI - Isn't there something better than suing? PMID- 10118831 TI - What's really wrong with Canadian health care? PMID- 10118832 TI - Is there any reason not to participate in Medicare? PMID- 10118833 TI - The courts warn: make sure you're telling patients enough. PMID- 10118834 TI - A major crisis looms for labs. PMID- 10118836 TI - Special report, Part II. Fight or flight? Laboratorians' response to the shortage. PMID- 10118835 TI - Special report, Part I. Lab staffing in the shortage era. AB - Respondents to MLO's exclusive survey indicate that trends identified three years ago continue. To no one's surprise, a serious shortage looms large. Here's how labs are coping. PMID- 10118837 TI - Lab administrators' role in retaining professionals. AB - When a climate survey identified problems in recruitment and retention, this lab QA director set out to correct them. Her insights and tactics might work for your lab, too. PMID- 10118838 TI - 8 1/2 steps to employee retention. AB - Motivation, that elusive goal, is derived from far more than grand salary raises. Since retention is crucial to surviving the staffing crunch, how can you keep employees satisfied enough to stay? PMID- 10118839 TI - Seven forces reshaping the clinical laboratory. PMID- 10118840 TI - Complying with the new OSHA regs. Part II. Safety protocols no lab can ignore. AB - By federal fiat, laboratorians must be protected in many ways from occupational exposure to bloodborne pathogens. Is your facility following all the rules? PMID- 10118841 TI - I'm sick and can't come to work today. PMID- 10118842 TI - For high visibility and low-cost recruitment, talk to students. AB - Skillfully planned presentations at high schools engender respect for the field and may spark young people's interest in joining the ranks of clinical laboratory professionals. PMID- 10118843 TI - An automated system for record keeping, test reporting, and QC in gyn cytology. PMID- 10118844 TI - 'Distressed' hospitals likely targets. PMID- 10118845 TI - N.J. lawmakers trounce hospital-curb plan. PMID- 10118846 TI - Pa. health data agency appears doomed by budget maneuvers. PMID- 10118847 TI - Federal ruling on surcharges puts N.J. bond sales on hold. PMID- 10118848 TI - Calif. hospitals, nursing homes are bracing for big budget cuts. PMID- 10118849 TI - Columbia to sell $135 million in notes. PMID- 10118850 TI - Recapitalization helps AMI double earnings in 3rd quarter. PMID- 10118851 TI - OrNda moving headquarters to Nashville. PMID- 10118852 TI - HealthTrust earnings rise 40% for quarter; operations improve. PMID- 10118853 TI - Critical Care, MCI assuage skeptical Wall St. PMID- 10118854 TI - Greenery takes over Healthcare Int'l board. PMID- 10118856 TI - Federal judge delays Fla. venture fee cap. PMID- 10118855 TI - Hospital closures aren't closing off access to care. AB - Last month, the AHA released its annual list of closed acute-care hospitals. The report showed that the number of closings dropped to 45 hospitals in 1991 from 50 hospitals in the previous year, continuing a downward trend. A MODERN HEALTHCARE special report takes a look at last year's shuttered facilities and also identifies some noteworthy correlations among the rates of hospital closures, mergers and profits. PMID- 10118857 TI - House subcommittee passes Dem health reform proposal. PMID- 10118858 TI - Hospitals now merge rather than close. PMID- 10118859 TI - Hospitals should have strategies for safer physician incentives. PMID- 10118860 TI - Top nurse execs net top pay hikes. AB - Vice presidents of patient services received a 10.1% salary increase this year, and directors of nursing received an 8.5% salary hike, making them the big winners in this year's Hay/MODERN HEALTHCARE Nurse Compensation Survey. Meanwhile, pay hikes for registered nurses showed moderation across the board, especially for nursing supervisors, who saw a sharp drop from past double-digit increases. PMID- 10118861 TI - Homedco to acquire Glasrock for $72 million. PMID- 10118862 TI - Report for Senate subcommittee questions financial stability, practices of Blues plans. PMID- 10118863 TI - Health programs target needs of mature adults. AB - Those in the 50- to 64-year-old age bracket are beginning to worry about health concerns and are seeking out hospitals they can turn to for care. Some hospitals are responding by creating wellness and prevention programs that cater to the pre Medicare individuals in this niche. The move represents a departure from hospital's past approach of seeking to secure the allegiance of young adults. PMID- 10118864 TI - Bill may require automation of patient records. AB - Hospitals that have been delaying investments in clinical information systems may not be able to wait much longer. A bill drafted by HHS and introduced in the Senate last month would require hospitals to computerize their medical records by Jan. 1, 1996. Although the bill has some loopholes to give some facilities until 1998, it certainly would turn hospitals into motivated buyers of such systems. PMID- 10118865 TI - FHA working to streamline hospital loan guarantee program. PMID- 10118866 TI - Pa. hospitals await impact of abortion ruling. PMID- 10118867 TI - Psych hospital suit attacks Medicare formula. PMID- 10118868 TI - Pa. facility pays $400,000 to settle false claims charges. PMID- 10118869 TI - JCAHO profits jump 45% in 1991; non-survey revenues continue to grow. PMID- 10118870 TI - AmHS loan pool innovation hits a snag; customers look elsewhere. PMID- 10118871 TI - Intensive psychotherapy of psychosis in a decade of change. AB - The past decade has brought extraordinarily rapid changes to the treatment of patients with severe mental illnesses. Changes evolved from advances in technologic and pharmacologic understanding as well as from complex fiscal and political pressures. Increasingly, regimented standardization in approach narrows the range of treatment options. Both within and outside of psychiatry, some disparage psychodynamic approaches. Psychiatrists are required to accept as plausible standardized and constricted time frames for evaluation and treatment. Thus we are asked to view the mind's storms as strictly neuronally based and to view our patients as passively compliant. By implication, treatment alliance is to be cemented by a prescription and authority. This paper presents clinical material drawn from hospital-based experience at The Chestnut Lodge Hospital, Rockville, Maryland, meant to place current trends in an historic context. The author offers possible alternatives to resignation in the face of current pressures. PMID- 10118872 TI - Child and adolescent inpatient units in medical schools: staffing patterns, length of stay, and utilization rates. AB - This study examines staffing patterns, lengths of stay, and utilization rates in medical school-based psychiatric hospital treatment of children and adolescents. Results of surveys taken in 1984 and 1988 show that lengths of stay decreased during these four years, but utilization rates and number of beds tended to remain the same or increase. As economic pressures force hospitals to consider reducing staff, it is important to establish baseline data to evaluate and plan staffing patterns for child and adolescent inpatient units. PMID- 10118873 TI - The effects of psychiatric hospitalization on behaviorally disordered children: a preliminary evaluation. AB - The importance of outcome research in the field of children's mental health treatment has increased in recent years because of enhanced consumer awareness, a decrease in available resources, and payers' demand for accountability. The present study evaluated the treatment program of a child psychiatric unit in a public university hospital in the southeastern United States. The research used a single-group, pre- and post-test design and the Child Behavior Checklist (CBCL) as the outcome measure. Children receiving inpatient psychiatric treatment demonstrated statistically significant improvements in CBCL scores. The strengths and limitations of this study are discussed. PMID- 10118874 TI - Advantages and risks of design/build contracts. PMID- 10118875 TI - How hospitals get in trouble without really trying. AB - The following is a tongue-in-cheek collection of opinions, philosophies and comments too often made by well-meaning hospital administrators about their construction projects. Some of these ideas have resulted in significantly higher construction costs and have brought about disputes and claims on projects that deserved a better fate. After reading the following article, hospitals may be able to avoid similar pitfalls in future projects. PMID- 10118876 TI - County hospital sees black. AB - If it wasn't for the profits from vending machines the first year, this Tennessee hospital would have seen red. With the completion of an expansion and renovation project, hospital officials pride themselves in keeping charges low and remaining self-funded. PMID- 10118877 TI - Mural, mural on the wall. PMID- 10118878 TI - Starting over at St. Jude. AB - Its $127 million expansion project will be complete in 1995 and will be six times larger than when it opened in 1962; almost none of the original building will remain. PMID- 10118879 TI - Is anybody listening? Interiors made easy. AB - The good interior designer should listen to your needs, save you money and provide you with timeless renovation for your entire hospital. PMID- 10118880 TI - The bottom line. What ailing hospitals should know. AB - Hospitals hire consultants to bail them out because they bring new perspective. But CEO's and department heads should prepare themselves for sweeping changes that will impact the bottom line. PMID- 10118881 TI - The driving force of physician partners. AB - The administrative team admits that involvement with physician partnerships requires a different set of management skills, but it's worth the effort to share common goals. PMID- 10118882 TI - The comfort zone. AB - Meet the patient comfort team at this South Carolina hospital and see how a simple idea evolved into a major program. PMID- 10118883 TI - Restructuring. The change feels good. PMID- 10118884 TI - Invest in the long term. AB - Shrinking hospital resources have forced hospitals to develop ways to integrate their strategic, operational and financial goals. South Carolina's Richland Memorial Hospital has implemented such a plan. PMID- 10118885 TI - Healthcare uniform service market poised for expansion. AB - An estimated 500,000 establishments and approximately 5.6 million workers in the healthcare profession and related industries are affected by the new OSHA ruling on bloodborne pathogens. That's a lot of potential uniform wearers. But what should they be wearing? The answer is this: it all depends. A roundup of healthcare uniform manufacturers finds new choices in healthcare garments. PMID- 10118886 TI - 1992 Dodge/Sweet's construction volume update. PMID- 10118887 TI - The new health-care quality: value, outcomes, and continuous improvement. AB - No longer convinced that their viewpoint on quality is the only one, different stakeholders in the health-care arena are sharing perspectives to piece together the quality picture. Although still preoccupied with the cost of health care, purchasers are concerned about value--efficiency, appropriateness, and effectiveness--as well as price. Faced with evidence of medically unnecessary procedures and unexamined medical theory, practitioners are searching for appropriateness guidelines, useful outcome measures, and methods to elicit informed patient preferences about elective surgeries. Underlying this search for reliable indicators of quality--now expanded to include patient satisfaction--is a new interest in the Japanese notion of "Kaizen" or continuous quality improvement. The end product of this ferment may determine whether good medicine drives out the bad--or vice versa. PMID- 10118888 TI - Ethics committees: is there a role for them in the laboratory? AB - Ethics committees are commonly found in United States health-care institutions. As multidisciplinary committees within the medical staff structure, they are active in education, policy development, and case consultation. Clinical pathology laboratories face a number of ethically sensitive issues, including the confidentiality of sensitive data, problems of patient-caregiver or caregiver patient transfer of the human immunodeficiency virus (HIV), and conflicts about allocating scarce resources such as blood. Ethics committees can be an important resource to clinical laboratorians seeking to develop ethically defensible policies and procedures. PMID- 10118889 TI - Overcoming the four toughest management challenges. Increase your effectiveness by using situational leadership. AB - The high-pressure work environment of the clinical laboratory presents significant challenges for managers. Often thrust into supervisory roles without formal management training, laboratory managers must find ways to delegate tasks, mediate conflict, minimize office politics, and build effective teams out of employees who may be quite diverse in their experience levels, motivation levels, and cultural backgrounds. This article explores the concept of situational leadership, which was developed by Ken Blanchard and Paul Hersey, and its applicability within the clinical laboratory. This practical paradigm involves matching one of four distinct management styles to the four development levels of employees. Each leadership style is explained, along with guidelines for giving performance feedback to employees, so that managers can evaluate their own supervisory styles. Finally, step-by-step recommendations for coping with the four management roles of delegator, referee, influencer, and team builder are presented. PMID- 10118890 TI - Achieving the top: women in management. AB - Because of its unique structure, the health-care industry can take the lead in creating a responsive organizational environment where women can achieve top level positions. This requires greater flexibility from both the organization and the individual. This article examines gender-related obstacles (e.g., a male defined workplace and the inability of women to divorce themselves from family responsibilities) to career advancement and suggests some options to eliminate and overcome these obstacles (e.g., compressed and flexible time and mentoring). PMID- 10118891 TI - The cure for employee malaise--motivation. AB - Although working conditions, hours, pay, and advancement opportunities are better now than in the 1950s--the "golden age" of American business--today's workers are significantly less satisfied. Why? The authors believe the cause of this malaise is lack of motivation. This article examines several techniques to cure employee malaise and discusses the long-term benefits of these techniques, which include empowerment, recognition, career development, the Pygmalion effect, incentives, and rewards. By making a commitment to these motivational techniques, managers will boost the morale and enthusiasm of their employees and their organization. This motivational process is not quick and easy; developing your employees is an ongoing process. PMID- 10118892 TI - The Rural Clinical Laboratory Personnel Shortage Act. PMID- 10118893 TI - Vitek Microbiology System. PMID- 10118894 TI - CLMA (Clinical Laboratory Management Association) and the coming shortage of pathologists. PMID- 10118895 TI - Government description of technicians. PMID- 10118896 TI - A report on the National Commission on Cytotoxic Exposure. PMID- 10118898 TI - Strategic planning. PMID- 10118897 TI - Using self-evaluation to maintain competence. AB - This limited study examined differences in pharmacists' competencies through self assessment. By using self-assessment with specified objectives, pharmacists can target areas for CE programs. Pharmacists can then improve and maintain their competencies in these specific areas. A future study could focus on discovering the reasons some pharmacists do not feel comfortable in giving advice/information to other healthcare professionals. PMID- 10118899 TI - 1992 program survey. Eighth Annual Air Medical Program Survey. PMID- 10118900 TI - 1992 transport charge survey. PMID- 10118901 TI - Avionics and airframe survey. PMID- 10118902 TI - Programs and pregnancy: a survey of policies. AB - If a woman becomes pregnant while on flight status, a potential conflict exists between the needs and desires of the program and those of the flight crew member. Association of Air Medical Services (AAMS) member programs were surveyed to determine the extent of pregnancy policy standards within the air medical profession. A survey was mailed to 150 AAMS program directors in the fall of 1988. The survey was followed with a second mailing and a telephone follow-up for clarification. Replies were received from 110 program directors. Fifty-five percent of those responding noted they had a policy on flight crew member (FCM) pregnancy. Thirty percent noted a date prior to term that the pregnant FCM (PFCM) would be removed from flight status. Seventy percent of the programs noted that they had not previously had a PFCM. Over half of the programs allowed PFCMs to fly until the third trimester, with just under a quarter allowing flights until 38 weeks or greater. There are few articles specifically referring to air medical FCM pregnancy, and policies regarding FCM pregnancy differ widely among the AAMS member programs. PMID- 10118903 TI - Getting through: development of a communication strategy. PMID- 10118904 TI - History of the Royal Masonic Hospital. PMID- 10118905 TI - Major mental hospital sees rapid return on investment. PMID- 10118906 TI - Automation with coal firing. PMID- 10118907 TI - Legionella pneumophila. Implications with regard to cold and hot water distribution systems and process water systems. PMID- 10118908 TI - The case for fan and pump motor speed control. AB - For many years buildings were designed to use standard plant and provide good operational conditions, without consideration of the efficient use of energy. This might have been acceptable when energy was cheap, but with rising energy costs, and recent government instruction to reduce consumption levels, it is necessary to actively consider plant running costs. PMID- 10118909 TI - Update: pentamidine booths. PMID- 10118910 TI - Respirators for protection against TB. PMID- 10118911 TI - Changes in the structure of wages in the 1980's: an evaluation of alternative explanations. AB - During the 1980's, a period in which the average level of real wage rates was roughly stagnant, there were large changes in the structure of relative wages, most notably a huge increase in the relative wages of highly educated workers. This paper attempts to assess the power of several alternative explanations of the observed relative wage changes in the context of a theoretical framework that nests all of these explanations. Our conclusion is that their major cause was a shift in the skill structure of labor demand brought about by biased technological change. PMID- 10118912 TI - Advance directives. Hospitals learn how to apply PSDA via research and education. AB - The Health Care Financing Administration (HCFA) published its final interim rule covering the Patient Self-Determination Act (PSDA) in the March 6 Federal Register, more than two months after the law went into effect. The following articles summarize the AHA's response to the interim rule, how a children's hospital applies the PSDA, some research on how aging parents relinquish decision making to their adult children, how Minnesota applies the PSDA to the mentally ill, and how one hospital conducted an educational program on advance directives. PMID- 10118913 TI - Reports uncover disreputable charges of fraud in records. AB - Recent articles in the media have disclosed charges of unethical practices related to tampering with patient medical and administrative management records to enhance the institution's stature in the eyes of accrediting and quality assurance bodies, and of questionable practices regarding referrals and insurance abuse at psychiatric facilities. The following articles and regulations that have emerged summarize some of these specific charges and efforts to stem these practices. PMID- 10118914 TI - Rationing persists in face of health care reform goal. PMID- 10118915 TI - Public shows support for euthanasia, but hedges on assisted suicide. AB - Americans think about right-to-die questions in two very distinct ways--as a public policy issue generally in support of euthanasia, and as an issue of personal choice for themselves, which they would prefer to avoid. The following articles summarize the factors affecting public choice, the public's attitude toward Kevorkian, Washington's new natural death act, political fallout from the failure of Initiative 119, and Derek Humphry's plea for physicians to join in the suicide rights battle. PMID- 10118916 TI - States, church, and courts struggle with life-support laws. AB - In recent months, various state legislatures have tried to revise their laws on the removal of life support in cases where the patient's decision-making capacity is compromised. The following articles summarize some of these legislative attempts, as well as a response from one faction of the Catholic Church, and a document prepared to guide state courts in deciding on such cases. PMID- 10118917 TI - Writing and coordinating hospital policies in a multihospital system. PMID- 10118918 TI - 10 steps to managing risk in long-term care. PMID- 10118919 TI - The pharmacist's role in risk management. AB - The role of risk management is vitally important in the hospital. As institutions grow and the field of health care advances into the future, the number of patient associated risks will continue to multiply. In response, the Joint Commission has changed its policies to reflect the importance of patient outcomes. This new Joint Commission focus, coupled with the increasing number of patient risks, will create the need for health care professionals to recognize their role in risk management. In anticipation of the future, pharmacy has been guiding itself toward that role for some time. With a large portion of the profession participating in activities such as DUE and QA programs, pharmacists can be a useful resource to the risk manager. Participation in retrospective analysis such as ADRs and peer review committees also aids the pharmacy profession in establishing guidelines that will decrease future patient risks. Future trends in drug development will increase the pharmacist's role in drug selection, in an effort to ensure both safety and cost containment. The profession's continuing development and implementation of practice standards will ensure that pharmacy remains dedicated to improving patient outcomes and decreasing patient risks. In addition, by learning to use the risk manager as both a source of information and a partner in identifying pharmacy-related areas of risk, the pharmacy profession will be able to continue its pursuit of improved quality of patient care. PMID- 10118920 TI - Data systems on a shoestring: cost-effective solutions for risk management software. PMID- 10118921 TI - Retinopathy of prematurity: current risk management issues. PMID- 10118922 TI - Medicare program; recognition of the Community Health Accreditation Program standards for home care organizations--HCFA. Final notice. AB - This final notice recognizes accreditation by the Community Health Accreditation Program (CHAP), a subsidiary of the National League for Nursing (NLN), for home health agencies (HHAs) that wish to participate in the Medicare Program. As a result of this recognition, HHAs accredited by CHAP are deemed to meet the Medicare conditions of participation for HHAs to the extent described in this notice. This final notice sets forth certain specific requirements with which CHAP must comply to maintain Medicare recognition of its HHA accreditation program. PMID- 10118923 TI - Federal employees health benefits program: miscellaneous changes--Office of Personnel Management. Final rulemaking. AB - The Office of Personnel Management (OPM) is issuing final regulations which implement a number of miscellaneous changes to the Federal Employees Health Benefits (FEHB) Program regulations. The regulations will improve the administration of the FEHB Program and result in better service to enrollees. PMID- 10118924 TI - Managing Medicaid. AB - State medicaid officials are eager to take advantage of cost control techniques offered by managed care health plans. But advocates for medicaid patients oppose the easing of safeguards against possible abuses. PMID- 10118925 TI - Image digitizing in conventional radiology. AB - Since early 1991 a new procedure has been tested at the Hopital du St-Sacrement that uses a phosphorous plate instead of a standard x-ray cassette. The phosphorous plate is exposed to x-rays using standard equipment and is then read by a computer that transfers the resulting image onto either a plate or a cathode screen. This new technology lends importance to the radiology technician's role in image manipulation and determination of the ideal sensitometric curve for each x-ray examination. The technician can generate an image with adjustments in latitude and contrast, depending on the radiologist's needs and notwithstanding the technical parameter settings used during the x-rays. PMID- 10118926 TI - What is teamwork? AB - This article is a summary of a presentation given by Herbert Dixon at the Northwest Conference of Radiologic Technologists held in Edmonton in September 1991. The author discusses interdependent relationships in the workplace and how such relationships can help find solutions to problems and encourage a co operative atmosphere. PMID- 10118927 TI - The future of the health professions. PMID- 10118928 TI - Balancing the budget in the specialty group practice clinical laboratory. AB - A four-physician group had developed a very successful practice model, but cost accounting was not well-developed as general ledger and accounts payable activities were performed using manual methods and financial statements were prepared on a spreadsheet program. The purpose of this case study is to describe the steps taken to develop a cost management system for the laboratory and the corrective action taken to reduce a loss from operations. PMID- 10118929 TI - Antitrust issues for medical groups. AB - Many medical groups may not regularly seek legal advice in regard to all the various business transactions in which they participate. Unlike hospitals, medical groups do not usually retain specialized health care law firms. As this professional paper illustrates, it is important for medical group administrators to have some familiarity with antitrust issues. This knowledge is important for administrators in two contexts: First, to keep their own groups from having antitrust problems; and second, to keep a watch on their competitors to be sure that the group's position is not compromised by any illegal activities engaged in by these entities. PMID- 10118930 TI - Criteria for determining medical practice management skills requirements: a case study. AB - Faced with the responsibility of filling a management void, the group could not reach a consensus as to what level of manager to recruit. While some physicians felt that the vacancy should be filled with an office manager-type individual (possibly promoting from within), others felt that the scope of lay management should be expanded. PMID- 10118931 TI - The job outlook in brief 1990-2005. AB - Every 2 years, the Bureau of Labor Statistics publishes a summary of the expected change in employment for about 250 occupations. Here are the most recent projections, along with the available information on the expected competition for jobs. PMID- 10118932 TI - The 7 C's of successful fund raising. PMID- 10118933 TI - On FDA's front lines. Investigators protect public. PMID- 10118934 TI - Critical thinking in health care supervision. AB - Henry Ford is reputed to have said that thinking is the hardest work there is, which is probably why so few people engage in it. Perhaps many people have felt this way sometimes, especially when they viewed the foibles of the human race displayed prominently on the evening television news. Some people do stupid things; some people seem to be mindless in what they do. This applies also to some in managerial and supervisory positions in health care organizations. The percentage of these thoughtless managers and supervisors is probably comparable to the percentage of the thoughtless people in the general population. Fortunately every normal functioning human being is capable of becoming a more critical thinker. Of course, no amount of effort is adequate to the development of critical thinking when a person lacks fundamental good sense. On the other hand, no amount of genius suffices when someone does not put forth adequate effort to become a more critical thinker. PMID- 10118935 TI - The role of the assessment nurse: one hospital's vision for meeting Joint Commission standards. AB - In evaluating the progress made during one year, it is clear that the position of assessment nurse has been an extremely valuable, effective role. The staff nurses' perception is that they not only understand the importance of the nursing process more thoroughly, but they also view the role of nursing administration as that of trying to help the registered professional nurse at the bedside. It is key in today's health care climate that the nursing administrator be visible. One method to assure visibility is for staff to actually see a role model serving as an extension of the nurse administrator. If nurse administrators truly value the importance of the nursing process, then they need to ensure that this message is being communicated throughout the entire nursing service organization. Such an innovative position can function as a liaison between nursing management and the staff. There is no better method of communicating this than having someone who visibly echoes the values of the nurse administrator. It also should be noted here that Shore Memorial Hospital's Nursing Division received a perfect Joint Commission survey evaluation in April 1990. The Nursing Division attributes this to the efforts made regarding implementation of the nursing process, and the forward thinking of a systems change with implementation of a computerized nursing information system that incorporates the nursing process with everyday documentation. Nurse administrators must effect change and demonstrate leadership within their respective organizations. Organizational change can be slow and difficult at times; however, the end result is worth the effort. It is important that the values of the nurse administrator be disseminated throughout the organization.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10118936 TI - The hospital manager as enthusiast. AB - The "race" in hospital operations is increasingly going not to the swift but to those who finish. In this environment, leadership may soon outpace management as the vehicle that inspires slower hospitals over the finish line. The manager as enthusiast is becoming a necessity rather than an option as regards survival of the hospital. Fortunately, hospital managers need only look--really look--inside themselves and their institutions to find the requisite energy for this transformation. PMID- 10118937 TI - The education of health care professionals in the year 2000 and beyond: Part 2: The curriculum solution. AB - The education of the health care professional is of interest and concern to the health care professional, but most significantly, that of the health care consumer. Nurse educators have been immersed in curriculum development for the present and the future and have found that a theory-driven, process-oriented curriculum has the best chance of preparing graduates who are consumer oriented. This model was explicated for the education of all health care professionals. Readers who have a son or daughter finishing the second grade in school have within their households a member of the graduating class of 2000. How close to reality and to the wants and needs of the consumers will be the stated behavioral expectations for health care professionals in the few years remaining in the 20th century? Will the graduates of the Class of 2000 who will pursue academic experiences to realize the behavioral expectations satisfy the consumers of health care? The consumers will let us know. PMID- 10118938 TI - The use of epidemiology in decision making by hospital executives. AB - The study has shown that epidemiological data are not used as often as they should be. The results suggest that education level has an impact on the use of epidemiology in long-term and short-term decision making. The higher the education level, the more use of epidemiology is suggested. Individuals with an MPH (Master's of Public Health) degree used epidemiological data on a higher frequency than did their peers. A possible suggestion as to why this occurs is that those individuals who had an MPH more than likely have had a course in epidemiology and understand how to utilize it. Of the individuals who did not use epidemiology, 98.7 percent attributed that to either cost or language that was unfamiliar to them. Of these individuals, 65.8 percent said they would be interested in learning more about epidemiology, and 64.5 percent said they would use it if they were more familiar. A need for instruction in epidemiology was revealed by this survey. Epidemiology should be used to perform studies on the regional population to identify the needs of the hospital's consumers. Without the knowledge base, this is not being done; possible continuing education for administrators covering the uses of epidemiology could work toward correcting the problem. PMID- 10118939 TI - Boundary fighting: territorial conflicts in health organizations. AB - If health institutions are to be healthy places to work and study, managers in these institutions will have to take the lead to revamp old tradition-based boundaries. Health problems now rarely require the exclusive care of one specialist. Health care and rehabilitation require that many health care specialists work together. And, prevention crosses all disciplinary boundaries. Similarly, our changing society requires a more flexible workplace with job sharing, teaming, multicompetent personnel, and an environment that is dedicated more to meeting the needs of consumers than those of health professionals. Boundaries in health institutions must change if these institutions are to meet the needs of a changing society and attract and retain health care professionals who want to experience the opportunities of new, more permeable boundaries without the ordeal of warfare. PMID- 10118940 TI - Teaching tools for the Marker Model for standards development and the Umbrella Model for quality assurance. AB - The learning process benefits adults more when the material is presented in the presence of "positive conditions." Teaching standards developed and QA provides ample opportunity to provide positive conditions. The Marker Model is easily adapted to all practice settings and can often be taught by using unit-specific or patient population-specific examples; however, developing these specific examples can be time-consuming. Instruction is often given to groups of nurses from different clinical areas, so unit- or patient population-specific examples are therefore inappropriate. Development of the "universal" example has also provided humor for the presentation. The Head of Household Standards model and the Quality Assurance Plan for Head of Household are applicable to almost all adults and are easily understood (see boxes). They supply further humor in their "audit" formats (Figures 3 and 4). PMID- 10118941 TI - Quality: a watchword for the 1990s or the same old song? AB - For reasons suggested throughout these pages some attempts to implement TQM will fail and, for some people, quality will gather dust in the old-management approach graveyard along with all the other techniques that were tried, half heartedly applied, and discarded. Some attempts, however, will succeed. And those organizations that are successful in implementing TQM will find themselves among the stronger, more adaptable institutions in the health field for years to come. PMID- 10118942 TI - A supervisor asks: "Employee communication and interaction.". PMID- 10118943 TI - Bibliography on AIDS-related bereavement and grief. AB - This annotated bibliography on AIDS-related bereavement and grief was compiled to address a steadily increasing population: survivors of persons who have died of AIDS. Bibliographical entries were located by searching printed indexes, including Cumulative Index to Nursing and Allied Health Literature, Hospital Literature Index, Index Medicus, International Nursing Index, Psychological Abstracts, Social Science Index, Social Work Abstracts, and Sociological Abstracts. Databases searched included ERIC (Department of Education), Med-Line (National Library of Medicine), and Psych-Lit (American Psychological Association). References cited at the end of each work were also checked. This bibliography includes publications of studies using the survey method of social research and the case-study approach. It also includes experiences of professionals personally affected by the loss of someone to AIDS, and informational articles and chapters. To be included in this bibliography the work must have dealt exclusively or largely with the topic of AIDS-related bereavement and grief, or it must have addressed some aspect of it not previously covered anywhere in the literature. The topic of AIDS-related bereavement and grief refers to the loss of someone to (or with, as is the case with suicide) Acquired Immune Deficiency Syndrome, and its psychological, emotional, physical, and social effects on the survivor(s). This bibliography does not include publications that deal with related topics such as thanatology, anticipatory grief and mourning, and mortality rates and trends. This work is meant to serve as a resource for professionals in a variety of fields (e.g., nursing, pastoral care, mental health, and social work) involved in social research, bereavement counseling, ministry, and group intervention. It can be useful as a literature search for students in a variety of disciplines and for the AIDS-bereaved themselves. The bibliography is accompanied by an overview of the current state of the literature and a summary of the areas still in need of research and publication. PMID- 10118944 TI - Death education in selected health professions. AB - Health professionals have a high probability of working with populations experiencing death and other types of loss. Surveys of medical, nursing, pharmacy, dental, and social work schools in the United States to determine their offerings in thanatology revealed that the majority (with the exception of dentistry) offer some education on death and dying. Because most of the offerings are limited to one or two lectures, a high percentage of students are graduating with limited formal exposure in this area. However, offerings have come a long way since the early 1970s. PMID- 10118945 TI - Strategic marketing for charitable organizations. AB - A new marketing strategy unites major for-profit corporations with charitable organizations in such a way that both benefit. Most major charitable organizations are finding cause related marketing a new strategy for fund raising. The largest charities in the country including the Red Cross, Special Olympics and the American Heart Association have all become involved with cause related marketing and have all realized its benefits. With these benefits come some risks. The decade of the 1990s should include increased awareness and participation among charitable organizations regarding cause related marketing. PMID- 10118946 TI - History and process of the Medicare reimbursement programs. PMID- 10118947 TI - A perspective for understanding moral commitment: the physicians' case. AB - For an exchange to occur in a commercial setting between a salesperson and a customer is one thing; for an exchange to occur in a health care setting between a physician and a patient is another matter. Traditional marketing exchange literature is mostly concerned about discrete relationships in commercial settings. Such concern has encouraged a narrow view of loyalty toward the customer. This paper borrows ideas from marketing and other related sources, and examines the physician's commitment to the patient, stressing in the process the importance of moral commitment. PMID- 10118948 TI - Benefit segmentation of the fitness market. AB - While considerate attention is being paid to the fitness and wellness needs of people by healthcare and related marketing organizations, little research attention has been directed to identifying the market segments for fitness based upon consumers' perceived benefits of fitness. This article describes three distinct segments of fitness consumers comprising an estimated 50 percent of households. Implications for marketing strategies are also presented. PMID- 10118949 TI - Maximizing satisfaction and managing dissatisfaction in mental health and human services: a model for administrative practice. AB - The production satisfaction is central to the delivery of mental health and human service. The most critical factor in service delivery is providing quality care. However, the ways in which services are delivered impacts the perception of quality. This paper provides a model for maximizing satisfaction among client and other important public of mental health and human service organizations. PMID- 10118950 TI - Perceptions of the community on the pricing of community mental health services. AB - In the past few years there has been a decrease in governmental support of Community Mental Health centers. Because of this, there has been some concern, on the part of Community Mental Health professionals, as to the overall impact of this decreased governmental support. Research has been conducted that speculates on how best to handle this mini-crisis. One article suggests moving to an overall marketing approach to help combat this dollar support decline (Day and Ford 1988). Others provide methods for surveying Community Mental Health users (Ludke, Curry & Saywell 1983). William Winston (1988) suggests an overall psychographic segmentation approach to developing market targets. There has also been research detailing promotional methods for expanded marketing coverage (Moldenhauer 1988), however little has been written defining the pricing impact on Community Mental Health services. This study addresses the perceptions of Community Mental Health Center users toward the price variable of the marketing mix. PMID- 10118951 TI - Marketing mental health: a case study of the INTERACT mental health newsletter. PMID- 10118952 TI - Employee wellness program marketing: an organizational theory perspective. AB - An employee wellness program (EWP) marketing system can be analyzed as an adhocracy, an organizational form proposed by Mintzberg and is characterized by sharing of power, mutual adjustment among its members, and ability to innovate. The design parameters of informal behavior, planning and control, liaison, and decentralization appear to be particularly important to the success of EWPs. PMID- 10118953 TI - HMO versus private care medical systems: a study to determine the aging consumers' satisfaction with medical care under these two systems. AB - In one community, 175 aging persons (44 HMO and 132 private medical care patients) completed a 20-item scale that measured satisfaction with medical care. Data on demographics, health care utilization, and self-assessed health status were collected to determine whether these variables would relate to HMO membership. Satisfaction scores were compared between HMO and private care medical groups by multivariate analysis of variance. Satisfaction with the doctor patient relationship and convenience of care was higher in the private medical care group, whereas satisfaction with cost was higher in the HMO group. Furthermore, the HMO group evaluated private medical care and HMO care similarly. The private medical care group rated HMO care less favorably. Additional comments reveal specific areas of satisfaction/dissatisfaction. PMID- 10118954 TI - The influence of older consumers' information search activities on their use of health care innovations. AB - Research has yet to consider the relationship between the older consumers' information search and their use of health care innovations, despite suggestions that such a characterization may prove useful to marketing practitioners. In this investigation of a national sample of autonomous elderly consumers, distinct patterns of information search behavior are observed which distinguish adopters from nonusers of a pair of health care innovations. Implications for marketing health care innovations are discussed. PMID- 10118955 TI - A multivariate analysis of long-term care nursing services. AB - Marketing, as a useful conceptual framework, has been extended to a variety of nonprofit sectors including the health care industry. Despite ever growing literature devoted to general health care marketing, there appears to be a death of specific application-oriented studies. This paper illustrates the development and application of a multiple discriminant analysis model in the context of long term care (LTC) facilities. Empirical findings are presented and factors affecting the occupancy rates are discussed with implications for marketers, managers and administrators of skilled LTC nursing homes. PMID- 10118956 TI - Money matters. PMID- 10118957 TI - Hospitals are often unaware of legal rights in insurance recovery. PMID- 10118958 TI - Evaluation of an antibiotic restriction policy using a special drug request form. AB - At a university teaching hospital, a study was undertaken to assess the frequency and appropriateness of restricted antibiotic use using a special drug request (SDR) form to collect the data. The usefulness of the SDR form itself was also assessed for its ability to provide valuable information about patient care and cost effectiveness. The results of this study are presented below. PMID- 10118959 TI - Reporting elder abuse: should it be mandatory or voluntary? PMID- 10118960 TI - Medical waste regulatory enforcement: hospitals must remain vigilant. Jersey City Medical Center. PMID- 10118961 TI - Multiple employer welfare arrangements: health insurance black holes. PMID- 10118962 TI - Health insurance company administrative expenses: what do they pay for? PMID- 10118963 TI - As they see it. Experts forecast trends and challenges. PMID- 10118964 TI - Outlook bright for provider-owned systems. PMID- 10118965 TI - Changing the structure of daily operations: the work-flow model of the future. PMID- 10118966 TI - Affiliates help guide public policy agenda. PMID- 10118967 TI - Increased protection of patient rights. PMID- 10118968 TI - Initiatives to facilitate hospital cooperation. PMID- 10118970 TI - Management's commitment to workplace safety. PMID- 10118969 TI - The organized healthcare system. PMID- 10118971 TI - 1992 management consultants directory. PMID- 10118972 TI - Evaluation of ACHE (American College of Healthcare Executives) completed. PMID- 10118973 TI - Cafeteria 'expands' its services, seating using same amount of space. PMID- 10118974 TI - New fire-safety rules fuel furniture debate: are they worth the cost? PMID- 10118975 TI - Building automation: how to select the right system. PMID- 10118976 TI - Complying with OSHA's new pathogens standard. PMID- 10118977 TI - How to conduct mock accreditation surveys. PMID- 10118978 TI - Study: nearly 66% of facilities contract for 'hotel' services. PMID- 10118979 TI - Worksheet reveals refrigerant-recovery savings. PMID- 10118980 TI - Housekeeping time standards justify staff levels. PMID- 10118981 TI - Housekeeping chiefs dictate laundry-supply buys. PMID- 10118982 TI - What is a reasonable demand on health care resources? Designing a basic package of benefits. PMID- 10118983 TI - Prospective autonomy: on the limits of shaping one's postcompetence medical fate. PMID- 10118984 TI - Informed consent and risk management in dermatology: to what extent do dermatologists disclose alternate diagnostic and treatment options to their patients? PMID- 10118985 TI - No fault compensation for medical injuries. PMID- 10118986 TI - Criminalizing HIV transmission: lessons from history and a model for the future. PMID- 10118987 TI - The emerging effects of the Drug Price Competition and Patent Term Restoration Act of 1984. PMID- 10118988 TI - Liability implications of utilization review as a cost containment mechanism. PMID- 10118989 TI - The Patient Self-Determination Act of 1990: health care's own Miranda. PMID- 10118990 TI - Murder, she wrote or was it merely selective nontreatment? PMID- 10118991 TI - Strategic control: a problem looking for a solution. AB - There are a number of complex issues surrounding strategic control and this article attempts to address some of the key aspects. Control as a generic concept and process is considered first. The main control elements of measurement, evaluation and feedback are equally relevant to both the short and the long term. Nevertheless specific questions or issues can vary for strategic and operational controls, and issues of particular relevance to strategic control are identified. Different types of strategic control are explored in a discussion of 'strategic momentum control' and 'strategic leap control'. The findings of some empirical research are discussed and barriers to strategic control identified. The article concludes by briefly looking at the problems associated with the use of financial measures for strategic control. PMID- 10118992 TI - Riding the whirlwind: managing turbulence. Interview by Bruce Lloyd. PMID- 10118993 TI - Meeting the challenges of information systems planning. AB - Strategic information systems planning (SISP) is the process of deciding the objectives of computing for an organization and then identifying the applications that the organization should computerize. SISP has become increasingly important as information systems have begun to play a more critical role in implementing business strategies. However, SISP is beset with problems that hinder organizations from determining their computing objectives and applications. This article identifies the impediments to SISP and offers some constructive actions for business planners to take to increase their chances of success. It also suggests that planners may face greater difficulties implementing their information systems plans than in initially creating them. PMID- 10118994 TI - Strategic planning--the role of the chief executive. AB - Failure to see strategic planning as a process and ineffective CEO involvement are two reasons for failures in strategic planning. This article outlines the stages in an effective strategic planning process, discusses the appropriate role or roles for the CEO or leader in each stage, and defines the expected results from effective strategic planning. PMID- 10118995 TI - Inflation hits British private medicine. PMID- 10118996 TI - Utilization review's effectiveness from a physician standpoint. PMID- 10118997 TI - Medical marketing: yesterday, today, tomorrow. AB - Of all the tools available to practice leaders, marketing programs make the biggest, most direct and longest lasting contributions to profits, writes Meryl Luallin as she looks at marketing's history, present and future. In addition, Kevin Sullivan describes how to sell a marketing plan to physicians. PMID- 10118998 TI - Value marketing in your group practice. AB - The negative association with marketing in group practice is generally unavoidable writes Eileen Chiama, M.S., and dates back to the turn of the century. Medical groups are now, however, starting to effectively use marketing, especially as a means of adding value to their product. PMID- 10118999 TI - Using specialty advertising in a niche marketing plan. AB - While niche marketing is not a new strategy, an increasing number of competitors are pursuing the same niches, resulting in stiff competition within the health care industry, writes C. Ronald Schwisow. This means marketers need to be resourceful to maximize their communications efforts. One such approach is specialty advertising. PMID- 10119000 TI - Marketing your practice through community involvement. AB - How do you get beyond "Marketing 101" to make an impression that will distinguish your practice from all others? Author Andrea Eliscu believes that it is time for group practices to move beyond marketing basics and expand the definition to include community integration. PMID- 10119001 TI - Marketing the academic medical center group practice. AB - From a marketing perspective, there are many differences between private and academic medical center (AMC) group practices. Given the growing competition between the two, write John Eudes and Kathy Divis, it is important for the AMC group practice to understand and use these differences to develop a competitive market advantage. PMID- 10119002 TI - A marketing approach to physician recruitment. AB - Physician recruiting can be a time-consuming and frustrating task, writes Stephen Wilhide, M.S.W., M.P.H., and thus it requires careful planning. A marketing approach to recruiting is one way to assure that all the necessary steps are taken for a successful conclusion to the process. PMID- 10119003 TI - Managing prescription drug costs in medical groups. PMID- 10119004 TI - The art of the merger. AB - In part one of a two-part series, Keith Korenchuk, J.D., M.P.H., looks specifically at the conceptual basis and pertinent issues involved once a decision has been made to consider a merger. Part two, appearing next issue, will then look at the implementation process and players involved in a merger. PMID- 10119005 TI - Avoiding potential pitfalls in mergers and acquisitions. AB - The single most important factor in determining the success of mergers and acquisitions, write Joy Glanstein, Ph.D., and Mary Sallis, is the human equation and in particular benefit plans--the focus of this article. PMID- 10119006 TI - Motivating medical employees toward high quality work. AB - In her continuing series on human relation, Joan Wagner Zinober, Ph.D., M.B.A., discusses the intricacies of motivating medical staff. This article looks at the principles of motivation and provides ideas for improving the quality and quantity of employee work. PMID- 10119007 TI - Health Index Plus: a CD-ROM product for consumer health information. AB - Health Index Plus, a consumer health information CD-ROM database, was field tested by staff and patrons at a public library in Harrisburg, Pennsylvania. Ease of-use, database content and quality, and appropriateness for audience were evaluated. Overall, patrons found the database simple to use. The contents focus on topics of popular interest and provide access to scientific material that is normally not available or comprehended by many public library users. Although some indexing problems and other shortcomings were noted, the database is recommended for public and other libraries providing consumer health information. PMID- 10119008 TI - Hospital and corporate information services: introducing a new column. AB - Successful hospital and corporate libraries offer customized resources and services to meet the needs of their dynamic organizations. Concepts such as customer-driven, service-oriented and value-added are central to these libraries. Serving decision makers and integrating the library into the decision-making process of the organization is critical. Future articles in this new column will further explore the underlying philosophies and the specialized resources and services that characterize these libraries. PMID- 10119009 TI - ORs prepare to meet OSHA's bloodborne pathogen standard. PMID- 10119010 TI - OR managers, staffs handle injuries from Los Angeles riots. PMID- 10119011 TI - President honors surgical tech program. PMID- 10119012 TI - Floor plans establish traffic patterns for people and supplies. PMID- 10119013 TI - Materials handling systems. PMID- 10119014 TI - What makes a case cart system work? PMID- 10119015 TI - Managing the balance between technical and human excellence. PMID- 10119016 TI - Coaching and counseling employees. PMID- 10119017 TI - Measuring physician satisfaction with radiology services. AB - During 1991 the AHRA Statistical Resource Committee received requests from association members for guidance on aspects of radiology service delivery that risk losing business. With the assistance of interested members, the Committee developed a process for addressing this issue. This article discusses the rationale for surveying referring physicians and presents the results of a pilot physician satisfaction survey. Through review of the results of the pilot survey, the Committee believes that we can assist radiologists and radiology administrators in developing methods to improve total quality. PMID- 10119018 TI - Graduate technologists and customer service: a 1991 survey. PMID- 10119019 TI - Equipment evaluation for ultrasound. PMID- 10119020 TI - A '90s kind of leader. PMID- 10119021 TI - Recovering from disaster: an ounce of prevention takes a ton of planning. AB - This article, reprinted from Connect: Journal of Departmental Computing at the University of Cincinnati, addresses the issue of computer failures and preventing or minimizing the effect of such disasters. Since so many radiology departments use radiology information systems and so many managers depend on the information stored in their personal computers, this valuable advice may enable you to take steps to prevent a "crisis" in your organization. PMID- 10119022 TI - On excluding the AIDS crisis. AB - Many insurers are imposing restrictions on AIDS coverage during policy renewal in the form of outright exclusions or as caps on benefits levels. PMID- 10119023 TI - The NLRB's proposed rule for the determination of health care bargaining units: is the AHA barking up the wrong tree? PMID- 10119024 TI - Clinical database: an interim step to the computer-based patient record. PMID- 10119025 TI - Establishing statewide and communitywide health information systems. PMID- 10119026 TI - Translating data into information: a primer of preparatory concepts and skills. AB - Consider data as content, as the parts required for building "something." But data alone are not the something. Data are a part, not the whole. Consider information as context. It is akin to having the something. But information is dependent on data for building the something, the whole. Thus, translating data into information requires being aware of and respecting the content and context relationship and dependency of data and information. Finally, translating data into information requires an understanding of people and how people communicate. Data and information are effective means for people to express, exchange, and communicate ideas. When data and resulting information communicate to and inspire people, ideas originate. Thus, data and information are essential for communication to occur and function as the origin of ideas of the future. PMID- 10119027 TI - The role of E-codes in injury prevention. PMID- 10119028 TI - Health information management using optical storage technology: case studies. AB - All the health care facilities examined in the case studies addressed several important organizational issues before and during the installation of their systems. All the facilities examined employee commitment. The prudent managers considered how easily their employees adapt to changes in their jobs and work environment. They considered how enthusiastic cooperation can be fostered in the creation of a liberated and reengineered office. This was determined not only by each individual's reaction to change, but also by the health care facility's track record with other system installations. For example, document image, diagnostic image, and coded data processing systems allow the integration of divergent health care information systems within complex institutions. Unfortunately, many institutions are currently struggling with how to create an information management architecture that will integrate their mature systems, such as their patient care and financial systems. Information managers must realize that if optical storage technology-based systems are used in a strategic and planned fashion, these systems can act as focal points for systems integration, not as promises to further confuse the issue. Another issue that needed attention in all the examples was the work environment. The managers considered how the work environment was going to affect the ability to integrate optical image and data systems into the institution. For example, many of these medical centers have created alliances with clinics, HMOs, and large corporate users of medical services. This created a demand for all or part of the health information outside the confines of the original institution. Since the work environment is composed of a handful of factors such as merged medical services, as many work environment factors as possible were addressed before application of the optical storage technology solution in the institutions. And finally, the third critical issue was the organization of work. "Organizations that understand their business processes are having no trouble whatsoever justifying the cost of optical storage-based information management systems," said Thornton May, director of imaging research at Nolan Norton Institute. "It is only confusing to organizations that do not have a feel for what is happening in the flow of work in the company. If an organization has on-line performance measurements with regard to time, cost, quality, error rates, and customer service, the move to optical image and data management technology is a no-brainer."(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 10119029 TI - Voice-activated reporting systems: an innovative technology. PMID- 10119030 TI - Research review: differentiation of roles and functions of medical record practitioners. AB - The purpose of this study was to determine whether the actual and appropriate roles and functions of medical record practitioners varied by credential, current position, years of medical record experience, and size of facility. The actual role describes what practitioners are currently doing in the workplace; the appropriate role describes what practitioners believe they should be doing in the workplace. For both the actual and appropriate roles, current position was the most discriminating variable, and credential was the least discriminating variable. Lack of discrimination is most likely due to the similarity in the professional components of medical record administration and medical record technician educational programs. PMID- 10119031 TI - Techniques for dataset design: a utilization management system model. AB - Designing a clinical information system offers a sense of accomplishment similar to that of a dramatic performance. The development of the data dictionary and proposed system description requires the same attention to detail as stage directions in a script. The people involved in daily system operation are of key importance in developing a clear understanding of how things actually happen in the information flow and decision process. Once the business rules are defined and edits and conditions are developed to ensure data integrity, it is time to step back and let the performance begin. The real power of the user-designed system, like that of a performance before a live audience, comes with the ability to query the data for answers to issues and problems decision makers did not face at the time of the initial system design. PMID- 10119032 TI - Legal review: the medical records implications of state and federal anti-dumping provisions. AB - Federal and state enforcement agencies have increased their scrutiny of hospitals to make certain they are complying with anti-dumping law. Medical record practitioners can assist their institutions by providing policies that require appropriate documentation of compliance. Given the potential sanctions imposed by anti-dumping laws, these policies should be reviewed carefully by hospital administrative, medical, and legal personnel. PMID- 10119033 TI - Developing a human resource plan. PMID- 10119034 TI - Who's knocking at the door? The IRS issues new audit guidelines. AB - The IRS is arming its agents with a detailed blueprint for exemption audits and has announced that it is stepping up the number of examinations it will undertake. A spokesman for the IRS recently announced that the service is not actively seeking to revoke exemptions. However, this statement offers only partial comfort. Merely increasing audit activity and the depth of the examinations will mean more time and expense for hospital administrators regardless of the outcome. The moral of this story is clear: Things will get tougher when the IRS auditor knocks on your door, and the likelihood of that knock has increased. As I stated in my previous Trustee article (see Health Law, p.10, January issue), hospital trustees and administrators need to get their houses in order. Your hospital should be imposing these audit guidelines on itself before an IRS examining agent does it for you. My earlier article sets forth specific suggestions in this regard. Recent developments--including the new IRS guidelines--only emphasize the importance of preparing for the IRS. PMID- 10119035 TI - Contingencies go up under new JCAHO standards. PMID- 10119036 TI - Capital spending takes a back seat in health reform debate. PMID- 10119037 TI - CEO sabbatical: prescription for a healthier organization. PMID- 10119038 TI - What the board should expect from its CEO--Part two. PMID- 10119039 TI - Hospitals and community benefit: examples from the field. PMID- 10119040 TI - States take charge of health reform. PMID- 10119041 TI - CEO pay-for-performance in the era of public scrutiny. PMID- 10119042 TI - National Ambulatory Medical Care Survey: 1990 summary. PMID- 10119043 TI - Work program of the National Centre for Health Program Evaluation. PMID- 10119044 TI - The value of health care: what can we learn from Oregon? AB - The scarcity of health care resources leads to rationing amongst potential users by one means or another. When the market is rejected, rationing should be conducted on the basis of systematic and informed priority setting. It has been widely suggested that these priorities should be based on health benefits measured by quality adjusted life years (QALYs) and recently the US State of Oregon has attempted to use QALYs for setting priorities on a large scale. Values not normally associated with QALY analysis were also incorporated in the process. Their unique experience is of interest in Australia, as no attempt has been made here to prioritize medical interventions on the scale that was undertaken in Oregon. PMID- 10119045 TI - Are any numbers better than no numbers? The sorry state of willingness-to-pay and some major methodological shortcomings. AB - Willingness-to-pay (WTP) is grounded in welfare economics and is used to measure benefits in public decision-making. However, obtained values vary widely, differences between WTP and its obverse, willingness-to-accept, are very large, studies to validate the techniques are almost non-existent and methodologies to elicit values are underdeveloped. Major problems with WTP are discussed with emphasis on cognitive aspects of eliciting preferences and values. It is concluded that until its validity has been established, WTP must be rejected as a measure of economic value. PMID- 10119046 TI - Cost utility analysis: 'new directions' in setting health care priorities. AB - It is an inescapable fact of any health care system that consumers are not the agents who decide between technical alternatives. Consequently, the agents making choices need an acceptable framework for measuring and comparing costs and benefits of competing programs. Cost Utility Analysis (CUA) is proposed as the appropriate framework for health care decision making. It combines the significant aspects of health (quality and quantity of life) that are gained from an intervention. At present, there is no other methodology which does this in a way that permits decisions to be based on consumer preference. PMID- 10119047 TI - Health-related quality of life measures need content validity. AB - Health-related Quality of Life measures are being increasingly considered as tools to aid decisions of health resource allocation, given their potential to comprehensively assess the impact of a given illness or health intervention on the individual. The development of suitable measures requires an understanding of the way external and psychological variables interact to determine subjective well-being and necessitates careful determination of those variables most important to the patient. PMID- 10119048 TI - Assessing the quality of residential care for the aged. AB - The standard of quality of care in Australian nursing homes is assessed by standards monitoring teams who use their expert judgement and a set of guidelines based on seven objectives and thirty-one standards. In this article, the possibility of supplementing the teams' expert judgement with information gained from standardised questionnaires is explored. Following a review of environment focussed and resident-focussed instruments, an overview of the scales is provided and the idea of using standardised questionnaires in the standards monitoring process is discussed in terms of possible future developments. PMID- 10119049 TI - A prospective cost-effectiveness study of alternative work-up strategies in colorectal cancer screening. AB - Population screening for colorectal cancer has not yet been introduced in Australia, although there is considerable pressure to do so. A significant cost in these programs is the follow-up or confirmatory diagnostic testing for individuals who screened positive and there are many suggested or available strategies with widely differing costs and outcomes. This study is a prospective analysis of diagnostic work-up strategies and two dominant protocols are identified among the twenty-two candidates. The study also discusses extensions to the analysis. PMID- 10119050 TI - Increasing women's participation in Pap smear screening in Australia--how can we tell if the national policy is effective? AB - A national policy on the prevention of cervical cancer was launched in 1991. The success of the policy should be judged in terms of the extent that appropriate screening of the 'at risk' population is achieved by the screening program and the degree of reduction of differential screening rates between population groups. The relative cost-effectiveness of the various recruitment strategies chosen to meet the policy's objectives should also be evaluated. A necessary prerequisite for evaluation of the policy is the availability of data about the population screened. PMID- 10119051 TI - Promoting health and evaluating change. AB - Health promotion is a term that includes a range of approaches aimed at maintaining and promoting the population's health. In its broadest sense health promotion includes: health protection legislation and enforcement; healthy public policy; mass media communications; community development in health; health education; and preventive health services. The use of these approaches has been associated with improved health in Australia, but evaluating the effectiveness of health promotion is not easy. Multi-faceted approaches are most effective, but are difficult to evaluate using experimental or quasi-experimental designs. In addition, health promotion has yet to meet the challenge of measuring progress towards improving health and well-being, as distinct from reductions in disease and in behavioural risk factors for disease. This paper discusses health promotion, its strategies and impacts, and some issues involved in its evaluation. PMID- 10119052 TI - Incentive payments to nursing homes based on quality-of-care outcomes. AB - The federal Omnibus Budget Reconciliation Act of 1987 specifies that a state may establish a program to reward--through public recognition, incentive payments, or both--nursing facilities that provide the highest quality care to residents entitled to Medicaid. As state policymakers, providers, and advocates consider development of systems for rewarding quality in nursing homes, including incentive payments based on resident outcomes, theoretical and practical dilemmas must be addressed. The article examines the impetus for combining incentives with outcome measures and the conceptual dilemmas that outcome-based payments pose. Issues basic to successful implementation of incentive payments to nursing homes based on quality of care outcomes are also delineated. PMID- 10119053 TI - Effects of exposure to aggressive behavior on job satisfaction of health care staff. AB - This study examined the effects of exposure to the aggressive and disruptive behavior of institutionalized elderly patients on health care staff's job satisfaction. Aggressive behavior was defined as physical, verbal, or general disruptive behavior. Health care staff from a geriatric long-term care hospital were interviewed about their exposure to these types of aggressive behavior and the effect of this exposure on job satisfaction. Job satisfaction was significantly correlated with overall exposure to aggressive behavior. Although physical aggression was reported more frequently, exposure to verbal aggression correlated higher with job satisfaction. Exposure to aggressive behavior was the best predictor of job satisfaction, followed by level of education. These findings indicate that job satisfaction is negatively affected by exposure to aggressive behavior but positively affected by educational level. The role of educational programs in moderating the impact of exposure to aggressive behavior on job satisfaction is discussed. PMID- 10119055 TI - Creating designs that heal. PMID- 10119054 TI - The impact of companion animals in later life and considerations for practice. AB - Interaction with companion animals, or pets, is increasingly recognized as a contributor to well-being in later life. This article focuses on the actual impact of animal companionship on older adults' (institutionalized and community dwelling) physical, social, and psychological health. Considerations for practice are discussed, with particular emphasis on professionals' recognizing the effect of multiple life-course factors that may moderate the therapeutic value of companion animals. Such factors include older persons' health, financial status, housing situation, and current and previous attitudes and attachments to pets. PMID- 10119056 TI - Planetree patients come first in health care design. PMID- 10119057 TI - Productivity by design. PMID- 10119058 TI - OSHPD (Office of Statewide Health Planning and Development) to implement fully automated plan review. PMID- 10119059 TI - New technology allows hospitals to roll with mother nature. Base isolation shows promise in search for earthquake safety. PMID- 10119060 TI - A plan for earthquake-proofing your hospital. California Association of Hospitals and Health Systems. PMID- 10119061 TI - Unemployment insurance--then, now and tomorrow. PMID- 10119063 TI - Costing library services--towards a model for the NHS. Proceedings of a seminar and workshop held at the University of Newcastle upon Tyne 13 December 1990. PMID- 10119062 TI - Hospital design of the future--healing environments. AB - Predicting the future of hospital design is hardly a consensus forming art. Crystal ball visions of the 21st-century hospital vary from expert to expert. Perhaps that's simply a sign of the diversity of our health care system. Or perhaps it's a problem inherent in reading the future. For example, some hospital architects and facility planners say tomorrow's hospitals will be smaller due to technological advances. Others say those same advances will create larger hospitals brimming with high-tech equipment. Some say hospitals will be part of medical malls; others see them in a campus setting, perhaps accompanied by satellite facilities in the surrounding community. Yet, despite their often diverse views of the future, architects and planners do share common thoughts about hospital architecture in the decades ahead. Without question, they most commonly agree that hospitals will offer a more patient-friendly environment. Achieving that goal could take many forms, but it is expected to include the use of soothing colors, attractive landscaping, natural lighting, wayfinder lobbies and entrances, private rooms, quieter hallways and accommodations for family and friends. PMID- 10119064 TI - A comparison of the currency of secondary information sources in the biomedical literature. I. Weekly current awareness services. AB - Three biomedical current awareness products which are distributed on floppy disc, were studied over a period of 3 months. They were monitored for the speed with which primary journal issues were indexed, and for the coverage of the journals which were selected for study. Data on issues of 72 monthly journals (38 North American and 34 European) and nine weekly titles (four from North America and five from Europe) were recorded. The time to elapse between publication date and arrival of hard copy in the British libraries and appearance in secondary sources varied enormously. The findings suggest that monthly journal issues appear in the secondary sources on average 6-7 weeks after publication date and weekly journals appear after approximately 4 weeks. Indexing of North American monthly journals is 1 week ahead of European titles in the two products from the US, but the European service indexed European publications sooner. One product, Current Contents on Diskette, contained all issues included in the 3-month period covered by the study, but Reference Update omitted 9.1% of the issues and Medical Science Weekly 1.6%, including leading biomedical journals. PMID- 10119065 TI - Indigent medical care: current challenges and solutions. PMID- 10119066 TI - Models to promote medical health care delivery for indigent families: computerized tracking to case management. AB - Poor patient/parental medical compliance is one of the most important health care issues of today. Multiple interrelated factors contribute to this problem. Of prime importance is patient/parental maturity and knowledge. Reversal of this process is undoubtably harder than prevention. The cost effectiveness of various methods of intervention is discussed in relation to a large mid-south indigent population. Computerized patient tracking is cost efficient and effectively promotes compliance in a percentage of patients. Its additional utility is the identification and triage of patients, most in need of intervention, to existing social service personnel for family-centered case management. Family-centered case management holds the best hope of reversing the many factors adversely affecting patient compliance. However, this method is costly and requires a low ratio of clients to caseworkers in order to be effective. Community-centered patient management is less costly to implement and is very useful in tightly woven communities resistant to outside intervention. However, this method often has a high client to caseworker ratio and has less utility in dealing with complex medical problems. PMID- 10119067 TI - HIV infection and AIDS: another layer to consider in addressing indigent health care in the United States. AB - This paper will present the current status of the epidemic of HIV infection and AIDS and show relationships to indigent health care. Statistics of disproportionate race and ethnic minorities affected with poverty and HIV infection will be discussed. Projections of who will be affected and estimates of the impact will be included. Community planning in regard to legislative, service, and educational agenda will be suggested. PMID- 10119068 TI - Indigent health care: the increasing contribution of AIDS to the health care budget deficit. AB - With the number of AIDS cases in the United States exceeding 100,000 and rising, it is becoming more of a financial burden to take care of this population. The Regional Medical Center at Memphis, like most hospitals providing indigent care, sustains annually a large deficit for both outpatient and inpatient care of AIDS patients. With the establishment of a dedicated AIDS clinic, it is hoped to maximize outpatient care and the utilization of available financial resources. Implementation of this model may help obviate the financial disaster that is impending for the already overburdened public hospitals and their patients. PMID- 10119069 TI - Federal and state resources available to aid Mid-South families. PMID- 10119070 TI - Indigent health care plan for Tennessee. AB - The author describes the development of an Indigent Health Care Program for the State of Tennessee from the campaign pledge of the Governor, through the development of an Indigent Care Cabinet Council, to the development and enactment of appropriate legislation required to implement this program. The program deals with availability of health care services, accessibility to health care services and funding mechanisms. The backbone of the program is the involvement of the local community and the coordinating and networking of the existing private, community and state health care providers. PMID- 10119071 TI - Rural health care issues in the Lower Mississippi Delta: an agenda for the year 2000. AB - The 214 counties bordering both sides of the Lower Mississippi Delta from Cape Girardeau, Missouri, to New Orleans, Louisiana, currently represent one of the four major poverty regions in the United States. Despite the location of five major medical centers, the Lower Mississippi Delta continues to lag behind the rest of the country in important health indices. This paper presents comparative data on infant mortality rates and health care availability between the Lower Mississippi Delta and the rest of the nation. It also contains comparative data on the rural Lower Mississippi Delta and the rest of the rural U.S. Further comparisons of European and African-American infant mortality rates reveal necessary directions and important realities for future health efforts. Commission research, gathered in public hearings from the Delta, reveals a pattern of interrelated development factors that also seriously affect health care in rural Delta counties. PMID- 10119072 TI - Who bears the burden of uncompensated hospital care? AB - This paper considers the question of who bears the burden of uncompensated hospital care. The thesis is that the hospital that provides the services received by indigent patients may not be the one that eventually bears the financial burden. The various sources of funds available for the payment of indigent care are identified and the incidence of financial burden discussed. The paper ends by addressing several considerations that should be taken into account in evaluating how fairly the indigent care burden is distributed. PMID- 10119073 TI - Capital budgeting and income taxes. PMID- 10119074 TI - Selecting discount rates. PMID- 10119075 TI - HIM resources--practice tools: guidelines for documenting exposure incidents. PMID- 10119076 TI - Breach of confidentiality. AB - This has been a simple overview of confidentiality and documentation for health information leaders. However, it was no simple issue for 'Mary' or the health information manager. The important issue of confidentiality should not be neglected. We need to be concerned with confidentiality education and awareness for all healthcare employees. We are health information leaders, so we should take every opportunity to promote the tenets of confidentiality. PMID- 10119077 TI - Fax control: coping with the legal issues. PMID- 10119078 TI - The application layer. PMID- 10119079 TI - Self-assessment tool. Confidentiality and security in the computer-based patient record environment. PMID- 10119080 TI - National Healthcare Billing Audit Guidelines, adopted March 13, 1992. AHIMA, AHA, Association of Healthcare Internal Auditors, Blue Cross and Blue Shield Association, HFMA, and HIAA. PMID- 10119081 TI - HIM resources--practice tools: interpreting the Medicare hospital-specific mortality rates. PMID- 10119083 TI - Reengineering health information management: the first steps. AB - This is a partial view of how implementing new computer technology will put power into the hands of healthcare providers in the future. The article touches briefly on three concepts that will help health information management professionals restructure the data collection process. The restructuring process should be based on minimizing a task-orientation and emphasizing an outcome-oriented approach., In the course of making this change, old methods will have to be discarded and totally new systems implemented. This will make some people happy and will distress others, but it really needs to be done and the new technology is here to help us do it. 'It is time to stop paving cow paths ...' and start building new super highways from scratch. We can do this by computerizing, but we must base the design of these new health information management programs (both clinical and administrative) on guidelines like the ones explained here. PMID- 10119082 TI - Integrated clinical data management. PMID- 10119084 TI - Polishing your image for success as health information management professionals. PMID- 10119085 TI - Teambuilding for the health information manager. PMID- 10119086 TI - Automated information systems provide health information management support to veterans' healthcare. AB - The Veterans Health Administration has implemented a comprehsnsive DHCP which supports the VA healthcare system at both local and national levels. Numerous clinical and management modules have been developed; an overview was given of selected applications impacting health information managers. Continuing development includes an automated clinical record and expanded electronic data exchange. PMID- 10119088 TI - The computer-based patient record challenges the health information management profession. PMID- 10119087 TI - Computerized medical care: the HELP system at LDS Hospital. PMID- 10119089 TI - Computer instructions and the control unit. PMID- 10119090 TI - CPRI (Computer-Based Patient Record Institute) update. PMID- 10119091 TI - Memories and storage devices. PMID- 10119092 TI - Council on Education report: ART progression and long-range goals. AB - To answer the question of Accredited Record Technician long-range educational goals (including an indication for progression opportunities), the Council on Education (COE) of AHIMA in 1990 sent out a Request for Proposal for a needs assessment. Based on a proposal submitted in July 1990, a contract was awarded to The College of St. Scholastica. Shirley Eichenwald served as the project director. Kathleen LaTour was project associate and David Swenson was project consultant. A survey was developed and distributed with a deadline of February 1991. The findings from the survey were placed in a report entitled "Progression Potential and Educational Goals of ARTs: a Needs Assessment," dated April 1991, which was submitted to the Council on Education and reviewed at the August 1991 COE meeting. This article summarizes and highlights the key findings from this report. PMID- 10119093 TI - Legal opinion on offering medical record technician and medical record administrator certification exams in Spanish. PMID- 10119094 TI - Joint Commission activities: credential project questionnaire results. PMID- 10119095 TI - HIM resources--practice tools: mortality review. AB - As discussed here, HCFA mortality information is not a simple index of hospital performance. The data included are just one indicator of patient outcome for just one group of the total in-patient hospital population. With growing public interest in the quality of healthcare, however, it is in a hospital's best interest to analyze HCFA mortality data and respond to public inquiries regarding quality of care. PMID- 10119096 TI - Transcription: a strategic approach to the on-line medical record. PMID- 10119097 TI - An in-house training program for hospital-based medical transcriptionists. AB - Because of the demand for accountability and the necessity that the medical transcription department function as a revenue-generating entity within the hospital structure. HIM professionals are rejecting inadequate solutions and looking for long-term improvements in medical transcription quality and productivity. It has been our experience that many hospitals and clinics are opting to train in-house. This is a cost-effective solution which can quickly provide a return on investment if managed properly. Many HIM professionals choose this solution because it ultimately affords the highest level of control in areas of quality assurance and turnaround time. It is also seen as a long-term solution to continuing staffing shortages, particularly in areas where medical transcription courses offered by local educational facilities are inadequate or nonexistent. Thus, strategic planning to guarantee both quality medical transcription and revenue-generating levels of productivity may involve implementation of an in-house training program. Such a solution will undoubtedly factor into balancing the equation of supply and demand as it pertains to medical transcription staffing in the future. PMID- 10119098 TI - Transcription technology today. AB - A fascination with telecommunications and technology has enabled this author and her corporate information systems department to achieve system integration and simple functionality in a comprehensive and diverse medical transcription unit. PMID- 10119099 TI - Quality improvement, transcription, and security. PMID- 10119100 TI - Guest alliance--American Association for Medical Transcription: the state of the profession of medical transcription. PMID- 10119101 TI - Productivity methods and measurement standards in medical transcription: a study of Alabama hospitals. PMID- 10119102 TI - Standards in the medical transcription service industry. PMID- 10119103 TI - Transcription--the untamed frontier. AB - Health information managers must be more aggressive in defining the technology and standards for dictation and transcription equipment and services. The author offers many ideas on how to tame the technology jungle out there! PMID- 10119104 TI - Pitfalls of word processing implementation. AB - Technology is great, but people make the systems work. This is an example of what can go wrong when the users are not involved in decision making. But working as a team, the transcription and management staffs can create a happy ending! PMID- 10119105 TI - Connectivity, compatibility, and transcription services. AB - A transcription service must be able to access the dictation system and other systems in transcribing a client's medical dictation. Hence, connectivity and compatibility are vital considerations. PMID- 10119106 TI - Controlling transcription costs. AB - Understanding what transcription costs and controlling the costs are two interrelated subjects, yet two very different subjects. Understanding what it costs is critical for your budgeting activity. Controlling the cost is essential for your management effectiveness. PMID- 10119107 TI - The need to establish standards of measurement for transcription. PMID- 10119108 TI - Voice recognition: technology with a future. PMID- 10119109 TI - Medical transcription: a better way to get the job done. PMID- 10119110 TI - Volunteers' motivations: a functional strategy for the recruitment, placement, and retention of volunteers. AB - A psychological strategy for understanding the motivational underpinnings of volunteerism is described. In a presentation that merges the theoretical interests of researchers with the practical interests of volunteer administrators, six different motivational functions served by volunteerism are identified, and an inventory designed to measure these motivations is presented. The implications of this functional approach for the recruitment, placement, and retention of volunteers are then elaborated. Finally, recommendations are provided for volunteer administrators who seek to increase the number of people who volunteer and to improve their human resource management. PMID- 10119111 TI - Moral responsibilities of trustees: some first thoughts. AB - The role of a trustee is unclear to most people, including many trustees. The author proposes a view of trustees as persons who have public responsibility for private or independent provision of a public good. This is a moral definition of trusteeship; without trusteeship a pluralist society would be in trouble. The author argues that trustees should be constrained by fiduciary duties, the common good, an interpretative responsibility, and some procedural norms. PMID- 10119112 TI - Coping by nonprofit organizations during the Reagan years. AB - Contrary to expectations that a divested federal role would lead to the demise of nonprofit agencies, the relationship between nonprofit and government sectors in New York at the end of the 1980s was stronger than ever. This article presents longitudinal data for six nonprofit agencies in Rochester, New York, to demonstrate "management by groping along" during the Reagan years, behavior that resulted in increased reliance on state and local governments for funds and programs and in different ways of doing business. PMID- 10119113 TI - Health care reform: the debate goes on. PMID- 10119114 TI - The road to trauma center designation for the community hospital. PMID- 10119115 TI - What the doctor should do. AB - Domestic violence is an epidemic, but physicians say it's not their problem. The A.M.A. disagrees and wants to put them in an uncomfortable new role. PMID- 10119116 TI - Data watch. The range of dependent care benefits. PMID- 10119117 TI - High-cost children: the unknown liability. PMID- 10119118 TI - Is Dutch health care a model for the U.S. health system? AB - The Netherlands provides universal access and high-quality care, but the Dutch are reforming their system to encourage more competition among insurers. PMID- 10119119 TI - Employers push to manage prescription drug costs. PMID- 10119120 TI - Flexible benefits and managed care make natural partners. AB - "Managed flex" is being used by a growing number of employers seeking to combine cost containment with employee choice. PMID- 10119121 TI - Flexible plans help employers cut retirees' health costs. PMID- 10119122 TI - Medicare looks to combine forces with employers. Interview by Joyce Frieden. PMID- 10119123 TI - Coalition seeks quality before costs. PMID- 10119124 TI - Connecticut cost shift becomes permanent. PMID- 10119125 TI - Aging industries face retiree dilemmas. PMID- 10119126 TI - Resources in dependent care. PMID- 10119127 TI - Data watch. A report card on HMOs. PMID- 10119128 TI - Making employees better health care consumers. PMID- 10119129 TI - Health care fraud detection enters the information age. PMID- 10119130 TI - Practice parameters may benefit employers. PMID- 10119131 TI - HMOs and employers unite to collect outcomes data. PMID- 10119132 TI - Self-funded HMOs offer an alternative to paying premiums. PMID- 10119133 TI - Are Medicare HMOs the promise of the future? AB - Companies are looking at using HMOs to reduce their retiree medical costs. But first there are obstacles to overcome. PMID- 10119134 TI - Survey predicts troubled times ahead for high-priced HMOs. PMID- 10119135 TI - Coalition plans a model purchasing program. PMID- 10119137 TI - HMO resources. PMID- 10119136 TI - Washington state to adopt RBRVS formula. PMID- 10119138 TI - Shoppers: look for value in health care. PMID- 10119139 TI - Is my baby all right? Two controversial studies link a common prenatal test to birth defects. PMID- 10119140 TI - Occupational exposure to formaldehyde--OSHA. Response to Court remand; final rule. AB - By this action, the Occupational Safety and Health Administration (OSHA) hereby amends its existing regulation for occupational exposure to formaldehyde, 29 CFR 1910.1048, in response primarily to a remand by the U.S. Court of Appeals for the D.C. Circuit in UAW v. Pendergrass, 878 F.2d 389 (D.C. Cir. 1989). The final amendments lower the permissible exposure level for formaldehyde from 1 ppm (part per million) as an 8-hour time-weighted average (TWA) to an 8-hour time-weighted average of 0.75 ppm. The amendments also add medical removal protection provisions to supplement the existing medical surveillance requirements for those employees suffering significant eye, nose or throat irritation and for those suffering from dermal irritation or sensitization from occupational exposure to formaldehyde. In addition, certain changes have been made to the standard's hazard communication and employee training requirements. These amendments establish specific hazard labeling requirements for all forms of formaldehyde, including mixtures and solutions composed of 0.1% or greater of formaldehyde in excess of 0.1 ppm. Additional hazard labeling, including a warning that formaldehyde presents a potential cancer hazard, is required where formaldehyde levels, under reasonably foreseeable conditions of use, may potentially exceed 0.5 ppm. The final amendments also provide for annual training of all employees exposed to formaldehyde at levels of 0.1 ppm or higher. PMID- 10119141 TI - Medicare program; quarterly listing of program issuances and coverage decisions- HCFA. General notice. AB - This notice lists HCFA manual instructions, substantive and interpretive regulations and other Federal Register notices, and statements of policy that were published during January, February, and March 1992 that relate to the Medicare program. Section 1871(c) of the Social Security Act requires that we publish a list of our Medicare issuances in the Federal Register at least every 3 months. We also are providing the content of the revisions to the Medicare Coverage Issues Manual published during this quarter. On August 21, 1989 (54 FR 34555), we published the content of the Manual and indicated that we will publish quarterly any updates. Adding the Medicare Coverage Issues Manual changes to this listing allows us to fulfill this requirement in a manner that facilitates identification of coverage and other changes in our manuals. PMID- 10119142 TI - Recruitment of men in occupational therapy: past, present and future. PMID- 10119143 TI - Documentation of paediatric assessments using the occupational therapy guidelines for client-centred practice. AB - Although documentation is required in occupational therapy, there is little uniformity in content or format between therapists or facilities. The purpose of this article is to present a format that reflects the Canadian Guidelines for the Client-Centred approach to assessment and to share the experience of implementing this format at the Arbutus Society for Children in Victoria, British Columbia. It is hoped that client-centred documentation will facilitate role clarification, service promotion, and quality assurance. As the format reflects the conceptual framework described in the Occupational Therapy Guidelines for Client-Centred Practice (Canadian Association of Occupational Therapists, 1991b), it should be appropriate for use in other areas of practice. PMID- 10119144 TI - New PHO (physician hospital organization) concept eliminates middleman. AB - Four Denver-area hospitals are adding a new twist to the physician hospital organization concept, banding together to form "The Healthcare Initiative." This new coalition provides these independent institutions with the cost-containment and physician-control benefits of PHOs, while allowing a wider geographical service area. Such arrangements, however, require special information systems planning. PMID- 10119145 TI - Money for nothing ... and your chicks for free. AB - Picture archiving and communications systems promised "filmless" radiology departments, but factors including costly or impractical standards for integrating PACS with other hospital information systems left users wanting. A new "no money down, use what you've got" interface approach may turn PACS' dream into a reality. PMID- 10119146 TI - Survey targets 31 CIOs of Blue Cross Blue Shield plans. AB - Facing every-increasing costs, stiff competition from alternative healthcare plans, and pressure to provide new services, Blue Cross Blue Shield organizations are reengineering their organizational structures. But a recent survey shows that to meet the new requirements, these health insurance giants must also find new ways--and new technologies--to use information. PMID- 10119147 TI - Risky business: capital equipment acquisitions in the new regulatory climate. AB - Capital equipment acquisition has been paralyzed by three Medicare regulations. The Prospective Payment System, Resource-Based Relative Value Scale, and Safe Harbor rules could sink healthcare provider purchasing plans without proper navigational charting. PMID- 10119148 TI - Follow-up: transplantation. Twice blessed house enhances discharge planning. PMID- 10119149 TI - Medicare patients receive home health benefits. PMID- 10119150 TI - New Medigap laws. The open enrollment provisions. PMID- 10119151 TI - President's health reform plan advocates tax incentives and managed care. PMID- 10119152 TI - Complying with the WARN (Worker Adjustment and Retraining Notification) Act. PMID- 10119153 TI - Understanding multiemployer health and welfare plan financial statements. AB - The trustees of a health and welfare plan may choose to delegate monitoring of the plan's financial operations. Still, it is important that they have a basic understanding of welfare plan financial statements. PMID- 10119154 TI - Long-term care insurance--an emerging employee benefit. AB - As the need for this benefit increases, long-term care will continue to grow. This articles outlines an approach to plan design. PMID- 10119155 TI - Is your company paying too much for its medical insurance? PMID- 10119156 TI - History and structure of business groups on health. AB - In summary, business groups on health, given the strong financial and political support of key business decision makers, have shown that the competitive model can be used to encourage cost efficiencies in the health care system. It remains yet to be seen whether the growth of such organizations can produce needed change within a time frame that will make other approaches, such as national health insurance, unnecessary. PMID- 10119157 TI - Strategic management of health care plans. PMID- 10119158 TI - Recent COBRA developments in the courts. AB - The health care continuation provisions of COBRA have been a concern for employers since the law was enacted. These authors advise that, for guidance in complying with those provisions, it is important to look to court cases. PMID- 10119159 TI - Seeing the forest despite the trees. The benefit of exploratory data analysis to program evaluation research. AB - In the present article, it is argued that there is a benefit to applying techniques of exploratory data analysis (EDA) to program evaluation. To exemplify this, an evaluation of a rehabilitation program for people with rheumatoid arthritis is presented. The perceived health status of patients receiving intensive rehabilitation services from a major rehabilitation institute was compared with that of patients receiving customary office-based care over an 18 month period. The data were analyzed in a conventional way (analysis of variance) and then by way of EDA techniques (graphic display of medians and boxplots). The conventional analysis suggested that all patients improved over time and that intensive rehabilitation services provided no particular benefit or harm. The exploratory analysis showed that the distribution of the outcome variable was patently nonnormal, thus casting doubt on the validity of the conventional analysis. The EDA further showed that the rehabilitation group lagged behind the comparison group for a year, with a precipitious improvement at the 18-month period. This suggests that a selection factor was operating (i.e., those in the rehabilitation group could have been sicker) or that the patients in the rehabilitation group were made more aware of their condition by the intensive health services they received. The EDA provided an important insight. PMID- 10119160 TI - The assessment of professional competence. AB - Valid assessment of professional competence has proven to be an elusive goal. Objective tests, direct observation of performance, overall ratings of competence, and simulations have been tried and found wanting in one way or another. Objective test items are criticized as being unrealistic and therefore invalid. Direct observation tends to be very unreliable and therefore invalid. Simulations and overall ratings of competence share both of these flaws to some extent. Basically, you can't win. This article outlines some of the many ways to lose and some ways to cut these losses. In doing so, it proposes a general framework for evaluating the validity of measures of competence, and it uses this framework to examine the strengths and weaknesses of three approaches to the assessment of professional competence: direct observation, simulation, and objective testing. PMID- 10119161 TI - Evaluating policy change in physician manpower planning. AB - The decade of the 1980s witnessed a revitalization of free-market interest in the use of incentives and voluntary participation to promote activities in a wide range of fields. Because of its history of decentralized control over physician residency training, the state of New Jersey found such an approach appealing when it sought to restructure its graduate medical education system. Two statewide task forces spent a year developing policy changes designed to produce voluntary changes in such areas as the size and growth of the state system. However, a 2 year follow-up survey of the directors of state residency programs revealed little perceivable change. PMID- 10119162 TI - Work patterns of male and female pharmacists. A longitudinal analysis 1959-1989. AB - A demand for better data about pharmacists as working health professionals led the authors to study the work patterns of 1,146 pharmacists over a 30-year period from 1959 to 1989. Work history data were used to determine gender-specific participation rates as a function of age, years in the work force, and date. Percent full-time (as opposed to part-time) work as a gender-specific function of age was also determined. Participation rates for males and females, widely disparate in the 1960s, have converged and are not significantly different. Graduates of the 1980s, both male and female, are remaining with pharmacy as an occupation at a significantly higher rate than earlier graduates. Percent full time rates for women pharmacists are significantly lower than those for male pharmacists, although women have registered significant increases in percent full time work in each decade from the 1960s to the 1980s. An unexpected finding was the overall reduced participation by graduates of the years 1970 to 1979. The findings of the study are helpful in explaining recent controversies about the adequacy of the supply of pharmacists. The form of the data bases constructed for this study could be used as a model for the study of other health professionals. PMID- 10119163 TI - Physician-assisted suicide and the right to die with assistance. PMID- 10119164 TI - Clinical research depends on integration and support. PMID- 10119165 TI - Networks help assure survival. Interview by Donald E.L. Johnson. AB - Health care is increasingly a regional business rather than a national one, so hospitals should join or form local networks of providers, insurers and managed care entities, says Gary A. Mecklenburg, president and CEO of Northwestern Memorial Hospital, Chicago, in an interview with Health Care Strategic Management's Donald E.L. Johnson. Institutions that don't participate in the regionalization of health care could be left out. Mecklenburg, who is also president and CEO of the Northwestern Healthcare Network, expects hospital networks, insurers and managed care providers to form more exclusive or limited relationships. Northwestern Memorial is a 723-bed hospital and academic institution with a medical staff of 1,000 physicians. The Northwestern Healthcare Network is an organization formed in 1990 which brings together Northwestern Memorial, Children's Memorial, Evanston, Glenbrook and Highland Park Hospitals under a holding company. PMID- 10119166 TI - Why is decision making so much harder? PMID- 10119167 TI - Planning indicators. PPS works; worst fears not realized. PMID- 10119168 TI - How North General moved an entire hospital in two hours without incident. PMID- 10119169 TI - Practical training for employees recommended for improved fire safety. PMID- 10119170 TI - Product update: intrusion detection systems. PMID- 10119172 TI - Meet the quality gurus. PMID- 10119171 TI - Health care reform--where do nutrition services fit? PMID- 10119173 TI - Partnerships for survival. PMID- 10119174 TI - The management of hospital medical waste. How to increase efficiency through a medical waste audit. AB - Medical waste is a nightmare for hospital administrators, cutting across department boundaries and incorporating legal, financial, and community concerns. In this two-part article the author provides a stepwise approach to effective waste management. The first part gives background information on waste generation, storage, and disposal and delineates the framework of a medical waste audit. This audit is put to the test in the second part, where data from a pilot trial at an actual hospital are presented and discussed. PMID- 10119175 TI - Pricing policy in nonprofit hospitals. AB - The increasing complexity of reimbursement systems and other financial issues forces hospitals to obtain maximum reimbursement from third-party payers. What effect does this have on price-setting decisions? This article presents the results of a survey that sought to identify the key players in setting prices in nonprofit hospitals and the objectives pursued in setting those prices. PMID- 10119176 TI - Constructive performance appraisal feedback for healthcare employees. AB - For their own reasons, both healthcare managers and employees dislike performance evaluation interviews. Managers would rather avoid the role of appraiser, and employees often dispute the accuracy of their assessments. The resulting poorly handled interview often resembles a power struggle more than a performance review. This article describes several interview formats that might be appropriate to certain situations and advocates training for managers who must conduct performance evaluation interviews. PMID- 10119177 TI - Simulation of emergency medical service scheduling. AB - Efficient allocation of resources is essential in any activity, but experimenting to determine appropriate levels risks a reduction in services that could be dangerous in a healthcare operation. Computer simulations offer a risk-free environment for testing alternate resource levels and balancing costs and services. This article describes the use of a simulation to determine appropriate staffing levels for an emergency medical service. PMID- 10119178 TI - Creating the "spirit of service". AB - What does it take for a hospital to achieve excellence in the area of customer service? How can customer service be improved within a large and complex healthcare facility? Many hospitals are currently seeking answers to these questions. PMID- 10119179 TI - Economic credentialing--issues for hospital managers. PMID- 10119180 TI - Problem-solving techniques. PMID- 10119181 TI - Exercising choice for national healthcare. In the end, we'll get what we choose. AB - Whether we evolve toward a market model, a play-or-pay model, or a national model will depend largely upon our personal beliefs and perspectives. Unfortunately, in the hectic and fast-paced life that virtually all of us lead, we base many of our conclusions on unexamined bits and pieces of conventional wisdom. We have looked at but five of them. Yet these bits and pieces become the yardsticks by which we measure other plans and other people. Instead of listening to and studying the approaches proposed by others, we are often too quick to dismiss them with labels such as "too costly," or "too capitalist," or "too socialist," or "too whatever." As a consequence, we become prisoners of our own ideology. Would that we were more like Tillich's (1951) description of the famous theologian, Karl Barth, who "...strenuously tries not to become his own follower" (5). In other words, we would work to continually inform and correct ourselves in light of new understanding. Our healthcare problems--any social problems, for that matter--are never really solved. All we can do is do our best at meeting needs, even if it means that in meeting one set of needs we inadvertently create other needs. But that is why we are enriched when we accept the challenge of continuing to question our personal bits and pieces of conventional wisdom. In a recent column in the Houston Post, Richard Reeves cites statistical evidence, known to most who work in the healing professions, indicating that people who live alone tend to suffer from greater illness.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119182 TI - Neo-natal environments. PMID- 10119183 TI - Knowledge is power. The Women's Health Education Project. PMID- 10119184 TI - Teaching to live. Learning from ten years of AIDS. PMID- 10119185 TI - In his own voice. PMID- 10119186 TI - Wellbeing is our birthright. The meaning of empowerment for women of color. AB - The Brooklyn-based New York Black Women's Health Project is a chapter of the National Black Women's Health Project (NBWHP), which was founded in 1980 by Byllye Avery of Atlanta, Georgia, as a way of filling the void in both the mainstream health care system and the feminist health movement regarding the specific needs of African-American women. According to Avery, health education is "not just about giving information; people need something else ... We are dying inside ... Unless we are able to go inside ourselves and touch and breathe fire, breathe life into ourselves, [of] course, we couldn't be healthy. [We] started working on a workshop that we named 'Black and Female: What is the Reality?' This is a workshop that terrifies us all. And we are also terrified not to have it, because the conspiracy of silence is killing us." The NBWHP attempts to break this conspiracy of silence by giving African-American women an environment of supportive self-help groups in which women are able to express the whole of the condition of their lives and share their feeling with others who understand what it is like to be Black and female in this society. A basic philosophy of the organization is that health behavior is not simply a matter of knowing what to do or not to do and then making "rational choices;" rather, individual health reflects personal and social circumstances. Poor women often know the "facts" but feel powerless to make changes because their lives are conditioned by many levels of oppression and despair. PMID- 10119187 TI - Compliance with medication orders among the elderly after hospital discharge. AB - Patient compliance with medication prescriptions in the period immediately following hospital discharge should be of concern to all hospital personnel responsible for the appropriate use of medications, notably Pharmacy and Therapeutics and Quality Assurance Committees. We reviewed the medical records of patients over age 65 discharged from one acute-care hospital. Two days after discharge, we contacted subjects by phone and determined which medications they were taking and at what frequency. We compared discharge orders for medication use with actual use, as determined by self-reports. Of the 44 patients for whom we had complete data, 64% used at least one medication that was not ordered by the physician at discharge, and 73% failed to use at least one medication according to the way it was ordered. Of all drugs ordered at discharge, 32% were not taken at all. Hospital personnel should evaluate their discharge procedures and test techniques to improve compliance in discharged elderly patients. PMID- 10119188 TI - Department of pharmacy-initiated program for streamlining empirical antibiotic therapy. AB - The outcome of a department of pharmacy-initiated "streamlining" study designed to promote cost-conscious modifications of empirically selected antibiotic therapy is described. Two hundred forty-one evaluable adult patients started on restricted-use antibiotics at this university-affiliated community private teaching hospital were enrolled in a 9-week prospective streamlining study. Patients were alternately assigned to a Control (i.e., no pharmacist-initiated streamlining recommendations offered based on culture and susceptibility reports) or a Pharmacist Intervention group (i.e., pharmacist offers recommendations to streamline therapy). A statistically significant greater number of patients had their empiric antibiotic treatment courses modified to more appropriate antibiotic choices after receipt of culture and susceptibility reports among private prescribers in the Pharmacist Intervention group (83%) than in the Control group (38%) (p = .006). Additionally, pharmacists were overall successful in gaining prescriber acceptance for 64% of recommended changes of empiric antibiotic treatment courses before the receipt of culture and susceptibility reports (e.g., dose and/or frequency changes). There was no program effect observed with respect to improved physician response to microbiologic data that would allow streamlining empirical antibiotic choices in the Housestaff (i.e., medical or surgical residents), or infectious disease consultant prescriber groups. Projected overall annual cost savings that would be achieved as a result of continued efforts by pharmacists directed at streamlining empirical "restricted" antibiotic regimens is approximately +40,000. PMID- 10119189 TI - An analysis of potential and real cost savings by the addition of ranitidine to total parenteral nutrition solutions. AB - The results of two analyses that assessed the potential savings and the actual savings derived from the addition of ranitidine to total parenteral nutrition solutions are discussed. A clinical pharmacist determined on a daily basis the number of patients receiving concurrent total parenteral nutrition solutions and intermittent intravenous ranitidine in a critical care unit. The cost of each mode of administration was determined and the savings were calculated to be over +16,000/year. Once the practice of adding ranitidine to total parenteral nutrition solutions became routine, total parenteral nutrition solution orders for April-June 1991 were collected and the number of patient days were counted and the accrued savings were determined to be slightly more than +10,000 each year. Differences are explained by discrepancies in expected and true number of patient days. The authors conclude that there are savings to be realized by adding ranitidine, or any H2 antagonist, to total parenteral nutrition TPN solutions and avoiding intermittent infusions. PMID- 10119190 TI - Effect of clinical pharmacy input on physician prescribing habits in the nursing home care unit. AB - The goal of this study was to evaluate any changes in medication use in our 60 bed nursing home care unit as a result of eliminating clinical pharmacy services during a 2-week period. Information was obtained on patient medications and number of doses dispensed. All patients were found to have a 6% increase in average number of scheduled medications, a 3% increase in average total medications, and an increase in scheduled doses dispensed by 10% during the absence of clinical pharmacy services. These numbers declined by 16, 18, and 9%, respectively, 2 weeks after the return of clinical pharmacy services. When evaluating only those 37 patients present the entire 4 week period, average scheduled medications rose 5% and total medications rose 4% during the absence of clinical pharmacy services and declined 13 and 17%, respectively, upon return of services. Eleven patients showed an increase in total number of medications during the absence of clinical pharmacy services whereas 21 patients showed a decline in medications after the return of clinical pharmacy services (P less than 0.001). The authors conclude that clinical pharmacy services must be provided on a continuous basis to maintain good physician prescribing habits in the nursing home care unit. PMID- 10119191 TI - Enteral or parenteral nutrition? PMID- 10119192 TI - Indices for monitoring hospital outcomes in developed countries. AB - We discuss some of the challenges facing hospitals in developed nations, with special attention to the need to monitor and evaluate hospital performance. In particular, there is a need for quality indicators that measure the effects of treatment, and are risk-adjusted, so that valid comparisons of outcomes can be made across hospitals that treat different types of patients. Until recently, only very crude quality indicators have been available for comparing the performance of different hospitals. We describe three risk-adjusted indices for comparing the outcomes of hospital care, focusing on the construction and validation of these measures. We discuss the uses of these tools for identifying problems and for monitoring outcomes of care within a hospital, including screening medical records for peer review, identifying variations in outcomes across various subgroups of physicians, and comparing changes in outcomes following various changes in the delivery system. Possible applications at the regional, national and international levels are then discussed, with special emphasis on the use of these tools for measuring the size of the gap between the efficacy of a technology, as determined through randomized controlled trials under stringent protocols, and the effectiveness of the same technology once it is exported, and then used under true practice conditions in another country. PMID- 10119193 TI - Competitive bidding for health insurance contracts. AB - The determination of the payment or premium to be paid to the insurer by a large purchaser of care must accurately represent the risk of the enrolled persons. One approach is a risk-adjusted payment established by a mathematical formula, which estimates the effect of many variables on total care costs, and for different groups of persons determine an average cost. This method has several problems, and an alternative is competitive bidding. Market forces pressure providers to offer the lowest possible bids while attempting to remain fiscally viable and provide high-quality services. Research from the U.S. demonstrates that competitive contracting effectively lowered the costs of health care for those sectors of the health care system that used this strategy. Bidding by area gave far more equitable results than could have been obtained with a state-wide system with crude adjustments for each area. It is an alternative which can create strong incentives for innovation and cost-containment, and at the same time allows insurers to take into account local variation in supply and demand of care. As a potential alternative to a regulatory system, competitive bidding should be considered for regional experimentation in health insurer payment. PMID- 10119194 TI - DRGs: the road to hospital efficiency. AB - In this paper, the effects of using diagnosis-related groups (DRGs) as the basis of a hospital funding mechanism and within a global budgeting mechanism are reviewed. Most forthcoming is the indeterminate effect of DRGs as a funding mechanism. By controlling only the price of hospital care, such systems remain vulnerable to compensatory increases in patient throughout, cost shifting and patient-shifting. Whether the use of DRGs has substantially reduced hospital cost per case is also not clear cut. Effects on patient outcome have not been adequately assessed. At this stage, use of DRGs within a system of global budgeting will simply focus attention on the current average costs of treating cases without consideration of whether such average costs represent efficient clinical practice. Efficient clinical practice is better established through use of less sophisticated techniques, such as clinical budgeting and cost effectiveness analysis. The failure of more global budgeting in the past has been that patient outcome has not been monitored. Data on outcome are crucial to determining efficiency. Once efficient clinical practice is established through budgeting, DRGs could be calculated according to efficiency criteria rather than current average cost. PMID- 10119195 TI - Fixed price contracts: the case of pediatric acute lymphoblastic leukemia. AB - This paper describes a new type of hospital contract. It is a contract made with payers and represents an attempt to tackle the issues of cost-containment, physicians' dissatisfaction with control over their practise, cost-effective care and quality of care. The case chosen for this attempt is pediatric acute lymphoblastic leukemia. The basis for setting the price of treatment is the division of the illness into episodes of care that correspond to medical events. There is a fixed fee schedule for each episode, and this fee schedule covers all the expenditures incurred during the episode. The fee schedule is fixed at the onset of the disease and depends solely on medical risk factors. Physicians can use the combination of resources they consider best for their patients and hospital management must find a cost-effective way to provide the required care. The advantage to patients is that they no longer have to obtain payers' agreement but receive state-of-the-art treatment in a teaching hospital. PMID- 10119196 TI - The cost of preventing coronary heart disease. AB - The incidence of coronary heart disease (CHD) can be reduced by preventive measures. We know what it costs to treat CHD, but lack even the most rudimentary estimates of what it might cost to reduce the incidence by means of population wide strategies of prevention. American and Australian experience shows that such strategies achieve results. Even in Britain, where official spending on prevention is relatively small, health publicity has succeeded in bringing about marked reductions in the household consumption of animal fats and in cigarette smoking. Yet we know virtually nothing about the cost of bringing about a given reduction in CHD mortality by preventive measures. Estimates of such costs would be useful in persuading public authorities to spend more on prevention. PMID- 10119197 TI - Hospitals, GPOs look to cut costs with refurbished beds. PMID- 10119198 TI - Glove prices on the rise. PMID- 10119199 TI - Materials managers clip contrast media costs. PMID- 10119200 TI - Materials management and laboratory must work together under auspices of new rules. PMID- 10119201 TI - Hospitals cut costs by consolidating disinfectants. PMID- 10119202 TI - Issuance of HHS's Safe Harbor regulations resulted from several court cases. AB - Earlier articles covered the background of the Safe Harbor regulations issued by HHS in July 1991. These articles also contained some details of the provisions of the regulations that are of concern to hospital materials managers. In this dialogue, Dr. Decker briefs several major cases that preceded the regulations and reflect the reasons for their being issued. This is Part 3 of a three-part series. PMID- 10119203 TI - Stockless momentum gains in first quarter. PMID- 10119204 TI - The health debate USA. AB - The debate about the future of health care in the USA is raging. Newspaper headlines reveal horror stories of the cost or inaccessibility of health care. Every day, someone announces new plans or ideas for tackling the problems. Alan Randall, a Harkness Fellow, visited the USA in 1991. PMID- 10119205 TI - Waiting lists--the primary care solution. PMID- 10119206 TI - Professional values in health care. AB - All professionals subscribe to certain values and have concerns about their freedom and autonomy. When professionals work in large and complex organisations such as hospitals, differences in the values of various groups are reflected in disagreement. Tony Kennerley argues that the manager's task is to create harmony out of such dissonance. PMID- 10119207 TI - Emergency ambulance service performance standards. AB - From April 1991, district health authorities (HAs) have been negotiating specific contracts with ambulance services for the provision of emergency ambulance services. It is important that performance standards for monitoring these services are developed and that performances standards are clinically meaningful. Andrew Rouse describes the contract drawn up in Cornwall. PMID- 10119208 TI - Management. AB - Driving across the North Yorkshire moors in the course of a working day has its attractions, but the size of the largest FHSA in England and Wales can make for communication problems that need careful handling. For Chris Town, General Manager, North Yorkshire FHSA, management is about the art of diplomacy. PMID- 10119209 TI - Who likes hospital advertising--consumer or physician? AB - Both consumers and physicians have favorable attitudes toward advertising in general, but their attitudes toward hospital advertising differ considerably. In particular, the two groups differ in their opinions about the influence of advertising on hospital choice, the value of the information being advertised, and the economic impact of advertising on hospitals. PMID- 10119210 TI - Using promotion to increase dental practices. AB - Providers of professional services are beginning to experiment with promotional activities as a means to increase business and to remain competitive in the 1990s. The authors report the results of a nationwide survey of dentists that was conducted to identify the incidence and impact of promotional tool use among dental professionals. Of particular interest is the effect of different promotional tools on dentists' patient contact activity. Interestingly, dentists employed a variety of promotional tools in their practices and generally viewed promotion as acceptable. Yet, only dentists who used publicity as their sole promotional mechanism reported significantly improved patient contact activity. PMID- 10119211 TI - What is the health care product? AB - Because of the current competitive environment, health care providers (hospitals, HMOs, physicians, and others) are constantly searching for better products and better means for delivering them. The health care product is often loosely defined as a service. The authors develop a more precise definition of the health care product, product line, and product mix. A bundle-of-elements concept is presented for the health care product. These conceptualizations help to address how health care providers can segment their market and position, promote, and price their products. Though the authors focus on hospitals, the concepts and procedures developed are applicable to other health care organizations. PMID- 10119212 TI - Stockless inventory systems for the health care provider: three successful applications. AB - Three large hospital-based stockless inventory systems are described. First, the method of stockless inventory is described in some detail and differentiated from the just-in-time (JIT) method of inventory management. Second, three hospital case studies involving successful stockless systems are summarized and evaluated. Finally, some important implications for the implementation of stockless inventory systems are summarized for hospital management. PMID- 10119213 TI - Getting patients to answer: what affects response rates? AB - Even scientifically validated and reliable surveys are an exercise in futility if response rates are low. The author's study raises the issue of whether the hospital experience itself, among other factors, influences the likelihood of patients' willingness to respond to surveys about their hospital experience. The research questions are framed as testable hypotheses with guidelines for future research. Examining these hypotheses contributes valuable insights for improving the response rates in patient satisfaction surveys. PMID- 10119214 TI - Physician peer review surveys: a management tool for improving quality of patient care. AB - An increasing number of patients are presenting multiple medical problems requiring the collaboration of two or more physician specialists or subspecialists for effective treatment. The quality of care delivered to multiple problem patients depends greatly on how well the physician specialists interact with one another. The Cleveland Clinic Foundation (CCF) has developed and implemented a physician peer review survey that enables physicians to receive anonymous feedback on the service they provide to their colleagues. The survey has been implemented in both medical and surgical departments. Colleagues have identified areas for improvement to increase collaboration and enhance effectiveness in treating multiproblem patients. The data have led to a variety of specific service-related improvements and changes in physician behavior. Though originally conceived as a quality improvement technique, the physician review survey has become an internal marketing and management tool for physician managers. PMID- 10119215 TI - Selection of licensing candidates in the pharmaceutical industry: an application of the analytic hierarchy process. AB - The ethical (prescription) pharmaceutical industry depends on a stream of innovative, patent-protected products to maintain growth and profitability. With Sterling Drug's entry into a new therapeutic area (oncology, the study and treatment of cancer), licensing and research collaborations have become an important part of the process of developing a pipeline of potential new drugs. The application of the analytic hierarchy process has led to improved articulation of the relevant criteria and better definition of organizational procedures, thereby benefiting Sterling's decision-making process. PMID- 10119216 TI - Looking at innovative multihospital systems: how marketing differs. AB - Multihospital systems are an important and growing component in the health care delivery system in the United States. Because formalized marketing is relatively new in multihospital systems, the potential to increase the marketing productivity of member hospitals is great. The more is known about how these systems function, the more effective will be the public and private decision making involving these systems. To that end, the authors position marketing in multihospital systems as an innovative technology and examine comparative profiles of innovative and noninnovative multihospital systems. More innovative systems, scoring higher on the marketing innovation attribute index, are characterized by greater information systems and communication support, as well as a stronger commitment to the marketing function. Strategic implications and future research directions are explored. PMID- 10119217 TI - Spend your dollars wisely. PMID- 10119218 TI - The space race. PMID- 10119219 TI - Wants, motivations, values. An informal look at the front-line provider. PMID- 10119220 TI - Bright lights, big noise. How effective are vehicle warning systems? PMID- 10119221 TI - Defending your life. How to manage violent patients and scenes. PMID- 10119222 TI - Pre-admission programs for involuntary residents. PMID- 10119223 TI - Preserving and encouraging resident autonomy. PMID- 10119224 TI - Turnover among nursing assistants: why they leave and why they stay. AB - Overall, the data from the study show that nursing assistants who were planning to leave their present employment within the next three months were younger, had been in their positions less time, were paid less, and were better educated than those who were planning to stay in their present jobs. Also, the assistants who were planning to leave were not planning to stay in nursing as a life's career. They were planning to leave their present jobs because they had less input into the planning of care and conferences on care, attended fewer in-service programs, and ranked their own nursing skills lower than their peers. Changing patient assignments on a daily basis was more often associated with plans to leave than was changing patient assignments weekly or never. Finally, nursing assistants who were planning to leave cared for more patients per shift than those who were planning to stay. Nursing assistants who were planning to leave their jobs imminently had been employed for 12 or fewer months more frequently than nursing assistants who were planning to stay. The leavers were also in their first nursing job more frequently than the latter group and seemed to be a more critical group as well: 27% of those who were leaving reported that they criticized the policy or procedure of their facility sometimes or even frequently, a higher percentage than almost any other variable tested in the study. Another variable that was different between the two groups was what they considered most important to them.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119225 TI - Community care givers' attitudes toward nursing homes. PMID- 10119226 TI - Respite care in the long-term care continuum. AB - Respite care preserves the physical and mental strength of the care giver while delaying institutionalization. However, anticipated growth of the elderly population will dramatically increase the demand for these services. PMID- 10119227 TI - Career ladder: tool for recruitment, retention, and recognition. PMID- 10119228 TI - Meeting the challenge: involuntary residents in the nursing home. AB - This study has shown that involuntary residents feel they have no personal choices and experience emotional distress. Subjects did not develop effective relationships with staff or other residents, and they delayed renegotiation of relationships with the staff. They suffered more falls, more depression, and more weight loss than did voluntary residents. Finally, they used more resources than did voluntary residents. These results suggest that staff need to identify this "high risk" group at the start and increase the opportunities for personal control. PMID- 10119229 TI - Glutaraldehyde overexposure: myth or reality? One hospital-wide study. PMID- 10119230 TI - When manufacturers have to change medical packaging for environmental reasons. PMID- 10119231 TI - Are sterilization containers cost-effective? PMID- 10119232 TI - LAN maximizes materiel management processes hospital-wide. PMID- 10119233 TI - Vascular ultrasonic scanners. ECRI. PMID- 10119234 TI - CFC tax: is it fair to healthcare providers? PMID- 10119235 TI - Rapid readout biological monitoring system. PMID- 10119236 TI - Sexual harassment: join me in the quagmire. PMID- 10119237 TI - EtO emergencies. PMID- 10119238 TI - Quality improvement and health care: an annotated bibliography. AB - W. Edwards Deming's theories of continuous quality improvement, using statistical analysis to identify problems or errors in operational processes, are in the early stages of development in service organizations after substantial success in industry, especially in Japan. Information on continuous quality improvement for libraries is sparse. The articles in this annotated bibliography will help interested readers learn more about this theory and its application in the health care business. PMID- 10119239 TI - NLM's MeSH vocabulary file. PMID- 10119240 TI - Everyone can use a little extra cache. PMID- 10119241 TI - Beyond online: primary research as a value-added service. AB - Information specialists should provide a value-added service by supplementing their online searches with primary research. Primary research results in more up to-date information from a broader spectrum of sources. The requester benefits from primary research by receiving a cost-effective and more comprehensive information package. The information professional benefits by acquiring a more in depth knowledge of the subject, increasing awareness of important projects within the organization, and achieving recognition as a key information analyst. PMID- 10119242 TI - MHA Vision Project: Health Care 2000. Critical choices: a design for health care reform. PMID- 10119243 TI - The costs of running our system--a key element of health care cost containment. PMID- 10119244 TI - Engler outlines plans for a healthy Michigan. PMID- 10119245 TI - Health care: tinkering won't help. PMID- 10119246 TI - Community service award winners: making a difference. PMID- 10119248 TI - How to avoid mistakes in the interview process. PMID- 10119247 TI - Survey findings: Michigan's smaller and rural hospitals. PMID- 10119249 TI - AHA's reform plan: glimpse of tomorrow. PMID- 10119250 TI - Promising, and delivering, health care value. AB - It came as no surprise a year or so ago to read in Physician Executive that "Clinical decision-making is no longer the exclusive domain of the health care practitioner." The authors pointed out that consumers, as patients and as business-payers, are insisting on provider accountability, both in quality and in appropriate cost. They used the phrase "health care value" to show a balance between cost containment and quality. One managed care operation has decided to operate on the premise of health care value. PMID- 10119251 TI - Efforts to implement national health reform in the United States. AB - Beginning in this issue and carrying forth during the year, the author will trace the history of the development of a national health policy in the United States. In beginning this new feature, Physician Executive recognizes the potential impact of national health reform on physician executives and the need to contribute to informed discussion on the current national health reform debate. In this first article, the authors sets the stage for the series, establishing the historical precedents for national health care reform and some of the groundrules for the articles to follow. PMID- 10119252 TI - National Practitioner Data Bank--incomplete and future cloudy. AB - Nearly six years after the National Practitioner Data Bank was authorized by Congress in the Health Care Quality Improvement Act of 1986, and more than a year after its actual creation, the device is still only partially operational. What is more, the success of even those limited efforts is being questioned, and the timetable for future developments remains to be firmed up. Also, the costs are much higher than estimated. PMID- 10119253 TI - Analyzing vendor and supplier contracts. AB - Contracts increasingly govern the way medical groups operate their businesses. While physician employment contracts and contracts with HMOs and PPOs usually receive significant scrutiny and analysis, little attention has been paid to the myriad contractual relationships by which physicians secure services for their own practices. PMID- 10119254 TI - Physician support groups in a multispecialty group practice setting. AB - With a moderate expenditure of time and energy on the part of a physician executive, the group support concept can be used in any organization to help physicians overcome social obstacles and learn to cope with the disturbing changes that are occurring in medicine. By selecting the most suitable candidates, anticipating obstacles, and simply beginning an effort, one can bring about optimal change for physician members of an organization despite their apparent reluctance. The optimal time for suggesting help in this group support manner is when the problem is acute and significant, i.e., "a crisis." PMID- 10119255 TI - Do the benefits of the new OSHA HIV/HBV standard justify the costs? AB - On December 6, 1991, OSHA published its "final standard" for controlling occupational exposure to HIV and HBV. While the main thrust of the standard is sound, in some physicians' assessment, some of the detailed emphasis may be misdirected. They fear that the burdens imposed by the standard may be greater than the benefits derived from it. "Health Law" is a regular feature of Physician Executive contributed by Epstein, Becker, and Green. Mark Lutes of the firm's Washington, D.C., offices serves as editor for the column. PMID- 10119256 TI - Attrition survey of physiotherapists in Ontario. AB - This study examined demographic differences between practising and non-practising physiotherapists, reasons for leaving the profession and factors that might influence return. A mailed survey was sent to three groups of Ontario physiotherapists: 1) those who had not renewed registration to practice (Cancelled); 2) those who were registered but not practising (Inactive); and 3) a group of actively practising therapists randomly selected (Control). The overall response rate was 76%. Significant differences among the three groups were in personal income and membership in the professional association (CPA). The majority of those not practising were not working outside the home and approximately half planned to return. The two most important reasons for not working in physiotherapy were: a) raising a family; and b) the desire for new challenges and further education. The most important factors that would influence return were: a) opportunity for flexible hours for those planning to return; and b) upgrading of the profession for those not planning to return. Family related and professional/job issues for those not working in physiotherapy and differences between practising and non-practising groups are discussed. Strategies for retention and return are recommended. PMID- 10119257 TI - Observer variation in an audit of charts of patients with rheumatoid arthritis. AB - Arthritis Society physiotherapists (PTs) in Ontario adopted Problem Oriented Records (POR) to monitor patient care; goals were to encourage patient specific treatment plans and standardized records. After nine months in practice, the POR system was evaluated by an audit on charts of patients with Rheumatoid Arthritis. Audit teams of two PTs were created within each of five geographic areas. Auditors attended an audit instruction workshop. Two charts, selected randomly from the discharged patients of each of 38 therapists, were independently scored on 56 items by an audit team. The extent of agreement within the auditor team (observer variation) was measured, and adequacy scores computed for each chart. Adequate reliability of the audit instrument was established before examination of adequacy scores and making inferences about quality of care. The auditor agreement measures (kappa) varied from 0.13 to 0.97, mean = 0.74 and SD = 0.16; these estimates were indicative of adequate reliability of the audit form, although agreement scores were different amongst the five areas (P2 less than .01). POR adequacy scores varied from 10.0 to 93.1, mean = 64.5 and SD = 16.9. There were no differences in adequacy scores amongst the five areas (P2 = .61). To reduce observer variation, increased pre-audit emphasis is needed on auditor guidelines and training for items relating to assessment findings, problem identification, and treatment planning. PMID- 10119258 TI - Staking our claim in the new frontiers. PMID- 10119259 TI - Smoothing the transition from hospital to home. Patient Learning Center increases quality of care. University of Minnesota Hospital and Clinic. PMID- 10119260 TI - Reaching out to the sneezing and wheezing. Four-pronged strategy brings patients to asthma/allergy center. Johns Hopkins Medical Institutions. PMID- 10119262 TI - Making a heart center a household name. Patient tracking verifies promotion's effectiveness. Jewish Hospital, Louisville, KY. PMID- 10119261 TI - Marketing during the national healthcare debate. Crisis or opportunity? PMID- 10119263 TI - Capital campaigning north of the border. Capital campaigns in the 90s: Part two of a three-part series. PMID- 10119264 TI - Fitness club brings gains and no pains. Hospital's wellness center builds profits and clientele. Winter Park Memorial Hospital, FL. PMID- 10119265 TI - A niche in time can save dimes. Niche marketing brings success for heart center and new birthing unit. St. Mary's Hospital, Huntington, WV. PMID- 10119266 TI - Getting back to baby basics. Promotion of new maternity center ties in total family care. St. Elizabeth Medical Center, Yakima, WA. PMID- 10119267 TI - Designing with residents in mind. PMID- 10119268 TI - Master plans help manage facility development, growth. PMID- 10119269 TI - Fair value rental system ensures full property reimbursement costs. PMID- 10119270 TI - New law obligates providers to inform residents of rights. PMID- 10119271 TI - Lack of privacy, control may trigger aggressive behaviors. PMID- 10119272 TI - Horticulture therapy promotes 'wellness,' autonomy in residents. PMID- 10119273 TI - Prescribing practices critical in preventing falls. PMID- 10119274 TI - High-tech services meet needs of facility pediatric unit. PMID- 10119275 TI - How to hire the right people. Part II. PMID- 10119276 TI - 1992 annual guide. America's best hospitals. PMID- 10119277 TI - Mayo minus snow. PMID- 10119278 TI - Taking control of your pain. PMID- 10119279 TI - A case for cooperation. Less stress for patients with partners. PMID- 10119280 TI - Military medicine. The image and the reality of veterans' hospitals. PMID- 10119281 TI - Emergency help. Advance planning will get you to the right place in a crisis. PMID- 10119282 TI - 1992 annual guide. The best hospitals. PMID- 10119283 TI - 1992 annual guide. A guide to the best. AB - Here are miniprofiles of the 43 hospitals that emerged as the top choices of doctors surveyed in 16 specialties. Phone numbers let you follow up with questions of your own. PMID- 10119284 TI - Office visits to internists, 1989. PMID- 10119285 TI - Managing the maze: case management and service delivery. AB - The author discusses case management as the most recent social work effort to make manageable the pluralistic and proliferating array of human services. She notes that social work now claims case management as part of its long defined territory. The ability to make this function work is based upon an educational curriculum which prepares the professional in both direct interventive skills and management capability. Problematically, social work education usually provides the student with only one or the other sets of professional preparation. The importance of the power dimension must be acknowledged and honed if the case manager is to be successful working within a chaotic social service delivery system. PMID- 10119286 TI - The unclear status of nonprofit directors: an empirical survey of director liability. AB - Nonprofit boards of directors are fiduciaries for the organization. However, there have been various legal interpretations of their duties. The authors review the conflicting standards of conduct that exist, and they report the results of a survey which sampled director opinion concerning the liability issue. The proposition that directors were unaware of their legal responsibilities was supported, and the implications of this finding for organizational procedures and public policy are discussed. PMID- 10119287 TI - Ready, fire, aim!: current perspectives on strategic planning. PMID- 10119288 TI - More on breaching ethical behavior. PMID- 10119290 TI - Dispelling the fog of myth. PMID- 10119289 TI - Health care and AIDS. AB - The acquired immune deficiency syndrome (AIDS) is a harbinger for change in health care. There are many powerful forces poised to transform the industrialized health care structure of the twentieth century, and AIDS may act as either a catalyst or an amplifier for these forces. AIDS could, for example, swamp local resources and thereby help trigger national reform in a health care system that has already lost public confidence. AIDS can also hasten the paradigm shift that is occurring throughout health care. Many of the choices society will confront when dealing with AIDS carry implications beyond health care. Information about who has the disease, for example, already pits traditional individual rights against group interests. Future information systems could make discrimination based upon medical records a nightmare for a growing number of individuals. Yet these systems also offer the hope of accelerated progress against not only AIDS but other major health threats as well. The policy choices that will define society's response to AIDS can best be made in the context of a clearly articulated vision of a society that reflects our deepest values. PMID- 10119291 TI - Who will temper public demand? PMID- 10119292 TI - Consolidation. The future of HMO's. PMID- 10119293 TI - New marketing channels: HMOs & PPOs. PMID- 10119294 TI - A blessing or a curse? PMID- 10119295 TI - Clinical radioimmunoscintigraphy. AB - In summary, radioimmunoscintigraphy has emerged into clinical practice, has many advantages and relatively few side effects. Its use in the routine practice is not going to be limited to the areas of oncology, but will also be used in other disease states such as infections, thrombus detection and infarcts. PMID- 10119296 TI - AFROC (Association of Freestanding Radiation Oncology Centers) pushes for change. PMID- 10119297 TI - Minute by minute. PMID- 10119298 TI - How to achieve buy-in from the board. PMID- 10119299 TI - The role of medical staff departments in peer review. PMID- 10119300 TI - Perspectives. Managed competition vies for first place. PMID- 10119301 TI - Perspectives. The health of the nation: mixed. PMID- 10119302 TI - Convention diary: Clinton promises health care for all. PMID- 10119303 TI - Perspectives. Easing the way toward managed care: point of service. PMID- 10119304 TI - Perspectives. HCFA: where it's been, where it's going. PMID- 10119306 TI - CIO compensation: what to expect. PMID- 10119305 TI - Accounting systems: for more than just the money. PMID- 10119307 TI - Spanning the schism between departments: IS & marketing. PMID- 10119308 TI - Say good-bye to the hospital of today. PMID- 10119309 TI - EIS (executive information system): the one system no hospital administrator should be without. PMID- 10119310 TI - Trends in healthcare computing. AB - Almost 550 healthcare professionals were polled for their perceptions of information technology--as it relates to their facilities--at the 1992 Annual Healthcare Information and Management Systems Society Conference. Conducted by J.C. Pollock Associates, Princeton, N.J., and commissioned by HIMSS and Hewlett Packard Co., the survey responses reflect general optimism about information system procurement and use in America's hospitals. Actual responses to multiple choice, technology-related survey questions are charted on this and following pages. PMID- 10119311 TI - Caveat emptor! Don't become a casualty of vendor pricing wars. PMID- 10119312 TI - Physician database eases staffing headaches. PMID- 10119314 TI - Doctor orders prescription for physicians, patient education. PMID- 10119313 TI - Deming: health care and quality compatible. PMID- 10119315 TI - Survey reveals patients ready to sacrifice for health care changes. PMID- 10119316 TI - Education, fun among resources given physician office managers. PMID- 10119317 TI - Triage and equality: an historical reassessment of utilitarian analyses of triage. AB - We distinguish and review aspects of the history of two models of triage: egalitarian and utilitarian. Egalitarian triage is widely and successfully practiced in battlefield medicine, as well as in the emergency room and the ICU. Utilitarian triage has been sporadically practiced and typically collapses under the pressure of public scrutiny. Unfortunately, the two models tend to be conflated, confusing our understanding of the past and confounding our ability to plan for the future. PMID- 10119318 TI - Universal health care, American style: a single fund approach to health care reform. AB - With increasing momentum for health care reform, attention is shifting to finance reform that will provide for direct methods for controlling health care spending. This article outlines the two principal paths to direct cost control and outlines a national plan that retains our multiple sources of payment, yet also contains a powerful direct cost control technique: a single fund to finance all health care. PMID- 10119319 TI - Nursing ethics: a selected bibliography, 1987 to present. PMID- 10119320 TI - Affiliated societies of the Alabama Hospital Association. Number 3 in a series. PMID- 10119321 TI - Pros and CONS: is there still a need for certificate of need? AB - Alabama's CON program grew out of federal measures enacted in the 80's. The federal laws are gone, but CON remains. Is it a concept whose time has passed? PMID- 10119323 TI - Electrical systems for health care facilities. PMID- 10119322 TI - Grassroots care: how local public hospitals make it work. AB - City- and county-owned hospitals are the lifelines for many communities. It's a daunting responsibility. Here's how they pull it off. PMID- 10119324 TI - Medicare program; payment for federally qualified health center services--HCFA. Final rule with comment period. AB - These regulations establish a new category of facility known as a Federally qualified health center (FQHC), the services of which are covered under the Medicare program. This new type of entity is one that is receiving a grant under section 329, 330, or 340 of the Public Health Service (PHS) Act, a non-grant receiving entity that is determined by the Secretary to meet the PHS Act requirements for receiving such a grant, and certain facilities that have previously been identified as Federally funded health centers. These regulations also establish requirements for coverage and payment of FQHC services under the Medicare program. Related Medicaid rules are being developed in a separate rulemaking document. These regulations implement section 4161 of the Omnibus Budget Reconciliation Act of 1990 (OBRA Omnibus Budget Reconciliation Act of 1990 (OBRA '90), Public Law 101-508. PMID- 10119325 TI - Public information collection requirements submitted to the Office of Management and Budget for clearance--HCFA. Supporting statement for the CLIA application forms, HCFA-114 AND HCFA-116. PMID- 10119326 TI - Medicare program; Peer Review Organizations: revised scopes of work for the District of Columbia, Puerto Rico, the Virgin Islands, and all states except Delaware, Florida, Missouri, Montana, Nebraska, Nevada, Oklahoma, Rhode Island, South Carolina, Washington, and Wyoming--HCFA. Final notice. AB - This notice describes requirements for the review activities of Utilization and Quality Control Peer Review Organizations (PROs) under contract extensions of the Scope of Work for the District of Columbia, Puerto Rico, the Virgin Islands and all States except Delaware, Florida, Missouri, Montana, Nebraska, Nevada, Oklahoma, Rhode Island, South Carolina, Washington, and Wyoming. Section 1153(h)(1) of the Social Security Act requires us to publish any new policy or procedure adopted by the Secretary that affects substantially the performance of PRO contract obligations at least 30 days before the date the policy or procedure is to be used. Specifically, this notice describes the way in which PRO contract requirements are changed and explains significant changes in the PRO program (e.g., the way in which cases will be selected for review) and also describes continuing requirements. This notice also implements provisions of the Omnibus Budget Reconciliation Act of 1990. PMID- 10119327 TI - Recovery of cost of hospital and medical care and treatment furnished by the United States--Department of Justice. Final rule. AB - This order amends Department of Justice regulations to increase the settlement and waiver authority delegated to heads of departments and agencies of the United States responsible for the furnishing of hospital, medical, surgical, or dental care. This change responds to the increase in medical costs since 1978, when the current level of delegated settlement and waiver authority was fixed, and will further the efficient operation of the government. PMID- 10119328 TI - Health rip-offs. PMID- 10119329 TI - Subjective quality of life measures for evaluating medical intervention. AB - Medical interventions are usually evaluated in terms of mortality and morbidity data, but there is recent interest in going beyond medical data to assess the impact of the therapy on the objective and subjective quality of the patient's life. Objective quality of life measures such as employment and functional status are relatively straightforward, but measuring subjective quality of life is a more complex task. This article reviews psychometric issues relevant to using subjective quality of life scales developed by Bradburn and by Campbell, Converse, and Rodgers for research with patient populations. The evidence indicates that these relatively brief scales assess both affective and cognitive aspects of subjective quality of life, that they are measuring something more stable than mood but less enduring than personality, and that they can be as sensitive as physiological measures in distinguishing among treatment groups. It is concluded that these scales offer a useful complement to more objective measures of patient status for research evaluating medical interventions. PMID- 10119330 TI - Assessing the value of Medicaid prescreening in a county public health unit. AB - The purpose of this study was to determine if already-existing staff in a rural health department could effectively increase access of their clients to Medicaid. All "sliding fee" patients seeking services were asked a series of questions to determine their categorical eligibility for Medicaid. Those identified as potentially eligible were formally referred for complete financial eligibility determination, and outcomes of those referrals were examined to determine the number of patients newly insured. The study revealed that the majority of poor clients being served in the health department were categorically ineligible for Medicaid and that the majority of potentially eligible patients declined to complete the application process. The process cost the health department twice as much in staff time as it could possibly have recouped in Medicaid reimbursements. PMID- 10119331 TI - Individual and community rights in anonymous unlinked HIV seroprevalence research: a response to Dr. Emson. PMID- 10119332 TI - Keep the promise. AB - Our communities have told us they want change. By holding true to our deepest values, Texas hospitals will be leaders in the challenge of health care reform. PMID- 10119333 TI - Executive forecast. PMID- 10119334 TI - What about a management company? PMID- 10119335 TI - TDH (Texas Department of Health) rules can reduce special waste volume and cost. PMID- 10119336 TI - Texas outreach programs promote cancer control. PMID- 10119337 TI - Health management consultancy. Pros and cons. PMID- 10119338 TI - Health management consultancy. Tyranny of the five-letter word: bleep. PMID- 10119339 TI - Health management consultancy. Re: apocalypse. PMID- 10119340 TI - Health management consultancy. To spar or to dance? PMID- 10119341 TI - Frozen assets. PMID- 10119342 TI - London weighting. PMID- 10119343 TI - Health for all? PMID- 10119345 TI - Staff planning. Just the job for new recruits. PMID- 10119344 TI - Staff planning. People who need people. PMID- 10119346 TI - Bells and alarums. PMID- 10119347 TI - 'I wish I had been an accountant.'. PMID- 10119348 TI - Patch workers. PMID- 10119349 TI - More bricks in the wall. PMID- 10119350 TI - Infant science, adult problem. PMID- 10119351 TI - Yorkshire--the velvet revolution. PMID- 10119352 TI - Freedom, fault and default. PMID- 10119353 TI - Rationale for rationing. PMID- 10119354 TI - Seeking social justice. PMID- 10119355 TI - Dilemmas and decisions. PMID- 10119356 TI - Prospects for prevention. PMID- 10119357 TI - Fear of rationing. PMID- 10119358 TI - Health care 2001: America's leading futurists on the 21st century. PMID- 10119359 TI - Doctors fatten their employees' pay. PMID- 10119360 TI - How to save big on medical equipment. PMID- 10119361 TI - Do HMOs make doctoring easier? Let me count the ways. PMID- 10119362 TI - You're reading right: I love RBRVS! PMID- 10119363 TI - Why you aren't shielded from the law's bad apples. PMID- 10119364 TI - It sure feels good to be back in private practice. PMID- 10119365 TI - What it will take to really control health costs. PMID- 10119366 TI - The status of women in the laboratory. Part I. Job satisfaction in the field: women speak out. PMID- 10119367 TI - The status of women in the laboratory. Part II. Parenthood, harassment, and other workplace distractions. PMID- 10119368 TI - Technician or technologist? Sorting out overlapping roles in the lab. PMID- 10119369 TI - Complying with the new OSHA regs. Part III. Compiling employee safety records that will satisfy OSHA. PMID- 10119370 TI - Thoughts on maternity leave from a mother-manager. PMID- 10119371 TI - A well-designed maternity leave form prevents confusion and disappointment. PMID- 10119372 TI - Personal computers in the lab: what will the future bring? PMID- 10119373 TI - Role of the physician in encouraging use of advance directives. AB - Advance directives provide patients with the chance to tailor health care decisions to their own values even after they have lost the capacity to make decisions. Federal legislation enacted in 1990 and now effective will ensure widespread awareness of this opportunity. However, the extent to which advance directives actually contribute to improving patient care will depend much more on how physicians educate and counsel their patients than on what the law mandates. PMID- 10119374 TI - The Fourth PRO Scope of Work: automating the medical review process through the Uniform Clinical Data Set. AB - With the advent of the Fourth Scope of Work, peer review organizations are beginning to implement the Uniform Clinical Data Set, an automated medical review system designed to collect standardized data from Medicare medical records and provide a data base to determine the most effective treatment for a given illness or disease. In this article, the author discusses the Health Care Financing Administration's development of the Uniform Clinical Data Set and its proposed application within the context of the Health Care Quality Improvement Initiative and the Fourth Scope of Work. PMID- 10119375 TI - Medical staff and hospital: a delicate relationship. AB - The relationship between hospitals and medical staffs has become increasingly delicate over the last several years. The interests of the hospital and the medical staff are diverging and may conflict. It is important to acknowledge these differing interests before solutions can be reached and a stronger relationship built. PMID- 10119376 TI - The COBRA patient anti-dumping law: Part II--Impact on physician liability. AB - This is the second part of a two-part article examining the federal patient anti dumping statute, under which physicians are required to treat a hospital's emergency patients, including women in labor, and to comply with certain requirements that dictate when it is appropriate to transfer a patient. Part I discussed in detail the provisions of the statute. Part II analyzes various court interpretations of the law and its potential impact on physician liability. PMID- 10119377 TI - Physician recruitment: the elements of a successful search. AB - Before attempting to recruit a new physician for a practice, it is important to gain a background in the elements involved in a successful search--such as physician supply data, recruitment strategies, and incentives. Armed with an understanding of the physician market, recruiters are better prepared to proceed with a search that will meet the needs of potential candidates, as well as their own requirements. PMID- 10119378 TI - Structuring group medical practices: tax planning aspects. AB - This article is the first in a series addressing the structuring of group medical practice entities, shareholder relationships, and general representation factors. In this article, a general background in federal tax planning is provided, including strategies for minimization of income tax payment and the potential problems that may be encountered when a group practice is not carefully structured. PMID- 10119379 TI - Avoiding malpractice claims for lack of informed consent. AB - While malpractice claims alleging lack of informed consent are proliferating, the courts are requiring more detailed information regarding the risks of proposed treatment. Increased use of consent forms and brochures designed to provide comprehensive, objective information for specific procedures could help physicians avoid most of these types of claims. PMID- 10119380 TI - Medicare fee schedule for physicians' services. PMID- 10119381 TI - "Insider-out": private inurement and the medical staff physician. PMID- 10119382 TI - Medical malpractice environment in the 1990s. PMID- 10119383 TI - AHA polling members on how to react to reclassification move. PMID- 10119384 TI - Ohio hospitals balk at antitrust exemption law. PMID- 10119385 TI - Venture may bid for Texas program. PMID- 10119386 TI - Humana board authorizes study of splitting company. PMID- 10119387 TI - No. 1 management firm Quorum Health Group purchases no. 2 player. PMID- 10119388 TI - Ill. passes new provider tax for Medicaid. PMID- 10119389 TI - Providers launch PR campaign. PMID- 10119390 TI - Groups in Cedar Rapids, Iowa, forming 15-member planning panel. PMID- 10119391 TI - AHA drops support of play-or-pay mandate from reform proposal. PMID- 10119392 TI - Federal merger study offers little guidance on antitrust. PMID- 10119393 TI - 6 facilities' officers start discussion group. PMID- 10119394 TI - Bush administration lambasted for lack of AIDS funds, leadership. PMID- 10119395 TI - Five AMI hospitals to reveal prices as part of settlement. PMID- 10119397 TI - Much to learn from Canada's plan. PMID- 10119396 TI - Malpractice reform's chances look slim for rest of this year. PMID- 10119398 TI - The candidates' recipes for healthcare reform. PMID- 10119399 TI - American Health seeks buyer for N.Y. psych facility. PMID- 10119400 TI - Malpractice record at HMOs in line with rest of industry, results of recent study show. PMID- 10119401 TI - Low interest boosts healthcare bond sales. PMID- 10119402 TI - Aurora Health Care, Milwaukee psych facility to begin affiliation talks. PMID- 10119403 TI - Christian Health Services negotiating agreements with two Missouri hospitals. PMID- 10119404 TI - Suits slow progress of La. restructuring. PMID- 10119405 TI - Humana to face challenges if it pursues plan to split. PMID- 10119406 TI - Complaint hits insurance form question on AIDS virus. PMID- 10119407 TI - Groups hope tentative bailout will save employees' annuities. PMID- 10119408 TI - Foundation strengthens grip in Calif. with Century offer. PMID- 10119409 TI - Exemption fight targets well-paid Mass. execs. PMID- 10119410 TI - Jury orders Dean Witter to pay defunct Texas hospital $3.5 million. PMID- 10119412 TI - Medicare payments for MRIs promote proliferation--GAO. PMID- 10119411 TI - Manager certification program to begin. PMID- 10119413 TI - Two measures for hospitals included in panel's legislation. AB - Health care reform legislation that recently cleared the House Ways and Means health subcommittee includes two measures that have been sought by hospitals--the restoration of separate payments to physicians for interpretation of electrocardiograms and the reauthorization of the federal grant program aimed at developing networks of primary-and acute-care hospitals in rural areas, known as the "each/peach" program. PMID- 10119414 TI - Fear of regulation spurs activity on reform alternatives. AB - A variety of programs and proposals designed to head off governmental intervention are being touted as answers to the vexing problems of healthcare delivery--specifically cost and access. Among the market-based initiatives are those based on the concept of "managed competition," which aims to match large groups of consumers with cost-conscious healthcare providers and allow them to compete for patients based on quality and efficiency. PMID- 10119415 TI - Used pacemakers: who's keeping track? AB - When a medical device salesman was indicted for selling mislabeled and used cardiac pacemakers as new, no one said how he obtained the devices. The incident raises concerns about the standard procedures used by hospitals for the disposal of pacemakers that may be removed from patients. While each hospital has its own rules for disposals, the Safe Medical Devices Act is changing that by requiring the tracking of pacemakers and other medical devices. PMID- 10119416 TI - IRS is making it easier for hospitals to borrow tax-exempt working capital. AB - Updated regulations recently issued by the Internal Revenue Service spell out how hospitals and other not-for-profit borrowers can issue debt to boost their cash flow. While hospitals probably won't be rushing out to borrow money for working capital, the new rules will provide significant help for facilities. They clarify several issues that had confused hospitals in the past and will give them more latitude in the future. PMID- 10119417 TI - Columbia closes one deal and opens another. PMID- 10119418 TI - 3 more hospitals overbilled Medicare--IG. PMID- 10119419 TI - Champion Healthcare to buy 13 hospitals from Humana. PMID- 10119420 TI - Dems temporarily shelve healthcare differences. PMID- 10119421 TI - Moody's downgrades ratings of two hospitals in California. PMID- 10119422 TI - Va. hospitals join list of facilities reporting profits. PMID- 10119423 TI - Getting results from your third-party administrator. PMID- 10119424 TI - The growing demand for managed care. PMID- 10119425 TI - American Laundry Digest buyer's guide. PMID- 10119426 TI - Sexual harassment: guidelines for laboratory managers. AB - Sexual harassment can poison a work environment, create legal problems, and cause productivity to suffer. Excellent clinical laboratories recognize its potentially disruptive effects and develop proactive strategies to deal with sexual harassment while enacting policies that prevent its occurrence. This article outlines steps to be taken when sexual harassment is alleged. A sample organizational policy on sexual harassment is also included. PMID- 10119427 TI - Ethics in health care, Part I: The process of ethics committees. AB - More than 60% of hospitals now have ethics committees, and this percentage will continue to grow. Based on personal experience as a member of several ethics committees, I suggest that ethics committees have at least 10 members and no more than 25; that active physician involvement is necessary for an effective committee; and that diversity of perspective will help a committee in performing its tasks. The functions of an ethics committee are education, policy formulation, retrospective case review, case consultation, and psychological support. Ethics committees should not have to enforce their policies, and they should not be legally liable if they do not attempt to practice medicine. PMID- 10119428 TI - The Yellow IRIS (International Remote Imaging Systems) Model 250 urinalysis workstation. PMID- 10119430 TI - What managers can do to avert sexual harassment. PMID- 10119429 TI - Implementing TQM. AB - Total quality management (TQM) is an organized, systematic approach to problem solving and continuous improvement. American corporations have found that TQM is an excellent way to improve competitiveness, lower operating costs, and improve productivity. Increasing numbers of laboratories are investigating the benefits of TQM. For this month's column, we asked our respondents: What steps has your laboratory taken to implement TQM? PMID- 10119431 TI - CLMA position on laboratory direction. Clinical Laboratory Management Association. AB - In July 1991, CLMA's National Affairs Committee (NAC) developed a proposed position statement on the laboratory director standard. The proposed statement was submitted to the 24-member National Affairs Reactor Panel and, based on their input, appropriate revisions were made. In August 1991, CLMA surveyed the full membership, and, as a result, the following position was adopted. NAC members include Royal A. Crystal, Chair; Linda D. Bielitzki, J.D., Vice Chair; Michael G. Bissell, M.D., Ph.D.; Earl C. Buck; Michael A. Maffetone, D.A.; Timothy Murray; Laurence J. Peterson; Marianne C. Watters; and Martha A. Feichter, National Affairs Analyst. PMID- 10119432 TI - Role of the RHAs (Regional Health Authorities). PMID- 10119433 TI - 'Daunting and stimulating' time for ambulance services. PMID- 10119435 TI - Sympathetic extension preserves and enhances hospital's features. PMID- 10119434 TI - Does a health service have any business in research? A comment. PMID- 10119436 TI - The revolutionary C.H.I.P.: a community health information package. PMID- 10119437 TI - The transition to Crown Health Enterprises. PMID- 10119438 TI - Challenging issues for health managers. AB - The reform of New Zealand's health system is raising a number of challenging issues for managers who will be responsible for implementing and managing change to make the market work. In this article Peter Holland, a Health Care consultant in Deloitte Ross Tohmatsu's Sydney office, who worked for some years in the British National Health Service and has had extensive hospital management experience, discusses the agenda facing health managers in New Zealand. He recently visited New Zealand and had the opportunity to discuss the detail of the reforms with representatives from several Area Health Boards. PMID- 10119439 TI - Planning Canterbury's new medium secure unit. Interview by Terry Olsen. PMID- 10119440 TI - Providing better health care. National Interim Provider Board. PMID- 10119441 TI - Who should run worksite health programmes in hospitals? AB - The authors discuss the pros and cons of having each of the following occupational groups heading a worksite health promotion in a hospital: health educators/promoters, nurses, managers, external consultants. The authors draw on recently completed research in New Zealand organisations to suggest that: 1) Health educators have the necessary diagnosing and programme planning skills, but may not have a good grasp of workplace issues and hazards; 2) Nurses have an extensive medical background, but may lack the skills of consultation and/or the ability to see worker-clients in the context of the total environment; they may be biased towards changing the individual worker rather than an unhealthy environment; 3) Managers may understand the client population at the workplace, and have the power to make comprehensive, system-wide changes, but may not have an extensive medical or health background, requiring ongoing liaison with resources that do; 4) External consultants are probably able to bring in fresh ideas borrowed from similar organisations and may have excellent initiative and coordination for recreational events. They may be expensive, and may not be familiar or powerful enough with an organisation to be able to make organisation wide changes for health. Multiple factors must be considered when a health programme leader is chosen. The situation in each organisation will require a unique blending of the roles and skills for the smoothest implementation of the programme. An example is offered of how these could come together in a hypothetical hospital situation. PMID- 10119442 TI - Christchurch's paediatric area with a difference. PMID- 10119443 TI - Politicians' role in reformed health system. PMID- 10119444 TI - Improving the competitiveness of hospitals. PMID- 10119445 TI - The measuring of work in New Zealand's public health services. PMID- 10119446 TI - Albumin audit results and guidelines for use. University Medical Center, Tucson, Arizona. AB - OBJECTIVE: To identify patients receiving albumin, develop guidelines for albumin use, and examine distribution and billing procedures. DESIGN: Case series. SETTING: Tertiary care center. PATIENTS: All patients received albumin in a four week period. Patients were identified concurrently using intensive care unit surveys and the pharmacy computer system, and retrospectively using billing statements. Data were analyzed from 73 of 79 patients (92.4 percent); 6 (7.6 percent) had no record of albumin being ordered or administered. Pediatric patient data were used only in the financial calculations. DATA COLLECTION: Demographics and albumin dosages were recorded for all patients. Prescribing service and indications for use were recorded in adults. Albumin administered was compared with the amount billed to each patient. MAIN RESULTS: Sixty adult patients aged 14-91 y (median 62) received 1-69 units (median 4 units [1 unit = 12.5 g albumin]) and 470 total units. Surgical services prescribed albumin in 73 percent and medical services in 27 percent of the patients. Common indications for albumin included volume expansion (65 percent), as intraoperative fluid (13 percent), and to increase urine output (10 percent). The pharmacy computer system identified 63 percent of the patients. Of these, 13 percent were not billed for albumin they received. Examinations of patient billing statements found that up to $17,740 a year (15 percent) of albumin administered is not billed. The floor stock distribution system used in the intensive care units contributed to most errors. CONCLUSIONS: Recommendations addressing the problems identified in this audit were made to the pharmacy, medical, nursing, and billing departments. Guidelines for albumin use were formulated and approved by the hospital's pharmacy and therapeutics committee. PMID- 10119447 TI - Grateful Med: a user-friendly, on-line literature search system. PMID- 10119448 TI - Perspectives. Minnesota aims for health care utopia. PMID- 10119449 TI - Alternative dispute resolution. New hope emerges for controlling litigation in the construction industry. PMID- 10119450 TI - Medical records automation, with a systems plan in mind. PMID- 10119452 TI - HL7 (Health Level 7). PMID- 10119451 TI - Emerging technology in health information management: integration offers total solution. PMID- 10119453 TI - Patient information standards development: a progress report from ASTM. PMID- 10119454 TI - Construction of a common clinical data catalogue. PMID- 10119455 TI - Executive information systems technology and the health information management professional. PMID- 10119456 TI - Electronic medical records and social benefit records: issues of standardization and confidentiality. PMID- 10119457 TI - Pen computing contributes to improved patient care. PMID- 10119458 TI - The human factor: ergonomics and the coding function. PMID- 10119459 TI - Busses: information flow inside a computer. PMID- 10119460 TI - The residency experience: the woman's perspective. AB - The surgical residency. Every surgeon has been through it: the long hours, the heavy caseload, the three-in-the-morning emergencies, the probing questions on rounds, the snatches of sleep in the on-call room, the physical and emotional rigors of the OR. Many surgeons characterize residency training as brutal, uncompromising, even harassing. It's no different for men or women. Or is it? PMID- 10119461 TI - The PPRC: 1992 update. PMID- 10119462 TI - Tetanus prophylaxis in the United States, 1992. PMID- 10119463 TI - The healing arts in New Orleans. PMID- 10119464 TI - The new Medicare fee schedule--Part III. PMID- 10119465 TI - Message from the President. Canada's health care facilities and agencies face a host of difficult challenges in the 1990's. PMID- 10119466 TI - Healthy hospitals: well, why not? PMID- 10119467 TI - The facility's safety net. Canadian Council on Health Facilities Accreditation. AB - The article concludes a six-part series on the first Canadian accreditation standards for governing boards of health care facilities. The preceding articles appeared in Hospital Trustee beginning January 1991. This article discusses standards VI through X, which identify the board's responsibilities for the facility's quality management, health and safety, and emergency preparedness. It is the board's role to ensure that these programs are in place and to monitor their results on a regular basis. PMID- 10119468 TI - Strong leadership is key to success. Interview by Krista Forrester. PMID- 10119469 TI - Specific board policies improve effectiveness. AB - Lay hospital boards face increasing expectations from the health care system, yet typically lack the means with which to meet these expectations effectively. The article discusses this difficulty by first describing the role of boards, their statutory obligations, and their responsibilities as identified in the 1991 Canadian Council on Health Facilities Accreditation standards. The article then describes how the board of the Matsqui-Sumas-Abbotsford General Hospital has developed specific policies to address these responsibilities and expectations. PMID- 10119470 TI - The pre-admission program: a proactive approach to management. AB - Spiralling health care costs are forcing hospital administrators to find creative alternatives to traditional health care delivery systems. One of the most recent innovations rapidly gaining favour is the pre-admission program. The article describes how a well-developed pre-admission program can have a significantly positive impact on bed utilization, diagnostic services, patient satisfaction and overall quality of care, and provides examples from a successful pre-admission program implemented at the University of Alberta Hospitals. PMID- 10119471 TI - New tools for decision making in the 1990s. AB - The article is the final installment in a three-part series describing the methods by which hospital trustees and CEO's may enable their facilities to address the health care demands of the 1990s. The first two articles appeared in CHA's Hospital Trustee in 1991. In this article, the authors identify and discuss the emerging intelligence tools which will help hospital trustees and CEO's make more effective management decisions. PMID- 10119472 TI - Doing it write: rural issues promoted in print. PMID- 10119473 TI - The Moncton Hospital's experience with workplace child care. AB - Making child care available in the workplace is a concept that is becoming increasingly popular with both employers and employees. It has particular appeal to hospital employees who work shifts or irregular hours. As a result, they often have great difficulty in finding dependable, quality child care that can accommodate their needs. In 1991, The Moncton Hospital established an in-house child care centre--the first to operate in a New Brunswick hospital. This article outlines the steps taken to make that centre a reality. PMID- 10119474 TI - Blackout! Are you prepared? AB - Mount Sinai Hospital in Toronto, Ontario, found itself stranded without electrical power for one hour when a transformer blew up in an Ontario Hydro station and hospital emergency generators failed due to inadequate ventilation. This article discusses the impact of the power loss in a facility that relies on sophisticated technology and equipment. Because the article describes the actions that were taken following the incident and presents the audit that has been developed, it may be used by other facilities to assess preparedness and develop improvement plans. PMID- 10119475 TI - Quality control for the board of directors. AB - At the Metropolitan General Hospital in Windsor, Ontario, a 69-point methodology has been developed and implemented to evaluate whether the board is discharging its principal responsibilities effectively. This process has received an initial positive assessment by the board, and its benefits to the board include clearer expectations about performance and improved information. This article describes the development and assessment of the evaluation methodology. PMID- 10119476 TI - The best in the world? PMID- 10119477 TI - The future role of the health record professional. AB - The quality, effectiveness and efficiency of health care can now be measured and monitored with information technology. This has created new opportunities and challenges for Canada's health record professionals. Recently the Canadian Health Record Association developed a new role statement to clarify and redefine the future role of the health record professional. This article describes the process used and the conclusions. PMID- 10119478 TI - Building a decision-support system. AB - To make decisions in today's dynamic health care environment, hospital managers rely on accurate and timely information--much of it compiled from hospital discharge data. For hospitals, the problem is not the lack of data but the inability to convert it to information useful to hospital management. This article describes how to build a cost-effective decision-support system that can transform HMRI (Hospital Medical Records Institute) data into a powerful management tool. PMID- 10119479 TI - Rural trustees brave the health care funding crisis. Interview by Matthew D. Pavelich. AB - Ole Ramstead, FCA, this issue's interview subject, is board chair at Parkland Regional Care Centre in Melfort, Saskatchewan. He is also a chartered accountant and income tax specialist. Mr. Ramstead discusses potential changes in Canadian health care directions--such as the amalgamation of hospital governing boards and administrations--and their special impact on rural facilities. PMID- 10119480 TI - CEO selection trends in the 1990's. AB - Amid the rapid changes in our health care system there are growing demands on executives. No one can be certain the skills demanded of a CEO in the years ahead will match those required today. In the future CEO's may have a wider range of experience and come from a more varied background than has traditionally been the case. This article will help trustees to prepare for their next CEO appointment, and will alert health care organizations to the challenges of selecting a CEO from outside the health care field. PMID- 10119481 TI - Information management: a long-term investment. AB - Conventional information processes are inadequate to meet today's health care demands. To allocate scarce resources, new approaches to information management are needed. This article explains how tapping the horizontal flow of information- across departments, services and programs--presents the greatest opportunities and challenges for health care management. New information infrastructures can integrate the entire health care system, and ultimately lead to enhanced affordability. PMID- 10119482 TI - The newest member of the senior management team. AB - The introduction and operation of an effective information system can be difficult. To meet this challenge health care organizations are beginning to add information specialists to their staff. This article describes the role of the newest member of the senior management team--the chief information officer. It details the background credentials of a good CIO and explains why the position is essential to the development and success of a comprehensive information system. PMID- 10119483 TI - Baby makers Inc. AB - The in vitro fertilization business is taking off. But is it ripe for abuse? PMID- 10119484 TI - Method for evaluating and establishing reimbursement rates for health care services authorized under the Indian Health Service contract health services regulations--selected IHS sites--IHS. Addition of sites to the IHS pilot project. AB - The Indian Health Service (IHS) issues this notice to inform the public that additional sites will be added to the IHS Pilot Project now being conducted in the Portland Area. This Pilot Project is to determine whether an alternative method of evaluating and establishing reimbursement rates for contract health services (CHS) will result in greater participation and lower cost to the IHS. The additional sites include the Alaska Native Medical Center and other selected locations within the Alaska Area IHS; the metropolitan Billings, Montana vicinity and other selected locations within the Billings Area IHS; and the Cherokee Service Unit, within the Nashville Area IHS. PMID- 10119485 TI - Medicaid program; coordination of Medicaid with Special Supplemental Food program for Women, Infants, and Children (WIC)--HCFA. Final regulations. AB - This rule requires State Medicaid agencies to coordinate the operation of the Medicaid program with the State's operation of the Special Supplemental Food Program for Women, Infants, and Children (WIC) under section 17 of the Child Nutrition Act of 1966. State Medicaid agencies also are required to notify certain individuals of WIC benefits and refer them to the local WIC agencies. This requirement ensures that all Medicaid-eligible individuals who might be WIC eligible are aware of WIC benefits and how to obtain them. The rule implements section 6406 of the Omnibus Budget Reconciliation Act of 1989. PMID- 10119486 TI - Occupational exposure to bloodborne pathogens; correction--OSHA. Final rule, correction. AB - The Occupational Safety and Health Administration is correcting errors in the regulatory text of the final rule for Occupational Exposure to Bloodborne Pathogens which appeared in the Federal Register on December 6, 1991 (56 FR 64004). PMID- 10119487 TI - Medicare program; schedule of limits on home health agency costs per visit for cost reporting periods beginning on or after July 1, 1992--HCFA. Notice with comment period. AB - This notice sets forth a revised schedule of limits on home health agency costs that may be paid under the Medicare program. This revised schedule of limits applies to cost reporting periods beginning on or after July 1, 1992. As required by section 4207(d)(3)(B) of the Omnibus Budget Reconciliation Act of 1990 (Pub. L. 101-508), this revised schedule of limits incorporates a blended hospital wage index. PMID- 10119488 TI - The control of medical devices in Canada. Canadian Society of Laboratory Technologists. AB - Medical devices should not be allowed into Canada until they have been approved by a Canadian Regulatory Agency. The approval process should be carried out expeditiously in order to ensure timely availability of medical devices to Canadians, BUT the protection of the public must always be paramount in regulatory decisions. Premarket review of devices should include: a) Testing by the manufacturer to ensure that they operate efficiently b) testing by the manufacturer to validate that they can be operated effectively by the targeted user group(s) c) review of published reports d) investigation of experience with the device in other jurisdictions, through a network of contacts with regulatory agencies in other countries e) if the agency requires it, independent testing of the device should be performed at the expense of the manufacturer Post market surveillance should include: a) adverse incident reporting by health professionals which must be confidential b) review of published reports c) ongoing review of experience with the device in other jurisdictions d) dissemination of adverse experience reports to health care professionals Availability of medical devices should be restricted to situations where they are prescribed and monitored by appropriately-trained health care professionals. The effectiveness of the existing Bureau of Medical Devices should be evaluated. Adequate resources must be provided to a Canadian Regulatory Agency to enable it to ensure that medical devices meet the public's expectations for safety and effectiveness. PMID- 10119489 TI - The greening of one lab. PMID- 10119490 TI - Laboratory workload measurement system. PMID- 10119491 TI - I'm okay--you're ok? PMID- 10119492 TI - Searching the scientific literature. AB - This article reviews three strategies for reviewing the available literature to identify relevant articles. The use of Index Medicus/Medline, Science Citation Index/SciSearch and Exerpta Medica/EMBASE is discussed, using a sample question to illustrate the process. PMID- 10119493 TI - Comparison of two rapid methods used in the identification of Haemophilus and Moraxella species. AB - Both Haemophilus influenzae and Moraxella catarrhalis cause pneumonia in children and adults. The timely isolation and identification of these two organisms is important for the initiation of antibiotic therapy. This paper compares two commercial systems with traditional biochemical methods with respect to accuracy, cost and turn-around-time. PMID- 10119494 TI - 1991 CCHFA standards and risk management: Part II. PMID- 10119495 TI - Integrating rehabilitation into the care team. AB - The role of rehabilitative services in the home has been evolutionary. From consultants to home care in the 1960s, therapists have developed into integral elements of the health care team. What issues does this pose? PMID- 10119496 TI - Physical therapy interaction in the home. AB - How can providers ensure that a client's physical therapy program is successful? With an integrated team approach--the involvement and interaction of the patient and all professional and family caregivers, who share the same clear set of objectives and procedures. PMID- 10119497 TI - The psychosocial aspects of rehabilitation. AB - Physical therapy is not only about the healing of the body; ramifications to the patient's and family's emotional and social lives also must be considered. The following case examples from Wellmark Healthcare Services, Inc. exemplify the positive results of addressing psychosocial issues in rehabilitation. PMID- 10119498 TI - Rehabilitation nursing: a curriculum for home care nurses. AB - Elderly patients look to nurses for the majority of their home care, including rehabilitative services. This model curriculum in geriatric rehabilitation nursing incorporates both clinical skills and case management and provides hands on agency experience to enhance the learning process. PMID- 10119499 TI - Building a home care therapy department. AB - Therapy services have been less visible in home care than other services, which raises the question of a serious patient need that is not being met. Agencies need to put more emphasis on therapy, including recruiting and retaining quality therapists to address community and patient needs. PMID- 10119500 TI - The Massachusetts Easter Seal Society. The first statewide nonprofit agency. AB - A home care agency with the capacity to serve people in communities all over Massachusetts seemed like an impossible dream 10 years ago. Today the Massachusetts Easter Seal Society is doing it. The reason? Need. Increasing need. PMID- 10119501 TI - Establishing standard rehabilitation evaluation forms. Arizona Association for Home Care. AB - Contract therapists work with several agencies, providing the same services to patients. Evaluation forms for these different agencies are many and varied, although the forms ask for the same information. Therapists' time would be better served--and thus so would patients--with the institution of standardized forms. PMID- 10119502 TI - The journey to quality improvement in home care. AB - In a creative approach to establishing an agency quality improvement program, the journey to excellence in home care services was enhanced by a collaborative effort between a home care vice president and a quality assurance expert. The result was a methodology that has been incorporated into a five-year commitment to a plan for quality improvement through out the agency. PMID- 10119503 TI - Forecasting the medical care costs of the HIV epidemic. AB - The 1991 average cost of treating an AIDS patient was $32,000 a year, including inpatient, outpatient, home care, and other services. The figures in this first comprehensive forecast of the cost of treating all people with HIV is relevant for the policymakers developing budgets for health services--and thus helping to shape the home care industry. PMID- 10119504 TI - Information systems help knowledge workers work even harder at productivity. AB - Information systems are here to stay, but their full benefits continue to elude healthcare users. Multimillion dollar systems--for all of their promise--tend to create more work. Some even require significant additional staffing to maintain them. How can healthcare knowledge workers measure and increase their productivity? PMID- 10119505 TI - Survey reveals portrait of today's healthcare CIO. AB - I/S executives in community hospitals across the United States have reason to celebrate! They are finally moving into the executive suite, with the titles, reporting status, staffing levels and salary to prove it. PMID- 10119506 TI - Preparing medical informaticians: a cross-disciplinary approach. AB - Information systems are a necessity in tomorrow's healthcare environment--but who will be trained to use them and use them well? A whole generation of practitioners is backing away from the challenge--how are they to become educated? PMID- 10119507 TI - Interactive videodiscs: a new approach to healthcare education. AB - Linking computer and video technology has produced a new way to educate healthcare providers. These keyboard classrooms offer faster comprehension, better retention and lower costs than most traditional methods. PMID- 10119508 TI - Federal government calls for computer-based patient records. AB - Congressional and Health and Human Services leaders are spearheading an effort to institute a nationwide electronic claims network. The ultimate result, however, could be something healthcare information system professionals have dreamed of for years--a national computer-based patient record system. PMID- 10119509 TI - Close a prison--open minds. AB - When Oakalla Prison closed in 1991, Burnaby Hospital helped stage a celebration which raised both funds and awareness of the hospital's needs. PMID- 10119510 TI - Special report on taxation. IRS issues stricter guidelines for audits of tax exempt hospitals. AB - The new audit guidelines serve as yet another reminder to tax-exempt hospitals that great care must be taken in structuring and documenting business arrangements with physicians and executives so as to withstand scrutiny by the IRS with regard to exempt status. Since increased census and utilization, and enhancement of the hospital's financial position, are no longer acceptable justifications for such activities as physician recruitment incentives (being suggestive of payment for referrals), it is important that hospitals make an effort to ensure that board minutes, recruitment policies, internal memoranda, and other documentation set forth the reasons--other than the benefits to the institution's bottom line--for having entered into such transactions. Hospitals must establish and document a community need for each physician recruited. Hospitals that actively recruit should be armed with studies evaluating recruiting needs in each clinical area, based on objective criteria, taking into consideration managed care contracting needs and the provision of services to the poor and needy. Finally, hospitals should re-examine all joint ventures and other business relationships with physicians to determine whether such arrangements resulted from arm's length negotiation, involve fair market value for goods and services, and conform, insofar as possible, with the Medicare fraud and abuse safe harbor regulations. Under GCM 39862 and the new guidelines, "aggressive" arrangements may not only create exposure under fraud and abuse laws, but could jeopardize the provider's tax-exempt status as well. PMID- 10119511 TI - The rising cost of care: a universal problem. PMID- 10119512 TI - Training tomorrow's physicians. PMID- 10119513 TI - Who's to blame for the policy gridlock in Washington? PMID- 10119514 TI - A war for cognitive services. PMID- 10119515 TI - Rising health care costs. American Society of Internal Medicine. PMID- 10119516 TI - Why do we spend so much on health care? PMID- 10119517 TI - Surfactant replacement therapy: development of criteria for appropriate use. Ohio State University Hospitals. AB - At The Ohio State University (OSU) Hospitals, DUE criteria were established when colfosceril palmitate, a synthetic surfactant, was added to the formulary in January 1991. The DUE criteria were designed to assure appropriate drug use, educate physicians, and establish an effective way to monitor drug use and patient outcome (ie, response rate and complications). The criteria include a mechanism for evaluation and modification of the guidelines, as necessary. In addition, a review process will be used to determine the therapy's cost effectiveness and to serve as a guideline for making recommendations on other surfactant formulations as they become available. PMID- 10119518 TI - Establishing a more formal adverse drug reaction reporting system. PMID- 10119519 TI - As long as it comes out all right. PMID- 10119520 TI - Outcry over outcomes. PMID- 10119521 TI - Outcomes management. The search for what works. PMID- 10119522 TI - Operational restructuring: 19 pioneering models. PMID- 10119523 TI - Executives look in the mirror. PMID- 10119524 TI - Benchmarking--targeting "best practices". PMID- 10119525 TI - Lighting the way. Part 2. PMID- 10119526 TI - Process intervention--applying TQM to clinical care. PMID- 10119527 TI - Human change by design. Interview by Joe Flower. PMID- 10119528 TI - The return of the 'white plague' revives old tuberculosis policy problems. PMID- 10119529 TI - Proposed restrictions on physician referrals to clinical labs: important areas left unclarified. PMID- 10119530 TI - Florida as health care bellwether: the state's new laws foreshadow U.S. trends. PMID- 10119531 TI - A wake-up call for systemic reform. PMID- 10119532 TI - Health insurance: partial reform or total change? PMID- 10119533 TI - Global economy pressures U.S. industry, healthcare. PMID- 10119534 TI - Removing life support: motivations, obligations. An opinion on NCCB Committee for Pro-Life Activities' statement on artificial hydration and nutrition. AB - In April 1992 the Committee for Pro-Life Activities of the National Conference of Catholic Bishops issued a resource paper titled "Nutrition and Hydration: Moral and Pastoral Reflections." At best, this document and its conclusions may be viewed as a pastoral statement, offering some tentative reasoning and conclusions to be considered in cases that concern the use of medically assisted nutrition and hydration. When discussing the question, is the withholding or withdrawing of medically assisted hydration and nutrition always direct killing? the document applies two principles--"no reasonable hope of benefit" and "involving excessive burdens." The document's crucial part is its admission that artificial hydration and nutrition may be removed without the intention of causing death, and that "this kind of decision should not be equated with a decision to kill or with suicide." The committee assigns decision-making responsibility to patients, families, and healthcare professionals, but continues its discussion for 20 pages and offers cautions conclusions concerning removal of such therapy. Two assumptions seem to underlie the document's overly cautious conclusions, the first being that mere vegetative function mandates continued life support. The first assumption overemphasizes the value of physiological functioning insofar as the purpose of human life is concerned. It also is contrary to the goal of medicine, which envisions restoration of cognitive-affective function as an element of successful therapy. The second assumption is that withdrawal of artificial hydration and nutrition from persons in PVS may lead to euthanasia. But mandating the continuation of nonbeneficial therapy simply because it prolongs physiological function seems to lead people to favor euthanasia rather than reject it.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119535 TI - Providers question PROs' effectiveness. Critics contend peer review organizations are too costly and fail to improve the quality of care. AB - The Health Care Financing Administration (HCFA) established physician review organizations (PROs) to ensure that Medicare recipients receive care that is medically necessary, of high quality, and provided in the appropriate setting. While arguing that oversight is necessary, many healthcare professionals believe PROs do not accomplish what they were set up to do because physicians focus on the possibility of being penalized rather than on improving patient care. PRO critics claim that the program's peer reviewers are not peers of the physician under review and that, to be effective, they should come from the same local area. They contend the best peer review is conducted within the hospital. They believe intrafacility review can be more effective at bringing about improvement because hospital peer reviewers act as supportive, nonthreatening consultants. The confidentiality of the physician-patient relationship is another issue PRO critics raise. HCFA staffers say hospitalized Medicare patients are required to sign a waiver allowing inspection of their charts, but critics counter that waivers are only for the release of records for payment claims. Changes encouraging cooperation between PROs and hospitals could improve the PRO program and enhance quality of care. PMID- 10119536 TI - Defining the value of community benefits. Analyzing the kinds of goods society produces clarifies hospitals' charity care contribution. AB - Community benefits occur when a hospital bears all or part of the relatively unquantifiable costs of promoting, sponsoring, or engaging in religious, educational, scientific, or health-related activities designed to improve community health. By the very nature of their health-related activities, not-for profit hospitals make extensive and varied contributions to community benefit. When a hospital free clinic inoculates a child for measles, the community as a whole benefits because the inoculation reduces the chance that measles will spread. Not-for-profit hospitals also provide many goods that are "undersupplied" by the for-profit private sector or the public sector, such as research, trauma centers used disproportionately by self-pay patients, and advocacy to rid the community of health hazards. Moreover, a number of factors impose a legal and normative obligation on not-for-profit hospitals to engage in activities that benefit the community. These include Internal Revenue Service rules governing tax exemption, hospitals' fiduciary responsibilities to philanthropic donors, their obligations as "institutional actors" in their communities, and their mission to reach out to the poor and underserved. PMID- 10119537 TI - The final chapter. Sound management procedures facilitate a hospital's closure. AB - The closure of a healthcare institution affects employees, patients, and the community. When St. Mary's Health Center, Emporia, KS, closed in 1991, those who administered the closure followed a procedure that lessened the burden on all involved. Because of the health center's deteriorating financial picture, CSJ Health System of Wichita (of which St. Mary's was a member) decided to close the facility. Once the system's board of trustees and the ordinary of the Archdiocese of Kansas City, KS (in which Emporia is located), approved the closure, facility and system leaders planned the procedures for announcing the closure and helping employees and patients through the difficult times ahead. On announcement day the CSJ Health System president and St. Mary's chief executive officer met with department heads to inform them that no new patients would be accepted and to explain the dismissal and transfer processes. Department heads were also asked to tell those they supervised about the closure and about meetings for employees later that day. Counselors were available to help department heads and employees through that emotional day and during the weeks and months ahead. Employees received packets of information describing severance benefits. Human resources personnel sponsored a job fair at which many former employees found jobs. A closing ceremony was held at a local chapel. During the ceremony employees voiced their appreciation of the way in which the closure had been completed and the openness and supportiveness of the sisters, the system, and St. Mary's administrators.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119538 TI - The case for nutritional support. Eliminating hospital-acquired malnutrition improves outcomes and reduces costs. AB - Taking steps to eliminate hospital-acquired malnutrition in patients with disease or trauma significantly improves treatment outcomes. Patients' ability to recover from trauma or illness and respond to therapy depends on how well they synthesize proteins necessary to regain homeostasis. It is possible for patients to die from complications of progressive hospital-acquired malnutrition. Hospital executives and clinical personnel must understand that timely intervention with nonvolitional feeding in appropriately selected patients will decrease morbidity and length of stay. Hospitals that ignore nutritional support therapy for patients may be in violation of quality-of-care standards. And hospitals that do not have hyperalimentation or nutritional support teams, or that have disbanded such teams for economic reasons, are putting their critically ill patients at risk for malnutrition. PMID- 10119539 TI - Rural system addresses social, economic needs. Cooperation, education, and advocacy revitalize a region's healthcare delivery. AB - In recent years leaders at Presentation Health System (PHS), Sioux Falls, SD, have expanded their mission to help strengthen local communities economically and socially. PHS now offers support to rural leaders in business, politics, and healthcare through its Center for Rural Health and Economic Development. In addition, educational outreach coordinators have created programs that address the needs of the entire rural community. To establish an effective network of services in the region, two of the system's tertiary care hospitals are collaborating to provide emergency helicopter service. These larger facilities also extend outreach services to rural hospitals and clinics. PHS assists rural hospitals in grant writing and in adapting to changing government reimbursement rules. In addition, the healthcare system coordinates a group purchasing program and a debt collection agency. An important voice for its region's healthcare needs, PHS has worked with the state of South Dakota to address problems and concerns about emergency medical services. The system also publishes Report, a quarterly newsletter that keeps rural residents abreast of healthcare issues affecting them. Two years ago, PHS's Center for Rural Health and Economic Development sponsored its first Invitational Rural Health Leadership Conference. These annual conferences bring together leaders to examine ways to improve rural healthcare delivery by strengthening the social and economic fabric of rural communities. PMID- 10119540 TI - Power, paradigm, and partnership: the three steps to change. PMID- 10119541 TI - St. John's Regional Health Center. Photographs with a personal touch create pleasant surroundings. PMID- 10119542 TI - Technology assessment and equipment planning in Kaiser Permanente, Northern California Region. AB - Hospitals face a significant challenge to select and appropriately place clinically warranted, safe, and cost-effective medical devices. To meet this challenge, the Kaiser Permanente, Northern California Region developed a comprehensive medical device technology assessment and equipment planning program. This paper discusses the structure of the program, physician leadership and accountability, the role of clinical engineers and other support personnel, and the program's influence on strategic planning and policy development. PMID- 10119543 TI - 1992 survey of salaries & responsibilities for hospital biomedical/clinical engineering & technology personnel. AB - The Journal of Clinical Engineering has conducted its seventh annual survey of the salaries paid to biomedical/clinical engineering and technology personnel in U.S. hospitals. This paper reports the salary and work responsibility data obtained from 1,482 professionals in relationship to: Certification; Region of the U.S.; Teaching versus Nonteaching Facilities; Years of Experience; Education; Union Membership; and Gender. Data are included on Wage Increases and Job Responsibilities. Data are as of 12/31/91 and are compared to 12/31/90. This year, new job categories were introduced for the overall department or group Director or Manager and the BMET Specialist. The average BMET I has 2.4 years of experience and earns $23,647 +/- $4,442 (Std. Dev.). The average BMET II has 6.6 years of experience and earns $30,128 +/- $5,696. The average BMET III has 12.9 years of experience and earns $35,855 +/- $5,942. The average BMET Specialist has 13.5 years of experience and earns $40,910 +/- $8,938. The average BMET Supervisor has 13.3 years of experience and earns $37,905 +/- $6,786. The average Clinical Engineer has 7.4 years of experience and earns $40,413 +/- $7,899. CE Supervisors have an average 12.2 years of experience and an average salary of $46,927 +/- $9,935. The overall group or department Director or Manager has 15 years of experience and earns $49,096 +/- $17,333 on average. Wages are the highest on the West Coast. This year, the lowest wages were in the Southeast. Because of survey changes in supervisor survey categories, year-to-year changes for supervisor wages cannot be evaluated. BMET wages, however, advanced 6% to 9%, year to year. The highest quartile of Director/Managers now earns between $53,000 and $245,000 per year. Certified individuals generally earn up to $3,257 more than noncertified, except for BMET Specialists where the certified respondents earned less than the noncertified. PMID- 10119544 TI - Developing analytical skills by computer. AB - Management of the health services increasingly requires a more analytical and planned approach. David Reed describes how a computer model can help managers develop the necessary skills. PMID- 10119545 TI - Implementing the post-hospital age. AB - A 650-bed teaching hospital abolished and a programme for enhancement of the role of primary health care: these are some of the organisational changes taking place in New Zealand at present. Laurence Malcolm and John Mollett report. PMID- 10119546 TI - Assessing the quality of discharge procedures for elderly people. PMID- 10119547 TI - Management ... working day of a health services manager. PMID- 10119548 TI - Putting value analysis to work for you. PMID- 10119549 TI - Infectious waste. Doing your best for the environment, your employees and your bottom line. PMID- 10119550 TI - Partnering with your suppliers. A lesson from industry. PMID- 10119551 TI - Urethral catheters. ECRI. PMID- 10119552 TI - A moral obligation to standardize? PMID- 10119553 TI - Continuous quality improvement: teams. PMID- 10119554 TI - Disinfectants. PMID- 10119555 TI - A poignant absence: sexual harassment in the health care literature. PMID- 10119556 TI - Truth's search for power in health policy: critical applications to community oriented primary care and small area analysis. PMID- 10119557 TI - Speaking in tongues: integrating economics and psychology into health and mental health services outcomes research. PMID- 10119558 TI - An institutional perspective on rational myths and organizational change in health care. PMID- 10119559 TI - Why every group needs a strategic plan. PMID- 10119560 TI - What are your greatest malpractice risks? PMID- 10119561 TI - Finding affordable health insurance for your practice. PMID- 10119562 TI - There's no quick fix for our health-care system. PMID- 10119563 TI - Get started now on your own RBRVS. PMID- 10119564 TI - This form helps patients make the hardest decision. PMID- 10119565 TI - Interactive instruments to help labs 'work smarter'. PMID- 10119566 TI - How we made the quality and quantity of applicants soar. PMID- 10119567 TI - Motivating staff: proactive and reactive techniques. PMID- 10119568 TI - Biodecontamination of a clinical laboratory. PMID- 10119569 TI - Casting your net for optimal networking. PMID- 10119570 TI - Settlement reached in suit over Ohio hospital. PMID- 10119571 TI - Healthcare credit card firm accused of fraud. PMID- 10119572 TI - Coalition seeks changes in drug price law. PMID- 10119573 TI - Charter's public after debt-stock swap. PMID- 10119574 TI - N.Y. Blues plan seeks to stave off takeover. PMID- 10119575 TI - States, federal agencies step up scrutiny of Blues plans' health. PMID- 10119576 TI - Healthcare, insurance PAC gifts show big rise. PMID- 10119577 TI - Agreement with city gives HHC (New York City Health and Hospitals Corp.) freedom. PMID- 10119578 TI - Ill. slashes data group staff budget. PMID- 10119579 TI - Takeover of Miami hospital abandoned. PMID- 10119580 TI - Number of distressed hospitals stays steady. PMID- 10119581 TI - Judge bars retroactive GME reaudits. PMID- 10119582 TI - Qual-Med poised to acquire Health Net. PMID- 10119583 TI - Mich. system awaits decision on $145 million building plans. PMID- 10119584 TI - NME sues insurers over psychiatric bills. PMID- 10119585 TI - Task force sees electronic claims hurdles. PMID- 10119586 TI - Hospital of the future. AB - It's the year 2002. How have America's hospitals changed over the past 10 years, and what are the pressing problems? Has the healthcare system been "reformed"? A special section takes a look at the issues making headlines and what one public hospital and one suburban hospital are doing to adapt to the new challenges and address the healthcare needs of their communities. PMID- 10119587 TI - HCA earnings soar in second quarter. PMID- 10119588 TI - Hospitals that develop strong group practices can help physician organizations thrive. AB - Seeking support in the face of RBRVS, physicians are demanding more support services and more cooperation from hospitals in developing pricing mechanisms for direct contracting. But organizational models intended to meet these needs won't work because of the deep chasm that typically exists between hospitals and physicians. Rather, a strong physician group practice aids in their success. PMID- 10119589 TI - Price list given antitrust clearance. PMID- 10119590 TI - Surgery center settles advertising charges. PMID- 10119591 TI - Employers more willing to trade workers' choice of providers for genuine cost containment. PMID- 10119592 TI - Program brings out medicine's human side. AB - In what may sound like a summer camp for physicians and hospital administrators, the Institute of Medicine and Humanities, located in Montana, is employing a serene setting and the works of notables such as Aristotle, Hemingway and Bergman in an innovative program designed to fill hospital corridors with greater insight into the human side of caregiving. PMID- 10119593 TI - X-ray technician error may be wasting film. PMID- 10119594 TI - Philanthropic support is built into the design of some projects. PMID- 10119595 TI - Okla. official says CEO took five free trips. PMID- 10119596 TI - GME payment plan aims to aid primary care. PMID- 10119597 TI - Qual-Med planning to sue Health Net over planned acquisition of HMO firm. PMID- 10119598 TI - House OKs $25.3 billion HHS hike, $150 million in provider user fees. PMID- 10119599 TI - N.Y. group studying effects of global budgeting. PMID- 10119600 TI - Justice Dept. grills CEOs of merging hospitals. PMID- 10119601 TI - Several Los Angeles-area projects aim to open skilled-nursing-level AIDS beds. PMID- 10119602 TI - AHA board neutral on reclassification rule. PMID- 10119603 TI - Mayo Clinic, Wisc. hospital reach agreement on merger. PMID- 10119604 TI - HCA agreement gives it preferred prices on Baxter bedside computing systems. PMID- 10119605 TI - Los Angeles County awards architectural, design pacts for $1.6 billion hospital job. PMID- 10119606 TI - Huge write-off for psychiatric operations causes NME's first quarterly loss in 6 years. PMID- 10119607 TI - 8 insurers sue NME for unneeded treatments. PMID- 10119608 TI - Creditors expect to OK Laventhol settlement. PMID- 10119609 TI - Court orders N.Y. to pay back underpayments. PMID- 10119610 TI - Labor Dept. sues Charter's chairman over sale of his family's stock to ESOP. PMID- 10119611 TI - Changes at the top point to new pressures, more caution in home healthcare industry. PMID- 10119613 TI - Administration officials begin to hit Clinton's health record. PMID- 10119612 TI - Big profit doesn't preclude exemption--Calif. court. PMID- 10119614 TI - Trauma centers are the victims in battle for scarce federal money. PMID- 10119615 TI - Public must understand basic issues before reform proceeds. PMID- 10119616 TI - Fitness campaign or fraud scheme? Postal inspector, state of California investigating promotion that may have cost hospitals $1 million. AB - The U.S. postal inspector and California authorities are investigating whether a San Francisco-based company called the National Fitness Campaign may have bilked more than 120 hospitals across the country out of nearly $1 million through a physical fitness and wellness promotion. Since 1990, scores of hospitals have paid thousands of dollars for shabby, incomplete or, in many cases, non-existent exercise equipment. PMID- 10119617 TI - Providing more than just care to neighborhoods. AB - The riots in Los Angeles focused new attention on the needs of inner cities. Many urban hospitals have played an active role in responding to and attempting to alleviate the woes afflicting cities. They've volunteered personnel and helped to develop programs ranging from job creation to property development to neighborhood beautification. Hospitals' efforts have benefited both neighborhoods and facilities. PMID- 10119618 TI - Empire Blues suing New York to obtain higher rate increase. PMID- 10119619 TI - Poor regulation, mismanagement cited in W.Va. failure. PMID- 10119620 TI - Atlanta's Grady renovating for the future. AB - Grady Memorial Hospital in Atlanta has opened a new emergency-care center, designed around a fast-track system. It's only part of a massive $318 million renovation affecting nearly every department in the public hospital. When the project is completed in 1995, it will allow Grady to meet building codes, increase its total number of beds to 1,024 and eliminate duplicative services. PMID- 10119622 TI - CHAMPUS updates mental healthcare coverage rules. PMID- 10119621 TI - Small Mass. hospital gets a big rating. PMID- 10119623 TI - Laser personalization can impact patient receivables. AB - In contrast to computer-generated form letters and data mailers, personalized letters from a laser printing source can enhance and improve the collections process. PMID- 10119624 TI - The road to capital financing. PMID- 10119625 TI - Provider Magazine surveys top 40 nursing facility chains. AB - Provider magazine's annual survey of the Top 40 nursing facility chains in the United States has found that while occupancy rates have gone up from an average of 89.4 percent in 1990 to 90.3 percent last year, total reported revenues have decreased. In 1990, reported revenues totaled $7.4 billion. Last year that figure fell to $6.9 billion. Part of the reason for the change may be the drop in the percentage of private pay residents, which fell an average of 3 percent over the last year. There was one new player in the Top 10 in 1991--VHA Long Term Care, which moved up from number 26 in 1990. Growth was reported among other Top 20 chains also, which garnered an increase in beds of nearly 12,000, to 345,142. The Forum Group jumped from number 35 in 1990 to 16 last year with an increase of more than 3,000 beds. Also of significance was a 50 percent increase in the number of companies going public, bringing the total of publicly held nursing facility corporations to 15. The new public players are Mediplex, Integrated Health Services, Inc., GranCare, Genesis Health Ventures, and Health and Retirement Corporation (HCR). PMID- 10119626 TI - Nurse education partnerships benefit facilities, colleges. PMID- 10119627 TI - Successful reimbursement systems require separating costs, goals. PMID- 10119628 TI - Preventing discrimination charges requires knowledge, preparation. PMID- 10119629 TI - Nursing intervention helps residents quit smoking. PMID- 10119630 TI - Successful activities program requires resident input. PMID- 10119631 TI - Pharmacists help identify, treat drug-related malnutrition. PMID- 10119632 TI - Adult day care serves elderly in non-residential setting. PMID- 10119633 TI - CON in the 1990s: focusing on cost cutting and innovation. PMID- 10119634 TI - AHCA (American Health Care Association) leaders look to the year ahead. AB - During the past 15 months, long term care providers have worked diligently to implement the nursing facility reform provisions of the Omnibus Budget Reconciliation Act of 1987 (OBRA). Other significant events, such as the release of final rules clarifying OBRA and state funding shortfalls, promise to keep the industry busy in the coming years. Provider interviewed leaders of the American Health Care Association (AHCA) to assess the present state of the industry and talk about the Association's goals. PMID- 10119635 TI - Program to enhance ADL skills improves resident self esteem. PMID- 10119636 TI - Today's banking relationships rely on good management. PMID- 10119637 TI - Act requires facilities to file reports on medical devices. PMID- 10119638 TI - Communication improves care for terminally ill residents. PMID- 10119639 TI - Pediatric unit helps children function at highest level. PMID- 10119640 TI - Choice: it's the resident's right. AB - Facilities nationwide are affirming the independence, respect, and autonomy of long term care residents, regardless of disability or impairment, by involving them directly in the decisionmaking process about their care and living environment. This effort toward greater resident autonomy has resulted in serious ethical dilemmas for nursing facilities. This feature explores some of those situations. PMID- 10119641 TI - OSHA training must reflect employee education, literacy levels. PMID- 10119642 TI - Streamlining PEN (parenteral and enteral nutrition) direct billing improves services, cash flow. PMID- 10119643 TI - Appropriate policies reduce risk of sex discrimination, harassment. PMID- 10119644 TI - Cooking program promotes dignity through socialization, therapy. PMID- 10119645 TI - Tuberculin skin test identifies residents with tuberculosis. PMID- 10119646 TI - Assisted living units provide increased market potential. PMID- 10119647 TI - Nursing and the future of health care: the independent practice imperative. PMID- 10119648 TI - 1992 bond defaults provide key lessons for other hospitals. PMID- 10119649 TI - Trustees explain their hospitals' mission to the federal legislature. PMID- 10119650 TI - Ethics issues in rural health care. PMID- 10119651 TI - Joint venture is practical approach to use of high-tech equipment. PMID- 10119652 TI - Openness--key to trustee bonding. PMID- 10119653 TI - AHA's Davidson on health reform. Interview by Mary Grayson. PMID- 10119654 TI - Medicaid managed care--stepping stone to health reform? PMID- 10119655 TI - Explaining the health cost story. PMID- 10119656 TI - How collaboration is influencing boards' strategic plans. PMID- 10119657 TI - Medicine by the book. A gusher of guidelines for doctors can educate patients, too. PMID- 10119658 TI - Johns Hopkins Ambulatory Care Groups (ACGs). A case-mix system for UR, QA and capitation adjustment. AB - This paper describes a new ambulatory case-mix system developed at The Johns Hopkins University and known as Ambulatory Care Groups (ACGs). ACGs categorize a person into one of 51 categories based on the diseases and conditions for which they received treatment over a period of time, such as a year. ACGs can be used to describe the "illness-burden" of a population and are up to ten times more predictive of ambulatory care resource use than age and sex alone. ACGs can be determined using a computerized "grouper" software package based on ICD-9-CM diagnosis codes and demographic information presently found in virtually all claims or encounter data systems. They were developed and tested at four HMOs and a state's Medicaid program. This paper discusses the potential application of ACGs to analysis, financing, and management of ambulatory care, specifically as it relates to utilization review (UR), quality assurance (QA) and the adjustment of capitation payment within managed care settings. PMID- 10119659 TI - High cost HMO enrollees. Analysis of one physician's panel. AB - This report examines health care costs in the panel of one HMO physician in relation to enrollee health status. High cost enrollees, 15% of the practice panel, accounted for 64% of total costs. For all 722 patients included in the study, the components of costs were: ambulatory visits, 40% of total costs; impatient care, 31%; pharmacy services, 10%; radiology services, 5%; and laboratory services, 4%. Patients with severe physical disease (8% of all enrollees) accounted for about one-third of total costs, while those with moderate physical disease (27% of all enrollees) accounted for an additional one third. Patients treated for 12 chronic conditions accounted for almost two-thirds of total costs. These conditions were (in order of the contribution of patients with each condition to total costs): hypertension, cancer, abdominal pain, heart disease, diabetes, back pain, headache, depression, arthritis, chronic obstructive pulmonary disease, fatigue, and anxiety. Enrollees treated for one or more of these 12 conditions (37% of the practice panel) accounted for 61% of the high cost enrollees and 63% of total costs. Controlling health care costs will require cost effective systems of care for these common chronic conditions. At present, HMOs typically rely on individual providers to manage these common chronic conditions on a case by case basis, rather than organizing clinic-and HMO wide systems of care. HMO research and quality improvement programs aimed at improving cost effectiveness might productively focus on how practice teams, clinics and the delivery system as a whole could improve the management of the common chronic conditions which affect high cost enrollees. PMID- 10119660 TI - Health care reform, politics, and prepaid groups. PMID- 10119661 TI - Who is responsible for health care in the nineties? PMID- 10119662 TI - A pediatric cardiac risk team. PMID- 10119663 TI - Six-week weight management program. PMID- 10119664 TI - Algorithm-based clinical quality improvement. Clinical guidelines and continuous quality improvement. AB - Evidence documenting unexplained variation in clinical practices and outcomes has led to a proliferation of clinical practice guidelines in the hope that such efforts will lead to decreased variation, improved care, better outcomes, and lower costs. At Harvard Community Health Plan we have developed a clinical guideline development effort that focuses on the development of clinical algorithms and guidelines in a quality improvement model. The formal quality improvement process that we have described requires; (1) clear project definition and organization, (2) guideline development based on an understanding of patient needs, scientific evidence and clinical experience, (3) thorough analysis of potential problems with active implementation efforts, and (4) measurement and evaluation of results. By incorporating clinical guideline development into a quality improvement model and integrating such efforts with a total quality management strategy, we can substantially increase the likelihood of successfully implementing clinical practice guidelines and improving the quality of care that we deliver. PMID- 10119666 TI - Teaching ways to measure outcome. PMID- 10119665 TI - Benchmarking: beating the best. PMID- 10119667 TI - Without CEO commitment, TQM fails. PMID- 10119669 TI - The licitness (according to Roman Catholic premises) of inducing the non-viable anencephalic fetus: reflections on Professor Drane's policy proposals. AB - James Drane's policy proposals for Roman Catholic hospitals, which would allow induction of a firmly diagnosed anencephalic fetus upon the mother's considered request, are defended. Drane's defense of his proposals, by focussing upon the empirical facts of anencephaly and attempting to abstract from the question of whether or not the anencephalic is a potential person, is held to be untenable. However, examination of the Roman Catholic proscription against abortion shows that it applies to humans who are, or might be, persons or potential persons. And the facts of anencephaly show that the anencephalic does not have the biological substrate to be a potential person. Hence the proscription does not apply to induction of the anencephalic fetus. PMID- 10119668 TI - Anencephaly and the interruption of pregnancy: policy proposals for HECs. AB - This article is directed to hospital communities where absolute proscriptions exist against abortion. The assumption is that many will be Catholic institutions and therefore Catholic moral teachings are examined carefully. By addressing anti abortion arguments in the context of anencephaly, I hope to show that within even the most conservative moral traditions, humane exceptions to absolute proscriptions against abortion can be justified. More specifically, the article is directed to HECs which either have unstated or ambiguous policies on abortion. It will attempt to show what a reasonable policy could look like and how it could be defended. For committee members not involved in policy questions about abortion, it may stimulate some ethical discussion. PMID- 10119670 TI - The health ethics network of Oregon: a model to enhance healthcare ethics committee collaboration. PMID- 10119671 TI - Due process in ethics committee case review. PMID- 10119673 TI - Special report. Convention diary: GOP gathers to renominate Bush, bash Clinton. PMID- 10119672 TI - New business for ethics committees. PMID- 10119674 TI - Operator considerations when adding an air medical program. PMID- 10119675 TI - Changing operators: are you ready? PMID- 10119676 TI - Post-traumatic stress disorder. PMID- 10119677 TI - AMPA (Air Medical Physicians Association): a new birth. PMID- 10119678 TI - Is hospital competition wasteful? AB - Recent attention has been given to the hypothesis that local hospital competition takes the form of costly duplication of specialized services--the "medical arms race." This contrasts with the hypothesis that the supply of specialized services is determined solely by "the extent of the market." We develop a model predicting the provision of specialized services in local markets. Our analysis of California hospitals provides minimal support for the medical arms race hypothesis while suggesting substantial scale economies for many services. Our results emphasize the importance of properly specifying the extent of the market. Failure to do so leads one to overestimate the importance of competition. PMID- 10119679 TI - ISDN--telecommunication in hospital. PMID- 10119680 TI - Leasing hospital roofs. PMID- 10119681 TI - A general proposition on the legionella-scalding dilemma. PMID- 10119682 TI - An updated communication system at the New Pietralata Hospital in Rome. PMID- 10119683 TI - New developments in hospital fire safety. PMID- 10119684 TI - New Age meets Hippocrates. Medicine gets serious about unconventional therapy. PMID- 10119685 TI - Medicaid program; home and community-based services waivers for individuals age 65 or older--HCFA. Interim final rule with comment period. AB - This interim final rule amends current Medicaid regulations to permit States to offer, under a Secretarial waiver, a wide array of home and community-based services to individuals age 65 or older who are determined, but for the provision of these services, to be likely to require the level of care furnished in a skilled nursing facility (SNF) or intermediate care facility (ICF) (nursing facility (NF) effective October 1, 1990). The rule allows Federal payment for these and other long term care services, up to an amount specified in section 1915(d)(5)(B) of the Social Security Act, subject to HCFA's approval of the States' requests for waivers and certain assurances made by the States. Once granted, waivers are in effect for 3 years, unless terminated by the State with notice to the Secretary, and are renewable for periods of 5 years. Periodic evaluation, assessment, and review of the care furnished under the waivers is required. This rule implements section 4102 of the Omnibus Budget Reconciliation Act of 1987, as modified by section 411(k) of the Medicare Catastrophic Coverage Act of 1988, section 8432 of the Technical and Miscellaneous Revenue Act of 1988, and section 4741(b) of the Omnibus Budget Reconciliation Act of 1990. This rule is being issued in final and, for the most part, without a delay in the effective date for the reasons explained in section IV, "Waiver of Proposed Rulemaking and Delay in the Effective Date." PMID- 10119686 TI - Use of database management software in a management information system. AB - If information is to play a useful role in the decision making process, an organization must design a system for capturing, organizing and presenting information from daily activities to its managers. Use of relational database management software to design a custom application as part of a management information system is both practical and cost effective. Designing a database management application is very challenging but well worth the effort, asserts the author of this case study. PMID- 10119687 TI - A fiduciary's guide to retirement plan management. AB - Most group practices have a retirement plan as part of their benefit package. However, groups have responsibilities well beyond funding to keep the plan qualified and in good standing with regulatory agencies. An additional complication is the federal government's frequent changes in the qualified pension laws. With these changes, compliance has become more complex and confusing. PMID- 10119689 TI - The military as a partner. AB - The Pentagon has authorized the military to contract with private medical groups to supply board certified and board eligible physicians and support personnel to military hospitals to administer specialty medical services. The arrangement, known as a partnership agreement, provides volume to the civilian medical groups and reduces military medical outlays for expensive services at civilian hospitals. This professional paper addresses the initiation, procurement, and execution of a partnership agreement. PMID- 10119688 TI - Marketing a specialty practice--a must for the '90s. AB - Although the patient is the focal point of any practice, the main marketing target of any specialty practice is the referring physician. Competition for the referred patient has become so intense that every physician must be concerned about the source of patients, retaining patients and successfully building a professional network. Increasingly sophisticated marketing strategies will be necessary for health care organizations to survive and flourish in a competitive marketplace. PMID- 10119690 TI - Comprehensive clinical pharmacy documentation in an out-patient cancer facility. AB - Clinical pharmacy activities that affect patient outcome are a high priority in pharmacy practice. A relatively simple method of documentation for analysis of these clinical pharmacy activities in an out-patient oncology setting is described. Policies and procedures for clinical pharmacy activities were developed and formalized in an effort to standardize pharmaceutical care in the cancer facility. Consultations or drug information questions originating outside the pharmacy, as well as interventions initiated by a pharmacist were all documented on a comprehensive activity form on a daily basis by each pharmacist. All medication counseling sessions by a pharmacist were also recorded. During a 12 month study period, a total of 1828 activities were recorded. Of these, 343 (18.8%) were pharmacist-initiated interventions to drug therapy. Recommendations were accepted by physicians in 293 (85.4%) of these interventions. In 125 (36.4%) cases, potentially serious negative patient outcomes were avoided by this clinical pharmacy activity. PMID- 10119691 TI - Clinical pharmacy services provided to an emergency department. PMID- 10119692 TI - Employee assistance programs: an employer's guide to emerging liability issues. AB - Increasing numbers of employers are implementing employee assistance programs (EAPs) designed to assist employees with personal issues that affect their work performance. Studies show that EAPs can dramatically increase employee productivity, but the benefits from EAPs have been accompanied by a less welcome development: lawsuits filed against employers by employees who allege that they suffered harm in the course of obtaining services through their employers' EAPs. Although the potential for liability will always exist, the employer that adheres to certain guidelines will be able to minimize its risk and make its EAP well worth the investment. PMID- 10119693 TI - Rules of the road in dealing with personnel records. PMID- 10119694 TI - The dilemma: what is an "appropriate" disinfectant according to OSHA's occupational bloodborne pathogens standard? PMID- 10119695 TI - Viral hepatitis risks. PMID- 10119696 TI - Making a chef a valuable staff resource. PMID- 10119697 TI - A foodservice challenge: AIDS education. PMID- 10119698 TI - Hospital foodservice: under examination. AB - FM recently talked with several foodservice directors facing the growing demands for cost reduction and improved quality. In this issue are case studies of some of the innovative approaches that are being used in this time of unprecedented change. PMID- 10119699 TI - Downsizing dramatically at the Institute of Living, Hartford, CT. PMID- 10119700 TI - Adding services, not staff at HCA Wesley Medical Center, Wichita, KS. PMID- 10119701 TI - Doing a lot with a little at St. Mary's Hospital, West Palm Beach, FL. PMID- 10119702 TI - Targeting patient satisfaction at ARA Healthcare Nutrition Services accounts. PMID- 10119703 TI - Leaping labor hurdles at Veterans Affairs medical centers. PMID- 10119704 TI - Passing an inspection at Cooper Hospital University Medical Center, Camden, NJ. PMID- 10119705 TI - FDA in the global village. PMID- 10119706 TI - The not-so-routine physical. PMID- 10119707 TI - Finding new ways to sell more. PMID- 10119708 TI - Welfare gains from user charges for government health services. AB - The World Bank's Financing health services in developing countries emphasizes demand-side issues--highlighting user fees, insurance, and the private sector as tools for strengthening the health sector. That approach is a major departure from the focus on the supply side--public sector spending, costs, management, and efficiency--that has dominated the international health finance agenda for many years. An important set of empirical papers by Paul Gertler and his co-authors coincided with the release of the policy paper. Gertler's work has questioned a policy of greater dependence on user fees by emphasizing the potential welfare costs to consumers of higher fees for medical services. Many health professionals have adopted the jargon of this new approach without understanding the underlying analysis. This article attempts to demystify the debate that has ensued by illustrating economists' idiosyncratic approach to welfare, explaining how the policy paper and Gertler differ, and suggesting alternative approaches to testing the feasibility of the policy paper's prescriptions. PMID- 10119709 TI - Are we ignoring population density in health planning? The issues of availability and accessibility. AB - Availability of health facilities is commonly expressed in terms of the number of persons dependent on one unit. Whether that unit is actually accessible to those persons depends, however, on the population density. Some examples illustrate the precise relationship. A measure of accessibility is obtained by expressing the availability of facilities as 'one unit within x km distance' (for the average- or, preferably, the median--person). This measure is therefore to be preferred. PMID- 10119710 TI - Are you a strategist or just a manager? AB - Perhaps the greatest strategist of all time was not a business executive but a general. Helmuth von Moltke, chief of the Prussian and German general staffs from 1858 to 1888, issued "directives" to his officers rather than specific commands. These guidelines for autonomous decision making encouraged Moltke's subordinates to show individual initiative. In this article, Hans Hinterhuber and Wolfgang Popp translate Moltke's example into business terms. According to Moltke, strategy is applied common sense and cannot be taught. The authors suggest that good entrepreneurs and managers--along with generals--are born with the qualities that make them successful. But even if managers have the potential to be good strategists, they must develop and hone their natural talents. And CEOs and top management can help by identifying and promoting such talents in their employees. Hinterhuber and Popp have created a questionnaire that helps measure strategic management competence. Managers and entrepreneurs take this test themselves, answering ten questions such as, "Do I have an entrepreneurial vision?", "Do I have a corporate philosophy?", and "Do I have competitive advantages?" Using the questionnaire, company management can evaluate managers being considered for a promotion. At the same time, those who take the test can use it to determine their own performance as strategists. Strategic managers provide subordinates with general guidelines, just as Helmuth von Moltke issued directives to his officers. And outstanding entrepreneurs create a corporate culture in which their vision, philosophy, and business strategies are implemented by employees who think independently. PMID- 10119711 TI - British privatization--taking capitalism to the people. AB - From 1983 to 1986, John Moore served in the Thatcher government in Britain, launching that country's privatization program. In "British Privatization--Taking Capitalism to the People, " he describes the thinking behind privatization, the objections raised against it, and the actual measures taken to implement it. With privatization, corporate performance has improved and the government has been able to focus on regulation, not ownership. But in the end, says Moore, the greatest success of British privatization was that it transformed the public's attitude toward ownership and economic responsibility. PMID- 10119712 TI - Does the Baldrige Award really work? PMID- 10119713 TI - The case of the unpopular pay plan. AB - Three years after launching the team-based Quality For All program, Top Chemical Company CEO Sam Verde was searching for a team-based compensation system that would reflect his company's new philosophy. With a committee gathered to discuss the issue, Verde confronts the fact that changing pay plans is an issue few people can agree on. "Very simply," explains vice president for compensation Gilbert Porterfield, "the plan is designed to give employees working on teams real incentives for constant improvement and overall excellence. The variable aspect of the system pays employees for the performance of their group." This doesn't sit well with the others. "It's going to punish teams like mine for the failings of others instead of rewarding us for the work we do and have already done," says packaging team representative Ruth Gibson. Another committee member feels that team-based anything is a "motivational happy land that doesn't square with how people really work." While Verde likes the proposed pay plan, he has doubts over whether his employees will accept the risk. Upper management has no problem basing 60% of its pay on TopChem's performance. But getting line employees to risk part of their salaries--even as little as 4%--on the ups and downs of the chemical industry may be more trouble than it's worth. Four experts on compensation reveal where Top Chemical went wrong in its plan and how Sam Verde might bring about change successfully. PMID- 10119714 TI - The balanced scorecard--measures that drive performance. AB - Frustrated by the inadequacies of traditional performance measurement systems, some managers have abandoned financial measures like return on equity and earnings per share. "Make operational improvements and the numbers will follow," the argument goes. But managers do not want to choose between financial and operational measures. Executives want a balanced presentation of measures that allow them to view the company from several perspectives simultaneously. During a year-long research project with 12 companies at the leading edge of performance measurement, the authors developed a "balanced scorecard," a new performance measurement system that gives top managers a fast but comprehensive view of the business. The balanced scorecard includes financial measures that tell the results of actions already taken. And it complements those financial measures with three sets of operational measures having to do with customer satisfaction, internal processes, and the organization's ability to learn and improve--the activities that drive future financial performance. Managers can create a balanced scorecard by translating their company's strategy and mission statements into specific goals and measures. To create the part of the scorecard that focuses on the customer perspective, for example, executives at Electronic Circuits Inc. established general goals for customer performance: get standard products to market sooner, improve customers' time-to-market, become customers' supplier of choice through partnerships, and develop innovative products tailored to customer needs. Managers translated these elements of strategy into four specific goals and identified a measure for each. PMID- 10119715 TI - Successful change programs begin with results. AB - Most corporate improvement programs have a negligible impact on operational and financial performance because management focuses on the activities, not the results. By initiating activities-centered programs, such as seven-step problem solving, statistical process control, and total quality management training, managers falsely assume that one day results will materialize. But because there is no explicit connection between action and outcome, improvements seldom do materialize. The authors argue for an alternative approach: results-driven improvement programs that focus on achieving specific, measurable operational improvements within a few months. While both activity-centered and results-driven programs aim to strengthen fundamental corporate competitiveness, the approaches differ dramatically. Activity-centered programs rely on broad-based policies and are more concerned with time-consuming preparations than with measurable gains. Results-driven programs, on the other hand, rely on an incremental approach to change, building on what works and discarding what doesn't. As a result, successes come quickly, and managers build their skills and gain the support of their employees for future changes. Because results-driven improvements require minimal investment, there is no excuse for postponing action. Indeed, there is always an abundance of underexploited capability and dissipated resources within the organization that management can tap into to get the program off the ground. The authors give a few pointers for how to get started: translate the long-term vision into doable but ambitious short-term goals; periodically review strategy, learning from both successes and failures; and institutionalize the changes that work and get rid of the rest. PMID- 10119716 TI - U.S. industrial policy: inevitable and ineffective. AB - In the realm of political economy, much of the 1980s in the United States was spent debating the pros and cons of industrial policy. According to Kevin P. Phillips, the debate is now over. Regardless of who wins the 1992 presidential election, the United States will have some kind of industrial policy--but not the one it needs. In "U.S. Industrial Policy: Inevitable and Ineffective," Phillips details the economic and political forces that are propelling the U.S. toward industrial policy--and the forces that will keep the policy from being effective. PMID- 10119717 TI - CEO pay: how much is enough? PMID- 10119718 TI - The case of the combative CFO. AB - Minute Publishing Chairman and CEO Neil Harcum has a right to be proud of his new national newspaper, America Today. It has won three Pulitzer Prizes and attracted one million readers in just three years of publication. But, as CFO Peter Rawson points out, it's also losing $100 million a year and has broken Minute's 20-year string of earnings gains. In the process, the company has been split between two warring factions: one is backing Harcum and favors continuing the paper. The other agrees with Rawson that the project must be stopped. The board of directors has been assembled to decide the newspaper's fate. In his speech to the board, Rawson says it's time to cut Minute's losses and put an end to America Today. And Wall Street agrees. Several brokerage houses have taken Minute off their buy lists, and rating agencies are about to down-grade the company's debt. "America Today is not a good investment," Rawson argues. "Certainly, it isn't in keeping with our commitment to deliver maximum value to our shareholders." But Harcum thinks Rawson is way out of line. "We cannot allow our bean-counters to set policy," he claims. Harcum sees the newspaper as a product of the future that has created its own market. It's only a matter of time before America Today attracts enough advertising to put it in the black. He has a successful track record, and he doesn't want the board to lose faith in him now.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119719 TI - Nothing prepared me to manage AIDS. AB - Articles and seminars about AIDS in the workplace are not adequate preparation for the genuine problems faced by actual managers in real organizations. There are no easy, win-win solutions to the impossible dilemmas AIDS presents, only various forms of damage control and, at best, more or less humane compromises. Gary Banas knows. Over a period of four years, two of his direct reports developed AIDS, and he watched them suffer through debility, slowly deteriorating performance, and eventual death. He also watched the gradual decline of their subordinates' productivity and morale. He found that, to different degrees, both men refused to acknowledge their illness and their decreasing organizational effectiveness. One of them resisted the author's efforts to give him an easier job at no loss in salary. Both insisted on confidentiality long after the rumor mill had identified their problem. In the course of these two consecutive ordeals, Banas discovered that AIDS patients fall into no single, neat category. AIDS is not an issue but a disease, and the people who get it are human beings first and victims second. He also learned that AIDS affects everyone around the sick individual and that almost every choice a manager makes will injure someone. Finally, he came to understand that while managers have an unequivocal obligation to treat AIDS-afflicted employees with compassion and respect, they have an equally unequivocal obligation to keep their organizations functioning. "Don't let anyone kid you," Banas warns. "When you confront AIDS in the workplace, you will face untenable choices that seem to pit your obligation to humanity against your obligation to your organization.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119720 TI - The "barbarians" in the boardroom. AB - According to conventional wisdom, the corporate raiders and buyout specialists who flourished in the 1980s were the antithesis of good management. Their goals of realizing quick profits from the acquisition of major companies--frequently through rapid cost-cutting and the breakup of conglomerates--made them the bane of old-school corporate leaders. Long-term management, it seemed, was being sacrificed on the altar of short-term profits. With the abatement of takeovers in recent times, top corporate managers have hailed a return to business-as-usual. But the takeover artists have not, in fact, retreated. Instead, these corporate acquirers, many of whom own large stakes in major industrial companies, are assuming board seats and switching their emphasis to overseeing the companies they control--with an eye toward the long term. In this new role, the takeover experts are not plunderers, nor are they creating quick profit at the expense of companies' long-term health; rather, they are defying expectations and, in a number of important respects, successfully implementing the agenda of the gurus of good management. Setting the pace in this new arena is the most powerful takeover group of the 1980s, the leveraged buyout firm of Kohlberg Kravis Roberts & Company. KKR's partners hold board seats at nine different companies with $1 billion a year or more in sales.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119721 TI - High-performance marketing: an interview with Nike's Phil Knight. Interview by Geraldine E. Willigan. AB - Nike's advertising slogans--"Bo Knows," "Just Do It," and "There Is No Finish Line"--have moved beyond advertising into popular expression. Its athletic footwear and clothing have become a piece of Americana. Its brand name is as well known around the world as IBM and Coke. Behind the slogans and the flashy TV commercials is the vision of its founder, chairman, and CEO, Phil Knight. Since forming the company in 1962, Knight has taken Nike from a small-time distributor of Japanese track shoes to the top of the athletic shoe and apparel market. But not without a stumble. Along the way, Knight discovered that technological innovation alone could not continue to drive growth. When sales stagnated in the mid-1980s, Knight and Nike learned several hard lessons on how to build brands and understand consumers, and they transformed their technology company into a marketing company whose product is its most important marketing tool. "Ultimately," says Knight, "we wanted Nike to be the world's best sports and fitness company. Once you say that, you have a focus. You don't end up making wing tips or sponsoring the next Rolling Stones world tour." To keep the company growing, Nike began splitting its brands into sub-brands. In tennis, Nike divided its shoes into Challenge Court--for younger, more active players--and Supreme Court--for older, more mature players. That approach brought the company to a broader range of consumers while preserving the customer base. And to create an emotional tie with the consumer, Nike started advertising on TV. "Sports is at the heart of American culture," Knight says. "You can't explain much in 60 seconds, but when you show Michael Jordan, you don't have to. It's that simple." PMID- 10119722 TI - Two hospitals win in district courts in infant abduction suits. PMID- 10119723 TI - Growing role for security dept in hospitals seen by new IAHSS president. International Association for Healthcare Security and Safety. PMID- 10119724 TI - Experts warn: bombings and bomb threats may be entering new phase. PMID- 10119725 TI - Hospitals warned about need to protect lab blood supplies. PMID- 10119727 TI - Team spirit. PMID- 10119726 TI - Healthcare in Europe: Greece. Achilles' heel. PMID- 10119728 TI - The missing link. PMID- 10119729 TI - More luck than judgement. PMID- 10119730 TI - North by northeast. PMID- 10119731 TI - EEEAAR ache. PMID- 10119733 TI - Facilities management. The outsourcer's guide to the galaxy. PMID- 10119732 TI - Soma care. PMID- 10119734 TI - Facilities management. Space: the final frontier. PMID- 10119735 TI - Therapeutic heparin monitoring service in a small community hospital. AB - Upon the request of members of the medical staff, the Pharmacy and Therapeutics Committee at Tawas St. Joseph Hospital began monitoring patients receiving full dose continuous intravenous heparin therapy. Problems were noted in the usage of activated partial thromboplastin times and the resultant changes in heparin therapy. The problems identified during this quality assurance activity were addressed by a heparin protocol developed by a clinical pharmacist. The protocol includes giving patients a heparin loading dose of 50-100 units/kg actual body weight, an initial infusion rate of 15-20 units/kg/hr, and drawing the first activated partial thromboplastin time 6 hours later. After the results of the activated partial thromboplastin times are known, the protocol provides for further patient management and changes in infusion rates, if needed. A review of the heparin protocol use at 6 months after initial implementation, and 6 months after minor changes in the protocol, showed that clinical pharmacists improved heparin therapy in the patients they treated. Pharmacists used larger initial continuous infusion rates, less activated partial thromboplastin times during treatment, and patients they managed reached therapeutic activated partial thromboplastin time ranges earlier than patients treated by physicians. When voluntarily prescribed by physicians, full-dose continuous intravenous heparin therapy initiated and monitored by clinical pharmacists improved the quality of patient's anticoagulation treatment during hospitalization. PMID- 10119736 TI - Quality assurance for home parenteral and enteral therapy. PMID- 10119737 TI - Patient dumping by specialized care facilities: compliance efforts riddled with uncertainties. PMID- 10119738 TI - New 'right to die' regulations give health care industry little guidance. PMID- 10119739 TI - New diagnostic center brings radiology, lab services into the '90s. PMID- 10119740 TI - Health care construction. Do you need a project manager? PMID- 10119741 TI - Health care construction. Which approach should you take? PMID- 10119742 TI - Health care construction. Which architect should you pick? PMID- 10119743 TI - Health care construction. How does the process work? PMID- 10119744 TI - Health care construction. What about cost control/budgets? PMID- 10119745 TI - Health care construction. What about the cost of materials? PMID- 10119746 TI - Health care construction. How do you stay on schedule? PMID- 10119747 TI - Experience key to compliance-consultant choice. PMID- 10119748 TI - Modular option offers fixed-price speed, flexibility. PMID- 10119749 TI - Realistic goals key to big construction cleanup. PMID- 10119750 TI - Renovation work makes up 72% of 1991 projects. PMID- 10119751 TI - Self-perceived competence of Canadian public health nutritionists. AB - This study investigated the self-perceived competence of public health nutritionists employed in provincial and municipal/regional departments of health in Canada. One hundred and fifty-three (78%) of all eligible Canadian public health nutritionists responded to a mailed questionnaire. Nutritionists were asked to rate their level of competence on 10 competency scales and to indicate sources of their knowledge and skill development. Respondents gave the highest ratings to their interpersonal and communication skills and the lowest ratings to their research and information management abilities. T-tests showed that nutritionists who had completed a postgraduate degree felt significantly more competent in their managerial and administrative (p less than .05), organizational (p less than .01), program planning/evaluation (p less than .001), research (p less than .001), and supervisory/leadership/facilitating skills (p less than .05) than those with only a bachelor's degree. One-way ANOVA revealed significant effects of geographical location for eight competency scales. The results of this study identify continuing education needs and have implications for the graduate education of public health nutritionists. PMID- 10119752 TI - Organizational culture: does it affect employee and organizational outcomes? AB - This study determined the type of organizational culture (bureaucratic, innovative, or supportive), and determined the relationships among organizational commitment, and behavioural outcomes (turnover, absenteeism, and productivity) in hospital foodservice departments. The sample included 423 foodservice employees from nine hospitals in eastern Canada and nine hospitals in East Tennessee. Two research instruments were used for data collection. The historical data instrument, completed by the department director, obtained data to calculate productivity, turnover, and absenteeism rates. The four-part employee instrument included the 24-item Organizational Culture Index, the 15-item Organizational Commitment Questionnaire, five questions to determine perceptions of job satisfaction, and demographic items. Multiple linear regression analysis tested relationships among variables. The predominant culture was bureaucratic (14.9 +/- 4.3 of a possible 24). Means were lower for innovative (13.2 +/- 4.3) and supportive (12.7 +/- 5.0) cultures. Supportive and innovative cultures had positive relationships with both job satisfaction and organizational commitment. Organizational culture was not related to turnover, absenteeism, or productivity. Mean productivity was 3.8 +/- 3.2 meals per labour hour, ranging from 0.8 to 15.1. Employees rated satisfaction with co-workers highest, and satisfaction with pay lowest. These findings will help hospital foodservice managers understand the relationship of culture to organizational and employee outcomes; changing culture may improve desired outcomes. PMID- 10119753 TI - Weight control counselling in children: is it effective? AB - This study evaluates the results of weight control/obesity counselling in the outpatient nutrition clinic of a children's hospital. Using a retrospective design, 96 randomly selected patients referred to the clinic were followed for up to four years using their hospital charts or through information obtained from the referring physician on current weights and heights. At initial assessment, 87 of 96 (91%) children were classified as obese or severely obese at greater than 120% of their Ideal Body Weight (IBW); eight other children would be classified as overweight and one child was within normal weight for height. Forty-nine referrals (51%) did not return for a follow-up visit after the initial assessment; weights were available on 18 (37%). On follow-up of 65 patients; 8% of patients achieved an IBW; a further 34% lost weight; 46% gained weight; and 12% maintained their weight. There was no difference in weight gain or loss by amount of participation in the program or by age or gender. We conclude that the weight control/obesity counselling program in our hospital is ineffective. A multidisciplinary program, based on a nutrition education theory and which includes an evaluation framework and addresses reasons for attrition and family needs, should be developed. PMID- 10119754 TI - Facilitating practice-based research in clinical nutrition. AB - This paper presents observations on the main difficulties and areas of concern in doing practice-based research for dietitians in one teaching hospital and suggests strategies that may support practice-based research in clinical nutrition. PMID- 10119756 TI - The impact of physician characteristics in conditional choice models for hospital care. AB - Recent research has investigated the determinants of the specific hospitals to which patients are admitted. Data limitations have led researchers to examine the effects of patient and hospital characteristics while ignoring the role of physician characteristics. In this study we analyze the effects of all three sets of factors on hospital choice in the greater Phoenix area during 1989. Our results suggest that physician characteristics are strong determinants of hospital choice, accounting for much of the explained variation. Differences in hospital quality and cost, on the other hand, exert significant effects on hospital choice but explain relatively little variation. PMID- 10119755 TI - A risk-based prospective payment system that integrates patient, hospital and national costs. AB - We suggest that a desirable form for prospective payment for inpatient care is hospital average cost plus a linear combination of individual patient and national average cost. When the coefficients are chosen to minimize mean squared error loss between payment and costs, the payment has efficiency and access incentives. The coefficient multiplying patient costs is a hospital specific measure of financial risk of the patient. Access is promoted since providers receive higher reimbursements for risky, high cost patients. Historical cost data can be used to obtain estimates of payment parameters. The method is applied to Medicare data on psychiatric inpatients. PMID- 10119757 TI - An econometric analysis of health care expenditure: a cross-section study of the OECD countries. AB - This paper is an empirical examination of the determinants of aggregate health care expenditure. The paper presents a systematic analysis of relationships across 19 OECD countries, showing the effects of aggregate income, institutional and socio-demographic factors on health care expenditure. The results indicate that institutional factors of the health systems, in addition to per capita Gross Domestic Product (GDP), contribute significantly to the explanation of the health care expenditure variation between countries; for example the way physicians in outpatient care are paid, and the mixture of public/private funding and inpatient/outpatient care. PMID- 10119758 TI - An alternative framework for evaluating welfare losses in the health care market. AB - A recurring theme in the health economics literature is that 'excess' health insurance reduces society's welfare. This proposition is considered to be a truism by most health economists. Feldman and Morrisey (1990) report that two thirds of American and Canadian health economists surveyed agree with the statement that, 'the level and type of health insurance held by most U.S. families generate substantial welfare loss due to over-consumption of medical services'. Consequently, most research in the area has attempted to identify the exact dollar value of this welfare loss. In this note, I will try to show that the traditional method of calculating welfare losses from excess health insurance is severely flawed because it is based on assumptions about consumer behavior that are not supported by the available empirical evidence. Furthermore, the methodology masks other, potentially greater societal welfare losses that are likely to exist in the health care sector, and blinds us from seeking the most effective public policy remedies. This note suggests an alternative framework for considering welfare losses based on researchers' evaluations of medical necessity. PMID- 10119759 TI - Utilisation as a measure of equity by Mooney, Hall, Donaldson and Gerard. PMID- 10119761 TI - Entrance and exit of obstetrics providers in rural Alabama. AB - In Alabama between 1985 and 1989, a total of 94 physicians outside of the four largest cities in the state dropped the obstetrics portion of their practices or left practice in their communities altogether. During the same period 82 physicians entered obstetrics practice in this area. The study presented here used survey and archival data to compare practice characteristics of generalists and specialists in rural and town counties who made different decisions about providing obstetrics care. More generalists left and more specialists entered practice both in town and in rural counties. Rural counties lost more obstetrics providers because more generalists provided the obstetrics care in these areas. Across both specialty and county categories, physicians in group practice who accepted Medicaid and had local access to larger numbers of patients were more likely to remain or begin new obstetric practices. During this period, some obstetrics specialists moved into rural communities that had previously supported only generalist physicians. These findings suggest that the options for organizing successful obstetrics practices have narrowed, putting solo and generalist physicians who operate small-scale obstetrics practices at a disadvantage. These physicians also face competition from obstetrics specialists who are beginning to enter practice in the rural areas of the state. Designing policies that effectively improve geographic access to care requires a realistic understanding of the practice constraints faced by obstetrics providers. For example, as centralized specialist group practices serve residents from surrounding rural areas, programs that facilitate linkages, such as satellite clinics and use of mid-level practitioners, can be promoted.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119760 TI - Geographic barriers to child health services in rural northern New England: 1980 to 1989. AB - Despite substantial recent increases in the number of rural physicians, it is unknown whether rural children still face significant barriers to medical care. To address this question, we determined travel times in 1980 and in 1989 to child health services for the rural pediatric population of northern New England--the area with the highest per-capita primary care physician supply of any non metropolitan region in the United States. The study population in 1989 included 363,443 children living in 936 nonmetropolitan towns. The study revealed important spatial relationships in health service supply and demand not identified using other methods of assessing physician availability. Although travel times to physicians decreased slightly during the decade, we found that 15.5 percent of the children in our population were more than 30 minutes from pediatricians in 1989, and travel time to emergency rooms was more than 30 minutes for 9.9 percent of the children. In contrast, only 1.8 percent of children faced excessive travel times to family/general practitioners. While towns with pediatricians were likely to also have a family physician or an emergency room, the majority of towns with family physicians had neither a pediatrician nor an emergency room. Towns with poor geographic access to pediatricians and emergency rooms had low population densities and were distant from metropolitan areas. The analysis indicates that even in rural areas of high physician supply, access to pediatricians and emergency rooms for many children remains limited, and family physicians are the dominant medical providers for children.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10119762 TI - Small rural hospitals with long-term care: 1983 to 1987. AB - Rural hospitals were under tremendous stress in the 1980s, as evidenced by decreasing use and closures. Rural populations increased in the two proportions of people older than 65 years relative to urban areas. Rural communities had more chronically ill residents than urban areas. Population aging and hospital stress have opened an option for small rural hospitals to develop long-term care units. Analysis of a national cohort of 750 small rural hospitals was undertaken in 1983, 1985, and 1987 to identify the characteristics of these hospitals, their communities, and the relative contribution of the small rural hospital to long term care bed supply. Hospitals more likely to have long-term care during this period of time had lower occupancy rates and higher expenses per admission both prior to and after developing long-term care. While only 14 percent of the 750 hospitals studied had long-term care, they contributed nearly 30 percent of the total long-term care bed supply in their counties. Population-based need and bed supply measures were not significantly different in counties having a small rural hospital with long-term care. Areas of further analysis of the small rural hospital as a resource for long-term care are suggested. The implications for the health care system of small rural hospitals with long-term care are discussed. PMID- 10119763 TI - Maternal care coordination for migrant farmworker women: program structure and evaluation of effects on use of prenatal care and birth outcome. AB - Nearly three fourths of the migrant farmworkers in the U.S. are Hispanic. Cultural and social barriers, along with constant travel, make coordination of care a significant concern for migrant health centers providing perinatal services to female farmworkers. As part of a demonstration project, a migrant specific maternal care coordination program was developed that used bilingual staff, outreach services, lay health advisers, and a multistate tracking system. Following the initiation of the project, first-trimester entry into prenatal care and number of prenatal visits increased over a five-year period among the target population. Successful tracking methods provided outcome data on more than 80 percent of participants during the project period. The results of this study suggest that migrant health centers should focus on employing public health oriented bilingual or bicultural health professionals and that an outreach strategy must be an integral part of a health care delivery system serving migrant farmworkers. Without these key ingredients, health care services will not be accessible or acceptable for this hard-to-reach population. Collaboration among the National Migrant Resource Program, the Migrant Clinicians Network, and the National Perinatal Association can facilitate development of a regionwide perinatal service system for female migrant farmworkers. PMID- 10119764 TI - Multihospital system affiliation as a survival strategy for rural hospitals under the prospective payment system. AB - The introduction of Medicare's Prospective Payment System (PPS) has disproportionately increased financial pressures on rural hospitals and posed challenges to the survival of these institutions. Increasingly, rural hospitals are seeking strategies that can enhance their chances for survival in a turbulent and hostile environment. This study examined the survival effects of one such strategy, multihospital system affiliation. Specifically, we assessed: (1) whether and how different types of system affiliation in the post-PPS era affect the likelihood of rural hospital survival; (2) whether particular structural, environmental and hospital performance characteristics moderate the effects of system affiliation on rural hospital survival; and (3) whether systematic selection by rural hospitals into multihospital systems potentially accounts for observed relationships between system affiliation and survival. Proportional hazards analyses indicate that system affiliation with investor-owned systems significantly reduces survival probabilities of rural hospitals. Affiliation with not-for-profit systems or system affiliation under contract management arrangements does not affect survival probabilities of rural hospitals. These general findings are moderated by the effects of hospital ownership and size at the time of affiliation. Finally, study findings indicated that systematic selection by poor performing rural hospitals into investor-owned systems has occurred in the post-PPS era. No evidence of selection into not-for-profit systems was discovered. PMID- 10119765 TI - A transformation within the welfare state. PMID- 10119766 TI - Calif. budget crisis blamed for Ch. 11 filing. PMID- 10119767 TI - Moody's reviewing NME debt for possible rating downgrade. PMID- 10119768 TI - AHA's quality project is terminated. PMID- 10119769 TI - Coalition begins discussions on new N.J. payment system. PMID- 10119770 TI - Judge gives Calif. partial victory in OBRA suit. PMID- 10119771 TI - House bills would restore separate EKG payments. PMID- 10119772 TI - Ruling made in Virginia dispute over waiting lists for donor hearts. PMID- 10119773 TI - Special legislative panel in Texas won't conduct public hearings. PMID- 10119774 TI - Western N.Y. Blue Shield to merge with Blue Cross. PMID- 10119775 TI - Sacramento facility pursuing affiliation. PMID- 10119776 TI - Two Southern Calif. hospitals won't encounter Justice Dept. challenge to merger plans. PMID- 10119777 TI - Proposed changes in bylaws upset hospital's medical staff. PMID- 10119778 TI - Rejection of Oregon plan appears to diminish chances for state reform initiatives. PMID- 10119779 TI - Medicaid drug price requirement hurts public hospitals. PMID- 10119780 TI - Senate panel kills plan to add more preadmission services to hospitals' PPS payments. PMID- 10119781 TI - JCAHO undercutting role of safety management, life safety. PMID- 10119782 TI - Competition getting rough in rehab. AB - It's becoming showdown time in more markets as not-for-profit hospitals face new competitors for rehabilitation patients--the large, investor-owned rehab chains. Not-for-profits argue the chains are adding unneeded beds and that their admission decisions focus only on the insured. The chains defend their record of indigent care and say they're not in the habit of building unnecessary facilities. PMID- 10119783 TI - Fewer hospitals giving helicopters a whirl. AB - The number of hospital helicopter programs--often viewed as prestigious flying billboards and initially considered an effective way to fill beds--is hovering or even descending as more hospitals decide to consolidate or ground their programs. They often have sky-high costs without matching revenues, and even the publicity they generate can land a hospital in trouble. PMID- 10119784 TI - Smaller, struggling HMOs lure suitors. AB - It's becoming a buyers' market again for managed-care companies on the prowl for strategic acquisitions. In the coming months, more operators of multimarket prepaid health plans are expected to feast on smaller, usually undercapitalized health maintenance organizations that may not be able to raise premiums high enough to offset next year's expected rises in medical costs, analysts said. PMID- 10119785 TI - FDA considering new rules that may clamp down on early showings of works in progress. PMID- 10119786 TI - Mass. bill provides break for two merging hospitals. AB - Massachusetts lawmakers have approved special legislation to aid the merger of two hospitals in Lowell. The legislation forgives $11 million to $15 million in payments owed by St. John's Hospital and St. Joseph's Hospital to the state's uncompensated-care pool. The measure was opposed by Gov. William Weld, who fears the measure will set a bad precedent. PMID- 10119787 TI - Hot campaign topic: whose plan is better? PMID- 10119788 TI - Johnson Foundation awards grants to test plans. PMID- 10119789 TI - Ariz. hospitals form alliance. PMID- 10119790 TI - N.Y. law eases access to insurance. PMID- 10119791 TI - Humana execs will be ready if board OKs split in operations. PMID- 10119792 TI - Columbia buys HCA facility in El Paso. PMID- 10119793 TI - Universal Health Services purchases first surgery center for new division. PMID- 10119794 TI - Consultant to write Rx for district's deficit. PMID- 10119795 TI - District to disclose indigent spending. PMID- 10119796 TI - Hospital profits continue to show improvement. PMID- 10119797 TI - Medical suppliers praise free trade pact. PMID- 10119798 TI - Now Calif. hospitals can't even get IOUs. PMID- 10119800 TI - Negotiations give Pa. cost council reprieve. PMID- 10119799 TI - Two financially sound Blues plans in Indiana and Kentucky announce merger intentions. PMID- 10119801 TI - Providers, HCFA hit plan to 'open' VA system. PMID- 10119802 TI - Hamot Medical Center selling office building following settlement of tax exemption case. PMID- 10119803 TI - AHA acknowledges large '92 deficit will force layoffs. PMID- 10119804 TI - FDA user fee plan gets some support from drug makers. PMID- 10119805 TI - Senate proposal would reduce drug prices for federal agencies. PMID- 10119806 TI - Pricing, reporting practices are doing hospitals no favors. PMID- 10119808 TI - Oregon governor beseeches Bush on waiver. PMID- 10119807 TI - Ownership issues blurring the future of imaging centers. AB - Federal "safe harbor" regulations, rulings from the Internal Revenue Service and various state initiatives on self-referrals are setting the stage for a massive unraveling of physician and hospital-physician joint ventures that own diagnostic imaging centers. Such changes, especially an increase in corporate ownership of freestanding centers, could raise the competition for outpatient business to new heights. PMID- 10119809 TI - Human resources execs making strides. AB - Hospital human resources executives are making more money and more of them are reporting directly to chief executive officers, according to a recent study by an executive search firm. Both trends are seen as an indication that hospitals are placing greater importance on the human resources function and are considering human resources executives to be members of their senior management teams. PMID- 10119810 TI - Blues plans trying to extract better deals from hospitals. AB - Stung by recent reports indicating that several health insurance plans sponsored by the Blue Cross and Blue Shield Association may be on the brink of insolvency, some Blues plans are putting the squeeze on hospitals by demanding better prices. The Blues are getting tougher with hospitals because they want to slow the increases in their customers' medical bills. PMID- 10119811 TI - Bond insurer expands access to financing. AB - Connie Lee Insurance Co., the newest player in the healthcare bond insurance market, is expanding access to credit enhancements for investment-grade teaching hospitals that may have been overlooked by other insurers. The company, a subsidiary of the College Construction Loan Insurance Association, also has been able to save facilities money over competing bond insurance programs. PMID- 10119812 TI - Bill seeks insurance relief for small businesses. PMID- 10119813 TI - House Dems working to reach compromise. PMID- 10119814 TI - IRS drops approval of plan to sell services to physicians. PMID- 10119815 TI - Blues Assn. urges coverage for PET scans. PMID- 10119816 TI - Houston coalition to study hospitals' quality. PMID- 10119817 TI - Public hospitals hit hard by side effects of Medicaid cost-cut push. PMID- 10119818 TI - Donation-law provisions mirrored in rule draft. PMID- 10119819 TI - Infected worker sues over firing. PMID- 10119820 TI - Blues plan to float Medi-Cal bridge loans. PMID- 10119822 TI - N.Y. group proposes statewide managed-care system. PMID- 10119821 TI - Nashville officials vote to merge 2 hospitals. PMID- 10119823 TI - Justice Dept. approves Illinois merger. PMID- 10119824 TI - Two California hospitals reach settlement in five-year dispute. PMID- 10119825 TI - State storm passes; Twin Cities merger is on. PMID- 10119826 TI - Cap, allocations proposed for residencies. PMID- 10119827 TI - Judge OKs docs' bid for Chicago hospital. PMID- 10119828 TI - Missouri public hospital to pay former CEO $1.06 million settlement to thwart lawsuit. PMID- 10119829 TI - Humana to lay off 400 in Louisville headquarters. PMID- 10119830 TI - Emergency rooms aren't violence victims--study. PMID- 10119831 TI - HealthVest reports loss for 2nd quarter. PMID- 10119832 TI - Medicaid rule worries providers. PMID- 10119833 TI - Hospitals should re-evaluate participation in primary care. PMID- 10119834 TI - States lurch toward revamping Medicaid donation programs. AB - States that are facing federal deadlines for revamping their Medicaid provider tax and donation programs have taken on the task with varying degrees of success. Only a few have enacted new programs to comply with a 1991 law aimed at curbing perceived abuses. And those that have crafted new programs have done so without the guidance of HCFA's rules. PMID- 10119835 TI - Contract management survey. AB - More hospitals are looking to contract management firms for help in controlling rising costs and handling complex reimbursement systems. Companies are responding to hospitals' changing needs by providing innovative services. Total hospital contracts rose 10.4% last year, according to the 94 companies responding to MODERN HEALTHCARE's 1992 contract management survey. PMID- 10119836 TI - GOP blesses Bush plan, bashes Democrats' plan. PMID- 10119837 TI - New advertising campaign takes look at healthcare reform trade-offs. PMID- 10119838 TI - Loretto struggles to regain market support. AB - Ten months after the Sisters of St. Casimir transferred sponsorship of Loretto Hospital in Chicago to a for-profit management company, the inner-city hospital has stabilized its operations through layoffs, increased admissions, streamlined operations and improved billing and collections. Now, Loretto is working to regain the support that it lost over years of million-dollar losses. PMID- 10119839 TI - Equipment maintenance programs offered. PMID- 10119840 TI - Grand jury finds no Medicare fraud at two Calif. home health agencies. PMID- 10119841 TI - Nurse compensation is new target of probe. PMID- 10119842 TI - Court cases testing scope of federal law's peer review immunity. PMID- 10119843 TI - Medlantic launches plan to regain A rating. AB - By completing the first part of a two-part debt restructuring, Medlantic Healthcare Group has taken another step toward regaining the top-flight debt rating that it had as recently as three years ago. The effort comes one year after the hospital system overhauled its corporate structure to create a more efficient organization and shed itself of unprofitable operations. PMID- 10119844 TI - Profiles of four new surgical suites. PMID- 10119845 TI - Communication key during OR renovation. PMID- 10119846 TI - Recovery care centers finding market niche. PMID- 10119847 TI - Tissue transplantation. Quality assurance in the banking and utilization of musculoskeletal allografts. AB - Tissue allografts are being used more frequently, and, as a consequence, an increasing number of hospitals and physician assistants must face the difficult and perplexing task of evaluating their effectiveness and safety. Quality assurance programs are designed to enhance patient care during the transplantation process and should outline the responsibilities of both the tissue bank and the hospital using the allograft. Recommendations for the establishment of quality assurance programs at hospitals are made based on guidelines established by national certifying agencies. It is of paramount importance to recognize the areas of responsibility and to delineate acceptable standards of practice when developing and implementing quality assurance programs for tissue transplantation. PMID- 10119848 TI - How unclear terms affect survey data. AB - Although writing clear questions is accepted as a general goal in surveys, procedures to ensure that each key term is consistently understood are not routine. Researchers who do not adequately test respondent understanding of questions must assume that ambiguity will not have a large or systematic effect on their results. Seven questions that were drawn from questions used in national health surveys were subjected to special pretest procedures and found to contain one or more poorly defined terms. When the questions were revised to clarify the definition of key terms, significantly different estimates resulted. The implication is that unclear terms are likely to produce biased estimates. The results indicate that evaluation of survey questions to identify key terms that are not consistently understood and defining unclear terms are ways to reduce systematic error in survey measurement. PMID- 10119849 TI - Health-care chains shuffle assets in quest for profits. PMID- 10119850 TI - Reimbursing new technologies: why are the courts judging experimental medicine? PMID- 10119851 TI - Prevalence of major digestive disorders and bowel symptoms, 1989. PMID- 10119852 TI - Telephone calls and appointment requests. Predictability in an unpredictable world. AB - HMO member-initiated requests for service, including telephone calls and appointments, were studied. Telephone calls to medical offices were found to be directly proportional by a constant factor to the number of members using the facility. The number of member requests for appointments for medical problems and routine physical examinations was also predictable. A method of planning and effectively providing outpatient office appointments is proposed. PMID- 10119853 TI - Utilization of mental health services. Attrition versus aggregation. AB - Mental health services are utilized in the context of opposing trends of decline and accumulation in caseload. A rapid attrition in frequency of contact is counterbalanced by a slower aggregation of cases failing to reach termination. These opposite, simultaneous forces mean that a mental health service may be meeting its goal of containing the duration of treatment while its practitioners are contending with a sizable caseload resistant to closure. This phenomenon is empirically described. PMID- 10119854 TI - Evaluation of wellness in an eating disorders program. AB - The evaluation of treatment effectiveness in an educational or mental health program remains an elusive and too often ignored program component. Therefore, our team of practitioners and educators in an HMO eating disorders program has developed a practical and visual evaluation method which we call the "Circle of Wellness." We define wellness in terms of physical and mental health. Wellness, in this context, is a reduction of eating disorder symptoms and improvement of quality of life and the client. The "Circle of Wellness" is not intended as a test but as a visual representation of a client's progress (pre- and post program) for client and clinician to discuss. The tool helps identify areas to emphasize in future planning. PMID- 10119856 TI - Using systems to select systems: consultants that automate the RFP process. PMID- 10119855 TI - A challenge to HMOs. AB - Outcomes research is needed to evaluate variations in medical care. When there is more than one reasonable option for treatment, Wennberg points out the need to base decisions on the patient's preferences. A shared decision-making model requires that patients be informed of their options, and empowered to make real choices. HMOs are presented with this challenge. PMID- 10119857 TI - Measuring up: on-line tools enable IS quality initiatives. PMID- 10119858 TI - Computerized medical device tracking--ways to comply with SMDA (Safe Medical Devices Act of 1990). PMID- 10119859 TI - What's UPS doc? PMID- 10119860 TI - Managing outcomes with on-line expertise. PMID- 10119862 TI - Top 50. The leading healthcare information system vendors in America. PMID- 10119861 TI - Panacea or placebo? UNIX in healthcare. PMID- 10119863 TI - UNIX/RDBMS combination feels like "power ... ownership" to system users. PMID- 10119864 TI - Progressive facility finds open alternatives. PMID- 10119865 TI - What we can learn from the European privacy standard. PMID- 10119866 TI - Northern discomfort: the ills of the Canadian health system. AB - Here is a cool-headed, logical argument against using the Canadian health care system as a model for reform in the U.S. offered by a leading Heritage Foundation expert. PMID- 10119867 TI - A new payment paradigm for Medicare. Interview by John Herrmann. AB - Here is a controversial health care pricing approach that its author believes offers incentives to encourage providers to find the most efficient and effective ways to manage patient care across the entire episode of illness. PMID- 10119868 TI - Health care and hospitals: things to come. PMID- 10119869 TI - State health reform: no more "Mr. Nice Guy". PMID- 10119870 TI - A hospital takes a bit out of crime. Interview by John Herrmann. AB - A Humana-sponsored local community anti-gang grass roots movement with a hospital as its centerpiece is working to prevent what has happened in Los Angeles and other state drug capitals. PMID- 10119871 TI - Health care, the California primary, and the 1992 election. AB - Voters in the June 2 last-in-the-nation California primary indicated that candidates' character, experience, and leadership ability have become more significant than their stands on such issues as health reform. However, among substantive campaign issues, health care ranked second, behind the economy. That is consistent with previous poll results from New Hampshire, the nation's first primary state. PMID- 10119872 TI - The best of both worlds: merging competition and regulation. AB - Criticism of the "play-or-play" model of health system reform has focused on the potential damage to small business, employment, and innovation in health care delivery. By making some important alterations to that basic model, policymakers can address these concerns while still guaranteeing access to care for all Americans and controlling the rate of growth in health care expenditures. PMID- 10119873 TI - Federal mandatory spending caps vital for health care reform. AB - Rising health spending creates an increasing burden on families, businesses, and government. Federal health spending--chiefly on Medicare and Medicaid--is a major contributor to a budget deficit that threatens to exceed $400 billion. In order to control that deficit, the President and the Congress must cap mandatory spending, excluding Social Security. In turn, policymakers should adopt health reforms to fit spending within the cap including enrolling more consumers in managed care plans, resolving medical liability disputes in arbitration instead of courts, and increasing assessment of research into cost-effective new technology. PMID- 10119874 TI - School (but not Congress) is out for the summer. AB - Keeping with our annual tradition (okay, it's only our second year), the editorial staff of the Journal of American Health Policy is issuing its 1992 Report Card. In our first issue, we graded the health policymakers of the Bush Administration. Since those people have only recently begun talking to us again, we thought it would be a good idea to turn our red pen to Congress' healthmeisters. Grades relate to leadership, ability to advance an agenda, and knowledge of and thoughtfulness about health care issues. And, yes, we graded on a curve. PMID- 10119875 TI - A more flexible approach to health reform. AB - The United States spends $817 billion on health care and yet has tremendous gaps in coverage. The system must be reformed without spending increasingly huge sums of money on health care. By combining national spending limits apportioned among the states and state-devised all-payer cost containment, the U.S. can afford to expand coverage to the uninsured without a stratospheric increase in spending. PMID- 10119876 TI - A county's response to the uninsured. AB - The need for primary care for the uninsured in Florida's Hillsborough County spurred the County Commission to tackle the issue locally. It appointed a Health Care Advisory Board to create a new means of providing primary care services that would be easily accessible to people who are uninsured and have incomes below the federal poverty line. The Board established a system to provide primary health care and enacted a local sales tax to pay for it. PMID- 10119877 TI - America's health care, social solidarity, and reform. AB - As Americans debate how their country's health care system should evolve, foreign systems are frequently adduced as possible models. Since the underlying political idea that guides almost all exportable foreign systems is the notion of social solidarity, there is a need for a broad national engagement over this principle before the U.S. becomes preoccupied with the technical details of a new health care delivery system. The question "why?" must be answered before the question "how?" PMID- 10119878 TI - Selecting a healthcare consultant, Part II: Developing the request for proposal. AB - In part II of this series, Janet Scheuerman of Herman Smith Associates and Vaughan A. Smith, president of the American Association of Healthcare Consultants, continue their detailed analysis of how to select a healthcare consultant. Focusing on the request for proposal (RFP), the authors cover such practical considerations as how many copies of the RFP will be required and what contacts should be listed. A comprehensive outline of how to write a statement of purpose and describe the project and scope of work is presented. The article concludes with suggestions for interviewing candidates and checking references. PMID- 10119879 TI - Nosocomial pneumonia: interdisciplinary quality monitoring. AB - Nosocomial pneumonia is a serious and potentially fatal occurrence in the hospital today. Medical and nursing management influence the susceptibility of an individual as well the outcome of the episode. Due to the importance of the actions of the nurse and of the physician, monitoring the risk factors of the patient, the events preceding the episode and the pneumonia management may provide an opportunity to improve patient care. A study was conducted on patients with nosocomial pneumonia that identified areas of deficits and focused educational efforts. PMID- 10119880 TI - Complying with Joint Commission nursing standards: practical documentation tools. AB - The need for accurate and complete documentation of nursing care has grown as hospitals seek to comply with the new requirements of the Joint Commission on Accreditation of Healthcare Organizations. As of January 1991, the Joint Commission implemented standards for nursing services that include documentation of the planning and delivery of nursing care. While the new JCAHO standards do not call for a separate nursing care plan, they nevertheless involve enough changes to require modification of most currently used documentation forms. This article describes the methods used to design new forms at the Carl T. Hayden Veterans Affairs Medical Center in Phoenix, AZ. The newly developed forms are reviewed and compared with the Joint Commission's new standards and scoring guidelines. PMID- 10119881 TI - Can there be mutual support between hospital marketing and continuous quality improvement? AB - Marketing the results of continuous quality improvement in hospitals builds a growing bank of loyal customers in an increasingly competitive and quality oriented environment: If healthcare institutions want to survive and flourish, they must develop a lasting relationship with their customers. The long-term goal of CQI is to provide quality products and services. If marketing managers can sell these improved services, hospitals will build a solid client foundation. PMID- 10119882 TI - AIDS and confidentiality: a legal/ethical dilemma. AB - The AIDS epidemic has created difficult ethical and legal problems. A particularly acute conflict for the healthcare professional occurs when the obligation to maintain HIV-patient confidentiality is at odds with the need to protect the ignorant sexual partner from infection. In spite of counseling, the AIDS patient may continue to engage in unsafe sexual practices with partners who are unaware of the individual's HIV status. The Centers for Disease Control and medical organizations such as the American Medical Association are in general agreement that the sexual partner of an HIV-positive patient must be notified. The legal strictures regarding confidentiality, however, vary from state to state. PMID- 10119883 TI - W. Edwards Deming and total quality management: an interpretation for nursing practice. AB - The purpose of this article is to introduce nurses to W. Edwards Deming and the 14 points of his management philosophy, the basis of total quality management (TQM) (Deming, 1986). Each of Deming's points has been subject to in-depth analysis from business executives for the past 40 years. Quality improvement is at the very center of TQM. To adopt TQM will require a major thought transformation for many nursing leaders, but the benefits that nurses and the profession as a whole can reap from this revolutionary style of management make the effort to change worthwhile. If you are not satisfied with the status quo and are looking for a better way to conduct business, the information in this article will begin to define quality improvement and will help you strive for the highest possible level of service to your ultimate customer--the patient. PMID- 10119884 TI - Benchmark matrix and guide: Part III. AB - The final article in the "Benchmark Matrix and Guide" series developed by Headquarters Air Force Logistics Command completes the discussion of the last three categories that are essential ingredients of a successful total quality management (TQM) program. Detailed behavioral objectives are listed in the areas of recognition, process improvement, and customer focus. These vertical categories are meant to be applied to the levels of the matrix that define the progressive stages of the TQM: business as usual, initiation, implementation, expansion, and integration. By charting the horizontal progress level and the vertical TQM category, the quality management professional can evaluate the current state of TQM in any given organization. As each category is completed, new goals can be defined in order to advance to a higher level. The benchmarking process is integral to quality improvement efforts because it focuses on the highest possible standards to evaluate quality programs. PMID- 10119885 TI - Integrating the nursing process into a nursing quality improvement program. AB - In 1991, the Joint Commission's nursing services standards scoring guidelines went into effect. Nancy Claflin discusses the changes in the nursing process needed to meet these revised standards under the rubrics of assessment, planning, intervention, and evaluation. She then presents an extensive implementation plan for integrating this revised nursing process into a nursing QI program. The focus of this article is both on the principles of quality improvement and the exigencies of aspects of care, standards of nursing practice, and indicators. PMID- 10119886 TI - Statistical process control: a practical application for hospitals. AB - A six-step plan based on using statistics was designed to improve quality in the central processing and distribution department of a 223-bed hospital in Oakland, CA. This article describes how the plan was implemented sequentially, starting with the crucial first step of obtaining administrative support. The QI project succeeded in overcoming beginners' fear of statistics and in training both managers and staff to use inspection checklists, Pareto charts, cause-and-effect diagrams, and control charts. The best outcome of the program was the increased commitment to quality improvement by the members of the department. PMID- 10119887 TI - QA in home care: the staff nurse's challenge. AB - The home healthcare staff nurse faces formidable challenges that can be met only by an extraordinary commitment to quality care. Functioning autonomously much of the time, the home healthcare nurse must act as the client's case manager. Coordination of multiple services and extensive client education are vital to positive outcomes, and intervention decisions must be based on a holistic view of the client's needs and environment. Reimbursement issues under Medicare often conflict with the delivery of high-quality care. To achieve the goals of the home healthcare agency and perform optimally, the home healthcare nurse needs a supportive QA program and frequent peer review procedures. PMID- 10119888 TI - COAD (clinical outcome assessment documentation) charting: using the quality improvement process to meet the new JCAHO nursing standards. AB - The shortage of nurses has prompted departments across the nation to examine nursing practices in individual healthcare facilities and to initiate changes where relevant. Saint Thomas Hospital, a 571-bed tertiary-care facility, developed a number of strategies designed to allow nurses to focus on skills consistent with professional practice and to reassign technical and clerical duties to other members of the healthcare team. One of the changes implemented was the clinical outcome assessment documentation (COAD) system, which communicates the plan of care without the use of a separate form, expedites charting times, and eliminates duplication. This system also facilitates the documentation of the patient's progress toward outcome-oriented goals. Evaluation of the COAD system after implementation showed improvement in documentation of the nursing process, staff satisfaction with the system, and compliance with the Joint Commission's 1991 nursing standards. PMID- 10119889 TI - QA automation: what must be considered. AB - As healthcare quality assurance programs grow, so too does the need to gather and provide vast amounts of information. To meet this challenge, QA programs have turned to the use of computer systems. As this article makes clear, QA automation involves more than simply the purchase of computer hardware and software. Much time, planning, research, preparation, testing, and education are required to create an effectively automated QA program. The author provides a realistic review of the major stages and elements of the QA automation process, beginning with the search for appropriate software and concluding with the diversification possibilities of a fully integrated program. PMID- 10119890 TI - PRO monopoly. PMID- 10119891 TI - The ABCs of DME: a home care durable medical equipment/home oxygen program. AB - With the evolution of high-tech healthcare in the home setting, patients and families now need to learn the skills to perform the tasks that previously were done in hospital settings by health professionals. Numerous private and federally funded home health organizations are offering services to this patient population. The mission of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) is to improve the quality of care provided to the public (JCAHO, 1991b). In 1988, the commission implemented standards for the accreditation of home care and began to survey home care providers (JCAHO, 1988). Standards governing the provision of durable medical equipment are included in the JCAHO Accreditation Manual for Home Care (1991a). The article describes an effective collaborative approach used to develop a comprehensive durable medical equipment/home oxygen (DME/home O2) program at the Department of Veterans Affairs Medical Center (DVAMC), now called the Veterans Health Administration Medical Center, in East Orange, NJ. Project management principles were used by the quality management (QM) staff to develop and implement the DME/home O2 program successfully. PMID- 10119892 TI - A system to manage records for credentialed providers. AB - There has been a rapid growth in and evolution of information management to assure appropriate and timely awarding of privileges for credentialed providers. Proprietary software might not meet the needs of a particular facility. In this article, Jackie Walker and William F. Perry describe how, using commercially available database management software, information management can be tailored to the needs of an individual institution and altered as necessary. PMID- 10119893 TI - Improving the quality of medical record documentation. AB - Accurate and complete medical record documentation is essential in any healthcare setting. In addition to communicating vital patient care information, the medical record provides documentation of appropriate evaluation, treatment, and services. It also is used to evaluate practitioner performance, to monitor resource use, and to determine reimbursement. In this article, Carol Ann Martin describes the efforts of one hospital to revise and upgrade its medical record documentation by means of continuous quality improvement strategies. PMID- 10119894 TI - Resident assessments: a new tool for measuring and improving nursing home quality. AB - The United States is adopting a resident assessment instrument nationwide that holds great potential for the measurement and improvement of nursing home quality. The steps necessary to ultimately use the assessment instrument to evaluate institutional quality at the facility level are discussed. Drawing from experience with a standardized resident assessment system used in Virginia since 1983, Anne Glass describes how assessments were employed in an exploratory project to examine the relative performance of 135 facilities. A model of nursing home quality is included to explain how indicators drawn from assessments relate to quality. Advantages of using a resident-assessment-based system to evaluate institutional quality are outlined. When computerized, this wealth of data will help clarify facility norms and support continuous quality improvement. PMID- 10119895 TI - Establishing a people-centered health service in Gwent, Wales. AB - The Welsh Health Planning Forum has developed a "Strategic Intent and Direction for the NHS in Wales." The aim is "to take the people of Wales into the 21st Century with a level of health on course to compare with the best in Europe" (Welsh Office NHS Directorate, The Welsh Health Planning Forum, 1989). Gwent Health, one of the nine health authorities in Wales, provides a comprehensive health service to its population of 445,000 and was chosen to develop a prototype for the provision of cancer services. Gwent residents were invited to seminars to express their opinions of the health service that was provided and describe the type of service they would like to have in the future. The response was encouraging enough to engender the planning of future seminars. PMID- 10119896 TI - Quality assurance and quality improvement: the 1990s and beyond. AB - Quality assurance and quality improvement are two highly visible indicators of the significant forces that are remolding the American healthcare delivery system. Edward K. Jeffer reviews the current status of these disciplines and makes projections on how they will affect the structure and practice of healthcare in the next century. Some speculations are presented as to why the future appears so bleak to so many healthcare providers. A more optimistic outlook is suggested, and the key role of quality assurance professionals is emphasized. PMID- 10119897 TI - Preparing nursing for the Joint Commission's return: a reporting system. PMID- 10119898 TI - Quality indicators: an approach to quality improvement in home healthcare. AB - In this article, Donna Wagner discusses using quality indicators as a means of improving quality in home healthcare. Stressing the need for an organization to have a thorough foundation in total quality management as its working context, the article demonstrates how to use quality indicators as part of a quality improvement program. Monitoring quality indicators in a home health agency will provide specific information on aspects of care that the agency has identified as measures of quality. This cost-effective monitoring can be a means of incorporating QI activities into daily work patterns. PMID- 10119899 TI - Age-appropriate care: a system designed to make it happen. AB - In 1991, the Joint Commission on Accreditation of Healthcare Organizations governing board standards required that a process be designed to ensure that all individuals responsible for the assessment, treatment, or care of patients are competent in age-appropriate care. To meet this requirement, Humana Hospital Overland Park in Overland Park, KS, developed a process to educate, evaluate, and report competence of staff to the governing board in an efficient and useful way. The focus of this article is to discuss how the process was developed and implemented successfully. PMID- 10119900 TI - Validating the quality of emergency room services. AB - An inappropriate patient transfer from the emergency room results in less-than quality care, cost concerns, and patient and staff dissatisfaction. The emergency room physicians at a 162-bed community hospital reported that patients were being transferred needlessly from the emergency room to other acute care facilities. An investigation of the issue documented lost revenues and concerns about the quality of patient care. Based on the findings of the investigation, specific recommendations were proposed to monitor and evaluate the quality of patient care provided in the emergency room. PMID- 10119901 TI - Implementing an interdisciplinary healthcare quality project. AB - Bringing together healthcare professionals from several disciplines for a quality project can provide many benefits. This article describes the collaborative process between nursing and dental services at a Department of Veterans Affairs Medical Center as they assessed and evaluated the practice of oral hygiene among 120 long-term care patients. Enhancement of interdisciplinary collaboration occurred through appropriate disciplinary representation and leadership, clarification of disciplinary vocabularies, firsthand empirical assessment, and timely feedback. With each discipline combining resources, fostering open communication, and evaluating the project, the collaborative process was optimized. Benefits of this interdisciplinary quality project included (a) more comprehensive and holistic evaluation of patients' oral hygiene practices, (b) quality assessment in a timely fashion, (c) establishment of rapport between individuals who otherwise might not have an opportunity to interact, (d) improved communication and understanding between disciplines, and (e) development of better patient care indicators. PMID- 10119902 TI - Computerizing drug usage evaluation. AB - Drug usage evaluation (DUE) has been computerized at the Department of Veterans Affairs Medical Center in Coatesville, PA. This article describes the implementation of a simple, cost-effective process and provides examples of facility-wide and provider-specific reports that can be used at the time of reappointment for privileges. As a result of computerization and the involvement of all pharmacists, the number of drug reviews have increased dramatically, and there is more consistency in the reviews. PMID- 10119903 TI - Integration of intradisciplinary quality assessment into a multidisciplinary approach. AB - One challenge for the QA professional in healthcare today is initiating, coordinating, and facilitating QA programs that cross traditional departmental and discipline barriers and bring together multidisciplinary teams. When looking at healthcare from a customer's perspective, the QA professional must not isolate what nursing does for the patient, what the medical staff does for the patient, what pharmacy does for the patient, and so on. The imperative, instead, is to evaluate the healthcare as it truly is perceived and delivered-as a team effort. This article presents one method that uses the Joint Commission on Accreditation of Healthcare Organizations' 10-step model to create an effective multidisciplinary QA program. PMID- 10119904 TI - Consumer satisfaction survey: an outcome measure for work services. AB - This article describes a consumer satisfaction survey of work services in a community mental health center. The development of a satisfaction survey tool is discussed, the results from 41 respondents are given, and the implications of the survey's results are outlined. PMID- 10119905 TI - Documenting JCAHO standards in assigning nursing staff. AB - The Joint Commission on Accreditation of Healthcare Organizations Standards address seven factors (patient dynamics, complexity of care, assignment complexity, technology, the patient care environment, supervision, and staff competence) to be considered when making nursing staff assignments. This article describes a form that is being used in the special care units of a medical center for this purpose. PMID- 10119906 TI - HQEF (Healthcare Quality Educational Foundation) update: quality through education. PMID- 10119907 TI - The patient-focused hospital. Management engineers: the choice is yours. PMID- 10119908 TI - Telecom management: managers must plan for the future. PMID- 10119909 TI - An annotated bibliography: total quality management. PMID- 10119912 TI - Data watch. A snapshot of executive poll results. PMID- 10119911 TI - Role of the management engineer in the patient-focused hospital. AB - Patient focused healthcare is coming. Based on the criteria John Nesbitt put forth in his book, MEGATRENDS, PFH is a TREND not a fad. By building on the principles of continuous quality improvement the PFH model strives to redesign hospitals and focus their operations on their customers, the patients. By doing this the PFH creates a stronger, more flexible organization that will be better able to respond to differing market demands. Improved quality, service, employee satisfaction and financial performance are early results reported by hospitals implementing the PFH model. MEs have the capability and motivation to play a major role in the conversion of traditional health care systems into PFH models. MEs must shift roles, create a new job description and get to work on the quality transformation. PMID- 10119910 TI - Patient care redesign. World class healthcare--revolutionizing the way hospitals do business. PMID- 10119913 TI - Employers seek alternative treatments for adolescent mental health care. PMID- 10119914 TI - Managed care is right course, employers say. PMID- 10119915 TI - Hospitals and employers cut costs by direct contracting. PMID- 10119916 TI - Coalition's perseverance fosters cost control. PMID- 10119917 TI - Florida grapples with universal health care. PMID- 10119918 TI - Confessions of a hospital administrator. PMID- 10119919 TI - New reimbursement system incorporates cutbacks. PMID- 10119920 TI - Where to turn for long-term care insurance. PMID- 10119921 TI - Power outage. Medicaid overload forces providers to pull out. PMID- 10119922 TI - Drive a bargain. Leasing stretches facilities' purchasing power. PMID- 10119923 TI - A new twist to an old concept. Provider opens temporary nurse agency. PMID- 10119924 TI - Fine tuning management skills. Empowering staff improves harmony. PMID- 10119925 TI - Adding infusion therapy. How to plan and train for i.v.s. PMID- 10119926 TI - New bloodborne pathogens regulations from OSHA. PMID- 10119927 TI - A chalet of warmth and friendliness. The birth, development and success of an AIDS facility. PMID- 10119928 TI - Caught in the middle. A profile of licensed practical nurses in home care. AB - Licensed practical nurses are the smallest major segment of the home care industry, providing services with registered nurses and home care aides. Although they report high job satisfaction, LPNs are caught at a middle stage in the health care system. With new demographics, labor market considerations, and recruitment experiences, this report points out the discrepancy between the stalled LPN status and their industry growth. PMID- 10119929 TI - Adding high-tech home care services to your agency. AB - The rapid development of high-tech programs in home care reflects the industry's response to advanced technology, escalating health care costs, and consumer preferences. As third-party payors scrutinize the use of the insurance dollar, high-tech home care is often considered the most viable treatment option available. PMID- 10119930 TI - The emancipation of at-home dialysis. AB - Dialysis providers have responded to the home care movement by making peritoneal dialysis an option for their patients desiring home therapy. By joining forces, home care nurses and dialysis nurses can provide the best possible care to these patients while allowing them to maintain a higher degree of normalcy and independence in their lives. PMID- 10119931 TI - Empowering people--key to the future. AB - In summary, corporations large and small that hope to survive and prosper in the future will be those that learn how to unleash the awesome power of their employees. This involves introducing a healthy dose of democracy into the workplace. It involves focusing on the employees and helping them to perfect their talents--to be all that they can be. It involves caring about them and doing everything possible to assist them. It involves bringing them in as partners and replacing old competitive and adversarial relationships with cooperative ones. It involves giving them some share in all aspects of the business from planning to marketing. It involves reinstituting trust and faith between labor and management. Those corporations that choose to empower their employees will find that the investment pays handsome and immediate returns. In the end, the workers, management, and the nation will be the beneficiaries as America again takes its place as the greatest economic power in the history of the world. PMID- 10119932 TI - Placing decisionmaking in the hands of those who can make a difference. PMID- 10119933 TI - Nursing & technology. Moving into the 21st century. AB - The world of health care will increasingly be a world of high technology. Yet nurses and other home care providers often find themselves struggling to balance the high-tech aspect of their jobs with the caring aspect. If nursing education can address the issue, nurses and their coworkers will have a solid basis to provide high touch with high-tech care. PMID- 10119934 TI - Managing codependent behaviors--a key to empowerment. AB - Managers may unwittingly hamper employee empowerment when their own work styles encourage codependent behaviors among staff. Identifying and understanding the different ways in which people respond to others in the workplace can enhance management and employee growth. PMID- 10119935 TI - Implementing a clinical ladder program. AB - Reward and recognition are powerful motivators in any employment setting. Long understood in the business world, it is only recently that the nursing field has come to recognize the need to go beyond the intrinsic reward system based upon patient care delivery to a more tangible system including monetary incentive and peer evaluation. PMID- 10119936 TI - Empowering employees to take charge of their performances. AB - To retain staff and operate effectively, an agency must reward and develop its personnel. One Wisconsin agency worked with its staff to develop a review tool that enabled the staff to take part in their own evaluation and thus perform to their best abilities. PMID- 10119937 TI - Empowering home care nurses through education. AB - The recent increase in specialized patient care creates a need to produce well rounded home care nurses who are able to provide quality holistic care to their patients. Empowering the nursing staff to provide this care generates the need to develop creative modes of teaching and updating patient assessment skills. One visiting nurse association implemented a two-day nursing skills lab to achieve this goal. PMID- 10119938 TI - Bone marrow transplant therapy in the home. AB - All of the psychological, physical, and economic complications of bone marrow transplant must be understood to ensure comprehensive management and continuity of care to each BMT recipient. Caregivers in both the hospital and home care setting need to be cognizant of each patient's issues and health care needs. PMID- 10119939 TI - High-tech home care with a homemade twist. AB - Usher's syndrome is a rare genetic condition involving hearing loss and gradual progressive blindness due to retinitis pigmentosa--a situation in which self-care at home would seem impossible. Yet innovative methods developed by a creative home care team have allowed a deaf-blind patient to self-administer infusion therapy and chemotherapy in the home setting. PMID- 10119940 TI - Infant medical day care. A natural extension of home care. AB - A special population of children exists that has skilled nursing needs: they may be called chronically ill, medically fragile, technology assisted, or health vulnerable. Unlike conventional child care centers, which often refuse admission to these children, a center in New Jersey has found a way to serve them effectively. PMID- 10119941 TI - Preparing for Medicare hospice benefit certification. AB - When the Visiting Nurse Association of Central Illinois staff began to investigate Medicare Hospice Benefit Certification, they had to start from scratch. In this first-person account, they share their experience and valuable informational shortcuts to help others streamline their process and assure adequate preparation for the certification survey and subsequent operation. PMID- 10119942 TI - An examination of practice referral rates in relation to practice structure, patient demography and case mix. AB - This paper examines the variation in practice referral rates from 53 practices over a twelve-month period. Data from the Second National Morbidity Study were used in relation to practice structure; age, sex and Social Class composition of the patient population; and the case mix by practice. The results show that the age of the patient is an important determinant of the probability of referral, whereas Social Class has little influence. Analysis of the practice-based data showed that practices were highly concordant in their referral activity across sex and age (greater or less than 45 years), sex and Social Class (manual or non manual), and across chapters of the disease classification. This degree of concordance points to characteristics of the practices rather than patients, and their problems as the main source of variation in practice referral behaviour. PMID- 10119943 TI - The permanent indwelling catheter: a domiciliary survey. AB - A survey of non-hospitalised patients with indwelling catheters was undertaken by the District Nursing Sisters in the Portsmouth and South East Hampshire District. The distribution, pathology and workload arising from these patients is analysed, and the findings suggest that periodic review of management of particular patients would help to improve their quality of life. PMID- 10119944 TI - General anaesthesia in the accident and emergency department. AB - This paper describes the results of a survey in 1990 which examined the practice of general anaesthesia in Accident and Emergency Departments. Data were obtained concerning the anaesthetics induced during the previous year, specifically the number of procedures undertaken, the equipment, the facilities and the personnel involved, including any complications. These findings are discussed in relation to recommendations for minimum standards in anaesthetic practice. PMID- 10119945 TI - Can knee replacements be assessed by post? AB - The audit of knee replacement surgery requires long-term follow-up. The aim of this Bristol study was to examine whether an accurate assessment of knee replacement surgery could be undertaken by post, thus obviating the need for patients to visit hospital. A patient's questionnaire was designed to complement the clinic therapist's assessment form currently in use, and this was completed by 73 patients without supervision prior to the therapist's assessment. A comparison of the two assessments shows a significant discrepancy between their results, particularly in the assessment of pain, walking distance, and range of movement. The authors conclude that postal follow-up of knee replacements should be viewed with caution. PMID- 10119946 TI - The contribution of medical nitrous oxide to the greenhouse effect. AB - Nitrous oxide is now recognised as an important contributor to the 'greenhouse' effect. Each year the medical profession unwittingly adds a very small burden of this gas to the atmosphere. Unfortunately, the long lifetime of nitrous oxide means that all emissions into the atmosphere are significant. By making small changes in their practices, anaesthetists are well-placed to help reduce the potential environmental damage. PMID- 10119947 TI - Inter-specialty rotation in anaesthetics. AB - It has never been easy to attract junior doctors to training posts in anaesthetics in small District General Hospitals. This paper discusses the benefits of introducing an internal hospital rotation within general medicine. PMID- 10119948 TI - The impact of a music festival on local health services. AB - A music festival was held in July 1989 near Liskeard in Cornwall. This paper comments on some of the organisational problems, and documents the workload of voluntary workers and professional medical agencies serving the festival. At least 467 of attenders (greater than 1%) sought aid, and 15 patients required hospital admission. There were two deaths and one birth at the site. It is suggested that, in addition to the services provided by voluntary agencies, organisers of mass gatherings should provide suitably qualified medical and nursing personnel on site. PMID- 10119949 TI - Hospital care among ethnic minorities in Britain. AB - This study examined ethnic differences in the levels of inpatient admission and outpatient attendance in Great Britain using the latest national data available from the General Household Surveys of 1983-87. Inpatient admissions in immigrants (Indian, Pakistani and West Indian) did not differ significantly from whites, except for a marked excess in Pakistani women of childbearing ages. The pattern was quite different for outpatient attendance, with immigrant children and young adults having lower attendance rates than whites, and middle-aged immigrant adults showing higher rates. Levels of hospital-based care among immigrant groups may be lower than expected. As monitoring of the health status of ethnic groups, and their use of services, receives increasing recognition, it is important that information on ethnic origin is included in routine health information systems. PMID- 10119950 TI - Artificial nutrition support for patients in the Cambridge Health District. AB - This paper describes the results of a one-year prospective survey of patients who received artificial enteral and parenteral nutritional support at home and in the hospitals of the Cambridge Health District. Enteral tube feeding accounted for most of the artificial nutritional support provided both in hospital and in the community. The findings of the study suggest that nutritional support is an important adjunct to the treatment of serious clinical disorders, and that the care of such patients can be improved by the establishment of a multidisciplinary enteral and parenteral nutrition team. Suggestions are made for establishing a structured home nutritional service. PMID- 10119951 TI - Fee-for-service: first stop--patient billing. PMID- 10119952 TI - When your customer is a physician. PMID- 10119953 TI - Reduce the stress of firing. PMID- 10119954 TI - Is your job hazardous to your health? PMID- 10119955 TI - The not-for-profit debate. AB - Across the country, not-for-profit hospitals are being subjected to unprecedented scrutiny. From local school boards to the Internal Revenue Service, government entities are challenging tax-exempt status. Some financially pressed states and cities are eyeing these hospitals as sources of additional revenue. Other entities want to see tax policy drive social policy by promoting more charity care. Tax-exempt status also is under fire from consumers and legislators. In the wake of the competitive '80s, many people perceive non-profit hospitals as behaving more like businesses than charities. Or, as attorney Brian W. FitzSimons recently wrote in Trustee, they suspect "the fund-raising tail is wagging the medical care dog." The standards for granting tax-exempt status have come under intense examination from all levels. Congress, the IRS, consumers, state legislators and judges, local tax authorities, the Texas attorney general and non profit hospitals themselves have all joined in the debate. PMID- 10119956 TI - U.S. residents go south of the border for health care. AB - This article covers one dimension of a study about U.S. residents traveling outside the country to obtain care. University of Houston-Clear Lake graduate students Mandy Cavanaugh, Michael Young and Diana Tantingco, as well as A. R. Kahn Jr., D.V.M. of Laredo, were direct field participants in gathering the following information. Additional research support was provided by graduate students Stephen Chandler, Jan Keisma and Henry Tsoi. The study is being funded, in part, by a grant from Houston's Hermann Hospital. PMID- 10119957 TI - Successful fund raising, straight from the heart. PMID- 10119958 TI - Action can stop spread of TB in hospitals. PMID- 10119959 TI - The Swedish health care system--an economist's view. AB - This article compares the organization of the Swedish health care system with that in three other countries, the U.S., the U.K., and Canada, focussing on three main areas: (1) the provision and financing (public or private) of health insurance, including the question of the quality of the insurance protection offered; (2) the organization of the production of health services, and the economic incentives on the system's decision-makers (doctors, hospital managers, politicians, etc.). Possible answers are suggested to the question why one country (the U.K.) is able to provide health care to its population at an average cost considerably below that of the others: Differences in the quality of the insurance protection and health services; in the incentives on the system managers to exercise cost control; and in the incentives on service providers such as physicians, to consider cost-effectiveness when making treatment decisions. An attempt is made to suggest lessons for health care reform in Sweden and elsewhere. PMID- 10119960 TI - Reforming the Swedish health services: the international context. AB - This article reviews the performance of Swedish health services in the international context. It notes that Sweden stands out as a country which has made a major commitment to the welfare state. Nowhere is this more evident than in the health services. Expenditure on health care is high by international standards and over 90% of expenditure derives from public sources. Despite Sweden's achievement in providing comprehensive health care to its population, a number of problems have emerged in recent years. In response to these problems, there has been a debate about options for reform. It is suggested that management reforms may offer the best way forward in improving the performance of health services. Policy makers should take advantage of the decentralised nature of the Swedish system to initiate and evaluate different reforms in different county councils. PMID- 10119961 TI - Reforming Swedish health care in the 1990s: the emerging role of 'public firms'. AB - A growing number of Swedish county councils have started to develop more flexible methods by which to produce and deliver health services. This paper explores the current status of this reform process both empirically and conceptually. Empirically, it draws upon data obtained by a 1990 questionnaire from all 26 county councils to chart the level of movement across the entire system. Conceptually, it distills from this reform activity a key element that provides an organizational basis for the future, namely the transformation of provider institutions into 'public firms'. The paper concludes that while the precise outcome may be hard to predict, the reform process itself is well underway. PMID- 10119962 TI - Growth of private medicine in Sweden: the new diversity and the new challenge. AB - The growth of private medical care in Sweden has occurred despite the lack of overt encouragement by the long-term Social Democrat government. This can be documented from official government statistics, private insurance sales, media sources, membership growth in the private doctors association, purchase of private risk insurance, growth of private health care organizations and services, and particularly an increase in public sector private contracting. While the percent of the population with private insurance is close to 1%, it is probable that over 20% of physicians engage in some form of private practice. Explanations range from increasing criticism of poor service orientation in the public system, long waiting lists and the reduced rate of public spending, to a general atmosphere that asserts more individual choice. With the Social Democrats now out of power, it is likely that the Moderate coalition will officially promote some forms of privatization. What will be the impact on the long-cherished Swedish principle of equity? PMID- 10119963 TI - Corporatism and health care: a comparison of Sweden and Mexico. AB - Up to now, the Swedish health care system has been used as a model for comparisons with other developed nations, chiefly in Northern Europe and the United States. This article departs from the mainstream and poses that similarities along the political factor of corporatism warrant a comparative analysis between the Swedish and Mexican cases. The most widely accepted definitions and typologies of corporatism are reviewed. The arena of manpower policy is used to illustrate the effects of alternative modes of interest representation on health care organization. The final aim of this comparative exercise is to enrich the empirical basis required to build a theory about the complex determinants of health care systems. State corporatism has acted in Mexico largely unchecked by geographical interest representation, in contrast with Sweden where centralist and decentralist forces are more balanced. This finding helps to understand why Sweden and Mexico mark extreme points along the health equity continuum. The comparison underscores the need for Sweden to avoid the risk of weakening the equity basis of its health care system as it moves along its current reform. The importance of these transformations go beyond Sweden, since they will undoubtedly offer new models of thinking and acting for the rest of the world. PMID- 10119964 TI - Future directions. AB - In this final paper, we summarise briefly the principal conclusions to emerge from the conference. We also review possible future directions in the light of the contributions of different authors and discussions at the conference. The paper argues that changes in the Swedish health services are both inevitable and desirable. The challenge is to maintain the strengths of the existing system while tackling widely acknowledged weaknesses. It is not yet clear what will emerge from the process of reform but the probable outcome is a period of innovation and experimentation leading to greater diversity in service provision. We argue that diversity is most likely to develop within the context of a continuing commitment to equity and comprehensiveness in the delivery of health care. PMID- 10119965 TI - Swedish health care in perspective. AB - The evolution and current problems of the Swedish health services are placed in an international comparative perspective with other industrially developed democratic states as to cost control, distribution of facilities and personnel, management of waiting lists for services, and differences in use of services. All of these countries are experiencing the same aforementioned problems differing mainly in degree. It is suggested that Sweden as well as other countries needs to reconceptualize the meaning of equality of access relative to the apparent emergence of private insurance as waiting lists grow for quality of life procedures such as lens and hip replacement. A concept of a basic service for everybody and so-called luxury service for those who wish to buy it needs to be faced in political debate. It is clear that government is unable to finance and supply the range of demand of a consumption good represented by a modern medicine. In so far as Sweden has been regarded as a model it appears that no country is a model anymore. The complexities of a modern health service has overwhelmed all countries and can be regarded as a sublime loss of innocence. PMID- 10119966 TI - The chief information officer in Canadian hospitals: fact or fancy? AB - Although the title "chief information officer" (CIO) has enjoyed some success in the private sector, it is not yet a common term in Canadian health care. However, with the explosion of information technology, the particular responsibilities of the person overseeing hospital information are significantly different from those using the title "chief financial officer", "chief operating officer" or "associate/assistant executive director". To determine the popularity of the term in Canada, 146 hospitals with more than 200 beds were surveyed. In all, the person handling hospital information had 40 different titles, with 11 appearing more than once. Only two respondents used CIO as a title. It is suggested that a CIO is a bridge between older systems and models, and new technologies and techniques. The future success of CIOs in Canadian health care, however, depends partly on those holding the positions today, and their acceptance that information is both a resource and a strategic opportunity. PMID- 10119967 TI - Paradigms and nursing management, analysis of the current organizational structure in a large hospital. AB - Hospitals developed over the period of time when positivism become a predominant world view. Positivism was founded by four Western trends: preponderance of hierarchy and autocracy, popularization of bureaucracy, extensive application of a machine orientation to work and predominance of "scientific" inquiry. Organizational theory developed largely from quantitative research findings arising from a positivistic world view. A case study, analyzing a current nursing organizational structure at one large hospital, is presented. Nursing management was found to be based upon the positivistic paradigm. The predominance of a machine orientation, and an autocratic and bureaucratic structure are evidence of this. A change to shared governance had been attempted, indicating a shift to a more modern organizational structure based on a different paradigm. The article concludes by emphasizing that managers are largely responsible for facilitating change; change that will meet internal human resource needs and the cost effectiveness crises of hospitals today through more effective use of human resources. PMID- 10119968 TI - Cephalosporin prices climb at slower rate in 1992. PMID- 10119969 TI - Hospitals using specialty systems to automate par levels, requisitions and materials transport. PMID- 10119970 TI - Single-use vs. reusable personal protective equipment decisions involve more than pricing. PMID- 10119971 TI - Hospitals choose used equipment to cut costs. PMID- 10119972 TI - The purchase order does not stand alone as formal contract obligation, HCFA says. AB - A controversy has developed over whether a purchase order for a large item of movable equipment amounts to an obligation under the new Medicare Capital Prospective Payment System (PPS) of the Health Care Financing Agency (HCFA). HCFA's draft revision to the Provider Reimbursement Manual indicates that a p.o. doesn't stand alone as a binding contract and that such purchases should be by formal contract. Some hospital trade groups argue that, in the normal practice of most hospitals, the p.o. is a contract to buy and should be treated as an obligation under the Medicare rules. In this dialogue, Dr. Decker addresses the issues of this controversy. PMID- 10119973 TI - Scripps Clinic: in transition to the on-line medical record. AB - The TMI system was implemented at our main campus on March 4, 1991, and at this point we are very pleased with all aspects of system performance. Since the conversion, the number of jobs dictated by our physicians has increased 20%, and we interpret this increase as an objective measure of physician satisfaction with the system. An increasing number of physicians are accessing lab results and documents from home via modem to review the next day's patients or while on-call. Transcription productivity has improved and enthusiasm for the system is high. Requests for chart documentation from our business office have decreased 60% due to the ability to access and print documents directly from the mainframe. The next phase in our information plan involves the installation of the TMI system at our regional clinics and our inpatient transcription unit. Further steps in the transition to on-line medical records, such as the conversion of 600,000 active and archived records, awaits the further development of technology in order to be feasible and cost effective. Our experience has shown that developing complex applications such as the TMI demands perseverance and a willingness to work closely with multiple vendors and products in order to identify the best options in a rapidly developing field. Extensive involvement of end users early in the planning process helped us to secure and implement a system with a high level of user acceptance and satisfaction. PMID- 10119974 TI - Primary Care Health Information System: a hybrid electronic-paper medical record system. AB - In summary, PCHIS is a hybrid electronic-paper medical record system that is clinically useful to health care providers. The paper chart still contains the bulk of information but the key facts about any given patient (diagnoses, surgeries, medications, allergies) and about the process of care (frequency of visits, referral patterns, test ordering, etc.) are readily available in electronic form. These key data are easily coded, are quickly and simultaneously accessible in multiple locations, serve as an excellent chart substitute whenever the paper chart is unavailable, and can be retrieved for in-depth analysis at any time, whether for clinical, administrative, research, or quality assurance purposes. The process of care can be studied and, to some extent, can also be modified by the system, as demonstrated by the physician response to the reminder system within PCHIS. The medical record chart summary, mandated by Joint Commission for ambulatory patient charts, is easily provided in hard copy as well as electronically. Whereas physician compliance in providing data to the system was initially sporadic, physician support has increased tremendously as the system has become more clinically useful to them. It is a system that exists and functions well within a patchwork of multiple different medical information systems. It is a system with sufficient intrinsic flexibility that it can and will continue to evolve in response to the needs of physicians and administrators. PMID- 10119975 TI - Implementation of electronic medical records: the "people" factor. PMID- 10119977 TI - Voice-recognition/knowledgebase reporting systems for ambulatory care patient records. AB - Speech recognition technology coupled with knowledgebase templates for the evaluation of specific patient complaints together constitute a technology that is currently available for patient reporting in the ambulatory care center. A system based on this technology offers advantages in legibility, speed of record creation, risk management, and reimbursement. It has both direct and indirect educational benefits for the clinician. While training requirements and system costs are reasonable, they continue to be the major stumbling block to widespread use of such systems. PMID- 10119976 TI - The ambulatory medical record project at Group Health Cooperative: what did a decade of experience teach us? AB - Computer-based record systems are documented to improve patient care (Barnett, 1984; McDonald & Tierney, 1988) and their importance in the future is widely accepted. The report of the Institute of Medicine on patient computer-based record systems (Detmer, 1991) will help guide the development of future computer based record systems and will likely stimulate renewed interest in them. We believe computing systems have great value to an HMO but understand that the benefits do not come without the risk of setbacks. We plan to build on what we have learned from our decade of experience. PMID- 10119978 TI - Computerized medical record systems in ambulatory care. PMID- 10119979 TI - Electronic medical records: a Joint Commission perspective. PMID- 10119980 TI - Scoring guideline MA.1.3.1 in the Accreditation Manual for Home Care. PMID- 10119981 TI - New policy addresses document falsification: loss of accreditation at stake. PMID- 10119982 TI - Nursing care standards address hospital use of agency nurses. PMID- 10119983 TI - Health care system tackles implementation of quality improvement. PMID- 10119984 TI - Are these malpractice bombs ticking in your office? PMID- 10119985 TI - This doctor went bare, then went bankrupt. PMID- 10119986 TI - These moves could head off a crisis in primary care. PMID- 10119987 TI - Why was this busy practice headed for disaster? PMID- 10119988 TI - The faces of group practice. Academic practice plans struggling with challenges. PMID- 10119989 TI - The faces of group practice. How employers enter the health care field. PMID- 10119990 TI - The faces of group practice. Managed care at nucleus of health care change. PMID- 10119991 TI - The faces of group practice. Interest in 'group without walls' continues to grow. PMID- 10119992 TI - Investor-owned practice offers business expertise. PMID- 10119993 TI - The faces of group practice. Regional model continues to grow in popularity. AB - Typically, regional medical groups are multispecialty in nature with a strong primary care base, writes Marilee Aust. This allows these groups to offer a "department store" variety of services. PMID- 10119994 TI - Physician compensation and production research provides valuable information. PMID- 10119995 TI - The faces of group practice. Medical groups, hospitals affiliate to survive. PMID- 10119996 TI - The faces of group practice. Contracts important to primary care groups. PMID- 10119997 TI - The faces of group practice. The transformation and progression of physician organizations. AB - The future will bring an increase in the economic forces which drive the succession of organizational forms. Migrating to integrated models of medical practice will become a survival technique for more and more physicians. This is a frightening prospect for individuals trained to be independent and self reliant. Fortunately, there are a variety of organizational models through which physicians can progress to ease the transition from solo to larger integrated practice forms. Regardless of the evolutionary course, successful physician organizations of the future will be primary care-based, geographically distributed, meaningfully partnered with hospital entities, equipped to accept risk, and lead by strong, business-savvy physician leaders and administrators. This organization will have the ability to flourish within a radically changing climate and will result in the delivery of measurably superior health care to its community. PMID- 10119998 TI - The faces of group practice. The art of successfully completing the merger. PMID- 10119999 TI - The faces of group practice. Single specialty groups 'doing battle' to survive. PMID- 10120000 TI - The faces of group practice. Physician/hospital medical foundations. A future model for integrated health care. PMID- 10120001 TI - Consider alternative modes of compensation. PMID- 10120002 TI - Specimen pathway analysis aids quality and efficiency. PMID- 10120003 TI - How to qualify as a praise master. PMID- 10120004 TI - Performance standards based on quality, not quantity. PMID- 10120005 TI - Reaching out to bring people in. Misericordia Hospital, Philadelphia, PA. PMID- 10120006 TI - Network makes fans of physicians. Children's Hospital Medical Center, Akron, OH. PMID- 10120007 TI - A hospital makes business its business. HCA Centennial Medical Center, Nashville, TN. PMID- 10120008 TI - When a public hospital goes to the public. Santa Clara Valley Medical Center, San Jose, CA. PMID- 10120009 TI - Fighting cancer's gloom and doom image. Nurses line up to work in bone marrow transplant unit. University of Nebraska Medical Center, Omaha. PMID- 10120010 TI - Letting fingers do the talking. Computer makes patient satisfaction surveys a snap. Rose Medical Center, Denver, CO. PMID- 10120011 TI - Seniors 'rocking' to good health. Columbia Hospital, Milwaukee, WI. PMID- 10120012 TI - Health news you can use. San Juan Regional Medical Center, Farmington, NM. PMID- 10120013 TI - Suburban hospital fights off big-city challenger. North Hills Passavant Hospital, Pittsburgh, PA. PMID- 10120014 TI - Technology diffusion in the 1990s. PMID- 10120015 TI - Radiation therapy maintenance. A successful in-house program. AB - With the development of complex equipment technologies in the medical care industry and particularly in radiation therapy, the costs required to keep equipment in proper operating condition are substantial. An "in-house" radiation therapy maintenance program can provide significant savings in equipment maintenance costs as compared to the cost of maintenance contracts. Additionally, the skills of the personnel providing this maintenance program can be used for ancillary areas of the therapy department. PMID- 10120016 TI - Radiation dose. PMID- 10120017 TI - CEO turnover up 3.9%. PMID- 10120018 TI - To lead or lag? AB - Health care policy is the hottest of all emerging issues. Although the largest foundations have changed to meet the challenge, one question remains: should health funders advocate as well as explore solutions? PMID- 10120019 TI - AHA posts financial loss for second straight year. PMID- 10120021 TI - The bioethics committee in long-term care institutions for the developmentally disabled. PMID- 10120020 TI - The ethics of placebos in AIDS drug trials. PMID- 10120022 TI - Development of a county pre-hospital DNR program: contributions of a bioethics network. PMID- 10120023 TI - A survey on awareness and effectiveness of bioethics resources. PMID- 10120024 TI - Point and counterpoint. Should HECs be designed primarily to assist the health care team and institution rather than the patient? PMID- 10120025 TI - Institutional ethics committees in the Netherlands. PMID- 10120026 TI - Ethics committees in Italy. PMID- 10120027 TI - Health-care libraries under review: are we in the picture? PMID- 10120028 TI - Children in hospital: I. Survey of library and book provision. AB - Between 1989 and 1991 two related research projects were undertaken by the authors at the Department of Information and Library Studies, Aberystwyth, into services for children in hospital. This article summarizes the findings of the first of the projects, a survey of book and library services to children in hospital, giving a national profile of provision. It demonstrates a substantial provision of reading and other materials available to children in hospital but a small number of library services, as such. Nurses, teachers and hospital play staff generally exploited these materials for pleasure, educational and therapeutic purposes. The survey was based on questionnaires sent to all hospitals in the UK which treated children and was addressed, where possible, to hospital librarians, otherwise to the senior paediatric nurse. A shorter questionnaire was also addressed to all local authority Young People's and Schools Library services for a public library or school library perspective. Where there was evidence of the use of reading therapy, a further questionnaire was sent to explore its practice. A second article will discuss the results of the second project, which was devoted to a further exploration of reading therapy with children in hospital. PMID- 10120029 TI - Impact of executive and management compensation trends on the first-line supervisor. AB - The myriad complex issues facing health care today require that hospitals and other health care organizations be able to attract and retain the most competent executive and management talent. These individuals are seeking recognition and reward for their successes. They are unafraid of working within the parameters of specific, well-defined goals and objectives and indeed welcome the opportunity to prove their abilities. They do not respond to the traditional annual longevity increase. This change in attitude has come as a shock to "old school" health care professionals and trustees who felt altruism and service motives should transcend compensation. But even these individuals now recognize that the times and conditions require more progressive and realistic attitudes on their part. On the other hand, those health care managers who are averse to risk and competition find the changing attitudes and programs traumatic. As dedicated as these individuals are to their professions and institutions, they will have to become accustomed to working within systems that heretofore may have been foreign to them. When such programs are implemented in their institutions they will not find solace in leaving for another organization. The respite will be short lived before the times catch up with them again. PMID- 10120030 TI - Health care organization drug testing. AB - Health care managers are being required to respond to the growing concerns of the public about alcohol and drug use in the health care workplace. To this end, the following recommendations are offered. A drug testing policy should be developed with input from and support of employees and unions. "For cause" testing should be used because it results in more definitive results and better employee acceptance. Unless there are compelling reasons for random testing, "for cause" testing is the preferable method. All levels of employees and the medical staff should be subject to the drug-testing policy. Rehabilitation rather than punishment should be emphasized in dealing with employees with alcohol and drug problems. PMID- 10120031 TI - Using group dynamics to manage nursing aides. AB - With management and group dynamics education, peer and administrative support, and clear expectations, RNs can manage NAs. Without these supports, NAs may deliver the kind of care they see fit. Unfortunately, NAs have not been educated, socialized, or licensed into the nursing profession and do not necessarily hold the same values of quality of care that professional RNs hold. Older consumers in nursing homes deserve no less. PMID- 10120032 TI - Motivating the burned out employee. PMID- 10120033 TI - When the manager encounters "We can't do it!". AB - This article has described the importance of increasing staff feelings of self worth, of promoting feelings of personal power, involving staff actively in practice issues, of increasing staff knowledge of the health care and agency system, and of setting limits on negative discussion in a group. When nurses feel power in the health care system, it not only has the benefit of increasing job satisfaction but increases positive responses on the job. On the other hand, nursing staff who are unable to conquer the feeling of powerlessness may respond to assignments with statements signifying the subjective state experienced: "We can't do it!" Such staff are unlikely to experience personal and professional rewards and may ultimately leave the health care field. This negative process may be blocked by the manager who assists staff to develop feelings of worth, professional autonomy, and control and who can appropriately handle negative feelings expressed in a group. PMID- 10120034 TI - Do more with less: strategies for improving productivity in community health nursing. AB - Nursing productivity in all types of health care organizations is difficult to define and to measure. However, the difficulty of the task must not deter the first-line nurse supervisor from the task. The process of defining and measuring productivity will help Eve to develop the strategies needed to solve her dilemma. This critical activity will help to ensure the nurses' survival in today's tight economic climate and create a vision of the nurse's place in the health care setting of the future. Before data collection methods and productivity expectations can be standardized in community health nursing, nurses must communicate, through publication, their concerns regarding nursing productivity, their data collection methods, and their productivity expectations so that the methods and expectations can be standardized. Such cross-fertilization of ideas is an essential part of the process of managing nurse productivity. PMID- 10120035 TI - An evaluation of single-room maternity care. AB - Patients appreciated the opportunity to give feedback. Nurses felt they were doing a good job and also that the decision to move into SRMC had been the right one. This project also highlighted for the nursing community the benefits for nursing practice that can result when representatives from education and service collaborate in research and evaluation. PMID- 10120036 TI - Joint appointment: an example of a cooperative effort between service and education. AB - Joint appointments are not a new phenomenon. Such positions were implemented during the past two decades in an attempt to bridge the gap that exists between service and education. The uniqueness of the joint appointment position that was described in this article is the following: this particular appointment was between a community hospital and a community college; this joint appointee's primary job was as a clinical staff nurse at the hospital; different methods of salary administration were explored, with two levels of salary being developed; the joint appointee maintains salary and benefits from the hospital; and this joint appointee will function as a clinical preceptor to newly employed graduate nurses at the hospital during summer months. The literature has documented that the success of such appointments is dependent on the cooperation and the commitment of both parties. The concepts of joint appointments must also be supported fiscally, and individuals selected for such appointments must have expertise in carrying out dual roles. Experience with this joint appointment indicates continued collaboration. It is clear that a permanent bridge has been built between the two organizations. PMID- 10120037 TI - Computer applications for nursing staff education departments. AB - The computer has many applications for the management of a staff education department. One essential application is the recording and monitoring of the nursing staff's educational activities. Other pertinent activities may include the preparation of budget and department activities statistics reports. However, the array of computer software programs that is available for the management of data and administrative functions can be intimidating. By networking with users whose computer applications needs are similar to your own, and by communicating with members of your computer services department, the list of applications can be refined to a few software programs. These programs can provide efficiency and accuracy for monitoring and reporting on nursing staff education activities. PMID- 10120038 TI - Running small meetings: an overlooked technique for making them productive and keeping them short. AB - Those who have learned the rules and appreciate their benefits have a responsibility to lead others and encourage them to use the rules at their meetings. Consistent use will enable small groups to accomplish more with seemingly less effort and also will help them to make informed, careful decisions as they face complex challenges in the health care field today. PMID- 10120039 TI - The supervisor's performance appraisal: evaluating the evaluator. AB - The focus of much performance appraisal in the coming decade or so will likely be on the level of customer satisfaction achieved through performance. Ultimately, evaluating the evaluator--that is, appraising the supervisor--will likely become a matter of assessing how well the supervisor's department meets the needs of its customers. Since meeting the needs of one's customers can well become the strongest determinant of organizational success or failure, it follows that relative success in ensuring these needs are met can become the primary indicator of one's relative success as a supervisor. This has the effect of placing the emphasis on supervisory performance exactly at the point it belongs, right on the bottom-line results of the supervisor's efforts. PMID- 10120040 TI - Health care: a leader or a follower? Reducing disposable waste. AB - We clearly have the means to examine and reduce the amounts and types of disposable medical waste that health care institutions are creating. Although there may be special circumstances that prevent specific hospitals, or specific departments within a hospital, from converting to alternative products, much improvement can still be made. There are several strong examples of hospitals across the United States with programs that have drastically cut the amount of waste they are generating. They have eliminated disposable cups and eating utensils from the cafeterias, shifted to reusable underpads and surgical linens, and established recycling programs for paper and cardboard. These few cases are not enough. We cannot be lulled into believing that these exceptional efforts on the part of a few institutions are all that is needed. We should remember that if Mother Nature had intended for us to pat ourselves on the back, our hinges would be different. What is needed is a clear statement from the health care industry of its responsibility to society with regard to managing its waste. Leadership begins with action. If the health care industry does not take steps to regulate its disposable waste, the government undoubtedly will. We do not need to wait for our supervisors or administrators to fashion credos for us. All staff members know there are numerous ways that they can affect the amount of waste produced at their hospitals. They can also begin to affect the attitudes of those working around them. The consequences of inaction are simply too great. As fictional as half-empty grocery stores may have sounded at the beginning of this article, the problems that we face with waste disposal are certainly as grim. If we wait for our state and federal governments to solve the problems, it may be too late; and if it is too late, the solutions that they develop will certainly be extreme. We have the technology and the ability to cut dramatically the amount of disposable waste that health care generates. In practically every case, the lower-waste options also save the institution money. It is time that we honestly challenged our need for today's convenience at the expense of tomorrow's quality of life. PMID- 10120041 TI - A common sense approach to linen management. PMID- 10120042 TI - Switching back to reusable underpads. PMID- 10120043 TI - Reusable linens in the surgery. PMID- 10120044 TI - Converting to knit contour sheets. PMID- 10120045 TI - Switching from linen rental to NOG (not our goods). PMID- 10120046 TI - Conservation and laundry: using outside vendors to clean reusable linens. AB - Using outside laundry facilities is a viable and efficient means for hospitals to clean and sanitize soiled linens. Such services also allow hospitals to achieve cost-effective linen systems. All kinds of linen products, including gowns, sheets, blankets, pillowcases, mops, diapers, and surgical textiles, are easily processed through such purveyors. Even newer fabrics with improved barrier protection qualities can be serviced. The three elements that make up the laundry cost equation are purchasing, processing, and usage. Improvements and reductions in any one of these areas positively affect the other two. With this in mind, a hospital and an outside laundry service should work closely together to improve linen management, to control usage, and to remove waste, thus reducing hospitals' per-patient-day costs. Close interaction and teamwork will make the relationship work with dynamic results. Together, both parties will grow and meet the ever evolving needs of the health care industry. PMID- 10120047 TI - Can computerization of linen management save real dollars? AB - Software designed for linen management is readily available to linen managers. Each has a variety of features and benefits. It is important that the linen manager discover a system that will return the type of information he or she is looking for and deliver it with minimum effort and maximum efficiency. Software systems can, indeed, prove beneficial to linen managers in bringing a new level of control to circulating linen at the hospital facility. PMID- 10120048 TI - Electronic data interchange in hospital materiel management. AB - The survey findings reported here support the continued trend toward increasing application of computer linkages in hospital operations. A majority of the hospitals surveyed already had some sort of computer linkages with their suppliers, possibly an EOE system. There were strong indications of expanding computer linkages to other health care institutions, financial institutions, business partners (i.e., insurance companies), purchasing groups, supporting agencies (i.e., libraries, research laboratories, and counseling agencies), electronic mail, and patient billing. Private hospitals, especially nonprofit hospitals, were more aggressive in the implementation of computer linkages. The initial costs of electronic linkage systems seemed to be affordable, or well justified, as indicated by the relatively large number of medium-size hospitals already linked electronically to other institutions. Top management attention was positively related to the implementation of computer linkages to suppliers but played a lesser role in establishing other types of linkages. The overall optimism concerning future expansion of computer linkages suggests an increasingly important role for electronic linkages in materiel management. PMID- 10120049 TI - Body support testing and rating. AB - The REF, C, and score are a means to give quantitative values for product performance. Other product variables defined as humidity control factor, shear control factor, differential temperature control factor, product life factor, and cost factor were not addressed as part of this study. Additional variables include delivery, maintenance, and warranties. These components can be added to the score in some weighted manner as they become clinically founded. Interface pressures and shears were not measured for beds that are gatched. Each product tested will have characteristics pertinent to its own design that must be addressed to minimize sacral and coccyx skin breakdown when subjects are in this posture because some pneumatic pads bottom out to give excessive sacral and coccyx pressure while others wrinkle when used in this position. This is of major concern when one considers that the coccyx is more susceptible to pressure than any other bony prominence. There may be some aversion to labeling support product performance because it will allow the purchaser to know what is being bought. This initial study indicates the feasibility of quantitating what all patients require: a valid interface support surface for each specific need. The user can be adequately informed before the purchase as to a product's merits without being influenced by the results of inadequate testing, referrals, or sales media influences. Although cushions, shoes, or other prosthetic/orthotic devices were not part of this study, it is appropriate to rate all these devices in a similar manner by simply comparing pressure relief attained to that desired, expressing the result as a percentage of the worst case, and then labeling the product accordingly. Those subjects with sensation can rate comfort as part of the overall score. For cushions, ischial tuberosity pressure relief can be expressed as a percentage of the maximum attainable relief. Metatarsal head relief during gait as well as during static testing can be measured, and claims can be made for shoes and sneakers. Where impact loads and shear forces are paramount, the score must comprise appropriate parameters. Similarly, amputee distal stump relief as a percentage of worst case could be specified by the fitter. Iliac crest relief as a percentage of worst case can also be specified by the fitter. In all instances the score is not a subjective rating but one that can be measured correctly. All body support products can be given an REF, C value, and score as well as other qualifying values where appropriate instrumentation and sufficient subject sampling is used. PMID- 10120050 TI - Phased renovation and expansion make clinic a sight for sore eyes. PMID- 10120051 TI - NFPA and JCAHO look at medical gas systems. PMID- 10120052 TI - Wayfinding: are your staff and visitors lost in space? PMID- 10120053 TI - JCAHO revises safety, security, power standards. PMID- 10120055 TI - Survey: facilities recycle even though it's not profitable. PMID- 10120054 TI - How to shut down your cooling tower for winter. PMID- 10120056 TI - Buying linen? Formula reveals true cost per use. PMID- 10120057 TI - Monitrend offers fourth-quarter operations data. PMID- 10120058 TI - Career opportunities in clinical engineering. AB - The varied career opportunities open to clinical engineers are described in this paper. Many of these opportunities are within the medical device industry in research, development, manufacturing design, regulatory activities, production, operations, sales, marketing, service, and management. Additional opportunities are available in hospitals, with the Veterans Administration, or working as an entrepreneur or a consultant. Each of these careers requires specific training and skills, and they all require a fundamental scientific knowledge of physical principles and mathematics. Research and management, however, require different educational preparation. The research emphasis should be on theoretical principles and creativity; the management emphasis should be on financial and labor problems. In all clinical engineering careers, the individual is a problem solver. PMID- 10120059 TI - Becoming an effective clinical engineering or biomedical technology manager. AB - The BMET or CE Supervisor is a technical manager who is close to the actual work of a biomedical or clinical engineering department. The MPTI is a management training tool that has identified differences between the effective and less effective technical managers. These behaviors or styles can be considered and applied to the clinical engineering and BMET work environments. Effective BMET or CE Supervisors have a management identity. They are both people-oriented and task oriented. They are good problem-solvers, and will plan and structure the work tasks and environment. When the situation requires a change in plans, however, they can adapt to the new situation easily. If a decision needs to be made that affects the organization, they will check with higher management or peer managers. Less-effective BMET or CE Supervisors will make important decisions alone, without checking with others. They plan and structure tasks and the work environment, but they are less willing to change when faced with a new situation. They are not people-oriented, and their ability to assess social situations is low. Their need for achievement recognition is often too high. The work environment has an effect on how the competence of a manager is perceived. A "one desk manager" in a small, one-person biomedical engineering department has more autonomy than a CE Supervisor in a large department. Working for a medical device manufacturing firm often requires a greater management identity. An engineering consultant is often a managing specialist, rather than a traditional manager.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 10120060 TI - Technical note: preventive maintenance quality assurance. AB - Performance improvements in healthcare and, specifically, in clinical engineering are required by the Joint Commission on the Accreditation of Healthcare Organizations' Plant Technology and Safety Management (PTSM) documents. The goals of healthcare service quality assurance are to establish performance requirements and improve patient outcomes. It is important that these goals be kept in the forefront of the design of clinical engineering quality assurance planning. Indicator/threshold pairs must be carefully chosen on the basis of some logical relation to the desired goals of the overall program. PMID- 10120061 TI - A serial interface design to integrate bedside devices into patient monitoring systems. AB - While substantial progress has been made toward the development of the Medical Information Bus (MIB), there is a pressing need, today, to integrate bedside devices into patient monitoring systems. To help meet this need, SpaceLabs Inc. has developed serial interfaces that integrate various stand-alone devices into a patient monitoring system. The company makes available a Universal Flexport Protocol to manufacturers who wish to make their devices compatible with the SpaceLabs patient monitoring systems. This paper describes the design of the Flexport serial interfaces and the Universal Flexport Protocol. PMID- 10120062 TI - Carving your niche in orthopaedics. PMID- 10120063 TI - Money down the drain? AB - Recent City scandals have left NHS trusts largely unscathed but not unaffected. BCCI's demise highlighted two weaknesses in most trust's approaches to treasury management. Tom Jones explains. PMID- 10120064 TI - Orthopaedics. PMID- 10120065 TI - Using audit in a district-wide management system. AB - As a consequence of the NHS reforms, the budgeting and competitive tendering of clinical services between districts requires accurate accumulation of data. John Mosley and Roger Fairbanks describe how data obtained by clinicians from their own audit has been used to construct a casemix solution that provides the necessary financial information for a district. PMID- 10120066 TI - Modelling in strategic analysis. PMID- 10120067 TI - Management ... working day of a health services manager. AB - A varied day for one of the NHS's first marketing managers is in store for Christine Miles, Middlesex Hospital. A key message to get across is that marketing is not just promotion or selling: it is matching the strengths of the organisation to the unmet needs of 'customers'. PMID- 10120069 TI - 1992 ambulance manufacturers directory. PMID- 10120068 TI - Feds focus on medical devices. PMID- 10120070 TI - This is not your father's ambulance. A look at the new Ford E-350. PMID- 10120071 TI - Will QI work where QA won't? PMID- 10120072 TI - The data game. Making the most of early defibrillation. PMID- 10120073 TI - Effective communication. So to speak. PMID- 10120074 TI - HIV testing. Whose right to know? PMID- 10120075 TI - Hi mom, I'm home. Controversies in clinical care. PMID- 10120076 TI - Assessing the need for infection control programs: a diagnostic approach. AB - By using the PRECEDE model, we concluded that the need for standardized infection control programs in long-term care facilities is imminent and believe that the PRECEDE model has wide applicability in infection prevention and control. For example, it could be used to plan continuing education needs for the infection control department in a facility, or to plan a program to improve compliance with universal precautions or handwashing. Its use is limited only by the creativity of the planner. PMID- 10120077 TI - The research process in long-term care facilities. AB - The benefits of research in the nursing home often outweigh the inconveniences. The authors describe what to expect when researchers visit your facility. PMID- 10120078 TI - Is the word "motivator" in your job description? PMID- 10120079 TI - Making service a priority. PMID- 10120080 TI - Teamwork needed to treat and manage urinary incontinence. PMID- 10120081 TI - Data bank confirms competence of health care professionals. PMID- 10120082 TI - Watchful nursing staff helps improve quality of sleep. PMID- 10120083 TI - Special activities brighten residents' holiday season. PMID- 10120084 TI - Drug quality assurance programs focus on unnecessary use. PMID- 10120085 TI - Child care centers enrich lives of young and old. PMID- 10120086 TI - Selecting suitable furnishings requires input from users. PMID- 10120087 TI - Energy saving projects improve environment, reduce costs. PMID- 10120088 TI - Variety of financial tests evaluate facility's health. PMID- 10120089 TI - Survey management lowers risk of litigation. PMID- 10120090 TI - Music therapy provides comfort, stimulation for residents. PMID- 10120091 TI - Assisted living communities care for residents aging in place. PMID- 10120092 TI - Nurses must take lead in quality approach to care. PMID- 10120093 TI - The rewards of restorative care. AB - Implementation of the nursing facility reforms of the Omnibus Budget Reconciliation Act of 1987 has ushered in a new era of resident care. Restorative care programs are leading the way for more autonomy and independence for today's nursing facility residents. PMID- 10120094 TI - Training increases sensitivity to aging, resident needs. PMID- 10120095 TI - Taxes and donations rules may curtail Medicaid reimbursement. PMID- 10120096 TI - Asbestos management assures staff, resident safety. PMID- 10120097 TI - Restorative dining promotes independence, self esteem. PMID- 10120098 TI - Crafts program utilizes abilities of cognitively disabled. PMID- 10120099 TI - Self-administration policy ensures resident safety. PMID- 10120100 TI - Advance directives program helps residents prepare for future. PMID- 10120101 TI - Rehabilitation services enhance resident care, marketability. PMID- 10120102 TI - Nursing facilities play role in continuum of AIDS care. PMID- 10120103 TI - Computerizing the resident assessment instrument. Software evaluation--September 1991. PMID- 10120104 TI - Challenges in LTC nursing today. AB - The role of the nurse--the primary caregiver in the nation's nursing facilities- barely resembles that of just 10 years ago. In that time, nurses have become an important member of the management team, providing expertise in infection control, training and recruitment, quality assurance, and resident care. Provider takes a look at the evolving role of the long term care nurse. PMID- 10120105 TI - Customer service approach emphasizes people skills. PMID- 10120106 TI - Active approach to purchasing reduces costs of supplies. PMID- 10120107 TI - Understanding fire safety rules leads to successful surveys. PMID- 10120109 TI - Computers boost efficiency for consultant pharmacists. PMID- 10120108 TI - Dog shows involve residents in pet therapy program. PMID- 10120111 TI - Resident bathing systems can overcome physical limitations. PMID- 10120110 TI - Education increases acceptance of residents with AIDS. PMID- 10120112 TI - Who's the boss? Reversing the hierarchy. AB - According to the author, radiology managers can improve staff morale, increase commitment to patient care and decrease their workloads by "reversing the hierarchy" and empowering their staff. Despite what some managers may think, she says, employees can make good decisions and stay committed if they are given authority, encouragement and trust. She also describes some of the steps managers can take to reverse the hierarchy at their organizations. PMID- 10120113 TI - There's change and then there's change. AB - Citing recent shifts in the economic and sociopolitical landscape, Mr. Hage claims that the pace and magnitude of future changes will only increase with the coming of the new millennium. Like the steam engine and other technologies driving change during the industrial revolution, he says, the computer is dramatically altering our lives today. The author describes both advances in computer technology and software limitations that will affect RIS. PMID- 10120114 TI - Toward the year 2000 and beyond: AHRA (American Healthcare Radiology Administration) strategic planning and management. AB - This report, from the Chairman of the 1991-92 Long Range Planning Committee, outlines the AHRA's strategic plan. Mr. Schwartz presents some strategic management challenges and self-assessment models and identifies the key trends impacting radiology management. He also defines the AHRA's customers and competitors, products and services, strengths and weaknesses, and presents the AHRA's "distinctive competence" statement, which identifies the major assets of the association. He concludes with an outline of the AHRA's five primary businesses. PMID- 10120115 TI - Coaching and counseling employees. AB - "To be effective, coaches need to exercise different forms of power," writes Dr. Herakovic in lesson two of his correspondence course on coaching and counseling employees. According to the professor, power has five forms: reward, coercive, legitimate, referent (charismatic) and expert power. He defines the five types of power and describes the uses and abuses of each type. PMID- 10120116 TI - Quality improvement: the JCAHO model. AB - Mr. Schwartz's article chronicles the development of continuous quality improvement in healthcare. Beginning with a discussion of the Joint Commission's shift from quality assurance to CQI, Mr. Schwartz goes on to explore the theories of Crosby, Deming, Juran and others whose ideas have shaped the CQI movement. He also identifies quality assessment and improvement standards, statistical methods favored by the JCAHO, ways of demonstrating CQI, and the differences between QA and CQI/TQM. In addition, he provides suggestions on implementing a CQI action plan and describes some of the obstacles faced by managers trying to execute such programs. PMID- 10120117 TI - An annual strategy for total quality. AB - The total quality management (TQM) revolution that is fueling the interest of CEOs and the JCAHO will present big leadership challenges to department administrators. Successfully implementing TQM concepts will require basic changes in operational methods and highly visible leadership commitment. Lasting change can only occur with a strategy that is understood by all employees and is periodically updated. Operational improvements will result from actions you take to better serve internal and external customers, as well as personal commitment from each employee. Quality teams are the core of TQM philosophy. Any strategy to implement TQM will require extensive training and/or study of quality improvement tools and methods, as well as a plan for managing cultural change. Aligning the department within the organization requires input from the rank and file as well as those at the executive level. PMID- 10120118 TI - Updating a QA program to meet new JCAHO standards. AB - This article discusses the changes in standards of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) that will affect medical imaging departments' quality assurance programs. It presents an imaging manager's view of how to integrate the new quality assessment and improvement requirements with a departmental plan that meets departmental standards. The ten steps of monitoring and evaluation are discussed with some practical examples of how to develop a QA program. PMID- 10120119 TI - Quality assessment and improvement in nuclear medicine. AB - "In order to comply with the JCAHO's new emphasis on quality assessment and improvement, nuclear medicine departments must identify important aspects of care and ... define performance indicators," concludes Ms. Gilbert. In her article she shows how the newly revised quality assurance standards apply to nuclear medicine departments. Included are figures depicting the categorization of, and performance indicators for, important aspects of care. PMID- 10120120 TI - Meeting inspection requirements for outpatient imaging centers. AB - This article, by a manager of outpatient services, provides an overview of the inspection requirements for outpatient imaging centers. According to the author, while most freestanding centers are not currently inspected by the JCAHO, they must follow the guidelines of several other agencies. The author provides a list of 57 questions asked by JCAHO surveyors during a recent inspection of her facility. PMID- 10120121 TI - CQI for imaging services: Part I, An introduction. AB - In continuous quality improvement (CQI), all employees involved in the provision of services cooperate in evaluating and understanding the processes associated with these services. Through such cooperation, organizations can improve service quality on a continuous basis. A good way for radiology managers to prepare for CQI implementation is to review W.E. Deming's fourteen principles of continuous quality improvement. To be successful, a CQI program requires direct, hands-on involvement by managers. A program that is implemented correctly will enable a radiology facility to become more competitive. Quality improvements typically result in increased worker productivity, which allows a facility to perform more work with fewer resources. PMID- 10120122 TI - CQI for imaging services: Part II, Obstacles to success. AB - Continuous quality improvement (CQI) as an operations philosophy is quickly gaining acceptance in the American healthcare industry. But despite successes with this type of program in Japan and certain American industries, the quality improvement process is not problem free. In fact, there will be obstacles for many who implement such a program. For example, changes in work systems frequently stimulate emotional reactions from those affected. And while fear, apprehension and resistance can be addressed by the radiology manager, lack of corporate and administrative support will limit or prevent a CQI program's success. However, radiology managers must overcome such problems to survive in today's healthcare environment. PMID- 10120123 TI - OSHA's bloodborne pathogens standard: new job-safety requirements for healthcare. AB - This article outlines the OSHA requirements set forth by the new Occupational Exposure to Bloodborne Pathogens Standard. While some states administer their own occupational safety and health programs, they must adopt standards and enforce requirements that are at least as effective as federal requirements. PMID- 10120124 TI - HCFA releases long-awaited regulations for the PSDA. PMID- 10120125 TI - Potential liability issues tied to rejection of valid anatomical gifts. PMID- 10120126 TI - Gift giving comes under scrutiny. PMID- 10120127 TI - State lawmakers and citizen groups choose sides in euthanasia debate. PMID- 10120128 TI - College approves guidelines for chaplain's role in bioethics. PMID- 10120129 TI - JCAHO spurs new committees and educational needs. PMID- 10120130 TI - Pain management finally receiving official recognition and study. PMID- 10120131 TI - Ethics consultations and changes in bioethics come under scrutiny. PMID- 10120132 TI - Ethical problems arise over clinical trials on new drugs. PMID- 10120133 TI - Use of advance directives object of new studies. PMID- 10120134 TI - Supreme Court affirms abortion rights; allows most state limits. PMID- 10120135 TI - Kevorkian ruling raises doubts over public-professional consensus. PMID- 10120136 TI - Rationing plan put on back burner. PMID- 10120137 TI - Planned giving at medical schools. Implications for all healthcare providers. PMID- 10120138 TI - Fund raising in U.S. psychiatric facilities. PMID- 10120139 TI - Can you waltz with an elephant? PMID- 10120140 TI - The continuing influence of Minerva. PMID- 10120141 TI - To retreat or not to retreat? That is the question. PMID- 10120142 TI - The fall and rise of endowment investment. PMID- 10120143 TI - Meeting common challenges together. PMID- 10120144 TI - The mystique of reciprocity. PMID- 10120145 TI - Tax assessment records. Panning for gold. PMID- 10120146 TI - Fund raising initiatives in public hospitals. PMID- 10120147 TI - Percentage based compensation. Fund raising ethics and the law. PMID- 10120148 TI - Benefit concert "jump starts" philanthropy program. PMID- 10120149 TI - Task force report: legislative professional practice retention guidelines for health information. PMID- 10120150 TI - Record retention statutes and regulations by state. PMID- 10120151 TI - Position Statement: Credentialed medical record professionals in long term care. American Health Information Management Association. PMID- 10120152 TI - Position statement: Confidentiality of the computer-based patient record. American Health Information Management Association. PMID- 10120153 TI - Position statement: Record retention. American Health Information Management Association. PMID- 10120154 TI - Florida members lobby on new records law. PMID- 10120155 TI - Health law: legal authorization for the electronic signature or computer generated signature code on medical records in Illinois. PMID- 10120156 TI - Joint Commission activities--data variance: impact on reliability. PMID- 10120157 TI - Physicians need your help. AB - Health information professionals have a lot to offer physicians and their office staff. This is one example of an active physician support service department and the valuable contributions it makes in educating physicians and staff.